WO2009012375A2 - Squarate kinase inhibitors - Google Patents

Squarate kinase inhibitors Download PDF

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WO2009012375A2
WO2009012375A2 PCT/US2008/070312 US2008070312W WO2009012375A2 WO 2009012375 A2 WO2009012375 A2 WO 2009012375A2 US 2008070312 W US2008070312 W US 2008070312W WO 2009012375 A2 WO2009012375 A2 WO 2009012375A2
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amino
cyclobut
pyridin
ylamino
ene
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PCT/US2008/070312
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French (fr)
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WO2009012375A3 (en
Inventor
Frank Eldridge Lovering
Steven John Kirincich
Weiheng Wang
Jean-Baptiste Telliez
Lynn Resnick
Joan E. Sabalski
Annette L. Banker
John Butera
Iain Mcfadyen
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Wyeth
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    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/44—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having three double bonds between ring members or between ring members and non-ring members
    • C07D207/444—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having three double bonds between ring members or between ring members and non-ring members having two doubly-bound oxygen atoms directly attached in positions 2 and 5
    • C07D207/456—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having three double bonds between ring members or between ring members and non-ring members having two doubly-bound oxygen atoms directly attached in positions 2 and 5 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 other ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no 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
    • C07D211/56—Nitrogen atoms
    • C07D211/58—Nitrogen atoms attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole 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
    • C07D231/38—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/42—One nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
    • C07D261/10—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more 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
    • C07D261/14—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the invention relates to squarate kinase inhibitors, and methods for making and using them.
  • Mitogen activated protein (MAP) kinases are a large and diverse group of Ser/Thr kinases separated into three major subgroups, which include the extracellular signal regulated kinases (ERKs), the c-Jun N-terminal kinases (JNKs)/stress-activated protein kinases (JNKs) and p38/reactivating kinases (RK).
  • ERKs extracellular signal regulated kinases
  • JNKs c-Jun N-terminal kinases
  • JNKs stress-activated protein kinases
  • RK p38/reactivating kinases
  • the ERKs are activated by mitogens and growth factors, whereas the INKs/SAPKs and p38/RK are activated by bacterial lipopolysaccharide (LPS, interleukin-1 (IL-I), tumor necrosis factor- ⁇ (TNF- ⁇ ) and cellular stresses such as heat shock, osmotic shock, or UV damage. Exposure of cells to these factors results in the increased production of proinflammatory cytokines.
  • LPS bacterial lipopolysaccharide
  • IL-I interleukin-1
  • TNF- ⁇ tumor necrosis factor- ⁇
  • UV damage cellular stresses
  • SB203580 also prevents the activation of MAP kinase activated protein kinase 2 (MK2, MAPKAPK 2), suggesting that this kinase is activated by p38 (see, e.g., Cuenda, A., et al. (1995) FEBS Letters 364, 229-233, which is incorporated by reference in its entirety).
  • mice engineered to be homozygously-deficient in MK2 show a reduction in TNF- ⁇ , interferon- ⁇ , IL-I ⁇ , and IL-6 production and an increased rate of survival upon challenge with LPS, suggesting that this enzyme is a key component in the inflammatory process and a potential target for anti-inflammatory therapy (Kotlyarov, A., et al. (1999) Nat. Cell. Biol. 1, 94-97, which is incorporated by reference in its entirety).
  • Activation of MK2 results in the production of cytokines by regulating the translation and or stability of the encoding mRNAs through the AU- rich elements of the 3 '-untranslated regions of the gene (Neininger, A., et al.
  • MK2 also phosphorylates the transcription factor CREB, as well as leukocyte specific protein- 1 and heat shock protein 25/27, which are involved in the regulation of actin polymerization and cell migration. See, e.g., Tan, Y., et al. (1996) EMBO J. 15, 4629-4642; Lavoie, J. et al. (1993) J. Biol. Chem. 268, 24210-24214; Stokoe, D. et al. (1992) FEBS Letters 313, 307-313; Ben-Levy, R., et al. (1995) EMBO J.
  • MK2 is a multi-domain protein consisting of an N-terminal proline-rich domain, a catalytic domain, an autoinhibitory domain and at the C-terminus a nuclear export signal (NES) and nuclear localization signal (NLS).
  • NES nuclear export signal
  • NLS nuclear localization signal
  • MK2 is located in the nucleus of the cell and upon binding and phosphorylation by p38, the MK2 NES becomes functional and both kinases are co-transported out of the nucleus to the cytoplasm (see, e.g., Stokoe, D., et al. (1992) EMBO J. 11, 3985-3994, which is incorporated by reference in its entirety).
  • transport of the MK2/p38 complex does not require catalytically active MK2, as the active site mutant, Asp207Ala, is still transported to the cytoplasm.
  • Certain squarate compounds are kinase inhibitors.
  • they are inhibitors of MK2, also known as MAPKAP kinase 2.
  • the present invention provides a compound of Formula (I):
  • H ⁇ t is a heteroaryl group or a heterocyclyl group, wherein at least one ring atom in said heteroaryl group or said heterocyclyl group is N, and wherein Het is optionally substituted by 1-4 substituents independently selected from R 5 ;
  • R 4 is cycloalkyl, cycloalkenyl, or heterocyclyl, each of which is optionally substituted with 1-5 substituents independently selected from R a ; or R 4 is -C(R')(R 2 )R 3 ; or R 4 is C 1-6 alkyl or C 2-6 alkenyl, wherein said C 1-6 alkyl and C 2-6 alkenyl are each optionally substituted by 1 or 2 R ⁇ groups;
  • R 9 is H, alkyl, cycloalkyl, or perfluoroalkyl
  • R 10 is H, alkyl, cycloalkyl, or perfluoroalkyl
  • R 4 and R 9 taken together with the nitrogen atom to which they are attached are 4- to 7- membered heterocyclyl optionally substituted with 1-5 substituents independently selected from
  • R a ; or R 9 and R 10 taken together are -(CR 7 R 8 ) p -, wherein p is 1, 2, or 3;
  • R 1 is -H, halogen, -CN, -CHO, C 1 -C 6 alkyl, C 1 -C 6 perfluoroalkyl, C 2 -C 6 alkenyl,
  • the present invention provides a compound of Formula (I), wherein:
  • Het can be a heteroaryl group or a heterocyclyl group, where at least one ring atom is N, and where Het is optionally substituted by 1-4 substituents independently selected from R 5 .
  • R 4 can be -C(R')(R 2 )R 3 , or R 4 can be cycloalkyl, cycloalkenyl, or heterocyclyl, each of which is optionally substituted with 1-5 substituents independently selected from R a ;
  • R 9 is H, alkyl, cycloalkyl, or perfluoroalkyl
  • R 10 is H, alkyl, cycloalkyl, or perfluoroalkyl; alternatively, R 4 and R 9 can be taken together with the nitrogen atom to which they are attached to form a 4- to 7- membered heterocyclyl optionally substituted with 1-5 substituents independently selected from R a . or R 9 and R 10 taken together are -(CR 7 R 8 ) P -, wherein p is 1, 2, or 3;
  • R 1 can be -H, halogen, -CN, -CHO, C 1 -C 6 alkyl, C 1 -C 6 perfluoroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkenyl, aryl, heteroaryl, heterocyclyl, -C(O)-R b , -C(O)O-R", -C(O)N(R 7 )-R b , -SO m -R b , -SO 2 -N(R 7 )-R b , -(CR 7 R 8 ) n OR 7 , or -C(O)N(R 7 )R 8 .
  • R b can be -H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkenyl, -(CH 2 ) n -aryl, -(CH 2 ) n -heteroaryl, or -(CH 2 ) n -heterocyclyl.
  • each occurrence of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclyl can be optionally substituted with 1-5 substituents independently selected from R a .
  • R 2 can be -H, halogen, -CN, -CHO, C 1 -C 6 alkyl, C 1 -C 6 perfluoroalkyl, C 2 -C 6 alkenyl,
  • R c can be -H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkenyl, -(CH 2 ) n -aryl, -(CH 2 ) n -heteroaryl, or -(CH 2 ) n -heterocyclyl.
  • each occurrence of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclyl can be optionally substituted with 1-5 substituents independently selected from R a .
  • R 3 can be -(CR 7 R 8 ) n -aryl, -(CR 7 R 8 ) n -heteroaryl, -(CR 7 R 8 ) n -(C 3 -C 8 cycloalkyl), or -(CR 7 R 8 ) n -heterocyclyl.
  • R 3 can be optionally substituted with 1-5 substituents independently selected from R a .
  • Each R 5 can be halogen, oxo, -CN, -CHO, -OH, -NO 2 , -N 3 , -OCF 3 , -OR 7 , C 1 -C 6 alkyl, C 1 -C 6 perfluoroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl,
  • R d can be -H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkenyl, -(CH 2 ) n -aryl, -(CH 2 ) n -heteroaryl, or -(CH 2 ) n -heterocyclyl.
  • Each R 5 can be, independently, optionally substituted with 1-5 substituents independently selected from R a .
  • Each R 7 can be -H, C 1 -C 6 perfluoroalkyl, -(CH 2 ) n -(C 1 -C 6 alkyl), -(CH 2 ) n -(C 3 -C 8 cycloalkyl), -(CH 2 ) n -(C 3 -C 8 cycloalkenyl), -(CH 2 ) n -aryl, -(CH 2 ) n -heteroaryl, or -(CH 2 ) n -heterocyclyl.
  • Each R 7 can be optionally substituted by 1 to 3 substituents selected from the group consisting of halogen, oxo, -CN, -CHO, -CF 3 , -OH, -NO 2 , -N 3 , C 1 -C 6 alkyl, -OCF 3 , -0-(C 1 -C 6 alkyl), -0-(C 3 -C 8 cycloalkyl), -0-(C 3 -C 8 cycloalkenyl), -NH 2 , -NH(C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl) 2 , -NHC(O)-(C 1 -C 6 alkyl), -SO m (C 1 -C 6 alkyl), -SO m NH(C,-C 6 alkyl), and -SO m N(C 1 -C 6 alkyl) 2 .
  • substituents selected from the group consisting of halogen,
  • Each R 8 can be -H, C 1 -C 6 perfluoroalkyl, -(CH 2 ) n -(C 1 -C 6 alkyl), -(CH 2 ) n -(C 3 -C 8 cycloalkyl), -(CH 2 ) n -(C 3 -C 8 cycloalkenyl), -(CH 2 ) n -aryl, -(CH 2 ) n -heteroaryl, or -(CH 2 ) n -heterocyclyl.
  • Each R 8 can be optionally substituted by 1 to 3 substituents selected from the group consisting of halogen, oxo, -CN, -CHO, -CF 3 , -OH, -NO 2 , -N 3 , C 1 -C 6 alkyl, -OCF 3 , -0-(C 1 -C 6 alkyl), -0-(C 3 -C 8 cycloalkyl), -0-(C 3 -C 8 cycloalkenyl), -NH 2 , -NH(C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl) 2 , -NHC(O)-(C 1 -C 6 alkyl), -SO m (C 1 -C 6 alkyl), -SO m NH(C 1 -C 6 alkyl), and -SO m N(C 1 -C 6 alkyl) 2 .
  • R e can be -H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkenyl, -(CH 2 ) n -aryl, -(CH 2 ) n -heteroaryl, or -(CH 2 ) n -heterocyclyl.
  • Each n, independently, is O, 1, 2, 3 or 4.
  • Each m, independently, is O, 1, or 2.
  • the present invention provides a compound of Formula (I), wherein:
  • Het is pyridin-4-yl optionally substituted by 1-4 substituents independently selected from R 5 ;
  • R 4 is -C(R')(R 2 )R 3 , or R 4 is cycloalkyl, cycloalkenyl, or heterocyclyl, each of which is optionally substituted with 1-5 substituents independently selected from R a ; or R 4 and R 9 taken together with the nitrogen atom to which they are attached are 4- to 7- membered heterocyclyl optionally substituted with 1-5 substituents independently selected from R a ;
  • R 1 is -H, halogen, -CN, -CHO, C 1 -C 6 alkyl, C 1 -C 6 perfluoroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkenyl, aryl, heteroaryl, heterocyclyl, -C(0)-R b , -C(0)0-R b , -C(0)N(R 7 )-R b , -SO m -R b , -SO 2 -N(R 7 )-R b , -(CR 7 R s ) n -OR 7 , or -C(O)N(R 7 )R 8 ; wherein R b is -H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -
  • each R 8 independently, is optionally substituted by 1 to 3 substituents selected from the group consisting of halogen, oxo, -CN, -CHO, -CF 3 , -OH, -NO 2 , -N 3 , C 1 -C 6 alkyl, -OCF 3 , -0-(C 1 -C 6 alkyl), -0-(C 3 -C 8 cycloalkyl), -0-(C 3 -C 8 cycloalkenyl), -NH 2 , -NH(C 1 -C 6 alkyl), -
  • R 9 is H, alkyl, cycloalkyl, or perfluoroalkyl
  • R 10 is H, alkyl, cycloalkyl, or perfluoroalkyl; or R 9 and R 10 taken together are -(CR 7 R 8 ) P -, wherein p is 1, 2, or 3; each R a , independently, is halogen, oxo, -CN, -CHO, -OH, -NO 2 , -N 3 , -OCF 3 , C 1 -C 6 alkyl, C 1 -C 6 perfluoroalkyl, -(CH 2 ) n -(C 3 -C 8 cycloalkyl), -(CH 2 ) n -(C 3 -C 8 cycloalkenyl), -(CH 2 ) n CO 2 R 8 , -(CH 2 ) n -aryl, -(CH 2 ) n -heteroaryl, -(CH 2 ) n -heterocyclyl, -(CH 2 ) n
  • the compound can be in the form of a pharmaceutically acceptable salt.
  • the compound is not 3-(5-bromo-pyridin-3-ylamino)-4-(l- phenylethylamino)cyclobut-3-ene-1,2-dione, 3-(l-phenylethylamino)-4-(pyridin-4-ylamino)- cyclobut-3-ene-1,2-dione, 3-(bicyclo[2.2.1]hept-2-ylamino)-4-(pyridin-4-ylamirio)-cyclobut-3- ene-1,2-dione; quadratic acid 1,2-bis(pyridyl)amide, quadratic acid 1,2- bis(pyridylmethylene)amide; 3-chloro-N-(l- ⁇ [3,4-dioxo-2-(5-pyrimidinylamino)-1-cyclobuten- 1 -yl] amino ⁇ -2 ,2-dimethylpropyl)benzamide, N-( 1 - ⁇ [3
  • Het is 4-hydroxy-2-oxo-N-methyl-1,2-dihydropyridm-5-yl, S-dimethylaminocarbonyM-hydroxypyridin-S-yl, 5-hydroxy-6-
  • R 4 is neither 1,2-dimethylpropyl nor 1-phenylpropyl.
  • Het is pyridin-4-yl optionally substituted by 1-4 substituents independently selected from R 5 .
  • R 4 , R 9 , and R 10 can each be defined as above.
  • the compound can be in the form of a pharmaceutically acceptable salt.
  • the compound is not 3 ⁇ (5-bromo-pyridin-3-ylamino)-4-(l- phenylethylamino)cyclobut-3-ene-1,2-dione, 3-(l-phenylethylamino)-4-(pyridin-4-ylamino)- cyclobut-3-ene-1,2-dione, or 3-(bicyclo[2.2.1]hept-2-ylamino)-4-(pyridin-4-ylamino)-cyclobut- 3-ene-1,2-dione.
  • Het is pyridinyl, piperidinyl, pyrimidinyl, oxazolinyl, pyrazolyl, isoquinolinyl, or quinolinyl, optionally substituted by 1-4 substituents independently selected from R 5 .
  • Het is pyridin-4-yl optionally substituted by 1-4 substituents independently selected from R 5 .
  • Het is pyridin-4-yl optionally substituted at the 2-position by R 5 .
  • R 5 can be -OR 7 , -N(R 7 )R 8 , aryl, heteroaryl, or -N(R 7 )C(O)R 8 .
  • R 4 can be -C(R')(R 2 )R 3 .
  • each R 5 is, independently, methyl, methoxy, hydroxyl, chloro, bromo, carboxamide, azido, tert- butoxycarbonyl, 4-benzyl-1H-1,2,3-triazol-1-yl, morpholin-4-yl, phenyl, 2-fluorophenyl, 3- flurophenyl, 4-chlorophenyl, 4-methylphenyl, 3-methylphenyl, l-benzofuran-2-yl, furan-2-yl, 3- trifluoromethylphenyl, 4-trifluoromethylphenyl, 3-methoxyphenyl, 4-(hydroxymethyl)phenyl, 4- (hydroxymethyl)-1H-l,2,3-triazol-1-yl, 4-phenyl-1H-1,2,3-triazol-1-yl, 4- (cyclopentylaminocarbonyl)phenyl, 4-acetamidophenyl, 2-(4-chlorophenyl)vinyl, phen
  • R 2 is -H, C 1 -C 6 alkyl, or -C(O)N(R 7 )-R c . In some embodiments, R 2 is -H, methyl, or -C(O)NH 2 , or -C(O)NH-(C 1 -C 6 alkyl).
  • R 3 is aryl, heteroaryl, C 3 -C 8 cycloalkyl, or heterocyclyl, wherein R 3 is optionally substituted with 1-5 substituents independently selected from R a . In some embodiments, R 3 is aryl optionally substituted with 1-5 substituents independently selected from R a . In some embodiments, R 3 is phenyl optionally substituted with 1-5 substituents independently selected from R a .
  • R 3 is phenyl optionally substituted with 1-5 substituents selected from C 1 -C 6 alkyl, C 1 -C 6 perfluoroalkyl, halogen, -0-(C 1 -C 6 alkyl), -OH, -NO 2 , -CN, -N(R 7 )R e , -(CH 2 ) n -C(O)OR 8 , aryl, heteroaryl, or heterocyclyl.
  • R 3 is -(CR 7 R 8 ) n -aryl, -(CR 7 R 8 ) n -heteroaryl, -(CR 7 R 8 ) n -(C 3 -C 8 cycloalkyl), or -(CR 7 R 8 ) n -heterocyclyl; wherein R 3 is optionally substituted with 1, 2, or 3 substituents independently selected from R a .
  • R 4 is -C(R 1 )(R 2 )R 3 .
  • R 4 and R 9 taken together with the nitrogen atom to which they are attached are 4- to 7- membered heterocyclyl optionally substituted with 1-5 substituents independently selected from R a .
  • R 1 is -H. In some embodiments, R 2 is-H, C 1 -C 6 alkyl, or -C(O)N(R 7 )-R c . In some embodiments, R 2 is-H, methyl, or -C(O)NH 2 , or -C(O)NH-(C 1 -C 6 alkyl). In some embodiments, R 1 is -H or C 1 -C 6 alkyl. In some embodiments, R 1 is -H or C 1 -C 6 alkyl; R 2 is -H, C 1 -C 6 alkyl, or -C(O)N(R 7 )-R c ;
  • R 3 is phenyl optionally substituted with 1-5 substituents independently selected from R a ; and Het is pyridin-4-yl optionally substituted at the 2-position by aryl, heteroaryl, -NH-aryl, or -NH-heteroaryl, wherein aryl and heteroaryl are each optionally substituted with 1-5 substituents independently selected from R a .
  • R 1 is -H or C 1 -C 6 alkyl
  • R 2 is -CH 3 , -CH 2 CH 3 , -CH 2 OH,
  • R 3 is phenyl optionally substituted with 1-5 substituents independently selected from C 1 -C 6 alkyl, halogen, hydroxy, -NHC(O)NHCH 3 , aminophenyl, acetylamino, phenyl, and furyl; and Het is pyridin-4-yl optionally substituted at the 2-position by methoxyphenyl, thienyl, pyridinyl, hydroxymethylphenylamino, aminocarbonylphenylamino, pyridinylamino, fluorophenyl, pyrimidinylamino, pyrazinyl, or furyl
  • Het is pyridin-4-yl, isooxazol-5-yl, piperidin-4-yl, pyrimidin-4-yl, 1H-pyrazol-3-yl, isoquinolin-5-yl, or thieno[2,3-d]pyridin-4-yl, each of which is optionally substituted by 1 to 4 independently selected R 5 groups.
  • Het is pyridin-4-yl, isooxazol-5-yl, pi ⁇ eridin-4-yl, pyrimidin-4-yl, 1H-pyrazol-3-yl, isoquinolin-5-yl, or thieno[2,3-d]pyridin-4-yl, each of which is optionally substituted by a R 5 group.
  • each R 7 in each R 5 group is -H.
  • each R a in each R 5 group independently, is halogen, C 1 -C 6 alkyl,
  • each R a is, independently, halogen, -CN, -OH, -NO 2 , C 1 -C 6 alkyl, C 1 -C 6 perfluoroalkyl, -(CH 2 ) n -(C 3 -C 8 cycloalkyl), -(CH 2 ) n -aryl, -(CH 2 ) n -heteroaryl, -(CH 2 ) n -heterocyclyl, -O-R e , -C(O)N(R 7 )-R e , -N(R 7 )R e , -N(R 7 )C(0)-R e , -N(R 7 )-C(O)-N(R 7 )(R 8 ), -N(R 7 )-SO m -R e , or -C(O)O-R 6 .
  • each R d in each R 5 group is, independently, -H, C 1 -C 6 alkyl, -(CH 2 ) n -aryl, or -(CH 2 ) n -heteroaryl.
  • each R e in each R 5 group is, independently, -H, C 1 -C 6 alkyl, or C3-C8 cycloalkyl.
  • each n, independently, is O or 1.
  • each m independently, is O.
  • each R c is -H, C 1 -C 6 alkyl, or -(CH 2 ) n -heterocyclyl; each R 7 is, independently, -H or -(CH 2 ) n -(C 1 -C 6 alkyl); each n, independently, is 0 or 1; and each R 8 is, independently, -H, -(CH 2 ) n -(C 1 -C 6 alkyl), -(CH 2 ) ⁇ -(C 3 -C 8 cycloalkyl), -(CH 2 ) n -aryl, or -(CH 2 ) n -heteroaryl; wherein each of which is optionally substituted by a substituent selected from halogen.
  • each R e is -H or C 1 -C 6 alkyl
  • each R 7 independently, is -H or C 1 -C 6 alkyl
  • each n independently, is 0 or 1
  • each R 8 independently, is -H or C 1 -C 6 alkyl.
  • each R c in each R 2 group is -H, C 1 -C 6 alkyl, or -(CH 2 ) n -heterocyclyl.
  • each R 7 in each R 2 group is, independently, -H or -(CH 2 ) n -(C 1 -C 6 alkyl).
  • each R 8 in each R 2 is, independently, -H, -(CH 2 )n-(C 1 -C 6 alkyl), -(CH 2 ) n -(Cs-C 8 cycloalkyl), -(CH 2 ) n -aryl, or -(CH 2 ) n -heteroaryl; wherein each of which is optionally substituted by a substituent selected from halogen.
  • each R a in each R 3 group is, independently, halogen, -CN, -OH, -NO 2 , C 1 -C 6 alkyl, C 1 -C 6 perfluoroalkyl, -(CH 2 ) n -(C 3 -C 8 cycloalkyl), -(CH 2 ) n -aryl, -(CH 2 ) n -heteroaryl, -(CH 2 ) n -heterocyclyl, -O-R e , -C(O)N(R 7 )-R e , -N(R 7 )R e , -N(R 7 )C(O)-R e , -N(R 7 )-C(O)-N(R 7 )(R 8 ), -N(R 7 ) n SO m -R e , or -C(O)O-R 6 .
  • each R e in each R 3 group is -H or C 1 -C 6 alkyl.
  • each R 7 in each R 3 group is -H or C 1 -C 6 alkyl.
  • each R 8 in each R 3 group is -H or C 1 -C 6 alkyl.
  • each R e in each R 3 group is -H or methyl.
  • each R 7 in each R 3 group independently, is -H or methyl.
  • each R 8 in each R 3 group independently, is -H or methyl.
  • each R c is -H, C 1 -C 6 alkyl, or -(CH 2 ) n -heterocyclyl; each R 7 is, independently, -H or -(CH 2 ) n -(C 1 -C 6 alkyl); each n, independently, is 0 or 1 ; and each R 8 is, independently, -H, -(CH 2 ) n -(C 1 -C 6 alkyl), -(CH 2 ) n -(C 3 -C 8 cycloalkyl), -(CH 2 ) n -aryI, or -(CH 2 ) n -heteroaryl; wherein each of which is optionally substituted by a substituent selected from halogen.
  • each R e is -H or C 1 -C 6 alkyl
  • each R 7 independently, is -H or C 1 -C 6 alkyl
  • each n independently, is 0 or 1
  • each R 8 independently, is -H or C 1 -C 6 alkyl.
  • R 4 is -CCR 1 XR 2 )R 3 ;
  • R 4 and R 9 taken together with the nitrogen atom to which they are attached are 4- to 7- membered heterocyclyl optionally substituted with 1-5 substituents independently selected from R a .
  • R 1 is -H or C 1 -C 6 alkyl
  • R 2 is -H, C 1 -C 6 alkyl, aryl, heteroaryl, -C(O)-R c , -C(O)O-R c , -(CR 7 RVOR 7 , or -C(O)N(R 7 )R 8
  • each R c is -H, C 1 -C 6 alkyl, or -(CH 2 ) n -heterocyclyl
  • each R 7 is, independently, -H or -(CH 2 ) n -(C 1 -C 6 alkyl)
  • each R 8 is, independently, -H, -(CH 2 ) n -(C 1 -C 6 alkyl), -(CH 2 ) n -(C 3 -C 8 cycloalkyl),
  • R 3 is -(CR 7 R 8 ) n -aryl, -(CR 7 R 8 ) n -heteroaryl, -(CR 7 R 8 ⁇ -(C 3 -C 8 cycloalkyl), or -(CR 7 R 8 ) n -heterocyclyl; wherein R 3 is optionally substituted with 1, 2, or 3 substituents independently selected from R a ; each R a is, independently, halogen, -CN, -OH, -NO 2 , C 1 -C 6 alkyl, C 1 -C 6 perfluoroalkyl, -(CH 2 ) n -(C 3 -C 8 cycloalkyl), -(CH 2 ) n -aryl, -(CH 2 ) n -heteroaryl, -(CH 2 )n-heterocyclyl, -O-R e , -C(0)N(R 7 )-R e
  • R 1 is -H or C 1 -C 6 alkyl
  • R 2 is -H, C 1 -C 6 alkyl, or -C(0)N(R 7 )-R°;
  • R 3 is phenyl optionally substituted with 1-5 substituents independently selected from R a ;
  • Het is pyridin-4-yl optionally substituted at the 2-position by aryl, heteroaryl, -NH-aryl, or -NH-heteroaryl, wherein aryl and heteroaryl are each optionally substituted with 1-5 substituents independently selected from R a .
  • R 1 is -H or C 1 -C 6 alkyl
  • R 2 is -CH 3 , -CH 2 CH 3 , -CH 2 OH, -C(O)NH 2 , -C(O)NH-(C 1 -C 6 alkyl), -C(O)NH-(CH 2 ) n -chlorophenyl, -C(O)NH-(CH 2 ) n -pyridyl, or -C(CH 3 ) 2 OH;
  • R 3 is phenyl optionally substituted with 1-5 substituents independently selected from C 1 -C 6 alkyl, halogen, hydroxy, -NHC(O)NHCH 3 , aminophenyl, acetylamino, phenyl, and furyl; and Het is pyridin-4-yl optionally substituted at the 2- ⁇ osition by methoxyphenyl, thienyl, pyridinyl, hydroxymethylphenylamino, aminocarbonylphenylamino, pyridinylamino, fluorophenyl, pyrimidinylamino, pyrazinyl, or furyl.
  • Het can be ⁇ yridin-4-yl optionally substituted at the 2-position by R 5 ;
  • R 4 can be -C(R')(R 2 )R 3 , where R 1 is H and R 2 and R 3 are as defined above; and R 9 and R 10 are each H.
  • R 3 can be aryl optionally substituted with 1-5 substituents independently selected from R a .
  • the compound can be selected from the group consisting of: 2- ⁇ [3,4-dioxo-2 ⁇ (pyridin-4- ylamino)cyclobut- 1 -en- 1 -yl] amino ⁇ -2-phenyl-N-(pyridm-4-ylmethyl)acetamide, 2- ⁇ [3 ,4-dioxo- 2-(pyridin-4-ylamino)cyclobut- 1 -en- 1 -yl] amino ⁇ -N-isobutyl-2-phenylacetamide, 3 - [(3 - methylbenzyl)amino]-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2-dione, (2S)-2-(4-chlorophenyl)- 2- ⁇ [3,4-dioxo-2-(pyridin-4-ylamino)cyclobut-1-en-1-yl]amino ⁇ acetamide, 3- ⁇ [(1R)-1-
  • the compound can be selected from the group consisting of N-[2-(4-chlorophenyl)ethyl]- 2- ⁇ [3,4-dioxo-2-(pyridin-4-ylamino)cyclobut-1-en-1-yl]amino ⁇ -2-phenylacetamide, 3- ⁇ [(1R)-1- (4-bromophenyl)ethyl]amino ⁇ -4-(pyridin-4-ylamino)cyclobut-3-ene-1,2-dione, 3- ⁇ [(1S)-2- hydroxy- 1 -phenylethyl] amino ⁇ -4-(pyridin-4-ylamino)cyclobut-3 -ene- 1 ,2-dione, 2- ⁇ [3 ,4-dioxo- 2-(pyridin-4-ylamino)cyclobut- 1 -en- 1 -yl]amino ⁇ -N-methyl-2-phenylacetamide, 3- ⁇ [(1R
  • the compound can be selected from the group consisting of 3- ⁇ [(1R)-1- phenylpropyl] amino ⁇ -4-( ⁇ yridin-4-ylamino)cyclobut-3 -ene- 1 ,2-dione, 3- ⁇ [(1R)-1-(4- fluorophenyl)ethyl]amino ⁇ -4-(pyridin-4-ylamino)cyclobut-3-ene-1,2-dione, 3- ⁇ [l-(4- hydroxyphenyl)ethyl]amino ⁇ -4-(pyridin-4-ylamino)cyclobut-3-ene-1,2-dione, 2-(3-chloro-4- fluorophenyl)-2- ⁇ [3,4-dioxo-2-(pyridin-4-ylamino)cyclobut-1-en-1-yl]amino ⁇ acetamide, 2- ⁇ [3,4-dioxo-2-(pyridin-4-ylamino)cycl
  • the compound is selected from:
  • the compound is selected from:
  • the compound is selected from:
  • a pharmaceutical composition includes a pharmaceutically acceptable carrier and a compound having Formula (I) as defined above, or a pharmaceutically acceptable salt thereof.
  • a method of treating a patient in need of MK2 inhibition includes administering to the patient an amount effective for MK2 inhibition of a compound having Formula (T) as defined above, or a pharmaceutically acceptable salt thereof.
  • the patient can be in need of treatment or prevention of a TNF ⁇ mediated disease or disorder.
  • the TNF ⁇ mediated disease or disorder can be a connective tissue disorder, a joint disorder, a neoplasia disorder, a cardiovascular disorder, an otic disorder, an ophthalmic disorder, a respiratory disorder, a gastrointestinal disorder, an angiogenesis-related disorder, an immunological disorder, an allergic disorder, a nutritional disorder, an infectious disease, an endocrine disorder, a metabolic disorder, a neurological disorder, a neurodegenerative disorder, a psychiatric disorder, a hepatic disorder, a biliary disorder, a musculoskeletal disorder, a genitourinary disorder, a gynecologic disorder, an obstetric disorder, an injury, a trauma, a surgical disorder, a dental disorder, an oral disorder, a sexual dysfunction disorder, a dermatologic disorder, a hematological disorder, or a poisoning disorder.
  • the TNF ⁇ mediated disease or disorder can be arthritis, rheumatoid arthritis, spondyloarthopathies, gouty arthritis, osteoarthritis, systemic lupus erythematosus, juvenile arthritis, asthma, bronchitis, menstrual cramps, tendinitis, bursitis, connective tissue injuries or disorders, skin related conditions, psoriasis, eczema, burns, dermatitis, gastrointestinal conditions, inflammatory bowel disease, gastric ulcer, gastric varices, Crohn's disease, gastritis, irritable bowel syndrome, ulcerative colitis, cancer, colorectal cancer, herpes simplex infections, HIV, pulmonary edema, kidney stones, minor injuries, wound healing, vaginitis, candidiasis, lumbar spondylanhrosis, lumbar spondylarthrosis, vascular diseases, migraine headaches, sinus headaches, tension headaches, dental pain, periarteriti
  • the TNF ⁇ mediated disease or disorder can be rheumatoid arthritis, psoriasis, lupus, inflammatory bowel disease, asthma, or chronic obstructive pulmonary disease.
  • alkyl refers to a straight-chain or branched-chain alkyl radical containing 1 to 10, 1 to 6, or 1 to 4, carbon atoms.
  • examples of such radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl, octyl, decyl and the like.
  • Alkyl groups can be optionally substitued.
  • alkenyl refers to a straight-chain or branched-chain alkenyl radical containing 2 to 10, 2 to 6, or 2 to 4, carbon atoms.
  • examples of such radicals include ethenyl, E- and Z-propenyl, isopropenyl, E- and Z-butenyl, E- and Z-isobutenyl, E- and Z-pentenyl, decenyl and the like.
  • Alkenyl radicals can include more than one unsaturated bond, e.g., a butadienyl radical or but-1-yn-3-enyl radical. Alkenyl groups can be optionally substitued.
  • alkynyl refers to a straight-chain or branched-chain alkynyl radical containing 2 to 10, 2 to 6, or 2 to 4, carbon atoms.
  • examples of such radicals include ethynyl (acetylenyl), propynyl, propargyl, butynyl, hexynyl, decynyl and the like.
  • Alkynyl radicals can include more than one unsaturated bond, e.g., a butadiynyl radical or but-1- yn-3-enyl radical. Alkynyl groups can be optionally substitued.
  • cycloalkyl refers to a cyclic alkyl radical containing 3 to 10, 3 to 8, or 3 to 6, carbon atoms.
  • examples of such cycloalkyl radicals include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like; and bicylic groups including bicyclo[3.4.0]nonyl, bicyclo[2.2.2]octyl, norbornyl, spiro[4.5]decyl, and the like. Cycloalkyl groups can be optionally substitued.
  • cycloalkenyl refers to a cyclic carbocycle containing 4 to 10, 4 to 8, or 5 or 6, carbon atoms and one or more double bonds.
  • examples of such cycloalkenyl radicals include cyclopentenyl, cyclohexenyl, cyclopentadienyl, and bicyclic groups such as norbornenyl, and the like. Cycloalkenyl groups can be optionally substitued.
  • aryl refers to a carbocyclic aromatic group, and includes fused bicyclic or tricyclic systems
  • An aryl group can have from 6 to 14 carbon atoms m the ring system, or from 6 to 10 atoms in the ⁇ ng system In fused systems, one or more rings may not be aromatic, e g , mdanyl, or all ⁇ ngs may be aromatic, e g , naphthyl and anthracenyl
  • aryl groups include phenyl, naphthyl, mdenyl, mdanyl, azulenyl, fluorenyl, and anthracenyl
  • Aryl groups can be optionally substitued
  • heteroaryl refers to a heterocyclic aromatic group, and includes fused bicyclic or tricyclic systems
  • a heteroaryl group can have from 5 to 14 ⁇ ng members
  • one or more ⁇ ngs may not be aromatic, e g , indolmyl or benzodioxolyl, or all nngs may be aromatic, e g , benzimidazolyl, benzofuranyl, or dibenzofuranyl
  • heteroaryl groups include furyl, thienyl, pyridyl, pyrrolyl, oxazolyly, thiazolyl, lmidazolyl, pyrazolyl, 2- pyrazolmyl, pyrazolidnyl, isoxazolyl, lsothiazolyl, 1,2,3-oxadiazolyl, 1,2,3-tnazolyl, 1,3,4- thiadiazolyl, pyndazmyl, p
  • heterocyclyl refers to a saturated or unsaturated monocyclic, bicyclic or tricychc non-aromatic group including 1 to 5 heteroatoms selected from O, N, and S
  • the heteroatom can be an oxidized heteroatom, for example, when the heteroatom is N, it can be an N-oxide, or when the heteroatom is S, it can be a sulfoxide or sulfone
  • Bicyclic and tricyclic heterocyclyl groups can include an aromatic ⁇ ng, e g , 2,3-dihydrobenzofuranyl, or 2,3- dihydronaphtho[2,3-b]furanyl
  • a heterocyclyl group can have from 3 to 14 ⁇ ng members
  • a monocyclic heterocyclyl group can have from 3 to 8 ⁇ ng members, or from 3 to 6 ⁇ ng members
  • a bicyclic or tricyclic heterocyclyl group can have from 7 to 14 n
  • heterocyclyl groups include monocyclic groups such as, for example, morpholmo, tetrahydrofuranyl, pyrrolidmyl, 2,3-dihydropyrrolyl, piperidmyl, 1,4- dihydropyridmyl, tetrahydrothienyl, thiomorpholmo, tetrahydropyranyl, butyrolactonyl, caprolactonyl, caprolactamyl, succinimidyl, maleimidyl, 2,3-dihydropyranyl, 2,3- dihydropyrrolidyl, 1,2-dihydropyridinyl, maleimidiyl, and the like; bicyclic heterocyclyl groups including, for example, fused bicyclic groups (e.g., octahydrobenzofuranyl, octahydro-lff- indolyl, hexahydro-2J ⁇ -furo[2,3-
  • amino refers to a group of formula -NEk-
  • C n -C 1n' alkylamino refers to a group of formula — NH(alkyl), wherein the alkyl group has n' to m' carbon atoms.
  • di-C n -C m -alkylamino refers to a group of formula -N(alkyl) 2 , wherein each alkyl group independently has n' to m' carbon atoms.
  • C n - C n , ' alkoxy refers to a group of formula -O(alkyl), wherein the alkyl group has n' to m' carbon atoms.
  • diC n' -C m -alkylaminosulfonyl refers to a group of formula -
  • hydroxyl refers to a group of formula -OH.
  • treating refers to any indicia of success in amelioration of an injury, pathology, or condition, including any objective or subjective parameter such as abatement; remission; diminishing of symptoms or making the injury, pathology, or condition more tolerable to the patient; slowing in the rate of degeneration or decline; making the final point of degeneration less debilitating; or improving a subject's physical or mental well-being.
  • the treatment or amelioration of symptoms can be based on objective or subjective parameters; including the results of a physical examination, neurological examination, and/or psychiatric evaluation.
  • Treating includes inhibiting the symptoms of the disorder (slowing or arresting its development), providing relief from the symptoms or side-effects of the disorder (including palliative treatment), and/or relieving the symptoms of the disorder (causing regression).
  • the term “treating” includes the administration of the compounds of Formula (I) to a subject to alleviate, or to arrest or inhibit development of the symptoms or conditions associated with a disorder.
  • a skilled medical practitioner will know how to use standard methods to identify a subject in need of treatment.
  • the term “preventing” refers to preventing the onset of symptoms in a subject that may be predisposed to a disorder but does not yet experience or exhibit symptoms of the disorder (prophylactic treatment).
  • the term “preventing” includes the administration of the compounds of formula (I) to a subject to prevent or delay symptoms or conditions associated with a disorder.
  • a skilled medical practitioner will know how to use standard methods to identify a subject in need of prevention.
  • the compounds can be prepared in different isomeric forms, including stereoisomers (e.g., diastereomers, members of an enantiomeric pair, or mixtures of enantiomers, such as racemic mixtures; or as E-/Z-isomers differing in configuration about a double bond), or tautomers (e.g., forms that differ by location of a dissociable proton).
  • stereoisomers e.g., diastereomers, members of an enantiomeric pair, or mixtures of enantiomers, such as racemic mixtures; or as E-/Z-isomers differing in configuration about a double bond
  • tautomers e.g., forms that differ by location of a dissociable proton.
  • a reference to a compound or group of compounds, whether by name, structure or otherwise is intended to include all such forms.
  • certain compounds of the present invention may exist in solvated, for example hydrated, as well as unsolvated forms. It will further be understood that
  • Certain squarates can modulate (i.e., increase, decrease, or otherwise alter) the activity of protein kinases.
  • Protein kinases are a class of enzymes that catalyze the transfer of a phosphate group from ATP to a tyrosine, serine, threonine or histidine residue located on a protein substrate.
  • squarates can modulate the kinase activity of MK2 (MAPKAPK2).
  • MK2 is a direct substrate of p38 ⁇ and p38 ⁇ MAP kinases and is responsible for many of the signaling events that follow the activation of these MAPKs. Indeed, MK2 was the first substrate of p38 ⁇ to be identified. The physiological implications of MK2 activation are most clearly revealed by the targeted disruption of the MK2 gene in mice. MK2 deficient cells derived from mice have shown defects in motility, chemotaxis and cytokine production (Kotlyarov et al. Nat. Cell. Biol. 1999, which is incorporated by reference in its entirety).
  • AREs AU-rich elements
  • UTR 3' untranslated region
  • TNF ⁇ is a pro-inflammatory cytokine that is involved in inflammation in a number of disease states like rheumatoid arthritis (RA).
  • Protein therapeutics such as etanercept, are currently available to treat patients with RA or other inflammatory diseases.
  • small molecule that inhibits TNF ⁇ production is desirable, particularly an orally available small molecule.
  • TNF ⁇ mediated diseases or disorders are connective tissue and joint disorders, neoplasia disorders, cardiovascular disorders, otic disorders, ophthalmic disorders, respiratory disorders, gastrointestinal disorders, angiogenesis-related disorders, immunological disorders, allergic disorders, nutritional disorders, infectious diseases and disorders, endocrine disorders, metabolic disorders, neurological and neurodegenerative disorders, psychiatric disorders, hepatic and biliary disorders, musculoskeletal disorders, genitourinary disorders, gynecologic and obstetric disorders, injury and trauma disorders, surgical disorders, dental and oral disorders, sexual dysfunction disorders, dermatologic disorders, hematological disorders, or poisoning disorders.
  • TNF ⁇ mediated diseases or disorders are connective tissue and joint disorders, neoplasia disorders, cardiovascular disorders, otic disorders, ophthalmic disorders, respiratory disorders, gastrointestinal disorders, angiogenesis-related disorders, immunological disorders, allergic disorders, nutritional disorders, infectious diseases and disorders, endocrine disorders, metabolic disorders, neurological and neurodegenerative disorders, psychiatric disorders,
  • TNF ⁇ mediated diseases or disorders are arthritis, rheumatoid arthritis, spondyloarthopathies, gouty arthritis, osteoarthritis, systemic lupus erythematosus, juvenile arthritis, asthma, bronchitis, menstrual cramps, tendinitis, bursitis, connective tissue injuries or disorders, skin related conditions, psoriasis, eczema, burns, dermatitis, gastrointestinal conditions, inflammatory bowel disease, gastric ulcer, gastric varices, Crohn's disease, gastritis, irritable bowel syndrome, ulcerative colitis, cancer, colorectal cancer, herpes simplex infections, HIV, pulmonary edema, kidney stones, minor injuries, wound healing, vaginitis, candidiasis, lumbar spondylanhrosis, lumbar spondylarthrosis, vascular diseases, migraine headaches, sinus headaches, tension headaches, dental pain, periarteritis
  • diseases or disorders include rheumatoid arthritis (RA), psoriasis, lupus (SLE), inflammatory bowel disease (IBD), asthma or chronic obstructive pulmonary disease (COPD).
  • RA rheumatoid arthritis
  • SLE psoriasis
  • IBD inflammatory bowel disease
  • COPD chronic obstructive pulmonary disease
  • the disorder or disease is selected from rheumatoid arthritis, psoriasis, lupus, inflammatory bowel disease, asthma, and chronic obstructive pulmonary disease.
  • the present invention provides a kit comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and instructions, wherein said instructions comprise a direction to administer said compound, or pharmaceutically salt thereof, to a patient in need of treatment for a disease or disorder selected from arthritis, rheumatoid arthritis, spondyloarthopathies, gouty arthritis, osteoarthritis, systemic lupus erythematosus, juvenile arthritis, asthma, bronchitis, menstrual cramps, tendinitis, bursitis, connective tissue injuries or disorders, skin related conditions, psoriasis, eczema, bums, dermatitis, gastrointestinal conditions, inflammatory bowel disease, gastric ulcer, gastric varices, Crohn's disease, gastritis, irritable bowel syndrome, ulcerative colitis, cancer, colorectal cancer, herpes simplex infections, HTV, pulmonary edema, kidney stones, minor injuries, wound healing, va
  • the disorder or disease is selected from rheumatoid arthritis, psoriasis, lupus, inflammatory bowel disease, asthma, and chronic obstructive pulmonary disease.
  • the present invention provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in a method of treating a disease or disorder selected from arthritis, rheumatoid arthritis, spondyloarthopathies, gouty arthritis, osteoarthritis, systemic lupus erythematosus, juvenile arthritis, asthma, bronchitis, menstrual cramps, tendinitis, bursitis, connective tissue injuries or disorders, skin related conditions, psoriasis, eczema, burns, dermatitis, gastrointestinal conditions, inflammatory bowel disease, gastric ulcer, gastric varices, Crohn's disease, gastritis, irritable bowel syndrome, ulcerative colitis, cancer, colorectal cancer, herpes simplex infections, HIV, pulmonary edema, kidney stones, minor injuries, wound healing, vaginitis, candidiasis, lumbar spondylarthrosis, lumbar spondy
  • the disorder or disease is selected from rheumatoid arthritis, psoriasis, lupus, inflammatory bowel disease, asthma, and chronic obstructive pulmonary disease.
  • Compounds of Formula I can be used in the form of pharmaceutically acceptable salts derived from inorganic and/or organic acids and/or bases. Included among such acid salts are the following: acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfo ⁇ ate, nicotinate, oxalate, pamoate, pectinate,
  • Base salts include ammonium salts, alkali metal salts, such as sodium and potassium salts, alkaline earth metal salts, such as calcium and magnesium salts, salts with organic bases, such as dicyclohexylamine salts, N-methyl-D-glucamine, and salts with amino acids such as argmine, lysine, and so forth.
  • the basic nitrogen-containing groups can be quaternized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates, such as dimethyl, diethyl, dibutyl and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides, such as benzyl and phenethyl bromides or others. Water- or oil-soluble or dispersible products can be obtained in this way.
  • lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides
  • dialkyl sulfates such as dimethyl, diethyl, dibutyl and diamyl sulfates, long chain hal
  • the compound may be formulated into pharmaceutical compositions that may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir.
  • parenteral includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. See, for example, Remington: The Science and Practice of Pharmacy, 21st ed. 2005, Lippincott Williams & Wilkins, which is incorporated by reference in its entirety.
  • Pharmaceutical compositions can include a compound of Formula (I), or a pharmaceutically acceptable salt thereof, together with any pharmaceutically acceptable carrier.
  • the pharmaceutical composition consists essentially of a compound of Formula (I) and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition can consist of a compound of Formula (T) and a pharmaceutically acceptable carrier.
  • carrier includes acceptable adjuvants and vehicles.
  • Pharmaceutically acceptable carriers that may be used in the pharmaceutical compositions include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol or wool fat.
  • ion exchangers alumina, aluminum stearate, lecithin
  • serum proteins such as human serum albumin
  • buffer substances such as phosphates, glycine, sorb
  • the pharmaceutical compositions maybe in the form of a sterile injectable preparation, for example, a sterile injectable aqueous or oleaginous suspension.
  • This suspension maybe formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butanediol.
  • the acceptable vehicles and solvents that maybe employed are water, Ringer's solution or isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil maybe employed including synthetic mono- or di-glycerides.
  • Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions.
  • These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant.
  • compositions can be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions.
  • carriers which are commonly used include lactose or corn starch.
  • Lubricating agents such as magnesium stearate, are also typically added.
  • useful diluents include lactose and dried corn starch.
  • aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.
  • compositions may be administered in the form of suppositories for rectal administration.
  • suppositories for rectal administration.
  • suppositories can be prepared by mixing the agent with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and therefore will melt in the rectum to release the drug.
  • suitable non-irritating excipient include cocoa butter, beeswax or polyethylene glycols.
  • compositions may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.
  • Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically-transdermal patches may also be used.
  • the pharmaceutical compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers.
  • Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water.
  • the pharmaceutical compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers.
  • Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
  • the pharmaceutical compositions may be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, as solutions in isotonic, pH adjusted sterile saline, either with or without a preservative such as benzylalkonium chloride.
  • the pharmaceutical compositions may be formulated in an ointment such as petrolatum.
  • compositions may also be administered by nasal aerosol or inhalation through the use of a nebulizer, a dry powder inhaler or a metered dose inhaler.
  • a nebulizer a dry powder inhaler or a metered dose inhaler.
  • Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, or other conventional solubilizing or dispersing agents.
  • the amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated, and the particular mode of administration. It should be understood, however, that a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated. The amount of active ingredient may also depend upon the therapeutic or prophylactic agent, if any, with which the ingredient is coadministered.
  • a pharmaceutical composition can include an effective amount of a compound of Formula I.
  • An effective amount can be defined as an amount sufficient to confer a therapeutic effect on the treated patient, and will depend on a variety of factors, such as the nature of the inhibitor, the size of the patient, the goal of the treatment, the nature of the pathology to be treated, the specific pharmaceutical composition used, and the judgment of the treating physician. For reference, see Freireich et al., Cancer Chemother. Rep. 1966, 50, 219 and Scientific Tables, Geigy Pharmaceuticals, Ardley, N. Y., 1970, 537, which is incorporated by reference in its entirety. Dosage levels of between about 0.001 and about 100 mg/kg body weight per day, preferably between about 0.1 and about 10 mg/kg body weight per day, of the active ingredient compound can be used.
  • diethyl squarate is sequentially reacted with two amines, one of which includes the Het group, the other including the R 4 group.
  • Scheme 1 illustrates a sequence in which the Het group is added first; however, the opposite order is also possible.
  • the R groups can optionally be further modified.
  • One example of such a modification is shown in Scheme 2, where a carboxylic acid group in R 4 is reacted with an amine to form an amide group.
  • Preparative HPLC was run using a Waters reverse phase preperative HPLC (Xterra Cl 8 5 ⁇ m, 3O x 100 mm column; water/CH 3 CN/0.1% formic acid). Purity in two solvent systems was determined using Agilent 1100 reverse phase HPLC with Agilent Zorbax SB-C 18 5 ⁇ m, 4.6 x 30mm column at 254 nm [Gradient: 5-95% in 7min @ 0.8mL/min, H 2 O/CH 3 CN (method 1) and H 2 OMeOH (method 2)].
  • XPHOS 2- (dicyclohexylphosphino)-2', 4', 6'-tri-I- ⁇ ropyl-l, 1 '-biphenyl-;
  • Xantphos 9, 9-dimethyl-4, 5- bis(diphenylphosphino)xanthene;
  • Pd 2 (dba) 3 tris(dibenzylideneacetone)dipalladium.
  • Example 1 3- ⁇ [l-(4-fluorophenyl)ethyI]amino ⁇ -4-(pyridin-4-ylamino)cyclobut-3-ene-1,2-dione
  • a solution of 3-ethoxy-4-(pyridin-4-ylamino)-cyclobut-3-ene-1,2-dione (prepared as described in /. Med. Chem. 2000, 45, 1187-1202, which is incorporated by reference in its entirety) (50 mg, 229 ⁇ mol) in EtOH (2 mL) was added (D,L)-4-fluoro- ⁇ -methylbenzylamine (31 ⁇ L, 236 ⁇ mol).
  • the reaction mixture was heated to 100 °C for 3h and then stirred at room temperature overnight.
  • Example 59 3-( ⁇ 2-hydroxy-1-[4-(trifluoromethyl)phenyl]ethyl ⁇ amino)-4-(pyridiii-4-ylainino)cyclobut-3- ene-1,2-dione
  • Example 72 (25)-2-(4-chlorophenyl)-2- ⁇ [3,4-dioxo-2-(pyridin-4-ylamino)cycIobut-1-en-1- yl] amino ⁇ acetamide
  • Example 70 The title compound was synthesized in a manner similar to that of Example 70 with 3- chloro-4-fluoro-DL-phenylglycine) as the starting material.
  • the product was isolated by removal of solvent in vacuo, followed by purification by HPLC (C 1 sjlO - 100% gradient,
  • Example 70 The title compound was synthesized in a manner similar to that of Example 70 with 4- trifluoromethyl-DL-phenylglycine as the starting material.
  • the product was isolated by removal of solvent in vacuo, followed by purification by HPLC (C ]8 ;10 - 100% gradient, H 2 O/ACN with
  • Example 70 The title compound was synthesized in a manner similar to that of Example 70 with 3,4,5-trifluoro-DL-phenylglycine as the starting material.
  • the product was isolated by removal of solvent in vacuo, followed by purification by HPLC (C 18 ;10 - 100% gradient, H 2 O/ ACN with
  • Step 1 [3,4-Dioxo-2-(pyridin-4-ylamino)-cyclobut-1-enylamino]-phenyl-acetic acid
  • 2-phenylglycine 381 mg, 2.52 mmol
  • the reaction mixture was heated to 60 °C and stirred overnight.
  • the reaction mixture was concentrated to a solid and then triturated with a mixture of EtOAc/EtOH/hexane to give 220 mg (27% yield) of the title compound.
  • the product was purified by HPLC (C 1 s, gradient 10 - 100%
  • Example 83 3-[(2-oxo-1-phenyl-2-pyrrolidin-1-ylethyl)amino]-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2- dione Using essentially the same procedures described in Example 81 but using pyrrolidine in place of the amine, the title compound was obtained and identified by HPLC and mass spectral analysis (12% yield) M+H, 377, time (mm) 1 5
  • Step 1 3-Ethoxy-4-(2-methoxy-pyridin-4-ylamino)-cyclobut-3-ene-1,2-dione
  • EtOH 50 mL
  • 2-methoxy-pyridin-4-ylamine 3.16 g, 25.0 mmol
  • the reaction mixture was heated to reflux for 4 h and then cooled to room temperature and stirred overnight. The mixture was filtered, and the precipitate was collected and dried in vacuo to provide 1.73 g (28% yield) of the title compound.
  • Step 2 3-[(2-Methoxypyridin-4-yl)amino]-4- ⁇ [(1R)-1-phenylethyl]amino ⁇ cyclobut-3- ene-1,2-dione
  • step 1 The product of step 1 described above (500 mg, 2.01 mmol) was dissolved in EtOH (15 mL) and a solution of (R)-(+)- ⁇ -methylbenzylamine (247 mg, 2.03 mmol) in EtOH (5 mL) was added dropwise. The mixture was stirred at 60 °C overnight and then cooled and filtered. The precipitate was collected and dried in vacuo to provide 614 mg of the title compound (94% yield).
  • Step 1 A solution of diethyl squarate (500 mg, 2.9 nimol) in EtOH (15 mL) was heated at reflux and a solution of 5-amino-3-methylisoxazole (288 mg, 1.0 eq) in EtOH (5 mL) was added via syringe pump at a rate of 1 mL/h. The solution was cooled, evaporated, and flash chromato graphed (silica, ethyl acetate, acetonitrile, methanol, water (70/10/5/5) to provide the title compound (38 mg, 6%).
  • Step 2 A solution of 3-ethoxy-4-[(3-methylisoxazol-5-yl)amino]cyclobut-3-ene-1,2- dione (38 mg, 0.2 mmol) and (R)-1-phenylethanamine (65 ⁇ L, 3 eq) in EtOH was stirred at RT overnight. Evaporation and flash chromatography (silica, 5% MeOH/DCM) provided the title compound (23 mg, 69%) as a yellow solid.
  • Step 1 3-ethoxy-4-[methyl(pyridm-4-yl)amino]cyclobut-3-ene-1,2-dione Following step 1 of Example 91, diethyl squarate (500 mg, 2.9 mmol) and 4-
  • Step 2 Following step 2 of Example 91, 3-ethoxy-4-[methyl(pyridin-4- yl)amino]cyclobut-3-ene-1,2-dione (40 mg, 0.17 mmol) and (R)-1-phenylethanamine (66 ⁇ L, 3 eq) provided the title compound (47 mg, 90%).
  • Step 1 3-ethoxy-4-[(2,2,6,6-tetramethylpiperidin-4-yl)amino]cyclobut-3-ene-l ,2-dione
  • diethyl squarate 300 mg, 1.8 mmol
  • 4-amino-2,2,6,6- tetramethylpiperidine 331 mg, 1.2 eq
  • EtOH 3 mL
  • Step 2 Following step 2 of Example 91, 3-ethoxy-4-[(2,2,6,6-tetramethylpiperidin-4- yl)amino]cyclobut-3-ene-1,2-dione (460 mg, 1.6 mmol) and (R)-1-phenylethanamine (420 ⁇ L, 2 eq) provided the title compound (260 mg, 46%).
  • Step 1 3-ethoxy-4-(pyrimidin-4-ylamino)cyclobut-3-ene- 1 ,2-dione
  • Step 2 Following step 2 of Example 91, 3-ethoxy-4-(pyrimidin-4-ylamino)cyclobut-3- ene-1,2-dione (16 mg, 0.07 mmol) and (R)-1-phenylethanamine (28 ⁇ L, 3 eq) provided the title compound (5 mg, 23%).
  • Step 1 3-ethoxy-4-[(5-methyl-lfl r -pyrazol-3-yl)amino]cyclobut-3-ene-1,2-dione
  • diethyl squarate 400 mg, 2.4 mmol
  • 3-amino-5- methylpyrazole (274 mg, 1.2 eq) provided the title compound (362 mg, 68%) as a yellow solid.
  • Step 2 A solution of 3-ethoxy-4-[(5-methyl- 1H-pyrazol-3-yl)amino]cyclobut-3-ene-1,2- dione (362 mg, 1.6 mmol) and (R)-1-phenylethanamine (271 mg, 1.3 eq) were heated in a microwave reactor (140 °C, 15 min) to provide the title compound (216 mg, 46%) as a white foam.
  • Step 1 3-ethoxy-4- ⁇ [(liJ)-1-phenylethyl]amino ⁇ cyclobut-3-ene-1,2-dione
  • Step 2 Following step 2 of Example 95, 3-ethoxy-4- ⁇ [(1R)-1- phenylethyl]amino ⁇ cyclobut-3-ene-1,2-dione 500 mg, 2 mmol) and 4-amino-1-N-Boc-piperidine
  • Step 1 3-ethoxy-4-(tributylstannyl)cyclobut-3-ene-1,2-dione was prepared following methods described in /. Org. Chem, 1990, 55, 5359-5364, which is incorporated by reference in its entirety.
  • 1 H NMR 400 MHz, chloroform-cf
  • ppm 0.86 - 0.97 m, 6 H
  • 1.15 - 1.23 m, 5 H
  • Step 2 3- ⁇ [(1R)-l -phenylethyl] amino ⁇ -4-(tributylstannyl)cyclobut-3-ene- 1 ,2-dione
  • 3-ethoxy-4-(tributylstannyl)cyclobut-3-ene-1,2-dione (4.0 g, 10 mmol) and (R)-I -phenyl ethanamine (1.8 g, 1.5 eq) provided the title compound (3.50 g, 71%) as an amber oil after flash chromatography (silica, 10% ethyl acetate / hexanes).
  • Step 3 A solution of 3- ⁇ [(1R)-1-phenylethyl]amino ⁇ -4-(tributylstannyl)cyclobut-3-ene-
  • Step 2 Following step 2 of Example 95, 3-ethoxy-4-(li7-pyrazol-3-ylamino)cyclobut-3- ene-1,2-dione 200 mg, 1.0 mmol) and (R)-1-phenylethanamine (160 ⁇ L, 1.3 eq) provided the title compound (268 mg, 95%) after flash chromatography (silica, 2% acetic acid / ethyl acetate).
  • Step 1 3-[(2-chloropyridin-4-yl)ammo]-4-ethoxycyclobut-3-ene-1,2-dione
  • diethyl squarate 1.0 g, 6.0 mmol
  • 2-chloro-4- aminopyridine 756 mg, 1.0 eq
  • the title compound 938 mg, 21%) after flash chromatography (silica, 50% ethyl acetate / hexanes).
  • Step 2 Following step 2 of Example 95, 3-[(2-chloropyridin-4-yl)amino]-4- ethoxycyclobut-3-ene-1,2-dione (250 mg, 1 mmol) and (R)-1-phenylethanamine (256 ⁇ L, 2.0 eq) provided the title compound (270 mg, 83%) after collecting the resulting precipitate.
  • Step 1 l-(4-cyclohexylphenyl)ethanone oxime
  • l-(4-cyclohexylphenyl)ethanone oxime
  • hydroxylamine hydrochloride (1.04 g, 1.5 eq)
  • pyridine 1.2 g, 1.5 eq
  • the cooled solution was diluted with water (100 mL) and the resulting precipitate was collected to provide the title compound (2.16 g, 100%) as a white solid.
  • Step 3 Following step 2 of Example 95, l-(4-cyclohexylphenyl)ethanartiine (219 mg, 1 mmol) and 3-ethoxy-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2-dione (141 mg, 0.6 eq) provided the title compound (192 mg, 51%) as a pale-yellow solid after collecting the resulting precipitate.
  • Step 1 Following step 1 of Example 91, diethyl squarate (400 mg, 2.4 mmol) and biphenyl-3 -amine (55 mg, 1.1 eq) provided the title compound (200 mg, 24%) after collecting the resulting precipitate by filtration.
  • Step 2 Following step 2 of Example 95, 3-(biphenyl-3-ylamino)-4-ethoxycyclobut-3- ene-1,2-dione (200 mg, 0.7 mmol) and (R)-1-phenylethanamine (174 ⁇ L, 2.0 eq) provided the title compound (223 mg, 86%) as a white solid after collecting the resulting precipitate.
  • Step 1 3-[(2-bromopyridin-4-yl)amino]-4-ethoxycyclobut-3-ene-1,2-dione
  • 2-bromo-4-amino ⁇ yridine 5 g, 29 mmol
  • diethyl squarate 4.9 g, 1.0 eq
  • the title compound (1.51 g, 18%) as a yellow foam after flash chromatography (silica, 40% ethyl acetate / hexanes).
  • Step 2 Following step 2 of Example 95, 3-[(2-bromopyridin-4-yi)amino]-4- ethoxycyclobut-3-ene-1,2-dione (1.20 g, 4 mmol) and (R)-1-phenylethanamine (1.3 mL, 2.5 eq) provided the title compound (1.14 g, 77%) as a pale-yellow solid after collecting the resulting precipitate by filtration.
  • Example 105 3-[(l-methyl-1-phenylethyl)amino]-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2-dione Following step 2 of Example 95, 3-ethoxy-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2- dione (100 mg, 0.5 mmol) and cumylatnine (155 mg, 2.5 eq) provided the title compound (60 mg, 42%) as a fluffy yellow solid after reverse phase HPLC purification.
  • Step 2 4-aminopyridine-2-carboxamide A solution of 4-nitropyridme-2-carboxamide (0.65 g, 4 mmol) and PtO 2 (20 mg) in EtOH
  • Step 3 4-[(2-ethoxy-3,4-dioxocyclobut- 1 -en- 1 -yl)amino]pyridine-2-carboxamide
  • diethyl squarate (722 mg, 4 mmol) and 4- aminopyridine-2-carboxamide (582 mg, 1 eq) provided the title compound (120 mg, 10%) as an orange solid.
  • Step 4 4- [(3 ,4-dioxo-2- ⁇ [( 1 R)- 1 -phenylethyl] amino ⁇ cyclobut- 1 -en- 1 -yl)amino]pyridine- 2-carboxamide
  • Step 3 Following step 2 of Example 91, 3-ethoxy-4-(pyridin-4-ylamino)cyclobut-3-ene- 1 ,2-dione (100 mg, .50 mmol) and 2-amino-2-(3-hydroxyphenyl)acetamide (76 mg, 1.0 eq) provided the title compound (136 mg, 87%) as a yellow solid after collecting the resulting precipitate.
  • Example 123 3- ⁇ [l-(4'-chlorobiphenyl-3-yl)ethyl]amino ⁇ -4-(pyridin-4-ylamino)cyclobut-3-ene-1,2-dione
  • 3-(l-(3-bromophenyl)ethylamino)-4-( ⁇ yridin-4- ylamino)cyclobut-3-ene-1,2-dione 100 mg, 0.27 mmol
  • 4-chlorophenylboronic acid 63 mg, 1.5 eq
  • Example 124 3- ⁇ [l-(2'-methylbiphenyl-3-yI)ethyl]amino ⁇ -4-(pyridin-4-ylamino)cyclobut-3-ene-1,2-dione
  • 3-(l-(3-bromophenyl)ethylamino)-4-(pyridin-4- ylamino)cyclobut-3-ene-1,2-dione 100 mg, 0.27 mmol
  • 2-methylbenzeneboronic acid 55 mg, 1.5 eq
  • Step 2 3- ⁇ [l-(4-iodophenyl)ethyl]amino ⁇ -4-( ⁇ yridin-4-ylamino)cyclobut-3-ene-1,2- dione
  • the title compound was prepared as illustrated by Example 136, but using L- alanineamide hydrochloride. The precipitated solid was filtered and washed with EtOH and ethyl ether to give the product (84 mg, 68%) as a yellow solid.
  • Example 140 7V 2 -[3,4-dioxo-2-(pyridin-4-ylamino)cyclobut-1-eii-1-yl]-L-serinamide
  • the title compound was prepared as illustrated by Example 136, but using L-serinamide hydrochloride. Purification (RP-HPLC, CH 3 CN/H 2 O/0.1% formic acid) afforded the product (6.5 mg, 5%) as a yellow solid.
  • Example 145 l-flS ⁇ -dioxo-1- ⁇ yridin- ⁇ ylaminoJcyclobut-1-en-1-yllaminoJ-1-P-thienylJacetamide
  • the title compound was prepared as illustrated by Example 136, but using 2-(3- thienyl)acetamide.
  • Step 1 To a microwave vial was added 4-acetylpyridine ( 1.9 g, lO mmoles), 95% EtOH (15 mL), hydroxylamine hydrochloride (1.0 g, 15 mmoles, 1.5 eq) and Et 3 N (2.1 mL, 15 mmoles, 1.5 eq). The mixture was heated at 120 °C in microwave reactor for 20 min. EtOH was removed in vacuo. Working up (EtOAc/H 2 O) afforded l-(pyridin-4-yl)ethanone oxime (620 mg, 46%) as a white solid.
  • Step 2 To a Parr ® shaker bottle was added the oxime (200 mg, 1.5 mmoles), 95% EtOH (15 mL), ammonium hydroxide (0.3 mL) and Raney nickel (300 mg). The mixture was shaken at rt in a hydrogen atmosphere (50 PSI) for two days. The reaction was filtered through Celite ® followed by MeOH washing. The solution was evaporated. l-(pyridin-4-yl)ethanamine (140 mg, 78%) was obtained as a white solid.
  • Step 3 The title compound was prepared as illustrated by Example 141. Purification by chromatography (silica, 10-14% MeOH/CH 2 Cl 2 ) afforded the product (123 mg, 65%) as a yellow solid.
  • Example 147 The title compound was prepared as illustrated by Example 141. Purification by chromatography (silica, 10-14% MeOH/CH 2 Cl 2 ) afforded the product (123 mg, 65%)
  • Step 1 The oxime was prepared according to Step 1 of Example 146, but using 1- benzofuran-2-yl-ethylamine as the starting material.
  • Step 2 The amine intermediate was prepared according to Step 2 of Example 146.
  • Step 3 The title compound was prepared as illustrated by Example 141. Purification by chromatography (silica, 2-6% MeOH/CH 2 Cl 2 ) afforded the product (210 mg g, 88%) as a yellow solid.
  • Example 148 3- ⁇ [l-(4-morpholin-4-ylphenyl)ethyl]amino ⁇ -4-(pyridin-4-ylamino)cyclobut-3-ene-1,2-dione Step 1: The oxime was prepared according to Step 1 of Example 146, but using l-(4- morpholin-4-yl-phenyl)-ethylamine as the starting material.
  • Step 2 The amine intermediate was prepared according to Step 2 of Example 146.
  • Step 3 The title compound was prepared as illustrated by Example 141. The precipitated solid was filtered, washed with EtOH and Et 2 ⁇ to afford the product (160 mg 86%) as a yellow solid.
  • Step 1 The oxime was prepared according to Step 1 of Example 146, but using [4-(l- amino-ethyl)-phenyl]-dimethyl-amine as the starting material.
  • Step 2 The amine intermediate was prepared according to Step 2 of Example 146.
  • Step 3 The title compound was prepared as illustrated by Example 141. The precipitated solid was filtered, washed with EtOH and Et 2 O to afford the product (120 mg 78%) as a yellow solid.
  • Example 150 Example 150
  • Step 1 The oxime was prepared according to Step 1 of Example 146, but using 1- cyclohexyl-ethylamine as the starting material.
  • Step 2 The amine intermediate was prepared according to Step 2 of Example 146.
  • Step 3 The title compound was prepared as illustrated by Example 141. Purification by chromatography (silica, 5-10% MeOH/CH 2 Cl 2 ) afforded the product (120 mg, 87%) as a yellow solid. 1 H NMR (400 MHz, MeOD) ⁇ ppm 1.08 - 1.52 (m, 8 H) 1.49 - 1.88 (m, 2 H) 1.86 - 2.09
  • Step 1 The oxime was prepared according to Step 1 of Example 146, but l-pyrazin-2-yl- ethylamine was used as the starting material.
  • Step 2 The amine intermediate was prepared according to Step 2 of Example 146.
  • Step 3 The title compound was prepared as illustrated by Example 141. Purification by chromatography (silica, 10-15% MeOH/CH 2 Cl 2 ) afforded the product (58 mg, 52%) as a yellow solid.
  • Step 1 The oxime was prepared according to Step 1 of Example 146, but l-(4-imidazol- l-yl-phenyl)-ethylamine was used as the starting material.
  • Step 2 The amine intermediate was prepared according to Step 2 of Example 146.
  • Ste ⁇ 3 The title compound was prepared as illustrated by Example 141. Purification by chromatography (silica, 10-15% MeOH/CH 2 Cl 2 ) afforded the product (0.10 g, 73%) as a yellow solid.
  • 1 H NMR (400 MHz, MeOD) ⁇ ppm 1.79 (d, J 7.1 Hz, 3 H) 5.45 - .71 (m, 1 H) 7.24 (d,
  • Step 1 The oxime was prepared according to Step 1 of Example 146, but l-thiophen-3- yl-ethylamine was used as the starting material.
  • Step 2 The amine intermediate was prepared according to Step 2 of Example 146.
  • Step 3 The title compound was prepared as illustrated by Example 141. Purification by chromatography (silica, 2-10% MeOH/CH 2 Cl 2 ) afforded the product (80 mg, 67%) as a yellow solid.
  • Step 1 The oxime was prepared according to Step 1 of Example 146, but 1-(1-Methyl-
  • Step 2 The amine intermediate was prepared according to Step 2 of Example 146.
  • Step 3 The title compound was prepared as illustrated by Example 141. Purification by chromatography (silica, 2-10% MeOH/CH 2 Cl 2 ) afforded the product (95 mg, 67%) as a yellow solid.
  • 1 H NMR (400 MHz, MeOD) ⁇ ppm 1.51 (d, J 6.8 Hz, 3 H) 3.52 (s, 3 H) 5.11 - 5.31 (m, 1 H) 5.91 - 6.05 (m, 1 H) 6.43 - 6.68 (m, 2 H) 7.26 - 7.55 (m, 2 H) 8.12 - 8.38 (m, 2 H); HPLC purity (Method 1 : 98%, Method 2: 98%); HRMS: calcd for C 16 Hi 6 N 4 O 2 + H+, 297.13460; found (ESI-FTMS, [M+H] 1+ ), 297.1351.
  • Example 155 3- ⁇ [l-(3-methylpyrazin-2-yl)ethyl]a ⁇ iino ⁇
  • Step 1 The oxime was prepared according to Step 1 of Example 146, but l-(3-methyl- pyrazin-2-yl)-ethylamine was used as the starting material.
  • Step 2 The amine intermediate was prepared according to Step 2 of Example 146.
  • Step 3 The title compound was prepared as illustrated by Example 141. Purification by chromatography (silica, 3-8% MeOH/CH 2 Cl 2 ) afforded the product (70 mg, 47%) as a yellow solid.
  • Step 1 The oxime was prepared according to Step 1 of Example 146, but 1- benzo[b]thiophen-3-yl-ethylamine was used as the starting material.
  • Step 2 The amine intermediate was prepared according to Step 2 of Example 146.
  • Step 3 The title compound was prepared as illustrated by Example 141. Purification (RP-HPLC, CH 3 CN/H 2 O/0.1% formic acid) afforded the product (19 mg, 13%) as a yellow solid.
  • 1 H NMR (400 MHz, MeOD) ⁇ ppm 2.00 (d, / 6.9 Hz, 3 H) 5.86 - 6.11 (m, 1 H) 7.48 - 7.64 (m, 2 H) 7.71 - 7.81 (m, 2 H) 7.84 (s, 1 H) 8.00 - 8.13 (m, 2 H) 8.30 - 8.42 (m, 2 H) 8.46 - 8.60 (m, 2 H); HPLC purity (Method 1: 100%, Method 2: 99%); HRMS: calcd for C 19 H 15 N 3 O 2 S + H+, 350.09577; found (ESI-FTMS, [M+H] 1+ ), 350.0958.
  • Example 157 Example 157
  • Step 1 The oxime was prepared according to Step 1 of Example 146, but l-thiazol-2-yl- ethylamine was used as the starting material.
  • Step 2 The amine intermediate was prepared according to Step 2 of Example 146.
  • Step 3 The title compound was prepared as illustrated by Example 141. Purification
  • Step 1 The oxime was prepared according to Step 1 of Example 146, but 3-(l-amino- ethyl)-phenylamine was used as the starting material.
  • Step 2 The amine intermediate was prepared according to Step 2 of Example 146.
  • Example 159 3- ⁇ [l-(2-fluorophenyl)ethyl]amlno ⁇ -4-(pyridin
  • Step 1 The oxime was prepared according to Step 1 of Example 146, but l-(2-fluoro- phenyl)-ethylamine was used as the starting material.
  • Step 2 The amine intermediate was prepared according to Step 2 of Example 146.
  • Step 3 The title compound was prepared as illustrated by Example 141. Purification (RP-HPLC, CH 3 CN/H 2 O/0.1% formic acid) afforded the product (72 mg, 56%) as a yellow solid.
  • Step 1 The oxime was prepared according to Step 1 of Example 146, but 2-(l-amino- ethyl)-phenol was used as the starting material.
  • Step 2 The amine intermediate was prepared according to Step 2 of Example 146.
  • Step 3 The title compound was prepared as illustrated by Example 141. Purification (RP-HPLC, CH 3 CN/H 2 O/0.1% formic acid) afforded the product (34 mg, 23%) as a yellow solid.
  • Step 1 The oxime was prepared according to Step 1 of Example 146, but l-(1H-indol-3- yl)-ethylamine was used as the starting material.
  • Step 2 The amine intermediate was prepared according to Step 2 of Example 146.
  • Step 3 The title compound was prepared as illustrated by Example 141. Purification (RP-HPLC, CH 3 CN/H 2 O/0.1% formic acid) afforded the product (4.3 mg, 3%) as a yellow solid.
  • Step 1 The oxime was prepared according to Step 1 of Example 146, but 1 -(2,6- difluoro-phenyl)-ethylamine was used as the starting material.
  • Step 2 The amine intermediate was prepared according to Step 2 of Example 146.
  • Step 3 The title compound was prepared as illustrated by Example 141. Purification (RP-HPLC, CH 3 CN/H 2 O/0.1 % formic acid) afforded the product (92 mg, 61 %) as a yellow solid.
  • Example 163 3- ⁇ [l-(
  • Step 1 The oxime was prepared according to Step 1 of Example 146, but l-(3-Fluoro- phenyl)-ethylamine was used as the starting material.
  • Step 2 The amine intermediate was prepared according to Step 2 of Example 146.
  • Step 3 The title compound was prepared as illustrated by Example 141. Purification (RP-HPLC, CH 3 CN/H 2 O/0.1 % formic acid) afforded the product (68 mg, 49%) as a yellow solid.
  • Step 1 The oxime was prepared according to Step 1 of Example 146, but 3-(l-amino- ethyl)-phenol was used as the starting material.
  • Step 2 The amine intermediate was prepared according to Step 2 of Example 146.
  • Step 3 The title compound was prepared as illustrated by Example 141. Purification
  • Step 1 The oxime was prepared according to Step 1 of Example 146, but l-(3- trifluoromethyl-phenyl)-ethylamine was used as the starting material.
  • Step 2 The amine intermediate was prepared according to Step 2 of Example 146.
  • Step 3 The title compound was prepared as illustrated by Example 141. Purification (RP-HPLC, CH 3 CN/H 2 O/0.1% formic acid) afforded the product (132 mg, 80%) as a yellow solid.
  • Example 167 3- ⁇ [(1R)-1-phenylethyl]amino ⁇ -4- ⁇ [2-(4-phenyl-l ⁇ -1,2,3-triazol-1-yl)pyridin-4- yl]amino ⁇ cyclobut-3-ene-1,2-dione
  • 3-[(2-azidopyridin-4-yl)amino]-4- ⁇ [(1R)-1- phenylethyl]amino ⁇ cyclobut-3-ene-1,2-dione 70 mg, 0.21 mmole), DMF (3 mL), water (1 mL), phenylacetylene (21 mg, 0.21 mmole, 1.0 eq), copper (II) sulfate pentahydrate (0.52 mg, 0.002 mmole, 0.01 eq) and sodium ascorbate (2.1 mg, 0.01 mmole, 0.05 eq).
  • Example 170 3- ⁇ [l-(3-methylphe ⁇ yl)ethyl]amino ⁇ -4-(pyridin-4-ylamino)cyclobut-3-ene-1,2-dione Step 1: The oxime was prepared according to Step 1 of Example 146, but using 1-m- Tolyl-ethylamine was used as the starting material.
  • Step 2 The amine intermediate was prepared according to Step 2 of Example 146.
  • Step 3 The title compound was prepared as illustrated by Example 141. Purification (RP-HPLC, CH 3 CN/H 2 O/0.1% formic acid) afforded the product (115 mg, 81%) as a yellow solid.
  • Example 171 Example 171
  • Step 1 The oxime was prepared from 3-chloroacetophenone according to Step 1 of Example 146, but using 1-Phenyl-ethylamine as the starting material.
  • Step 2 The amine intermediate was prepared according to Step 2 of Example 146. Most of aromatic chloride was also reduced to provide major product 1-phenyl-ethylamine and minor l-(3-chloro-phenyl)-ethylamine. They were carried to next reaction without separation.
  • Example 172 Example 172
  • Step 1 The oxime was prepared according to Step 1 of Example 146, but using l-(3- chloro-phenyl)-ethylamine as the starting material.
  • Step 2 The amine intermediate was prepared according to Step 2 of Example 146.
  • Step 3 The title compound was prepared as illustrated by Example 141. Purification (RP-HPLC, CH 3 CN/H 2 O/0.1% formic acid) afforded the product (60 mg, 40%) as a yellow solid.
  • Step 1 To a solution of 3-aminoacetophenone (1.0 g, 7.4 mmoles) and Et 3 N (1.2 mL, 8.9 mmoloes, 1.2 eq) in CH 2 CI 2 (20 mL) was added methanesulfonyl chloride (0.7 mL, 8.9 mmoles, 1.2 eq) at 0 °C. The mixture was stirred for 2.5 hours. Purification by chromatography (silica, 30-50% EtOAc/hexanes) afforded N-(3-acetylphenyl)methanesulfonamide (0.93 g, 59%) as a colorless oil.
  • Step 2 The oxime was prepared according to Step 1 of Example 146, but using N-[3-(l- amino-ethyl)-phenyl]-methanesulfonamide as the starting material.
  • Step 3 The amine intermediate was prepared according to Step 2 of Example 146.
  • Step 4 The title compound was prepared as illustrated by Example 141. Purification (RP-HPLC, CH 3 CN/H 2 O/0.1% formic acid) afforded the product (63 mg, 35%) as a yellow solid.
  • 1 H NMR (400 MHz, MeOD) ⁇ ppm 1.67 (d, 3 H) 2.94 - 3.05 (m, 3 H) 5.30 - 5.52 (m, 1 H) 7.14 - 7.32 (m, 3 H) 7.32 - 7.44 (m, 2 H) 7.70 (s, 2 H) 8.25 (s, 2 H) 8.40 (d, / 6.1Hz, 2 H); HPLC purity (Method 1: 100%, Method 2: 100%); HRMS: calcd for C 18 Hi 8 N 4 O 4 S + H+, 387.11215; found (ESI-FTMS, [M+H] 1+ ), 387.1124.
  • Example 174 methyl 3-(l- ⁇ [3,4-dioxo-2-(pyridin-4-ylamino
  • Step 1 The mixture of 3-acetylbenzoic acid (1.0 g, 6.1 mmoles), MeOH (100 mL) and cone. H 2 SO 4 (1 mL) was refluxed overnight. MeOH was evaporated in vacuo. Working up (EtO Ac/saturated NaHCO 3 and H 2 O) afforded methyl 3-acetylbenzoate as a brown solid in 100% yield.
  • Step 2 The oxime was prepared according to Step 1 of Example 146, but using 3-(l- amino-ethyl)-benzoic acid methyl ester as the starting material.
  • Step 3 The amine intermediate was prepared according to Step 2 of Example 146.
  • Step 4 The title compound was prepared as illustrated by Example 141. Purification (RP-HPLC, CH 3 CN/H 2 O/0.1% formic acid) afforded the product (230 mg, 90%) as a yellow solid.
  • Example 175 TV-IS-fl-fP ⁇ -dioso-1-tpyridin- ⁇ yla ⁇ iiiioJcyclobut-1-en-1-yllaminoJethyOphenylJacetamide Step 1: The oxime was prepared according to Step 1 of Example 146, but using N-[3-(l- amino-ethyl)-phenyl]-acetamide as the starting material.
  • Step 2 The amine intermediate was prepared according to Step 2 of Example 146.
  • Step 3 The title compound was prepared as illustrated by Example 141. Purification (RP-HPLC, CH 3 CN/H 2 O/0.1% formic acid) afforded the product (19 mg, 12%) as a yellow solid.
  • Step 1 The oxime was prepared according to Step 1 of Example 146, but using l-(3- bromo-phenyl)-ethylamine as the starting material.
  • Step 2 The amine intermediate was prepared according to Step 2 of Example 146.
  • Example 178 The title compound was
  • Step 1 The mixture of 3-acetylbenzonitrile (2.0 g, 13.7 mmoles), dibutyltin oxide (341 mg, 1.4 mmoles, 0.1 eq), toluene (50 tnL) and azidotrimethylsilane (3.6 mL, 27.4 mmoles, 2.0 eq) was refluxed overnight. The filtrate was concentrated and solidified from EtOAc to give 1- (3-(2H-tetrazol-5-yl)phenyl)ethanone (0.8 g, 30%) as a yellow solid.
  • Step 2 The oxime was prepared according to Step 1 of Example 146, but using .1-[3-(2H- tetrazol-5-yl)-phenyl]-ethylamine as the starting material.
  • Step 3 The amine intermediate was prepared according to Step 2 of Example 146, except that the reaction took 10 days.
  • Step 4 The title compound was prepared as illustrated by Example 141. Purification (RP-HPLC, CH 3 CN/H 2 O/0.1 % formic acid) afforded the product (7.5 mg, 5%) as a yellow solid.
  • Step 1 To a mixture of 3-acetylbenzonitrile (1.0 g, 6.9 mmoles), NaOH (69 mg, 1.7 mmoles, 0.25 eq), EtOH (10 mL) and water (3.4 mL) was added dropwise hydrogen peroxide (30%, 2.8 mL, 24.8 mmoles, 3.6 eq). The mixture was stirred for 1 hour at 5O°C and neutralized with diluted H 2 SO 4 . The solvents were removed. Working up (CH 2 Cl 2 /small amount of water) afforded 3-acetylbenzamide (0.7 g, 63%) as a white solid.
  • Step 2 The oxime was prepared according to Step 1 of Example 146, but using 3-(l- ammo-ethyl)-benzarmde as the starting material.
  • Step 3 The amine intermediate was prepared according to Step 2 of Example 146.
  • Step 4 The title compound was prepared as illustrated by Example 141. Purification
  • Step 1 The oxime was prepared according to Step 1 of Example 146, but using 4-(l- Amino-ethyl)-3-methoxy-phenol as the starting material.
  • Step 2 The amine intermediate was prepared according to Step 2 of Example 146.
  • Step 3 The title compound was prepared as illustrated by Example 141. Purification (RP-HPLC, CH 3 CN/H 2 O/0.1% formic acid) afforded the product (110 mg, 68%) as a yellow solid.
  • Step 1 The mixture of 3,4-dihydroxyacetophenone (406 mg, 2.7 mmoles), lithium carbonate (493 mg, 6.7 mmoles, 2.5 eq), iodomethane (0.4 mL, 6.7 mmoles, 2.5 eq) and DMF (7 mL) was heated at 55 °C for 1 day. Purification by chromatography (silica, 20-40% EtOAc/hexanes) afforded l-(3-hydroxy-4-methoxyphenyl)ethanone (0.2 g, 45%) as a white solid.
  • Step 2 The oxime was prepared according to Step 1 of Example 146, but using 5-(l- amino-ethyl)-2-methoxy-phenol as the starting material.
  • Step 3 The amine intermediate was prepared according to Step 2 of Example 146.
  • Step 4 The title compound was prepared as illustrated by Example 141. Purification
  • Step 1 The oxime was prepared according to Step 1 of Example 146, but using 2-(l - amino-ethyl)-benzene-1,4-diol as the starting material.
  • Step 2 The amine intermediate was prepared according to Step 2 of Example 146.
  • Step 3 The title compound was prepared as illustrated by Example 141. Purification
  • Step 1 The oxime was prepared according to Step 1 of Example 146, but using 5-(l- amino-ethyl)-benzene-1,3-diol as the starting material.
  • Step 2 The amine intermediate was prepared according to Step 2 of Example 146.
  • Step 3 The title compound was prepared as illustrated by Example 141. Purification
  • Step 1 l-(3-hydroxy-5-methoxyphenyi)ethanone was prepared according to Step 1 of Example 181.
  • Step 2 The oxime was prepared according to Step 1 of Example 146, but using 3-(l- amino-ethyl)-5-methoxy-phenol as the starting material.
  • Step 3 The amine intermediate was prepared according to Step 2 of Example 146.
  • Step 4 The title compound was prepared as illustrated by Example 141. Purification (RP-HPLC, CH 3 CN/H 2 O/0.1% formic acid) afforded the product (46 mg, 45%) as a lightly yellow solid.
  • 1 H NMR 400 MHz, MeOD
  • Step 1 The mixture of 3-aminoacetophenone (1.0 g, 7.4 mmoles), Hunig's base (1.5 mL,
  • Step 2 The oxime was prepared according to Step 1 of Example 146, but using l-[3-(l- amino-ethyl)-phenyl]-3-methyl-urea as the starting material.
  • Step 3 The amine intermediate was prepared according to Step 2 of Example 146.
  • Step 4 The title compound was prepared as illustrated by Example 141. Purification (RP-HPLC, CH 3 CNZH 2 O with 10 mM NH 4 OAc) afforded the product (27 mg, 16%) as a pale yellow solid.
  • Example 186 3- ⁇ [l-(3-amino-4-methylphenyl)ethyl]amino ⁇ -4-(pyridin-4-ylamino)cyclobut-3-ene-1,2- dione
  • Step 1 4-methyl-3-nitroacetophenone (5.0 g, 27.9 mmoles) was taken up in EtOH (200 mL). Ti (H) chloride (15.9 g, 83.7 mmoles, 3 eq) was added. The mixture was refluxed for 1 hour and cooled to room temperature. Saturated NaHCO 3 was added to bring pH up to 7-8. The precipitated solid was discarded and the filtrate was concentrated. Working up (EtOAcZH 2 O) afforded l-(3-amino-4-methylphenyl)ethanone as a yellow solid in 100% yield.
  • Step 2 The oxime was prepared according to Step 1 of Example 146, but using 5-(l- amino-ethyl)-2-methyl-phenylamine as the starting material.
  • Step 3 The amine intermediate was prepared according to Step 2 of Example 146.
  • Step 4 The title compound was prepared as illustrated by Example 141. Purification (RP-HPLC, CH 3 CN/H 2 O with 10 mM NH 4 OAc) afforded the product (3.5 mg, 2%) as a yellow solid.
  • Step 1 The oxime was prepared according to Step 1 of Example 146, but using l-(4- methyl-3-m ' tro-phenyl)-ethylamine as the starting material.
  • Step 2 The amine intermediate was prepared according to Step 2 of Example 146.
  • Step 3 The title compound was prepared as illustrated by Example 141. Purification
  • Step 1 Diazotisation of l-(3-amino-4-methylphenyi)ethanone (0.5 g, 3.4 mmoles) with NaNO 2 (254 mg in 0.5 mL H 2 O, 3.7 mmoles, 1.1 eq) and c. H 2 SO 4 ZH 2 O (0.74 mL/1 mL) at 0 °C followed by hydrolysis with 50% H 2 SO 4, boiling for 5 min. Neutralization, working up (EtOAc/H 2 O) and purification (silica, 10-30% EtOAc/hexane) afforded l-(3-hydroxy-4- methylphenyl)ethanone (205 mg, 41%) as a yellow solid.
  • Step 2 The oxime was prepared according to Step 1 of Example 146, but using 5-(l- amino-ethyl)-2-methyl-phenol as the starting material.
  • Step 3 The amine intermediate was prepared according to Step 2 of Example 146.
  • Step 4 The title compound was prepared as illustrated by Example 141. Purification (RP-HPLC, CH 3 CNZH 2 O with 10 mM NH 4 OAc) afforded the product (90 mg, 61%) as an off- white solid.
  • 1 H NMR 400 MHz, MeOD
  • Example 193 3- ⁇ [(1R)-1-phenylethyl]amino ⁇ -4- ⁇ [2-(pyrimidin-4-ylaimno)pyridin-4-yl]amino ⁇ cyc]obut-3- ene-1,2-dione
  • the title compound was prepared as illustrated by Example 191, but using pyrimidin-4- amine, to afford 0.004 g, 3% as an off white powder.
  • Example 196 S-JKl ⁇ -1-phenylethyllaminoJ ⁇ -iP-Opyridin-1-ylaminoJpyridin-4-yllamino ⁇ cyclobut-S- ene-1,2-dione
  • the title compound was prepared as illustrated by Example 191, but using 2- aminopyridine, to afford 0.02 g, 17% as an off white powder.
  • Example 199 N-(4-(2-((R)-1-phenyIethylamino)-3,4-dioxocyclobut-1-enylammo)pyridin-2-yl)acetamide
  • reaction was stirred under microwave irradiation at 150 °C for 2h.
  • the reaction mixture was filtered through aplug of silica (1% triethylamine/ 10%MeOH/ CH 2 Cl 2 ) and concentrated. Purfication by RP-HPLC (CH 3 CN/H 2 O) afforded the title compound as an off white solid (0.035 g, 28 %).
  • Example 204 3- ⁇ [2-(3-fluorophenyl)pyridin-4-yI]amino ⁇ -4- ⁇ [(1R)-1-phenylethyl]aniiiio ⁇ cyclobut-3-ene- 1,2-dione
  • 3-[(2-chloropyridin-4-yl)ammo]-4- ⁇ [(1R)-1- phenylethyl]amino ⁇ cyclobut-3-ene-1,2-dione (0.111, 0.34 mmol)
  • 2-Benzofuranboronic acid 0.065 g, 1.2 eq
  • Pd(dppf)Cl 2 :CH 2 Cl 2 0.033 g, 0.12 eq).
  • Dioxane (degassed, 2 rnL) and DMF (degassed, 0.2 niL) was then added. The reaction was microwaved for total 4,000 sec at 150 °C, filtered through a plug of Celite ® and concentrated.
  • the vessel was evacuated and purged with nitrogen twice. A solvent mixture of DME/H 2 O/EtOH (7:3:2) (degassed, 4 rnL) was then added. The reaction was microwaved at 150 °C for 300 sec, filtered through Celite ® plug and concentrated to give crude residue. This crude material was purified by RP-HPLC (CH 3 CN- H 2 O with 0.1% formic acid) to afford 0.036 g (18%) of title compound as a yellow solid.
  • Example 222 3-[(2-biphenyl-3-yIpyridin-4-yl)amino]-4- ⁇ [(1R)-1-phenylethyl]amino ⁇ cyclobut-3-ene-1,2- dione
  • the title compound was prepared as outlined for Example 214, but using 3- biphenylboronic acid, to afford 0.059 g (52%) as a yellow solid.
  • Example 226 3-(2,2'-bipyridin-4-ylamino)-4- ⁇ [(1R)-1-phenylethyl]amino ⁇ cyclobut-3-ene-1,2-dione
  • 3-[(2-bromopyridin-4-yl)amino]-4- ⁇ [(1R)-1- phenylethyl]amino ⁇ cyclobut-3-ene-1,2-dione 0.075 g, 0.20 mmol
  • Pd(PPh 3 ) 0.15 g, 0.02 mmol
  • the vessel was evacuated and purged with nitrogen twice, then dioxane (degassed, 2 mL) and DMF (degassed, 0.2 mL) was then added. Finally 2-(tripropylstannyl)pyridine (0.089 g, 0.24 mmol) was added to the reaction which was microwaved for total of 2,400 sec at 150 °C. Workup consisted of filtering the reaction mixture through a plug of silica and evaporation of the solvent. Purification (RP-HPLC, CH 3 CN/H 2 O with 0.1% formic acid) afforded the title compound (0.012g, 16%) as brown solid.
  • Example 229 l-f ⁇ bromophenylJ-1-JIS ⁇ -dioxo-1-fpyridin-4-ylaminoJcyclobut-1-en-1-yllaminoJacetainide
  • 3-ethoxy-4-(pyridin-4-ylamino)-cyclobut-3-ene-1,2-dione 0.05 g, 2.77 mmol
  • 2-amino-2-(4-bromophenyl)acetamide 0.35g, 2.77 mmol
  • the vessel was evacuated and purged with nitrogen twice. A solvent mixture of DME/H 2 O/EtOH (7:3:2) (degassed, 3 mL) was then added. The reaction was microwaved at 150 °C for 300 sec, filtered through Celite ® plug and solution as evaporated to give crude residue. This crude material was purified by RP-HPLC (CH 3 CN-H 2 O with 0.1% formic acid) to afford 0.022 g (30%) of title compound as a yellow solid.

Abstract

The present application provides compounds of Formula (I): and pharmaceutically acceptable salts thereof and pharmaceutical compositions thereof, wherein Het, R4, R9, and R10 are defined herein. Compounds of formula (I) are useful as inhibitors of MAP kinase activated protein kinase 2 (MK2).

Description

SQUARATE KINASE INHIBITORS
TECHNICAL FIELD
The invention relates to squarate kinase inhibitors, and methods for making and using them.
BACKGROUND
Mitogen activated protein (MAP) kinases are a large and diverse group of Ser/Thr kinases separated into three major subgroups, which include the extracellular signal regulated kinases (ERKs), the c-Jun N-terminal kinases (JNKs)/stress-activated protein kinases (JNKs) and p38/reactivating kinases (RK). The ERKs are activated by mitogens and growth factors, whereas the INKs/SAPKs and p38/RK are activated by bacterial lipopolysaccharide (LPS, interleukin-1 (IL-I), tumor necrosis factor-α (TNF-α) and cellular stresses such as heat shock, osmotic shock, or UV damage. Exposure of cells to these factors results in the increased production of proinflammatory cytokines. Analysis of a specific inhibitor of p38 MAP kinase, SB203580, reveals that it inhibits LPS-induced cytokine synthesis in human monocytes, thus indicating that p38 is the MAP kinase responsible for stress-induced cytokine production (see, e.g., Lee, J. C, et al. (1994) Nature 372, 739-746, and U.S. Patent Application Publication No. 2004/0091872, each of which is incorporated by reference in its entirety). SB203580 also prevents the activation of MAP kinase activated protein kinase 2 (MK2, MAPKAPK 2), suggesting that this kinase is activated by p38 (see, e.g., Cuenda, A., et al. (1995) FEBS Letters 364, 229-233, which is incorporated by reference in its entirety).
Mice engineered to be homozygously-deficient in MK2 show a reduction in TNF-α, interferon-γ, IL-I β, and IL-6 production and an increased rate of survival upon challenge with LPS, suggesting that this enzyme is a key component in the inflammatory process and a potential target for anti-inflammatory therapy (Kotlyarov, A., et al. (1999) Nat. Cell. Biol. 1, 94-97, which is incorporated by reference in its entirety). Activation of MK2 results in the production of cytokines by regulating the translation and or stability of the encoding mRNAs through the AU- rich elements of the 3 '-untranslated regions of the gene (Neininger, A., et al. (2002) J. Biol. Chem. 277, 3065-3068, which is incorporated by reference in its entirety). MK2 also phosphorylates the transcription factor CREB, as well as leukocyte specific protein- 1 and heat shock protein 25/27, which are involved in the regulation of actin polymerization and cell migration. See, e.g., Tan, Y., et al. (1996) EMBO J. 15, 4629-4642; Lavoie, J. et al. (1993) J. Biol. Chem. 268, 24210-24214; Stokoe, D. et al. (1992) FEBS Letters 313, 307-313; Ben-Levy, R., et al. (1995) EMBO J. 14, 5920-5930; Hedges, J. C, et al. (1999) J. Biol. Chem. 274, 24211- 24219; and Kotlyarov, A. et al. (2002) MoI. Cell. Biol. 22, 4827-4835, each of which is incorporated by reference in its entirety.
MK2 is a multi-domain protein consisting of an N-terminal proline-rich domain, a catalytic domain, an autoinhibitory domain and at the C-terminus a nuclear export signal (NES) and nuclear localization signal (NLS). See, for example, Stokoe, D., et al. (1993) Biochem. J. 296, 843-849; Engel, K., et al. (1998) EMBO J. 17, 3363-3371; Ben-Levy, R., et al. (1998) Curr. Biol. 8, 1049-1057; Engel, K., et al. (1993) FEBS Letters 336, 143-147; and Veron, M., et al. (1993) Proc. Natl. Acad. Sci. 90, 10618-10622, each of which is incorporated by reference in its entirety. Two isoforms of human MK2 have been characterized. One isoform consists of 400 amino acids and the other isoform 370 residues which is thought to be a splice variant missing the C-terminal NLS (see, e.g., Zu, Y.-L., et al. (1994) Biochem. Biophys. Res. Commun. 200, 1118-1124, which is incorporated by reference in its entirety). MK2 is located in the nucleus of the cell and upon binding and phosphorylation by p38, the MK2 NES becomes functional and both kinases are co-transported out of the nucleus to the cytoplasm (see, e.g., Stokoe, D., et al. (1992) EMBO J. 11, 3985-3994, which is incorporated by reference in its entirety). Interestingly, transport of the MK2/p38 complex does not require catalytically active MK2, as the active site mutant, Asp207Ala, is still transported to the cytoplasm. Phosphorylation of human MK2 by p38 on residues T222, S272 and T334 is thought to activate the enzyme by inducing a conformational change of the autoinhibitory domain thus exposing the active site for substrate binding (see, e.g., Engel, K., et al. (1995) J. Biol. Chem. 270, 27213-27221, which is incorporated by reference in its entirety). Mutations of two autoinhibitory domain residues W332A and K326E in murine MK2 demonstrate an increase in basal activity and a C-terminal deletion of the autoinhibitory domain renders the enzyme constitutively active, providing additional evidence to the role of this domain in inhibition of MK2 activity.
SUMMARY
Certain squarate compounds are kinase inhibitors. In particular, they are inhibitors of MK2, also known as MAPKAP kinase 2.
In one aspect, the present invention provides a compound of Formula (I):
Figure imgf000004_0001
or a pharmaceutically acceptable salt thereof; wherein:
Hβt is a heteroaryl group or a heterocyclyl group, wherein at least one ring atom in said heteroaryl group or said heterocyclyl group is N, and wherein Het is optionally substituted by 1-4 substituents independently selected from R5; R4 is cycloalkyl, cycloalkenyl, or heterocyclyl, each of which is optionally substituted with 1-5 substituents independently selected from Ra; or R4 is -C(R')(R2)R3; or R4 is C1-6 alkyl or C2-6 alkenyl, wherein said C1-6 alkyl and C2-6 alkenyl are each optionally substituted by 1 or 2 Rε groups;
R9 is H, alkyl, cycloalkyl, or perfluoroalkyl; R10 is H, alkyl, cycloalkyl, or perfluoroalkyl; or R4 and R9 taken together with the nitrogen atom to which they are attached are 4- to 7- membered heterocyclyl optionally substituted with 1-5 substituents independently selected from
Ra; or R9 and R10 taken together are -(CR7R8)p-, wherein p is 1, 2, or 3; R1 is -H, halogen, -CN, -CHO, C1-C6 alkyl, C1-C6 perfluoroalkyl, C2-C6 alkenyl,
C2-C6 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, aryl, heteroaryl, heterocyclyl, -C(O)-Rb, -C(O)O-Rb, -C(O)N(R7)-Rb, -SOm-Rb, -SO2-N(R7)-Rb, -(CR7RVOR7, or -C(O)N(R7)R8; wherein Rb is -H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, -(CH2)n-aryl, -(CH2)n-heteroaryl, or -(CH2)n-heterocyclyl; wherein each of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclyl is optionally substituted with 1-5 substituents independently selected from Ra; R2 is -H, halogen, -CN, -CHO, C1-C6 alkyl, C1-C6 perfluoroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, aryl, heteroaryl, heterocyclyl, -C(O)-Rc, -C(O)O-Rc, -C(O)N(R7)-Rc, -SOm-Rc, -SO2-N(R7)-Rc, -(CR7R8)n-OR7, or -C(O)N(R7)R8; wherein Rc is -H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, -(CH2)n-aryl, -(CH2)n-heteroaryl, or -(CH2)n-heterocyclyl; wherein each of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclyl is optionally substituted with 1-5 substituents independently selected from Ra; or R1 and R2 together form an oxo group;
R3 is -(CR7RVaryl, -(CR7R8)n-heteroaryl, -(CR7R8)n-(C3-C8 cycloalkyl), or -(CR7Rs)n-heterocyclyl; wherein R3 is optionally substituted with 1-5 substituents independently selected from Rf; each R5, independently, is halogen, oxo, -CN, -CHO, -OH, -NO2, -N3, -OCF3, -OR7, C1-C6 alkyl, C1-C6 perfluoroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, aryl, heteroaryl, heterocyclyl, -CH=CH-aryl, -CH=CH-heteroaryl, -O-Rd, -OC(O)-Rd, -C(0)-Rd, -C(0)0-Rd, -C(0)N(R7)-Rd, -N(R7)Rd, -N(R7)C(O)-Rd, -N(R7)-SOmRd, -SOm-Rd, -SO2-N(R7)-Rd, -(CR7R8)n-OR7, -C(O)OR7, or -C(O)N(R7)R8; wherein Rd is -H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, -(CH2)n-aryl, -(CH2)n-heteroaryl, or -(CH2)n-heterocyclyl; wherein each R5 is, independently, optionally substituted with 1-5 substituents independently selected from Ra; each R7, independently, is -H, C1-C6 perfluoroalkyl, -(CH2)n-(C1-C6 alkyl), -(CH2)n-(C3-C8 cycloalkyl), -(CH2)n-(C3-C8 cycloalkenyl), -(CH2)n-aryl, -(CH2)n-heteroaryl, or -(CH2)n-heterocyclyl; wherein each R7, independently, is optionally substituted by 1 to 3 substituents selected from the group consisting of halogen, oxo, -CN, -CHO, -CF3, -OH, -NO2, -N3, C1-C6 alkyl, -OCF3, -0-( C1-C6 alkyl), -0-(C3-C8 cycloalkyl), -0-(C3-C8 cycloalkenyl), -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -NHC(O)-( C1-C6 alkyl), -SOm(C,-C6 alkyl), -SOmNH(C1-C6 alkyl), and -SOmN( C1-C6 alkyl)2; each R8, independently, is -H, C1-C6 perfluoroalkyl, -(CH2)n-(C1-C6 alkyl), -(CH2)n-(C3-C8 cycloalkyl), -(CH2)n-(C3-C8 cycloalkenyl), -(CH2)n-aryl, -(CH2)n-heteroaryl, or -(CH2)n-heterocyclyl; wherein each Rs, independently, is optionally substituted by 1 to 3 substituents selected from the group consisting of halogen, oxo, -CN, -CHO, -CF3, -OH, -NO2, -N3, C1-C6 alkyl, -OCF3, -0-(C1-C6 alkyl), -0-(C3-C8 cycloalkyl), -0-(C3-C8 cycloalkenyl), -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -NHC(O)-(C1-C6 alkyl), -SO1n(C1-C6 alkyl), -SOn1NH(C1-C6 alkyl), and -SOraN(C1-C6 alkyl)2; each Ra, independently, is halogen, oxo, -CN, -CHO, -OH, -NO2, -N3, -OCF3, C1-C6 alkyl, C1-C6 perfluoroalkyl, -(CH2)n-(C3-C8 cycloalkyl), -(CH2Jn-(C3-C8 cycloalkenyl), -(CH2)n-CO2R8, -(CH2)n-aryl, -(CH2)n-heteroaryl, -(CH2)n-heterocyclyl, -(CH2)n-OR7, -(CH2)n-N(R7)(Rs), -(CH2)n-C(=NR7)N(R7)(R8), -O-Re, -C(O)-Rc, -C(0)N(R7)-Re, -C(O)-N(R7)-SOm-R8, -O(CH2)n-N(R7)(R8), -N(R7)Re, -N(R7)C(0)-Re, -N(R7)-C(O)-N(R7)(R8), -N(R7)-SOm-Re, -SH, -SOm-Re, -SO2-N(R7)-Re, -0C(0)-Re, -C(O)O-R6, -(CR7R8)n-OR7, or -OPO3(R7)(R8); wherein Re is -H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, -(CH2)n-aryl, -(CH2)n-heteroaryl, or -(CH2)n-heterocyclyl; each Rf, independently, is halogen, oxo, -CN, -CHO, -OH, -NO2, -N3, -OCF3, C1-C6 alkyl, C1-C6 perfluoroalkyl, -(CH2)n-(C3-C8 cycloalkyl), -(CH2)n-(C3-C8 cycloalkenyl), -(CH2)n-CO2R8, -(CH2)n-aryl, -(CH2)n-heteroaryl, -(CH2)n-heterocyclyl, -(CH2)n-OR7, -(CH2)n-N(R7)(R8), -(CH2)n-C(=NR7)N(R7)(R8), -O-Re, -C(O)-Re, -C(0)N(R7)-Re, -C(O)-N(R7)-SOra-R8, -O(CH2)n-N(R7)(R8), -N(R7)Re, -N(R7)C(0)-Re, -N(R7)-C(O)-N(R7)(R8), -N(R7)-SOm-Re, -SH, -SOm-Re, -SO2-N(R7)-Re, -OC(O)-R6, -C(O)O-R6, -(CR7R8Jn-OR7, or -OPO3(R7XR8); wherein said -(CH2)n-heteroaryl and -(CH2)n-aryl are each further optionally substituted by a group selected from halogen, -CN, Q-C4 alkyl, C1-C4 alkoxy, amino, C1-C4- alkylamino, di-C1-C4-alkylaino, aminosulfonyl, C1-C4-alkylaminosulfonyl, di-C1-C4- alkylaminosulfonyl, C1-C4 alkylsulfonylamino, heterocyclylcarbonyl, C1-C4 alkylcarbonyl, and C1-C4 alkoxycarbonylamino; each R8 group is independently selected from carbamyl and hydroxyl; each n, independently, is O, 1, 2, 3 or 4; and each m, independently, is O, 1, or 2; provided that the compound is not 3-(5-bromo-pyridin-3-ylamino)-4-(l- phenylethylamino)cyclobut-3-ene-1,2-dione, 3-(l-phenylethylamino)-4-(pyridin-4-ylamino)- cyclobut-3-ene-1,2-dione, or 3-(bicyclo[2.2.1]hept-2-ylamino)-4-(pyridin-4-ylamino)-cyclobut- 3-ene-1,2-dione; provided that the compound is not quadratic acid 1,2-bis(ρyridyl)amide, quadratic acid 1 ,2-bis(pyridylmethylene)amide; provided that the compound is not 3-chloro-N-(l-{[3,4-dioxo-2-(5-pyrimidinylamino)-1- cyclobuten-1-yl]amino}-2,2-dimethylpropyl)benzamide, N-(l-{[3,4-dioxo-2-(5- pyrimidmylamino)-1-cyclobuten-1-yl]amino}-2,2-dimethylpropyl)-3,5-difluorobenzamide, or N- (l-{[3,4-dioxo-2-(2-pyrazinylamino)-1-cyclobuten-1-yl]amino}-2,2-dimethylpropyl)-3,5- difluorobenzamide; provided that when Het is 4-hydroxy-2-oxo-N-methyl-1,2-dihydropyridin-5-yl, 5- dimethylaminocarbonyl-4-hydroxypyridin-3-yl, 5-hydroxy-6- (dimethylaminocarbonyl)pyrimidin-4-yl, or 5-dimemylaminocarbonyl-4-hydroxy-1-methyl- pyrazol-3-yl, R4 is neither 1,2-dimethylpropyl nor 1-phenylpropyl.
In another aspect, the present invention provides a compound of Formula (I), wherein:
Het can be a heteroaryl group or a heterocyclyl group, where at least one ring atom is N, and where Het is optionally substituted by 1-4 substituents independently selected from R5. R4 can be -C(R')(R2)R3, or R4 can be cycloalkyl, cycloalkenyl, or heterocyclyl, each of which is optionally substituted with 1-5 substituents independently selected from Ra;
R9 is H, alkyl, cycloalkyl, or perfluoroalkyl;
R10 is H, alkyl, cycloalkyl, or perfluoroalkyl; alternatively, R4 and R9 can be taken together with the nitrogen atom to which they are attached to form a 4- to 7- membered heterocyclyl optionally substituted with 1-5 substituents independently selected from Ra. or R9 and R10 taken together are -(CR7R8)P-, wherein p is 1, 2, or 3;
R1 can be -H, halogen, -CN, -CHO, C1-C6 alkyl, C1-C6 perfluoroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, aryl, heteroaryl, heterocyclyl, -C(O)-Rb, -C(O)O-R", -C(O)N(R7)-Rb, -SOm-Rb, -SO2-N(R7)-Rb, -(CR7R8)nOR7, or -C(O)N(R7)R8. Rb can be -H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, -(CH2)n-aryl, -(CH2)n-heteroaryl, or -(CH2)n-heterocyclyl. In R1, each occurrence of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclyl can be optionally substituted with 1-5 substituents independently selected from Ra. R2 can be -H, halogen, -CN, -CHO, C1-C6 alkyl, C1-C6 perfluoroalkyl, C2-C6 alkenyl,
C2-C6 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, aryl, heteroaryl, heterocyclyl, -C(O)-Rc, -C(O)O-Rc, -C(O)N(R7)-Rc, -SOm-Rc, -SO2-N(R7)-Rc, -(CR7R8)n-OR7, or -C(O)N(R7)R8. Rc can be -H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, -(CH2)n-aryl, -(CH2)n-heteroaryl, or -(CH2)n-heterocyclyl. In R2, each occurrence of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclyl can be optionally substituted with 1-5 substituents independently selected from Ra.
R3 can be -(CR7R8)n-aryl, -(CR7R8)n-heteroaryl, -(CR7R8)n-(C3-C8 cycloalkyl), or -(CR7R8)n-heterocyclyl. R3 can be optionally substituted with 1-5 substituents independently selected from Ra.
Each R5, independently, can be halogen, oxo, -CN, -CHO, -OH, -NO2, -N3, -OCF3, -OR7, C1-C6 alkyl, C1-C6 perfluoroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl,
C3-C8 cycloalkenyl, aryl, heteroaryl, heterocyclyl, -CH=CH-aryl, -CH=CH-heteroaryl, -O-Ra, -0C(0)-Rd, -C(0)-Rd, -C(O)O-Rd, -C(0)N(R7)-Rd, -N(R7)Rd, -N(R7)C(O)-Rd, -N(R7)-SOmRd, -SOm-Rd, -SO2-N(R7)-Rd, -(CR7R8)n-OR7, -C(O)OR7, or -C(O)N(R7)R8. Rd can be -H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, -(CH2)n-aryl, -(CH2)n-heteroaryl, or -(CH2)n-heterocyclyl. Each R5 can be, independently, optionally substituted with 1-5 substituents independently selected from Ra.
Each R7, independently, can be -H, C1-C6 perfluoroalkyl, -(CH2)n-(C1-C6 alkyl), -(CH2)n-(C3-C8 cycloalkyl), -(CH2)n-(C3-C8 cycloalkenyl), -(CH2)n-aryl, -(CH2)n-heteroaryl, or -(CH2)n-heterocyclyl. Each R7, independently, can be optionally substituted by 1 to 3 substituents selected from the group consisting of halogen, oxo, -CN, -CHO, -CF3, -OH, -NO2, -N3, C1-C6 alkyl, -OCF3, -0-(C1-C6 alkyl), -0-(C3-C8 cycloalkyl), -0-(C3-C8 cycloalkenyl), -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -NHC(O)-(C1-C6 alkyl), -SOm(C1-C6 alkyl), -SOmNH(C,-C6 alkyl), and -SOmN(C1-C6 alkyl)2.
Each R8, independently, can be -H, C1-C6 perfluoroalkyl, -(CH2)n-(C1-C6 alkyl), -(CH2)n-(C3-C8 cycloalkyl), -(CH2)n-(C3-C8 cycloalkenyl), -(CH2)n-aryl, -(CH2)n-heteroaryl, or -(CH2)n-heterocyclyl. Each R8, independently, can be optionally substituted by 1 to 3 substituents selected from the group consisting of halogen, oxo, -CN, -CHO, -CF3, -OH, -NO2, -N3, C1-C6 alkyl, -OCF3, -0-(C1-C6 alkyl), -0-(C3-C8 cycloalkyl), -0-(C3-C8 cycloalkenyl), -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -NHC(O)-(C1-C6 alkyl), -SOm(C1-C6 alkyl), -SOmNH(C1-C6 alkyl), and -SOmN(C1-C6 alkyl)2. Each Ra, independently, can be halogen, oxo, -CN, -CHO, -OH, -NO2, -N3, -OCF3, C1-C6 alkyl, C1-C6 perfluoroalkyl, -(CH2)H-(C3-C8 cycloalkyl), -(CH2X1-(C3-C8 cycloalkenyl), -(CH2)n-CO2R8, -(CH2)n-aryl, -(CH2)n-heteroaryl, -(CH2)n-heterocyclyl, -(CH2)n-OR7, -(CH2)n-N(R7)(R8), -(CH2)n-C(=NR7)N(R7)(Rs), -0-RE, -C(O)-Re, -C(O)N(R7)-Re, -C(O)-N(R7)-SOm-Rs, -O(CH2)n-N(R7)(RB), -N(R7)Re, -N(R7)C(O)-Re, -N(R7)-C(O)-N(R7)(R8), -N(R7)-SOra-Re, -SH, -SOm-Re, -SO2-N(R7)-Re, -OC(O)-R6, -C(0)0-Re, -(CR7R8)n-OR7, or -OPO3(R7)(R8). Re can be -H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, -(CH2)n-aryl, -(CH2)n-heteroaryl, or -(CH2)n-heterocyclyl.
Each n, independently, is O, 1, 2, 3 or 4. Each m, independently, is O, 1, or 2. In another aspect, the present invention provides a compound of Formula (I), wherein:
Het is pyridin-4-yl optionally substituted by 1-4 substituents independently selected from R5;
R4 is -C(R')(R2)R3, or R4 is cycloalkyl, cycloalkenyl, or heterocyclyl, each of which is optionally substituted with 1-5 substituents independently selected from Ra; or R4 and R9 taken together with the nitrogen atom to which they are attached are 4- to 7- membered heterocyclyl optionally substituted with 1-5 substituents independently selected from Ra;
R1 is -H, halogen, -CN, -CHO, C1-C6 alkyl, C1-C6 perfluoroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, aryl, heteroaryl, heterocyclyl, -C(0)-Rb, -C(0)0-Rb, -C(0)N(R7)-Rb, -SOm-Rb, -SO2-N(R7)-Rb, -(CR7Rs)n-OR7, or -C(O)N(R7)R8; wherein Rb is -H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, -(CH2)n-aryl, -(CH2)n-heteroaryl, or -(CH2)n-heterocyclyl; wherein each of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclyl is optionally substituted with 1-5 substituents independently selected from Ra; R2 is -H, halogen, -CN, -CHO, C1-C6 alkyl, C1-C6 perfluoroalkyl, C2-C6 alkenyl,
C2-C6 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, aryl, heteroaryl, heterocyclyl, -C(0)-Rc, -C(O)O-Rc, -C(0)N(R7)-R°, -SOm-Rc, -SO2-N(R7)-Rc, -(CR7R8)n-OR7, or -C(O)N(R7)R8; wherein Rc is -H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, -(CH2)n-aryl, -(CH2)n-heteroaryl, or -(CH2)n-heterocyclyl; wherein each of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclyl is optionally substituted with 1-5 substituents independently selected from Ra; R3 is -(CR7R8)n-aryl, -(CR7R8)n-heteroaryl, -(CR7R8)n-(C3-C8 cycloalkyl), or -(CR7R8)n-heterocyclyl; wherein R3 is optionally substituted with 1-5 substituents independently selected from Ra; each R5, independently, is halogen, oxo, -CN, -CHO, -OH, -NO2, -N3, -OCF3, -OR7, C1-C6 alkyl, C1-C6 perfluoroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl,
C3-C8 cycloalkenyl, aryl, heteroaryl, heterocyclyl, -CH=CH-aryl, -CH=CH-heteroaryl, -O-Rd, -OC(O)-Rd, -C(O)-Rd, -C(O)O-R", -C(0)N(R7)-Rd, -N(R7)Rd, -N(R7)C(0)-Rd, -N(R7)-SOraRd, -SOm-Rd, -SO2-N(R7)-Rd, -(CR7R8)n-OR7, -C(O)OR7, or -C(O)N(R7)R8; wherein Rd is -H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, -(CH2)n-aryl, -(CH2)n-heteroaryl, or -(CH2)n-heterocyclyl; wherein each R5 is, independently, optionally substituted with 1-5 substituents independently selected from Ra; each R7, independently, is -H, C1-C6 perfluoroalkyl, -(CH2)n-(C1-C6 alkyl), -(CH2)n-(C3-C8 cycloalkyl), -(CH2)n-(C3-C8 cycloalkenyl), -(CH2)naryl, -(CH2)nheteroaryl, or -(CH2)nheterocyclyl; wherein each R7, independently, is optionally substituted by 1 to 3 substituents selected from the group consisting of halogen, oxo, -CN, -CHO, -CF3, -OH, -NO2, -N3, C1-C6 alkyl, -OCF3, -0-(C1-C6 alkyl), -0-(C3-C8 cycloalkyl), -0-(C3-C8 cycloalkenyl), -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -NHC(O)-(C1-C6 alkyl), -SO111(C1-C6 alkyl), -SOmNH(C1-C6 alkyl), and -SOmN(C1-C6 alkyl)2; each R8, independently, is -H, C1-C6 perfluoroalkyl, -(CH2)n-(C1-C6 alkyl),
-(CH2)n-(C3-C8 cycloalkyl), -(CHz)n-(C3-C8 cycloalkenyl), -(CH2)n-aryl, -(CH2)n-heteroaryl, or -(CH2)n-heterocyclyl; wherein each R8, independently, is optionally substituted by 1 to 3 substituents selected from the group consisting of halogen, oxo, -CN, -CHO, -CF3, -OH, -NO2, -N3, C1-C6 alkyl, -OCF3, -0-(C1-C6 alkyl), -0-(C3-C8 cycloalkyl), -0-(C3-C8 cycloalkenyl), -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -NHC(O)-(C1-C6 alkyl), -SO1n(C1-C6 alkyl), -SOmNH(C1-C6 alkyl), and -SO1nN(C1-C6 alkyl)2;
R9 is H, alkyl, cycloalkyl, or perfluoroalkyl;
R10 is H, alkyl, cycloalkyl, or perfluoroalkyl; or R9 and R10 taken together are -(CR7R8)P-, wherein p is 1, 2, or 3; each Ra, independently, is halogen, oxo, -CN, -CHO, -OH, -NO2, -N3, -OCF3, C1-C6 alkyl, C1-C6 perfluoroalkyl, -(CH2)n-(C3-C8 cycloalkyl), -(CH2)n-(C3-C8 cycloalkenyl), -(CH2)nCO2R8, -(CH2)n-aryl, -(CH2)n-heteroaryl, -(CH2)n-heterocyclyl, -(CH2)n-OR7, -(CH2)n-N(R7)(R8), -(CH2)n-C(=NR7)N(R7)(R8), -O-Re, -C(O)-Re, -C(0)N(R7)-Re, -C(O)-N(R7)-SOm-R8, -O(CH2)nN(R7)(R8), -N(R7)Re, -N(R7)C(0)-Re, -N(R7)-C(O)-N(R7)(R8), -N(R7)-SOm-Re, -SH1 -SOm-Re, -SO2-N(R7)-Re, -OC(O)-Re, -C(O)O-R=, -(CR7R8)nOR7, or -OPO3(R7)(R8); wherein Re is -H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, -(CH2)n-aryl, -(CH2)n-heteroaryl, or -(CH2)n-heterocyclyl; each n, independently, is 0, 1, 2, 3 or 4; and each m, independently, is 0, 1, or 2; provided that the compound is not 3-(5-bromo-pyridm-3-ylamino)-4-(l- phenylethylamino)cyclobut-3-ene-1,2-dione, 3-(l-phenylethylamino)-4-(pyridin-4-ylamino)- cyclobut-3-ene-1,2-dione, or 3-(bicyclo[2.2.1]hept-2-ylamino)-4-(pyridin-4-ylamino)-cyclobut- 3-ene-1,2-dione.
In some embodiments, the compound can be in the form of a pharmaceutically acceptable salt.
In some embodiments, the compound is not 3-(5-bromo-pyridin-3-ylamino)-4-(l- phenylethylamino)cyclobut-3-ene-1,2-dione, 3-(l-phenylethylamino)-4-(pyridin-4-ylamino)- cyclobut-3-ene-1,2-dione, 3-(bicyclo[2.2.1]hept-2-ylamino)-4-(pyridin-4-ylamirio)-cyclobut-3- ene-1,2-dione; quadratic acid 1,2-bis(pyridyl)amide, quadratic acid 1,2- bis(pyridylmethylene)amide; 3-chloro-N-(l-{[3,4-dioxo-2-(5-pyrimidinylamino)-1-cyclobuten- 1 -yl] amino } -2 ,2-dimethylpropyl)benzamide, N-( 1 - { [3 ,4-dioxo-2-(5 -pyrimidinylamino)- 1 - cyclobuten-1-yl]amino}-2,2-dimethylpropyl)-3,5-difluorobenzamide, or N-(I- {[3,4-dioxo-2-(2- pyrazinylamino)-1-cyclobuten-1-yl]amino}-2,2-dimethylpropyl)-3,5-difluorobenzamide.
In some embodiments, when Het is 4-hydroxy-2-oxo-N-methyl-1,2-dihydropyridm-5-yl, S-dimethylaminocarbonyM-hydroxypyridin-S-yl, 5-hydroxy-6-
(dimethylaminocarbonyl)pyrimidin-4-yl, or 5 -dimethylaminocarbonyl-4-hydroxy- 1 -methyl- pyrazol-3-yl, R4 is neither 1,2-dimethylpropyl nor 1-phenylpropyl.
In some embodiments, Het is pyridin-4-yl optionally substituted by 1-4 substituents independently selected from R5. R4, R9, and R10 can each be defined as above. The compound can be in the form of a pharmaceutically acceptable salt. In some embodiments, the compound is not 3~(5-bromo-pyridin-3-ylamino)-4-(l- phenylethylamino)cyclobut-3-ene-1,2-dione, 3-(l-phenylethylamino)-4-(pyridin-4-ylamino)- cyclobut-3-ene-1,2-dione, or 3-(bicyclo[2.2.1]hept-2-ylamino)-4-(pyridin-4-ylamino)-cyclobut- 3-ene-1,2-dione. In some embodiments, Het is pyridinyl, piperidinyl, pyrimidinyl, oxazolinyl, pyrazolyl, isoquinolinyl, or quinolinyl, optionally substituted by 1-4 substituents independently selected from R5. In some embodiments, Het is pyridin-4-yl optionally substituted by 1-4 substituents independently selected from R5. Fn some embodiments, Het is pyridin-4-yl optionally substituted at the 2-position by R5. In some circumstances, R5 can be -OR7, -N(R7)R8, aryl, heteroaryl, or -N(R7)C(O)R8. R4 can be -C(R')(R2)R3. In some embodiments, each R5, independently, is halogen, -OH, -N3, C1-C6 alkyl, aryl, heteroaryl, heterocyclyl, -CH=CH-aryl, -O-Rd, -C(O)O-Rd, -C(O)N(R7)-Rd, -N(R7)Rd, -N(R7)C(O)-Rd, or -SOm-Rd; wherein each R5 is, independently, optionally substituted with 1-5 substituents independently selected from Ra. In some embodiments, each R5 is, independently, methyl, methoxy, hydroxyl, chloro, bromo, carboxamide, azido, tert- butoxycarbonyl, 4-benzyl-1H-1,2,3-triazol-1-yl, morpholin-4-yl, phenyl, 2-fluorophenyl, 3- flurophenyl, 4-chlorophenyl, 4-methylphenyl, 3-methylphenyl, l-benzofuran-2-yl, furan-2-yl, 3- trifluoromethylphenyl, 4-trifluoromethylphenyl, 3-methoxyphenyl, 4-(hydroxymethyl)phenyl, 4- (hydroxymethyl)-1H-l,2,3-triazol-1-yl, 4-phenyl-1H-1,2,3-triazol-1-yl, 4- (cyclopentylaminocarbonyl)phenyl, 4-acetamidophenyl, 2-(4-chlorophenyl)vinyl, phenylthio, 3- (benzyloxy)phenyl, biphenyl-3-yl, anilino, 4-trifluoromethylanilino, 2-pyrimidin-4-ylamino, 3- (hydroxymethyl)anilino, 3-carbamylanilino, pyridin-3-ylamino, pyridin-2-ylamino, pyridin-4- ylamino, 4-methyl-1,2,3-triazol-2-ylamino, quinolin-2-ylamino, pyrimidin-2-ylamino, acetamido, pyridin-4-yl, pyridin-3-yl, pyridin-2-yl, benzamido, or nicotinamido. In some embodiments, R2 is -H, C1-C6 alkyl, aryl, heteroaryl, -C(O)-Rc, -C(O)O-Rc,
-(CR7R8)n-OR7, or -C(O)N(R7)R8. In some embodiments, R2 is -H, C1-C6 alkyl, or -C(O)N(R7)-Rc. In some embodiments, R2 is -H, methyl, or -C(O)NH2, or -C(O)NH-(C1-C6 alkyl).
In some embodiments, R3 is aryl, heteroaryl, C3-C8 cycloalkyl, or heterocyclyl, wherein R3 is optionally substituted with 1-5 substituents independently selected from Ra. In some embodiments, R3 is aryl optionally substituted with 1-5 substituents independently selected from Ra. In some embodiments, R3 is phenyl optionally substituted with 1-5 substituents independently selected from Ra. In some embodiments, R3 is phenyl optionally substituted with 1-5 substituents selected from C1-C6 alkyl, C1-C6 perfluoroalkyl, halogen, -0-(C1-C6 alkyl), -OH, -NO2, -CN, -N(R7)Re, -(CH2)n-C(O)OR8, aryl, heteroaryl, or heterocyclyl. In some embodiments, R3 is -(CR7R8)n-aryl, -(CR7R8)n-heteroaryl, -(CR7R8)n-(C3-C8 cycloalkyl), or -(CR7R8)n-heterocyclyl; wherein R3 is optionally substituted with 1, 2, or 3 substituents independently selected from Ra.
In some embodiments, R4 is -C(R1)(R2)R3.
In some embodiments, R4 and R9 taken together with the nitrogen atom to which they are attached are 4- to 7- membered heterocyclyl optionally substituted with 1-5 substituents independently selected from Ra.
In some embodiments, R1 is -H. In some embodiments, R2 is-H, C1 -C6 alkyl, or -C(O)N(R7)-Rc. In some embodiments, R2 is-H, methyl, or -C(O)NH2, or -C(O)NH-(C1-C6 alkyl). In some embodiments, R1 is -H or C1-C6 alkyl. In some embodiments, R1 is -H or C1-C6 alkyl; R2 is -H, C1-C6 alkyl, or -C(O)N(R7)-Rc;
R3 is phenyl optionally substituted with 1-5 substituents independently selected from Ra; and Het is pyridin-4-yl optionally substituted at the 2-position by aryl, heteroaryl, -NH-aryl, or -NH-heteroaryl, wherein aryl and heteroaryl are each optionally substituted with 1-5 substituents independently selected from Ra. In some embodiments, R1 is -H or C1-C6 alkyl; R2 is -CH3, -CH2CH3, -CH2OH,
-C(O)NH2, -C(O)NH-(C1-C6 alkyl), -C(O)NH-(CH2)n-chlorophenyl, -C(O)NH-(CH2)n-pyridyl, or -C(CH3)2OH; R3 is phenyl optionally substituted with 1-5 substituents independently selected from C1-C6 alkyl, halogen, hydroxy, -NHC(O)NHCH3, aminophenyl, acetylamino, phenyl, and furyl; and Het is pyridin-4-yl optionally substituted at the 2-position by methoxyphenyl, thienyl, pyridinyl, hydroxymethylphenylamino, aminocarbonylphenylamino, pyridinylamino, fluorophenyl, pyrimidinylamino, pyrazinyl, or furyl.
In some embodiments, Het is pyridin-4-yl, isooxazol-5-yl, piperidin-4-yl, pyrimidin-4-yl, 1H-pyrazol-3-yl, isoquinolin-5-yl, or thieno[2,3-d]pyridin-4-yl, each of which is optionally substituted by 1 to 4 independently selected R5 groups. In some embodiments, Het is pyridin-4-yl, isooxazol-5-yl, piρeridin-4-yl, pyrimidin-4-yl, 1H-pyrazol-3-yl, isoquinolin-5-yl, or thieno[2,3-d]pyridin-4-yl, each of which is optionally substituted by a R5 group.
In some embodiments, each R7 in each R5 group, independently, is -H. In some embodiments,each Ra in each R5 group, independently, is halogen, C1-C6 alkyl,
C1-C6 perfluoroalkyl, -(CH2)n-aryl, -(CH2)n-OR7, -O-Re, -C(O)N(R7)-Re, or -N(R7)C(O)-Re.
In some embodiments, each Rais, independently, halogen, -CN, -OH, -NO2, C1-C6 alkyl, C1-C6 perfluoroalkyl, -(CH2)n-(C3-C8 cycloalkyl), -(CH2)n-aryl, -(CH2)n-heteroaryl, -(CH2)n-heterocyclyl, -O-Re, -C(O)N(R7)-Re, -N(R7)Re, -N(R7)C(0)-Re, -N(R7)-C(O)-N(R7)(R8), -N(R7)-SOm-Re, or -C(O)O-R6.
In some embodiments, each Rd in each R5 group is, independently, -H, C1-C6 alkyl, -(CH2)n-aryl, or -(CH2)n-heteroaryl. hi some embodiments, each Re in each R5 group is, independently, -H, C1-C6 alkyl, or C3-C8 cycloalkyl. In some embodiments, each n, independently, is O or 1.
In some embodiments, each m, independently, is O.
In some embodiments, within each R5 group, or substituents thereof: each R7, independently, is -H; each Ra, independently, is halogen, C1-C6 alkyl, C1-C6 perfluoroalkyl, -(CH2)n-aryl, -(CH2)n-OR7, -O-Re, -C(0)N(R7)-Re, or -N(R7)C(O)-Re; each Rd is, independently, -H, C1-C6 alkyl, -(CH2)n-aryl, or -(CH2)n-heteroaryl; each Re is, independently, -H, C1-C6 alkyl, or C3-C8 cycloalkyl; each n, independently, is 0 or 1; and each m, independently, is 0. In some embodiments, within each R2 group, or substituents thereof: each Rc is -H, C1-C6 alkyl, or -(CH2)n-heterocyclyl; each R7 is, independently, -H or -(CH2)n-(C1-C6 alkyl); each n, independently, is 0 or 1; and each R8 is, independently, -H, -(CH2)n-(C1-C6 alkyl), -(CH2)^-(C3-C8 cycloalkyl), -(CH2)n-aryl, or -(CH2)n-heteroaryl; wherein each of which is optionally substituted by a substituent selected from halogen. In some embodiments, within each R3 group, or substituents thereof: each Re is -H or C1-C6 alkyl; each R7, independently, is -H or C1-C6 alkyl; each n, independently, is 0 or 1; and each R8, independently, is -H or C1-C6 alkyl.In some embodiments, each Rc in each R2 group is -H, C1-C6 alkyl, or -(CH2)n-heterocyclyl.
In some embodiments, each R7 in each R2 group is, independently, -H or -(CH2)n-(C1-C6 alkyl).
In some embodiments, each R8 in each R2 is, independently, -H, -(CH2)n-(C1-C6 alkyl), -(CH2)n-(Cs-C8 cycloalkyl), -(CH2)n-aryl, or -(CH2)n-heteroaryl; wherein each of which is optionally substituted by a substituent selected from halogen.
In some embodiments, each Rain each R3 group is, independently, halogen, -CN, -OH, -NO2, C1-C6 alkyl, C1-C6 perfluoroalkyl, -(CH2)n-(C3-C8 cycloalkyl), -(CH2)n-aryl, -(CH2)n-heteroaryl, -(CH2)n-heterocyclyl, -O-Re, -C(O)N(R7)-Re, -N(R7)Re, -N(R7)C(O)-Re, -N(R7)-C(O)-N(R7)(R8), -N(R7)nSOm-Re, or -C(O)O-R6.
In some embodiments, each Re in each R3 group is -H or C1-C6 alkyl.
In some embodiments, each R7 in each R3 group, independently, is -H or C1-C6 alkyl.
In some embodiments, each R8 in each R3 group, independently, is -H or C1-C6 alkyl.
In some embodiments, each Re in each R3 group is -H or methyl. In some embodiments, each R7 in each R3 group, independently, is -H or methyl.
In some embodiments, each R8 in each R3 group, independently, is -H or methyl.
In some embodiments: each R7, independently, is -H; each Ra, independently, is halogen, C1-C6 alkyl, C1-C6 perfluoroalkyl, -(CH2)n-aryl, -(CH2)n-OR7, -O-Rc, -C(0)N(R7)-Re, or -N(R7)C(0)-Rc; each Rd is, independently, -H, C1-C6 alkyl, -(CH2)n-aryl, or -(CH2)n-heteroaryl; each Re is, independently, -H, C1-C6 alkyl, or C3-C8 cycloalkyl; each n, independently, is O or 1 ; and each m, independently, is O. In some embodiments: each Rc is -H, C1-C6 alkyl, or -(CH2)n-heterocyclyl; each R7 is, independently, -H or -(CH2)n-(C1-C6 alkyl); each n, independently, is 0 or 1 ; and each R8 is, independently, -H, -(CH2)n-(C1-C6 alkyl), -(CH2)n-(C3-C8 cycloalkyl), -(CH2)n-aryI, or -(CH2)n-heteroaryl; wherein each of which is optionally substituted by a substituent selected from halogen.
In some embodiments: each Re is -H or C1-C6 alkyl; each R7, independently, is -H or C1-C6 alkyl; each n, independently, is 0 or 1; and each R8, independently, is -H or C1-C6 alkyl.
In some embodiments:
Het is pyridin-4-yl, isooxazol-5-yl, piperidin-4-yl, pyrimidin-4-yl, 1H-pyrazol-3-yl, isoquinolin-5-yl, or thieno[2,3-d]pyridin-4-yl, each of which is optionally substituted by 1 to 4 independently selected C1-C6 alkyl groups; or Het is pyridin-4-yl, isooxazol-5-yl, piperidin-4-yl, pyrimidin-4-yl, 1H-pyrazol-3-yl, isoquinolin-5-yl, or thieno[2,3-d]pyridin-4-yl, each of which is optionally substituted by a R5 group; each R5, independently, is halogen, -OH, -N3, C1-C6 alkyl, aryl, heteroaryl, heterocyclyl, -CH=CH-aryl, -O-Rd, -C(O)O-Rd, -C(0)NH-Rd, -NHRd, -NHC(O)-Rd, or -SOm-Rd; wherein each R5 is, independently, optionally substituted with 1-5 substituents independently selected from Rla; each Rla, independently, is halogen, C1-C6 alkyl, C1-C6 perfluoroalkyl, -(CH2)n-aTyI, -(CH2)n-OH, -O-Re, -C(O)NH-R6, or -NHC(O)-R6; each Rd is, independently, -H, C1-C6 alkyl, -(CH2)n-aryl, or -(CH2)n-heteroaryl; each n, independently, is 0 or 1; each m, independently, is 0;
R4 is -CCR1XR2)R3; or
R4 and R9 taken together with the nitrogen atom to which they are attached are 4- to 7- membered heterocyclyl optionally substituted with 1-5 substituents independently selected from Ra.
R1 is -H or C1-C6 alkyl; R2 is -H, C1-C6 alkyl, aryl, heteroaryl, -C(O)-Rc, -C(O)O-Rc, -(CR7RVOR7, or -C(O)N(R7)R8; each Rc is -H, C1-C6 alkyl, or -(CH2)n-heterocyclyl; each R7 is, independently, -H or -(CH2)n-(C1-C6 alkyl); each R8 is, independently, -H, -(CH2)n-(C1-C6 alkyl), -(CH2)n-(C3-C8 cycloalkyl),
-(CH2)n-aryl, or -(CH2)n-heteroaryl; wherein each of which is optionally substituted by a substituent selected from halogen;
R3 is -(CR7R8)n-aryl, -(CR7R8)n-heteroaryl, -(CR7R8^-(C3-C8 cycloalkyl), or -(CR7R8)n-heterocyclyl; wherein R3 is optionally substituted with 1, 2, or 3 substituents independently selected from Ra; each Rais, independently, halogen, -CN, -OH, -NO2, C1-C6 alkyl, C1-C6 perfluoroalkyl, -(CH2)n-(C3-C8 cycloalkyl), -(CH2)n-aryl, -(CH2)n-heteroaryl, -(CH2)n-heterocyclyl, -O-Re, -C(0)N(R7)-Re, -N(R7)Re, -N(R7)C(0)-Re, -N(R7)-C(O)-N(R7)(R8), -N(R7)-SOra-Re, or -C(O)O-Rc; and each Re is, independently, -H, C1-C6 alkyl, or C3-C8 cycloalkyl.
In some embodiments:
R1 is -H or C1-C6 alkyl;
R2 is -H, C1-C6 alkyl, or -C(0)N(R7)-R°;
R3 is phenyl optionally substituted with 1-5 substituents independently selected from Ra; and
Het is pyridin-4-yl optionally substituted at the 2-position by aryl, heteroaryl, -NH-aryl, or -NH-heteroaryl, wherein aryl and heteroaryl are each optionally substituted with 1-5 substituents independently selected from Ra.
In some embodiments: R1 is -H or C1-C6 alkyl;
R2 is -CH3, -CH2CH3, -CH2OH, -C(O)NH2, -C(O)NH-(C1-C6 alkyl), -C(O)NH-(CH2)n-chlorophenyl, -C(O)NH-(CH2)n-pyridyl, or -C(CH3)2OH;
R3 is phenyl optionally substituted with 1-5 substituents independently selected from C1-C6 alkyl, halogen, hydroxy, -NHC(O)NHCH3, aminophenyl, acetylamino, phenyl, and furyl; and Het is pyridin-4-yl optionally substituted at the 2-ρosition by methoxyphenyl, thienyl, pyridinyl, hydroxymethylphenylamino, aminocarbonylphenylamino, pyridinylamino, fluorophenyl, pyrimidinylamino, pyrazinyl, or furyl.
In some circumstances, Het can be ρyridin-4-yl optionally substituted at the 2-position by R5; R4 can be -C(R')(R2)R3, where R1 is H and R2 and R3 are as defined above; and R9 and R10 are each H. R3 can be aryl optionally substituted with 1-5 substituents independently selected from Ra.
The compound can be selected from the group consisting of: 2-{[3,4-dioxo-2~(pyridin-4- ylamino)cyclobut- 1 -en- 1 -yl] amino } -2-phenyl-N-(pyridm-4-ylmethyl)acetamide, 2- { [3 ,4-dioxo- 2-(pyridin-4-ylamino)cyclobut- 1 -en- 1 -yl] amino }-N-isobutyl-2-phenylacetamide, 3 - [(3 - methylbenzyl)amino]-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2-dione, (2S)-2-(4-chlorophenyl)- 2-{[3,4-dioxo-2-(pyridin-4-ylamino)cyclobut-1-en-1-yl]amino}acetamide, 3-{[(1R)-1- phenylethyl]amino}-4-[(2-phenylpyridin-4-yl)amino]cyclobut-3-ene-l ,2-dione, 3- {[(1R)-1- phenylethyl]amino}-4-{[2-(pyrimidin-4-ylamino)pyridin-4-yl]ammo}cyclobut-3-ene-l;2-dione, 3-{[(1R)-l -phenylethyl] amino } -4- { [2-(pyrazin-2-ylamino)pyridin-4-yl] amino } cyclobut-3 -ene- 1 ,2-dione, 3- { [ 1 -(3-hydroxyphenyl)ethyl]amino} -4-(pyridin-4-ylamino)cyclobut-3-ene- 1 ,2- dione, 3 - { [2-(2-furyl)pyridin-4-yl] amino }-4-{[(1R)-l -phenylethyl] amino } cyclobut-3 -ene- 1 ,2- dione, 2- { [3 ,4-dioxo-2-(pyridin-4-ylamino)cyclobut- 1 -en- 1 -yl] amino } -2-(3 - hydroxyphenyl)acetamide, 3-{[(1R)-l -phenylethyl] amino } -4- { [2-(pyrimidin-2-ylamino)pyridin- 4-yl]amino}cyclobut-3-ene-1,2-dione, 2-(4-bromophenyl)-2-{[3,4-dioxo-2-(pyridin-4- ylamino)cyclobut-1-en-1-yl]amino}acetamide, N-[2-(4-chlorophenyl)ethyl]-2-{[3,4-dioxo-2- (pyridin-4-ylamino)cyclobut- 1 -en- 1 -yl] amino} -2-phenylacetamide, 3 - { [( 1 i?)- 1 -(4- bromophenyl)ethyl]amino}-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2-dione, 3-{[(1S)-2-hydroxy- l-phenylethyl]amino}-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2-dione, 2-{[3,4-dioxo-2-(pyridin- 4-ylamino)cyclobut- 1 -en- 1 -yl] amino } -iV-methyl-2-phenylacetamide, 3 - { [( 1 K)- 1 -(4- methylphenyl) ethyl] amino } -4-(pyridin-4-ylamino)cyclobut-3 -ene- 1 ,2-dione, (2S)-2- { [3 ,4-dioxo- 2-(pyridin-4-ylamino)cyclobut- 1 -en- 1 -yl] amino } -N-methyl-2-phenylacetamide, 2-{[3,4-dioxo-2- (pyridin-4-ylamino)cyclobut-1-en-1-yl]amino}-N-ethyl-2-phenylacetamide, 2-(3,4- dichlorophenyl)-2-{[3,4-dioxo-2-(ρyridin-4-ylamino)cyclobut-1-en-1-yl]amino}acetamide (trifluoracetate salt), 2-(4-chlorophenyl)-2-{[3,4-dioxo-2-(pyridin-4-ylamino)cyclobut-1-en-1- yl] amino }acetamide (trifluoracetate salt), 2-{[3,4-dioxo-2-(pyridin-4-ylamino)cyclobut-1-en-1- yl] amino } -2-(4-fluorophenyl)acetamide, 2- { [3 ,4-dioxo-2-(pyridin-4-ylamino)cyclobut- 1 -en- 1 - yl]amino}-2-(3,4,5-trifluorophenyl)acetamide, 3-{[(1S)-2-hydroxy-2-methyl-1- phenylpropyl]amino}-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2-dione, 3-{[2-(3- methoxyphenyl)pyridin-4-yl] amino }-4-{[(1R)-l -phenylethyl] amino } cyclobut-3 -ene- 1 ,2-dione, 3 - { [2-(3-fluorophenyl)pyridin-4-yl] amino }-4-{[(1R)-l -phenylethyl] amino } cyclobut-3 -ene- 1 ,2- dione, 3-(2,3'-bipyridin-4-ylamino)-4-{[(1R)-1-phenylethyl]amino}cyclobut-3-ene-1,2-dione, 3- [(2-{[3-(hydroxymethyl)phenyl]amino}pyridin-4-yl)amino]-4-{[(1R)-1- phenylethyl] amino } cyclobut-3 -ene- 1 ,2-dione, 3 -( {4- [(3 ,4-dioxo-2- { [( 1 R)- 1 - phenylethyl] amino } cyclobut- 1 -en- 1 -yl)amino]pyridin-2-yl } amino)benzamide, 3- [( 1 -methyl- 1 - phenylethyl)amino]-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2-dione, 3-([(1R)-I- phenylethyl]amino}-4-{[2-(pyridin-2-ylamino)pyridin-4-yl]amino}cyclobut-3-ene-l>2-dione, 3- (2,4'-bipyridin-4-ylamino)-4-{[(1R)-1-phenylethyl]amino}cyclobut-3-ene-1,2-dione, 3-{[2-(2- fluorophenyl)pyridin-4-yl] amino }-4-{[(1R)-l -phenylethyl] amino } cyclobut-3 -ene- 1 ,2-dione, N- [3-(l-{[3,4-dioxo-2-(pyridin-4-ylamino)cyclobut-1-en-1-yl]amino}ethyl)phenyl]acetamide, 2- {[3,4-dioxo-2-(pyridin-4-ylamino)cyclobut-1-en-1-yl]amino}-2-[4-(3-furyl)phenyl]acetamide, 2- biphenyl-4-yl-2- { [3 ,4-dioxo-2-(pyridin-4-ylamino)cyclobut- 1 -en- 1 -yl] amino } acetamide, 3 - {[(1R)-1-phenylpropyl]amino}-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2-dione, 3-{[(1R)-1-(4- fluorophenyl)ethyl]amino}-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2-dione, 3-{[l-(4- hydroxyphenyl)ethyl]amino}-4-(ρyridin-4-ylamino)cyclobut-3-βne-1,2-dione, 2-(3-chloro-4- fluorophenyl)-2-{[3,4-dioxo-2-(pyridin-4-ylaminoJcyclobut-1-en-1-ylJaminoJacetamide, 2- {[3,4-dioxo-2-(pyridin-4-ylamino)cyclobut-1-en-1-yl]amino}-2-(2-fluorophenyl)acetamide, 3- { [ 1 -(3-fluorophenyl)ethyl]amino} -4-(pyridin-4-ylamino)cyclobut-3-ene- 1 ,2-dione, 3- { [ 1 -(2- fluorophenyl)ethyl]amino}-4-(pyridin-4-ylamino)cyclobut-3-ene-l ,2-dione, N-[3-(l-{[3,4-dioxo- 2-(pyridin-4-ylamino)cyclobut- 1 -en- 1 -yl] amino} ethyl)phenyl] -.N'-methylurea, 3 - { [ 1 -(3-hydroxy- 4-methylphenyl)ethyl] amino } -4-(pyridin-4-ylamino)cyclobut-3 -ene- 1,2-dione, 3-{[l-(3'- aminobiphenyl-4-yl)ethyl]amino}-4-(pyridin-4-ylamino)cyclobut-3-ene-l ,2-dione, and pharmaceutically acceptable salts thereof.
The compound can be selected from the group consisting of N-[2-(4-chlorophenyl)ethyl]- 2-{[3,4-dioxo-2-(pyridin-4-ylamino)cyclobut-1-en-1-yl]amino}-2-phenylacetamide, 3-{[(1R)-1- (4-bromophenyl)ethyl]amino}-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2-dione, 3-{[(1S)-2- hydroxy- 1 -phenylethyl] amino } -4-(pyridin-4-ylamino)cyclobut-3 -ene- 1 ,2-dione, 2- { [3 ,4-dioxo- 2-(pyridin-4-ylamino)cyclobut- 1 -en- 1 -yl]amino} -N-methyl-2-phenylacetamide, 3- {[(1R)- 1 -(4- methylphenyl)ethyl] amino } -4-(pyridin-4-ylamino)cyclobut-3 -ene- 1 ,2-dione, (2S)-2- { [3 ,4-dioxo- 2-(pyridin-4-ylamino)cyclobut- 1 -en- 1 -yl] amino } -iV-methyl-2-phenylacetamide, 2- { [3 ,4-dioxo-2- (pyridin-4-ylamino)cyclobut- 1 -en- 1 -yl] amino } -iV-ethyl-2-phenylacetamide, 2-(3 ,4- dichlorophenyl)-2-{[3,4-dioxo-2-(pyridin-4-ylamino)cyclobut-1-en-1-yl]amino}acetamide (trifluoracetate salt), 2-(4-chlorophenyl)-2-{[3,4-dioxo-2-(pyridin-4-ylamino)cyclobut-1-en-1- yl] amino }acetamide (trifluoracetate salt), 2-{[3,4-dioxo-2-(pyridin-4-ylamino)cyclobut-1-en-1- yl]amino}-2-(4-fluorophenyl)acetamide, 2-{[3,4-dioxo-2-(pyridin-4-ylamino)cyclobut-1-en-1- yl]amino}-2-(3,4,5-trifluorophenyl)acetamide, 3-{[(1S)-2-hydroxy-2-methyl-1- phenylpropyl]amino}-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2-dione, 3-{[2-(3- methoxyphenyl)pyridin-4-yl] amino }-4-{[(1R)-l -phenylethyl] amino } cyclobut-3-ene- 1 ,2-dione, 3-{[2-(3-fluorophenyl)ρyridin-4-yl]amino}-4-{[(1R)-1-phenylethyl]amino}cyclobut-3-ene-1,2- dione, 3-(2,3'-bipyridin-4-ylamino)-4-{[(1R)-1-phenylethyl]amino}cyclobut-3-ene-1,2-dione, 3- [(2-{[3-(hydroxymethyl)phenyl]amino}pyridm-4-yl)amino]-4-{[(1R)-1- phenylethyl]amino}cyclobut-3-ene-1,2-dione, 3-({4-[(3,4-dioxo-2-{[(1R)-1- phenylethyl] amino } cyclobut- 1 -en- 1 -yl)amino]pyridin-2-yl} amino)benzamide, 3 - [( 1 -methyl- 1 - phenylethyl)amino]-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2-dione, 3-{[(1R)-1- phenylethyl] amino } -4- { [2-(pyridm-2-ylamino)pyridin-4-yl] amino } cyclobut-3-ene- 1 ,2-dione, 3 - (2,4'-bipyridin-4-ylamino)-4-{[(1R)-1-phenylethyl]amino}cyclobut-3-ene-1,2-dione, 3-{[2-(2- fluorophenyl)pyridin-4-yl] amino }-4-{[(1R)-l -phenylethyl] amino } cyclobut-3 -ene- 1 ,2-dione, N- [3-(l-{[3,4-dioxo-2-(pyridin-4-ylamino)cyclobut-1-en-1-yl]amino}ethyl)phenyl]acetainide, 2- {[3,4-dioxo-2-(pyridin-4-ylamino)cyclobut-1-en-1-yl]amino}-2-[4-(3-furyl)phenyl]acetamide, 2- biphenyl-4-yl-2- { [3 ,4-dioxo-2-(pyridin-4-ylamino)cyclobut- 1 -en- 1 -yl] amino } acetamide, 3 - {[(1R)-1-phenylpropyl]amino}-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2-dione, 3-{[(1R)-1-(4- fluorophenyl)ethyl]amino}-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2-dione, 3-{[l-(4- hydroxyphenyl)ethyl]amino}-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2-dione, 2-(3-chloro-4- fluorophenyl)-2- { [3 ,4-dioxo-2-(pyridin-4-ylamino)cyclobut- 1 -en- 1 -yl] amino } acetamide, 2- { [3 ,4-dioxo-2-(pyridin-4-ylamino)cyclobut- 1 -en- 1 -yl] amino } -2-(2-fluorophenyl)acetamide, 3 - { [ 1 -(3-fluorophenyl)ethyl]amino} -4-(pyridin-4-ylamino)cyclobut-3-ene-l ,2-dione, 3- { [ 1 -(2- fluorophenyl)ethyl]amino}-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2-dione, N-[3-(l-{[3,4-dioxo- 2-(pyridin-4-ylamino)cyclobut- 1 -en- 1 -yl] amino} ethyl)phenyl] -N'-methylurea, 3 - { [ 1 -(3-hydroxy- 4-methylphenyl)ethyl]amino}-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2-dione, 3-{[l-(3'- aminobiphenyl-4-yl)ethyl]amiπo}-4-(pyridin-4-ylainino)cyclobut-3-ene-1,2-dione, and pharmaceutically acceptable salts thereof.
The compound can be selected from the group consisting of 3-{[(1R)-1- phenylpropyl] amino } -4-(ρyridin-4-ylamino)cyclobut-3 -ene- 1 ,2-dione, 3-{[(1R)-1-(4- fluorophenyl)ethyl]amino}-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2-dione, 3-{[l-(4- hydroxyphenyl)ethyl]amino}-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2-dione, 2-(3-chloro-4- fluorophenyl)-2-{[3,4-dioxo-2-(pyridin-4-ylamino)cyclobut-1-en-1-yl]amino}acetamide, 2- {[3,4-dioxo-2-(pyridin-4-ylamino)cyclobut-1-en-1-yl]amino}-2-(2-fluorophenyl)acetamide, 3- {[l-(3-fluorophenyl)ethyl]amino}-4-(pyridin-4-ylammo)cyclobut-3-ene-1,2-dione, 3-{[l-(2- fluorophenyl)ethyl] amino } -4-(pyridin-4-ylamino)cyclobut-3 -ene- 1 ,2-dione, N- [3 -( 1 - { [3 ,4-dioxo- 2-(pyridin-4-ylamino)cyclobut- 1 -en- 1 -yl] amino } ethyl)phenyl] -N-methylurea, 3 - { [ 1 -(3-hydroxy- 4-methylphenyl)ethyl]amino}-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2-dione, 3-{[l-(3'- aminobiphenyl-4-yl)ethyl] amino } -4-(pyridin-4-ylamino)cyclobut-3 -ene- 1 ,2-dione, and pharmaceutically acceptable salts thereof. In another aspect, a compound can be selected from the group consisting of l-(3,4-dioxo-
2-(pyridin-4-ylamino)cyclobuten-1-yl)amir!o-2-metiiylpropane; l-(3,4-dioxo-2-(pyridin-4- ylamino)cyclobuten- 1 -yl)aminoprop-2-ene; 1 -(3,4-dioxo-2-(pyridin-4-ylamino)cyclobuten- 1 - yl)amino- 1 -(aminocarbonyl)-3-methylbutane; 1 -(3 ,4-dioxo-2-(ρyridin-4-ylamino)cyclobuten- 1 - yl)amino- 1 -(aminocarbonyl)-ethane; and 1 -(3,4-dioxo-2-(pyridin-4-ylamino)cyclobuten- 1 - yl)amino- 1 -(aminocarbonyl)-ethan-2-ol; and pharmaceutically acceptable salts thereof.
In some embodiments, the compound is selected from:
3-{[l-(4-fluorophenyl)ethyl]amino}-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2-dione;
3-[(cyclohexyhnethyl)amino]-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2-dione;
3-(2,3-dihydro- IH-iaάβn- 1 -ylamino)-4-(ρyridin-4-ylamino)cyclobut-3-ene- 1 ,2-dione; 3-(pyridin-4-ylamino)-4-[(tetrahydrofuran-2-ylmethyl)amino]cyclobut-3-ene-1,2-dione;
3-[(1,3-benzodioxol-5-ylmethyl)amino]-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2-dione;
3-(pyridin-4-ylamino)-4-[(pyridin-2-ylmethyl)amino]cyclobut-3-ene-1,2-dione;
3-(pyridin-4-ylamino)-4-[(ρyridin-3-ylmethyl)ammo]cyclobut-3-ene-1,2-dione;
3-(pyridin-4-ylamino)-4-[(ρyridin-4-ylmethyl)amino]cyclobut-3-ene-1,2-dione; 3-[(diphenylmethyl)amino]-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2-dione;
3-(benzylamino)-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2-dione; 3-[(2-methylbenzyl)amino]-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2-dione;
3-(pyridin-4-ylamino)-4-{[3-(trifluoromethyl)benzyl]amino}cyclobut-3-ene-1,2-dione;
3-[(3-methylbenzyl)amino]-4-(ρyridin-4-ylamino)cyclobut-3-ene-1,2-dione;
3-[(4-fluorobenzyl)amino]-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2-dione; 3-[(4-methylbenzyl)amino]-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2-dione;
3-{[2-(4-methylphenyl)ethyl]amino}-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2-dione;
3-[(2,4-difluorobenzyl)amino]-4-(pyridin-4-ylainino)cyclobut-3-eπe-1,2-dione;
3-[(2,5-difluorobenzyl)amino]-4-(pyridiπ-4-ylamino)cyclobut-3-ene-1,2-dione;
3-[(3,4-difluorobeπzyl)amino]-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2-dione; 3 -(pyridin-4-ylamino)-4- { [4-(trifluoromethyl)benzyl] amino } cyclobut-3 -ene- 1 ,2-dionei
3-[(2,4-dimethylbenzyl)amino]-4-(ρyridin-4-ylamino)cyclobut-3-ene-1,2-dione;
3-[(3,4-dimethylbenzyl)amino]-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2-dione;
3-[(4-tert-butylbenzyl)amino]-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2-dione;
3-[(3,5-di£luorobenzyl)amino]-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2-dione; 3-(pyridin-4-ylamino)-4-(1,2,3,4-tetrahydronaphthalen-1-ylamino)cyclobut-3-ene-1,2- dione;
3-{[(1R)-2-hydroxy-1-phenylethyl]amino}-4-(pyridin-4-ylammo)cyclobut-3-ene-1,2- dione;
3-[(1,2-diphenylethyl)amino]-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2-dione; 2-{[3,4-dioxo-2-(pyridin-4-ylamino)cyclobut-1-en-1-yl]amino}-2-phenylacetamide;
3-{methyl[(1R)-1-phenylethyl]amino}-4-(ρyridin-4-ylamino)cyclobut-3-ene-1,2-dione;
3-{[(1R)-1-(4-bromophenyl)ethyl]amino}-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2- dione;
3- { [(1S)-2-hydroxy- 1 -phenylethyl]amino} -4-(pyridin-4-ylamino)cyclobut-3-ene- 1 ,2- dione;
3-{[(1S)-1-phenylpropyl]amino}-4-(pyridin-4-ylammo)cyclobut-3-ene-1,2-dione;
3-{[(1R)-l -phenylpropyl] amino } -4-(pyridin-4-ylamino)cyclobut-3 -ene- 1 ,2-dione;
3-{[(1R)-1-(2-naphthyl)ethyl]amino}-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2-dione;
3-[(1R)-2,3-dihydro- 1H-inden-1-ylamino]-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2- dione; 3- {[(I R)-I -(4-chlorophenyl)ethyl] amino } -4-(pyridin-4-ylamino)cyclobut-3 -ene- 1,2- dione;
3-{[(1S)-1-(4-chlorophenyl)ethyl]amino}-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2- dione; 3-{[(1R)-1-(3-methoxyphenyl)ethyl]amino}-4-(ρyridin-4-ylamino)cyclobut-3-ene-1,2- dione;
3-{[(1R)-1-(4-methoxyphenyl)ethyl]ammo}-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2- dione;
3-[(4-bromobenzyl)amino]-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2-dione; 3-[(4-chlorobenzyl)amino]-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2-dione;
3-[(4-methoxybenzyl)ammo]-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2-dione;
2-{[3,4-dioxo-2-(pyridin-4-ylammo)cyclobut-1-en-1-yl]ammo}-iV-niethyl-2- phenylacetamide;
3-{[(1R)-1-(4-fluorophenyl)ethyl]amino}-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2- dione;
3-{[l-(4-hydroxyphenyl)ethyl]amino}-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2-dione;
3 - { [ 1 -( 1 -naphthyl)ethyl] amino } -4-(pyridin-4-ylamino)cyclobut-3-ene- 1 ,2-dione;
3-{[(1R)-1-(4-methylphenyl)ethyl]amino}-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2- dione; 3-{[(1R)-1-(4-nitrophenyl)ethyl]amino}-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2-dione;
3- {[ 1 -(4-fluorophenyl)-2-hydroxyethyl]amino} -4-(pyridin-4-ylamino)cyclobut-3-ene- 1,2-dione;
3- {[ 1 -(4-chlorophenyl)-2-hydroxyethyl]amino} -4-(pyridin-4-ylamino)cyclobut-3-ene- 1,2-dione; 3-{[l-(2-fluorophenyl)-2-hydroxyethyl]amino}-4-(pyridin-4-ylamino)cyclobut-3-ene-
1,2-dione;
3 -( {2-hydroxy- 1 - [4-(trifluoromethyl)phenyl] ethyl} amino)-4-(pyridin-4- ylamino)cyclobut-3-ene-1,2-dione;
3 - { [2-hydroxy- 1 -(4-methylphenyl)ethyl] amino } -4-(pyridin-4-ylamino)cyclobut-3 -ene- 1,2-dione; 3 - { [ 1 -(3 -chloro-4-fluorophenyl)-2-hydroxyethyl] amino } -4-(ρyridin-4-ylamino)cyclobut- 3-ene-1,2-dione;
3- {[2-hydroxy-l -(3 ,4,5-trifluorophenyl)ethyl] amino} -4-(pyridin-4-ylamino)cyclobut-3- ene-1,2-dione; 3-{[(1S',2Λ)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]amino}-4-(pyridin-4- ylamino)cyclobut-3-ene- 1 ,2-dione;
3 - { [2-(4-chlorophenyl)- 1 -methylethyl] amino } -4-(pyridin-4-ylamino)cyclobut-3-ene- 1 ,2- dione;
4-( 1 - {[3,4-dioxo-2-(ρyridin-4-ylamino)cyclobut- 1 -en- 1 -yl]amino} ethyl)benzonitrile; 3-{[(1S)-2-hydroxy-2-methyl-1-phenylρropyl]amino}-4-(pyridin-4-ylamino)cyclobut-3- ene-1,2-dione;
3-{[(1R)-2-hydroxy-2-methyl-1-phenylpropyl]amino}-4-(pyridin-4-ylamino)cyclobut-3- ene-1,2-dione;
(2R)-2- {[3,4-dioxo-2-(pyridin-4-ylamino)cyclobut- 1 -en- 1 -yl] amino} -N-methyl-2- phenylacetamide ;
(2 S)-2- { [3,4-dioxo-2-(pyridin-4-ylamino)cyclobut- 1 -en- 1 -yl] amino } -iV-methyl-2- phenylacetamide;
2-(3 ,4-dichlorophenyl)-2- {[3,4-dioxo-2-(pyridin-4-ylamino)cyclobut- 1 -en- 1 - yl] amino } acetamide; 2-(4-chlorophenyl)-2-{[3,4-dioxo-2-(pyridm-4-ylamino)cyclobut-1-en-1- yl] amino } acetamide
(2S)-2-(4-chlorophenyl)-2-{[3,4-dioxo-2-(pyridin-4-ylamino)cyclobut-1-en-1- y 1] amino } acetamide ;
(2S)-2-(4-chlorophenyl)-2-{ [3,4-dioxo-2-(pyridin-4-ylamino)cyclobut- 1 -en- 1 - yl]amino}acetamide;
2-(3-chloro-4-fluorophenyl)-2-{[3,4-dioxo-2-(pyridin-4-ylamino)cyclobut-1-en-1- yl] amino } acetamide;
2- {[3,4-dioxo-2-(pyridin-4-ylamino)cyclobut-l -en-1 -yl]amino} -2-[4- (trifluoromethyl)phenyl] acetamide; 2-{[3,4-dioxo-2-(pyridin-4-ylamino)cyclobut-1-en-1-yl]amino}-2-(4- fluorophenyl)acetamide; 2-{[3,4-dioxo-2-(pyridin-4-ylammo)cyclobut-1-en-1-yl]amino}-2-(2- fluorophenyl)acetamide;
2- { [3 ,4-dioxo-2-(pyridin-4-ylamino)cyclobut- 1 -en- 1 -yl] amino } -2-(3 ,4, 5 - trifluorophenyl)acetamide; 2-(4-chlorophenyl)-2-{[3,4-dioxo-2-(pyridin-4-ylamino)cyclobut-1-en-1-yl]amino}-N- methylacetamide;
2-{[3,4-dioxo-2-(pyridin-4-ylamino)cyclobut-1-en-1-yl]amino}-Λf-ethyl-2- phenylacetamide;
^-(cyclohexylmethyl)^- { [3 ,4-dioxo-2-(pyridin-4-ylamino)cyclobut- 1 -en- 1 -yl] amino } -2- phenylacetamide;
N-(4-chlorobenzyl)-2-{[3,4-dioxo-2-(pyridin-4-ylamino)cyclobut-1-en-1-yl]amino}-2- phenylacetamide;
3-[(2-OXO- 1 -phenyl-2-pyrrolidin- 1 -ylethyl)amino]-4-(pyridin-4-ylamino)cyclobut-3-ene- 1,2-dione; 2- { [3 ,4-dioxo-2-(pyridin-4-ylamino)cyclobut- 1 -en- 1 -yl] amino } -i\yV-dimethyl-2- phenylacetamide; N-[2-(4-chlorophenyl)ethyl] -2- { [3,4-dioxo-2-(pyridin-4-ylamino)cyclobut- 1 -en- 1 - yl] amino } -2-phenylacetamide;
2- { [3 ,4-dioxo-2-(pyridin-4-ylamino)cyclobut- 1 -en- 1 -yl] amino } -2-phenyl-iV-(pyridin-4- ylmethyl)acetamide;
2-{[3,4-dioxo-2-(pyridm-4-ylammo)cyclobuM-en-1-yl]ammo}-iV-isobutyl-2- phenylacetamide;
3-[(2-methoxypyridin-4-yl)amino]-4-{[(1R)-1-phenylethyl]amino}cyclobut-3-ene-1,2- dione; (R)-3-(2-hydroxypyridin-4-ylamino)-4-(l-phenylethylamino)cyclobut-3-ene-1,2-dione;
3 - { [ liϊ-imidazol-2-yl(phenyl)methyl] amino } -4-(pyridin-4-ylamino)cyclobut-3 -ene- 1,2- dione;
3-[(3-methylisoxazol-5-yl)amino]-4-{[(1R)-1-phenylethyl]amino}cyclobut-3-ene-1,2- dione; 3-[methyl(pyridin-4-yl)amino]-4-{[(1R)-1-phenylethyl]amino}cyclobut-3-ene-1,2-dione; 3-{[(1R)-1-phenylethyl]amino}-4-[(2,2,6,6-tetramethylpiperidin-4-yl)amino]cyclobut-3- ene-1,2-dione;
3-{[(1R)-1-phenylethyl]amino}-4-(pyrimidin-4-ylamino)cyclobut-3-ene-1,2-dione;
3-[(5-methyl-1H-pyrazol-3-yl)amino]-4-{[(1R)-1-phenylethyl]amino}cyclobut-3-ene- 1,2-dione; tert-butyl 4-[(3,4-dioxo-2-{[(1R)-1-phenylethyl]amino}cyclobut-1-en-1- yl)amino]piperidine-1-carboxylate;
3-{[(1R)-1-phenylethyl]amino}-4-(1H-pyrazol-3-ylamino)cyclobut-3-ene- 1,2-dione;
3-[(2-chloropyridin-4-yl)amino]-4-{[(1R)-1-phenylethyl]amino}cyclobut-3-eπe-1,2- dione;
3- { [ 1 -(4-cyclohexylphenyl)ethyl] amino } -4-(pyridin-4-ylamino)cyclobut-3 -ene- 1 ,2-dione;
3-{[(1R)-l -cyclohexylethyl] amino } -4-(pyridin-4-ylamino)cyclobut-3-ene- 1 ,2-dione;
3 -[(2-bromopyridin-4-yl)amino] -4- { [( 1 R)- 1 -phenylethyl] amino} cyclobut-3 -ene- 1 ,2- dione; 3 - [(2-morpholin-4-ylpyridin-4-yl) amino] -4- { [( 1 R)- 1 -phenylethyl] amino } cyclobut-3-ene-
1,2-dione;
3-[(l-methyl-1-phenylethyl)amino]-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2-dione;
3 - { [( 1 R)- 1 -phenylethyl] amino} -4- { [2-(phenylthio)pyridin-4-yl] amino } cyclobut-3 -ene- 1,2-dione; 4- [(3 ,4-dioxo-2- { [( 1 R)- 1 -phenylethyl] amino } cyclobut- 1 -en- 1 -yl)amino]pyridine-2- carboxamide;
3-{[(1R)-1-phenylethyl]amino}-4-(piperidin-4-ylamino)cyclobut-3-ene-1,2-dione; tert-butyl (2S)- { [3 ,4-dioxo-2-(pyridin-4-ylamino)cyclobut- 1 -en-1 - yljamino} (phenyl)acetate; (2S)-{[3,4-dioxo-2-(pyridin-4-ylamino)cyclobut-1-en-1-yl]amino}(phenyl)acetic acid;
2- { [ 3 ,4-dioxo-2-(pyridin-4-ylamino)cyclobut- 1 -en- 1 -yl] amino } -2-(3 - hydroxyphenyl)acetamide;
2-(3 -bromophenyl)-2- { [3 ,4-dioxo-2-(pyridin-4-ylamino)cyclobut- 1 -en- 1 - yl] amino } acetamide; 2-biphenyl-3-yl-2-{[3,4-dioxo-2-(pyridin-4-ylamino)cyclobut-1-en-1- yl] amino } acetamide; 2-{[3,4-dioxo-2-(pyridin-4-ylamino)cyclobut-1-en-1-yl]amino}-2-[3-(3- thienyl)phenyl] acetamide;
3-[(l-biphenyl-3-ylethyl)amino]-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2-dione;
3-(pyridin-4-ylamino)-4-({l-[3-(3-thienyl)phenyl]ethyl}ammo)cyclobut-3-ene-1,2-dione; 3-(pyridin-4-ylamino)-4-{[l-(3-pyridin-3-ylphenyl)ethyl]amino}cyclobut-3-ene-1,2- dione;
3-[(l-biphenyl-4-ylethyl)amino]-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2-dioπe;
3-({l-[4-(3-furyl)phenyl]ethyl}amino)-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2-dione;
3 -(pyridin-4-ylamino)-4-( { 1 - [4-(3 -thienyl)phenyl] ethyl } amino)cyclobut-3 -ene- 1 ,2-dione; 2-{[3,4-dioxo-2-(pyridin-4-ylamino)cyclobut-1-en-1-yl]amino}-2-(3-methyl-2- thienyl)acetamide;
2- { [3 ,4-dioxo-2-(pyridin-4-ylamino)cyclobut- 1 -en- 1 -yl] amino } -2-(3 -furyl)acetamide;
3-[(25)-2-(hydroxymethyl)pyrrolidin-1-yl]-4-(ρyridin-4-ylamino)cyclobut-3-ene-1,2- dione; 3-(2-methylpyrrolidin-1-yl)-4-(ρyridin-4-ylamino)cyclobut-3-ene-1,2-dione;
3-[2-(hydroxymethyl)piperidin-1-yl]-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2-dione;
3-(2-methylpiperidin-1-yl)-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2-dione;
2-{[3,4-dioxo-2-(pyridin-4-ylaπiino)cyclobut-1-en-1-yl]amino}-2-(3-thienyl)acetaraide;
3-(pyridin-4-ylamino)-4-[(l-pyridin-4-ylethyl)amino]cyclobut-3-ene-1,2-dione; 3-{[l-(l-benzoiuτan-2-yl)ethyl]ammo}-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2-dione;
3-{[l-(4-morpholin-4-ylphenyl)ethyl]amino}-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2- dione;
3-( { 1 -[4-(dimethylamino)phenyl]ethyl} ammo)-4-(pyridin-4-ylamino)cyclobut-3-ene- 1 ,2- dione; 3-[(l-cyclohexylethyl)amino]-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2-dione;
3-[(l-pyrazin-2-ylethyl)amino]-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2-dione;
3-({l-[4-(l/^-imidazol-1-yl)phenyl]ethyl}amino)-4-(pyridin-4-ylamino)cyclobut-3-ene- 1,2-dione;
3-(pyridin-4-ylamino)-4-{[l-(3-thienyl)ethyl]amino}cyclobut-3-ene-1,2-dione; 3-{[l-(l-methyl-lif-pyrrol-3-yl)ethyl]amino}-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2- dione; 3-{[l-(3-methylρyrazm-2-yl)ethyl]amino}-4-(pyridm-4-ylamino)cyclobut-3-ene-1,2- dione,
3 - { [ 1 -( 1 -benzothien-3 -yl)ethyl] ammo } -4-(pyridm-4-ylammo)cyclobut-3 -ene- 1 ,2-dione, 3-(pyridm-4-ylammo)-4-{[l-(1,3-thiazol-2-yl)ethyl]ammo}cyclobut-3-ene-1,2-dione, 3- { [ 1 -(3 -ammopheπyl)ethyl] ammo } -4-(pyndm-4-ylammo)cyclobut-3 -ene- 1 ,2-dione,
3 - { [ 1 -(2-fluorophenyl)ethyl] ammo } -4-(pyridm-4-ylamino)cyclobut-3 -ene- 1 ,2-dione, 3-{[l-(2-hydroxyphenyl)ethyl]ammo}-4-(pyridin-4-ylammo)cyclobut-3-ene-1,2-dione, 3-{[l-(li/-mdol-3-yl)ethyl]ammo}-4-(pyridin-4-ylammo)cyclobut-3-ene-1,2-dione, 3-{[l-(2,6-difluorophenyl)emyl]ammo}-4-(pyridm-4-ylammo)cyclobut-3-ene-1,2-dione, 3-{[l-(3 -fluorophenyl)ethyl] amino } -4-(pyridm-4-ylamino)cyclobut-3 -ene- 1 ,2-dione,
3-{[l-(3-hydroxyphenyl)ethyl]amino}-4-(pyndm-4-ylamino)cyclobut-3-ene-1,2-dione, 3-(pyridin-4-ylammo)-4-({l-[3-(trifluoromethyl)phenyl]ethyl}amino)cyclobut-3-ene-1,2- dione,
3-[(2-azidopyndm-4-yl)ammo]-4-{[(1R)-1-phenylethyl]ammo}cyclobut-3-ene-1,2-dione, 3-{[(1R)-1-phenylethyl]ammo}-4-{[2-(4-phenyl- 1H-1,2,3-triazol-1-yl)pyndm-4- yl]ammo}cyclobut-3-ene-1,2-dione,
3-{[2-(4-benzyl- 1H-1,2,3-tnazol-1-yl)pyndin-4-yl]ammo}-4-{[(1R)-1- phenylethyl] amino} cyclobut-3-ene-1,2-dione,
3-({2-[4-(hydroxymethyl)-l//-1,2,3-triazol-1-yl]pyridm-4-yl}ammo)-4-{[(1R)-1- phenylethyl] ammo} cyclobut-3-ene- 1 ,2-dione,
3 - { [ 1 -(3 -methylphenyl)ethyl] amino } -4-(pyridin-4-ylammo)cyclobut-3 -ene- 1 ,2-dione, 3-[(l-phenylethyl)ammo]-4-(pyndin-4-ylammo)cyclobut-3-ene-1,2-dione, 3-{tl-(3-chlorophenyl)ethyl]ammo}-4-{pyridm-4-ylammo)cyclobut-3-ene-1,2-dione N-[3 -( 1 - { [3 ,4-dioxo-2-(pyndm-4-ylamino)cyclobut- 1 -en- 1 -yl] amino } ethyl)phenyl] methanesulfonamide, methyl 3 -( 1 - { [3 ,4-dioxo-2-(pyridm-4-ylammo)cyclobut- 1 -en- 1 -yl] amino} ethyl)benzoate, N-[3-(l-{[3,4-dioxo-2-(pyndin-4-ylammo)cyclobut-1-en-1- yl] ammo } ethyl)phenyl] acetamide,
3 -( 1 - { [3 ,4-dioxo-2-(pyridm-4-ylammo)cyclobut- 1 -en- 1 -yl] ammo } ethyl)benzoic acid, 3-{[l-(3-bromophenyl)ethyl]ammo}-4-(pyridm-4-ylammo)cyclobut-3-ene-1,2-dione> 3-(pyridin-4-ylamino)-4-({l-[3-(2J?-tetrazol-5-yl)phenyl]ethyl}amino)cyclobut-3-ene- 1,2-dione;
3-(l-{[3,4-dioxo-2-(pyridin-4-ylamino)cyclobut-1-en-1-yl]amino}ethyl)benzamide;
3-{[l-(5-hydroxy-2-methoxyphenyl)ethyl]amino}-4-(pyridin-4-ylamino)cyclobut-3-ene- 1,2-dione;
3-{[l-(3-hydroxy-4-methoxyphenyl)ethyl]amino}-4-(pyridin-4-ylamino)cyclobut-3-ene- 1,2-dione;
3-{[l-(2,5-dihydroxyphenyl)ethyl]amino}-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2- dione; 3-{[l-(3 , 5-dihydroxyphenyl)ethyl] amino } -4-(pyridin-4-ylamino)cyclobut-3-ene- 1 ,2- dione;
3- {[ 1 -(3-hydroxy-5-methoxyphenyl)ethyl]amino} -4-(pyridin-4-ylamino)cyclobut-3-ene- 1,2-dione;
N-[3-(l-{[3,4-dioxo-2-(pyridin-4-ylamino)cyclobut-1-en-1-yl]amino}ethyl)phenyl]-N'- methylurea;
3-{[l-(3-amino-4-methylphenyl)ethyl]amino}-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2- dione;
3-{[l-(4-methyl-3-nitrophenyl)ethyl]amino}-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2- dione; 3-{[l-(3-hydroxy-4-methylphenyl)ethyl]amino}-4-(pyridin-4-ylamino)cyclobut-3-ene-
1,2-dione;
3-({2-[(E)-2-(4-chlorophenyl)vinyl]pyridin-4-yl}amino)-4-{[(1R)-1- phenylethyl]amino}cyclobut-3-ene-1,2-dione;
3 - { [2-(3 -methoxyphenyl)pyridin-4-yl] amino }-4-{[(1R)-l -phenylethyl] amino } cyclobut-3 - ene- 1,2-dione;
3 - [(2-anilinopyridm-4-yl)amino] -4- { [( 1 R)- 1 -phenylethyl] amino } cyclobut-3 -ene- 1,2- dione;
3-{[(1R)-l -phenylethyl] amino } -4- [(2- { [4-(trifluoromethyl)phenyl] amino }pyridin-4- yl)amino]cyclobut-3-ene-1,2-dione; 3-{[(1R)-l -phenylethyl] amino } -4- { [2-(pyrimidin-4-ylamino)pyridin-4- yl]amino}cyclobut-3-ene-1,2-dione; 3-[(2-{[3-(hydroxymethyl)phenyl]amino}pyridin-4-yl)amino]-4-{[(1R)-1- phenylethyl] amino } cyclobut-3 -ene- 1 ,2-dione;
3-({4-[(3,4-dioxo-2-{[(1R)-1-phenylethyl]amino}cyclobut-1-en-1-yl)amino]pyridin-2- yl} amino)benzamide; 3-{[(1R)-l -phenylethyl] amino } -4- { [2-(pyridin-2-ylamino)pyridm-4-yl] amino } cyclobut-
3-ene-1,2-dione;
3-{[(1R)-1-phenylethyl]ammo}-4-{[2-(pyridin-3-ylamino)pyridin-4-yl]amino}cyclobut- 3-ene-1,2-dione;
3-{[(1R)-l -phenylethyl] amino } -4- { [2-(pyrazin-2-ylamino)pyridin-4-yl] amino } cyclobut- 3-ene-1,2-dione;
N-(4-(2-((R)-1-phenylethylamino)-3,4-dioxocyclobut-1-enylamino)pyridin-2- yl)acetamide;
N-{4-[(3,4-dioxo-2-{[(1R)-1-phenylethyl]amino}cyclobut-1-en-1-yl)amino]pyridin-2- yljbenzamide; N-{4-[(3,4-dioxo-2-{[(1R)-1-phenylethyl]amino}cyclobut-1-en-1-yl)amino]pyridin-2- yl} nicotinamide;
2-(l-phenylethyl)-6-pyridin-4-yl-2,6-diazabicyclo[5.2.0]non-l(7)-ene-8,9-dione;
3-{[(1R)-l -phenylethyl] amino } -4- [(2-phenylpyridin-4-yl)amino]cyclobut-3 -ene- 1 ,2- dione; 3-{[2-(3 -fluorophenyl)pyridin-4-yl] amino }-4-{[(1R)-l -phenylethyl] amino } cyclobut-3 - ene-1,2-dione;
3 - { [2-( 1 -benzofuran-2-yl)pyridin-4-yl] amino} -4-{[(1R)-l -phenylethyl] amino } cyclobut- 3-ene-1,2-dione;
3 - { [2-(3 -fluorophenyl)pyridin-4-yl] amino} -4- { [( 1 R)- 1 -phenylethyl] amino } cyclobut-3- ene-1,2-dione;
3-(2,3'-bipyridin-4-ylamino)-4-{[(1R)-1-phenylethyl]ammo}cyclobut-3-ene-1,2-dione;
3-{[(1R)-1-phenylethyl]amino}-4-({2-[3-(trifluoromethyl)phenyl]pyridin-4- yl}amino)cyclobut-3-ene-1,2-dione;
3-{[(1R)-1-phenylethyl]amino}-4-({2-[4-(trifluoromethyl)phenyl]pyridm-4- yl}amino)cyclobut-3-ene-1,2-dione; 3-{[(1R)-l -phenylethyl] amino } -4- { [2-(pyridin-4-ylamino)pyridin-4-yl] amino} cyclobut- 3-ene-1,2-dione;
3-({2-[(4-methyl-1,3-thiazol-2-yl)ammo]pyridin-4-yl}amino)-4-{[(1R)-1- phenylethyl]amino}cyclobut-3-ene-1,2-dione; 3-{[(1R)-l -phenylethyl] amino } -4- { [2-(quinolin-2-ylamino)pyridin-4-yl] amino } cyclobut-
3-ene-1,2-dione;
3-{[(1R)-1-phenylethyl]amino}-4-{[2-(pyrimidin-2-ylamino)pyridin-4- yl]amino}cyclobut-3-ene-1,2-dione;
3-{[2-(2-fluorophenyl)ρyridin-4-yl]amino}-4-{[(1R)-1-phenylethyl]amino}cyclobut-3- ene-1,2-dione;
3- { [2-(2-fiiryl)pyridin-4-yl] amino }-4-{[(1R)-l -phenylethyl] amino } cyclobut-3 -ene- 1 ,2- dione;
3 - { [2-(4-methylphenyl)pyridin-4-yl] amino} -4-{[(1R)-l -phenylethyl] amino } cyclobut-3- ene-1,2-dione; N-(4-{4-[(3,4-dioxo-2-{[(1R)-1-phenylethyl]amino}cyclobut-1-en-1-yl)amino]pyridin-2- yl}phenyl)acetamide;
3- { [2-(3 -methylphenyl)pyridin-4-yl] amino} -4- { [( 1 R)- 1 -phenylethyl] amino } cyclobut-3 - ene-1,2-dione;
3-(2,4'-bipyridin-4-ylamino)-4-{[(1R)-1-phenylethyl]amino}cyclobut-3-ene-1,2-dione; 3-({2-[4-(hydroxymethyl)phenyl]pyridin-4-yl}amino)-4-{[(1R)-1- phenylethyl] amino} cyclobut-3-ene- 1 ,2-dione;
3-({2-[3-(benzyloxy)phenyl]pyridin-4-yl}amino)-4-{[(1R)-l phenylethyl] amino} cyclobut-3-ene- 1 ,2-dione;
3-[(2-biphenyl-3-ylpyridin-4-yl)amino]-4-{[(1R)-1-phenylethyl]amino}cyclobut-3-ene- 1 ,2-dione;
3-[(2-biphenyl-3-ylpyridin-4-yl)amino]-4-{[(1R)-1-phenylethyl]amino}cyclobut-3-ene- 1,2-dione;
N-cyclopentyl-4- {4- [(3 ,4-dioxo-2- { [( 1 R)- 1 -phenylethyl] amino } cyclobut- 1 -en- 1 - yl)amino]pyridin-2-yl}benzamide; 3 - { [2-(4-chlorophenyl)pyridin-4-yl] amino }-4-{[(1R)-l -phenylethyl] amino } cyclobut-3- ene-1,2-dione; 3-{2,2'-bipyridm-4-ylammo)-4-{[(1R)-1-phenylethyl]amino}cyclobut-3-ene-1,2-dione,
2-{[3,4-dioxo-2-(pyndm-4-ylammo)cyclobut-1-en-1-yl]ammo}-2-(4-pyndin-3- ylphenyl)acetamide,
2-biphenyl-4-yl-2- { [3 ,4-dioxo-2-(pyndm-4-ylammo)cyclobut- 1 -en- 1 - yl] amino} acetamide,
2-(4-bromophenyl)-2-{[3,4-dioxo-2-(ρyndin-4-ylamino)cyclobut-1-en-1- yl] amino } acetamide,
2-{[3,4-dioxo-2-(pyndin-4-ylammo)cyclobut-1-en-1-yl]ammo}-2-[4-(3- thienyl)phenyl]acetamide, 2- {[3,4-dioxo-2-(pyridin-4-ylainino)cyclobut- 1 -en-1 -yljammo} -2-[4-(3- fiiryl)phenyl] acetamide,
3-{[(1R)-1-phenylethyl]ammo}-4-(thieno[2,3-b]pyndui-4-ylammo)cyclobut-3-ene-1,2- dione,
3-{[l-(4-iodophenyl)ethyl]amino}-4-(pyridm-4-ylammo)cyclobut-3-ene-1,2-dione, and pharmaceutically acceptable salts thereof
In some embodiments, the compound is selected from
2-{[3,4-dioxo-2-(pyridm-4-ylammo)cyclobut-1-en-1-yl]ammo}-2-(3'-methylbiphenyl-3- yl)acetamide,
2-{3'-[(dimethylammo)sulfonyl]biphenyl-3-yl}-2-{[3,4-dioxo-2-(pyridin-4- ylammo)cyclobut- 1 -en- 1 -yl] ammo } acetamide,
2- { [3 ,4-dioxo-2-(pyridm-4-ylamino)cyclobut- 1 -en- 1 -yl] ammo } -2-(2'-methylbiphenyl-3- yl)acetamide,
2-(3'-cyanobiphenyl-3-yl)-2-{[3,4-dioxo-2-(pyridm-4-ylammo)cyclobut-1-en-1- yl] ammo } acetamide, 2-{[3,4-dioxo-2-(pyndm-4-ylammo)cyclobut-1-en-1-yl]ammo}-2-(4'-methylbiphenyl-3- yl)acetamide,
3 '-( 1 - { [ 3 ,4-dioxo-2-(pyridin-4-ylammo)cyclobut- 1 -en- 1 -yl] ammo } ethyl)biphenyl-3 - carbomtrile,
3- {[ 1 -(4'-acetylbiphenyl-3-yl)ethyl]ammo}-4-(ρyridm-4-ylammo)cyclobut-3-ene-1,2- dione, 3-{[l-(4'-chlorobiphenyl-3-yl)ethyl]amino}-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2- dione;
3-{[l-(2'-methylbiphenyl-3-yl)ethyl]amino}-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2- dione; 3-{[l-(4'-methylbiphenyl-3-yl)ethyl]amino}-4-(pyridin-4-ylamino)cyclobnt-3-ene-1,2- dione;
3-{[l-(3'-methoxybiphenyl-3-yl)ethyl]amino}-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2- dione; tert-butyl [3'-( 1 - { [3 ,4-dioxo-2-(pyridin-4-ylamino)cyclobut- 1 -en- 1 - yl] amino } ethyl)biphenyl-4-yl] carbamate;
3-{[l-(3'-aminobiphenyl-4-yl)ethyl]amino}-4-(pyridin-4-ylammo)cyclobut-3-ene-1,2- dione;
3-{[l-(4'-chlorobiphenyl-4-yl)ethyl]ammo}-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2- dione; 2-{[3,4-dioxo-2-(pyridin-4-ylamino)cyclobut-1-en-1-yl]aniino}-2-[4'-(morpholm-4- ylcarbonyl)biphenyl-4-yl]acetamide;
2-{[3,4-dioxo-2-(pyridin-4-ylamino)cyclobut-1-en-1-yl]amino}-2-{3'- [(methylsulfonyl)amino]biphenyl-4-yl}acetamide;
2- {3'-[(dimethylamino)sulfonyl]biphenyl-4-yl} -2- {[3,4-dioxo-2-(pyridin-4- ylamino)cyclobut-1-en-1-yl]amino}acetamide;
2- { [3 ,4-dioxo-2-(pyridin-4-ylamino)cyclobut- 1 -en- 1 -yl] amino } -2- [3 '-(morpholin-4- ylcarbonyl)biphenyl-4-yl]acetamide;
2- {[3 ,4-dioxo-2-(pyridin-4-ylamino)cyclobut- 1 -en- 1 -yl]amino} -2- {3 '- [(ethylamino)sulfonyl]biphenyl-4-yl}acetamide; 2-(2'-aminobiphenyl-4-yl)-2- { [3,4-dioxo-2-(pyridin-4-ylamino)cyclobut- 1 -en- 1 - yl] amino } acetamide; N-[3,4-dioxo-2-(pyridin-4-ylamino)cyclobut-1-en-1-yl]-L-phenylalaninamide;
Λ^-[3,4-dioxo-2-(pyridin-4-ylammo)cyclobut-1-en-1-yl]-D-phenylalaninamide; and pharmaceutically acceptable salts thereof. In some embodiments, the compound is selected from:
3-(isobutylamino)-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2-dione; 3-(allylamino)-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2-dione; (R)-3-(Pyridin-4-ylamino)-4-(1,2,2-trimethyl-propylamino)- cyclobut-3-ene-1,2-dione; N2-[3,4-dioxo-2-(pyridin-4-ylamino)cyclobut-1-en-1-yl]-L-leucinamide; N2-[3,4-dioxo-2-(pyridin-4-ylamino)cyclobut-1-en-1-yl]-L-alaninamide; N2-[3,4-dioxo-2-(pyridin-4-ylamino)cyclobut-1-en-1-yl]-L-serinamide; and pharmaceutically acceptable salts thereof.
In another aspect, a pharmaceutical composition includes a pharmaceutically acceptable carrier and a compound having Formula (I) as defined above, or a pharmaceutically acceptable salt thereof. In another aspect, a method of treating a patient in need of MK2 inhibition includes administering to the patient an amount effective for MK2 inhibition of a compound having Formula (T) as defined above, or a pharmaceutically acceptable salt thereof. The patient can be in need of treatment or prevention of a TNFα mediated disease or disorder.
The TNFα mediated disease or disorder can be a connective tissue disorder, a joint disorder, a neoplasia disorder, a cardiovascular disorder, an otic disorder, an ophthalmic disorder, a respiratory disorder, a gastrointestinal disorder, an angiogenesis-related disorder, an immunological disorder, an allergic disorder, a nutritional disorder, an infectious disease, an endocrine disorder, a metabolic disorder, a neurological disorder, a neurodegenerative disorder, a psychiatric disorder, a hepatic disorder, a biliary disorder, a musculoskeletal disorder, a genitourinary disorder, a gynecologic disorder, an obstetric disorder, an injury, a trauma, a surgical disorder, a dental disorder, an oral disorder, a sexual dysfunction disorder, a dermatologic disorder, a hematological disorder, or a poisoning disorder.
The TNFα mediated disease or disorder can be arthritis, rheumatoid arthritis, spondyloarthopathies, gouty arthritis, osteoarthritis, systemic lupus erythematosus, juvenile arthritis, asthma, bronchitis, menstrual cramps, tendinitis, bursitis, connective tissue injuries or disorders, skin related conditions, psoriasis, eczema, burns, dermatitis, gastrointestinal conditions, inflammatory bowel disease, gastric ulcer, gastric varices, Crohn's disease, gastritis, irritable bowel syndrome, ulcerative colitis, cancer, colorectal cancer, herpes simplex infections, HIV, pulmonary edema, kidney stones, minor injuries, wound healing, vaginitis, candidiasis, lumbar spondylanhrosis, lumbar spondylarthrosis, vascular diseases, migraine headaches, sinus headaches, tension headaches, dental pain, periarteritis nodosa, thyroiditis, aplastic anemia, Hodgkin's disease, sclerodoma, rheumatic fever, type I diabetes, myasthenia gravis, multiple sclerosis, sarcoidosis, nephrotic syndrome, Behcet's syndrome, polymyositis, gingivitis, hypersensitivity, swelling occurring after injury, myocardial ischemia, ophthalmic diseases, retinitis, retinopathies, conjunctivitis, uveitis, ocular photophobia, acute injury to the eye tissue, pulmonary inflammation, viral infections, cystic fibrosis, central nervous system disorders, cortical dementias, or Alzheimer's disease.
The TNFα mediated disease or disorder can be rheumatoid arthritis, psoriasis, lupus, inflammatory bowel disease, asthma, or chronic obstructive pulmonary disease.
As used herein, the term "alkyl," alone or in combination, refers to a straight-chain or branched-chain alkyl radical containing 1 to 10, 1 to 6, or 1 to 4, carbon atoms. Examples of such radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl, octyl, decyl and the like. Alkyl groups can be optionally substitued.
The term "alkenyl," alone or in combination, refers to a straight-chain or branched-chain alkenyl radical containing 2 to 10, 2 to 6, or 2 to 4, carbon atoms. Examples of such radicals include ethenyl, E- and Z-propenyl, isopropenyl, E- and Z-butenyl, E- and Z-isobutenyl, E- and Z-pentenyl, decenyl and the like. Alkenyl radicals can include more than one unsaturated bond, e.g., a butadienyl radical or but-1-yn-3-enyl radical. Alkenyl groups can be optionally substitued. The term "alkynyl," alone or in combination, refers to a straight-chain or branched-chain alkynyl radical containing 2 to 10, 2 to 6, or 2 to 4, carbon atoms. Examples of such radicals include ethynyl (acetylenyl), propynyl, propargyl, butynyl, hexynyl, decynyl and the like.
Alkynyl radicals can include more than one unsaturated bond, e.g., a butadiynyl radical or but-1- yn-3-enyl radical. Alkynyl groups can be optionally substitued.
The term "cycloalkyl," alone or in combination, refers to a cyclic alkyl radical containing 3 to 10, 3 to 8, or 3 to 6, carbon atoms. Examples of such cycloalkyl radicals include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like; and bicylic groups including bicyclo[3.4.0]nonyl, bicyclo[2.2.2]octyl, norbornyl, spiro[4.5]decyl, and the like. Cycloalkyl groups can be optionally substitued.
The term "cycloalkenyl," alone or in combination, refers to a cyclic carbocycle containing 4 to 10, 4 to 8, or 5 or 6, carbon atoms and one or more double bonds. Examples of such cycloalkenyl radicals include cyclopentenyl, cyclohexenyl, cyclopentadienyl, and bicyclic groups such as norbornenyl, and the like. Cycloalkenyl groups can be optionally substitued. The term "aryl" refers to a carbocyclic aromatic group, and includes fused bicyclic or tricyclic systems An aryl group can have from 6 to 14 carbon atoms m the ring system, or from 6 to 10 atoms in the πng system In fused systems, one or more rings may not be aromatic, e g , mdanyl, or all πngs may be aromatic, e g , naphthyl and anthracenyl Examples of aryl groups include phenyl, naphthyl, mdenyl, mdanyl, azulenyl, fluorenyl, and anthracenyl Aryl groups can be optionally substitued
The term "heteroaryl" refers to a heterocyclic aromatic group, and includes fused bicyclic or tricyclic systems A heteroaryl group can have from 5 to 14 πng members In fused systems, one or more πngs may not be aromatic, e g , indolmyl or benzodioxolyl, or all nngs may be aromatic, e g , benzimidazolyl, benzofuranyl, or dibenzofuranyl Examples of such heteroaryl groups include furyl, thienyl, pyridyl, pyrrolyl, oxazolyly, thiazolyl, lmidazolyl, pyrazolyl, 2- pyrazolmyl, pyrazolidnyl, isoxazolyl, lsothiazolyl, 1,2,3-oxadiazolyl, 1,2,3-tnazolyl, 1,3,4- thiadiazolyl, pyndazmyl, pynmidmyl, pyrazmyl, 1,3,5-tnazmyl, 1,3,5-rnthianyl, mdohzmyl, mdolyl, isoindolyl, 3H-mdolyl, mdolmyl, benzo[b]furanyl, 2,3-dihydrobenzofuranyl, benzo[b]thiophenyl, 1H-indazolyl, benzimidazolyl, benztmazolyl, purinyl, 4H-qumohzinyl, qumolmyl, lsoqumolmyl, cnnolnyl, phthalazmyl, qumazolmyl, qumoxalmyl, 1,8- naphthyndmyl, pteridmyl, carbazolyl, acndmyl, phenazinyl, phenothiazinyl, and phenoxazmyl Heteroaryl groups can be optionally substitued
The term "halogen" means fluorine, chlorine, bromine or iodme The term "heterocyclyl" refers to a saturated or unsaturated monocyclic, bicyclic or tricychc non-aromatic group including 1 to 5 heteroatoms selected from O, N, and S The heteroatom can be an oxidized heteroatom, for example, when the heteroatom is N, it can be an N-oxide, or when the heteroatom is S, it can be a sulfoxide or sulfone Bicyclic and tricyclic heterocyclyl groups can include an aromatic πng, e g , 2,3-dihydrobenzofuranyl, or 2,3- dihydronaphtho[2,3-b]furanyl A heterocyclyl group can have from 3 to 14 πng members A monocyclic heterocyclyl group can have from 3 to 8 πng members, or from 3 to 6 πng members A bicyclic or tricyclic heterocyclyl group can have from 7 to 14 nng members
Some examples of heterocyclyl groups include monocyclic groups such as, for example, morpholmo, tetrahydrofuranyl, pyrrolidmyl, 2,3-dihydropyrrolyl, piperidmyl, 1,4- dihydropyridmyl, tetrahydrothienyl, thiomorpholmo, tetrahydropyranyl, butyrolactonyl, caprolactonyl, caprolactamyl, succinimidyl, maleimidyl, 2,3-dihydropyranyl, 2,3- dihydropyrrolidyl, 1,2-dihydropyridinyl, maleimidiyl, and the like; bicyclic heterocyclyl groups including, for example, fused bicyclic groups (e.g., octahydrobenzofuranyl, octahydro-lff- indolyl, hexahydro-2J¥-furo[2,3-δ]pyrrolyl, 3a,4,5,6,7,7a-hexahydro-1H-indolyl), bridged bicyclic groups (e.g., 2-oxa-bicyclo[2.2.1]heptanyl, 2-aza-bicyclo[2.2.1]heptanyl, and the like), or spiro bicyclic groups. Tricyclic groups can include rings that are fused, bridged, or spiro.
As used herein, the term "amino" refers to a group of formula -NEk-
As used herein, the term "Cn-C1n' alkylamino" refers to a group of formula — NH(alkyl), wherein the alkyl group has n' to m' carbon atoms.
As used herein, the term "di-Cn-Cm-alkylamino" refers to a group of formula -N(alkyl)2, wherein each alkyl group independently has n' to m' carbon atoms. As used herein the term "Cn- Cn,' alkoxy" refers to a group of formula -O(alkyl), wherein the alkyl group has n' to m' carbon atoms.
As used herein, the term "Cn--Cm-alkylammosulfonyl" refers to a group of formula - S(=O)2NH(alkyl), wherein the alkyl group has n' to m' carbon atoms. As used herein, the term "diCn'-Cm-alkylaminosulfonyl" refers to a group of formula -
S(=O)2N(alkyl)2, wherein the alkyl group has n' to m' carbon atoms.
As used herein, the term "Cn'-Cm-alkylsulfonylamino" refers to a group of formula - NHS(=O)2(alkyl), wherein the alkyl group has n' to m'carbon atoms.
As used herein, the term "Cn'-Cm-alkoxycarbonylamino" refers to a group of formula - NHC(=O)O(alkyl), wherein the alkyl group has n' to m' carbon atoms.
As used herein, the term "Cn'-C1m' alkylcarbonyl" refers to a group of formula - C(=O)alkyl, wherein said alkyl group has n' to m' carbon atoms.
As used herein, the term "heterocyclylcarbonyl" refers to a group of formula - C(=O)heterocyclyl. As used herein, the term "carbamyl" refers to a group of formula -C(=O)NH2.
As used herein, the term "hydroxyl" refers to a group of formula -OH.
The term "treating" or "treatment" refers to any indicia of success in amelioration of an injury, pathology, or condition, including any objective or subjective parameter such as abatement; remission; diminishing of symptoms or making the injury, pathology, or condition more tolerable to the patient; slowing in the rate of degeneration or decline; making the final point of degeneration less debilitating; or improving a subject's physical or mental well-being. The treatment or amelioration of symptoms can be based on objective or subjective parameters; including the results of a physical examination, neurological examination, and/or psychiatric evaluation. "Treating" includes inhibiting the symptoms of the disorder (slowing or arresting its development), providing relief from the symptoms or side-effects of the disorder (including palliative treatment), and/or relieving the symptoms of the disorder (causing regression).
Accordingly, the term "treating" includes the administration of the compounds of Formula (I) to a subject to alleviate, or to arrest or inhibit development of the symptoms or conditions associated with a disorder. A skilled medical practitioner will know how to use standard methods to identify a subject in need of treatment. The term "preventing" refers to preventing the onset of symptoms in a subject that may be predisposed to a disorder but does not yet experience or exhibit symptoms of the disorder (prophylactic treatment). Accordingly, the term "preventing" includes the administration of the compounds of formula (I) to a subject to prevent or delay symptoms or conditions associated with a disorder. A skilled medical practitioner will know how to use standard methods to identify a subject in need of prevention.
Throughout the application, unless otherwise specified, the terms "include" and "including" are used in an open-ended sense; e.g., "including" means "including but not limited to."
A person of ordinary skill in the art will recognize that the compounds can be prepared in different isomeric forms, including stereoisomers (e.g., diastereomers, members of an enantiomeric pair, or mixtures of enantiomers, such as racemic mixtures; or as E-/Z-isomers differing in configuration about a double bond), or tautomers (e.g., forms that differ by location of a dissociable proton). Unless indicated to be limited, a reference to a compound or group of compounds, whether by name, structure or otherwise, is intended to include all such forms. It will also be understood that certain compounds of the present invention may exist in solvated, for example hydrated, as well as unsolvated forms. It will further be understood that the present invention encompasses all such solvated forms of the compounds of the Formula (I).
Other features, objects, and advantages will be apparent from the following description, and from the claims. DETAILED DESCRIPTION
Certain squarates (derivatives of squaric acid, 3,4-dihydro-3-cyclobutene-1,2-dione) can modulate (i.e., increase, decrease, or otherwise alter) the activity of protein kinases. Protein kinases are a class of enzymes that catalyze the transfer of a phosphate group from ATP to a tyrosine, serine, threonine or histidine residue located on a protein substrate. In particular, squarates can modulate the kinase activity of MK2 (MAPKAPK2).
MK2 is a direct substrate of p38α and p38β MAP kinases and is responsible for many of the signaling events that follow the activation of these MAPKs. Indeed, MK2 was the first substrate of p38α to be identified. The physiological implications of MK2 activation are most clearly revealed by the targeted disruption of the MK2 gene in mice. MK2 deficient cells derived from mice have shown defects in motility, chemotaxis and cytokine production (Kotlyarov et al. Nat. Cell. Biol. 1999, which is incorporated by reference in its entirety). Several studies using MK2-deficient mice strongly support the central role of this kinase in the production of inflammatory cytokines such as TNFα, IL-6 and IFNγ. AU-rich elements (AREs) have been identified in the 3' untranslated region (UTR) of several cytokine mRNAs and are known to regulate mRNA stability and translation. In the case of TNFα, IL-6 and IFNγ it has been shown that MK2 regulates their expression by targeting their mRNA AREs.
TNFα is a pro-inflammatory cytokine that is involved in inflammation in a number of disease states like rheumatoid arthritis (RA). Protein therapeutics, such as etanercept, are currently available to treat patients with RA or other inflammatory diseases. However, small molecule that inhibits TNFα production is desirable, particularly an orally available small molecule.
Accordingly, compounds of Formula (I) are useful in methods of inhibiting MK2 and for the prevention and treatment of diseases or disorders mediated by tumor necrosis factor-α (TNFα) or other cytokines. Among TNFα mediated diseases or disorders are connective tissue and joint disorders, neoplasia disorders, cardiovascular disorders, otic disorders, ophthalmic disorders, respiratory disorders, gastrointestinal disorders, angiogenesis-related disorders, immunological disorders, allergic disorders, nutritional disorders, infectious diseases and disorders, endocrine disorders, metabolic disorders, neurological and neurodegenerative disorders, psychiatric disorders, hepatic and biliary disorders, musculoskeletal disorders, genitourinary disorders, gynecologic and obstetric disorders, injury and trauma disorders, surgical disorders, dental and oral disorders, sexual dysfunction disorders, dermatologic disorders, hematological disorders, or poisoning disorders. Also among TNFα mediated diseases or disorders are arthritis, rheumatoid arthritis, spondyloarthopathies, gouty arthritis, osteoarthritis, systemic lupus erythematosus, juvenile arthritis, asthma, bronchitis, menstrual cramps, tendinitis, bursitis, connective tissue injuries or disorders, skin related conditions, psoriasis, eczema, burns, dermatitis, gastrointestinal conditions, inflammatory bowel disease, gastric ulcer, gastric varices, Crohn's disease, gastritis, irritable bowel syndrome, ulcerative colitis, cancer, colorectal cancer, herpes simplex infections, HIV, pulmonary edema, kidney stones, minor injuries, wound healing, vaginitis, candidiasis, lumbar spondylanhrosis, lumbar spondylarthrosis, vascular diseases, migraine headaches, sinus headaches, tension headaches, dental pain, periarteritis nodosa, thyroiditis, aplastic anemia, Hodgkin's disease, sclerodoma, rheumatic fever, type I diabetes, myasthenia gravis, multiple sclerosis, sarcoidosis, nephrotic syndrome, Behcet's syndrome, polymyositis, gingivitis, hypersensitivity, swelling occurring after injury, myocardial ischemia, ophthalmic diseases, retinitis, retinopathies, conjunctivitis, uveitis, ocular photophobia, acute injury to the eye tissue, pulmonary inflammation, viral infections, cystic fibrosis, central nervous system disorders, cortical dementias, and Alzheimer's disease. In particular, such diseases or disorders include rheumatoid arthritis (RA), psoriasis, lupus (SLE), inflammatory bowel disease (IBD), asthma or chronic obstructive pulmonary disease (COPD). In some embodiments, the disorder or disease is selected from rheumatoid arthritis, psoriasis, lupus, inflammatory bowel disease, asthma, and chronic obstructive pulmonary disease.
In some embodiments, the present invention provides a kit comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and instructions, wherein said instructions comprise a direction to administer said compound, or pharmaceutically salt thereof, to a patient in need of treatment for a disease or disorder selected from arthritis, rheumatoid arthritis, spondyloarthopathies, gouty arthritis, osteoarthritis, systemic lupus erythematosus, juvenile arthritis, asthma, bronchitis, menstrual cramps, tendinitis, bursitis, connective tissue injuries or disorders, skin related conditions, psoriasis, eczema, bums, dermatitis, gastrointestinal conditions, inflammatory bowel disease, gastric ulcer, gastric varices, Crohn's disease, gastritis, irritable bowel syndrome, ulcerative colitis, cancer, colorectal cancer, herpes simplex infections, HTV, pulmonary edema, kidney stones, minor injuries, wound healing, vaginitis, candidiasis, lumbar spondylanhrosis, lumbar spondylarthrosis, vascular diseases, migraine headaches, sinus headaches, tension headaches, dental pain, periarteritis nodosa, thyroiditis, aplastic anemia, Hodgkin's disease, sclerodoma, rheumatic fever, type I diabetes, myasthenia gravis, multiple sclerosis, sarcoidosis, nephrotic syndrome, Behcet's syndrome, polymyositis, gingivitis, hypersensitivity, swelling occurring after injury, myocardial ischemia, ophthalmic diseases, retinitis, retinopathies, conjunctivitis, uveitis, ocular photophobia, acute injury to the eye tissue, pulmonary inflammation, viral infections, cystic fibrosis, central nervous system disorders, cortical dementias, and Alzheimer's disease In some embodiments, the disease or disorder is rheumatoid arthritis, psoriasis, lupus, inflammatory bowel disease, asthma, or chronic obstructive pulmonary disease hi some embodiments, the disorder or disease is selected from rheumatoid arthritis, psoriasis, lupus, inflammatory bowel disease, asthma, and chronic obstructive pulmonary disease In some embodiments, the present invention provides use of a compound of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for the preparation of medicament for use in a method of treating a disease or disorder selected from arthritis, rheumatoid arthritis, spondyloarthopathies, gouty arthritis, osteoarthritis, systemic lupus erythematosus, juvenile arthritis, asthma, bronchitis, menstrual cramps, tendinitis, bursitis, connective tissue injuries or disorders, skin related conditions, psoriasis, eczema, burns, dermatitis, gastrointestinal conditions, inflammatory bowel disease, gastric ulcer, gastric varices, Crohn's disease, gastritis, irritable bowel syndrome, ulcerative colitis, cancer, colorectal cancer, herpes simplex infections, HIV, pulmonary edema, kidney stones, minor injuries, wound healing, vaginitis, candidiasis, lumbar spondylanhrosis, lumbar spondylarthrosis, vascular diseases, migraine headaches, sinus headaches, tension headaches, dental pain, periarteritis nodosa, thyroiditis, aplastic anemia, Hodgkin's disease, sclerodoma, rheumatic fever, type I diabetes, myasthenia gravis, multiple sclerosis, sarcoidosis, nephrotic syndrome, Behcet's syndrome, polymyositis, gingivitis, hypersensitivity, swelling occurring after injury, myocardial ischemia, ophthalmic diseases, retinitis, retinopathies, conjunctivitis, uveitis, ocular photophobia, acute injury to the eye tissue, pulmonary inflammation, viral infections, cystic fibrosis, central nervous system disorders, cortical dementias, and Alzheimer's disease In some embodiments, the disease or disorder is rheumatoid arthritis, psoriasis, lupus, inflammatory bowel disease, asthma, or chronic obstructive pulmonary disease.
In some embodiments, the disorder or disease is selected from rheumatoid arthritis, psoriasis, lupus, inflammatory bowel disease, asthma, and chronic obstructive pulmonary disease.
In some embodiments, the present invention provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in a method of treating a disease or disorder selected from arthritis, rheumatoid arthritis, spondyloarthopathies, gouty arthritis, osteoarthritis, systemic lupus erythematosus, juvenile arthritis, asthma, bronchitis, menstrual cramps, tendinitis, bursitis, connective tissue injuries or disorders, skin related conditions, psoriasis, eczema, burns, dermatitis, gastrointestinal conditions, inflammatory bowel disease, gastric ulcer, gastric varices, Crohn's disease, gastritis, irritable bowel syndrome, ulcerative colitis, cancer, colorectal cancer, herpes simplex infections, HIV, pulmonary edema, kidney stones, minor injuries, wound healing, vaginitis, candidiasis, lumbar spondylarthrosis, lumbar spondylarthrosis, vascular diseases, migraine headaches, sinus headaches, tension headaches, dental pain, periarteritis nodosa, thyroiditis, aplastic anemia, Hodgkin's disease, sclerodoma, rheumatic fever, type I diabetes, myasthenia gravis, multiple sclerosis, sarcoidosis, nephrotic syndrome, Behcet's syndrome, polymyositis, gingivitis, hypersensitivity, swelling occurring after injury, myocardial ischemia, ophthalmic diseases, retinitis, retinopathies, conjunctivitis, uveitis, ocular photophobia, acute injury to the eye tissue, pulmonary inflammation, viral infections, cystic fibrosis, central nervous system disorders, cortical dementias, and Alzheimer's disease. In some embodiments, the disease or disorder is rheumatoid arthritis, psoriasis, lupus, inflammatory bowel disease, asthma, or chronic obstructive pulmonary disease.
In some embodiments, the disorder or disease is selected from rheumatoid arthritis, psoriasis, lupus, inflammatory bowel disease, asthma, and chronic obstructive pulmonary disease.
Compounds of Formula I can be used in the form of pharmaceutically acceptable salts derived from inorganic and/or organic acids and/or bases. Included among such acid salts are the following: acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfoπate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3 -phenyl-propionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate and undecanoate. Base salts include ammonium salts, alkali metal salts, such as sodium and potassium salts, alkaline earth metal salts, such as calcium and magnesium salts, salts with organic bases, such as dicyclohexylamine salts, N-methyl-D-glucamine, and salts with amino acids such as argmine, lysine, and so forth. Also, the basic nitrogen-containing groups can be quaternized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates, such as dimethyl, diethyl, dibutyl and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides, such as benzyl and phenethyl bromides or others. Water- or oil-soluble or dispersible products can be obtained in this way.
The compound may be formulated into pharmaceutical compositions that may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. The term "parenteral" includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. See, for example, Remington: The Science and Practice of Pharmacy, 21st ed. 2005, Lippincott Williams & Wilkins, which is incorporated by reference in its entirety. Pharmaceutical compositions can include a compound of Formula (I), or a pharmaceutically acceptable salt thereof, together with any pharmaceutically acceptable carrier. In some cases, the pharmaceutical composition consists essentially of a compound of Formula (I) and a pharmaceutically acceptable carrier. The pharmaceutical composition can consist of a compound of Formula (T) and a pharmaceutically acceptable carrier. The term "carrier" includes acceptable adjuvants and vehicles. Pharmaceutically acceptable carriers that may be used in the pharmaceutical compositions include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol or wool fat.
The pharmaceutical compositions maybe in the form of a sterile injectable preparation, for example, a sterile injectable aqueous or oleaginous suspension. This suspension maybe formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that maybe employed are water, Ringer's solution or isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil maybe employed including synthetic mono- or di-glycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant.
The pharmaceutical compositions can be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, carriers which are commonly used include lactose or corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.
Alternatively, the pharmaceutical compositions may be administered in the form of suppositories for rectal administration. These can be prepared by mixing the agent with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and therefore will melt in the rectum to release the drug. Such materials include cocoa butter, beeswax or polyethylene glycols.
The pharmaceutical compositions may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.
Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically-transdermal patches may also be used.
For topical applications, the pharmaceutical compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers. Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, the pharmaceutical compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water. For ophthalmic use, the pharmaceutical compositions may be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, as solutions in isotonic, pH adjusted sterile saline, either with or without a preservative such as benzylalkonium chloride. Alternatively, for ophthalmic uses, the pharmaceutical compositions may be formulated in an ointment such as petrolatum. The pharmaceutical compositions may also be administered by nasal aerosol or inhalation through the use of a nebulizer, a dry powder inhaler or a metered dose inhaler. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, or other conventional solubilizing or dispersing agents.
The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated, and the particular mode of administration. It should be understood, however, that a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated. The amount of active ingredient may also depend upon the therapeutic or prophylactic agent, if any, with which the ingredient is coadministered.
A pharmaceutical composition can include an effective amount of a compound of Formula I. An effective amount can be defined as an amount sufficient to confer a therapeutic effect on the treated patient, and will depend on a variety of factors, such as the nature of the inhibitor, the size of the patient, the goal of the treatment, the nature of the pathology to be treated, the specific pharmaceutical composition used, and the judgment of the treating physician. For reference, see Freireich et al., Cancer Chemother. Rep. 1966, 50, 219 and Scientific Tables, Geigy Pharmaceuticals, Ardley, N. Y., 1970, 537, which is incorporated by reference in its entirety. Dosage levels of between about 0.001 and about 100 mg/kg body weight per day, preferably between about 0.1 and about 10 mg/kg body weight per day, of the active ingredient compound can be used.
The compounds of Formula (I) can be prepared according to Scheme 1. Scheme 1
Figure imgf000046_0001
Generally, diethyl squarate is sequentially reacted with two amines, one of which includes the Het group, the other including the R4 group. Scheme 1 illustrates a sequence in which the Het group is added first; however, the opposite order is also possible. The R groups can optionally be further modified. One example of such a modification is shown in Scheme 2, where a carboxylic acid group in R4 is reacted with an amine to form an amide group.
Scheme 2
Figure imgf000046_0002
Compounds of the formula HN(R9)R4 can be prepared according to methods known in the art. For example, some transformations suitable for preparing compounds of the formula HN(R9)R4 are shown in Scheme 3.
Scheme 3
Figure imgf000047_0001
Examples
Reactions were run using commercially available starting materials and anhydrous solvents, without further purification. Proton NMR spectra were recorded on a 400 MHz Bruker AV-400 spectrometer using TMS (δ 0.0) as an internal reference. High resolution mass spectra were obtained using a Bruker APEXIII Fourier transform ion cyclotron resonance (FT-ICR) mass spectrometer equipped with an actively shielded 7 Tesla superconducting magnet (Magnex Scientific Ltd., UK) and an external Bruker APOLLO electrospray ionization (ESI) source. Preparative HPLC was run using a Waters reverse phase preperative HPLC (Xterra Cl 8 5 μm, 3O x 100 mm column; water/CH3CN/0.1% formic acid). Purity in two solvent systems was determined using Agilent 1100 reverse phase HPLC with Agilent Zorbax SB-C 18 5 μm, 4.6 x 30mm column at 254 nm [Gradient: 5-95% in 7min @ 0.8mL/min, H2O/CH3CN (method 1) and H2OMeOH (method 2)]. The following abbreviations were used: XPHOS = 2- (dicyclohexylphosphino)-2', 4', 6'-tri-I-ρropyl-l, 1 '-biphenyl-; Xantphos = 9, 9-dimethyl-4, 5- bis(diphenylphosphino)xanthene; Pd2(dba)3 = tris(dibenzylideneacetone)dipalladium.
The present application claims the benefit of priority of U.S. Provisional Application 60/950,680, filed July 19, 2007, which is incorporated herein by reference in its entirety.
Example 1 3-{[l-(4-fluorophenyl)ethyI]amino}-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2-dione To a solution of 3-ethoxy-4-(pyridin-4-ylamino)-cyclobut-3-ene-1,2-dione (prepared as described in /. Med. Chem. 2000, 45, 1187-1202, which is incorporated by reference in its entirety) (50 mg, 229 μmol) in EtOH (2 mL) was added (D,L)-4-fluoro-α-methylbenzylamine (31 μL, 236 μmol). The reaction mixture was heated to 100 °C for 3h and then stirred at room temperature overnight. The reaction mixture was filtered and the precipitate was collected and dried in vacuo to give 55 mg (77% yield) of the title compound. MS (ES) m/z 312.1 (M+l). Example 2 3-[(cyclohexylmethyl)amino]-4-(pyridiπ-4-ylaιnino)cyclobut-3-eiie-1,2-dione
The title compound was synthesized in a manner similar to that of Example 1 but aminomethylcyclohexane was used in place of the amine (yield = 66%). MS (ES) m/z 284.1 (M- H).
Example 3 3-(2,3-dihydro-l/Z-inden-1-ylaminoJ^-^yridin-4-ylaminoJcyclobuW-ene-ljl-dione
The title compound was synthesized in a manner similar to that of Example 1 but (+/-)- 1- aminoindane was used in place of the amine (yield = 39%). MS (ES) m/z 306.1 (M+l). Example 4 3-(pyridiu-4-ylamino)-4-[(tetrahydrofuran-2-y]methyl)amino]cycIobut-3-ene-1,2-dione
The title compound was synthesized in a manner similar to that of Example 1 but (+/-)-2- (aminomethyl)tetrahydrofuran was used in place of the amine (yield = 50%). MS (ES) m/z 21 A.1 (M+l). Example 5 3-[(1,3-benzodioxol-5-yImethyl)amino]-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2-dione
The title compound was synthesized in a manner similar to that of Example 1 but 1,3- benzodioxol-5-yl-methylamine was used in place of the amine (yield = 55%). MS (ES) m/z 324.1 (M+l).
Example 6 3-(pyridin-4-ylamino)-4-[(pyridin-2-ylmethyl)amino]cyc]obut-3-ene-1,2-dione
The title compound was synthesized in a manner similar to that of Example 1 but 2- (aminomethyl)-pyridine was used in place of the amine (yield = 17%). MS (ES) m/z 279.1 (M-I). Example 7
3-(pyridin-4-ylaniino)-4-[(pyridin-3-ylmethyl)amino]cyclobut-3-ene-1,2-dione The title compound was synthesized in a manner similar to that of Example 1 but 3- (aminomethyl)-pyridine was used in place of the amine (yield = 70%). MS (ES) m/z 279.1 (M-I). Example 8
3-(pyridin-4-ylamino)-4-[(pyridin-4-ylmethyI)amino]cyclobut-3-ene-1,2-dione The title compound was synthesized in a manner similar to that of Example 1 but 4-
(aminomethyl)-pyridine was used in place of the amine (yield = 28%). MS (ES) m/z 279.1 (M-I).
Example 9
3-[(diphenylmethyl)amino]-4-(pyridin-4-ylainino)cyclobut-3-ene-1,2-dione
The title compound was synthesized in a manner similar to that of Example 1 but 1,1- diphenylmethylamine was used in place of the amine (yield = 69%). MS (ES) m/z 354.1 (M-I). Example 10 3-(benzylamino)-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2-dione
The title compound was synthesized in a manner similar to that of Example 1 but benzylamine was used in place of the amine (yield = 70%).MS (ES) m/z 278.1 (M-I). Example 11
3-[(2-methyIbenzyl)amino]-4-(pyridin-4-yIamino)cyclobut-3-ene-1,2-dione
The title compound was synthesized in a manner similar to that of Example 1 but 2- methylbenzylamine was used in place of the amine (yield = 61%). MS (ES) m/z 294.1 (M+1) Example 12
3-(pyridin-4-ylaπiino)-4-{[3-(trifluoromethyl)benzyl]amino}cyclobut-3-ene-1,2-dione
The title compound was synthesized in a manner similar to that of Example 1 but 3- (trifluoromethyl)-benzylamine was used in place of the amine (yield = 50%). MS (ES) m/z 348.1 (M+l) Example 13
3-[(3-methylbenzyl)amino]-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2-dione
The title compound was synthesized in a manner similar to that of Example 1 but 3- methylbenzylamine was used in place of the amine (yield = 70%). MS (ES) m/z 294.1 (M+l) Example 14 3-[(4-fluorobenzyl)amino]-4-(pyridin-4-ylaπiiiio)cyclobut-3-ene-1,2-dione The title compound was synthesized in a manner similar to that of Example 1 but A- fluorobenzylamine was used in place of the amine (yield = 85%). MS (ES) m/z 298.1 (M+l) Example 1S
3-[(4-methylbenzyl)amino]-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2-dione The title compound was synthesized in a manner similar to that of Example 1 but A- methylbenzylamine was used in place of the amine (yield = 89%). MS (ES) m/z 292.1 (M-I) Example 16 3-(isobutylamino)-4-(pyridin-4-ylamino)cycIobut-3-ene-1,2-dione
The title compound was synthesized in a manner similar to that of Example 1 but isobutylamine was used in place of the amine (yield = 69%). MS (ES) m/z 246.1 (M+l) Example 17 3-{[2-(4-methylpheny])ethyl]amino}-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2-dione
The title compound was synthesized in a manner similar to that of Example 1 but 2-(4- methylphenyl)-ethylamine was used in place of the amine (yield = 87%). MS (ES) m/z 306.1(M- 1)
Example 18 3-(allylamino)-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2-dione
The title compound was synthesized in a manner similar to that of Example 1 but allylamine was used in place of the amine (yield = 67%). MS (ES) m/z 228.1 (M-I) Example 19
3-[(2,4-difluorobenzyl)amino]-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2-dione
The title compound was synthesized in a manner similar to that of Example 1 but 2,4- difluorobenzylamine was used in place of the amine (yield = 84%). MS (ES) m/z 314.1 (M-I) Example 20 3-[(2,5-difluorobenzyl)amino]-4-(pyridiιi-4-ylamino)cyclobut-3-ene-1,2-dione
The title compound was synthesized in a manner similar to .that of Example 1 but 2,5- difluorobenzylamine was used in place of the amine (yield = 73%). MS (ES) m/z 314.1 (M-I) Example 21
3-[(3,4-difluorobenzyl)amino]-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2-dioiie The title compound was synthesized in a manner similar to that of Example 1 but 3,4- difluorobenzylamine was used in place of the amine (yield = 89%). MS (ES) m/z 314.1 (M-I) Example 22 3-(pyridin-4-ylamino)-4-{[4-(trifluoromethyI)benzyl]amino}cyclobut-3-ene-1,2-dione
The title compound was synthesized in a manner similar to that of Example 1 but 4- (trifluoromethyl)-benzylamine was used in place of the amine (yield = 83%). MS (ES) m/z 346.1 (M-I)
Example 23 3-[(2,4-dimethylbenzyI)amino]-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2-dione
The title compound was synthesized in a manner similar to that of Example 1 but 2,4- dimethylbenzylamine was used in place of the amine (yield = 77%). MS (ES) m/z 306.1 (M-I) Example 24
3-[(3,4-dimethylbenzyI)amino]-4-(pyridiii-4-ylamino)cycIobut-3-ene-1,2-dione
The title compound was synthesized in a manner similar to that of Example 1 but 3,4- dimethylbenzylamine was used in place of the amine (yield = 68%). MS (ES) m/z 306.1 (M-I) Example 25 3-[(4-tert-butylbenzyl)amino]-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2-dione
The title compound was synthesized in a manner similar to that of Example 1 but 4-tert- butylbenzylamine was used in place of the amine (yield = 83%). MS (ES) m/z 334.1 (M-I) Example 26
3-[(3,5-difluorobenzyl)amino]-4-(pyridiii-4-ylamino)cyclobut-3-ene-1,2-dione The title compound was synthesized in a manner similar to that of Example 1 but 3,5- difluorobenzylamine was used in place of the amine (yield = 87%). MS (ES) m/z 316.1 (M+l) Example 27 3-{[(1S)-1-phenylethyl]amino}-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2-dione
The title compound was synthesized in a manner similar to that of Example 1 but (S)(-)- α-methylbenzylamine was used in place of the amine (yield = 55%). MS (ES) m/z 294.1 (M+l) Example 28 3-((R)-1-Phenyl-ethylamino)-4-(pyridin-4-ylamino)-cyclobut-3-ene-1,2-dione
The title compound was synthesized in a manner similar to that of Example 1 but (R)(+)- α-methylbenzylamine was used in place of the amine (yield = 64%). MS (ES) m/z 292.1 (M-I) Example 29
3-(pyridin-4-yIamino)-4-(1,2,3,4-tetrahydronaphtha]en-1-ylamino)cyclobut-3-ene-1,2-dione The title compound was synthesized in a manner similar to that of Example 1 but 1,2,3,4- tetrahydro-1-naphthylamine was used in place of the amine (yield = 71%). MS (ES) m/z 318.2 (M-I)
Example 30 3-{[(1R)-2-hydroxy-1-phenyIethyI]amino}-4-(pyridin-4-ylamino)cyc]obut-3-ene-1,2-dione
The title compound was synthesized in a manner similar to that of Example 1 but R-(-)-2- phenylglycinol was used in place of the amine (yield = 80%). MS (ES) m/z 308.1 (M-I) Example 31
3-[(1,2-diphenylethyl)amino]-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2-dione The title compound was synthesized in a manner similar to that of Example 1 but 1,2- diphenylethylamine was used in place of the amine (yield = 86%). MS (ES) m/z 368.2 (M-I) Example 32 2-{[3,4-dioxo-2-(pyridin-4-ylamino)cycIobut-1-en-1-yl]amino}-2-phenylacetamide
The title compound was synthesized in a manner similar to that of Example 1 but 2- amino-2-phenylacetamide was used in place of the amine (yield = 57%). MS (ES) m/z 321.1 (M-I)
Example 33 3-{methyl[(1R)-1-phenylethyl]amino}-4-(pyridin-4-yIamino)cyclobut-3-ene-1,2-dione
The title compound was synthesized in a manner similar to that of Example 1 but (R)-(+)- N-α-dimethylbenzylamine was used in place of the amine (yield = 65%). MS (ES) m/z 306.2 (M-I)
Example 34 3-{[(1R)-1-(4-bromophenyl)ethyl]amino}-4-(pyridin-4-ylainino)cyclobut-3-ene-1,2-dione
The title compound was synthesized in a manner similar to that of Example 1 but (R)-(+)- l-(4-bromophenyl)ethylamine was used in place of the amine (yield = 92%). MS (ES) m/z 370.0 (M-2) Example 35 3-{[(1S)-2-hydroxy-1-phenylethyl]amino}-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2-dione
The title compound was synthesized in a manner similar to that of Example 1 but (S)-(+)- 2-phenylglycinol was used in place of the amine (yield = 28%). MS (ES) m/z 308.1 (M-I) Example 36 3-{[(1S)-1-phenylpropyllaπύno}-4-(pyridin-4-ylamino)cyclobut-S-ene-1,2-dione
The title compound was synthesized in a manner similar to that of Example 1 but (S)-α- phenylpropylamine was used in place of the amine (yield = 43%). MS (ES) m/z 306.1 (M-I) Example 37 3-{[(ϋ?)-1-phenyIpropyl]amino}-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2-dione
The title compound was synthesized in a manner similar to that of Example 1 but (R)-α- phenylpropylamine was used in place of the amine (yield = 45%). MS (ES) m/z 306.1 (M-I) Example 38
3-{[(1R)-1-(2-naphthyl)ethyl]amino}-4-(pyridiii-4-ylamrao)cyclobut-3-ene-1,2-dione The title compound was synthesized in a manner similar to that of Example 1 but (R)-(+)- l-(2-naphthyl)ethylamine was used in place of the amine (yield = 90%). MS (ES) m/z 341.1 (M-
2)
Example 39
3-[(1R)-2,3-dihydro- 1H-inden-1-ylaniino]-4-(pyridm-4-ylamino)cyclobut-3-ene-1,2-dione The title compound was synthesized in a manner similar to that of Example 1 but (R)-(-)-
(l)-aminoindane was used in place of the amine (yield = 69%). MS (ES) m/z 304.1 (M-I)
Example 40
3-{[(1R)-1-(4-chlorophenyl)ethyl]amino}-4-(pyridin-4-ylainino)cycIobut-3-ene-1,2-dione
The title compound was synthesized in a manner similar to that of Example 1 but (R)-(+)- 4-chloro-α-methylbenzylamine was used in place of the amine (yield = 93%). MS (ES) m/z
326.1 (M-I)
Example 41
3-{[(1S)-1-(4-chlorophenyl)ethyI]amino}-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2-dione
The title compound was synthesized in a manner similar to that of Example 1 but (S)-(-)- 4-chloro-α-methylbenzylamine was used in place of the amine (yield = 72%). MS (ES) m/z
326.1 (M-I)
Example 42
3-{[(1R)-1-(3-methoxyphenyI)ethylJamino}-4-(pyridin-4-ylainino)cyclobut-3-ene-1,2-dione The title compound was synthesized in a manner similar to that of Example 1 but (R)-3- methoxy-α-methylbenzylamine was used in place of the amine (yield = 32%). MS (ES) m/z
322.1 (M-I) Example 43
3-{[(1R)-1-(4-methoxyphenyl)ethyI]amino}-4-(pyridin-4-ylainino)cyclobiit-3-ene-1,2-dione
The title compound was synthesized in a manner similar to that of Example 1 but (R)-4- methoxy-α-methylbenzylamine was used in place of the amine (yield = 80%). MS (ES) m/z 322.1 (M-I) Example 44 (R)-3-(Pyridin-4-yIamino)-4-(1,2,2-trimethyl-propy]amino)- cyclobut-3-ene-1,2-dione
The title compound was synthesized in a manner similar to that of Example 1 but (R)-(-)- 3,3-dimethyl-2-butylamine was used in place of the amine (yield = 80%). MS (ES) m/z 272.1 (M-I)
Example 45 3-[(4-bromobenzyl)amino]-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2-dione
The title compound was synthesized in a manner similar to that of Example 1 but 4- bromobenzylamine hydrochloric acid was used in place of the amine, and 1.2 equivalents of triethylamine was added to the reaction mixture (yield = 90%). MS (ES) m/z 356.0 (M-2) Example 46 3-[(4-chlorobenzyI)amino]-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2-dione
The title compound was synthesized in a manner similar to that of Example 1 but 4- chlorobenzylamine was used in place of the amine (yield = 85%). MS (ES) m/z 314.1 (M+l) Example 47
3-[(4-methoxybenzyl)ainino]-4-(pyridiii-4-ylamino)cyclobut-3-ene-1,2-dione
The title compound was synthesized in a manner similar to that of Example 1 but 4- methoxybenzylamine was used in place of the amine (yield = 85%). MS (ES) m/z 310.1 (M+l) Example 48 N-[3,4-dioxo-2-(pyridin-4-ylainino)cyclobut-1-en-1-yI]-L-phenylalaninamide
The title compound was synthesized in a manner similar to that of Example 1 but L- phenylalininamide hydrochloric acid was used in place of the amine (yield = 83%). MS (ES) m/z 337.1 (M+l) Example 49
2-{[3,4-dioxo-2-(pyridin-4-ylamino)cyclobut-1-en-1-yl]amino}-N-methyl-2-phenylacetamide The title compound was synthesized in a manner similar to that of Example 1 but 2- amino-N-methyl-2-phenyl-acetamide was used in place of the amine (yield = 51%). MS (ES) m/z 337.1 (M+l)
Example 50 N-[3,4-dioxo-2-(pyridiii-4-ylaιnino)cyclobut-1-en-1-yl]-D-phenylalaninamide
The title compound was synthesized in a manner similar to that of Example 1 but D- phenylalaninamide was used in place of the amine (yield = 50%). MS (ES) m/z 337.1 (M+l)
Example 51
3-{[(1R)-1-(4-fluorophenyl)ethyl]amino}-4-(pyridin-4-ylainino)cyclobut-3-ene-1,2-dione The title compound was synthesized in a manner similar to that of Example 1 but (R)-I-
(4-fluorophenyl)ethylamine was used in place of the amine (yield = 83%). MS (ES) m/z 312.1
(M+l)
Example 52
3-{[l-(4-hydroxyphenyl)ethyl]amino}-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2-dione The title compound was synthesized in a manner similar to that of Example 1 but 4-(l- aminoethyl)phenol was used in place of the amine (yield = 70%). MS (ES) m/z 310.1 (M+l)
Example 53
3-{[l-(l-naphthyl)ethyl]amino}-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2-dione
The title compound was synthesized in a manner similar to that of Example 1 but DL-I- (l-naphthyl)ethylamine was used in place of the amine (yield = 61%). MS (ES) m/z 344.1
(M+l)
Example 54
3-{[(1R)-1-(4-methylphenyI)ethyI]amino}-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2-dione
The title compound was synthesized in a manner similar to that of Example 1 but (R)-(+)- α-4-dimethylbenzylamine was used in place of the amine (yield = 64%). MS (ES) m/z 308.1
(M+l)
Example 55
3-{[(lJJ)-1-(4-nitrophenyl)ethyl]amino}-4-(pyridin-4-ylaπiino)cyclobut-3-ene-1,2-dione
The title compound was synthesized in a manner similar to that of Example 1 but (R)-α- methyl-4-nitrobenzylamine hydrochloride was used in place of the amine (yield = 86%). MS
(ES) m/z 339.1 (M+l) Example 56
3-{[l-(4-fluorophenyl)-2-hydroxyethyl]amino}-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2- dione
To a 0 °C solution of lithium borohydride (360 μL, 2N in THF, 0.72 mmol) in THF (1 mL) was added chlorotrimethylsilane (184 μL, 1.45 mmol). The mixture was stirred for 10 min at 0 °C, then at room temperature for 30 min. This solution was added to a suspension of 4- fluoro-DL-phenylglycine (60 mg, 0.35 mmol) in THF (3 mL) at 0 °C and the mixture was stirred at 0 °C for 10 min, then at room temperature overnight. The reaction mixture was quenched with
MeOH and the solvent was removed in vacuo. To the residue was added IN NaOH (3 mL) and the product was extracted with CHCI3 (3 x 2mL). The combined organic extracts were dried
(MgSO,)) and concentrated to give 30 mg (50%) of 2-amino-2-(4-fluoro-phenyl)-ethanol. The crude alcohol was dissolved in EtOH (1 mL) and added to a solution of 3-ethoxy-4-(pyridin-4- ylamino)-cyclobut-3-ene-1,2-dione (41 mg, 188 μmol) in EtOH (1 mL). The reaction mixture was heated to 95 °C for 3 h. After cooling to room temperature, the mixture was filtered and the precipitate was collected and dried in vacuo to give 18 mg (29%) of the title compound. MS
(ES) m/z 328.1 (M+l)
Example 57
3-{[l-(4-chlorophenyl)-2-hydroxyethyl]amino}-4-(pyridin-4-yIamino)cycIobut-3-ene-1,2- dione The title compound was synthesized in a manner similar to that of Example 56 with 4- chloro-DL-phenylglycine as the amino acid starting material (yield = 67%). MS (ES) m/z 344.0
(M+l)
Example 58
3-{[l-(2-fluorophenyl)-2-hydroxyethyl]amino}-4-(pyridin-4-ylamino)cyclobnt-3-ene-1,2- dione
The title compound was synthesized in a manner similar to that of Example 56 with DL-
2-fluorophenylglycine as the amino acid starting material (yield = 24%). MS (ES) m/z 328.1
(M+l)
Example 59 3-({2-hydroxy-1-[4-(trifluoromethyl)phenyl]ethyl}amino)-4-(pyridiii-4-ylainino)cyclobut-3- ene-1,2-dione The title compound was synthesized in a manner similar to that of Example 56 with 4- (trifluoromethyl)phenylglycine) as the amino acid starting material (yield = 40%). MS (ES) m/z
378.1 (M+l) Example 60 3-{[2-hydroxy-1-(4-methylphenyl)ethyl]amin.o}-4-(pyridin-4-ylammo)cyclobut-3-ene-1,2- dione
The title compound was synthesized in a manner similar to that of Example 56 with 4- methylphenylglycine as the amino acid starting material (yield = 42%). MS (ES) m/z 324.1
(M+l) Example 61
3-{[l-(3-chloro-4-fluorophenyl)-2-hydroxyethyI]amiπo}-4-(pyridiπ-4-ylamino)cyclobut-3- ene-1,2-dione
The title compound was synthesized in a manner similar to that of Example 56 with 3- chloro-4-fluoro-DL-phenylglycine as the amino acid starting material (yield = 29%). MS m/z 360.1 (M-I)
Example 62
3-{[2-hydroxy-1-(3,4,5-trifluorophenyl)ethyl]amino}-4-(pyridin-4-ylainino)cyclobut-3-ene-
1,2-dione
The title compound was synthesized in a manner similar to that of Example 56 with 3,4,5-trifluoro-DL-phenylglycine as the amino acid starting material (yield = 59%). MS (ES) m/z 364.0 (M+l)
Example 63
3-{[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyI]amino}-4-(pyridin-4- ylamino)cyclobut-3-ene-1,2-dione The title compound was synthesized in a manner similar to that of Example 1 but (±)-α-
(l-aminoethyl)-4-hydroxybenzyl alcohol hydrochloric acid was used in place of the amine, and
1.1 equivalents of triethylamine was added to the reaction mixture (yield = 80%). MS (ES) m/z
340.2 (M+l) Example 64 3-{[2-(4-chlorophenyI)-1-methylethyl]amino}-4-(pyridin-4-ylamino)cycIobut-3-ene-1,2- dione The title compound was synthesized in a manner similar to that of Example 1 but 4- chloroamphetamine hydrochloric acid hydrochloric acid was used in place of the amine, and 1.1 equivalents of triethylamine was added to the reaction mixture (yield = 77%). MS (ES) m/z
342.2 Example 65
4-(l-{[3,4-dioxo-2-(pyridin-4-yIamino)cyclobut-1-en-1-yI]amino}ethyl)benzoiiitrile
The title compound was synthesized in a manner similar to that of Example 1 but 4-(l- amino-ethyl)-benzonitrile was used in place of the amine (yield = 78%). MS (ES) m/z 319.1
(M+l) Example 66
3-{[(1S )-2-hydroxy-2-methyl-1-phenylpropyl]amino}-4-(pyridin-4-yIamino)cyclobut-3-ene-
1,2-dione
The title compound was synthesized in a manner similar to that of Example 1 but (IS)-I- amino-2-methyl-1-phenyl-propan-2-ol (prepared as described in WO 95/18112, which is incorporated by reference in its entirety) was used in place of the amine (yield = 74%). [α]D 25 =
-103.6° (c = 1% solution, DMSO); MS (ES) m/z 338.1 (M+l)
Example 67
3-{[(1R)-2-hydroxy-2-methyH-phenylpropyl]amlno}-4-(pyridin-4-ylainino)cyclobut-3-ene-
1,2-dione The title compound was synthesized in a manner similar to that of Example 1 but (IR)-I- amino-2-methyl-1-phenyl-propan-2-ol (prepared as described in WO 95/18112, which is incorporated by reference in its entirety) was used in place of the amine (yield = 82%).
[α]D 25 = +101.6° (c = 1% solution, DMSO); MS (ES) m/z 338.1 (M+l)
Example 68 (2R)-2-{[3,4-dioxo-2-(pyridin-4-yIamino)cyclobut-1-en-1-yl]amino}-N-methyl-2- phenylacetamide
The title compound was synthesized in a manner similar to that of Example 1 but (R)-2- amino-N-methyl-2-phenyl-acetamide (prepared from the reaction of (R)-(-)-2-phenylglycine methyl ester with 40% CH3NH2 in water) was used in place of the amine. The product was isolated by removal of solvent in vacuo, followed by trituration with ether (yield = 80%). MS
(ES) m/z 335.1 (M-I) Example 69
(25)-2-{[3,4-dioxo-2-(pyridin-4-ylamino)cyclobut-1-en-1-yl]amino}-iV-methyI-2- phenylacetamide
The title compound was synthesized in a manner similar to that of Example 1 but (S)-2- amino-N-methyl-2-phenyl-acetamide (prepared from the reaction of (S)-(+)-2-phenylglycine methyl ester with 40% CH3NH2 in water) was used in place of the amine. The product was isolated by removal of solvent in vacuo, followed by trituration with ether (yield = 94%). MS (ES) m/z 335.1 (M-I) Example 70 2-(3,4-dichlorophenyl)-2-{[3,4-dioxo-2-(pyridin-4-ylamino)cyclobut-1-eii-1- yl]amino}acetamide(trifluoroacetic acid salt)
To 2-amino-(3,4-dichlorophenyl)acetic acid hydrochloric acid (0.25 g, 0.97 mmol) in MeOH (13 mL) was added thionyl chloride (0.49 niL, 2 M in CH2Cl2). The mixture was refluxed overnight, cooled, then concentrated in vacuo. The solid was triturated with dichloromethane and filtered. To the resulting methyl ester was added saturated ammonia in methanol (10 mL). After 24 h the mixture was concentrated and the resulting solid, which contains 2-amino-2-(3,4-dichloro-phenyl)-acetamide hydrochloride and ammonium chloride, was obtained. A portion of this intermediate (75 mg) was added to a solution of 3-ethoxy-4- (pyridin-4-ylamino)-cyclobut-3-ene-1,2-dione (64 mg, 280 μmol) in EtOH (4 mL). The reaction mixture was stirred at 60 °C for 18 h, and then concentrated in vacuo. Purification by HPLC
(C18; 10 - 100% gradient, H2O/ACN with 0.1% TFA) provided the title compound (49 mg, 43% yield). MS (ES) m/z 390.1 (M-I) Example 71 2-(4-chIorophenyl)-2-{[3,4-dioxo-2-(pyridin-4-ylamino)cyclobut-1-en-1-yl]amino}acetamide (trifluoroacetic acid salt)
The title compound was synthesized in a manner similar to that of Example 70 with DL- 2-(4-chlorophenyl)glycine) as the starting material. The product was isolated by removal of solvent in vacuo, followed by purification by HPLC (C18; 10 - 100% gradient, H2O/ ACN with 0.1% TFA) (yield = 42%). MS (ES) m/z 355.1 (M-I) Example 72 (25)-2-(4-chlorophenyl)-2-{[3,4-dioxo-2-(pyridin-4-ylamino)cycIobut-1-en-1- yl] amino} acetamide
The title compound was prepared by chiral HPLC separation of 2-(4-chlorophenyl)-2-
{ [3 ,4-dioxo-2-(pyridin-4-ylamino)cyclobut- 1 -en- 1 -yl] amino} acetamide (trifluoroacetic acid salt). HPLC conditions: Varian Prep; Chiralcel AD, 2 x 25 cm column at 23 °C; 1.7 niL injection; Mobile phase: EtOH; Flow rate 15 mL/min; Detection: 280 nm DAD. Retention time:
4.5 min; MS (ES) m/z 357.1 (M+l)
Example 73
(2Λ)-2-(4-chlorophenyl)-2-{[3,4-dioxo-2-(pyridin-4-ylamino)cyclobut-1-eii-1- yl]aπiino} acetamide
The title compound was prepared by chiral HPLC separation of 2-(4-chlorophenyl)-2-
{ [3,4-dioxo-2-(pyridin-4-ylamino)cyclobut- 1 -en-1 -yl] amino} acetamide (trifluoroacetic acid salt). HPLC conditions: Varian Prep; Chiralcel AD, 2 x 25 cm column at 23 °C; 1.7 niL injection; Mobile phase: EtOH; Flow rate 15 mL/min; Detection: 280 nm DAD. Retention time: 8.9 min; MS (ES) m/z 357.1 (M+l)
Example 74
2-(3-chloro-4-fluorophenyl)-2-{[3,4-dioxo-2-(pyridin-4-ylamino)cyclobut-1-en-1- yl] amino} acetamide
The title compound was synthesized in a manner similar to that of Example 70 with 3- chloro-4-fluoro-DL-phenylglycine) as the starting material. The product was isolated by removal of solvent in vacuo, followed by purification by HPLC (C1sjlO - 100% gradient,
H2O/ACN with 0.1% TFA) (yield = 44%). MS (ES) m/z 375.1 (M+l)
Example 75
2-{[3,4-dioxo-2-(pyridin-4-ylamino)cyclobut-1-en-1-yl]amino}-2-[4- (triflιioromethyl)phenyl]acetamide
The title compound was synthesized in a manner similar to that of Example 70 with 4- trifluoromethyl-DL-phenylglycine as the starting material. The product was isolated by removal of solvent in vacuo, followed by purification by HPLC (C]8;10 - 100% gradient, H2O/ACN with
0.1% TFA) (yield = 32%). MS (ES) m/z 391.1 (M+l) Example 76
2-{[3,4-dioxo-2-(pyridin-4-ylamino)cycIobut-1-en-1-yl]amino}-2-(4-fluorophenyl)acetainide The title compound was synthesized in a manner similar to that of Example 70 with DL-
2-fluorophenylglycine as the starting material. The product was isolated by removal of solvent in vacuo, followed by purification by HPLC (C18;10 - 100% gradient, H2CVACN with 0.1%
TFA) (yield = 40%). MS (ES) m/z 341.1 (M+ 1) Example 77
2-{[3,4-dioxo-2-(pyridin-4-yIamino)cyclobut-1-en-1-yl]amino}-2-(2-fluorophenyl)acetamide The title compound was synthesized in a manner similar to that of Example 70 with 4- fluoro-DL-phenylglycine as the starting material. The product was isolated by removal of solvent in vacuo, followed by purification by HPLC (C18;10 - 100% gradient, H2CVACN with 0.1% TFA) (yield = 16%). MS (ES) m/z 341.1 (M+ 1)
Example 78
2-{[3,4-dioxo-2-(pyridin-4-ylamino)cyc]obut-1-en-1-yl]amino}-2-(3,4,5- trifluorophenyl)acetamide
The title compound was synthesized in a manner similar to that of Example 70 with 3,4,5-trifluoro-DL-phenylglycine as the starting material. The product was isolated by removal of solvent in vacuo, followed by purification by HPLC (C18;10 - 100% gradient, H2O/ ACN with
0.1% TFA) (yield = 41%). MS (ES) m/z 375.1 (M-I)
Example 79
2-(4-chlorophenyl)-2-{[3,4-dioxo-2-(pyridin-4-ylamino)cycIobut-1-en-1-yl]amino}-N- methylacetamide
The title compound was synthesized in a manner similar to that of Example 70 with DL-
2-(4-chlorophenyl)glycine as the amino acid starting material and 40% methylamine in water instead of saturated ammonia solution. The product was isolated by removal of solvent in vacuo, followed by purification by HPLC (C18;10 - 100% gradient, H2CVACN with 0.1% TFA) (yield = 52%). MS (ES) m/z 369.1 (M-I)
Example 80
2-{[3,4-dioxo-2-(pyridin-4-ylamino)cycIobut-1-en-1-yl]amino}-iV-ethyl-2-phenylacetainlde The title compound was synthesized in a manner similar to that of Example 70 with phenylglycine as the starting material and 70% ethylamine in water instead of ammonia solution (yield = 84%). MS (ES) m/z 349.1 (M-I)
Example 81 N-(cyclohexylmethyl)-2-{[3,4-dioxo-2-(pyridin-4-ylamino)cyclobut-1-en-1-yl]ainiiio}-2- phenylacetaniifie
Step 1 : [3,4-Dioxo-2-(pyridin-4-ylamino)-cyclobut-1-enylamino]-phenyl-acetic acid To 3-ethoxy-4-(pyridin-4-ylamino)-cyclobut-3-ene-1,2-dione (550 mg, 2.52 mmol) dissolved in EtOH (2 mL) was added 2-phenylglycine (381 mg, 2.52 mmol). The reaction mixture was heated to 60 °C and stirred overnight. The reaction mixture was concentrated to a solid and then triturated with a mixture of EtOAc/EtOH/hexane to give 220 mg (27% yield) of the title compound. Alternatively, the product was purified by HPLC (C1s, gradient 10 - 100%
ACN in H2O, 0.1% TFA) and isolated as the TFA salt. Step 2: N-(cyclohexyknethyl)-2-{[3,4-dioxo-2-(pyridin-4-ylamino)cyclobut-1-en-1- yl] amino } -2-phenylacetamide
To [3,4-dioxo-2-(pyridin-4-ylamino)-cyclobut-1-enylamino]-phenyl-acetic acid (50 mg,
114 μmol) in DMF (4 mL) was added cyclohexyl-methylamine (45 μL, 340 μmol), N- cyclohexylcarbodiimide-N'-propyloxymethyl polystyrene (PS-CDI, Argonaut Technologies) (1.2 mmol/g, 190 mg, 228 μmol) and l-hydroxybenzotriazole-6-sulfonamidomethyl polystyrene
(PS-HOBT, Argonaut Technologies) (0.98 mmol/g, 232 mg, 228 mmol) and the reaction mixture was heated overnight at 50 °C. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The resulting residue was purified by HPLC to give 4.3 mg (7% yield) of the title product, identified by HPLC and mass spectral analysis. HPLC conditions: Hewlett Packard 1100; Luna C18 (5 μ), 2 x 30 mm column at 23 °C; 3 μL injection; Solvent A: 0.1%
HOOH/water; Solvent B: 0.1% HOOH/ ACN; Gradient: 10-100% solvent B (ACN) in 3 min.
Flow rate 0.6 mL/min; Detection: 254 and 230 nm DAD. M+H, 420; time (min) 1.88
Example 82
N-(4-chlorobenzyl)-2-{[3,4-dioxo-2-(pyridin-4-ylamino)cyclobut-1-en-1-yl]amino}-2- phenylacetatnide
Using essentially the same procedures described for Example 81 but using 4-chloro- benzylamine in place of the amine, the title compound was obtained and identified by HPLC and mass spectral analysis (17% yield). M+H, 447; time (min) 1.9
Example 83 3-[(2-oxo-1-phenyl-2-pyrrolidin-1-ylethyl)amino]-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2- dione Using essentially the same procedures described in Example 81 but using pyrrolidine in place of the amine, the title compound was obtained and identified by HPLC and mass spectral analysis (12% yield) M+H, 377, time (mm) 1 5
Example 84 2-{[3,4-dioxo-2-(pyridin-4-ylamino)cyclobut-1-en-1-yl]amino}-ΛyV-dimethyl-2- phenylacetamide
Using essentially the same procedures described in Example 81 but using dimethylamine m place of the amine, the title compound was obtained and identified by HPLC and mass spectral analysis (56% yield) M+H, 351, time (mm) 1 3 Example 85
N-[2-(4-chlorophenyl)ethyl]-2-{[3,4-dioxo-2-(pyridin-4-ylamino)cyclobut-1-en-1-yl] amino}-
2-phenylacetamide
Using essentially the same procedures described in Example 81 but usmg 2-(4-chloro- phenyl)-ethylamine in place of the amine, the title compound was obtained and identified by HPLC and mass spectral analysis (46% yield)
M+H, 461 , time (mm) 3 0
Example 86
2-{[3,4-dioxo-2-(pyridin-4-y]amino)cyclobut-1-en-1-yl]amino}-2-phenyI-iV-(pyridin-4- ylmethyl)acetamide Using essentially the same procedures described in Example 81 but using pyndin-4-yl- methylamine m place of the amine, the title compound was obtained and identified by HPLC and mass spectral analysis (18% yield)
M+H, 414, time (mm) 03
Example 87 2-{[3,4-dioxo-2-(pyridin-4-ylamino)cyclobut-1-en-1-yl]amino}-N-isobutyl-2- phenylacetamide
Usmg essentially the same procedures described in Example 81 but usmg isobutylamme in place of the amine, the title compound was obtained and identified by HPLC and mass spectral analysis (14% yield) M+H, 379, tune (mm) 1 6
Example 88 3-[(2-methoxypyridin-4-yl)amiiio]-4-{[(1R)-1-phenylethyl]ainino}cycIobut-3-ene-1,2-dione
Step 1: 3-Ethoxy-4-(2-methoxy-pyridin-4-ylamino)-cyclobut-3-ene-1,2-dione To a solution of 3,4-diethoxy-3-cyclobutene-1,2-dione (4.26 g, 25.0 mmol) in EtOH (50 mL) was added a solution of 2-methoxy-pyridin-4-ylamine (3.16 g, 25.0 mmol) (prepared as described in J. Heterocyclic Chem. (1985), 22(1), 145-147, which is incorporated by reference in its entirety) in EtOH (50 mL). The reaction mixture was heated to reflux for 4 h and then cooled to room temperature and stirred overnight. The mixture was filtered, and the precipitate was collected and dried in vacuo to provide 1.73 g (28% yield) of the title compound.
Step 2: 3-[(2-Methoxypyridin-4-yl)amino]-4-{[(1R)-1-phenylethyl]amino}cyclobut-3- ene-1,2-dione
The product of step 1 described above (500 mg, 2.01 mmol) was dissolved in EtOH (15 mL) and a solution of (R)-(+)-α-methylbenzylamine (247 mg, 2.03 mmol) in EtOH (5 mL) was added dropwise. The mixture was stirred at 60 °C overnight and then cooled and filtered. The precipitate was collected and dried in vacuo to provide 614 mg of the title compound (94% yield). [α]D 25 = -34.00° (c = 1% solution, DMSO); MS (ES) m/z 324.1 (M+l) Example 89 (R)-3-(2-hydroxypyridin-4-ylainino)-4-(l-phenylethylaπiino)cyclobut-3-ene-1,2-dione
To a solution of 3-[(2-methoxypyridin-4-yl)amino]-4-{[(1R)-1- phenylethyl]amino}cyclobut-3-ene-1,2-dione (300 mg, 928 μmol) in DMF (4 mL) was added a solution of iodotrimethylsilane (380 μL, 2.78 mmol) in DMF (1 mL). The reaction mixture was heated to 80 °C for 6 h. DMF was removed in vacuo and the residue was dissolved in CH2Ct Sodium thiosulfate was added and the mixture was stirred for 3 h. CH2CI2 was removed in vacuo and then water and EtOAc were added to the residue. A precipitate formed and the mixture was filtered. The precipitate was collected and dried in vacuo to give 232 mg of the title compound (81% yield). MS (ES) m/z 310.2 (M+l) Example 90
3-{[lfl-imidazol-2-yl(phenyl)methyl]amino}-4-(pyridin-4-ylainino)cyclobut-3-ene-1,2-dioiie The title compound was synthesized in a manner similar to that of Example 1 but C-(1H- imidazol-2-yl)-C-phenyl-methylamine (prepared in a similar manner to that described in DE4443892, which is incorporated by reference in its entirety) was used in place of the amine (yield = 86%). MS (ES) m/z 346.1 (M+l) Example 91
3-[(3-methylisoxazoI-5-yl)amino]-4-{[(1R)-1-phenylethyl]amino}cycIobut-3-ene-
1,2-dione
Step 1: A solution of diethyl squarate (500 mg, 2.9 nimol) in EtOH (15 mL) was heated at reflux and a solution of 5-amino-3-methylisoxazole (288 mg, 1.0 eq) in EtOH (5 mL) was added via syringe pump at a rate of 1 mL/h. The solution was cooled, evaporated, and flash chromato graphed (silica, ethyl acetate, acetonitrile, methanol, water (70/10/5/5) to provide the title compound (38 mg, 6%).
Step 2: A solution of 3-ethoxy-4-[(3-methylisoxazol-5-yl)amino]cyclobut-3-ene-1,2- dione (38 mg, 0.2 mmol) and (R)-1-phenylethanamine (65 μL, 3 eq) in EtOH was stirred at RT overnight. Evaporation and flash chromatography (silica, 5% MeOH/DCM) provided the title compound (23 mg, 69%) as a yellow solid. 1H NMR (400 MHz, OMSO-d6) δ ppm 1.58 (d, /=6.82 Hz, 3 H) 2.16 (s, 3 H) 5.20 - 5.36 (m, 1 H) 6.09 (s, 1 H) 7.26 - 7.35 (m, 1 H) 7.36 - 7.44 (m, 4 H) 8.00 (bs, 1 H) 10.82 (bs, 1 H); HPLC purity (Method 1: 97%, Method 2: 96%); HRMS: calcd for C16H15N3O3 + H+, 298.1186; found (ESI-FTMS, [M+H]l+), 298.1186 Example 92
3-[methyl(pyridin-4-yl)amino]-4-{[(1R)-1-phenylethyl]amino}cyclobut-3-ene-1,2- dione
Step 1 : 3-ethoxy-4-[methyl(pyridm-4-yl)amino]cyclobut-3-ene-1,2-dione Following step 1 of Example 91, diethyl squarate (500 mg, 2.9 mmol) and 4-
(methylammo)pyridine (316 mg, 1.0 eq) provided the title compound (43 mg, 6.4%) as a yellow solid. 1H NMR (400 MHz, DMSO-rf,;) δ ppm 1.38 (t, /=7.1 Hz, 3 H), 3.64 (s, 3 H), 4.75 (q, /=7.1 Hz, 2 H), 7.28 (dd, /=4.7, 1.6 Hz, 2 H), 8.55 (dd, /=4.7, 1.6 Hz, 2 H).
Step 2: Following step 2 of Example 91, 3-ethoxy-4-[methyl(pyridin-4- yl)amino]cyclobut-3-ene-1,2-dione (40 mg, 0.17 mmol) and (R)-1-phenylethanamine (66 μL, 3 eq) provided the title compound (47 mg, 90%). 1H NMR (400 MHz, OMSO-d6) δ ppm 1.54 (d, /=6.82 Hz, 3 H) 3.56 (s, 3 H) 6.92 - 6.98 (m, 2 H) 7.23 - 7.32 (m, 1 H) 7.33 - 7.47 (m, 4 H) 8.11 (s, 1 H) 8.44 (d, /=6.06 Hz, 2 H); HPLC purity (Method 1: 100%, Method 2: 99%); HRMS: calcd for C18H17N3O2 + H+, 308.1394; found (ESI-FTMS, [M+H]l+), 308.1394 Example 93
3-{[(1R)-1-phenylethyl]amino}-4-[(2,2,6,6-tetramethylpiperidin-4- yl)amino]cyclobut-3-ene-1,2-dione
Step 1 : 3-ethoxy-4-[(2,2,6,6-tetramethylpiperidin-4-yl)amino]cyclobut-3-ene-l ,2-dione Following step 1 of Example 91, diethyl squarate (300 mg, 1.8 mmol) and 4-amino-2,2,6,6- tetramethylpiperidine (331 mg, 1.2 eq) in EtOH (3 mL) provided the title compound (460 mg, 91%) after collecting the precipitate formed during the reaction. 1H NMR (400 MHz, DMSO-dβ) δ ppm 1.03 (s, 6 H), 1.09 - 1.16 (m, /=3.0 Hz, 6 H), 1.26 (bs, 1 H), 1.31 - 1.40 (m, 3 H), 1.71 (dd, J=I 1.9, 3.5 Hz, 2 H), 2.47 - 2.54 (m, 2 H), 4.66 (q, /=6.9 Hz, 2 H)
Step 2: Following step 2 of Example 91, 3-ethoxy-4-[(2,2,6,6-tetramethylpiperidin-4- yl)amino]cyclobut-3-ene-1,2-dione (460 mg, 1.6 mmol) and (R)-1-phenylethanamine (420 μL, 2 eq) provided the title compound (260 mg, 46%). 1H NMR (400 MHz, DMSO-fifc) δ ppm 0.95 - 1.05 (m, 6 H) 1.09 - 1.17 (m, 6 H) 1.23 (s, 1 H) 1.54 (d, /=6.82 Hz, 3 H) 1.79 (d, /=11.37 Hz, 2 H) 3.33 (s, 3 H) 4.24 (s, 1 H) 5.13 - 5.26 (m, 1 H) 7.26 - 7.33 (m, 1 H) 7.34 - 7.41 (m, 4 H); HPLC purity (Method 1: 85%, Method 2: 98%); HRMS: calcd for C2IH29N3O2 + H+, 356.2332; found (ESI-FTMS, [M+H]l+), 356.2333 Example 94
3-{[(1R)-1-phenylethyl]amino}-4-(pyrimidin-4-yIamino)cyclobut-3-ene-1,2-dione
Step 1 : 3-ethoxy-4-(pyrimidin-4-ylamino)cyclobut-3-ene- 1 ,2-dione
Following step 1 of Example 91, diethyl squarate (500 mg, 3.1 mmol) and 4-aminopyrimidine (291 mg, 1.0 eq) provided the title compound (16 mg, 2.3%) as a yellow solid. Step 2: Following step 2 of Example 91, 3-ethoxy-4-(pyrimidin-4-ylamino)cyclobut-3- ene-1,2-dione (16 mg, 0.07 mmol) and (R)-1-phenylethanamine (28 μL, 3 eq) provided the title compound (5 mg, 23%). 1H NMR (400 MHz, MeOD) δ ppm 1.74 (d, /=7.07 Hz, 3 H) 5.57 (q, /=6.99 Hz, 1 H) 7.19 (d, /=5.31 Hz, 1 H) 7.31 - 7.38 (m, 1 H) 7.44 (t, /=7.71 Hz, 2 H) 7.48 - 7.53 (m, 2 H) 8.53 (d, /=4.80 Hz, 1 H) 8.83 (s, 1 H); HPLC purity (Method 1: 100%, Method 2: 96%); HRMS: CaICd IOr C16Hi4N4O2 + H+, 295.1190; found (ESI-FTMS, [M+H]l+), 295.1189 Example 95
S-IfS-methyl-1H-pyrazol-S-yOaminol^-fK1RVl-phenylethyllaminoJcyclobut-S-ene- 1 ,2-dione
Step 1: 3-ethoxy-4-[(5-methyl-lflr-pyrazol-3-yl)amino]cyclobut-3-ene-1,2-dione Following step 1 of Example 91, diethyl squarate (400 mg, 2.4 mmol) and 3-amino-5- methylpyrazole (274 mg, 1.2 eq) provided the title compound (362 mg, 68%) as a yellow solid. 1H NMR (400 MHz, DMSO-iitf) δ ppm 1.38 (t, 7=7.1 Hz, 3 H), 2.16 - 2.23 (m, 4 H), 4.71 (q,
/=7.1 Hz, 2 H), 10.93 (s, 1 H), 12.20 (s, 1 H)
Step 2: A solution of 3-ethoxy-4-[(5-methyl- 1H-pyrazol-3-yl)amino]cyclobut-3-ene-1,2- dione (362 mg, 1.6 mmol) and (R)-1-phenylethanamine (271 mg, 1.3 eq) were heated in a microwave reactor (140 °C, 15 min) to provide the title compound (216 mg, 46%) as a white foam. 1H NMR (400 MHz, OMSO-d6) δ ppm 1.56 (d, /=6.82 Hz, 3 H) 2.19 (s, 3 H) 5.29 - 5.41
(m, 1 H) 7.25 - 7.34 (m, 1 H) 7.36 - 7.42 (m, 5 H) 12.23 (s, 1 H); HPLC purity (Method 1: 95%,
Method 2: 97%); HRMS: calcd for C16H16N4O2 + H+, 297.1345; found (ESI-FTMS, [M+H]l+),
297.1346 Example 96 tert-butyl 4-[(3,4-dioxo-2-{[(1R)-1-phenylethyl]amino}cyclobut-1-en-1-yl)amino]piperidine-
1-carboxylate
Step 1 : 3-ethoxy-4- {[(liJ)-1-phenylethyl]amino}cyclobut-3-ene-1,2-dione
Following step 1 of Example 91, diethyl squarate (3.0 g, 18 mmol) and (R)-1-phenylethanamine (2.0 g, 0.95 eq) provided the title compound (3.76 g, 87%) as an oil after flash chromatography
(silica, 30% ethyl acetate / hexanes). 1H NMR (400 MHz, CD2Cl2) δ ppm 1.40 (t, /=7.1 Hz, 3
H), 1.65 (d, /=6.8 Hz, 3 H), 4.73 (q, /=7.1 Hz, 2 H), 4.89 (bs, 1 H), 7.09 (bs, 1 H), 7.27 - 7.41
(m, 5 H)
Step 2: Following step 2 of Example 95, 3-ethoxy-4-{[(1R)-1- phenylethyl]amino}cyclobut-3-ene-1,2-dione 500 mg, 2 mmol) and 4-amino-1-N-Boc-piperidine
(410 mg, 1.1 eq) provided the title compound (730 mg, 91%) as a white solid after collecting the resulting precipitate. 1H NMR (400 MHz, DMSO-ctø δ ppm 1.29 - 1.42 (m, 4 H) 1.40 (s, 9 H)
1.54 (d, /=7.07 Hz, 3 H) 1.87 (d, J=I 1.37 Hz, 2 H) 2.88 (s, 2 H) 3.79 - 3.96 (m, 3 H) 5.20 (s, 1
H) 7.26 - 7.43 (m, 5 H); HPLC purity (Method 1: 94%, Method 2: 94%); HRMS: calcd for C22H29N3O4 + H+, 400.2231 ; found (ESI-FTMS, [M+H] 1+), 400.2230
Example 97
3-isoquinolin-5-yl-4-{[(1R)-1-phenylethyl]amino}cyclobut-3-ene-1,2-dione
Step 1: 3-ethoxy-4-(tributylstannyl)cyclobut-3-ene-1,2-dione was prepared following methods described in /. Org. Chem, 1990, 55, 5359-5364, which is incorporated by reference in its entirety. 1H NMR (400 MHz, chloroform-cf) δ ppm 0.86 - 0.97 (m, 6 H), 1.15 - 1.23 (m, 5 H),
1.28 - 1.40 (m, 8 H), 1.43 - 1.67 (m, 11 H), 4.77 (q, /=7.1 Hz, 2 H) Step 2: 3-{[(1R)-l -phenylethyl] amino } -4-(tributylstannyl)cyclobut-3-ene- 1 ,2-dione Following step 2 of Example 91, 3-ethoxy-4-(tributylstannyl)cyclobut-3-ene-1,2-dione (4.0 g, 10 mmol) and (R)-I -phenyl ethanamine (1.8 g, 1.5 eq) provided the title compound (3.50 g, 71%) as an amber oil after flash chromatography (silica, 10% ethyl acetate / hexanes). Step 3 A solution of 3-{[(1R)-1-phenylethyl]amino}-4-(tributylstannyl)cyclobut-3-ene-
1,2-dione (100 mg, 0.2 mmol), 5-iodoisoquinoline (57 mg, 1.1 eq), benzylchlorobis(triphenylphosphine)palladium(π) (9 mg, 6 mol%), and coρper(I) iodide (4 mg, 9 mol%) in DMF was stirred at RT for 5h. See J. Org. Chem, 1990, 55, 5359-5364, which is incorporated by reference in its entirety. The reaction was diluted with ethyl acetate, washed with water, aq. KF, and brine, dried, evaporated and flash chromatographed (silica, 100% ethyl acetate) to provide the title compound (49 mg, 75%) as a yellow-brown oil. 1H NMR (400 MHz, chloroform-D) δ ppm 1.78 (d, /=4.80 Hz, 3 H) 5.71 (bs, 1 H) 6.67 (s, 1 H) 7.02 (bs, 1 H) 7.32 - 7.70 (m, 7 H) 7.84 (bs, 1 H) 8.01 (bs, 1 H) 8.31 (bs, 1 H); HPLC purity (Method 1: 91%, Method 2: 92%); HRMS: calcd for C2IHi6N2O2 + H+, 329.1285; found (ESI-FTMS, [M+H]l+), 329.1284. Example 98
3-{[(1R)-l -phenylethyl] amino}-4-(1H-pyrazol-3-ylamino)cyclobut-3-ene-1,2-dione Step l:3-ethoxy-4-(l_ff-ρyrazol-3-ylamino)cyclobut-3-ene-1,2-dione Following step 1 of Example 91, diethyl squarate (400 mg, 2.4 mmol) and 3- aminopyrazole (235 mg, 1.2 eq) provided the title compound (458 mg, 92%) as a pale yellow solid after collecting the resulting precipitate. 1H NMR (400 MHz, DMSO-<4) δ ppm 1.39 (t, /=7.1 Hz, 3 H), 4.72 (q, /=7.1 Hz, 2 H), 6.28 (s, 1 H), 7.61 - 7.71 (m, 1 H), 11.03 (s, 1 H), 12.52 (s, 1 H)
Step 2: Following step 2 of Example 95, 3-ethoxy-4-(li7-pyrazol-3-ylamino)cyclobut-3- ene-1,2-dione 200 mg, 1.0 mmol) and (R)-1-phenylethanamine (160 μL, 1.3 eq) provided the title compound (268 mg, 95%) after flash chromatography (silica, 2% acetic acid / ethyl acetate). 1H NMR (400 MHz, DMSO-rfff) δ ppm 1.57 (d, /=6.82 Hz, 3 H) 5.25 - 5.46 (m, 1 H) 7.25 - 7.35 (m, 1 H) 7.35 - 7.44 (m, 4 H) 7.67 (d, /=2.27 Hz, 1 H) 12.52 (s, 1 H); HPLC purity (Method 1 : 96%, Method 2: 98%); HRMS: calcd for C15Hi4N4O2 + H+, 283.1190; found (ESI-FTMS, [M+H]l+), 283.1189 Example 99 3- [(2-chloropy ridin-4-yl)amino] -4- { [(I R)-1-phenylethyl] amino} cycIobut-3-ene-l ,2- dione
Step 1 : 3-[(2-chloropyridin-4-yl)ammo]-4-ethoxycyclobut-3-ene-1,2-dione Following step 1 of Example 91, diethyl squarate (1.0 g, 6.0 mmol) and 2-chloro-4- aminopyridine (756 mg, 1.0 eq) provided the title compound (938 mg, 21%) after flash chromatography (silica, 50% ethyl acetate / hexanes). 1H NMR (400 MHz, DMSO-^) δ ppm 1.45 (t, J=I.1 Hz, 3 H), 4.81 (q, /=7.1 Hz, 2 H), 7.39 (dd, /=5.6, 2.0 Hz, 1 H), 7.55 (d, /=2.0 Hz, 1 H), 8.28 (d, /=5.8 Hz, 1 H), 11.17 (s, 1 H)
Step 2: Following step 2 of Example 95, 3-[(2-chloropyridin-4-yl)amino]-4- ethoxycyclobut-3-ene-1,2-dione (250 mg, 1 mmol) and (R)-1-phenylethanamine (256 μL, 2.0 eq) provided the title compound (270 mg, 83%) after collecting the resulting precipitate. 1H NMR (400 MHz, DMSO-rfβ) δ ppm 1.56 - 1.65 (m, /=6.82 Hz, 3 H) 5.24 - 5.37 (m, 1 H) 7.23 - 7.46 (m, 6 H) 7.65 (s, 1 H) 8.18 - 8.32 (m, 2 H) 10.01 (bs, 1 H); HPLC purity (Method 1: 99%, Method 2: 99%); HRMS: calcd for CnHi4ClN3O2 + H+, 328.08473; found (ESI-FTMS, [M+H]l+), 328.0848. Example 100
3-{[l-(4-cyclohexylphenyI)ethyl]amino}-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2- dione
Step 1: l-(4-cyclohexylphenyl)ethanone oxime A solution of l-(4-cyclohexylphenyl)ethanone (2.0 g, 10 mmol), hydroxylamine hydrochloride (1.04 g, 1.5 eq), and pyridine (1.2 g, 1.5 eq) in ethanol (20 mL) was heated in the microwave reactor (120 °C, 20 min). The cooled solution was diluted with water (100 mL) and the resulting precipitate was collected to provide the title compound (2.16 g, 100%) as a white solid. 1H NMR (400 MHz, chloroform-rf) δ ppm 1.18 - 1.51 (m, 5 H), 1.70 - 1.93 (m, 5 H), 2.28 (s, 3 H), 2.52 (bs, 1 H), 7.22 (d, /=7.8 Hz, 2 H), 7.55 (d, /=7.8 Hz, 2 H) Step 2: l-(4-cyclohexylphenyl)ethanamine
A solution of l-(4-cyclohexylphenyl)ethanone oxime (300 mg, 1.4 mmol), zinc dust (900 mg, 10 eq), and acetic acid (2 mL), were heated in the microwave reactor (120 °C, 20 min). The heterogeneous solution was filtered through Celite®, neutralized with aq. NH4OH, evaporated, diluted with water and extracted with dichloromethane to provide the title compound (238 mg, 83%) as a clear, colorless oil, 1H NMR (400 MHz, chloroform-*/) δ ppm 1.32 - 1.55 (m, 8 H), 1.69 - 1.90 (m, 5 H), 2.48 (bs, 1 H), 4.08 (q, /=6.6 Hz, 1 H), 7.17 (d, ./=7.8 Hz, 2 H), 7.23 - 7.28 (m, 2 H)
Step 3: Following step 2 of Example 95, l-(4-cyclohexylphenyl)ethanartiine (219 mg, 1 mmol) and 3-ethoxy-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2-dione (141 mg, 0.6 eq) provided the title compound (192 mg, 51%) as a pale-yellow solid after collecting the resulting precipitate. 1H NMR (400 MHz, DMSO-^5) δ ppm 1.17 - 1.47 (m, 5 H) 1.59 (d, ./=6.82 Hz, 3 H) 1.65 - 1.84 (m, 5 H) 5.20 - 5.30 (m, 1 H) 7.23 - 7.29 (m, 2 H) 7.31 - 7.36 (m, 2 H) 7.42 (d, /=5.31 Hz, 2 H) 8.41 (d, /=6.06 Hz, 2 H) 9.82 (s, 1 H); HPLC purity (Method 1: 99%, Method 2: 99%); HRMS: calcd for C23H25N3O2 + H+, 376.2020; found (ESI-FTMS, [M+H]l+), 376.2017 Example 101
3-{[(1R)-1-cyclohexylethyl]amino}-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2-dione
Following step 2 of Example 95, 3-ethoxy-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2- dione (200 mg, 0.9 mmol) and (R)-1-cyclohexylethanamine (152 mg, 1.3 eq) provided the title compound (145 mg, 54%) as a pale-yellow solid. 1H NMR (400 MHz, DMSO-ιiβ) δ ppm 0.89 - 1.28 (m, 5 H) 1.21 (d, /=6.82 Hz, 3 H) 1.32 - 1.47 (m, 1 H) 1.63 (d, /=12.13 Hz, 1 H) 1.66 - 1.80 (m, 4 H) 3.88 - 4.04 (m, 1 H) 7.45 (d, /=6.06 Hz, 2 H) 7.75 (d, /=9.09 Hz, 1 H) 8.41 (d, /=6.32 Hz, 2 H) 9.79 (s, 1 H); HPLC purity (Method 1: 100%, Method 2: 100%); HRMS: calcd for C17H2]N3O2 + H+, 300.1707; found (ESI-FTMS, [M+H]l+), 300.1706 Example 102 (R)-3-(biphenyI-3-ylamlno)-4-(l-phenyIethylamino)cyclobut-3-ene-1,2-dione 3-(biphenyl-3-yIamino)-4-ethoxycyclobut-3-ene-1,2-dione
Step 1 : Following step 1 of Example 91, diethyl squarate (400 mg, 2.4 mmol) and biphenyl-3 -amine (55 mg, 1.1 eq) provided the title compound (200 mg, 24%) after collecting the resulting precipitate by filtration. 1H NMR (400 MHz, OMSO-d6) δ ppm 1.42 (t, /=7.2 Hz, 3 H), 4.80 (q, /=7.1 Hz, 2 H), 7.30 - 7.52 (m, 6 H), 7.65 - 7.71 (m, 2 H), 7.73 (s, 1 H), 10.86 (s, 1 H)
Step 2: Following step 2 of Example 95, 3-(biphenyl-3-ylamino)-4-ethoxycyclobut-3- ene-1,2-dione (200 mg, 0.7 mmol) and (R)-1-phenylethanamine (174 μL, 2.0 eq) provided the title compound (223 mg, 86%) as a white solid after collecting the resulting precipitate. 1H NMR (400 MHz,
Figure imgf000070_0001
δ ppm 1.61 (d, /=7.07 Hz, 3 H) 5.27 - 5.36 (m, 1 H) 7.28 - 7.51 (m, 10 H) 7.67 - 7.72 (m, 2 H) 7.83 (s, 1 H) 8.12 (s, 1 H) 9.69 (s, 1 H); HPLC purity (Method 1:
98%, Method 2: 98%).
Example 103
3-[(2-bromopyridin-4-yl)amino]-4-{[(1R)-1-phenyIethyl]amino}cyclobut-3-ene-1,2- dione
Step 1 : 3-[(2-bromopyridin-4-yl)amino]-4-ethoxycyclobut-3-ene-1,2-dione Following step 1 of Example 91, 2-bromo-4-aminoρyridine (5 g, 29 mmol) and diethyl squarate (4.9 g, 1.0 eq) provided the title compound (1.51 g, 18%) as a yellow foam after flash chromatography (silica, 40% ethyl acetate / hexanes). 1H NMR (400 MHz, OMSO-d6) δ ppm 1.45 (t, 7=7.1 Hz, 3 H), 4.81 (q, /=7.1 Hz, 2 H), 7.39 - 7.43 (m, 1 H), 7.69 (d, /=2.0 Hz, 1 H),
8.22 - 8.32 (m, 1 H), 11.15 (s, 1 H)
Step 2: Following step 2 of Example 95, 3-[(2-bromopyridin-4-yi)amino]-4- ethoxycyclobut-3-ene-1,2-dione (1.20 g, 4 mmol) and (R)-1-phenylethanamine (1.3 mL, 2.5 eq) provided the title compound (1.14 g, 77%) as a pale-yellow solid after collecting the resulting precipitate by filtration. 1H NMR (400 MHz, DMSO-4j) δ ppm 1.61 (d, J=6.82 Hz, 3 H) 5.23 -
5.37 (m, 3 H) 7.23 - 7.48 (m, 5 H) 8.14 - 8.32 (m, 2 H) 9.95 (s, 1 H); HPLC purity (Method 1:
75%, Method 2: 72%);
Example 104
3-[(2-morpholin-4-ylpyridin-4-yl)ammo]-4-{[(1R)-1-phenylethyl]amino}cyclobut-3- ene-1,2-dione
A solution of 3 - [(2-bromoρyridin-4-yl)amino] -4-{[(1R)-l -phenylethyl] amino } cyclobut-
3-ene-1,2 -dione (50 mg, 0.13 mmol) and morpholine (28 μL, 2.4 eq) in DMF (1 mL) were heated in the microwave reactor (200 °C, 20 min). Reverse phase HPLC purification provided the title compound (13 mg, 26%). 1H NMR (400 MHz, DMSO-^s) δ ppm 1.60 (d, /=6.82 Hz, 3 H) 3.33 - 3.49 (m, 4 H) 3.62 - 3.75 (m, 4 H) 5.24 - 5.37 (m, 1 H) 6.62 (dd, /=5.56, 1.77 Hz, 1 H) 7.07 (s,
1 H) 7.27 - 7.36 (m, 1 H) 7.41 (d, 4 H) 7.99 (d, /=5.56 Hz, 1 H) 8.16 (s, 1 H) 8.35 (d, /=7.58 Hz,
1 H); HPLC purity (Method 1: 97%, Method 2: 97%); HRMS: calcd for C2IH22N4O3 + H+,
379.17647; found (ESI-FTMS, [M+H]l+), 379.1778.
Example 105 3-[(l-methyl-1-phenylethyl)amino]-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2-dione Following step 2 of Example 95, 3-ethoxy-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2- dione (100 mg, 0.5 mmol) and cumylatnine (155 mg, 2.5 eq) provided the title compound (60 mg, 42%) as a fluffy yellow solid after reverse phase HPLC purification. 1H NMR (400 MHz, OMSO-d6) δ ppm 1.79 (s, 6 H) 7.28 (t, /=7.07 Hz, 1 H) 7.38 (t, /=7.71 Hz, 2 H) 7.43 - 7.51 (m, 4 H) 8.43 (d, /=5.81 Hz, 3 H); HPLC purity (Method 1 : 99%, Method 2: 99%); HRMS: calcd for C18H17N3O2 + H+, 308.13935; found (ESI-FTMS, [M+H]l+), 308.1397. Example 106
3-{[(1R)-1-phenylethyl]amino}-4-{[2-(phenylthio)pyridin-4-yI]amino}cyclobut-3- ene-1,2-dione A solution of 3-[(2-bromopyridin-4-yl)amino]-4-{[(1R)-1-phenylethyl]amino}cyclobut-
3-ene-1,2-dione (200 mg, 0.54 mmol), benzenethiol (83 μL, 1.5 eq), and sodium hydride (32 mg, 1.5 eq) were heated in the microwave reactor (200 °C, 20 min). Reverse phase HPLC purification provided the title compound (83 mg, 38%) as a yellow foam. 1H NMR (400 MHz, DMSO-<4) δ ppm 1.57 (d, /=6.82 Hz, 3 H) 5.21 - 5.30 (m, 1 H) 6.84 (d, /=2.02 Hz, 1 H) 7.27 - 7.42 (m, 6 H) 7.46 - 7.52 (m, 3 H) 7.56 - 7.62 (m, 2 H) 8.17 (d, /=7.83 Hz, 1 H) 8.24 (d, /=5.81 Hz, 1 H) 9.79 (s, 1 H); HPLC purity (Method 1 : 95%, Method 2: 95%); HRMS: calcd for C23Hi9N3O2S + H+, 402.12707; found (ESI-FTMS, [M+H]l+), 402.1278. Example 107 4-[(3,4-dioxo-2-{[(1R)-1-phenylethyl]amino}cyclobut-1-en-1-yl)amino]pyridine-2- carboxamide
Step 1 : 4-nitropyridine-2-carboxamide
A solution of 4-nitropicolinic acid (1.0 g, 7.2 mmol) and carbonyldiimidazole (2.35 g, 2 eq) in THF (30 mL) was heated at 60 °C for Ih. The solution was cooled, aq. NH4OH (2 mL) was added and the reaction was stirred at RT overnight. The solution was purged with a stream ofN2 for 15 minutes, diluted with DCM, washed with water and brine, dried, filtered, and evaporated to provide the title compound (0.75g, 62%) as an off-white solid. 1H NMR (400 MHz, OMSO-d6) δ ppm 8.00 (bs, 1 H), 8.32 (dd, /=5.3, 2.3 Hz, 1 H), 8.37 (bs, 1 H), 8.54 (d, /=1.5 Hz, 1 H), 9.02 (d, /=5.3 Hz, 1 H)
Step 2: 4-aminopyridine-2-carboxamide A solution of 4-nitropyridme-2-carboxamide (0.65 g, 4 mmol) and PtO2 (20 mg) in EtOH
(50 mL) was shaken under a H2 atmosphere (50 PSI, RT, 2 h). The solution was filtered and evaporated to provide the title compound (0.52 g, 97%) as a tan solid. 1H NMR (400 MHz, DMSO-40 δ ppm 6.28 (s, 2 H), 6.58 (d, /=5.6 Hz, 1 H), 7.20 (s, 1 H), 7.39 (s, 1 H), 7.88 (s, 1 H), 8.00 (d, /=5.6 Hz, I H)
Step 3 : 4-[(2-ethoxy-3,4-dioxocyclobut- 1 -en- 1 -yl)amino]pyridine-2-carboxamide Following step 1 of Example 91, diethyl squarate (722 mg, 4 mmol) and 4- aminopyridine-2-carboxamide (582 mg, 1 eq) provided the title compound (120 mg, 10%) as an orange solid. 1H NMR (400 MHz,
Figure imgf000073_0001
δ ppm 1.46 (t, J=I.1 Hz, 3 H), 4.82 (q, /=7.0 Hz, 2 H), 7.57 - 7.69 (m, /=18.9 Hz, 2 H), 8.09 (s, 2 H), 8.50 (d, /=5.3 Hz, 1 H), 11.17 (s, 1 H)
Step 4 : 4- [(3 ,4-dioxo-2- { [( 1 R)- 1 -phenylethyl] amino } cyclobut- 1 -en- 1 -yl)amino]pyridine- 2-carboxamide
Following step 2 of Example 95, 4-[(2-ethoxy-3,4-dioxocyclobut-1-en-1- yl)amino]pyridine-2-carboxamide (120 mg, .5 mmol) and (R)-1-phenylethanamine (174 μL, 3 eq) provided the title compound (120 mg, 78%) as a pale-yellow solid. 1H NMR (400 MHz, DMSO-rftf) δ ppm 1.61 (d, /=6.82 Hz, 3 H), 5.21 - 5.39 (m, 1 H), 7.28 - 7.47 (m, 5 H), 7.64 (s, 1 H), 7.71 (s, 1 H), 7.91 (s, 1 H), 8.06 (s, 1 H), 8.13 - 8.24 (m, 1 H), 8.46 (d, /=5.56 Hz, 1 H),
10.04 (s, 1 H); HPLC purity (Method 1: 89%, Method 2: 86%); HRMS: calcd for C18Hi6N4O3 + H+, 337.12952; found (ESI-FTMS, [M+H]l+), 337.1301. Example 108 3-{[(1R)-1-phenyIethyl]amino}-4-(piperidin-4-ylamino)cyclobnt-3-ene-1,2-dione trifluoroacetic acid salt
A solution of (R)-tert-butyl 4-(3,4-dioxo-2-(l-phenylethylamino)cyclobut-1- enylamino)piρeridine-1-carboxylate (250 mg, 0.6 mmol) and TFA (2 mL) in DCE (2 mL) was stirred at RT overnight. The solution was evaporated and diluted with DCM and water. The aqueous layer was lyophilized to provide the title compound (66 mg, 27%) 1H NMR (400 MHz, OMSO-d6) δ ppm 1.53 (d, /=6.82 Hz, 3 H), 1.62 (t, /=12.51 Hz, 2 H), 1.99 (d, /=11.62 Hz, 2 H), 2.81 - 2.95 (m, 2 H), 3.21 (d, /=13.39 Hz, 2 H), 3.90 - 4.07 (m, 1 H), 5.18 - 5.30 (m, 1 H), 7.23 - 7.33 (m, 1 H), 7.32 - 7.43 (m, 4 H), 8.22 (s, 1 H), 8.47 (s, 1 H); HPLC purity (Method 1: 98%, Method 2: 98%); HRMS: calcd for CnH2IN3O2 + H+, 300.17065; found (ESI-FTMS, [M+H]l+), 300.1709. Example 109 tert-butyl (2S)-{[3,4-dioxo-2-(pyridin-4-ylamino)cyclobut-1-en-1-yl]amino}(phenyl)acetate A solution of 3-ethoxy-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2-dione (200 mg, 0.9 mmol), (S)-tert-butyl 2-amino-2-phenylacetate hydrochloride salt (300 mg, 1.3 eq), and TEA (380 μL, 3 eq) in EtOH (20 niL) was heated at reflux for 48 h. The solution was evaporated and reverse phase HPLC provided the title compound (81 mg, 23 %) as a yellow solid. 1H NMR (400 MHz, DMSO-tfu) δ ppm 1.34 - 1.44 (m, 9 H), 3.33 (bs, 1 H), 7.35 - 7.54 (m, 6 H), 8.39 - 8.46 (m, 2 H), 8.64 (d, /=8.08 Hz, 1 H), 10.12 (bs, 1 H); HPLC purity (Method 1 : 91%, Method 2: 86%); HRMS: calcd for C21H21N3O4 + R+, 380.16048; found (ESI-FTMS, [M+H]l+), 380.1618. Example 110 (2S)-{[3,4-dioxo-2-(pyridin-4-ylamino)cyclobut-1-en-1-yI]amino}(phenyl)acetic acid A solution of tert-butyl (2S)-{[3,4-dioxo-2-(pyridin-4-ylamino)cyclobut-1-en-1- yl]amino}(phenyl)acetate (41 mg, 0.1 mmol) and TFA (1 mL) in DCM (2 niL) was stirred at RT for 3h. The solvent was evaporated to provide the title compound (34 mg, 100%) as a pale- yellow solid. 1H NMR (400 MHz, DMSCW15) δ ppm 5.76 (s, 1 H), 5.82 (d, /=8.1 Hz, 1 H), 7.37 - 7.50 (m, 5 H), 7.78 (d, /=6.6 Hz, 2 H), 8.62 (d, /=7.1 Hz, 2 H), 8.98 (d, /=7.6 Hz, 1 H); HPLC purity (Method 1: 85%, Method 2: 79%); Example 111
2-{[3,4-dioxo-2-(pyridin-4-ylamiπo)cyclobut-1-en-1-yl]amino}-2-(3- hydroxyphenyl)acetamide Step 1 : methyl amino(3-hydroxyphenyl)acetate
To a stirred solution of crude amino(3-hydroxyphenyl)acetic acid hydrochloride (24.36 g, 0.12 mol) in methanol (300 mL) was added thionyl chloride (15 mL, 1.8 eq) dropwise. The solution was heated at reflux for 3 h, stirred at RT overnight, evaporated, dissolved in DCM, and neutralized with aq. NaHCC>3. The organic layer was dried evaporated, and flash chromatographed (silica, 5-15% MeOH / ethyl acetate) to provide the title compound (8.16 g, 30%, 3 steps) as an off-white solid.1H NMR (400 MHz, DMSO-ck) δ ppm 3.59 (s, 3 H), 4.42 (s, 1 H), 6.62 - 6.68 (m, 1 H), 6.74 - 6.80 (m, 2 H), 7.11 (t, /=8.1 Hz, 1 H), 9.39 (s, 1 H) Step 2: 2-amino-2-(3-hydroxyphenyl)acetamide A solution of methyl amino(3-hydroxyphenyl)acetate (6.90 g, 38 mmol) was dissolved in methanol (300 mL) and thionyl chloride (8.3 mL, 3 eq) was added dropwise. The solution was stirred for 30 min and was evaporated. The resulting hydrochloride salt was dissolved in aq NH4OH (200 mL) and was stirred overnight. The solution was evaporated to provide the crude title compound (6.35 g, 100%) 1H NMR (400 MHz, OMSO-d6) δ ppm 4.18 (bs, 1 H), 6.56 - 6.66 (m, 1 H), 6.77 - 6.84 (m, 2 H), 6.99 (bs, 1 H), 7.03 - 7.11 (m, 1 H), 7.41 (s, 1 H), 9.29 (s, 1 H)
Step 3: Following step 2 of Example 91, 3-ethoxy-4-(pyridin-4-ylamino)cyclobut-3-ene- 1 ,2-dione (100 mg, .50 mmol) and 2-amino-2-(3-hydroxyphenyl)acetamide (76 mg, 1.0 eq) provided the title compound (136 mg, 87%) as a yellow solid after collecting the resulting precipitate. 1H NMR (400 MHz, DMSO-rf*) δ ppm 5.72 (d, /=8.6 Hz, 1 H), 6.65 - 6.74 (m, 1 H), 6.83 - 6.93 (m, 2 H), 7.17 (t, ./=7.8 Hz, 1 H), 7.41 - 7.49 (m, 3 H), 8.03 (s, 1 H), 8.42 (d, ./=6.1 Hz, 1 H), 8.75 (d, /=8.6 Hz, 2 H), 9.55 (s, 1 H), 10.30 (s, 1 H); HPLC purity (Method 1: 98%, Method 2: 94%); HRMS: calcd for CnHi4N4O4 + H+, 339.1088; found (ESI-FTMS, [M+H]l+), 339.1087. Example 112
2-(3-bromophenyl)-2-{[3,4-dioxo-2-(pyridin-4-ylamino)cyclobut-1-en-1-yl]ainino}acetaπiide Following step 2 of Example 91, 3-ethoxy-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2- dione (220 mg, 1 mmol) and 2-amino-2-(3-bromophenyl)acetamide (229 mg, 1 eq) were heated at 80° C overnight to provide the title compound (219 mg, 55%) as a yellow solid. 1H NMR (400 MHz, DMSO-rftf) δ ppm 7.35 - 7.41 (m, 2 H), 7.42 - 7.48 (m, 3 H), 7.52 - 7.59 (m, 2 H), 7.68 (t, /=1.8 Hz, 1 H), 8.13 (s, 1 H), 8.40 - 8.45 (m, 2 H), 8.84 (d, /=8.3 Hz, 1 H), 10.30 (s, 1 H); HPLC purity (Method 1: 100%, Method 2: 100%); HRMS: calcd for C17Hi3BrN4O3 + H+, 401.0244; found (ESI-FTMS, [MH-H]I+), 401.0245. Example 113 2-biphenyl-3-yl-2-{[3,4-dioxo-2-(pyridin-4-ylanrino)cyclobut-1-eii-1-yl]amino}acetainide
A solution of 2-(3-bromophenyl)-2-{[3,4-dioxo-2-(pyridm-4-ylammo)cyclobut-1-en-1- yl]amino}acetamide (75 mg, 0.19 mmol), dichlorobis(triphenylphosphine)palladium(II) (13 mg, 0.1 eq), phenylboronic acid (30 mg, 1.3 eq), and sodium carbonate (26 mg, 1.3 eq) in DME / H2O / EtOH (7:3:1, 3 mL) was heated in the microwave reactor (120 °C, 30 min). Reverse phase HPLC provided the title compound (7 mg, 9%) as a yellow solid. 1H NMR (400 MHz, DMSO- d6) δ ppm 5.89 (d, /=6.3 Hz, 1 H), 7.20 - 7.54 (m, 7 H), 7.59 - 7.68 (m, 3 H), 7.77 (dd, /=8.1, 1.5 Hz, 1 H), 7.81 (s, 1 H), 8.09 (s, 1 H), 8.27 (s, 1 H), 8.41 (d, /=6.1 Hz, 2 H), 9.08 (d, /=7.1 Hz, 1 H); HPLC purity (Method 1 : 95%, Method 2: 95%); HRMS: calcd for C23Hi8N4O3 + H+, 399.1452; found (ESI-FTMS, [M+H]l+), 399.1448. Example 114
2-{[3,4-dioxo-2-(pyridin-4-ylamino)cyclobut-1-en-1-yI]amino}-2-[3-(3- thienyl)pheny 1] acetamide
Utilizing the method of Example 113, 2-(3-bromophenyl)-2-{[3,4-dioxo-2-(pyridin-4- ylamino)cyclobut-l -en- 1-yl] amino} acetamide (75 mg, 0.19 mmol) and 3-thiophene boronic acid (36 mg, 1.5 eq) were converted to the title compound (20 mg, 26%). 1H NMR (400 MHz, DMSO-rfβ) δ ppm 5.85 (d, /=8.1 Hz, 1 H), 7.34 - 7.39 (m, 1 H), 7.43 - 7.48 (m, 3 H), 7.49 - 7.55 (m, 2 H), 7.65 - 7.72 (m, 2 H), 7.79 - 7.86 (m, 2 H), 8.09 (s, 1 H), 8.19 (s, 1 H), 8.42 (dd, /=4.8, 1.5 Hz, 2 H), 8.95 (d, /=8.6 Hz, 1 H); HPLC purity (Method 1: 98%, Method 2: 98%); HRMS: calcd for C2IHi6N4O3S + H+, 405.1016; found (ESI-FTMS, [M+H]l+), 405.1013. Example 115
2-{[3,4-dioxo-2-(pyridin-4-ylammo)cyclobut-1-en-1-yI]amino}-2-(3'-methylbiphenyl-3- yl)acetamide
Utilizing the method of Example 113, 2-(3-bromophenyl)-2-{[3,4-dioxo-2-(pyridin-4- ylamino)cyclobut-1-en-1-yl]ammo}acetamide (75 mg, 0.19 mmol) and m-tolylboronic acid (38 mg, 1.5 eq) were converted to the title compound (3 mg, 4%). 1H NMR (400 MHz, OMSO-d6) δ ppm 2.39 (s, 3 H), 5.89 (s, 1 H), 7.21 (d, /=7.6 Hz, 1 H), 7.33 - 7.55 (m, 8 H), 7.57 - 7.66 (m, 1 H), 7.79 (s, 1 H), 8.09 (s, 1 H), 8.27 (s, 1 H), 8.41 (dd, /=4.8, 1.5 Hz, 2 H), 9.07 (s, 1 H); HPLC purity (Method 1: 92%, Method 2: 91%); HRMS: calcd for C24H20N4O3 + H+, 413.1608; found (ESI-FTMS, [M+H]l+), 413.161. Example 116
2-{3'-[(dimethy]amino)sulfonyl]biphenyl-3-yl}-2-{[3)4-dioxo-2-(pyridiii-4-yIamino)cyclobut- l-en-1-yl] amino} acetamide
Utilizing the method of Example 113, 2-(3-bromophenyl)-2-{[3,4-dioxo-2-(pyridin-4- ylamino)cyclobut- l-en-1-yl] amino} acetamide (75 mg, 0.19 mmol) and N,N-dimethyl 3- boronobenzenesulfonamide (69 mg, 1.5 eq) were converted to the title compound (11 mg, 11%). 1H NMR (400 MHz, OMSO-d6) δ ppm 2.66 (s, 6 H), 5.92 (d, /=7.8 Hz, 1 H), 7.45 (dd, /=4.8, 1.5 Hz, 2 H), 7.49 - 7.59 (m, 3 H), 7.69 - 7.75 (m, 1 H), 7.79 (dd, 2 H), 7.87 (s, 1 H), 7.93 (s, 1 H), 7.97 - 8.04 (m, 1 H), 8.15 (dd, 1 H), 8.41 (dd, /=4.8, 1.5 Hz, 2 H), 9.04 (d, /=8.3 Hz, 1 H); HPLC purity (Method 1 : 96%, Method 2: 95%); HRMS: calcd for C25H23N5O5S + H+, 506.14927; found (ESI-FTMS, [MH-H]I+), 506.1497. Example 117
2-{[3,4-dioxo-2-(pyridin-4-ylamino)cycIobut-1-en-1-yl]amiiio}-2-(2'-methylbiphenyl-3- yl)acetamide
Utilizing the method of Example 113, 2-(3-bromophenyl)-2-{[3,4-dioxo-2-(pyridin-4- ylamino)cyclobut-1-en-1-yl]amino}acetamide (75 mg, 0.19 mmol) and 2-methylbenzeneboronic acid (38 mg, 1.5 eq) were converted to the title compound (19 mg, 24%). 1H NMR (400 MHz, DMSO-rf,j) δ ppm 2.22 (s, 3 H), 5.87 (d, /=8.6 Hz, 1 H), 7.17 - 7.23 (m, 1 H), 7.23 - 7.35 (m, 4 H), 7.39 - 7.56 (m, 6 H), 8.08 - 8.13 (m, 1 H), 8.34 - 8.47 (m, 2 H), 8.88 (d, /=8.3 Hz, 1 H), 10.32 (s, 1 H); HPLC purity (Method 1: 95%, Method 2: 94%); HRMS: calcd for C24H20N4O3 + H+, 413.1608; found (ESI-FTMS, [M+H]l+), 413.1604. Example 118
2-(3'-cyanobiphenyl-3-yl)-2-{[3,4-dioxo-2-(pyridin-4-ylamino)cyclobut-1-en-1- yl]amino}acetamide
Utilizing the method of Example 113 , 2-(3 -bromophenyl)-2- { [3 ,4-dioxo-2-(pyridin-4- ylamino)cyclobut-1-en-1-yl]amino}acetamide (75 mg, 0.19 mmol) and 3-cyanophenylboronci acid (41 mg, 1.5 eq) were converted to the title compound (18 mg, 22%). 1H NMR (400 MHz, DMSO-rftf) δ ppm 5.89 (d, /=8.3 Hz, 1 H), 7.45 (dd, J=4.8, 1.5 Hz, 2 H), 7.47 - 7.52 (m, 1 H), 7.51 - 7.58 (m, ./=7.7, 7.7 Hz, 2 H), 7.69 - 7.76 (m, 2 H), 7.85 - 7.90 (m, 2 H), 7.97 - 8.03 (m, 1 H), 8.09 (s, 1 H), 8.11 - 8.13 (m, 1 H), 8.38 - 8.47 (m, 2 H), 8.92 (d, /=8.3 Hz, 1 H), 10.33 (s, 1 H); HPLC purity (Method 1 : 98%, Method 2: 98%); HRMS: calcd for C24HnN5O3 + H+, 424.1404; found (ESI-FTMS, [M+H]l+), 424.1399. Example 119
2-{[3,4-dioxo-2-(pyridin-4-yIamino)cyclobut-1-en-1-yl]amino}-2-(4'-methylbiphenyl-3- yl)acetamide Utilizing the method of Example 113, 2-(3-bromophenyl)-2- {[3,4-dioxo-2-(pyridin-4- ylamino)cyclobut-1-en-1-yl]amino}acetamide (75 mg, 0.19 mmol) and p-tolylboronic acid (38 mg, 1.5 eq) were converted to the title compound (5 mg, 6%). 1H NMR (400 MHz, DMSO-fifc) δ ppm 2.35 (s, 3 H), 5.87 (d, /=7.6 Hz, 1 H), 7.31 (d, /=7.8 Hz, 2 H), 7.37 - 7.64 (m, 8 H), 7.78 (s, 1 H), 8.09 (s, 1 H), 8.41 (d, /=6.3 Hz, 2 H), 8.98 (d, /=7.3 Hz, 1 H), 10.43 (bs, 1 H); HPLC purity (Method 1: 97%, Method 2: 96%); HRMS: calcd for C24H20N4O3 + H+, 413.1608; found (ESI-FTMS, [M+H]l+), 413.1607. Example 120 3-[(l-biphenyI-3-ylethyl)amiπo]-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2-dione
Utilizing the method of Example 113, 3-(l-(3-bromophenyl)ethylamino)-4-(pyridin-4- ylamino)cyclobut-3-ene-1,2-dione (100 mg, 0.27 mmol) and phenylboronic acid (49 mg, 1.5 eq) were converted to the title compound (23 mg, 23%). 1H NMR (400 MHz, OMSO-d6) δ ppm
1.66 (d, /=6.8 Hz, 3 H), 5.29 - 5.45 (m, 1 H), 7.35 - 7.53 (m, 8 H), 7.61 (d, J=7.6 Hz, 1 H), 7.64 - 7.74 (m, 3 H), 8.39 (d, /=6.1 Hz, 2 H), 8.58 (d, /=8.3 Hz, 1 H); HPLC purity (Method 1: 91%, Method 2: 91%); HRMS: calcd for C23H19N3O2 + H+, 370.1550; found (ESI-FTMS, [M+H]l+), 370.1547. Example 121
S'^l-fβ^-dioxo-1-føyridin-4-ylaminoJcyclobut-1-en-1-yllaminoJethyObiphenyl- 3-carbonitrile
Utilizing the method of Example 113, 3-(l-(3-bromophenyl)ethylamino)-4-(ρyridin-4- ylamino)cyclobut-3-ene-1,2-dione (100 mg, 0.27 mmol) and 3-cyanophenylboronic acid (59 mg, 1.5 eq) were converted to the title compound (49 mg, 46%). 1H NMR (400 MHz, DMSO-<4) δ ppm 1.67 (d, /=6.8 Hz, 3 H), 5.32 - 5.45 (m, 1 H), 7.43 (d, /=5.1 Hz, 2 H), 7.47 - 7.58 (m, 2 H), 7.69 (t, /=7.8 Hz, 2 H), 7.81 (s, 1 H), 7.84 - 7.88 (m, 1 H), 8.05 (d, /=8.1 Hz, 1 H), 8.21 (s, 1 H),
8.40 (d, /=6.1 Hz, 2 H); HPLC purity (Method 1: 97%, Method 2: 96%); HRMS: calcd for C24Hi8N4O2 + H+, 395.1503; found (ESI-FTMS, [M+H]l+), 395.1502. Example 122
3-{[l-(4'-acetylbiphenyl-3-yl)ethyl]amino}-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2-dione Utilizing the method of Example 113, 3-(l-(3-bromophenyl)ethylamino)-4-(pyridin-4- ylamino)cyclobut-3-ene-1,2-dione (100 mg, 0.27 mmol) and 4-acetylphenylboronic acid (66 mg,
1.5 eq) were converted to the title compound (50 mg, 45%). 1H NMR (400 MHz, DMSO-rfβ) δ ppm 1.67 (d, /=6.8 Hz, 3 H), 2.62 (s, 3 H), 5.31 - 5.46 (m, 1 H), 7.43 (d, /=4.8 Hz, 2 H), 7.53 (d,
2 H), 7.70 (d, /=7.6 Hz, 1 H), 7.80 (s, 1 H), 7.85 (d, /=8.1 Hz, 2 H), 8.06 (d, /=8.6 Hz, 2 H),
8.41 (d, /=6.1 Hz, 2 H); HPLC purity (Method 1: 97%, Method 2: 98%); HRMS: calcd for C25H2IN3O3 + H+, 412.1656; found (ESI-FTMS, [M+H]l+), 412.1656.
Example 123 3-{[l-(4'-chlorobiphenyl-3-yl)ethyl]amino}-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2-dione Utilizing the method of Example 113, 3-(l-(3-bromophenyl)ethylamino)-4-(ρyridin-4- ylamino)cyclobut-3-ene-1,2-dione (100 mg, 0.27 mmol) and 4-chlorophenylboronic acid (63 mg, 1.5 eq) were converted to the title compound (50 mg, 46%). 1H NMR (400 MHz, DMSCWs) δ ppm 1.66 (d, /=6.8 Hz, 3 H), 5.32 - 5.44 (m, 1 H), 7.41 - 7.48 (m, /=7.8 Hz, 3 H), 7.48 - 7.57 (m, 3 H), 7.62 (d, /=7.8 Hz, 1 H), 7.69 - 7.75 (m, 3 H), 8.40 (d, /=5.8 Hz, 2 H), 8.57 (d, /=6.8 Hz, 1 H); HPLC purity (Method 1 : 97%, Method 2: 95%); HRMS: calcd for C23Hi8ClN3O2 + H+, 404.1160; found (ESI-FTMS, [M+H]l+), 404.1162. Example 124 3-{[l-(2'-methylbiphenyl-3-yI)ethyl]amino}-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2-dione Utilizing the method of Example 113, 3-(l-(3-bromophenyl)ethylamino)-4-(pyridin-4- ylamino)cyclobut-3-ene-1,2-dione (100 mg, 0.27 mmol) and 2-methylbenzeneboronic acid (55 mg, 1.5 eq) were converted to the title compound (41 mg, 40%). 1H NMR (400 MHz, DMSO-rftf) δ ppm 1.64 (d, /=6.8 Hz, 3 H), 2.23 (s, 3 H), 5.29 - 5.44 (m, 1 H); 7.18 - 7.34 (m, 5 H), 7.38 (s, 1 H), 7.40 - 7.53 (m, 4 H), 8.37 - 8.48 (m, /=5.6 Hz, 3 H); HPLC purity (Method 1: 97%, Method 2: 97%); HRMS: calcd for C24H2iN3O2 + H+, 384.1707; found (ESI-FTMS, [M+H]l+), 384.1706. Example 125
3-{[l-(4'-methylbiphenyl-3-yl)ethyl]amino}-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2-dione Utilizing the method of Example 113, 3-(l-(3-bromophenyl)ethylamino)-4-(pvridin-4- ylamino)cyclobut-3-ene-1,2-dione (100 mg, 0.27 mmol) andju-tolylboronic acid (55 mg, 1.5 eq) were converted to the title compound (21 mg, 20%). 1H NMR (400 MHz, DMSO-cfe) δ ppm 1.66 (d, /=6.8 Hz, 3 H), 2.35 (s, 3 H), 5.28 - 5.45 (m, 1 H), 7.29 (d, /=7.8 Hz, 2 H), 7.37 - 7.52 (m, 4 H), 7.58 (d, /=7.6 Hz, 3 H), 7.68 (s, 1 H), 8.40 (d, /=5.6 Hz, 3 H); HPLC purity (Method 1: 98%, Method 2: 99%); HRMS: calcd for C24H2iN3O2 + H+, 384.1707; found (ESI-FTMS, [M+H]l+), 384.1706. Example 126 3-(pyridin-4-ylamino)-4-({l-[3-(3-thienyl)phenyl]ethyl}amino)cyclobut-3-ene-1,2-dione
Utilizing the method of Example 113, 3-(l-(3-bromophenyl)ethylamino)-4-(pyridin-4- ylamino)cyclobut-3-ene-1,2-dione (100 mg, 0.27 mmol) and 3-thiophenephenylboronic acid hydrate (52 mg, 1.5 eq) were converted to the title compound (61 mg, 60%). 1H NMR (400 MHz, DMSO-<4) δ ppm 1.66 (d, /=6.8 Hz, 3 H), 5.28 - 5.41 (m, 1 H), 7.36 (d, /=7.6 Hz, 1 H), 7.45 (t, /=7.6 Hz, 3 H), 7.59 (d, /=4.8 Hz, 1 H), 7.63 - 7.71 (m, 2 H), 7.77 (s, 1 H), 7.91 (s, 1 H), 8.32 (d, /=8.8 Hz, 2 H), 8.37 - 8.46 (m, /=5.6 Hz, 2 H); HPLC purity (Method 1 : 97%, Method 2: 97%); HRMS: calcd for C2]Hi7N3O2S + H+, 376.1114; found (ESI-FTMS, [M+H]l+), 376.1111. Example 127
3-{[l-(3'-methoxybiphenyI-3-yl)ethyl]amino}-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2- dione
Utilizing the method of Example 113, 3-(l-(3-bromophenyl)ethylamino)-4-(pyridin-4- ylamino)cyclobut-3-ene-1,2-dione (100 mg, 0.27 mmol) and 3-methoxyphenylboronic acid (62 mg, 1.5 eq) were converted to the title compound (72 mg, 67%). 1H NMR (400 MHz, DMSO- d6) δ ppm 1.67 (d, /=6.8 Hz, 3 H), 3.83 (s, 3 H), 5.30 - 5.43 (m, 1 H), 6.28 - 6.38 (m, 1 H), 6.96 (dd, /=8.2, 2.4 Hz, 1 H), 7.17 - 7.29 (m, 2 H), 7.36 - 7.47 (m, 4 H), 7.50 (d, /=7.6 Hz, 1 H), 7.61 (d, /=7.3 Hz, 1 H), 7.71 (s, 1 H), 8.35 - 8.47 (m, /=5.6 Hz, 3 H); HPLC purity (Method 1 : 97%, Method 2: 97%); HRMS: calcd for C24H21N3O3 + H+, 400.1656; found (ESI-FTMS, [M+H]l+), 400.1655. Example 128
3-(pyridin-4-ylamino)-4-{[l-(3-pyridin-3-ylphenyl)ethyI]aπiino}cyclobut-3-ene-1,2-dione Utilizing the method of Example 113, 3-(l-(3-bromophenyl)ethylamino)-4-(pyridin-4- ylamino)cyclobut-3-ene-1,2-dione (100 mg, 0.27 mmol) and pyridine-3-boronic acid (50 mg, 1.5 eq) were converted to the title compound (65 mg, 65%). 1H NMR (400 MHz, OMSO-d6) δ ppm 1.68 (d, /=6.8 Hz, 3 H), 5.35 - 5.45 (m, 1 H), 7.40 - 7.46 (m, 2 H), 7.46 - 7.59 (m, 4 H), 7.68 (d, /=7.8 Hz, 1 H), 7.79 (s, 1 H), 8.07 - 8.14 (m, 1 H), 8.41 (d, /=5.3 Hz, 3 H), 8.59 (dd, /=4.7, 1.6 Hz, 1 H), 8.92 (d, /=1.5 Hz, 1 H); HPLC purity (Method 1: 96%, Method 2: 96%); HRMS: calcd for C22H]8N4O2 + H+, 371.15025; found (ESI-FTMS, [M+H]l+), 371.1502. Example 129 tert-butyl [3'-(l-{[3,4-dioxo-2-(pyridiii-4-ylainino)cyclobut-1-eιi-1-yl]amino}ethyl)biphenyl- 4-yl] carbamate
Utilizing the method of Example 113, 3-(l-(3-bromophenyl)ethylamino)-4-(pyridin-4- ylamino)cyclobut-3-ene-1,2-dione (100 mg, 0.27 mmol) and 4- butoxycarbonylaminophenylboronic acid (52 mg, 1.5 eq) were converted to the title compound (32 mg, 25%). 1H NMR (400 MHz, DMSO-cfc) δ ppm 1.49 (s, 9 H), 1.60 (d, /=6.8 Hz, 3 H), 5.38 (dd, /=8.6, 6.8 Hz, 1 H), 7.34 - 7.40 (m, 1 H), 7.42 (t, J=I.1 Hz, 1 H), 7.50 - 7.59 (m, 5 H), 7.59 - 7.65 (m, 2 H), 7.73 (s, 1 H), 8.34 - 8.41 (m, ./=6.3 Hz, 2 H), 9.46 (s, 1 H), 9.95 (d, /=8.6 Hz, 1 H); HPLC purity (Method 1 : 98%, Method 2: 98%); HRMS: calcd for C28H28N4O4 + H+, 485.2183; found (ESI-FTMS, [M+H]l+), 485.2186. Example 130
3-{[l-(4-iodophenyl)ethyl]amino}-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2-dione Step 1: l-(4-iodophenyl)ethanamine
A mixture of 4-Iodoacetophenone (10 g, 41 mmol), formamide (7.32 g, 4 eq), and formic acid (3 mL) was heated at 160 °C for 18h. The cooled solution was diluted with toluene, washed with water, dried, filtered, and evaporated to provide crude N-(l-(4-iodophenyl)ethyl)formamide as a tan solid. This product was suspended in cone. HCl (50 mL) and heated at reflux for 1 h and at RT overnight. The solution was washed with toluene, neutralized with aq. KOH, extracted with ethyl acetate, dried and evaporated to provide the title compound (7.1 g, 70%, 2 steps) as a clear, tan oil. See, e.g., Eur. J. Med. Chem. 2001, 36, 265, which is incorporated by reference in its entirety. 1H NMR (400 MHz, chloroform-Λ?) δ ppm 1.35 (d, /=6.6 Hz, 3 H), 1.50 (bs, 2 H), 4.07 (q, /=6.6 Hz, 1 H), 7.11 (d, /=8.3 Hz, 2 H), 7.64 (d, /=8.3 Hz, 2 H)
Step 2: 3-{[l-(4-iodophenyl)ethyl]amino}-4-(ρyridin-4-ylamino)cyclobut-3-ene-1,2- dione
Following step 2 of Example 95, 3-ethoxy-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2- dione (2.0 g, 9.2 mmol) and l-(4-iodophenyl)ethanamine (2.50 g, 1.1 eq) were converted to the title compound (1.16 g, 30%) after flash chromatography (silica, ethyl acetate, acetonitrile, methanol, water, 70 / 10 / 5 / 5). 1H NMR (400 MHz, DMSO-rfβ) δ ppm 1.57 (d, /=7.1 Hz, 3 H), 5.13 - 5.33 (m, 1 H), 7.23 (d, /=8.3 Hz, 2 H), 7.42 (s, 2 H), 7.76 (d, /=8.1 Hz, 2 H), 8.21 (d, /=7.1 Hz, 1 H), 8.41 (d, /=5.3 Hz, 2 H), 9.83 (s, 1 H); HPLC purity (Method 1: 95%, Method 2: 91%); HRMS: calcd for C17H14IN3O2 + H+, 420.0204; found (ESI-FTMS, [MH-H]I+), 420.0201. Example 131 3-[(l-biphenyl-4-ylethyl)amino]-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2-dione
Utilizing the method of Example 113, 3-{[l-(4-iodophenyl)ethyl]amino}-4-(pyridin-4- ylamino)cyclobut-3-ene-1,2-dione (75 mg, 0.2 mmol) and phenylboronic acid (33 mg, 1.5 eq ) was converted to the title compound (8 mg, 8%). 1H NMR (400 MHz, OMSO-d6) δ ppm 1.64 (d, /=7.1 Hz, 3 H), 5.28 - 5.51 (m, 1 H), 7.37 (t, /=7.3 Hz, 1 H), 7.42 - 7.55 (m, 6 H), 7.62 - 7.74 (m, /=13.0, 7.7 Hz, 4 H), 8.41 (d, ./=5.8 Hz, 2 H); HPLC purity (Method 1: 98%, Method 2: 98%); HRMS: calcd for C23H19N3O2 + H+, 370.1550; found (ESI-FTMS, [M+H]l+), 370.1551. Example 132
3-({l-[4-(3-furyl)phenyI]ethyl}amino)-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2-dione Utilizing the method of Example 113, 3-{[l-(4-iodophenyl)ethyl]amino}-4-(pyridin-4- ylamino)cyclobut-3-ene-1,2-dione (75 mg, 0.2 mmol) and furan-3-boronic acid (30 mg, 1.5 eq ) was converted to the title compound (17 mg, 26%). 1H NMR (400 MHz, OMSO-d6) δ ppm 1.61 (d, /=6.8 Hz, 3 H), 5.23 - 5.38 (m, 1 H), 6.96 (d, /=1.0 Hz, 1 H), 7.36 - 7.49 (m, 4 H), 7.64 (d, /=8.1 Hz, 2 H), 7.74 (t, /=1.6 Hz, 1 H), 8.19 (s, 1 H), 8.41 (d, /=5.8 Hz, 2 H), 8.49 (d, /=7.8 Hz, 1 H); HPLC purity (Method 1: 98%, Method 2: 99%); HRMS: calcd for C2IHnN3O3 + H+, 360.1343; found (ESI-FTMS, [M+H]l+), 360.1345. Example 133
3-{[l-(3'-aminobiphenyl-4-yl)ethy]]amino}-4-(pyridin-4-ylaniino)cyclobut-3-ene-1,2-dione Utilizing the method of Example 113, 3-{[l-(4-iodophenyl)ethyl]amino}-4-(pyridin-4- ylamino)cyclobut-3-ene-1,2-dione (75 mg, 0.2 mmol) and 3-aminophenylboronic acid (42 mg, 1.5 eq ) was converted to the title compound (23 mg, 43%). 1H NMR (400 MHz, OMSO-d6) δ ppm 1.63 (d, /=6.8 Hz, 3 H), 5.27 - 5.41 (m, 1 H), 6.53 - 6.60 (m, 1 H), 6.77 (d, /=7.6 Hz, 1 H), 6.82 (t, /=1.9 Hz, 1 H), 7.09 (t, /=7.8 Hz, 1 H), 7.39 - 7.53 (m, 4 H), 7.53 - 7.63 (m, 2 H), 8.35 - 8.53 (m, 3 H); HPLC purity (Method 1 : 98%, Method 2: 96%); HRMS: calcd for C23H20N4O2 + H+, 385.1659; found (ESI-FTMS1 [M+H]l+), 385.1659. Example 134
3-{[l-(4'-chIorobiphenyl-4-yl)ethyl]araino}-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2-dione Utilizing the method of Example 113, 3-{[l-(4-iodophenyl)ethyl]amino}-4-(pyridin-4- ylamino)cyclobut-3-ene-1,2-dione (75 mg, 0.2 mmol) and 4-chlorophenylboronic acid (42 mg, 1.5 eq ) was converted to the title compound (12 mg, 17%). 1H NMR (400 MHz, Σ>MSO-d6) δ ppm 1.62 (d, /=7.1 Hz, 3 H), 5.32 - 5.46 (m, 1 H), 7.44 - 7.56 (m, 6 H), 7.69 (dd, /=8.5, 2.1 Hz, 4 H), 8.39 (d, /=5.6 Hz, 2 H), 9.20 (d, /=4.3 Hz, 1 H); HPLC purity (Method 1 : 97%, Method 2: 97%); HRMS: calcd for C23Hi8ClN3O2 + H+, 404.1161; found (ESI-FTMS, [MH-H]I+), 404.1171. Example 135
3-(pyridin-4-ylamino)-4-({l-[4-(3-thienyI)phenyI]ethyl}amino)cycIobut-3-ene-1,2-dione Utilizing the method of Example 113, 3-{[l-(4-iodophenyl)emyl]amino}-4-(pyridin-4- ylamino)cyclobut-3-ene-1,2-dione (75 mg, 0.2 mmol) and thiophene-3-boronic acid (28 mg, 1.5 eq ) was converted to the title compound (24 mg, 36%). 1H NMR (400 MHz, OMSO-d6) δ ppm 1.62 (d, /=6.8 Hz, 3 H), 5.26 - 5.40 (m, 1 H), 7.40 - 7.50 (m, /=8.3 Hz, 4 H), 7.56 (dd, /=5.1, 1.3 Hz, 1 H), 7.64 (dd, /=5.1, 3.0 Hz, 1 H), 7.74 (d, /=8.3 Hz, 2 H), 7.87 (dd, /=2.9, 1.4 Hz, 1 H), 8.41 (d, /=5.8 Hz, 2 H), 8.53 (d, /=7.1 Hz, 1 H); HPLC purity (Method 1 : 98%, Method 2: 98%); HRMS: calcd for C2]Hi7N3O2S + H+, 376.1114; found (ESI-FTMS, [M+H]l+), 376.1117. Example 136 N2-P^-dioxo-1-φyridin-^ylaminoJcyclobut-1-eii-1-ylJ-L-leucin amide The mixture of 3-ethoxy-4-(pyridin-4-ylamino)-cyclobut-3-ene-1,2-dione (104 mg, 0.48 mmole), L-leucinamide hydrochloride (119 mg, 0.71 mmole, 1.5 eq) and Et3N (99 μL, 0.71 mmole, 1.5 eq) was refluxed in EtOH (5 mL) overnight. The solid resulting after EtOH was removed was washed with water and ethyl ether to give the title compound (40 mg, 27%) as a yellow solid. 1H NMR (400 MHz, MeOD) δ ppm 0.91 (d, /=3.8 Hz, 6 H) 1.52 - 1.76 (m, /=2.8 Hz, 3 H) 7.47 (s, 2 H) 8.32 (d, 2 H); HPLC purity (Method 1: 100%, Method 2: 100%); HRMS: calcd for C15Hi8N4O3 + H+, 303.14517; found (ESI-FTMS, [M+H]1+), 303.1456. Example 137 N2-β^-dioxo-1-føyridin-^ylamnoJcyclobut-1-en-1-yll-L-alan in amide
The title compound was prepared as illustrated by Example 136, but using L- alanineamide hydrochloride. The precipitated solid was filtered and washed with EtOH and ethyl ether to give the product (84 mg, 68%) as a yellow solid. 1H NMR (400 MHz, DMSO-rftf) δ ppm 1.40 (d, /=6.6 Hz, 3 H) 4.70 (d, /=6.1 Hz, 1 H) 7.17 - 7.58 (m, 3 H) 7.81 (s, 1 H) 8.15 - 8.56 (m, 3 H) 10.27 (s, 1 H); HPLC purity (Method 1 : 100%, Method 2: 100%); HRMS: calcd for C12Hi2N4O3 + H+, 261.09822; found (ESI-FTMS, [M+H]1+), 261.0986. Example 138
2-{[3,4-dioxo-2-(pyridin-4-yIamino)cyclobut-1-en-1-yl]amino}-2-(3-methyl-2- thienyl)acetamide
The title compound was prepared as illustrated by Example 136, but using 2-amino-2-(3- methylthiophen-2-yl)acetonitrile. Purification by chromatography (silica, EtOAc:CH3CN : MeOH : H2O, 70:10:5:5) and further trituration with EtOAc afforded the product (41 mg, 24%) as a brown solid. 1H NMR (400 MHz, DMSO-<4) δ ppm 2.31 (s, 3 H) 6.06 (d, /=8.6 Hz, 1 H) 6.86 (d, /=5.3 Hz, 1 H) 7.33 - 7.49 (m, 3 H) 7.51 (s, 1 H) 7.98 (s, 1 H) 8.42 (d, /=6.3 Hz, 2 H) 8.66 (d, J=8.8 Hz, 1 H) 10.21 (s, 1 H); HPLC purity (Method 1: 98%, Method 2: 95%); HRMS: calcd for C16Hi4N4O3S + H+, 343.08594; found (ESI-FT/MS, [MH-H]1+), 343.0859. Example 139 2-{[3,4-dioxo-2-(pyridin-4-ylamino)cyclobut-1-en-1-yl]amino}-2-(3-furyl)acetamide
The title compound was prepared as illustrated by Example 136, but using 2-amino-2- (furan-3-yl)acetamide hydrochloride. Purification by chromatography (silica, EtOAc:CH3CN : MeOH : H2O, 70:10:5:5) and further trituration with EtOAc afforded the product (45 mg, 31%) as a brown solid. 1H NMR (400 MHz, DMS0-<4) δ ppm 5.77 (none, 1 H) 6.50 (s, 1 H) 7.38 - 7.57 (m, 3 H) 7.59 - 7.78 (m, 2 H) 8.02 (s, 1 H) 8.42 (s, 2 H) 8.62 (s, 1 H) 10.28 (s, 1 H); HPLC purity (Method 1 : 98%, Method 2: 99%); HRMS: calcd for C15Hi2N4O4 + H+, 313.09313; found (ESI-FT/MS, [M+H]1+), 313.0935. Example 140 7V2-[3,4-dioxo-2-(pyridin-4-ylamino)cyclobut-1-eii-1-yl]-L-serinamide The title compound was prepared as illustrated by Example 136, but using L-serinamide hydrochloride. Purification (RP-HPLC, CH3CN/H2O/0.1% formic acid) afforded the product (6.5 mg, 5%) as a yellow solid. 1H NMR (400 MHz, DMSO-rf<s) δ ppm 3.60 - 3.82 (m, 2 H) 4.55 - 4.78 (m, 1 H) 5.21 (s, 1 H) 7.36 (s, 1 H) 7.40 - 7.56 (m, 2 H) 7.74 (s, 1 H) 8.31 (d, ./=8.1 Hz, 1 H) 8.41 (d, J=6.3 Hz, 2 H) 10.40 (s, 1 H); HRMS: calcd for C12Hi2N4O4 + H+, 277.09313; found (ESI-FTMS, [MH-H]1+), 277.0933. Example 141 J-ffl^^-^ydroxymethylJpyrrolidiii-1-yll^-^yridin-4-ylaininoJcyclobut-S-ene-l^-dione
To a microwave vial was added 3-ethoxy-4-(pyridin-4-ylamino)-cyclobut-3-ene-1,2- dione (100 mg, 0.5 mmole), 95% EtOH (5 mL) and (s)-(+)- 2-pyrrolidinemethanol (68 μL, 1.5 eq). The mixture was heated at 125 °C in microwave reactor for 30 min. The precipitated solid at rt was filtered and washed by ethyl ether to give the product (80 mg, 64%) as a yellow solid. 1H NMR (400 MHz, MeOD) δ ppm 1.82 (s, 1 H) 1.96 - 2.36 (m, 3 H) 3.56 - 4.07 (m, 3 H) 4.23 - 4.58 (m, 2 H) 7.46 (dd, XS-, 1.52 Hz, 2 H) 8.39 (d, /=6.6 Hz, 2 H); HPLC purity (Method 1: 100%, Method 2: 96%); HRMS: calcd for C14Hi5N3O3 + H+, 274.11862; found (ESI-FTMS, [M+H]1+), 274.1188. Example 142 S-^-methylpyrrolidin-1-yl^-tøyridin-4-ylamiiioJcyclobut-S-ene-l^-dioiie
The title compound was prepared as illustrated by Example 141, but using 2- methylpyrrolidine to afford 60 mg, 51% as a yellow solid. 1H NMR (400 MHz, MeOD) δ ppm 0.98 - 1.39 (m, 4 H) 1.44 - 2.27 (m, 4 H) 3.56 - 4.10 (m, /=94.0 Hz, 2 H) 4.28 - 4.58 (m, 1 H) 7.12 - 7.45 (m, 2 H) 8.04 - 8.38 (m, 2 H); HPLC purity (Method 1: 100%, Method 2: 100%); HRMS: calcd for C14Hi5N3O2 + H+, 258.12370; found (ESI-FTMS, [M+H]1+), 258.1235; Example 143
S-ll-OiydroxymethylJpiperidin-1-yll^-φyridin-^ylaminoJcyclobut-S-ene-ljl-dione The title compound was prepared as illustrated by Example 141, but using 2- hydroxymethylpiperidine. Purification by chromatography (silica, 10-14% MeOHZCH2Cl2) afforded the product (50 mg, 38%) as a yellow solid. 1H NMR (400 MHz, MeOD) δ ppm 1.41 - 1.91 (m, 6 H) 3.12 - 3.29 (m, 3 H) 3.52 (d, /=7.6 Hz, 1 H) 3.87 - 4.09 (m, 1 H) 7.17 (d, /=6.6 Hz, 2 H) 8.20 (dd, /=5.1, 1.5 Hz, 2 H); HPLC purity (Method 1: 100%, Method 2: 100%); HRMS: calcd for C15HnN3O3 + H+, 288.13427; found (ESI-FTMS, [M+H]1+), 288.1343. Example 144
3-(2-methylpiperidin-1-yl)-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2-dione
The title compound was prepared as illustrated by Example 141, but using 2- methylpiperidine. Purification by chromatography (silica, 10-12% MeOH/CH2Cl2) afforded the product (77 mg, 62%) as a yellow solid. 1H NMR (400 MHz, MeOD) δ ppm 1.20 - 1.35 (m, 3 H) 1.47 - 1.96 (m, 6 H) 3.15 - 3.24 (m, 3 H) 3.27 - 3.49 (m, 1 H) 6.99 - 7.23 (m, 2 H) 8.18 (d,
/=4.6 Hz, 2 H); HPLC purity (Method 1: 99%, Method 2: 99%); HRMS: calcd for C15HnN3O2 + H+, 272.13935; found (ESI-FTMS, [M+H]14), 272.1392. Example 145 l-flS^-dioxo-1-φyridin-^ylaminoJcyclobut-1-en-1-yllaminoJ-1-P-thienylJacetamide The title compound was prepared as illustrated by Example 136, but using 2-(3- thienyl)acetamide. Purification (RP-HPLC, CH3CN/H2O/0.1% formic acid) afforded the product (13.2 mg, 7%) as a yellow solid. 1H NMR (400 MHz, MeOD) δ ppm 5.94 (s, 1 H) 7.12 (dd, /=5.1, 1.3 Hz, 1 H) 7.37 (dd, /=5.1, 3.0 Hz, 1 H) 7.42 - 7.53 (m, 3 H) 8.27 (d, /=5.6 Hz, 2 H) 8.46 (s, 1 H); HPLC purity (Method 1: 91%, Method 2: 90%); HRMS: calcd for C15Hi2N4O3S + H+, 329.07029; found (ESI-FTMS, [M+H] 1+), 329.0703. Example 146 S-φyridin-4-ylamino^-Kl-pyridin-4-ylethylJaminolcyclobut-S-ene-l^-dione
Step 1: To a microwave vial was added 4-acetylpyridine ( 1.9 g, lO mmoles), 95% EtOH (15 mL), hydroxylamine hydrochloride (1.0 g, 15 mmoles, 1.5 eq) and Et3N (2.1 mL, 15 mmoles, 1.5 eq). The mixture was heated at 120 °C in microwave reactor for 20 min. EtOH was removed in vacuo. Working up (EtOAc/H2O) afforded l-(pyridin-4-yl)ethanone oxime (620 mg, 46%) as a white solid.
Step 2: To a Parr® shaker bottle was added the oxime (200 mg, 1.5 mmoles), 95% EtOH (15 mL), ammonium hydroxide (0.3 mL) and Raney nickel (300 mg). The mixture was shaken at rt in a hydrogen atmosphere (50 PSI) for two days. The reaction was filtered through Celite® followed by MeOH washing. The solution was evaporated. l-(pyridin-4-yl)ethanamine (140 mg, 78%) was obtained as a white solid.
Step 3 : The title compound was prepared as illustrated by Example 141. Purification by chromatography (silica, 10-14% MeOH/CH2Cl2) afforded the product (123 mg, 65%) as a yellow solid. 1H NMR (400 MHz, MeOD) δ ppm 1.57 (d, /=7.1 Hz, 3 H) 5.22 - 5.41 (m, 1 H) 7.28 - 7.51 (m, 4 H) 8.26 (dd, /=4.8, 1.5 Hz, 2 H) 8.39 - 8.51 (m, 2 H); HPLC purity (Method 1: 100%, Method 2: 100%); HRMS: calcd for C16H14N4O2 + H+, 295.11895; found (ESI-FTMS, [M+H]1+), 295.1188. Example 147
3-{[l-(l-benzofuran-2-yl)ethyI]amino}-4-(pyridin-4-yIamino)cyclobut-3-ene-1,2-dione Step 1: The oxime was prepared according to Step 1 of Example 146, but using 1- benzofuran-2-yl-ethylamine as the starting material.
Step 2: The amine intermediate was prepared according to Step 2 of Example 146. Step 3: The title compound was prepared as illustrated by Example 141. Purification by chromatography (silica, 2-6% MeOH/CH2Cl2) afforded the product (210 mg g, 88%) as a yellow solid. 1H NMR (400 MHz, DMSO-<25) δ ppm 1.71 (d, J=IA Hz, 3 H) 5.42 - 5.65 (m, 1 H) 6.92 (s, 1 H) 7.18 - 7.38 (m, 2 H) 7.43 (d, ./=5.6 Hz, 2 H) 7.61 (dd, ./=21.1, 7.7 Hz, 2 H) 8.42 (d, /=6.1 Hz, 3 H) 9.76 - 9.93 (m, 1 H); HPLC purity (Method 1: 97%, Method 2: 99%); HRMS: calcd for C19Hi5N3O3 + H+, 334.11862; found (ESI-FTMS, [M+H]1+), 334.119. Example 148 3-{[l-(4-morpholin-4-ylphenyl)ethyl]amino}-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2-dione Step 1: The oxime was prepared according to Step 1 of Example 146, but using l-(4- morpholin-4-yl-phenyl)-ethylamine as the starting material.
Step 2: The amine intermediate was prepared according to Step 2 of Example 146.
Step 3: The title compound was prepared as illustrated by Example 141. The precipitated solid was filtered, washed with EtOH and Et2θ to afford the product (160 mg 86%) as a yellow solid. 1H NMR (400 MHz, OMSO-d6) δ ppm 1.57 (d, /=6.8 Hz, 3 H) 3.09 (d, ./=4.3 Hz, 4 H) 3.56 - 3.91 (m, 4 H) 5.05 - 5.35 (m, 1 H) 6.97 (d, /=8.3 Hz, 2 H) 7.28 (d, /=8.3 Hz, 2 H) 7.36 - 7.59 (m, 2 H) 8.13 (s, 1 H) 8.41 (s, 2 H) 9.81 (s, 1 H); HPLC purity (Method 1: 100%, Method 2: 100%); HRMS: calcd for C2]H22N4O3 + H+, 379.17647; found (ESI-FTMS, [MH-H]1+), 379.1766. Example 149
3-({l-[4-(dimethylamino)phenyl] ethyl} amiπo)-4-(pyridiιi-4-ylainino)cyclobut-3-ene-1,2- dione
Step 1: The oxime was prepared according to Step 1 of Example 146, but using [4-(l- amino-ethyl)-phenyl]-dimethyl-amine as the starting material.
Step 2: The amine intermediate was prepared according to Step 2 of Example 146.
Step 3: The title compound was prepared as illustrated by Example 141. The precipitated solid was filtered, washed with EtOH and Et2O to afford the product (120 mg 78%) as a yellow solid. 1H NMR (400 MHz, OMSO-d6) δ ppm 1.57 (d, /=6.1 Hz, 3 H) 2.88 (s, 6 H) 5.06 - 5.29 (m, 1 H) 6.58 - 6.88 (m, 2 H) 7.23 (d, /=8.1 Hz, 2 H) 7.31 - 7.53 (m, 2 H) 8.11 (s, 1 H) 8.41 (s, 2 H) 9.63 - 9.95 (m, 1 H); HPLC purity (Method 1: 100%, Method 2: 100%); HRMS: calcd for C19H20N4O2 + H+, 337.16590; found (ESI-FTMS, [M+H]1+), 337.1657. Example 150
3-[(l-cyclohexylethyl)amino]-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2-dione Step 1 : The oxime was prepared according to Step 1 of Example 146, but using 1- cyclohexyl-ethylamine as the starting material.
Step 2: The amine intermediate was prepared according to Step 2 of Example 146.
Step 3: The title compound was prepared as illustrated by Example 141. Purification by chromatography (silica, 5-10% MeOH/CH2Cl2) afforded the product (120 mg, 87%) as a yellow solid. 1H NMR (400 MHz, MeOD) δ ppm 1.08 - 1.52 (m, 8 H) 1.49 - 1.88 (m, 2 H) 1.86 - 2.09
(m, 4 H) 4.12 - 4.40 (m, 1 H) 7.59 - 7.75 (m, 2 H) 8.50 (dd, /=4.9, 1.6 Hz, 2 H); HPLC purity (Method 1: 100%, Method 2: 94%); HRMS: calcd for C17H2)N3O2 + H+, 300.17065; found (ESI-
FTMS, [M+H]1+), 300.171.
Example 151
3-[(l-pyrazm-2-ylethyl)ainino]-4-(pyridiii-4-ylamino)cyclobut-3-ene-1,2-dione Step 1 : The oxime was prepared according to Step 1 of Example 146, but l-pyrazin-2-yl- ethylamine was used as the starting material.
Step 2: The amine intermediate was prepared according to Step 2 of Example 146. Step 3: The title compound was prepared as illustrated by Example 141. Purification by chromatography (silica, 10-15% MeOH/CH2Cl2) afforded the product (58 mg, 52%) as a yellow solid. 1H NMR (400 MHz, MeOD) δ ppm 1.69 (d, /=6.8 Hz, 3 H) 5.61 (d, /=6.6 Hz, 1 H) 7.54
(d, /=6.3 Hz, 2 H) 8.36 (dd, /=4.8, 1.52 Hz, 2 H) 8.57 (d, /=2.5 Hz, 1 H) 8.62 - 8.71 (m, 1 H)
8.74 (d, J=1.5 Hz, 1 H); HPLC purity (Method 1: 97%, Method 2: 99%); HRMS: calcd for C15Hi3N5O2 + H+, 296.11420; found (ESI-FTMS, [MH-H]1+), 296.1142.
Example 152 3-({l-[4-(lff-imidazol-1-yl)phenyl]ethyl}amino)-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2- dione
Step 1 : The oxime was prepared according to Step 1 of Example 146, but l-(4-imidazol- l-yl-phenyl)-ethylamine was used as the starting material.
Step 2: The amine intermediate was prepared according to Step 2 of Example 146. Steρ 3: The title compound was prepared as illustrated by Example 141. Purification by chromatography (silica, 10-15% MeOH/CH2Cl2) afforded the product (0.10 g, 73%) as a yellow solid. 1H NMR (400 MHz, MeOD) δ ppm 1.79 (d, J=7.1 Hz, 3 H) 5.45 - .71 (m, 1 H) 7.24 (d,
/=1.0 Hz, 1 H) 7.61 (s, 1 H) 7.62 - 7.78 (m, 6 H) 8.13 - 8.29 (m, 1 H) 8.44 (dd, /=4.8, 1.5 Hz, 2
H); HPLC purity (Method 1: 100%, Method 2: 100%); HRMS: calcd for C20Hi7N5O2 + H+, 360.14550; found (ESI-FTMS, [MH-H]1+), 360.1456.
Example 153
3-(pyridin-4-ylamino)-4-{[l-(3-thienyl)ethyl]ainino}cyclobut-3-ene-1,2-dione
Step 1 : The oxime was prepared according to Step 1 of Example 146, but l-thiophen-3- yl-ethylamine was used as the starting material. Step 2: The amine intermediate was prepared according to Step 2 of Example 146. Step 3: The title compound was prepared as illustrated by Example 141. Purification by chromatography (silica, 2-10% MeOH/CH2Cl2) afforded the product (80 mg, 67%) as a yellow solid. 1H NMR (400 MHz, MeOD) δ ppm 1.59 (d, J=6.8 Hz, 3 H) 5.30 - 5.50 (m, 1 H) 7.03 - 7.13 (m, 1 H) 7.22 - 7.52 (m, 4 H) 8.26 (d, ./=6.6 Hz, 2 H); HPLC purity (Method 1: 87%, Method 2: 86%); HRMS: calcd for C15H13N3O2S + H+, 300.08012; found (ESI-FTMS, [M+H]1+), 300.0802; Example 154
3-{[l-(l-methyl-l/r-pyrroI-3-yI)ethyI]amino}-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2- dione Step 1: The oxime was prepared according to Step 1 of Example 146, but 1-(1-Methyl-
1H-pyrrol-3-yl)-ethylamine was used as the starting material.
Step 2: The amine intermediate was prepared according to Step 2 of Example 146.
Step 3: The title compound was prepared as illustrated by Example 141. Purification by chromatography (silica, 2-10% MeOH/CH2Cl2) afforded the product (95 mg, 67%) as a yellow solid. 1H NMR (400 MHz, MeOD) δ ppm 1.51 (d, J=6.8 Hz, 3 H) 3.52 (s, 3 H) 5.11 - 5.31 (m, 1 H) 5.91 - 6.05 (m, 1 H) 6.43 - 6.68 (m, 2 H) 7.26 - 7.55 (m, 2 H) 8.12 - 8.38 (m, 2 H); HPLC purity (Method 1 : 98%, Method 2: 98%); HRMS: calcd for C16Hi6N4O2 + H+, 297.13460; found (ESI-FTMS, [M+H]1+), 297.1351. Example 155 3-{[l-(3-methylpyrazin-2-yl)ethyl]aπiino}-4-(pyridm-4-ylainino)cyclobut-3-ene-1,2-dione
Step 1: The oxime was prepared according to Step 1 of Example 146, but l-(3-methyl- pyrazin-2-yl)-ethylamine was used as the starting material.
Step 2: The amine intermediate was prepared according to Step 2 of Example 146.
Step 3: The title compound was prepared as illustrated by Example 141. Purification by chromatography (silica, 3-8% MeOH/CH2Cl2) afforded the product (70 mg, 47%) as a yellow solid. 1H NMR (400 MHz, MeOD) δ ppm 1.74 (d, J=6.6 Hz, 3 H) 2.82 (s, 3 H) 5.79 - 6.03 (m, J=6.6 Hz, 1 H) 7.69 (d, /=5.3 Hz, 2 H) 8.49 (d, J=5.6 Hz, 2 H) 8.56 (d, /=2.0 Hz, 1 H) 8.63 (s, 1 H); HPLC purity (Method 1 : 100%, Method 2: 100%); HRMS: calcd for C16H15N5O2 + H+, 310.12985; found (ESI-FTMS, [M+H]1+), 310.1299. Example 156
3-{[l-(l-benzothien-3-yl)ethyl]amino}-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2-dione Step 1 : The oxime was prepared according to Step 1 of Example 146, but 1- benzo[b]thiophen-3-yl-ethylamine was used as the starting material.
Step 2: The amine intermediate was prepared according to Step 2 of Example 146.
Step 3: The title compound was prepared as illustrated by Example 141. Purification (RP-HPLC, CH3CN/H2O/0.1% formic acid) afforded the product (19 mg, 13%) as a yellow solid. 1H NMR (400 MHz, MeOD) δ ppm 2.00 (d, /=6.9 Hz, 3 H) 5.86 - 6.11 (m, 1 H) 7.48 - 7.64 (m, 2 H) 7.71 - 7.81 (m, 2 H) 7.84 (s, 1 H) 8.00 - 8.13 (m, 2 H) 8.30 - 8.42 (m, 2 H) 8.46 - 8.60 (m, 2 H); HPLC purity (Method 1: 100%, Method 2: 99%); HRMS: calcd for C19H15N3O2S + H+, 350.09577; found (ESI-FTMS, [M+H]1+), 350.0958. Example 157
3-(pyridin-4-ylamino)-4-{[l-(1,3-thiazoI-2-yI)ethyl]amino}cyclobut-3-ene-1,2-dione
Step 1: The oxime was prepared according to Step 1 of Example 146, but l-thiazol-2-yl- ethylamine was used as the starting material.
Step 2: The amine intermediate was prepared according to Step 2 of Example 146. Step 3: The title compound was prepared as illustrated by Example 141. Purification
(RP-HPLC, CH3CN/H2O/0.1% formic acid) afforded the product (52 mg, 38%) as a yellow solid. 1H NMR (400 MHz, MeOD) 5 ppm 1.82 (d, /=7.1 Hz, 3 H) 5.66 - 5.89 (m, 1 H) 7.61 (d, /=3.0 Hz, 2 H) 7.66 - 7.94 (m, 2 H) 8.18 - 8.35 (m, 2 H) 8.44 (d, /=6.3 Hz, 2 H); HPLC purity (Method 1 : 100%, Method 2: 99%); HRMS: calcd for C14H12N4O2S + H+, 301.07537; found (ESI-FTMS, [M+H]1+), 301.0757. Example 158 3-{[l-(3-aminophenyl)ethyl]amino}-4-(pyridin-4-ylainino)cyclobut-3-ene-1,2-dione
Step 1: The oxime was prepared according to Step 1 of Example 146, but 3-(l-amino- ethyl)-phenylamine was used as the starting material. Step 2: The amine intermediate was prepared according to Step 2 of Example 146.
Step 3: The title compound was prepared as illustrated by Example 141. Purification by chromatography (silica, 10-12% MeOH/CH2Cl2) afforded the product (30 mg, 23%) as a yellow solid.Η NMR (400 MHz, MeOD) δ ppm 1.53 (d, /=6.8 Hz, 3 H) 5.09 - 5.32 (m, 1 H) 6.40 - 6.71 (m, /=2.0 Hz, 3 H) 6.86 - 7.13 (m, 1 H) 7.26 - 7.65 (m, 2 H) 8.24 (d, /=6.3 Hz, 2 H); HPLC purity (Method 1 : 98%, Method 2: 100%); HRMS: calcd for C17Hi6N4O2 + H+, 309.13460; found (ESI-FTMS, [M+H]1+), 309.1348. Example 159 3-{[l-(2-fluorophenyl)ethyl]amlno}-4-(pyridin-4-ylamino)cycLobut-3-ene-1,2-dione
Step 1: The oxime was prepared according to Step 1 of Example 146, but l-(2-fluoro- phenyl)-ethylamine was used as the starting material. Step 2: The amine intermediate was prepared according to Step 2 of Example 146.
Step 3: The title compound was prepared as illustrated by Example 141. Purification (RP-HPLC, CH3CN/H2O/0.1% formic acid) afforded the product (72 mg, 56%) as a yellow solid. 1H NMR (400 MHz, MeOD) δ ppm 1.66 (d, /=6.8 Hz, 3 H) 5.56 - 5.71 (m, 1 H) 7.04 - 7.27 (m, 2 H) 7.26 - 7.38 (m, 1 H) 7.38 - 7.53 (m, /=1.8 Hz, 1 H) 7.66 (d, /=4.6 Hz, 2 H) 8.07 - 8.25 (m, 2 H) 8.36 (d, /=6.3 Hz, 2 H); HPLC purity (Method 1: 100%, Method 2: 100%); HRMS: calcd for C17H14FN3O2 + H+, 312.11428; found (ESI-FTMS, [M+H]ϊ+), 312.1141. Example 160 3-{[l-(2-hydroxyphenyl)ethyl]amino}-4-(pyridin-4-ylamino)cyclobnt-3-ene-1,2-dione
Step 1: The oxime was prepared according to Step 1 of Example 146, but 2-(l-amino- ethyl)-phenol was used as the starting material.
Step 2: The amine intermediate was prepared according to Step 2 of Example 146. Step 3: The title compound was prepared as illustrated by Example 141. Purification (RP-HPLC, CH3CN/H2O/0.1% formic acid) afforded the product (34 mg, 23%) as a yellow solid. 1H NMR (400 MHz, MeOD) δ ppm 1.78 (d, /=6.8 Hz, 3 H) 5.55 - 5.76 (m, 1 H) 6.92 (dd, /=8.1, 1.0 Hz, 2 H) 7.22 (d, /=1.5 Hz, 1 H) 7.28 - 7.39 (m, 1 H) 7.72 (d, /=5.6 Hz, 2 H) 8.23 - 8.42 (m, 1 H) 8.46 (d, /=5.6 Hz, 2 H); HPLC purity (Method 1: 100%, Method 2: 100%); HRMS: calcd for C17H15N3O3 + H+, 310.11862; found (ESI-FTMS, [M+H]1+), 310.1189. Example 161
S-tll-flfl-indol-S-yOethyllaminoJ^-φyridin-4-ylaminoJcyclobut-S-ene-ljΣ-dione Step 1: The oxime was prepared according to Step 1 of Example 146, but l-(1H-indol-3- yl)-ethylamine was used as the starting material.
Step 2: The amine intermediate was prepared according to Step 2 of Example 146. Step 3: The title compound was prepared as illustrated by Example 141. Purification (RP-HPLC, CH3CN/H2O/0.1% formic acid) afforded the product (4.3 mg, 3%) as a yellow solid. 1H NMR (400 MHz, MeOD) δ ppm 1.74 (d, 3 H) 6.89 - 7.11 (m, 3 H) 7.22 - 7.32 (m, 3 H) 7.44 - 7.59 (m, 4 H); HPLC purity (Method 1: 95%, Method 2: 96%); HRMS: calcd for C19Hi6N4O2 + H+, 333.13460; found (ESI-FTMS, [M+H]1+), 333.1347. Example 162
3-{[l-(2,6-difluoropheπyI)ethyl]amino}-4-(pyridin-4-ylaπiino)cyclobut-3-ene-1,2-dione Step 1: The oxime was prepared according to Step 1 of Example 146, but 1 -(2,6- difluoro-phenyl)-ethylamine was used as the starting material.
Step 2: The amine intermediate was prepared according to Step 2 of Example 146.
Step 3: The title compound was prepared as illustrated by Example 141. Purification (RP-HPLC, CH3CN/H2O/0.1 % formic acid) afforded the product (92 mg, 61 %) as a yellow solid. 1H NMR (400 MHz, MeOD) δ ppm 1.72 (d, 3 H) 5.78 - 6.10 (m, /=6.8 Hz, 1 H) 6.93 - 7.11 (m, 2 H) 7.29 - 7.46 (m, 1 H) 7.65 - 7.88 (m, /=4.8 Hz, 2 H) 8.19 - 8.30 (m, 2 H) 8.42 (d, ./=6.1 Hz, 2 H); HPLC purity (Method 1 : 100%, Method 2: 100%); HRMS: calcd for CnHi3F2N3O2 + H+, 330.10486; found (ESI-FTMS, [M+H]1+), 330.1054. Example 163 3-{[l-(3-fluorophenyl)ethyl]amino}-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2-dione
Step 1: The oxime was prepared according to Step 1 of Example 146, but l-(3-Fluoro- phenyl)-ethylamine was used as the starting material.
Step 2: The amine intermediate was prepared according to Step 2 of Example 146.
Step 3: The title compound was prepared as illustrated by Example 141. Purification (RP-HPLC, CH3CN/H2O/0.1 % formic acid) afforded the product (68 mg, 49%) as a yellow solid. 1H NMR (400 MHz, MeOD) δ ppm 1.67 (d, /=6.8 Hz, 3 H) 5.32 - 5.52 (m, 1 H) 6.98 - 7.14 (m, 1 H) 7.12 - 7.31 (m, 2 H) 7.33 - 7.49 (m, 1 H) 7.69 - 7.93 (m, 2 H) 8.21 - 8.36 (m, 2 H) 8.41 (d, /=5.8 Hz, 2 H) HPLC purity (Method 1: 100%, Method 2: 100%); HRMS: calcd for CnHi4FN3O2 + H+, 312.11428; found (ESI-FTMS, [M+H]1+), 312.1144. Example 164
S-^l-fS-hydroxypheny^ethyllaminoJ^-φyridin-4-ylaminoJcyclobut-S-ene-l^-dione
Step 1: The oxime was prepared according to Step 1 of Example 146, but 3-(l-amino- ethyl)-phenol was used as the starting material.
Step 2: The amine intermediate was prepared according to Step 2 of Example 146. Step 3: The title compound was prepared as illustrated by Example 141. Purification
(RP-HPLC, CH3CN/H2O/0.1 % formic acid) afforded the product (75 mg, 56%) as a white solid. 1H NMR (400 MHz, OMSO-d6) δ ppm 1.56 (d, /=6.8 Hz, 3 H) 5.08 - 5.31 (m, 1 H) 6.70 (dd, /=8.1, 1.8 Hz, 1 H) 6.76 - 6.89 (m, 2 H) 7.19 (t, J=7.8 Hz, 1 H) 7.45 (d, ./=5.8 Hz, 2 H) 8.07 - 8.24 (m, 2 H) 8.41 (d, /=6.1 Hz, 3 H); HPLC purity (Method 1: 100%, Method 2: 100%); HRMS: calcd for CnH15N3O3 + H+, 310.11862; found (ESI-FTMS, [M+H]1+), 310.1186. Example 165
3-(pyridin-4-yIamino)-4-({l-[3-(trifluoromethyl)phenyl]ethyl}amino)cyclobut-3-ene-1,2- dione
Step 1 : The oxime was prepared according to Step 1 of Example 146, but l-(3- trifluoromethyl-phenyl)-ethylamine was used as the starting material. Step 2: The amine intermediate was prepared according to Step 2 of Example 146.
Step 3: The title compound was prepared as illustrated by Example 141. Purification (RP-HPLC, CH3CN/H2O/0.1% formic acid) afforded the product (132 mg, 80%) as a yellow solid. 1H NMR (400 MHz, MeOD) δ ppm 1.53 (d, /=7.1 Hz, 3 H) 5.25 - 5.44 (m, 1 H) 7.32 - 7.51 (m, 2 H) 7.49 - 7.67 (m, 4 H) 8.07 (s, 2 H) 8.23 (d, /=5.8 Hz, 2 H); HPLC purity (Method 1: 100%, Method 2: 100%); HRMS: calcd for C18Hi4F3N3O2 + H+, 362.11109; found (ESI-FTMS, [M+H]1+), 362.1114. Example 166
3-[(2-azidopyridin-4-yl)amino]-4-{[(lJf)-1-phenylethyl]amino}cycIobut-3-ene-1,2-dione To a microwave vial was added (R)-3-(2-chloropyridin-4-ylamino)-4-(l- phenylethylamino)cyclobut-3-ene-1,2-dione (1.0 g, 3.1 mmoles), DMF (10 mL), sodium azide (409 mg, 6.3 mmoles, 2.0 eq) and ammonium chloride (202 mg, 3.8 mmoles, 1.2 eq). The mixture was heated at 140 °C in microwave reactor for 2.5 hours. Purification (RP-HPLC, CH3CN/H2O/0.1% formic acid) afforded the product (0.4 g, 35%) as an off-white solid. 1H NMR (400 MHz, DMSO-rfβ) δ ppm 1.62 (d, /=6.8 Hz, 3 H) 5.19 - 5.45 (m, 1 H) 7.23 - 7.52 (m, 6 H) 8.04 (s, 1 H) 8.44 - 8.60 (m, 1 H) 9.19 (d, /=7.6 Hz, 1 H) 10.21 - 10.63 (m, 1 H); HPLC purity (Method 1: 96%, Method 2: 96%); HRMS: calcd for CnHi4N6O2 + H+, 335.12510; found (ESI- FTMS, [M+H]1+), 335.1248. Example 167 3-{[(1R)-1-phenylethyl]amino}-4-{[2-(4-phenyl-lβ-1,2,3-triazol-1-yl)pyridin-4- yl]amino}cyclobut-3-ene-1,2-dione To a microwave vial was added 3-[(2-azidopyridin-4-yl)amino]-4- {[(1R)-1- phenylethyl]amino}cyclobut-3-ene-1,2-dione (70 mg, 0.21 mmole), DMF (3 mL), water (1 mL), phenylacetylene (21 mg, 0.21 mmole, 1.0 eq), copper (II) sulfate pentahydrate (0.52 mg, 0.002 mmole, 0.01 eq) and sodium ascorbate (2.1 mg, 0.01 mmole, 0.05 eq). The mixture was heated at 135 °C in microwave reactor for 1 hour. Purification (RP-HPLC, CH3CN/H2O/0.1% formic acid) afforded the product (10 mg, 11%) as an off-white solid. 1H NMR (400 MHz, DMSO-<4) δ ppm 2.50 (d, 3 H) 5.24 - 5.47 (m, 1 H) 7.25 - 7.55 (m, 8 H) 7.55 - 7.72 (m, 1 H) 8.04 (d, /=7.3 Hz, 2 H) 8.14 - 8.29 (m, 1 H) 8.34 - 8.54 (m, 1 H) 8.68 - 9.10 (m, 1 H) 9.24 - 9.39 (m, 1 H) 10.60 - 11.20 (m, 1 H); HPLC purity (Method 1 : 100%, Method 2 : 100%); HRMS : calcd for C25H20N6O2 + H+, 437.17205; found (ESI-FTMS, [M+H]1+), 437.1716. Example 168
3-{[2-(4-benzyl- 1H-1,2,3-triazoI-1-yl)pyridin-4-yl]amino}-4-{[(1R)-1-phenylethyI]amino} cycIobut-3-ene-1,2-dione
The title compound was prepared as illustrated by Example 167, but 3-phenyl-1-propyne was used as the alkyne. Purification (RP-HPLC, CH3CN/H2O/0.1% formic acid) afforded the product (10 mg, 11%) as an off-white solid. 1H NMR (400 MHz, MeOD) δ ppm 1.59 (d, /=6.8 Hz, 3 H) 4.04 (s, 2 H) 5.22 - 5.45 (m, 1 H) 7.04 - 7.42 (m, 10 H) 7.51 (s, 1 H) 8.03 (s, 1 H) 8.19 (d, /=5.6 Hz, 1 H) 8.29 (s, 1 H) 8.48 (s, 1 H); HPLC purity (Method 1: 100%, Method 2: 100%); HRMS: calcd for C26H22N6O2 + H+, 451.18770; found (ESI-FTMS, [M+H]1+), 451.1871. Example 169
3-({2-[4-(hydroxymethyl)-l£r-1,2,3-triazol-1-yl]pyridin-4-yl}amino)-4-{[(1R)-1- phenylethyl]amino}cyclobut-3-ene-1,2-dione
The title compound was prepared as illustrated by Example 167, but propargyl alcohol was used as the alkyne. Purification (RP-HPLC, CH3CN/H2O/0.1% formic acid) afforded the product (1.6 mg, 2%) as a yellow solid. 1H NMR (400 MHz, MeOD) δ ppm 1.68 (d, /=6.8 Hz, 3 H) 4.59 (s, 2 H) 5.34 - 5.50 (m, 1 H) 7.24 - 7.48 (m, 4 H) 7.65 (s, 1 H) 8.16 (s, 1 H) 8.35 (s, 1 H) 8.59 (d, /=32.3 Hz, 2 H); HPLC purity (Method 1 : 93%, Method 2: 93%); HRMS: calcd for C20Hi8N6O3 + H+, 391.15132; found (ESI-FTMS, [M+H]1+), 391.1511. Example 170 3-{[l-(3-methylpheπyl)ethyl]amino}-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2-dione Step 1: The oxime was prepared according to Step 1 of Example 146, but using 1-m- Tolyl-ethylamine was used as the starting material.
Step 2: The amine intermediate was prepared according to Step 2 of Example 146.
Step 3: The title compound was prepared as illustrated by Example 141. Purification (RP-HPLC, CH3CN/H2O/0.1% formic acid) afforded the product (115 mg, 81%) as a yellow solid. 1H NMR (400 MHz, MeOD) δ ppm 1.85 (d, 3 H) 2.48 - 2.65 (m, 3 H) 5.50 - 5.68 (m, /=6.6 Hz, 1 H) 7.33 (d, /=7.3 Hz, 1 H) 7.38 - 7.56 (m, 3 H) 7.93 (s, 2 H) 8.46 (s, 2 H) 8.60 (d, /=6.1 Hz, 2 H); HPLC purity (Method 1 : 100%, Method 2: 100%); HRMS: calcd for C8H17N3O2 + H+, 308.13935; found (ESI-FTMS, [M+H]1+), 308.1398. Example 171
3-[(l-phenyIethyl)amino]-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2-dione
Step 1 : The oxime was prepared from 3-chloroacetophenone according to Step 1 of Example 146, but using 1-Phenyl-ethylamine as the starting material.
Step 2: The amine intermediate was prepared according to Step 2 of Example 146. Most of aromatic chloride was also reduced to provide major product 1-phenyl-ethylamine and minor l-(3-chloro-phenyl)-ethylamine. They were carried to next reaction without separation.
Step 3: The title compounds were prepared as illustrated in Example 141. Purification and separation (RP-HPLC, CH3CN/H2O/0.1% formic acid) afforded the title compound (60 mg, 40%) as a yellow solid; 1H NMR (400 MHz, MeOD) δ ppm 1.51 (d, /=7.1 Hz, 3 H) 5.26 (d, J=6.6 Hz, 1 H) 7.11 - 7.31 (m, 5 H) 7.56 (d, /=3.3 Hz, 2 H) 8.08 (s, 1 H) 8.23 (d, /=6.1 Hz, 3 H); HPLC purity (Method 1: 100%, Method 2: 100%); HRMS: calcd for CnH15N3O2 + H+, 294.12370; found (ESI-FTMS, [M+H]1+), 294.1234. Example 172
3-{[l-(3-chlorophenyl)ethyl]amino}-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2-dione Step 1: The oxime was prepared according to Step 1 of Example 146, but using l-(3- chloro-phenyl)-ethylamine as the starting material.
Step 2: The amine intermediate was prepared according to Step 2 of Example 146.
Step 3: The title compound was prepared as illustrated by Example 141. Purification (RP-HPLC, CH3CN/H2O/0.1% formic acid) afforded the product (60 mg, 40%) as a yellow solid. 1H NMR (400 MHz, MeOD) δ ppm 1.57 (d, /=7.1 Hz, 3 H) 5.20 - 5.42 (m, /=6.6 Hz, 1 H) 7.18 - 7.59 (m, 6 H) 8.13 - 8.43 (m, /=5.1 Hz, 4 H); HPLC purity (Method 1: 99%, Method 2: 99%); HRMS: calcd for C17Hi4ClN3O2 + H+, 328.08473; found (ESI-FTMS, [M+H]1+), 328.0846. Example 173
N-[3-(l-{[3,4-dioxo-2-(pyridin-4-ylamino)cyclobut-1-en-1-yl]amino}ethyl)phenyl] methanesulfonamide
Step 1: To a solution of 3-aminoacetophenone (1.0 g, 7.4 mmoles) and Et3N (1.2 mL, 8.9 mmoloes, 1.2 eq) in CH2CI2 (20 mL) was added methanesulfonyl chloride (0.7 mL, 8.9 mmoles, 1.2 eq) at 0 °C. The mixture was stirred for 2.5 hours. Purification by chromatography (silica, 30-50% EtOAc/hexanes) afforded N-(3-acetylphenyl)methanesulfonamide (0.93 g, 59%) as a colorless oil.
Step 2: The oxime was prepared according to Step 1 of Example 146, but using N-[3-(l- amino-ethyl)-phenyl]-methanesulfonamide as the starting material.
Step 3: The amine intermediate was prepared according to Step 2 of Example 146.
Step 4: The title compound was prepared as illustrated by Example 141. Purification (RP-HPLC, CH3CN/H2O/0.1% formic acid) afforded the product (63 mg, 35%) as a yellow solid. 1H NMR (400 MHz, MeOD) δ ppm 1.67 (d, 3 H) 2.94 - 3.05 (m, 3 H) 5.30 - 5.52 (m, 1 H) 7.14 - 7.32 (m, 3 H) 7.32 - 7.44 (m, 2 H) 7.70 (s, 2 H) 8.25 (s, 2 H) 8.40 (d, /=6.1Hz, 2 H); HPLC purity (Method 1: 100%, Method 2: 100%); HRMS: calcd for C18Hi8N4O4S + H+, 387.11215; found (ESI-FTMS, [M+H]1+), 387.1124. Example 174 methyl 3-(l-{[3,4-dioxo-2-(pyridin-4-ylamino)cycIobut-1-en-1-yl]amino}ethyl)benzoate
Step 1: The mixture of 3-acetylbenzoic acid (1.0 g, 6.1 mmoles), MeOH (100 mL) and cone. H2SO4 (1 mL) was refluxed overnight. MeOH was evaporated in vacuo. Working up (EtO Ac/saturated NaHCO3 and H2O) afforded methyl 3-acetylbenzoate as a brown solid in 100% yield.
Step 2: The oxime was prepared according to Step 1 of Example 146, but using 3-(l- amino-ethyl)-benzoic acid methyl ester as the starting material.
Step 3: The amine intermediate was prepared according to Step 2 of Example 146.
Step 4: The title compound was prepared as illustrated by Example 141. Purification (RP-HPLC, CH3CN/H2O/0.1% formic acid) afforded the product (230 mg, 90%) as a yellow solid. 1H NMR (400 MHz, MeOD) δ ppm 1.69 (d, 3 H) 3.90 - 3.92 (m, 3 H) 5.40 - 5.60 (m, /=6.6 Hz, 1 H) 7.53 (t, /=7.7 Hz, 1 H) 7.70 (d, /=7.8 Hz, 3 H) 7.98 (d, /=7.8 Hz, 1 H) 8.12 (s, 1 H) 8.25 (s, 1 H) 8.40 (d, /=6.6 Hz, 2 H); HPLC purity (Method 1: 100%, Method 2: 99%); HRMS: calcd for C19H17N3O4 + H+, 352.12918; found (ESI-FTMS, [M+H]1+), 352.1296. Example 175 TV-IS-fl-fP^-dioso-1-tpyridin-^ylaπiiiioJcyclobut-1-en-1-yllaminoJethyOphenylJacetamide Step 1: The oxime was prepared according to Step 1 of Example 146, but using N-[3-(l- amino-ethyl)-phenyl]-acetamide as the starting material.
Step 2: The amine intermediate was prepared according to Step 2 of Example 146. Step 3: The title compound was prepared as illustrated by Example 141. Purification (RP-HPLC, CH3CN/H2O/0.1% formic acid) afforded the product (19 mg, 12%) as a yellow solid. 1H NMR (400 MHz, acetic acid-d4) δ ppm 1.71 (d, /=6.8 Hz, 3 H) 2.20 - 2.30 (m, 3 H) 5.39 - 5.56 (m, 1 H) 7.18 - 7.30 (m, 1 H) 7.37 (t, /=7.9 Hz, 1 H) 7.54 - 7.72 (m, /=22.2 Hz, 2 H) 8.11 (s, 2 H) 8.52 (d, /=7.3 Hz, 2 H); HPLC purity (Method 1: 100%, Method 2: 99%); HRMS: calcd for C19Hi8N4O3 + H+, 351.14517; found (ESI-FTMS, [M+H]1+), 351.1453. Example 176
3-(l-{[3,4-dioxo-2-(pyridin-4-ylamino)cyclobut-1-eii-1-yl]ainino}ethyl)benzoic acid
Methyl 3-( 1 - { [3 ,4-dioxo-2-(pyridin-4-ylamino)cyclobut- 1 -en- 1 -yl] amino } ethyl)benzoate (190 mg) was hydrolyzed with 1 NNaOH (1 mL) in MeOH (10 mL) at 60 °C overnight to afford the title compound as a yellow solid. 1H NMR (400 MHz, MeOD) δ ppm 1.87 - 1.96 (m, 3 H) 5.60 - 5.78 (m, 1 H) 7.60 - 7.90 (m, 4 H) 8.18 (d, /=7.3 Hz, 1 H) 8.32 (s, 1 H) 8.51 - 8.67 (m, 4 H); HPLC purity (Method 1: 97%, Method 2: 97%); HRMS: calcd for C18H15N3O4 + H+, 338.11353; found (ESI-FTMS, [M+H]1+), 338.1143. Example 177
3-{[l-(3-bromophenyl)ethyl]amino}-4-(pyridin-4-yIainino)cyclobut-3-ene-1,2-dione Step 1 : The oxime was prepared according to Step 1 of Example 146, but using l-(3- bromo-phenyl)-ethylamine as the starting material.
Step 2: The amine intermediate was prepared according to Step 2 of Example 146. Step 3: The title compound was prepared as illustrated by Example 141. Purification (RP-HPLC, CH3CN/H2O/0.1% formic acid) afforded the product (39 mg, 9%) as a yellow solid.'H NMR (400 MHz, DMSO-<fd) δ ppm 1.59 (d, /=6.8 Hz, 3 H) 5.20 - 5.41 (m, 1 H) 7.26 - 7.58 (m, 5 H) 7.64 (s, 1 H) 8.24 (s, 1 H) 8.40 (d, /=5.3 Hz, 2 H) 8.89 (s, 1 H); HPLC purity (Method 1: 98%, Method 2: 99%); HRMS: calcd for CnH14BrN3O2 + H+, 372.03421; found (ESI-FTMS, [M+H]1+), 372.0337. Example 178
3-(pyridin-4-ylamino)-4-({l-[3-(2/?-tetrazol-5-yl)phenyl]ethyl}amino)cyclobut-3-ene-1,2- dione
Step 1: The mixture of 3-acetylbenzonitrile (2.0 g, 13.7 mmoles), dibutyltin oxide (341 mg, 1.4 mmoles, 0.1 eq), toluene (50 tnL) and azidotrimethylsilane (3.6 mL, 27.4 mmoles, 2.0 eq) was refluxed overnight. The filtrate was concentrated and solidified from EtOAc to give 1- (3-(2H-tetrazol-5-yl)phenyl)ethanone (0.8 g, 30%) as a yellow solid. Step 2: The oxime was prepared according to Step 1 of Example 146, but using .1-[3-(2H- tetrazol-5-yl)-phenyl]-ethylamine as the starting material.
Step 3: The amine intermediate was prepared according to Step 2 of Example 146, except that the reaction took 10 days.
Step 4: The title compound was prepared as illustrated by Example 141. Purification (RP-HPLC, CH3CN/H2O/0.1 % formic acid) afforded the product (7.5 mg, 5%) as a yellow solid. 1H NMR (400 MHz,
Figure imgf000098_0001
δ ppm 1.62 (d, /=6.8 Hz, 3 H) 5.24 - 5.45 (m, 1 H) 7.22 - 7.44 (m, 2 H) 7.50 (s, 2 H) 7.81 - 7.95 (m, 1 H) 8.04 (s, 1 H) 8.28 (s, 2 H) 8.39 (s, 2 H) 9.16 (s, 1 H); HPLC purity (Method 1: 93%, Method 2: 93%); HRMS: calcd for C18H15N7O2 + H+, 362.13600; found (ESI-FTMS, [M+H]14), 362.1359. Example 179
S-fl-JIS^-dioxo-1-φyridm^-ylaminoJcyclobnt-1-en-1-yllaminoJethylJbenzamide
Step 1: To a mixture of 3-acetylbenzonitrile (1.0 g, 6.9 mmoles), NaOH (69 mg, 1.7 mmoles, 0.25 eq), EtOH (10 mL) and water (3.4 mL) was added dropwise hydrogen peroxide (30%, 2.8 mL, 24.8 mmoles, 3.6 eq). The mixture was stirred for 1 hour at 5O°C and neutralized with diluted H2SO4. The solvents were removed. Working up (CH2Cl2/small amount of water) afforded 3-acetylbenzamide (0.7 g, 63%) as a white solid.
Step 2: The oxime was prepared according to Step 1 of Example 146, but using 3-(l- ammo-ethyl)-benzarmde as the starting material.
Step 3: The amine intermediate was prepared according to Step 2 of Example 146. Step 4: The title compound was prepared as illustrated by Example 141. Purification
(RP-HPLC, CH3CN/H2O/0.1% formic acid) afforded the product (61 mg, 39%) as an off-white solid. 1H NMR (400 MHz, OMSO-d6) 6 ppm 1.61 (d, J=6.9Hz, 3 H) 5.24 - 5.46 (m, J=I.3 Hz, 1 H) 7.39 - 7.51 (m, 3 H) 7.57 (d, ./=7.6 Hz, 2 H) 7.81 (d, J=7.6 Hz, 1 H) 7.93 (s, 1 H) 8.04 (s, 1 H) 8.18 (s, 1 H) 8.41 (d, ./=6.1 Hz, 2 H) 8.55 (s, 1 H); HPLC purity (Method 1: 96%, Method 2: 100%); HRMS: calcd for C18Hi6N4O3 + H+, 337.12952; found (ESI-FTMS, [M+H]1+), 337.1294. Example 180
3-{[l-(5-hydroxy-2-methoxyphenyl)ethyl]amino}-4-(pyridin-4-ylainino)cyclobut-3-ene-1,2- dione
Step 1 : The oxime was prepared according to Step 1 of Example 146, but using 4-(l- Amino-ethyl)-3-methoxy-phenol as the starting material.
Step 2: The amine intermediate was prepared according to Step 2 of Example 146.
Step 3: The title compound was prepared as illustrated by Example 141. Purification (RP-HPLC, CH3CN/H2O/0.1% formic acid) afforded the product (110 mg, 68%) as a yellow solid. 1H NMR (400 MHz, DMS0-rf«) δ ppm 1.50 (d, /=6.8 Hz, 3 H) 3.68 - 3.79 (m, 3 H) 5.33 - 5.57 (m, 1 H) 6.66 (dd, /=8.7, 2.9 Hz, 1 H) 6.76 (d, J=2.8 Hz, 1 H) 6.86 (d, J=8.8 Hz, 1 H) 7.47 (d, J=5.8 Hz, 2 H) 8.21 (s, 1 H) 8.40 (d, J=6.1 Hz, 2 H) 8.46 (d, J=8.3 Hz, 1 H); HPLC purity (Method 1: 99%, Method 2: 100%); HRMS: calcd for C18H17N3O4 + H+, 340.12918; found (ESI- FTMS, [M+H]1+), 340.1295. Example 181 3-{[l-(3-hydroxy-4-methoxyphenyl)ethyl]amino}-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2- dione
Step 1: The mixture of 3,4-dihydroxyacetophenone (406 mg, 2.7 mmoles), lithium carbonate (493 mg, 6.7 mmoles, 2.5 eq), iodomethane (0.4 mL, 6.7 mmoles, 2.5 eq) and DMF (7 mL) was heated at 55 °C for 1 day. Purification by chromatography (silica, 20-40% EtOAc/hexanes) afforded l-(3-hydroxy-4-methoxyphenyl)ethanone (0.2 g, 45%) as a white solid.
Step 2: The oxime was prepared according to Step 1 of Example 146, but using 5-(l- amino-ethyl)-2-methoxy-phenol as the starting material.
Step 3: The amine intermediate was prepared according to Step 2 of Example 146. Step 4: The title compound was prepared as illustrated by Example 141. Purification
(RP-HPLC, CH3CN/H2O/0.1% formic acid) afforded the product (83 mg, 54%) as a lightly yellow solid. 1H NMR (400 MHz, DMSO-tf«,)'δ ppm 1.54 (d, /=6.8 Hz, 3 H) 3.70 - 3.80 (m, 4
H) 5.00 - 5.28 (m, 1 H) 6.76 - 6.87 (m, 2 H) 6.92 (d, /=8.1 Hz, 1 H) 7.47 (d, /=5.1 Hz, 2 H) 8.19
(s, 1 H) 8.40 (d, /=5.6 Hz, 2 H) 8.62 (d, /=8.1 Hz, 1 H) HPLC purity (Method 1: 100%, Method
2: 100%); HRMS: calcd for C18HnN3O4 + H+, 340.12918; found (ESI-FTMS, [M+H]1+), 340.1287.
Example 182
3-{[l-(2,5-dihydroxyphenyl)ethyI]amino}-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2-dione Step 1 : The oxime was prepared according to Step 1 of Example 146, but using 2-(l - amino-ethyl)-benzene-1,4-diol as the starting material. Step 2: The amine intermediate was prepared according to Step 2 of Example 146.
Step 3: The title compound was prepared as illustrated by Example 141. Purification
(RP-HPLC, CH3CN/H2O/0.1% formic acid) afforded the product (18 mg, 11%) as a lightly yellow solid. 1H NMR (400 MHz, MeOD) δ ppm 1.68 (d, /=6.8 Hz, 3 H) 5.43 - 5.61 (m, /=6.6
Hz, 1 H) 6.51 - 6.79 (m, 3 H) 7.61 - 7.76 (m, 2 H) 8.16 - 8.46 (m, /=56.3 Hz, 6 H); HPLC purity (Method 1: 97%, Method 2: 99%); HRMS: calcd for C17H15N3O4 + H+, 326.11353; found (ESI-
FTMS, [M+H]1+), 326.1133.
Example 183
3-{[l-(3,5-dihydroxyphenyl)ethyl]ammo}-4-(pyridin-4-ylamino)cycIobut-3-ene-1,2-dione
Step 1: The oxime was prepared according to Step 1 of Example 146, but using 5-(l- amino-ethyl)-benzene-1,3-diol as the starting material.
Step 2: The amine intermediate was prepared according to Step 2 of Example 146. Step 3: The title compound was prepared as illustrated by Example 141. Purification
(RP-HPLC, CH3CN/H2O/0.1% formic acid) afforded the product (96 mg, 64%) as a lightly yellow solid. 1H NMR (400 MHz, MeOD) δ ppm 1.63 (d, /=7.1 Hz, 3 H) 5.16 - 5.37 (m, 1 H) 6.22 (s, 1 H) 6.36 (d, /=1.8 Hz, 2 H) 7.56 - 7.81 (m, 2 H) 8.11 - 8.26 (m, 3 H) 8.41 (d, /=5.3 Hz,
2 H); HPLC purity (Method 1: 100%, Method 2: 100%); HRMS: calcd for CnHi5N3O4 + H+,
326.11353; found (ESI-FTMS, [M+H]1+), 326.1134.
Example 184
3-{[l-(3-hydroxy-5-methoxyphenyl)ethyl]amino}-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2- dione Step 1: l-(3-hydroxy-5-methoxyphenyi)ethanone was prepared according to Step 1 of Example 181.
Step 2: The oxime was prepared according to Step 1 of Example 146, but using 3-(l- amino-ethyl)-5-methoxy-phenol as the starting material. Step 3: The amine intermediate was prepared according to Step 2 of Example 146.
Step 4: The title compound was prepared as illustrated by Example 141. Purification (RP-HPLC, CH3CN/H2O/0.1% formic acid) afforded the product (46 mg, 45%) as a lightly yellow solid. 1H NMR (400 MHz, MeOD) δ ppm 1.64 (d, /=6.9 Hz, 3 H) 3.77 (s, 3 H) 5.16 - 5.48 (m, /=1.0 Hz, 1 H) 6.32 (s, 1 H) 6.47 (d, /=10.9 Hz, 2 H) 7.69 (s, 2 H) 8.23 (s, 2 H) 8.40 (d, /=5.8Hz, 2 H); HPLC purity (Method 1: 100%, Method 2: 100%); HRMS: calcd for C18Hi7N3O4
+ H+, 340.12918; found (ESI-FTMS, [M+H]1+), 340.1289. Example 185
N-^-(l-fP^-dioxo-Σ-fpyridin-^ylamino^ycIobut-1-eii-1-ylJaininoJethylJphenylJ-TV- methylurca Step 1: The mixture of 3-aminoacetophenone (1.0 g, 7.4 mmoles), Hunig's base (1.5 mL,
8.9 mmoles, 1.2 eq) and methyl isocyanate (0.5 g, 8.8 mmoles, 1.2 eq) in CH2CI2 (10 mL) was stirred for 3 hours. The precipitated solid was filtered, washed with CH2CI2 and ether to give 1- (3-acetylphenyl)-3-methylurea (365 mg, 26%) as a white solid.
Step 2: The oxime was prepared according to Step 1 of Example 146, but using l-[3-(l- amino-ethyl)-phenyl]-3-methyl-urea as the starting material.
Step 3: The amine intermediate was prepared according to Step 2 of Example 146. Step 4: The title compound was prepared as illustrated by Example 141. Purification (RP-HPLC, CH3CNZH2O with 10 mM NH4OAc) afforded the product (27 mg, 16%) as a pale yellow solid. 1H NMR (400 MHz, DMSO-<4) δ ppm 1.56 (d, /=6.8 Hz, 3 H) 1.85 (s, 2 H) 2.63 (d, /=4.6 Hz, 3 H) 5.12 - 5.37 (m, /=6.8 Hz, 1 H) 6.03 (s, 1 H) 6.86 - 7.02 (m, 1 H) 7.22 (t, /=7.9 Hz, 1 H) 7.30 - 7.46 (m, 2 H) 7.46 - 7.57 (m, 2 H) 8.38 (d, /=5.8 Hz, 2 H) 8.59 (s, 1 H); HPLC purity (Method 1: 100%, Method 2: 97%); HRMS: calcd for C19Hi9N5O3 + H+, 366.15607; found (ESI-FTMS, [M+H]1+), 366.1562. Example 186 3-{[l-(3-amino-4-methylphenyl)ethyl]amino}-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2- dione Step 1 : 4-methyl-3-nitroacetophenone (5.0 g, 27.9 mmoles) was taken up in EtOH (200 mL). Ti (H) chloride (15.9 g, 83.7 mmoles, 3 eq) was added. The mixture was refluxed for 1 hour and cooled to room temperature. Saturated NaHCO3 was added to bring pH up to 7-8. The precipitated solid was discarded and the filtrate was concentrated. Working up (EtOAcZH2O) afforded l-(3-amino-4-methylphenyl)ethanone as a yellow solid in 100% yield.
Step 2: The oxime was prepared according to Step 1 of Example 146, but using 5-(l- amino-ethyl)-2-methyl-phenylamine as the starting material.
Step 3: The amine intermediate was prepared according to Step 2 of Example 146.
Step 4: The title compound was prepared as illustrated by Example 141. Purification (RP-HPLC, CH3CN/H2O with 10 mM NH4OAc) afforded the product (3.5 mg, 2%) as a yellow solid. 1H NMR (400 MHz, MeOD) δ ppm 1.96 (d, 3 H) 2.16 (s, 3 H) 5.15 - 5.41 (m, 1 H) 6.70 (dd, /=7.8, 1.8 Hz, 1 H) 6.79 (d, /=1.8 Hz, 1 H) 7.03 (d, J=I.6 Hz, 1 H) 7.57 (s, 2 H) 8.36 (s, 2 H); HPLC purity (Method 1: 93%, Method 2: 93%); HRMS: calcd for C18H18N4O2 + H+, 323.15025; found (ESI-FTMS, [M+H]1+), 323.1502. Example 187
3-{[l-(4-methyI-3-nitrophenyl)ethyl]amino}-4-(pyridin-4-ylamino)cycIobut-3-ene-1,2-dione
Step 1 : The oxime was prepared according to Step 1 of Example 146, but using l-(4- methyl-3-m'tro-phenyl)-ethylamine as the starting material.
Step 2: The amine intermediate was prepared according to Step 2 of Example 146. Step 3: The title compound was prepared as illustrated by Example 141. Purification
(RP-HPLC, CH3CN/H2O with 10 mM NH4OAc) afforded the product (97.8 mg, 60%) as a pale yellow solid. 1H NMR (400 MHz, DMSO-<4) δ ppm 1.62 (d, J=6Λ Hz, 3 H) 2.50 (s, 3 H) 5.19 - 5.47 (m, 1 H) 7.41 (s, 2 H) 7.46 - 7.58 (m, 1 H) 7.62 - 7.78 (m, 1 H) 8.02 (s, 1 H) 8.15 - 8.60 (m, 3 H) 9.86 (s, 1 H); HPLC purity (Method 1: 100%, Method 2: 100%); HRMS: calcd for C18Hi6N4O4 + H+, 353.12443; found (ESI-FTMS, [M+H]1+), 353.1247. Example 188
3-{[l-(3-hydroxy-4-methylphenyl)ethyl]amino}-4-(pyridin-4-yIamino)cyclobut-3-ene-1,2- dione
Step 1 : Diazotisation of l-(3-amino-4-methylphenyi)ethanone (0.5 g, 3.4 mmoles) with NaNO2 (254 mg in 0.5 mL H2O, 3.7 mmoles, 1.1 eq) and c. H2SO4ZH2O (0.74 mL/1 mL) at 0 °C followed by hydrolysis with 50% H2SO4, boiling for 5 min. Neutralization, working up (EtOAc/H2O) and purification (silica, 10-30% EtOAc/hexane) afforded l-(3-hydroxy-4- methylphenyl)ethanone (205 mg, 41%) as a yellow solid.
Step 2: The oxime was prepared according to Step 1 of Example 146, but using 5-(l- amino-ethyl)-2-methyl-phenol as the starting material. Step 3: The amine intermediate was prepared according to Step 2 of Example 146.
Step 4: The title compound was prepared as illustrated by Example 141. Purification (RP-HPLC, CH3CNZH2O with 10 mM NH4OAc) afforded the product (90 mg, 61%) as an off- white solid. 1H NMR (400 MHz, MeOD) δ ppm 1.65 (d, /=6.6 Hz, 3 H) 2.18 (s, 3 H) 5.16 - 5.42 (m, 1 H) 6.73 - 6.90 (m, 2 H) 7.10 (d, ./=7.6 Hz, 1 H) 7.60 - 7.77 (m, 2 H) 8.05 - 8.30 (m, 2 H) 8.34 - 8.49 (m, 2 H); HPLC purity (Method 1 : 100%, Method 2: 100%); HRMS: calcd for C18HnN3O3 + H+, 324.13427; found (ESI-FTMS, [M+H]1+), 324.1343. Example 189
3-({2-[(E)-2-(4-chlorophenyl)vinyl]pyridin-4-yl}amino)-4-{[(1R)-1- phenylethy]]amino}cyclobut-3-ene-1,2-dione To a reaction vessel was added 3-[(2-chloropyridin-4-yl)amino]-4-{[(1R)-1- phenylethyl]amino}cyclobut-3-ene-1,2-dione (0.09 g, 0.27 mmol), Pd(dppf)Cl2:CH2Cl2 (0.022 g, 0.01 eq), cesium carbonate (0.27g, 2 eq) and trans-2-(4-chloropheny)vinyl boronic acid (0.075 g, 1.5 eq). The vessel as evacuated and purged with nitrogen 3x. DMF (degassed, 0.6 mL) is then added. The reaction as stirred at 100 °C overnight, filtered and taken up in THF. The solution was then adsorbed onto silica. Chromatography (silica, 25% THF/CH2C12) afforded the title compound (0.06g, 51%) as a pale yellow solid. 1H NMR (400 MHz, DMSO-J6) δ ppm 1.62 (d, ./=6.8 Hz, 3 H), 5.26 - 5.37 (m, 1 H), 7.26 (d, /=15.9 Hz, 1 H), 7.30 - 7.49 (m, 9 H), 7.63 (d, /=16.2 Hz, 1 H), 7.70 (d, /=8.6 Hz, 1 H), 8.25 (d, /=9.9 Hz, 1 H), 8.42 (d, /=5.6 Hz, 1 H), 9.90 (s, 1 H); ); HPLC purity (Method 1: 100%, Method 2: 97%); HRMS: calcd for C25H20ClN3O2 + H+, 430.13168; found (ESI-FTMS, [M+H]l+), 430.1329. Example 190
3-{[2-(3-methoxyphenyl)pyridin-4-yl]amino}-4-{[(1R)-1-phenylethyl]amino}cycIobut-3-ene- 1,2-dione
The title compound was prepared as outlined by Example 189, but using 3- methoxyphenylboronic acid as the boronic acid, to afford 0.39 g, 36% as a yellow solid. 1H
NMR (400 MHz, DMSO-^6) δ ppm 1.62 (d, /=6.6 Hz, 4 H), 3.83 (s, 3 H), 5.25 - 5.39 (m, 1 H), 7.02 (d, /=8.1 Hz, 1 H), 7.24 (d, /=5.1 Hz, 1 H), 7.28 - 7.69 (m, 8 H), 8.17 (s, 1 H), 8.30 (d, /=9.3 Hz, 1 H), 8.50 (d, /=5.3 Hz, 2 H), 9.99 (s, 1 H); ); HPLC purity (Method 1: 99%, Method 2: 98%); HRMS: calcd for C24H21N3O3 + H+, 400.16557; found (ESI-FTMS, [M+H]l+), 400.1661. Example 191
3-[(2-anilinopyridin-4-yI)amino]-4-{[(1R)-1-phenylethyl]ainino}cycIobut-3-ene-1,2-dione
To a reaction vessel was added of 3-[(2-chloropvridin-4-yl)amino]-4-{[(1R)-1- phenylethyl]amino}cyclobut-3-ene-1,2-dione (O.lg, 0.3 mmol), Pd2(dba)3 (0.028 g, 0.031 mmol), XPHOS (0.044 g, 0.09 mmol), sodium tert-butoxide (0.06g, 0.63 mmol) and aniline (0.034 g, 0.36 mmol). The vessel was evacuated and purged with nitrogen 3x. Dioxane
(degassed, 1 mL) and DMF (degassed, 0.2 mL) was then added. The reaction was stirred at 100 °C overnight, filtered through a plug of silica and concentrated. Purification (RP-HPLC, CH3CN/H2O/0.1% formic acid) afforded the title compound (0.03g, 17%) as an off white solid. 1H NMR (400 MHz, DMSCW6) δ ppm 1.60 (d, /=6.8 Hz, 3 H), 5.25 - 5.36 (m, 1 H), 6.74 (s, 1 H), 6.88 (app t, /=7.3 Hz, 1 H), 7.00 (d, /=4.5 Hz, 1 H), 7.23 (d, /=8.3 Hz, 2 H), 7.25 - 7.27 (m, 1 H), 7.28 - 7.46 (m, 10 H), 7.62 (dd, /=8.6, 1.0 Hz, 2 H), 8.02 (d, /=5.6 Hz, 1 H), 8.27 (d, /=8.1 Hz, 1 H), 8.96 (s, 1 H), 9.78 (s, 1 H); HPLC purity (Method 1 : 97%, Method 2: 97%); HRMS: calcd for C23H20N4O2 + H+, 385.16590; found (ESI-FTMS, [M+H]l+), 385.1664. Example 192 3-{[(1R)-1-phenyIethyl]amino}-4-[(2-{[4-(trifluoromethyl)phenyl]amino}pyridiii-4- yl)amino]cyclobut-3-ene-1,2-dione
The title compound was prepared as illustrated by Example 191, but using 4- (trifluoromethyl)aniline, to afford 0.04 g, 29% as an off white powder. 1H NMR (400 MHz, DMSO-J6) δ ppm 1.61 (d, /=7.1 Hz, 3 H), 5.26 - 5.36 (m, 1 H), 6.87 (s, 1 H), 7.06 (d, /=6.1 Hz, 1 H), 7.28 - 7.46 (m, 6 H), 7.57 (d, /=8.6 Hz, 2 H), 7.88 (d, /=8.3 Hz, 2 H), 8.09 (d, /=5.6 Hz, 1 H), 8.45 (d, /=6.8 Hz, 1 H), 9.47 (s, 1 H), 10.00 (s, 1 H)HPLC purity (Method 1 : 99%, Method 2: 99%); HRMS: calcd for C24Hi9F3N4O2 + H+, 453.15329; found (ESI-FTMS, [M+H]l+), 453.1535. Example 193 3-{[(1R)-1-phenylethyl]amino}-4-{[2-(pyrimidin-4-ylaimno)pyridin-4-yl]amino}cyc]obut-3- ene-1,2-dione The title compound was prepared as illustrated by Example 191, but using pyrimidin-4- amine, to afford 0.004 g, 3% as an off white powder. 1H NMR (400 MHz, DMSCW6) δ ppm 1.60 (d, /=7.1 Hz, 3 H), 5.26 - 5.37 (m, 1 H), 7.28 - 7.35 (m, 1 H), 7.37 - 7.46 (m, 4 H), 7.52 (d, ./=4.0 Hz, 1 H), 7.58 - 7.65 (m, 2 H), 8.17 (d, /=5.6 Hz, 1 H), 8.40 (d, /=6.1 Hz, 1 H), 8.65 (d, /=6.6 Hz, 1 H), 8.70 (d, /=1.0 Hz, 1 H), 10.23 (s, 1 H), 10.32 (s, 1 H); HPLC purity (Method 1: 99%, Method 2: 99%); HRMS: calcd for C2IHi8N6O2 + H+, 387.15640; found (ESI-FTMS, [M+H]l+), 387.1561. Example 194 3-[(2-{[3-(hydroxymethyl)phenyl]amino}pyridin-4-yI)amino]-4-{[(1R)-1- phenylethyl]amino}cyclobut-3-ene-1,2-dione
The title compound was prepared as illustrated by Example 191, but using 3- (hydroxymethyl)aniline, to afford 0.003 g, 3% as an off white powder. 1H NMR (400 MHz, DMSO-4) δ ppm 1.60 (d, /=7.1 Hz, 3 H), 4.46 (d, /=2.3 Hz, 2 H), 5.12 (s, 1 H), 5.26 - 5.36 (m, 1 H), 6.75 (s, 1 H), 6.83 (d, /=7.6 Hz, 1 H), 7.03 (d, /=5.1 Hz, 1 H), 7.18 (dd, /=8.8, 7.6 Hz, 1 H), 7.28 - 7.34 (m, 1 H), 7.37 - 7.46 (m, 4 H), 7.51 - 7.57 (m, 2 H), 8.02 (d, /=5.8 Hz, 1 H), 8.54 (d, /=7.6 Hz, 1 H), 8.95 (s, 1 H), 10.03 (s, 1 H); HPLC purity (Method 1: 100%, Method 2: 100%); HRMS: calcd for C24H22N4O3 + H+, 415.17647; found (ESI-FTMS, [M+H]l+), 415.1766. Example 195 3-({4-[(3,4-dioxo-2-{[(1R)-1-phenylethy]]amino}cyclobut-1-en-1-yl)amino]pyridin-2- y]}amino)benzamide
The title compound was prepared as illustrated by Example 191, but using 3- aminobenzamide, to afford 0.025 g, 19% as an off white powder. 1H NMR (400 MHz, DMSO- ck) δ ppm 1.60 (d, /=7.1 Hz, 3 H), 5.26 - 5.35 (m, 1 H), 6.74 (d, /=1.3 Hz, 1 H), 7.05 (d, /=5.6 Hz, 1 H), 7.25 - 7.46 (m, 9 H), 7.84 - 7.90 (m, 2 H), 7.99 - 8.02 (m, 1 H), 8.04 (d, /=5.8 Hz, 1 H), 8.37 (d, /=10.6 Hz, 1 H), 9.13 (s, 1 H), 9.89 (s, 1 H); HPLC purity (Method 1: 100%, Method 2: 100%); HRMS: calcd for C24HuN5O3 + H+, 428.17172; found (ESI-FTMS, [M+H]l+), 428.1723. Example 196 S-JKl^-1-phenylethyllaminoJ^-iP-Opyridin-1-ylaminoJpyridin-4-yllaminoϊcyclobut-S- ene-1,2-dione The title compound was prepared as illustrated by Example 191, but using 2- aminopyridine, to afford 0.02 g, 17% as an off white powder. 1H NMR (400 MHz, DMSO-4) δ ppm 1.60 (d, /=6.8 Hz, 3 H), 5.25 - 5.35 (m, 1 H), 6.86 (ddd, /=4.8, 2.3, 1.0 Hz, 1 H), 7.27 - 7.48 (m, 5 H), 7.54 (d, /=8.3 Hz, 1 H), 7.62 (d, /=1.8 Hz, 1 H), 7.63 - 7.65 (m, 1 H), 7.66 (d, /=2.0 Hz, 1 H), 8.10 (d, /=5.8 Hz, 1 H), 8.15 (s, 1 H), 8.21 (ddd, /=5.1, 2.0, 0.8 Hz, 1 H), 8.31 (d, /=8.3 Hz, 1 H), 9.69 (s, 1 H), 9.92 (s, 1 H); HPLC purity (Method 1: 99.6%, Method 2: 97%); HRMS: calcd for C22H19N5O2 + H+, 386.16115; found (ESI-FTMS, [M+H]l+), 386.1618. Example 197 S-fK1R^l-phenylethyllaminof^-fP-φyridin-S-ylaminoipyridin-4-yllaininoJcydobut-S- ene-1,2-dione
The title compound was prepared as illustrated by Example 191, but using 3- aminopyridine, to afford 0.032 g, 27% as an off white powder. 1H NMR (400 MHz, DMSCW6) δ ppm 1.61 (d, /=6.8 Hz, 3 H), 5.26 - 5.35 (m, 1 H), 6.82 (s, 1 H), 6.99 (d, /=4.5 Hz, 1 H), 7.26 (dd, /=8.3, 4.8 Hz, 1 H), 7.29 - 7.47 (m, 8 H), 8.05 (d, /=5.6 Hz, 1 H), 8.08 (dd, /=4.7, 1.4 Hz, 1 H), 8.18 (ddd, /=8.4, 2.5, 1.3 Hz, 1 H), 8.26 (d, /=8.3 Hz, 1 H), 8.77 (d, /=2.5 Hz, 1 H), 9.20 (s, 1 H), 9.81 (s, 1 H); HPLC purity (Method 1: 99%, Method 2: 99%); HRMS: calcd for C22Hi9N5O2 + H+, 386.16115; found (ESI-FTMS, [M+H]l+), 386.1618. Example 198 3-{[(1R)-1-phenylethyl]amino}-4-{[2-(pyrazin-2-ylamino)pyridin-4-yI]amino}cyclobut-3- ene-1,2-dione
The title compound was prepared as illustrated in Example 191, but using 2- aminopyrazine, to afford 0.022 g, 19% as an off white powder. 1H NMR (400 MHz, DMSO-^6) δ ppm 1.61 (d, /=6.8 Hz, 3 H), 5.25 - 5.35 (m, 1 H), 7.29 - 7.50 (m, 6 H), 7.61 (d, /=2.0 Hz, 1 H), 8.07 (d, /=2.8 Hz, 1 H), 8.16 (d, /=5.8 Hz, 1 H), 8.21 (dd, /=2.8, 1.5 Hz, 1 H), 8.25 (d, /=8.3 Hz, 1 H), 8.89 (d, /=1.3 Hz, 1 H), 9.91 (s, 1 H), 10.09 (s, 1 H); HPLC purity (Method 1: 95%, Method 2: 95%); HRMS: calcd for C2iHi8N6O2 + H+, 387.15640; found (ESI-FTMS, [M+H]l+), 387.1564. Example 199 N-(4-(2-((R)-1-phenyIethylamino)-3,4-dioxocyclobut-1-enylammo)pyridin-2-yl)acetamide A reaction vessel containing 3-[(2-chloroρyridm-4-yl)amino]-4-{[(1R)-1- phenylethyl]amino}cyclobut-3-ene-1,2-dione (0.1 g, 0.3 mmol), acetamide (0.08 g, 1.4 mmol), Pd2dba (0.04 g, 0.04 mmol), XPHOS (0.04 g, 0.08 mmol) and cesium carbonate (0.2 g, 0.62mmol) was purged with nitrogen. Dioxane:DMF (1.2 mL, 5:1, degassed) was then added. The reaction was stirred under microwave irradiation at 150 °C for 2h. The reaction mixture was filtered through a plug of silica (1% triethylamine/ 10%MeOH/ CH2CI2) and concentrated. Purfication by RP-HPLC (CH3CN/H2O) afforded the title compound as an off white solid (0.02 g, 19%). 1H NMR (400 MHz, DMSCW6) δ ppm 1.59 (d, /=6.8 Hz, 3 H), 5.21 - 5.34 (m, 1 H), 7.25 - 7.47 (m, 5 H), 7.64 (d, /=3.3 Hz, 1 H), 7.81 (s, 1 H), 8.17 (d, /=6.1 Hz, 1 H), 8.34 (s, 1 H), 10.13 (s, 1 H), 10.62 (s, 1 H); HPLC purity (Method 1: 97%, Method 2: 98%); HRMS: calcd for C19Hi8N4O3 + H+, 351.14517; found (ESI-FTMS, [M+H]l+), 351.1453. Example 200
N-{4-[(3,4-dioxo-2-{[(1R)-1-phenylethyl]amino}cydobut-1-en-1-yl)amino]pyridin-2- yl}benzamide
A reaction vessel containing 3-[(2-chloropyridin-4-yl)amino]-4-{[(1R)-1- phenylethyl]amino}cyclobut-3-ene-1,2-dione (O.lg, 0.3 mmol), benzamide (0.07 g, 0.6 mmol), Pd2dba (0.28 g, 0.03 mmol), XantPHOS (0.036 g, 0.06 mmol) and potassium carbonate (tribasic, fluka brand, 0.12 g, 0.57 mmol) was purged with nitrogen. Dioxane:DMF (1.2 mL, 5:1, degassed) was then added. The reaction was stirred under microwave irradiation at 150 °C for 2h. The reaction mixture was filtered through aplug of silica (1% triethylamine/ 10%MeOH/ CH2Cl2) and concentrated. Purfication by RP-HPLC (CH3CN/H2O) afforded the title compound as an off white solid (0.035 g, 28 %). 1H NMR (400 MHz, DMSO-^6) δ ppm 1.61 (d, /=6.8 Hz, 3 H), 5.26 - 5.35 (m, 1 H), 7.29 - 7.63 (m, 9 H), 7.67 (d, /=5.6 Hz, 1 H), 7.98 - 8.05 (m, 2 H), 8.25 (d, /=5.6 Hz, 1 H), 8.32 (d, /=8.3 Hz, 1 H), 10.15 (s, 1 H), 10.77 (s, 1 H)); HRMS: calcd for C24H20N4O3 + H+, 413.16082; found (ESI-FTMS, [M+H]l+), 413.1614. Example 201 N-{4-[(3,4-dioxo-2-{[(1R)-1-phenylethyl]ainino}cyclobut-1-eii-1-yl)aιnino]pyridin-2- yljnicolinamide
The title compound was prepared as illustrated by Example 200, but using nicotinamide, to afford 0.028 g, 22 % as an off white powder. 1H NMR (400 MHz, OMSO-d6) δ ppm 1.61 (d, /=6.82 Hz, 3 H) 5.28 - 5.34 (m, 1 H) 7.29 - 7.46 (m, 5 H) 7.54 (ddd, /=7.89, 4.86, 0.88 Hz, 1 H) 7.68 (d, /=4.29 Hz, 1 H) 8.03 (d, J=I .77 Hz, 1 H) 8.27 (d, /=5.56 Hz, 1 H) 8.33 (ddd, /=8.08, 2.02, 1.77 Hz, 1 H) 8.75 (dd, /=4.80, 1.52 Hz, 1 H) 9.12 (dd, /=2.27, 0.76 Hz, 1 H) 10.13 (s, 1 H) 11.08 (s, 1 H) HPLC purity (Method 1 : 100%, Method 2: 100%); HRMS: calcd for C23Hi9N5O3 + H+, 414.15607; found (ESI-FTMS, [M+H]l+), 414.1562. Example 202
2-(l-phenylethyl)-6-pyridin-4-yl-2,6-diazabicyclo[5.2.0]non-l(7)-ene-8,9-dione A reaction vessel containing 2-(l-phenylethyl)-6-pyridin-4-yl-2,6- diazabicyclo[5.2.0]non-l(7)-ene-8,9-dione (0.07g, 0.27 mmol), CuI (0.024g, 0.2 mmol), and potassium carbonate (tribasic, fluka brand, 0.23 g, 1.1 mmol) was purged with nitrogen. DMF (1 mL, degassed) and N-N'-dimethylethylenediamine (0.026 mL, 0.35 mmol) was added and the reaction was stirred at 105 CC for 3h. The reaction mixture was filtered (Celite®) and concentrated. Purification by RP-HPLC (CH3CN/H2O) afforded the title compound (0.033 g, 36%) as an off white solid. 1H NMR (400 MHz, DMSO-^6) δ ppm 1.67 (d, /=7.1 Hz, 3 H), 1.93 - 2.14 (m, 2 H), 2.94 - 3.03 (m, 1 H), 3.42 - 3.51 (m, 1 H), 3.84 - 3.90 (m, 2 H), 6.13 (q, /=7.0 Hz, 1 H), 7.23 (dd, /=4.8, 1.5 Hz, 2 H), 7.42 (d, /=1.5 Hz, 2 H), 7.43 - 7.46 (m, 3 H), 8.50 (d, /=5.3 Hz, 2 H); HPLC purity (Method 1 : 98%, Method 2: 99%). Example 203
3-{[(1R)-1-phenylethyl]amino}-4-[(2-phenylpyridin-4-yl)amino]cyclobut-3-ene-1,2-dione
To a reaction vessel was added (R)-3-ammo-4-(l-phenylethylamino)cyclobut-3-ene-1,2- dione (0.103, 0.48 mmol), 4-bromo-2-phenyl pyridine (0.112 g, 1.0 eq), K2HPO4 (0.171 g, 2.05 eq), CuI (0.094 g, 1.03 eq) andN,N-dimethylethane-1,2-diamine (0.16 mL, 0.132 mg, 1.5 eq). The vessel was evacuated and purged with nitrogen twice. DMF (degassed, 2 mL) was then added. The reaction was stirred at 110 °C for 6.5 hours, filtered through a Celite® plug and taken up in THF. The solution was then adsorbed onto silica. Chromatography (silica, 5% MeOH-95% CH2Cl2) afforded the title compound (0.046 g, 32%) as a pale orange powder solid. 1H NMR (400 MHz, DMSCW6) δ ppm 1.62 (d, /=7.07 Hz, 3 H) 5.08 - 5.47 (m, 1 H) 7.17 - 7.27 (m, 1 H) 7.28 - 7.58 (m, 8 H) 8.00 - 8.10 (m, 3 H) 8.20 - 8.35 (m, 1 H) 8.50 (d, /=5.56 Hz, 1 H) 9.94 (s, 1 H); HPLC purity (Method 1: 99%, Method 2: 99%); HRMS: calcd for C23Hi9N3O2 + H+, 370.15500; found (ESI-FTMS, [M+H]l+), 370.1562. Example 204 3-{[2-(3-fluorophenyl)pyridin-4-yI]amino}-4-{[(1R)-1-phenylethyl]aniiiio}cyclobut-3-ene- 1,2-dione To a reaction vessel was added 3-[(2-chloropyridin-4-yl)ammo]-4-{[(1R)-1- phenylethyl]amino}cyclobut-3-ene-1,2-dione (0.111, 0.34 mmol), 2-Benzofuranboronic acid (0.065 g, 1.2 eq), 0.7 mL 2M Cs2CO3 (2.05 eq) and Pd(dppf)Cl2:CH2Cl2 (0.033 g, 0.12 eq). The vessel was evacuated and purged with nitrogen twice. DMF (degassed, 4 mL) was then added. The reaction was stirred at 80 °C for 13 hours, filtered through a Celite® plug and concentrated to give a crude residue. This material was purified by RP-HPLC (CH3CN-H2O with 0.1% formic acid) to afford 0.012 g (18%) as a light orange solid. 1H NMR (400 MHz, DMSO-^6) δ ppm 1.62 (d, /=6.82 Hz, 3 H) 5.19 - 5.54 (m, 1 H) 7.21 - 7.36 (m, 3 H) 7.37 - 7.49 (m, 4 H) 7.50 - 7.60 (m, 1 H) 7.78 - 7.86 (m, 1 H) 7.89 (d, ,7=8.08 Hz, 1 H) 8.18 (s, 1 H) 8.30 (s, 1 H) 8.51 (d, /=5.56 Hz, 1 H) 10.01 (s, 1 H); HPLC purity (Method 1: 100%, Method 2: 100%); HRMS: calcd for C23Hi8FN3O2 + H+, 388.14558; found (ESI-FTMS, [M+H]l+), 388.1453. Example 205
3-{[2-(l-benzofuran-2-yl)pyridin-4-yl]amino}-4-{[(1R)-1-phenylethyl]amino}cyclobut-3- ene-1,2-dione The title compound was prepared as outlined Example 204, but using benzofuran-2- ylboronic acid, to afford 0.026 g, 13% as a light orange solid. 1H NMR (400 MHz, DMSO-^6) δ ppm 1.63 (d, /=6.82 Hz, 3 H) 5.11 - 5.43 (m, 1 H) 5.76 (s, 1 H) 7.27 - 7.48 (m, 7 H) 7.52 (s, 1 H) 7.58 - 7.69 (m, 1 H) 7.74 (d, /=7.07 Hz, 1 H) 7.99 (s, 1 H) 8.18 - 8.33 (m, 1 H) 8.51 (d, /=5.56 Hz, 1 H) 10.08 (s, 1 H); HPLC purity (Method 1 : 99%, Method 2: 98%); HRMS: calcd for C25H19N3O3 + H+, 410.14992; found (ESI-FTMS, [M+H]l+), 410.1502. Example 206
3-{[2-(3-fluorophenyl)pyridin-4-yI]amino}-4-{[(1R)-1-phenylethyl]amino}cyclobut-3-ene- 1,2-dione
The title compound was prepared as outlined for Example 204, but using 3-thiophene boronic acid, to afford 0.032 g (28%) as an off white solid. 1H NMR (400 MHz, DMSO-^6) δ ppm 1.62 (d, /=6.82 Hz, 3 H) 5.07 - 5.51 (m, 1 H) 7.13 - 7.50 (m, 6 H) 7.67 (d, /=2.02 Hz, 2 H) 7.90 - 8.14 (m, 2 H) 8.27 (d, /=8.34 Hz, 1 H) 8.42 (d, /=5.56 Hz, 1 H) 9.93 (s, 1 H); HPLC purity (Method 1: 99%, Method 2: 99%); HRMS: calcd for C23Hi8FN3O2 + H+, 388.14558; found (ESI-FTMS, [M+H]l+), 388.1453. Example 207
3-(2,3'-bipyridin-4-ylamino)-4-{[(1R)-1-phenylethyl]amino}cyclobut-3-ene-1,2-dione The title compound was prepared as outlined for Example 204, but using 3-pyridine boronic acid, to afford 0.026 g (13%) as a yellow solid. 1H NMR (400 MHz, DMSO-J6) δ ppm
1.62 (d, /=6.82 Hz, 3 H) 5.33 (s, 1 H) 7.06 - 7.71 (m, 7 H) 8.00 - 8.75 (m, 5 H) 9.22 (s, 1 H)
10.10 (s, 1 H); HPLC purity (Method 1: 99%, Method 2: 99%); HRMS: calcd for C22Hi8N4O2 + H+, 371.15025; found (ESI-FTMS, [M+H]l+), 371.1508.
Example 208
3-{[(1R)-1-phenylethyl]amino}-4-({2-[3-(trifluoromethyI)pheπyl]pyridin-4- yl}amino)cycIobut-3-ene-1,2-dione
The title compound was prepared as outlined for Example 204, but using 3- (trifluoromethyl)phenylboronic acid, to afford 0.020 g (10%) as a yellow solid. 1H NMR (400
MHz, DMSO-<4) δ ppm 1.62 (d, ./=6.82 Hz, 3 H) 5.15 - 5.47 (m, 1 H) 7.22 - 7.48 (m, 3 H) 7.52 -
7.66 (m, 4 H) 7.72 - 7.86 (m, 2 H) 8.15 - 8.45 (m, 3 H) 8.54 (d, J=5.56 Hz, 1 H) 10.02 (s, 1 H);
HPLC purity (Method 1.: 99%, Method 2: 97%); HRMS: calcd for C24Hi8F3N3O2 + H+,
438.14239; found (ESI-FTMS, [M+H]l+), 438.1435. Example 209
3-{[(1R)-1-pheπylethyl]amino}-4-({2-[4-(trifluoromethyl)phenyl]pyridin-4- yl}amino)cyclobut-3-ene-1,2-dione
The title compound was prepared as outlined for Example 204, but using 4-
(trifluoromethyl)phenylboronic acid, to afford 0.015 g (8%) as an off white solid. 1H NMR (400 MHz, DMSO-^6) δ ppm 1.62 (d, /=6.82 Hz, 3 H) 4.99 - 5.70 (m, 1 H) 7.17 - 7.50 (m, 6 H) 7.88
(d, J=8.34 Hz, 2 H) 8.09 - 8.31 (m, 3 H) 8.39 - 8.66 (m, 2 H) 10.22 (s, 1 H); HPLC purity
(Method 1: 98%, Method 2: 98%); HRMS: calcd for C24Hi8F3N3O2 + H+, 438.14239; found
(ESI-FTMS, [M+H]l+), 438.1433.
Example 210 3-{[(1R)-1-phenylethyl]amino}-4-{[2-(pyridin-4-ylamino)pyridin-4-yl]amino}cyclobut-3- ene-1,2-dione
To a reaction vessel was added 3-[(2-chloropyridin-4-yl)amino]-4-{[(1R)-1- phenylethyl]amino}cyclobut-3-ene-1,2-dione (0.106 g, 0.32 mmol), Pd2(dba)3 (0.030 g, 0.031 mmol), XPHOS (0.044 g, 0.09 mmol), sodium tert-butoxide (0.057g, 0.60 mmol) and 4- aminopyridine (0.034 g, 0.36 mmol). The vessel was evacuated and purged with nitrogen twice.
Dioxane (degassed, 2 mL) and DMF (degassed, 0.2 mL) was then added. The reaction was microwaved for total of 4,000 sec at 165 °C, filtered through a plug of silica and concentrated. Purification (RP-HPLC, CH3CN/H2O with 0.1% formic acid) afforded the title compound (0.031g, 25%) as an off white solid. HPLC purity (Method 1: 96%, Method 2: 96%); HRMS: calcd for C22H]9N5O2 + H+, 386.16115; found (ESI-FTMS, [M+H]l+), 386.1619. Example 211
3-({2-[(4-methyl-1,3-thiazol-2-yl)amino]pyridin-4-yl}amino)-4-{[(1R)-1- phenylethyl]amino}cyclobut-3-ene-1,2-dione
To a reaction vessel was added 3-[(2-chloropyridin-4-yi)amino]-4-{[(1R)-1- phenylethyl]amino}cyclobut-3-ene-1,2-dione (0.104 g, 0.32 mmol), Pd2(dba)3 (0.036g, 0.040 mmol), XANTPHOS (0.057 g, 0.10 mmol), sodium carbonate (0.047g, 0.45 mmol) and 4- methylthiazol-2-amine (0.045g, 0.40 mmol). The vessel was evacuated and purged with nitrogen twice. Dioxane (degassed, 2 mL) and DMF (degassed, 0.2 mL) was then added. The reaction was microwaved for total 4,000 sec at 150 °C, filtered through a plug of Celite® and concentrated. Purification (RP-HPLC, CH3CNZH2O with 0.1% formic acid) afforded 0.034 g (26%) as a dark yellow solid. 1H NMR (400 MHz, DMSO-^6) δ ppm 1.60 (d, /=6.82 Hz, 3 H) 2.25 (s, 3 H) 5.15 - 5.48 (m, 1 H) 6.59 (s, 1 H) 6.86 (s, 1 H) 7.23 - 7.54 (m, 7 H) 8.03 - 8.22 (m, 1 H) 8.56 (br. s., 1 H) 10.30 (br. s., 1 H); HPLC purity (Method 1: 96%, Method 2: 94%); HRMS: calcd for C2IH]9N5O2S + H+, 406.13322; found (ESI-FTMS, [M+H]l+), 406.1347. Example 212 3-{[(1R)-1-phenylethyl]ammo}-4-{[2-(quinolin-2-ylamino)pyridin-4-yl]ainino}cyclobut-3- ene-1,2-dione
To a reaction vessel was added 3-[(2-chloropyridin-4-yl)amino]-4-{[(1R)-1- phenylethyl]amino}cyclobut-3-ene-1,2-dione (0.107 g, 0.33 mmol), Pd2(dba)3 (0.037 g, 0.040 mmol), XANTPHOS (0.056 g, 0.10 mmol), sodium carbonate (0.047 g, 0.45 mmol) and 2- aminoquinoline (0.058 g, 0.40 mmol). The vessel was evacuated and purged with nitrogen twice. Dioxane (degassed, 2 ML) and DMF (degassed, 0.2 ML) was then added. The reaction was microwaved for total of 4,000 sec at 150 °C, filtered through a plug of Celite® and concentrated. Purification (RP-HPLC, CH3CNZH2O with 0.1% formic acid) afforded 0.034 g (26%) as an orange solid. 1H NMR (400 MHz, OMSO-df) δ ppm 1.61 (d, /=7.1 Hz, 3 H) 5.30 - 5.41 (m, 1 H) 7.28 - 7.55 (m, 9 H) 7.58 - 7.69 (m, 1 H) 7.77 (d, /=8.3 Hz, 1 H) 7.89 (d, /=8.3 Hz, 1 H) 8.09 - 8.17 (m, 2 H) 8.10 - 8.17 (m, 3 H) 8.20 (s, 1 H) 8.44 (d, /=1.8 Hz, 1 H) 8.71 (s, 1 H) 10.03 (s, 1 H) 10.34 (s, 1 H); HPLC purity (Method 1 : 98%, Method 2: 99%); HRMS: calcd for C26H2IN5O2 + H+, 436.17680; found (ESI-FTMS, [M+H]l+), 436.1768. Example 213
3-{[(1R)-1-phenylethyl]amino}-4-{[2-(pyrimidin-2-ylamino)pyridin-4-yl]ainiπo}cyc]obut-3- ene-1,2-dione
To a reaction vessel was added 3-[(2-chloropyridin-4-yl)amino]-4-{[(1R)-1- phenylethyl]amino}cyclobut-3-ene-1,2-dione (0.106 g, 0.33 mmol), Pd2(dba)3 (0.037 g, 0.040 mmol), XANTPHOS (0.059 g, 0.10 mmol), sodium carbonate (0.047 g, 0.45 mmol) and pyrimidin-2-amine (0.038 g, 0.40 mmol). The vessel was evacuated and purged with nitrogen twice. Dioxane (degassed, 2 rnL) and DMF (degassed, 0.2 niL) was then added. The reaction was microwaved for total 4,000 sec at 150 °C, filtered through a plug of Celite® and concentrated. Purification (RP-HPLC, CH3CWH2O with 0.1% formic acid) afforded 0.048 g ( 38%) as an orange solid.Η NMR (400 MHz, DMSO-(Z6) δ ppm 1.60 (d, /=6.8 Hz, 3 H) 5.02 - 5.66 (m, 1 H) 6.97 (t, /=4.8 Hz, 1 H) 7.22 - 7.62 (m, 6 H) 7.93 - 8.29 (m, 2 H) 8.37 (d, /=6.8 Hz, 1 H) 8.56 (d, /=4.8 Hz, 2 H) 9.82 (s, 1 H) 10.07 (s, 1 H); HPLC purity (Method 1 : 99%, Method 2: 99%); HRMS: calcd for C2]H18N6O2 + H+, 387.15640; found (ESI-FTMS, [M+H]l+), 387.1563. Example 214
3-{[2-(2-fluorophenyl)pyridin-4-yl]amino}-4-{[(1R)-1-phenylethyI]amino}cyclobut-3-ene- 1,2-dione To a reaction vessel was added 3-[(2-bromopyridin-4-yl)amino]-4- {[(1R)-1- phenylethyl]amino}cyclobut-3-ene-1,2-dione (0.74 g, 0.20 mmol), 2-fluoroboronic acid (0.036 g, 1.3eq), Na2CO3 (0.034 g, 2.05 eq) and Pd(PPh3) (0.024 g, 0.2eq). The vessel was evacuated and purged with nitrogen twice. A solvent mixture of DME/H2O/EtOH (7:3:2) (degassed, 4 rnL) was then added. The reaction was microwaved at 150 °C for 300 sec, filtered through Celite® plug and concentrated to give crude residue. This crude material was purified by RP-HPLC (CH3CN- H2O with 0.1% formic acid) to afford 0.036 g (18%) of title compound as a yellow solid. 1H NMR (400 MHz, DMSO-rftf) δ ppm 1.61 (d, /=7.07 Hz, 3 H) 5.23 - 5.40 (m, 1 H) 7.23 - 7.57 (m, 9 H) 7.78 (s, 1 H) 7.94 (t, /=7.71 Hz, 1 H) 8.27 (s, 1 H) 8.55 (d, /=5.56 Hz, 1 H) 10.01 (s, 1 H); HRMS: calcd for C23H18FN3O2 + H+, 388.14558; found (ESI-FTMS, [M+H]l+), 388.1458. Example 215
3-{[2-(2-furyl)pyridin-4-yl]amino}-4-{[(1R)-1-phenylethyl]amino}cyclobut-3-ene-1,2-dione The title compound was prepared as outlined for Example 214, but using furan-2- ylboronic acid, to afford 0.035 g (62%) as a dark yellow solid. 1H NMR (400 MHz, OMSO-d6) δ ppm 1.60 (d, /=6.8 Hz, 3 H) 5.11 - 5.66 (m, 1 H) 6.65 (s, J=LO Hz, 1 H) 7.04 (d, /=2.8 Hz, 1 H) 7.19 - 7.62 (m, 6 H) 7.85 (d, /=4.3 Hz, 2 H) 8.39 (d, /=5.6 Hz, 1 H) 8.83 (s, 1 H) 10.54 (s, 1 H); HPLC purity (Method 1 : 99%, Method 2: 99%); HRMS: calcd for C2IHnN3O3 + H+, 360.13427; found (ESI-FTMS, [M+H]l+), 360.1343. Example 216
3-{[2-(4-tnethylphenyl)pyridin-4-yl]amino}-4-{[(1R)-1-phenylethyl]ainino}cyclobut-3-ene- 1,2-dione The title compound was prepared as outlined for Example 214, but using p-tolylboronic acid, to afford 0.016 g (22%) as a yellow solid. 1H NMR (400 MHz, OMSO-dδ) δ ppm 1.61 (d, /=6.8 Hz, 3 H) 2.36 (s, 3 H) 4.99 - 5.62 (m, 1 H) 7.16 - 7.51 (m, 9 H) 7.95 (d, /=8.1 Hz, 2 H) 8.46 (d, /=5.6 Hz, 1 H) 8.52 - 8.63 (m, 1 H) 10.23 (s, 1 H); HPLC purity (Method 1: 99%, Method 2: 99%); HRMS: calcd for C24H2]N3O2 + H+, 384.17065; found (ESI-FTMS, [M+H]l+), 384.1708. Example 217
N-(4-{4-[(3,4-dioxo-2-{[(1R)-1-phenylethyl]amino}cycIobut-1-en-1-yl)amino]pyridin-2- yl}phenyl)acetamide
The title compound was prepared as outlined for Example 214, but using A- acetamidophenylboronic acid, to afford 0.036 g (42%) as a bright yellow solid. 1H NMR (400 MHz, DMSO-rftf) δ ppm 1.61 (d, /=7.1 Hz, 3 H) 2.07 (s, 3 H) 5.27 - 5.41 (m, 1 H) 7.22 - 7.51 (m, 7 H) 7.56 - 7.77 (m, J=I 1.4 Hz, 2 H) 8.06 (s, 1 H) 8.26 - 8.38 (m, 1 H) 8.48 (d, /=5.6 Hz, 1 H) 8.83 (s, 1 H) 10.08 (s, 1 H) 10.52 (s, 1 H); HPLC purity (Method 1: 99%, Method 2: 98%); HRMS: calcd for C25H22N4O3 + H+, 427.17647; found (ESI-FTMS, [M+H]l+), 427.1767. Example 218
3-{[2-(3-methylphenyl)pyridin-4-yl]amino}-4-{[(1R)-1-phenylethyl]amino}cycIobut-3-ene- 1,2-dione
The title compound was prepared as outlined for Example 214, but using m-tolylboronic acid, to afford 0.023 g (39%) as a yellow solid. 1H NMR (400 MHz, DMSO-<4) δ ppm 1.61 (d, /=6.82 Hz, 3 H) 2.39 (s, 3 H) 5.27 - 5.41 (m, 1 H) 7.09 - 7.62 (m, 8 H) 7.83 (d, /=7.83 Hz, 1 H) 7.89 (s, 1 H); 8.32 (s, 1 H) 8.47 (d, /=5.56 Hz, 1 H) 8.88 (s, 1 H) 10.56 (s, 1 H); HPLC purity (Method 1: 98%, Method 2: 99%); HRMS: calcd for C24H2]N3O2 + H+, 384.17065; found (ESI-
FTMS, [M+H]l+), 384.1706.
Example 219
3-(2,4'-bipyridin-4-ylamino)-4-{[(1R)-1-phenylethyl]ainino}cyclobut-3-ene-1,2-dione The title compound was prepared as outlined for Example 214, but using 4-ρyridine boronic acid, to afford 0.008 g (14%) as a brown solid. 1H NMR (400 MHz, DMSCW,;) δ ppm
1.61 (d, ./=6.82 Hz, 6 H) 5.18 - 5.44 (m, 1 H) 7.24 - 7.50 (m, 9 H) 7.99 (d, /=6.06 Hz, 2 H) 8.21 -
8.34 (m, 1 H) 8.50 (d, 7=7.83 Hz, 1 H) 8.57 (d, /=5.56 Hz, 1 H) 8.73 (d, /=6.06 Hz, 2 H) 10.20 -
10.36 (m, 1 H); HPLC purity (Method 1 : 99%, Method 2: 92%); HRMS: calcd for C22Hi8N4O2 + H+, 371.15025; found (ESI-FTMS, [M+H]l+), 371.1502.
Example 220
3-({2-[4-(hydroxymethyl)phenyl]pyridin-4-yl}amino)-4-{[(1R)-1- phenyIethyl]amino}cyclobut-3-ene-1,2-dione
The title compound was prepared as outlined for Example 214,but using 4- (hydroxymethyl)phenylboronic acid, to afford 0.023 g (30%) as a yellow solid. 1H NMR (400
MHz, DMSO-ctø δ ppm 1.60 (d, /=6.82 Hz, 3 H) 4.56 (s, 2 H) 5.03 - 5.55 (m, 2 H) 7.09 - 7.54
(m, 8 H) 8.01 (d, /=8.34 Hz, 2 H) 8.20 (s, 1 H) 8.46 (d, /=5.56 Hz, 1 H) 9.31 (s, 1 H) 10.99 (s, 1
H); HPLC purity (Method 1: 99%, Method 2: 99%); HRMS: calcd for C24H2IN3O3 + H+,
400.16557; found (ESI-FTMS, [M+H]l+), 400.1656. Example 221
3-({2-[3-(benzyloxy)phenyl]pyridin-4-yl}amino)-4-{[(1R)-l phenyIethyl]amino}cycIobut-3- cne-1,2-diouc
The title compound was prepared as outlined for Example 214, but using 3- benzyloxyphenylboronic acid, to afford 0.045 g (47%) as a yellow solid. 1H NMR (400 MHz, DMSO-J6) δ ppm 1.62 (d, /=6.82 Hz, 3 H) 5.19 (s, 2 H) 5.23 - 5.50 (m, 1 H) 7.09 (dd, /=7.83,
2.53 Hz, 1 H) 7.19 - 7.55 (m, 12 H) 7.63 (d, /=7.58 Hz, 1 H) 7.73 (s, 1 H) 8.17 (s, 1 H) 8.33 (s, 1
H) 8.49 (d, /=5.56 Hz, 1 H) 10.02 (s, 1 H); HPLC purity (Method 1: 99%, Method 2: 99%);
HRMS: calcd for C30H25N3O3 + H+, 476.19687; found (ESI-FTMS, [M+H] 1+), 476.1976.
Example 222 3-[(2-biphenyl-3-yIpyridin-4-yl)amino]-4-{[(1R)-1-phenylethyl]amino}cyclobut-3-ene-1,2- dione The title compound was prepared as outlined for Example 214, but using 3- biphenylboronic acid, to afford 0.059 g (52%) as a yellow solid. 1H NMR (400 MHz, DMSO-^6) δ ppm 1.62 (d, J=LOl Hz, 3 H) 5.14 - 5.58 (m, 1 H) 7.22 - 7.65 (m, 11 H) 7.75 (d, /=7.33 Hz, 2 H) 8.06 (d, 7=8.08 Hz, 1 H) 8.26 - 8.41 (m, 2 H) 8.53 (d, /=5.56 Hz, 2 H) 10.22 (s, 1 H); HPLC purity (Method 1: 97%, Method 2: 97%); HRMS: calcd for C29H23N3O2 + H+, 446.18630; found (ESI-FTMS, [M+H]l+), 446.1866. Example 223
3-[(2-biphenyl-3-ylpyridin-4-yl)amino]-4-{[(1R)-1-phenylethyI]ainino}cyclobut-3-ene-1,2- dione The title compound was prepared as outlined for Example 214, but using 3-
(hydroxymethyl)phenylboronic acid, to afford 0.030 g (38%) as a yellow solid.1H NMR (400 MHz, DMSO-«?6) δ ppm 1.62 (d, J=6.82 Hz, 3 H) 4.58 (d, 7=5.31 Hz, 2 H) 5.08 - 5.49 (m, 2 H) 7.23 - 7.50 (m, 8 H) 7.90 (d, 7=7.58 Hz, 1 H) 8.05 (s, 1 H) 8.37 (s, 1 H) 8.49 (d, 7=5.56 Hz, 1 H) 10.07 (s, 1 H); HPLC purity (Method 1: 98%, Method 2: 97%); HRMS: calcd for C24H2IN3O3 + H+, 400.16557; found (ESI-FTMS1 [MH-H]I+), 400.1658. Example 224
N-cyclopentyl-4-{4-[(3,4-dioxo-2-{[(1R)-1-phenylethyl]amino}cyclobut-1-en-1- yI)amino]pyridin-2-yl}benzamide
The title compound was prepared as outlined for Example 214, but using A- (cyclopentylaminocarbonyl)phenylboronic acid, to afford 0.52g (54%) as a yellow solid. 1H
NMR (400 MHz, DMSO-rf6) δ ppm 1.33 - 2.13 (m, 11 H) 4.24 (s, 1 H) 5.34 (d, 7=6.57 Hz, 1 H) 7.20 - 7.51 (m, 6 H) 7.96 (d, 7=8.34 Hz, 2 H) 8.11 (d, 2 H) 8.18 - 8.24 (m, 1 H) 8.21 (s, 1 H) 8.36 (d, 7=7.33 Hz, 1 H) 8.52 (d, 7=5.56 Hz, 2 H) 10.24 (s, 1 H); HRMS: calcd for C29H28N4O3 + H+, 481.22342; found (ESI-FTMS, [M+H]l+), 481.2242. Example 225
3-{[2-(4-chlorophenyl)pyridin-4-yl]amino}-4-{[(1R)-1-pheny]ethyl]ainino}cyclobut-3-ene- 1,2-dione
The title compound was prepared as outlined for Example 214, but using 4- chlorophenylboronic acid, to afford 0.030 g (36%) as an off white solid. 1H NMR (400 MHz, DMSO-<4) δ ppm 1.61 (d, 7=6.8 Hz, 3 H) 5.26 - 5.42 (m, 1 H) 7.21 - 7.50 (m, 6 H) 7.57 (d, 7=8.6 Hz, 2 H) 8.06 (d, 7=8.6 Hz, 2 H); 8.16 (s, 1 H) 8.49 (d, 7=5.6 Hz, 2 H) 10.20 (s, 1 H); HPLC purity (Method 1 : 98%, Method 2: 98%); HRMS: calcd for C23H18ClN3O2 + H+, 404.11603; found (ESI-FTMS, [M+H]l+), 404.1166. Example 226 3-(2,2'-bipyridin-4-ylamino)-4-{[(1R)-1-phenylethyl]amino}cyclobut-3-ene-1,2-dione To a reaction vessel was added 3-[(2-bromopyridin-4-yl)amino]-4-{[(1R)-1- phenylethyl]amino}cyclobut-3-ene-1,2-dione (0.075 g, 0.20 mmol) and Pd(PPh3) (0.015 g, 0.02 mmol). The vessel was evacuated and purged with nitrogen twice, then dioxane (degassed, 2 mL) and DMF (degassed, 0.2 mL) was then added. Finally 2-(tripropylstannyl)pyridine (0.089 g, 0.24 mmol) was added to the reaction which was microwaved for total of 2,400 sec at 150 °C. Workup consisted of filtering the reaction mixture through a plug of silica and evaporation of the solvent. Purification (RP-HPLC, CH3CN/H2O with 0.1% formic acid) afforded the title compound (0.012g, 16%) as brown solid. 1H NMR (400 MHz, DMSO-cfc) δ ppm 1.61 (d, /=6.8 Hz, 3 H) 5.20 - 5.43 (m, /=8.3 Hz, 1 H) 7.23 - 7.53 (m, 6 H) 7.70 (s, 1 H) 7.94 (t, /=6.9 Hz, 1 H) 8.18 (s, 1 H) 8.27 (d, ./=2.0 Hz, 1 H) 8.32 - 8.48 (m, 2 H) 8.53 (d, J=5.6 Hz, 1 H) 8.67 (d, /=4.8 Hz, 1 H) 10.30 (s, 1 H); HPLC purity (Method 1 : 98%, Method 2: 96%); HRMS: calcd for C22H18N4O2 + H+, 371.15025; found (ESI-FTMS, [M+H]l+), 371. Example 227
2-{[3,4-dioxo-2-(pyridin-4-y]amino)cyclobut-1-en-1-yl]amino}-2-(4-pyridin-3- ylplienyl)acetaπiide To a reaction vessel was added 3-ethoxy-4-(pyridin-4-ylamino)-cyclobut-3-ene-1,2-dione
(0.083 g, 0.38 mmol) and 2-amino-2-(4-(pyridin-3-yl)phenyl) acetamide (0.157 g, 0.38 mmol). The vessel was evacuated and purged with nitrogen, then EtOH (15 mL) was added. The reaction was refluxed at 100 °C overnight. Workup consisted of evaporating the solvent and purifying the crude solid by RP-HPLC (CH3CN-H2O with 0.01% formic acid) to afford 0.075 g (49%) as a yellow solid. 1H NMR (400 MHz, DMSO-^6) δ ppm 5.91 (d, /=8.1 Hz, 1 H) 7.35 - 7.55 (m, 5 H) 7.62 (s, 1 H) 7.90 (dd, /=8.3 Hz, 1 H) 7.98 - 8.10 (m, 3 H) 8.14 - 8.21 (m, /=6.8 Hz, 1 H) 8.34 - 8.51 (m, 2 H) 8.77 (d, /=2.0 Hz, 1 H) 8.92 (d, /=8.3 Hz, 1 H) 10.29 - 10.47 (m, /=1.3 Hz, 1 H); HPLC purity (Method 1 : 98%, Method 2: 98%); HRMS: calcd for C22HnN5O3 + H+, 400.1404; found (ESI-FTMS, [M+H]l+),400.1406. Example 228
2-biphenyl-4-yl-2-{[3,4-dioxo-2-(pyridin-4-ylammo)cyclobut-1-en-1-yl]amino}acetainide The title compound was prepared from 2-amino-2-(biphenyl)acetamide as outlined for Example 227. Purification by RP-HPLC (CH3CN-H2O with 0.01% formic acid) to afford 0.251 g (69%) as a yellow solid. 1H NMR (400 MHz, DMSO-rf,;) δ ppm 5.87 (d, /=8.3 Hz, 1 H) 7.27 - 7.59 (m, 8 H) 7.67 (dd, /=14.3, 7.7 Hz, 4 H) 8.06 - 8.19 (m, 1 H) 8.42 (dd, /=4.8, 1.5 Hz, 2 H) 8.89 (d, /=8.6 Hz, 1 H) 10.36 (s, 1 H); HPLC purity (Method 1 : 99%, Method 2: 98%); HRMS: calcd for C23H18N4O3 + H+, 399.1452; found (ESI-FTMS, [M+H]l+), 399.1439. Example 229 l-f^bromophenylJ-1-JIS^-dioxo-1-fpyridin-4-ylaminoJcyclobut-1-en-1-yllaminoJacetainide To a reaction vessel was added 3-ethoxy-4-(pyridin-4-ylamino)-cyclobut-3-ene-1,2-dione (0.605 g, 2.77 mmol) and 2-amino-2-(4-bromophenyl)acetamide (0.635g, 2.77 mmol). The vessel was evacuated and purged with nitrogen, then EtOH (40 mL) as added. The reaction was refluxed at 100 °C overnight. Workup consisted of cooling mixture in an ice bath and filtering solid to give the title compound (0.94Og, 85%) as a yellow solid. 1H NMR (400 MHz, DMSO- d6) δ ppm 5.80 (d, 7=8.1 Hz, 1 H) 7.35 - 7.47 (m, 4 H) 7.55 (s, 1 H) 7.60 (d, /=8.3 Hz, 2 H) 8.09 (s, 1 H) 8.40 (d, /=6.3 Hz, 2 H) 8.80 (d, /=8.6 Hz, 1 H) 10.30 (s, 1 H); HPLC purity (Method 1:94 %, Method 2:100%). Example 230
2-{[3,4-dioxo-2-(pyridin-4-yIamino)cyclobut-1-en-1-yl]amino}-2-[4-(3- th ienyl)phen yl] acetamide To a reaction vessel was added 2-(4-bromophenyi)-2-{[3,4-dioxo-2-(pyridin-4- ylamino)cyclobut-1-en-1-yl]amino}acetamide (0.071 g, 0.18 mmol), 3-thiopheneboronic acid (0.032 g, 1.4eq), Na2CO3 (0.028g, 1.5 eq) and Pd(PPh3)2Cl2 (0.025 g, 0.2eq). The vessel was evacuated and purged with nitrogen twice. A solvent mixture of DME/H2O/EtOH (7:3:2) (degassed, 3 mL) was then added. The reaction was microwaved at 150 °C for 300 sec, filtered through Celite® plug and solution as evaporated to give crude residue. This crude material was purified by RP-HPLC (CH3CN-H2O with 0.1% formic acid) to afford 0.022 g (30%) of title compound as a yellow solid. 1H NMR (400 MHz, DMSO-40 δ ppm 5.83 (d, /=8.3 Hz, 1 H) 7.42 - 7.58 (m, 7 H) 7.64 (dd, /=5.1, 3.0 Hz, 1 H) 7.74 (d, /=8.3 Hz, 2 H) 7.87 (dd, /=2.9, 1.4 Hz, 1 H) 8.09 (s, 1 H) 8.42 (d, /=6.3 Hz, 2 H) 8.85 (d, /=8.6 Hz, 1 H) 10.33 (s, 1 H); HPLC purity (Method 1: 100%, Method 2: 100%); HRMS: calcd for C2iH16N4O3S + H+, 405.1016; found (ESI-FTMS, [M+H]l+), 405.1019. Example 231
2-{[3,4-dioxo-2-(pyridin-4-ylamino)cyclobut-1-en-1-yl]amino}-2-[4'-(morpholin-4- yIcarbonyl)bipheny]-4-yl]acetamide
The title compound was prepared as outlined for Example 230, but using 4-(morpholine- 4-carbonyl)phenylboronic acid, to afford 0.014g ( 15%) as a yellow solid. 1H NMR (400 MHz,
DMSCW6) δ ppm 3.16 - 3.78 (m, 8 H) 5.88 (d, /=8.59 Hz, 1 H) 7.43 - 7.64 (m, 7 H) 7.73 (d,
/=8.34 Hz, 4 H) 8.13 (s, 1 H) 8.46 (d, /=6.32 Hz, 2 H) 8.94 (d, /=8.34 Hz, 1 H) 10.53 (s, 1 H);
HPLC purity (Method 1: 98%, Method 2: 96%); HRMS: calcd for C28H25N5O5 + H+, 512.1929; found (ESI-FTMS, [M+H]l+), 512.1935. Example 232
2-{[3,4-dioxo-2-(pyridin-4-ylanπno)cycIobut-1-en-1-yl]amino}-2-[4-(3- furyl)phenyl] acetamidc
The title compound was prepared as outlined for Example 230, but using furan-3- ylboronic acid, to afford 0.015g (22%) as a yellow solid. 1H NMR (400 MHz, DMSO-rfs) δ ppm 5.81 (d, /=8.3 Hz, 1 H) 6.95 (d, /=1.8 Hz, 1 H) 7.40 - 7.68 (m, 7 H) 7.74 (t, /=1.6 Hz, 1 H) 8.08
(s, 1 H) 8.18 (s, 1 H) 8.48 (d, /=6.1 Hz, 2 H) 8.92 (d, /=8.3 Hz, 1 H) 10.60 (s, 1 H); HPLC purity
(Method 1 : 95%, Method 2: 99%); HRMS: calcd for C2IHi6N4O4 + H+, 389.12443; found (ESI-
FTMS, [M+H]l+), 389.1246.
Example 233 2-{[3,4-dioxo-2-(pyridin-4-ylamino)cyclobut-1-en-1-yl]amino}-2-{3'-
[(methylsulfonyl)amino]biphenyl-4-yl}acetamide
The title compound was prepared as outlined for Example 230, but using 4- methansulfonylaminophenyl boronic acid, to afford 0.016g (18%) as a yellow solid. 1H NMR
(400 MHz, DMSO-^6) δ ppm 3.03 (s, 3 H) 7.11 - 7.28 (m, 1 H) 7.34 - 7.50 (m, 6 H) 7.50 - 7.66 (m, 6 H) 8.42 (dd, /=4.80, 1.52 Hz, 2 H) 9.01 (s, 1 H) 10.50 (s, 1 H); HPLC purity (Method 1:
94%, Method 2: 89%); HRMS: calcd for C24H21N5O5S + H+, 492.1336; found (ESI-FTMS,
[M+H]l+), 492.1345.
Example 234
2-{3'-[(dimethylamino)sulfoπyl]biphenyl-4-yI}-2-{[3,4-dioxo-2-(pyridiii-4-ylamino)cyclobut- l-en-1-yl]amino}acetamide The title compound was prepared as outlined for Example 230, but using 3-(N,N- dimethylsulphonamido)phenyl boronic acid to afford 0.016g (18%) as a yellow solid. 1H NMR (400 MHz, OMSO-dβ) δ ppm 2.64 (s, 6 H) 5.90 (d, /=8.1 Hz, 1 H) 7.45 (dd, /=4.8, 1.5 Hz, 2 H) 7.55 (s, 1 H) 7.61 (d, /=8.3 Hz, 2 H) 7.70 - 7.82 (m, 4 H) 7.91 (s, 1 H) 7.97 - 8.07 (m, 1 H) 8.11 - 8.20 (m, 1 H) 8.34 - 8.58 (m, 2 H) 8.94 (d, /=7.8 Hz, 1 H) 10.40 (s, 1 H); HPLC purity (Method 1: 99%, Method 2: 98%); HRMS: calcd for C25H23N5O5S + H+, 506.1493; found (ESI-FTMS, [M+H]l+), 506.1499. Example 235 2-{[3,4-dioxo-2-(pyridin-4-ylamino)cyclobut-1-en-1-yl]amino}-2-[3'-(morphoIin-4- ylcarbonyI)biphenyl-4-yl] acetamide
The title compound was prepared as outlined for Example 230, but using 2- aminophenylboronic acid, to afford 0.016g (17%) as a yellow solid. 1H NMR (400 MHz, DMSO-^6) δ ppm 2.99 - 3.87 (m, 8 H) 5.88 (d, /=7.33 Hz, 1 H) 7.36 - 7.78 (m, 11 H) 8.07 - 8.16 (m, 1 H) 8.37 - 8.46 (m, 2 H) 8.85 - 9.08 (m, 1 H) 10.47 (s, 1 H); HPLC purity (Method 1: 100%, Method 2: 94%); HRMS: calcd for C28H25N5O5 + H+, 512.1929; found (ESI-FTMS, [M+H]l+), 512.1939. Example 236
2-{[3,4-dioxo-2-(pyridin-4-ylamino)cyclobut-1-en-1-yl]amino}-2-{3'- [(ethylamino)sulfonyI]bipheny]-4-yl} acetamide The title compound was prepared as outlined for Example 230, but using ethyl-3- boronbenzenesulfonamide, to afford 0.016g (18%) as a yellow solid. 1H NMR (400 MHz, DMSO-Cf6) δ ppm 5.89 (d, /=7.83 Hz, 1 H) 7.46 (dd, /=4.67, 1.64 Hz, 2 H) 7.51 - 7.69 (m, 5 H) 7.71 - 7.81 (m, 2 H) 7.81 - 7.98 (m, 4 H) 8.42 (dd, /=4.67, 1.64 Hz, 2 H) 8.96 (d, /=5.05 Hz, 1 H) 10.44 (s, 1 H); HPLC purity (Method 1: 96%, Method 2: 98%); HRMS: calcd for C25H23N5O5S + H+, 506.1493; found (ESI-FTMS, [M+H]l+), 506.1507. Example 237
2-(2'-aminobiphenyl-4-yl)-2-{[3,4-dioxo-2-(pyridin-4-ylamino)cyclobut-1-en-1- yl] amino} acetamide
The title compound was prepared as outlined for Example 230, but using 3-(morpholine- 4-carbonyl)phenylboronic acid, to afford 0.013g (18%) as a yellow solid. 1H NMR (400 MHz, DMSO-4) δ ppm 4.79 (s, 2 H) 5.88 (d, /=8.08 Hz, 1 H) 6.56 - 6.68 (m, 1 H) 6.75 (dd, /=8.08, 1.01 Hz, 1 H) 6.97 (dd, /=7.58, 1.52 Hz, 1 H) 7.00 - 7.07 (m, 1 H) 7.34 - 7.61 (m, 8 H) 8.35 - 8.50 (m, 2 H) 8.87 - 9.21 (m, 1 H) 10.44 (s, 1 H); HPLC purity (Method 1: 97%, Method 2: 97%); HRMS: calcd for C23Hi9N5O3 + H+, 414.1554; found (ESI-FTMS, [M+H]l+), 414.1561. Example 238 3-{[(lA)-1-phenylethyl]amino}-4-(thieno[2,3-b]pyridin-4-ylamino)cyc]obut-3-ene-1,2-dione Step 1 : 4-Iodo-(2,3-b)-thienoρyridine
4-Chloro-(2,3-b)-thienopyridine (882 mg, 5.20 mmol) was protonated by stirring in methanolic HCl for 15 minutes. Solvent concentration gave a colorless solid that was combined with MeCN (30 mL) and NaI (4.013 g, 26.7 mmol), and the resultant heterogeneous mixture was heated at 80 °C for 2d. It was then cooled to r.t, and NaHSO3 (sat aq) and NaHCO3 (sat aq) were added sequentially giving a biphasic mixture that produced slight pink ppt upon stirring. The heterogeneous mixture was extracted with CH2CI2 (3x) and the pooled organics were dried (Na2CO3) and concentrated giving a highly colored solid, which was recrystallized in MeCN to give product (200 mg, 0.766 mmol, 14%) as colorless rods. Step 2: 3-{[(1R)-1-phenylethyl]amino}-4-(thieno[2,3-b]pyridin-4-ylamino)cyclobut-3- ene-1,2-dione
3-{[(1R)-1-phenylethyl]amino}-4-amino-cyclobut-3-ene-1,2-dione (138 mg, 0.638 mmol), 4-iodo-(2,3-b)-thienoρyridine (166 mg, 0.636 mmol) and N,N'-dimethyl- ethylenediamine (69 μL, 0.64 mmol) were combined in DMF (3 mL) and freeze-thaw degassed (3x). CuI (66 mg, 0.35 mmol) was then added and the mixture was freeze-thaw degassed (Ix) giving a blue mixture that was heated at 80 °C. The reaction was monitored by LCMS, resulting in the following additions: Id: Iodide (unknown quantity), CuI (138 mg) and N,N'-dimethyl- ethylenediamine (140 μL) in DMF (0.5 mL) were added to the reaction. 2d: More iodide (245 mg in total) in DMF (1/2 mL) was added to the reaction. After 3d the reaction was cooled, diluted with MeOH and filtered. This crude reaction mixture was purified via HPLC to afford the title compound (39.8 mg, 0.11 mmol, 18%) as a yellow solid; 1H NMR (400 MHz, MeOD) δ ppm 1.69 (d, /=6.82 Hz, 3 H) 5.44 (q, /=6.48 Hz, 1H) 7.27 - 7.34 (m, 3 H) 7.36 - 7.42 (m, 2 H) 7.42 - 7.48 (m, 2 H) 7.53 (d, /=5.81 Hz, 1 H) 7.62 (d, /=6.06 Hz, 1 H) 7.91 (d, /=5.05 Hz, 1 H) 8.23 - 8.36 (m, 1 H). Example 239 Characterization of MK2 kinase inhibitors by ELISA was conducted using purified rhMK241-400 or rhMK2 41-353. MK2 inhibitory activity was assayed using: 250 pM MK2 (41-400) after a phosphorylation/activation step using 27 pM p38, or 100 nM MK2 (41-353) (MK2 (41-353) is constitutively active and does not need a phosphorylation/activation step with p38); 200 nM LSP 1 peptide 1323 as a substrate; and 1 μM ATP in IX kinase buffer (20 mM Hepes, pH 7.5, 10 mM MgCl2, 2 mM DTT, and 0.05% Brij35). The phosphorylation of the LSP 1 peptide 1323 substrate, which takes place on serine residue 252, was measured via quantification of the phosphorylated peptide by ELISA, using a phospho-specific antibody. The results were compared to staurosporine which was used as a reference compound. The phosphorylation/activation step of MK2 (41-400) by p38 was performed using: 60 nM activated GST-p38, 550 nM MK2 (41-400); 2 mM DTT 20 ; 25 μM ATP; in IX kinase buffer (20 mM Hepes, pH 7.5, 10 mM MgCl2, 2 mM DTT, and 0.05% Brij35). The activation mix was incubated for 1 hour at room temperature, then put on ice for stability.
The kinase assay was performed on a 96 well plate which was washed four times (250 μL) in PBS (with 0.1% Triton Xl 00) beforehand. The assay was carried out using the following steps. 6.6 mL of mix (enough for 110 reactions) were prepared by combining 1100 μL 1OX kinase buffer, 30 μL DDT (1 M), 11 μL ATP (1 mM), 100 μL activation mix, and balance of H2O. 60 μL of mix and 20 μL compounds were mixed and then preincubated for 20 minutes. Then, the kinase reaction was started with the addition of 20 μL substrate solution (1 μM peptide 1323, Bio-RTPKLARQASIELPSM; LSP-I aa 243-258; Ser 252 is the phosphorylation site). After 30 minutes incubation, the reaction was stopped by addition of 10 μL EDTA (0.5 M), and the 96 well plate was washed again four times (250 μL) in PBS (with 0.1% Triton XlOO).
Antibody detection was carried out using the following steps: 100 μL of blocking/ Ab buffer (10 mM MOPS 7.5, 150 mM NaCl, 0.05% Tween 20, 0.1% Gelatin, 1% BSA, 0.02% NaN3) with purified antibody 60521 (0.46 mg/mL) at 1 :20,000 dilution and europium-labeld Anti-rabbit at 1 :4000 dilution (PE Life Sciences) were added to the detection plate and incubated for 1 hour at room temperature with shaking; then, the detection plate was washed 6 times with PBS 0.1% Tween 20; then, 100 μL of Enhancement solution (Wallac Cat# 1244- 105) were added and incubated for 10 minutes at room temperature with shaking. Europium signal was measured using a Wallac Victor II reader (HTS Europium protocol). Table 1
Figure imgf000122_0001
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Figure imgf000128_0001
Figure imgf000129_0001
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Figure imgf000131_0001
Figure imgf000132_0001
Figure imgf000133_0001
Figure imgf000134_0001
Figure imgf000135_0001
Figure imgf000136_0001
Figure imgf000137_0001
Figure imgf000138_0001
Figure imgf000139_0001
Figure imgf000140_0001
Figure imgf000141_0001
Figure imgf000142_0001
Figure imgf000143_0001
Figure imgf000144_0001
Figure imgf000145_0001
Figure imgf000146_0001
Figure imgf000147_0001
Figure imgf000148_0001
Figure imgf000149_0001
Figure imgf000150_0001
Figure imgf000151_0001
Figure imgf000152_0001
Figure imgf000153_0001
Figure imgf000154_0001
Figure imgf000155_0001
Figure imgf000156_0001
Figure imgf000157_0001
Figure imgf000158_0001
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Figure imgf000164_0001
Figure imgf000165_0001
Figure imgf000166_0001
Figure imgf000167_0001
Figure imgf000168_0001
Figure imgf000169_0001
Other embodiments are within the scope of the following claims.

Claims

WHAT IS CLAIMED IS:
1. A compound of Formula (I) :
Figure imgf000170_0001
or a pharmaceutically acceptable salt thereof; wherein:
Het is a heteroaryl group or a heterocyclyl group, wherein at least one ring atom in said heteroaryl group or said heterocyclyl group is N, and wherein Het is optionally substituted by 1-4 substituents independently selected from R5;
R4 is cycloalkyl, cycloalkenyl, or heterocyclyl, each of which is optionally substituted with 1-5 substituents independently selected from Ra; or R4 is -C(R')(R2)R3; or R4 is Cμ6 alkyl or C2-6 alkenyl, wherein said C1-6 alkyl and C2-6 alkenyl are each optionally substituted by 1 or 2 RB groups;
R9 is H, alkyl, cycloalkyl, or perfluoroalkyl;
R10 is H, alkyl, cycloalkyl, or perfluoroalkyl; or R4 and R9 taken together with the nitrogen atom to which they are attached are 4- to 7- membered heterocyclyl optionally substituted with 1-5 substituents independently selected from
Ra; or R9 and R10 taken together are -(CR7R8)P-, wherein p is 1 , 2, or 3;
R1 is -H, halogen, -CN, -CHO, C1-C6 alkyl, C1-C6 perfluoroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, aryl, heteroaryl, heterocyclyl, -C(0)-Rb, -C(O)O-Rb, -C(0)N(R7)-Rb, -SOm-Rb, -SO2-N(R7)-Rb, -(CR7R8^-OR7, or -C(O)N(R7)R8; wherein Rb is -H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, -(CH2)n-aryl, -(CH2),,-heteroaryl, or -(CH2)n-heterocyclyl; wherein each of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclyl is optionally substituted with 1-5 substituents independently selected from Ra;
R2 is -H, halogen, -CN, -CHO, C1-C6 alkyl, C1 -C6 perfluoroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, aryl, heteroaryl, heterocyclyl, -C(0)-Rc, -C(O)O-Rc, -C(O)N(R7)-Rc, -SO111-Rc, -SO2-N(R7)-R°, -(CR7R8)n-OR7, or -C(O)N(R7)R8; wherein Rc is -H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, -(CH2)n-aryl, -(CH2)n-heteroaryl, or -(CH2)n-heterocyclyl; wherein each of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclyl is optionally substituted with 1-5 substituents independently selected from Ra; or R1 and R2 together form an oxo group;
R3 is -(CR7RVaryl, -(CR7R8)n-heteroaryl, -(CR7RV(C3-C8 cycloalkyl), or -(CR7R Vheterocyclyl; wherein R3 is optionally substituted with 1-5 substituents independently selected from Rf; each R5, independently, is halogen, oxo, -CN, -CHO, -OH, -NO2, -N3, -OCF3, -OR7, C1-C6 alkyl, C1-C6 perfluoroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, aryl, heteroaryl, heterocyclyl, -CH=CH-aryL -CH=CH-heteroaryl, -O-Rd, -OC(O)-Rd, -C(O)-Rd, -C(O)O-Rd, -C(O)N(R7)-Rd, -N(R7)Rd, -N(R7)C(0)-Rd, -N(R7)-SOraRd, -SOm-Rd, -SO2-N(R7)-Rd, -(CR7R8)n-OR7, -C(O)OR7, or -C(O)N(R7)R8; wherein Rd is -H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, -(CH2)n-aryl, -(CH2)n-heteroaryl, or -(CH2)n-heterocyclyl; wherein each R5 is, independently, optionally substituted with 1-5 substituents independently selected from Ra; each R7, independently, is -H, C1-C6 perfluoroalkyl, -(CH2)n-(C1-C6 alkyl), -(CH2)n-(C3-C8 cycloalkyl), -(CH2)n-(C3-C8 cycloalkenyl), -(CH2)n-aryl, -(CH2)n-heteroaryl, or -(CH2)n-heterocyclyl; wherein each R7, independently, is optionally substituted by 1 to 3 substituents selected from the group consisting of halogen, oxo, -CN, -CHO, -CF3, -OH, -NO2, -N3, C1-C6 alkyl, -OCF3, -0-(C1-C6 alkyl), -0-(C3-C8 cycloalkyl), -0-(C3-C8 cycloalkenyl), -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -NHC(O)-(C1-C6 alkyl), -SOm(C1-C6 alkyl), -SO1nNH(C1-C6 alkyl), and -SOmN(C1-C6 alkyl)2; each R8, independently, is -H, C1-C6 perfluoroalkyl, -(CH2)n-(C1-C6 alkyl), -(CH2)n-(C3-C8 cycloalkyl), -(CH2)^-(C3-C8 cycloalkenyl), -(CH2)n-aryl, -(CH2)n-heteroaryl, or -(CH2)n-heterocyclyl; wherein each R8, independently, is optionally substituted by 1 to 3 substituents selected from the group consisting of halogen, oxo, -CN, -CHO, -CF3, -OH, -NO2, -N3, C1-C6 alkyl, -OCF3, -O-(C,-C6 alkyl), -0-(C3-C8 cycloalkyl), -0-(C3-C8 cycloalkenyl), -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -NHC(O)-(C1-C6 alkyl), -SO111(C1-C6 alkyl), -SO1nNH(C1-C6 alkyl), and -SO1nN(C1-C6 alkyl)2; each Ra, independently, is halogen, oxo, -CN, -CHO, -OH, -NO2, -N3, -OCF3, C1-C6 alkyl, C1-C6 perfluoroalkyl, -(CH2)n-(C3-C8 cycloalkyl), -(CH2)n-(C3-C8 cycloalkenyl), -(CH2)n-CO2R8, -(CH2)n-aryl, -(CH2)n-heteroaryl, -(CH2)n-heterocyclyl, -(CH2X1-OR7, -(CH2)n-N(R7)(R8), -(CH2)n-C(=NR7)N(R7)(Rs), -O-Re, -C(O)-R6, -C(0)N(R7)-Re, -C(O)-N(R7)-SOm-R8, -O(CH2)n-N(R7)(R8), -N(R7)Re, -N(R7)C(0)-Re, -N(R7)-C(O)-N(R7)(R8), -N(R7)-SOm-Re, -SH, -SOm-Re, -SO2-N(R7)-Re, -OC(O)-R', -C(0)0-Re, -(CR7R8)n-OR7, or -OPO3(R7)(R8); wherein Re is -H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, -(CH2)n-aryl, -(CH2)n-heteroaryl, or -(CH2)n-heterocyclyl; each Rf, independently, is halogen, oxo, -CN, -CHO, -OH, -NO2, -N3, -OCF3, C1-C6 alkyl, Q-C6 perfluoroalkyl, -(CH2X1-(C3-C8 cycloalkyl), -(CH2)n-(C3-C8 cycloalkenyl), -(CHz)n-CO2R8, -(CHOn-aryl, -(CH2)n-heteroaryl, -(CH2)n-heterocyclyl, -(CH2X1-OR7, -(CH2)n-N(R7)(R8), -(CH2)n-C(=NR7)N(R7)(R8), -O-Re, -C(O)-Re, -C(0)N(R7)-Re, -C(O)-N(R7)-SOπ,-R8, -O(CH2)n-N(R7)(R8), -N(R7)Re, -N(R7)C(0)-Re, -N(R7)-C(O)-N(R7)(R8), -N(R7)-SOm-Re, -SH, -SOm-Re, -SO2-N(R7)-Re, -OC(O)-R6, -C(O)O-Re, -(CR7R8Jn-OR7, or -OPO3(R7)(R8); wherein said -(CH2)n-heteroaryl and -(CH2)n-aryl are each further optionally substituted by a group selected from halogen, -CN, C1-C4 alkyl, C1-C4 alkoxy, amino, C1-C4- alkylamino, di-C].C4-alkylaino, aminosulfonyl, C1-C4-alkylaminosulfonyl, di-C1XV alkylaminosulfonyl, C1-C4 alkylsulfonylamino, heterocyclylcarbonyl, C1-C4alkylcarbonyl, and C1-C4 alkoxycarbonylamino; each RE group is independently selected from carbamyl and hydroxyl; each n, independently, is O, 1, 2, 3 or 4; and each m, independently, is 0, 1, or 2; provided that the compound is not 3-(5-bromo-pyridin-3-ylamino)-4-(l- phenylethylamino)cyclobut-3-ene-1,2-dione, 3-(l-phenylethylamino)-4-(ρyridin-4-ylamino)- cyclobut-3-ene-1,2-dione, or 3-(bicyclo[2.2.1]hept-2-ylamino)-4-(pyridin-4-ylamino)-cyclobut- 3-ene-1,2-dione; provided that the compound is not quadratic acid 1,2-bis(pyridyl)amide, quadratic acid 1 ,2-bis(pyridylmethylene)amide; provided that the compound is not 3-chloro-N-(l-{[3,4-dioxo-2-(5-pyrimidinylamino)-1- cyclobuten-1-yl]amino}-2,2-dimethylpropyl)benzamide, N-(l-{[3,4-dioxo-2-(5- pyrimidinylamino)-1-cyclobuten-1-yl]amino}-2,2-dimethylpropyl)-3,5-difluorobeπzamide, or N- ( 1 - { [3 ,4-dioxo-2-(2-ρyrazinylamino)- 1 -cyclobuten- 1 -yl] amino } -2,2-dimethylpropyl)-3 ,5- difluorobenzamide; provided that when Het is 4-hydroxy-2-oxo-N-methyl-1,2-dihydropyridin-5-yl, 5- dimethylaminocarbonyl-4-hydroxypyridin-3-yl, 5-hydroxy-6-
(dimethylaminocarbonyl)pyrimidin-4-yl, or S-dimethylaminocarbonyM-hydroxy-1-methyl- pyrazol-3-yl, R4 is neither 1,2-dimethylpropyl nor 1-phenylpropyl.
2. The compound of claim 1, or pharmaceutically acceptable salt thereof; wherein:
Het is a heteroaryl group or a heterocyclyl group, wherein at least one ring atom is N, and wherein Het is optionally substituted by 1-4 substituents independently selected from R5;
R4 is cycloalkyl, cycloalkenyl, or heterocyclyl, each of which is optionally substituted with 1-5 substituents independently selected from Ra; or R4 is -C(R')(R2)R3;
R9 is H, alkyl, cycloalkyl, or perfluoroalkyl;
R10 is H, alkyl, cycloalkyl, or perfluoroalkyl; or R4 and R9 taken together with the nitrogen atom to which they are attached are 4- to 7- membered heterocyclyl optionally substituted with 1-5 substituents independently selected from Ra; or R9 and R10 taken together are -(CR7R8)P-, wherein p is 1, 2, or 3;
R' is -H, halogen, -CN, -CHO, C1-C6 alkyl, C1-C6 perfluoroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, aryl, heteroaryl, heterocyclyl, -C(O)-Rb, -C(O)O-R", -C(0)N(R7)-Rb, -SOm-Rb, -SO2-N(R7)-Rb, -(CR7RVOR7, or -C(O)N(R7)R8; wherein Rb is -H, Q-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, -(CH2)n-aryl, -(CH2)n-heteroaryl, or -(CH2)n-heterocyclyl; wherein each of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclyl is optionally substituted with 1-5 substituents independently selected from Ra;
R2 is -H, halogen, -CN, -CHO, C1-C6 alkyl, C1-C6 perfluoroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, aryl, heteroaryl, heterocyclyl, -C(O)-Rc, -C(O)O-Rc, -C(0)N(R7)-R°, -SOm-Rc, -SO2-N(R7)-R°, -(CR7R8)n-OR7, or -C(O)N(R7)R8; wherein Rc is -H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, -(CH2)n-aryl, -(CH2)n-heteroaryl, or -(CH2)n-heterocyclyl; wherein each of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclyl is optionally substituted with 1-5 substituents independently selected from Ra;
R3 is -(CR7R8)n-aryl, -(CR'R^-heteroaryl, -(CR7R8)n-(C3-C8 cycloalkyl), or -(CR7R8)n-heterocyclyl; wherein R3 is optionally substituted with 1-5 substituents independently selected from Ra; each R5, independently, is halogen, oxo, -CN, -CHO, -OH, -NO2, -N3, -OCF3, -OR7, C1-C6 alkyl, C1-C6 perfluoroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl,' C3-C8 cycloalkenyl, aryl, heteroaryl, heterocyclyl, -CH=CH-aryl, -CH=CH-heteroaryl, -O-Rd, -OC(O)-Rd, -C(O)-Rd, -C(O)O-R", -C(0)N(R7)-Rd, -N(R7)Rd, -N(R7)C(0)-Rd, -N(R7J-SOmR", -SOm-R", -SO2-N(R7)-Rd, -(CR7R8)n-OR7, -C(O)OR7, or -C(O)N(R7)R8; wherein Rd is -H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C3-Cj cycloalkenyl, -(CH2)n-aryl, -(CH2)n-heteroaryl, or -(CH2)n-heterocyclyl; wherein each R5 is, independently, optionally substituted with 1-5 substituents independently selected from Ra; each R7, independently, is -H, C1-C6 perfluoroalkyl, -(CH2)n-(C1-C6 alkyl), -(CH2)n-(C3-C8 cycloalkyl), -(CH2)n-(C3-C8 cycloalkenyl), -(CH2)n-aryl, -(CH2)n-heteroaryl, or -(CH2)n-heterocyclyl; wherein each R7, independently, is optionally substituted by 1 to 3 substituents selected from the group consisting of halogen, oxo, -CN, -CHO, -CF3, -OH, -NO2, -N3, C1-C6 alkyl, -OCF3, -0-(C1-C6 alkyl), -0-(C3-C8 cycloalkyl), -0-(C3-C8 cycloalkenyl), -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -NHC(O)-(C1-C6 alkyl), -SOm(C1-C6 alkyl), -SOmNH(C1-C6 alkyl), and -SO1nN(C1-C6 alkyl)2; each R8, independently, is -H, C1-C6 perfluoroalkyl, -(CH2)n-(C1-C6 alkyl), -(CH2)n-(C3-C8 cycloalkyl), -(CH2)n-(C3-C8 cycloalkenyl), -(CH2)n-aryl, -(CH2)n-heteroaryl, or -(CH2)n-heterocyclyl; wherein each R8, independently, is optionally substituted by 1 to 3 substituents selected from the group consisting of halogen, oxo, -CN, -CHO, -CF3, -OH, -NO2, -N3, C1-C6 alkyl, -OCF3, -0-(C1-C6 alkyl), -0-(C3-C8 cycloalkyl), -0-(C3-C8 cycloalkenyl), -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -NHC(O)-(C1-C6 alkyl), -SOm(C1-C6 alkyl), -SO1nNH(C1-C6 alkyl), and -SO1nN(C1-C6 alkyl)2; each Ra, independently, is halogen, oxo, -CN, -CHO, -OH, -NO2, -N3, -OCF3, C1-C6 alkyl, C1-C6 perfluoroalkyl, -(CH2)n-(C3-C8 cycloalkyl), -(CH2)n-(C3-C8 cycloalkenyl), -(CH2)n-CO2R8, -(CH2)n-aryl, -(CH2)n-heteroaryl, -(CH2)n-heterocyclyl, -(CH2)n-OR7, -(CH2)n-N(R7)(R8), -(CH2)n-C(=NR7)N(R7)(R8), -O-Re, -C(O)-R6, -C(O)N(R7)-Re, -C(O)-N(R7)-SOm-R8, -O(CH2)n-N(R7)(R8), -N(R7)Re, -N(R7)C(O)-Re, -N(R7)-C(O)-N(R7)(R8), -N(R7)-SOm-Re, -SH, -SOm-Re, -SO2-N(R7)-Re, -OC(O)-R6, -C(O)O-R6, -(CR7R8)n-OR7, or -OPO3(R7XR8); wherein R6 is -H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, -(CH2)n-aryl, -(CH2)n-heteroaryl, or -(CH2)n-heterocyclyl; each n, independently, is 0, 1, 2, 3 or 4; and each m, independently, is 0, 1, or 2.
3. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein Het is pyridinyl, piperidinyl, pyrimidinyl, oxazolinyl, pyrazolyl, isoquinolinyl, or quinolinyl, wherein Het is optionally substituted by 1-4 substituents independently selected from R5.
4. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein Het is pyridin-4-yl optionally substituted at the 2-position by R5.
5. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein Het is pyridin-4-yl, isooxazol-5-yl, piperidin-4-yl, pyrimidin-4-yl, 1H-pyrazol-3-yl, isoquinolin- 5-yl, or thieno[2,3-d]pyridin-4-yl, each of which is optionally substituted by 1 to 4 independently selected R5 groups.
6. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein Het is pyridin-4-yl, isooxazol-5-yl, piperidin-4-yl, pyrimidin-4-yl, 1H-pyrazol-3-yl, isoquinolin- 5-yl, or thieno[2,3-d]pyridin-4-yl, each of which is optionally substituted by a R5 group.
7. The compound of any one of claims 2 to 6, or a pharmaceutically acceptable salt thereof, wherein R5 is -OR7, -N(R7)R8, aryl, heteroaryl, or -N(R7)C(O)R8.
8. The compound of any one of claims 2 to 6, or a pharmaceutically acceptable salt thereof, wherein each R5, independently, is halogen, -OH, -N3, C1-C6 alkyl, aryl, heteroaryl, heterocyclyl, -CH=CH-aryl, -O-Rd, -C(O)O-Rd, -C(0)N(R7)-Rd, -N(R7)Rd, -N(R7)C(0)-Rd, or -SOm-Rd; wherein each R5 is, independently, optionally substituted with 1-5 substituents independently selected from Ra.
9. The compound of any one of claims 2 to 6, or a pharmaceutically acceptable salt thereof, wherein each R5 is, independently, methyl, methoxy, hydroxyl, chloro, bromo, carboxamide, azido, tert-butoxycarbonyl, 4-benzyl-1H-1,2,3-triazol-1-yl, moipholin-4-yl, phenyl, 2-fluorophenyl, 3-flurophenyl, 4-chlorophenyl, 4-methylphenyl, 3-methylphenyl, 1- benzofuran-2-yl, furan-2-yl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 3- methoxyphenyl, 4-(hydroxymethyl)phenyl, 4-(hydroxymethyl)-1H-1,2,3-triazol-1-yl, 4-phenyl- 1H-1,2,3-triazol-1-yl, 4-(cyclopentylaminocarbonyl)phenyl, 4-acetamidophenyl, 2-(4- chlorophenyl)vinyl, phenylthio, 3-(benzyloxy)phenyl, biphenyl-3-yl, anilino, A- trifluoromethylanilino, 2-pyrimidin-4-ylamino, 3-(hydroxymethyl)anilino, 3-carbamylanilino, pyridin-3-ylamino, pyridin-2-ylamino, pyridin-4-ylamino, 4-methyl-1,2,3-triazol-2-ylamino, quinolin-2-ylamino, pyrimidin-2-ylamino, acetamido, pyridin-4-yl, pyridin-3-yl, pyridin-2-yl, benzamido, or nicotinamido.
10. The compound of any one of claims 2 to 9, or a pharmaceutically acceptable salt thereof, wherein R4 is -C(R1XR^R3.
11. The compound of any one of claims 2 to 9, or a pharmaceutically acceptable salt thereof, wherein R4 and R9 taken together with the nitrogen atom to which they are attached are 4- to 7- membered heterocyclyl optionally substituted with 1-5 substituents independently selected from Ra.
12. The compound of any one of claims 2 to 9, or a pharmaceutically acceptable salt thereof, wherein R3 is aryl, heteroaryl, C3-C8 cycloalkyl, or heterocyclyl, wherein R3 is optionally substituted with 1-5 substituents independently selected from Ra.
13. The compound of any one of claims 2 to 9, or a pharmaceutically acceptable salt thereof, , v wherein R3 is aryl optionally substituted with 1-5 substituents independently selected from Ra.
14. The compound of any one of claims 2 to 9, or a pharmaceutically acceptable salt thereof, wherein R3 is phenyl optionally substituted with 1-5 substituents independently selected from Ra.
15. The compound of any one of claims 2 to 9, or a pharmaceutically acceptable salt thereof, wherein R3 is phenyl optionally substituted with 1-5 substituents selected from C1-C6 alkyl, C1-C6 perfluoroalkyl, halogen, -0-(C1-C6 alkyl), -OH, -NO2, -CN, -N(R7)Re, -(CH2)n-C(O)OR8, aryl, heteroaryl, or heterocyclyl.
16. The compound of claim 2 to 9, or a pharmaceutically acceptable salt thereof, wherein R3 is -(CR7R8)n-aryl, -(CR7R8)n-heteroaryl, -(CR7R8)n-(C3-C8 cycloalkyl), or -(CR7R8)n-heterocyclyl; wherein R3 is optionally substituted with 1, 2, or 3 substituents independently selected from Ra.
17. The compound of claim 2 to 16, or a pharmaceutically acceptable salt thereof, wherein each Rais, independently, halogen, -CN, -OH, -NO2, C1-C6 alkyl, C1-C6 perfluoroalkyl, -(CHz)11-(C3-C8 cycloalkyl), -(CH2)n-aryl, -(CH2)n-heteroaryl, -(CH2)n-heterocyclyl, -O-Re, -C(0)N(R7)-Re, -N(R7)Re, -N(R7)C(0)-Re, -N(R7)-C(O)-N(R7)(R8), -N(R7)-SOm-Re, or -C(0)0-Re.
18. The compound of claim 2 to 16, or a pharmaceutically acceptable salt thereof, wherein R1 is -H or C1-C6 alkyl.
19. The compound of any one of claims 2 to 16, or a pharmaceutically acceptable salt thereof, wherein R1 is H.
20. The compound of any one of claims 2 to 16, wherein R1 is -H or C1-C6 alkyl; R2 is -H, C1-C6 alkyl, or -C(O)N(R7)-Rc; R3 is phenyl optionally substituted with 1-5 substituents independently selected from R3; and Het is pyridin-4-yl optionally substituted at the 2-position by aryl, heteroaryl, -NH-aryl, or -NH-heteroaryl, wherein aryl and heteroaryl are each optionally substituted with 1-5 substituents independently selected from Ra.
21. The compound of any one of claims 2 to 16, wherein R1 is -H or C1-C6 alkyl; R2 is -CH3, -CH2CH3, -CH2OH, -C(O)NH2, -C(O)NH-(C1-C6 alkyl), -C(O)NH-(CH2)n-chlorophenyl, -C(O)NH-(CH2)n-pyridyl, or -C(CH3)2OH; R3 is phenyl optionally substituted with 1-5 substituents independently selected from C1-C6 alkyl, halogen, hydroxy, -NHC(0)NHCH3, aminophenyl, acetylamino, phenyl, and furyl; and Het is pyridin-4-yl optionally substituted at the 2-position by methoxyphenyl, thienyl, pyridinyl, hydroxymethylphenylamino, aminocarbonylphenylamino, pyridinylamino, fluorophenyl, pyrimidinylamino, pyrazinyl, or furyl.
22. The compound of any one of claims 2 to 21, or a pharmaceutically acceptable salt thereof, wherein R2 is -H, C1-C6 alkyl, or -C(O)N(R7)-Rc.
23. The compound of any one of claims 2 to 21 , or a pharmaceutically acceptable salt thereof, wherein R2 is -H, methyl, or -C(O)NH2, or -C(O)NH-(C1-C6 alkyl).
24. The compound of claim 2 to 21, or a pharmaceutically acceptable salt thereof, wherein R2 is -H, C1-C6 alkyl, aryl, heteroaryl, -C(O)-Rc, -C(O)O-Rc, -(CR7Rs)n-OR7, or -C(O)N(R7)R8.
25. The compound of any one of claims 2 to 24, or a pharmaceutically acceptable salt thereof, wherein, within each R5 group, or substituents thereof: each R7, independently, is -H; each Ra, independently, is halogen, C1-Cg alkyl, C1-C6 perfluoroalkyl, -(CH2)n-aryl, -(CH2)n-OR7, -O-Re, -C(0)N(R7)-Re, or -N(R7)C(O)-Re; each Rd is, independently, -H, C1-C6 alkyl, -(CH2)n-aryl, or -(CH2)n-heteroaryl; each Re is, independently, -H, C1-C6 alkyl, or C3-C8 cycloalkyl; each n, independently, is O or 1; and each m, independently, is O.
26. The compound of any one of claims 2 to 24, or a pharmaceutically acceptable salt thereof, wherein within each R2 group, or substituents thereof: each Rc is -H, C1-C6 alkyl, or -(CH2)n-heterocyclyl; each R7 is, independently, -H or -(CH2)n-(C1-C6 alkyl); each n, independently, is 0 or 1; and each R8 is, independently, -H, -(CH2)n-(C1-C6 alkyl), -(CH2)n-(C3-C8 cycloalkyl), -(CH2)n-aryl, or -(CH2)n-heteroaryl; wherein each of which is optionally substituted by a substituent selected from halogen.28.The compound of any one of claims 2 to 25, or a pharmaceutically acceptable salt thereof, wherein within each R3 group, or substituents thereof: each Re is -H or C1-C6 alkyl; each R7, independently, is -H or C1-C6 alkyl; each n, independently, is 0 or 1; and each R8, independently, is -H or Q-C6 alkyl.
27. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein Het is ρyridin-4-yl, isooxazol-5-yl, piperidin-4-yl, pyrimidin-4-yl, 1H-pyrazol-3-yl, isoquinolin-5-yl, or thieno[2,3-d]pyridin-4-yl, each of which is optionally substituted by 1 to 4 independently selected C1-C6 alkyl groups; or
Het is pyridin-4-yl, isooxazol-5-yl, piperidin-4-yl, pyrimidin-4-yl, 1H-pyrazol-3-yl, isoquinolin-5-yl, or thieno[2,3-d]pyridin-4-yl, each of which is optionally substituted by a R5 group; each R5, independently, is halogen, -OH, -N3, C1-C6 alkyl, aryl, heteroaryl, heterocyclyl, -CH=CH-aryl, -O-Rd, -C(O)O-Rd, -C(0)NH-Rd, -NHRd, -NHC(O)-R", or -SOra-Rd; wherein each R5 is, independently, optionally substituted with 1-5 substituents independently selected from Rla; each Rla, independently, is halogen, C1-C6 alkyl, C1-C6 perfluoroalkyl, -(CH2)n-aryl, -(CHz)n-OH, -O-Re, -C(O)NH-R6, or -NHC(0)-Re; each Rd is, independently, -H, C1-C6 alkyl, -(CH2)n-aryl, or -(CH2yheteroaryl; each n, independently, is O or 1 ; each m, independently, is O; R4 is -C(R1XR2)!^; or
R4 and R9 taken together with the nitrogen atom to which they are attached are 4- to 7- membered heterocyclyl optionally substituted with 1-5 substituents independently selected from
Ra;
R1 is -H or C1-C6 alkyl;
R2 is -H, C1-C6 alkyl, aryl, heteroaryl, -C(O)-Rc, -C(O)O-R=, -(CR7R8)n-OR7, or -C(O)N(R7)R8; each Rc is -H, C1-C6 alkyl, or -(CH2)n-heterocyclyl; each R7 is, independently, -H or -(CH2)n-(C1-C6 alkyl); each R8 is, independently, -H, -(CHb)n-(C1-C6 alkyl), -(CH2)n-(C3-C8 cycloalkyl), -(CH2)n-aryl, or -(CH2)n-heteroaryl; wherein each of which is optionally substituted by a substituent selected from halogen;
R3 is -(CR7R8)n-aryl, -(CR7R8)n-heteroaryl, -(CR7RV(C3-C8 cycloalkyl), or -(CR7R8)n-heterocyclyl; wherein R3 is optionally substituted with 1, 2, or 3 substituents independently selected from Ra; each Rais, independently, halogen, -CN, -OH, -NO2, C1-C6 alkyl, C1-C6 perfluoroalkyl, -(CH2)n-(C3-C8 cycloalkyl), -(CH2)n-aryl, -(CH2)n-heteroaryl, -(CH2)n-heterocyclyl, -O-Re, -C(0)N(R7)-Re, -N(R7)Re, -N(R7)C(0)-Re, -N(R7)-C(O)-N(R7)(R8), -N(R7)-SOm-Re, or -C(O)O-R6; and each Re is, independently, -H, C1-C6 alkyl, or C3-C8 cycloalkyl.
28. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein Het is pyridin-4-yl optionally substituted by 1-4 substituents independently selected from R5.
29. The compound of claim 28, or a pharmaceutically acceptable salt thereof, wherein R5 is -OR7, -N(R7)R8, aryl, heteroaryl, or -N(R7)C(O)R8.
30. The compound of any one of claims 28 to 29, or a pharmaceutically acceptable salt thereof, wherein R4 is -C(R1J(R^R3.
31. The compound of any one of claims 28 to 30, or a pharmaceutically acceptable salt thereof, wherein R3 is aryl, heteroaryl, C3-C8 cycloalkyl, or heterocyclyl, wherein R3 is optionally substituted with 1-5 substituents independently selected from Ra.
32. The compound of any one of claims 28 to 30, or a pharmaceutically acceptable salt thereof, wherein R3 is aryl optionally substituted with 1-5 substituents independently selected from Ra.
33. The compound of any one of claims 28 to 30, or a pharmaceutically acceptable salt ther reeooff,, wwhheenrein R3 is phenyl optionally substituted with 1-5 substituents independently selected from Ra.
34. The compound of any one of claims 28 to 30, or a pharmaceutically acceptable salt thereof, wherein R3 is phenyl optionally substituted with 1-5 substituents selected from C1-C6 alkyl, C1-C6 perfluoroalkyl, halogen, -0-(C1-C6 alkyl), -OH, -NO2, -CN, -N(R7)Re, -(CH2)nC(O)OR8, aryl, heteroaryl, or heterocyclyl.
35. The compound of any one of claims 28 to 34, or a pharmaceutically acceptable salt thereof, wherein R1 is H.
36. The compound of any one of claims 28 to 35, or a pharmaceutically acceptable salt thereof, wherein R2 is -H, C1-C6 alkyl, or -C(O)N(R7)-Rc.
37. The compound of any one of claims 28 to 35, or a pharmaceutically acceptable salt thereof, wherein R2 is -H, methyl, or -C(O)NH2, or -C(O)NH-(C1-C6 alkyl).
38. The compound of claim 28, or a pharmaceutically acceptable salt thereof, wherein:
R1 is -H or C1-C6 alkyl;
R2 is -H, C1-C6 alkyl, or -C(O)N(R7)-Rc; R3 is phenyl optionally substituted with 1-5 substituents independently selected from Ra; and
Het is ρyridin-4-yl optionally substituted at the 2-position by aryl, heteroaryl, -NH-aryl, or -NH-heteroaryl, wherein aryl and heteroaryl are each optionally substituted with 1-5 substituents independently selected from Ra.
39. The compound of claim 28, or a pharmaceutically acceptable salt thereof, wherein:
R' is -H or C1-C6 alkyl;
R2 is -CH3, -CH2CH3, -CH2OH, -C(O)NH2, -C(O)NH-(CrC6 alkyl), -C(O)NH-(CH2)n-chlorophenyl, -C(O)NH-(CH2)n-pyridyl, or -C(CH3)2OH;
R3 is phenyl optionally substituted with 1-5 substituents independently selected from C1-C6 alkyl, halogen, hydroxy, -NHC(0)NHCH3, aminophenyl, acetylamino, phenyl, and furyl; and Het is pyridin-4-yl optionally substituted at the 2-position by methoxyphenyl, thienyl, pyridinyl, hydroxymethylphenylamino, aminocarbonylphenylamino, pyridinylamino, fluorophenyl, pyrimidinylamino, pyrazinyl, or furyl.
40. A compound according to claim 1, which is selected from: 3-{[l-(4-fluorophenyl)ethyl]amino}-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2-dione; 3-[(cyclohexyhnethyl)amino]-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2-dione; 3-(2,3-dihydro-liϊ-inden-1-ylamino)-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2-dione; 3-(pyridin-4-ylamino)-4-[(tetrahydrofuran-2-ylmethyl)amino]cyclobut-3-ene-1,2-dione; 3-[(1,3-benzodioxol-5-ylmethyl)amino]-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2-dione; 3-(pyridin-4-ylamino)-4-[(pyridin-2-ylmethyl)amino]cyclobut-3-ene-1,2-dione; S-φyridin-4-ylaminoJ^-fφyridin-S-ylmethy^aminoJcyclobut-S-ene-l^-dione; 3-(pyridin-4-ylamino)-4-[(pyridin-4-ylmethyl)amino]cyclobut-3-ene-1,2-dione;
3 -[(diphenylmethyl)amino] -4-(pyridin-4-ylamino)cyclobut-3 -ene- 1 ,2-dione ;
3-(benzylamino)-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2-dione;
3-[(2-methylbenzyl)amino]-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2-dione;
3-(pyridin-4-ylamino)-4-{[3-(trifluoromethyl)benzyl]amino}cyclobut-3-ene-1,2-dione;
3-[(3-methylbenzyl)amino]-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2-dione; 3-[(4-fluorobenzyl)amino]-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2-dione;
3-[(4-methylbeπzyl)amino]-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2-dione;
3-{[2-(4-methylphenyl)ethyl]amino}-4-(pyridin-4-ylatnino)cyclobut-3-ene-1,2-dione;
3-[(2,4-difluorobeπzyl)amino]-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2-dione;
3-[(2,5-difluorobenzyl)amino]-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2-dione;
3-[(3,4-difluorobenzyl)amino]-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2-dione;
3-(pyridin-4-ylamino)-4- {[4-(trifluoromethyl)benzyl]amino} cyclobut-3-ene-l ,2-dione;
3-[(2,4-dimethylbenzyl)amino]-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2-dione;
3-[(3,4-dimethylbenzyl)amino]-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2-dione;
3-[(4-tert-butylbenzyl)amino]-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2-dione;
3-[(3,5-difluorobenzyl)amino]-4-(ρyridin-4-ylamino)cyclobut-3-ene-1,2-dione;
3-(pyridin-4-ylamino)-4-(1,2,3,4-tetrahydronaphthalen-1-ylamino)cyclobut-3-ene-1,2- dione;
3-{[(1R)-2-hydroxy-1-phenylethyl]amino}-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2- dione;
3-[(1,2-diphenylethyl)amino]-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2-dione; 2-{[3,4-dioxo-2-(pyridin-4-ylamino)cyclobut-1-en-1-yl]amino}-2-phenylacetamide;
3-{me(hyl[(1R)-1-phenylethyl]amino}-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2-dione;
3-{[(1R)-1-(4-bromophenyl)ethyl]amino}-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2- dione;
3 - { [( 1 S)-2-hydtoxy- 1 -phenylethyl] amino } -4-(pyridin-4-ylamino)cyclobut-3 -ene- 1,2- dione;
3-{[(15)-1-phenylpropyl]amino}-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2-dione;
3-{[(1R)-1-phenylpropyl]amino}-4-(pyridm-4-ylamino)cyclobut-3-ene-1,2-dione;
3-{[(1R)-1-(2-naphthyl)ethyl]amino}-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2-dione;
34(l^)-2,3-dihydro-li?-inden-1-ylainino]-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2- dione;
3-{[(1R)-l -(4-chlorophenyl)ethyl] amino } -4-(pyridin-4-ylamino)cyclobut-3 -ene- 1,2- dione;
3-{[(15)-1-(4-chlorophenyl)ethyl]amino}-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2- dione; 3- { [( LR)- 1 -(3 -methoxyphenyl)ethyl] amino } -4-(pyridin-4-ylamino)cyclobut-3 -ene- 1 ,2- dione;
3-{[(lfi)-1-(4-methoxyphenyl)ethyl]amino}-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2- dione;
3-[(4-bromobenzyl)amino]-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2-dione;
3-[(4-chlorobenzyl)amino]-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2-dione;
3-[(4-methoxybenzyl)amino]-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2-dione;
2- { [3 ,4-dioxo-2-(pyridin-4-ylamino)cyclobut- 1 -en- 1 -yl] amino } -iV-methyl-2- phenylacetamide;
3-{[(1R)-1-(4-fluorophenyl)ethyl]amino}-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2- dione;
3-{[l-(4-hydroxyphenyl)ethyl]amino}-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2-dione;
3-{[l-(l -naphthyl)ethyl] amino } -4-(pyridin-4-ylamino)cyclobut-3-ene- 1 ,2-dione;
3-{[(1R)-1-(4-methylphenyl)ethyl]amino}-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2- dione;
3-{[(1R)-1-(4-nitrophenyl)ethyl]amino}-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2-dione;
3-{[l-(4-fluorophenyl)-2-hydroxyethyl]amino}-4-(pyridin-4-ylamino)cyclobut-3-ene- 1,2-dione;
3-{[l-(4-chlorophenyl)-2-hydroxyethyl]amino}-4-(pyridin-4-ylamino)cyclobut-3-ene- 1,2-dione;
3-{[l-(2-fluorophenyl)-2-hydroxyethyl]amino}-4-(pyridin-4-ylamino)cyclobut-3-ene- 1,2-dione;
3-({2-hydroxy-1-[4-(trifluoromethyl)phenyl]ethyl}amino)-4-(pyridin-4- ylamino)cyclobut-3-ene- 1 ,2-dionei
3-{[2-hydroxy-1-(4-methylphenyl)ethyl]amino}-4-(pyridin-4-ylamino)cyclobut-3-ene- 1,2-dione;
3-{[l-(3-chloro-4-fluorophenyl)-2-hydroxyethyl]amino}-4-(pyridin-4-ylamino)cyclobut- 3-ene-1,2-dione;
3-{[2-hydroxy-1-(3,4,5-trifluorophenyl)ethyl]amino}-4-(pyridin-4-ylaniino)cyclobut-3- ene- 1,2-dione; 3-{[(15',2Λ)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]amiπo}-4-(pyridin-4- ylamino)cyclobut-3-ene- 1 ,2-dione;
3-{[2-(4-chlorophenyl)-1-methylethyl]amino}-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2- dione;
4-(l-{[3,4-dioxo-2-(ρyridin-4-ylamino)cyclobut-1-en-1-yl]amino}ethyl)benzonitrile;
3 - { [( 15)-2-hydroxy-2-methyl- 1 -phenylpropyl] amino } -4-(pyridin-4-ylamino)cyclobut-3- ene-1,2-dione;
3-{[(l/J)-2-hydroxy-2-methyl-1-phenylpropyl]ammo}-4-(pyridin-4-ylamino)cyclobut-3- ene-1,2-dione;
(2i?)-2-{[3,4-dioxo-2-(pyridin-4-ylammo)cyclobut-1-en-1-yl]ammo}-iV-methyl-2- phenylacetamide;
(25)-2-{[3,4-dioxo-2-(pyridin-4-ylamino)cyclobut-1-en-1-yl]amino}-iV-methyl-2- phenylacetamide;
2-(3,4-dichlorophenyl)-2-{[3,4-dioxo-2-(pyridin-4-ylamino)cyclobut-1-en-1- yl] amino } acetamide;
2-(4-chlorophenyl)-2-{[3,4-dioxo-2-(pyridin-4-ylamino)cyclobut-1-en-1- yl] amino } acetamide
(25)-2-(4-chlorophenyl)-2- { [3,4-dioxo-2-(pyridin-4-ylamino)cyclobut- 1 -en- 1 - yl]amino}acetamide;
(2Λ)-2-(4-chlorophenyl)-2-{[3,4-dioxo-2-(pyridin-4-ylamino)cyclobut-1-en-1- yl] amino } acetamide;
2-(3-chloro-4-fluorophenyl)-2-{[3,4-dioxo-2-(pyridin-4-ylamino)cyclobut-1-en-1- yl] amino } acetamide;
2-{[3,4-dioxo-2-(pyridin-4-ylamino)cyclobut-1-en-1-yl]amino}-2-[4- (trifluoromethyl)phenyl]acetamide;
2- { [3 ,4-dioxo-2-(pyridin-4-ylamino)cyclobut- 1 -en- 1 -yl] amino } -2-(4- fluorophenyl)acetamide;
2-{[3,4-dioxo-2-(pyridin-4-ylammo)cyclobut-1-en-1-yl]amino}-2-(2- fluorophenyl)acetamide;
2-{[3,4-dioxo-2-(pyridin-4-ylamino)cyclobut-1-en-1-yl]amino}-2-(3,4,5- trifluorophenyl)acetamide; 2-(4-chlorophenyl)-2-{[3,4-dioxo-2-(pyridin-4-ylamino)cyclobut-1-en-1-yl]amino}-N- methylacetamide;
2-{[3,4-dioxo-2-(pyridm-4-ylammo)cyclobut-1-en-1-yl]amino}-λ'-ethyl-2- phenylacetamide; iV-(cyclohexylmethyl)-2-{[3,4-dioxo-2-(pyridin-4-ylamino)cyclobut-1-en-1-yl]amino}-2- phenylacetamide; iV-(4-chlorobenzyl)-2- { [3,4-dioxo-2-(pyridin-4-ylamino)cyclobut- 1 -en- 1 -yl]amino} -2- phenylacetamide;
3- [(2-OXO- 1 -phenyl-2-ρyrrolidin- 1 -ylethyl)amino]-4-(pyridin-4-ylamino)cyclobut-3-ene- 1,2-dione;
2- { [3 ,4-dioxo-2-(pyridin-4-ylamino)cyclobut- 1 -en- 1 -yl] amino } -ΛyV-dimethyl-2- phenylacetamide; N-[2-(4-chlorophenyl)ethyl]-2-{[3,4-dioxo-2-(pyridin-4-ylamino)cyclobut-1-en-1- yl] amino } -2-phenylacetamide;
2- { [3,4-dioxo-2-(pyridin-4-ylamino)cyclobut- 1 -en- 1 -yl]amino} -2-phenyl-iV-(pyridin-4- ylmethyl)acetamide;
2- { [3,4-dioxo-2-(pyridin-4-ylamino)cyclobut- 1 -en- 1 -yljamino} -iV-isobutyl-2- phenylacetamide;
3-[(2-methoxypyridin-4-yl)ammo]-4-{[(liJ)-1-phenylethyl]amino}cyclobut-3-ene-1,2- dione;
(R)-3-(2-hydroxypyridin-4-ylamino)-4-(l-phenylethylamino)cyclobut-3-ene-1,2-dione;
3-{[l/Λimidazol-2-yl(phenyl)memyl]amino}-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2- dione;
3-[(3-methylisoxazol-5-yl)amino]-4-{[(1R)-1-phenylethyl]amino}cyclobut-3-ene-1,2- dione;
3-[methyl(pyridin-4-yl)amino]-4-{[(1R)-1-phenylethyl]amino}cyclobut-3-ene-1,2-dione;
3-{[(1R)-1-phenylethyl]amino}-4-[(2,2,6,6-tetramethylpiperidin-4-yl)amino]cyclobut-3- ene-1,2-dione;
3-{[(1R)-1-phenylethyl]amino}-4-(ρyrimidin-4-ylamino)cyclobut-3-ene-1,2-dione;
3-[(5-methyl-1H-pyrazol-3-yl)amino]-4-{[(1R)-1-phenylethyl]amino}cyclobut-3-ene- 1,2-dione; tert-butyl 4-[(3,4-dioxo-2-{[(1R)-1-phenylethyl]amino}cyclobut-1-en-1- yl)amino]piperidiπe- 1 -carboxylate;
3-{[(1R)-1-phenylethyl]aniino}-4-(1H-pyrazol-3-ylamino)cyclobut-3-ene-1,2-dione;
3-[(2-chloropyridin-4-yl)amino]-4-{[(1R)-1-phenylethyl]amino}cyclobut-3-ene-1,2- dione;
3-{[l-(4-cyclohexylphenyl)ethyl]amino}-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2-dione;
3-{[(1R)-1-cyclohexylethyl]amino}-4-(pyridin-4-ylainmo)cyclobut-3-ene-1,2-dione;
3-[(2-bromopyridin-4-yl)ammo]-4-{[(1R)-1-phenylethyl]amino}cyclobut-3-ene-1,2- dione;
3 - [(2-morpholin-4-ylρyridin-4-yl)amino] -4- { [( 1 R)- 1 -phenylethyl] amino } cyclobut-3 -ene- 1,2-dione;
3-[(l-methyl-1-phenylethyl)amino]-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2-dione;
3-{[(1R)-1-phenylethyl]amino}-4-{[2-(phenylthio)pyridin-4-yl]amino}cyclobut-3-ene- 1,2-dione;
4-[(3,4-dioxo-2-{[(1R)-1-phenylethyl]amino}cyclobut-1-en-1-yl)amino]pyridine-2- carboxamide;
3-{[(1R)-l -phenylethyl] amino } -4-(piperidin-4-ylamino)cyclobut-3 -ene- 1 ,2-dione; tert-butyl (2S)- { [3 ,4-dioxo-2-(pyridin-4-ylamino)cyclobut- 1 -en- 1 - yl]amino}(phenyl)acetate;
(2S)-{[3,4-dioxo-2-(pyridin-4-ylamino)cyclobut-1-en-1-yl]amino}(phenyl)acetic acid;
2-{[3,4-dioxo-2-(pyridin-4-ylamino)cyclobut-1-en-1-yl]amino}-2-(3- hydroxyphenyl)acetamide;
2-(3-bromophenyl)-2-{[3,4-dioxo-2-(pyridm-4-ylamino)cyclobut-1-en-1- yl] amino } acetamide;
2-biphenyl-3-yl-2-{[3,4-dioxo-2-(pyridin-4-ylamino)cyclobut-1-en-1- yl] amino } acetamide;
2-{[3,4-dioxo-2-(pyridin-4-ylamino)cyclobut-1-en-1-yl]amino}-2-[3-(3- thienyl)phenyl]acetamide;
3-[(l-biphenyl-3-ylethyl)amino]-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2-dione;
3-(pyridin-4-ylamino)-4-({l-[3-(3-thienyl)phenyl]ethyl}amino)cyclobut-3-ene-1,2-dione; 3-(pyridin-4-ylamino)-4-{[l-(3-pyridin-3-ylphenyl)ethyl]amino}cyclobut-3-ene-1,2- dione;
3-[(l-biphenyl-4-ylethyl)amino]-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2-dione;
3-({l-[4-(3-fiiryl)phenyl]ethyl}amino)-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2-dione;
3-(pyridin-4-ylamino)-4-({l-[4-(3-thienyl)phenyl]ethyl}amino)cyclobut-3-ene-1,2-dione;
2-{[3,4-dioxo-2-(pyridin-4-ylamino)cyclobut-1-en-1-yl]amino}-2-(3-methyl-2- thienyl)acetamide;
2-{[3,4-dioxo-2-(pyridin-4-ylamino)cyclobut-1-en-1-yl]ammo}-2-(3-furyl)acetainide;
3-[(25)-2-(hydroxymethyl)pyrrolidin-1-yl]-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2- dione;
3-(2-methylpyrrolidin- 1 -yl)-4-(pyridin-4-ylamino)cyclobut-3-ene- 1 ,2-dione;
3- [2-(hydroxymethyl)piperidin- 1 -yl]-4-(pyridin-4-ylamino)cyclobut-3-ene- 1 ,2-dione;
3-(2-methylpiperidin-1-yl)-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2-dione;
2- { [3,4-dioxo-2-(pyridin-4-ylamino)cyclobut-l -en- 1 -yl] amino} -2-(3-thienyl)acetamide;
3-(pyridin-4-ylamino)-4-[(l-pyridin-4-ylethyl)amino]cyclobut-3-ene-1,2-dione;
3-{[l-(l -benzofuran-2-yl)ethyl] amino } -4-(pyridin-4-ylamino)cyclobut-3 -ene- 1 ,2-dione;
3 - { [ 1 -(4-morpholin-4-ylphenyl)ethyl] amino } -4-(pyridin-4-ylamino)cyclobut-3 -ene- 1 ,2- dione;
3-({l-[4-(dimethylamino)phenyl]etnyl}amino)-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2- dione;
3-[(l-cyclohexylethyl)amino]-4-(pyridin-4-ylammo)cyclobut-3-ene-1,2-dione;
3-[(l-pyrazin-2-ylethyl)amino]-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2-dione;
3-( { 1 -[4-(l//-imidazol- 1 -yl)phenyl]ethyl} amino)-4-(pyridin-4-ylamino)cyclobut-3-ene- 1,2-dione;
3-(pyridin-4-ylamino)-4-{[l-(3-thienyl)ethyl]amino}cyclobut-3-ene-1,2-dione;
3-{[l-(l-methyl-l//-pyrrol-3-yl)ethyl]amino}-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2- dione;
3-{[l-(3-methylpyrazin-2-yl)ethyl]amino}-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2- dione;
3-{[l-(l-benzothien-3-yl)ethyl]amino}-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2-dione;
3-(pyridin-4-ylamino)-4-{[l-(1,3-thiazol-2-yl)ethyl]amino}cyclobut-3-ene-1,2-dione; 3 - { [ 1 -(3 -aminophenyl)ethyl] amino } -4-(pyridin-4-ylamino)cyclobut-3 -ene- 1 ,2-dione;
3-{[l-(2-fluorophenyl)ethyl]amino}-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2-dione;
3-{[l-(2-hydroxyphenyl)ethyl]amino}-4-(pyridin-4-ylainino)cyclobut-3-ene-1,2-dione;
3-{[l-(l//-mdol-3-yl)ethyl]ammo}-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2-dione;
3-{[l-(2,6-difluorophenyl)ethyl]amino}-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2-dione;
3-{[l-(3-fluorophenyl)ethyl]amino}-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2-dione;
3-{[l-(3-hydroxyphenyl)ethyl]amino}-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2-dione;
3-(pyridin-4-ylamino)-4-({l-[3-(trifluoromethyl)phenyl]ethyl}ammo)cyclobut-3-ene-1,2- dione;
3-[(2-azidopyridiπ-4-yl)amino]-4-{[(1R)-1-phenylethyl]amino}cyclobut-3-ene-1,2-dione;
3-{[(1R)-1-pheπylethyl]amino}-4-{[2-(4-phenyl-l/f-1,2,3-triazol-1-yl)pyridin-4- yl] amino } cyclobut-3 -ene- 1 ,2-dione;
3-{[2-(4-benzyl-l//-1,2,3-triazol-1-yl)pyridin-4-yl]amino}-4-{[(1R)-1- phenylethyl] amino} cyclobut-3-ene-1,2-dione;
3-({2-[4-(hydroxymethyl)-l/y-1,2,3-triazol-1-yl]pyridin-4-yl}amino)-4-{[(1R)-1- phenylethyl]amino}cyclobut-3-ene-1,2-dione;
3-{[l-(3-methylphenyl)ethyl]amino}-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2-dione;
3-[(l-phenylethyl)amino]-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2-dione;
3- { [ 1 -(3 -chlorophenyl)ethyl] amino } -4-(pyridin-4-ylamino)cyclobut-3-ene- 1 ,2-dione
Λ^-[3-(l-{[3,4-dioxo-2-(pyridin-4-ylamino)cyclobut-1-en-1-yl]amino}ethyl)phenyl] methanesulfonamide; methyl 3-(l-{[3,4-dioxo-2-(pyridin-4-ylamino)cyclobut-1-en-1-yl]amino}ethyl)benzoate;
N-[3-( 1 - { [3 ,4-dioxo-2-(pyridin-4-ylamino)cyclobut- 1 -en- 1 - yl] amino} ethyl)phenyl]acetamide;
3-( 1 - { [3 ,4-dioxo-2-(pyridin-4-ylamino)cyclobut- 1 -en- 1 -yl] amino } ethyl)benzoic acid;
3-{[l-(3 -bromophenyl)ethyl] amino } -4-(pyridin-4-ylamino)cyclobut-3 -ene- 1 ,2-dione;
3-(pyridin-4-ylamino)-4-({l-[3-(2i7-tetrazol-5-yl)phenyl]ethyl}amino)cyclobut-3-ene- 1,2-dione;
3 -( 1 - { [ 3 ,4-dioxo-2-(pyridin-4-ylamino)cyclobut- 1 -en- 1 -yl] amino } ethyl)benzamide;
3-{[l-(5-hydroxy-2-methoxyphenyl)ethyl]amino}-4-(pyridin-4-ylamino)cyclobut-3-ene- 1,2-dione; 3-{[l-(3-hydroxy-4-methoxyphenyl)ethyl]amino}-4-(pyridin-4-ylamino)cyclobut-3-ene- 1,2-dione;
3-{[l-(2,5-dihydroxyphenyl)ethyl]amino}-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2- dione;
3-{[l-(3,5-dihydroxyphenyl)ethyl]amino}-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2- dione;
3-{[l-(3-hydroxy-5-methoxyphenyl)ethyl]amino}-4-(pyridin-4-ylamino)cyclobut-3-ene- 1,2-dione;
N-[Z-(I- {[3 ,4-dioxo-2-(pyridin-4-ylamino)cyclobut- 1 -en- 1 -yl] amino } ethyl)phenyl] -JV- methylurea;
3-{[l-(3-amino-4-methylphenyl)ethyl]amino}-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2- dione;
3-{[l-(4-methyl-3-nitrophenyl)ethyl]amino}-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2- dione;
3-{[l-(3-hydroxy-4-methylphenyl)ethyl]amino}-4-(pyridin-4-ylamino)cyclobut-3-ene- 1,2-dione;
3-({2-[(E)-2-(4-chlorophenyl)vinyl]pyridin-4-yl}amino)-4-{[(1R)-1- phenylethyl]amiπo}cyclobut-3-ene-1,2-dione;
3- { [2-(3 -methoxyphenyl)pyridin-4-yl] amino } -4- { [( 1 R)- 1 -phenylethyl] amino } cyclobut-3 - ene- 1,2-dione;
3- [(2-anilinopyridin-4-yl)amino] -4- { [( 1 R)- 1 -phenylethyl] amino } cyclobut-3-ene- 1,2- dione;
3-{[(1R)-l -phenylethyl] amino } -4-[(2- { [4-(trifluoromethyl)phenyl] amino} pyridin-4- yl)amino]cyclobut-3-ene-1,2-dione;
3 - { [( 1 R)- 1 -phenylethyl] amino } -4- { [2-(pyrimidin-4-ylamino)pyridin-4- yl]amino}cyclobut-3-ene-1,2-dione;
3 - [(2- { [3-(hydroxymethyl)phenyl] amino } pyridin-4-yl)amino] -4- { [( 1 R)- 1 - phenylethyl] amino } cyclobut-3 -ene- 1 ,2-dione;
3-({4-[(3,4-dioxo-2-{[(1R)-1-phenylethyl]amino}cyclobut-1-en-1-yl)amino]pyridin-2- yl}amino)benzamide; 3 - { [( 1 R)- 1 -phenylethyl] amino } -4- { [2-(pyridin-2-ylamino)pyridin-4-yl] amino } cyclobut- 3-ene-1,2-dione;
3-{[(1R)-l -phenylethyl] amino } -4- { [2-(pyridin-3 -ylamino)pyridin-4-yl] amino } cyclobut- 3-ene-1,2-dione;
3-{[(1R)-l -phenylethyl] amino } -4- { [2-(pyrazin-2-ylamino)pyridin-4-yl] amino } cyclobut- 3-ene-1,2-dione;
N-(4-(2-((R)- 1 -phenylethylamino)-3,4-dioxocyclobut- 1 -enylamino)pyridin-2- yl)acetamide;
N-{4-[(3,4-dioxo-2-{[(1R)-1-phenylethyl]amino}cyclobut-1-en-1-yl)amino]pyridin-2- yl}benzamide;
N-{4-[(3,4-dioxo-2-{[(1R)-1-phenylethyl]amino}cyclobut-1-en-1-yl)amino]pyridin-2- yl}nicotinamide;
2-(l-phenylethyl)-6-pyridin-4-yl-2,6-diazabicyclo[5.2.0]non-l(7)-ene-8,9-dione;
3-{[(1R)-1-phenylethyl]amino}-4-[(2-phenylpyridin-4-yl)amino]cyclobut-3-ene-1,2- dione;
3 - { [2-(3 -fluorophenyl)pyridin-4-yl] amino }-4-{[(l R)- 1 -phenylethyl] amino } cyclobut-3 - ene-1,2-dione;
3-{[2-(l-benzofuran-2-yl)pyridin-4-yl]amino}-4-{[(1R)-1-phenylethyl]amino}cyclobut- 3-ene-1,2-dione;
3- { [2-(3 -fluorophenyl)pyridin-4-yl] amino }-4-{[(l R)- 1 -phenylethyl] amino } cyclobut-3- ene-1,2-dione;
3-(2)3'-biρyridin-4-ylamino)-4-{[(1R)-1-phenylethyl]amino}cyclobut-3-ene-1,2-dione;
3-{[(1R)-1-phenylethyl]amino}-4-({2-[3-(trifluoromethyl)phenyl]ρyridin-4- yl}amino)cyclobut-3-ene-1,2-dione;
3-{[(1R)-1-phenylethyl]amino}-4-({2-[4-(trifluoromethyl)phenyl]pyridin-4- yl}amino)cyclobut-3-ene-1,2-dione;
3-{[(1R)-l -phenylethyl] amino} -4- { [2-(pyridin-4-ylamino)pyridin-4-yl] amino } cyclobut- 3-ene-1,2-dione;
3-({2-[(4-methyl-1,3-thiazol-2-yl)amino]pyridin-4-yl}amino)-4-{[(1R)-1- phenylethyl]amino}cyclobut-3-ene-1,2-dione; 3-{[(1R)-1-phenylethyl]amino}-4-{[2-(quinolin-2-ylamino)pyridin-4-yl]amino}cyclobut-
3-ene-1,2-dione;
3-{[(1R)-l -phenylethyl] amino } -4- { [2-(pyrimidin-2-ylamino)pyridin-4- yl]amino}cyclobut-3-ene-1,2-dione;
3-{[2-(2-fluorophenyl)pyridin-4-yl]amino}-4-{[(1R)-1-phenylethyl]amino}cyclobut-3- ene-1,2-dione;
3-{[2-(2-furyl)pyridin-4-yl]amino}-4-{[(1R)-1-phenylethyl]amino}cyclobut-3-ene-1,2- dione;
3 - { [2-(4-methylphenyl)pyridin-4-yl] amino } -4- { [( 1 R)- 1 -phenylethyl] amino } cyclobut-3- ene-1,2-dione;
N-(4-{4-[(3,4-dioxo-2-{[(1R)-1-phenylethyl]amino}cyclobut-1-en-1-yl)amino]pyridin-2- yl}phenyl)acetamide;
3 - { [2-(3-methylphenyl)pyridin-4-yl] amino } -4- { [( 1 R)- 1 -phenylethyl] amino } cyclobut-3 - ene-1,2-dione;
3-(2,4'-bipyridin-4-ylamino)-4-{[(1R)-1-phenylethyl]amino}cyclobut-3-ene-l)2-dione;
3-( {2-[4-(hydroxymethyl)phenyl]pyridin-4-yl} amino)-4- {[(1 R)- 1 - phenylethyl]amino}cyclobut-3-ene-1,2-dione;
3 -( {2- [3 -(benzyloxy)phenyl]pyridin-4-yl} amino)-4- { [( 1 R)- 1 phenylethyl] amino } cyclobut-3 -ene- 1 ,2-dione;
3-[(2-biphenyl-3-ylpyridin-4-yl)amino]-4-{[(1R)-1-phenylethyl]amino}cyclobut-3-ene- 1,2-dione;
3 - [(2-biphenyl-3 -ylpyridin-4-yl)amino] -4- { [( 1 R)- 1 -phenylethyl] amino } cyclobut-3 -ene- 1,2-dione;
N-cyclopentyl-4-{4-[(3,4-dioxo-2-{[(1R)-1-phenylethyl]amino}cyclobut-1-en-1- yl)amino]pyridin-2-yl}benzamide;
3 - { [2-(4-chlorophenyl)pyridin-4-yl] amino }-4-{[(1R)-l -phenylethyl] amino } cyclobut-3- ene-1,2-dione;
3-(2,2'-bipyridin-4-ylamino)-4-{[(1R)-1-phenylethyl]amino}cyclobut-3-ene-l>2-dione;
2- { [3 ,4-dioxo-2-(pyridin-4-ylamino)cyclobut- 1 -en-1 -yljamino} -2-(4-pyridin-3- ylphenyl)acetamide; 2-biphenyl-4-yl-2- { [3 ,4-dioxo-2-(pyridin-4-ylamino)cyclobut- 1 -en- 1 - yl]amino} acetamide;
2-(4-bromophenyl)-2- { [3 ,4-dioxo-2-(pyridin-4-ylamino)cyclobut- 1 -en- 1 - yljamino} acetamide;
2-{[3,4-dioxo-2-(pyridin-4-ylamino)cyclobut-1-en-1-yl]amino}-2-[4-(3- thienyl)phenyl] acetamide ;
2- { [3 ,4-dioxo-2-(pyridin-4-ylamino)cyclobut- 1 -en- 1 -yl] amino } -2- [4-(3 - furyl)phenyl] acetamide;
3-{[(1R)-1-phenylethyl]amino}-4-(thieno[2,3-b]pyridin-4-ylamino)cyclobut-3-ene-1,2- dione;
3-{[l-(4-iodophenyl)ethyl]amino}-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2-dione; and pharmaceutically acceptable salts thereof.
41. A compound according to claim 1 , which is selected from:
2-{[3,4-dioxo-2-(pyridin-4-ylamino)cyclobut-1-en-1-yl]amino}-2-(3'-methylbiphenyl-3- yl)acetamide;
2- {3'-[(dimethylamino)sulfonyl]biphenyl-3-yl} -2- {[3,4-dioxo-2-(pyridin-4- ylamino)cyclobut-1-en-1-yl]amino} acetamide;
2-{[3,4-dioxo-2-(pyridin-4-ylamino)cyclobut-1-en-1-yl]amino}-2-(2'-methylbiphenyl-3- yl)acetamide;
2-(3'-cyanobiphenyl-3-yl)-2-{[3,4-dioxo-2-(pyridin-4-ylamino)cyclobut-1-en-1- yl]amino}acetamide;
2- { [3 ,4-dioxo-2-(pyridin-4-ylamino)cyclobut- 1 -en- 1 -yl] amino } -2-(4'-methylbiphenyl-3 - yl)acetamide;
3'-( 1 - { [3 ,4-dioxo-2-(pyridin-4-ylamino)cyclobut- 1 -en- 1 -yl] amino } ethyl)biphenyl-3 - carbonitrile;
3-{[l-(4'-acetylbiphenyl-3-yl)ethyl]amino}-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2- dione;
3-{[l-(4'-chlorobiphenyl-3-yl)ethyl]amino}-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2- dione; 3-{[l-(2'-methylbiphenyl-3-yl)ethyl]amino}-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2- dione;
3- { [ 1 -(4'-methylbiphenyl-3 -yl)ethyl] amino } -4-(pyridin-4-ylamino)cyclobut-3-ene- 1,2- dione;
3-{[l-(3'-methoxybiphenyl-3-yl)ethyl]amino}-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2- dione; tert-butyl [3 '-( 1 - { [3 ,4-dioxo-2-(pyridin-4-ylamino)cyclobut- 1 -en- 1 - yl] amino } ethyl)biphenyl-4-yl] carbamate;
3-{[l-(3'-aminobiphenyl-4-yl)ethyl]amino}-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2- dione;
3- { [ 1 -(4'-chlorobiphenyl-4-yl)ethyl]amino} -4-(pyridin-4-ylamino)cyclobut-3-ene- 1 ,2- dione;
2-{[3,4-dioxo-2-(pyridin-4-ylamino)cyclobut-1-en-1-yl]amino}-2-[4'-(morpholin-4- ylcarbonyl)biphenyl-4-yl]acetamide;
2- { [3 ,4-dioxo-2-(pyridin-4-ylamino)cyclobut- 1 -en- 1 -yl] amino} -2- {3 '- [(methylsulfonyl)amino]biphenyl-4-yl}acetamide;
2-{3'-[(dimethylamino)sulfonyl]biphenyl-4-yl}-2-{[3,4-dioxo-2-(pyridin-4- ylamino)cyclobut- 1 -en- 1 -yl]amino } acetamide;
2-{[3,4-dioxo-2-(pyridin-4-ylamino)cyclobut-1-en-1-yl]amino}-2-[3'-(morpholin-4- ylcarbonyl)biphenyl-4-yl]acetamide;
2- { [3 ,4-dioxo-2-(pyridin-4-ylamino)cyclobut- 1 -en- 1 -yl] amino } -2- { 3 '- [(ethylamino)sulfonyl]biphenyl-4-yl} acetamide;
2-(2'-aminobiphenyl-4-yl)-2- { [3,4-dioxo-2-(ρyridin-4-ylamino)cyclobut- 1 -en- 1 - yl]amino} acetamide;
Λ^[3,4-dioxo-2-(pyridin-4-ylamino)cyclobut-1-en-1-yl]-L-phenylalaninamide;
N-[3,4-dioxo-2-(pyridin-4-ylamino)cyclobut-1-en-1-yl]-D-phenylalaninamide; and pharmaceutically acceptable salts thereof.
42. A compound of claim 1 , selected from:
3-(isobutylamino)-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2-dione;
3-(allylamino)-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2-dione; (R)-3-(Pyndm-4-ylammo)-4 (1,2,2-trimethyl-propylamino)- cyclobut-3-ene-1,2-dione, TV2- [3 ,4-dioxo-2-(pyndm-4-ylammo)cyclobut- 1 -en- 1 -yl] -L-leucmamide, N2-[3,4-dioxo-2-(pyndm-4-ylammo)cyclobut-1-en-1-yl]-L-alanmamide, N2-[3,4-dioxo-2-(pyridin-4-ylammo)cyclobut-1-en-1-yl]-L-serinainide, and pharmaceutically acceptable salts thereof
43 A pharmaceutical composition composing a pharmaceutically acceptable earner and a compound according to any one of claims 1 to 42, or a pharmaceutically acceptable salt thereof
44 A pharmaceutical composition comprising a pharmaceutically acceptable earner and a compound according to claim 2, or a pharmaceutically acceptable salt thereof
45 A method of treating a disease or disorder selected from rheumatoid arthritis, psonasis, lupus, inflammatory bowel disease, asthma, and chrome obstructive pulmonary disease m a patient in need thereof, compnsmg admimstenng to said patient a therapeutically effective amount of a compound according to any one of claims 1 to 42, or a pharmaceutically acceptable salt thereof
46 A kit compnsmg a compound according to any one of claims 1 to 42, or a pharmaceutically acceptable salt thereof, and instructions, wherein said instructions compnse a direction to administer said compound, or pharmaceutically salt thereof, to a patient m need of treatment for a disease or disorder selected from rheumatoid arthritis, psonasis, lupus, inflammatory bowel disease, asthma, and chrome obstructive pulmonary disease
47 Use of a compound according to any one of claims 1 to 42, or a pharmaceutically acceptable salt thereof, for the preparation of medicament for use m a method of treating a disease or disorder selected from rheumatoid arthntis, psonasis, lupus, inflammatory bowel disease, asthma, and chrome obstructive pulmonary disease
48. A compound according to any one of claims 1 to 42, or a pharmaceutically acceptable salt thereof, for use in a method of treating a disease or disorder selected from rheumatoid arthritis, psoriasis, lupus, inflammatory bowel disease, asthma, and chronic obstructive pulmonary disease.
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