Claims
- 1. A process of making a compound, wherein:
the compound corresponds in structure to Formula Ia or Ib: 115R1 is phenyl substituted with one or more substituents selected from the group consisting of halo, alkoxy, alkylthio, cyano, CF3, OCF3, alkyl, SO2CH3, SO2NH2, SO2NHCOalkyl, SO2NHCOalkyl, alkenyl, and alkynyl; R2 is selected from the group consisting of pyridyl, pyrimidyl, triazinyl, hydrogen, halo, alkyl, and 6-membered heterocycle, wherein the heterocycle is substituted with one or two substituents selected from the group consisting of halo, alkoxy, alkylthio, cyano, CF3, OCF3, alkyl, alkylamino, dialkylamino, and phenyl substituted with one or two substituents selected from the group consisting of halo, alkoxy, alkylthio, cyano, CF3, OCF3, alkyl, alkylamino, and dialkylamino; R3 is selected from the group consisting of hydrogen, alkyl, and phenyl, wherein the alkyl and phenyl may optionally be substituted by one or more substituents selected from the group consisting of SO2CH3, halo, alkyl, alkoxy, alkylthio, cyano, CF3, OCF3, and SO2NH2; R4 and R5 taken together form piperazine substituted with one or two alkyl; and the process comprises:
reacting an organometallic reagent of the formula R2CH2M (wherein M is selected from the group consisting of Li, Na, K, and Mg) with an activated form of a carboxylic acid to produce a ketone of Formula Ic: 116treating the ketone of Formula Ic with a mixture of carbon disulfide and dihalomethane in the presence of a base and a solvent to produce a dithietane derivative of Formula Id: 117reacting the dithietane derivative of Formula Id with an amine of formula R4—NH—R5 to produce a thioamide of Formula Ie, If, or Ig: 118condensing the thioamide of Formula Ie, If, or Ig with hydrazine or substituted hydrazine.
- 2. The process of claim 1, wherein:
R1 is phenyl substituted with one or more substituents selected from the group consisting of halo, C1-6 alkoxy, C1-6 alkylthio, cyano, CF3, OCF3, C1-3 alkyl, SO2CH3, SO2NH2, SO2NHCOC1-4 alkyl, SO2NHCOC1-4 alkyl, C2-4 alkenyl, and C2-4 alkynyl; R2 is selected from the group consisting of pyridyl, pyrimidyl, triazinyl, hydrogen, halo, C1-6, alkyl, and 6-membered heterocycle substituted with 1 to 2 substituents selected from the group consisting of halo, C1-6 alkoxy, C1-6 alkylthio, cyano, CF3, OCF3, C1-6 alkyl, C1-6 alkylamino, C1-6 dialkylamino, phenyl substituted with one or two substituents selected from the group consisting of halo, C1-6 alkoxy, C1-6 alkylthio, cyano, CF3, OCF3, C1-6 alkyl, C1-6 alkylamino, and C1-6 dialkylamino; R3 is selected from the group consisting of hydrogen, C1-6 alkyl, and phenyl, wherein the C1-6 alkyl and phenyl may be optionally substituted by one or more substituents selected from the group consisting of SO2CH3, halo, C1-3 alkyl, C1-3 alkoxy, C1-3 alkylthio, cyano, CF3, OCF3, and SO2NH2; and R4 and R5 taken together form piperazine substituted with one or two methyl.
- 3. The process of claim 1, wherein the dihalomethane is dibromomethane.
- 4. The process of claim 1, wherein the dihalomethane is iodochloromethane.
- 5. The process of claim 1, wherein the process comprises making a compound selected from the group consisting of:
- 6. A process of making a compound, wherein:
the compound corresponds in structure to Formula IIa or IIb: 124R1 is phenyl substituted with one or more substituents selected from the group consisting of hydrogen, halo, alkoxy, alkylthio, cyano, CF3, OCF3, alkyl, SO2CH3, SO2NH2, SO2NHCOalkyl, SO2NHCOalkyl, alkenyl, and alkynyl; R2 is selected from the group consisting of pyridyl, pyrimidyl, triazinyl, hydrogen, halo, alkyl, and 6-membered heterocycle, wherein the heterocycle is substituted with one or two substituents is selected from the group consisting of halo, alkoxy, alkylthio, cyano, CF3, OCF3, alkyl, alkylamino, dialkylamino, and phenyl, wherein the phenyl is substituted with one or two substituents selected from the group consisting of halo, alkoxy, alkylthio, cyano, CF3, OCF3, alkyl, alkylamino2 and dialkylamino; R3 is selected from the group consisting of hydrogen, alkyl, and phenyl wherein the alkyl and phenyl may optionally be substituted by one or more substituents selected from the group consisting of SO2CH3, halo, alkyl, alkoxy, alkylthio, cyano, CF3, OCF3, and SO2NH2; R6 is selected from the group consisting of hydrogen, alkyl, phenyl, cycloalkyl, and heterocyclyl which may be optionally substituted by one or more substituents selected from the group consisting of phenyl, substituted phenyl, alkoxycarbonyl, acyl, halo, OH, NH2, NHR3, N(R3)2, and cyano, cycloalkyl, heterocycloalkyl, and 3-7 membered heterocycle ring; and the process comprises:
reacting an organometallic reagent of the formula R2CH2M (wherein M is selected from the group consisting of Li, Na, K, and Mg) with an activated form of a carboxylic acid to produce a ketone of Formula IIc: 125treating the ketone of Formula IIc with a mixture of carbon disulfide and dihalo methane such as dibromomethane or iodochloromethane in the presence of a base and a solvent to produce a dithietane derivative of Formula IId: 126reacting the dithietane derivative of Formula IId with NaOR6 to produce a compound of Formula IIe: 127condensing the compound of Formula IIe with hydrazine or substituted hydrazine.
- 7. The process of claim 6, wherein:
R1 is phenyl substituted by one or more substituents selected from the group consisting of halo, C1-6 alkoxy, C1-6 alkylthio, cyano, CF3, OCF3, C1-3 alkyl, SO2CH3, SO2NH2, SO2NHCOC1-4 alkyl, SO2NHCOC1-4 alkyl, C2-4 alkenyl, and C2-4 alkynyl; R2 is selected from the group consisting of pyridyl, pyrimidyl, triazinyl, hydrogen, halo, C1-6 alkyl, and 6-membered heterocycle, wherein the heterocycle is substituted with one or two substituents selected from the group consisting of halo, C1-6 alkoxy, C1-6 alkylthio, cyano, CF3, OCF3, C1-6 alkyl, C1-6 alkylamino, C1-6 dialkylamino, and phenyl substituted with one or two substituents selected from the group consisting of halo, C1-6 alkoxy, C1-6 alkylthio, cyano, CF3, OCF3, C1-6 alkyl, C1-6 alkylamino, and C1-6 dialkylamino; R3 is selected from the group consisting of hydrogen, C1-6 alkyl, and phenyl, wherein the C1-6 alkyl and phenyl may optionally be substituted by one or more substituents selected from the group consisting of SO2CH3, halo, C1-3 alkyl, C1-3 alkoxy, C1-3 alkylthio, cyano, CF3, OCF3, and SO2NH2; and R6 is, selected from the group consisting of hydrogen and C1-6 alkyl which may be optionally substituted by one or more substituents selected from the group consisting of phenyl, substituted phenyl, halo, OH, NH2, NHR3, N(R3)2, and cyano, C3-7 cycloalkyl, C3-7 heterocycloalkyl, and 3-7 membered heterocycle ring.
- 8. The process of claim 6, wherein the dihalomethane is dibromomethane.
- 9. The process of claim 6, wherein the dihalomethane isiodochloromethane.
- 10. The process of claim 6, wherein the dithietane is added to a solution of sodium alkoxide.
- 11. The process of claim 6, the process comprises making a compound selected from the group consisting of:
- 12. A process of making compounds of a compound, wherein:
the compound corresponds in structure to Formula IIIa or IIIb: 130R1 is phenyl substituted with one or more substituents selected from the group consisting of halo, alkoxy, alkylthio, cyano, CF3, OCF3, alkyl, SO2CH3, SO2NH2, SO2NHCOalkyl, SO2NHCOalkyl, alkenyl, and alkynyl; R2 is selected from the group consisting of pyridyl, pyrimidyl, triazinyl, hydrogen, halo, alkyl, 6-membered heterocycle, wherein the heterocycle is substituted with one or two substituents selected from the group consisting of halo, alkoxy, alkylthio, cyano, CF3, OCF3, alkyl, alkylamino, dialkylamino, and phenyl, wherein the phenyl is substituted substituted with one or two substituents selected from the group consisting of halo, alkoxy, alkylthio, cyano, CF3, OCF3, alkyl, alkylamino, and dialkylamino; R3 is selected from the group consisting of hydrogen, alkyl, and phenyl, wherein the alkyl and phenyl may be optionally substituted by one or more of the group consisting of SO2CH3, halo, alkyl, alkoxy, alkylthio, cyano, CF3, OCF3, and SO2NH2; R6 is selected from the group consisting of hydrogen, alkyl, phenyl, cycloalkyl, and heterocyclyl which may be optionally substituted by one or more substituents selected from the group consisting of phenyl, substituted phenyl, halo, alkoxycarbonyl, acyl, OH, NH2, NHR3, N(R3)2, and cyano, cycloalkyl, heterocycloalkyl, and 3-7 membered heterocycle ring; and the process comprises:
reacting an organometallic reagent of the formula R2CH2M (wherein M is selected from the group consisting of Li, Na, K, and Mg) with an activated form of a carboxylic acid to produce a ketone of Formula IIIc: 131treating the ketone of Formula IIIc with a mixture of carbon disulfide and dihalomethane in the presence of a base and a solvent to produce a dithietane derivative of Formula IIId: 132reacting the dithietane derivative of Formula IIId with R3NHNH2 to produce a heterocycle of the formula IIIe or IIIf and their tautomers: 133reacting the heterocycle of the formula IIIe or IIIf with an activated form of R6 in the presence of a base and a solvent.
- 13. The process of claim 12, wherein:
R1 is phenyl substituted with one or more substituents selected from the group consisting of halo, C1-6 alkoxy, C1-6 alkylthio, cyano, CF3, OCF3, C1-3 alkyl, SO2CH3, SO2NH2, SO2NHCOC1-4 alkyl, SO2NHCOC1-4 alkyl, C2-4 alkenyl, and C2-4 alkynyl; R2 is selected from the group consisting of pyridyl, pyrimidyl, triazinyl, hydrogen, halo, C1-6 alkyl, 6-membered heterocycle, wherein the heterocycle is substituted with one or two substients selected from the group consisting of halo, C1-6 alkoxy, C1-6alkylthio, cyano, CF3, OCF3, C1-6 alkyl, C1-6 alkylamino, C1-6 dialkylamino, and phenyl, wherein the phenyl is substituted with one or two substituents selected from the group consisting of halo, C1-6 alkoxy, C1-6 alkylthio, cyano, CF3, OCF3, C1-6 alkyl, C1-6 alkylamino, and C1-6 dialkylamino; R3 is selected from the group consisting of hydrogen, C1-6 alkyl, and phenyl, wherein the C1-6 alkyl and phenyl may be optionally substituted by one or more substituents selected from the group consisting of SO2CH3, halo, C1-3 alkyl, C1-3 alkoxy, C1-3 alkylthio, cyano, CF3, OCF3, and SO2NH2; and R6 is selected from the group consisting of hydrogen and C1-6 alkyl which may be optionally substituted by one or more substituents selected from the group consisting of phenyl, substituted phenyl, halo, OH, NH2, NHR3, N(R3)2, and cyano, C1-7 cycloalkyl, C1-7 heterocycloalkyl, and 3-7 membered heterocycle ring.
- 14. The process of claim 12, wherein the dihalomethane is dibromomethane.
- 15. The process of claim 12, wherein the dihalomethane is iodochloromethane.
- 16. The process of claim 12, wherein the process comprising making a compound selected from the group consisting of:
Parent Case Info
[0001] This application claims priority to U.S. Provisional Application No. 60/109,177 filed Nov. 20, 1998.
Provisional Applications (1)
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Number |
Date |
Country |
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60109177 |
Nov 1998 |
US |
Divisions (2)
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Number |
Date |
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Parent |
09633726 |
Aug 2000 |
US |
Child |
09772743 |
Jan 2001 |
US |
Parent |
09442971 |
Nov 1999 |
US |
Child |
09633726 |
Aug 2000 |
US |
Continuations (3)
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Parent |
10268818 |
Oct 2002 |
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Child |
10778432 |
Feb 2004 |
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Parent |
09922819 |
Aug 2001 |
US |
Child |
10268818 |
Oct 2002 |
US |
Parent |
09772743 |
Jan 2001 |
US |
Child |
09922819 |
Aug 2001 |
US |