WO2009012375A2 - Inhibiteurs de la squarate kinase - Google Patents

Inhibiteurs de la squarate kinase 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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WO2009012375A3 (fr
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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.

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Abstract

L'invention concerne des composés de Formule (I) :, ainsi que des sels pharmaceutiquement acceptables et des compositions pharmaceutiques de ceux-ci, dans laquelle Het, R4, R9 et R10 sont tels que définis dans la description. Ces composés de Formula (I) sont utiles en tant qu'inhibiteurs de la protéine kinase 2 activée par la MAP kinase (MK2).
PCT/US2008/070312 2007-07-19 2008-07-17 Inhibiteurs de la squarate kinase WO2009012375A2 (fr)

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US9018261B2 (en) 2011-09-02 2015-04-28 Novartis Ag Choline salt of an anti-inflammatory substituted cyclobutenedione compound
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