GLYCOSIDASE INHIBITORS

Abstract

The disclosure relates to compounds of formula (I) useful in the treatment of tauopathies and Alzheimer's disease

##STR00001##

wherein A, R, W, Q, n, and m are described herein.

Claims

1. A compound of formula (I) ##STR00437## 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; A denotes one of the following groups: ##STR00438## X is Nor CR′; X.sup.1, X.sup.2 is N or CR′″; X.sup.3 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, 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.sub.3, S, SO, SO.sub.2, CO, COO, OCO, CONR.sup.3, NR.sup.3CO and wherein 1 to 5 hydrogen atoms may be replaced by Hal, NR.sup.3R.sup.4 or NO.sub.2; R′″″ denotes H, Hal, NR.sup.3R.sup.4, CHR.sup.3R.sup.4, CN, 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.sub.3, S, SO, SO.sub.2, CO, COO, OCO, CONR.sup.3, NR.sup.3CO and wherein 1 to 5 hydrogen atoms may be replaced by Hal, NR.sup.3R.sup.4 or NO.sub.2. Preferably, R′″″ is H, Hal or alkyl; 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: ##STR00439## Z.sup.1 is S, O, NR.sup.3; Z.sup.2, Z.sup.3 independently denote CR.sup.5, CR.sup.6 or N; Z.sup.2′ is CR.sup.5′ or N; T is N, CH or CR.sup.7; R.sup.5, R.sup.6, R.sup.7 independently denote H, Hal, NR.sup.3R.sup.4, NO.sub.2, 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, CO, COO, OCO, CONR.sup.3, NR.sup.3CO 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 denote Ar, Het or Cyc; R.sup.5′ denotes H, Hal, NR.sup.3R.sup.4, NO.sub.2, a straight chain or branched alkyl having 2 to 12 carbon atoms, or a straight chain or branched alkyl having 1 to 12 carbon atoms, wherein 1 to 3 CH.sub.2-groups are replaced by a group selected from O, NR.sup.3, S, SO, SO.sub.2, CO, COO, OCO, CONR.sup.3, NR.sup.3CO and/or wherein 1 to 5 hydrogen atoms are replaced by Hal, NR.sup.3R.sup.4, NO.sub.2, OR.sup.3, Het, Ar Cyc, or R.sup.5′ denotes Ar, Het or Cyc; R.sup.5′ may also denote methyl, in cases where R is other than methyl and/or W is CH and/or A is other than ##STR00440## and/or n or m are 0, 2 or 3 and/or Z.sup.1 is O or NR.sub.3 and/or Z.sup.2 is N and/or Z.sup.3 is CR.sup.5 and/or R.sup.5 is other than H and/or the compound of formula I is not a racemate; R.sup.8 denotes H, methyl or straight chain or branched alkyl having 2 to 12 carbon atoms, wherein 1 to 3 CH.sub.2-groups may be replaced by a group selected from O, NR.sub.3, S, SO, SO.sub.2, CO, COO, OCO, CONR.sup.3, NR.sup.3CO and wherein 1 to 5 hydrogen atoms may be replaced by Hal, NR.sup.3R.sup.4 or NO.sub.2; 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 bicylic aromatic ring system, which is optionally substituted by 1 to 3 substituents independently selected from R.sup.5, OR.sup.3 and Hal; Cyc denotes a saturated 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 and pharmaceutically usable derivatives, solvates, salts, tautomers, enantiomers, racemates and stereoisomers thereof, including mixtures thereof in all ratios and compounds of formula I, wherein one or more H atoms are replaced by D (deuterium).

2. A compound of formula Ia and Ib: ##STR00441## wherein A, R, W, Q, 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, n and m, in equal or unequal amounts.

4. A compound of formula I according to claim 1, wherein R is methyl and/or W is N.

5. A compound of formula I according to claim 1, wherein A denotes one of the following groups: ##STR00442## wherein R′ and R″ have the meaning given in claim 1.

6. A compound of formula I according to claim 1, wherein Q denotes one of the following groups: ##STR00443## ##STR00444## wherein X, R′″, R″″, R.sup.5, 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 H, Hal, NR.sub.3R.sub.4, NH.sub.2, N(CH.sub.3).sub.2, phenyl, 2-,3- or 4-hydroxy or methoxyphenyl, alkyl, CF.sub.3, alkoxy (Oalkyl), hydroxyalkylen, alkoxyalkylen, COOH, COOalkyl, CONHalkyl, CONH.sub.2, CON(CH.sub.3).sub.2, NHCOalkyl, NHalkyl, 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, substituted or unsubstituted Cyc or Het.

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: TABLE-US-00003 Configuration No Structure specification 1 Racemic 2 Racemic 3 Racemic 4 Racemic 5 Racemic 6 Racemic 7 Racemic 8 Racemic 9 Racemic 10 Racemic 11 Racemic 12 Racemic 13 Racemic 14 Racemic 15 Chiral HPLC Method C: 2nd eluting compound 16 Racemic 17 Racemic 18 Racemic 19 Racemic 20 Racemic 21 Racemic 22 Racemic 23 Racemic 24 Racemic 25 Racemic 26 Chiral HPLC Method D: 2nd eluting compound 27 Racemic 28 Racemic 29 Racemic 30 Racemic 31 Racemic 32 Racemic 33 Racemic 34 Chiral HPLC Method D: 2nd eluting compound 35 Racemic 36 Racemic 37 Racemic 38 Racemic 39 Racemic 40 Racemic 41 Racemic 42 Racemic 43 Racemic 44 Racemic 45 Racemic 46 Racemic 47 Racemic 48 Racemic 49 Rcemic 50 Racemic 51 Racemic 52 Racemic 53 Racemic 54 Racemic 55 Racemic 56 Chiral HPLC Method E: 2nd eluting compound 57 Chiral HPLC Method E: 2nd eluting compound 58 Racemic 59 Chiral HPLC Method D: 1st eluting compound 60 Chiral HPLC Method D: 2nd eluting compound 61 Chiral HPLC Method D: 2nd eluting compound 62 Chiral HPLC Method A: 1st eluting compound 63 Chiral HPLC Method D: 1st eluting compound 64 Chiral HPLC Method D: 2nd eluting compound 65 Chiral HPLC Method D: 1st eluting compound 66 Chiral HPLC Method D: 2nd eluting compound 67 Racemic 68 Chiral HPLC Method D: 1st eluting compound 69 Chiral HPLC Method D: 2nd eluting compound 70 Racemic 71 Chiral HPLC Method D: 2nd eluting compound 72 Racemic 73 Racemic 74 Chiral HPLC Method D: 1st eluting compound 75 Chiral HPLC Method D: 2nd eluting compound 77 Chiral HPLC Method L: 1st eluting compound 78 Chiral HPLC Method L: 2nd eluting compound 79 Racemic 80 Racemic 81 Chiral HPLC Method B: 2nd eluting compound 82 Racemic 83 Racemic 84 Racemic 85 Racemic 86 Racemic 89 Chiral HPLC Method D: 2nd eluting compound 90 Racemic 91 Racemic 92 Racemic 93 Racemic 94 Racemic 95 Chiral HPLC Method D: 2nd eluting compound 96 Racemic 97 Racemic 98 Racemic 99 Racemic 100 Racemic 101 Racemic 102 Racemic 103 Racemic 104 Chiral HPLC Method L: 2nd eluting compound 105 Racemic 106 Racemic 107 Racemic 108 Racemic 109 Racemic 110 Racemic 111 Racemic 112 Racemic 113 Racemic 114 Racemic 115 Racemic 116 Racemic 117 Racemic 118 Racemic 119 Racemic 120 Racemic 121 Racemic 122 Racemic 123 Racemic 124 Racemic 125 Racemic 126 Racemic 127 Racemic 128 Racemic 129 Racemic 130 Racemic 131 Racemic 132 S configuration; synthesized from Intermediate 16 133 Chiral HPLC Method D: 2nd eluting compound 134 S configuration; synthesized from Intermediate 16 135 Racemic 136 S configuration; synthesized from Intermediate 16 137 S configuration; synthesized from Intermediate 16 138 S configuration; Synthesized from Intermediate 16 139 S configuration; synthesized from Intermediate 16 140 Racemic 141 S configuration; synthesized from Intermediate 16 142 S configuration; synthesized from Intermediate 16 143 R configuration; synthesized+nlf rom Intermediate 24 145 146 147 148 Racemic 149 150 151 152 153 154 155 156 157 158 159 160 161 162 163 164 165 Racemic 166 Racemic 167 Racemic 168 Racemic 169 Racemic 170 Racemic 171 S configuration; synthesized from Intermediate 16 172 Racemic 173 S configuration; synthesized from Intermediate 16 174 Racemic 175 S configuration; synthesized from Intermediate 16 176 S configuration; synthesized from Intermediate 16 177 S configuuration; synthesized from Intermediate 16 178 Racemic 179 Racemic 180 S configuration; synthesized from Intermediate 16 181 S confuguration; synthesized from Intermediate 16 182 S configuration; synthesized from Intermediate 16 183 S configuration; synthesized from Intermediate 16 184 S configuration; synthesized from Intermediate 16 185 S configuration; synthesized from Intermediate 16 186 S configuration; synthesized from Intermediate 16 187 S configuration; synthesized from Intermediate 16 188 S configuration; synthesized from Interemdiate 16 189 S configuration; synthesized from Intermediate 16 190 S configuration; synthesized form Intermediate 16 191 S configuration; synthesized from Intermediate 16 192 S configuration; synthesized from Intermediate 16 193 S configuration; synthesized from Intermediate 16 194 S configuration; synthesized from Intermediate 16 195 S configuration; synthesized from Intermediate 16 196 Racemic 197 Chiral HPLC Method J: 2nd eluting compound 198 Chiral HPLC Method J: 1st eluting compound 199 Racemic 200 Racemic 201 Racemic 202 Racemic and/or and pharmaceutically usable derivatives, solvates, salts, tautomers, enantiomers, racemates and stereoisomers thereof, including mixtures thereof in all ratios.

10. A compound of formula (I) according to claim 1 for use as a medicament.

11. A compound of formula (I) according to claim 1 and pharmaceutically usable derivatives, solvates, salts, tautomers, enantiomers, racemates and stereoisomers thereof, including mixtures thereof in all ratios for use in a treatment of a condition selected from neurodegenerative diseases, diabetes, cancer and stress.

12. A compound for use in a treatment of a condition according to claim 11, wherein the condition is selected from the group of one or more tauopathies and Alzheimer's disease, Dementia, Amyotrophic lateral sclerosis (ALS), Amyotrophic lateral sclerosis with cognitive impairment (ALSci), Argyrophilic grain dementia, Bluit disease, Corticobasal degeneration (CBP), Dementia pugilistica, Diffuse neurofibrillary tangles with calcification, Down's syndrome, Familial British dementia, Familial Danish dementia, Frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), Gerstmann-Straussler-Scheinker disease, Guadeloupean parkinsonism, Hallevorden-Spatz disease (neurodegeneration with brain iron accumulation type 1), Multiple system atrophy, Myotonic dystrophy, Niemann-Pick disease (type C), Pallido-ponto-nigral degeneration, Parkinsonism-dementia complex of Guam, Pick's disease (PiD), Postencephalitic parkinsonism (PEP), Prion diseases (including Creutzfeldt-Jakob Disease (GJD), Variant Creutzfeldt-Jakob Disease (vCJD), Fatal Familial Insomnia, Kuru, Progressive supercortical gliosis, Progressive supranuclear palsy (PSP), Steele-Richardson-Olszewski syndrome, Subacute sclerosing panencephalitis, Tangle-only dementia, Huntington's disease and Parkinson's disease, preferably one or more tauopathies and Alzheimer's disease.

13. A method for treating a tauopathy, wherein a compound defined in claim 1 is administered to a mammal in need of such treatment.

14. A method for inhibiting a glycosidase, wherein a system expressing the glycosidase is contacted with a compound as defined in claim 1 under in-vitro conditions such that the glycosidase is inhibited.

15. 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

[0177] 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.

[0178] 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.

[0179] The HPLC, MS and NMR data provided in the examples described below are obtained as followed:

[0180] .sup.1H NMR analyses were carried out using BRUKER NMR, model AV-II and AV-Ill 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).

[0181] The MS data provided in the examples described below were obtained as followed: Mass spectrum: LC/MS Agilent (ESI/APCI), Chemstration, 1200 Series.

[0182] LCMS Methods:

[0183] Method A

[0184] Method: A—0.1% TFA in H.sub.2O, B—0.1% TFA in ACN: Flow—2.0 mL/min.

[0185] Column: XBridge C8 (50×4.6 mm, 3.5 μm+ve mode

[0186] Method B

[0187] Method: A—10 mM NH.sub.4HCO.sub.3 in H.sub.2O, B—ACN: Flow—1.0 mL/min.

[0188] Column: XBridge C8 (50×4.6 mm, 3.5 μm), +ve mode

[0189] Method C

[0190] Method: A—10 mM NH.sub.4HCO.sub.3 in H.sub.2O, B—ACN: Flow—1.0 mL/min.

[0191] Column: XBridge C8 (50×4.6 mm, 3.5 μm), −ve mode

[0192] HPLC analyses were obtained using Agilent 1200 Series instruments as followed using % with UV detection (maxplot).

[0193] Method A

[0194] Method: A—0.1% TFA in H.sub.2O, B—0.1% TFA in ACN: Flow—2.0 mL/min.

[0195] Column: XBridge C8 (50×4.6 mm, 3.5 μm).

[0196] Method B

[0197] Method: A—10 mM NH.sub.4HCO.sub.3 in H.sub.2O, B—ACN: Flow—1.0 mL/min.

[0198] Column: XBridge C8 (50×4.6 mm, 3.5 μm).

[0199] Method C

[0200] Method: Gradient from 70% H.sub.2O (10 mM K.sub.2HPO.sub.4): 30% MeCN to 70% MeCN over 15 minutes, Flow: 1 mL/min. Column: XTERRA RP18 (250×4.6) mm, 5 μm

[0201] Chiral HPLC

[0202] Method A

[0203] Mobile Phase: 0.1% DEA in n-HEXANE:IPA: 60:40; COLUMN: CHIRALPAK AD-H (250×4.6) mm, 5 μm, FLOW: 1.0 mL/min

[0204] Method B:

[0205] Mobile Phase: n-HEXANE:EtOH: 90:10: FLOW: 1.0 mL\min; COLUMN: CHIRALPAK IC (250×4.6) mm, 5 μm

[0206] Method C:

[0207] Mobile Phase: 0.1% TFA in n-HEXANE:IPA: 60:40; COLUMN: CHIRALcell OD-H (250×4.6) mm, 5 μm, FLOW: 1.0 mL/min

[0208] Method D:

[0209] Mobile Phase: 0.1% DEA in Hexane:EtOH: 80:20; FLOW: 1.0 mL\min; COLUMN: Chiralcell OJ-H column (250×4.6) mm, 5 μm

[0210] Method E:

[0211] Mobile Phase: 0.1% DEA in Hexane:EtOH: 80:20; FLOW: 1.0 mL\min; COLUMN: Chiralcell AY-H column (250×4.6) mm, 5 μm

[0212] Method F:

[0213] Mobile Phase: 0.1% DEA in Hexane:EtOH: 70:30; FLOW: 1.0 mL\min; COLUMN: Chiralpak IA (250×4.6) mm, 5 μm

[0214] Method G:

[0215] Mobile Phase: 0.1% DEA in Hexane:EtOH: 60:40; FLOW: 1.0 mL\min; COLUMN: Chiralcel OD-H (250×4.6) mm, 5 μm

[0216] Method H:

[0217] Mobile Phase: 0.1% DEA in n-Hexane:EtOH: 80:20; FLOW: 1.0 mL\min; COLUMN: CHIRALPAK IC (250×4.6) mm, 5 μm General flash chromatography conditions used for the purification of intermediates or compounds of Formula I: silica gel 230-400 mesh; gradients used as eluent: 10 to 80% EtOAc in Petroleum ether or 1 to 15% MeOH in DCM

[0218] MD Autoprep Conditions

[0219] The mass directed preparative HPLC purifications were performed with a mass directed autopurification Fractionlynx from Waters.

[0220] Method A

[0221] 0.1% HCOOH in H.sub.2O, B-MeOH or ACN, Column: Symmetry C8 (300 mm×19 mm), 7 μm

[0222] Method B

[0223] 0.1% TFA in H.sub.2O, B-MeOH or ACN, Column: Symmetry C8 (300 mm×19 mm), 7 μm

[0224] Method C

[0225] 10 mM NH.sub.4HCO.sub.3 in H.sub.2O, B-MeOH or ACN, Column: Symmetry C8 (300 mm×19 mm), 7 μm

[0226] Method D

[0227] 10 mM NH.sub.4OAC in H.sub.2O, B-MeOH or ACN, Column: Symmetry C8 (300 mm×19 mm), 7 μm Preparative HPLC Conditions

[0228] Method PA

[0229] 0.1% TFA in H.sub.2O, B-MeOH or ACN. Column: Sunfire C8 (19 mm×250 mm) 5 μm or Sunfire C18 (30 mm×250 mm) 10 μm.

[0230] Method PB

[0231] 10 mM NH.sub.4HCO.sub.3 in H.sub.2O, B-MeOH or ACN, Column: Sunfire C8 (19 mm×250 mm) 5 μm or Sunfire C18 (30 mm×250 mm) 10 μm.

[0232] Chiral Preparative Method PC

[0233] Mobile phase: n-Hexane, IPA; Column: Chiral pak AD-H (20×250) mm, 5 micron, Flow: 12 mL/min

[0234] Chiral Preparative Method PD:

[0235] Mobile phase: n-Hexane, IPA; Column: Chiral pak AD-H (20×250) mm, 5 micron, Flow: 12 mL/min

[0236] Chiral Preparative Method PE:

[0237] Mobile phase: n-Hexane, IPA; Column: Chiralcell OD-H (20×250) mm, 5 micron, Flow: 12 mL/min

[0238] Chiral Preparative Method PF:

[0239] Mobile Phase: 0.1% DEA in Hexane:EtOH: 80:20; FLOW: 12.0 mL\min; COLUMN: Chiralcell OJ-H column (250×20) mm, 5 μm

[0240] Chiral Preparative Method PG:

[0241] Mobile Phase: 0.1% DEA in Hexane:EtOH: 80:20; FLOW: 20.0 mL\min; COLUMN: Chiralcell AY-H column (250×30) mm, 5 μm

[0242] Chiral Preparative Method PH:

[0243] Mobile Phase: n-HEXANE: ETOH: 90:10: FLOW: 20.0 mL\min; COLUMN: CHIRALPAK IC (250×30) mm, 5 μm

[0244] Chiral Preparative Method P1:

[0245] Mobile Phase: 0.1% DEA in Hexane:EtOH: 80:20; FLOW: 12.0 mL\min; COLUMN: Lux Cellulose C4 (250×21.2) mm, 5 μm

[0246] Chiral Preparative Method PJ:

[0247] Mobile Phase: 0.1% DEA in Hexane:EtOH: 70:30; FLOW: 12.0 mL\min; COLUMN: Chiralpak IA (250×20) mm, 5 μm

[0248] Chiral Preparative Method PK:

[0249] Mobile Phase: 0.1% DEA In Hexane:EtOH: 50:50; FLOW: 10.0 mL/min; COLUMN: Chiralpac IC (250×21) mm, 5 μm

[0250] The SFC purifications were performed with a Prep SFC, THAR-SFC 80 and THAR-SFC 200.

[0251] The microwave chemistry was performed on a single mode microwave reactor Initiator™ Sixty from Biotage.

[0252] General Procedure for Ester Reduction of Heterocycles: Procedure A

[0253] To a stirred solution of ester (1 equiv) in dry THF (20 to 35 mL), lithium triethylborohydride (1 M solution in THF, 1.7 equiv) was added slowly at 0° C. The reaction mixture was stirred at room temperature for 2 h. The completion of the reaction was monitored by TLC. Reaction mixture was cooled to 0° C. and quenched using 10% ammonium chloride solution. Solvent was removed under vacuum and resulting residue was purified by flash column chromatography to afford the desired product.

[0254] General Procedure for Chlorination of Hetrocyclic Alcohol: Procedure B

[0255] To a stirred solution of alcohol (1 equiv) in dry DCM (10 to 20 mL), thionyl chloride (1.7 to 3 equiv) was added slowly at 0° C. The reaction mixture was warmed to rt and was refluxed for 1 h. The reaction mixture was concentrated under vacuum and the resulting residue was diluted with DCM (20 to 50 mL). The DCM layer was washed with water (5 to 10 mL), brine solution (5 to 10 mL), dried over anhydrous Na.sub.2SO.sub.4 and concentrated under vacuum to give chloro compound.

[0256] General Procedure for Reductive Amination: Procedure C

[0257] To a solution of aldehyde (1 equiv) in dry THF (4 to 10 mL), amine (0.8 to 1.1 equiv), acetic acid (7 equiv) was added at room temperature and stirred for 30 min. Then the reaction mixture was cooled to 0° C. and sodium triacetoxy borohydride (1.2 equiv) was added slowly. The resulting reaction mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated, the crude product was diluted with (10 to 20 mL) EtOAc and the organic layer was washed with (10-20 mL) of brine. The organic layer was separated, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under vacuum. The crude products were purified by flash column chromatography to afford the desired product.

[0258] General Procedure for N-Alkylation: Procedure D

[0259] To a stirred solution of amine (1 mmol/0.8 to 1 equiv) in dry DMF (5 to 10 mL), chloro compound (1.0 to 1.2 equiv) and potassium carbonate (2 equiv) were added at rt. The resulting mixture was heated at 90° C. for 16 h. It was concentrated under vacuum and the resulting residue was diluted with DCM (20 to 50 mL). The DCM layer was washed with water (5 to 10 mL), brine solution (5 to 10 mL), dried over anhydrous Na.sub.2SO.sub.4 and concentrated under vacuum. The crude products were purified by flash chromatography to afford the desired product.

[0260] General Procedure for N-Alkylation: Procedure E

[0261] To a stirred solution of amine (1 mmol/1 equiv) in acetonitrile (5 to 10 mL), chloro compound (1.5 to 2 equiv), triethyl amine (2 equiv) were added at rt. The resulting mixture was stirred at rt to 60° C. for 16 h. It was diluted with water (15 mL) and extracted with EtOAc (2×20 mL). The organic layer was dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure. The resulting crude product was purified by flash chromatography to afford the desired product.

Intermediates Synthesis

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

[0262] ##STR00230##

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

[0263] To a stirred solution of 3, 4-methylenedioxy acetophenone (4.5 g, 27 mmol, Alfa aesar) in dry MeOH (50 mL), NaBH.sub.4 (1.08 g, 42 mmol, Loba chemie) was added slowly at 0° C. The reaction mixture was stirred at room temperature for 1 h. Then the reaction mixture was concentrated under vacuum and diluted with DCM. The DCM layer was washed with water, brine and dried over anhydrous Na.sub.2SO.sub.4. The solvent was removed under reduced pressure and resulting crude alcohol was used as such in the next step. Yield: 90% (4.0 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).

[0264] LCMS: (Method B) 149.0 (Hydroxy elimination mass), Rt. 2.51 min, 98.6% (Max). HPLC: (Method A) Rt. 2.499 min, 99.5% (Max).

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

[0265] The title compound was synthesized by following general procedure B. It was used for next step without further purification. Yield: 72% (1.2 g, colorless 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=8.0 Hz, 1H), 1.74 (d, J=8.0 Hz, 3H). LCMS: (Method B) 149.0 (Cl-Elimination mass), Rt. 3.71 min, 80.15% (Max).

Intermediate 2: 1-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazine hydrochloride

[0266] ##STR00231##

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

[0267] The title compound was synthesized following general procedure D, starting with Intermediate 1 and N-boc piperazine. The crude product was purified by flash chromatography, affording the title compound (yellow 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 (m, 2H), 3.37-3.36 (m, 1H), 3.27 (br. s, 4H), 2.28-2.21 (m, 4H), 1.37 (s, 9H), 1.25 (d, 3H, J=6.8 Hz). LCMS: (Method A) 335.2 (M+H), Rt. 3.10 min, 93.15% (Max). HPLC: (Method A) Rt. 3.12 min, 95.01% (Max).

Step 2: 1-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazine hydrochloride

[0268] To a stirred solution of tert-butyl 4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazine-1-carboxylate (1.8 g, 5.38 mmol) in dry dioxane (10 mL), HCl in dioxane (10 mL, 4 M, Spectrochem) was added at rt and stirred for 2 h at same temperature. The reaction mixture was concentrated under vacuum and the resulting crude product was washed with diethyl ether to afford the title product as hydrochloride salt. Yield: 82% (1.2 g, off white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 12.29 (s, 1H), 7.34 (s, 1H), 7.08 (d, 1H, J=7.7 Hz), 7.00 (d, 1H, J=7.9 Hz), 6.07 (s, 2H), 4.54 (br. s, 1H), 3.81 (br. s, 1H), 3.49-3.42 (m, 3H), 3.33 (br. s, 2H), 3.12 (br. s, 1H), 2.99 (br. s, 1H), 1.67 (d, 3H, J=5.7 Hz). LCMS: (Method A) 235.0 (M+H), Rt. 1.65 min, 98.08% (Max). HPLC: (Method A) Rt. 1.56 min, 99.86% (Max).

Intermediate 3: 6-(1-chloroethyl)-2,3-dihydrobenzo[b][1,4]dioxine

[0269] ##STR00232##

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

[0270] The title compound was synthesized with same protocol as described for Intermediate 1, Step 1, using 1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethan-1-one (2.0 g, 11.2 mmol) and NaBH.sub.4 (0.49 g, 13 mmol). The resulting crude alcohol was used as such in the next step. Yield: 99% (2.0 g, colorless liquid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 6.80 (s, 1H), 6.79-6.76 (m, 2H), 4.59 (q, J=5.6 Hz, 1H), 4.20 (s, 4H), 1.26 (d, J=5.6 Hz, 3H). LCMS: (Method B) 163.0 (Hydroxy elimination mass), Rt. 2.51 min, 99.4% (Max).

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

[0271] The title compound was synthesized according to the general procedure B. It was used in the next step without further purification. Yield: 90% (2.2 g, brown liquid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 6.97 (s, 1H), 6.96-6.92 (m, 1H), 6.84-6.82 (m, 1H), 5.26 (t, J=6.7 Hz, 1H), 4.23 (s, 4H), 1.75 (d, J=6.7 Hz, 3H). LCMS: (Method A) 163.0 (Cl-Elimination mass), Rt. 3.66 min, 95.3% (Max).

Intermediate 4: 1-(1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)piperazine hydrochloride

[0272] ##STR00233##

Step 1: t-Butyl 4-(1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)piperazine-1-carboxylate

[0273] The title compound was synthesized according to the general procedure D, starting with Intermediate 3 (5 g, 25.2 mmol) and N-boc piperazine (3.96 g, 21.2 mmol). The crude product was purified by flash chromatography, affording the title compound. Yield: 52% (4.6 g, brown liquid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 6.80-6.71 (m, 3H), 4.21 (s, 5H), 3.34-3.26 (m, 4H), 2.27-2.24 (m, 4H), 1.37 (s, 9H), 1.23 (d, J=6.7 Hz, 3H). LCMS: (Method A) 349.2 (M+H), Rt. 3.19 min, 80.9% (Max).

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

[0274] To a stirred solution of tert-butyl 4-(1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)piperazine-1-carboxylate (4.6 g, 13.20 mmol) in dry dioxane (5.0 mL), HCl in dioxane (10.0 mL, 4 M, Spectrochem) was added at 0° C. The reaction mixture was stirred at rt for 2 h. The completion of the reaction was monitored by TLC. The reaction mixture was concentrated. Diethyl ether was added and was evaporated again, affording the title compound. Yield: 89% (3.8 g, off white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 12.08 (br. s, 1H), 9.48-9.18 (m, 2H), 7.18 (s, 1H), 7.03 (s, 1H), 6.92 (d, J=10.6 Hz, 1H), 4.49 (s, 1H), 4.24 (s, 4H), 3.41-3.15 (m, 4H), 2.91-2.71 (m, 4H), 1.64 (s, 3H). LCMS: (Method A) 249.2 (M+H), Rt. 1.64 min, 92.6% (Max).

Intermediate 5: 5-(1-chloroethyl)-2,3-dihydrobenzofuran

[0275] ##STR00234##

Step 1: 1-(2,3-dihydrobenzofuran-5-yl)ethan-1-ol

[0276] To a stirred solution of 1-(2,3-dihydrobenzofuran-5-yl)ethan-1-one (2.0 g, 13.0 mmol) in dry MeOH (20 mL), NaBH.sub.4 (0.68 g, 26.0 mmol, Loba chemie) was added slowly at 0° C. The reaction mixture was stirred at rt for 1 h. It was then concentrated under vacuum and the resulting crude product was dissolved in DCM (50 mL), washed with water, brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure. The crude product was used in the next step without further purification. Yield: 91% (1.83 g).

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

[0277] The title compound was synthesized following the general procedure B. The reaction mixture was concentrated under vacuum and the resulting crude mixture was used without further purification. Yield: 72% (0.6 g, colorless liquid). LCMS: (Method B) 149.0 (chloro elimination mass), Rt. 3.705 min, 80.15% (Max).

Intermediate 6: 6-(1-chloroethyl)quinoxaline

[0278] ##STR00235##

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

[0279] 6-Bromo quinoxaline (2.0 g, 9.5 mmol) in toluene (20 mL) was degassed for 30 min. To this solution, 1-ethoxy vinyl tributyltin (3.8 g, 10.5 mmol) and bis(triphenylphosphine)palladium dichloride (0.67 g, 0.95 mmol) were added at rt and stirred for 16 hours at 90° C. The reaction mixture was cooled to rt and filtered through celite. After evaporation of the solvent, 6 N HCl solution in water (20 mL) was added and the mixture was stirred for 1 hour at rt. It was concentrated and neutralized with sat. NaHCO.sub.3. The desired product was extracted with DCM (100 mL), dried over Na.sub.2SO.sub.4 and concentrated. The crude product was purified by flash column chromatography to afford the title compound (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 (t, J=2.8 Hz, 1H), 8.16 (d, J=11.6 Hz, 1H), 2.97 (s, 3H). LCMS: (Method A) 173 (M+H), Rt. 2.25 min, 99.06% (Max).

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

[0280] To a stirred solution of 1-(quinoxalin-6-yl)ethan-1-one (0.8 g, 4.65 mmol) in dry MeOH (20 mL), sodium borohydride (0.36 g, 9.3 mmol) was added portion wise at 0° C. and the resulting mixture was stirred for 1 h. It was then concentrated, diluted with DCM (80 mL), washed with water (20 mL), dried over Na.sub.2SO.sub.4 and concentrated. The crude product was taken for next step without 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), 4.97 (t, J=6.2 Hz, 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

[0281] 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 hour. The reaction mixture was evaporated to dryness and was used without 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 (M+H), Rt. 3.41 min, 71.4% (Max).

Intermediate 7: N-(5-(piperazin-1-yl)-1,3,4-thiadiazol-2-yl)acetamide hydrochloride

[0282] ##STR00236##

Step 1: tert-Butyl 4-(5-amino-1,3,4-thiadiazol-2-yl)piperazine-1-carboxylate

[0283] To a stirred solution of 2-amino 5-bromo-1, 3, 4-thiadiazole (10.0 g, 55.5 mmol) in dry DMF (100 mL), K.sub.2CO.sub.3 (15.3 g, 111.1 mmol) and 1-boc piperazine (12.4 g, 66.65 mmol) were added at 0° C. The reaction mixture was stirred overnight at 80° C. The reaction mixture was concentrated under vacuum. To the resulting crude solids, DCM (200 mL) was added. The DCM layer was washed with water (100 mL), brine (100 mL) and, dried over anhydrous Na.sub.2SO.sub.4 and concentrated. The crude product was purified by silica gel column chromatography to afford the title compound. Yield: 76% (12 g, pale brown solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 6.51 (s, 2H), 3.39 (d, J=6.9 Hz, 4H), 3.19 (d, J=7.7 Hz, 4H), 1.39 (s, 9H). LCMS: (Method A) 286.1 (M+H), Rt. 2.71 min, 97.6% (Max).

Step 2: tert-Butyl 4-(5-acetamido-1,3,4-thiadiazol-2-yl)piperazine-1-carboxylate

[0284] To a stirred solution of tert-butyl 4-(5-amino-1,3,4-thiadiazol-2-yl)piperazine-1-carboxylate (12.0 g, 42.09 mmol) in pyridine (120 mL), acetic anhydride (5.1 g, 50.5 mmol) was added at 0° C. The reaction mixture was stirred overnight at 50° C. The reaction mixture was concentrated under vacuum and triturated with diethyl ether (100 mL). The solid obtained was filtered, washed with diethyl ether (20 mL), dried and taken for next step without any further purification. Yield: 87% (12 g, off white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 12.07 (br. s, 1H), 3.45-3.34 (m, 8H), 2.11 (s, 3H), 1.42 (s, 9H). LCMS: (Method A) 328.0 (M+H), Rt. 3.11 min, 86.3% (Max).

Step 3: N-(5-(Piperazin-1-yl)-1,3,4-thiadiazol-2-yl)acetamide hydrochloride

[0285] To a stirred solution of tert-butyl 4-(5-acetamido-1,3,4-thiadiazol-2-yl)piperazine-1-carboxylate (12.0 g) in dry dioxane (100 mL), HCl in dioxane (100 mL, 4 N) was added and the reaction mixture was stirred at rt for 3 h. The reaction mixture was concentrated under vacuum and the resulting crude product was suspended diethyl ether (50 mL). The title compound was obtained after evaporation of the solvent. Yield: 93% (9 g, white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 12.07 (br. s, 1H), 3.67 (s, 4H), 3.21 (s, 4H), 2.13 (s, 3H). LCMS: (Method A) 228.0 (M+H), Rt. 0.71 min, 85.3% (Max).

Intermediate 8: Ethyl 2-(piperazin-1-yl)thiazole-5-carboxylate hydrochloride

[0286] ##STR00237##

Step 1: Ethyl 2-(4-(tert-butoxycarbonyl)piperazin-1-yl)thiazole-5-carboxylate

[0287] To a stirred solution of ethyl 2-bromothiazole-5-carboxylate (4.0 g, 17.0 mmol) in dry DMF (40 mL), triethylamine (7.3 mL, 51.0 mmol, Spectrochem), followed by N-Boc piperazine (3.6 g, 19.0 mmol, GLRscientific) were added. The resulting mixture was heated at 90° C. for 12 h. It was then concentrated, diluted with DCM (200 mL), washed with water (100 mL) and dried over Na.sub.2SO.sub.4.

[0288] After evaporation of the solvents, the crude product was purified by flash chromatography (3% methanol in DCM) to afford the title compound. Yield: 77% (4.5 g, white solid). LCMS: (Method A) 342.0 (M+H), Rt. 4.42 min, 99.5% (Max). .sup.1H NMR (400 MHz, CDCl.sub.3): δ 7.88 (s, 1H), 4.30 (q, J=7.2 Hz, 2H), 3.57 (s, 8H), 1.49 (s, 9H), 1.35 (t, J=7.2 Hz, 3H).

Step 2: Ethyl 2-(piperazin-1-yl)thiazole-5-carboxylate hydrochloride

[0289] To a stirred solution of ethyl 2-(4-(tert-butoxycarbonyl)piperazin-1-yl)thiazole-5-carboxylate (4.5 g, 13.0 mmol) in dry dioxane (20 mL), HCl in dioxane (4 N, 50 mL) was added at 0° C. and the reaction mixture was stirred at rt for 2 h. The reaction mixture was concentrated and the resulting solid was washed with diethyl ether and dried under vacuum. Yield: 90% (5.4 g, off white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.32 (s, 2H), 7.88 (s, 1H), 4.21 (q, J=9.4 Hz, 2H), 3.96-3.73 (m, 4H), 3.55-2.41 (m, 4H), 1.24 (t, J=7.0 Hz, 3H). LCMS: (Method B) 242.0 (M+H), Rt. 2.11 min, 99.8% (Max).

Intermediate 9: 7-(1-chloroethyl)quinoline

[0290] ##STR00238##

Step 1: 1-(quinolin-7-yl)ethan-1-one

[0291] The title compound was synthesized according to the protocol described for the synthesis of Intermediate 6, step 1, using 7-bromo quinoline (2 g, 9.56 mmol, Harvechem) as starting material. The crude product was purified by flash chromatography to afford the title compound (brown solid). .sup.1H NMR (300 MHz, DMSO-d.sub.6): δ 9.02 (d, J=3.2 Hz, 1H), 8.63 (s, 1H), 8.46-8.10 (m, 1H), 8.08-8.03 (m, 2H), 7.68-7.50 (m, 1H), 2.68 (s, 3H). LCMS: (Method A) 172.0 (M+H), Rt. 1.49 min, 84.1% (Max).

Step 2: 1-(quinolin-7-yl)ethan-1-ol

[0292] The title compound was synthesized according to the protocol described for the synthesis of Intermediate 6, step 2, using 1-(quinolin-7-yl)ethan-1-one as starting material. The crude product was taken for next step without further purification (brown solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.86-8.85 (m, 1H), 8.31 (d, J=8.1 Hz, 1H), 7.92 (t, J=8.5 Hz, 2H), 7.60 (d, J=8.4 Hz, 1H), 7.47 (dd, J=4.2, 8.2 Hz, 1H), 5.39 (d, J=4.2 Hz, 1H), 4.90-4.96 (m, 1H), 1.41 (d, J=6.4 Hz, 3H).

[0293] LCMS: (Method A) 174.0 (M+H), Rt. 1.34 min, 99.2% (Max).

Step 3: 7-(1-chloroethyl)quinoline

[0294] The title compound was synthesized according to the protocol described for the synthesis of Intermediate 6, step 3, using 1-(quinolin-7-yl)ethan-1-ol as starting material. The crude product was taken for next step without further purification. Yield: 96% (260 mg, grey solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.19 (d, J=3.5 Hz, 1H), 8.88 (d, J=7.6 Hz, 1H), 8.27 (d, J=6.6 Hz, 2H), 7.60 (d, J=8.4 Hz, 1H), 7.93 (dt, J=6.0, Hz, 2H), 5.71-5.68 (m, 1H), 1.91 (d, J=6.7 Hz, 3H). LCMS: (Method A) 192.0 (M+H), Rt. 2.27 min, 98.7% (Max).

Intermediate 10: N-(2-(piperazin-1-yl)pyrimidin-5-yl)acetamide, hydrochloride

[0295] ##STR00239##

Step 1: Tert-butyl 4-(5-nitropyrimidin-2-yl)piperazine-1-carboxylate

[0296] To a stirred solution of 2-chloro-5-nitro-pyrimidine (2.2 g, 13.7 mmol) in dry DMF (25 mL), triethylamine (5.7 mL, 41.3 mmol, Spectrochem) followed by N-Boc piperazine (2.8 g, 15.7 mmol) were added and the resulting mixture was heated at 90° C. for 12 h. It was concentrated and the residue was diluted with DCM (50 mL), washed with water (15 mL) and dried over Na.sub.2SO.sub.4. After evaporation of the solvents, the crude product was washed with ACN with 5% methanol to afford the title compound (brown solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.12 (s, 2H), 3.92-3.88 (m, 4H), 3.45-3.42 (m, 4H), 1.4 (s, 9H). LCMS: (Method A) 254.0 (M-(t-butyl)+H), Rt. 4.43 min, 98.03% (Max).

Step 2: Tert-butyl 4-(5-aminopyrimidin-2-yl)piperazine-1-carboxylate

[0297] To a stirred solution of tert-butyl 4-(5-nitropyrimidin-2-yl)piperazine-1-carboxylate (2.1 g, 6.79 mmol) in methanol (25 mL), Pd/C (10%, 0.210 g, Aldrich) was added and the reaction mixture was stirred under H.sub.2 atmosphere for 3 h. The reaction completion was monitored by TLC. The reaction mixture was filtered through celite and evaporated under vacuum. The crude product was used without further purification. Yield: 95% (1.8 g, pale brown solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.88 (s, 2H), 4.62 (s, 2H), 3.48-3.45 (m, 4H), 3.35-3.28 (m, 4H), 1.33 (s, 9H). LCMS: (Method A) 280 (M+H), Rt. 2.66 min, 98.82% (Max).

Step 3: Tert-butyl 4-(5-acetamidopyrimidin-2-yl)piperazine-1-carboxylate

[0298] To a stirred solution of tert-butyl 4-(5-aminopyrimidin-2-yl)piperazine-1-carboxylate (1.8 g, 6.44 mmol) in dry DCM (18 mL), pyridine (0.7 mL, 9.67 mmol, spectrochem), acetic anhydride (0.9 mL, 9.67 mmol, spectrochem) and dimethyl aminopyridine (0.036 g, 2%, spectrochem) were added. The resulting mixture was stirred at rt for 12 h. The reaction mixture was concentrated under reduced pressure and the resulting solid was suspended in HCl (1.5 N in water, 15 mL). The solid was filtered and washed with water (200 mL) to afford the title compound. Yield: 87% (1.8 g, off white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.85 (s, 1H), 8.51 (s, 2H), 3.66-3.61 (m, 4H), 3.33-3.31 (m, 4H), 2.00 (s, 3H), 1.41 (s, 9H). LCMS: (Method A) 322 (M+H), Rt. 3.1 min, 98.4% (Max).

Step 4: N-(2-(piperazin-1-yl)pyrimidin-5-yl)acetamide

[0299] To a stirred solution of tert-butyl 4-(5-acetamidopyrimidin-2-yl)piperazine-1-carboxylate (1.8 g, 5.6 mmol) in dry dioxane (5 mL) at 0° C., a solution of HCl in dioxane (4 N, 15 mL) was added and the reaction mixture was stirred 3 h at rt. It was concentrated and the resulting product washed with diethyl ether, affording the title compound. Yield: 83% (1.8 g, off white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 10.9 (s, 1H), 9.92 (s, 1H), 8.86 (s, 2H), 3.22-3.17 (m, 4H), 3.02-2.78 (m, 4H), 2.06 (s, 3H). LCMS: (Method B) 222.0 (M+H), Rt. 2.36 min, 95.34% (Max)

Intermediate 11: 6-(1-(piperazin-1-yl)ethyl)quinoxaline hydrochloride

[0300] ##STR00240##

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

[0301] 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 Intermediate 6 (4 g, 20.83 mmol) were added at rt and the reaction mixture was stirred overnight at 90° C. The reaction mixture was cooled to rt and concentrated under vacuum. To this crude mixture, water (50 mL) was added and the product was extracted with DCM (150 mL). Organic layer was dried over anhydrous Na.sub.2SO.sub.4 and concentrated to get the crude product. The crude product was purified by flash column chromatography to afford the title compound (brown solid). LCMS: (Method A) 343.2 (M+H), Rt. 2.59 min, 75.3% (Max).

Step 2: 6-(1-(piperazin-1-yl) ethyl) quinoxaline hydrochloride

[0302] To a solution of tert-butyl 4-(1-(quinoxalin-6-yl) ethyl) piperazine-1-carboxylate (3.5 g, 10.23 mmol) in methanol (5 mL), dioxane HCl (35 mL, 10 V) was added at rt and the reaction mixture was stirred at for 2 h. The reaction mixture was concentrated under reduced pressure and then 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. 1.36 min, 95.02% (Max).

Intermediate 12: 4-chloro-7-(1-chloroethyl)quinoline

[0303] ##STR00241##

Step 1—1-(4-chloroquinolin-7-yl)ethan-1-one

[0304] 7-Bromo-4-chloroquinoline (1 g, 4.12 mmol, combiblock) in toluene (5 mL) was degassed for 30 min. To this solution, 1-ethoxy vinyl tributyltin (1.6 mL, 4.53 mmol) and bis(triphenylphosphine)palladium dichloride (3.38 g, 4.76 mmol) were added at rt and stirred for 12 hours at 90° C. The reaction mixture was cooled to rt and filtered through celite. The resulting crude product was suspended in 6 N HCl in water (10 mL) and stirred for 1 hour at rt. The mixture was concentrated and neutralized with saturated aqueous solution of NaHCO.sub.3. The desired product was extracted with DCM (50 mL), dried over Na.sub.2SO.sub.4 and concentrated. The crude product was purified by flash column chromatography to afford the title compound (pale yellow solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): 8.98 (d, J=4.6 Hz, 2H), 8.72 (s, 1H), 8.33 (d, J=8.7 Hz, 1H), 8.21 (d, J=8.7 Hz, 1H), 7.92 (d, J=4.6 Hz, 1H), 2.78 (s, 3H). LCMS: (Method A) 206.0 (M+H), Rt. 2.98 min, 96.8% (Max).

Step-2—1-(4-chloroquinolin-7-yl)ethan-1-ol

[0305] To a stirred solution of 1-(4-chloroquinolin-7-yl)ethan-1-one (0.39 g, 1.92 mmol) in dry MeOH (5 mL), sodium borohydride (0.108 g, 2.88 mmol) was added portion wise at 0° C. and stirred for 1 h. The reaction mixture was concentrated, diluted with DCM (50 mL) and washed with water (20 mL). The organic layer was dried over Na.sub.2SO.sub.4 and concentrated. The crude product was taken for next step without further purification. Yield: 95% (0.38 g, colourless liquid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.81 (d, J=6.3 Hz, 1H), 8.15-8.30 (m, 1H), 8.02 (s, 1H), 7.69-7.78 (m, 2H), 5.47 (d, J=5.8 Hz, 1H), 4.92-5.00 (m, 1H), 1.42 (t, J=8.6 Hz, 3H).

Step-3: 4-chloro-7-(1-chloroethyl)quinoline

[0306] To a stirred solution of 1-(4-chloroquinolin-7-yl)ethan-1-ol (0.38 g, 1.82 mmol) in dry DCM (10 mL), thionyl chloride (0.4 mL, 5.4 mmol) was added dropwise at 0° C. and stirred at rt for 1 hour. The reaction mixture was concentrated and dried under vacuum and used as such for next step without any further purification. Yield: 97% (0.4 g, colourless liquid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): 8.89 (d, J=6.3 Hz, 1H), 8.21-8.26 (m, 2H), 7.87-7.92 (m, 2H), 5.63 (q, J=8.8 Hz, 1H), 1.91 (s, 3H). LCMS: (Method A) 226.0 (M+H), Rt. 3.54 min, 94.58% (Max).

Intermediate 13: 5-(1-chloroethyl) benzo[c][1,2,5]oxadiazole

[0307] ##STR00242##

Step 1: 1-(benzo[c][1,2,5]oxadiazol-5-yl)ethan-1-one

[0308] A solution of 5-bromobenzo[c][1,2,5]oxadiazole (3 g, 15.0 mmol, Combiblocks) in toluene (10 mL) was degassed for 30 min. 1-Ethoxy vinyl tributyltin (6.01 mL, 16.5 mole, Frontier Scientific) and bis(triphenylphosphine)palladium(II) dichloride (1.16 g, 1.65 mmol) were added at rt and the resulting mixture was stirred at 90° C. overnight. It was cooled to rt and filtered through celite. HCl aqueous solution (20 mL, 6N) was added and the mixture was stirred for 1 hour at rt. It was concentrated and neutralized with sat. NaHCO.sub.3 solution (25 mL). The product was extracted with DCM (100 mL), dried over Na.sub.2SO.sub.4 and concentrated. The crude product was purified by flash column chromatography to afford the title compound. Yield: 60% (1.5 g, pale yellow solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.90 (s, 1H), 8.14 (d, J=9.6 Hz, 1H), 7.98-7.39 (m, 1H), 2.72 (s, 3H). LCMS: (Method B) 162.0 (M+H), Rt. 4.6 min, 98.01% (Max).

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

[0309] To a stirred solution of 1-(benzo[c][1,2,5]oxadiazol-5-yl)ethan-1-one (1.4 g, 8.53 mmol) in dry MeOH (20 mL), sodium borohydride (0.48 g, 12.7 mmol, spectrochem) was added portion wise at 0° C. and stirred for 1 h. The reaction mixture was concentrated, diluted with DCM (60 mL) and washed with water (10 mL). The organic layer was dried over Na.sub.2SO.sub.4 and concentrated. The crude product was taken for next step without any further purification. Yield: 98% (1.3 g, pale yellow solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 6.85-6.82 (m, 2H), 6.71 (s, 1H), 4.36-4.30 (m, 1H), 1.43 (d, J=6.4 Hz, 3H).

Step 3: 5-(1-chloroethyl) benzo[c][1,2,5]oxadiazole

[0310] To a stirred solution of 1-(benzo[c][1,2,5]oxadiazol-5-yl)ethan-1-ol (1 g, 6.09 mmol) in dry DCM (10 mL), thionyl chloride (1.3 mL, 1.82 mmol, spectrochem) was added dropwise at 0° C. and stirred at rt for 1 hour. The reaction mixture was concentrated and used for next step without any further purification. Yield: 91% (1.01 g, brown liquid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.77-7.75 (m, 1H), 7.64 (s, 1H), 7.24-7.19 (m, 1H), 4.86-4.82 (m, 1H), 1.87 (d, J=6.7 Hz, 3H).

Intermediate 14: 7-(1-chloroethyl)-3, 4-dihydro-2H-benzo[b][1,4]dioxepine

[0311] ##STR00243##

Step 1: 1-(3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)ethan-1-one

[0312] The title compound was synthesized following the same protocol as Intermediate 13, Step 1, using 7-bromo-3,4-dihydro-2H-benzo[b][1,4]dioxepine (3 g, 13.0 mmol, Alfa aesar) as starting material. The crude product was purified by flash column chromatography to afford the title compound. Yield: 50% (1.25 g, yellow solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.57-7.52 (m, 2H), 7.05 (d, J=8.3 Hz, 1H), 4.25-4.18 (m, 4H), 2.16 (t, J=5.7 Hz, 2H), 1.73 (s, 3H). LCMS: (Method A) 193.0 (M+H), Rt. 3.2 min, 91.5% (Max).

Step 2: 1-(3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)ethan-1-ol

[0313] The title compound was synthesized following the same protocol as Intermediate 13, Step 2, using 1-(3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)ethan-1-one (1.21 g, 6.2 mmol) as starting material. The crude product was taken for next step without any further purification. Yield: 94% (1.1 g, Brown liquid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.57-7.52 (m, 2H), 7.03 (d, J=8.1 Hz, 1H). 5.65 (s, 1H), 5.28-5.23 (m, 1H), 4.13-4.10 (m, 4H), 2.14 (t, J=11.2 Hz, 2H), 1.71 (d, J=6.7 Hz, 3H).

Step 3: 7-(1-chloroethyl)-3,4-dihydro-2H-benzo[b][1,4]dioxepine

[0314] The title compound was synthesized following the same protocol as Intermediate 13, Step 3, using 1-(3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)ethan-1-ol (1.15 g, 5.92 mmol) as starting material. The crude product was used without any further purification. Yield: 90% (1.0 g, brown liquid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.06-7.02 (m, 2H), 6.93 (d, J=8.1 Hz, 1H), 5.28-5.23 (m, 1H), 4.13-4.10 (m, 4H), 2.14 (t, J=11.2 Hz, 2H), 1.73 (d, J=6.7 Hz, 3H).

Intermediate 15: 8-(1-chloroethyl)quinolone

[0315] ##STR00244##

Step 1: 1-(quinolin-8-yl) ethan-1-one

[0316] A solution of 8-bromo quinoline (3 g, 14.4 mmol, Combiblock) in toluene (10 mL) was degassed for 30 min. To this solution, 1-ethoxy vinyl tributyltin (5.72 mL, 15.8 mmol, Frontier Scientific) and bis(triphenylphosphine)palladium(II) dichloride (1.01 g, 1.44 mmol) were added at rt and stirred overnight at 90° C. The reaction mixture was cooled to rt and filtered through celite. HCl aqueous solution (20 mL, 6 N) was added and the mixture was stirred for 1 hour at rt. It was concentrated and neutralized with saturated NaHCO.sub.3 solution (25 mL). The desired product was extracted with DCM (100 mL), dried over anhydrous Na.sub.2SO.sub.4 and concentrated. The crude product was purified by flash column chromatography to afford the title compound. Yield: 60% (1.5 g, brown liquid). .sup.1H NMR (300 MHz, DMSO-d.sub.6): δ 9.01-8.99 (m, 1H), 8.46 (d, J=8.3 Hz, 1H), 8.16 (d, J=8.1 Hz, 1H), 7.86 (d, J=7.1 Hz, 1H), 7.70-7.62 (m, 2H), 2.82 (s, 3H). LCMS: (Method A) 172.0 (M+H), Rt. 0.82 min, 98.9% (Max).

Step 2: 1-(quinolin-8-yl) ethan-1-ol

[0317] To a stirred solution of 1-(quinolin-8-yl) ethan-1-one (1.5 g, 8.72 mmol) in dry MeOH (20 mL), sodium borohydride (0.49 g, 13.0 mmol, Spectrochem) was added portion wise at 0° C. and the resulting mixture was stirred for 1 h. It was concentrated, diluted with DCM (60 mL), washed with water (10 mL) and dried over Na.sub.2SO.sub.4. After evaporation of the solvents, the crude product was taken for next step without any further purification. Yield: 79% (1.2 g, brown liquid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.02-8.95 (m, 1H), 8.49 (d, J=8.1 Hz, 1H), 7.90 (t, J=8.5 Hz, 2H), 7.75 (d, J=8.4 Hz, 1H), 7.63-7.60 (m, 1H), 5.17 (d, J=4.2 Hz, 1H), 4.90-4.95 (m, 1H), 1.41 (d, J=6.4 Hz, 3H). LCMS: (Method A) 174.0 (M+H), Rt. 1.31 min, 95.4% (Max).

Step 3: 8-(1-chloroethyl)quinoline

[0318] To a stirred solution of 1-(quinolin-8-yl) ethan-1-ol (0.30 g, 1.72 mmol) in dry DCM (10 mL), thionyl chloride (0.4 mL, 2.89 mmol, spectrochem) was added dropwise at 0° C. and the resulting mixture was stirred at rt for 1 hour. It was concentrated and the resulting product was used in the next step without any further purification. Yield: 96% (0.28 g, grey liquid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.02 (d, J=1.7 Hz, 1H), 8.50 (d, J=4.1 Hz, 1H), 8.08-8.02 (m, 2H), 7.73-7.64 (m, 2H), 6.64 (t, J=8.0 Hz, 1H), 1.96 (d, J=6.7 Hz, 3H). LCMS: (Method A) 192.0 (M+H), Rt 2.81 min, 95.7% (Max).

Intermediate 16: (S)-1-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazine hydrochloride

[0319] ##STR00245##

Step 1: (R)—N-(1-(benzo[d][1,3]dioxol-5-yl)ethylidene)-2-methylpropane-2-sulfinamide

[0320] To a mixture of 1-(benzo[d][1,3]dioxol-5-yl)ethan-1-one (105.7 g, 644.6 mmol), (R)-(+)-2-methyl-2-propanesulfinamide (85.79 g, 709 mmol) in THF (1.0 L), titanium(IV) ethoxide (294.06 g, 1289.2 mmol) was added at rt over 30 min and refluxed for 35 h. The reaction was monitored by HPLC. The reaction mixture was cooled to rt and slowly quenched with water (500 mL). The precipitate observed was filtered through celite bed (100 g) and washed with EtOAc (2.0 L). The organic layer was washed with water (500 mL), brine solution (300 mL) and dried over Na.sub.2SO.sub.4. (100 g) and evaporated under vacuum at 50° C. The resulting crude product was codistilled with toluene (2×500 mL) and used as such for next step without any further purification (164 g, brown liquid). LCMS: (Method A) 268.0 (M+H), Rt. 3.87 min, 83.05% (Max).

[0321] HPLC: (Method A) Rt. 3.81 min, 57.62% (Max).

Step 2: (R)—N—((S)-1-(benzo[d][1,3]dioxol-5-yl)ethyl)-2-methylpropane-2-sulfinamide

[0322] To a stirred solution of (R)—N-(1-(benzo[d][1,3]dioxol-5-yl)ethylidene)-2-methylpropane-2-sulfinamide (96 g, 359 mmol) in THF (960 mL), L-Selectride (539 mL, 539 mmol, 1 M solution in THF) was added under nitrogen atmosphere at −50° C. over 30 min and stirred for 1 h. The completion of the reaction was confirmed by TLC. The reaction mixture was quenched with methanol (150 mL), water (750 mL) and stirred overnight at rt. The aqueous layer was extracted with EtOAc (2×300 mL). The combined organic layer was washed with sat. NH.sub.4Cl (2×250 mL), brine (250 mL), dried over Na.sub.2SO.sub.4 and evaporated under vacuum at 50° C. The resulting crude product (as light brown thick oil) was diluted with pet ether (250 mL) and stirred at −20° C. for 30 min. The resulting precipitate was filtered and washed with pet ether (2×100 mL). It was dried under vacuum to give the title compound. Yield: 70.2% (68 g, Off white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 6.89 (s, 1H), 6.83-6.77 (m, 2H), 5.99-5.95 (m, 2H), 5.25 (d, J=5.2 Hz, 1H), 4.30 (q, J=6.0 Hz, 1H), 1.39 (d, J=1.6 Hz, 3H), 1.11-1.06 (m, 9H). LCMS: (Method A) 270.0 (M+H), Rt. 3.66 min, 99.65% (Max). HPLC: (Method A) Rt. 3.62 min, 99.69% (Max). Chiral HPLC: (Method C) Rt. 9.71 min, 100%.

Step 3: (S)-1-(benzo[d][1,3]dioxol-5-yl)ethan-1-amine

[0323] To a stirred solution of (R.sub.S)—N—((S)-1-(benzo[d][1,3]dioxol-5-yl)ethyl)-2-methylpropane-2-sulfinamide (68 g, 252 mmol) in MeOH (680 mL), thionyl chloride (74.3 g, 630 mmol) was added at 0° C. over 15 min and the resulting mixture was stirred at rt for 1 h. The completion of the reaction was confirmed by TLC. The reaction mixture was concentrated under vacuum at 50° C. The resulting residue was suspended in EtOAc (300 mL), filtered and washed with EtOAc (150 mL). The product was basified with 30% aqueous ammonia solution (300 mL) and extracted with EtOAc (2×250 mL). The combined organic layer was washed with brine solution (1×150 mL) and dried over Na.sub.2SO.sub.4. The solvent was evaporated at under vacuum to give the title compound. Yield: 92.84% (38.3 g, brown liquid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 6.95 (s, 1H), 6.81-6.77 (m, 2H), 5.95 (s, 2H), 3.90 (q, J=6.56 Hz, 1H), 1.85 (s, 2H), 1.19 (m, J=6.56 Hz, 3H). LCMS: (Method A) 149.0 (M-16), Rt. 1.65 min, 99.56% (Max). HPLC: (Method A) Rt. 1.60 min, 99.61% (Max). Chiral HPLC: (Method B) Rt 11.11 min, 100%.

Step 4: (S)-1-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)-4-tosylpiperazine

[0324] To a stirred solution of (S)-1-(benzo[d][1,3]dioxol-5-yl)ethan-1-amine (41 g, 248 mmol) in DIPEA (86.6 mL, 496 mmol), N,N-bis(2-chloroethyl)-p-toluene sulfonamide (80.74 g, 273 mmol) was added at rt and the resulting mixture was heated at 105° C. overnight. The completion of the reaction was confirmed by TLC and the reaction mixture was diluted with water (1000 mL) and extracted with EtOAc (2×500 mL). The combined organic layer was washed with water (200 mL), brine solution (200 mL) and dried over Na.sub.2SO.sub.4. After evaporation of the solvent, the resulting crude solid was suspended in pet ether (350 mL) and stirred for 10 min at rt. The suspension was filtered and was washed with Et.sub.2O (2×200 mL) and dried under vacuum to give the title compound. Yield: 63.2% (61 g, Off white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.59 (d, J=8.2 Hz, 2H), 7.45 (d, J=8.2 Hz, 2H), 6.81-6.77 (m, 1H), 6.69 (d, J=7.4 Hz, 1H), 5.96 (s, 2H), 3.32 (q, J=7.76 Hz, 1H), 2.81-2.80 (m, 4H), 2.42 (s, 3H), 2.36-2.32 (m, 4H), 1.18 (d, J=6.4 Hz, 3H). LCMS: (Method A) 389.2 (M+H), Rt. 3.40 min, 98.09% (Max). HPLC: (Method A) Rt. 3.30 min, 98.69% (Max). Chiral HPLC: (Method D) Rt. 15.79 min, 100.00%

Step 5: (S)-1-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazine hydrochloride

[0325] To a mixture of (S)-1-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)-4-tosylpiperazine (61 g, 157 mmol) and 4-hydroxy benzoic acid (65.01 g, 471 mmol), HBr in acetic acid (244 mL) was added at 0° C. and the reaction mixture was stirred at rt overnight. The completion of the reaction was confirmed by TLC. The reaction mixture was diluted with water (400 mL). The precipitate was filtered through celite bed and washed with water (200 mL). The aqueous filterate was washed with EtOAc (4×300 mL) and basified up to pH 11 with NaOH pellet (30 g) at 0° C. (during basification the colour of aqeuous was converted to light back). The product was extracted with EtOAc (4×300 mL). The combined organic layer was dried over Na.sub.2SO.sub.4 and evaporated under vacuum. The resulting light black oil was diluted in 1,4 Dioxane (50 mL) and cooled to 0° C. and 4.5 N HCl solution in dioxane (100 mL) was added and stirred for 15 min at rt. The solvent was evaporated at 45° C. under reduced pressure to get the title compound (pale brown solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 12.11 (s, 1H), 7.32 (s, 1H), 7.06-6.99 (m, 2H), 6.07 (s, 2H), 4.55-4.52 (m, 1H), 3.80-3.61 (m, 2H), 3.05-2.95 (m, 2H), 2.51-2.50 (m 4H), 1.68 (s, 3H). LCMS: (Method A) 235.3 (M+H), Rt. 1.53 min, 95.85% (Max). HPLC: (Method A) Rt. 1.52 min, 95.06% (Max). Chiral HPLC: (Method A) Rt. 8.11 min, 100%.

Intermediate 17: 5-(1-chloroethyl)benzo[d]thiazole

[0326] ##STR00246##

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

[0327] The title compound was prepared according to the procedure described for Intermediate 6, Step 1, using 5-bromobenzo[d]thiazole (3 g, 14 mmol) as starting material. The crude product was purified by flash chromatography to give the title compound. Yield: 64.5% (1.6 g, pale yellow solid). LCMS: (Method A) 178.0 (M+H), Rt. 2.61 min, 81.8% (Max).

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

[0328] To a stirred solution of 1-(benzo[d]thiazol-5-yl)ethan-1-one (1.6 g, 9.0 mmol) in methanol (20 mL), sodium borohydride (683 mg, 18 mmol) was added slowly at 0° C. and stirred 1.5 h. The completion of the reaction was monitored by TLC and the solvents were evaporated at 45° C. under vacuum. The residue was diluted with EtOAc (50 mL) and washed with water (50 mL), brine solution (50 mL) and dried over Na.sub.2SO.sub.4. The organic layer was evaporated at 40° C. to give the title compound. Yield: 91.9% (1.49 g, pale brown solid). LCMS: (Method A) 180.0 (M+H), Rt. 2.35 min, 92.8% (Max).

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

[0329] The title was synthesized from 1-(benzo[d]thiazol-5-yl)ethan-1-ol (1.49 g, 8.3 mmol), according the general procedure B. The crude product was used in the next step without further purification. Yield: quantitative (1.64 g, pale yellow solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.43 (s, 1H), 8.19-8.17 (m, 2H), 7.63-7.61 (m, 1H), 5.57-5.52 (m, 1H), 1.87 (d, J=6.7 Hz, 3H). LCMS: (Method A) 198.0 (M+H), Rt. 3.98 min, 62.0% (Max).

Intermediate 18: 5-(1-chloroethyl)-2,2-difluorobenzo[d][1,3]dioxole

[0330] ##STR00247##

Step 1: 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)ethan-1-one

[0331] The title compound was prepared according to the procedure described for Intermediate 6, Step 1, using 5-bromo-2,2-difluorobenzo[d][1,3]dioxole (3 g, 12.6 mmol) as starting material. The crude product was purified by flash chromatography to give the title compound. Yield: 94.86% (2.4 g, pale brown solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.94-7.91 (m, 1H), 7.90-7.88 (m, 1H), 7.55 (d, J=8.4 Hz), 2.57 (s, 3H).

Step 2: 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)ethan-1-ol

[0332] The title compound was prepared according to the procedure described for Intermediate 17, Step 2, using 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)ethan-1-one (2.5 g, 12.4 mmol) as starting material. After evaporation of the solvent, the title product was isolated and used in the next without further purification. Yield: 91.08% (2.3 g, Black liquid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.34-7.30 (m, 2H), 7.17-7.14 (m, 1H), 4.75-4.69 (m, 1H), 1.29 (d, J=6.4 Hz, 3H).

Step 3: 5-(1-chloroethyl)-2,2-difluorobenzo[d][1,3]dioxole

[0333] The title compound was synthesized from 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)ethan-1-ol (1 g, 4.9 mmol), according the general procedure B. Yield: 92.5% (1 g, black gel). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.59 (d, J=2 Hz, 1H), 7.41-7.38 (m, 1H), 7.34-7.31 (m, 1H), 5.38 (q, J=6.8 Hz, 1H), 1.78 (d, J=8 Hz, 3H).

Intermediate 19: 5-(1-chloroethyl)benzo[c][1,2,5]thiadiazole

[0334] ##STR00248##

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

[0335] The title compound was prepared according to the procedure described for Intermediate 6, Step 1, using 5-bromobenzo[c][1,2,5]thiadiazole (3 g, 13.9 mmol) as starting material. The crude product was purified by flash chromatography to give the title compound. Yield: 76.61% (1.9 g, pale brown solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.84 (s, 1H), 8.20-8.13 (m, 2H), 2.76 (s, 3H). LCMS: (Method A) 178.9 (M+H), Rt. 4.81 min, 43.23% (Max).

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

[0336] The title compound was prepared according to the procedure described for Intermediate 17, Step 2, using 1-(benzo[c][1,2,5]thiadiazol-5-yl)ethan-1-one (1.9 g, 10.6 mmol) as starting material. After evaporation of the solvent, the title compound was isolated and used without further purification. Yield: 88.5% (1.7 g, dark brown liquid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.02 (d, J=9.08 Hz, 1H), 7.95 (s, 1H), 7.74-7.71 (m, 1H), 5.50 (d, J=4.36 Hz, 1H), 4.93-4.88 (m, 1H), 1.40 (d, J=6.48 Hz, 3). LCMS: (Method A) 181.0 (M+H), Rt. 2.05 min, 95.01% (Max).

Step 3: 5-(1-chloroethyl)benzo[c][1,2,5]thiadiazole

[0337] The title compound was synthesized from 1-(benzo[c][1,2,5]thiadiazol-5-yl)ethan-1-ol (1.7 g, 9.4 mmol), according the general procedure B. The crude product was used in the next step without further purification. Yield: quantitative (1.9 g, brown oil). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.17-8.12 (m, 2H), 7.88-7.85 (m, 1H), 5.62-5.57 (m, 1H), 1.89 (d, J=6.76 Hz, 3H).

Intermediate 20: 3-chloro-7-(1-chloroethyl)quinoline

[0338] ##STR00249##

Step 1: 1-(3-chloroquinolin-7-yl)ethan-1-one

[0339] The title compound was prepared according to the procedure described for Intermediate 6, Step 1, using 7-bromo-3-chloroquinoline (1 g, 4.12 mmol) as starting material. The crude product was purified by flash chromatography to give the title compound. Yield: 71.5% (0.6 g, pale yellow solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.02 (s, 1H), 8.69-8.66 (m, 2H), 8.14-8.07 (m, 2H), 2.75 (s, 3H).

Step 2: 1-(3-chloroquinolin-7-yl)ethan-1-ol

[0340] The title compound was prepared according to the procedure described for Intermediate 17, Step 2, using 1-(3-chloroquinolin-7-yl)ethan-1-one (0.6 g, 2.9 mmol) as starting material. After evaporation of the solvent, the title compound was isolated and used without further purification. Yield: 99.2% (0.6 g, pale yellow oil). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.87-8.86 (d, J=2.48 Hz, 1H), 8.54 (s, 1H), 7.98-7.93 (m, 2H), 7.69-7.67 (m, 1H), 5.45 (d, J=4.4 Hz, 1H), 4.95-4.93 (m, 1H), 1.41 (d, J=6.48 Hz, 3H). LCMS: (Method A) 208.0 (M+H), Rt. 2.59 min, 96.46% (Max).

Step 3: 3-chloro-7-(1-chloroethyl)quinoline

[0341] The title was synthesized from 1-(3-chloroquinolin-7-yl)ethan-1-ol (0.600 g, 2.89 mmol), according to the general procedure B. The crude product was used in the next step without further purification. Yield: quantitative (0.655 g, pale yellow oil). LCMS: (Method A) 227.9 (M+H), Rt. 4.55 min, 90.09% (Max).

Intermediate 21: 6-(1-chloroethyl)-2,3-dihydrobenzofuran

[0342] ##STR00250##

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

[0343] The title compound was prepared according to the procedure described for Intermediate 6, Step 1, using 6-bromo-2,3-dihydro-1-benzofuran (1 g, 5.03 mmol) as starting material. The crude product was purified by flash chromatography to give the title compound. Yield: 73.7% (0.6 g, pale yellow solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.48 (d, J=7.64 Hz, 1H), 7.37-7.35 (d, J=7.68 Hz, 1H), 7.26 (s, 1H), 4.58 (t, J=8.76 Hz, 2H), 3.24 (t, J=8.76 Hz, 2H), 2.53 (s, 3H). LCMS: (Method A) 163.2 (M+H), Rt. 3.01 min, 97.60% (Max).

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

[0344] The title compound was prepared according to the procedure described for Intermediate 17, Step 2, using 1-(2,3-dihydrobenzofuran-6-yl)ethan-1-one (0.6 g, 3.7 mmol) as starting material. After evaporation of the solvent, the title compound was isolated and used without further purification. Yield: 88.30% (0.53 g, colourless liquid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.11 (d, J=7.6 Hz, 1H), 6.77-6.75 (m, 1H), 6.71 (s, 1H), 5.04 (d, J=4.4 Hz, 1H), 4.63-4.61 (m, 1H), 4.48 (t, J=8.8 Hz, 2H), 3.11 (t, J=8.8 Hz, 2H), 1.25 (d, J=6.4 Hz, 3H). LCMS: (Method A) 147.0 (M-17H), Rt. 2.64 min, 89.95% (Max).

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

[0345] The title compound was synthesized from 1-(2,3-dihydrobenzofuran-6-yl)ethan-1-ol (0.53 g, 3.23 mmol), according to the general procedure B. The crude product was used in the next step without further purification. Yield: quantitative (0.58 g, brown oil). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.20 (d, J=7.56 Hz, 1H), 6.93-6.91 (m, 1H), 6.87 (s, 1H), 5.29-5.24 (m, 1H), 4.53 (t, J=8.72 Hz, 2H), 3.15 (t, J=8.76 Hz, 2H), 1.75 (d, J=6.76 Hz, 3H). LCMS: (Method A) 147.0 (M-35H), Rt. 3.76 min, 83.62% (Max).

Intermediate 22: 1,2-Dichloro-4-(1-chloroethyl)benzene

[0346] ##STR00251##

Step 1: 1-(3,4-Dichlorophenyl)ethan-1-ol

[0347] To a stirred solution of 3,4-dichloroacetophenone (4 g, 21.15 mmol, Aldrich) in dry MeOH (80 mL), sodium borohydride (0.96 g, 25.39 mmol, spectrochem) was added portionwise at 0° C. The reaction mixture was stirred at rt overnight. It was cooled to 0° C. and quenched using ice water (10 mL). Solvents were removed under reduced pressure and resulting residue was dissolved in DCM (50 mL). The organic layer was washed with water (25 mL), brine (20 mL), dried over Na.sub.2SO.sub.4 and concentrated. The crude product was used for next step without further purification. Yield: 95% (3.8 g, colorless liquid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.57-7.55 (m, 2H), 7.33 (d, J=1.9 Hz, 1H), 5.38 (d, J=4.4 Hz, 1H), 4.76-4.70 (m, 1H), 1.30 (d, J=6.4 Hz, 3H).

Step 2: 1,2-Dichloro-4-(1-chloroethyl)benzene

[0348] The title compound was synthesized by following general procedure B, using 1-(3,4-dichlorophenyl)ethan-1-ol (1.5 g, 7.85 mmol) and thionyl chloride (1.14 mL, 15.7 mmol) as starting materials. It was used in the next step without further purification. Yield: 97% (1.6 g, colorless liquid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.75 (s, 1H), 7.65-7.43 (m, 2H), 5.74-5.32 (m, 1H), 1.35 (d, J=8.5 Hz, 3H).

Intermediate 23: 3-(1-chloroethyl)quinoline

[0349] ##STR00252##

Step 1: 1-(quinolin-3-yl)ethan-1-ol

[0350] To a stirred solution of 1-(quinolin-3-yl)ethan-1-one (1 g, 5.85 mmol) in methanol (10 mL), sodium borohydride (442 mg, 11.7 mmol) was added slowly at 0° C. The reaction was stirred for 2 h at rt. The completion of reaction was monitored by TLC. The reaction mixture was evaporated at 45° C. under vacuum. The resulting mixture was diluted with EtOAc (100 mL), washed with water (50 mL), brine (50 mL) and dried over anhydrous Na.sub.2SO.sub.4. After evaporation of the solvents, the title compound was isolated and used for the next step without any further purification. Yield: 89.1% (900 mg, pale brown solid). LCMS: (Method A) 174.0 (M+H), Rt. 1.37 min, 99.3% (Max).

Step 2: 3-(1-chloroethyl)quinoline

[0351] The compound 3-(1-chloroethyl)quinoline was synthesized from 1-(quinolin-3-yl)ethan-1-ol (900 mg, 5.2 mmol), according to the general procedure B. Yield: quantitative (993 mg, off white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.64 (s, 1H), 6.90-6.85 (m, 2H), 6.77-6.73 (m, 1H), 5.78-5.75 (m, 2H), 4.13-4.09 (m, 1H), 3.19-3.15 (m, 4H), 2.53-2.49 (m, 4H), 1.27 (d, J=6.6 Hz, 3H). LCMS: (Method A) 192.0 (M+H), Rt. 2.28 min, 99.4% (Max).

Intermediate 24: (R)-1-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazine

[0352] ##STR00253##

Step 1: (R)—N-(1-(benzo[d][1,3]dioxol-5-yl)ethylidene)-2-methylpropane-2-sulfinamide

[0353] To a mixture of 1-(benzo[d][1,3]dioxol-5-yl)ethan-1-one (260 g, 1584 mmol), (R)-(+)-2-Methyl-2-propanesulfinamide (210.3 g, 1742 mmol) in THF (2.3 L) titanium(IV)ethoxide (722 g, 3168 mmol) was added at rt over 30 min and refluxed for 30 h. Reaction was monitored by HPLC. The reaction mass was cooled to rt and slowly quenched with water (1000 mL). The precipitate observed was filtered through celite bed (350 g) and the filtration cake was washed with ethylacetate (2×1.5 L). The combined organic layer was washed with water (1.5 L), brine solution (1.5 L) and dried over sodium sulfate (250 g) and evaporated under vacuum at 50° C. The resulted crude was co-distilled with toluene (2×1000 mL) and used as such for next step. Yield: quantitative (580 g, brown liquid). HPLC: (Method A) Rt. 3.83 min, 53.3% (Max).

Step 2: (R)—N—((R)-1-(benzo[d][1,3]dioxol-5-yl)ethyl)-2-methylpropane-2-sulfinamide

[0354] To a stirred solution of (R)—N-(1-(benzo[d][1,3]dioxol-5-yl)ethylidene)-2-methylpropane-2-sulfinamide (6 g, 22.0 mmol) in THF (100 mL), sodium borohydride (2.5 g, 67.4 mmol) was added slowly at 0° C. and then stirred at rt for 1 h. Completion of the reaction was confirmed by TLC. The precipitate observed was filtered through celite bed (30 g) and was washed with EtOAc (2×50 mL). The organic layer was washed with water (50 mL), brine (50 mL) and dried over Na.sub.2SO.sub.4 (20 g) and evaporated under vacuum at 50° C. The resulting crude product was purified by flash chromatography (25% EtOAc in pet ether) to give the title compound. Yield: 66.2% (4 g, off white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 6.97 (s, 1H), 6.83-6.77 (m, 2H), 5.97-5.96 (m, 2H), 5.25 (d, J=7.1 Hz, 1H), 4.30-4.23 (m, 1H), 1.33 (d, J=6.8 Hz, 3H), 1.08 (s, 9H). LCMS: (Method A) 270.0 (M+H), Rt. 3.79 min, 96.41% (Max). HPLC: (Method A) Rt. 3.76 min, 96.84% (Max). Chiral HPLC: (Method C) Rt. 7.71 min, 97.5%.

Step 3: (R)-1-(benzo[d][1,3]dioxol-5-yl)ethan-1-amine

[0355] To a stirred solution of (R)—N—((R)-1-(benzo[d][1,3]dioxol-5-yl)ethyl)-2-methylpropane-2-sulfinamide (4 g, 14.86 mmol) in MeOH (20 mL), methanolic hydrochloride (18.5 mL, 74.3 mmol, 4M) was added at 0° C. over 15 min and stirred at rt for 1 h. Completion of the reaction was confirmed by TLC. Then the reaction mixture was concentrated under vacuum at 50° C. To the resulting crude, EtOAc (50 mL) was added and filtered and filtration cake was washed with EtOAc (50 mL). The solid hydrochloride salt was basified by aq. ammonia (30% w/v, 25 mL) and extracted with EtOAC (2×50 mL). The combined organic layer was washed with brine solution (1×50 mL) and dried over Na.sub.2SO.sub.4. The solvent was evaporated at under vacuum to give the title compound. Yield: 85% (2.1 g, brown liquid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 6.95 (s, 1H), 6.81-6.77 (m, 2H), 5.95-5.93 (m, 2H), 3.90 (q, J=6.5 Hz, 1H), 1.86-1.85 (brs, 2H), 1.17 (d, J=6.5 Hz, 3H). LCMS: (Method A) 149.0 (M-16), Rt. 1.66 min, 96.9% (Max). HPLC: (Method A) Rt. 1.59 min, 96.86% (Max). Chiral HPLC: (Method B) Rt. 7.12 min, 97.76%.

Step 3: (R)-1-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)-4-tosylpiperazine

[0356] To a stirred solution of (R)-1-(benzo[d][1,3]dioxol-5-yl)ethan-1-amine (2 g, 12.1 mmol) in DIPEA (4.22 mL, 24.2 mmol), N,N-bis(2-chloroethyl)-p-toluene sulfonamide (3.9 g, 13.3 mmol) was added at rt and the resulting mixture was heated to 105° C. for 18 h. Completion of the reaction was confirmed by TLC. Reaction mixture was diluted with water (30 mL) and extracted with EtOAc (2×50 mL). The combined organic layer was dried over Na.sub.2SO.sub.4 and evaporated under vacuum. To the resulting crude solid hexane (50 mL) was added, and the resulting mixture was stirred for 10 min at rt. It was filtered and the solid was washed with Et.sub.2O (2×50 mL) and dried under vacuum to give the title compound. Yield: 63.8% (3 g, off white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.59 (d, J=8.4 Hz, 2H), 7.45 (d, J=8.0 Hz, 2H), 6.81-6.77 (m, 2H), 6.69-6.6 (m, 1H), 5.97-5.95 (m, 2H), 3.35-3.31 (m, 1H), 2.81-2.80 (m, 4H), 2.42 (s, 3H), 2.36-2.32 (m, 4H), 1.18 (d, J=6.8 Hz, 3H). LCMS: (Method A) 389.0 (M+H), Rt. 3.39 min, 98.9% (Max). HPLC: (Method A) Rt. 3.30 min, 99.53% (Max), Chiral HPLC: (Method A) Rt. 15.54 min, 97.58%.

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

[0357] To the reaction mixture of (R)-1-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)-4-tosylpiperazine (2.7 g, 6.9 mmol) and 4-hydroxy benzoic acid (2.8 g, 20.8 mmol), HBr in acetic acid (30% w/v, 14 mL) was added at 0° C. and stirred overnight at rt. Completion of the reaction was confirmed by TLC.

[0358] Reaction mixture was diluted with water (60 mL) and the resulting precipitate was filtered through a celite bed. The celite bed was washed with water (50 mL). The aqueous layer was washed with EtOAc (4×50 mL) and basified up to pH 11 with NaOH pellet (10 g) at 0° C. The product was extracted with EtOAc (3×30 mL). The combined organic layer was dried over Na.sub.2SO.sub.4 and evaporated under vacuum to give the title compound. Yield: 92% (1.5 g, Dark brown solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 6.84-6.81 (m, 2H), 6.72-6.71 (m, 1H), 5.97-5.95 (m, 2H), 3.29-3.23 (m, 2H), 2.64-2.62 (m, 4H), 2.26-2.19 (m, 4H), 1.22 (d, J=6.8 Hz, 3H). LCMS: (Method A) 235.3 (M+H), Rt. 1.56 min, 96.9% (Max). HPLC: (Method A) Rt. 1.50 min, 96.9% (Max). Chiral HPLC: (Method A) Rt. 10.13 min, 98.04%.

Intermediate 25: 2-(piperazin-1-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-4(5H)-one dihydrochloride

[0359] ##STR00254##

Step 1: tert-butyl 3-bromo-2,4-dioxopiperidine-1-carboxylate

[0360] To a stirred solution of tert-butyl 2,4-dioxopiperidine-1-carboxylate (1 g, 4.69 mmol) in dry CCl.sub.4 (10 mL), N-bromosuccinimide (0.83 g, 4.69 mmol) was added at 10° C. The reaction mixture was stirred at 10-15° C. for 2 h. It was then evaporated under reduced pressure. Water (10 mL) was added and the desired product was extracted with EtOAc (2×30 mL). The combined organic layer was dried over Na.sub.2SO.sub.4 and concentrated. The resulting crude product was purified by flash column chromatography, affording the title product. Yield: 99% (1.4 g, off white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 5.50 (s, 1H), 3.74-3.71 (m, 2H), 2.69-2.66 (m, 2H), 1.46 (s, 9H). LCMS: (Method A) 193.8 (M-Boc+H), Rt. 2.93 min, 81.51% (Max).

Step 2: tert-butyl-2-(4-(tert-butoxycarbonyl)piperazin-1-yl)-4-oxo-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate

[0361] To a stirred solution of tert-butyl 4-carbamothioylpiperazine-1-carboxylate (synthesized according to Example 5, Step 1, 1.31 g, 5.36 mmol) in isopropanol (15 mL), tert-butyl 3-bromo-2,4-dioxopiperidine-1-carboxylate obtained in the first step (1.3 g, 4.46 mmol) was added at rt. The reaction mixture was stirred overnight at 90° C. It was cooled down to rt and evaporated under reduced pressure. Water (10 mL) was added and the desired product was extracted with diethyl ether (2×30 mL), dried over Na.sub.2SO.sub.4 and concentrated, affording the title product. Yield: 74% (1.42 g, yellow solid). LCMS: (Method A) 239.0 (M-Boc+H), Rt. 0.70 min, 48.39% (Max).

Step 3: 2-(piperazin-1-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-4(5H)-one dihydrochloride

[0362] To a stirred solution of tert-butyl-2-(4-(tert-butoxycarbonyl)piperazin-1-yl)-4-oxo-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate obtained in previous step (1.3 g, 2.96 mmol) in 1,4-dioxane (10 mL), HCl in dioxane (4 M solution, 13 mL, 10 V) was added at 0° C. The reaction mixture was stirred for 2 h at rt. It was evaporated and DCM (15 mL) was added and evalopated. This procedure was repeated twice, affording the title product which was used without any further purification. Yield: 99% (0.82 g, off white solid).

Intermediate 26: 5-(1-chloroethyl)-2-methylbenzo[d]thiazole

[0363] ##STR00255##

Step 1: 2-methylbenzo[d]thiazole-5-carboxylic Acid

[0364] 4-Chloro-3-nitrobenzoic acid (10 g, 50.25 mmol) and sodium sulfide (33.3 g, 427 mmol) were heated up to melting and stirred for 20 min. Then reaction mixture was cooled to rt and acetic anhydride (11.7 mL, 115 mmol) and acetic acid (4.3 mL, 75.3 mmol) were added. The resulting reaction mixture was refluxed for 20 min and cooled to rt. Water (50 mL) and EtOAc (100 mL) were added and the mixture was stirred for 20 min. The resulting mass was filtered through celite, washed with EtOAc (50 mL). The combined filtrate was washed with brine (30 mL), dried over Na.sub.2SO.sub.4 and concentrated. The celite plug was further washed with EtOH (3×100 mL) and the filtrate was filtered through silica gel and concentrated under reduced pressure. Both fractions were mixed and taken for next step without further purification (brown solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.88 (s, 1H), 8.33 (s, 1H), 7.92-7.88 (m, 2H), 2.79 (s, 3H). LCMS: (Method A) 194.0 (M+H), Rt. 2.73 min, 59.03% (Max).

Step 2: (2-methylbenzo[d]thiazol-5-yl)methanol

[0365] To a stirred solution of 2-methylbenzo[d]thiazole-5-carboxylic acid obtained in the previous step 3.7 g, 19.7 mmol) in dry THF (35 mL), lithium aluminium hydride (2 M in THF, 19.2 mL, 38.34 mmol) was added at 0° C. and the resulting mixture was stirred at rt for 1 h. It was cooled to 0° C., quenched with saturated Na.sub.2SO.sub.4 solution and filtered through celite. The filtrate was diluted with EtOAc (50 mL), washed with brine (10 mL), water (10 mL) and dried over Na.sub.2SO.sub.4. After evaporation of the solvent, the resulting crude product was taken for next step without further purification (yellow oil). LCMS: (Method A) 180.0 (M+H), Rt. 1.95 min, 40.76% (Max).

Step 3: 2-methylbenzo[d]thiazole-5-carbaldehyde

[0366] To a stirred solution of (2-methylbenzo[d]thiazol-5-yl)methanol (0.6 g, 3.35 mmol) in dry DCM (6 mL), NaHCO.sub.3 (1.12 g, 13.4 mmol) followed by Dess-Martin periodinane (2.84 g, 6.70 mmol) were added and the reaction mixture was stirred at rt for 2 h. It was diluted with DCM (50 mL) and washed with water (15 mL), 10% NaHCO.sub.3 solution (15 mL), brine (15 mL) and dried over Na.sub.2SO.sub.4. The title product was obtained after evaporation of the solvents. Yield: 99% (0.65 g, brown liquid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 10.12 (s, 1H), 8.25 (s, 1H), 7.80-7.79 (m, 2H), 2.86 (s, 3H). LCMS: (Method A) 178.0 (M+H), Rt. 2.84 min, 81.57% (Max).

Step 4: 1-(2-methylbenzo[d]thiazol-5-yl)ethan-1-ol

[0367] To a stirred solution of 2-methylbenzo[d]thiazole-5-carbaldehyde (0.65 g, 3.67 mmol) in THF (6 mL), methyl magnesium bromide (1.4M in THF:Toluene 1:3 mixture, 3.9 mL, 5.50 mmol) was added at 0° C. The reaction mixture was stirred for 1 h at rt and was then quenched with saturated NH.sub.4Cl (5 mL) at 0° C. It was diluted with EtOAc (30 mL), washed with water (10 mL), brine (10 mL) and dried over Na.sub.2SO.sub.4. The title product was obtained after evaporation of the solvents (brown liquid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ7.97-7.95 (m, 1H), 7.51-7.50 (m, 2H), 5.29 (d, J=4.4 Hz, 1H), 4.87-4.86 (m, 1H), 2.78 (s, 3H), 1.37 (d, J=6.4 Hz, 3H). LCMS: (Method A) 194.0 (M+H), Rt. 2.53 min, 73.53% (Max).

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

[0368] To a stirred solution of 1-(2-methylbenzo[d]thiazol-5-yl)ethan-1-ol (0.35 g, 3.67 mmol) in DCM (5 mL), thionyl chloride (0.27 mL, 3.62 mmol) was added at 0° C. The reaction mixture was stirred for 1 h at rt and concentrated. DCM (15 mL) was added and was evaporated. This procedure was repeated a second time, affording the title product. It was used in the next step without any further purification. Yield: 90% (0.38 g, brown liquid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.01-8.00 (m, 2H), 7.54-7.52 (m, 1H), 5.53-5.51 (m, 1H), 2.80 (s, 3H), 1.86 (d, J=6.8 Hz, 3H). LCMS: (Method A) 212.0 (M+H), Rt. 2.61 min, 58.89% (Max).

Intermediate 27: 6-(1-chloroethyl)benzo[d]thiazole

[0369] ##STR00256##

Step 1: 1-(benzo[d]thiazol-6-yl)ethan-1-one

[0370] A solution of 6-bromobenzo[d]thiazole (1.2 g, 5.61 mmol) in dry toluene was put under inter atmosphere. 1-Ethoxy vinyl tributyltin (3.0 g, 8.41 mmol) and bis(triphenylphosphine)palladium dichloride (0.39 g, 0.56 mmol) were added at rt and the resulting mixture was stirred overnight at 90° C. It was cooled to rt and filtered through celite. The filtrate was concentrated under vacuum and the resulting crude product was stirred in HCl aqueous solution (6 N, 20 mL) for 1 h at rt. The solution was concentrated and neutralized with saturated NaHCO.sub.3 solution. The desired product was extracted with DCM (60 mL), dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure. It was purified by flash column chromatography to afford the title compound. Yield: 60% (0.6 g, yellow solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.59 (s, 1H), 8.88 (s, 1H), 8.17 (d, J=8.0 Hz, 1H), 8.06 (d, J=8.0 Hz, 1H), 2.75 (s, 3H). LCMS: (Method A) 178.0 (M+H), Rt. 1.97 min, 94.50% (Max).

Step 2: 1-(benzo[d]thiazol-6-yl)ethan-1-ol

[0371] To a stirred solution of 1-(benzo[d]thiazol-6-yl)ethan-1-one, obtained in the previous step (0.6 g, 3.39 mmol) in dry MeOH (20 mL), sodium borohydride (0.38 g, 10.2 mmol) was added portion wise at 0° C. and the mixture was stirred at rt for 1 h. It was concentrated, diluted with DCM (50 mL), washed with water (15 mL), brine (10 mL) and dried over Na.sub.2SO.sub.4. After evaporation of the solvent, the title product was obtained and was used in the next step without any further purification. Yield: 66% (0.4 g, brown liquid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.39 (s, 1H), 8.40 (s, 1H), 7.80 (d, J=2.0 Hz, 1H), 7.78 (d, J=2.0 Hz, 1H), 4.88 (d, J=2.8 Hz, 1H), 4.37 (d, J=2.8 Hz, 1H), 1.92 (s, 3H).

Step 3: 6-(1-chloroethyl)benzo[d]thiazole

[0372] To a stirred solution of 1-(benzo[d]thiazol-6-yl)ethan-1-ol (0.4 g, 2.25 mmol) in dry DCM (20 mL), thionyl chloride (0.3 mL, 4.5 mmol) was added dropwise at 0° C. and the resulting reaction mixture was stirred at rt for 1 h. It was concentrated. DCM (5 mL) was added and was evaporated again. This procedure was repeated twice, affording the title product that was used without any further purification. Yield: 98% (430 mg, brown liquid).

Intermediate 28: 7-(1-Chloroethyl)-3-methylquinoline

[0373] ##STR00257##

Step 1: 7-Bromo-3-methylquinoline

[0374] To a solution of 4-bromo-2-nitrobenzaldehyde (5 g, 21.7 mmol) in ethanol (50 mL), iron powder (4.85 g, 86.9 mmol) was added followed by HCl aqueous solution (0.1 N, 15 mL). The resulting reaction mixture was vigorously stirred at 95° C. for 2 h. The reaction progression was followed by TLC. When the reduction was completed, propionaldehyde (1.5 mL, 21.7 mmol) and KOH (1.46 g, 26.0 mmol, in two portions) were added at rt. The reaction mixture was stirred at 95° C. overnight. It was cooled to rt, diluted with DCM (30 mL) and filtered through celite. The filtrate was washed with water (50 mL) 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 reduced pressure. The resulting crude product was purified by flash chromatography, affording the title compound. Yield: 52% (2.5 g, Pale yellow solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.81 (s, 1H), 8.18-8.17 (m, 2H), 7.89 (d, J=8.7 Hz, 1H), 7.72 (dd, J=1.9, 8.7 Hz, 1H), 2.50 (s, 3H). LCMS: (Method D) 223.9 (M+H), Rt. 2.48 min, 99.58% (Max).

Step 2: 1-(3-Methylquinolin-7-yl)ethan-1-one

[0375] A stirred solution of 7-bromo-3-methylquinoline obtained in previous step (2 g, 9.0 mmol) in toluene (20 mL) was flushed with nitrogen for 15-20 min. 1-Ethoxy-1-(tributylstannyl) ethylene (3.9 mL, 11.7 mmol) and bis(triphenylphosphine)palladium dichloride (0.31 g, 0.45 mmol) were added and the resulting reaction mixture was stirred at 90° C. for 12 h. It was cooled to rt, filtered through celite and concentrated under reduced pressure. HCl aqueous solution (6 N, 30 mL) was added and the mixture was stirred at room temperature for 1 h. The solution was neutralized with the addition of solid sodium bicarbonate and was extracted with EtOAc (2×50 mL). The combined organic layer was dried over anhydrous Na.sub.2SO.sub.4 and concentrated. The crude product was purified by flash chromatography, affording the title compound. Yield: 60% (1.1 g, pale yellow solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.90 (s, 1H), 8.61 (s, 1H), 8.21 (s, 1H), 8.04-7.98 (m, 2H), 2.76 (s, 3H), 2.52 (s, 3H). LCMS: (Method D) 186.0 (M+H), Rt. 1.88 min, 99.85% (Max).

Step 3: 1-(3-Methylquinolin-7-yl)ethan-1-ol

[0376] To a stirred solution of 1-(3-methylquinolin-7-yl)ethan-1-one obtained in previous step (1.1 g, 5.9 mmol) in MeOH (12 mL), sodium borohydride (0.26 g, 7.1 mmol) was added portion wise at 0° C. and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure and the resulting crude water was added and extracted with DCM (2×50 mL). The combined organic layer was dried over anhydrous sodium sulphate, concentrated under reduced pressure and the crude mass was purified by column chromatography to afford the title compound. Yield: 55% (0.8 g, yellow solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.73 (s, 1H), 8.07 (s, 1H), 7.89 (s, 1H), 7.82 (d, J=8.4 Hz, 1H), 7.56 (d, J=8.4 Hz, 1H), 5.33 (d, J=4.4 Hz, 1H), 4.94-4.89 (m, 1H), 2.47 (s, 3H), 1.41 (d, J=6.4 Hz, 3H). LCMS: (Method D) 188.1 (M+H), Rt. 0.83 min, 94.19% (Max).

Step 4: 7-(1-Chloroethyl)-3-methylquinoline

[0377] To a stirred solution of 1-(3-methylquinolin-7-yl)ethan-1-ol obtained in previous step (0.8 g, 4.2 mmol) in DCM (8 mL), thionyl chloride (0.61 mL, 8.5 mmol) was added drop wise at 0° C. and the resulting mixture stirred at room temperature for 1 h. The reaction completion was confirmed by TLC. The reaction mixture was concentrated under reduced pressure and the resulting crude product was used in the next step without any further purification. Yield: 85% (0.75 g, brown solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.06 (s, 1H), 8.60 (s, 1H), 8.18 (s, 1H), 8.13 (d, J=8.8 Hz, 1H), 7.90 (d, J=8.4 Hz, 1H), 5.68-5.63 (m, 1H), 2.57 (s, 3H), 1.90 (d, J=6.8 Hz, 3H). LCMS: (Method D) 206.0 (M+H), Rt. 2.12 min, 91.94% (Max).

Intermediate 29: 1-(3-(Trifluoromethyl)pyridin-2-yl)piperazine

[0378] ##STR00258##

[0379] To a stirred solution of 2-chloro-3-(trifluoromethyl)pyridine (1 g, 5.50 mmol) in n-Butanol (10 mL), 1-piperazine (6.63 g, 77.12 mmol) was added and the reaction mixture was stirred at 100° C. for 24 h. The reaction completion was confirmed by TLC. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The resulting mixture was diluted with ethyl acetate (30 mL) and neutralized with saturated sodium bicarbonate solution (4 mL), and extracted with EtOAc (2×50 mL). The combined organic layer was dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure. The crude was purified by column chromatography to afford the title compound. Yield: 63% (0.8 g, colorless gum). .sup.1HNMR (400 MHz, DMSO-d.sub.6): δ 8.50 (d, J=3.6 Hz, 1H), 8.03 (dd, J=7.8, 2.0 Hz, 1H), 7.16-7.13 (m, 1H), 3.11-3.08 (m, 4H), 2.81-2.79 (m, 4H). LCMS: (Method F) 232.0 (M+H), Rt. 2.10 min, 96.01% (Max).

EXAMPLES

Example 1: 2-(1-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperidin-4-yl)-4-methylthiazole

[0380] ##STR00259##

Step 1: 1-(tert-Butoxycarbonyl)piperidine-4-carboxylic Acid

[0381] To a stirred solution of isonipecotic acid (6.0 g, 46.6 mmol) in tert-BuOH (18 mL), NaOH solution (12 mL, 3.71 g, 92.8 mmol in 12 mL water) was added at 10-15° C., followed by di-tert-butyl dicarbonate (10.1 g, 46.6 mmol) and the mixture was stirred at rt for 3 h. The completion of the reaction was monitored by TLC. The reaction mixture was diluted with water and washed with petroleum ether (3×25 mL). The pH of the aqueous layer was adjusted to 6-6.5 using citric acid and was extracted with DCM. The organic layer was dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure to afford the title compound. Yield: 73% (10.0 g, white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 12.25 (s, 1H), 3.83-3.80 (m, 2H), 2.80-2.49 (m, 2H), 2.39-2.36 (m, 1H), 1.79-1.75 (m, 2H), 1.41-1.34 (m, 11H).

Step 2: tert-Butyl 4-carbamoylpiperidine-1-carboxylate

[0382] To a stirred solution of 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (10.0 g, 43.6 mmol) in dry THF (150 mL), CDI (9.95 g, 65.6 mmol) was added at 0-5° C. and the reaction mixture was stirred at rt for 16 h. Then the reaction mixture was cooled to 0-5° C. and a continuous flow of ammonia was applied to the solution for 2 h. MeOH (30 mL) was added and the flow of ammonia was applied for 2 additional hours at the same temperature. The reaction mixture was then stirred at rt for 16 h. It was concentrated under reduced pressure and the resulting crude mixture was dissolved in EtOAc and washed with 10% citric acid, 10% sodium bicarbonate, water, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under vacuum to afford the title compound (white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 6.77 (s, 2H), 3.91-3.88 (m, 2H), 2.71-2.49 (m, 2H), 2.25-2.17 (m, 1H), 1.66-1.62 (m, 2H), 1.39-1.35 (m, 13H). LCMS: (Method A) 130.2 (M+H), Rt. 2.62 min, 99.0% (Max).

Step 3: tert-Butyl 4-carbamothioylpiperidine-1-carboxylate

[0383] To a stirred solution of tert-butyl 4-carbamoylpiperidine-1-carboxylate (1.3 g, 5.7 mmol) in THF (16 mL), Lawssen's reagent 2.53 g, 6.27 mmol) was added. The reaction mixture was refluxed for 6 h and then stirred at rt for 16 h. The completion of the reaction was monitored by TLC. The reaction mixture was diluted with ethyl acetate and was washed with 10% citric acid, 10% sodium bicarbonate, water and brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under vacuum to afford the title compound. Yield: 78% (1.09 g, colorless oil). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.41 (s, 1H), 9.11 (s, 1H), 4.03-3.97 (m, 1H), 2.66-2.61 (m, 2H), 1.64-1.52 (m, 4H), 1.40 (s, 9H), 1.38-1.34 (m, 2H). LCMS: (Method A) 245.2 (M+H), Rt. 3.38 min, 93.5% (Max).

Step 4: tert-Butyl 4-(4-methylthiazol-2-yl)piperidine-1-carboxylate

[0384] To a stirred solution of tert-butyl 4-carbamothioylpiperidine-1-carboxylate (1.0 g, 4.1 mmol) in dioxane (10 mL), triethyl amine (0.62 g, 6.5 mmol) and bromo acetone (0.84 g, 6.5 mmol) were added and stirred at 90° C. for 16 h. The completion of the reaction was monitored by TLC. The reaction mixture was quenched with water and extracted with DCM with 10% MeOH (5×25 mL). The organic layer was separated, dried over anhydrous Na.sub.2SO.sub.4 concentrated under vacuum and was purified by flash chromatography (30% EtOAc in petroleum ether) to afford the title compound (colorless oil). LCMS: (Method A) 283.0 (M+H), Rt. 3.35 min, 93.5% (Max).

Step 5: 4-Methyl-2-(piperidin-4-yl)thiazole hydrochloride

[0385] To a stirred solution of tert-butyl 4-(4-methylthiazol-2-yl)piperidine-1-carboxylate (0.39 g, 1.38 mmol) in dry dioxane (2 mL), HCl in dioxane (3 N, 10 mL) was added at rt and the reaction mixture was stirred for 2 h. It was then concentrated under reduced pressure and the crude product was triturated in diethyl ether, filtrated and dried under vacuum to afford the title compound. Yield: 99% (0.3 g, white oil).

[0386] LCMS: (Method B) 183.0 (M+H), Rt. 3.21 min, 92.5% (Max).

Step 6: 2-(1-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperidin-4-yl)-4-methylthiazole

[0387] The title compound was synthesized by following general procedure E, using 4-methyl-2-(piperidin-4-yl)thiazole hydrochloride (0.3 g, 1.37 mmol) and Intermediate 1 (0.379 g, 2.0 mmol). The reaction mixture was stirred at 60° C. for 16 h. The crude product was purified by flash chromatography, affording the title compound (colorless oil). .sup.1H NMR (400 MHz, CDCl.sub.3): δ 6.90 (s, 1H), 6.76-6.74 (m, 3H), 5.96 (s, 2H), 3.41-3.39 (m, 1H), 3.17-3.14 (m, 1H), 2.94-2.92 (m, 2H), 2.42 (s, 3H), 2.14-2.02 (m, 4H), 1.92-1.74 (m, 2H), 1.37 (d, J=6.8 Hz, 3H). LCMS: (Method A) 331.0 (M+H), Rt. 2.54 min, 95.5% (Max). HPLC: (Method A) Rt. 2.54 min, 97.3% (Max).

Example 2: 2-(1-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperidin-4-yl)-5-methyl-1,3,4-oxadiazole

[0388] ##STR00260##

Step 1: Ethyl 1-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperidine-4-carboxylate

[0389] The title compound was synthesized by following general procedure D, using 4-piperidine carboxylic acid ester (25 g, 159 mmol) and Intermediate 1 (49.87 g, 271 mmol). The crude product was purified by flash chromatography, affording the title compound (pale brown liquid). LCMS: (Method A) 306.0 (M+H), Rt. 2.71 min, 29.4% (Max).

Step 2: 1-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperidine-4-carbohydrazide

[0390] To a stirred solution of ethyl 1-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperidine-4-carboxylate (4.3 g, 3.79 mmol) in ethanol (4 mL), hydrazine hydrate (3.79 g, 75 mmol) was added at rt and stirred at 90° C. for 3 h. The completion of the reaction was monitored by TLC. The reaction mixture was concentrated under reduced pressure and the resulting crude product was dissolved in EtOAc, washed with water and dried over anhydrous Na.sub.2SO.sub.4. After evaporation of the solvents, the crude product was purified by flash chromatography to afford the title compound (colorless oil). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.88 (s, 1H), 6.83-6.81 (m, 2H), 6.73-6.71 (m, 1H), 5.98 (s, 2H), 4.12 (m, 2H), 2.93-2.91 (m, 1H), 2.76-2.73 (m, 1H), 1.94 (m, 1H), 1.87-1.83 (m, 1H), 1.74 (m, 1H), 1.57-1.48 (m, 4H), 1.24-1.22 (d, J=6.5 Hz, 3H). LCMS: (Method A) 292.0 (M+H), Rt. 1.71 min, 96.0% (Max).

Step 3: 2-(1-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperidin-4-yl)-5-methyl-1,3,4-oxadiazole

[0391] A solution of 1-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperidine-4-carbohydrazide (0.18 g, 0.62 mmol) in triethyl ortho acetate (1.8 mL) was stirred at 110° C. for 16 h. The reaction mixture was concentrated under reduced pressure. The resulting crude product was dissolved in EtOAc, washed with water and dried over anhydrous Na.sub.2SO.sub.4. After evaporation of the solvents, the crude product was purified by flash chromatography to afford the title compound (pale brown oil). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 6.86 (s, 1H), 6.82 (d, J=8.0 Hz, 1H), 6.73 (d, J=8.0 Hz, 1H), 5.97 (m, 2H), 3.42-3.39 (m, 1H), 2.90-2.88 (m, 1H), 2.83-2.75 (m, 2H), 2.43 (s, 3H), 2.06-1.86 (m, 4H), 1.72-1.59 (m, 2H), 1.25 (d, J=6.8 Hz, 3H). LCMS: (Method A) 316.0 (M+H), Rt. 2.10 min, 95.5% (Max). HPLC: (Method A) Rt. 2.10 min, 96.9% (Max).

Example 3: 1-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)-4-(4-methyl-1H-pyrazol-1-yl)piperidine

[0392] ##STR00261##

Step 1: tert-Butyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate

[0393] To a stirred solution of 1-boc-4-hydroxy piperidine (6.0 g, 29.8 mmol) in dry DCM (100 mL), TEA (8.48 g, 89.5 mmol) and mesyl chloride (5.12 g, 44.78 mmol) were added slowly at 0° C. The reaction mixture was stirred at rt for 1 h. It was concentrated under vacuum and the resulting crude product was dissolved in DCM. The resulting solution was washed with brine, water, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under vacuum to afford the title compound. Yield: 99% (8.32 g, off white solid). LCMS: (Method A) 180.2 (M+H), Rt. 3.79 min, 99.2% (Max).

Step 2: tert-Butyl 4-(4-methyl-1H-pyrazol-1-yl)piperidine-1-carboxylate

[0394] To a stirred solution of tert-butyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate (6.8 g, 24 mmol) in dry DMF (80 mL), Cs.sub.2CO.sub.3 (23.45 g, 72 mmol) and 4-methyl pyrazole (2 g, 24 mmol) were added and the reaction mixture was stirred at 80° C. for 4 h. The completion of the reaction was monitored by TLC. The reaction mixture was concentrated under vacuum and resulting crude product was dissolved in DCM. The resulting solution washed with brine, water, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under vacuum to afford the title compound (colorless oil). LCMS: (Method A) 166.3 (Boc elimination mass), Rt. 3.92 min, 96.3% (Max).

Step 3: 4-(4-Methyl-1H-pyrazol-1-yl)piperidine hydrochloride

[0395] To a stirred solution of tert-butyl 4-(4-methyl-1H-pyrazol-1-yl)piperidine-1-carboxylate (0.81 g, 3.06 mmol) in dry dioxane (2 mL), HCl in dioxane (10 mL) was added and the reaction mixture was stirred at rt for 2 h. The reaction mixture was concentrated under vacuum and the crude product was washed with diethyl ether to afford the title compound. Yield: 82% (0.61 g, white oil). LCMS: (Method A) 166.3 (M+H), Rt. 1.41 min, 95.2% (Max).

Step 4: 1-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)-4-(4-methyl-1H-pyrazol-1-yl)piperidine

[0396] The title compound was synthesized by following general procedure D, using 4-(4-methyl-1H-pyrazol-1-yl)piperidine hydrochloride and Intermediate 1. The crude product was purified by flash chromatography, affording the title compound (brown oil). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.29 (s, 1H), 7.20 (s, 1H), 6.89 (s, 1H), 6.76 (s, 1H), 5.95 (m, 2H), 4.06-4.00 (m, 1H), 3.43-3.42 (m, 1H), 3.16-3.14 (m, 1H), 2.97-2.94 (m, 1H), 2.15-2.07 (m, 2H), 2.04-2.00 (m, 4H), 1.99-1.92 (m, 3H), 1.37 (d, J=6.8 Hz, 3H). LCMS: (Method A) 314.0 (M+H), Rt. 2.76 min, 93.6% (Max). HPLC: (Method A) Rt 2.78 min, 97.0% (Max).

Example 4: 5-(1-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperidin-4-yl)-3-methyl-1,2,4-oxadiazole

[0397] ##STR00262##

Step 1: Ethyl 1-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperidine-4-carboxylate

[0398] The title compound was synthesized by following general procedure D, using 4-piperidine carboxylic acid ester (25 g, 159 mmol) and Intermediate 1 (49.87 g, 271 mmol). The crude product was purified by flash chromatography, affording the title compound (pale brown liquid). LCMS: (Method A) 306.0 (M+H), Rt. 2.71 min, 29.4% (Max).

Step 2: 1-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperidine-4-carboxylic Acid

[0399] To a stirred solution of ethyl 1-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperidine-4-carboxylate (1.0 g, 3.2 mmol) in dioxane (15 mL), NaOH in water (0.256 g, 6.5 mmol, 1 mL water) was added at 0° C. and stirred for 20 h at rt. Reaction mixture was evaporated at 40° C. To the resulting crude product, DCM (30 mL) and water (15 mL) were added and pH was adjusted to 6.5-7.0 using citric acid. The reaction mixture was extracted with 10% MeOH in DCM (30 mL) and evaporated under reduced pressure to afford the title compound. (pale brown oil). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.04-6.72 (m, 3H), 5.99-5.95 (m, 2H), 5.08-5.06 (m, 1H), 4.64-4.50 (m, 1H), 2.15-2.08 (m, 4H), 1.90-1.50 (m, 2H), 1.46-1.44 (m, 2H), 1.35 (d, J=7.6 Hz, 3H). LCMS: (Method B) 278.0 (M+H), Rt. 2.721 min, 70.13% (Max).

Step 3: 5-(1-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperidin-4-yl)-3-methyl-1,2,4-oxadiazole

[0400] To a stirred solution of 1-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperidine-4-carboxylic acid (290 mg, 1.05 mmol) in ACN (5 mL), HOBt (163 mg, 1.21 mmol) and EDC.HCl (241 mg, 1.26 mmol) were added at rt and stirred for 30 min. Then N′-hydroxyacetimidamide was added and stirred for overnight at rt. The reaction mixture was concentrated under vacuum and the resulting residue was dissolved in EtOAc (50 mL). The EtOAc layer was washed with water (10 mL), brine solution (10 mL), dried over anhydrous Na.sub.2SO.sub.4 and concentrated under vacuum. The crude product was purified by preparative HPLC (Method PB) to afford the title compound (pale brown oil). .sup.1H NMR (400 MHz, CDCl.sub.3): δ 6.87 (s, 1H), 6.75 (s, 2H), 5.95 (m, 2H), 3.40-3.38 (m, 1H), 3.07-3.02 (m, 1H), 2.90-2.85 (m, 2H), 2.38 (s, 3H), 2.13-1.85 (m, 6H), 1.35 (d, J=6.4 Hz, 3H). LCMS: (Method A) 316.2 (M+H), Rt. 2.401 min, 97.43% (Max). HPLC: (Method A) Rt. 2.452 min, 97.90% (Max).

Example 5: 2-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-4-phenylthiazole

[0401] ##STR00263##

Step 1: tert-butyl 4-carbamothioylpiperazine-1-carboxylate

[0402] To a solution of 1-boc piperazine (5.0 g, 26.88 mmol) in dry THF (50 mL), 1,1-thio carbonylimidazole (5.48 g, 29.56 mmol) was added at room temperature and stirred for 2 h. The reaction mixture was heated at 50° C. for 1 h. It was cooled down to 0° C. and methanolic ammonia solution (50 mL, 7 N) was added. The mixture was stirred at 60° C. for 20 h. It was then diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous Na.sub.2SO.sub.4 and concentrated under vacuum. The crude product was purified by flash chromatography to give the title compound. Yield: 92% (4.0 g, white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.2 (m, 2H), 3.16-3.14 (m, 2H), 2.49-2.48 (m, 6H), 1.30 (s, 9H). LCMS: (Method A) 246.2 (M+H), Rt. 2.93 min, 95.3% (Max).

Step 2: tert-Butyl 4-(4-phenylthiazol-2-yl)piperazine-1-carboxylate

[0403] To a stirred solution of tert-butyl 4-carbamothioylpiperazine-1-carboxylate (0.5 g, 2.08 mmol) in dioxane (10 mL), triethyl amine (0.22 mL, 2.6 mmol) and 2-bromo-1-phenylethan-1-one (0.52 g, 2.6 mmol) were added at rt. The resulting mixture was stirred at 90° C. for 20 h. The completion of the reaction was monitored by TLC. It was diluted with water and extracted with EtOAc. The organic layer was separated, dried over anhydrous Na.sub.2SO.sub.4, concentrated under vacuum. The resulting crude product was taken as such for the next step. Yield: 86% (0.5 g, colorless liquid).

Step 3: 4-Phenyl-2-(piperazin-1-yl)thiazole hydrochloride

[0404] To a stirred solution of tert-butyl 4-(4-phenylthiazol-2-yl)piperazine-1-carboxylate (0.5 g) in dry dioxane (2 mL), HCl in dioxane (10 mL, 4 N) was added at room temperature and stirred for 3 h at same temperature. The reaction mixture was concentrated under reduced pressure and the resulting crude product was suspended in diethyl ether (10 mL). It was filtered and dried under vacuum to afford the title compound. Yield: 75% (350 mg, yellow solid). LCMS: (Method A) 246.2 (M+H), Rt. 2.85 min, 71.5% (Max).

Step 4: 2-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-4-phenylthiazole

[0405] The title compound was synthesized by following general procedure E, using 4-phenyl-2-(piperazin-1-yl)thiazole hydrochloride (0.2 g, 0.8 mmol) and Intermediate 1 (0.3 g, 1.6 mmol). The reaction mixture was stirred at rt for 16 h. The crude product was purified by flash chromatography, affording the title compound (yellow solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.84-7.82 (m, 2H), 7.40-7.36 (m, 3H), 7.30-7.26 (m, 1H), 7.14-6.99 (m, 3H), 6.06 (s, 2H), 4.61-4.48 (m, 1H), 4.18-3.98 (m, 2H), 3.43-3.33 (m, 2H) 3.12-2.98 (m, 2H), 2.59-2.49 (m, 2H), 1.63 (br.s, 3H). LCMS: (Method A) 394.0 (M+H), Rt. 3.87 min, 98.3% (Max). HPLC: (Method A) Rt. 3.89 min, 99.3% (Max).

Example 6: 2-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-4-(4-methoxyphenyl)thiazole

[0406] ##STR00264##

Step 1: tert-butyl 4-(4-(4-methoxyphenyl)thiazol-2-yl)piperazine-1-carboxylate

[0407] To a stirred solution of tert-butyl 4-carbamothioylpiperazine-1-carboxylate (synthesized according to Example 5, Step 1, 1.0 g, 4.0 mmol) in dioxane (20 mL), triethyl amine (0.6 mL, 8.3 mmol) and 2-bromo-1-(4-methoxyphenyl)ethan-1-one (1.2 g, 5.3 mmol) was added at rt and stirred at 90° C. for 20 h. The completion of the reaction was monitored by TLC. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (2×25 mL). The organic layer was separated, dried over anhydrous Na.sub.2SO.sub.4. After evaporation of the solvents, the resulting crude product was taken as such for the next step. Yield: 53% (0.8 g, pale yellow liquid).

Step 2: 4-(4-Methoxyphenyl)-2-(piperazin-1-yl)thiazole hydrochloride

[0408] To a stirred solution of tert-butyl 4-(4-(4-methoxyphenyl)thiazol-2-yl)piperazine-1-carboxylate (0.8 g) in dry dioxane (5 mL), HCl in dioxane (4 M, 10 mL) was added at rt and stirred for 3 h. The reaction mixture was concentrated under vacuum. The resulting crude product was triturated in diethyl ether (10 mL), filtrated and dried under vacuum to afford the title compound. Yield: 68% (400 mg, yellow solid). LCMS: (Method A) 276.0 (M+H), Rt. 2.82 min, 69.9% (Max).

Step 3: 2-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-4-(4-methoxyphenyl)thiazole

[0409] The title compound was synthesized by following general procedure E, using 4-(4-methoxyphenyl)-2-(piperazin-1-yl)thiazole hydrochloride (0.5 g, 2.7 mmol) and Intermediate 1 (0.9 g, 5.4 mmol). The reaction mixture was stirred at rt for 16 h. The crude product was purified by flash chromatography, affording the title compound (pale yellow solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.76 (d, J=8.4 Hz, 2H), 7.07 (s, 1H), 6.94-6.91 (m, 3H), 6.86-6.84 (m, 1H), 6.78-6.76 (m, 1H), 5.99 (m, 2H), 3.76 (s, 3H), 3.43-3.42 (m, 5H), 2.50 (m, 2H) 2.42-2.41 (m, 2H), 1.30 (d, J=6.8 Hz, 3H). LCMS: (Method A) 424.0 (M+H), Rt. 3.86 min, 98.7% (Max). HPLC: (Method A) Rt. 3.85 min, 99.3% (Max).

Example 7: 2-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)thiazole

[0410] ##STR00265##

[0411] To a stirred solution of Intermediate 2 (0.1 g, 0.37 mmol) in dry DMSO (5 mL), K.sub.2CO.sub.3 (0.15 g, 11.11 mmol) and 2-bromo thiazole (0.066 g, 0.407 mmol) were added. The reaction mixture was heated in a microwave at 150° C. for 3 h. The reaction mixture was cooled and concentrated under vacuum. The resulting crude product was purified by MD Autoprep (Method B) to afford the title compound (off white solid). .sup.1H NMR (400 MHz, CDCl.sub.3): δ 7.20 (d, J=4.0 Hz, 1H), 6.90 (s, 1H), 6.77 (s, 2H), 6.57 (s, 1H), 5.97 (s, 2H), 3.48 (s, 4H), 3.36 (s, 1H), 2.60-2.53 (m, 4H), 1.37 (s, 3H). LCMS: (Method A) 318.0 (M+H), Rt. 2.04 min, 94.4% (Max). HPLC: (Method A) Rt. 2.04 min, 98.6% (Max).

Example 8: -5-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-2-iodopyrimidine

[0412] ##STR00266##

[0413] To a stirred solution of Intermediate 2 (0.14 g, 0.51 mmol) in i-propyl alcohol (5 mL), TEA (0.22 g, 2.20 mmol) and 2-iodo-5-chloro-pyrimidine (0.1 g, 0.415 mmol) were added and the reaction mixture was heated in a microwave at 140° C. for 40 min. The reaction mixture was cooled down to rt and concentrated under vacuum. The resulting crude product was purified by flash chromatography to afford the title compound. Yield: 60% (83.46 mg, pale brown oil). .sup.1H NMR (400 MHz, CDCl.sub.3): δ 8.47 (s, 2H), 6.89 (d, J=1.6 Hz, 1H), 6.83 (d, J=8.0 Hz, 1H), 6.74 (d, J=8.0 Hz, 1H), 5.99 (s, 2H), 3.66-3.64 (m, 4H), 3.37-3.35 (m, 1H), 2.44-2.38 (m, 2H) 2.35-2.30 (m, 2H), 1.27 (d, J=6.4 Hz, 3H). LCMS: (Method A) 439.0 (M+H), Rt. 3.40 min, 98.3% (Max). HPLC: (Method A) Rt. 3.43 min, 98.6% (Max).

Example 9: 2-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-4-methylpyrimidine

[0414] ##STR00267##

[0415] To a stirred solution of Intermediate 2 (0.1 g, 0.37 mmol) in dry DMF (5 mL), DIPEA (0.22 g, 1.7 mmol) and 2-chloro-4-methyl pyrimidine (0.109 g, 0.8 mmol) were added at rt and the reaction mixture was stirred at 120° C. for 12 h. It was cooled down to rt and concentrated under vacuum. The resulting crude product was purified by flash chromatography to afford the title compound (brown oil). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.17 (d, J=4.8 Hz, 1H), 6.89 (s, 1H), 6.84 (d, J=8.0 Hz, 1H), 6.76-6.74 (m, 1H), 6.48 (d, J=4.8 Hz, 1H), 5.99 (m, 2H), 3.70-3.66 (m, 4H), 3.40-3.34 (m, 1H), 2.43-2.39 (m, 2H), 2.34-2.31 (m, 2H) 2.24 (s, 3H), 1.28 (d, J=6.4 Hz, 3H). LCMS: (Method A) 327.0 (M+H), Rt. 2.57 min, 98.1% (Max). HPLC: (Method A) Rt. 2.59 min, 98.6% (Max).

Example 10: 1-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)-4-(pyridin-2-yl)piperazine

[0416] ##STR00268##

[0417] The title compound was synthesized by following general procedure D, using 1-pyridyl-2-piperazine (0.2 g, 1.3 mmol) and Intermediate 1 (0.3 g, 1.63 mmol). The resulting crude product was purified by silicagel column, affording the title compound (colorless oil). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.07 (dd, J=2.0, 4.8 Hz, 1H), 7.51-7.46 (m, 1H), 6.88 (s, 1H), 6.84-6.82 (m, 1H), 6.76-6.74 (m, 2H), 6.61-6.58 (m, 1H), 5.98 (m, 2H), 3.43-3.40 (m, 4H), 3.34-3.33 (m, 1H), 2.47-2.44 (m, 2H), 2.39-2.35 (m, 2H), 1.28 (d, J=6.8 Hz, 3H). LCMS: (Method A) 312.0 (M+H), Rt. 1.83 min, 98.0% (Max). HPLC: (Method A) Rt. 1.82 min, 98.4% (Max).

Example 11: 2-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)pyrimidine

[0418] ##STR00269##

[0419] The title compound was synthesized by following general procedure D, using 2-(piperazin-1-yl)pyrimidine (0.2 g, 1.21 mmol) and Intermediate 1 (0.366 g, 1.82 mmol). The resulting crude product was purified by MD Autoprep (Method B), affording the title compound (colourless oil). .sup.1H NMR (400 MHz, MeOH-d.sub.4): δ 8.36 (d, J=4.8 Hz, 2H), 6.96 (s, 1H), 6.90-6.84 (m, 2H), 6.66 (t, J=4.8 Hz, 1H), 5.99 (s, 2H), 3.92-3.90 (m, 4H), 3.33 (m, 1H), 2.83 (m, 4H), 1.59 (d, J=6.0 Hz, 3H). LCMS: (Method A) 313.2 (M+H), Rt. 2.45 min, 99.4% (Max). HPLC: (Method A) Rt. 2.44 min, 99.8% (Max).

[0420] As can be seen from the following comparison, the compound of Example 11 exhibits a highly increased OGA inhibitor activity as compared to the similar compound of Example 1 of U.S. Pat. No. 3,299,067, and is thus significantly more effective than said compound of U.S. Pat. No. 3,299,067 in the indications mentioned in this specification:

TABLE-US-00002 U.S. Pat. No. 3,299,067 (Example 1) [00270] OGA IC.sub.50 = 998 nM Present Invention (Example 11) [00271] OGA IC.sub.50 = 125 nM

Example 12: 2-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-4-isopropylthiazole

[0421] ##STR00272##

Step 1: t-Butyl 4-(4-isopropylthiazol-2-yl)piperazine-1-carboxylate

[0422] To a stirred solution of tert-butyl 4-carbamothioylpiperazine-1-carboxylate (synthesized according to Example 5, Step 1, 1.2 g, 4.01 mmol) in THF (10 mL), triethyl amine (0.5 mL, 5.3 mmol) and 1-bromo-3-methylbutan-2-one (1.0 mL, 5.3 mmol) were added at rt. The resulting mixture was stirred for 16 h at 90° C. The completion of the reaction was monitored by TLC. The reaction mixture was quenched with water and extracted with EtOAc. The organic layer was dried over anhydrous Na.sub.2SO.sub.4, concentrated under vacuum and the resulting crude product was taken as such for next step. Yield: 80% (0.8 g, pale yellow oil). LCMS: (Method A) 312.0 (M+H), Rt. 3.24 min, 95.2% (Max).

Step 2: 4-Isopropyl-2-(piperazin-1-yl)thiazole hydrochloride

[0423] To a stirred solution of tert-butyl 4-(4-isopropylthiazol-2-yl)piperazine-1-carboxylate (0.8 g, 2.4 mmol) in dry dioxane (2 mL), HCl in dioxane (4 N, 10 mL) was added at rt and stirred for 2 h at same temperature. The reaction mixture was concentrated under vacuum and the crude product was washed with diethyl ether to afford the title compound. Yield: 93% (1.2 g, pale yellow oil).

Step 3: 2-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-4-isopropylthiazole

[0424] The title compound was synthesized by following general procedure D, using 4-isopropyl-2-(piperazin-1-yl)thiazole hydrochloride (0.57 g, 2.3 mmol) and Intermediate 1 (0.5 g, 2.3 mmol). The resulting crude product was purified by MD Autoprep (Method C), affording the title compound (pale yellow oil). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 6.89 (s, 1H), 6.84 (d, J=8.0 Hz, 1H), 6.76 (d, J=8.0 Hz, 1H), 6.33 (s, 1H), 5.98 (m, 2H), 3.41-3.11 (m, 5H), 2.74-2.72 (m, 1H), 2.46-2.38 (m, 4H), 1.27 (d, J=6.8 Hz, 3H), 1.15 (d, J=6.8 Hz, 3H). LCMS: (Method A) 360.0 (M+H), Rt. 2.71 min, 94.5% (Max). HPLC: (Method A) Rt. 2.69 min, 98.8% (Max).

Example 13: 2-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-4-(trifluoromethyl)thiazole

[0425] ##STR00273##

Step 1: tert-Butyl 4-(4-(trifluoromethyl)thiazol-2-yl)piperazine-1-carboxylate

[0426] To a stirred solution of tert-butyl 4-carbamothioylpiperazine-1-carboxylate (synthesized according to Example 5, Step 1, 2 g, 13.75 mmol) in dioxane (20 mL), triethyl amine (1.7 mL, 12.24 mmol) and 1-bromo-3,3,3-trifluoro acetone (3.2 g, 16.5 mmol) were added and stirred at 90° C. for 3 h. The completion of the reaction was monitored by TLC. The reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (2×25 mL). The organic layer was separated, dried over anhydrous Na.sub.2SO.sub.4, concentrated under vacuum and was used as such for next step. Yield: 75% (1.0 g, white solid). .sup.1H NMR (300 MHz, DMSO-d.sub.6): δ 7.57 (s, 1H), 3.42 (m, 8H), 1.40 (s, 9H). LCMS: (Method A) 338.0 (M+H), Rt. 5.37 min, 99.0% (Max).

Step 2: 2-(Piperazin-1-yl)-4-(trifluoromethyl)thiazole hydrochloride

[0427] To a stirred solution of tert-butyl 4-(4-(trifluoromethyl)thiazol-2-yl)piperazine-1-carboxylate (1.0 g, 2.93 mmol) in dry dioxane, HCl in dioxane (4 N, 15 mL) was added and the reaction mixture was stirred at rt for 1 h. The reaction mixture was concentrated under vacuum and the resulting crude product was triturated in diethyl ether, filtrated and dried under vacuum to afford the title compound. Yield: 99% (700 mg, white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.22 (br. s, 2H), 7.66 (s, 1H), 3.68-3.64 (m, 4H), 3.21 (m, 4H). LCMS: (Method A) 238.0 (M+H), Rt. 2.33 min, 99.7% (Max).

Step 3: 2-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-4-(trifluoromethyl)thiazole

[0428] To a stirred solution of 2-(piperazin-1-yl)-4-(trifluoromethyl)thiazole hydrochloride (0.26 g, 1.07 mmol) in dry DMF (3 mL), Intermediate 1 (0.19 g, 1.07 mmol) and triethyl amine (0.272 g, 2.69 mmol) were added and the reaction mixture was stirred at 80° C. for 16 h. The reaction mixture was concentrated, the crude product was diluted with ethyl acetate (10 mL) and the organic layer was washed with brine (10 mL). The organic layer was separated, dried over anhydrous Na.sub.2SO.sub.4 and concentrated to afford the title compound (colorless oil). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 6.96 (s, 1H), 6.88 (s, 1H), 6.76-7.75 (m, 2H), 5.91 (s, 2H), 3.55-3.45 (m, 4H), 3.38 (q, J=6.4 Hz, 1H), 2.62-2.49 (m, 4H), 2.56-2.51 (m, 4H), 1.36 (d, J=6.4 Hz, 3H). LCMS: (Method A) 386.0 (M+H), Rt. 3.55 min, 97.4% (Max). HPLC: (Method A) Rt. 3.54 min, 98.7% (Max).

Example 14: 1-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)-4-(5-methylpyridin-2-yl)piperazine

[0429] ##STR00274##

[0430] The title compound was synthesized according the general procedure D, using Intermediate 2 and 2-fluoro-5-methyl pyridine. The crude product was purified by flash chromatography to afford the title compound (off white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.92 (s, 1H), 7.36-7.33 (m, 1H), 6.89 (s, 1H), 6.84 (d, J=8.0 Hz, 1H), 6.76 (d, J=7.6 Hz, 1H), 6.70 (d, J=8.4 Hz, 1H), 5.99 (m, 2H), 3.37-3.35 (m, 5H), 2.47-2.44 (m, 2H), 2.38-2.36 (m, 2H), 2.12 (s, 3H), 1.28 (d, J=6.8 Hz, 3H). LCMS: (Method A) 326.2 (M+H), Rt. 1.96 min, 97.6% (Max). HPLC: (Method A) Rt. 1.96 min, 98.1% (Max).

Example 15: (R)-2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-4-methylthiazole or (S)-2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-4-methylthiazole

[0431] ##STR00275##

[0432] The two enantiomers of Example A were separated by chiral preparative HPLC (Method PE). The first eluting compound has Rt. 5.76 min (Method C) (colorless oil). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 6.89 (s, 1H), 6.84 (d, J=8.0 Hz, 1H), 6.76 (d, J=8.0 Hz, 1H), 6.35 (s, 1H), 5.99-5.98 (m, 2H), 3.40-3.36 (m, 1H), 3.32-3.29 (m, 4H), 2.47-2.44 (m, 2H), 2.41-2.37 (m, 2H), 2.11 (s, 3H), 1.26 (d, J=6.4 Hz, 3H). LCMS: (Method A) 332.0 (M+H), Rt. 2.06 min, 96.3% (Max). HPLC: (Method A) Rt 2.05 min, 99.5% (Max), 99.4% (254 nm). HPLC chiral purity: (Method C) Rt. 5.76 min, 100% (Max). Example 15 is the second eluting compound with Rt. 7.44 min (Method C) (colorless oil). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 6.89 (s, 1H), 6.84 (d, J=8.0 Hz, 1H), 6.76 (d, J=8.0 Hz, 1H), 6.35 (s, 1H), 5.99 (s, 2H), 3.42-3.37 (m, 1H), 3.32-3.30 (m, 4H), 2.47-2.44 (m, 2H), 2.40-2.36 (m, 2H), 2.11 (s, 3H), 1.26 (d, J=6.8 Hz, 3H). LCMS: (Method A) 332.0 (M+H), Rt. 2.04 min, 99.2% (Max).

[0433] HPLC: (Method A) Rt. 2.05 min, 99.2% (Max). HPLC chiral purity: (Method C) Rt. 7.44 min, 99.83% (Max).

Example 16: 2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-4-(tert-butyl)thiazole

[0434] ##STR00276##

Step 1: tert-butyl 4-(4-(tert-butyl)thiazol-2-yl)piperazine-1-carboxylate

[0435] To a stirred solution of tert-butyl 4-carbamothioylpiperazine-1-carboxylate (synthesized according to Example 5, Step 1, 1.3 g, 5.3 mmol) in dioxane (10 mL), TEA (1 mL, 7 mmol) and 1-bromo-3,3-dimethylbutan-2-one (0.94 mL, 6.8 mmol) were added at rt and stirred for 16 h at 90° C. The completion of the reaction was monitored by TLC. The reaction mixture was quenched with water and extracted with EtOAc. The organic layer was dried over anhydrous Na.sub.2SO.sub.4, concentrated under vacuum and the resulting crude product was taken as such for next step without further purification. Yield: 88% (1.5 g, black liquid). LCMS: (Method A) 326.2 (M+H), Rt. 3.75 min, 60.4% (Max).

Step 2: 4-(tert-Butyl)-2-(piperazin-1-yl)thiazole hydrochloride

[0436] To a stirred solution of tert-butyl 4-(4-(tert-butyl)thiazol-2-yl)piperazine-1-carboxylate (1.5 g, 4.61 mmol) in dry dioxane (2 mL), HCl in dioxane (4 N, 10 mL) was added and the reaction mixture was stirred at rt for 2 h. The reaction mixture was concentrated under vacuum and the resulting crude product was triturated in diethyl ether (100 mL), filtered and dried under vacuum to afford the title compound. Yield: 63% (1.02 g, black solid).

Step 3: 2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-4-(tert-butyl)thiazole

[0437] The title compound was synthesized following the general procedure D, using 4-(tert-butyl)-2-(piperazin-1-yl)thiazole hydrochloride (0.732 g, 2.8 mmol) and Intermediate 1 (0.28 g, 2.8 mmol) and the crude product was purified by flash chromatography (pale yellow oil). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 6.89 (s, 1H), 6.85 (d, J=7.6 Hz), 6.76 (d, J=7.6 Hz, 1H), 6.33 (s, 1H), 5.99 (m, 2H), 3.40 (m, 1H), 3.37-3.30 (m, 4H), 2.49-2.46 (m, 2H), 2.43-2.40 (m, 2H), 1.28 (d, J=6.8 Hz, 3H), 1.19 (s, 9H). LCMS: (Method A) 374.0 (M+H), Rt. 3.40 min, 98.6% (Max). HPLC: (Method A) Rt. 3.39 min, 99.7% (Max).

Example 17: Ethyl 2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)thiazole-4-carboxylate

[0438] ##STR00277##

Step 1: Ethyl 2-(4-(tert-butoxycarbonyl)piperazin-1-yl)thiazole-4-carboxylate

[0439] To a stirred solution of tert-butyl 4-carbamothioylpiperazine-1-carboxylate (synthesized according to Example 5, Step 1, 3.0 g, 12 mmol) in dioxane (10 mL), TEA (2.6 mL, 16 mmol) and 3-bromo-ethyl pyruvate (2.1 mL, 16 mmol) were added at rt and the mixture was stirred at 90° C. for 16 h. The completion of the reaction was monitored by TLC. The reaction mixture was quenched with water and extracted with EtOAc. The organic layer was dried over anhydrous Na.sub.2SO.sub.4, concentrated under vacuum and the resulting crude product was taken as such for next step. Yield: 95% (4 g, black solid).

Step 2: Ethyl 2-(piperazin-1-yl)thiazole-4-carboxylate hydrochloride

[0440] To a stirred solution of ethyl 2-(4-(tert-butoxycarbonyl)piperazin-1-yl)thiazole-4-carboxylate (4.0 g, 11.73 mmol) in dry dioxane (2 mL), HCl in dioxane (4 N, 10 mL) was added at rt and stirred for 2 h. The reaction mixture was concentrated under vacuum and the resulting crude product was triturated in diethyl ether (25 mL), filtered and dried under vacuum to afford the title compound. Yield: 90% (3.2 g, black solid). LCMS: (Method A) 242.0 (M+H), Rt. 1.88 min, 90.7% (Max).

Step 3: Ethyl 2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)thiazole-4-carboxylate

[0441] The title compound was synthesized following the general procedure D, using ethyl 2-(piperazin-1-yl)thiazole-4-carboxylate hydrochloride and Intermediate 1 and the crude product was purified by flash chromatography followed by MD Autoprep (Method B) (yellow solid). .sup.1HNMR (400 MHz, DMSO-d.sub.6): δ 7.66 (d, J=2.0 Hz, 1H), 6.88 (s, 1H), 6.84 (d, J=8.0 Hz, 1H), 6.75 (d, J=8.0 Hz, 1H), 5.98 (m, 2H), 4.21-4.20 (m, 2H), 3.38-3.32 (m, 5H), 2.49-2.40 (m, 4H), 1.26-1.23 (m, 6H). LCMS: (Method A) 390.0 (M+H), Rt. 2.99 min, 97.8% (Max). HPLC: (Method A) Rt. 2.95 min, 98.9% (Max).

Example 18: 2-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)thiazole-4-carboxylic Acid

[0442] ##STR00278##

[0443] To a stirred solution of Example 17 (0.2 g) in dry THF (10 mL), 5% NaOH in water (5 mL) was added slowly at rt and the mixture was stirred for 16 h at same temperature. It was then concentrated under vacuum, neutralised to pH=6 with 2N HCl and extracted with DCM (20 mL). The organic layer was washed with brine (10 mL), water (10 mL), dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure. The crude product was purified by flash chromatography followed by MD Autoprep (Method B) to afford the title compound (off white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.58 (s, 1H), 6.90 (s, 1H), 6.88 (d, J=8.0 Hz, 1H). 6.76 (d, J=8.0 Hz, 1H), 6.00-5.99 (m, 2H), 3.35-3.36 (m, 5H), 2.51-2.49 (m, 2H), 2.44-2.40 (m, 2H), 1.29-1.27 (d, J=6.8 Hz, 3H). LCMS: (Method A) 362.0 (M+H), Rt. 2.29 min, 95.5% (Max). HPLC: (Method A) Rt. 2.30 min, 95.9% (Max).

Example 19: 2-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-4-ethylthiazole

[0444] ##STR00279##

Step 1: t-Butyl 4-(4-ethylthiazol-2-yl)piperazine-1-carboxylate

[0445] To a stirred solution of tert-butyl 4-carbamothioylpiperazine-1-carboxylate (synthesized according to Example 5, Step 1, 2.0 g, 8.16 mmol) in dioxane (20 mL), TEA (1.7 mL, 10.6 mmol) and 1-bromobutan-2-one (1.2 mL, 10 mmol) were added and stirred at 80° C. for 16 h. The completion of the reaction was monitored by TLC. The reaction mixture was quenched with water (10 mL) and extracted with EtOAc (2×25 mL). The organic layer was separated, dried over anhydrous Na.sub.2SO.sub.4, concentrated under vacuum. The resulting product was taken as such for next step. Yield: 86% (2.1 g, pale yellow solid). LCMS: (Method A) 298.0 (M+H), Rt. 2.94 min, 93.1% (Max).

Step 2: 4-Ethyl-2-(piperazin-1-yl)thiazole hydrochloride

[0446] To a stirred solution of tert-butyl 4-(4-ethylthiazol-2-yl)piperazine-1-carboxylate (1.9 g, 6.3 mmol) in dry dioxane (2 mL), HCl in dioxane (4 N, 10 mL) was added and the reaction mixture was stirred at rt for 2 h. The reaction mixture was concentrated under vacuum and the crude product was triturated in diethyl ether (15 mL), filtered and dried under vacuum to afford the title compound. Yield: 53% (0.8 g, black solid).

Step 3: 2-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-4-ethylthiazole

[0447] The title compound was synthesized following the general procedure D, using 4-ethyl-2-(piperazin-1-yl)thiazole hydrochloride (1.1 g, 4.7 mmol) and Intermediate 1 (0.9 g, 4.7 mmol). The crude product was purified by flash chromatography (pale yellow oil). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 6.89 (d, J=1.6 Hz, 1H), 6.84 (d, J=7.6 Hz, 1H), 6.75 (d, J=7.5 Hz, 1H), 6.35 (s, 1H), 5.98 (m, 2H), 3.40-3.37 (m, 1H), 3.37-3.30 (m, 4H), 2.51-2.38 (m, 6H), 1.28 (d, J=6.8 Hz, 3H), 1.23 (t, J=7.6 Hz, 3H). LCMS: (Method A) 346.0 (M+H), Rt. 2.31 min, 98.0% (Max). HPLC: (Method A) Rt. 2.34 min, 99.4% (Max).

Example 20: 1-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)-4-(6-chloropyridin-3-yl)piperazine

[0448] ##STR00280##

[0449] The title compound was synthesized following the general procedure D, using Intermediate 1 and 1-(5-chloro-2-pyridyl) piperazine. The crude product was purified by flash chromatography (off white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.07 (d, J=2.4 Hz, 1H), 7.57-7.54 (m, 1H), 6.88-6.74 (m, 4H), 5.98 (m, 2H), 3.42 (q, J=6.4 Hz, 1H), 2.46-2.43 (m, 2H), 2.37-2.34 (m, 2H), 1.28 (d, J=6.4 Hz, 3H). LCMS: (Method A) 346.0 (M+H), Rt. 3.27 min, 98.7% (Max). HPLC: (Method A) Rt 3.25 min, 99.2% (Max).

Example 21: 1-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)-4-(6-methylpyridin-2-yl)piperazine

[0450] ##STR00281##

[0451] To a stirred solution of Intermediate 2 (0.12 g, 0.5 mmol) in dry DMF (2 mL), 2-fluoro-6-methyl pyridine (0.11 g, 0.99 mmol) and DIPEA (0.26 g, 2.4 mmol) were added at rt and the reaction mixture was stirred at 120° C. for 16 h. The reaction mixture was cooled to rt and concentrated under vacuum. The resulting crude product was purified by flash chromatography followed by preparative HPLC (Method PA) to afford the title compound (brown liquid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.40-7.36 (m, 1H), 6.90 (s, 1H), 6.85 (d, J=7.6 Hz, 1H), 6.77 (d, J=7.6 Hz, 1H), 6.55-6.46 (m, 2H), 5.98 (s, 2H), 3.410-3.415 (m, 5H), 2.38-2.37 (m, 4H), 2.28-2.30 (m, 3H), 1.29 (d, J=7.2 Hz, 3H). LCMS: (Method A) 326.2 (M+H), Rt. 1.89 min, 94.9% (Max). HPLC: (Method A) Rt 1.91 min, 96.6% (Max).

Example 22: 2-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)pyrimidin-4-amine

[0452] ##STR00282##

[0453] The title compound was synthesized by following procedure D, using Intermediate 2 (0.228 g, 0.85 mmol) and 4-amino-2-chloro pyrimidine (0.1 g, 0.77 mmol). The crude product was purified by flash chromatography followed by MD Autoprep (Method B) (white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.70 (d, J=5.2 Hz, 1H), 6.88 (s, 1H), 6.83 (d, J=8.0 Hz, 1H), 6.75 (d, J=7.6 Hz, 1H), 6.36 (s, 2H), 5.98 (m, 2H), 5.69 (d, J=5.6 Hz, 1H), 3.6-3.58 (m, 4H), 3.33-3.32 (m, 1H), 2.38-2.34 (m, 2H), 2.31-2.27 (m, 2H), 1.27 (d, J=6.8 Hz, 3H). LCMS: (Method A) 328.0 (M+H), Rt. 1.85 min, 97.2% (Max). HPLC: (Method A) Rt. 1.84 min, 97.1% (Max).

Example 23: N-(2-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)pyrimidin-4-yl)acetamide

[0454] ##STR00283##

Step 1: N-(2-Chloropyrimidin-4-yl)acetamide

[0455] To a stirred solution of 4-amino-2-chloro pyrimidine (0.6 g, 4.65 mmol) in DCM (5 mL), pyridine (1.8 mL) and acetic anhydride (0.71 g, 6.9 mmol) were added at 0° C. and stirred at 75° C. for 6 h. The reaction mixture was concentrated under vacuum and the resulting crude product was dissolved in EtOAc (15 mL). The organic layer was washed with water (10 mL), brine (10 mL) and dried over anhydrous Na.sub.2SO.sub.4. After concentration under vacuum, the crude product was taken as such for next step. Yield: 56.9% (0.45 g, pale brown solid). LCMS: (Method A) 172.0 (M+H), Rt. 1.58 min, 80.2% (Max).

Step 2: N-(2-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)pyrimidin-4-yl)acetamide

[0456] The title compound was synthesized following procedure D and using Intermediate 2 (0.25 g, 0.93 mmol) and N-(2-chloropyrimidin-4-yl)acetamide (0.19 g, 1.12 mmol). The crude product was purified by flash chromatography followed by MD Autoprep (Method B) (white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 10.30 (s, 1H), 8.18 (d, J=5.6 Hz, 1H), 7.21 (d, J=5.6 Hz, 1H), 6.89 (d, J=1.6 Hz, 1H), 6.84 (d, J=7.6 Hz, 1H), 6.75 (dd, J=1.6, 8 Hz, 1H), 5.98 (m, 2H), 3.68-3.66 (m, 4H), 3.37-3.36 (m, 1H), 2.42-2.38 (m, 2H), 2.35-2.31 (m, 2H), 2.07 (s, 3H), 1.28 (d, J=6.8 Hz, 3H). LCMS: (Method A) 370.0 (M+H), Rt. 2.26 min, 97.5% (Max). HPLC: (Method A) Rt. 2.21 min, 98.9% (Max).

Example 24: 4-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-6-chloropyrimidine

[0457] ##STR00284##

[0458] To a stirred solution of Intermediate 2 (0.2 g, 0.74 mmol) in DMF (5 mL), TEA (0.5 mL, 3.70 mmol) and 4,6-dichloro pyrimidine (0.11 g, 0.74 mmol) were added and the resulting mixture was stirred at 120° C. for 2 h. It was concentrated under vacuum and the resulting crude product was dissolved in DCM and washed with water, dried over anhydrous Na.sub.2SO.sub.4, and concentrated under vacuum. The crude product was purified by flash chromatography to afford the title product (brown oil). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.30 (s, 1H), 6.91 (s, 1H), 6.89 (s, 1H), 6.84 (d, J=8.0 Hz, 1H), 6.75 (d, J=8.0 Hz, 1H), 5.98 (m, 2H), 3.55-3.52 (m, 4H), 3.39-3.37 (m, 1H), 2.43-2.39 (m, 2H), 2.36-2.32 (m, 2H), 1.27 (d, J=6.8 Hz, 3H). LCMS: (Method A) 347.0 (M+H), Rt. 2.55 min, 98.7% (Max). HPLC: (Method A) Rt. 2.57 min, 99.7% (Max).

Example 25: 2-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-6-chloropyrazine

[0459] ##STR00285##

[0460] To a stirred solution of Intermediate 2 (0.2 g, 0.74 mmol) in DMF (5 mL), TEA (0.5 mL, 3.70 mmol) and 2,5-dichloro pyrazine (0.11 g, 0.74 mmol) was added and stirred at 120° C. for 2 h. The reaction mixture was concentrated under vacuum and the resulting crude product was dissolved in DCM. It was washed with water, dried over anhydrous Na.sub.2SO.sub.4, and concentrated under vacuum. The crude product was purified by flash chromatography to afford the title compound (brown oil). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.23 (s, 1H), 7.81 (s, 1H), 6.88 (d, J=1.2 Hz, 1H), 6.84 (d, J=8.0 Hz, 1H), 6.74 (dd, J=1.6, 8.0 Hz, 1H), 5.97 (s, 2H), 3.54-3.52 (m, 4H), 3.39-3.37 (m, 1H), 2.45-2.44 (m, 2H), 2.39-2.37 (m, 2H), 1.27 (d, J=6.4 Hz, 3H). LCMS: (Method A) 347.0 (M+H), Rt. 3.03 min, 97.9% (Max). HPLC: (Method A) Rt. 3.05 min, 97.6% (Max).

Example 26: (R)-2-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)pyrimidine or (S)-2-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)pyrimidine

[0461] ##STR00286##

[0462] The two enantiomers of Example 11 were separated by chiral preparative HPLC (Method PF). The first eluting compound has Rt. 8.50 min (colorless oil). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.32 (d, J=4.8 Hz, 2H), 6.88 (s, 1H), 6.83 (d, J=8.0 Hz, 1H), 6.74 (d, J=8.0 Hz, 1H), 6.58 (t, J=4.4 Hz, 1H), 5.97 (m, 2H), 3.68-3.67 (m, 4H), 3.37-3.35 (m, 1H), 2.49-2.38 (m, 2H), 2.35-2.30 (m, 2H), 1.27 (d, J=6.4 Hz, 3H). LCMS: (Method A) 313.0 (M+H), Rt. 2.45 min, 99.5% (Max). HPLC: (Method A) Rt. 2.47 min, 99.5% (Max). HPLC chiral purity: (Method D) Rt. 8.50 min, 100% (Max). Example 26 is the second eluting compound, with Rt. 13.33 min (colorless oil). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.32 (d, J=4.8 Hz, 2H), 6.88 (s, 1H), 6.83 (d, J=8.0 Hz, 1H), 6.74 (d, J=8.0 Hz, 1H), 6.58 (t, J=4.4 Hz, 1H), 5.97 (m, 2H), 3.68-3.67 (m, 4H), 3.36-3.33 (m, 1H), 2.49-2.38 (m, 2H), 2.35-2.30 (m, 2H), 1.27 (d, J=6.4 Hz, 3H). LCMS: (Method A) 313.0 (M+H), Rt. 2.44 min, 99.5% (Max). HPLC: (Method A) Rt. 2.47 min, 99.8% (Max). HPLC chiral purity: (Method D) Rt. 13.33 min, 100% (Max).

Example 27: Ethyl 2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)thiazole-5-carboxylate

[0463] ##STR00287##

Step 1: Ethyl 2-bromothiazole-5-carboxylate

[0464] To a stirred solution of ethyl-2-amino thiazole-5-carboxylate (10.0 g, 46.45 mmol, Combi block) in 48% HBr (75 mL), sodium nitrite (4.80 g, 69.68 mmol) in water (50 mL) was added dropwise at 0° C. and the reaction mixture was stirred at 0° C. for 15 min. Copper (I)bromide (6.66 g, 46.45 mmol) in 48% HBr (75 mL) was added dropwise at 0° C. and the reaction mixture was stirred at rt for 4 h. The reaction mixture was diluted with DCM (200 mL) and washed with water (50 mL), brine (50 mL), dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The crude product was purified by flash chromatography (100% CHCl.sub.3) to afford the title compound. Yield: 50.18% (5.5 g, yellow liquid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.16 (s, 1H), 4.38 (q, J=7.16 Hz, 2H), 1.40 (t, J=7.12 Hz, 3H). LCMS: (Method A) 235.9 (M+H), Rt. 3.85 min, 98.6% (Max).

Step 2: Ethyl 2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)thiazole-5-carboxylate

[0465] To a stirred solution of Intermediate 2 (1.5 g, 6.40 mmol) in dry DMF (15 mL), ethyl 2-bromothiazole-5-carboxylate (1.96 g, 8.32 mmol) and TEA (3.5 mL, 25.6 mmol) were added at rt and the reaction mixture was stirred at 120° C. for overnight. The reaction mixture was cooled to rt and was diluted with EtOAc. The organic layer was washed with brine (10 mL), water (10 mL), dried over anhydrous Na.sub.2SO.sub.4 and concentrated under vacuum. The crude product was purified by column chromatography to afford the title compound (off white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.83 (s, 1H), 6.89 (s, 1H), 6.89 (d, J=8.0 Hz, 1H). 6.76 (d, J=8.0 Hz, 1H), 5.99 (s, 2H), 4.19 (q, J=6.8 Hz, 2H), 3.50-3.42 (m, 5H), 2.51-2.46 (m, 2H), 2.44-2.33 (m, 2H), 1.30-1.22 (m, 6H). LCMS: (Method A) 247.2 (M+H), Rt. 3.17 min, 78.6% (Max).

Example 28: (2-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)thiazol-5-yl)methanol

[0466] ##STR00288##

[0467] The title compound was synthesized following the general procedure A starting from Example 27. The crude product was purified by flash chromatography followed by MD Autoprep (Method B) (off white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 6.96 (s, 1H), 6.89 (s, 1H), 6.84 (d, J=7.6 Hz, 1H), 6.75 (d, J=7.6 Hz, 1H), 5.98 (m, 2H), 5.21 (t, J=5.6 Hz, 1H), 4.44 (d, J=5.6 Hz, 2H), 3.40-3.37 (m, 1H), 3.34-3.31 (m, 4H), 2.46-2.42 (m, 2H), 2.41-2.38 (m, 2H), 1.28 (d, J=6.4 Hz, 3H). LCMS: (Method A) 348.0 (M+H), Rt. 1.91 min, 96.3% (Max). HPLC: (Method A) Rt. 1.89 min, 95.1% (Max).

Example 29: (2-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)thiazol-4-yl)methanol

[0468] ##STR00289##

[0469] The title compound was synthesized following general procedure A, starting with Example 17 (0.5 g) and the crude product was purified by flash chromatography (pale yellow oil). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 6.89 (s, 1H), 6.85 (d, J=8.0 Hz, 1H), 6.75 (dd, J=1.6, 8.0 Hz, 1H), 6.52 (s, 1H), 5.99 (m, 2H), 5.11-5.09 (t, J=8.0 Hz, 1H), 4.31 (d, J=8.0 Hz, 2H), 3.40-3.34 (m, 5H). 2.51-2.49 (m, 2H), 2.42-2.32 (m, 2H), 1.28 (d, J=6.8 Hz, 3H). LCMS: (Method A) 348.0 (M+H), Rt. 1.98 min, 94.8% (Max). HPLC: (Method A) Rt. 1.99 min, 96.0% (Max).

Example 30: 2-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-N-methylthiazole-4-carboxamide

[0470] ##STR00290##

[0471] To a stirred solution of Example 18 (0.3 g, 0.5 mmol) in DCM (10 mL), DIPEA (0.6 mL, 2 mmol) and HATU (0.56 g, 1.48 mmol) were added slowly at 0° C. The reaction mixture was stirred at 0° C. for 20 min. Methyl amine in THF (0.6 mL, 1.48 mmol) was added and the reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with EtOAc (10 mL) and washed with water (10 mL) and brine (10 mL). The organic layer was dried over anhydrous Na.sub.2SO.sub.4, concentrated under vacuum. The crude product was purified by flash chromatography followed by MD Autoprep (Method B) to afford the title compound (off white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.96 (d, J=4.8 Hz, 1H), 7.33 (s, 1H), 6.89 (s, 1H). 6.85 (d, J=8.0 Hz, 1H), 6.75 (dd, J=1.6, 8.0 Hz, 1H), 5.98 (m, 2H), 3.43-3.38 (m, 5H), 2.72 (d, J=4.8 Hz, 3H), 2.41-2.39 (m, 4H), 1.27 (d, J=6.4, 3H). LCMS: (Method A) 375.0 (M+H), Rt. 2.34 min, 98.2% (Max). HPLC: (Method A) Rt. 2.32 min, 99.0% (Max).

Example 31: 3-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-6-chloropyridazine

[0472] ##STR00291##

[0473] The title compound was synthesized following general procedure D, using Intermediate 2 and 3,6-dichloro pyridazine. The crude product was purified by flash chromatography (off white solid). .sup.1H NMR (DMSO-d.sub.6): δ 7.65 (d, J=9.6 Hz, 1H), 7.46 (d, J=9.6 Hz, 1H), 7.21 (s, 1H), 7.01-6.98 (m, 2H), 6.08 (s, 2H), 4.50-4.44 (m, 1H), 4.39-4.36 (m, 1H), 3.80-3.75 (m, 1H), 3.45-3.42 (m, 1H), 3.28-3.25 (m, 1H), 3.18-3.15 (m, 1H), 3.11-3.08 (m, 1H), 3.01-2.98 (m, 1H), 2.92-2.86 (m, 1H), 1.67 (d, J=6.8 Hz, 3H). LCMS: (Method A) 347.0 (M+H), Rt. 2.55 min, 96.5% (Max). HPLC: (Method A) Rt. 2.58 min, 95.5% (Max).

Example 32: 2-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-N-isopropylthiazole-4-carboxamide

[0474] ##STR00292##

[0475] The title compound was synthesized by following the same procedure as described for Example 30, using Example 18 (0.3 g, 0.9 mmol) and isopropyl amine (0.09 mL, 1.08 mmol) as starting material (off white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.62 (d, J=8.4 Hz, 1H), 7.35 (s, 1H), 6.90 (s, 1H), 6.85 (d, J=8.0 Hz, 1H), 6.77 (d, J=8.0 Hz, 1H), 5.99 (m, 2H), 4.04-3.99 (m, 1H), 3.43-3.34 (m, 5H), 2.50-2.42 (m, 4H), 1.29 (d, J=6.8 Hz, 3H), 1.14-1.07 (m, 6H). LCMS: (Method A) 403.0 (M+H), Rt. 2.90 min, 95.5% (Max). HPLC: (Method A) Rt. 2.91 min, 96.5% (Max).

Example 33: 2-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-N-cyclohexylthiazole-4-carboxamide

[0476] ##STR00293##

[0477] The title compound was synthesized by following the same procedure as described for Example 30, using Example 18 (0.3 g, 0.9 mmol) and cyclohexyl amine (0.12 mL, 1.08 mmol) as starting material (off white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.60 (d, J=8.4 Hz, 1H), 7.35 (s, 1H), 6.90 (s, 1H), 6.85 (d, J=7.6 Hz, 1H), 6.77 (d, J=7.6 Hz, 1H), 5.99 (s, 2H), 3.68-3.67 (m, 1H), 3.42 (br.s, 4H), 2.50-2.42 (m, 4H), 1.74-1.70 (m, 4H), 1.59-1.56 (m, 1H), 1.36-1.23 (m, 8H), 1.13-1.09 (m, 1H). LCMS: (Method A) 443.0 (M+H), Rt. 3.57 min, 97.9% (Max). HPLC: (Method A) Rt. 3.62 min, 99.3% (Max).

Example 34: (R)-2-(4-(1-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)piperazin-1-yl)pyrimidine or (S)-2-(4-(1-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)piperazin-1-yl)pyrimidine

[0478] ##STR00294##

[0479] The title compound was synthesized by following procedure D, using Intermediate 3 (2.2 g, 11 mmol) and 1-(2-pyrimidyl) piperazine (1.8 g, 11 mmol). The crude product was purified by flash chromatography followed by preparative chiral HPLC (Method PF) to separate the two enanatiomers. The first eluting compound has Rt. 7.90 min (Method D) (off white solid). .sup.1H NMR 400 MHz, DMSO-d.sub.6): δ 8.32 (d, J=4.4 Hz, 2H), 6.78-6.75 (m, 3H), 6.59 (t, J=9.6 Hz, 1H), 4.21-4.20 (m, 4H), 3.68-3.67 (m, 4H), 3.36-3.26 (m, 1H), 2.49-2.39 (m, 2H), 2.34-2.32 (m, 2H), 1.25 (d, J=6.4 Hz, 3H). LCMS: (Method A) 327.2 (M+H), Rt. 2.51 min, 98.7% (Max). HPLC: (Method A) Rt. 2.54 min, 99.3% (Max). HPLC chiral purity: (Method D) Rt. 7.90 min, 100.0% (Max). Example 34 corresponds to the second eluting compound, with Rt. 13.92 min (Method D) (off white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.32 (d, J=4.4 Hz, 2H), 6.80-6.75 (m, 3H), 6.59 (t, J=9.6 Hz, 1H), 4.21-4.20 (m, 4H), 3.69-3.66 (m, 4H), 3.33-3.32 (m, 1H), 2.44-2.38 (m, 2H), 2.36-2.31 (m, 2H), 1.26 (d, J=6.8 Hz, 3H). LCMS: (Method A) 327.0 (M+H), Rt. 2.51 min, 99.1% (Max). HPLC: (Method A) Rt. 2.49 min, 99.2% (Max). HPLC chiral purity: (Method D) Rt. 13.92 min, 99.88% (Max).

Example 35: 2-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)thiazole-4-carboxamide

[0480] ##STR00295##

[0481] The title compound was synthesized by following the same procedure as described for Example 30, using Example 18 (0.3 g, 0.9 mmol) and ammonia in THF (4.5 mL, 9 mmol, 2 M in THF) as starting material. The crude mixture was purified by flash chromatography (off white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.39 (br s, 2H), 7.37 (s, 1H), 6.90 (s, 1H), 6.85 (d, J=7.6 Hz, 1H), 6.77 (d, J=7.2 Hz, 1H), 5.99 (br s, 2H), 3.41-3.34 (m, 5H), 2.50-2.43 (m, 4H), 1.30 (d, J=6.8 Hz, 3H). LCMS: (Method A) 361.0 (M+H), Rt. 2.19 min, 94.8% (Max). HPLC: (Method A) Rt. 2.17 min, 98.0% (Max).

Example 36: 5-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-2-methylthiazole

[0482] ##STR00296##

[0483] The title compound was synthesized following general procedure D, using 2-bromo-5-methyl thiazole and Intermediate 2. The crude product was purified by flash chromatography (brown solid). .sup.1H NMR (DMSO-d.sub.6): δ 6.89 (s, 1H), 6.85 (d, J=7.6 Hz, 1H), 6.80 (d, J=7.6 Hz, 1H), 6.76-6.74 (m, 1H), 5.99 (m, 2H), 3.40-3.36 (m, 1H), 3.29-3.26 (m, 4H), 2.46-2.45 (m, 2H), 2.42-2.38 (m, 2H), 2.23 (s, 3H), 1.28-1.27 (m, 3H). LCMS: (Method A) 332.0 (M+H), Rt. 2.13 min, 96.0% (Max). HPLC: (Method A) Rt. 2.11 min, 97.4% (Max).

Example 37: 5-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-2-methylthiazole

[0484] ##STR00297##

[0485] The mixture of 5-bromo-2-methyl thiazole (150 mg, 0.84 mmol), Intermediate 2 (200 mg, 0.84 mmol) and TEA (344 mg, 3.4 mmol) in DMF (4 mL) was heated at 130° C. for overnight. It was concentrated under vacuum and to the resulting crude product was dissolved in EtOAc (10 mL) and washed with water (10 mL). The organic layer was dried over Na.sub.2SO.sub.4 and concentrated. The crude product was purified by flash column chromatography (brown solid). .sup.1H NMR (DMSO-d.sub.6): δ 6.90 (s, 1H), 6.85-6.78 (m, 3H), 5.95 (br s, 2H), 3.55-3.51 (m, 1H), 3.12-3.11 (m, 4H), 2.80-2.65 (m, 4H), 2.54 (s, 3H), 1.44 (d, J=5.6 Hz, 3H). LCMS: (Method A) 332.0 (M+H), Rt. 5.71 min, 97.35% (Max). HPLC: (Method B) Rt. 5.64 min, 96.8% (Max).

Example 38: 5-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-2-chloropyrimidine

[0486] ##STR00298##

[0487] The title compound was synthesized following the general procedure D, using Intermediate 2 and 2,5-dichloropyrimidine. The crude product was purified by flash chromatography (off white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.38 (s, 2H), 6.88 (s, 1H), 6.83 (d, J=8.0 Hz, 1H), 6.75 (m, J=8.0 Hz, 1H), 5.98 (m, 2H), 3.68-3.65 (m, 4H), 3.38-3.369 (m, 1H), 2.44-2.39 (m, 1H), 2.36-2.32 (m, 2H), 1.27 (d, J=6.8 Hz, 3H). LCMS: (Method A) 347.0 (M+H), Rt. 3.24 min, 98.3% (Max). HPLC: (Method A) Rt. 3.22 min, 99.6% (Max).

Example 39: 2-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-4-methoxypyrimidine

[0488] ##STR00299##

[0489] The title compound was synthesized following general procedure D, using Intermediate 2 and 2-chloro-5-methoxy pyrimidine. The crude product was purified by flash chromatography (white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.04 (d, J=5.6 Hz, 1H), 6.88-0 (s, 1H), 6.83 (d, J=8.0 Hz, 1H), 6.74 (d, J=8.0 Hz, 1H), 6.02 (d, J=5.6 Hz, 1H), 5.98 (br s, 2H), 3.79 (s, 3H), 3.72-3.66 (m, 4H), 3.37-3.39 (m, 1H), 2.43-2.39 (m, 2H), 2.34-2.30 (m, 2H), 1.28-1.26 (d, J=6.4 Hz, 3H). LCMS: (Method A) 343.0 (M+H), Rt. 2.27 min, 99.6% (Max). HPLC: (Method A) Rt. 2.27 min, 99.4% (Max).

Example 40: 4-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-2-chloropyrimidine

[0490] ##STR00300##

[0491] The title compound was synthesized following the general procedure D, using Intermediate 2 and 2,4-dichloropyrimidine. The crude product was purified by flash chromatography (yellow oil). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.04 (d, J=7.6 Hz, 1H), 6.89 (s, 1H), 6.85 (d, J=8.0 Hz, 1H), 6.80-6.75 (m, 2H), 5.99 (m, 2H), 3.59 (br.s, 4H), 3.39 (q, J=6.4 Hz, 1H), 2.45-2.42 (m, 2H), 2.38-2.33 (m, 2H), 1.29-1.27 (d, J=6.8 Hz, 3H). LCMS: (Method A) 347.0 (M+H), Rt. 2.59 min, 96.4% (Max). HPLC: (Method A) Rt. 2.51 min, 98.2% (Max).

Example 41: 5-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-1,3,4-thiadiazol-2-amine

[0492] ##STR00301##

[0493] The title compound was synthesized following the general procedure D, using Intermediate 2 and 2-amino-5-bromo-1,3,4-thiadiazole. The crude product was purified by recrystallisation. Yield: 81% (2.0 g, off white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 6.88-6.87 (m, 1H), 6.85-6.83 (m, 1H), 6.76-6.73 (m, 1H), 6.47 (s, 2H) 5.99 (s, 2H), 3.40-3.34 (m, 1H), 3.19-3.17 (m, 4H), 2.47-2.43 (m, 2H), 2.40-2.36 (m, 2H), 1.27 (d, J=6.4 Hz, 3H). LCMS: (Method A) 334.0 (M+H), Rt. 1.84 min, 96.5% (Max). HPLC: (Method A) Rt. 1.83 min, 98.2% (Max).

Example 42: 2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-N,N-dimethylthiazole-4-carboxamide

[0494] ##STR00302##

[0495] The title compound was synthesized following the same procedure as described for Example 30, using Example 18 (0.3 g, 0.9 mmol) and dimethyl amine (0.9 mL, 1.8 mmol, 2 M in THF) as starting material (pale yellow solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.16 (s, 1H), 6.89 (s, 1H), 6.85 (d, J=7.6 Hz, 1H), 6.76 (d, J=8.0 Hz, 1H), 5.99 (br s, 2H), 3.41-3.34 (m, 5H), 3.30 (s, 3H), 2.90 (s, 3H), 2.43-2.42 (m, 4H), 1.28 (d, J=6.8 Hz, 3H). LCMS: (Method A) 389.0 (M+H), Rt. 2.41 min, 95.1% (Max). HPLC: (Method A) Rt. 2.38 min, 94.3% (Max).

Example 43: 2-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-N-isopropylthiazole-5-carboxamide

[0496] ##STR00303##

Step 1: 2-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)thiazole-5-carboxylic Acid

[0497] To a stirred solution of Example 27 (0.8 g, 2.05 mmol) in dioxane (24 mL), NaOH (2M in water, 3 mL) was added slowly. The reaction mixture was stirred overnight at room temperature. It was then concentrated under vacuum and neutralized with HCl (1.5 N) up to pH=6 and was extracted with DCM (25 mL). The organic layer was washed with water (15 mL), brine (15 mL), dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure to afford the title compound (off white solid). LCMS: (Method A) 362.0 (M+H), Rt. 2.30 min, 77.6% (Max).

Step 2: 2-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-N-isopropylthiazole-5-carboxamide

[0498] To a solution of 2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)thiazole-5-carboxylic acid (0.1 g, 0.277 mmol) in dry DCM (2 mL), HATU (0.16 g, 0.41 mmol) was added and the resulting mixture was stirred at room temperature for 1 h. Isopropyl amine (0.02 g, 0.36 mmol) and DIPEA (0.14 mL, 0.83 mmol) were added at 0° C. and the mixture was stirred overnight at room temperature. The reaction was quenched with water (10 mL) and extracted with EtOAc (25 mL). The organic layer was dried over anhydrous Na.sub.2SO.sub.4 and concentrated under vacuum. The resulting crude product was purified by MD Autoprep (Method B) to afford the title compound (off white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.96 (d, J=7.6 Hz, 1H), 7.78 (s, 1H), 6.89 (s, 1H), 6.85 (d, J=7.6 Hz, 1H), 6.75 (d, J=8.0 Hz, 1H), 5.99 (br s, 2H), 3.98-3.96 (m, 1H), 3.42-3.41 (m, 5H), 2.42-2.38 (m, 4H), 1.28 (d, J=6.8 Hz, 3H), 1.11 (d, J=6.8 Hz, 6H). LCMS: (Method A) 403 (M+H), Rt. 2.72 min, 97.81% (Max). HPLC: (Method A) Rt. 2.70 min, 98.62% (Max).

Example 44: N-(5-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-1,3,4-thiadiazol-2-yl)acetamide

[0499] ##STR00304##

[0500] To a stirred solution of Example 41 (0.06 g, 0.7 mmol), diisopropylethylamine (0.4 mL, 0.32 mmol) in dry DCM (4.0 mL), acetic anhydride (0.96 mL, 1.05 mmol) was added at 0° C. and the resulting mixture was stirred for 5 h at rt. The completion of the reaction was monitored by TLC. The reaction mixture was concentrated and the crude products were purified by flash chromatography to afford the title compound (colorless oil). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 12.03 (m, 1H), δ 6.89 (m, 1H), 6.86-6.84 (m, 1H), 6.77-6.75 (m, 1H), 5.99 (m, 2H), 3.41-3.40 (m, 5H), 2.51-2.50 (m, 2H), 2.43-2.40 (m, 2H), 2.10 (s, 3H), 1.28 (d, J=6.8 Hz, 3H). LCMS: (Method A) 376.0 (M+H), Rt. 2.512 min, 96.77% (Max). HPLC: (Method A) Rt. 2.262 min, 98.69% (Max).

Example 45: 2-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-N-propylpyrimidin-4-amine

[0501] ##STR00305##

Step 1: 2-chloro-N-propylpyrimidin-4-amine

[0502] To a stirred solution of 2,4-dichloro pyrimidine (0.2 g, 1.34 mmol) in dry THF (10 mL), TEA (0.54 g, 5.36 mmol) and propyl amine (0.088 g, 1.34 mmol) were added and the resulting mixture was stirred at room temperature for 10 h. It was diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous Na.sub.2SO.sub.4 and concentrated under vacuum to afford the title compound. Yield: 70% (0.18 g, colorless oil). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.92-7.85 (m, 2H), 6.49-6.41 (m, 1H), 3.21 (t, J=6.4 Hz 2H), 1.56-1.47 (m, 2H), 0.91-0.87 (t, J=7.36 Hz, 3H). LCMS: (Method A) 172.0 (M+H), Rt. 2.07 min, 99.5% (Max).

Step 2: 2-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-N-propylpyrimidin-4-amine

[0503] To a stirred solution of Intermediate 2 (0.2 g, 0.9 mmol) in dry DMF (4.0 mL), 2-chloro-N-propylpyrimidin-4-amine (0.18 g, 1.04 mmol) and TEA (0.5 mL, 3.2 mmol) were added at 0° C. The reaction mixture was stirred at 130° C. for overnight. It was then concentrated and the crude product was purified by flash chromatography to afford the title compound (colorless oil). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.65 (s, 1H), 6.89-6.75 (m, 3H), 6.12-5.95 (m, 3H), 5.83 (br. s, 1H), 3.62 (m, 4H), 3.20 (s, 3H), 2.51-2.49 (m, 4H), 1.50 (qm, 2H), 1.28-1.24 (m, 3H), 0.88 (t, J=8.0 Hz, 3H). LCMS: (Method A) 370.0 (M+H), Rt. 2.604 min, 97.37% (Max). HPLC: (Method A) Rt. 2.54 min, 99.78% (Max).

Example 46: 4-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)pyrimidin-2-amine

[0504] ##STR00306##

[0505] The title compound was synthesized following the general procedure D, using Intermediate 2 and 2-amino-4-chloropyrimidine. The crude product was purified by flash chromatography (off white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.72 (d, 1H, J=6.0 Hz), 6.88 (s, 1H), 6.84 (d, J=8.0 Hz, 1H), 6.75 (d, J=8.0 Hz, 1H), 5.98-5.95 (m, 5H), 3.46-3.45 (m, 4H), 3.37-3.35 (m, 1H), 2.40-2.37 (m, 2H), 2.33-2.29 (m, 2H), 1.27 (d, J=6.4 Hz, 3H). LCMS: (Method A) 328.0 (M+H), Rt. 1.86 min, 97.06% (Max). HPLC: (Method A) Rt. 1.81 min, 97.5% (Max).

Example 47: 2-(4-(1-(Benzo[d](1,3)dioxol-5-yl)ethyl)piperazin-1-yl)-N,N-dimethylthiazole-5-carboxamide

[0506] ##STR00307##

[0507] To a stirred solution of 2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)thiazole-5-carboxylic acid (Example 43, Step 1, 0.155 g, 0.4 mmol) and HATU (0.206 g, 1.2 mmol) in dry DMF (3 mL), DIPEA (0.1 mL, 0.8 mmol) was added and the resulting mixture was stirred for 30 min at room temperature. Dimethylamine in THF (0.5 mL, 8.4 mmol) was then added at 0° C. The reaction mixture was stirred overnight at room temperature. Solvents were evaporated and the resulting crude mixture was diluted with EtOAc, washed with water, 10% sodium bicarbonate solution, brine and dried over Na.sub.2SO.sub.4. After evaporation of the solvents, the resulting crude product was purified by MD Autoprep (Method B) to afford the title compound (off white solid). .sup.1H NMR (400 MHz, CDCl.sub.3): δ 7.47 (s, 1H), 6.87 (s, 1H), 6.77-6.76 (m, 2H), 5.96 (s, 2H), 3.52-3.51 (m, 4H), 3.37-3.36 (m, 1H), 3.17 (s, 6H), 2.57-2.52 (m, 4H), 2.26 (s, 3H). LCMS: (Method B) 389 (M+H), Rt. 5.049 min, 98.02% (Max). HPLC: (Method A) Rt. 2.42 min, 98.49% (Max).

Example 48: 2-(4-(1-(Benzo[d](1,3)dioxol-5-yl)ethyl)piperazin-1-yl)thiazole-5-carboxamide

[0508] ##STR00308##

[0509] To a solution of 2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)thiazole-5-carboxylic acid (Example 43, Step 1, 0.15 g, 0.4 mmol) in dry DMF (3 mL), HATU (0.206 g, 1.2 mmol) was added and stirred at room temperature for 20 min. Ammonia in THF (5 mL) and DIPEA (0.14 mL, 0.83 mmol) were then added at 0° C. The resulting reaction mixture was stirred at room temperature overnight. It was concentrated under reduced pressure. EtOAc was added to the resulting mixture and was washed with water, 10% sodium bicarbonate solution, brine and dried over Na.sub.2SO.sub.4. After evaporation of the solvents, the crude product was purified by MD Autoprep (Method C) to afford the title compound (off white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.76 (s, 1H), 7.67 (br s, 1H), 7.11 (br s, 1H), 6.89 (s, 1H), 6.84 (d, J=7.6 Hz, 1H), 6.76 (d, J=7.6 Hz, 1H), 5.99 (br s, 2H), 3.41-3.40 (m, 5H), 2.50-2.39 (m, 4H), 1.28 (d, J=8.0 Hz, 3H). LCMS: (Method A) 361.0 (M+H), Rt. 2.01 min, 99.2% (Max). HPLC: (Method A) Rt. 2.03 min, 98.5% (Max).

Example 49: 2-(4-(1-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)piperazin-1-yl)thiazole-4-carboxamide

[0510] ##STR00309##

Step 1: Ethyl-2-(4-(1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)piperazin-1-yl)thiazole-4-carboxylate

[0511] The title compound was synthesized following general procedure D, using ethyl 2-(piperazin-1-yl)thiazole-4-carboxylate hydrochloride (Example 17, Step 2, 5.0 g, 20.4 mmol) and Intermediate 3 (4.97 g, 24 mmol). The crude product was purified by flash chromatography. Yield: 54% (4.5 g, black oil).

Step 2: 2-(4-(1-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)piperazin-1-yl)thiazole-4-carboxylic Acid

[0512] To a stirred solution of ethyl-2-(4-(1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)piperazin-1-yl)thiazole-4-carboxylate (4.5 g, 11.1 mmol) in THF (20 mL), 10% NaOH (50 mL) was added slowly. The reaction mixture was stirred at room temperature for overnight. It was concentrated under vacuum, neutralized with HCl (2 N in water) to pH=6 and extracted with DCM (25 mL). The organic layer was washed with water (10 mL), brine (25 mL), dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure afford the title compound (pale yellow solid). .sup.1H NMR (400 MHz, CDCl.sub.3): δ 7.44 (s, 1H), 6.94-6.76 (m, 3H), 4.26 (s, 4H), 3.65-3.49 (m, 5H), 2.59-3.54 (m, 4H), 2.49-2.45 (m, 4H), 1.26 (d, J=4.8 Hz, 3H), LCMS: (Method A) 376.0 (M+H), Rt. 2.36 min, 79.7% (Max).

Step 3: 2-(4-(1-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)piperazin-1-yl)thiazole-4-carboxamide

[0513] The title compound was synthesized according to the same procedure as described for Example 30, using 2-(4-(1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)piperazin-1-yl)thiazole-4-carboxylic acid and NH.sub.3 in THF. The crude product was purified by flash chromatography (off white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.39 (br s, 2H), 7.35 (s, 1H), 6.80-6.76 (m, 3H), 4.21 (s, 4H), 3.38-3.38 (m, 5H), 2.49-2.45 (m, 4H), 1.27-1.23 (m, 3H). LCMS: (Method A) 375.0 (M+H), Rt. 2.21 min, 96.1% (Max). HPLC: (Method A) Rt. 2.28 min, 96.6% (Max).

Example 50: 2-(4-(1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)piperazin-1-yl)-N-methylthiazole-4-carboxamide

[0514] ##STR00310##

[0515] The title compound was synthesized according to the same procedure as described for Example 30, using 2-(4-(1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)piperazin-1-yl)thiazole-4-carboxylic acid and MeNH.sub.2 in THF. The crude product was purified by flash chromatography (yellow oil). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.07 (q, J=4.0 Hz, 1H), 7.33 (s, 1H), 6.76-6.39 (m, 3H), 4.21 (s, 4H), 3.38-3.32 (m, 5H), 2.75-2.71 (m, 3H), 2.49-2.48 (m, 4H), 1.26-1.25 (m, 3H). LCMS: (Method A) 389.0 (M+H), Rt. 2.38 min, 95.9% (Max). HPLC: (Method A) Rt. 2.46 min, 97.7% (Max).

Example 51: Ethyl 2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)pyrimidine-5-carboxylate

[0516] ##STR00311##

Step 1: tert-Butyl 4-(5-bromopyrimidin-2-yl)piperazine-1-carboxylate

[0517] To a stirred solution of 1-boc-piperazine (6.0 g, 31.5 mmol) in DMF (50 mL), triethyl amine (7 mL, 46.00 mmol) and 5-bromo-2-chloropyrimidine (6.3 g, 37.00 mmol) were added and the reaction mixture was stirred at 90° C. for 8 h. The reaction mixture was concentrated under reduced pressure. Water (50 mL) was added and the desired product was extracted with DCM (150 mL). The organic layer was dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The crude product was purified by flash chromatography (10% EtOAc in pet ether) to afford the title compound. Yield: 76% (7 g, white). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.46 (s, 2H), 3.68-3.67 (m, 4H), 3.39-3.37 (m, 4H), 1.40 (s, 9H). LCMS: (Method A) 289.0 (M+H), Rt. 5.19 min, 99.05% (Max).

Step 2: 2-(4-(t-Butoxycarbonyl)piperazin-1-yl)pyrimidine-5-carboxylic Acid

[0518] To a stirred solution of tert-butyl 4-(5-bromopyrimidin-2-yl)piperazine-1-carboxylate (5 g, 14.5 mmol) in dry THF (50 mL), n-BuLi (13.5 mL, 21.7 mmol, 1.6 M in THF) was added dropwise at −75° C. and stirred for 2 h at the same temperature. Dry CO.sub.2 gas was passed through the reaction mixture for 1 h. The reaction was stirred for 30 min at same temperature and 30 min at rt. It was cooled to 0° C. and quenched by using 10% ammonium chloride solution. The product was extracted with DCM (150 mL). The organic layer was washed with water (50 mL), brine (50 mL) and dried over anhydrous Na.sub.2SO.sub.4. After evaporation of the solvents, the title compound was isolated and used in the next step without further purification. Yield: 55% (2.5 g, pale yellow oil). LCMS: (Method A) 308.0 (M+H), Rt. 3.61 min, 55.64% (Max).

Step 3: Ethyl 2-(piperazin-1-yl)pyrimidine-5-carboxylate

[0519] To a stirring solution of 2-(4-(tert-butoxycarbonyl)piperazin-1-yl)pyrimidine-5-carboxylic acid (2.0 g, 6.0 mmol) in EtOH (250 mL), SOCl.sub.2 (1.7 mL, 16.23 mmol) was added slowly at 0° C. and the mixture was stirred at 90° C. for 15 h. It was concentrated under reduced pressure to afford the title compound (off white solid). LCMS: (Method A) 236 (M+H), Rt. 2.14, 49.8% (Max).

Step 4: Ethyl 2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)pyrimidine-5-carboxylate

[0520] To a stirring solution of ethyl 2-(piperazin-1-yl)pyrimidine-5-carboxylate (2.5 g, 9.0 mmol), diisopropyl ethyl amine (5.9 mL, 27.0 mmol) in dry acetonitrile (50 mL), Intermediate 1 (2.08 g, 11.0 mmol) was added at rt and the reaction mixture was stirred at 80° C. overnight. The reaction mixture was concentrated under vacuum and the resulting crude product was purified by flash chromatography (50% EtOAC in pet ether) to afford the title compound (yellow solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.75 (s, 2H), 6.90 (s, 1H), 6.85-6.83 (d, J=7.6 Hz, 1H), 6.75 (d, J=7.6 Hz, 1H), 6.05 (d, J=2.8 Hz, 1H), 5.91 (d, J=2.8 Hz, 1H), 4.28-4.23 (q, J=7.2 Hz, 2H), 3.82-3.81 (m, 4H), 3.49 (q, J=6.8 Hz, 1H), 2.55-2.44 (m, 2H), 2.43-2.33 (m, 2H), 1.29-1.24 (m, 6H). LCMS: (Method A) 385 (M+H), Rt. 3.23 min, 94.1% (Max). HPLC: (Method A) Rt. 3.23 min, 99.14% (Max).

Example 52: (2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)pyrimidin-5-yl)methanol

[0521] ##STR00312##

[0522] The title compound was synthesized following general procedure A from Example 51. The crude product was purified by flash chromatography (30% EtOAc in pet ether) to afford the title compound (off white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.27 (s, 2H), 6.89 (s, 1H), 6.84 (d, J=8 Hz, 1H), 6.75 (d, J=8.0 Hz, 1H), 5.99 (m, 2H), 5.05 (t, J=5.2 Hz, 1H), 4.30 (d, J=5.2 Hz, 2H), 3.67 (s, 4H), 3.36-3.34 (m, 1H), 2.43-3.32 (m, 4H), 1.27 (d, J=6.8 Hz, 3H). LCMS: (Method A) 343.0 (M+H), Rt. 2.16 min, 95.05% (Max). HPLC: (Method A) Rt. 2.11 min, 97.35% (Max).

Example 53: 2-(4-(1-(2,3-dihydrobenzofuran-5-yl)ethyl)piperazin-1-yl)pyrimidine

[0523] ##STR00313##

[0524] To a solution of 2-(piperazin-1-yl)pyrimidine (0.8 g, 4.8 mmol), diisopropylethylamine (3.0 mL, 5.7 mmol) in ACN (20 mL), Intermediate 5 (1.04 g, 5.7 mmol) was added at rt and the resulting mixture was stirred overnight. It was diluted with water (5 mL) and extracted with DCM (2×50 mL). The combined organic layer was dried over Na.sub.2SO.sub.4 and concentrated under vacuum. The crude product was purified by MD Autoprep (Method B) to afford the title compound (white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.31 (d, J=4.8 Hz, 2H), 7.16 (s, 1H), 6.99 (d, J=8.4 Hz, 1H), 6.67 (d, J=8.0 Hz, 1H), 6.58 (t, J=4.8 Hz, 1H), 4.48 (t, J=8.8 Hz, 2H), 3.67 (m, 4H), 3.34 (t, J=6.8 Hz, 1H), 3.14 (m, 2H), 2.42-2.38 (m, 2H), 2.35-2.31 (m, 2H), 1.28 (d, J=6.8 Hz, 3H). LCMS: (Method A) 311.2 (M+H), Rt. 2.511 min, 98.68% (Max).

[0525] HPLC: (Method A) Rt. 2.52 min, 99.82% (Max).

Example 54: N-(4-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)pyrimidin-2-yl)acetamide

[0526] ##STR00314##

[0527] To a stirred solution of Example 46 (0.35 g, 1.0 mmol) in dry DCM (3.5 mL), pyridine (0.2 mL, 2.1 mmol), acetic anhydride (0.12 mL, 1.3 mmol) and DMAP (0.006 g, 0.5 mmol) were added at rt. The resulting mixture was stirred for 5 h at rt and overnight at 50° C. It was diluted with ethyl acetate (100 mL) and washed with HCl (1.5N), water, brine, dried over Na.sub.2SO.sub.4 and concentrated under vacuum. The resulting crude product was purified by MD Autoprep (Method C) to afford the title compound (off white solid). .sup.1H NMR (400 MHz, MeOH-d.sub.4): δ 7.99 (s, 1H), 6.88 (s, 1H), 6.77 (s, 2H), 6.54 (br. s, 1H), 5.93 (s, 2H), 3.71 (s, 4H), 3.40 (q, J=6.8 Hz, 1H), 2.61-2.57 (m, 2H), 2.51-2.47 (m, 2H), 2.24 (s, 3H), 1.38 (d, J=6.8 Hz, 3H). LCMS: (Method A) 370.2 (M+H), Rt. 1.88 min, 95.01% (Max). HPLC: (Method A) Rt. 1.83 min, 98.7% (Max).

Example 55: 1-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)-4-(5-nitropyridin-2-yl)piperazine

[0528] ##STR00315##

[0529] To a stirred solution of Intermediate 2 (0.2 g, 2.1 mmol), Et.sub.3N (1.2 mL, 8.5 mmol) in dry DMF (5 mL), 2-chloro-5-nitropyridine (0.44 g, 2.8 mmol) was added at rt. The resulting mixture was stirred at 120° C. for 20 h. The completion of the reaction was monitored by TLC. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (25 mL). The organic layer was dried over anhydrous Na.sub.2SO.sub.4 and concentrated under vacuum. The resulting crude product was purified by flash chromatography to afford the title compound (yellow solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.93 (d, J=2.8 Hz, 1H), 8.19 (dd, J=9.6, 2.8 Hz, 1H), 6.91-6.89 (m, 2H), 6.85 (d, J=8.0 Hz, 1H), 6.76 (d, J=8.0 Hz, 1H), 5.99 (br s, 2H), 3.73 (s, 4H), 3.40 (q, J=6.4 Hz, 1H), 2.41-2.38 (m, 4H), 1.29 (d, J=6.4 Hz, 3H). LCMS: (Method A) 357.0 (M+H), Rt. 2.98 min, 96.03% (Max). HPLC: (Method A) Rt. 3.03 min, 95.35% (Max).

Example 56: (R)-2-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-N-methylthiazole-4-carboxamide or (S)-2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-N-methylthiazole-4-carboxamide

[0530] ##STR00316##

[0531] The two enantiomers of Example 30 were separated by chiral preparative HPLC (Method PG). The first eluting compound has a Rt. 15.74 min (white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.99 (q, J=4.8 Hz, 1H), 7.34 (s, 1H), 6.90 (d, J=1.2 Hz, 1H), 6.85 (d, J=8.0 Hz, 1H), 6.76 (dd, J=8.0, 1.2 Hz, 1H), 5.99 (s, 2H), 3.50-3.42 (m, 5H), 2.72 (d, J=4.8 Hz, 3H), 2.50-2.49 (m, 4H), 1.29 (d, J=6.8 Hz, 3H). LCMS: (Method A) 375 (M+H), Rt. 2.35 min, 98.15% (Max). HPLC: (Method A) Rt. 2.38 min, 97.08% (Max), 96.58% (254 nm). Chiral HPLC: (Method E) Rt. 15.74 min, 100.00%. Example 56 corresponds to the second eluting compound, with Rt. 28.85 min (white solid). .sup.1HNMR (400 MHz, DMSO-d.sub.6): δ 7.99 (q, J=4.8 Hz, 1H), 7.34 (s, 1H), 6.90 (d, J=1.2 Hz, 1H), 6.85 (d, J=7.6 Hz, 1H), 6.76 (dd, J=8.0, 1.2 Hz, 1H), 5.99 (s, 2H), 3.50-3.41 (m, 5H), 2.72 (d, J=4.8 Hz, 3H), 2.50-2.43 (m, 4H), 1.29 (d, J=6.8 Hz, 3H). LCMS: (Method A) 375.0 (M+H), Rt. 2.34 min, 99.94% (Max). HPLC: (Method A) Rt. 2.37 min, 99.77% (Max). Chiral HPLC: (Method E) Rt. 28.85 min, 100.00%

Example 57: (R)-2-(4-(1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)piperazin-1-yl)-N-methylthiazole-4-carboxamide or (S)-2-(4-(1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)piperazin-1-yl)-N-methylthiazole-4-carboxamide

[0532] ##STR00317##

[0533] The two enantiomers of Example 50 were separated by chiral preparative HPLC (Method PG). The first eluting compound has a Rt. 16.29 min (yellow solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.98 (q, J=4.4 Hz, 1H), 7.34 (s, 1H), 6.81-6.74 (m, 3H), 4.22 (s, 4H), 3.42-3.39 (m, 5H), 2.73 (d, J=4.8 Hz, 3H), 2.48-2.41 (m, 4H), 1.27 (t, J=6.4 Hz, 3H). LCMS: (Method A). 389.0 (M+H), Rt. 2.40 min, 99.14% (Max). HPLC: (Method A) Rt. 2.36 min, 99.63% (Max). Chiral HPLC: (Method E) Rt, 16.29 min, 100% (max). Example 57 corresponds to the second eluting compound, with Rt. 33.49 min (yellow solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.98 (d, J=4.4 Hz, 1H), 7.34 (s, 1H), 6.81-6.74 (m, 3H), 4.21 (s, 4H), 3.42-3.37 (m, 5H), 2.73 (d, J=4.8 Hz, 3H), 2.46-2.41 (m, 4H), 1.26 (t, J=6.4 Hz, 3H). LCMS: (Method A). 389.0 (M+H), Rt. 2.34 min, 98.58% (Max). HPLC: (Method A) Rt. 2.37 min, 99.28% (Max). Chiral HPLC: (Method E) Rt. 33.49 min, 99.66% (max).

Example 58: 6-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)pyridin-3-amine

[0534] ##STR00318##

[0535] To a stirred solution of Example 55 (0.20 g, 5.6 mmol) in methanol (4.0 mL), Pd/C (0.02 g, 10% w/w) was added at rt and the mixture was stirred overnight under hydrogen atmosphere (5 Kg/cm.sup.2) at rt. The reaction mixture was filtered through celite and washed with methanol (10 mL). The organic layer was dried over anhydrous Na.sub.2SO.sub.4 and concentrated under vacuum. The resulted crude product was purified by MD Autoprep (Method C) to afford the title compound (dark oil). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.57 (d, J=2.8 Hz, 1H), 6.90-6.88 (m, 2H), 6.84 (d, J=8.0 Hz, 1H), 6.76 (d, J=8.0 Hz, 1H), 6.57 (d, J=8.8 Hz, 1H), 5.98 (m, 2H), 4.55 (s, 2H), 3.33 (br m, 1H), 3.18 (s, 4H), 2.38-2.36 (m, 4H), 1.27 (d, J=6.4 Hz, 3H). LCMS: (Method A) 327.2 (M+H), Rt. 1.85 min, 98.76% (Max). HPLC: (Method A) Rt. 1.81 min, 99.66% (Max).

Example 59 and Example 60: (R)-2-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-N-ethylthiazole-5-carboxamide and (S)-2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-N-ethylthiazole-5-carboxamide

[0536] ##STR00319##

Step 1: Lithium 2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)thiazole-5-carboxylate

[0537] To a stirred solution of Example 27 (1.8 g, 3.86 mmol) in THF (14 mL) MeOH (4 mL) and H.sub.2O (2 mL) was added LiOH.H.sub.2O (395 mg, 9.65 mmol). The reaction mixture was stirred at 50° C. for 3 h. The completion of the reaction was monitored by TLC. The reaction mixture was concentrated under vacuum. The resulting crude product was suspended in toluene and the solvents were evaporated again. It was used in the next step without any further purification. Yield: 89% (1.5 g, off white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.73 (s, 1H), 6.88-6.82 (m, 2H), 6.75-6.73 (m, 1H), 5.97 (s, 2H), 3.67-3.32 (m, 5H), 2.87-2.59 (m, 4H), 1.32-1.15 (m, 3H). LCMS: (Method A) 362.0 (M+H), Rt. 2.26 min, 88.6% (Max).

Step 2: (R)-2-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-N-ethylthiazole-5-carboxamide and (S)-2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-N-ethylthiazole-5-carboxamide

[0538] To a stirred solution of lithium 2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)thiazole-5-carboxylate (500 mg, 1.33 mmol) in DMF (10 mL), DIPEA (0.7 mL, 3.99 mmol), ethyl amine (2 M in THF, 1 mL, 2.00 mmol) and HATU (607 mg, 1.60 mmol) were added at 0° C. The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under vacuum and diluted with DCM. It was washed with water, brine and dried over anhydrous Na.sub.2SO.sub.4. The crude product was purified by flash chromatography. Both enantiomers were separated by chiral preparative HPLC (Method PF). Example 59 corresponds to the first eluting compound with a Rt. 17.99 min (white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.19 (t, J=5.6 Hz, 1H), 7.74 (s, 1H), 6.90 (s, 1H), 6.85 (d, J=8.0 Hz, 1H), 6.76 (d, J=6.4 Hz, 1H), 5.99 (s, 2H), 3.21-3.17 (m, 2H), 2.48-2.39 (m, 4H), 1.28 (d, J=6.4 Hz, 3H), 1.07 (t, J=7.2 Hz, 3H). LCMS: (Method A) 389.2 (M+H), Rt. 2.47 min, 97.4% (Max). HPLC: (Method A) Rg. 2.43 min, 99.9% (Max). Chiral HPLC: (Method D) Rt. 17.99 min, 100.00%. Example 60 corresponds to the second eluting compound with a Rt. 19.92 min (white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.19 (t, J=5.6 Hz, 1H), 7.74 (s, 1H), 6.90 (s, 1H), 6.85 (d, J=8.0 Hz, 1H), 6.76 (d, J=6.8 Hz, 1H), 5.99 (s, 2H), 3.21-3.17 (m, 2H), 2.48-2.33 (m, 4H), 1.28 (d, J=6.8 Hz, 3H), 1.07 (t, J=7.2 Hz, 3H). LCMS: (Method A) 389.0 (M+H), Rt. 2.46 min, 99.3% (Max). HPLC: (Method A) Rt. 2.43 min, 99.9% (Max). Chiral HPLC: (Method D) Rt. 19.92 min, 100.00%.

Example 61: (R)-2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-N,N-dimethylthiazole-5-carboxamide or (S)-2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-N,N-dimethylthiazole-5-carboxamide

[0539] ##STR00320##

[0540] The two enantiomers of Example 47 were separated by chiral preparative HPLC (Method PF). The first eluting compound has a Rt. 14.07 min (white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.58 (s, 1H), 6.90 (s, 1H), 6.85 (s, 1H), 6.76 (s, 1H), 5.99 (s, 2H), 3.44-3.42 (m, 5H), 3.07 (br m, 6H), 2.47-2.39 (m, 4H), 1.28 (d, J=6.8 Hz, 3H). LCMS: (Method A) 389.0 (M+H), Rt. 2.39 min, 99.5% (Max). HPLC: (Method A) Rt. 2.37 min, 99.6% (Max). Chiral HPLC: (Method D) Rt. 14.07 min, 100.00%. Example 61 corresponds to the second eluting compound with Rt. 16.06 min (white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.58 (s, 1H), 6.90 (s, 1H), 6.85 (s, 1H), 6.76 (s, 1H), 5.99 (s, 2H), 3.44-3.42 (m, 5H), 3.07 (br m, 6H), 2.50-2.39 (m, 4H), 1.28 (d, J=6.4 Hz, 3H). LCMS: (Method A) 389.2 (M+H), Rt. 2.44 min, 95.3% (Max). HPLC: (Method A) Rt. 2.37 min, 99.9% (Max). Chiral HPLC: (Method D) Rt. 16.06 min, 99.7%.

Example 62: (S)-2-(4-(1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)piperazin-1-yl)-N-ethylthiazole-5-carboxamide or (R)-2-(4-(1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)piperazin-1-yl)-N-ethylthiazole-5-carboxamide

[0541] ##STR00321##

Step 1: Ethyl 2-(4-(1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)piperazin-1-yl)thiazole-5-carboxylate

[0542] To a stirred solution of Intermediate 4 (3.4 g, 11.94 mmol) in dry DMF (50 mL), ethyl 2-bromothiazole-5-carboxylate (Example 27, Step 1, 2.8 g, 11.94 mmol) and TEA (5.0 mL, 35.82 mmol) were added at 0° C. The resulting mixture was stirred at 120° C. overnight. It was cooled to rt, diluted with EtOAc, washed with water, brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under vacuum. The resulting crude product was purified by flash chromatography to afford the title compound. Yield: 64% (3.1 g, pale brown solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.81 (s, 1H), 6.79-6.74 (m, 3H), 4.19-4.14 (m, 7H), 3.48-3.32 (m, 4H), 2.42-2.36 (m, 4H), 1.26-1.19 (m, 6H). LCMS: (Method A) 404.0 (M+H), Rt. 3.19 min, 96.5% (Max).

Step 2: Lithium 2-(4-(1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)piperazin-1-yl)thiazole-5-carboxylate

[0543] The title compound was synthesized according to the protocol described for Example 60, Step 1, using ethyl 2-(4-(1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)piperazin-1-yl)thiazole-5-carboxylate as starting material. The resulting product was used in the next step without further purification. Yield: 86% (2.5 g, off white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.16 (s, 1H), 6.79-6.72 (m, 3H), 4.20 (s, 4H), 3.34-3.29 (m, 5H), 2.44-2.28 (m, 4H), 1.24 (d, J=8.8 Hz, 3H). LCMS: (Method A) 376.0 (M+H), Rt. 2.34 min, 97.4% (Max).

Step 3: (S)-2-(4-(1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)piperazin-1-yl)-N-ethylthiazole-5-carboxamide or (R)-2-(4-(1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)piperazin-1-yl)-N-ethylthiazole-5-carboxamide

[0544] The title compound was synthesized according to the protocol described for Example 60, Step 2, using lithium 2-(4-(1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)piperazin-1-yl)thiazole-5-carboxylate as starting material. The crude mixture was purified by flash chromatography followed by chiral preparative HPLC (Method PE) to separate both enantiomers. The first fraction was concentrated to give Example 62 (Rt. 19.00 min) (white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.19 (t, J=5.2 Hz, 1H), 7.74 (s, 1H), 6.81-6.74 (m, 3H), 4.22 (s, 4H), 3.42-3.35 (m, 5H), 3.22-3.16 (m, 2H), 2.50-2.33 (m, 4H), 1.27 (d, J=6.8 Hz, 3H), 1.07 (t, J=7.2 Hz, 3H). LCMS: (Method A) 403.0 (M+H), Rt. 2.50 min, 98.4% (Max). HPLC: (Method A) Rt. 2.47 min, 98.2% (Max). Chiral HPLC: (Method A) Rt. 19.00 min, 100%. The second enantiomer had a Rt. 29.37 min (white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.19 (t, J=5.6 Hz, 1H), 7.74 (s, 1H), 6.81-6.74 (m, 3H), 4.22 (s, 4H), 3.42-3.37 (m, 5H), 3.22-3.17 (m, 2H), 2.50-2.41 (m, 4H), 1.27 (d, J=6.4 Hz, 3H), 1.07 (t, J=7.2 Hz, 3H). LCMS: (Method A) 403.2 (M+H), Rt. 2.51 min, 99.6% (Max). HPLC: (Method A) Rt. 2.47 min, 98.9% (Max).

[0545] Chiral HPLC: (Method A) Rt. 29.37 min, 100%.

Example 63 and Example 64: (R)-2-(4-(1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)piperazin-1-yl)-N,N-dimethylthiazole-5-carboxamide and (S)-2-(4-(1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)piperazin-1-yl)-N,N-dimethylthiazole-5-carboxamide

[0546] ##STR00322##

[0547] The title compounds were synthesized according to the protocol described for Example 59 and Example 60, Step 2, using lithium 2-(4-(1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)piperazin-1-yl)thiazole-5-carboxylate (Example 62, Step 2) and dimethyl amine as starting material. The crude mixture was purified by flash chromatography. Both enantiomers were separated by chiral preparative HPLC (Method PF). The first fraction corresponds to Example 63 (Rt. 17.78 min) (white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.58 (s, 1H), 6.81-6.75 (m, 3H), 4.22 (s, 4H), 3.44-3.38 (m, 5H), 3.06 (br. s, 6H), 2.47-2.39 (m, 4H), 1.27 (d, J=6.8 Hz, 3H). LCMS: (Method A) 403.0 (M+H), Rt. 2.42 min, 99.3% (Max). HPLC: (Method A) Rt. 2.41 min, 99.6% (Max). Chiral HPLC: (Method D) Rt. 17.78 min, 100.00%. The second fraction corresponds to Example 64 (Rt. 21.09 min) (white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.58 (s, 1H), 6.81-6.77 (m, 3H), 4.22 (s, 4H), 3.44-3.38 (m, 5H), 3.12-2.99 (m, 6H), 2.46-2.39 (m, 4H), 1.27 (d, J=6.40 Hz, 3H). LCMS: (Method A) 403.0 (M+H), Rt. 2.43 min, 99.8% (Max). HPLC: (Method A) Rt. 2.40 min, 99.8% (Max). Chiral HPLC: (Method D) Rt. 21.09 min, 97.38%.

Example 65 and Example 66: (R)-2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-N-methylthiazole-5-carboxamide and (S)-2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-N-methylthiazole-5-carboxamide

[0548] ##STR00323##

[0549] The title compounds were synthesized according to the procedure described for Example 59 and Example 60 using methyl amine (2M in THF) as reagent. The crude mixture was purified by flash chromatography followed by chiral preparative HPLC (Method PF) to separate enantiomers. The first fraction was concentrated to give Example 65 (white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.16 (d, J=4.4 Hz, 1H), 7.72 (s, 1H), 6.89 (s, 1H), 6.85 (d, J=7.6 Hz, 1H), 6.76 (d, J=8.0 Hz, 1H), 5.99 (br s, 2H), 3.43-3.42 (m, 5H), 2.69 (d, J=4.4 Hz, 3H), 2.47-2.33 (m, 4H), 1.28 (d, J=6.4 Hz, 3H). LCMS: (Method A) 375.0 (M+H), Rt. 2.23 min, 99.0% (Max). HPLC: (Method A) Rt. 2.19 min, 99.6% (Max). Chiral HPLC: (Method D) Rt. 15.48 min, 98.91%.

[0550] The second fraction was concentrated to give Example 66 (white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.16 (q, J=4.8 Hz, 1H), 7.72 (s, 1H), 6.90 (s, 1H), 6.85 (d, J=8.0 Hz, 1H), 6.76 (d, J=8.0 Hz, 1H), 5.99 (br s, 2H), 3.43-3.41 (m, 5H), 2.69 (d, J=4.8 Hz, 3H), 2.48-2.39 (m, 4H), 1.28 (d, J=6.8 Hz, 3H). LCMS: (Method A) 375.0 (M+H), Rt. 2.23 min, 97.4% (Max). HPLC: (Method A) Rt. 2.19 min, 96.9% (Max). Chiral HPLC: (Method D) Rt. 18.44 min, 100.00%

Example 67: (2-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)thiazol-5-yl)(morpholino)methanone

[0551] ##STR00324##

[0552] The title compound was synthesized according to the procedure described for Example 59 and Example 60 using morpholine as reagent. Both enantiomers were not separated in this example (pale brown solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.55 (s, 1H), 6.90 (s, 1H), 6.85 (d, J=8.0 Hz, 1H), 6.76 (d, J=7.6 Hz, 1H), 5.99 (s, 2H), 3.61 (br m, 8H), 3.45-3.42 (m, 5H), 2.47-2.40 (m, 4H), 1.29 (d, J=6.4 Hz, 3H). LCMS: (Method A) 431.0 (M+H), Rt. 2.41 min, 98.6% (Max). HPLC: (Method A) Rt. 2.38 min, 97.1% (Max).

Example 68 and Example 69: (R)—N-(5-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-1,3,4-thiadiazol-2-yl)acetamide and (S)—N-(5-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-1,3,4-thiadiazol-2-yl)acetamide

[0553] ##STR00325##

[0554] To a stirred solution of Example 41 (0.6 g, 1.8 mmol) in dry DCM (10 mL), acetic anhydride (0.22 mL, 2.3 mmol) and DIPEA (0.615 mL, 3.6 mmol) were added at 0° C. and the reaction mixture was stirred at room temperature for 4 h. It was concentrated under vacuum and the crude product was purified by recrystallization followed by enantiomer separation by SFC. The first fraction was collected as Example 68 (off white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 11.66 (br s, 1H), 6.89 (s, 1H), 6.85 (d, J=8.0 Hz, 1H), 6.76 (d, J=8.0 Hz, 1H), 5.99 (m, 2H), 3.42-3.34 (m, 5H), 2.51-2.50 (m, 2H), 2.43-2.33 (m, 2H), 2.09 (s, 3H), 1.27 (d, J=6.4 Hz, 3H). LCMS: (Method A) 376.0 (M+H), Rt. 2.27 min, 97.4% (Max). HPLC: (Method A) Rt. 2.29 min, 98.2% (Max). HPLC chiral purity: (Method D) Rt. 24.02 min, 99.3% (Max). The second fraction was collected as Example 69 (off white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 11.66 (br s, 1H), 6.89 (s, 1H), 6.85 (d, J=8.0 Hz, 1H), 6.76 (dd, J=8.0, 1.2 Hz, 1H), 5.99 (m, 2H), 3.41-3.34 (m, 5H), 2.55-2.47 (m, 2H), 2.43-2.39 (m, 2H), 2.09 (s, 3H), 1.27 (d, J=6.4 Hz, 3H). LCMS: (Method A) 376.0 (M+H), Rt. 2.28 min, 95.8% (Max). HPLC: (Method A) Rt. 2.29 min, 97.1% (Max). HPLC chiral purity: (Method D) Rt. 26.57 min, 97.5% (Max).

Example 70: 2-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)pyrimidin-5-amine

[0555] ##STR00326##

Step 1: 2-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-4-nitropyrimidine

[0556] To a stirred solution of Intermediate 2 (1 g, 4.2 mmol) in dry DMF (10 mL), Et.sub.3N (2.3 mL, 16.8 mmol) and 2-chloro-5-nitropyrimidine (0.74 g, 4.6 mmol) were added at rt and the resulting mixture was stirred at 120° C. for 20 h. It was diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous Na.sub.2SO.sub.4 and concentrated under vacuum. The resulting crude product was purified by flash chromatography to give the title compound (yellow solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.08 (s, 2H), 6.92 (s, 1H), 6.85-6.83 (m, 1H), 6.77 (s, 1H), 5.98 (m, 2H), 3.89 (s, 4H), 3.50 (s, 1H), 2.45-2.44 (m, 4H), 1.30 (br s, 3H). LCMS: (Method A) 358.0 (M+H), Rt. 3.00 min, 94.23% (Max).

Step 2: 2-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)pyrimidin-5-amine

[0557] To a stirred solution of 2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-4-nitropyrimidine (0.70 g, 1.9 mmol) in methanol (14 mL), Pd/C (0.07 g, 10% w/w) was added at rt and the resulting mixture was stirred under hydrogen atmosphere (5 kg/cm.sup.2) overnight at rt. The reaction mixture was filtered through celite and washed with methanol. The filtrate was dried over anhydrous Na.sub.2SO.sub.4 and concentrated under vacuum. The crude product was purified by flash chromatography to afford the title compound (yellow solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.86 (s, 2H), 6.88 (s, 1H), 6.84 (d, J=8.0 Hz, 1H), 6.75 (d, J=7.6 Hz, 1H), 6.46 (s, 2H), 5.98 (m, 2H), 3.48-3.45 (m, 4H), 2.43-2.42 (m, 2H), 2.34-2.31 (m, 2H), 1.27 (d, J=6.8 Hz, 3H). LCMS: (Method A) 328.2 (M+H), Rt. 1.91 min, 96.83% (Max). HPLC: (Method A) Rt. 1.88 min, 95.85% (Max).

Example 71: (R)-2-(4-(1-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)piperazin-1-yl)-N-(2-(dimethylamino)ethyl)-N-methylthiazole-5-carboxamide or (S)-2-(4-(1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)piperazin-1-yl)-N-(2-(dimethylamino)ethyl)-N-methylthiazole-5-carboxamide

[0558] ##STR00327##

[0559] The title compound was synthesized according to the procedure described for Example 62, using N,N,N trimethyl ethylene diamine as reagent. The crude product was purified by flash chromatography, followed by chiral preparative HPLC using (Method PF) to separate both enantiomers. The first eluting compound had Rt. 14.56 min (pale brown oil). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.57 (s, 1H), 6.80-6.73 (m, 3H), 4.21 (s, 4H), 3.52 (t, J=6.4 Hz, 2H), 3.50-3.38 (m, 5H), 3.16-3.11 (m, 3H), 2.56-2.50 (m, 1H), 2.49-2.38 (m, 5H), 2.32-2.10 (m, 6H), 1.26 (d, J=6.8 Hz, 3H). LCMS: (Method A) 460.2 (M+H), Rt. 2.12 min, 95.2% (Max). HPLC: (Method A) Rt. 2.02 min, 96.9% (Max). Chiral HPLC: (Method D) Rt. 14.56 min, 97.43%. The second eluting compound corresponds to Example 71 (Rt. 16.81 min) (pale brown oil). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.56 (s, 1H), 6.80-6.73 (m, 3H), 4.21 (s, 4H), 3.50 (t, J=6.8 Hz, 2H), 3.48-3.36 (m, 5H), 3.09 (br. s, 3H), 2.55-2.50 (m, 1H), 2.49-2.38 (m, 5H), 2.13 (s, 6H), 1.26 (d, J=6.8 Hz, 3H). LCMS: (Method A) 460.2 (M+H), Rt. 2.13 min, 95.4% (Max). HPLC: (Method A) Rt. 2.03 min, 97.5% (Max). Chiral HPLC: (Method D) Rt. 16.81 min, 98.36%.

Example 72: N-(2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)pyrimidin-5-yl)acetamide

[0560] ##STR00328##

[0561] To a stirred solution of Example 70 (180 mg, 0.54 mmol) in dry pyridine (1.35 mL), acetic anhydride (0.06 mL, 0.65 mmol) was added at room temperature and the resulting mixture was stirred at 50° C. overnight. It was diluted with ethyl acetate (100 mL) and washed with HCl (1.5 N), water, brine and dried over Na.sub.2SO.sub.4. After evaporation of the solvents, the crude product was purified by flash chromatography to afford the title compound (yellow solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.82 (s, 1H), 8.46 (d, J=0.4 Hz, 2H), 6.89 (s, 1H), 6.84 (d, J=7.6 Hz, 1H), 6.76 (d, J=7.6 Hz, 1H), 5.98 (m, 2H), 3.64-3.62 (m, 4H), 3.36-3.34 (m, 1H), 2.45-2.32 (m, 4H), 2.00 (s, 3H), 1.25 (d, J=6.8 Hz, 3H). LCMS: (Method A) 370.2 (M+H), Rt. 2.30 min, 94.42% (Max). HPLC: (Method A) Rt. 2.22 min, 95.29% (Max).

Example 73: (2-(4-(1-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)piperazin-1-yl)thiazol-5-yl)(4-hydroxypiperidin-1-yl)methanone

[0562] ##STR00329##

Step 1: 1-(2-(4-(1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)piperazin-1-yl)thiazole-5-carbonyl)piperidin-4-one

[0563] The title compound was synthesized according to the same procedure as described for Example 62 using piperidine-4-one, hydrochloride, mono hydrate as starting material (off white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.61 (s, 1H), 6.81-6.77 (m, 3H), 4.22 (s, 4H), 3.89 (t, J=6.1 Hz, 4H), 3.71 (t, J=6.1 Hz, 1H), 3.60 (t, J=4.2 Hz, 4H), 2.34-2.33 (m, 8H), 1.27 (d, J=6.7 Hz, 3H). LCMS: (Method A) 457.0 (M+H), Rt. 2.42 min, 90.5% (Max).

Step 2: (2-(4-(1-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)piperazin-1-yl)thiazol-5-yl)(4-hydroxypiperidin-1-yl)methanone

[0564] To a stirred solution of 1-(2-(4-(1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)piperazin-1-yl)thiazole-5-carbonyl)piperidin-4-one (480 mg, 1.0 mmol) in dry MeOH (100 mL), NaBH.sub.4 (59 mg, 1.5 mmol) was added slowly at 0° C. The reaction mixture was stirred at room temperature for 2 h. It was then concentrated under vacuum and the resulting crude product was dissolved in DCM, washed with water, brine and dried over anhydrous Na.sub.2SO.sub.4. The solvent was removed under reduced pressure to get the title compound. Yield: 69% (325 mg, off white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.48 (s, 1H), 6.80-6.73 (m, 3H), 4.78 (br. s, 1H), 4.21 (s, 4H), 3.92-3.88 (m, 2H), 3.72 (br s, 1H), 3.42-3.35 (m, 4H), 3.33-3.25 (m, 2H), 2.46-2.38 (m, 4H), 1.75-1.74 (m, 2H), 1.34-1.31 (m, 2H), 1.25 (d, J=6.8 Hz, 3H). LCMS: (Method A) 459.0 (M+H), Rt. 2.32 min, 95.8% (Max). HPLC: (Method A) Rt. 2.33 min, 97.7% (Max).

Example 74 and Example 75: (R)-(2-(4-(1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)piperazin-1-yl)thiazol-5-yl)(4-methylpiperazin-1-yl)methanone and (S)-(2-(4-(1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)piperazin-1-yl)thiazol-5-yl)(4-methylpiperazin-1-yl)methanone

[0565] ##STR00330##

[0566] The title compounds were synthesized according to the same procedure as described for Example 62, using N-methyl piperazine as starting material. The crude mixture was purified by column chromatography followed by chiral preparative HPLC using (Method PF) to separate both enantiomers. The first eluting fraction was concentrated to give Example 74 (off white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.52 (s, 1H), 6.81-6.77 (m, 3H), 4.22 (s, 4H), 3.60 (br. s, 4H), 3.43-3.38 (m, 5H), 2.45-2.33 (m, 8H), 2.19 (s, 3H), 1.27 (d, J=6.4 Hz, 3H). LCMS: (Method A) 458.2 (M+H), Rt. 2.02 min, 99.2% (Max). HPLC: (Method A) Rt. 2.01 min, 99.7% (Max). Chiral HPLC: (Method D) Rt. 14.95 min, 98.36%. The second eluting fraction was concentrated to give Example 75 (pale brown oil). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.52 (s, 1H), 6.81-6.74 (m, 3H), 4.22 (s, 4H), 3.60-3.59 (m, 4H), 3.43-3.37 (m, 5H), 2.50-2.31 (m, 8H), 2.19 (s, 3H), 1.27 (d, J=6.4 Hz, 3H). LCMS: (Method A) 458.2 (M+H), Rt. 2.02 min, 98.3% (Max). HPLC: (Method A) Rt. 2.01 min, 99.2% (Max). Chiral HPLC: (Method D) Rt. 17.10 min, 97.39%.

Example 76: N-(5-(4-(1-(3,4-difluorophenyl)ethyl)piperazin-1-yl)-1,3,4-thiadiazol-2-yl)acetamide

[0567] ##STR00331##

Step 1: 1-(3,4-Difluorophenyl)ethan-1-ol

[0568] To a stirred solution of 1-(3,4-difluorophenyl)ethan-1-one (2.0 g, 12.81 mmol, Combi Blocks) in dry MeOH (40.0 mL), sodium borohydride (0.58 g, 15.32 mmol, Loba chemie) was added portion wise at 0° C. The reaction mixture was stirred at rt for 4 h. The reaction mixture was concentrated. The residue was dissolved in DCM, washed with water, brine solution, dried over anhydrous sodium sulfate and concentrated to afford the title compound. Yield: 98% (2.0 g, colorless liquid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.38-7.29 (m, 2H), 7.17-7.13 (m, 1H), 5.31 (d, J=5.9 Hz, 3H), 4.68 (q, J=8.3 Hz, 1H), 1.27 (d, J=8.3 Hz, 3H).

Step 2: 4-(1-chloroethyl)-1,2-difluorobenzene

[0569] To a stirred solution of 1-(3,4-difluorophenyl)ethan-1-ol (2.0 g, 12.64 mmol) in dry DCM (100.0 mL), thionyl chloride (1.9 mL, 34.81 mmol, Spectrochem) was added slowly at 0° C. The reaction mixture was stirred at rt for 1 h. The completion of the reaction was monitored by TLC. The reaction mixture was concentrated and resulting crude product was taken as such for next step. Yield: 90% (2.0 g, colorless liquid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.64-7.58 (m, 1H), 7.48-7.41 (m, 1H), 7.37-7.34 (m, 1H), 5.36 (q, J=6.6 Hz, 1H), 1.78 (d, J=6.6 Hz, 3H).

Step 3: N-(5-(4-(1-(3,4-difluorophenyl)ethyl)piperazin-1-yl)-1,3,4-thiadiazol-2-yl)acetamide

[0570] The title compound was synthesized by using general procedure D, using 4-(1-chloroethyl)-1,2-difluorobenzene and Intermediate 7 as starting materials. The crude product was purified by flash chromatography (off white solid).). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 12.02 (s, 1H), 7.42-7.35 (m, 2H), 7.18-7.16 (m, 1H), 3.53 (q, J=6.4 Hz, 1H), 3.36-3.34 (m, 4H), 2.51-2.40 (m, 4H), 2.09 (s, 3H), 1.30 (d, J=6.4 Hz, 3H). LCMS: (Method A) 368.0 (M+H), Rt. 2.48 min, 97.02% (Max). HPLC: (Method A) Rt. 2.51 min, 98.31% (Max).

Example 77 and Example 78: (R)—N-(2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)pyrimidin-5-yl)acetamide and (S)—N-(2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)pyrimidin-5-yl)acetamide

[0571] ##STR00332##

[0572] Example 72 was submitted to chiral preparative HPLC (Method PD). The first eluting fraction was concentrated, affording Example 77 (pale yellow solid). .sup.1H NMR (400 MHz, DMSO-d6): δ 9.81 (s, 1H), 8.46 (s, 2H), 6.89 (s, 1H), 6.84 (d, J=8.0 Hz, 1H), 6.76 (d, J=8.0 Hz, 1H), 5.98 (m, 2H), 3.63 (t, J=4.8 Hz, 4H), 3.31 (s, 1H), 2.44-2.33 (m, 4H), 2.00 (s, 3H), 1.26 (d, J=6.0 Hz, 3H). LCMS: (Method A) 370.2 (M+H), Rt. 2.33 min, 99.5% (Max). HPLC: (Method A) Rt. 2.24 min, 99.7% (Max). Chiral HPLC: (Method F) Rt. 31.24 min, 99.05%. The second eluting fraction was concentrated, affording Example 78 (pale yellow solid). 1H NMR (400 MHz, DMSO-d.sub.6: δ 9.81 (s, 1H), 8.46 (s, 2H), 6.89 (s, 1H), 6.84 (d, J=8.0 Hz, 1H), 6.76 (d, J=8.0 Hz, 1H), 5.98 (m, 2H), 3.63 (t, J=4.8 Hz, 4H), 3.31 (s, 1H), 2.41-2.32 (m, 4H), 2.00 (s, 3H), 1.26 (d, J=6.0 Hz, 3H). LCMS: (Method A) 370.2 (M+H), Rt. 2.31 min, 99.5% (Max). HPLC: (Method A) Rt. 2.25 min, 99.8% (Max). Chiral HPLC: (Method F) Rt. 21.26 min, 100.00%.

Example 79: 4-((2-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)thiazol-5-yl)methyl)morpholine

[0573] ##STR00333##

Step 1: (2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)thiazol-5-yl)methanol

[0574] To a stirred solution of Example 27 (6.0 g, 16.4 mmol) in dry THF (70 mL), Super hydride (65 mL, 65.0 mmol) was added slowly at 0° C. The reaction mixture was stirred at rt for 2 h. The reaction mixture was quenched with saturated NH.sub.4Cl and extracted with ethyl acetate. The organic layer was separated, dried over anhydrous Na.sub.2SO.sub.4, concentrated under vacuum. The crude product was purified by silica gel column chromatography (10% MeOH in DCM) to afford the title compound (white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 6.93 (s, 1H), 6.87-6.84 (d, J=12.8 Hz, 1H), 6.81-6.75 (m, 1H), 6.74-6.72 (d, J=8.8 Hz, 1H), 5.96-5.96 (d, J=1.2 Hz, 2H), 5.18-5.16 (d, J=7.8 Hz, 1H), 3.41-3.28 (m, 3H), 2.52-2.37 (m, 8H), 2.25 (s, 1H). LCMS: (Method A) 348.0 (M+H), Rt. 1.95 min, 97.02% (Max).

Step 2: 2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-5-(chloromethyl)thiazole

[0575] To a stirred solution of (2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)thiazol-5-yl)methanol (4.0 g, 11.5 mmol) in DCM (50 mL), SOCl.sub.2 (1.6 mL, 23.0 mmol) was added slowly at 0° C. and the resulting mixture was stirred at rt for 1 h. It was concentrated under vacuum. The resulting crude product was taken for next step reaction without further purification. Yield: 96% (4.8 g, Yellow solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 11.69 (s, 1H), 7.36-7.33 (m, 1H), 7.13-6.98 (m, 2H), 6.07 (s, 2H), 4.46 (d, J=12.8 Hz, 2H), 4.04-3.69 (m, 4H), 3.54-3.27 (m, 1H), 3.12-292 (m, 3H), 1.69 (d, J=6.0 Hz, 3H). LCMS: (Method A) 363 (M+H), Rt. 2.49 min, 86.01% (Max).

Step 3: 4-((2-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)thiazol-5-yl)methyl)morpholine

[0576] To a stirred solution of 2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-5-(chloromethyl)thiazole (0.8 g, 2.0 mmol) in dry ACN (20 mL), DIPEA (1.8 mL, 8.0 mmol) and morpholine (0.22 mL, 2.4 mmol) were added and the reaction mixture was stirred at rt overnight. The reaction mixture was diluted with EtOAc and washed with water. It was dried over anhydrous Na.sub.2SO.sub.4 and concentrated under vacuum. The crude product was purified by flash chromatography (10% MeOH in DCM) to afford the title compound (pale yellow solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 6.95 (s, 1H), 6.88 (s, 1H), 6.84 (d, J=8.0 Hz, 1H), 6.75 (d, J=8.0 Hz, 1H), 5.99 (m, 2H), 3.54-3.53 (m, 4H), 3.48 (s, 2H), 3.39 (q, J=6.8 Hz, 1H), 3.25-3.40 (m, 4H), 2.40-2.33 (m, 4H), 1.28-1.27 (d, J=6.4 Hz, 3H). LCMS: (Method A) 418.0 (M+H), Rt. 1.99 min, 97.82% (Max). HPLC: (Method A) Rt. 1.78 min, 95.19% (Max).

Example 80: N-((2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)thiazol-5-yl)methyl)-N-methylacetamide

[0577] ##STR00334##

Step 1: 1-(2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)thiazol-5-yl)-N-methylmethanamine

[0578] To a stirred solution of 2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-5-(chloromethyl)thiazole (Example 79, Step 3, 1.2 g, 3.1 mmol) in dry ACN (20 mL), DIPEA (2.3 mL, 12.4 mmol) and methyl amine (5.0 mL, 9.3 mmol, 2 M in THF) were added dropwise. The resulting mixture was stirred at rt overnight. It was diluted with water and extracted with ethyl acetate. The organic layer was separated, dried over anhydrous Na.sub.2SO.sub.4, concentrated under vacuum. The crude product was purified by flash chromatography (10% MeOH in DCM) to afford the title compound (yellow solid). LCMS: (Method A) 362.0 (M+H), Rt. 1.96 min, 25.6% (Max).

Step 2: N-((2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)thiazol-5-yl)methy)-N-methylacetamide

[0579] To a stirred solution of 1-(2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)thiazol-5-yl)-N-methylmethanamine (0.1 g, 0.27 mmol), DIPEA (0.3 mL, 0.8 mmol) in dry DCM (10 mL), acetic anhydride (0.3 mL, 0.8 mmol) was added portion wise and the reaction mixture was stirred at rt for 12 h. It was quenched with water (10 mL) and extracted with ethyl acetate (25 mL). The organic layer was dried over anhydrous Na.sub.2SO.sub.4 and concentrated under vacuum. The resulting crude product was purified by flash chromatography (10% MeOH in DCM) to afford the title compound (pale yellow solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.05 (d, J=9.6 Hz, 1H), 6.88 (s, 1H), 6.84 (d, J=8.0 Hz, 1H), 6.75 (d, J=8.0 Hz, 1H), 5.99-5.98 (m, 2H), 4.40 (s, 2H), 3.39 (q, J=6.0 Hz, 1H), 3.33-3.30 (m, 4H), 2.88 (s, 3H), 2.50-2.37 (m, 4H), 1.97 (s, 3H), 1.27 (d, J=6.8 Hz, 3H). LCMS: (Method A) 403.0 (M+H), Rt. 2.19 min, 97.19% (Max). HPLC: (Method A) Rt. 2.14 min, 98.5% (Max).

Example 81: (R)-(2-(4-(1-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)piperazin-1-yl)thiazol-5-yl)(4-hydroxypiperidin-1-yl)methanone or (S)-(2-(4-(1-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)piperazin-1-yl)thiazol-5-yl)(4-hydroxypiperidin-1-yl)methanone

[0580] ##STR00335##

[0581] The two enantiomers of Example 73 were separated by chiral preparative HPLC, (Method PH). The first eluting compound had Rt. 32.84 min (pale brown solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.49 (s, 1H), 6.79-6.77 (m, 3H), 4.78 (br. s, 1H), 4.22 (s, 4H), 3.93-3.90 (m, 2H), 3.73-3.72 (m, 1H), 3.42-3.38 (m, 5H), 3.34-3.28 (m, 2H), 2.50-2.39 (m, 4H), 1.78-1.74 (m, 2H), 1.38-1.26 (m, 5H). LCMS: (Method A) 459.0 (M+H), Rt. 2.32 min, 95.9% (Max). HPLC: (Method A) Rt. 2.21 min, 94.4% (Max). Chiral HPLC: (Method B) Rt. 32.84 min, 100%. The second eluting compound was isolated as Example 81 with Rt. 36.77 min (off white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.49 (s, 1H), 6.80-6.74 (m, 3H), 4.78 (br. s, 1H), 4.22 (s, 4H), 3.94-3.88 (m, 2H), 3.74-3.72 (m, 1H), 3.43-3.38 (m, 5H), 3.33-3.26 (m, 2H), 2.50-2.39 (m, 4H), 1.78-1.74 (m, 2H), 1.36-1.32 (m, 2H), 1.27 (d, J=6.4 Hz, 3H). LCMS: (Method A) 459.0 (M+H), Rt. 2.32 min, 98.9% (Max). HPLC: (Method A) Rt. 2.23 min, 99.8% (Max). Chiral HPLC: (Method B) Rt. 36.77 min, 94.52%.

Example 82: N-(5-(4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-1,3,4-thiadiazol-2-yl)acetamide

[0582] ##STR00336##

[0583] To a stirred solution of Intermediate 7 (0.4 g, 1.52 mmol) in dry ACN (10 mL), DIPEA (0.9 mL, 4.9 mmol) and Intermediate 6 (0.29 g, 1.52 mmol) were added at rt and the reaction mixture was stirred at 80° C. for 16 h. It was cooled to rt and concentrated. The resulting mixture was dissolved in ethyl acetate (70 mL), washed with water (10 mL), brine (10 mL), dried over anhydrous sodium sulfate and concentrated. The crude product was purified by flash chromatography to afford the title compound (orange solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 12.03 (s, 1H), 8.94 (dd, J=1.6, 7.0 Hz, 2H), 8.09 (d, J=8.8 Hz, 1H), 8.01 (d, J=1.6 Hz, 1H), 7.91 (dd, J=2.0, 8.6 Hz, 1H), 3.83-3.78 (m, 1H), 3.39-3.33 (m, 4H), 2.67-2.60 (m, 2H), 2.56-2.50 (m, 2H), 2.09 (s, 3H), 1.44 (d, J=6.8 Hz, 3H). LCMS: (Method A) 384.2 (M+H), Rt. 1.87 min, 98.4% (Max). HPLC: (Method A) Rt. 1.76 min, 99.0% (Max).

Example 83: 6-(1-(4-(pyrimidin-2-yl)piperazin-1-yl)ethyl)quinoxaline

[0584] ##STR00337##

[0585] To a stirred solution of 2-(piperazin-1-yl)pyrimidine hydrochloride (0.25 g, 1.52 mmol) in dry ACN (10 mL), DIPEA (0.9 mL, 4.9 mmol) and Intermediate 6 (0.29 g, 1.52 mmol) were added at rt and the reaction mixture was stirred at 80° C. for 16 h. It was cooled to rt and concentrated. The crude mixture was dissolved in ethyl acetate (70 mL), washed with water (10 mL), brine (10 mL) and dried over anhydrous sodium sulfate. After evaporation of the solvents, the crude product was purified by flash chromatography to afford the title compound (orange solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.95-8.92 (m, 2H), 8.33 (d, J=4.8 Hz, 2H), 8.09 (d, J=8.8 Hz, 1H), 8.00 (d, J=2.0 Hz, 1H), 7.92 (dd, J=1.6, 8.8 Hz, 1H), 6.60 (t, J=4.8 Hz, 1H), 3.77-3.71 (m, 5H), 2.60-2.55 (m, 2H), 2.45-2.35 (m, 2H), 1.44 (d, J=6.8 Hz, 3H). LCMS: (Method A) 321.0 (M+H), Rt. 2.01 min, 98.45% (Max). HPLC: (Method A) Rt. 1.92 min, 99.1% (Max).

Example 84: (2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)thiazol-4-yl)methanamine

[0586] ##STR00338##

Step 1: 2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-4-(chloromethyl)thiazole

[0587] To a stirred solution of Example 29 (1 g, 2.88 mmol) in dry DCM at 0° C., thionylchloride (0.4 mL, 8.64 mmol, spectrochem) was added dropwise. The reaction mixture was stirred at rt for 2 h. It was then concentrated and the resulting crude product was used without further purification. Yield: quantitative (1.2 g, pink solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.73-7.35 (m, 1H), 7.31-6.95 (m, 2H), 6.05 (s, 2H), 5.74 (s, 1H), 5.01-4.96 (m, 1H), 4.46 (s, 1H), 3.97-3.58 (m, 4H), 3.35-3.07 (m, 4H), 1.21 ((d, J=8.8 Hz, 3H). LCMS: (Method A) 362.0 (M−H), Rt. 2.45 min, 77.9% (Max).

Step 2: 4-(azidomethyl)-2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)thiazole

[0588] To a stirred solution of 2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-4-(chloromethyl)thiazole (1.2 g, 3.28 mmol) in dry DCM at 0° C., sodium azide (0.32 g, 4.9 mmol, spectrochem) was added in portion. The resulting mixture was heated at 80° C. for 12 h. It was then concentrated. The residue was dissolved in DCM (50 mL), washed with water (15 mL) and dried over Na.sub.2SO.sub.4. After evaporation of the solvents, the crude product was used without further purification. Yield: (1.1 g, colorless liquid). LCMS: (Method A) 373.0 (M+H), Rt. 2.96 min, 78.9% (Max).

Step 3: (2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)thiazol-4-yl)methanamine

[0589] To a stirred solution of 4-(azidomethyl)-2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)thiazole (1.1 g, 2.95 mmol) in THF (18 mL) and water (2 mL), triphenylphosphine (1.16 g, 4.4 mmol, spectrochem) was added in portion and the resulting mixture was heated at 60° C. for 12 h. The reaction mixture was concentrated in a vacuum. The residue was dissolved in DCM (25 mL), washed with water (10 mL) and dried over Na.sub.2SO.sub.4. After evaporation of the solvents, the crude product was purified by MD Autoprep (Method B) (off white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 6.88 (t, J=2.4 Hz, 2H), 6.86-6.83 (m, 1H), 6.75 (d, J=8.0 Hz, 1H), 5.98 (m, 2H), 3.70 (s, 2H), 3.40 (t, J=6.8 Hz, 1H), 3.33-3.28 (m, 4H), 2.42-2.37 (m, 4H), 1.90 (s, 2H), 1.26 (d, J=6.8 Hz, 3H). LCMS: (Method A) 347.0 (M+H), Rt. 2.59 min, 98.65% (Max). HPLC: (Method A) Rt. 1.86 min, 98.9% (Max).

Example 85: N-((2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)thiazol-4-yl)methyl)acetamide

[0590] ##STR00339##

[0591] To a solution of Example 84 (0.08 g, 0.23 mmol) in dry dichloromethane (5 mL), pyridine (0.01 mL, 0.11 mmol, spectrochem) and acetic anhydride (0.01 mL, 0.11 mmol, spectrochem) were added and the resulting mixture was stirred at rt for 12 h. It was concentrated. The crude residue was dissolved in DCM (15 mL), washed with water (5 mL) and dried over Na.sub.2SO.sub.4. After evaporation of the solvents, the crude product was purified by MD Autoprep (Method C) (off white solid). .sup.1H NMR (400 MHz, CDCl3): δ 7.00 (s, 1H), 6.90 (s, 1H), 6.77 (s, 2H), 5.97 (s, 2H), 5.77 (s, 1H), 4.43 (d, J=4.6 Hz, 2H), 3.48 (t, J=3.6 Hz, 5H), 2.56 (s, 4H), 2.00 (s, 3H), 1.41 (s, 3H). LCMS: (Method A) 389.2 (M+H), Rt. 2.02 min, 94.37% (Max). HPLC: (Method A) Rt. 1.94 min, 92.8% (Max).

Example 86: N-(5-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)thiazol-2-yl)acetamide

[0592] ##STR00340##

Step 1: 5-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)thiazol-2-amine

[0593] The title compound was synthesized following the general procedure D, using Intermediate 2 and 2-amino-5-bromo thiazole, hydrobromide salt as starting materials. Yield: 66% (0.85 g, black solid). LCMS: (Method A) 333.0 (M+H), Rt. 1.99 min, 57.8% (Max).

Step 2: N-(5-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)thiazol-2-yl)acetamide

[0594] The title compound was synthesized via same procedure as described for Example 44, using 5-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)thiazol-2-amine as starting material (off white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 11.68 (s, 1H), 6.89 (s, 1H), 6.85 (d, J=8.0 Hz, 1H), 6.76 (d, J=7.6 Hz, 1H), 6.57 (s, 1H), 5.99 (s, 2H), 3.38-3.33 (m, 1H), 3.02-2.92 (m, 4H), 2.50-2.43 (m, 4H), 2.06 (s, 3H), 1.27 (d, J=6.4 Hz, 3H). LCMS: (Method A) 375.0 (M+H), Rt. 2.49 min, 97.9% (Max). HPLC: (Method A) Rt. 2.41 min, 97.5% (Max).

Example 87: N-(2-(4-(1-(3,4-Dichlorophenyl)ethyl)piperazin-1-yl)thiazol-5-yl)acetamide

[0595] ##STR00341##

[0596] The title compound was synthesized according to the general procedure D, using Intermediate 22 and Intermediate 2 as starting materials. The crude product was purified by column chromatography (yellow solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 11.68 (s, 1H), 7.61-7.57 (m, 2H), 7.33 (dd, J=8.4, 1.6 Hz, 1H), 6.58 (s, 1H), 3.53 (q, J=6.8 Hz, 1H), 2.99-2.96 (m, 4H), 2.44-2.41 (m, 4H), 2.06 (s, 3H), 1.29 (d, J=6.8 Hz, 3H). LCMS: (Method A) 399.0 (M+H), Rt. 3.26 min, 97.0% (Max), 96.7% (220 nm). HPLC: (Method A) Rt. 3.16 min, 97.5% (Max).

Example 88: N-(5-(4-(1-(4-chloro-3-methoxyphenyl)ethyl)piperazin-1-yl)-1,3,4-thiadiazol-2-yl)acetamide

[0597] ##STR00342##

Step 1: 4-chloro-N,3-dimethoxy-N-methylbenzamide

[0598] To a stirred solution of 4-chloro-3-methoxy benzoic acid (2 g, 10.7 mmol) in dry DCM (20 mL), triethylamine (4.4 mL, 32.1 mmol), N,O-dimethylhydroxylamine, hydrochloride (1.15 g, 11.7 mmol), propylphosphonic anhydride (T.sub.3P) were added successively at 0° C. The resulting mixture was stirred overnight at rt. It was diluted with ethylacetate (50 mL), washed with water and dried over anhydrous Na.sub.2SO.sub.4. After evaporation of the solvents, the resulting crude product was purified by flash chromatography (40% EtOAc in Hexane), affording the title compound. Yield: 73% (1.8 g, pale brown liquid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.49 (d, J=8.0 Hz, 1H), 7.30 (d, J=1.6 Hz, 1H), 7.18-7.15 (m, 1H), 3.88 (s, 3H), 3.56 (s, 3H), 3.25 (s, 3H). LCMS: (Method A) 230.0 (M+H), Rt. 3.43 min, 94.92% (Max).

Step 2: 1-(4-chloro-3-methoxyphenyl)ethan-1-one

[0599] To a stirred solution of 4-chloro-N,3-dimethoxy-N-methylbenzamide (2 g, 8.70 mmol) in dry tetrahydrofuran (20 mL), methyl magnesium bromide (3 M in Et.sub.2O, 5.8 mL, 17.4 mmol) was added dropwise at 0° C. and the resulting mixture was stirred at rt for 1 h. It was quenched with saturated ammonium chloride solution (10 mL) and extracted with EtOAc (25 mL). The organic layer was washed with brine (15 mL), dried over anhydrous Na.sub.2SO.sub.4 and concentrated under vacuum. The crude product was purified by flash column chromatography (45% EtOAc in hexane) to afford the titled product (white solid). .sup.1H NMR (300 MHz, DMSO-d.sub.6): δ 7.71-7.60 (m, 1H), 7.52 (d, J=8.0 Hz, 3=1H), 7.11 (s, 3H), 3.88 (s, 3H), 2.50 (s, 3H).

Step 3: 1-(4-chloro-3-methoxyphenyl)ethan-1-ol

[0600] The title compound was synthesized according to the general procedure A starting with 1-(4-chloro-3-methoxyphenyl)ethan-1-one. The resulting crude product was used without further purification. Yield: 98% (0.44 g, white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.45 (d, J=24.0 Hz, 1H), 6.91-6.90 (m, 2H), 4.58-4.42 (m, 1H), 3.88 (s, 3H), 1.48 (d, J=8.0, 3H).

Step 4: 1-chloro-4-(1-chloroethyl)-2-methoxybenzene

[0601] The title compound was synthesized using the general procedure B, starting with 1-(4-chloro-3-methoxyphenyl)ethan-1-ol. The resulting crude product was used without further purification. Yield: 88% (0.3 g, colorless liquid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.43 (d, J=8.2 Hz, 1H), 7.25 (d, J=2.0 Hz, 1H), 7.10-7.07 (m, 1H), 5.38-5.36 (m, 1H), 3.88 (s, 3H), 1.80 (d, J=6.8 Hz, 3H).

Step 5: N-(5-(4-(1-(4-chloro-3-methoxyphenyl)ethyl)piperazin-1-yl)-1,3,4-thiadiazol-2-yl)acetamide

[0602] The title compound was synthesized by following general procedure D, using 1-chloro-4-(1-chloroethyl)-2-methoxybenzene and Intermediate 2 as starting materials. The crude product was purified by flash chromatography (8% MeOH in DCM) to afford the title compound (off white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 12.02 (s, 1H), 7.37 (d, J=8.4 Hz, 1H), 7.09 (d, J=1.2 Hz, 1H), 6.92 (d, J=1.2, 8.4 Hz, 1H), 3.87 (s, 3H), 3.49 (q, J=6.4 Hz, 1H), 3.35 (t, J=4.8 Hz, 4H), 2.46-2.42 (m, 4H), 2.10 (s, 3H), 1.31 (d, J=6.8 Hz, 3H). LCMS: (Method A) 396.0 (M+H), Rt. 2.86 min, 98.8% (Max). HPLC: (Method A) Rt. 2.83 min, 98.9% (Max).

Example 89: (R)—N-(5-(4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-1,3,4-thiadiazol-2-yl)acetamide or (S)—N-(5-(4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-1,3,4-thiadiazol-2-yl)acetamide

[0603] ##STR00343##

[0604] The two enantiomers of Example 82 were separated by chiral preparative HPLC (Method PF). The first eluting compound has a retention time of 15.34 min (Method D) (yellow solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): 12.02 (s, 1H), 8.93 (d, J=6.8 Hz, 2H), 8.09 (d, J=8.8 Hz, 1H), 8.01 (s, 1H), 7.91 (d, J=8.4 Hz, 1H), 3.80 (q, J=6.8 Hz, 1H), 3.39-3.37 (m, 4H), 2.63-2.60 (m, 2H), 2.47-2.46 (m, 2H), 2.09 (s, 3H), 1.43 (d, J=6.8 Hz, 3H). LCMS: (Method B) 384.2 (M+H), Rt. 1.88 min, 99.56% (Max). HPLC: (Method A) Rt. 1.77 min, 98.74% (Max). Chiral HPLC: (Method D) Rt. 15.34 min, 99.77%. The second eluting compound corresponds to Example 89 (yellow solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): 11.94 (s, 1H), 8.93 (dd, J=1.6, 2.0 Hz, 2H), 8.09 (d, J=8.4 Hz, 1H), 8.00 (s, 1H), 7.91 (dd, J=1.6, 2.0 Hz, 1H), 3.80 (q, 1H, J=6.8 Hz), 3.39-3.37 (m, 4H), 2.63-2.60 (m, 2H), 2.47 (m, 2H), 2.09 (s, 3H), 1.43 (d, J=6.8 Hz, 3H). LCMS: (Method B) 384.2 (M+H), Rt. 1.88 min, 99.62% (Max).

[0605] HPLC: (Method A) Rt. 1.77 min, 99.50% (Max). Chiral HPLC: (Method D) Rt. 17.11 min, 99.08%.

Example 90: Ethyl-2-(4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)thiazole-5-carboxylate

[0606] ##STR00344##

[0607] To a stirred solution of Intermediate 6 (0.5 g, 2.6 mmol) in dry ACN (18 mL), triethylamine (2.1 mL, 13.0 mmol, Spectrochem) and Intermediate 8 (1.08 g, 3.8 mmol) were added and the resulting mixture was heated at 90° C. for 12 h. It was concentrated, diluted with DCM (50 mL), washed with water (20 mL) and dried over anhydrous Na.sub.2SO.sub.4. After evaporation of the solvents, the resulting crude product was purified by flash chromatography (4% methanol in DCM) to afford the title compound. Yield: 58% (0.6 g, white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6: δ 8.86 (s, 2H), 8.12 (d, J=8.8 Hz, 1H), 8.03 (s, 1H), 7.90 (d, J=8.8 Hz, 1H), 7.87 (s, 1H), 4.30 (q, J=7.2 Hz, 2H), 3.76 (d, J=5.6 Hz, 1H), 3.59-3.58 (m, 4H), 2.71-2.70 (m, 2H), 2.60-2.59 (m, 2H), 1.51 (d, J=6.0 Hz, 3H), 1.34 (t, J=7.2 Hz, 3H). LCMS: (Method A) 398.2 (M+H), Rt. 2.61 min, 98.9% (Max). HPLC: (Method A) Rt. 2.64 min, 99.4% (Max).

Example 91: 7-(1-(4-(pyrimidin-2-yl)piperazin-1-yl)ethyl)quinoline

[0608] ##STR00345##

[0609] To a stirred solution of 2-(piperazin-1-yl)pyrimidine (0.17 g, 1.03 mmol) in dry DMF (10 mL), DIPEA (0.6 mL, 3.13 mmol) and Intermediate 9 (0.2 g, 1.03 mmol) were added at rt and the reaction mixture was stirred at 80° C. overnight. It was cooled to rt and concentrated. The resulting mixture was diluted in EtOAc (50 mL), washed with water (50 mL) and dried over anhydrous Na.sub.2SO.sub.4. After evaporation of the solvents, the crude product was purified by flash chromatography to afford the title compound (off white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.88 (t, J=2.8 Hz, 1H), 8.87-8.31 (m, 3H), 7.91-7.96 (m, 2H), 7.626-7.64 (m, 1H), 7.51-7.48 (m, 1H), 6.58 (t, J=4.8 Hz, 1H), 3.66-3.72 (m, 5H), 2.53-2.56 (m, 2H), 2.37-2.43 (m, 2H), 1.42 (d, J=6.8 Hz, 3H). LCMS: (Method A) 320.2 (M+H), Rt. 1.65 min, 99.0% (Max). HPLC: (Method A) Rt. 1.56 min, 98.7% (Max).

Example 92: N-methyl-2-(4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)thiazole-5-carboxamide

[0610] ##STR00346##

Step 1: 2-(4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)thiazole-5-carboxylic Acid

[0611] To a stirred solution of Example 90 (0.5 g, 1.25 mmol) in dioxane (5 mL), NaOH (10% in water, 2 mL) was added and the mixture was stirred at rt for 12 h. It was neutralized with 5 N HCl solution (25 mL) and extracted with DCM (20 mL). The organic phase was dried over anhydrous Na.sub.2SO.sub.4. After evaporation of the solvents, the crude product was used without further purification. Yield: 50% (0.2 g, colourless oil). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 10.9 (s, 1H), 9.92 (s, 1H), 8.86 (s, 2H), 3.22-3.17 (m, 4H), 3.02-2.78 (m, 4H), 2.06 (s, 3H). LCMS: (Method B) 370.0 (M+H), Rt. 1.90 min, 67.5% (Max).

Step 2: N-methyl-2-(4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)thiazole-5-carboxamide

[0612] To a stirred solution of 2-(4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)thiazole-5-carboxylic acid (0.2 g, 0.5 mmol) in DCM (10 mL), DIPEA (0.5 mL, 2.0 mmol), methyl amine (2 M in THF, spectrochem, 0.03 mL, 1.00 mmol) and HATU (0.29 g, 0.7 mmol, spectrochem) were added at 0° C. The reaction mixture was stirred at room temperature for 12 h. The completion of the reaction was monitored by TLC. The reaction mixture was concentrated under vacuum, diluted with DCM (25 mL), washed with water, brine and dried over anhydrous Na.sub.2SO.sub.4. After evaporation of the solvents, the crude product was purified by flash chromatography to afford pure title product. Yield: 50% (100 mg, of white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6: δ 8.94-8.93 (d, J=5.2 Hz, 2H), 8.15-8.14 (d, J=4.4 Hz, 1H), 8.10-8.08 (d, J=8.8 Hz, 1H), 8.00 (s, 1H), 7.92-7.90 (q, J=1.6 Hz, 1H), 7.71 (s, 1H), 3.82-3.81 (d, J=6.8 Hz, 1H), 3.46-3.45 (d, J=4.8 Hz, 4H), 2.69-2.68 (d, J=4.4 Hz, 3H), 2.60 (t, J=6.4 Hz, 2H), 2.46 (s, 2H), 1.44-1.43 (d, J=6.8 Hz, 3H). LCMS: (Method A) 383.2 (M+H), Rt. 1.86 min, 99.1% (Max). HPLC: (Method A) Rt. 1.73 min, 99.3% (Max).

Example 93: N-(2-(4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)pyrimidin-5-yl)acetamide

[0613] ##STR00347##

[0614] To a stirred solution of Intermediate 10 (0.66 g, 2.6 mmol) in dry DMF (10 mL), triethylamine (1.4 mL, 10.4 mmol, Spectrochem) and Intermediate 6 (0.5 g, 2.6 mmol) were added and the resulting mixture was heated at 90° C. for 12 h. It was concentrated and the resulting residue was diluted with DCM (25 mL), washed with water (10 mL) and dried over Na.sub.2SO.sub.4. After evaporation of the solvents, the crude product was purified by MD Autoprep (Method B) to afford the title compound (off white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6: δ 9.80 (s, 1H), 8.91 (dd, J=2, 7.4 Hz, 2H), 8.45 (s, 2H), 8.08 (d, J=8.4 Hz, 1H), 7.99 (d, J=1.6 Hz, 1H), 7.92-7.90 (m, 1H), 3.82 (d, J=2 Hz, 1H), 3.65 (m, 4H), 2.55-2.51 (m, 2H), 2.49-2.42 (m, 2H), 1.99 (s, 3H), 1.42 (d, J=6.8 Hz, 3H). LCMS: (Method A) 378.3 (M+H), Rt. 1.71 min, 99.83% (Max). HPLC: (Method A) Rt 1.80 min, 99.66% (Max).

Example 94: 6-(1-(4-(4-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)ethyl)quinoxaline

[0615] ##STR00348##

[0616] To a stirred solution of 2-(piperazin-1-yl)-4-(trifluoromethyl)pyrimidine hydrochloride (699 mg, 2.6 mmol) in DMF (10 mL), TEA (1.4 mL, 10.38 mmol) and Intermediate 6 (500 mg, 2.6 mmol) were added and the resulting mixture was stirred at 90° C. overnight. It was concentrated under vacuum and the residue was dissolved in DCM (15 mL), washed with water (10 mL) and dried over anhydrous Na.sub.2SO.sub.4. After evaporation of the solvents, the crude product was purified by flash chromatography to afford the title compound (brown oil). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.92 (dd, J=8.8, 1.6 Hz, 2H), 8.64 (d, J=4.4 Hz, 1H), 8.07 (d, J=8.8 Hz, 1H), 7.99 (d, J=1.6 Hz, 1H), 7.91 (d, J=8.8, 1.6 Hz, 1H), 6.98 (d, J=4.4 Hz, 1H), 3.79-3.75 (m, 5H), 2.59-2.54 (m, 2H), 2.48-2.41 (m, 2H), 1.43 (d, J=6.8 Hz, 3H). LCMS: (Method A) 389.30 (M+H), Rt. 3.09 min, 99.40% (Max). HPLC: (Method A) Rt 3.07 min, 99.89% (Max).

Example 95: (S)-7-(1-(4-(pyrimidin-2-yl)piperazin-1-yl)ethyl)quinolone or (R)-7-(1-(4-(pyrimidin-2-yl)piperazin-1-yl)ethyl)quinoline

[0617] ##STR00349##

[0618] To a stirred solution of 1-(2-pyrimidylpiperazine) (1.11 g, 6.8 mmol) in dry DMF (20 mL), DIPEA (3.66 mL, 20.28 mmol) and Intermediate 9 (1.3 g, 6.8 mmol) were added and the reaction mixture was stirred at 80° C. overnight. It was concentrated under vacuum and the crude residue was dissolved in EtOAc (60 mL), washed with water (20 mL) and dried over anhydrous Na.sub.2SO.sub.4. After evaporation of the solvent, the crude product was purified by flash chromatography followed by chiral preparative HPLC (Method PF) to separate both enantiomers. Example 95 corresponds to the second eluting fraction (pale yellow solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.89 (dd, J=4.4, 1.6 Hz, 1H), 8.35-8.31 (m, 3H), 7.95 (d, J=8.4 Hz, 1H), 7.91 (s, 1H), 7.66 (dd, J=8.4, 1.6 Hz, 1H), 7.49 (dd, J=8.0, 4.0 Hz, 1H), 6.59 (t, J=4.8 Hz, 1H), 3.72-3.68 (m, 5H), 2.56-2.51 (m, 2H), 2.43-2.37 (m, 2H), 1.42 (d, J=6.8 Hz, 3H). LCMS: (Method A) 320.2 (M+H), Rt. 1.63 min, 99.56% (Max). HPLC: (Method A) Rt. 1.54 min, 99.3% (Max). Chiral HPLC: (Method D) Rt 12.96 min, 100%.

Example 96: N-(2-(4-(1-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)piperazin-1-yl)pyrimidin-5-yl)acetamide

[0619] ##STR00350##

[0620] To a stirred solution of Intermediate 10 (320 mg, 1.24 mmol) in dry ACN (5 mL), DIPEA (3.66 mL, 20.28 mmol) and Intermediate 3 (270 mg, 1.36 mmol) were added and the reaction mixture was stirred at 80° C. overnight. It was concentrated under vacuum and the crude product was dissolved in EtOAc (30 mL), washed with water (10 mL) and dried over anhydrous Na.sub.2SO.sub.4. After evaporation of the solvents, the crude product was purified by flash chromatography to afford the title compound (pale yellow solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.79 (s, 1H), 8.44 (s, 2H), 6.76-6.74 (m, 3H), 4.19 (s, 4H), 3.61 (s, 4H), 2.38-2.31 (m, 4H), 1.98 (s, 3H), 1.24 (d, J=6.4 Hz, 3H). LCMS: (Method A) 384.2 (M+H), Rt. 2.27 min, 99.82% (Max). HPLC: (Method A) Rt. 2.26 min, 98.35% (Max).

Example 97: N-(5-(4-(1-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)piperazin-1-yl)-1,3,4-thiadiazol-2-yl)acetamide

[0621] ##STR00351##

[0622] The title compound was synthesized according the same procedure as Example 96, using Intermediate 7 and Intermediate 3 as starting materials. The crude product was purified by flash chromatography followed by MD Autoprep (Method B) to give the title compound (off white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 12.02 (s, 1H), 6.80-6.74 (m, 3H), 4.21 (s, 4H), 3.37-3.33 (m, 5H), 2.43-2.39 (m, 4H), 2.09 (s, 3H), 1.26 (d, J=6.8 Hz, 3H). LCMS: (Method A) 390.0 (M+H), Rt. 2.39 min, 98.62% (Max). HPLC: (Method A) Rt. 2.27 min, 97.05% (Max).

Example 98: 2-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-N-methylpyrimidine-5-carboxamide

[0623] ##STR00352##

Step 1: Ethyl 2-(methylthio)pyrimidine-5-carboxylate

[0624] To a stirred solution of ethyl-4-chloro-(2-methyl thio pyrimidine) 5-carboxylate (10 g, 42.9 mmol) in THF/water (8:2, 100 mL), zinc powder (14.0 g, 0.21 mmol) followed by t-BuOH (2 mL) were added and the resulting mixture was heated at 90° C. for overnight. The reaction completion was monitored by LCMS. The mixture was filtered through celite and evaporated under vacuum. The crude product was dissolved in dichloromethane (100 mL), washed with water (50 mL) and dried over Na.sub.2SO.sub.4. After evaporation of the solvents, the crude product was purified by MD Autoprep (Method B) (colorless liquid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): 9.03 (s, 2H), 4.35 (q, J=7.1 Hz, 2H), 2.58 (s, 3H), 1.33 (t, J=7.08 Hz, 3H). LCMS: (Method A) 199.0 (M+H), Rt. 3.50 min, 99.7% (Max).

Step 2: Ethyl 2-(methylsulfonyl)pyrimidine-5-carboxylate

[0625] To a stirred solution of ethyl 2-(methylthio)pyrimidine-5-carboxylate (2.8 g, 14.2 mmol) in tetrahydrofuran at 0° C., 3-chloroperbenzoic acid (7.8 g, 60.7 mmol, spectrochem) was added and the resulting solution was stirred at rt for 3 h. It was concentrated. DCM was added and was washed with water (25 mL) and 10% sodium bicarbonate solution (20 mL) and dried over Na.sub.2SO.sub.4. After evaporation of the solvents, the crude product was purified by flash chromatography to afford the titled product. Yield: 50.7% (1.65 g, off white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): 9.48 (s, 2H), 4.43 (q, J=7.0 Hz, 2H), 3.48 (s, 3H), 1.37 (t, J=7.1 Hz, 3H), LCMS: (Method A) 230.9 (M+H), Rt. 2.33 min, 97.48% (Max).

Step 3: Ethyl 2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)pyrimidine-5-carboxylate

[0626] To a stirred solution of Intermediate 2 (1.87 g, 6.94 mmol) in dry acetonitrile, potassium carbonate (2.87 g, 20.8 mmol, spectrochem) and ethyl 2-(methylsulfonyl)pyrimidine-5-carboxylate were added and the resulting mixture was at rt for 12 h. It was filtered through celite and concentrated. Dichloromethane (25 mL) was added and the solution was washed with water, brine and dried over Na.sub.2SO.sub.4. After evaporation of the solvents, the crude product was purified by flash column chromatography to afford the title compound (white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): 8.74 (s, 2H), 6.85 (t, J=7.8 Hz, 2H), 6.75 (d, J=7.8 Hz, 1H), 5.98 (s, 2H), 4.25 (q, J=6.8 Hz, 2H), 3.81 (s, 4H), 3.32 (s, 1H), 2.37-2.42 (m, 4H), 1.28 (d, J=6.6 Hz, 6H). LCMS: (Method A) 385.2 (M+H), Rt. 3.22 min, 98.88% (Max).

Step 4: Lithium 2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)pyrimidine-5-carboxylate

[0627] To a stirred solution of ethyl 2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)pyrimidine-5-carboxylate (0.9 g, 2.34 mmol) in MeOH (2 mL), THF (7 mL) and water (1 mL) mixture, lithium hydroxide (0.24 g, 5.85 mmol, spectrochem) was added at 0° C. The resulting mixture was stirred at rt for 12 h. It was concentrated and the crude product was used without further purification. Yield: 90% (0.52 g, off white solid). LCMS: (Method A) 357.0 (M+H), Rt. 2.38 min, 99.21% (Max).

Step 5: 2-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-N-methylpyrimidine-5-carboxamide

[0628] To a stirred solution of lithium 2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)pyrimidine-5-carboxylate (300 mg, 0.82 mmol) in dry DMF (5 mL), methyl amine (0.09 mL, 0.988 mmol, 2M in THF), DIPEA (0.45 mL, 2.47 mmol) and HATU (471 mg, 1.29 mmol) were added and the resulting mixture was stirred at rt for 12 h. It was concentrated under vacuum and the crude product was diluted with DCM (20 mL), washed with water (15 mL) and dried over anhydrous Na.sub.2SO.sub.4. After evaporation of the solvents, the crude product was purified by MD Autoprep (Method B) to give the title compound (off white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.71 (s, 2H), 8.29 (q, J=4.4 Hz, 1H), 6.90 (d, J=1.6 Hz, 1H), 6.84 (d, J=7.6 Hz, 1H), 6.75 (dd, J=8.0, 1.2 Hz, 1H), 5.98 (m, 2H), 3.78-3.76 (m, 4H), 3.39 (q, J=6.4 Hz, 1H), 2.74 (d, J=4.8 Hz, 3H), 2.45-2.42 (m, 2H), 2.37-2.32 (m, 2H), 1.28 (d, J=6.4 Hz, 3H). LCMS: (Method A) 370.2 (M+H), Rt. 2.24 min, 97.69% (Max). HPLC: (Method A) Rt. 2.19 min, 99.52% (Max).

Example 99: 2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-N,N-dimethylpyrimidine-5-carboxamide

[0629] ##STR00353##

[0630] The title compound was synthesized according the same protocol as Example 98, using dimethyl amine (2 M in THF) as reagent. The crude product was purified by MD Autoprep (Method B) to afford the title compound (white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.45 (s, 2H), 6.90 (d, J=1.2 Hz, 1H), 6.84 (d, J=7.6 Hz, 1H), 6.75 (dd, J=8.0, 1.2 Hz, 1H), 5.98 (m, 2H), 3.77-3.74 (m, 4H), 3.39 (q, J=6.4 Hz, 1H), 2.97 (s, 6H), 2.47-2.42 (m, 2H), 2.38-2.33 (m, 2H), 1.28 (d, J=6.4 Hz, 3H). LCMS: (Method A) 384.0 (M+H), Rt. 2.51 min, 99.94% (Max). HPLC: (Method A) Rt. 2.35 min, 99.85% (Max).

Example 100: N-(5-(4-(1-(4-chloroquinolin-7-yl)ethyl)piperazin-1-yl)-1,3,4-thiadiazol-2-yl)acetamide

[0631] ##STR00354##

[0632] To a stirred solution of Intermediate 7 (231 mg, 0.88 mmol) in dry ACN (10 mL), DIPEA (0.5 mL, 2.64 mmol) and Intermediate 12 (200 mg, 0.88 mmol) were added at rt and the reaction mixture was stirred at 90° C. overnight. It was concentrated under vacuum and the resulting crude product was diluted with DCM (25 mL), washed with water (10 mL), brine (10 mL) and dried over anhydrous Na.sub.2SO.sub.4. After evaporation of the solvents, the crude product was purified by MD Autoprep (Method B) to give the title compound (off white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 12.00 (s, 1H), 8.83 (d, J=4.8 Hz, 1H), 8.19 (d, J=8.8 Hz, 1H), 8.0 (br s, 1H), 7.81 (dd, J=8.8, 1.6 Hz, 1H), 7.74 (d, J=4.8 Hz, 1H), 3.77 (q, J=6.4 Hz, 1H), 3.38-3.35 (m, 4H), 2.67-2.59 (m, 4H), 2.08 (s, 3H), 1.42 (d, J=6.4 Hz, 3H). LCMS: (Method A) 417.0 (M+H), Rt. 2.35 min, 96.55% (Max). HPLC: (Method A) Rt. 2.31 min, 96.43% (Max).

Example 101: N-(2-(4-(1-(4-chloroquinolin-7-yl)ethyl)piperazin-1-yl)pyrimidin-5-yl)acetamide

[0633] ##STR00355##

[0634] The title compound was synthesized according the same protocol as described for the synthesis of Example 100, using Intermediate 10 and Intermediate 12 as starting materials. The crude product was purified by MD Autoprep (Method B) to give the title compound (off white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.8 (s, 1H), 8.82 (d, J=4.8 Hz, 1H), 8.46 (s, 2H), 8.19 (d, J=8.8 Hz, 1H), 7.99 (s, 1H), 7.82 (d, J=8.8 Hz, 1H), 7.73 (d, J=4.8 Hz, 1H), 3.77 (q, J=6.4 Hz, 1H), 3.67-3.65 (m, 4H), 2.53-2.41 (m, 4H), 1.99 (s, 3H), 1.41 (d, J=6.8 Hz, 3H). LCMS: (Method A) 411.0 (M+H), Rt. 2.35 min, 97.54% (Max). HPLC: (Method A) Rt. 2.29 min, 98.92% (Max).

Example 102: 6-(1-(4-(5-Methylpyrimidin-2-yl)piperazin-1-yl)ethyl)quinoxaline

[0635] ##STR00356##

[0636] To a stirred solution of Intermediate 11 (600 mg, 2.16 mmol) in dry DMF (10 mL), TEA (1.2 mL, 8.66 mmol) and 2-chloro-5-methylpyrimidine (280 mg, 2.16 mmol) were added at rt and the reaction mixture was stirred at 90° C. overnight. It was concentrated under vacuum and the resulting crude mixture was diluted with EtOAc (40 mL), washed with water (10 mL), brine (10 mL) and dried over anhydrous Na.sub.2SO.sub.4. After evaporation of the solvents, the crude product was purified by flash chromatography to give the title compound (brown oil). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.91 (d, J=7.2 Hz, 2H), 8.18 (s, 2H), 8.07 (s, J=8.8 Hz 1H), 7.99 (s, 1H), 7.90 (d, J=8.8 Hz, 1H), 3.67-3.66 (m, 4H), 2.54-2.49 (m, 2H), 2.40-2.38 (m, 2H), 2.05 (s, 3H), 1.42 (d, J=6.8 Hz, 3H). LCMS: (Method A) 335.2 (M+H), Rt. 2.14 min, 99.24% (Max). HPLC: (Method A) Rt. 2.21 min, 99.26% (Max).

Example 103: 6-(1-(4-(5-ethylpyrimidin-2-yl)piperazin-1-yl)ethyl)quinoxaline

[0637] ##STR00357##

[0638] The title compound was synthesized according the same protocol as described for the synthesis of Example 102, using Intermediate 11 and 2-chloro-5-ethylpyrimidine as starting materials. The crude product was purified by flash chromatography to give the title compound (brown oil). .sup.1HNMR (400 MHz, DMSO-d.sub.6): δ 8.93 (d, J=6.0 Hz, 2H), 8.18 (s, 2H), 8.07 (d, J=8.4 Hz, 1H), 8.00 (s, 1H), 7.92 (d, J=8.4 Hz, 1H), 3.75 (q, J=6.8 Hz, 1H), 3.69-3.66 (m, 4H), 2.52-2.50 (m, 2H), 2.41-2.39 (m, 4H), 1.41 (d, J=6.8 Hz, 3H), 1.11 (t, J=7.2 Hz, 3H). LCMS: (Method A) 349.2 (M+H), Rt. 2.47 min, 98.68% (Max). HPLC: (Method A) Rt. 2.47 min, 99.26% (Max).

Example 104: (S)-6-(1-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)ethyl)quinoxaline or (R)-6-(1-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)ethyl)quinoxaline

[0639] ##STR00358##

[0640] To a stirred solution of 2-(piperazin-1-yl)-5-(trifluoromethyl)pyrimidine hydrochloride (500 mg, 1.86 mmol) in dry DMF (10 mL), TEA (1.3 mL, 5.58 mmol) and Intermediate 6 (394 mg, 2.05 mmol) were added at rt and the reaction mixture was stirred at 90° C. overnight. The reaction mixture was concentrated under vacuum and the resulting residue was diluted with EtOAc (30 mL), washed with water (10 mL), brine (10 mL) and dried over anhydrous Na.sub.2SO.sub.4. After evaporation of the solvents, the crude product was purified by flash chromatography followed by chiral preparative HPLC (Method PJ) to separate both enantiomers. The second eluting fraction was concentrated to give the title compound (pale brown solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.90 (dd, J=6.8, 1.6 Hz, 2H), 8.65 (d, J=0.8, Hz, 2H), 8.07 (d, J=8.4 Hz, 1H), 7.99 (d, J=1.6 Hz, 1H), 7.91 (d, J=8.4 Hz, 1H), 3.83-3.77 (m, 5H), 2.59-2.43 (m, 4H), 1.42 (d, J=6.8 Hz, 3H). LCMS: (Method A) 389.2 (M+H), Rt. 2.95 min, 99.43% (Max). HPLC: (Method A) Rt. 2.99 min, 99.71% (Max). Chiral HPLC: (Method F) Rt 17.91 min, 99.63%.

Example 105: N-(5-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-1,3,4-thiadiazol-2-yl)propionamide

[0641] ##STR00359##

[0642] To a stirred solution of Example 41 (310 mg, 1.2 mmol) in dry DCM (10 mL), TEA (0.4 mL, 2.78 mmol) and propionyl chloride (94 mg, 1.02 mmol) were added at 0° C. and the resulting mixture was stirred at rt overnight. The reaction mixture was concentrated under vacuum and the resulting crude product was purified by flash chromatography to give the title compound (white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 11.96 (s, 1H), 6.83 (s, 1H), 6.83 (d, J=8.0 Hz, 1H), 6.72 (d, J=8.0 Hz, 1H), 5.98 (m, 2H), 3.34-3.32 (m, 5H), 2.51-2.37 (m, 6H), 1.28 (d, J=6.8 Hz, 3H), 1.04 (d, J=7.2 Hz, 3H). LCMS: (Method A) 390.0 (M+H), Rt. 2.57 min, 99.27% (Max). HPLC: (Method A) Rt. 2.48 min, 99.7% (Max).

Example 106: N-(5-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-1,3,4-thiadiazol-2-yl)butyramide

[0643] ##STR00360##

[0644] The title compound was synthesized according the same protocol as described for the synthesis of Example 105, using butyryl chloride as acylating agent. The resulting crude product was purified by flash column chromatography followed by MD Autoprep (Method B) to give the title compound (off white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 11.98 (s, 1H), 6.89 (d, J=1.6 Hz, 1H), 6.85 (d, J=8.0 Hz, 1H), 6.76 (dd, J=8.0, 1.6 Hz, 1H), 5.98 (m, 2H), 3.39 (q, J=5.6 Hz, 1H), 3.35-3.33 (m, 4H), 2.56-2.40 (m, 4H), 2.36 (t, J=7.6 Hz, 2H), 1.61-1.55 (m, 2H), 1.28 (d, J=6.4 Hz, 3H), 0.86 (t, J=7.2 Hz, 3H). LCMS: (Method A) 404.2 (M+H), Rt. 2.81 min, 97.58% (Max). HPLC: (Method A) Rt. 2.84 min, 99.12% (Max).

Example 107: N-(5-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-1,3,4-thiadiazol-2-yl)isobutyramide

[0645] ##STR00361##

[0646] The title compound was synthesized according the same protocol as described for the synthesis of Example 105, using isobutyryl chloride as acylating agent. The crude product was purified by flash chromatography to give the title compound (white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 11.99 (s, 1H), 6.89 (d, J=1.2 Hz, 1H), 6.85 (d, J=8.0 Hz, 1H), 6.76 (dd, J=8.0, 1.2 Hz, 1H), 5.99 (m, 2H), 3.43 (q, J=6.8 Hz, 1H), 3.80-3.33 (m, 4H), 2.72-2.65 (m, 1H), 2.44-2.32 (m, 4H), 1.28 (d, J=6.8 Hz, 3H), 1.09 (d, J=6.8 Hz, 6H). LCMS: (Method A) 404.2 (M+H), Rt. 2.82 min, 98.33% (Max). HPLC: (Method A) Rt. 2.75 min, 99.73% (Max).

Example 108: N-(5-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-1,3,4-thiadiazol-2-yl)cyclo propanecarboxamide

[0647] ##STR00362##

[0648] The title compound was synthesized according the same protocol as described for the synthesis of Example 105, using cyclopropane carbonyl chloride as acylating agent. The crude product was purified by flash chromatography followed by MD Autoprep (Method B) to give the title compound (off white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 12.30 (s, 1H), 6.89 (d, J=1.6 Hz, 1H), 6.84 (d, J=8.0 Hz, 1H), 6.76 (dd, J=8.0, 1.6 Hz, 1H), 5.99 (m, 2H), 3.39 (q, J=6.4 Hz, 1H), 3.33-3.28 (m, 4H), 2.56-2.39 (m, 4H), 1.88-1.87 (m, 1H), 1.28 (d, J=6.4 Hz, 3H), 0.90-0.83 (m, 4H). LCMS: (Method A) 402.2 (M+H), Rt. 2.63 min, 99.66% (Max). HPLC: (Method A) Rt. 2.66 min, 99.76% (Max).

Example 109: 2-(4-(1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)piperazin-1-yl)-N-methylthiazole-5-carboxamide

[0649] ##STR00363##

[0650] To a stirred solution of lithium 2-(4-(1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)piperazin-1-yl)thiazole-5-carboxylate (0.7 g, 18.37 mmol, Example 62, Step 2) in dry DMF (7 mL), methyl amine (2M in THF, 1.3 mL, 27.55 mmol), HATU (0.83 g, 22.0 mmol) and DIPEA (0.9 mL, 55.1 mmol) were added and the reaction mixture was stirred overnight at rt. It was cooled to rt and concentrated. Water (15 mL) was added to the resulting mixture and was extracted with EtOAc (2×30 mL). The organic layer was dried over anhydrous Na.sub.2SO.sub.4. After evaporation of the solvents, the crude product was purified by MD Autoprep HPLC (Method B) to afford the title compound as off white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.14 (q, J=4.0, 1H), 7.70 (s, 1H), 6.77-6.74 (m, 3H), 4.40 (s, 4H), 3.39-3.38 (m, 5H), 2.67 (d, J=4.4 Hz, 3H), 2.49-2.48 (m, 2H), 2.44-2.38 (m, 2H), 1.25 (d, J=6.4 Hz, 3H). LCMS: (Method A) 389.2 (M+H), Rt. 2.26 min, 97.94% (Max). HPLC: (Method A) Rt. 2.23 min, 98.53% (Max).

Example 110: N-(5-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-1,3,4-thiadiazol-2-yl)-4-chlorobenzamide

[0651] ##STR00364##

[0652] To a stirred solution of Example 41 (0.40 g, 1.2 mmol) in dry DCM (10 mL), TEA (0.4 mL, 0.45 mmol) and 4-chlorobenzoyl chloride (0.28 g, 1.65 mmol) were added at 0° C. and the resulting mixture was stirred overnight at rt. It was concentrated under vacuum and the resulting crude product was purified by flash chromatography to give the title compound (off white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): 12.69 (s, 1H), 8.06 (d, J=8.4 Hz, 2H), 7.60 (d, J=8.8 Hz, 2H), 6.75-6.89 (m, 3H), 5.99 (t, J=0.4 Hz, 2H), 3.39-3.42 (m, 5H), 2.42-2.45 (m, 4H), 1.28 (d, J=6.80 Hz, 3H), LCMS: (Method A) 471.1 (M+H), Rt. 3.59 min, 98.8% (Max). HPLC: (Method A) Rt. 3.56 min, 98.7% (Max).

Example 111: 5-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-N-(4-chlorobenzyl)-1,3,4-thiadiazol-2-amine

[0653] ##STR00365##

[0654] To a stirred solution of Example 41 (0.3 g, 0.90 mmol) in dry 1,2-dichloroethane (3 mL), titanium isopropoxide (0.8 mL, 2.71 mmol) and 4-chlorobenzaldehyde (0.19 g, 1.35 mmol) were added and the reaction mixture was refluxed for 8 h. It was cooled to 0° C. and sodium borohydride (0.17 g, 4.51 mmol) was added and the mixture was stirred at rt for 2 h. It was concentrated and water (15 mL) was added to the resulting crude product. It was extracted with EtOAc (2×30 mL). The organic layer was dried over anhydrous Na.sub.2SO.sub.4. After evaporation of the solvents, the crude product was purified by MD Autoprep HPLC (Method B) to afford the title compound as off white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.58 (t, J=6.0 Hz, 1H), 7.39-7.32 (m, 4H), 6.86 (s, 1H), 6.83 (d, J=8.0 Hz, 1H), 6.73 (d, J=8.0 Hz, 1H), 6.97-6.97 (m, 2H), 4.33 (m, 2H), 3.32-3.21 (m, 1H), 3.19-3.16 (m, 4H), 2.43-2.21 (m, 4H), 1.25 (d, J=6.4 Hz, 3H). LCMS: (Method B) 458.0 (M+H), Rt. 6.16 min, 96.93% (Max). HPLC: (Method A) Rt. 3.21 min, 96.02% (Max).

Example 112: 5-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-N-ethyl-1,3,4-thiadiazol-2-amine

[0655] ##STR00366##

[0656] The title compound was synthesized following the same procedure as Example 111, using acetaldehyde (0.17 mL, 1.35 mmol) as starting material. After evaporation of the solvents, the crude product was purified by flash chromatography to afford the title compound as off white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 6.99 (t, J=5.2 Hz, 1H), 6.88 (d, J=1.2 Hz, 1H), 6.84 (d, J=7.6 Hz, 1H), 6.74 (dd, J=7.6, 1.2 Hz, 1H), 5.99-5.98 (m, 2H), 3.37 (d, J=6.4 Hz, 1H), 3.19-3.13 (m, 6H), 2.45-2.32 (m, 4H), 1.25 (d, J=6.4 Hz, 3H), 1.11 (t, d, J=6.8 Hz, 3H). LCMS: (Method A) 362.0 (M+H), Rt. 2.01 min, 96.31% (Max). HPLC: (Method A) Rt. 1.98 min, 94.56% (Max).

Example 113: 2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine

[0657] ##STR00367##

[0658] To a stirred solution of Intermediate 2 (0.3 g, 11.15 mmol) in dry NMP (3 mL), DIPEA (0.8 mL, 44.6 mmol) and 2-chloro-7H-pyrrolo[2,3-d]pyrimidine (0.17 g, 11.15 mmol) were added at rt and the reaction mixture was stirred at 220° C. for 6 h in microwave. It was cooled to rt and concentrated. The resulting mixture was diluted with EtOAc (30 mL), washed with water (10 mL) and dried over anhydrous Na.sub.2SO.sub.4. After evaporation of the solvents, the crude product which was purified by MD Autoprep HPLC (Method B) to afford the title compound (off white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.57 (s, 1H), 7.07 (t, J=2.8 Hz, 1H), 6.90 (s, 1H), 6.84 (d, J=7.6 Hz, 1H), 6.76 (d, J=8 Hz, 1H), 6.30 (m, 1H), 5.97 (dd, J=3.2 Hz, 2H), 3.67 (t, J=4.8 Hz, 4H), 3.37-3.35 (m, 1H), 2.45-2.44 (m, 2H), 2.38-2.36 (m, 2H), 1.28 (d, J=76.4 Hz, 3H). LCMS: (Method A) 352.2 (M+H), Rt 2.10 min, 99.36% (Max). HPLC: (Method A) Rt. 2.01 min, 99.36% (Max).

Example 114: N-(5-(4-(1-(benzo[d]thiazol-5-yl)ethyl)piperazin-1-yl)-1,3,4-thiadiazol-2-yl)acetamide

[0659] ##STR00368##

[0660] To a stirred solution of Intermediate 7 (0.5 g, 1.9 mmol) in DMF (5 mL), DIPEA (0.99 mL, 5.6 mmol) and Intermediate 17 (0.374 g, 1.9 mmol) were added at 0-5° C. The reaction mixture was stirred at 100° C. overnight. The completion of the reaction was confirmed by TLC. The reaction mixture was evaporated at 50° C. under reduced pressure and diluted with ethyl acetate (30 mL). The organic layer washed with water (10 mL), brine solution (10 mL) and dried over Na.sub.2SO.sub.4. After evaporation of the solvents, the crude product was purified by flash chromatography (5-8% MeOH in DCM) to give the title compound (pale brown solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 12.01 (s, 1H), 9.38 (s, 1H), 8.11 (d, J=8.4 Hz, 1H), 8.01 (s, 1H), 7.48 (d, J=8.4 Hz, 1H), 3.69-3.65 (m, 1H), 3.36-3.32 (m, 4H), 2.58-2.50 (m, 2H), 2.50-2.43 (m, 2H), 2.08 (s, 3H), 1.39 (d, J=6.4 Hz, 3H). LCMS: (Method A) 389.0 (M+H), Rt. 2.17 min, 99.5% (Max). HPLC: (Method A) Rt 2.04 min, 99.2% (Max).

Example 115: N-(5-(4-(1-(quinolin-7-yl)ethyl)piperazin-1-yl)-1,3,4-thiadiazol-2-yl)acetamide

[0661] ##STR00369##

[0662] The title compound was synthesized according the protocol used for Example 114, using Intermediate 7 (0.39 g, 2.05 mmol) and Intermediate 9 (0.5 g, 2.6 mmol) as starting materials. The crude product was purified by MD Autoprep (Method B) to afford title compound as white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 12.03 (s, 1H), 8.9 (dd, J=1.6, 4.4 Hz, 1H), 8.35 (t, J=1.2 Hz, 1H), 7.96 (d, J=8.8 Hz, 1H), 7.92 (s, 1H), 7.65 (dd, J=5.2, 6.8 Hz, 1H), 7.51 (dd, J=4.4, 8.4 Hz, 1H), 3.76-3.71 (m, 1H), 3.39-3.35 (m, 4H), 2.62-2.58 (m, 2H), 2.48-2.45 (m, 2H), 2.09 (s, 3H), 1.43 (d, J=6.8 Hz, 3H). LCMS: (Method B) 383.0 (M+H), Rt. 4.4 min, 96.3% (Max). HPLC: (Method B) Rt. 4.3 min, 95.4% (Max).

Example 116: N-(2-(4-(1-(benzo[d]thiazol-5-yl)ethyl)piperazin-1-yl)pyrimidin-5-yl)acetamide

[0663] ##STR00370##

[0664] The title compound was synthesized according the protocol used for Example 114, using Intermediate 10 (0.5 g, 1.9 mmol) and Intermediate 17 (0.383 g, 1.9 mmol) as starting materials. The crude product was purified by flash chromatography (7% MeOH in DCM) followed by MD Autoprep HPLC (Method B) to afford title compound (off white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.81 (s, 1H), 9.38 (s, 1H), 8.46 (s, 1H), 8.11 (d, J=8.4 Hz, 1H), 8.02 (s, 1H), 7.52-7.48 (m, 1H), 3.66-3.63 (m, 5H), 2.52-2.50 (m, 2H), 2.40-2.37 (m, 2H), 2.00 (s, 3H), 1.40 (d, J=6.8 Hz, 3H). LCMS: (Method A) 383.0 (M+H), Rt. 2.17 min, 93.53% (Max). HPLC: (Method A) Rt. 2.05 min, 94.64% (Max).

Example 117: N-(5-(4-(1-(benzo[d]thiazol-5-yl)ethyl)piperazin-1-yl)-1,3,4-thiadiazol-2-yl)acetamide

[0665] ##STR00371##

[0666] The title compound was synthesized according the protocol used for Example 114, using Intermediate 7 (0.5 g, 1.9 mmol) and Intermediate 18 (0.418 g, 1.9 mmol). The crude product was purified by flash chromatography (5-8% MeOH in DCM) to give the title compound (pale brown solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 12.01 (s, 1H), 7.38-7.33 (m, 2H), 7.15 (d, J=8.4 Hz, 1H), 3.55-3.51 (m, 1H), 3.35-3.32 (m, 4H), 2.56-2.42 (m, 2H), 2.41-2.32 (m, 2H), 2.09 (s, 3H), 1.30 (d, J=8.0 Hz, 3H). LCMS: (Method A) 412.3 (M+H), Rt. 3.06 min, 99.3% (Max). HPLC: (Method A) Rt. 2.98 min, 98.6% (Max).

Example 118: N-(5-(4-(1-(benzo[d]thiazol-5-yl)ethyl)piperazin-1-yl)-1,3,4-thiadiazol-2-yl)acetamide

[0667] ##STR00372##

[0668] The title compound was synthesized according the protocol used for Example 114, using Intermediate 10 (0.5 g, 1.9 mmol) and Intermediate 18 (0.418 g, 1.9 mmol) as starting material. The crude product was purified by flash chromatography (5-8% MeOH in DCM) to give the title compound (pale brown solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.81 (s, 1H), 8.461 (s, 2H), 7.38-7.32 (m, 2H), 7.16 (d, J=6.8 Hz, 1H), 3.63 (t, J=9.6 Hz, 4.8 Hz, 4H), 3.50-3.47 (m, 1H), 2.50-2.43 (m, 2H), 2.36-2.32 (m, 2H), 1.99 (s, 3H), 1.30 (d, J=6.8 Hz, 3H). LCMS: (Method A) 406.2 (M+H), Rt. 3.05 min, 99.2% (Max). HPLC: (Method A) Rt. 2.98 min, 99.6% (Max).

Example 119: 2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)quinazoline

[0669] ##STR00373##

[0670] To a stirred solution of Intermediate 2 (0.3 g, 1.28 mmol) in dry DMF (10 mL), TEA (1.5 mL, 1.09 mmol) and 2-chloroquinazoline (0.5 g, 2.74 mmol) were added at rt and the resulting mixture was stirred at 80° C. for 12 h. It was cooled to rt, and concentrated. The crude residue was diluted with dichloromethane (50 mL), was washed with brine (10 mL), and dried over anhydrous Na.sub.2SO.sub.4. After evaporation of the solvents, the crude product was purified by MD Autoprep HPLC (Method B) (off white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): 9.17 (s, 1H), 7.81 (d, J=7.6 Hz, 1H), 7.70 (t, J=8.0 Hz, 1H), 7.47 (d, J=8.4 Hz, 1H), 7.25 (t, J=7.6 Hz, 1H), 6.90 (s, 1H), 6.84 (d, J=8.0 Hz, 1H), 6.76 (d, J=8.0 Hz, 1H), 5.98 (d, J=2.4 Hz, 2H), 3.83 (t, J=5.6 Hz, 4H), 3.38 (t, J=6.0 Hz, 1H), 2.37-2.40 (m, 4H), 1.23 (d, J=2.4 Hz, 3H), LCMS: (Method A) 363.3 (M+H), Rt. 2.94 min, 99.0% (Max). HPLC: (Method A) Rt. 2.95 min, 98.5% (Max).

Example 120: N-(2-(4-(1-(quinolin-7-yl)ethyl)piperazin-1-yl)pyrimidin-5-yl)acetamide

[0671] ##STR00374##

[0672] To a stirred solution of Intermediate 10 (0.72 g, 2.80 mmol) in dry ACN (10 mL), DIPEA (2 mL, 11.20 mmol) and Intermediate 9 (0.54 g, 2.80 mmol) were added at rt and the reaction mixture was stirred overnight at 80° C. It was cooled to rt and concentrated. The resulting mixture was diluted with EtOAc (50 mL), washed with water (15 mL) and dried over anhydrous Na.sub.2SO.sub.4. After evaporation of the solvents, the crude product was purified by flash column chromatography to afford the title compound (brown solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.81 (s, 1H), 8.89-8.88 (m, 1H), 8.46 (s, 2H), 8.34 (d, J=8.0 Hz, 1H), 7.95 (d, J=8.4 Hz, 1H), 7.91 (s, 1H), 7.67-7.65 (m, 1H), 7.51-7.50 (m, 1H), 3.67-3.66 (m, 5H), 2.51-2.50 (m, 2H), 2.42-2.40 (m, 2H), 2.02 (s, 3H), 1.42 (d, J=6.8 Hz, 3H). LCMS: (Method A) 377.2 (M+H), Rt. 1.42 min, 99.10% (Max). HPLC: (Method A) Rt. 1.40 min, 96.61% (Max).

Example 121: N-(2-(4-(1-(benzo[c][1,2,5]oxadiazol-5-yl)ethyl)piperazin-1-yl)pyrimidin-5-yl)acetamide

[0673] ##STR00375##

[0674] To a stirred solution of Intermediate 10 (0.59 g, 2.68 mmol) in dry DMF (10 mL), TEA (1.4 mL, 10.7 mmol) and Intermediate 13 (0.5 g, 2.68 mmol) were added at rt and the reaction mixture was stirred at 90° C. for 12 h. It was cooled to rt and concentrated. The crude product was diluted with dichloromethane (50 mL), washed with brine (10 mL) and dried over anhydrous Na.sub.2SO.sub.4. After evaporation of the solvents, the crude product was purified by MD Autoprep HPLC (Method B) (off white solid). .sup.1H NMR (400 MHz, DMSO-d6): 9.83 (s, 2H), 8.48 (s, 2H), 7.90 (s, 1H), 7.71 (dd, J=1.2, 9.2 Hz, 1H), 3.63-3.68 (m, 5H), 2.39-2.50 (m, 4H), 2.01 (s, 3H), 1.37 (d, J=6.4 Hz, 3H), LCMS: (Method A) 368.0 (M+H), Rt. 2.08 min, 98.5% (Max). HPLC: (Method A) Rt. 2.05 min, 95.9% (Max).

Example 122: N-(2-(4-(1-(benzo[c][1,2,5]thiadiazol-5-yl)ethyl)piperazin-1-yl)pyrimidin-5-yl)acetamide

[0675] ##STR00376##

[0676] The title compound was synthesized according the protocol used for Example 114, using Intermediate 10 (0.3 g, 1.16 mmol) and Intermediate 19 (0.323 g, 1.6 mmol) as starting material. The crude product was purified by flash chromatography (7% MeOH in DCM) and then again purified by MD Autoprep HPLC (Method C) to give the title compound (off white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.81 (s, 1H), 8.46 (s, 2H), 8.05 (d, J=8.8 Hz, 1H), 7.96 (s, 1H), 7.79 (d, J=8.8 Hz, 1H), 3.69-3.65 (m, 5H), 2.55-2.53 (m, 2H), 2.43-2.38 (m, 2H), 1.99 (s, 3H), 1.40 (d, J=6.4 Hz, 3H). LCMS: (Method A) 384.2 (M+H), Rt. 2.20 min, 97.23% (Max). HPLC: (Method A) Rt. 2.13 min, 98.37% (Max).

Example 123: N-(5-(4-(1-(benzo[c][1,2,5]thiadiazol-5-yl)ethyl)piperazin-1-yl)-1,3,4-thiadiazol-2-yl)acetamide

[0677] ##STR00377##

[0678] The title compound was synthesized according the protocol used for Example 114, using Intermediate 7 (0.5 g, 1.8 mmol) and Intermediate 19 (0.527 g, 2.65 mmol) as starting materials. The crude product was purified by flash chromatography (7% MeOH in DCM) to give the title compound (pale brown solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 12.03 (s, 1H), 8.05 (d, J=9.2 Hz, 1H), 7.98 (s, 1H), 7.80 (dd, J=9.2, 1.2 Hz, 1H), 3.77-3.72 (m, 1H), 3.39-3.34 (m, 4H), 2.63-2.59 (m, 2H), 2.53-2.46 (m, 2H), 2.09 (s, 3H), 1.41 (d, J=6.4 Hz, 3H). LCMS: (Method A) 390.0 (M+H), Rt. 2.19 min, 99.17% (Max). HPLC: (Method A) Rt. 2.13 min, 98.91% (Max).

Example 124: N-(5-(4-(1-(benzo[c][1,2,5]thiadiazol-5-yl)ethyl)piperazin-1-yl)-1,3,4-thiadiazol-2-yl)acetamide

[0679] ##STR00378##

[0680] The title compound was synthesized according the protocol used for Example 114, using Intermediate 7 (0.250 g, 0.9 mmol) and Intermediate 20 (0.30 g, 1.3 mmol) as starting materials. The crude product was purified by flash chromatography (7% MeOH in DCM) to give the title compound (pale brown solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 12.02 (s, 1H), 8.88-8.87 (m, 1H), 8.56-8.55 (m, 1H), 7.98-7.95 (m, 2H), 7.72 (d, J=8.4 Hz, 1H), 3.75 (q, J=6.8 Hz, 1H), 3.37 (t, J=4.4 Hz, 4H), 2.61-2.58 (m, 2H), 2.51-2.45 (m, 2H), 2.09 (s, 3H), 1.41 (d, J=6.8 Hz, 3H). LCMS: (Method A) 417.0 (M+H), Rt. 2.65 min, 98.42% (Max). HPLC: (Method A) Rt. 2.58 min, 98.73% (Max).

Example 125: N-(2-(4-(1-(3-chloroquinolin-7-yl)ethyl)piperazin-1-yl)pyrimidin-5-yl)acetamide

[0681] ##STR00379##

[0682] The title compound was synthesized according the protocol used for Example 114, using Intermediate 10 (0.250 g, 0.9 mmol) and Intermediate 20 (0.307 g, 1.3 mmol) as starting materials. The crude product was purified by MD Autoprep HPLC (Method B) to give the title compound (pale brown solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.81 (s, 1H), 8.87 (d, J=2.4 Hz, 1H), 8.55 (d, J=2.4 Hz, 1H), 8.46 (s, 2H), 7.97-7.95 (m, 2H), 7.73 (d, J=7.6 Hz, 1H), 3.70-3.65 (m, 5H), 2.50-2.41 (m, 2H), 2.42-2.37 (m, 2H), 2.00 (s, 3H), 1.41 (d, J=6.4 Hz, 3H). LCMS: (Method A) 411.2 (M+H), Rt. 2.60 min, 99.12% (Max). HPLC: (Method A) Rt. 2.59 min, 98.33% (Max).

Example 126: N-(2-(4-(1-(3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)ethyl)piperazin-1-yl)pyrimidin-5-yl)acetamide

[0683] ##STR00380##

[0684] The title compound was synthesized according the same protocol as described for the synthesis of Example 121, using Intermediate 14 and Intermediate 10 as starting materials. The crude product was purified by MD Autoprep HPLC (Method C) (off white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.80 (s, 1H), 8.45 (s, 2H), 6.88 (d, J=4.8 Hz, 3H), 4.10-4.08 (m, 3H), 337-3.38 (m, 2H), 3.32-3.29 (m, 4H), 2.49-2.48 (m, 2H), 2.46-2.44 (m, 2H), 2.07-2.01 (m, 2H), 1.99 (s, 3H), 1.24 (d, J=6.4 Hz, 3H). LCMS: (Method A) 397.3 (M+H), Rt. 2.43 min, 98.43% (Max). HPLC: (Method A) Rt. 2.41 min, 97.8% (Max).

Example 127: N-(2-(4-(1-(quinolin-8-yl)ethyl)piperazin-1-yl)pyrimidin-5-yl)acetamide

[0685] ##STR00381##

[0686] To a stirred solution of Intermediate 10 (0.4 g, 1.57 mmol) in dry DMF (10 mL), DIPEA (0.8 mL, 3.13 mmol) and Intermediate 15 (0.3 g, 1.57 mmol) were added at rt and the resulting reaction mixture was stirred at 80° C. for 12 h. It was cooled to rt and concentrated. The crude product was diluted with dichloromethane (50 mL), washed with brine (10 mL) and dried over anhydrous Na.sub.2SO.sub.4. After evaporation of the solvents, the crude product was purified by flash column chromatography to afford the title compound (off white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.81 (s, 1H), 8.91 (dd, J=4.0, 1.6 Hz, 1H), 8.46 (s, 2H), 8.37 (dd, J=8.0, 1.6 Hz, 1H), 7.92 (d, J=6.8 Hz 1H), 7.86 (d, J=8.0 Hz, 1H), 7.66-7.62 (m, 1H), 7.54 (dd, J=8.0, 4.0 Hz, 1H), 4.98 (q, J=6.4 Hz, 1H), 3.66-3.65 (m, 4H), 2.57-2.42 (m, 4H), 2.01 (s, 3H), 1.38 (d, J=6.4 Hz, 3H). LCMS: (Method A) 377.2 (M+H), Rt. 2.47 min, 98.0% (Max). HPLC: (Method A) Rt. 2.43 min, 97.5% (Max).

Example 128: N-(5-(4-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)-1,3,4-thiadiazol-2-yl)acetamide

[0687] ##STR00382##

[0688] The title compound was synthesized according the protocol used for Example 114, using Intermediate 7 (0.3 g, 1.14 mmol) and Intermediate 21 (0.269 g, 1.48 mmol) as starting materials. The crude product was purified by flash chromatography (7% MeOH in DCM) followed by MD Autoprep HPLC (Method B) to give the title compound (off white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 12.02 (s, 1H), 7.12 (d, J=7.2 Hz, 1H), 6.76 (d, J=87.6 Hz, 1H), 6.71 (s, 1H), 4.51 (t, J=8.4 Hz, 2H), 3.39-3.28 (m, 5H), 3.14 (t, J=8.4 Hz, 2H), 2.42-2.39 (m, 4H), 2.09 (s, 3H), 1.28 (d, J=6.4 Hz, 3H). LCMS: (Method A) 374.2 (M+H), Rt. 2.34 min, 99.62% (Max). HPLC: (Method A) Rt. 2.32 min, 96.03% (Max).

Example 129: N-(2-(4-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)pyrimidin-5-yl)acetamide

[0689] ##STR00383##

[0690] The title compound was synthesized according the protocol used for Example 114, using Intermediate 10 (0.3 g, 1.16 mmol) and Intermediate 21 (0.274 g, 1.51 mmol) as starting materials. The crude product was purified by flash chromatography (10% MeOH in DCM) followed by MD Autoprep HPLC (Method B) to give the title compound (off white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.80 (s, 1H), 8.45 (s, 2H), 7.13 (d, J=7.6 Hz, 1H), 6.75-6.70 (m, 1H), 4.49 (t, J=8.4 Hz, 2H), 3.63-3.61 (m, 4H), 3.12 (t, J=8.4 Hz, 3H), 2.44-2.30 (m, 4H), 1.99 (s, 3H), 1.26 (d, J=6.4 Hz, 3H). LCMS: (Method A) 368.3 (M+H), Rt. 2.34 min, 99.74% (Max). HPLC: (Method A) Rt. 2.33 min, 99.52% (Max).

Example 130: 2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)benzo[d]thiazole

[0691] ##STR00384##

[0692] To a stirred solution of Intermediate 2 (0.5 g, 2.13 mmol) in dry DMF (10 mL), DIPEA (0.8 mL, 6.3 mmol) and 2-bromo benzothiazole (0.5 g, 2.13 mmol) were added at rt and the reaction mixture was stirred at 90° C. for 12 h. It was cooled to rt and concentrated. The crude product was diluted with dichloromethane (50 mL), washed with brine (10 mL) and dried over anhydrous Na.sub.2SO.sub.4. After evaporation of the solvents, the crude product was purified by flash chromatography to give the title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.74 (d, J=0.8 Hz, 1H), 7.43 (d, J=7.6 Hz, 1H), 7.28-7.24 (m, 1H), 7.09-7.04 (m, 1H), 6.91 (d, J=1.6 Hz, 1H), 6.83 (d, J=8 Hz, 1H), 6.86-6.73 (m, 1H), 5.91 (d, J=1.6 Hz, 2H), 3.56-3.51 (m, 4H), 3.44-3.36 (m, 1H), 2.47-2.41 (m, 4H), 1.28 (d, J=6.8 Hz, 3H). LCMS: (Method A) 368.2 (M+H), Rt. 3.34 min, 95.18% (Max). HPLC: (Method A) Rt. 3.34 min, 97.15% (Max).

Example 131: N-(2-(4-(1-(quinolin-3-yl)ethyl)piperazin-1-yl)pyrimidin-5-yl)acetamide

[0693] ##STR00385##

[0694] To a stirred solution of Intermediate 10 (0.5 g, 1.9 mmol) in DMF (5 mL), DIPEA (1.65 mL, 9.5 mmol) and Intermediate 23 (0.496 g, 2.59 mmol) were added at 0-5° C. The reaction mixture was stirred at 100° C. overnight. It was then concentrated under reduced pressure. The crude product was diluted with DCM (100 mL), washed with water (2×25 mL) and dried over Na.sub.2SO.sub.4. After evaporation of the solvents, the crude product was purified by flash chromatography (7% MeOH in DCM). It was triturated with ACN (5 mL) and diethyl ether (2×15 mL) to give the title compound as pale brown solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.81 (s, 1H), 8.93-8.91 (m, 1H), 8.459 (s, 2H), 8.24-8.22 (m, 1H), 7.99 (t, J=8.0 Hz, 2H), 7.73-7.71 (m, 1H), 7.60-7.58 (m, 1H), 3.79-3.73 (m, 1H), 3.67-3.65 (m, 4H), 2.55-2.50 (m, 2H), 2.50-2.40 (m, 2H), 2.02 (s, 3H), 1.44 (d, J=6.4 Hz, 3H). LCMS: (Method A) 377.2 (M+H), Rt. 1.80 min, 94.43% (Max). HPLC: (Method A) Rt. 1.82 min, 94.95% (Max).

Example 132: (S)-5-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-1,3,4-thiadiazol-2-amine

[0695] ##STR00386##

[0696] To a stirred solution of Intermediate 16 (3 g, 11.1 mmol) in ACN (30 mL), TEA (3.36 g, 33.3 mmol) and 5-bromo-1,3,4-thiadiazol-2-amine (2.19 g, 12.2 mmol) were added at rt and the mixture was heated at 85° C. overnight. The completion of the reaction was confirmed by TLC. The reaction mixture was evaporated under vacuum and the resulting crude solid was diluted with water (30 mL) and extracted with EtOAc (3×30 mL). The combined organic layer was washed with brine (30 mL), dried over Na.sub.2SO.sub.4 and evaporated at 45° C. under vacuum. The crude product was purified by flash chromatography (7% MeOH in DCM) to give the title compound (pale brown solid). .sup.1H NMR (400 MHz, DMSO-d6): δ 6.88-6.83 (m, 2H), 6.76-6.74 (m, 1H), 6.46 (s, 2H), 5.91 (d, J=1.6 Hz, 2H), 3.39-3.37 (m, 1H), 3.20-3.17 (m, 4H), 2.46-2.30 (m, 4H), 1.25 (d, J=6.5 Hz, 3H). LCMS: (Method A) 334.0 (M+H), Rt. 1.85 min, 96.47% (Max). HPLC: (Method A) Rt. 1.79 min, 96.77% (Max). Chiral HPLC: (Method D) Rt. 20.96 min, 100.00%

Example 133: (S)—N-(5-(4-(1-(benzo[d]thiazol-5-yl)ethyl)piperazin-1-yl)-1,3,4-thiadiazol-2-yl)acetamide or ((R)—N-(5-(4-(1-(benzo[d]thiazol-5-yl)ethyl)piperazin-1-yl)-1,3,4-thiadiazol-2-yl)acetamide

[0697] ##STR00387##

[0698] The two enantiomers of Example 114 were separated by chiral preparative HPLC (Method PF). Example 133 corresponds to the second eluting fraction (off white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 12.01 (s, 1H), 9.34 (s, 1H), 8.12 (d, J=8.0 Hz, 1H), 8.02 (s, 1H), 7.50 (d, J=8.4 Hz, 1H), 3.67 (d, J=6.0 Hz, 1H), 3.37-3.35 (m, 4H), 2.56-2.57 (m, 4H), 2.09 (s, 3H), 1.40 (d, J=6.8 Hz, 3H). LCMS: (Method A) 389.0 (M+H), Rt. 2.09 min, 96.5% (Max). HPLC: (Method A) Rt. 2.08 min, 97.4% (Max). Chiral HPLC: (Method D) Rt 15.28 min, 99.82%.

Example 134: (S) 2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-N-methylpyrimidine-5-carboxamide

[0699] ##STR00388##

Step 1: Ethyl (S)-2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)pyrimidine-5-carboxylate

[0700] To a stirred solution of Intermediate 16 (1.87 g, 6.94 mmol) in dry acetonitrile (10 mL), potassium carbonate (2.87 g, 20.8 mmol, Spectrochem) and ethyl 2-(methylsulfonyl) pyrimidine-5-carboxylate (1.6 g, 6.94 mmol, synthesis described in Example 98, steps, 1 and 2) were added. The resulting mixture was stirred at rt for 3 h. It was then filtered through celite and concentrated. The crude product was diluted with dichloromethane (25 mL), washed with water and dried over anhydrous Na.sub.2SO.sub.4. After evaporation of the solvent, the crude product was purified by flash column chromatography to afford the title compound (white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.74 (s, 1H), 6.78-6.72 (m, 2H), 5.97 (s, 1H), 4.38-4.36 (m, 1H), 3.81 (s, 2H), 2.37-2.47 (m, 9H), 1.26 (d, J=2.84 Hz, 3H), LCMS: (Method A) 385.2 (M+H), Rt. 3.22 min, 98.6% (Max).

Step 2: Lithium (S)-2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)pyrimidine-5-carboxylate

[0701] To a stirred solution of ethyl (S)-2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)pyrimidine-5-carboxylate (1.6 g, 17.5 mmol) in a mixture of MeOH (2 mL), THF (7 mL) and water (1 mL), lithium hydroxide (0.431 g, 5.20 mmol, Spectrochem) was added at 0° C. and the resulting mixture was stirred at rt for 12 h. It was concentrated and the resulting product was taken for next step without any further purification. Yield: 96% (0.61 g, off white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.61 (s, 1H), 6.81-6.88 (m, 4H), 5.97 (d, J=1.8 Hz, 2H), 3.68 (d, J=6.2 Hz, 2H), 3.22-3.21 (m, 1H), 2.28-2.35 (m, 6H), 1.26 (d, J=8.9 Hz, 3H), LCMS: (Method A) 357.0 (M+H), Rt. 2.41 min, 97.1% (Max)

Step 3: (S) 2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-N-methylpyrimidine-5-carboxamide

[0702] To a stirred solution of lithium (S)-2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)pyrimidine-5-carboxylate (0.3 g, 0.82 mmol) in dry DCM (10 mL), triethylamine (0.34 mL) and methylamine in THF (2 M, 1.6 mL, 3.32 mmol) were added at 0° C. The reaction mixture was stirred at rt for 1 h. The reaction progression was monitored by TLC. After completion of the reaction, the mixture was diluted with 10% sodium bicarbonate solution (10 mL) and extracted with DCM (20 mL). The organic layer was dried over Na.sub.2SO.sub.4 and evaporated to dryness. The crude product was purified by flash column chromatography. Yield: 56% (0.17 g, off white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.71 (s, 2H), 8.28 (d, J=4.8 Hz, 1H), 6.90-6.83 (m, 2H), 6.77-6.75 (m, 1H), 5.98 (d, J=2.0 Hz, 2H), 3.77 (t, J=4.8 Hz, 4H), 3.41-3.38 (m, 1H), 2.74 (d, J=4.4 Hz, 3H), 2.38-2.33 (m, 4H), 1.28 (d, J=6.8 Hz, 3H). LCMS: (Method A) 370.2 (M+H), Rt. 2.21 min, 98.9% (Max). HPLC: (Method A) Rt. 2.18 min, 99.3% (Max). Chiral HPLC: (Method G) Rt. 5.51 min, 100.00%

Example 135: 2-(4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)benzo[d]thiazole

[0703] ##STR00389##

[0704] To a stirred solution of Intermediate 11 (0.26 g, 0.93 mmol) in dry DMF (3 mL), TEA (0.4 mL, 2.81 mmol) and 2-bromobenzothiazole (0.2 g, 0.93 mmol, combi blocks) were added at rt and the reaction mixture was stirred overnight at 95° C. It was cooled to rt and concentrated. To the resulting mixture, water (20 mL) was added and the product was extracted with EtOAc (2×40 mL). The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4 and concentrated. The crude product was purified by flash column chromatography to afford the title compound (brown solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.92 (d, J=4.0 Hz, 2H), 8.09 (d, J=8.8 Hz, 1H), 8.01 (s, 1H), 7.92 (d, J=8.0 Hz, 1H), 7.73 (d, J=8.0 Hz, 1H), 7.42 (d, J=8.0 Hz, 1H), 7.25 (t, J=7.6 Hz, 1H), 7.04 (t, J=7.6 Hz, 1H), 3.83-3.81 (m, 1H), 3.56 (t, J=4.8 Hz, 4H), 2.64-2.63 (m, 2H), 2.49 (m, 2H), 1.44 (d, J=6.8 Hz, 3H). LCMS: (Method A) 376.3 (M+H), Rt. 2.71 min, 99.382% (Max). HPLC: (Method A) Rt. 2.69 min, 98.44% (Max).

Example 136: (S)-2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)benzo[d]thiazole

[0705] ##STR00390##

[0706] To a stirred solution of Intermediate 16 (0.3 g, 1.27 mmol) in dry DMF (10 mL), TEA (0.67 mL, 3.82 mmol) and 2-bromo benzothiazole (0.27 g, 1.27 mmol) were added at rt and the reaction mixture was stirred at 90° C. for 12 h. It was cooled to rt, concentrated. The resulting mixture was diluted with dichloromethane (50 ml), washed with brine (10 ml) and dried over anhydrous Na.sub.2SO.sub.4. After evaporation of the solvents, the crude product was purified by flash chromatography to give the title compound (off white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.74 (d, J=7.6 Hz, 1H), 7.43 (d, J=8.0 Hz, 1H), 7.27 (t, 1H), 7.05 (t, J=7.6 Hz, 1H), 6.90 (s, 1H), 6.83 (d, J=8.0 Hz, 1H), 6.77 (d, J=8.4 Hz, 1H), 5.91 (d, J=1.6 Hz, 2H), 3.53 (t, J=7.6 Hz, 4H), 3.44-3.38 (m, 1H), 2.47-2.44 (m, 4H), 1.28 (d, J=6.8 Hz, 3H). LCMS: (Method A) 368.0 (M+H), Rt. 3.28 min, 96.86% (Max). HPLC: (Method A) Rt. 3.33 min, 97.08% (Max). Chiral HPLC: (Method G) Rt. 8.00 min, 100.00%

Example 137: (S)-2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-N,N-dimethylpyrimidine-5-carboxamide

[0707] ##STR00391##

[0708] The title compound was synthesized using the same procedure as described for Example 134, using lithium (S)-2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)pyrimidine-5-carboxylate and N,N-dimethyl amine as solution in THE as starting materials. The crude product was purified by flash column chromatography (off white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.45 (s, 2H), 6.90 (s, 1H), 6.84 (d, J=8.0 Hz, 1H), 6.74 (d, J=7.6 Hz, 1H), 5.98 (d, J=1.6 Hz, 2H), 3.76 (t, J=4.8 Hz, 4H), 3.39-3.37 (m, 1H), 2.97 (s, 6H), 2.44-2.43 (m, 2H), 2.37-2.35 (m, 2H), 1.28 (d, J=6.8 Hz, 3H). LCMS: (Method A) 384.2 (M+H), Rt. 2.44 min, 98.2% (Max). HPLC: (Method A) Rt. 2.44 min, 98.3% (Max). Chiral HPLC: (Method G) Rt. 6.98 min, 100.00%

Example 138: (S)-2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-1H-benzo[d]imidazole

[0709] ##STR00392##

[0710] To a stirred solution of Intermediate 13 (0.25 g, 0.92 mmol) in dry DMF (3 mL), TEA (0.5 mL, 3.71 mmol) and 2-bromo-1H-benzoimidazole (0.18 g, 0.92 mmol, Arbor chemicals) were added at rt and the reaction mixture was stirred at 100° C. overnight. It was cooled to rt and concentrated. This crude product was purified by flash column chromatography to afford the title compound (brown solid). .sup.1H NMR (400 MHz, CDCl.sub.3): δ7.33 (m, 2H), 7.07-7.06 (m, 2H), 6.86 (d, J=1.2 Hz, 1H), 6.76-6.74 (m, 2H), 5.97-5.96 (m, 2H), 3.59-3.58 (m, 4H), 3.35-3.34 (m, 1H), 2.60-2.59 (m, 2H), 2.52-2.51 (m, 2H), 1.35 (d, J=8.0 Hz, 3H). LCMS: (Method A) 351.2 (M+H), Rt. 2.29 min, 95.81% (Max).

[0711] HPLC: (Method A) Rt. 2.19 min, 96.33% (Max).

Example 139: (S)-2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)thiazolo[4,5-c]pyridine

[0712] ##STR00393##

[0713] To a stirred solution of Intermediate 13 (0.189 g, 0.64 mmol) in dry DMF (5 mL), TEA (0.23 mL, 1.75 mmol) and 2-chlorothiazolo[4,5-C]pyridine (0.1 g, 0.58 mmol) were added at rt and the reaction mixture was stirred overnight at 100° C. It was cooled to rt and concentrated under vacuum. To this crude residue, water (5 mL) was added and extracted with EtOAc (2×25 mL). The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4 and concentrated. The crude product was purified by flash column chromatography to afford the title compound (off white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): 1HNMR (400 MHz, DMSO-d6): δ 8.66 (s, 1H), 8.18 (d, J=5.2 Hz, 1H), 7.84 (d, J=5.2 Hz, 1H), 6.91 (d, J=1.2 Hz, 1H), 6.85 (d, J=8.0 Hz, 1H), 6.77 (d, J=8.0, 1.2 Hz, 1H), 5.60-5.99 (m, 2H), 3.59-3.57 (m, 2H), 3.45 (q, J=6.8 Hz, 1H), 2.51-2.46 (m, 4H), 1.29 (d, J=6.8 Hz, 3H). LCMS: (Method A) 369.0 (M+H), Rt. 1.90 min, 99.501% (Max). HPLC: (Method A) Rt. 1.82 min, 99.73% (Max). Chiral HPLC: (Method G) Rt. 8.31 min, 100.00%

Example 140: 2-(4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)thiazolo[4,5-c]pyridine

[0714] ##STR00394##

[0715] To a stirred solution of Intermediate 11 (0.169 g, 0.58 mmol) in dry DMF (5 mL), TEA (0.23 mL, 1.75 mmol) and 2-chlorothiazolo[4,5-C]pyridine (0.18 g, 0.60 mmol) were added at rt and the reaction mixture was stirred overnight at 100° C. The reaction mixture was cooled to rt and concentrated under vacuum. To the crude residue, water (5 mL) was added and extracted with EtOAc (2×25 mL). The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4 and concentrated. The crude product was purified by MD Autoprep HPLC (Method B) to afford the title compound (off white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.94 (d, J=7.2 Hz, 1H), 8.92 (d, J=7.2 Hz, 1H), 8.65 (s, 1H), 7.16 (d, J=5.2 Hz, 1H), 8.09 (d, J=8.4 Hz, 1H), 7.91 (dd, J=8.3, 2.0 Hz, 1H), 7.83 (d, J=5.4 Hz, 1H), 3.84 (q, J=6.8 Hz, 1H), 3.62-3.60, 2.61-2.48 (m, 4H), 1.29 (d, J=6.8 Hz, 3H). LCMS: (Method A) 377.2 (M+H), Rt. 1.48 min, 99.79% (Max). HPLC: (Method A) Rt. 1.481 min, 99.10% (Max).

Example 141: (S)-5-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-N-ethyl-1,3,4-thiadiazol-2-amine

[0716] ##STR00395##

[0717] To a stirred solution of Example 132 (0.7 g, 2.1 mmol) in THF (14 mL), acetaldehyde (0.84 mL, 5M in THF) and titanium(IV)ethoxide (0.958 g, 4.2 mmol) were added and the resulting mixture was stirred at rt overnight. The completion of the reaction was confirmed by TLC. The reaction mixture was cooled to 0° C. and sodium borohydride (0.238 g, 6.3 mmol) was added. The reaction mixture was stirred 2 h at rt. It was quenched with water (10 mL) and filtered through celite. The celite bed washed with EtOAc (2×50 mL) and the filtrate was washed with water (10 mL), brine (10 mL), dried over Na.sub.2SO.sub.4. It was evaporated at 50° C. under vacuum. The crude product was purified by MD Autoprep HPLC (Method D) to give the title compound (off white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 6.98 (t, J=5.2 Hz, 2H), 6.88 (d, J=1.2 Hz, 1H), 6.84 (d, J=8.0 Hz, 1H), 6.75 (dd, J=8.0, 1.2 Hz, 1H), 5.99-5.98 (m, 2H), 3.37 (q, J=6.8 Hz, 2H), 3.20-3.14 (m, 6H), 2.47-2.36 (m, 4H), 1.26 (d, J=6.8 Hz, 3H), 1.11 (t, J=7.2 Hz, 3H). LCMS: (Method A) 362.0 (M+H), Rt. 2.01 min, 99.75% (Max). HPLC: (Method A) Rt. 2.02 min, 97.69% (Max). Chiral HPLC: (Method B) Rt. 3.90 min, 100%

Example 142: (S)-5-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-N-propyl-1,3,4-thiadiazol-2-amine

[0718] ##STR00396##

[0719] To a stirred solution of Example 132 (0.5 g, 1.5 mmol) in THF (10 mL), propionaldehyde (0.17 g, 3.0) and titanium(IV)ethoxide (0.684 g, 3.0 mmol) were added at rt and stirred overnight. The completion of the reaction was confirmed by TLC. The reaction mixture was cooled to 0° C. and sodium borohydride (0.17 g, 4.4 mmol) was added. The reaction mixture was stirred for 2 h at rt. It was quenched with water (10 mL) and filtered through celite. The celite bed washed with EtOAc (2×50 mL) and the filtrate was washed with water (10 mL), brine solution (10 mL) and dried over Na.sub.2SO.sub.4. It was evaporated at 50° C. under vacuum. The crude product was purified by MD Autoprep HPLC (Method D) to give the title compound (off white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.02 (t, J=5.2 Hz, 2H), 6.88 (d, J=1.6 Hz, 1H), 6.84 (d, J=7.6 Hz, 1H), 6.75 (dd, J=7.6, 1.6 Hz, 1H), 5.99-5.98 (m, 2H), 3.41 (q, J=6.4 Hz, 2H), 3.20-3.17 (m, 4H), 3.11-3.06 (m, 2H), 2.45-2.32 (m, 4H), 1.56-1.47 (m, 2H), 1.26 (d, J=6.4 Hz, 3H), 0.86 (t, J=7.6 Hz, 3H). LCMS: (Method A) 376.0.0 (M+H), Rt. 2.23 min, 99.08% (Max). HPLC: (Method A) Rt. 2.21 min, 97.11% (Max).

[0720] Chiral HPLC: (Method B) Rt. 3.61. min, 100%.

Example 143: (R)-5-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-1,3,4-thiadiazol-2-amine

[0721] ##STR00397##

[0722] To a stirred solution of Intermediate 24 (1 g, 4.27 mmol) in ACN (10 mL), TEA (1.75 mL, 12.8 mmol) and 5-bromo-1,3,4-thiadiazol-2-amine (0.764 g, 4.27 mmol) were added at rt and the resulting mixture was heated at 85° C. overnight. Completion of the reaction was confirmed by TLC. Reaction mixture was evaporated under vacuum. To the resulting crude solid, water (50 mL) was added and stirred for 15 min. Then the reaction mixture was filtered and filtration cake was washed with water (20 mL) and pet ether (2×20 mL). The crude product was triturated with Et.sub.2O (2×20 mL), filtered and dried under vacuum. The title compound was isolated as brown solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 6.88-6.83 (m, 2H), 6.76-6.74 (m, 1H), 6.46 (s, 2H), 5.99-5.97 (m, 2H), 3.36 (m, 1H), 3.20-3.17 (m, 4H), 2.50-2.33 (m, 4H), 1.26 (d, J=6.8 Hz, 3H). LCMS: (Method A) 334.0 (M+H), Rt. 1.82 min, 94.96% (Max). HPLC: (Method A) Rt. 1.81 min, 93.22% (Max). Chiral HPLC: (Method A) Rt. 18.36 min, 97.38%.

Example 144: 2-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-4-methylthiazole

[0723] ##STR00398##

Step 1: tert-Butyl 4-(4-methylthiazol-2-yl)piperazine-1-carboxylate

[0724] To a stirred solution of tert-butyl 4-carbamothioylpiperazine-1-carboxylate (synthesized according to Example 5, Step 1, 1.0 g, 4.08 mmol) in dioxane (10 mL), TEA (0.58 g, 5.3 mmol) and bromo acetone (0.67 mL, 5.3 mmol) were added at rt and the resulting mixture was stirred at 90° C. for 16 h. The completion of the reaction was monitored by TLC. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (2×25 mL). The organic layer was dried over anhydrous Na.sub.2SO.sub.4, concentrated under vacuum. The crude product was taken as such for next step. Yield: 77% (0.9 g, pale yellow solid). LCMS: (Method A) 284.0 (M+H), Rt. 2.74 min, 83.2% (Max).

Step 2: 4-Methyl-2-(piperazin-1-yl)thiazole hydrochloride

[0725] To a stirred solution of tert-butyl 4-(4-methylthiazol-2-yl)piperazine-1-carboxylate (1.0 g, 3.53 mmol) in dry dioxane (2 mL), HCl in dioxane (4 N, 10 mL) was added at rt and the resulting mixture was stirred for 3 h. It was concentrated under vacuum and the resulting crude product was triturated in Et.sub.2O, filtrated and dried under vacuum to afford the title compound. Yield: 75% (500 mg, off white solid).

Step 3: 2-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-4-methylthiazole

[0726] The title compound was synthesized by following general procedure D, using 4-methyl-2-(piperazin-1-yl)thiazole hydrochloride (1.01 g, 5.41 mmol) and Intermediate 1 (1.0 g, 5.41 mmol). The crude product was purified by flash chromatography (1.2-1.5% MeOH in DCM) to afford the title compound (colorless oil). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 6.88 (s, 1H), 6.83 (d, J=8.0 Hz, 1H), 6.75 (d, J=7.6 Hz, 1H), 6.34 (s, 1H), 5.97 (s, 2H), 3.39-3.37 (m, 1H), 3.32-3.29 (m, 4H), 2.46-2.43 (m, 2H), 2.41-2.37 (m, 2H), 2.10 (s, 1H), 1.26 (d, J=6.8 Hz, 3H). LCMS: (Method A) 332.0 (M+H), Rt. 2.04 min, 99.1% (Max). HPLC: (Method A) Rt. 2.02 min, 99.6% (Max).

Example 148: 2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-4(5H)-one

[0727] ##STR00399##

[0728] To a stirred solution of Intermediate 25 (0.75 g, 2.43 mmol) in dry DMF (7 mL), TEA (1.4 mL, 7.30 mmol) and Intermediate 1 (0.9 g, 4.87 mmol) were added at rt. The resulting mixture was stirred overnight at 120° C. It was cooled to rt and DMF was evaporated under reduced pressure. Resulting crude product was purified by flash column chromatography followed by MD Autoprep HPLC (Method B), affording the title product (off white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.32 (s, 1H), 6.86-6.84 (m, 3H), 5.99-5.98 (m, 2H), 3.45-3.44 (m, 4H), 3.38-3.34 (m, 2H), 2.70-2.67 (m, 2H), 2.50-2.59 (m, 4H), 1.28-1.23 (m, 3H). LCMS: (Method A) 387.2 (M+H), Rt. 2.15 min, 96.71% (Max). HPLC: (Method A) Rt. 2.11 min, 94.32% (Max).

Example 165: 6-(1-(4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)ethyl)quinoxaline

[0729] ##STR00400##

[0730] To a stirred solution of Intermediate 11 (0.3 g, 1.23 mmol) in dry DMF (5 mL), TEA (0.5 mL, 3.71 mmol) and 2-chloro-5(trifluoromethyl) pyridine (0.22 g, 1.23 mmol) were added at rt. The resulting mixture was stirred at 90° C. overnight. It was cooled to rt and solvents were evaporated. Water (20 mL) was added and the desired product was extracted with EtOAc (2×30 mL). The resulting organic layer was dried over Na.sub.2SO.sub.4 and concentrated. The crude product was purified by flash column chromatography, affording the title compound (brown oil). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.94-8.93 (m, 2H), 8.38 (s, 1H), 8.09 (d, J=8.8 Hz, 1H), 8.01 (s, 1H), 7.93-7.91 (m, 1H), 7.77-7.75 (m, 1H), 6.91 (d, J=9.2 Hz, 1H), 3.78-3.77 (m, 1H), 3.62 (m, 4H), 2.58-2.57 (m, 2H), 2.46-2.44 (m, 2H), 1.44 (d, J=6.8 Hz, 3H). LCMS: (Method A) 388.0 (M+H), Rt. 3.17 min, 97.92% (Max). HPLC: (Method A) Rt 3.10 min, 96.45% (Max).

Example 166: (S)-1-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)-4-(5-(trifluoromethyl)pyridin-2-yl)piperazine

[0731] ##STR00401##

[0732] To a stirred solution of Intermediate 16 (0.25 g, 0.93 mmol) in dry DMF (5 mL), TEA (0.4 mL, 2.7 mmol) and 2-chloro-5-fluoro methyl pyridine (0.16 g, 9.3 mmol) were added at rt. The resulting reaction mixture was stirred at 90° C. for 12 h. It was cooled to rt, concentrated and diluted with dichloromethane (30 mL). The resulting solution was washed with saturated NaCl solution (10 mL), dried over anhydrous Na.sub.2SO.sub.4 and concentrated. The resulting crude product was purified by flash chromatography affording the title compound (brown oil). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.38 (s, 1H), 7.78 (dd, J=9.2, 2.4 Hz, 1H), 6.88 (d, J=8.0 Hz, 2H), 6.84 (d, J=8.0 Hz, 1H), 6.77-6.75 (m, 1H), 5.99-5.98 (m, 2H), 3.60 (t, J=4.8 Hz, 4H), 3.40-3.37 (m, 1H), 2.48-2.44 (m, 4H), 1.27 (d, J=6.4 Hz, 3H). LCMS: (Method A) 380.0 (M+H), Rt. 3.73 min, 98.89% (Max). HPLC: (Method A) Rt. 3.67 min, 99.06% (Max).

Example 167: (S)-1-(2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)pyrimidin-5-yl)ethan-1-one

[0733] ##STR00402##

Step 1: 1-(2-chloropyrimidin-5-yl)ethan-1-one

[0734] 5-Bromo 2-chloro pyrimidine (2 g, 10.33 mmol, Combi-Blocks) was degassed for 30 min. 1-Ethoxy vinyl tributyltin (4.1 mL, 11.3 mmol, Frontier Scientific) and bis(triphenylphosphine)palladium dichloride (0.36 g, 0.51 mmol) were added at rt. The resulting mixture was stirred overnight at 90° C. It was cooled to rt and filtered through celite. An aqueous HCl solution (6 N, 10 mL) was added and the mixture was stirred for 1 hour at rt. It was neutralized with sat. NaHCO.sub.3 solution (15 mL), extracted with DCM (50 mL), dried over anhydrous Na.sub.2SO.sub.4 and concentrated. The crude product was purified by flash column chromatography to afford the title compound (pale yellow solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.90 (s, 2H), 2.65 (s, 3H). LCMS: (Method B) 162.0 (M+H), Rt. 4.6 min, 98.01% (Max).

Step 2: (S)-1-(2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)pyrimidin-5-yl)ethan-1-one

[0735] To a stirred solution of Intermediate 16 (1.14 g, 4.24 mmol) in dry DMF (10 mL), TEA (1.1 mL, 16.5 mmol) and 1-(2-chloropyrimidin-5-yl)ethan-1-one obtained in the previous step (0.6 g, 3.85 mmol) were added at rt. The resulting mixture was heated to 90° C. for 12 h. It was cooled to rt and concentrated. Dichloromethane (50 mL) was added and was washed with a saturated NaCl solution (10 mL), dried over anhydrous Na.sub.2SO.sub.4 and concentrated. The crude product was purified by flash chromatography, affording the title compound (off white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.83 (s, 2H), 6.90 (s, 1H), 6.84 (d, J=7.6 Hz, 1H), 6.74 (dd, J=8.0, 1.2 Hz, 1H), 5.99-5.98 (m, 2H), 3.84 (t, J=4.8 Hz, 4H), 3.40-3.36 (m, 1H), 2.49-2.47 (m, 5H), 2.38-2.35 (m, 2H), 1.27 (d, J=6.8 Hz, 3H). LCMS: (Method A) 355.0 (M+H), Rt. 2.61 min, 99.78% (Max). HPLC: (Method A) Rt. 2.55 min, 99.51% (Max).

Example 168: 1-(2-(4-((S)-1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)pyrimidin-5-yl)ethan-1-ol

[0736] ##STR00403##

[0737] To a stirred solution of Example 167 (0.2 g, 0.56 mmol) in dry MeOH (5 mL), sodium borohydride (0.48 g, 0.84 mmol, spectrochem) was added portion wise at 0° C. The resulting mixture was stirred at rt for 1 h. It was concentrated, diluted with DCM (20 mL) and washed with brine solution (5 mL) and dried over Na.sub.2SO.sub.4. After evaporation of the solvent, the crude product was purified by flash column chromatography to afford the titled compound. Yield: 77% (0.154 g, brown oil). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.29 (s, 2H), 6.89 (s, 1H), 6.84 (d, J=8.0 Hz, 1H), 6.76 (dd, J=8.0, 1.6 Hz, 1H), 5.99-5.98 (m, 2H), 5.12 (d, J=4.4 Hz, 1H), 4.62-4.59 (m, 1H), 3.67 (t, J=5.2 Hz, 4H), 3.39-3.37 (m, 1H), 2.42-2.40 (m, 2H), 2.35-2.32 (m, 2H), 1.32-1.27 (m, 6H). LCMS: (Method A) 357.2 (M+H), Rt. 2.38 min, 99.04% (Max). HPLC: (Method A) Rt. 2.31 min, 98.15% (Max).

Example 169: N-(2-(4-(1-(2-methylbenzo[d]thiazol-5-yl)ethyl)piperazin-1-yl)pyrimidin-5-yl)acetamide

[0738] ##STR00404##

[0739] To a stirred solution of Intermediate 10 (0.17 g, 0.66 mmol) in dry DMF (3 mL), TEA (0.45 mL, 1.99 mmol) and Intermediate 26 (0.21 g, 0.99 mmol) were added at rt. The resulting reaction mixture was stirred at 120° C. overnight. It was cooled to rt and concentrated under reduced pressure. The resulting crude product was purified by flash column chromatography, followed by MD Autoprep HPLC (Method B), affording the title product (brown oil). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.80 (s, 1H), 8.45 (s, 2H), 7.95 (d, J=8.0 Hz, 1H), 7.83 (s, 1H), 7.38 (d, J=8.4 Hz, 1H), 3.58-3.57 (m, 5H), 2.78 (s, 3H), 3.36-2.35 (m, 4H), 1.99 (s, 3H), 1.37 (d, J=6.8 Hz, 3H). LCMS: (Method A) 397.2 (M+H), Rt. 2.38 min, 98.23% (Max). HPLC: (Method A) Rt. 2.31 min, 96.17% (Max).

Example 170: N-(5-(4-(1-(2-methylbenzo[d]thiazol-5-yl)ethyl)Piperazin-1-yl)-1,3,4-thiadiazol-2-yl)acetamide

[0740] ##STR00405##

[0741] To a stirred solution of Intermediate 7 (0.17 g, 0.64 mmol) in dry DMF (3 mL), TEA (0.3 mL, 1.93 mmol) and Intermediate 26 (0.21 g, 0.96 mmol) were added at rt and the reaction mixture was stirred at 120° C. overnight. The resulting reaction mixture was cooled to rt and the solvents were concentrated under reduced pressure. The resulting crude product was purified by flash chromatography followed by MD Autoprep HPLC (Method B) affording the title product (brown oil). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 12.01 (s, 1H), 7.97 (d, J=8.0 Hz, 1H), 7.84 (d, J=1.6 Hz, 1H), 7.39-7.37 (m, 1H), 3.64-3.62 (m, 1H), 3.36-3.33 (m, 4H), 2.79 (s, 3H), 2.53-2.52 (m, 2H), 2.49-2.47 (m, 2H), 2.07 (s, 3H), 1.38 (d, J=6.8 Hz, 3H). LCMS: (Method A) 403.0 (M+H), Rt. 2.45 min, 98.38% (Max). HPLC: (Method A) Rt. 2.32 min, 98.57% (Max).

Example 171: 2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-4(5H)-one

[0742] ##STR00406##

[0743] To a stirred solution of 3-hydroxypropionaic acid (97 mg, 1.0 mmol) in dry NMP (5 mL), Example 132 (300 mg, 0.9 mmol), triethylamine (0.18 mg, 1.8 mmol) and HATU (513 mg, 1.3 mmol) were added at 0° C. The resulting mixture was stirred at rt for 1 h. It was diluted with water (15 mL) and extracted with EtOAc (2×15 mL). Combined organic layers was dried over Na.sub.2SO.sub.4. After evaporation of the solvents, the crude product was further purified by MD Autoprep HPLC (Method B), affording the title compound (off white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ11.98 (s, 1H), 6.88 (s, 1H), 6.84 (d, J=8.0 Hz, 1H), 6.75 (d, J=8.0 Hz, 1H), 5.98-5.97 (m, 2H), 4.71 (t, J=5.2 Hz, 1H), 3.69-3.64 (m, 2H), 3.40-3.32 (m, 5H), 2.54-2.32 (m, 6H), 1.25 (d, J=6.4 Hz, 3H). LCMS: (Method A) 406.0 (M+H), Rt. 2.15 min, 99.05% (Max). HPLC: (Method A) Rt. 2.11 min, 98.88% (Max).

Example 172: 6-(1-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl)ethyl)quinoxaline

[0744] ##STR00407##

[0745] To the stirred solution of Intermediate 11 (0.25 g, 1.03 mmol) in dry DMF (3 mL), TEA (0.43 mL, 3.09 mmol) and 2-chloro-5-fluoropyrimidine (0.15 g, 1.13 mmol) were added at rt and the resulting mixture was stirred at 120° C. overnight. It was cooled to rt and solvent was evaporated under reduced pressure. The resulting crude product was purified by flash chromatography to afford the title product (brown oil). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.93-8.91 (m, 2H), 8.41 (s, 2H), 8.07 (d, J=8.4 Hz, 1H), 7.99 (s, 1H), 7.91 (d, J=8.8 Hz, 1H), 3.75-3.74 (m, 1H), 3.68-3.65 (m, 4H), 2.56-2.53 (m, 2H), 2.42-2.41 (m, 2H), 1.42 (d, J=6.8 Hz, 3H). LCMS: (Method A) 339.0 (M+H), Rt. 2.32 min, 99.29% (Max). HPLC: (Method A) Rt. 2.23 min, 99.19% (Max).

Example 173: (S)-2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)Piperazin-1-yl)-5-fluoropyrimidine

[0746] ##STR00408##

[0747] To a stirred solution of Intermediate 16 (0.4 g, 1.50 mmol) in dry DMF (10 mL), TEA (0.6 mL, 4.5 mmol) and 2-chloro-5-fluoro pyrimidine (0.2 g, 1.5 mmol) were added at rt and the reaction mixture was stirred at 90° C. for 12 h. It was cooled to rt and concentrated. Dichloromethane (50 mL) was added and the mixture was washed with sat NaCl solution (10 mL) dried over anhydrous Na.sub.2SO.sub.4. After evaporation of the solvents, the crude product was purified by flash chromatography to give the title compound (colourless oil). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.42 (s, 2H), 7.43 (d, J=7.6 Hz, 1H), 6.89-6.85 (m, 1H), 6.75 (dd, J=7.6, 1.2 Hz, 1H), 5.99-5.98 (m, 2H), 3.65 (t, J=5.2 Hz, 4H), 3.37-3.35 (m, 1H), 2.43-2.41 (m, 2H), 2.37-2.35 (m, 2H), 1.28 (d, J=6.4 Hz, 3H). LCMS: (Method A) 331.0 (M+H), Rt. 2.88 min, 99.79% (Max). HPLC: (Method A) Rt. 2.82 min, 99.93% (Max).

Example 174: N-(2-(4-(1-(benzo[d]thiazol-6-yl)ethyl)piperazin-1-v)pyrimidin-5-yl)acetamide

SGN020494-01-00045-078N01:

[0748] ##STR00409##

[0749] To a stirred solution of Intermediate 10 (0.22 g, 0.85 mmol) in dry DMF (10 mL), DIPEA (0.6 mL, 3.43 mmol) and Intermediate 27 (0.25 g, 1.28 mmol) were added at rt and the reaction mixture was stirred overnight at 120° C. It was cooled to rt and the solvent was evaporated under reduced pressure. The resulting crude product was purified by flash column chromatography to afford the title product (off white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.81 (s, 1H), 9.35 (s, 1H), 8.46 (s, 2H), 8.11 (s, 1H), 8.04 (d, J=8.4 Hz, 1H), 7.55-7.53 (m, 1H), 3.65-3.62 (m, 5H), 2.52-2.51 (m, 2H), 2.34-2.33 (m, 2H), 2.00 (s, 3H), 1.39 (d, J=6.4 Hz, 3H). LCMS: (Method A) 383.3 (M+H), Rt. 2.03 min, 98.47% (Max). HPLC: (Method A) Rt. 1.98 min, 98.35% (Max).

Example 175: (S)-2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)Piperazin-1-yl)-5-bromopyrimidine

[0750] ##STR00410##

[0751] To a stirred solution of Intermediate 16 (4.1 g, 15.5 mmol) in dry DMF (30 mL), TEA (6.4 mL, 46.5 mmol) and 5-bromo-2-chloro pyrimidine (3 g, 15.5 mmol) were added at rt and the reaction mixture was stirred at 90° C. for 12 h. It was cooled to rt and concentrated under reduced pressure. Dichloromethane (150 mL) was added. The solution was washed with brine (50 mL) and dried over anhydrous Na.sub.2SO.sub.4. After evaporation of the solvents, the crude product was purified by flash chromatography affording the title compound. Yield: 57% (3.5 g, white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.43 (s, 2H), 6.83-6.89 (m, 2H), 6.76 (d, J=7.8 Hz, 1H), 5.99-5.98 (m, 2H), 3.67 (t, J=4.8 Hz, 4H), 3.37-3.33 (m, 1H), 2.41-2.33 (m, 4H), 1.28 (d, J=6.6 Hz, 3H). LCMS: (Method A) 391.0 (M+H), Rt. 3.25 min, 99.9% (Max).

Example 176: (S)-2-(2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)pyrimidin-5-yl)propan-2-ol

[0752] ##STR00411##

[0753] To a stirred solution of Example 175 (0.5 g, 1.28 mmol) in dry THF (10 mL) cooled at −78° C., n-BuLi (1.6 M, 1.2 mL, 19.2 mmol, Aldrich) was added. The mixture was stirred at −78° C. for 1 h. Dry acetone in THF (0.89 g, 1.53 mmol, Aldrich) was then added at the same temperature and the mixture was stirred for 10 minutes. The temperature was increased to rt over 1 h. The reaction mixture was quenched with saturated ammonium chloride solution (10 mL). The desired product was extracted with EtOAc (50 mL), washed with sat NaCl solution (20 mL) and dried over anhydrous Na.sub.2SO.sub.4. After evaporation of the solvents, the crude product was purified by MD Autoprep HPLC (Method D), affording the title product (off white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): 8.33 (s, 2H), 6.89-6.83 (m, 2H), 6.77-6.74 (m, 1H), 5.99-5.98 (m, 2H), 5.05 (s, 1H), 3.66 (d, J=4.8 Hz, 4H), 3.38-3.35 (m, 1H), 2.45-2.43 (m, 2H), 2.35-2.32 (m, 2H), 1.59 (s, 6H), 1.28 (d, J=6.8 Hz, 3H). LCMS: (Method A) 371.2 (M+H), Rt. 2.5 min, 99.51% (Max). HPLC: (Method A) Rt. 2.46 min, 98.9% (Max).

Example 177: (S)—N-(2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)pyrimidin-5-yl)-3-hydroxypropanamide

[0754] ##STR00412##

Step 1: (S)-2-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-4-nitropyrimidine

[0755] To a stirred solution of Intermediate 16 (4.8 g, 18.7 mmol) in dry ACN (15 mL), Et.sub.3N (10.5 mL, 75.0 mmol) and 2-chloro-5-nitropyrimidine (3.0 g, 18.7 mmol) were added at rt. The mixture was heated at 80° C. overnight. It was cooled to rt, diluted with DCM (20 mL), washed with water (15 mL) and brine (15 mL), and dried over anhydrous Na.sub.2SO.sub.4. After evaporation of the solvents, the crude product was triturated with MeOH, filtered and dried under vacuum, affording the title compound. Yield: 75% (3.8 g, pale yellow solid). LCMS: (Method A) 358.3 (M+H), Rt. 2.94 min, 98.07% (Max).

Step 2: (S)-2-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)pyrimidin-5-amine

[0756] To a stirred solution of (S)-2-(4-(1-(Benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-4-nitropyrimidine obtained in the previous step (1.0 g, 62.9 mmol) in a mixture of methanol (100 mL) and THF (100 mL), 10% Pd/C (200 mg, 20% w/w) was added at rt. The reaction mixture was stirred under hydrogen atmosphere (1 kg/cm.sup.2) at rt overnight. Completion of the reaction was confirmed by TLC. The reaction mixture was filtered through celite and washed with methanol. After evaporation of the solvents, the title compound was obtained and used in the next step without further purification. Yield: 96% (1.0 g, pale brown solid). LCMS: (Method A) 328.2 (M+H), Rt. 1.52 min, 90.58% (Max).

Step 3: (S)—N-(2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)pyrimidin-5-yl)-3-hydroxypropanamide

[0757] To a stirred solution of 3-hydroxypropionic acid (132 mg, 1.0 mmol) in dry DMF (2 mL), (S)-2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)pyrimidin-5-amine obtained in the previous step (400 mg, 1.2 mmol), DIPA (236 mg, 1.83 mmol) and HATU (557 mg, 1.83 mmol) were added at 0° C. The reaction mixture was stirred at rt overnight. The completion of the reaction was monitored by TLC. The reaction mixture was diluted water (10 mL) and extracted with DCM (15 mL). The organic layer was dried over anhydrous Na.sub.2SO.sub.4 and evaporated. The crude product was purified by preparative HPLC (Method B), affording the title product (off white solid). .sup.1H NMR (400 MHz, CDCl.sub.3): δ 8.40 (s, 2H), 7.79 (br s, 1H), 6.88 (s, 1H), 6.75 (s, 2H), 5.96-5.95 (m, 2H), 3.97 (t, J=6.8 Hz, 2H), 3.77 (t, J=4.8 Hz, 4H), 3.35 (q, J=6.8 Hz, 1H), 2.56-2.62 (m, 2H), 2.48-2.55 (m, 2H), 2.42-2.51 (m, 2H), 1.37 (d, J=6.8 Hz, 3H). LCMS: (Method A) 400.2 (M+H), Rt. 2.11 min, 99.42% (Max). HPLC: (Method A) Rt. 2.06 min, 98.9% (Max).

Example 178: 2-(4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-4(5H)-one

[0758] ##STR00413##

[0759] To a stirred solution of Intermediate 25 (0.7 g, 2.57 mmol) in dry DMF (10 mL), TEA (1.1 mL, 7.71 mmol) and Intermediate 6 (0.49 g, 2.57 mmol) were added at rt and the reaction mixture was stirred at 90° C. overnight. The reaction mixture was cooled to rt and concentrated. Water (50 mL) was added and the desired product was extracted with DCM (150 mL) and dried over anhydrous Na.sub.2SO.sub.4. After evaporation of the solvents, the crude product was purified by MD Autoprep HPLC (Method B), affording the title compound (off white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.94 (d, J=6.0 Hz, 2H), 8.09 (d, J=8.4 Hz, 1H), 8.01 (s, 1H), 7.91 (d, J=8.4 Hz, 1H), 7.73 (s, 1H), 3.83-3.82 (m, 1H), 3.49-3.47 (m, 4H) 2.70-2.67 (m, 2H), 2.60-2.58 (m, 2H), 2.51-2.49 (m, 4H), 1.42 (d, J=6.8 Hz, 3H). LCMS: (Method A) 395.2 (M+H), Rt. 1.74 min, 99.66% (Max). HPLC: (Method A) Rt. 1.70 min, 99.19% (Max).

Example 179: N-(5-(4-(1-(benzo[d]thiazol-6-yl)ethyl)Piperazin-1-yl)-1,3,4-thiadiazol-2-yl)acetamide

[0760] ##STR00414##

[0761] To a stirred solution of Intermediate 7 (0.22 g, 0.83 mmol) in dry DMF (3 mL), DIPEA (0.6 mL, 3.34 mmol) and Intermediate 27 (0.25 g, 1.25 mmol) were added at rt. The reaction mixture was stirred at 120° C. overnight. It was cooled to rt and DMF was evaporated under reduced pressure. The resulting crude product was purified by flash chromatography followed by MD Autoprep HPLC (Method B), affording the title product (off white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.34 (s, 1H), 8.10 (s, 1H), 8.03 (d, J=8.4 Hz, 1H), 7.52 (d, J=8.4 Hz, 1H), 3.63-3.61 (m, 1H), 3.29-3.28 (m, 4H), 2.56-2.53 (m, 2H), 2.43-2.42 (m, 2H), 1.93 (s, 3H), 1.37 (d, J=6.8 Hz, 3H). LCMS: (Method A) 389.0 (M+H), Rt. 2.04 min, 96.53% (Max). HPLC: (Method A) Rt. 1.93 min, 97.68% (Max).

Example 180: (S)-1-(2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)pyrimidin-5-yl)cyclohexan-1-ol

[0762] ##STR00415##

[0763] To a stirred solution of Example 175 (0.5 g, 1.28 mmol) in dry THF (10 mL) at −78° C., n-BuLi (1.6M, 0.9 mL, 15.3 mmol, Aldrich) was added and the reaction mixture was stirred at −78° C. for 1 h. Cyclohexanone (0.15 g, 1.53 mmol, Aldrich) in dry THF (1 mL) was added at −78° C. and the mixture was stirred for 10 minutes. The temperature was increased to rt over 1 h. The reaction completion was monitored by TLC. The reaction was quenched with saturated ammonium chloride solution (10 mL) and was extracted with EtOAc (50 mL). The organic layer was washed with sat NaCl solution (20 mL) dried over anhydrous Na.sub.2SO.sub.4 and the solvents were evaporated under reduced pressure. The crude product was purified by flash column chromatography to afford the title compound (off white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.38 (s, 2H), 6.88 (s, 1H), 6.83 (d, J=7.6 Hz, 1H), 6.74 (d, J=7.6 Hz, 1H), 5.98-5.97 (m, 2H), 4.73 (s, 1H), 3.65-3.63 (m, 4H), 3.33-3.31 (m, 1H), 2.40-2.38 (m, 2H), 2.34-2.32 (m, 2H), 1.65-1.60 (m, 6H), 1.45-1.42 (m, 2H), 1.28-1.22 (m, 5H). LCMS: (Method A) 411.2 (M+H), Rt. 3.25 min, 96.51% (Max). HPLC: (Method A) Rt. 3.14 min, 97.88% (Max).

Example 181: (S)-1-(2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)pyrimidin-5-yl)cyclopentan-1-ol

[0764] ##STR00416##

[0765] The title compound was prepared according to the protocol described for the preparation of Example 180, replacing cyclohexanone with cyclopentanone (0.12 g, 1.53 mmol, Aldrich). The crude product was purified by flash column chromatography to afford the title compound (brown oil). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.38 (s, 2H), 6.88 (s, 1H), 6.83 (d, J=7.6 Hz, 1H), 6.74 (d, J=7.6 Hz, 1H), 5.98-5.97 (m, 2H), 4.80 (s, 1H), 3.65-3.63 (m, 4H), 3.32-3.30 (m, 1H), 2.49-2.45 (m, 2H), 2.34-2.32 (m, 2H), 1.82-1.7 (m, 8H), 1.28 (d, J=6.8 Hz, 3H). LCMS: (Method A) 397.2 (M+H), Rt. 2.90 min, 98.83% (Max). HPLC: (Method A) Rt. 2.87 min, 99.10% (Max).

Example 182: (S)-2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine

[0766] ##STR00417##

Step 1: tert-butyl-4-((trimethylsilyl)oxy)-3,6-dihydropyridine-1(2H)-carboxylate

[0767] To a stirred solution of N-boc piperidone (5 g, 25.09 mmol) in dry DMF (50 mL), TEA (6.95 mL, 50.18 mmol) and trimethylsilyl chloride (6.35 mL, 50.18 mmol) were added slowly at 0° C. and the mixture was stirred at 90° C. overnight. Solvents were evaporated under reduced pressure and EtOAc (70 mL) was added. This solution was washed with water (25 mL), 10% sodium bicarbonate solution (25 mL), (15 mL) and was dried over Na.sub.2SO.sub.4. Solvents were evaporated, affording the title product that was used in the next step without further purification. Yield: 99% (7.49 g, brown oil). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 4.80 (s, 1H), 3.62-3.59 (m, 2H), 3.44-3.41 (m, 2H), 2.02-2.00 (m, 2H), 1.40 (s, 9H), 0.17 (s, 9H).

Step 2: tert-butyl 3-bromo-4-oxopiperidine-1-carboxylate

[0768] To a stirred solution of tert-butyl-4-((trimethylsilyl)oxy)-3,6-dihydropyridine-1(2H)-carboxylate, obtained in step 1, (7.48 g, 27.60 mmol) in dry CCl.sub.4 (80 mL, 10 V), N-bromosuccinimide (5.42 g, 30.36 mmol) was added at 10° C. The reaction mixture was stirred at 10-15° C. for 2 h. It was evaporated under reduced pressure. Water (30 mL) was added and the desired product was extracted with EtOAc (2×60 mL). Organic layer was dried over Na.sub.2SO.sub.4 and the solvents were evaporated. The resulting crude product was purified by flash chromatography affording the title product (white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 4.74 (s, 1H), 4.02-4.00 (m, 2H), 3.60-3.58 (m, 2H), 2.69-2.68 (m, 2H), 1.39 (s, 9H).

Step 3: (S)-4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazine-1-carbothioamide

[0769] To stirred solution of Intermediate 16 (5 g, 18.51 mmol) in THF (50 mL), TEA (8.8 mL, 55.55 mmol) followed by N,N′-thiocarbonyldiimidazole (3.8 g, 22.22 mmol, Arbor chemicals) were added at rt and the mixture was stirred overnight at rt. Ammonia solution in methanol (7 N, 50 mL, 350 mmol) was added and the mixture was stirred overnight at 50° C. It was evaporated under reduced pressure, diluted with EtOAc (100 mL), washed with water (25 mL) and dried over Na.sub.2SO.sub.4. The title product was obtained after evaporation of the solvents and was used without further purification. Yield: 58% (3.6 g, brown liquid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.61 (s, 2H), 6.99 (s, 1H), 6.70 (d, J=8.0 Hz, 2H), 5.97-5.96 (m, 2H), δ 3.67-3.65 (m, 1H), 3.40-3.37 (m, 2H), 2.77-2.75 (m, 2H), δ 2.33-2.25 (m, 4H), 1.24-1.22 (m, 3H). LCMS: (Method A) 294.00 (M+H), Rt. 2.03 min, 55.70% (Max).

Step 4: tert-butyl(S)-2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate

[0770] To a stirred solution of (S)-4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazine-1-carbothioamide (Example 182, Step 3, 3.6 g, 12.28 mmol) in isopropanol (35 mL), tert-butyl 3-bromo-4-oxopiperidine-1-carboxylate (Example 182, Step 2, 3.4 g, 12.28 mmol) was added at rt. The reaction mixture was stirred overnight at 90° C. After evaporation of the solvents, the crude product was purified by flash column chromatography to afford the title product (yellow liquid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 6.88-6.87 (m, 2H), 6.85 (s, 1H), 5.99-5.98 (m, 2H), 4.35-4.34 (m, 1H), 4.06-4.04 (m, 2H), 3.57-3.56 (m, 2H), 3.42-3.41 (m, 2H), δ 3.32-3.29 (m, 2H), 2.49-2.46 (m, 2H), 2.41-2.40 (m, 4H), 1.42 (s, 9H), 1.24-1.22 (m, 3H). LCMS: (Method A) 473.0 (M+H), Rt. 3.54 min, 71.96% (Max).

Step 5: (S)-2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine

[0771] To a stirred solution of tert-butyl(S)-2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate obtained in previous step (1.7 g, 3.60 mmol) in 1,4-dioxane (17 mL), HCl in dioxane (4 N, 40 mmol, 10 mL, 6V) was added at 0° C. The reaction mixture was stirred for 2 h at rt. It was concentrated under reduced pressure. DCM was added (15 mL) and was evaporated. This process was repeated a second time. Saturated sodium bicarbonate solution (20 mL) was added and the mixture was stirred for 2 h. Resulting free amine was extracted with DCM (100 mL), washed with brine (15 mL) and dried over Na.sub.2SO.sub.4. After evaporation of the solvent, the resulting crude product was purified by flash column chromatography to afford the title compound (brown oil). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 6.88 (d, J=1.2 Hz, 1H), 6.85-6.83 (m, 1H), 6.76-6.74 (m, 1H), 5.99-5.98 (m, 2H), 3.68 (s, 2H), 3.42-3.40 (m, 1H), 3.30-3.27 (m, 4H), 2.91 (t, J=5.6 Hz, 4H), 2.40-2.38 (m, 4H), 1.27 (d, J=6.8 Hz, 3H). LCMS: (Method A) 373.3 (M+H), Rt. 1.82 min, 99.52% (Max). HPLC: (Method A) Rt. 1.80 min, 99.18% (Max).

Example 183: Ethyl (S)-6-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)nicotinate

[0772] ##STR00418##

[0773] To a stirred solution of Intermediate 16 (1.0 g, 3.71 mmol) in dry DMF (10 mL), TEA (1.54 mL, 11.1 mmol) and ethyl-6-chloro nicotinate (0.69 g, 3.71 mmol) were added at rt and the reaction mixture was heated at 90° C. for 12 h. It was cooled to rt and concentrated. DCM (50 mL) was added and the resulting solution was washed with brine (30 mL) and dried over anhydrous Na.sub.2SO.sub.4. After evaporation of the solvents, the crude product was purified by flash chromatography to give the title compound (off white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.61 (d, J=2.4 Hz, 1H), 7.92-7.90 (m, 1H), 6.89 (d, J=1.6 Hz, 1H), 6.85-6.81 (m, 2H), 6.77-6.75 (m, 1H), 5.99-5.98 (m, 2H), 4.27 (q, J=7.2 Hz, 2H) 3.61 (t, J=4.8 Hz, 4H), 3.39-3.37 (m, 1H), 2.45-2.33 (m, 5H), 1.29-1.26 (m, 3H). LCMS: (Method A) 384.2 (M+H), Rt. 3.14 min, 98.30% (Max). HPLC: (Method A) Rt. 3.11 min, 98.88% (Max).

Example 184: (S)-1-(2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)ethan-1-one

[0774] ##STR00419##

[0775] To a stirred solution of Example 182 (0.18 g, 0.48 mmol) in dry DCM (2 mL), TEA (0.13 mL, 0.96 mmol) and acetic anhydride (0.07 mL, 0.72 mmol) were added at 0° C. and the reaction mixture was stirred at rt overnight. It was diluted with DCM (50 mL), washed with water (15 mL), brine (15 mL) and dried over anhydrous Na.sub.2SO.sub.4. After evaporation of the solvents, the crude product was purified by flash chromatography to give the title compound (brown oil). .sup.1H NMR (400 MHz, DMSO-d.sub.6, performed at 80° C.): δ 6.87 (d, J=1.6 Hz, 1H), 6.84 (d, J=8.0 Hz, 1H), 6.75 (dd, J=1.6, 8.0 Hz, 1H), 5.99-5.98 (m, 2H), 4.48 (s, 2H), 3.71-3.65 (m, 2H), 3.47-3.43 (m, 1H), 3.35-3.30 (m, 4H), 2.60-2.54 (m, 2H), 2.47-2.40 (m, 4H), 2.06 (s, 3H), 1.29 (d, J=6.4 Hz, 3H). LCMS: (Method A) 415.3 (M+H), Rt. 2.20 min, 96.80% (Max). HPLC: (Method A) Rt 2.15 min, 97.88% (Max).

Example 185: (S)-(6-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)pyridin-3-yl)methanol

[0776] ##STR00420##

[0777] To a stirred solution of Example 183 (0.2 g, 0.56 mmol) in dry MeOH (5 mL) cooled at 0° C., was added lithium aluminium hydride (2.4 M, 0.24 mL, 1.17 mmol, spectrochem) dropwise and the mixture was stirred for 1 h at the same temperature. The reaction mixture was quenched with saturated ammonium chloride (5 mL) and extracted with ethyl acetate (20 mL). The organic phase was washed with brine solution (5 mL), dried over Na.sub.2SO.sub.4 and concentrated. The crude product was purified by flash column chromatography to afford the titled compound. Yield: 66% (88 mg, colorless oil). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.04 (d, J=2.0 Hz, 1H), 7.46 (dd, J=8.8, 2.4 Hz, 1H), 6.88-6.86 (m, 1H), 6.84-6.82 (m, 1H), 6.76-6.73 (m, 2H), 5.98-5.97 (m, 2H), 4.96 (t, J=5.6 Hz, 1H) 4.32 (d, J=5.6 Hz, 2H), 3.41 (t, J=9.6 Hz, 4H), 3.34-3.32 (m, 1H), 2.49-2.45 (m, 2H), 2.39-2.37 (m, 2H), 1.28 (d, J=6.8 Hz, 3H). LCMS: (Method A) 342.3 (M+H), Rt. 1.74 min, 99.28% (Max). HPLC: (Method A) Rt. 1.71 min, 98.49% (Max).

Example 186: (S)-6-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-N-methylnicotinamide

[0778] ##STR00421##

Step 1: Lithium (S)-6-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)nicotinate

[0779] Example 183 (1 g, 2.62 mmol) was dissolved in a mixture of MeOH (2 mL), THF (7 mL) and water (1 mL). The resulting mixture was cooled to 0° C. and lithium hydroxide (0.32 g, 7.86 mmol, spectrochem) was added. The resulting mixture was heated at 90° C. for 2 h. It was then concentrated and used as such in next step. Yield: 85% (0.8 g, off white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.52 (d, J=2.3 Hz, 1H), 7.89-7.86 (m, 1H), 6.88-6.59 (m, 4H), 5.97-5.96 (m, 2H), 3.43-3.33 (m, 5H), 2.36-2.28 (m, 4H), 1.26 (d, J=8.7 Hz, 3H). LCMS: (Method A) 354.0 (M+H), Rt. 3.639 min, 93.32% (Max).

Step 2: (S)-6-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-N-methylnicotinamide

[0780] To a stirred solution of lithium (S)-6-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)nicotinate (0.3 g, 8.32 mmol) in dry DCM (10 mL) cooled to 0° C., were added triethylamine (0.5 mL, 3.72 mmol), methylamine in THF (2 M, 2 mL, 2.24 mmol) followed by T.sub.3P (0.6 mL, 3.72 mmol). The resulting mixture was stirred at rt for 1 h. Reaction completion was monitored by TLC. The reaction mixture was washed with 10% sodium bicarbonate solution (10 mL). The organic layer was dried over Na.sub.2SO.sub.4, and evaporated to dryness. The crude product was purified by flash column chromatography (white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.54 (d, J=2.0 Hz, 1H), 8.18 (d, J=4.4 Hz, 1H), 7.89 (dd, J=2.4, 9.2 Hz, 1H), 6.89 (d, J=1.2 Hz, 1H), 6.85-6.77 (m, 1H), 6.77-6.74 (m, 2H), 5.99-5.98 (m, 2H), 3.54 (t, J=4.8 Hz, 4H), 3.37-3.35 (m, 1H), 2.73 (d, J=4.4 Hz, 3H), 2.45-2.43 (m, 2H), 2.39-2.32 (m, 2H), 1.28 (d, J=6.8 Hz, 3H). LCMS: (Method A) 369.2 (M+H), Rt. 2.05 min, 98.6% (Max). HPLC: (Method A) Rt. 2.00 min, 98.3% (Max).

Example 187: (S)-6-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)Piperazin-1-yl)-N,N-dimethylnicotinamide

[0781] ##STR00422##

[0782] To a stirred solution of lithium (S)-6-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)nicotinate (Example 186, Step 1, 0.5 g, 1.38 mmol) in dry DCM (10 mL) at 0° C., were added triethylamine (2.6 mL, 4.14 mmol), dimethylamine in THF (2 M, 2 mL, 2.24 mmol) followed by T.sub.3P (2.6 mL, 4.14 mmol). The resulting mixture was stirred at rt for 1 h. Reaction completion was monitored by TLC. The reaction mixture was washed with 10% sodium bicarbonate solution (10 mL). The organic layer was dried over Na.sub.2SO.sub.4, and evaporated to dryness. The crude product was purified by flash column chromatography. Yield: 52% (279 mg, off white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.19 (d, J=2.4 Hz, 1H), 7.59 (dd, J=2.4, 8.8 Hz, 1H), 6.90 (s, 1H), 6.85 (d, J=8.0 Hz, 1H), 6.78 (t, J=7.2 Hz, 2H), 5.99-5.98 (m, 2H), 3.54-3.51 (m, 4H), 3.38-3.33 (m, 1H), 2.96 (s, 6H), 2.47-2.46 (m, 2H), 2.41-2.34 (m, 2H), 1.29 (d, J=6.8 Hz, 3H). LCMS: (Method A) 383.3 (M+H), Rt. 2.19 min, 99.8% (Max). HPLC: (Method A) Rt. 2.14 min, 99.6% (Max).

Example 188: (S)-4-(2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)pyrimidin-5-yl)tetrahydro-2H-pyran-4-ol

[0783] ##STR00423##

[0784] To a stirred solution of Example 175 (0.5 g, 1.28 mmol) in dry THF (10 mL) at −78° C. was added n-BuLi (1.6 M, 1.2 mL, 1.92 mmol, Aldrich) and the resulting mixture was stirred to −78° C. for 1 h. Tetrahydrofuran-4H-pyran-4-one (0.15 g, 1.53 mmol, Aldrich) in THF (5 mL) was added at −78° C. for 10 minutes. The temperature was increased to rt over 1 h. The reaction completion was monitored by TLC. The reaction mixture was quenched with saturated ammonium chloride solution (10 mL). It was extracted with EtOAc (50 mL). The organic phase was washed with saturated NaCl solution (20 mL) and dried over anhydrous Na.sub.2SO.sub.4. The crude product was purified by flash column chromatography to afford the title compound (off white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.42 (s, 2H), 6.90 (s, 1H), 6.84 (d, J=8.0 Hz, 1H), 6.76 (d, J=8.0 Hz, 1H), 5.99-5.98 (m, 2H), 5.07 (s, 1H), 3.77-3.66 (m, 8H), 3.39-3.37 (m, 1H), 2.44-2.40 (m, 2H), 2.37-2.33 (m, 2H), 1.95-1.87 (m, 2H), 1.57-1.54 (m, 2H), 1.28 (d, J=6.8 Hz, 3H). LCMS: (Method A) 413.3 (M+H), Rt. 2.32 min, 99.65% (Max). HPLC: (Method A) Rt. 2.27 min, 99.23% (Max).

Example 189: 3-(2-(4-((S)-1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)pyrimidin-5-yl)tetrahydrofuran-3-ol

[0785] ##STR00424##

[0786] Example 189 was prepared according the same procedure as Example 188, replacing tetrahydrofuran-4H-pyran-4-one with dihydrofuran(2H)-one (0.13 g, 1.53 mmol, Aldrich). The crude product was purified by flash column chromatography to afford the title compound (off white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.41 (s, 2H), 6.90 (d, J=1.2 Hz, 1H), 6.84 (d, J=7.6 Hz, 1H), 6.76 (d, J=7.6 Hz, 1H), 5.99-5.98 (m, 2H), 3.97-3.93 (m, 2H), 3.78-3.76 (m, 1H), 3.68-3.65 (m, 6H), 2.50-2.42 (m, 1H), 2.35-2.32 (m, 4H), 2.33-2.32 (m, 1H), 2.11-2.06 (m, 1H), 1.28 (d, J=6.4 Hz, 3H). LCMS: (Method A) 399.0 (M+H), Rt. 2.32 min, 97.39% (Max). HPLC: (Method A) Rt. 2.22 min, 97.15% (Max).

Example 190: (S)-2-(6-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)pyridin-3-yl)propan-2-ol

[0787] ##STR00425##

[0788] To a stirred solution of Example 183 (0.3 g, 0.78 mmol) in dry THF (10 mL) at 0° C. was added methyl magnesium bromide solution in THF (1.4 M, 0.8 mL, 1.17 mmol, Aldrich). The resulting mixture was stirred at 0° C. for 1 h. The temperature was increased to rt and the mixture was stirred 12 h at that temperature. The reaction completion was monitored by TLC. The reaction mixture was quenched with saturated ammonium chloride solution (10 mL) and extracted with EtOAc (50 mL). The organic layer was washed with sat NaCl solution (20 mL) and dried over anhydrous Na.sub.2SO.sub.4. The crude product was purified by flash column chromatography, yielding the title compound. Yield: 61% (0.178 g, colorless oil). .sup.1H NMR (400 MHz, DMSO-d.sub.6): b 8.17 (d, J=2.0 Hz, 1H), 7.59-7.57 (m, 1H), 6.89-6.83 (m, 2H), 6.78-6.70 (m, 2H), 5.99-5.98 (m, 2H), 4.92 (s, 1H), 3.39 (t, J=4.8 Hz, 5H), 2.40-2.36 (m, 4H), 1.39 (s, 6H), 1.29 (d, J=6.8 Hz, 3H). LCMS: (Method A) 370.2 (M+H), Rt. 1.94 min, 99.3% (Max). HPLC: (Method A) Rt. 1.92 min, 99.60% (Max).

Example 191: (S)-1-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)-4-(5-bromopyridin-2-yl)piperazine

[0789] ##STR00426##

[0790] To a stirred solution of Intermediate 16 (5.5 g, 20.68 mmol) in dry DMF (50 mL), TEA (7.1 mL, 51.45 mmol) and 5-bromo-2-fluoropyridine (3 g, 17.24 mmol) were added at rt and the reaction mixture was stirred at 90° C. overnight. The reaction mixture was cooled to rt and concentrated under reduced pressure. Water (30 mL) was added and the compound was extracted with EtOAc (100 mL). The organic layer was dried over anhydrous Na.sub.2SO.sub.4 and concentrated. The resulting crude product was purified by flash chromatography to afford the title compound (white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.14 (d, J=2.4 Hz, 1H), 7.66-7.65 (m, 1H), 6.87 (d, J=1.2 Hz, 1H), 6.84 (d, J=7.6 Hz, 1H), 6.77-6.55 (m, 2H), 5.99-5.98 (m, 2H), 3.43 (t, J=4.8 Hz, 4H), 3.36-3.34 (m, 1H), 2.47-2.45 (m, 2H), 2.38-2.35 (m, 2H), 1.28 (d, J=6.8 Hz, 3H). LCMS: (Method A) 392.0 (M+H), Rt. 3.32 min, 99.88% (Max). HPLC: (Method A) Rt. 3.26 min, 99.96% (Max).

Example 192: (S)-1-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)-4-(5-(methylthio)pyridin-2-yl)piperazine

[0791] ##STR00427##

[0792] To a stirred solution of Example 191 (3.0 g, 7.71 mmol) in dry THF (30 mL), n-BuLi (6.0 mL, 9.2 mmol) was added at −78° C. and stirred for 1 h. Dimethyl disulphide (45 mL) was added at same temperature and stirred for 1 h at rt. The reaction mixture was quenched with saturated NH.sub.4Cl and extracted with EtOAc. The organic layer was washed with water and dried over anhydrous Na.sub.2SO.sub.4 and concentrated. The resulting crude was purified by flash column chromatography to afford the title compound. Yield: 90% (2.58 g, yellow solid). .sup.1H NMR (400 MHz, CDCl.sub.3): δ 8.21 (d, J=2.4 Hz, 1H), 7.52-7.51 (m, 1H), 6.89 (s, 1H), 6.76 (s, 2H), 6.56 (d, J=8.8 Hz, 1H), 5.96-5.94 (m, 2H), 3.52 (m, 4H), 3.34 (d, J=6.0 Hz, 1H), 2.57-2.50 (m, 4H), 2.38 (s, 3H), 1.36 (d, J=6.4 Hz, 3H). LCMS: (Method A) 358.3.0 (M+H), Rt. 2.61 min, 97.99% (Max). HPLC: (Method A) Rt. 2.56 min, 97.57% (Max).

Example 193: (S)-2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-5-(methylsulfonyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine

[0793] ##STR00428##

[0794] To a stirred solution of Example 182 (0.1 g, 0.26 mmol) in dry DCM (5 mL), TEA (0.07 mL, 0.54 mmol) and methane sulfonyl chloride (0.22 mL, 0.29 mmol) were added at 0° C. and the reaction mixture was stirred at rt for 1 h. The resulting reaction mixture was diluted with DCM (50 mL) and washed with 10% sodium bicarbonate solution (15 mL), water (15 mL) and brine (15 mL). The organic layer was dried over anhydrous Na.sub.2SO.sub.4 and concentrated. The resulting crude product was purified by flash column chromatography to afford the title compound (off white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 6.87 (d, J=8.0 Hz, 1H), 6.85 (d, J=8.0 Hz, 1H), 6.76 (d, J=8.0 Hz, 1H), 5.99-5.98 (m, 2H), 4.26 (s, 2H), 3.46-3.44 (m, 2H), 3.41-3.39 (m, 1H), 2.98-2.93 (m, 3H), 2.67-2.65 (m, 4H), 2.54-2.52 (m, 2H), 2.39-2.38 (s, 4H), 1.27 (d, J=6.8 Hz, 3H). LCMS: (Method A) 451.2 (M+H), Rt. 2.46 min, 98.64% (Max). HPLC: (Method A) Rt. 2.56 min, 97.91% (Max).

Example 194: (S)-2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)Piperazin-1-yl)-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine

[0795] ##STR00429##

[0796] To a stirred solution of Example 182 (0.1 g, 2.61 mmol) in dry THF (2 mL), sodium triacetoxy borohydride (0.17 g, 8.06 mmol) and formaldehyde (0.05 mL, 5.37 mmol, 40% solution in water) were added at rt and the reaction mixture was stirred at this temperature overnight. The reaction mixture was diluted with EtOAc (30 mL) and was washed with water (5 mL), brine (5 mL), dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure. The resulting crude product was purified by flash column chromatography to afford the title compound (brown oil). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 6.88 (s, 1H), 6.84 (d, J=8.0 Hz, 1H), 6.75 (d, J=8.0 Hz, 1H), 5.97 (m, 2H), 3.38-3.36 (m, 5H), 3.30-3.27 (m, 4H), 2.62-2.60 (m, 2H), 2.46-2.44 (m, 2H), 2.40-2.38 (m, 2H), 2.32 (s, 3H), 1.27 (d, J=6.8 Hz, 3H). LCMS: (Method A) 387.2 (M+H), Rt. 1.84 min, 99.86% (Max). HPLC: (Method A) Rt. 1.85 min, 99.51% (Max).

Example 195: (S)-2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)-5-methoxypyrimidine

[0797] ##STR00430##

[0798] To a stirred solution of Intermediate 16 (0.55 g, 2.07 mmol) in dry DMF (5 mL), triethylamine (0.9 mL, 6.21 mmol, spectrochem) and 2-chloro-5-methoxy pyrimidine (0.3 g, 2.07 mmol, Combi-Blocks) were added and the resulting mixture was heated to 90° C. for 12 h. The reaction mixture was cooled down to rt and concentrated. Dichloromethane (25 mL) was added and the resulting solution was washed with water (20 mL), brine (20 mL) and dried over Na.sub.2SO.sub.4. After evaporation of the solvents, the crude product was purified by flash column chromatography to afford the title compound (brown solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.18 (s, 2H), 6.87 (m, 2H), 6.76 (d, J=8.0 Hz, 1H), 5.99-5.98 (m, 2H), 3.76 (s, 3H), 3.58 (t, J=4.8 Hz, 4H), 3.38-3.36 (m, 1H), 2.45-2.42 (m, 2H), 2.36-2.33 (m, 2H), 1.28 (d, J=6.8 Hz, 3H). LCMS: (Method A) 343.2 (M+H), Rt. 2.73 min, 99.83% (Max). HPLC: (Method A) Rt. 2.71 min, 99.41% (Max).

Example 196: (S)-2-(4-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)Piperazin-1-yl)-5-methoxypyrimidine

[0799] ##STR00431##

[0800] To a stirred solution of Intermediate 11 (0.2 g, 0.8 mmol) in dry DMF (2 mL), triethylamine (0.57 mL, 4.0 mmol, spectrochem) and 2-chloro-5-methoxy pyrimidine (0.14 g, 0.9 mmol, Combi-Blocks) were added and the resulting mixture was heated at 90° C. overnight. The reaction mixture was cooled down to rt and concentrated. Dichloromethane (25 mL) was added and the resulting mixture was washed with water (20 mL), brine (20 mL) and dried over Na.sub.2SO.sub.4. After evaporation of the solvents, the crude product was purified by flash chromatography to afford the title compound (gray solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.93-8.91 (m, 2H), 8.17 (s, 2H), 8.07 (d, J=8.8 Hz, 1H), 7.99 (s, 1H), 7.90 (d, J=8.8 Hz, 1H), 3.75-3.74 (m, 1H), 3.74 (s, 3H), 3.62-3.60 (m, 4H), 2.52-2.49 (m, 4H), 1.42 (d, J=6.8 Hz, 3H). LCMS: (Method A) 351.0 (M+H), Rt. 2.38 min, 99.86% (Max). HPLC: (Method A) Rt. 2.17 min, 98.71% (Max).

Example 197 and 198: (S)-1-(2-(4-((S)-1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)pyrimidin-5-yl)ethan-1-ol and (S)-1-(2-(4-((R)-1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazin-1-yl)pyrimidin-5-yl)ethan-1-ol

[0801] ##STR00432##

[0802] Example 168 was submitted to chiral preparative HPLC Method PK to separate both enantiomers. The first eluting compound was concentrated to give Example 198 (brown oil). .sup.1H NMR (400 MHz, DMSO d.sub.6): δ 8.29 (s, 2H), 6.89 (s, 1H), 6.84 (d, J=7.9 Hz, 1H), 6.75 (d, J=7.9 Hz, 1H), 5.99-5.98 (m, 2H), 5.12 (d, J=4.4 Hz, 1H), 4.62-4.61 (m, 1H), 3.67-3.65 (m, 4H), 3.38-3.36 (m, 1H), 2.51-2.33 (m, 4H), 1.31 (d, J=6.4 Hz, 3H), 1.28 (d, J=6.4 Hz, 3H). LCMS: (Method A) 357.2 (M+H), Rt. 2.30 min, 99.37% (Max). HPLC: (Method A) Rt. 2.30 min, 98.05% (Max). Chiral HPLC: (Method H) Rt. 7.06 min, 100%. The second eluting compound was concentrated to give Example 197 (brown oil). .sup.1H NMR (400 MHz, DMSO d.sub.6): δ 8.29 (s, 2H), 6.89 (s, 1H), 6.84 (d, J=8.0 Hz, 1H), 6.75 (d, J=8.0 Hz, 1H), 5.99-5.98 (m, 2H), 5.11 (d, J=4.4 Hz, 1H), 4.62-4.59 (m, 1H), 3.68-3.65 (m, 4H), 3.38-3.36 (m, 1H), 2.35-2.32 (m, 4H), 1.31 (d, J=6.4 Hz, 3H), 1.28 (d, J=6.8 Hz, 3H). LCMS: (Method A) 357.2 (M+H), Rt. 2.29 min, 99.93% (Max). HPLC: (Method N) Rt. 2.26 min, 99.62% (Max). Chiral HPLC: (Method H) Rt 7.60 min, 100%.

Example 199: 1-(4-Bromo-3-methoxyphenyl)-4-(1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethylpiperazine

[0803] ##STR00433##

[0804] To a stirred solution of Intermediate 4 (0.3 g, 1.056 mmol) in DMSO (6 mL), Cs.sub.2CO.sub.3 (1.38 g, 4.22 mmol) and 3-bromo-6-chloro-2-methoxypyridine (0.258 g, 1.16 mmol) were added at rt and the mixture was heated to 120° C. for 12 h. It was diluted with water (10 mL), extracted with EtOAc (25 mL) and dried over Na.sub.2SO.sub.4. After evaporation of the solvents, the crude product was purified by MD Autoprep (Method B) affording the title product (off white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.60 (d, J=8.4 Hz, 1H), 6.79-6.73 (m, 3H), 6.25 (d, J=8.4 Hz, 1H), 4.21 (s, 4H), 3.80 (s, 3H), 3.42-3.32 (m, 5H), 2.55-2.45 (m, 4H), 1.26 (d, J=6.8 Hz, 3H). LCMS: (Method B) 434.0 (M+1), Rt. 7.151 min, 96.67% (Max). HPLC: (Method B) Rt. 6.24 min, 95.29% (Max).

Example 200: 1-(1-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)-4-(3-methoxyphenyl)piperazine

[0805] ##STR00434##

[0806] The title product was prepared according to the protocol described for Example 199, replacing 3-bromo-6-chloro-2-methoxypyridine with 2-chloro-6-methoxypyridine. The crude product was purified by MD Autoprep (Method B), affording the title product (brown solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.40 (t, J=8.0 Hz, 1H), 6.78-6.73 (m, 3H), 6.24 (d, J=8.0 Hz, 1H), 5.99 (d, J=8.0 Hz, 1H), 4.21 (s, 4H), 3.73 (s, 3H), 3.42-3.37 (m, 5H), 2.37-2.32 (m, 4H), 1.26 (d, J=6.8 Hz, 3H). LCMS: (Method B) 356 (M+H), Rt. 6.622 min, 98.55% (Max). HPLC: (Method A) Rt. 3.23 min, 96.44% (Max).

Example 201: 3-Methyl-7-(14-(pyrimidin-2-yl)piperazin-1-yl)ethyl)quinoline

[0807] ##STR00435##

[0808] To a stirred solution of 2-(piperazin-1-yl)pyrimidine (0.16 g, 0.97 mmol) in DMF (5 mL), TEA (0.4 mL, 2.9 mmol) and Intermediate 28 (0.3 g, 1.46 mmol) were added at room temperature. The reaction mixture was stirred at 100° C. for 16 h. The reaction completion was confirmed by TLC. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The resulting crude mixture was diluted with EtOAc (50 mL), washed with water (10 mL), brine solution (10 mL), dried over anhydrous Na.sub.2SO.sub.4 and concentrated. The crude product was purified by flash chromatography to afford the title compound (off white solid). .sup.1HNMR (400 MHz, DMSO-d.sub.6): δ 8.75 (d, J=2.0 Hz, 1H), 8.32 (d, J=4.8 Hz, 2H), 8.09 (s, 1H), 7.86 (d, J=8.0 Hz, 2H), 7.61 (d, J=10.0 Hz, 1H), 6.59 (t, J=4.8 Hz, 1H), 3.72-3.66 (m, 5H), 2.58-2.55 (m, 2H), 2.48 (s, 3H), 2.42-2.38 (m, 2H), 1.42 (d, J=6.8 Hz, 3H). LCMS: (Method A) 334.2 (M+H), Rt. 1.79 min, 99.76% (Max). HPLC: (Method A) Rt 1.73 min, 99.84% (Max).

Example 202: 3-Methyl-7-(1-(4-(3-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)ethyl)quinolone

[0809] ##STR00436##

[0810] To a stirred solution of Intermediate 29 (0.3 g, 1.29 mmol) in DMSO (5 mL), TEA (0.56 mL, 3.8 mmol) and Intermediate 28 (0.4 g, 1.94 mmol) were added at room temperature and the reaction mixture was stirred at 120° C. for 16 h. The reaction progression was followed by TLC. The reaction mixture was diluted with water (5 mL) and extracted with EtOAc (2×50 mL). The combined organic layer was dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure. The crude mass was purified by flash chromatography (gradient used: 1% MeOH in DCM), to afford the title compound (colorless gum). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.75 (d, J=2.0 Hz, 1H), 8.50 (d, J=5.2 Hz, 1H), 8.10 (s, 1H), 8.03 (d, J=7.6 Hz, 1H), 7.86 (d, J=8.4 Hz, 2H), 7.61 (d, J=8.0 Hz, 1H), 7.16 (dd, J=2.8, 7.6 Hz, 1H), 3.68 (q, J=6.8 Hz, 1H), 3.21-3.18 (m, 4H), 2.63-2.60 (m, 2H), 2.50-2.48 (m, 5H), 1.42 (d, J=6.8 Hz, 3H). LCMS: (Method A) 401.2 (M+H), Rt. 2.63 min, 99.88% (Max). HPLC: (Method A) Rt 2.57 min, 99.84% (Max).

Example B01: Human O-GlcNAcase Enzyme Inhibition Assay

[0811] 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)

[0812] 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.

[0813] 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.

[0814] Total Protein O-GlcNAcylation Immunoassay:

[0815] 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

[0816] (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.

[0817] (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.

[0818] (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.4.2H.sub.2O, 28.48 g of Na.sub.2HPO.sub.4.12H.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.

[0819] (D) Ointment: 500 mg of an active ingredient according to the invention were mixed with 99.5 g of Vaseline under aseptic conditions.

[0820] (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.

[0821] (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.

[0822] (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.

[0823] (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.

[0824] (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.