[go: up one dir, main page]

US20150051185A1 - Chemical Compounds 251 - Google Patents

Chemical Compounds 251 Download PDF

Info

Publication number
US20150051185A1
US20150051185A1 US14/339,981 US201414339981A US2015051185A1 US 20150051185 A1 US20150051185 A1 US 20150051185A1 US 201414339981 A US201414339981 A US 201414339981A US 2015051185 A1 US2015051185 A1 US 2015051185A1
Authority
US
United States
Prior art keywords
thiazolidine
dione
phenyl
methylidene
methyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
US14/339,981
Inventor
Leslie Dakin
James Edward Dowling
Michelle Laurae LAMB
Jon Read
Qibin Su
XiaoLan Zheng
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
AstraZeneca AB
Original Assignee
AstraZeneca AB
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=41050276&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=US20150051185(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by AstraZeneca AB filed Critical AstraZeneca AB
Priority to US14/339,981 priority Critical patent/US20150051185A1/en
Assigned to ASTRAZENECA PHARMACEUTICALS LP reassignment ASTRAZENECA PHARMACEUTICALS LP ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: READ, JON, DOWLING, JAMES EDWARD, LAMB, MICHELLE, SU, QIBIN, ZHENG, XIAOLAN, DAKIN, LESLIE
Assigned to ASTRAZENECA AB reassignment ASTRAZENECA AB ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: ASTRAZENECA PHARMACEUTICALS LP
Publication of US20150051185A1 publication Critical patent/US20150051185A1/en
Abandoned legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/426—1,3-Thiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/34—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the invention relates to chemical compounds of formula I,
  • the invention relates to inhibitors or modulators of PIM-1 and/or PIM-2, and/or PIM-3 protein kinase activity or enzyme function.
  • the invention relates to pharmaceutical compositions comprising compounds disclosed herein, and their use in the prevention and treatment of PIM kinase related conditions and diseases, preferably cancer.
  • PIM-1 gene was first identified as a proviral insertion site in Moloney murine leukemia virus-induced T-cell lymphoma.
  • PIM-1 gene translates a Ser/Thr protein kinase.
  • the known PIM kinase family also includes PIM-2 and PIM-3.
  • Mice studies suggest that physiologically the PIM kinases are involved in growth factor and cytokine signaling.
  • Deregulated PIM kinase expression occurs a in large number of hematopoietic tumors, such as myeloid and lymphoblastic leukemias and lyphomas.
  • PIM kinases are also expressed in solid tumors, such as prostate cancer and pancreatic cancer, and transgenic mice which express PIM-1 develop T-cell lymphoma.
  • the invention relates to chemical compounds of formula I,
  • the invention relates to inhibitors or modulators of PIM-1 and/or PIM-2, and/or PIM-3 protein kinase activity or enzyme function.
  • the invention relates to pharmaceutical compositions comprising compounds disclosed herein, and their use in the prevention and treatment of PIM kinase related conditions and diseases, preferably cancer.
  • the invention relates to a method of treating or preventing cancer comprising,
  • R 1 is selected from a carbocyclyl, aryl, and heterocyclyl, wherein R 1 is optionally substituted with one or more, the same or different, R 2 ;
  • R 2 is selected from C 1-6 alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylamino, (C 1-6 alkyl) 2 amino, C 1-6 alkylsulfamoyl, arylsulfamoyl, carbocyclyl, aryl, and heterocyclyl, wherein R 2 is optionally substituted with one or more, the same or different, R 3 ;
  • R 3 is selected from C 1-6 alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylamino, (C 1-6 alkyl) 2 amino, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, and heterocyclyl,
  • R 3 is optionally substituted with one or more, the same or different, R 4 ;
  • R 4 is selected from C 1-6 alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylamino, (C 1-6 alkyl) 2 amino, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, and heterocyclyl, wherein R 4 is optionally substituted with one or more, the same or different, R 5 ; and
  • R 5 is selected from halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulf
  • the invention relates to a method of treating or preventing cancer comprising,
  • R 1 is selected from a carbocyclyl, aryl, and heterocyclyl, wherein R 1 is optionally substituted with one or more, the same or different, R 2 ;
  • R 2 is selected from halogen, C 1-6 alkyl, halogenated C 1-6 alkyl, amino, C 1-6 alkylamino, (C 1-6 alkyl) 2 amino, and heterocyclyl, wherein R 2 is optionally substituted with one or more, the same or different, R 3 ;
  • R 3 is selected from C 1-6 alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylamino, (C 1-6 alkyl) 2 amino, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, and heterocyclyl, wherein R 3 is optionally substituted with one or more, the same or different, R 4 ;
  • R 4 is selected from C 1-6 alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylamino, (C 1-6 alkyl) 2 amino, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, and heterocyclyl, wherein R 4 is optionally substituted with one or more, the same or different, R 5 ; and
  • R 5 is selected from halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulf
  • the invention relates to a method of treating cancer comprising administering to a subject in need thereof a pharmaceutical composition comprising a compound of the formula disclosed herein, wherein said cancer is selected from a leukemia, lymphoma, prostate cancer, pancreatic cancer or other solid tumors.
  • the invention relates to a compound of formula IA,
  • n is selected from 0, 1, or 2;
  • n is selected from 0, 1, or 2;
  • A is selected from N and CR 7 ;
  • X is selected from O, S, CHR 10 and NR 11 ;
  • Y is selected from N, CH, and C;
  • R 5 , R 6 , and R 7 are each individually and independently from hydrogen, C 1-6 alkyl, halogen, cyano, nitro, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylamino, (C 1-6 alkyl) 2 amino, carbocyclyl, aryl, and heterocyclyl, wherein R 5 , R 6 , and R 7 are each optionally substituted with one or more, the same or different, R 12 ;
  • R 8 and R 9 are each individually and independently selected from hydrogen, amino, hydroxyl, mercapto, C 1-6 alkyl, C 1-6 alkylamino, carbocyclyl, aryl, and heterocyclyl wherein R 8 and R 9 are each optionally substituted with one or more, the same or different, R 15 ;
  • R 10 is selected from hydrogen, C 1-6 alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylamino, (C 1-6 alkyl) 2 amino, C 1-6 alkylsulfamoyl, arylsulfamoyl, carbocyclyl, aryl, and heterocyclyl, wherein R 10 is optionally substituted with one or more, the same or different, R 12 ;
  • R 11 is selected from hydrogen, formyl, C 1-6 alkyl, C 1-6 alkanoyl, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, arylsulfonyl, C 1-6 alkoxycarbonyl, carbocyclyl, aryl, and heterocyclyl, wherein R 11 is optionally substituted with one or more, the same or different, R 12 ;
  • R 12 is selected from halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulf
  • R 15 is selected from C 1-6 alkyl, C 1-6 alkanoyl, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, arylsulfonyl, and C 1-6 alkoxycarbonyl wherein R 15 is optionally substituted with one or more, the same or different, R 12 ;
  • R 16 is selected from halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, aminomethyl, aminoethyl, aminopropyl, aminobutyl, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethyls
  • R 5 , R 6 , and R 7 are not all hydrogen and
  • the compound is not 5-((5-nitro-2-(1-piperidinyl)phenyl)methylene)-2,4-thiazolidinedione or 5-((2-(4-morpholinyl)-5-nitrophenyl)methylene)-2,4-thiazolidinedione.
  • the invention relates to a compound of formula ID,
  • n is selected from 0, 1, or 2;
  • A is selected from N and CR 7 ;
  • X is selected from O, S, CHR 10 and NR 11 ;
  • R 5 , R 6 , and R 7 are each individually and independently from hydrogen, C 1-6 alkyl, halogen, cyano, nitro, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylamino, (C 1-6 alkyl) 2 amino, carbocyclyl, aryl, and heterocyclyl, wherein R 5 , R 6 , and R 7 are each optionally substituted with one or more, the same or different, R 12 ;
  • R 8 and R 9 are each individually and independently selected from hydrogen, amino, hydroxyl, mercapto, C 1-6 alkyl, C 1-6 alkylamino, carbocyclyl, aryl, and heterocyclyl wherein R 8 and R 9 are each optionally substituted with one or more, the same or different, R 15 ;
  • R 10 is selected from hydrogen, C 1-6 alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylamino, (C 1-6 alkyl) 2 amino, C 1-6 alkylsulfamoyl, arylsulfamoyl, carbocyclyl, aryl, and heterocyclyl, wherein R 10 is optionally substituted with one or more, the same or different, R 12 ;
  • R 11 is selected from hydrogen, formyl, C 1-6 alkyl, C 1-6 alkanoyl, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, arylsulfonyl, C 1-6 alkoxycarbonyl, carbocyclyl, aryl, and heterocyclyl, wherein R 11 is optionally substituted with one or more, the same or different, R 12 ;
  • R 12 is selected from halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulf
  • R 15 is selected from C 1-6 alkyl, C 1-6 alkanoyl, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, arylsulfonyl, and C 1-6 alkoxycarbonyl wherein R 15 is optionally substituted with one or more, the same or different, R 12 ;
  • R 16 is selected from halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, aminomethyl, aminoethyl, aminopropyl, aminobutyl, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethyls
  • R 5 , R 6 , and R 7 are not all hydrogen.
  • R 5 , R 6 , and R 7 are not 5-((5-nitro-2-(1-piperidinyl)phenyl)methylene)-2,4-thiazolidinedione or 5-((2-(4-morpholinyl)-5-nitrophenyl)methylene)-2,4-thiazolidinedione.
  • the invention relates to a compound of formula IB,
  • n is selected from 0, 1, or 2;
  • X is selected from O, CHR 10 and NR 11 ;
  • R 5 , R 6 , and R 7 are each individually and independently from hydrogen, halogen, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mes
  • R 8 and R 9 are each individually and independently selected from hydrogen, amino, C 1-6 alkyl, C 1-6 alkylamino, wherein R 8 and R 9 are each optionally substituted with one or more, the same or different, R 15 ;
  • R 10 is selected from hydrogen, C 1-6 alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylamino, (C 1-6 alkyl) 2 amino, C 1-6 alkylsulfamoyl, arylsulfamoyl, carbocyclyl, aryl, and heterocyclyl, wherein R 10 is optionally substituted with one or more, the same or different, R 12 ;
  • R 11 is selected from hydrogen, C 1-6 alkyl, C 1-6 alkanoyl, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, arylsulfonyl, C 1-6 alkoxycarbonyl, carbocyclyl, aryl, and heterocyclyl, wherein R 11 is optionally substituted with one or more, the same or different, R 12 ;
  • R 12 is selected from halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulf
  • R 15 is selected from C 1-6 alkyl, C 1-6 alkanoyl, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, arylsulfonyl, and C 1-6 alkoxycarbonyl wherein R 15 is optionally substituted with one or more, the same or different, R 12 ;
  • R 16 is selected from halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulf
  • said compound is not, 5-[[2-(4-methyl-1-piperazinyl)phenyl]methylene]-2,4-thiazolidinedione or 5-[[2-[(2,6-dichloro-3-methylphenyl)amino]phenyl]methylene]-2,4-thiazolidinedione.
  • the invention relates to a compound of formula IC,
  • n is selected from 0, 1, 2, 3, 4, 5, 6, 7 or 8;
  • X is selected from O, S, CHR 10 and NR 11 ;
  • Y is selected from O, S, and NR 13 ;
  • R 5 , R 6 , and R 7 are each individually and independently from C 1-6 alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylamino, C 1-6 dialkylamino, carbocyclyl, aryl, and heterocyclyl, wherein R 5 , R 6 , and R 7 are each optionally substituted with one or more, the same or different, R 12 ;
  • R 10 is selected from hydrogen, C 1-6 alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylamino, (C 1-6 alkyl) 2 amino, C 1-6 alkylsulfamoyl, arylsulfamoyl, carbocyclyl, aryl, and heterocyclyl, wherein R 10 is optionally substituted with one or more, the same or different, R 12 ;
  • R 11 , R 13 , and R 14 are each individually and independently selected from hydrogen, C 1-6 alkyl, C 1-6 alkanoyl, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, arylsulfonyl, and C 1-6 alkoxycarbonyl wherein R 11 is optionally substituted with one or more, the same or different, R 12 ;
  • R 11 and R 14 taken together with the atoms to which they are attached form a five, six, or seven membered heterocyclic ring optionally substituted with one or more, the same or different, R 12 ;
  • R 12 is selected from halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulf
  • Y is NR 13 , wherein R 13 is a C 1-6 alkyl.
  • R 5 is a halogenated C 1-6 alkyl.
  • R 7 is a halogen
  • the invention relates to a compound of formula IX,
  • R 5 is selected from hydrogen, C 1-6 alkoxy, carbamoyl, and halogenated C 1-6 alkyl;
  • R 6 is selected from hydrogen, halogen, C 1-6 alkoxy, and 2-(1-piperidyl)ethoxy;
  • R 7 is selected from hydrogen, halogen, and C 1-6 alkoxy
  • R 17 is a heterocarbocylcyl, wherein R 17 is optionally substituted with one or more, the same or different, R 18 ;
  • R 18 is selected from halogen, formyl, amino, C 1-6 alkyl, C 1-6 alkylamino, (C 1-6 alkyl) 2 amino, carbocyclyl, aryl, heterocyclyl, wherein R 18 is optionally substituted with one or more, the same or different, R 19 ;
  • R 19 is selected from amino, C 1-6 alkyl, hydroxy, carbocyclyl, and heterocyclyl wherein R 19 is optionally substituted with one or more, the same or different, R 20 ;
  • R 20 is selected from amino, C 1-6 alkyl, and halogen.
  • R 17 is selected from (3R)-3-aminopyrrolidin-1-yl, (3R)-3-dimethylaminopyrrolidin-1-yl, (3S)-3-(3-aminopropylamino)pyrrolidin-1-yl, (3S)-3-(5-aminopentanoylamino)pyrrolidin-1-yl, (3S)-3-amino-1-piperidyl, (3S)-3-aminopyrrolidin-1-yl, (3S)-3-dimethylaminopyrrolidin-1-yl, (3S,5R)-3,5-dimethylpiperazin-1-yl, 1,4-diazepan-1-yl, 2-(1-piperidyl)ethoxy, 2-diethylaminoethoxy, 2-dimethylaminoethyl-methyl-amino, 2-hydroxyethoxy, 2-morpholinoethoxy, 3-(2-aminoethylamino
  • the invention relates to a compound selected from:
  • the invention relates to any of the compounds disclosed herein that are in the (Z) isomer.
  • the invention relates to any of the compounds disclosed herein that are in the (E) isomer.
  • the invention relates to compositions comprising a mixture of the (Z) and (E) isomers.
  • the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a substituted 5-(3-halo-2-[piperidin-1-yl]phenylmethylidene)-1,3-thiazolidine-2,4-dione functioning to inhibit a PIM kinase.
  • the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula I, IA, IB, IC, ID, or IX or a pharmaceutically acceptable salt thereof.
  • the invention relates to a method of inhibiting a PIM kinase comprising, providing a compound of formula I, IA, IB, IC, ID, or IX, as defined herein, and mixing a PIM kinase and said compound under conditions such that PIM kinase phosphorylation is inhibited.
  • said method is an in vitro method.
  • said method is an in vivo method.
  • the invention relates to a method of inhibiting a PIM kinase in a subject comprising administering to the subject a therapeutically effective amount of a compound of any of the formula disclosed herein or a pharmaceutically acceptable salt thereof.
  • said PIM kinase is selected from PIM-1, PIM-2, and PIM-3.
  • the invention relates to the use of a compound of the formula I, IA, IB, IC, ID, or IX, or a pharmaceutically acceptable salt thereof, as defined herein, for the manufacture of a medicament for the production of a PIM kinase inhibitory effect in a subject.
  • the invention relates to the use of a compound of the formula I, IA, IB, IC, ID, or IX, or a pharmaceutically acceptable salt thereof, as disclosed herein, for the manufacture of a medicament for the production of an anti-cancer effect in a subject.
  • the invention relates to a method of making a compound of formula IA as defined herein,
  • composition comprising a compound of formula XIII
  • said metal halide is selected from lithium chloride and magnesium bromide.
  • said boronic ester is a dialkyl boronic ester, such as diethyl boronic ester, or a cyclic boronic ester, such as the boronic ester of 1,2-alkyldiols, such as 1,3,2-dioxaborolane, or cycloalkyldiols which may be optionally substituted.
  • the invention relates to a method of making a compound of formula ID, or salt thereof comprising
  • composition comprising a compound of formula IV,
  • the invention relates to a method of making a compound of formula IC, or salt thereof comprising a) mixing a compound of formula V,
  • the invention relates to compounds of formula I, IA, IB, IC, ID, or IX provided that they are not selected from 5-((2-dipropylamino-5-nitrophenyl)methylene)-2,4-thiazolidinedione; 5-((5-nitro-2-(1-piperidinyl)phenyl)methylene)-2,4-thiazolidinedione; 5-((2-(4-morpholinyl)-5-nitrophenyl)methylene)-2,4-thiazolidinedione; 5-[[2-(4-methyl-1-piperazinyl)phenyl]methylene]-2,4-thiazolidinedione; 5-[[2-[(2,6-dichloro-3-methylphenyl)amino]phenyl]methylene]-2,4-thiazolidinedione; [2S-[2 ⁇ (Z),4 ⁇ ]]-1-([1,1′-biphenyl]-4-ylsulfonyl
  • WO 2001002377 discloses 5-((2-dipropylamino-5-nitrophenyl)methylene)-2,4-thiazolidinedione, 5-((5-nitro-2-(1-piperidinyl)phenyl)methylene)-2,4-thiazolidinedione, and 5-((2-(4-morpholinyl)-5-nitrophenyl)methylene)-2,4-thiazolidinedione.
  • WO 9814433 discloses 5-[[2-(4-methyl-1-piperazinyl)phenyl]methylene]-2,4-thiazolidinedione.
  • WO 9705135 discloses, [2S-[2 ⁇ (Z),4 ⁇ ]]-1-([1,1′-biphenyl]-4-ylsulfonyl)-N-[2-[(2,4-dioxo-5-thiazolidinylidene)methyl]phenyl]-4-(methylthio)-2-pyrrolidinemethanamine, 1,1-dimethylethyl ester [[2S-[2 ⁇ (Z),4 ⁇ ]]-3-[[1-([1,1′-biphenyl]-4-ylsulfonyl)-4-(methylthio)-2-pyrrolidinyl]methyl]amino]-4-[(2,4-dioxo-5-thiazolidinylidene)methyl]phenyl]-carbamic acid, and [2S-[2 ⁇ (Z),4 ⁇ ]]-N-[5-amino-2-[(2,4-dioxo-5-thiazolidinyliden
  • compounds disclosed herein could be used in the clinic either as a single agent by itself or in combination with other clinically relevant agents. This compound could also prevent the potential cancer resistance mechanisms that may arise due to mutations in a set of genes.
  • anti-cancer treatment may be applied as a sole therapy or may involve, in addition to the compound of the invention, conventional surgery or radiotherapy or chemotherapy.
  • chemotherapy may include one or more of the following categories of anti-tumour agents:
  • antiproliferative/antineoplastic drugs and combinations thereof, as used in medical oncology such as alkylating agents (for example cis-platin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulfan and nitrosoureas); antimetabolites (for example antifolates such as fluoropyrimidines like 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosine arabinoside and hydroxyurea); antitumour antibiotics (for example anthracyclines like adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin and mithramycin); antimitotic agents (for example vinca alkaloids like vincristine, vinblastine, vindesine and vinorelbine and taxoids like taxol and
  • cytostatic agents such as antioestrogens (for example tamoxifen, toremifene, raloxifene, droloxifene and iodoxyfene), oestrogen receptor down regulators (for example fulvestrant), antiandrogens (for example bicalutamide, flutamide, nilutamide and cyproterone acetate), LHRH antagonists or LHRH agonists (for example goserelin, leuprorelin and buserelin), progestogens (for example megestrol acetate), aromatase inhibitors (for example as anastrozole, letrozole, vorazole and exemestane) and inhibitors of 5 ⁇ -reductase such as finasteride;
  • antioestrogens for example tamoxifen, toremifene, raloxifene, droloxifene and iodoxyfene
  • agents which inhibit cancer cell invasion for example metalloproteinase inhibitors like marimastat and inhibitors of urokinase plasminogen activator receptor function;
  • inhibitors of growth factor function include growth factor antibodies, growth factor receptor antibodies (for example the anti-erbb2 antibody trastuzumab [HerceptinTM] and the anti-erbb1 antibody cetuximab [C225]), farnesyl transferase inhibitors, tyrosine kinase inhibitors and serine/threonine kinase inhibitors, for example inhibitors of the epidermal growth factor family (for example EGFR family tyrosine kinase inhibitors such as:
  • inhibitors of the platelet-derived growth factor family and for example inhibitors of the hepatocyte growth factor family for example inhibitors or phosphotidylinositol 3-kinase (PI3K) and for example inhibitors of mitogen activated protein kinase kinase (MEK1/2) and for example inhibitors of protein kinase B (PKB/Akt), for example inhibitors of Src tyrosine kinase family and/or Abelson (Abl) tyrosine kinase family such as AZD0530 and dasatinib (BMS-354825) and imatinib mesylate (GleevecTM); and any agents that modify STAT signaling.
  • PI3K phosphotidylinositol 3-kinase
  • MEK1/2 mitogen activated protein kinase kinase
  • PBB/Akt protein kinase B
  • antiangiogenic agents such as those which inhibit the effects of vascular endothelial growth factor, (for example the anti-vascular endothelial cell growth factor antibody bevacizumab [AvastinTM], compounds such as those disclosed in International Patent Applications WO 97/22596, WO 97/30035, WO 97/32856 and WO 98/13354) and compounds that work by other mechanisms (for example linomide, inhibitors of integrin ⁇ v ⁇ 3 function and angiostatin);
  • vascular endothelial growth factor for example the anti-vascular endothelial cell growth factor antibody bevacizumab [AvastinTM]
  • vastinTM anti-vascular endothelial cell growth factor antibody bevacizumab
  • compounds that work by other mechanisms for example linomide, inhibitors of integrin ⁇ v ⁇ 3 function and angiostatin
  • vascular damaging agents such as Combretastatin A4 and compounds disclosed in International Patent Applications WO 99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO 02/04434 and WO 02/08213;
  • antisense therapies for example those which are directed to the targets listed above, such as ISIS 2503, an anti-ras antisense;
  • gene therapy approaches including for example approaches to replace aberrant genes such as aberrant p53 or aberrant BRCA1 or BRCA2, GDEPT (gene-directed enzyme pro-drug therapy) approaches such as those using cytosine deaminase, thymidine kinase or a bacterial nitroreductase enzyme and approaches to increase patient tolerance to chemotherapy or radiotherapy such as multi-drug resistance gene therapy; and
  • GDEPT gene-directed enzyme pro-drug therapy
  • immunotherapy approaches including for example ex-vivo and in-vivo approaches to increase the immunogenicity of patient tumour cells, such as transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor, approaches to decrease T-cell anergy, approaches using transfected immune cells such as cytokine-transfected dendritic cells, approaches using cytokine-transfected tumour cell lines and approaches using anti-idiotypic antibodies, and approaches using the immunomodulatory drugs thalidomide and lenalidomide [Revlimid®].
  • cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor
  • approaches to decrease T-cell anergy approaches using transfected immune cells such as cytokine-transfected dendritic cells
  • approaches using cytokine-transfected tumour cell lines and approaches using anti-idiotypic antibodies and approaches using the immunomodulatory drugs thalidomide and le
  • Such conjoint treatment may be achieved by way of the simultaneous, sequential or separate dosing of the individual components of the treatment.
  • Such combination products employ the compounds of this invention, or pharmaceutically acceptable salts thereof, within the dosage range described hereinbefore and the other pharmaceutically-active agent within its approved dosage range.
  • the invention relates to phosphorylation inhibitors of PIM kinases.
  • the invention relates to pharmaceutical composition comprising compounds disclosed herein and their use in the prevention and treatment of cancer.
  • compositions disclosed herein may exist in solid and solution form tautomers.
  • imidazole and imidazole containing heterocycles may be drawn in a formula such that one or the other of the nitrogens contain a hydrogen atom.
  • embodiments of such a formula are considered to encompass alternative tautomeric forms.
  • alkyl means a noncyclic straight chain or branched, unsaturated or saturated hydrocarbon such as those containing from 1 to 10 carbon atoms, while the term “lower alkyl” or “C 1-6 alkyl” has the same meaning as alkyl but contains from 1 to 6 carbon atoms. The term “higher alkyl” has the same meaning as alkyl but contains from 7 to 10 carbon atoms.
  • saturated straight chain alkyls include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-septyl, n-octyl, n-nonyl, and the like; while saturated branched alkyls include isopropyl, sec-butyl, isobutyl, tert-butyl, isopentyl, and the like.
  • Unsaturated alkyls contain at least one double or triple bond between adjacent carbon atoms (referred to as an “alkenyl” or “alkynyl”, respectively).
  • Representative straight chain and branched alkenyls include ethylenyl, propylenyl, 1-butenyl, 2-butenyl, isobutylenyl, 1-pentenyl, 2-pentenyl, 3-methyl-1-butenyl, 2-methyl-2-butenyl, 2,3-dimethyl-2-butenyl, and the like; while representative straight chain and branched alkynyls include acetylenyl, propynyl, 1-butyryl, 2-butyryl, 1-pentynyl, 2-pentynyl, 3-methyl-1-butynyl, and the like.
  • halogenated alkyl refers to an alkyl group where one or more or all of the hydrogen(s) are substituted with halogen(s).
  • a representative halogenated alkyl includes trifluoromethyl (i.e., —CF 3 ).
  • Non-aromatic mono or polycyclic alkyls are referred to herein as “carbocycles” or “carbocyclyl” groups.
  • Representative saturated carbocycles include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like; while unsaturated carbocycles include cyclopentenyl and cyclohexenyl, aryls and the like.
  • Heterocarbocycles or heterocarbocyclyl groups are carbocycles which contain from 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur which may be saturated or unsaturated (but not aromatic), monocyclic or polycyclic, and wherein the nitrogen and sulfur heteroatoms may be optionally oxidized, and the nitrogen heteroatom may be optionally quaternized.
  • Heterocarbocycles include morpholinyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydroprimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, and the like.
  • Aryl means an aromatic carbocyclic monocyclic or polycyclic ring such as phenyl or naphthyl.
  • heteroaryl refers an aromatic heterocarbocycle having 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur, and containing at least 1 carbon atom, including both mono- and polycyclic ring systems.
  • Polycyclic ring systems may, but are not required to, contain one or more non-aromatic rings, as long as one of the rings is aromatic.
  • heteroaryls are furyl, benzofuranyl, thiophenyl, benzothiophenyl, pyrrolyl, indolyl, isoindolyl, azaindolyl, pyridyl, quinolinyl, isoquinolinyl, oxazolyl, isooxazolyl, benzoxazolyl, pyrazolyl, imidazolyl, benzimidazolyl, thiazolyl, benzothiazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, cinnolinyl, phthalazinyl, and quinazolinyl. It is contemplated that the use of the term “heteroaryl” includes N-alkylated derivatives such as a 1-methylimidazol-5-yl substituent.
  • heterocycle or “heterocyclyl” refers to mono- and polycyclic ring systems having 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur, and containing at least 1 carbon atom.
  • the mono- and polycyclic ring systems may be aromatic, non-aromatic or mixtures of aromatic and non-aromatic rings.
  • Heterocycle includes heterocarbocycles, heteroaryls, and the like.
  • Alkylthio refers to an alkyl group as defined above with the indicated number of carbon atoms attached through a sulfur bridge.
  • An example of an alkylthio is methylthio, (i.e., —S—CH 3 ).
  • Alkoxy refers to an alkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge.
  • alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, n-pentoxy, and s-pentoxy.
  • Preferred alkoxy groups are methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy.
  • Alkylamino refers an alkyl group as defined above with the indicated number of carbon atoms attached through an amino bridge.
  • An example of an alkylamino is methylamino, (i.e., —NH—CH 3 ).
  • Alkanoyl refers to an alkyl as defined above with the indicated number of carbon atoms attached through a carbonyl bride (i.e., —(C ⁇ O)alkyl).
  • Alkylsulfonyl refers to an alkyl as defined above with the indicated number of carbon atoms attached through a sulfonyl bridge (i.e., —S( ⁇ O) 2 alkyl) such as mesyl and the like, and “Arylsulfonyl” refers to an aryl attached through a sulfonyl bridge (i.e., —S( ⁇ O) 2 aryl).
  • Alkylsulfamoyl refers to an alkyl as defined above with the indicated number of carbon atoms attached through a sulfamoyl bridge (i.e., —NHS( ⁇ O) 2 alkyl), and an “Arylsulfamoyl” refers to an alkyl attached through a sulfamoyl bridge (i.e., (i.e., —NHS( ⁇ O) 2 aryl).
  • Alkylsulfinyl refers to an alkyl as defined above with the indicated number of carbon atoms attached through a sulfinyl bridge (i.e. —S( ⁇ O)alkyl).
  • substituted refers to a molecule wherein at least one hydrogen atom is replaced with a substituent. When substituted, one or more of the groups are “substituents.” The molecule may be multiply substituted. In the case of an oxo substituent (“ ⁇ O”), two hydrogen atoms are replaced.
  • Example substituents within this context may include halogen, hydroxy, alkyl, alkoxy, nitro, cyano, oxo, carbocyclyl, carbocycloalkyl, heterocarbocyclyl, heterocarbocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, —NR a R b , —NR a C( ⁇ O)R b , —NR a C( ⁇ O)NR a NR b , —NR a C( ⁇ O)OR b , —NR a SO 2 R b , —C( ⁇ O)R a , —C( ⁇ O)OR a , —C( ⁇ O)NR a R b , —OC( ⁇ O)NR a R b , —OR a , —SR a , —SOR a , —S( ⁇ O) 2 R a , —OS( ⁇
  • R a and R b in this context may be the same or different and independently hydrogen, halogen hydroxyl, alkyl, alkoxy, alkyl, amino, alkylamino, dialkylamino, carbocyclyl, carbocycloalkyl, heterocarbocyclyl, heterocarbocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl.
  • the terms “prevent” and “preventing” include the prevention of the recurrence, spread or onset. It is not intended that the present invention be limited to complete prevention. In some embodiments, the onset is delayed, or the severity of the disease is reduced.
  • the terms “treat” and “treating” are not limited to the case where the subject (e.g. patient) is cured and the disease is eradicated. Rather, embodiments, of the present invention also contemplate treatment that merely reduces symptoms, and/or delays disease progression.
  • salts refer to derivatives of the disclosed compounds where the parent compound is modified making acid or base salts thereof.
  • salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines, alkylamines, or dialkylamines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
  • the salts are conventional non-toxic pharmaceutically acceptable salts including the quaternary ammonium salts of the parent compound formed, and non-toxic inorganic or organic acids.
  • Preferred salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.
  • inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like
  • organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic,
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound that contains a basic or acidic moiety by conventional chemical methods.
  • such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred.
  • Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, the disclosure of which is hereby incorporated by reference.
  • Subject means any animal, preferably a human patient, livestock, or domestic pet.
  • Cancer refers any of various cellular diseases with malignant neoplasms characterized by the proliferation of cells. It is not intended that the diseased cells must actually invade surrounding tissue and metastasize to new body sites. Cancer can involve any tissue of the body and have many different forms in each body area. Within the context of certain embodiments, whether “cancer is reduced” may be identified by a variety of diagnostic manners known to one skill in the art including, but not limited to, observation the reduction in size or number of tumor masses or if an increase of apoptosis of cancer cells observed, e.g., if more than a 5% increase in apoptosis of cancer cells is observed for a sample compound compared to a control without the compound. It may also be identified by a change in relevant biomarker or gene expression profile, such as PSA for prostate cancer, her2 for breast cancer, or others.
  • compositions can take the form of solutions, suspensions, emulsion, tablets, pills, pellets, capsules, capsules containing liquids, powders, sustained-release formulations, suppositories, emulsions, aerosols, sprays, suspensions, or any other form suitable for use.
  • Administration may be topical, i.e., substance is applied directly where its action is desired, enteral or oral, i.e., substance is given via the digestive tract, parenteral, i.e., substance is given by other routes than the digestive tract such as by injection.
  • the active compound and optionally another therapeutic or prophylactic agent are formulated in accordance with routine procedures as pharmaceutical compositions adapted for intravenous administration to human beings.
  • the active compound for intravenous administration are solutions in sterile isotonic aqueous buffer.
  • the compositions can also include a solubilizing agent.
  • Compositions for intravenous administration can optionally include a local anesthetic such as lignocaine to ease pain at the site of the injection.
  • the ingredients are supplied either separately or mixed together in unit dosage form, for example, as a dry lyophilized powder or water free concentrate in a hermetically sealed container such as an ampoule.
  • the active compound is to be administered by infusion, it can be dispensed, for example, with an infusion bottle containing sterile pharmaceutical grade water or saline.
  • an ampoule of sterile water for injection or saline can be provided so that the ingredients can be mixed prior to administration.
  • compositions for oral delivery can be in the form of tablets, lozenges, aqueous or oily suspensions, granules, powders, emulsions, capsules, syrups, or elixirs, for example.
  • Orally administered compositions can contain one or more optional agents, for example, sweetening agents such as fructose, aspartame or saccharin; flavoring agents such as peppermint, oil of wintergreen, or cherry; coloring agents; and preserving agents, to provide a pharmaceutically palatable preparation.
  • a time delay material such as glycerol monostearate or glycerol stearate can also be used.
  • Oral compositions can include standard vehicles such as mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, and the like. Such vehicles are preferably of pharmaceutical grade.
  • compositions for use in accordance with the present invention can be formulated in conventional manner using one or more physiologically acceptable carriers or excipients.
  • the compound and optionally another therapeutic or prophylactic agent and their physiologically acceptable salts and solvates can be formulated into pharmaceutical compositions for administration by inhalation or insufflation (either through the mouth or the nose) or oral, parenteral or mucosol (such as buccal, vaginal, rectal, sublingual) administration.
  • parenteral or mucosol such as buccal, vaginal, rectal, sublingual
  • local or systemic parenteral administration is used.
  • compositions can take the form of, for example, tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g., pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g., lactose, microcrystalline cellulose or calcium hydrogen phosphate); lubricants (e.g., magnesium stearate, talc or silica); disintegrants (e.g., potato starch or sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulfate).
  • binding agents e.g., pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose
  • fillers e.g., lactose, microcrystalline cellulose or calcium hydrogen phosphate
  • lubricants e.g., magnesium stearate, talc or silica
  • disintegrants e.g., potato starch or
  • Liquid preparations for oral administration can take the form of, for example, solutions, syrups or suspensions, or they can be presented as a dry product for constitution with water or other suitable vehicle before use.
  • Such liquid preparations can be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, cellulose derivatives or hydrogenated edible fats); emulsifying agents (e.g., lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters, ethyl alcohol or fractionated vegetable oils); and preservatives (e.g., methyl or propyl-p-hydroxybenzoates or sorbic acid).
  • the preparations can also contain buffer salts, flavoring, coloring and sweetening agents as appropriate.
  • Example 6 The following examples were prepared by the procedure of Example 1, using the appropriate starting materials.
  • the following parent compounds obtained after chromatography may be converted to their corresponding hydrochloride salts using the procedure in Example 6, or a similar procedure.
  • Example 6 The following examples were prepared by the procedure of Example 6, using the appropriate starting materials.
  • the following parent compounds obtained after chromatography may be converted to their corresponding hydrochloride salt in a manner similar as described in example 6.
  • Example 33 The following examples were prepared by the procedure of Example 33, using the appropriate starting materials.
  • the following parent compounds obtained after chromatography (normal or reverse phase) may be converted to its corresponding hydrochloride salt as described in example 33, or similar procedure.
  • Example 85 The following examples were prepared by the procedure of Example 85, using the appropriate starting materials.
  • the following parent compounds obtained after chromatography may be converted to their corresponding hydrochloride salt in a manner similar as described in example 85, or similar procedure.
  • Example 123 The following examples were prepared by the procedure of Example 123, using the appropriate starting materials.
  • the following parent compounds obtained after chromatography may be converted to their corresponding hydrochloride salt in a manner similar as described in example 123.
  • Example 132 The following examples were prepared by the procedure of Example 132 using the appropriate starting materials.
  • PIM1 Universality of Dundee, Scotland
  • baculovirus system with a typical yield of >85% purity.
  • ATP Enzyme/Substrate/adenosine triphosphate
  • Stop mix consisting of 100 mM HEPES, 121 mM ethylenediamine tetraacetic acid, 0.8% Coatin Reagent 3 (Caliper, Mass.), and 0.01% Tween.
  • separation buffer consisting of 100 mM HEPES, 16 mM ethylenediamine tetraacetic acid, 0.1% Coatin Reagent 3 (Caliper, Mass.), 0.015% Brij-35, 5% DMSO, and 5.6 mM MgCl 2 .
  • PIM2 produced at AstraZeneca, R&D Boston
  • E. coli cells with a typical yield of >90% purity.
  • ATP Enzyme/Substrate/adenosine triphosphate
  • preferred compounds disclosed herein generally have an IC 50 for PIM1 of less that 5 micromolar (uM), and even more preferred of less than 1 micromolar.
  • uM 5 micromolar
  • the table 1 below provides the percent inhibition of PIM1 at 0.3 micromolar for Examples provided herein. Several examples were tested more than once. Variations in the experimental outcomes, negative values, or values over 100% inhibition are presumably due to experimental error inherent in the assay.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Hematology (AREA)
  • Oncology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Thiazole And Isothizaole Compounds (AREA)

Abstract

The invention relates to chemical compounds of formula I,
Figure US20150051185A1-20150219-C00001
and salts thereof. In some embodiments, the invention relates to inhibitors or modulators of PIM-1 and/or PIM-2, and/or PIM-3 protein kinase activity or enzyme function. In still further embodiments, the invention relates to pharmaceutical compositions comprising compounds disclosed herein, and their use in the prevention and treatment of PIM kinase related conditions and diseases, preferably cancer.

Description

  • This application is a continuation of U.S. application Ser. No. 13/000,138, issuing, filed on May 25, 2011, which claims the benefit under 35 U.S.C. §119(a)-(d) of International Application No. PCT/GB2009/050773, filed on Jul. 2, 2009, which claims the benefit of U.S. Application No. 61/183,278, filed Jun. 2, 2009 and U.S. Patent Application No. 61/077,639, filed Jul. 2, 2008. The contents of each of the foregoing applications are incorporated herein by reference in their entirety.
    • FIELD OF INVENTION
  • The invention relates to chemical compounds of formula I,
  • Figure US20150051185A1-20150219-C00002
  • and salts thereof. In some embodiments, the invention relates to inhibitors or modulators of PIM-1 and/or PIM-2, and/or PIM-3 protein kinase activity or enzyme function. In still further embodiments, the invention relates to pharmaceutical compositions comprising compounds disclosed herein, and their use in the prevention and treatment of PIM kinase related conditions and diseases, preferably cancer.
    • BACKGROUND
  • PIM-1 gene was first identified as a proviral insertion site in Moloney murine leukemia virus-induced T-cell lymphoma. PIM-1 gene translates a Ser/Thr protein kinase. The known PIM kinase family also includes PIM-2 and PIM-3. Mice studies suggest that physiologically the PIM kinases are involved in growth factor and cytokine signaling. Deregulated PIM kinase expression occurs a in large number of hematopoietic tumors, such as myeloid and lymphoblastic leukemias and lyphomas. PIM kinases are also expressed in solid tumors, such as prostate cancer and pancreatic cancer, and transgenic mice which express PIM-1 develop T-cell lymphoma. Dhanasekaran et al., (2001). Nature 412: 822-826 and Li et al., (2006) Cancer Res 66: 6741-6747. Accordingly, it is believed that PIM Kinase inhibitors will be useful in the treatment and/or prevention of cancer. Thus, there is a need to identify inhibitors of PIM kinases.
    • SUMMARY OF INVENTION
  • The invention relates to chemical compounds of formula I,
  • Figure US20150051185A1-20150219-C00003
  • and salts thereof. In some embodiments, the invention relates to inhibitors or modulators of PIM-1 and/or PIM-2, and/or PIM-3 protein kinase activity or enzyme function. In still further embodiments, the invention relates to pharmaceutical compositions comprising compounds disclosed herein, and their use in the prevention and treatment of PIM kinase related conditions and diseases, preferably cancer.
    • DETAILED DESCRIPTION
  • The invention relates to a method of treating or preventing cancer comprising,
  • a) providing a pharmaceutical composition comprising a compound of formula I,
  • Figure US20150051185A1-20150219-C00004
  • or pharmaceutically acceptable salts thereof, functioning to inhibit a PIM kinase, wherein
  • R1 is selected from a carbocyclyl, aryl, and heterocyclyl, wherein R1 is optionally substituted with one or more, the same or different, R2;
  • R2 is selected from C1-6alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, C1-6alkoxy, C1-6alkylthio, C1-6alkylamino, (C1-6alkyl)2amino, C1-6alkylsulfamoyl, arylsulfamoyl, carbocyclyl, aryl, and heterocyclyl, wherein R2 is optionally substituted with one or more, the same or different, R3;
  • R3 is selected from C1-6alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, C1-6alkoxy, C1-6alkylthio, C1-6alkylamino, (C1-6alkyl)2amino, C1-6alkylsulfinyl, C1-6alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, and heterocyclyl,
  • wherein R3 is optionally substituted with one or more, the same or different, R4;
  • R4 is selected from C1-6alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, C1-6alkoxy, C1-6alkylthio, C1-6alkylamino, (C1-6alkyl)2amino, C1-6alkylsulfinyl, C1-6alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, and heterocyclyl, wherein R4 is optionally substituted with one or more, the same or different, R5; and
  • R5 is selected from halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, and heterocyclyl; and
  • b) administering said pharmaceutical composition to a subject diagnosed with, exhibiting symptoms of, or at risk for cancer with the proviso that said compound of formula I is not 5-[[2-[(2,6-dichloro-3-methylphenyl)amino]phenyl]methylene]-2,4-thiazolidinedione.
  • In some embodiments, the invention relates to a method of treating or preventing cancer comprising,
  • a) providing a pharmaceutical composition comprising a compound of formula I,
  • Figure US20150051185A1-20150219-C00005
  • or salts thereof, functioning to inhibit a PIM kinase, wherein
  • R1 is selected from a carbocyclyl, aryl, and heterocyclyl, wherein R1 is optionally substituted with one or more, the same or different, R2;
  • R2 is selected from halogen, C1-6alkyl, halogenated C1-6alkyl, amino, C1-6alkylamino, (C1-6alkyl)2amino, and heterocyclyl, wherein R2 is optionally substituted with one or more, the same or different, R3;
  • R3 is selected from C1-6alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, C1-6alkoxy, C1-6alkylthio, C1-6alkylamino, (C1-6alkyl)2amino, C1-6alkylsulfinyl, C1-6alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, and heterocyclyl, wherein R3 is optionally substituted with one or more, the same or different, R4;
  • R4 is selected from C1-6alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, C1-6alkoxy, C1-6alkylthio, C1-6alkylamino, (C1-6alkyl)2amino, C1-6alkylsulfinyl, C1-6alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, and heterocyclyl, wherein R4 is optionally substituted with one or more, the same or different, R5; and
  • R5 is selected from halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, and heterocyclyl; and
  • b) administering said pharmaceutical composition to a subject diagnosed with, exhibiting symptoms of, or at risk for cancer under conditions such that cancer is reduced or prevented.
  • In further embodiments, the invention relates to a method of treating cancer comprising administering to a subject in need thereof a pharmaceutical composition comprising a compound of the formula disclosed herein, wherein said cancer is selected from a leukemia, lymphoma, prostate cancer, pancreatic cancer or other solid tumors.
  • In further embodiments, the invention relates to a compound of formula IA,
  • Figure US20150051185A1-20150219-C00006
  • or salts thereof, wherein,
  • --- is individually at each occurrence selected from a single and double bond;
  • n is selected from 0, 1, or 2;
  • m is selected from 0, 1, or 2;
  • A is selected from N and CR7;
  • X is selected from O, S, CHR10 and NR11;
  • Y is selected from N, CH, and C;
  • R5, R6, and R7 are each individually and independently from hydrogen, C1-6alkyl, halogen, cyano, nitro, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, C1-6alkoxy, C1-6alkylthio, C1-6alkylamino, (C1-6alkyl)2amino, carbocyclyl, aryl, and heterocyclyl, wherein R5, R6, and R7 are each optionally substituted with one or more, the same or different, R12;
  • R8 and R9 are each individually and independently selected from hydrogen, amino, hydroxyl, mercapto, C1-6alkyl, C1-6alkylamino, carbocyclyl, aryl, and heterocyclyl wherein R8 and R9 are each optionally substituted with one or more, the same or different, R15;
  • R10 is selected from hydrogen, C1-6alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, C1-6alkoxy, C1-6alkylthio, C1-6alkylamino, (C1-6alkyl)2amino, C1-6alkylsulfamoyl, arylsulfamoyl, carbocyclyl, aryl, and heterocyclyl, wherein R10 is optionally substituted with one or more, the same or different, R12;
  • R11 is selected from hydrogen, formyl, C1-6alkyl, C1-6alkanoyl, C1-6alkylsulfinyl, C1-6alkylsulfonyl, arylsulfonyl, C1-6alkoxycarbonyl, carbocyclyl, aryl, and heterocyclyl, wherein R11 is optionally substituted with one or more, the same or different, R12;
  • R12 is selected from halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, and heterocyclyl, wherein R12 is optionally substituted with one or more, the same or different, R16;
  • R15 is selected from C1-6alkyl, C1-6alkanoyl, C1-6alkylsulfinyl, C1-6alkylsulfonyl, arylsulfonyl, and C1-6alkoxycarbonyl wherein R15 is optionally substituted with one or more, the same or different, R12;
  • R16 is selected from halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, aminomethyl, aminoethyl, aminopropyl, aminobutyl, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, and N-methyl-N-ethylsulfamoyl; and
  • provided that R5, R6, and R7 are not all hydrogen and
  • provided the compound is not 5-((5-nitro-2-(1-piperidinyl)phenyl)methylene)-2,4-thiazolidinedione or 5-((2-(4-morpholinyl)-5-nitrophenyl)methylene)-2,4-thiazolidinedione.
  • In some embodiments, the invention relates to a compound of formula ID,
  • Figure US20150051185A1-20150219-C00007
  • or salts thereof, wherein,
  • n is selected from 0, 1, or 2;
  • A is selected from N and CR7;
  • X is selected from O, S, CHR10 and NR11;
  • R5, R6, and R7 are each individually and independently from hydrogen, C1-6alkyl, halogen, cyano, nitro, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, C1-6alkoxy, C1-6alkylthio, C1-6alkylamino, (C1-6alkyl)2amino, carbocyclyl, aryl, and heterocyclyl, wherein R5, R6, and R7 are each optionally substituted with one or more, the same or different, R12;
  • R8 and R9 are each individually and independently selected from hydrogen, amino, hydroxyl, mercapto, C1-6alkyl, C1-6alkylamino, carbocyclyl, aryl, and heterocyclyl wherein R8 and R9 are each optionally substituted with one or more, the same or different, R15;
  • R10 is selected from hydrogen, C1-6alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, C1-6alkoxy, C1-6alkylthio, C1-6alkylamino, (C1-6alkyl)2amino, C1-6alkylsulfamoyl, arylsulfamoyl, carbocyclyl, aryl, and heterocyclyl, wherein R10 is optionally substituted with one or more, the same or different, R12;
  • R11 is selected from hydrogen, formyl, C1-6alkyl, C1-6alkanoyl, C1-6alkylsulfinyl, C1-6alkylsulfonyl, arylsulfonyl, C1-6alkoxycarbonyl, carbocyclyl, aryl, and heterocyclyl, wherein R11 is optionally substituted with one or more, the same or different, R12;
  • R12 is selected from halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, and heterocyclyl, wherein R12 is optionally substituted with one or more, the same or different, R16;
  • R15 is selected from C1-6alkyl, C1-6alkanoyl, C1-6alkylsulfinyl, C1-6alkylsulfonyl, arylsulfonyl, and C1-6alkoxycarbonyl wherein R15 is optionally substituted with one or more, the same or different, R12;
  • R16 is selected from halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, aminomethyl, aminoethyl, aminopropyl, aminobutyl, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, and N-methyl-N-ethylsulfamoyl.
  • In some embodiments with regard to any of the compound formula provided herein, R5, R6, and R7 are not all hydrogen.
  • In some embodiments with regard to any of the compound formula provided herein, R5, R6, and R7 are not 5-((5-nitro-2-(1-piperidinyl)phenyl)methylene)-2,4-thiazolidinedione or 5-((2-(4-morpholinyl)-5-nitrophenyl)methylene)-2,4-thiazolidinedione.
  • In some embodiments, the invention relates to a compound of formula IB,
  • Figure US20150051185A1-20150219-C00008
  • or salts thereof, wherein,
  • n is selected from 0, 1, or 2;
  • X is selected from O, CHR10 and NR11;
  • R5, R6, and R7 are each individually and independently from hydrogen, halogen, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, and N-methyl-N-ethylsulfamoyl;
  • R8 and R9 are each individually and independently selected from hydrogen, amino, C1-6alkyl, C1-6alkylamino, wherein R8 and R9 are each optionally substituted with one or more, the same or different, R15;
  • R10 is selected from hydrogen, C1-6alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, C1-6alkoxy, C1-6alkylthio, C1-6alkylamino, (C1-6alkyl)2amino, C1-6alkylsulfamoyl, arylsulfamoyl, carbocyclyl, aryl, and heterocyclyl, wherein R10 is optionally substituted with one or more, the same or different, R12;
  • R11 is selected from hydrogen, C1-6alkyl, C1-6alkanoyl, C1-6alkylsulfinyl, C1-6alkylsulfonyl, arylsulfonyl, C1-6alkoxycarbonyl, carbocyclyl, aryl, and heterocyclyl, wherein R11 is optionally substituted with one or more, the same or different, R12;
  • R12 is selected from halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, and heterocyclyl, wherein R12 is optionally substituted with one or more, the same or different, R16;
  • R15 is selected from C1-6alkyl, C1-6alkanoyl, C1-6alkylsulfinyl, C1-6alkylsulfonyl, arylsulfonyl, and C1-6alkoxycarbonyl wherein R15 is optionally substituted with one or more, the same or different, R12;
  • R16 is selected from halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, and N-methyl-N-ethylsulfamoyl.
  • In some embodiments, with regard to any of the compound formula provided herein, said compound is not, 5-[[2-(4-methyl-1-piperazinyl)phenyl]methylene]-2,4-thiazolidinedione or 5-[[2-[(2,6-dichloro-3-methylphenyl)amino]phenyl]methylene]-2,4-thiazolidinedione.
  • In further embodiments, the invention relates to a compound of formula IC,
  • Figure US20150051185A1-20150219-C00009
  • or salts thereof, wherein,
  • n is selected from 0, 1, 2, 3, 4, 5, 6, 7 or 8;
  • X is selected from O, S, CHR10 and NR11;
  • Y is selected from O, S, and NR13;
  • R5, R6, and R7 are each individually and independently from C1-6alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, C1-6alkoxy, C1-6alkylthio, C1-6alkylamino, C1-6dialkylamino, carbocyclyl, aryl, and heterocyclyl, wherein R5, R6, and R7 are each optionally substituted with one or more, the same or different, R12;
  • R10 is selected from hydrogen, C1-6alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, C1-6alkoxy, C1-6alkylthio, C1-6alkylamino, (C1-6alkyl)2amino, C1-6alkylsulfamoyl, arylsulfamoyl, carbocyclyl, aryl, and heterocyclyl, wherein R10 is optionally substituted with one or more, the same or different, R12;
  • R11, R13, and R14 are each individually and independently selected from hydrogen, C1-6alkyl, C1-6alkanoyl, C1-6alkylsulfinyl, C1-6alkylsulfonyl, arylsulfonyl, and C1-6alkoxycarbonyl wherein R11 is optionally substituted with one or more, the same or different, R12;
  • or R11 and R14, taken together with the atoms to which they are attached form a five, six, or seven membered heterocyclic ring optionally substituted with one or more, the same or different, R12;
  • R12 is selected from halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, and heterocyclyl.
  • In some embodiments with regard to any of the compound formula provided herein, Y is NR13, wherein R13 is a C1-6alkyl.
  • In some embodiments with regard to any of the compound formula provided herein, R5 is a halogenated C1-6alkyl.
  • In some embodiments with regard to any of the compound formula provided herein, R7 is a halogen.
  • In some embodiments, the invention relates to a compound of formula IX,
  • Figure US20150051185A1-20150219-C00010
  • or salts thereof, wherein
  • R5 is selected from hydrogen, C1-6alkoxy, carbamoyl, and halogenated C1-6alkyl;
  • R6 is selected from hydrogen, halogen, C1-6alkoxy, and 2-(1-piperidyl)ethoxy;
  • R7 is selected from hydrogen, halogen, and C1-6alkoxy;
  • R17 is a heterocarbocylcyl, wherein R17 is optionally substituted with one or more, the same or different, R18;
  • R18 is selected from halogen, formyl, amino, C1-6alkyl, C1-6alkylamino, (C1-6alkyl)2amino, carbocyclyl, aryl, heterocyclyl, wherein R18 is optionally substituted with one or more, the same or different, R19;
  • R19 is selected from amino, C1-6alkyl, hydroxy, carbocyclyl, and heterocyclyl wherein R19 is optionally substituted with one or more, the same or different, R20; and
  • R20 is selected from amino, C1-6alkyl, and halogen.
  • In further embodiments, R17 is selected from (3R)-3-aminopyrrolidin-1-yl, (3R)-3-dimethylaminopyrrolidin-1-yl, (3S)-3-(3-aminopropylamino)pyrrolidin-1-yl, (3S)-3-(5-aminopentanoylamino)pyrrolidin-1-yl, (3S)-3-amino-1-piperidyl, (3S)-3-aminopyrrolidin-1-yl, (3S)-3-dimethylaminopyrrolidin-1-yl, (3S,5R)-3,5-dimethylpiperazin-1-yl, 1,4-diazepan-1-yl, 2-(1-piperidyl)ethoxy, 2-diethylaminoethoxy, 2-dimethylaminoethyl-methyl-amino, 2-hydroxyethoxy, 2-morpholinoethoxy, 3-(2-aminoethylamino)pyrrolidin-1-yl, 3-(2-hydroxyethylamino)pyrrolidin-1-yl, 3-(2-methylaminoethylamino)pyrrolidin-1-yl, 3-(3-aminopropanoylamino)pyrrolidin-1-yl, 3-(3-aminopropylamino)pyrrolidin-1-yl, 3-(3-methyl-1,2,4-oxadiazol-5-yl)-1-piperidyl, 3-(aminomethyl)-1-piperidyl, 3-(aminomethyl)pyrrolidin-1-yl, 3-acetamidopyrrolidin-1-yl, 3-aminopyrrolidin-1-yl, 3-dimethylaminopropoxy, 3-dimethylaminopropyl-methyl-amino, 3-dimethylaminopyrrolidin-1-yl, 3-hydroxypyrrolidin-1-yl, 3-pyridyl, 4-(1-methyl-4-piperidyl)piperazin-1-yl, 4-(1-piperidyl)-1-piperidyl, 4-(2-aminoethyl)piperazin-1-yl, 4-(2-hydroxyethyl)-1,4-diazepan-1-yl, 4-(2-hydroxyethyl)-1-piperidyl, 4-(2-hydroxyethyl)piperazin-1-yl, 4-(2-methylaminoethyl)piperazin-1-yl, 4-(2-morpholinoethyl)piperazin-1-yl, 4-(3-aminopropanoyl)-1,4-diazepan-1-yl, 4-(3-aminopropanoyl)piperazin-1-yl, 4-(3-aminopropyl)piperazin-1-yl, 4-(3-hydroxypropyl)piperazin-1-yl, 4-(3-methyl-1,2,4-oxadiazol-5-yl)-1-piperidyl, 4-(4-aminobutanoyl)-1,4-diazepan-1-yl, 4-(4-aminobutanoyl)piperazin-1-yl, 4-(4-chloro-2-fluoro-phenyl)piperazin-1-yl, 4-(4-fluorophenyl)piperazin-1-yl, 4-(4-pyridylmethyl)piperazin-1-yl, 445-aminopentanoyl)-1,4-diazepan-1-yl, 4-(5-aminopentanoyl)piperazin-1-yl, 4-(azetidine-3-carbonyl)piperazin-1-yl, 4-(benzo[1,3]dioxol-5-ylmethyl)piperazin-1-yl, 4-(cyclopropylmethyl)piperazin-1-yl, 4-(hydroxymethyl)-1-piperidyl, 4-(piperidine-3-carbonyl)-1,4-diazepan-1-yl, 4-(piperidine-3-carbonyl)piperazin-1-yl, 4-(piperidine-4-carbonyl)piperazin-1-yl, 4-[(2-chlorophenyl)methyl]piperazin-1-yl, 4-[3-(aminomethyl)benzoyl]piperazin-1-yl, 4-[4-(piperazin-1-ylmethyl)benzoyl]piperazin-1-yl, 4-acetylpiperazin-1-yl, 4-amino-1-piperidyl, 4-butyl-1,4-diazepan-1-yl, 4-cyclopentylpiperazin-1-yl, 4-dimethylamino-1-piperidyl, 4-hydroxy-1-piperidyl, 4-isobutylpiperazin-1-yl, 4-isopropylpiperazin-1-yl, 4-methylpiperazin-1-yl, 4-morpholino-1-piperidyl, 4-pyridyl, 4-pyrrolidin-1-yl-1-piperidyl, 4-tert-butoxycarbonylpiperazin-1-yl, 4-tert-butylpiperazin-1-yl, morpholino, piperazin-1-yl, and pyrrolidin-1-yl.
  • In further embodiments, the invention relates to a compound selected from:
    • 5-({2-[(3S)-3-aminopiperidin-1-yl]-3-chloro-5-(trifluoromethyl)phenyl}methylidene)-1,3-thiazolidine-2,4-dione;
    • 5-({2-[(3R)-3-aminopiperidin-1-yl]-3-chloro-5-(trifluoromethyl)phenyl}methylidene)-1,3-thiazolidine-2,4-dione;
    • 5-{[2-(4-aminopiperidin-1-yl)-3-chloro-5-(trifluoromethyl)phenyl]methylidene}-1,3-thiazolidine-2,4-dione;
    • 5-({2-[3-(aminomethyl)piperidin-1-yl]-3-chloro-5-(trifluoromethyl)phenyl}methylidene)-1,3-thiazolidine-2,4-dione;
    • 5-{[3-chloro-2-(1,4-diazepan-1-yl)-5-(trifluoromethyl)phenyl]methylidene}-1,3-thiazolidine-2,4-dione;
    • 5-{[3-chloro-2-(4-cyclopentylpiperazin-1-yl)-5-(trifluoromethyl)phenyl]methylidene}-1,3-thiazolidine-2,4-dione;
    • 5-({3-chloro-2-[4-(4-fluorophenyl)piperazin-1-yl]-5-(trifluoromethyl)phenyl}methylidene)-1,3-thiazolidine-2,4-dione;
    • 5-({2-[4-(1,3-benzodioxol-5-ylmethyl)piperazin-1-yl]-3-chloro-5-(trifluoromethyl)phenyl}methylidene)-1,3-thiazolidine-2,4-dione;
    • 5-({3-chloro-2-[4-(3-methyl-1,2,4-oxadiazol-5-yl)piperidin-1-yl]-5-(trifluoromethyl)phenyl}methylidene)-1,3-thiazolidine-2,4-dione;
    • 5-{[3-chloro-2-(4-pyrrolidin-1-ylpiperidin-1-yl)-5-(trifluoromethyl)phenyl]methylidene}-1,3-thiazolidine-2,4-dione;
    • 5-({3-chloro-2-[4-(1-methylethyl)piperazin-1-yl]-5-(trifluoromethyl)phenyl}methylidene)-1,3-thiazolidine-2,4-dione;
    • 5-({3-chloro-2-[4-(2-methylpropyl)piperazin-1-yl]-5-(trifluoromethyl)phenyl}methylidene)-1,3-thiazolidine-2,4-dione;
    • 5-({3-chloro-2-[4-(2-hydroxyethyl)piperidin-1-yl]-5-(trifluoromethyl)phenyl}methylidene)-1,3-thiazolidine-2,4-dione;
    • 5-({3-chloro-2-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]-5-(trifluoromethyl)phenyl}methylidene)-1,3-thiazolidine-2,4-dione;
    • 5-({3-chloro-2-[4-(4-chloro-2-fluorophenyl)piperazin-1-yl]-5-(trifluoromethyl)phenyl}methylidene)-1,3-thiazolidine-2,4-dione;
    • 5-({3-chloro-2-[3-(3-methyl-1,2,4-oxadiazol-5-yl)piperidin-1-yl]-5-(trifluoromethyl)phenyl}methylidene)-1,3-thiazolidine-2,4-dione;
    • 5-({3-chloro-2-[4-(pyridin-4-ylmethyl)piperazin-1-yl]-5-(trifluoromethyl)phenyl}methylidene)-1,3-thiazolidine-2,4-dione;
    • 5-({3-chloro-2-[4-(2-chlorobenzyl)piperazin-1-yl]-5-(trifluoromethyl)phenyl}methylidene)-1,3-thiazolidine-2,4-dione;
    • 5-({3-chloro-2-[4-(1-methylpiperidin-4-yl)piperazin-1-yl]-5-(trifluoromethyl)phenyl}methylidene)-1,3-thiazolidine-2,4-dione;
    • 5-({3-chloro-2-[4-(2-morpholin-4-ylethyl)piperazin-1-yl]-5-(trifluoromethyl)phenyl}methylidene)-1,3-thiazolidine-2,4-dione;
    • 5-({3-chloro-2-[4-(cyclopropylmethyl)piperazin-1-yl]-5-(trifluoromethyl)phenyl}methylidene)-1,3-thiazolidine-2,4-dione;
    • 5-{[3-chloro-2-(4-morpholin-4-ylpiperidin-1-yl)-5-(trifluoromethyl)phenyl]methylidene}-1,3-thiazolidine-2,4-dione;
    • 5-({3-chloro-2-[4-(3-hydroxypropyl)piperazin-1-yl]-5-(trifluoromethyl)phenyl}methylidene)-1,3-thiazolidine-2,4-dione;
    • 5-({3-chloro-2-[4-(dimethylamino)piperidin-1-yl]-5-(trifluoromethyl)phenyl}methylidene)-1,3-thiazolidine-2,4-dione;
    • 5-{[3-chloro-2-{[3-(dimethylamino)propyl](methyl)amino}-5-(trifluoromethyl)phenyl]methylidene}-1,3-thiazolidine-2,4-dione;
    • 5-({3-chloro-2-[4-(2-hydroxyethyl)-1,4-diazepan-1-yl]-5-(trifluoromethyl)phenyl}methylidene)-1,3-thiazolidine-2,4-dione;
    • 5-{[2-(4-butyl-1,4-diazepan-1-yl)-3-chloro-5-(trifluoromethyl)phenyl]methylidene}-1,3-thiazolidine-2,4-dione;
    • 5-({3-chloro-2-[4-(2-hydroxyethyl)piperazin-1-yl]-5-(trifluoromethyl)phenyl}methylidene)-1,3-thiazolidine-2,4-dione;
    • 5-{[3-chloro-2-morpholin-4-yl-5-(trifluoromethyl)phenyl]methylidene}-1,3-thiazolidine-2,4-dione;
    • 5-{[2-(4-tert-butylpiperazin-1-yl)-3-chloro-5-(trifluoromethyl)phenyl]methylidene}-1,3-thiazolidine-2,4-dione;
    • 5-{[2-(1,4′-bipiperidin-1′-yl)-3-chloro-5-(trifluoromethyl)phenyl]methylidene}-1,3-thiazolidine-2,4-dione;
    • 5-{[3-chloro-2-(4-methylpiperazin-1-yl)-5-(trifluoromethyl)phenyl]methylidene}-1,3-thiazolidine-2,4-dione;
    • 5-({3-bromo-2-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]phenyl}methylidene)-1,3-thiazolidine-2,4-dione; and
    • 5-({2-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-5-(trifluoromethyl)phenyl}methylidene)-1,3-thiazolidine-2,4-dione;
    • (5Z)-5-({2-[(3S)-3-aminopyrrolidin-1-yl]-3-chloro-5-(trifluoromethyl)phenyl}methylidene)-1,3-thiazolidine-2,4-dione,
    • (5Z)-5-({3-[3-(4-methylpiperazin-1-yl)propoxy]phenyl}methylidene)-1,3-thiazolidine-2,4-dione;
    • 2-{3-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]phenoxy}acetamide;
    • (5Z)-5-{[3-(3-piperidin-1-ylpropoxy)phenyl]methylidene}-1,3-thiazolidine-2,4-dione;
    • (5Z)-5-({3-[(4-methylpiperazin-1-yl)methyl]phenyl}methylidene)-1,3-thiazolidine-2,4-dione;
    • N-[2-(dimethylamino)ethyl]-2′-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]-N-methylbiphenyl-4-sulfonamide;
    • 5-({2-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]-5-methoxyphenyl}methylidene)-1,3-thiazolidine-2,4-dione;
    • 5-({2-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]-5-(trifluoromethyl)phenyl}methylidene)-1,3-thiazolidine-2,4-dione;
    • 5-({5-chloro-2-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]phenyl}methylidene)-1,3-thiazolidine-2,4-dione;
    • 5-({2-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]-4-methylphenyl}methylidene)-1,3-thiazolidine-2,4-dione;
    • 5-({2-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]-5-fluorophenyl}methylidene)-1,3-thiazolidine-2,4-dione;
    • 5-({2-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]-5-methylphenyl}methylidene)-1,3-thiazolidine-2,4-dione;
    • 5-({5-bromo-2-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]phenyl}methylidene)-1,3-thiazolidine-2,4-dione;
    • 5-({2-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]-3-fluorophenyl}methylidene)-1,3-thiazolidine-2,4-dione;
    • 5-({2-chloro-6-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]phenyl}methylidene)-1,3-thiazolidine-2,4-dione;
    • (5Z)-5-({2-[(3R)-3-(aminomethyl)pyrrolidin-1-yl]-3-chlorophenyl}methylidene)-1,3-thiazolidine-2,4-dione;
    • (5Z)-5-({2-[(3S)-3-(aminomethyl)pyrrolidin-1-yl]-3-chlorophenyl}methylidene)-1,3-thiazolidine-2,4-dione;
    • (5Z)-5-({2-[(3R)-3-aminopiperidin-1-yl]-3-chlorophenyl}methylidene)-1,3-thiazolidine-2,4-dione;
    • (5Z)-5-({2-[(3R)-3-aminopiperidin-1-yl]-3-methoxyphenyl}methylidene)-1,3-thiazolidine-2,4-dione;
    • (5Z)-5-({2-[(3R)-3-aminopiperidin-1-yl]-3-bromophenyl}methylidene)-1,3-thiazolidine-2,4-dione;
    • (5Z)-5-({2-[(3R)-3-aminopyrrolidin-1-yl]-3-chlorophenyl}methylidene)-1,3-thiazolidine-2,4-dione;
    • (5Z)-5-({2-[(3S)-3-aminopyrrolidin-1-yl]-3-bromophenyl}methylidene)-1,3-thiazolidine-2,4-dione;
    • (5Z)-5-({2-[(3R)-3-aminopiperidin-1-yl]-3-ethoxyphenyl}methylidene)-1,3-thiazolidine-2,4-dione;
    • (5Z)-5-({2-[(3R)-3-aminopiperidin-1-yl]-3-(2-methylpropoxy)phenyl}methylidene)-1,3-thiazolidine-2,4-dione;
    • (5Z)-5-({2-[(3R)-3-aminopiperidin-1-yl]-3-(cyclohexylmethoxy)phenyl}methylidene)-1,3-thiazolidine-2,4-dione;
    • (5Z)-5-({2-[(3R)-3-aminopiperidin-1-yl]-3-(cyclohexyloxy)phenyl}methylidene)-1,3-thiazolidine-2,4-dione;
    • (5Z)-5-({2-[(3R,4R)-3-amino-4-hydroxypiperidin-1-yl]-3-chlorophenyl}methylidene)-1,3-thiazolidine-2,4-dione;
    • (5Z)-5-{[3-chloro-2-(1,4-diazepan-1-yl)phenyl]methylidene}-1,3-thiazolidine-2,4-dione;
    • (5Z)-5-({2-[(3R)-3-aminopiperidin-1-yl]-3-(1-methylethoxy)phenyl}methylidene)-1,3-thiazolidine-2,4-dione;
    • (5Z)-5-({2-[(3S)-3-aminopyrrolidin-1-yl]-3-(1-methylethoxy)phenyl}methylidene)-1,3-thiazolidine-2,4-dione;
    • (5Z)-5-({2-[(3S)-3-aminopyrrolidin-1-yl]-3-ethoxyphenyl}methylidene)-1,3-thiazolidine-2,4-dione;
    • (5Z)-5-({2-[(3R)-3-{[4-(aminomethyl)benzyl]amino}piperidin-1-yl]-3-chlorophenyl}methylidene)-1,3-thiazolidine-2,4-dione;
    • (5Z)-5-({3-chloro-2-[(3R)-3-{[2-(methylamino)ethyl]amino}piperidin-1-yl]phenyl}methylidene)-1,3-thiazolidine-2,4-dione;
    • (5Z)-5-({2-[(3S,4S)-3-amino-4-hydroxypyrrolidin-1-yl]-3-chlorophenyl}methylidene)-1,3-thiazolidine-2,4-dione;
    • (5Z)-5-({3-chloro-2-[4-methyl-3-(methylamino)piperidin-1-yl]phenyl}methylidene)-1,3-thiazolidine-2,4-dione;
    • (5Z)-5-{[2-(3-amino-4-methylpiperidin-1-yl)-3-chlorophenyl]methylidene}-1,3-thiazolidine-2,4-dione;
    • (5Z)-5-({2-[(3R)-3-aminopiperidin-1-yl]phenyl}methylidene)-1,3-thiazolidine-2,4-dione;
    • (5Z)-5-({2-[(3S)-3-aminopyrrolidin-1-yl]phenyl}methylidene)-1,3-thiazolidine-2,4-dione;
    • (5Z)-5-({2-[(3R)-3-aminopiperidin-1-yl]-3-(2,2,2-trifluoroethoxy)phenyl}methylidene)-1,3-thiazolidine-2,4-dione;
    • (5Z)-5-({2-[(3S)-3-aminopyrrolidin-1-yl]-3-(2,2,2-trifluoroethoxy)phenyl}methylidene)-1,3-thiazolidine-2,4-dione;
    • (5Z)-5-({2-[(3R)-3-aminopiperidin-1-yl]-3-(2-methoxyethoxy)phenyl}methylidene)-1,3-thiazolidine-2,4-dione;
    • (5Z)-5-({2-[(3S)-3-aminopyrrolidin-1-yl]-3-(2-methoxyethoxy)phenyl}methylidene)-1,3-thiazolidine-2,4-dione;
    • (5Z)-5-({2-[(3R)-3-aminopiperidin-1-yl]-3-(cyclopentyloxy)phenyl}methylidene)-1,3-thiazolidine-2,4-dione;
    • (5Z)-5-({2-[(3R)-3-aminopiperidin-1-yl]-3-(cyclobutyloxy)phenyl}methylidene)-1,3-thiazolidine-2,4-dione;
    • 4-[(3R)-3-aminopiperidin-1-yl]-3-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]benzamide;
    • 4-[(3S)-3-aminopiperidin-1-yl]-3-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]benzamide;
    • 4-[(3R)-3-aminopiperidin-1-yl]-3-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]benzoic acid;
    • 4-[(3S)-3-aminopyrrolidin-1-yl]-3-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]benzoic acid;
    • (5Z)-5-({2-[(3R)-3-aminopiperidin-1-yl]biphenyl-3-yl}methylidene)-1,3-thiazolidine-2,4-dione;
    • 5-{[2-(3-aminopropoxy)-5-methoxyphenyl]methylidene}-1,3-thiazolidine-2,4-dione;
    • N-{4-[3-(dimethylamino)pyrrolidin-1-yl]-3-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]phenyl}acetamide;
    • (5Z)-5-[(3-chloro-2-{(3R)-3-[(2-hydroxyethyl)amino]piperidin-1-yl}phenyl)methylidene]-1,3-thiazolidine-2,4-dione;
    • (5Z)-5-[(3-chloro-2-{(3R)-3-[(3-hydroxypropyl)amino]piperidin-1-yl}phenyl)methylidene]-1,3-thiazolidine-2,4-dione;
    • N-[(3S)-1-{2-chloro-6-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]phenyl}pyrrolidin-3-yl]-1-methyl-1H-imidazole-2-carboxamide;
    • N-[(3S)-1-{2-chloro-6-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]phenyl}pyrrolidin-3-yl]-2-methoxyacetamide;
    • N-[(3S)-1-{2-chloro-6-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]phenyl}pyrrolidin-3-yl]-1-methyl-1H-pyrazole-3-carboxamide;
    • N2-carbamoyl-N-[(3S)-1-{2-chloro-6-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]phenyl}pyrrolidin-3-yl]glycinamide;
    • N-[(3S)-1-{2-chloro-6-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]phenyl}pyrrolidin-3-yl]-2-pyridin-3-ylacetamide;
    • N-[(3S)-1-{2-chloro-6-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]phenyl}pyrrolidin-3-yl]-2-pyridin-4-ylacetamide;
    • N-[(3S)-1-{2-chloro-6-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]phenyl}pyrrolidin-3-yl]-1-methyl-1H-pyrazole-4-carboxamide;
    • N-[(3S)-1-{2-chloro-6-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]phenyl}pyrrolidin-3-yl]-2-(1-oxidothiomorpholin-4-yl)acetamide;
    • N-[(3S)-1-{2-chloro-6-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]phenyl}pyrrolidin-3-yl]-4-sulfamoylbutanamide;
    • N′-[(3S)-1-{2-chloro-6-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]phenyl}pyrrolidin-3-yl]-N,N-dimethylbutanediamide;
    • N-[(3S)-1-{2-chloro-6-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]phenyl}pyrrolidin-3-yl]-N˜2˜,N˜2˜-dimethylglycinamide;
    • N-[(3S)-1-{2-chloro-6-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]phenyl}pyrrolidin-3-yl]-2-cyanoacetamide;
    • N2-acetyl-N-[(3S)-1-{2-chloro-6-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]phenyl}pyrrolidin-3-yl]glycinamide;
    • (5Z)-5-({3-chloro-2-[(3R)-3-(dipropylamino)piperidin-1-yl]phenyl}methylidene)-1,3-thiazolidine-2,4-dione;
    • (5Z)-5-[(3-chloro-2-{(3R)-3-[(3,3,3-trifluoropropyl)amino]piperidin-1-yl}phenyl)methylidene]-1,3-thiazolidine-2,4-dione;
    • 5-[(5-methoxy-2-{3-[(1-methylethyl)amino]propoxy}phenyl)methylidene]-1,3-thiazolidine-2,4-dione;
    • (5Z)-5-({5-amino-2-[3-(dimethylamino)pyrrolidin-1-yl]phenyl}methylidene)-1,3-thiazolidine-2,4-dione; and
    • 5-[(2-amino-4,5-dimethoxyphenyl)methylidene]-1,3-thiazolidine-2,4-dione,
  • or salts thereof.
  • In some embodiments, the invention relates to any of the compounds disclosed herein that are in the (Z) isomer.
  • In some embodiments, the invention relates to any of the compounds disclosed herein that are in the (E) isomer.
  • In some embodiments, the invention relates to compositions comprising a mixture of the (Z) and (E) isomers.
  • In some embodiments, the invention relates to a pharmaceutical composition comprising a substituted 5-(3-halo-2-[piperidin-1-yl]phenylmethylidene)-1,3-thiazolidine-2,4-dione functioning to inhibit a PIM kinase.
  • In further embodiments, the invention relates to a pharmaceutical composition comprising a compound of formula I, IA, IB, IC, ID, or IX or a pharmaceutically acceptable salt thereof.
  • In further embodiments, the invention relates to a method of inhibiting a PIM kinase comprising, providing a compound of formula I, IA, IB, IC, ID, or IX, as defined herein, and mixing a PIM kinase and said compound under conditions such that PIM kinase phosphorylation is inhibited.
  • In further embodiments, said method is an in vitro method.
  • In further embodiments, said method is an in vivo method.
  • In further embodiments, the invention relates to a method of inhibiting a PIM kinase in a subject comprising administering to the subject a therapeutically effective amount of a compound of any of the formula disclosed herein or a pharmaceutically acceptable salt thereof.
  • In further embodiments, said PIM kinase is selected from PIM-1, PIM-2, and PIM-3.
  • In further embodiments, the invention relates to the use of a compound of the formula I, IA, IB, IC, ID, or IX, or a pharmaceutically acceptable salt thereof, as defined herein, for the manufacture of a medicament for the production of a PIM kinase inhibitory effect in a subject.
  • In further embodiments, the invention relates to the use of a compound of the formula I, IA, IB, IC, ID, or IX, or a pharmaceutically acceptable salt thereof, as disclosed herein, for the manufacture of a medicament for the production of an anti-cancer effect in a subject.
  • In some embodiments, the invention relates to a method of making a compound of formula IA as defined herein,
  • Figure US20150051185A1-20150219-C00011
  • or salt thereof, comprising
  • a) mixing a compound of formula XI,
  • Figure US20150051185A1-20150219-C00012
      • or salt thereof, wherein E is a halogen, and R5, R6, and A are defined herein, with a compound of formula XII,
  • Figure US20150051185A1-20150219-C00013
  • or salt thereof, wherein
      • ---, R8, R9, n, m, Y and X are defined herein,
      • if Y is N, then R21 is hydrogen,
      • if Y is C, then R21 is selected from boronic acid and a boronic ester, and
      • if Y is CH, then R21 is selected from a metal halide,
  • under conditions such that composition comprising a compound of formula XIII,
  • Figure US20150051185A1-20150219-C00014
  • or salt thereof, is formed; and
  • b) mixing the compound of formula XIII and thiazolidine-2,4-dione under conditions such that a compound of formula IA is formed.
  • In further embodiments, said metal halide is selected from lithium chloride and magnesium bromide.
  • In further embodiments, said boronic ester is a dialkyl boronic ester, such as diethyl boronic ester, or a cyclic boronic ester, such as the boronic ester of 1,2-alkyldiols, such as 1,3,2-dioxaborolane, or cycloalkyldiols which may be optionally substituted.
  • In further embodiments, the invention relates to a method of making a compound of formula ID, or salt thereof comprising
  • a) mixing a compound of formula II,
  • Figure US20150051185A1-20150219-C00015
  • or salt thereof, wherein R5, R6, and A are defined herein,
    with a compound of formula III,
  • Figure US20150051185A1-20150219-C00016
  • or salt thereof, wherein R8, R9, n, and X are defined herein, under conditions such that composition comprising a compound of formula IV,
  • Figure US20150051185A1-20150219-C00017
  • or salt thereof, is formed; and
    b) mixing the compound of formula IV and thiazolidine-2,4-dione under conditions such that a compound of formula ID is formed.
  • In further embodiments, the invention relates to a method of making a compound of formula IC, or salt thereof comprising a) mixing a compound of formula V,
  • Figure US20150051185A1-20150219-C00018
  • or salt thereof, wherein R5, R6, and R7 are defined herein,
    with a compound of formula VI,
  • Figure US20150051185A1-20150219-C00019
  • or salt thereof, wherein R14, n, X and Y are defined herein, under conditions such that a composition comprising a compound of formula VIII,
  • Figure US20150051185A1-20150219-C00020
  • or salt thereof, is formed; and
    b) mixing the compound of formula VIII and thiazolidine-2,4-dione under conditions such that a compound of formula IC is formed.
  • In some embodiments, the invention relates to compounds of formula I, IA, IB, IC, ID, or IX provided that they are not selected from 5-((2-dipropylamino-5-nitrophenyl)methylene)-2,4-thiazolidinedione; 5-((5-nitro-2-(1-piperidinyl)phenyl)methylene)-2,4-thiazolidinedione; 5-((2-(4-morpholinyl)-5-nitrophenyl)methylene)-2,4-thiazolidinedione; 5-[[2-(4-methyl-1-piperazinyl)phenyl]methylene]-2,4-thiazolidinedione; 5-[[2-[(2,6-dichloro-3-methylphenyl)amino]phenyl]methylene]-2,4-thiazolidinedione; [2S-[2α(Z),4α]]-1-([1,1′-biphenyl]-4-ylsulfonyl)-N-[2-[(2,4-dioxo-5-thiazolidinylidene)methyl]phenyl]-4-(methylthio)-2-pyrrolidinemethanamine; 1,1-dimethylethyl ester [[2S-[2α(Z),4α]]-3-[[[1-([1,1′-biphenyl]-4-ylsulfonyl)-4-(methylthio)-2-pyrrolidinyl]methyl]amino]-4-[(2,4-dioxo-5-thiazolidinylidene)methyl]phenyl]carbamic acid; and [2S-[2α(Z),4α]]-N-[5-amino-2-[(2,4-dioxo-5-thiazolidinylidene)methyl]phenyl]-1-([1,1′-biphenyl]-4-ylsulfonyl)-4-(methylthio)-2-pyrrolidinemethanamine.
  • It is the Applicants understanding that WO 2001002377 discloses 5-((2-dipropylamino-5-nitrophenyl)methylene)-2,4-thiazolidinedione, 5-((5-nitro-2-(1-piperidinyl)phenyl)methylene)-2,4-thiazolidinedione, and 5-((2-(4-morpholinyl)-5-nitrophenyl)methylene)-2,4-thiazolidinedione.
  • It is the Applicants understanding that WO 9814433 discloses 5-[[2-(4-methyl-1-piperazinyl)phenyl]methylene]-2,4-thiazolidinedione.
  • It is the Applicants understanding that U.S. Pat. No. 6,211,209 discloses, 5-[[2-[(2,6-dichloro-3-methylphenyl)amino]phenyl]methylene]-2,4-thiazolidinedione.
  • It is the Applicants understanding that WO 9705135 discloses, [2S-[2α(Z),4α]]-1-([1,1′-biphenyl]-4-ylsulfonyl)-N-[2-[(2,4-dioxo-5-thiazolidinylidene)methyl]phenyl]-4-(methylthio)-2-pyrrolidinemethanamine, 1,1-dimethylethyl ester [[2S-[2α(Z),4α]]-3-[[[1-([1,1′-biphenyl]-4-ylsulfonyl)-4-(methylthio)-2-pyrrolidinyl]methyl]amino]-4-[(2,4-dioxo-5-thiazolidinylidene)methyl]phenyl]-carbamic acid, and [2S-[2α(Z),4α]]-N-[5-amino-2-[(2,4-dioxo-5-thiazolidinylidene)methyl]phenyl]-1-([1,1′-biphenyl]-4-ylsulfonyl)-4-(methylthio)-2-pyrrolidinemethanamine.
  • The preceding understandings are not intended to be admissions.
  • In some embodiments, compounds disclosed herein could be used in the clinic either as a single agent by itself or in combination with other clinically relevant agents. This compound could also prevent the potential cancer resistance mechanisms that may arise due to mutations in a set of genes.
  • The anti-cancer treatment defined herein may be applied as a sole therapy or may involve, in addition to the compound of the invention, conventional surgery or radiotherapy or chemotherapy. Such chemotherapy may include one or more of the following categories of anti-tumour agents:
  • (i) antiproliferative/antineoplastic drugs and combinations thereof, as used in medical oncology, such as alkylating agents (for example cis-platin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulfan and nitrosoureas); antimetabolites (for example antifolates such as fluoropyrimidines like 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosine arabinoside and hydroxyurea); antitumour antibiotics (for example anthracyclines like adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin and mithramycin); antimitotic agents (for example vinca alkaloids like vincristine, vinblastine, vindesine and vinorelbine and taxoids like taxol and taxotere); and topoisomerase inhibitors (for example epipodophyllotoxins like etoposide and teniposide, amsacrine, topotecan and camptothecin); and proteosome inhibitors (for example bortezomib [Velcade®]); and the agent anegrilide [Agrylin®]; and the agent alpha-interferon
  • (ii) cytostatic agents such as antioestrogens (for example tamoxifen, toremifene, raloxifene, droloxifene and iodoxyfene), oestrogen receptor down regulators (for example fulvestrant), antiandrogens (for example bicalutamide, flutamide, nilutamide and cyproterone acetate), LHRH antagonists or LHRH agonists (for example goserelin, leuprorelin and buserelin), progestogens (for example megestrol acetate), aromatase inhibitors (for example as anastrozole, letrozole, vorazole and exemestane) and inhibitors of 5α-reductase such as finasteride;
  • (iii) agents which inhibit cancer cell invasion (for example metalloproteinase inhibitors like marimastat and inhibitors of urokinase plasminogen activator receptor function);
  • (iv) inhibitors of growth factor function, for example such inhibitors include growth factor antibodies, growth factor receptor antibodies (for example the anti-erbb2 antibody trastuzumab [Herceptin™] and the anti-erbb1 antibody cetuximab [C225]), farnesyl transferase inhibitors, tyrosine kinase inhibitors and serine/threonine kinase inhibitors, for example inhibitors of the epidermal growth factor family (for example EGFR family tyrosine kinase inhibitors such as:
    • N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine (gefitinib, AZD1839),
    • N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine (erlotinib, OSI-774), and
    • 6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)quinazolin-4-amine (CI 1033),
  • for example inhibitors of the platelet-derived growth factor family and for example inhibitors of the hepatocyte growth factor family, for example inhibitors or phosphotidylinositol 3-kinase (PI3K) and for example inhibitors of mitogen activated protein kinase kinase (MEK1/2) and for example inhibitors of protein kinase B (PKB/Akt), for example inhibitors of Src tyrosine kinase family and/or Abelson (Abl) tyrosine kinase family such as AZD0530 and dasatinib (BMS-354825) and imatinib mesylate (Gleevec™); and any agents that modify STAT signaling.
  • (v) antiangiogenic agents such as those which inhibit the effects of vascular endothelial growth factor, (for example the anti-vascular endothelial cell growth factor antibody bevacizumab [Avastin™], compounds such as those disclosed in International Patent Applications WO 97/22596, WO 97/30035, WO 97/32856 and WO 98/13354) and compounds that work by other mechanisms (for example linomide, inhibitors of integrin αvβ3 function and angiostatin);
  • (vi) vascular damaging agents such as Combretastatin A4 and compounds disclosed in International Patent Applications WO 99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO 02/04434 and WO 02/08213;
  • (vii) antisense therapies, for example those which are directed to the targets listed above, such as ISIS 2503, an anti-ras antisense;
  • (viii) gene therapy approaches, including for example approaches to replace aberrant genes such as aberrant p53 or aberrant BRCA1 or BRCA2, GDEPT (gene-directed enzyme pro-drug therapy) approaches such as those using cytosine deaminase, thymidine kinase or a bacterial nitroreductase enzyme and approaches to increase patient tolerance to chemotherapy or radiotherapy such as multi-drug resistance gene therapy; and
  • (ix) immunotherapy approaches, including for example ex-vivo and in-vivo approaches to increase the immunogenicity of patient tumour cells, such as transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor, approaches to decrease T-cell anergy, approaches using transfected immune cells such as cytokine-transfected dendritic cells, approaches using cytokine-transfected tumour cell lines and approaches using anti-idiotypic antibodies, and approaches using the immunomodulatory drugs thalidomide and lenalidomide [Revlimid®].
  • Such conjoint treatment may be achieved by way of the simultaneous, sequential or separate dosing of the individual components of the treatment. Such combination products employ the compounds of this invention, or pharmaceutically acceptable salts thereof, within the dosage range described hereinbefore and the other pharmaceutically-active agent within its approved dosage range.
  • The invention relates to phosphorylation inhibitors of PIM kinases. In still further embodiments, the invention relates to pharmaceutical composition comprising compounds disclosed herein and their use in the prevention and treatment of cancer.
  • It is understood the compositions disclosed herein may exist in solid and solution form tautomers. For example, imidazole and imidazole containing heterocycles may be drawn in a formula such that one or the other of the nitrogens contain a hydrogen atom. However, as provided herein, embodiments of such a formula are considered to encompass alternative tautomeric forms.
  • As used herein, “alkyl” means a noncyclic straight chain or branched, unsaturated or saturated hydrocarbon such as those containing from 1 to 10 carbon atoms, while the term “lower alkyl” or “C1-6alkyl” has the same meaning as alkyl but contains from 1 to 6 carbon atoms. The term “higher alkyl” has the same meaning as alkyl but contains from 7 to 10 carbon atoms. Representative saturated straight chain alkyls include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-septyl, n-octyl, n-nonyl, and the like; while saturated branched alkyls include isopropyl, sec-butyl, isobutyl, tert-butyl, isopentyl, and the like. Unsaturated alkyls contain at least one double or triple bond between adjacent carbon atoms (referred to as an “alkenyl” or “alkynyl”, respectively). Representative straight chain and branched alkenyls include ethylenyl, propylenyl, 1-butenyl, 2-butenyl, isobutylenyl, 1-pentenyl, 2-pentenyl, 3-methyl-1-butenyl, 2-methyl-2-butenyl, 2,3-dimethyl-2-butenyl, and the like; while representative straight chain and branched alkynyls include acetylenyl, propynyl, 1-butyryl, 2-butyryl, 1-pentynyl, 2-pentynyl, 3-methyl-1-butynyl, and the like.
  • A “halogenated alkyl” refers to an alkyl group where one or more or all of the hydrogen(s) are substituted with halogen(s). A representative halogenated alkyl includes trifluoromethyl (i.e., —CF3).
  • Non-aromatic mono or polycyclic alkyls are referred to herein as “carbocycles” or “carbocyclyl” groups. Representative saturated carbocycles include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like; while unsaturated carbocycles include cyclopentenyl and cyclohexenyl, aryls and the like.
  • “Heterocarbocycles” or heterocarbocyclyl” groups are carbocycles which contain from 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur which may be saturated or unsaturated (but not aromatic), monocyclic or polycyclic, and wherein the nitrogen and sulfur heteroatoms may be optionally oxidized, and the nitrogen heteroatom may be optionally quaternized. Heterocarbocycles include morpholinyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydroprimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, and the like.
  • “Aryl” means an aromatic carbocyclic monocyclic or polycyclic ring such as phenyl or naphthyl.
  • As used herein, “heteroaryl” refers an aromatic heterocarbocycle having 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur, and containing at least 1 carbon atom, including both mono- and polycyclic ring systems. Polycyclic ring systems may, but are not required to, contain one or more non-aromatic rings, as long as one of the rings is aromatic. Representative heteroaryls are furyl, benzofuranyl, thiophenyl, benzothiophenyl, pyrrolyl, indolyl, isoindolyl, azaindolyl, pyridyl, quinolinyl, isoquinolinyl, oxazolyl, isooxazolyl, benzoxazolyl, pyrazolyl, imidazolyl, benzimidazolyl, thiazolyl, benzothiazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, cinnolinyl, phthalazinyl, and quinazolinyl. It is contemplated that the use of the term “heteroaryl” includes N-alkylated derivatives such as a 1-methylimidazol-5-yl substituent.
  • As used herein, “heterocycle” or “heterocyclyl” refers to mono- and polycyclic ring systems having 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur, and containing at least 1 carbon atom. The mono- and polycyclic ring systems may be aromatic, non-aromatic or mixtures of aromatic and non-aromatic rings. Heterocycle includes heterocarbocycles, heteroaryls, and the like.
  • “Alkylthio” refers to an alkyl group as defined above with the indicated number of carbon atoms attached through a sulfur bridge. An example of an alkylthio is methylthio, (i.e., —S—CH3).
  • “Alkoxy” refers to an alkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, n-pentoxy, and s-pentoxy. Preferred alkoxy groups are methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy.
  • “Alkylamino” refers an alkyl group as defined above with the indicated number of carbon atoms attached through an amino bridge. An example of an alkylamino is methylamino, (i.e., —NH—CH3).
  • “Alkanoyl” refers to an alkyl as defined above with the indicated number of carbon atoms attached through a carbonyl bride (i.e., —(C═O)alkyl).
  • “Alkylsulfonyl” refers to an alkyl as defined above with the indicated number of carbon atoms attached through a sulfonyl bridge (i.e., —S(═O)2alkyl) such as mesyl and the like, and “Arylsulfonyl” refers to an aryl attached through a sulfonyl bridge (i.e., —S(═O)2aryl).
  • “Alkylsulfamoyl” refers to an alkyl as defined above with the indicated number of carbon atoms attached through a sulfamoyl bridge (i.e., —NHS(═O)2alkyl), and an “Arylsulfamoyl” refers to an alkyl attached through a sulfamoyl bridge (i.e., (i.e., —NHS(═O)2aryl).
  • “Alkylsulfinyl” refers to an alkyl as defined above with the indicated number of carbon atoms attached through a sulfinyl bridge (i.e. —S(═O)alkyl).
  • The term “substituted” refers to a molecule wherein at least one hydrogen atom is replaced with a substituent. When substituted, one or more of the groups are “substituents.” The molecule may be multiply substituted. In the case of an oxo substituent (“═O”), two hydrogen atoms are replaced. Example substituents within this context may include halogen, hydroxy, alkyl, alkoxy, nitro, cyano, oxo, carbocyclyl, carbocycloalkyl, heterocarbocyclyl, heterocarbocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, —NRaRb, —NRaC(═O)Rb, —NRaC(═O)NRaNRb, —NRaC(═O)ORb, —NRaSO2Rb, —C(═O)Ra, —C(═O)ORa, —C(═O)NRaRb, —OC(═O)NRaRb, —ORa, —SRa, —SORa, —S(═O)2Ra, —OS(═O)2Ra and —S(═O)2ORa. Ra and Rb in this context may be the same or different and independently hydrogen, halogen hydroxyl, alkyl, alkoxy, alkyl, amino, alkylamino, dialkylamino, carbocyclyl, carbocycloalkyl, heterocarbocyclyl, heterocarbocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl.
  • The term “optionally substituted,” as used herein, means that substitution is optional and therefore it is possible for the designated atom to be unsubstituted.
  • As used herein, the terms “prevent” and “preventing” include the prevention of the recurrence, spread or onset. It is not intended that the present invention be limited to complete prevention. In some embodiments, the onset is delayed, or the severity of the disease is reduced.
  • As used herein, the terms “treat” and “treating” are not limited to the case where the subject (e.g. patient) is cured and the disease is eradicated. Rather, embodiments, of the present invention also contemplate treatment that merely reduces symptoms, and/or delays disease progression.
  • As used herein, “salts” refer to derivatives of the disclosed compounds where the parent compound is modified making acid or base salts thereof. Examples of salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines, alkylamines, or dialkylamines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. In preferred embodiment the salts are conventional non-toxic pharmaceutically acceptable salts including the quaternary ammonium salts of the parent compound formed, and non-toxic inorganic or organic acids. Preferred salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.
  • The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound that contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, the disclosure of which is hereby incorporated by reference.
  • “Subject” means any animal, preferably a human patient, livestock, or domestic pet.
  • “Cancer” refers any of various cellular diseases with malignant neoplasms characterized by the proliferation of cells. It is not intended that the diseased cells must actually invade surrounding tissue and metastasize to new body sites. Cancer can involve any tissue of the body and have many different forms in each body area. Within the context of certain embodiments, whether “cancer is reduced” may be identified by a variety of diagnostic manners known to one skill in the art including, but not limited to, observation the reduction in size or number of tumor masses or if an increase of apoptosis of cancer cells observed, e.g., if more than a 5% increase in apoptosis of cancer cells is observed for a sample compound compared to a control without the compound. It may also be identified by a change in relevant biomarker or gene expression profile, such as PSA for prostate cancer, her2 for breast cancer, or others.
  • The present pharmaceutical compositions can take the form of solutions, suspensions, emulsion, tablets, pills, pellets, capsules, capsules containing liquids, powders, sustained-release formulations, suppositories, emulsions, aerosols, sprays, suspensions, or any other form suitable for use.
  • Administration may be topical, i.e., substance is applied directly where its action is desired, enteral or oral, i.e., substance is given via the digestive tract, parenteral, i.e., substance is given by other routes than the digestive tract such as by injection.
  • In a preferred embodiment, the active compound and optionally another therapeutic or prophylactic agent are formulated in accordance with routine procedures as pharmaceutical compositions adapted for intravenous administration to human beings. Typically, the active compound for intravenous administration are solutions in sterile isotonic aqueous buffer. Where necessary, the compositions can also include a solubilizing agent. Compositions for intravenous administration can optionally include a local anesthetic such as lignocaine to ease pain at the site of the injection. Generally, the ingredients are supplied either separately or mixed together in unit dosage form, for example, as a dry lyophilized powder or water free concentrate in a hermetically sealed container such as an ampoule. Where the active compound is to be administered by infusion, it can be dispensed, for example, with an infusion bottle containing sterile pharmaceutical grade water or saline. Where the active compound is administered by injection, an ampoule of sterile water for injection or saline can be provided so that the ingredients can be mixed prior to administration.
  • Compositions for oral delivery can be in the form of tablets, lozenges, aqueous or oily suspensions, granules, powders, emulsions, capsules, syrups, or elixirs, for example. Orally administered compositions can contain one or more optional agents, for example, sweetening agents such as fructose, aspartame or saccharin; flavoring agents such as peppermint, oil of wintergreen, or cherry; coloring agents; and preserving agents, to provide a pharmaceutically palatable preparation. A time delay material such as glycerol monostearate or glycerol stearate can also be used. Oral compositions can include standard vehicles such as mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, and the like. Such vehicles are preferably of pharmaceutical grade.
  • Compositions for use in accordance with the present invention can be formulated in conventional manner using one or more physiologically acceptable carriers or excipients. Thus, the compound and optionally another therapeutic or prophylactic agent and their physiologically acceptable salts and solvates can be formulated into pharmaceutical compositions for administration by inhalation or insufflation (either through the mouth or the nose) or oral, parenteral or mucosol (such as buccal, vaginal, rectal, sublingual) administration. In one embodiment, local or systemic parenteral administration is used.
  • For oral administration, the compositions can take the form of, for example, tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g., pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g., lactose, microcrystalline cellulose or calcium hydrogen phosphate); lubricants (e.g., magnesium stearate, talc or silica); disintegrants (e.g., potato starch or sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulfate). The tablets can be coated by methods well known in the art. Liquid preparations for oral administration can take the form of, for example, solutions, syrups or suspensions, or they can be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations can be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, cellulose derivatives or hydrogenated edible fats); emulsifying agents (e.g., lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters, ethyl alcohol or fractionated vegetable oils); and preservatives (e.g., methyl or propyl-p-hydroxybenzoates or sorbic acid). The preparations can also contain buffer salts, flavoring, coloring and sweetening agents as appropriate.
    • EXPERIMENTAL
  • The following is intended to provide examples on methods of making and using embodiments of the invention. It is not intended to limit the scope.
    • Example 1
  • Figure US20150051185A1-20150219-C00021
    • (S,Z)-5-(2-(3-aminopiperidin-1-yl)-3-chloro-5-(trifluoromethyl)benzylidene)thiazolidine-2,4-dione trifluoroacetate
  • A 40 mL vial was charged with a magnetic stir bar, 3-chloro-2-fluoro-5-(trifluoromethyl)benzaldehyde (0.134 ml, 1.10 mmol), acetonitrile (2.76 ml), (S)-tert-butyl piperidin-3-ylcarbamate (0.221 g, 1.10 mmol), and K2CO3 (0.229 g, 1.66 mmol). The vial was heated to 70° C. with stirring for 2 h. The vessel was cooled to rt and the mixture was diluted with DCM and filtered. The filtrate was conc. in vacuo to afford the substituted aldehyde which was dissolved in EtOH (2.76 ml). Thiazolidine-2,4-dione (0.155 g, 1.32 mmol) and piperidine (9.40 mg, 0.11 mmol) were then added. The mixture was heated to reflux for 4 h before being allowed to cool to rt and the mixture was conc. in vacuo. The product was dissolved DCM (2 mL) and TFA (1 mL) and stirred at rt for 1 h before being conc. in vacuo. The residue was dissolved in DMSO (˜2 mL) and purified via reverse phase HPLC to afford (S,Z)-5-(2-(3-aminopiperidin-1-yl)-3-chloro-5-(trifluoromethyl)benzylidene)thiazolidine-2,4-dione trifluoroacetate (0.214 g, 37.3%). 1H NMR (300 MHz, DMSO-D6) δ ppm 12.78 (s, 1H) 7.95 (m, 3H) 7.79 (s, 1H) 7.62 (s, 1H) 3.40-3.20 (s, 5H) 2.12-2.06 (m, 1H) 1.79-1.70 (m 1H) 1.65-1.60 (m, 1H) 1.52-1.41 (m, 1H); m/z 406.
  • The following examples were prepared by the procedure of Example 1, using the appropriate starting materials. The following parent compounds obtained after chromatography may be converted to their corresponding hydrochloride salts using the procedure in Example 6, or a similar procedure.
  • Ex. Compound 1H NMR (300 MHz) m/z SM
    2  (R,Z)-5-(2-(3- 12.79 (s, 1 H) 7.98 (s, 2 406 (R)-tert-butyl piperidin-
    aminopiperidin-1-yl)- H) 7.95 (s, 1 H) 7.79 (s, 1 3-ylcarbamate
    3-chloro-5-(trifluoromethyl) benzylidene)thiazolidine- 2,4-dione trifluoroacetate
    Figure US20150051185A1-20150219-C00022
         		H) 7.62 (s, 1 H) 3.31- 3.20 (m, 5 H) 2.12-2.09 (m, 1 H) 1.85-1.77 (m, 1 H) 1.66-1.63 (m, 1 H) 1.45-1.40 (m, 1 H)
    Figure US20150051185A1-20150219-C00023
    3  (Z)-5-(2-(4- 12.76 (s, 1 H) 7.99 (s, 1 406 tert-butyl piperidin-4-
    aminopiperidin-1-yl)- H) 7.91 (s, 2 H) 7.78 (s, 1 ylcarbamate
    3-chloro-5-(trifluoromethyl) benzylidene)thiazolidine- 2,4-dione trifluoroacetate
    Figure US20150051185A1-20150219-C00024
         		H) 7.60 (s, 1 H) 3.33- 3.18 (m, 5 H) 1.94 (d, 2 H) 1.71-1.60 (m, 2 H)
    Figure US20150051185A1-20150219-C00025
    4  (Z)-5-(2-(3- 12.78 (s, 1 H) 7.93 (s, 1 421 tert-butyl piperidin-3-
    (aminomethyl) H) 7.84 (s, 1 H) 7.75 (s, 1 ylmethylcarbamate
    piperidin-1-yl)-3-chloro-5- (trifluoromethyl) benzylidene)thiazolidine- 2,4-dione trifluoroacetate
    Figure US20150051185A1-20150219-C00026
         		H) 7.61 (s, 1 H) 3.31- 3.05 (m, 6 H) 2.79-2.71 (m, 1 H) 1.95-1.89 (m, 2 H) 1.72-1.55 (m, 2 H) 1.29-1.10 (m, 1 H)
    Figure US20150051185A1-20150219-C00027
    5A (Z)-5-(3-chloro-2- 12.83 (brs, 1 H) 9.20 405 tert-butyl 1,4-diazepane-
    (1,4-diazepan-1-yl)- (brs, 2 H) 8.05 (d, 1 H) 1-carboxylate
    5-(trifluoromethyl) benzylidene)thiazolidine- 2,4-dione hydrochloride
    Figure US20150051185A1-20150219-C00028
         		7.90 (s, 1 H) 7.66 (d, 1 H) 3.51 (brs, 2 H) 3.35 (d, 2 H) 3.26-3.03 (m, 4 H) 2.27-1.99 (m, 2 H)
    Figure US20150051185A1-20150219-C00029
    5B (S,Z)-5-(2-(3- 12.73 (brs, 1 H) 8.29 392 tert-butyl (3S)-
    aminopyrrolidin-1- (brs, 3 H) 7.93 (s, 1 H) pyrrolidin-3-ylcarbamate
    yl)-3-chloro-5-(trifluoromethyl) benzylidene)thiazolidine-2,4-dione
    Figure US20150051185A1-20150219-C00030
         		7.83 (s, 1 H) 7.66 (s, 1 H) 3.88 (brs, 1 H) 3.66 (dd, 1 H), 3.52-3.27 (m, 3 H) 2.42-2.19 (m, 1 H) 2.12- 1.88 (m, 1 H)
    Figure US20150051185A1-20150219-C00031
    • Example 6
  • Figure US20150051185A1-20150219-C00032
    • (Z)-5-(3-chloro-2-(4-cyclopentylpiperazin-1-yl)-5-(trifluoromethyl)benzylidene)thiazolidine-2,4-dione hydrochloride
  • A 40 mL vial was charged with a magnetic stir bar, 3-chloro-2-fluoro-5-(trifluoromethyl)benzaldehyde (0.134 ml, 1.10 mmol), acetonitrile (2.76 ml), 1-cyclopentylpiperazine (0.213 g, 1.38 mmol), and K2CO3 (0.229 g, 1.66 mmol). The vial was heated to 70° C. with stirring for 2 h. The vessel was then cooled to rt and the mixture was diluted with DCM and filtered. The filtrate was conc. in vacuo to afford the substituted aldehyde which was dissolved in EtOH (2.76 ml). Thiazolidine-2,4-dione (0.155 g, 1.32 mmol) and piperidine (9.40 mg, 0.11 mmol) were then added and the mixture was heated to reflux for 4 h before being allowed to cool to rt. The mixture was then conc. in vacuo to afford the product which was dissolved in DMSO (˜2 mL) and purified via reverse phase HPLC to afford fractions that were conc. in vacuo, suspended in methanol (˜5 mL) and 1N HCl in diethyl ether (˜2 mL). This mixture was conc. in vacuo to afford (Z)-5-(3-chloro-2-(4-cyclopentylpiperazin-1-yl)-5-(trifluoromethyl)benzylidene)thiazolidine-2,4-dione hydrochloride (0.215 g, 39.3%). 1H NMR (300 MHz, DMSO-D6) δ ppm 12.78 (s, 1H) 7.96 (s, 1H) 7.83 (s, 1H) 7.63 (s, 1H) 3.77-3.50 (m, 5H) 3.30-3.22 (m, 2H) 3.08-2.99 (m, 2H) 2.03-1.99 (m, 2H) 1.84-1.61 (m, 4H) 1.60-1.50 (m, 2H); m/z 461.
  • The following examples were prepared by the procedure of Example 6, using the appropriate starting materials. The following parent compounds obtained after chromatography may be converted to their corresponding hydrochloride salt in a manner similar as described in example 6.
  • Ex. Compound 1H NMR m/z SM
     7 (Z)-5-(3-chloro-2-(4- 12.74 (s, 1 H) 7.89-8.01 486 1-(4-
    (4-fluorophenyl)piperazin- (m, 2 H) 7.62 (s, 1 H) fluorophenyl)piperazine
    1-yl)-5-(trifluoromethyl) benzylidene)thiazolidine-2,4-dione
    Figure US20150051185A1-20150219-C00033
         		6.99-7.13 (m, 4 H) 3.34- 3.23 (m, 8 H)
    Figure US20150051185A1-20150219-C00034
     8 (Z)-5-(2-(4-(benzo[d][1,3]dioxol- 12.77 (s, 1 H) 7.97 (d, 1 526 1-(benzo[d][1,3]dioxol-
    5-ylmethyl)piperazin- H) 7.97 (s, 1 H) 7.77 (s, 1 5-ylmethyl)piperazine
    1-yl)-3-chloro-5-(trifluoromethyl) benzylidene)thiazolidine- 2,4-dione trifluoroacetate
    Figure US20150051185A1-20150219-C00035
         		H) 7.63 (s, 1 H) 7.10 (s, 1 H) 7.02 (s, 2 H) 6.08 (s, 2 H) 4.34 (s, 2 H) 3.58- 3.11 (m, 8 H)
    Figure US20150051185A1-20150219-C00036
     9 (Z)-5-(3-chloro-2-(4-(3-methyl-1,2,4- 12.72 (s, 1 H) 7.91 (s, 1 473 3-methyl-5-(piperidin-4-
    oxadiazol-5-yl)piperidin-1-yl)-5- H) 7.84 (s, 1 H) 7.61 (s, 1 yl)-1,2,4-oxadiazole
    (trifluoromethyl)benzylidene) thiazolidine-2,4-dione
    Figure US20150051185A1-20150219-C00037
         		H) 3.33-3.18 (m, 4 H) 2.79-2.71 (m, 1 H) 2.33 (s, 3 H) 2.06 (d, 2 H) 1.98-1.80 (m, 2 H)
    Figure US20150051185A1-20150219-C00038
    10 (Z)-5-(3-chloro-2-(4-(pyrrolidin-1- 12.78 (s, 1 H) 7.92 (s, 1 461 4-(pyrrolidin-1-
    yl)piperidin-1-yl)-5-(trifluoromethyl) H) 7.79 (s, 1 H) 7.60 (s, 1 yl)piperidine
    benzylidene)thiazolidine- 2,4-dione hydrochloride
    Figure US20150051185A1-20150219-C00039
         		H) 3.33-3.20 (m, 5 H) 3.12-3.03 (m, 4 H) 2.09 (d, 2 H) 1.97-1.78 (m, 6 H)
    Figure US20150051185A1-20150219-C00040
    11 (Z)-5-(3-chloro-2-(4- 12.80 (s, 1 H) 7.96 (s, 1 434 1-isopropylpiperazine
    isopropylpiperazin-1- yl)-5-(trifluoromethyl) benzylidene)thiazolidine- 2,4-dione hydrochloride
    Figure US20150051185A1-20150219-C00041
         		H) 7.82 (s, 1 H) 7.62 (s, 1 H) 3.85 (t, 2 H) 3.55-3.52 (m, 1 H) 3.41 (d, 2 H) 3.26 (d, 2 H) 3.10-3.06 (m, 2 H) 1.32 (d, 6 H)
    Figure US20150051185A1-20150219-C00042
    12 (Z)-5-(3-chloro-2-(4- 12.80 (s, 1 H) 7.96 (d, 1 450 1-isobutylpiperazine
    isobutylpiperazin-1- yl)-5-(trifluoromethyl) benzylidene)thiazolidine- 2,4-dione hydrochloride
    Figure US20150051185A1-20150219-C00043
         		H) 7.80 (s, 1 H) 7.63 (s, 1 H) 3.87 (brs, 2 H) 3.52 (d, 2 H) 3.27 (brs, 2 H) 3.11-3.00 (m, 4 H) 2.10 (qq, 1 H) 1.00 (d, 6 H)
    Figure US20150051185A1-20150219-C00044
    13 (Z)-5-(3-chloro-2-(4- 12.73 (s, 1 H) 7.87 (s, 1 437 2-(piperidin-4-yl)ethanol
    (2-hydroxyethyl)piperidin- 1-yl)-5-(trifluoromethyl) benzylidene)thiazolidine-2,4-dione
    Figure US20150051185A1-20150219-C00045
         		H) 7.83 (s, 1 H) 7.59 (s, 1 H) 3.46 (t, 2 H) 3.23 (t, 2 H) 3.07 (brs, 2 H) 1.70 (d, 2 H) 1.61-1.52 (m, 1 H) 1.42 (q, 2 H) 1.33- 1.20 (m, 2 H)
    Figure US20150051185A1-20150219-C00046
    14 (S,Z)-5-(3-chloro-2-(3-(dimethylamino) 12.65 (s, 1 H) 7.82 (s, 1 421 (S)-N,N-
    pyrrolidin-1-yl)-5-(trifluoromethyl) H) 7.72 (s, 1 H) 7.53 (s, 1 dimethylpyrrolidin-3-
    benzylidene)thiazolidine- H) 3.59-3.50 (m, 1 H) amine
    2,4-dione hydrochloride
    Figure US20150051185A1-20150219-C00047
         		3.38-3.30 (m, 4 H) 2.56 (s, 6 H) 2.31-2.28 (m, 1 H) 2.09-2.01 (m, 1 H)
    Figure US20150051185A1-20150219-C00048
    15 (Z)-5-(3-chloro-2-(4-(4-chloro-2- 12.75 (brs, 1 H) 8.06- 520 1-(4-chloro-2-
    fluorophenyl)piperazin-1-yl)-5- 7.90 (m, 2 H) 7.64 (d, 1 fluorophenyl)piperazine
    (trifluoromethyl) benzylidene)thiazolidine- 2,4-dione hydrochloride
    Figure US20150051185A1-20150219-C00049
         		H) 7.38 (dd, 1 H) 7.23 (dd, 1 H) 7.11 (t, 1 H) 3.42 (m, 4 H) 3.15 (d, 4 H)
    Figure US20150051185A1-20150219-C00050
    16 (Z)-5-(3-chloro-2-(3-(3-methyl-1,2,4- 471 3-methyl-5-(piperidin-3-
    oxadiazol-5-yl)piperidin-1-yl)-5- yl)-1,2,4-oxadiazole
    (trifluoromethyl) benzylidene)thiazolidine- 2,4-dione hydrochloride
    Figure US20150051185A1-20150219-C00051
    Figure US20150051185A1-20150219-C00052
    17 (Z)-5-(3-chloro-2-(4-(pyridin-4- 12.75 (brs, 1H) 8.78 (d, 2 483 1-(pyridin-4-
    ylmethyl)piperazin-1- H) 7.98 (s, 1 H) 7.74 ylmethyl)piperazine
    yl)-5-(trifluoromethyl) benzylidene)thiazolidine- 2,4-dione hydrochloride
    Figure US20150051185A1-20150219-C00053
         		(brs, 1 H) 7.71 (s, 1 H) 7.64 (s, 1 H) 4.44 (brs, 2 H) 3.44 (brs, 4 H) 3.17 (s, 4 H)
    Figure US20150051185A1-20150219-C00054
    18 (Z)-5-(3-chloro-2-(4-(2-chlorobenzyl) 7.98 (d, 1 H) 7.73 (dd, 1 517 1-(2-
    piperazin-1-yl)-5-(trifluoromethyl) H) 7.68-7.59 (m, 2 H) chlorobenzyl)piperazine
    benzylidene)thiazolidine- 2,4-dione hydrochloride
    Figure US20150051185A1-20150219-C00055
         		7.58-7.42 (m, 3 H) 4.53 (brs, 2 H) 3.75-3.30 (m, 8 H)
    Figure US20150051185A1-20150219-C00056
    19 (Z)-5-(3-chloro-2-(4- 10.68 (brs, 1 H) 7.92 (d, 489 1-(1-methylpiperidin-4-
    (1-methylpiperidin-4- 1 H) 7.78 (brs, 1 H) 7.58 yl)piperazine
    yl)piperazin-1-yl)-5-(trifluoromethyl) benzylidene)thiazolidine- 2,4-dione hydrochloride
    Figure US20150051185A1-20150219-C00057
         		(s, 1 H) 3.73-3.63 (m, 1 H) 3.61-3.41 (m, 6 H) 3.10 (brs, 3 H) 2.93 (brs, 3 H) 2.67 (s, 3 H) 2.39- 2.18 (m, 2 H) 2.07 (brs, 2 H)
    Figure US20150051185A1-20150219-C00058
    20 (Z)-5-(3-chloro-2-(4-(2-morpholinoethyl) 11.12 (brs, 1 H) 7.91 (d, 505 4-(2-(piperazin-1-
    piperazin-1-yl)-5-(trifluoromethyl) 1 H) 7.79 (brs, 1 H) 7.59 yl)ethyl)morpholine
    benzylidene)thiazolidine- 2,4-dione hydrochloride
    Figure US20150051185A1-20150219-C00059
         		(s, 1 H) 3.80-2.81 (m, 20 H)
    Figure US20150051185A1-20150219-C00060
    21 (Z)-5-(3-chloro-2-(4-(cyclopropylmethyl) 12.59 (brs, 1 H) 7.76 (d, 447 1-(cyclopropylmethyl)
    piperazin-1-yl)-5-(trifluoromethyl) 1 H) 7.61 (brs, 1 H) 7.43 piperazine
    benzylidene)thiazolidine- 2,4-dione hydrochloride
    Figure US20150051185A1-20150219-C00061
         		(s, 1 H) 3.62 (brs, 2 H) 3.44-3.24 (m, 2 H) 3.10 (brs, 2 H) 2.87 (d, 4 H) 0.94 (brs, 1 H) 0.54- 0.31 (m, 2 H) 0.32-0.08 (m, 2 H)
    Figure US20150051185A1-20150219-C00062
    22 (Z)-5-(3-chloro-2-(4-morpholinopiperidin- 12.92 (brs, 1 H) 8.08 (d, 476 4-(piperidin-4-
    1-yl)-5-(trifluoromethyl) 1 H) 7.95 (brs, 1 H) 7.76 yl)morpholine
    benzylidene)thiazolidine- 2,4-dione hydrochloride
    Figure US20150051185A1-20150219-C00063
         		(s, 1 H) 4.14 (brs, 3 H) 3.98 (brs, 2 H) 3.58 (brs, 3 H) 3.53-3.34 (m, 3 H) 3.28 (brs, 2 H) 2.32 (brs, 2 H) 1.92 (d, 2 H)
    Figure US20150051185A1-20150219-C00064
    23 (Z)-5-(3-chloro-2-(4-(3-hydroxypropyl) 12.90 (brs, 1 H) 10.52 450 3-(piperazin-1-yl)propan-
    piperazin-1-yl)-5-(trifluoromethyl) (brs, 1 H) 7.98 (d, 1 H) 1-ol
    benzylidene)thiazolidine- 2,4-dione hydrochloride
    Figure US20150051185A1-20150219-C00065
         		7.84 (brs, 1 H) 7.65 (s, 1 H) 3.90-3.65 (m, 2 H) 3.57-3.41 (m, 5 H) 3.30-3.06 (m, 5 H) 1.96-1.73 (m, 2 H)
    Figure US20150051185A1-20150219-C00066
    24 (Z)-5-(3-chloro-2-(4-(dimethylamino) 12.79 (brs, 1 H) 7.94 (d, 434 N,N-dimethylpiperidin-4-
    piperidin-1-yl)-5-(trifluoromethyl) 1 H) 7.82 (s, 1 H) 7.61 (s, amine
    benzylidene)thiazolidine- 2,4-dione hydrochloride
    Figure US20150051185A1-20150219-C00067
         		1 H) 3.84 (brs, 1 H) 3.46- 3.18 (m, 4 H) 2.75 (d, 6 H) 2.10 (d, 2 H) 1.74 (dd, 2 H)
    Figure US20150051185A1-20150219-C00068
    25 (Z)-5-(3-chloro-2-((3-(dimethylamino) 12.81 (brs, 1 H) 7.98 (d, 422 N1,N1,N3-
    propyl)(methyl)amino)-5-(trifluoromethyl) 1 H) 7.81 (s, 1 H) 7.65 trimethylpropane-1,3-
    benzylidene)thiazolidine- (d, 1 H) 3.15 (t, 2 H) 3.02 diamine
    2,4-dione hydrochloride
    Figure US20150051185A1-20150219-C00069
         		(brs, 2 H) 2.89 (s, 3 H) 2.72 (d, 6 H) 1.99-1.74 (m, 2 H)
    Figure US20150051185A1-20150219-C00070
    26 (Z)-5-(3-chloro-2-(4-(2-hydroxyethyl)-1,4- 8.04 (brs, 1 H) 7.79 (d, 1 451 2-(1,4-diazepan-1-
    diazepan-1-yl)-5-(trifluoromethyl) H) 7.63 (s, 1 H) 3.83 (t, 3 yl)ethanol
    benzylidene)thiazolidine- 2,4-dione hydrochloride
    Figure US20150051185A1-20150219-C00071
         		H) 3.71 (m, 2 H) 3.56 (m, 3 H) 3.33 (m, 6 H) 2.21 (m, 2 H)
    Figure US20150051185A1-20150219-C00072
    27 (Z)-5-(2-(4-butyl-1,4-diazepan-1-yl)-3- 10.76 (brs, 1 H) 8.06 (d, 463 1-butyl-1,4-diazepane
    chloro-5-(trifluoromethyl) benzylidene)thiazolidine- 2,4-dione hydrochloride
    Figure US20150051185A1-20150219-C00073
         		1 H) 7.91 (brs, 1 H) 7.66 (d, 1 H) 3.69 (m, 3 H) 3.57 (brs, 1 H) 3.46 (m, 3 H) 3.14 (m, 3 H) 2.34 (brs, 1 H) 2.16 (brs, 1 H) 1.73 (d, 2 H) 1.32 (m, 2 H) 0.93 (t, 3 H)
    Figure US20150051185A1-20150219-C00074
    28 (Z)-5-(3-chloro-2-(4-(2-hydroxyethyl) 7.98 (d, 1 H) 7.82 (brs, 1 436 2-(piperazin-1-yl)ethanol
    piperazin-1-yl)-5-(trifluoromethyl) benzylidene)thiazolidine- 2,4-dione hydrochloride
    Figure US20150051185A1-20150219-C00075
         		H) 7.64 (d, 1 H) 5.40 (brs, 1 H) 3.74 (m, 4 H) 3.56 (m, 3 H) 3.27 (m, 3 H) 3.18 (brs, 1 H) 3.11 (brs, 1 H)
    Figure US20150051185A1-20150219-C00076
    29 (Z)-5-(3-chloro-2-morpholino-5- 12.76 (brs, 1 H) 7.94 (m, 394 morpholine
    (trifluoromethyl) benzylidene)thiazolidine-2,4-dione
    Figure US20150051185A1-20150219-C00077
         		2 H) 7.63 (d, 1 H) 3.71 (t, 4 H) 3.20 (brs, 4 H)
    Figure US20150051185A1-20150219-C00078
    30 (Z)-5-(2-(4-tert-butylpiperazin-1-yl)- 12.80 (brs, 1 H) 8.00 (d, 449 1-tert-butylpiperazine
    3-chloro-5-(trifluoromethyl) benzylidene)thiazolidine- 2,4-dione hydrochloride
    Figure US20150051185A1-20150219-C00079
         		1 H) 7.85 (brs, 1 H) 7.65 (d, 1 H) 3.82 (m, 2 H) 3.56 (d, 2 H) 3.29 (dd, 2 H) 3.04 (m, 2 H) 1.39 (s, 9 H)
    Figure US20150051185A1-20150219-C00080
    31 (Z)-5-(2-(1,4′-bipiperidin-1′-yl)-3- 9.75 (brs, 1 H) 7.94 (d, 1 474 1,4′-bipiperidine
    chloro-5-(trifluoromethyl) benzylidene)thiazolidine- 2,4-dione hydrochloride
    Figure US20150051185A1-20150219-C00081
         		H) 7.81 (brs, 1 H) 7.62 (s, 1 H) 3.29 (m, 7 H) 2.96 (m, 2 H) 2.14 (d, 2 H) 1.78 (m, 7 H) 1.44 (brs, 1 H)
    Figure US20150051185A1-20150219-C00082
    32 (Z)-5-(3-chloro-2-(4-methylpiperazin-1- 7.94 (brs, 1 H) 7.75 406 1-methylpiperazine
    yl)-5-(trifluoromethyl) benzylidene)thiazolidine- 2,4-dione hydrochloride
    Figure US20150051185A1-20150219-C00083
         		(d, 1 H) 7.63 (s, 1 H) 3.56-3.38 (m, 3 H) 3.31- 3.21 (m, 5 H) 2.92 (s, 3 H)
    Figure US20150051185A1-20150219-C00084
    • Example 33
  • Figure US20150051185A1-20150219-C00085
    • (S,Z)-5-(3-bromo-2-(3-(dimethylamino)pyrrolidin-1-yl)benzylidene)thiazolidine-2,4-dione hydrochloride
  • A 100 mL round bottom flask was charged with a magnetic stir bar, (S)-3-bromo-2-(3-(dimethylamino)pyrrolidin-1-yl)benzaldehyde (Method 1) (0.370 g, 1.24 mmol), thiazolidine-2,4-dione (0.146 g, 1.24 mmol), and ethanol (4.15 ml). Piperidine (0.012 ml, 0.12 mmol) was then added and the reaction was heated to reflux for 2 h. Once the reaction was judged to be complete by LCMS, it was allowed to cool to rt and was conc. in vacuo to afford the product which was purified on 40 g of silica gel using ethyl acetate/methanol (3:1) as eluent to afford the free base which was suspended in methanol (˜5 mL) and 1N HCl in diethyl ether (2 mL) and conc. in vacuo to afford (S,Z)-5-(3-bromo-2-(3-(dimethylamino)pyrrolidin-1-yl)benzylidene)thiazolidine-2,4-dione hydrochloride (0.141 g, 26.2%). 1H NMR (300 MHz, DMSO-D6) δ ppm 12.68 (s, 1H) 7.91 (s, 1H) 7.77 (d, 1H) 7.48 (d, 1H) 7.33 (t, 1H) 4.10-4.02 (m, 1H) 3.62 (t, 2H) 3.50-3.45 (m, 2H) 2.81 (s, 6H) 2.42-2.38 (m, 1H) 2.31-2.21 (m, 1H); m/z 398.
  • The following examples were prepared by the procedure of Example 33, using the appropriate starting materials. The following parent compounds obtained after chromatography (normal or reverse phase) may be converted to its corresponding hydrochloride salt as described in example 33, or similar procedure.
  • Ex. Compound 1H NMR m/z SM
    34 (Z)-5-(2-((3S,5R)-3,5- dimethylpiperazin-1- yl)-5- (trifluoromethyl) benzylidene) thiazolidine- 2,4-dione hydrochloride  
    Figure US20150051185A1-20150219-C00086
         		12.63 (s, 1 H) 8.99-8.94 (m, 1 H) 7.77 (d, 1 H) 7.72 (s, 2 H) 7.40 (d, 1 H) 3.49-3.43 (m, 2 H) 3.32 (d, 2 H) 2.92 (t, 2 H) 1.25 (d, 6 H) 387 2-((3S,5R)-3,5- dimethylpiperazin-1-yl)- 5-(trifluoromethyl) benzaldehyde Method 2  
    Figure US20150051185A1-20150219-C00087
    35 (Z)-5-(2-((3S,5R)-3,5- dimethylpiperazin-1- yl)-3- methoxybenzylidene) thiazolidine-2,4- dione  
    Figure US20150051185A1-20150219-C00088
         		7.87 (brs, 1 H) 7.24 (t, 1 H) 7.20-7.10 (m, 1 H) 7.02 (d, 1 H) 3.81 (s, 3 H) 3.48-3.23 (m, 2 H) 3.17 (t, 2 H) 2.89 (d, 2 H) 1.30-1.09 (m, 6 H) 348 2-((3S,5R)-3,5- dimethylpiperazin-1-yl)- 3-methoxybenzaldehyde Method 3  
    Figure US20150051185A1-20150219-C00089
    36 (S,Z)-5-(2-(3- (dimethylamino) pyrrolidin-1-yl)-3- methoxybenzylidene) thiazolidine-2,4- dione  
    Figure US20150051185A1-20150219-C00090
         		7.89 (s, 1 H) 7.26 (m, 1 H) 7.10 (m, 2 H) 3.84 (s, 3 H) 3.41-3.29 (m, 7 H) 3.24-3.13 (m, 4 H) 2.18 (m, 1 H) 1.99 (m, 1 H) 348 (S)-2-(3- (dimethylamino) pyrrolidin-1-yl)-3- methoxybenzaldehyde Method 4  
    Figure US20150051185A1-20150219-C00091
    37 (Z)-5-(3-chloro-2- ((3S,5R)-3,5- dimethylpiperazin-1- yl)benzylidene) thiazolidine-2,4-dione  
    Figure US20150051185A1-20150219-C00092
         		7.80 (s, 1 H) 7.50 (brs, 1 H) 7.38 (d, 1 H) 7.30 (brs, 1 H) 3.34-3.02 (m, 6 H) 1.26-1.09 (m, 6 H) 352 3-chloro-2-((3S,5R)-3,5- dimethylpiperazin-1- yl)benzaldehyde Method 5  
    Figure US20150051185A1-20150219-C00093
    38 (S,Z)-5-(3-chloro-2- (3- (dimethylamino) pyrrolidin-1- yl)benzylidene) thiazolidine-2,4-dione  
    Figure US20150051185A1-20150219-C00094
         		7.73 (s, 1 H) 7.52-7.47 (m, 2 H) 7.47 (s, 1 H) 7.33-7.31 (m, 1 H) 3.58- 3.52 (m, 1 H) 3.48 (m, 1 H) 3.37-3.27 (m, 3 H) 2.56 (s, 6 H) 2.26-2.35 (m, 1 H) 2.08 (m, 1 H) 352 (S)-3-chloro-2-(3- (dimethylamino) pyrrolidin-1-yl) benzaldehyde Method 6  
    Figure US20150051185A1-20150219-C00095
    39 (R,Z)-5-(2-(3- (dimethylamino) pyrrolidin-1-yl)-4,5- dimethoxybenzylidene) thiazolidine-2,4- dione  
    Figure US20150051185A1-20150219-C00096
         		7.75 (s, 1 H) 6.98 (s, 1 H) 6.68 (s, 1 H) 3.83 (s, 3 H) 3.72 (s, 3 H) 3.24-3.06 (m, 4 H) 2.50 (m, 1 H) 2.32 (s, 6 H) 2.12 (m, 1 H) 1.84 (m, 1 H) 378 (R)-2-(3- (dimethylamino) pyrrolidin-1-yl)-4,5- dimethoxybenzaldehyde Method 7  
    Figure US20150051185A1-20150219-C00097
    40 (S,Z)-5-(2-(3- (dimethylamino) pyrrolidin-1-yl)-4,5- dimethoxybenzylidene) thiazolidine-2,4- dione  
    Figure US20150051185A1-20150219-C00098
         		7.76 (s, 1 H) 6.98 (s, 1 H) 6.68 (s, 1 H) 3.83 (s, 3 H) 3.72 (s, 3 H) 3.26-3.01 (m, 5 H) 2.32 (s, 6 H) 2.15-2.09 (m, 1 H) 1.90- 1.81 (m, 1 H) 378 (S)-2-(3- (dimethylamino) pyrrolidin-1-yl)-4,5- dimethoxybenzaldehyde Method 8  
    Figure US20150051185A1-20150219-C00099
    41 (5Z)-5-{2-[4- (hydroxymethyl) piperidin-1-yl]-4,5- dimethoxybenzylidene}- 1-,3-thiazolidine- 2,4-dione  
    Figure US20150051185A1-20150219-C00100
         		12.44 (brs, 1 H) 7.94 (s, 1 H) 7.05-6.87 (m, 1 H) 6.80 (s, 1 H) 4.54 (t, 1 H) 3.85 (s, 3H) 3.76 (s, 3 H) 3.17 (d, 1 H) 3.03 (d, 2 H) 2.71 (t, 2 H) 1.75 (brs, 2 H) 1.56-1.26 (m, 3 H) 379 2-(4- (hydroxymethyl) piperidin-1-yl)-4,5- dimethoxybenzaldehyde Method 9  
    Figure US20150051185A1-20150219-C00101
    42 (5Z)-5-[2-(4- hydroxypiperidin-1- dimethoxybenzylidene]- 1,3-thiazolidine- 2,4-dione  
    Figure US20150051185A1-20150219-C00102
         		12.50 (brs, 1 H) 8.02 (s, 1 H) 6.99 (s, 1 H) 6.92- 6.82 (m, 1 H) 4.79 (d, 1 H) 3.90 (s, 3 H) 3.82 (s, 3 H) 3.74-3.58 (m, 1 H) 3.13-2.96 (m, 2 H) 2.88- 2.71 (m, 2 H) 2.01- 1.81 (m, 2 H) 1.78-1.58 (m, 2 H) 365 2-(4-hydroxypiperidin-1- yl)-4,5- dimethoxybenzaldehyde Method 10  
    Figure US20150051185A1-20150219-C00103
    43 (5Z)-5-{2-[3- (dimethylamino) pyrrolidin-1-yl]-5- methoxybenzylidene]- 1,3-thiazolidine-2,4- dione  
    Figure US20150051185A1-20150219-C00104
         		7.51 (s, 1 H) 7.03 (d, 1 H) 6.99 (d, 1 H) 6.84 (dd, 1 H) 3.72 (s, 3 H) 3.09- 3.21 (m, 1 H) 2.82-3.09 (m, 4 H) 2.23 (s, 6 H) 2.06 (d, 1 H) 1.73-1.85 (m, 1 H) 348 2-(3- (dimethylamino) pyrrolidin-1-yl)-5- methoxybenzaldehyde Method 11  
    Figure US20150051185A1-20150219-C00105
    44 (5Z)-5-{2-[4- (dimethylamino) piperidin-1-yl]-5- methoxybenzylidene] 1,3-thiazolidine-2,4- dione  
    Figure US20150051185A1-20150219-C00106
         		7.59 (s, 1 H) 7.11-6.99 (m, 2 H) 6.85 (dd, 1 H) 3.75 (s, 3 H) 3.03 (m, 2 H) 2.64-2.54 (m, 2 H) 2.44-2.33 (m, 7 H) 1.91 (s, 2 H) 1.62 (dd, 2 H) 362 2-(4- (dimethylamino)piperidin- 1-yl)-5- methoxybenzaldehyde Method 12  
    Figure US20150051185A1-20150219-C00107
    45 (5Z)-5-[2-(3- hydroxypyrrolidin-1- yl)-4,5- dimethoxybenzylidene]- 1,3-thiazolidine- 2,4-dione  
    Figure US20150051185A1-20150219-C00108
         		12.32 (brs, 1 H) 7.88 (s, 1 H) 6.93 (s, 1 H) 6.66 (s, 1 H) 4.34 (brs, 1 H) 3.83 (s, 3 H) 3.72 (s, 3 H) 3.55- 3.29 (m, 3 H) 3.22 (brs, 1 H) 2.90 (d, 1 H) 2.16- 1.94 (m, 1 H) 1.84 (d, 1 H) 351 2-(3-hydroxypyrrolidin- 1-yl)-4,5- dimethoxybenzaldehyde Method 13  
    Figure US20150051185A1-20150219-C00109
    46 (5Z)-5-(4,5- dimethoxy-2- pyrrolidin-1- ylbenzylidene)-1,3- thiazolidine-2,4- dione  
    Figure US20150051185A1-20150219-C00110
         		12.21 (brs, 1 H) 7.86 (s, 1 H) 6.94 (s, 1 H) 6.65 (s, 1 H) 3.83 (s, 3 H) 3.72 (s,3 H) 3.12 (brs, 4 H) 1.90 (brs, 4 H) 335 4,5-dimethoxy-2- (pyrrolidin-1- yl)benzaldehyde Method 14  
    Figure US20150051185A1-20150219-C00111
    47 (5Z)-5-{2-[[2- (dimethylamino)ethyl] (methyl)amino] benzylidene}-1,3- thiazolidine-2,4- dione  
    Figure US20150051185A1-20150219-C00112
         		7.62 (s, 1 H) 7.48 (d, 1 H) 7.32 (t, 1 H) 7.17 (d, 1 H) 7.10 (t, 1 H) 3.06 (t, 2 H) 2.86-2.62 (m, 5 H) 2.36 (s, 6 H) 306 2-((2- (dimethylamino)ethyl) (methyl)amino) benzaldehyde Method 15  
    Figure US20150051185A1-20150219-C00113
    48 (5Z)-5-{2-[3- (dimethylamino) pyrrolidin-1- yl]benzylidene}-1,3- thiazolidine-2,4- dione  
    Figure US20150051185A1-20150219-C00114
         		7.52 (s, 1 H) 7.27-7.21 (m, 1 H) 7.14-7.05 (m, 1 H) 6.84 (d, 1 H) 6.77 (t, 1 H) 3.17 (s, 1 H) 3.16- 3.09 (m, 1 H) 3.06-2.94 (m, 2 H) 2.86-2.77 (m, 1 H) 2.16-2.11 (m, 6 H) 2.03-1.92 (m, 1 H) 1.66 (dd, 1 H) 318 2-(3- (dimethylamino)pyrrolidin- 1-yl)benzaldehyde Method 16  
    Figure US20150051185A1-20150219-C00115
    49 (5Z)-5-{2-[4- (dimethylamino) piperidin-1- yl]benzylidene}-1,3- thiazolidine-2,4- dione  
    Figure US20150051185A1-20150219-C00116
         		7.64 (s, 1 H) 7.50 (d, 1 H) 7.35-7.27 (m, 1 H) 7.12 (t, 2 H) 3.22 (m, 2 H) 2.88 (m, 1 H) 2.68 (t, 2 H) 2.63 (s, 6 H) 2.04 (s, 2 H) 1.73 (td, 2 H) 332 2-(4- (dimethylamino)piperidin- 1-yl)benzaldehyde Method 17  
    Figure US20150051185A1-20150219-C00117
    50 (5Z)-5-[2-(4- isopropylpiperazin-1- yl)benzylidene]-1,3- thiazolidine-2,4- dione  
    Figure US20150051185A1-20150219-C00118
         		7.80 (s, 1 H) 7.49-7.43 (m, 1 H) 7.43-7.39 (m, 1 H) 7.22-7.13 (m, 2 H) 2.99-2.88 (m, 5 H) 2.80 (s, 4 H) 1.13-1.04 (m, 6 H) 332 2-(4-isopropylpiperazin- 1-yl)benzaldehyde Method 18  
    Figure US20150051185A1-20150219-C00119
    51 (5Z)-5-{2-[[2- (dimethylamino)ethyl] (methyl)amino]-4,5- dimethoxybenzylidene}- 1,3-thiazolidine- 2,4-dione  
    Figure US20150051185A1-20150219-C00120
         		7.78 (s, 1 H) 7.02 (s, 1 H) 6.85 (s, 1 H) 3.83 (s, 3 H) 3.76 (s, 3 H) 3.11-2.98 (m, 2 H) 2.76-2.65 (m, 5 H) 2.37 (s, 6 H) 364 2-((2- (dimethylamino)ethyl) (methyl)amino)-4,5- dimethoxybenzaldehyde Method 19  
    Figure US20150051185A1-20150219-C00121
    52 (5Z)-5-{2-[3- (dimethylamino) pyrrolidin-1-yl]-4,5- dimethoxybenzylidone- 1,3-thiazolidine- 2,4-dione  
    Figure US20150051185A1-20150219-C00122
         		7.76 (s, 1 H), 6.98 (s, 1 H), 6.68 (s, 1 H), 3.83 (s, 3 H), 3.72 (s, 3 H), 3.25 (m, 1 H), 3.13 (m, 2 H), 3.06 (m, 2 H), 2.32 (s, 6 H), 2.15-2.09 (m, 1 H) 1.90-1.81 (m, 1 H) 378 2-(3- (dimethylamino) pyrrolidin-1-yl)-4,5- dimethoxybenzaldehyde Method 20  
    Figure US20150051185A1-20150219-C00123
    53 (5Z)-5-{2-(4- isopropylpiperazin-1- yl)-4,5- dimethoxybenzylidene}- thiazolidine-2,4- dione  
    Figure US20150051185A1-20150219-C00124
         		7.86 (s, 1 H) 6.95 (s, 1 H) 6.77 (s, 1 H) 3.81 (s, 3 H) 3.76-3.67 (m, 3 H) 2.91- 2.79 (m, 5 H) 2.71 (s, 4 H) 1.08-1.00 (m, 6 H) 392 2-(4-isopropylpiperazin- 1-yl)-4,5- dimethoxybenzaldehyde Method 21  
    Figure US20150051185A1-20150219-C00125
    54 (5Z)-5-{2-(4- (dimethylamino) piperidin-1-yl)-4,5- dimethoxybenzylidene}- thiazolidine-2,4- dione  
    Figure US20150051185A1-20150219-C00126
         		7.48 (s, 1 H) 6.82 (s, 1 H) 6.51 (s, 1 H) 3.58 (s, 3 H) 3.51 (s, 3 H) 2.87 (d, 2 H) 2.47 (m, 3 H) 2.35 (s, 6 H) 1.79 (d, 2 H) 1.49 (d, 2 H) 392 2-(4- (dimethylamino)piperidin- 1-yl)-4,5- dimethoxybenzaldehyde Method 22  
    Figure US20150051185A1-20150219-C00127
    55 (Z)-tert-butyl 4-(2- ((2,4- dioxothiazolidin-5- ylidene)methyl)-4- (trifluoromethyl) phenyl)piperazine-1- carboxylate  
    Figure US20150051185A1-20150219-C00128
         		12.65 (s, 1 H) 7.82 (s, 1 H) 7.72 (s, 1 H) 7.53 (s, 1 H) 3.59-3.50 (m, 1 H) 3.38-3.30 (m, 4 H) 2.56 (s, 6 H) 2.31-2.28 (m, 1 H) 2.09-2.01 (m, 1 H) 458 tert-butyl 4-(2-formyl-4- (trifluoromethyl)phenyl) piperazine-1-carboxylate Method 23  
    Figure US20150051185A1-20150219-C00129
    56 (Z)-5-(2-(3- (dimethylamino) pyrrolidin-1-yl)-5- nitrobenzylidene) thiazolidine-2,4-dione hydrochloride  
    Figure US20150051185A1-20150219-C00130
         		12.64 (s, 1 H) 8.22 (d, 1 H) 8.12 (d, 1 H) 7.95 (d, 1 H) 7.04 (d, 1 H) 3.95- 3.90 (m, 1 H) 3.70-3.65 (m, 2 H) 3.56-3.51 (m, 2 H) 2.79 (s, 6 H) 2.41- 2.35 (m, 1 H) 2.34-2.22 (m, 1 H) 363 2-(3- (dimethylamino) pyrrolidin-1-yl)-5- nitrobenzaldehyde Method 24  
    Figure US20150051185A1-20150219-C00131
    57 (Z)-4-(3- (dimethylamino) pyrrolidin-1-yl)-3-((2,4- dioxothiazolidin-5- ylidene)methyl) benzamide hydrochloride  
    Figure US20150051185A1-20150219-C00132
         		12.47 (s, 1 H) 7.92-7.84 (m, 4 H) 7.23 (s, 1 H) 7.03 (d, 1 H) 3.98-3.91 (m, 1 H) 3.53-3.49 (m, 2 H) 3.46-3.39 (m, 2 H) 2.79 (s, 6 H) 2.34-2.19 (m, 2 H) 361 4-(3- (dimethylamino) pyrrolidin-1-yl)-3- formylbenzamide Method 25  
    Figure US20150051185A1-20150219-C00133
    58 (Z)-tert-butyl 4-(2- ((2,4- dioxothiazolidin-5- ylidene)methyl) phenyl)piperazine-1- carboxylate  
    Figure US20150051185A1-20150219-C00134
         		12.55 (s, 1 H) 7.92 (s, 1 H) 7.46-7.44 (m, 2 H) 7.21-7.18 (m, 2 H) 3.48 (brs, 4 H) 2.86 (brs, 4 H) 1.43 (s, 9 H) 389 tert-butyl 4-(2- formylphenyl)piperazine- 1-carboxylate Method 26  
    Figure US20150051185A1-20150219-C00135
    59 (Z)-5-(3-methoxy-4- (2-(piperidin-1- yl)ethoxy)benzylidene) thiazolidine-2,4- dione  
    Figure US20150051185A1-20150219-C00136
         		7.78 (s, 1 H) 7.27 (s, 1 H) 7.21 (s, 2 H) 4.47 (t, 2 H) 3.84 (s, 3 H) 3.49 (t, 4 H) 3.04 (brs, 2H) 1.80 (d, 4 H) 1.64 (brs, 1 H) 1.43 (brs, 1 H) 363 3-methoxy-4-(2- (piperidin-1- yl)ethoxy)benzaldehyde Commercial  
    Figure US20150051185A1-20150219-C00137
    60 (Z)-5-(2-(2- hydroxyethoxy) benzylidene) thiazolidine- 2,4-dione  
    Figure US20150051185A1-20150219-C00138
         		12.58 (brs, 1 H) 8.06 (s, 1 H) 7.57-7.32 (m, 2 H) 7.26-7.03 (m, 2 H) 4.95 (brs, 1 H) 4.13 (t, 2 H) 3.77 (brs, 2 H) 266 2-(2- hydroxyethoxy) benzaldehyde Commercial  
    Figure US20150051185A1-20150219-C00139
    61 (Z)-5-(5-methoxy-2- (2-(piperidin-1- yl)ethoxy) benzylidene) thiazolidine-2,4- dione  
    Figure US20150051185A1-20150219-C00140
         		7.80 (s, 1 H) 7.10 (d, 1 H) 7.04-6.95 (m, 2 H) 4.22 (t, 2 H) 3.75 (s, 3 H) 3.07 (t, 2 H) 2.84 (s, 4 H) 1.62 (dq, 4 H) 1.46 (d, 2 H) 363 5-methoxy-2-(2- (piperidin-1- yl)ethoxy)benzaldehyde Method 27  
    Figure US20150051185A1-20150219-C00141
    62 (Z)-5-(5-methoxy-2- (2- morpholinoethoxy) benzylidene) thiazolidine-2,4-dione  
    Figure US20150051185A1-20150219-C00142
         		7.99 (s, 1 H) 7.22-7.10 (m, 1 H) 7.09-6.97 (m, 1 H) 6.91 (d, 1 H) 4.17 (t, 2 H) 3.76 (s, 3 H) 3.64- 3.51 (m, 4 H) 2.75 (t, 2 H) 2.51-2.62 (m, 4 H) 365 5-methoxy-2-(2- morpholinoethoxy) benzaldehyde Method 28  
    Figure US20150051185A1-20150219-C00143
    63 (Z)-5-(2-(2- (diethylamino)ethoxy)- 5-methoxybenzylidene) thiazolidine-2,4- dione  
    Figure US20150051185A1-20150219-C00144
         		7.77 (s, 1 H) 7.08-7.05 (m, 1 H) 7.03-6.95 (m, 2 H) 4.19 (t, 2 H) 3.75 (s, 3 H) 3.25-3.14 (m, 2 H) 2.95 (q, 4 H) 1.17-1.08 (m, 6 H) 352 2-(2- (diethylamino)ethoxy)-5 methoxybenzaldehyde Method 29  
    Figure US20150051185A1-20150219-C00145
    64 (Z)-5-(2-(2- (diethylamino) ethoxy)benzylidene) thiazolidine-2,4-dione  
    Figure US20150051185A1-20150219-C00146
         		7.84 (s, 1 H) 7.47 (d, 1 H) 7.43-7.35 (m, 1 H) 7.14-7.04 (m, 2 H) 4.24 (t, 2 H) 3.20 (m, 2 H) 2.90 (q, 4 H) 1.13 (t, 6 H) 321 2-(2- (diethylamino)ethoxy) benzaldehyde Method 30  
    Figure US20150051185A1-20150219-C00147
    65 (Z)-5-(4,5- dimethoxy-2- (pyridin-3- yl)benzylidene) thiazolidine-2,4-dione  
    Figure US20150051185A1-20150219-C00148
         		12.55 (brs, 1 H) 8.73- 8.61 (m, 1 H) 8.58 (brs, 1 H) 7.81 (dd, 1 H) 7.53 (dd, 1 H) 7.46 (s, 1 H) 7.13 (d, 2 H) 3.89 (d, 6 H) 343 4,5-dimethoxy-2- (pyridin-3- yl)benzaldehyde Method 31  
    Figure US20150051185A1-20150219-C00149
    66 (Z)-5-(4,5- dimethoxy-2- (pyridin-4- yl)benzylidene) thiazolidine-2,4-dione  
    Figure US20150051185A1-20150219-C00150
         		12.58 (brs, 1 H) 8.67 (d, 2 H) 7.48 (d, 1 H) 7.41 (d, 2 H) 7.12 (d, 2 H) 3.89 (s, 6 H) 343 4,5-dimethoxy-2- (pyridin-4- yl)benzaldehyde Method 32  
    Figure US20150051185A1-20150219-C00151
    67 (Z)-5-((1H-indol-3- yl)methylene) thiazolidine-2,4-dione  
    Figure US20150051185A1-20150219-C00152
         		7.21 (dddd, 2 H) 7.50 (d, 1 H) 7.71 (d, 1 H) 7.87 (d, 1 H) 7.99 (s, 1 H) 12.07 (brs, 2 H) 245 1H-indole-3- carbaldehyde Commercial  
    Figure US20150051185A1-20150219-C00153
    68 (Z)-5-((1H-indazol-3- yl)methylene) thiazolidine-2,4-dione  
    Figure US20150051185A1-20150219-C00154
         		7.28 (t, 1 H) 7.52-7.39 (m, 1 H) 7.64 (d, 1 H) 8.22-8.03 (m, 2 H) 12.41 (d, 1 H) 13.96 (s, 1 H) 246 1H-indazole-3- carbaldehyde Commercial  
    Figure US20150051185A1-20150219-C00155
    69 (Z)-5-((6-oxo-1,6- dihydropyridin-3- yl)methylene) thiazolidine-2,4-dione  
    Figure US20150051185A1-20150219-C00156
         		11.99 (brs, 1 H) 7.74 (brs, 1 H) 7.69-7.58 (m, 1 H) 7.27 (s, 1 H) 6.43 (d, 1 H) 223 6-oxo-1,6- dihydropyridine-3- carbaldehyde Commercial  
    Figure US20150051185A1-20150219-C00157
    70 (Z)-5-((2-oxo-1,2- dihydropyridin-3- yl)methylene) thiazolidine-2,4-dione  
    Figure US20150051185A1-20150219-C00158
         		12.43 (brs, 1 H) 12.16 (brs, 1 H) 7.73 (s, 1 H) 7.69 (dd, 1 H) 7.57 (d, 1 H) 6.38 (t, 1 H) 223 2-oxo-1,2- dihydropyridine-3- carbaldehyde Commercial  
    Figure US20150051185A1-20150219-C00159
    71 (Z)-5-((1H-pyrazol-4- yl)methylene) thiazolidine-2,4-dione  
    Figure US20150051185A1-20150219-C00160
         		13.51 (brs, 1 H) 12.37 (brs, 1 H) 8.20 (s, 1 H) 7.82 (s, 1 H) 7.74 (s, 1 H) 196 1H-pyrazole-4- carbaldehyde Commercial  
    Figure US20150051185A1-20150219-C00161
    72 (Z)-5-(pyridin-4- ylmethylene) thiazolidine-2,4-dione  
    Figure US20150051185A1-20150219-C00162
         		12.61 (brs, 1 H) 8.71 (d, 2 H) 7.74 (s, 1 H) 7.53 (d, 2 H) 207 4- pyridinecarboxaldehyde Commercial  
    Figure US20150051185A1-20150219-C00163
    73 (5Z)-5-[(1-methyl- 1H-1,2,3- benzotriazol-5- yl)methylene]-1,3- thiazolidine-2,4- dione  
    Figure US20150051185A1-20150219-C00164
         		12.65 (brs, 1 H) 8.28 (s, 1 H) 8.00-7.98 (m, 2 H) 7.76 (d, 1 H) 4.33 (s, 3 H) 259 1-methyl-1H- benzo[d][1,2,3]triazole- 5-carbaldehyde Commercial  
    Figure US20150051185A1-20150219-C00165
    74 (5Z)-5-(3,4- dimethoxybenzylidene)- 1,3-thiazolidine- 2,4-dione  
    Figure US20150051185A1-20150219-C00166
         		12.51 (brs, 1 H) 7.74 (s, 1 H) 7.19-7.09 (m, 3 H) 3.82 (s, 3 H) 3.80 (s, 3 H) 266 3,4- dimethoxybenzaldehyde Commercial  
    Figure US20150051185A1-20150219-C00167
    75 (5Z)-5-[(1-methyl- 1H-indol-6- yl)methylene]-1,3- thiazolidine-2,4- dione  
    Figure US20150051185A1-20150219-C00168
         		12.49 (brs, 1 H) 7.92 (s, 1 H) 7.68 (d, 1 H) 7.54 (s 1 H) 7.25 (d, 1 H) 6.50 (s, 1 H) 3.84 (s, 3 H) 1-methyl-1H-indole-6- carbaldehyde Commercial  
    Figure US20150051185A1-20150219-C00169
    76 (5Z)-5-[(1-methyl- 1H-indol-5- yl)methylene]-1,3- thiazolidine-2,4- dione  
    Figure US20150051185A1-20150219-C00170
         		12.45 (brs, 1 H) 7.90 (s, 1 H) 7.84 (d, 1 H) 7.59 (d, 1 H) 7.44 (d, 1 H) 7.38 (d 1 H) 6.57 (d, 1 H) 3.82 (s, 3 H) 259 1-methyl-1H-indole-5- carbaldehyde Commercial  
    Figure US20150051185A1-20150219-C00171
    77 (5Z)-5-(quinolin-6- ylmethylene)-1,3- thiazolidine-2,4- dione trifluoroacetate  
    Figure US20150051185A1-20150219-C00172
         		12.70 (brs, 1 H) 8.97 (d, 1 H) 8.51 (d, 1 H) 8.24 (s, 1 H) 8.12 (d, 1 H) 7.96-7.93 (m, 2 H) 7.64- 7.61 (m, 1 H) 257 quinoline-6-carbaldehyde Commercial  
    Figure US20150051185A1-20150219-C00173
    78 (5Z)-5-(1H-indol-5- ylmethylene)-1,3- thiazolidine-2,4- dione  
    Figure US20150051185A1-20150219-C00174
         		12.43 (brs, 1 H) 11.44 (brs, 1 H) 7.85 (d, 1 H) 7.53-7.51 (m, 2 H) 7.45- 7.44 (m, 1 H) 7.33 (d, 1 H) 6.56 (s, 1 H) 245 1H-indole-5- carbaldehyde Commercial  
    Figure US20150051185A1-20150219-C00175
    79 (5Z)-5-(1H-indol-6- ylmethylene)-1,3- thiazolidine-2,4- dione trifluoroacetate  
    Figure US20150051185A1-20150219-C00176
         		12.47 (brs, 1 H) 11.48 (brs, 1 H) 7.90 (s, 1 H) 7.69-7.66 (m, 2 H) 7.55- 7.52 (m, 1 H) 7.23 (d, 1 H) 6.51 (s, 1 H) 245 1H-indole-6- carbaldehyde Commercial  
    Figure US20150051185A1-20150219-C00177
    80 (5Z)-5-(1H- pyrrolo[2,3- b]pyridin-5- ylmethylene)-1,3- thiazolidine-2,4- dione  
    Figure US20150051185A1-20150219-C00178
         		12.02 (brs, 1 H) 8.49 (d, 1 H) 8.15 (d, 1 H) 7.92 (s, 1 H) 7.58 (t, 1 H) 6.59 (brs, 1 H) 246 1H-pyrrolo[2,3- b]pyridine-5- carbaldehyde Commercial  
    Figure US20150051185A1-20150219-C00179
    81 (5Z)-5-{2-[3- (dimethylamino) propoxy]benzylidene}- 1,3-thiazolidine-2,4- dione  
    Figure US20150051185A1-20150219-C00180
         		8.16 (s, 1 H) 7.76 (s, 1 H) 7.48 (d, 1 H) 7.34 (s, 1 H) 7.08 (d, 1 H) 4.11 (t, 2 H) 2.86 (1, 2 H) 2.53 (s, 6 H) 2.10-1.98 (m, 2 H) 307 2-[3- (dimethylamino) propoxy]benzaldehyde Commercial  
    Figure US20150051185A1-20150219-C00181
    82 (5Z)-5-(2-morpholin- 4-ylbenzylidene)-1,3- thiazolidine-2,4- dione  
    Figure US20150051185A1-20150219-C00182
         		7.89 (s, 1 H) 7.46 (d, 1 H) 7.45-7.41 (m, 1 H) 7.22-7.14 (m, 2 H) 3.80- 3.69 (m, 4 H) 2.93- 2.82 (m, 4 H) 291 2-morpholin-4- ylbenzaldehyde Commercial  
    Figure US20150051185A1-20150219-C00183
    83 (5Z)-5-(3-morpholin- 4-ylbenzylidene)-1,3- thiazolidine-2,4- dione trifluoroacetate  
    Figure US20150051185A1-20150219-C00184
         		12.58 (brs, 1 H) 7.74 (s, 1 H) 7.37 (t, 1 H) 7.12 (s, 1 H) 7.07 (dd, 1 H) 7.00 (d, 1 H) 3.79-3.69 (m, 4 H) 3.20-3.09 (m, 4 H) 290 3-morpholin-4- ylbenzaldehyde Commercial  
    Figure US20150051185A1-20150219-C00185
    84A (5Z)-5-[2-(4- methylpiperazin-1- yl)benzylidene]-1,3- thiazolidine-2,4- dione  
    Figure US20150051185A1-20150219-C00186
         		7.78 (s, 1 H) 7.46 (d, 1 H) 7.42-7.35 (m, 1 H) 7.19-7.11 (m, 2 H) 2.94 (t, 4 H) 2.70 (brs, 4 H) 2.40 (s, 3 H) 304 2-(4-methylpiperazin-1- yl)benzaldehyde Commercial  
    Figure US20150051185A1-20150219-C00187
    84B (Z)-5-(3-(3-(4- methylpiperazin-1- yl)propoxy)benzylidene) thiazolidine-2,4- dione  
    Figure US20150051185A1-20150219-C00188
         		11.37 (brs, 1 H) 7.54 (s, 1 H) 7.38 (t, 1 H) 7.12 (m, 2 H), 6.96 (m, 1 H) 4.58 (s, 3 H) 4.05 (t, 2 H) 3.00- 2.55 (m, 10 H) 1.93 (m, 2 H) 362 3-(3-(4-methylpiperazin- 1- yl)propoxy)benzaldehyde hydrochloride  
    Figure US20150051185A1-20150219-C00189
    84C (Z)-2-(3-((2,4- dioxothiazolidin-5- ylidene)methyl) phenoxy)acetamide  
    Figure US20150051185A1-20150219-C00190
         		12.62 (s, 1 H) 7.73 (s, 1 H) 7.60 (s, 1 H) 7.44 (t, 1 H) 7.41 (s, 1 H) 7.19 (d, 1 H) 7.14 (m, 1 H) 7.05 (dd, 1 H) 4.48 (s, 2 H) 279 2-(3- formylphenoxy)acetamide  
    Figure US20150051185A1-20150219-C00191
    84D (Z)-5-(3-(3- (piperidin-1- yl)propoxy)benzylidene) thiazolidine-2,4- dione  
    Figure US20150051185A1-20150219-C00192
         		7.30 (t, 1 H) 7.24 (s, 1 H) 7.08 (m, 2 H) 6.85 (dd, 1 H) 4.01 (t, 2 H) 2.45 (t, 2 H) 2.40 (m, 4 H) 1.88 (m, 2H) 1.50 (m, 4 H) 1.38 (m, 2 H) 347 3-(3-(piperidin-1- yl)propoxy)bcnzaldehyde hydrochloride  
    Figure US20150051185A1-20150219-C00193
    84E (Z)-5-(3-((4- methylpiperazin-1- yl)methyl)benzylidene) thiazolidine-2,4- dione  
    Figure US20150051185A1-20150219-C00194
         		7.59 (s, 1 H) 7.51 (s, 1 H) 7.46 (m, 2 H) 7.34 (m, 1 H) 3.59 (s, 2 H) 2.96 (m, 4 H) 2.59 (m, 4 H) 2.58 (s, 3 H) 318 3-((4-methylpiperazin-1- yl)methyl)benzaldehyde  
    Figure US20150051185A1-20150219-C00195
    84F (Z)-N-(2- (dimethylamino) ethyl)-2′-((2,4- dioxothiazolidin-5- ylidene)methyl)-N- methylbiphenyl-4- sulfonamide  
    Figure US20150051185A1-20150219-C00196
         		7.90 (d, 2 H) 7.69 (d, 1 H) 7.65-7.49 (m, 4 H) 7.49-7.40 (m, 1 H) 7.31 (s, 1 H) 3.24 (t, 2 H) 2.83 (t, 2 H) 2.78 (s, 3 H) 2.48 (s, 6 H) 445 N-(2- (dimethylamino)ethyl)- 2′-formyl-N- methylbiphenyl-4- sulfonamide Method 32B  
    Figure US20150051185A1-20150219-C00197
    84G (S)-5-(2-(3- (dimethylamino) pyrrolidin-1-yl)-5- methoxybenzylidene) thiazolidine-2,4- dione  
    Figure US20150051185A1-20150219-C00198
         		348 (S)-2-(3- (dimethylamino) pyrrolidin-1-yl)-5- methoxybenzaldehyde Method 104  
    Figure US20150051185A1-20150219-C00199
    84H (S)-5-(2-(3- (dimethylamino) pyrrolidin-1-yl)-5- (trifluoromethyl) benzylidene)thiazolidine- 2,4-dione  
    Figure US20150051185A1-20150219-C00200
         		12.55 (s, 1 H) 11.25 (brs, 1 H) 7.95 (s, 1 H) 7.78 (s, 1 H) 7.60 (m, 1 H), 7.15 (m, 1 H) 4.00 (m, 1 H) 3.65 (m, 2 H) 3.40 (m, 1 H) 3.32 (m, 1 H) 2.80 (s, 6 H) 2.35 (m, 1 H) 2.20 (m, 1 H) 386 (S)-2-(3- (dimethylamino) pyrrolidin-1-yl)-5- (trifluoromethyl) benzaldehyde Method 105  
    Figure US20150051185A1-20150219-C00201
    84I (S)-5-(5-chloro-2-(3- (dimethylamino) pyrrolidin-1- yl)benzylidene) thiazolidine-2,4-dione  
    Figure US20150051185A1-20150219-C00202
         		12.55 (s, 1 H) 7.81 (s, 1H), 7.93 (m, 2H), 7.12 (m, 1H), 3.90 (m, 1H), 3.45-3.30 (m, 2H), 3.29 (m, 1H), 3.15 (m, 1H), 2.80 (s, 6H), 2.35 (m, 1H), 2.20 (m, 1H) 352 (S)-5-chloro-2-(3- (dimcthylamino) pyrrolidin-1- yl)benzaldehyde Method 106  
    Figure US20150051185A1-20150219-C00203
    84J (S)-5-(2-(3- (dimethylamino) pyrrolidin-1-yl)-4- methylbenzylidene) thiazolidine-2,4-dione  
    Figure US20150051185A1-20150219-C00204
         		332 (S)-2-(3- (dimethylamino) pyrrolidin-1-yl)-4- methylbenzaldehyde Method 107  
    Figure US20150051185A1-20150219-C00205
    84K (S)-5-(2-(3- (dimethylamino) pyrrolidin-1-yl)-5- fluorobenzylidene) thiazolidine-2,4-dione  
    Figure US20150051185A1-20150219-C00206
         		12.55 (s, 1 H) 11.40 (s, 1 H) 7.80 (s, 1 H) 7.30- 7.15 (m, 3 H) 3.92 (m, 1 H) 3.45 (m, 1 H) 3.35 (m, 1 H) 3.18 (m, 1 H) 3.15 (m, 1 H) 3.80 (d, 6 H) 2.30 (m, 1 H), 2.20 (m, 1H) 336 (S)-2-(3- (dimethylamino) pyrrolidin-1-yl)-5- fluorobenzaldehyde Method 108  
    Figure US20150051185A1-20150219-C00207
    84L (S)-5-(2-(3- (dimethylamino) pyrrolidin-1-yl)-5- methylbenzylidene) thiazolidine-2,4-dione  
    Figure US20150051185A1-20150219-C00208
         		332 (S)-2-(3- (dimethylamino) pyrrolidin-1-yl)-5- methylbenzaldehyde Method 109  
    Figure US20150051185A1-20150219-C00209
    84M (S)-5-(5-bromo-2-(3- (dimethylamino) pyrrolidin-1- yl)benzylidene) thiazolidine-2,4-dione  
    Figure US20150051185A1-20150219-C00210
         		397 (S)-5-bromo-2-(3- (dimethylamino) pyrrolidin-1-yl) benzaldehyde Method 110  
    Figure US20150051185A1-20150219-C00211
    84N (S)-5-(2-(3- (dimethylamino) pyrrolidin-1-yl)-3- fluorobenzylidene) thiazolidine-2,4-dione  
    Figure US20150051185A1-20150219-C00212
         		12.55 (s, 1 H) 10.34 (s, 1 H) 7.87 (d, 1H) 7.33-7.21 (m, 3 H) 3.93 (m, 1 H) 3.40 (m, 2 H) 3.25 (m, 1 H) 3.18 (m, 1 H) 2.79 (s, 6 H) 2.26 (m, 1H) 2.12 (m, 1H) 336 (S)-2-(3- (dimethylamino) pyrrolidin-1-yl)-3- fluorobenzaldehyde Method 111  
    Figure US20150051185A1-20150219-C00213
    84O (S)-5-(2-chloro-6-(3- (dimethylamino) pyrrolidin-1- yl)benzylidene) thiazolidine-2,4-dione  
    Figure US20150051185A1-20150219-C00214
         		352 (S)-2-chloro-6-(3- (dimethylamino) pyrrolidin-1-yl) benzaldehyde Method 112  
    Figure US20150051185A1-20150219-C00215
    • Example 85
  • Figure US20150051185A1-20150219-C00216
    • (S,Z)-5-(2-(3-aminopyrrolidin-1-yl)-4-chlorobenzylidene)thiazolidine-2,4-dione hydrochloride
  • A 100 mL round bottom flask was charged with a magnetic stir bar, (S,Z)-tert-butyl 1-(5-chloro-2-((2,4-dioxothiazolidin-5-ylidene)methyl)phenyl)pyrrolidin-3-ylcarbamate (Method 33) (1.300 g, 3.07 mmol), MeOH (10.22 ml), and a 1N sol'n of HCl in diethyl ether (2.294 ml, 46.00 mmol). The reaction mixture was allowed to stir overnight at rt before being conc. in vacuo to afford the product as its hydrochloride salt. This material was dissolved in DMSO and purified via reverse phase HPLC to afford fractions that were conc. in vacuo, suspended in methanol (˜5 mL) and 1N HCl in diethyl ether (˜2 mL). This mixture was conc. in vacuo to afford (S,Z)-5-(2-(3-aminopyrrolidin-1-yl)-4-chlorobenzylidene)thiazolidine-2,4-dione hydrochloride (0.710 g, 64.3%). 1H NMR (300 MHz, DMSO-D6) δ ppm 12.51 (s, 1H) 8.36 (s, 2H) 7.85 (s, 1H) 7.35 (d, 1H) 6.96 (dd, 2H) 3.90-3.75 (m, 1H) 3.55-3.47 (m, 1H) 3.40 (dd, 1H) 3.31-3.21 (m, 1H) 3.18-3.10 (m, 1H) 2.29-2.18 (m, 1H) 2.10-1.96 (m, 1H); m/z 325.
  • The following examples were prepared by the procedure of Example 85, using the appropriate starting materials. The following parent compounds obtained after chromatography may be converted to their corresponding hydrochloride salt in a manner similar as described in example 85, or similar procedure.
  • Ex. Compound 1H NMR m/z SM
    86 (S,Z)-5-(2-(3- aminopyrrolidin-1- yl)-3- chlorobenzylidene) thiazolidine-2,4-dione hydrochloride  
    Figure US20150051185A1-20150219-C00217
         		12.69 (s, 1 H) 8.35 (brs, 2 H) 7.94 (s 1 H) 7.57 (d, 1 H) 7.41-7.35 (m, 2 H) 3.95-3.88 (m, 1 H) 3.53- 3.26 (m, 4 H) 2.37- 2.31 (m, 1 H) 2.08-2.01 (m, 1 H) 324 (S,Z)-tert-butyl 1-(2- chloro-6-((2,4- dioxothiazolidin-5- ylidene)methyl)phenyl) pyrrolidin-3-ylcarbamate Method 34  
    Figure US20150051185A1-20150219-C00218
    87 (Z)-5-(2-(piperazin-1- yl)-5- (trifluoromethyl) benzylidene) thiazolidine- 2,4-dione hydroehloride  
    Figure US20150051185A1-20150219-C00219
         		12.69 (s, 1 H) 9.32 (brs, 2 H) 7.79 (d, 1 H) 7.71 (d, 2 H) 7.37 (d, 1 H) 3.23 (s, 8 H) 358 (Z)-tert-butyl 4-(2-((2,4- dioxothiazolidin-5- ylidene)methyl)-4- (trifluoromethyl)phenyl) piperazine-1-carboxylate Method 35  
    Figure US20150051185A1-20150219-C00220
    88 (S,Z)-5-(2-(3- aminopyrrolidin-1- yl)-5- (trifluoromethyl) benzylidene) thiazolidine- 2,4-dione hydrochloride  
    Figure US20150051185A1-20150219-C00221
         		12.53 (s, 1 H) 8.17 (brs, 2 H) 7.95 (s, 1 H) 7.65 (s, 1 H) 7.59 (d 1 H) 7.05 (d, 1 H) 3.90-3.81 (m, 1 H) 3.56 (q, 1 H) 3.47-3.35 (m, 2 H) 3.18 (dd, 1 H) 2.33-2.18 (m, 1 H) 2.09- 1.99 (m, 1 H) 358 (S,Z)-tert-butyl 1-(2- ((2,4-dioxothiazolidin-5- ylidene)methyl)-4- (trifluoromethyl)phenyl) pyrrolidin-3-ylcarbamate Method 36  
    Figure US20150051185A1-20150219-C00222
    89 (Z)-5-((2-(piperazin- 1-yl)pyridin-3- yl)methylene) thiazolidine-2,4-dione hydrochloride  
    Figure US20150051185A1-20150219-C00223
         		12.65 (s, 1 H) 8.39 (s, 1 H) 8.33 (d, 1 H) 7.83 (d, 1 H) 7.63 (s, 1 H) 7.15 (dd, 1 H) 3.41 (brs, 4 H) 3.17 (brs, 4 H) 291 (Z)-tert-butyl 4-(3-((2,4- dioxothiazolidin-5- ylidene)methyl)pyridin- 2-yl)piperazine-1- carboxylate Method 37  
    Figure US20150051185A1-20150219-C00224
    90 (Z)-5-((2-(4-(3- aminopropanoyl) piperazin-1-yl)pyridin-3- yl )methylene) thiazolidine-2,4-dione trifluoroacetate  
    Figure US20150051185A1-20150219-C00225
         		12.60 (s, 1 H) 8.32 (d, 1 H) 7.82 (s, 1 H) 7.68 (s, 1 H) 7.63 (brs, 2 H) 7.12 (dd, 1 H) 3.57 (d, 4 H) 3.17 (d, 4 H) 3.00 (q, 2 H) 2.70 (t, 2 H) 362 (Z)-tert-butyl 3-(4-(3- ((2,4-dioxothiazolidin-5- ylidene)methyl)pyridin- 2-yl)piperazin-1-yl)-3- oxopropylcarbamate Method 38  
    Figure US20150051185A1-20150219-C00226
    91 (Z)-5-(2-(4- (piperidine-4- carbonyl)piperazin-1- yl)benzylidene) thiazolidine-2,4-dione  
    Figure US20150051185A1-20150219-C00227
         		9.00 (brs, 1 H) 8.67 (brs, 1 H) 8.18 (s, 1 H) 7.57- 7.52 (m, 1 H) 7.30-7.16 (m, 1 H) 3.71 (s, 1 H) 3.63 (s, 1 H) 3.34 (s, 3 H) 3.31-3.22 (m, 2 H) 3.13 (s, 3 H) 3.01-2.87 (m, 5 H) 1.85-1.77 (m, 4 H) 401 (Z)-tert-butyl 4-(4-(2- ((2,4-dioxothiazolidin-5- ylidene)methyl)phenyl) piperazine-1- carbonyl)piperidine-1- carboxylate Method 39  
    Figure US20150051185A1-20150219-C00228
    92 (Z)-5-(2-(4- (piperidine-3- carbonyl)piperazin-1- yl)-5- (trifluoromethyl) benzylidene) thiazolidine- 2,4-dione hydrochloride  
    Figure US20150051185A1-20150219-C00229
         		12.68 (s, 1 H) 8.87 (s, 1 H) 7.78-7.69 (m, 3 H) 7.32 (d, 1 H) 3.68-3.64 (m, 8 H) 3.38 (tt, 1 H) 3.13-2.98 (m, 4 H) 1.75- 1.56 (m, 4 H) 469 (Z)-tert-butyl 3-(4-(2- ((2,4-dioxothiazolidin-5- ylidene)methyl)-4- (trifluoromethyl)phenyl) piperazine-1- carbonyl)piperidine-1- carboxylate Method 40  
    Figure US20150051185A1-20150219-C00230
    93 (Z)-5-(2-(4-(3- aminopropanoyl) piperazin-1-yl)-5- (trifluoromethyl) benzylidene) thiazolidine- 2,4-dione hydrochloride  
    Figure US20150051185A1-20150219-C00231
         		12.67 (s 1 H) 7.93 (brs, 2 H) 7.78-7.68 (m, 3 H) 7.32 (d, 1 H) 3.69-3.59 (m, 8 H) 3.00-2.74 (m, 4 H) 429 (Z)-tert-butyl 3-(4-(2- ((2,4-dioxothiazolidin-5- ylidene)methyl)-4- (trifluoromethyl)phenyl) piperazin-1-yl)-3- oxopropylcarbamate Method 41  
    Figure US20150051185A1-20150219-C00232
    94 (Z)-5-(2-(4-(3- aminopropanoyl) piperazin-1-yl)-3- methoxybenzylidene) thiazolidine-2,4- dione hydrochloride  
    Figure US20150051185A1-20150219-C00233
         		12.53 (brs, 1 H) 8.21 (s, 1 H), 7.58 (brs, 3 H), 7.24 (t, 1 H) 7.11 (d, 1 H) 7.00 (d, 1 H) 3.75 (s, 3 H) 3.35 (brs, 4 H) 3.09- 2.85 (m, 4 H) 2.65 (brs, 2 H) 391 (Z)-tert-butyl 3-(4-(2- ((2,4-dioxothiazolidin-5- ylidene)methyl)-6- methoxyphenyl) piperazin-1-yl)-3- oxopropylcarbamate Method 42  
    Figure US20150051185A1-20150219-C00234
    95 (Z)-5-(2-(4-(3- aminopropanoyl) piperazin-1-yl)-3- chlorobenzylidene) thiazolidine-2,4-dione hydrochloride  
    Figure US20150051185A1-20150219-C00235
         		12.69 (brs, 1 H) 8.12 (s, 1 H) 7.67 (brs, 2 H) 7.55 (dd, 1 H) 7.49-7.40 (m, 1 H) 7.35 (t, 1 H) 4.17 (brs, 1 H) 3.75 (brs, 1 H) 3.35 (brs, 3 H) 3.13- 2.84 (m, 5 H) 2.74 (brs, 2 H) 395 (Z)-tert-butyl 3-(4-(2- chloro-6-((2,4- dioxothiazolidin-5- ylidene)methyl)phenyl) piperazin-1-yl)-3- oxopropylcarbamate Method 43  
    Figure US20150051185A1-20150219-C00236
    96 (S,Z)-5-(2-(3- aminopyrrolidin-1- yl)-3- methoxybenzylidene) thiazolidine-2.4- dione hydrochloride  
    Figure US20150051185A1-20150219-C00237
         		12.43 (s, 1 H) 7.94 (s, 1 H) 7.86 (brs, 1 H) 7.16 (t, 1 H) 7.05 (d, 1 H) 6.91 (d, 1 H) 3.71 (s, 3 H) 3.30 (dd, 1 H) 3.17-3.08 (m, 1 H) 3.08-2.91 (m, 2 H) 2.23-2.06 (m, 2 H), 1.80-1.75 (m, 1 H) 320 (S,Z)-tert-butyl 1-(2- ((2,4-dioxothiazolidin-5- ylidene)methyl)-6- methoxyphenyl) pyrrolidin-3-ylcarbamate Method 44  
    Figure US20150051185A1-20150219-C00238
    97 (Z)-5-(3-methoxy-2- (piperazin-1- yl)benzylidene) thiazolidine-2,4-dione hydrochloride  
    Figure US20150051185A1-20150219-C00239
         		12.45 (brs, 1 H) 8.59 (brs, 1 H) 7.99 (s, 1 H) 7.15 (t, 1 H) 7.02 (d, 1 H) 6.89 (d, 1 H) 3.67 (s, 3 H) 3.17-2.99 (m, 8 H) 320 (Z)-tert-butyl 4-(2-((2,4- dioxothiazolidin-5- ylidene)methyl)-6- methoxyphenyl) piperazine-1-carboxylate Method 45  
    Figure US20150051185A1-20150219-C00240
    98 (Z)-5-(3-chloro-2- (piperazin-1- yl)benzylidene) thiazolidine-2,4-dione hydrochloride  
    Figure US20150051185A1-20150219-C00241
         		12.72 (brs, 1 H) 9.19 (brs, 1 H) 8.01 (s, 1 H) 7.57 (dd, 1 H) 7.50-7.40 (m, 1 H) 7.36 (t, 1 H) 3.60 (brs, 2 H), 3.51- 3.29 (m, 1 H) 3.29-3.12 (m, 2 H) 3.06 (brs, 3 H) 324 (Z)-tert-butyl 4-(2- chloro-6-((2,4- dioxothiazolidin-5- ylidene)methyl)phenyl) piperazine-1-carboxylate Method 46  
    Figure US20150051185A1-20150219-C00242
    99 (Z)-5-(2-(3- (aminomethyl)pyrrolidin- 1-yl)-4,5- dimethoxybenzylidene) thiazolidine-2,4- dione hydrochloride  
    Figure US20150051185A1-20150219-C00243
         		12.40 (s, 1 H) 9.25 (s, 1 H) 7.88 (s, 1 H) 6.97 (s, 1 H) 6.73 (s, 1 H) 3.85 (s, 3 H) 3.81 (m, 1 H) 3.74 (s, 3 H) 3.40-3.31 (m, 2 H) 3.25-3.13 (m, 2 H) 2.59 (t, 3 H) 2.31 (dd, 1 H) 2.08 (d, 1 H) 364 (Z)-tert-butyl (1-(2-((2,4- dioxothiazolidin-5- ylidene)methyl)-4,5- dimethoxyphenyl) pyrrolidin-3- yl)methylcarbamate Method 47  
    Figure US20150051185A1-20150219-C00244
    100 (R,Z)-5-(2-(3- aminopyrrolidin-1- yl)-4,5- dimethoxybenzylidene) thiazolidine-2,4- dione hydrochloride  
    Figure US20150051185A1-20150219-C00245
         		12.39 (s, 1 H) 8.06 (s, 2 H) 7.89 (s, 1 H) 6.96 (s, 1 H) 6.65 (s, 1 H) 3.84 (s, 4 H) 3.73 (s, 3 H) 3.35 (d, 2 H) 3.20 (s, 1 H) 3.07 (d, 1 H) 2.28 (s, 1 H) 1.97 (s, 1 H) 350 (R,Z)-tert-butyl 1-(2- ((2,4-dioxothiazolidin-5- ylidene)methyl)-4,5- dimethoxyphenyl) pyrrolidin-3-ylcarbamate Method 48  
    Figure US20150051185A1-20150219-C00246
    101 (S,Z)-5-(2-(3- aminopyrrolidin-1- yl)-4,5- dimethoxybenzylidene) thiazolidine-2,4- dione hydrochloride  
    Figure US20150051185A1-20150219-C00247
         		12.39 (s, 1 H) 8.08 (s, 2 H) 7.89 (s, 1 H) 6.96 (s, 1 H) 6.65 (s, 1 H) 3.84 (s, 4 H) 3.73 (s, 3 H) 3.45- 3.30 (m, 2 H) 3.24-3.14 (m, 1 H) 3.12-3.00 (m, 1 H) 2.28 (s, 1 H) 1.98 (s, 1H) 350 (S,Z)-tert-butyl 1-(2- ((2,4-dioxothiazolidin-5- ylidene)methyl)-4,5- dimethoxyphenyl) pyrrolidin-3- ylcarbamate Method 49  
    Figure US20150051185A1-20150219-C00248
    102 (Z)-5-(2-(4- (piperidine-3- carbonyl)-1,4- diazepan-1- yl)benzylidene) thiazolidine-2,4-dione hydrochloride  
    Figure US20150051185A1-20150219-C00249
         		12.49 (s, 1 H) 8.47 (s, 1 H) 7.82 (d, 1 H) 7.39- 7.30 (m, 2 H) 7.16 (dd, 1 H) 7.06 (td, 1 H) 3.63- 3.54 (m, 4 H) 3.29-3.06 (m, 9 H) 1.88-1.48 (m, 6H) 415 (Z)-tert-butyl 3-(4-(2- ((2,4-dioxothiazolidin-5- ylidene)methyl)phenyl)- 1,4-diazepane-1- carbonyl)piperidine-1- carboxylate Method 50  
    Figure US20150051185A1-20150219-C00250
    103 (Z)-5-(2-(4-(5- aminopentanoyl)-1,4- diazepan-1- yl)benzylidene) thiazolidine-2,4-dione hydrochloride  
    Figure US20150051185A1-20150219-C00251
         		12.57 (s, 1 H) 7.90 (d, 1 H) 7.76 (s, 2 H) 7.47- 7.36 (m, 2 H) 7.22 (t, 1 H) 7.12 (d, 1 H) 3.63 (d, 4 H) 3.22 (s, 1 H) 3.17 (s, 1 H) 3.05 (s, 2 H) 2.80 (s, 2 H) 2.41 (s, 1 H) 2.34 (s, 1 H) 1.91 (s, 1 H) 1.85 (s, 1 H) 1.57 (d, 4 H) 403 (Z)-tert-butyl 5-(4-(2- ((2,4-dioxothiazolidin-5- ylidene)methyl)phenyl)- 1,4-diazepan-1-yl)-5- oxopentylcarbamate Method 51  
    Figure US20150051185A1-20150219-C00252
    104 (Z)-5-(2-(4-(4- aminobutanoyl)-1,4- diazepan-1- yl)benzylidene) thiazolidine-2,4-dione hydrochloride  
    Figure US20150051185A1-20150219-C00253
         		12.49 (s, 1 H) 7.83 (d, 1 H) 7.65 (s, 2 H) 7.39- 7.30 (m, 2 H) 7.20-7.12 (m, 1 H) 7.09-7.01 (m, 1 H) 3.61-3.50 (m, 4 H) 3.18-3.07 (m, 2 H) 2.98 (d, 2 H) 2.77 (ddd, 2 H) 2.37 (t, 2 H) 1.85-1.66 (m, 4 H). 389 (Z)-tert-butyl 4-(4-(2- ((2,4-dioxothiazolidin-5- ylidene)methyl)phenyl)- 1,4-diazepan-1-yl)-4- oxobutylcarbamate Method 52  
    Figure US20150051185A1-20150219-C00254
    105 (Z)-5-(2-(4-(3- aminopropanoyl)-1,4- diazepan-1- yl)benzylidene) thiazolidine-2,4-dione hydrochloride  
    Figure US20150051185A1-20150219-C00255
         		12.50 (s, 1 H) 7.83 (s, 1 H) 7.63 (s, 2 H) 7.39- 7.31 (m, 2 H) 7.16 (dd, 1 H) 7.10-7.01 (m, 1 H) 3.64-3.52 (m, 4 H) 3.20- 3.09 (m, 2 H) 2.97 (dt, 4 H) 2.65 (dt, 2 H) 1.87- 1.81 (m, 2 H) 375 (Z)-tert-butyl 3-(4-(2- ((2,4-dioxothiazolidin-5- ylidene)methyl)phenyl)- 1,4-diazepan-1-yl)-3- oxopropylcarbamate Method 53  
    Figure US20150051185A1-20150219-C00256
    106 (Z)-5-(2-(1,4- diazepan-1- yl)benzylidene) thiazolidine-2,4-dione hydrochloride  
    Figure US20150051185A1-20150219-C00257
         		12.57 (s, 1 H) 9.31 (s, 1 H) 7.91 (s, 1 H) 7.46- 7.40 (m, 2 H) 7.26 (d, 1 H) 7.18-7.09 (m, 1 H) 3.36 (d, 2 H) 3.27 (d, 4 H) 3.19 (dd, 2 H) 2.10- 2.01 (m, 2 H) 304 (Z)-tert-butyl 4-(2-((2,4- dioxothiazolidin-5- ylidene)methyl)phenyl)- 1,4-diazepane-1- carboxylate Method 54  
    Figure US20150051185A1-20150219-C00258
    107 (Z)-5-(2-(4-(4- aminobutanoyl) piperazin-1- yl)benzylidene) thiazolidine-2,4-dione hydrochloride  
    Figure US20150051185A1-20150219-C00259
         		12.60 (s, 1 H) 7.95 (s, 4 H) 7.53-7.44 (m, 2 H) 7.26-7.17 (m, 2 H) 3.66- 3.57 (m, 5 H) 2.89 (m, 4 H) 2.85-2.76 (m, 3 H) 1.85-1.76 (m, 2 H) 375 (Z)-tert-butyl 4-(4-(2- ((2,4-dioxothiazolidin-5- ylidene)methyl)phenyl) piperazin-1-yl)-4- oxobutylcarbamate Method 55  
    Figure US20150051185A1-20150219-C00260
    108 (Z)-5-(2-(4-(5- aminopentanoyl) piperazin-1- yl)benzylidene) thiazolidine-2,4-dione hydrochloride  
    Figure US20150051185A1-20150219-C00261
         		12.66 (s, 1 H) 8.10 (s, 2 H) 7.99 (s, 1 H) 7.52 (s, 1 H) 7.51-7.47 (m, 1 H) 7.25 (t, 2 H) 3.67 (s, 4 H) 2.92-2.81 (m, 6 H) 2.44 (t, 2 H) 1.62 (s, 4 H) 389 (Z)-tert-butyl 5-(4-(2- ((2,4-dioxothiazolidin-5- ylidene)methyl)phenyl) piperazin-1-yl)-5- oxopentylcarbamate Method 56  
    Figure US20150051185A1-20150219-C00262
    109 (Z)-5-(2-(4-(4- (piperazin-1- ylmethyl)benzoyl) piperazin-1- yl)benzylidene) thiazolidine-2,4-dione hydrochloride  
    Figure US20150051185A1-20150219-C00263
         		12.57 (brs, 1 H) 9.70 (brs, 1 H) 7.94 (s, 1 H) 7.75 (d, 2 H) 7.52 (m, 2 H) 7.49-7.41 (m, 2 H) 7.21 (t, 2 H) 4.45 (brs, 2 H) 3.81 (brs, 2 H) 3.54- 3.35 (m, 8 H) 3.27 (brs, 2 H) 2.89 (brs, 4 H) 492 (Z)-tert-butyl 4-(4-(4-(2- ((2,4-dioxothiazolidin-5- ylidene)methyl)phenyl) piperazine-1- carbonyl)benzyl)piperazine- 1-carboxylate Method 57  
    Figure US20150051185A1-20150219-C00264
    110 (Z)-5-(2-(4-(3- (aminomethyl) benzoyl)piperazin-1- yl)benzylidene) thiazolidine-2,4-dione hydrochloride  
    Figure US20150051185A1-20150219-C00265
         		12.56 (s, 1 H) 8.18 (brs, 2 H) 7.95 (s, 1 H) 7.64- 7.38 (m, 6 H) 7.36-7.11 (m, 2 H) 4.19-4.02 (m, 2 H) 3.82 (brs, 2 H) 3.52 (brs, 2 H) 2.92 (brs, 4 H) 423 (Z)-tert-butyl 3-(4-(2- ((2,4-dioxothiazolidin-5- ylidene)methyl)phenyl) piperazine-1- carbonyl)benzylcarbamate Method 58  
    Figure US20150051185A1-20150219-C00266
    111 (Z)-5-(2-(3-(2- aminoethylamino) pyrrolidin-1-yl)-4,5- dimethoxybenzylidene) thiazolidine-2,4- dione hydrochloride  
    Figure US20150051185A1-20150219-C00267
         		12.38 (s, 1 H) 9.99 (s, 1 H) 8.44 (s, 2 H) 7.86 (s, 1 H) 6.96 (s, 1 H) 6.76 (s, 1 H) 3.93 (s, 1 H) 3.84 (s, 3 H) 3.73 (s, 3 H) 3.45- 3.33 (m, 2 H) 3.28-3.16 (m, 6 H) 2.32 (s, 1 H) 2.15 (s, 1 H) 393 (Z)-tert-butyl 2-(1-(2- ((2,4-dioxothiazolidin-5- ylidene)methyl)-4,5- dimethoxyphenyl) pyrrolidin-3- ylamino)ethylcarbamate Method 59  
    Figure US20150051185A1-20150219-C00268
    112 (Z)-5-(2-(4-(2- aminoethyl)piperazin- 1-yl)benzylidene) thiazolidine-2,4-dione hydrochloride  
    Figure US20150051185A1-20150219-C00269
         		12.70 (s, 1 H) 11.43 (s, 1 H) 8.38 (s, 3 H) 7.86 (s, 1 H) 7.49 (m, 2 H) 7.25 (m, 2 H) 3.67 (m, 2 H) 3.42- 3.30 (m, 8 H) 333 (Z)-tert-butyl 2-(4-(2- ((2,4-dioxothiazolidin-5- ylidene)methyl)phenyl) piperazin-1- yl)ethylcarbamate Method 60  
    Figure US20150051185A1-20150219-C00270
    113 (Z)-5-(4,5- dimethoxy-2-(3-(2- (methylamino) ethylamino)pyrrolidin-1- yl)benzylidene) thiazolidine-2,4-dione hydrochloride  
    Figure US20150051185A1-20150219-C00271
         		12.39 (s, 1 H) 9.93 (brs, 1 H) 9.42 (brs, 1 H) 7.87 (s, 1 H) 6.98 (s, 1 H) 6.77 (s, 1 H) 4.00-3.91 (m, 1 H) 3.85 (s, 3 H) 3.74 (s, 3 H) 3.44-3.16 (m, 8 H) 2.62 (s, 3H) 2.40-2.31 (m, 1 H) 2.20-2.14 (m, 1 H) 407 (Z)-tert-butyl 2-(1-(2- ((2,4-dioxothiazolidin-5- ylidene)methyl)-4,5- dimethoxyphenyl) pyrrolidin-3- ylamino)ethyl)methyl) carbamate Method 61  
    Figure US20150051185A1-20150219-C00272
    114 (Z)-5-(2-(4-(2- (methylamino)ethyl) piperazin-1- yl)benzylidene) thiazolidine-2,4-dione hydrochloride  
    Figure US20150051185A1-20150219-C00273
         		12.62 (s, 1 H) 11.28 (s, 1 H) 9.28 (s, 1 H) 7.87 (s, 1 H) 7.50 (t, 1 H) 7.26 (t, 1 H) 3.71 (m, 4 H) 3.57 (m, 2 H) 3.45 (m, 2 H) 3.26 (m, 4 H) 2.62 (s, 3 H) 347 (Z)-tert-butyl 2-(4-(2- ((2,4-dioxothiazolidin-5- ylidene)methyl)phenyl) piperazin-1- yl)ethyl)methyl)carbamate Method 62  
    Figure US20150051185A1-20150219-C00274
    115 (5Z)-5-(2-piperazin- 1-ylbenzylidene)-1,3- thiazolidine-2,4- dione hydrochloride  
    Figure US20150051185A1-20150219-C00275
         		12.61 (s, 1 H) 9.21 (s, 1 H) 7.86 (s, 1 H) 7.49 (t, 2 H) 7.24 (t, 2 H), 3.25 (s, 4 H) 3.12 (s, 4 H) 290 tert-butyl-4-{2-[(Z)-(2,4- dioxo-1,3-thiazolidin-5- ylidene)methyl]phenyl} piperazine-1-carboxylate Example 58  
    Figure US20150051185A1-20150219-C00276
    116 5-(2-(4-(piperidine-3- carbonyl)piperazin-1- yl)benzylidene) thiazolidine-2,4-dione hydrochloride  
    Figure US20150051185A1-20150219-C00277
         		12.60 (s, 1 H) 9.10 (s, 1 H) 8.90 (s, 1 H) 7.94 (s, 1 H) 7.51-7.43 (m, 1 H) 7.21 (t, 2 H) 5.14 (m, 4 H) 3.67 (m, 3 H) 3.17 (m, 2 H) 2.91-2.88 (m, 4 H) 1.86 (s, 1 H) 1.81-1.71 (m, 2 H) 1.57 (d, 1 H) 401 tert-butyl 3-(4-(2-((2,4- dioxothiazolidin-5- ylidene)methyl)phenyl) piperazine-1- carbonyl)piperidine-1- carboxylate Method 63  
    Figure US20150051185A1-20150219-C00278
    117 (5Z)-5-{2-[4- (azetidin-3- ylcarbonyl)piperazin- 1-yl]benzylidene}- 1,3-thiazolidine-2,4- dione hydrochloride  
    Figure US20150051185A1-20150219-C00279
         		12.59 (s, 1 H) 9.15 (s, 1 H) 8.86 (s, 1 H) 7.93 (s, 1 H) 7.47 (ddd, 2 H) 7.25- 7.16 (m, 1 H) 4.15-4.05 (m, 4 H) 4.01-3.91 (m, 1 H) 3.71 (m, 2 H) 3.42 (s, 2 H) 2.89 (d, 4 H) 373 tert-butyl 3-(4-(2-((2,4- dioxothiazolidin-5- ylidene)methyl)phenyl) piperazine-1- carbonyl)azetidine-1- carboxylate Method 64  
    Figure US20150051185A1-20150219-C00280
    118 (5Z)-5-[2-(3- aminopyrrolidin-1- yl)-4,5- dimethoxybenzylidene]- 1,3-thiazolidine- 2,4-dione hydrochloride  
    Figure US20150051185A1-20150219-C00281
         		12.38 (s, 1 H) 8.34 (s, 2 H) 7.90 (s, 1 H) 6.96 (s, 1 H) 6.68 (s, 1 H) 3.89- 3.80 (m, 4 H) 3.73 (s, 3 H) 3.46-3.34 (m, 2 H) 3.23-3.13 (m, 1 H) 3.10 (dd, 1 H) 2.28 (dd, 1 H) 2.01 (d, 1 H) 351 tert-butyl 1-(2-((2,4- dioxothiazolidin-5- ylidene)methyl)-4,5- dimethoxyphenyl) pyrrolidin-3-ylcarbamate Method 65  
    Figure US20150051185A1-20150219-C00282
    119 (R,Z)-5-amino-N-(1- (2-((2,4- dioxothiazolidin-5- ylidene)methyl)-4,5- dimethoxyphenyl) pyrrolidin-3- yl)pentanamide hydrochloride  
    Figure US20150051185A1-20150219-C00283
         		12.24 (s, 1 H) 8.07 (d, 1 H) 7.79 (s, 1 H) 7.60 (brs, 2 H) 6.88 (s, 1 H) 6.55 (s, 1 H) 4.22 (d, 1 H) 3.76 (s, 3 H) 3.65 (s, 3 H) 3.30-3.15 (m, 2 H) 3.15-2.98 (m, 1 H) 2.86 (dd, 1 H) 2.70 (d, 2 H) 2.17-1.92 (m, 3 H) 1.76 (brs, 1 H) 1.52-1.25 (m, 4 H) 449 (R,Z)-tert-butyl 5-(1-(2- ((2,4-dioxothiazolidin-5- ylidene)methyl)-4,5- dimethoxyphenyl) pyrrolidin-3-ylamino)-5- oxopentylcarbamate Method 66  
    Figure US20150051185A1-20150219-C00284
    120 (S,Z)-5-amino-N-(1- (2-((2,4- dioxothiazolidin-5- ylidene)methyl)-4,5- dimethoxyphenyl) pyrrolidin-3- yl)pentanamide hydrochloride  
    Figure US20150051185A1-20150219-C00285
         		12.24 (s, 1 H) 8.07 (d, 1 H) 7.79 (s, 1 H) 7.60 (brs, 2 H) 6.88 (s, 1 H) 6.55 (s, 1 H) 4.22 (d, 1 H) 3.76 (s, 3 H) 3.65 (s, 3 H) 3.30-3.15 (m, 2 H) 3.15-2.98 (m, 1 H) 2.86 (dd, 1 H) 2.70 (d, 2 H) 2.17-1.92 (m, 3 H) 1.76 (brs, 1 H) 1.52-1.25 (m, 4 H) 449 (S,Z)-tert-butyl 5-(1-(2- ((2,4-dioxothiazolidin-5- ylidene)methyl)-4,5- dimethoxyphenyl) pyrrolidin-3-ylamino)-5- oxopentylcarbamate Method 67  
    Figure US20150051185A1-20150219-C00286
    121 (S,Z)-5-(2-(3-(3- aminopropylamino) pyrrolidin-1-yl)-4,5- dimethoxybenzylidene) thiazolidine-2,4- dione hydrochloride  
    Figure US20150051185A1-20150219-C00287
         		12.50 (s, 1 H) 9.78 (s, 1 H) 7.92 (s, 1 H) 7.05 (s, 1 H) 6.85 (s, 1 H) 4.21- 4.11 (m, 1 H) 3.93 (s, 3 H) 3.83 (s, 3 H) 3.42- 3.25 (m, 8 H) 2.45 (m, 1 H) 2.20 (m, 1 H) 1.32 (m, 2 H) 407 (S,Z)-tert-butyl 3-(1-(2- ((2,4-dioxothiazolidin-5- ylidene)methyl)-4,5- dimethoxyphenyl) pyrrolidin-3- ylamino)propylcarbamate Method 68  
    Figure US20150051185A1-20150219-C00288
    122A (R,Z)-5-(2-(3-(3- aminopropylamino) pyrrolidin-1-yl)-4,5- dimethoxybenzylidene) thiazolidine-2,4- dione hydrochloride  
    Figure US20150051185A1-20150219-C00289
         		12.44 (s, 1 H) 9.78 (s, 1 H) 7.92 (s, 1 H) 7.05 (s, 1 H) 6.85 (s, 1 H) 4.21- 4.11 (m, 1 H) 3.93 (s, 3 H) 3.83 (s, 3 H) 3.42- 3.25 (m, 8 H) 2.45 (m, 1 H) 2.20 (m, 1 H) 1.32 (m, 2 H) 407 (R,Z)-tert-butyl 3-(1-(2- ((2,4-dioxothiazolidin-5- ylidene)methyl)-4,5- dimethoxyphenyl) pyrrolidin-3- ylamino)propylcarbamate Method 69  
    Figure US20150051185A1-20150219-C00290
    122B (R,Z)-5-(2-(3- (aminomethyl) pyrrolidin-1-yl)-3- chlorobenzylidene) thiazolidine-2,4-dione  
    Figure US20150051185A1-20150219-C00291
         		(400 MHz, MeOD) ppm 8.08 (s, 1 H) 7.49 (dd, 2 H) 7.31 (t, 1 H) 3.56 (t, 1 H) 3.42-3.51 (m, 1 H) 3.38 (td, 1 H) 3.09-3.15 (m, 2 H) 2.71-2.78 (m, 1 H) 2.26-2.36 (m, 1 H) 1.86-1.96 (m, 1 H) 1.31 (dd, 1 H) 338 (R,Z)-tert-butyl (1-(2- chloro-6-((2,4- dioxothiazolidin-5- ylidene)methyl)phenyl) pyrrolidin-3- yl)methylcarbamate Method 132  
    Figure US20150051185A1-20150219-C00292
    122C (S,Z)-5-(2-(3- (aminomethyl) pyrrolidin-1-yl)-3- chlorobenzylidene) thiazolidine-2,4-dione  
    Figure US20150051185A1-20150219-C00293
         		(400 MHz, MeOD) ppm 8.07 (s, 1 H) 7.49 (dd, 2 H) 7.31 (t, 1 H) 3.56 (t, 1 H) 3.42-3.51 (m, 2 H) 3.38 (td, 1 H) 3.07-3.16 (m, 2 H) 2.67-2.79 (m, 1 H) 2.24-2.36 (m, 1 H) 1.90 (dd, 1 H) 338 (S,Z)-tert-butyl (1-(2- chloro-6-((2,4- dioxothiazolidin-5- ylidene)mcthyl)phenyl) pyrrolidin-3- yl)methylcarbamate Method 133  
    Figure US20150051185A1-20150219-C00294
    122D (R,Z)-5-(2-(3- aminopiperidin-1-yl)- 3-chlorobenzylidene) thiazolidine-2,4-dione hydrochloride  
    Figure US20150051185A1-20150219-C00295
         		12.70 (s, 1 H) 8.17 (brs, 3 H) 8.01 (s, 1 H) 7.52 (d, 1 H) 7.41-7.31 (m, 2 H) 3.40-3.10 (m, 4 H) 2.84- 2.81 (m, 1 H) 2.12-2.10 (m, 1 H) 1.80-1.58 (m, 3 H) 338 (R,Z)-tert-butyl 1-(2- chloro-6-((2,4- dioxothiazolidin-5- ylidene)methyl)phenyl) piperidin-3-ylcarbamate Method 134  
    Figure US20150051185A1-20150219-C00296
    122E (R,Z)-5-(2-(3- aminopiperidin-1-yl)- 3-methoxybenzylidene) thiazolidine-2,4- dione hydrochloride  
    Figure US20150051185A1-20150219-C00297
         		12.60 (s, 1 H) 8.12 (brs, 4 H) 7.28-7.02 (m, 3 H) 3.82 (s, 3 H) 3.18-2.87 (m, 5 H) 2.10-2.07 (m, 1 H) 1.75-1.38 (m, 3 H) 334 (R,Z)-tert-butyl 1-(2- ((2,4-dioxothiazolidin-5- ylidene)methyl)-6- methoxyphenyl)piperidin- 3-ylcarbamate Method 135  
    Figure US20150051185A1-20150219-C00298
    122F (R,Z)-5-(2-(3- aminopiperidin-1-yl)- 3-bromobenzylidene) thiazolidine-2,4-dione hydrochloride  
    Figure US20150051185A1-20150219-C00299
         		12.70 (s, 1 H) 8.15 (brs, 3 H) 8.01 (s, 1 H) 7.74- 7.69 (m, 1 H) 7.46 (d, 1 H) 7.26 (t, 1 H) 3.27-2.99 (m, 4 H) 2.82-2.80 (m, 1 H) 2.12-2.10 (m, 1 H) 1.76-1.40 (m, 3 H) 383 (R,Z)-tert-butyl 1-(2- bromo-6-((2,4- dioxothiazolidin-5- ylidene)methyl)phenyl) piperidin-3-ylcarbamate Method 136  
    Figure US20150051185A1-20150219-C00300
    122G (R,Z)-5-(2-(3- aminopyrrolidin-1- yl)-3- chlorobrnzylidene) thiazolidine-2,4-dione hydrochloride  
    Figure US20150051185A1-20150219-C00301
         		12.67 (brs, 1 H) 8.30 (brs, 3 H) 7.93 (s, 1 H) 7.55 (d, 1 H) 7.41-7.31 (m, 2 H) 3.87 (brs, 1 H) 3.50-3.27 (m, 4 H) 2.40- 2.28 (m, 1 H) 2.08-1.95 (m, 1 H) 324 (R,Z)-tert-butyl 1-(2- chloro-6-((2,4- dioxothiazolidin-5- ylidene)methyl)phenyl) pyrrolidin-3-ylcarbamate Method 137  
    Figure US20150051185A1-20150219-C00302
    122H (S,Z)-5-(2-(3- aminopyrrolidin-1- yl)-3- bromobenzylidene) thiazolidine-2,4-dione hydrochloride  
    Figure US20150051185A1-20150219-C00303
         		12.68 (brs, 1 H) 8.31 (brs, 3 H) 7.90 (s, 1 H) 7.75 (d, 1 H) 7.46 (d, 1 H) 7.29 (t, 1 H) 3.75 (brs, 1 H) 3.55 (t, 1 H) 3.38- 3.25 (m, 3 H) 2.40-2.32 (m, 1 H) 2.12-2.02 (m, 1 H) 370 (S,Z)-tert-butyl 1-(2- bromo-6-((2,4- dioxothiazolidin-5- ylidene)methyl)phenyl) pyrrolidin-3-ylcarbamate Method 138  
    Figure US20150051185A1-20150219-C00304
    122I (R,Z)-5-(2-(3- aminopiperidin-1-yl)- 3-ethoxybenzylidene) thiazolidine-2,4-dione hydrochloride  
    Figure US20150051185A1-20150219-C00305
         		12.58 (s, 1 H) 8.13-8.09 (m, 4 H) 7.26-7.24 (m, 1 H) 7.16-7.14 (m, 1 H) 7.03-7.01 (m, 1 H) 4.07 (q, 2 H) 3.78-3.67 (m, 2 H) 3.22-3.07 (m, 3 H) 2.10-2.07 (m, 1 H) 1.76- 1.55 (m, 3 H) 1.38 (t, 3 H) 348 (R,Z)-tert-butyl 1-(2- ((2,4-dioxothiazolidin-5- ylidene)methyl)-6- ethoxyphenyl)piperidin- 3-ylcarbamate Method 139  
    Figure US20150051185A1-20150219-C00306
    122J (R,Z)-tert-butyl 1-(2- ((2,4- dioxothiazolidin-5- ylidene)methyl)-6- isobutoxyphenyl) piperidin-3-ylcarbamate hydrochloride  
    Figure US20150051185A1-20150219-C00307
         		12.60 (s, 1 H) 8.18 (brs, 3 H) 8.15 (s, 1 H) 7.26 (t, 1 H) 7.15 (d, 1 H) 7.02 (d, 1 H) 3.84-3.74 (m, 2 H) 3.20-3.02 (m, 4 H) 2.74 (d, 1 H) 2.14-2.07 (m, 2 H) 1.73-1.21 (m, 3 H) 1.03 (d, 6 H) 376 (R,Z)-tert-butyl 1-(2- ((2,4-dioxothiazolidin-5- ylidene)methyl)-6- isobutoxyphenyl) piperidin-3-ylcarbamate Method 140  
    Figure US20150051185A1-20150219-C00308
    122K (R,Z)-5-(2-(3- aminopiperidin-1-yl)- 3-(cyclohexylmethoxy) benzylidene) thiazolidine-2,4-dione hydrochloride  
    Figure US20150051185A1-20150219-C00309
         		12.60 (s, 1 H) 8.14 (brs, 4 H) 7.25 (t, 1 H) 7.14 (d, 1 H) 7.00 (d, 1 H) 3.82 (brs, 2 H) 3.29-3.00 (m, 4 H) 2.75-2.72 (m, 1 H) 2.12-2.10 (m, 1 H) 1.86- 1.50 (m, 8 H) 1.35-1.03 (m, 6 H) 416 (R,Z)-tert-butyl 1-(2- (cyclohexylmethoxy)-6- ((2,4-dioxothiazolidin-5- ylidene)methyl)phenyl) piperidin-3-ylcarbamate Method 141  
    Figure US20150051185A1-20150219-C00310
    122L (R,Z)-5-(2-(3- aminopiperidin-1-yl)- 3-(cyclohexyloxy) benzylidene)thiazolidine- 2,4-dione hydrochloride  
    Figure US20150051185A1-20150219-C00311
         		402 (R,Z)-tert-butyl 1-(2- (cyclohexyloxy)-6-((2,4- dioxothiazolidin-5- ylidene)methyl)phenyl) piperidin-3-ylcarbamate Method 142  
    Figure US20150051185A1-20150219-C00312
    122M (±)-(Z)-5-(2-3-amino- 4-hydroxypiperidin- 1-yl)-3- chlorobenzylidene) thiazolidine-2,4-dione hydrochloride  
    Figure US20150051185A1-20150219-C00313
         		12.68 (s, 1 H) 8.01 (brs, 4 H) 7.53 (d, 1 H) 7.44- 7.42 (m, 1 H) 7.35 (t, 1 H) 5.72-5.70 (m, 1 H) 3.32-3.22 (m, 2 H) 3.20- 3.11 (m, 3 H) 1.96-1.94 (m, 1 H) 1.40-1.37 (m, 1 H) 354 (±)-tert-butyl-1-(2- chloro-6-((Z)-(2,4- dioxothiazolidin-5- ylidene)methyl)phenyl)- 4-hydroxypiperidin-3- ylcarbamate Method 143  
    Figure US20150051185A1-20150219-C00314
    122N (Z)-5-(3-chloro-2- (1,4-diazepan-1- yl)benzylidene) thiazolidine-2,4-dione hydrochloride  
    Figure US20150051185A1-20150219-C00315
         		12.73 (brs, 1 H), 9.18 (brs, 2 H), 8.04 (s, 1 H), 7.62 (d, 1 H), 7.41 (dt, 2 H), 3.65 (brs, 1 H), 3.34- 3.30 (m, 5 H), 3.04 (brs, 2 H), 2.14 (brs, 2 H) 338 (Z)-tert-butyl 4-(2- chloro-6-((2,4- dioxothiazolidin-5- ylidene)methyl)phenyl)- 1,4-diazepane-1- carboxylate Method 144  
    Figure US20150051185A1-20150219-C00316
    122O (R,Z)-5-(2-(3- aminopiperidin-1-yl)- 3-isopropoxybenzylidene) thiazolidine-2,4- dione hydrochloride  
    Figure US20150051185A1-20150219-C00317
         		12.61 (brs, 1 H) 8.33 (brs, 3 H) 8.15 (brs, 1 H) 7.34-7.09 (m, 2 H) 6.99 (d, 1 H) 4.67 (ddd 1 H) 3.28 (brs, 1 H) 3.07 (brs, 3 H) 2.70 (brs, 1 H) 2.12 (brs, 1 H) 1.73 (brs, 1 H) 1.57 (brs, 1 H) 1.51- 1.21 (m, 7 H) 362 (R,Z)-tert-butyl 1-(2- ((2,4-dioxothiazolidin-5- ylidene)methyl)-6- isopropoxyphenyl) piperidin-3-ylcarbamate Method 145  
    Figure US20150051185A1-20150219-C00318
    122P (S,Z)-5-(2-(3- aminopyrrolidin-1- yl)-3- isopropoxybenzylidene) thiazolidine-2,4- dione hydrochloride  
    Figure US20150051185A1-20150219-C00319
         		12.58 (brs, 1 H) 8.52 (brs, 3 H) 8.08 (s, 1 H) 7.39-7.10 (m, 2 H) 6.99 (d, 1 H) 4.70 (d, 1 H) 3.78 (brs, 1 H) 3.52-3.33 (m, 1 H) 3.33-3.03 (m, 3 H) 2.28 (brs, 1 H) 2.00 (d, 1 H) 1.32 (d, 6 H) 348 (S,Z)-tert-butyl 1-(2- ((2,4-dioxothiazolidin-5- ylidene)methyl)-6- isopropoxyphenyl) pyrrolidin-3-ylcarbamate Method 146  
    Figure US20150051185A1-20150219-C00320
    122Q (S,Z)-5-(2-(3- aminopyrrolidin-1- yl)-3- ethoxybenzylidene) thiazolidine-2,4-dione hydrochloride  
    Figure US20150051185A1-20150219-C00321
         		12.58 (brs, 1 H) 8.48 (brs, 3 H) 8.09 (s, 1 H) 7.26 (t, 1 H) 7.16 (d, 1 H) 7.02 (d, 1 H) 4.09 (q, 2 H) 3.80 (d, 1 H) 3.47 (dd, 1 H) 3.28 (m, 1 H) 3.21 (dd, 1 H) 2.29 (d, 1 H) 2.01 (dd, 1 H) 1.40 (t, 3 H) 334 (S,Z)-tert-butyl 1-(2- ((2,4-dioxothiazolidin-5- ylidene)methyl)-6- ethoxyphenyl)pyrrolidin- 3-ylcarbamate Method 147  
    Figure US20150051185A1-20150219-C00322
    122R (R,Z)-5-(2-(3-(4- (aminomethyl) benzylamino)piperidin-1- yl)-3- chlorobenzylidene) thiazolidine-2,4-dione hydrochloride  
    Figure US20150051185A1-20150219-C00323
         		9.62 (brs, 1 H) 8.46 (brs, 3 H) 7.66-7.49 (m, 5 H) 7.47-7.34 (m, 2 H) 4.26- 4.12 (m, 2 H) 4.09-3.94 (m, 2 H) 3.42-3.25 (m, 4 H) 2.83 (brs, 1 H) 2.36 (s, 1 H) 1.85 (m, 1 H) 1.62 (d, 2 H) 457 (R,Z)-tert-butyl 4-((1-(2- chloro-6-((2,4- dioxothiazolidin-5- ylidene)methyl)phenyl) piperidin-3- ylamino)methyl) benzylcarbamate Example 167  
    Figure US20150051185A1-20150219-C00324
    122S (R,Z)-5-(3-chloro-2- (3-(2- (methylamino) ethylamino)piperidin-1- yl)benzylidene) thiazolidine-2,4-dione hydrochloride  
    Figure US20150051185A1-20150219-C00325
         		12.68 (brs, 1 H) 9.68 (brs, 2H) 9.21 (brs, 2 H) 8.05 (s, 1 H) 7.56 (d, 1 H) 7.50-7.42 (m, 1 H) 7.37 (t, 1 H) 3.75-3.65 (m, 5 H) 3.63-3.57 (m, 2 H) 3.16 (d, 1 H) 2.82 (brs, 1 H) 2.60 (brs, 3 H) 2.37-2.28 (m, 1 H) 1.80 (d, 1 H) 1.65 (m, 1H) 1.54 (brs, 1 H) 395 (R,Z)-tert-butyl 2-(1-(2- chloro-6-((2,4- dioxothiazolidin-5- ylidene)methyl)phenyl) piperidin-3- ylamino)ethyl)methyl) carbamate Example 168  
    Figure US20150051185A1-20150219-C00326
    122T (Z)-5-(2-((3S,4S)-3- amino-4- hydroxypyrrolidin-1- yl)-3- chlorobenzylidene) thiazolidine-2,4-dione hydrochloride  
    Figure US20150051185A1-20150219-C00327
         		12.68 (brs, 1 H) 8.50 (brs, 3 H) 8.10-7.81 (m, 1 H) 7.58 (dd, 1 H) 7.51- 7.27 (m, 2 H) 4.56-4.28 (m, 1 H) 3.84 (brs, 1 H) 3.66-3.40 (m, 4 H) 3.39- 3.23 (m, 1 H) 339 tert-butyl (3S,4S)-1-(2- chloro-6-((Z)-(2,4- dioxothiazolidin-5- ylidene)methyl)phenyl)- 4-hydroxypyrrolidin-3- ylcarbamate Method 151  
    Figure US20150051185A1-20150219-C00328
    122U (Z)-5-(3-chloro-2-(4- methyl-3- (methylamino) piperidin-1- yl)benzylidene) thiazolidine-2,4-dione hydrochloride  
    Figure US20150051185A1-20150219-C00329
         		12.69 (brs, 1 H) 8.63 (brs, 2 H) 8.02 (s, 1 H) 7.57 (d, 1 H) 7.47-7.31 (m, 2 H) 3.58 (m, 1 H) 3.07 (m, 1 H) 2.67 (brs, 1 H) 2.58 (brs, 3 H) 2.40 (m, 1 H) 1.87 (m, 1 H) 1.68 (m, 1 H) 1.29 (m, 1 H) 1.07 (d, 3 H) 0.87 (d, 1 H) 365 (Z)-tert-butyl 1-(2- chloro-6-((2,4- dioxothiazolidin-5- ylidene)methyl)phenyl)- 4-methylpiperidin-3- yl)methyl)carbamate Method 152  
    Figure US20150051185A1-20150219-C00330
    122V (Z)-5-(2-(3-amino-4- methylpiperidin-1- yl)-3- chlorobenzylidene) thiazolidine-2,4-dione hydrochloride  
    Figure US20150051185A1-20150219-C00331
         		351 (Z)-tert-butyl 1-(2- chloro-6-((2,4- dioxothiazolidin-5- ylidene)methyl)phenyl)- 4-methylpiperidin-3- ylcarbamate Method 153  
    Figure US20150051185A1-20150219-C00332
    122W (R,Z)-5-(2-(3- aminopiperidin-1- yl)benzylidene) thiazolidine-2,4-dione hydrochloride  
    Figure US20150051185A1-20150219-C00333
         		12.58 (s, 1 H), 8.44 (brs, 3 H) 7.89 (s, 1 H) 7.54- 7.34 (m, 2 H) 7.27-7.05 (m, 2 H) 3.26 (d, 2 H) 2.94 (d, 1 H), 2.87-2.61 (m, 2 H) 2.05 (brs, 1 H) 1.85 (brs, 1 H) 1.75-1.47 (m, 2 H) 304 (R,Z)-tert-butyl 1-(2- ((2,4-dioxothiazolidin-5- ylidene)methyl)phenyl) piperidin-3-ylcarbamate Method 154  
    122X (S,Z)-5-(2-(3- aminopyrrolidin-1- yl)benzylidene) thiazolidine-2,4-dione hydrochloride  
    Figure US20150051185A1-20150219-C00334
         		12.49 (s, 1 H) 8.50 (brs, 3 H) 7.91 (s, 1 H) 7.44- 7.22 (m, 2 H) 7.07-6.79 (m, 2 H) 3.83 (d, 1 H) 3.51-3.29 (m, 2 H) 3.28- 3.17 (m, 2 H) 2.27 (dd, 1 H), 2.11-1.94 (m, 1 H) 290 (S,Z)-tert-butyl 1-(2- ((2,4-dioxothiazolidin-5- ylidene)methyl)phenyl) pyrrolidin-3-ylcarbamate Method 155  
    Figure US20150051185A1-20150219-C00335
    122Y (R,Z)-5-(2-(3- aminopiperidin-1-yl)- 3-(2,2,2- trifluoroethoxy) benzylidene) thiazolidine- 2,4-dione hydrochloride  
    Figure US20150051185A1-20150219-C00336
         		12.57 (brs, 1 H) 8.03 (brs, 1 H) 7.90 (brs, 3 H) 7.36-7.13 (m, 2 H) 7.07 (d, 1 H) 4.85-4.55 (m, 2 H) 2.98 (brs, 4 H) 2.74 (brs, 1 H) 2.02 (d, 1 H) 1.69 (d, 1 H) 1.54 (d, 1 H) 1.30 (brs, 1 H) 402 (R,Z)-tert-butyl 1-(2- ((2,4-dioxothiazolidin-5- ylidene)methyl)-6-(2,2,2- trifluoroethoxy)phenyl) piperidin-3-ylcarbamate Method 156  
    Figure US20150051185A1-20150219-C00337
    122Z (S,Z)-5-(2-(3- aminopyrrolidin-1- yl)-3-(2,2,2- trifluoroethoxy) benzylidene)thiazolidine- 2,4-dione hydrochloride  
    Figure US20150051185A1-20150219-C00338
         		12.52 (brs, 1 H) 8.21- 7.91 (m, 4 H) 7.34-7.14 (m, 2 H) 7.07 (d, 1 H) 4.88-4.72 (m, 2 H) 3.74 (d, 1 H) 3.40 (dd, 1 H) 3.22 (td, 1 H) 3.18-3.10 (m, 1 H) 3.06 (dd, 1 H) 2.30-2.10 (m, 1 H) 1.90 (dd, 1 H) 388 (S,Z)-tert-butyl 1-(2- ((2,4-dioxothiazolidin-5- ylidene)methyl)-6-(2,2,2- trifluoroethoxy)phenyl) pyrrolidin-3-ylcarbamate Method 157  
    Figure US20150051185A1-20150219-C00339
    122AA (R,Z)-5-(2-(3- aminopiperidin-1-yl)- 3-(2- methoxyethoxy) benzylidene)thiazolidine- 2,4-dione hydrochloride  
    Figure US20150051185A1-20150219-C00340
         		12.67 (brs, 1 H) 8.30 (brs, 3 H) 8.20 (brs, 1 H) 7.33 (brs, 1 H) 7.25 (brs, 1 H) 7.10 (d, 1 H) 4.68 (brs, 3 H) 4.22 (t, 2 H) 3.91-3.65 (m, 2 H) 3.42 (s, 3 H) 3.29 (brs, 1 H) 2.80 (brs, 1 H) 2.18 (brs, 1 H) 1.81 (brs, 1 H) 1.68 (brs, 1 H) 1.48 (brs, 1 H) 378 (R,Z)-tert-butyl 1-(2- ((2,4-dioxothiazolidin-5- ylidene)methyl)-6-(2- methoxyethoxy)phenyl) piperidin-3-ylcarbamate Method 158  
    Figure US20150051185A1-20150219-C00341
    122AB (S,Z)-5-(2-(3- aminopyrrolidin-1- yl)-3-(2- methoxyethoxy) benzylidene)thiazolidine- 2,4-dione hydrochloride  
    Figure US20150051185A1-20150219-C00342
         		12.58 (brs, 1 H) 8.42 (brs, 3 H) 8.10 (s, 1 H) 7.28 (t, 1 H) 7.23-7.11 (m, 1 H) 7.04 (d, 1 H) 4.27-3.97 (m, 2 H) 3.85 (d, 1 H) 3.78-3.63 (m, 2 H) 3.49 (dd, 1 H) 3.34 (s, 3 H) 3.27 (td, 1 H) 3.22- 3.06 (m, 2 H) 2.30 (dd, 1 H) 2.02 (dd, 1 H) 364 (S,Z)-tert-butyl 1-(2- ((2,4-dioxothiazolidin-5- ylidene)methyl)-6-(2- methoxyethoxy)phenyl) pyrrolidin-3-ylcarbamate Method 159  
    Figure US20150051185A1-20150219-C00343
    122AC (R,Z)-5-(2-(3- aminopiperidin-1-yl)- 3-(cyclopentyloxy) benzylidene)thiazolidine- 2,4-dione hydrochloride  
    Figure US20150051185A1-20150219-C00344
         		12.37 (brs, 1 H) 8.00 (brs, 3H) 7.93 (s, 1 H) 7.02 (d, 1 H) 6.91 (d, 1 H) 6.77 (d, 1 H) 3.02- 2.91 (m, 1 H) 2.82 (d, 3 H) 2.48 (brs, 1 H) 1.89- 1.40 (m, 12 H) 1.16 (brs, 1 H) 388 (R,Z)-ten-butyl 1-(2- (cyclopentyloxy)-6-((2,4- dioxothiazolidin-5- ylidene)methyl)phenyl) piperidin-3-ylcarbamate Method 160  
    Figure US20150051185A1-20150219-C00345
    122AD (R,Z)-5-(2-(3- aminopiperidin-1-yl)- 3-cyclobutoxybenzylidene) thiazolidine-2,4- dione hydrochloride  
    Figure US20150051185A1-20150219-C00346
         		12.60 (brs, 1 H) 8.14 (brs, 4 H) 7.23 (d, 1 H) 7.00 (dd, 2 H), 4.86-4.67 (m, 1 H) 3.25 (m, 1 H) 3.05 (m, 2 H) 2.74 (brs, 1 H) 2.49-2.35 (m, 2 H) 2.21-1.95 (m, 3 H) 1.93- 1.76 (m, 2 H) 1.67 (td, 3 H) 1.42 (brs, 1 H) 374 (R,Z)-tert-butyl 1-(2- cyclobutoxy-6-((2,4- dioxothiazolidin-5- ylidene)methyl)phenyl) piperidin-3-ylcarbamate Method 161  
    Figure US20150051185A1-20150219-C00347
    122AE (R,Z)-4-(3- aminopipcridin-1-yl)- 3-((2,4- dioxothiazolidin-5- ylidene)methyl) benzamide hydrochloride  
    Figure US20150051185A1-20150219-C00348
         		347 (R,Z)-tert-butyl 1-(4- carbamoyl-2-((2,4- dioxothiazolidin-5- ylidene)methyl)phenyl) piperidin-3-ylcarbamate Method 162  
    Figure US20150051185A1-20150219-C00349
    122AF (S,Z)-4-(3- aminopiperidin-1-yl)- 3-((2,4- dioxothiazolidin-5- ylidene)methyl) benzamide hydrochloride  
    Figure US20150051185A1-20150219-C00350
         		347 (S,Z)-tert-butyl 1-(4- carbamoyl-2-((2,4- dioxothiazolidin-5- ylidene)methyl)phenyl) piperidin-3-ylcarbamate Method 163  
    Figure US20150051185A1-20150219-C00351
    122AG (R,Z)-4-(3- aminopiperidin-1-yl)- 3-((2,4- dioxothiazolidin-5- ylidene)methyl) benzoic acid hydrochloride  
    Figure US20150051185A1-20150219-C00352
         		348 (R,Z)-4-(3-(tert- butoxycarbonylamino) piperidin-1-yl)-3-((2,4- dioxothiazolidin-5- ylidene)methyl)benzoic acid Method 164  
    Figure US20150051185A1-20150219-C00353
    122AH (S,Z)-4-(3- aminopyrrolidin-1- yl)-3-((2,4- dioxothiazolidin-5- ylidene)methyl) benzoic acid  
    Figure US20150051185A1-20150219-C00354
         		333 (S,Z)-4-(3-(tert- butoxycarbonylamino) pyrrolidin-1-yl)-3-((2,4- dioxothiazolidin-5- ylidene)methyl) benzoic acid Method 165  
    Figure US20150051185A1-20150219-C00355
    122AI (R,Z)-5-((2-(3- aminopiperidin-1- yl)biphenyl-3- yl)methylene) thiazolidine-2,4- dione  
    Figure US20150051185A1-20150219-C00356
         		12.64 (brs, 1 H) 8.09 (brs, 3 H) 7.92 (s, 1 H) 7.56-7.36 (m, 4 H) 7.36- 7.16 (m, 4 H) 3.06 (brs, 1 H) 3.00 (brs, 1 H) 2.72 (d, 1 H) 2.35 (brs, 2 H) 2.05 (brs, 1 H) 1.58 (brs, 2 H) 1.32-1.15 (m, 1 H) 380 (R,Z)-tert-butyl 1-(3- ((2,4-dioxothiazolidin-5- ylidene)methyl)biphenyl- 2-yl)piperidin-3- ylcarbamate Method 166  
    Figure US20150051185A1-20150219-C00357
    • Example 123
  • Figure US20150051185A1-20150219-C00358
    • (S,Z)-5-(2-(3-(3-aminopropylamino)pyrrolidin-1-yl)-5-(trifluoromethyl)benzylidene)thiazolidine-2,4-dione hydrochloride
  • A 25 mL round bottom flask was charged with a magnetic stir bar, (S,Z)-5-(2-(3-(3-(1,3-dioxoisoindolin-2-yl)propylamino)pyrrolidin-1-yl)-5-(trifluoromethyl)benzylidene)thiazolidine-2,4-dione (Method 70) (0.271 g, 0.50 mmol), EtOH (2.488 ml), and hydrazine (0.023 ml, 0.75 mmol). The reaction was stirred at rt for 30 min and then filtered through a bed of Celite. The filtrate was conc. in vacuo and purified via reverse phase HPLC (MeCN/water) to afford fractions that were conc. in vacuo, suspended in methanol (˜5 mL) and 1N HCl in diethyl ether (˜2 mL) and conc. in vacuo to afford (S,Z)-5-(2-(3-(3-aminopropylamino)pyrrolidin-1-yl)-5-(trifluoromethyl)benzylidene)thiazolidine-2,4-dione hydrochlride (0.071 g, 29.3%). 1H NMR (300 MHz, DMSO-D6) δ ppm 12.52 (s, 1H) 9.49 (s, 1H) 8.08 (brs, 2H) 7.93 (s, 1H) 7.67 (s, 1H) 7.61 (d, 1H) 7.08 (d, 1H) 3.88-3.81 (m, 1H) 3.53-3.33 (m, 4H) 3.08-3.05 (m, 2H) 2.92-2.89 (m, 2H) 2.33-2.19 (m, 2H) 2.04-1.96 (m, 2H); m/z 415.
  • The following examples were prepared by the procedure of Example 123, using the appropriate starting materials. The following parent compounds obtained after chromatography may be converted to their corresponding hydrochloride salt in a manner similar as described in example 123.
  • Ex. Compound 1H NMR m/z SM
    124
    Figure US20150051185A1-20150219-C00359
         		12.59 (brs, 1 H) 9.30 (brs, 1 H) 8.09 (s, 1 H) 8.07 (brs, 1 H) 7.32 (t, 1 H) 7.21 (d, 1 H) 7.08 (d, 1 H) 3.87 (s, 3 H) 3.46-3.44 (m, 1 H) 3.39-3.25 (m, 2 H) 3.17-2.99 (m, 4 H) 2.96-2.91 (m 2 H) 2.19-2.10 (m, 2 H) 2.08-1.99 (m, 2 H) 377
    Figure US20150051185A1-20150219-C00360
    125
    Figure US20150051185A1-20150219-C00361
         		12.72 (brs, 1 H) 9.50 (brs, 1 H) 8.10 (brs, 2 H) 7.96 (s, 1 H) 7.60 (d, 1 H) 7.46-7.39 (m, 2 H) 3.95-3.91 (m, 1 H) 3.51-3.20 (m, 4 H) 2.99- 2.92 (m, 2 H) 2.44-2.38 (m, 2 H) 2.21-2.11 (m, 2 H) 2.08-1.99 (m, 2 H) 382
    Figure US20150051185A1-20150219-C00362
    126
    Figure US20150051185A1-20150219-C00363
         		12.40 (s, 1 H) 9.78 (s, 1 H) 7.92 (s, 1 H) 7.05 (s, 1 H) 6.85 (s, 1 H) 4.21-4.11 (m, 1 H) 3.93 (s, 3 H) 3.83 (s, 3 H) 3.42-3.25 (m, 8 H) 2.45 (m, 1 H) 2.20 (m, 1 H) 1.32 (m, 2 H) 407
    Figure US20150051185A1-20150219-C00364
    127
    Figure US20150051185A1-20150219-C00365
         		12.64 (s, 1 H) 11.50 (s, 1 H) 8.27 (s, 1 H) 7.85 (s, 1 H) 7.49 (t, 2 H) 7.24 (t, 2 H) 3.55 (d, 2 H) 3.32- 3.16 (m, 8 H) 2.93 (d, 2 H) 2.18-2.07 (m, 2 H) 347
    Figure US20150051185A1-20150219-C00366
    128
    Figure US20150051185A1-20150219-C00367
         		12.34 (s, 1 H) 8.46 (d, 1 H) 7.86 (s, 3 H) 6.95 (s, 1 H) 6.63 (s, 1 H) 4.36-4.26 (m, 1 H) 3.84 (s, 3 H) 3.72 (s, 3 H), 3.32-3.21 (m, 3 H) 3.02-2.93 (m, 3 H) 2.18 (dd, 2 H) 1.86 (dd, 1 H) 421
    Figure US20150051185A1-20150219-C00368
    129A
    Figure US20150051185A1-20150219-C00369
         		12.59 (s, 1 H) 7.94 (s, 1 H) 7.82 (s, 2 H) 7.51- 7.44 (m, 2 H) 7.26-7.17 (m, 2 H) 3.66 (m, 2 H) 3.59 (m, 2 H) 3.08-2.97 (m, 2 H) 2.96-2.86 (m, 4 H) 2.74 (m, 2 H) 361
    Figure US20150051185A1-20150219-C00370
    129B
    Figure US20150051185A1-20150219-C00371
         		12.69 (brs, 1 H) 9.31 (brs, 1 H) 8.05 (s, 3 H) 7.56 (d, 1 H) 7.49-7.41 (m, 1 H) 7.37 (t, 1 H) 3.76-3.65 (m, 3 H) 3.16 (brs, 1 H) 3.04 (brs, 2 H) 2.94-2.75 (m, 3 H) 2.33 (brs, 1 H) 2.04-1.92 (m, 2 H) 1.78 (d, 1 H) 1.65 (m, 1 H), 1.50 (m, 1 H) 395
    Figure US20150051185A1-20150219-C00372
    129C
    Figure US20150051185A1-20150219-C00373
         		12.64 (brs, 1 H) 7.94 (brs, 4 H) 7.11 (m, 2 H) 6.93 (s, 1 H) 4.13 (m, 2 H) 3.77 (s, 3 H) 2.97 (m, 2 H) 2.06 (m, 2 H) 309
    Figure US20150051185A1-20150219-C00374
    • Example 130
  • Figure US20150051185A1-20150219-C00375
  • (5Z)-5-[2-(4-acetylpiperazin-1-yl)benzylidene]-1,3-thiazolidine-2,4-dione: To a mixture of (57)-5-(2-piperazin-1-ylbenzylidene)-1,3-thiazolidine-2,4-dione (Example 115) and acetyl chloride (36.1 mg, 0.46 mmol) was added triethylamine (93 mg, 0.92 mmol) at room temperature. The reaction mixture was stirred at room temperature overnight and was then treated with sat'd aqueous NaHCO3 (˜25 mL). This mixture was allowed to stir at room temperature for 10 min, and was then extracted with DCM (3×25 mL). The combined organic extract was dried over anhydrous Na2SO4, filtered through a bed of Celite, and the filtrate was conc. in vacuo to afford the product which was purified via reverse phase HPLC (acetonitrile:water: 0.1% TFA=5% to 70%) to afford the title compound as a pale yellow solid (40.0 mg, 35.4%). 1H NMR (300 MHz, DMSO-D6) δ ppm 12.58 (brs, 1H) 7.94 (s, 1H) 7.47 (d, 2H) 7.30-7.07 (m, 2H) 3.60 (brs, 4H) 2.90 (brs, 2H) 2.85 (brs, 2H) 2.04 (s, 3H); m/z 331.
  • The following examples were prepared by the procedure of Example 130, using the appropriate starting materials.
  • Ex. Compound 1H NMR m/z SM
    131A
    Figure US20150051185A1-20150219-C00376
         		12.29 (brs, 1 H) 8.13 (d, 1 H) 7.85 (s, 1 H) 6.94 (s, 1 H) 6.61 (s, 1 H) 4.27 (d, 1 H) 3.83 (s, 3 H) 3.72 (s, 3 H) 3.43-3.14 (m, 4 H) 2.94 (dd, 1 H) 2.30-2.05 (m, 1 H) 1.82 (s, 3 H) 392
    Figure US20150051185A1-20150219-C00377
    131B
    Figure US20150051185A1-20150219-C00378
         		9.86 (s, 1 H) 7.68 (s, 1 H) 7.56 (s, 1 H) 7.49-7.47 (d, 1 H) 6.96-6.94 (d, 1 H) 3.23 (m, 1 H) 3.00 (m, 4 H) 2.51 (s, 6 H) 2.15 (m, 1 H) 2.01 (s, 3 H) 1.55 (m, 1 H) 375
    Figure US20150051185A1-20150219-C00379
    • Example 132
  • Figure US20150051185A1-20150219-C00380
    • (Z)-5-(2-(3-(2-hydroxyethylamino)pyrrolidin-1-yl)-4,5-dimethoxybenzylidene)thiazolidine-2,4-dione
  • A mixture of (Z)-5-(2-(3-(2-(tert-butyldimethylsilyloxy)ethylamino)pyrrolidin-1-yl)-4,5-dimethoxybenzylidene)thiazolidine-2,4-dione (Method 77) (120 mg, 0.24 mmol) in 5 mL of 1.25 M HCl in methanol was stirred at room temperature for 30 min. The mixture was then conc. in vacuo to afford the product which was purified via reverse phase HPLC (acetonitrile:water: 0.1% NH4OAc=5% to 55%) to yield the title compound as a yellow solid (45.0 mg, 48.4%). 1H NMR (300 MHz, DMSO-D6) δ ppm 7.40 (s, 1H) 7.07 (s, 1H) 6.57 (s, 1H) 3.78 (s, 3H) 3.70 (s, 3H) 3.45 (m, 2H) 3.27-3.15 (m, 4H) 2.92 (m, 1H) 2.59 (m, 2H) 2.08 (m, 1H) 1.66 (m, 1H); m/z 394.
  • The following examples were prepared by the procedure of Example 132 using the appropriate starting materials.
  •
    133
    Figure US20150051185A1-20150219-C00381
         		8.81 (brs, 2 H) 7.96 (s, 1 H) 7.48 (d, 1 H) 7.40-7.32 (m, 1 H) 7.31-7.25 (m, 1 H) 3.63-3.55 (m, 2 H) 3.46-3.38 (m, 2 H) 3.08 (brs, 2 H) 2.96 (d, 2 H) 2.75 (brs, 1 H) 2.20 (m, 1H) 1.72 (brs, 1 H) 1.56 (brs, 1 H) 1.44 (brs, 1 H) 382
    Figure US20150051185A1-20150219-C00382
    134
    Figure US20150051185A1-20150219-C00383
         		12.69 (brs, 1 H) 8.84 (brs, 1 H) 8.04 (s, 1 H) 7.56 (d, 1 H) 7.49-7.39 (m, 1 H) 7.36 (t, 1 H) 3.69 (dd, 2 H) 3.17 (brs, 2 H) 3.00 (brs, 2 H) 2.83 (brs, 1 H) 2.26 (brs, 1 H) 1.93-1.72 (m, 4 H) 1.66 (brs, 1 H) 1.50 (brs, 1 H)
    Figure US20150051185A1-20150219-C00384
    • Example 135
  • Figure US20150051185A1-20150219-C00385
    • (S,Z)—N-(1-(2-chloro-6-((2,4-dioxothiazolidin-5-ylidene)methyl)phenyl)pyrrolidin-3-yl)-1-methyl-1H-imidazole-2-carboxamide
  • To a 50 mL vial charged with a magnetic stir bar was added (S,Z)-5-(2-(3-aminopyrrolidin-1-yl)-3-chlorobenzylidene)thiazolidine-2,4-dione (75 mg, 0.23 mmol) (Example 86), 1-methyl-1H-imidazole-2-carboxylic acid (87 mg, 0.69 mmol), HATU (220 mg, 0.58 mmol) and dichloromethane (5 mL). Hunig's base (0.202 mL, 1.16 mmol) was then added and the mixture was stirred at rt for 4 h. The reaction was then diluted with dichloromethane and washed with water. The mixture was separated with a phase separator tube and the organic phase was evaporated to dryness. The residue was purified by reverse phase chromatography to afford the title compound as a yellow solid (21 mg, 21%). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.89 (s, 1H) 7.51 (dd, 1H) 7.41 (dd, 1H) 7.18-7.27 (m, 2H) 7.01 (s, 1H) 4.67-4.77 (m, 1H) 4.00 (s, 3H) 3.63-3.75 (m, 2H) 3.47-3.54 (m, 1H) 3.36-3.47 (m, 1H) 2.39-2.51 (m, 1H) 2.14 (dd, 1H); m/z 432.
  • The following examples were prepared by the procedure of 135 using the appropriate starting materials.
  •
    136
    Figure US20150051185A1-20150219-C00386
         		7.89 (s, 1 H) 7.52 (dd, 1 H) 7.41 (dd, 1 H) 7.25 (t, 1 H) 4.58-4.67 (m, 1 H) 3.93 (s, 2 H) 3.65 (dd, 1 H) 3.36- 3.46 (m, 5 H) 3.13 (dd, 1 H) 2.38 (dd, 1 H) 2.01-2.13 (m, 1 H) 396
    Figure US20150051185A1-20150219-C00387
    Figure US20150051185A1-20150219-C00388
    137
    Figure US20150051185A1-20150219-C00389
         		7.93 (s, 1 H) 7.61 (d, 1 H) 7.52 (dd, 1 H) 7.42 (dd, 1 H) 7.25 (t, 1 H) 6.73 (d, 1 H) 4.73-4.83 (m, 1 H) 3.92-3.99 (m, 3 H) 3.71 (dd, 1 H) 3.38-3.50 (m, 2 H) 3.23 (dd, 1 H) 2.38-2.50 (m, 1 H) 2.09-2.21 (m, 1 H) 432
    Figure US20150051185A1-20150219-C00390
    Figure US20150051185A1-20150219-C00391
    138
    Figure US20150051185A1-20150219-C00392
         		7.93 (s, 1 H) 7.52 (dd, 1 H) 7.41 (dd, 1 H) 7.25 (t, 1 H) 4.53 (ddd, 1 H) 3.83-3.92 (m, 2 H) 3.65-3.70 (m, 1 H) 3.42-3.49 (m, 1 H) 3.35-3.42 (m, 1 H) 3.07 (dd, 1 H) 2.37 (dt, 1 H) 1.98- 2.10 (m, 1 H) 424
    Figure US20150051185A1-20150219-C00393
    Figure US20150051185A1-20150219-C00394
    139
    Figure US20150051185A1-20150219-C00395
         		8.44 (br. S., 2 H) 8.02 (s, 1 H) 7.83 (d, 1 H) 7.50 (dd, 1 H) 7.34-7.46 (m, 3 H) 7.25 (t, 1 H) 4.51 (t, 1 H) 3.60-3.69 (m, 3 H) 3.37-3.48 (m, 2 H) 3.08 (dd, 1 H) 2.31-2.43 (m, 1 H) 2.03 (dd, 1 H) 443
    Figure US20150051185A1-20150219-C00396
    Figure US20150051185A1-20150219-C00397
    140
    Figure US20150051185A1-20150219-C00398
         		8.47 (br. S., 1 H) 7.98 (s, 1 H) 7.53 (dd, 1 H) 7.41 (dd, 3 H) 7.25 (t, 1 H) 4.53 (t, 1 H) 3.64-3.71 (m, 3 H) 3.39-3.48 (m, 2 H) 3.07 (dd, 1 H) 2.32-2.44 (m, 1 H) 2.03 (dd, 1 H) 443
    Figure US20150051185A1-20150219-C00399
    Figure US20150051185A1-20150219-C00400
    141
    Figure US20150051185A1-20150219-C00401
         		8.17 (s, 1 H) 8.07 (s, 1 H) 7.94 (s, 1 H) 7.47 (ddd, 2 H) 7.27 (t, 1 H) 4.67-4.78 (m, 1 H) 3.89-3.97 (m, 3 H) 3.73 (dd, 1 H) 3.44 (t, 2 H) 3.19 (dd, 1 H) 2.42 (dd, 1 H) 2.14 (dd, 1 H) 432
    Figure US20150051185A1-20150219-C00402
    Figure US20150051185A1-20150219-C00403
    142
    Figure US20150051185A1-20150219-C00404
         		7.91 (s, 1 H) 7.56 (dd, 1 H) 7.43 (dd, 1 H) 7.27 (t, 1 H) 4.62 (t, 1 H) 3.67- 3.78 (m, 2 H) 3.41-3.48 (m, 2 H) 3.19-3.22 (m, 2 H) 3.10-3.17 (m, 5 H) 2.92-2.98 (m, 2 H) 2.81-2.86 (m, 1 H) 2.37-2.48 (m, 1 H) 2.02-2.13 (m, 1 H) 483
    Figure US20150051185A1-20150219-C00405
    Figure US20150051185A1-20150219-C00406
    143
    Figure US20150051185A1-20150219-C00407
         		7.18 (s, 1 H) 6.70 (dd, 1 H) 6.62 (dd, 1 H) 6.45 (t, 1 H) 3.71 (s, 1 H) 2.84 (dd, 1 H) 2.56- 2.66 (m, 2 H) 2.29-2.36 (m, 2 H) 2.26 (dd, 1 H) 1.64 (t, 2 H) 1.57 (d, 1 H) 1.25-1.37 (m, 2 H) 1.20 (d, 1 H) 473
    Figure US20150051185A1-20150219-C00408
    Figure US20150051185A1-20150219-C00409
    144
    Figure US20150051185A1-20150219-C00410
         		8.01 (s, 1 H) 7.50 (d, 1 H) 7.44 (d, 1 H) 7.26 (t, 1 H) 4.47-4.58 (m, 1 H) 3.62 (t, 1 H) 3.42 (t, 2 H) 3.02-3.15 (m, 4 H) 2.92 (s, 3 H) 2.67 (d, 2 H) 2.56 (t, 2 H) 2.36 (dd, 1 H) 2.02 (dd, 1 H) 451
    Figure US20150051185A1-20150219-C00411
    Figure US20150051185A1-20150219-C00412
    145
    Figure US20150051185A1-20150219-C00413
         		7.07 (s, 1 H) 6.69-6.74 (m, 1 H) 6.59 (dd, 1 H) 6.43 (t, 1 H) 3.76 (br. S., 1 H) 2.85-2.94 (m, 2 H) 2.84 (d, 1 H) 2.36 (br. S., 1 H) 2.29 (dd, 2 H) 1.52-1.64 (m, 7 H) 1.18-1.28 (m, 1 H) 409
    Figure US20150051185A1-20150219-C00414
    Figure US20150051185A1-20150219-C00415
    146
    Figure US20150051185A1-20150219-C00416
         		7.95 (s, 1 H) 7.52 (dd, 1 H) 7.42 (dd, 1 H) 7.26 (t, 1 H) 4.50 (ddd, 1 H) 3.68-3.78 (m, 1 H) 3.64 (dd, 1 H) 3.44- 3.50 (m, 1 H) 3.40 (t, 1 H) 3.22 (q, 1 H) 3.09 (dd, 1 H) 2.39 (dt, 1 H) 2.03 (d, 1 H) 391
    Figure US20150051185A1-20150219-C00417
    Figure US20150051185A1-20150219-C00418
    147
    Figure US20150051185A1-20150219-C00419
         		7.89 (s, 1 H) 7.54 (dd, 1 H) 7.39 (dd, 1 H) 7.24 (t, 1 H) 4.49- 4.60 (m, 1 H) 3.86- 3.98 (m, 1 H) 3.65 (dd, 1 H) 3.36-3.48 (m, 2 H) 3.17- 3.25 (m, 1 H) 3.07-3.16 (m, 1 H) 2.31-2.43 (m, 1 H) 1.96-2.09 (m, 4 H) 423
    Figure US20150051185A1-20150219-C00420
    Figure US20150051185A1-20150219-C00421
    • Example 148
  • Figure US20150051185A1-20150219-C00422
    • (R,Z)-5-(3-chloro-2-(3-(dipropylamino)piperidin-1-yl)benzylidene)thiazolidine-2,4-dione
  • A mixture of (R,Z)-5-(2-(3-aminopiperidin-1-yl)-3-chlorobenzylidene)thiazolidine-2,4-dione (122D) (100 mg, 0.27 mmol) and propionaldehyde (20.17 mg, 0.35 mmol) in CH2Cl2 (15 mL) was stirred at 50° C. for 20 min. before sodium triacetoxyborohydride (170 mg, 0.80 mmol) was added. The mixture was then stirred at 50° C. for 4 h. before sat'd aqueous K2CO3 (˜50 mL) was added to the mixture. This solution was poured into a separatory funnel and extracted with CHCl3/isopropanol (5/1) (2×50 mL). The combined organic extract was dried over anhydrous Na2SO4, filtered, and conc. in vacuo affording the product. It was purified with Gilson (0.1% TFA in water:0.1% TFA in CAN=30% to 80%; UV absorption at 322) to yield the title compound as a yellow solid (94 mg, 77%). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.96 (s, 1H) 7.48 (d, 1H) 7.41-7.34 (m, 1H) 7.29 (t, 1H) 3.67-3.58 (m, 2H) 3.44-3.37 (m, 2H) 3.03-2.78 (m, 5H) 2.21 (brs, 1H), 1.79 (d, 1H) 1.61 (d, 6H) 0.84-0.79 (m, 6H). m/z 422.
  • He following examples were prepared by the procedure of 148, using the appropriate starting materials.
  •
    149
    Figure US20150051185A1-20150219-C00423
         		12.65 (brs, 1 H) 9.35 (brs, 1H) 8.05 (s, 1 H) 7.56 (d, 1 H) 7.44 (brs, 1 H) 7.37 (t, 1 H) 3.75-3.63 (m, 2 H) 3.53-3.45 (m, 2 H) 3.23 (m, 1 H) 2.85- 2.65 (m, 4 H) 2.30 (brs, 1 H) 1.85-1.76 (m, 1 H) 1.67 (brs, 1 H) 1.49 (brs, 1 H) 433
    Figure US20150051185A1-20150219-C00424
    Figure US20150051185A1-20150219-C00425
    150
    Figure US20150051185A1-20150219-C00426
         		12.65 (s, 1H), 8.91 (s, br, 2H), 7.91 (s, 1H), 7.10 (m, 2H), 7.85 (s, 1H), 4.17 (m, 2H), 3.65 (m, 4H), 3.05 (m, 2H), 2.14 (m, 2H), 1.22 (m, 6H) 351
    Figure US20150051185A1-20150219-C00427
    Figure US20150051185A1-20150219-C00428
    • Example 151
  • Figure US20150051185A1-20150219-C00429
    • (Z)-5-(5-amino-2-(3-(dimethylamino)pyrrolidin-1-yl)benzylidene)thiazolidine-2,4-dione
  • To a mixture of (Z)-5-(2-(3-(dimethylamino)pyrrolidin-1-yl)-5-nitrobenzylidene)thiazolidine-2,4-dione (100 mg, 0.28 mmol) (Method 149) and iron (154 mg, 2.76 mmol) chip in MeOH (10 mL) was added 5 drops of conc. HCl and 5 drops of water. The mixture was stirred at 80° C. for 1 hr. The mixture was loaded into silica gel, purified with ISCO (100% ethyl acetate to methanol/ethyl acetate=50%) to yield a red solid which was repurified with Gilson (acetonitrile:water:0.1% TFA=0% to 50% fro 7 min) to yield a yellow solid as (Z)-5-(5-amino-2-(3-(dimethylamino)pyrrolidin-1-yl)benzylidene)thiazolidine-2,4-dione (51.0 mg, 38.6%). 1H NMR (400 MHz, DMSO-d6) d ppm 12.55 (brs, 1H), 11.32 (brs, 1H), 10.30 (brs, 2H), 7.80 (s, 1H), 7.42 (m, 2H), 7.19 (m, 1H), 3.95 (m, 1H), 3.39-3.27 (m, 4H), 2.78 (s, 6H), 2.30-2.10 (m, 2H); m/z 333.
  • The following intermediates were prepared by the procedure of Example 151 using the appropriate starting materials.
  • Ex Compound 1H NMR m/z SM
    152
    Figure US20150051185A1-20150219-C00430
         		12.45 (brs, 1 H) 7.87 (s, 1 H) 6.80 (s, 1H) 6.79 (s, 1 H) 3.78 (s, 3 H) 3.73 (s, 3 H) 280
    Figure US20150051185A1-20150219-C00431
    • Methods Section
  • Figure US20150051185A1-20150219-C00432
    • Method 1 (S)-3-bromo-2-(3-(dimethylamino)pyrrolidin-1-yl)benzaldehyde
  • A 50 mL round bottom flask was charged with a magnetic stir bar, 3-bromo-2-fluorobenzaldehyde (0.555 g, 2.73 mmol), (S)—N,N-dimethylpyrrolidin-3-amine (0.312 g, 2.73 mmol), DMSO (5.47 ml), and potassium carbonate (0.378 g, 2.73 mmol). The mixture was heated to 85° C. overnight with stirring. The reaction was allowed to cool to ambient temperature, was diluted with water, and extracted into methylene chloride. The combined organic extract was dried with MgSO4, filtered, and conc. in vacuo to provide the product which was purified via silica gel chromatography (40 g) using ethyl acetate/MeOH (10:1) as eluent to afford (S)-3-bromo-2-(3-(dimethylamino)pyrrolidin-1-yl)benzaldehyde (0.369 g, 45.4%).
  • The following intermediates were prepared by the procedure of Method 1, using the appropriate starting materials.
  • Method Compound 1H NMR m/z SM
    2
    Figure US20150051185A1-20150219-C00433
         		287
    Figure US20150051185A1-20150219-C00434
    3
    Figure US20150051185A1-20150219-C00435
         		249
    Figure US20150051185A1-20150219-C00436
    4
    Figure US20150051185A1-20150219-C00437
         		249
    Figure US20150051185A1-20150219-C00438
    5
    Figure US20150051185A1-20150219-C00439
         		254
    Figure US20150051185A1-20150219-C00440
    6
    Figure US20150051185A1-20150219-C00441
         		253
    Figure US20150051185A1-20150219-C00442
    7
    Figure US20150051185A1-20150219-C00443
         		279
    Figure US20150051185A1-20150219-C00444
    8
    Figure US20150051185A1-20150219-C00445
         		279
    Figure US20150051185A1-20150219-C00446
    9
    Figure US20150051185A1-20150219-C00447
         		280
    Figure US20150051185A1-20150219-C00448
    10
    Figure US20150051185A1-20150219-C00449
         		266
    Figure US20150051185A1-20150219-C00450
    11
    Figure US20150051185A1-20150219-C00451
         		249
    Figure US20150051185A1-20150219-C00452
    12
    Figure US20150051185A1-20150219-C00453
         		263
    Figure US20150051185A1-20150219-C00454
    13
    Figure US20150051185A1-20150219-C00455
         		253
    Figure US20150051185A1-20150219-C00456
    14
    Figure US20150051185A1-20150219-C00457
         		236
    Figure US20150051185A1-20150219-C00458
    15
    Figure US20150051185A1-20150219-C00459
         		207
    Figure US20150051185A1-20150219-C00460
    16
    Figure US20150051185A1-20150219-C00461
         		219
    Figure US20150051185A1-20150219-C00462
    17
    Figure US20150051185A1-20150219-C00463
         		233
    Figure US20150051185A1-20150219-C00464
    18
    Figure US20150051185A1-20150219-C00465
         		233
    Figure US20150051185A1-20150219-C00466
    19
    Figure US20150051185A1-20150219-C00467
         		267
    Figure US20150051185A1-20150219-C00468
    20
    Figure US20150051185A1-20150219-C00469
         		279
    Figure US20150051185A1-20150219-C00470
    21
    Figure US20150051185A1-20150219-C00471
         		293
    Figure US20150051185A1-20150219-C00472
    22
    Figure US20150051185A1-20150219-C00473
         		293
    Figure US20150051185A1-20150219-C00474
    23
    Figure US20150051185A1-20150219-C00475
         		359
    Figure US20150051185A1-20150219-C00476
    24
    Figure US20150051185A1-20150219-C00477
         		264
    Figure US20150051185A1-20150219-C00478
    25
    Figure US20150051185A1-20150219-C00479
         		262
    Figure US20150051185A1-20150219-C00480
    26
    Figure US20150051185A1-20150219-C00481
         		291
    Figure US20150051185A1-20150219-C00482
    79
    Figure US20150051185A1-20150219-C00483
         		326
    Figure US20150051185A1-20150219-C00484
    80
    Figure US20150051185A1-20150219-C00485
         		359
    Figure US20150051185A1-20150219-C00486
    81
    Figure US20150051185A1-20150219-C00487
         		359
    Figure US20150051185A1-20150219-C00488
    82
    Figure US20150051185A1-20150219-C00489
         		292
    Figure US20150051185A1-20150219-C00490
    83
    Figure US20150051185A1-20150219-C00491
         		322
    Figure US20150051185A1-20150219-C00492
    84
    Figure US20150051185A1-20150219-C00493
         		321
    Figure US20150051185A1-20150219-C00494
    85
    Figure US20150051185A1-20150219-C00495
         		326
    Figure US20150051185A1-20150219-C00496
    86
    Figure US20150051185A1-20150219-C00497
         		365
    Figure US20150051185A1-20150219-C00498
    87
    Figure US20150051185A1-20150219-C00499
         		351
    Figure US20150051185A1-20150219-C00500
    88
    Figure US20150051185A1-20150219-C00501
         		351
    Figure US20150051185A1-20150219-C00502
    89
    Figure US20150051185A1-20150219-C00503
         		305
    Figure US20150051185A1-20150219-C00504
    90
    Figure US20150051185A1-20150219-C00505
         		351
    Figure US20150051185A1-20150219-C00506
    91
    Figure US20150051185A1-20150219-C00507
         		339
    Figure US20150051185A1-20150219-C00508
    92
    Figure US20150051185A1-20150219-C00509
         		339
    Figure US20150051185A1-20150219-C00510
    93
    Figure US20150051185A1-20150219-C00511
         		339
    Figure US20150051185A1-20150219-C00512
    94
    Figure US20150051185A1-20150219-C00513
         		335
    Figure US20150051185A1-20150219-C00514
    95
    Figure US20150051185A1-20150219-C00515
         		385
    Figure US20150051185A1-20150219-C00516
    96
    Figure US20150051185A1-20150219-C00517
         		325
    Figure US20150051185A1-20150219-C00518
    97
    Figure US20150051185A1-20150219-C00519
         		371
    Figure US20150051185A1-20150219-C00520
    98
    Figure US20150051185A1-20150219-C00521
         		349
    Figure US20150051185A1-20150219-C00522
    99
    Figure US20150051185A1-20150219-C00523
         		377
    Figure US20150051185A1-20150219-C00524
    100
    Figure US20150051185A1-20150219-C00525
         		417
    Figure US20150051185A1-20150219-C00526
    101
    Figure US20150051185A1-20150219-C00527
         		403
    Figure US20150051185A1-20150219-C00528
    102
    Figure US20150051185A1-20150219-C00529
         		354
    Figure US20150051185A1-20150219-C00530
    103
    Figure US20150051185A1-20150219-C00531
         		10.49 (s, 1 H), 7.75 (d, 1 H), 7.63 (d, 1 H), 7.25 (t, 1 H), 3.37 (brs, 4 H), 1.88 (brs, 2 H), 1.53 (s, 9 H) 339
    Figure US20150051185A1-20150219-C00532
    104
    Figure US20150051185A1-20150219-C00533
         		249
    Figure US20150051185A1-20150219-C00534
    105
    Figure US20150051185A1-20150219-C00535
         		287
    Figure US20150051185A1-20150219-C00536
    106
    Figure US20150051185A1-20150219-C00537
         		253
    Figure US20150051185A1-20150219-C00538
    107
    Figure US20150051185A1-20150219-C00539
         		233
    Figure US20150051185A1-20150219-C00540
    108
    Figure US20150051185A1-20150219-C00541
         		237
    Figure US20150051185A1-20150219-C00542
    109
    Figure US20150051185A1-20150219-C00543
         		233
    Figure US20150051185A1-20150219-C00544
    110
    Figure US20150051185A1-20150219-C00545
         		298
    Figure US20150051185A1-20150219-C00546
    111
    Figure US20150051185A1-20150219-C00547
         		237
    Figure US20150051185A1-20150219-C00548
    112
    Figure US20150051185A1-20150219-C00549
         		253
    Figure US20150051185A1-20150219-C00550
    113
    Figure US20150051185A1-20150219-C00551
         		363
    Figure US20150051185A1-20150219-C00552
    114
    Figure US20150051185A1-20150219-C00553
         		349
    Figure US20150051185A1-20150219-C00554
    115
    Figure US20150051185A1-20150219-C00555
         		334
    Figure US20150051185A1-20150219-C00556
    116
    Figure US20150051185A1-20150219-C00557
         		263
    Figure US20150051185A1-20150219-C00558
    117
    Figure US20150051185A1-20150219-C00559
         		10.30 (s, 1 H) 7.76 (dd, 1 H) 7.65 (dd, 1 H) 7.29-7.24 (m, 1 H) 5.05 (brs, 1 H) 4.41 (brs, 1 H) 4.20 (brs, 1 H) 3.87 (dd, 1 H) 3.78 (dd, 1 H) 3.64-3.47 (m, 1 H) 3.36 (brs, 1 H) 3.21 (dd, 1 H) 1.50 (s, 9 H) 341
    Figure US20150051185A1-20150219-C00560
    118
    Figure US20150051185A1-20150219-C00561
         		367
    Figure US20150051185A1-20150219-C00562
    119
    Figure US20150051185A1-20150219-C00563
         		310
    Figure US20150051185A1-20150219-C00564
    120
    Figure US20150051185A1-20150219-C00565
         		305
    Figure US20150051185A1-20150219-C00566
    121
    Figure US20150051185A1-20150219-C00567
         		291
    Figure US20150051185A1-20150219-C00568
    122
    Figure US20150051185A1-20150219-C00569
         		403
    Figure US20150051185A1-20150219-C00570
    123
    Figure US20150051185A1-20150219-C00571
         		389
    Figure US20150051185A1-20150219-C00572
    124
    Figure US20150051185A1-20150219-C00573
         		379
    Figure US20150051185A1-20150219-C00574
    125
    Figure US20150051185A1-20150219-C00575
         		365
    Figure US20150051185A1-20150219-C00576
    126
    Figure US20150051185A1-20150219-C00577
         		389
    Figure US20150051185A1-20150219-C00578
    127
    Figure US20150051185A1-20150219-C00579
         		375
    Figure US20150051185A1-20150219-C00580
    128
    Figure US20150051185A1-20150219-C00581
         		348
    Figure US20150051185A1-20150219-C00582
    129
    Figure US20150051185A1-20150219-C00583
         		348
    Figure US20150051185A1-20150219-C00584
    130
    Figure US20150051185A1-20150219-C00585
         		348
    Figure US20150051185A1-20150219-C00586
    131
    Figure US20150051185A1-20150219-C00587
         		334
    Figure US20150051185A1-20150219-C00588
  • Figure US20150051185A1-20150219-C00589
    • Method 27 5-methoxy-2-(2-(piperidin-1-yl)ethoxy)benzaldehyde
  • A mixture of 2-hydroxy-5-methoxybenzaldehyde (0.761 g, 5 mmol), 1-(2-chloroethyl)piperidine hydrochloride (0.921 g, 5.00 mmol), K2CO3 (2.07 g, 14.99 mmol), and sodium iodide (0.075 g, 0.50 mmol) in acetonitrile (40 mL) was stirred at 100° C. overnight. The reaction was allowed to cool to ambient temperature and sat'd aqueous K2CO3 was added to the reaction mixture. The mixture was poured into a reparatory funnel and extracted with EtOAc. The organic phase was dried over anhydrous MgSO4, filtered through a bed of Celite, and conc. in vacuo to yield the product which was purified via silica gel chromatography (80 g) using EtOAc/hexanes (4:1) as eluent to yield the title compound as a brown oil (0.551 g, 42%); m/z 264.
  • The following intermediates were prepared by the procedure of Method 27, using the appropriate starting materials.
  • Method Compound 1H NMR m/z SM
    28 5-methoxy-2-(2- 266 2-hydroxy-5-
    morpholinoethoxy) methoxy-
    benzaldehyde benzaldehyde
    Figure US20150051185A1-20150219-C00590
    Figure US20150051185A1-20150219-C00591
    and 4-(2-
    chloroethyl)morpholine
    hydrochloride
    Figure US20150051185A1-20150219-C00592
    29 2-(2- 252 2-hydroxy-5-
    (diethylamino) methoxy-
    ethoxy)-5- benzaldehyde
    methoxybenzaldehyde
    Figure US20150051185A1-20150219-C00593
    Figure US20150051185A1-20150219-C00594
    and
    2-chloro-N,N-
    diethylethanamine
    Figure US20150051185A1-20150219-C00595
    30A 2-(2- 222 Salicylaldehyde
    (diethylamino)ethoxy)
    benzaldehyde
    Figure US20150051185A1-20150219-C00596
    Figure US20150051185A1-20150219-C00597
    and
    2-chloro-N,N-
    diethylethanamine
    Figure US20150051185A1-20150219-C00598
    30B 2-(3-(1,3- 10.18 (s, 1 H) 7.69 (m, 4 340 2-hydroxy-5-
    dioxoisoindolin-2- H) 7.11 (m, 2 H) 6.97 (d, methoxybenzaldehyde
    yl)propoxy)-5- 1 H) 4.05 (m, 2 H) 3.83
    methoxybenzaldehyde (m, 2 H) 3.67 (s, 3 H)
    2.12 (m, 2 H)
    Figure US20150051185A1-20150219-C00599
    Figure US20150051185A1-20150219-C00600
    and 2-(3-
    bromopropyl)
    isoindoline-1,3-dione
    Figure US20150051185A1-20150219-C00601
  • Figure US20150051185A1-20150219-C00602
    • Method 31 4,5-dimethoxy-2-(pyridin-3-yl)benzaldehyde
  • A mixture of 2-bromo-4,5-dimethoxybenzaldehyde (0.368 g, 1.5 mmol), pyridin-3-ylboronic acid (0.246 g, 2.0 mmol), Pd(PPh3)4 (0.173 g, 0.150 mmol), and cesium carbonate (0.977 g, 3 mmol) were suspended in dioxane (4 mL) and water (1 mL). The mixture was heated to 140° C. in a microwave for 1 h. The reaction vessel was allowed to cool to ambient temperature, diluted with ethyl acetate (˜25 mL), filtered through a bed of Celite, and conc. in vacuo to afford the aldehyde which was purified via SiO2 chromatography (40 g) using ethyl acetate/hexanes (5:1) as eluent to afford the title compound as a white solid (0.340 g, 93%); m/z 244.
  • The following intermediates were prepared by the procedure of Method 31, using the appropriate starting materials.
  • Method Compound 1H NMR m/z SM
    32A 4,5-dimethoxy-2- 244 2-bromo-4,5-
    (pyridin-4- dimethoxy-
    yl)benzaldehyde benzaldehyde
    Figure US20150051185A1-20150219-C00603
    Figure US20150051185A1-20150219-C00604
    and
    pyridin-4-ylboronic acid
    Figure US20150051185A1-20150219-C00605
    32B N-(2- 9.95 (s, 1 H), 8.05 (d, 1 346 N-(2-
    (dimethylamino)ethyl)- H), 7.96 (d, 2 H), 7.72- (dimethylamino)ethyl)-
    2′-formyl-N- 7.83 (m, 1 H), 7.57- N-methyl-4-(4,4,5,5-
    methylbiphenyl-4- 7.72 (m, 3 H), 7.53 (d, 1 tetramethyl-1,3,2-
    sulfonamide H), 3.24 (t, 2 H), 2.79- dioxaborolan-2-
    2.91 (m, 3 H), 2.65 (t, 2 yl)benzenesulfonamide
    H), 2.37 (s, 6 H)
    Figure US20150051185A1-20150219-C00606
    Figure US20150051185A1-20150219-C00607
    And
    2-bromobenzaldehyde
    Figure US20150051185A1-20150219-C00608
  • Figure US20150051185A1-20150219-C00609
    • Method 33 (S,Z)-tert-butyl 1-(5-chloro-2-((2,4-dioxothiazolidin-5-ylidene)methyl)phenyl)pyrrolidin-3-ylcarbamate
  • A 100 mL round bottom flask was charged with a magnetic stir bar, (S)-tert-butyl 1-(5-chloro-2-formylphenyl)pyrrolidin-3-ylcarbamate (Method 78) (1.100 g, 3.39 mmol), thiazolidine-2,4-dione (0.397 g, 3.39 mmol), and ethanol (11.29 ml). Piperidine (0.034 mL, 0.34 mmol) was added and the reaction was heated to reflux for 2 h. Once the reaction was judged to be complete by LCMS, it was allowed to cool to ambient temperature and conc. in vacuo to afford the title compound (1.310 g, 91%) which was used in the next step without further purification.; m/z 425.
  • The following intermediates were prepared by the procedure of Method 33, using the appropriate starting materials.
  • Method Compound 1H NMR m/z SM
    34 (S,Z)-tert-butyl 1-(2- 425 tent-butyl [(3S)-1-(2-
    chloro-6-((2,4- chloro-6-
    dioxothiazolidin-5- formylphenyl)pyrrolidin-
    ylidene)methyl)phenyl) 3-yl]carbamate
    pyrrolidin-3-ylcarbamate Method 79
    Figure US20150051185A1-20150219-C00610
    Figure US20150051185A1-20150219-C00611
    35 (Z)-tert-butyl 4-(2-((2,4- 459 tert-butyl4-[2-formyl-4-
    dioxothiazolidin-5- (trifluoromethyl)phenyl]
    ylidene)methyl)-4- piperazine-1-carboxylate
    (trifluoromethyl)phenyl) Method 80
    piperazine-1-carboxylate
    Figure US20150051185A1-20150219-C00612
    Figure US20150051185A1-20150219-C00613
    36 (S,Z)-tert-butyl 1-(2- 459 tert-butyl {(3S)-1-[2-
    ((2,4-dioxothiazolidin-5- formyl-4-
    ylidene)methyl)-4- (trifluoromethyl)phenyl]
    (trifluoromethyl)phenyl) pyrrolidin-3-yl} carbamate
    pyrrolidin-3-ylcarbamate Method 81
    Figure US20150051185A1-20150219-C00614
    Figure US20150051185A1-20150219-C00615
    37 (Z)-tert-butyl 4-(3-((2,4- 391 tert-butyl 4-(3-
    dioxothiazolidin-5- formylpyridin-2-
    ylidene)methyl)pyridin- yl)piperazine-1-
    2-yl)piperazine-1- carboxylate
    carboxylate Method 82
    Figure US20150051185A1-20150219-C00616
    Figure US20150051185A1-20150219-C00617
    44 (S,Z)-tert-butyl 1-(2- 421 tert-butyl [(3S)-1-(2-
    ((2,4-dioxothiazolidin-5- formyl-6-
    ylidene)methyl)-6- methoxyphenyl)
    methoxyphenyl) pyrrolidin-3-yl]carbamate
    pyrrolidin-3-ylcarbamate Method 83
    Figure US20150051185A1-20150219-C00618
    Figure US20150051185A1-20150219-C00619
    45 (Z)-tert-butyl 4-(2-((2,4- 421 tert-butyl 4-(2-formyl-6-
    dioxothiazolidin-5- methoxyphenyl)piperazine-
    ylidene)methyl)-6- 1-caboxylate
    methoxyphenyl)piperazine- Method 84
    1-carboxylate
    Figure US20150051185A1-20150219-C00620
    Figure US20150051185A1-20150219-C00621
    46 (Z)-tert-butyl 4-(2- 425 tert-butyl 4-(2-chloro-6-
    chloro-6-((2,4- formylphenyl)piperazine-
    dioxothiazolidin-5- 1-carboxylate
    ylidene)methyl)phenyl) Method 85
    piperazine-1-carboxylate
    Figure US20150051185A1-20150219-C00622
    Figure US20150051185A1-20150219-C00623
    47 (Z)-tert-butyl (1-(2-((2,4- 465 tert-butyl (1-(2-formyl-
    dioxothiazolidin-5- 4,5-
    ylidene)methyl)-4,5- dimethoxyphenyl)
    dimethoxyphenyl) pyrrolidin-3-
    pyrrolidin-3- yl)methylcarbamate
    yl)methylcarbamate Method 86
    Figure US20150051185A1-20150219-C00624
    Figure US20150051185A1-20150219-C00625
    48 (R,Z)-tert-butyl 1-(2- 451 (R)-tert-butyl 1-(2-
    ((2,4-dioxothiazolidin-5- formyl-4,5-
    ylidene)methyl)-4,5- dimethoxyphenyl)
    dimethoxyphenyl) pyrrolidin-3-ylcarbamate
    pyrrolidin-3-ylcarbamate Method 87
    Figure US20150051185A1-20150219-C00626
    Figure US20150051185A1-20150219-C00627
    49 (S,Z)-tert-butyl 1-(2- 451 (S)-tert-butyl 1-(2-
    ((2,4-dioxothiazolidin-5- formyl-4,5-
    ylidene)methyl)-4,5- dimethoxyphenyl)
    dimethoxyphenyl) pyrrolidin-3-ylcarbamate
    pyrrolidin-3-ylcarbamate Method 88
    Figure US20150051185A1-20150219-C00628
    Figure US20150051185A1-20150219-C00629
    54 (Z)-tert-butyl 4-(2-((2,4- 404 tert-butyl 4-(2-
    dioxothiazolidin-5- formylphenyl)-1,4-
    ylidene)methyl)phenyl)- diazepane-1-carboxylate
    1,4-diazepane-1- Method 89
    carboxylate
    Figure US20150051185A1-20150219-C00630
    Figure US20150051185A1-20150219-C00631
    65 tert-butyl 1-(2-((2,4- 451 tert-butyl 1-(2-formyl-
    dioxothiazolidin-5- 4,5-
    ylidene)methyl)-4,5- dimethoxyphenyl)
    dimethoxyphenyl) pyrrolidin-3-carbamate
    pyrrolidin-3-ylcarbamate Method 90
    Figure US20150051185A1-20150219-C00632
    Figure US20150051185A1-20150219-C00633
    132 (R,Z)-tert-butyl (1-(2- 439 (R)-tert-butyl (1-(2-
    chloro-6-((2,4- chloro-6-
    dioxothiazolidin-5- formylphenyl)pyrrolidin-
    ylidene)methyl)phenyl) 3-yl)methylcarbamate
    pyrrolidin-3-yl) Method 91
    methylcarbamate
    Figure US20150051185A1-20150219-C00634
    Figure US20150051185A1-20150219-C00635
    133 (S,Z)-tert-butyl (1-(2- 439 (S)-tert-butyl (1-(2-
    chloro-6-((2,4- chloro-6-
    dioxothiazolidin-5- formylphenyl)pyrrolidin-
    ylidene)methyl)phenyl) 3-yl)methylcarbamate
    pyrrolidin-3-yl)methylcarbamate Method 92
    Figure US20150051185A1-20150219-C00636
    Figure US20150051185A1-20150219-C00637
    134 (R,Z)-tert-butyl 1-(2- 438 (R)-tert-butyl 1-(2-
    chloro-6-((2,4- chloro-6-
    dioxothiazolidin-5- formylphenyl)piperidin-
    ylidene)methyl)phenyl) 3-ylcarbamate
    piperidin-3-ylcarbamate Method 93
    Figure US20150051185A1-20150219-C00638
    Figure US20150051185A1-20150219-C00639
    135 (R,Z)-tert-butyl 1-(2- 434 (R)-tert-butyl 1-(2-
    ((2,4-dioxothiazolidin-5- formyl-6-
    ylidene)methyl)-6- methoxyphenyl)piperidin-
    methoxyphenyl) 3-ylcarbamate
    pyrrolidin-3-ylcarbamate Method 94
    Figure US20150051185A1-20150219-C00640
    Figure US20150051185A1-20150219-C00641
    136 (R,Z)-tert-butyl 1-(2- 484 (R)-tert-butyl
    bromo-6-((2,4- bromo-6-
    dioxothiazolidin-5- formylphenyl)piperidin-
    ylidene)methyl)phenyl) 3-ylcarbamate
    piperidin-3-ylcarbamate Method 95
    Figure US20150051185A1-20150219-C00642
    Figure US20150051185A1-20150219-C00643
    137 (R,Z)-tert-butyl 1-(2- 424 (R)-tert-butyl 1-(2-
    chloro-6-((2,4- chloro-6-
    dioxothiazolidin-5- formylphenyl)pyrrolidin-
    ylidene)methyl)phenyl) 3-ylcarbamate
    pyrrolidin-3-ylcarbamate Method 96
    Figure US20150051185A1-20150219-C00644
    Figure US20150051185A1-20150219-C00645
    138 (S,Z)-tert-butyl 1-(2- 470 (S)-tert-butyl 1-(2-
    bromo-6-((2,4- bromo-6-
    dioxothiazolidin-5- formylphenyl)pyrrolidin-
    ylidene)methyl)phenyl) 3-ylcarbamate
    pyrrolidin-3-ylcarbamate Method 97
    Figure US20150051185A1-20150219-C00646
    Figure US20150051185A1-20150219-C00647
    139 (R,Z)-tert-butyl 1-(2- 448 (R)-tert-butyl 1-(2-
    ((2,4-dioxothiazolidin-5- ethoxy-6-
    ylidene)methyl)-6- formylphenyl)piperidin-
    ethoxyphenyl) 3-ylcarbamate
    piperidin-3-ylcarbamate Method 98
    Figure US20150051185A1-20150219-C00648
    Figure US20150051185A1-20150219-C00649
    140 (R,Z)-tert-butyl 1-(2- 476 (R)-tert-butyl 1-(2-
    ((2,4-dioxothiazolidin-5- formyl-6-
    ylidene)methyl)-6- isobutoxyphenyl)piperidin-
    isobutoxyphenyl) 3-ylcarbamate
    piperidin-3-ylcarbamate Method 99
    Figure US20150051185A1-20150219-C00650
    Figure US20150051185A1-20150219-C00651
    141 (R,Z)-tert-butyl 1-(2- 516 (R)-tert-butyl 1-(2-
    (cyclohexylmethoxy)-6- (cyclohexylmethoxy)-6-
    ((2,4-dioxothiazolidin-5- formylphenyl)piperidin-
    ylidene)methyl)phenyl) 3-ylcarbamate
    piperidin-3-ylcarbamate Method 100
    Figure US20150051185A1-20150219-C00652
    Figure US20150051185A1-20150219-C00653
    142 (R,Z)-tert-butyl 1-(2- 501 (R)-tert-butyl 1-(2-
    (cyclohexyloxy)-6-((2,4- (cyclohexyloxy)-6-
    dioxothiazolidin-5- formylphenyl)piperidin-
    ylidene)methyl)phenyl) 3-ylcarbamate
    piperidin-3-ylcarbamate Method 101
    Figure US20150051185A1-20150219-C00654
    Figure US20150051185A1-20150219-C00655
    143 (±)-tert-butyl 1-(2- 454 (±)-tert-butyl-1-(2-
    chloro-6-((Z)-((2,4- chloro-6-formylphenyl)-
    dioxothiazolidin-5- 4-hydroxypiperidin-3-
    ylidene)methyl)phenyl)- ylcarbamate
    4-hydroxypiperidin-3- Method 102
    ylcarbamate
    Figure US20150051185A1-20150219-C00656
    Figure US20150051185A1-20150219-C00657
    144 (Z)-tert-butyl 4-(2- 8.66 (brs, 438 tert-butyl 4-(2-chloro-6-
    chloro-6-((2,4- 1 H), 8.36 formylphenyl)-1,4-
    dioxothiazolidin-5- (brs, 1 H), diazepane-1-carboxylate
    ylidene)methyl)phenyl)- 7.47 (d, 1 Method 103
    1,4-diazepane-1- H), 7.39
    carboxylate (d, 1 H),
    7.22 (t,
    1 H), 3.61
    (brs, 3 H),
    3.52 (brs,
    2 H), 3.27
    (brs, 3 H),
    1.91 (brs,
    2 H), 1.52
    (s, 9 H)
    Figure US20150051185A1-20150219-C00658
    Figure US20150051185A1-20150219-C00659
    145 (R,Z)-tert-butyl 1-(2- 462 (R)-tert-butyl 1-(2-
    ((2,4-dioxothiazolidin-5- formyl-6-
    ylidene)methyl)-6- isopropoxyphenyl)
    isopropoxyphenyl) piperidin-3-ylcarbamate
    piperidin-3-ylcarbamate Method 113
    Figure US20150051185A1-20150219-C00660
    Figure US20150051185A1-20150219-C00661
    146 (S,Z)-tert-butyl 1-(2- 448 (S)-tert-butyl 1-(2-
    ((2,4-dioxothiazolidin-5- formyl-6-
    ylidene)methyl)-6- isopropoxyphenyl)
    isopropoxyphenyl) pyrrolidin-3-ylcarbamate
    pyrrolidin-3-ylcarbamate Method 114
    Figure US20150051185A1-20150219-C00662
    Figure US20150051185A1-20150219-C00663
    147 (S,Z)-tert-butyl 1-(2- 334 (S)-tert-butyl 1-(2-
    ((2,4-dioxothiazolidin-5- ethoxy-6-
    ylidene)methyl)-6- formylphenyl)pyrrolidin-
    ethoxyphenyl) 3-tlcarbamate
    pyrrolidin-3-ylcarbamate Method 115
    Figure US20150051185A1-20150219-C00664
    Figure US20150051185A1-20150219-C00665
    148 5-(2-(3-(1,3- 12.54 (s, 438 2-(3-(1,3-
    dioxoisoindolin-2- 1 H) 7.83- dioxoisoindolin-2-
    yl)propoxy)-5- 7.79 (m, 5 yl)propoxy)-5-
    methoxybenzylidene) H) 7.04 (s, methoxybenzaldehyde
    thiazolidine-2,4-dione 2 H) 6.86 Method 30B
    (s, 1 H)
    4.08 (m,
    2 H) 3.80-
    3.75 (m,
    5 H) 2.11
    (m, 2 H)
    Figure US20150051185A1-20150219-C00666
    Figure US20150051185A1-20150219-C00667
    149 5-(2-(3- 8.20 (s, 1 363 2-(3-
    (dimethylamino)pyrrolidin- H) 8.07 (d, (dimethylamino)pyrrolidin-
    1-yl)-5- 1 H) 7.82 1-yl)-5-
    nitrobenzylidene) (s, 1 H) nitrobenzaldehyde
    thiazolidine-2,4-dione 6.96 (d, Method 116
    1H) 3.58-
    3.51 (m, 3H)
    3.36 (m,
    1 H) 3.04
    (m, 1 H)
    2.51 (s, 6
    H), 2.40
    (m, 1 H),
    1.86 (m, 1
    H)
    Figure US20150051185A1-20150219-C00668
    Figure US20150051185A1-20150219-C00669
    150 (Z)-5-(4,5-dimethoxy-2- 8.32 (s, 1 309 4,5-dimethoxy-2-
    nitrobenzylidene) H) 8.25 nitrobenzaldehyde
    thiazolidene-2,4-dione (brs, 1 H)
    7.79 (s, 1
    H) 7.02 (s,
    1 H) 4.03
    (s, 6 H)
    Figure US20150051185A1-20150219-C00670
    Figure US20150051185A1-20150219-C00671
    151 tert-butyl (3S,4S)-1-(2- 8.30 (s, 1 H) 439 tert-butyl (3S,4S)-1-(2-
    chloro-6-((Z)-(2,4- 7.49 (d, chloro-6-formylphenyl)-
    dioxothiazolidin-5- 1 H) 7.42 4-hydroxypyrrolidin-3-
    ylidene)methyl)phenyl)- (d, 1 H) ylcarbamate
    4-hydroxypyrrolidin-3- 7.28-7.20 Method 117
    ylcarbamate (m, 1 H)
    5.01 (d,
    1 H) 4.39
    (brs, 1 H)
    4.27 (brs, 1
    H) 4.05 (s,
    1 H) 3.83
    (dd, 1 H)
    3.69 (dd, 1
    H) 3.27
    (brs, 1 H)
    3.19 (dd,
    1 H), 1.50
    (s, 9 H)
    Figure US20150051185A1-20150219-C00672
    Figure US20150051185A1-20150219-C00673
    152 (Z)-tert-butyl 1-(2- 465 tert-butyl 1-(2-chloro-6-
    chloro-6-(2,4- formylphenyl)-4-
    dioxothiazolidin-5- methylpiperidin-3-
    ylidene)methyl)phenyl)- yl(methyl)carbamate
    4-methylpiperidin-3- Method 118
    yl(methyl)carbamate
    Figure US20150051185A1-20150219-C00674
    Figure US20150051185A1-20150219-C00675
    153 (Z)-tert-butyl 1-(2- 451 tert-butyl 1-(2-chloro-6-
    chloro-6-((2,4- formylphenyl)-4-
    dioxothiazolidin-5- methylpiperidin-3-
    ylidene)methyl)phenyl)- ylcarbamate
    4-methylpiperidin-3- Method 119
    ylcarbamate
    Figure US20150051185A1-20150219-C00676
    Figure US20150051185A1-20150219-C00677
    154 (R,Z)-tert-butyl 1-(2- 404 (R)-tert-butyl 1-(2-
    ((2,4-dioxothiazolidin-5- formylphenyl)piperidin-
    ylidene)methyl)phenyl)- 3-ylcarbamate
    piperidin-3-ylcarbamate Method 120
    Figure US20150051185A1-20150219-C00678
    Figure US20150051185A1-20150219-C00679
    155 (S,Z)-tert-butyl 1-(2- 390 (S)-tert-butyl 1-(2-
    ((2,4-dioxothiazolidin-5- formylphenyl)pyrrolidin-
    ylidene)methyl)phenyl)- 3-ylcarbamate
    pyrrolidin-3-ylcarbamate Method 121
    Figure US20150051185A1-20150219-C00680
    Figure US20150051185A1-20150219-C00681
    156 (R,Z)-tert-butyl 1-(2- 502 (R)-tert-butyl 1-(2-
    ((2,4-dioxothiazolidin-5- formyl-6-(2,2,2-
    ylidene)methyl)-6-(2,2,2- trifluoroethoxy)phenyl)
    trifluoroethoxy)phenyl) piperidin-3-ylcarbamate
    piperidin-3-ylcarbamate Method 122
    Figure US20150051185A1-20150219-C00682
    Figure US20150051185A1-20150219-C00683
    157 (S,Z)-tert-butyl 1-(2- 488 (S)-tert-butyl 1-(2-
    ((2,4-dioxothiazolidin-5- formyl-6-(2,2,2-
    ylidene)methyl)-6-(2,2,2- trifluoroethoxy)phenyl)
    trifluoroethoxy)phenyl) pyrrolidin-3-ylcarbamate
    pyrrolidin-3-ylcarbamate Method 123
    Figure US20150051185A1-20150219-C00684
    Figure US20150051185A1-20150219-C00685
    158 (R,Z)-tert-butyl 1-(2- 478 (R)-tert-butyl 1-(2-
    ((2,4-dioxothiazolidin-5- formyl-6-(2-
    ylidene)methyl)-6-(2- methoxyethoxy)phenyl)
    methoxyethoxy)phenyl) piperidin-3-ylcarbamate
    piperidin-3-ylcarbamate Method 124
    Figure US20150051185A1-20150219-C00686
    Figure US20150051185A1-20150219-C00687
    159 (S,Z)-tert-butyl 1-(2- 464 (S)-tert-butyl 1-(2-
    ((2,4-dioxothiazolidin-5- formyl-6-(2-
    ylidene)methyl)-6-(2- methoxyethoxy)phenyl)
    methoxyethoxy)phenyl) pyrrolidin-3-ylcarbamate
    pyrrolidin-3-ylcarbamate Method 125
    Figure US20150051185A1-20150219-C00688
    Figure US20150051185A1-20150219-C00689
    160 (R,Z)-tert-butyl 1-(2- 488 (R)-tert-butyl 1-(2-
    (cyclopentyloxy)-6-((2,4- (cyclopentyloxy)-6-
    dioxothiazolidin-5- formylphenyl)piperidin-
    ylidene)methyl)phenyl) 3-ylcarbamate
    piperidin-3-ylcarbamate Method 126
    Figure US20150051185A1-20150219-C00690
    Figure US20150051185A1-20150219-C00691
    161 (R,Z)-tert-butyl 1-(2- 474 (R)-tert-butyl 1-(2-
    cyclobutoxy)-6-((2,4- cyclobutoxy-6-
    dioxothiazolidin-5- formylphenyl)
    ylidene)methyl)phenyl) piperidin-3-ylcarbamate
    piperidin-3-ylcarbamate Method 127
    Figure US20150051185A1-20150219-C00692
    Figure US20150051185A1-20150219-C00693
    162 (R,Z)-tert-butyl 1-(2- 447 (R)-tert-butyl 1-(4-
    carbamoyl-2-((2,4- carbamoyl-2-
    dioxothiazolidin-5- formylphenyl)
    ylidene)methyl)phenyl) piperidin-3-ylcarbamate
    piperidin-3-ylcarbamate Method 128
    Figure US20150051185A1-20150219-C00694
    Figure US20150051185A1-20150219-C00695
    163 (S,Z)-tert-butyl 1-(4- 447 (S)-tert-butyl 1-(4-
    carbamoyl-2-((2,4- carbamoyl-2-
    dioxothiazolidin-5- formylphenyl)
    ylidene)methyl)phenyl) piperidin-3-ylcarbamate
    piperidin-3-ylcarbamate Method 129
    Figure US20150051185A1-20150219-C00696
    Figure US20150051185A1-20150219-C00697
    164 (R,Z)-4-(3-(tert- 447 (R)-4-(3-(tert-
    butoxycarbonylamino) butoxycarbonylamino)
    piperidin-1-yl)-3-((2,4- piperidin-1-yl)-3-
    dioxothiazolidin-5- formylbenzoic acid
    ylidene)methyl)benzoic Method 130
    acid
    Figure US20150051185A1-20150219-C00698
    Figure US20150051185A1-20150219-C00699
    165 (S,Z)-4-(3-(tert- 433 (S)-4-(3-(tert-
    butoxycarbonylamino) butoxycarbonylamino)
    pyrrolidin-1-yl)-3-((2,4- pyrrolidin-1-yl)-3-
    dioxothiazolidin-5- formylbenzoic acid
    ylidene)methyl)benzoic Method 131
    acid
    Figure US20150051185A1-20150219-C00700
    Figure US20150051185A1-20150219-C00701
    166 (R,Z)-tert-butyl 1-(3- 480 (R)-tert-butyl 1-(3-
    ((2,4-dioxothiazolidin-5- formylbiphenyl-2-
    ylidene)methyl)biphenyl- yl)piperidin-3-
    2-yl)piperidin-3- ylcarbamate
    ylcarbamate Method 201
    Figure US20150051185A1-20150219-C00702
    Figure US20150051185A1-20150219-C00703
  • Figure US20150051185A1-20150219-C00704
    • Method 38 (Z)-tert-butyl 3-(4-(3-((2,4-dioxothiazolidin-5-ylidene)methyl)pyridin-2-yl)piperazin-1-yl)-3-oxopropylcarbamate
  • A 50 mL vial was charged with a magnetic spin bar, (Z)-5-((2-(piperazin-1-yl)pyridin-3-yl)methylene)thiazolidine-2,4-dione hydrochloride (Example 89) (0.125 g, 0.38 mmol), 3-(tert-butoxycarbonylamino)propanoic acid (0.109 g, 0.57 mmol), DMF (1.912 ml), and diisopropylethylamine (0.334 ml, 1.91 mmol). With stirring, HATU (0.291 g, 0.76 mmol) was added and the reaction was warmed to 50° C. for 3 h. The reaction was then diluted with water and extracted with ethyl acetate (3×50 mL). The combined organic extract was dried with MgSO4, filtered through a bed of Celite, and conc. in vacuo to yield the product which was purified via silica gel chromatography (80 g) using ethyl acetate/hexanes (1:1) as eluent to provide the title compound as an off white solid. (0.080 g, 45.3%); m/z 462.
  • The following intermediates were prepared by the procedure of Method 38, using the appropriate starting materials.
  • Method Compound 1H NMR m/z SM
    39 (Z)-tert-butyl 4-(4-(2- 502 (5Z)-5-(2-piperazin-1-
    ((2,4-dioxothiazolidin-5- ylbenzylidene)-1,3-
    ylidene)methyl)phenyl) thiazolidine-2,4-dione
    piperazine-1-
    carbonyl)piperidine-1-
    carboxylate
    Figure US20150051185A1-20150219-C00705
    Figure US20150051185A1-20150219-C00706
    Example 115
    and 1-(tert-
    butoxycarbonyl)piperidine-
    4-carboxylic acid
    Figure US20150051185A1-20150219-C00707
    40 (Z)-tert-butyl 3-(4-(2- 560 (Z)-5-(2-(piperazin-1-yl)-
    ((2,4-dioxothiazolidin-5- 5-(trifluoromethyl)
    ylidene)methyl)-4- benzylidene)
    (trifluoromethyl)phenyl) thiazolidine-2,4-
    piperazine-1- dione
    carbonyl)piperidine-1-
    carboxylate
    Figure US20150051185A1-20150219-C00708
    Figure US20150051185A1-20150219-C00709
    Example 87
    and 1-(tert-
    butoxycarbonyl)piperidine-
    3-carboxylic acid
    Figure US20150051185A1-20150219-C00710
    41 (Z)-tert-butyl 3-(4-(2- 530 (Z)-5-(2-(piperazin-1-yl)-
    ((2,4-dioxothiazolidin-5- 5-(trifluoromethyl)
    ylidene)methyl)-4- benzylidene)
    (trifluoromethyl)phenyl) thiazolidine-2,4-
    piperazin-1-yl)-3- dione
    oxopropylcarbamate
    Figure US20150051185A1-20150219-C00711
    Figure US20150051185A1-20150219-C00712
    Example 87
    and 3-[(tert-
    butoxycarbonyl)amino]
    propanoic acid
    Figure US20150051185A1-20150219-C00713
    42 (Z)-tert-butyl 3-(4-(2- 492 (Z)-5-(3-methoxy-2-
    ((2,4-dioxothiazolidin-5- (piperazin-1-yl)-
    ylidene)methyl)-6- benzylidene)
    methoxyphenyl)piperazin- thiazolidine-2,4-
    1-yl)-3- dione
    oxopropylcarbamate
    Figure US20150051185A1-20150219-C00714
    Figure US20150051185A1-20150219-C00715
    Example 97
    and 3-[(tert-
    butoxycarbonyl)amino]
    propanoic acid
    Figure US20150051185A1-20150219-C00716
    43 (Z)-tert-butyl 3-(4-(2- 496 (Z)-5-(3-chloro-2-
    chloro-6-((2,4- (piperazin-1-yl)-
    dioxothiazolidin-5- benzylidene)
    ylidene)methyl)phenyl) thiazolidine-2,4-
    piperazin-1-yl)-3- dione
    oxopropylcarbamate
    Figure US20150051185A1-20150219-C00717
    Figure US20150051185A1-20150219-C00718
    Example 98
    and 3-[(tert-
    butoxycarbonyl)amino]
    propanoic acid
    Figure US20150051185A1-20150219-C00719
    50 (Z)-tert-butyl 3-(4-(2- 516 (Z)-5-(2-(1,4-diazepan-1-
    ((2,4-dioxothiazolidin-5- yl)benzylidene)
    ylidene)methyl)phenyl)- thiazolidine-2,4-dione
    1,4-diazepane-1-
    carbonyl)piperidine-1-
    carboxylate
    Figure US20150051185A1-20150219-C00720
    Figure US20150051185A1-20150219-C00721
    Example 106
    and 1-(tert-
    butoxycarbonyl)piperidine-
    3-carboxylic acid
    Figure US20150051185A1-20150219-C00722
    51 (Z)-tert-butyl 5-(4-(2- 504 (Z)-5-(2-(1,4-diazepan-1-
    ((2,4-dioxothiazolidin-5- yl)benzylidene)
    ylidene)methyl)phenyl)- thiazolidine-2,4-dione
    1,4-diazepan-1-yl)-5-
    oxopentylcarbamate
    Figure US20150051185A1-20150219-C00723
    Figure US20150051185A1-20150219-C00724
    Example 106
    and 5-[(tert-
    butoxycarbonyl)amino]
    pentanoic acid
    Figure US20150051185A1-20150219-C00725
    52 (Z)-tert-butyl 4-(4-(2- 490 (Z)-5-(2-(1,4-diazepan-1-
    ((2,4-dioxothiazolidin-5- yl)benzylidene)
    ylidene)methyl)phenyl)- thiazolidine-2,4-dione
    1,4-diazepan-1-yl)-4-
    oxobutylcarbamate
    Figure US20150051185A1-20150219-C00726
    Figure US20150051185A1-20150219-C00727
    Example 106
    and 4-[(tert-
    butoxycarbonyl)amino]
    butanoic acid
    Figure US20150051185A1-20150219-C00728
    53 (Z)-tert-butyl 3-(4-(2- 475 (Z)-5-(2-(1,4-diazepan-1-
    ((2,4-dioxothiazolidin-5- yl)benzylidene)
    ylidene)methyl)phenyl)- thiazolidine-2,4-dione
    1,4-diazepan-1-yl)-3-
    oxopropylcarbamate
    Figure US20150051185A1-20150219-C00729
    Figure US20150051185A1-20150219-C00730
    Example 106
    and 3-[(tert-
    butoxycarbonyl)amino]
    propanoic acid
    Figure US20150051185A1-20150219-C00731
    55 (Z)-tert-butyl 4-(4-(2- 476 (5Z)-5-(2-piperazin-1-
    ((2,4-dioxothiazolidin-5- yl)benzylidene)-1,3-
    ylidene)methyl)phenyl) thiazolidine-2,4-dione
    piperazin-1-yl)-4-
    oxobutylcarbamate
    Figure US20150051185A1-20150219-C00732
    Figure US20150051185A1-20150219-C00733
    Example 115
    and 4-[(tert-
    butoxycarbonyl)amino]
    butanoic acid
    Figure US20150051185A1-20150219-C00734
    56 (Z)-tert-butyl 5-(4-(2- 490 (5Z)-5-(2-piperazin-1-
    ((2,4-dioxothiazolidin-5- ylbenzylidene)-1,3-
    ylidene)methyl)phenyl) thiazolidine-2,4-dione
    piperazin-1-yl)-5-
    oxopentylcarbamate
    Figure US20150051185A1-20150219-C00735
    Figure US20150051185A1-20150219-C00736
    Example 115
    and nd 5-[(tert-
    butoxycarbonyl)amino]
    pentanoic acid
    Figure US20150051185A1-20150219-C00737
    57 (Z)-tert-butyl 4-(4-(4-(2- 593 (5Z)-5-(2-piperazin-1-
    ((2,4-dioxothiazolidin-5- ylbenzylidene)-1,3-
    ylidene)methyl)phenyl) thiazolidine-2,4-dione
    piperazine-1-
    carbonyl)benzyl)
    piperazine-1-carboxylate
    Figure US20150051185A1-20150219-C00738
    Figure US20150051185A1-20150219-C00739
    Example 115
    and 4-{[4-(tert-
    butoxycarbonyl)piperazin-
    1-yl]methyl}benzoic
    acid
    Figure US20150051185A1-20150219-C00740
    58 (Z)-tert-butyl 3-(4-(2- 524 (5Z)-5-(2-piperazin-1-
    ((2,4-dioxothiazolidin-5- yl)benzylidene)-1,3-
    ylidene)methyl)phenyl) thiazolidine-2,4-dione
    piperazine-1-
    carbonyl)benzylcarbamate
    Figure US20150051185A1-20150219-C00741
    Figure US20150051185A1-20150219-C00742
    Example 115
    and 3-{[(tert-
    butoxycarbonyl)amino)
    methyl}benzoic acid
    Figure US20150051185A1-20150219-C00743
    63 tert-butyl 3-(4-(2- 501 (5Z)-5-(2-piperazin-1-
    ((2,4-dioxothiazolidin-5- ylbenzylidene)-1,3-
    ylidene)methyl)phenyl) thiazolidine-2,4-dione
    piperazine-1-
    carbonyl)piperidine-1-
    carboxylate
    Figure US20150051185A1-20150219-C00744
    Figure US20150051185A1-20150219-C00745
    Example 115
    And 1-(tert-
    butoxycarbonyl)piperidine-
    3-carboxylic acid
    Figure US20150051185A1-20150219-C00746
    64 tert-butyl 3-(4-(2- 473 (5Z)-5-(2-piperazin-1-
    ((2,4-dioxothiazolidin-5- ylbenzylidene)-1,3-
    ylidene)methyl)phenyl) thiazolidine-2,4-dione
    piperazine-1-
    carbonyl)azetidine-1-
    carboxylate
    Figure US20150051185A1-20150219-C00747
    Figure US20150051185A1-20150219-C00748
    Example 115
    And 1-(tert-
    butoxycarbonyl)azetidine-
    3-carboxylic acid
    Figure US20150051185A1-20150219-C00749
    66 (R,Z)-tert-butyl 5-(1-(2- 550 (R,Z)-5-(2-(3-
    ((2,4-dioxothiazolidin-5- aminopyrrolidin-1-yl)-
    ylidene)methyl)-4,5- 4,5-
    dimethoxyphenyl) dimethoxybenzylidene)
    pyrrolidin-3-ylamino)-5- thiazolidine-2,4-dione
    oxopentylcarbamate
    Figure US20150051185A1-20150219-C00750
    Figure US20150051185A1-20150219-C00751
    Example 100
    And 5-[(tert-
    butoxycarbonyl)amino]
    pentanoic acid
    Figure US20150051185A1-20150219-C00752
    67 (S,Z)-tert-butyl 5-(1-(2- 550 (S,Z)-5-(2-(3-
    ((2,4-dioxothiazolidin-5- aminopyrrolidin-1-yl)-
    ylidene)methyl)-4,5- 4,5-
    dimethoxyphenyl) dimethoxybenzylidene)
    pyrrolidin-3-ylamino)-5- thiazolidine-2,4-dione
    oxopentylcarbamate
    Figure US20150051185A1-20150219-C00753
    Figure US20150051185A1-20150219-C00754
    Example 101
    And 5-[(tert-
    butoxycarbonyl)amino]
    pentanoic acid
    Figure US20150051185A1-20150219-C00755
    75 (Z)-3-(1,3- 552 (5Z)-5-[2-(3-
    dioxoisoindolin-2-yl)-N- aminopyrrolidin-1-yl)-
    (1-(2-((2,4- 4,5-
    dioxothiazolidin-5- dimethoxybenzylidene]-
    ylidene)methyl)-4,5- 1,3-thiazolidine-2,4-dione
    dimethoxyphenyl)
    pyrrolidin-3-yl)
    propanamide
    Figure US20150051185A1-20150219-C00756
    Figure US20150051185A1-20150219-C00757
    Example 118
    and 3-(1,3-dioxo-1,3-
    dihydro-2H-isoindol-2-
    yl)propanoic acid
    Figure US20150051185A1-20150219-C00758
    76 5Z)-(2-(4-(3-(1,3- (5Z)-5-(2-piperazin-1-
    dioxoisoindolin-2- ylbenzylidene)-1,3-
    yl)propanoyl)piperazin-1- thiazolidine-2,4-dione
    yl)benzylidene)
    thiazolidine-2,4-dione
    Figure US20150051185A1-20150219-C00759
    Figure US20150051185A1-20150219-C00760
    Example 115
    and 3-(1,3-dioxo-1,3-
    dihydro-2H-isoindol-2-
    yl)propanoic acid
    Figure US20150051185A1-20150219-C00761
  • Figure US20150051185A1-20150219-C00762
    • Method 59 (Z)-tert-butyl 2-(1-(2-((2,4-dioxothiazolidin-5-ylidene)methyl)-4,5-dimethoxyphenyl)pyrrolidin-3-ylamino)ethylcarbamate
  • A mixture of (5Z)-5-{2-[3-(dimethylamino)pyrrolidin-1-yl]-4,5-dimethoxybenzylidene}-1,3-thiazolidine-2,4-dione (Example 52) (120 mg, 0.31 mmol) and tert-butyl 2-oxoethylcarbamate (198 mg, 1.24 mmol) in CH2Cl2 (20 mL) were heated to reflux for 15 min followed by the addition of sodium triacetoxyhydroborate (65.9 mg, 0.31 mmol). The reaction mixture was refluxed overnight before being allowed to cool to ambient temperature. Water (˜0.5 mL) was added and the mixture was allowed to stir for 15 min before being loaded onto a silica gel column which was eluted with ethyl acetate/hexane (10:1) to yield the title compound as an orange solid as (60.0 mg, 39.2%); m/z 493.
  • The following intermediates were prepared by the procedure of Method 59, using the appropriate starting materials.
  • Method Compound 1H NMR m/z SM
     60
    Figure US20150051185A1-20150219-C00763
         		433
    Figure US20150051185A1-20150219-C00764
     61
    Figure US20150051185A1-20150219-C00765
         		507
    Figure US20150051185A1-20150219-C00766
     62
    Figure US20150051185A1-20150219-C00767
         		448
    Figure US20150051185A1-20150219-C00768
     68
    Figure US20150051185A1-20150219-C00769
         		507
    Figure US20150051185A1-20150219-C00770
     69
    Figure US20150051185A1-20150219-C00771
         		507
    Figure US20150051185A1-20150219-C00772
     70
    Figure US20150051185A1-20150219-C00773
         		545
    Figure US20150051185A1-20150219-C00774
     71
    Figure US20150051185A1-20150219-C00775
         		508
    Figure US20150051185A1-20150219-C00776
     72
    Figure US20150051185A1-20150219-C00777
         		512
    Figure US20150051185A1-20150219-C00778
     73
    Figure US20150051185A1-20150219-C00779
         		507
    Figure US20150051185A1-20150219-C00780
     74
    Figure US20150051185A1-20150219-C00781
         		477
    Figure US20150051185A1-20150219-C00782
     77
    Figure US20150051185A1-20150219-C00783
         		509
    Figure US20150051185A1-20150219-C00784
    167
    Figure US20150051185A1-20150219-C00785
         		557
    Figure US20150051185A1-20150219-C00786
    168
    Figure US20150051185A1-20150219-C00787
         		496
    Figure US20150051185A1-20150219-C00788
    169
    Figure US20150051185A1-20150219-C00789
         		496
    Figure US20150051185A1-20150219-C00790
    170
    Figure US20150051185A1-20150219-C00791
         		510
    Figure US20150051185A1-20150219-C00792
    171
    Figure US20150051185A1-20150219-C00793
         		525
    Figure US20150051185A1-20150219-C00794
  • Figure US20150051185A1-20150219-C00795
    • Method 172 3-ethoxy-2-fluorobenzaldehyde
  • A 200 mL round bottom flask was charged with a magnetic stir bar, 3-ethoxy-2-fluorobenzonitrile (1.000 g, 6.05 mmol), and anhydrous toluene (12.92 ml). The sol'n was placed under argon and cooled to 0° C. with an ice bath. DIBAL-H (7.27 ml, 7.27 mmol) (1M in PhMe) was then added drop wise via syringe and the reaction was allowed to stir to rt overnight. To this mixture was added 10% HCl until the sol'n reached a pH of ˜2. The resulting mixture was then left to stir for 0.5 h. and was then poured into a separatory funnel and extracted with ethyl acetate (2×200 mL). The combined organic extract was dried with MgSO4, filtered, and conc. in vacuo to yield the crude product which was purified via silica gel chromatography (80 g) using ethyl acetate/hexanes (1:4) as eluent to provide pure 3-ethoxy-2-fluorobenzaldehyde (0.810 g, 80%). m/z 196.
  • The following intermediates were prepared by the procedure of Method 172, using the appropriate starting materials.
  •
    173
    Figure US20150051185A1-20150219-C00796
         		197
    Figure US20150051185A1-20150219-C00797
    174
    Figure US20150051185A1-20150219-C00798
         		237
    Figure US20150051185A1-20150219-C00799
    175
    Figure US20150051185A1-20150219-C00800
         		223
    Figure US20150051185A1-20150219-C00801
    176
    Figure US20150051185A1-20150219-C00802
         		183
    Figure US20150051185A1-20150219-C00803
    177
    Figure US20150051185A1-20150219-C00804
         		223
    Figure US20150051185A1-20150219-C00805
    178
    Figure US20150051185A1-20150219-C00806
         		10.32 (s, 1 H) 7.56- 7.35 (m, 2 H) 7.13- 6.96 (m, 1 H) 4.33- 4.22 (m, 2 H) 3.84- 3.77 (m, 2 H) 3.42 (s, 3 H) 199
    Figure US20150051185A1-20150219-C00807
    179
    Figure US20150051185A1-20150219-C00808
         		195
    Figure US20150051185A1-20150219-C00809
    180
    Figure US20150051185A1-20150219-C00810
         		10.31 (s, 1 H) 7.41- 7.36 (m, 2 H) 7.05- 7.03 (m, 1 H) 4.94- 4.85 (m, 1 H) 2.01- 1.83 (m, 8 H) 209
    Figure US20150051185A1-20150219-C00811
    • Method 181
  • Figure US20150051185A1-20150219-C00812
  • A 100 mL round bottom flask was charged with a magnetic stir bar, 2-fluoro-3-hydroxybenzonitrile (0.500 g, 3.65 mmol), MeCN (13.89 ml), 1-bromo-2-methylpropane (0.699 ml, 7.29 mmol), and K2CO3 (1.008 g, 7.29 mmol). The mixture was then placed in an oil bath and heated to 60° C. with stirring overnight. This mixture was then cooled to rt, filtered through a bed of Celite, and conc. In vacuo. The crude material was purified via silica gel chromatography (40 g) using ethyl acetate/hexanes (1:4) as eluent to afford pure 2-fluoro-3-isobutoxybenzonitrile (0.610 g, 87%) as a colorless oil. M/z 194.
  • The following intermediates were prepared by the procedure of Method 181, using the appropriate starting materials.
  •
    182
    Figure US20150051185A1-20150219-C00813
         		234
    Figure US20150051185A1-20150219-C00814
    183
    Figure US20150051185A1-20150219-C00815
         		220
    Figure US20150051185A1-20150219-C00816
    184
    Figure US20150051185A1-20150219-C00817
         		179
    Figure US20150051185A1-20150219-C00818
    185
    Figure US20150051185A1-20150219-C00819
         		196
    Figure US20150051185A1-20150219-C00820
    186
    Figure US20150051185A1-20150219-C00821
         		192
    Figure US20150051185A1-20150219-C00822
    187
    Figure US20150051185A1-20150219-C00823
    Figure US20150051185A1-20150219-C00824
    • Method 188
  • Figure US20150051185A1-20150219-C00825
    • (±)-tert-butyl-4-hydroxypyrrolidin-3-ylcarbamate
  • A racemic mixture of trans-benzyl 3-(tert-butoxycarbonylamino)-4-hydroxypyrrolidine-1-carboxylate (3.36 g, 9.99 mmol) (Method 190) in MeOH (40 mL) was degassed, then 10 wt % Pd/C (3.19 g, 3.00 mmol) was added. The mixture was degassed, charged with H2, and stirred overnight. The mixture was filtered through a bed of Celite, washed with methanol, the filtrate was dried over anhydrous Na2SO4, filtered and conc. in vacuo to yield a white solid as racemic tert-butyl-4-hydroxypyrrolidin-3-ylcarbamate (2.020 g, 100%). 1H NMR (400 MHz, MeOD) δ □ppm 4.13 (dt, 1H), 3.89-3.75 (m, 1H), 3.35 (brs, 1H), 3.14 (dd, 1H), 2.93-2.73 (m, 2H), 1.46 (s, 10H); m/z 203.
  • The following intermediates were prepared by the procedure of Method 188, using the appropriate starting materials.
  • Method Compound 1H NMR m/z SM
    189
    Figure US20150051185A1-20150219-C00826
         		216
    Figure US20150051185A1-20150219-C00827
    • Method 190
  • Figure US20150051185A1-20150219-C00828
    • (±)-benzyl 3-(tert-butoxycarbonylamino)-4-hydroxypyrrolidine-1-carboxylate
  • To a mixture of racemic trans-benzyl 3-amino-4-hydroxypyrrolidine-1-carboxylate (2.67 g, 11.30 mmol) (Method 193) and di-tert-butyl dicarbonate (3.70 g, 16.95 mmol) in CH2Cl2 (50 mL) was added Et3N (4.73 mL, 33.90 mmol) at 0° C. The mixture was then stirred at rt for 48 h. The reaction mixture was then conc. in vacuo giving a residue which was purified via silica gel chromatography (40% to 90% ethyl acetate/hexane) to yield a white solid as (±)-benzyl 3-(tert-butoxycarbonylamino)-4-hydroxypyrrolidine-1-carboxylate (3.36 g, 88%). 1H NMR (400 MHz, Dichloromethane-d2) δ □ppm 7.48-7.32 (m, 5H), 5.21-5.00 (m, 2H), 4.78 (brs, 1H), 4.29-4.18 (m, 1H), 3.84 (dd, 1H), 3.74 (d, 1H), 3.41-3.12 (m, 2H), 1.49-1.33 (m, 9H); m/z 337
  • The following starting materials were prepared by the procedure of Method 190 using the appropriate starting materials.
  • Method Compound 1H NMR m/z SM
    191
    Figure US20150051185A1-20150219-C00829
         		350
    Figure US20150051185A1-20150219-C00830
    192
    Figure US20150051185A1-20150219-C00831
         		352
    Figure US20150051185A1-20150219-C00832
    • Method 193
  • Figure US20150051185A1-20150219-C00833
    • (±)-benzyl 3-amino-4-hydroxypyrrolidine-1-carboxylate
  • A mixture of racemic trans-benzyl 3-azido-4-hydroxypyrrolidine-1-carboxylate (2.96 g, 11.29 mmol) (Method 195) and triphenylphosphine (3.11 g, 11.85 mmol) in THF (25 mL) was stirred at rt for 7 h. Water (2 mL, 111 mmol) was then added and the mixture then stirred at 50° C. overnight. The mixture was then concentrated under reduced pressure, and the residue was purified via silica gel chromatography (100% DCM to 37:3:60/methanol:Et3N:DCM) to yield the title compound (2.96 g, 11.29 mmol) as an oil. 1H NMR (400 MHz, Dichloromethane-d2) δ ppm 7.38-7.19 (m, 5H), 5.02 (s, 2H), 3.89 (brs, 1H), 3.62 (dd, 2H), 3.29-3.15 (m, 2H), 3.12-3.01 (m, 1H); m/z 236.
  • The following starting materials were prepared by the procedure of Method 193 using the appropriate starting materials.
  • Method Compound 1H NMR m/z SM
    194
    Figure US20150051185A1-20150219-C00834
         		250
    Figure US20150051185A1-20150219-C00835
    • Method 195
  • Figure US20150051185A1-20150219-C00836
    • (±)-benzyl 3-azido-4-hydroxypyrrolidine-1-carboxylate
  • To a stirred mixture of benzyl 6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate (5.2 g, 23.72 mmol) (Method 197) in DMF (30 mL) was added sodium azide (2.313 g, 35.58 mmol) in a mixture of acetone (20.00 mL) and water (10.00 mL). The resulting mixture was stirred at 80° C. for 24 h. The mixture was then diluted with water and ether, separated, and the organic layer was washed with brine, dried and conc. invacuo. The resulting material was purified via silica gel chromatography (eluted with 15% to 35% ethyl acetate/hexane), yielding the title compound as a yellow solid (4.10 g, 65.9%). 1H NMR (400 MHz, dichloromethane-d2) δ □ppm 7.50-7.25 (m, 5H), 5.43-5.25 (m, 2H), 4.31 (brs, 1H), 4.00 (brs, 1H), 3.77 (dd, 1H), 3.69 (dd, 1H), 3.53 (d, 1H), 3.44 (dd, 1H), 2.17 (brs, 1H); m/z 263.
  • The following starting materials were prepared by the procedure of Method 195 using the appropriate starting materials.
  • Method Compound 1H NMR m/z SM
    196
    Figure US20150051185A1-20150219-C00837
         		276
    Figure US20150051185A1-20150219-C00838
    • Method 197
  • Figure US20150051185A1-20150219-C00839
    • benzyl 6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate
  • To a stirred mixture of benzyl 2,5-dihydro-1H-pyrrole-1-carboxylate (5 g, 24.60 mmol) in DCM (80 mL) was added 3-chlorobenzoperoxoic acid (6.89 g, 30.75 mmol) at 0° C. The mixture was then stirred at rt overnight. The reaction mixture was then filtered through a bed of Celite and the filtrate was washed with sat'd aqueous Na2CO3 and brine. The organic was then separated and dried over anhydrous Na2SO4, filtered, and conc. in vacuo to yield the title compound that was used for next step without further purification.
  • The following starting materials were prepared by the procedure of Method 197 using the appropriate starting materials.
  • Method Compound 1H NMR m/z SM
    198
    Figure US20150051185A1-20150219-C00840
         		217
    Figure US20150051185A1-20150219-C00841
    • Method 199
  • Figure US20150051185A1-20150219-C00842
    • 2-(3-amino-4-methylpiperidin-1-yl)-3-chlorobenzaldehyde
  • To a stirred solution of methyl 1-(2-chloro-6-formylphenyl)-4-methylpiperidin-3-ylcarbamate (220 mg, 0.71 mmol) (Method 119) in MeOH (3 ml) was added 40% aqueous solution of KOH (10 ml) drop wise, and the resulting mixture was heated at reflux for 16 h. The mixture was allowed to cool to rt, diluted with water, and extracted with DCM. The combined organic extract was dried over anhydrous Na2SO4, filtered, and conc. in vacuo. The resulting residue was purified via silica gel chromatography (100% ethyl acetate to 10% methanol in ethyl acetate) to yield the title compound as a light yellow gum (0.057 g, 31.9%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.44 (s, 1H), 7.40 (t, 2H), 7.07 (t, 1H), 4.29 (d, 1H), 3.58 (ddd, 1H), 3.38 (dd, 1H), 3.11 (td, 1H), 2.81 (d, 1H), 2.20-1.91 (m, 1H), 1.31-1.14 (m, 1H), 1.08 (d, 3H), 0.63-0.37 (m, 1H).
    • Method 200
  • Figure US20150051185A1-20150219-C00843
    • 2-fluoro-3-(2,2,2-trifluoroethoxy)benzonitrile
  • A stirred solution of 2-fluoro-3-hydroxybenzonitrile (800 mg, 5.83 mmol) in DMF (10 mL) at 0° C. was treated portionwise with NaH (280 mg, 7.00 mmol) (60% oil dispersion). The reaction mixture was then stirred for 0.5 h and 2,2,2-trifluoroethyl trifluoromethanesulfonate (1490 mg, 6.42 mmol) was added. The reaction was allowed to warm to rt overnight with stirring. The reaction mixture was then treated with water (40 mL) and brine (5 mL) and extracted with ethyl acetate (˜50 mL). The organic extract was washed with water, dried over anhydrous Na2SO4, filtered and conc. in vacuo to afford a residue which was purified via silica gel chromatography (10% to 30% ethyl acetate/hexanes) to yield the title compound as a white solid (1040 mg, 81%). 1H NMR (400 MHz, MeOD) δ ppm 7.56 (td, 1H), 7.47-7.38 (m, 1H), 7.38-7.24 (m, 1H), 4.73 (q, 2H); m/z 220.
    • Method 201 (R)-tert-butyl 1-(3-formylbiphenyl-2-yl)piperidin-3-ylcarbamate
  • Figure US20150051185A1-20150219-C00844
  • A mixture of (R)-tert-butyl 1-(2-bromo-6-formylphenyl)piperidin-3-yl carbamate (Method 95) (300 mg, 0.78 mmol), phenylboronic acid (143 mg, 1.17 mmol), 1,1′-bis(di-tert-butyllphosphino)ferrocenedichloro palladium (II) complex (40.8 mg, 0.06 mmol), and Na2CO3 (124 mg, 1.17 mmol) was suspended in dioxane (5 mL) and water (1.50 mL) and stirred at 110° C. for overnight under an atmosphere of nitrogen. The reaction was cooled to rt and water (˜50 mL) and ethyl acetate (˜50 mL) was added to the mixture. The organic phase was separated, dried over anhydrous MgSO4, filtered, and conc. in vacuo affording a residue purified with via silica gel chromatography (40 g) using a gradient of 5% to 30% ethyl acetate/hexanes to yield the title compound as a low melting solid (168 mg, 56.4%); m/z 381.
  • One may purify examples provided above by reverse-phase HPLC in a solvent contain varying concentrations of trifluoroacetic acid or hydrochloric acid. Thus the examples above may be isolated as, the freebase, hydrochloride salt, or trifluoroacetate salt.
  • PIM 1 and 2 enzyme assay descriptions:
    • PIM1 In-Vitro Mobility Shift Assay
  • One may determine the activity of purified human His-PIM1 [2-313] enzyme in-vitro using a mobility shift assay on a Caliper LC3000 reader (Caliper, Mass.), which measures fluorescence of a phosphorylated and unphosphorylated FL-Ahx-Bad (FITC-(AHX)RSRHSSYPAGT-COOH, Primm 200606-00289, Primm Biotech, MA) and calculates a ratiometric value to determine percent turnover. One may express PIM1 (University of Dundee, Scotland) in baculovirus system with a typical yield of >85% purity.
  • One determines phosphorylation of the FL-Ahx-Bad in the presence and absence of the compound of interest. One preincubates 5 ul of Enzyme/Substrate/adenosine triphosphate (ATP) mix consisting of 2.4 nM PIM1, 3.6 uM FL-Ahx-Bad, and 240 uM ATP in 1.2× buffer with 2 ul of compound for 20 minutes at 25° C. One initiates reactions with 5 ul of Metal mix consisting of 24 mM MgCl2 in 1.2× buffer and incubated at 25° C. for 90 minutes and stops the reactions by addition of 5 ul of Stop mix consisting of 100 mM HEPES, 121 mM ethylenediamine tetraacetic acid, 0.8% Coatin Reagent 3 (Caliper, Mass.), and 0.01% Tween. One detects phosphorylated and unphosphorylated substrate by a Caliper LC3000 reader (Caliper, Mass.) in the presence of separation buffer consisting of 100 mM HEPES, 16 mM ethylenediamine tetraacetic acid, 0.1% Coatin Reagent 3 (Caliper, Mass.), 0.015% Brij-35, 5% DMSO, and 5.6 mM MgCl2. One may use the following separation conditions for a Caliper LC3000: −1.0 PSI, −2000 V upstream voltage, −400 V downstream voltage, 0.2 second sample sip, 45 second post sip, 10% laser strength.
    • PIM2 In-Vitro Mobility Shift Assay
  • One may determine the activity of purified human His-PIM2 [23-299] enzyme in-vitro using a mobility shift assay on a Caliper LC3000 reader (Caliper, Mass.), which measures fluorescence of a phosphorylated and unphosphorylated FL-Ahx-Bad (FITC-(AHX)RSRHSSYPAGT-COOH, Primm 200606-00289, Primm Biotech, MA) and calculates a ratiometric value to determine percent turnover. One may express PIM2 (produced at AstraZeneca, R&D Boston) in E. coli cells with a typical yield of >90% purity.
  • One determines phosphorylation of the FL-Ahx-Bad in the presence and absence of the compound of interest. One preincubates 5 uL of Enzyme/Substrate/adenosine triphosphate (ATP) mix consisting of 2.4 nM PIM1, 3.6 uM FL-Ahx-Bad, and 12 uM ATP in 1.2× buffer with 2 ul of compound for 20 minutes at 25° C. One initiates reactions with 5 uL of Metal mix consisting of 24 mM MgCl2 in 1.2× buffer and incubates at 25° C. for 90 minutes. One stops reactions by addition of 5 uL of Stop mix consisting of 100 mM HEPES, 121 mM ethylenediamine tetraacetic acid, 0.8% Coatin Reagent 3 (Caliper, Mass.), and 0.01% Tween. One detects phosphorylated and unphosphorylated substrate by a Caliper LC3000 reader (Caliper, Mass.) in the presence of separation buffer consisting of 100 mM HEPES, 16 mM ethylenediamine tetraacetic acid, 0.1% Coatin Reagent 3 (Caliper, Mass.), 0.015% Brij-35, 5% DMSO, and 5.6 mM MgCl2. One may use the following separation conditions for a Caliper LC3000: −1.0 PSI, −2000 V upstream voltage, −400 V downstream voltage, 0.2 second sample sip, 45 second post sip, 10% laser strength.
  • Using the above described assays, or appropriate modifications thereof, preferred compounds disclosed herein generally have an IC50 for PIM1 of less that 5 micromolar (uM), and even more preferred of less than 1 micromolar. The table 1 below provides the percent inhibition of PIM1 at 0.3 micromolar for Examples provided herein. Several examples were tested more than once. Variations in the experimental outcomes, negative values, or values over 100% inhibition are presumably due to experimental error inherent in the assay.
  • TABLE 1
    Example number PIM1 % I at 0.3 uM PIM2 % I at 0.3 uM
     1 >95 77.7
     2 >95 >95
     3 >95 58.0
     4 >95 79.6
     5A >95 79.9
     5B >95 >95
     6 79.4 9.5
     7 5.4 <5
     8 16.3 <5
     9 6.9 <5
     10 >95 50.1
     11 89.4 17.9
     12 80.2 <5
     13 <5 <5
     14 >95 69.9
     15 12.9 <5
     16 13.9 <5
     17 29.8 <5
     18 <5 <5
     19 >95 38.3
     20 86.5 19.1
     21 82.9 15.8
     22 81.9 8.5
     23 87.6 19.7
     24 >95 44.3
     25 >95 68.4
     26 >95 49.6
     27 90.8 25.1
     28 90.0 27.4
     29 92.8
     30 90.8 15.6
     31 92.8 23.3
     32 94.0 31.9
     33 >95 >95
     34 >95 39.3
     35 <5 <5
     36 >95 >95
     37 89.7 69.4
     38 >95 92.9
     39 89.4 57.3
     40 >95 89.8
     41 74.0 25.1
     42 58.8 23.3
     43 55.4 14.7
     44 83.8 46.7
     45 40.1 14.3
     46 13.4 15.7
     47 50.0 26.3
     48 84.4 41.3
     49 >95 86.3
     50 93.7 45.4
     51 85.5 80.6
     52 >95 93.5
     53 92.3 82.1
     54 88.1 73.1
     55 11.0 <5
     56 90.7 33.5
     57 53.3 42.6
     58 16.0 7.1
     59 <5 6.6
     60 35.4 11.3
     61 81.8 28.1
     62 62.1 17.5
     63 79.2 21.5
     64 86.5 25.7
     65 45.3 18.9
     66 50.3 20.9
     67 <5
     68 41.9 9.0
     69 <5 16.3
     70 <5 <5
     71 <5 <5
     72 <5 <5
     73 <5 <5
     74
     75 >95 69.5
     76 59.6 27.6
     77 51.2 22.7
     78 71.4 30.0
     79 90.0 60.7
     80 <5
     81 <5
     82 87.4 58.2
     83 34.0
     84A 92.9 54.3
     84B
     84C 47.8 29.6
     84D 27.8 <5
     84E 11.7 6.1
     84F 87.4 52.4
     84G 92.0 63.0
     84H >95 67.0
     84I >95 82.7
     84J 93.3 40.4
     84K >95 90.8
     84L >95 55.2
     84M >95 80.9
     84N 92.8 81.4
     84O <5 <5
     85 >95 82.4
     86 >95 >95
     87 >95 84.2
     88 >95 88.4
     89 48.4 21.5
     90 78.2 86.3
     91 6.6 16.4
     92 >95 81.5
     93 >95 66.3
     94 >95 >95
     95 >95 >95
     96 >95 >95
     97 >95 86.4
     98 >95 81.4
     99 >95 >95
    100 93.0 93.9
    101 >95 >95
    102 93.3 91.9
    103 >95 88.7
    104 >95 92.4
    105 >95 92.4
    106 >95 92.8
    107 >95 >95
    108 >95 >95
    109 64.2 65.8
    110 90.9 90.7
    111 >95 >95
    112 >95 >95
    113 >95 >95
    114 >95 >95
    115 93.3 76.1
    116 >95 >95
    117 >95 >95
    118 >95 >95
    119 56.2 20.1
    120 58.9 22.2
    121 >95 87.4
    122A 88.2 55.0
    122B >95 92.3
    122C >95 >95
    122D >95 >95
    122E >95 >95
    122F >95 >95
    122G >95 92.1
    122H >95 >95
    122I >95 >95
    122J >95 >95
    122K >95 >95
    122L >95 >95
    122M >95 >95
    122N >95 >95
    1220 >95 >95
    122P >95 >95
    122Q >95 >95
    122R >95 89.6
    122S >95 >95
    122T >95 >95
    122U >95 >95
    122V >95 >95
    122W >95 >95
    122X >95 67.1
    122Y >95 >95
    122Z >95 >95
    122AA >95 >95
    122AB >95 >95
    122AC >95 >95
    122AD >95 >95
    122AE >95 >95
    122AF 83.9 87.9
    122AG 68.9 86.7
    122AH 19.0 14.0
    122AI >95 >95
    123 >95 >95
    124 >95 >95
    125 >95 >95
    126 >95 >95
    127 >95 >95
    128 81.2 49.0
    129A >95 >95
    129B >95 >95
    129C 85.0 52.1
    130 66.2 45.5
    131A 27.1 <5
    131B <5 <5
    132 93.0 88.1
    133 >95 93.4
    134 >95 85.2
    135 42.5 10.8
    136 82.8 44.6
    137 55.1 18.6
    138 87.9 63.2
    139 58.1 15.1
    140 73.3 52.0
    141 34.9 <5
    142 86.1 75.2
    143 85.9 49.8
    144 63.2 21.2
    145 >95 80.1
    146 88.9 48.5
    147 74.3 36.4
    148 91.5 60.8
    149 >95 75.4
    150 79.8 31.7
    151 31.5 13.5
    152 10.8 16.7

Claims (15)

1. A method of treating or preventing cancer comprising,
a) providing a pharmaceutical composition comprising a compound of formula I,
Figure US20150051185A1-20150219-C00845
or salts thereof, functioning to inhibit a PIM kinase, wherein
R1 is selected from a carbocyclyl, aryl, and heterocyclyl, wherein R1 is optionally substituted with one or more, the same or different, R2;
R2 is selected from halogen, C1-6alkyl, halogenated C1-6alkyl, amino, C1-6alkylamino, (C1-6alkyl)2amino, and heterocyclyl, wherein R2 is optionally substituted with one or more, the same or different, R3;
R3 is selected from C1-6alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, C1-6alkoxy, C1-6alkylthio, C1-6alkylamino, (C1-6alkyl)2amino, C1-6alkylsulfinyl, C1-6alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, and heterocyclyl, wherein R3 is optionally substituted with one or more, the same or different, R4;
R4 is selected from C1-6alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, C1-6alkoxy, C1-6alkylthio, C1-6alkylamino, (C1-6alkyl)2amino, C1-6alkylsulfinyl, C1-6alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, and heterocyclyl, wherein R4 is optionally substituted with one or more, the same or different, R5; and
R5 is selected from halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, and heterocyclyl; and
b) administering said pharmaceutical composition to a subject diagnosed with, exhibiting symptoms of, or at risk for cancer.
2. A compound of formula IA,
Figure US20150051185A1-20150219-C00846
or salts thereof, wherein,
--- is individually at each occurrence selected from a single and double bond;
n is selected from 0, 1, or 2;
m is selected from 0, 1, or 2;
A is selected from N and CR7;
X is selected from O, S, CHR10 and NR11;
Y is selected from N, CH, and C;
R5, R6, and R7 are each individually and independently from hydrogen, C1-6alkyl, halogen, cyano, nitro, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, C1-6alkoxy, C1-6alkylthio, C1-6alkylamino, (C1-6alkyl)2amino, carbocyclyl, aryl, and heterocyclyl, wherein R5, R6, and R7 are each optionally substituted with one or more, the same or different, R12;
R8 and R9 are each individually and independently selected from hydrogen, amino, hydroxyl, mercapto, C1-6alkyl, C1-6alkylamino, carbocyclyl, aryl, and heterocyclyl wherein R8 and R9 are each optionally substituted with one or more, the same or different, R15;
R10 is selected from hydrogen, C1-6alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, C1-6alkoxy, C1-6alkylthio, C1-6alkylamino, (C1-6alkyl)2amino, C1-6alkylsulfamoyl, arylsulfamoyl, carbocyclyl, aryl, and heterocyclyl, wherein R10 is optionally substituted with one or more, the same or different, R12;
R11 is selected from hydrogen, formyl, C1-6alkyl, C1-6alkanoyl, C1-6alkylsulfinyl, C1-6alkylsulfonyl, arylsulfonyl, C1-6alkoxycarbonyl, carbocyclyl, aryl, and heterocyclyl, wherein R11 is optionally substituted with one or more, the same or different, R12;
R12 is selected from halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, and heterocyclyl, wherein R12 is optionally substituted with one or more, the same or different, R16;
R15 is selected from C1-6alkyl, C1-6alkanoyl, C1-6alkylsulfinyl, C1-6alkylsulfonyl, arylsulfonyl, and C1-6alkoxycarbonyl wherein R15 is optionally substituted with one or more, the same or different, R12;
R16 is selected from halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, aminomethyl, aminoethyl, aminopropyl, aminobutyl, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, and N-methyl-N-ethylsulfamoyl; and
provided that R5, R6, and R7 are not all hydrogen and
provided the compound is not 5-((5-nitro-2-(1-piperidinyl)phenyl)methylene)-2,4-thiazolidinedione or 5-((2-(4-morpholinyl)-5-nitrophenyl)methylene)-2,4-thiazolidinedione.
3. A compound of formula IB,
Figure US20150051185A1-20150219-C00847
or salts thereof, wherein,
n is selected from 0, 1, or 2;
X is selected from O, CHR10 and NR11;
R5, R6, and R7 are each individually and independently from hydrogen, halogen, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, and N-methyl-N-ethylsulfamoyl;
R8 and R9 are each individually and independently selected from hydrogen, amino, C1-6alkyl, C1-6alkylamino, wherein R8 and R9 are each optionally substituted with one or more, the same or different, R15;
R10 is selected from hydrogen, C1-6alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, C1-6alkoxy, C1-6alkylthio, C1-6alkylamino, (C1-6alkyl)2amino, C1-6alkylsulfamoyl, arylsulfamoyl, carbocyclyl, aryl, and heterocyclyl, wherein R10 is optionally substituted with one or more, the same or different, R12;
R11 is selected from hydrogen, C1-6alkyl, C1-6alkanoyl, C1-6alkylsulfinyl, C1-6alkylsulfonyl, arylsulfonyl, C1-6alkoxycarbonyl, carbocyclyl, aryl, and heterocyclyl, wherein R11 is optionally substituted with one or more, the same or different, R12;
R12 is selected from halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, and heterocyclyl, wherein R12 is optionally substituted with one or more, the same or different, R16;
R15 is selected from C1-6alkyl, C1-6alkanoyl, C1-6alkylsulfinyl, C1-6alkylsulfonyl, arylsulfonyl, and C1-6alkoxycarbonyl wherein R15 is optionally substituted with one or more, the same or different, R12;
R16 is selected from halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, and N-methyl-N-ethylsulfamoyl.; and
provided that said compound is not,
5-[[2-(4-methyl-1-piperazinyl)phenyl]methylene]-2,4-thiazolidinedione or
5-[[2-[(2,6-dichloro-3-methylphenyl)amino]phenyl]methylene]-2,4-thiazolidinedione.
4. A compound of formula IC,
Figure US20150051185A1-20150219-C00848
or salts thereof, wherein,
n is selected from 0, 1, 2, 3, 4, 5, 6, 7 or 8;
X is selected from O, S, CHR10 and NR11;
Y is selected from O, S, and NR13;
R5, R6, and R7 are each individually and independently from C1-6alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, C1-6alkoxy, C1-6alkylthio, C1-6alkylamino, C1-6dialkylamino, carbocyclyl, aryl, and heterocyclyl, wherein R5, R6, and R7 are each optionally substituted with one or more, the same or different, R12;
R10 is selected from hydrogen, C1-6alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, C1-6alkoxy, C1-6alkylthio, C1-6alkylamino, (C1-6alkyl)2amino, C1-6alkylsulfamoyl, arylsulfamoyl, carbocyclyl, aryl, and heterocyclyl, wherein R10 is optionally substituted with one or more, the same or different, R12;
R11, R13, and R14 are each individually and independently selected from hydrogen, C1-6alkyl, C1-6alkanoyl, C1-6alkylsulfinyl, C1-6alkylsulfonyl, arylsulfonyl, and C1-6alkoxycarbonyl wherein R11 is optionally substituted with one or more, the same or different, R12;
or R11 and R14, taken together with the atoms to which they are attached form a five, six, or seven membered heterocyclic ring optionally substituted with one or more, the same or different, R12;
R12 is selected from halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, and heterocyclyl.
5. A compound of formula IC as defined in claim 4, or salts thereof, wherein Y is NR13.
6. A compound of formula IA, IB, or IC, as defined in claims 2-4, or salts thereof, wherein R5 is a halogenated C1-6alkyl.
7. A compound of formula IA, IB, or IC, as defined in claims 2-4, or salts thereof, wherein R7 is a halogen.
8. A compound of formula IX,
Figure US20150051185A1-20150219-C00849
or salts thereof, wherein
R5 is selected from hydrogen, C1-6alkoxy, carbamoyl, and halogenated C1-6alkyl;
R6 is selected from hydrogen, halogen, C1-6alkoxy, and 2-(1-piperidyl)ethoxy;
R7 is selected from hydrogen, halogen, and C1-6alkoxy;
R17 is a heterocarbocylcyl, wherein R17 is optionally substituted with one or more, the same or different, R18;
R18 is selected from halogen, formyl, amino, C1-6alkyl, C1-6alkylamino, (C1-6alkyl)2amino, carbocyclyl, aryl, heterocyclyl, wherein R18 is optionally substituted with one or more, the same or different, R19;
R19 is selected from amino, C1-6alkyl, hydroxy, carbocyclyl, and heterocyclyl wherein R19 is optionally substituted with one or more, the same or different, R20; and
R20 is selected from amino, C1-6alkyl, and halogen.
9. The compound of claim 8, or salts thereof, wherein, R17 is selected from (3R)-3-aminopyrrolidin-1-yl, (3R)-3-dimethylaminopyrrolidin-1-yl, (3S)-3-(3-aminopropylamino)pyrrolidin-1-yl, (3S)-3-(5-aminopentanoylamino)pyrrolidin-1-yl, (3S)-3-amino-1-piperidyl, (3S)-3-aminopyrrolidin-1-yl, (3S)-3-dimethylaminopyrrolidin-1-yl, (3S,5R)-3,5-dimethylpiperazin-1-yl, 1,4-diazepan-1-yl, 2-(1-piperidyl)ethoxy, 2-diethylaminoethoxy, 2-dimethylaminoethyl-methyl-amino, 2-hydroxyethoxy, 2-morpholinoethoxy, 3-(2-aminoethylamino)pyrrolidin-1-yl, 3-(2-hydroxyethylamino)pyrrolidin-1-yl, 3-(2-methylaminoethylamino)pyrrolidin-1-yl, 3-(3-aminopropanoylamino)pyrrolidin-1-yl, 3-(3-aminopropylamino)pyrrolidin-1-yl, 3-(3-methyl-1,2,4-oxadiazol-5-yl)-1-piperidyl, 3-(aminomethyl)-1-piperidyl, 3-(aminomethyl)pyrrolidin-1-yl, 3-acetamidopyrrolidin-1-yl, 3-aminopyrrolidin-1-yl, 3-dimethylaminopropoxy, 3-dimethylaminopropyl-methyl-amino, 3-dimethylaminopyrrolidin-1-yl, 3-hydroxypyrrolidin-1-yl, 3-pyridyl, 4-(1-methyl-4-piperidyl)piperazin-1-yl, 4-(1-piperidyl)-1-piperidyl, 4-(2-aminoethyl)piperazin-1-yl, 4-(2-hydroxyethyl)-1,4-diazepan-1-yl, 4-(2-hydroxyethyl)-1-piperidyl, 4-(2-hydroxyethyl)piperazin-1-yl, 4-(2-methylaminoethyl)piperazin-1-yl, 4-(2-morpholinoethyl)piperazin-1-yl, 4-(3-aminopropanoyl)-1,4-diazepan-1-yl, 4-(3-aminopropanoyl)piperazin-1-yl, 4-(3-aminopropyl)piperazin-1-yl, 4-(3-hydroxypropyl)piperazin-1-yl, 4-(3-methyl-1,2,4-oxadiazol-5-yl)-1-piperidyl, 4-(4-aminobutanoyl)-1,4-diazepan-1-yl, 4-(4-aminobutanoyl)piperazin-1-yl, 4-(4-chloro-2-fluoro-phenyl)piperazin-1-yl, 4-(4-fluorophenyl)piperazin-1-yl, 4-(4-pyridylmethyl)piperazin-1-yl, 4-(5-aminopentanoyl)-1,4-diazepan-1-yl, 4-(5-aminopentanoyl)piperazin-1-yl, 4-(azetidine-3-carbonyl)piperazin-1-yl, 4-(benzo[1,3]dioxol-5-ylmethyl)piperazin-1-yl, 4-(cyclopropylmethyl)piperazin-1-yl, 4-(hydroxymethyl)-1-piperidyl, 4-(piperidine-3-carbonyl)-1,4-diazepan-1-yl, 4-(piperidine-3-carbonyl)piperazin-1-yl, 4-(piperidine-4-carbonyl)piperazin-1-yl, 4-[(2-chlorophenyl)methyl]piperazin-1-yl, 4-[3-(aminomethyl)benzoyl]piperazin-1-yl, 4-[4-(piperazin-1-ylmethyl)benzoyl]piperazin-1-yl, 4-acetylpiperazin-1-yl, 4-amino-1-piperidyl, 4-butyl-1,4-diazepan-1-yl, 4-cyclopentylpiperazin-1-yl, 4-dimethylamino-1-piperidyl, 4-hydroxy-1-piperidyl, 4-isobutylpiperazin-1-yl, 4-isopropylpiperazin-1-yl, 4-methylpiperazin-1-yl, 4-morpholino-1-piperidyl, 4-pyridyl, 4-pyrrolidin-1-yl-1-piperidyl, 4-tert-butoxycarbonylpiperazin-1-yl, 4-tert-butylpiperazin-1-yl, morpholino, piperazin-1-yl, and pyrrolidin-1-yl.
10. A compound selected from:
5-({2-[(3S)-3-aminopiperidin-1-yl]-3-chloro-5-(trifluoromethyl)phenyl}methylidene)-1,3-thiazolidine-2,4-dione;
5-({2-[(3R)-3-aminopiperidin-1-yl]-3-chloro-5-(trifluoromethyl)phenyl}methylidene)-1,3-thiazolidine-2,4-dione;
5-{[2-(4-aminopiperidin-1-yl)-3-chloro-5-(trifluoromethyl)phenyl]methylidene}-1,3-thiazolidine-2,4-dione;
5-({2-[3-(aminomethyl)piperidin-1-yl]-3-chloro-5-(trifluoromethyl)phenyl}methylidene)-1,3-thiazolidine-2,4-dione;
5-{[3-chloro-2-(1,4-diazepan-1-yl)-5-(trifluoromethyl)phenyl]methylidene}-1,3-thiazolidine-2,4-dione;
5-{[3-chloro-2-(4-cyclopentylpiperazin-1-yl)-5-(trifluoromethyl)phenyl]methylidene}-1,3-thiazolidine-2,4-dione;
5-({3-chloro-2-[4-(4-fluorophenyl)piperazin-1-yl]-5-(trifluoromethyl)phenyl}methylidene)-1,3-thiazolidine-2,4-dione;
5-({2-[4-(1,3-benzodioxol-5-ylmethyl)piperazin-1-yl]-3-chloro-5-(trifluoromethyl)phenyl}methylidene)-1,3-thiazolidine-2,4-dione;
5-({3-chloro-2-[4-(3-methyl-1,2,4-oxadiazol-5-yl)piperidin-1-yl]-5-(trifluoromethyl)phenyl}methylidene)-1,3-thiazolidine-2,4-dione;
5-{[3-chloro-2-(4-pyrrolidin-1-ylpiperidin-1-yl)-5-(trifluoromethyl)phenyl]methylidene}-1,3-thiazolidine-2,4-dione;
5-({3-chloro-2-[4-(1-methylethyl)piperazin-1-yl]-5-(trifluoromethyl)phenyl}methylidene)-1,3-thiazolidine-2,4-dione;
5-({3-chloro-2-[4-(2-methylpropyl)piperazin-1-yl]-5-(trifluoromethyl)phenyl}methylidene)-1,3-thiazolidine-2,4-dione;
5-({3-chloro-2-[4-(2-hydroxyethyl)piperidin-1-yl]-5-(trifluoromethyl)phenyl}methylidene)-1,3-thiazolidine-2,4-dione;
5-({3-chloro-2-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]-5-(trifluoromethyl)phenyl}methylidene)-1,3-thiazolidine-2,4-dione;
5-({3-chloro-2-[4-(4-chloro-2-fluorophenyl)piperazin-1-yl]-5-(trifluoromethyl)phenyl}methylidene)-1,3-thiazolidine-2,4-dione;
5-({3-chloro-2-[3-(3-methyl-1,2,4-oxadiazol-5-yl)piperidin-1-yl]-5-(trifluoromethyl)phenyl}methylidene)-1,3-thiazolidine-2,4-dione;
5-({3-chloro-2-[4-(pyridin-4-ylmethyl)piperazin-1-yl]-5-(trifluoromethyl)phenyl}methylidene)-1,3-thiazolidine-2,4-dione;
5-({3-chloro-2-[4-(2-chlorobenzyl)piperazin-1-yl]-5-(trifluoromethyl)phenyl}methylidene)-1,3-thiazolidine-2,4-dione;
5-({3-chloro-2-[4-(1-methylpiperidin-4-yl)piperazin-1-yl]-5-(trifluoromethyl)phenyl}methylidene)-1,3-thiazolidine-2,4-dione;
5-({3-chloro-2-[4-(2-morpholin-4-ylethyl)piperazin-1-yl]-5-(trifluoromethyl)phenyl}methylidene)-1,3-thiazolidine-2,4-dione;
5-({3-chloro-2-[4-(cyclopropylmethyl)piperazin-1-yl]-5-(trifluoromethyl)phenyl}methylidene)-1,3-thiazolidine-2,4-dione;
5-{[3-chloro-2-(4-morpholin-4-ylpiperidin-1-yl)-5-(trifluoromethyl)phenyl]methylidene}-1,3-thiazolidine-2,4-dione;
5-({3-chloro-2-[4-(3-hydroxypropyl)piperazin-1-yl]-5-(trifluoromethyl)phenyl}methylidene)-1,3-thiazolidine-2,4-dione;
5-({3-chloro-2-[4-(dimethylamino)piperidin-1-yl]-5-(trifluoromethyl)phenyl}methylidene)-1,3-thiazolidine-2,4-dione;
5-{[3-chloro-2-{[3-(dimethylamino)propyl] (methyl)amino}-5-(trifluoromethyl)phenyl]methylidene}-1,3-thiazolidine-2,4-dione;
5-({3-chloro-2-[4-(2-hydroxyethyl)-1,4-diazepan-1-yl]-5-(trifluoromethyl)phenyl}methylidene)-1,3-thiazolidine-2,4-dione;
5-{[2-(4-butyl-1,4-diazepan-1-yl)-3-chloro-5-(trifluoromethyl)phenyl]methylidene}-1,3-thiazolidine-2,4-dione;
5-({3-chloro-2-[4-(2-hydroxyethyl)piperazin-1-yl]-5-(trifluoromethyl)phenyl}methylidene)-1,3-thiazolidine-2,4-dione;
5-{[3-chloro-2-morpholin-4-yl-5-(trifluoromethyl)phenyl]methylidene}-1,3-thiazolidine-2,4-dione;
5-{[2-(4-tert-butylpiperazin-1-yl)-3-chloro-5-(trifluoromethyl)phenyl]methylidene}-1,3-thiazolidine-2,4-dione;
5-{[2-(1,4′-bipiperidin-1′-yl)-3-chloro-5-(trifluoromethyl)phenyl]methylidene}-1,3-thiazolidine-2,4-dione;
5-{[3-chloro-2-(4-methylpiperazin-1-yl)-5-(trifluoromethyl)phenyl]methylidene}-1,3-thiazolidine-2,4-dione;
5-({3-bromo-2-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]phenyl}methylidene)-1,3-thiazolidine-2,4-dione;
5-({2-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-5-(trifluoromethyl)phenyl}methylidene)-1,3-thiazolidine-2,4-dione;
(5Z)-5-({2-[(3S)-3-aminopyrrolidin-1-yl]-3-chloro-5-(trifluoromethyl)phenyl}methylidene)-1,3-thiazolidine-2,4-dione;
(5Z)-5-({3-[3-(4-methylpiperazin-1-yl)propoxy]phenyl}methylidene)-1,3-thiazolidine-2,4-dione;
2-{3-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]phenoxy}acetamide;
(5Z)-5-{[3-(3-piperidin-1-ylpropoxy)phenyl]methylidene}-1,3-thiazolidine-2,4-dione;
(5Z)-5-({3-[(4-methylpiperazin-1-yl)methyl]phenyl}methylidene)-1,3-thiazolidine-2,4-dione;
N-[2-(dimethylamino)ethyl]-2′-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]-N-methylbiphenyl-4-sulfonamide;
5-({2-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]-5-methoxyphenyl}methylidene)-1,3-thiazolidine-2,4-dione;
5-({2-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]-5-(trifluoromethyl)phenyl}methylidene)-1,3-thiazolidine-2,4-dione;
5-({5-chloro-2-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]phenyl}methylidene)-1,3-thiazolidine-2,4-dione;
5-({2-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]-4-methylphenyl}methylidene)-1,3-thiazolidine-2,4-dione;
5-({2-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]-5-fluorophenyl}methylidene)-1,3-thiazolidine-2,4-dione;
5-({2-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]-5-methylphenyl}methylidene)-1,3-thiazolidine-2,4-dione;
5-({5-bromo-2-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]phenyl}methylidene)-1,3-thiazolidine-2,4-dione;
5-({2-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]-3-fluorophenyl}methylidene)-1,3-thiazolidine-2,4-dione;
5-({2-chloro-6-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]phenyl}methylidene)-1,3-thiazolidine-2,4-dione;
(5Z)-5-({2-[(3R)-3-(aminomethyl)pyrrolidin-1-yl]-3-chlorophenyl}methylidene)-1,3-thiazolidine-2,4-dione;
(5Z)-5-({2-[(3S)-3-(aminomethyl)pyrrolidin-1-yl]-3-chlorophenyl}methylidene)-1,3-thiazolidine-2,4-dione;
(5Z)-5-({2-[(3R)-3-aminopiperidin-1-yl]-3-chlorophenyl}methylidene)-1,3-thiazolidine-2,4-dione;
(5Z)-5-({2-[(3R)-3-aminopiperidin-1-yl]-3-methoxyphenyl}methylidene)-1,3-thiazolidine-2,4-dione;
(5Z)-5-({2-[(3R)-3-aminopiperidin-1-yl]-3-bromophenyl}methylidene)-1,3-thiazolidine-2,4-dione;
(5Z)-5-({2-[(3R)-3-aminopyrrolidin-1-yl]-3-chlorophenyl}methylidene)-1,3-thiazolidine-2,4-dione;
(5Z)-5-({2-[(3S)-3-aminopyrrolidin-1-yl]-3-bromophenyl}methylidene)-1,3-thiazolidine-2,4-dione;
(5Z)-5-({2-[(3R)-3-aminopiperidin-1-yl]-3-ethoxyphenyl}methylidene)-1,3-thiazolidine-2,4-dione;
(5Z)-5-({2-[(3R)-3-aminopiperidin-1-yl]-3-(2-methylpropoxy)phenyl}methylidene)-1,3-thiazolidine-2,4-dione;
(5Z)-5-({2-[(3R)-3-aminopiperidin-1-yl]-3-(cyclohexylmethoxy)phenyl}methylidene)-1,3-thiazolidine-2,4-dione;
(5Z)-5-({2-[(3R)-3-aminopiperidin-1-yl]-3-(cyclohexyloxy)phenyl}methylidene)-1,3-thiazolidine-2,4-dione;
(5Z)-5-({2-[(3R,4R)-3-amino-4-hydroxypiperidin-1-yl]-3-chlorophenyl}methylidene)-1,3-thiazolidine-2,4-dione;
(5Z)-5-{[3-chloro-2-(1,4-diazepan-1-yl)phenyl]methylidene}-1,3-thiazolidine-2,4-dione;
(5Z)-5-({2-[(3R)-3-aminopiperidin-1-yl]-3-(1-methylethoxy)phenyl}methylidene)-1,3-thiazolidine-2,4-dione;
(5Z)-5-({2-[(3S)-3-aminopyrrolidin-1-yl]-3-(1-methylethoxy)phenyl}methylidene)-1,3-thiazolidine-2,4-dione;
(5Z)-5-({2-[(3S)-3-aminopyrrolidin-1-yl]-3-ethoxyphenyl}methylidene)-1,3-thiazolidine-2,4-dione;
(5Z)-5-({2-[(3R)-3-{[4-(aminomethyl)benzyl]amino}piperidin-1-yl]-3-chlorophenyl}methylidene)-1,3-thiazolidine-2,4-dione;
(5Z)-5-({3-chloro-2-[(3R)-3-{[2-(methylamino)ethyl]amino}piperidin-1-yl]phenyl}methylidene)-1,3-thiazolidine-2,4-dione;
(5Z)-5-({2-[(3S,4S)-3-amino-4-hydroxypyrrolidin-1-yl]-3-chlorophenyl}methylidene)-1,3-thiazolidine-2,4-dione;
(5Z)-5-({3-chloro-2-[4-methyl-3-(methylamino)piperidin-1-yl]phenyl}methylidene)-1,3-thiazolidine-2,4-dione;
(5Z)-5-{[2-(3-amino-4-methylpiperidin-1-yl)-3-chlorophenyl]methylidene}-1,3-thiazolidine-2,4-dione;
(5Z)-5-({2-[(3R)-3-aminopiperidin-1-yl]phenyl}methylidene)-1,3-thiazolidine-2,4-dione;
(5Z)-5-({2-[(3S)-3-aminopyrrolidin-1-yl]phenyl}methylidene)-1,3-thiazolidine-2,4-dione;
(5Z)-5-({2-[(3R)-3-aminopiperidin-1-yl]-3-(2,2,2-trifluoroethoxy)phenyl}methylidene)-1,3-thiazolidine-2,4-dione;
(5Z)-5-({2-[(3S)-3-aminopyrrolidin-1-yl]-3-(2,2,2-trifluoroethoxy)phenyl}methylidene)-1,3-thiazolidine-2,4-dione;
(5Z)-5-({2-[(3R)-3-aminopiperidin-1-yl]-3-(2-methoxyethoxy)phenyl}methylidene)-1,3-thiazolidine-2,4-dione;
(5Z)-5-({2-[(3S)-3-aminopyrrolidin-1-yl]-3-(2-methoxyethoxy)phenyl}methylidene)-1,3-thiazolidine-2,4-dione;
(5Z)-5-({2-[(3R)-3-aminopiperidin-1-yl]-3-(cyclopentyloxy)phenyl}methylidene)-1,3-thiazolidine-2,4-dione;
(5Z)-5-({2-[(3R)-3-aminopiperidin-1-yl]-3-(cyclobutyloxy)phenyl}methylidene)-1,3-thiazolidine-2,4-dione;
4-[(3R)-3-aminopiperidin-1-yl]-3-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]benzamide;
4-[(3S)-3-aminopiperidin-1-yl]-3-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]benzamide;
4-[(3R)-3-aminopiperidin-1-yl]-3-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]benzoic acid;
4-[(3S)-3-aminopyrrolidin-1-yl]-3-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]benzoic acid;
(5Z)-5-({2-[(3R)-3-aminopiperidin-1-yl]biphenyl-3-yl}methylidene)-1,3-thiazolidine-2,4-dione;
5-{[2-(3-aminopropoxy)-5-methoxyphenyl]methylidene}-1,3-thiazolidine-2,4-dione;
N-{4-[3-(dimethylamino)pyrrolidin-1-yl]-3-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]phenyl}acetamide;
(5Z)-5-[(3-chloro-2-{(3R)-3-[(2-hydroxyethyl)amino]piperidin-1-yl}phenyl)methylidene]-1,3-thiazolidine-2,4-dione;
(5Z)-5-[(3-chloro-2-{(3R)-3-[(3-hydroxypropyl)amino]piperidin-1-yl}phenyl)methylidene]-1,3-thiazolidine-2,4-dione;
N-[(3S)-1-{2-chloro-6-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]phenyl}pyrrolidin-3-yl]-1-methyl-1H-imidazole-2-carboxamide;
N-[(3S)-1-{2-chloro-6-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]phenyl}pyrrolidin-3-yl]-2-methoxyacetamide;
N-[(3S)-1-{2-chloro-6-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]phenyl}pyrrolidin-3-yl]-1-methyl-1H-pyrazole-3-carboxamide;
N2-carbamoyl-N-[(3S)-1-{2-chloro-6-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]phenyl}pyrrolidin-3-yl]glycinamide;
N-[(3S)-1-{2-chloro-6-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]phenyl}pyrrolidin-3-yl]-2-pyridin-3-ylacetamide;
N-[(3S)-1-{2-chloro-6-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]phenyl}pyrrolidin-3-yl]-2-pyridin-4-ylacetamide;
N-[(3S)-1-{2-chloro-6-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]phenyl}pyrrolidin-3-yl]-1-methyl-1H-pyrazole-4-carboxamide;
N-[(3S)-1-{2-chloro-6-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]phenyl}pyrrolidin-3-yl]-2-(1-oxidothiomorpholin-4-yl)acetamide;
N-[(3S)-1-{2-chloro-6-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]phenyl}pyrrolidin-3-yl]-4-sulfamoylbutanamide;
N′-[(3S)-1-{2-chloro-6-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]phenyl}pyrrolidin-3-yl]-N,N-dimethylbutanediamide;
N-[(3S)-1-{2-chloro-6-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]phenyl}pyrrolidin-3-yl]-N˜2˜,N˜2˜-dimethylglycinamide;
N-[(3S)-1-{2-chloro-6-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]phenyl}pyrrolidin-3-yl]-2-cyanoacetamide;
N2-acetyl-N-[(3S)-1-{2-chloro-6-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]phenyl}pyrrolidin-3-yl]glycinamide;
(5Z)-5-({3-chloro-2-[(3R)-3-(dipropylamino)piperidin-1-yl]phenyl}methylidene)-1,3-thiazolidine-2,4-dione;
(5Z)-5-[(3-chloro-2-{(3R)-3-[(3,3,3-trifluoropropyl)amino]piperidin-1-yl}phenyl)methylidene]-1,3-thiazolidine-2,4-dione;
5-[(5-methoxy-2-{3-[(1-methylethyl)amino]propoxy}phenyl)methylidene]-1,3-thiazolidine-2,4-dione;
(5Z)-5-({5-amino-2-[3-(dimethylamino)pyrrolidin-1-yl]phenyl}methylidene)-1,3-thiazolidine-2,4-dione; and
5-[(2-amino-4,5-dimethoxyphenyl)methylidene]-1,3-thiazolidine-2,4-dione,
or salts thereof.
11. A pharmaceutical composition comprising a compound of formula I, IA, IB, IC, or IX, as defined in claims 1-10, or a pharmaceutically acceptable salt thereof.
12. A method of inhibiting a PIM kinase comprising, providing a compound of formula I, IA, IB, IC, or IX, as defined in claims 1-10 comprising mixing a PIM kinase and said compound under conditions such that PIM kinase phosphorylation is inhibited.
13. The use of a compound of the formula I, IA, IB, IC, or IX, or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1-10, for the manufacture of a medicament for the production of an anti-cancer effect in a subject.
14. A method of making a compound of formula IA as defined in claim 2,
Figure US20150051185A1-20150219-C00850
or salt thereof, comprising
a) mixing a compound of formula XI,
Figure US20150051185A1-20150219-C00851
or salt thereof, wherein E is a halogen, and R5, R6, and A are defined in claim 2,
with a compound of formula XII,
Figure US20150051185A1-20150219-C00852
or salt thereof, wherein
---, R8, R9, n, m, Y and X are defined in claim 2,
if Y is N, then R21 is hydrogen,
if Y is C, then R21 is selected from boronic acid and a boronic ester, and
if Y is CH, then R21 is selected from a metal halide,
under conditions such that composition comprising a compound of formula XIII,
Figure US20150051185A1-20150219-C00853
or salt thereof, is formed; and
b) mixing the compound of formula XIII and thiazolidine-2,4-dione under conditions such that a compound of formula IA is formed.
15. A method of making a compound of formula IC, or salt thereof comprising a) mixing a compound of formula V,
Figure US20150051185A1-20150219-C00854
or salt thereof, wherein R5, R6, and R7 are defined in claim 4,
with a compound of formula VI,
Figure US20150051185A1-20150219-C00855
or salt thereof, wherein R14, n, X and Y are defined in claim 4, under conditions such that a composition comprising a compound of formula VIII,
Figure US20150051185A1-20150219-C00856
or salt thereof, is formed; and
b) mixing the compound of formula VIII and thiazolidine-2,4-dione under conditions such that a compound of formula IC is formed.
US14/339,981 2008-07-02 2014-07-24 Chemical Compounds 251 Abandoned US20150051185A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US14/339,981 US20150051185A1 (en) 2008-07-02 2014-07-24 Chemical Compounds 251

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
US7763908P 2008-07-02 2008-07-02
US18327809P 2009-06-02 2009-06-02
PCT/GB2009/050773 WO2010001169A2 (en) 2008-07-02 2009-07-02 Chemical compounds 251
US201113000138A 2011-05-25 2011-05-25
US14/339,981 US20150051185A1 (en) 2008-07-02 2014-07-24 Chemical Compounds 251

Related Parent Applications (2)

Application Number Title Priority Date Filing Date
PCT/GB2009/050773 Continuation WO2010001169A2 (en) 2008-07-02 2009-07-02 Chemical compounds 251
US13/000,138 Continuation US8901307B2 (en) 2008-07-02 2009-07-02 Chemical compounds 251

Publications (1)

Publication Number Publication Date
US20150051185A1 true US20150051185A1 (en) 2015-02-19

Family

ID=41050276

Family Applications (2)

Application Number Title Priority Date Filing Date
US13/000,138 Expired - Fee Related US8901307B2 (en) 2008-07-02 2009-07-02 Chemical compounds 251
US14/339,981 Abandoned US20150051185A1 (en) 2008-07-02 2014-07-24 Chemical Compounds 251

Family Applications Before (1)

Application Number Title Priority Date Filing Date
US13/000,138 Expired - Fee Related US8901307B2 (en) 2008-07-02 2009-07-02 Chemical compounds 251

Country Status (27)

Country Link
US (2) US8901307B2 (en)
EP (1) EP2310010A2 (en)
JP (2) JP5261575B2 (en)
KR (1) KR20110031367A (en)
CN (2) CN102137666B (en)
AR (1) AR072791A1 (en)
AU (1) AU2009265362B2 (en)
BR (1) BRPI0914599A2 (en)
CA (1) CA2729557A1 (en)
CL (1) CL2010001636A1 (en)
CO (1) CO6341555A2 (en)
CR (1) CR20110016A (en)
DO (1) DOP2010000408A (en)
EA (1) EA018989B1 (en)
EC (1) ECSP10010735A (en)
HN (1) HN2010002786A (en)
IL (1) IL210127A0 (en)
MX (1) MX2010014233A (en)
MY (1) MY155961A (en)
NI (1) NI201100007A (en)
NZ (1) NZ590859A (en)
PE (1) PE20120304A1 (en)
SV (1) SV2011003786A (en)
TW (1) TWI461423B (en)
UY (1) UY31952A (en)
WO (1) WO2010001169A2 (en)
ZA (1) ZA201100844B (en)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11034669B2 (en) 2018-11-30 2021-06-15 Nuvation Bio Inc. Pyrrole and pyrazole compounds and methods of use thereof
WO2023039170A1 (en) * 2021-09-09 2023-03-16 Musc Foundation For Research Development Selective targeting of cd38 activity as an immunostimulatory and antitumor strategy

Families Citing this family (60)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3838903B1 (en) 2005-12-13 2023-11-22 Incyte Holdings Corporation Pyrrolo[2,3-d]pyrimidine derivative as janus kinase inhibitor
CN101932582B (en) 2007-06-13 2013-09-25 因塞特公司 Janus kinase inhibitor (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropane Nitrile salt
TWI461423B (en) * 2008-07-02 2014-11-21 Astrazeneca Ab Thiazolidinedione compounds useful in the treatment of pim kinase related conditions and diseases
US8716303B2 (en) 2009-05-22 2014-05-06 Incyte Corporation N-(hetero)aryl-pyrrolidine derivatives of pyrazol-4-yl-pyrrolo[2,3-d]pyrimidines and pyrrol-3-yl-pyrrolo[2,3-d]pyrimidines as janus kinase inhibitors
RS59632B1 (en) 2009-05-22 2020-01-31 Incyte Holdings Corp 3-[4-(7h-pyrrolo[2,3-d]pyrimidin-4-yl)-1h-pyrazol-1-yl]octane- or heptane-nitrile as jak inhibitors
TW201113285A (en) 2009-09-01 2011-04-16 Incyte Corp Heterocyclic derivatives of pyrazol-4-yl-pyrrolo[2,3-d]pyrimidines as janus kinase inhibitors
ME02386B (en) 2010-03-10 2016-09-20 Incyte Holdings Corp Piperidin-4-yl azetidine derivatives as JAK1 inhibitors
NZ603686A (en) 2010-05-21 2014-11-28 Incyte Corp Topical formulation for a jak inhibitor
TW201249845A (en) 2010-11-19 2012-12-16 Incyte Corp Cyclobutyl substituted pyrrolopyridine and pyrrolopyrimidine derivatives as JAK inhibitors
JP5917544B2 (en) 2010-11-19 2016-05-18 インサイト・ホールディングス・コーポレイションＩｎｃｙｔｅ Ｈｏｌｄｉｎｇｓ Ｃｏｒｐｏｒａｔｉｏｎ Heterocyclic substituted pyrrolopyridines and pyrrolopyrimidines as JAK inhibitors
KR20140040819A (en) 2011-06-20 2014-04-03 인사이트 코포레이션 Azetidinyl phenyl, pyridyl or pyrazinyl carboxamide derivatives as jak inhibitors
TW201313721A (en) 2011-08-18 2013-04-01 Incyte Corp Cyclohexyl azetidine derivatives as JAK inhibitors
UA111854C2 (en) 2011-09-07 2016-06-24 Інсайт Холдінгс Корпорейшн METHODS AND INTERMEDIATE COMPOUNDS FOR JAK INHIBITORS
TW201319063A (en) * 2011-10-04 2013-05-16 Yakult Honsha Kk Medicinal agent comprising thiazolidine derivative or salt thereof as active ingredient
MY158040A (en) * 2012-03-30 2016-08-30 Rohto Pharma Novel benzylidene azolidine derivative or salt thereof
TW201406761A (en) 2012-05-18 2014-02-16 Incyte Corp Piperidinylcyclobutyl substituted pyrrolopyridine and pyrrolopyrimidine derivatives as JAK inhibitors
JO3407B1 (en) 2012-05-31 2019-10-20 Eisai R&D Man Co Ltd Tetrahydropyrazolopyrimidines
JP6299591B2 (en) * 2012-07-03 2018-03-28 小野薬品工業株式会社 Compound having somatostatin receptor agonist activity and pharmaceutical use thereof
US10166191B2 (en) 2012-11-15 2019-01-01 Incyte Corporation Sustained-release dosage forms of ruxolitinib
ES2649156T3 (en) 2013-01-14 2018-01-10 Incyte Holdings Corporation Bicyclic aromatic carboxamide compounds useful as Pim kinase inhibitors
TW201932456A (en) 2013-01-15 2019-08-16 美商英塞特控股公司 Thiazole carboxamides and pyridine carboxamide compounds useful as PIM kinase inhibitors
DK2964650T3 (en) 2013-03-06 2019-02-11 Incyte Holdings Corp PROCEDURES AND INTERMEDIATES FOR THE MANUFACTURE OF A JAK INHIBITOR
JP6378918B2 (en) * 2013-04-03 2018-08-22 株式会社ヤクルト本社 Pim inhibitor comprising thiazolidine derivative or salt thereof as active ingredient
US9198898B2 (en) 2013-06-24 2015-12-01 Tigercat Pharma, Inc. Use of NK-1 receptor antagonists in pruritus
US8906951B1 (en) 2013-06-24 2014-12-09 Tigercat Pharma, Inc. Use of NK-1 receptor antagonists in pruritus
SI3030227T1 (en) 2013-08-07 2020-08-31 Incyte Corporation Sustained release dosage forms for a jak1 inhibitor
MX2016002367A (en) 2013-08-23 2016-10-28 Incyte Corp Furo- and thieno-pyridine carboxamide compounds useful as pim kinase inhibitors.
TW201601763A (en) * 2013-09-27 2016-01-16 樂敦製藥股份有限公司 Composition for external use on skin
WO2015046389A1 (en) * 2013-09-27 2015-04-02 ロート製薬株式会社 Composition for external application to skin containing novel benzylidene azolidine derivative or salt thereof
JPWO2015122504A1 (en) * 2014-02-13 2017-03-30 国立大学法人 東京大学 Kinase inhibitor
WO2015184305A1 (en) 2014-05-30 2015-12-03 Incyte Corporation TREATMENT OF CHRONIC NEUTROPHILIC LEUKEMIA (CNL) AND ATYPICAL CHRONIC MYELOID LEUKEMIA (aCML) BY INHIBITORS OF JAK1
JP5857104B2 (en) * 2014-06-17 2016-02-10 ロート製薬株式会社 External composition for skin comprising benzylidene azolidine derivative or salt thereof
US9580418B2 (en) 2014-07-14 2017-02-28 Incyte Corporation Bicyclic aromatic carboxamide compounds useful as Pim kinase inhibitors
WO2016010897A1 (en) 2014-07-14 2016-01-21 Incyte Corporation Bicyclic heteroaromatic carboxamide compounds useful as pim kinase inhibitors
US10195189B2 (en) 2014-12-15 2019-02-05 Prosetta Antiviral, Inc. 2-phenethenyltetrahydro isoquinolines useful as anti-HIV compounds
CN105985298B (en) * 2015-02-10 2018-02-23 湖南大学 2 [(base of 5 halogen thiazole 2) imino group] 5 benzal thiazolinones and preparation method and application
HK1249052A1 (en) 2015-03-06 2018-10-26 BeyondSpring Pharmaceuticals Inc. Method of treating cancer associated with a ras mutation
CN106032365B (en) * 2015-03-11 2018-03-23 湖南大学 Benzal thiazolinone of 2 (base of thiazole 2) imino group 5 and preparation method and application
US9540347B2 (en) 2015-05-29 2017-01-10 Incyte Corporation Pyridineamine compounds useful as Pim kinase inhibitors
JP6969848B2 (en) 2015-07-13 2021-11-24 ビヨンドスプリング ファーマシューティカルズ，インコーポレイテッド Prinabrin composition
TWI734699B (en) 2015-09-09 2021-08-01 美商英塞特公司 Salts of a pim kinase inhibitor
US9920032B2 (en) 2015-10-02 2018-03-20 Incyte Corporation Heterocyclic compounds useful as pim kinase inhibitors
BR112018016054A2 (en) 2016-02-08 2019-02-12 Beyondspring Pharmaceuticals, Inc. pharmaceutical compositions and / or methods for treating cancer and / or for disrupting cancer-associated tumor vasculature in an individual
WO2017176812A1 (en) 2016-04-05 2017-10-12 Immune Sensor, Llc cGAS ANTAGONIST COMPOUNDS
RU2760348C2 (en) 2016-06-06 2021-11-24 Бейондспринг Фармасьютикалс, Инк. Method for reducing neutropenia
MA45244A (en) 2016-06-13 2019-04-17 Cancer Research Tech Ltd SUBSTITUTED PYRIDINES USED AS DNMT1 INHIBITORS
EP3565812B1 (en) 2017-01-06 2023-12-27 Beyondspring Pharmaceuticals, Inc. Tubulin binding compounds and therapeutic use thereof
WO2018144764A1 (en) 2017-02-01 2018-08-09 Beyondspring Pharmaceuticals, Inc. Method of reducing neutropenia
PH12019502776A1 (en) * 2017-06-30 2020-10-26 Univ California Compositions and methods for modulating hair growth
WO2019090205A1 (en) 2017-11-06 2019-05-09 Snap Bio, Inc. Pim kinase inhibitor compositions, methods, and uses thereof
US10596161B2 (en) 2017-12-08 2020-03-24 Incyte Corporation Low dose combination therapy for treatment of myeloproliferative neoplasms
CN112135614A (en) 2018-01-24 2020-12-25 大连万春布林医药有限公司 Compositions and methods for reducing thrombocytopenia by administering plinabulin
LT3746429T (en) 2018-01-30 2022-05-10 Incyte Corporation (1- (3-FLUORO-2- (TRIFLUORMETHYL) ISONICOTINYL) PIPERIDIN-4-ONO)
MY206999A (en) 2018-03-30 2025-01-23 Incyte Corp Treatment of hidradenitis suppurativa using jak inhibitors
WO2019209083A1 (en) * 2018-04-26 2019-10-31 재단법인 의약바이오컨버젼스연구단 Novel compound as mtor inhibitor and use thereof
US11833155B2 (en) 2020-06-03 2023-12-05 Incyte Corporation Combination therapy for treatment of myeloproliferative neoplasms
US20230382891A1 (en) * 2020-10-20 2023-11-30 Blacksmith Medicines, Inc. Glutaminyl-peptide cyclotransferase like (qpctl) protein inhibitors and uses thereof
CA3215047A1 (en) 2021-04-09 2022-10-13 Lan Huang Therapeutic compositions and methods for treating tumors
CN116354901B (en) * 2023-04-12 2024-04-26 郑州大学 A thiazolidinedione compound and its preparation method and application
WO2025017207A1 (en) 2023-07-20 2025-01-23 Cemm - Forschungszentrum Für Molekulare Medizin Gmbh Inhibitors of smndc1 and their therapeutic use

Family Cites Families (26)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IE62214B1 (en) * 1988-05-25 1995-01-11 Warner Lambert Co Arylmethylenyl derivatives of thiazolidinones, imidazolidinones and oxazolidinones useful as antiallergy agents and antiinflammatory agents
NO305987B1 (en) 1994-04-11 1999-08-30 Sankyo Co Heterocyclic compounds with antidiabetic activity, their use and pharmaceutical preparations containing these
JP3668291B2 (en) * 1995-06-16 2005-07-06 久光製薬株式会社 Novel piperidine derivatives
GB9624482D0 (en) 1995-12-18 1997-01-15 Zeneca Phaema S A Chemical compounds
JP4471404B2 (en) 1996-02-13 2010-06-02 アストラゼネカ ユーケイ リミテッド Quinazoline derivatives as VEGF inhibitors
KR100489174B1 (en) 1996-03-05 2005-09-30 제네카-파마 소시에떼아노님 4-anilinoquinazoline derivatives
GB9718972D0 (en) 1996-09-25 1997-11-12 Zeneca Ltd Chemical compounds
UA56185C2 (en) 1996-09-30 2003-05-15 Пфайзер Інк. Aralkyl- and aralkylidene heterocyclic lactams and imids, a pharmaceutical composition and a treatment method
TW577875B (en) * 1997-01-31 2004-03-01 Shionogi & Co Pyrrolidine derivatives with inhibitory activity for phospholipase A2
GB9714249D0 (en) 1997-07-08 1997-09-10 Angiogene Pharm Ltd Vascular damaging agents
GB9900334D0 (en) 1999-01-07 1999-02-24 Angiogene Pharm Ltd Tricylic vascular damaging agents
GB9900752D0 (en) 1999-01-15 1999-03-03 Angiogene Pharm Ltd Benzimidazole vascular damaging agents
CN1321153A (en) * 1999-07-01 2001-11-07 杰龙公司 Telomerase inhibitors and method of their use
TW593293B (en) * 1999-08-23 2004-06-21 Kyorin Seiyaku Kk Substituted benzylthiazolidine-2,4-dione derivatives
DE60020381T2 (en) * 1999-08-23 2006-01-26 Kyorin Pharmaceutical Co., Ltd. SUBSTITUTED BENZYLTHIAZOLIDINE-2,4-DION DERIVATIVES
WO2001034133A2 (en) 1999-11-11 2001-05-17 Eli Lilly And Company Oncolytic combinations for the treatment of cancer
BR0111230A (en) 2000-05-31 2003-06-10 Astrazeneca Ab Compound, and, use and process for the preparation thereof
SK52003A3 (en) 2000-07-07 2003-07-01 Angiogene Pharm Ltd Colchinol derivatives as angiogenesis inhibitors, method for their preparation and pharmaceutical composition comprising the same
BR0112224A (en) 2000-07-07 2003-06-10 Angiogene Pharm Ltd Compound, pharmaceutical composition, use of a compound or a pharmaceutically acceptable salt, solvate or prodrug thereof, and process for preparing a compound
US6452014B1 (en) * 2000-12-22 2002-09-17 Geron Corporation Telomerase inhibitors and methods of their use
EA011807B1 (en) 2002-07-10 2009-06-30 Лаборатуар Сероно Са Azolidinone-vinyl fused-benzene derivatives
WO2004093809A2 (en) * 2003-04-18 2004-11-04 Incyte San Diego Incorporated Substituted isochroman compounds for the treatment of metabolic disorders, cancer and other diseases
EP1751133B1 (en) * 2004-04-28 2010-04-14 Vertex Pharmaceuticals Incorporated Compositions useful as inhibitors of rock and other protein kinases
WO2006069186A2 (en) 2004-12-22 2006-06-29 The Ohio State Research Foundation Small molecule bcl-xl/bcl-2 binding inhibitors
WO2009064486A2 (en) * 2007-11-15 2009-05-22 Musc Foundation For Research Development Inhibitors of pim protein kinases, compositions, and methods for treating cancer
TWI461423B (en) * 2008-07-02 2014-11-21 Astrazeneca Ab Thiazolidinedione compounds useful in the treatment of pim kinase related conditions and diseases

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11034669B2 (en) 2018-11-30 2021-06-15 Nuvation Bio Inc. Pyrrole and pyrazole compounds and methods of use thereof
WO2023039170A1 (en) * 2021-09-09 2023-03-16 Musc Foundation For Research Development Selective targeting of cd38 activity as an immunostimulatory and antitumor strategy

Also Published As

Publication number Publication date
CA2729557A1 (en) 2010-01-07
TW201004949A (en) 2010-02-01
EA201100119A1 (en) 2011-08-30
IL210127A0 (en) 2011-02-28
HN2010002786A (en) 2013-01-28
BRPI0914599A2 (en) 2017-06-06
UY31952A (en) 2010-01-29
WO2010001169A2 (en) 2010-01-07
KR20110031367A (en) 2011-03-25
ZA201100844B (en) 2011-10-26
EP2310010A2 (en) 2011-04-20
US20110218182A1 (en) 2011-09-08
CR20110016A (en) 2011-03-11
CN102137666B (en) 2014-03-12
CL2010001636A1 (en) 2011-07-15
JP5261575B2 (en) 2013-08-14
DOP2010000408A (en) 2011-02-28
JP2013139459A (en) 2013-07-18
WO2010001169A3 (en) 2010-08-05
CO6341555A2 (en) 2011-11-21
AR072791A1 (en) 2010-09-22
JP2011526616A (en) 2011-10-13
MX2010014233A (en) 2011-03-25
AU2009265362A1 (en) 2010-01-07
TWI461423B (en) 2014-11-21
PE20120304A1 (en) 2012-04-22
MY155961A (en) 2015-12-31
ECSP10010735A (en) 2011-01-31
EA018989B1 (en) 2013-12-30
NZ590859A (en) 2012-08-31
NI201100007A (en) 2011-12-15
CN102137666A (en) 2011-07-27
US8901307B2 (en) 2014-12-02
SV2011003786A (en) 2011-05-13
CN103804371A (en) 2014-05-21
AU2009265362B2 (en) 2012-07-19

Similar Documents

Publication Publication Date Title
US8901307B2 (en) Chemical compounds 251
US11390618B2 (en) Inhibitors of cyclin-dependent kinases
JP7093438B2 (en) ERK1 and ERK2 heterocyclic inhibitors and their use in cancer treatment
US7399780B2 (en) 3-Heterocyclyl-indole inhibitors of glycogen synthase kinase-3
US11713312B2 (en) Substituted bicyclic compounds as farnesoid X receptor modulators
KR20010031896A (en) Aminothiazole inhibitors of cyclin dependent kinases
CN110156770A (en) Aminopyrazole derivatives as TAM race kinase inhibitor
US10934282B2 (en) Heteroaromatic modulators of the retinoid-related orphan receptor gamma
US12227496B2 (en) Substituted bicyclic compounds as farnesoid X receptor modulators
KR20220152159A (en) Novel heterocyclic compound and use thereof
WO2022130352A1 (en) Novel compounds suitable for the treatment of dyslipidemia
HK40005345A (en) Heteroaromatic modulators of the retinoid-related orphan receptor gamma

Legal Events

Date Code Title Description
AS Assignment

Owner name: ASTRAZENECA PHARMACEUTICALS LP, DELAWARE

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:READ, JON;DAKIN, LESLIE;DOWLING, JAMES EDWARD;AND OTHERS;SIGNING DATES FROM 20110412 TO 20110505;REEL/FRAME:033953/0017

Owner name: ASTRAZENECA AB, SWEDEN

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:ASTRAZENECA PHARMACEUTICALS LP;REEL/FRAME:033953/0061

Effective date: 20110510

STCB Information on status: application discontinuation

Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION