Glycosidase inhibitors

Abstract

Compounds of formula (I), wherein A, R, W, Q, n and m have the meaning according to the claims, can be employed, inter alia, for the treatment of tauopathies and Alzheimer's disease. ##STR00001##

Claims

1. A compound of formula (I) ##STR00651## 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 is: ##STR00652## X is N or CR′″; X.sup.1, X.sup.2 is N or CR′″; X.sup.3 is N or CR′″″; X.sup.4 is N or CR.sup.9; R.sup.9 is Hal, NR.sup.3R.sup.4, CHR.sup.3R.sup.4, OR.sup.3, CN, or straight chain or branched alkyl having 1 to 12 carbon atoms, wherein 1 to 3 CH.sub.2-groups may be replaced by a group selected from O, NR.sub.3, S, SO, SO.sub.2, S(O)(NH), CO, COO, OCO, CONR.sup.3, and NR.sup.3CO; and wherein 1 to 5 hydrogen atoms may be replaced by Hal, NR.sup.3R.sup.4 or NO.sub.2; Y is O, S, SO, or SO.sub.2; R′, R″ are, independently, H, Hal, or straight chain or branched alkyl having 1 to 12 carbon atoms; R′″, R″″ are, independently, H, Hal, NR.sup.3R.sup.4, CHR.sup.3R.sup.4, OR.sup.3, CN, or straight chain or branched alkyl having 1 to 12 carbon atoms, wherein 1 to 3 CH.sub.2-groups may be replaced by a group selected from O, NR.sub.3, S, SO, SO.sub.2, S(O)(NH), CO, COO, OCO, CONR.sup.3, and 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′″″ is H, Hal, NR.sup.3R.sup.4, CHR.sup.3R.sup.4, CN, or straight chain or branched alkyl having 1 to 12 carbon atoms, wherein 1 to 3 CH.sub.2-groups may be replaced by a group selected from O, NR.sub.3, S, SO, SO.sub.2, S(O)(NH), CO, COO, OCO, CONR.sup.3, and 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.sup.3, R.sup.4 are, independently, H or a straight chain or branched alkyl group having 1 to 12 carbon atoms; Q is: ##STR00653## ##STR00654## Z.sup.2 is CR.sup.5, CR.sup.6, or N; Z.sup.4 is N, CH, CON, or COCH; Z.sup.5 is S, O, NR.sup.8, SO.sub.2, or CHR.sup.5; Z.sup.6 is CH.sub.2 or CO; s is 0 or 1; T is N, CH, or CR.sup.7; R.sup.3′ is H or a straight chain or branched alkyl group having 1 to 12 carbon atoms, wherein 1 to 3 CH.sub.2-groups may be replaced by a group selected from SO.sub.2, CO, and O; and wherein 1 to 5 hydrogen atoms may be replaced by Hal; R.sup.3″ is a straight chain or branched alkyl group having 1 to 12 carbon atoms, wherein 1 to 3 CH.sub.2-groups are replaced by a group selected from SO.sub.2, CO, and O; and wherein 1 to 5 hydrogen atoms may be replaced by Hal; R.sup.5, R.sup.6, R.sup.7 are, independently, H, Hal, NR.sup.3R.sup.4, NO.sub.2, Ar, Het, Cyc, 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, S(O)(NH), CO, COO, OCO, CONR.sup.3, and 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, or Cyc; R.sup.8 is 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.sup.3, S, SO, SO.sub.2, CO, COO, OCO, CONR.sup.3, and 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 is F, Cl, Br, or I; Het is 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 is a 6-membered carbocyclic aromatic ring or a fused or non-fused bicyclic aromatic ring system, which is optionally substituted by 1 to 3 substituents independently selected from R.sup.5, OR.sup.3, and Hal; Cyc is a saturated or an unsaturated carbocyclic ring having from 3 to 8 carbon atoms which is optionally substituted by 1 to 3 substituents independently selected from R.sup.5, Hal, and OH; or a solvate, salt, tautomer, enantiomer, racemate, stereoisomer, or any mixture thereof in any ratio.

2. A compound of formula Ia or Ib: ##STR00655## wherein A, R, W, and Q have the meaning given in claim 1.

3. A mixture comprising compounds Ia and Ib according to claim 2, in equal or unequal amounts, wherein: the A groups in (Ia) and (Ib) are identical; the R groups in (Ia) and (Ib) are identical; the W groups in (Ia) and (Ib) are identical; and the Q groups in (Ia) and (Ib) are identical.

4. The compound according to claim 1, wherein R is methyl and/or W is N.

5. The compound according to claim 1, wherein A is: ##STR00656## wherein R′ and R″ have the meaning given in claim 1.

6. The compound according to claim 1, wherein Q is: ##STR00657## ##STR00658## wherein R.sup.3′, R.sup.7 and R.sup.8 have the meaning given in claim 1.

7. The compound according to claim 1, wherein R.sup.5, R.sup.6, and 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, hydroxyalkylene, alkoxyalkylene, 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 Cyc or Het, or unsubstituted Cyc or Het.

8. The compound according to claim 1, wherein the compound is selected from the group consisting of: TABLE-US-00003 Configuration No Structure specification 1 racemic 2 racemic 3 racemic 4 racemic 135 136 137 138 139 140 141 142 143 144 145 146 147 148 149 150 151 152 153 154 155 156 157 158 159 160 161 162 163 164 165 166 167 168 169 170 171 172 173 174 175 176 177 178 179 180 181 182 183 214 215 216 217 231 S-enantiomer 232 S-enantiomer 233 S-enantiomer 234 S-enantiomer 235 S-enantiomer 236 S-enantiomer 237 S-enantiomer 238 S-enantiomer 239 S-enantiomer 240 S-enantiomer 241 S-enantiomer 242 S-enantiomer 243 S-enantiomer 244 S-enantiomer 245 S-enantiomer 246 S-enantiomer 247 S-enantiomer 248 S-enantiomer 249 S-enantiomer 250 S-enantiomer 251 S-enantiomer 252 S-enantiomer 253 S-enantiomer 254 S-enantiomer 255 S-enantiomer 256 S-enantiomer 257 S-enantiomer 258 S-enantiomer 259 S-enantiomer 260 S-enantiomer 261 S-enantiomer 262 S-enantiomer 263 S-enantiomer 264 S-enantiomer 265 S-enantiomer 266 S-enantiomer 267 S-enantiomer 268 S-enantiomer 269 S-enantiomer 270 S-enantiomer 271 S-enantiomer 272 S-enantiomer 273 S-enantiomer 274 S-enantiomer 275 S-enantiomer 276 S-enantiomer 277 S-enantiomer 278 S-enantiomer 279 S-enantiomer 280 S-enantiomer 281 S-enantiomer 282 S-enantiomer 283 S-enantiomer 284 S-enantiomer 285 S-enantiomer 286 S-enantiomer 287 S-enantiomer or a solvate, salt, tautomer, enantiomer, racemate, or stereoisomer thereof, including mixtures thereof in any ratio.

9. A method for inhibiting a glycosidase, comprising contacting a system expressing the glycosidase with a compound of claim 1 under in-vitro conditions such that the glycosidase is inhibited.

10. A pharmaceutical composition comprising as active ingredient a compound according to claim 1 together with pharmaceutically tolerable adjuvants and/or excipients.

11. The pharmaceutical composition of claim 10, further comprising one or more additional active ingredients.

Description

EXPERIMENTAL PART

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

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

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

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

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

(6) LCMS Methods:

(7) LCMS Method A

(8) Method: A—0.1% TFA in H.sub.2O, B—0.1% TFA in ACN: Flow—2.0 mL/min.

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

(10) LCMS Method B

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

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

(13) LCMS Method C

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

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

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

(17) HPLC Method A

(18) Method: A—0.1% TFA in H.sub.2O, B—0.1% TFA in ACN: Flow—2.0 mL/min.

(19) Column: XBridge C8 (50×4.6 mm, 3.5 μm).

(20) HPLC Method B

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

(22) Column: XBridge C8 (50×4.6 mm, 3.5 μm).

(23) The chiral HPLC methods described below may preferably be performed on an Agilent 1260 DAD instrument.

(24) Chiral HPLC (Method A):

(25) 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

(26) Chiral HPLC (Method B):

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

(28) Chiral HPLC (Method C):

(29) 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

(30) Chiral HPLC (Method D):

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

(32) Chiral HPLC (Method P):

(33) Mobile Phase: 0.1% TFA in n-Hexane:EtOH: 60:40; COLUMN: CHIRALPAK AD-H (250×4.6) mm, 5 μm; FLOW: 1.0 mL\min

(34) Chiral HPLC (Method R):

(35) Mobile Phase: 0.1% DEA in Hexane:IPA: 80:20; COLUMN: Chiralcell OJ-H column (250×4.6) mm, 5 μm; FLOW: 12.0 mL\min

(36) MD Autoprep HPLC Conditions

(37) The mass directed preparative HPLC purifications were performed with a mass directed autopurification Fractionlynx from Waters.

(38) MD Autoprep HPLC Method A

(39) 0.1% HCOOH in H.sub.2O, B-MeOH or ACN, Column: Symmetry C8 (300 mm×19 mm), 7 μm

(40) MD Autoprep HPLC Method B

(41) 0.1% TFA in H.sub.2O, B-MeOH or ACN, Column: Symmetry C8 (300 mm×19 mm), 7 μm

(42) MD Autoprep HPLC Method C

(43) 10 mM NH.sub.4HCO.sub.3 in H.sub.2O, B-MeOH or ACN, Column: Symmetry C8 (300 mm×19 mm), 7 μm

(44) MD Autoprep HPLC Method D

(45) 10 mM NH.sub.4OAc in H.sub.2O, B-MeOH or ACN, Column: Symmetry C8 (300 mm×19 mm), 7 μm

(46) Prep-HPLC Conditions

(47) Mobile phase: A—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.

(48) The chiral HPLC SFC analysis may preferably be performed on a THAR SFC AMDS Instrument.

(49) Chiral HPLC SFC Method A

(50) COLUMN: YMC Cellulose SB (250×4.6) mm, 5 μm; CO-SOLVENTS: 0.5% DEA in Methanol; FLOW: 10 mL/min

(51) Chiral HPLC SFC Method B:

(52) COLUMN: Lux C2 (250×4.6) mm, 5 μm; CO-SOLVENTS: 20 mM Ammonia in Methanol FLOW: 10 mL/min

(53) Chiral HPLC SFC Method C:

(54) COLUMN: YMC Cellulose C (250×4.6) mm, 5 μm; CO-SOLVENTS: 20 mM Ammonia in Methanol; FLOW: 10 mL/min

(55) Chiral HPLC SFC Method D:

(56) COLUMN: YMC Amylose SA (250×4.6) mm, 5 μm; CO-SOLVENTS: 20 mM Ammonia in IPA; FLOW: 10 mL/min

(57) Chiral HPLC SFC Method E:

(58) COLUMN: YMC Amylose SA (250×4.6) mm, 5 μm; CO-SOLVENTS: 20 mM Ammonia in MeOH; FLOW: 3 mL/min

(59) Chiral HPLC SFC Method F:

(60) COLUMN: Lux C3 (250×4.6) mm, 5 μm; CO-SOLVENTS: 20 mM Ammonia in Methanol; FLOW: 4 mL/min;

(61) Chiral HPLC SFC Method G:

(62) COLUMN: YMC Cellulose SB (250×4.6) mm, 5 μm; CO-SOLVENTS: 20 mM Ammonia in MeOH; FLOW: 4 mL/min

(63) Chiral HPLC SFC Method H:

(64) COLUMN: Chiralpak ADH (250×4.6) mm, 5 μm; CO-SOLVENTS: 20 mM Ammonia in IPA; FLOW: 4 mL/min

(65) Chiral HPLC SFC Method I:

(66) COLUMN: Lux A1 (250×4.6) mm, 5 μm; CO-SOLVENTS: 20 mM Ammonia in IPA; FLOW: 4 mL/min;

(67) Chiral HPLC SFC Method J:

(68) COLUMN: YMC Cellulose SB (250×4.6) mm 5 μm; CO-SOLVENTS: 0.5% DEA in Methanol FLOW: 5 mL/min

(69) Chiral HPLC SFC Method K:

(70) COLUMN: YMC Cellulose SB (250×4.6) mm, 5 μm; CO-SOLVENTS: 0.5% DEA in Methanol 40%; FLOW: 4 mL/min;

(71) The SFC purifications were performed with a Prep SFC, THAR-SFC 80 and THAR-SFC 200.

(72) SFC Preparative Chiral Method PA:

(73) COLUMN: YMC Cellulose SB (250×30) mm, 5 μm; CO-SOLVENTS: 0.5% DEA in Methanol 40%; FLOW: 60 mL/min;

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

(75) 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

Intermediate 1: 6-(1-chloroethyl)quinoxaline

(76) ##STR00297##

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

(77) 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 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

(78) 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

(79) 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 2: 6-(1-(piperazin-1-yl)ethyl)quinoxaline hydrochloride

(80) ##STR00298##

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

(81) 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 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

(82) 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 3: 5-(1-chloroethyl)benzo[d]thiazole

(83) ##STR00299##

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

(84) 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 column 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

(85) 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

(86) 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 4: 6-(1-chloroethyl)-2,3-dihydrobenzofuran

(87) ##STR00300##

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

(88) To a stirred solution of 1,4-dibromo-2-fluorobenzene (100 g, 395.2 mmol) in ethylene glycol (510 mL), NMP (50 mL) was added at rt under N.sub.2 atmosphere. Then tBuOK (155.2 g, 1383.0 mmol) was added slowly over 10 min at 10° C. The reaction mixture was heated at 100° C. for 12 h. The completion of the reaction was monitored by TLC. The reaction mixture was cooled to rt and diluted with water (200 mL) and stirred for 15 min at rt. The resulting solid was filtered and washed with ethylene glycol (2×30 mL). Water (2200 mL) was added to the filtrate, the solution was cooled to 15° C. and stirred for 1 h. The resulting precipitate was filtered and washed with water (2×100 mL), pet ether (2×100 mL) and dried. It was further dried with the addition of toluene and its evaporation (3×200 mL). It was then use in the next step without further purification. Yield: 77.5% (90 g, pale brown solid). .sup.1H NMR (400 MHz, CDCl.sub.3): δ 7.41 (d, J=8.4 Hz, 1H), 7.06 (d, J=2.0 Hz, 1H), 7.02 (dd, J=8.4, 2.4 Hz, 1H), 4.14 (t, J=4.4 Hz, 2H), 4.03-4.00 (m, 2H), 2.36 (t, J=6.4 Hz, 1H).

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

(89) ##STR00301##

(90) To a stirred solution of 2-(2,5-dibromophenoxy)ethan-1-ol (45 g, 152 mmol) in toluene (315 mL) under inert atmosphere, PBr.sub.3 (18.47 g, 68.0 mmol) was added slowly at 0° C. The resulting mixture was heated at 90° C. for 2 h. It was cooled to 0° C. and PBr.sub.3 (8.2 g, 30.0 mmol) and water (0.9 mL) were added slowly and the heating was continued at 90° C. for 8 h. Completion of the reaction was monitored by TLC. The reaction mixture was cooled to 10° C. and quenched with 1N NaOH solution (270 mL). The organic phase was separated and was washed with water (150 mL), brine (150 mL), dried over Na.sub.2SO.sub.4 and evaporated at 45° C. under vacuum to give the title compound. Yield: 90.8% (99 g, off white solid). .sup.1H NMR (400 MHz, CDCl.sub.3): δ 7.43 (d, J=8.8 Hz, 1H), 7.05-7.02 (m, 2H), 4.34 (t, J=6.4 Hz, 2H), 3.70 (t, J=6.4 Hz, 2H).

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

(91) To a stirred solution of 1,4-dibromo-2-(2-bromoethoxy)benzene (99 g, 275.9 mmol) in dry THF (990 mL) under inert atmosphere and cooled down to −78° C., n-butyl lithium (189 mL, 303.5 mmol, 1.6 M in hexane) was added slowly over 30 min. After 1 h, the same amount of n-butyl lithium (189 mL, 303.5 mmol, 1.6 M in hexane) was added slowly over 30 min at −78° C. The reaction mixture was stirred 1 h at −78° C. DMF (40.3 g, 551.8 mmol) was then added slowly and the temperature was maintained 45 min at −78° C. Reaction mixture was then warmed to 10° C. and quenched with a saturated solution of NH.sub.4Cl (450 mL). The reaction mixture was extracted with EtOAc (2×200 mL). The combined organic layer was washed with water (200 mL), brine solution (200 mL), dried over Na.sub.2SO.sub.4 and evaporated at 40° C. under reduced pressure to give the title compound. Yield: crude (40.8 g, Pale brown solid). .sup.1H NMR (400 MHz, CDCl.sub.3): δ 9.93 (s, 1H), 7.41-7.39 (m, 2H), 7.28-7.27 (m, 1H), 4.66 (t, J=8.8 Hz, 2H), 3.30 (t, J=8.8 Hz, 2H).

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

(92) To a stirred solution 2,3-dihydrobenzofuran-6-carbaldehyde (30 g, 202 mmol) in dry THF (300 mL) under inert atmosphere, methyl magnesium chloride solution (135 mL, 404 mmol, 3 M in THF) was added slowly over 30 min at 0° C. The reaction mixture was stirred for 2 h at the same temperature. Completion of the reaction was monitored by TLC. Reaction mixture was quenched by using a saturated solution of NH.sub.4Cl (250 mL) and extracted with EtOAc (2×100 mL). The combined organic layer was washed with water (100 mL), brine (100 mL), dried over Na.sub.2SO.sub.4 and evaporated at 40° C. under reduced pressure. The resulting crude product was purified by flash chromatography (22% EtOAc in pet ether) to give the title compound. Yield: 58.6% (19.5 g, Pale Yellow liquid). .sup.1H NMR (300 MHz, CDCl.sub.3): δ 7.18 (d, J=7.5 Hz, 1H), 6.87 (dd, J=9.4, 1.2 Hz, 2H), 4.89-4.83 (m, 1H), 4.59 (t, J=8.7 Hz, 2H), 3.21 (t, J=8.7 Hz, 2H), 1.51-1.50 (m, 3H). LCMS: (Method A) 147.2 (M+H-H.sub.2O), Rt. 2.63 min, 94.7% (Max). HPLC: (Method A) Rt 2.61 min, 96.5% (Max).

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

(93) To a stirred solution of 1-(2,3-dihydrobenzofuran-6-yl)ethan-1-ol (9 g, 54.0 mmol) in DCM (180 mL), SOCl.sub.2 (19.4 g, 165 mmol) was added at 0° C. The reaction mixture was stirred at rt for 1 h. Completion of the reaction was monitored by TLC. The reaction mixture was concentrated under reduced pressure at 40° C. The resulting crude mixture was dissolved in DCM and evaporated two times (2×100 mL) and dried at 40° C. under reduced pressure to give the title compound. Yield: crude (100%) (9.98 g, dark brown liquid). .sup.1H NMR (400 MHz, CDCl.sub.3): δ 7.16 (d, J=7.6 Hz, 1H), 6.92-6.88 (m, 2H), 5.06 (q, J=6.8 Hz, 1H), 4.59 (t, J=8.8 Hz, 2H), 3.21 (t, J=8.8 Hz, 2H), 1.84 (d, J=6.8 Hz, 3H).

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

(94) ##STR00302##

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

(95) 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

(96) 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

(97) 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 6: 2-(piperazin-1-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-4(5H)-one dihydrochloride

(98) ##STR00303##

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

(99) 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 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

(100) 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

(101) 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 the resulting solid was triturated with EtOAc (3×20 mL) to afford titled compound which was used without further purification. Yield: 99% (crude) (2.25 g, white solid). LCMS: (Method A) 239.0 (M+H), Rt. 0.663 min, 82.012% (Max).

Intermediate 7: 7-(1-chloroethyl) imidazo [1,2-a] pyridine

(102) ##STR00304##

Step 1: 7-bromoimidazo [1, 2-a] pyridine

(103) To a stirred solution of 4-bromopyridin-2-amine (5 g, 28.9 mmol, Molekula Biokem Ltd) in EtOH (50 mL), added sodium bicarbonate (7.28 g, 86.7 mmol) and chloroacetaldehyde (5 mL, 115 mmol) and refluxed for 16 h. The reaction mixture was evaporated under vacuum and water (25 mL) was added to the crude mixture. The resulting solution was extracted with EtOAc (2×50 mL). The organic layer was dried over anhydrous Na.sub.2SO.sub.4 and concentrated. The resulting crude product was purified by flash chromatography. Yield: 63% (3.6 g, brown solid). LCMS: (Method B) 199.0 (M+H), Rt. 3.92 min, 94.50% (Max).

Step 2: 1-(imidazo [1, 2-a] pyridin-7-yl) ethan-1-one

(104) To a stirred solution of 7-bromoimidazo [1, 2-a] pyridine (3.6 g, 18.7 mmol) in toluene (35 mL), 1-ethoxy vinyl tributyltin (7.3 mL, 20.1 mmol) and bis(triphenylphosphine)palladium chloride (0.64 g, 0.90 mmol) were added under inert atmosphere. The reaction mixture was refluxed at 90° C. for 16 h. It was evaporated under vacuum and 6 N HCl solution (20 mL) was added. The resulting mixture was stirred at rt for 1 h and concentrated under vacuum. It was neutralized with saturated solution of NaHCO.sub.3 (20 mL) and was extracted with EtOAc (2×50 mL). The organic layer was dried over anhydrous Na.sub.2SO.sub.4 and concentrated. The crude product was purified by flash chromatography. Yield: 73% (2.1 g, yellow solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.62-8.61 (m, 1H), 8.34 (d, J=0.8 Hz, 1H), 8.14 (d, J=0.8 Hz, 1H), 7.81 (s, 1H), 7.32-7.31 (m, 1H), 2.65 (s, 3H). LCMS: (Method B) 161.0 (M+H), Rt. 3.140 min, 95.59% (Max).

Step 3: 1-(imidazo [1, 2-a] pyridin-7-yl) ethan-1-ol

(105) To a stirred solution of 1-(imidazo [1, 2-a] pyridin-7-yl) ethan-1-one (2.1 g, 13.1 mmol) in MeOH (20 mL), sodium borohydride (0.65 g, 17.0 mmol) was added at 0° C. and the mixture was stirred at rt for 1 h. It was evaporated under vacuum and water (10 mL) was added. The product was extracted with DCM (2×50 mL) and the organic layer was washed with brine (10 mL) and dried over anhydrous Na.sub.2SO.sub.4. Solvent was evaporated, affording the titled product. Yield: 98% (2 g, brown liquid). .sup.1H NMR (400 MHz, DMSO-d6): δ 8.46-8.44 (m, 1H), 7.85 (s, 1H), 7.49 (d, J=1.5 Hz, 1H), 7.41 (d, J=1.0 Hz, 1H), 6.86-6.85 (m, 1H), 5.34 (d, J=5.9 Hz, 1H), 4.73-4.71 (m, 1H), 1.33 (d, J=8.6 Hz, 3H). LCMS: (Method B) 163.2 (M+H), Rt. 2.83 min, 96.00% (Max).

Step 4: 7-(1-chloroethyl) imidazo [1, 2-a] pyridine

(106) To a stirred solution of 1-(imidazo [1, 2-a] pyridin-7-yl) ethan-1-ol (1.1 g, 6.78 mmol) in DCM (10 mL), thionyl chloride was added at 0° C. and the mixture was stirred at rt for 1 h. Volatiles were evaporated under vacuum and the crude product was dissolved in DCM (10 mL). This process was repeated twice to remove any excess of thionyl chloride. Yield: 93% (1.12 g, brown solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.93 (d, J=9.4 Hz, 1H), 8.36 (d, J=2.5 Hz, 1H), 8.21 (d, J=2.7 Hz, 1H), 8.03 (s, 1H), 7.65-7.63 (m, 1H), 5.63-5.61 (m, 1H), 1.82 (d, J=9.0 Hz, 3H). LCMS: (Method A) 181.0 (M+H), Rt. 1.72 min, 97.41% (Max).

Intermediate 8: 7-(1-(Piperazin-1-yl)ethyl)imidazo[1,2-a]pyridine hydrochloride

(107) ##STR00305##

Step 1: tert-butyl4-(1-(imidazo [1, 2-a] pyridin-7-yl) ethyl) piperazine-1-carboxylate

(108) To a stirred solution of 1-Boc piperazine (1.1 g, 6.11 mmol) in DMF was added TEA (2.3 mL, 16.6 mmol) and Intermediate 7 (1.0 g, 5.55 mmol) and stirred at 80° C. for 16 h. The reaction mixture was evaporated under vacuum and water (5 mL) was added. The product was extracted with EtOAc (2×25 mL) and the organic layer was dried over anhydrous Na.sub.2SO.sub.4 and concentrated. The resulting crude product was purified by flash chromatography, affording the title compound (off white solid). .sup.1H NMR (400 MHz, CDCl.sub.3): δ 8.13 (d, J=7.0 Hz, 1H), 7.66 (s, 1H), 7.60-7.58 (m, 2H), 7.06 (d, J=6.5 Hz, 1H), 3.53-3.51 (m, 5H), 2.54-2.44 (m, 4H), 1.46-1.42 (m, 12H). LCMS: (Method A) 331.2 (M+H), Rt. 1.71 min, 75.51% (Max).

Step 2: 7-(1-(Piperazin-1-yl)ethyl)imidazo[1,2-a]pyridine hydrochloride

(109) To a stirred solution of tert-butyl 4-(1-(imidazo[1,2-a]pyridin-7-yl)ethyl)piperazine-1-carboxylate (0.7 g, 2.12 mmol) 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 in diethyl ether (50 mL). The title compound was obtained after evaporation of the solvent. Yield: 99% (0.47 g, off white solid). LCMS: (Method A) 231.3 (M+H), Rt. 0.49 min, 86.4% (Max).

Intermediate 9: Methyl 6-(piperazin-1-yl) nicotinate hydrochloride

(110) ##STR00306##

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

(111) A stirred solution of 1-Boc piperazine (9.5 g, 51.28 mmol, Symax fine chemicals) in dry DMF (80 mL), TEA (12.9 mL, 93.24 mmol) and methyl 6-chloronicotinate (8 g, 46.62 mmol, combi block chemicals) were added. The reaction mixture was stirred at 80° C. for 14 h. The resulting reaction mixture was cooled to rt and poured in to water (100 mL). The formed precipitate was filtered to afford the title product. Yield: 96.7% (14.5 g, off white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.66 (d, J=2.2 Hz, 1H), 7.97 (dd, J=9.1, 2.4 Hz, 1H), 6.88 (d, J=9.1 Hz, 1H), 3.79 (s, 3H), 3.66 (t, J=4.7 Hz, 4H), 3.43 (t, J=5.2 Hz, 4H), 1.43 (s, 9H). LCMS: (Method A) 322.3 (M+H), Rt. 2.42 min, 99.42% (Max).

Step 2: Methyl 6-(piperazin-1-yl) nicotinate hydrochloride

(112) A stirred solution of tert-butyl 4-(5-(methoxycarbonyl) pyridin-2-yl) piperazine-1-carboxylate (14.5 g, 45.11 mmol) in 1, 4-dioxane (50 mL), HCl in dioxane (4N in dioxane, 145 mL, 10V) was added at rt and the resulting mixture was stirred for 3 h. The white precipitate formed was filtered and washed with diethyl ether (25 mL) and EtOAc (2×20 mL) and dried over Na.sub.2SO.sub.4 to afford the title product. Yield: 94.6% (11 g, pale brown solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.29 (br s, 2H), 8.69 (d, J=2.0 Hz, 1H), 8.04 (dd, J=8.8, 2.0 Hz, 1H), 6.99 (d, J=8.8 Hz, 1H), 3.90 (t, J=4.8 Hz, 4H), 3.81 (s, 3H), 3.18 (br s, 4H). LCMS: (Method A) 222.1 (M-35), Rt. 1.40 min, 98.40% (Max).

Intermediate 10: Ethyl 1-(piperidin-4-yl)-1H-pyrazole-4-carboxylate hydrochloride

(113) ##STR00307##

Step 1: Tert-butyl 4-((methylsulfonyl)-oxy) piperidine-1-carboxylate

(114) To a stirred solution of 4-hydroxy N-Boc-piperidine (8.0 g, 39.7 mmol) and TEA (14 mL, 99.3 mmol) in DCM (80 mL), methane sulfonyl chloride (3.6 mL, 47.6 mmol) was added dropwise at 0° C. and the mixture was stirred for 2 h at rt. The completion of the reaction was monitored by TLC. The reaction mixture was quenched with water. The organic layer was washed with water (50 mL) and brine (50 mL), dried over Na.sub.2SO.sub.4 and concentrated. The resulting title product was taken for the next step without any further purification. Yield: 85% (9.9 g, pale brown oil). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 4.85-4.81 (m, 1H), 3.64-3.60 (m, 2H), 3.20 (s, 3H), 3.18-3.16 (m, 2H), 1.94-1.89 (m, 2H), 1.64-1.50 (m, 2H), 1.40 (s, 9H). LCMS: (Method A) 180.0 (M-boc), Rt. 2.63 min, 99.8% (ELSD).

Step 2: Tert-butyl 4-(4-(ethoxycarbonyl)-1H-pyrazol-1-yl) piperidine-1-carboxylate

(115) ##STR00308##

(116) To a stirred solution of ethyl-1-H pyrazole carboxylate (5.0 g, 3.7 mmol) in DMF (50 mL), Cs.sub.2CO.sub.3 (23 g, 71.35 mmol) and tert-butyl 4-((methylsulfonyl)-oxy) piperidine-1-carboxylate (9.9 g, 35.6 mmol) were added at 5° C. and reaction mixture was stirred at 90° C. overnight. The completion of the reaction was confirmed by TLC. The reaction mixture was poured into ice cold water. The resulting solid was filtered, washed with water (50 mL) and dried under reduced pressure. It was used in the next step without any further purification. Yield:

(117) 87% (10 g, off white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6: δ 8.39 (s, 1H), 7.87 (s, 1H), 4.45-4.39 (m, 1H), 4.21 (q, J=7.2 Hz, 2H), 4.05-4.02 (m, 2H), 2.01-1.98 (m, 2H), 1.85-1.78 (m, 2H), 1.42 (s, 9H), 1.26 (t, J=7.2 Hz, 3H). LCMS: (Method A) 222.0 (M-Boc), Rt. 2.77 min, 92.86% (Max).

Step 3: Ethyl 1-(piperidin-4-yl)-1H-pyrazole-4-carboxylate hydrochloride

(118) A stirred solution of tert-butyl 4-(4-(ethoxycarbonyl)-1H-pyrazol-1-yl) piperidine-1-carboxylate (10 g, 30.92 mmol) in 1,4-dioxane (50 mL), HCl in dioxane (4 M, 100 mL, 10V) was added and the resulting mixture was stirred at rt for 2 h. The white precipitate formed was filtered and washed with diethyl ether (25 mL) and EtOAc (2×20 mL) to afford the title product. Yield: 92% (7.4 g, off white solid). .sup.1H NMR (400 MHz, DMSO-d6): δ 9.12 (br s, 1H), 8.92 (br s, 1H), 8.35 (s, 1H), 7.91 (s, 1H), 4.57-4.52 (m, 1H), 4.21 (q, J=7.2 Hz, 2H), 3.04-2.88 (m, 4H), 2.19-2.13 (m, 4H), 1.25 (t, J=7.2 Hz, 3H).

(119) LCMS: (Method A) 224.2 (M-35), Rt. 1.88 min, 95.2% (Max).

Intermediate 11: N-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)acetamide hydrochloride

(120) ##STR00309##

Step 1: tert-butyl 4-(4-nitro-1H-pyrazol-1-yl)piperidine-1-carboxylate

(121) To a stirred solution of 4-nitro-1H-pyrazole (2.0 g, 17.7 mmol, combi block) in dry MeCN (20 mL), potassium carbonate (7.3 g, 53.4 mmol) and tert-butyl 4-((methylsulfonyl)-oxy) piperidine-1-carboxylate (obtained as described in Step 1 of Intermediate 10, 4.9 g, 17.6 mmol) were added at 0° C. The reaction mixture was stirred overnight at 80° C. The reaction mixture was concentrated under vacuum and DCM (200 mL) was added to the resulting crude solid. The solution was washed with water (100 mL), brine (100 mL), dried over anhydrous Na.sub.2SO.sub.4 and concentrated. The resulting crude product was purified by flash chromatography to get the titled compound. Yield: 58% (3 g, pale brown solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.95 (s, 1H), 8.28 (s, 1H), 4.48-4.43 (m, 1H), 4.05-4.02 (m, 2H), 2.89-2.86 (m, 2H), 2.04-2.01 (m, 2H), 1.85-1.75 (m, 2H), 1.41 (s, 9H).

Step 2: tert-butyl 4-(4-amino-1H-pyrazol-1-yl)piperidine-1-carboxylate

(122) To a stirred solution of tert-butyl 4-(4-nitro-1H-pyrazol-1-yl)piperidine-1-carboxylate (2.5 g, 6.7 mmol) in dry MeOH (30 mL), was added 10% palladium on charcoal (250 mg) under nitrogen atmosphere. The reaction was stirred at rt for 3 h under hydrogen atmosphere. The reaction progress was monitored by TLC. After completion of reaction, the reaction mixture was filtered through celite and washed with MeOH. The filtrate was concentrated to get the title compound. Yield: 70% (2 g, brown solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.06 (s, 1H), 6.91 (s, 1H), 4.16-4.08 (m, 1H), 4.01-3.98 (m, 2H), 3.77 (br s, 2H), 3.21-2.87 (m, 2H), 1.92-1.89 (m, 2H), 1.72-1.41 (m, 2H), 1.40 (s, 9H). LCMS: (Method A) 267.3 (M+H), Rt. 1.98 min, 93.97% (Max).

Step 3: tert-Butyl 4-(4-acetamido-1H-pyrazol-1-yl)piperidine-1-carboxylate

(123) To a stirred solution of tert-butyl 4-(4-amino-1H-pyrazol-1-yl)piperidine-1-carboxylate (1.6 g, 6.0 mmol) in DCM, N-methyl morpholin (0.72 mL, 6.6 mmol) and acetic anhydride (0.56 mL, 6.0 mmol) were added at 0° C. The reaction mixture was stirred at rt for 2 h. The reaction mixture was concentrated under vacuum and triturated with diethyl ether (10 mL). The resulting solid was filtered, washed with hexane (20 mL), dried and taken for next step without any further purification. Yield: 91.7% (1.7 g, brown solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.90 (s, 1H), 7.87 (s, 1H), 7.40 (s, 1H), 4.32-4.27 (m, 1H), 4.03-4.00 (m, 2H), 3.21-2.87 (m, 2H), 1.96 (s, 3H), 1.95-1.91 (m, 2H), 1.75-1.71 (m, 2H), 1.42 (s, 9H). LCMS: (Method A) 309.2 (M+H), Rt. 3.01 min, 96.36% (Max).

Step 4: N-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)acetamide hydrochloride

(124) To a stirred solution of tert-butyl 4-(4-acetamido-1H-pyrazol-1-yl)piperidine-1-carboxylate (1.7 g) in dry dioxane (10 mL), HCl in dioxane (17 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 triturated in diethyl ether (20 mL) and dried under vacuum, affording the title product. Yield: 94.2% (1.2 g, off white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 10.10 (s, 1H), 9.32 (br s, 1H), 7.88 (s, 1H), 7.43 (s, 1H), 4.46-4.42 (m, 1H), 3.36-3.32 (m, 2H), 3.05-3.01 (m, 2H), 2.15-2.10 (m, 4H), 1.97 (s, 3H). LCMS: (Method B) 209.2 (M+H), Rt. 1.33 min, 98.71% (Max).

Intermediate 12: Methyl 2-(piperazin-1-yl)pyrimidine-5-carboxylate hydrochloride

(125) ##STR00310##

Step 1: 5-(4-(1-(imidazo[1,2-a]pyridin-7-yl)ethyl)piperazin-1-yl)-1,3,4-thiadiazol-2-amine

(126) To a stirred solution of methyl 2-chloropyrimidine-5-carboxylate (5 g, 28.97 mmol) in dry DMF (60 mL), TEA (12.09 mL, 86.92 mmol) and tert-butyl piperazine-1-carboxylate (5.93 g, 31.87 mmol) were added at 0° C. The reaction mixture was heated at 100° C. overnight. It was concentrated to half of the volume and filtered. The resulting solid was dissolved in DCM (35 mL) and washed with water (20 mL), dried over Na.sub.2SO.sub.4 and concentrated affording the title product. Yield: 70% (7 g, off white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.81 (s, 2H), 3.84 (t, J=4.8 Hz, 4H), 8.80 (s, 3H), 3.48-3.38 (m, 4H), 1.42 (s, 9H). LCMS: (Method A) 323.3 (M+H), Rt. 4.31 min, 99.89% (Max).

Step 2: Methyl 2-(piperazin-1-yl)pyrimidine-5-carboxylate hydrochloride

(127) To a stirred solution of 5-(4-(1-(imidazo[1,2-a]pyridin-7-yl)ethyl)piperazin-1-yl)-1,3,4-thiadiazol-2-amine (6.9 g, 21.42 mmol) in dry dioxane (30 mL), HCl in dioxane (50 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: 98% (4.7 g, off white solid). LCMS: (Method A) 223.3 (M-Boc), Rt. 1.62 min, 99.83% (Max).

Intermediate 13: 1-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazine dihydrochloride

(128) ##STR00311##

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

(129) To a stirred solution of N-boc piperazine (5.5 g, 29.5 mmol), TEA (11.9 g, 11.8 mmol) in DMF (55 mL), Intermediate 4 (7.5 g, 41.3 mmol) was added at rt and the resulting mixture was heated at 70° C. overnight. Completion of the reaction was monitored by TLC. The reaction mixture was concentrated under reduced pressure and the resulting crude mixture was dissolved in EtOAc (100 mL). The organic layer was washed with water (50 mL), brine (50 mL), dried over Na.sub.2SO.sub.4 and concentrated. The crude product was purified by flash chromatography (12% EtOAc in pet ether as eluent) to give the title compound. Yield: 52% (58% purity) (5.1 g, brown thick oil). .sup.1H NMR (400 MHz, CDCl.sub.3): δ 7.19-7.12 (m, 1H), 6.88-6.77 (m, 2H), 4.62-4.59 (m, 2H), 3.42-3.39 (m, 4H), 3.36-3.31 (m, 1H), 3.23-3.18 (m, 2H), 2.44-2.34 (m, 4H), 1.46 (s, 9H), 1.35 (d, J=6.4 Hz, 3H). LCMS: (Method A) 333.3 (M+H), Rt. 3.12 min, 58.09% (Max).

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

(130) To a stirred solution of tert-butyl 4-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazine-1-carboxylate (5.1 g, 15.3 mmol) in 1,4 dioxane (25 mL), HCl solution in dioxane (4 M, 10 V) was added at 0° C. The resulting mixture was stirred at rt for 2 h. Completion of the reaction was monitored by TLC. The reaction mixture was evaporated at 40° C. under reduced pressure. The resulting product was triturated with n-hexanes (2×100 mL) and decanted two times. It was then dried at 40° C. under reduced pressure to give the title compound. Yield: 66.2% (3.1 g, Off white solid). .sup.1H NMR (400 MHz, DMSO-d6): δ 7.15 (d, J=7.2 Hz, 1H), 6.76-6.71 (m, 2H), 4.36-4.30 (m, 2H), 3.55-3.53 (m, 4H), 3.43-3.41 (m, 1H), 3.15-3.11 (m, 2H), 2.53-2.43 (m, 4H), 1.31-1.29 (m, 3H). LCMS: (Method A) 233.2 (M+H), Rt. 1.67 min, 90.31% (Max).

Intermediate 14: 5-bromo-2-(piperazin-1-yl)pyrimidine hydrochloride

(131) ##STR00312##

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

(132) To a stirred solution of 1-boc piperazine (10.42 g, 56.86 mmol, Symax fine chemicals) in dry DMF (100 mL), TEA (14.43 mL, 103.39 mmol) and 5-bromo-2-chloropyrimidine (10 g, 51.69 mmol, Oakwood chemicals) were added at rt and the reaction mixture was stirred at 80° C. for 14 h. The reaction mixture was cooled to rt and poured into water (100 mL). The formed precipitate was filtered and washed with diethyl ether (50 mL) to afford the title product. Yield: 84.5% (15 g, off white solid). .sup.1H NMR (400 MHz, DMSO-d6): δ 8.49 (s, 2H), 3.69 (t, J=5.2 Hz, 4H), 3.40 (t, J=5.1 Hz, 4H), 1.42 (s, 9H). LCMS: (Method A) 345.23 (M+2), Rt. 4.92 min, 99.6% (Max).

Step 2: 5-bromo-2-(piperazin-1-yl)pyrimidine hydrochloride

(133) To a stirred solution of tert-butyl-4-(5-bromopyrimidin-2-yl) piperazine-1-carboxylate (15.0 g, 43.7 mmol) in 1,4-dioxane (50 mL), HCl in dioxane (150 mL, 10V, 4N) was added at 0° C. and stirred at rt for 4 h. The resulting white precipitate was filtered and was washed with Et.sub.2O (25 mL), EtOAc (2×20 mL) to afford the title product. Yield: 98.2% (12.0 g, off white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.40 (br s, 2H), 8.54 (s, 2H), 3.93 (t, J=4.8 Hz, 4H), 3.13 (br s, 4H). LCMS: (Method A) 244.9 (M-35), Rt. 1.71 min, 99.8% (Max).

Intermediate 15: 2-(Piperazin-1-yl)-5-trityl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine

(134) ##STR00313##

Step 1: Benzyl 4-carbamothioylpiperazine-1-carboxylate

(135) To a stirred solution of 1-Z-piperazine (8.5 g, 38.5 mmol) in dry THF (100 mL), 1,1-thiocarbonyldimidazole (12.37 g, 69.4 mmol) was added and the mixture was stirred at 60° C. for 5 h. It was concentrated under vacuum and NH.sub.3 in EtOH (2 N, 300 mL) was added at 0° C. The resulting mixture was stirred at 55° C. for 8 h in an autoclave. It was diluted with water (100 mL) and extracted with DCM (2×100 mL). The DCM layer was washed with water (100 mL), dried over in anhydrous Na.sub.2SO.sub.4 and concentrated. The resulting crude product was purified by flash chromatography to afford the title product. Yield: 87% (7 g, white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.51 (s, 2H), 7.38-7.31 (m, 5H), 5.1 (s, 2H), 3.78 (m, 4H), 3.43-3.33 (m, 4H). LCMS: (Method A) 280.2 (M+H), Rt. 2.33 min, 95.4% (Max).

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

(136) To a stirred solution of benzyl 4-carbamothioylpiperazine-1-carboxylate (7.0 g, 20.43 mmol) in dry THF (50 mL), triethylamine (5.2 mL, 37.5 mmol) and 3-bromo-4-oxo-piperidine-1-carboxylic acid tert-butyl ester (8.3 g, 30.0 mmol) were added at 0° C. and the mixture was stirred for 8 h at 90° C. The reaction mixture was concentrated under vacuum. DCM (200 mL) was added and the resulting solution was washed with water (100 mL), brine (100 mL), dried over anhydrous Na.sub.2SO.sub.4 and concentrated. The crude product was purified by flash chromatography to give the title product. Yield: 70% (8 g, White solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.37-7.31 (m, 5H), 5.1 (s, 2H), 4.37 (s, 2H), 3.59-3.51 (m, 6H), 3.37-3.30 (m, 4H), 1.4 (s, 9H). LCMS: (Method A) 459.2.2 (M+H), Rt. 2.65 min, 97.3% (Max).

Step 3: Benzyl 4-(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)piperazine-1-carboxylate

(137) To a stirred solution of tert-butyl 2-(4-((benzyloxy)carbonyl)piperazin-1-yl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate (3.5 g, 7.6 mmol) in DCM, TFA (20% in DCM, 50 mL) was added at 0° C. and the mixture was stirred for 4 h at rt. Completion of the reaction was monitored by TLC. It was concentrated and DCM (200 mL) was added. The resulting solution was washed with NaHCO.sub.3 (100 mL), brine (100 mL), dried over anhydrous Na.sub.2SO.sub.4 and concentrated. The resulting crude product was used in the next step without further purification. Yield: 96% (2.6 g, brown solid). LCMS: (Method B) 359.2 (M+H), Rt. 2.0, 98.7% (Max). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.37-7.31 (m, 5H), 5.1 (s, 2H), 3.7 (s, 2H), 3.6-3.59 (m, 4H), 3.35-3.32 (m, 4H), 2.93 (t, J=5.6 Hz, 2H), 2.49-2.48 (m, 2H).

Step 4: Benzyl 4-(5-trityl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)piperazine-1-carboxylate

(138) To a stirred solution of benzyl 4-(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)piperazine-1-carboxylate (2.9 g, 8.1 mmol) in dry DCM (50 mL), triethylamine (3 mL, 20.2 mmol) and trityl chloride (2.92 g, 10.0 mmol) were added at 0° C. The reaction mixture was stirred at rt for 2 h. It was quenched with iced water. The phases were separated and the organic phase was washed with water (100 mL), brine (100 mL), dried over anhydrous Na.sub.2SO.sub.4 and concentrated. The resulting crude product was used in the next step without further purification. Yield: 58% (3 g, White solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.45-7.05 (m, 20H), 5.1 (s, 2H), 3.55-3.1 (m, 4H), 3.33-3.27 (m, 4H), 3.22 (m, 2H), 2.8-2.7 (m, 2H), 2.49-2.48 (m, 2H). LCMS: (Method A) 600.8 (M+H), Rt. 8.4.min, 47.70% (Max).

Step 5: 2-(Piperazin-1-yl)-5-trityl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine

(139) To a stirred solution of benzyl 4-(5-trityl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)piperazine-1-carboxylate (3.0 g, 5 mmol) in dry ethanol (50 mL), 6N NaOH (15 mL) was added at 0° C. The reaction mixture was stirred at 85° C. for 8 h. Completion of the reaction was monitored by TLC. The reaction mixture was concentrated and DCM (200 mL) was added. The resulting solution was washed with water (100 mL), brine (100 mL), dried over anhydrous Na.sub.2SO.sub.4. After evaporation of the solvents, the crude product was purified by flash chromatography affording the title product. Yield: 78% (1.5 g, off-white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.44 (d, J=7.0 Hz, 6H), 7.32 (t, J=7.4 Hz, 6H), 7.20 (t, J=7.0 Hz, 3H), 3.21-3.15 (m, 6H), 2.80-2.72 (m, 4H), 2.68-2.65 (m, 2H), 2.50-2.42 (m, 3H). LCMS: (Method A) 467.0 (M+H), Rt. 7.26.min, 99.4% (Max).

Intermediate 16: 1-(5-bromopyridin-2-yl)piperazine hydrochloride

(140) ##STR00314##

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

(141) To a stirred solution of 1-Boc piperazine (10.6 g, 57.29 mmol, Symax fine chemicals) in dry DMF (100 mL), TEA (14.43 mL, 103.39 mmol) and 5-bromo-2-chloropyrimidine (10 g, 52.08 mmol, Oakwood chemicals) were added and the reaction mixture was stirred at 80° C. for 14 h. It was cooled down to rt and poured on iced water (100 mL). The resulting precipitate was filtered and washed with hexane (50 mL) to afford the title compound. Yield: 58.8% (10 g, off white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.60 (s, 1H), 8.13 (dd, J=8.6, 2.4 Hz, 1H), 7.54 (dd, J=8.4, 0.4 Hz, 1H), 3.22-3.20 (m, 4H), 2.61-2.59 (m, 4H), 1.42 (s, 9H). LCMS: (Method A) 343.9 (M+2H), Rt. 5.58 min, 98.9% (Max).

Step 2: 1-(5-bromopyridin-2-yl)piperazine hydrochloride

(142) To a stirred solution of tert-butyl 4-(5-bromopyridin-2-yl)piperazine-1-carboxylate (10 g, 29.21 mmol) in 1,4-dioxane (50 mL), 4N HCl solution in dioxane (100 mL, 10V) was added and the mixture was stirred 4 h at rt. The white precipitate formed was filtered and residue was washed with diethyl ether (25 mL) to afford the title compound. Yield: 95.2% (9 g, off white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 10.05 (br s, 2H), 8.21 (d, J=2.4 Hz, 1H), 7.82 (dd, J=9.2, 2.4 Hz, 1H), 6.99 (d, J=9.2 Hz, 1H), 3.80-3.77 (m, 4H), 3.33-3.13 (m, 4H). LCMS: (Method A) 243.9 (M+2H), Rt. 1.69 min, 99.3% (Max).

Intermediate 17: Tert-butyl 2-chloro-7, 8-dihydropyrido [4, 3-d] pyrimidine-6(5H)-carboxylate

(143) ##STR00315##

Step 1: 6-benzyl-5, 6, 7, 8-tetrahydropyrido [4, 3-d] pyrimidine-2, 4(1H, 3H)-dione

(144) A stirred solution of ethyl-1-benzyl-4-oxo-3-piperidine carboxylate, hydrochloride (15 g, 50.4 mmol, combi blocks) and urea (6.36 g, 105 mmol) in dry MeOH (110 mL), sodium methoxide (16.4 mL, 75.14 mmol, and 25% wt. in methanol) was added drop wise at rt and the mixture was refluxed for 40 h. It was cooled to 0° C. and filtered. The residue was stirred with water (40 mL) for 30 min at rt and again cooled to 0° C. and filtered. The residue was washed with diethyl ether (2×20 mL) and dried, affording the title compound. Yield: 60% (7.2 g, Off white solid). .sup.1H NMR (400 MHz, DMSO-d6): δ 9.03 (s, 2H), 7.33-7.32 (m, 4H), 7.26-7.25 (m, 1H), 3.56 (s, 2H), 2.68 (s, 2H), 2.55 (t, J=5.2 Hz, 2H), 2.26 (t, J=5.2 Hz, 2H). LCMS: (Method A) 258.2 (M+2), Rt. 1.31 min, 99.60% (Max).

Step 2: 6-benzyl-2, 4-dichloro-5, 6, 7, 8-tetrahydropyrido [4, 3-d] pyrimidine

(145) To 6-benzyl-5, 6, 7, 8-tetrahydropyrido [4, 3-d] pyrimidine-2, 4(1H, 3H)-dione (7.2 g, 27.9 mmol), POCl.sub.3 (45 mL, 6V) was added slowly at 0° C. and refluxed for 4 h. The reaction mixture was evaporated under vacuum. EtOAc (200 mL) was added and the solution was poured over cold 3M NaOH solution. The resulting organic layer was separated and washed with brine (30 mL), dried over anhydrous Na.sub.2SO.sub.4 and evaporated, affording the title compound. Yield: 79% (6.5 g, brown solid). .sup.1H NMR (400 MHz, DMSO-d6): δ 7.33-7.32 (m, 5H), 3.77 (s, 2H), 3.56 (s, 2H), 2.94 (t, J=7.2 Hz, 2H), 2.80 (t, J=6.8 Hz, 2H). LCMS: (Method A) 296.3 (M+2), Rt. 2.50 min, 97.94% (Max).

Step 3: 6-benzyl-2-chloro-5, 6, 7, 8-tetrahydropyrido [4, 3-d] pyrimidine

(146) To the stirred solution of 6-benzyl-2, 4-dichloro-5, 6, 7, 8-tetrahydropyrido [4, 3-d] pyrimidine (6 g, 20.4 mmol) in EtOH (120 mL), zinc powder (10.65 g, 163 mmol) and ammonium hydroxide (14.2 mL, 102 mmol) were added at rt and the mixture was stirred at 78° C. for 15 h. It was cooled to rt and filtered through celite. Resulting filtrate was evaporated under vacuum. The resulting crude mixture was diluted with EtOAc (150 mL) and washed with water (15 mL). The organic layer was dried over anhydrous anhydrous Na.sub.2SO.sub.4 and evaporated under vacuum. The resulting crude product was purified by flash chromatography. Yield: 52% (2.7 g, off white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.48 (s, 1H), 7.32-7.31 (m, 5H), 3.71 (s, 2H), 3.57 (s, 2H), 2.89 (t, J=7.6 Hz, 2H), 2.79 (t, J=7.2 Hz, 2H). LCMS: (Method A) 260.2 (M+2), Rt. 1.86 min, 97.15% (Max).

Step 4: 2-chloro-5, 6, 7, 8-tetrahydropyrido [4, 3-d] pyrimidine hydrochloride

(147) To the stirred solution of 6-benzyl-2-chloro-5, 6, 7, 8-tetrahydropyrido [4, 3-d] pyrimidine (2.7 g, 10.4 mmol) in dry DCM (60 mL), 1-chloroethyl chloroformate (1.47 mL, 13.5 mmol) was added at 0° C. The reaction mixture was stirred at 0° C. for 15 min and then refluxed for 2 h. The reaction mixture was evaporated under vacuum and resulting crude mixture was refluxed with MeOH (30 mL) for 1 h. Then the reaction mixture was cooled to rt and evaporated under vacuum to give title compound. Yield: 70% (crude) (1.5 g, brown thick oil). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.45 (s, 1H), 3.84 (d, J=5.6 Hz, 2H), 3.01 (t, J=8.0 Hz, 2H), 2.76 (t, J=8.0 Hz, 2H). LCMS: (Method B) 170.0 (M+2), Rt. 2.16 min, 81.936% (Max).

Step 5: tert-butyl 2-chloro-7, 8-dihydropyrido [4, 3-d] pyrimidine-6(5H)-carboxylate

(148) To the stirred solution of 2-chloro-5, 6, 7, 8-tetrahydropyrido [4, 3-d] pyrimidine hydrochloride (1.8 g, 8.73 mmol) in dry THF (20 mL), TEA (6.1 mL, 43.6 mmol) and Boc anhydride (3.8 mL, 17.4 mmol) were added at 0° C. The reaction mixture was stirred at rt overnight. It was diluted with EtOAc (30 mL) and washed with water (10 mL). The organic layer was dried over anhydrous Na.sub.2SO.sub.4 and evaporated under vacuum. The resulting crude product was purified by flash chromatography to give the title compound. Yield: 60% (0.9 g, off white solid). .sup.1H NMR (400 MHz, DMSO-d6): δ 8.45 (s, 1H), 4.56 (s, 2H), 3.66 (t, J=8.0 Hz, 2H), 2.88 (t, J=8.0 Hz, 2H), 1.50 (s, 9H). LCMS: (Method A) 270.2 (M+2), Rt. 3.68 min, 76.45% (Max).

Intermediate 18: 2-methyl-1-(6-(piperazin-1-yl)pyridin-3-yl)propan-1-ol hydrochloride

(149) ##STR00316##

Step 1: tert-butyl 4-(5-(1-hydroxy-2-methylpropyl)pyridin-2-yl)piperazine-1-carboxylate

(150) To a solution of tert-butyl 4-(5-formylpyridin-2-yl)piperazine-1-carboxylate (1.4 g, 4.81 mmol) in dry THF (14 mL), isopropyl magnesium chloride (2M in Et.sub.2O) (2.9 mL, 5.77 mmol) was added at −10° C. and the reaction mixture was stirred at 0° C. for 2 h. Upon completion (monitored by TLC), the reaction mixture was quenched with saturated ammonium chloride solution (10 mL) and the layers were separated. The organic layer was diluted with ethylacetate (15 mL), washed with brine (15 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated. The crude product was purified by flash column chromatography to afford the titled compound. Yield: 69% (1.1 g, off white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.00 (d, J=2.8 Hz, 1H), 7.49-7.45 (m, 1H), 6.79-6.82 (m, 1H), 5.00 (d, J=6.0 Hz, 1H), 4.13 (t, J=8.4 Hz, 1H), 3.43-3.33 (m, 8H), 1.78-1.74 (m, 1H), 1.42 (s, 9H), 0.87 (d, J=8.80 Hz, 3H), 0.70 (d, J=8.80 Hz, 3H). LCMS: (Method A) 336.2 (M+H), Rt. 2.97 min, 96.7% (Max).

Step 2: 2-methyl-1-(6-(piperazin-1-yl)pyridin-3-yl)propan-1-ol hydrochloride

(151) To a 0° C. solution of tert-butyl 4-(5-(1-hydroxy-2-methylpropyl)pyridin-2-yl)piperazine-1-carboxylate (1.1 g, 3.28 mmol) in dry 1,4-dioxane (11 mL), 4 M HCl in dioxane (4 mL) was added and the reaction mixture was stirred at rt for 3 h. Upon completion (monitored by TLC), the reaction mixture was concentrated and triturated with diethylether (15 mL). The solid was filtered affording the titled compound. Yield: 99% (0.9 g, off white solid). LCMS: (Method A) 236.2 (M+H), Rt. 1.32 min, 96.6% (Max).

Intermediate 19: 6-bromo-3-methylimidazo[1,5-a]pyridine

(152) ##STR00317##

Step 1: (5-bromopyridin-2-yl)methanamine

(153) To a solution of 5-bromopicolinonitrile (5 g, 27.32 mmol) in THF, BH.sub.3.THF (1M solution) (163.92 mL, 163.92 mmol) was added at rt and the mixture was heated to reflux for 2 h. It was then cooled to 0° C. and MeOH (20 mL) and 1N HCl solution were added. The mixture was further refluxed for 7 h. It was quenched with 10% K.sub.2CO.sub.3 solution (500 mL) and extracted with DCM (6×100 mL). The combined organic layer was dried over Na.sub.2SO.sub.4 and concentrated under vacuum affording the title product. It was taken for next step without any further purification (Yellow solid). LCMS: (Method A) 187.3 (M+H), Rt. 1.33 min, 77.38% (Max).

Step 2: N-((5-bromopyridin-2-yl)methyl)acetamide

(154) To a stirred solution of (5-bromopyridin-2-yl)methanamine (2 g, 10.69 mmol) in DCM, Et.sub.3N (2.23 mL, 16.03 mmol) followed by acetyl chloride (0.91 mL, 12.83 mmol) were added at 0° C. The reaction mixture was stirred at rt for 3 h. It was then diluted with water (15 mL) and extracted with DCM (2×20 mL). The combined organic layer was dried over Na.sub.2SO.sub.4 and concentrated under vacuum to give crude product which was taken for next step without further purification. Yield: 54% (1.3 g, Yellow solid). LCMS: (Method A) 229.3 (M+H), Rt. 1.61 min, 69.56% (Max).

Step 3: 6-bromo-3-methylimidazo[1,5-a]pyridine

(155) To a stirred solution of N-((5-bromopyridin-2-yl)methyl)acetamide (1.3 g, 5.67 mmol) in toluene (20 mL) at 0° C., POCl.sub.3 (1.05 mL, 11.34 mmol) was added dropwise over 5 min and the mixture was refluxed at 110° C. for 6 h. It was then quenched with water (15 mL) and concentrated under reduced pressure. A saturated NaHCO.sub.3 solution (15 mL) was added and was extracted with DCM (2×20 mL). The combined organic layer was dried over Na.sub.2SO.sub.4 and concentrated under vacuum. The crude product was purified by flash chromatography (eluent: 2-3% MeOH in DCM), to give the title product (yellow solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.42 (s, 1H), 7.50 (t, J=12.8 Hz, 1H), 7.32 (s, 1H), 6.78 (dd, J=12.4, 7.2 Hz, 1H), 2.58 (s, 3H). LCMS: (Method A) 213.0 (M+H), Rt. 1.54 min, 99.10% (Max).

Intermediate 20: 2-methyl-1-(2-(piperazin-1-yl)pyrimidin-5-yl)propan-1-ol dihydrochloride

(156) ##STR00318##

(157) The title compound was synthesized according to the procedure described for Intermediate 18, starting from methyl 2-chloropyrimidine-5-carboxylate. Yield: 100% (crude) (200 mg, pale yellow solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.28 (s, 2H), 8.32 (s, 2H), 4.19-4.18 (m, 1H), 3.95-3.92 (m, 4H), 3.14-3.13 (m, 4H), 1.83-1.81 (m, 1H), 0.85 (d, J=6.4 Hz, 3H), 0.73 (d, J=6.8 Hz, 3H). LCMS: (Method A) 237.3 (M+H-2HCl), Rt. 1.81 min, 58.32% (Max). HPLC: (Method A) Rt 1.79 min, 89.12% (Max).

Intermediate 21: 4-(4-(methylsulfonyl)-1H-pyrazol-1-yl)piperidine hydrochloride

(158) ##STR00319##

(159) The title compound was synthesized according to the procedure described for Intermediate 10, starting from 4-(methylsulfonyl)-1H-pyrazole. Yield: 92% (0.9 g, white solid). LCMS: (Method A) 230.0 (M+H), Rt. 1.89 min, 90.68% (Max).

Intermediate 22: 1-(2-chloropyrimidin-5-yl)cyclohexan-1-ol

(160) ##STR00320##

(161) To a stirred solution of 5-bromo-2-chloropyrimidine (1 g, 5.2 mmol) in Et.sub.2O cooled to −100° C. was added n-BuLi (1.6 M) (3.88 mL, 6.2 mmol) over a period of 20 min. The mixture was stirred for 45 min at −100° C. Cyclohexanone (1.014 g, 10.34 mmol) was added dropwise at −100° C. and the mixture was stirred 1 h at the same temperature. It was quenched with a saturated solution of NH.sub.4Cl (10 mL) and extracted with EtOAc (2×20 mL). Combined organic layer was washed with brine (10 mL) and dried over Na.sub.2SO.sub.4. After evaporation of the solvent, the crude product was purified by flash chromatography (eluent: 30% EtOAc in petroleum ether) affording the title compound (yellow thick oil). LCMS: (Method A) 213.3 (M+H), Rt. 2.908 min, 98.455% (Max).

Intermediate 23: 4-(2-chloropyrimidin-5-yl)tetrahydro-2H-pyran-4-ol

(162) ##STR00321##

(163) The title compound was synthesized according to the procedure described for Intermediate 22, with the addition of tetrahydro pyran-4-one as ketone (yellow solid). LCMS: (Method A) 214.9 (M+2H), Rt. 1.47 min, 72.0% (Max).

Intermediate 24: 4-(6-chloropyridin-3-yl)tetrahydro-2H-pyran-4-ol

(164) ##STR00322##

(165) The title compound was synthesized according to the procedure described for Intermediate 22, starting with 5-bromo-2-chloropyridine and the addition of tetrahydro pyran-4-one as ketone (off white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.78-8.52 (m, 1H), 7.96-7.92 (m, 1H), 7.49-7.46 (m, 1H), 5.35 (s, 1H), 3.78-3.72 (m, 4H), 2.04-1.94 (m, 2H), 1.57-1.53 (m, 2H). LCMS: (Method A) 214.0 (M+H), Rt. 2.08 min, 76.24% (Max).

Intermediate 25: 3-(6-chloropyridin-3-yl)tetrahydrofuran-3-ol

(166) ##STR00323##

(167) The title compound was synthesized according to the procedure described for Intermediate 22, starting with 5-bromo-2-chloropyridine and the addition of tetrahydrofuran-3-one as ketone. Yield: 62% (440 mg, Colourless liquid). LCMS: (Method A) 200.0 (M+H), Rt. 1.91 min, 99.02% (Max).

Intermediate 26: 3-(6-chloropyridin-3-yl)oxetan-3-ol

(168) ##STR00324##

(169) The title compound was synthesized according to the procedure described for Intermediate 22, starting with 5-bromo-2-chloropyridine and the addition of oxetan-3-one as ketone (colourless liquid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.61 (d, J=2.8 Hz, 1H), 8.03 (q, J=8.4 Hz, 1H), 7.55 (d, J=8.4 Hz, 1H), 6.66 (s, 1H), 4.78 (d, J=7.2 Hz, 2H), 4.69 (d, J=7.2 Hz, 2H). LCMS: (Method A) 185.9 (M+H), Rt. 1.61 min, 99.20% (Max).

Intermediate 27: 1-(6-chloropyridin-3-yl)cyclohexan-1-ol

(170) ##STR00325##

(171) The title compound was synthesized according to the procedure described for Intermediate 22, starting with 5-bromo-2-chloropyridine and the addition of cyclohexanone as ketone (white solid). .sup.1HNMR (400 MHz, DMSO-d.sub.6): δ 8.51 (s, 1H), 7.91 (dd, J=2.8, 8.2 Hz, 1H), 7.44 (d, J=8.4 Hz, 1H), 5.01 (s, 1H), 1.75-1.61 (m, 8H), 1.50 (t, J=4.4 Hz, 2H). LCMS: (Method A) 212.0 (M+H), Rt. 2.44 min, 96.05% (Max).

Intermediate 28: 3-(2-chloropyrimidin-5-yl)tetrahydrofuran-3-ol

(172) ##STR00326##

(173) The title compound was synthesized according to the procedure described for Intermediate 22, with the addition of dihydrofuran-3(2H)-one as ketone (yellow thick oil). LCMS: (Method A) 201.2 (M+H), Rt. 1.421 min, 96.024% (Max).

Intermediate 29: 2-(1-chloroethyl)-1,8-naphthyridine

(174) ##STR00327##

Step 1: 2-methyl-1,8-naphthyridine

(175) To a stirred solution of 2-amino-3-formyl pyridine (7 g, 57 mmol) in acetone (70 mL), a saturated solution of KOH in methanol (0.5 mL) was added and the mixture was stirred at 55° C. for 6 h. Completion of the reaction was monitored by TLC. The mixture was concentrated and the resulting crude product was purified by flash chromatography (Elutant: 65-85% EtOAc in pet ether) to give the title compound. Yield: 88.3% (7.3 g, pale brown solid). .sup.1H NMR (400 MHz, CDCl.sub.3): δ 9.10-9.09 (m, 1H), 8.18-8.15 (m, 1H), 8.09 (d, J=8.4 Hz, 1H), 7.47-7.39 (m, 1H), 7.29-7.28 (m, 1H), 2.84 (s, 3H). LCMS: (Method B) 145.0 (M+H), Rt. 3.06 min, 97.85% (Max). HPLC: (Method B) Rt 2.98 min, 98.09% (Max).

Step 2: 1, 8-naphthyridine-2-carbaldehyde

(176) A solution of selenium dioxide (8.61 g, 77.56 mmol) in 1,4 dioxane (140 mL) with 0.5 mL of water was stirred at 100° C. for 5 min. The mixture was cooled down to 0° C. and 2-Methyl-1,8-naphthyridine (7 g, 48.5 mmol) was added dropwise. The mixture was heated again at 100° C. for 5 h. Completion of the reaction was monitored by TLC. The reaction mixture was filtered through celite bed, washed with EtOAc (50 mL) and concentrated. The resulting crude mixture was dissolved in EtOAc (150 mL) and washed with water (3×60 mL), brine (30 mL), dried over Na.sub.2SO.sub.4 and concentrated to give the title compound (brown solid). .sup.1H NMR (300 MHz, DMSO-d.sub.6): δ 10.18 (s, 1H), 9.28-9.27 (m, 1H), 8.74 (d, J=8.1 Hz, 1H), 8.63 (d, J=8.1 Hz, 1H), 8.11 (dd, J=8.4, 1.2 Hz, 1H), 7.83-7.79 (m, 1H). LCMS: (Method B) 159.0 (M+H), Rt. 2.44 min, 91.59% (Max). HPLC: (Method B) Rt 2.41 min, 87.86% (Max).

Step 3: 1-(1,8-naphthyridin-2-yl)ethan-1-ol

(177) To a stirred solution of 1,8-naphthyridine-2-carbaldehyde (3.3 g, 20.8 mmol) in dry THF (100 mL), methyl magnesium chloride in THF (14 mL, 41.7 mmol, 3M) was added at 0° C. and stirred 2 h at rt. Completion of the reaction was monitored by TLC. The reaction mixture was quenched with saturated NH.sub.4Cl solution (20 mL) and extracted with EtOAc. The EtOAc layer was washed with water (2×25 mL), brine (25 mL), dried over Na.sub.2SO.sub.4 and concentrated. The resulting crude product was purified by flash chromatography (Elutant: 65-80% EtOAc in pet ether) to give the title compound. Yield: 60.6% (2.2 g, brown thick oil). .sup.1H NMR (300 MHz, CDCl.sub.3): δ 9.16-9.13 (m, 1H), 8.27-8.23 (m, 2H), 7.57-7.53 (m, 2H), 5.17-5.10 (m, 1H), 1.68-1.48 (m, 3H). LCMS: (Method B) 175.0 (M+H), Rt. 2.86 min, 51.51% (Max). HPLC: (Method A) Rt 0.73 min, 63.62% (Max).

Step 4: 2-(1-chloroethyl)-1,8-naphthyridine

(178) To a stirred solution of 1-(1,8-naphthyridin-2-yl)ethan-1-ol (500 mg, 2.87 mmol) in DCM (10 mL), thionyl chloride was added at 0° C. and stirred 1.5 h at rt. Completion of the reaction was monitored by TLC. The reaction mixture was concentrated under vacuum. DCM (20 mL) was added and evaporated. This process was repeated twice, affording the title product. Yield: 100% (550 mg, brown thick oil). .sup.1H NMR (300 MHz, DMSO-d.sub.6): δ 9.29-9.27 (m, 1H), 8.89 (dd, J=8.1, 1.8 Hz, 1H), 8.76 (d, J=8.4 Hz, 1H), 8.04 (d, J=8.4 Hz, 1H), 7.96-7.92 (m, 1H), 5.63-5.61 (m, 1H), 1.96 (d, J=6.6 Hz, 3H). LCMS: (Method A) 193.0 (M+H), Rt. 1.99 min, 75.76% (Max).

Intermediate 30: 1-(6-chloropyridin-3-yl)cyclopentan-1-ol

(179) ##STR00328##

(180) The title compound was synthesized according to the procedure described for Intermediate 22, starting with 5-bromo-2-chloropyridine and the addition of cyclopentanone as ketone (white solid). .sup.1H NMR (400 MHz, CDCl.sub.3): δ 8.52 (s, 1H), 7.80 (dd, J=2.4, 8.2 Hz, 1H), 7.31 (dd, J=0.4, 8.0 Hz, 1H), 2.04-1.99 (m, 6H), 1.92-1.89 (m, 2H). LCMS: (Method A) 198.2 (M+H), Rt. 2.29 min, 89.7% (Max).

Intermediate 31: 1-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperidin-4-yl methanesulfonate

(181) ##STR00329##

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

(182) To a stirred solution of 4-Hydroxy piperidine (2.5 g, 24.7 mmol) in dry acetonitrile (10 mL), were added TEA (10.3 mL, 74.1 mmol) and 6-(1-chloroethyl)-2,3-dihydrobenzofuran, (4.5 g, 24.7 mmol) at rt and the mixture was stirred overnight. The reaction mixture was concentrated under vacuum. To the resulting crude mixture, DCM (50 mL) was added and was washed with water (20 mL), brine (20 mL), dried over anhydrous Na.sub.2SO.sub.4 and concentrated. The crude product was purified by silica gel column chromatography to afford the titled compound (off white solid). .sup.1H NMR (400 MHz, CDCl.sub.3): δ 7.15 (s, 1H), 6.74-6.73 (m, 2H), 4.54-4.48 (m, 4H), 3.14 (t, J=11.6 Hz, 2H), 1.96 (d, J=9.6 Hz, 2H), 1.80-1.61 (m, 3H), 1.41-1.20 (m, 6H). LCMS: (Method A) 248.1 (M+H), Rt. 1.67 min, 97.8% (Max).

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

(183) To a stirred solution of step 1:1-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperidin-4-ol (0.2 g, 0.8 mmol) in dry DCM (4 mL) were added TEA (0.33 mL, 2.4 mmol) and methane sulphonyl chloride (0.12 mL, 1.6 mmol, Spectro chem) at 0° C. The reaction mixture was stirred at rt for 4 h. The reaction progress was monitored by TLC. After the completion of reaction, the reaction mixture was diluted with DCM (30 mL) and washed with 10% NaHCO.sub.3 (30 mL) solution. The organic layer was washed with water (30 mL), brine (30 mL) and dried over Na.sub.2SO.sub.4. After evaporation of the solvent, the title compound was obtained and was used without further purification. Yield: 80.2% (0.2 g, brown thick oil). LCMS: (Method A) 326.3 (M+H), Rt. 2.72 min, 55.05% (Max).

Intermediate 33: N-(2-(2-chloropyrimidin-5-yl)propan-2-yl)acetamide

(184) ##STR00330##

Step 1: 2-(2-chloropyrimidin-5-yl) propan-2-ol

(185) To the reaction mixture of methyl 2-chloropyrimidine-5-carboxylate (2.5 g, 14.487 mmol) in THF (10 mL), methyl magnesium chloride (14.487 mL, 43.463 mmol) was added drop wise at 0° C. and the mixture was stirred at rt for 30 min. After completion of reaction the reaction mixture was poured into 50 mL of 1N HCl and extracted with ether. The ether layer was washed with water, dried over anhydrous Na.sub.2SO.sub.4 and concentrated. The resulting crude product was purified by flash chromatography (Elutant: 55-60% EtOAc in pet ether) to afford title compound (pale yellow solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 1.48 (s, 6H), 5.51 (s, 1H), 8.84 (s, 2H). LCMS: (Method A) 173.0 (M+H), Rt. 1.659 min, 98.64% (Max).

Step 2: N-(2-(2-chloropyrimidin-5-yl)propan-2-yl)acetamide

(186) To a solution of 2-(2-chloropyrimidin-5-yl) propan-2-ol (1.1 g, 6.376 mmol) in MeCN, conc. H.sub.2SO.sub.4 (2.37 mL, 44.637 mmol) was added dropwise at 0° C. and the mixture was stirred at rt for 24 h. After completion of reaction, the reaction mixture was cooled to 0° C. and diluted with NH.sub.4OH solution slowly. Then the reaction mixture was extracted with ether. The ether layer was washed with water, dried over Na.sub.2SO.sub.4 and concentrated. The resulting crude product was purified by flash chromatography to afford title compound (off white). LCMS: (Method A) 214.2 (M+H), Rt. 1.662 min, 98.72% (Max).

Intermediate 34: 3-(2-chloropyrimidin-5-yl)oxetan-3-ol

(187) ##STR00331##

(188) The title compound was synthesized according to the procedure described for Intermediate 22, using oxetan-3-one as ketone (off white crystals). .sup.1H NMR (300 MHz, DMSO-d.sub.6): δ 8.95 (s, 2H), 6.85 (s, 1H), 4.78 (s, 4H). LCMS: (Method A) 187.0 (M+H), Rt. 1.321 min, 84.213% (Max).

Intermediate 35: 6-(piperazin-1-yl)isoindolin-1-one, hydrochloride

(189) ##STR00332##

Step 1: tert-butyl 4-(3-oxoisoindolin-5-yl)piperazine-1-carboxylate

(190) To a degassed solution of 6-bromoisoindolin-1-one (0.7 g, 3.3 mmol), 1-Boc piperazine (0.921 g, 4.9 mmol) and sodium tert butoxide (0.95 g, 2.5 mmol) in toluene (10 mL), Pd.sub.2(dba).sub.3 (0.151 g, 0.165 mmol) and BINAP (0.205 g, 0.33 mmol) were added at rt and heated to 80° C. overnight in sealed tube. Then the reaction mixture was filtered through celite and concentrated. Water (4 mL) was added and was extracted with EtOAc (2×10 mL). The combined organic layer was dried over Na.sub.2SO.sub.4 and concentrated under vacuum. The resulting crude product was purified by flash chromatography (Eluent: 5-6% MeOH in DCM). After evaporation, the resulting solid was triturated in Et.sub.2O and filtered, affording the title product (white solid). .sup.1H NMR (400 MHz, CDCl.sub.3): δ 8.72-8.70 (m, 1H), 7.79 (d, J=1.6 Hz, 1H), 7.56 (d, J=8.4 Hz, 1H), 7.26-7.23 (m, 1H), 4.26 (s, 2H), 3.49-3.46 (m, 4H), 3.18-3.13 (m, 4H), 1.43 (s, 9H). LCMS: (Method A) 318.0 (M+H), Rt. 2.26 min, 39.9% (Max).

Step 2: 6-(piperazin-1-yl)isoindolin-1-one, hydrochloride

(191) To a stirred solution of tert-butyl 4-(5-acetamido-1,3,4-thiadiazol-2-yl)piperazine-1-carboxylate (0.35 g 0.9 mmol) in dry dioxane (4 mL), HCl in dioxane (5 mL, 4 N) was added at rt 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 with Et.sub.2O (20 mL) to get the title compound. Yield: 50% (120 mg, Yellow solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.95 (s, 2H), 7.47-7.44 (m, 1H), 7.06-7.02 (m, 1H), 6.76 (s, 1H), 4.35-4.28 (m, 2H), 3.41-3.39 (m, 4H), 3.30-3.20 (m, 4H). LCMS: (Method A) 218.2 (M+H), Rt. 1.05 min, 65.4% (Max).

Intermediate 36: 5-(piperazin-1-yl)-1, 3,4-thiadiazol-2(3H)-one hydrochloride

(192) ##STR00333##

Step 1: tert-butyl 4-(hydrazinocarbonothioyl)piperazine-1-carboxylate

(193) To the stirred solution of tert-butyl piperazine-1-carboxylate (5.0 g, 26.845 mmol) in THF (50 mL), triethylamine (22.6 mL, 161.072 mmol) and thiocarbonyldiimidazole (9.568 g, 53.690 mmol) were added and stirred for 2 h at rt. Hydrazine hydrate (2.68 mL, 53.690 mmol) was added and the reaction mixture was further stirred for 2 h at room temperature. The reaction the reaction mixture was poured into 50 mL of brine solution and extracted with EtOAc. The EtOAc layer was dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure to get crude compound. The resulting crude product was purified by flash chromatography (Elutant: 1-2% MeOH in DCM) to afford title compound (off white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.10 (s, 1H), 4.43 (s, 2H), 3.84-0.00 (m, 4H), 3.57-3.50 (m, 4H), 1.49 (s, 9H). LCMS: (Method A) 262.0 (M+H), Rt. 1.659 min, 92.71% (Max).

Step 2: tert-butyl 4-(5-oxo-4,5-dihydro-1,3,4-thiadiazol-2-yl)piperazine-1-carboxylate

(194) To the tert-butyl 4-(hydrazinocarbonothioyl)piperazine-1-carboxylate (2.0 g, 7.692 mmol) in DCM (20 mL), triethylamine (3.2 mL, 23.076 mmol) and carbonyldiimidazole (3.74 g, 23.076 mmol) were added at rt and stirred for 4 h at rt. After completion of reaction, the reaction mixture was poured into 50 mL of brine solution and extracted with EtOAc. The EtOAc layer was dried over Na.sub.2SO.sub.4 and concentrated. The resulting crude product was purified by flash chromatography (Elutant: 1-2% MeOH in DCM) to afford title compound. Yield: 52.2% (1.1 g, off white). .sup.1H NMR: (400 MHz, DMSO-d.sub.6): δ 3.54-3.50 (m, 4H), 3.28-3.25 (m, 4H), 1.49 (s, 9H). LCMS: (Method A) 287.0 (M+H), Rt. 2.406 min, 99.95% (Max).

Step 3: 5-(piperazin-1-yl)-1, 3,4-thiadiazol-2(3H)-one hydrochloride

(195) The stirred solution of tert-butyl 4-(hydrazinocarbonothioyl)piperazine-1-carboxylate (1.0 g, mmol) in 1,4 dioxane (10 mL), hydrochloric acid in dioxane (4 M, 10 mL) was added at 0° C. and the mixture was stirred for 4 h at rt. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to get tittle compound. Yield: 87.0% (550 mg, off white). .sup.1H NMR: (400 MHz, DMSO-d.sub.6): δ 11.96 (s, 1H), 9.57 (s, 2H), 3.47-3.45 (m, 4H), 3.44-3.15 (m, 4H). LCMS: (Method A) 186.9 (M+H), Rt. 0.549 min, 98.72% (Max).

Intermediate 37: 5-(piperidin-4-yl)-1, 3,4-oxadiazol-2(3H)-one hydrochloride

(196) ##STR00334##

Step 1: tert-butyl 4-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)piperidine-1-carboxylate

(197) To tert-butyl 4-(hydrazinocarbonyl)piperidine-1-carboxylate (1.0 g, 4.112 mmol) in DCM (10 mL), triethylamine (1.7 mL, 12.337 mmol) and carbonyldiimidazole (2.0 g, 12.337 mmol) were added and the mixture was stirred for 4 h at rt. After completion of reaction, the reaction mixture was poured into 50 mL of brine solution and extracted with EtOAc. The EtOAc layer was dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure to get crude compound. The resulting crude was purified by flash chromatography (Elutant: 1-2% MeOH in DCM) to afford title compound. Yield: 55.4% (610 mg, off white). .sup.1H NMR: (400 MHz, DMSO-d.sub.6) δ 12.10 (br, 1H), 3.84-3.92 (m, 2H), 2.80-2.95 (m, 3H), 1.83-1.91 (m, 2H), 1.38-1.50 (m, 2H), 1.39 (5, 9H). LCMS: (Method A) 170.2 (M+H), Rt. 2.382 min, 94.3% (Max).

Step 2: 5-(piperidin-4-yl)-1, 3,4-oxadiazol-2(3H)-one hydrochloride

(198) To the tert-butyl 4-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)piperidine-1-carboxylate (520 mg, 2.512 mmol) in 1,4 dioxane (5 mL), 4M hydrochloric acid in dioxane (5 mL) was added at 0° C. The reaction mixture was stirred for 4 h at rt. After completion of reaction, the reaction mixture was concentrated to get tittle compound. Yield: 95.0% (311 mg, off white). LCMS: (Method A) 170.2 (M+H), Rt. 0.610 min, 77.0% (Max).

Intermediate 38: 7-(piperazin-1-yl)-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one

(199) ##STR00335##

Step 1: Methyl 2-(2-chloro-5-nitropyridin-4-yl)oxy)acetate

(200) To a stirred solution of 2,4-dichloro-5-nitropyridine (26 mmol, 5 g) and methyl glycolate (31.2 mmol, 2.41 mL) in DMF at 0° C., sodium hydride was added (60% in mineral oil, 31.2 mmol, 1.25 g) and the mixture was stirred at rt overnight. The reaction mixture was quenched with ammonium chloride solution (30 mL) and extracted with EtOAc (3×50 mL). The combined organic layer was dried over Na.sub.2SO.sub.4 and concentrated under vacuum. The resulting crude product was purified by column chromatography affording the title product (yellow solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.93 (s, 1H), 7.71 (s, 1H), 5.23 (s, 2H), 3.74 (s, 3H). LCMS: (Method A) 247.0 (M+H), Rt. 2.436 min, 83.5% (Max).

Step 2: 7-chloro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one

(201) To a stirred suspension of methyl 2-((2-chloro-5-nitropyridin-4-yl)oxy)acetate (10 mmol, 2.5 g) in ethanol (25 mL), acetic acid (10 mL) and iron powder (50 mmol, 2.8 g) were added at rt and the mixture was heated to 80° C. for 20 h. The reaction mixture was filtered through celite and concentrated. The resulting product was purified by flash chromatography, affording the title product. Yield: 77% (1.4 g, pale brown solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 11.03 (s, 1H), 7.84 (s, 1H), 7.15 (s, 1H), 4.75 (s, 2H). LCMS: (Method B) 185 (M+H), Rt. 2.078 min, 98.29% (Max).

Step 3: 7-(piperazin-1-yl)-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one

(202) To a stirred solution of methyl 2-((2-chloro-5-nitropyridin-4-yl)oxy)acetate (1.0 g 5.43 mmol) in NMP (4 mL) was added piperazine (27 mmol, 2.3 g mmol) at rt and the mixture was heated at 150° C. overnight. The completion of the reaction was confirmed by TLC. The reaction mixture was evaporated under reduced pressure. The resulting crude mixture was suspended in water (2 mL) and extracted with EtOAc (2×10 mL). The organic layer was dried over Na.sub.2SO.sub.4 and concentrated. The resulting product was purified by column chromatography (yellow solid). LCMS: (Method A) 235.3 (M+H), Rt. 0.516 min, 54.4% (Max).

Intermediate 39: (S)-1-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazine hydrochloride

(203) ##STR00336##

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

(204) 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).

(205) 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

(206) 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

(207) 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

(208) 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

(209) 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 40: (S)-1-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazine

(210) ##STR00337##

(211) The hydrochloride salt of 1-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazine (20 g) was suspended in NaOH solution (1 M, 150 mL) and extracted with EtOAc (150 mL). The water layer was further extracted two times with EtOAc (50 mL). The combined organic layers were dried over MgSO.sub.4 and filtered off. After evaporation of the solvent, the title compound was isolated as an oil (10 g). The aqueous layer was further basified to pH 12 (pH after the extraction was around 7-8) by addition of 2 M NaOH solution and further extracted with EtOAc. A second batch of the title compound (5 g) was isolated.

Example 1: 6-(4-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)-3-methylimidazo[1,5-a]pyridine

(212) ##STR00338##

(213) To a degassed solution of Intermediate 13 (178 mg, 0.77 mmol), Intermediate 19 (125 mg, 0.59 mmol) and sodium tert-butoxide (170 mg, 1.77 mmol) in 1,4 dioxane (4 mL), Pd.sub.2(dba).sub.3 (27 mg, 0.03 mmol) and Xphos (28 mg, 0.05 mmol) were added at rt and the mixture was heated in sealed tube at 100° C. overnight. The reaction mixture was filtered through celite and concentrated. The crude mixture was diluted with water (4 mL) and extracted with DCM (2×10 mL). The combined organic layer was dried over Na.sub.2SO.sub.4 and concentrated. The crude product was purified by flash chromatography, followed by preparative HPLC, affording the title product (yellow solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.37 (d, J=10.0 Hz, 1H), 7.16 (q, J=14.4 Hz, 3H), 6.79-6.70 (m, 3H), 4.51 (t, J=8.4 Hz, 2H), 3.49-3.35 (m, 1H), 3.14 (t, J=8.4 Hz, 2H), 3.11-2.83 (m, 4H), 2.67-2.51 (m, 4H), 2.50-2.33 (m, 3H), 1.31 (d, J=6.4 Hz, 3H). LCMS: (Method A) 363.3 (M+H), Rt. 2.15 min, 97.41% (Max). HPLC: (Method A) Rt 2.32 min, 96.88% (Max).

Example 2: 6-(4-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)isoindolin-1-one

(214) ##STR00339##

(215) The title compound was synthesized according to the procedure described for Example 12, starting from Intermediate 4 and Intermediate 35 (brown solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.42 (s, 1H), 7.38 (d, J=8.4 Hz, 1H), 7.20-7.16 (m, 2H), 7.07 (s, 1H), 6.78 (d, J=7.6 Hz, 1H), 6.73 (s, 1H), 6.54 (s, 1H), 4.51 (t, J=8.8 Hz, 2H), 4.24 (s, 2H), 3.19-3.10 (m, 6H), 2.62-2.55 (m, 2H), 2.49-2.42 (m, 2H), 1.30 (d, J=6.80 Hz, 3H). LCMS: (Method A) 364.2 (M+H), Rt. 2.50 min, 93.23% (Max). HPLC: (Method A) Rt 2.56 min, 91.88% (Max).

Example 3:7-(4-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one

(216) ##STR00340##

(217) The title compound was synthesized according to the procedure described for Example 12, starting from Intermediate 4 and Intermediate 38 (off white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 10.58 (s, 1H), 7.65 (s, 1H), 7.15 (d, J=7.2 Hz, 1H), 6.74 (t, J=7.6 Hz, 2H), 6.39 (s, 1H), 4.60-4.53 (m, 2H), 3.34-3.32 (m, 2H), 2.68 (s, 7H), 2.48-2.46 (m, 2H), 1.27 (d, J=6.8 Hz, 3H). LCMS: (Method A) 381.2 (M+H), Rt. 2.013 min, 99.2% (Max). HPLC: (Method A) Rt 2.04 min, 99.5% (Max).

Example 4: 6-(4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)isoindolin-1-one

(218) ##STR00341##

(219) The title compound was synthesized according to the procedure described for Example 12, starting from Intermediate 1 and Intermediate 35 (white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.93 (dd, J=1.6, −7.4 Hz, 2H), 8.41 (s, 1H), 8.09 (d, J=8.8 Hz, 1H), 8.01 (d, J=1.2 Hz, 1H), 7.92 (dd, J=1.6, 8.6 Hz, 1H), 7.37 (d, J=8.4 Hz, 1H), 7.19 (dd, J=2.0, 8.4 Hz, 1H), 7.07 (d, J=2.0 Hz, 1H), 4.23 (s, 2H), 3.77-3.75 (m, 1H), 3.19-3.16 (m, 4H), 2.67-2.65 (m, 4H), 1.44 (d, J=6.40 Hz, 3H). LCMS: (Method A) 374.2 (M+H), Rt. 1.93 min, 99.2% (Max). HPLC: (Method A) Rt 2.01 min, 99.35% (Max).

Example 5: 1-(2-(4-(1-(2,3-dihydrobenzofuran-5-yl)ethyl) piperazin-1-yl)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)ethan-1-one

(220) ##STR00342##

(221) The title compound was synthesized according to the procedure described for Example 10, starting from Example 7. The resulting crude was purified by flash chromatography to give the title compound (yellow solid). .sup.1H NMR (400 MHz, DMSO-d6): δ 8.18 (s, 1H), 7.14 (d, J=7.6 Hz, 1H), 6.75 (d, J=7.2 Hz, 1H), 6.71 (s, 1H), 4.50 (t, J=8.8 Hz, 2H), 4.43 (s, 2H), 4.43-3.66 (m, 7H), 3.13 (t, J=8.4 Hz, 2H), 2.73 (t, J=6.0 Hz, 2H), 2.61-2.59 (m, 2H), 2.34-2.31 (m, 2H), 2.08 (s, 3H), 1.27 (d, J=6.40 Hz, 3H). LCMS: (Method A) 408.2 (M+H), Rt. 2.56 min, 97.96% (Max). HPLC: (Method A) Rt. 2.49 min, 97.69% (Max).

Example 6: 1-(2-(4-(1-(quinoxalin-6-yl) ethyl) piperazin-1-yl)-7, 8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)ethan-1-one

(222) ##STR00343##

(223) The title compound was synthesized according to the procedure described for Example 10, starting from Example 8. The final product was purified by flash chromatography (off white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.94-8.92 (dd, J=7.2, 2.0 Hz, 2H), 8.18 (s, 1H), 8.09 (d, J=8.8 Hz, 1H), 8.00 (s, 1H), 7.92 (dd, J=8.8, 1.6 Hz, 1H), 4.48-4.43 (m, 2H), 3.77-3.75 (m, 1H), 3.70-3.69 (m, 6H), 2.73 (t, J=6.0 Hz, 2H), 2.51 (t, J=1.6 Hz, 2H), 2.41 (t, J=4.80 Hz, 2H), 2.07 (s, 3H), 1.43 (d, J=6.80 Hz, 3H). LCMS: (Method A) 418.2 (M+H), Rt. 1.94 min, 99.44% (Max). HPLC: (Method A) Rt. 1.99 min, 99.23% (Max).

Example 7: 2-(4-(1-(2,3-dihydrobenzofuran-5-yl)ethyl)piperazin-1-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine

(224) ##STR00344##

(225) The title compound was synthesized according to the procedure described for Example 8, starting from Intermediate 13 and Intermediate 17. Yield: 65% (0.095 g, pale yellow solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.05 (s, 1H), 7.13 (d, J=7.6 Hz, 1H), 6.74 (d, J=8.0 Hz, 1H), 6.70 (s, 1H), 4.49 (t, J=8.8 Hz, 2H), 3.75 (s, 2H), 3.63-3.63 (m, 5H), 3.12 (t, J=8.8 Hz, 2H), 3.04 (t, J=6.0 Hz, 2H), 2.60 (t, J=5.6 Hz, 2H), 2.45-2.41 (m, 4H), 1.26 (d, J=6.8 Hz, 3H). LCMS: (Method A) 366.3 (M+H), Rt. 1.98 min, 95.91% (Max). HPLC: (Method A) Rt. 2.021 min, 95.60% (Max).

Example 8: 2-(4-(1-(quinoxalin-6-yl) ethyl) piperazin-1-yl)-5, 6, 7, 8-tetrahydropyrido [4,3-d]pyrimidine

(226) ##STR00345##

Step 1: Tert-butyl 2-(4-(1-(quinoxalin-6-yl) ethyl) piperazin-1-yl)-7, 8-dihydropyrido [4, 3-d] pyrimidine-6(5H)-carboxylate

(227) To the stirred solution of Intermediate 2 (1.7 g, 6.28 mmol) in dry DMF (15 mL), TEA (2.67 mL, 19.33 mmol) and Intermediate 17 (1.3 g, 4.83 mmol) were added at rt and stirred at 80° C. overnight. The reaction mixture was evaporated under vacuum. The resulting crude mixture was diluted with EtOAc (30 mL) and washed with water (10 mL), dried over anhydrous Na.sub.2SO.sub.4 and evaporated under vacuum. The resulting crude product was purified by flash chromatography to give title compound. Yield: 36% (0.6 g, Brown thick oil). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.94 (d, J=2.4 Hz, 2H), 8.17 (s, 1H), 7.93-7.90 (m, 3H), 4.34 (s, 2H), 3.76-3.74 (m, 5H), 3.57 (t, J=7.6 Hz, 2H), 2.89-2.89 (m, 2H), 2.43-2.41 (m, 4H), 1.45 (s, 9H), 1.43 (d, J=11.2 Hz, 3H). LCMS: (Method A) 476.2 (M+2), Rt. 3.44 min, 87.38% (Max).

Step 2: 2-(4-(1-(quinoxalin-6-yl) ethyl) piperazin-1-yl)-5, 6, 7, 8-tetrahydropyrido [4, 3-d] pyrimidine

(228) To the stirred solution of tert-butyl 2-(4-(1-(quinoxalin-6-yl) ethyl) piperazin-1-yl)-7, 8-dihydropyrido [4, 3-d] pyrimidine-6(5H)-carboxylate (0.6 g, 1.26 mmol) in 1,4-dioxane (2 mL), 4M HCl in dioxane (5 mL) was added and the mixture was stirred at rt for 2 h. It was evaporated under vacuum. To the resulting crude mixture MeOH (10 mL) was added and the solution was basified with 10% NaOH solution (2 mL). It was concentrated and the resulting crude mixture was purified by flash chromatography to give title compound. Yield: 78% (0.37 g, brown solid). .sup.1H NMR (400 MHz, DMSO-d6): δ 8.94-8.92 (m, 2H), 8.10 (s, 1H), 8.01 (d, J=9.6 Hz, 2H), 7.93-7.91 (m, 1H), 3.72-3.72 (m, 1H), 3.67-3.65 (m, 6H), 3.33 (s, 1H), 2.94 (t, J=6.0 Hz, 2H), 2.68 (t, J=1.6 Hz, 2H), 2.55 (t, J=5.6 Hz, 2H), 2.34 (t, J=1.60 Hz, 2H), 1.43 (d, J=6.40 Hz, 3H). LCMS: (Method A) 376.3 (M+2), Rt. 1.53 min, 97.74% (Max). HPLC: (Method A) Rt. 1.54 min, 99.50% (Max).

Example 9: 6-methyl-2-(4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine

(229) ##STR00346##

(230) To the stirred solution of Example 8 (0.15 g, 0.40 mmol) in 1,2-dichloroethane (3 mL), p-formaldehyde (0.024 g, 0.80 mmol) was added at rt and the mixture was stirred at rt. After 2 h, sodium triacetoxy borohydride (0.25 g, 1.20 mmol) was added and the mixture was stirred at rt overnight. The reaction mixture was diluted with DCM (10 mL) and washed with water (2 mL), dried over anhydrous Na.sub.2SO.sub.4 and evaporated under vacuum. The resulting crude product was purified by flash chromatography affording the title compound (brown solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.94-8.92 (m, 2H), 8.09 (d, J=8.4 Hz, 1H), 8.05 (s, 1H), 8.00 (s, 1H), 7.92 (d, J=6.8 Hz, 1H), 3.88-3.85 (m, 1H), 3.75 (t, J=6.8 Hz, 4H), 3.32 (t, J=5.2 Hz, 2H), 2.68-2.66 (m, 2H), 2.63 (t, J=12.8 Hz, 2H), 2.54-2.51 (m, 2H), 2.42-2.41 (m, 2H), 2.33 (s, 3H), 1.43 (d, J=6.8 Hz, 3H). LCMS: (Method A) 390.2 (M+2), Rt. 1.51 min, 97.08% (Max). HPLC: (Method A) Rt. 1.55 min, 96.75% (Max).

Example 10: 1-(2-(4-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)ethan-1-one

(231) SGN020616-01

(232) ##STR00347##

(233) To a stirred solution of Example 15 (150 mg, 0.4 mmol) in DCM, TEA (0.11 mL, 0.81 mmol) and acetyl chloride (0.038 mg, 0.48 mmol) were added at 0° C. and the mixture was stirred for 2 h at rt. It was quenched with iced water and the two phases were separated. The organic phase was washed with NaHCO.sub.3 (10 mL), brine (10 mL) and dried over anhydrous Na.sub.2SO.sub.4. After evaporation of the solvent, the crude product was purified by MD Autoprep HPLC (Method C), affording the title product (white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6: δ 7.15 (d, J=7.6 Hz, 1H), 6.75 (d, J=7.6 Hz, 1H), 6.71 (s, 1H), 4.53-4.46 (m, 4H), 3.71-3.65 (m, 2H), 3.39-3.37 (m, 1H), 3.33-3.30 (m, 4H), 3.13 (t, J=8.4 Hz, 2H), 2.51-2.50 (m, 5H), 2.08 (s, 3H), 1.27 (d, J=6.40 Hz, 3H). LCMS: (Method A) 413.3 (M+H), Rt. 2.2 min, 97.8% (Max). HPLC: (Method A) Rt 2.3 min, 98.9% (Max).

Example 11: 1-(2-(4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)ethan-1-one

(234) ##STR00348##

(235) The title compound was synthesized according to the procedure described for Example 10, starting from Example 19 (yellow solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.94 (dd, J=2.0, 7.0 Hz, 2H), 8.09 (d, J=8.8 Hz, 1H), 8.00 (s, 1H), 7.91 (dd, J=2.0, 8.6 Hz, 1H), 4.48 (d, J=14.8 Hz, 2H), 3.81-3.79 (m, 1H), 3.70-3.65 (m, 2H), 3.40-3.33 (m, 4H), 2.61-2.58 (m, 2H), 2.51-2.50 (m, 4H), 2.08 (s, 3H), 1.44 (d, J=6.80 Hz, 3H). LCMS: (Method A) 423.3 (M+H), Rt. 1.81 min, 99.2% (Max). HPLC: (Method A) Rt 1.85 min, 98.9% (Max).

Example 12: 2-(4-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-4(5H)-one

(236) ##STR00349##

(237) To a stirred solution of Intermediates 6 (0.5 g, 1.61 mmol) in DMF (5 mL, 10V), TEA (0.89 mL, 6.4 mmol) and Intermediate 4 (0.44 g, 2.41 mmol) were added at rt and the mixture was stirred at 80° C. for 12 h. It was concentrated under vacuum and resulting crude mixture was purified by MD Autoprep HPLC (Method C) to afford titled compound (off white solid). .sup.1H NMR (400 MHz, DMSO-d6): δ 7.29 (s, 1H), 7.16 (d, J=7.2 Hz, 1H), 6.76 (d, J=7.6 Hz, 1H), 6.72 (s, 1H), 4.51 (t, J=8.8 Hz, 2H), 3.46-3.42 (m, 4H), 3.38-3.36 (m, 4H), 3.14 (t, J=8.8 Hz, 2H), 2.69 (t, J=7.2 Hz, 2H), 2.44-2.43 (m, 2H), 1.28 (d, J=6.80 Hz, 3H). LCMS: (Method A) 358.0 (M+H), Rt. 2.324 min, 97.963% (Max). HPLC: (Method A) Rt. 2.279 min, 99.224% (Max).

Example 13: 2-(4-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)-5-methyl-6,7-dihydrothiazolo[5,4-c]pyridin-4(5H)-one

(238) ##STR00350##

(239) To a stirred solution of Example 12 (0.3 g, 0.78 mmol) in THF (3 mL, 10V), NaH (0.125 g, 3.12 mmol) was added at 0° C. and the mixture was stirred for 1 h. Then Mel (0.22 g, 1.56 mmol) was added at same temperature and the stirring was continued for 12 h. The reaction mixture was quenched with iced water (3 mL) and extracted with EtOAc (2×10 mL). The combined organic layer was washed with brine, dried over Na.sub.2SO.sub.4 and concentrated under vacuum. After flash chromatograghy, the resulting product was further purified by MD Autoprep HPLC (Method C) to afford titled compound (dark yellow thick oil). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.15 (d, J=7.6 Hz, 1H), 6.75 (d, J=7.6 Hz, 1H), 6.71 (s, 1H), 4.50 (t, J=8.4 Hz, 2H), 3.49-3.44 (m, 7H), 3.18-3.11 (m, 2H), 2.87 (s, 3H), 2.80-2.78 (m, 2H), 2.41-2.39 (m, 4H), 1.27 (d, J=6.8 Hz, 3H). LCMS: (Method A) 399.2 (M+H), Rt. 2.857 min, 97.21% (Max). HPLC: (Method A) Rt. 2.512 min, 98.36% (Max).

Example 14: 5-methyl-2-(4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-4(5H)-one

(240) ##STR00351##

(241) The title compound was synthesized according to the procedure described for Example 13, starting from Intermediates 1 and 6 (dark yellow thick oil). .sup.1H NMR (400 MHz, DMSO-d6): δ 8.94 (d, J=6.8 Hz, 2H), 8.10 (d, J=8.4 Hz, 1H), 8.01 (s, 1H), 7.92 (d, J=8.8 Hz, 1H), 3.83 (d, J=6.8 Hz, 1H), 3.49-3.48 (m, 6H), 2.87 (s, 3H), 2.79 (t, J=7.2 Hz, 2H), 2.62-2.61 (m, 4H), 1.44 (d, J=6.4 Hz, 3H). LCMS: (Method A) 409.2 (M+H), Rt. 1.956 min, 99.033% (Max). HPLC: (Method A) Rt. 2.003 min, 99.291% (Max).

Example 15: 2-(4-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine

(242) ##STR00352##

Step 1: 2-(4-(1-(2,3-Dihydrobenzofuran-7-yl)ethyl)piperazin-1-yl)-5-trityl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine

(243) To a stirred solution of Intermediate 15 (1.5 g, 3.2 mmol) in DMF (10 mL), TEA (1.3 mL, 9.6 mmol) and Intermediate 4 (0.878 g, 4.8 mmol), were added at 0-5° C. and the mixture was stirred at 100° C. overnight. It was concentrated and EtOAc (30 mL) was added. 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 chromatography affording the title product (yellow solid). LCMS: (Method A) 612.8 (M+H), Rt. 8.6.min, 35.4% (Max).

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

(244) To a stirred solution of 2-(4-(1-(2,3-dihydrobenzofuran-7-yl)ethyl)piperazin-1-yl)-5-trityl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine (0.2 g, 0.32 mmol) in DCM, TFA (20% in DCM, 8 mL) was added at 0° C. and the mixture was stirred for 2 h at rt. The reaction mixture was concentrated and DCM (200 mL) was added. The resulting solution was washed with NaHCO.sub.3 (10 mL), brine (10 mL), dried over anhydrous Na.sub.2SO.sub.4 and concentrated. The crude product was purified by MD Autoprep HPLC (Method C). Yield: 62% (70 mg, Yellow solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.15 (d, J=7.6 Hz, 1H), 6.75 (d, J=7.6 Hz, 1H), 6.71 (s, 1H), 4.51 (t, J=8.8 Hz, 2H), 3.67 (s, 2H), 3.39-3.37 (m, 1H), 3.34-3.29 (m, 4H), 3.14 (t, J=8.4 Hz, 2H), 2.90 (t, J=5.6 Hz, 2H), 2.47-2.46 (m, 2H), 2.40-2.30 (m, 4H), 1.27 (d, J=6.80 Hz, 3H). LCMS: (Method A) 371.2 (M+H), Rt. 2.0 min, 96.4% (Max). HPLC: (Method A) Rt 1.97 min, 97.8% (Max).

Example 16: 2-(4-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine

(245) ##STR00353##

(246) To a stirred solution of Example 15 (0.15 g, 0.4 mmol) in MeOH, para formaldehyde (0.36 mg, 1.2 mmol) and sodium cyanoborohydride (0.038 mg, 0.6 mmol) were added at 0° C. and the mixture was stirred for 2 h at rt. It was concentrated and DCM was added. The resulting solution was washed with water (10 mL), brine (10 mL), dried over anhydrous Na.sub.2SO.sub.4. After evaporation of the solvents, the crude product was purified by MD Autoprep HPLC (Method C), affording the title product (pale brown). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.15 (d, J=7.6 Hz, 1H), 6.75 (d, J=7.6 Hz, 1H), 6.71 (s, 1H), 4.51 (t, J=8.8 Hz, 2H), 3.39-3.37 (m, 4H), 3.34-3.29 (m, 4H), 3.14 (t, J=8.4 Hz, 2H), 2.62 (t, J=5.6 Hz, 2H), 2.56 (t, J=1.6 Hz, 2H), 2.51-2.50 (m, 2H), 2.33 (s, 3H), 1.27 (d, J=6.80 Hz, 3H). LCMS: (Method A) 385.2 (M+H), Rt. 1.96 min, 96.9% (Max). HPLC: (Method A) Rt 1.99 min, 96.5% (Max).

Example 17 and 18: (S)-2-(4-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine and (R)-2-(4-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine

(247) ##STR00354##

(248) The racemic mixture of Example 15 was separated by chiral preparative HPLC, using the chiral preparative HPLC (Method X).

(249) The first eluting compound correspond to Example 17 (yellow solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.15 (d, J=7.6 Hz, 1H), 6.75 (d, J=7.6 Hz, 1H), 6.71 (s, 1H), 4.50 (t, J=8.8 Hz, 2H), 3.66 (s, 2H), 3.38-3.37 (m, 1H), 3.30-3.27 (m, 4H), 3.13 (t, J=8.8 Hz, 2H), 2.89 (t, J=5.6 Hz, 2H), 2.47-2.45 (m, 2H), 2.40-2.37 (m, 4H), 1.27 (d, J=6.40 Hz, 3H). LCMS: (Method A) 371.2 (M+H), Rt. 1.95 min, 97.9% (Max). HPLC: (Method A) Rt 1.98 min, 98.8% (Max). CHIRAL HPLC: (Method P) Rt. 7.15 min, 100% (Max).

(250) The second eluting compound correspond to Example 18 (yellow solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.15 (d, J=7.6 Hz, 1H), 6.75 (d, J=7.6 Hz, 1H), 6.71 (s, 1H), 4.50 (t, J=8.8 Hz, 2H), 3.66 (s, 2H), 3.38-3.37 (m, 1H), 3.30-3.27 (m, 4H), 3.13 (t, J=8.8 Hz, 2H), 2.89 (t, J=6.0 Hz, 2H), 2.47-2.45 (m, 2H), 2.40-2.37 (m, 4H), 1.27 (d, J=6.40 Hz, 3H). LCMS: (Method A) 371.2 (M+H), Rt. 1.95 min, 99.5% (Max). HPLC: (Method A) Rt 1.99 min, 99.4% (Max). CHIRAL HPLC: (Method P) Rt. 20.9 min, 100% (Max).

Example 19: 2-(4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine

(251) ##STR00355##

(252) The title compound was synthesized according to the procedure described for Example 15, starting from Intermediate 1 and Intermediate 15 (brown solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.93 (dd, J=2.0, 5.2 Hz, 2H), 8.08 (dd, J=2.0, 8.8 Hz, 1H), 7.99 (s, 1H), 7.90 (d, J=8.8 Hz, 1H), 3.79-3.77 (m, 1H), 3.66 (s, 2H), 3.37-3.30 (m, 4H), 2.91 (t, J=5.6 Hz, 2H), 2.59-2.56 (m, 2H), 2.56-2.40 (m, 5H), 1.42 (d, J=6.40 Hz, 3H). LCMS: (Method A) 381.2 (M+H), Rt. 1.47 min, 99.5% (Max). HPLC: (Method A) Rt 1.52 min, 99.04% (Max).

Example 20: 5-Methyl-2-(4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine

(253) ##STR00356##

(254) The title compound was synthesized according to the procedure described for Example 16, starting from Example 19 (white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.94 (dd, J=2.0, 7.0 Hz, 2H), 8.08 (d, J=8.4 Hz, 1H), 7.99 (s, 1H), 7.90 (d, J=8.4 Hz, 1H), 3.79-3.78 (m, 1H), 3.39 (s, 2H), 3.36-3.30 (m, 4H), 2.66-2.64 (m, 4H), 2.45-2.44 (m, 4H), 2.34 (s, 3H), 1.42 (s, 3H). LCMS: (Method A) 395.2 (M+H), Rt. 1.5 min, 98.9% (Max). HPLC: (Method A) Rt 1.52 min, 99.1% (Max).

Example 21: 5-(4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-1,3,4-thiadiazol-2(3H)-one

(255) ##STR00357##

(256) The title compound was synthesized according to the procedure described for Example 12, starting from Intermediate 1 and Intermediate 36 (pale brown solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.87 (s, 2H), 8.51 (s, 1H), 8.12 (d, J=8.4 Hz, 1H), 8.03 (s, 1H), 7.89 (d, J=8.8 Hz, 1H), 3.74 (d, J=6.0 Hz, 1H), 3.38-3.21 (m, 4H), 2.68-2.66 (m, 2H), 2.56-2.54 (m, 2H), 1.50 (d, J=6.0 Hz, 3H). LCMS: (Method A) 343.2 (M+H), Rt. 1.63 min, 98.23% (Max). HPLC: (Method A) Rt. 1.69 min, 98.3% (Max).

Example 22: 5-(1-(1-(quinoxalin-6-yl)ethylpiperidin-4-yl)-1,3,4-oxadiazol-2(3H)-one

(257) ##STR00358##

(258) The title compound was synthesized according to the procedure described for Example 12, starting from Intermediate 1 and Intermediate 37 (dark brown solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 12.06 (s, 1H), 8.93 (s, 2H), 8.07-7.89 (m, 3H), 3.81 (s, 1H), 2.98 (s, 1H), 2.81 (s, 1H), 2.11-0.00 (m, 2H), 1.91-1.83 (m, 2H), 1.61-0.00 (m, 2H), 1.42-0.00 (m, 3H). LCMS: (Method A) 326.3 (M+H), Rt. 1.55 min, 96.75% (Max). HPLC: (Method A) Rt. 3.48 min, 96.9%.

Example 23: 2-(1-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-4-yl)-5-methyl-1,3,4-oxadiazole

(259) ##STR00359##

(260) The title compound was synthesized according to the procedure described for Example 24, starting from Intermediate 4 (dark yellow solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.13 (d, J=7.2 Hz, 1H), 6.73 (d, J=7.6 Hz, 1H), 6.69 (s, 1H), 4.49 (t, J=8.8 Hz, 2H), 3.40-3.37 (m, 1H), 3.12 (t, J=8.8 Hz, 2H), 2.93-2.90 (m, 1H), 2.80-2.74 (m, 2H), 2.43 (s, 3H), 2.04-1.88 (m, 4H), 1.69-1.59 (m, 2H), 1.25 (d, J=6.80 Hz, 3H). LCMS: (Method A) 314.2 (M+1) Rt. 2.263 min, 95.868% (Max). HPLC: (Method A) Rt. 2.220 min, 94.865% (Max).

Example 24: 2-methyl-5-(1-(1-(quinoxalin-6-yl)ethylpiperidin-4-yl)-1,3,4-oxadiazole

(261) ##STR00360##

(262) To a stirred solution of 2-methyl-5-(piperidin-4-yl)-1,3,4-oxadiazole hydrochloride (0.3 g, 1.47 mmol, ABCR) in DMF (3 mL, 10V), cooled to 0° C., TEA (0.82 mL, 5.89 mmol) followed by Intermediate 1 (0.57 g, 2.94 mmol) were added and the mixture was stirred at 80° C. for 12 h. It was then concentrated. Water (3 mL) was added and was extracted with EtOAc (2×10 mL). The combined organic layer was washed with brine (5 mL) and dried over Na.sub.2SO.sub.4. After evaporation of the solvents, the resulting crude product was purified by flash chromatography to afford titled compound (dark yellow solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.94 (d, J=1.6 Hz, 1H), 8.92 (d, J=2.0 Hz, 1H), 8.08 (d, J=8.8 Hz, 1H), 7.98 (s, 1H), 7.91 (d, J=8.8 Hz, 1H), 3.82-3.81 (m, 1H), 3.00-2.97 (m, 1H), 2.86-2.84 (m, 2H), 2.44 (s, 3H), 2.18-2.16 (m, 2H), 2.00-1.97 (m, 2H), 1.78-1.74 (m, 2H), 1.43 (d, J=6.80 Hz, 3H). LCMS: (Method A) 324.2 (M+1) Rt. 1.624 min, 97.172% (Max). HPLC: (Method A) Rt. 1.665 min, 97.713% (Max).

Example 25: N-(1-(1-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-4-yl)-1H-pyrazol-4-yl)acetamide

(263) ##STR00361##

(264) To a stirred solution of Intermediate 11 (0.25 g, 1.2 mmol) in DMF (10 mL), TEA (0.5 mL, 3.6 mmol) and Intermediate 4 (0.22 g, 1.2 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 the resulting crude mixture was diluted with EtOAc (30 mL). The organic layer was washed with water (10 mL), brine (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 (yellow solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.88 (s, 1H), 7.83 (s, 1H), 7.38 (s, 1H), 7.16-6.71 (m, 3H), 4.55-4.49 (m, 2H), 4.12-3.99 (m, 1H), 3.43-3.41 (m, 1H), 3.16-3.12 (m, 2H), 3.11-3.01 (m, 1H), 2.84-2.82 (m, 1H), 2.33-1.80 (m, 9H), 1.26 (d, J=5.20 Hz, 3H). LCMS: (Method A) 355.2 (M+H), Rt. 2.22 min, 97.98% (Max). HPLC: (Method A), Rt. 2.26 min, 96.08% (Max).

Example 26: N-((1-(1-(1-(2,3-dihydrobenzofuran-5-yl)ethyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)acetamide

(265) ##STR00362##

(266) The title compound was synthesized according to the procedure described for Example 112, starting from Example 33. Yield: 62.08% (35 mg, colorless solid thick oil). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.06 (d, J=4.4 Hz, 1H), 7.62 (s, 1H), 7.31 (s, 1H), 7.15 (d, J=7.2 Hz, 1H), 6.76 (d, J=7.6 Hz, 1H), 6.72 (s, 1H), 4.51 (t, J=8.8 Hz, 2H), 4.06-4.04 (m, 3H), 3.43-3.41 (m, 1H), 3.16-3.12 (m, 2H), 3.03 (d, J=10.80 Hz, 1H), 2.84 (d, J=9.60 Hz, 1H), 2.08-2.02 (m, 1H), 1.97-1.87 (m, 5H), 1.80 (s, 3H), 1.3 (t, J=6.8 Hz, 3H). LCMS: (Method A) 369.2 (M+H), Rt. 2.161 min, 99.71% (Max). HPLC: (Method A), Rt. 2.204 min, 98.24% (Max).

Example 27: N-(1-(1-(1-(quinoxalin-6-yl)ethyl)piperidin-4-yl)-1H-pyrazol-4-yl)acetamide

(267) ##STR00363##

(268) To a stirred solution of Intermediate 11 (0.5 g, 2.4 mmol) in DMF (10 mL), TEA (1.0 mL, 7.2 mmol) and Intermediate 1 (0.46 g, 2.4 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 EtOAc (30 mL). The organic layer was washed with water (10 mL), brine (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 (yellow solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.88 (s, 1H), 8.93 (dd, J=7.2, 1.6 Hz, 2H), 8.08 (d, J=8.8 Hz, 1H), 8.00 (s, 1H), 7.93 (dd, J=8.8, 1.6 Hz, 1H), 7.84 (s, 1H), 7.38 (s, 1H), 4.12-4.04 (m, 1H), 3.84-3.83 (m, 1H), 3.09-3.06 (m, 1H), 2.90-2.87 (m, 1H), 2.14-2.12 (m, 2H), 1.95 (s, 3H), 1.90-1.88 (m, 4H), 1.44 (d, J=6.80 Hz, 3H). LCMS: (Method A) 365.2 (M+H), Rt. 1.73 min, 97.63% (Max). HPLC: (Method A), Rt. 1.74 min, 97.46% (Max).

Example 28: (1-(1-(1-(2, 3-dihydrobenzofuran-6-yl) ethyl) piperidin-4-yl)-1H-pyrazol-4-yl) methanol

(269) ##STR00364##

(270) To a stirred solution of Example 32 (0.4 g, 1.08 mmol) in dry THF: MeOH mixture (4:1, 10 mL), lithium borohydride (0.81 mL, 1.62 mmol, 2M in THF) was added at 0° C. and reaction was stirred at rt for 10 h. The reaction mixture was quenched with ice cooled water (10 mL) and extracted with EtOAc (25 mL). The organic layer was washed with brine (4 mL), dried over anhydrous Na.sub.2SO.sub.4 and concentrated. The resulting crude product was purified by flash chromatography to afford the title compound. Yield: 56.4% (0.2 g, off white solid). .sup.1H NMR (400 MHz, DMSO-d6): δ 7.62 (s, 1H), 7.33 (s, 1H), 7.15 (d, J=7.6 Hz, 1H), 6.76 (d, J=7.2 Hz, 1H), 6.72 (s, 1H), 4.76 (t, J=5.2 Hz, 1H), 4.51 (t, J=8.4 Hz, 2H), 4.32 (d, J=5.6 Hz, 2H), 3.99 (q, J=6.8 Hz, 1H), 3.42 (d, J=6.4 Hz, 1H), 3.14 (t, J=8.4 Hz, 2H), 3.03 (d, J=10.80 Hz, 1H), 2.84 (d, J=10.0 Hz, 1H), 2.08-2.02 (m, 1H), 1.97-1.81 (m, 5H), 1.3 (d, J=6.8 Hz, 3H). LCMS: (Method A) 328.3 (M+H), Rt. 2.14 min, 96.83% (Max). HPLC: (Method A) Rt. 2.14 min, 98.26% (Max).

Example 29: 1-(1-(2,3-Dihydrobenzofuran-6-yl)ethyl)-4-(4-(trifluoromethyl)-1H-pyrazol-1-yl) piperidine

(271) ##STR00365##

(272) To a stirred solution of 4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)piperidine hydrochloride (0.25 g, 0.98 mmol, Anichem) in dry MeCN (5 mL), TEA (0.4 mL, 2.94 mmol) and Intermediate 31 (0.27 g, 1.47 mmol) were added at rt. The reaction mixture was stirred at 60° C. for 14 h. Then the reaction mixture was cooled to rt and partitioned between water (5 mL) and EtOAc (60 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated. The resulting crude product was purified by MD Autoprep HPLC (Method C) (yellow thick oil). .sup.1H NMR (400 MHz, MeOD): δ 8.15 (s, 1H), 7.77 (s, 1H), 7.22 (d, J=7.2 Hz, 1H), 6.86 (d, J=7.2 Hz, 1H), 6.81 (s, 1H), 4.57 (t, J=8.4 Hz, 2H), 4.31-4.30 (m, 1H), 3.81-3.80 (m, 1H), 3.44-3.43 (m, 1H), 3.21 (t, J=8.8 Hz, 2H), 3.21-3.19 (m, 1H), 2.50-2.49 (m, 2H), 2.22-2.13 (m, 4H), 1.53 (d, J=6.0 Hz, 3H).

(273) LCMS: (Method A) 366.3 (M+H), Rt. 3.36 min, 97.15% (Max). HPLC: (Method A) Rt. 3.31 min, 95.61% (Max).

Example 30: 1-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)-4-(4-fluoro-1H-pyrazol-1-yl)piperidine

(274) ##STR00366##

(275) The title compound was synthesized according to the procedure described for Example 29, starting from Intermediate 31 and 4-fluoro-1H-pyrazole. The crude product was purified by MD auto prep (Method B) to get the title compound (brown thick oil). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.92 (d, J=4.4 Hz, 1H), 7.42 (d, J=4.0 Hz, 1H), 7.14 (d, J=7.2 Hz, 1H), 6.76-6.71 (m, 2H), 4.50 (t, J=8.4 Hz, 2H), 3.95 (s, 1H), 3.42-3.40 (m, 1H), 3.16-3.11 (m, 2H), 3.04-3.02 (m, 1H), 2.84-2.81 (m, 1H), 2.04 (t, J=9.60 Hz, 1H), 1.94-1.83 (m, 4H), 1.80-1.77 (m, 1H), 1.27 (d, J=6.40 Hz, 3H). LCMS: (Method A) 316.2 (M+H), Rt. 2.79 min, 98.82% (Max). HPLC: (Method A), Rt. 2.77 min, 98.59% (Max).

Example 31: 6-(1-(4-(4-(Trifluoromethyl)-1H-pyrazol-1-yl)piperazin-1-yl)ethyl)quinoxaline

(276) ##STR00367##

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

(277) To a stirred suspension of 4-(trifluoromethyl)-1H-pyrazole (0.4 g, 2.93 mmol) in dry DMF (8 mL), Cs.sub.2CO.sub.3 (1.91 g, 5.87 mmol) and tert-butyl 4-((methylsulfonyl)-oxy) piperidine-1-carboxylate (obtained as described in Step 1 of Intermediate 10, 1.23 g, 5.87 mmol) were added at 0° C. The reaction mixture was stirred at 80° C. overnight, and the reaction mixture was diluted with water (10 mL). The product was extracted with EtOAc (2×10 mL). The combined organic layer was dried over anhydrous Na.sub.2SO.sub.4 and concentrated under vacuum. The crude product was purified by flash chromatography on silica gel (230-400 mesh) to afford the title compound. Yield: 73% (0.69 g, pale brown solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.71 (s, 1H), 7.90 (s, 1H), 4.44 (q, J=7.6 Hz, 1H), 4.04-4.06 (m, 2H), 3.10-2.69 (m, 2H), 2.02-2.08 (d, 2H), 1.84-1.75 (m, 2H), 1.42 (s, 9H). LCMS: (Method A) 264.2 (M-56), Rt. 4.82 min, 91.18% (Max).

Step 2: 4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)piperidine hydrochloride

(278) To a stirred solution of tert-butyl 4-(4-(trifluoromethyl)-1H-pyrazol-1-yl) piperidine-1-carboxylate (0.68 g, 2.12 mmol) in dry dioxane (2 mL), HCl in dioxane (5 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 in diethyl ether (15 mL) and filtered, affording the title compound. Yield: 94% (0.51 g, off white solid). LCMS: (Method A) 220.2 (M+H), Rt. 2.29 min, 87.95% (Max).

Step 3: 6-(1-(4-(4-(Trifluoromethyl)-1H-pyrazol-1-yl)piperazin-1-yl)ethyl)quinoxaline

(279) To a stirred solution of 4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)piperidine hydrochloride (0.3 g, 1.17 mmol) in DMF (6 mL), TEA (0.5 mL, 3.52 mmol) and Intermediate 1 (0.27 g, 1.41 mmol) were added at 0° C. The reaction mixture was stirred at 80° C. for 16 h. The completion of the reaction was monitored by TLC. The reaction mixture was evaporated under reduced pressure and diluted with EtOAc (10 mL). The organic layer was washed with water (5 mL), brine solution (5 mL) and dried over Na.sub.2SO.sub.4. After evaporation of the solvents, the crude product was purified by flash chromatography on silica gel (230-400 mesh) using 55-60% EtOAc in pet ether as eluent, affording the title compound (off white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.01-8.82 (m, 2H), 8.44 (s, 1H), 8.09 (d, J=8.8 Hz, 1H), 8.01 (s, 1H), 7.92 (d, J=8.8 Hz, 1H), 7.88 (s, 1H), 4.31-4.07 (m, 1H), 3.86 (d, J=6.4 Hz, 1H), 3.10-3.12 (m, 1H), 2.92-2.94 (m, 1H), 2.16-2.18 (m, 2H), 2.03-1.99 (m, 4H), 1.45 (d, J=6.40 Hz, 3H). LCMS: (Method A) 376.3 (M+H), Rt. 2.79 min, 98.0% (Max). HPLC: (Method A) Rt 2.86 min, 97.1% (Max).

Example 32: Ethyl 1-(1-(1-(2, 3-dihydrobenzofuran-6-yl) ethyl) piperidin-4-yl)-1H-pyrazole-4-carboxylate

(280) ##STR00368##

(281) To a stirred solution of Intermediate 10 (2 g, 7.70 mmol) in dry DMF (20 mL), TEA (3.2 mL, 23.10 mmol) and Intermediate 4 (1.54 g, 8.47 mmol) were added. The reaction mixture was stirred at 60° C. overnight. After cooling down the mixture at rt, the solvent was evaporated. Resulting crude mixture was diluted with EtOAc (50 mL) and washed with water (20 mL). The 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 (off white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.33 (s, 1H), 7.85 (s, 1H), 7.15 (d, J=7.2 Hz, 1H), 6.76 (d, J=7.6 Hz, 1H), 6.72 (s, 1H), 4.51 (t, J=8.8 Hz, 2H), 4.20 (q, J=7.2 Hz, 2H), 4.14-4.10 (m, 1H), 3.46 (q, J=6.8 Hz, 1H), 3.14 (t, J=8.4 Hz, 2H), 3.03-3.06 (m, 1H), 2.85-2.87 (m, 1H), 2.08-2.02 (m, 1H), 1.98-1.77 (m, 5H), 1.36-1.24 (m, 6H). LCMS: (Method A) 370.2 (M+H), Rt. 2.95 min, 97.6% (Max). HPLC: (Method A), Rt. 3.05 min, 97.08% (Max).

Example 33: (1-(1-(1-(2,3-dihydrobenzofuran-5-yl)ethyl)piperidine-4-yl)-1H-pyrazol-4-yl) methanamine

(282) ##STR00369##

(283) The title compound was synthesized according to the procedure described for Example 126, starting from Example 28 (colorless solid). .sup.1H NMR (400 MHz, DMSO-d6): δ 7.57 (s, 1H), 7.30 (s, 1H), 7.14 (d, J=7.2 Hz, 1H), 6.75 (dd, J=7.6, 1.2 Hz, 1H), 6.71 (s, 1H), 4.50 (t, J=8.8 Hz, 2H), 3.96 (br s, 1H), 3.53 (s, 2H), 3.13 (t, J=8.8 Hz, 2H), 3.03-3.00 (m, 1H), 2.82-2.81 (m, 1H), 2.04-2.03 (m, 1H), 1.96-1.77 (m, 6H), 1.26 (d, J=6.80 Hz, 3H). LCMS: (Method A) 327.0 (M+H), Rt. 4.26 min, 96.2% (Max).

Example 34: 1-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)-4-(4-(methylsulfonyl)-1H-pyrazol-1-yl)piperidine

(284) ##STR00370##

(285) The title compound was synthesized according to the procedure described for Example 12, starting from Intermediate 4 and Intermediate 21 (pale yellow thick oil). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.43 (s, 1H), 7.90 (s, 1H), 7.14 (d, J=7.6 Hz, 1H), 6.76-6.71 (m, 2H), 4.50-4.48 (m, 2H), 4.16 (t, J=10.8 Hz, 1H), 3.46-3.43 (m, 1H), 3.17-3.11 (m, 5H), 3.02 (d, J=10.8 Hz, 1H), 2.85 (d, J=11.2 Hz, 1H), 2.08-1.83 (m, 6H), 1.27 (d, J=6.80 Hz, 3H). LCMS: (Method A) 376.2 (M+H), Rt. 2.40 min, 97.18% (Max). HPLC: (Method A) Rt. 2.40 min, 97.83% (Max).

Example 35: 1-(6-(4-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)pyridazin-3-yl)ethan-1-ol

(286) ##STR00371##

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

(287) To a stirred solution of Intermediate 13 (700 mg, 2.3 mmol) in DMF (10 mL), TEA (929 mg, 9.2 mmol) and 3-chloro-6-iodopyridazine (826 mg, 3.4 mmol) were added at rt and the resulting mixture was heated at 60° C. overnight. Completion of the reaction was monitored by TLC. Reaction mixture was evaporated. The resulting crude product was triturated with DCM (15 mL) and filtered. The solid was dried under reduced pressure, affording the title compound (off white solid). LCMS: (Method A) 437.3 (M+H), Rt. 2.71 min, 79.38% (Max).

Step 2: 1-(6-(4-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)pyridazin-3-yl)ethan-1-one

(288) The title compound was prepared according to the procedure described for Example 36, step 1, starting from 3-(4-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)-6-iodopyridazine. The crude product was purified by flash chromatography (eluent: 50% EtOAc in pet ether), affording the title compound that was directly used in the next step. (pale brown oil). LCMS: (Method A) 353.2 (M+H), Rt. 2.51 min, 23.74% (Max).

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

(289) The title compound was prepared according to the procedure described for Example 36, step 2, starting from 1-(6-(4-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)pyridazin-3-yl)ethan-1-one. The crude was purified by flash chromatography (elutant: 6% MeOH in DCM), affording the title product (beige solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.42 (d, J=9.6 Hz, 1H), 7.22 (d, J=9.6 Hz, 1H), 7.14 (d, J=7.6 Hz, 1H), 6.77-6.71 (m, 2H), 5.32 (d, J=4.8 Hz, 1H), 4.81-4.78 (m, 1H), 4.49 (t, J=8.8 Hz, 2H), 3.51-3.35 (m, 5H), 3.12 (t, J=8.4 Hz, 2H), 2.66-2.32 (m, 4H), 1.34-1.23 (m, 6H). LCMS: (Method A) 355.2 (M+H), Rt. 1.93 min, 96.62% (Max). HPLC: (Method A) Rt 1.93 min, 97.83% (Max).

Example 36: 1-(6-(4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)pyridazin-3-yl)ethan-1-ol

(290) ##STR00372##

Step 1: 1-(6-(4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)pyridazin-3-yl)ethan-1-one

(291) A stirred solution of Example 43 (500 mg, 1.12 mmol) in dry toluene was degassed for 15 min with nitrogen. 1-ethoxy vinyl tributyltin (450 mg, 1.23 mmol) and bis(triphenylphosphine)palladium(II) dichloride (80 mg, 0.12 mmol) were added at rt. The reaction mixture was stirred for overnight at 90° C. It was cooled to rt and filtered through celite. The filtrate was concentrated under vacuum and HCl solution (50 mL, 6N) was added. The mixture was stirred 1 h at rt and was neutralized with a saturated solution of NaHCO.sub.3. It was extracted with DCM (100 mL), the organic layer was dried over anhydrous Na.sub.2SO.sub.4 and concentrated. The crude product was purified by flash chromatography to afford the title compound (pale brown solid). LCMS: (Method A) 173.0 (M+H), Rt. 2.20 min, 95.3% (Max).

Step 2: 1-(6-(4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)pyridazin-3-yl)ethan-1-ol

(292) To a stirred solution of 1-(6-(4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)pyridazin-3-yl)ethan-1-one (100 mg, 0.21 mmol) in dry MeOH (2 mL), sodium borohydride (15 mg, 0.41 mmol, spectrochem) was added portion wise at 0° C. and the resulting mixture was stirred for 1 h. It was concentrated under vacuum. The resulting residue was dissolved in DCM (20 mL), washed with brine (5 mL), dried over Na.sub.2SO.sub.4 and concentrated. The crude product was purified by MD Autoprep HPLC (Method D) to afford the titled compound (brown thick oil). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.94 (dd, J=7.2, 1.6 Hz, 2H), 8.10 (d, J=8.4 Hz, 1H), 8.02 (s, 1H), 7.93 (d, J=8.8 Hz, 1H), 7.44 (d, J=9.6 Hz, 1H), 7.25 (d, J=9.2 Hz, 1H), 5.34 (d, J=4.8 Hz, 1H), 4.80 (t, J=4.8 Hz, 1H), 3.78 (d, J=6.4 Hz, 1H), 3.55-3.51 (m, 4H), 2.64-2.61 (m, 2H), 2.51-2.33 (m, 2H), 1.45 (d, J=6.80 Hz, 3H), 1.35 (d, J=6.8 Hz, 3H). LCMS: (Method A) 365.2 (M+H), Rt. 1.43 min, 99.32% (Max). HPLC: (Method A) Rt. 1.46 min, 98.77% (Max).

Example 37: (5-(4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-1,3,4-thiadiazol-2-yl)methanol

(293) ##STR00373##

(294) The title compound was synthesized according to the procedure described for Example 113, starting from Example 120 (brown solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.93 (d, J=6.4 Hz, 2H), 8.08 (d, J=8.8 Hz, 1H), 8.00 (s, 1H), 7.90 (d, J=8.8 Hz, 1H), 4.56 (d, J=38.4 Hz, 2H), 3.89-3.75 (m, 1H), 3.50-3.38 (m, 4H), 2.70-2.65 (m, 2H), 2.49-2.42 (m, 2H), 1.43 (d, J=6.4 Hz, 3H). LCMS: (Method A) 357.2 (M+H), Rt. 1.50 min, 99.4% (Max). HPLC: (Method A) Rt 1.52 min, 99.30% (Max).

Example 38: (S)-6-(4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)pyridazin-3(2H)-one or (R)-6-(4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)pyridazin-3(2H)-one

(295) ##STR00374##

(296) The racemic mixture of Example 39 was separated by chiral preparative HPLC, using the chiral preparative HPLC (Method Q).

(297) The first eluting compound correspond to Example 38. Yield: 28% (14.32 mg, off white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 12.06 (s, 1H), 8.93 (d, J=6.8 Hz, 2H), 8.08 (d, J=8.8 Hz, 1H), 7.99 (s, 1H), 7.89 (d, J=8.8 Hz, 1H), 7.45 (d, J=10.4 Hz, 1H), 6.74 (d, J=10.0 Hz, 1H), 3.79-3.71 (m, 1H), 3.18-3.16 (m, 4H), 2.61-2.59 (m, 4H), 1.43 (d, J=6.40 Hz, 3H). LCMS: (Method A) 337.2 (M+H), Rt. 1.463 min, 99.315% (Max). HPLC: (Method A) Rt. 1.549 min, 98.517% (Max). CHIRAL HPLC: (Method P) Rt. 11.173 min, 99.708% (Max).

(298) Second eluting compound: Yield: 28% (14.17 mg, off white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 12.06 (s, 1H), 8.93 (d, J=5.6 Hz, 2H), 8.08 (d, J=8.4 Hz, 1H), 7.99 (s, 1H), 7.90 (d, J=7.6 Hz, 1H), 7.45 (d, J=10.4 Hz, 1H), 6.74 (d, J=11.2 Hz, 1H), 3.76-3.74 (m, 1H), 3.19-3.16 (m, 4H), 2.60-2.57 (m, 4H), 1.43 (d, J=7.20 Hz, 3H). LCMS: (Method A) 337.2 (M+H), Rt. 1.462 min, 99.692% (Max). HPLC: (Method A) Rt. 1.554 min, 99.192% (Max). CHIRAL HPLC: (Method P) Rt. 17.953 min, 99.333% (Max).

Example 39: 2-amino-1-(4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)ethan-1-one

(299) ##STR00375##

Step 1: 6-(1-(4-(6-chloropyridazin-3-yl)piperazin-1-yl)ethyl)quinoxaline

(300) To a stirred solution of Intermediate 2 (0.4 g, 1.43 mmol, IS00537-008) in THF (8 mL, 20 V), TEA (0.598 mL, 4.3 mmol) and 3,6-dichloropyridazine (0.427 g, 2.86 mmol) were added at rt and the mixture was stirred at 70° C. for 12 h. It was evaporated under vacuum. Water (5 mL) was added to the resulting crude mixture and was extracted with EtOAc (2×15 mL). The combined EtOAc layer was washed with brine and dried over Na.sub.2SO.sub.4 concentrated under vacuum. The crude product was purified by flash chromatography to afford title compound (yellow thick oil). .sup.1H NMR (400 MHz, DMSO-d6): δ 300 MHz, DMSO-d6: δ 8.94 (d, J=3.6 Hz, 2H), 8.11-8.08 (m, 3H), 7.52 (dd, J=2.7, 9.6 Hz, 1H), 7.35 (d, J=9.6 Hz, 1H), 3.80-3.78 (m, 1H), 3.58-3.44 (m, 4H), 2.73-2.59 (m, 4H), 1.45 (d, J=6.6 Hz, 3H). LCMS: (Method A) 355.2 (M+H), Rt. 1.989 min, 93.235% (Max).

Step 2: 2-amino-1-(4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)ethan-1-one

(301) To a stirred solution of 6-(1-(4-(6-chloropyridazin-3-yl)piperazin-1-yl)ethyl)quinoxaline in AcOH (2.3 mL), NaOAc (0.106 g, 1.29 mmol) was added and the mixture was stirred at 200° C. in microwave reactor for 10 min. Reaction mixture was concentrated under vacuum. 10% MeOH in THF (3 mL) and KOH (0.072 g, 1.29 mmol) were added and the mixture was refluxed for 1 h. After evaporation of the solvents, the crude product was purified by flash chromatography to afford the title product (brown thick oil). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 12.06 (s, 1H), 8.94 (q, J=1.6 Hz, 2H), 8.09 (d, J=8.8 Hz, 1H), 8.00 (d, J=1.6 Hz, 1H), 7.91 (q, J=2.0 Hz, 1H), 7.46 (d, J=10.0 Hz, 1H), 6.76 (d, J=10.0 Hz, 1H), 3.77-3.76 (m, 1H), 3.19 (t, J=5.2 Hz, 4H), 2.56-2.55 (m, 4H), 1.44 (d, J=6.40 Hz, 3H). LCMS: (Method A) 337.0 (M+H), Rt. 1.540 min, 96.804% (Max). HPLC: (Method A) Rt 1.509 min, 99.272% (Max).

Example 40: 3-(4-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)-6-(trifluoromethyl)pyridazine

(302) SGN020581-01-00501-018N01:

(303) ##STR00376##

(304) To a stirred solution of Intermediate 13 (250 mg, 0.81 mmol), in DMF (3 mL), TEA (330 mg, 3.26 mmol) and 3-chloro-6-(trifluoromethyl)pyridazine (224 mg, 1.2 mmol) were added at rt. The resulting mixture was heated at 85° C. overnight. Completion of the reaction was monitored by TLC. Reaction mixture was evaporated. Water (10 mL) was added and extracted with EtOAc (2×30 mL). The combined organic layer was washed with water (10 mL), brine (10 mL), dried over Na.sub.2SO.sub.4 and evaporated. The crude product was purified by flash chromatography (elutant: 2-3% MeOH in DCM) to afford the title product (off white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.77 (d, J=9.6 Hz, 1H), 7.35 (d, J=9.6 Hz, 1H), 7.15 (d, J=7.6 Hz, 1H), 6.77-6.73 (m, 2H), 4.50 (t, J=8.4 Hz, 2H), 3.68 (t, J=5.2 Hz, 4H), 3.39-3.32 (m, 1H), 3.13 (t, J=8.4 Hz, 2H), 2.44-2.39 (m, 4H), 1.29 (d, J=6.8 Hz, 3H). LCMS: (Method A) 379.2 (M+H), Rt. 3.06 min, 95.18% (Max). HPLC: (Method A) Rt. 3.12 min, 98.21% (Max).

Example 41: 6-(1-(4-(6-Fluoropyridazin-3-yl)piperazin-1-yl)ethyl)quinoxaline

(305) ##STR00377##

(306) To a stirred solution of Intermediate 2 (0.2 g, 0.8 mmol) in dry DMF (5 mL), TEA (0.36 ml, 2.85 mmol) and 3,6-difluropyridazine (0.19 g, 1.90 mmol) were added at rt and the reaction mixture was stirred at 90° C. overnight. The resulting reaction mixture was cooled to rt and DMF was evaporated under reduced pressure. To the resulting crude product, water (20 mL) was added and product was extracted with EtOAc (2×30 mL). The organic layer was dried over Na.sub.2SO.sub.4 and concentrated. The crude product was purified by flash chromatography to afford the title compound (pale brown thick oil). .sup.1H NMR (400 MHz, CDCl.sub.3): δ 8.12 (d, J=8.8 Hz, 1H), 8.05 (d, J=1.6 Hz, 1H), 7.92 (dd, J=8.6, 1.6 Hz, 1H), 7.06 (dd, J=9.6, 6.0 Hz, 1H), 7.00 (dd, J=7.4, 3.2 Hz, 1H), 3.75-3.68 (m, 1H), 3.67-3.56 (m, 4H), 2.76-2.70 (m, 2H), 2.62-2.57 (m, 2H), 1.52 (d, J=6.8 Hz, 3H). LCMS: (Method A) 339.2 (M+H), Rt. 1.77 min, 98.68% (Max). HPLC: (Method A) Rt 1.80 min, 97.59% (Max).

Example 42: 6-(1-(4-(6-(trifluoromethyl)pyridazin-3-yl)piperazin-1-yl)ethyl)quinoxaline

(307) ##STR00378##

(308) To a stirred solution of Intermediate 2 (0.2 g, 0.8 mmol) in dry DMF (5 mL), TEA (0.36 ml, 2.85 mmol) and 2-chloro-5(trifluoromethyl) pyridazine (0.19 g, 1.90 mmol) were added at rt and the reaction mixture was stirred at 90° C. overnight. The resulting reaction mixture was cooled to rt and DMF was evaporated under reduced pressure. To the resulting crude product, water (20 mL) was added and the product was extracted with EtOAc (2×30 mL). The organic layer was dried over Na.sub.2SO.sub.4 and concentrated. This product was purified by flash chromatography to afford the title compound (off white solid). .sup.1H NMR (400 MHz, CDCl.sub.3): δ 8.87 (s, 2H), 8.14 (d, J=8.8 Hz, 1H), 8.06 (s, 1H), 7.94 (s, 1H), 7.47 (d, J=9.6 Hz, 1H), 6.90 (d, J=9.6 Hz, 1H), 3.80-3.82 (m, 5H), 2.68-2.70 (m, 1H), 1.54-1.52 (br s, 6.8 Hz, 3H). LCMS: (Method A) 389.2 (M+H), Rt. 2.50 min, 99.68% (Max). HPLC: (Method A) Rt. 2.53 min, 98.79% (Max).

Example 43: 6-(1-(4-(6-(trifluoromethyl)pyridazin-3-yl)piperazin-1-yl)ethyl)quinoxaline

(309) ##STR00379##

(310) To a stirred solution of Intermediate 2 (0.25 g, 0.8 mmol) in dry DMF (5 mL), TEA (0.36 ml, 2.85 mmol) and 3-chloro-6-iodopyridazine (0.123 g, 0.99 mmol) were added at rt and the reaction mixture was stirred at 90° C. overnight. The resulting reaction mixture was cooled to rt and DMF was evaporated under reduced pressure. To the resulting crude mixture, water (20 mL) was added and the product was extracted with EtOAc (2×30 mL). The resulting organic layer was dried over Na.sub.2SO.sub.4 and concentrated. This crude product was purified by flash column chromatography to afford the title compound (off white solid). .sup.1H NMR (400 MHz, CDCl.sub.3): δ 8.86-8.84 (m, 2H), 8.11 (d, J=8.8 Hz, 1H), 8.03 (d, J=2.0 Hz, 1H), 7.90 (dd, J=8.8, 2.0 Hz, 1H), 7.45 (d, J=9.6 Hz, 1H), 6.60 (d, J=9.6 Hz, 1H), 3.65-3.58 (m, 5H), 2.73-2.67 (m, 2H), 2.59-2.54 (m, 2H), 1.51 (d, J=6.8 Hz, 3H). LCMS: (Method A) 447.0 (M+H), Rt. 2.13 min, 99.59% (Max). HPLC: (Method A) Rt. 2.16 min, 98.99% (Max).

Example 44: 6-(1-(4-(6-Methylpyridazin-3-yl)piperazin-1-yl)ethyl)quinoxaline

(311) ##STR00380##

(312) The stirred solution of Example 43 (100 mg, 0.22 mmol) in dry toluene was degassed for 15 min with nitrogen. Tetramethyl tin (79.0 mg, 0.44 mmol) and bis(triphenylphosphine)palladium dichloride (14 mg, 0.02 mmol) were added at rt and the resulting mixture was stirred overnight at 90° C. The reaction mixture was cooled to rt and filtered through celite. This filtrate was concentrated and an aqueous solution of HCl (6 N, 50 mL) was added. The resulting mixture was stirred for 1 h at rt and was neutralized with a saturated solution of NaHCO.sub.3. It was extracted with DCM (100 mL). The organic layer was dried over anhydrous Na.sub.2SO.sub.4 and concentrated. The crude was purified by flash chromatography to afford the title compound (brown thick oil). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.94 (d, J=5.2 Hz, 2H), 8.10 (d, J=8.8 Hz, 1H), 8.02 (s, 1H), 7.92 (t, J=6.8 Hz, 1H), 7.26 (d, J=9.2 Hz, 1H), 7.17 (d, J=9.6 Hz, 1H), 3.88 (d, J=15.8 Hz, 1H), 3.50 (br s, 4H), 2.60 (br s, 4H), 2.41 (s, 3H), 1.45 (d, J=5.60 Hz, 3H). LCMS: (Method A) 335.2 (M+H), Rt. 1.43 min, 96.15% (Max). HPLC: (Method A) Rt. 1.42 min, 96.07% (Max).

Example 45: 3-(4-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)-6-(methylsulfonyl)pyridazine

(313) ##STR00381##

(314) To a stirred solution of Intermediate 13 (150 mg, 0.49 mmol), TEA (198 mg, 1.96 mmol) in MeCN (5 mL), 3-chloro-6-(methylsulfonyl)pyridazine (142 mg, 0.73 mmol) was added at rt and the resulting mixture was stirred overnight at rt. Completion of the reaction was monitored by TLC. Reaction mass was evaporated. Water (10 mL) was added and was extracted with EtOAc (2×30 mL). The combined organic layer was washed with water (10 mL), brine solution (10 mL), dried over Na.sub.2SO.sub.4 and evaporated. The crude product was purified by flash chromatography (elutant: 75% EtOAc in pet ether) and further purified by MD Autoprep HPLC (Method C) to afford the title product (off white solid). .sup.1H NMR (400 MHz, DMSO-d6): δ 7.81 (d, J=9.6 Hz, 1H), 7.36 (d, J=9.6 Hz, 1H), 7.15 (d, J=7.2 Hz, 1H), 6.76 (d, J=7.6 Hz, 1H), 6.72 (s, 1H), 4.50 (t, J=8.4 Hz, 2H), 3.72-3.70 (m, 4H), 3.39-3.38 (m, 1H), 3.28 (s, 3H), 3.13 (t, J=9.2 Hz, 2H), 2.44-2.32 (m, 4H), 1.29 (d, J=6.80 Hz, 3H). LCMS: (Method A) 389.2 (M+H), Rt. 2.35 min, 97.79% (Max). HPLC: (Method A) Rt. 2.37 min, 97.46% (Max).

Example 46: N-(6-(4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)pyridin-3-yl)acetamide

(315) ##STR00382##

(316) The title compound was synthesized according to the procedure described for Example 40, starting from Intermediate 2 and N-(6-bromopyridin-2-yl)acetamide (off white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.89 (s, 1H), 8.94 (d, J=2.0 Hz, 1H), 8.93 (d, J=1.6 Hz, 1H), 8.09 (d, J=8.8 Hz, 1H), 8.01 (s, 1H), 7.93 (d, J=8.8 Hz, 1H), 7.47 (d, J=8.0 Hz, 1H), 7.32 (s, 1H), 6.44 (d, J=8.0 Hz, 1H), 3.77-3.72 (m, 1H), 3.51-3.45 (m, 4H), 2.58-2.53 (m, 2H), 2.49-2.44 (m, 2H), 2.04 (s, 3H), 1.44 (d, J=6.80 Hz, 3H). LCMS: (Method A) 377.2 (M+H), Rt. 1.998 min, 95.756% (Max).

(317) HPLC: (Method A) Rt. 2.057 min, 95.464% (Max).

Example 47: 1-(6-(4-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)pyridin-3-yl)ethan-1-ol

(318) ##STR00383##

Step 1: 1-(5-bromopyridin-2-yl)-4-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazine

(319) To a stirred solution of 2-chloro-5-bromopyridine (5.4 g, 19.7 mmol) in dry DMF (25 mL), TEA (11.6 mL, 77.5 mmol) and Intermediate 13 (3 g, 16.4 mmol) were added at rt and the mixture was stirred at 80° C. overnight. The reaction mixture was evaporated under vacuum and the resulting crude mixture was dissolved in EtOAc (100 mL), washed with water (20 mL), dried over anhydrous Na.sub.2SO.sub.4 and concentrated. 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 8.13 (d, J=2.4 Hz, 1H), 7.64 (dd, J=9.2, 2.4 Hz, 1H), 7.15-7.11 (m, 1H), 6.78-6.71 (m, 3H), 4.52-4.48 (m, 3H), 3.43-3.41 (m, 4H), 3.17-3.11 (m, 2H), 2.46-2.43 (m, 2H), 2.38-2.32 (m, 2H), 1.28-1.25 (m, 3H). LCMS: (Method A) 388.0 (M+H), Rt. 2.34 min, 90.08% (Max).

Step 2: 1-(6-(4-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)pyridin-3-yl)ethan-1-one

(320) The title compound was synthesized according to the procedure described for Example 36, step 1, starting with 1-(5-bromopyridin-2-yl)-4-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazine (0.8 g, 2.00 mmol). The resulting crude product was purified by flash chromatography, affording the title compound. Yield: 53% (0.5 g, yellow solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.69 (s, 1H), 7.94 (d, J=9.2 Hz, 1H), 7.15 (d, J=7.6 Hz, 1H), 6.83 (d, J=8.8 Hz, 1H), 6.76 (d, J=7.2 Hz, 1H), 6.72 (s, 1H), 4.53-4.48 (m, 3H), 3.65-3.64 (m, 4H), 3.16-3.11 (m, 2H), 2.51-2.50 (m, 4H), 2.40 (s, 3H), 1.31 (d, J=9.20 Hz, 3H). LCMS: (Method A) 352.0 (M+H), Rt. 2.00 min, 98.60% (Max).

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

(321) The title compound was synthesized according to the procedure described for Example 36, step 2, starting with 1-(6-(4-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)pyridin-3-yl)ethan-1-one (0.1 g, 0.27 mmol) in dry MeOH (5 mL). The crude was purified by MD Autoprep HPLC (Method C) to get the title compound (off white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.02 (s, 1H), 7.48 (d, J=8.0 Hz, 1H), 7.14 (d, J=8.0 Hz, 1H), 6.76-6.71 (m, 3H), 4.99 (d, J=3.6 Hz, 1H), 4.52-4.47 (m, 3H), 3.40-3.38 (m, 5H), 3.15-3.11 (m, 2H), 2.37-2.36 (m, 4H), 1.27 (dd, J=6.2, 2.8 Hz, 6H). LCMS: (Method B) 354.0 (M+H), Rt. 5.06 min, 97.55% (Max). HPLC: (Method A) Rt. 1.98 min, 98.32% (Max).

Example 48: 2-(6-(4-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)pyridin-3-yl)propan-2-ol

(322) ##STR00384##

(323) The title compound was synthesized according to the procedure described for Example 85, starting from Example 62 (0.3 g, 0.39 mmol). The crude product was purified by flash chromatography to get the title compound (off white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.17 (s, 1H), 7.58 (d, J=8.8 Hz, 1H), 7.15 (d, J=6.8 Hz, 1H), 6.78-6.70 (m, 3H), 4.92 (s, 1H), 4.51 (t, J=8.0 Hz, 2H), 3.39-3.34 (m, 5H), 3.14 (t, J=8.4 Hz, 2H), 2.39-2.38 (m, 4H), 1.39 (s, 6H), 1.28 (d, J=5.60 Hz, 3H). LCMS: (Method B) 368.0 (M+H), Rt. 5.28 min, 98.92% (Max). HPLC: (Method A) Rt. 2.07 min, 98.89% (Max).

Example 49: 1-(6-(4-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)pyridin-3-yl)-2-methylpropan-1-ol

(324) ##STR00385##

(325) The title compound was synthesized according to the procedure described for Example 12, starting from Intermediate 4 and Intermediate 18 (pale brown solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.96 (s, 1H), 7.43 (dd, J=8.80, 2.00 Hz, 1H), 7.15 (d, J=7.60 Hz, 1H), 6.78-6.72 (m, 3H), 4.96 (d, J=4.00 Hz, 1H), 4.51 (t, J=8.80 Hz, 2H), 4.10 (t, J=4.40 Hz, 1H), 3.49-3.36 (m, 4H), 3.14 (t, J=8.80 Hz, 2H), 2.47-2.46 (m, 2H), 2.39-2.34 (m, 2H), 1.79-1.74 (m, 1H), 1.28 (d, J=6.80 Hz, 3H), 0.87 (d, J=6.80 Hz, 3H), 0.70 (d, J=6.80 Hz, 3H). LCMS: (Method A) 382.3 (M+H), Rt. 2.33 min, 98.4% (Max). HPLC: (Method A) Rt 2.38 min, 99.4% (Max).

Example 50: 1-(6-(4-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)pyridin-3-yl)-2,2,2-trifluoroethan-1-ol

(326) ##STR00386##

(327) The title compound was synthesized according to the procedure described for Example 87, starting from Example 62 (pale brown solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.13 (s, 1H), 7.57 (d, J=8.80 Hz, 1H), 7.14 (d, J=7.60 Hz, 1H), 6.81-6.74 (m, 2H), 6.71-6.67 (m, 2H), 5.02 (s, 1H), 4.49 (t, J=8.80 Hz, 2H), 3.52-3.40 (m, 5H), 3.13 (t, J=8.40 Hz, 2H), 2.46-2.33 (m, 4H), 1.27 (d, J=6.40 Hz, 3H). LCMS: (Method A) 408.0 (M+H), Rt. 2.73 min, 94.3% (Max). HPLC: (Method A) Rt 2.67 min, 97.8% (Max).

Example 51: 2-(6-(4-(1-(quinoxalin-6-yl) ethyl) piperazin-1-yl) pyridin-3-yl) propan-2-ol

(328) ##STR00387##

(329) The title compound was synthesized according to the procedure described for Example 85, starting from Example 66 (off white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.93 (d, J=5.2 Hz, 2H), 8.16 (s, 1H), 8.08 (d, J=8.8 Hz, 1H), 8.00 (s, 1H), 7.92 (d, J=8.4 Hz, 1H), 7.57 (t, J=6.8 Hz, 1H), 6.71 (d, J=9.2 Hz, 1H), 4.89 (d, J=6.0 Hz, 1H), 3.74 (d, J=6.8 Hz, 1H), 3.42 (br s, 4H), 2.50 (br s, 4H), 1.43 (d, J=6.4 Hz, 3H), 1.37 (s, 6H). LCMS: (Method A) 378.3 (M+H), Rt. 1.651 min, 98.83% (Max). HPLC: (Method A), Rt. 1.644 min, 98.54% (Max).

Example 52: 1-(6-(4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)pyridin-3-yl)ethan-1-ol

(330) ##STR00388##

(331) The title compound was synthesized according to the procedure described for Example 84, starting from Intermediate 1 and Intermediate 16 (brown solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.94-8.93 (m, 2H), 8.08 (d, J=8.8 Hz, 1H), 8.01 (d, J=9.6 Hz, 2H), 7.91 (d, J=8.8 Hz, 1H), 7.48 (d, J=8.4 Hz, 1H), 6.74 (d, J=8.8 Hz, 1H), 4.99 (d, J=4.0 Hz, 1H), 4.62-4.59 (m, 1H), 3.75-3.73 (m, 1H), 3.43-3.39 (m, 4H), 2.60-2.57 (m, 2H), 2.45-2.44 (m, 2H), 1.43 (d, J=6.40 Hz, 3H), 1.28 (d, J=6.40 Hz, 3H). LCMS: (Method B) 364.0 (M+H), Rt. 4.16 min, 98.12% (Max). HPLC: (Method A) Rt. 1.54 min, 99.11% (Max).

Example 53: 6-(1-(4-(6-methoxypyridin-3-yl)piperazin-1-yl)ethyl)quinoxaline

(332) ##STR00389##

(333) The title compound was synthesized according to the procedure described for Example 12, starting from Intermediate 1 and 1-(5-methoxy-2-pyridinyl)piperazine (brown solid). 1H NMR (400 MHz, DMSO-d.sub.6): δ 8.93 (q, J=1.6 Hz, 2H), 8.08 (d, J=8.8 Hz, 1H), 8.00 (s, 1H), 7.91 (q, J=1.6 Hz, 1H), 7.74 (d, J=3.2 Hz, 1H), 7.40 (q, J=2.8 Hz, 1H), 6.68 (d, J=8.8 Hz, 1H), 3.75 (s, 4H), 3.08-3.03 (m, 4H), 2.66-2.61 (m, 4H), 1.44 (d, J=6.40 Hz, 3H). LCMS: (Method A) 350.0 (M+H), Rt. 1.908 min, 97.686% (Max). HPLC: (Method A) Rt. 1.856 min, 98.999% (Max).

Example 54: 5-(4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)pyridin-2(1H)-one

(334) ##STR00390##

(335) To a stirred solution of Example 53 (0.04 g, 0.114 mmol) in DCM (0.4 mL) cooled to 0° C. was added BBr.sub.3 in DCM (1M) (0.24 mL, 0.228 mmol) and the mixture was stirred at rt for 18 h. Reaction mixture was cooled to 0° C. and quenched with a saturated solution of NaHCO.sub.3 (1 mL) and extracted with DCM (2×10 mL), washed with brine (2 mL) and dried over Na.sub.2SO.sub.4. The resulting crude product was purified by flash chromatography (eluent: 10% MeOH in DCM), to afford the title product (dark fluffy solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 11.16 (s, 1H), 8.93 (d, J=6.8 Hz, 2H), 8.08 (d, J=8.4 Hz, 1H), 7.99 (s, 1H), 7.89 (d, J=8.4 Hz, 1H), 7.38 (q, J=3.2 Hz, 1H), 6.70 (s, 1H), 6.27 (d, J=9.6 Hz, 1H), 3.75-3.73 (m, 1H), 2.88-2.81 (m, 4H), 2.62-2.56 (m, 4H), 1.42 (d, J=6.80 Hz, 3H). LCMS: (Method A) 336.2 (M+H), Rt. 1.555 min, 97.205% (Max). HPLC: (Method A) Rt. 1.523 min, 99.129% (Max).

Example 55: 2-methyl-1-(6-(4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)pyridin-3-yl)propan-1-ol

(336) ##STR00391##

(337) The title compound was synthesized according to the procedure described for Example 12, starting from Intermediate 1 and Intermediate 18 (pale brown solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.94 (dd, J=7.20, 2.00 Hz, 2H), 8.09 (d, J=8.40 Hz, 1H), 8.01 (d, J=1.20 Hz, 1H), 7.93 (d, J=2.00 Hz, 1H), 7.91 (d, J=1.60 Hz, 1H), 7.43 (dd, J=8.80, 2.40 Hz, 1H), 6.75 (d, J=8.80 Hz, 1H), 4.96 (d, J=4.40 Hz, 1H), 4.11-4.09 (m, 1H), 3.76-3.74 (m, 1H), 3.52-3.38 (m, 4H), 2.59-2.57 (m, 2H), 2.48-2.45 (m, 2H), 1.78-1.73 (m, 1H), 1.44 (d, J=6.80 Hz, 3H), 0.86 (d, J=6.80 Hz, 3H), 0.69 (d, J=6.80 Hz, 3H). LCMS: (Method A) 392.3 (M+H), Rt. 1.93 min, 99.2% (Max). HPLC: (Method A) Rt 1.97 min, 99.6% (Max).

Example 56: 2,2,2-trifluoro-1-(6-(4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)pyridin-3-yl)ethan-1-ol

(338) ##STR00392##

(339) The title compound was synthesized according to the procedure described for Example 87, starting from Example 66 (pale brown solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.94-8.93 (m, 2H), 8.14 (s, 1H), 8.09 (d, J=8.40 Hz, 1H), 8.01 (s, 1H), 7.93 (d, J=8.80 Hz, 1H), 7.58 (d, J=8.80 Hz, 1H), 6.82 (d, J=8.80 Hz, 1H), 6.69 (d, J=5.60 Hz, 1H), 5.03 (t, J=6.40 Hz, 1H), 3.77-3.75 (m, 1H), 3.54-3.45 (m, 4H), 2.60-2.59 (m, 4H), 1.44 (d, J=6.80 Hz, 3H). LCMS: (Method A) 418.2 (M+H), Rt. 2.12 min, 99.3% (Max). HPLC: (Method A) Rt 2.16 min, 99.3% (Max).

Example 57: 4-(6-(4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)pyridin-3-yl)tetrahydro-2H-pyran-4-ol

(340) ##STR00393##

(341) To a degassed solution of Intermediate 24 (125 mg, 0.58 mmol), Intermediate 2 (212 mg, 0.76 mmol) and sodium tert butoxide (432 mg, 1.46 mmol) in 1,4 dioxane (4 mL) at rt, Pd.sub.2(dba).sub.3 (27 mg, 0.03 mmol) and BINAP (36 mg, 0.05 mmol) were added. The reaction mixture was sealed and heated to 100° C. overnight. It was then filtered through celite and concentrated. Water (4 mL) was added and was extracted with EtOAc (2×10 mL). The combined organic layer was dried over Na.sub.2SO.sub.4 and concentrated. The crude product was purified by flash chromatography (eluent: 5-6% MeOH in DCM). After trituration in Et.sub.2O and filtration, the title product was isolated (brown solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.93 (d, J=5.2 Hz, 2H), 8.18 (s, 1H), 8.08 (d, J=8.8 Hz, 1H), 8.00 (s, 1H), 7.91 (d, J=8.8 Hz, 1H), 7.62-7.50 (m, 1H), 6.74 (d, J=9.2 Hz, 1H), 4.92 (s, 1H), 3.77-3.71 (m, 3H), 3.70-3.65 (m, 2H), 3.50-3.39 (m, 4H), 2.63-2.52 (m, 4H), 1.91-1.87 (m, 2H), 1.53-1.50 (m, 2H), 1.43 (d, J=6.40 Hz, 3H). LCMS: (Method A) 420.2 (M+H), Rt. 1.62 min, 95.40% (Max). HPLC: (Method A) Rt 1.59 min, 98.75% (Max).

Example 58: 3-(6-(4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)pyridin-3-yl)tetrahydrofuran-3-ol

(342) ##STR00394##

(343) The title compound was synthesized according to the procedure described for Example 57, starting from Intermediate 2 and Intermediate 25 (brown solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.93 (dd, J=6.4, 2.6 Hz, 2H), 8.18 (d, J=2.0 Hz, 1H), 8.08 (d, J=8.4 Hz, 1H), 8.00 (s, 1H), 7.91 (d, J=8.4 Hz, 1H), 7.56 (dd, J=8.8, 5.6 Hz, 1H), 6.75 (d, J=8.8 Hz, 1H), 3.98-3.92 (m, 2H), 3.80-3.71 (m, 2H), 3.64 (d, J=8.8 Hz, 1H), 3.50-3.37 (m, 4H), 2.59-2.55 (m, 2H), 2.47-2.39 (m, 3H), 2.19-2.13 (m, 1H), 2.08-2.04 (m, 1H), 1.4 (d, J=6.8 Hz, 3H). LCMS: (Method A) 406.2 (M+H), Rt. 1.55 min, 99.00% (Max). HPLC: (Method A) Rt 1.53 min, 99.39% (Max).

Example 59: 3-(6-(4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)pyridin-3-yl)oxetan-3-ol

(344) ##STR00395##

(345) The title compound was synthesized according to the procedure described for Example 57, starting from Intermediate 2 and Intermediate 26 (pale brown solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.94-8.82 (m, 2H), 8.26 (d, J=2.4 Hz, 1H), 8.08 (d, J=8.4 Hz, 1H), 8.00 (s, 1H), 7.92 (d, J=8.4 Hz, 1H), 7.68-7.65 (m, 1H), 6.81 (d, J=9.2 Hz, 1H), 6.22 (d, J=2.0 Hz, 1H), 4.70-4.64 (m, 4H), 3.80-3.70 (m, 1H), 3.58-3.40 (m, 4H), 2.64-2.57 (m, 2H), 2.49-2.43 (m, 2H), 1.43 (d, J=6.80 Hz, 3H). LCMS: (Method A) 392.2 (M+H), Rt. 1.51 min, 98.29% (Max). HPLC: (Method A) Rt 1.49 min, 98.37% (Max).

Example 60: 1-(6-(4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)pyridin-3-yl)cyclohexan-1-ol

(346) ##STR00396##

(347) The title compound was synthesized according to the procedure described for Example 57, starting from Intermediate 2 and Intermediate 27 (off white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.93 (dd, J=7.2, 1.6 Hz, 2H), 8.18 (d, J=2.4 Hz, 1H), 8.09 (d, J=8.4 Hz, 1H), 8.01 (s, 1H), 7.93-7.91 (m, 1H), 7.58 (d, J=2.4, 8.8 Hz, 1H), 6.72 (d, J=8.8 Hz, 1H), 4.59 (s, 1H), 3.76-3.74 (m, 1H), 3.48-3.43 (m, 4H), 2.60-2.56 (m, 2H), 2.46-2.43 (m, 2H), 1.69-1.66 (m, 3H), 1.63-1.60 (m, 4H), 1.45-1.43 (m, 5H), 1.30-1.20 (m, 1H). LCMS: (Method A) 418.2 (M+H), Rt. 2.18 min, 98.2% (Max). HPLC: (Method A) Rt 2.16 min, 98.9% (Max).

Example 61: 1-(6-(4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)pyridin-3-yl)cyclopentan-1-ol

(348) ##STR00397##

(349) The title compound was synthesized according to the procedure described for Example 57, starting from Intermediate 2 and Intermediate 30 (yellow solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.94 (dd, J=1.6, 7.0 Hz, 2H), 8.18 (d, J=2.0 Hz, 1H), 8.09 (d, J=8.4 Hz, 1H), 8.01 (s, 1H), 7.92 (dd, J=1.6, 8.4 Hz, 1H), 7.57 (dd, J=2.8, 8.8 Hz, 1H), 6.73 (d, J=8.8 Hz, 1H), 4.68 (s, 1H), 3.76-3.74 (m, 1H), 3.45-3.44 (m, 4H), 2.61-2.58 (m, 2H), 2.45-2.43 (m, 2H), 1.83-1.80 (m, 6H), 1.77-1.68 (m, 2H), 1.44 (d, J=6.40 Hz, 3H). LCMS: (Method A) 404.2 (M+H), Rt. 1.9 min, 98.6% (Max). HPLC: (Method A) Rt 1.8 min, 99.44% (Max).

Example 62: Methyl 6-(4-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)nicotinate

(350) ##STR00398##

(351) The title compound was synthesized according to the procedure described for Example 66, replacing Intermediate 1 with Intermediate 4 (off white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.61 (d, J=2.4 Hz, 1H), 7.91 (dd, J=9.2, 2.4 Hz, 1H), 7.14 (d, J=7.6 Hz, 1H), 6.82 (d, J=9.2 Hz, 1H), 6.76-6.71 (m, 2H), 4.49 (t, J=8.8 Hz, 2H), 3.77 (s, 3H), 3.62-3.61 (m, 4H), 3.37-3.32 (m, 1H), 3.12 (t, J=8.8 Hz, 2H), 2.46-2.33 (m, 4H), 1.27 (d, J=6.80 Hz, 3H). LCMS: (Method A) 368.3 (M+H), Rt. 2.83 min, 99.73% (Max). HPLC: (Method A) Rt 2.89 min, 99.60% (Max).

Example 63: 6-(4-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)-N,N-dimethylnicotinamide

(352) ##STR00399##

(353) To a stirred solution of Example 65 (250 mg, 0.7 mmol) in DMF (3 mL), HATU (322 mg, 0.84 mmol) was added at rt. The mixture was cooled to 0° C. and a solution of dimethylamine in THF (1.75 mL, 3.5 mmol, 2M) and DIPEA (271 mg, 2.1 mmol) were added. The resulting mixture was stirred at rt overnight. Completion of the reaction was monitored by TLC. Reaction mixture was evaporated. The resulting crude mixture was dissolved in EtOAc (40 mL), washed with water (5 mL), a solution of 10% NaHCO.sub.3 (5 mL), dried over Na.sub.2SO.sub.4 and evaporated. The crude product was purified by flash chromatography (3-4% MeOH in DCM as eluent) and further purified by MD Autoprep HPLC (Method C) to afford the title product (beige thick oil). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.20-8.17 (m, 1H), 7.57 (dd, J=8.8, 2.4 Hz, 1H), 7.14 (d, J=7.2 Hz, 1H), 6.78-6.71 (m, 3H), 4.49 (t, J=8.8 Hz, 2H), 3.52-3.51 (m, 4H), 3.16-3.10 (m, 3H), 2.95 (s, 6H), 2.39-2.32 (m, 4H), 1.27 (d, J=6.8 Hz, 3H). LCMS: (Method A) 381.2 (M+H), Rt. 2.24 min, 97.05% (Max). HPLC: (Method A) Rt. 2.28 min, 99.83% (Max).

Example 64: 6-(4-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)-N-methylnicotinamide

(354) ##STR00400##

(355) Example 64 was synthesized according to the protocol followed for Example 63, replacing the dimethylamine with a methylamine solution in THF (1.75 mL, 3.5 mmol, 2M). The crude product was purified by flash chromatography (2% MeOH in DCM as eluent) to afford the title product (pale brown solid). .sup.1H NMR (400 MHz, DMSO-d6): δ 8.54 (d, J=2.4 Hz, 1H), 8.17 (d, J=4.4 Hz, 1H), 7.89 (dd, J=9.0, 2.0 Hz, 1H), 7.14 (d, J=7.6 Hz, 1H), 6.79-6.71 (m, 3H), 4.50 (t, J=8.4 Hz, 2H), 3.55-3.35 (m, 4H), 3.13 (t, J=8.8 Hz, 2H), 2.73 (d, J=4.4 Hz, 3H), 2.55-2.34 (m, 4H), 1.28 (d, J=6.40 Hz, 3H). LCMS: (Method A) 367.3 (M+H), Rt. 2.14 min, 98.04% (Max). HPLC: (Method A) Rt. 2.16 min, 96.78% (Max).

Example 65: 6-(4-(1-(2,3-Dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)nicotinic acid

(356) ##STR00401##

(357) To a stirred solution of Example 62 (750 mg, 2.0 mmol) in THF:H.sub.2O mixture (9:1, 5 mL), LiOH (128 mg, 3.06 mmol) was added at rt and the resulting mixture was heated to 55° C. overnight. Completion of the reaction was monitored by TLC. Reaction mixture was neutralized with citric acid and evaporated at 45° C. under reduced pressure. The residue was dissolved in 10% MeOH in DCM (50 mL), filtrated and evaporated under reduced pressure. The resulting crude product was purified by MD Autoprep HPLC (Method B) to afford the title product. Yield: 83% (600 mg, pale brown solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.50 (s, 1H), 7.86 (d, J=8.4 Hz, 1H), 7.14 (d, J=7.6 Hz, 1H), 6.77-6.71 (m, 2H), 6.60 (d, J=8.4 Hz, 1H), 4.49 (t, J=8.4 Hz, 2H), 3.43-3.37 (m, 4H), 3.32-3.31 (m, 1H), 3.13 (t, J=8.4 Hz, 2H), 2.45-2.33 (m, 4H), 1.27 (d, J=6.80 Hz, 3H). LCMS: (Method A) 354.2 (M+H), Rt. 2.30 min, 99.16% (Max). HPLC: (Method A) Rt. 2.33 min, 99.61% (Max).

Example 66: Methyl-6-(4-(1-(quinoxalin-6-yl) ethyl) piperazin-1-yl) nicotinate

(358) ##STR00402##

(359) To a stirred solution of Intermediate 9 (5.35 g, 20.76 mmol) in dry DMF (55 mL), TEA (14.46 mL, 103.81 mmol) and Intermediate 1 (4 g, 20.76 mmol) were added. The reaction mixture was stirred at 80° C. overnight. Resulting reaction mixture was cooled to rt and solvent was evaporated under vacuum. The crude product was dissolved in EtOAc (200 mL) and washed with water (40 mL). The organic layer was dried over anhydrous Na.sub.2SO.sub.4 and concentrated. The product was purified by flash chromatography to afford the title compound (off white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.94 (dd, J=6.8, 1.6 Hz, 2H), 8.62 (s, 1H), 8.10 (d, J=8.8 Hz, 1H), 8.01 (s, 1H), 7.92 (d, J=11.6 Hz, 2H), 6.84 (d, J=8.8 Hz, 1H), 3.79 (br s, 1H), 3.78 (s, 3H), 3.65 (br s, 4H), 2.61-2.56 (m, 2H), 2.51-2.43 (m, 2H), 1.45 (d, J=6.40 Hz, 3H). LCMS: (Method A) 378.3 (M+H), Rt. 2.24 min, 99.68% (Max). HPLC: (Method A), Rt. 2.30 min, 99.34% (Max).

Example 67: 6-(4-(1-(quinoxalin-6-yl) ethyl) piperazin-1-yl) nicotinic acid

(360) ##STR00403##

(361) To a stirred solution of Example 66 (1.2 g, 3.179 mmol) in THF (12 mL), MeOH (6 mL) and water (2 mL), LiOH—H.sub.2O (0.2 g, 4.768 mmol) was added at rt and the resulting mixture was stirred for 14 h at same temperature. The reaction mixture was evaporated under vacuum and the resulting crude mixture was acidified to pH=4 with 1.5 N HCl solution. It was extracted with 10% methanol in DCM (30 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 give title compound. Yield: 51% (600 mg, off white solid). .sup.1H NMR (400 MHz, MEOD): δ 8.98 (s, 2H), 8.75 (d, J=2.0 Hz, 1H), 8.31-8.27 (m, 2H), 8.11 (dd, J=9.0, 2.4 Hz, 1H), 8.02 (dd, J=2.0, 9.0 Hz, 1H), 6.90 (d, J=8.8 Hz, 1H), 4.80 (q, J=6.8 Hz, 1H), 4.57-0.00 (m, 8H), 1.94 (d, J=6.8 Hz, 3H). LCMS: (Method A) 364.2 (M+H), Rt. 1.74 min, 99.73% (Max). HPLC: (Method A), Rt. 1.75 min, 99.87% (Max).

Example 68: N-methyl-6-(4-(1-(quinoxalin-6-yl)ethyl piperazin-1-yl) picolinamide

(362) ##STR00404##

(363) A stirred solution of Intermediate 2 (0.6 g, 1.91 mmol) in dry 1,4-dioxane (10 mL), was added cesium carbonate (1.9 g, 5.88 mmol) followed by 6-chloro-N-methylpicolinamide (0.25 g, 1.47 mmol, ABCR). Nitrogen was flushed into the solution for 20 min and Pd(OAc).sub.2 (0.016 g, 0.07 mmol) and 2-2′-bis (diphenylphosphino)-1-1′-binaphthyl (0.091 g, 0.14 mmol) were added. The reaction mixture was stirred at 100° C. for 12 h. The resulting reaction mixture was filtered through celite and evaporated under vacuum. Water (5 mL) was added and the mixture was extracted with EtOAc (50 mL). The organic layer was dried over anhydrous Na.sub.2SO.sub.4 and evaporated. The resulting crude product was purified by column chromatography (brown solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.94-8.92 (m, 2H), 8.41 (d, J=4.0 Hz, 1H), 8.09 (d, J=8.8 Hz, 1H), 8.01 (s, 1H), 7.94-7.94 (m, 1H), 7.63 (t, J=8.4 Hz, 1H), 7.25-7.23 (m, 1H), 6.94 (d, J=8.4 Hz, 1H), 3.79-3.77 (m, 1H), 3.58-3.58 (m, 4H), 2.77 (d, J=4.80 Hz, 3H), 2.59-2.58 (m, 2H), 2.49-2.45 (m, 2H), 1.45 (d, J=6.80 Hz, 3H). LCMS: (Method A) 377.2 (M+H), Rt. 2.14 min, 95.23% (Max). HPLC: (Method A) Rt. 2.07 min, 96.75% (Max).

Example 69: N, N-dimethyl-6-(4-(1-(quinoxalin-6-yl) ethyl) piperazin-1-yl) picolinamide

(364) ##STR00405##

(365) The title compound was synthesized according to the procedure described for Example 68, starting from Intermediate 2 and 6-chloro-N,N-dimethylpicolinamide. The resulting crude product was purified by MD Autoprep HPLC (Method C). (yellow solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.94 (d, J=5.2 Hz, 2H), 8.09 (d, J=8.8 Hz, 1H), 8.01 (s, 1H), 7.93 (d, J=8.8 Hz, 1H), 7.60 (t, J=8.0 Hz, 1H), 6.84 (d, J=8.4 Hz, 1H), 6.75 (d, J=7.2 Hz, 1H), 3.78-3.76 (m, 1H), 3.50-3.49 (m, 4H), 2.95-2.92 (m, 6H), 2.60 (t, J=5.20 Hz, 2H), 2.46-2.45 (m, 2H), 1.45 (d, J=6.40 Hz, 3H), LCMS: (Method A) 391.2 (M+H), Rt. 99.57 min, 98.20% (Max). HPLC: (Method A) Rt. 2.06 min, 99.57% (Max).

Example 70: Methyl 6-(4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)picolinate

(366) ##STR00406##

(367) The title compound was synthesized according to the procedure described for Example 40, starting from Intermediate 2 and methyl 6-chloropicolinate The crude product was purified by flash chromatography (Eluent: 2.3% MeOH in DCM), to afford the title compound (off white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.94 (d, J=5.2 Hz, 2H), 8.10 (d, J=8.4 Hz, 1H), 8.02 (s, 1H), 7.93 (d, 8.2 Hz, 1H), 7.66 (t, J=8.4 Hz, 1H), 7.29 (d, J=7.2 Hz, 1H), 7.04 (d, J=8.8 Hz, 1H), 3.81-3.75 (m, 4H), 3.60-3.40 (m, 4H), 2.68-2.51 (m, 2H), 2.39-2.33 (m, 2H), 1.45 (d, J=6.80 Hz, 3H). LCMS: (Method A) 378.2 (M+H), Rt. 2.46 min, 97.78% (Max). HPLC: (Method A) Rt. 2.38 min, 97.32% (Max).

Example 71: 1-(5-(methylsulfonyl)pyridin-2-yl)-4-(1-(2,3,3a,7a-tetrahydrobenzofuran-6-yl)ethyl)piperazine

(368) ##STR00407##

(369) The title compound was synthesized according to the procedure described for Example 40, starting from Intermediate 13 and 2-chloro-5-(methylsulfonyl)-pyridine (off white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.47 (d, J=2.4 Hz, 1H), 7.86 (dd, J=9.2, 2.4 Hz, 1H), 7.15 (d, J=7.6 Hz, 1H), 6.91 (d, J=9.2 Hz, 1H), 6.77-6.72 (m, 2H), 4.51 (t, J=8.8 Hz, 2H), 3.64 (t, J=4.8 Hz, 4H), 3.38 (d, J=6.8 Hz, 1H), 3.18-3.11 (m, 5H), 2.47-2.35 (m, 4H), 1.29 (d, J=6.80 Hz, 3H). LCMS: (Method A) 388.0 (M+H), Rt. 2.63 min, 97.77% (Max). HPLC: (Method A) Rt 2.61 min, 99.72% (Max).

Example 72: 6-(1-(4-(5-(methylsulfonyl)pyridin-2-yl)piperazin-1-yl)ethyl)quinoxaline

(370) ##STR00408##

(371) The title compound was synthesized according to the procedure described for Example 40, starting from Intermediate 2 and 2-chloro-5-(methylsulfonyl)-pyridine (off white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.93 (dd, J=6.8, 1.6 Hz, 2H), 8.46 (d, J=2.8 Hz, 1H), 8.09 (d, J=8.8 Hz, 1H), 8.00 (s, 1H), 7.91 (dd, J=8.6, 2.0 Hz, 1H), 7.85 (dd, J=9.2, 2.8 Hz, 1H), 3.78 (d, J=6.8 Hz, 1H), 3.67 (s, 4H), 3.13 (s, 3H), 2.67-2.55 (m, 2H), 2.46-2.32 (m, 2H), 1.44 (d, J=6.40 Hz, 3H). LCMS: (Method A) 398.0 (M+H), Rt. 2.04 min, 98.07% (Max). HPLC: (Method A) Rt 2.01 min, 99.13% (Max).

Example 73: (2-(4-(1-(benzo[d]thiazol-5-yl)ethyl)piperazin-1-yl)pyrimidin-5-yl)methanol

(372) ##STR00409##

(373) The title compound was synthesized according to the procedure described for Examples 98 and 75, starting from Intermediate 3 and Intermediate 12 (brown thick oil). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.37 (s, 1H), 8.26 (s, 2H), 8.11 (d, J=8.40 Hz, 1H), 8.01 (s, 1H), 7.49 (d, J=8.40 Hz, 1H), 5.03 (t, J=5.20 Hz, 1H), 4.29 (d, J=5.60 Hz, 2H), 3.71-3.68 (m, 4H), 3.66-3.63 (m, 1H), 2.46-2.38 (m, 4H), 1.39 (d, J=6.40 Hz, 3H). LCMS: (Method A) 356.3 (M+1), Rt. 1.97 min, 97.5% (Max). HPLC: (Method A) Rt 2.07 min, 98.2% (Max).

Example 74: 2-(2-(4-(1-(2, 3-dihydrobenzofuran-6-yl) ethyl) piperazin-1-yl) pyrimidin-5-yl) propan-2-ol

(374) ##STR00410##

(375) The title compound was synthesized according to the procedure described for Example 85, starting from Example 98 (0.2 g, 0.54 mmol). The crude product was purified by flash chromatography to get the title compound (pale yellow solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.38 (s, 2H), 7.13 (d, J=7.2 Hz, 1H), 6.75 (d, J=7.6 Hz, 1H), 6.70 (s, 1H), 5.04 (s, 1H), 4.49 (t, J=8.8 Hz, 2H), 3.64-3.63 (m, 5H), 3.12 (t, J=8.8 Hz, 2H), 2.44-2.42 (m, 4H), 1.38 (s, 6H), 1.25 (d, J=6.4 Hz, 3H). LCMS: (Method A) 369.2 (M+H), Rt. 2.52 min, 98.68% (Max). HPLC: (Method A) Rt. 2.59 min, 99.01% (Max).

Example 75: (2-(4-(1-(2,3-Dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl) pyrimidin-5-yl) methanol

(376) ##STR00411##

(377) To a stirred solution of Example 98 (0.1 g, 0.27 mmol) in dry THF (4 mL) cooled at −10° C., lithium aluminium hydride (0.17 mL, 0.35 mmol, 2M in THF, Symax Fine Chemicals) was added drop wise and the reaction mixture was stirred at same temperature for 10 min. The resulting reaction mixture was quenched with a saturated solution of NH.sub.4Cl (3 mL) and extracted with EtOAc (20 mL). The organic layer was washed with brine (4 mL), dried over anhydrous Na.sub.2SO.sub.4 and concentrated. The resulting crude product was purified by flash chromatography (off white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.26 (s, 2H), 7.13 (d, J=7.6 Hz, 1H), 6.73 (d, J=7.2 Hz, 1H), 6.70 (s, 1H), 5.02 (s, 1H), 4.49 (t, J=8.8 Hz, 2H), 4.27 (d, J=5.2 Hz, 2H), 3.66 (t, J=4.4 Hz, 4H), 3.12 (t, J=8.8 Hz, 2H), 2.44-2.43 (m, 4H), 1.26 (d, J=6.4 Hz, 3H). LCMS: (Method A) 341.1 (M+H), Rt. 2.22 min, 99.42% (Max). HPLC: (Method A) Rt. 2.24 min, 99.45% (Max).

Example 76: 1-(2-(4-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)pyrimidin-5-yl)cyclopropan-1-ol

(378) ##STR00412##

(379) To a stirred solution of Example 98 (200 mg, 0.5 mmol) in THF (3 mL), titanium iso propoxide (78 mg, 0.27 mmol) was added. Then ethyl magnesium bromide in diethyl ether (0.54 mL, 1.6 mmol, 3M) was added slowly at 20° C. for 1 h and the mixture was stirred 3 h at the same temperature. Completion of the reaction was monitored by TLC. The reaction mixture was quenched with saturated ammonium chloride solution (10 mL), the product was extracted with EtOAc (2×20 mL). Combined organic layer was dried over Na.sub.2SO.sub.4 and concentrated. The resulting crude product was purified by flash chromatography (Eluant: 3-5% MeOH in DCM) and further purified by preparative HPLC (Method B) to afford the title product (pale yellow solid).

(380) .sup.1H NMR (400 MHz, DMSO-d6): δ 8.24 (s, 2H), 7.15 (d, J=7.2 Hz, 1H), 6.76 (dd, J=7.6, 1.2 Hz, 1H), 6.72 (s, 1H), 5.91 (s, 1H), 4.50 (t, J=8.8 Hz, 2H), 3.67-3.65 (m, 4H), 3.35-3.34 (m, 1H), 3.13 (t, J=8.8 Hz, 2H), 2.45-2.32 (m, 4H), 1.28 (d, J=6.4 Hz, 3H), 0.99-0.96 (m, 2H), 0.87-0.84 (m, 2H). LCMS: (Method A) 367.3 (M+H), Rt. 2.55 min, 99.03% (Max). HPLC: (Method A) Rt 2.60 min, 98.90% (Max).

Example 77: 1-(2-(4-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)pyrimidin-5-yl)-2,2,2-trifluoroethan-1-ol

(381) ##STR00413##

(382) The title compound was synthesized according to the procedure described for Example 87, starting from Example 75 (pale green solid). .sup.1H NMR (400 MHz, DMSO-d6): δ 8.37 (s, 2H), 7.14 (d, J=7.6 Hz, 1H), 6.84 (d, J=5.6 Hz, 1H), 6.76-6.71 (m, 2H), 5.07 (t, J=6.8 Hz, 1H), 4.50 (t, J=8.8 Hz, 2H), 3.71-3.69 (m, 4H), 3.37-3.31 (m, 1H), 3.13 (t, J=8.8 Hz, 2H), 2.44-2.32 (m, 4H), 1.27 (d, J=6.40 Hz, 3H). LCMS: (Method A) 409.2 (M+H), Rt. 3.04 min, 97.18% (Max). HPLC: (Method A) Rt 3.15 min, 99.10% (Max).

Example 78: 1-(2-(4-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)pyrimidin-5-yl)-2-methylpropan-1-ol

(383) ##STR00414##

(384) The title compound was synthesized according to the procedure described for Example 12, starting from Intermediate 4 and Intermediate 20 (pale yellow solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.22 (s, 2H), 7.14 (d, J=7.6 Hz, 1H), 6.76-6.71 (m, 2H), 5.08 (d, J=4.4 Hz, 1H), 4.49 (t, J=8.4 Hz, 2H), 4.12-4.09 (m, 1H), 3.67-3.65 (m, 4H), 3.32-3.31 (m, 1H), 3.12 (t, J=8.8 Hz, 2H), 2.45-2.32 (m, 4H), 1.80-1.78 (m, 1H), 1.27 (d, J=6.40 Hz, 3H), 0.85 (d, J=6.40 Hz, 3H), 0.71 (d, J=6.40 Hz, 3H). LCMS: (Method A) 383.3 (M+H), Rt. 2.93 min, 99.74% (Max). HPLC: (Method A) Rt 3.01 min, 99.32% (Max).

Example 79: 3-(2-(4-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)pyrimidin-5-yl)tetrahydrofuran-3-ol

(385) ##STR00415##

(386) The title compound was synthesized according to the procedure described for Example 40, starting from Intermediate 13 and Intermediate 28 (brown solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.40 (s, 2H), 7.14 (d, J=7.6 Hz, 1H), 6.75 (d, J=7.6 Hz, 1H), 6.71 (s, 1H), 5.39 (s, 1H), 4.49 (t, J=8.8 Hz, 2H), 3.95-3.94 (m, 2H), 3.77-3.75 (m, 1H), 3.68-3.67 (m, 4H), 3.16-3.15 (m, 2H), 2.44-2.43 (m, 2H), 2.34-2.33 (m, 2H), 2.21-2.01 (m, 4H), 1.27 (d, J=6.80 Hz, 2H). LCMS: (Method A) 397.2 (M+H), Rt. 2.331 min, 97.394% (Max). HPLC: (Method A) Rt. 2.375 min, 96.579% (Max).

Example 80: 1-(2-(4-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)pyrimidin-5-yl)cyclohexan-1-ol

(387) ##STR00416##

(388) The title compound was synthesized according to the procedure described for Example 40, starting from Intermediate 13 and Intermediate 22 (brown thick oil). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.40 (s, 2H), 7.15 (d, J=7.6 Hz, 1H), 6.76 (d, J=7.2 Hz, 1H), 6.72 (s, 1H), 4.74 (s, 1H), 4.50 (t, J=8.8 Hz, 2H), 3.66 (t, J=4.8 Hz, 4H), 3.34 (s, 1H), 3.13 (t, J=8.8 Hz, 2H), 2.44-2.43 (m, 2H), 2.34 (q, J=4.80 Hz, 2H), 1.67-1.64 (m, 7H), 1.46-1.43 (m, 2H), 1.28 (d, J=6.40 Hz, 3H). LCMS: (Method A) 409.2 (M+H), Rt. 3.185 min, 99.358% (Max). HPLC: (Method A) Rt. 3.253 min, 99.334% (Max).

Example 81: 4-(2-(4-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)pyrimidin-5-yl)tetrahydro-2H-pyran-4-ol

(389) ##STR00417##

(390) The title compound was synthesized according to the procedure described for Example 40, starting from Intermediate 13 and Intermediate 23. The crude product was purified by MD Autoprep HPLC (Method B) to get the title compound (yellow solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.40 (d, J=6.4 Hz, 2H), 7.14 (d, J=7.6 Hz, 1H), 6.76-6.71 (m, 2H), 5.06 (s, 1H), 4.49 (t, J=8.8 Hz, 2H), 3.74-3.65 (m, 8H), 3.34-3.31 (m, 1H), 3.12 (t, J=8.8 Hz, 2H), 2.43-2.39 (m, 2H), 2.34-2.31 (m, 2H), 1.90-1.89 (m, 2H), 1.56-1.53 (m, 2H), 1.27 (d, J=6.80 Hz, 3H). LCMS: (Method A) 411.2 (M+H), Rt. 2.38 min, 98.92% (Max). HPLC: (Method A) Rt. 2.43 min, 98.50% (Max).

Example 82: 3-(2-(4-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)pyrimidin-5-yl)oxetan-3-ol

(391) ##STR00418##

(392) The title compound was synthesized according to the procedure described for Example 40, starting from Intermediate 13 and Intermediate 34. The resulting crude product was purified by column chromatography (eluent: 3% MeOH in DCM) to afford the title compound (off white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.49 (s, 2H), 7.15 (d, J=7.6 Hz, 1H), 6.76 (d, J=7.6 Hz, 1H), 6.72 (s, 1H), 6.35 (s, 1H), 4.70 (s, 4H), 4.50 (t, J=8.8 Hz, 2H), 3.70 (t, J=4.8 Hz, 4H), 3.36-0.00 (m, 1H), 3.13 (t, J=8.4 Hz, 2H), 2.45-2.44 (m, 2H), 2.37-2.36 (m, 2H), 1.28 (d, J=6.80 Hz, 3H). LCMS: (Method A) 383.3 (M+H), Rt. 2.317 min, 98.76% (Max). HPLC: (Method A) Rt. 2.334 min, 99.04% (Max).

Example 83: 1-(2-(4-(1-(1,8-naphthyridin-2-yl)ethyl)piperazin-1-yl)pyrimidin-5-yl)-2,2,2-trifluoroethan-1-ol

(393) ##STR00419##

(394) The title compound was synthesized according to the procedure described for Example 87, starting from Intermediate 29 (pale brown solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.05-9.04 (m, 1H), 8.44 (d, J=8.8 Hz, 2H), 8.38 (s, 2H), 7.80 (d, J=8.4 Hz, 1H), 7.62-7.59 (m, 1H), 6.84 (d, J=6.0 Hz, 1H), 5.09-5.06 (m, 1H), 3.89-3.87 (m, 1H), 3.75-3.74 (m, 4H), 2.67-2.57 (m, 2H), 2.50-2.32 (m, 2H), 1.43 (d, J=6.80 Hz, 3H). LCMS: (Method A) 419.2 (M+H), Rt. 2.25 min, 96.08% (Max). HPLC: (Method A) Rt 2.27 min, 97.02% (Max).

Example 84: 1-(2-(4-(1-(quinoxalin-6-yl) ethyl) piperazin-1-yl) pyrimidin-5-yl) ethan-1-ol

(395) ##STR00420##

Step 1: 6-(1-(4-(5-bromopyrimidin-2-yl) piperazin-1-yl) ethyl) quinoxaline

(396) To a stirred solution of Intermediate 14 (2.5 g, 8.99 mmol) in dry DMF (25 mL), TEA (4.9 mL, 35.9 mmol) and Intermediate 1 (2.6 g, 13.4 mmol) were added at rt. The resulting mixture was heated at 80° C. overnight. It was concentrated under vacuum and the resulting crude mixture was dissolved in EtOAc (100 mL), washed with water (20 mL), dried over anhydrous Na.sub.2SO.sub.4 and concentrated. The crude product was purified by flash chromatography, affording the title compound (yellow solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.92 (d, J=5.6 Hz, 2H), 8.30 (s, 2H), 8.19 (d, J=8.4 Hz, 1H), 7.99 (s, 1H), 7.91 (d, J=8.4 Hz, 1H), 3.69-3.67 (m, 5H), 2.77-2.75 (m, 4H), 1.42 (d, J=6.8 Hz, 3H). LCMS: (Method A) 401.2 (M+H), Rt. 2.60 min, 70.09% (Max).

Step 2: 1-(2-(4-(1-(quinoxalin-6-yl) ethyl) piperazin-1-yl) pyrimidin-5-yl) ethan-1-one

(397) The title compound was synthesized according to the procedure described for Example 36, step 1, starting with 6-(1-(4-(5-bromopyrimidin-2-yl) piperazin-1-yl) ethyl) quinoxaline (0.8 g, 2.00 mmol). The resulting crude product was purified by flash chromatography, affording the title compound (yellow solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.93 (d, J=5.2 Hz, 2H), 8.83 (s, 2H), 8.09 (d, J=8.8 Hz, 1H), 8.00 (s, 1H), 7.92 (d, J=8.8 Hz, 1H), 3.88-3.86 (m, 5H), 2.57-2.56 (m, 2H), 2.50-2.49 (m, 5H), 1.44 (d, J=6.8 Hz, 3H). LCMS: (Method A) 363.3 (M+H), Rt. 2.02 min, 90.62% (Max).

Step 3: 1-(2-(4-(1-(quinoxalin-6-yl) ethyl) piperazin-1-yl) pyrimidin-5-yl) ethan-1-ol

(398) The title compound was synthesized according to the procedure described for Example 36, step 2, starting with 1-(2-(4-(1-(quinoxalin-6-yl) ethyl) piperazin-1-yl) pyrimidin-5-yl) ethan-1-one (0.1 g, 0.27 mmol) in dry THF: MeOH (1:1, 5 mL). The crude was purified by flash chromatography to give the title product. Yield: 67% (0.067 g, off white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.92 (dd, J=5.6 Hz, 2H), 8.28 (s, 2H), 8.08 (d, J=8.8 Hz, 1H), 7.99 (s, 1H), 7.91 (d, J=8.8 Hz, 1H), 5.05 (d, J=4.4 Hz, 1H), 4.61-4.58 (m, 1H), 3.74-3.69 (m, 5H), 2.59-2.57 (m, 2H), 2.42-2.40 (m, 2H), 1.42 (d, J=6.8 Hz, 3H), 1.39 (d, J=6.4 Hz, 3H). LCMS: (Method A) 365.2 (M+H), Rt. 1.87 min, 99.74% (Max). HPLC: (Method A) Rt. 1.89 min, 99.44% (Max).

Example 85: 2-(2-(4-(1-(quinoxalin-6-yl) ethyl) piperazin-1-yl) pyrimidin-5-yl) propen-2-ol

(399) ##STR00421##

(400) To a stirred solution of Example 105 (0.15 g, 0.39 mmol) in dry THF (5 mL), methyl magnesium chloride (0.4 mL, 1.19 mmol, 3M in THF, Symax Fine Chemicals) was added drop wise at −40° C. and the resulting mixture was stirred at rt for 2 h. It was quenched with a saturated solution of NH.sub.4Cl (3 mL) and was extracted with EtOAc (20 mL). The organic phase was washed with brine (5 mL), dried over anhydrous Na.sub.2SO.sub.4 and concentrated. The resulting crude product was purified by flash chromatography followed by MD Autoprep HPLC (Method C), affording the title compound (off white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.93-8.91 (m, 2H), 8.38 (s, 2H), 8.08 (d, J=8.8 Hz, 1H), 7.99 (s, 1H), 7.90 (d, J=8.8 Hz, 1H), 5.04 (s, 1H), 3.74-3.72 (m, 5H), 2.55-2.53 (m, 2H), 2.41-2.40 (m, 2H), 1.42 (d, J=6.8 Hz, 3H), 1.38 (s, 6H). LCMS: (Method A) 379.0 (M+H), Rt. 2.10 min, 99.26% (Max). HPLC: (Method A) Rt. 2.04 min, 99.15% (Max).

Example 86: (2-(4-(1-(Quinoxalin-6-yl)ethyl)piperazin-1-yl)pyrimidin-5-yl) methanol

(401) ##STR00422##

(402) The title product was prepared according to the protocol described for Example 75, starting from Example 105. The resulting crude product was purified by flash chromatography (brown thick oil). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.92 (d, J=5.6 Hz, 2H), 8.76 (s, 2H), 8.08 (d, J=12.0 Hz, 1H), 7.99 (s, 1H), 7.91 (d, J=8.8 Hz, 1H), 5.04 (t, J=5.6 Hz, 1H), 4.27 (d, J=5.2 Hz, 2H), 3.73 (t, J=6.8 Hz, 5H), 2.40 (t, J=5.2 Hz, 4H), 1.42 (d, J=6.4 Hz, 3H). LCMS: (Method A) 351.2 (M+H), Rt. 1.689 min, 97.79% (Max). HPLC: (Method A) Rt. 1.72 min, 99.19% (Max).

Example 87: 2, 2, 2-trifluoro-1-(2-(4-(1-(quinoxalin-6-yl) ethyl) piperazin-1-yl)pyrimidin-5-yl)ethan-1-ol

(403) ##STR00423##

Step 1: 2-(4-(1-(quinoxalin-6-yl) ethyl) piperazin-1-yl) pyrimidine-5-carbaldehyde

(404) A stirred solution of Example 86 (0.65 g, 1.85 mmol) in dry DCM (110 mL), Desmartin periodinane (1.58 g, 3.71 mmol) was added at 0° C. and the mixture was stirred for 1 h at the same temperature. The reaction mixture was diluted with DCM (30 mL) and washed with a saturated solution of NaHCO.sub.3 (2×5 mL). The resulting DCM layer was dried over anhydrous Na.sub.2SO.sub.4 and evaporated under vacuum. The crude product was purified by flash chromatography, affording the title compound. Yield: 50% (0.33 g, yellow thick oil). .sup.1H NMR (400 MHz, DMSO-d6: δ 9.79 (s, 1H), 8.94 (d, J=4.8 Hz, 2H), 8.84 (s, 1H), 8.77-8.77 (m, 2H), 8.12-8.09 (m, 2H), 4.23-4.18 (m, 5H), 3.97-3.91 (m, 4H), 1.45 (d, J=19.6 Hz, 3H). LCMS: (Method A) 349.0 (M+2), Rt. 1.98 min, 64.53% (Max).

Step 2: 2, 2, 2-trifluoro-1-(2-(4-(1-(quinoxalin-6-yl) ethyl) piperazin-1-yl)pyrimidin-5-yl)ethan-1-ol

(405) A stirred solution of 2-(4-(1-(quinoxalin-6-yl) ethyl) piperazin-1-yl) pyrimidine-5-carbaldehyde (0.15 g, 0.43 mmol) in dry DMF (2 mL), K.sub.2CO.sub.3 (0.118 g, 0.86 mmol) and (trifluoromethyl) trimethylsilane (0.122 g, 0.86 mmol) were added at 10° C. and the mixture was stirred at rt for 1 h. It was quenched with water (2 mL) and extracted with EtOAc (15 mL). The EtOAc layer was dried over anhydrous Na.sub.2SO.sub.4 and evaporated under vacuum. The resulting crude was purified by flash chromatography followed by MD Autoprep HPLC (Method C) (off white solid). .sup.1H NMR (400 MHz, DMSO-d6): δ 8.93 (dd, J=1.6, 2H), 8.39 (s, 2H), 8.09 (d, J=8.8 Hz, 1H), 8.01 (d, J=1.6 Hz, 1H), 7.94-7.94 (m, 1H), 6.83 (d, J=6.0 Hz, 1H), 5.09 (t, J=6.8 Hz, 1H), 3.78-3.77 (m, 5H), 2.52-2.51 (m, 2H), 2.50-2.50 (m, 2H), 1.44 (d, J=6.40 Hz, 3H). LCMS: (Method A) 419.2 (M+2), Rt. 2.46 min, 99.11% (Max). HPLC: (Method A) Rt. 2.53 min, 99.48% (Max).

Example 88: 2-methyl-1-(2-(4-(1-(quinoxalin-6-yl)ethyl) piperazin-1-yl) pyrimidin-5-yl) propan-1-ol

(406) ##STR00424##

(407) The title compound was synthesized according to the procedure described for Example 12, starting from Intermediate 1 and Intermediate 20 (off white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.94 (dd, J=7.2, 1.6 Hz, 2H), 8.23 (s, 2H), 8.09 (d, J=8.8 Hz, 1H), 8.01 (s, 1H), 7.93 (dd, J=8.8, 1.6 Hz, 1H), 5.09 (d, J=4.4 Hz, 1H), 4.13-4.12 (m, 1H), 3.77-3.75 (m, 1H), 3.71 (t, J=4.4 Hz, 4H), 2.44-2.43 (m, 4H), 1.80-1.79 (m, 1H), 1.44 (d, J=6.80 Hz, 3H), 0.86 (d, J=6.80 Hz, 3H), 0.72 (d, J=6.80 Hz, 3H). LCMS: (Method A) 393.2 (M+H), Rt. 2.37 min, 96.65% (Max). HPLC: (Method A) Rt. 2.43 min, 99.62% (Max).

Example 89: 4-(2-(4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)pyrimidin-5-yl)tetrahydro-2H-pyran-4-ol

(408) ##STR00425##

(409) The title compound was synthesized according to the procedure described for Example 40, starting from Intermediate 2 and Intermediate 23 (44 mg, pale brown solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.93-8.92 (m, 2H), 8.41 (s, 2H), 8.08 (d, J=8.4 Hz, 1H), 7.99 (s, 1H), 7.91 (d, J=8.4 Hz, 1H), 5.06 (s, 1H), 3.76-3.66 (m, 9H), 2.42-2.40 (m, 4H), 1.92-1.89 (m, 2H), 1.55-1.52 (m, 2H), 1.43 (d, J=6.00 Hz, 3H). LCMS: (Method A) 421.2 (M+2H), Rt. 1.96 min, 98.37% (Max). HPLC: (Method A) Rt. 1.92 min, 99.41% (Max).

Example 90: 2-(4-(1-(2, 3-dihydrobenzofuran-6-yl) ethyl) piperazin-1-yl)-5-methylpyrimidine

(410) ##STR00426##

(411) To a stirred solution of Example 98 (0.3 g, 0.82 mmol) in dry THF (6 mL), lithium aluminium hydride solution (0.17 mL, 0.35 mmol, 2M in THF, Symax Fine Chemicals) was added drop wise at 0° C. and the resulting mixture was stirred at rt for 1 h. It was quenched with a saturated solution of NH.sub.4Cl (10 mL) and extracted with EtOAc (35 mL). The organic layer was washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated. The resulting crude product was purified by flash chromatography, affording the title compound (off white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): 8.19 (s, 2H), 7.14 (d, J=7.6 Hz, 1H), 6.75 (d, J=8.4 Hz, 1H), 6.71 (s, 1H), 4.49 (t, J=8.4 Hz, 2H), 3.63-3.61 (m, 5H), 3.12 (t, J=8.8 Hz, 2H), 2.51-2.49 (m, 2H), 2.40-2.39 (m, 2H), 2.05 (s, 3H), 1.26 (d, J=6.4 Hz, 3H). LCMS: (Method A) 325.2 (M+H), Rt. 2.75 min, 98.02% (Max). HPLC: (Method A) Rt. 2.77 min, 98.513% (Max).

Example 91: 7-(1-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)ethyl)imidazo[1,2-a]pyridine

(412) ##STR00427##

(413) To a stirred solution of 2-chloro-5-(trifluoromethyl)pyrimidine (0.15 g, 0.83 mmol) in dry DMF (7 mL), TEA (0.43 mL, 3.12 mmol) and Intermediate 8 (0.24 g, 1.04 mmol) were added at 0° C. The reaction mixture was stirred at 100° C. for 12 h. The reaction mixture was concentrated under vacuum to give a crude product, which was purified by flash column chromatography using 2-3% MeOH in DCM as eluent. The title compound was isolated after evaporation of the solvents (dark brown thick oil). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.66 (s, 2H), 8.48 (d, J=7.2 Hz, 1H), 7.88 (s, 1H), 7.52 (s, 1H), 7.43 (s, 1H), 6.93 (d, J=6.8 Hz, 1H), 3.82 (t, J=4.4 Hz, 4H), 3.60-3.50 (m, 1H), 2.59-2.51 (m, 2H), 2.49-2.38 (m, 2H), 1.34 (d, J=6.8 Hz, 3H). LCMS: (Method A) 377.2 (M+H), Rt. 2.29 min, 99.4% (Max). HPLC: (Method A) Rt 2.33 min, 99.18% (Max).

Example 92: 2-(1-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)ethyl)-1,8-naphthyridine

(414) ##STR00428##

(415) The title compound was synthesized according to the procedure described for Example 12, using Intermediate 29 and 2-(1-piperazinyl)-5-(trifluoromethyl)-pyrimidine (brown thick oil). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.06-9.04 (m, 1H), 8.67 (s, 2H), 8.46 (d, J=8.4 Hz, 2H), 7.81 (d, J=8.4 Hz, 1H), 7.63-7.60 (m, 1H), 3.92-3.90 (m, 1H), 3.85-3.84 (m, 4H), 2.64-2.60 (m, 2H), 2.47-2.43 (m, 2H), 1.45 (d, J=6.8 Hz, 3H). LCMS: (Method A) 389.2 (M+H), Rt. 2.72 min, 98.07% (Max). HPLC: (Method A) Rt. 2.76 min, 98.46% (Max).

Example 94: 6-(1-(4-(5-(cyclopent-1-en-1-yl)pyrimidin-2-yl)piperazin-1-yl)ethyl)quinoxaline

(416) ##STR00429##

Step 1: tert-butyl 4-(5-(1-hydroxycyclopentyl)pyrimidin-2-yl)piperazine-1-carboxylate

(417) A solution of the tert-butyl 4-(5-bromopyrimidin-2-yl)piperazine-1-carboxylate (1.5 g, 4.37 mmol) in dry diethyl ether was cooled to −80° C. and kept under inert atmosphere. n-BuLi (1.6 mL, 5.24 mmol, 2.5 m in Hexane) was added dropwise. The solution was allowed stand at −80° C. for 1 h and cyclopentanone (1.2 equiv) was added slowly to reaction mixture at same temperature. After 15 min, the temperature was increased to rt and the mixture was stirred for 1 h at rt. It was quenched with a saturated solution of NH.sub.4Cl (3 mL) and extracted with EtOAc (3×50 mL). The organic phase was washed with brine (5 mL), dried over anhydrous Na.sub.2SO.sub.4 and concentrated. The crude product was purified by flash chromatography to afford the title compound. .sup.1H NMR 400 MHz, DMSO-d.sub.6: δ 8.48 (s, 2H), 3.83 (t, J=5.2 Hz, 4H), 3.52 (t, J=5.2 Hz, 4H), 2.02-1.94 (m, 6H), 1.85-1.84 (m, 2H). LCMS: (Method A) 349.0 (M+H), Rt. 2.39 min, 98.13% (Max).

Step 2: 5-(cyclopent-1-en-1-yl)-2-(piperazin-1-yl)pyrimidine hydrochloride

(418) To a stirred solution of tert-butyl 4-(5-(1-hydroxycyclopentyl)pyrimidin-2-yl)piperazine-1-carboxylate (250 mg, 0.71 mmol) in 1,4-dioxane (5 mL), HCl in 1,4-dioxane (2.5 mL, 4.0 M in dioxane) was added slowly at rt, and the reaction mixture was stirred at rt for 2 h. The reaction mixture was concentrated under vacuum. The resulting crude product was triturated with diethyl ether (15 mL) to afford the title compound. Yield: 88% (150 mg, white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.55 (s, 2H), 6.25 (br s, 1H), 3.19-3.16 (m, 4H), 2.66-2.55 (m, 4H), 2.50-2.46 (m, 4H), 1.97-1.92 (m, 2H). LCMS: (Method A) 231.0 (M+H), Rt. 2.07 min, 95.97% (Max).

Step 3: 6-(1-(4-(5-(cyclopent-1-en-1-yl)pyrimidin-2-yl)piperazin-1-yl)ethyl)quinoxaline

(419) The title compound was synthesized according to the procedure described for Example 12, starting from Intermediate 1 and 5-(cyclopent-1-en-1-yl)-2-(piperazin-1-yl)pyrimidine hydrochloride (white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.92 (dd, J=2.0, −7.2 Hz, 2H), 8.45 (s, 2H), 8.08 (d, J=8.8 Hz, 1H), 8.00 (d, J=1.6 Hz, 1H), 7.91 (dd, J=8.8, 2.0 Hz, 1H), 6.15 (s, 1H), 3.77-3.72 (m, 4H), 2.67-2.49 (m, 4H), 2.45-2.32 (m, 4H), 1.91 (t, J=7.2 Hz, 2H), 1.43 (d, J=6.80 Hz, 3H). LCMS: (Method B) 387.0 (M+H), Rt. 6.36 min, 98.06% (Max). HPLC: (Method A) Rt. 3.36 min, 98.14% (Max).

Example 95: Methyl 2-(4-(1-(benzo[d]thiazol-5-yl)ethyl)piperazin-1-yl)pyrimidine-5-carboxylate

(420) ##STR00430##

(421) The title compound was synthesized according to the procedure described for Example 12, starting from Intermediate 3 and Intermediate 12 (white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.39 (s, 1H), 8.76 (s, 2H), 8.12 (d, J=8.00 Hz, 1H), 8.03 (s, 1H), 7.50 (d, J=8.40 Hz, 1H), 3.85 (t, J=4.80 Hz, 4H), 3.79 (s, 3H), 3.70-3.65 (m, 1H), 2.53-2.51 (m, 2H), 2.45-2.41 (m, 2H), 1.41 (d, J=6.80 Hz, 3H). LCMS: (Method A) 384.0 (M+1), Rt. 2.71 min, 97.0% (Max). HPLC: (Method A) Rt 2.66 min, 97.8% (Max).

Example 96: 2-(4-(1-(benzo[d]thiazol-5-yl)ethyl)piperazin-1-yl)-N-methylpyrimidine-5-carboxamide

(422) ##STR00431##

(423) The title compound was synthesized according to the procedure described for Examples 65 and 64, starting from Example 95 (white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6: δ 9.38 (s, 1H), 8.70 (s, 2H), 8.27 (d, J=4.40 Hz, 1H), 8.11 (d, J=8.00 Hz, 1H), 8.02 (s, 1H), 7.49 (d, J=8.00 Hz, 1H), 3.81-3.78 (m, 4H), 3.67-3.64 (m, 1H), 2.73 (d, J=4.40 Hz, 3H), 2.45-2.32 (m, 4H), 1.40 (d, J=6.80 Hz, 3H). LCMS: (Method A) 383.0 (M+H), Rt. 2.16 min, 99.2% (Max). HPLC: (Method A) Rt 2.11 min, 97.8% (Max).

Example 97: 2-(4-(1-(benzo[d]thiazol-5-yl)ethyl)piperazin-1-yl)-N,N-dimethylpyrimidine-5-carboxamide

(424) ##STR00432##

(425) The title compound was synthesized according to the procedure described for Examples 65 and 63, starting from Example 95 (white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6: δ 9.38 (d, J=1.20 Hz, 1H), 8.44 (d, J=1.20 Hz, 2H), 8.11 (d, J=8.40 Hz, 1H), 8.02 (s, 1H), 7.50 (d, J=8.00 Hz, 1H), 3.79-3.75 (m, 4H), 3.73-3.66 (m, 1H), 2.96 (s, 6H), 2.45-2.39 (m, 4H), 1.40 (d, J=6.40 Hz, 3H). LCMS: (Method A) 397.2 (M+H), Rt. 2.29 min, 99.3% (Max). HPLC: (Method A) Rt 2.23 min, 99.3% (Max).

Example 98: Methyl 2-(4-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)pyrimidine-5-carboxylate

(426) ##STR00433##

(427) To a stirred solution of Intermediate 12 (1 g, 3.87 mmol) in dry DMF (10 mL), TEA (1.94 mL, 13.95 mmol) and Intermediate 4 (0.24 g, 1.04 mmol) were added at 0° C. The reaction mixture was heated at 100° C. for 12 h. Then the reaction mixture was concentrated under vacuum. The resulting crude product was purified by column chromatography (2-3% MeOH in DCM as eluent) to afford the title compound (off white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.76 (s, 2H), 7.15 (d, J=7.2 Hz, 1H), 6.76 (d, J=7.6 Hz, 1H), 6.72 (s, 1H), 4.50 (t, J=8.8 Hz, 2H), 3.82 (t, J=4.8 Hz, 4H), 3.79 (s, 3H), 3.50-3.42 (m, 1H), 3.13 (t, J=8.8 Hz, 2H), 2.49-2.44 (m, 2H), 2.42-2.33 (m, 2H), 1.28 (d, J=6.80 Hz, 3H). LCMS: (Method A) 369.2 (M+H), Rt. 2.96 min, 98.9% (Max). HPLC: (Method A) Rt. 2.95 min, 98.8% (Max).

Example 99: 2-(4-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)-N-methylpyrimidine-5-carboxamide

(428) ##STR00434##

Step 1: 2-(4-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)pyrimidine-5-carboxylic acid

(429) To a stirred solution of Example 98 (0.840 g, 2.28 mmol) in dioxane (2 mL), LiOH (10 M, 1.14 mL, 1.14 mmol) was added at rt and the resulting mixture was stirred for 4 h. The completion of reaction was monitored by TLC. Solvent was evaporated and the product was further dried by azeotropic evaporation of toluene (3×2 mL). The resulting product was used in the next step without any further purification. Yield: 99.1% (0.90 g, off white solid). LCMS: (Method A) 355 (M+H), Rt. 2.421 min 90.06% (Max).

Step 2: 2-(4-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)-N-methylpyrimidine-5-carboxamide

(430) Example 99 was synthesized according to the protocol described for Example 63, starting with 2-(4-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)pyrimidine-5-carboxylic acid and replacing the dimethylamine with a methylamine solution in THF (3.175 ml, 6.35 mmol). The crude product was purified by flash chromatography (2% MeOH in DCM as eluent) to afford the title product (off white solid). LCMS: (Method A) 368 (M+H), Rt 2.413 min 94.23% (Max). HPLC: (Method A), Rt 2.344 min, 96.76% (Max). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.70 (s, 2H), 8.27 (d, J=4.4 Hz, 1H), 7.14 (d, J=7.6 Hz, 1H), 6.76-6.74 (m, 2H), 4.49 (t, J=8.8 Hz, 2H), 3.78-3.76 (m, 4H), 3.32 (s, 1H), 3.14 (t, J=8.8 Hz, 2H), 2.74-2.73 (m, 3H), 2.42-2.36 (m, 4H), 1.27 (d, J=6.80 Hz, 3H).

Example 100: 2-(4-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)-N,N-dimethylpyrimidine-5-carboxamide

(431) ##STR00435##

(432) Example 100 was synthesized according to the protocol described for Example 63, starting with 2-(4-(1-(2, 3-di hydrobenzofuran-6-yl)ethyl)piperazin-1-yl)pyrimidine-5-carboxylic acid (example 99, step 1). The crude product was purified by flash chromatography (2% MeOH in DCM as eluent) to afford the title product (brown solid). LCMS: (Method A) 382 (M+H), Rt. 2.436 min 98.34% (Max). HPLC: (Method A), Rt. 2.473 min, 97.0% (Max). .sup.1H NMR: (400 MHz, DMSO-d.sub.6): δ 8.45 (s, 2H), 7.15 (d, J=7.2 Hz, 1H), 6.75 (t, J=7.2 Hz, 1H), 4.50 (t, J=8.8 Hz, 2H), 3.77-3.76 (m, 4H), 3.13 (t, J=8.8 Hz, 2H), 3.11-2.97 (m, 7H), 1.29-1.27 (m, 3H).

Example 101: 2-(4-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)-N,N-dimethylpyrimidine-4-carboxamide

(433) ##STR00436##

(434) Example 101 was synthesized according to the protocol described for Example 100, starting with Example 102. Yield: 62% (321 mg, off white solid). .sup.1H NMR (400 MHz, DMSO-d6): δ 8.43 (d, J=5.2 Hz, 1H), 7.14 (d, J=7.2 Hz, 1H), 6.75 (d, J=7.6 Hz, 1H), 6.71 (s, 1H), 6.63-6.62 (m, 1H), 4.49 (t, J=8.8 Hz, 2H), 3.68-3.67 (m, 4H), 3.36-3.32 (m, 1H), 3.12 (t, J=8.8 Hz, 2H), 2.94 (s, 3H), 2.89 (s, 3H), 2.45-2.33 (m, 4H), 1.27 (d, J=6.40 Hz, 3H). LCMS: (Method A) 382.2 (M+H), Rt. 2.60 min, 97.9% (Max). HPLC: (Method A) Rt 2.55 min, 99.26% (Max).

Example 102: Methyl 2-(4-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)pyrimidine-4-carboxylate

(435) ##STR00437##

(436) The title compound was synthesized according to the procedure described for Example 40, starting from Intermediate 13 and methyl 2-chloropyrimidine-4-carboxylate. The crude product was purified by flash chromatography (Elutant: 55-75% EtOAc in pet ether), affording the title product. Yield: 68.1% (574 mg, pale yellow thick oil). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.56-8.55 (m, 1H), 7.14 (d, J=7.6 Hz, 1H), 7.07-7.05 (m, 1H), 6.75 (d, J=7.6 Hz, 1H), 6.71 (s, 1H), 4.49 (t, J=8.8 Hz, 2H), 3.84 (s, 3H), 3.73-3.72 (m, 4H), 3.37-3.32 (m, 1H), 3.12 (t, J=8.8 Hz, 2H), 2.38-2.32 (m, 4H), 1.28 (d, J=6.80 Hz, 3H). LCMS: (Method A) 369.2 (M+H), Rt. 2.83 min, 98.25% (Max). HPLC: (Method A) Rt 2.88 min, 98.43% (Max).

Example 103: 2-(4-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)-N-methylpyrimidine-4-carboxamide

(437) ##STR00438##

(438) Example 103 was synthesized according to the protocol described for Example 99, starting with Example 102. The crude product was purified by flash chromatography (Elutant: 90% EtOAc in pet ether) to afford the title compound (pale yellow solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.69 (d, J=4.4 Hz, 1H), 8.52 (d, J=4.8 Hz, 1H), 7.15 (d, J=7.2 Hz, 1H), 7.06 (d, J=4.8 Hz, 1H), 6.77 (dd, J=7.6, 1.2 Hz, 1H), 6.73 (s, 1H), 4.51 (t, J=8.4 Hz, 2H), 3.80-3.79 (m, 4H), 3.40-3.38 (m, 1H), 3.14 (t, J=8.8 Hz, 2H), 2.79 (d, J=4.80 Hz, 3H), 2.45-2.33 (m, 4H), 1.30 (d, J=6.80 Hz, 3H). LCMS: (Method A) 368.2 (M+H), Rt. 2.62 min, 97.33% (Max). HPLC: (Method A) Rt 2.58 min, 99.41% (Max).

Example 104: N-(2-(2-(1-(4-(quinoxalin-6-yl)piperazin-1-yl)ethyl)pyrimidin-5-yl)propan-2-yl)acetamide

(439) ##STR00439##

(440) The title compound was synthesized according to the procedure described for Example 40, starting from Intermediate 13 and Intermediate 33 (off-White solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.26 (s, 1H), 8.04 (s, 1H), 7.15 (d, J=7.6 Hz, 3H), 6.72-6.76 (m, 2H), 4.51 (t, J=8.4 Hz, 2H), 3.64-3.65 (m, 4H), 3.14 (t, J=8.4 Hz, 2H), 2.42-2.44 (m, 2H), 2.31-2.33 (m, 2H), 1.79 (s, 3H), 1.49 (s, 6H), 1.28 (t, J=6.4 Hz, 3H). LCMS: (Method A) 410.5 (M+H), Rt. 2.58 min, 98.25% (Max). HPLC: (Method A) Rt. 2.61 min, 99.51% (Max).

Example 105: Methyl 2-(4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)pyrimidine-5-carboxylate

(441) ##STR00440##

(442) To a stirred solution of Intermediate 1 (0.1 g, 0.51 mmol) in dry DMF (5.0 mL), TEA (0.21 mL, 1.5 mmol) and Intermediate 12 (0.115 g, 0.5 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 vacuum. To this resulting crude mixture, water (50 mL) was added and product was extracted with DCM (150 mL). Organic layer was dried over anhydrous Na.sub.2SO.sub.4 and concentrated. 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 8.94 (d, J=5.6 Hz, 2H), 8.77 (s, 2H), 8.10 (d, J=8.8 Hz, 1H), 8.01 (s, 1H), 7.93 (d, J=8.8 Hz, 1H), 3.89-3.86 (m, 4H), 3.82-3.78 (m, 1H), 3.79 (s, 3H), 2.56-2.57 (m, 2H), 2.46-2.44 (m, 2H), 1.44 (d, J=6.4 Hz, 3H). LCMS: (Method A) 379.2 (M+H), Rt. 2.27 min, 99.84% (Max). HPLC: (Method A) Rt. 2.33 min, 98.75% (Max).

Example 106: 2-(4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)pyrimidine-5-carboxylic acid

(443) ##STR00441##

(444) To a stirred solution of Example 105 (1.5 g, 5.96 mmol) in THF (15.0 mL), methanol (4.5 mL) and water (4.5 mL), LiOH (330 mg; 7.92 mmol) was added at the resulting mixture was stirred for 12 h at rt. After completion of the reaction, the reaction mixture was acidified to pH 4 with a 1N HCl solution. The resulting precipitate was filtered and dissolved in DCM (100 mL). The DCM solution was washed with water (1.0 mL), dried over Na.sub.2SO.sub.4 and concentrated to afford the titled compound (yellow solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 12.84 (s, 1H), 8.93 (dd, J=2.0, 7.2 Hz, 2H), 8.73 (s, 2H), 8.09 (d, J=8.8 Hz, 1H), 8.01 (d, J=1.6 Hz, 1H), 7.93 (dd, J=2.0, 8.6 Hz, 1H), 3.85 (t, J=5.2 Hz, 4H), 3.79 (d, J=6.8 Hz, 1H), 2.60-2.55 (m, 2H), 2.50-2.43 (m, 2H), 1.44 (d, J=6.80 Hz, 3H). LCMS: (Method A) 365.2 (M+H), Rt. 1.84 min, 99.36% (Max). HPLC: (Method A) Rt. 1.88 min, 98.35% (Max).

Example 107: N-(2-(2-(4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)pyrimidin-5-yl)propan-2-yl)acetamide

(445) ##STR00442##

(446) The title compound was synthesized according to the procedure described for Example 40, starting from Intermediate 2 and Intermediate 33 (pale Brown solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.95 (d, J=1.6 Hz, 1H), 8.93 (d, J=1.6 Hz, 1H), 8.26 (s, 2H), 8.10-8.01 (m, 3H), 7.93 (dd, J=1.6, 8.8 Hz, 1H), 3.76-3.69 (m, 5H), 2.57-2.54 (m, 2H), 2.43-2.40 (m, 2H), 1.79 (s, 3H), 1.49-1.43 (m, 9H). LCMS: (Method A) 420.2 (M+H), Rt. 2.05 min, 97.13% (Max). HPLC: (Method A) Rt. 2.09 min, 98.84% (Max).

Examples 108 and 109: (R)—N-(5-(4-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)-1,3,4-thiadiazol-2-yl)acetamide and (S)—N-(5-(4-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)-1,3,4-thiadiazol-2-yl)acetamide

(447) ##STR00443##

(448) The title compound was synthesized according to the procedure described for Example 105, starting from Intermediate 4 and Intermediate 5. The crude product was purified by flash chromatography to give the racemic mixture of the title compound.

(449) Both enantiomers were further separated by SFC using the preparative chiral method PA.

(450) The first eluting compound correspond to Example 108 (off white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 11.99 (s, 1H), 7.14 (d, J=7.6 Hz, 1H), 6.75 (d, J=7.2 Hz, 1H), 6.71 (s, 1H), 4.50 (t, J=8.8 Hz, 2H), 3.38-3.36 (m, 1H), 3.35-3.33 (m, 4H), 3.13 (t, J=8.4 Hz, 2H), 2.42-2.38 (m, 4H), 2.07 (s, 3H), 1.27 (d, J=6.80 Hz, 3H). LCMS: (Method A) 374.2 (M+H), Rt. 2.31 min, 99.4% (Max). HPLC: (Method A) Rt 2.34 min, 99.7% (Max). CHIRAL HPLC: (SFC Method K) Rt. 2.81 min, 100% (Max).

(451) The second eluting compound corresponds to Example 109 (white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 12.05 (s, 1H), 7.14 (d, J=7.6 Hz, 1H), 6.75 (d, J=7.6 Hz, 1H), 6.70 (s, 1H), 4.49 (t, J=8.8 Hz, 2H), 3.37-3.36 (m, 1H), 3.32-3.31 (m, 4H), 3.13 (t, J=8.8 Hz, 2H), 2.41-2.38 (m, 4H), 2.08 (s, 3H), 1.27 (d, J=6.40 Hz, 3H). LCMS: (Method A) 374.2 (M+H), Rt. 2.31 min, 99.37% (Max). HPLC: (Method A) Rt 2.35 min, 99.59% (Max). CHIRAL HPLC: (SFC Method K) Rt. 3.45 min, 99.42% (Max).

Example 110: (N-((5-(4-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)-1,3,4-thiadiazol-2-yl)methyl)acetamide

(452) ##STR00444##

(453) The title compound was synthesized according to the procedure described for Example 112, starting from Example 124 (brown thick oil). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.70-8.59 (m, 1H), 7.15 (d, J=7.60 Hz, 1H), 6.75 (d, J=7.60 Hz, 1H), 6.71 (s, 1H), 4.50 (t, J=8.80 Hz, 2H), 4.37 (d, J=6.00 Hz, 2H), 3.39-3.36 (m, 5H), 3.17-3.11 (m, 2H), 2.42-2.38 (m, 4H), 1.83 (s, 3H), 1.27 (d, J=6.80 Hz, 3H). LCMS: (Method A) 388.3 (M+H), Rt. 2.07 min, 96.1% (Max). HPLC: (Method A) Rt 2.09 min, 95.8% (Max).

Example 112: N-((5-(4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-1,3,4-thiadiazol-2-yl)methyl)acetamide

(454) ##STR00445##

(455) To a stirred solution of Example 126 (150 mg, 0.42 mmol) in DCM (2 mL) at 0° C., pyridine (0.07 mL) followed by acetic anhydride (0.06 mL, 0.63 mmol) were added. The reaction mixture was stirred at rt overnight. It was quenched with water (3 mL) and extracted with DCM (2×5 mL). The combined organic layer was dried over anhydrous Na.sub.2SO.sub.4. After evaporation of the solvents, the crude product was purified by flash chromatography (eluent: 6-7% MeOH in DCM) affording the title product (yellow solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.93 (dd, J=6.8, 2.4 Hz, 2H), 8.64 (t, J=6.0 Hz, 1H), 8.08 (d, J=8.4 Hz, 1H), 8.00 (d, J=1.2 Hz, 1H), 7.91-7.89 (m, 1H), 4.37 (d, J=6.0 Hz, 2H), 3.80 (q, J=6.8 Hz, 1H), 3.40 (t, J=4.8 Hz, 4H), 2.62-2.58 (m, 4H), 1.83 (s, 3H), 1.42 (d, J=6.80 Hz, 3H). LCMS: (Method A) 398.3 (M+H), Rt. 1.55 min, 98.91% (Max). HPLC: (Method A) Rt 1.58 min, 98.72% (Max).

Example 113: (5-(4-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)-1,3,4-thiadiazol-2-yl)methanol

(456) SGN020621-01-00536-031N01:

(457) ##STR00446##

(458) To a stirred solution of Example 117 (0.21 g, 5.40 mmol) in methanol (4 mL), sodium borohydride (62 mg, 1.62 mmol) was added at 0° C. and the mixture was stirred at rt for 2 h. It was concentrated under vacuum. EtOAc (10 mL) was added and was washed with water (10 mL), brine (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 7.15 (d, J=7.6 Hz, 1H), 6.75 (d, J=7.6 Hz, 1H), 6.71 (s, 1H), 5.86 (t, J=5.6 Hz, 1H), 4.60 (d, J=6.0 Hz, 2H), 4.50 (t, J=8.4 Hz, 2H), 3.39-3.37 (m, 5H), 3.13 (t, J=8.8 Hz, 2H), 2.43-2.39 (m, 4H), 1.27 (d, J=6.8 Hz, 3H). LCMS: (Method A) 347.2 (M+H), Rt. 2.08 min, 96.5% (Max). HPLC: (Method A) Rt 2.04 min, 96.3% (Max).

Example 114: 1-(5-(4-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)-1,3,4-thiadiazol-2-yl)ethan-1-ol

(459) ##STR00447##

(460) The title compound was synthesized according to the procedure described for Example 115, starting from Example 113 (white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.14 (d, J=7.60 Hz, 1H), 6.75 (d, J=7.60 Hz, 1H), 6.70 (s, 1H), 6.00 (d, J=4.80 Hz, 1H), 4.86-4.83 (m, 1H), 4.49 (t, J=8.80 Hz, 2H), 3.38-3.35 (m, 5H), 3.12 (t, J=8.40 Hz, 2H), 2.41-2.38 (m, 4H), 1.39 (d, J=6.40 Hz, 3H), 1.27 (d, J=6.80 Hz, 3H). LCMS: (Method A) 361.2 (M+H), Rt. 2.20 min, 97.8% (Max). HPLC: (Method A) Rt 2.17 min, 98.5% (Max).

Example 115: 1-(5-(4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-1,3,4-thiadiazol-2-yl)ethan-1-ol

(461) ##STR00448##

Step 1: (5-(4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-1,3,4-thiadiazol-2-yl)methanol

(462) The title compound was obtained following the same procedure as described for Example 113, starting from Example 120. The crude product was purified by flash chromatography (eluent: 4-5% MeOH in DCM) affording the title compound (brown solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.95-8.96 (m, 2H), 8.10 (d, J=8.8 Hz, 1H), 8.01 (s, 1H), 7.91 (dd, J=8.8, 5.2 Hz, 1H), 5.88 (t, J=6.0 Hz, 1H), 4.61 (d, J=6.0 Hz, 2H), 3.82 (q, J=13.6 Hz, 1H), 3.43 (t, J=4.8 Hz, 4H), 2.65-2.60 (m, 2H), 2.60-2.51 (m, 2H), 1.44 (d, J=6.80 Hz, 3H). LCMS: (Method A) 357.2 (M+H), Rt. 1.48 min, 99.13% (Max).

Step 2: 5-(4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-1,3,4-thiadiazole-2-carbaldehyde

(463) To a stirred solution of (5-(4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-1,3,4-thiadiazol-2-yl)methanol (0.4 g, 1.12 mmol) in dry DCM (8 mL), Dess-Martin periodinane (571 mg, 1.34 mmol) was added at 0° C. and the resulting mixture was stirred at rt for 6 h. After completion of the reaction, the reaction mixture was quenched with saturated NaHCO.sub.3 solution (10 mL) and extracted with DCM (3×10 mL). The combined organic layer was dried over Na.sub.2SO.sub.4 and concentrated. The resulting crude product was purified by flash chromatography (3-4% MeOH in DCM), affording the title compound. Yield: 93% (350 mg, brown solid). LCMS: (Method A) 355.0 (M+H), Rt. 4.44 min, 89% (Max).

Step 3: 1-(5-(4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-1,3,4-thiadiazol-2-yl)ethan-1-ol

(464) To a stirred solution of 5-(4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-1,3,4-thiadiazole-2-carbaldehyde (100 mg, 1.55 mmol) in dry THF (12 mL) cooled down to −10° C., methyl magnesium chloride (3M in Et.sub.2O, 0.5 mL, 1.41 mmol) was added and the mixture was stirred at rt for 3 h. After completion of the reaction, the reaction mixture was quenched with water (2 mL) and concentrated under vacuum. The crude product was dissolved in DCM (10 mL), washed with saturated NH.sub.4Cl solution (4 mL) and dried over Na.sub.2SO.sub.4. After evaporation of the solvent, the crude product was purified by flash chromatography (eluent: 5-6% MeOH in DCM), affording the title compound (brown solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.94-8.93 (m, 2H), 8.09 (d, J=8.8 Hz, 1H), 8.01 (s, 1H), 7.91 (d, J=8.8 Hz, 1H), 6.02 (d, J=4.8 Hz, 1H), 4.86 (t, J=5.2 Hz, 1H), 3.81 (t, J=6.4 Hz, 1H), 3.42 (s, 4H), 2.68-2.58 (m, 2H), 2.49-2.43 (m, 2H), 1.45-1.40 (m, 6H). LCMS: (Method A) 371.0 (M+H), Rt. 1.71 min, 96.06% (Max). HPLC: (Method A) Rt 1.68 min, 97.89% (Max).

Example 116: 2-methyl-5-(4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-1,3,4-thiadiazolequinoxaline

(465) ##STR00449##

(466) To a stirred solution of Intermediate 2 (0.1 g, 0.4 mmol) in dry DMF (5 mL), TEA (0.15 mL, 1.03 mmol) and 2-chloro-5-methyl-1,3,4-thiadiazole (0.066 g, 0.4 mmol) was added at rt and the reaction mixture was stirred at 90° C. overnight. The resulting reaction mixture was cooled to rt and DMF was evaporated under reduced pressure. To the resulting crude mixture, EtOAc (60 mL) was added and washed with water. The organic layer was dried over Na.sub.2SO.sub.4 and concentrated. The crude product was purified by flash chromatography to afford the title compound (pale brown solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.94 (dd, J=6.9, 2.0 Hz, 2H), 8.09 (d, J=8.8 Hz, 1H), 8.01 (s, 1H), 7.91 (d, J=8.8 Hz, 1H), 3.82 (q, J=6.4 Hz, 1H), 3.41-3.40 (m, 4H), 2.62-2.60 (m, 4H), 2.51 (s, 3H), 1.44 (d, J=6.8 Hz, 3H). LCMS: (Method A) 341.2 (M+H), Rt. 1.69 min, 99.6% (Max). HPLC: (Method A) Rt 1.74 min, 98.6% (Max).

Example 117: Ethyl 5-(4-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)-1,3,4-thiadiazole-2-carboxylate

(467) ##STR00450##

(468) To a stirred solution of ethyl 5-chloro-1,3,4-thiadiazole-2-carboxylate (0.25 g, 1.29 mmol) in dry DMF (2.5 mL), K.sub.2CO.sub.3 (0.54 g, 3.89 mmol) and Intermediate 13 (0.59 g, 1.93 mmol) were added at rt. The reaction mixture was stirred overnight at 80° C. It was then concentrated under vacuum. EtOAc (10 mL) was added and the resulting solution was washed with water (10 mL), brine (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. Yield: 51% (0.26 g, off white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.15 (d, J=7.60 Hz, 1H), 6.75 (d, J=7.60 Hz, 1H), 6.71 (s, 1H), 4.50 (t, J=8.80 Hz, 2H), 4.33 (q, J=6.80 Hz, 2H), 3.54 (t, J=5.20 Hz, 4H), 3.43-3.41 (m, 1H), 3.13 (t, J=8.40 Hz, 2H), 2.45-2.32 (m, 4H), 1.31-1.27 (m, 6H). LCMS: (Method A) 389.2 (M+H), Rt. 2.88 min, 95.7% (Max). HPLC: (Method A) Rt 2.81 min, 96.5% (Max).

Example 118: 5-(4-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)-N-methyl-1,3,4-thiadiazole-2-carboxamide

(469) ##STR00451##

(470) The title compound was synthesized according to the procedure described for Example 121, starting from Example 117 (brown thick oil). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.74 (q, J=4.8 Hz, 1H), 7.16 (d, J=7.2 Hz, 1H), 6.76 (d, J=1.2 Hz, 1H), 6.72 (s, 1H), 4.51 (t, J=8.40 Hz, 2H), 3.49 (t, J=4.80 Hz, 4H), 3.43-3.41 (m, 1H), 3.14 (t, J=8.80 Hz, 2H), 2.75 (d, J=4.8 Hz, 3H), 2.53-2.51 (m, 2H), 2.46-2.42 (m, 2H), 1.28 (d, J=6.8 Hz, 3H). LCMS: (Method A) 374.0 (M+H), Rt. 2.35 min, 96.4% (Max).

(471) HPLC: (Method A) Rt 2.30 min, 98.2% (Max).

Example 119: 5-(4-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)-N,N-dimethyl-1,3,4-thiadiazole-2-carboxamide

(472) ##STR00452##

(473) The title compound was synthesized according to the procedure described for Example 122, starting from Example 117 (pale yellow solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.15 (d, J=8.0 Hz, 1H), 6.75 (d, J=8.0 Hz, 1H), 6.71 (s, 1H), 4.50 (t, J=8.4 Hz, 2H), 3.48 (t, J=4.80 Hz, 4H), 3.39-3.98 (m, 4H), 3.13 (t, J=9.20 Hz, 2H), 2.99 (s, 3H), 2.63-2.58 (m, 2H), 2.42-2.41 (m, 2H), 1.27 (d, J=6.80 Hz, 3H). LCMS: (Method A) 388.0 (M+H), Rt. 2.53 min, 99.3% (Max). HPLC: (Method A) Rt 2.48 min, 98.9% (Max).

Example 120: Ethyl 5-(4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-1,3,4-thiadiazole-2-carboxylate

(474) ##STR00453##

(475) To a stirred solution of Intermediate 2 (2.62 g, 9.40 mmol) in dry DMF (25 mL), TEA (2.8 mL, 20.15 mmol) and ethyl 5-chloro-1,3,4-thiadiazole-2-carboxylate (1.2 g, 6.71 mmol) were added at 0° C. The reaction mixture was stirred at 100° C. overnight. The reaction mixture was concentrated under vacuum. The resulting crude mixture was dissolved in DCM (35 mL), washed with water (20 mL) and dried over Na.sub.2SO.sub.4. After evaporation of the solvent, the resulting product was triturated in Et.sub.2O (2×4 mL), affording the title compound. Yield: 50% (1.3 g, off white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.93 (d, J=6.0 Hz, 2H), 8.09 (d, J=8.8 Hz, 1H), 8.01 (s, 1H), 7.91 (d, J=8.8 Hz, 1H), 4.33 (q, J=7.2 Hz, 2H), 3.85 (t, J=6.0 Hz, 1H), 3.58 (s, 4H), 2.70-2.58 (m, 2H), 2.58-2.50 (m, 2H), 1.44 (d, J=6.4 Hz, 3H), 1.29 (t, J=6.80 Hz, 3H). LCMS: (Method A) 399.2 (M+H), Rt. 2.22 min, 96.96% (Max). HPLC: (Method A) Rt 2.27 min, 96.97% (Max).

Example 121: N-methyl-5-(4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-1,3,4-thiadiazole-2-carboxamide

(476) ##STR00454##

(477) To a solution of Example 120 (0.22 g, 0.55 mmol) and methyl amine (2M in THF, 0.94 mL, 1.83 mmol) in dry toluene (3 mL), bis-trimethyl aluminium 1,4 diazabicylco [2,2,2,] octane adduct (241 mg, 0.94 mmol) was added at 0° C. and the resulting mixture was heated at 100° C. overnight in a sealed tube. After completion of the reaction, solvents are evaporated. Water was added and was extracted with EtOAc (2×8 mL). The combined organic layer was dried over Na2SO4 and concentrated. The resulting residue was purified by MD Autoprep HPLC (Method ?), affording the title compound (off white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.95 (dd, J=7.2, 2.6 Hz, 2H), 8.74 (d, J=4.8 Hz, 1H), 8.10 (d, J=8.8 Hz, 1H), 8.01 (s, 1H), 7.91 (dd, J=8.4, 5.2 Hz, 1H), 3.84 (q, J=13.2 Hz, 1H), 3.53 (t, J=4.8 Hz, 4H), 2.75 (d, J=4.4 Hz, 3H), 2.68-2.61 (m, 2H), 2.57-2.51 (m, 2H), 1.44 (d, J=6.40 Hz, 3H). LCMS: (Method A) 384.2 (M+H), Rt. 1.74 min, 99.16% (Max). HPLC: (Method A) Rt 1.77 min, 99.41% (Max).

Example 122: N,N-dimethyl-5-(4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-1,3,4-thiadiazole-2 carboxamide

(478) ##STR00455##

(479) Example 122 was synthesized according to the protocol described for Example 121, replacing the methyl amine solution with a dimethyl amine solution in THF (2M, 3 mL, 6.27 mmol). The crude product was purified by flash chromatography (eluent: 3-4% MeOH in DCM), affording the title compound (off white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.94 (d, J=5.2 Hz, 2H), 8.10 (d, J=8.8 Hz, 1H), 8.01 (s, 1H), 7.93-7.83 (m, 1H), 3.93-3.76 (m, 1H), 3.54 (t, J=4.8 Hz, 4H), 3.42 (s, 3H), 3.00 (s, 3H), 2.65-2.61 (m, 4H), 1.45 (d, J=6.8 Hz, 3H). LCMS: (Method A) 398.0 (M+H), Rt. 1.99 min, 96.23% (Max). HPLC: (Method A) Rt 1.95 min, 96.55% (Max).

Example 123: 1-(5-(4-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)-1,3,4-thiadiazol-2-yl)-N,N-dimethylmethanamine

(480) ##STR00456##

Step 1: (5-(4-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)-1,3,4-thiadiazol-2-yl)methyl methanesulfonate

(481) To a solution of Example 113 (0.1 g, 0.29 mmol) in dry DCM (2 mL), DIPEA (0.15 mL, 0.86 mmol) and methanesulphonyl chloride (0.027 mL, 0.34 mmol) were added at 0° C. and the reaction mixture was stirred at rt for 2 h. Upon completion of reaction, 10% solution of NaHCO.sub.3 (2 mL) was added and the mixture was stirred for 5 minutes. Two layers were separated and the organic layer was washed with brine (2 mL) and dried over Na.sub.2SO.sub.4. The evaporation of the solvent afforded the title compound that was used directly in the following step. Yield: 85% (0.12 g, brown thick oil). LCMS: (Method A) 365.0 (M+H), Rt. 2.66 min, 87.5% (Max).

Step 2: 1-(5-(4-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)-1,3,4-thiadiazol-2-yl)-N,N-dimethylmethanamine

(482) To a stirred solution of (5-(4-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)-1,3,4-thiadiazol-2-yl)methyl methanesulfonate (0.1 g, 0.24 mmol) in dry THF (1 mL), N,N-dimethylamine solution (2M in THF, 0.12 mL, 1.22 mmol) was added at rt and the reaction mixture was heated to 80° C. for 6 h in sealed tube. The reaction mixture was cooled to rt and concentrated under vacuum. The resulting residue was dissolved in DCM (5 ml) and washed with brine (5 mL) and dried over anhydrous Na.sub.2SO.sub.4. After evaporation, the crude product was purified by flash chromatography to get the title compound (brown thick oil). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.16 (d, J=7.60 Hz, 1H), 6.76 (d, J=7.60 Hz, 1H), 6.72 (s, 1H), 4.51 (t, J=8.40 Hz, 2H), 3.62 (s, 2H), 3.45-3.36 (m, 5H), 3.14 (t, J=8.40 Hz, 2H), 2.61-2.56 (m, 2H), 2.47-2.39 (m, 2H), 2.20 (s, 6H), 1.28 (d, J=6.80 Hz, 3H). LCMS: (Method A) 374.2 (M+H), Rt. 1.86 min, 97.0% (Max). HPLC: (Method A) Rt 1.89 min, 97.2% (Max).

Example 124: (5-(4-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)-1,3,4-thiadiazol-2-yl)methanamine

(483) ##STR00457##

(484) The title compound was synthesized according to the procedure described for Example 123, starting from Example 113, replacing N,N-dimethylamine solution with NaN.sub.3 in DMF. The resulting azidomethyl analogue was reduced with Pd/C (10% wt/wt) under H.sub.2 atmosphere (yellow solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.14 (d, J=7.60 Hz, 1H), 6.75 (d, J=7.60 Hz, 1H), 6.70 (s, 1H), 4.49 (t, J=8.80 Hz, 2H), 3.86 (s, 2H), 3.41-3.34 (m, 5H), 3.13 (t, J=8.40 Hz, 2H), 2.42-2.37 (m, 4H), 1.27 (d, J=6.40 Hz, 3H). LCMS: (Method A) 346.3 (M+H), Rt. 1.84 min, 97.7% (Max). HPLC: (Method A) Rt 1.82 min, 97.9% (Max).

Example 125: N,N-dimethyl-1-(5-(4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-1,3,4-thiadiazol-2-yl)methanamine

(485) ##STR00458##

(486) The title compound was synthesized according to the procedure described for Example 123, starting from Example 115, step 1 product (37 mg, brown solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.95 (dd, J=6.8, 2.6 Hz, 2H), 8.10 (dd, J=8.4, Hz, 1H), 8.01 (s, 1H), 7.91 (dd, J=8.8, 5.2 Hz, 1H), 3.88-3.72 (m, 1H), 3.62 (s, 2H), 3.42 (t, J=4.8 Hz, 5H), 2.63-2.61 (m, 3H), 2.19 (s, 6H), 1.44 (d, J=6.8 Hz, 3H). LCMS: (Method A) 384.0 (M+H), Rt. 1.44 min, 96.27% (Max). HPLC: (Method A) Rt 1.43 min, 98.70% (Max).

Example 126: (5-(4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-1,3,4-thiadiazol-2-yl)methanamine

(487) ##STR00459##

(488) The title compound was synthesized according to the procedure described for Example 123, starting from Example 115, step 1 product, replacing N,N-dimethylamine solution with NaN.sub.3 in DMF. The resulting azidomethyl analogue was reduced with Pd/C (10% wt/wt) under H.sub.2 atmosphere. Yield: 83% (190 mg, off white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.93 (d, J=5.2 Hz, 2H), 8.08 (d, J=8.8 Hz, 1H), 8.00 (s, 1H), 7.90 (d, J=8.2 Hz, 1H), 3.89-3.72 (m, 3H), 3.39 (t, J=4.8 Hz, 4H), 2.65-2.52 (m, 4H), 1.43 (d, J=6.4 Hz, 3H). LCMS: (Method A) 356.3 (M+H), Rt. 1.35 min, 97.28% (Max). HPLC: (Method A) Rt 1.37 min, 97.78% (Max).

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

(490) TABLE-US-00002 TABLE 2 Config- uration specifi- Ex Structure cation 1H NMR 288 0 Racemic .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.90 (d, J = 7.6 Hz, 1H), 7.16 (d, J = 7.6 Hz, 1H), 6.87 (s, 1H), 6.79-6.73 (m, 2H), 6.59 (d, J = 8.0 Hz, 1H), 6.50 (s, 1H), 4.51 (t, J = 8.4 Hz, 2H), 3.40-3.30 (m, 4H), 3.15 (t, J = 8.4 Hz, 2H), 3.15-2.99 (m, 4H), 2.52 (s, 3H), 2.52-2.49 (m, 4H), 1.29 (d, J = 6.40 Hz, 3H). 289 Racemic .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 12.26 (s, 1H), 8.51 (s, 1H), 8.06 (s, 1H), 7.15 (d, J = 7.6 Hz, 1H), 6.77 (d, J = 8.4 Hz, 1H), 6.76-6.68 (m, 2H), 4.50 (t, J = 8.4 Hz, 2H), 3.37-3.32 (m, 5H), 3.13 (t, J = 8.4 Hz, 2H), 2.43- 2.39 (m, 4H), 1.29-1.28 (m, 3H). 290 Racemic .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.04 (d, J = 1.2 Hz, 1H), 8.38 (s, 1H), 8.28 (s, 1H), 7.17 (d, J = 7.6 Hz, 1H), 6.79 (d, J = 7.2 Hz, 1H), 6.75 (s, 1H), 4.54-4.49 (m, 2H), 4.40-4.35 (m, 2H), 3.39-3.29 (m, 5H), 3.15 (t, J = 8.4 Hz, 2H), 2.61-2.60 (m, 2H), 2.58-2.48 (m, 2H), 1.37-1.30 (m, 6H). 291 Racemic .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.21 (s, 1H), 7.14 (d, J = 7.2 Hz, 1H), 7.25 (d, J = 7.6 Hz, 1H), 6.71 (s, 1H), 4.50 (t, J = 8.8 Hz, 2H), 3.97 (s, 2H), 3.87 (s, 2H), 3.75-3.60 (m, 4H), 3.29-3.27 (m, 1H), 3.13 (t, J = 8.8 Hz, 2H), 2.44-2.40 (m, 2H), 2.36-2.33 (m, 2H), 1.27 (d, J = 6.40 Hz, 3H). 292 Chiral HPLC SFC Method D: 1st eluting com- pound .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.68 (s, 2H), 7.15 (d, J = 8.2 Hz, 1H), 6.77-6.73 (m, 2H), 4.50 (t, J = 8.8 Hz, 2H), 3.85-3.83 (m, 4H), 3.40-3.37 (m, 1H), 3.21 (s, 3H), 3.13 (t, J = 8.7 Hz, 2H), 2.40-2.33 (m, 4H), 1.28 (d, J = 6.8 Hz, 3H). 293 Chiral HPLC SFC Method D: 2nd eluting com- pound .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.68 (s, 2H), 7.15 (d, J = 8.2 Hz, 1H), 6.77-6.73 (m, 2H), 4.50 (t, J = 8.8 Hz, 2H), 3.85-3.83 (m, 4H), 3.40-3.37 (m, 1H), 3.21 (s, 3H), 3.13 (t, J = 8.7 Hz, 2H), 2.40-2.33 (m, 4H), 1.28 (d, J = 6.8 Hz, 3H). 294 Racemic .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.05-9.04 (m, 1H), 8.68 (s, 2H), 8.43- 8.41 (m, 2H), 7.80 (d, J = 8.4 Hz, 1H), 7.63-7.60 (m, 1H), 3.92-3.88 (m, 5H), 3.20 (s, 3H), 2.65-2.50 (m, 4H), 1.44 (d, J = 6.8 Hz, 3H) 295 Racemic .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.38 (s, 1H), 8.67 (s, 2H), 8.12 (d, J = 8.4 Hz, 1H), 8.02 (s, 1H), 7.50 (dd, J = 8.2, 1.2 Hz, 1H), 3.87-3.85 (m, 4H), 3.68 (d, J = 6.8 Hz, 1H), 3.20 (s, 3H), 2.56-2.33 (m, 4H), 1.40 (d, J = 6.8 Hz, 3H). 296 Racemic .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.94 (s, 1H), 8.70 (s, 1H), 8.56 (d, J = 4.4 Hz, 1H), 8.29 (s, 1H), 7.16 (d, J = 7.2 Hz, 1H), 6.79 (d, J = 7.6 Hz, 1H), 6.74 (s, 1H), 4.51 (t, J = 8.8 Hz, 2H), 3.38-3.37 (m, 1H), 3.31-3.30 (m, 4H), 3.14 (t, J = 8.80 Hz, 2H), 2.81 (d, J = 4.40 Hz, 3H), 2.59-2.56 (m, 2H), 2.51-2.50 (m, 2H), 1.30 (d, J = 6.40 Hz, 3H). 297 Chiral HPLC SFC Method A: 1st eluting com- pound .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.83 (dd, J = 9.6, 1.6 Hz, 1H), 7.38 (d, J = 9.6 Hz, 1H), 7.16 (d, J = 7.20 Hz, 1H), 6.75 (d, J = 8.0 Hz, 1H), 6.78 (s, 1H), 4.51 (t, J = 8.80 Hz, 2H), 3.74-3.72 (m, 4H), 3.41-3.38 (m, 1H), 3.30 (s, 3H), 3.14 (t, J = 8.80 Hz, 2H), 2.45-2.41 (m, 4H), 1.30 (d, J = 6.80 Hz, 3H). 298 0 Chiral HPLC SFC Method A: 2nd eluting com- pound .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.84 (dd, J = 9.6, 1.6 Hz, 1H), 7.38 (d, J = 9.6 Hz, 1H), 7.16 (d, J = 7.2 Hz, 1H), 6.75 (d, J = 8.0 Hz, 1H), 6.73 (s, 1H), 4.51 (t, J = 8.8 Hz, 2H), 3.72-3.69 (m, 4H), 3.51-3.47 (m, 1H), 3.30 (s, 3H), 3.14 (t, J = 8.8 Hz, 2H), 2.45-2.41 (m, 4H), 1.310 (d, J = 6.8 Hz, 3H). 299 Racemic .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.80 (s, 1H), 7.61 (d, J = 5.2 Hz, 2H), 7.18-7.16 (m, 1H), 6.79 (d, J = 7.6 Hz, 1H), 6.75 (s, 1H), 5.46-5.44 (m, 1H), 5.12 (t, J = 6.4 Hz, 1H), 4.54-4.51 (m, 2H), 3.39-3.37 (m, 1H), 3.35- 3.20 (m, 4H), 3.15 (t, J = 8.40 Hz, 2H), 2.59-2.56 (m, 4H), 1.58 (d, J = 6.40 Hz, 3H), 1.30 (d, J = 6.80 Hz, 3H). 300 Racemic .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.92 (s, 1H), 8.44 (d, J = 1.6 Hz, 1H), 7.84 (s, 1H), 7.16 (d, J = 7.6 Hz, 1H), 6.78 (d, J = 7.6 Hz, 1H), 6.73 (s, 1H), 4.51 (t, J = 8.0 Hz, 2H), 4.32-4.30 (m, 2H), 3.38-3.32 (m, 1H), 3.26 (br s, 4H), 3.17-3.12 (m, 2H), 2.57-2.55 (m, 2H), 2.46-2.32 (m, 2H), 1.33-1.23 (m, 6H). 301 Racemic .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.68 (s, 2H), 7.16 (d, J = 7.6 Hz, 1H), 6.76 (d, J = 7.6 Hz, 1H), 6.73 (s, 1H), 4.51 (t, J = 8.8 Hz, 2H), 3.85-3.84 (m, 4H), 3.38-3.35 (m, 1H), 3.21 (s, 3H), 3.14 (t, J = 8.8 Hz, 2H), 2.39- 2.35 (m, 4H), 1.29 (d, J = 6.80 Hz, 3H). 302 Chiral HPLC SFC Method B: 1st eluting com- pound .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.27 (s, 2H), 8.05 (s, 1H), 7.15 (d, J = 5.6 Hz, 1H), 6.77 (d, J = 6.8 Hz, 1H), 6.73 (s, 1H), 4.51 (t, J = 8.4 Hz, 2H), 3.65 (s, 4H), 3.17-3.11 (m, 2H), 2.50-2.42 (m, 2H), 2.35-2.33 (m, 2H), 1.79 (s, 3H), 1.49 (s, 6H), 1.28 (d, J = 6.40 Hz, 3H). 303 Chiral HPLC SFC Method B: 2nd eluting com- pound .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.27 (s, 2H), 8.02 (s, 1H), 7.15 (d, J = 7.2 Hz, 1H), 6.78-6.73 (m, 2H), 4.51 (t, J = 8.8 Hz, 2H), 3.82-3.52 (m, 4H), 3.16-3.14 (m, 2H), 2.49-2.29 (m, 4H), 1.80 (d, J = 4.0 Hz, 3H), 1.50 (s, 6H), 1.28 (d, J = 5.60 Hz, 3H). 304 Racemic .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.57 (s, 2H), 7.14 (d, J = 7.6 Hz, 1H), 6.75 (d, J = 7.6 Hz, 1H), 6.71 (s, 1H), 4.50 (t, J = 8.4 Hz, 2H), 3.74 (t, J = 7.2 Hz, 2H), 3.66 (t, J = 4.8 Hz, 4H), 3.35-3.32 (m, 1H), 3.13 (t, J = 8.8 Hz, 2H), 2.46-2.42 (m, 4H), 2.40-2.33 (m, 2H), 2.06 (t, J = 7.6 Hz, 2H), 1.27 (d, J = 6.4 Hz, 3H). 305 Racemic .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.39 (s, 1H), 8.13 (s, 1H), 8.09 (d, J = 6.4 Hz, 1H), 8.01 (s, 1H), 7.49 (d, J = 10.8 Hz, 1H), 3.83 (s, 2H), 3.68- 3.66 (m, 5H), 3.11 (t, J = 7.2 Hz, 2H), 2.65-2.63 (m, 2H), 2.39-2.37 (m, 4H), 1.40 (d, J = 8.80 Hz, 3H). 306 Chiral HPLC Method D: 1st eluting com- pound .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.02 (s, 1H), 7.14 (d, J = 7.2 Hz, 1H), 6.75 (dd, J = 7.6, 1.2 Hz, 1H), 6.71 (s, 1H), 4.50 (t, J = 8.8 Hz, 2H), 3.67- 3.65 (m, 5H), 3.18-3.17 (m, 2H), 2.95 (t, J = 6.0 Hz, 2H), 2.56-2.54 (m, 2H), 2.51-2.48 (m, 4H), 2.33-2.32 (m, 2H), 1.27 (d, J = 6.8 Hz, 3H). 307 Chiral HPLC Method D: 2nd eluting com- pound .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.01 (s, 1H), 7.14 (d, J = 7.6 Hz, 1H), 6.75 (dd, J = 7.6, 1.2 Hz, 1H), 6.71 (s, 1H), 4.50 (t, J = 8.8 Hz, 2H), 3.66- 3.64 (m, 5H), 3.13 (t, J = 8.8 Hz, 2H), 2.94 (t, J = 6.0 Hz, 2H), 2.55-2.54 (m, 2H), 2.42-2.40 (m, 4H), 2.35-2.33 (m, 2H), 1.27 (d, J = 6.4 Hz, 3H). 308 0 Chiral HPLC SFC Method C: 1st eluting com- pound .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.39 (s, 1H), 8.72 (s, 2H), 8.39-8.22 (m, 1H), 8.13 (d, J = 8.4 Hz, 1H), 8.03 (s, 1H), 7.51 (d, J = 8.0 Hz, 1H), 3.85-3.76 (m, 4H), 3.72-3.63 (m, 1H), 2.75 (d, J = 3.6 Hz, 3H), 2.51-2.36 (m, 4H), 1.41 (d, J = 6.4 Hz, 3H). 309 Chiral HPLC SFC Method C: 2nd eluting com- pound .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.39 (s, 1H), 8.71 (s, 2H), 8.38-8.22 (m, 1H), 8.12 (d, J = 8.4 Hz, 1H), 8.03 (s, 1H), 7.51 (d, J = 7.2 Hz, 1H), 3.82-3.79 (m, 4H), 3.72-3.62 (m, 1H), 2.74 (d, J = 4.4 Hz, 3H), 2.51-2.37 (m, 4H), 1.41 (d, J = 6.4 Hz, 3H). 310 Racemic .sup.1H NMR (400 MHz, CDCl.sub.3): δ 9.13-9.12 (m, 1H), 8.22-8.18 (m, 2H), 7.82 (d, J = 8.4 Hz, 1H), 7.52-7.49 (m, 1H), 7.20 (s, 1H), 6.93 (s, 1H), 4.01- 3.96 (m, 1H), 3.84 (s, 3H), 3.05-2.87 (m, 4H), 2.87-2.75 (m, 2H), 2.69- 2.59 (m, 2H), 1.56 (d, J = 6.8 Hz, 3H). 311 Racemic .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.39 (s, 1H), 8.13 (d, J = 8.4 Hz, 1H), 8.03 (s, 1H), 7.50 (d, J = 8.4 Hz, 1H), 7.31 (s, 1H), 3.74-3.72 (m, 1H), 3.49-3.48 (m, 4H), 3.36 (t, J = 6.8 Hz, 2H), 2.69 (t, J = 6.8 Hz, 2H), 2.59- 2.58 (m, 2H), 2.46-2.44 (m, 2H), 1.41 (d, J = 6.40 Hz, 3H). 312 Racemic .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.05 (s, 1H), 7.14 (d, J = 7.6 Hz, 1H), 6.75 (d, J = 7.6 Hz, 1H), 6.71 (s, 1H), 4.53-4.47 (m, 4H), 3.88 (t, J = 5.6 Hz, 2H), 3.65 (t, J = 9.2 Hz, 4H), 3.17-3.11 (m, 3H), 2.67-2.63 (m, 2H), 2.42-2.39 (m, 2H), 1.23-1.23 (m, 3H). 313 Chiral HPLC Method R: 2nd eluting com- pound .sup.1H NMR: (400 MHz, DMSO-d.sub.6): δ 11.71 (s, 1H), 7.15 (d, J = 7.2 Hz, 1H), 6.75 (d, J = 7.6 Hz, 1H), 6.70 (s, 1H), 4.51 (t, J = 8.4 Hz, 2H), 3.45-3.30 (m, 1H), 3.17-3.12 (m, 6H), 2.47-2.34 (m, 4H), 1.26 (d, J = 6.8 Hz, 3H), 314 Racemic .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.39 (d, J = 6.8 Hz, 1H), 8.58 (d, J = 6.8 Hz, 1H), 8.12 (d, J = 10.8 Hz, 1H), 8.03 (s, 1H), 7.80-7.65 (m, 1H), 7.51- 7.49 (m, 1H), 3.90-3.78 (m, 4H), 3.73-3.63 (m, 1H), 3.40-3.35 (m, 2H), 2.80-2.73 (m, 2H), 2.30-2.13 (m, 4H), 1.41 (d, J = 8.80 Hz, 3H). 315 Racemic .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.05 (s, 1H), 8.58 (s, 1H), 8.45 (d, J = 8.0 Hz, 2H), 7.81 (d, J = 8.4 Hz, 1H), 7.69 (s, 1H), 7.67-7.52 (m, 1H), 3.99-3.73 (m, 1H), 3.43-3.36 (m, 6H), 2.80-2.77 (m, 2H), 2.67-2.57 (m, 2H), 2.44-2.38 (m, 2H), 1.45 (d, J = 5.6 Hz, 3H). 316 Racemic .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.39 (s, 1H), 8.18 (s, 1H), 8.13 (d, J = 2.4 Hz, 1H), 8.02 (s, 1H), 7.50 (d, J = 8.4 Hz, 1H), 4.48-4.43 (m, 2H), 4.12-4.12 (m, 1H), 3.69-3.68 (m, 6H), 3.19-3.18 (m, 2H), 2.73-2.72 (m, 1H), 2.68-2.67 (m, 1H), 2.45-2.34 (m, 2H), 2.08 (s, 3H), 1.40 (d, J = 4.40 Hz, 3H). 317 Racemic .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.39 (s, 1H), 8.12 (d, J = 8.4 Hz, 1H), 8.05 (s, 1H), 8.02 (s, 1H), 7.50 (d, J = 8.4 Hz, 1H), 4.49 (br s, 1H), 3.67- 3.63 (m, 5H), 3.58-3.56 (m, 2H), 3.44-3.44 (m, 2H), 2.72-2.67 (m, 4H), 2.51-2.51 (m, 2H), 2.39-2.37 (m, 4H), 1.40 (d, J = 6.40 Hz, 3H). 318 0 Racemic .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.39 (s, 1H), 8.12 (d, J = 8.4 Hz, 1H), 8.04-8.02 (m, 2H), 7.50 (d, J = 8.4 Hz, 1H), 3.67-3.64 (m, 5H), 3.31 (s, 2H), 2.68-2.66 (m, 2H), 2.59-2.58 (m, 2H), 2.38-2.32 (m, 4H), 2.32 (s, 3H), 1.40 (d, J = 6.8 Hz, 3H). 319 Racemic .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.05 (d, J = 3.2 Hz, 1H), 8.44 (d, J = 8.0 Hz, 2H), 8.32 (s, 1H), 7.80 (d, J = 8.4 Hz, 1H), 7.63-7.61 (m, 1H), 4.43 (s, 2H), 4.38 (s, 2H), 3.88 (d, J = 6.4 Hz, 1H), 3.80-3.70 (m, 4H), 2.69-2.45 (m, 4H), 1.44 (d, J = 6.40 Hz, 3H). 320 Racemic .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.31 (s, 1H), 7.14 (d, J = 7.2 Hz, 1H), 6.75 (d, J = 7.2 Hz, 1H), 6.71 (s, 1H), 4.50 (t, J = 8.4 Hz, 2H), 4.43 (s, 2H), 4.38 (s, 2H), 3.60-3.72 (m, 4H), 3.17-3.10 (m, 3H), 2.45-2.33 (m, 4H), 1.27 (d, J = 6.8 Hz, 3H). 321 Racemic .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.83 (s, 1H), 9.06-9.04 (m, 1H), 8.50- 8.41 (m, 4H), 7.81 (d, J = 8.8 Hz, 1H), 7.68-7.56 (m, 1H), 3.91-3.85 (m, 1H), 3.75-3.62 (m, 4H), 2.62-2.58 (m, 2H), 2.47-2.43 (m, 2H), 2.01 (s, 3H), 1.23 (d, J = 10.8 Hz, 3H). 322 Racemic .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.22-9.20 (m, 1H), 8.01-7.99 (m, 2H), 7.15 (d, J = 7.6 Hz, 1H), 6.77 (d, J = 7.6 Hz, 1H), 6.72 (s, 1H), 4.51 (t, J = 8.4 Hz, 2H), 3.60-3.45 (m, 4H), 3.31-3.28 (m, 1H), 3.14 (t, J = 8.4 Hz, 2H), 2.51-2.42 (m, 2H), 2.38-2.30 (m, 2H), 1.28 (d, J = 6.4 Hz, 3H). 323 Racemic .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.18 (s, 2H), 7.14 (d, J = 7.6 Hz, 1H), 6.75 (d, J = 7.6 Hz, 1H), 6.71 (s, 1H), 4.86 (t, J = 5.6 Hz, 1H), 4.51-4.49 (m, 2H), 3.98-3.93 (m, 2H), 3.69-3.62 (m, 2H), 3.61-3.53 (m, 4H), 3.17- 3.11 (m, 2H), 2.46-2.39 (m, 2H), 2.38-2.30 (m, 2H), 1.27 (d, J = 6.8 Hz, 3H). 324 Racemic .sup.1H NMR: (400 MHz, DMSO-d.sub.6): δ 11.73 (s, 1H), 9.04 (d, J = 2.8 Hz, 1H), 8.44 (d, J = 8.4 Hz, 2H), 7.76 (d, J = 8.4 Hz, 1H), 7.61 (t, J = 3.6 Hz, 1H), 3.91-3.89 (m, 1H), 3.19-3.16 (m, 4H), 2.62-2.60 (m, 2H), 2.50-2.46 (m, 2H), 1.43 (d, J = 6.4 Hz, 3H). 325 Racemic .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 11.71 (s, 1H), 9.04 (d, J = 8.4 Hz, 1H), 8.47-8.47 (m, 2H), 8.01 (s, 1H), 7.48 (d, J = 8.4 Hz, 1H), 3.69 (q, J = 6.4 Hz, 1H), 3.24-3.12 (m, 4H), 2.68-2.64 (m, 2H), 2.43-2.40 (m, 2H), 1.39 (d, J = 6.8 Hz, 3H). 326 Racemic .sup.1H NMR (400 MHz, DMSO-d.sub.6) : δ 9.39 (s, 1H), 8.12 (d, J = 8.0 Hz, 1H), 8.06 (s, 1H), 8.02 (s, 1H), 7.50 (d, J = 8.0 Hz, 1H), 4.54 (s, 2H), 3.89 (t, J = 5.6 Hz, 2H), 3.70-3.60 (m, 5H), 2.71-2.60 (m, 2H), 2.50-2.30 (m, 4H), 1.41 (d, J = 6.8 Hz, 3H). 327 Racemic .sup.1H NMR (400 MHz, DMSO-d.sub.6) : δ 9.39 (s, 1H), 8.59-8.57 (m, 2H), 8.12 (d, J = 8.0 Hz, 1H), 8.03 (s, 1H), 7.51 (d, J = 8.4 Hz, 1H), 3.79-3.52 (m, 7H), 2.45-2.36 (m, 6H), 2.07 (t, J = 7.6 Hz, 2H), 1.41 (d, J = 6.4 Hz, 3H). 328 00 Racemic .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.39 (s, 1H), 8.72 (s, 2H), 8.30 (t, J = 5.2 Hz, 1H), 8.12 (d, J = 8.4 Hz, 1H), 8.03 (s, 1H), 7.50 (d, J = 8.4 Hz, 1H), 3.82-3.78 (m, 4H), 3.67-3.63 (m, 1H), 3.28-3.21 (m, 4H), 2.46-2.36 (m, 2H), 1.41 (d, J = 6.8 Hz, 3H), 1.10 (t, J = 7.2 Hz, 3H). 329 01 Racemic .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.46 (s, 2H), 7.15 (d, J = 7.6 Hz, 1H), 6.75 (d, J = 7.6 Hz, 1H), 6.71 (s, 1H), 4.50 (t, J = 8.4 Hz, 1H), 3.66-3.62 (m, 4H), 3.12 (t, J = 8.4 Hz, 2H), 2.42-2.44 (m, 2H), 2.37-2.28 (m, 2H), 1.32 (s, 6H), 1.28 (t, J = 6.4 Hz, 3H). 330 02 Racemic .sup.1H NMR (400 MHz, DMSO-d6): δ 9.06 (s, 1H), 8.59 (s, 2H), 8.46 (d, J = 8.0 Hz, 2H), 7.81 (d, J = 8.4 Hz, 1H), 7.62 (dd, J = 7.4, 4.3 Hz, 1H), 3.41- 3.35 (m, 1H), 3.78-3.62 (m, 6H), 2.62-2.58 (m, 2H), 2.45-2.38 (m, 4H), 2.10-2.00 (m, 2H), 1.45 (d, J = 5.6 Hz, 3H). 331 03 Racemic .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.38 (s, 1H), 8.11 (d, J = 8.4 Hz, 1H), 8.01 (s, 1H), 7.48 (d, J = 7.6 Hz, 1H), 4.01-4.09 (m, 1H), 3.71-3.63 (m, 3H), 3.32-3.29 (m, 4H), 3.17 (s, 1H), 2.94 (t, J = 5.6 Hz, 2H), 2.44-2.42 (m, 4H), 1.39 (d, J = 6.4 Hz, 3H). 332 04 Racemic .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.38 (s, 1H), 8.11 (d, J = 8.0 Hz, 1H), 8.01 (s, 1H), 7.49 (d, J = 8.0 Hz, 1H), 3.69-3.66 (m, 1H), 3.39-3.36 (m, 2H), 3.32-3.25 (m, 5H), 3.17 (s, 1H), 2.61 (t, J = 5.2 Hz, 2H), 2.59-2.41 (m, 4H), 2.31 (s, 3H), 1.39 (d, J = 6.8 Hz, 3H). 333 05 Racemic .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.38 (s, 1H), 8.12 (d, J = 8.0 Hz, 1H), 8.01 (s, 1H), 7.49 (d, J = 8.0 Hz, 1H), 4.48-4.45 (m, 2H), 3.70-3.64 (m, 3H), 3.36-3.33 (m, 4H), 2.55-2.60 (m, 2H), 2.49-2.39 (m, 4H), 2.07-2.03 (m, 3H), 1.40 (d, J = 6.4 Hz, 3H). 334 06 Racemic .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.38 (s, 1H), 8.11 (d, J = 8.4 Hz, 1H), 8.01 (s, 1H), 7.48 (d, J = 8.4 Hz, 1H), 4.51-4.39 (m, 1H), 3.69-3.66 (m, 1H), 3.54-3.48 (m, 4H), 3.32-3.28 (m, 4H), 2.73-2.70 (m, 2H), 2.59-2.52 (m, 6H), 2.46-2.40 (m, 2H), 1.39 (d, J = 6.4 Hz, 3H). 335 07 Racemic .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.93 (s, 1H), 8.78 (d, J = 4.4 Hz, 1H), 8.04 (d, J = 4.4 Hz, 1H), 7.15 (d, J = 7.6 Hz, 1H), 6.74 (d, J = 13.6 Hz, 1H), 6.77 (s, 1H), 4.50 (t, J = 8.8 Hz, 2H), 3.51 (t, J = 4.8 Hz, 4H), 3.38- 3.35 (m, 1H), 3.13 (t, J = 8.8 Hz, 2H), 2.61-2.49 (m, 2H), 2.44-2.40 (m, 2H), 1.28 (d, J = 6.8 Hz, 3H). 336 08 Racemic .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.05-9.05 (m, 1H), 8.44 (d, J = 8.4 Hz, 2H), 8.26 (s, 2H), 8.02 (s, 1H), 7.81 (d, J = 8.4 Hz, 1H), 7.63-7.61 (m, 1H), 3.87-3.86 (m, 1H), 3.71-3.69 (m, 4H), 2.60-2.59 (m, 2H), 2.47-2.46 (m, 2H), 1.78 (s, 3H), 1.49 (s, 6H), 1.44 (d, J = 6.4 Hz, 3H). 337 09 Racemic .sup.1HNMR (400 MHz, DMSO-d.sub.6): δ 9.04 (t, J = 2.4 Hz, 1H), 8.44 (d, J = 8.4 Hz, 2H), 8.06 (s, 1H), 7.80 (d, J = 12.0 Hz, 1H), 7.63-7.62 (m, 1H), 4.53 (s, 2H), 3.90-3.88 (m, 3H), 3.71-3.69 (m, 4H), 2.69-2.66 (m, 2H), 2.59- 2.58 (m, 2H), 2.46-2.45 (m, 2H), 1.43 (d, J = 6.4 Hz, 3H). 338 0 Racemic .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.05 (d, J = 2.0 Hz, 1H), 8.72 (s, 2H), 8.45 (d, J = 8.0 Hz, 2H), 8.29-8.27 (m, 1H), 7.80 (d, J = 8.4 Hz, 1H), 7.62- 7.61 (m, 1H), 3.82-3.73 (m, 5H), 2.74-2.73 (m, 3H), 2.67-2.49 (m, 4H), 1.45 (d, J = 5.6 Hz, 3H). 339 Racemic .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.05-9.04 (m, 1H), 8.72 (s, 2H), 8.45 (d, J = 8.8 Hz, 2H), 8.04 (d, J = 7.6 Hz, 1H), 7.80 (d, J = 8.4 Hz, 1H), 7.63- 7.60 (m, 1H), 4.05-4.01 (m, 1H), 3.90-3.87 (m, 1H), 3.82-3.79 (m, 4H), 2.67-2.58 (m, 2H), 2.49-2.32 (m, 2H), 1.44 (d, J = 6.8 Hz, 3H), 1.13 (d, J = 6.4 Hz, 6H). 340 Racemic .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.05-9.01 (m, 1H), 8.74 (s, 2H), 8.45 (d, J = 8.4 Hz, 2H), 8.32-8.30 (m, 1H), 7.81 (d, J = 8.4 Hz, 1H), 7.63-7.60 (m, 1H), 4.71 (t, J = 5.2 Hz, 1H), 3.90-3.87 (m, 1H), 3.82-3.79 (m, 4H), 3.50-3.45 (m, 2H), 3.32-3.26 (m, 2H), 2.62-2.58 (m, 2H), 2.50-2.45 (m, 2H), 1.44 (d, J = 6.8 Hz, 3H). 341 Racemic .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.05-9.01 (m, 1H), 8.72 (s, 2H), 8.45 (d, J = 8.4 Hz, 2H), 8.32-8.30 (m, 1H), 7.81 (d, J = 8.4 Hz, 1H), 7.63-7.60 (m, 1H), 3.90-3.89 (m, 1H), 3.82-3.79 (m, 4H), 3.26-3.22 (m, 2H), 2.66- 2.58 (m, 2H), 2.45-2.32 (m, 2H), 1.44 (d, J = 6.8 Hz, 3H), 1.09 (t, J = 7.2 Hz, 3H). 342 Racemic .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.38 (s, 2H), 7.14 (d, J = 6.0 Hz, 1H), 6.77-6.72 (m, 2H), 6.51-6.49 (m, 1H), 4.50-4.50 (m, 4H), 4.36-4.34 (m, 1H), 3.70-3.69 (m, 5H), 3.42-3.40 (m, 2H), 3.31-3.10 (m, 2H), 2.33-2.31 (m, 4H), 1.25 (d, J = 13.2 Hz, 3H). 343 Racemic .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.16 (d, J = 7.6 Hz, 1H), 6.76 (d, J = 7.6 Hz, 1H), 6.72 (s, 1H), 4.51 (t, J = 8.8 Hz, 2H), 4.26-4.24 (m, 2H), 3.51- 3.45 (m, 4H), 3.44-3.42 (m, 1H), 3.14 (t, J = 8.4 Hz, 2H), 2.45-2.44 (m, 4H), 1.28 (d, J = 6.8 Hz, 3H), 1.24 (t, J = 7.2 Hz, 3H). 344 Racemic .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.38 (d, J = 4.0 Hz, 1H), 7.17-7.15 (m, 1H), 6.77 (d, J = 7.6 Hz, 1H), 6.72 (s, 1H), 4.51 (t, J = 9.2 Hz, 2H), 3.42- 3.40 (m, 5H), 3.14 (t, J = 8.4 Hz, 2H), 2.70-2.68 (m, 3H), 2.43-2.40 (m, 4H), 1.29 (d, J = 6.8 Hz, 3H). 345 Racemic .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.39 (s, 1H), 8.94 (s, 1H), 8.79 (d, J = 4.4 Hz, 1H), 8.13 (d, J = 8.4 Hz, 1H), 8.05 (d, J = 4.8 Hz, 2H), 7.52 (d, J = 8.0 Hz, 1H), 3.72-3.68 (m, 1H), 3.56-3.54 (m, 4H), 2.59-2.56 (m, 4H), 1.42 (d, J = 6.4 Hz, 3H). 346 Racemic .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.38 (s, 1H), 8.25 (s, 2H), 8.11 (d, J = 8.0 Hz, 1H), 8.02-7.95 (m, 2H), 7.50 (d, J = 8.4 Hz, 1H), 3.67-3.64 (m, 5H), 2.50-2.32 (m, 4H), 1.78 (s, 3H), 1.48 (s, 6H), 1.40 (d, J = 6.0 Hz, 3H). 347 Racemic 1H NMR (400 MHz, DMSO-d.sub.6): δ 10.12 (s, 1H), 7.40 (s, 1H), 7.31 (s, 1H), 7.14 (d, J = 7.2 Hz, 1H), 6.75 (d, J = 7.2 Hz, 1H), 6.70 (s, 1H), 4.51 (t, J = 8.8 Hz, 2H), 3.90 (s, 2H), 3.52-3.49 (m, 5H), 3.15 (t, J = 8.0 Hz, 2H), 2.36-2.30 (m, 4H), 1.25 (d, J = 5.20 Hz, 3H). 348 0 Racemic .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.15 (d, J = 7.6 Hz, 1H), 6.75 (d, J = 7.2 Hz, 1H), 6.70 (s, 1H), 4.68-4.58 (m, 2H), 4.51 (t, J = 8.8 Hz, 2H), 4.04- 4.01 (m, 1H), 3.93-3.91 (m, 2H), 3.34-3.31 (m, 2H), 3.24-3.21 (m, 4H), 3.14 (t, J = 8.8 Hz, 2H), 2.44-2.41 (m, 2H), 2.37-2.33 (m, 2H), 2.13-2.09 (m, 3H), 1.27 (d, J = 6.4 Hz, 3H). 349 Racemic 1H NMR (400 MHz, DMSO-d.sub.6): δ 8.92 (s, 1H), 7.15 (d, J = 7.6 Hz, 1H), 6.77-6.72 (m, 2H), 4.93 (s, 2H), 4.74 (s, 2H), 4.50 (t, J = 8.4 Hz, 2H), 3.71-3.68 (m, 4H), 3.17-3.11 (m, 3H), 2.46-2.40 (m, 2H), 2.37-2.31 (m, 2H), 1.28 (d, J = 6.80 Hz, 3H). 350 Racemic 1H NMR (400 MHz, DMSO-d.sub.6): δ 9.05-9.04 (m, 1H), 8.44 (d, J = 8.4 Hz, 2H), 8.29 (s, 1H), 7.80 (d, J = 8.4 Hz, 1H), 7.63-7.60 (m, 1H), 4.92 (s, 2H), 4.73 (s, 2H), 3.88-3.86 (m, 1H), 3.74-3.72 (m, 4H), 2.60-2.56 (m, 2H), 2.46-2.43 (m, 2H), 1.43 (d, J = 6.40 Hz, 3H). 351 Racemic .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 10.57 (s, 1H), 7.79 (s, 1H), 7.15 (d, J = 7.6 Hz, 1H), 6.75 (d, J = 7.6 Hz, 1H), 6.71 (s, 1H), 4.76 (s, 2H), 4.51 (t, J = 8.8 Hz, 2H), 3.59-3.53 (m, 4H), 3.34-3.32 (m, 1H), 3.13 (t, J = 8.4 Hz, 2H), 2.42-2.39 (m, 2H), 2.33-2.30 (m, 2H), 1.27 (d, J = 6.80 Hz, 3H). 352 Racemic .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 10.56 (s, 1H), 9.05 (d, J = 2.0 Hz, 1H), 8.47-8.45 (m, 2H), 7.82-7.78 (m, 2H), 7.63-7.59 (m, 1H), 4.75 (s, 2H), 3.87-3.85 (m, 1H), 3.71-3.61 (m, 4H), 2.50-2.48 (m, 2H), 2.47-2.43 (m, 2H), 1.43 (d, J = 6.4 Hz, 3H). 353 Racemic .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 10.57 (s, 1H), 9.39 (s, 1H), 8.12 (d, J = 8.4 Hz, 1H), 8.01 (s, 1H), 7.78 (s, 1H), 7.49 (d, J = 8.0 Hz, 1H), 4.76 (s, 2H), 3.64-3.58 (m, 5H), 2.51-2.47 (m, 2H), 2.38-2.34 (m, 2H), 1.40 (d, J = 6.40 Hz, 3H). 354 Racemic .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 10.14 (s, 1H), 9.39 (s, 1H), 8.12 (d, J = 8.4 Hz, 1H), 8.01 (s, 1H), 7.49 (d, J = 8.0 Hz, 1H), 7.40 (s, 1H), 7.33 (s, 1H), 3.89 (s, 2H), 3.61 (d, J = 6.8 Hz, 1H), 3.59-3.55 (m, 4H), 2.45-2.40 (m, 4H), 1.39 (d, J = 6.8 Hz, 3H). 355 Racemic .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.98 (d, J = 8.4 Hz, 1H), 7.85 (s, 1H), 7.39 (d, J = 8.0 Hz, 1H), 7.32 (s, 1H), 3.68-3.66 (m, 1H), 3.56-3.42 (m, 4H), 2.79 (s, 3H), 2.71-2.67 (m, 2H), 2.61-2.53 (m, 2H), 2.48-2.42 (m, 4H), 1.39 (d, J = 6.8 Hz, 3H). 356 Racemic .sup.1H NMR (400 MHz, DMSO-d.sub.6) : δ 10.59 (s, 1H), 7.97 (d, J = 8.4 Hz, 1H), 7.84 (s, 1H), 7.65 (s, 1H), 7.38 (d, J = 8.4 Hz, 1H), 6.40 (s, 1H), 4.60 (s, 2H), 3.60-3.55 (m, 1H), 3.40-3.35 (m, 4H), 3.34 (s, 3H), 2.41-2.34 (m, 4H), 1.38 (d, J = 6.8 Hz, 3H). 357 Racemic .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.58 (s, 1H), 7.97 (d, J = 8.4 Hz, 1H), 7.85 (s, 1H), 7.71 (s, 1H), 7.39 (d, J = 8.4 Hz, 1H), 3.92-3.75 (m, 4H), 3.64-3.60 (m, 1H), 3.42-3.35 (m, 2H), 2.79 (s, 3H), 2.79-2.75 (m, 2H), 2.49-2.35 (m, 4H), 1.39 (d, J = 6.4 Hz, 3H). 358 0 Racemic .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.72 (s, 2H), 8.29 (d, J = 4.4 Hz, 1H), 7.97 (d, J = 8.0 Hz, 1H), 7.85 (s, 1H), 7.39 (dd, J = 8.4, 1.2 Hz, 1H), 3.80 (t, J = 4.8 Hz, 4H), 3.64-3.60 (m, 1H), 2.79 (s, 3H), 2.76-2.74 (m, 3H), 2.49-2.47 (m, 2H), 2.42-2.37 (m, 2H), 1.39 (d, J = 6.8 Hz, 3H). 359 Racemic .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.19 (s, 1H), 7.97 (d, J = 8.4 Hz, 1H), 7.84 (s, 1H), 7.39 (d, J = 8.0 Hz, 1H), 5.31-5.30 (m, 1H), 4.49 (t, J = 5.2 Hz, 2H), 3.89-3.76 (m, 2H), 3.70-3.66 (m, 2H), 3.66-3.55 (m, 3H), 3.42- 3.40 (m, 4H), 3.35-3.31 (m, 2H), 2.79 (s, 3H), 2.68-2.68 (m, 2H), 2.51- 2.51 (m, 2H), 1.40 (d, J = 5.2 Hz, 3H). 360 Racemic .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.26 (s, 2H), 8.04 (s, 1H), 7.97 (d, J = 8.4 Hz, 1H), 7.85 (s, 1H), 7.40 (dd, J = 8.4, 1.2 Hz, 1H), 3.67 (t, J = 4.4 Hz, 4H), 3.62-3.57 (m, 1H), 2.79 (s, 3H), 2.49-2.47 (m, 2H), 2.40-2.34 (m, 2H), 1.79 (s, 3H), 1.49 (s, 6H), 1.39 (d, J = 6.8 Hz, 3H). 361 Racemic .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.92 (t, J = 1.6 Hz, 1H), 8.78 (s, 2H), 7.15 (d, J = 7.6 Hz, 1H), 6.77-6.72 (m, 2H), 4.50 (t, J = 8.0 Hz, 2H), 4.09- 4.05 (m, 2H), 3.80 (t, J = 4.8 Hz, 4H), 3.36 (t, J = 8.0 Hz, 1H), 3.13 (t, J = 8.8 Hz, 2H), 2.53-2.47 (m, 2H), 2.46-2.33 (m, 2H), 1.28 (d, J = 6.40 Hz, 3H). 362 Racemic .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.40 (s, 2H), 7.14 (d, J = 7.6 Hz, 1H), 6.77-6.72 (m, 2H), 4.50 (t, J = 6.8 Hz, 2H), 3.76-3.74 (m, 4H), 3.49-3.46 (m, 4H), 3.15-3.12 (m, 2H), 2.50-2.44 (m, 2H), 2.38-2.30 (m, 7H), 2.25- 2.10 (m, 3H), 1.28 (d, J = 6.4 Hz, 3H). 363 Racemic .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.43 (s, 2H), 7.15 (d, J = 7.6 Hz, 1H), 6.76 (d, J = 8.8 Hz, 1H), 6.73 (s, 1H), 4.50 (t, J = 8.8 Hz, 2H), 3.76 (t, J = 10.0 Hz, 4H), 3.59 (d, J = 8.0 Hz, 4H), 3.54-3.45 (m, 4H), 3.42-3.38 (m, 1H), 3.18-3.11 (m, 2H), 2.52-2.50 (m, 2H), 2.38-2.33 (m, 2H), 1.28 (s, 3H). 364 Racemic .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.39 (s, 1H), 8.29 (s, 1H), 8.12 (d, J = 8.4 Hz, 1H), 8.03 (s, 1H), 7.51 (d, J = 8.4 Hz, 1H), 4.92 (s, 2H), 4.73 (s, 2H), 3.74-3.60 (m, 5H), 2.45-2.51 (m, 2H), 2.41-2.38 (m, 2H), 1.41 (d, J = 6.8 Hz, 3H). 365 Racemic .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 12.97-12.71 (m, 1H), 7.15 (d, J = 7.6 Hz, 1H), 6.76 (d, J = 7.6 Hz, 1H), 6.71 (s, 1H), 6.23-5.89 (m, 1H), 4.50 (t, J = 6.8 Hz, 2H), 4.29-4.21 (m, 2H), 3.15 (t, J = 6.8 Hz, 2H), 3.33-3.32 (m, 1H), 3.11-3.07 (m, 4H), 2.50-2.39 (m, 4H), 1.29-1.26 (m, 6H). 366 Racemic .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 12.49-12.37 (m, 1H), 8.24-8.23 (m, 1H), 7.15 (d, J = 7.6 Hz, 1H), 6.76 (d, J = 7.6 Hz, 1H), 6.71 (s, 1H), 6.17- 5.79 (m, 1H), 4.50 (t, J = 8.8 Hz, 2H), 3.32-3.30 (m, 1H), 3.17-3.10 (m, 2H), 3.10-3.00 (m, 4H), 2.75-2.65 (m, 3H), 2.50-2.45 (m, 2H), 2.42-2.35 (m, 2H), 1.27 (d, J = 6.4 Hz, 3H). 367 Racemic .sup.1H NMR (400 MHz, DMSO-d.sub.6) : δ 10.57 (s, 1H), 9.38 (s, 1H), 8.11 (dd, J = 8.0, 3.6 Hz, 1H), 8.01 (s, 1H), 7.64 (d, J = 3.2 Hz, 1H), 7.49 (d, J = 6.4 Hz, 1H), 6.39 (s, 1H), 4.59 (s, 2H), 3.67-3.60 (m, 1H), 3.40-3.30 (m, 4H), 2.70-2.67 (m, 1H), 2.40-2.35 (m, 2H), 2.20-2.10 (m, 1H), 1.39 (d, J = 2.8 Hz, 3H). 368 0 Racemic .sup.1H NMR (400 MHz, DMSO-d.sub.6) : δ 10.59 (s, 1H), 9.06 (d, J = 4.0 Hz, 1H), 8.45 (t, J = 5.2 Hz, 2H), 7.79 (d, J = 8.4 Hz, 1H), 7.65 (s, 1H), 7.62 (dd, J = 8.0, 4.4 Hz, 1H), 6.41 (s, 1H), 4.60 (s, 2H), 3.85 (q, J = 6.8 Hz, 1H), 3.40-3.30 (m, 4H), 2.65-2.57 (m, 2H), 2.50-2.40 (m, 2H), 1.44 (d, J = 6.8 Hz, 3H). 369 Racemic .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 10.56 (s, 1H), 7.96 (d, J = 8.0 Hz, 1H), 7.83 (d, J = 1.2 Hz, 1H), 7.78 (s, 1H), 7.38 (dd, J = 8.4, 1.6 Hz, 1H), 4.75 (s, 2H), 3.59-3.57 (m, 5H), 2.79 (s, 3H), 2.52-2.49 (m, 2H), 2.34-2.31 (m, 2H), 1.37 (d, J = 6.80 Hz, 3H). 370 Racemic .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.14 (d, J = 7.6 Hz, 1H), 6.93-6.90 (m, 1H), 6.74 (d, J = 7.6 Hz, 1H), 6.70 (s, 1H), 4.49 (t, J = 8.8 Hz, 2H), 4.19 (s, 2H), 4.06 (s, 2H), 3.64 (br s, 4H), 3.38-3.33 (m, 1H), 3.12 (t, J = 8.8 Hz, 2H), 2.79 (d, J = 4.4 Hz, 3H), 2.33-2.30 (m, 4H), 1.27 (d, J = 6.40 Hz, 3H).-1H missing. 371 Racemic .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.15 (d, J = 7.6 Hz, 1H), 6.77-6.72 (m, 2H), 4.50 (t, J = 8.4 Hz, 2H), 4.36 (s, 2H), 4.20 (s, 2H), 3.88 (s, 3H), 3.71 (br s, 4H), 3.38-3.34 (m, 1H), 3.13 (t, J = 8.0 Hz, 2H), 2.36-2.33 (m, 4H), 1.28 (d, J = 6.80 Hz, 3H). 372 Racemic .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.46 (s, 1H), 7.16 (d, J = 7.2 Hz, 1H), 6.77-6.72 (m, 2H), 4.60 (s, 2H), 4.51 (t, J = 8.8 Hz, 2H), 4.42 (s, 2H), 3.58 (br s, 4H), 3.38 (t, J = 6.4 Hz, 1H), 3.18-3.12 (m, 2H), 2.40-2.34 (m, 4H), 1.28 (d, J = 6.80 Hz, 3H). 373 Chiral HPLC SFC Method C: 1st eluting com- pound .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.39 (s, 1H), 8.72 (s, 2H), 8.38-8.27 (m, 1H), 8.12 (d, J = 8.4 Hz, 1H), 8.03 (s, 1H), 7.51 (d, J = 8.4 Hz, 1H), 3.88-3.75 (m, 4H), 3.73-3.63 (m, 1H), 3.28-3.19 (m, 2H), 2.67-2.53 (m, 2H), 2.45-2.39 (m, 2H), 1.41 (d, J = 6.80 Hz, 3H), 1.10 (t, J = 7.20 Hz, 3H). 374 Chiral HPLC SFC Method C: 2nd eluting com- pound .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.39 (s, 1H), 8.72 (s, 2H), 8.31 (t, J = 5.2 Hz, 1H), 8.12 (d, J = 8.0 Hz, 1H), 8.03 (s, 1H), 7.51 (d, J = 8.4 Hz, 1H), 3.89-3.76 (m, 4H), 3.75-3.60 (m, 1H), 3.30-3.21 (m, 2H), 2.67-2.52 (m, 2H), 2.47-2.37 (m, 2H), 1.41 (d, J = 6.40 Hz, 3H), 1.10 (t, J = 7.20 Hz, 3H). 375 Chiral HPLC SFC Method E: 1st eluting com- pound .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.06 (t, J = 2.4 Hz, 1H), 8.44 (d, J = 8.4 Hz, 2H), 8.07 (s, 1H), 7.80 (d, J = 12.0 Hz, 1H), 7.63 (s, 1H), 4.54 (s, 2H), 3.90-3.88 (m, 3H), 3.71-3.69 (m, 4H), 2.67-2.65 (m, 2H), 2.59-2.58 (m, 4H), 1.44 (d, J = 6.4 Hz, 3H). 376 Chiral HPLC SFC Method E: 2nd eluting com- pound .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.04 (t, J = 2.4 Hz, 1H), 8.44 (d, J = 8.4 Hz, 2H), 8.06 (s, 1H), 7.80 (d, J = 12.0 Hz, 1H), 7.63-7.62 (m, 1H), 4.53 (s, 2H), 3.90-3.88 (m, 3H), 3.71-3.69 (m, 4H), 2.69-2.66 (m, 2H), 2.59- 2.58 (m, 2H), 2.46-2.45 (m, 2H), 1.43 (d, J = 6.4 Hz, 3H). 377 Racemic .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.14 (d, J = 7.6 Hz, 1H), 6.75 (d, J = 7.6 Hz, 1H), 6.70 (s, 1H), 6.13 (s, 1H), 4.50 (t, J = 8.8 Hz, 2H), 4.13 (t, J = 6.0 Hz, 2H), 3.69 (t, J = 5.6 Hz, 2H), 3.32-0.00 (m, 1H), 3.13 (t, J = 8.8 Hz, 2H), 3.10-3.00 (m, 4H), 2.95 (s, 3H), 2.46-2.33 (m, 4H), 1.26 (d, J = 6.80 Hz, 3H). 378 0 Racemic .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.38 (s, 1H), 8.30 (d, J = 5.6 Hz, 1H), 8.11 (d, J = 7.2 Hz, 1H), 7.49 (d, J = 6.4 Hz, 1H), 6.13 (s, 1H), 4.15-4.12 (m, 2H), 3.71-3.68 (m, 2H), 3.63-3.62 (m, 1H), 3.10-3.05 (m, 4H), 2.95 (s, 3H), 2.6-2.5 (m, 2H), 2.44-2.42 (m, 2H), 1.40-1.39 (m, 3H). 379 Racemic .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.74 (d, J = 2.0 Hz, 2H), 8.33 (t, J = 4.8 Hz, 1H), 7.15 (d, J = 7.20 Hz, 1H), 6.76 (d, J = 7.60 Hz, 1H), 6.72 (s, 1H), 4.73-4.72 (m, 1H), 4.53-4.49 (m, 2H), 3.79-3.78 (m, 4H), 3.49-3.48 (m, 2H), 3.38-3.36 (m, 1H), 3.31-3.28 (m, 2H), 3.16-3.11 (m, 2H), 2.46-2.44 (m, 2H), 2.37-2.33 (m, 2H), 1.29-1.28 (m, 3H). 380 Racemic .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.37 (s, 1H), 8.72 (s, 2H), 8.31 (t, J = 8.4 Hz, 1H), 8.11 (d, J = 8.4 Hz, 1H), 8.02 (s, 1H), 7.50 (d, J = 8.0 Hz, 1H), 4.70 (t, 1H, J = 5.6 Hz), 3.79-3.78 (m, 4H), 3.49-3.45 (m, 3H), 3.28-3.25 (m, 2H), 2.50-2.36 (m, 4H), 1.40 (d, J = 6.8 Hz, 3H). 381 Racemic .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.05 (d, J = 5.6 Hz, 1H), 7.15 (d, J = 7.6 Hz, 1H), 6.76 (dd, J = 7.6, 1.2 Hz, 1H), 6.72 (s, 1H), 6.03 (d, J = 5.6 Hz, 1H), 4.50 (t, J = 8.4 Hz, 2H), 3.80 (s, 3H), 3.68 (t, J = 4.8 Hz, 4H), 3.37- 3.35 (m, 1H), 3.13 (t, J = 8.4 Hz, 2H), 2.43-2.39 (m, 2H), 2.36-2.32 (m, 2H), 1.28 (d, J = 6.8 Hz, 3H). 382 Racemic .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.14 (d, J = 3.2 Hz, 1H), 7.15 (d, J = 7.2 Hz, 1H), 6.76 (d, J = 7.6 Hz, 1H), 6.72 (s, 1H), 4.51 (t, J = 8.8 Hz, 2H), 3.91 (s, 3H), 3.62-3.65 (m, 4H), 3.14 (t, J = 8.8 Hz, 2H), 2.45-2.25 (m, 4H), 1.28 (d, J = 6.4 Hz, 3H). 383 Racemic .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.66 (s, 1H), 7.15 (d, J = 7.6 Hz, 1H), 6.87 (s, 1H), 6.75 (d, J = 7.6 Hz, 1H), 6.71 (s, 1H), 5.70 (d, J = 6.0 Hz, 1H), 4.51 (t, J = 8.8 Hz, 2H), 3.62-3.52 (m, 4H), 3.34 (s, 1H), 3.14 (t, J = 8.4 Hz, 2H), 2.73-2.68 (m, 3H), 2.38-2.30 (m, 4H), 1.28 (d, J = 6.4 Hz, 3H). 384 Racemic .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.71 (t, J = 1.6 Hz, 1H), 7.20 (d, J = 4.0 Hz, 1H), 7.15 (d, J = 7.6 Hz, 1H), 6.75 (d, J = 7.2 Hz, 1H), 6.71 (s, 1H), 4.51 (t, J = 8.8 Hz, 2H), 3.62-3.34 (m, 4H), 3.32 (s, 1H), 3.14 (t, J = 8.8 Hz, 2H), 2.79 (d, J = 4.4 Hz, 3H), 2.33-2.29 (m, 4H), 1.28 (d, J = 6.8 Hz, 3H). 385 Racemic .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.08-8.98 (m, 1H), 8.21 (s, 1H), 8.11 (s, 1H), 8.05-7.85 (m, 1H), 7.61-7.45 (m, 1H), 4.27 (s, 2H), 4.20 (s, 2H), 3.92-3.40 (m, 5H), 2.69-2.38 (m, 4H), 1.44 (d, J = 7.2 Hz, 3H). 386 Racemic .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 10.53 (s, 1H), 7.81 (s, 1H), 7.15 (d, J = 7.60 Hz, 1H), 6.76 (d, J = 7.20 Hz, 1H), 6.71 (s, 1H), 4.93 (dd, J = 13.80, 7.20 Hz, 1H), 4.51 (t, J = 8.80 Hz, 2H), 3.57 (t, J = 4.80 Hz, 4H), 3.29 (s, 1H), 3.14 (t, J = 8.40 Hz, 2H), 2.44-2.40 (m, 2H), 2.34-2.30 (m, 2H), 1.46 (d, J = 7.20 Hz, 3H), 1.26 (t, J = 8.00 Hz, 3H). 387 Racemic .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 10.53 (s, 1H), 9.39 (s, 1H), 8.12 (d, J = 8.4 Hz, 1H), 8.02 (s, 1H), 7.80 (s, 1H), 7.50 (d, J = 8.4 Hz, 1H), 4.93 (dd, J = 13.6, 6.8 Hz, 1H), 3.64-3.60 (m, 5H), 2.51-2.47 (m, 2H), 2.38-2.34 (m, 2H), 1.45 (d, J = 6.8 Hz, 3H), 1.40 (d, J = 6.8 Hz, 3H). 388 0 Chiral HPLC SFC Method F: 1st eluting com- pound .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.58 (s, 1H), 7.97 (d, J = 8.0 Hz, 1H), 7.85 (s, 1H), 7.69 (s, 1H), 7.39 (d, J = 8.4 Hz, 1H), 3.82-3.81 (m, 4H), 3.63-3.62 (m, 1H), 3.37-3.36 (m, 2H), 2.79 (s, 3H), 2.79-2.75 (m, 2H), 2.44-2.41 (m, 2H), 2.42-2.41 (m, 2H), 1.39 (d, J = 6.4 Hz, 3H). 389 Chiral HPLC SFC Method F: 2nd eluting com- pound .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.58 (s, 1H), 7.97 (d, J = 8.0 Hz, 1H), 7.85 (s, 1H), 7.69 (s, 1H), 7.39 (d, J = 8.4 Hz, 1H), 3.82-3.80 (m, 4H), 3.63-3.62 (m, 1H), 3.38-3.36 (m, 2H), 2.79 (s, 3H), 2.79-2.77 (m, 2H), 2.48-2.46 (m, 2H), 2.41-2.39 (m, 2H), 1.39 (d, J = 6.4 Hz, 3H). 390 Chiral HPLC SFC Method F: 2nd eluting com- pound .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 10.89-10.39 (m, 1H), 7.97 (d, J = 8.4 Hz, 1H), 7.83 (s, 1H), 7.77 (s, 1H), 7.38 (d, J = 8.0 Hz, 1H), 4.74 (s, 2H), 3.67-3.52 (m, 5H), 2.79 (s, 3H), 2.47-2.40 (m, 2H), 2.40-2.34 (m, 2H), 1.38 (d, J = 6.8 Hz, 3H). 391 Racemic .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.11 (s, 1H), 7.15 (d, J = 7.2 Hz, 1H), 6.76 (d, J = 7.2 Hz, 1H), 6.72 (s, 1H), 4.51 (t, J = 8.8 Hz, 2H), 4.31 (s, 2H), 3.75-3.65 (m, 4H), 3.40-3.30 (m, 2H), 3.60-3.50 (m, 1H), 3.20-3.10 (m, 4H), 2.30-2.20 (m, 4H), 1.28 (d, J = 6.4 Hz, 3H). 392 Racemic .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.93 (s, 1H), 8.13-8.11 (m, 2H), 8.02 (s, 1H), 7.50 (d, J = 8.4 Hz, 1H), 4.30-4.25 (m, 2H), 3.70-3.60 (m, 4H), 3.60-3.55 (m, 1H), 3.40-3.35 (m, 2H), 3.20-3.10 (m, 2H), 2.40-2.37 (m, 4H), 1.40 (d, J = 6.40 Hz, 3H). 393 Racemic .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 12.03 (s, 1H), 8.73 (s, 1H), 7.77-7.65 (m, 2H), 7.40 (d, J = 8.4 Hz, 1H), 3.67-3.55 (m, 1H), 3.34-3.24 (m, 4H), 2.52-2.46 (m, 4H), 2.09 (s, 3H), 1.38 (d, J = 4.0 Hz, 3H). 394 Racemic .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.71 (s, 1H), 8.58 (s, 1H), 7.76-7.69 (m, 3H), 7.41 (dd, J = 8.0, 1.6 Hz, 1H), 3.82-3.72 (m, 4H), 3.64 (t, J = 6.8 Hz, 1H), 3.38-3.33 (m, 2H), 2.78 (t, J = 6.4 Hz, 2H), 2.41-2.37 (m, 4H), 1.38 (d, J = 6.8 Hz, 3H). 395 Racemic .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 12.03 (s, 1H), 8.73 (s, 1H), 7.73 (d, J = 8.4 Hz, 2H), 7.43 (d, J = 8.4 Hz, 1H), 3.68-3.63 (m, 1H), 3.37-3.36 (m, 4H), 2.50-2.40 (m, 4H), 2.10 (s, 3H), 1.38 (d, J = 6.8 Hz, 3H). 396 Racemic .sup.1H NMR (400 MHz, DMSO-d.sub.6) : δ 8.73 (s, 1H), 8.59 (s, 1H), 7.74 (s, 1H), 7.71 (d, J = 4.4 Hz, 2H), 7.44 (d, J = 8.4 Hz, 1H), 3.88-3.80 (m, 4H), 3.66- 3.61 (m, 1H), 3.40-3.30 (m, 2H), 2.78 (t, J = 6.4 Hz, 2H), 2.40-2.30 (m, 4H), 1.39 (d, J = 6.80 Hz, 3H). 397 Racemic .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 10.50 (s, 1H), 7.81 (s, 1H), 7.15 (d, J = 8.0 Hz, 1H), 6.76 (d, J = 8.4 Hz, 1H), 6.72 (s, 1H), 4.51 (t, J = 8.8 Hz, 2H), 3.56 (d, J = 4.4 Hz, 4H), 3.14 (t, J = 8.4 Hz, 2H), 2.65-2.55 (m, 3H), 2.50- 2.48 (m, 2H), 1.46 (s, 6H), 1.27 (d, J = 6.4 Hz, 3H). 398 0 Racemic .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 10.50 (s, 1H), 9.39 (s, 1H), 8.12 (d, J = 8.4 Hz, 1H), 8.02 (s, 1H), 7.81 (s, 1H), 7.50 (d, J = 7.2 Hz, 1H), 3.64-3.58 (m, 5H), 2.50-2.42 (m, 2H), 2.40-2.30 (m, 2H), 1.46 (s, 6H), 1.40 (d, J = 6.8 Hz, 3H). 399 Racemic .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 10.08 (s, 1H), 7.42 (d, J = 4.0 Hz, 2H), 7.14 (d, J = 7.2 Hz, 1H), 6.74 (d, J = 7.6 Hz, 1H), 6.69 (s, 1H), 4.50 (t, J = 8.8 Hz, 2H), 4.02-4.00 (m, 1H), 3.54-3.51 (m, 5H), 3.13 (t, J = 8.8 Hz, 2H), 2.36-2.32 (m, 4H), 1.30-1.28 (m, 6H). 400 Racemic .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.55 (s, 2H), 8.04 (d, J = 2.4 Hz, 1H), 7.78 (d, J = 2.4 Hz, 1H), 7.14 (d, J = 7.6 Hz, 1H), 6.76 (d, J = 7.6 Hz, 1H), 6.72 (s, 1H), 4.50 (dt, J = 8.8, 2.4 Hz, 2H), 3.84 (d, J = 2.8 Hz, 3H), 3.70- 3.65 (m, 4H), 3.38-3.30 (m, 1H), 3.13 (t, J = 8.8 Hz, 2H), 2.50-2.40 (m, 2H), 2.39-2.30 (m, 2H), 1.28 (d, J = 8.8 Hz, 3H). 401 Racemic .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.395 (s, 1H), 8.57 (s, 2H), 8.13 (d, J = 8.4 Hz, 1H), 8.04 (d, J = 8.4 Hz, 2H), 7.80 (s, 1H), 7.52 (d, J = 7.2 Hz, 1H), 3.85 (s, 3H), 3.75-3.70 (m, 4H), 3.68-3.63 (m, 1H), 2.45-2.40 (m, 4H), 1.42 (d, J = 6.8 Hz, 3H). 402 Racemic .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 12.94 (s, 1H), 9.38 (s, 1H), 8.59 (s, 2H), 8.11 (d, J = 8.0 Hz, 2H), 8.02 (s, 1H), 7.85 (s, 1H), 7.50 (d, J = 8.0 Hz, 1H), 3.71-3.63 (m, 5H), 2.51-2.49 (m, 2H), 2.42-2.39 (m, 2H), 1.45 (d, J = 2.4 Hz, 3H). 403 Chiral HPLC SFC Method G: 1st eluting com- pound .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.38 (s, 1H), 8.57 (s, 1H), 8.12 (d, J = 8.4 Hz, 1H), 8.02 (s, 1H), 7.68 (s, 1H), 7.50 (d, J = 8.4 Hz, 1H), 3.83-3.81 (m, 4H), 3.67-3.66 (m, 1H), 3.35-3.33 (m, 2H), 2.77 (t, J = 5.2 Hz, 2H), 2.46-2.40 (m, 4H), 1.40 (d, J = 5.2 Hz, 3H). 404 Chiral HPLC SFC Method G: 2nd eluting com- pound .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.39 (s, 1H), 8.58 (s, 1H), 8.12 (d, J = 8.0 Hz, 1H), 8.03 (s, 1H), 7.68 (s, 1H), 7.50 (d, J = 8.0 Hz, 1H), 3.83-3.81 (m, 4H), 3.68-3.67 (m, 1H), 3.35 (t, J = 6.8 Hz, 2H), 2.78 (t, J = 6.8 Hz, 2H), 2.47-2.40 (m, 4H), 1.41 (d, J = 6.40 Hz, 3H). 405 Racemic .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.92 (s, 1H), 7.81 (d, J = 8.8 Hz, 1H), 7.59 (d, J = 8.4 Hz, 1H), 4.30 (s, 3H), 3.71-3.69 (m, 1H), 3.37-3.35 (m, 4H), 2.56-2.53 (m, 2H), 2.46-2.43 (m, 2H), 2.10 (s, 3H), 1.40 (d, J = 6.8 Hz, 3H). 406 Racemic .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 12.05 (s, 1H), 12.04 (s, 1H), 8.10 (d, J = 6.4 Hz, 2H), 7.60 (s, 1H), 7.53 (d, J = 8.0 Hz, 1H), 3.66 (t, J = 6.4 Hz, 1H), 3.38-3.34 (m, 4H), 2.68-2.57 (m, 2H), 2.47-2.44 (m, 2H), 2.10 (s, 3H), 1.37 (d, J = 6.4 Hz, 3H). 407 Racemic .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.42-7.37 (m, 1H), 7.13 (d, J = 7.2 Hz, 1H), 6.74 (d, J = 7.20 Hz, 1H), 6.69 (s, 1H), 4.50 (t, J = 8.4 Hz, 2H), 3.45- 3.39 (m, 4H), 3.29-3.27 (m, 1H), 3.16-3.11 (m, 2H), 2.41-2.30 (m, 4H), 1.25 (d, J = 6.40 Hz, 3H). 408 0 Racemic .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 10.51 (s, 1H), 7.64 (s, 1H), 7.14 (d, J = 7.6 Hz, 1H), 6.75 (d, J = 7.6 Hz, 1H), 6.70 (s, 1H), 6.40 (s, 1H), 4.729 (t, J = 6.8 H, 1H), 4.50 (t, J = 8.8 Hz, 2H), 3.32-3.19 (m, 5H), 3.13 (t, J = 8.8 Hz, 2H), 2.45-2.33 (m, 4H), 1.39 (s, 3H), 1.27 (d, J = 6.8 Hz, 3H). 409 Racemic .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 10.53 (s, 1H), 9.39 (s, 1H), 8.12 (d, J = 8.0 Hz, 1H), 8.02 (s, 1H), 7.66 (s, 1H), 7.50 (d, J = 8.4 Hz, 1H), 6.42 (s, 1H), 4.75-4.70 (m, 1H), 3.65-3.60 (m, 1H), 3.36-3.34 (m, 4H), 2.41-2.39 (m, 4H), 1.41 (d, J = 6.0 Hz, 3H), 1.40 (s, 3H). 410 Racemic .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 10.06 (s, 1H), 9.37 (s, 1H), 8.10 (d, J = 8.4 Hz, 1H), 8.00 (s, 1H), 7.48 (d, J = 8.4 Hz, 1H), 7.45-7.40 (m, 2H), 4.02-4.00 (m, 1H), 3.61-3.59 (m, 5H), 2.46-2.44 (m, 2H), 2.35-2.33 (m, 2H), 1.38 (d, J = 6.8 Hz, 3H), 1.28 (d, J = 6.8 Hz, 3H). 411 Racemic .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 10.05 (s, 1H), 9.39 (s, 1H), 8.12 (d, J = 8.4 Hz, 1H), 8.02 (s, 1H), 7.50 (d, J = 8.0 Hz, 1H), 7.46-7.42 (m, 2H), 3.62-3.60 (m, 5H), 2.47-2.46 (m, 2H), 2.36-2.35 (m, 2H), 1.39 (d, J = 6.8 Hz, 3H), 1.30 (s, 6H). 412 Racemic .sup.1H NMR (400 MHz, DMSO-d.sub.6) : δ 10.50 (s, 1H), 7.66 (s, 1H), 7.15 (d, J = 7.6 Hz, 1H), 6.76 (d, J = 7.2 Hz, 1H), 6.72 (s, 1H), 6.39 (s, 1H), 4.51 (t, J = 8.4 Hz, 2H), 3.40-3.30 (m, 5H), 3.14 (t, J = 8.4 Hz, 2H), 2.49-2.40 (m, 2H), 2.38-2.30 (m, 2H), 1.41 (s, 6H), 1.28 (d, J = 6.4 Hz, 3H). 413 Racemic .sup.1H NMR (400 MHz, DMSO-d.sub.6) : δ 10.48 (s, 1H), 9.38 (s, 1H), 8.11 (d, J = 8.4 Hz, 1H), 8.01 (s, 1H), 7.64 (s, 1H), 7.49 (d, J = 8.0 Hz, 1H), 6.38 (s, 1H), 3.63-3.58 (m, 1H), 3.40-3.30 (m, 4H), 2.39-2.33 (m, 4H), 1.39- 1.35 (m, 9H). 414 Racemic .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 12.39 (s, 1H), 7.15 (d, J = 7.6 Hz, 1H), 6.76 (d, J = 7.2 Hz, 1H), 6.71 (s, 1H), 5.90 (s, 1H), 4.93 (s, 1H), 4.51 (t, J = 8.4 Hz, 2H), 3.57-3.10 (m, 5H), 3.26-2.96 (m, 9H), 2.51-2.39 (m, 4H), 1.27 (d, J = 6.0 Hz, 3H). 415 Racemic .sup.1H NMR (400 MHz, CDCl.sub.3): δ 7.12 (d, J = 7.6 Hz, 1H), 6.75 (d, J = 7.2 Hz, 1H), 6.68 (s, 1H), 4.89 (d, J = 5.6 Hz, 1H), 3.34-3.31 (m, 4H), 3.24 (s, 1H), 2.78-2.76 (m, 2H), 2.51-2.43 (m, 4H), 2.10 (s, 3H), 1.39 (d, J = 4.0 Hz, 3H), 1.28 (d, J = 6.0 Hz, 3H). 416 Racemic .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.58 (s, 1H), 7.69 (s, 1H), 7.11 (d, J = 7.6 Hz, 1H), 6.75(d, J = 7.2 Hz, 1H), 6.68 (s, 1H), 4.89-4.87 (m, 1H), 3.80-3.79 (m, 4H), 3.38-3.24 (m, 5H), 2.80-2.67 (m, 4H), 2.46-2.43 (m, 1H), 2.37-2.33 (m, 1H), 1.39-1.37 (m, 3H), 1.28 (d, J = 6.8 Hz, 3H). 417 Racemic .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.57 (s, 1H), 7.87 (d, J = 8.8 Hz, 1H), 7.77 (s, 1H), 7.69 (s, 1H), 7.46 (d, J = 8.4 Hz, 1H), 3.80-3.78 (m, 4H), 3.65 (t, J = 6.4 Hz, 1H), 3.37-3.34 (m, 3H), 2.77 (t, J = 6.8 Hz, 2H), 2.52- 2.49 (m, 2H), 2.40-2.37 (m, 2H), 1.38 (d, J = 6.4 Hz, 3H). 418 0 Racemic .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.24 (s, 1H), 7.15 (d, J = 6.8 Hz, 1H), 6.81 (s, 2H), 4.59 (t, J = 8.80 Hz, 2H), 3.95 (s, 3H), 3.86-3.76 (m, 4H), 3.51-3.40 (m, 1H), 3.21 (t, J = 8.00 Hz, 2H), 2.58-2.51 (m, 4H), 1.31- 1.26 (m,3H). 419 Racemic .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.73 (s, 2H), 7.15 (d, J = 7.2 Hz, 1H), 6.76 (d, J = 7.2 Hz, 1H), 6.73 (s, 1H), 4.51 (t, J = 8.8 Hz, 2H), 3.82-3.80 (m, 4H), 3.39-3.37 (m, 1H), 3.14 (t, J = 8.8 Hz, 2H), 2.40-2.34 (m, 4H), 1.29 (d, J = 6.8 Hz, 3H). 420 Chiral HPLC SFC Method F: 1st eluting com- pound .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.39 (s, 1H), 8.13-8.10 (m, 2H), 8.02 (s, 1H), 7.50 (d, J = 8.4 Hz, 1H), 4.31-4.30 (m, 2H), 3.80-3.71 (m, 4H), 3.64 (q, J = 5.6 Hz 1H), 3.48-3.45 (m, 2H), 3.15-3.12 (m, 2H), 2.40-2.37 (m, 4H), 1.40 (d, J = 5.6 Hz, 3H). 421 Chiral HPLC SFC Method F: 2nd eluting com- pound .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.39 (s, 1H), 8.13-8.10 (m, 2H), 8.02 (s, 1H), 7.50 (d, J = 8.4 Hz, 1H), 4.31-4.30 (m, 2H), 3.80-3.71 (m, 4H), 3.65 (q, J = 5.6 Hz 1H), 3.48-3.45 (m, 2H), 3.15-3.12 (m, 2H), 2.40-2.37 (m, 4H), 1.40 (d, J = 5.6 Hz, 3H). 422 Racemic .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 12.35 (s, 1H), 7.15 (d, J = 7.2 Hz, 1H), 6.76 (d J = 7.1 Hz, 1H), 6.71 (ms, 1H), 6.00 (s, 1H), 4.51 (t, J = 8.8 Hz, 2H), 3.35-3.3 (m, 1H), 3.19-3.14 (m, 5H), 3.12-2.95 (m, 6H), 2.41-2.33 (m, 4H), 1.55 (d, J = 6.0 Hz, 3H). 423 Racemic .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.45 (s, 1H), 7.16 (d, J = 7.2 Hz, 1H), 6.74 (d, J = 7.6 Hz, 1H), 6.71 (s, 1H), 4.60 (s, 1H), 4.50 (t, J = 8.6 Hz, 2H), 4.42 (s, 2H), 3.58-3.56 (m, 4H), 3.34-3.33 (m, 2H), 3.13 (t, J = 8.0 Hz, 2H), 2.40 (t, J = 39.2 Hz, 4H), 1.28 (d, J = 6.8 Hz, 3H). 424 S-enan- tiomer .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.71 (s, 2H), 7.14 (d, J = 7.2 Hz, 1H), 6.75 (d, J = 7.6 Hz, 1H), 6.71 (s, 1H), 4.48 (t, J = 6.8 Hz, 2H), 3.81-3.79 (m, 4H), 3.36 (q, J = 6.8 Hz, 1H), 3.13 (t, J = 8.4 Hz, 2H), 2.45-2.39 (m, 4H), 1.28 (d, J = 6.4 Hz, 3H). 425 Racemic .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 12.48-12.44 (m, 1H), 8.24-7.77 (m, 1H), 7.15 (d, J = 7.6 Hz, 1H), 6.76 (d, J = 8.0 Hz, 1H), 6.71 (s, 1H), 6.24- 5.81 (m, 1H), 4.74-4.72 (q, J = 6.8 Hz, 1H), 4.51 (t, J = 8.4 Hz, 2H), 3.48- 3.45 (m, 2H), 3.34-3.30 (m, 1H), 3.18-3.14 (m, 4H), 3.10-3.04 (m, 4H), 2.50-2.34 (m, 4H), 1.28 (d, J = 6.8 Hz, 3H). 426 Racemic .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.15 (d, J = 7.6 Hz, 1H), 6.76 (d, J = 1.2 Hz, 1H), 6.71 (s, 1H), 4.51 (t, J = 8.8 Hz, 2H), 4.22 (t, J = 4.8 Hz, 2H), 3.72 (t, J = 4.8 Hz, 2H), 3.39-3.34 (m, 1H), 3.16-3.09 (m, 6H), 2.96 (s, 3H), 2.51-2.33 (m, 4H), 1.28 (d, J = 6.80 Hz, 3H). 427 Racemic .sup.1H NMR (400 MHz, DMSO-d.sub.6): 8.38 (d, J = 4.4 Hz, 1H), 7.55 (d, J = 4.4 Hz, 1H), 7.16 (d, J = 7.2 Hz, 1H), 6.77 (d, J = 7.2 Hz, 1H), 6.73 (s, 1H), 4.51 (t, J = 8.8 Hz, 2H), 4.03 (s, 3H), 3.47-3.38 (m, 4H), 3.36-3.34 (m, 1H), 3.16 (t, J = 8.4 Hz, 2H), 2.43-2.34 (m, 4H), 1.29 (d, J = 6.8 Hz, 3H). 428 00 Racemic .sup.1HNMR (400 MHz, DMSO-d6): δ 11.70 (s, 1H), 7.62 (d, J = 5.6 Hz, 1H), 7.15 (d, J = 7.6 Hz, 1H), 6.95 (d, J = 5.6 Hz, 1H), 6.76 (d, J = 8.4 Hz, 1H), 6.72 (s, 1H), 4.50 (t, J = 8.4 Hz, 2H), 3.48-4.34 (m, 4H), 3.13 (t, J = 8.8 Hz, 2H), 2.49-2.33 (m, 4H), 1.28 (d, J = 6.8 Hz, 3H). 429 01 Racemic .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.07 (s, 1H), 7.96 (d, J = 8.4 Hz, 1H), 7.83 (s, 1H), 7.38 (dd, J = 8.6, 1.6 Hz, 1H), 4.22-4.10 (m, 2H), 3.90 (s, 1H), 3.71-3.69 (m, 4H), 3.60 (q, J = 6.8 Hz, 1H), 3.40-3.25 (m, 2H), 3.06 (t, J = 6.8 Hz, 2H), 2.79 (s, 3H), 2.45-2.33 (m, 4H), 1.38 (d, J = 6.8 Hz, 3H). 430 02 Racemic .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.38 (s, 1H), 8.11 (d, J = 8.4 Hz, 1H), 8.07 (s, 1H), 8.02 (d, J = 8.4 Hz, 1H), 7.51-7.48 (dd, J = 8.4, 1.6 Hz, 1H), 4.18-4.08 (m, 2H), 3.90 (s, 1H), 3.72-3.64 (m, 5H), 3.36-3.29 (m, 2H), 3.06 (t, J = 6.4 Hz, 2H), 2.52-2.39 (m, 4H), 1.39 (d, J = 6.80 Hz, 3H). 431 03 Racemic .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.08 (s, 1H), 7.14 (d, J = 7.6 Hz, 1H), 6.75 (d, J = 7.6 Hz, 1H), 6.71 (s, 1H), 4.50 (t, J = 8.8 Hz, 2H), 4.22-4.10 (m, 2H), 3.91 (s, 1H), 3.69-3.67 (m, 4H), 3.40-3.30 (m, 2H), 3.18-3.05 (m, 5H), 2.50-2.31 (m, 4H), 1.27 (d, J = 6.4 Hz, 3H). 432 04 Racemic .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.40 (s, 1H), 8.77 (s, 2H), 8.33 (s, 1H), 8.13 (d, J = 7.2 Hz, 1H), 8.04 (s, 1H), 7.74 (s, 1H), 7.52 (d, J = 6.8 Hz, 1H), 6.54 (s, 1H), 3.37-3.67 (m, 5H), 2.68-2.34 (m, 4H), 1.43 (d, J = 4.8 Hz, 3H). 433 05 Racemic .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.38 (s, 1H), 8.16 (s, 2H), 8.12 (d, J = 8.4 Hz, 1H), 8.02 (s, 1H), 7.50 (d, J = 8.4 Hz, 1H), 4.00 (q, J = 6.8 Hz, 2H), 3.64-3.62 (m, 5H), 2.45-2.39 (m, 4H), 1.40 (d, J = 6.8 Hz, 3H), 1.28 (t, J = 6.8 Hz, 3H). 434 06 Racemic .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.38 (s, 1H), 8.15 (s, 2H), 8.12 (d, J = 8.4 Hz, 1H), 8.02 (s, 1H), 7.50 (d, J = 8.4 Hz, 1H), 4.44-4.43 (m, 1H), 3.63-3.61 (m, 5H), 2.45-2.39 (m, 4H), 1.40 (d, J = 6.8 Hz, 3H), 1.21 (d, J = 6.0 Hz, 6H). 435 07 Racemic .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.38 (s, 1H), 8.27 (s, 2H), 8.12 (d, J = 8.4 Hz, 1H), 8.02 (s, 1H), 7.50 (dd, J = 8.4, 1.6 Hz, 1H), 4.73 (q, J = 8.8 Hz, 2H), 3.65-3.64 (m, 5H), 2.45-2.39 (m, 4H), 1.40 (d, J = 6.8 Hz, 3H). 436 08 Racemic .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 12.00 (s, 1H), 7.09 (d, J = 7.6 Hz, 1H), 6.73 (d, J = 7.6 Hz, 1H), 6.63 (s, 1H), 3.37-3.33 (m, 4H), 2.96 (s, 2H), 2.50-2.35 (m, 4H), 2.09 (s, 3H), 1.40 (s, 3H), 1.39(s, 3H), 1.27 (d, J = 6.4 Hz, 3H). 437 09 Racemic .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.58 (s, 1H), 7.70 (s, 1H), 7.10 (d, J = 7.6 Hz, 1H), 6.74 (d, J = 7.2 Hz, 1H), 6.65 (s, 1H), 3.80-3.79 (s, 4H), 3.37-3.36 (d, J = 4.0 Hz, 1H), 2.96 (s, 2H), 2.37-2.34 (m, 4H), 1.40 (d, J = 2.8 Hz, 6H), 1.28 (d, J = 6.8 Hz, 3H). 438 0 Chiral HPLC SFC Method 1: 1st eluting com- pound .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.14 (d, J = 7.2 Hz, 1H), 6.73 (d, J = 8.0 Hz, 1H), 6.70 (s, 1H), 6.46 (s, 2H), 4.52-4.48 (m, 2H), 3.37-3.365 (m, 1H), 3.19-3.11 (m, 6H), 2.45-2.36 (m, 4H), 1.25 (d, J = 6.8 Hz, 3H). 439 Racemic .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 12.03 (s, 1H), 7.61-7.59 (m, 2H), 7.32 (d, J = 9.6 Hz, 1H), 3.62-3.60 (m, 1H), 3.47-3.35 (m, 4H), 2.6 (s, 3H), 2.45-2.41 (m, 4H), 2.10 (s, 3H), 1.37 (d, J = 6.8 Hz, 3H). 440 Racemic .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.57 (s, 1H), 7.70 (s, 1H), 7.60-7.58 (m, 2H), 7.32 (d, J = 8.0 Hz, 1H), 3.88-3.75 (m, 4H), 3.60 (q, J = 6.8 Hz, 1H), 3.43-3.33 (m, 2H), 2.78 (t, J = 6.8 Hz, 2H), 2.60 (s, 3H), 2.38- 2.22 (m, 4H), 1.37 (d, J = 6.8 Hz, 3H). 441 Racemic .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.67 (s, 2H), 7.59-7.57 (m, 2H), 7.31 (dd, J = 8.6, 0.8 Hz, 1H), 3.84 (t, J = 5.2 Hz, 4H), 3.61-3.59 (m, 1H), 3.20 (s, 3H), 2.59 (s, 3H), 2.50-2.48 (m, 2H), 2.41-2.37 (m, 2H), 1.36 (d, J = 6.8 Hz, 3H). 442 Racemic .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.10 (s, 1H), 7.60-7.58 (m, 2H), 7.31 (d, J = 8.4 Hz, 1H), 4.30 (s, 2H), 3.75-3.66 (m, 4H), 3.58-3.56 (m, 1H), 3.47 (t, J = 6.0 Hz, 2H), 3.14 (t, J = 6.8 Hz, 2H), 2.60 (s, 3H), 2.44-2.29 (m, 4H), 1.37 (d, J = 6.4 Hz, 3H). 443 Racemic .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.39 (s, 1H), 8.47 (d, J = 2.4 Hz, 1H), 8.13 (d, J = 6.4 Hz, 1H), 8.03 (s, 1H), 7.86 (d, J = 6.8 Hz, 1H), 7.50 (d, J = 8.0 Hz, 1H), 6.92 (d, J = 9.6 Hz, 1H), 3.75-3.67 (m, 5H), 3.14 (s, 3H), 2.55-2.51 (m, 2H), 2.44-2.41 (m, 2H), 1.41 (d, J = 6.4 Hz, 3H). 444 Racemic .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.47 (d, J = 1.6 Hz, 1H), 7.97 (d, J = 8.4 Hz, 1H), 7.87-7.85 (m, 2H), 7.39 (d, J = 7.2 Hz, 1H), 6.91 (d, J = 9.2 Hz, 1H), 3.67-3.61 (m, 5H), 3.13 (s, 3H), 2.79 (s, 3H), 2.55-2.55 (m, 2H), 2.45-2.43 (m, 2H), 1.39 (d, J = 6.4 Hz, 3H). 445 Racemic .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.69-8.67 (m, 2H), 7.97 (d, J = 8.4 Hz, 1H), 7.85 (s, 1H), 7.39 (d, J = 8.0 Hz, 1H), 3.92-3.86 (m, 4H), 3.64-3.63 (m, 1H), 3.21 (s, 3H), 2.80 (s, 3H), 2.43-2.40 (m, 4H), 1.39 (d, J = 6.8 Hz, 3H). 446 Racemic .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.84 (s, 1H), 7.16 (d, J = 7.6 Hz, 1H), 6.77 (d, J = 7.6 Hz, 1H), 6.73 (s, 1H), 6.33 (s, 1H), 4.51 (t, J = 8.8 Hz, 1H), 3.54-3.51 (m, 4H), 3.42-3.20 (m, 1H), 3.14 (t, J = 8.8 Hz, 2H), 2.40- 2.30 (m, 4H), 1.29 (d, J = 6.8 Hz, 3H). 447 Chiral HPLC SFC Method G: 1st eluting com- pound .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.39 (s, 1H), 8.67 (s, 2H), 8.11 (d, J = 8.4 Hz, 1H), 8.02 (s, 1H), 7.50 (dd, J = 8.4, 1.6 Hz 1H), 3.87-3.85 (m, 4H), 3.68 (q, d, J = 6.8 Hz, 1H), 3.20 (s, 3H), 2.56-2.41 (m, 4H), 1.42 (d, J = 6.8 Hz, 3H). 448 0 Racemic .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.76 (s, 1H), 8.67 (s, 1H), 7.16 d, J = 7.6 Hz, 1H), 6.93 (d, J = 7.6 Hz, 2H), 4.80-4.70 (m, 2H), 4.40-4.38 (m, 1H), 4.15 (t, J = 4.4 Hz, 3H), 3.75 (m, 1H), 2.85-2.75 (m, 10H), 1.92 (t, J = 5.6 Hz, 2H), 1.61 (d, J = 6.8 Hz, 3H). 449 S-enan- tiomer .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.58 (s, 1H), 7.69 (s, 1H), 7.15 (d, J = 7.6 Hz, 1H), 6.76 (d, J = 7.6 Hz, 1H), 6.72 (s, 1H), 4.50 (t, J = 8.8 Hz, 2H), 3.81-3.76 (m, 4H), 3.38-3.37 (m, 3H), 3.13 (t, J = 8.8 Hz, 2H), 2.78 (t, J = 6.4 Hz, 2H), 2.42-2.38 (m, 4H), 1.28 (d, J = 6.80 Hz, 3H). 450 S-enan- tiomer .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.38 (s, 1H), 8.60 (s, 1H), 8.12 (d, J = 8.4 Hz, 1H), 8.02 (s, 1H), 7.50 (d, J = 8.4 Hz, 1H), 3.84-3.71 (m, 4H), 3.68 (d, J = 7.2 Hz, 1H), 3.32 (d, J = 4.4 Hz, 2H), 2.96 (s, 3H), 2.46-2.33 (m, 2H), 1.41 (d, J = 6.8 Hz, 3H), 1.19 (s, 6H). 451 Racemic .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.38 (s, 1H), 8.58 (s, 1H), 8.12 (d, J = 8.0 Hz, 1H), 8.02 (s, 1H), 7.50 (d, J = 8.0 Hz, 1H), 3.88-3.77 (m, 4H), 3.64-3.63 (m, 1H), 3.55-3.44 (m, 2H), 2.94 (s, 3H), 2.87-2.84 (m, 2H), 2.45-2.42 (m, 2H), 1.40 (d, J = 6.8 Hz, 3H). 452 S-enan- tiomer .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.16 (s, 2H), 7.14 (d, J = 7.6 Hz, 1H), 6.76 (d, J = 7.6 Hz, 1H), 6.71 (s, 1H), 4.90 (q, J = 7.2 Hz 1H), 4.50 (t, J = 8.8 Hz, 2H), 3.67 (s, 3H), 3.59 (t, J = 4.8 Hz, 3H), 3.13 (t, J = 8.4 Hz, 2H), 2.46-2.42 (m, 2H), 2.36-2.32 (m, 2H), 1.47 (d, J = 6.80 Hz, 3H), 1.28 (t, J = 6.4 Hz, 3H). 453 S-enan- tiomer .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.26 (s, 2H), 8.04 (q, J = 4.4 Hz, 1H), 7.15 (d, J = 7.6 Hz, 3H), 6.75 (d, J = 7.6 Hz, 1H), 6.71 (s, 1H), 4.58 (q, J = 6.8 Hz, 1H), 4.50 (t, J = 8.8 Hz, 2H), 3.60-3.58 (m, 4H), 3.14 (t, J = 8.8 Hz, 2H) 2.60 (d, J = 8.8 Hz, 3H), 2.45-2.33 (m, 2H), 1.38 (d, J = 6.8 Hz, 3H), 1.28 (t, J = 8.0 Hz, 3H). 454 S-enan- tiomer .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.17 (s, 2H), 7.15 (d, J = 7.2 Hz, 1H), 6.76 (d, J = 7.6 Hz, 1H), 6.72 (s, 1H), 4.91 (d, J = 6.8 Hz, 1H), 4.51 (t, J = 8.8 Hz, 2H), 3.67 (s, 3H), 3.61-3.58 (m, 4H), 3.33-3.29 (m, 1H), 3.14 (t, J = 8.4 Hz, 2H), 2.46-2.42 (m, 4H), 1.48 (d, J = 6.8 Hz, 3H), 1.26 (t, J = 6.8 Hz, 3H),. 455 S-enan- tiomer .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.15 (s, 2H), 8.05 (s, 1H), 7.15 (d, J = 7.2 Hz, 1H), 6.76 (d, J = 7.2 Hz, 1H), 6.72 (s, 1H), 4.58 (q, J = 6.4 Hz, 1H), 4.51 (t, J = 8.8 Hz, 2H), 3.59-3.57 (m, 4H), 3.18-3.11 (m, 3H), 2.67- 2.59 (m, 3H), 2.35-2.34 (m, 4H), 1.38 (d, J = 6.4 Hz, 3H), 1.28 (d, J = 6.4 Hz, 3H). 456 S-enan- tiomer .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.39 (s, 1H), 8.72 (s, 2H), 8.12 (d, J = 8.0 Hz, 1H), 8.02 (s, 1H), 7.50 (dd, J = 8.2, 1.2 Hz, 2H), 3.83 (t, J = 4.8 Hz, 4H), 3.65 (q, J = 6.8 Hz, 1H), 2.46-2.42 (m, 4H), 1.41 (d, J = 6.8 Hz, 3H). 457 S-enan- tiomer .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.38 (s, 1H), 8.39 (s, 2H), 8.11 (d, J = 8.8 Hz, 1H), 8.02 (s, 1H), 7.50 (d, J = 8.2 Hz, 1H), 3.70-3.66 (m, J = 4.8 Hz, 5H), 2.50-2.33 (m, 4H), 1.40 (d, J = 6.4 Hz, 3H). 458 0 S-enan- tiomer .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.39 (s, 1H), 8.75-8.74 (m, 2H), 8.12 (d, J = 8.4 Hz, 1H), 8.03 (d, J = 1.2 Hz, 1H), 7.82 (s, 1H), 7.50 (dd, J = 8.4, 1.2 Hz, 1H), 7.26 (s, 1H), 3.81 (t, J = 4.8 Hz, 4H), 3.67 (q, J = 6.4 Hz, 1H), 2.56-2.39 (m, 4H), 1.41 (d, J = 6.8 Hz, 3H). 459 Racemic .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.58 (s, 1H), 8.11 (d, J = 5.2 Hz, 1H), 7.70 (s, 1H), 6.97 (d, J = 4.0 Hz, 1H), 6.75 (s, 1H), 3.83-3.50 (m, 7H), 3.48 (q, J = 5.8 Hz, 1H), 3.38-3.28 (m, 2H), 2.80-2.77 (m, 2H), 2.51-2.45 (m, 2H), 2.39-2.33 (m, 2H), 1.29 (d, J = 6.8 Hz, 3H). 460 Racemic .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.57 (s, 1H), 8.40 (s, 1H), 7.84 (s, 1H), 7.70 (s, 1H), 6.74 (s, 1H), 3.81-3.79 (m, 4H), 3.71-3.69 (m, 1H), 3.38- 3.36 (m, 2H), 2.78 (t, J = 6.4 Hz, 2H), 2.51 (s, 3H), 2.51-2.46 (m, 4H), 1.40 (d, J = 6.80 Hz, 3H). 461 Racemic .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.40 (s, 1H), 7.84 (s, 1H), 6.75 (s, 1H), 3.72-3.51 (m, 1H), 3.36 (t, J = 4.8 Hz, 4H), 2.51 (s, 3H), 2.47-2.42 (m, 4H), 2.12 (s, 3H), 1.40 (d, J = 6.8 Hz, 3H). 462 Racemic .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.39 (s, 1H), 8.61 (s, 2H), 8.12 (d, J = 8.4 Hz, 1H), 8.03 (s, 1H), 7.50 (d, J = 8.4 Hz, 1H), 7.32 (s, 2H), 3.83-3.81 (m, 4H), 3.68-3.66 (m, 1H), 2.55-2.38 (m, 4H), 1.40 (d, J = 6.8 Hz, 3H). 463 S-enan- tiomer .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.62 (s, 2H), 7.33 (s, 2H), 7.15 (d, J = 7.6 Hz, 1H), 6.77-6.72 (m, 2H), 4.50 (t, J = 8.8 Hz, 2H), 3.80-3.80 (m, 4H), 3.38-3.36 (m, 1H), 3.13 (t, J = 8.4 Hz, 2H), 2.46-2.35 (m, 4H), 1.28 (d, J = 6.8 Hz, 3H). 464 Racemic .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.38 (s,lH), 8.57 (s, 2H), 8.12 (dd, J = 8.2, 1.2 Hz, 1H), 8.03 (s, 1H), 7.50 (d, J = 8.4 Hz, 1H), 7.37-7.36 (m, 1H), 3.85-3.82 (m, 4H), 3.68 (q, J = 6.4 Hz, 1H), 2.56 (s, 3H), 2.45-2.41 (m, 4H), 1.41 (d, J = 6.4 Hz, 3H). 465 S-enan- tiomer .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.58 (s, 2H), 7.36 (d, J = 5.2 Hz, 1H), 7.15 (d, J = 7.6 Hz, 1H), 6.76 (d, J = 7.6 Hz, 1H), 6.72 (s, 1H), 4.50 (t, J = 8.8 Hz, 2H), 3.82-3.79 (m, 4H), 3.52-3.32 (m, 1H), 3.13 (t, J = 8.8 Hz, 2H), 2.48-2.37 (m, 7H), 1.28 (d, J = 6.4 Hz, 3H). 466 Racemic .sup.1H NMR (400 MHz, CDCl.sub.3): δ 7.98 (s, 1H), 7.19 (s, 1H), 5.07-5.05 (m, 1H), 3.70-3.65 (m, 4H), 3.49-3.43 (m, 1H), 3.30-3.18 (m, 1H), 2.99-2.93 (m, 1H), 2.77-2.74 (m, 4H), 2.34 (s, 3H), 1.55 (d, J = 3.6 Hz, 3H), 1.27 (d, J = 5.20 Hz, 3H). 467 Racemic .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 12.30 (s, 1H), 8.99 (s, 1H), 8.24 (s, 1H), 7.15 (d, J = 7.2 Hz, 1H), 6.77 (d, J = 7.6 Hz, 1H), 6.73 (s, 1H), 4.51 (t, J = 8.8 Hz, 2H), 3.85-3.84 (m, 4H), 3.38 (q, J = 6.8 Hz, 1H), 3.14 (t, J = 8.4 Hz, 2H), 2.50-2.34 (m, 4H), 1.29 (d, J = 6.4 Hz, 3H). 468 0 Racemic .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.41 (s, 1H), 8.52 (s, 2H), 8.12 (d, J = 8.0 Hz, 1H), 8.03 (s, 1H), 7.51 (d, J = 8.4 Hz, 1H), 6.94 (m, 1H), 3.80- 3.79 (m, 4H), 3.66 (q, J = 6.4 Hz, 1H), 2.43-2.39 (m, 4H), 1.41 (d, J = 6.4 Hz, 3H). 469 Racemic .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.41 (d, J = 6.0 Hz, 1H), 8.58 (d, J = 2.8 Hz, 1H), 8.39 (d, J = 2.0 Hz, 1H), 8.14-8.12 (m, 1H), 8.05 (s, 1H), 7.62 (s, 1H), 7.52 (d, J = 8.4 Hz, 1H), 3.69 (q, J = 6.8 Hz, 1H), 3.35-3.30 (m, 4H), 2.67-2.61 (m, 4H), 1.43 (s, 3H). 470 S-enan- tiomer .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.58 (d, J = 2.8 Hz, 1H), 8.39 (d, J = 1.6 Hz, 1H), 7.62-7.60 (m, 1H), 7.16 (d, J = 7.6 Hz, 1H), 6.78 (d, J = 7.6 Hz, 1H), 6.74 (s, 1H), 4.51 (t, J = 8.8 Hz, 2H), 3.39-3.37 (m, 1H), 3.33-3.29 (m, 7H), 3.14 (t, J = 8.4 Hz, 2H), 2.57-2.55 (m, 2H), 2.50-2.44 (m, 2H), 1.30 (d, J = 6.8 Hz, 3H). 471 Racemic .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 12.02 (s, 1H), 7.11 (d, J = 7.2 Hz, 1H), 6.74 (d, J = 7.2 Hz, 1H), 6.67 (s, 1H), 4.89 (t, J = 6.0 Hz, 1H), 3.38-3.24 (m, 6H), 2.74 (q, J = 7.6 Hz, 1H), 2.43-2.40 (m, 4H), 2.10 (s, 3H), 1.38 (t, J = 2.0 Hz, 3H), 1.26 (t, J = 6.8 Hz, 3H). 472 Racemic .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.58 (d, J = 2.8 Hz, 1H), 7.70 (s, 1H), 7.11 (d, J = 7.6 Hz, 1H), 6.74 (d, J = 7.6 Hz, 1H), 6.68 (s, 1H), 4.88 (q, J = 8.0 Hz, 1H), 3.80-3.79 (m, 4H), 3.38-3.23 (m, 4H), 2.80-2.71 (m, 3H), 2.51-2.37 (m, 4H), 1.38 (t, J = 2.8 Hz, 3H), 1.27 (d, J = 6.4 Hz, 3H). 473 S-enan- tiomer .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.40 (s, 1H), 8.12 (d, J = 8.4 Hz, 1H), 8.04 (s, 1H), 7.82 (d, J = 9.2 Hz, 1H), 7.51 (t, J = 7.6 Hz, 1H), 7.24 (d, J = 10 Hz, 1H) ,3.86 (s, 3H), 3.75-3.72 (m, 4H), 3.70-3.68 (m, 1H), 2.61-2.55 (m, 2H), 2.48-2.45 (m, 2H), 1.42 (d, J = 6.8 Hz, 3H) 474 Chiral HPLC SFC Method F: 1st eluting com- pound .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 12.03 (s, 1H), 7.12 (d, J = 7.6 Hz, 1H), 6.75 (d, J = 7.6 Hz, 1H), 6.68 (s, 1H), 4.89 (q, J = 6.4 Hz, 1H), 3.40-3.24 (m, 5H), 2.77-2.68 (m, 1H), 2.44-2.39 (m, 7H), 2.10 (s, 3H), 1.39 (d, J = 6.0 Hz, 3H), 1.27 (t, J = 6.40 Hz, 3H). 475 Chiral HPLC SFC Method F: 2nd eluting com- pound .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 12.03 (s, 1H), 7.12 (d, J = 7.2 Hz, 1H), 6.75 (d, J = 7.6 Hz, 1H), 6.68 (s, 1H), 4.90 (q, J = 8.0 Hz, 1H), 3.40-3.24 (m, 5H), 2.77-2.68 (m, 1H), 2.42-2.34 (m, 4H), 2.09 (s, 3H), 1.38 (d, J = 6.0 Hz, 3H), 1.27 (t, J = 6.8 Hz, 3H). 476 Chiral HPLC SFC Method F: 1st eluting com- pound .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.58 (s, 1H), 7.69 (s, 1H), 7.11 (d, J = 7.6 Hz, 1H), 6.74 (d, J = 7.6 Hz, 1H), 6.68 (d, J = Hz, 1H), 4.89 (q, J = 7.2 Hz, 1H), 3.80-3.78 (m, 4H), 3.37-3.33 (m, 3H), 2.80-2.77 (m, 3H), 2.37- 2.34 (m, 4H), 1.37 (d, J = 6.4 Hz, 3H), 1.28 (d, J = 6.40 Hz, 3H). 477 S-enan- tiomer .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.39 (s, 1H), 8.14-8.12 (m, 2H), 8.04 (s, 1H), 7.81 (d, J = 9.6 Hz, 1H), 7.52-7.50 (m, 2H), 7.28 (d, J = 9.6 Hz, 1H), 3.70-3.3.68 (m, 5H), 2.51-2.50 (m, 4H), 1.41 (d, J = 6.8 Hz, 3H). 478 0 S-enan- tiomer .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.38 (s, 1H), 8.62 (s, 1H), 8.32 (s, 1H), 8.12 (d, J = 8.0 Hz, 1H), 8.03 (s, 1H), 8.51 (d, J = 8.0 Hz, 1H), 3.80 (s, 3H), 3.73-3.3.68 (m, 5H), 2.57-2.43 (m, 4H), 1.41 (d, J = 6.8 Hz, 3H).

Example B01: Human O-GlcNAcase enzyme inhibition assay

(491) 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)

(492) 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.

(493) 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.

(494) Total protein O-GlcNAcylation immunoassay:

(495) 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

(496) (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.

(497) (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.

(498) (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.

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

(500) (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.

(501) (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.

(502) (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.

(503) (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.

(504) (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.