KDM1A inhibitors for the treatment of disease
11578059 · 2023-02-14
Assignee
Inventors
- Amy E. Tapper (San Carlos, CA, US)
- Cassandra Celatka (Hull, MA)
- Michael Clare (Skokie, IL)
- Hugh Y. Rienhoff, Jr. (San Carlos, CA)
Cpc classification
C07D491/107
CHEMISTRY; METALLURGY
A61K45/06
HUMAN NECESSITIES
A61K31/501
HUMAN NECESSITIES
A61K31/541
HUMAN NECESSITIES
C07D241/08
CHEMISTRY; METALLURGY
A61K31/5377
HUMAN NECESSITIES
A61K9/0053
HUMAN NECESSITIES
C07D403/04
CHEMISTRY; METALLURGY
C07D403/10
CHEMISTRY; METALLURGY
A61K31/506
HUMAN NECESSITIES
C07D401/04
CHEMISTRY; METALLURGY
International classification
A61K9/00
HUMAN NECESSITIES
A61K31/501
HUMAN NECESSITIES
A61K31/506
HUMAN NECESSITIES
A61K31/5377
HUMAN NECESSITIES
A61K31/541
HUMAN NECESSITIES
A61K45/06
HUMAN NECESSITIES
C07D241/08
CHEMISTRY; METALLURGY
C07D401/04
CHEMISTRY; METALLURGY
C07D403/04
CHEMISTRY; METALLURGY
C07D403/10
CHEMISTRY; METALLURGY
Abstract
The present disclosure relates to compounds and methods which may be useful as inhibitors of KDM1A for the treatment or prevention of diseases. Methods of inhibition of KDM1A, methods of increasing gamma globin gene expression, and methods to induce differentiation in cancer cells in a human or animal subject are also provided for treatment of disease such as acute myelogenous leukemia.
Claims
1. A compound of structural Formula I: ##STR00386## or a salt thereof, wherein: m is chosen from 0, 1, 2, 3, and 4; R.sup.1 is a nitrogen-containing heterocycloalkyl or heteroaryl, either of which is optionally substituted with 1, 2, or 3 R.sup.5 groups; R.sup.2 is H, or is chosen from alkyl, cycloalkyl, haloalkyl, heterocycloalkyl, aryl, and heteroaryl, any of which is optionally substituted with 1, 2, or 3 R.sup.6 groups; R.sup.3 is chosen from aryl and heteroaryl, either of which is optionally substituted with 1, 2, or 3 R.sup.7 groups; R.sup.4 is chosen from hydrogen, alkyl, alkenyl, alkynyl, and cycloalkyl; each R.sup.5 is independently chosen from halogen, alkyl, alkenyl, alkynyl, hydroxy, amino, oxo, cyano, COR.sup.8, CONR.sup.8R.sup.9, COOR.sup.8, NHCOR.sup.8, NHCONR.sup.8R.sup.9, SOR.sup.8, SO.sub.2R.sup.8, NHSO.sub.2R.sup.8, and SO.sub.2NR.sup.8R.sup.9; each R.sup.6 is independently chosen from hydrogen, halogen, alkyl, alkylsulfonylaryl, alkenyl, alkynyl, cycloalkyl, haloalkyl, haloalkoxy, haloaryl, alkoxyaryl, aryl, aryloxy, aralkyl, heterocycloalkyl, heteroaryl, alkylheteroaryl, heteroarylalkyl, cyano, alkoxy, alkoxyaryl, amino, alkylamino, dialkylamino, oxo, COR.sup.8, SO.sub.2R.sup.8, NHSO.sub.2R.sup.8, NHSO.sub.2NHR.sup.8, SO.sub.2NR.sup.8R.sup.9, NHCOR.sup.8, NHCONHR.sup.8, CONHR.sup.8, and CONR.sup.8R.sup.9; each R.sup.7 is independently chosen from alkyl, amino, cyano, halo, and hydroxy; and each R.sup.8 and R.sup.9 is independently chosen from hydrogen, aryl, and lower alkyl; or R.sup.8 and R.sup.9 may be taken together to form a nitrogen-containing heterocycloalkyl or heteroaryl ring, which is optionally substituted with lower alkyl.
2. The compound as recited in claim 1, or a salt thereof, wherein R.sup.4 is hydrogen.
3. The compound as recited in claim 2, or a salt thereof, wherein R.sup.3 is phenyl, and is optionally substituted with 1 or 2 R.sup.7 groups.
4. The compound as recited in claim 3, or a salt thereof, wherein R.sup.7 is fluorine.
5. The compound as recited in claim 1, or a salt thereof, having structural Formula II: ##STR00387## or a salt thereof, wherein: R.sup.1 is a nitrogen-containing heterocycloalkyl or heteroaryl, either of which is optionally substituted with 1, 2, or 3 R.sup.5 groups; R.sup.2 is H, or is chosen from alkyl, cycloalkyl, haloalkyl, heterocycloalkyl, aryl, and heteroaryl, any of which is optionally substituted with 1, 2, or 3 R.sup.6 groups; R.sup.4 is chosen from hydrogen, alkyl, alkenyl, alkynyl, and cycloalkyl; each R.sup.5 is independently chosen from halogen, alkyl, alkenyl, alkynyl, hydroxy, amino, oxo, cyano, COR.sup.8, CONR.sup.8R.sup.9, COOR.sup.8, NHCOR.sup.8, NHCONR.sup.8R.sup.9, SOR.sup.8, SO.sub.2R.sup.8, NHSO.sub.2R.sup.8, and SO.sub.2NR.sup.8R.sup.9; each R.sup.6 is independently chosen from hydrogen, halogen, alkyl, alkylsulfonylaryl, alkenyl, alkynyl, cycloalkyl, haloalkyl, haloalkoxy, haloaryl, alkoxyaryl, aryl, aryloxy, aralkyl, heterocycloalkyl, heteroaryl, alkylheteroaryl, heteroarylalkyl, cyano, alkoxy, alkoxyaryl, amino, alkylamino, dialkylamino, oxo, COR.sup.8, SO.sub.2R.sup.8, NHSO.sub.2R.sup.8, NHSO.sub.2NHR.sup.8, SO.sub.2NR.sup.8R.sup.9, NHCOR.sup.8, NHCONHR.sup.8, CONHR.sup.8, and CONR.sup.8R.sup.9; each R.sup.7 is independently chosen from hydrogen, alkyl, amino, cyano, halo, and hydroxy; and each R.sup.8 and R.sup.9 is independently chosen from hydrogen, aryl, and lower alkyl; or R.sup.8 and R.sup.9 may be taken together to form a nitrogen-containing heterocycloalkyl or heteroaryl ring, which is optionally substituted with lower alkyl.
6. The compound as recited in claim 5, or a salt thereof, wherein R.sup.4 is hydrogen.
7. The compound as recited in claim 6, or a salt thereof, wherein R.sup.1 is a nitrogen-containing heterocycloalkyl, which is optionally substituted with 1, 2, or 3 R.sup.5 groups.
8. The compound as recited in claim 7, or a salt thereof, wherein R.sup.1 is chosen from: ##STR00388## and is optionally substituted with 1, 2, or 3 R.sup.5 groups.
9. The compound as recited in claim 8, or a salt thereof, wherein each R.sup.5 is independently chosen from halogen, alkyl, hydroxy, amino, oxo, cyano, COR.sup.8, CONR.sup.8R.sup.9, COOR.sup.8, NHCOR.sup.8, NHCONR.sup.8R.sup.9, SOR.sup.8, SO.sub.2R.sup.8, NHSO.sub.2R.sup.8, and SO.sub.2NR.sup.8R.sup.9.
10. The compound as recited in claim 9, or a salt thereof, wherein each R.sup.5 is independently chosen from alkyl, oxo, CONR.sup.8R.sup.9, COOR.sup.8, SOR.sup.8, and SO.sub.2R.sup.8.
11. The compound as recited in claim 7, or a salt thereof, wherein R.sup.1, with substitution R.sup.5 where appropriate, and further with substitutions R.sup.8 and R.sup.9 where appropriate, is chosen from: ##STR00389##
12. The compound as recited in claim 7, or a salt thereof, wherein R.sup.1, with substitution R.sup.5 where appropriate, and further with substitutions R.sup.8 and R.sup.9 where appropriate, is chosen from: ##STR00390##
13. The compound as recited in claim 7, or a salt thereof, wherein R.sup.1, with substitution R.sup.5 where appropriate, and further with substitutions R.sup.8 and R.sup.9 where appropriate, is chosen from: ##STR00391##
14. The compound as recited in claim 6, or a salt thereof, wherein R.sup.1 is a nitrogen-containing heteroaryl, which is optionally substituted with 1, 2, or 3 R.sup.5 groups.
15. The compound as recited in claim 14, or a salt thereof, wherein R.sup.1 is chosen from: ##STR00392##
16. The compound as recited in claim 6, or a salt thereof, wherein R.sup.2 is H.
17. The compound as recited in claim 16, or a salt thereof, wherein R.sup.1 is chosen from piperidine, morpholine, thiomorpholine, piperazine, pyrrolidine, azetidine, 2-azaspiro[3.3]heptane, 2,6-diazaspiro[3.3]heptane, and 2-oxa-6-azaspiro[3.3]heptane, and is optionally substituted with 1, 2, or 3 R.sup.5 groups.
18. The compound as recited in claim 17, or a salt thereof, wherein each R.sup.5 is independently chosen from halogen, alkyl, hydroxy, amino, oxo, cyano, COR.sup.8, CONR.sup.8R.sup.9, COOR.sup.8, NHCOR.sup.8, NHCONR.sup.8R.sup.9, SOR.sup.8, SO.sub.2R.sup.8, NHSO.sub.2R.sup.8, and SO.sub.2NR.sup.8R.sup.9.
19. The compound as recited in claim 18, or a salt thereof, wherein each R.sup.5 is independently chosen from alkyl, oxo, CONR.sup.8R.sup.9, COOR.sup.8, SOR.sup.8, and SO.sub.2R.sup.8.
20. The compound as recited in claim 19, or a salt thereof, wherein R.sup.1 is chosen from: ##STR00393## and is optionally substituted with 1, 2, or 3 R.sup.5 groups.
21. The compound as recited in claim 16, or a salt thereof, wherein R.sup.1, with substitution R.sup.5 where appropriate, and further with substitutions R.sup.8 and R.sup.9 where appropriate, is chosen from: ##STR00394##
22. The compound as recited in claim 16, or a salt thereof, wherein R.sup.1, with substitution R.sup.5 where appropriate, and further with substitutions R.sup.8 and R.sup.9 where appropriate, is chosen from: ##STR00395##
23. The compound as recited in claim 16, or a salt thereof, wherein R.sup.1, with substitution R.sup.5 where appropriate, and further with substitutions R.sup.8 and R.sup.9 where appropriate, is chosen from: ##STR00396##
24. A compound chosen from: ##STR00397## ##STR00398## ##STR00399## ##STR00400## ##STR00401## or a salt thereof.
25. A method of treatment of a KDM1A-mediated disease, comprising the administration of a therapeutically effective amount of a compound as recited in claim 1, or a salt thereof, to a patient having a KDM1A-mediated disease.
26. A method of treatment of a KDM1A-mediated disease, comprising the administration of: a therapeutically effective amount of a compound as recited in claim 1, or a salt thereof; and another therapeutic agent to a patient having a KDM1A-mediated disease.
27. A method of treatment of a globin-mediated disease comprising the administration of a therapeutically effective amount of a compound as recited in claim 1, or a salt thereof, to a patient having a globin-mediated disease.
28. A pharmaceutical composition comprising a compound as recited in claim 1, or a salt thereof, together with a pharmaceutically acceptable carrier.
29. A method for achieving an effect in a patient comprising the administration of a therapeutically effective amount of a compound, or a salt thereof, as disclosed herein, or a salt thereof, to a patient, wherein the effect is chosen from an elevation of red blood cell count, an elevation of the red blood cell count of red cells containing fetal hemoglobin, an elevation in the total concentration of fetal hemoglobin in red cells, an elevation in the total concentration of fetal hemoglobin in reticulocytes, an increase in the transcription of the gamma globin gene in bone marrow-derived red cell precursors, a reduction in the number of sickle cell crises a patient experiences over a unit period of time, a halt to or prevention of tissue damage in the heart, spleen, brain or kidney caused by sickling cells, a reduction in the proportion of red cells that undergo sickling under physiological conditions of relative hypoxia as measured using patient blood in an in vitro assay, an increase in the amount of histone 3 lysine methylation at lysine position 4 (H3K4me1 and H3K4me2), and/or a decrease in the amount of histone 3 methylation at lysine position 9 (H3K9me1 or H3K4me2) near or at the gamma globin promoter as assayed by ChIP using cells derived from a treated patient.
30. A method of inhibiting at least one KDM1A function comprising the step of contacting KDM1A with a compound as recited in claim 1, or a salt thereof, wherein the inhibition is measured by phenotype of red cells or their precursors, either cultured or in vivo, in humans or mouse or transgenic mice containing the human beta globin locus or portions thereof, the ability of cancer cells to proliferate, become differentiated, or induced to undergo apoptosis, the expression of specific genes known to be regulated by KDM1A activity, a change in the histone methylation states, a change in the methylation state of proteins known to be demethylated by KDM1A, expression of KDM1A-regulated genes, or binding of KDM1A with a natural binding partner.
Description
EXAMPLES
Chromatographic Procedures
(1) The following chromatographic procedures may be employed to purify the compounds disclosed below.
(2) Procedure A: Sunfire Prep C18 OBD Column, 10 μm, 19×250 mm, mobile phase H.sub.2O (0.05% TFA)/CH.sub.3CN, flow rate: 20 mL/min, detector, UV 254/210 nm.
(3) Procedure B: (2 #-AnalyseHPLC-SHIMADZU (HPLC-10)), XBridge C18 OBD Prep column, pore size: 100 Å, particle size: 10 μm, column size: 19 mm×250 mm, mobile phase: H.sub.2O (0.05% TFA)/CH.sub.3CN, detector, UV 254/220 nm.
(4) Procedure C: (2 #-AnalyseHPLC-SHIMADZU (HPLC-10)), XBridge C18 OBD Prep column, pore size: 100 Å, particle size: 10 μm, column size: 19 mm×250 mm, mobile phase: H.sub.2O (10 mM NaHCO.sub.3)/CH.sub.3CN, detector, UV 254/220 nm.
(5) Procedure D: (2 #-AnalyseHPLC-SHIMADZU (HPLC-10)), XBridge Shield RP18 OBD column, pore size: 130 Å, particle size 10 μm, column size: 19×250 mm, mobile phase: H.sub.2O (0.05% TFA)/CH.sub.3CN, flow rate: 25 mL/min, detector, UV 254/220 nm.
(6) Procedure E: (2 #-AnalyseHPLC-SHIMADZU (HPLC-10)), XBridge Shield RP18 OBD column, pore size: 130 Å, particle size 10 μm, column size: 19×250 mm, mobile phase: H.sub.2O (10 mM NaHCO.sub.3)/CH.sub.3CN, flow rate: 25 mL/min, detector, UV 254/220 nm.
(7) Procedure F: (2 #SHIMADZU (HPLC-01)): Column, Xselect CSH OBD Column, particle size 5 μm, column size: 30×150 mm; mobile phase, H.sub.2O (0.05% TFA) and CH.sub.3CN, flow rate 60 mL/min, Detector, UV 220/254 nm.
(8) Procedure G: (2 #SHIMADZU (HPLC-01)): Column: Xselect CSH Fluoro Phenyl OBD Column, particle size 5 μm, column size: 19×250 mm, 5 um; mobile phase H.sub.2O (0.05% TFA) and CH.sub.3CN, flow rate: 25 mL/min, Detector 254/210 nm.
Example 1
(9) ##STR00031##
1-[4-Fluorobenzyl]-5-[3-([(1R,2S)-2-(4-fluorophenyl)cyclopropyl]amino)propyl]-3-[4-methylpiperazin-1-yl]pyrazin-2(1H)-one
(10) ##STR00032##
(11) 2-[((4-Fluorophenyl)methyl)amino]acetonitrile A mixture of 2-chloroacetonitrile (6.6 g, 87.90 mmol, 1.1 equiv), (4-fluorophenyl)methanamine (10 g, 79.91 mmol, 1 equiv), K.sub.2CO.sub.3 (33.1 g, 239.72 mmol, 3 equiv), and NaI (119.8 mg, 0.80 mmol, 0.01 equiv) in CH.sub.3CN (200 mL) was stirred for 16 hr at 80° C. The solids were removed by filtration, and the filtrate was concentrated under vacuum. The residue was dissolved in 200 mL of Et.sub.2O. The resulting solution was diluted with 50 mL of HCl in dioxane. The solid that formed was collected by filtration, affording 10 g (62.37%) of the title compound as a yellow solid.
(12) ##STR00033##
(13) 1-((4-Fluorophenyl)methyl)-3,5-dibromopyrazin-2(1H)-one A solution of the product from the previous step (12 g, 59.81 mmol, 1 equiv) and oxalyl bromide (64.5 g, 299.04 mmol, 5 equiv) in toluene (200 mL) was stirred for 16 hr at 55° C., then concentrated under vacuum. The residue was dissolved in 200 mL of CH.sub.2Cl.sub.2, washed with 2×100 ml of aq Na.sub.2CO.sub.3, and dried over anhydrous Na.sub.2SO.sub.4. The residue was purified with silica gel chromatography using EtOAc/petroleum ether (1:3) to afford 10 g (46.19%) of the title compound as a yellow oil.
(14) ##STR00034##
(15) 3-(4-Methylpiperazin-1-yl)-5-bromo-1-((4-fluorophenyl)methyl)pyrazin-2(1H)-one (Intermediate 1-3) A solution of the product from the previous step (10 g, 27.62 mmol, 1.00 equiv) in IPA (500 mL), 1-methylpiperazine (3.31 g, 33.15 mmol, 1.20 equiv), and DIEA (7.13 g, 55.25 mmol, 2.01 equiv) was stirred overnight at 90° C. The residue was purified with silica gel chromatography using EtOAc/petroleum ether (5:1), affording 10 g (95%) of the title compound as a yellow oil.
(16) ##STR00035##
(17) Ethyl (2E)-3-[6-(4-methylpiperazin-1-yl)-5(4H)-oxo-4-((4-fluorophenyl)-methyl)pyrazin-2-yl]propenoate (Intermediate 1-4) A mixture of the product from the previous step (6 g, 15.75 mmol, 1 equiv), ethyl (2E)-3-(tetramethyl-1,3,2-dioxaborolan-2-yl)prop-2-enoate (5.34 g, 23.62 mmol, 1.5 equiv), K.sub.2CO.sub.3 (6.52 g, 47.24 mmol, 3 equiv), Pd(dppf)Cl.sub.2 (1.15 g, 1.57 mmol, 0.1 equiv), dioxane (300 mL), and H.sub.2O (100 mL) was stirred overnight at 90° C. under N.sub.2. The residue was purified with silica gel chromatography using EtOAc/petroleum ether to afford 3 g (48%) of the title compound as a yellow oil.
(18) ##STR00036##
(19) Ethyl 3-[6-(4-methylpiperazin-1-yl)-5(4H)-oxo-4-((4-fluorophenyl)methyl)-pyrazin-2-yl]propanoate (Intermediate 1-5) A solution of the product from the previous step (3 g, 7.5 mmol, 1.00 equiv) in MeOH (50 mL) was stirred for 1 h over Pd/C (1.0 g) under an H.sub.2 atmosphere at rt. The solids were removed by filtration, and the filtrate was concentrated under vacuum to afford 2.6 g (86%) of the title compound as a yellow oil.
(20) ##STR00037##
(21) 3-[6-(4-Methylpiperazin-1-yl)-4-((4-fluorophenyl)methyl)-5(4H)-oxopyrazin-2-yl]propan-1-ol (Intermediate 1-6) To a stirred solution of the product from the previous step (1.3 g, 3.23 mmol, 1 equiv) in MeOH (50 mL) was added NaBH.sub.4 (2.46 g, 64.68 mmol, 20 equiv) in portions. The resulting solution was stirred for 16 hr at rt. The reaction was then quenched by the addition of 200 mL of H.sub.2O. The resulting solution was extracted with 3×100 ml of CH.sub.2Cl.sub.2, then concentrated under reduced pressure. The residue was purified with silica gel chromatography using CH.sub.2Cl.sub.2/MeOH (10:1) to afford 700 mg (60%) of the title compound as a yellow solid.
(22) ##STR00038##
(23) 3-[6-(4-Methylpiperazin-1-yl)-4-((4-fluorophenyl)methyl)-5(4H)-oxopyrazin-2-yl]propanal (Intermediate 1-7) A solution of the product from the previous step (600 mg, 1.67 mmol, 1.00 equiv) and Dess-Martin reagent (848 mg, 2.00 mmol, 1.20 equiv) in CH.sub.2Cl.sub.2 (30 mL) was stirred for 1 h at rt, then concentrated under vacuum and purified with silica gel chromatography using CH.sub.2Cl.sub.2/MeOH (10:1) to afford 400 mg (67%) of the title compound as a yellow solid.
(24) ##STR00039##
(25) 1-[4-Fluorobenzyl]-5-[3-([(1R,2S)-2-(4-fluorophenyl)cyclopropyl]amino)-propyl]-3-[4-methylpiperazin-1-yl]pyrazin-2(1H)-one (Example 1) A solution of the product from the previous step (400 mg, 1.12 mmol, 1 equiv) and (1R,2S)-2-(4-fluorophenyl)-cyclopropan-1-amine (202 mg, 1.34 mmol, 1.2 equiv) in MeOH (20 mL) was stirred for 30 min at rt. To the solution was then added NaBH(OAc).sub.3 (568 mg, 2.68 mmol, 2.4 equiv) at rt. The resulting solution was stirred for 30 min at rt. The reaction was then quenched by the addition of 30 mL of H.sub.2O. The resulting solution was extracted with 3×30 ml of CH.sub.2Cl.sub.2. The organic layers were combined, concentrated under reduced pressure, and purified using chromatographic Procedure A (30% to 33% CH.sub.3CN in 9 min), to afford 88.2 mg (9%) of the title compound as a yellow oil.
(26) LC-MS: (ES, m/z): 494 [M+H].sup.+. .sup.1H NMR (400 MHz, MeOD-d.sub.4) δ ppm: 7.39-7.36 (m, 2H), 7.18-7.15 (m, 2H), 7.07-7.01 (m, 5H), 5.04 (s, 2H), 4.87-4.81 (m, 2H), 3.52-3.47 (m, 2H), 3.21-3.12 (m, 6H), 2.94-2.90 (m, 4H), 2.53-2.42 (m, 3H), 2.06-1.98 (m, 2H), 1.49-1.32 (m, 2H).
Example 2
(27) ##STR00040##
5-[3-([(1R,2S)-2-(4-fluorophenyl)cyclopropyl]amino)propyl] 3-[4-methylpiperazin-1-yl]-pyrazin-2(1H)-one
(28) ##STR00041##
5-Bromo-3-(4-methylpiperazin-1-yl)-pyrazin-2(1H)-one (Intermediate 2-1)
(29) A solution of 3,5-dibromo-1,2-dihydropyrazin-2-one (10 g, 39.84 mmol, 1.00 equiv), 1-methylpiperazine (4.38 g, 1.1 eq), and DIEA (15.41 g, 3.0 equiv) in IPA (50 mL) was stirred for 16 h at 90° C., then cooled and concentrated under vacuum, to afford 10 g (91%) of the title compound as an off-white solid.
(30) ##STR00042##
(31) 5-Bromo-3-(4-methylpiperazin-1-yl)-1-[(2-(trimethylsilyl)ethoxy)methyl]-pyrazin-2(1H)-one (Intermediate 2-2) To a solution of the product from the previous step (10 g, 36.76 mmol, 1 equiv), in DMF (500 mL) was added NaH (60%) (2.21 g, 55.25 mmol, 1.5 equiv). The resulting solution was stirred for 1 hr at 0° C., then a solution of [2-(chloromethoxy)ethyl]trimethylsilane (9.15 g, 55.12 mmol, 1.5 equiv) in DMF (100 mL) was added dropwise with stirring over 30 min. The resulting solution was stirred for an additional 4 hr at rt, then diluted 500 ml of H.sub.2O and extracted with 3×500 ml of EtOAc. The combined organic layers were concentrated and purified with silica gel chromatography using EtOAc/petroleum ether (1:3) to afford 10.5 g (55.08%) of the title compound as a yellow oil.
(32) ##STR00043##
(33) Ethyl (2E)-3-[6-(4-methylpiperazin-1-yl)-5(4H)-oxo-4-[(2-(trimethylsilyl)-ethoxy)methyl]-pyrazin-2-yl]propenoate (Intermediate 2) The procedure for preparing Intermediate 1-4 was used with the product from the previous step (5 g, 12.39 mmol). The crude product was purified with silica gel chromatography using EtOAc/petroleum ether (1:3) to afford 2.5 g (55%) of the title compound as a light yellow solid.
(34) ##STR00044##
(35) Ethyl 3-[6-(4-methylpiperazin-1-yl)-5(4H)-oxo-4-[(2-(trimethylsilyl)ethoxy)-methyl]-pyrazin-2-yl]propanoate (Intermediate 2-4) The procedure for preparing Intermediate 1-5 was used with Intermediate 2-3 (2.5 g, 5.92 mmol, 1.00 equiv) to afford 2.2 g (93%) of the title compound as a solid.
(36) ##STR00045##
(37) 3-[6-(4-Methylpiperazin-1-yl)-5(4H)-oxo-4-[[2-(trimethylsilyl)ethoxy]methyl]pyrazin-2-yl]propan-1-ol (Intermediate 2-5) The procedure for preparing Intermediate 1-6 was used with Intermediate 2-4 (2.2 g, 5.92 mmol, 1.00 equiv). The crude product was purified with silica gel chromatography using CH.sub.2Cl.sub.2/MeOH (1:10) to afford 1.3 g (52%) of the title compound as a solid.
(38) ##STR00046##
(39) 3-[6-(4-Methylpiperazin-1-yl)-5(4H)-oxo-4-[[2-(trimethylsilyl)ethoxy]methyl]pyrazin-2-yl]propanal (Intermediate 2-6) The procedure for preparing Intermediate 1-7 was used with Intermediate 2-5 (1.3 g, 3.40 mmol, 1.00 equiv). The crude product was purified with silica gel chromatography using EtOAc/petroleum ether (1:3) to afford 700 mg (74%) of the title compound as a light yellow solid.
(40) ##STR00047##
(41) 5-(3-[[(1R,2S)-2-(4-Fluorophenyl)cyclopropyl]amino]propyl)-3-(4-methyl-piperazin-1-yl)-1-[[2-(trimethylsilyl)ethoxy]methyl]pyrazin-2(1H)-one (Intermediate 2-7) The reductive amination step for preparing Example 1 from Intermediate 1-7 was used with Intermediate 2-6 (700 mg, 1.84 mmol, 1.00 equiv). The residue was purified using silica gel chromatography using EtOAc/petroleum ether (1:3) to afford 400 mg (69%) of the title compound as a light yellow solid.
(42) ##STR00048##
(43) 5-[3-([(1R,2S)-2-(4-fluorophenyl)cyclopropyl]amino)propyl] 3-[4-methylpiperazin-1-yl]-pyrazin-2(1H)-one (Example 2) A solution of Intermediate 2-7 (300 mg, 0.58 mmol, 1.00 equiv) in aq HCl (25 mL)/CH.sub.2Cl.sub.2 (25 mL) was stirred for 1 h at rt. The resulting mixture was concentrated under vacuum, then purified using chromatographic Procedure E (28% to 60% CH.sub.3CN in 7 min), Rt: 6.20 min, to afford 44.1 mg (20%) of the title compound as an off-white solid.
(44) LC-MS: (ES, m/z): 386 [M+H].sup.+. .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.06-7.03 (m, 2H), 6.97-6.93 (m, 2H), 6.65-6.62 (s, 1H), 3.82-3.72 (s, 4H), 2.78-2.72 (m, 2H), 2.58-2.50 (m, 4H), 2.48-2.42 (m, 2H), 2.36-2.30 (m, 4H), 1.90-1.85 (m, 3H), 1.10-1.02 (m, 1H), 1.02-0.95 (m, 1H).
Example 3
(45) ##STR00049##
5-[3-([(1R,2S)-2-(4-fluorophenyl)cyclopropyl]amino)propyl]-3-[4-(methylsulfonyl)piperazin-1-yl]pyrazin-2(1H)-one
(46) ##STR00050##
(47) 5-Bromo-3-(4-(methylsulfonyl)piperazin-1-yl)-pyrazin-2(1H)-one (Intermediate 3-1) The procedure for preparing Intermediate 2-1 was used with 3,5-dibromo-1,2-dihydropyrazin-2-one (10 g, 39.39 mmol, 1.00 equiv) and 1-(methylsulfonyl)-piperazine (7.80 g, 47.56 mmol, 1.21 equiv). The crude product was purified with silica gel chromatography using EtOAc/petroleum ether (4:1) to afford 10 g (75%) of the title compound as a off-white solid.
(48) ##STR00051##
(49) 5-Bromo-3-(4-(methylsulfonyl)piperazin-1-yl)-1-[(2-(trimethylsilyl)ethoxy)-methyl]-pyrazin-2(1H)-one (Intermediate 3-2) The procedure for preparing Intermediate 2-2 was used with Intermediate 3-1. The crude product was purified with silica gel chromatography using EtOAc/petroleum ether (1:3) to afford 8.2 g (59%) of the title compound as a yellow oil.
(50) ##STR00052##
(51) (E)-5-[[3-((tert-butyldimethyl)silyl)oxy]propen-1-yl]-3-(4-(methylsulfonyl)-piperazin-1-yl)-1-[(2-(trimethylsilyl)ethoxy)methyl]-pyrazin-2(1H)-one (Intermediate 3-3) A mixture of Intermediate 3-2 (8.2 g, 17.56 mmol, 1 equiv), tert-butyldimethyl[([2E]-3-[tetramethyl-1,3,2-dioxaborolan-2-yl]prop-2-en-1-yl)oxy]silane (7.85 g, 26.34 mmol, 1.5 equiv), K.sub.2CO.sub.3 (7.27 g, 52.68 mmol, 3 equiv), Pd(dppf)Cl.sub.2 (1.28 g, 1.74 mmol, 0.1 equiv), dioxane (450 mL), and H.sub.2O (150 mL) was stirred overnight at 90° C., concentrated under vacuum, and purified with silica gel chromatography using EtOAc/petroleum ether (1:2) to afford 3.2 g (33%) of the title compound as a yellow oil.
(52) ##STR00053##
(53) 5-[[3-((tert-butyldimethyl)silyl)oxy]propyl]-3-(4-(methylsulfonyl)piperazin-1-yl)-1-[(2-(trimethylsilyl)ethoxy)methyl]-pyrazin-2(1H)-one (Intermediate 3-4) A solution of Intermediate 3-3 (1.5 g, 2.68 mmol, 1.00 equiv) in EtOAc (100 mL) was stirred over Pd/C (0.15 g) under an H.sub.2 atmosphere for 2 h at rt. The solids were removed by filtration, and the filtrate was concentrated under vacuum, to afford 1.2 g (80%) of the title compound as a yellow oil.
(54) ##STR00054##
(55) 3-[6-(4-(methylsulfonyl)piperazin-1-yl)-5(4H)-oxo-4-[(2-(trimethylsilyl)-ethoxy)methyl]-pyrazin-2-yl]-propan-1-ol (Intermediate 3-5) A solution of Intermediate 3-4 (1.2 g, 2.14 mmol, 1 equiv) and TBAF (10 mL, THF) in THF (50 mL) was stirred for 2 hr at rt. The residue was purified with silica gel chromatography using CH.sub.3CN/H.sub.2O (1:3) to afford 750 mg (78%) of the title compound as an off-white solid.
(56) ##STR00055##
(57) 3-[6-(4-(methylsulfonyl)piperazin-1-yl)-5(4H)-oxo-4-[(2-(trimethylsilyl)-ethoxy)methyl]-pyrazin-2-yl]-propanal The procedure for preparing Intermediate 1-7 was used with Intermediate 3-5 (600 mg, 1.34 mmol) to afford 400 mg (67%) of the title compound as a yellow oil.
(58) ##STR00056##
5-(3-[[(1R,2S)-2-(4-Fluorophenyl)cyclopropyl]amino]propyl)-3-(4-(methyl-sulfonyl)piperazin-1-yl)-1-[[2-(trimethylsilyl)ethoxy]methyl]pyrazin-2(1H)-one
(59) The reductive amination step for preparing Example 1 from Intermediate 1-7 was used with the product from the previous step (400 mg, 0.899 mmol, 1 equiv). The crude reaction product was purified with silica gel chromatography using EtOAc/petroleum ether (2:1) to afford 300 mg (58%) of the title compound as a yellow solid.
(60) ##STR00057##
(61) 5-[3-([(1R,2S)-2-(4-fluorophenyl)cyclopropyl]amino)propyl]-3-[4-(methylsulfonyl)piperazin-1-yl]pyrazin-2(1H)-one A solution of the product from the previous step (300 mg, 0.52 mmol, 1 equiv) and TFA (2 mL) in CH.sub.2Cl.sub.2 (10 mL) was stirred for 1 h at rt. The crude product (5 mL) was purified using chromatographic Procedure B (10.0% to 29.0% CH.sub.3CN in 9 min), to afford 49.1 mg (21%) of the title compound as a yellow oil.
(62) LC-MS: (ES, m/z): 450 [M+H].sup.+. .sup.1H NMR (400 MHz, MeOD-d.sub.4) δ ppm: 7.20-7.17 (m, 2H), 7.07-7.02 (m, 2H), 6.69 (s, 1H), 3.89-3.80 (m, 4H), 3.30-3.27 (m, 4H), 3.26-3.22 (m, 2H), 2.98-2.94 (m, 1H), 2.85 (s, 3H), 2.55-2.51 (m, 2H), 2.47-2.42 (m, 1H), 2.08-2.01 (m, 2H), 1.50-1.46 (m, 1H), 1.40-1.34 (m, 1H).
Example 4
(63) ##STR00058##
5-[3-([(1R,2S)-2-(4-fluorophenyl)cyclopropyl]amino)propyl]-3-morpholinopyrazin-2(1H)-one
(64) ##STR00059##
(65) 5-Bromo-3-(morpholin-4-yl)-pyrazin-2(1H)-one (Intermediate 4-1) The procedure for preparing Intermediate 2-1 was used with 3,5-dibromo-1,2-dihydropyrazin-2-one (10 g, 39.39 mmol, 1.00 equiv) and morpholine (5.1 g, 58.54 mmol, 1.50 equiv), using 2 h of reaction time at 90° C., affording 9 g (88%) of the title compound as a light yellow solid.
(66) ##STR00060##
(67) 5-Bromo-3-(morpholin-4-yl)-1-[(2-(trimethylsilyl)ethoxy)methyl]-pyrazin-2(1H)-one (Intermediate 4-2) A mixture of Intermediate 4-1 (9 g, 34.60 mmol, 1.00 equiv), NaH (2.4 g, 100.00 mmol, 3.00 equiv), and [2-(chloromethoxy)ethyl]trimethylsilane (8.6 g, 51.58 mmol, 1.50 equiv) in DMF (80 mL) was stirred for 3 h at 0-10° C. The reaction was quenched and diluted with 500 mL of EtOAc. The resulting mixture was washed with 5×200 mL of H.sub.2O. The organic phase was dried over Na.sub.2SO.sub.4 and concentrated under vacuum, to afford 7 g (52%) of the title compound as light yellow oil.
(68) ##STR00061##
(69) (E)-5-[[3-((tert-butyldimethyl)silyl)oxy]propen-1-yl]-3-(morpholin-4-yl)-1-[(2-(trimethylsilyl)ethoxy)methyl]-pyrazin-2(1H)-one (Intermediate 4-3 The procedure for preparing Intermediate 3-3 was used with Intermediate 4-2 (7 g, 17.93 mmol), using 2 hr of reaction time at 90° C., to afford 3.6 g (42%) of the title compound as a light yellow oil.
(70) ##STR00062##
(71) 5-[[3-((tert-butyldimethyl)silyl)oxy]propyl]-3-(morpholin-4-yl)-1-[(2-(trimethylsilyl)ethoxy)methyl]-pyrazin-2(1H)-one (Intermediate 4-4) The procedure for preparing Intermediate 3-4 was used with Intermediate 4-3 (3.6 g, 7.47 mmol, 1.00 equiv) to afford 3.2 g (89%) of the title compound as a light yellow oil.
(72) ##STR00063##
(73) 3-[6-(morpholin-4-yl)-5(4H)-oxo-4-[(2-(trimethylsilyl)ethoxy)methyl]-pyrazin-2-yl]-propan-1-ol (Intermediate 4-5) A solution of Intermediate 4-4 (1.4 g, 2.89 mmol, 1.00 equiv) and TBAF (5 mL, 1.20 equiv) in THF (30 mL) was stirred for 2 h at 25° C. The residue was purified with silica gel column using H.sub.2O/MeCN (2:1) to afford 0.73 g (68%) of the title compound as a light yellow oil.
(74) ##STR00064##
(75) 3-[6-(morpholin-4-yl)-5(4H)-oxo-4-[(2-(trimethylsilyl)ethoxy)methyl]-pyrazin-2-yl]-propanal (Intermediate 4-6) The procedure for preparing Intermediate 1-7 was used with Intermediate 4-5 (700 mg, 1.89 mmol, 1.00 equiv) to afford 0.35 g (50%) of the title compound as a light yellow solid.
(76) ##STR00065##
(77) 5-(3-[[(1R,2S)-2-(4-Fluorophenyl)cyclopropyl]amino]propyl)-3-(morpholin-4-yl)-1-[[2-(trimethylsilyl)ethoxy]methyl]pyrazin-2(1H)-one (Intermediate 4-7) A mixture of Intermediate 4-6 (350 mg, 0.95 mmol, 1.00 equiv), (1R,2S)-2-(4-fluoro-phenyl)cyclopropan-1-amine (170 mg, 1.12 mmol, 1.10 equiv), NaBH(OAc).sub.3 (480 mg, 2.26 mmol, 2.40 equiv), and MeOH (20 mL) was stirred for 2 h at 25° C., then diluted with 100 mL of CH.sub.2Cl.sub.2, washed with 3×20 mL of H.sub.2O, dried over Na.sub.2SO.sub.4, and concentrated under reduced pressure to afford 0.32 g (67%) of the title compound as a light yellow oil.
(78) ##STR00066##
(79) 5-[3-([(1R,2S)-2-(4-fluorophenyl)cyclopropyl]amino)propyl]-3-morpholinopyrazin-2(1H)-one The deprotection step for preparing Example 2 from Intermediate 2-7 was used with the product from the previous step (320 mg, 0.64 mmol). The crude product (5 mL) was purified using chromatographic Procedure B (30.0% to 50.0% CH.sub.3CN in 8 min), to afford 115.4 mg (49%) of the title compound as a white solid.
(80) LC-MS: (ES, m/z): 373 [M+H].sup.+. .sup.1H NMR (300 MHz, MeOD-d.sub.4) δ ppm: 7.23-7.13 (m, 2H), 7.13-6.96 (m, 2H), 6.70-6.60 (s, 1H), 3.80-3.68 (m, 8H), 3.22-3.18 (m, 1H), 3.00-2.82 (m, 1H), 2.59-2.36 (m, 3H), 2.07-1.97 (m, 3H), 1.52-1.30 (m, 2H).
Example 5
(81) ##STR00067##
3-[Azetidin-1-yl]-5-[3-([(1R,2S)-2-(4-fluorophenyl)cyclopropyl]amino)propyl]-pyrazin-2(1H)-one
(82) ##STR00068##
(83) 5-Bromo-3-(azetidin-1-yl)-pyrazin-2(1H)-one The procedure for preparing Intermediate 2-1 was used with 3,5-dibromo-1,2-dihydropyrazin-2-one (10 g, 39.39 mmol, 1.00 equiv) and azetidine (2.75 g, 47.56 mmol, 1.21 equiv). The crude product was purified with silica gel chromatography using EtOAc/petroleum ether (4:1) to afford 7.1 g (78.1%) of the title compound as a white solid.
(84) ##STR00069##
(85) 5-Bromo-3-(azetidin-1-yl)-1-[(2-(trimethylsilyl)ethoxy)methyl]-pyrazin-2(1H)-one The procedure for preparing Intermediate 2-2 was used with the product from the previous step (7.1 g, 30.87 mmol, 1 equiv), to afford 7.2 g (64.8%) of the title compound as a yellow oil.
(86) ##STR00070##
(87) (E)-5-[[3-((tert-butyldimethyl)silyl)oxy]propen-1-yl]-3-(azetidin-1-yl)-1-[(2-(trimethylsilyl)ethoxy)methyl]-pyrazin-2(1H)-one The procedure for preparing Intermediate 3-3 was used with the product from the previous step (7.2 g, 20.0 mmol) to afford 3.30 g (36.4%) of the title compound as a yellow oil.
(88) ##STR00071##
(89) 5-[[3-((tert-butyldimethyl)silyl)oxy]propyl]-3-(azetidin-1-yl)-1-[(2-(trimethylsilyl)ethoxy)methyl]-pyrazin-2(1H)-one The procedure for preparing Intermediate 3-4 was used with the product from the previous step (3.30 g, 7.30 mmol, 1.00 equiv) to afford 3.10 g (94%) of the title compound as an orange oil.
(90) ##STR00072##
(91) 3-[6-(azetidin-1-yl)-5(4H)-oxo-4-[(2-(trimethylsilyl)ethoxy)methyl]-pyrazin-2-yl]-propan-1-ol The procedure for preparing Intermediate 3-5 was used with the product from the previous step (3.0 g, 6.61 mmol, 1 equiv) to afford 1.5 g (66.76%) of the title compound as an off-white solid.
(92) ##STR00073##
(93) 3-[6-(azetidin-1-yl)-5(4H)-oxo-4-[(2-(trimethylsilyl)ethoxy)methyl]-pyrazin-2-yl]-propanal The procedure for preparing Intermediate 1-7 was used with the product from the previous step (1.00 g, 2.94 mmol, 1.00 equiv) to afford 0.6 g (60.35%) of the title compound as a yellow oil.
(94) ##STR00074##
(95) 5-(3-[[(1R,2S)-2-(4-Fluorophenyl)cyclopropyl]amino]propyl)-3-(azetidin-1-yl)-1-[[2-(trimethylsilyl)ethoxy]methyl]pyrazin-2(1H)-one The reductive amination step for preparing Example 1 from Intermediate 1-7 was used with the product from the previous step (600 mg, 1.78 mmol). The crude product was purified with silica gel chromatography using EtOAc/petroleum ether (2:1) to afford 500 mg (59.6%) of the title compound as a yellow solid.
(96) ##STR00075##
(97) 3-[Azetidin-1-yl]-5-[3-([(1R,2S)-2-(4-fluorophenyl)cyclopropyl]amino)propyl]-pyrazin-2(1H)-one The deprotection step for preparing Example 2 from Intermediate 2-7 was used with the product from the previous step (500 mg, 1.06 mmol, 1 equiv). The crude product (5 mL) was purified using chromatographic Procedure A (10% to 58% CH.sub.3CN), to afford 39.1 mg (10.81%) of the title compound as a white solid.
(98) LC-MS: (ES, m/z): 343 [M+H].sup.+. .sup.1H NMR (400 MHz, MeOD-d.sub.4) δ ppm: 7.23-7.18 (m, 2H), 7.05 (t, J=8.6 Hz, 2H), 6.42 (s, 1H), 4.61 (s, 4H), 3.22 (t, J=8.6 Hz, 2H), 2.98-2.94 (m, 1H), 2.55-2.42 (m, 5H), 2.04-1.96 (m, 2H), 1.54-1.47 (m, 1H), 1.40-1.33 (m, 1H).
Example 6
(99) ##STR00076##
5-[3-([(1R,2S)-2-(4-fluorophenyl)cyclopropyl]amino)propyl]-3-[piperidin-1-yl]pyrazin-2(1H)-one
(100) ##STR00077##
(101) 5-Bromo-3-(piperidin-1-yl)-pyrazin-2(1H)-one (Intermediate 6-1) The procedure for preparing Intermediate 2-1 was used with 3,5-dibromo-1,2-dihydropyrazin-2-one (15 g, 59.08 mmol, 1 equiv) and piperidine (7.5 g, 88.62 mmol, 1.5 equiv), to afford 12 g (78.69%) of the title compound as an off-white solid.
(102) ##STR00078##
(103) 5-Bromo-3-(piperidin-1-yl)-1-[(2-(trimethylsilyl)ethoxy)methyl]-pyrazin-2(1H)-one The procedure for preparing Intermediate 4-2 was used with the product from the previous step (3.9 g, 15.11 mmol). The crude product was purified with silica gel chromatography using EtOAc/petroleum ether (1:30) to afford 4.2 g (71.6%) of the title compound as a light yellow oil.
(104) ##STR00079##
(105) (E)-5-[[3-((tert-butyldimethyl)silyl)oxy]propen-1-yl]-3-(piperidin-1-yl)-1-[(2-(trimethylsilyl)ethoxy)methyl]-pyrazin-2(1H)-one The procedure for preparing Intermediate 3-3 was used with the product from the previous step (4 g, 10.30 mmol), using 12 hr of reaction time at 90° C., to afford 1.2 g (24.3%) of the title compound as a light yellow oil.
(106) ##STR00080##
(107) 5-[[3-((tert-butyldimethyl)silyl)oxy]propyl]-3-(piperidin-1-yl)-1-[(2-(trimethylsilyl)ethoxy)methyl]-pyrazin-2(1H)-one The procedure for preparing Intermediate 3-4 was used with the product from the previous step (1.2 g, 2.50 mmol, 1 equiv) to afford 1.1 g (91.28%) of the title compound as a light yellow oil.
(108) ##STR00081##
(109) 3-[6-(piperidin-1-yl)-5(4H)-oxo-4-[(2-(trimethylsilyl)ethoxy)methyl]-pyrazin-2-yl]-propan-1-ol The procedure for preparing Intermediate 3-5 was used with the product from the previous step (1.1 g, 2.28 mmol, 1 equiv) to afford 0.51 g (60.78%) of the title compound as a light yellow solid.
(110) ##STR00082##
(111) 3-[6-(piperidin-1-yl)-5(4H)-oxo-4-[(2-(trimethylsilyl)ethoxy)methyl]-pyrazin-2-yl]-propanal The procedure for preparing Intermediate 1-7 was used, with 2 hr of stirring, with the product from the previous step (510 mg, 1.39 mmol) to afford 300 mg (59%) of the title compound as a light yellow oil.
(112) ##STR00083##
(113) 5-(3-[[(1R,2S)-2-(4-Fluorophenyl)cyclopropyl]amino]propyl)-3-(piperidin-1-yl)-1-[[2-(trimethylsilyl)ethoxy]methyl]pyrazin-2(1H)-one The procedure for preparing Intermediate 4-7 was used with the product from the previous step (300 mg, 0.82 mmol, 1 equiv) to afford 210 mg (51.10%) of the title compound as a light yellow oil.
(114) ##STR00084##
(115) 5-[3-([(1R,2S)-2-(4-fluorophenyl)cyclopropyl]amino)propyl]-3-[piperidin-1-yl]pyrazin-2(1H)-one The deprotection step for preparing Example 2 from Intermediate 2-7 was used with the product from the previous step (210 mg, 0.42 mmol, 1 equiv). The crude product (5 mL) was purified using chromatographic Procedure D (10% to 51% CH.sub.3CN in 7 min), to afford 19.2 mg (9.77%) of the title compound as a light yellow oil.
(116) LC-MS: (ES, m/z): 371 [M+H].sup.+. .sup.1H NMR (300 MHz, MeOD-d.sub.4) δ ppm: 7.28-7.15 (m, 2H), 7.15-6.99 (m, 2H), 6.70-6.61 (m, 1H), 3.86-3.65 (m, 4H), 3.28-3.20 (m, 2H), 3.02-2.98 (m, 1H), 2.66-2.36 (m, 3H), 2.16-1.96 (m, 2H), 1.80-1.59 (m, 6H), 1.59-1.31 (m, 2H).
Example 7
(117) ##STR00085##
5-[3-([(1R,2S)-2-(4-fluorophenyl)cyclopropyl]amino)propyl]-3-[2-oxa-6-azaspiro[3.3]heptan-6-yl]pyrazin-2(1H)-one
(118) ##STR00086##
(119) 5-Bromo-3-(2-Oxa-6-azaspiro[3.3]heptan-6-yl)-pyrazin-2(1H)-one (Intermediate 7-1) The procedure for preparing Intermediate 2-1 was used with 3,5-dibromo-1,2-dihydropyrazin-2-one (10 g, 39.39 mmol, 1.00 equiv) and 2-oxa-6-azaspiro[3.3]heptane (5.9 g, 59.52 mmol, 1.50 equiv), using 6 hr reaction time at 90° C. The crude product was purified with silica gel chromatography using EtOAc/petroleum ether (4:1) to afford 9 g (84%) of the title compound as a yellow solid.
(120) ##STR00087##
(121) 5-Bromo-3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-1-[(2-(trimethylsilyl)ethoxy)-methyl]-pyrazin-2(1H)-one The procedure for preparing Intermediate 2-2 was used with Intermediate 7-1 (9 g, 33.08 mmol, 1.00 equiv) to afford 3.6 g (27%) of the title compound as off-white oil.
(122) ##STR00088##
(123) Ethyl (2E)-3-[6-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-5(4H)-oxo-4-[(2-(trimethylsilyl)ethoxy)methyl]-pyrazin-2-yl]propenoate The procedure for preparing Intermediate 1-4 was used with the product from the previous step (3.6 g, 8.95 mmol, 1.00 equiv) to afford 2.8 g (74%) of the title compound as a yellow oil.
(124) ##STR00089##
(125) Ethyl 3-[6-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-5(4H)-oxo-4-[(2-(trimethylsilyl)ethoxy)methyl]-pyrazin-2-yl]propanoate The procedure for preparing Intermediate 1-5 was used with the product from the previous step (2.8 g, 6.64 mmol, 1.00 equiv) to afford 2.7 g (96%) of the title compound as a yellow oil.
(126) ##STR00090##
(127) 3-[6-(2-Oxa-6-azaspiro[3.3]heptan-6-yl)-5(4H)-oxo-4-[(2-(trimethylsilyl)-ethoxy)methyl]-pyrazin-2-yl]-propan-1-ol The procedure for preparing Intermediate 1-6 was used with the product from the previous step (2.7 g, 6.37 mmol, 1.00 equiv) to afford 1.8 g (74%) of the title compound as a yellow oil.
(128) ##STR00091##
(129) 3-[6-(2-Oxa-6-azaspiro[3.3]heptan-6-yl)-5(4H)-oxo-4-[(2-(trimethylsilyl)-ethoxy)methyl]-pyrazin-2-yl]-propanal The procedure for preparing Intermediate 1-7 was used with the product from the previous step (1.8 g, 4.72 mmol, 1.00 equiv) to afford 0.5 g (28%) of the title compound, for which the SEM group had been cleaved under the reaction conditions, as a white solid.
(130) ##STR00092##
(131) 5-[3-([(1R,2S)-2-(4-fluorophenyl)cyclopropyl]amino)propyl]-3-[2-oxa-6-azaspiro[3.3]heptan-6-yl]pyrazin-2(1H)-one The reductive amination step for preparing Example 1 from Intermediate 1-7 was used with the product from the previous step (500 mg, 1.32 mmol, 1.00 equiv). The crude product (3 mL) was purified by Prep-HPLC (Column: XBridge Prep Phenyl OBD, particle size: 5 m, column size 19×150 mm, H.sub.2O (20 mM NH.sub.4HCO.sub.3)/CH.sub.3CN, flow rate: 20 mL/min, gradient: 25% to 30% CH.sub.3CN in 10 min, Rt: 11.3 min, detector, UV 254 nm), to afford 50 mg (10%) of the title compound as a white solid.
(132) LCMS: (ES, m/z): 385 [M+H].sup.+. .sup.1H NMR (300 MHz, Methanol-d.sub.4) δ ppm: 7.09-6.97 (m, 2H), 7.03-6.87 (m, 2H), 6.37 (s, 1H), 4.83-4.78 (m, 4H), 4.45-4.25 (m, 4H), 2.74-2.63 (m, 2H), 2.35 (m, 2H), 2.3-2.2 (m, 1H), 1.93-1.63 (m, 3H), 1.09-0.88 (m, 2H).
Example 8
(133) ##STR00093##
1-Cyclopropyl-3-[1,1-dioxidothiomorpholino]-5-[3-([(1R,2S)-2-(4-fluorophenyl)cyclopropyl]amino)propyl]pyrazin-2(1H)-one
(134) ##STR00094##
(135) 5-Bromo-3-(1,1-dioxothiomorpholin-4-yl)-pyrazin-2(1H)-one (Intermediate 8-1) The procedure for preparing Intermediate 2-1 was used with 3,5-dibromo-1,2-dihydropyrazin-2-one (10 g, 39.39 mmol, 1.00 equiv) and 4-thiomorpholine-1,1-dione (6.43 g, 47.56 mmol, 1.21 equiv). The crude product was purified with silica gel chromatography using EtOAc/petroleum ether (4:1) to afford 4.0 g (33%) of the title compound as a white solid.
(136) ##STR00095##
(137) 5-Bromo-3-(1,1-dioxothiomorpholin-4-yl)-1-[(2-(trimethylsilyl)ethoxy)-methyl]-pyrazin-2(1H)-one (Intermediate 8-2) The procedure for preparing Intermediate 2-2 was used with Intermediate 8-1 (3.0 g, 9.74 mmol, 1 equiv) to afford 2.35 g (55.08%) of the title compound as a yellow oil.
(138) ##STR00096##
(139) Ethyl (2E)-3-[6-(1,1-dioxothiomorpholin-4-yl)-5(4H)-oxo-4-[(2-(trimethylsilyl)ethoxy)methyl]-pyrazin-2-yl]propenoate (Intermediate 8-3 The procedure for preparing Intermediate 1-4 was used with Intermediate 8-2 (2.35 g, 5.36 mmol, 1 equiv) to afford 1.80 g (73.25%) of the title compound as an orange oil.
(140) ##STR00097##
(141) Ethyl 3-[6-(1,1-dioxothiomorpholin-4-yl)-5(4H)-oxo-4-[(2-(trimethylsilyl)-ethoxy)methyl]-pyrazin-2-yl]propanoate (Intermediate 8-4) The procedure for preparing Intermediate 1-5 was used with Intermediate 8-3 (1.80 g, 3.93 mmol, 1.00 equiv) to afford 1.80 g (99%) of the title compound as an orange oil.
(142) ##STR00098##
(143) 3-[6-(1,1-dioxothiomorpholin-4-yl)-5(4H)-oxo-4-[(2-(trimethylsilyl)ethoxy)-methyl]-pyrazin-2-yl]-propan-1-ol (Intermediate 8-5) The procedure for preparing Intermediate 1-6 was used with Intermediate 8-4 (1.8 g, 3.92 mmol, 1 equiv) with 2 hr reaction time. The crude product was purified with silica gel chromatography using EtOAc/petroleum ether (3:2) to afford 1.3 g (79.47%) of the title compound as an off-white solid.
(144) ##STR00099##
(145) 3-[6-(1,1-dioxothiomorpholin-4-yl)-5(4H)-oxo-4-[(2-(trimethylsilyl)ethoxy)-methyl]-pyrazin-2-yl]-propanal (Intermediate 8-6) The procedure for preparing Intermediate 1-7 was used with Intermediate 8-5 (1.30 g, 3.11 mmol, 1.00 equiv) to afford 1.0 g (77.29%) of the title compound as a yellow oil.
(146) ##STR00100##
(147) 5-(3-[[(1R,2S)-2-(4-Fluorophenyl)cyclopropyl] (2-propen-1-yl)amino]propyl)-3-(1,1-dioxothiomorpholin-4-yl)-1-[[2-(trimethylsilyl)ethoxy]methyl]pyrazin-2(1H)-one (Intermediate 8-7) The reductive amination step for preparing Example 1 from Intermediate 1-7 was used with Intermediate 8-6 (1.0 g, 2.40 mmol, 1 equiv) to afford 900 mg (63.35%) of the title compound as an orange oil.
(148) ##STR00101##
(149) 5-(3-[[(1R,2S)-2-(4-Fluorophenyl)cyclopropyl] (2-propen-1-yl)amino]propyl)-3-(1,1-dioxothiomorpholin-4-yl)-pyrazin-2(1H)-one (Intermediate 8-8) The deprotection step for preparing Example 2 from Intermediate 2-7 was used with Intermediate 8-7 (900 mg, 1.52 mmol, 1 equiv). The crude product was purified with silica gel chromatography using CH.sub.2Cl.sub.2/MeOH (15:1) to afford 700 mg (99.71%) of the title compound as an orange solid.
(150) ##STR00102##
(151) 5-(3-[[(1R,2S)-2-(4-Fluorophenyl)cyclopropyl] (2-propen-1-yl)amino]propyl)-3-(1,1-dioxothiomorpholin-4-yl)-1-cyclopropylpyrazin-2(1H)-one (Intermediate 8-9 Intermediate 8-8 (700 mg, 1.52 mmol, 1 equiv) was combined with cyclopropylboronic acid (196 mg, 2.28 mmol, 1.5 equiv), Cu(OAc).sub.2 (276.0 mg, 1.52 mmol, 1 equiv), and TEA (461.5 mg, 4.56 mmol, 3 equiv) in CH.sub.2Cl.sub.2 (40 mL). Oxygen was added to the mixture, and the resulting solution was stirred for 16 h at rt, then purified with silica gel chromatography using EtOAc/petroleum ether (1:1) to afford 300 mg (39.43%) of the title compound as a yellow oil.
(152) ##STR00103##
(153) 1-Cyclopropyl-3-[1,1-dioxidothiomorpholino]-5-[3-([(1R,2S)-2-(4-fluorophenyl)cyclopropyl]amino)propyl]pyrazin-2(1H)-one A solution of the product from the previous step (300 mg, 0.60 mmol, 1 equiv), 1,3-dimethyl-1,3-diazinane-2,4,6-trione (280.5 mg, 1.80 mmol, 3 equiv), and Pd(PPh.sub.3).sub.4 (140 mg, 0.12 mmol, 0.2 equiv) in THF (30 mL) was stirred for 2 hr under N.sub.2 at 50° C. The crude product was purified using chromatographic Procedure A (10% to 58% CH.sub.3CN in 9 min), to afford 52.1 mg (18.88%) of the title compound as a light yellow solid.
(154) LC-MS: (ES, m/z): 461 [M+H].sup.+. .sup.1H NMR (300 MHz, MeOD-d.sub.4) δ ppm: 7.18-7.14 (m, 2H), 7.05-6.99 (m, 2H), 6.87 (s, 1H), 4.28-4.26 (m, 4H), 3.28-3.19 (m, 3H), 3.16-3.11 (m, 4H), 2.96-2.91 (m, 1H), 2.53-2.48 (m, 2H), 2.45-2.38 (m, 1H), 2.06-1.98 (m, 2H), 1.46-1.34 (m, 2H), 1.08-1.03 (m, 2H), 0.87-0.82 (m, 2H).
Example 9
(155) ##STR00104##
3-(1,1-Dioxidothiomorpholino)-5-(3-(((1R,2S)-2-phenylcyclopropyl)amino)propyl)pyrazin-2(1H)-one
(156) ##STR00105##
(157) 3-[6-(1,1-dioxothiomorpholin-4-yl)-5(4H)-oxopyrazin-2-yl]-propanal The deprotection step for preparing Example 2 from Intermediate 2-7 was used with Intermediate 8-6 (600 mg, 1.44 mmol). The crude product was purified with silica gel chromatography using CH.sub.2Cl.sub.2/MeOH (15:1) to afford 400 mg (96.97%) of the title compound as an orange oil.
(158) ##STR00106##
(159) 3-(1,1-Dioxidothiomorpholino)-5-(3-(((1R,2S)-2-phenylcyclopropyl)amino)-propyl)pyrazin-2(1H)-one The reductive amination step for preparing Example 1 from Intermediate 1-7 used with the product from the previous step (400 mg, 1.40 mmol, 1 equiv). The crude product (5 mL) was purified using chromatographic Procedure E (28% to 50% CH.sub.3CN in 8 min, Rt: 7.02 min), to afford 85.3 mg (15%) of the title compound as a white solid.
(160) LC-MS: (ES, m/z): 403 [M+H].sup.+. .sup.1H NMR (300 MHz, MeOD-d.sub.4) δ ppm: 7.27-7.17 (m, 2H), 7.13-7.06 (m, 1H), 7.02-6.99 (m, 2H), 6.66 (s, 1H), 4.27-4.24 (m, 4H), 3.11-3.04 (m, 4H), 2.73-2.68 (m, 2H), 2.46-2.40 (m, 2H), 2.30-2.25 (m, 1H), 1.90-1.80 (m, 3H), 1.06-0.94 (m, 2H).
Example 10
(161) ##STR00107##
1-[6-(3-[([1R,2S]-2-[4-fluorophenyl]cyclopropyl)amino]propyl)-3-oxo-3,4-dihydropyrazin-2-yl]piperidine-4-carboxylic acid
(162) ##STR00108##
(163) Methyl 1-(6-bromo-3(4H)-oxopyrazin-2-yl)piperidine-4-carboxylate (Intermediate 10-1) The procedure for preparing Intermediate 2-1 was used with 3,5-dibromo-1,2-dihydropyrazin-2-one (10 g, 39.39 mmol, 1.00 equiv) and methyl piperidine-4-carboxylate (8.4 g, 58.67 mmol, 1.49 equiv), using 12 h of reaction time at 90° C., affording 10 g (80%) of the title compound as a light yellow solid.
(164) ##STR00109##
(165) Methyl 1-(6-bromo-3(4H)-oxo-4-[[2-(trimethylsilyl)ethoxy]methyl]-pyrazin-2-yl)piperidine-4-carboxylate The procedure for preparing Intermediate 4-2 was used with Intermediate 10-1 (5 g, 15.82 mmol, 1.00 equiv) to afford 4 g (57%) of the title compound as a light yellow oil.
(166) ##STR00110##
(167) Methyl 1-[6-[(1E)-3-[(tert-butyldimethylsilyl)oxy]prop-1-en-1-yl]-3(4H)-oxo-4-[[2-(trimethylsilyl)ethoxy]methyl]-3,4-dihydropyrazin-2-yl]piperidine-4-carboxylate The procedure for preparing Intermediate 3-3 was used with the product from the previous step (4 g, 8.96 mmol), using 2 hr reaction time, to afford 1.7 g (35%) of the title compound as a light yellow oil.
(168) ##STR00111##
(169) Methyl 1-(6-[3-[(tert-butyldimethylsilyl)oxy]propyl]-3(4H)-oxo-4-[[2-(trimethylsilyl)ethoxy]methyl]-pyrazin-2-yl)piperidine-4-carboxylate The procedure for preparing Intermediate 3-4 was used with the product from the previous step (1.8 g, 3.35 mmol, 1.00 equiv) to afford 1.7 g (94%) of the title compound as a light yellow oil.
(170) ##STR00112##
(171) Methyl 1-[6-(3-hydroxypropyl)-3(4H)-oxo-4-[[2-(trimethylsilyl)ethoxy]methyl]-pyrazin-2-yl]piperidine-4-carboxylate The procedure for preparing Intermediate 3-5 was used with the product from the previous step (1.7 g, 3.15 mmol, 1.00 equiv) to afford 0.8 g (60%) of the title compound as a light yellow oil.
(172) ##STR00113##
Methyl 1-(3(4H)-oxo-6-(3-oxopropyl)-pyrazin-2-yl)piperidine-4-carboxylate
(173) The procedure for preparing Intermediate 1-7 was used with the product from the previous step (800 mg, 1.88 mmol, 1.00 equiv) to afford 0.45 g (82%) of the title compound as a light yellow oil.
(174) ##STR00114##
(175) Methyl 1-[6-(3-[[(1R,2S)-2-(4-fluorophenyl)cyclopropyl]amino]propyl)-3(4H)-oxopyrazin-2-yl]piperidine-4-carboxylate The procedure for preparing Intermediate 4-7 was used with the product from the previous step (450 mg, 1.53 mmol, 1.00 equiv) afford 0.3 g (46%) of the title compound as a light yellow oil, which was carried forward without further purification.
(176) ##STR00115##
(177) 1-[6-(3-[([1R,2S]-2-[4-fluorophenyl]cyclopropyl)amino]propyl)-3-oxo-3,4-dihydropyrazin-2-yl]piperidine-4-carboxylic acid A solution of the product from the previous step (300 mg, 0.70 mmol, 1.00 equiv) and LiOH (80 mg, 3.34 mmol, 5.00 equiv) in THF (20 mL) and H.sub.2O (3 mL) was stirred for 2 h at 25° C., then concentrated under vacuum and purified using chromatographic Procedure C (38.0% to 50.0% CH.sub.3CN in 8.2 min), to afford 82.6 mg (28%) of the title compound as a light yellow solid.
(178) LC-MS: (ES, m/z): 415 [M+H].sup.+. .sup.1H NMR (300 MHz, MeOD-d.sub.4) δ ppm: 7.23-7.07 (m, 2H), 7.07-6.93 (m, 2H), 6.82-6.69 (s, 1H), 4.78-4.32 (m, 2H), 3.02-2.78 (m, 4H), 2.72-2.55 (m, 1H), 2.52-2.28 (m, 3H), 2.27-2.02 (m, 1H), 2.02-1.81 (m, 4H), 1.81-1.51 (m, 2H), 1.38-1.01 (m, 2H).
Example 11
(179) ##STR00116##
1-[4-Fluorophenyl]-3-[piperidin-1-yl]-5-[3-([(1R,2S)-2-(4-fluorophenyl)cyclopropyl]amino)propyl]-pyrazin-2(1H)-one
(180) ##STR00117##
(181) Ethyl (2E)-3-[6-(piperidin-1-yl)-5(4H)-oxopyrazin-2-yl]propenoate The procedure for preparing Intermediate 1-4 was used with Intermediate 6-1 to afford 2 g (47%) of the title compound as a yellow oil.
(182) ##STR00118##
(183) Ethyl (2E)-3-[4-(4-fluorophenyl)-6-(piperidin-1-yl)-5(4H)-oxopyrazin-2-yl]-propenoate The procedure for preparing Intermediate 8-9 was used with the product from the previous step (2 g, 7.22 mmol, 1 equiv) and 4-fluorophenylboronic acid to afford 1 g (37%) of the title compound as a yellow oil.
(184) ##STR00119##
(185) Ethyl (2E)-3-[4-(4-fluorophenyl)-6-(piperidin-1-yl)-5(4H)-oxopyrazin-2-yl]-propanoate The procedure for preparing Intermediate 3-4 was used with the product from the previous step (1 g, 2.70 mmol, 1.00 equiv) to afford 1 g (99%) of the title compound as a yellow oil.
(186) ##STR00120##
(187) (2E)-3-[4-(4-Fluorophenyl)-6-(piperidin-1-yl)-5(4H)-oxopyrazin-2-yl]propan-1-ol The procedure for preparing Intermediate 1-6 was used with the product from the previous step (1 g, 2.68 mmol, 1 equiv), with 6 hr reaction time, to afford 500 mg (56%) of the title compound as a yellow solid.
(188) ##STR00121##
(189) (2E)-3-[4-(4-Fluorophenyl)-6-(piperidin-1-yl)-5(4H)-oxopyrazin-2-yl]-propanal The procedure for preparing Intermediate 1-7 was applied to the product from the previous step (500 mg, 1.51 mmol, 1.00 equiv) to afford 300 mg (60%) of the title compound as a yellow oil.
(190) ##STR00122##
(191) 1-[4-Fluorophenyl]-3-[piperidin-1-yl]-5-[3-([(1R,2S)-2-(4-fluorophenyl)-cyclopropyl]amino)propyl]-pyrazin-2(1H)-one The reductive amination step for preparing Example 1 from Intermediate 1-7 was used with the product from the previous step (300 mg, 0.912 mmol, 1 equiv). The crude product (5 mL) was purified using chromatographic Procedure A (35% to 40% CH.sub.3CN in 10 min, Rt: 8.12 min), to afford 68.9 mg (11%) of the title compound as a yellow oil.
(192) LC-MS: (ES, m/z): 465 [M+H].sup.+. .sup.1H NMR (400 MHz, MeOD-d.sub.4) δ ppm: 7.45-7.42 (m, 2H), 7.30-7.26 (t, J=17.2 Hz, 2H), 7.23-7.20 (m, 2H), 7.09-7.04 (t, J=17.2 Hz, 2H), 6.81 (s, 1H), 3.77-3.75 (m, 4H), 3.30-3.28 (m, 2H), 3.02-2.98 (m, 1H), 2.58-2.54 (m, 2H), 2.49-2.46 (m, 1H), 2.12-2.08 (m, 2H), 1.67-1.65 (m, 6H), 1.53-1.48 (m, 1H), 1.41-1.36 (m, 1H).
Example 12
(193) ##STR00123##
1-[4-Fluorophenyl]-5-[3-([(1R,2S)-2-(4-fluorophenyl)cyclopropyl]amino)propyl]-3-[2-oxa-6-azaspiro[3.3]heptan-6-yl]pyrazin-2(1H)-one
(194) ##STR00124##
(195) Ethyl (E)-3-(6-[2-oxa-6-azaspiro[3.3]heptan-6-yl]-5(4H)-oxopyrazin-2-yl)prop-2-enoate (Intermediate 12-1) The procedure for preparing Intermediate 1-4 was used with Intermediate 7-1 (3.6 g, 13.23 mmol) with 2 h of reaction time at 90° C. The crude product was purified with silica gel chromatography using EtOAc/petroleum ether (1:1) to afford 1.7 g (44%) of the title compound as a yellow solid.
(196) ##STR00125##
(197) Ethyl (E)-3-[4-(4-fluorophenyl)-6-[2-oxa-6-azaspiro[3.3]heptan-6-yl]-5(4H)-oxopyrazin-2-yl]prop-2-enoate The procedure for preparing Intermediate 8-9 was used with Intermediate 12-1 (2 g, 6.87 mmol, 1.00 equiv) and 4-fluorophenylboronic acid (1.4 g, 10.01 mmol, 1.50 equiv). The crude product was purified using silica gel chromatography using EtOAc/petroleum ether (1:1) to afford 0.7 g (26%) of the title compound as a yellow solid.
(198) ##STR00126##
(199) Ethyl 3-[4-(4-fluorophenyl)-6-[2-oxa-6-azaspiro[3.3]heptan-6-yl]-5(4H)-oxo-pyrazin-2-yl]propanoate The procedure for preparing Intermediate 1-5 was used with the product from the previous step (850 mg, 2.21 mmol, 1.00 equiv) to afford 0.7 g (82%) of the title compound as a yellow oil.
(200) ##STR00127##
(201) 3-[4-(4-Fluorophenyl)-6-[2-oxa-6-azaspiro[3.3]heptan-6-yl]-5(4H)-oxo-pyrazin-2-yl]propan-1-ol The procedure for preparing Intermediate 1-6 was used with the product of the previous step (700 mg, 1.81 mmol, 1.00 equiv), to afford 0.4 g (64%) of the title compound as colorless oil.
(202) ##STR00128##
(203) 3-[4-(4-Fluorophenyl)-6-[2-oxa-6-azaspiro[3.3]heptan-6-yl]-5(4H)-oxo-pyrazin-2-yl]propanal The procedure for preparing Intermediate 1-7 was used with the product from the previous step (500 mg, 1.45 mmol, 1.00 equiv) to afford 0.28 g (56%) of the title compound as a yellow oil.
(204) ##STR00129##
(205) 1-[4-Fluorophenyl]-5-[3-([(1R,2S)-2-(4-fluorophenyl)cyclopropyl]amino)propyl]-3-[2-oxa-6-azaspiro[3.3]heptan-6-yl]pyrazin-2(1H)-one The reductive amination step for preparing Example 1 from Intermediate 1-7 was used with the product from the previous step (280 mg, 0.82 mmol, 1.00 equiv). The crude product (5 mL) was purified using chromatographic Procedure C (35.0% to 52.0% CH.sub.3CN in 8.8 min), to afford 75.9 mg (19%) of the title compound as a light yellow solid.
(206) LCMS: (ES, m/z): 479 [M+H].sup.+. .sup.1H NMR (300 MHz, Methanol-d.sub.4) δ ppm: 7.45-7.31 (m, 2H), 7.29-7.14 (m, 2H), 7.09-6.98 (m, 2H), 7.00-6.85 (m, 2H), 6.55 (s, 1H), 4.70 (s, 4H), 4.40 (s, 4H), 2.79-2.68 (m, 2H), 2.38 (t, J=7.2 Hz, 2H), 2.33-2.23 (m, 1H), 1.95-1.74 (m, 3H), 1.10-0.89 (m, 2H).
Example 13
(207) ##STR00130##
5-[3-([(1R,2S)-2-(4-fluorophenyl)cyclopropyl]amino)propyl]-1-[4-(methylsulfonyl)phenyl]-3-[2-oxa-6-azaspiro[3.3]heptan-6-yl]pyrazin-2(1H)-one
(208) ##STR00131##
(209) Ethyl (E)-3-[4-(4-methylsulfonylphenyl)-6-[2-oxa-6-azaspiro[3.3]heptan-6-yl]-5(4H)-oxopyrazin-2-yl]prop-2-enoate (Intermediate 13-1) A solution of Intermediate 12-1 (2 g, 6.87 mmol, 1.00 equiv), 1-bromo-4-methanesulfonylbenzene (2.4 g, 10.21 mmol, 1.50 equiv), N,N-dimethylethylenediamine (480 mg, 5.45 mmol, 0.80 equiv), K.sub.3PO.sub.4 (4.3 g, 20.26 mmol, 3.00 equiv), CuI (520 mg, 2.73 mmol, 0.40 equiv) in dioxane (100 mL) was stirred for 6 h at 90° C. The resulting mixture was concentrated under vacuum, and purified with silica gel chromatography using EtOAc/petroleum ether (1:1) to afford 1.3 g (43%) of the title compound as a yellow solid.
(210) ##STR00132##
(211) Ethyl 3-[4-(4-methylsulfonylphenyl)-6-[2-oxa-6-azaspiro[3.3]heptan-6-yl]-5(4H)-oxopyrazin-2-yl]propanoate The procedure for preparing Intermediate 1-5 was used with the product from the previous step (1.3 g, 2.92 mmol, 1.00 equiv) to afford 1.0 g (77%) of the title compound as a yellow solid.
(212) ##STR00133##
(213) 3-[4-(4-Methylsulfonylphenyl)-6-[2-oxa-6-azaspiro[3.3]heptan-6-yl]-5(4H)-oxopyrazin-2-yl]propan-1-ol The procedure for preparing Intermediate 1-6 was used with the product of the previous step (1.0 g, 2.23 mmol, 1.00 equiv), using 4 hr of reaction time at rt, to afford 0.4 g (44%) of the title compound as a yellow oil.
(214) ##STR00134##
(215) 3-[4-(4-Methylsulfonylphenyl)-6-[2-oxa-6-azaspiro[3.3]heptan-6-yl]-5(4H)-oxopyrazin-2-yl]propanal The procedure for preparing Intermediate 1-7 was used with the product from the previous step (400 mg, 0.99 mmol, 1.00 equiv) to afford 150 mg (38%) of the title compound as a colorless oil.
(216) ##STR00135##
(217) 5-[3-([(1R,2S)-2-(4-fluorophenyl)cyclopropyl]amino)propyl]-1-[4-(methyl-sulfonyl)phenyl]-3-[2-oxa-6-azaspiro[3.3]heptan-6-yl]pyrazin-2(1H)-one The procedure for preparing Intermediate 4-7 was used with the product from the previous step (150 mg, 0.37 mmol). The crude product was purified using chromatographic Procedure E (42% to 45% CH.sub.3CN in 7 min, Rt: 6.7 min) to afford 11.1 mg (6%) of the title compound as a light yellow solid.
(218) LCMS: (ES, m/z): 539 [M+H].sup.+. .sup.1H NMR (300 MHz, Methanol-d.sub.4) δ ppm: 8.12-8.01 (m, 2H), 7.72-7.62 (m, 2H), 7.09-6.86 (m, 4H), 6.62 (s, 1H), 4.72 (s, 4H), 4.42 (s, 4H), 3.14 (s, 3H), 2.73 (t, J=7.5 Hz, 2H), 2.39 (t, J=7.2 Hz, 2H), 2.31-2.22 (m, 1H), 1.89-1.79 (m, 3H), 1.10-0.88 (m, 2H).
Example 14
(219) ##STR00136##
4-[5-(3-[([1R,2S]-2-[4-fluorophenyl]cyclopropyl)amino]propyl)-2-oxo-3-(piperazin-1-yl)pyrazin-1(2H)-yl]-N,N-dimethylbenzenesulfonamide
(220) ##STR00137##
(221) tert-Butyl 4-(6-bromo-3(4H)-oxopyrazin-2-yl)piperazine-1-carboxylate (Intermediate 14-1) The procedure for preparing Intermediate 2-1 was used with 3,5-dibromo-1,2-dihydropyrazin-2-one (20 g, 78.78 mmol, 1.00 equiv) and tert-butyl piperazine-1-carboxylate (22 g, 118.12 mmol, 1.50 equiv). The crude product was purified with silica gel chromatography using EtOAc/petroleum ether (1:20) to afford 25 g (88%) of the title compound as a yellow solid.
(222) ##STR00138##
(223) tert-Butyl 4-[6-[(E)-3-ethoxy-3-oxoprop-1-en-1-yl]-3(4H)-oxopyrazin-2-yl]-piperazine-1-carboxylate (Intermediate 14-2) The procedure for preparing Intermediate 1-4 was used with Intermediate 14-1 (4 g, 11.14 mmol). The crude product was purified with silica gel chromatography using EtOAc/petroleum ether (1:10) to afford 1 g (24%) of the title compound as a yellow solid.
(224) ##STR00139##
(225) tert-Butyl 4-[4-[4-((dimethylamino)sulfonyl)phenyl]-6-[(E)-3-ethoxy-3-oxoprop-1-en-1-yl]-3(4H)-oxo-pyrazin-2-yl]piperazine-1-carboxylate (Intermediate 14-3) The procedure for preparing Intermediate 13-1 was used with Intermediate 14-2 (2 g, 5.29 mmol, 1.00 equiv) and 4-bromo-N,N-dimethylbenzene-1-sulfonamide (2.1 g, 7.95 mmol, 1.50 equiv). The crude product was purified with silica gel chromatography using EtOAc/petroleum ether (10:1) to afford 1 g (34%) of the title compound as a yellow solid.
(226) ##STR00140##
(227) tert-Butyl 4-[4-[4-((dimethylamino)sulfonyl)phenyl]-6-(3-ethoxy-3-oxopropyl)-3(4H)-oxopyrazin-2-yl]piperazine-1-carboxylate (Intermediate 1-4) The procedure for preparing Intermediate 1-5 was used with Intermediate 14-3 (1 g, 1.78 mmol, 1.00 equiv) to afford 0.8 g (80%) of the title compound as a yellow solid.
(228) ##STR00141##
(229) tert-Butyl 4-[4-[4-((dimethylamino)sulfonyl)phenyl]-6-(3-hydroxypropyl)-3(4H)-oxopyrazin-2-yl]piperazine-1-carboxylate (Intermediate 14-5) The procedure for preparing Intermediate 1-6 was used with Intermediate 14-4 (800 mg, 1.42 mmol, 1.00 equiv) to afford 520 mg (70%) of the title compound as a yellow solid.
(230) ##STR00142##
(231) tert-Butyl 4-[4-[4-((dimethylamino)sulfonyl)phenyl]-3(4H)-oxo-6-(3-oxopropyl)-pyrazin-2-yl]piperazine-1-carboxylate (Intermediate 14-6) The procedure for preparing Intermediate 1-7 was used with Intermediate 14-5 (520 mg, 1.00 mmol, 1.00 equiv) to afford 370 mg (71%) of the title compound as a yellow solid.
(232) ##STR00143##
(233) tert-Butyl 4-[4-[4-((dimethylamino)sulfonyl)phenyl]-6-(3-[[(1R,2S)-2-(4-fluorophenyl)cyclopropyl]amino]propyl)-3(4H)-oxopyrazin-2-yl]piperazine-1-carboxylate (Intermediate 14-7) The reductive amination step for preparing Example 1 from Intermediate 1-7 was used with Intermediate 14-6 (370 mg, 0.71 mmol). The crude product was purified with silica gel chromatography using EtOAc, to afford 300 mg (64%) of the title compound as a yellow solid.
(234) ##STR00144##
(235) 4-[5-(3-[([1R,2S]-2-[4-fluorophenyl]cyclopropyl)amino]propyl)-2-oxo-3-(piperazin-1-yl)pyrazin-1(2H)-yl]-N,N-dimethylbenzenesulfonamide (Example 14) A solution of Intermediate 14-7 (300 mg, 0.46 mmol, 1.00 equiv) and TFA (3 mL) in CH.sub.2Cl.sub.2 (15 mL) was stirred for 1 h at 25° C. The pH was adjusted to 7 with NaHCO.sub.3 (5 mM). The resulting mixture was concentrated under vacuum. The crude product (2 mL) was purified by Prep-HPLC (2 #-AnalyseHPLC-SHIMADZU (HPLC-10), column: Atlantis HILIC OBD, particle size: 5 M, column size: 19×150 mm, mobile phase: H.sub.2O (10 mM NH.sub.4HCO.sub.3+0.1% NH.sub.3)/CH.sub.3CN, 42.0% to 44.0% CH.sub.3CN in 8 min, detector, UV 254/210 nm), to afford 56.9 mg (22%) of the title compound as a yellow solid.
(236) LC-MS: (ES, m/z): 555 [M+H].sup.+. .sup.1H NMR (400 MHz, MeOD-d.sub.4) δ ppm: 7.96-7.89 (m, 2H), 7.72-7.64 (m, 2H), 7.06 (m, 2H), 7.00-6.90 (m, 2H), 6.85 (s, 1H), 3.77 (m, 4H), 2.91 (m, 4H), 2.81-2.71 (m, 8H), 2.47 (m, 2H), 2.29 (m, 1H), 1.90 (m, 3H), 1.10-0.92 (m, 2H).
Example 15
(237) ##STR00145##
4-[5-(3-[([1R,2S]-2-[4-fluorophenyl]cyclopropyl)amino]propyl)-3-(4-methylpiperazin-1-yl)-2-oxopyrazin-1(2H)-yl]-N,N-dimethylbenzenesulfonamide
(238) ##STR00146##
5-Bromo-3-(4-methylpiperazin-1-yl)-pyrazin-2(1H)-one (Intermediate 15-1)
(239) The procedure for preparing Intermediate 2-1 was used with 3,5-dibromo-1,2-dihydropyrazin-2-one (10 g, 39.39 mmol, 1.00 equiv) and 1-methylpiperazine (4.78 g, 47.72 mmol, 1.21 equiv), to afford 10.2 g (95%) of the title compound as a tan solid.
(240) ##STR00147##
(241) Ethyl (E)-3-[6-(4-methylpiperazin-1-yl)-5(4H)-oxopyrazin-2-yl]prop-2-enoate (Intermediate 15-2) The procedure for preparing Intermediate 1-4 was used with Intermediate 15-1 (5 g, 18.31 mmol, 1.00 equiv) to afford 2 g (37%) of the title compound as a light yellow solid.
(242) ##STR00148##
(243) Ethyl (E)-3-[4-(4-[N,N-dimethylsulfamoyl]phenyl)-6-(4-methylpiperazin-1-yl)-5-oxo-4,5-dihydropyrazin-2-yl) prop-2-enoate (Intermediate 15-3) The procedure for preparing Intermediate 13-1 was used with Intermediate 15-2 (2.0 g, 6.84 mmol, 1.00 equiv) and 4-bromo-N,N-dimethylbenzene-1-sulfonamide and 4-bromo-N,N-dimethylbenzene-1-sulfonamide (2.7 g, 10.26 mmol, 1.50 equiv), using 16 h of reaction time at 90° C. The crude product was purified with silica gel chromatography using CH.sub.2Cl.sub.2/MeOH (10:1) to afford 1.25 g (38.4%) of the title compound as a light yellow solid.
(244) ##STR00149##
(245) Ethyl 3-[4-(4-[N,N-dimethylsulfamoyl]phenyl)-6-(4-methylpiperazin-1-yl)-5-oxo-4,5-dihydropyrazin-2-yl]propanoate The procedure for preparing Intermediate 1-5 was used with Intermediate 15-3 (1.25 g, 2.63 mmol, 1.00 equiv) and Pd/C (125 mg), with 2 h reaction time, to afford 1.2 g (95%) of the title compound as a light yellow solid.
(246) ##STR00150##
(247) 4-[5-(3-Hydroxypropyl)-3-(4-methylpiperazin-1-yl]-2-oxopyrazin-1(2H)-yl]-N,N-dimethylbenzenesulfonamide The procedure for preparing Intermediate 1-6 was used with the product from the previous step (1.2 g, 2.52 mmol, 1.00 equiv), using 5 h reaction time at rt, to afford 600 mg (55%) of the title compound as a light yellow solid.
(248) ##STR00151##
(249) N,N-dimethyl-4-[3-(4-methylpiperazin-1-yl)-2-oxo-5-(3-oxopropyl)pyrazin-1(2H)-yl]benzenesulfonamide The procedure for preparing Intermediate 1-7 was used with the product from the previous step (600 mg, 1.38 mmol, 1.00 equiv) to afford 300 mg (78%) of the title compound as a light yellow solid.
(250) ##STR00152##
(251) 4-[5-(3-[([1R,2S]-2-[4-fluorophenyl]cyclopropyl)amino]propyl)-3-(4-methyl-piperazin-1-yl)-2-oxopyrazin-1(2H)-yl]-N,N-dimethylbenzenesulfonamide The procedure for preparing Intermediate 4-7 was used with the product from the previous step (300 mg, 0.69 mmol, 1.00 equiv). The crude product (5 mL) was purified using chromatographic Procedure B (10.0% to 29.0% CH.sub.3CN in 8 min), affording 15.1 mg (4%) of the title compound as an off-white solid.
(252) LC-MS: (ES, m/z): 569 [M+H].sup.+. .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 7.95-7.92 (m, 2H), 7.71-7.67 (m, 2H), 7.23-7.16 (m, 2H), 7.08-6.99 (m, 2H), 4.95-4.80 (m, 2H), 3.65-3.45 (s, 2H), 3.35-3.15 (m, 6H), 3.00-2.90 (m, 4H), 2.76-2.71 (s, 6H), 2.62-2.54 (m, 2H), 2.54-2.45 (m, 1H), 2.15-2.05 (m, 2H), 1.55-1.47 (m, 1H), 1.41-1.32 (m, 1H).
Example 16
(253) ##STR00153##
5-[3-([(1R,2S)-2-(4-fluorophenyl)cyclopropyl]amino)propyl]-1-[4-(pyrimidin-2-yl)phenyl]-3-[2-oxa-6-azaspiro[3.3]heptan-6-yl]pyrazin-2(1H)-one
(254) ##STR00154##
(255) Ethyl (E)-3-(6-[2-oxa-6-azaspiro[3.3]heptan-6-yl]-5(4H)-oxo-4-[4-(pyrimidin-2-yl)phenyl]-pyrazin-2-yl)prop-2-enoate The procedure for preparing Intermediate 15-3 was used with Intermediate 13-1 and 2-(4-bromophenyl)pyrimidine with 6 h reaction time at 90° C. The crude product was purified with silica gel chromatography using EtOAc/petroleum ether (1:1) to afford 2.0 g (44%) of the title compound as a yellow solid.
(256) ##STR00155##
(257) Ethyl 3-(6-[2-oxa-6-azaspiro[3.3]heptan-6-yl]-5(4H)-oxo-4-[4-(pyrimidin-2-yl)phenyl]-pyrazin-2-yl)propanoate The procedure for preparing Intermediate 1-5 was used with the product from the previous step (2 g, 4.49 mmol, 1.00 equiv) to afford 1.8 g (90%) of the title compound as a yellow solid.
(258) ##STR00156##
(259) 3-[4-(4-(Pyrimidin-2-yl)phenyl)-6-[2-oxa-6-azaspiro[3.3]heptan-6-yl]-5(4H)-oxopyrazin-2-yl]propan-1-ol The procedure for preparing Intermediate 1-6 was used with the product of the previous step (1.8 g, 4.02 mmol, 1.00 equiv) to afford 0.4 g (25%) of the title compound as an off-white solid.
(260) ##STR00157##
(261) 3-[4-(4-(Pyrimidin-2-yl)phenyl)-6-[2-oxa-6-azaspiro[3.3]heptan-6-yl]-5(4H)-oxopyrazin-2-yl]propanal The procedure for preparing Intermediate 1-7 was used with the product from the previous step (400 mg, 0.99 mmol, 1.00 equiv) to afford 0.12 g (30%) of the title compound as a light yellow oil.
(262) ##STR00158##
(263) 1-(4-(Pyrimidin-2-yl)-phenyl)-3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-5-(3-[[(1R,2S)-2-(4-fluorophenyl)cyclopropyl]amino]propyl) pyrazin-2(1H)-one The reductive amination step for preparing Example 1 from Intermediate 1-7 was used with the product from the previous step (120 mg, 0.30 mmol). The crude product (4 mL) was purified using chromatographic Procedure E (50% to 55% CH.sub.3CN in 7 min, Rt: 6.35 min), to afford 13.1 mg (8%) of the title compound as a light yellow solid.
(264) LCMS: (ES, m/z): 539 [M+H].sup.+. .sup.1H NMR (300 MHz, Methanol-d.sub.4) δ ppm: 8.85 (d, J=4.8 Hz, 2H), 8.59-8.48 (m, 2H), 7.56-7.46 (m, 2H), 7.37 (m, 1H), 7.10-6.86 (m, 4H), 6.65 (s, 1H), 4.83 (s, 4H), 4.43 (s, 4H), 2.75 (t, J=7.2 Hz, 2H), 2.41 (t, J=7.2 Hz, 2H), 2.33-2.24 (m, 1H), 1.96-1.76 (m, 3H), 1.11-0.90 (m, 2H).
Example 17
(265) ##STR00159##
1-[4-(1H-1,2,3-triazol-1-yl)phenyl]-5-[3-([(1R,2S)-2-(4-fluorophenyl)-cyclopropyl]amino)propyl]-3-[4-methylpiperazin-1-yl]pyrazin-2(1H)-one
(266) ##STR00160##
(267) 5-Bromo-3-(4-methylpiperazin-1-yl)-pyrazin-2(1H)-one (Intermediate 17-1) The procedure for preparing Intermediate 2-1 was used with 3,5-dibromo-1,2-dihydropyrazin-2-one (20 g, 78.78 mmol, 1.00 equiv) and 1-methylpiperazine (9.49 g, 94.90 mmol, 1.20 equiv). The crude product was purified using silica gel chromatography using EtOAc/petroleum ether (8:1) to afford 16.0 g (74.1%) of the title compound as a white solid.
(268) ##STR00161##
(269) Ethyl (E)-3-[6-(4-methylpiperazin-1-yl)-5(4H)-oxopyrazin-2-yl]prop-2-enoate (Intermediate 17-2) The procedure for preparing Intermediate 1-4 was used with Intermediate 17-1 (16.0 g, 58.61 mmol). The crude product was purified with silica gel chromatography using EtOAc/petroleum ether (6:1) to afford 9.0 g (52.4%) of the title compound as a yellow oil.
(270) ##STR00162##
(271) Ethyl 3-[6-(4-methylpiperazin-1-yl)-5(4H)-oxopyrazin-2-yl]propanoate (Intermediate 17-3) The procedure for preparing Intermediate 1-5 was used with Intermediate 17-2 (9.0 g, 30.72 mmol, 1.00 equiv) to afford 8.9 g (98.2%) of the title compound as a yellow oil.
(272) ##STR00163##
(273) Ethyl 3-(4-(4-(1H-1,2,3-triazol-1-yl)phenyl)-6-(4-methylpiperazin-1-yl)-5(4H)-oxopyrazin-2-yl)propanoate The procedure for preparing Intermediate 13-1 was used with Intermediate 17-3 (2.9 g, 9.83 mmol, 1 equiv) and 1-(4-bromophenyl)-1H-1,2,3-triazole (3.3 g, 14.73 mmol, 1.5 equiv). The crude product was purified with silica gel chromatography using EtOAc/petroleum ether (1:1) to afford 1.2 g (27.9%) of the title compound as a yellow solid.
(274) ##STR00164##
(275) 3-(4-(4-(1H-1,2,3-Triazol-1-yl)phenyl)-6-(4-methylpiperazin-1-yl)-5(4H)-oxopyrazin-2-yl)propan-1-ol The procedure for preparing Intermediate 1-6 was used with the product from the previous step (1.2 g, 2.74 mmol, 1 equiv) to afford 400 mg (36.9%) of the title compound as a yellow solid.
(276) ##STR00165##
(277) 3-(4-(4-(1H-1,2,3-Triazol-1-yl)phenyl)-6-(4-methylpiperazin-1-yl)-5(4H)-oxopyrazin-2-yl)propanal The procedure for preparing Intermediate 1-7 was used with the product from the previous step (350 mg, 0.88 mmol, 1.00 equiv) to afford 160 mg (46. %) of the title compound as a yellow solid.
(278) ##STR00166##
(279) 1-[4-(1H-1,2,3-triazol-1-yl)phenyl]-5-[3-([(1R,2S)-2-(4-fluorophenyl)cyclo-propyl]amino)propyl]-3-[4-methylpiperazin-1-yl]pyrazin-2(1H)-one The reductive amination step for preparing Example 1 from Intermediate 1-7 was used with the product from the previous step (150 mg, 0.41 mmol). The crude product (5 mL) was purified using chromatographic Procedure E (27% to 60% CH.sub.3CN, Rt: 10.13 min), to afford 42.8 mg (21.25%) of the title compound as a white solid.
(280) LC-MS: (ES, m/z): 529 [M+H].sup.+. .sup.1H NMR (300 MHz, MeOD-d.sub.4) δ ppm: 8.60 (s, 1H), 8.05-7.95 (m, 2H), 7.91 (s, 1H), 7.67-7.57 (m, 2H), 7.06-7.01 (m, 2H), 6.97-6.88 (m, 2H), 6.85 (s, 1H), 3.78 (m, 4H), 2.75 (t, J=7.4 Hz, 2H), 2.56-2.40 (m, 6H), 2.29 (s, 3H), 2.30-2.21 (m, 1H), 1.95-1.79 (m, 3H), 1.10-0.88 (m, 2H).
Example 18
(281) ##STR00167##
5-[3-([(1R,2S)-2-(4-fluorophenyl)cyclopropyl]amino)propyl]-3-[4-methylpiperazin-1-yl]-1-[4-(pyrimidin-2-yl)phenyl]pyrazin-2(1H)-one
(282) ##STR00168##
(283) Ethyl 3-(4-(Pyrimidin-2-yl)phenyl)-6-(4-methylpiperazin-1-yl)-5(4H)-oxopyrazin-2-yl)propanoate The procedure for preparing Intermediate 13-1 was used with Intermediate 17-3 (2.2 g, 7.46 mmol, 1 equiv) and 2-(4-bromophenyl)pyrimidine (2.63 g, 11.12 mmol, 1.5 equiv). The crude product was purified with silica gel chromatography using EtOAc/petroleum ether (1:1) to afford 1.0 g (29.86%) of the title compound as a yellow solid.
(284) ##STR00169##
(285) 3-(4-(4-(Pyrimidin-2-yl)phenyl)-6-(4-methylpiperazin-1-yl)-5(4H)-oxopyrazin-2-yl)propan-1-ol The procedure for preparing Intermediate 1-6 was used with the product from the previous step (800 mg, 1.78 mmol, 1 equiv) to afford 300 mg (41.37%) of the title compound as a yellow solid.
(286) ##STR00170##
(287) 3-(4-(4-(Pyrimidin-2-yl)phenyl)-6-(4-methylpiperazin-1-yl)-5(4H)-oxopyrazin-2-yl)propanal The procedure for preparing Intermediate 1-7 was used with the product from the previous step (300 mg, 0.74 mmol, 1.00 equiv) to afford 150 mg (50.25%) of the title compound as a yellow solid.
(288) ##STR00171##
(289) 5-[3-([(1R,2S)-2-(4-fluorophenyl)cyclopropyl]amino)propyl]-3-[4-methyl-piperazin-1-yl]-1-[4-(pyrimidin-2-yl)phenyl]pyrazin-2(1H)-one The reductive amination step for preparing Example 1 from Intermediate 1-7 was used with the product from the previous step (150 mg, 0.37 mmol). The crude product (5 mL) was purified using chromatographic Procedure D (27% to 60% CH.sub.3CN, Rt: 10.13 min), to afford 51.5 mg (25.75%) of the title compound as a white solid.
(290) LC-MS: (ES, m/z): 540 [M+H].sup.+. .sup.1H NMR (300 MHz, MeOD-d.sub.4) δ ppm: 8.86 (d, J=4.9 Hz, 2H), 8.58-8.52 (m, 2H), 7.57-7.50 (m, 2H), 7.38 (t, J=4.9 Hz, 1H), 7.21-7.13 (m, 2H), 7.07-6.97 (m, 3H), 4.92-4.85 (m, 2H), 3.60-3.47 (m, 2H), 3.25-3.12 (m, 6H), 3.00-2.85 (m, 4H), 2.57 (t, J=7.3 Hz, 2H), 2.50-2.40 (m, 1H), 2.13-2.00 (m, 2H), 1.53-1.42 (m, 1H), 1.40-1.23 (m, 1H).
Example 19
(291) ##STR00172##
1-[4-Fluorophenyl]-5-[3-([(1R,2S)-2-(4-fluorophenyl)cyclopropyl]amino)propyl]-3-[4-methylpiperazin-1-yl]pyrazin-2(1H)-one
(292) ##STR00173##
(293) 5-Bromo-3-(4-methylpiperazin-1-yl)-pyrazin-2(1H)-one The procedure for preparing Intermediate 2-1 was used with 3,5-dibromo-1,2-dihydropyrazin-2-one (10 g, 39.37 mmol, 1.00 equiv) and 1-methylpiperazine (4.72 g, 47.24 mmol, 1.20 equiv). The crude product was purified using silica gel chromatography using EtOAc/petroleum ether (8:1) to afford 10 g (93%) of the title compound as a off-white solid.
(294) ##STR00174##
Ethyl (E)-3-[6-(4-methylpiperazin-1-yl)-5(4H)-oxopyrazin-2-yl]prop-2-enoate
(295) The procedure for preparing Intermediate 1-4 was used with the product from the previous step (10 g, 36.63 mmol). The crude product was purified using silica gel chromatography using EtOAc/petroleum ether (6:1) to afford 5.6 g (52%) of the title compound as a yellow oil.
(296) ##STR00175##
(297) Ethyl 3-[6-(4-methylpiperazin-1-yl)-5(4H)-oxopyrazin-2-yl]propanoate The procedure for preparing Intermediate 1-5 was used with the product from the previous step (5.6 g, 19.18 mmol, 1.00 equiv) to afford 5.5 g (98%) of the title compound as a yellow oil.
(298) ##STR00176##
(299) Ethyl 3-(4-(4-fluorophenyl)-6-(4-methylpiperazin-1-yl)-5(4H)-oxopyrazin-2-yl)propanoate The procedure for preparing Intermediate 8-9 was used with the product from the previous step (1.5 g, 5.10 mmol, 1 equiv) and 4-fluorophenylboronic acid (1.07 g, 7.65 mmol, 1.5 equiv). The crude product was purified with silica gel chromatography using EtOAc/petroleum ether (1:1) to afford 1 g (51%) of the title compound as a yellow oil.
(300) ##STR00177##
(301) 3-(4-(4-(4-Fluorophenyl)-6-(4-methylpiperazin-1-yl)-5(4H)-oxopyrazin-2-yl)propan-1-ol The procedure for preparing Intermediate 1-6 was used with the product from the previous step (1 g, 2.58 mmol, 1 equiv) to afford 600 mg (67%) of the title compound as a yellow solid.
(302) ##STR00178##
(303) 3-(4-(4-Fluorophenyl)-6-(4-methylpiperazin-1-yl)-5(4H)-oxopyrazin-2-yl)propanal The procedure for preparing Intermediate 1-7 was used with the product from the previous step (600 mg, 1.73 mmol, 1.00 equiv) to afford 300 mg (50%) of the title compound as a yellow solid.
(304) ##STR00179##
1-[4-Fluorophenyl]-5-[3-([(1R,2S)-2-(4-fluorophenyl)cyclopropyl]amino)propyl]-3-[4-methylpiperazin-1-yl]pyrazin-2(1H)-one
(305) The reductive amination step for preparing Example 1 from Intermediate 1-7 was used with the product from the previous step (300 mg, 0.87 mmol). The crude product was purified using chromatographic Procedure B (48% to 70% CH.sub.3CN over 9 min), to afford 34 mg (8%) of the title compound as a yellow oil.
(306) LC-MS: (ES, m/z): 480 [M+H].sup.+. .sup.1H NMR (400 MHz, MeOD-d.sub.4) δ ppm: 7.47-7.44 (s, 2H), 7.31-7.27 (t, J=17.2 Hz, 2H), 7.23-7.20 (m, 2H), 7.08-7.04 (t, J=17.6 Hz, 2H), 6.98 (s, 1H), 4.93-4.88 (m, 2H), 3.59-3.54 (s, 2H), 3.33-3.24 (m, 6H), 3.00-2.96 (m, 4H), 2.61-2.57 (m, 2H), 2.53-2.48 (m, 1H), 2.15-2.07 (m, 2H), 1.52-1.49 (m, 1H), 1.41-1.37 (m, 1H).
Example 20
(307) ##STR00180##
5-[3-([(1R,2S)-2-(4-fluorophenyl)cyclopropyl]amino)propyl]-3-[4-methylpiperazin-1-yl]-1-[4-(pyridazin-3-yl)phenyl]pyrazin-2(1H)-one
(308) ##STR00181##
(309) 5-(3-Hydroxypropyl)-3-(4-methylpiperazin-1-yl)pyrazin-2(1H)-one The procedure for preparing Intermediate 1-6 was used with Intermediate 17-3 (1.0 g, 3.34 mmol, 1 equiv) with 1 hr reaction time, to afford 600 mg (69.96%) of the title compound as a yellow oil.
(310) ##STR00182##
(311) 3-(4-(4-(Pyridazin-3-yl)phenyl)-6-(4-methylpiperazin-1-yl)-5(4H)-oxopyrazin-2-yl)propan-1-ol The procedure for preparing Intermediate 13-1 was used with the product from the previous step (600 mg, 2.37 mmol, 1 equiv) and 3-(4-bromophenyl)pyridazine (836 mg, 3.56 mmol, 1.5 equiv), using an overnight reaction time at 90° C. The crude product was purified with silica gel chromatography using CH.sub.2Cl.sub.2/MeOH (10:1) to afford 600 mg (61.2%) of the title compound as a yellow solid.
(312) ##STR00183##
(313) 3-(4-(4-(Pyridazin-3-yl)phenyl)-6-(4-methylpiperazin-1-yl)-5(4H)-oxopyrazin-2-yl)propanal The procedure for preparing Intermediate 1-7 was used with the product from the previous step (300 mg, 0.74 mmol, 1.00 equiv) to afford 150 mg (50.3%) of the title compound as a yellow solid.
(314) ##STR00184##
(315) 5-[3-([(1R,2S)-2-(4-fluorophenyl)cyclopropyl]amino)propyl]-3-[4-methyl-piperazin-1-yl]-1-[4-(pyridazin-3-yl)phenyl]pyrazin-2(1H)-one The reductive amination step for preparing Example 1 from Intermediate 1-7 was used with the product from the previous step (150 mg, 0.37 mmol). The crude product (5 mL) was purified using chromatographic Procedure E (31% to 68% CH.sub.3CN in 8 min, Rt: 7.13 min), to afford 29.7 mg (14.85%) of the title compound as a white solid.
(316) LC-MS: (ES, m/z): 540 [M+H].sup.+. .sup.1H NMR (300 MHz, MeOD-d.sub.4) δ ppm: 9.16 (dd, J=4.9, 1.5 Hz, 1H), 8.28-8.18 (m, 3H), 7.85-7.77 (m, 1H), 7.62-7.54 (m, 2H), 7.09-6.98 (m, 2H), 6.96-6.84 (m, 3H), 3.85-3.73 (m, 4H), 2.76 (t, J=7.4 Hz, 2H), 2.57-2.41 (m, 6H), 2.34-2.24 (m, 4H), 1.95-1.82 (m, 3H), 1.10-0.89 (m, 2H).
Example 21
(317) ##STR00185##
1-[6-(3-[([1R,2S]-2-[4-fluorophenyl]cyclopropyl)amino]propyl)-3-oxo-4-(4-[pyrimidin-2-yl]phenyl)-3,4-dihydropyrazin-2-yl]azetidine-3-carboxamide
(318) ##STR00186##
(319) Methyl 1-(6-bromo-3(4H)-oxopyrazin-2-yl)azetidine-3-carboxylate The procedure for preparing Intermediate 2-1 was used with 3,5-dibromo-1,2-dihydropyrazin-2-one (10 g, 39.39 mmol, 1.00 equiv) and methyl azetidine-3-carboxylate (6.8 g, 59.36 mmol, 1.50 equiv), using 2 hr reaction time at 90° C., affording 8 g (67%) of the title compound as a light yellow solid.
(320) ##STR00187##
(321) (E)-Methyl 1-(6-(3-(tert-butyldimethylsilyloxy)prop-1-enyl)-3(4H)-oxopyrazin-2-yl)azetidine-3-carboxylate The procedure for preparing Intermediate 3-3 was used with the product from the previous step (8 g, 31.63 mmol), using a 2 hr reaction time at 90° C. The crude product was purified with silica gel chromatography using EtOAc/petroleum ether (1:20) to afford 3 g (28.4%) of the title compound as a light yellow oil.
(322) ##STR00188##
(323) (E)-Methyl 1-(6-(3-(tert-butyldimethylsilyloxy)prop-1-enyl)-3(4H)-oxo-4-(4-(pyrimidin-2-yl)phenyl)-pyrazin-2-yl)azetidine-3-carboxylate The procedure for preparing Intermediate 13-1 was used with the product from the previous step (3 g, 9.81 mmol, 1.00 equiv), and 2-(4-bromophenyl)pyrimidine (3.1 g, 14.89 mmol, 1.50 equiv). The crude product was purified with silica gel chromatography using EtOAc/petroleum ether to afford 2.3 g (53%) of the title compound as a yellow oil.
(324) ##STR00189##
(325) Methyl 1-(6-(3-(tert-butyldimethylsilyloxy)propyl)-3(4H)-oxo-4-(4-(pyrimidin-2-yl)phenyl)-pyrazin-2-yl)azetidine-3-carboxylate The procedure for preparing Intermediate 1-5 was used with the product from the previous step (2.3 g, 3.38 mmol, 1.00 equiv) to afford 2.1 g (89%) of the title compound as a light yellow oil.
(326) ##STR00190##
(327) 1-(6-(3-(tert-butyldimethylsilyloxy)propyl)-3(4H)-oxo-4-(4-(pyrimidin-2-yl)phenyl)-pyrazin-2-yl)azetidine-3-carboxamide A solution of the product from the previous step (2.1 g, 3.02 mmol, 1.00 equiv) in MeOH (10 mL) was combined with a solution of NH.sub.3 (4 g, 5.00 equiv) in MeOH (5 mL). The resulting solution was stirred for 16 h at 90° C., then cooled and concentrated under vacuum, to afford 1.5 g (70%) of the title compound as a light yellow oil.
(328) ##STR00191##
(329) 1-(6-(3-Hydroxypropyl)-3(4H)-oxo-4-(4-(pyrimidin-2-yl)phenyl)-pyrazin-2-yl)azetidine-3-carboxamide A solution of the product from the previous step (1.5 g, 2.00 mmol, 1.00 equiv) in THF (20 mL) was combined with a solution of HCl (3 mL, 2.00 equiv) in H.sub.2O (1 mL). The resulting solution was stirred for 1 h at 25° C. The pH value of the solution was adjusted to 7 with 1 M Na.sub.2CO.sub.3, and the residue was then purified with silica gel chromatography using H.sub.2O/CH.sub.3CN (5:1) to afford 760 mg (64%) of the title compound as a light yellow solid.
(330) ##STR00192##
(331) 1-(3(4H)-oxo-6-(3-oxopropyl)-4-(4-(pyrimidin-2-yl)phenyl)-pyrazin-2-yl)-azetidine-3-carboxamide The procedure for preparing Intermediate 1-7 was used with the product from the previous step (760 mg, 1.15 mmol), affording 360 mg (47%) of the title compound as a light yellow solid.
(332) ##STR00193##
(333) 1-[6-(3-[([1R,2S]-2-[4-fluorophenyl]cyclopropyl)amino]propyl)-3-oxo-4-(4-[pyrimidin-2-yl]phenyl)-3,4-dihydropyrazin-2-yl]azetidine-3-carboxamide The procedure for preparing Intermediate 4-7 was used with the product from the previous step (126 mg, 0.83 mmol, 1.20 equiv). The crude product (3 mL) was purified using chromatographic Procedure C (38.0% to 50.0% CH.sub.3CN in 8 min), to afford 47.7 mg (10%) of the title compound as a light yellow solid.
(334) LC-MS: (ES, m/z): 540 [M+H].sup.+. .sup.1H NMR (300 MHz, MeOD-d.sub.4) δ ppm: 8.95-8.61 (m, 2H), 8.65-8.45 (m, 2H), 7.62-7.48 (m, 2H), 7.48-7.31 (m, 1H), 7.11-6.89 (m, 4H), 6.82 (s, 1H), 4.66-4.19 (s, 4H), 3.59-3.40 (m, 1H), 2.85-2.65 (m, 2H), 2.62-2.36 (m, 2H), 2.36-2.17 (m, 1H), 2.00-1.61 (m, 3H), 1.12-0.89 (m, 2H).
Example 22
(335) ##STR00194##
1-[4-(1H-1,2,3-triazol-1-yl)phenyl]-5-[3-([(1R,2S)-2-(4-fluorophenyl)-cyclopropyl)amino]propyl)-3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pyrazin-2(1H)-one
(336) ##STR00195##
(337) 5-(E)-[3-[(tert-Butyldimethylsilyl)oxy]propyl]-3-[2-oxa-6-azaspiro[3.3]heptan-6-yl]-pyrazin-2(1H)one (Intermediate 22-1) The procedure for preparing Intermediate 3-3 was used with Intermediate 7-1 (4 g, 14.70 mmol). The crude product was purified with silica gel chromatography using EtOAc/petroleum ether (1:15) to afford 1 g (19%) of the title compound as a light yellow oil.
(338) ##STR00196##
(339) 5-(E)[3-[(tert-Butyldimethylsilyl)oxy]prop-1-en-1-yl]-3-[2-oxa-6-azaspiro[3.3]-heptan-6-yl]-1-[4-(1H-1,2,3-triazol-1-yl)phenyl]-pyrazin-2(1H)one (Intermediate 22-2) The procedure for preparing Intermediate 13-1 was used with Intermediate 22-1 (1 g, 2.75 mmol, 1.00 equiv) and 1-(4-bromophenyl)-1H-1,2,3-triazole (950 mg, 4.24 mmol, 1.50 equiv), using 16 hr of reaction time at 90° C. The crude product was purified with silica gel chromatography using EtOAc/petroleum ether (1:20) to afford 1 g (72%) of the title compound as a light yellow oil.
(340) ##STR00197##
(341) 5-[3-[(tert-Butyldimethylsilyl)oxy]propyl]-3-[2-oxa-6-azaspiro[3.3]heptan-6-yl]-1-[4-(1H-1,2,3-triazol-1-yl)phenyl]-pyrazin-2(1H)-one (Intermediate 22-3) The procedure for preparing Intermediate 1-5 was used with Intermediate 22-2 (1 g, 1.97 mmol, 1.00 equiv) to afford 0.9 g (90%) of the title compound as a light yellow oil.
(342) ##STR00198##
(343) 3-(6-[2-Oxa-6-azaspiro[3.3]heptan-6-yl]-5(4H)-oxo-4-[4-(1H-1,2,3-triazol-1-yl)phenyl]-pyrazin-2-yl)propan-1-ol (Intermediate 22-4) A solution of Intermediate 22-3 (900 mg, 1.77 mmol, 1.00 equiv) and Bu.sub.4NF (700 mg, 2.68 mmol, 1.50 equiv) in THF (20 mL). was stirred for 1 h at 25° C., then purified with silica gel chromatography using with H.sub.2O/MeCN (5:1), to afford 0.52 g (75%) of the title compound as a light yellow solid.
(344) ##STR00199##
(345) 3-(6-[2-Oxa-6-azaspiro[3.3]heptan-6-yl]-5(4H)-oxo-4-[4-(1H-1,2,3-triazol-1-yl)phenyl]-pyrazin-2-yl)propanal The procedure for preparing Intermediate 1-7 was used with the product from the previous step (520 mg, 1.32 mmol, 1.00 equiv) to afford 300 mg (58%) of the title compound as a light yellow solid.
(346) ##STR00200##
(347) 1-[4-(1H-1,2,3-triazol-1-yl)phenyl]-5-[3-([(1R,2S)-2-(4-fluorophenyl)cyclo-propyl)amino]propyl)-3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pyrazin-2(1H)-one The procedure for preparing Intermediate 4-7 was used with the product from the previous step (300 mg, 0.76 mmol). The crude product (2 mL) was purified using chromatographic Procedure C (38.0% to 50.0% CH.sub.3CN in 8 min), to afford 11.8 mg (3%) of the title compound as a white solid.
(348) LC-MS: (ES, m/z): 528 [M+H].sup.+. .sup.1H NMR (300 MHz, MeOD-d.sub.4) δ ppm: 8.70-8.51 (m, 1H), 8.11-7.99 (m, 2H), 7.99-7.80 (m, 1H), 7.79-7.47 (m, 2H), 7.13-6.80 (m, 4H), 6.64 (s, 1H), 4.82 (s, 4H), 4.43 (s, 4H), 2.88-2.58 (m, 2H), 2.52-2.35 (m, 2H), 2.35-2.20 (s, 1H), 2.09-1.71 (m, 3H), 1.12-0.82 (m, 2H).
Example 23
(349) ##STR00201##
1-[4-(1H-1,2,3-triazol-1-yl)phenyl]-3-[azetidin-1-yl]-5-[3-([(1R,2S)-2-(4-fluorophenyl)cyclopropyl]amino)propyl]pyrazin-2(1H)-one
(350) ##STR00202##
(351) 5-Bromo-3-(azetidin-1-yl)-pyrazin-2(1H)-one The procedure for preparing Intermediate 2-1 was used with 3,5-dibromo-1,2-dihydropyrazin-2-one (5.0 g, 19.76 mmol, 1 equiv) and azetidine (1.46 g, 25.61 mmol, 1.3 equiv), to afford 4.0 g (88%) of the title compound as a light yellow solid.
(352) ##STR00203##
(353) 5-(E)-[3-[(tert-Butyldimethylsilyl)oxy]propyl]-3-(azetidin-1-yl)-pyrazin-2(1H)one The procedure for preparing Intermediate 3-3 was used with the product from the previous step (4 g, 17.39 mmol), with 16 hr of reaction time at 90° C. The crude product was purified with silica gel chromatography using EtOAc/petroleum ether (1:4) to afford 1.4 g (25.04%) of the title compound as a brown oil.
(354) ##STR00204##
(355) 5-(E)[3-[(tert-Butyldimethylsilyl)oxy]prop-1-en-1-yl]-3-(azetidin-1-yl)-1-[4-(1H-1,2,3-triazol-1-yl)phenyl]-pyrazin-2(1H)one The procedure for preparing Intermediate 13-1 was used with the product from the previous step (1.4 g, 4.35 mmol, 1 equiv) and 1-(4-bromophenyl)-1H-1,2,3-triazole (1.46 g, 6.53 mmol, 1.5 equiv), using 16 hr of reaction time at 90° C. The crude product was purified with silica gel chromatography using EtOAc/petroleum ether to afford 1.1 g (54.37%) of the title compound as a yellow solid.
(356) ##STR00205##
(357) 5-[3-[(tert-Butyldimethylsilyl)oxy]propyl]-3-(azetidin-1-yl)-2(1H)-oxo-1-[4-(1H-1,2,3-triazol-1-yl)phenyl]-pyrazine The procedure for preparing Intermediate 1-5 was used with the product from the previous step (1.0 g, 2.15 mmol, 1 equiv) to afford 1.0 g (99.57%) of the title compound as a yellow oil.
(358) ##STR00206##
(359) 3-(6-(azetidin-1-yl)-5(4H)-oxo-4-[4-(1H-1,2,3-triazol-1-yl)phenyl]-pyrazin-2-yl)propan-1-ol A solution of the product from the previous step (900 mg, 1.93 mmol, 1 equiv) and 2 N aq HCl (3 mL) in THF (30 mL) was stirred for 15 min at rt. The pH value of the solution was adjusted to 8 with Na.sub.2CO.sub.3. The resulting solution was extracted with 3×30 mL of CH.sub.2Cl.sub.2, and the combined organic layers were purified with silica gel chromatography using CH.sub.2Cl.sub.2/MeOH (8:1) to afford 400 mg (58.84%) of the title compound as a light yellow solid.
(360) ##STR00207##
(361) 3-(6-(azetidin-1-yl)-5(4H)-oxo-4-[4-(1H-1,2,3-triazol-1-yl)phenyl]-pyrazin-2-yl)propanal The procedure for preparing Intermediate 1-7 was used with the product from the previous step (380 mg, 1.08 mmol, 1.00 equiv) to afford 200 mg (52.9%) of the title compound as a yellow solid.
(362) ##STR00208##
(363) 1-[4-(1H-1,2,3-triazol-1-yl)phenyl]-3-[azetidin-1-yl]-5-[3-([(1R,2S)-2-(4-fluorophenyl)cyclopropyl]amino)propyl]pyrazin-2(1H)-one The reductive amination step for preparing Example 1 from Intermediate 1-7 was used with the product from the previous step (200 mg, 0.57 mmol). The crude product was purified using chromatographic Procedure E (30.0% to 65.0% CH.sub.3CN in 8.1 min), to afford 7.9 mg (2.85%) of the title compound as a white solid.
(364) LC-MS: (ES, m/z): 486 [M+H].sup.+. .sup.1H NMR (400 MHz, MeOD-d.sub.4) δ ppm: 8.62 (s, 1H), 8.03 (d, J=8.8 Hz, 2H), 7.93 (s, 1H), 7.64 (d, J=8.8 Hz, 2H), 7.15-7.10 (m, 2H), 6.99 (t, J=8.8 Hz, 2H), 6.65 (s, 1H), 4.42-4.27 (m, 4H), 3.04-2.96 (m, 2H), 2.65-2.56 (m, 1H), 2.47 (t, J=6.8 Hz, 2H), 2.41-2.30 (m, 2H), 2.20-2.10 (m, 1H), 2.00-1.92 (m, 2H), 1.20-1.10 (m, 2H).
Example 24
(365) ##STR00209##
5-[3-([(1R,2S)-2-(4-fluorophenyl)cyclopropyl]amino)propyl]-1-[pyrimidin-5-yl]-3-[2-oxa-6-azaspiro[3.3]heptan-6-yl]pyrazin-2(1H)-one
(366) ##STR00210##
(367) 5-(E)[3-[(tert-Butyldimethylsilyl)oxy]prop-1-en-1-yl]-3-[2-oxa-6-azaspiro[3.3]-heptan-6-yl]-1-(pyrimidin-5-yl)-pyrazin-2(1H)one The procedure for preparing Intermediate 8-9 was used with Intermediate 22-1 (2 g, 5.51 mmol, 1 equiv) and (pyrimidin-5-yl)boronic acid (1.1 g, 8.26 mmol, 1.5 equiv). The crude product was purified using silica gel chromatography using CH.sub.2Cl.sub.2/MeOH (1.10) to afford 1 g (41.1%) of the title compound as a solid.
(368) ##STR00211##
(369) 5-[3-[(ter-Butyldimethylsilyl)oxy]propyl]-3-[2-oxa-6-azaspiro[3.3]heptan-6-yl]-1-(pyrimidin-5-yl)-pyrazin-2(1H)-one The procedure for preparing Intermediate 1-5 was used with the product from the previous step (g, 2.27 mmol, 1 equiv) to afford 900 mg (89.6%) of the title compound as a yellow solid.
(370) ##STR00212##
(371) 3-(6-[2-Oxa-6-azaspiro[3.3]heptan-6-yl]-5(4H)-oxo-4-(pyrimidin-5-yl)-pyrazin-2-yl)propan-1-ol The procedure for preparing Intermediate 22-4 was used with the product from the previous step (900 mg, 2.03 mmol). The crude product (10 mL) was purified by Flash-Prep-HPLC (Intel Flash-1: MeCN/H.sub.2O=1:10 increasing to MeCN/H.sub.2O=5:10 within 40 min; Detector, 220 nm), affording 400 mg (59.86%) of the title compound as a yellow solid.
(372) ##STR00213##
(373) 3-(6-[2-Oxa-6-azaspiro[33]heptan-6-yl]-5(4H)-oxo-4-(pyrimidin-5-yl)-pyrazin-2-yl)propanal The procedure for preparing Intermediate 1-7 was used with the product from the previous step (400 mg, 1.21 mmol, 1 equiv) to afford 200 mg (50.31%) of the title compound as a light yellow solid.
(374) ##STR00214##
(375) 5-[3-([(1R,2S)-2-(4-fluorophenyl)cyclopropyl]amino)propyl]-1-[pyrimidin-5-yl]-3-[2-oxa-6-azaspiro[3.3]heptan-6-yl]pyrazin-2(1H)-one The reductive amination step for preparing Example 1 from Intermediate 1-7 was used with the product from the previous step (200 mg, 0.61 mmol). The crude product (5 mL) was purified using chromatographic Procedure C (38.0% to 52.0% CH.sub.3CN in 7 min), to afford 24.8 mg (8.78%) of the title compound as a light yellow solid.
(376) LC-MS: (ES, m/z): 463 [M+H].sup.+. .sup.1H NMR (400 MHz, MeOD-d.sub.4) δ ppm: 9.20 (s, 1H), 8.97 (s, 2H), 7.11-7.055 (m, 2H) 7.01-6.94 (m, 2H), 6.73 (s, 1H), 4.83 (s, 4H), 4.09 (brs, 4H), 2.82-2.73 (m, 2H), 2.48-2.39 (m, 2H), 2.35-2.27 (m, 1H), 1.98-1.82 (m, 3H), 1.12-1.04 (m, 1H), 1.03-0.96 (m, 1H).
Example 25
(377) ##STR00215##
1-[6-(3-[[(1R,2S)-2-(4-Fluorophenyl)cyclopropyl]amino]propyl)-3-oxo-4-[4-(pyrimidin-2-yl)phenyl]-3,4-dihydropyrazin-2-yl]piperidine-4-carboxamide
(378) ##STR00216##
(379) Methyl 1-[6-[(E)-3-[(tert-butyldimethylsilyl)oxy]prop-1-en-1-yl]-3(4H)-oxopyrazin-2-yl]piperidine-4-carboxylate The procedure for preparing Intermediate 3-3 was used with Intermediate 10-1 (10 g, 31.63 mmol), using 3 hr of reaction time at 90° C. The crude product was purified with silica gel chromatography using EtOAc/petroleum ether (1:20) to afford 4 g (31%) of the title compound as a light yellow oil.
(380) ##STR00217##
(381) Methyl 1-[6-[(E)-3-[(tert-butyldimethylsilyl)oxy]prop-1-en-1-yl]-3(4H)-oxo-4-[4-(pyrimidin-2-yl)phenyl]-pyrazin-2-yl]piperidine-4-carboxylate The procedure for preparing Intermediate 13-1 was used with the product from the previous step (4 g, 9.81 mmol, 1.00 equiv) and 2-(4-bromophenyl)pyrimidine (3.5 g, 14.89 mmol, 1.50 equiv), using 16 hr of reaction time at 90° C. The crude product was purified with silica gel chromatography using EtOAc/petroleum ether to afford 1.9 g (34%) of the title compound as a yellow oil.
(382) ##STR00218##
(383) Methyl 1-(6-[3-[(tert-butyldimethylsilyl)oxy]propyl]-3(4H)-oxo-4-[4-(pyrimidin-2-yl)phenyl]-pyrazin-2-yl)piperidine-4-carboxylate The procedure for preparing of Intermediate 1-5 was used with the product from the previous step (1.9 g, 3.38 mmol, 1.00 equiv) to afford 1.7 g (89%) of the title compound as a light yellow oil.
(384) ##STR00219##
(385) 1-(6-[3-[(tert-Butyldimethylsilyl)oxy]propyl]-3(4H)-oxo-4-[4-(pyrimidin-2-yl)phenyl]-pyrazin-2-yl)piperidine-4-carboxamide A solution of the product from the previous step (1.7 g, 3.02 mmol, 1.00 equiv) in MeOH (10 mL) was combined with a solution of NH.sub.3 (4 g, 5.00 equiv) in MeOH (5 mL). The resulting solution was stirred for 96 h at 90° C., then cooled and concentrated under vacuum to afford 1.1 g (66%) of the title compound as a light yellow oil.
(386) ##STR00220##
(387) 1-[6-(3-Hydroxypropyl)-3(4H)-oxo-4-[4-(pyrimidin-2-yl)phenyl]-pyrazin-2-yl]piperidine-4-carboxamide A solution of the product from the previous step (1.1 g, 2.00 mmol, 1.00 equiv), HCl (3 mL, 2.00 equiv) in H.sub.2O (1 mL) and THF (20 mL), was stirred for 1 h at 25° C. The pH adjusted to 7 with Na.sub.2CO.sub.3 (1 M). The crude product was purified with silica gel chromatography with H.sub.2O/MeCN (5:1) to afford 500 mg (57%) of the title compound as a light yellow solid.
(388) ##STR00221##
(389) 1-[3(4H)-Oxo-6-(3-oxopropyl)-4-[4-(pyrimidin-2-yl)phenyl]-pyrazin-2-yl]-piperidine-4-carboxamide The procedure for preparing Intermediate 1-7 was used with the product from the previous step (500 mg, 1.15 mmol, 1.00 equiv) to afford 300 mg (60%) of the title compound as a light yellow solid.
(390) ##STR00222##
(391) 1-[6-(3-[[(1R,2S)-2-(4-Fluorophenyl)cyclopropyl]amino]propyl)-3-oxo-4-[4-(pyrimidin-2-yl)phenyl]-3,4-dihydropyrazin-2-yl]piperidine-4-carboxamide The procedure for preparing Intermediate 4-7 was used with the product from the previous step (300 mg, 0.69 mmol). The crude product (3 mL) was purified using chromatographic Procedure C (38.0% to 50.0% CH.sub.3CN in 8 min), to afford 73.9 mg (19%) of the title compound as a light yellow solid.
(392) LC-MS: (ES, m/z): 568 [M+H].sup.+. .sup.1H NMR (300 MHz, MeOD-d.sub.4) δ ppm: 8.95-8.61 (d, J=4.8 Hz, 2H), 8.65-8.45 (m, 2H), 7.62-7.48 (m, 2H), 7.48-7.31 (m, 1H), 7.11-6.89 (m, 4H), 6.82 (s, 1H), 4.82-4.66 (m, 2H), 2.95-2.85 (m, 2H), 2.85-2.69 (m, 2H), 2.62-2.45 (m, 3H), 2.29 (s, 1H), 2.01-1.61 (m, 7H), 1.12-0.92 (m, 2H).
Example 26
(393) ##STR00223##
1-[4-Fluorophenyl]-5-[3-([(1R,2S)-2-(4-fluorophenyl)cyclopropyl]amino)propyl]-3-(piperazin-1-yl)pyrazin-2(1H)-one
(394) ##STR00224##
(395) tert-Butyl 4-[6-[(E)-3-ethoxy-3-oxoprop-1-en-1-yl]-4-(4-fluorophenyl)-3(4H)-oxo-pyrazin-2-yl]piperazine-1-carboxylate The procedure for preparing Intermediate 8-9 was used with Intermediate 14-2 (2.5 g, 6.61 mmol, 1.00 equiv) and (4-fluorophenyl)boronic acid (1.65 g, 11.79 mmol, 1.50 equiv). The crude product was purified using silica gel chromatography using EtOAc/petroleum ether (1:1) to afford 1.6 g (51%) of the title compound as a yellow oil.
(396) ##STR00225##
(397) tert-Butyl 4-[6-(3-ethoxy-3-oxopropyl)-4-(4-fluorophenyl)-3(4H)-oxopyrazin-2-yl]piperazine-1-carboxylate (Intermediate 26-2) The procedure for preparing Intermediate 1-5 was used with the product from the previous step (1.6 g, 3.39 mmol, 1.00 equiv) to afford 1.5 g (93%) of the title compound as a yellow solid.
(398) ##STR00226##
(399) tert-Butyl 4-[4-(4-fluorophenyl)-6-(3-hydroxypropyl)-3(4H)-oxopyrazin-2-yl]piperazine-1-carboxylate The procedure for preparing Intermediate 1-6 was used with the product of the previous step (1.5 g, 3.16 mmol, 1.00 equiv) to afford 1.1 g (80%) of the title compound as a yellow oil.
(400) ##STR00227##
(401) tert-Butyl 4-[4-(4-fluorophenyl)-3(4H)-oxo-6-(3-oxopropyl)-pyrazin-2-yl]-piperazine-1-carboxylate The procedure for preparing Intermediate 1-7 was used with the product from the previous step (600 mg, 1.39 mmol, 1.00 equiv) to afford 400 mg (66.98%) of the title compound as a yellow oil.
(402) ##STR00228##
(403) tert-Butyl 4-[4-(4-fluorophenyl)-6-(3-[[(1R,2S)-2-(4-fluorophenyl)-cyclopropyl]amino]propyl)-3(4H)-oxopyrazin-2-yl]piperazine-1-carboxylate The reductive amination step for preparing Example 1 from Intermediate 1-7 was used with the product from the previous step (400 mg, 0.93 mmol), affording 300 mg (57%) of the title compound as a yellow oil, which was carried forward without further purification.
(404) ##STR00229##
(405) 1-[4-Fluorophenyl]-5-[3-([(1R,2S)-2-(4-fluorophenyl)cyclopropyl]amino)-propyl]-3-(piperazin-1-yl)pyrazin-2(1H)-one The deprotection step for preparing Example 14 from Intermediate 14-7 was used with the product from the previous step (300 mg, 0.53 mmol, 1.00 equiv). The crude product (3 mL) was purified using chromatographic Procedure D (15% to 60% CH.sub.3CN in 6.5 min, Rt: 6.88 min), to afford 113.4 mg (46%) of the title compound as a light yellow solid.
(406) LCMS: (ES, m/z): 466 [M+H].sup.+. .sup.1H NMR (300 MHz, Methanol-d.sub.4) δ ppm: 7.51-7.41 (m, 2H), 7.30-7.27 (m, 2H), 7.27-7.17 (m, 2H), 7.07-7.0 (m, 2H), 6.98 (s, 1H), 4.10-4.0 (m, 4H), 3.40-3.20 (m, 6H), 3.04-2.94 (m, 1H), 2.60-2.50 (m, 2H), 2.56-2.46 (m, 1H), 2.11-2.0 (m, 2H), 1.58-1.47 (m, 1H), 1.44-1.29 (m, 1H).
Example 27
(407) ##STR00230##
1-[4-(1H-1,2,3-triazol-1-yl)phenyl]-5-[3-([(1R,2S)-2-(4-fluorophenyl)-cyclopropyl]amino)propyl]-3-[piperazin-1-yl]pyrazin-2(1H)-one
(408) ##STR00231##
(409) tert-Butyl 4-(4-(4-(1H-1,2,3-triazol-1-yl)phenyl)-6-(3-ethoxy-3-oxopropyl)-3(4H)-oxopyrazin-2-yl)piperazine-1-carboxylate (Intermediate 27-1) The procedure for preparing Intermediate 13-1 was used with Intermediate 26-2 (1.5 g, 3.95 mmol, 1 equiv) and 1-(4-bromophenyl)-1H-1,2,3-triazole (1.34 g, 5.92 mmol, 1.5 equiv). The crude product was purified with silica gel chromatography using EtOAc/petroleum ether (1:1) to afford 0.7 g (33.98%) of the title compound as a yellow solid.
(410) ##STR00232##
(411) tert-Butyl 4-(4-(4-(1H-1,2,3-triazol-1-yl)phenyl)-6-(3-hydroxypropyl)-3(4H)-oxopyrazin-2-yl)piperazine-1-carboxylate The procedure for preparing Intermediate 1-6 was used with the product from the previous step (0.7 g, 1.34 mmol, 1 equiv) with 1 hr reaction time, to afford 400 mg (62.21%) of the title compound as a yellow solid.
(412) ##STR00233##
(413) tert-Butyl 4-(4-(4-(1H-1,2,3-triazol-1-yl)phenyl)-3(4H)-oxo-6-(3-oxopropyl)-pyrazin-2-yl)piperazine-1-carboxylate The procedure for preparing Intermediate 1-7 was used with the product from the previous step (400 mg, 0.83 mmol, 1.00 equiv) to afford 300 mg (75.37%) of the title compound as a yellow solid.
(414) ##STR00234##
(415) tert-Butyl 4-[4-(4-[1H-1,2,3-triazol-1-yl]phenyl)-6-(3-[(1R,2S)-2-(4-fluoro-phenyl)cyclopropylamino]propyl)-3(4H)-oxopyrazin-2-yl]piperazine-1-carboxylate The reductive amination step for preparing Example 1 from Intermediate 1-7 was used with the product from the previous step (300 mg, 0.63 mmol). The crude product was purified with silica gel chromatography using CH.sub.2Cl.sub.2/MeOH (10:1) to afford 220 mg (57%) of the title compound as a white solid.
(416) ##STR00235##
(417) 1-[4-(1H-1,2,3-triazol-1-yl)phenyl]-5-[3-([(1R,2S)-2-(4-fluorophenyl)cyclo-propyl]amino)propyl]-3-[piperazin-1-yl]pyrazin-2(1H)-one The deprotection step for preparing Example 14 from Intermediate 14-7 was used with the product from the previous step (220 mg, 0.41 mmol, 1 equiv). The crude product (5 mL) was purified using chromatographic Procedure E (27% to 60% CH.sub.3CN, Rt: 10.13 min), to afford 52 mg (18.44%) of the title compound as a white solid.
(418) LC-MS: (ES, m/z): 515 [M+H].sup.+. .sup.1H NMR (300 MHz, MeOD-d.sub.4) δ ppm: 8.59 (s, 1H), 8.03-8.01 (d, J=8.7 Hz, 2H), 7.90 (s, 1H) 7.63-7.60 (d, J=8.7 Hz, 2H), 7.08-6.89 (m, 2H), 6.97-6.87 (m, 2H), 6.86-6.83 (s, 1H), 3.78-3.68 (m, 4H), 2.92-2.84 (m, 4H), 2.79-2.71 (m, 2H), 2.50-2.41 (m, 2H), 2.31-2.23 (m, 1H), 1.95-1.80 (m, 3H), 1.10-0.95 (m, 2H).
Example 28
(419) ##STR00236##
5-[3-([(1R,2S)-2-(4-fluorophenyl)cyclopropyl]amino)propyl]-3-[piperazin-1-yl]-1-[4-(pyrimidin-2-yl)phenyl]pyrazin-2(1H)-one
(420) ##STR00237##
(421) 2-(4-Bromophenyl)pyrimidine A solution of 4-bromophenylboronic acid (5.0 g, 25.12 mmol, 1 equiv), 2-bromopyrimidine (5.92 g, 37.68 mmol, 1.5 equiv), K.sub.2CO.sub.3 (10.40 g, 75.37 mmol, 3 equiv), and Pd(dppf)Cl.sub.2 (1.84 g, 2.51 mmol, 0.1 equiv) in dioxane (450 mL)/H.sub.2O (100 mL) was stirred overnight at 90° C. under N.sub.2. The residue was purified using silica gel chromatography using EtOAc/petroleum ether (6:1) to afford 2.0 g (34%) of the title compound as a yellow oil.
(422) ##STR00238##
(423) tert-Butyl 4-(6-(3-ethoxy-3-oxopropyl)-3(4H)-oxo-4-(4-(pyrimidin-2-yl)phenyl)-pyrazin-2-yl)piperazine-1-carboxylate The procedure for preparing Intermediate 13-1 was used with Intermediate 27-1 (1.79 g, 4.72 mmol, 1.1 equiv) and 2-(4-bromophenyl)pyrimidine (1.0 g, 4.29 mmol, 1 equiv). The crude product was purified with silica gel chromatography using EtOAc/petroleum ether (1:1) to afford 0.6 g (27.87%) of the title compound as a yellow solid.
(424) ##STR00239##
(425) tert-Butyl 4-(6-(3-hydroxypropyl)-3(4H)-oxo-4-(4-(pyrimidin-2-yl)phenyl)-pyrazin-2-yl)piperazine-1-carboxylate The procedure for preparing Intermediate 1-6 was used with the product from the previous step (0.6 g, 2.74 mmol, 1 equiv), with 1 hr reaction time, to afford 350 mg (39.8%) of the title compound as a yellow solid.
(426) ##STR00240##
(427) tert-Butyl 4-(3(4H)-oxo-6-(3-oxopropyl)-4-(4-(pyrimidin-2-yl)phenyl)-pyrazin-2-yl)piperazine-1-carboxylate The procedure for preparing Intermediate 1-7 was used with the product from the previous step (350 mg, 0.71 mmol, 1.00 equiv) to afford 210 mg (60%) of the title compound as a yellow solid.
(428) ##STR00241##
(429) tert-Butyl 4-(6-(3-((1R,2S)-2-(4-fluorophenyl)cyclopropylamino)propyl)-3(4H)-oxo-4-(4-(pyrimidin-2-yl)phenyl)-pyrazin-2-yl)piperazine-1-carboxylate The reductive amination step for preparing Example 1 from Intermediate 1-7 was used with the product from the previous step (210 mg, 0.41 mmol), affording 190 mg (52%) of the title compound as a white solid, which was carried forward without further purification.
(430) ##STR00242##
(431) 5-[3-([(1R,2S)-2-(4-fluorophenyl)cyclopropyl]amino)propyl]-3-[piperazin-1-yl]-1-[4-(pyrimidin-2-yl)phenyl]pyrazin-2(1H)-one The deprotection step for preparing Example 14 from Intermediate 14-7 was used with the product from the previous step (190 mg, 0.30 mmol, 1 equiv). The crude product (5 mL) was purified using chromatographic Procedure D (27% to 60% CH.sub.3CN, Rt: 8.3 min), to afford 23.8 mg (14.96%) of the title compound as a white solid.
(432) LC-MS: (ES, m/z): 526 [M+H].sup.+. .sup.1H NMR (300 MHz, MeOD-d.sub.4) δ ppm: 8.95-8.90 (m, 2H), 8.62-8.56 (m, 2H), 7.64-7.56 (m, 2H), 7.49-7.43 (m, 1H), 7.27-7.17 (m, 2H), 7.10-7.01 (m, 3H), 4.14-4.04 (m, 4H), 3.43-3.32 (m, 4H), 3.31-3.23 (m, 2H), 3.05-2.95 (m, 1H), 2.68-2.52 (m, 3H), 2.23-2.09 (m, 2H), 1.62-1.52 (m, 1H), 1.42-1.32 (m, 1H).
Example 29
(433) ##STR00243##
5-[3-([(1R,2S)-2-(4-fluorophenyl)cyclopropyl]amino)propyl]-3-[piperazin-1-yl]-1-[4-(pyridazin-3-yl)phenyl]pyrazin-2(1H)-one
(434) ##STR00244##
(435) tert-Butyl 4-(6-bromo-3(4H)-oxopyrazin-2-yl)piperazine-1-carboxylate The procedure for preparing Intermediate 2-1 was used with 3,5-dibromo-1,2-dihydropyrazin-2-one (5 g, 19.84 mmol, 1.00 equiv) and tert-butyl piperazine-1-carboxylate (4.06 g, 21.82 mmol, 1.1 equiv). The crude product was purified with silica gel chromatography using EtOAc/petroleum ether (4:1) to afford 5 g (70%) of the title compound as a white solid.
(436) ##STR00245##
(437) tert-Butyl 4-[6-[(E)-3-ethoxy-3-oxoprop-1-en-1-yl]-3(4H)-oxopyrazin-2-yl]-piperazine-1-carboxylate The procedure for preparing Intermediate 1-4 was used with the product from the previous step (5.0 g, 13.96 mmol, 1 equiv). The crude product was purified with silica gel chromatography using EtOAc/petroleum ether (1:2) to afford 2.20 g (41%) of the title compound as an orange oil.
(438) ##STR00246##
(439) tert-Butyl 4-(6-(3-ethoxy-3-oxopropyl)-3(4H)-oxopyrazin-2-yl)piperazine-1-carboxylate The procedure for preparing Intermediate 1-5 was used with the product from the previous step (2.20 g, 5.82 mmol, 1.00 equiv) to afford 2.1 g (95%) of the title compound as an orange oil.
(440) ##STR00247##
(441) tert-Butyl 4-[6-(3-hydroxypropyl)-3(4H)-oxopyrazin-2-yl]piperazine-1-carboxylate The procedure for preparing Intermediate 1-6 was used with the product of the previous step (1.5 g, 3.94 mmol, 1.00 equiv) to afford 700 mg (52%) of the title compound as a light yellow solid.
(442) ##STR00248##
(443) tert-Butyl 4-[6-(3-hydroxypropyl)-3(4H)-oxo-4-[4-(pyridazin-3-yl)phenyl]-pyrazin-2-yl]piperazine-1-carboxylate The procedure for preparing Intermediate 13-1 was used with the product from the previous step (700 mg, 2.07 mmol, 1.00 equiv) and 3-(4-bromophenyl)pyridazine (723 mg, 3.08 mmol, 1.49 equiv). The crude product was purified with silica gel chromatography using EtOAc/petroleum ether (1:3) to afford 400 mg (39%) of the title compound as a light yellow solid.
(444) ##STR00249##
(445) tert-Butyl 4-[3(4H)-oxo-6-(3-oxopropyl)-4-[4-(pyridazin-3-yl)phenyl]-pyrazin-2-yl]piperazine-1-carboxylate The procedure for preparing Intermediate 1-7 was used with the product from the previous step (400 mg, 0.81 mmol, 1.00 equiv) to afford 350 mg (88%) of the title compound as a light yellow solid.
(446) ##STR00250##
(447) tert-Butyl 4-[6-(3-[[(1R,2S)-2-(4-fluorophenyl)cyclopropyl]amino]propyl)-3(4H)-oxo-4-[4-(pyridazin-3-yl)phenyl]-pyrazin-2-yl]piperazine-1-carboxylate The reductive amination step for preparing Example 1 from Intermediate 1-7 was used with the product from the previous step (350 mg, 0.71 mmol). The crude product was purified using silica gel chromatography using CH.sub.2Cl.sub.2/MeOH (1:10) to afford 300 mg (67%) of the title compound as a light yellow solid.
(448) ##STR00251##
(449) 5-[3-([(1R,2S)-2-(4-fluorophenyl)cyclopropyl]amino)propyl]-3-[piperazin-1-yl]-1-[4-(pyridazin-3-yl)phenyl]pyrazin-2(1H)-one The deprotection step for preparing Example 14 from Intermediate 14-7 was used with the product from the previous step (400 mg, 0.64 mmol, 1.00 equiv). The crude product (2 mL) was purified by Flash-Prep-HPLC (IntelFlash-1, column: silica gel, detector, UV 254 nm) to afford 57.4 mg (17%) of the title compound as a light yellow solid.
(450) LC-MS: (ES, m/z): 526 [M+H].sup.+. .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ 9.25-9.22 (s, 1H), 8.34-8.28 (m, 3H), 7.92-7.86 (m, 1H), 7.68-7.64 (m, 2H), 7.25-7.19 (m, 2H), 7.11-7.04 (m, 3H), 4.11-4.03 (m, 4H), 3.41-3.33 (m, 4H), 3.32-3.27 (m, 2H), 3.03-2.97 (m, 1H), 2.67-2.59 (m, 2H), 2.56-2.48 (m, 1H), 2.20-2.09 (m, 2H), 1.58-1.49 (m, 1H), 1.44-1.36 (m, 1H)
Example 30
(451) ##STR00252##
4-[5-(3-[[(1R,2S)-2-(4-Fluorophenyl)cyclopropyl]amino]propyl)-3-(4-methanesulfonylpiperazin-1-yl)-2(1H)-oxopyrazin-1-yl]-N,N-dimethylbenzene-1-sulfonamide
(452) ##STR00253##
(453) tert-Butyl 4-[4-[4-((dimethylamino)sulfonyl)phenyl]-6-(3-[[(1R,2S)-2-(4-fluorophenyl)cyclopropyl](prop-2-en-1-yl)amino]propyl)-3(4H)-oxopyrazin-2-yl]-piperazine-1-carboxylate The reductive amination step for preparing Example 1 from Intermediate 1-7 was used with Intermediate 14-6 (760 mg, 1.46 mmol, 1.00 equiv) and (1R,2S)-2-(4-fluorophenyl)-N-(prop-2-en-1-yl)cyclopropan-1-amine (560 mg, 2.93 mmol, 2.00 equiv). The crude product was purified with silica gel chromatography using EtOAc/petroleum ether (1:1), to afford 0.8 g (79%) of the title compound as a light yellow oil.
(454) ##STR00254##
4-[5-(3-[[(1R,2S)-2-(4-Fluorophenyl)cyclopropyl](prop-2-en-1-yl)amino]-propyl)-2(1H)-oxo-3-(piperazin-1-yl)-pyrazin-1-yl]-N,N-dimethylbenzene-1-sulfonamide
(455) The deprotection step for preparing Example 14 from Intermediate 14-7 was used with the product from the previous step (800 mg, 1.15 mmol, 1.00 equiv). The crude product was purified with silica gel chromatography using CH.sub.2Cl.sub.2/MeOH (10:1), to afford 560 mg (82%) of the title compound as a brown oil.
(456) ##STR00255##
(457) 4-[5-(3-[[(1R,2S)-2-(4-Fluorophenyl)cyclopropyl](prop-2-en-1-yl)amino]propyl)-3-(4-methanesulfonylpiperazin-1-yl)-2(1H)-oxopyrazin-1-yl]-N,N-dimethylbenzene-1-sulfonamide A solution of the compound from the previous step (560 mg, 0.94 mmol, 1.00 equiv) and Et.sub.3N (286 mg, 2.83 mmol, 3.00 equiv) in CH.sub.2Cl.sub.2 (10 mL) was stirred for 30 min at 0° C., then CH.sub.3SO.sub.2Cl (161 mg, 1.41 mmol, 1.50 equiv) was added. The resulting solution was stirred for 60 min at rt and extracted with 3×30 mL of CH.sub.2Cl.sub.2. The combined organic layers were dried over Na.sub.2SO.sub.4 and purified with silica gel chromatography using EtOAc/petroleum ether (1:10), to afford 0.5 g (79%) of the title compound as a light yellow oil.
(458) ##STR00256##
(459) 4-[5-(3-[[(1R,2S)-2-(4-Fluorophenyl)cyclopropyl]amino]propyl)-3-(4-methanesulfonylpiperazin-1-yl)-2(1H)-oxopyrazin-1-yl]-N,N-dimethylbenzene-1-sulfonamide A solution of the product from the previous step (500 mg, 0.74 mmol, 1.00 equiv), Pd(PPh.sub.3).sub.4 (172 mg, 0.15 mmol, 0.20 equiv), and 1,3-dimethyl-1,3-diazinane-2,4,6-trione (348 mg, 2.23 mmol, 3.00 equiv) in THF (15 mL) was stirred for 2 h at 50° C. under N.sub.2. The crude product was purified first with silica gel chromatography using CH.sub.2Cl.sub.2/MeOH (50:1), and then with chromatographic Procedure E (28% to 80% CH.sub.3CN, Rt: 7.75 min), to afford 182 mg (39%) of the title compound as a white solid.
(460) LCMS: (ES, m/z): 633 [M+H].sup.+. .sup.1H NMR (300 MHz, Methanol-d.sub.4) δ ppm: 7.96-7.85 (d, J=8.4 Hz, 2H), 7.71-7.60 (d, J=8.4 Hz, 2H), 7.09-6.84 (m, 5H), 3.85 (m, 4H), 3.26 (m, 4H), 2.85-2.65 (m, 11H), 2.45-2.31 (m, 2H), 2.29-2.21 (m, 1H), 1.95-1.78 (m, 3H), 1.10-0.88 (m, 2H).
Example 31
(461) ##STR00257##
5-[3-([(1R,2S)-2-(4-fluorophenyl)cyclopropyl]amino)propyl]-3-[piperazin-1-yl]pyrazin-2(1H)-one
(462) ##STR00258##
(463) tert-Butyl 4-(6-bromo-3(4H)-oxo-4-[[2-(trimethylsilyl)ethoxy]methyl]-pyrazin-2-yl)piperazine-1-carboxylate The procedure for preparing Intermediate 2-2 was used with Intermediate 14-1 (10 g, 27.84 mmol, 1.00 equiv) and [2-(chloromethoxy)-ethyl]trimethylsilane (6.8 g, 40.79 mmol, 1.50 equiv). The crude product was purified with silica gel chromatography using EtOAc/petroleum ether (1:30) to afford 10.5 g (77%) of the title compound as an off-white oil.
(464) ##STR00259##
(465) tert-Butyl 4-[6-[(1E)-3-[(tert-butyldimethylsilyl)oxy]prop-1-en-1-yl]-3(4H)-oxo-4-[[2-(trimethylsilyl)ethoxy]methyl]-pyrazin-2-yl]piperazine-1-carboxylate The procedure for preparing Intermediate 3-3 was used with the product from the previous step (4 g, 8.17 mmol). The crude product was purified with silica gel chromatography using EtOAc/petroleum ether (1:50) to afford 1.5 g (32%) of the title compound as a light yellow oil.
(466) ##STR00260##
(467) tert-butyl 4-(6-[3-[(tert-butyldimethylsilyl)oxy]propyl]-3(4H)-oxo-4-[[2-(trimethylsilyl)ethoxy]methyl]-pyrazin-2-yl)piperazine-1-carboxylate The procedure for preparing of Intermediate 3-4 was used with the product from the previous step (1.5 g, 2.58 mmol, 1.00 equiv) to afford 1.0 g (66%) of the title compound as a light yellow oil.
(468) ##STR00261##
(469) tert-Butyl 4-[6-(3-hydroxypropyl)-3(4H)-oxo-4-[[2-(trimethylsilyl)ethoxy]-methyl]-pyrazin-2-yl]piperazine-1-carboxylate The procedure for preparing Intermediate 22-4 was used with the product from the previous step (1 g, 1.72 mmol, 1.00 equiv) to afford 0.6 g (75%) of the title compound as a light yellow oil.
(470) ##STR00262##
(471) tert-Butyl 4-[3(4H)-oxo-6-(3-oxopropyl)-4-[[2-(trimethylsilyl)ethoxy]methyl]-pyrazin-2-yl]piperazine-1-carboxylate The procedure for preparing Intermediate 1-7 was used with the product from the previous step (600 mg, 1.28 mmol, 1.00 equiv) to afford 0.3 g (50%) of the title compound as a light yellow solid.
(472) ##STR00263##
(473) tert-Butyl 4-[6-(3-[[(1R,2S)-2-(4-fluorophenyl)cyclopropyl]amino]propyl)-3(4H)-oxo-4-[[2-(trimethylsilyl)ethoxy]methyl]-pyrazin-2-yl]piperazine-1-carboxylate The procedure for preparing Intermediate 4-7 was used with the product from the previous step (300 mg, 0.64 mmol), affording 0.2 g (52%) of the title compound as a light yellow oil. The product was carried forward without further purification.
(474) ##STR00264##
(475) 5-[3-([(1R,2S)-2-(4-fluorophenyl)cyclopropyl]amino)propyl]-3-[piperazin-1-yl]pyrazin-2(1H)-one The deprotection step for preparing Example 14 from Intermediate 14-7 was used with the product from the previous step (200 mg, 0.17 mmol, 1.00 equiv). The crude product (5 mL) was purified using chromatographic Procedure B (30.0% to 50.0% CH.sub.3CN in 8 min), to afford 114.6 mg (45%) of the title compound as a light yellow oil.
(476) LC-MS: (ES, m/z): 372 [M+H].sup.+. .sup.1H NMR (300 MHz, MeOD-d.sub.4) δ ppm: 7.23-7.07 (m, 2H), 7.07-6.93 (m, 2H), 6.82-6.69 (s, 1H), 4.02-3.89 (m, 4H), 3.28-3.14 (m, 6H), 2.99-2.81 (m, 1H), 2.66-2.31 (m, 3H), 2.13-1.89 (m, 2H), 1.60-1.41 (m, 1H), 1.41-1.22 (m, 1H).
Example 32
(477) ##STR00265##
3-[1,1-Dioxidothiomorpholino]-5-[3-([(1R,2S)-2-(4-fluorophenyl)cyclopropyl]amino)propyl]pyrazin-2(1H)-one
(478) ##STR00266##
(479) 5-(3-[[(1R,2S)-2-(4-Fluorophenyl)cyclopropyl]amino]propyl)-3-(1,1-dioxothiomorpholin-4-yl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-pyrazin-2(1H)-one The reductive amination step for preparing Example 1 from Intermediate 1-7 was used with Intermediate 8-6 (150 mg, 0.36 mmol, 1 equiv) and (1R,2S)-2-(4-fluorophenyl)-cyclopropan-1-amine (109 mg, 0.72 mmol). The crude product was purified with silica gel chromatography using EtOAc/petroleum ether (3:2) to afford 140 mg (70.46%) of the title compound as an orange oil.
(480) ##STR00267##
(481) 3-[1,1-Dioxidothiomorpholino]-5-[3-([(1R,2S)-2-(4-fluorophenyl)cyclopropyl]-amino)propyl]pyrazin-2(1H)-one The deprotection step for preparing Example 2 from Intermediate 2-7 was used with the product from the previous step (140 mg, 0.25 mmol, 1 equiv). The crude product (5 mL) was purified using chromatographic Procedure C (20.0% to 50.0% CH.sub.3CN in 8 min), to afford 61 mg (28%) of the title compound as a white solid.
(482) LC-MS: (ES, m/z): 421 [M+H].sup.+. .sup.1H NMR (300 MHz, MeOD-d.sub.4) δ ppm: 7.04-6.95 (m, 2H), 6.93-6.89 (m, 2H), 6.66 (s, 1H), 4.29-4.25 (m, 4H), 3.13-3.09 (m, 4H), 2.74-2.68 (m, 2H), 2.46-2.41 (m, 2H), 2.29-2.24 (m, 1H), 1.92-1.80 (m, 3H), 1.06-0.92 (m, 2H).
Example 33
(483) ##STR00268##
5-[3-([(1R,2S)-2-(4-Fluorophenyl)cyclopropyl]amino)propyl]-3-(pyridin-4-yl)-1-[4-(pyrimidin-2-yl)phenyl]pyrazin-2(1H)-one
(484) ##STR00269##
(485) 5-bromo-3-(pyridin-4-yl)pyrazin-2(1H)-one (Intermediate 33-1) A solution of 3,5-dibromo-1,2-dihydropyrazin-2-one (20 g, 0.08 mmol, 1 equiv), (pyridin-4-yl)boronic acid (10.7 g, 0.09 mmol, 1.11 equiv), K.sub.2CO.sub.3 (32.7 g, 0.24 mmol, 3 equiv), and Pd(dppf)Cl.sub.2 (11.5 g, 0.02 mmol, 0.2 equiv) in dioxane (200 mL) and H.sub.2O (50 mL) was stirred for 16 h at 100° C. under N.sub.2. The resulting mixture was concentrated and purified with silica gel chromatography using CH.sub.2Cl.sub.2/MeOH (10:1) to afford 4 g (20%) of the title compound as a yellow oil.
(486) ##STR00270##
(487) (E)-5-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-1-yl)-3-(pyridin-4-yl)pyrazin-2(1H)-one (Intermediate 33-2) The procedure for preparing Intermediate 3-3 was used with Intermediate 33-1 (4 g, 15.87 mmol). The crude product was purified with silica gel chromatography using CH.sub.2Cl.sub.2/MeOH (10:1) to afford 1.5 g (28%) of the title compound as a yellow solid.
(488) ##STR00271##
(489) (E)-5-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-1-yl)-3-(pyridin-4-yl)-1-(4-(pyrimidin-2-yl)phenyl)pyrazin-2(1H)-one (Intermediate 33-3) The procedure for preparing Intermediate 13-1 was used with Intermediate 33-2 (1.5 g, 4.37 mmol, 1 equiv) and 2-(4-bromophenyl)pyrimidine (1.23 g, 5.24 mmol, 1.200 equiv). The crude product was purified with silica gel chromatography using EtOAc/petroleum ether (1:1) to afford 800 mg (37%) of the title compound as a yellow solid.
(490) ##STR00272##
(491) 5-(3-((tert-Butyldimethylsilyl)oxy)propyl)-3-(pyridin-4-yl)-1-(4-(pyrimidin-2-yl)phenyl)pyrazin-2(1H)-one (Intermediate 33-4) A solution of Intermediate 33-3 (600 mg, 1.15 mmol, 1 equiv) in MeOH (20 mL) was stirred over Pd/C (59.7 mg, 0.56 mmol, 0.49 equiv) under an H.sub.2 atmosphere for 60 min at rt. The product was filtered, and the filtrate was concentrated to afford 400 mg (70%) of the title compound as a yellow solid.
(492) ##STR00273##
(493) 5-(3-Hydroxypropyl)-3-(pyridin-4-yl)-1-(4-(pyrimidin-2-yl)phenyl)pyrazin-2(1H)-one (Intermediate 33-5) A solution of Intermediate 33-4 (400 mg, 0.18 mmol), in HCl (2N, 4 mL) and THF (8 mL) was stirred for 60 min at rt. The pH was adjusted to 7 with Na.sub.2CO.sub.3. The resulting solution was extracted with 3×30 mL of CH.sub.2Cl.sub.2. The combined organic layers were concentrated to afford 210 mg (88%) of the title compound as a yellow oil.
(494) ##STR00274##
(495) 3-(5-Oxo-6-(pyridin-4-yl)-4-(4-(pyrimidin-2-yl)phenyl)-4,5-dihydropyrazin-2-yl)propanal The procedure for preparing Intermediate 1-7 was used with Intermediate 33-5 (210 mg, 0.54 mmol, 1 equiv) and Dess-Martin reagent (346.6 mg, 0.82 mmol, 1.5 equiv). The crude product was purified with silica gel chromatography using EtOAc/petroleum ether (1:1) to afford 140 mg (67%) of the title compound as a yellow solid.
(496) ##STR00275##
(497) 5-[3-([(1R,2S)-2-(4-fluorophenyl)cyclopropyl]amino)propyl]-3-(pyridin-4-yl)-1-[4-(pyrimidin-2-yl)phenyl]pyrazin-2(1H)-one The reductive amination step for preparing Example 1 from Intermediate 1-7 was used with the product from the previous step (140 mg, 0.37 mmol, 1 equiv) and (1R,2S)-2-(4-fluorophenyl)cyclopropan-1-amine (99.4 mg, 0.66 mmol, 1.8 equiv). The crude product was purified using chromatographic Procedure E (42% to 45% CH.sub.3CN in 7 min), to afford 49.2 mg (25.98%) of the title compound as a yellow solid.
(498) LCMS: (ES, m/z): 519 [M+H].sup.+. .sup.1H NMR (300 MHz, Methanol-d.sub.4) δ ppm: 8.92-8.90 (d, J=4.8 Hz, 2H), 8.75-8.64 (m, 5H), 8.77-8.33 (m, 2H), 7.74-7.61 (t, J=8.7 Hz, 3H), 7.49-7.34 (t, J=4.8 Hz, 1H), 7.11-6.68 (m, 4H), 2.90-2.81 (t, J=7.35 Hz, 2H), 2.81-2.71 (t, J=7.35 Hz, 2H), 2.39-2.29 (m, 1H), 2.1-1.88 (m, 3H), 1.16-0.94 (m, 2H).
Example 34
(499) ##STR00276##
5-[3-([(1R,2S)-2-(4-fluorophenyl)cyclopropyl]amino)propyl]-1-[4-(methylsulfonyl)phenyl]-3-(pyrimidin-5-yl)pyrazin-2(1H)-one
(500) ##STR00277##
(501) 5-bromo-3-(pyrimidin-5-yl)pyrazin-2(1H)-one (Intermediate 34-1) A solution of 3,5-dibromo-1,2-dihydropyrazin-2-one (20 g, 78.78 mmol, 1 equiv), K.sub.2CO.sub.3 (32.7 g, 236.60 mmol, 3.003 equiv), (pyrimidin-5-yl)boronic acid (14.6 g, 117.83 mmol, 1.496 equiv), and Pd(dppf)Cl.sub.2 (5.8 g, 7.93 mmol, 0.101 equiv) in dioxane (200 mL) and H.sub.2O (20 mL) was stirred for 2 hr at 90° C., then concentrated to afford 8 g (40%) of the title compound as a light yellow oil.
(502) ##STR00278##
(503) (E)-5-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-1-yl)-3-(pyrimidin-5-yl)pyrazin-2(1H)-one (Intermediate 32-2) The procedure for preparing Intermediate 3-3 was used with the product from the previous step (4.5 g, 17.78 mmol). The Crude product was purified with silica gel chromatography using EtOAc/petroleum ether (4:1) to afford 3.8 g (61.99%) of the title compound as a yellow oil.
(504) ##STR00279##
(505) (E)-5-(3-((tert-butyidimethylsilyl)oxy)prop-1-en-1-yl)-1-(4-(methylsulfonyl)-phenyl)-3-(pyrimidin-5-yl)pyrazin-2(1H)-one A solution of product from the previous step (3.8 g, 11.03 mmol 1 equiv), 1-bromo-4-methanesulfonylbenzene (3.9 g, 16.55 mmol, 1.5 equiv). CuI (2.1 g, 11.03 mmol, 1 equiv), DMEDA (0.9 g, 22.06 mmol, 2 equiv), and K.sub.3PO.sub.4 (7.0 g, 33.09 mmol, 3 equiv) in dioxane (50 mL) was stirred for 16 hr at 90° C., then concentrated and purified with silica gel chromatography using CH.sub.2Cl.sub.2/MeOH (1:10). A second batch was submitted to the same reaction and purification conditions to afford an overall yield of 800 mg (7.3%) of the title compound as a light yellow solid.
(506) ##STR00280##
(507) 5-(3-((tert-Butyldimethylsilyl)oxy)propyl)-1-(4-(methylsulfonyl)phenyl)-3-(pyrimidin-5-yl)pyrazin-2(1H)-one The procedure for preparing Intermediate 3-4 was used with the product from the previous step (800 mg, 0.40 mmol, 1 equiv) to afford 600 mg (79.6%) of the title compound as a light yellow solid.
(508) ##STR00281##
(509) 5-(3-Hydroxypropyl)-1-(4-(methylsulfonyl)phenyl)-3-(pyrimidin-5-yl)pyrazin-2(1H)-one The procedure for preparing Intermediate 33-5 was used with the product from the previous step (600 mg). The crude product was purified with silica gel chromatography using CH.sub.2Cl.sub.2/MeOH (1:10) to afford 300 mg (64.7%) of the title compound as a light yellow solid.
(510) ##STR00282##
(511) 3-(4-(4-(Methylsulfonyl)phenyl)-5-oxo-6-(pyrimidin-5-yl)-4,5-dihydropyrazin-2-yl)propanal The procedure for preparing Intermediate 1-7 was used with the product from the previous step (300 mg, 0.77 mmol, 1 equiv) and Dess-Martin reagent (394.4 mg, 0.93 mmol, 1.2 equiv). The crude product was purified with silica gel chromatography using CH.sub.2Cl.sub.2/MeOH (1:10) to afford 200 mg (67.45%) of the title compound as a light yellow solid.
(512) ##STR00283##
(513) 5-[3-([(1R,2S)-2-(4-fluorophenyl)cyclopropyl]amino)propyl]-1-[4-(methyl-sulfonyl)phenyl]-3-(pyrimidin-5-yl)pyrazin-2(1H)-one The procedure for preparing Intermediate 4-7 was used with the product from the previous step (200 mg, 0.52 mmol, 1 equiv) and (1R,2S)-2-(4-fluorophenyl)cyclopropan-1-amine (1180 mg, 0.78 mmol, 1.5 equiv). The crude product was purified using chromatographic Procedure F (18% to 28% CH.sub.3CN in 7 min), to afford 20.9 mg (7.7%) of the title compound as a light yellow solid.
(514) LC-MS: (ES, m/z): 520 [M+H].sup.+
(515) .sup.1H NMR (300 MHz, MeOD-d.sub.4) δ ppm: 9.67 (s, 2H), 9.21 (s, 1H), 8.19-8.16 (d, J=9.0 Hz, 2H), 7.84-7.81 (d, J=9.0 Hz, 2H), 7.63 (s, 1H), 7.20-7.16 (m, 2H), 7.04-6.99 (m, 2H), 3.36-3.30 (m, 2H), 3.20 (s, 3H), 3.17-2.98 (m, 1H), 2.85-2.80 (m, 2H), 2.49-2.44 (m, 1H), 2.24-2.19 (m, 2H), 1.50-1.37 (m, 2H).
Example 35
(516) ##STR00284##
4-[5-(3-[([1R,2S]-2-[4-fluorophenyl]cyclopropyl)amino]propyl)-2-oxo-3-(pyrimidin-5-yl)pyrazin-1(2H)-yl]-N,N-dimethylbenzenesulfonamide
(517) ##STR00285##
(518) (E)-4-(5-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-1-yl)-2-oxo-3-(pyrimidin-5-yl)pyrazin-1(2H)-yl)-N,N-dimethylbenzenesulfonamide The procedure for preparing Intermediate 13-1 was used with Intermediate 34-2 (2.6 g, 7.55 mmol, 1 equiv) and 4-bromo-N,N-dimethylbenzene-1-sulfonamide (3.0 g, 11.32 mmol, 1.5 equiv). The crude product was purified with silica gel chromatography using EtOAc/petroleum ether (2:1) to afford 550 mg (10.13%) of the title compound as a light yellow oil.
(519) ##STR00286##
(520) 4-(5-(3-((tert-Butyldimethylsilyl)oxy)propyl)-2-oxo-3-(pyrimidin-5-yl)pyrazin-1(2H)-yl)-N,N-dimethylbenzenesulfonamide The procedure for preparing Intermediate 3-4 was used with the product from the previous step (550 mg, 1.04 mmol, 1 equiv) to afford 420 mg (76.07%) of the title compound as a light yellow oil.
(521) ##STR00287##
(522) 4-(5-(3-Hydroxypropyl)-2-oxo-3-(pyrimidin-5-yl)pyrazin-1(2H)-yl)-N,N-dimethylbenzenesulfonamide The procedure for preparing Intermediate 33-5 was used with the product from the previous step (420 mg, 0.79 mmol, 1 equiv) to afford 180 mg (55%) of the title compound as a light yellow oil.
(523) ##STR00288##
(524) N,N-Dimethyl-4-(2-oxo-5-(3-oxopropyl)-3-(pyrimidin-5-yl)pyrazin-1(2H)-yl)benzenesulfonamide The procedure for preparing Intermediate 1-7 was used with the product from the previous step (180 mg, 0.43 mmol, 1 equiv) and Dess-Martin reagent (220.5 mg, 0.52 mmol, 1.20 equiv). The crude product was purified with silica gel chromatography using CH.sub.2Cl.sub.2/MeOH (40:1) to afford 120 mg (67%) of the title compound as a light yellow oil.
(525) ##STR00289##
(526) 4-(5-(3-(((1R,2S)-2-(4-fluorophenyl)cyclopropyl)amino)propyl)-2-oxo-3-(pyrimidin-5-yl)pyrazin-1(2H)-yl)-N,N-dimethylbenzenesulfonamide The procedure for preparing Intermediate 4-7 was used with the product from the previous step (120 mg, 0.29 mmol, 1 equiv) and (1R,2S)-2-(4-fluorophenyl)cyclopropan-1-amine (52.9 mg, 0.35 mmol, 1.2 equiv). The crude product was purified using chromatographic Procedure A (15% to 45% CH.sub.3CN), to afford 13.3 mg (5.57%) of the title compound as a colorless solid.
(527) LC-MS: (ES, m/z): 549 [M+H].sup.+. .sup.1H NMR (300 MHz, MeOD-d.sub.4) δ ppm: 9.67 (s, 2H), 9.21 (s, 1H), 8.19-8.16 (d, J=9.0 Hz, 2H), 7.84-7.81 (d, J=9.0 Hz, 2H), 7.63 (s, 1H), 7.20-7.16 (m, 2H), 7.04-6.99 (m, 2H), 3.36-3.30 (m, 2H), 3.29-3.21 (m, 3H), 3.17-2.98 (m, 1H), 2.85-2.80 (m, 2H), 2.78 (s, 6H), 2.49-2.44 (m, 1H), 2.24-2.19 (m, 2H), 1.50-1.37 (m, 2H).
Example 36
(528) ##STR00290##
1-[4-fluorophenyl]-5-[3-([(1R,2S)-2-(4-fluorophenyl)cyclopropyl]amino)propyl]-3-[1H-pyrazol-4-yl]pyrazin-2(1H)-one
(529) ##STR00291##
5-Bromo-3-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)pyrazin-2(1H)-one
(530) A solution of 3,5-dibromo-1,2-dihydropyrazin-2-one (4.8 g, 19.10 mmol, 1 equiv), 1-[(4-methoxyphenyl)methyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (6 g, 19.10 mmol, 1 equiv), K.sub.2CO.sub.3 (7.9 g, 57.29 mmol, 3 equiv), and Pd(dppf)Cl.sub.2 (1.4 g, 1.91 mmol, 0.1 equiv) in dioxane (100 mL) and H.sub.2O (10 mL) was stirred for 4 hr under N.sub.2 at 90° C. The resulting mixture was concentrated under vacuum and purified with silica gel chromatography using CH.sub.2Cl.sub.2/MeOH (30:1) to afford 2.4 g (34.8%) of the title compound as a yellow oil.
(531) ##STR00292##
(532) 5-Bromo-1-(4-fluorophenyl)-3-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)pyrazin-2(1H)-one A solution of the product from the previous step (2.4 g, 6.64 mmol, 1 equiv), (4-fluorophenyl)boronic acid (1.9 g, 13.29 mmol, 2.00 equiv), TEA (1.3 g, 13.29 mmol, 2 equiv), and Cu(OAc).sub.2 (1.8 g, 9.97 mmol, 1.5 equiv) in CH.sub.2Cl.sub.2 (50 mL) was stirred for 16 hr at rt, then concentrated under vacuum and purified with silica gel chromatography using CH.sub.2Cl.sub.2/MeOH (50:1) to afford 1.4 g (46.3%) of the title compound as a yellow oil.
(533) ##STR00293##
(534) (E)-5-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-1-yl)-1-(4-fluorophenyl)-3-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)pyrazin-2(1H)-one The procedure for preparing Intermediate 3-3 was used with the product from the previous step (1.3 g, 2.86 mmol). The crude product was purified with silica gel chromatography using CH.sub.2Cl.sub.2/MeOH (20:1) to afford 1 g (64%) of the title compound as a yellow oil.
(535) ##STR00294##
(536) 5-(3-((tert-Butyldimethylsilyl)oxy)propyl)-1-(4-fluorophenyl)-3-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)pyrazin-2(1H)-one The procedure for preparing Intermediate 3-4 was used with the product from the previous step (1 g, 1.83 mmol, 1 equiv) to afford 900 mg (90%) of the title compound as a yellow oil.
(537) ##STR00295##
(538) 1-(4-Fluorophenyl)-5-(3-hydroxypropyl)-3-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)pyrazin-2(1H)-one A solution of the product from the previous step (800 mg, 1.46 mmol, 1 equiv) and HCl (2 mL, 4 M in dioxane) in dioxane (2 mL) was stirred for 2 hr at rt, then concentrated under vacuum to afford 400 mg (63.2%) of the title compound as a yellow oil.
(539) ##STR00296##
(540) 3-(4-(4-Fluorophenyl)-6-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-5-oxo-4,5-dihydropyrazin-2-yl)propanal The procedure for preparing Intermediate 1-7 was used with the product from the previous step (350 mg, 0.81 mmol, 1 equiv) and Dess-Martin reagent (410.0 mg, 0.97 mmol, 1.2 equiv), with 4 hr reaction time. The crude product was purified with silica gel chromatography using CH.sub.2Cl.sub.2/MeOH (10:1) to afford 250 mg (71.8%) of the title compound as a yellow oil.
(541) ##STR00297##
(542) 1-(4-Fluorophenyl)-5-(3-(((1R,2S)-2-(4-fluorophenyl)cyclopropyl)amino)propyl)-3-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)pyrazin-2(1H)-one The procedure for preparing Intermediate 4-7 was used with the product from the previous step (250 mg, 0.58 mmol, 1 equiv) and (1R,2S)-2-(4-fluorophenyl)cyclopropan-1-amine (104.9 mg, 0.69 mmol, 1.2 equiv), with 16 hr of reaction time. The crude product was purified with silica gel chromatography using CH.sub.2Cl.sub.2/MeOH (5:1) to afford 200 mg (61%) of the title compound as a yellow oil.
(543) ##STR00298##
(544) 1-(4-Fluorophenyl)-5-(3-(((1R,2S)-2-(4-fluorophenyl)cyclopropyl)amino)propyl)-3-(1H-pyrazol-4-yl)pyrazin-2(1H)-one A solution of the product from the previous step (200 mg, 0.35 mmol, 1 equiv) in a mixture of TFA (1 mL), TfOH (1 mL), and CH.sub.2Cl.sub.2 (5 mL) was stirred for 6 hr at rt. The resulting mixture was concentrated under vacuum. The crude product (200 mg) was purified using chromatographic Procedure F (25% to 35% CH.sub.3CN in 7 min), to afford 18.6 mg (9.4%) of the title compound as a yellow solid.
(545) LC-MS: (ES, m/z): 448 [M+H].sup.+ 1H NMR (300 MHz, MeOD-d.sub.4) δ ppm: 8.47 (s, 2H), 7.57-7.52 (m, 2H), 7.36-7.30 (m, 3H), 7.22-7.17 (m, 2H), 7.06-7.01 (t, J=8.7 Hz, 2H), 3.37-3.34 (m, 2H), 3.03-2.98 (m, 1H), 2.79-2.71 (t, J=7.2 Hz, 2H), 2.51-2.44 (m, 1H), 2.36-2.18 (m, 2H), 1.54-1.47 (m, 1H), 1.43-1.31 (m, 1H).
Example 37
(546) ##STR00299##
1-(4-Fluorophenyl)-5-(3-(((1R,2S)-2-(4-fluorophenyl)cyclopropyl)amino)propyl)-3-(4-(methylsulfonyl)piperazin-1-yl)pyrazin-2(1H)-one
(547) ##STR00300##
(548) (E)-5-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-1-yl)-3-(4-(methylsulfonyl)-piperazin-1-yl)pyrazin-2(1H)-one (Intermediate 37-1) The procedure for preparing Intermediate 3-3 was used with Intermediate 3-1 (10 g, 29.66 mmol) with 3 h reaction time at 90° C. The crude product was purified with silica gel chromatography using EtOAc/petroleum ether (1:1) to afford 2.8 g (22%) of the title compound as a yellow oil.
(549) ##STR00301##
(550) (E)-5-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-1-yl)-1-(4-fluorophenyl)-3-(4-(methylsulfonyl)piperazin-1-yl)pyrazin-2(1H)-one The procedure for preparing Intermediate 8-9 was used with the product from the previous step and 4-fluorophenylboronic acid (1.1 g, 1.5 equiv). The crude product was purified with silica gel chromatography using EtOAc/petroleum ether (1:3) to afford 1.6 g (58%) of the title compound as a yellow oil.
(551) ##STR00302##
(552) 5-(3-((tert-Butyldimethylsilyl)oxy)propyl)-1-(4-fluorophenyl)-3-(4-(methyl-sulfonyl)piperazin-1-yl)pyrazin-2(1H)-one The procedure for preparing Intermediate 3-4 was used with the product from the previous step (1.6 g, 1.0 equiv) to afford 1 g (60%) of the title compound as a yellow oil.
(553) ##STR00303##
(554) 1-(4-Fluorophenyl)-5-(3-hydroxypropyl)-3-(4-(methylsulfonyl)piperazin-1-yl)pyrazin-2(1H)-one The procedure for preparing Intermediate 33-5 was used with the product from the previous step (1 g, 1.0 equiv). The crude product was purified with silica gel chromatography using EtOAc/petroleum ether (1:1) to afford 390 mg of the title compound as a yellow solid.
(555) ##STR00304##
(556) 3-(4-(4-Fluorophenyl)-6-(4-(methylsulfonyl)piperazin-1-yl)-5-oxo-4,5-dihydropyrazin-2-yl)propanal The procedure for preparing Intermediate 1-7 was used with the product from the previous step (380 mg, 0.93 mmol, 1 equiv) and Dess-Martin reagent (589.0 mg, 1.39 mmol, 1.500 equiv). The crude product was purified with silica gel chromatography using EtOAc/petroleum ether (1:1) to afford 340 mg (89.9%) of the title compound as a yellow oil.
(557) ##STR00305##
(558) 1-(4-Fluorophenyl)-5-(3-(((1R,2S)-2-(4-fluorophenyl)cyclopropyl)amino)-propyl)-3-(4-(methylsulfonyl)piperazin-1-yl)pyrazin-2(1H)-one The reductive amination step for preparing Example 1 from Intermediate 1-7 was used with the product from the previous step (340 mg, 0.83 mmol, 1 equiv) and (1R,2S)-2-(4-fluorophenyl)-cyclopropan-1-amine (226.5 mg, 1.50 mmol, 1.8 equiv). The crude product was purified using chromatographic Procedure C (40% to 56% CH.sub.3CN in 16.5 min), to afford 67.1 mg (14.9%) of the title compound as a white solid.
(559) LCMS: (ES, m/z): 544 [M+H].sup.+. .sup.1H NMR (300 MHz, Methanol-d.sub.4) δ ppm: 7.50-7.39 (m, 2H), 7.35-7.22 (m, 2H), 7.13-6.91 (m, 4H), 6.86 (s, 1H), 3.91-3.81 (m, 4H), 3.32-3.30 (m, 4H), 2.87 (s, 3H), 2.84-2.73 (t, J=7.5 Hz, 2H), 2.50 (t, J=7.3 Hz, 2H), 2.36-2.26 (m, 1H), 1.95-1.85 (m, 3H), 1.14-0.93 (m, 2H).
Example 38
(560) ##STR00306##
3-(1,1-dioxidothiomorpholino)-1-(4-fluorobenzyl)-5-[3-([(1R,2S)-2-(4-fluorophenyl)cyclopropyl]amino)propyl]pyrazin-2(1H)-one
(561) ##STR00307##
(562) 5-bromo-3-(1,1-dioxidothiomorpholino)-1-(4-fluorobenzyl)pyrazin-2(1H)-one A solution of thiomorpholine-1,1-dioxide (2.8 g, 20.72 mmol, 1.5 equiv), 3,5-dibromo-1-[(4-fluorophenyl)methyl]-1,2-dihydropyrazin-2-one (5 g, 13.81 mmol, 1 equiv), IPA (30 mL), DIEA (5.4 g, 41.44 mmol, 3 equiv). The resulting solution was stirred for 2 hr at 90° C. The resulting mixture was concentrated. The solid that formed was washed with 100 ml CH.sub.2Cl.sub.2. The solids were collected by filtration to afford 4 g (70%) of the title compound as a light yellow solid.
(563) ##STR00308##
(564) (E)-5-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-1-yl)-3-(1,1-dioxido-thiomorpholino)-1-(4-fluorobenzyl)pyrazin-2(1H)-one The procedure for preparing Intermediate 3-3 was used with the product from the previous step (4 g, 9.61 mmol), using 2 hr reaction time at 90° C. The crude product was purified with silica gel chromatography using EtOAc/petroleum ether (1:4) to afford 3 g (61%) of the title compound as alight yellow oil.
(565) ##STR00309##
(566) 5-(3-((tert-Butyldimethylsilyl)oxy)propyl)-3-(1,1-dioxidothiomorpholino)-1-(4-fluorobenzyl)pyrazin-2(1H)-one The procedure for preparing Intermediate 3-4 was used with the product from the previous step (3 g, 5.91 mmol, 1 equiv) to afford 2.5 g (83%) of the title compound as a light yellow oil.
(567) ##STR00310##
(568) 3-(1,1-Dioxidothiomorpholino)-1-(4-fluor benzyl)-5-(3-hydroxypropyl)pyrazin-2(1H)-one The procedure for preparing Intermediate 22-4 was used with the product from the previous step (2.5 g, 490 mmol), using 2 hr reaction time. The crude product was purified using C.sub.18 reverse phase chromatography using H.sub.2O/MeCN (3:1) to afford 1.2 g (61.9%) of the title compound as a light yellow oil.
(569) ##STR00311##
(570) 3-(6-(1,1-Dioxidothiomorpholino)-4-(4-fluorobenzyl)-5-oxo-4,5-dihydropyrazin-2-yl)propanal The procedure for preparing Intermediate 1-7 was used with the product from the previous step (600 mg, 1.52 mmol, 1 equiv) and Dess-Martin reagent (772.2 mg, 1.82 mmol, 1.200 equiv), using 2 hr of reaction time. The crude product was purified with silica gel chromatography using EtOAc/petroleum ether (1:2) to afford 400 mg (67%) of the title compound as a light yellow oil.
(571) ##STR00312##
(572) 3-(1,1-Dioxidothiomorpholino)-1-(4-fluorobenzyl)-5-(3-(((1R,2S)-2-(4-fluoro-phenyl)cyclopropyl)amino)propyl)pyrazin-2(1H)-one The procedure for preparing Intermediate 4-7 was used with the product from the previous step (400 mg, 1.02 mmol, 1 equiv) and (1R,2S)-2-(4-fluorophenyl)cyclopropan-1-amine (184.4 mg, 1.22 mmol, 1.2 equiv). The crude product was purified using chromatographic Procedure E (44% to 74% CH.sub.3CN), to afford 69.3 mg (12.9%) of the title compound as an off-white semi-solid.
(573) LC-MS: (ES, m/z): 529 [M+H].sup.+. .sup.1H NMR (300 MHz, MeOD-d.sub.4) δ ppm: 7.41-7.36 (m, 2H), 7.09-7.02 (m, 4H), 7.02-6.93 (m, 3H), 5.12-5.00 (s, 2H), 4.31-4.28 (m, 4H), 3.20-3.10 (m, 4H), 2.73-2.66 (t, J=7.2 Hz, 2H), 2.48-2.43 (t, J=7.2 Hz, 2H), 2.29-2.24 (m, 1H), 2.09-1.82 (m, 3H), 1.06-0.95 (m, 2H).
Example 39
(574) ##STR00313##
1-(4-fluorobenzyl)-5-[3-([(1R,2S)-2-(4-fluorophenyl)cyclopropyl]amino)propyl]-3-[4-(methylsulfonyl)piperazin-1-yl]pyrazin-2(1H)-one
(575) ##STR00314##
(576) 5-Bromo-1-(4-fluorobenzyl)-3-(4-(methylsulfonyl)piperazin-1-yl)pyrazin-2(1H.sub.1)-one The procedure for preparing Intermediate 2-1 was used with 3,5-dibromo-1-[(4-fluorophenyl)methyl]-1,2-dihydropyrazin-2-one (5 g, 13.81 mmol, 1 equiv) and 1-methanesulfonylpiperazine (3.4 g, 0.02 mmol, 1.5 equiv). The crude product was purified with silica gel chromatography using EtOAc/petroleum ether (1:1) to afford 4.8 g (78%) of the title compound as a yellow oil.
(577) ##STR00315##
(578) (E)-5-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-1-yl)-1-(4-fluorobenzyl)-3-(4-(methylsulfonyl)piperazin-1-yl)pyrazin-2(1H)-one The procedure for preparing Intermediate 3-3 was used with the product from the previous step (4.8 g, 10.78 mmol), using 4 hr of reaction time at 90° C. The crude product was purified with silica gel chromatography using EtOAc/petroleum ether (1:1) to afford 3 g (49.78%) of the title compound as a yellow oil.
(579) ##STR00316##
(580) 5-(3-((tert-Butyldimethylsilyl)oxy)propyl)-1-(4-fluorobenzyl)-3-(4-(methyl-sulfonyl)piperazin-1-yl)pyrazin-2(1H)-one The procedure for preparing Intermediate 3-4 was used with the product from the previous step (3 g, 5.58 mmol, 1.0 equiv) to afford 2 g (63%) of the title compound as a yellow oil.
(581) ##STR00317##
(582) 1-(4-Fluorobenzyl)-5-(3-hydroxypropyl)-3-(4-(methylsulfonyl)piperazin-1-yl)pyrazin-2(1H)-one The procedure for preparing Intermediate 33-5 was used with the product from the previous step (2 g, 3.72 mmol), to afford 360 mg (23%) of the title compound as a yellow oil.
(583) ##STR00318##
(584) 3-(4-(4-Fluorobenzyl)-6-(4-(methylsulfonyl)piperazin-1-yl)-5-oxo-4,5-dihydropyrazin-2-yl)propanal The procedure for preparing Intermediate 1-7 was used with the product from the previous step (360 mg, 0.85 mmol, 1 equiv). The crude product was purified with silica gel chromatography using EtOAc/petroleum ether (1:1) to afford 300 mg (83.73%) of the title compound as a white solid.
(585) ##STR00319##
(586) 1-(4-Fluorobenzyl)-5-(3-(((1R,2S)-2-(4-fluorophenyl)cyclopropyl)amino)-propyl)-3-(4-(methylsulfonyl)piperazin-1-yl)pyrazin-2(1H)-one The reductive amination step for preparing Example 1 from Intermediate 1-7 was used with the product from the previous step (300 mg, 0.71 mmol, 1 equiv) and (1R,2S)-2-(4-fluorophenyl)-cyclopropan-1-amine (128.8 mg, 0.85 mmol, 1.20 equiv). The crude product was purified using chromatographic Procedure G (25% B to 37% CH.sub.3CN in 8 min), to afford 135.7 mg (35.5%) of the title compound as brown oil.
(587) LCMS: (ES, m/z): 558 [M+H].sup.+. .sup.1H NMR (300 MHz, Methanol-d.sub.4) δ ppm: 7.44-7.34 (m, 2H), 7.25-7.14 (m, 2H), 7.14-7.02 (m, 4H), 7.00 (s, 1H), 5.06 (s, 2H), 3.87-3.78 (m, 4H), 3.40-3.18 (m, 6H), 3.02-2.92 (m, 1H), 2.87 (s, 3H), 2.63-2.31 (m, 3H), 2.11-2.01 (m, 2H), 1.53-1.43 (m, 1H), 1.42-1.32 (m, 1H).
Example 40
(588) ##STR00320##
1-[4-(4-fluorobenzyl)-6-(3-(((1R,2S)-2-(4-fluorophenyl)cyclopropyl)amino)propyl)-3-oxo-3,4-dihydropyrazin-2-yl)piperidine-4-carboxamide
(589) ##STR00321##
(590) 1-(6-Bromo-4-(4-fluorobenzyl)-3-oxo-3,4-dihydropyrazin-2-yl)piperidine-4-carboxamide The procedure for preparing Intermediate 2-1 was used with 3,5-dibromo-1-(4-fluorobenzyl)pyrazin-2(1H)-one (5 g, 13.81 mmol, 1.00 equiv) and piperidine-4-carboxamide (1.94 g, 15.19 mmol, 1.10 equiv), using 3 h reaction time at 90° C., to afford 5 g (88%) of the title compound as an off-white solid.
(591) ##STR00322##
(592) (E)-1-(6-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-1-yl)-4-(4-fluorobenzyl)-3-oxo-3,4-dihydropyrazin-2-yl)piperidine-4-carboxamide The procedure for preparing Intermediate 3-3 was used with the product from the previous step (5 g, 12.2 mmol, 1.00 equiv) and tert-butyldimethyl([2E]-3-[tetramethyl-1,3,2-dioxaborolan-2-yl]prop-2-en-1-yl)oxy]silane (4.73 g, 15.88 mmol, 1.30 equiv), using 1 hr reaction time at 90° C. The crude product was purified with silica gel chromatography using EtOAc/petroleum ether (1:3) to afford 2.2 g (24%) of the title compound as a yellow solid.
(593) ##STR00323##
(594) 1-(6-(3-((tert-Butyldimethylsilyl)oxy)propyl)-4-(4-fluorobenzyl)-3-oxo-3,4-dihydropyrazin-2-yl)piperidine-4-carboxamide The procedure for preparing Intermediate 3-4 was used with the product from the previous step (2.2 g, 1.78 mmol, 1.00 equiv) to afford 2 g (80%) of the title compound as a light yellow solid.
(595) ##STR00324##
(596) 1-(4-(4-Fluorobenzyl)-6-(3-hydroxypropyl)-3-oxo-3,4-dihydropyrazin-2-yl)-piperidine-4-carboxamide The procedure for preparing Intermediate 33-5 was used with the product from the previous step (2 g, 1.42 mmol, 1.00 equiv), using 2 h of reaction time at 25° C. The crude product was purified with silica gel chromatography using EtOAc to afford 1.1 g (70%) of the title compound as a yellow solid.
(597) ##STR00325##
(598) 1-(4-(4-Fluorobenzyl)-3-oxo-6-(3-oxopropyl)-3,4-dihydropyrazin-2-yl)piperidine-4-carboxamide The procedure for preparing Intermediate 1-7 was used with the product from the previous step (1 g, 1.00 mmol, 1.00 equiv). The crude product was purified with silica gel chromatography using EtOAc/petroleum ether (2:1) to afford 310 mg (71%) of the title compound as a yellow solid.
(599) ##STR00326##
(600) 1-(4-(4-Fluorobenzyl)-6-(3-(((1R,2S)-2-(4-fluorophenyl)cyclopropyl)amino)-propyl)-3-oxo-3,4-dihydropyrazin-2-yl)piperidine-4-carboxamide The reductive amination step for preparing Example 1 from Intermediate 1-7 was used with the product from the previous step (310 mg, 0.71 mmol, 1.00 equiv) and (1R, 2S)-2-(4-fluoro-phenyl)cyclopropan-1-amine (162 mg, 1.07 mmol, 1.50 equiv). The crude product (4 mL) was purified using chromatographic Procedure F (22% to 32% CH.sub.3CN in 7 min), to afford 40 mg (22%) of the title compound as a yellow solid.
(601) LC-MS: (ES, m/z): 522 [M+H].sup.+. .sup.1H NMR (300 MHz, MeOD-d.sub.4) δ ppm: 7.38-7.33 (m, 2H), 7.19-7.14 (m, 2H), 7.08-7.01 (m, 4H), 6.87 (s, 1H), 5.01 (s, 2H), 4.88-4.71 (m, 2H), 3.31-3.29 (m, 2H), 2.96-2.88 (m, 3H), 2.51-2.41 (m, 4H), 2.05-1.99 (m, 2H), 1.77-1.74 (m, 4H), 1.45-1.33 (m, 2H).
Example 41
(602) ##STR00327##
5-[3-([(1R,2S)-2-(4-fluorophenyl)cyclopropyl]amino)propyl]-3-[4-methyl-3-oxopiperazin-1-yl]pyrazin-2(1H)-one
(603) ##STR00328##
(604) 5-Bromo-3-(4-methyl-3-oxopiperazin-1-yl)pyrazin-2(1H)-one The procedure for preparing Intermediate 2-1 was used with 3,5-dibromo-1,2-dihydropyrazin-2-one (20 g, 78.78 mmol, 1 equiv) and 1-methylpiperazin-2-one (10.8 g, 94.54 mmol, 1.20 equiv), using 6 hr of reaction time at 90° C., to afford 18 g (80%) of the title compound as a yellow solid.
(605) ##STR00329##
(606) 5-Bromo-3-(4-methyl-3-oxopiperazin-1-yl)-1-((2-(trimethylsilyl)ethoxy)-methyl)pyrazin-2(1H)-one A mixture of the product from the previous step (12 g, 41.80 mmol, 1 equiv) and NaH (5.0 g, 125.4 mmol, 3.0 equiv) in DMF (200 mL) was stirred for 1 h at 0° C., [2-(chloromethoxy)ethyl]trimethylsilane (10.5 g, 62.7 mmol, 1.5 equiv) was then added, and the mixture was stirred an additional hr at rt. The reaction was quenched and extracted with 5×500 ml EtOAc. The resulting mixture was concentrated, to afford 6 g (34%) of the title compound as a yellow oil.
(607) ##STR00330##
(608) (E)-5-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-1-yl)-3-(4-methyl-3-oxo-piperazin-1-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)pyrazin-2(1H)-one The procedure for preparing Intermediate 3-3 was used with the product from the previous step (6 g, 14.38 mmol). The crude product was purified with silica gel chromatography using EtOAc/petroleum ether (1:3) (o afford 6 g (82%) of the title compound as a yellow oil.
(609) ##STR00331##
(610) 5-(3-((tert-Butyldimethylsilyl)oxy)propyl)-3-(4-methyl-3-oxopiperazin-1-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)pyrazin-2(1H)-one The procedure for preparing Intermediate 1-5 was used with the product from the previous step (6 g, 11.81 mmol, 1.0 equiv) to afford 5.5 g (91%) of the title compound as a yellow oil.
(611) ##STR00332##
(612) 5-(3-Hydroxypropyl)-3-(4-methyl-3-oxopiperazin-1-yl)-1-((2-(trimethylsilyl)-ethoxy)methyl)pyrazin-2(1H)-one The procedure for preparing Intermediate 22-4 was used with the product from the previous step (5.5 g, 10.78 mmol), using 6 hr of reaction time. The crude product was purified by HP-Flash with MeCN/H.sub.2O to afford 4 g (63%) of the title compound as a yellow oil.
(613) ##STR00333##
(614) 3-(6-(4-Methyl-3-oxopiperazin-1-yl)-5-oxo-4-((2-(trimethylsilyl)ethoxy)-methyl)-4,5-dihydropyrazin-2-yl)propanal The procedure for preparing Intermediate 1-7 was used with the product from the previous step (1.5 g, 3.78 mmol). The crude product was purified with silica gel chromatography using EtOAc/petroleum ether (1:1) to afford 800 mg (80.03%) of the title compound as a light yellow oil.
(615) ##STR00334##
(616) 5-(3-(((1R,2S)-2-(4-fluorophenyl)cyclopropyl)amino)propyl)-3-(4-methyl-3-oxopiperazin-1-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)pyrazin-2(1H)-one The reductive amination step for preparing Example 1 from Intermediate 1-7 was used with the product from the previous step (800 mg, 2.03 mmol, 1 equiv) and (1R,2S)-2-(4-fluorophenyl)cyclopropan-1-amine (551.8 mg, 3.65 mmol, 1.8 equiv). The crude product was purified by TLC with MeOH/CH.sub.2Cl.sub.2 (5:1) to afford 350 mg (32.62%) of the title compound as a yellow oil.
(617) ##STR00335##
(618) 5-(3-(((1R,2S)-2-(4-fluorophenyl)cyclopropyl)amino)propyl)-3-(4-methyl-3-oxopiperazin-1-yl)pyrazin-2(1H)-one A solution of the product from the previous step (320 mg, 603 mmol, 1 equiv) in HCl (4N, 10 mL) and CH.sub.2Cl.sub.2 (20 mL) was stirred for 2 hr at rt. The pH was adjusted with Na.sub.2CO.sub.3 to 7. The resulting mixture was concentrated. The crude product was purified using chromatographic Procedure B (15% B to 43% CH.sub.3CN in 7 min), to afford 85 mg (10.5%) of the title compound as a yellow oil.
(619) LCMS: (ES, m/z): 400 [M+H].sup.+. .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ ppm: 7.25-7.17 (m, 2H), 7.07 (t, J=6.8 Hz, 2H), 6.72 (s, 1H), 4.25 (s, 2H), 4.23-4.16 (m, 2H), 3.51-3.49 (t, J=5.6 Hz, 2H), 3.30-3.22 (m, 2H), 3.03-2.99 (m, 4H), 2.61-2.55 (m, 2H), 2.51-2.41 (m, 1H), 2.12-2.02 (m, 2H), 1.54-1.45 (m, 1H), 1.45-1.35 (m, 1H).
Example 42
(620) ##STR00336##
5-[3-([(1R,2S)-2-(4-fluorophenyl)cyclopropyl]amino)propyl]-1-[4-methoxybenzyl]-3-[3-oxopiperazin-1-yl]pyrazin-2(1H)-one
(621) ##STR00337##
(622) 5-bromo-1-(4-methoxybenzyl)-3-(3-oxopiperazin-1-yl)pyrazin-2(1H)-one The procedure for preparing Intermediate 2-1 was used with 3,5-dibromo-1-(4-methoxy-benzyl)pyrazin-2(1H)-one (6 g, 16.04 mmol, 1.00 equiv) and piperazin-2-one (1.6 g, 19.28 mmol, 1.20 equiv), using 3 h of reaction time at 90° C., to afford 6.0 g (88%) of the title compound as a light yellow solid.
(623) ##STR00338##
(624) (E)-5-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-1-yl)-1-(4-methoxybenzyl)-3-(3-oxopiperazin-1-yl)pyrazin-2(1H)-one The procedure for preparing Intermediate 3-3 was used with the product from the previous step (4.3 g, 11.14 mmol, 1.00 equiv), using 1 hr of reaction time at 90° C. The crude product was purified with silica gel chromatography using EtOAc/petroleum ether (1:1) to afford 1.7 g (24%) of the title compound as an orange solid.
(625) ##STR00339##
(626) 5-(3-((tert-Butyldimethylsilyl)oxy)propyl)-1-(4-methoxybenzyl)-3-(3-oxo-piperazin-1-yl)pyrazin-2(1H)-one The procedure for preparing Intermediate 3-4 was used with the product from the previous step (1.7 g, 1.78 mmol, 1.00 equiv) to afford 1.3 g (80%) of the title compound as a light yellow oil.
(627) ##STR00340##
(628) 5-(3-Hydroxypropyl)-1-(4-methoxybenzyl)-3-(3-oxopiperazin-1-yl)pyrazin-2(1H.sub.1)-one The procedure for preparing Intermediate 33-5 was used with the product from the previous step. The crude product was purified with silica gel chromatography using EtOAc to afford 500 mg (70%) of the title compound as yellow solid.
(629) ##STR00341##
(630) 3-(4-(4-Methoxybenzyl)-5-oxo-6-(3-oxopiperazin-1-yl)-4,5-dihydropyrazin-2-yl)propanal The procedure for preparing Intermediate 1-7 was used with the product from the previous step (300 mg, 1.00 mmol). The crude product was purified with silica gel chromatography using EtOAc/petroleum ether (2:1) to afford 220 mg (71%) of the title compound as a yellow solid.
(631) ##STR00342##
(632) 5-(3-(((1R,2S)-2-(4-fluorophenyl)cyclopropyl)amino)propyl)-1-(4-methoxy-benzyl)-3-(3-oxopiperazin-1-yl)pyrazin-2(1H)-one The reductive amination step for preparing Example 1 from Intermediate 1-7 was used with the product from the previous step (220 mg, 0.71 mmol, 1.00 equiv) and (1R, 2S)-2-(4-fluorophenyl) cyclopropan-1-amine (162 mg, 1.07 mmol, 1.50 equiv). The crude product was purified using chromatographic Procedure C (45% to 60% CH.sub.3CN in 7 min), to afford 16.4 mg (22%) of the title compound as a yellow solid.
(633) LC-MS: (ES, m/z): 506 [M+H].sup.+. .sup.1H NMR (300 MHz, MeOD-d.sub.4) δ ppm: 7.28-7.25 (d, J=9.0 Hz, 2H), 7.01-6.84 (m, 7H), 5.00 (s, 2H), 4.25 (s, 2H), 4.04-4.00 (td, J=5.0, 1.7 Hz, 2H), 3.74 (s, 3H), 3.42-3.38 (t, J=5.4 Hz, 2H), 2.70-2.65 (t, J=7.5 Hz, 2H), 2.44-2.39 (t, J=7.2 Hz, 2H), 2.26-2.21 (m, 1H), 1.88-1.79 (m, 3H), 1.14-0.90 (m, 2H).
Example 43
(634) ##STR00343##
4-[5-(3-[([1R,2S]-2-[4-fluorophenyl]cyclopropyl)amino]propyl)-3-(4-[methylsulfonyl]piperazin-1-yl)-2-oxopyrazin-1(2H)-yl]benzonitrile
(635) ##STR00344##
(636) (E)-4-(5-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-1-yl)-3-(4-(methylsulfonyl)piperazin-1-yl)-2-oxopyrazin-1(2H)-yl)benzonitrile The procedure for preparing Intermediate 8-9 was used with Intermediate 37-1 (9 g, 21.00 mmol, 1 equiv) and (4-cyanophenyl)boronic acid (3.6 g, 25.2 mmol, 1.2 equiv). The crude product was purified with silica gel chromatography using PE/EtOAc (3:1) to afford the title compound (1.2 g, 10.79%) as a dark brown semi-solid.
(637) ##STR00345##
(638) 4-(5-(3-((tert-Butyldimethylsilyl)oxy)propyl)-3-(4-(methylsulfonyl)piperazin-1-yl)-2-oxopyrazin-1(2H)-yl)benzonitrile The procedure for preparing Intermediate 3-4 was used with the product from the previous step (900 mg, 1.0 equiv) (o afford 600 mg of the title compound as a yellow oil.
(639) ##STR00346##
(640) 4-(5-(3-Hydroxypropyl)-3-(4-(methylsulfonyl)piperazin-1-yl)-2-oxopyrazin-1(2H)-yl)benzonitrile The procedure for preparing Intermediate 33-5 was used with the product from the previous step (600 mg, 1.0 equiv). The crude product was purified with silica gel chromatography using CHCl.sub.3/MeOH (15:1) to afford 330 mg of the title compound as a yellow oil.
(641) ##STR00347##
(642) 4-(3-(4-(Methylsulfonyl)piperazin-1-yl)-2-oxo-5-(3-oxopropyl)pyrazin-1(2H)-yl)benzonitrile The procedure for preparing Intermediate 1-7 was used with the product from the previous step (300 mg, 0.72 mmol, 1 equiv) and Dess-Martin reagent (396.2 mg, 0.93 mmol, 1.300 equiv). The crude product was purified with silica gel chromatography using EtOAc/petroleum ether (1:1) to afford 230 mg (77.04%) of the title compound as a light yellow oil.
(643) ##STR00348##
(644) 4-(5-(3-(((1R,2S)-2-(4-fluorophenyl)cyclopropyl)amino)propyl)-3-(4-(methylsulfonyl)piperazin-1-yl)-2-oxopyrazin-1(2H)-yl)benzonitrile The procedure for preparing Intermediate 4-7 was used with the product from the previous step (230 mg, 0.55 mmol, 1 equiv) and (1R,2S)-2-(4-fluorophenyl)cyclopropan-1-amine (125.5 mg, 0.83 mmol, 1.5 equiv). The crude product was purified using chromatographic Procedure E (44% to 74% CH.sub.3CN in 8 min), to afford 78.5 mg (25.75%) of the title compound as a light yellow solid.
(645) LC-MS: (ES, m/z): 551 [M+H].sup.+. .sup.1H NMR (300 MHz, MeOD-d.sub.4) δ ppm: 8.02-7.82 (d, J=6.0 Hz, 2H), 7.75-7.52 (d, J=6.0 Hz, 2H), 7.16-7.03 (m, 2H), 7.03-6.95 (m, 2H), 6.88 (s, 1H), 4.00-3.80 (m, 4H), 3.32-3.28 (m, 4H), 2.87 (s, 3H), 2.88-2.72 (t, J=7.2 Hz, 2H), 2.63-2.40 (t, J=7.2 Hz, 2H), 2.39-2.20 (m, 1H), 2.00-1.80 (m, 3H), 1.15-0.89 (m, 2H).
Example 44
(646) ##STR00349##
4-[5-(3-[([1R,2S]-2-[4-fluorophenyl]cyclopropyl)amino]propyl)-2-oxo-3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pyrazin-1(2H)-yl]benzonitrile
(647) ##STR00350##
(648) 5-Bromo-3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pyrazin-2(1H)-one The procedure for preparing Intermediate 2-1 was used with 3,5-dibromo-1,2-dihydropyrazin-2-one (20 g, 78.78 mmol, 1 equiv) and 2-oxa-6-azaspiro[3.3]heptane (11.7 g, 118.17 mmol, 1.5 equiv), using 2 h of reaction time at 90° C., affording 18 g (83.97%) of the title compound as an off-white solid.
(649) ##STR00351##
(650) (E)-5-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-1-yl)-3-(2-oxa-6-azaspiro-[3.3]heptan-6-yl)pyrazin-2(1H)-one The procedure for preparing Intermediate 3-3 was used with the product from the previous step (8 g, 29.40 mmol), using 2 hr of reaction time at 90° C. The crude product was purified with silica gel chromatography using EtOAc/petroleum ether (4:1) to afford 2.5 g (23.4%) of the title compound as a light yellow oil.
(651) ##STR00352##
(652) (E)-4-(5-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-1-yl)-2-oxo-3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pyrazin-1(2H)-yl)benzonitrile The procedure for preparing Intermediate 8-9 was used with the product from the previous step (2.1 g, 5.78 mmol, 1 equiv) and (4-cyanophenyl)boronic acid (1.3 g, 0.01 mmol, 1.5 equiv), using 6 hr reaction time at rt. The crude product was purified with silica gel chromatography using EtOAc/petroleum ether (1:3) to afford 1.0 g (37.26%) of the title compound as a yellow solid.
(653) ##STR00353##
(654) 4-(5-(3-((tert-Butyldimethylsilyl)oxy)propyl)-2-oxo-3-(2-oxa-6-azaspiro[3.3]-heptan-6-yl)pyrazin-1(2H)-yl)benzonitrile The procedure for preparing Intermediate 3-4 was used with the product from the previous step (1 g, 1 equiv) to afford 800 mg (79%) of the title compound as a yellow oil.
(655) ##STR00354##
(656) 4-(5-(3-Hydroxypropyl)-2-oxo-3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pyrazin-1(2H)-yl)benzonitrile The procedure for preparing Intermediate 22-4 was used with the product from the previous step (800 mg). The resulting mixture was concentrated and purified by HP-Flash with MeCN/H.sub.2O to afford 540 mg (53%) of the title compound as a yellow solid.
(657) ##STR00355##
(658) 4-(2-Oxo-5-(3-oxopropyl)-3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pyrazin-1(2H)-yl)benzonitrile The procedure for preparing Intermediate 1-7 was used with the product from the previous step (470 mg, 1.33 mmol, 1 equiv) and Dess-Martin reagent (848.6 mg, 2.00 mmol, 1.5 equiv). The crude product was purified with silica gel chromatography using EtOAc/petroleum ether (1:3) to afford 280 mg (59.92%) of the title compound as a yellow oil.
(659) ##STR00356##
(660) 4-(5-(3-(((1R,2S)-2-(4-fluorophenyl)cyclopropyl)amino)propyl)-2-oxo-3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pyrazin-1(2H)-yl)benzonitrile The reductive amination step for preparing Example 1 from Intermediate 1-7 was used with the product from the previous step (280 mg, 0.80 mmol, 1 equiv) and (1R,2S)-2-(4-fluorophenyl)cyclopropan-1-amine (218.7 mg, 1.45 mmol, 1.8 equiv). The crude product was purified using chromatographic Procedure C (43% to 60% CH.sub.3CN in 7 min), to afford 43.9 mg (11.25%) of the title compound as a yellow solid.
(661) LCMS: (ES, m/z): 486 [M+H].sup.+. .sup.1H NMR (400 MHz, Methanol-d.sub.4) δ ppm: 7.94-7.87 (d, J=2.0 Hz, 2H), 7.68-7.61 (d, J=2.0 Hz, 2H), 7.12-7.04 (m, 2H), 7.03-6.92 (m, 2H), 6.65 (s, 1H), 4.82 (s, 4H), 4.46 (s, 4H), 2.77 (t, J=7.5 Hz, 2H), 2.43 (t, J=7.4 Hz, 2H), 2.36-2.26 (m, 1H), 1.98-1.81 (m, 3H), 1.12-1.04 (m, 1H), 1.04-0.96 (m, 1H).
Example 45
(662) ##STR00357##
5-(3-(((1R,2S)-2-(4-Fluorophenyl)cyclopropyl)amino)propyl)-1-(4-methoxybenzyl)-3-(4-(methylsulfonyl)piperazin-1-yl)pyrazin-2(1H)-one
(663) ##STR00358##
(664) 2-((4-Methoxybenzyl)amino)acetonitrile hydrochloride A mixture of (4-methoxyphenyl)methanamine (60 g, 437.37 mmol, 1 equiv), 2-chloroacetonitrile (39.6 g, 524.85 mmol, 1.2 equiv), NaI (6.57 g, 43.74 mmol, 0.1 equiv), and K.sub.2CO.sub.3 (78.6 g, 568.58 mmol, 1.3 equiv) in CH.sub.3CN (400 mL) was stirred for 18 h at 80° C. The reaction was monitored by LCMS. The mixture was allowed to cool to rt. The resulting mixture was filtered; the filter cake was washed with CH.sub.3CN (3×350 mL). The filtrate was concentrated under reduced pressure. The resulting mixture was diluted with Et.sub.2O (400 mL). HCl (1N, 300 mL) was added to the solution. The precipitated solids were collected by filtration and washed with Et.sub.2O (3×70 mL) to afford the title compound (51 g, 66.17%) as a grey solid.
(665) ##STR00359##
(666) 3,5-dibromo-1-(4-methoxybenzyl)pyrazin-2(1H)-one To a 500 mL round-bottom flask containing toluene (200 mL) was added oxalic dibromide (150 g, 693.6 mmol, 3.0 equiv) dropwise over 30 min at rt. The resulting mixture was stirred for additional 15 min at this temperature. To the stirred solution was added the product from the previous step (49.2 g, 231.33 mmol, 1 equiv) in portions at rt. The resulting mixture was stirred for 18 h at 50° C. The reaction was monitored by LCMS. The mixture was allowed to cool to rt, and was then diluted with sat. NaH.sub.2PO.sub.4 (500 mL). The aqueous layer was extracted with EtOAc (4×400 mL). The combined organic layers were washed with 500 mL of brine and dried over Na.sub.2SO.sub.4. The resulting mixture was filtered; the filter cake was washed with EtOAc (2×400 mL). The filtrate was concentrated under reduced pressure. The residue was purified with silica gel chromatography using PE/EtOAc (5:1) to afford the title compound (9 g, 10.40%) as a dark yellow oil.
(667) ##STR00360##
(668) 5-Bromo-1-(4-methoxybenzyl)-3-(4-(methylsulfonyl)piperazin-1-yl)pyrazin-2(1H)-one The procedure for preparing Intermediate 1-3 was used with the product from the previous step (6.9 g, 18.45 mmol, 1 equiv) and 1-methanesulfonylpiperazine (3.6 g, 22.14 mmol, 1.2 equiv), using 2 hr of reaction time at 90° C., to afford the title compound (6.6 g, crude) as a yellow solid.
(669) ##STR00361##
(670) (E)-5-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-1-yl)-1-(4-methoxybenzyl)-3-(4-(methylsulfonyl)piperazin-1-yl)pyrazin-2(1H)-one The procedure for preparing Intermediate 3-3 was used with the product from the previous step (4.5 g, 9.84 mmol), using 1 hr of reaction time at 90° C. The crude product was purified with silica gel chromatography using PE/EtOAc (5:1) to afford the title compound (3.9 g, 72.23%) as a yellow oil.
(671) ##STR00362##
(672) 5-(3-((tert-Butyldimethylsilyl)oxy)propyl)-1-(4-methoxybenzyl)-3-(4-(methyl-sulfonyl)piperazin-1-yl)pyrazin-2(1H)-one The procedure for preparing Intermediate 3-4 was used with the product from the previous step (3.5 g, 6.38 mmol, 1 equiv) to afford the title compound (3.3 g, 93.94%) as a yellow oil.
(673) ##STR00363##
(674) 5-(3-Hydroxypropyl)-1-(4-methoxybenzyl)-3-(4-(methylsulfonyl)piperazin-1-yl)pyrazin-2(1H)-one The procedure for preparing Intermediate 22-4 was used with the product from the previous step (3.3 g, 5.99 mmol). The crude product was purified by MPLC with the following conditions (Mobile Phase A: Water, Mobile Phase B: CH.sub.3CN; Flow rate: 100 mL/min; Gradient: 0 B to 100% B in 50 min; 220/254 nm; Rt: 31.26 min) to afford the title compound (1.1 g, 42.06%) as a yellow oil.
(675) ##STR00364##
(676) 3-(4-(4-Methoxybenzyl)-6-(4-(methylsulfonyl)piperazin-1-yl)-5-oxo-4,5-dihydropyrazin-2-yl)propanal The procedure for preparing Intermediate 1-7 was used with the product from the previous step (500 mg, 1.15 mmol, 1 equiv) and Dess-Martin reagent (583.0 mg, 1.37 mmol, 1.2 equiv). The crude product was purified with silica gel chromatography using CH.sub.2Cl.sub.2/EtOAc (1:5) to afford the title compound (380 mg, 76%) as an off-white solid.
(677) ##STR00365##
(678) 5-(3-(((1R,2S)-2-(4-fluorophenyl)cyclopropyl)amino)propyl)-1-(4-methoxy-benzyl)-3-(4-(methylsulfonyl)piperazin-1-yl)pyrazin-2(1H)-one The reductive amination step for preparing Example 1 from Intermediate 1-7 was used with the product from the previous step (380 mg, 0.87 mmol, 1 equiv) and (1R,2S)-2-(4-fluorophenyl)-cyclopropan-1-amine (246 mg, 1.63 mmol, 1.861 equiv). The crude product (380 mg) was purified using chromatographic Procedure C (44% to 54% CH.sub.3CN 10 min), to afford the title compound (69.6 mg, 13.98%) as off-white solid.
(679) LC-MS: (ES, m/z): 570 [M+H].sup.+. .sup.1H NMR (300 MHz, MeOD-d.sub.4) δ ppm: 7.30 (d, J=8.7 Hz, 2H), 7.07-6.88 (m, 7H), 5.01 (s, 2H), 3.84-3.80 (m, 4H), 3.78 (s, 3H), 3.35-3.29 (m, 4H), 2.87 (s, 3H), 2.71 (t, J=7.2 Hz, 2H), 2.45 (t, J=7.2 Hz, 2H), 2.29-2.24 (m, 1H), 1.90-1.82 (m, 3H), 1.06-0.96 (m, 2H).
Example 46
(680) ##STR00366##
1-benzyl-5-[3-([(1R,2S)-2-(4-fluorophenyl)cyclopropyl]amino)propyl]-3-[3-oxopiperazin-1-yl]pyrazin-2(1H)-one
(681) ##STR00367##
(682) 2-(Benzylamino)acetonitrile hydrochloride A mixture of benzylamine (40 g, 291.58 mmol, 1 equiv), 2-chloroacetonitrile (26.4 g, 349.9 mmol, 1.2 equiv), NaI (4.37 g, 29.16 mmol, 0.1 equiv), and K.sub.2CO.sub.3 (52.4 g, 379.06 mmol, 1.3 equiv) in CH.sub.3CN (200 mL) was stirred for 18 h at 80° C. The reaction was monitored by LCMS. The mixture was allowed to cool down to rt. The resulting mixture was filtered; the filter cake was washed with CH.sub.3CN (3×150 mL). The filtrate was concentrated under reduced pressure. The resulting mixture was diluted with Et.sub.2O (200 mL). HCl (2 M, 100 mL) was then added to the solution. The solid that formed was collected by filtration and washed with Et.sub.2O (3×70 mL) to afford the title compound (34 g, 66.17%) as a grey solid.
(683) ##STR00368##
(684) 1-benzyl-3,5-dibromopyrazin-2(1H)-one To a 500 mL round-bottom flask containing toluene (200 mL) was added oxalic dibromide (100 g, 462.40 mol, 3.0 equiv) dropwise over 30 min at rt. The resulting mixture was stirred for additional 15 min at this temperature. To the stirred solution was added the product from the previous step (32.8 g, 154.22 mmol, 1 equiv) in portions at rt. The resulting mixture was stirred for 18 h at 50° C. The reaction was monitored by LCMS. The mixture was allowed to cool to rt. The resulting mixture was diluted with sat. NaH.sub.2PO.sub.4 (500 mL). The aqueous layer was extracted with EtOAc (4×200 mL). The combined organic layers were washed with 500 mL of brine and dried over Na.sub.2SO.sub.4. The resulting mixture was filtered; the filter cake was washed with EtOAc (2×200 mL). The filtrate was concentrated under reduced pressure. The residue was purified with silica gel chromatography using PE/EtOAc (5:1) to afford the title compound (6 g, 10%) as a dark yellow oil.
(685) ##STR00369##
(686) tert-Butyl 4-(4-benzyl-6-bromo-3-oxo-3,4-dihydropyrazin-2-yl)-2-oxopiperazine-1-carboxylate The procedure for preparing Intermediate 4-1 was used with the product from the previous step (5 g, 14.5 mmol, 1.00 equiv) and tert-butyl 2-oxopiperazine-1-carboxylate (4.36 g, 21.8 mmol, 1.50 equiv), affording 3.5 g (88%) of the title compound as a light yellow solid.
(687) ##STR00370##
(688) tert-Butyl(E)-4-(4-benzyl-6-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-1-yl)-3-oxo-3,4-dihydropyrazin-2-yl)-2-oxopiperazine-1-carboxylate The procedure for preparing Intermediate 3-3 was used with the product from the previous step (3.5 g, 11.14 mmol, 1.00 equiv) and tert-butyldimethyl[([2E]-3-[tetramethyl-1,3,2-dioxaborolan-2-yl]pop-2-en-1-yl)oxy]silane (3.3 g, 14.60 mmol, 1.30 equiv), using 1 hr reaction time at 90° C. The crude product was purified with silica gel chromatography using EtOAc/petroleum ether (1:1) to afford 2.3 g (24%) of the title compound as orange oil.
(689) ##STR00371##
(690) tert-Butyl 4-(4-benzyl-6-(3-((tert-butyldimethylsilyl)oxy)propyl)-3-oxo-3,4-dihydropyrazin-2-yl)-2-oxopiperazine-1-carboxylate The procedure for preparing Intermediate 3-4 was used with the product from the previous step (2.3 g, 1.78 mmol, 1.00 equiv) to afford 2 g (80%) of the title compound as a light yellow oil.
(691) ##STR00372##
(692) tert-Butyl 4-(4-benzyl-6-(3-hydroxypropyl)-3-oxo-3,4-dihydropyrazin-2-yl)piperazine-1-carboxylate The procedure for preparing Intermediate 22-4 was used with the product from the previous step (2 g, 1.42 mmol). The crude product was purified with silica gel chromatography using EtOAc/petroleum ether (1:2) to afford 1.1 g (70%) of the title compound as a yellow oil.
(693) ##STR00373##
(694) tert-Butyl 4-(4-benzyl-3-oxo-6-(3-oxopropyl)-3,4-dihydropyrazin-2-yl)-2-oxopiperazine-1-carboxylate The procedure for preparing Intermediate 1-7 was used with the product from the previous step (800 mg, 1.00 mmol, 1.00 equiv). The crude product was purified with silica gel chromatography using EtOAc/petroleum ether (2:1) to afford 400 mg (71%) of the title compound as a yellow solid.
(695) ##STR00374##
(696) tert-Butyl 4-(4-benzyl-3-oxo-6-(3-(((1R,2S)-2-phenylcyclopropyl)amino)-propyl)-3,4-dihydropyrazin-2-yl)-2-oxopiperazine-1-carboxylate The reductive amination step for preparing Example 1 from Intermediate 1-7 was used with the product from the previous step (400 mg, 0.71 mmol, 1.00 equiv) and (1R,2S)-2-(4-fluorophenyl)-cyclopropan-1-amine (162 mg, 1.07 mmol, 1.50 equiv). The crude product was purified by Prep-TLC with EtOAc to afford 310 mg (22%) of the title compound as a yellow solid.
(697) ##STR00375##
(698) 1-Benzyl-5-(3-(((1R,2S)-2-(4-fluorophenyl)cyclopropyl)amino)propyl)-3-(3-oxopiperazin-1-yl)pyrazin-2(1H)-one The deprotection step for preparing Example 14 from Intermediate 14-7 was used with the product from the previous step (100 mg, 0.71 mmol, 1.00 equiv). The crude product was purified using chromatographic Procedure F (22% to 32% CH.sub.3CN), to afford 35.6 mg (22%) of the title compound as a yellow solid.
(699) LC-MS: (ES, m/z): 476[M+H].sup.+. .sup.1H NMR (300 MHz, MeOD-d.sub.4) δ ppm: 7.32-7.30 (m, 5H), 7.29-6.99 (m, 4H), 6.94 (s, 1H), 5.10 (s, 2H), 4.22 (s, 2H), 4.13-4.09 (t, J=5.4 Hz, 2H), 3.42-3.40 (t, J=5.4 Hz, 2H), 3.24-3.18 (m, 2H), 2.96-2.93 (m, 1H), 2.53-2.50 (t, J=7.2 Hz, 2H), 2.50-2.37 (m, 1H), 2.05-2.0 (m, 2H), 1.47-1.34 (m, 2H).
Example 47
(700) ##STR00376##
5-[3-([(1R,2S)-2-(4-fluorophenyl)cyclopropyl]amino)propyl]-1-[4-methoxyphenyl]-3-[4-(methylsulfonyl)piperazin-1-yl]pyrazin-2(1H)-one
(701) ##STR00377##
(702) 5-Bromo-3-(4-(methylsulfonyl)piperazin-1-yl)pyrazin-2(1H)-one The procedure for preparing Intermediate 4-1 was used with 3,5-dibromo-1,2-dihydropyrazin-2-one (20 g, 78.8 mmol, 1 equiv), 1-methanesulfonylpiperazine (15.6 g, 94.54 mmol, 1.2 equiv), to afford the title compound (16 g, 60%) as a dark yellow solid.
(703) ##STR00378##
(704) (E)-5-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-1-yl)-3-(4-(methylsulfonyl)-piperazin-1-yl)pyrazin-2(1H)-one The procedure for preparing Intermediate 3-3 was used with the product from the previous step (8 g, 23.73 mmol), using 1 hr of reaction time at 90° C. The crude product was purified with silica gel chromatography using PE/EtOAc (1:1) to afford the title compound (4.26 g, 41.9%) as a yellow oil.
(705) ##STR00379##
(706) (E)-5-(3-((tert-butyldimethylsilyl)oxy)prop-1-en-1-yl)-1-(4-methoxyphenyl)-3-(4-(methylsulfonyl)piperazin-1-yl)pyrazin-2(1H)-one The procedure for preparing Intermediate 8-9 was used with the product from the previous step (3.5 g, 8.17 mmol, 1 equiv) and (4-methoxyphenyl)boronic acid (1.5 g, 9.80 mmol, 1.2 equiv). The crude product was purified with silica gel chromatography using PE/EtOAc (1:1) to afford the title compound (2.1 g, 48%) as a yellow solid.
(707) ##STR00380##
(708) 5-(3-((tert-Butyldimethylsilyl)oxy)propyl)-1-(4-methoxyphenyl)-3-(4-(methyl-sulfonyl)piperazin-1-yl)pyrazin-2(1H)-one The procedure for preparing Intermediate 3-4 was used with the product from the previous step (2.1 g, 3.92 mmol, 1.0 equiv) to afford the title compound (1.9 g, 95%) as an off-white solid.
(709) ##STR00381##
(710) 5-(3-hydroxypropyl)-1-(4-methoxyphenyl)-3-(4-(methylsulfonyl)piperazin-1-yl)pyrazin-2(1H)-one The procedure for preparing Intermediate 33-5 was used with the product from the previous step (1.9 g, 3.54 mmol, 1.0 equiv), affording 1.06 g (71%) of the title compound as an off-white solid.
(711) ##STR00382##
(712) 3-(4-(4-Methoxyphenyl)-6-(4-(methylsulfonyl)piperazin-1-yl)-5-oxo-4,5-dihydropyrazin-2-yl)propanal The procedure for preparing Intermediate 1-7 was used with the product from the previous step (500 mg, 1.18 mmol). The crude product was purified with silica gel chromatography using EtOAc/petroleum ether (1:1) to afford 380 mg (76%) of the title compound as a yellow oil.
(713) ##STR00383##
(714) 5-(3-(((1R,2S)-2-(4-fluorophenyl)cyclopropyl)amino)propyl)-1-(4-methoxy-phenyl)-3-(4-(methylsulfonyl)piperazin-1-yl)pyrazin-2(1H)-one The procedure for preparing Intermediate 4-7 was used with the product from the previous step (380 mg, 0.90 mmol, 1 equiv) and (1R,2S)-2-(4-fluorophenyl)cyclopropan-1-amine (204.9 mg, 1.36 mmol, 1.500 equiv). The crude product was purified using chromatographic Procedure C (49% B in 8 min), to afford 66.7 mg (13.3%) of the title compound as an off-white solid.
(715) LCMS: (ES, m/z): 556 [M+H].sup.+. .sup.1H NMR (300 MHz, Methanol-d.sub.4) δ ppm: 7.36-7.26 (d, J=2.1 Hz, 2H), 7.13-6.91 (m, 6H), 6.85 (s, 1H), 3.90-3.80 (m, 7H), 3.30-3.20 (m, 4H), 2.87 (s, 3H), 2.84-2.73 (m, 2H), 2.49 (t, J=6.6 Hz, 2H), 2.36-2.26 (m, 1H), 1.95-1.85 (m, 3H), 1.14-0.93 (m, 2H).
Example 48
(716) ##STR00384##
5-[3-([(1R,2S)-2-(4-fluorophenyl)cyclopropyl]amino)propyl]-3-[3-oxopiperazin-1-yl]pyrazin-2(1H)-one
(717) ##STR00385##
(718) A solution of 5-(3-(((1R,2S)-2-(4-fluorophenyl)cyclopropyl)amino)propyl)-1-(4-methoxybenzyl)-3-(3-oxopiperazin-1-yl)pyrazin-2(1H)-one (Example 42, 400 mg, 0.79 mmol, 1 equiv), TFA (10 mL), and TfOH (5 mL) in CH.sub.2Cl.sub.2 (20 mL) was stirred for 1 h at 25° C. The resulting mixture was concentrated under vacuum. The residue was diluted with sat. NaHCO.sub.3 (100 mL). The aqueous layer was extracted with EtOAc (4×50 mL). The combined organic layers were washed with 1×100 mL of brine, dried over Na.sub.2SO.sub.4, and purified using chromatographic Procedure C (25% to 35% CH.sub.3CN in 7 min), to afford 78.5 mg (33%) of the title compound as white solid.
(719) LC-MS: (ES, m/z): 386 [M+H].sup.+. .sup.1H NMR (300 MHz, MeOD-d.sub.4) δ ppm: 7.09-6.93 (m, 4H), 6.69-6.66 (m, 1H), 4.36 (s, 2H), 4.12-4.05 (m, 2H), 3.43-3.42 (t, J=5.4 Hz, 2H), 2.76-2.71 (t, J=7.5 Hz, 2H), 2.49-2.44 (t, J=7.3 Hz, 2H), 2.32-2.27 (m, 1H), 1.94-1.82 (m, 3H), 1.09-0.95 (m, 2H).
(720) The activity of the compounds in Examples 1-32 as KDM1A inhibitors is illustrated in the following assay. The other compounds listed above, which have not yet been made and/or tested, are predicted to have activity in this assay as well.
Biological Activity Assay
(721) The activity of the Examples above may be illustrated in the following assays. Compounds listed above, which may not yet have been made and/or tested, are predicted to have activity in these assays.
(722) Assaying the inhibition of KDM1A can be determined in vitro, in cultured cells, and in animals. There are a variety of spectrophotometric methods to detect the results of demethylation of methylated lysines, viz., detecting the products of KDM1A demethylase oxidative activity on a peptide fragment of at least 18 amino acid representing the N-terminus of the histone H.sub.3 substrate that contains a monomethyl at the fourth lysine residue. Hydrogen peroxide, one product of the KDM1A demethylase reaction, reacts with horseradish peroxidase and dihydroxyphenoxazine (ADHP) to produce the fluorescent compound resorufin (excitation=530-560 nm:emission=590 nm). The KDM1A demethylase enzyme activity can obtained from mammalian cells or tissues expressing KDM1A from an endogenous or recombinant gene and purified or assayed from a whole cell extract. These methods can be used to determine the concentration of the disclosed compounds can inhibit fifty percent of the enzyme activity (IC.sub.50). In one aspect, the disclosed compounds exhibit inhibition fifty percent of the KDM1A enzyme activity at a concentration of less than 500 nM, less than 100 nM, less than 50 nM or less than 10 nM.
(723) The association of KDM1A with other proteins can be determined by a variety of both in vitro and in vivo methods known to one skilled in the art. For example, the disruption of KDM1A with associated proteins can be determined in an electromobility shift assay (EMSA). In various aspects, the disruption of the physical association of KDM1A with CoRest by the disclosed compounds can be observed using EMSA. In another example, the disruption of KDM1A with associated proteins can be determined by immunoprecipitation followed by separation of the co-precipitated proteins by mass spectroscopy or by get electrophoresis. In another example, the disruption of KDM1A association with CoRest can be determined by the ability of KDM1A to act on a nucleosomal substrate containing K4 or K9 methylated histone H.sub.3, a substrate that requires the presence of both KDM1A and CoRest. The disclosed compounds could be used to assay inhibition of CoRest association with KDM1A using nucleosomal substrate; such compounds may not inhibit KDM1A enzymatic activity as determined by the use of the histone H3 K4 methylated peptide substrate.
(724) The inhibition of KDM1A can be determined in a cell-based assay. For example, KDM1A is an essential enzyme and prolonged inhibition of KDM1A will result in cell death, thus cell growth inhibition, arrest of cell growth or cell death can be assayed. In another aspect, genes induced by androgens and estrogens require KDM1A activity; inhibition by the disclosed compounds of KDM1A will abrogate the induction of gene expression in cells treated with androgens or estrogens. These effects can be measured, e.g., using quantitative PCR of mRNA to measure the magnitude of gene expression for androgen- and estrogen-dependent genes. KDM1A activity is required for the repression of transcription of specific genes. Inhibition of KDM1A by the disclosed compounds could de-repress the expression such genes in cell. These genes include Meis1, VEG-A, AIM1, HMOX1, VIM, SKAP1, BMP, EOMES, FOXA2, HNF4, SOX17, GH, PSA, pS2, GREB1, GR-1b, PRL, TSHB, SYN1, HBG, SCN1A, SCN2a, and SCN3A the expression of which can be assayed using quantitative PCR of mRNA before and at various time following the treatment of cells with the disclosed compounds. In another aspect, KDM1A is a regulator of leukemic stem cell potential and is required for oncogenic transformation of myeloid cells to acute myeloid leukemia (AML) by MLL-AF9. Inhibition of KDM1A in MLL-AF9-transformed cells grown in culture overcomes the arrest in differentiation to resulting in a more mature cell expressing the CD11b surface antigen, a monocytic cell antigen. Thus, inhibition of KDM1A can be assayed using an AML cell line such as THP-1 grown in culture quantifying the proportion of cells newly expressing the CD11b antigen using fluorescence activated cell sorting (FACS). A similar assay using FACS to count cells displaying the CD14 or CD86 can be also used, each of which are characteristic of more mature cells along the macrophage/monocytic lineage. Other cells lines derived from patients with acute myeloid leukemia such as MV4; 11 or MOLM-13 cells can be used for this assay. Other markers of differentiation along the macrophage/monocyte lineage can be similarly assayed by FACS such as CD14 and CD86. Other AML cell lines such as MPLM-13 or MV4; 11 can be assayed for the induction of either specific genes mentioned above or the differentiation markers as well as cell growth or apoptosis by Annexin V staining and FACS enumeration.
(725) The selectivity of the disclosed compounds for KDM1A can be determined by assaying the IC.sub.50 of the disclosed compounds for other FAD-dependent aminoxidases such as monoamine oxidase A (MAO-A), monoamine oxidase B (MAO-B), IL4I1, KDM1B, or SMOX. As such, a disclosed compound would inhibit KDM1A with an IC.sub.50 that is 50-fold, or 100-fold or 250-fold or 500-fold less than for MAO-A or MAO-B.
(726) Additional Demethylase Assays
(727) The histone demethylase assay can be performed essentially as described in Shi, Y et al. Cell 199, 941-953 (2004). Briefly, bulk histones, histone peptides or nucleosomes are incubated with purified human recombinant KDM1A, in the histone demethylase activity (HDM) assay buffer 1 (50 mM Tris pH 8.5, 50 mM KCl, 5 mM MgCl, 0.5% BSA, and 5% glycerol) from 30 minutes to 4 hours at 37° C. A typical reaction is conducted in 100 microliters in which either 20 micrograms of purified bulk histones or 3 micrograms of modified histone peptides are used as substrates. Different amounts of KDM1A ranging from 1-20 micrograms are used in the reaction along with, as necessary, other co-factors such as FAD or CoREST, depending on the chosen substrate. The reaction mixture is analyzed by SDS-PAGE and Western blotting using histone methyl-specific antibodies or by formaldehyde formation assay to examine the removal and conversion of the methyl group to formaldehyde, or by mass spectrometry in the case of peptide substrates to identify the demethylated histone peptide.
(728) Bulk histones (e.g., 4 mg) are incubated with the indicated amounts of recombinant proteins or complexes in histone demethylase (HDM) assay buffer A (50 mM Tris pH8.5, 50 mM KCl, 5 mM MgCl, 5% glycerol, 0.2 mM phenylmethylsulphonyl fluoride and 1 mM dithiothreitol) in a final volume of 10 ml for 12-16 h at 37 8 C. For nucleosomes (0.3 mg) or mononucleosome (0.3 mg), HDM buffer A containing 0.1% NP40 can be used. The reaction mixture can then be analyzed by SDS-PAGE followed by Western blotting. Antibodies against mono- or di-methyl K4 in histone H.sub.3 and acetyl-K9/K14 of histone H.sub.3 are used to detect the degree of methylation and acetylation, respectively. Western blots are then quantified by densitometry or by intensity of luminescence.
(729) Alternatively, a standard flurogenic assay can be used in which the methylated histone substrate is tethered to the bottom of a 96 well plate (or to beads resting in the plate) using biotin conjugated to the histone methylated substrate and strepavidin (SA) on beads or SA attached to the plate to secure the biotinylated substrate. After incubation of the KDM1A enzyme in histone demethylase buffer A, the demethylated histone substrate can be detected using antibodies specific for demethylated H.sub.3K4 substrate conjugated to a fluor or some other agent that can be detected. A variation on that assay method would employ an antibody directed against the methylated version of the histone in which the amount of substrate is quantified before and after incubation with the enzyme. Yet another version of a similar assay would employ a fluorescence resonance energy transfer (FRET) system of detection in which the antibody recognizing the methylated version is conjugated or otherwise linked to an entity, e.g., a bead or a large carrier molecule on which a fluorophore (donor) is attached and the fluorophore (acceptor) is bound to an entity linked to the substrate.
(730) Alternatively, the production of H.sub.2O.sub.2 during the KDM1A reaction can be detected fluometrically. In this system, the production of H.sub.2O.sub.2 is detected in the HDM assay buffer after exposure to substrate, co-factor and enzyme using ADHP (10-Acetyl-3, 7-dihydroxyphenoxazine) as a fluorogenic substrate for horse radish peroxidase (HRP). ADHP (also known as Amplex Red Reagent) is the most stable and sensitive fluorogenic substrate for HRP. The florescent product is resorufin. Sensitivity can be as low as 10.sup.−15 M of target protein. The signal is read using a fluorescence microplate reader at excitation and emission wavelengths of 530-560 nm and 590 nm, respectively.
(731) Additionally, the KDM1A reaction can include other factors which may influence the activity of KDM1A. Such factors might include CoREST, NuRD complexes, DNMT1, HDAC1, HDAC2, and HDAC3, for example, as proteins known to associate with KDM1A or KDM1A-containing complexes. Interactions that influence any aspect of the KDM1A activity including specificity for template, substrate, K.sub.m, K.sub.cat, or sensitivity to FAD concentrations can be assayed. For example, an in vitro interaction assay between KDM1A and CoREST can be performed adding recombinant KDM1A (e.g., 10 mg) and CoREST (e.g., 5 mg) mixed and incubated for 1 h at 4-8° C., fractionated by Superdex 200 gel filtration column in a buffer containing 20 mM Tris-HCl pH 7.9, 500 mM KCl, 10% glycerol, 0.2 mM EDTA, 1 mM dithiothreitol, 0.1% Nonidet P40 and 0.2 mM phenylmethylsulphonyl fluoride, and then analyzed by silver staining.
(732) For co-immunoprecipitation of mononucleosomes with KDM1A and CoREST, nucleosomes (1.5 mg) can be digested with micrococcal nuclease and incubated with recombinant KDM1A (e.g., 1 mg), CoREST (e.g., 500 ng) or both proteins in HDM buffer A containing 0.1% NP40 for 1 h at 4-8° C. Antibodies directed against KDM1A or CoREST attached to an affinity resin are added and after extensive washing with HDM buffer A containing 0.1% NP40, the bound proteins are eluted with a wash buffer. KDM1A activity can be assayed in the eluate or the concentration of KDM1A can be determined by quantitative Western blotting.
(733) Compounds were tested in a 10-dose IC.sub.50 mode fluorescence coupling enzyme assay with 3-fold serial dilution in duplicate starting at 100 μM. The production of FAD-dependent H.sub.2O.sub.2 as a result of demethylase activity of LSD1 on 10 M histone H.sub.3(1-21)K4me2 peptide substrate was measured by coupling with HRP and Amplex Red to yield resorufin (fluorescence measured at Ex/Em=535/590 nm on EnVision, Perkin Elmer). Results are given below in Table 1.
(734) TABLE-US-00001 TABLE 1 LSD1 Activity Example # RB LSD1 ave, nM 1 2 2 28 3 7 4 7 5 12 6 N.D. 7 16 8 48 9 6 10 300 11 7 12 7 13 6 14 10 15 19 16 9 17 4 18 3 19 0.7 20 6 21 0.6 22 2 23 9 24 91 25 10 26 4 27 17 28 6 29 2 30 2 31 4 32 9 33 17 34 11 35 11 36 13 37 24 38 7 39 12 40 78 41 24 42 18 43 <0.1 44 6 45 18 46 7 47 9 48 15
(735) All references, patents or applications, U.S. or foreign, cited in the application are hereby incorporated by reference as if written herein in their entireties. Where any inconsistencies arise, material literally disclosed herein controls.
(736) From the foregoing description, one skilled in the art can easily ascertain the essential characteristics of this disclosure, and without departing from the spirit and scope thereof, can make various changes and modifications of the disclosure to adapt it to various usages and conditions.