SQUARATE KINASE INHIBITORS

TECHNICAL FIELD

The invention relates to squarate kinase inhibitors, and methods for making and using them.

BACKGROUND

Mitogen activated protein (MAP) kinases are a large and diverse group of Ser/Thr kinases separated into three major subgroups, which include the extracellular signal regulated kinases (ERKs), the c-Jun N-terminal kinases (JNKs)/stress-activated protein kinases (JNKs) and p38/reactivating kinases (RK). The ERKs are activated by mitogens and growth factors, whereas the INKs/SAPKs and p38/RK are activated by bacterial lipopolysaccharide (LPS, interleukin-1 (IL-I), tumor necrosis factor-α (TNF-α) and cellular stresses such as heat shock, osmotic shock, or UV damage. Exposure of cells to these factors results in the increased production of proinflammatory cytokines. Analysis of a specific inhibitor of p38 MAP kinase, SB203580, reveals that it inhibits LPS-induced cytokine synthesis in human monocytes, thus indicating that p38 is the MAP kinase responsible for stress-induced cytokine production (see, e.g., Lee, J. C, et al. (1994) Nature 372, 739-746, and U.S. Patent Application Publication No. 2004/0091872, each of which is incorporated by reference in its entirety). SB203580 also prevents the activation of MAP kinase activated protein kinase 2 (MK2, MAPKAPK 2), suggesting that this kinase is activated by p38 (see, e.g., Cuenda, A., et al. (1995) FEBS Letters 364, 229-233, which is incorporated by reference in its entirety).

Mice engineered to be homozygously-deficient in MK2 show a reduction in TNF-α, interferon-γ, IL-I β, and IL-6 production and an increased rate of survival upon challenge with LPS, suggesting that this enzyme is a key component in the inflammatory process and a potential target for anti-inflammatory therapy (Kotlyarov, A., et al. (1999) Nat. Cell. Biol. 1, 94-97, which is incorporated by reference in its entirety). Activation of MK2 results in the production of cytokines by regulating the translation and or stability of the encoding mRNAs through the AU- rich elements of the 3 '-untranslated regions of the gene (Neininger, A., et al. (2002) J. Biol. Chem. 277, 3065-3068, which is incorporated by reference in its entirety). MK2 also phosphorylates the transcription factor CREB, as well as leukocyte specific protein- 1 and heat

shock protein 25/27, which are involved in the regulation of actin polymerization and cell migration. See, e.g., Tan, Y., et al. (1996) EMBO J. 15, 4629-4642; Lavoie, J. et al. (1993) J. Biol. Chem. 268, 24210-24214; Stokoe, D. et al. (1992) FEBS Letters 313, 307-313; Ben-Levy, R., et al. (1995) EMBO J. 14, 5920-5930; Hedges, J. C, et al. (1999) J. Biol. Chem. 274, 24211- 24219; and Kotlyarov, A. et al. (2002) MoI. Cell. Biol. 22, 4827-4835, each of which is incorporated by reference in its entirety.

MK2 is a multi-domain protein consisting of an N-terminal proline-rich domain, a catalytic domain, an autoinhibitory domain and at the C-terminus a nuclear export signal (NES) and nuclear localization signal (NLS). See, for example, Stokoe, D., et al. (1993) Biochem. J. 296, 843-849; Engel, K., et al. (1998) EMBO J. 17, 3363-3371; Ben-Levy, R., et al. (1998) Curr. Biol. 8, 1049-1057; Engel, K., et al. (1993) FEBS Letters 336, 143-147; and Veron, M., et al. (1993) Proc. Natl. Acad. Sci. 90, 10618-10622, each of which is incorporated by reference in its entirety. Two isoforms of human MK2 have been characterized. One isoform consists of 400 amino acids and the other isoform 370 residues which is thought to be a splice variant missing the C-terminal NLS (see, e.g., Zu, Y.-L., et al. (1994) Biochem. Biophys. Res. Commun. 200, 1118-1124, which is incorporated by reference in its entirety). MK2 is located in the nucleus of the cell and upon binding and phosphorylation by p38, the MK2 NES becomes functional and both kinases are co-transported out of the nucleus to the cytoplasm (see, e.g., Stokoe, D., et al. (1992) EMBO J. 11, 3985-3994, which is incorporated by reference in its entirety). Interestingly, transport of the MK2/p38 complex does not require catalytically active MK2, as the active site mutant, Asp207Ala, is still transported to the cytoplasm. Phosphorylation of human MK2 by p38 on residues T222, S272 and T334 is thought to activate the enzyme by inducing a conformational change of the autoinhibitory domain thus exposing the active site for substrate binding (see, e.g., Engel, K., et al. (1995) J. Biol. Chem. 270, 27213-27221, which is incorporated by reference in its entirety). Mutations of two autoinhibitory domain residues W332A and K326E in murine MK2 demonstrate an increase in basal activity and a C-terminal deletion of the autoinhibitory domain renders the enzyme constitutively active, providing additional evidence to the role of this domain in inhibition of MK2 activity.

SUMMARY

Certain squarate compounds are kinase inhibitors. In particular, they are inhibitors of MK2, also known as MAPKAP kinase 2.

In one aspect, the present invention provides a compound of Formula (I):

or a pharmaceutically acceptable salt thereof; wherein:

Hβt is a heteroaryl group or a heterocyclyl group, wherein at least one ring atom in said heteroaryl group or said heterocyclyl group is N, and wherein Het is optionally substituted by 1-4 substituents independently selected from 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 ^ε groups;

R ⁹ is H, alkyl, cycloalkyl, or perfluoroalkyl; R ¹⁰ is H, alkyl, cycloalkyl, or perfluoroalkyl; 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 ; 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,

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 ^b , -C(O)N(R ⁷ )-R ^b , -SO _m -R ^b , -SO ₂ -N(R ⁷ )-R ^b , -(CR ⁷ RVOR 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 -C ₈ cycloalkyl, C ₃ -C ₈ cycloalkenyl, -(CH ₂ ) _n -aryl, -(CH ₂ ) _n -heteroaryl, or -(CH ₂ ) _n -heterocyclyl; wherein each of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclyl is optionally substituted with 1-5 substituents independently selected from R ^a ;

R ² 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(O)-R ^c , -C(O)O-R ^c , -C(O)N(R ⁷ )-R ^c , -SO _m -R ^c , -SO ₂ -N(R ⁷ )-R ^c , -(CR ⁷ R ⁸ ) _n -OR ⁷ , or -C(O)N(R ⁷ )R ⁸ ; wherein R ^c is -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; wherein each of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclyl is optionally substituted with 1-5 substituents independently selected from R ^a ; or R ¹ and R ² together form an oxo group;

R ³ is -(CR ⁷ RVaryl, -(CR ⁷ R ⁸ ) _n -heteroaryl, -(CR ⁷ R ⁸ ) _n -(C ₃ -C ₈ cycloalkyl), or -(CR ⁷ R ^s ) _n -heterocyclyl; wherein R ³ is optionally substituted with 1-5 substituents independently selected from R ^f ; each R ⁵ , independently, is 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, C ₃ -C ₈ cycloalkenyl, aryl, heteroaryl, heterocyclyl, -CH=CH-aryl, -CH=CH-heteroaryl, -O-R ^d , -OC(O)-R ^d , -C(0)-R ^d , -C(0)0-R ^d , -C(0)N(R ⁷ )-R ^d , -N(R ⁷ )R ^d , -N(R ⁷ )C(O)-R ^d , -N(R ⁷ )-SO _m R ^d , -SO _m -R ^d , -SO ₂ -N(R ⁷ )-R ^d , -(CR ⁷ R ⁸ ) _n -OR ⁷ , -C(O)OR ⁷ , or -C(O)N(R ⁷ )R ⁸ ; wherein R ^d is -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; wherein each R ⁵ is, independently, optionally substituted with 1-5 substituents independently selected from R ^a ; each R ⁷ , independently, is -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; wherein each R ⁷ , 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), -N(C ₁ -C ₆ alkyl) ₂ , -NHC(O)-( C ₁ -C ₆ alkyl), -SO _m (C,-C ₆ alkyl), -SO _m NH(C ₁ -C ₆ alkyl), and -SO _m N( C ₁ -C ₆ alkyl) ₂ ; each R ⁸ , independently, is -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; wherein each R ^s , 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), -N(C ₁ -C ₆ alkyl) ₂ , -NHC(O)-(C ₁ -C ₆ alkyl), -SO _1n (C ₁ -C ₆ alkyl), -SOn ₁ NH(C ₁ -C ₆ alkyl), and -SO _ra N(C ₁ -C ₆ alkyl) ₂ ; 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 J _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 -OR ⁷ , -(CH ₂ ) _n -N(R ⁷ )(R ^s ), -(CH ₂ ) _n -C(=NR ⁷ )N(R ⁷ )(R ⁸ ), -O-R ^e , -C(O)-R ^c , -C(0)N(R ⁷ )-R ^e , -C(O)-N(R ⁷ )-SO _m -R ⁸ , -O(CH ₂ ) _n -N(R ⁷ )(R ⁸ ), -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 , -SH, -SO _m -R ^e , -SO ₂ -N(R ⁷ )-R ^e , -0C(0)-R ^e , -C(O)O-R ⁶ , -(CR ⁷ R ⁸ ) _n -OR ⁷ , or -OPO ₃ (R ⁷ )(R ⁸ ); wherein R ^e is -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 ^f , 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 -OR ⁷ , -(CH ₂ ) _n -N(R ⁷ )(R ⁸ ), -(CH ₂ ) _n -C(=NR ⁷ )N(R ⁷ )(R ⁸ ), -O-R ^e , -C(O)-R ^e , -C(0)N(R ⁷ )-R ^e , -C(O)-N(R ⁷ )-SO _ra -R ⁸ , -O(CH ₂ ) _n -N(R ⁷ )(R ⁸ ), -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 , -SH, -SO _m -R ^e , -SO ₂ -N(R ⁷ )-R ^e , -OC(O)-R ⁶ , -C(O)O-R ⁶ , -(CR ⁷ R ⁸ J _n -OR ⁷ , or -OPO ₃ (R ⁷ XR ⁸ ); wherein said -(CH ₂ ) _n -heteroaryl and -(CH ₂ ) _n -aryl are each further optionally substituted by a group selected from halogen, -CN, Q-C ₄ alkyl, C ₁ -C ₄ alkoxy, amino, C ₁ -C ₄ - alkylamino, di-C ₁ -C ₄ -alkylaino, aminosulfonyl, C ₁ -C ₄ -alkylaminosulfonyl, di-C ₁ -C ₄ - alkylaminosulfonyl, C ₁ -C ₄ alkylsulfonylamino, heterocyclylcarbonyl, C ₁ -C ₄ alkylcarbonyl, and C ₁ -C ₄ alkoxycarbonylamino; each R ⁸ group is independently selected from carbamyl and hydroxyl; each n, independently, is O, 1, 2, 3 or 4; and each m, independently, is O, 1, or 2; provided that the compound is not 3-(5-bromo-pyridin-3-ylamino)-4-(l- phenylethylamino)cyclobut-3-ene-1,2-dione, 3-(l-phenylethylamino)-4-(pyridin-4-ylamino)- cyclobut-3-ene-1,2-dione, or 3-(bicyclo[2.2.1]hept-2-ylamino)-4-(pyridin-4-ylamino)-cyclo but- 3-ene-1,2-dione;

provided that the compound is not quadratic acid 1,2-bis(ρyridyl)amide, quadratic acid 1 ,2-bis(pyridylmethylene)amide; provided that the compound is not 3-chloro-N-(l-{[3,4-dioxo-2-(5-pyrimidinylamino)-1- cyclobuten-1-yl]amino}-2,2-dimethylpropyl)benzamide, N-(l-{[3,4-dioxo-2-(5- pyrimidmylamino)-1-cyclobuten-1-yl]amino}-2,2-dimethylpropyl )-3,5-difluorobenzamide, or N- (l-{[3,4-dioxo-2-(2-pyrazinylamino)-1-cyclobuten-1-yl]amino} -2,2-dimethylpropyl)-3,5- difluorobenzamide; provided that when Het is 4-hydroxy-2-oxo-N-methyl-1,2-dihydropyridin-5-yl, 5- dimethylaminocarbonyl-4-hydroxypyridin-3-yl, 5-hydroxy-6- (dimethylaminocarbonyl)pyrimidin-4-yl, or 5-dimemylaminocarbonyl-4-hydroxy-1-methyl- pyrazol-3-yl, R ⁴ is neither 1,2-dimethylpropyl nor 1-phenylpropyl.

In another aspect, the present invention provides a compound of Formula (I), wherein:

Het can be a heteroaryl group or a heterocyclyl group, where at least one ring atom is N, and where Het is optionally substituted by 1-4 substituents independently selected from 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. In R ¹ , 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,

C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, C ₃ -C ₈ cycloalkenyl, aryl, heteroaryl, heterocyclyl, -C(O)-R ^c ,

-C(O)O-R ^c , -C(O)N(R ⁷ )-R ^c , -SO _m -R ^c , -SO ₂ -N(R ⁷ )-R ^c , -(CR ⁷ R ⁸ ) _n -OR ⁷ , or -C(O)N(R ⁷ )R ⁸ . 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. In R ² , 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 , independently, 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,

C ₃ -C ₈ cycloalkenyl, aryl, heteroaryl, heterocyclyl, -CH=CH-aryl, -CH=CH-heteroaryl, -O-R ^a , -0C(0)-R ^d , -C(0)-R ^d , -C(O)O-R ^d , -C(0)N(R ⁷ )-R ^d , -N(R ⁷ )R ^d , -N(R ⁷ )C(O)-R ^d , -N(R ⁷ )-SO _m R ^d , -SO _m -R ^d , -SO ₂ -N(R ⁷ )-R ^d , -(CR ⁷ R ⁸ ) _n -OR ⁷ , -C(O)OR ⁷ , or -C(O)N(R ⁷ )R ⁸ . 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 , independently, 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 , independently, 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 .

Each R ⁸ , independently, 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 , independently, 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 .

Each R ^a , independently, can be halogen, oxo, -CN, -CHO, -OH, -NO ₂ , -N ₃ , -OCF ₃ , C ₁ -C ₆ alkyl, C ₁ -C ₆ perfluoroalkyl, -(CH ₂ )H-(C ₃ -C ₈ cycloalkyl), -(CH ₂ X ₁ -(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 -OR ⁷ , -(CH ₂ ) _n -N(R ⁷ )(R ⁸ ), -(CH ₂ ) _n -C(=NR ⁷ )N(R ⁷ )(R ^s ), -0-R ^E , -C(O)-R ^e , -C(O)N(R ⁷ )-R ^e , -C(O)-N(R ⁷ )-SO _m -R ^s , -O(CH ₂ ) _n -N(R ⁷ )(R ^B ), -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 )-SO _ra -R ^e , -SH, -SO _m -R ^e , -SO ₂ -N(R ⁷ )-R ^e , -OC(O)-R ⁶ , -C(0)0-R ^e , -(CR ⁷ R ⁸ ) _n -OR ⁷ , or -OPO ₃ (R ⁷ )(R ⁸ ). 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. In another aspect, the present invention provides a compound of Formula (I), wherein:

Het is pyridin-4-yl optionally substituted by 1-4 substituents independently selected from 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 -C ₈ cycloalkyl, C ₃ -C ₈ cycloalkenyl, -(CH ₂ ) _n -aryl, -(CH ₂ ) _n -heteroaryl, or -(CH ₂ ) _n -heterocyclyl; wherein each of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclyl is optionally substituted with 1-5 substituents independently selected from R ^a ; R ² 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 ^c , -C(O)O-R ^c , -C(0)N(R ⁷ )-R°, -SO _m -R ^c , -SO ₂ -N(R ⁷ )-R ^c , -(CR ⁷ R ⁸ ) _n -OR ⁷ , or -C(O)N(R ⁷ )R ⁸ ; wherein R ^c is -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; wherein each of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclyl is optionally substituted with 1-5 substituents independently selected from R ^a ;

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 1-5 substituents independently selected from R ^a ; each R ⁵ , independently, is 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,

C ₃ -C ₈ cycloalkenyl, aryl, heteroaryl, heterocyclyl, -CH=CH-aryl, -CH=CH-heteroaryl, -O-R ^d , -OC(O)-R ^d , -C(O)-R ^d , -C(O)O-R", -C(0)N(R ⁷ )-R ^d , -N(R ⁷ )R ^d , -N(R ⁷ )C(0)-R ^d , -N(R ⁷ )-SO _ra R ^d , -SO _m -R ^d , -SO ₂ -N(R ⁷ )-R ^d , -(CR ⁷ R ⁸ ) _n -OR ⁷ , -C(O)OR ⁷ , or -C(O)N(R ⁷ )R ⁸ ; wherein R ^d is -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; wherein each R ⁵ is, independently, optionally substituted with 1-5 substituents independently selected from R ^a ; each R ⁷ , independently, is -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; wherein each R ⁷ , 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), -N(C ₁ -C ₆ alkyl) ₂ , -NHC(O)-(C ₁ -C ₆ alkyl), -SO ₁₁₁ (C ₁ -C ₆ alkyl), -SO _m NH(C ₁ -C ₆ alkyl), and -SO _m N(C ₁ -C ₆ alkyl) ₂ ; each R ⁸ , independently, is -H, C ₁ -C ₆ perfluoroalkyl, -(CH ₂ ) _n -(C ₁ -C ₆ alkyl),

-(CH ₂ ) _n -(C ₃ -C ₈ cycloalkyl), -(CHz) _n -(C ₃ -C ₈ cycloalkenyl), -(CH ₂ ) _n -aryl, -(CH ₂ ) _n -heteroaryl, or -(CH ₂ ) _n -heterocyclyl; wherein 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), -N(C ₁ -C ₆ alkyl) ₂ , -NHC(O)-(C ₁ -C ₆ alkyl), -SO _1n (C ₁ -C ₆ alkyl), -SO _m NH(C ₁ -C ₆ alkyl), and -SO _1n N(C ₁ -C ₆ alkyl) ₂ ;

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 -OR ⁷ , -(CH ₂ ) _n -N(R ⁷ )(R ⁸ ), -(CH ₂ ) _n -C(=NR ⁷ )N(R ⁷ )(R ⁸ ), -O-R ^e , -C(O)-R ^e , -C(0)N(R ⁷ )-R ^e , -C(O)-N(R ⁷ )-SO _m -R ⁸ , -O(CH ₂ ) _n N(R ⁷ )(R ⁸ ), -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 , -SH ₁ -SO _m -R ^e , -SO ₂ -N(R ⁷ )-R ^e , -OC(O)-R ^e , -C(O)O-R=, -(CR ⁷ R ⁸ ) _n OR ⁷ , or -OPO ₃ (R ⁷ )(R ⁸ ); wherein R ^e is -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 0, 1, 2, 3 or 4; and each m, independently, is 0, 1, or 2; provided that the compound is not 3-(5-bromo-pyridm-3-ylamino)-4-(l- phenylethylamino)cyclobut-3-ene-1,2-dione, 3-(l-phenylethylamino)-4-(pyridin-4-ylamino)- cyclobut-3-ene-1,2-dione, or 3-(bicyclo[2.2.1]hept-2-ylamino)-4-(pyridin-4-ylamino)-cyclo but- 3-ene-1,2-dione.

In some embodiments, the compound can be in the form of a pharmaceutically acceptable salt.

In some embodiments, the compound is not 3-(5-bromo-pyridin-3-ylamino)-4-(l- phenylethylamino)cyclobut-3-ene-1,2-dione, 3-(l-phenylethylamino)-4-(pyridin-4-ylamino)- cyclobut-3-ene-1,2-dione, 3-(bicyclo[2.2.1]hept-2-ylamino)-4-(pyridin-4-ylamirio)-cycl obut-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-cyclobute n- 1 -yl] amino } -2 ,2-dimethylpropyl)benzamide, N-( 1 - { [3 ,4-dioxo-2-(5 -pyrimidinylamino)- 1 - cyclobuten-1-yl]amino}-2,2-dimethylpropyl)-3,5-difluorobenza mide, or N-(I- {[3,4-dioxo-2-(2- pyrazinylamino)-1-cyclobuten-1-yl]amino}-2,2-dimethylpropyl) -3,5-difluorobenzamide.

In some embodiments, when Het is 4-hydroxy-2-oxo-N-methyl-1,2-dihydropyridm-5-yl, S-dimethylaminocarbonyM-hydroxypyridin-S-yl, 5-hydroxy-6-

(dimethylaminocarbonyl)pyrimidin-4-yl, or 5 -dimethylaminocarbonyl-4-hydroxy- 1 -methyl- pyrazol-3-yl, R ⁴ is neither 1,2-dimethylpropyl nor 1-phenylpropyl.

In some embodiments, Het is pyridin-4-yl optionally substituted by 1-4 substituents independently selected from 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.

In some embodiments, the compound is not 3~(5-bromo-pyridin-3-ylamino)-4-(l- phenylethylamino)cyclobut-3-ene-1,2-dione, 3-(l-phenylethylamino)-4-(pyridin-4-ylamino)- cyclobut-3-ene-1,2-dione, or 3-(bicyclo[2.2.1]hept-2-ylamino)-4-(pyridin-4-ylamino)-cyclo but- 3-ene-1,2-dione. In some embodiments, Het is pyridinyl, piperidinyl, pyrimidinyl, oxazolinyl, pyrazolyl, isoquinolinyl, or quinolinyl, optionally substituted by 1-4 substituents independently selected from R ⁵ . In some embodiments, Het is pyridin-4-yl optionally substituted by 1-4 substituents independently selected from R ⁵ . Fn some embodiments, Het is pyridin-4-yl optionally substituted at the 2-position by R ⁵ . In some circumstances, 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 . In some embodiments, each R ⁵ , independently, is halogen, -OH, -N ₃ , C ₁ -C ₆ alkyl, aryl, heteroaryl, heterocyclyl, -CH=CH-aryl, -O-R ^d , -C(O)O-R ^d , -C(O)N(R ⁷ )-R ^d , -N(R ⁷ )R ^d , -N(R ⁷ )C(O)-R ^d , or -SO _m -R ^d ; wherein each R ⁵ is, independently, optionally substituted with 1-5 substituents independently selected from R ^a . In some embodiments, 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, phenylthio, 3- (benzyloxy)phenyl, biphenyl-3-yl, anilino, 4-trifluoromethylanilino, 2-pyrimidin-4-ylamino, 3- (hydroxymethyl)anilino, 3-carbamylanilino, pyridin-3-ylamino, pyridin-2-ylamino, pyridin-4- ylamino, 4-methyl-1,2,3-triazol-2-ylamino, quinolin-2-ylamino, pyrimidin-2-ylamino, acetamido, pyridin-4-yl, pyridin-3-yl, pyridin-2-yl, benzamido, or nicotinamido. In some embodiments, R ² is -H, C ₁ -C ₆ alkyl, aryl, heteroaryl, -C(O)-R ^c , -C(O)O-R ^c ,

-(CR ⁷ R ⁸ ) _n -OR ⁷ , or -C(O)N(R ⁷ )R ⁸ . 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 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 . In some embodiments, 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. In some embodiments, 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 .

In some embodiments, R ⁴ is -C(R ¹ )(R ² )R ³ .

In some embodiments, 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 .

In some embodiments, 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 . In some embodiments, 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-position by methoxyphenyl, thienyl, pyridinyl, hydroxymethylphenylamino, aminocarbonylphenylamino, pyridinylamino, fluorophenyl, pyrimidinylamino, pyrazinyl, or furyl.

In some embodiments, Het is pyridin-4-yl, isooxazol-5-yl, piperidin-4-yl, pyrimidin-4-yl, 1H-pyrazol-3-yl, isoquinolin-5-yl, or thieno[2,3-d]pyridin-4-yl, each of which is optionally substituted by 1 to 4 independently selected R ⁵ groups.

In some embodiments, Het is pyridin-4-yl, isooxazol-5-yl, piρeridin-4-yl, pyrimidin-4-yl, 1H-pyrazol-3-yl, isoquinolin-5-yl, or thieno[2,3-d]pyridin-4-yl, each of which is optionally substituted by a R ⁵ group.

In some embodiments, each R ⁷ in each R ⁵ group, independently, is -H. In some embodiments,each R ^a in each R ⁵ group, independently, is halogen, C ₁ -C ₆ alkyl,

C ₁ -C ₆ perfluoroalkyl, -(CH ₂ ) _n -aryl, -(CH ₂ ) _n -OR ⁷ , -O-R ^e , -C(O)N(R ⁷ )-R ^e , or -N(R ⁷ )C(O)-R ^e .

In some embodiments, 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 .

In some embodiments, 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. hi some embodiments, each R ^e in each R ⁵ group is, independently, -H, C ₁ -C ₆ alkyl, or C3-C8 cycloalkyl. In some embodiments, each n, independently, is O or 1.

In some embodiments, each m, independently, is O.

In some embodiments, within each R ⁵ group, or substituents thereof: each R ⁷ , independently, is -H; each R ^a , independently, is halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ perfluoroalkyl, -(CH ₂ ) _n -aryl, -(CH ₂ ) _n -OR ⁷ , -O-R ^e , -C(0)N(R ⁷ )-R ^e , or -N(R ⁷ )C(O)-R ^e ; each R ^d is, independently, -H, C ₁ -C ₆ alkyl, -(CH ₂ ) _n -aryl, or -(CH ₂ ) _n -heteroaryl; each R ^e is, independently, -H, C ₁ -C ₆ alkyl, or C ₃ -C ₈ cycloalkyl; each n, independently, is 0 or 1; and each m, independently, is 0. In some embodiments, within each R ² group, or substituents thereof: 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.

In some embodiments, within each R ³ group, or substituents thereof: 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; and each R ⁸ , independently, is -H or C ₁ -C ₆ alkyl.In some embodiments, each R ^c in each R ² group is -H, C ₁ -C ₆ alkyl, or -(CH ₂ ) _n -heterocyclyl.

In some embodiments, each R ⁷ in each R ² group is, independently, -H or -(CH ₂ ) _n -(C ₁ -C ₆ alkyl).

In some embodiments, 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.

In some embodiments, 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 .

In some embodiments, each R ^e in each R ³ group is -H or C ₁ -C ₆ alkyl.

In some embodiments, each R ⁷ in each R ³ group, independently, is -H or C ₁ -C ₆ alkyl.

In some embodiments, each R ⁸ in each R ³ group, independently, is -H or C ₁ -C ₆ alkyl.

In some embodiments, each R ^e in each R ³ group is -H or methyl. In some embodiments, each R ⁷ in each R ³ group, independently, is -H or methyl.

In some embodiments, each R ⁸ in each R ³ group, independently, is -H or methyl.

In some embodiments: each R ⁷ , independently, is -H; each R ^a , independently, is halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ perfluoroalkyl, -(CH ₂ ) _n -aryl, -(CH ₂ ) _n -OR ⁷ , -O-R ^c , -C(0)N(R ⁷ )-R ^e , or -N(R ⁷ )C(0)-R ^c ; each R ^d is, independently, -H, C ₁ -C ₆ alkyl, -(CH ₂ ) _n -aryl, or -(CH ₂ ) _n -heteroaryl; each R ^e is, independently, -H, C ₁ -C ₆ alkyl, or C ₃ -C ₈ cycloalkyl; each n, independently, is O or 1 ; and each m, independently, is O. In some embodiments: 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.

In some embodiments: 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; and each R ⁸ , independently, is -H or C ₁ -C ₆ alkyl.

In some embodiments:

Het is pyridin-4-yl, isooxazol-5-yl, piperidin-4-yl, pyrimidin-4-yl, 1H-pyrazol-3-yl, isoquinolin-5-yl, or thieno[2,3-d]pyridin-4-yl, each of which is optionally substituted by 1 to 4 independently selected C ₁ -C ₆ alkyl groups; or Het is pyridin-4-yl, isooxazol-5-yl, piperidin-4-yl, pyrimidin-4-yl, 1H-pyrazol-3-yl, isoquinolin-5-yl, or thieno[2,3-d]pyridin-4-yl, each of which is optionally substituted by a R ⁵ group; each R ⁵ , independently, is halogen, -OH, -N ₃ , C ₁ -C ₆ alkyl, aryl, heteroaryl, heterocyclyl, -CH=CH-aryl, -O-R ^d , -C(O)O-R ^d , -C(0)NH-R ^d , -NHR ^d , -NHC(O)-R ^d , or -SO _m -R ^d ; wherein each R ⁵ is, independently, optionally substituted with 1-5 substituents independently selected from R ^la ; each R ^la , independently, is halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ perfluoroalkyl, -(CH ₂ ) _n -aTyI, -(CH ₂ ) _n -OH, -O-R ^e , -C(O)NH-R ⁶ , or -NHC(O)-R ⁶ ; each R ^d is, independently, -H, C ₁ -C ₆ alkyl, -(CH ₂ ) _n -aryl, or -(CH ₂ ) _n -heteroaryl; each n, independently, is 0 or 1; each m, independently, is 0;

R ⁴ is -CCR ¹ XR ² )R ³ ; 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 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),

-(CH ₂ ) _n -aryl, or -(CH ₂ ) _n -heteroaryl; wherein each of which is optionally substituted by a substituent selected from halogen;

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 , -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 _ra -R ^e , or -C(O)O-R ^c ; and each R ^e is, independently, -H, C ₁ -C ₆ alkyl, or C ₃ -C ₈ cycloalkyl.

In some embodiments:

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 ; 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 .

In some embodiments: 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-ρosition by methoxyphenyl, thienyl,

pyridinyl, hydroxymethylphenylamino, aminocarbonylphenylamino, pyridinylamino, fluorophenyl, pyrimidinylamino, pyrazinyl, or furyl.

In some circumstances, Het can be ρyridin-4-yl optionally substituted at the 2-position by 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- phenylethyl]amino}-4-[(2-phenylpyridin-4-yl)amino]cyclobut-3 -ene-l ,2-dione, 3- {[(1R)-1- phenylethyl]amino}-4-{[2-(pyrimidin-4-ylamino)pyridin-4-yl]a mmo}cyclobut-3-ene-l _; 2-dione, 3-{[(1R)-l -phenylethyl] amino } -4- { [2-(pyrazin-2-ylamino)pyridin-4-yl] amino } cyclobut-3 -ene- 1 ,2-dione, 3- { [ 1 -(3-hydroxyphenyl)ethyl]amino} -4-(pyridin-4-ylamino)cyclobut-3-ene- 1 ,2- dione, 3 - { [2-(2-furyl)pyridin-4-yl] amino }-4-{[(1R)-l -phenylethyl] amino } cyclobut-3 -ene- 1 ,2- dione, 2- { [3 ,4-dioxo-2-(pyridin-4-ylamino)cyclobut- 1 -en- 1 -yl] amino } -2-(3 - hydroxyphenyl)acetamide, 3-{[(1R)-l -phenylethyl] amino } -4- { [2-(pyrimidin-2-ylamino)pyridin- 4-yl]amino}cyclobut-3-ene-1,2-dione, 2-(4-bromophenyl)-2-{[3,4-dioxo-2-(pyridin-4- ylamino)cyclobut-1-en-1-yl]amino}acetamide, N-[2-(4-chlorophenyl)ethyl]-2-{[3,4-dioxo-2- (pyridin-4-ylamino)cyclobut- 1 -en- 1 -yl] amino} -2-phenylacetamide, 3 - { [( 1 i?)- 1 -(4- bromophenyl)ethyl]amino}-4-(pyridin-4-ylamino)cyclobut-3-ene -1,2-dione, 3-{[(1S)-2-hydroxy- l-phenylethyl]amino}-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2 -dione, 2-{[3,4-dioxo-2-(pyridin- 4-ylamino)cyclobut- 1 -en- 1 -yl] amino } -iV-methyl-2-phenylacetamide, 3 - { [( 1 K)- 1 -(4- methylphenyl) ethyl] amino } -4-(pyridin-4-ylamino)cyclobut-3 -ene- 1 ,2-dione, (2S)-2- { [3 ,4-dioxo- 2-(pyridin-4-ylamino)cyclobut- 1 -en- 1 -yl] amino } -N-methyl-2-phenylacetamide, 2-{[3,4-dioxo-2- (pyridin-4-ylamino)cyclobut-1-en-1-yl]amino}-N-ethyl-2-pheny lacetamide, 2-(3,4- dichlorophenyl)-2-{[3,4-dioxo-2-(ρyridin-4-ylamino)cyclobut -1-en-1-yl]amino}acetamide (trifluoracetate salt), 2-(4-chlorophenyl)-2-{[3,4-dioxo-2-(pyridin-4-ylamino)cyclob ut-1-en-1- yl] amino }acetamide (trifluoracetate salt), 2-{[3,4-dioxo-2-(pyridin-4-ylamino)cyclobut-1-en-1- yl] amino } -2-(4-fluorophenyl)acetamide, 2- { [3 ,4-dioxo-2-(pyridin-4-ylamino)cyclobut- 1 -en- 1 -

yl]amino}-2-(3,4,5-trifluorophenyl)acetamide, 3-{[(1S)-2-hydroxy-2-methyl-1- phenylpropyl]amino}-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2- dione, 3-{[2-(3- methoxyphenyl)pyridin-4-yl] amino }-4-{[(1R)-l -phenylethyl] amino } cyclobut-3 -ene- 1 ,2-dione, 3 - { [2-(3-fluorophenyl)pyridin-4-yl] amino }-4-{[(1R)-l -phenylethyl] amino } cyclobut-3 -ene- 1 ,2- dione, 3-(2,3'-bipyridin-4-ylamino)-4-{[(1R)-1-phenylethyl]amino}cy clobut-3-ene-1,2-dione, 3- [(2-{[3-(hydroxymethyl)phenyl]amino}pyridin-4-yl)amino]-4-{[ (1R)-1- phenylethyl] amino } cyclobut-3 -ene- 1 ,2-dione, 3 -( {4- [(3 ,4-dioxo-2- { [( 1 R)- 1 - phenylethyl] amino } cyclobut- 1 -en- 1 -yl)amino]pyridin-2-yl } amino)benzamide, 3- [( 1 -methyl- 1 - phenylethyl)amino]-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2-d ione, 3-([(1R)-I- phenylethyl]amino}-4-{[2-(pyridin-2-ylamino)pyridin-4-yl]ami no}cyclobut-3-ene-l _> 2-dione, 3- (2,4'-bipyridin-4-ylamino)-4-{[(1R)-1-phenylethyl]amino}cycl obut-3-ene-1,2-dione, 3-{[2-(2- fluorophenyl)pyridin-4-yl] amino }-4-{[(1R)-l -phenylethyl] amino } cyclobut-3 -ene- 1 ,2-dione, N- [3-(l-{[3,4-dioxo-2-(pyridin-4-ylamino)cyclobut-1-en-1-yl]am ino}ethyl)phenyl]acetamide, 2- {[3,4-dioxo-2-(pyridin-4-ylamino)cyclobut-1-en-1-yl]amino}-2 -[4-(3-furyl)phenyl]acetamide, 2- biphenyl-4-yl-2- { [3 ,4-dioxo-2-(pyridin-4-ylamino)cyclobut- 1 -en- 1 -yl] amino } acetamide, 3 - {[(1R)-1-phenylpropyl]amino}-4-(pyridin-4-ylamino)cyclobut-3 -ene-1,2-dione, 3-{[(1R)-1-(4- fluorophenyl)ethyl]amino}-4-(pyridin-4-ylamino)cyclobut-3-en e-1,2-dione, 3-{[l-(4- hydroxyphenyl)ethyl]amino}-4-(ρyridin-4-ylamino)cyclobut-3- βne-1,2-dione, 2-(3-chloro-4- fluorophenyl)-2-{[3,4-dioxo-2-(pyridin-4-ylaminoJcyclobut-1- en-1-ylJaminoJacetamide, 2- {[3,4-dioxo-2-(pyridin-4-ylamino)cyclobut-1-en-1-yl]amino}-2 -(2-fluorophenyl)acetamide, 3- { [ 1 -(3-fluorophenyl)ethyl]amino} -4-(pyridin-4-ylamino)cyclobut-3-ene- 1 ,2-dione, 3- { [ 1 -(2- fluorophenyl)ethyl]amino}-4-(pyridin-4-ylamino)cyclobut-3-en e-l ,2-dione, N-[3-(l-{[3,4-dioxo- 2-(pyridin-4-ylamino)cyclobut- 1 -en- 1 -yl] amino} ethyl)phenyl] -.N'-methylurea, 3 - { [ 1 -(3-hydroxy- 4-methylphenyl)ethyl] amino } -4-(pyridin-4-ylamino)cyclobut-3 -ene- 1,2-dione, 3-{[l-(3'- aminobiphenyl-4-yl)ethyl]amino}-4-(pyridin-4-ylamino)cyclobu t-3-ene-l ,2-dione, and pharmaceutically acceptable salts thereof.

The compound can be selected from the group consisting of N-[2-(4-chlorophenyl)ethyl]- 2-{[3,4-dioxo-2-(pyridin-4-ylamino)cyclobut-1-en-1-yl]amino} -2-phenylacetamide, 3-{[(1R)-1- (4-bromophenyl)ethyl]amino}-4-(pyridin-4-ylamino)cyclobut-3- ene-1,2-dione, 3-{[(1S)-2- hydroxy- 1 -phenylethyl] amino } -4-(pyridin-4-ylamino)cyclobut-3 -ene- 1 ,2-dione, 2- { [3 ,4-dioxo- 2-(pyridin-4-ylamino)cyclobut- 1 -en- 1 -yl]amino} -N-methyl-2-phenylacetamide, 3- {[(1R)- 1 -(4-

methylphenyl)ethyl] amino } -4-(pyridin-4-ylamino)cyclobut-3 -ene- 1 ,2-dione, (2S)-2- { [3 ,4-dioxo- 2-(pyridin-4-ylamino)cyclobut- 1 -en- 1 -yl] amino } -iV-methyl-2-phenylacetamide, 2- { [3 ,4-dioxo-2- (pyridin-4-ylamino)cyclobut- 1 -en- 1 -yl] amino } -iV-ethyl-2-phenylacetamide, 2-(3 ,4- dichlorophenyl)-2-{[3,4-dioxo-2-(pyridin-4-ylamino)cyclobut- 1-en-1-yl]amino}acetamide (trifluoracetate salt), 2-(4-chlorophenyl)-2-{[3,4-dioxo-2-(pyridin-4-ylamino)cyclob ut-1-en-1- yl] amino }acetamide (trifluoracetate salt), 2-{[3,4-dioxo-2-(pyridin-4-ylamino)cyclobut-1-en-1- yl]amino}-2-(4-fluorophenyl)acetamide, 2-{[3,4-dioxo-2-(pyridin-4-ylamino)cyclobut-1-en-1- yl]amino}-2-(3,4,5-trifluorophenyl)acetamide, 3-{[(1S)-2-hydroxy-2-methyl-1- phenylpropyl]amino}-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2- dione, 3-{[2-(3- methoxyphenyl)pyridin-4-yl] amino }-4-{[(1R)-l -phenylethyl] amino } cyclobut-3-ene- 1 ,2-dione, 3-{[2-(3-fluorophenyl)ρyridin-4-yl]amino}-4-{[(1R)-1-phenyl ethyl]amino}cyclobut-3-ene-1,2- dione, 3-(2,3'-bipyridin-4-ylamino)-4-{[(1R)-1-phenylethyl]amino}cy clobut-3-ene-1,2-dione, 3- [(2-{[3-(hydroxymethyl)phenyl]amino}pyridm-4-yl)amino]-4-{[( 1R)-1- phenylethyl]amino}cyclobut-3-ene-1,2-dione, 3-({4-[(3,4-dioxo-2-{[(1R)-1- phenylethyl] amino } cyclobut- 1 -en- 1 -yl)amino]pyridin-2-yl} amino)benzamide, 3 - [( 1 -methyl- 1 - phenylethyl)amino]-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2-d ione, 3-{[(1R)-1- phenylethyl] amino } -4- { [2-(pyridm-2-ylamino)pyridin-4-yl] amino } cyclobut-3-ene- 1 ,2-dione, 3 - (2,4'-bipyridin-4-ylamino)-4-{[(1R)-1-phenylethyl]amino}cycl obut-3-ene-1,2-dione, 3-{[2-(2- fluorophenyl)pyridin-4-yl] amino }-4-{[(1R)-l -phenylethyl] amino } cyclobut-3 -ene- 1 ,2-dione, N- [3-(l-{[3,4-dioxo-2-(pyridin-4-ylamino)cyclobut-1-en-1-yl]am ino}ethyl)phenyl]acetainide, 2- {[3,4-dioxo-2-(pyridin-4-ylamino)cyclobut-1-en-1-yl]amino}-2 -[4-(3-furyl)phenyl]acetamide, 2- biphenyl-4-yl-2- { [3 ,4-dioxo-2-(pyridin-4-ylamino)cyclobut- 1 -en- 1 -yl] amino } acetamide, 3 - {[(1R)-1-phenylpropyl]amino}-4-(pyridin-4-ylamino)cyclobut-3 -ene-1,2-dione, 3-{[(1R)-1-(4- fluorophenyl)ethyl]amino}-4-(pyridin-4-ylamino)cyclobut-3-en e-1,2-dione, 3-{[l-(4- hydroxyphenyl)ethyl]amino}-4-(pyridin-4-ylamino)cyclobut-3-e ne-1,2-dione, 2-(3-chloro-4- fluorophenyl)-2- { [3 ,4-dioxo-2-(pyridin-4-ylamino)cyclobut- 1 -en- 1 -yl] amino } acetamide, 2- { [3 ,4-dioxo-2-(pyridin-4-ylamino)cyclobut- 1 -en- 1 -yl] amino } -2-(2-fluorophenyl)acetamide, 3 - { [ 1 -(3-fluorophenyl)ethyl]amino} -4-(pyridin-4-ylamino)cyclobut-3-ene-l ,2-dione, 3- { [ 1 -(2- fluorophenyl)ethyl]amino}-4-(pyridin-4-ylamino)cyclobut-3-en e-1,2-dione, N-[3-(l-{[3,4-dioxo- 2-(pyridin-4-ylamino)cyclobut- 1 -en- 1 -yl] amino} ethyl)phenyl] -N'-methylurea, 3 - { [ 1 -(3-hydroxy- 4-methylphenyl)ethyl]amino}-4-(pyridin-4-ylamino)cyclobut-3- ene-1,2-dione, 3-{[l-(3'-

aminobiphenyl-4-yl)ethyl]amiπo}-4-(pyridin-4-ylainino)cy clobut-3-ene-1,2-dione, and pharmaceutically acceptable salts thereof.

The compound can be selected from the group consisting of 3-{[(1R)-1- phenylpropyl] amino } -4-(ρyridin-4-ylamino)cyclobut-3 -ene- 1 ,2-dione, 3-{[(1R)-1-(4- fluorophenyl)ethyl]amino}-4-(pyridin-4-ylamino)cyclobut-3-en e-1,2-dione, 3-{[l-(4- hydroxyphenyl)ethyl]amino}-4-(pyridin-4-ylamino)cyclobut-3-e ne-1,2-dione, 2-(3-chloro-4- fluorophenyl)-2-{[3,4-dioxo-2-(pyridin-4-ylamino)cyclobut-1- en-1-yl]amino}acetamide, 2- {[3,4-dioxo-2-(pyridin-4-ylamino)cyclobut-1-en-1-yl]amino}-2 -(2-fluorophenyl)acetamide, 3- {[l-(3-fluorophenyl)ethyl]amino}-4-(pyridin-4-ylammo)cyclobu t-3-ene-1,2-dione, 3-{[l-(2- fluorophenyl)ethyl] amino } -4-(pyridin-4-ylamino)cyclobut-3 -ene- 1 ,2-dione, N- [3 -( 1 - { [3 ,4-dioxo- 2-(pyridin-4-ylamino)cyclobut- 1 -en- 1 -yl] amino } ethyl)phenyl] -N-methylurea, 3 - { [ 1 -(3-hydroxy- 4-methylphenyl)ethyl]amino}-4-(pyridin-4-ylamino)cyclobut-3- ene-1,2-dione, 3-{[l-(3'- aminobiphenyl-4-yl)ethyl] amino } -4-(pyridin-4-ylamino)cyclobut-3 -ene- 1 ,2-dione, and pharmaceutically acceptable salts thereof. In another aspect, a compound can be selected from the group consisting of l-(3,4-dioxo-

2-(pyridin-4-ylamino)cyclobuten-1-yl)amir!o-2-metiiylprop ane; l-(3,4-dioxo-2-(pyridin-4- ylamino)cyclobuten- 1 -yl)aminoprop-2-ene; 1 -(3,4-dioxo-2-(pyridin-4-ylamino)cyclobuten- 1 - yl)amino- 1 -(aminocarbonyl)-3-methylbutane; 1 -(3 ,4-dioxo-2-(ρyridin-4-ylamino)cyclobuten- 1 - yl)amino- 1 -(aminocarbonyl)-ethane; and 1 -(3,4-dioxo-2-(pyridin-4-ylamino)cyclobuten- 1 - yl)amino- 1 -(aminocarbonyl)-ethan-2-ol; and pharmaceutically acceptable salts thereof.

In some embodiments, the compound is selected from:

3-{[l-(4-fluorophenyl)ethyl]amino}-4-(pyridin-4-ylamino)c yclobut-3-ene-1,2-dione;

3-[(cyclohexyhnethyl)amino]-4-(pyridin-4-ylamino)cyclobut -3-ene-1,2-dione;

3-(2,3-dihydro- IH-iaάβn- 1 -ylamino)-4-(ρyridin-4-ylamino)cyclobut-3-ene- 1 ,2-dione; 3-(pyridin-4-ylamino)-4-[(tetrahydrofuran-2-ylmethyl)amino]c yclobut-3-ene-1,2-dione;

3-[(1,3-benzodioxol-5-ylmethyl)amino]-4-(pyridin-4-ylamin o)cyclobut-3-ene-1,2-dione;

3-(pyridin-4-ylamino)-4-[(pyridin-2-ylmethyl)amino]cyclob ut-3-ene-1,2-dione;

3-(pyridin-4-ylamino)-4-[(ρyridin-3-ylmethyl)ammo]cyclob ut-3-ene-1,2-dione;

3-(pyridin-4-ylamino)-4-[(ρyridin-4-ylmethyl)amino]cyclo but-3-ene-1,2-dione; 3-[(diphenylmethyl)amino]-4-(pyridin-4-ylamino)cyclobut-3-en e-1,2-dione;

3-(benzylamino)-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2-d ione;

3-[(2-methylbenzyl)amino]-4-(pyridin-4-ylamino)cyclobut-3 -ene-1,2-dione;

3-(pyridin-4-ylamino)-4-{[3-(trifluoromethyl)benzyl]amino }cyclobut-3-ene-1,2-dione;

3-[(3-methylbenzyl)amino]-4-(ρyridin-4-ylamino)cyclobut- 3-ene-1,2-dione;

3-[(4-fluorobenzyl)amino]-4-(pyridin-4-ylamino)cyclobut-3 -ene-1,2-dione; 3-[(4-methylbenzyl)amino]-4-(pyridin-4-ylamino)cyclobut-3-en e-1,2-dione;

3-{[2-(4-methylphenyl)ethyl]amino}-4-(pyridin-4-ylamino)c yclobut-3-ene-1,2-dione;

3-[(2,4-difluorobenzyl)amino]-4-(pyridin-4-ylainino)cyclo but-3-eπe-1,2-dione;

3-[(2,5-difluorobenzyl)amino]-4-(pyridiπ-4-ylamino)cyclo but-3-ene-1,2-dione;

3-[(3,4-difluorobeπzyl)amino]-4-(pyridin-4-ylamino)cyclo but-3-ene-1,2-dione; 3 -(pyridin-4-ylamino)-4- { [4-(trifluoromethyl)benzyl] amino } cyclobut-3 -ene- 1 ,2-dionei

3-[(2,4-dimethylbenzyl)amino]-4-(ρyridin-4-ylamino)cyclo but-3-ene-1,2-dione;

3-[(3,4-dimethylbenzyl)amino]-4-(pyridin-4-ylamino)cyclob ut-3-ene-1,2-dione;

3-[(4-tert-butylbenzyl)amino]-4-(pyridin-4-ylamino)cyclob ut-3-ene-1,2-dione;

3-[(3,5-di£luorobenzyl)amino]-4-(pyridin-4-ylamino)cyclo but-3-ene-1,2-dione; 3-(pyridin-4-ylamino)-4-(1,2,3,4-tetrahydronaphthalen-1-ylam ino)cyclobut-3-ene-1,2- dione;

3-{[(1R)-2-hydroxy-1-phenylethyl]amino}-4-(pyridin-4-ylam mo)cyclobut-3-ene-1,2- dione;

3-[(1,2-diphenylethyl)amino]-4-(pyridin-4-ylamino)cyclobu t-3-ene-1,2-dione; 2-{[3,4-dioxo-2-(pyridin-4-ylamino)cyclobut-1-en-1-yl]amino} -2-phenylacetamide;

3-{methyl[(1R)-1-phenylethyl]amino}-4-(ρyridin-4-ylamino )cyclobut-3-ene-1,2-dione;

3-{[(1R)-1-(4-bromophenyl)ethyl]amino}-4-(pyridin-4-ylami no)cyclobut-3-ene-1,2- dione;

3- { [(1S)-2-hydroxy- 1 -phenylethyl]amino} -4-(pyridin-4-ylamino)cyclobut-3-ene- 1 ,2- dione;

3-{[(1S)-1-phenylpropyl]amino}-4-(pyridin-4-ylammo)cyclob ut-3-ene-1,2-dione;

3-{[(1R)-l -phenylpropyl] amino } -4-(pyridin-4-ylamino)cyclobut-3 -ene- 1 ,2-dione;

3-{[(1R)-1-(2-naphthyl)ethyl]amino}-4-(pyridin-4-ylamino) cyclobut-3-ene-1,2-dione;

3-[(1R)-2,3-dihydro- 1H-inden-1-ylamino]-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2- dione;

3- {[(I R)-I -(4-chlorophenyl)ethyl] amino } -4-(pyridin-4-ylamino)cyclobut-3 -ene- 1,2- dione;

3-{[(1S)-1-(4-chlorophenyl)ethyl]amino}-4-(pyridin-4-ylam ino)cyclobut-3-ene-1,2- dione; 3-{[(1R)-1-(3-methoxyphenyl)ethyl]amino}-4-(ρyridin-4-ylami no)cyclobut-3-ene-1,2- dione;

3-{[(1R)-1-(4-methoxyphenyl)ethyl]ammo}-4-(pyridin-4-ylam ino)cyclobut-3-ene-1,2- dione;

3-[(4-bromobenzyl)amino]-4-(pyridin-4-ylamino)cyclobut-3- ene-1,2-dione; 3-[(4-chlorobenzyl)amino]-4-(pyridin-4-ylamino)cyclobut-3-en e-1,2-dione;

3-[(4-methoxybenzyl)ammo]-4-(pyridin-4-ylamino)cyclobut-3 -ene-1,2-dione;

2-{[3,4-dioxo-2-(pyridin-4-ylammo)cyclobut-1-en-1-yl]ammo }-iV-niethyl-2- phenylacetamide;

3-{[(1R)-1-(4-fluorophenyl)ethyl]amino}-4-(pyridin-4-ylam ino)cyclobut-3-ene-1,2- dione;

3-{[l-(4-hydroxyphenyl)ethyl]amino}-4-(pyridin-4-ylamino) cyclobut-3-ene-1,2-dione;

3 - { [ 1 -( 1 -naphthyl)ethyl] amino } -4-(pyridin-4-ylamino)cyclobut-3-ene- 1 ,2-dione;

3-{[(1R)-1-(4-methylphenyl)ethyl]amino}-4-(pyridin-4-ylam ino)cyclobut-3-ene-1,2- dione; 3-{[(1R)-1-(4-nitrophenyl)ethyl]amino}-4-(pyridin-4-ylamino) cyclobut-3-ene-1,2-dione;

3- {[ 1 -(4-fluorophenyl)-2-hydroxyethyl]amino} -4-(pyridin-4-ylamino)cyclobut-3-ene- 1,2-dione;

3- {[ 1 -(4-chlorophenyl)-2-hydroxyethyl]amino} -4-(pyridin-4-ylamino)cyclobut-3-ene- 1,2-dione; 3-{[l-(2-fluorophenyl)-2-hydroxyethyl]amino}-4-(pyridin-4-yl amino)cyclobut-3-ene-

1,2-dione;

3 -( {2-hydroxy- 1 - [4-(trifluoromethyl)phenyl] ethyl} amino)-4-(pyridin-4- ylamino)cyclobut-3-ene-1,2-dione;

3 - { [2-hydroxy- 1 -(4-methylphenyl)ethyl] amino } -4-(pyridin-4-ylamino)cyclobut-3 -ene- 1,2-dione;

3 - { [ 1 -(3 -chloro-4-fluorophenyl)-2-hydroxyethyl] amino } -4-(ρyridin-4-ylamino)cyclobut- 3-ene-1,2-dione;

3- {[2-hydroxy-l -(3 ,4,5-trifluorophenyl)ethyl] amino} -4-(pyridin-4-ylamino)cyclobut-3- ene-1,2-dione; 3-{[(1S',2λ)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]am ino}-4-(pyridin-4- ylamino)cyclobut-3-ene- 1 ,2-dione;

3 - { [2-(4-chlorophenyl)- 1 -methylethyl] amino } -4-(pyridin-4-ylamino)cyclobut-3-ene- 1 ,2- dione;

4-( 1 - {[3,4-dioxo-2-(ρyridin-4-ylamino)cyclobut- 1 -en- 1 -yl]amino} ethyl)benzonitrile; 3-{[(1S)-2-hydroxy-2-methyl-1-phenylρropyl]amino}-4-(pyridi n-4-ylamino)cyclobut-3- ene-1,2-dione;

3-{[(1R)-2-hydroxy-2-methyl-1-phenylpropyl]amino}-4-(pyri din-4-ylamino)cyclobut-3- ene-1,2-dione;

(2R)-2- {[3,4-dioxo-2-(pyridin-4-ylamino)cyclobut- 1 -en- 1 -yl] amino} -N-methyl-2- phenylacetamide ;

(2 S)-2- { [3,4-dioxo-2-(pyridin-4-ylamino)cyclobut- 1 -en- 1 -yl] amino } -iV-methyl-2- phenylacetamide;

2-(3 ,4-dichlorophenyl)-2- {[3,4-dioxo-2-(pyridin-4-ylamino)cyclobut- 1 -en- 1 - yl] amino } acetamide; 2-(4-chlorophenyl)-2-{[3,4-dioxo-2-(pyridm-4-ylamino)cyclobu t-1-en-1- yl] amino } acetamide

(2S)-2-(4-chlorophenyl)-2-{[3,4-dioxo-2-(pyridin-4-ylamin o)cyclobut-1-en-1- y 1] amino } acetamide ;

(2S)-2-(4-chlorophenyl)-2-{ [3,4-dioxo-2-(pyridin-4-ylamino)cyclobut- 1 -en- 1 - yl]amino}acetamide;

2-(3-chloro-4-fluorophenyl)-2-{[3,4-dioxo-2-(pyridin-4-yl amino)cyclobut-1-en-1- yl] amino } acetamide;

2- {[3,4-dioxo-2-(pyridin-4-ylamino)cyclobut-l -en-1 -yl]amino} -2-[4- (trifluoromethyl)phenyl] acetamide; 2-{[3,4-dioxo-2-(pyridin-4-ylamino)cyclobut-1-en-1-yl]amino} -2-(4- fluorophenyl)acetamide;

2-{[3,4-dioxo-2-(pyridin-4-ylammo)cyclobut-1-en-1-yl]amin o}-2-(2- fluorophenyl)acetamide;

2- { [3 ,4-dioxo-2-(pyridin-4-ylamino)cyclobut- 1 -en- 1 -yl] amino } -2-(3 ,4, 5 - trifluorophenyl)acetamide; 2-(4-chlorophenyl)-2-{[3,4-dioxo-2-(pyridin-4-ylamino)cyclob ut-1-en-1-yl]amino}-N- methylacetamide;

2-{[3,4-dioxo-2-(pyridin-4-ylamino)cyclobut-1-en-1-yl]amino} -λ ^f -ethyl-2- phenylacetamide;

^-(cyclohexylmethyl)^- { [3 ,4-dioxo-2-(pyridin-4-ylamino)cyclobut- 1 -en- 1 -yl] amino } -2- phenylacetamide;

N-(4-chlorobenzyl)-2-{[3,4-dioxo-2-(pyridin-4-ylamino)cyc lobut-1-en-1-yl]amino}-2- phenylacetamide;

3-[(2-OXO- 1 -phenyl-2-pyrrolidin- 1 -ylethyl)amino]-4-(pyridin-4-ylamino)cyclobut-3-ene- 1,2-dione; 2- { [3 ,4-dioxo-2-(pyridin-4-ylamino)cyclobut- 1 -en- 1 -yl] amino } -i\yV-dimethyl-2- phenylacetamide; N-[2-(4-chlorophenyl)ethyl] -2- { [3,4-dioxo-2-(pyridin-4-ylamino)cyclobut- 1 -en- 1 - yl] amino } -2-phenylacetamide;

2- { [3 ,4-dioxo-2-(pyridin-4-ylamino)cyclobut- 1 -en- 1 -yl] amino } -2-phenyl-iV-(pyridin-4- ylmethyl)acetamide;

2-{[3,4-dioxo-2-(pyridm-4-ylammo)cyclobuM-en-1-yl]ammo}-i V-isobutyl-2- phenylacetamide;

3-[(2-methoxypyridin-4-yl)amino]-4-{[(1R)-1-phenylethyl]a mino}cyclobut-3-ene-1,2- dione; (R)-3-(2-hydroxypyridin-4-ylamino)-4-(l-phenylethylamino)cyc lobut-3-ene-1,2-dione;

3 - { [ liϊ-imidazol-2-yl(phenyl)methyl] amino } -4-(pyridin-4-ylamino)cyclobut-3 -ene- 1,2- dione;

3-[(3-methylisoxazol-5-yl)amino]-4-{[(1R)-1-phenylethyl]a mino}cyclobut-3-ene-1,2- dione; 3-[methyl(pyridin-4-yl)amino]-4-{[(1R)-1-phenylethyl]amino}c yclobut-3-ene-1,2-dione;

3-{[(1R)-1-phenylethyl]amino}-4-[(2,2,6,6-tetramethylpipe ridin-4-yl)amino]cyclobut-3- ene-1,2-dione;

3-{[(1R)-1-phenylethyl]amino}-4-(pyrimidin-4-ylamino)cycl obut-3-ene-1,2-dione;

3-[(5-methyl-1H-pyrazol-3-yl)amino]-4-{[(1R)-1-phenylethy l]amino}cyclobut-3-ene- 1,2-dione; tert-butyl 4-[(3,4-dioxo-2-{[(1R)-1-phenylethyl]amino}cyclobut-1-en-1- yl)amino]piperidine-1-carboxylate;

3-{[(1R)-1-phenylethyl]amino}-4-(1H-pyrazol-3-ylamino)cyc lobut-3-ene- 1,2-dione;

3-[(2-chloropyridin-4-yl)amino]-4-{[(1R)-1-phenylethyl]am ino}cyclobut-3-eπe-1,2- dione;

3- { [ 1 -(4-cyclohexylphenyl)ethyl] amino } -4-(pyridin-4-ylamino)cyclobut-3 -ene- 1 ,2-dione;

3-{[(1R)-l -cyclohexylethyl] amino } -4-(pyridin-4-ylamino)cyclobut-3-ene- 1 ,2-dione;

3 -[(2-bromopyridin-4-yl)amino] -4- { [( 1 R)- 1 -phenylethyl] amino} cyclobut-3 -ene- 1 ,2- dione; 3 - [(2-morpholin-4-ylpyridin-4-yl) amino] -4- { [( 1 R)- 1 -phenylethyl] amino } cyclobut-3-ene-

1,2-dione;

3-[(l-methyl-1-phenylethyl)amino]-4-(pyridin-4-ylamino)cy clobut-3-ene-1,2-dione;

3 - { [( 1 R)- 1 -phenylethyl] amino} -4- { [2-(phenylthio)pyridin-4-yl] amino } cyclobut-3 -ene- 1,2-dione; 4- [(3 ,4-dioxo-2- { [( 1 R)- 1 -phenylethyl] amino } cyclobut- 1 -en- 1 -yl)amino]pyridine-2- carboxamide;

3-{[(1R)-1-phenylethyl]amino}-4-(piperidin-4-ylamino)cycl obut-3-ene-1,2-dione; tert-butyl (2S)- { [3 ,4-dioxo-2-(pyridin-4-ylamino)cyclobut- 1 -en-1 - yljamino} (phenyl)acetate; (2S)-{[3,4-dioxo-2-(pyridin-4-ylamino)cyclobut-1-en-1-yl]ami no}(phenyl)acetic acid;

2- { [ 3 ,4-dioxo-2-(pyridin-4-ylamino)cyclobut- 1 -en- 1 -yl] amino } -2-(3 - hydroxyphenyl)acetamide;

2-(3 -bromophenyl)-2- { [3 ,4-dioxo-2-(pyridin-4-ylamino)cyclobut- 1 -en- 1 - yl] amino } acetamide; 2-biphenyl-3-yl-2-{[3,4-dioxo-2-(pyridin-4-ylamino)cyclobut- 1-en-1- yl] amino } acetamide;

2-{[3,4-dioxo-2-(pyridin-4-ylamino)cyclobut-1-en-1-yl]ami no}-2-[3-(3- thienyl)phenyl] acetamide;

3-[(l-biphenyl-3-ylethyl)amino]-4-(pyridin-4-ylamino)cycl obut-3-ene-1,2-dione;

3-(pyridin-4-ylamino)-4-({l-[3-(3-thienyl)phenyl]ethyl}am mo)cyclobut-3-ene-1,2-dione; 3-(pyridin-4-ylamino)-4-{[l-(3-pyridin-3-ylphenyl)ethyl]amin o}cyclobut-3-ene-1,2- dione;

3-[(l-biphenyl-4-ylethyl)amino]-4-(pyridin-4-ylamino)cycl obut-3-ene-1,2-dioπe;

3-({l-[4-(3-furyl)phenyl]ethyl}amino)-4-(pyridin-4-ylamin o)cyclobut-3-ene-1,2-dione;

3 -(pyridin-4-ylamino)-4-( { 1 - [4-(3 -thienyl)phenyl] ethyl } amino)cyclobut-3 -ene- 1 ,2-dione; 2-{[3,4-dioxo-2-(pyridin-4-ylamino)cyclobut-1-en-1-yl]amino} -2-(3-methyl-2- thienyl)acetamide;

2- { [3 ,4-dioxo-2-(pyridin-4-ylamino)cyclobut- 1 -en- 1 -yl] amino } -2-(3 -furyl)acetamide;

3-[(25)-2-(hydroxymethyl)pyrrolidin-1-yl]-4-(ρyridin-4-y lamino)cyclobut-3-ene-1,2- dione; 3-(2-methylpyrrolidin-1-yl)-4-(ρyridin-4-ylamino)cyclobut-3 -ene-1,2-dione;

3-[2-(hydroxymethyl)piperidin-1-yl]-4-(pyridin-4-ylamino) cyclobut-3-ene-1,2-dione;

3-(2-methylpiperidin-1-yl)-4-(pyridin-4-ylamino)cyclobut- 3-ene-1,2-dione;

2-{[3,4-dioxo-2-(pyridin-4-ylaπiino)cyclobut-1-en-1-yl]a mino}-2-(3-thienyl)acetaraide;

3-(pyridin-4-ylamino)-4-[(l-pyridin-4-ylethyl)amino]cyclo but-3-ene-1,2-dione; 3-{[l-(l-benzoiuτan-2-yl)ethyl]ammo}-4-(pyridin-4-ylamino)c yclobut-3-ene-1,2-dione;

3-{[l-(4-morpholin-4-ylphenyl)ethyl]amino}-4-(pyridin-4-y lamino)cyclobut-3-ene-1,2- dione;

3-( { 1 -[4-(dimethylamino)phenyl]ethyl} ammo)-4-(pyridin-4-ylamino)cyclobut-3-ene- 1 ,2- dione; 3-[(l-cyclohexylethyl)amino]-4-(pyridin-4-ylamino)cyclobut-3 -ene-1,2-dione;

3-[(l-pyrazin-2-ylethyl)amino]-4-(pyridin-4-ylamino)cyclo but-3-ene-1,2-dione;

3-({l-[4-(l/^-imidazol-1-yl)phenyl]ethyl}amino)-4-(pyridi n-4-ylamino)cyclobut-3-ene- 1,2-dione;

3-(pyridin-4-ylamino)-4-{[l-(3-thienyl)ethyl]amino}cyclob ut-3-ene-1,2-dione; 3-{[l-(l-methyl-lif-pyrrol-3-yl)ethyl]amino}-4-(pyridin-4-yl amino)cyclobut-3-ene-1,2- dione;

3-{[l-(3-methylρyrazm-2-yl)ethyl]amino}-4-(pyridm-4-ylam ino)cyclobut-3-ene-1,2- dione,

3 - { [ 1 -( 1 -benzothien-3 -yl)ethyl] ammo } -4-(pyridm-4-ylammo)cyclobut-3 -ene- 1 ,2-dione, 3-(pyridm-4-ylammo)-4-{[l-(1,3-thiazol-2-yl)ethyl]ammo}cyclo but-3-ene-1,2-dione, 3- { [ 1 -(3 -ammopheπyl)ethyl] ammo } -4-(pyndm-4-ylammo)cyclobut-3 -ene- 1 ,2-dione,

3 - { [ 1 -(2-fluorophenyl)ethyl] ammo } -4-(pyridm-4-ylamino)cyclobut-3 -ene- 1 ,2-dione, 3-{[l-(2-hydroxyphenyl)ethyl]ammo}-4-(pyridin-4-ylammo)cyclo but-3-ene-1,2-dione, 3-{[l-(li/-mdol-3-yl)ethyl]ammo}-4-(pyridin-4-ylammo)cyclobu t-3-ene-1,2-dione, 3-{[l-(2,6-difluorophenyl)emyl]ammo}-4-(pyridm-4-ylammo)cycl obut-3-ene-1,2-dione, 3-{[l-(3 -fluorophenyl)ethyl] amino } -4-(pyridm-4-ylamino)cyclobut-3 -ene- 1 ,2-dione,

3-{[l-(3-hydroxyphenyl)ethyl]amino}-4-(pyndm-4-ylamino)cy clobut-3-ene-1,2-dione, 3-(pyridin-4-ylammo)-4-({l-[3-(trifluoromethyl)phenyl]ethyl} amino)cyclobut-3-ene-1,2- dione,

3-[(2-azidopyndm-4-yl)ammo]-4-{[(1R)-1-phenylethyl]ammo}c yclobut-3-ene-1,2-dione, 3-{[(1R)-1-phenylethyl]ammo}-4-{[2-(4-phenyl- 1H-1,2,3-triazol-1-yl)pyndm-4- yl]ammo}cyclobut-3-ene-1,2-dione,

3-{[2-(4-benzyl- 1H-1,2,3-tnazol-1-yl)pyndin-4-yl]ammo}-4-{[(1R)-1- phenylethyl] amino} cyclobut-3-ene-1,2-dione,

3-({2-[4-(hydroxymethyl)-l//-1,2,3-triazol-1-yl]pyridm-4- yl}ammo)-4-{[(1R)-1- phenylethyl] ammo} cyclobut-3-ene- 1 ,2-dione,

3 - { [ 1 -(3 -methylphenyl)ethyl] amino } -4-(pyridin-4-ylammo)cyclobut-3 -ene- 1 ,2-dione, 3-[(l-phenylethyl)ammo]-4-(pyndin-4-ylammo)cyclobut-3-ene-1, 2-dione, 3-{tl-(3-chlorophenyl)ethyl]ammo}-4-{pyridm-4-ylammo)cyclobu t-3-ene-1,2-dione N-[3 -( 1 - { [3 ,4-dioxo-2-(pyndm-4-ylamino)cyclobut- 1 -en- 1 -yl] amino } ethyl)phenyl] methanesulfonamide, methyl 3 -( 1 - { [3 ,4-dioxo-2-(pyridm-4-ylammo)cyclobut- 1 -en- 1 -yl] amino} ethyl)benzoate, N-[3-(l-{[3,4-dioxo-2-(pyndin-4-ylammo)cyclobut-1-en-1- yl] ammo } ethyl)phenyl] acetamide,

3 -( 1 - { [3 ,4-dioxo-2-(pyridm-4-ylammo)cyclobut- 1 -en- 1 -yl] ammo } ethyl)benzoic acid, 3-{[l-(3-bromophenyl)ethyl]ammo}-4-(pyridm-4-ylammo)cyclobut -3-ene-1,2-dione _>

3-(pyridin-4-ylamino)-4-({l-[3-(2J?-tetrazol-5-yl)phenyl] ethyl}amino)cyclobut-3-ene- 1,2-dione;

3-(l-{[3,4-dioxo-2-(pyridin-4-ylamino)cyclobut-1-en-1-yl] amino}ethyl)benzamide;

3-{[l-(5-hydroxy-2-methoxyphenyl)ethyl]amino}-4-(pyridin- 4-ylamino)cyclobut-3-ene- 1,2-dione;

3-{[l-(3-hydroxy-4-methoxyphenyl)ethyl]amino}-4-(pyridin- 4-ylamino)cyclobut-3-ene- 1,2-dione;

3-{[l-(2,5-dihydroxyphenyl)ethyl]amino}-4-(pyridin-4-ylam ino)cyclobut-3-ene-1,2- dione; 3-{[l-(3 , 5-dihydroxyphenyl)ethyl] amino } -4-(pyridin-4-ylamino)cyclobut-3-ene- 1 ,2- dione;

3- {[ 1 -(3-hydroxy-5-methoxyphenyl)ethyl]amino} -4-(pyridin-4-ylamino)cyclobut-3-ene- 1,2-dione;

N-[3-(l-{[3,4-dioxo-2-(pyridin-4-ylamino)cyclobut-1-en-1- yl]amino}ethyl)phenyl]-N'- methylurea;

3-{[l-(3-amino-4-methylphenyl)ethyl]amino}-4-(pyridin-4-y lamino)cyclobut-3-ene-1,2- dione;

3-{[l-(4-methyl-3-nitrophenyl)ethyl]amino}-4-(pyridin-4-y lamino)cyclobut-3-ene-1,2- dione; 3-{[l-(3-hydroxy-4-methylphenyl)ethyl]amino}-4-(pyridin-4-yl amino)cyclobut-3-ene-

1,2-dione;

3-({2-[(E)-2-(4-chlorophenyl)vinyl]pyridin-4-yl}amino)-4- {[(1R)-1- phenylethyl]amino}cyclobut-3-ene-1,2-dione;

3 - { [2-(3 -methoxyphenyl)pyridin-4-yl] amino }-4-{[(1R)-l -phenylethyl] amino } cyclobut-3 - ene- 1,2-dione;

3 - [(2-anilinopyridm-4-yl)amino] -4- { [( 1 R)- 1 -phenylethyl] amino } cyclobut-3 -ene- 1,2- dione;

3-{[(1R)-l -phenylethyl] amino } -4- [(2- { [4-(trifluoromethyl)phenyl] amino }pyridin-4- yl)amino]cyclobut-3-ene-1,2-dione; 3-{[(1R)-l -phenylethyl] amino } -4- { [2-(pyrimidin-4-ylamino)pyridin-4- yl]amino}cyclobut-3-ene-1,2-dione;

3-[(2-{[3-(hydroxymethyl)phenyl]amino}pyridin-4-yl)amino] -4-{[(1R)-1- phenylethyl] amino } cyclobut-3 -ene- 1 ,2-dione;

3-({4-[(3,4-dioxo-2-{[(1R)-1-phenylethyl]amino}cyclobut-1 -en-1-yl)amino]pyridin-2- yl} amino)benzamide; 3-{[(1R)-l -phenylethyl] amino } -4- { [2-(pyridin-2-ylamino)pyridm-4-yl] amino } cyclobut-

3-ene-1,2-dione;

3-{[(1R)-1-phenylethyl]ammo}-4-{[2-(pyridin-3-ylamino)pyr idin-4-yl]amino}cyclobut- 3-ene-1,2-dione;

3-{[(1R)-l -phenylethyl] amino } -4- { [2-(pyrazin-2-ylamino)pyridin-4-yl] amino } cyclobut- 3-ene-1,2-dione;

N-(4-(2-((R)-1-phenylethylamino)-3,4-dioxocyclobut-1-enyl amino)pyridin-2- yl)acetamide;

N-{4-[(3,4-dioxo-2-{[(1R)-1-phenylethyl]amino}cyclobut-1- en-1-yl)amino]pyridin-2- yljbenzamide; N-{4-[(3,4-dioxo-2-{[(1R)-1-phenylethyl]amino}cyclobut-1-en- 1-yl)amino]pyridin-2- yl} nicotinamide;

2-(l-phenylethyl)-6-pyridin-4-yl-2,6-diazabicyclo[5.2.0]n on-l(7)-ene-8,9-dione;

3-{[(1R)-l -phenylethyl] amino } -4- [(2-phenylpyridin-4-yl)amino]cyclobut-3 -ene- 1 ,2- dione; 3-{[2-(3 -fluorophenyl)pyridin-4-yl] amino }-4-{[(1R)-l -phenylethyl] amino } cyclobut-3 - ene-1,2-dione;

3 - { [2-( 1 -benzofuran-2-yl)pyridin-4-yl] amino} -4-{[(1R)-l -phenylethyl] amino } cyclobut- 3-ene-1,2-dione;

3 - { [2-(3 -fluorophenyl)pyridin-4-yl] amino} -4- { [( 1 R)- 1 -phenylethyl] amino } cyclobut-3- ene-1,2-dione;

3-(2,3'-bipyridin-4-ylamino)-4-{[(1R)-1-phenylethyl]ammo} cyclobut-3-ene-1,2-dione;

3-{[(1R)-1-phenylethyl]amino}-4-({2-[3-(trifluoromethyl)p henyl]pyridin-4- yl}amino)cyclobut-3-ene-1,2-dione;

3-{[(1R)-1-phenylethyl]amino}-4-({2-[4-(trifluoromethyl)p henyl]pyridm-4- yl}amino)cyclobut-3-ene-1,2-dione;

3-{[(1R)-l -phenylethyl] amino } -4- { [2-(pyridin-4-ylamino)pyridin-4-yl] amino} cyclobut- 3-ene-1,2-dione;

3-({2-[(4-methyl-1,3-thiazol-2-yl)ammo]pyridin-4-yl}amino )-4-{[(1R)-1- phenylethyl]amino}cyclobut-3-ene-1,2-dione; 3-{[(1R)-l -phenylethyl] amino } -4- { [2-(quinolin-2-ylamino)pyridin-4-yl] amino } cyclobut-

3-ene-1,2-dione;

3-{[(1R)-1-phenylethyl]amino}-4-{[2-(pyrimidin-2-ylamino) pyridin-4- yl]amino}cyclobut-3-ene-1,2-dione;

3-{[2-(2-fluorophenyl)ρyridin-4-yl]amino}-4-{[(1R)-1-phe nylethyl]amino}cyclobut-3- ene-1,2-dione;

3- { [2-(2-fiiryl)pyridin-4-yl] amino }-4-{[(1R)-l -phenylethyl] amino } cyclobut-3 -ene- 1 ,2- dione;

3 - { [2-(4-methylphenyl)pyridin-4-yl] amino} -4-{[(1R)-l -phenylethyl] amino } cyclobut-3- ene-1,2-dione; N-(4-{4-[(3,4-dioxo-2-{[(1R)-1-phenylethyl]amino}cyclobut-1- en-1-yl)amino]pyridin-2- yl}phenyl)acetamide;

3- { [2-(3 -methylphenyl)pyridin-4-yl] amino} -4- { [( 1 R)- 1 -phenylethyl] amino } cyclobut-3 - ene-1,2-dione;

3-(2,4'-bipyridin-4-ylamino)-4-{[(1R)-1-phenylethyl]amino }cyclobut-3-ene-1,2-dione; 3-({2-[4-(hydroxymethyl)phenyl]pyridin-4-yl}amino)-4-{[(1R)- 1- phenylethyl] amino} cyclobut-3-ene- 1 ,2-dione;

3-({2-[3-(benzyloxy)phenyl]pyridin-4-yl}amino)-4-{[(1R)-l phenylethyl] amino} cyclobut-3-ene- 1 ,2-dione;

3-[(2-biphenyl-3-ylpyridin-4-yl)amino]-4-{[(1R)-1-phenyle thyl]amino}cyclobut-3-ene- 1 ,2-dione;

3-[(2-biphenyl-3-ylpyridin-4-yl)amino]-4-{[(1R)-1-phenyle thyl]amino}cyclobut-3-ene- 1,2-dione;

N-cyclopentyl-4- {4- [(3 ,4-dioxo-2- { [( 1 R)- 1 -phenylethyl] amino } cyclobut- 1 -en- 1 - yl)amino]pyridin-2-yl}benzamide; 3 - { [2-(4-chlorophenyl)pyridin-4-yl] amino }-4-{[(1R)-l -phenylethyl] amino } cyclobut-3- ene-1,2-dione;

3-{2,2'-bipyridm-4-ylammo)-4-{[(1R)-1-phenylethyl]amino}c yclobut-3-ene-1,2-dione,

2-{[3,4-dioxo-2-(pyndm-4-ylammo)cyclobut-1-en-1-yl]ammo}- 2-(4-pyndin-3- ylphenyl)acetamide,

2-biphenyl-4-yl-2- { [3 ,4-dioxo-2-(pyndm-4-ylammo)cyclobut- 1 -en- 1 - yl] amino} acetamide,

2-(4-bromophenyl)-2-{[3,4-dioxo-2-(ρyndin-4-ylamino)cycl obut-1-en-1- yl] amino } acetamide,

2-{[3,4-dioxo-2-(pyndin-4-ylammo)cyclobut-1-en-1-yl]ammo} -2-[4-(3- thienyl)phenyl]acetamide, 2- {[3,4-dioxo-2-(pyridin-4-ylainino)cyclobut- 1 -en-1 -yljammo} -2-[4-(3- fiiryl)phenyl] acetamide,

3-{[(1R)-1-phenylethyl]ammo}-4-(thieno[2,3-b]pyndui-4-yla mmo)cyclobut-3-ene-1,2- dione,

3-{[l-(4-iodophenyl)ethyl]amino}-4-(pyridm-4-ylammo)cyclo but-3-ene-1,2-dione, and pharmaceutically acceptable salts thereof

In some embodiments, the compound is selected from

2-{[3,4-dioxo-2-(pyridm-4-ylammo)cyclobut-1-en-1-yl]ammo} -2-(3'-methylbiphenyl-3- yl)acetamide,

2-{3'-[(dimethylammo)sulfonyl]biphenyl-3-yl}-2-{[3,4-diox o-2-(pyridin-4- ylammo)cyclobut- 1 -en- 1 -yl] ammo } acetamide,

2- { [3 ,4-dioxo-2-(pyridm-4-ylamino)cyclobut- 1 -en- 1 -yl] ammo } -2-(2'-methylbiphenyl-3- yl)acetamide,

2-(3'-cyanobiphenyl-3-yl)-2-{[3,4-dioxo-2-(pyridm-4-ylamm o)cyclobut-1-en-1- yl] ammo } acetamide, 2-{[3,4-dioxo-2-(pyndm-4-ylammo)cyclobut-1-en-1-yl]ammo}-2-( 4'-methylbiphenyl-3- yl)acetamide,

3 '-( 1 - { [ 3 ,4-dioxo-2-(pyridin-4-ylammo)cyclobut- 1 -en- 1 -yl] ammo } ethyl)biphenyl-3 - carbomtrile,

3- {[ 1 -(4'-acetylbiphenyl-3-yl)ethyl]ammo}-4-(ρyridm-4-ylammo)cyc lobut-3-ene-1,2- dione,

3-{[l-(4'-chlorobiphenyl-3-yl)ethyl]amino}-4-(pyridin-4-y lamino)cyclobut-3-ene-1,2- dione;

3-{[l-(2'-methylbiphenyl-3-yl)ethyl]amino}-4-(pyridin-4-y lamino)cyclobut-3-ene-1,2- dione; 3-{[l-(4'-methylbiphenyl-3-yl)ethyl]amino}-4-(pyridin-4-ylam ino)cyclobnt-3-ene-1,2- dione;

3-{[l-(3'-methoxybiphenyl-3-yl)ethyl]amino}-4-(pyridin-4- ylamino)cyclobut-3-ene-1,2- dione; tert-butyl [3'-( 1 - { [3 ,4-dioxo-2-(pyridin-4-ylamino)cyclobut- 1 -en- 1 - yl] amino } ethyl)biphenyl-4-yl] carbamate;

3-{[l-(3'-aminobiphenyl-4-yl)ethyl]amino}-4-(pyridin-4-yl ammo)cyclobut-3-ene-1,2- dione;

3-{[l-(4'-chlorobiphenyl-4-yl)ethyl]ammo}-4-(pyridin-4-yl amino)cyclobut-3-ene-1,2- dione; 2-{[3,4-dioxo-2-(pyridin-4-ylamino)cyclobut-1-en-1-yl]aniino }-2-[4'-(morpholm-4- ylcarbonyl)biphenyl-4-yl]acetamide;

2-{[3,4-dioxo-2-(pyridin-4-ylamino)cyclobut-1-en-1-yl]ami no}-2-{3'- [(methylsulfonyl)amino]biphenyl-4-yl}acetamide;

2- {3'-[(dimethylamino)sulfonyl]biphenyl-4-yl} -2- {[3,4-dioxo-2-(pyridin-4- ylamino)cyclobut-1-en-1-yl]amino}acetamide;

2- { [3 ,4-dioxo-2-(pyridin-4-ylamino)cyclobut- 1 -en- 1 -yl] amino } -2- [3 '-(morpholin-4- ylcarbonyl)biphenyl-4-yl]acetamide;

2- {[3 ,4-dioxo-2-(pyridin-4-ylamino)cyclobut- 1 -en- 1 -yl]amino} -2- {3 '- [(ethylamino)sulfonyl]biphenyl-4-yl}acetamide; 2-(2'-aminobiphenyl-4-yl)-2- { [3,4-dioxo-2-(pyridin-4-ylamino)cyclobut- 1 -en- 1 - yl] amino } acetamide; N-[3,4-dioxo-2-(pyridin-4-ylamino)cyclobut-1-en-1-yl]-L-phen ylalaninamide;

λ^-[3,4-dioxo-2-(pyridin-4-ylammo)cyclobut-1-en-1-yl]-D- phenylalaninamide; and pharmaceutically acceptable salts thereof. In some embodiments, the compound is selected from:

3-(isobutylamino)-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2 -dione;

3-(allylamino)-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2-dione ; (R)-3-(Pyridin-4-ylamino)-4-(1,2,2-trimethyl-propylamino)- cyclobut-3-ene-1,2-dione; N ² -[3,4-dioxo-2-(pyridin-4-ylamino)cyclobut-1-en-1-yl]-L-leuci namide; N ² -[3,4-dioxo-2-(pyridin-4-ylamino)cyclobut-1-en-1-yl]-L-alani namide; N ² -[3,4-dioxo-2-(pyridin-4-ylamino)cyclobut-1-en-1-yl]-L-serin amide; and pharmaceutically acceptable salts thereof.

In another aspect, a pharmaceutical composition includes a pharmaceutically acceptable carrier and a compound having Formula (I) as defined above, or a pharmaceutically acceptable salt thereof. In another aspect, a method of treating a patient in need of MK2 inhibition includes administering to the patient an amount effective for MK2 inhibition of a compound having Formula (T) as defined above, or a pharmaceutically acceptable salt thereof. The patient can be in need of treatment or prevention of a TNFα mediated disease or disorder.

The TNFα mediated disease or disorder can be a connective tissue disorder, a joint disorder, a neoplasia disorder, a cardiovascular disorder, an otic disorder, an ophthalmic disorder, a respiratory disorder, a gastrointestinal disorder, an angiogenesis-related disorder, an immunological disorder, an allergic disorder, a nutritional disorder, an infectious disease, an endocrine disorder, a metabolic disorder, a neurological disorder, a neurodegenerative disorder, a psychiatric disorder, a hepatic disorder, a biliary disorder, a musculoskeletal disorder, a genitourinary disorder, a gynecologic disorder, an obstetric disorder, an injury, a trauma, a surgical disorder, a dental disorder, an oral disorder, a sexual dysfunction disorder, a dermatologic disorder, a hematological disorder, or a poisoning disorder.

The TNFα mediated disease or disorder can be arthritis, rheumatoid arthritis, spondyloarthopathies, gouty arthritis, osteoarthritis, systemic lupus erythematosus, juvenile arthritis, asthma, bronchitis, menstrual cramps, tendinitis, bursitis, connective tissue injuries or disorders, skin related conditions, psoriasis, eczema, burns, dermatitis, gastrointestinal conditions, inflammatory bowel disease, gastric ulcer, gastric varices, Crohn's disease, gastritis, irritable bowel syndrome, ulcerative colitis, cancer, colorectal cancer, herpes simplex infections, HIV, pulmonary edema, kidney stones, minor injuries, wound healing, vaginitis, candidiasis, lumbar spondylanhrosis, lumbar spondylarthrosis, vascular diseases, migraine headaches, sinus headaches, tension headaches, dental pain, periarteritis nodosa, thyroiditis, aplastic anemia,

Hodgkin's disease, sclerodoma, rheumatic fever, type I diabetes, myasthenia gravis, multiple sclerosis, sarcoidosis, nephrotic syndrome, Behcet's syndrome, polymyositis, gingivitis, hypersensitivity, swelling occurring after injury, myocardial ischemia, ophthalmic diseases, retinitis, retinopathies, conjunctivitis, uveitis, ocular photophobia, acute injury to the eye tissue, pulmonary inflammation, viral infections, cystic fibrosis, central nervous system disorders, cortical dementias, or Alzheimer's disease.

The TNFα mediated disease or disorder can be rheumatoid arthritis, psoriasis, lupus, inflammatory bowel disease, asthma, or chronic obstructive pulmonary disease.

As used herein, the term "alkyl," alone or in combination, refers to a straight-chain or branched-chain alkyl radical containing 1 to 10, 1 to 6, or 1 to 4, carbon atoms. Examples of such radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl, octyl, decyl and the like. Alkyl groups can be optionally substitued.

The term "alkenyl," alone or in combination, refers to a straight-chain or branched-chain alkenyl radical containing 2 to 10, 2 to 6, or 2 to 4, carbon atoms. Examples of such radicals include ethenyl, E- and Z-propenyl, isopropenyl, E- and Z-butenyl, E- and Z-isobutenyl, E- and Z-pentenyl, decenyl and the like. Alkenyl radicals can include more than one unsaturated bond, e.g., a butadienyl radical or but-1-yn-3-enyl radical. Alkenyl groups can be optionally substitued. The term "alkynyl," alone or in combination, refers to a straight-chain or branched-chain alkynyl radical containing 2 to 10, 2 to 6, or 2 to 4, carbon atoms. Examples of such radicals include ethynyl (acetylenyl), propynyl, propargyl, butynyl, hexynyl, decynyl and the like.

Alkynyl radicals can include more than one unsaturated bond, e.g., a butadiynyl radical or but-1- yn-3-enyl radical. Alkynyl groups can be optionally substitued.

The term "cycloalkyl," alone or in combination, refers to a cyclic alkyl radical containing 3 to 10, 3 to 8, or 3 to 6, carbon atoms. Examples of such cycloalkyl radicals include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like; and bicylic groups including bicyclo[3.4.0]nonyl, bicyclo[2.2.2]octyl, norbornyl, spiro[4.5]decyl, and the like. Cycloalkyl groups can be optionally substitued.

The term "cycloalkenyl," alone or in combination, refers to a cyclic carbocycle containing 4 to 10, 4 to 8, or 5 or 6, carbon atoms and one or more double bonds. Examples of such cycloalkenyl radicals include cyclopentenyl, cyclohexenyl, cyclopentadienyl, and bicyclic groups such as norbornenyl, and the like. Cycloalkenyl groups can be optionally substitued.

The term "aryl" refers to a carbocyclic aromatic group, and includes fused bicyclic or tricyclic systems An aryl group can have from 6 to 14 carbon atoms m the ring system, or from 6 to 10 atoms in the πng system In fused systems, one or more rings may not be aromatic, e g , mdanyl, or all πngs may be aromatic, e g , naphthyl and anthracenyl Examples of aryl groups include phenyl, naphthyl, mdenyl, mdanyl, azulenyl, fluorenyl, and anthracenyl Aryl groups can be optionally substitued

The term "heteroaryl" refers to a heterocyclic aromatic group, and includes fused bicyclic or tricyclic systems A heteroaryl group can have from 5 to 14 πng members In fused systems, one or more πngs may not be aromatic, e g , indolmyl or benzodioxolyl, or all nngs may be aromatic, e g , benzimidazolyl, benzofuranyl, or dibenzofuranyl Examples of such heteroaryl groups include furyl, thienyl, pyridyl, pyrrolyl, oxazolyly, thiazolyl, lmidazolyl, pyrazolyl, 2- pyrazolmyl, pyrazolidnyl, isoxazolyl, lsothiazolyl, 1,2,3-oxadiazolyl, 1,2,3-tnazolyl, 1,3,4- thiadiazolyl, pyndazmyl, pynmidmyl, pyrazmyl, 1,3,5-tnazmyl, 1,3,5-rnthianyl, mdohzmyl, mdolyl, isoindolyl, 3H-mdolyl, mdolmyl, benzo[b]furanyl, 2,3-dihydrobenzofuranyl, benzo[b]thiophenyl, 1H-indazolyl, benzimidazolyl, benztmazolyl, purinyl, 4H-qumohzinyl, qumolmyl, lsoqumolmyl, cnnolnyl, phthalazmyl, qumazolmyl, qumoxalmyl, 1,8- naphthyndmyl, pteridmyl, carbazolyl, acndmyl, phenazinyl, phenothiazinyl, and phenoxazmyl Heteroaryl groups can be optionally substitued

The term "halogen" means fluorine, chlorine, bromine or iodme The term "heterocyclyl" refers to a saturated or unsaturated monocyclic, bicyclic or tricychc non-aromatic group including 1 to 5 heteroatoms selected from O, N, and S The heteroatom can be an oxidized heteroatom, for example, when the heteroatom is N, it can be an N-oxide, or when the heteroatom is S, it can be a sulfoxide or sulfone Bicyclic and tricyclic heterocyclyl groups can include an aromatic πng, e g , 2,3-dihydrobenzofuranyl, or 2,3- dihydronaphtho[2,3-b]furanyl A heterocyclyl group can have from 3 to 14 πng members A monocyclic heterocyclyl group can have from 3 to 8 πng members, or from 3 to 6 πng members A bicyclic or tricyclic heterocyclyl group can have from 7 to 14 nng members

Some examples of heterocyclyl groups include monocyclic groups such as, for example, morpholmo, tetrahydrofuranyl, pyrrolidmyl, 2,3-dihydropyrrolyl, piperidmyl, 1,4- dihydropyridmyl, tetrahydrothienyl, thiomorpholmo, tetrahydropyranyl, butyrolactonyl, caprolactonyl, caprolactamyl, succinimidyl, maleimidyl, 2,3-dihydropyranyl, 2,3-

dihydropyrrolidyl, 1,2-dihydropyridinyl, maleimidiyl, and the like; bicyclic heterocyclyl groups including, for example, fused bicyclic groups (e.g., octahydrobenzofuranyl, octahydro-lff- indolyl, hexahydro-2J¥-furo[2,3-δ]pyrrolyl, 3a,4,5,6,7,7a-hexahydro-1H-indolyl), bridged bicyclic groups (e.g., 2-oxa-bicyclo[2.2.1]heptanyl, 2-aza-bicyclo[2.2.1]heptanyl, and the like), or spiro bicyclic groups. Tricyclic groups can include rings that are fused, bridged, or spiro.

As used herein, the term "amino" refers to a group of formula -NEk-

As used herein, the term "C _n -C _1n' alkylamino" refers to a group of formula — NH(alkyl), wherein the alkyl group has n' to m' carbon atoms.

As used herein, the term "di-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. As used herein the term "C _n - C _n , _' alkoxy" refers to a group of formula -O(alkyl), wherein the alkyl group has n' to m' carbon atoms.

As used herein, the term "C _n --C _m -alkylammosulfonyl" refers to a group of formula - S(=O) ₂ NH(alkyl), wherein the alkyl group has n' to m' carbon atoms. As used herein, the term "diC _n' -C _m -alkylaminosulfonyl" refers to a group of formula -

S(=O) ₂ N(alkyl) ₂ , wherein the alkyl group has n' to m' carbon atoms.

As used herein, the term "C _n' -C _m -alkylsulfonylamino" refers to a group of formula - NHS(=O) ₂ (alkyl), wherein the alkyl group has n' to m'carbon atoms.

As used herein, the term "C _n' -C _m -alkoxycarbonylamino" refers to a group of formula - NHC(=O)O(alkyl), wherein the alkyl group has n' to m' carbon atoms.

As used herein, the term "C _n' -C _1m' alkylcarbonyl" refers to a group of formula - C(=O)alkyl, wherein said alkyl group has n' to m' carbon atoms.

As used herein, the term "heterocyclylcarbonyl" refers to a group of formula - C(=O)heterocyclyl. As used herein, the term "carbamyl" refers to a group of formula -C(=O)NH ₂ .

As used herein, the term "hydroxyl" refers to a group of formula -OH.

The term "treating" or "treatment" refers to any indicia of success in amelioration of an injury, pathology, or condition, including any objective or subjective parameter such as abatement; remission; diminishing of symptoms or making the injury, pathology, or condition more tolerable to the patient; slowing in the rate of degeneration or decline; making the final point of degeneration less debilitating; or improving a subject's physical or mental well-being.

The treatment or amelioration of symptoms can be based on objective or subjective parameters; including the results of a physical examination, neurological examination, and/or psychiatric evaluation. "Treating" includes inhibiting the symptoms of the disorder (slowing or arresting its development), providing relief from the symptoms or side-effects of the disorder (including palliative treatment), and/or relieving the symptoms of the disorder (causing regression).

Accordingly, the term "treating" includes the administration of the compounds of Formula (I) to a subject to alleviate, or to arrest or inhibit development of the symptoms or conditions associated with a disorder. A skilled medical practitioner will know how to use standard methods to identify a subject in need of treatment. The term "preventing" refers to preventing the onset of symptoms in a subject that may be predisposed to a disorder but does not yet experience or exhibit symptoms of the disorder (prophylactic treatment). Accordingly, the term "preventing" includes the administration of the compounds of formula (I) to a subject to prevent or delay symptoms or conditions associated with a disorder. A skilled medical practitioner will know how to use standard methods to identify a subject in need of prevention.

Throughout the application, unless otherwise specified, the terms "include" and "including" are used in an open-ended sense; e.g., "including" means "including but not limited to."

A person of ordinary skill in the art will recognize that the compounds can be prepared in different isomeric forms, including stereoisomers (e.g., diastereomers, members of an enantiomeric pair, or mixtures of enantiomers, such as racemic mixtures; or as E-/Z-isomers differing in configuration about a double bond), or tautomers (e.g., forms that differ by location of a dissociable proton). Unless indicated to be limited, a reference to a compound or group of compounds, whether by name, structure or otherwise, is intended to include all such forms. It will also be understood that certain compounds of the present invention may exist in solvated, for example hydrated, as well as unsolvated forms. It will further be understood that the present invention encompasses all such solvated forms of the compounds of the Formula (I).

Other features, objects, and advantages will be apparent from the following description, and from the claims.

DETAILED DESCRIPTION

Certain squarates (derivatives of squaric acid, 3,4-dihydro-3-cyclobutene-1,2-dione) can modulate (i.e., increase, decrease, or otherwise alter) the activity of protein kinases. Protein kinases are a class of enzymes that catalyze the transfer of a phosphate group from ATP to a tyrosine, serine, threonine or histidine residue located on a protein substrate. In particular, squarates can modulate the kinase activity of MK2 (MAPKAPK2).

MK2 is a direct substrate of p38α and p38β MAP kinases and is responsible for many of the signaling events that follow the activation of these MAPKs. Indeed, MK2 was the first substrate of p38α to be identified. The physiological implications of MK2 activation are most clearly revealed by the targeted disruption of the MK2 gene in mice. MK2 deficient cells derived from mice have shown defects in motility, chemotaxis and cytokine production (Kotlyarov et al. Nat. Cell. Biol. 1999, which is incorporated by reference in its entirety). Several studies using MK2-deficient mice strongly support the central role of this kinase in the production of inflammatory cytokines such as TNFα, IL-6 and IFNγ. AU-rich elements (AREs) have been identified in the 3' untranslated region (UTR) of several cytokine mRNAs and are known to regulate mRNA stability and translation. In the case of TNFα, IL-6 and IFNγ it has been shown that MK2 regulates their expression by targeting their mRNA AREs.

TNFα is a pro-inflammatory cytokine that is involved in inflammation in a number of disease states like rheumatoid arthritis (RA). Protein therapeutics, such as etanercept, are currently available to treat patients with RA or other inflammatory diseases. However, small molecule that inhibits TNFα production is desirable, particularly an orally available small molecule.

Accordingly, compounds of Formula (I) are useful in methods of inhibiting MK2 and for the prevention and treatment of diseases or disorders mediated by tumor necrosis factor-α (TNFα) or other cytokines. Among TNFα mediated diseases or disorders are connective tissue and joint disorders, neoplasia disorders, cardiovascular disorders, otic disorders, ophthalmic disorders, respiratory disorders, gastrointestinal disorders, angiogenesis-related disorders, immunological disorders, allergic disorders, nutritional disorders, infectious diseases and disorders, endocrine disorders, metabolic disorders, neurological and neurodegenerative disorders, psychiatric disorders, hepatic and biliary disorders, musculoskeletal disorders, genitourinary disorders, gynecologic and obstetric disorders, injury and trauma disorders,

surgical disorders, dental and oral disorders, sexual dysfunction disorders, dermatologic disorders, hematological disorders, or poisoning disorders. Also among TNFα mediated diseases or disorders are arthritis, rheumatoid arthritis, spondyloarthopathies, gouty arthritis, osteoarthritis, systemic lupus erythematosus, juvenile arthritis, asthma, bronchitis, menstrual cramps, tendinitis, bursitis, connective tissue injuries or disorders, skin related conditions, psoriasis, eczema, burns, dermatitis, gastrointestinal conditions, inflammatory bowel disease, gastric ulcer, gastric varices, Crohn's disease, gastritis, irritable bowel syndrome, ulcerative colitis, cancer, colorectal cancer, herpes simplex infections, HIV, pulmonary edema, kidney stones, minor injuries, wound healing, vaginitis, candidiasis, lumbar spondylanhrosis, lumbar spondylarthrosis, vascular diseases, migraine headaches, sinus headaches, tension headaches, dental pain, periarteritis nodosa, thyroiditis, aplastic anemia, Hodgkin's disease, sclerodoma, rheumatic fever, type I diabetes, myasthenia gravis, multiple sclerosis, sarcoidosis, nephrotic syndrome, Behcet's syndrome, polymyositis, gingivitis, hypersensitivity, swelling occurring after injury, myocardial ischemia, ophthalmic diseases, retinitis, retinopathies, conjunctivitis, uveitis, ocular photophobia, acute injury to the eye tissue, pulmonary inflammation, viral infections, cystic fibrosis, central nervous system disorders, cortical dementias, and Alzheimer's disease. In particular, such diseases or disorders include rheumatoid arthritis (RA), psoriasis, lupus (SLE), inflammatory bowel disease (IBD), asthma or chronic obstructive pulmonary disease (COPD). In some embodiments, the disorder or disease is selected from rheumatoid arthritis, psoriasis, lupus, inflammatory bowel disease, asthma, and chronic obstructive pulmonary disease.

In some embodiments, the present invention provides a kit comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and instructions, wherein said instructions comprise a direction to administer said compound, or pharmaceutically salt thereof, to a patient in need of treatment for a disease or disorder selected from arthritis, rheumatoid arthritis, spondyloarthopathies, gouty arthritis, osteoarthritis, systemic lupus erythematosus, juvenile arthritis, asthma, bronchitis, menstrual cramps, tendinitis, bursitis, connective tissue injuries or disorders, skin related conditions, psoriasis, eczema, bums, dermatitis, gastrointestinal conditions, inflammatory bowel disease, gastric ulcer, gastric varices, Crohn's disease, gastritis, irritable bowel syndrome, ulcerative colitis, cancer, colorectal cancer, herpes simplex infections,

HTV, pulmonary edema, kidney stones, minor injuries, wound healing, vaginitis, candidiasis, lumbar spondylanhrosis, lumbar spondylarthrosis, vascular diseases, migraine headaches, sinus headaches, tension headaches, dental pain, periarteritis nodosa, thyroiditis, aplastic anemia, Hodgkin's disease, sclerodoma, rheumatic fever, type I diabetes, myasthenia gravis, multiple sclerosis, sarcoidosis, nephrotic syndrome, Behcet's syndrome, polymyositis, gingivitis, hypersensitivity, swelling occurring after injury, myocardial ischemia, ophthalmic diseases, retinitis, retinopathies, conjunctivitis, uveitis, ocular photophobia, acute injury to the eye tissue, pulmonary inflammation, viral infections, cystic fibrosis, central nervous system disorders, cortical dementias, and Alzheimer's disease In some embodiments, the disease or disorder is rheumatoid arthritis, psoriasis, lupus, inflammatory bowel disease, asthma, or chronic obstructive pulmonary disease hi some embodiments, the disorder or disease is selected from rheumatoid arthritis, psoriasis, lupus, inflammatory bowel disease, asthma, and chronic obstructive pulmonary disease In some embodiments, the present invention provides use of a compound of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for the preparation of medicament for use in a method of treating a disease or disorder selected from arthritis, rheumatoid arthritis, spondyloarthopathies, gouty arthritis, osteoarthritis, systemic lupus erythematosus, juvenile arthritis, asthma, bronchitis, menstrual cramps, tendinitis, bursitis, connective tissue injuries or disorders, skin related conditions, psoriasis, eczema, burns, dermatitis, gastrointestinal conditions, inflammatory bowel disease, gastric ulcer, gastric varices, Crohn's disease, gastritis, irritable bowel syndrome, ulcerative colitis, cancer, colorectal cancer, herpes simplex infections, HIV, pulmonary edema, kidney stones, minor injuries, wound healing, vaginitis, candidiasis, lumbar spondylanhrosis, lumbar spondylarthrosis, vascular diseases, migraine headaches, sinus headaches, tension headaches, dental pain, periarteritis nodosa, thyroiditis, aplastic anemia, Hodgkin's disease, sclerodoma, rheumatic fever, type I diabetes, myasthenia gravis, multiple sclerosis, sarcoidosis, nephrotic syndrome, Behcet's syndrome, polymyositis, gingivitis, hypersensitivity, swelling occurring after injury, myocardial ischemia, ophthalmic diseases, retinitis, retinopathies, conjunctivitis, uveitis, ocular photophobia, acute injury to the eye tissue, pulmonary inflammation, viral infections, cystic fibrosis, central nervous system disorders, cortical dementias, and Alzheimer's disease In some embodiments, the disease or disorder is

rheumatoid arthritis, psoriasis, lupus, inflammatory bowel disease, asthma, or chronic obstructive pulmonary disease.

In some embodiments, the disorder or disease is selected from rheumatoid arthritis, psoriasis, lupus, inflammatory bowel disease, asthma, and chronic obstructive pulmonary disease.

In some embodiments, the present invention provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in a method of treating a disease or disorder selected from arthritis, rheumatoid arthritis, spondyloarthopathies, gouty arthritis, osteoarthritis, systemic lupus erythematosus, juvenile arthritis, asthma, bronchitis, menstrual cramps, tendinitis, bursitis, connective tissue injuries or disorders, skin related conditions, psoriasis, eczema, burns, dermatitis, gastrointestinal conditions, inflammatory bowel disease, gastric ulcer, gastric varices, Crohn's disease, gastritis, irritable bowel syndrome, ulcerative colitis, cancer, colorectal cancer, herpes simplex infections, HIV, pulmonary edema, kidney stones, minor injuries, wound healing, vaginitis, candidiasis, lumbar spondylarthrosis, lumbar spondylarthrosis, vascular diseases, migraine headaches, sinus headaches, tension headaches, dental pain, periarteritis nodosa, thyroiditis, aplastic anemia, Hodgkin's disease, sclerodoma, rheumatic fever, type I diabetes, myasthenia gravis, multiple sclerosis, sarcoidosis, nephrotic syndrome, Behcet's syndrome, polymyositis, gingivitis, hypersensitivity, swelling occurring after injury, myocardial ischemia, ophthalmic diseases, retinitis, retinopathies, conjunctivitis, uveitis, ocular photophobia, acute injury to the eye tissue, pulmonary inflammation, viral infections, cystic fibrosis, central nervous system disorders, cortical dementias, and Alzheimer's disease. In some embodiments, the disease or disorder is rheumatoid arthritis, psoriasis, lupus, inflammatory bowel disease, asthma, or chronic obstructive pulmonary disease.

In some embodiments, the disorder or disease is selected from rheumatoid arthritis, psoriasis, lupus, inflammatory bowel disease, asthma, and chronic obstructive pulmonary disease.

Compounds of Formula I can be used in the form of pharmaceutically acceptable salts derived from inorganic and/or organic acids and/or bases. Included among such acid salts are the following: acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate,

hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfoπate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3 -phenyl-propionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate and undecanoate. Base salts include ammonium salts, alkali metal salts, such as sodium and potassium salts, alkaline earth metal salts, such as calcium and magnesium salts, salts with organic bases, such as dicyclohexylamine salts, N-methyl-D-glucamine, and salts with amino acids such as argmine, lysine, and so forth. Also, the basic nitrogen-containing groups can be quaternized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates, such as dimethyl, diethyl, dibutyl and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides, such as benzyl and phenethyl bromides or others. Water- or oil-soluble or dispersible products can be obtained in this way.

The compound may be formulated into pharmaceutical compositions that may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. The term "parenteral" includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. See, for example, Remington: The Science and Practice of Pharmacy, 21st ed. 2005, Lippincott Williams & Wilkins, which is incorporated by reference in its entirety. Pharmaceutical compositions can include a compound of Formula (I), or a pharmaceutically acceptable salt thereof, together with any pharmaceutically acceptable carrier. In some cases, the pharmaceutical composition consists essentially of a compound of Formula (I) and a pharmaceutically acceptable carrier. The pharmaceutical composition can consist of a compound of Formula (T) and a pharmaceutically acceptable carrier. The term "carrier" includes acceptable adjuvants and vehicles. Pharmaceutically acceptable carriers that may be used in the pharmaceutical compositions include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol,

sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol or wool fat.

The pharmaceutical compositions maybe in the form of a sterile injectable preparation, for example, a sterile injectable aqueous or oleaginous suspension. This suspension maybe formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that maybe employed are water, Ringer's solution or isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil maybe employed including synthetic mono- or di-glycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant.

The pharmaceutical compositions can be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, carriers which are commonly used include lactose or corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.

Alternatively, the pharmaceutical compositions may be administered in the form of suppositories for rectal administration. These can be prepared by mixing the agent with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and therefore will melt in the rectum to release the drug. Such materials include cocoa butter, beeswax or polyethylene glycols.

The pharmaceutical compositions may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application,

including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.

Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically-transdermal patches may also be used.

For topical applications, the pharmaceutical compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers. Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, the pharmaceutical compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water. For ophthalmic use, the pharmaceutical compositions may be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, as solutions in isotonic, pH adjusted sterile saline, either with or without a preservative such as benzylalkonium chloride. Alternatively, for ophthalmic uses, the pharmaceutical compositions may be formulated in an ointment such as petrolatum. The pharmaceutical compositions may also be administered by nasal aerosol or inhalation through the use of a nebulizer, a dry powder inhaler or a metered dose inhaler. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, or other conventional solubilizing or dispersing agents.

The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated, and the particular mode of administration. It should be understood, however, that a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician

and the severity of the particular disease being treated. The amount of active ingredient may also depend upon the therapeutic or prophylactic agent, if any, with which the ingredient is coadministered.

A pharmaceutical composition can include an effective amount of a compound of Formula I. An effective amount can be defined as an amount sufficient to confer a therapeutic effect on the treated patient, and will depend on a variety of factors, such as the nature of the inhibitor, the size of the patient, the goal of the treatment, the nature of the pathology to be treated, the specific pharmaceutical composition used, and the judgment of the treating physician. For reference, see Freireich et al., Cancer Chemother. Rep. 1966, 50, 219 and Scientific Tables, Geigy Pharmaceuticals, Ardley, N. Y., 1970, 537, which is incorporated by reference in its entirety. Dosage levels of between about 0.001 and about 100 mg/kg body weight per day, preferably between about 0.1 and about 10 mg/kg body weight per day, of the active ingredient compound can be used.

The compounds of Formula (I) can be prepared according to Scheme 1. Scheme 1

Generally, 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.

Scheme 2

Compounds of the formula HN(R ⁹ )R ⁴ can be prepared according to methods known in the art. For example, some transformations suitable for preparing compounds of the formula HN(R ⁹ )R ⁴ are shown in Scheme 3.

Scheme 3

Examples

Reactions were run using commercially available starting materials and anhydrous solvents, without further purification. Proton NMR spectra were recorded on a 400 MHz Bruker AV-400 spectrometer using TMS (δ 0.0) as an internal reference. High resolution mass spectra were obtained using a Bruker APEXIII Fourier transform ion cyclotron resonance (FT-ICR) mass spectrometer equipped with an actively shielded 7 Tesla superconducting magnet (Magnex Scientific Ltd., UK) and an external Bruker APOLLO electrospray ionization (ESI) source. Preparative HPLC was run using a Waters reverse phase preperative HPLC (Xterra Cl 8 5 μm, 3O x 100 mm column; water/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 μm, 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)]. The following abbreviations were used: XPHOS = 2- (dicyclohexylphosphino)-2', 4', 6'-tri-I-ρropyl-l, 1 '-biphenyl-; Xantphos = 9, 9-dimethyl-4, 5- bis(diphenylphosphino)xanthene; Pd ₂ (dba) ₃ = tris(dibenzylideneacetone)dipalladium.

The present application claims the benefit of priority of U.S. Provisional Application 60/950,680, filed July 19, 2007, which is incorporated herein by reference in its entirety.

Example 1 3-{[l-(4-fluorophenyl)ethyI]amino}-4-(pyridin-4-ylamino)cycl obut-3-ene-1,2-dione

To a solution of 3-ethoxy-4-(pyridin-4-ylamino)-cyclobut-3-ene-1,2-dione (prepared as described in /. Med. Chem. 2000, 45, 1187-1202, which is incorporated by reference in its entirety) (50 mg, 229 μmol) in EtOH (2 mL) was added (D,L)-4-fluoro-α-methylbenzylamine (31 μL, 236 μmol). The reaction mixture was heated to 100 °C for 3h and then stirred at room temperature overnight. The reaction mixture was filtered and the precipitate was collected and dried in vacuo to give 55 mg (77% yield) of the title compound. MS (ES) m/z 312.1 (M+l). Example 2 3-[(cyclohexylmethyl)amino]-4-(pyridiπ-4-ylaιnino)cyclobut -3-eiie-1,2-dione

The title compound was synthesized in a manner similar to that of Example 1 but aminomethylcyclohexane was used in place of the amine (yield = 66%). MS (ES) m/z 284.1 (M- H).

Example 3 3-(2,3-dihydro-l/Z-inden-1-ylaminoJ^-^yridin-4-ylaminoJcyclo buW-ene-ljl-dione

The title compound was synthesized in a manner similar to that of Example 1 but (+/-)- 1- aminoindane was used in place of the amine (yield = 39%). MS (ES) m/z 306.1 (M+l). Example 4 3-(pyridiu-4-ylamino)-4-[(tetrahydrofuran-2-y]methyl)amino]c ycIobut-3-ene-1,2-dione

The title compound was synthesized in a manner similar to that of Example 1 but (+/-)-2- (aminomethyl)tetrahydrofuran was used in place of the amine (yield = 50%). MS (ES) m/z 21 A.1 (M+l). Example 5 3-[(1,3-benzodioxol-5-yImethyl)amino]-4-(pyridin-4-ylamino)c yclobut-3-ene-1,2-dione

The title compound was synthesized in a manner similar to that of Example 1 but 1,3- benzodioxol-5-yl-methylamine was used in place of the amine (yield = 55%). MS (ES) m/z 324.1 (M+l).

Example 6 3-(pyridin-4-ylamino)-4-[(pyridin-2-ylmethyl)amino]cyc]obut- 3-ene-1,2-dione

The title compound was synthesized in a manner similar to that of Example 1 but 2- (aminomethyl)-pyridine was used in place of the amine (yield = 17%). MS (ES) m/z 279.1 (M-I). Example 7

3-(pyridin-4-ylaniino)-4-[(pyridin-3-ylmethyl)amino]cyclo but-3-ene-1,2-dione

The title compound was synthesized in a manner similar to that of Example 1 but 3- (aminomethyl)-pyridine was used in place of the amine (yield = 70%). MS (ES) m/z 279.1 (M-I). Example 8

3-(pyridin-4-ylamino)-4-[(pyridin-4-ylmethyI)amino]cyclob ut-3-ene-1,2-dione The title compound was synthesized in a manner similar to that of Example 1 but 4-

(aminomethyl)-pyridine was used in place of the amine (yield = 28%). MS (ES) m/z 279.1 (M-I).

Example 9

3-[(diphenylmethyl)amino]-4-(pyridin-4-ylainino)cyclobut- 3-ene-1,2-dione

The title compound was synthesized in a manner similar to that of Example 1 but 1,1- diphenylmethylamine was used in place of the amine (yield = 69%). MS (ES) m/z 354.1 (M-I). Example 10 3-(benzylamino)-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2-dion e

The title compound was synthesized in a manner similar to that of Example 1 but benzylamine was used in place of the amine (yield = 70%).MS (ES) m/z 278.1 (M-I). Example 11

3-[(2-methyIbenzyl)amino]-4-(pyridin-4-yIamino)cyclobut-3 -ene-1,2-dione

The title compound was synthesized in a manner similar to that of Example 1 but 2- methylbenzylamine was used in place of the amine (yield = 61%). MS (ES) m/z 294.1 (M+1) Example 12

3-(pyridin-4-ylaπiino)-4-{[3-(trifluoromethyl)benzyl]ami no}cyclobut-3-ene-1,2-dione

The title compound was synthesized in a manner similar to that of Example 1 but 3- (trifluoromethyl)-benzylamine was used in place of the amine (yield = 50%). MS (ES) m/z 348.1 (M+l) Example 13

3-[(3-methylbenzyl)amino]-4-(pyridin-4-ylamino)cyclobut-3 -ene-1,2-dione

The title compound was synthesized in a manner similar to that of Example 1 but 3- methylbenzylamine was used in place of the amine (yield = 70%). MS (ES) m/z 294.1 (M+l) Example 14 3-[(4-fluorobenzyl)amino]-4-(pyridin-4-ylaπiiiio)cyclobut-3 -ene-1,2-dione

The title compound was synthesized in a manner similar to that of Example 1 but A- fluorobenzylamine was used in place of the amine (yield = 85%). MS (ES) m/z 298.1 (M+l) Example 1S

3-[(4-methylbenzyl)amino]-4-(pyridin-4-ylamino)cyclobut-3 -ene-1,2-dione The title compound was synthesized in a manner similar to that of Example 1 but A- methylbenzylamine was used in place of the amine (yield = 89%). MS (ES) m/z 292.1 (M-I) Example 16 3-(isobutylamino)-4-(pyridin-4-ylamino)cycIobut-3-ene-1,2-di one

The title compound was synthesized in a manner similar to that of Example 1 but isobutylamine was used in place of the amine (yield = 69%). MS (ES) m/z 246.1 (M+l) Example 17 3-{[2-(4-methylpheny])ethyl]amino}-4-(pyridin-4-ylamino)cycl obut-3-ene-1,2-dione

The title compound was synthesized in a manner similar to that of Example 1 but 2-(4- methylphenyl)-ethylamine was used in place of the amine (yield = 87%). MS (ES) m/z 306.1(M- 1)

Example 18 3-(allylamino)-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2-dione

The title compound was synthesized in a manner similar to that of Example 1 but allylamine was used in place of the amine (yield = 67%). MS (ES) m/z 228.1 (M-I) Example 19

3-[(2,4-difluorobenzyl)amino]-4-(pyridin-4-ylamino)cyclob ut-3-ene-1,2-dione

The title compound was synthesized in a manner similar to that of Example 1 but 2,4- difluorobenzylamine was used in place of the amine (yield = 84%). MS (ES) m/z 314.1 (M-I) Example 20 3-[(2,5-difluorobenzyl)amino]-4-(pyridiιi-4-ylamino)cyclobu t-3-ene-1,2-dione

The title compound was synthesized in a manner similar to .that of Example 1 but 2,5- difluorobenzylamine was used in place of the amine (yield = 73%). MS (ES) m/z 314.1 (M-I) Example 21

3-[(3,4-difluorobenzyl)amino]-4-(pyridin-4-ylamino)cyclob ut-3-ene-1,2-dioiie The title compound was synthesized in a manner similar to that of Example 1 but 3,4- difluorobenzylamine was used in place of the amine (yield = 89%). MS (ES) m/z 314.1 (M-I)

Example 22 3-(pyridin-4-ylamino)-4-{[4-(trifluoromethyI)benzyl]amino}cy clobut-3-ene-1,2-dione

The title compound was synthesized in a manner similar to that of Example 1 but 4- (trifluoromethyl)-benzylamine was used in place of the amine (yield = 83%). MS (ES) m/z 346.1 (M-I)

Example 23 3-[(2,4-dimethylbenzyI)amino]-4-(pyridin-4-ylamino)cyclobut- 3-ene-1,2-dione

The title compound was synthesized in a manner similar to that of Example 1 but 2,4- dimethylbenzylamine was used in place of the amine (yield = 77%). MS (ES) m/z 306.1 (M-I) Example 24

3-[(3,4-dimethylbenzyI)amino]-4-(pyridiii-4-ylamino)cycIo but-3-ene-1,2-dione

The title compound was synthesized in a manner similar to that of Example 1 but 3,4- dimethylbenzylamine was used in place of the amine (yield = 68%). MS (ES) m/z 306.1 (M-I) Example 25 3-[(4-tert-butylbenzyl)amino]-4-(pyridin-4-ylamino)cyclobut- 3-ene-1,2-dione

The title compound was synthesized in a manner similar to that of Example 1 but 4-tert- butylbenzylamine was used in place of the amine (yield = 83%). MS (ES) m/z 334.1 (M-I) Example 26

3-[(3,5-difluorobenzyl)amino]-4-(pyridiii-4-ylamino)cyclo but-3-ene-1,2-dione The title compound was synthesized in a manner similar to that of Example 1 but 3,5- difluorobenzylamine was used in place of the amine (yield = 87%). MS (ES) m/z 316.1 (M+l) Example 27 3-{[(1S)-1-phenylethyl]amino}-4-(pyridin-4-ylamino)cyclobut- 3-ene-1,2-dione

The title compound was synthesized in a manner similar to that of Example 1 but (S)(-)- α-methylbenzylamine was used in place of the amine (yield = 55%). MS (ES) m/z 294.1 (M+l) Example 28 3-((R)-1-Phenyl-ethylamino)-4-(pyridin-4-ylamino)-cyclobut-3 -ene-1,2-dione

The title compound was synthesized in a manner similar to that of Example 1 but (R)(+)- α-methylbenzylamine was used in place of the amine (yield = 64%). MS (ES) m/z 292.1 (M-I) Example 29

3-(pyridin-4-yIamino)-4-(1,2,3,4-tetrahydronaphtha]en-1-y lamino)cyclobut-3-ene-1,2-dione

The title compound was synthesized in a manner similar to that of Example 1 but 1,2,3,4- tetrahydro-1-naphthylamine was used in place of the amine (yield = 71%). MS (ES) m/z 318.2 (M-I)

Example 30 3-{[(1R)-2-hydroxy-1-phenyIethyI]amino}-4-(pyridin-4-ylamino )cyc]obut-3-ene-1,2-dione

The title compound was synthesized in a manner similar to that of Example 1 but R-(-)-2- phenylglycinol was used in place of the amine (yield = 80%). MS (ES) m/z 308.1 (M-I) Example 31

3-[(1,2-diphenylethyl)amino]-4-(pyridin-4-ylamino)cyclobu t-3-ene-1,2-dione The title compound was synthesized in a manner similar to that of Example 1 but 1,2- diphenylethylamine was used in place of the amine (yield = 86%). MS (ES) m/z 368.2 (M-I) Example 32 2-{[3,4-dioxo-2-(pyridin-4-ylamino)cycIobut-1-en-1-yl]amino} -2-phenylacetamide

The title compound was synthesized in a manner similar to that of Example 1 but 2- amino-2-phenylacetamide was used in place of the amine (yield = 57%). MS (ES) m/z 321.1 (M-I)

Example 33 3-{methyl[(1R)-1-phenylethyl]amino}-4-(pyridin-4-yIamino)cyc lobut-3-ene-1,2-dione

The title compound was synthesized in a manner similar to that of Example 1 but (R)-(+)- N-α-dimethylbenzylamine was used in place of the amine (yield = 65%). MS (ES) m/z 306.2 (M-I)

Example 34 3-{[(1R)-1-(4-bromophenyl)ethyl]amino}-4-(pyridin-4-ylainino )cyclobut-3-ene-1,2-dione

The title compound was synthesized in a manner similar to that of Example 1 but (R)-(+)- l-(4-bromophenyl)ethylamine was used in place of the amine (yield = 92%). MS (ES) m/z 370.0 (M-2) Example 35 3-{[(1S)-2-hydroxy-1-phenylethyl]amino}-4-(pyridin-4-ylamino )cyclobut-3-ene-1,2-dione

The title compound was synthesized in a manner similar to that of Example 1 but (S)-(+)- 2-phenylglycinol was used in place of the amine (yield = 28%). MS (ES) m/z 308.1 (M-I) Example 36

3-{[(1S)-1-phenylpropyllaπύno}-4-(pyridin-4-ylamino)cyc lobut-S-ene-1,2-dione

The title compound was synthesized in a manner similar to that of Example 1 but (S)-α- phenylpropylamine was used in place of the amine (yield = 43%). MS (ES) m/z 306.1 (M-I) Example 37 3-{[(ϋ?)-1-phenyIpropyl]amino}-4-(pyridin-4-ylamino)cyclobu t-3-ene-1,2-dione

The title compound was synthesized in a manner similar to that of Example 1 but (R)-α- phenylpropylamine was used in place of the amine (yield = 45%). MS (ES) m/z 306.1 (M-I) Example 38

3-{[(1R)-1-(2-naphthyl)ethyl]amino}-4-(pyridiii-4-ylamrao )cyclobut-3-ene-1,2-dione The title compound was synthesized in a manner similar to that of Example 1 but (R)-(+)- l-(2-naphthyl)ethylamine was used in place of the amine (yield = 90%). MS (ES) m/z 341.1 (M-

2)

Example 39

3-[(1R)-2,3-dihydro- 1H-inden-1-ylaniino]-4-(pyridm-4-ylamino)cyclobut-3-ene-1,2- dione The title compound was synthesized in a manner similar to that of Example 1 but (R)-(-)-

(l)-aminoindane was used in place of the amine (yield = 69%). MS (ES) m/z 304.1 (M-I)

Example 40

3-{[(1R)-1-(4-chlorophenyl)ethyl]amino}-4-(pyridin-4-ylai nino)cycIobut-3-ene-1,2-dione

The title compound was synthesized in a manner similar to that of Example 1 but (R)-(+)- 4-chloro-α-methylbenzylamine was used in place of the amine (yield = 93%). MS (ES) m/z

326.1 (M-I)

Example 41

3-{[(1S)-1-(4-chlorophenyl)ethyI]amino}-4-(pyridin-4-ylam ino)cyclobut-3-ene-1,2-dione

The title compound was synthesized in a manner similar to that of Example 1 but (S)-(-)- 4-chloro-α-methylbenzylamine was used in place of the amine (yield = 72%). MS (ES) m/z

326.1 (M-I)

Example 42

3-{[(1R)-1-(3-methoxyphenyI)ethylJamino}-4-(pyridin-4-yla inino)cyclobut-3-ene-1,2-dione The title compound was synthesized in a manner similar to that of Example 1 but (R)-3- methoxy-α-methylbenzylamine was used in place of the amine (yield = 32%). MS (ES) m/z

322.1 (M-I)

Example 43

3-{[(1R)-1-(4-methoxyphenyl)ethyI]amino}-4-(pyridin-4-yla inino)cyclobiit-3-ene-1,2-dione

The title compound was synthesized in a manner similar to that of Example 1 but (R)-4- methoxy-α-methylbenzylamine was used in place of the amine (yield = 80%). MS (ES) m/z 322.1 (M-I) Example 44 (R)-3-(Pyridin-4-yIamino)-4-(1,2,2-trimethyl-propy]amino)- cyclobut-3-ene-1,2-dione

The title compound was synthesized in a manner similar to that of Example 1 but (R)-(-)- 3,3-dimethyl-2-butylamine was used in place of the amine (yield = 80%). MS (ES) m/z 272.1 (M-I)

Example 45 3-[(4-bromobenzyl)amino]-4-(pyridin-4-ylamino)cyclobut-3-ene -1,2-dione

The title compound was synthesized in a manner similar to that of Example 1 but 4- bromobenzylamine hydrochloric acid was used in place of the amine, and 1.2 equivalents of triethylamine was added to the reaction mixture (yield = 90%). MS (ES) m/z 356.0 (M-2) Example 46 3-[(4-chlorobenzyI)amino]-4-(pyridin-4-ylamino)cyclobut-3-en e-1,2-dione

The title compound was synthesized in a manner similar to that of Example 1 but 4- chlorobenzylamine was used in place of the amine (yield = 85%). MS (ES) m/z 314.1 (M+l) Example 47

3-[(4-methoxybenzyl)ainino]-4-(pyridiii-4-ylamino)cyclobu t-3-ene-1,2-dione

The title compound was synthesized in a manner similar to that of Example 1 but 4- methoxybenzylamine was used in place of the amine (yield = 85%). MS (ES) m/z 310.1 (M+l) Example 48 N-[3,4-dioxo-2-(pyridin-4-ylainino)cyclobut-1-en-1-yI]-L-phe nylalaninamide

The title compound was synthesized in a manner similar to that of Example 1 but L- phenylalininamide hydrochloric acid was used in place of the amine (yield = 83%). MS (ES) m/z 337.1 (M+l) Example 49

2-{[3,4-dioxo-2-(pyridin-4-ylamino)cyclobut-1-en-1-yl]ami no}-N-methyl-2-phenylacetamide

The title compound was synthesized in a manner similar to that of Example 1 but 2- amino-N-methyl-2-phenyl-acetamide was used in place of the amine (yield = 51%). MS (ES) m/z 337.1 (M+l)

Example 50 N-[3,4-dioxo-2-(pyridiii-4-ylaιnino)cyclobut-1-en-1-yl]-D-p henylalaninamide

The title compound was synthesized in a manner similar to that of Example 1 but D- phenylalaninamide was used in place of the amine (yield = 50%). MS (ES) m/z 337.1 (M+l)

Example 51

3-{[(1R)-1-(4-fluorophenyl)ethyl]amino}-4-(pyridin-4-ylai nino)cyclobut-3-ene-1,2-dione The title compound was synthesized in a manner similar to that of Example 1 but (R)-I-

(4-fluorophenyl)ethylamine was used in place of the amine (yield = 83%). MS (ES) m/z 312.1

(M+l)

Example 52

3-{[l-(4-hydroxyphenyl)ethyl]amino}-4-(pyridin-4-ylamino) cyclobut-3-ene-1,2-dione The title compound was synthesized in a manner similar to that of Example 1 but 4-(l- aminoethyl)phenol was used in place of the amine (yield = 70%). MS (ES) m/z 310.1 (M+l)

Example 53

3-{[l-(l-naphthyl)ethyl]amino}-4-(pyridin-4-ylamino)cyclo but-3-ene-1,2-dione

The title compound was synthesized in a manner similar to that of Example 1 but DL-I- (l-naphthyl)ethylamine was used in place of the amine (yield = 61%). MS (ES) m/z 344.1

(M+l)

Example 54

3-{[(1R)-1-(4-methylphenyI)ethyI]amino}-4-(pyridin-4-ylam ino)cyclobut-3-ene-1,2-dione

The title compound was synthesized in a manner similar to that of Example 1 but (R)-(+)- α-4-dimethylbenzylamine was used in place of the amine (yield = 64%). MS (ES) m/z 308.1

(M+l)

Example 55

3-{[(lJJ)-1-(4-nitrophenyl)ethyl]amino}-4-(pyridin-4-yla� �iino)cyclobut-3-ene-1,2-dione

The title compound was synthesized in a manner similar to that of Example 1 but (R)-α- methyl-4-nitrobenzylamine hydrochloride was used in place of the amine (yield = 86%). MS

(ES) m/z 339.1 (M+l)

Example 56

3-{[l-(4-fluorophenyl)-2-hydroxyethyl]amino}-4-(pyridin-4 -ylamino)cyclobut-3-ene-1,2- dione

To a 0 °C solution of lithium borohydride (360 μL, 2N in THF, 0.72 mmol) in THF (1 mL) was added chlorotrimethylsilane (184 μL, 1.45 mmol). The mixture was stirred for 10 min at 0 °C, then at room temperature for 30 min. This solution was added to a suspension of 4- fluoro-DL-phenylglycine (60 mg, 0.35 mmol) in THF (3 mL) at 0 °C and the mixture was stirred at 0 °C for 10 min, then at room temperature overnight. The reaction mixture was quenched with

MeOH and the solvent was removed in vacuo. To the residue was added IN NaOH (3 mL) and the product was extracted with CHCI ₃ (3 x 2mL). The combined organic extracts were dried

(MgSO,)) and concentrated to give 30 mg (50%) of 2-amino-2-(4-fluoro-phenyl)-ethanol. The crude alcohol was dissolved in EtOH (1 mL) and added to a solution of 3-ethoxy-4-(pyridin-4- ylamino)-cyclobut-3-ene-1,2-dione (41 mg, 188 μmol) in EtOH (1 mL). The reaction mixture was heated to 95 °C for 3 h. After cooling to room temperature, the mixture was filtered and the precipitate was collected and dried in vacuo to give 18 mg (29%) of the title compound. MS

(ES) m/z 328.1 (M+l)

Example 57

3-{[l-(4-chlorophenyl)-2-hydroxyethyl]amino}-4-(pyridin-4 -yIamino)cycIobut-3-ene-1,2- dione The title compound was synthesized in a manner similar to that of Example 56 with 4- chloro-DL-phenylglycine as the amino acid starting material (yield = 67%). MS (ES) m/z 344.0

(M+l)

Example 58

3-{[l-(2-fluorophenyl)-2-hydroxyethyl]amino}-4-(pyridin-4 -ylamino)cyclobnt-3-ene-1,2- dione

The title compound was synthesized in a manner similar to that of Example 56 with DL-

2-fluorophenylglycine as the amino acid starting material (yield = 24%). MS (ES) m/z 328.1

(M+l)

Example 59 3-({2-hydroxy-1-[4-(trifluoromethyl)phenyl]ethyl}amino)-4-(p yridiii-4-ylainino)cyclobut-3- ene-1,2-dione

The title compound was synthesized in a manner similar to that of Example 56 with 4- (trifluoromethyl)phenylglycine) as the amino acid starting material (yield = 40%). MS (ES) m/z

378.1 (M+l) Example 60 3-{[2-hydroxy-1-(4-methylphenyl)ethyl]amin.o}-4-(pyridin-4-y lammo)cyclobut-3-ene-1,2- dione

The title compound was synthesized in a manner similar to that of Example 56 with 4- methylphenylglycine as the amino acid starting material (yield = 42%). MS (ES) m/z 324.1

(M+l) Example 61

3-{[l-(3-chloro-4-fluorophenyl)-2-hydroxyethyI]amiπo}-4- (pyridiπ-4-ylamino)cyclobut-3- ene-1,2-dione

The title compound was synthesized in a manner similar to that of Example 56 with 3- chloro-4-fluoro-DL-phenylglycine as the amino acid starting material (yield = 29%). MS m/z 360.1 (M-I)

Example 62

3-{[2-hydroxy-1-(3,4,5-trifluorophenyl)ethyl]amino}-4-(py ridin-4-ylainino)cyclobut-3-ene-

1,2-dione

The title compound was synthesized in a manner similar to that of Example 56 with 3,4,5-trifluoro-DL-phenylglycine as the amino acid starting material (yield = 59%). MS (ES) m/z 364.0 (M+l)

Example 63

3-{[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyI]a mino}-4-(pyridin-4- ylamino)cyclobut-3-ene-1,2-dione The title compound was synthesized in a manner similar to that of Example 1 but (±)-α-

(l-aminoethyl)-4-hydroxybenzyl alcohol hydrochloric acid was used in place of the amine, and

1.1 equivalents of triethylamine was added to the reaction mixture (yield = 80%). MS (ES) m/z

340.2 (M+l) Example 64 3-{[2-(4-chlorophenyI)-1-methylethyl]amino}-4-(pyridin-4-yla mino)cycIobut-3-ene-1,2- dione

The title compound was synthesized in a manner similar to that of Example 1 but 4- chloroamphetamine hydrochloric acid hydrochloric acid was used in place of the amine, and 1.1 equivalents of triethylamine was added to the reaction mixture (yield = 77%). MS (ES) m/z

342.2 Example 65

4-(l-{[3,4-dioxo-2-(pyridin-4-yIamino)cyclobut-1-en-1-yI] amino}ethyl)benzoiiitrile

The title compound was synthesized in a manner similar to that of Example 1 but 4-(l- amino-ethyl)-benzonitrile was used in place of the amine (yield = 78%). MS (ES) m/z 319.1

(M+l) Example 66

3-{[(1S )-2-hydroxy-2-methyl-1-phenylpropyl]amino}-4-(pyridin-4-yIam ino)cyclobut-3-ene-

1,2-dione

The title compound was synthesized in a manner similar to that of Example 1 but (IS)-I- amino-2-methyl-1-phenyl-propan-2-ol (prepared as described in WO 95/18112, which is incorporated by reference in its entirety) was used in place of the amine (yield = 74%). [α] _D ²⁵ =

-103.6° (c = 1% solution, DMSO); MS (ES) m/z 338.1 (M+l)

Example 67

3-{[(1R)-2-hydroxy-2-methyH-phenylpropyl]amlno}-4-(pyridi n-4-ylainino)cyclobut-3-ene-

1,2-dione The title compound was synthesized in a manner similar to that of Example 1 but (IR)-I- amino-2-methyl-1-phenyl-propan-2-ol (prepared as described in WO 95/18112, which is incorporated by reference in its entirety) was used in place of the amine (yield = 82%).

[α] _D ²⁵ = +101.6° (c = 1% solution, DMSO); MS (ES) m/z 338.1 (M+l)

Example 68 (2R)-2-{[3,4-dioxo-2-(pyridin-4-yIamino)cyclobut-1-en-1-yl]a mino}-N-methyl-2- phenylacetamide

The title compound was synthesized in a manner similar to that of Example 1 but (R)-2- amino-N-methyl-2-phenyl-acetamide (prepared from the reaction of (R)-(-)-2-phenylglycine methyl ester with 40% CH ₃ NH ₂ in water) was used in place of the amine. The product was isolated by removal of solvent in vacuo, followed by trituration with ether (yield = 80%). MS

(ES) m/z 335.1 (M-I)

Example 69

(25)-2-{[3,4-dioxo-2-(pyridin-4-ylamino)cyclobut-1-en-1-y l]amino}-iV-methyI-2- phenylacetamide

The title compound was synthesized in a manner similar to that of Example 1 but (S)-2- amino-N-methyl-2-phenyl-acetamide (prepared from the reaction of (S)-(+)-2-phenylglycine methyl ester with 40% CH ₃ NH ₂ in water) was used in place of the amine. The product was isolated by removal of solvent in vacuo, followed by trituration with ether (yield = 94%). MS (ES) m/z 335.1 (M-I) Example 70 2-(3,4-dichlorophenyl)-2-{[3,4-dioxo-2-(pyridin-4-ylamino)cy clobut-1-eii-1- yl]amino}acetamide(trifluoroacetic acid salt)

To 2-amino-(3,4-dichlorophenyl)acetic acid hydrochloric acid (0.25 g, 0.97 mmol) in MeOH (13 mL) was added thionyl chloride (0.49 niL, 2 M in CH ₂ Cl ₂ ). The mixture was refluxed overnight, cooled, then concentrated in vacuo. The solid was triturated with dichloromethane and filtered. To the resulting methyl ester was added saturated ammonia in methanol (10 mL). After 24 h the mixture was concentrated and the resulting solid, which contains 2-amino-2-(3,4-dichloro-phenyl)-acetamide hydrochloride and ammonium chloride, was obtained. A portion of this intermediate (75 mg) was added to a solution of 3-ethoxy-4- (pyridin-4-ylamino)-cyclobut-3-ene-1,2-dione (64 mg, 280 μmol) in EtOH (4 mL). The reaction mixture was stirred at 60 °C for 18 h, and then concentrated in vacuo. Purification by HPLC

(C ₁₈ ; 10 - 100% gradient, H ₂ O/ACN with 0.1% TFA) provided the title compound (49 mg, 43% yield). MS (ES) m/z 390.1 (M-I) Example 71 2-(4-chIorophenyl)-2-{[3,4-dioxo-2-(pyridin-4-ylamino)cyclob ut-1-en-1-yl]amino}acetamide (trifluoroacetic acid salt)

The title compound was synthesized in a manner similar to that of Example 70 with DL- 2-(4-chlorophenyl)glycine) as the starting material. The product was isolated by removal of solvent in vacuo, followed by purification by HPLC (C ₁₈ ; 10 - 100% gradient, H ₂ O/ ACN with 0.1% TFA) (yield = 42%). MS (ES) m/z 355.1 (M-I) Example 72

(25)-2-(4-chlorophenyl)-2-{[3,4-dioxo-2-(pyridin-4-ylamin o)cycIobut-1-en-1- yl] amino} acetamide

The title compound was prepared by chiral HPLC separation of 2-(4-chlorophenyl)-2-

{ [3 ,4-dioxo-2-(pyridin-4-ylamino)cyclobut- 1 -en- 1 -yl] amino} acetamide (trifluoroacetic acid salt). HPLC conditions: Varian Prep; Chiralcel AD, 2 x 25 cm column at 23 °C; 1.7 niL injection; Mobile phase: EtOH; Flow rate 15 mL/min; Detection: 280 nm DAD. Retention time:

4.5 min; MS (ES) m/z 357.1 (M+l)

Example 73

(2λ)-2-(4-chlorophenyl)-2-{[3,4-dioxo-2-(pyridin-4-ylami no)cyclobut-1-eii-1- yl]aπiino} acetamide

The title compound was prepared by chiral HPLC separation of 2-(4-chlorophenyl)-2-

{ [3,4-dioxo-2-(pyridin-4-ylamino)cyclobut- 1 -en-1 -yl] amino} acetamide (trifluoroacetic acid salt). HPLC conditions: Varian Prep; Chiralcel AD, 2 x 25 cm column at 23 °C; 1.7 niL injection; Mobile phase: EtOH; Flow rate 15 mL/min; Detection: 280 nm DAD. Retention time: 8.9 min; MS (ES) m/z 357.1 (M+l)

Example 74

2-(3-chloro-4-fluorophenyl)-2-{[3,4-dioxo-2-(pyridin-4-yl amino)cyclobut-1-en-1- yl] amino} acetamide

The title compound was synthesized in a manner similar to that of Example 70 with 3- chloro-4-fluoro-DL-phenylglycine) as the starting material. The product was isolated by removal of solvent in vacuo, followed by purification by HPLC (C ₁ sjlO - 100% gradient,

H ₂ O/ACN with 0.1% TFA) (yield = 44%). MS (ES) m/z 375.1 (M+l)

Example 75

2-{[3,4-dioxo-2-(pyridin-4-ylamino)cyclobut-1-en-1-yl]ami no}-2-[4- (triflιioromethyl)phenyl]acetamide

The title compound was synthesized in a manner similar to that of Example 70 with 4- trifluoromethyl-DL-phenylglycine as the starting material. The product was isolated by removal of solvent in vacuo, followed by purification by HPLC (C _]8 ;10 - 100% gradient, H ₂ O/ACN with

0.1% TFA) (yield = 32%). MS (ES) m/z 391.1 (M+l) Example 76

2-{[3,4-dioxo-2-(pyridin-4-ylamino)cycIobut-1-en-1-yl]ami no}-2-(4-fluorophenyl)acetainide

The title compound was synthesized in a manner similar to that of Example 70 with DL-

2-fluorophenylglycine as the starting material. The product was isolated by removal of solvent in vacuo, followed by purification by HPLC (C ₁₈ ;10 - 100% gradient, H ₂ CVACN with 0.1%

TFA) (yield = 40%). MS (ES) m/z 341.1 (M+ 1) Example 77

2-{[3,4-dioxo-2-(pyridin-4-yIamino)cyclobut-1-en-1-yl]amino} -2-(2-fluorophenyl)acetamide The title compound was synthesized in a manner similar to that of Example 70 with 4- fluoro-DL-phenylglycine as the starting material. The product was isolated by removal of solvent in vacuo, followed by purification by HPLC (C ₁₈ ;10 - 100% gradient, H ₂ CVACN with 0.1% TFA) (yield = 16%). MS (ES) m/z 341.1 (M+ 1)

Example 78

2-{[3,4-dioxo-2-(pyridin-4-ylamino)cyc]obut-1-en-1-yl]ami no}-2-(3,4,5- trifluorophenyl)acetamide

The title compound was synthesized in a manner similar to that of Example 70 with 3,4,5-trifluoro-DL-phenylglycine as the starting material. The product was isolated by removal of solvent in vacuo, followed by purification by HPLC (C ₁₈ ;10 - 100% gradient, H ₂ O/ ACN with

0.1% TFA) (yield = 41%). MS (ES) m/z 375.1 (M-I)

Example 79

2-(4-chlorophenyl)-2-{[3,4-dioxo-2-(pyridin-4-ylamino)cyc Iobut-1-en-1-yl]amino}-N- methylacetamide

The title compound was synthesized in a manner similar to that of Example 70 with DL-

2-(4-chlorophenyl)glycine as the amino acid starting material and 40% methylamine in water instead of saturated ammonia solution. The product was isolated by removal of solvent in vacuo, followed by purification by HPLC (C ₁₈ ;10 - 100% gradient, H ₂ CVACN with 0.1% TFA) (yield = 52%). MS (ES) m/z 369.1 (M-I)

Example 80

2-{[3,4-dioxo-2-(pyridin-4-ylamino)cycIobut-1-en-1-yl]ami no}-iV-ethyl-2-phenylacetainlde The title compound was synthesized in a manner similar to that of Example 70 with phenylglycine as the starting material and 70% ethylamine in water instead of ammonia solution (yield = 84%). MS (ES) m/z 349.1 (M-I)

Example 81

N-(cyclohexylmethyl)-2-{[3,4-dioxo-2-(pyridin-4-ylamino)c yclobut-1-en-1-yl]ainiiio}-2- phenylacetaniifie

Step 1 : [3,4-Dioxo-2-(pyridin-4-ylamino)-cyclobut-1-enylamino]-pheny l-acetic acid To 3-ethoxy-4-(pyridin-4-ylamino)-cyclobut-3-ene-1,2-dione (550 mg, 2.52 mmol) dissolved in EtOH (2 mL) was added 2-phenylglycine (381 mg, 2.52 mmol). The reaction mixture was heated to 60 °C and stirred overnight. The reaction mixture was concentrated to a solid and then triturated with a mixture of EtOAc/EtOH/hexane to give 220 mg (27% yield) of the title compound. Alternatively, the product was purified by HPLC (C ₁ s, gradient 10 - 100%

ACN in H ₂ O, 0.1% TFA) and isolated as the TFA salt. Step 2: N-(cyclohexyknethyl)-2-{[3,4-dioxo-2-(pyridin-4-ylamino)cycl obut-1-en-1- yl] amino } -2-phenylacetamide

To [3,4-dioxo-2-(pyridin-4-ylamino)-cyclobut-1-enylamino]-pheny l-acetic acid (50 mg,

114 μmol) in DMF (4 mL) was added cyclohexyl-methylamine (45 μL, 340 μmol), N- cyclohexylcarbodiimide-N'-propyloxymethyl polystyrene (PS-CDI, Argonaut Technologies) (1.2 mmol/g, 190 mg, 228 μmol) and l-hydroxybenzotriazole-6-sulfonamidomethyl polystyrene

(PS-HOBT, Argonaut Technologies) (0.98 mmol/g, 232 mg, 228 mmol) and the reaction mixture was heated overnight at 50 °C. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The resulting residue was purified by HPLC to give 4.3 mg (7% yield) of the title product, identified by HPLC and mass spectral analysis. HPLC conditions: Hewlett Packard 1100; Luna C ₁₈ (5 μ), 2 x 30 mm column at 23 °C; 3 μL injection; Solvent A: 0.1%

HOOH/water; Solvent B: 0.1% HOOH/ ACN; Gradient: 10-100% solvent B (ACN) in 3 min.

Flow rate 0.6 mL/min; Detection: 254 and 230 nm DAD. M+H, 420; time (min) 1.88

Example 82

N-(4-chlorobenzyl)-2-{[3,4-dioxo-2-(pyridin-4-ylamino)cyc lobut-1-en-1-yl]amino}-2- phenylacetatnide

Using essentially the same procedures described for Example 81 but using 4-chloro- benzylamine in place of the amine, the title compound was obtained and identified by HPLC and mass spectral analysis (17% yield). M+H, 447; time (min) 1.9

Example 83 3-[(2-oxo-1-phenyl-2-pyrrolidin-1-ylethyl)amino]-4-(pyridin- 4-ylamino)cyclobut-3-ene-1,2- dione

Using essentially the same procedures described in Example 81 but using pyrrolidine in place of the amine, the title compound was obtained and identified by HPLC and mass spectral analysis (12% yield) M+H, 377, time (mm) 1 5

Example 84 2-{[3,4-dioxo-2-(pyridin-4-ylamino)cyclobut-1-en-1-yl]amino} -λyV-dimethyl-2- phenylacetamide

Using essentially the same procedures described in Example 81 but using dimethylamine m place of the amine, the title compound was obtained and identified by HPLC and mass spectral analysis (56% yield) M+H, 351, time (mm) 1 3 Example 85

N-[2-(4-chlorophenyl)ethyl]-2-{[3,4-dioxo-2-(pyridin-4-yl amino)cyclobut-1-en-1-yl] amino}-

2-phenylacetamide

Using essentially the same procedures described in Example 81 but usmg 2-(4-chloro- phenyl)-ethylamine in place of the amine, the title compound was obtained and identified by HPLC and mass spectral analysis (46% yield)

M+H, 461 , time (mm) 3 0

Example 86

2-{[3,4-dioxo-2-(pyridin-4-y]amino)cyclobut-1-en-1-yl]ami no}-2-phenyI-iV-(pyridin-4- ylmethyl)acetamide Using essentially the same procedures described in Example 81 but using pyndin-4-yl- methylamine m place of the amine, the title compound was obtained and identified by HPLC and mass spectral analysis (18% yield)

M+H, 414, time (mm) 03

Example 87 2-{[3,4-dioxo-2-(pyridin-4-ylamino)cyclobut-1-en-1-yl]amino} -N-isobutyl-2- phenylacetamide

Usmg essentially the same procedures described in Example 81 but usmg isobutylamme in place of the amine, the title compound was obtained and identified by HPLC and mass spectral analysis (14% yield) M+H, 379, tune (mm) 1 6

Example 88

3-[(2-methoxypyridin-4-yl)amiiio]-4-{[(1R)-1-phenylethyl] ainino}cycIobut-3-ene-1,2-dione

Step 1: 3-Ethoxy-4-(2-methoxy-pyridin-4-ylamino)-cyclobut-3-ene-1,2- dione To a solution of 3,4-diethoxy-3-cyclobutene-1,2-dione (4.26 g, 25.0 mmol) in EtOH (50 mL) was added a solution of 2-methoxy-pyridin-4-ylamine (3.16 g, 25.0 mmol) (prepared as described in J. Heterocyclic Chem. (1985), 22(1), 145-147, which is incorporated by reference in its entirety) in EtOH (50 mL). The reaction mixture was heated to reflux for 4 h and then cooled to room temperature and stirred overnight. The mixture was filtered, and the precipitate was collected and dried in vacuo to provide 1.73 g (28% yield) of the title compound.

Step 2: 3-[(2-Methoxypyridin-4-yl)amino]-4-{[(1R)-1-phenylethyl]amin o}cyclobut-3- ene-1,2-dione

The product of step 1 described above (500 mg, 2.01 mmol) was dissolved in EtOH (15 mL) and a solution of (R)-(+)-α-methylbenzylamine (247 mg, 2.03 mmol) in EtOH (5 mL) was added dropwise. The mixture was stirred at 60 °C overnight and then cooled and filtered. The precipitate was collected and dried in vacuo to provide 614 mg of the title compound (94% yield). [α] _D ²⁵ = -34.00° (c = 1% solution, DMSO); MS (ES) m/z 324.1 (M+l) Example 89 (R)-3-(2-hydroxypyridin-4-ylainino)-4-(l-phenylethylaπiino) cyclobut-3-ene-1,2-dione

To a solution of 3-[(2-methoxypyridin-4-yl)amino]-4-{[(1R)-1- phenylethyl]amino}cyclobut-3-ene-1,2-dione (300 mg, 928 μmol) in DMF (4 mL) was added a solution of iodotrimethylsilane (380 μL, 2.78 mmol) in DMF (1 mL). The reaction mixture was heated to 80 °C for 6 h. DMF was removed in vacuo and the residue was dissolved in CH ₂ Ct Sodium thiosulfate was added and the mixture was stirred for 3 h. CH ₂ CI ₂ was removed in vacuo and then water and EtOAc were added to the residue. A precipitate formed and the mixture was filtered. The precipitate was collected and dried in vacuo to give 232 mg of the title compound (81% yield). MS (ES) m/z 310.2 (M+l) Example 90

3-{[lfl-imidazol-2-yl(phenyl)methyl]amino}-4-(pyridin-4-y lainino)cyclobut-3-ene-1,2-dioiie The title compound was synthesized in a manner similar to that of Example 1 but C-(1H- imidazol-2-yl)-C-phenyl-methylamine (prepared in a similar manner to that described in DE4443892, which is incorporated by reference in its entirety) was used in place of the amine (yield = 86%). MS (ES) m/z 346.1 (M+l)

Example 91

3-[(3-methylisoxazoI-5-yl)amino]-4-{[(1R)-1-phenylethyl]a mino}cycIobut-3-ene-

1,2-dione

Step 1: A solution of diethyl squarate (500 mg, 2.9 nimol) in EtOH (15 mL) was heated at reflux and a solution of 5-amino-3-methylisoxazole (288 mg, 1.0 eq) in EtOH (5 mL) was added via syringe pump at a rate of 1 mL/h. The solution was cooled, evaporated, and flash chromato graphed (silica, ethyl acetate, acetonitrile, methanol, water (70/10/5/5) to provide the title compound (38 mg, 6%).

Step 2: A solution of 3-ethoxy-4-[(3-methylisoxazol-5-yl)amino]cyclobut-3-ene-1,2- dione (38 mg, 0.2 mmol) and (R)-1-phenylethanamine (65 μL, 3 eq) in EtOH was stirred at RT overnight. Evaporation and flash chromatography (silica, 5% MeOH/DCM) provided the title compound (23 mg, 69%) as a yellow solid. ¹ H NMR (400 MHz, OMSO-d ₆ ) δ ppm 1.58 (d, /=6.82 Hz, 3 H) 2.16 (s, 3 H) 5.20 - 5.36 (m, 1 H) 6.09 (s, 1 H) 7.26 - 7.35 (m, 1 H) 7.36 - 7.44 (m, 4 H) 8.00 (bs, 1 H) 10.82 (bs, 1 H); HPLC purity (Method 1: 97%, Method 2: 96%); HRMS: calcd for C16H15N3O3 + H ⁺ , 298.1186; found (ESI-FTMS, [M+H]l+), 298.1186 Example 92

3-[methyl(pyridin-4-yl)amino]-4-{[(1R)-1-phenylethyl]amin o}cyclobut-3-ene-1,2- dione

Step 1 : 3-ethoxy-4-[methyl(pyridm-4-yl)amino]cyclobut-3-ene-1,2-dion e Following step 1 of Example 91, diethyl squarate (500 mg, 2.9 mmol) and 4-

(methylammo)pyridine (316 mg, 1.0 eq) provided the title compound (43 mg, 6.4%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-rf,;) δ ppm 1.38 (t, /=7.1 Hz, 3 H), 3.64 (s, 3 H), 4.75 (q, /=7.1 Hz, 2 H), 7.28 (dd, /=4.7, 1.6 Hz, 2 H), 8.55 (dd, /=4.7, 1.6 Hz, 2 H).

Step 2: Following step 2 of Example 91, 3-ethoxy-4-[methyl(pyridin-4- yl)amino]cyclobut-3-ene-1,2-dione (40 mg, 0.17 mmol) and (R)-1-phenylethanamine (66 μL, 3 eq) provided the title compound (47 mg, 90%). ¹ H NMR (400 MHz, OMSO-d ₆ ) δ ppm 1.54 (d, /=6.82 Hz, 3 H) 3.56 (s, 3 H) 6.92 - 6.98 (m, 2 H) 7.23 - 7.32 (m, 1 H) 7.33 - 7.47 (m, 4 H) 8.11 (s, 1 H) 8.44 (d, /=6.06 Hz, 2 H); HPLC purity (Method 1: 100%, Method 2: 99%); HRMS: calcd for C18H17N3O2 + H ⁺ , 308.1394; found (ESI-FTMS, [M+H]l+), 308.1394 Example 93

3-{[(1R)-1-phenylethyl]amino}-4-[(2,2,6,6-tetramethylpipe ridin-4-

yl)amino]cyclobut-3-ene-1,2-dione

Step 1 : 3-ethoxy-4-[(2,2,6,6-tetramethylpiperidin-4-yl)amino]cyclobu t-3-ene-l ,2-dione Following step 1 of Example 91, diethyl squarate (300 mg, 1.8 mmol) and 4-amino-2,2,6,6- tetramethylpiperidine (331 mg, 1.2 eq) in EtOH (3 mL) provided the title compound (460 mg, 91%) after collecting the precipitate formed during the reaction. ¹ H NMR (400 MHz, DMSO-d _β ) δ ppm 1.03 (s, 6 H), 1.09 - 1.16 (m, /=3.0 Hz, 6 H), 1.26 (bs, 1 H), 1.31 - 1.40 (m, 3 H), 1.71 (dd, J=I 1.9, 3.5 Hz, 2 H), 2.47 - 2.54 (m, 2 H), 4.66 (q, /=6.9 Hz, 2 H)

Step 2: Following step 2 of Example 91, 3-ethoxy-4-[(2,2,6,6-tetramethylpiperidin-4- yl)amino]cyclobut-3-ene-1,2-dione (460 mg, 1.6 mmol) and (R)-1-phenylethanamine (420 μL, 2 eq) provided the title compound (260 mg, 46%). ¹ H NMR (400 MHz, DMSO-fifc) δ ppm 0.95 - 1.05 (m, 6 H) 1.09 - 1.17 (m, 6 H) 1.23 (s, 1 H) 1.54 (d, /=6.82 Hz, 3 H) 1.79 (d, /=11.37 Hz, 2 H) 3.33 (s, 3 H) 4.24 (s, 1 H) 5.13 - 5.26 (m, 1 H) 7.26 - 7.33 (m, 1 H) 7.34 - 7.41 (m, 4 H); HPLC purity (Method 1: 85%, Method 2: 98%); HRMS: calcd for C _2I H ₂₉ N ₃ O ₂ + H ⁺ , 356.2332; found (ESI-FTMS, [M+H]l+), 356.2333 Example 94

3-{[(1R)-1-phenylethyl]amino}-4-(pyrimidin-4-yIamino)cycl obut-3-ene-1,2-dione

Step 1 : 3-ethoxy-4-(pyrimidin-4-ylamino)cyclobut-3-ene- 1 ,2-dione

Following step 1 of Example 91, diethyl squarate (500 mg, 3.1 mmol) and 4-aminopyrimidine (291 mg, 1.0 eq) provided the title compound (16 mg, 2.3%) as a yellow solid. Step 2: Following step 2 of Example 91, 3-ethoxy-4-(pyrimidin-4-ylamino)cyclobut-3- ene-1,2-dione (16 mg, 0.07 mmol) and (R)-1-phenylethanamine (28 μL, 3 eq) provided the title compound (5 mg, 23%). ¹ H NMR (400 MHz, MeOD) δ ppm 1.74 (d, /=7.07 Hz, 3 H) 5.57 (q, /=6.99 Hz, 1 H) 7.19 (d, /=5.31 Hz, 1 H) 7.31 - 7.38 (m, 1 H) 7.44 (t, /=7.71 Hz, 2 H) 7.48 - 7.53 (m, 2 H) 8.53 (d, /=4.80 Hz, 1 H) 8.83 (s, 1 H); HPLC purity (Method 1: 100%, Method 2: 96%); HRMS: CaICd IOr C ₁₆ Hi ₄ N ₄ O ₂ + H ⁺ , 295.1190; found (ESI-FTMS, [M+H]l+), 295.1189 Example 95

S-IfS-methyl-1H-pyrazol-S-yOaminol^-fK1RVl-phenylethyllam inoJcyclobut-S-ene- 1 ,2-dione

Step 1: 3-ethoxy-4-[(5-methyl-lfl ^r -pyrazol-3-yl)amino]cyclobut-3-ene-1,2-dione Following step 1 of Example 91, diethyl squarate (400 mg, 2.4 mmol) and 3-amino-5- methylpyrazole (274 mg, 1.2 eq) provided the title compound (362 mg, 68%) as a yellow solid.

¹ H NMR (400 MHz, DMSO-ii _tf ) δ ppm 1.38 (t, 7=7.1 Hz, 3 H), 2.16 - 2.23 (m, 4 H), 4.71 (q,

/=7.1 Hz, 2 H), 10.93 (s, 1 H), 12.20 (s, 1 H)

Step 2: A solution of 3-ethoxy-4-[(5-methyl- 1H-pyrazol-3-yl)amino]cyclobut-3-ene-1,2- dione (362 mg, 1.6 mmol) and (R)-1-phenylethanamine (271 mg, 1.3 eq) were heated in a microwave reactor (140 °C, 15 min) to provide the title compound (216 mg, 46%) as a white foam. ¹ H NMR (400 MHz, OMSO-d ₆ ) δ ppm 1.56 (d, /=6.82 Hz, 3 H) 2.19 (s, 3 H) 5.29 - 5.41

(m, 1 H) 7.25 - 7.34 (m, 1 H) 7.36 - 7.42 (m, 5 H) 12.23 (s, 1 H); HPLC purity (Method 1: 95%,

Method 2: 97%); HRMS: calcd for C ₁₆ H ₁₆ N ₄ O ₂ + H ⁺ , 297.1345; found (ESI-FTMS, [M+H]l+),

297.1346 Example 96 tert-butyl 4-[(3,4-dioxo-2-{[(1R)-1-phenylethyl]amino}cyclobut-1-en-1-y l)amino]piperidine-

1-carboxylate

Step 1 : 3-ethoxy-4- {[(liJ)-1-phenylethyl]amino}cyclobut-3-ene-1,2-dione

Following step 1 of Example 91, diethyl squarate (3.0 g, 18 mmol) and (R)-1-phenylethanamine (2.0 g, 0.95 eq) provided the title compound (3.76 g, 87%) as an oil after flash chromatography

(silica, 30% ethyl acetate / hexanes). ¹ H NMR (400 MHz, CD ₂ Cl ₂ ) δ ppm 1.40 (t, /=7.1 Hz, 3

H), 1.65 (d, /=6.8 Hz, 3 H), 4.73 (q, /=7.1 Hz, 2 H), 4.89 (bs, 1 H), 7.09 (bs, 1 H), 7.27 - 7.41

(m, 5 H)

Step 2: Following step 2 of Example 95, 3-ethoxy-4-{[(1R)-1- phenylethyl]amino}cyclobut-3-ene-1,2-dione 500 mg, 2 mmol) and 4-amino-1-N-Boc-piperidine

(410 mg, 1.1 eq) provided the title compound (730 mg, 91%) as a white solid after collecting the resulting precipitate. ¹ H NMR (400 MHz, DMSO-ctø δ ppm 1.29 - 1.42 (m, 4 H) 1.40 (s, 9 H)

1.54 (d, /=7.07 Hz, 3 H) 1.87 (d, J=I 1.37 Hz, 2 H) 2.88 (s, 2 H) 3.79 - 3.96 (m, 3 H) 5.20 (s, 1

H) 7.26 - 7.43 (m, 5 H); HPLC purity (Method 1: 94%, Method 2: 94%); HRMS: calcd for C ₂₂ H ₂₉ N ₃ O ₄ + H ⁺ , 400.2231 ; found (ESI-FTMS, [M+H] 1+), 400.2230

Example 97

3-isoquinolin-5-yl-4-{[(1R)-1-phenylethyl]amino}cyclobut- 3-ene-1,2-dione

Step 1: 3-ethoxy-4-(tributylstannyl)cyclobut-3-ene-1,2-dione was prepared following methods described in /. Org. Chem, 1990, 55, 5359-5364, which is incorporated by reference in its entirety. ¹ H NMR (400 MHz, chloroform-cf) δ ppm 0.86 - 0.97 (m, 6 H), 1.15 - 1.23 (m, 5 H),

1.28 - 1.40 (m, 8 H), 1.43 - 1.67 (m, 11 H), 4.77 (q, /=7.1 Hz, 2 H)

Step 2: 3-{[(1R)-l -phenylethyl] amino } -4-(tributylstannyl)cyclobut-3-ene- 1 ,2-dione Following step 2 of Example 91, 3-ethoxy-4-(tributylstannyl)cyclobut-3-ene-1,2-dione (4.0 g, 10 mmol) and (R)-I -phenyl ethanamine (1.8 g, 1.5 eq) provided the title compound (3.50 g, 71%) as an amber oil after flash chromatography (silica, 10% ethyl acetate / hexanes). Step 3 A solution of 3-{[(1R)-1-phenylethyl]amino}-4-(tributylstannyl)cyclobut-3- ene-

1,2-dione (100 mg, 0.2 mmol), 5-iodoisoquinoline (57 mg, 1.1 eq), benzylchlorobis(triphenylphosphine)palladium(π) (9 mg, 6 mol%), and coρper(I) iodide (4 mg, 9 mol%) in DMF was stirred at RT for 5h. See J. Org. Chem, 1990, 55, 5359-5364, which is incorporated by reference in its entirety. The reaction was diluted with ethyl acetate, washed with water, aq. KF, and brine, dried, evaporated and flash chromatographed (silica, 100% ethyl acetate) to provide the title compound (49 mg, 75%) as a yellow-brown oil. ¹ H NMR (400 MHz, chloroform-D) δ ppm 1.78 (d, /=4.80 Hz, 3 H) 5.71 (bs, 1 H) 6.67 (s, 1 H) 7.02 (bs, 1 H) 7.32 - 7.70 (m, 7 H) 7.84 (bs, 1 H) 8.01 (bs, 1 H) 8.31 (bs, 1 H); HPLC purity (Method 1: 91%, Method 2: 92%); HRMS: calcd for C _2I Hi ₆ N ₂ O ₂ + H ⁺ , 329.1285; found (ESI-FTMS, [M+H]l+), 329.1284. Example 98

3-{[(1R)-l -phenylethyl] amino}-4-(1H-pyrazol-3-ylamino)cyclobut-3-ene-1,2-dione Step l:3-ethoxy-4-(l_ff-ρyrazol-3-ylamino)cyclobut-3-ene-1,2-dio ne Following step 1 of Example 91, diethyl squarate (400 mg, 2.4 mmol) and 3- aminopyrazole (235 mg, 1.2 eq) provided the title compound (458 mg, 92%) as a pale yellow solid after collecting the resulting precipitate. ¹ H NMR (400 MHz, DMSO-<4) δ ppm 1.39 (t, /=7.1 Hz, 3 H), 4.72 (q, /=7.1 Hz, 2 H), 6.28 (s, 1 H), 7.61 - 7.71 (m, 1 H), 11.03 (s, 1 H), 12.52 (s, 1 H)

Step 2: Following step 2 of Example 95, 3-ethoxy-4-(li7-pyrazol-3-ylamino)cyclobut-3- ene-1,2-dione 200 mg, 1.0 mmol) and (R)-1-phenylethanamine (160 μL, 1.3 eq) provided the title compound (268 mg, 95%) after flash chromatography (silica, 2% acetic acid / ethyl acetate). ¹ H NMR (400 MHz, DMSO-rf _ff ) δ ppm 1.57 (d, /=6.82 Hz, 3 H) 5.25 - 5.46 (m, 1 H) 7.25 - 7.35 (m, 1 H) 7.35 - 7.44 (m, 4 H) 7.67 (d, /=2.27 Hz, 1 H) 12.52 (s, 1 H); HPLC purity (Method 1 : 96%, Method 2: 98%); HRMS: calcd for C ₁₅ Hi ₄ N ₄ O ₂ + H ⁺ , 283.1190; found (ESI-FTMS, [M+H]l+), 283.1189 Example 99

3- [(2-chloropy ridin-4-yl)amino] -4- { [(I R)-1-phenylethyl] amino} cycIobut-3-ene-l ,2- dione

Step 1 : 3-[(2-chloropyridin-4-yl)ammo]-4-ethoxycyclobut-3-ene-1,2-di one Following step 1 of Example 91, diethyl squarate (1.0 g, 6.0 mmol) and 2-chloro-4- aminopyridine (756 mg, 1.0 eq) provided the title compound (938 mg, 21%) after flash chromatography (silica, 50% ethyl acetate / hexanes). ¹ H NMR (400 MHz, DMSO-^) δ ppm 1.45 (t, J=I.1 Hz, 3 H), 4.81 (q, /=7.1 Hz, 2 H), 7.39 (dd, /=5.6, 2.0 Hz, 1 H), 7.55 (d, /=2.0 Hz, 1 H), 8.28 (d, /=5.8 Hz, 1 H), 11.17 (s, 1 H)

Step 2: Following step 2 of Example 95, 3-[(2-chloropyridin-4-yl)amino]-4- ethoxycyclobut-3-ene-1,2-dione (250 mg, 1 mmol) and (R)-1-phenylethanamine (256 μL, 2.0 eq) provided the title compound (270 mg, 83%) after collecting the resulting precipitate. ¹ H NMR (400 MHz, DMSO-rfβ) δ ppm 1.56 - 1.65 (m, /=6.82 Hz, 3 H) 5.24 - 5.37 (m, 1 H) 7.23 - 7.46 (m, 6 H) 7.65 (s, 1 H) 8.18 - 8.32 (m, 2 H) 10.01 (bs, 1 H); HPLC purity (Method 1: 99%, Method 2: 99%); HRMS: calcd for C _n Hi ₄ ClN ₃ O ₂ + H+, 328.08473; found (ESI-FTMS, [M+H]l+), 328.0848. Example 100

3-{[l-(4-cyclohexylphenyI)ethyl]amino}-4-(pyridin-4-ylami no)cyclobut-3-ene-1,2- dione

Step 1: l-(4-cyclohexylphenyl)ethanone oxime A solution of l-(4-cyclohexylphenyl)ethanone (2.0 g, 10 mmol), hydroxylamine hydrochloride (1.04 g, 1.5 eq), and pyridine (1.2 g, 1.5 eq) in ethanol (20 mL) was heated in the microwave reactor (120 °C, 20 min). The cooled solution was diluted with water (100 mL) and the resulting precipitate was collected to provide the title compound (2.16 g, 100%) as a white solid. ¹ H NMR (400 MHz, chloroform-rf) δ ppm 1.18 - 1.51 (m, 5 H), 1.70 - 1.93 (m, 5 H), 2.28 (s, 3 H), 2.52 (bs, 1 H), 7.22 (d, /=7.8 Hz, 2 H), 7.55 (d, /=7.8 Hz, 2 H) Step 2: l-(4-cyclohexylphenyl)ethanamine

A solution of l-(4-cyclohexylphenyl)ethanone oxime (300 mg, 1.4 mmol), zinc dust (900 mg, 10 eq), and acetic acid (2 mL), were heated in the microwave reactor (120 °C, 20 min). The heterogeneous solution was filtered through Celite ^® , neutralized with aq. NH ₄ OH, evaporated, diluted with water and extracted with dichloromethane to provide the title compound (238 mg, 83%) as a clear, colorless oil, ¹ H NMR (400 MHz, chloroform-*/) δ ppm 1.32 - 1.55 (m, 8 H),

1.69 - 1.90 (m, 5 H), 2.48 (bs, 1 H), 4.08 (q, /=6.6 Hz, 1 H), 7.17 (d, ./=7.8 Hz, 2 H), 7.23 - 7.28 (m, 2 H)

Step 3: Following step 2 of Example 95, l-(4-cyclohexylphenyl)ethanartiine (219 mg, 1 mmol) and 3-ethoxy-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2-dione (141 mg, 0.6 eq) provided the title compound (192 mg, 51%) as a pale-yellow solid after collecting the resulting precipitate. ¹ H NMR (400 MHz, DMSO-^ ₅ ) δ ppm 1.17 - 1.47 (m, 5 H) 1.59 (d, ./=6.82 Hz, 3 H) 1.65 - 1.84 (m, 5 H) 5.20 - 5.30 (m, 1 H) 7.23 - 7.29 (m, 2 H) 7.31 - 7.36 (m, 2 H) 7.42 (d, /=5.31 Hz, 2 H) 8.41 (d, /=6.06 Hz, 2 H) 9.82 (s, 1 H); HPLC purity (Method 1: 99%, Method 2: 99%); HRMS: calcd for C ₂₃ H ₂₅ N ₃ O ₂ + H ⁺ , 376.2020; found (ESI-FTMS, [M+H]l+), 376.2017 Example 101

3-{[(1R)-1-cyclohexylethyl]amino}-4-(pyridin-4-ylamino)cy clobut-3-ene-1,2-dione

Following step 2 of Example 95, 3-ethoxy-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2- dione (200 mg, 0.9 mmol) and (R)-1-cyclohexylethanamine (152 mg, 1.3 eq) provided the title compound (145 mg, 54%) as a pale-yellow solid. ¹ H NMR (400 MHz, DMSO-ιi _β ) δ ppm 0.89 - 1.28 (m, 5 H) 1.21 (d, /=6.82 Hz, 3 H) 1.32 - 1.47 (m, 1 H) 1.63 (d, /=12.13 Hz, 1 H) 1.66 - 1.80 (m, 4 H) 3.88 - 4.04 (m, 1 H) 7.45 (d, /=6.06 Hz, 2 H) 7.75 (d, /=9.09 Hz, 1 H) 8.41 (d, /=6.32 Hz, 2 H) 9.79 (s, 1 H); HPLC purity (Method 1: 100%, Method 2: 100%); HRMS: calcd for C ₁₇ H ₂ ]N ₃ O ₂ + H ⁺ , 300.1707; found (ESI-FTMS, [M+H]l+), 300.1706 Example 102 (R)-3-(biphenyI-3-ylamlno)-4-(l-phenyIethylamino)cyclobut-3- ene-1,2-dione 3-(biphenyl-3-yIamino)-4-ethoxycyclobut-3-ene-1,2-dione

Step 1 : Following step 1 of Example 91, diethyl squarate (400 mg, 2.4 mmol) and biphenyl-3 -amine (55 mg, 1.1 eq) provided the title compound (200 mg, 24%) after collecting the resulting precipitate by filtration. ¹ H NMR (400 MHz, OMSO-d ₆ ) δ ppm 1.42 (t, /=7.2 Hz, 3 H), 4.80 (q, /=7.1 Hz, 2 H), 7.30 - 7.52 (m, 6 H), 7.65 - 7.71 (m, 2 H), 7.73 (s, 1 H), 10.86 (s, 1 H)

Step 2: Following step 2 of Example 95, 3-(biphenyl-3-ylamino)-4-ethoxycyclobut-3- ene-1,2-dione (200 mg, 0.7 mmol) and (R)-1-phenylethanamine (174 μL, 2.0 eq) provided the title compound (223 mg, 86%) as a white solid after collecting the resulting precipitate. ¹ H NMR (400 MHz, δ ppm 1.61 (d, /=7.07 Hz, 3 H) 5.27 - 5.36 (m, 1 H) 7.28 - 7.51 (m,

10 H) 7.67 - 7.72 (m, 2 H) 7.83 (s, 1 H) 8.12 (s, 1 H) 9.69 (s, 1 H); HPLC purity (Method 1:

98%, Method 2: 98%).

Example 103

3-[(2-bromopyridin-4-yl)amino]-4-{[(1R)-1-phenyIethyl]ami no}cyclobut-3-ene-1,2- dione

Step 1 : 3-[(2-bromopyridin-4-yl)amino]-4-ethoxycyclobut-3-ene-1,2-di one Following step 1 of Example 91, 2-bromo-4-aminoρyridine (5 g, 29 mmol) and diethyl squarate (4.9 g, 1.0 eq) provided the title compound (1.51 g, 18%) as a yellow foam after flash chromatography (silica, 40% ethyl acetate / hexanes). ¹ H NMR (400 MHz, OMSO-d ₆ ) δ ppm 1.45 (t, 7=7.1 Hz, 3 H), 4.81 (q, /=7.1 Hz, 2 H), 7.39 - 7.43 (m, 1 H), 7.69 (d, /=2.0 Hz, 1 H),

8.22 - 8.32 (m, 1 H), 11.15 (s, 1 H)

Step 2: Following step 2 of Example 95, 3-[(2-bromopyridin-4-yi)amino]-4- ethoxycyclobut-3-ene-1,2-dione (1.20 g, 4 mmol) and (R)-1-phenylethanamine (1.3 mL, 2.5 eq) provided the title compound (1.14 g, 77%) as a pale-yellow solid after collecting the resulting precipitate by filtration. ¹ H NMR (400 MHz, DMSO-4j) δ ppm 1.61 (d, J=6.82 Hz, 3 H) 5.23 -

5.37 (m, 3 H) 7.23 - 7.48 (m, 5 H) 8.14 - 8.32 (m, 2 H) 9.95 (s, 1 H); HPLC purity (Method 1:

75%, Method 2: 72%);

Example 104

3-[(2-morpholin-4-ylpyridin-4-yl)ammo]-4-{[(1R)-1-phenyle thyl]amino}cyclobut-3- ene-1,2-dione

A solution of 3 - [(2-bromoρyridin-4-yl)amino] -4-{[(1R)-l -phenylethyl] amino } cyclobut-

3-ene-1,2 -dione (50 mg, 0.13 mmol) and morpholine (28 μL, 2.4 eq) in DMF (1 mL) were heated in the microwave reactor (200 °C, 20 min). Reverse phase HPLC purification provided the title compound (13 mg, 26%). ¹ H NMR (400 MHz, DMSO-^s) δ ppm 1.60 (d, /=6.82 Hz, 3 H) 3.33 - 3.49 (m, 4 H) 3.62 - 3.75 (m, 4 H) 5.24 - 5.37 (m, 1 H) 6.62 (dd, /=5.56, 1.77 Hz, 1 H) 7.07 (s,

1 H) 7.27 - 7.36 (m, 1 H) 7.41 (d, 4 H) 7.99 (d, /=5.56 Hz, 1 H) 8.16 (s, 1 H) 8.35 (d, /=7.58 Hz,

1 H); HPLC purity (Method 1: 97%, Method 2: 97%); HRMS: calcd for C _2I H ₂₂ N ₄ O ₃ + H+,

379.17647; found (ESI-FTMS, [M+H]l+), 379.1778.

Example 105 3-[(l-methyl-1-phenylethyl)amino]-4-(pyridin-4-ylamino)cyclo but-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. ¹ H NMR (400 MHz, OMSO-d ₆ ) δ ppm 1.79 (s, 6 H) 7.28 (t, /=7.07 Hz, 1 H) 7.38 (t, /=7.71 Hz, 2 H) 7.43 - 7.51 (m, 4 H) 8.43 (d, /=5.81 Hz, 3 H); HPLC purity (Method 1 : 99%, Method 2: 99%); HRMS: calcd for C ₁₈ H ₁₇ N ₃ O ₂ + H+, 308.13935; found (ESI-FTMS, [M+H]l+), 308.1397. Example 106

3-{[(1R)-1-phenylethyl]amino}-4-{[2-(phenylthio)pyridin-4 -yI]amino}cyclobut-3- ene-1,2-dione A solution of 3-[(2-bromopyridin-4-yl)amino]-4-{[(1R)-1-phenylethyl]amino} cyclobut-

3-ene-1,2-dione (200 mg, 0.54 mmol), benzenethiol (83 μL, 1.5 eq), and sodium hydride (32 mg, 1.5 eq) were heated in the microwave reactor (200 °C, 20 min). Reverse phase HPLC purification provided the title compound (83 mg, 38%) as a yellow foam. ¹ H NMR (400 MHz, DMSO-<4) δ ppm 1.57 (d, /=6.82 Hz, 3 H) 5.21 - 5.30 (m, 1 H) 6.84 (d, /=2.02 Hz, 1 H) 7.27 - 7.42 (m, 6 H) 7.46 - 7.52 (m, 3 H) 7.56 - 7.62 (m, 2 H) 8.17 (d, /=7.83 Hz, 1 H) 8.24 (d, /=5.81 Hz, 1 H) 9.79 (s, 1 H); HPLC purity (Method 1 : 95%, Method 2: 95%); HRMS: calcd for C ₂₃ Hi ₉ N ₃ O ₂ S + H+, 402.12707; found (ESI-FTMS, [M+H]l+), 402.1278. Example 107 4-[(3,4-dioxo-2-{[(1R)-1-phenylethyl]amino}cyclobut-1-en-1-y l)amino]pyridine-2- carboxamide

Step 1 : 4-nitropyridine-2-carboxamide

A solution of 4-nitropicolinic acid (1.0 g, 7.2 mmol) and carbonyldiimidazole (2.35 g, 2 eq) in THF (30 mL) was heated at 60 °C for Ih. The solution was cooled, aq. NH ₄ OH (2 mL) was added and the reaction was stirred at RT overnight. The solution was purged with a stream ofN ₂ for 15 minutes, diluted with DCM, washed with water and brine, dried, filtered, and evaporated to provide the title compound (0.75g, 62%) as an off-white solid. ¹ H NMR (400 MHz, OMSO-d ₆ ) δ ppm 8.00 (bs, 1 H), 8.32 (dd, /=5.3, 2.3 Hz, 1 H), 8.37 (bs, 1 H), 8.54 (d, /=1.5 Hz, 1 H), 9.02 (d, /=5.3 Hz, 1 H)

Step 2: 4-aminopyridine-2-carboxamide A solution of 4-nitropyridme-2-carboxamide (0.65 g, 4 mmol) and PtO ₂ (20 mg) in EtOH

(50 mL) was shaken under a H ₂ atmosphere (50 PSI, RT, 2 h). The solution was filtered and

evaporated to provide the title compound (0.52 g, 97%) as a tan solid. ¹ H NMR (400 MHz, DMSO-40 δ ppm 6.28 (s, 2 H), 6.58 (d, /=5.6 Hz, 1 H), 7.20 (s, 1 H), 7.39 (s, 1 H), 7.88 (s, 1 H), 8.00 (d, /=5.6 Hz, I H)

Step 3 : 4-[(2-ethoxy-3,4-dioxocyclobut- 1 -en- 1 -yl)amino]pyridine-2-carboxamide Following step 1 of Example 91, diethyl squarate (722 mg, 4 mmol) and 4- aminopyridine-2-carboxamide (582 mg, 1 eq) provided the title compound (120 mg, 10%) as an orange solid. ¹ H NMR (400 MHz, δ ppm 1.46 (t, J=I.1 Hz, 3 H), 4.82 (q, /=7.0 Hz, 2 H), 7.57 - 7.69 (m, /=18.9 Hz, 2 H), 8.09 (s, 2 H), 8.50 (d, /=5.3 Hz, 1 H), 11.17 (s, 1 H)

Step 4 : 4- [(3 ,4-dioxo-2- { [( 1 R)- 1 -phenylethyl] amino } cyclobut- 1 -en- 1 -yl)amino]pyridine- 2-carboxamide

Following step 2 of Example 95, 4-[(2-ethoxy-3,4-dioxocyclobut-1-en-1- yl)amino]pyridine-2-carboxamide (120 mg, .5 mmol) and (R)-1-phenylethanamine (174 μL, 3 eq) provided the title compound (120 mg, 78%) as a pale-yellow solid. ¹ H NMR (400 MHz, DMSO-rf _tf ) δ ppm 1.61 (d, /=6.82 Hz, 3 H), 5.21 - 5.39 (m, 1 H), 7.28 - 7.47 (m, 5 H), 7.64 (s, 1 H), 7.71 (s, 1 H), 7.91 (s, 1 H), 8.06 (s, 1 H), 8.13 - 8.24 (m, 1 H), 8.46 (d, /=5.56 Hz, 1 H),

10.04 (s, 1 H); HPLC purity (Method 1: 89%, Method 2: 86%); HRMS: calcd for C ₁₈ Hi ₆ N ₄ O ₃ + H+, 337.12952; found (ESI-FTMS, [M+H]l+), 337.1301. Example 108 3-{[(1R)-1-phenyIethyl]amino}-4-(piperidin-4-ylamino)cyclobn t-3-ene-1,2-dione trifluoroacetic acid salt

A solution of (R)-tert-butyl 4-(3,4-dioxo-2-(l-phenylethylamino)cyclobut-1- enylamino)piρeridine-1-carboxylate (250 mg, 0.6 mmol) and TFA (2 mL) in DCE (2 mL) was stirred at RT overnight. The solution was evaporated and diluted with DCM and water. The aqueous layer was lyophilized to provide the title compound (66 mg, 27%) ¹ H NMR (400 MHz, OMSO-d ₆ ) δ ppm 1.53 (d, /=6.82 Hz, 3 H), 1.62 (t, /=12.51 Hz, 2 H), 1.99 (d, /=11.62 Hz, 2 H), 2.81 - 2.95 (m, 2 H), 3.21 (d, /=13.39 Hz, 2 H), 3.90 - 4.07 (m, 1 H), 5.18 - 5.30 (m, 1 H), 7.23 - 7.33 (m, 1 H), 7.32 - 7.43 (m, 4 H), 8.22 (s, 1 H), 8.47 (s, 1 H); HPLC purity (Method 1: 98%, Method 2: 98%); HRMS: calcd for C _n H _2I N ₃ O ₂ + H+, 300.17065; found (ESI-FTMS, [M+H]l+), 300.1709. Example 109 tert-butyl (2S)-{[3,4-dioxo-2-(pyridin-4-ylamino)cyclobut-1-en-1-yl]ami no}(phenyl)acetate

A solution of 3-ethoxy-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2-dione (200 mg, 0.9 mmol), (S)-tert-butyl 2-amino-2-phenylacetate hydrochloride salt (300 mg, 1.3 eq), and TEA (380 μL, 3 eq) in EtOH (20 niL) was heated at reflux for 48 h. The solution was evaporated and reverse phase HPLC provided the title compound (81 mg, 23 %) as a yellow solid. ¹ H NMR (400 MHz, DMSO-tfu) δ ppm 1.34 - 1.44 (m, 9 H), 3.33 (bs, 1 H), 7.35 - 7.54 (m, 6 H), 8.39 - 8.46 (m, 2 H), 8.64 (d, /=8.08 Hz, 1 H), 10.12 (bs, 1 H); HPLC purity (Method 1 : 91%, Method 2: 86%); HRMS: calcd for C ₂₁ H ₂ 1N ₃ O4 + R+, 380.16048; found (ESI-FTMS, [M+H]l+), 380.1618. Example 110 (2S)-{[3,4-dioxo-2-(pyridin-4-ylamino)cyclobut-1-en-1-yI]ami no}(phenyl)acetic acid A solution of tert-butyl (2S)-{[3,4-dioxo-2-(pyridin-4-ylamino)cyclobut-1-en-1- yl]amino}(phenyl)acetate (41 mg, 0.1 mmol) and TFA (1 mL) in DCM (2 niL) was stirred at RT for 3h. The solvent was evaporated to provide the title compound (34 mg, 100%) as a pale- yellow solid. ¹ H NMR (400 MHz, DMSCW ₁₅ ) δ ppm 5.76 (s, 1 H), 5.82 (d, /=8.1 Hz, 1 H), 7.37 - 7.50 (m, 5 H), 7.78 (d, /=6.6 Hz, 2 H), 8.62 (d, /=7.1 Hz, 2 H), 8.98 (d, /=7.6 Hz, 1 H); HPLC purity (Method 1: 85%, Method 2: 79%); Example 111

2-{[3,4-dioxo-2-(pyridin-4-ylamiπo)cyclobut-1-en-1-yl]am ino}-2-(3- hydroxyphenyl)acetamide Step 1 : methyl amino(3-hydroxyphenyl)acetate

To a stirred solution of crude amino(3-hydroxyphenyl)acetic acid hydrochloride (24.36 g, 0.12 mol) in methanol (300 mL) was added thionyl chloride (15 mL, 1.8 eq) dropwise. The solution was heated at reflux for 3 h, stirred at RT overnight, evaporated, dissolved in DCM, and neutralized with aq. NaHCC> ₃ . The organic layer was dried evaporated, and flash chromatographed (silica, 5-15% MeOH / ethyl acetate) to provide the title compound (8.16 g, 30%, 3 steps) as an off-white solid. ¹ H NMR (400 MHz, DMSO-ck) δ ppm 3.59 (s, 3 H), 4.42 (s, 1 H), 6.62 - 6.68 (m, 1 H), 6.74 - 6.80 (m, 2 H), 7.11 (t, /=8.1 Hz, 1 H), 9.39 (s, 1 H) Step 2: 2-amino-2-(3-hydroxyphenyl)acetamide A solution of methyl amino(3-hydroxyphenyl)acetate (6.90 g, 38 mmol) was dissolved in methanol (300 mL) and thionyl chloride (8.3 mL, 3 eq) was added dropwise. The solution was stirred for 30 min and was evaporated. The resulting hydrochloride salt was dissolved in aq

NH ₄ OH (200 mL) and was stirred overnight. The solution was evaporated to provide the crude title compound (6.35 g, 100%) ¹ H NMR (400 MHz, OMSO-d ₆ ) δ ppm 4.18 (bs, 1 H), 6.56 - 6.66 (m, 1 H), 6.77 - 6.84 (m, 2 H), 6.99 (bs, 1 H), 7.03 - 7.11 (m, 1 H), 7.41 (s, 1 H), 9.29 (s, 1 H)

Step 3: Following step 2 of Example 91, 3-ethoxy-4-(pyridin-4-ylamino)cyclobut-3-ene- 1 ,2-dione (100 mg, .50 mmol) and 2-amino-2-(3-hydroxyphenyl)acetamide (76 mg, 1.0 eq) provided the title compound (136 mg, 87%) as a yellow solid after collecting the resulting precipitate. ¹ H NMR (400 MHz, DMSO-rf*) δ ppm 5.72 (d, /=8.6 Hz, 1 H), 6.65 - 6.74 (m, 1 H), 6.83 - 6.93 (m, 2 H), 7.17 (t, ./=7.8 Hz, 1 H), 7.41 - 7.49 (m, 3 H), 8.03 (s, 1 H), 8.42 (d, ./=6.1 Hz, 1 H), 8.75 (d, /=8.6 Hz, 2 H), 9.55 (s, 1 H), 10.30 (s, 1 H); HPLC purity (Method 1: 98%, Method 2: 94%); HRMS: calcd for C _n Hi ₄ N ₄ O ₄ + H+, 339.1088; found (ESI-FTMS, [M+H]l+), 339.1087. Example 112

2-(3-bromophenyl)-2-{[3,4-dioxo-2-(pyridin-4-ylamino)cyclobu t-1-en-1-yl]ainino}acetaπiide Following step 2 of Example 91, 3-ethoxy-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2- dione (220 mg, 1 mmol) and 2-amino-2-(3-bromophenyl)acetamide (229 mg, 1 eq) were heated at 80° C overnight to provide the title compound (219 mg, 55%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-rft _f ) δ ppm 7.35 - 7.41 (m, 2 H), 7.42 - 7.48 (m, 3 H), 7.52 - 7.59 (m, 2 H), 7.68 (t, /=1.8 Hz, 1 H), 8.13 (s, 1 H), 8.40 - 8.45 (m, 2 H), 8.84 (d, /=8.3 Hz, 1 H), 10.30 (s, 1 H); HPLC purity (Method 1: 100%, Method 2: 100%); HRMS: calcd for C ₁₇ Hi ₃ BrN ₄ O ₃ + H+, 401.0244; found (ESI-FTMS, [MH-H]I+), 401.0245. Example 113 2-biphenyl-3-yl-2-{[3,4-dioxo-2-(pyridin-4-ylanrino)cyclobut -1-eii-1-yl]amino}acetainide

A solution of 2-(3-bromophenyl)-2-{[3,4-dioxo-2-(pyridm-4-ylammo)cyclobut- 1-en-1- yl]amino}acetamide (75 mg, 0.19 mmol), dichlorobis(triphenylphosphine)palladium(II) (13 mg, 0.1 eq), phenylboronic acid (30 mg, 1.3 eq), and sodium carbonate (26 mg, 1.3 eq) in DME / H ₂ O / EtOH (7:3:1, 3 mL) was heated in the microwave reactor (120 °C, 30 min). Reverse phase HPLC provided the title compound (7 mg, 9%) as a yellow solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 5.89 (d, /=6.3 Hz, 1 H), 7.20 - 7.54 (m, 7 H), 7.59 - 7.68 (m, 3 H), 7.77 (dd, /=8.1, 1.5 Hz, 1 H), 7.81 (s, 1 H), 8.09 (s, 1 H), 8.27 (s, 1 H), 8.41 (d, /=6.1 Hz, 2 H), 9.08 (d, /=7.1 Hz, 1 H); HPLC purity (Method 1 : 95%, Method 2: 95%); HRMS: calcd for C ₂₃ Hi ₈ N ₄ O ₃ + H+, 399.1452; found (ESI-FTMS, [M+H]l+), 399.1448.

Example 114

2-{[3,4-dioxo-2-(pyridin-4-ylamino)cyclobut-1-en-1-yI]ami no}-2-[3-(3- thienyl)pheny 1] acetamide

Utilizing the method of Example 113, 2-(3-bromophenyl)-2-{[3,4-dioxo-2-(pyridin-4- ylamino)cyclobut-l -en- 1-yl] amino} acetamide (75 mg, 0.19 mmol) and 3-thiophene boronic acid (36 mg, 1.5 eq) were converted to the title compound (20 mg, 26%). ¹ H NMR (400 MHz, DMSO-rfβ) δ ppm 5.85 (d, /=8.1 Hz, 1 H), 7.34 - 7.39 (m, 1 H), 7.43 - 7.48 (m, 3 H), 7.49 - 7.55 (m, 2 H), 7.65 - 7.72 (m, 2 H), 7.79 - 7.86 (m, 2 H), 8.09 (s, 1 H), 8.19 (s, 1 H), 8.42 (dd, /=4.8, 1.5 Hz, 2 H), 8.95 (d, /=8.6 Hz, 1 H); HPLC purity (Method 1: 98%, Method 2: 98%); HRMS: calcd for C _2I Hi ₆ N ₄ O ₃ S + H+, 405.1016; found (ESI-FTMS, [M+H]l+), 405.1013. Example 115

2-{[3,4-dioxo-2-(pyridin-4-ylammo)cyclobut-1-en-1-yI]amin o}-2-(3'-methylbiphenyl-3- yl)acetamide

Utilizing the method of Example 113, 2-(3-bromophenyl)-2-{[3,4-dioxo-2-(pyridin-4- ylamino)cyclobut-1-en-1-yl]ammo}acetamide (75 mg, 0.19 mmol) and m-tolylboronic acid (38 mg, 1.5 eq) were converted to the title compound (3 mg, 4%). ¹ H NMR (400 MHz, OMSO-d ₆ ) δ ppm 2.39 (s, 3 H), 5.89 (s, 1 H), 7.21 (d, /=7.6 Hz, 1 H), 7.33 - 7.55 (m, 8 H), 7.57 - 7.66 (m, 1 H), 7.79 (s, 1 H), 8.09 (s, 1 H), 8.27 (s, 1 H), 8.41 (dd, /=4.8, 1.5 Hz, 2 H), 9.07 (s, 1 H); HPLC purity (Method 1: 92%, Method 2: 91%); HRMS: calcd for C ₂₄ H ₂₀ N ₄ O ₃ + H+, 413.1608; found (ESI-FTMS, [M+H]l+), 413.161. Example 116

2-{3'-[(dimethy]amino)sulfonyl]biphenyl-3-yl}-2-{[3 ₎ 4-dioxo-2-(pyridiii-4-yIamino)cyclobut- l-en-1-yl] amino} acetamide

Utilizing the method of Example 113, 2-(3-bromophenyl)-2-{[3,4-dioxo-2-(pyridin-4- ylamino)cyclobut- l-en-1-yl] amino} acetamide (75 mg, 0.19 mmol) and N,N-dimethyl 3- boronobenzenesulfonamide (69 mg, 1.5 eq) were converted to the title compound (11 mg, 11%). ¹ H NMR (400 MHz, OMSO-d ₆ ) δ ppm 2.66 (s, 6 H), 5.92 (d, /=7.8 Hz, 1 H), 7.45 (dd, /=4.8, 1.5 Hz, 2 H), 7.49 - 7.59 (m, 3 H), 7.69 - 7.75 (m, 1 H), 7.79 (dd, 2 H), 7.87 (s, 1 H), 7.93 (s, 1 H), 7.97 - 8.04 (m, 1 H), 8.15 (dd, 1 H), 8.41 (dd, /=4.8, 1.5 Hz, 2 H), 9.04 (d, /=8.3 Hz, 1 H); HPLC purity (Method 1 : 96%, Method 2: 95%); HRMS: calcd for C ₂₅ H ₂₃ N ₅ O ₅ S + H+, 506.14927; found (ESI-FTMS, [MH-H]I+), 506.1497.

Example 117

2-{[3,4-dioxo-2-(pyridin-4-ylamino)cycIobut-1-en-1-yl]ami iio}-2-(2'-methylbiphenyl-3- yl)acetamide

Utilizing the method of Example 113, 2-(3-bromophenyl)-2-{[3,4-dioxo-2-(pyridin-4- ylamino)cyclobut-1-en-1-yl]amino}acetamide (75 mg, 0.19 mmol) and 2-methylbenzeneboronic acid (38 mg, 1.5 eq) were converted to the title compound (19 mg, 24%). ¹ H NMR (400 MHz, DMSO-rf,j) δ ppm 2.22 (s, 3 H), 5.87 (d, /=8.6 Hz, 1 H), 7.17 - 7.23 (m, 1 H), 7.23 - 7.35 (m, 4 H), 7.39 - 7.56 (m, 6 H), 8.08 - 8.13 (m, 1 H), 8.34 - 8.47 (m, 2 H), 8.88 (d, /=8.3 Hz, 1 H), 10.32 (s, 1 H); HPLC purity (Method 1: 95%, Method 2: 94%); HRMS: calcd for C ₂₄ H ₂₀ N ₄ O ₃ + H+, 413.1608; found (ESI-FTMS, [M+H]l+), 413.1604. Example 118

2-(3'-cyanobiphenyl-3-yl)-2-{[3,4-dioxo-2-(pyridin-4-ylam ino)cyclobut-1-en-1- yl]amino}acetamide

Utilizing the method of Example 113 , 2-(3 -bromophenyl)-2- { [3 ,4-dioxo-2-(pyridin-4- ylamino)cyclobut-1-en-1-yl]amino}acetamide (75 mg, 0.19 mmol) and 3-cyanophenylboronci acid (41 mg, 1.5 eq) were converted to the title compound (18 mg, 22%). ¹ H NMR (400 MHz, DMSO-rf _tf ) δ ppm 5.89 (d, /=8.3 Hz, 1 H), 7.45 (dd, J=4.8, 1.5 Hz, 2 H), 7.47 - 7.52 (m, 1 H), 7.51 - 7.58 (m, ./=7.7, 7.7 Hz, 2 H), 7.69 - 7.76 (m, 2 H), 7.85 - 7.90 (m, 2 H), 7.97 - 8.03 (m, 1 H), 8.09 (s, 1 H), 8.11 - 8.13 (m, 1 H), 8.38 - 8.47 (m, 2 H), 8.92 (d, /=8.3 Hz, 1 H), 10.33 (s, 1 H); HPLC purity (Method 1 : 98%, Method 2: 98%); HRMS: calcd for C ₂₄ H _n N ₅ O ₃ + H+, 424.1404; found (ESI-FTMS, [M+H]l+), 424.1399. Example 119

2-{[3,4-dioxo-2-(pyridin-4-yIamino)cyclobut-1-en-1-yl]amino} -2-(4'-methylbiphenyl-3- yl)acetamide Utilizing the method of Example 113, 2-(3-bromophenyl)-2- {[3,4-dioxo-2-(pyridin-4- ylamino)cyclobut-1-en-1-yl]amino}acetamide (75 mg, 0.19 mmol) and p-tolylboronic acid (38 mg, 1.5 eq) were converted to the title compound (5 mg, 6%). ¹ H NMR (400 MHz, DMSO-fifc) δ ppm 2.35 (s, 3 H), 5.87 (d, /=7.6 Hz, 1 H), 7.31 (d, /=7.8 Hz, 2 H), 7.37 - 7.64 (m, 8 H), 7.78 (s, 1 H), 8.09 (s, 1 H), 8.41 (d, /=6.3 Hz, 2 H), 8.98 (d, /=7.3 Hz, 1 H), 10.43 (bs, 1 H); HPLC purity (Method 1: 97%, Method 2: 96%); HRMS: calcd for C ₂₄ H ₂₀ N ₄ O ₃ + H+, 413.1608; found (ESI-FTMS, [M+H]l+), 413.1607.

Example 120 3-[(l-biphenyI-3-ylethyl)amiπo]-4-(pyridin-4-ylamino)cyclob ut-3-ene-1,2-dione

Utilizing the method of Example 113, 3-(l-(3-bromophenyl)ethylamino)-4-(pyridin-4- ylamino)cyclobut-3-ene-1,2-dione (100 mg, 0.27 mmol) and phenylboronic acid (49 mg, 1.5 eq) were converted to the title compound (23 mg, 23%). ¹ H NMR (400 MHz, OMSO-d ₆ ) δ ppm

1.66 (d, /=6.8 Hz, 3 H), 5.29 - 5.45 (m, 1 H), 7.35 - 7.53 (m, 8 H), 7.61 (d, J=7.6 Hz, 1 H), 7.64 - 7.74 (m, 3 H), 8.39 (d, /=6.1 Hz, 2 H), 8.58 (d, /=8.3 Hz, 1 H); HPLC purity (Method 1: 91%, Method 2: 91%); HRMS: calcd for C ₂₃ H ₁₉ N ₃ O ₂ + H+, 370.1550; found (ESI-FTMS, [M+H]l+), 370.1547. Example 121

S'^l-fβ^-dioxo-1-føyridin-4-ylaminoJcyclobut-1-en-1-yll aminoJethyObiphenyl- 3-carbonitrile

Utilizing the method of Example 113, 3-(l-(3-bromophenyl)ethylamino)-4-(ρyridin-4- ylamino)cyclobut-3-ene-1,2-dione (100 mg, 0.27 mmol) and 3-cyanophenylboronic acid (59 mg, 1.5 eq) were converted to the title compound (49 mg, 46%). ¹ H NMR (400 MHz, DMSO-<4) δ ppm 1.67 (d, /=6.8 Hz, 3 H), 5.32 - 5.45 (m, 1 H), 7.43 (d, /=5.1 Hz, 2 H), 7.47 - 7.58 (m, 2 H), 7.69 (t, /=7.8 Hz, 2 H), 7.81 (s, 1 H), 7.84 - 7.88 (m, 1 H), 8.05 (d, /=8.1 Hz, 1 H), 8.21 (s, 1 H),

8.40 (d, /=6.1 Hz, 2 H); HPLC purity (Method 1: 97%, Method 2: 96%); HRMS: calcd for C ₂₄ Hi ₈ N ₄ O ₂ + H+, 395.1503; found (ESI-FTMS, [M+H]l+), 395.1502. Example 122

3-{[l-(4'-acetylbiphenyl-3-yl)ethyl]amino}-4-(pyridin-4-y lamino)cyclobut-3-ene-1,2-dione Utilizing the method of Example 113, 3-(l-(3-bromophenyl)ethylamino)-4-(pyridin-4- ylamino)cyclobut-3-ene-1,2-dione (100 mg, 0.27 mmol) and 4-acetylphenylboronic acid (66 mg,

1.5 eq) were converted to the title compound (50 mg, 45%). ¹ H NMR (400 MHz, DMSO-rf _β ) δ ppm 1.67 (d, /=6.8 Hz, 3 H), 2.62 (s, 3 H), 5.31 - 5.46 (m, 1 H), 7.43 (d, /=4.8 Hz, 2 H), 7.53 (d,

2 H), 7.70 (d, /=7.6 Hz, 1 H), 7.80 (s, 1 H), 7.85 (d, /=8.1 Hz, 2 H), 8.06 (d, /=8.6 Hz, 2 H),

8.41 (d, /=6.1 Hz, 2 H); HPLC purity (Method 1: 97%, Method 2: 98%); HRMS: calcd for C ₂₅ H _2I N ₃ O ₃ + H+, 412.1656; found (ESI-FTMS, [M+H]l+), 412.1656.

Example 123 3-{[l-(4'-chlorobiphenyl-3-yl)ethyl]amino}-4-(pyridin-4-ylam ino)cyclobut-3-ene-1,2-dione

Utilizing the method of Example 113, 3-(l-(3-bromophenyl)ethylamino)-4-(ρyridin-4- ylamino)cyclobut-3-ene-1,2-dione (100 mg, 0.27 mmol) and 4-chlorophenylboronic acid (63 mg, 1.5 eq) were converted to the title compound (50 mg, 46%). ¹ H NMR (400 MHz, DMSCWs) δ ppm 1.66 (d, /=6.8 Hz, 3 H), 5.32 - 5.44 (m, 1 H), 7.41 - 7.48 (m, /=7.8 Hz, 3 H), 7.48 - 7.57 (m, 3 H), 7.62 (d, /=7.8 Hz, 1 H), 7.69 - 7.75 (m, 3 H), 8.40 (d, /=5.8 Hz, 2 H), 8.57 (d, /=6.8 Hz, 1 H); HPLC purity (Method 1 : 97%, Method 2: 95%); HRMS: calcd for C ₂₃ Hi ₈ ClN ₃ O ₂ + H+, 404.1160; found (ESI-FTMS, [M+H]l+), 404.1162. Example 124 3-{[l-(2'-methylbiphenyl-3-yI)ethyl]amino}-4-(pyridin-4-ylam ino)cyclobut-3-ene-1,2-dione Utilizing the method of Example 113, 3-(l-(3-bromophenyl)ethylamino)-4-(pyridin-4- ylamino)cyclobut-3-ene-1,2-dione (100 mg, 0.27 mmol) and 2-methylbenzeneboronic acid (55 mg, 1.5 eq) were converted to the title compound (41 mg, 40%). ¹ H NMR (400 MHz, DMSO-rf _tf ) δ ppm 1.64 (d, /=6.8 Hz, 3 H), 2.23 (s, 3 H), 5.29 - 5.44 (m, 1 H); 7.18 - 7.34 (m, 5 H), 7.38 (s, 1 H), 7.40 - 7.53 (m, 4 H), 8.37 - 8.48 (m, /=5.6 Hz, 3 H); HPLC purity (Method 1: 97%, Method 2: 97%); HRMS: calcd for C ₂₄ H ₂ iN ₃ O ₂ + H+, 384.1707; found (ESI-FTMS, [M+H]l+), 384.1706. Example 125

3-{[l-(4'-methylbiphenyl-3-yl)ethyl]amino}-4-(pyridin-4-ylam ino)cyclobut-3-ene-1,2-dione Utilizing the method of Example 113, 3-(l-(3-bromophenyl)ethylamino)-4-(pvridin-4- ylamino)cyclobut-3-ene-1,2-dione (100 mg, 0.27 mmol) andju-tolylboronic acid (55 mg, 1.5 eq) were converted to the title compound (21 mg, 20%). ¹ H NMR (400 MHz, DMSO-cfe) δ ppm 1.66 (d, /=6.8 Hz, 3 H), 2.35 (s, 3 H), 5.28 - 5.45 (m, 1 H), 7.29 (d, /=7.8 Hz, 2 H), 7.37 - 7.52 (m, 4 H), 7.58 (d, /=7.6 Hz, 3 H), 7.68 (s, 1 H), 8.40 (d, /=5.6 Hz, 3 H); HPLC purity (Method 1: 98%, Method 2: 99%); HRMS: calcd for C ₂₄ H ₂ iN ₃ O ₂ + H+, 384.1707; found (ESI-FTMS, [M+H]l+), 384.1706. Example 126 3-(pyridin-4-ylamino)-4-({l-[3-(3-thienyl)phenyl]ethyl}amino )cyclobut-3-ene-1,2-dione

Utilizing the method of Example 113, 3-(l-(3-bromophenyl)ethylamino)-4-(pyridin-4- ylamino)cyclobut-3-ene-1,2-dione (100 mg, 0.27 mmol) and 3-thiophenephenylboronic acid hydrate (52 mg, 1.5 eq) were converted to the title compound (61 mg, 60%). ¹ H NMR (400 MHz, DMSO-<4) δ ppm 1.66 (d, /=6.8 Hz, 3 H), 5.28 - 5.41 (m, 1 H), 7.36 (d, /=7.6 Hz, 1 H),

7.45 (t, /=7.6 Hz, 3 H), 7.59 (d, /=4.8 Hz, 1 H), 7.63 - 7.71 (m, 2 H), 7.77 (s, 1 H), 7.91 (s, 1 H), 8.32 (d, /=8.8 Hz, 2 H), 8.37 - 8.46 (m, /=5.6 Hz, 2 H); HPLC purity (Method 1 : 97%, Method 2: 97%); HRMS: calcd for C ₂ ]Hi ₇ N ₃ O ₂ S + H+, 376.1114; found (ESI-FTMS, [M+H]l+), 376.1111. Example 127

3-{[l-(3'-methoxybiphenyI-3-yl)ethyl]amino}-4-(pyridin-4- ylamino)cyclobut-3-ene-1,2- dione

Utilizing the method of Example 113, 3-(l-(3-bromophenyl)ethylamino)-4-(pyridin-4- ylamino)cyclobut-3-ene-1,2-dione (100 mg, 0.27 mmol) and 3-methoxyphenylboronic acid (62 mg, 1.5 eq) were converted to the title compound (72 mg, 67%). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 1.67 (d, /=6.8 Hz, 3 H), 3.83 (s, 3 H), 5.30 - 5.43 (m, 1 H), 6.28 - 6.38 (m, 1 H), 6.96 (dd, /=8.2, 2.4 Hz, 1 H), 7.17 - 7.29 (m, 2 H), 7.36 - 7.47 (m, 4 H), 7.50 (d, /=7.6 Hz, 1 H), 7.61 (d, /=7.3 Hz, 1 H), 7.71 (s, 1 H), 8.35 - 8.47 (m, /=5.6 Hz, 3 H); HPLC purity (Method 1 : 97%, Method 2: 97%); HRMS: calcd for C ₂₄ H ₂₁ N ₃ O ₃ + H+, 400.1656; found (ESI-FTMS, [M+H]l+), 400.1655. Example 128

3-(pyridin-4-ylamino)-4-{[l-(3-pyridin-3-ylphenyl)ethyI]aπi ino}cyclobut-3-ene-1,2-dione Utilizing the method of Example 113, 3-(l-(3-bromophenyl)ethylamino)-4-(pyridin-4- ylamino)cyclobut-3-ene-1,2-dione (100 mg, 0.27 mmol) and pyridine-3-boronic acid (50 mg, 1.5 eq) were converted to the title compound (65 mg, 65%). ¹ H NMR (400 MHz, OMSO-d ₆ ) δ ppm 1.68 (d, /=6.8 Hz, 3 H), 5.35 - 5.45 (m, 1 H), 7.40 - 7.46 (m, 2 H), 7.46 - 7.59 (m, 4 H), 7.68 (d, /=7.8 Hz, 1 H), 7.79 (s, 1 H), 8.07 - 8.14 (m, 1 H), 8.41 (d, /=5.3 Hz, 3 H), 8.59 (dd, /=4.7, 1.6 Hz, 1 H), 8.92 (d, /=1.5 Hz, 1 H); HPLC purity (Method 1: 96%, Method 2: 96%); HRMS: calcd for C ₂₂ H] ₈ N ₄ O ₂ + H+, 371.15025; found (ESI-FTMS, [M+H]l+), 371.1502. Example 129 tert-butyl [3'-(l-{[3,4-dioxo-2-(pyridiii-4-ylainino)cyclobut-1-eιi-1- yl]amino}ethyl)biphenyl- 4-yl] carbamate

Utilizing the method of Example 113, 3-(l-(3-bromophenyl)ethylamino)-4-(pyridin-4- ylamino)cyclobut-3-ene-1,2-dione (100 mg, 0.27 mmol) and 4- butoxycarbonylaminophenylboronic acid (52 mg, 1.5 eq) were converted to the title compound (32 mg, 25%). ¹ H NMR (400 MHz, DMSO-cfc) δ ppm 1.49 (s, 9 H), 1.60 (d, /=6.8 Hz, 3 H),

5.38 (dd, /=8.6, 6.8 Hz, 1 H), 7.34 - 7.40 (m, 1 H), 7.42 (t, J=I.1 Hz, 1 H), 7.50 - 7.59 (m, 5 H), 7.59 - 7.65 (m, 2 H), 7.73 (s, 1 H), 8.34 - 8.41 (m, ./=6.3 Hz, 2 H), 9.46 (s, 1 H), 9.95 (d, /=8.6 Hz, 1 H); HPLC purity (Method 1 : 98%, Method 2: 98%); HRMS: calcd for C ₂₈ H ₂₈ N ₄ O ₄ + H+, 485.2183; found (ESI-FTMS, [M+H]l+), 485.2186. Example 130

3-{[l-(4-iodophenyl)ethyl]amino}-4-(pyridin-4-ylamino)cyc lobut-3-ene-1,2-dione Step 1: l-(4-iodophenyl)ethanamine

A mixture of 4-Iodoacetophenone (10 g, 41 mmol), formamide (7.32 g, 4 eq), and formic acid (3 mL) was heated at 160 °C for 18h. The cooled solution was diluted with toluene, washed with water, dried, filtered, and evaporated to provide crude N-(l-(4-iodophenyl)ethyl)formamide as a tan solid. This product was suspended in cone. HCl (50 mL) and heated at reflux for 1 h and at RT overnight. The solution was washed with toluene, neutralized with aq. KOH, extracted with ethyl acetate, dried and evaporated to provide the title compound (7.1 g, 70%, 2 steps) as a clear, tan oil. See, e.g., Eur. J. Med. Chem. 2001, 36, 265, which is incorporated by reference in its entirety. ¹ H NMR (400 MHz, chloroform-λ?) δ ppm 1.35 (d, /=6.6 Hz, 3 H), 1.50 (bs, 2 H), 4.07 (q, /=6.6 Hz, 1 H), 7.11 (d, /=8.3 Hz, 2 H), 7.64 (d, /=8.3 Hz, 2 H)

Step 2: 3-{[l-(4-iodophenyl)ethyl]amino}-4-(ρyridin-4-ylamino)cyclo but-3-ene-1,2- dione

Following step 2 of Example 95, 3-ethoxy-4-(pyridin-4-ylamino)cyclobut-3-ene-1,2- dione (2.0 g, 9.2 mmol) and l-(4-iodophenyl)ethanamine (2.50 g, 1.1 eq) were converted to the title compound (1.16 g, 30%) after flash chromatography (silica, ethyl acetate, acetonitrile, methanol, water, 70 / 10 / 5 / 5). ¹ H NMR (400 MHz, DMSO-rfβ) δ ppm 1.57 (d, /=7.1 Hz, 3 H), 5.13 - 5.33 (m, 1 H), 7.23 (d, /=8.3 Hz, 2 H), 7.42 (s, 2 H), 7.76 (d, /=8.1 Hz, 2 H), 8.21 (d, /=7.1 Hz, 1 H), 8.41 (d, /=5.3 Hz, 2 H), 9.83 (s, 1 H); HPLC purity (Method 1: 95%, Method 2: 91%); HRMS: calcd for C ₁₇ H ₁₄ IN ₃ O ₂ + H+, 420.0204; found (ESI-FTMS, [MH-H]I+), 420.0201. Example 131 3-[(l-biphenyl-4-ylethyl)amino]-4-(pyridin-4-ylamino)cyclobu t-3-ene-1,2-dione

Utilizing the method of Example 113, 3-{[l-(4-iodophenyl)ethyl]amino}-4-(pyridin-4- ylamino)cyclobut-3-ene-1,2-dione (75 mg, 0.2 mmol) and phenylboronic acid (33 mg, 1.5 eq ) was converted to the title compound (8 mg, 8%). ¹ H NMR (400 MHz, OMSO-d ₆ ) δ ppm 1.64 (d, /=7.1 Hz, 3 H), 5.28 - 5.51 (m, 1 H), 7.37 (t, /=7.3 Hz, 1 H), 7.42 - 7.55 (m, 6 H), 7.62 - 7.74

(m, /=13.0, 7.7 Hz, 4 H), 8.41 (d, ./=5.8 Hz, 2 H); HPLC purity (Method 1: 98%, Method 2: 98%); HRMS: calcd for C ₂₃ H ₁₉ N ₃ O ₂ + H+, 370.1550; found (ESI-FTMS, [M+H]l+), 370.1551. Example 132

3-({l-[4-(3-furyl)phenyI]ethyl}amino)-4-(pyridin-4-ylamino)c yclobut-3-ene-1,2-dione Utilizing the method of Example 113, 3-{[l-(4-iodophenyl)ethyl]amino}-4-(pyridin-4- ylamino)cyclobut-3-ene-1,2-dione (75 mg, 0.2 mmol) and furan-3-boronic acid (30 mg, 1.5 eq ) was converted to the title compound (17 mg, 26%). ¹ H NMR (400 MHz, OMSO-d ₆ ) δ ppm 1.61 (d, /=6.8 Hz, 3 H), 5.23 - 5.38 (m, 1 H), 6.96 (d, /=1.0 Hz, 1 H), 7.36 - 7.49 (m, 4 H), 7.64 (d, /=8.1 Hz, 2 H), 7.74 (t, /=1.6 Hz, 1 H), 8.19 (s, 1 H), 8.41 (d, /=5.8 Hz, 2 H), 8.49 (d, /=7.8 Hz, 1 H); HPLC purity (Method 1: 98%, Method 2: 99%); HRMS: calcd for C _2I H _n N ₃ O ₃ + H+, 360.1343; found (ESI-FTMS, [M+H]l+), 360.1345. Example 133

3-{[l-(3'-aminobiphenyl-4-yl)ethy]]amino}-4-(pyridin-4-ylani ino)cyclobut-3-ene-1,2-dione Utilizing the method of Example 113, 3-{[l-(4-iodophenyl)ethyl]amino}-4-(pyridin-4- ylamino)cyclobut-3-ene-1,2-dione (75 mg, 0.2 mmol) and 3-aminophenylboronic acid (42 mg, 1.5 eq ) was converted to the title compound (23 mg, 43%). ¹ H NMR (400 MHz, OMSO-d ₆ ) δ ppm 1.63 (d, /=6.8 Hz, 3 H), 5.27 - 5.41 (m, 1 H), 6.53 - 6.60 (m, 1 H), 6.77 (d, /=7.6 Hz, 1 H), 6.82 (t, /=1.9 Hz, 1 H), 7.09 (t, /=7.8 Hz, 1 H), 7.39 - 7.53 (m, 4 H), 7.53 - 7.63 (m, 2 H), 8.35 - 8.53 (m, 3 H); HPLC purity (Method 1 : 98%, Method 2: 96%); HRMS: calcd for C ₂₃ H ₂₀ N ₄ O ₂ + H+, 385.1659; found (ESI-FTMS ₁ [M+H]l+), 385.1659. Example 134

3-{[l-(4'-chIorobiphenyl-4-yl)ethyl]araino}-4-(pyridin-4-yla mino)cyclobut-3-ene-1,2-dione Utilizing the method of Example 113, 3-{[l-(4-iodophenyl)ethyl]amino}-4-(pyridin-4- ylamino)cyclobut-3-ene-1,2-dione (75 mg, 0.2 mmol) and 4-chlorophenylboronic acid (42 mg, 1.5 eq ) was converted to the title compound (12 mg, 17%). ¹ H NMR (400 MHz, σ>MSO-d ₆ ) δ ppm 1.62 (d, /=7.1 Hz, 3 H), 5.32 - 5.46 (m, 1 H), 7.44 - 7.56 (m, 6 H), 7.69 (dd, /=8.5, 2.1 Hz, 4 H), 8.39 (d, /=5.6 Hz, 2 H), 9.20 (d, /=4.3 Hz, 1 H); HPLC purity (Method 1 : 97%, Method 2: 97%); HRMS: calcd for C ₂₃ Hi ₈ ClN ₃ O ₂ + H ⁺ , 404.1161; found (ESI-FTMS, [MH-H]I+), 404.1171. Example 135

3-(pyridin-4-ylamino)-4-({l-[4-(3-thienyI)phenyI]ethyl}am ino)cycIobut-3-ene-1,2-dione

Utilizing the method of Example 113, 3-{[l-(4-iodophenyl)emyl]amino}-4-(pyridin-4- ylamino)cyclobut-3-ene-1,2-dione (75 mg, 0.2 mmol) and thiophene-3-boronic acid (28 mg, 1.5 eq ) was converted to the title compound (24 mg, 36%). ¹ H NMR (400 MHz, OMSO-d ₆ ) δ ppm 1.62 (d, /=6.8 Hz, 3 H), 5.26 - 5.40 (m, 1 H), 7.40 - 7.50 (m, /=8.3 Hz, 4 H), 7.56 (dd, /=5.1, 1.3 Hz, 1 H), 7.64 (dd, /=5.1, 3.0 Hz, 1 H), 7.74 (d, /=8.3 Hz, 2 H), 7.87 (dd, /=2.9, 1.4 Hz, 1 H), 8.41 (d, /=5.8 Hz, 2 H), 8.53 (d, /=7.1 Hz, 1 H); HPLC purity (Method 1 : 98%, Method 2: 98%); HRMS: calcd for C ₂ ]Hi ₇ N ₃ O ₂ S + H ⁺ , 376.1114; found (ESI-FTMS, [M+H]l+), 376.1117. Example 136 N ² -P^-dioxo-1-φyridin-^ylaminoJcyclobut-1-eii-1-ylJ-L-leucin amide The mixture of 3-ethoxy-4-(pyridin-4-ylamino)-cyclobut-3-ene-1,2-dione (104 mg, 0.48 mmole), L-leucinamide hydrochloride (119 mg, 0.71 mmole, 1.5 eq) and Et ₃ N (99 μL, 0.71 mmole, 1.5 eq) was refluxed in EtOH (5 mL) overnight. The solid resulting after EtOH was removed was washed with water and ethyl ether to give the title compound (40 mg, 27%) as a yellow solid. ¹ H NMR (400 MHz, MeOD) δ ppm 0.91 (d, /=3.8 Hz, 6 H) 1.52 - 1.76 (m, /=2.8 Hz, 3 H) 7.47 (s, 2 H) 8.32 (d, 2 H); HPLC purity (Method 1: 100%, Method 2: 100%); HRMS: calcd for C ₁₅ Hi ₈ N ₄ O ₃ + H+, 303.14517; found (ESI-FTMS, [M+H] ¹⁺ ), 303.1456. Example 137 N ² -β^-dioxo-1-føyridin-^ylamnoJcyclobut-1-en-1-yll-L-alan in amide

The title compound was prepared as illustrated by Example 136, but using L- alanineamide hydrochloride. The precipitated solid was filtered and washed with EtOH and ethyl ether to give the product (84 mg, 68%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-rf _tf ) δ ppm 1.40 (d, /=6.6 Hz, 3 H) 4.70 (d, /=6.1 Hz, 1 H) 7.17 - 7.58 (m, 3 H) 7.81 (s, 1 H) 8.15 - 8.56 (m, 3 H) 10.27 (s, 1 H); HPLC purity (Method 1 : 100%, Method 2: 100%); HRMS: calcd for C ₁₂ Hi ₂ N ₄ O ₃ + H+, 261.09822; found (ESI-FTMS, [M+H] ¹⁺ ), 261.0986. Example 138

2-{[3,4-dioxo-2-(pyridin-4-yIamino)cyclobut-1-en-1-yl]ami no}-2-(3-methyl-2- thienyl)acetamide

The title compound was prepared as illustrated by Example 136, but using 2-amino-2-(3- methylthiophen-2-yl)acetonitrile. Purification by chromatography (silica, EtOAc:CH ₃ CN : MeOH : H ₂ O, 70:10:5:5) and further trituration with EtOAc afforded the product (41 mg, 24%) as a brown solid. ¹ H NMR (400 MHz, DMSO-<4) δ ppm 2.31 (s, 3 H) 6.06 (d, /=8.6 Hz, 1 H)

6.86 (d, /=5.3 Hz, 1 H) 7.33 - 7.49 (m, 3 H) 7.51 (s, 1 H) 7.98 (s, 1 H) 8.42 (d, /=6.3 Hz, 2 H) 8.66 (d, J=8.8 Hz, 1 H) 10.21 (s, 1 H); HPLC purity (Method 1: 98%, Method 2: 95%); HRMS: calcd for C ₁₆ Hi ₄ N ₄ O ₃ S + H+, 343.08594; found (ESI-FT/MS, [MH-H] ¹⁺ ), 343.0859. Example 139 2-{[3,4-dioxo-2-(pyridin-4-ylamino)cyclobut-1-en-1-yl]amino} -2-(3-furyl)acetamide

The title compound was prepared as illustrated by Example 136, but using 2-amino-2- (furan-3-yl)acetamide hydrochloride. Purification by chromatography (silica, EtOAc:CH ₃ CN : MeOH : H ₂ O, 70:10:5:5) and further trituration with EtOAc afforded the product (45 mg, 31%) as a brown solid. ¹ H NMR (400 MHz, DMS0-<4) δ ppm 5.77 (none, 1 H) 6.50 (s, 1 H) 7.38 - 7.57 (m, 3 H) 7.59 - 7.78 (m, 2 H) 8.02 (s, 1 H) 8.42 (s, 2 H) 8.62 (s, 1 H) 10.28 (s, 1 H); HPLC purity (Method 1 : 98%, Method 2: 99%); HRMS: calcd for C ₁₅ Hi ₂ N ₄ O ₄ + H+, 313.09313; found (ESI-FT/MS, [M+H] ¹⁺ ), 313.0935. Example 140 7V ² -[3,4-dioxo-2-(pyridin-4-ylamino)cyclobut-1-eii-1-yl]-L-seri namide 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. ¹ H NMR (400 MHz, DMSO-rf<s) δ ppm 3.60 - 3.82 (m, 2 H) 4.55 - 4.78 (m, 1 H) 5.21 (s, 1 H) 7.36 (s, 1 H) 7.40 - 7.56 (m, 2 H) 7.74 (s, 1 H) 8.31 (d, ./=8.1 Hz, 1 H) 8.41 (d, J=6.3 Hz, 2 H) 10.40 (s, 1 H); HRMS: calcd for C ₁₂ Hi ₂ N ₄ O ₄ + H+, 277.09313; found (ESI-FTMS, [MH-H] ¹⁺ ), 277.0933. Example 141 J-ffl^^-^ydroxymethylJpyrrolidiii-1-yll^-^yridin-4-ylaininoJ cyclobut-S-ene-l^-dione

To a microwave vial was added 3-ethoxy-4-(pyridin-4-ylamino)-cyclobut-3-ene-1,2- dione (100 mg, 0.5 mmole), 95% EtOH (5 mL) and (s)-(+)- 2-pyrrolidinemethanol (68 μL, 1.5 eq). The mixture was heated at 125 °C in microwave reactor for 30 min. The precipitated solid at rt was filtered and washed by ethyl ether to give the product (80 mg, 64%) as a yellow solid. ¹ H NMR (400 MHz, MeOD) δ ppm 1.82 (s, 1 H) 1.96 - 2.36 (m, 3 H) 3.56 - 4.07 (m, 3 H) 4.23 - 4.58 (m, 2 H) 7.46 (dd, XS-, 1.52 Hz, 2 H) 8.39 (d, /=6.6 Hz, 2 H); HPLC purity (Method 1: 100%, Method 2: 96%); HRMS: calcd for C ₁₄ Hi ₅ N ₃ O ₃ + H+, 274.11862; found (ESI-FTMS, [M+H] ¹⁺ ), 274.1188. Example 142

S-^-methylpyrrolidin-1-yl^-tøyridin-4-ylamiiioJcyclobut- S-ene-l^-dioiie

The title compound was prepared as illustrated by Example 141, but using 2- methylpyrrolidine to afford 60 mg, 51% as a yellow solid. ¹ H NMR (400 MHz, MeOD) δ ppm 0.98 - 1.39 (m, 4 H) 1.44 - 2.27 (m, 4 H) 3.56 - 4.10 (m, /=94.0 Hz, 2 H) 4.28 - 4.58 (m, 1 H) 7.12 - 7.45 (m, 2 H) 8.04 - 8.38 (m, 2 H); HPLC purity (Method 1: 100%, Method 2: 100%); HRMS: calcd for C ₁₄ Hi ₅ N ₃ O ₂ + H+, 258.12370; found (ESI-FTMS, [M+H] ¹⁺ ), 258.1235; Example 143

S-ll-OiydroxymethylJpiperidin-1-yll^-φyridin-^ylaminoJcyclo but-S-ene-ljl-dione The title compound was prepared as illustrated by Example 141, but using 2- hydroxymethylpiperidine. Purification by chromatography (silica, 10-14% MeOHZCH ₂ Cl ₂ ) afforded the product (50 mg, 38%) as a yellow solid. ¹ H NMR (400 MHz, MeOD) δ ppm 1.41 - 1.91 (m, 6 H) 3.12 - 3.29 (m, 3 H) 3.52 (d, /=7.6 Hz, 1 H) 3.87 - 4.09 (m, 1 H) 7.17 (d, /=6.6 Hz, 2 H) 8.20 (dd, /=5.1, 1.5 Hz, 2 H); HPLC purity (Method 1: 100%, Method 2: 100%); HRMS: calcd for C ₁₅ H _n N ₃ O ₃ + H+, 288.13427; found (ESI-FTMS, [M+H] ¹⁺ ), 288.1343. Example 144

3-(2-methylpiperidin-1-yl)-4-(pyridin-4-ylamino)cyclobut- 3-ene-1,2-dione

The title compound was prepared as illustrated by Example 141, but using 2- methylpiperidine. Purification by chromatography (silica, 10-12% MeOH/CH ₂ Cl ₂ ) afforded the product (77 mg, 62%) as a yellow solid. ¹ H NMR (400 MHz, MeOD) δ ppm 1.20 - 1.35 (m, 3 H) 1.47 - 1.96 (m, 6 H) 3.15 - 3.24 (m, 3 H) 3.27 - 3.49 (m, 1 H) 6.99 - 7.23 (m, 2 H) 8.18 (d,

/=4.6 Hz, 2 H); HPLC purity (Method 1: 99%, Method 2: 99%); HRMS: calcd for C ₁₅ H _n N ₃ O ₂ + H+, 272.13935; found (ESI-FTMS, [M+H] ¹⁴ ), 272.1392. Example 145 l-flS^-dioxo-1-φyridin-^ylaminoJcyclobut-1-en-1-yllaminoJ-1 -P-thienylJacetamide The title compound was prepared as illustrated by Example 136, but using 2-(3- thienyl)acetamide. Purification (RP-HPLC, CH ₃ CN/H ₂ O/0.1% formic acid) afforded the product (13.2 mg, 7%) as a yellow solid. ¹ H NMR (400 MHz, MeOD) δ ppm 5.94 (s, 1 H) 7.12 (dd, /=5.1, 1.3 Hz, 1 H) 7.37 (dd, /=5.1, 3.0 Hz, 1 H) 7.42 - 7.53 (m, 3 H) 8.27 (d, /=5.6 Hz, 2 H) 8.46 (s, 1 H); HPLC purity (Method 1: 91%, Method 2: 90%); HRMS: calcd for C ₁₅ Hi ₂ N ₄ O ₃ S + H+, 329.07029; found (ESI-FTMS, [M+H] ¹⁺ ), 329.0703. Example 146

S-φyridin-4-ylamino^-Kl-pyridin-4-ylethylJaminolcyclobut -S-ene-l^-dione

Step 1: To a microwave vial was added 4-acetylpyridine ( 1.9 g, lO mmoles), 95% EtOH (15 mL), hydroxylamine hydrochloride (1.0 g, 15 mmoles, 1.5 eq) and 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. ¹ H NMR (400 MHz, MeOD) δ ppm 1.57 (d, /=7.1 Hz, 3 H) 5.22 - 5.41 (m, 1 H) 7.28 - 7.51 (m, 4 H) 8.26 (dd, /=4.8, 1.5 Hz, 2 H) 8.39 - 8.51 (m, 2 H); HPLC purity (Method 1: 100%, Method 2: 100%); HRMS: calcd for C ₁₆ H ₁₄ N ₄ O ₂ + H+, 295.11895; found (ESI-FTMS, [M+H] ¹⁺ ), 295.1188. Example 147

3-{[l-(l-benzofuran-2-yl)ethyI]amino}-4-(pyridin-4-yIamin o)cyclobut-3-ene-1,2-dione Step 1: The oxime was prepared according to Step 1 of Example 146, but using 1- benzofuran-2-yl-ethylamine as the starting material.

Step 2: The amine intermediate was prepared according to Step 2 of Example 146. Step 3: The title compound was prepared as illustrated by Example 141. Purification by chromatography (silica, 2-6% MeOH/CH ₂ Cl ₂ ) afforded the product (210 mg g, 88%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-<2 ₅ ) δ ppm 1.71 (d, J=IA Hz, 3 H) 5.42 - 5.65 (m, 1 H) 6.92 (s, 1 H) 7.18 - 7.38 (m, 2 H) 7.43 (d, ./=5.6 Hz, 2 H) 7.61 (dd, ./=21.1, 7.7 Hz, 2 H) 8.42 (d, /=6.1 Hz, 3 H) 9.76 - 9.93 (m, 1 H); HPLC purity (Method 1: 97%, Method 2: 99%); HRMS: calcd for C ₁₉ Hi ₅ N ₃ O ₃ + H+, 334.11862; found (ESI-FTMS, [M+H] ¹⁺ ), 334.119. Example 148 3-{[l-(4-morpholin-4-ylphenyl)ethyl]amino}-4-(pyridin-4-ylam ino)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 θ to afford the product (160 mg 86%) as a yellow solid. ¹ H NMR (400 MHz, OMSO-d ₆ ) δ ppm 1.57 (d, /=6.8 Hz, 3 H) 3.09 (d, ./=4.3 Hz, 4 H) 3.56 - 3.91 (m, 4 H) 5.05 - 5.35 (m, 1 H) 6.97 (d, /=8.3 Hz, 2 H) 7.28 (d, /=8.3 Hz, 2 H) 7.36 - 7.59 (m, 2 H) 8.13 (s, 1 H) 8.41 (s, 2 H) 9.81 (s, 1 H); HPLC purity (Method 1: 100%, Method 2: 100%); HRMS: calcd for C ₂ ]H ₂₂ N ₄ O ₃ + H+, 379.17647; found (ESI-FTMS, [MH-H] ¹⁺ ), 379.1766. Example 149

3-({l-[4-(dimethylamino)phenyl] ethyl} amiπo)-4-(pyridiιi-4-ylainino)cyclobut-3-ene-1,2- dione

Step 1: The oxime was prepared according to Step 1 of Example 146, but using [4-(l- amino-ethyl)-phenyl]-dimethyl-amine as the starting material.

Step 2: The amine intermediate was prepared according to Step 2 of Example 146.

Step 3: The title compound was prepared as illustrated by Example 141. The precipitated solid was filtered, washed with EtOH and Et ₂ O to afford the product (120 mg 78%) as a yellow solid. ¹ H NMR (400 MHz, OMSO-d ₆ ) δ ppm 1.57 (d, /=6.1 Hz, 3 H) 2.88 (s, 6 H) 5.06 - 5.29 (m, 1 H) 6.58 - 6.88 (m, 2 H) 7.23 (d, /=8.1 Hz, 2 H) 7.31 - 7.53 (m, 2 H) 8.11 (s, 1 H) 8.41 (s, 2 H) 9.63 - 9.95 (m, 1 H); HPLC purity (Method 1: 100%, Method 2: 100%); HRMS: calcd for C ₁₉ H ₂₀ N ₄ O ₂ + H+, 337.16590; found (ESI-FTMS, [M+H] ¹⁺ ), 337.1657. Example 150

3-[(l-cyclohexylethyl)amino]-4-(pyridin-4-ylamino)cyclobu t-3-ene-1,2-dione Step 1 : The oxime was prepared according to Step 1 of Example 146, but using 1- cyclohexyl-ethylamine as the starting material.

Step 2: The amine intermediate was prepared according to Step 2 of Example 146.

Step 3: The title compound was prepared as illustrated by Example 141. Purification by chromatography (silica, 5-10% MeOH/CH ₂ Cl ₂ ) afforded the product (120 mg, 87%) as a yellow solid. ¹ H NMR (400 MHz, MeOD) δ ppm 1.08 - 1.52 (m, 8 H) 1.49 - 1.88 (m, 2 H) 1.86 - 2.09

(m, 4 H) 4.12 - 4.40 (m, 1 H) 7.59 - 7.75 (m, 2 H) 8.50 (dd, /=4.9, 1.6 Hz, 2 H); HPLC purity

(Method 1: 100%, Method 2: 94%); HRMS: calcd for C ₁₇ H ₂ )N ₃ O ₂ + H+, 300.17065; found (ESI-

FTMS, [M+H] ¹⁺ ), 300.171.

Example 151

3-[(l-pyrazm-2-ylethyl)ainino]-4-(pyridiii-4-ylamino)cycl obut-3-ene-1,2-dione Step 1 : The oxime was prepared according to Step 1 of Example 146, but l-pyrazin-2-yl- ethylamine was used as the starting material.

Step 2: The amine intermediate was prepared according to Step 2 of Example 146. Step 3: The title compound was prepared as illustrated by Example 141. Purification by chromatography (silica, 10-15% MeOH/CH ₂ Cl ₂ ) afforded the product (58 mg, 52%) as a yellow solid. ¹ H NMR (400 MHz, MeOD) δ ppm 1.69 (d, /=6.8 Hz, 3 H) 5.61 (d, /=6.6 Hz, 1 H) 7.54

(d, /=6.3 Hz, 2 H) 8.36 (dd, /=4.8, 1.52 Hz, 2 H) 8.57 (d, /=2.5 Hz, 1 H) 8.62 - 8.71 (m, 1 H)

8.74 (d, J=1.5 Hz, 1 H); HPLC purity (Method 1: 97%, Method 2: 99%); HRMS: calcd for C ₁₅ Hi ₃ N ₅ O ₂ + H+, 296.11420; found (ESI-FTMS, [MH-H] ¹⁺ ), 296.1142.

Example 152 3-({l-[4-(lff-imidazol-1-yl)phenyl]ethyl}amino)-4-(pyridin-4 -ylamino)cyclobut-3-ene-1,2- dione

Step 1 : The oxime was prepared according to Step 1 of Example 146, but l-(4-imidazol- l-yl-phenyl)-ethylamine was used as the starting material.

Step 2: The amine intermediate was prepared according to Step 2 of Example 146. Steρ 3: The title compound was prepared as illustrated by Example 141. Purification by chromatography (silica, 10-15% MeOH/CH ₂ Cl ₂ ) afforded the product (0.10 g, 73%) as a yellow solid. ¹ H NMR (400 MHz, MeOD) δ ppm 1.79 (d, J=7.1 Hz, 3 H) 5.45 - .71 (m, 1 H) 7.24 (d,

/=1.0 Hz, 1 H) 7.61 (s, 1 H) 7.62 - 7.78 (m, 6 H) 8.13 - 8.29 (m, 1 H) 8.44 (dd, /=4.8, 1.5 Hz, 2

H); HPLC purity (Method 1: 100%, Method 2: 100%); HRMS: calcd for C ₂₀ Hi ₇ N ₅ O ₂ + H+, 360.14550; found (ESI-FTMS, [MH-H] ¹⁺ ), 360.1456.

Example 153

3-(pyridin-4-ylamino)-4-{[l-(3-thienyl)ethyl]ainino}cyclo but-3-ene-1,2-dione

Step 1 : The oxime was prepared according to Step 1 of Example 146, but l-thiophen-3- yl-ethylamine was used as the starting material. Step 2: The amine intermediate was prepared according to Step 2 of Example 146.

Step 3: The title compound was prepared as illustrated by Example 141. Purification by chromatography (silica, 2-10% MeOH/CH ₂ Cl ₂ ) afforded the product (80 mg, 67%) as a yellow solid. ¹ H NMR (400 MHz, MeOD) δ ppm 1.59 (d, J=6.8 Hz, 3 H) 5.30 - 5.50 (m, 1 H) 7.03 - 7.13 (m, 1 H) 7.22 - 7.52 (m, 4 H) 8.26 (d, ./=6.6 Hz, 2 H); HPLC purity (Method 1: 87%, Method 2: 86%); HRMS: calcd for C ₁₅ H ₁₃ N ₃ O ₂ S + H+, 300.08012; found (ESI-FTMS, [M+H] ¹⁺ ), 300.0802; Example 154

3-{[l-(l-methyl-l/r-pyrroI-3-yI)ethyI]amino}-4-(pyridin-4 -ylamino)cyclobut-3-ene-1,2- dione Step 1: The oxime was prepared according to Step 1 of Example 146, but 1-(1-Methyl-

1H-pyrrol-3-yl)-ethylamine was used as the starting material.

Step 2: The amine intermediate was prepared according to Step 2 of Example 146.

Step 3: The title compound was prepared as illustrated by Example 141. Purification by chromatography (silica, 2-10% MeOH/CH ₂ Cl ₂ ) afforded the product (95 mg, 67%) as a yellow solid. ¹ H NMR (400 MHz, MeOD) δ ppm 1.51 (d, J=6.8 Hz, 3 H) 3.52 (s, 3 H) 5.11 - 5.31 (m, 1 H) 5.91 - 6.05 (m, 1 H) 6.43 - 6.68 (m, 2 H) 7.26 - 7.55 (m, 2 H) 8.12 - 8.38 (m, 2 H); HPLC purity (Method 1 : 98%, Method 2: 98%); HRMS: calcd for 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]aπiino}-4-(pyridm-4-ylain ino)cyclobut-3-ene-1,2-dione

Step 1: The oxime was prepared according to Step 1 of Example 146, but l-(3-methyl- pyrazin-2-yl)-ethylamine was used as the starting material.

Step 2: The amine intermediate was prepared according to Step 2 of Example 146.

Step 3: The title compound was prepared as illustrated by Example 141. Purification by chromatography (silica, 3-8% MeOH/CH ₂ Cl ₂ ) afforded the product (70 mg, 47%) as a yellow solid. ¹ H NMR (400 MHz, MeOD) δ ppm 1.74 (d, J=6.6 Hz, 3 H) 2.82 (s, 3 H) 5.79 - 6.03 (m, J=6.6 Hz, 1 H) 7.69 (d, /=5.3 Hz, 2 H) 8.49 (d, J=5.6 Hz, 2 H) 8.56 (d, /=2.0 Hz, 1 H) 8.63 (s, 1 H); HPLC purity (Method 1 : 100%, Method 2: 100%); HRMS: calcd for C ₁₆ H ₁₅ N ₅ O ₂ + H+, 310.12985; found (ESI-FTMS, [M+H] ¹⁺ ), 310.1299. Example 156

3-{[l-(l-benzothien-3-yl)ethyl]amino}-4-(pyridin-4-ylamin o)cyclobut-3-ene-1,2-dione

Step 1 : The oxime was prepared according to Step 1 of Example 146, but 1- benzo[b]thiophen-3-yl-ethylamine was used as the starting material.

Step 2: The amine intermediate was prepared according to Step 2 of Example 146.

Step 3: The title compound was prepared as illustrated by Example 141. Purification (RP-HPLC, 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) δ ppm 2.00 (d, /=6.9 Hz, 3 H) 5.86 - 6.11 (m, 1 H) 7.48 - 7.64 (m, 2 H) 7.71 - 7.81 (m, 2 H) 7.84 (s, 1 H) 8.00 - 8.13 (m, 2 H) 8.30 - 8.42 (m, 2 H) 8.46 - 8.60 (m, 2 H); HPLC purity (Method 1: 100%, Method 2: 99%); HRMS: calcd for C ₁₉ H ₁₅ N ₃ O ₂ S + H+, 350.09577; found (ESI-FTMS, [M+H] ¹⁺ ), 350.0958. Example 157

3-(pyridin-4-ylamino)-4-{[l-(1,3-thiazoI-2-yI)ethyl]amino }cyclobut-3-ene-1,2-dione

Step 1: The oxime was prepared according to Step 1 of Example 146, but l-thiazol-2-yl- ethylamine was used as the starting material.

Step 2: The amine intermediate was prepared according to Step 2 of Example 146. Step 3: The title compound was prepared as illustrated by Example 141. Purification

(RP-HPLC, CH ₃ CN/H ₂ O/0.1% formic acid) afforded the product (52 mg, 38%) as a yellow solid. ¹ H NMR (400 MHz, MeOD) 5 ppm 1.82 (d, /=7.1 Hz, 3 H) 5.66 - 5.89 (m, 1 H) 7.61 (d, /=3.0 Hz, 2 H) 7.66 - 7.94 (m, 2 H) 8.18 - 8.35 (m, 2 H) 8.44 (d, /=6.3 Hz, 2 H); HPLC purity (Method 1 : 100%, Method 2: 99%); HRMS: calcd for C ₁₄ H ₁₂ N ₄ O ₂ S + H+, 301.07537; found (ESI-FTMS, [M+H] ¹⁺ ), 301.0757. Example 158 3-{[l-(3-aminophenyl)ethyl]amino}-4-(pyridin-4-ylainino)cycl obut-3-ene-1,2-dione

Step 1: The oxime was prepared according to Step 1 of Example 146, but 3-(l-amino- ethyl)-phenylamine was used as the starting material. Step 2: The amine intermediate was prepared according to Step 2 of Example 146.

Step 3: The title compound was prepared as illustrated by Example 141. Purification by chromatography (silica, 10-12% MeOH/CH ₂ Cl ₂ ) afforded the product (30 mg, 23%) as a yellow solid.η NMR (400 MHz, MeOD) δ ppm 1.53 (d, /=6.8 Hz, 3 H) 5.09 - 5.32 (m, 1 H) 6.40 - 6.71 (m, /=2.0 Hz, 3 H) 6.86 - 7.13 (m, 1 H) 7.26 - 7.65 (m, 2 H) 8.24 (d, /=6.3 Hz, 2 H); HPLC purity (Method 1 : 98%, Method 2: 100%); HRMS: calcd for C ₁₇ Hi ₆ N ₄ O ₂ + H+, 309.13460; found (ESI-FTMS, [M+H] ¹⁺ ), 309.1348.

Example 159 3-{[l-(2-fluorophenyl)ethyl]amlno}-4-(pyridin-4-ylamino)cycL obut-3-ene-1,2-dione

Step 1: The oxime was prepared according to Step 1 of Example 146, but l-(2-fluoro- phenyl)-ethylamine was used as the starting material. Step 2: The amine intermediate was prepared according to Step 2 of Example 146.

Step 3: The title compound was prepared as illustrated by Example 141. Purification (RP-HPLC, CH ₃ CN/H ₂ O/0.1% formic acid) afforded the product (72 mg, 56%) as a yellow solid. ¹ H NMR (400 MHz, MeOD) δ ppm 1.66 (d, /=6.8 Hz, 3 H) 5.56 - 5.71 (m, 1 H) 7.04 - 7.27 (m, 2 H) 7.26 - 7.38 (m, 1 H) 7.38 - 7.53 (m, /=1.8 Hz, 1 H) 7.66 (d, /=4.6 Hz, 2 H) 8.07 - 8.25 (m, 2 H) 8.36 (d, /=6.3 Hz, 2 H); HPLC purity (Method 1: 100%, Method 2: 100%); HRMS: calcd for C ₁₇ H ₁₄ FN ₃ O ₂ + H+, 312.11428; found (ESI-FTMS, [M+H] ^ϊ+ ), 312.1141. Example 160 3-{[l-(2-hydroxyphenyl)ethyl]amino}-4-(pyridin-4-ylamino)cyc lobnt-3-ene-1,2-dione

Step 1: The oxime was prepared according to Step 1 of Example 146, but 2-(l-amino- ethyl)-phenol was used as the starting material.

Step 2: The amine intermediate was prepared according to Step 2 of Example 146. Step 3: The title compound was prepared as illustrated by Example 141. Purification (RP-HPLC, CH ₃ CN/H ₂ O/0.1% formic acid) afforded the product (34 mg, 23%) as a yellow solid. ¹ H NMR (400 MHz, MeOD) δ ppm 1.78 (d, /=6.8 Hz, 3 H) 5.55 - 5.76 (m, 1 H) 6.92 (dd, /=8.1, 1.0 Hz, 2 H) 7.22 (d, /=1.5 Hz, 1 H) 7.28 - 7.39 (m, 1 H) 7.72 (d, /=5.6 Hz, 2 H) 8.23 - 8.42 (m, 1 H) 8.46 (d, /=5.6 Hz, 2 H); HPLC purity (Method 1: 100%, Method 2: 100%); HRMS: calcd for C ₁₇ H ₁₅ N ₃ O ₃ + H+, 310.11862; found (ESI-FTMS, [M+H] ¹⁺ ), 310.1189. Example 161

S-tll-flfl-indol-S-yOethyllaminoJ^-φyridin-4-ylaminoJcyc lobut-S-ene-ljσ-dione Step 1: The oxime was prepared according to Step 1 of Example 146, but l-(1H-indol-3- yl)-ethylamine was used as the starting material.

Step 2: The amine intermediate was prepared according to Step 2 of Example 146. Step 3: The title compound was prepared as illustrated by Example 141. Purification (RP-HPLC, CH ₃ CN/H ₂ O/0.1% formic acid) afforded the product (4.3 mg, 3%) as a yellow solid. ¹ H NMR (400 MHz, MeOD) δ ppm 1.74 (d, 3 H) 6.89 - 7.11 (m, 3 H) 7.22 - 7.32 (m, 3 H) 7.44 -

7.59 (m, 4 H); HPLC purity (Method 1: 95%, Method 2: 96%); HRMS: calcd for C ₁₉ Hi ₆ N ₄ O ₂ + H+, 333.13460; found (ESI-FTMS, [M+H] ¹⁺ ), 333.1347. Example 162

3-{[l-(2,6-difluoropheπyI)ethyl]amino}-4-(pyridin-4-yla� �iino)cyclobut-3-ene-1,2-dione Step 1: The oxime was prepared according to Step 1 of Example 146, but 1 -(2,6- difluoro-phenyl)-ethylamine was used as the starting material.

Step 2: The amine intermediate was prepared according to Step 2 of Example 146.

Step 3: The title compound was prepared as illustrated by Example 141. Purification (RP-HPLC, CH ₃ CN/H ₂ O/0.1 % formic acid) afforded the product (92 mg, 61 %) as a yellow solid. ¹ H NMR (400 MHz, MeOD) δ ppm 1.72 (d, 3 H) 5.78 - 6.10 (m, /=6.8 Hz, 1 H) 6.93 - 7.11 (m, 2 H) 7.29 - 7.46 (m, 1 H) 7.65 - 7.88 (m, /=4.8 Hz, 2 H) 8.19 - 8.30 (m, 2 H) 8.42 (d, ./=6.1 Hz, 2 H); HPLC purity (Method 1 : 100%, Method 2: 100%); HRMS: calcd for C _n Hi ₃ F ₂ N ₃ O ₂ + H+, 330.10486; found (ESI-FTMS, [M+H] ¹⁺ ), 330.1054. Example 163 3-{[l-(3-fluorophenyl)ethyl]amino}-4-(pyridin-4-ylamino)cycl obut-3-ene-1,2-dione

Step 1: The oxime was prepared according to Step 1 of Example 146, but l-(3-Fluoro- phenyl)-ethylamine was used as the starting material.

Step 2: The amine intermediate was prepared according to Step 2 of Example 146.

Step 3: The title compound was prepared as illustrated by Example 141. Purification (RP-HPLC, CH ₃ CN/H ₂ O/0.1 % formic acid) afforded the product (68 mg, 49%) as a yellow solid. ¹ H NMR (400 MHz, MeOD) δ ppm 1.67 (d, /=6.8 Hz, 3 H) 5.32 - 5.52 (m, 1 H) 6.98 - 7.14 (m, 1 H) 7.12 - 7.31 (m, 2 H) 7.33 - 7.49 (m, 1 H) 7.69 - 7.93 (m, 2 H) 8.21 - 8.36 (m, 2 H) 8.41 (d, /=5.8 Hz, 2 H) HPLC purity (Method 1: 100%, Method 2: 100%); HRMS: calcd for C _n Hi ₄ FN ₃ O ₂ + H+, 312.11428; found (ESI-FTMS, [M+H] ¹⁺ ), 312.1144. Example 164

S-^l-fS-hydroxypheny^ethyllaminoJ^-φyridin-4-ylaminoJcyc lobut-S-ene-l^-dione

Step 1: The oxime was prepared according to Step 1 of Example 146, but 3-(l-amino- ethyl)-phenol was used as the starting material.

Step 2: The amine intermediate was prepared according to Step 2 of Example 146. Step 3: The title compound was prepared as illustrated by Example 141. Purification

(RP-HPLC, CH ₃ CN/H ₂ O/0.1 % formic acid) afforded the product (75 mg, 56%) as a white solid.

¹ H NMR (400 MHz, OMSO-d ₆ ) δ ppm 1.56 (d, /=6.8 Hz, 3 H) 5.08 - 5.31 (m, 1 H) 6.70 (dd, /=8.1, 1.8 Hz, 1 H) 6.76 - 6.89 (m, 2 H) 7.19 (t, J=7.8 Hz, 1 H) 7.45 (d, ./=5.8 Hz, 2 H) 8.07 - 8.24 (m, 2 H) 8.41 (d, /=6.1 Hz, 3 H); HPLC purity (Method 1: 100%, Method 2: 100%); HRMS: calcd for C _n H ₁₅ N ₃ O ₃ + H+, 310.11862; found (ESI-FTMS, [M+H] ¹⁺ ), 310.1186. Example 165

3-(pyridin-4-yIamino)-4-({l-[3-(trifluoromethyl)phenyl]et hyl}amino)cyclobut-3-ene-1,2- dione

Step 1 : The oxime was prepared according to Step 1 of Example 146, but l-(3- trifluoromethyl-phenyl)-ethylamine was used as the starting material. Step 2: The amine intermediate was prepared according to Step 2 of Example 146.

Step 3: The title compound was prepared as illustrated by Example 141. Purification (RP-HPLC, CH ₃ CN/H ₂ O/0.1% formic acid) afforded the product (132 mg, 80%) as a yellow solid. ¹ H NMR (400 MHz, MeOD) δ ppm 1.53 (d, /=7.1 Hz, 3 H) 5.25 - 5.44 (m, 1 H) 7.32 - 7.51 (m, 2 H) 7.49 - 7.67 (m, 4 H) 8.07 (s, 2 H) 8.23 (d, /=5.8 Hz, 2 H); HPLC purity (Method 1: 100%, Method 2: 100%); HRMS: calcd for C ₁₈ Hi ₄ F ₃ N ₃ O ₂ + H+, 362.11109; found (ESI-FTMS, [M+H] ¹⁺ ), 362.1114. Example 166

3-[(2-azidopyridin-4-yl)amino]-4-{[(lJf)-1-phenylethyl]amino }cycIobut-3-ene-1,2-dione To a microwave vial was added (R)-3-(2-chloropyridin-4-ylamino)-4-(l- phenylethylamino)cyclobut-3-ene-1,2-dione (1.0 g, 3.1 mmoles), DMF (10 mL), sodium azide (409 mg, 6.3 mmoles, 2.0 eq) and ammonium chloride (202 mg, 3.8 mmoles, 1.2 eq). The mixture was heated at 140 °C in microwave reactor for 2.5 hours. Purification (RP-HPLC, CH ₃ CN/H ₂ O/0.1% formic acid) afforded the product (0.4 g, 35%) as an off-white solid. ¹ H NMR (400 MHz, DMSO-rfβ) δ ppm 1.62 (d, /=6.8 Hz, 3 H) 5.19 - 5.45 (m, 1 H) 7.23 - 7.52 (m, 6 H) 8.04 (s, 1 H) 8.44 - 8.60 (m, 1 H) 9.19 (d, /=7.6 Hz, 1 H) 10.21 - 10.63 (m, 1 H); HPLC purity (Method 1: 96%, Method 2: 96%); HRMS: calcd for C _n Hi ₄ N ₆ O ₂ + H+, 335.12510; found (ESI- FTMS, [M+H] ¹⁺ ), 335.1248. Example 167 3-{[(1R)-1-phenylethyl]amino}-4-{[2-(4-phenyl-lβ-1,2,3-tria zol-1-yl)pyridin-4- yl]amino}cyclobut-3-ene-1,2-dione

To a microwave vial was added 3-[(2-azidopyridin-4-yl)amino]-4- {[(1R)-1- phenylethyl]amino}cyclobut-3-ene-1,2-dione (70 mg, 0.21 mmole), DMF (3 mL), water (1 mL), phenylacetylene (21 mg, 0.21 mmole, 1.0 eq), copper (II) sulfate pentahydrate (0.52 mg, 0.002 mmole, 0.01 eq) and sodium ascorbate (2.1 mg, 0.01 mmole, 0.05 eq). The mixture was heated at 135 °C in microwave reactor for 1 hour. Purification (RP-HPLC, CH ₃ CN/H ₂ O/0.1% formic acid) afforded the product (10 mg, 11%) as an off-white solid. ¹ H NMR (400 MHz, DMSO-<4) δ ppm 2.50 (d, 3 H) 5.24 - 5.47 (m, 1 H) 7.25 - 7.55 (m, 8 H) 7.55 - 7.72 (m, 1 H) 8.04 (d, /=7.3 Hz, 2 H) 8.14 - 8.29 (m, 1 H) 8.34 - 8.54 (m, 1 H) 8.68 - 9.10 (m, 1 H) 9.24 - 9.39 (m, 1 H) 10.60 - 11.20 (m, 1 H); HPLC purity (Method 1 : 100%, Method 2 : 100%); HRMS : calcd for C ₂₅ H ₂₀ N ₆ O ₂ + H+, 437.17205; found (ESI-FTMS, [M+H] ¹⁺ ), 437.1716. Example 168

3-{[2-(4-benzyl- 1H-1,2,3-triazoI-1-yl)pyridin-4-yl]amino}-4-{[(1R)-1-phenyle thyI]amino} cycIobut-3-ene-1,2-dione

The title compound was prepared as illustrated by Example 167, but 3-phenyl-1-propyne was used as the alkyne. Purification (RP-HPLC, CH ₃ CN/H ₂ O/0.1% formic acid) afforded the product (10 mg, 11%) as an off-white solid. ¹ H NMR (400 MHz, MeOD) δ ppm 1.59 (d, /=6.8 Hz, 3 H) 4.04 (s, 2 H) 5.22 - 5.45 (m, 1 H) 7.04 - 7.42 (m, 10 H) 7.51 (s, 1 H) 8.03 (s, 1 H) 8.19 (d, /=5.6 Hz, 1 H) 8.29 (s, 1 H) 8.48 (s, 1 H); HPLC purity (Method 1: 100%, Method 2: 100%); HRMS: calcd for C ₂₆ H ₂₂ N ₆ O ₂ + H+, 451.18770; found (ESI-FTMS, [M+H] ¹⁺ ), 451.1871. Example 169

3-({2-[4-(hydroxymethyl)-l£r-1,2,3-triazol-1-yl]pyridin- 4-yl}amino)-4-{[(1R)-1- phenylethyl]amino}cyclobut-3-ene-1,2-dione

The title compound was prepared as illustrated by Example 167, but propargyl alcohol was used as the alkyne. Purification (RP-HPLC, CH ₃ CN/H ₂ O/0.1% formic acid) afforded the product (1.6 mg, 2%) as a yellow solid. ¹ H NMR (400 MHz, MeOD) δ ppm 1.68 (d, /=6.8 Hz, 3 H) 4.59 (s, 2 H) 5.34 - 5.50 (m, 1 H) 7.24 - 7.48 (m, 4 H) 7.65 (s, 1 H) 8.16 (s, 1 H) 8.35 (s, 1 H) 8.59 (d, /=32.3 Hz, 2 H); HPLC purity (Method 1 : 93%, Method 2: 93%); HRMS: calcd for C ₂₀ Hi ₈ N ₆ O ₃ + H+, 391.15132; found (ESI-FTMS, [M+H] ¹⁺ ), 391.1511. Example 170 3-{[l-(3-methylpheπyl)ethyl]amino}-4-(pyridin-4-ylamino)cyc lobut-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. ¹ H NMR (400 MHz, MeOD) δ ppm 1.85 (d, 3 H) 2.48 - 2.65 (m, 3 H) 5.50 - 5.68 (m, /=6.6 Hz, 1 H) 7.33 (d, /=7.3 Hz, 1 H) 7.38 - 7.56 (m, 3 H) 7.93 (s, 2 H) 8.46 (s, 2 H) 8.60 (d, /=6.1 Hz, 2 H); HPLC purity (Method 1 : 100%, Method 2: 100%); HRMS: calcd for C ₈ H ₁₇ N ₃ O ₂ + H+, 308.13935; found (ESI-FTMS, [M+H] ¹⁺ ), 308.1398. Example 171

3-[(l-phenyIethyl)amino]-4-(pyridin-4-ylamino)cyclobut-3- ene-1,2-dione

Step 1 : The oxime was prepared from 3-chloroacetophenone according to Step 1 of Example 146, but using 1-Phenyl-ethylamine as the starting material.

Step 2: The amine intermediate was prepared according to Step 2 of Example 146. Most of aromatic chloride was also reduced to provide major product 1-phenyl-ethylamine and minor l-(3-chloro-phenyl)-ethylamine. They were carried to next reaction without separation.

Step 3: The title compounds were prepared as illustrated in Example 141. Purification and separation (RP-HPLC, CH ₃ CN/H ₂ O/0.1% formic acid) afforded the title compound (60 mg, 40%) as a yellow solid; ¹ H NMR (400 MHz, MeOD) δ ppm 1.51 (d, /=7.1 Hz, 3 H) 5.26 (d, J=6.6 Hz, 1 H) 7.11 - 7.31 (m, 5 H) 7.56 (d, /=3.3 Hz, 2 H) 8.08 (s, 1 H) 8.23 (d, /=6.1 Hz, 3 H); HPLC purity (Method 1: 100%, Method 2: 100%); HRMS: calcd for C _n H ₁₅ N ₃ O ₂ + H+, 294.12370; found (ESI-FTMS, [M+H] ¹⁺ ), 294.1234. Example 172

3-{[l-(3-chlorophenyl)ethyl]amino}-4-(pyridin-4-ylamino)c yclobut-3-ene-1,2-dione Step 1: The oxime was prepared according to Step 1 of Example 146, but using l-(3- chloro-phenyl)-ethylamine as the starting material.

Step 2: The amine intermediate was prepared according to Step 2 of Example 146.

Step 3: The title compound was prepared as illustrated by Example 141. Purification (RP-HPLC, CH ₃ CN/H ₂ O/0.1% formic acid) afforded the product (60 mg, 40%) as a yellow solid. ¹ H NMR (400 MHz, MeOD) δ ppm 1.57 (d, /=7.1 Hz, 3 H) 5.20 - 5.42 (m, /=6.6 Hz, 1 H) 7.18 - 7.59 (m, 6 H) 8.13 - 8.43 (m, /=5.1 Hz, 4 H); HPLC purity (Method 1: 99%, Method 2:

99%); HRMS: calcd for C ₁₇ Hi ₄ ClN ₃ O ₂ + H+, 328.08473; found (ESI-FTMS, [M+H] ¹⁺ ), 328.0846. Example 173

N-[3-(l-{[3,4-dioxo-2-(pyridin-4-ylamino)cyclobut-1-en-1- yl]amino}ethyl)phenyl] methanesulfonamide

Step 1: To a solution of 3-aminoacetophenone (1.0 g, 7.4 mmoles) and 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) δ ppm 1.67 (d, 3 H) 2.94 - 3.05 (m, 3 H) 5.30 - 5.52 (m, 1 H) 7.14 - 7.32 (m, 3 H) 7.32 - 7.44 (m, 2 H) 7.70 (s, 2 H) 8.25 (s, 2 H) 8.40 (d, /=6.1Hz, 2 H); HPLC purity (Method 1: 100%, Method 2: 100%); HRMS: calcd for 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)cycIobut-1-en-1-yl]ami no}ethyl)benzoate

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. ¹ H NMR (400 MHz, MeOD) δ ppm 1.69 (d, 3 H) 3.90 - 3.92 (m, 3 H) 5.40 - 5.60 (m,

/=6.6 Hz, 1 H) 7.53 (t, /=7.7 Hz, 1 H) 7.70 (d, /=7.8 Hz, 3 H) 7.98 (d, /=7.8 Hz, 1 H) 8.12 (s, 1 H) 8.25 (s, 1 H) 8.40 (d, /=6.6 Hz, 2 H); HPLC purity (Method 1: 100%, Method 2: 99%); HRMS: calcd for C ₁₉ H ₁₇ N ₃ O ₄ + H+, 352.12918; found (ESI-FTMS, [M+H] ¹⁺ ), 352.1296. Example 175 TV-IS-fl-fP^-dioso-1-tpyridin-^ylaπiiiioJcyclobut-1-en-1-yl laminoJethyOphenylJacetamide 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. ¹ H NMR (400 MHz, acetic acid-d ₄ ) δ ppm 1.71 (d, /=6.8 Hz, 3 H) 2.20 - 2.30 (m, 3 H) 5.39 - 5.56 (m, 1 H) 7.18 - 7.30 (m, 1 H) 7.37 (t, /=7.9 Hz, 1 H) 7.54 - 7.72 (m, /=22.2 Hz, 2 H) 8.11 (s, 2 H) 8.52 (d, /=7.3 Hz, 2 H); HPLC purity (Method 1: 100%, Method 2: 99%); HRMS: calcd for C ₁₉ Hi ₈ N ₄ O ₃ + H+, 351.14517; found (ESI-FTMS, [M+H] ¹⁺ ), 351.1453. Example 176

3-(l-{[3,4-dioxo-2-(pyridin-4-ylamino)cyclobut-1-eii-1-yl ]ainino}ethyl)benzoic acid

Methyl 3-( 1 - { [3 ,4-dioxo-2-(pyridin-4-ylamino)cyclobut- 1 -en- 1 -yl] amino } ethyl)benzoate (190 mg) was hydrolyzed with 1 NNaOH (1 mL) in MeOH (10 mL) at 60 °C overnight to afford the title compound as a yellow solid. ¹ H NMR (400 MHz, MeOD) δ ppm 1.87 - 1.96 (m, 3 H) 5.60 - 5.78 (m, 1 H) 7.60 - 7.90 (m, 4 H) 8.18 (d, /=7.3 Hz, 1 H) 8.32 (s, 1 H) 8.51 - 8.67 (m, 4 H); HPLC purity (Method 1: 97%, Method 2: 97%); HRMS: calcd for C ₁₈ H ₁₅ N ₃ O ₄ + H+, 338.11353; found (ESI-FTMS, [M+H] ¹⁺ ), 338.1143. Example 177

3-{[l-(3-bromophenyl)ethyl]amino}-4-(pyridin-4-yIainino)c yclobut-3-ene-1,2-dione Step 1 : The oxime was prepared according to Step 1 of Example 146, but using l-(3- bromo-phenyl)-ethylamine as the starting material.

Step 2: The amine intermediate was prepared according to Step 2 of Example 146. Step 3: The title compound was prepared as illustrated by Example 141. Purification (RP-HPLC, CH ₃ CN/H ₂ O/0.1% formic acid) afforded the product (39 mg, 9%) as a yellow solid.'H NMR (400 MHz, DMSO-<f _d ) δ ppm 1.59 (d, /=6.8 Hz, 3 H) 5.20 - 5.41 (m, 1 H) 7.26 - 7.58 (m, 5 H) 7.64 (s, 1 H) 8.24 (s, 1 H) 8.40 (d, /=5.3 Hz, 2 H) 8.89 (s, 1 H); HPLC purity

(Method 1: 98%, Method 2: 99%); HRMS: calcd for C _n H ₁₄ BrN ₃ O ₂ + H+, 372.03421; found (ESI-FTMS, [M+H] ¹⁺ ), 372.0337. Example 178

3-(pyridin-4-ylamino)-4-({l-[3-(2/?-tetrazol-5-yl)phenyl] ethyl}amino)cyclobut-3-ene-1,2- dione

Step 1: The mixture of 3-acetylbenzonitrile (2.0 g, 13.7 mmoles), dibutyltin oxide (341 mg, 1.4 mmoles, 0.1 eq), toluene (50 tnL) and azidotrimethylsilane (3.6 mL, 27.4 mmoles, 2.0 eq) was refluxed overnight. The filtrate was concentrated and solidified from EtOAc to give 1- (3-(2H-tetrazol-5-yl)phenyl)ethanone (0.8 g, 30%) as a yellow solid. Step 2: The oxime was prepared according to Step 1 of Example 146, but using .1-[3-(2H- tetrazol-5-yl)-phenyl]-ethylamine as the starting material.

Step 3: The amine intermediate was prepared according to Step 2 of Example 146, except that the reaction took 10 days.

Step 4: The title compound was prepared as illustrated by Example 141. Purification (RP-HPLC, CH ₃ CN/H ₂ O/0.1 % formic acid) afforded the product (7.5 mg, 5%) as a yellow solid. ¹ H NMR (400 MHz, δ ppm 1.62 (d, /=6.8 Hz, 3 H) 5.24 - 5.45 (m, 1 H) 7.22 - 7.44 (m, 2 H) 7.50 (s, 2 H) 7.81 - 7.95 (m, 1 H) 8.04 (s, 1 H) 8.28 (s, 2 H) 8.39 (s, 2 H) 9.16 (s, 1 H); HPLC purity (Method 1: 93%, Method 2: 93%); HRMS: calcd for C ₁₈ H ₁₅ N ₇ O ₂ + H+, 362.13600; found (ESI-FTMS, [M+H] ¹⁴ ), 362.1359. Example 179

S-fl-JIS^-dioxo-1-φyridm^-ylaminoJcyclobnt-1-en-1-yllami noJethylJbenzamide

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

(RP-HPLC, CH ₃ CN/H ₂ O/0.1% formic acid) afforded the product (61 mg, 39%) as an off-white

solid. ¹ H NMR (400 MHz, OMSO-d ₆ ) 6 ppm 1.61 (d, J=6.9Hz, 3 H) 5.24 - 5.46 (m, J=I.3 Hz, 1 H) 7.39 - 7.51 (m, 3 H) 7.57 (d, ./=7.6 Hz, 2 H) 7.81 (d, J=7.6 Hz, 1 H) 7.93 (s, 1 H) 8.04 (s, 1 H) 8.18 (s, 1 H) 8.41 (d, ./=6.1 Hz, 2 H) 8.55 (s, 1 H); HPLC purity (Method 1: 96%, Method 2: 100%); HRMS: calcd for C ₁₈ Hi ₆ N ₄ O ₃ + H+, 337.12952; found (ESI-FTMS, [M+H] ¹⁺ ), 337.1294. Example 180

3-{[l-(5-hydroxy-2-methoxyphenyl)ethyl]amino}-4-(pyridin- 4-ylainino)cyclobut-3-ene-1,2- dione

Step 1 : The oxime was prepared according to Step 1 of Example 146, but using 4-(l- Amino-ethyl)-3-methoxy-phenol as the starting material.

Step 2: The amine intermediate was prepared according to Step 2 of Example 146.

Step 3: The title compound was prepared as illustrated by Example 141. Purification (RP-HPLC, CH ₃ CN/H ₂ O/0.1% formic acid) afforded the product (110 mg, 68%) as a yellow solid. ¹ H NMR (400 MHz, DMS0-rf«) δ ppm 1.50 (d, /=6.8 Hz, 3 H) 3.68 - 3.79 (m, 3 H) 5.33 - 5.57 (m, 1 H) 6.66 (dd, /=8.7, 2.9 Hz, 1 H) 6.76 (d, J=2.8 Hz, 1 H) 6.86 (d, J=8.8 Hz, 1 H) 7.47 (d, J=5.8 Hz, 2 H) 8.21 (s, 1 H) 8.40 (d, J=6.1 Hz, 2 H) 8.46 (d, J=8.3 Hz, 1 H); HPLC purity (Method 1: 99%, Method 2: 100%); HRMS: calcd for C ₁₈ H ₁₇ N ₃ O ₄ + H+, 340.12918; found (ESI- FTMS, [M+H] ¹⁺ ), 340.1295. Example 181 3-{[l-(3-hydroxy-4-methoxyphenyl)ethyl]amino}-4-(pyridin-4-y lamino)cyclobut-3-ene-1,2- dione

Step 1: The mixture of 3,4-dihydroxyacetophenone (406 mg, 2.7 mmoles), lithium carbonate (493 mg, 6.7 mmoles, 2.5 eq), iodomethane (0.4 mL, 6.7 mmoles, 2.5 eq) and DMF (7 mL) was heated at 55 °C for 1 day. Purification by chromatography (silica, 20-40% EtOAc/hexanes) afforded l-(3-hydroxy-4-methoxyphenyl)ethanone (0.2 g, 45%) as a white solid.

Step 2: The oxime was prepared according to Step 1 of Example 146, but using 5-(l- amino-ethyl)-2-methoxy-phenol as the starting material.

Step 3: The amine intermediate was prepared according to Step 2 of Example 146. Step 4: The title compound was prepared as illustrated by Example 141. Purification

(RP-HPLC, CH ₃ CN/H ₂ O/0.1% formic acid) afforded the product (83 mg, 54%) as a lightly

yellow solid. ¹ H NMR (400 MHz, DMSO-tf _« ,) ^' δ ppm 1.54 (d, /=6.8 Hz, 3 H) 3.70 - 3.80 (m, 4

H) 5.00 - 5.28 (m, 1 H) 6.76 - 6.87 (m, 2 H) 6.92 (d, /=8.1 Hz, 1 H) 7.47 (d, /=5.1 Hz, 2 H) 8.19

(s, 1 H) 8.40 (d, /=5.6 Hz, 2 H) 8.62 (d, /=8.1 Hz, 1 H) HPLC purity (Method 1: 100%, Method

2: 100%); HRMS: calcd for C ₁₈ H _n N ₃ O ₄ + H+, 340.12918; found (ESI-FTMS, [M+H] ¹⁺ ), 340.1287.

Example 182

3-{[l-(2,5-dihydroxyphenyl)ethyI]amino}-4-(pyridin-4-ylam ino)cyclobut-3-ene-1,2-dione Step 1 : The oxime was prepared according to Step 1 of Example 146, but using 2-(l - amino-ethyl)-benzene-1,4-diol as the starting material. Step 2: The amine intermediate was prepared according to Step 2 of Example 146.

Step 3: The title compound was prepared as illustrated by Example 141. Purification

(RP-HPLC, CH ₃ CN/H ₂ O/0.1% formic acid) afforded the product (18 mg, 11%) as a lightly yellow solid. ¹ H NMR (400 MHz, MeOD) δ ppm 1.68 (d, /=6.8 Hz, 3 H) 5.43 - 5.61 (m, /=6.6

Hz, 1 H) 6.51 - 6.79 (m, 3 H) 7.61 - 7.76 (m, 2 H) 8.16 - 8.46 (m, /=56.3 Hz, 6 H); HPLC purity (Method 1: 97%, Method 2: 99%); HRMS: calcd for C ₁₇ H ₁₅ N ₃ O ₄ + H+, 326.11353; found (ESI-

FTMS, [M+H] ¹⁺ ), 326.1133.

Example 183

3-{[l-(3,5-dihydroxyphenyl)ethyl]ammo}-4-(pyridin-4-ylami no)cycIobut-3-ene-1,2-dione

Step 1: The oxime was prepared according to Step 1 of Example 146, but using 5-(l- amino-ethyl)-benzene-1,3-diol as the starting material.

Step 2: The amine intermediate was prepared according to Step 2 of Example 146. Step 3: The title compound was prepared as illustrated by Example 141. Purification

(RP-HPLC, CH ₃ CN/H ₂ O/0.1% formic acid) afforded the product (96 mg, 64%) as a lightly yellow solid. ¹ H NMR (400 MHz, MeOD) δ ppm 1.63 (d, /=7.1 Hz, 3 H) 5.16 - 5.37 (m, 1 H) 6.22 (s, 1 H) 6.36 (d, /=1.8 Hz, 2 H) 7.56 - 7.81 (m, 2 H) 8.11 - 8.26 (m, 3 H) 8.41 (d, /=5.3 Hz,

2 H); HPLC purity (Method 1: 100%, Method 2: 100%); HRMS: calcd for C _n Hi ₅ N ₃ O ₄ + H+,

326.11353; found (ESI-FTMS, [M+H] ¹⁺ ), 326.1134.

Example 184

3-{[l-(3-hydroxy-5-methoxyphenyl)ethyl]amino}-4-(pyridin- 4-ylamino)cyclobut-3-ene-1,2- dione

Step 1: l-(3-hydroxy-5-methoxyphenyi)ethanone was prepared according to Step 1 of Example 181.

Step 2: The oxime was prepared according to Step 1 of Example 146, but using 3-(l- amino-ethyl)-5-methoxy-phenol as the starting material. Step 3: The amine intermediate was prepared according to Step 2 of Example 146.

Step 4: The title compound was prepared as illustrated by Example 141. Purification (RP-HPLC, 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) δ ppm 1.64 (d, /=6.9 Hz, 3 H) 3.77 (s, 3 H) 5.16 - 5.48 (m, /=1.0 Hz, 1 H) 6.32 (s, 1 H) 6.47 (d, /=10.9 Hz, 2 H) 7.69 (s, 2 H) 8.23 (s, 2 H) 8.40 (d, /=5.8Hz, 2 H); HPLC purity (Method 1: 100%, Method 2: 100%); HRMS: calcd for C ₁₈ Hi ₇ N ₃ O ₄

+ H+, 340.12918; found (ESI-FTMS, [M+H] ¹⁺ ), 340.1289. Example 185

N-^-(l-fP^-dioxo-σ-fpyridin-^ylamino^ycIobut-1-eii-1-ylJ aininoJethylJphenylJ-TV- methylurca Step 1: The mixture of 3-aminoacetophenone (1.0 g, 7.4 mmoles), Hunig's base (1.5 mL,

8.9 mmoles, 1.2 eq) and methyl isocyanate (0.5 g, 8.8 mmoles, 1.2 eq) in CH ₂ CI ₂ (10 mL) was stirred for 3 hours. The precipitated solid was filtered, washed with CH ₂ CI2 and ether to give 1- (3-acetylphenyl)-3-methylurea (365 mg, 26%) as a white solid.

Step 2: The oxime was prepared according to Step 1 of Example 146, but using l-[3-(l- amino-ethyl)-phenyl]-3-methyl-urea as the starting material.

Step 3: The amine intermediate was prepared according to Step 2 of Example 146. Step 4: The title compound was prepared as illustrated by Example 141. Purification (RP-HPLC, CH ₃ CNZH ₂ O with 10 mM NH ₄ OAc) afforded the product (27 mg, 16%) as a pale yellow solid. ¹ H NMR (400 MHz, DMSO-<4) δ ppm 1.56 (d, /=6.8 Hz, 3 H) 1.85 (s, 2 H) 2.63 (d, /=4.6 Hz, 3 H) 5.12 - 5.37 (m, /=6.8 Hz, 1 H) 6.03 (s, 1 H) 6.86 - 7.02 (m, 1 H) 7.22 (t, /=7.9 Hz, 1 H) 7.30 - 7.46 (m, 2 H) 7.46 - 7.57 (m, 2 H) 8.38 (d, /=5.8 Hz, 2 H) 8.59 (s, 1 H); HPLC purity (Method 1: 100%, Method 2: 97%); HRMS: calcd for C ₁₉ Hi ₉ N ₅ O ₃ + H+, 366.15607; found (ESI-FTMS, [M+H] ¹⁺ ), 366.1562. Example 186 3-{[l-(3-amino-4-methylphenyl)ethyl]amino}-4-(pyridin-4-ylam ino)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. ¹ H NMR (400 MHz, MeOD) δ ppm 1.96 (d, 3 H) 2.16 (s, 3 H) 5.15 - 5.41 (m, 1 H) 6.70 (dd, /=7.8, 1.8 Hz, 1 H) 6.79 (d, /=1.8 Hz, 1 H) 7.03 (d, J=I.6 Hz, 1 H) 7.57 (s, 2 H) 8.36 (s, 2 H); HPLC purity (Method 1: 93%, Method 2: 93%); HRMS: calcd for C ₁₈ H ₁₈ N ₄ O ₂ + H+, 323.15025; found (ESI-FTMS, [M+H] ¹⁺ ), 323.1502. Example 187

3-{[l-(4-methyI-3-nitrophenyl)ethyl]amino}-4-(pyridin-4-y lamino)cycIobut-3-ene-1,2-dione

Step 1 : The oxime was prepared according to Step 1 of Example 146, but using l-(4- methyl-3-m ^' tro-phenyl)-ethylamine as the starting material.

Step 2: The amine intermediate was prepared according to Step 2 of Example 146. Step 3: The title compound was prepared as illustrated by Example 141. Purification

(RP-HPLC, CH ₃ CN/H ₂ O with 10 mM NH ₄ OAc) afforded the product (97.8 mg, 60%) as a pale yellow solid. ¹ H NMR (400 MHz, DMSO-<4) δ ppm 1.62 (d, J=6λ Hz, 3 H) 2.50 (s, 3 H) 5.19 - 5.47 (m, 1 H) 7.41 (s, 2 H) 7.46 - 7.58 (m, 1 H) 7.62 - 7.78 (m, 1 H) 8.02 (s, 1 H) 8.15 - 8.60 (m, 3 H) 9.86 (s, 1 H); HPLC purity (Method 1: 100%, Method 2: 100%); HRMS: calcd for C ₁₈ Hi ₆ N ₄ O ₄ + H+, 353.12443; found (ESI-FTMS, [M+H] ¹⁺ ), 353.1247. Example 188

3-{[l-(3-hydroxy-4-methylphenyl)ethyl]amino}-4-(pyridin-4 -yIamino)cyclobut-3-ene-1,2- dione

Step 1 : Diazotisation of l-(3-amino-4-methylphenyi)ethanone (0.5 g, 3.4 mmoles) with 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) δ ppm 1.65 (d, /=6.6 Hz, 3 H) 2.18 (s, 3 H) 5.16 - 5.42 (m, 1 H) 6.73 - 6.90 (m, 2 H) 7.10 (d, ./=7.6 Hz, 1 H) 7.60 - 7.77 (m, 2 H) 8.05 - 8.30 (m, 2 H) 8.34 - 8.49 (m, 2 H); HPLC purity (Method 1 : 100%, Method 2: 100%); HRMS: calcd for C ₁₈ H _n N ₃ O ₃ + H+, 324.13427; found (ESI-FTMS, [M+H] ¹⁺ ), 324.1343. Example 189

3-({2-[(E)-2-(4-chlorophenyl)vinyl]pyridin-4-yl}amino)-4-{[( 1R)-1- phenylethy]]amino}cyclobut-3-ene-1,2-dione To a reaction vessel was added 3-[(2-chloropyridin-4-yl)amino]-4-{[(1R)-1- phenylethyl]amino}cyclobut-3-ene-1,2-dione (0.09 g, 0.27 mmol), Pd(dppf)Cl ₂ :CH ₂ Cl ₂ (0.022 g, 0.01 eq), cesium carbonate (0.27g, 2 eq) and trans-2-(4-chloropheny)vinyl boronic acid (0.075 g, 1.5 eq). The vessel as evacuated and purged with nitrogen 3x. DMF (degassed, 0.6 mL) is then added. The reaction as stirred at 100 °C overnight, filtered and taken up in THF. The solution was then adsorbed onto silica. Chromatography (silica, 25% THF/CH ₂ C1 ₂ ) afforded the title compound (0.06g, 51%) as a pale yellow solid. ¹ H NMR (400 MHz, DMSO-J ₆ ) δ ppm 1.62 (d, ./=6.8 Hz, 3 H), 5.26 - 5.37 (m, 1 H), 7.26 (d, /=15.9 Hz, 1 H), 7.30 - 7.49 (m, 9 H), 7.63 (d, /=16.2 Hz, 1 H), 7.70 (d, /=8.6 Hz, 1 H), 8.25 (d, /=9.9 Hz, 1 H), 8.42 (d, /=5.6 Hz, 1 H), 9.90 (s, 1 H); ); HPLC purity (Method 1: 100%, Method 2: 97%); HRMS: calcd for C ₂₅ H ₂₀ ClN ₃ O ₂ + H+, 430.13168; found (ESI-FTMS, [M+H]l+), 430.1329. Example 190

3-{[2-(3-methoxyphenyl)pyridin-4-yl]amino}-4-{[(1R)-1-phe nylethyl]amino}cycIobut-3-ene- 1,2-dione

The title compound was prepared as outlined by Example 189, but using 3- methoxyphenylboronic acid as the boronic acid, to afford 0.39 g, 36% as a yellow solid. ¹ H

NMR (400 MHz, DMSO-^ ₆ ) δ ppm 1.62 (d, /=6.6 Hz, 4 H), 3.83 (s, 3 H), 5.25 - 5.39 (m, 1 H),

7.02 (d, /=8.1 Hz, 1 H), 7.24 (d, /=5.1 Hz, 1 H), 7.28 - 7.69 (m, 8 H), 8.17 (s, 1 H), 8.30 (d, /=9.3 Hz, 1 H), 8.50 (d, /=5.3 Hz, 2 H), 9.99 (s, 1 H); ); HPLC purity (Method 1: 99%, Method 2: 98%); HRMS: calcd for C24H21N3O3 + H+, 400.16557; found (ESI-FTMS, [M+H]l+), 400.1661. Example 191

3-[(2-anilinopyridin-4-yI)amino]-4-{[(1R)-1-phenylethyl]a inino}cycIobut-3-ene-1,2-dione

To a reaction vessel was added of 3-[(2-chloropvridin-4-yl)amino]-4-{[(1R)-1- phenylethyl]amino}cyclobut-3-ene-1,2-dione (O.lg, 0.3 mmol), Pd ₂ (dba) ₃ (0.028 g, 0.031 mmol), XPHOS (0.044 g, 0.09 mmol), sodium tert-butoxide (0.06g, 0.63 mmol) and aniline (0.034 g, 0.36 mmol). The vessel was evacuated and purged with nitrogen 3x. Dioxane

(degassed, 1 mL) and DMF (degassed, 0.2 mL) was then added. The reaction was stirred at 100 °C overnight, filtered through a plug of silica and concentrated. Purification (RP-HPLC, CH ₃ CN/H ₂ O/0.1% formic acid) afforded the title compound (0.03g, 17%) as an off white solid. ¹ H NMR (400 MHz, DMSCW ₆ ) δ ppm 1.60 (d, /=6.8 Hz, 3 H), 5.25 - 5.36 (m, 1 H), 6.74 (s, 1 H), 6.88 (app t, /=7.3 Hz, 1 H), 7.00 (d, /=4.5 Hz, 1 H), 7.23 (d, /=8.3 Hz, 2 H), 7.25 - 7.27 (m, 1 H), 7.28 - 7.46 (m, 10 H), 7.62 (dd, /=8.6, 1.0 Hz, 2 H), 8.02 (d, /=5.6 Hz, 1 H), 8.27 (d, /=8.1 Hz, 1 H), 8.96 (s, 1 H), 9.78 (s, 1 H); HPLC purity (Method 1 : 97%, Method 2: 97%); HRMS: calcd for C ₂₃ H ₂₀ N ₄ O ₂ + H+, 385.16590; found (ESI-FTMS, [M+H]l+), 385.1664. Example 192 3-{[(1R)-1-phenyIethyl]amino}-4-[(2-{[4-(trifluoromethyl)phe nyl]amino}pyridiii-4- yl)amino]cyclobut-3-ene-1,2-dione

The title compound was prepared as illustrated by Example 191, but using 4- (trifluoromethyl)aniline, to afford 0.04 g, 29% as an off white powder. ¹ H NMR (400 MHz, DMSO-J ₆ ) δ ppm 1.61 (d, /=7.1 Hz, 3 H), 5.26 - 5.36 (m, 1 H), 6.87 (s, 1 H), 7.06 (d, /=6.1 Hz, 1 H), 7.28 - 7.46 (m, 6 H), 7.57 (d, /=8.6 Hz, 2 H), 7.88 (d, /=8.3 Hz, 2 H), 8.09 (d, /=5.6 Hz, 1 H), 8.45 (d, /=6.8 Hz, 1 H), 9.47 (s, 1 H), 10.00 (s, 1 H)HPLC purity (Method 1 : 99%, Method 2: 99%); HRMS: calcd for C ₂₄ Hi ₉ F ₃ N ₄ O ₂ + H+, 453.15329; found (ESI-FTMS, [M+H]l+), 453.1535. Example 193 3-{[(1R)-1-phenylethyl]amino}-4-{[2-(pyrimidin-4-ylaimno)pyr idin-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. ¹ H NMR (400 MHz, DMSCW ₆ ) δ ppm 1.60 (d, /=7.1 Hz, 3 H), 5.26 - 5.37 (m, 1 H), 7.28 - 7.35 (m, 1 H), 7.37 - 7.46 (m, 4 H), 7.52 (d, ./=4.0 Hz, 1 H), 7.58 - 7.65 (m, 2 H), 8.17 (d, /=5.6 Hz, 1 H), 8.40 (d, /=6.1 Hz, 1 H), 8.65 (d, /=6.6 Hz, 1 H), 8.70 (d, /=1.0 Hz, 1 H), 10.23 (s, 1 H), 10.32 (s, 1 H); HPLC purity (Method 1: 99%, Method 2: 99%); HRMS: calcd for C _2I Hi ₈ N ₆ O ₂ + H+, 387.15640; found (ESI-FTMS, [M+H]l+), 387.1561. Example 194 3-[(2-{[3-(hydroxymethyl)phenyl]amino}pyridin-4-yI)amino]-4- {[(1R)-1- phenylethyl]amino}cyclobut-3-ene-1,2-dione

The title compound was prepared as illustrated by Example 191, but using 3- (hydroxymethyl)aniline, to afford 0.003 g, 3% as an off white powder. ¹ H NMR (400 MHz, DMSO-4) δ ppm 1.60 (d, /=7.1 Hz, 3 H), 4.46 (d, /=2.3 Hz, 2 H), 5.12 (s, 1 H), 5.26 - 5.36 (m, 1 H), 6.75 (s, 1 H), 6.83 (d, /=7.6 Hz, 1 H), 7.03 (d, /=5.1 Hz, 1 H), 7.18 (dd, /=8.8, 7.6 Hz, 1 H), 7.28 - 7.34 (m, 1 H), 7.37 - 7.46 (m, 4 H), 7.51 - 7.57 (m, 2 H), 8.02 (d, /=5.8 Hz, 1 H), 8.54 (d, /=7.6 Hz, 1 H), 8.95 (s, 1 H), 10.03 (s, 1 H); HPLC purity (Method 1: 100%, Method 2: 100%); HRMS: calcd for C ₂₄ H ₂₂ N ₄ O ₃ + H+, 415.17647; found (ESI-FTMS, [M+H]l+), 415.1766. Example 195 3-({4-[(3,4-dioxo-2-{[(1R)-1-phenylethy]]amino}cyclobut-1-en -1-yl)amino]pyridin-2- y]}amino)benzamide

The title compound was prepared as illustrated by Example 191, but using 3- aminobenzamide, to afford 0.025 g, 19% as an off white powder. ¹ H NMR (400 MHz, DMSO- ck) δ ppm 1.60 (d, /=7.1 Hz, 3 H), 5.26 - 5.35 (m, 1 H), 6.74 (d, /=1.3 Hz, 1 H), 7.05 (d, /=5.6 Hz, 1 H), 7.25 - 7.46 (m, 9 H), 7.84 - 7.90 (m, 2 H), 7.99 - 8.02 (m, 1 H), 8.04 (d, /=5.8 Hz, 1 H), 8.37 (d, /=10.6 Hz, 1 H), 9.13 (s, 1 H), 9.89 (s, 1 H); HPLC purity (Method 1: 100%, Method 2: 100%); HRMS: calcd for C ₂₄ HuN ₅ O ₃ + H+, 428.17172; found (ESI-FTMS, [M+H]l+), 428.1723. Example 196 S-JKl^-1-phenylethyllaminoJ^-iP-Opyridin-1-ylaminoJpyridin-4 -yllaminoϊcyclobut-S- ene-1,2-dione

The title compound was prepared as illustrated by Example 191, but using 2- aminopyridine, to afford 0.02 g, 17% as an off white powder. ¹ H NMR (400 MHz, DMSO-4) δ ppm 1.60 (d, /=6.8 Hz, 3 H), 5.25 - 5.35 (m, 1 H), 6.86 (ddd, /=4.8, 2.3, 1.0 Hz, 1 H), 7.27 - 7.48 (m, 5 H), 7.54 (d, /=8.3 Hz, 1 H), 7.62 (d, /=1.8 Hz, 1 H), 7.63 - 7.65 (m, 1 H), 7.66 (d, /=2.0 Hz, 1 H), 8.10 (d, /=5.8 Hz, 1 H), 8.15 (s, 1 H), 8.21 (ddd, /=5.1, 2.0, 0.8 Hz, 1 H), 8.31 (d, /=8.3 Hz, 1 H), 9.69 (s, 1 H), 9.92 (s, 1 H); HPLC purity (Method 1: 99.6%, Method 2: 97%); HRMS: calcd for C ₂₂ H ₁₉ N ₅ O ₂ + H+, 386.16115; found (ESI-FTMS, [M+H]l+), 386.1618. Example 197 S-fK1R^l-phenylethyllaminof^-fP-φyridin-S-ylaminoipyridin-4 -yllaininoJcydobut-S- ene-1,2-dione

The title compound was prepared as illustrated by Example 191, but using 3- aminopyridine, to afford 0.032 g, 27% as an off white powder. ¹ H NMR (400 MHz, DMSCW ₆ ) δ ppm 1.61 (d, /=6.8 Hz, 3 H), 5.26 - 5.35 (m, 1 H), 6.82 (s, 1 H), 6.99 (d, /=4.5 Hz, 1 H), 7.26 (dd, /=8.3, 4.8 Hz, 1 H), 7.29 - 7.47 (m, 8 H), 8.05 (d, /=5.6 Hz, 1 H), 8.08 (dd, /=4.7, 1.4 Hz, 1 H), 8.18 (ddd, /=8.4, 2.5, 1.3 Hz, 1 H), 8.26 (d, /=8.3 Hz, 1 H), 8.77 (d, /=2.5 Hz, 1 H), 9.20 (s, 1 H), 9.81 (s, 1 H); HPLC purity (Method 1: 99%, Method 2: 99%); HRMS: calcd for C ₂₂ Hi ₉ N ₅ O ₂ + H+, 386.16115; found (ESI-FTMS, [M+H]l+), 386.1618. Example 198 3-{[(1R)-1-phenylethyl]amino}-4-{[2-(pyrazin-2-ylamino)pyrid in-4-yI]amino}cyclobut-3- ene-1,2-dione

The title compound was prepared as illustrated in Example 191, but using 2- aminopyrazine, to afford 0.022 g, 19% as an off white powder. ¹ H NMR (400 MHz, DMSO-^ ₆ ) δ ppm 1.61 (d, /=6.8 Hz, 3 H), 5.25 - 5.35 (m, 1 H), 7.29 - 7.50 (m, 6 H), 7.61 (d, /=2.0 Hz, 1 H), 8.07 (d, /=2.8 Hz, 1 H), 8.16 (d, /=5.8 Hz, 1 H), 8.21 (dd, /=2.8, 1.5 Hz, 1 H), 8.25 (d, /=8.3 Hz, 1 H), 8.89 (d, /=1.3 Hz, 1 H), 9.91 (s, 1 H), 10.09 (s, 1 H); HPLC purity (Method 1: 95%, Method 2: 95%); HRMS: calcd for C ₂ iHi ₈ N ₆ O ₂ + H+, 387.15640; found (ESI-FTMS, [M+H]l+), 387.1564. Example 199 N-(4-(2-((R)-1-phenyIethylamino)-3,4-dioxocyclobut-1-enylamm o)pyridin-2-yl)acetamide A reaction vessel containing 3-[(2-chloroρyridm-4-yl)amino]-4-{[(1R)-1- phenylethyl]amino}cyclobut-3-ene-1,2-dione (0.1 g, 0.3 mmol), acetamide (0.08 g, 1.4 mmol),

Pd ₂ dba (0.04 g, 0.04 mmol), XPHOS (0.04 g, 0.08 mmol) and cesium carbonate (0.2 g, 0.62mmol) was purged with nitrogen. Dioxane:DMF (1.2 mL, 5:1, degassed) was then added. The reaction was stirred under microwave irradiation at 150 °C for 2h. The reaction mixture was filtered through a plug of silica (1% triethylamine/ 10%MeOH/ CH ₂ CI ₂ ) and concentrated. Purfication by RP-HPLC (CH ₃ CN/H ₂ O) afforded the title compound as an off white solid (0.02 g, 19%). ¹ H NMR (400 MHz, DMSCW ₆ ) δ ppm 1.59 (d, /=6.8 Hz, 3 H), 5.21 - 5.34 (m, 1 H), 7.25 - 7.47 (m, 5 H), 7.64 (d, /=3.3 Hz, 1 H), 7.81 (s, 1 H), 8.17 (d, /=6.1 Hz, 1 H), 8.34 (s, 1 H), 10.13 (s, 1 H), 10.62 (s, 1 H); HPLC purity (Method 1: 97%, Method 2: 98%); HRMS: calcd for C ₁₉ Hi ₈ N ₄ O ₃ + H+, 351.14517; found (ESI-FTMS, [M+H]l+), 351.1453. Example 200

N-{4-[(3,4-dioxo-2-{[(1R)-1-phenylethyl]amino}cydobut-1-e n-1-yl)amino]pyridin-2- yl}benzamide

A reaction vessel containing 3-[(2-chloropyridin-4-yl)amino]-4-{[(1R)-1- phenylethyl]amino}cyclobut-3-ene-1,2-dione (O.lg, 0.3 mmol), benzamide (0.07 g, 0.6 mmol), Pd ₂ dba (0.28 g, 0.03 mmol), XantPHOS (0.036 g, 0.06 mmol) and potassium carbonate (tribasic, fluka brand, 0.12 g, 0.57 mmol) was purged with nitrogen. Dioxane:DMF (1.2 mL, 5:1, degassed) was then added. The reaction was stirred under microwave irradiation at 150 °C for 2h. The reaction mixture was filtered through aplug of silica (1% triethylamine/ 10%MeOH/ 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 %). ¹ H NMR (400 MHz, DMSO-^ ₆ ) δ ppm 1.61 (d, /=6.8 Hz, 3 H), 5.26 - 5.35 (m, 1 H), 7.29 - 7.63 (m, 9 H), 7.67 (d, /=5.6 Hz, 1 H), 7.98 - 8.05 (m, 2 H), 8.25 (d, /=5.6 Hz, 1 H), 8.32 (d, /=8.3 Hz, 1 H), 10.15 (s, 1 H), 10.77 (s, 1 H)); HRMS: calcd for C ₂₄ H ₂₀ N ₄ O ₃ + H+, 413.16082; found (ESI-FTMS, [M+H]l+), 413.1614. Example 201 N-{4-[(3,4-dioxo-2-{[(1R)-1-phenylethyl]ainino}cyclobut-1-ei i-1-yl)aιnino]pyridin-2- yljnicolinamide

The title compound was prepared as illustrated by Example 200, but using nicotinamide, to afford 0.028 g, 22 % as an off white powder. ¹ H NMR (400 MHz, OMSO-d ₆ ) δ ppm 1.61 (d, /=6.82 Hz, 3 H) 5.28 - 5.34 (m, 1 H) 7.29 - 7.46 (m, 5 H) 7.54 (ddd, /=7.89, 4.86, 0.88 Hz, 1 H) 7.68 (d, /=4.29 Hz, 1 H) 8.03 (d, J=I .77 Hz, 1 H) 8.27 (d, /=5.56 Hz, 1 H) 8.33 (ddd, /=8.08, 2.02, 1.77 Hz, 1 H) 8.75 (dd, /=4.80, 1.52 Hz, 1 H) 9.12 (dd, /=2.27, 0.76 Hz, 1 H) 10.13 (s, 1

H) 11.08 (s, 1 H) HPLC purity (Method 1 : 100%, Method 2: 100%); HRMS: calcd for C ₂₃ Hi ₉ N ₅ O ₃ + H+, 414.15607; found (ESI-FTMS, [M+H]l+), 414.1562. Example 202

2-(l-phenylethyl)-6-pyridin-4-yl-2,6-diazabicyclo[5.2.0]non- l(7)-ene-8,9-dione A reaction vessel containing 2-(l-phenylethyl)-6-pyridin-4-yl-2,6- diazabicyclo[5.2.0]non-l(7)-ene-8,9-dione (0.07g, 0.27 mmol), CuI (0.024g, 0.2 mmol), and potassium carbonate (tribasic, fluka brand, 0.23 g, 1.1 mmol) was purged with nitrogen. DMF (1 mL, degassed) and N-N'-dimethylethylenediamine (0.026 mL, 0.35 mmol) was added and the reaction was stirred at 105 ^C C for 3h. The reaction mixture was filtered (Celite ^® ) and concentrated. Purification by RP-HPLC (CH ₃ CN/H ₂ O) afforded the title compound (0.033 g, 36%) as an off white solid. ¹ H NMR (400 MHz, DMSO-^ ₆ ) δ ppm 1.67 (d, /=7.1 Hz, 3 H), 1.93 - 2.14 (m, 2 H), 2.94 - 3.03 (m, 1 H), 3.42 - 3.51 (m, 1 H), 3.84 - 3.90 (m, 2 H), 6.13 (q, /=7.0 Hz, 1 H), 7.23 (dd, /=4.8, 1.5 Hz, 2 H), 7.42 (d, /=1.5 Hz, 2 H), 7.43 - 7.46 (m, 3 H), 8.50 (d, /=5.3 Hz, 2 H); HPLC purity (Method 1 : 98%, Method 2: 99%). Example 203

3-{[(1R)-1-phenylethyl]amino}-4-[(2-phenylpyridin-4-yl)am ino]cyclobut-3-ene-1,2-dione

To a reaction vessel was added (R)-3-ammo-4-(l-phenylethylamino)cyclobut-3-ene-1,2- dione (0.103, 0.48 mmol), 4-bromo-2-phenyl pyridine (0.112 g, 1.0 eq), K ₂ HPO ₄ (0.171 g, 2.05 eq), CuI (0.094 g, 1.03 eq) andN,N-dimethylethane-1,2-diamine (0.16 mL, 0.132 mg, 1.5 eq). The vessel was evacuated and purged with nitrogen twice. DMF (degassed, 2 mL) was then added. The reaction was stirred at 110 °C for 6.5 hours, filtered through a Celite ^® plug and taken up in THF. The solution was then adsorbed onto silica. Chromatography (silica, 5% MeOH-95% CH ₂ Cl ₂ ) afforded the title compound (0.046 g, 32%) as a pale orange powder solid. ¹ H NMR (400 MHz, DMSCW ₆ ) δ ppm 1.62 (d, /=7.07 Hz, 3 H) 5.08 - 5.47 (m, 1 H) 7.17 - 7.27 (m, 1 H) 7.28 - 7.58 (m, 8 H) 8.00 - 8.10 (m, 3 H) 8.20 - 8.35 (m, 1 H) 8.50 (d, /=5.56 Hz, 1 H) 9.94 (s, 1 H); HPLC purity (Method 1: 99%, Method 2: 99%); HRMS: calcd for C ₂₃ Hi ₉ N ₃ O ₂ + H+, 370.15500; found (ESI-FTMS, [M+H]l+), 370.1562. Example 204 3-{[2-(3-fluorophenyl)pyridin-4-yI]amino}-4-{[(1R)-1-phenyle thyl]aniiiio}cyclobut-3-ene- 1,2-dione

To a reaction vessel was added 3-[(2-chloropyridin-4-yl)ammo]-4-{[(1R)-1- phenylethyl]amino}cyclobut-3-ene-1,2-dione (0.111, 0.34 mmol), 2-Benzofuranboronic acid (0.065 g, 1.2 eq), 0.7 mL 2M Cs ₂ CO ₃ (2.05 eq) and Pd(dppf)Cl ₂ :CH ₂ Cl ₂ (0.033 g, 0.12 eq). The vessel was evacuated and purged with nitrogen twice. DMF (degassed, 4 mL) was then added. The reaction was stirred at 80 °C for 13 hours, filtered through a Celite ^® plug and concentrated to give a crude residue. This material was purified by RP-HPLC (CH ₃ CN-H ₂ O with 0.1% formic acid) to afford 0.012 g (18%) as a light orange solid. ¹ H NMR (400 MHz, DMSO-^ ₆ ) δ ppm 1.62 (d, /=6.82 Hz, 3 H) 5.19 - 5.54 (m, 1 H) 7.21 - 7.36 (m, 3 H) 7.37 - 7.49 (m, 4 H) 7.50 - 7.60 (m, 1 H) 7.78 - 7.86 (m, 1 H) 7.89 (d, ,7=8.08 Hz, 1 H) 8.18 (s, 1 H) 8.30 (s, 1 H) 8.51 (d, /=5.56 Hz, 1 H) 10.01 (s, 1 H); HPLC purity (Method 1: 100%, Method 2: 100%); HRMS: calcd for C ₂₃ Hi ₈ FN ₃ O ₂ + H+, 388.14558; found (ESI-FTMS, [M+H]l+), 388.1453. Example 205

3-{[2-(l-benzofuran-2-yl)pyridin-4-yl]amino}-4-{[(1R)-1-phen ylethyl]amino}cyclobut-3- ene-1,2-dione The title compound was prepared as outlined Example 204, but using benzofuran-2- ylboronic acid, to afford 0.026 g, 13% as a light orange solid. ¹ H NMR (400 MHz, DMSO-^ ₆ ) δ ppm 1.63 (d, /=6.82 Hz, 3 H) 5.11 - 5.43 (m, 1 H) 5.76 (s, 1 H) 7.27 - 7.48 (m, 7 H) 7.52 (s, 1 H) 7.58 - 7.69 (m, 1 H) 7.74 (d, /=7.07 Hz, 1 H) 7.99 (s, 1 H) 8.18 - 8.33 (m, 1 H) 8.51 (d, /=5.56 Hz, 1 H) 10.08 (s, 1 H); HPLC purity (Method 1 : 99%, Method 2: 98%); HRMS: calcd for C ₂₅ H ₁₉ N ₃ O ₃ + H+, 410.14992; found (ESI-FTMS, [M+H]l+), 410.1502. Example 206

3-{[2-(3-fluorophenyl)pyridin-4-yI]amino}-4-{[(1R)-1-phen ylethyl]amino}cyclobut-3-ene- 1,2-dione

The title compound was prepared as outlined for Example 204, but using 3-thiophene boronic acid, to afford 0.032 g (28%) as an off white solid. ¹ H NMR (400 MHz, DMSO-^ ₆ ) δ ppm 1.62 (d, /=6.82 Hz, 3 H) 5.07 - 5.51 (m, 1 H) 7.13 - 7.50 (m, 6 H) 7.67 (d, /=2.02 Hz, 2 H) 7.90 - 8.14 (m, 2 H) 8.27 (d, /=8.34 Hz, 1 H) 8.42 (d, /=5.56 Hz, 1 H) 9.93 (s, 1 H); HPLC purity (Method 1: 99%, Method 2: 99%); HRMS: calcd for C ₂₃ Hi ₈ FN ₃ O ₂ + H+, 388.14558; found (ESI-FTMS, [M+H]l+), 388.1453. Example 207

3-(2,3'-bipyridin-4-ylamino)-4-{[(1R)-1-phenylethyl]amino }cyclobut-3-ene-1,2-dione

The title compound was prepared as outlined for Example 204, but using 3-pyridine boronic acid, to afford 0.026 g (13%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-J ₆ ) δ ppm

1.62 (d, /=6.82 Hz, 3 H) 5.33 (s, 1 H) 7.06 - 7.71 (m, 7 H) 8.00 - 8.75 (m, 5 H) 9.22 (s, 1 H)

10.10 (s, 1 H); HPLC purity (Method 1: 99%, Method 2: 99%); HRMS: calcd for C ₂₂ Hi ₈ N ₄ O ₂ + H+, 371.15025; found (ESI-FTMS, [M+H]l+), 371.1508.

Example 208

3-{[(1R)-1-phenylethyl]amino}-4-({2-[3-(trifluoromethyI)p heπyl]pyridin-4- yl}amino)cycIobut-3-ene-1,2-dione

The title compound was prepared as outlined for Example 204, but using 3- (trifluoromethyl)phenylboronic acid, to afford 0.020 g (10%) as a yellow solid. ¹ H NMR (400

MHz, DMSO-<4) δ ppm 1.62 (d, ./=6.82 Hz, 3 H) 5.15 - 5.47 (m, 1 H) 7.22 - 7.48 (m, 3 H) 7.52 -

7.66 (m, 4 H) 7.72 - 7.86 (m, 2 H) 8.15 - 8.45 (m, 3 H) 8.54 (d, J=5.56 Hz, 1 H) 10.02 (s, 1 H);

HPLC purity (Method 1.: 99%, Method 2: 97%); HRMS: calcd for C ₂₄ Hi ₈ F ₃ N ₃ O ₂ + H+,

438.14239; found (ESI-FTMS, [M+H]l+), 438.1435. Example 209

3-{[(1R)-1-pheπylethyl]amino}-4-({2-[4-(trifluoromethyl) phenyl]pyridin-4- yl}amino)cyclobut-3-ene-1,2-dione

The title compound was prepared as outlined for Example 204, but using 4-

(trifluoromethyl)phenylboronic acid, to afford 0.015 g (8%) as an off white solid. ¹ H NMR (400 MHz, DMSO-^ ₆ ) δ ppm 1.62 (d, /=6.82 Hz, 3 H) 4.99 - 5.70 (m, 1 H) 7.17 - 7.50 (m, 6 H) 7.88

(d, J=8.34 Hz, 2 H) 8.09 - 8.31 (m, 3 H) 8.39 - 8.66 (m, 2 H) 10.22 (s, 1 H); HPLC purity

(Method 1: 98%, Method 2: 98%); HRMS: calcd for C ₂₄ Hi ₈ F ₃ N ₃ O ₂ + H+, 438.14239; found

(ESI-FTMS, [M+H]l+), 438.1433.

Example 210 3-{[(1R)-1-phenylethyl]amino}-4-{[2-(pyridin-4-ylamino)pyrid in-4-yl]amino}cyclobut-3- ene-1,2-dione

To a reaction vessel was added 3-[(2-chloropyridin-4-yl)amino]-4-{[(1R)-1- phenylethyl]amino}cyclobut-3-ene-1,2-dione (0.106 g, 0.32 mmol), Pd ₂ (dba) ₃ (0.030 g, 0.031 mmol), XPHOS (0.044 g, 0.09 mmol), sodium tert-butoxide (0.057g, 0.60 mmol) and 4- aminopyridine (0.034 g, 0.36 mmol). The vessel was evacuated and purged with nitrogen twice.

Dioxane (degassed, 2 mL) and DMF (degassed, 0.2 mL) was then added. The reaction was

microwaved for total of 4,000 sec at 165 °C, filtered through a plug of silica and concentrated. Purification (RP-HPLC, CH ₃ CN/H ₂ O with 0.1% formic acid) afforded the title compound (0.031g, 25%) as an off white solid. HPLC purity (Method 1: 96%, Method 2: 96%); HRMS: calcd for C ₂₂ H] ₉ N ₅ O ₂ + H+, 386.16115; found (ESI-FTMS, [M+H]l+), 386.1619. Example 211

3-({2-[(4-methyl-1,3-thiazol-2-yl)amino]pyridin-4-yl}amin o)-4-{[(1R)-1- phenylethyl]amino}cyclobut-3-ene-1,2-dione

To a reaction vessel was added 3-[(2-chloropyridin-4-yi)amino]-4-{[(1R)-1- phenylethyl]amino}cyclobut-3-ene-1,2-dione (0.104 g, 0.32 mmol), Pd ₂ (dba) ₃ (0.036g, 0.040 mmol), XANTPHOS (0.057 g, 0.10 mmol), sodium carbonate (0.047g, 0.45 mmol) and 4- methylthiazol-2-amine (0.045g, 0.40 mmol). The vessel was evacuated and purged with nitrogen twice. Dioxane (degassed, 2 mL) and DMF (degassed, 0.2 mL) was then added. The reaction was microwaved for total 4,000 sec at 150 °C, filtered through a plug of Celite ^® and concentrated. Purification (RP-HPLC, CH ₃ CNZH ₂ O with 0.1% formic acid) afforded 0.034 g (26%) as a dark yellow solid. ¹ H NMR (400 MHz, DMSO-^ ₆ ) δ ppm 1.60 (d, /=6.82 Hz, 3 H) 2.25 (s, 3 H) 5.15 - 5.48 (m, 1 H) 6.59 (s, 1 H) 6.86 (s, 1 H) 7.23 - 7.54 (m, 7 H) 8.03 - 8.22 (m, 1 H) 8.56 (br. s., 1 H) 10.30 (br. s., 1 H); HPLC purity (Method 1: 96%, Method 2: 94%); HRMS: calcd for C _2I H] ₉ N ₅ O ₂ S + H+, 406.13322; found (ESI-FTMS, [M+H]l+), 406.1347. Example 212 3-{[(1R)-1-phenylethyl]ammo}-4-{[2-(quinolin-2-ylamino)pyrid in-4-yl]ainino}cyclobut-3- ene-1,2-dione

To a reaction vessel was added 3-[(2-chloropyridin-4-yl)amino]-4-{[(1R)-1- phenylethyl]amino}cyclobut-3-ene-1,2-dione (0.107 g, 0.33 mmol), Pd ₂ (dba) ₃ (0.037 g, 0.040 mmol), XANTPHOS (0.056 g, 0.10 mmol), sodium carbonate (0.047 g, 0.45 mmol) and 2- aminoquinoline (0.058 g, 0.40 mmol). The vessel was evacuated and purged with nitrogen twice. Dioxane (degassed, 2 ML) and DMF (degassed, 0.2 ML) was then added. The reaction was microwaved for total of 4,000 sec at 150 °C, filtered through a plug of Celite ^® and concentrated. Purification (RP-HPLC, CH ₃ CNZH ₂ O with 0.1% formic acid) afforded 0.034 g (26%) as an orange solid. ¹ H NMR (400 MHz, OMSO-d _f ) δ ppm 1.61 (d, /=7.1 Hz, 3 H) 5.30 - 5.41 (m, 1 H) 7.28 - 7.55 (m, 9 H) 7.58 - 7.69 (m, 1 H) 7.77 (d, /=8.3 Hz, 1 H) 7.89 (d, /=8.3 Hz, 1 H) 8.09 - 8.17 (m, 2 H) 8.10 - 8.17 (m, 3 H) 8.20 (s, 1 H) 8.44 (d, /=1.8 Hz, 1 H) 8.71 (s, 1 H) 10.03 (s, 1

H) 10.34 (s, 1 H); HPLC purity (Method 1 : 98%, Method 2: 99%); HRMS: calcd for C ₂₆ H _2I N ₅ O ₂ + H+, 436.17680; found (ESI-FTMS, [M+H]l+), 436.1768. Example 213

3-{[(1R)-1-phenylethyl]amino}-4-{[2-(pyrimidin-2-ylamino) pyridin-4-yl]ainiπo}cyc]obut-3- ene-1,2-dione

To a reaction vessel was added 3-[(2-chloropyridin-4-yl)amino]-4-{[(1R)-1- phenylethyl]amino}cyclobut-3-ene-1,2-dione (0.106 g, 0.33 mmol), Pd ₂ (dba) ₃ (0.037 g, 0.040 mmol), XANTPHOS (0.059 g, 0.10 mmol), sodium carbonate (0.047 g, 0.45 mmol) and pyrimidin-2-amine (0.038 g, 0.40 mmol). The vessel was evacuated and purged with nitrogen twice. Dioxane (degassed, 2 rnL) and DMF (degassed, 0.2 niL) was then added. The reaction was microwaved for total 4,000 sec at 150 °C, filtered through a plug of Celite ^® and concentrated. Purification (RP-HPLC, CH ₃ CWH ₂ O with 0.1% formic acid) afforded 0.048 g ( 38%) as an orange solid.η NMR (400 MHz, DMSO-(Z ₆ ) δ ppm 1.60 (d, /=6.8 Hz, 3 H) 5.02 - 5.66 (m, 1 H) 6.97 (t, /=4.8 Hz, 1 H) 7.22 - 7.62 (m, 6 H) 7.93 - 8.29 (m, 2 H) 8.37 (d, /=6.8 Hz, 1 H) 8.56 (d, /=4.8 Hz, 2 H) 9.82 (s, 1 H) 10.07 (s, 1 H); HPLC purity (Method 1 : 99%, Method 2: 99%); HRMS: calcd for C ₂ ]H ₁₈ N ₆ O ₂ + H+, 387.15640; found (ESI-FTMS, [M+H]l+), 387.1563. Example 214

3-{[2-(2-fluorophenyl)pyridin-4-yl]amino}-4-{[(1R)-1-phenyle thyI]amino}cyclobut-3-ene- 1,2-dione To a reaction vessel was added 3-[(2-bromopyridin-4-yl)amino]-4- {[(1R)-1- phenylethyl]amino}cyclobut-3-ene-1,2-dione (0.74 g, 0.20 mmol), 2-fluoroboronic acid (0.036 g, 1.3eq), Na ₂ CO ₃ (0.034 g, 2.05 eq) and Pd(PPh ₃ ) (0.024 g, 0.2eq). 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. ¹ H NMR (400 MHz, DMSO-rf _tf ) δ ppm 1.61 (d, /=7.07 Hz, 3 H) 5.23 - 5.40 (m, 1 H) 7.23 - 7.57 (m, 9 H) 7.78 (s, 1 H) 7.94 (t, /=7.71 Hz, 1 H) 8.27 (s, 1 H) 8.55 (d, /=5.56 Hz, 1 H) 10.01 (s, 1 H); HRMS: calcd for C ₂₃ H ₁₈ FN ₃ O ₂ + H+, 388.14558; found (ESI-FTMS, [M+H]l+), 388.1458. Example 215

3-{[2-(2-furyl)pyridin-4-yl]amino}-4-{[(1R)-1-phenylethyl ]amino}cyclobut-3-ene-1,2-dione

The title compound was prepared as outlined for Example 214, but using furan-2- ylboronic acid, to afford 0.035 g (62%) as a dark yellow solid. ¹ H NMR (400 MHz, OMSO-d ₆ ) δ ppm 1.60 (d, /=6.8 Hz, 3 H) 5.11 - 5.66 (m, 1 H) 6.65 (s, J=LO Hz, 1 H) 7.04 (d, /=2.8 Hz, 1 H) 7.19 - 7.62 (m, 6 H) 7.85 (d, /=4.3 Hz, 2 H) 8.39 (d, /=5.6 Hz, 1 H) 8.83 (s, 1 H) 10.54 (s, 1 H); HPLC purity (Method 1 : 99%, Method 2: 99%); HRMS: calcd for C _2I H _n N ₃ O ₃ + H+, 360.13427; found (ESI-FTMS, [M+H]l+), 360.1343. Example 216

3-{[2-(4-tnethylphenyl)pyridin-4-yl]amino}-4-{[(1R)-1-phenyl ethyl]ainino}cyclobut-3-ene- 1,2-dione The title compound was prepared as outlined for Example 214, but using p-tolylboronic acid, to afford 0.016 g (22%) as a yellow solid. ¹ H NMR (400 MHz, OMSO-d _δ ) δ ppm 1.61 (d, /=6.8 Hz, 3 H) 2.36 (s, 3 H) 4.99 - 5.62 (m, 1 H) 7.16 - 7.51 (m, 9 H) 7.95 (d, /=8.1 Hz, 2 H) 8.46 (d, /=5.6 Hz, 1 H) 8.52 - 8.63 (m, 1 H) 10.23 (s, 1 H); HPLC purity (Method 1: 99%, Method 2: 99%); HRMS: calcd for C ₂₄ H ₂ ]N ₃ O ₂ + H+, 384.17065; found (ESI-FTMS, [M+H]l+), 384.1708. Example 217

N-(4-{4-[(3,4-dioxo-2-{[(1R)-1-phenylethyl]amino}cycIobut -1-en-1-yl)amino]pyridin-2- yl}phenyl)acetamide

The title compound was prepared as outlined for Example 214, but using A- acetamidophenylboronic acid, to afford 0.036 g (42%) as a bright yellow solid. ¹ H NMR (400 MHz, DMSO-rf _tf ) δ ppm 1.61 (d, /=7.1 Hz, 3 H) 2.07 (s, 3 H) 5.27 - 5.41 (m, 1 H) 7.22 - 7.51 (m, 7 H) 7.56 - 7.77 (m, J=I 1.4 Hz, 2 H) 8.06 (s, 1 H) 8.26 - 8.38 (m, 1 H) 8.48 (d, /=5.6 Hz, 1 H) 8.83 (s, 1 H) 10.08 (s, 1 H) 10.52 (s, 1 H); HPLC purity (Method 1: 99%, Method 2: 98%); HRMS: calcd for C ₂₅ H ₂₂ N ₄ O ₃ + H+, 427.17647; found (ESI-FTMS, [M+H]l+), 427.1767. Example 218

3-{[2-(3-methylphenyl)pyridin-4-yl]amino}-4-{[(1R)-1-phen ylethyl]amino}cycIobut-3-ene- 1,2-dione

The title compound was prepared as outlined for Example 214, but using m-tolylboronic acid, to afford 0.023 g (39%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-<4) δ ppm 1.61 (d, /=6.82 Hz, 3 H) 2.39 (s, 3 H) 5.27 - 5.41 (m, 1 H) 7.09 - 7.62 (m, 8 H) 7.83 (d, /=7.83 Hz, 1 H) 7.89 (s, 1 H); 8.32 (s, 1 H) 8.47 (d, /=5.56 Hz, 1 H) 8.88 (s, 1 H) 10.56 (s, 1 H); HPLC purity

(Method 1: 98%, Method 2: 99%); HRMS: calcd for C ₂₄ H ₂ ]N ₃ O ₂ + H+, 384.17065; found (ESI-

FTMS, [M+H]l+), 384.1706.

Example 219

3-(2,4'-bipyridin-4-ylamino)-4-{[(1R)-1-phenylethyl]ainino}c yclobut-3-ene-1,2-dione The title compound was prepared as outlined for Example 214, but using 4-ρyridine boronic acid, to afford 0.008 g (14%) as a brown solid. ¹ H NMR (400 MHz, DMSCW,;) δ ppm

1.61 (d, ./=6.82 Hz, 6 H) 5.18 - 5.44 (m, 1 H) 7.24 - 7.50 (m, 9 H) 7.99 (d, /=6.06 Hz, 2 H) 8.21 -

8.34 (m, 1 H) 8.50 (d, 7=7.83 Hz, 1 H) 8.57 (d, /=5.56 Hz, 1 H) 8.73 (d, /=6.06 Hz, 2 H) 10.20 -

10.36 (m, 1 H); HPLC purity (Method 1 : 99%, Method 2: 92%); HRMS: calcd for C ₂₂ Hi ₈ N ₄ O ₂ + H+, 371.15025; found (ESI-FTMS, [M+H]l+), 371.1502.

Example 220

3-({2-[4-(hydroxymethyl)phenyl]pyridin-4-yl}amino)-4-{[(1 R)-1- phenyIethyl]amino}cyclobut-3-ene-1,2-dione

The title compound was prepared as outlined for Example 214,but using 4- (hydroxymethyl)phenylboronic acid, to afford 0.023 g (30%) as a yellow solid. ¹ H NMR (400

MHz, DMSO-ctø δ ppm 1.60 (d, /=6.82 Hz, 3 H) 4.56 (s, 2 H) 5.03 - 5.55 (m, 2 H) 7.09 - 7.54

(m, 8 H) 8.01 (d, /=8.34 Hz, 2 H) 8.20 (s, 1 H) 8.46 (d, /=5.56 Hz, 1 H) 9.31 (s, 1 H) 10.99 (s, 1

H); HPLC purity (Method 1: 99%, Method 2: 99%); HRMS: calcd for C ₂₄ H ₂ IN ₃ O ₃ + H+,

400.16557; found (ESI-FTMS, [M+H]l+), 400.1656. Example 221

3-({2-[3-(benzyloxy)phenyl]pyridin-4-yl}amino)-4-{[(1R)-l phenyIethyl]amino}cycIobut-3- cne-1,2-diouc

The title compound was prepared as outlined for Example 214, but using 3- benzyloxyphenylboronic acid, to afford 0.045 g (47%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-J ₆ ) δ ppm 1.62 (d, /=6.82 Hz, 3 H) 5.19 (s, 2 H) 5.23 - 5.50 (m, 1 H) 7.09 (dd, /=7.83,

2.53 Hz, 1 H) 7.19 - 7.55 (m, 12 H) 7.63 (d, /=7.58 Hz, 1 H) 7.73 (s, 1 H) 8.17 (s, 1 H) 8.33 (s, 1

H) 8.49 (d, /=5.56 Hz, 1 H) 10.02 (s, 1 H); HPLC purity (Method 1: 99%, Method 2: 99%);

HRMS: calcd for C ₃₀ H ₂₅ N ₃ O ₃ + H+, 476.19687; found (ESI-FTMS, [M+H] 1+), 476.1976.

Example 222 3-[(2-biphenyl-3-yIpyridin-4-yl)amino]-4-{[(1R)-1-phenylethy l]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. ¹ H NMR (400 MHz, DMSO-^ ₆ ) δ ppm 1.62 (d, J=LOl Hz, 3 H) 5.14 - 5.58 (m, 1 H) 7.22 - 7.65 (m, 11 H) 7.75 (d, /=7.33 Hz, 2 H) 8.06 (d, 7=8.08 Hz, 1 H) 8.26 - 8.41 (m, 2 H) 8.53 (d, /=5.56 Hz, 2 H) 10.22 (s, 1 H); HPLC purity (Method 1: 97%, Method 2: 97%); HRMS: calcd for C ₂₉ H ₂₃ N ₃ O ₂ + H+, 446.18630; found (ESI-FTMS, [M+H]l+), 446.1866. Example 223

3-[(2-biphenyl-3-ylpyridin-4-yl)amino]-4-{[(1R)-1-phenyle thyI]ainino}cyclobut-3-ene-1,2- dione The title compound was prepared as outlined for Example 214, but using 3-

(hydroxymethyl)phenylboronic acid, to afford 0.030 g (38%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-«? ₆ ) δ ppm 1.62 (d, J=6.82 Hz, 3 H) 4.58 (d, 7=5.31 Hz, 2 H) 5.08 - 5.49 (m, 2 H) 7.23 - 7.50 (m, 8 H) 7.90 (d, 7=7.58 Hz, 1 H) 8.05 (s, 1 H) 8.37 (s, 1 H) 8.49 (d, 7=5.56 Hz, 1 H) 10.07 (s, 1 H); HPLC purity (Method 1: 98%, Method 2: 97%); HRMS: calcd for C ₂₄ H _2I N ₃ O ₃ + H+, 400.16557; found (ESI-FTMS ₁ [MH-H]I+), 400.1658. Example 224

N-cyclopentyl-4-{4-[(3,4-dioxo-2-{[(1R)-1-phenylethyl]ami no}cyclobut-1-en-1- yI)amino]pyridin-2-yl}benzamide

The title compound was prepared as outlined for Example 214, but using A- (cyclopentylaminocarbonyl)phenylboronic acid, to afford 0.52g (54%) as a yellow solid. ¹ H

NMR (400 MHz, DMSO-rf ₆ ) δ ppm 1.33 - 2.13 (m, 11 H) 4.24 (s, 1 H) 5.34 (d, 7=6.57 Hz, 1 H) 7.20 - 7.51 (m, 6 H) 7.96 (d, 7=8.34 Hz, 2 H) 8.11 (d, 2 H) 8.18 - 8.24 (m, 1 H) 8.21 (s, 1 H) 8.36 (d, 7=7.33 Hz, 1 H) 8.52 (d, 7=5.56 Hz, 2 H) 10.24 (s, 1 H); HRMS: calcd for C ₂₉ H ₂₈ N ₄ O ₃ + H+, 481.22342; found (ESI-FTMS, [M+H]l+), 481.2242. Example 225

3-{[2-(4-chlorophenyl)pyridin-4-yl]amino}-4-{[(1R)-1-phen y]ethyl]ainino}cyclobut-3-ene- 1,2-dione

The title compound was prepared as outlined for Example 214, but using 4- chlorophenylboronic acid, to afford 0.030 g (36%) as an off white solid. ¹ H NMR (400 MHz, DMSO-<4) δ ppm 1.61 (d, 7=6.8 Hz, 3 H) 5.26 - 5.42 (m, 1 H) 7.21 - 7.50 (m, 6 H) 7.57 (d, 7=8.6 Hz, 2 H) 8.06 (d, 7=8.6 Hz, 2 H); 8.16 (s, 1 H) 8.49 (d, 7=5.6 Hz, 2 H) 10.20 (s, 1 H);

HPLC purity (Method 1 : 98%, Method 2: 98%); HRMS: calcd for C ₂₃ H ₁₈ ClN ₃ O ₂ + H+, 404.11603; found (ESI-FTMS, [M+H]l+), 404.1166. Example 226 3-(2,2'-bipyridin-4-ylamino)-4-{[(1R)-1-phenylethyl]amino}cy clobut-3-ene-1,2-dione To a reaction vessel was added 3-[(2-bromopyridin-4-yl)amino]-4-{[(1R)-1- phenylethyl]amino}cyclobut-3-ene-1,2-dione (0.075 g, 0.20 mmol) and Pd(PPh ₃ ) (0.015 g, 0.02 mmol). The vessel was evacuated and purged with nitrogen twice, then dioxane (degassed, 2 mL) and DMF (degassed, 0.2 mL) was then added. Finally 2-(tripropylstannyl)pyridine (0.089 g, 0.24 mmol) was added to the reaction which was microwaved for total of 2,400 sec at 150 °C. Workup consisted of filtering the reaction mixture through a plug of silica and evaporation of the solvent. Purification (RP-HPLC, CH ₃ CN/H ₂ O with 0.1% formic acid) afforded the title compound (0.012g, 16%) as brown solid. ¹ H NMR (400 MHz, DMSO-cfc) δ ppm 1.61 (d, /=6.8 Hz, 3 H) 5.20 - 5.43 (m, /=8.3 Hz, 1 H) 7.23 - 7.53 (m, 6 H) 7.70 (s, 1 H) 7.94 (t, /=6.9 Hz, 1 H) 8.18 (s, 1 H) 8.27 (d, ./=2.0 Hz, 1 H) 8.32 - 8.48 (m, 2 H) 8.53 (d, J=5.6 Hz, 1 H) 8.67 (d, /=4.8 Hz, 1 H) 10.30 (s, 1 H); HPLC purity (Method 1 : 98%, Method 2: 96%); HRMS: calcd for C ₂₂ H ₁₈ N ₄ O ₂ + H+, 371.15025; found (ESI-FTMS, [M+H]l+), 371. Example 227

2-{[3,4-dioxo-2-(pyridin-4-y]amino)cyclobut-1-en-1-yl]ami no}-2-(4-pyridin-3- ylplienyl)acetaπiide To a reaction vessel was added 3-ethoxy-4-(pyridin-4-ylamino)-cyclobut-3-ene-1,2-dione

(0.083 g, 0.38 mmol) and 2-amino-2-(4-(pyridin-3-yl)phenyl) acetamide (0.157 g, 0.38 mmol). The vessel was evacuated and purged with nitrogen, then EtOH (15 mL) was added. The reaction was refluxed at 100 °C overnight. Workup consisted of evaporating the solvent and purifying the crude solid by RP-HPLC (CH ₃ CN-H ₂ O with 0.01% formic acid) to afford 0.075 g (49%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-^ ₆ ) δ ppm 5.91 (d, /=8.1 Hz, 1 H) 7.35 - 7.55 (m, 5 H) 7.62 (s, 1 H) 7.90 (dd, /=8.3 Hz, 1 H) 7.98 - 8.10 (m, 3 H) 8.14 - 8.21 (m, /=6.8 Hz, 1 H) 8.34 - 8.51 (m, 2 H) 8.77 (d, /=2.0 Hz, 1 H) 8.92 (d, /=8.3 Hz, 1 H) 10.29 - 10.47 (m, /=1.3 Hz, 1 H); HPLC purity (Method 1 : 98%, Method 2: 98%); HRMS: calcd for C ₂₂ H _n N ₅ O ₃ + H+, 400.1404; found (ESI-FTMS, [M+H]l+),400.1406. Example 228

2-biphenyl-4-yl-2-{[3,4-dioxo-2-(pyridin-4-ylammo)cyclobu t-1-en-1-yl]amino}acetainide

The title compound was prepared from 2-amino-2-(biphenyl)acetamide as outlined for Example 227. Purification by RP-HPLC (CH3CN-H ₂ O with 0.01% formic acid) to afford 0.251 g (69%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-rf,;) δ ppm 5.87 (d, /=8.3 Hz, 1 H) 7.27 - 7.59 (m, 8 H) 7.67 (dd, /=14.3, 7.7 Hz, 4 H) 8.06 - 8.19 (m, 1 H) 8.42 (dd, /=4.8, 1.5 Hz, 2 H) 8.89 (d, /=8.6 Hz, 1 H) 10.36 (s, 1 H); HPLC purity (Method 1 : 99%, Method 2: 98%); HRMS: calcd for C ₂₃ H ₁₈ N ₄ O ₃ + H+, 399.1452; found (ESI-FTMS, [M+H]l+), 399.1439. Example 229 l-f^bromophenylJ-1-JIS^-dioxo-1-fpyridin-4-ylaminoJcyclobut- 1-en-1-yllaminoJacetainide To a reaction vessel was added 3-ethoxy-4-(pyridin-4-ylamino)-cyclobut-3-ene-1,2-dione (0.605 g, 2.77 mmol) and 2-amino-2-(4-bromophenyl)acetamide (0.635g, 2.77 mmol). The vessel was evacuated and purged with nitrogen, then EtOH (40 mL) as added. The reaction was refluxed at 100 °C overnight. Workup consisted of cooling mixture in an ice bath and filtering solid to give the title compound (0.94Og, 85%) as a yellow solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 5.80 (d, 7=8.1 Hz, 1 H) 7.35 - 7.47 (m, 4 H) 7.55 (s, 1 H) 7.60 (d, /=8.3 Hz, 2 H) 8.09 (s, 1 H) 8.40 (d, /=6.3 Hz, 2 H) 8.80 (d, /=8.6 Hz, 1 H) 10.30 (s, 1 H); HPLC purity (Method 1:94 %, Method 2:100%). Example 230

2-{[3,4-dioxo-2-(pyridin-4-yIamino)cyclobut-1-en-1-yl]amino} -2-[4-(3- th ienyl)phen yl] acetamide To a reaction vessel was added 2-(4-bromophenyi)-2-{[3,4-dioxo-2-(pyridin-4- ylamino)cyclobut-1-en-1-yl]amino}acetamide (0.071 g, 0.18 mmol), 3-thiopheneboronic acid (0.032 g, 1.4eq), Na ₂ CO ₃ (0.028g, 1.5 eq) and Pd(PPh ₃ ) ₂ Cl ₂ (0.025 g, 0.2eq). 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. ¹ H NMR (400 MHz, DMSO-40 δ ppm 5.83 (d, /=8.3 Hz, 1 H) 7.42 - 7.58 (m, 7 H) 7.64 (dd, /=5.1, 3.0 Hz, 1 H) 7.74 (d, /=8.3 Hz, 2 H) 7.87 (dd, /=2.9, 1.4 Hz, 1 H) 8.09 (s, 1 H) 8.42 (d, /=6.3 Hz, 2 H) 8.85 (d, /=8.6 Hz, 1 H) 10.33 (s, 1 H); HPLC purity (Method 1: 100%, Method 2: 100%); HRMS: calcd for C ₂ iH ₁₆ N ₄ O ₃ S + H+, 405.1016; found (ESI-FTMS, [M+H]l+), 405.1019.

Example 231

2-{[3,4-dioxo-2-(pyridin-4-ylamino)cyclobut-1-en-1-yl]ami no}-2-[4'-(morpholin-4- yIcarbonyl)bipheny]-4-yl]acetamide

The title compound was prepared as outlined for Example 230, but using 4-(morpholine- 4-carbonyl)phenylboronic acid, to afford 0.014g ( 15%) as a yellow solid. ¹ H NMR (400 MHz,

DMSCW ₆ ) δ ppm 3.16 - 3.78 (m, 8 H) 5.88 (d, /=8.59 Hz, 1 H) 7.43 - 7.64 (m, 7 H) 7.73 (d,

/=8.34 Hz, 4 H) 8.13 (s, 1 H) 8.46 (d, /=6.32 Hz, 2 H) 8.94 (d, /=8.34 Hz, 1 H) 10.53 (s, 1 H);

HPLC purity (Method 1: 98%, Method 2: 96%); HRMS: calcd for C ₂₈ H ₂₅ N ₅ O ₅ + H+, 512.1929; found (ESI-FTMS, [M+H]l+), 512.1935. Example 232

2-{[3,4-dioxo-2-(pyridin-4-ylanπno)cycIobut-1-en-1-yl]am ino}-2-[4-(3- furyl)phenyl] acetamidc

The title compound was prepared as outlined for Example 230, but using furan-3- ylboronic acid, to afford 0.015g (22%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-rfs) δ ppm 5.81 (d, /=8.3 Hz, 1 H) 6.95 (d, /=1.8 Hz, 1 H) 7.40 - 7.68 (m, 7 H) 7.74 (t, /=1.6 Hz, 1 H) 8.08

(s, 1 H) 8.18 (s, 1 H) 8.48 (d, /=6.1 Hz, 2 H) 8.92 (d, /=8.3 Hz, 1 H) 10.60 (s, 1 H); HPLC purity

(Method 1 : 95%, Method 2: 99%); HRMS: calcd for C _2I Hi ₆ N ₄ O ₄ + H+, 389.12443; found (ESI-

FTMS, [M+H]l+), 389.1246.

Example 233 2-{[3,4-dioxo-2-(pyridin-4-ylamino)cyclobut-1-en-1-yl]amino} -2-{3'-

[(methylsulfonyl)amino]biphenyl-4-yl}acetamide

The title compound was prepared as outlined for Example 230, but using 4- methansulfonylaminophenyl boronic acid, to afford 0.016g (18%) as a yellow solid. ¹ H NMR

(400 MHz, DMSO-^ ₆ ) δ ppm 3.03 (s, 3 H) 7.11 - 7.28 (m, 1 H) 7.34 - 7.50 (m, 6 H) 7.50 - 7.66 (m, 6 H) 8.42 (dd, /=4.80, 1.52 Hz, 2 H) 9.01 (s, 1 H) 10.50 (s, 1 H); HPLC purity (Method 1:

94%, Method 2: 89%); HRMS: calcd for C ₂₄ H ₂₁ N ₅ O ₅ S + H+, 492.1336; found (ESI-FTMS,

[M+H]l+), 492.1345.

Example 234

2-{3'-[(dimethylamino)sulfoπyl]biphenyl-4-yI}-2-{[3,4-di oxo-2-(pyridiii-4-ylamino)cyclobut- l-en-1-yl]amino}acetamide

The title compound was prepared as outlined for Example 230, but using 3-(N,N- dimethylsulphonamido)phenyl boronic acid to afford 0.016g (18%) as a yellow solid. ¹ H NMR (400 MHz, OMSO-dβ) δ ppm 2.64 (s, 6 H) 5.90 (d, /=8.1 Hz, 1 H) 7.45 (dd, /=4.8, 1.5 Hz, 2 H) 7.55 (s, 1 H) 7.61 (d, /=8.3 Hz, 2 H) 7.70 - 7.82 (m, 4 H) 7.91 (s, 1 H) 7.97 - 8.07 (m, 1 H) 8.11 - 8.20 (m, 1 H) 8.34 - 8.58 (m, 2 H) 8.94 (d, /=7.8 Hz, 1 H) 10.40 (s, 1 H); HPLC purity (Method 1: 99%, Method 2: 98%); HRMS: calcd for C ₂₅ H ₂₃ N ₅ O ₅ S + H+, 506.1493; found (ESI-FTMS, [M+H]l+), 506.1499. Example 235 2-{[3,4-dioxo-2-(pyridin-4-ylamino)cyclobut-1-en-1-yl]amino} -2-[3'-(morphoIin-4- ylcarbonyI)biphenyl-4-yl] acetamide

The title compound was prepared as outlined for Example 230, but using 2- aminophenylboronic acid, to afford 0.016g (17%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-^ ₆ ) δ ppm 2.99 - 3.87 (m, 8 H) 5.88 (d, /=7.33 Hz, 1 H) 7.36 - 7.78 (m, 11 H) 8.07 - 8.16 (m, 1 H) 8.37 - 8.46 (m, 2 H) 8.85 - 9.08 (m, 1 H) 10.47 (s, 1 H); HPLC purity (Method 1: 100%, Method 2: 94%); HRMS: calcd for C ₂₈ H ₂₅ N ₅ O ₅ + H+, 512.1929; found (ESI-FTMS, [M+H]l+), 512.1939. Example 236

2-{[3,4-dioxo-2-(pyridin-4-ylamino)cyclobut-1-en-1-yl]amino} -2-{3'- [(ethylamino)sulfonyI]bipheny]-4-yl} acetamide The title compound was prepared as outlined for Example 230, but using ethyl-3- boronbenzenesulfonamide, to afford 0.016g (18%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-Cf ₆ ) δ ppm 5.89 (d, /=7.83 Hz, 1 H) 7.46 (dd, /=4.67, 1.64 Hz, 2 H) 7.51 - 7.69 (m, 5 H) 7.71 - 7.81 (m, 2 H) 7.81 - 7.98 (m, 4 H) 8.42 (dd, /=4.67, 1.64 Hz, 2 H) 8.96 (d, /=5.05 Hz, 1 H) 10.44 (s, 1 H); HPLC purity (Method 1: 96%, Method 2: 98%); HRMS: calcd for C ₂₅ H ₂₃ N ₅ O ₅ S + H+, 506.1493; found (ESI-FTMS, [M+H]l+), 506.1507. Example 237

2-(2'-aminobiphenyl-4-yl)-2-{[3,4-dioxo-2-(pyridin-4-ylam ino)cyclobut-1-en-1- yl] amino} acetamide

The title compound was prepared as outlined for Example 230, but using 3-(morpholine- 4-carbonyl)phenylboronic acid, to afford 0.013g (18%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-4) δ ppm 4.79 (s, 2 H) 5.88 (d, /=8.08 Hz, 1 H) 6.56 - 6.68 (m, 1 H) 6.75 (dd, /=8.08,

1.01 Hz, 1 H) 6.97 (dd, /=7.58, 1.52 Hz, 1 H) 7.00 - 7.07 (m, 1 H) 7.34 - 7.61 (m, 8 H) 8.35 - 8.50 (m, 2 H) 8.87 - 9.21 (m, 1 H) 10.44 (s, 1 H); HPLC purity (Method 1: 97%, Method 2: 97%); HRMS: calcd for C ₂₃ Hi ₉ N ₅ O ₃ + H+, 414.1554; found (ESI-FTMS, [M+H]l+), 414.1561. Example 238 3-{[(lA)-1-phenylethyl]amino}-4-(thieno[2,3-b]pyridin-4-ylam ino)cyc]obut-3-ene-1,2-dione Step 1 : 4-Iodo-(2,3-b)-thienoρyridine

4-Chloro-(2,3-b)-thienopyridine (882 mg, 5.20 mmol) was protonated by stirring in methanolic HCl for 15 minutes. Solvent concentration gave a colorless solid that was combined with MeCN (30 mL) and NaI (4.013 g, 26.7 mmol), and the resultant heterogeneous mixture was heated at 80 °C for 2d. It was then cooled to r.t, and NaHSO ₃ (sat aq) and NaHCO ₃ (sat aq) were added sequentially giving a biphasic mixture that produced slight pink ppt upon stirring. The heterogeneous mixture was extracted with CH ₂ CI ₂ (3x) and the pooled organics were dried (Na ₂ CO ₃ ) and concentrated giving a highly colored solid, which was recrystallized in MeCN to give product (200 mg, 0.766 mmol, 14%) as colorless rods. Step 2: 3-{[(1R)-1-phenylethyl]amino}-4-(thieno[2,3-b]pyridin-4-ylam ino)cyclobut-3- ene-1,2-dione

3-{[(1R)-1-phenylethyl]amino}-4-amino-cyclobut-3-ene-1,2-dio ne (138 mg, 0.638 mmol), 4-iodo-(2,3-b)-thienoρyridine (166 mg, 0.636 mmol) and N,N'-dimethyl- ethylenediamine (69 μL, 0.64 mmol) were combined in DMF (3 mL) and freeze-thaw degassed (3x). CuI (66 mg, 0.35 mmol) was then added and the mixture was freeze-thaw degassed (Ix) giving a blue mixture that was heated at 80 °C. The reaction was monitored by LCMS, resulting in the following additions: Id: Iodide (unknown quantity), CuI (138 mg) and N,N'-dimethyl- ethylenediamine (140 μL) in DMF (0.5 mL) were added to the reaction. 2d: More iodide (245 mg in total) in DMF (1/2 mL) was added to the reaction. After 3d the reaction was cooled, diluted with MeOH and filtered. This crude reaction mixture was purified via HPLC to afford the title compound (39.8 mg, 0.11 mmol, 18%) as a yellow solid; ¹ H NMR (400 MHz, MeOD) δ ppm 1.69 (d, /=6.82 Hz, 3 H) 5.44 (q, /=6.48 Hz, 1H) 7.27 - 7.34 (m, 3 H) 7.36 - 7.42 (m, 2 H) 7.42 - 7.48 (m, 2 H) 7.53 (d, /=5.81 Hz, 1 H) 7.62 (d, /=6.06 Hz, 1 H) 7.91 (d, /=5.05 Hz, 1 H) 8.23 - 8.36 (m, 1 H). Example 239

Characterization of MK2 kinase inhibitors by ELISA was conducted using purified rhMK241-400 or rhMK2 41-353. MK2 inhibitory activity was assayed using: 250 pM MK2 (41-400) after a phosphorylation/activation step using 27 pM p38, or 100 nM MK2 (41-353) (MK2 (41-353) is constitutively active and does not need a phosphorylation/activation step with p38); 200 nM LSP 1 peptide 1323 as a substrate; and 1 μM ATP in IX kinase buffer (20 mM Hepes, pH 7.5, 10 mM MgCl ₂ , 2 mM DTT, and 0.05% Brij35). The phosphorylation of the LSP 1 peptide 1323 substrate, which takes place on serine residue 252, was measured via quantification of the phosphorylated peptide by ELISA, using a phospho-specific antibody. The results were compared to staurosporine which was used as a reference compound. The phosphorylation/activation step of MK2 (41-400) by p38 was performed using: 60 nM activated GST-p38, 550 nM MK2 (41-400); 2 mM DTT 20 ; 25 μM ATP; in IX kinase buffer (20 mM Hepes, pH 7.5, 10 mM MgCl ₂ , 2 mM DTT, and 0.05% Brij35). The activation mix was incubated for 1 hour at room temperature, then put on ice for stability.

The kinase assay was performed on a 96 well plate which was washed four times (250 μL) in PBS (with 0.1% Triton Xl 00) beforehand. The assay was carried out using the following steps. 6.6 mL of mix (enough for 110 reactions) were prepared by combining 1100 μL 1OX kinase buffer, 30 μL DDT (1 M), 11 μL ATP (1 mM), 100 μL activation mix, and balance of H ₂ O. 60 μL of mix and 20 μL compounds were mixed and then preincubated for 20 minutes. Then, the kinase reaction was started with the addition of 20 μL substrate solution (1 μM peptide 1323, Bio-RTPKLARQASIELPSM; LSP-I aa 243-258; Ser 252 is the phosphorylation site). After 30 minutes incubation, the reaction was stopped by addition of 10 μL EDTA (0.5 M), and the 96 well plate was washed again four times (250 μL) in PBS (with 0.1% Triton XlOO).

Antibody detection was carried out using the following steps: 100 μL of blocking/ Ab buffer (10 mM MOPS 7.5, 150 mM NaCl, 0.05% Tween 20, 0.1% Gelatin, 1% BSA, 0.02% NaN ₃ ) with purified antibody 60521 (0.46 mg/mL) at 1 :20,000 dilution and europium-labeld Anti-rabbit at 1 :4000 dilution (PE Life Sciences) were added to the detection plate and incubated for 1 hour at room temperature with shaking; then, the detection plate was washed 6 times with PBS 0.1% Tween 20; then, 100 μL of Enhancement solution (Wallac Cat# 1244- 105) were added and incubated for 10 minutes at room temperature with shaking. Europium signal was measured using a Wallac Victor II reader (HTS Europium protocol).

Table 1

Other embodiments are within the scope of the following claims.