Cyclic pyrazoles for the inhibition of mitogen activated protein kinase-activated protein kinase-2

Description

BACKGROUND OF THE INVENTION

[0002] (1) Field of the Invention

[0003] The present invention relates to cyclic pyrazole compounds which inhibit mitogen-activated protein kinase-activated protein kinase-2 (MAPKAP-2, or MK-2), and also to methods of using such compounds to inhibit MK-2 and for the prevention and treatment of TNFα mediated diseases or disorders in subjects that are in need of such prevention and/or treatment.

[0004] (2) Description of the Related Art

[0005] Mitogen-activated protein kinases (MAPKs) are members of conserved signal transduction pathways that activate transcription factors, translation factors and other target molecules in response to a variety of extracellular signals. MAPKs are activated by phosphorylation at a dual phosphorylation motif with the sequence Thr-X-Tyr by mitogen-activated protein kinase kinases (MAPKKs). In higher eukaryotes, the physiological role of MAPK signaling has been correlated with cellular events such as proliferation, oncogenesis, development and differentiation. Accordingly, the ability to regulate signal transduction via these pathways could lead to the development of treatments and preventive therapies for human diseases associated with MAPK signaling, such as inflammatory diseases, autoimmune diseases and cancer.

[0006] In mammalian cells, three parallel MAPK pathways have been described. The best characterized pathway leads to the activation of the extracellular-signal-regulated kinase (ERK). Less well understood are the signal transduction pathways leading to the activation of the cJun N-terminal kinase (JNK) and the p38 MAPK. See, e.g., Davis, Trends Biochem. Sci. 19:470-473 (1994); Cano, et al., Trends Biochem. Sci. 20:117-122(1995).

[0007] The p38 MAPK pathway is potentially activated by a wide variety of stresses and cellular insults. These stresses and cellular insults include heat shock, UV irradiation, inflammatory cytokines (such as TNF and IL-1), tunicamycin, chemotherapeutic drugs (i.e., cisplatinum), anisomycin, sorbitol/hyperosmolarity, gamma irradiation, sodium arsenite, and ischaemia. See, Ono, K., et al, Cellular Signalling 12,1-13 (2000). Activation of the p38 pathway is involved in (1) production of proinflammatory cytokines, such as TNF-α; (2) induction of enzymes, such as Cox-2; (3) expression of an intracellular enzyme, such as iNOS, which plays an important role in the regulation of oxidation; (4) induction of adherent proteins, such as VCAM-1 and many other inflammatory-related molecules. Furthermore, the p38 pathway functions as a regulator in the proliferation and differentiation of cells of the immune system. See, Ono, K., et al., Id. at 7.

[0008] The p38 kinase is an upstream kinase of mitogen-activated protein kinase-activated protein kinase-2 (MAPKAP kinase-2 or MK-2). (See, Freshney, N. W., et al., J. Cell, 78:1039-1049 (1994)). MK-2 is a protein that appears to be predominantly regulated by p38 in cells. Indeed, MK-2 was the first substrate of p38 α to be identified. For example, in vitro phosphorylation of MK-2 by p38 α activates MK-2. The substrates that MK-2 acts upon, in turn, include heat shock protein 27, lymphocyte-specific protein 1.(LAP1), cAMP response element-binding protein (CREB), ATF1, serum response factor (SRF), and tyrosine hydroxylase. The substrate of MK-2 that has been best characterized is small heat shock protein 27 (hsp27).

[0009] The role of the p38 pathway in inflammatory-related diseases has been studied in several animal models. The pyridinyl imidazole compound SB203580 has been shown to be a specific inhibitor of p38 in vivo, and also has been shown to inhibit activation of MK-2, (See, Rouse, J., et al, Cell, 78:1027-1037 (1994); Cuenda, A., et al, Biochem. J., 333:11-15 (1998)), as well as a MAP kinase homologue termed reactivating kinase (RK). (See, Cuenda, A., et al., FEBS Lett., 364(2):229-233 (1995)). Inhibition of p38 by SB203580 can reduce mortality in a murine model of endotoxin-induced shock and inhibit the development of mouse collagen-induced arthritis and rat adjuvant arthritis. See, e.g., Badger, A. M., et al., J. Pharmacol Exp. Ther., 279:1453-1461 (1996). Another p38 inhibitor that has been utilized in an animal model that is believed to be more potent than SB203580 in its inhibitory effect on p38 is SB 220025. A recent animal study has demonstrated that SB 220025 caused a significant dose-dependent decrease in vascular density of granulomas in laboratory rats. (Jackson, J. R., et al, J. Pharmacol. Exp. Ther., 284:687-692 (1998)). The results of these animal studies indicated that p38, or the components of the p38 pathway, Can be useful therapeutic targets for the prevention or treatment of inflammatory disease.

[0010] Due to its integral role in the p38 signaling pathway, MK-2 has been used as a monitor for measuring the level of activation in the pathway. Because of its downstream location in the pathway, relative to p38, MK-2 has been measured as a more convenient, albeit indirect, method of assessing p38 activation. However, so far, research efforts exploring therapeutic strategies associated with the modulation of this pathway have focused mainly on the inhibition of p38 kinase.

[0011] Several compounds that inhibit the activity of p38 kinase have been described in U.S. Pat. Nos. 6,046,208, 6,251,914, and 6,335,340. These compounds have been suggested to be useful for the treatment of CSBP/RK/p38 kinase mediated disease. Commercial efforts to apply p38 inhibitors have centered around two p38 inhibitors, the pyridinylimidazole inhibitor SKF 86002, and the 2,4,5 triaryl imidazole inhibitor SB203580. See, Lee, J. C., et al, Immunopharmacology 47,185-192 (2000). Compounds possessing a similar structure have also been investigated as potential p38 inhibitors. Indeed, p38 MSP kinase's role in various disease states has been elucidated through the use of inhibitors.

[0012] Kotlyarov, A. et al, in Nat Cell Biol., 1(2):94-97 (1999) introduced a targeted mutation into a mouse MK-2 gene, resulting in MK-2-deficient mice. It was shown that mice lacking MK-2 possessed increased stress resistance and survived LPS-induced endotoxic shock better than MK-2+mice. The authors concluded that MK-2 was an essential component in the inflammatory response that regulates biosynthesis of TNFα at a post-transcriptional level. More recently, Lehner, M. D., et al, in J. Immunol., 168(9):4667-4673 (2002), reported that MK-2-deficient mice showed increased susceptibility to Listeria monocytogenes infection, and concluded that MK-2 had an essential role in host defense against intracellular bacteria, probably via regulation of TNF and IFN-gamma production required for activation of antibacterial effector mechanisms.

[0013] The location of MK-2 in the p38 signaling pathway at a point that is downstream of p38 offers the potential that MK-2 could act as a focal point for modulating the pathway without affecting as many substrates as would the regulation of an enzyme further upstream in the signaling cascade—such as p38 MAP kinase.

[0014] Accordingly, it would be useful to provide compounds and methods that could serve to modulate the activity of MK-2—in particular, to act as inhibitors of MK-2 activity. Such compounds and methods would be useful for the provision of benefits similar to p38 MAP kinase inhibitors, which benefits include the prevention and treatment of diseases and disorders that are mediated by TNFα. It would be even more useful to provide MK-2 inhibitors having improved potency and reduced undesirable side effects, relative to p38 inhibitors.

SUMMARY OF THE INVENTION

[0015] Briefly therefore, the present invention is directed to a novel a novel cyclic pyrazole MK-2 inhibiting compound having the structure:

[0016] where:

[0017] Ra and Rb join to form a ring structure selected from the group

[0018] consisting of:

[0019] A, E, G and J are carbon, or optionally, one of A, E, G and J is selected from nitrogen, sulfur, or oxygen;

[0020] when A, E, G, or J is oxygen or sulfur, no substituent groups are bonded to the oxygen or the sulfur;

[0021] when A, E, G, or J is nitrogen, the nitrogen is optionally unsubstituted, or is substituted with R9;

[0022] each of R1, R2, R4 and R6 is optionally absent, or is independently selected from the R3 groups;

[0023] R3, R5, R7, R8, R9, R40, R54 and R55 are each independently selected from —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, nitro C1-C6 alkyl, azido C1-C6 alkyl, amino, NHR10, NR11R12, C1-C6 alkyl-NHR10, C1-C6 -alkyl-NR11R12, nitro, cyano, O—R13, C1-C4 alkyl-OR13, aryl, heteroaryl, heterocyclyl, COR14, SR13, SOR14, SO2R14, C1-C6 alkyl-COR14, C1-C6 alkyl-SR13, C1-C6 alkyl-SOR14, C1-C6 alkyl-SO2R14, halo, halo C1-C6 alkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, arylalkyl, heteroarylalkyl, heterocyclylalkyl, arylalkenyl, heterocyclylalkenyl, arylheterocyclylalkenyl, heterocyclylarylalkenyl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R15;

[0024] R10, R11, are each independently selected from —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, amino, NHR16, NR16R17, C1-C6 alkyl-NHR16, C1-C6 alkyl-NR16R17, O—R18, C1-C4 alkyl-OR18, aryl, heteroaryl, heterocyclyl, CO2R19, COR20, CONHR19, CON(R19)2, SR18, SOR20, SO2R20, C1-C6 alkyl-CO2R19, C1-C6 alkyl-COR20, C1-C6 alkyl-CONHR19, C1-C6 alkyl-CON(R19)2, C1-C6 alkyl-SR18, C1-C6 alkyl-SOR20, C1-C6 alkyl-SO2R20, halo, halo C1-C6 alkyl, arylaryl, arylheteroaryl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, arylalkyl, heteroarylalkyl, heterocyclylalkyl, arylalkenyl, heterocyclylalkenyl, arylheterocyclylalkenyl, heterocyclylarylalkenyl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R21;

[0025] R12, R13 are each independently selected from —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl-NHR16, C1-C6 alkyl-NR16R17, C1-C4 alkyl-OR18, aryl, heteroaryl, heterocyclyl, CO2R19, COR20, CONHR19, CON(R19)2, SOR20, SO2R20, C1-C6 alkyl CO2R19, C1-C6 alkyl-COR20, C1-C6 alkyl-CONHR19, C1-C6 alkyl-CON(R19)2, C1-C6 alkyl-SR18, C1-C6 alkyl-SOR20, C1-C6 alkyl-SO2R20, halo C1-C6 alkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R21;

[0026] R14 is selected from —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, amino, NHR16, NR16R17, C1-C6 alkyl-NHR16, C1-C6 alkyl-NR16R17, O—R18, C1-C4 alkyl-OR18, aryl, heteroaryl, heterocyclyl, SR18, C1-C6 alkyl-CO2R19, C1-C6 alkyl-COR20, C1-C6 alkyl-CONHR19, C1-C6 alkyl-CON(R19)2, C1-C6 alkyl-SR18, C1-C6 alkyl-SOR20, C1-C6 alkyl-SO2R20, halo, halo C1-C6 alkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, arylalkyl, heteroarylalkyl, heterocyclylalkyl, arylalkenyl, heterocyclylalkenyl, arylheterocyclylalkenyl, heterocyclylarylalkenyl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R21;

[0027] R15 is selected from —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, amino, NHR10, NR11R12, C1-C6 alkyl-NHR10, C1-C6 alkyl-NR11R12, nitro, cyano, O—R13, C1-C4 alkyl-OR13, aryl, heteroaryl, heterocyclyl, COR14, SR13, SOR14, SO2R14, C1-C6 alkyl-COR14, C1-C6 alkyl-SR13, C1-C6 alkyl-SOR14, C1-C6 alkyl-SO2R14, halo, halo C1-C6 alkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, arylalkyl, heteroarylalkyl, heterocyclylalkyl, arylalkenyl, heterocyclylalkenyl, arylheterocyclylalkenyl, heterocyclylarylalkenyl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R21;

[0028] R16 and R17 are each independently selected from —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, amino, C1-C6 alkyl-NHR22, C1-C6 alkyl-NR22R23, C1, C4 alkyl-OR24, aryl, heteroaryl, heterocyclyl, CO2R25, COR26, CONHR25, CON(R25)2, SOR26, SO2R26, C1-C6 alkyl-CO2R25, C1-C6 alkyl-COR26, C1-C6 alkyl-CONHR25, C1-C6 alkyl-CON(R25)2, C1-C6 alkyl-SR24, C1-C6 alkyl-SOR26, C1-C6 alkyl-SO2R26, halo, halo C1-C6 alkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, arylalkyl, heteroarylalkyl, heterocyclylalkyl, arylalkenyl, heterocyclylalkenyl, arylheterocyclylalkenyl, heterocyclylarylalkenyl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R27;

[0029] R18, R19 are each independently selected from —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl-NHR22, C1-C6 alkyl-NR22R23, C1-C4 alkyl-OR24, aryl, heteroaryl, heterocyclyl, CO2R25, COR26, CONHR25, CON(R25)2, SOR26, SO2R27, C1-C6 alkyl-CO2R25, C1-C6 alkyl-COR26, C1-C6 alkyl-CONHR25, C1-C6 alkyl-CON(R25)2, C1-C6 alkyl-SR24, C1-C6 alkyl-SOR26, C1-C6 alkyl-SO2R26, halo C1-C6 alkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R27;

[0030] R20 is selected from —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, amino, NHR22, NR22R23, C1-C6 alkyl-NHR22, C1-C6 alkyl-NR22R23, O—R24, C1-C4 alkyl-OR24, aryl, heteroaryl, heterocyclyl, SR24, C1-C6 alkyl-CO2R25, C1-C6 alkyl-COR26, C1-C6 alkyl-CONHR25, C1-C6 alkyl-CON(R25)2, C1-C6 alkyl-SR24, C1-C6 alkyl-SOR26, C1-C6 alkyl-SO2R26, halo, halo C1-C6 alkyl, arylalkoxyalkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, arylalkyl, heteroarylalkyl, heterocyclylalkyl, arylalkenyl, heterocyclylalkenyl, arylheterocyclylalkenyl, heterocyclylarylalkenyl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R27;

[0031] R21 is selected from —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, amino, NHR22, NR22R23, C1-C6 alkyl-NHR22, C1-C6 alkyl-NR22R23, nitro, cyano, O—R24, C1-C4 alkyl-OR24, aryl, heteroaryl, heterocyclyl, COR26, SR24, SOR26, SO2R26, C1-C6 alkyl-COR26, C1-C6 alkyl-SR24, C1-C6 alkyl-SOR26, C1-C6 alkyl-SO2R26, halo, halo C1-C6 alkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, arylalkyl, heteroarylalkyl, heterocyclylalkyl, arylalkenyl, heterocyclylalkenyl, arylheterocyclylalkenyl, heterocyclylarylalkenyl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R27;

[0032] R22 and R23 are each independently selected from —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, amino, C1-C6 alkyl-NHR28, C1-C6 alkyl-NR28R29, C1-C4 alkyl-OR30, aryl, heteroaryl, heterocyclyl, CO2R31, COR32, CONHR31, CON(R31)2, SOR32, SO2R32, C1-C6 alkyl-CO2R31, C1-C6 alkyl-COR32, C1-C6 alkyl-CONHR31, C1-C6 alkyl-CON(R31)2, C1-C6 alkyl-SR30, C1-C6 alkyl-SOR32, C1-C6 alkyl-SO2R32, halo, halo C1-C6 alkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, arylalkyl, heteroarylalkyl, heterocyclylalkyl, arylalkenyl, heterocyclylalkenyl, arylheterocyclylalkenyl, heterocyclylarylalkenyl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R33;

[0033] R24 and R25 are each independently selected from —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl-NHR29, C1-C6 alkyl-NR28R29, C1-C4 alkyl-OR30, aryl, heteroaryl, heterocyclyl, CO2R31, COR32, CONHR31, CON(R31)2, SOR32, SO2R32, C1-C6 alkyl-CO2R31, C1-C6 alkyl-COR32, C1-C6 alkyl-CONHR31, C1-C6 alkyl-CON(R31)2, C1-C6 alkyl-SR30, C1-C6 alkyl-SOR32, C1-C6 alkyl-SO2R32, halo C1-C6 alkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R33;

[0034] R26 is selected from —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, amino, NHR28, NR28R29, C1-C6 alkyl-NHR28, C1-C6 alkyl-NR28R29, O—R30, C1-C4 alkyl-OR30, aryl, heteroaryl, heterocyclyl, SR30, C1-C6 alkyl-CO2R31, C1-C6 alkyl-COR32, C1-C6 alkyl-CONHR31, C1-C6 alkyl-CON(R31)2, C1-C6 alkyl-SR30, C1-C6 alkyl-SOR32, C1-C6 alkyl-SO2R32, halo, halo C1-C6 alkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, arylalkyl, heteroarylalkyl, heterocyclylalkyl, arylalkenyl, heterocyclylalkenyl, arylheterocyclylalkenyl, heterocyclylarylalkenyl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R33;

[0035] R27 is selected from —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, amino, NHR28, NR28R29, C1-C6 alkyl-NHR28, C1-C6 alkyl-NR28R29, nitro, cyano, O—R30, C1-C4 alkyl-OR30, aryl, heteroaryl, heterocyclyl, COR32, SR30, SOR32, SO2R32, C1-C6 alkyl-COR32, C1-C6 alkyl-SR30, C1-C6 alkyl-SOR32, C1-C6 alkyl-SO2R32, halo, halo C1-C6 alkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, arylalkyl, heteroarylalkyl, heterocyclylalkyl, arylalkenyl, heterocyclylalkenyl, arylheterocyclylalkenyl, heterocyclylarylalkenyl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic-cycloalkyl are optionally substituted with one or more of the groups defined by R33;

[0036] R28 and R29 are each independently selected from —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, amino, C1-C6 alkyl-NHR34, C1-C6 alkyl-NR34R35, C1-C4 alkyl-OR36, aryl, heteroaryl, heterocyclyl, CO2R37, COR38, CONHR37, CON(R37)2, SOR38, SO2R38, C1-C6 alkyl-CO2R37, C1-C6 alkyl-COR38, C1-C6 alkyl-CONHR37, C1-C6 alkyl-CON(R37)2, C1-C6 alkyl-SR36, C1-C6 alkyl-SOR38, C1-C6 alkyl-SO2R38, halo, halo C1-C6 alkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, arylalkyl, heteroarylalkyl, heterocyclylalkyl, arylalkenyl, heterocyclylalkenyl, arylheterocyclylalkenyl, heterocyclylarylalkenyl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R39;

[0037] R30 and R31 are each independently selected from —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl-NHR34, C1-C6 alkyl-NR34R35, C1-C4 alkyl-OR36, aryl, heteroaryl, heterocyclyl, CO2R37, COR38, CONHR37, CON(R37)2, SOR38, SO2R38, C1-C6 alkyl-CO2R37, C1-C6 alkyl-COR38, C1-C6 alkyl-CONHR37, C1-C6 alkyl-CON(R37)2, C1-C6 alkyl-SR36, C1-C6 alkyl-SOR38, C1-C6 alkyl-SO2R38, halo C1-C6 alkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R39;

[0038] R32 is selected from —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, amino, NHR34, NR34R35, C1-C6 alkyl-NHR34, C1-C6 alkyl-NR34R35, O—R36, C1-C4 alkyl-OR36, aryl, heteroaryl, heterocyclyl, SR36, C1-C6 alkyl-CO2R37, C1-C6 alkyl-COR38, C1-C6 alkyl-CONHR37, C1-C6 alkyl-CON(R37)2, C1-C6 alkyl-SR36, C1-C6 alkyl-SOR38, C1-C6 alkyl-SO2R38, halo, halo C1-C6 alkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, arylalkyl, heteroarylalkyl, heterocyclylalkyl, arylalkenyl, heterocyclylalkenyl, arylheterocyclylalkenyl, heterocyclylarylalkenyl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R39;

[0039] R33 is selected from —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, amino, NHR34, NR34R35, C1-C6 alkyl-NHR31, C1-C6 alkyl-NR34R35, nitro, cyano, O—R36, C1-C4 alkyl-OR36, aryl, heteroaryl, heterocyclyl, COR38, SR35, SOR38, SO2R38, C1-C6 alkyl-COR38, C1-C6 alkyl-SR36, C1-C6 alkyl-SOR38, C1-C6 alkyl-SO2R38, halo, halo C1-C6 alkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, arylalkyl, heteroarylalkyl, heterocyclylalkyl, arylalkenyl, heterocyclylalkenyl, arylheterocyclylalkenyl, heterocyclylarylalkenyl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R39;

[0040] R34, R35, R36 and R37 are each independently selected from —H, alkyl, alkenyl, alkynyl, aminoalkyl, hydroxyalkyl, alkylamino alkyl, dialkylaminoalkyl, alkoxyalkyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, arylalkyl, heterocyclylalkyl, heteroarylalkyl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R39;

[0041] R38 is selected from —H, alkyl, alkenyl, alkynyl, aminoalkyl, OH, alkoxy, amino, alkylamino, dialkylamino, hydroxyalkyl, alkylamino alkyl, dialkylaminoalkyl, alkoxyalkyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, arylalkyl, heterocyclylalkyl, heteroarylalkyl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R39;

[0042] R39 is selected from alkyl, alkenyl, alkynyl, aminoalkyl, OH, alkoxy, amino, nitro, cyano, halo, alkylamino, dialkylamino, hydroxyalkyl, alkylamino alkyl, dialkylaminoalkyl, alkoxyalkyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, arylalkyl, heterocyclylalkyl, arylalkenyl, heterocyclylalkenyl, arylheterocyclylalkenyl, heterocyclylarylalkenyl, or heteroarylalkyl; and

[0043] R2 and R3, or R8 and R9, optionally join to form a saturated or unsaturated ring of 5, 6, 7, or 8 atoms, where the atoms in the ring are independently selected from CR40, C(R40)2, C═O, N, NR40, O, S, C═S, S═O, or SO2.

[0044] The present invention is also directed to a novel cyclic pyrazole MK-2 inhibiting compound having the structure:

[0045] where:

[0046] Ra and Rb join to form a ring structure selected from the group consisting of:

[0047] A, E, G and J are carbon, or optionally, one of A, E, G and J is selected from nitrogen, sulfur, or oxygen;

[0048] when A, E, G, or J is oxygen or sulfur, no substituent groups are bonded to the oxygen or the sulfur;

[0049] when A, E, G, or J is nitrogen, the nitrogen is optionally unsubstituted, or is substituted with R9;

[0050] each of R1, R2, R4 and R6 is optionally absent, or is independently selected from the R3 groups;

[0051] R3, R5, R7, R8, R9, R40, R41, R42, R43, R44, R45, R46, R47, R48, R49, R50, R51, R52, R53, R54 and R55 are each independently selected from —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, nitro C1-C6 alkyl, azido C1-C6 alkyl, amino, NHR10, NR11R12, C1-C6 alkyl-NHR10, C1-C6 alkyl-NR11R12, nitro, cyano, O—R13, C1-C4 alkyl-OR13, aryl, heteroaryl, heterocyclyl, COR14, SR13, SOR14, SO2R14, C1-C6 alkyl-COR14, C1-C6 alkyl-SR13, C1-C6 alkyl-SOR14, C1-C6 alkyl-SO2R14, halo, halo C1-C6 alkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, arylalkyl, heteroarylalkyl, heterocyclylalkyl, arylalkenyl, heterocyclylalkenyl, arylheterocyclylalkenyl, heterocyclylarylalkenyl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R15, or R8 and R9 join to form a ring structure selected from:

[0052] R10, R11, are each independently selected from —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, amino, NHR16, NR16R17, C1-C6 alkyl-NHR16, C1-C6 alkyl-NR16R17, O—R18, C1-C4 alkyl-OR18, aryl, heteroaryl, heterocyclyl, CO2R19, COR20, CONHR19, CON(R19)2, SR18, SOR20, SO2R20, C1-C6 alkyl-CO2R19, C1-C6 alkyl-COR20, C1-C6 alkyl-CONHR19, C1-C6 alkyl-CON(R19)2, C1-C6 alkyl-SR18, C1-C6 alkyl-SOR20, C1-C6 alkyl-SO2R20, halo, halo C1-C6 alkyl, arylaryl, arylheteroaryl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, arylalkyl, heteroarylalkyl, heterocyclylalkyl, arylalkenyl, heterocyclylalkenyl, arylheterocyclylalkenyl, heterocyclylarylalkenyl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R21;

[0053] R12, R13 are each independently selected from —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl-NHR16, C1-C6 alkyl-NR16R17, C1-C4 alkyl-OR18, aryl, heteroaryl, heterocyclyl, CO2R19, COR20, CONHR19, CON(R19)2, SOR20, SO2R20, C1-C6 alkyl-CO2R19, C1-C6 alkyl-COR20, C1-C6 alkyl-CONHR19, C1-C6 alkyl-CON(R19)2, C1-C6 alkyl-SR18, C1-C6 alkyl-SOR20, C1-C6 alkyl-SO2R20, halo C1-C6 alkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R21;

[0054] R14 is selected from —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, amino, NHR16, NR16R17, C1-C6 alkyl-NHR16, C1-C6 alkyl-NR16R17, O—R18, C1-C4 alkyl-OR18, aryl, heteroaryl, heterocyclyl, SR18, C1-C6 alkyl-CO2R19, C1-C6 alkyl-COR20, C1-C6 alkyl-CONHR19, C1-C6 alkyl-CON(R19)2, C1-C6 alkyl-SR18, C1-C6 alkyl-SOR20, C1-C6 alkyl-SO2R20, halo, halo C1-C6 alkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, arylalkyl, heteroarylalkyl, heterocyclylalkyl, arylalkenyl, heterocyclylalkenyl, arylheterocyclylalkenyl, heterocyclylarylalkenyl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R21;

[0055] R15 is selected from —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, amino, NHR10, NR11R12, C1-C6 alkyl-NHR10, C1-C6 alkyl-NR11R12, nitro, cyano, O—R13, C1-C4 alkyl-OR13, aryl, heteroaryl, heterocyclyl, COR14, SR13, SOR14, SO2R14, C1-C6 alkyl-COR14, C1-C6 alkyl-SR13, C1-C6 alkyl-SOR14, C1-C6 alkyl-SO2R14, halo, halo C1-C6 alkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, arylalkyl, heteroarylalkyl, heterocyclylalkyl, arylalkenyl, heterocyclylalkenyl, arylheterocyclylalkenyl, heterocyclylarylalkenyl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R21;

[0056] R16 and R17 are each independently selected from —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, amino, C1-C6 alkyl-NHR22, C1-C6 alkyl-NR22R23, C1-C4 alkyl-OR24, aryl, heteroaryl, heterocyclyl, CO2R25, COR26, CONHR25, CON(R25)2, SOR26, SO2R26, C1-C6 alkyl-CO2R25, C1-C6 alkyl-COR26, C1-C6 alkyl-CONHR25, C1-C6 alkyl-CON(R25)2, C1-C6 alkyl-SR24, C1-C6 alkyl-SOR26, C1-C6 alkyl-SO2R26, halo, halo C1-C6 alkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, arylalkyl, heteroarylalkyl, heterocyclylalkyl, arylalkenyl, heterocyclylalkenyl, arylheterocyclylalkenyl, heterocyclylarylalkenyl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R27;

[0057] R18, R19 are each independently selected from —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl-NHR22, C1-C6 alkyl-NR22R23, C1-C4 alkyl-OR24, aryl, heteroaryl, heterocyclyl, CO2R25, COR26, CONHR25, CON(R25)2, SOR26, SO2R27, C1-C6 alkyl-CO2R25, C1-C6 alkyl-COR26, C1-C6 alkyl-CONHR25, C1-C6 alkyl-CON(R25)2, C1-C6 alkyl-SR24, C1-C6 alkyl-SOR26, C1-C6 alkyl-SO2R26, halo C1-C6 alkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R27;

[0058] R20 is selected from —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, amino, NHR22, NR22R23, C1-C6 alkyl-NHR22, C1-C6 alkyl-NR22R23, O—R24, C1-C4 alkyl-OR24, aryl, heteroaryl, heterocyclyl, SR24, C1-C6 alkyl-CO2R25, C1-C6 alkyl-COR26, C1-C6 alkyl-CONHR25, C1-C6 alkyl-CON(R25)2, C1-C6 alkyl-SR24, C1-C6 alkyl-SOR26, C1-C6 alkyl-SO2R26, halo, halo C1-C6 alkyl, arylalkoxyalkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, arylalkyl, heteroarylalkyl, heterocyclylalkyl, arylalkenyl, heterocyclylalkenyl, arylheterocyclylalkenyl, heterocyclylarylalkenyl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R27;

[0059] R21 is selected from —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, amino, NHR22, NR22R23, C1-C6 alkyl-NHR22, C1-C6 alkyl-NR22R23, nitro, cyano, O—R24, C1-C4 alkyl-OR24, aryl, heteroaryl, heterocyclyl, COR26, SR24, SOR26, SO2R26, C1-C6 alkyl-COR26, C1-C6 alkyl-SR24, C1-C6 alkyl-SOR26, C1-C6 alkyl-SO2R26, halo, halo C1-C6 alkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, arylalkyl, heteroarylalkyl, heterocyclylalkyl, arylalkenyl, heterocyclylalkenyl, arylheterocyclylalkenyl, heterocyclylarylalkenyl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R27;

[0060] R22 and R23 are each independently selected from —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, amino, C1-C6 alkyl-NHR28, C1-C6 alkyl-NR28R29, C1-C4 alkyl-OR30, aryl, heteroaryl, heterocyclyl, CO2R31, COR32, CONHR31, CON(R31)2, SOR32, SO2R32, C1-C6 alkyl-CO2R31, C1-C6 alkyl-COR32, C1-C6 alkyl-CONHR31, C1-C6 alkyl-CON(R31)2, C1-C6 alkyl-SR30, C1-C6 alkyl-SOR32, C1-C6 alkyl-SO2R32, halo, halo C1-C6 alkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, arylalkyl, heteroarylalkyl, heterocyclylalkyl, arylalkenyl, heterocyclylalkenyl, arylheterocyclylalkenyl, heterocyclylarylalkenyl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R33;

[0061] R24 and R25 are each independently selected from —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl-NHR28, C1-C6 alkyl-NR28R29, C1-C4 alkyl-OR30, aryl, heteroaryl, heterocyclyl, CO2R31, COR32, CONHR31, CON(R31)2, SOR32, SO2R32, C1-C6 alkyl-CO2R31, C1-C6 alkyl-COR32, C1-C6 alkyl-CONHR31, C1-C6 alkyl-CON(R31)2, C1-C6 alkyl-SR30, C1-C6 alkyl-SOR32, C1-C6 alkyl-SO2R32, halo C1-C6 alkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R33;

[0062] R26 is selected from —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, amino, NHR28, NR28R29, C1-C6 alkyl-NHR28, C1-C6 alkyl-NR28R29, O—R30, C1-C4 alkyl-OR30, aryl, heteroaryl, heterocyclyl, SR30, C1-C6 alkyl-CO2R31, C1-C6 alkyl-COR32, C1-C6 alkyl-CONHR31, C1-C6 alkyl-CON(R31)2, C1-C6 alkyl-SR30, C1-C6 alkyl-SOR32, C1-C6 alkyl-SO2R32, halo, halo C1-C6 alkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, arylalkyl, heteroarylalkyl, heterocyclylalkyl, arylalkenyl, heterocyclylalkenyl, arylheterocyclylalkenyl, heterocyclylarylalkenyl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R33;

[0063] R27 is selected from —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, amino, NHR28, NR28R29, C1-C6 alkyl-NHR28, C1-C6 alkyl-NR28R29, nitro, cyano, O—R30, C1-C4 alkyl-OR30, aryl, heteroaryl, heterocyclyl, COR32, SR30, SOR32, SO2R32, C1-C6 alkyl-COR32, C1-C6 alkyl-SR30, C1-C6 alkyl-SOR32, C1-C6 alkyl-SO2R32, halo, halo C1-C6 alkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, arylalkyl, heteroarylalkyl, heterocyclylalkyl, arylalkenyl, heterocyclylalkenyl, arylheterocyclylalkenyl, heterocyclylarylalkenyl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R33;

[0064] R28 and R29 are each independently selected from —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, amino, C1-C6 alkyl-NHR34, C1-C6 alkyl-NR34R35, C1-C4 alkyl-OR36, aryl, heteroaryl, heterocyclyl, CO2R37, COR38, CONHR37, CON(R37)2, SOR38, SO2R38, C1-C6 alkyl-CO2R37, C1-C6 alkyl-COR38, C1-C6 alkyl-CONHR37, C1-C6 alkyl-CON(R37)2, C1-C6 alkyl-SR36, C1-C6 alkyl-SOR38, C1-C6 alkyl-SO2R38, halo, halo C1-C6 alkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, arylalkyl, heteroarylalkyl, heterocyclylalkyl, arylalkenyl, heterocyclylalkenyl, arylheterocyclylalkenyl, heterocyclylarylalkenyl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R39;

[0065] R30 and R31 are each independently selected from —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl-NHR34, C1-C6 alkyl-NR34R35, C1-C4 alkyl-OR36, aryl, heteroaryl, heterocyclyl, CO2R37, COR38, CONHR37, CON(R37)2, SOR38, SO2R38, C1-C6 alkyl-CO2R37, C1-C6 alkyl-COR38, C1-C6 alkyl-CONHR37, C1-C6 alkyl-CON(R37)2, C1-C6 alkyl-SR36, C1-C6 alkyl-SOR38; C1-C6 alkyl-SO2R38, halo C1-C6 alkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R39;

[0066] R32 is selected from —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, amino, NHR34, NR34R35, C1-C6 alkyl-NHR34, C1-C6 alkyl-NR34R35, O—R36, C1-C4 alkyl-OR36, aryl, heteroaryl, heterocyclyl, SR36, C1-C6 alkyl-CO2R37, C1-C6 alkyl-COR38, C1-C6 alkyl-CONHR37, C1-C6 alkyl-CON(R37)2, C1-C6 alkyl-SR36, C1-C6 alkyl-SOR38, C1-C6 alkyl-SO2R38, halo, halo C1-C6 alkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, arylalkyl, heteroarylalkyl, heterocyclylalkyl, arylalkenyl, heterocyclylalkenyl, arylheterocyclylalkenyl, heterocyclylarylalkenyl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R39;

[0067] R33 is selected from —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, amino, NHR34, NR34R35, C1-C6 alkyl-NHR31, C1-C6 alkyl-NR34R35, nitro, cyano, O—R36, C1-C4 alkyl-OR36, aryl, heteroaryl, heterocyclyl, COR38, SR35, SOR38, SO2R38, C1-C6 alkyl-COR38, C1-C6 alkyl-SR36, C1-C6 alkyl-SOR38, C1-C6 alkyl-SO2R38, halo, halo C1-C6 alkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, arylalkyl, heteroarylalkyl, heterocyclylalkyl, arylalkenyl, heterocyclylalkenyl, arylheterocyclylalkenyl, heterocyclylarylalkenyl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R39;

[0068] R34, R35, R36 and R37 are each independently selected from —H, alkyl, alkenyl, alkynyl, aminoalkyl, hydroxyalkyl, alkylamino alkyl, dialkylaminoalkyl, alkoxyalkyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, arylalkyl, heterocyclylalkyl, heteroarylalkyl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R39;

[0069] R31 is selected from —H, alkyl, alkenyl, alkynyl, aminoalkyl, OH, alkoxy, amino, alkylamino, dialkylamino, hydroxyalkyl, alkylamino alkyl, dialkylaminoalkyl, alkoxyalkyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, arylalkyl, heterocyclylalkyl, heteroarylalkyl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R39;

[0070] R39 is selected from alkyl, alkenyl, alkynyl, aminoalkyl, OH, alkoxy, amino, nitro, cyano, halo, alkylamino, dialkylamino, hydroxyalkyl, alkylamino alkyl, dialkylaminoalkyl, alkoxyalkyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, arylalkyl, heterocyclylalkyl, arylalkenyl, heterocyclylalkenyl, arylheterocyclylalkenyl, heterocyclylarylalkenyl, or heteroarylalkyl; and

[0071] R2 and R3 optionally join to form a saturated or unsaturated ring of 5, 6, 7, or 8 atoms, where the atoms in the ring are independently selected from CR40, C(R40)2, C═O, N, NR40, O, S, C═S, S═O, or SO2.

[0072] The present invention is also directed to a novel method of inhibiting mitogen activated protein kinase-activated protein kinase-2 in a subject in need of such inhibition, the method comprising administering to the subject an MK-2 inhibiting compound having the structure shown above.

[0073] The present invention is also directed to a novel method of preventing or treating a TNFα mediated disease or disorder in a subject in need of such prevention or treatment, the method comprising administering to the subject an effective amount of an MK-2 inhibiting compound having the structure shown above

[0074] The present invention is also directed to a novel pharmaceutical composition comprising an MK-2 inhibiting compound comprising a pharmaceutical carrier and an MK-2 inhibiting compound having the structure shown above.

[0075] The present invention is also directed to a novel kit comprising a dosage form that includes an MK-2 inhibiting compound in a therapeutically effective amount, the MK-2 inhibiting compound having the structure shown above.

[0076] Among the several advantages found to be achieved by the present invention, therefore, may be noted the provision of a method that could serve to modulate the activity of MK-2—in particular, to inhibit MK-2 activity, and the provision of a method for the prevention and treatment of diseases and disorders that are mediated by TNFα.

BRIEF DESCRIPTION OF THE DRAWINGS

[0077]
FIG. 1 is a graph showing paw thickness as a function of time from day 0 to day 7 for MK2 (+/+) and MK2 (−/−) mice, which have received serum injection; and

[0078]
FIG. 2 is a bar chart showing paw thickness at seven days after injection for normal mice, MK2 (+/+) mice receiving serum, MK2 (−/−) mice receiving serum, and MK2 (+/+) mice receiving serum and anti-TNF antibody.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0079] In accordance with the present invention, it has been discovered that certain cyclic pyrazole compounds can inhibit the activity of MAPKAP kinase-2. Many of these compounds exhibit their inhibitory effect at low concentrations—having in vitro MK-2 inhibition IC50 values of under 10.0 EM, and with some having IC50 values of under about 1 μM, and even as low as about 0.2 μM. Accordingly, these compounds can be potent and effective drugs for use in the inhibition of MK-2, and of special value for administration to subjects where such inhibition would be useful. In particular, these compounds would be useful in methods to prevent or treat diseases and disorders that are mediated by TNFα. For example, they can be used for the prevention or treatment of arthritis.

[0080] Compounds that have a high degree of MK-2 inhibiting activity offer advantages in therapeutic uses, because lower amounts of the compounds can be used to obtain a therapeutic benefit than with less active compounds. Such highly active compounds might also offer fewer side effects, and a higher selectivity.

[0081] The terms “cyclic pyrazole MK-2 inhibitor”, or “cyclic pyrazole MK-2 inhibiting compound”, which may be used interchangeably herein, embrace certain fused bicyclic or tricyclic compounds wherein one of the rings is a pyrazole, which inhibit mitogen activated protein kinase-activated protein kinase-2, and also include pharmaceutically acceptable salts of those compounds. When the cyclic pyrazole compounds have three fused rings, the ring that is furthest from the pyrazole, Can be a phenyl ring, which, when substituted with an hydroxy group, is termed a phenoxy ring. Cyclic pyrazoles having such a phenoxy ring can be referred to here as “phenoxy pyrazoles”. Other tricyclic fused ring pyrazoles can have as the third ring another pyrazole (and can be referred to herein as pyrazolyl pyrazoles), or a pyridine (which can be referred to herein as pyridyl pyrazoles), or a pyrimidine ring (which can be referred to herein as pyrimidyl pyrazoles). Certain embodiments of the cyclic pyrazole MK-2 inhibitors of the present invention selectively inhibit MK-2 relative to MK-3.

[0082] In practice, the selectivity of a cyclic pyrazole MK-2 inhibitor varies depending upon the condition under which the test is performed and on the inhibitors being tested. However, for the purposes of this specification, the selectivity of a cyclic pyrazole MK-2 inhibitor inhibitor can be measured as a ratio of the in vitro or in vivo IC50 value for inhibition of MK-3, divided by the IC50 value for inhibition of MK-2 (IC50 MK-3/IC50 MK-2). As used herein, the term “IC50” refers to the concentration of a compound that is required to produce 50% inhibition of MK-2 or MK-3 activity. An MK-2 selective inhibitor is any inhibitor for which the ratio of IC50 MK-3 to IC50 MK-2 is greater than 1. In preferred embodiments, this ratio is greater than 2, more preferably greater than 5, yet more preferably greater than 10, still more preferably greater than 50, and more preferably still, is greater than 100. Such preferred selectivity may indicate an ability to reduce the incidence of side effects incident to the administration of an MK-2 inhibitor to a subject.

[0083] Also included within the scope of the present invention are compounds that act as prodrugs of the present cyclic pyrazole MK-2 inhibitors. As used herein in reference to cyclic pyrazole MK-2 inhibitors, the term “prodrug” refers to a chemical compound that can be converted into an active cyclic pyrazole MK-2 inhibitor by metabolic or simple chemical processes within the body of the subject.

[0084] Cyclic pyrazole MK-2 inhibiting compounds of the present invention include those having the structure shown in formula I:

[0085] Formula I:

[0086] A cyclic pyrazole MK-2 inhibiting compound having the structure:

[0087] where:

[0088] Ra and Rb join to form a ring structure selected from the group consisting of:

[0089] A, E, G and J are carbon, or optionally, one of A, E, G and J is selected from nitrogen, sulfur, or oxygen;

[0090] when A, E, G, or J is oxygen or sulfur, no substituent groups are bonded to the oxygen or the sulfur;

[0091] when A, E, G, or J is nitrogen, the nitrogen is optionally unsubstituted, or is substituted with R9;

[0092] each of R1, R2, R4 and R6 is optionally absent, or is independently selected from the R3 groups;

[0093] R3, R5, R7, R8, R9, R40, R54 and R55 are each independently selected from —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, nitro C1-C6 alkyl, azido C1-C6 alkyl, amino, NHR10, NR11R12, C1-C6 alkyl-NHR10, C1-C6-alkyl-NR11R12, nitro, cyano, O—R13, C1-C4 alkyl-OR13, aryl, heteroaryl, heterocyclyl, COR14, SR13, SOR14, SO2R14, C1-C6 alkyl-COR14, C1-C6 alkyl-SR13, C1-C6 alkyl-SOR14, C1-C6 alkyl-SO2R14, halo, halo C1-C6 alkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, arylalkyl, heteroarylalkyl, heterocyclylalkyl, arylalkenyl, heterocyclylalkenyl, arylheterocyclylalkenyl, heterocyclylarylalkenyl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R15;

[0094] R10, R11, are each independently selected from —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, amino, NHR16, NR16R17, C1-C6 alkyl-NHR16, C1-C6 alkyl-NR16R17, O—R18, C1-C4 alkyl-OR18, aryl, heteroaryl, heterocyclyl, CO2R19, COR20, CONHR19, CON(R19)2, SR18, SOR20, SO2R20, C1-C6 alkyl-CO2R19, C1-C6 alkyl-COR20, C1-C6 alkyl-CONHR19, C1-C6 alkyl-CON(R19)2, C1-C6 alkyl-SR18, C1-C6 alkyl-SOR20, C1-C6 alkyl-SO2R20, halo, halo C1-C6 alkyl, arylaryl, arylheteroaryl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, arylalkyl, heteroarylalkyl, heterocyclylalkyl, arylalkenyl, heterocyclylalkenyl, arylheterocyclylalkenyl, heterocyclylarylalkenyl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R21;

[0095] R12, R13 are each independently selected from —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl-NHR16, C1-C6 alkyl-NR16R17, C1-C4 alkyl-OR18, aryl, heteroaryl, heterocyclyl, CO2R19, COR20, CONHR19, CON(R19)2, SOR20, SO2R20, C1-C6 alkyl-CO2R19, C1-C6 alkyl-COR20, C1-C6 alkyl-CONHR19, C1-C6 alkyl-CON(R19)2, C1-C6 alkyl-SR18, C1-C6 alkyl-SOR20, C1-C6 alkyl-SO2R20, halo C1-C6 alkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R21;

[0096] R14 is selected from —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, amino, NHR16, NR16R17, C1-C6 alkyl-NHR16, C1-C6 alkyl-NR16R17, O—R18, C1-C4 alkyl-OR18, aryl, heteroaryl, heterocyclyl, SR18, C1-C6 alkyl-CO2R19, C1-C6 alkyl-COR20, C1-C6 alkyl-CONHR19, C1-C6 alkyl-CON(R19)2, C1-C6 alkyl-SR18, C1-C6 alkyl-SOR20, C1-C6 alkyl-SO2R20, halo, halo C1-C6 alkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, arylalkyl, heteroarylalkyl, heterocyclylalkyl, arylalkenyl, heterocyclylalkenyl, arylheterocyclylalkenyl, heterocyclylarylalkenyl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R21;

[0097] R15 is selected from —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, amino, NHR10, NR11R12, C1-C6 alkyl-NHR10, C1-C6 alkyl-NR11R12, nitro, cyano, O—R13, C1-C4 alkyl-OR13, aryl, heteroaryl, heterocyclyl, COR14, SR13, SOR14, SO2R14, C1-C6 alkyl-COR14, C1-C6 alkyl-SR13, C1-C6 alkyl-SOR14, C1-C6 alkyl-SO2R14, halo, halo C1-C6 alkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, arylalkyl, heteroarylalkyl, heterocyclylalkyl, arylalkenyl, heterocyclylalkenyl, arylheterocyclylalkenyl, heterocyclylarylalkenyl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R21;

[0098] R16 and R17 are each independently selected from —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, amino, C1-C6 alkyl-NHR22, C1-C6 alkyl-NR22R23, C1-C4 alkyl-OR24, aryl, heteroaryl, heterocyclyl, CO2R25, COR26, CONHR25, CON(R25)2, SOR26, SO2R26, C1-C6 alkyl-CO2R25, C1-C6 alkyl-COR26, C1-C6 alkyl-CONHR25, C1-C6 alkyl-CON(R25)2, C1-C6 alkyl-SR24, C1-C6 alkyl-SOR26, C1-C6 alkyl-SO2R26, halo, halo C1-C6 alkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, arylalkyl, heteroarylalkyl, heterocyclylalkyl, arylalkenyl, heterocyclylalkenyl, arylheterocyclylalkenyl, heterocyclylarylalkenyl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R27;

[0099] R18, R19 are each independently selected from —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl-NHR22, C1-C6 alkyl-NR22R23, C1-C4 alkyl-OR24, aryl, heteroaryl, heterocyclyl, CO2R25, COR26, CONHR25, CON(R25)2, SOR26, SO2R27, C1-C6 alkyl-CO2R25, C1-C6 alkyl-COR26, C1-C6 alkyl-CONHR25, C1-C6 alkyl-CON(R25)2, C1-C6 alkyl-SR24, C1-C6 alkyl-SOR26, C1-C6 alkyl-SO2R26, halo C1-C6 alkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R27;

[0100] R20 is selected from —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, amino, NHR22, NR22R23, C1-C6 alkyl-NHR22, C1-C6 alkyl-NR22R23, O—R24, C1-C4 alkyl-OR24, aryl, heteroaryl, heterocyclyl, SR24, C1-C6 alkyl-CO2R25, C1-C6 alkyl-COR26, C1-C6 alkyl-CONHR25, C1-C6 alkyl-CON(R25)2, C1-C6 alkyl-SR24, C1-Ca alkyl-SOR26, C1-C6 alkyl-SO2R26, halo, halo C1-C6 alkyl, arylalkoxyalkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, arylalkyl, heteroarylalkyl, heterocyclylalkyl, arylalkenyl, heterocyclylalkenyl, arylheterocyclylalkenyl, heterocyclylarylalkenyl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R27;

[0101] R21 is selected from —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, amino, NHR22, NR22R23, C1-C6 alkyl-NHR22, C1-C6 alkyl-NR22R23, nitro, cyano, O—R24, C1-C4 alkyl-OR24, aryl, heteroaryl, heterocyclyl, COR26, SR24, SOR26, SO2R26, C1-C6 alkyl-COR26, C1-C6 alkyl-SR24, C1-C6 alkyl-SOR26, C1-C6 alkyl-SO2R26, halo, halo C1-C6 alkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, arylalkyl, heteroarylalkyl, heterocyclylalkyl, arylalkenyl, heterocyclylalkenyl, arylheterocyclylalkenyl, heterocyclylarylalkenyl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R27;

[0102] R22 and R23 are each independently selected from —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, amino, C1-C6 alkyl-NHR28, C1-C6 alkyl-NR28R29, C1-C4 alkyl-OR30, aryl, heteroaryl, heterocyclyl, CO2R31, COR32, CONHR31, CON(R31)2, SOR32, SO2R32, C1-C6 alkyl-CO2R31, C1-C6 alkyl-COR32, C1-C6 alkyl-CONHR31, C1-C6 alkyl-CON(R31)2, C1-C6 alkyl-SR30, C1-C6 alkyl-SOR32, C1-C6 alkyl-SO2R32, halo, halo C1-C6 alkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, arylalkyl, heteroarylalkyl, heterocyclylalkyl, arylalkenyl, heterocyclylalkenyl, arylheterocyclylalkenyl, heterocyclylarylalkenyl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R33;

[0103] R24 and R25 are each independently selected from —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl-NHR28, C1-C6 alkyl-NR28R29, C1-C4 alkyl-OR30, aryl, heteroaryl, heterocyclyl, CO2R31, COR32, CONHR31, CON(R31)2, SOR32, SO2R32, C1-C6 alkyl-CO2R31, C1-C6 alkyl-COR32, C1-C6 alkyl-CONHR31, C1-C6 alkyl-CON(R31)2, C1-C6 alkyl-SR30, C1-C6 alkyl-SOR32, C1-C6 alkyl-SO2R32, halo C1-C6 alkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R33;

[0104] R26 is selected from —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, amino, NHR28, NR28R29, C1-C6 alkyl-NHR28, C1-C6 alkyl-NR28R29, O—R30, C1-C4 alkyl-OR30, aryl, heteroaryl, heterocyclyl, SR30, C1-C6 alkyl-CO2R31, C1-C6 alkyl-COR32, C1-C6 alkyl-CONHR31, C1-C6 alkyl-CON(R31)2, C1-C6 alkyl-SR30, C1-C6 alkyl-SOR32, C1-C6 alkyl-SO2R32, halo, halo C1-C6 alkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, arylalkyl, heteroarylalkyl, heterocyclylalkyl, arylalkenyl, heterocyclylalkenyl, arylheterocyclylalkenyl, heterocyclylarylalkenyl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R33;

[0105] R27 is selected from —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, amino, NHR28, NR25R29, C1-C6 alkyl-NHR28, C1-C6 alkyl-NR28R29, nitro, cyano, O—R30, C1-C4 alkyl-OR30, aryl, heteroaryl, heterocyclyl, COR32, SR30, SOR32, SO2R32, C1-C6 alkyl-COR32, C1-C6 alkyl-SR30, C1-C6 alkyl-SOR32, C1-C6 alkyl-SO2R32, halo, halo C1-C6 alkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, arylalkyl, heteroarylalkyl, heterocyclylalkyl, arylalkenyl, heterocyclylalkenyl, arylheterocyclylalkenyl, heterocyclylarylalkenyl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R33;

[0106] R28 and R29 are each independently selected from —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, amino, C1-C6 alkyl-NHR34, C1-C6 alkyl-NR34R35, C1-C4 alkyl-OR36, aryl, heteroaryl, heterocyclyl, CO2R37, COR38, CONHR37, CON(R37)2, SOR38, SO2R38, C1-C6 alkyl-CO2R37, C1-C6 alkyl-COR38, C1-C6 alkyl-CONHR37, C1-C6 alkyl-CON(R37)2, C1-C6 alkyl-SR36, C1-C6 alkyl-SOR38, C1-C6 alkyl-SO2R38, halo, halo C1-C6 alkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, arylalkyl, heteroarylalkyl, heterocyclylalkyl, arylalkenyl, heterocyclylalkenyl, arylheterocyclylalkenyl, heterocyclylarylalkenyl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R39;

[0107] R30 and R31 are each independently selected from —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl-NHR34, C1-C6 alkyl-NR34R35, C1-C4 alkyl-OR36, aryl, heteroaryl, heterocyclyl, CO2R37, COR38, CONHR37, CON(R37)2, SOR38, SO2R38, C1-C6 alkyl-CO2R37, C1-C6 alkyl-COR37, C1-C6 alkyl-CONHR37, C1-C6 alkyl-CON(R37)2, C1-C6 alkyl-SR36, C1-C6 alkyl-SOR38, C1-C6 alkyl-SO2R38, halo C1-C6 alkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R39;

[0108] R32 is selected from —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, amino, NHR34, NR34R35, C1-C6 alkyl-NHR34, C1-C6 alkyl-NR34R35, O—R36, C1-C4 alkyl-OR36, aryl, heteroaryl, heterocyclyl, SR36, C1-C6 alkyl-CO2R37, C1-C6 alkyl-COR38, C1-C6 alkyl-CONHR37, C1-C6 alkyl-CON(R37)2, C1-C6 alkyl-SR36, C1-C6 alkyl-SOR38, C1-C6 alkyl-SO2R38, halo, halo C1-C6 alkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, arylalkyl, heteroarylalkyl, heterocyclylalkyl, arylalkenyl, heterocyclylalkenyl, arylheterocyclylalkenyl, heterocyclylarylalkenyl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R39;

[0109] R33 is selected from —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, amino, NHR34, NR34R35, C1-C6 alkyl-NHR31, C1-C6 alkyl-NR34R35, nitro, cyano, O—R36, C1-C4 alkyl-OR36, aryl, heteroaryl, heterocyclyl, COR38, SR35, SOR38, SO2R38, C1-C6 alkyl-COR38, C1-C6 alkyl-SR36, C1-C6 alkyl-SOR38, C1-C6 alkyl-SO2R38, halo, halo C1-C6 alkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, arylalkyl, heteroarylalkyl, heterocyclylalkyl, arylalkenyl, heterocyclylalkenyl, arylheterocyclylalkenyl, heterocyclylarylalkenyl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R39;

[0110] R34, R35, R36 and R37 are each independently selected from —H, alkyl, alkenyl, alkynyl, aminoalkyl, hydroxyalkyl, alkylamino alkyl, dialkylaminoalkyl, alkoxyalkyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, arylalkyl, heterocyclylalkyl, heteroarylalkyl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R39;

[0111] R38 is selected from —H, alkyl, alkenyl, alkynyl, aminoalkyl, OH, alkoxy, amino, alkylamino, dialkylamino, hydroxyalkyl, alkylamino alkyl, dialkylaminoalkyl, alkoxyalkyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, arylalkyl, heterocyclylalkyl, heteroarylalkyl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R39;

[0112] R39 is selected from alkyl, alkenyl, alkynyl, aminoalkyl, OH, alkoxy, amino, nitro, cyano, halo, alkylamino, dialkylamino, hydroxyalkyl, alkylamino alkyl, dialkylaminoalkyl, alkoxyalkyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, arylalkyl, heterocyclylalkyl, arylalkenyl, heterocyclylalkenyl, arylheterocyclylalkenyl, heterocyclylarylalkenyl, or heteroarylalkyl; and

[0113] R2 and R3, or R8 and R9, optionally join to form a saturated or unsaturated ring of 5, 6, 7, or 8 atoms, where the atoms in the ring are independently selected from CR40, C(R40)2, C═O, N, NR40, O, S, C═S, S═O, or SO2.

[0114] The meaning of any substituent at any one occurrence in Formula I, or any other general chemical formula herein, is independent of its meaning, or any other substituent's meaning, at any other occurrence, unless specified otherwise.

[0115] The term “alkyl” is used, either alone or within other terms such as “haloalkyl” and “alkylsulfonyl”; it embraces linear or branched radicals having one to about twenty carbon atoms or, preferably, one to about twelve carbon atoms. More preferred alkyl radicals are “lower alkyl” radicals having one to about ten carbon atoms. Most preferred are lower alkyl radicals having one to about five carbon atoms. The number of carbon atoms can also be expressed as “C1-C5”, for example. Examples of such radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isoamyl, hexyl, octyl and the, like. The term “alkenyl” refers to an unsaturated, acyclic hydrocarbon radical, linear or branched, in so much as it contains at least one double bond. Unless otherwise noted, such radicals preferably contain from 2 to about 6 carbon atoms, preferably from 2 to about 4 carbon atoms, more preferably from 2 to about 3 carbon atoms. The alkenyl radicals may be optionally substituted with groups as defined below. Examples of suitable alkenyl radicals include propenyl, 2-chloropropylenyl, buten-1yl, isobutenyl, penten-1yl, 2-methylbuten-1-yl, 3-methylbuten-1-yl, hexen-1-yl, 3-hydroxyhexen-1-yl, hepten-1-yl, octen-1-yl, and the like. The term “alkynyl” refers to an unsaturated, acyclic hydrocarbon radical, linear or branched, in so much as it contains one or more triple bonds, such radicals preferably containing 2 to about 6 carbon atoms, more preferably from 2 to about 3 carbon atoms. The alkynyl radicals may be optionally substituted with groups as described below. Examples of suitable alkynyl radicals include ethynyl, proynyl, hydroxypropynyl, butyn-1-yl, butyn-2-yl, pentyn-1-yl, pentyn-2-yl, 4-methoxypentyn-2-yl, 3-methylbutyn-1-yl, hexyl-1-yl, hexyn-2-yl, hexyn-3-yl, 3,3-dimethylbutyn-1-yl radicals, and the like. The term “oxo” means a single double-bonded oxygen. The terms “hydrido”, “—H”, or “hydrogen”, denote a single hydrogen atom (H). This hydrido radical may be attached, for example, to an oxygen atom to form a hydroxyl radical, or two hydrido radicals may be attached to a carbon atom to form a methylene (—CH2—) radical. The term “halo” means halogens such as fluorine, Chlorine, and bromine or iodine atoms. The term “haloalkyl” embraces radicals wherein any one or more of the alkyl carbon atoms is substituted with halo as de-fined above. Specifically embraced are monohaloalkyl, dihaloalkyl, and polyhaloalkyl radicals. A monohaloalkyl radical, for one example, may have a bromo, Chloro, or a fluoro atom within the radical. Dihalo radicals may have two or more of the same halo atoms or a combination of different halo radicals and polyhaloalkyl radicals may have more than two of the same halo atoms or a combination of different halo radicals. The term “hydroxyalkyl” embraces linear or branched alkyl radicals having one to about ten carbon atoms any one of which may be substituted with one or more hydroxyl radicals. The terms “alkoxy” and “alkoxyalkyl” embrace linear or branched oxy-containing radicals each having alkyl portions of one to about ten carbon atoms, such as methoxy radical. The term “alkoxyalkyl” also embraces alkyl radicals having two or more alkoxy radicals attached to the alkyl radical, that is, to form monoalkoxyalkyl and dialkoxyalkyl radicals. The “alkoxy” or “alkoxyalkyl” radicals may be further substituted with one or more halo atoms, such as fluoro, Chloro, or bromo, to provide “haloalkoxy” or “haloalkoxyalkyl” radicals. Examples of “alkoxy” radicals include methoxy, butoxy, and trifluoromethoxy. Terms such as “alkoxy(halo)alkyl”, indicate a molecule having a terminal alkoxy that is bound to an alkyl, which is bonded to the parent molecule, while the alkyl also has a substituent halo group in a non-terminal location. In other words, both the alkoxy and the halo group are substituents of the alkyl chain. The term “aryl”, alone or in combination, means a carbocyclic aromatic system containing one, two, or three rings wherein such rings may be attached together in a pendent manner or may be fused. The term “aryl” embraces aromatic radicals such as phenyl, naphthyl, tetrahydronapthyl, indane, and biphenyl. The term “heterocyclyl” means a saturated or unsaturated mono- or multi-ring carbocycle wherein one or more carbon atoms is replaced by N, S, P, or O. This includes, for example, structures such as:

[0116] where Z, Z1, Z2, or Z3 is C, S, P, O, or N, with the proviso that one of Z, Z1, Z2, or Z3 is other than carbon, but is not O or S when attached to another Z atom by a double bond or when attached to another O or S atom. Furthermore, the optional substituents are understood to be attached to Z, Z1, Z2, or Z3 only when each is C. The term “heterocycle” also includes fully saturated ring structures, such as piperazinyl, dioxanyl, tetrahydrofuranyl, oxiranyl, aziridinyl, morpholinyl, pyrrolidinyl, piperidinyl, thiazolidinyl, and others. The term “heteroaryl” embraces unsaturated heterocyclic radicals. Examples of unsaturated heterocyclic radicals, also termed “heteroaryl” radicals include thienyl, pyrryl, furyl, pyridyl, pyrimidyl, pyrazinyl, pyrazolyl, oxazolyl, isoxazolyl, imidazolyl, thiazolyl, pyranyl, and tetrazolyl. The term also embraces radicals where heterocyclic radicals are fused with aryl radicals. Examples of such fused bicyclic radicals include benzofuran, benzothiophene, and the like. The terms aryl or heteroaryl, as appropriate, include the following structures:

[0117] where:

[0118] when n=1, m=1 and A1-A8 are each CRx or N, A9 and A10 are carbon;

[0119] when n=0, or 1, and m=0, or 1, one of A2-A4 and/or A5-A7 is optionally S, O, or NRx, and other ring members are CRx or N, with the proviso that oxygen cannot be adjacent to sulfur in a ring. A9 and A10 are carbon;

[0120] when n is greater than or equal to 0, and m is greater than or equal to 0, 1 or more sets of 2 or more adjacent atoms A1-A10 are sp3 O, S, NRx, CRxRy, or C═(O or S), with the proviso that oxygen and sulfur cannot be adjacent. The remaining A1-A8 are CRx or N, and A9 and A10 are carbon;

[0121] when n is greater than or equal to 0, and m greater than or equal to 0, atoms separated by 2 atoms (i.e., A1 and A4) are Sp3 O, S, NRx, CRxRy, and remaining A1-A8 are independently CRx or N, and A9 and A10 are carbon.

[0122] The term “sulfonyl”, whether used alone or linked to other terms such as alkylsulfonyl, denotes respectively divalent radicals —SO2—. “Alkylsulfonyl”, embraces alkyl radicals attached to a sulfonyl radical, where alkyl is defined as above. The term “arylsulfonyl” embraces sulfonyl radicals substituted with an aryl radical. The terms “sulfamyl” or “sulfonamidyl”, whether alone or used with terms such as “N-alkylsulfamyl”, “N-arylsulfamyl”, “N,N-dialkylsulfamyl” and “N-alkyl-N-arylsulfamyl”, denotes a sulfonyl radical substituted with an amine radical, forming a sulfonamide (—SO2—NH2), which may also be termed an “aminosulfonyl”. The terms “N-alkylsulfamyl” and “N,N-dialkylsulfamyl” denote sulfamyl radicals substituted, respectively, with one alkyl radical, a cycloalkyl ring, or two alkyl radicals. The terms “N-arylsulfamyl” and “N-alkyl-N-arylsulfamyl” denote sulfamyl radicals substituted, respectively, with one aryl radical, and one alkyl and one aryl radical. The terms “carboxy” or “carboxyl”, whether used alone or with other terms, such as “carboxyalkyl”, denotes —CO2—H. The term “carboxyalkyl” embraces radicals having a carboxyradical as defined above, attached to an alkyl radical. The term “carbonyl”, whether used alone or with other terms, such as “alkylcarbonyl”, denotes —(C═O)—. The term “alkylcarbonyl” embraces radicals having a carbonyl radical substituted with an alkyl radical. An example of an “alkylcarbonyl” radical is CH3— (CO)—. The term “alkylcarbonylalkyl” denotes an alkyl radical substituted with an “alkylcarbonyl” radical. The term “alkoxycarbonyl” means a radical containing an alkoxy radical, as defined above, attached via an oxygen atom to a carbonyl (C═O) radical. Examples of such “alkoxycarbonyl” radicals include (CH3)3—C—O—C═O)— and —(O═)C—OCH3. The term “alkoxycarbonylalkyl” embraces radicals having “alkoxycarbonyl”, as defined above substituted to an alkyl radical. Examples of such “alkoxycarbonylalkyl” radicals include (CH3)3C—OC(═O)—(CH2)2— and (CH2)2 (—O)COCH3. The terms “amido”, or “carbamyl”, when used alone or with other terms such as “amidoalkyl”, “N-monoalkylamido”, “N-monoarylamido”, “N,N-dialkylamido”, “N-alkyl-N-arylamido”, “N-alkyl-N-hydroxyamido” and “N-alkyl-N-hydroxyamidoalkyl”, embraces a carbonyl radical substituted with an amino radical. The terms “N-alkylamido” and “N,N-dialkylamido” denote amido groups which have been substituted with one alkylradical and with two alkyl radicals, respectively. The terms “N-monoarylamido” and “N-alkyl-N-arylamido” denote amido radicals substituted, respectively, with one aryl radical, and one alkyl and one aryl radical. The term “N-alkyl-N-hydroxyamido” embraces amido radicals substituted with a hydroxyl radical and with an alkyl radical. The term “N-alkyl-N-hydroxyamidoalkyl” embraces alkylradicals substituted with an N-alkyl-N-hydroxyamido radical. The term “amidoalkyl” embraces alkyl radicals substituted with amido radicals. The term “aminoalkyl” embraces alkyl radicals substituted with amino radicals. The term “alkylaminoalkyl” embraces aminoalkyl radicals having the nitrogen atom substituted with an alkyl radical. The term “amidino” denotes an —C(—NH)—NH2 radical. The term “cyanoamidin” denotes an —C(—N—CN)—NH2 radical. The term “heterocycloalkyl” embraces heterocyclic-substituted alkyl radicals such as pyridylmethyl and thienylmethyl. The terms “aralkyl”, or “arylalkyl” embrace aryl-substituted alkyl radicals such as benzyl, diphenylmethyl, triphenylmethyl, phenethyl, and diphenethyl. The terms benzyl and phenylmethyl are interchangeable. The term “cycloalkyl” embraces radicals having three to ten carbon atoms, such as cyclopropyl cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. The term “cycloalkenyl” embraces unsaturated radicals having three to ten carbon atoms, such as cylopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, and cycloheptenyl. The term “alkylthio” embraces radicals containing a linear or branched alkyl radical, of one to ten carbon atoms, attached to a divalent sulfur atom. An example of “alkylthio” is methylthio, (CH3—S—). The term “alkylsulfinyl” embraces radicals containing a linear or branched alkyl radical, of one to ten carbon atoms, attached to a divalent —S(—O)— atom. The terms “N-alkylamino” and “N,N-dialkylamino” denote amino groups which have been substituted with one alkyl radical and with two alkyl radicals, respectively. The term “acyl”, whether used alone, or within a term such as “acylamino”, denotes a radical provided by the residue after removal of hydroxyl from an organic acid. The term “acylamino” embraces an amino radical substituted with an acyl group. An examples of an “acylamino” radical is acetylamino (CH3—C(═O)—NH—).

[0123] In the naming of substituent groups for general chemical structures, the naming of the chemical components of the group is typically from the terminal group-toward the parent compound unless otherwise noted, as discussed below. In other words, the outermost chemical structure is named first, followed by the next structure in line, followed by the next, etc. until the structure that is connected to the parent structure is named. For example, a substituent group having a structure such as:

[0124] may be referred to generally as a “haloarylalkylaminocarboxylalkyl”. An example of one such group would be fluorophenylmethylcarbamylpentyl. The bonds having wavy lines through them represent the parent structure to which the alkyl is attached.

[0125] Substituent groups may also be named by reference to one or more “R” groups. The structure shown above would be included in a description, such as, “—C1-C6-alkyl-CORu, where Ru is defined to include —NH—C1-C4-alkylaryl-Ry, and where Ry is defined to include halo. In this scheme, atoms having an “R” group are shown with the “R” group being the terminal group (i.e., furthest from the parent).

[0126] In another embodiment, the present cyclic pyrazole MK-2 inhibiting compound has the structure:

[0127] where:

[0128] Ra and Rb join to form a ring structure selected from the group consisting of:

[0129] A, E, G and J are carbon, or optionally, one of A, E, G and J is selected from nitrogen, sulfur, or oxygen;

[0130] when A, E, G, or J is oxygen or sulfur, no substituent groups are bonded to the oxygen or the sulfur;

[0131] when A, E, G, or J is nitrogen, the nitrogen is optionally unsubstituted, or is substituted with R9;

[0132] each of R1, R2, R4 and R6 is optionally absent, or is independently selected from the R3 groups;

[0133] R3, R5, R7, R8, R9, R40, R41, R42, R43, R44, R45, R46, R47, R48, R49, R50, R51, R52, R53, R54 and R55 are each independently selected from —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, nitro C1-C6 alkyl, azido C1-C6 alkyl, amino, NHR10, NR11R12, C1-C6 alkyl-NHR10, C1-C6 alkyl-NR11R12, nitro, cyano, O—R13, C1-C4 alkyl-OR13, aryl, heteroaryl, heterocyclyl, COR14, SR13, SOR14, SO2R14, C1-C6 alkyl-COR14, C1-C6 alkyl-SR13, C1-C6 alkyl-SOR14, C1-C6 alkyl-SO2R14, halo, halo C1-C6 alkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, arylalkyl, heteroarylalkyl, heterocyclylalkyl, arylalkenyl, heterocyclylalkenyl, arylheterocyclylalkenyl, heterocyclylarylalkenyl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R15, or R8 and R9 join to form a ring structure selected from:

[0134] R10, R11, are each independently selected from —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, amino, NHR16, NR16R17, C1-C6 alkyl-NHR16, C1-C6 alkyl-NR16R17, O—R18, C1-C4 alkyl-OR18, aryl, heteroaryl, heterocyclyl, CO2R19, COR20, CONHR19, CON(R19)2, SR18, SOR20, SO2R20, C1-C6 alkyl-CO2R19, C1-C6 alkyl-COR20, C1-C6 alkyl-CONHR19, C1-C6 alkyl-CON(R19)2, C1-C6 alkyl-SR18, C1-C6 alkyl-SOR20, C1-C6 alkyl-SO2R20, halo, halo C1-C6 alkyl, arylaryl, arylheteroaryl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, arylalkyl, heteroarylalkyl, heterocyclylalkyl, arylalkenyl, heterocyclylalkenyl, arylheterocyclylalkenyl, heterocyclylarylalkenyl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R21;

[0135] R12, R13 are each independently selected from —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl-NHR16, C1-C6 alkyl-NR16R17, C1-C4 alkyl-OR18, aryl, heteroaryl, heterocyclyl, CO2R19, COR20, CONHR19, CON(R19)2, SOR20, SO2R20, C1-C6 alkyl-CO2R19, C1-C6 alkyl-COR20, C1-C6 alkyl-CONHR19, C1-C6 alkyl-CON(R19)2, C1-C6 alkyl-SR18, C1-C6 alkyl-SOR20, C1-C6 alkyl-SO2R20, halo C1-C6 alkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R21;

[0136] R14 is selected from —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, amino, NHR16, NR16R17, C1-C6 alkyl-NHR16, C1-C6 alkyl-NR16R17, O—R18, C1-C4 alkyl-OR18, aryl, heteroaryl, heterocyclyl, SR18, C1-C6 alkyl-CO2R19, C1-C6 alkyl-COR20, C1-C6 alkyl-CONHR19, C1-C6 alkyl-CON(R19)2, C1-C6 alkyl-SR18, C1-C6 alkyl-SOR20, C1-C6 alkyl-SO2R20, halo, halo C1-C6 alkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, arylalkyl, heteroarylalkyl, heterocyclylalkyl, arylalkenyl, heterocyclylalkenyl, arylheterocyclylalkenyl, heterocyclylarylalkenyl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R21;

[0137] R15 is selected from —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, amino, NHR10, NR11R12, C1-C6 alkyl-NHR10, C1-C6 alkyl-NR11R12, nitro, cyano, O—R13, C1-C4 alkyl-OR13, aryl, heteroaryl, heterocyclyl, COR14, SR13, SOR14, SO2R14, C1-C6 alkyl-COR14, C1-C6 alkyl-SR13, C1-C6 alkyl-SOR14, C1-C6 alkyl-SO2R14, halo, halo C1-C6 alkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, arylalkyl, heteroarylalkyl, heterocyclylalkyl, arylalkenyl, heterocyclylalkenyl, arylheterocyclylalkenyl, heterocyclylarylalkenyl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R21;

[0138] R16 and R17 are each independently selected from —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, amino, C1-C6 alkyl-NHR22, C1-C6 alkyl-NR22R23, C1-C4 alkyl-OR24, aryl, heteroaryl, heterocyclyl, CO2R25, COR26, CONHR25, CON(R25)2, SOR26, SO2R26, C1-C6 alkyl-CO2R25, C1-C6 alkyl-COR26, C1-C6 alkyl-CONHR25, C1-C6 alkyl-CON(R25)2, C1-C6 alkyl-SR24, C1-C6 alkyl-SOR26, C1-C6 alkyl-SO2R26, halo, halo C1-C6 alkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, arylalkyl, heteroarylalkyl, heterocyclylalkyl, arylalkenyl, heterocyclylalkenyl, arylheterocyclylalkenyl, heterocyclylarylalkenyl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R27;

[0139] R18, R19 are each independently selected from —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl-NHR22, C1-C6 alkyl-NR22R23, C1-C4 alkyl-OR24, aryl, heteroaryl, heterocyclyl, CO2R25, COR26, CONHR25, CON(R25)2, SOR26, SO2R27, C1-C6 alkyl-CO2R25, C1-C6 alkyl-COR26, C1-C6 alkyl-CONHR25, C1-C6 alkyl-CON(R25)2, C1-C6 alkyl-SR24, C1-C6 alkyl-SOR26, C1-C6 alkyl-SO2R26, halo C1-C6 alkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R27;

[0140] R20 is selected from —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, amino, NHR22, NR22R23, C1-C6 alkyl-NHR22, C1-C6 alkyl-NR22R23, O—R24, C1-C4 alkyl-OR24, aryl, heteroaryl, heterocyclyl, SR24, C1-C6 alkyl-CO2R25, C1-C6 alkyl-COR26, C1-C6 alkyl-CONHR25, C1-C6 alkyl-CON(R25)2, C1-C6 alkyl-SR24, C1-C6 alkyl-SOR26, C1-C6 alkyl-SO2R26, halo, halo C1-C6 alkyl, arylalkoxyalkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, arylalkyl, heteroarylalkyl, heterocyclylalkyl, arylalkenyl, heterocyclylalkenyl, arylheterocyclylalkenyl, heterocyclylarylalkenyl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R27;

[0141] R21 is selected from —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, amino, NHR22, NR22R23, C1-C6 alkyl-NHR22, C1-C6 alkyl-NR22R23, nitro, cyano, O—R24, C1-C4 alkyl-OR24, aryl, heteroaryl, heterocyclyl, COR26, SR24, SOR26, SO2R26, C1-C6 alkyl-COR26, C1-C6 alkyl-SR24, C1-C6 alkyl-SOR26, C1-C6 alkyl-SO2R26, halo, halo C1-C6 alkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, arylalkyl, heteroarylalkyl, heterocyclylalkyl, arylalkenyl, heterocyclylalkenyl, arylheterocyclylalkenyl, heterocyclylarylalkenyl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R27;

[0142] R22 and R23 are each independently selected from —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, amino, C1-C6 alkyl-NHR28, C1-C6 alkyl-NR28R29, C1-C4 alkyl-OR30, aryl, heteroaryl, heterocyclyl, CO2R31, COR32, CONHR31, CON(R31)2, SOR32, SO2R32, C1-C6 alkyl-CO2R31, C1-C6 alkyl-COR32, C1-C6 alkyl-CONHR31, C1-C6 alkyl-CON(R31)2, C1-C6 alkyl-SR30, C1-C6 alkyl-SOR32, C1-C6 alkyl-SO2R32, halo, halo C1-C6 alkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, arylalkyl, heteroarylalkyl, heterocyclylalkyl, arylalkenyl, heterocyclylalkenyl, arylheterocyclylalkenyl, heterocyclylarylalkenyl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R33;

[0143] R24 and R25 are each independently selected from —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl-NHR28, C1-C6 alkyl-NR28R29, C1-C4 alkyl-OR30, aryl, heteroaryl, heterocyclyl, CO2R31, COR32, CONHR31, CON(R31)2, SOR32, SO2R32, C1-C6 alkyl-CO2R31, C1-C6 alkyl-COR32, C1-C6 alkyl-CONHR31, C1-C6 alkyl-CON(R31)2, C1-C6 alkyl-SR30, C1-C6 alkyl-SOR32, C1-C6 alkyl-SO2R32, halo C1-C6 alkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R33;

[0144] R26 is selected from —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, amino, NHR28, NR28R29, C1-C6 alkyl-NHR28, C1-C6 alkyl-NR28R29, O—R30, C1-C4 alkyl-OR30, aryl, heteroaryl, heterocyclyl, SR30, C1-C6 alkyl-CO2R31, C1-C6 alkyl-COR32, C1-C6 alkyl-CONHR31, C1-C6 alkyl-CON(R32)2, C1-C6 alkyl-SR30, C1-C6 alkyl-SOR32, C1-C6 alkyl-SO2R32, halo, halo C1-C6 alkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, arylalkyl, heteroarylalkyl, heterocyclylalkyl, arylalkenyl, heterocyclylalkenyl, arylheterocyclylalkenyl, heterocyclylarylalkenyl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R33;

[0145] R27 is selected from —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, amino, NHR28, NR28R29, C1-C6 alkyl-NHR28, C1-C6 alkyl-NR28R29, nitro, cyano, O—R30, C1-C4 alkyl-OR30, aryl, heteroaryl, heterocyclyl, COR32, SR30, SOR32, SO2R32, C1-C6 alkyl-COR32, C1-C6 alkyl-SR30, C1-C6 alkyl-SOR32, C1-C6 alkyl-SO2R32, halo, halo C1-C6 alkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, arylalkyl, heteroarylalkyl, heterocyclylalkyl, arylalkenyl, heterocyclylalkenyl, arylheterocyclylalkenyl, heterocyclylarylalkenyl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R33;

[0146] R28 and R29 are each independently selected from —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, amino, C1-C6 alkyl-NHR34, C1-C6 alkyl-NR34R35, C1-C4 alkyl-OR36, aryl, heteroaryl, heterocyclyl, CO2R37, COR38, CONHR37, CON(R37)2, SOR38, SO2R38, C1-C6 alkyl-CO2R37, C1-C6 alkyl-COR38, C1-C6 alkyl-CONHR37, C1-C6 alkyl-CON(R37)2, C1-C6 alkyl-SR36, C1-C6 alkyl-SOR38, C1-C6 alkyl-SO2R38, halo, halo C1-C6 alkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, arylalkyl, heteroarylalkyl, heterocyclylalkyl, arylalkenyl, heterocyclylalkenyl, arylheterocyclylalkenyl, heterocyclylarylalkenyl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R39;

[0147] R30 and R31 are each independently selected from —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl-NHR34, C1-C6 alkyl-NR34R35, C1-C4 alkyl-OR36, aryl, heteroaryl, heterocyclyl, CO2R37, COR38, CONHR37, CON(R37)2, SOR38, SO2R38, C1-C6 alkyl-CO2R37, C1-C6 alkyl-COR38, C1-C6 alkyl-CONHR37, C1-C6 alkyl-CON(R37)2, C1-C6 alkyl-SR36, C1-C6 alkyl-SOR38, C1-C6 alkyl-SO2R38, halo C1-C6 alkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R39;

[0148] R32 is selected from —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, amino, NHR34, NR34R35, C1-C6 alkyl-NHR34, C1-C6 alkyl-NR34R35, O—R36, C1-C4 alkyl-OR36, aryl, heteroaryl, heterocyclyl, SR36, C1-C6 alkyl-CO2R37, C1-C6 alkyl-COR38, C1-C6 alkyl-CONHR37, C1-C6 alkyl-CON(R37)2, C1-C6 alkyl-SR36, C1-C6 alkyl-SOR38, C1-C6 alkyl-SO2R38, halo, halo C1-C6 alkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, arylalkyl, heteroarylalkyl, heterocyclylalkyl, arylalkenyl, heterocyclylalkenyl, arylheterocyclylalkenyl, heterocyclylarylalkenyl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R39;

[0149] R33 is selected from —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, amino, NHR34, NR34R35, C1-C6 alkyl-NHR31, C1-C6 alkyl-NR34R35, nitro, cyano, O—R36, C1-C4 alkyl-OR36, aryl, heteroaryl, heterocyclyl, COR38, SR35, SOR38, SO2R38, C1-C6 alkyl-COR38, C1-C6 alkyl-SR36, C1-C6 alkyl-SOR38, C1-C6 alkyl-SO2R38, halo, halo C1-C6 alkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, arylalkyl, heteroarylalkyl, heterocyclylalkyl, arylalkenyl, heterocyclylalkenyl, arylheterocyclylalkenyl, heterocyclylarylalkenyl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R39;

[0150] R34, R35, R36 and R37 are each independently selected from —H, alkyl, alkenyl, alkynyl, aminoalkyl, hydroxyalkyl, alkylamino alkyl, dialkylaminoalkyl, alkoxyalkyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, arylalkyl, heterocyclylalkyl, heteroarylalkyl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R39;

[0151] R38 is selected from —H, alkyl, alkenyl, alkynyl, aminoalkyl, OH, alkoxy, amino, alkylamino, dialkylamino, hydroxyalkyl, alkylamino alkyl, dialkylaminoalkyl, alkoxyalkyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, arylalkyl, heterocyclylalkyl, heteroarylalkyl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R39;

[0152] R39 is selected from alkyl, alkenyl, alkynyl, aminoalkyl, OH, alkoxy, amino, nitro, cyano, halo, alkylamino, dialkylamino, hydroxyalkyl, alkylamino alkyl, dialkylaminoalkyl, alkoxyalkyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, arylalkyl, heterocyclylalkyl, arylalkenyl, heterocyclylalkenyl, arylheterocyclylalkenyl, heterocyclylarylalkenyl, or heteroarylalkyl; and

[0153] R2 and R3 optionally join to form a saturated or unsaturated ring of 5, 6, 7, or 8 atoms, where the atoms in the ring are independently selected from CR40, C(R40)2, C═O, N, NR40, O, S, C═S, S═O, or SO2.

[0154] In another embodiment, the present cyclic pyrazole MK-2 inhibiting compound has the structure:

[0155] where:

[0156] Ra and Rb join to form a ring structure selected from the group consisting of:

[0157] A, E, G and J are carbon, or optionally, one of A, E, G and J is selected from nitrogen, sulfur, or oxygen;

[0158] when A, E, G, or J is oxygen or sulfur, no substituent groups are bonded to the oxygen or the sulfur;

[0159] when A, E, G, or J is nitrogen, the nitrogen is optionally unsubstituted, or is substituted with R9;

[0160] R1 is optionally absent, or is selected from —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, amino, NHR10, NR11R12, C1-C6 alkyl-NHR10, C1-C6 alkyl-NR11R12, nitro, cyano, O—R13, C1-C4 alkyl-OR13, COR14, SR13, SOR14, SO2R14, C1-C6 alkyl-COR14, C1-C6 alkyl-SR13, C1-C6 alkyl-SOR14, C1-C6 alkyl-SO2R14, halo, halo C1-C6 alkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, or C7-C10 mono- and bicyclic cycloalkyl, wherein mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R15;

[0161] each of R2, R4 and R6 is optionally absent, or is independently selected from the R3 groups;

[0162] R3, R5, R7, R8, R9, R40, R41, R42, R43, R44, R45, R46, R47, R48, R49, R50, R51, R52, R53, R54 and R55 are each independently selected from —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, nitro C1-C6 alkyl, azido C1-C6 alkyl, amino, NHR10, NR11R12, C1-C6 alkyl-NHR10, C1-C6 alkyl-NR11R12, nitro, cyano, O—R13, C1-C4 alkyl-OR13, aryl, heteroaryl, heterocyclyl, COR14, SR13, SOR14, SO2R14, C1-C6 alkyl-COR14, C1-C6 alkyl-SR13, C1-C6 alkyl-SOR14, C1-C6 alkyl-SO2R14, halo, halo C1-C6 alkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, arylalkyl, heteroarylalkyl, heterocyclylalkyl, arylalkenyl, heterocyclylalkenyl, arylheterocyclylalkenyl, heterocyclylarylalkenyl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R15; or R8 and R9 join to form a ring structure selected from:

[0163] R10, R11, are each independently selected from —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, amino, NHR16, NR16R17, C1-C6 alkyl-NHR16, C1-C6 alkyl-NR16R17, O—R18, C1-C4 alkyl-OR18, aryl, heteroaryl, heterocyclyl, CO2R19, COR20, CONHR19, CON(R19)2, SR18, SOR20, SO2R20, C1-C6 alkyl-CO2R19, C1-C6 alkyl-COR20, C1-C6 alkyl-CONHR19, C1-C6 alkyl-CON(R19)2, C1-C6 alkyl-SR18, C1-C6 alkyl-SOR20, C1-C6 alkyl-SO2R20, halo, halo C1-C6 alkyl, arylaryl, arylheteroaryl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, arylalkyl, heteroarylalkyl, heterocyclylalkyl, arylalkenyl, heterocyclylalkenyl, arylheterocyclylalkenyl, heterocyclylarylalkenyl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R20;

[0164] R12, R13 are each independently selected from —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl-NHR16, C1-C6 alkyl-NR16R17, C1-C4 alkyl-OR18, aryl, heteroaryl, heterocyclyl, CO2R19, COR20, CONHR19, CON(R19)2, SOR20, SO2R20, C1-C6 alkyl-CO2R19, C1-C6 alkyl-COR20, C1-C6 alkyl-CONHR19, C1-C6 alkyl-CON(R19)2, C1-C6 alkyl-SR18, C1-C6 alkyl-SOR20, C1-C6 alkyl-SO2R20, halo C1-C6 alkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R21;

[0165] R14 is selected from —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, amino, NHR16, NR16R17, C1-C6 alkyl-NHR16, C1-C6 alkyl-NR16R17, O—R18, C1-C4 alkyl-OR18, aryl, heteroaryl, heterocyclyl, SR18, C1-C6 alkyl-CO2R19, C1-C6 alkyl-COR20, C1-C6 alkyl-CONHR19, C1-C6 alkyl-CON(R19)2, C1-C6 alkyl-SR18, C1-C6 alkyl-SOR20, C1-C6 alkyl-SO2R20, halo, halo C1-C6 alkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, arylalkyl, heteroarylalkyl, heterocyclylalkyl, arylalkenyl, heterocyclylalkenyl, arylheterocyclylalkenyl, heterocyclylarylalkenyl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R21;

[0166] R15 is selected from —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, amino, NHR10, NR11R12, C1-C6 alkyl-NHR10, C1-C6 alkyl-NR11R12, nitro, cyano, O—R13, C1-C4 alkyl-OR13, aryl, heteroaryl, heterocyclyl, COR14, SR13, SOR14, SO2R14, C1-C6 alkyl-COR14, C1-C6 alkyl-SR13, C1-C6 alkyl-SOR14, C1-C6 alkyl-SO2R14, halo, halo C1-C6 alkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, arylalkyl, heteroarylalkyl, heterocyclylalkyl, arylalkenyl, heterocyclylalkenyl, arylheterocyclylalkenyl, heterocyclylarylalkenyl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R21;

[0167] R16 and R17 are each independently selected from —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, amino, C1-C6 alkyl-NHR22, C1-C6 alkyl-NR22R23, C1-C4 alkyl-OR24, aryl, heteroaryl, heterocyclyl, CO2R25, COR26, CONHR25, CON(R25)2, SOR26, SO2R26, C1-C6 alkyl-CO2R25, C1-C6 alkyl-COR26, C1-C6 alkyl-CONHR25, C1-C6 alkyl-CON(R25)2, C1-C6 alkyl-SR24, C1-C6 alkyl-SOR26, C1-C6 alkyl-SO2R26, halo, halo C1-C6 alkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, arylalkyl, heteroarylalkyl, heterocyclylalkyl, arylalkenyl, heterocyclylalkenyl, arylheterocyclylalkenyl, heterocyclylarylalkenyl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R27;

[0168] R18, R19 are each independently selected from —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl-NHR22, C1-C6 alkyl-NR22R23, C1-C4 alkyl-OR24, aryl, heteroaryl, heterocyclyl, CO2R25, COR26, CONHR25, CON(R25)2, SOR26, SO2R27, C1-C6 alkyl-CO2R25, C1-C6 alkyl-COR26, C1-C6 alkyl-CONHR25, C1-C6 alkyl-CON(R25)2, C1-C6 alkyl-SR24, C1-C6 alkyl-SOR26, C1-C6 alkyl-SO2R26, halo C1-C6 alkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R27;

[0169] R20 is selected from —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, amino, NHR22, NR22R23, C1-C6 alkyl-NHR22, C1-C6 alkyl-NR22R23, O—R24, C1-C4 alkyl-OR24, aryl, heteroaryl, heterocyclyl, SR24, C1-C6 alkyl-CO2R25, C1-C6 alkyl-COR26, C1-C6 alkyl-CONHR25, C1-C6 alkyl-CON(R25)2, C1-C6 alkyl-SR24, C1-C6 alkyl-SOR26, C1-C6 alkyl-SO2R26, halo, halo C1-C6 alkyl, arylalkoxyalkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, arylalkyl, heteroarylalkyl, heterocyclylalkyl, arylalkenyl, heterocyclylalkenyl, arylheterocyclylalkenyl, heterocyclylarylalkenyl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R27;

[0170] R21 is selected from —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, amino, NHR22, NR22R23, C1-C6 alkyl-NHR22, C1-C6 alkyl-NR22R23, nitro, cyano, O—R24, C1-C4 alkyl-OR24, aryl, heteroaryl, heterocyclyl, COR26, SR24, SOR26, SO2R26, C1-C6 alkyl-COR26, C1-C6 alkyl-SR24, C1-C6 alkyl-SOR26, C1-C6 alkyl-SO2R26, halo, halo C1-C6 alkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, arylalkyl, heteroarylalkyl, heterocyclylalkyl, arylalkenyl, heterocyclylalkenyl, arylheterocyclylalkenyl, heterocyclylarylalkenyl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R27;

[0171] R22 and R23 are each independently selected from —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, amino, C1-C6 alkyl-NHR28, C1-C6 alkyl-NR28R29, C1-C4 alkyl-OR30, aryl, heteroaryl, heterocyclyl, CO2R31, COR32, CONHR31, CON(R31)2, SOR32, SO2R32, C1-C6 alkyl-CO2R31, C1-C6 alkyl-COR32, C1-C6 alkyl-CONHR31, C1-C6 alkyl-CON(R31)2, C1-C6 alkyl-SR30, C1-C6 alkyl-SOR32, C1-C6 alkyl-SO2R32, halo, halo C1-C6 alkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, arylalkyl, heteroarylalkyl, heterocyclylalkyl, arylalkenyl, heterocyclylalkenyl, arylheterocyclylalkenyl, heterocyclylarylalkenyl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R33;

[0172] R24 and R25 are each independently selected from —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl-NHR28, C1-C6 alkyl-NR28R29, C1-C4 alkyl-OR30, aryl, heteroaryl, heterocyclyl, CO2R31, COR32, CONHR31, CON(R31)2, SOR32, SO2R32, C1-C6 alkyl-CO2R31, C1-C6 alkyl-COR32, C1-C6 alkyl-CONHR31, C1-C6 alkyl-CON(R31)2, C1-C6 alkyl-SR30, C1-C6 alkyl-SOR32, C1-C6 alkyl-SO2R32, halo C1-C6 alkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R33;

[0173] R26 is selected from —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, amino, NHR28, NR28R29, C1-C6 alkyl-NHR28, C1-C6 alkyl-NR28R29, O—R30, C1-C4 alkyl-OR30, aryl, heteroaryl, heterocyclyl, SR30, C1-C6 alkyl-CO2R31, C1-C6 alkyl-COR32, C1-C6 alkyl-CONHR31, C1-C6 alkyl-CON(R31)2, C1-C6 alkyl-SR30, C1-C6 alkyl-SOR32, C1-C6 alkyl-SO2R32, halo, halo C1-C6 alkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, arylalkyl, heteroarylalkyl, heterocyclylalkyl, arylalkenyl, heterocyclylalkenyl, arylheterocyclylalkenyl, heterocyclylarylalkenyl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R33;

[0174] R27 is selected from —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, amino, NHR28, NR28R29, C1-C6 alkyl-NHR28, C1-C6 alkyl-NR28R29, nitro, cyano, O—R30, C1-C4 alkyl-OR30, aryl, heteroaryl, heterocyclyl, COR32, SR30, SOR32, SO2R32, C1-C6 alkyl-COR32, C1-C6 alkyl-SR30, C1-C6 alkyl-SOR32, C1-C6 alkyl-SO2R32, halo, halo C1-C6 alkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, arylalkyl, heteroarylalkyl, heterocyclylalkyl, arylalkenyl, heterocyclylalkenyl, arylheterocyclylalkenyl, heterocyclylarylalkenyl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R33;

[0175] R28 and R29 are each independently selected from —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, amino, C1-C6 alkyl-NHR34, C1-C6 alkyl-NR34R35, C1-C4 alkyl-OR36, aryl, heteroaryl, heterocyclyl, CO2R37, COR38, CONHR37, CON(R37)2, SOR38, SO2R38, C1-C6 alkyl-CO2R37, C1-C6 alkyl-COR38, C1-C6 alkyl-CONHR37, C1-C6 alkyl-CON(R37)2, C1-C6 alkyl-SR36, C1-C6 alkyl-SOR38, C1-C6 alkyl-SO2R38, halo, halo C1-C6 alkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, arylalkyl, heteroarylalkyl, heterocyclylalkyl, arylalkenyl, heterocyclylalkenyl, arylheterocyclylalkenyl, heterocyclylarylalkenyl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R39;

[0176] R30 and R31 are each independently selected from —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl-NHR34, C1-C6 alkyl-NR34R35, C1-C4 alkyl-OR36, aryl, heteroaryl, heterocyclyl, CO2R37, COR38, CONHR37, CON(R37)2, SOR38, SO2R38, C1-C6 alkyl-CO2R37, C1-C6 alkyl-COR38, C1-C6 alkyl-CONHR37, C1-C6 alkyl-CON(R37)2, C1-C6 alkyl-SR36, C1-C6 alkyl-SOR38, C1-C6 alkyl-SO2R38, halo C1-C6 alkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R39;

[0177] R32 is selected from —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, amino, NHR34, NR34R35, C1-C6 alkyl-NHR34, C1-C6 alkyl-NR34R35, O—R36, C1-C4 alkyl-OR36, aryl, heteroaryl, heterocyclyl, SR36, C1-C6 alkyl-CC2R37, C1-C6 alkyl-COR38, C1-C6 alkyl-CONHR37, C1-C6 alkyl-CON(R37)2, C1-C6 alkyl-SR36, C1-C6 alkyl-SOR38, C1-C6 alkyl-SO2R38, halo, halo C1-C6 alkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, arylalkyl, heteroarylalkyl, heterocyclylalkyl, arylalkenyl, heterocyclylalkenyl, arylheterocyclylalkenyl, heterocyclylarylalkenyl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R39;

[0178] R33 is selected from —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, amino, NHR34, NR34R35, C1-C6 alkyl-NHR31, C1-C6 alkyl-NR34R35, nitro, cyano, O—R36, C1-C4 alkyl-OR36, aryl, heteroaryl, heterocyclyl, COR38, SR35, SOR38, SO2R38, C1-C6 alkyl-COR38, C1-C6 alkyl-SR36, C1-C6 alkyl-SOR38, C1-C6 alkyl-SO2R38, halo, halo C1-C6 alkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, arylalkyl, heteroarylalkyl, heterocyclylalkyl, arylalkenyl, heterocyclylalkenyl, arylheterocyclylalkenyl, heterocyclylarylalkenyl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R39;

[0179] R34, R35, R36 and R37 are each independently selected from —H, alkyl, alkenyl, alkynyl, aminoalkyl, hydroxyalkyl, alkylamino alkyl, dialkylaminoalkyl, alkoxyalkyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, arylalkyl, heterocyclylalkyl, heteroarylalkyl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R39;

[0180] R38 is selected from —H, alkyl, alkenyl, alkynyl, aminoalkyl, OH, alkoxy, amino, alkylamino, dialkylamino, hydroxyalkyl, alkylamino alkyl, dialkylaminoalkyl, alkoxyalkyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, arylalkyl, heterocyclylalkyl, heteroarylalkyl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R39;

[0181] R39 is selected from alkyl, alkenyl, alkynyl, aminoalkyl, OH, alkoxy, amino, nitro, cyano, halo, alkylamino, dialkylamino, hydroxyalkyl, alkylamino alkyl, dialkylaminoalkyl, alkoxyalkyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, arylalkyl, heterocyclylalkyl, arylalkenyl, heterocyclylalkenyl, arylheterocyclylalkenyl, heterocyclylarylalkenyl, or heteroarylalkyl; and

[0182] R2 and R3 optionally join to form a saturated or unsaturated ring of 5, 6, 7, or 8 atoms, where the atoms in the ring are independently selected from CR40, C(R40)2, C═O, N, NR40, O, S, C═S, S═O, or SO2.

[0183] In another embodiment, the present cyclic pyrazole MK-2 inhibiting compound has the structure:

[0184] where:

[0185] Ra and Rb join to form a ring structure selected from the group consisting of:

[0186] A, E, G and J are carbon, or optionally, one of A, E, G and J is selected from nitrogen, sulfur, or oxygen;

[0187] when A, E, G, or J is oxygen or sulfur, no substituent groups are bonded to the oxygen or the sulfur;

[0188] when A, E, G, or J is nitrogen, the nitrogen is optionally unsubstituted, or is substituted with R9;

[0189] each of R1, R2, R4 and R6 is optionally absent, or is independently selected from the R3 groups;

[0190] R3, R5, R7, R40, R41, R42, R43, R44, R54 and R55 are each independently selected from —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, nitro C1-C6 alkyl, azido C1-C6 alkyl, amino, NHR10, NR11R12, C1-C6 alkyl-NHR10, C1-C6 alkyl-NR11R12, nitro, cyano, O—R13, C1-C4 alkyl-OR13, aryl, heteroaryl, heterocyclyl, COR14, SR13, SOR14, SO2R14, C1-C6 alkyl-COR14, C1-C6 alkyl-SR13, C1-C6 alkyl-SOR14, C1-C6 alkyl-SO2R14, halo, halo C1-C6 alkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, arylalkyl, heteroarylalkyl, heterocyclylalkyl, arylalkenyl, heterocyclylalkenyl, arylheterocyclylalkenyl, heterocyclylarylalkenyl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R15;

[0191] R8 and R9 join to form the ring structure:

[0192] R10, R11, are each independently selected from —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, amino, NHR16, NR16R17, C1-C6 alkyl-NHR16, C1-C6 alkyl-NR16R17, O—R18, C1-C4 alkyl-OR18, aryl, heteroaryl, heterocyclyl, CO2R19, COR20, CONHR19, CON(R19)2, SR18, SOR20, SO2R20, C1-C6 alkyl-CO2R19, C1-C6 alkyl-COR20, C1-C6 alkyl-CONHR19, C1-C6 alkyl-CON(R19)2, C1-C6 alkyl-SR18, C1-C6 alkyl-SOR20, C1-C6 alkyl-SO2R20, halo, halo C1-C6 alkyl, arylaryl, arylheteroaryl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, arylalkyl, heteroarylalkyl, heterocyclylalkyl, arylalkenyl, heterocyclylalkenyl, arylheterocyclylalkenyl, heterocyclylarylalkenyl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R21;

[0193] R12, R13 are each independently selected from —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl-NHR16, C1-C6 alkyl-NR16R17, C1-C4 alkyl-OR18, aryl, heteroaryl, heterocyclyl, CO2R19, COR20, CONHR19, CON(R19)2, SOR20, SO2R20, C1-C6 alkyl-CO2R19, C1-C6 alkyl-COR20, C1-C6 alkyl-CONHR19, C1-C6 alkyl-CON(R19)2, C1-C6 alkyl-SR18, C1-C6 alkyl-SOR20, C1-C6 alkyl-SO2R20, halo C1-C6 alkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R21;

[0194] R14 is selected from —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, amino, NHR16, NR16R17, C1-C6 alkyl-NHR16, C1-C6 alkyl-NR16R17, O—R18, C1-C4 alkyl-OR18, aryl, heteroaryl, heterocyclyl, SR18, C1-C6 alkyl-CC2R19, C1-C6 alkyl-COR20, C1-C6 alkyl-CONHR19, C1-C6 alkyl-CON(R19)2, C1-C6 alkyl-SR18, C1-C6 alkyl-SOR20, C1-C6 alkyl-SO2R20, halo, halo C1-C6 alkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, arylalkyl, heteroarylalkyl, heterocyclylalkyl, arylalkenyl, heterocyclylalkenyl, arylheterocyclylalkenyl, heterocyclylarylalkenyl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R21;

[0195] R15 is selected from —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, amino, NHR10, NR11R12, C1-C6 alkyl-NHR10, C1-C6 alkyl-NR11R12, nitro, cyano, O—R13, C1-C4 alkyl-OR13, aryl, heteroaryl, heterocyclyl, COR14, SR13, SOR14, SO2R14, C1-C6 alkyl-COR14, C1-C6 alkyl-SR13, C1-C6 alkyl-SOR14, C1-C6 alkyl-SO2R14, halo, halo C1-C6 alkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, arylalkyl, heteroarylalkyl, heterocyclylalkyl, arylalkenyl, heterocyclylalkenyl, arylheterocyclylalkenyl, heterocyclylarylalkenyl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R21;

[0196] R16 and R17 are each independently selected from —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, amino, C1-C6 alkyl-NHR22, C1-C6 alkyl-NR22R23, C1-C4 alkyl-OR24, aryl, heteroaryl, heterocyclyl, CO2R25, COR26, CONHR25, CON(R25)2, SOR26, SO2R26, C1-C6 alkyl-CO2R25, C1-C6 alkyl-COR26, C1-C6 alkyl-CONHR25, C1-C6 alkyl-CON(R25)2, C1-C6 alkyl-SR24, C1-C6 alkyl-SOR26, C1-C6 alkyl-SO2R26, halo, halo C1-C6 alkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, arylalkyl, heteroarylalkyl, heterocyclylalkyl, arylalkenyl, heterocyclylalkenyl, arylheterocyclylalkenyl, heterocyclylarylalkenyl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R27;

[0197] R18, R19 are each independently selected from —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl-NHR22, C1-C6 alkyl-NR22R23, C1-C4 alkyl-OR24, aryl, heteroaryl, heterocyclyl, CO2R25, COR26, CONHR25, CON(R25)2, SOR26, SO2R27, C1-C6 alkyl-CO2R25, C1-C6 alkyl-COR26, C1-C6 alkyl-CONHR25, C1-C6 alkyl-CON(R25)2, C1-C6 alkyl-SR24, C1-C6 alkyl-SOR26, C1-C6 alkyl-SO2R26, halo C1-C6 alkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R27;

[0198] R20 is selected from —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, amino, NHR22, NR22R23, C1-C6 alkyl-NHR22, C1-C6 alkyl-NR22R23, O—R24, C1-C4 alkyl-OR24, aryl, heteroaryl, heterocyclyl, SR24, C1-C6 alkyl-CO2R25, C1-C6 alkyl-COR26, C1-C6 alkyl-CONHR25, C1-C6 alkyl-CON(R25)2, C1-C6 alkyl-SR24, C1-C6 alkyl-SOR26, C1-C6 alkyl-SO2R26, halo, halo C1-C6 alkyl, arylalkoxyalkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, arylalkyl, heteroarylalkyl, heterocyclylalkyl, arylalkenyl, heterocyclylalkenyl, arylheterocyclylalkenyl, heterocyclylarylalkenyl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R27;

[0199] R21 is selected from —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, amino, NHR22, NR22R23, C1-C6 alkyl-NHR22, C1-C6 alkyl-NR22R23, nitro, cyano, O—R24, C1-C4 alkyl-OR24, aryl, heteroaryl, heterocyclyl, COR26, SR24, SOR26, SO2R26, C1-C6 alkyl-COR24, C1-C6 alkyl-SR24, C1-C6 alkyl-SOR26, C1-C6 alkyl-SO2R26, halo, halo C1-C6 alkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, arylalkyl, heteroarylalkyl, heterocyclylalkyl, arylalkenyl, heterocyclylalkenyl, arylheterocyclylalkenyl, heterocyclylarylalkenyl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R27;

[0200] R22 and R23 are each independently selected from —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, amino, C1-C6 alkyl-NHR28, C1-C6 alkyl-NR28R29, C1-C4 alkyl-OR30, aryl, heteroaryl, heterocyclyl, CO2R31, COR32, CONHR31, CON(R31)2, SOR32, SO2R32, C1-C6 alkyl-CO2R31, C1-C6 alkyl-COR32, C1-C6 alkyl-CONHR31, C1-C6 alkyl-CON(R31)2, C1-C6 alkyl-SR30, C1-C6 alkyl-SOR32, C1-C6 alkyl-SO2R32, halo, halo C1-C6 alkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, arylalkyl, heteroarylalkyl, heterocyclylalkyl, arylalkenyl, heterocyclylalkenyl, arylheterocyclylalkenyl, heterocyclylarylalkenyl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R33;

[0201] R24 and R25 are each independently selected from —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl-NHR28, C1-C6 alkyl-NR28R29, C1-C4 alkyl-OR30, aryl, heteroaryl, heterocyclyl, CO2R31, COR32, CONHR31, CON(R31)2, SOR32, SO2R32, C1-C6 alkyl-CO2R31, C1-C6 alkyl-COR32, C1-C6 alkyl-CONHR31, C1-C6 alkyl-CON(R31)2, C1-C6 alkyl-SR30, C1-C6 alkyl-SOR32, C1-C6 alkyl-SO2R32, halo C1-C6 alkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R33;

[0202] R26 is selected from —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, amino, NHR28, NR28R29, C1-C6 alkyl-NHR28, C1-C6 alkyl-NR28R29, O—R30, C1-C4 alkyl-OR30, aryl, heteroaryl, heterocyclyl, SR30, C1-C6 alkyl-CO2R31, C1-C6 alkyl-COR32, C1-C6 alkyl-CONHR31, C1-C6 alkyl-CON(R31)2, C1-C6 alkyl-SR30, C1-C6 alkyl-SOR32, C1-C6 alkyl-SO2R32, halo, halo C1-C6 alkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, arylalkyl, heteroarylalkyl, heterocyclylalkyl, arylalkenyl, heterocyclylalkenyl, arylheterocyclylalkenyl, heterocyclylarylalkenyl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R33;

[0203] R27 is selected from —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, amino, NHR28, NR28R29, C1-C6 alkyl-NHR28, C1-C6 alkyl-NR28R29, nitro, cyano, O—R30, C1-C4 alkyl-OR30, aryl, heteroaryl, heterocyclyl, COR32, SR30, SOR32, SO2R32, C1-C6 alkyl-COR32, C1-C6 alkyl-SR30, C1-C6 alkyl-SOR32, C1-C6 alkyl-SO2R32, halo, halo C1-C6 alkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, arylalkyl, heteroarylalkyl, heterocyclylalkyl, arylalkenyl, heterocyclylalkenyl, arylheterocyclylalkenyl, heterocyclylarylalkenyl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R33;

[0204] R28 and R29 are each independently selected from —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, amino, C1-C6 alkyl-NHR34, C1-C6 alkyl-NR34R35, C1-C4 alkyl-OR35, aryl, heteroaryl, heterocyclyl, CO2R37, COR38, CONHR37, CON(R37)2, SOR38, SO2R38, C1-C6 alkyl-CO2R37, C1-C6 alkyl-COR38, C1-C6 alkyl-CONHR37, C1-C6 alkyl-CON(R37)2, C1-C6 alkyl-SR36, C1-C6 alkyl-SOR38, C1-C6 alkyl-SO2R38, halo, halo C1-C6 alkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, arylalkyl, heteroarylalkyl, heterocyclylalkyl, arylalkenyl, heterocyclylalkenyl, arylheterocyclylalkenyl, heterocyclylarylalkenyl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R39;

[0205] R30 and R31 are each independently selected from —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl-NHR34, C1-C6 alkyl-NR34R35, C1-C4 alkyl-OR36, aryl, heteroaryl, heterocyclyl, CO2R37, COR38, CONHR37, CON(R37)2, SOR38, SO2R38, C1-C6 alkyl-CO2R37, C1-C6 alkyl-COR38, C1-C6 alkyl-CONHR37, C1-C6 alkyl-CON(R37)2, C1-C6 alkyl-SR36, C1-C6 alkyl-SOR38, C1-C6 alkyl-SO2R38, halo C1-C6 alkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R39;

[0206] R32 is selected from —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, amino, NHR34, NR34R35, C1-C6 alkyl-NHR34, C1-C6 alkyl-NR34R35, O—R36, C1-C4 alkyl-OR36, aryl, heteroaryl, heterocyclyl, SR36, C1-C6 alkyl-CO2R37, C1-C6 alkyl-COR38, C1-C6 alkyl-CONHR37, C1-C6 alkyl-CON(R37)2, C1-C6 alkyl-SR36, C1-C6 alkyl-SOR38, C1-C6 alkyl-SO2R38, halo, halo C1-C6 alkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, arylalkyl, heteroarylalkyl, heterocyclylalkyl, arylalkenyl, heterocyclylalkenyl, arylheterocyclylalkenyl, heterocyclylarylalkenyl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R39;

[0207] R33 is selected from —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, amino, NHR34, NR34R35, C1-C6 alkyl-NHR31, C1-C6 alkyl-NR34R35, nitro, cyano, O—R36, C1-C4 alkyl-OR36, aryl, heteroaryl, heterocyclyl, COR38, SR35, SOR38, SO2R38, C1-C6 alkyl-COR38, C1-C6 alkyl-SR36, C1-C6 alkyl-SOR38, C1-C6 alkyl-SO2R38, halo, halo C1-C6 alkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, arylalkyl, heteroarylalkyl, heterocyclylalkyl, arylalkenyl, heterocyclylalkenyl, arylheterocyclylalkenyl, heterocyclylarylalkenyl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R39;

[0208] R34, R35, R36 and R37 are each independently selected from —H, alkyl, alkenyl, alkynyl, aminoalkyl, hydroxyalkyl, alkylamino alkyl, dialkylaminoalkyl, alkoxyalkyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, arylalkyl, heterocyclylalkyl, heteroarylalkyl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R39;

[0209] R38 is selected from —H, alkyl, alkenyl, alkynyl, aminoalkyl, OH, alkoxy, amino, alkylamino, dialkylamino, hydroxyalkyl, alkylamino alkyl, dialkylaminoalkyl, alkoxyalkyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, arylalkyl, heterocyclylalkyl, heteroarylalkyl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R39;

[0210] R39 is selected from alkyl, alkenyl, alkynyl, aminoalkyl, OH, alkoxy, amino, nitro, cyano, halo, alkylamino, dialkylamino, hydroxyalkyl, alkylamino alkyl, dialkylaminoalkyl, alkoxyalkyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, arylalkyl, heterocyclylalkyl, arylalkenyl, heterocyclylalkenyl, arylheterocyclylalkenyl, heterocyclylarylalkenyl, or heteroarylalkyl; and

[0211] R2 and R3 optionally join to form a saturated or unsaturated ring of 5, 6, 7, or 8 atoms, where the atoms in the ring are independently selected from CR40, C(R40)2, C═O, N, NR40, O, S, C═S, S═O, or SO2.

[0212] In another embodiment, the present cyclic pyrazole MK-2 inhibiting compound has the structure:

[0213] where:

[0214] Ra and Rb join to form a ring structure selected from the group consisting of:

[0215] A, E, G and J are carbon, or optionally, one of A, E, G and J is selected from nitrogen, sulfur, or oxygen;

[0216] when A, E, G, or J is oxygen or sulfur, no substituent groups are bonded to the oxygen or the sulfur;

[0217] when A, E, G, or J is nitrogen, the nitrogen is optionally unsubstituted, or is substituted with R9;

[0218] each of R1, R2, R4 and R6 is optionally absent, or is independently selected from the R3 groups;

[0219] R3, R5, R7, R40, R45, R46, R47, R48, R54 and R55 are each independently selected from —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, nitro C1-C6 alkyl, azido C1-C6 alkyl, amino, NHR10, NR11R12, C1-C6 alkyl-NHR10, C1-C6 alkyl-NR11R12, nitro, cyano, O—R13, C1-C4 alkyl-OR13, aryl, heteroaryl, heterocyclyl, COR14, SR13, SOR14, SO2R14, C1-C6 alkyl-COR14, C1-C6 alkyl-SR13, C1-C6 alkyl-SOR14, C1-C6 alkyl-SO2R14, halo, halo C1-C6 alkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, arylalkyl, heteroarylalkyl, heterocyclylalkyl, arylalkenyl, heterocyclylalkenyl, arylheterocyclylalkenyl, heterocyclylarylalkenyl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R15;

[0220] R8 and R9 join to form the ring structure:

[0221] R10, R11, are each independently selected from —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, amino, NHR16, NR16R17, C1-C6 alkyl-NHR16, C1-C6 alkyl-NR16R17, O—R18, C1-C4 alkyl-OR18, aryl, heteroaryl, heterocyclyl, CO2R19, COR20, CONHR19, CON(R19)2, SR19, SOR20, SO2R20, C1-C6 alkyl-CO2R19, C1-C6 alkyl-COR27, C1-C6 alkyl-CONHR19, C1-C6 alkyl-CON(R19)2, C1-C6 alkyl-SR18, C1-C6 alkyl-SOR20, C1-C6 alkyl-SO2R20, halo, halo C1-C6 alkyl, arylaryl, arylheteroaryl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, arylalkyl, heteroarylalkyl, heterocyclylalkyl, arylalkenyl, heterocyclylalkenyl, arylheterocyclylalkenyl, heterocyclylarylalkenyl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R21;

[0222] R12, R13 are each independently selected from —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl-NHR16, C1-C6 alkyl-NR16R17, C1-C4 alkyl-OR18, aryl, heteroaryl, heterocyclyl, CO2R19, COR20, CONHR19, CON(R19)2, SOR20, SO2R20, C1-C6 alkyl-CO2R19, C1-C6 alkyl-COR20, C1-C6 alkyl-CONHR19, C1-C6 alkyl-CON(R19)2, C1-C6 alkyl-SR18, C1-C6 alkyl-SOR20, C1-C6 alkyl-SO2R20, halo C1-C6 alkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R21;

[0223] R14 is selected from —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, amino, NHR16, NR16R17, C1-C6 alkyl-NHR16, C1-C6 alkyl-NR16R17, O—R18, C1-C4 alkyl-OR18, aryl, heteroaryl, heterocyclyl, SR18, C1-C6 alkyl-CO2R19, C1-C6 alkyl-COR20, C1-C6 alkyl-CONHR19, C1-C6 alkyl-CON(R19)2, C1-C6 alkyl-SR18, C1-C6 alkyl-SOR20, C1-C6 alkyl-SO2R20, halo, halo C1-C6 alkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, arylalkyl, heteroarylalkyl, heterocyclylalkyl, arylalkenyl, heterocyclylalkenyl, arylheterocyclylalkenyl, heterocyclylarylalkenyl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R21;

[0224] R15 is selected from —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, amino, NHR10, NR11R12, C1-C6 alkyl-NHR10, C1-C6 alkyl-NR11R12, nitro, cyano, O—R13, C1-C4 alkyl-OR13, aryl, heteroaryl, heterocyclyl, COR14, SR13, SOR14, SO2R14, C1-C6 alkyl-COR13, C1-C6 alkyl-SR14, C1-C6 alkyl-SOR14, C1-C6 alkyl-SO2R14, halo, halo C1-C6 alkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, arylalkyl, heteroarylalkyl, heterocyclylalkyl, arylalkenyl, heterocyclylalkenyl, arylheterocyclylalkenyl, heterocyclylarylalkenyl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R21;

[0225] R16 and R17 are each independently selected from —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, amino, C1-C6 alkyl-NHR22, C1-C6 alkyl-NR22R23, C1-C4 alkyl-OR24, aryl, heteroaryl, heterocyclyl, CO2R25, COR26, CONHR25, CON(R25)2, SOR26, SO2R26, C1-C6 alkyl-CO2R25, C1-C6 alkyl-COR26, C1-C6 alkyl-CONHR25, C1-C6 alkyl-CON(R25)2, C1-C6 alkyl-SR24, C1-C6 alkyl-SOR26, C1-C6 alkyl-SO2R26, halo, halo C1-C6 alkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, arylalkyl, heteroarylalkyl, heterocyclylalkyl, arylalkenyl, heterocyclylalkenyl, arylheterocyclylalkenyl, heterocyclylarylalkenyl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R27;

[0226] R18, R19 are each independently selected from —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl-NHR22, C1-C6 alkyl-NR22R23, C1-C4 alkyl-OR24, aryl, heteroaryl, heterocyclyl, CO2R25, COR26, CONHR25, CON(R25)2, SOR26, SO2R27, C1-C6 alkyl-CO2R25, C1-C6 alkyl-COR26, C1-C6 alkyl-CONHR25, C1-C6 alkyl-CON(R25)2, C1-C6 alkyl-SR24, C1-C6 alkyl-SOR26, C1-C6 alkyl-SO2R26, halo C1-C6 alkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R27;

[0227] R20 is selected from —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, amino, NHR22, NR22R23, C1-C6 alkyl-NHR22, C1-C6 alkyl-NR22R23, O—R24, C1-C4 alkyl-OR24, aryl, heteroaryl, heterocyclyl, SR24, C1-C6 alkyl-CO2R25, C1-C6 alkyl-COR26, C1-C6 alkyl-CONHR25, C1-C6 alkyl-CON(R25)2, C1-C6 alkyl-SR24, C1-C6 alkyl-SOR26, C1-C6 alkyl-SO2R26, halo, halo C1-C6 alkyl, arylalkoxyalkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, arylalkyl, heteroarylalkyl, heterocyclylalkyl, arylalkenyl, heterocyclylalkenyl, arylheterocyclylalkenyl, heterocyclylarylalkenyl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R27;

[0228] R21 is selected from —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, amino, NHR22, NR22R23, C1-C6 alkyl-NHR22, C1-C6 alkyl-NR22R23, nitro, cyano, O—R24, C1-C4 alkyl-OR24, aryl, heteroaryl, heterocyclyl, COR26, SR24, SOR26, SO2R26, C1-C6 alkyl-COR26, C1-C6 alkyl-SR24, C1-C6 alkyl-SOR26, C1-C6 alkyl-SO2R26, halo, halo C1-C6 alkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, arylalkyl, heteroarylalkyl, heterocyclylalkyl, arylalkenyl, heterocyclylalkenyl, arylheterocyclylalkenyl, heterocyclylarylalkenyl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R27;

[0229] R22 and R23 are each independently selected from —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, amino, C1-C6 alkyl-NHR28, C1-C6 alkyl-NR28R29, C1-C4 alkyl-OR30, aryl, heteroaryl, heterocyclyl, CO2R31, COR32, CONHR31, CON(R31)2, SOR32, SO2R32, C1-C6 alkyl-CO2R31, C1-C6 alkyl-COR32, C1-C6 alkyl-CONHR31, C1-C6 alkyl-CON(R31)2, C1-C6 alkyl-SR30, C1-C6 alkyl-SOR32, C1-C6 alkyl-SO2R32, halo, halo C1-C6 alkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, arylalkyl, heteroarylalkyl, heterocyclylalkyl, arylalkenyl, heterocyclylalkenyl, arylheterocyclylalkenyl, heterocyclylarylalkenyl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R33;

[0230] R24 and R25 are each independently selected from —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl-NHR28, C1-C6 alkyl-NR28R29, C1-C4 alkyl-OR30, aryl, heteroaryl, heterocyclyl, CO2R31, COR32, CONHR31, CON(R31)2, SOR32, SO2R32, C1-C6 alkyl-CO2R31, C1-C6 alkyl-COR32, C1-C6 alkyl-CONHR31, C1-C6 alkyl-CON(R31)2, C1-C6 alkyl-SR30, C1-C6 alkyl-SOR32, C1-C6 alkyl-SO2R32, halo C1-C6 alkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R33;

[0231] R26 is selected from —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, amino, NHR28, NR28R29, C1-C6 alkyl-NHR28, C1-C6 alkyl-NR28R29, O—R30, C1-C4 alkyl-OR30, aryl, heteroaryl, heterocyclyl, SR30, C1-C6 alkyl-CO2R31, C1-C6 alkyl-COR32, C1-C6 alkyl-CONHR31, C1-C6 alkyl-CON(R31)2, C1-C6 alkyl-SR30, C1-C6 alkyl-SOR32, C1-C6 alkyl-SO2R32, halo, halo C1-C6 alkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, arylalkyl, heteroarylalkyl, heterocyclylalkyl, arylalkenyl, heterocyclylalkenyl, arylheterocyclylalkenyl, heterocyclylarylalkenyl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R33;

[0232] R27 is selected from —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, amino, NHR28, NR28R29, C1-C6 alkyl-NHR28, C1-C6 alkyl-NR28R29, nitro, cyano, O—R30, C1-C4 alkyl-OR30, aryl, heteroaryl, heterocyclyl, COR32, SR30, SOR32, SO2R32, C1-C6 alkyl-COR32, C1-C6 alkyl-SR30, C1-C6 alkyl-SOR32, C1-C6 alkyl-SO2R32, halo, halo C1-C6 alkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, arylalkyl, heteroarylalkyl, heterocyclylalkyl, arylalkenyl, heterocyclylalkenyl, arylheterocyclylalkenyl, heterocyclylarylalkenyl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R33;

[0233] R28 and R29 are each independently selected from —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, amino, C1-C6 alkyl-NHR34, C1-C6 alkyl-NR34R35, C1-C4 alkyl-OR36, aryl, heteroaryl, heterocyclyl, CO2R37, COR38, CONHR37, CON(R37)2, SOR38, SO2R38, C1-C6 alkyl-CO2R37, C1-C6 alkyl-COR38, C1-C6 alkyl-CONHR37, C1-C6 alkyl-CON(R37)2, C1-C6 alkyl-SR36, C1-C6 alkyl-SOR38, C1-C6 alkyl-SO2R38, halo, halo C1-C6 alkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, arylalkyl, heteroarylalkyl, heterocyclylalkyl, arylalkenyl, heterocyclylalkenyl, arylheterocyclylalkenyl, heterocyclylarylalkenyl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R39;

[0234] R30 and R31 are each independently selected from —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl-NHR34, C1-C6 alkyl-NR34R35, C1-C4 alkyl-OR36, aryl, heteroaryl, heterocyclyl, CO2R37, COR38, CONHR37, CON(R37)2, SOR38, SO2R38, C1-C6 alkyl-CO2R37, C1-C6 alkyl-COR38, C1-C6 alkyl-CONHR37, C1-C6 alkyl-CON(R37)2, C1-C6 alkyl-SR36, C1-C6 alkyl-SOR38, C1-C6 alkyl-SO2R38, halo C1-C6 alkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R39;

[0235] R32 is selected from —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, amino, NHR34, NR34R35, C1-C6 alkyl-NHR34, C1-C6 alkyl-NR34R35, O—R36, C1-C4 alkyl-OR36, aryl, heteroaryl, heterocyclyl, SR36, C1-C6 alkyl-CO2R37, C1-C6 alkyl-COR38, C1-C6 alkyl-CONHR37, C1-C6 alkyl-CON(R37)2, C1-C6 alkyl-SR35, C1-C6 alkyl-SOR38, C1-C6 alkyl-SO2R38, halo, halo C1-C6 alkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, arylalkyl, heteroarylalkyl, heterocyclylalkyl, arylalkenyl, heterocyclylalkenyl, arylheterocyclylalkenyl, heterocyclylarylalkenyl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R39;

[0236] R33 is selected from —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, amino, NHR34, NR34R35, C1-C6 alkyl-NHR31, C1-C6 alkyl-NR34R35, nitro, cyano, O—R36, C1-C4 alkyl-OR36, aryl, heteroaryl, heterocyclyl, COR38, SR35, SOR38, SO2R38, C1-C6 alkyl-COR38, C1-C6 alkyl-SR36, C1-C6 alkyl-SOR38, C1-C6 alkyl-SO2R38, halo, halo C1-C6 alkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, arylalkyl, heteroarylalkyl, heterocyclylalkyl, arylalkenyl, heterocyclylalkenyl, arylheterocyclylalkenyl, heterocyclylarylalkenyl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R39;

[0237] R34, R35, R36 and R37 are each independently selected from —H, alkyl, alkenyl, alkynyl, aminoalkyl, hydroxyalkyl, alkylamino alkyl, dialkylaminoalkyl, alkoxyalkyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, arylalkyl, heterocyclylalkyl, heteroarylalkyl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R39;

[0238] R38 is selected from —H, alkyl, alkenyl, alkynyl, aminoalkyl, OH, alkoxy, amino, alkylamino, dialkylamino, hydroxyalkyl, alkylamino alkyl, dialkylaminoalkyl, alkoxyalkyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, arylalkyl, heterocyclylalkyl, heteroarylalkyl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R39;

[0239] R39 is selected from alkyl, alkenyl, alkynyl, aminoalkyl, OH, alkoxy, amino, nitro, cyano, halo, alkylamino, dialkylamino, hydroxyalkyl, alkylamino alkyl, dialkylaminoalkyl, alkoxyalkyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, arylalkyl, heterocyclylalkyl, arylalkenyl, heterocyclylalkenyl, arylheterocyclylalkenyl, heterocyclylarylalkenyl, or heteroarylalkyl; and

[0240] R2 and R3 optionally join to form a saturated or unsaturated ring of 5, 6, 7, or 8 atoms, where the atoms in the ring are independently selected from CR40, C(R40)2, C═O, N, NR40, O, S, C═S, S═O, or SO2.

[0241] Cyclic pyrazoles that are useful as the present MK-2 inhibiting compound have the structure:

[0242] where:

[0243] Ra and Rb join to form a ring structure selected from the group consisting of:

[0244] A, E, G and J are carbon, or optionally, one of A, E, G and J is selected from nitrogen, sulfur, or oxygen;

[0245] when A, E, G, or J is oxygen or sulfur, no substituent groups are bonded to the oxygen or the sulfur;

[0246] when A, E, G, or J is nitrogen, the nitrogen is optionally unsubstituted, or is substituted with R9;

[0247] each of R1, R2, R4 and R6 is optionally absent, or is independently selected from the R3 groups;

[0248] R3, R5, R7, R40, R49, R50, R51, R54 and R55 are each independently selected from —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, nitro C1-C6 alkyl, azido C1-C6 alkyl, amino, NHR10, NR11R12, C1-C6 alkyl-NHR10, C1-C6 alkyl-NR11R12, nitro, cyano, O—R13, C1-C4 alkyl-OR13, aryl, heteroaryl, heterocyclyl, COR14, SR13, SOR14, SO2R14, C1-C6 alkyl-COR14, C1-C6 alkyl-SR13, C1-C6 alkyl-SOR14, C1-C6 alkyl-SO2R14, halo, halo C1-C6 alkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, arylalkyl, heteroarylalkyl, heterocyclylalkyl, arylalkenyl, heterocyclylalkenyl, arylheterocyclylalkenyl, heterocyclylarylalkenyl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R15;

[0249] R8 and R9 join to form the ring structure:

[0250] R10, R11, are each independently selected from —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, amino, NHR16, NR16R17, C1-C6 alkyl-NHR16, C1-C6 alkyl-NR16R17, O—R18, C1-C4 alkyl-OR18, aryl, heteroaryl, heterocyclyl, CO2R19, COR20, CONHR19, CON(R19)2, SR18, SOR20, SO2R20, C1-C6 alkyl-CO2R19, C1-C6 alkyl-COR20, C1-C6 alkyl-CONHR19, C1-C6 alkyl-CON(R19)2, C1-C6 alkyl-SR18, C1-C6 alkyl-SOR20, C1-C6 alkyl-SO2R20, halo, halo C1-C6 alkyl, arylaryl, arylheteroaryl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, arylalkyl, heteroarylalkyl, heterocyclylalkyl, arylalkenyl, heterocyclylalkenyl, arylheterocyclylalkenyl, heterocyclylarylalkenyl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R21;

[0251] R12, R13 are each independently selected from —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl-NHR16, C1-C6 alkyl-NR16R17, C1-C4 alkyl-OR18, aryl, heteroaryl, heterocyclyl, CO2R19, COR20, CONHR19, CON(R19)2, SOR20, SO2R20, C1-C6 alkyl-CO2R19, C1-C6 alkyl-COR20, C1-C6 alkyl-CONHR19, C1-C6 alkyl-CON(R19)2, C1-C6 alkyl-SR18, C1-C6 alkyl-SOR20, C1-C6 alkyl-SO2R20, halo C1-C6 alkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R21;

[0252] R14 is selected from —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, amino, NHR16, NR16R17, C1-C6 alkyl-NHR16, C1-C6 alkyl-NR16R17, O—R18, C1-C4 alkyl-OR18, aryl, heteroaryl, heterocyclyl, SR18, C1-C6 alkyl-CO2R19, C1-C6 alkyl-COR20, C1-C6 alkyl-CONHR19, C1-C6 alkyl-CON(R19)2, C1-C6 alkyl-SR13, C1-C6 alkyl-SOR20, C1-C6 alkyl-SO2R20, halo, halo C1-C6 alkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, arylalkyl, heteroarylalkyl, heterocyclylalkyl, arylalkenyl, heterocyclylalkenyl, arylheterocyclylalkenyl, heterocyclylarylalkenyl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R20;

[0253] R15 is selected from —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, amino, NHR10, NR11R12, C1-C6 alkyl-NHR10, C1-C6 alkyl-NR11R12, nitro, cyano, O—R13, C1-C4 alkyl-OR13, aryl, heteroaryl, heterocyclyl, COR14, SR13, SOR14, SO2R14, C1-C6 alkyl-COR14, C1-C6 alkyl-SR13, C1-C6 alkyl-SOR14, C1-C6 alkyl-SO2R14, halo, halo C1-C6 alkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, arylalkyl, heteroarylalkyl, heterocyclylalkyl, arylalkenyl, heterocyclylalkenyl, arylheterocyclylalkenyl, heterocyclylarylalkenyl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R20;

[0254] R16 and R17 are each independently selected from —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, amino, C1-C6 alkyl-NHR22, C1-C6 alkyl-NR22R23, C1-C4 alkyl-OR24, aryl, heteroaryl, heterocyclyl, CO2R25, COR26, CONHR25, CON(R25)2, SOR26, SO2R26, C1-C6 alkyl-CO2R25, C1-C6 alkyl-COR26, C1-C6 alkyl-CONHR25, C1-C6 alkyl-CON(R25)2, C1-C6 alkyl-SR24, C1-C6 alkyl-SOR26, C1-C6 alkyl-SO2R26, halo, halo C1-C6 alkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, arylalkyl, heteroarylalkyl, heterocyclylalkyl, arylalkenyl, heterocyclylalkenyl, arylheterocyclylalkenyl, heterocyclylarylalkenyl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R27;

[0255] R18, R19 are each independently selected from —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl-NHR22, C1-C6 alkyl-NR22R23, C1-C4 alkyl-OR24, aryl, heteroaryl, heterocyclyl, CO2R25, COR26, CONHR25, CON(R25)2, SOR26, SO2R27, C1-C6 alkyl-CO2R25, C1-C6 alkyl-COR26, C1-C6 alkyl-CONHR25, C1-C6 alkyl-CON(R25)2, C1-C6 alkyl-SR24, C1-C6 alkyl-SOR26, C1-C6 alkyl-SO2R26, halo C1-C6 alkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R27;

[0256] R20 is selected from —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, amino, NHR22, NR22R23, C1-C6 alkyl-NHR22, C1-C6 alkyl-NR22R23, O—R24, C1-C4 alkyl-OR24, aryl, heteroaryl, heterocyclyl, SR24, C1-C6 alkyl-CO2R25, C1-C6 alkyl-COR26, C1-C6 alkyl-CONHR25, C1-C6 alkyl-CON(R25)2, C1-C6 alkyl-SR24, C1-C6 alkyl-SOR26, C1-C6 alkyl-SO2R26, halo, halo C1-C6 alkyl, arylalkoxyalkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, arylalkyl, heteroarylalkyl, heterocyclylalkyl, arylalkenyl, heterocyclylalkenyl, arylheterocyclylalkenyl, heterocyclylarylalkenyl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R27;

[0257] R21 is selected from —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, amino, NHR22, NR22R23, C1-C6 alkyl-NHR22, C1-C6 alkyl-NR22R23, nitro, cyano, O—R24, C1-C4 alkyl-OR24, aryl, heteroaryl, heterocyclyl, COR26, SR24, SOR26, SO2R26, C1-C6 alkyl-COR26, C1-C6 alkyl-SR24, C1-C6 alkyl-SOR26, C1-C6 alkyl-SO2R26, halo, halo C1-C6 alkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, arylalkyl, heteroarylalkyl, heterocyclylalkyl, arylalkenyl, heterocyclylalkenyl, arylheterocyclylalkenyl, heterocyclylarylalkenyl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R27;

[0258] R22 and R23 are each independently selected from —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, amino, C1-C6 alkyl-NHR25, C1-C6 alkyl-NR28R29, C1-C4 alkyl-OR30, aryl, heteroaryl, heterocyclyl, CO2R31, COR32, CONHR31, CON(R31)2, SOR32, SO2R32, C1-C6 alkyl-CO2R31, C1-C6 alkyl-COR32, C1-C6 alkyl-CONHR31, C1-C6 alkyl-CON(R31)2, C1-C6 alkyl-SR30, C1-C6 alkyl-SOR32, C1-C6 alkyl-SO2R32, halo, halo C1-C6 alkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, arylalkyl, heteroarylalkyl, heterocyclylalkyl, arylalkenyl, heterocyclylalkenyl, arylheterocyclylalkenyl, heterocyclylarylalkenyl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R33;

[0259] R24 and R25 are each independently selected from —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl-NHR28, C1-C6 alkyl-NR28R29., C1-C4 alkyl-OR30, aryl, heteroaryl, heterocyclyl, CO2R31, COR32, CONHR31, CON(R31)2, SOR32, SO2R32, C1-C6 alkyl-CO2R31, C1-C6 alkyl-COR32, C1-C6 alkyl-CONHR31, C1-C6 alkyl-CON(R31)2, C1-C6 alkyl-SR30, C1-C6 alkyl-SOR32, C1-C6 alkyl-SO2R32, halo C1-C6 alkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R33;

[0260] R26 is selected from —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, amino, NHR28, NR28R29, C1-C6 alkyl-NHR28, C1-C6 alkyl-NR28R29, O—R30, C1-C4 alkyl-OR30, aryl, heteroaryl, heterocyclyl, SR30, C1-C6 alkyl-CO2R31, C1-C6 alkyl-COR32, C1-C6 alkyl-CONHR31, C1-C6 alkyl-CON(R31)2, C1-C6 alkyl-SR30, C1-C6 alkyl-SOR32, C1-C6 alkyl-SO2R32, halo, halo C1-C6 alkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, arylalkyl, heteroarylalkyl, heterocyclylalkyl, arylalkenyl, heterocyclylalkenyl, arylheterocyclylalkenyl, heterocyclylarylalkenyl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R33;

[0261] R27 is selected from —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, amino, NHR28, NR28R29, C1-C6 alkyl-NHR28, C1-C6 alkyl-NR28R29, nitro, cyano, O—R30, C1-C4 alkyl-OR30, aryl, heteroaryl, heterocyclyl, COR32, SR30, SOR32, SO2R32, C1-C6 alkyl-COR32, C1-C6 alkyl-SR30, C1-C6 alkyl-SOR32, C1-C6 alkyl-SO2R32, halo, halo C1-C6 alkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, arylalkyl, heteroarylalkyl, heterocyclylalkyl, arylalkenyl, heterocyclylalkenyl, arylheterocyclylalkenyl, heterocyclylarylalkenyl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R33;

[0262] R28 and R29 are each independently selected from —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, amino, C1-C6 alkyl-NHR34, C1-C6 alkyl-NR34R35, C1-C4 alkyl-OR36, aryl, heteroaryl, heterocyclyl, CO2R37, COR38, CONHR37, CON(R37)2, SOR38, SO2R38, C1-C6 alkyl-CO2R37, C1-C6 alkyl-COR38, C1-C6 alkyl-CONHR37, C1-C6 alkyl-CON(R37)2, C1-C6 alkyl-SR36, C1-C6 alkyl-SOR38, C1-C6 alkyl-SO2R38, halo, halo C1-C6 alkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, arylalkyl, heteroarylalkyl, heterocyclylalkyl, arylalkenyl, heterocyclylalkenyl, arylheterocyclylalkenyl, heterocyclylarylalkenyl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R39;

[0263] R30 and R31 are each independently selected from —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl-NHR34, C1-C6 alkyl-NR34R35, C1-C4 alkyl-OR36, aryl, heteroaryl, heterocyclyl, CO2R37, COR38, CONHR37, CON(R37)2, SOR38, SO2R38, C1-C6 alkyl-CO2R37, C1-C6 alkyl-COR38, C1-C6 alkyl-CONHR37, C1-C6 alkyl-CON(R37)2, C1-C6 alkyl-SR36, C1-C6 alkyl-SOR38, C1-C6 alkyl-SO2R38, halo C1-C6 alkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R39;

[0264] R32 is selected from —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, amino, NHR34, NR34R35, C1-C6 alkyl-NHR34, C1-C6 alkyl-NR34R35, O—R36, C1-C4 alkyl-OR36, aryl, heteroaryl, heterocyclyl, SR36, C1-C6 alkyl-CO2R37, C1-C6 alkyl-COR38, C1-C6 alkyl-CONHR37, C1-C6 alkyl-CON(R37)2, C1-C6 alkyl-SR36, C1-C6 alkyl-SOR38, C1-C6 alkyl-SO2R38, halo, halo C1-C6 alkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, arylalkyl, heteroarylalkyl, heterocyclylalkyl, arylalkenyl, heterocyclylalkenyl, arylheterocyclylalkenyl, heterocyclylarylalkenyl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R39;

[0265] R33 is selected from —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, amino, NHR34, NR34R35, C1-C6 alkyl-NHR31, C1-C6 alkyl-NR34R35, nitro, cyano, O—R36, C1-C4 alkyl-OR36, aryl, heteroaryl, heterocyclyl, COR38, SR35, SOR38, SO2R38, C1-C6 alkyl-COR38, C1-C6 alkyl-SR36, C1-C6 alkyl-SOR38, C1-C6 alkyl-SO2R38, halo, halo C1-C6 alkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, arylalkyl, heteroarylalkyl, heterocyclylalkyl, arylalkenyl, heterocyclylalkenyl, arylheterocyclylalkenyl, heterocyclylarylalkenyl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R39;

[0266] R34, R35, R36 and R37 are each independently selected from —H, alkyl, alkenyl, alkynyl, aminoalkyl, hydroxyalkyl, alkylamino alkyl, dialkylaminoalkyl, alkoxyalkyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, arylalkyl, heterocyclylalkyl, heteroarylalkyl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R39;

[0267] R38 is selected from —H, alkyl, alkenyl, alkynyl, aminoalkyl, OH, alkoxy, amino, alkylamino, dialkylamino, hydroxyalkyl, alkylamino alkyl, dialkylaminoalkyl, alkoxyalkyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, arylalkyl, heterocyclylalkyl, heteroarylalkyl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R39;

[0268] R39 is selected from alkyl, alkenyl, alkynyl, aminoalkyl, OH, alkoxy, amino, nitro, cyano, halo, alkylamino, dialkylamino, hydroxyalkyl, alkylamino alkyl, dialkylaminoalkyl, alkoxyalkyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, arylalkyl, heterocyclylalkyl, arylalkenyl, heterocyclylalkenyl, arylheterocyclylalkenyl, heterocyclylarylalkenyl, or heteroarylalkyl; and

[0269] R2 and R3 optionally join to form a saturated or unsaturated ring of 5, 6, 7, or 8 atoms, where the atoms in the ring are independently selected from CR40, C(R40)2, C═O, N, NR40, O, S, C═S, S═O, or SO2.

[0270] Cyclic pyrazoles that are useful as the present MK-2 inhibiting compound have the structure:

[0271] where:

[0272] Ra and Rb join to form a ring structure selected from the group consisting of:

[0273] A, E, G and J are carbon, or optionally, one of A, E, G and J is selected from nitrogen, sulfur, or oxygen;

[0274] when A, E, G, or J is oxygen or sulfur, no substituent groups are bonded to the oxygen or the sulfur;

[0275] when A, E, G, or J is nitrogen, the nitrogen is optionally unsubstituted, or is substituted with R9;

[0276] each of R1, R2, R4 and R6 is optionally absent, or is independently selected from the R3 groups;

[0277] R3, R5, R7, R40, R52, R53, R54 and R55 are each independently selected from —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, nitro C1-C6 alkyl, azido C1-C6 alkyl, amino, NHR10, NR11R12, C1-C6 alkyl-NHR10, C1-C6 alkyl-NR11R12, nitro, cyano, O—R13, C1-C4 alkyl-OR13, aryl, heteroaryl, heterocyclyl, COR14, SR13, SOR14, SO2R14, C1-C6 alkyl-COR14, C1-C6 alkyl-SR13, C1-C6 alkyl-SOR14, C1-C6 alkyl-SO2R14, halo, halo C1-C6 alkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, arylalkyl, heteroarylalkyl, heterocyclylalkyl, arylalkenyl, heterocyclylalkenyl, arylheterocyclylalkenyl, heterocyclylarylalkenyl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R15;

[0278] R8 and R9 join to form a ring structure selected from:

[0279] R10, R11, are each independently selected from —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, amino, NHR16, NR16R17, C1-C6 alkyl-NHR16, C1-C6 alkyl-NR16R17, O—R18, C1-C4 alkyl-OR18, aryl, heteroaryl, heterocyclyl, CO2R19, COR20, CONHR19, CON(R19)2, SR18, SOR20, SO2R20, C1-C6 alkyl-CO2R0, C1-C6 alkyl-COR20, C1-C6 alkyl-CONHR19, C1-C6 alkyl-CON(R19)2, C1-C6 alkyl-SR18, C alkyl-SOR20, C1-C6 alkyl-SO2R20, halo, halo C1-C6 alkyl, arylaryl, arylheteroaryl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, arylalkyl, heteroarylalkyl, heterocyclylalkyl, arylalkenyl, heterocyclylalkenyl, arylheterocyclylalkenyl, heterocyclylarylalkenyl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R21;

[0280] R12, R13 are each independently selected from —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl-NHR16, C1-C6 alkyl-NR16R17, C1-C4 alkyl-OR18, aryl, heteroaryl, heterocyclyl, CO2R19, COR20, CONHR19, CON(R19)2, SOR20, SO2R20, C1-C6 alkyl-CO2R19, C1-C6 alkyl-COR20, C1-C6 alkyl-CONHR19, C1-C6 alkyl-CON(R19)2, C1-C6 alkyl-SR18, C1-C6 alkyl-SOR20, C1-C6 alkyl-SO2R20, halo C1-C6 alkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R21;

[0281] R14 is selected from —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, amino, NHR16, NR16R17, C1-C6 alkyl-NHR16, C1-C6 alkyl-NR16R17, O—R18, C1-C4 alkyl-OR18, aryl, heteroaryl, heterocyclyl, SR18, C1-C6 alkyl-CO2R19, C1-C6 alkyl-COR20, C1-C6 alkyl-CONHR19, C1-C6 alkyl-CON(R19)2, C1-C6 alkyl-SR18, C1-C6 alkyl-SOR20, C1-C6 alkyl-SO2R20, halo, halo C1-C6 alkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, arylalkyl, heteroarylalkyl, heterocyclylalkyl, arylalkenyl, heterocyclylalkenyl, arylheterocyclylalkenyl, heterocyclylarylalkenyl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R21;

[0282] R15 is selected from —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, amino, NHR10, NR11R12, C1-C6 alkyl-NHR10, C1-C6 alkyl-NR11R12, nitro, cyano, O—R13, C1-C4 alkyl-OR13, aryl, heteroaryl, heterocyclyl, COR14, SR13, SOR14, SO2R14, C1-C6 alkyl-COR14, C1-C6 alkyl-SR13, C1-C6 alkyl-SOR14, C1-C6 alkyl-SO2R14, halo, halo C1-C6 alkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, arylalkyl, heteroarylalkyl, heterocyclylalkyl, arylalkenyl, heterocyclylalkenyl, arylheterocyclylalkenyl, heterocyclylarylalkenyl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R21;

[0283] R16 and R17 are each independently selected from —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, amino, C1-C6 alkyl-NHR22, C1-C6 alkyl-NR22R23, C1-C4 alkyl-OR24, aryl, heteroaryl, heterocyclyl, CO2R25, COR26, CONHR25, CON(R25)2, SOR26, SO2R26, C1-C6 alkyl-CO2R25, C1-C6 alkyl-COR26, C1-C6 alkyl-CONHR25, C1-C6 alkyl-CON(R25)2, C1-C6 alkyl-SR24, C1-C6 alkyl-SOR26, C1-C6 alkyl-SO2R26, halo, halo C1-C6 alkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, arylalkyl, heteroarylalkyl, heterocyclylalkyl, arylalkenyl, heterocyclylalkenyl, arylheterocyclylalkenyl, heterocyclylarylalkenyl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R27;

[0284] R18, R19 are each independently selected from —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl-NHR22, C1-C6 alkyl-NR22R23, C1-C4 alkyl-OR24, aryl, heteroaryl, heterocyclyl, CO2R25, COR26, CONHR25, CON(R25)2, SOR26, SO2R27, C1-C6 alkyl-CO2R25, C1-C6 alkyl-COR26, C1-C6 alkyl-CONHR25, C1-C6 alkyl-CON(R25)2, C1-C6 alkyl-SR24, C1-C6 alkyl-SOR26, C1-C6 alkyl-SO2R26, halo C1-C6 alkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R27;

[0285] R20 is selected from —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, amino, NHR22, NR22R23, C1-C6 alkyl-NHR22, C1-C6 alkyl-NR22R23, O—R24, C1-C4 alkyl-OR24, aryl, heteroaryl, heterocyclyl, SR24, C1-C6 alkyl-CO2R25, C1-C6 alkyl-COR26, C1-C6 alkyl-CONHR25, C1-C6 alkyl-CON(R25)2, C1-C6 alkyl-SR24, C1-C6 alkyl-SOR26, C1-C6 alkyl-SO2R26, halo, halo C1-C6 alkyl, arylalkoxyalkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, arylalkyl, heteroarylalkyl, heterocyclylalkyl, arylalkenyl, heterocyclylalkenyl, arylheterocyclylalkenyl, heterocyclylarylalkenyl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R27;

[0286] R21 is selected from —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, amino, NHR22, NR22R23, C1-C6 alkyl-NHR22, C1-C6 alkyl-NR22R23, nitro, cyano, O—R24, C1-C4 alkyl-OR24, aryl, heteroaryl, heterocyclyl, COR26, SR24, SOR26, SO2R26, C1-C6 alkyl-COR26, C1-C6 alkyl-SR24, C1-C6 alkyl-SOR26, C1-C6 alkyl-SO2R26, halo, halo C1-C6 alkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, arylalkyl, heteroarylalkyl, heterocyclylalkyl, arylalkenyl, heterocyclylalkenyl, arylheterocyclylalkenyl, heterocyclylarylalkenyl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R27;

[0287] R22 and R23 are each independently selected from —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, amino, C1-C6 alkyl-NHR28, C1-C6 alkyl-NR28R29, C1-C4 alkyl-OR30, aryl, heteroaryl, heterocyclyl, CO2R31, COR32, CONHR31, CON(R31)2, SOR32, SO2R32, C1-C6 alkyl-CO2R31, C1-C6 alkyl-COR32, C1-C6 alkyl-CONHR31, C1-C6 alkyl-CON(R31)2, C1-C6 alkyl-SR30, C1-C6 alkyl-SOR32, C1-C6 alkyl-SO2R32, halo, halo C1-C6 alkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, arylalkyl, heteroarylalkyl, heterocyclylalkyl, arylalkenyl, heterocyclylalkenyl, arylheterocyclylalkenyl, heterocyclylarylalkenyl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R33;

[0288] R24 and R25 are each independently selected from —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl-NHR28, C1-C6 alkyl-NR28R29, C1-C4 alkyl-OR30, aryl, heteroaryl, heterocyclyl, CO2R31, COR32, CONHR31, CON(R31)2, SOR32, SO2R32, C1-C6 alkyl-CO2R31, C1-C6 alkyl-COR32, C1-C6 alkyl-CONHR31, C1-C6 alkyl-CON(R31)2, C1-C6 alkyl-SR30, C1-C6 alkyl-SOR32, C1-C6 alkyl-SO2R32, halo C1-C6 alkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R33;

[0289] R26 is selected from —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, amino, NHR28, NR28R29, C1-C6 alkyl-NHR28, C1-C6 alkyl-NR28R29, O—R30, C1-C4 alkyl-OR30, aryl, heteroaryl, heterocyclyl, SR30, C1-C6 alkyl-CO2R31, C1-C6 alkyl-COR32, C1-C6 alkyl-CONHR31, C1-C6 alkyl-CON(R31)2, C1-C6 alkyl-SR30, C1-C6 alkyl-SOR32, C1-C6 alkyl-SO2R32, halo, halo C1-C6 alkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, arylalkyl, heteroarylalkyl, heterocyclylalkyl, arylalkenyl, heterocyclylalkenyl, arylheterocyclylalkenyl, heterocyclylarylalkenyl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R33;

[0290] R27 is selected from —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, amino, NHR28, NR28R29, C1-C6 alkyl-NHR28, C1-C6 alkyl-NR28R29, nitro, cyano, O—R30, C1-C4 alkyl-OR30, aryl, heteroaryl, heterocyclyl, COR32, SR30, SOR32, SO2R32, C1-C6 alkyl-COR32, C1-C6 alkyl-SR30, C1-C6 alkyl-SOR32, C1-C6 alkyl-SO2R32, halo, halo C1-C6 alkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, arylalkyl, heteroarylalkyl, heterocyclylalkyl, arylalkenyl, heterocyclylalkenyl, arylheterocyclylalkenyl, heterocyclylarylalkenyl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R33;

[0291] R28 and R29 are each independently selected from —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, amino, C1-C6 alkyl-NHR34, C1-C6 alkyl-NR34R35, C1-C4 alkyl-OR36, aryl, heteroaryl, heterocyclyl, CO2R37, COR38, CONHR37, CON(R37)2, SOR38, SO2R38, C1-C6 alkyl-CO2R37, C1-C6 alkyl-COR38, C1-C6 alkyl-CONHR37, C1-C6 alkyl-CON(R37)2, C1-C6 alkyl-SR36, C1-C6 alkyl-SOR38, C1-C6 alkyl-SO2R38, halo, halo C1-C6 alkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, arylalkyl, heteroarylalkyl, heterocyclylalkyl, arylalkenyl, heterocyclylalkenyl, arylheterocyclylalkenyl, heterocyclylarylalkenyl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R39;

[0292] R30 and R31 are each independently selected from —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl-NHR34, C1-C6 alkyl-NR34R35, C1-C4 alkyl-OR36, aryl, heteroaryl, heterocyclyl, CO2R37, COR38, CONHR37, CON(R37)2, SOR38, SO2R38, C1-C6 alkyl-CO2R37, C1-C6 alkyl-COR38, C1-C6 alkyl-CONHR37, C1-C6 alkyl-CON(R37)2, C1-C6 alkyl-SR36, C1-C6 alkyl-SOR38, C1-C6 alkyl-SO2R38, halo C1-C6 alkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R39;

[0293] R32 is selected from —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, amino, NHR34, NR34R35, C1-C6 alkyl-NHR34, C1-C6 alkyl-NR34R35, O—R36, C1-C4 alkyl-OR36, aryl, heteroaryl, heterocyclyl, SR36, C1-C6 alkyl-CO2R37, C1-C6 alkyl-COR38, C1-C6 alkyl-CONHR37, C1-C6 alkyl-CON(R37)2, C1-C6 alkyl-SR36, C1-C6 alkyl-SOR38, C1-C6 alkyl-SO2R38, halo, halo C1-C6 alkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, arylalkyl, heteroarylalkyl, heterocyclylalkyl, arylalkenyl, heterocyclylalkenyl, arylheterocyclylalkenyl, heterocyclylarylalkenyl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R39;

[0294] R33 is selected from —H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, amino, NHR34, NR34R35, C1-C6 alkyl-NHR31, C1-C6 alkyl-NR34R35, nitro, cyano, O—R36, C1-C4 alkyl-OR35, aryl, heteroaryl, heterocyclyl, COR38, SR35, SOR38, SO2R38, C1-C6 alkyl-COR38, C1-C6 alkyl-SR36, C1-C6 alkyl-SOR38, C1-C6 alkyl-SO2R38, halo, halo C1-C6 alkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, arylalkyl, heteroarylalkyl, heterocyclylalkyl, arylalkenyl, heterocyclylalkenyl, arylheterocyclylalkenyl, heterocyclylarylalkenyl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R39;

[0295] R34, R35, R36 and R37 are each independently selected from —H, alkyl, alkenyl, alkynyl, aminoalkyl, hydroxyalkyl, alkylamino alkyl, dialkylaminoalkyl, alkoxyalkyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, arylalkyl, heterocyclylalkyl, heteroarylalkyl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R39;

[0296] R38 is selected from —H, alkyl, alkenyl, alkynyl, aminoalkyl, OH, alkoxy, amino, alkylamino, dialkylamino, hydroxyalkyl, alkylamino alkyl, dialkylaminoalkyl, alkoxyalkyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, arylalkyl, heterocyclylalkyl, heteroarylalkyl, or C1-C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl are optionally substituted with one or more of the groups defined by R39;

[0297] R39 is selected from alkyl, alkenyl, alkynyl, aminoalkyl, OH, alkoxy, amino, nitro, cyano, halo, alkylamino, dialkylamino, hydroxyalkyl, alkylamino alkyl, dialkylaminoalkyl, alkoxyalkyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylaryl, alkylheterocyclyl, alkylheteroaryl, arylalkyl, heterocyclylalkyl, arylalkenyl, heterocyclylalkenyl, arylheterocyclylalkenyl, heterocyclylarylalkenyl, or heteroarylalkyl; and

[0298] R2 and R3 optionally join to form a saturated or unsaturated ring of 5, 6, 7, or 8 atoms, where the atoms in the ring are independently selected from CR40, C(R40)2, C═O, N, NR40, O, S, C═S, S═O, or SO2.

[0299] Cyclic pyrazoles having IC50 MK-2 values of less than about 100 include compounds having the structure:

[0300] where:

[0301] Ra and Rb join to form the ring structure:

[0302] A, E, J and G are carbon;

[0303] R4, R5, and R6 are hydrogen;

[0304] R7 is selected from hydrogen or alkyl;

[0305] R8 and R9 join to form a ring structure that is selected from:

[0306] R1 is optionally absent, or is selected from alkyl, alkenyl, haloalkyl, hydroxyalkyl, carbamylaryl, or arylalkoxycarbonylpiperidyl;

[0307] R2 is optionally absent, or is selected from hydrogen, alkyl, alkenyl, aminoalkyl, alkoxyarylalkylaminoalkyl, alkylarylalkylaminoalkyl, haloalkylarylarylalkylaminoalkyl, nitroarylalkylaminoalkyl, aminoalkylarylarylalkylaminoalkyl, alkylsulfonylarylalkylaminoalkyl, alkylcarbonylarylalkylaminoalkyl, benzothienylarylalkylaminoalkyl, alkylfurylalkylaminoalkyl, cyanoarylalkylaminoalkyl, halothienylalkylaminoalkyl, haloarylalkylaminoalkyl, pyridylarylalkylaminoalkyl, haloarylalkylsulfonylaminoalkyl, arylalkylsulfonylaminoalkyl, arylarylalkylaminoalkyl, thienylalkylaminoalkyl, alkylarylarylalkylaminoalkyl, alkylarylarylalkylaminoalkyl, haloarylarylalkylaminoalkyl, haloalkylarylarylalkylaminoalkyl, furylarylalkylaminoalkyl, carboxylarylarylalkylaminoaryl, hydroxyalkyl, alkoxy(halo)arylalkylaminoalkyl, isoquinolinylaminoalkyl, hydroxyalkylcarbonylaminoalkyl, alkylaminoalkyl, alkoxycarbonylaminoalkyl, pyridylalkylaminoalkyl, aminoalkylarylaminoalkyl, alkenylaminoalkyl, aminoarylalkylaminoalkyl, alkoxyarylaminocarbonylaminoalkyl, cyclopropylalkylaminoalkyl, pyrroylalkylaminoalkyl, furylalkylaminoalkyl, piperidylalkyl, imidazolylalkylaminoalkyl, aminoarylaminoalkyl, pyridylcarbonylaminoalkyl, cyclopentylaminoalkyl, isoquinolinylalkylaminoalkyl, isoquinolinylamino(hydroxy)alkyl, pyrroylalkylaminoalkyl, arylalkylaminocarbonylaminoalkyl, cyanoalkyl, cyanoarylaminocarbonylaminoalkyl, haloalkyl, carboxy(amino)alkyl, aminocarbonylaminoalkyl, alkylsulfonylaminoalkyl, alkoxyarylalkylcarbonylaminoalkyl, thienylalkylamino(hydroxy)alkyl, cyano(amino)alkyl, pyridylaminoalkyl, alkoxycarbonylaminocarbonylaminoalkyl, carbamylpiperidylalkyl, carbamylalkyl, piperidyl, or arylalkylaminoalkyl;

[0308] R3 is selected from hydrogen, carboxyl, alkoxycarbonyl, carbamide, tetrazolyl, alkylthio, or R2 and R3 optionally join to form a 6 or 7 membered heterocycle having 2 nitrogen atoms in the ring and with at least one ring nitrogen or carbon being substituted with a group selected from hydrogen, alkyl, oxo, haloalkyl, thienylalkylaminoalkyl, hydroxyalkyl, azidoalkyl, haloarylalkylaminoalkyl, nitroalkyl, carbamyl, alkoxycarbonyl, haloarylalkylsulfonylamino, or aminoalkyl;

[0309] R41, R49 and R53 are hydrogen;

[0310] R42 is selected from hydrogen, nitroaryl, haloalkyl, haloaryl, cyanoaryl, nitroaryl, alkylsulfonylaryl, aminoaryl, alkylamino, alkylaryl, pyridyl, carboxyaryl, arylalkyl, hydroxyl, amino, carboxyalkyl, alkyl, haloarylalkyl, aminosulfonyl, imidazolyl, indazolyl, pyridyl, indolyl, pyrazolyl, or halo;

[0311] R43 is selected from hydroxy or alkoxy;

[0312] R44 is selected from hydrogen or halo;

[0313] R45 and R47 are absent;

[0314] R46 is selected from hydrogen, arylalkylthio, cyanoalkylthio, alkenylthio, imidazolyl, indazolyl, pyridyl, indolyl, pyrazolyl, or alkylthio;

[0315] R48 is selected from hydrogen or arylalkyl;

[0316] R49 and R51 are hydrogen;

[0317] R50 is selected from hydrogen, halo, alkyl, benzodioxol, alkoxy, alkylaminoalkyl, isoquinolinyl, nitroaryl, alkoxyaryl, alkylaminoaryl, arylalkyl, hydroxyaryl, quinolinyl, hydroxyarylalkenyl, alkylaryl, haloaryl, haloalkylaryl, pyrazolyl, alkylsulfonylaryl, cyanoaryl, benzofuranyl, arylamino, haloarylalkyl, alkenyl, alkoxy, aminoaryl, haloarylalkenyl, alkoxyarylalkenyl, alkylthio, heterocyclyl, alkoxyarylalkylamino, arylalkylamino, hydroxypiperidyl, pyrrolidyl, tetrahydropyrazinoyl, arylalkoxyaryl, aminoalkylamino, cyano, piperizinyl, alkylpiperidinyl, alkylpiperizinyl, imidazolyl, indazolyl, pyridyl, indolyl, pyrazolyl, or naphthyl;

[0318] R51 is selected from hydrogen, aryl, halo, alkyl, arylamino, alkylthio, or alkoxy;

[0319] R52 is selected from hydrogen, quinolinyl, benzodioxyl, alkoxyaryl, morpholinyl, dihydroisoquinolinyl, imidazolyl, indazolyl, pyridyl, indolyl, pyrazolyl, or aryl; and

[0320] R53 is selected from hydrogen, or halo.

[0321] Cyclic pyrazoles having IC50 MK-2 values of less than about 50 include compounds having the structure:

[0322] where:

[0323] Ra and Rb join to form the ring structure:

[0324] A, E, J and G are carbon;

[0325] R4, R5, and R6 are hydrogen;

[0326] R7 is selected from hydrogen or alkyl;

[0327] R8 and R9 join to form a ring structure that is selected from:

[0328] R1 is absent, or is optionally arylalkoxycarbonylpiperidyl;

[0329] R2 is selected from hydrogen, alkyl, alkenyl, aminoalkyl, alkoxyarylalkylaminoalkyl, alkylarylalkylaminoalkyl, haloalkylarylarylalkylaminoalkyl, nitroarylalkylaminoalkyl, aminoalkylarylarylalkylaminoalkyl, alkylsulfonylarylalkylaminoalkyl, alkylcarbonylarylalkylaminoalkyl, benzothienylarylalkylaminoalkyl, alkylfurylalkylaminoalkyl, cyanoarylalkylaminoalkyl, halothienylalkylaminoalkyl, haloarylalkylaminoalkyl, pyridylarylalkylaminoalkyl, haloarylalkylsulfonylaminoalkyl, arylalkylsulfonylaminoalkyl, arylarylalkylaminoalkyl, thienylalkylaminoalkyl, alkylarylarylalkylaminoalkyl, alkylarylarylalkylaminoalkyl, haloarylarylalkylaminoalkyl, haloalkylarylarylalkylaminoalkyl, furylarylalkylaminoalkyl, carboxylarylarylalkylaminoaryl, hydroxyalkyl, alkoxy(halo)arylalkylaminoalkyl, isoquinolinylaminoalkyl, hydroxyalkylcarbonylaminoalkyl, alkylaminoalkyl, alkoxycarbonylaminoalkyl, pyridylalkylaminoalkyl, aminoalkylarylaminoalkyl, alkenylaminoalkyl, aminoarylalkylaminoalkyl, alkoxyarylaminocarbonylaminoalkyl, cyclopropylalkylaminoalkyl, pyrroylalkylaminoalkyl, furylalkylaminoalkyl, piperidylalkyl, imidazolylalkylaminoalkyl, aminoarylaminoalkyl, pyridylcarbonylaminoalkyl, cyclopentylaminoalkyl, isoquinolinylalkylaminoalkyl, isoquinolinylamino(hydroxy)alkyl, pyrroylalkylaminoalkyl, arylalkylaminocarbonylaminoalkyl, cyanoalkyl, cyanoarylaminocarbonylaminoalkyl, haloalkyl, carboxy(amino)alkyl, aminocarbonylaminoalkyl, alkylsulfonylaminoalkyl, alkoxyarylalkylcarbonylaminoalkyl, thienylalkylamino(hydroxy)alkyl, cyano(amino)alkyl, pyridylaminoalkyl, alkoxycarbonylaminocarbonylaminoalkyl, carbamylpiperidylalkyl, carbamylalkyl, or arylalkylaminoalkyl;

[0330] R3 is selected from carboxyl, alkoxycarbonyl, carbamide, tetrazolyl, or R2 and R3 optionally join to form a 6 or 7 membered heterocycle having 2 nitrogen atoms in the ring and with at least one ring nitrogen or carbon being substituted with a group selected from hydrogen, alkyl, oxo, haloalkyl, thienylalkylaminoalkyl, hydroxyalkyl, azidoalkyl, haloarylalkylaminoalkyl, nitroalkyl, carbamyl, alkoxycarbonyl, or aminoalkyl;

[0331] R41, R49 and R53 are hydrogen;

[0332] R42 is selected from hydrogen, haloalkyl, haloaryl, cyanoaryl, nitroaryl, alkylsulfonylaryl, aminoaryl, alkylamino, alkylaryl, carboxyaryl, arylalkyl, hydroxyl, amino, carboxyalkyl, alkyl, imidazolyl, indazolyl, pyridyl, indolyl, pyrazolyl, or halo;

[0333] R43 is selected from hydroxy or alkoxy;

[0334] R44 is selected from hydrogen or halo;

[0335] R45 and R47 are absent;

[0336] R46 is selected from hydrogen, arylalkylthio, cyanoalkylthio, alkenylthio, imidazolyl, indazolyl, pyridyl, indolyl, pyrazolyl, or alkylthio;

[0337] R48 is selected from hydrogen or arylalkyl;

[0338] R49 and R51 are hydrogen;

[0339] R50 is selected from hydrogen, halo, alkyl, benzodioxol, alkoxy, alkylaminoalkyl, isoquinolinyl, nitroaryl, alkoxyaryl, alkylaminoaryl, arylalkyl, hydroxyaryl, quinolinyl, hydroxyarylalkenyl, alkylaryl, haloaryl, haloalkylaryl, pyrazolyl, alkylsulfonylaryl, cyanoaryl, benzofuranyl, arylamino, haloalkylaryl, alkenyl, alkoxy, aminoaryl, haloarylalkenyl, alkoxyarylalkenyl, alkylthio, heterocyclyl, alkoxyarylalkylamino, arylalkylamino, hydroxypiperidyl, pyrrolidyl, tetrhydropyrazinoyl, arylalkoxyaryl, imidazolyl, indazolyl, pyridyl, indolyl, pyrazolyl, or naphthyl;

[0340] R51 is selected from hydrogen, halo, alkyl, or alkoxy;

[0341] R52 is selected from hydrogen, quinolinyl, benzodioxyl, alkoxyaryl, morpholinyl, dihydroisoquinolinyl, imidazolyl, indazolyl, pyridyl, indolyl, pyrazolyl, or aryl; and

[0342] R53 is selected from hydrogen or halo.

[0343] Cyclic pyrazoles having IC50 MK-2 values of less than about 20 include compounds having the structure:

[0344] where:

[0345] Ra and Rb join to form the ring structure:

[0346] A, E, J and G are carbon;

[0347] R4, R5, and R6 are hydrogen;

[0348] R7 is selected from hydrogen or alkyl;

[0349] R8 and R9 join to form a ring structure that is selected from:

[0350] R1 is absent;

[0351] R2 is selected from alkyl, alkenyl, aminoalkyl, alkoxyarylalkylaminoalkyl, alkylarylalkylaminoalkyl, haloalkylarylarylalkylaminoalkyl, nitroarylalkylaminoalkyl, aminoalkylarylarylalkylaminoalkyl, alkylsulfonylarylalkylaminoalkyl, alkylcarbonylarylalkylaminoalkyl, benzothienylarylalkylaminoalkyl, alkylfurylalkylaminoalkyl, cyanoarylalkylaminoalkyl, halothienylalkylaminoalkyl, haloarylalkylaminoalkyl, pyridylarylalkylaminoalkyl, haloarylalkylsulfonylaminoalkyl, arylalkylsulfonylaminoalkyl, arylarylalkylaminoalkyl, thienylalkylaminoalkyl, alkylarylarylalkylaminoalkyl, alkylarylarylalkylaminoalkyl, haloarylarylalkylaminoalkyl, haloalkylarylarylalkylaminoalkyl, furylarylalkylaminoalkyl, carboxylarylarylalkylaminoaryl, hydroxyalkyl, alkoxy(halo)arylalkylaminoalkyl, isoquinolinylaminoalkyl, hydroxyalkylcarbonylaminoalkyl, hydrogen, alkylaminoalkyl, alkoxycarbonylaminoalkyl, pyridylalkylaminoalkyl, aminoalkylarylaminoalkyl, alkenylaminoalkyl, aminoarylalkylaminoalkyl, alkoxyarylaminocarbonylaminoalkyl, cyclopropylalkylaminoalkyl, pyrroylalkylaminoalkyl, furylalkylaminoalkyl, piperidylalkyl, imidazolylalkylaminoalkyl, aminoarylaminoalkyl, pyridylcarbonylaminoalkyl, cyclopentylaminoalkyl, isoquinolinylalkylaminoalkyl, isoquinolinylamino(hydroxy)alkyl, pyrroylalkylaminoalkyl, arylalkylaminocarbonylaminoalkyl, cyanoalkyl, or arylalkylaminoalkyl;

[0352] R3 is selected from carboxyl, alkoxycarbonyl, carbamide, tetrazolyl, or R2 and R3 optionally join to form a 6 or 7 membered heterocycle having 2 nitrogen atoms in the ring and with at least one ring nitrogen or carbon being substituted with a group selected from hydrogen, alkyl, oxo, haloalkyl, thienylalkylaminoalkyl, hydroxyalkyl, azidoalkyl, haloarylalkylaminoalkyl, nitroalkyl, carbamyl, alkoxycarbonyl, or aminoalkyl;

[0353] R41, R49 and R53 are hydrogen;

[0354] R42 is selected from hydrogen, haloalkyl, haloaryl, cyanoaryl, nitroaryl, alkylsulfonylaryl, aminoaryl, alkylamino, alkylaryl, imidazolyl, indazolyl, pyridyl, indolyl, pyrazolyl, or halo;

[0355] R43 is hydroxy;

[0356] R44 is selected from hydrogen or halo;

[0357] R45 and R47 are absent;

[0358] R46 is selected from hydrogen, arylalkylthio, cyanoalkylthio, alkenylthio, imidazolyl, indazolyl, pyridyl, indolyl, pyrazolyl, or alkylthio;

[0359] R48, R49 and R51 are hydrogen;

[0360] R50 is selected from hydrogen, halo, benzodioxol, alkoxy, alkylaminoalkyl, isoquinolinyl, nitroaryl, alkoxyaryl, alkylaminoaryl, arylalkyl, hydroxyaryl, quinolinyl, hydroxyarylalkenyl, alkylaryl, haloaryl, haloalkylaryl, pyrazolyl, alkylsulfonylaryl, cyanoaryl, benzofuranyl, arylamino, haloalkylaryl, alkenyl, alkoxy, aminoaryl, haloarylalkenyl, alkoxyarylalkenyl, alkylthio, heterocyclyl, alkoxyarylalkylamino, arylalkylamino, hydroxypiperidyl, imidazolyl, indazolyl, pyridyl, indolyl, pyrazolyl, or naphthyl;

[0361] R51 is selected from hydrogen, or alkoxy;

[0362] R52 is selected from hydrogen, quinolinyl, benzodioxyl, alkoxyaryl, morpholinyl, dihydroisoquinolinyl, imidazolyl, indazolyl, pyridyl, indolyl, pyrazolyl, or aryl; and

[0363] R53 is selected from hydrogen or halo.

[0364] Cyclic pyrazoles having IC50 MK-2 values of less than about 10 include compounds having the structure:

[0365] where:

[0366] Ra and Rb join to form the ring structure:

[0367] R8 and R9 join to form a ring structure that is selected from:

[0368] R1 is absent;

[0369] R2 is selected from alkyl, aminoalkyl, alkoxyarylalkylaminoalkyl, alkylarylalkylaminoalkyl, haloalkylarylarylalkylaminoalkyl, nitroarylalkylaminoalkyl, aminoalkylarylarylalkylaminoalkyl, alkylsulfonylarylalkylaminoalkyl, alkylcarbonylarylalkylaminoalkyl, benzothienylarylalkylaminoalkyl, alkylfurylalkylaminoalkyl, cyanoarylalkylaminoalkyl, halothienylalkylaminoalkyl, haloarylalkylaminoalkyl, pyridylarylalkylaminoalkyl, haloarylalkylsulfonylaminoalkyl, arylalkylsulfonylaminoalkyl, arylarylalkylaminoalkyl, thienylalkylaminoalkyl, alkylarylarylalkylaminoalkyl, alkylarylarylalkylaminoalkyl, haloarylarylalkylaminoalkyl, haloalkylarylarylalkylaminoalkyl, furylarylalkylaminoalkyl, carboxylarylarylalkylaminoaryl, hydroxyalkyl, alkoxy(halo)arylalkylaminoalkyl, isoquinolinylaminoalkyl, hydroxyalkylcarbonylaminoalkyl, hydrogen, alkylaminoalkyl, alkoxycarbonylaminoalkyl, pyridylalkylaminoalkyl, aminoalkylarylaminoalkyl, alkenylaminoalkyl, aminoarylalkylaminoalkyl, alkoxyarylaminocarbonylaminoalkyl, cyclopropylalkylaminoalkyl, pyrroylalkylaminoalkyl, furylalkylaminoalkyl, piperidylalkyl, imidazolylalkylaminoalkyl, aminoarylaminoalkyl, or arylalkylaminoalkyl;

[0370] R3 is selected from carboxyl, alkoxycarbonyl, carbamide, tetrazolyl, or R2 and R3 optionally join to form a 6 or 7 membered heterocycle having 2 nitrogen atoms in the ring and with at least one ring nitrogen or carbon being substituted with a group selected from hydrogen, alkyl, oxo, haloalkyl, thienylalkylaminoalkyl, hydroxyalkyl, azidoalkyl, haloarylalkylaminoalkyl, nitroalkyl, carbamyl, or aminoalkyl;

[0371] R41, R44, R49 and R53 are hydrogen;

[0372] R42 is selected from hydrogen, haloalkyl, haloaryl, cyanoaryl, nitroaryl, imidazolyl, indazolyl, pyridyl, indolyl, pyrazolyl, or halo;

[0373] R43 is hydroxy;

[0374] R45 and R47 are absent;

[0375] R46 is selected from hydrogen, arylalkylthio, cyanoalkylthio, imidazolyl, indazolyl, pyridyl, indolyl, pyrazolyl, or alkylthio;

[0376] R48, R49, R51 and R53 are hydrogen;

[0377] R50 is selected from hydrogen, halo, benzodioxol, alkoxy, alkylaminoalkyl, isoquinolinyl, nitroaryl, alkoxyaryl, alkylaminoaryl, arylalkyl, hydroxyaryl, quinolinyl, hydroxyarylalkenyl, alkylaryl, haloaryl, haloalkylaryl, pyrazolyl, alkylsulfonylaryl, cyanoaryl, benzofuranyl, arylamino, haloalkylaryl, alkenyl, alkoxy, aminoaryl, haloarylalkenyl, alkoxyarylalkenyl, alkylthio, heterocyclyl, alkoxyarylalkylamino, arylalkylamino, hydroxypiperidyl, imidazolyl, indazolyl, pyridyl, indolyl, pyrazolyl, or naphthyl;

[0378] R51 is selected from hydrogen, or alkoxy; and

[0379] R52 is selected from hydrogen, quinolinyl, benzodioxyl, alkoxyaryl, imidazolyl, indazolyl, pyridyl, indolyl, pyrazolyl, or aryl.

[0380] Cyclic pyrazoles having IC50 MK-2 values of less than about 1 include compounds having the structure:

[0381] where:

[0382] Ra and Rb join to form the ring structure:

[0383] R8 and R9 join to form a ring structure that is selected from:

[0384] R1 is absent;

[0385] R2 is selected from alkyl, aminoalkyl, alkoxyarylalkylaminoalkyl, alkylarylalkylaminoalkyl, haloalkylarylarylalkylaminoalkyl, nitroarylalkylaminoalkyl, aminoalkylarylarylalkylaminoalkyl, alkylsulfonylarylalkylaminoalkyl, alkylcarbonylarylalkylaminoalkyl, benzothienylarylalkylaminoalkyl, alkylfurylalkylaminoalkyl, cyanoarylalkylaminoalkyl, halothienylalkylaminoalkyl, haloarylalkylaminoalkyl, pyridylarylalkylaminoalkyl, haloarylalkylsulfonylaminoalkyl, arylalkylsulfonylaminoalkyl, arylarylalkylaminoalkyl, thienylalkylaminoalkyl, alkylarylarylalkylaminoalkyl, alkylarylarylalkylaminoalkyl, haloarylarylalkylaminoalkyl, haloalkylarylarylalkylaminoalkyl, furylarylalkylaminoalkyl, carboxylarylarylalkylaminoaryl, or hydroxyalkyl;

[0386] R3 is selected from carboxyl, carbamide, or R2 and R3 optionally join to form a 6 or 7 membered heterocycle having 2 nitrogen atoms in the ring and with at least one ring carbon being substituted with a group selected from hydrogen, oxo, thienylalkylaminoalkyl, hydroxyalkyl, or aminoalkyl;

[0387] R41, R44, R49 and R53 are hydrogen;

[0388] R42 is selected from imidazolyl, indazolyl, pyridyl, indolyl, pyrazolyl, or nitroaryl;

[0389] R43 is hydroxy;

[0390] R50 is selected from hydrogen, halo, benzodioxol, alkoxy, alkylaminoalkyl, isoquinolinyl, nitroaryl, alkoxyaryl, alkylaminoaryl, arylalkyl, hydroxyaryl, quinolinyl, hydroxyarylalkenyl, alkylaryl, haloaryl, haloalkylaryl, pyrazolyl, alkylsulfonylaryl, cyanoaryl, imidazolyl, indazolyl, pyridyl, indolyl, pyrazolyl, or naphthyl;

[0391] R50 is selected from hydrogen, or alkoxy; and

[0392] R52 is selected from hydrogen, quinolinyl, benzodioxyl, imidazolyl, indazolyl, pyridyl, indolyl, pyrazolyl, or aryl.

[0393] Examples of cyclic pyrazole MK-2 inhibitors of the present invention are shown in Tables 1-5. The tables include information about the chemical structure of the compound, and, if available, its chemical name and MK-2 and MK-3 inhibiting activity.

1TABLE 1Phenoxypyrazole MK-2 inhibitorsMK-2MK-3Avg, IC50Avg. IC50No.StructureaChemical Nameb(uM)(uM)1

2-(3-aminopropyl)-7-hydroxy-8-(3- nitrophenyl)-4,5-dihydro-2H- benzo[g]indazole-3-carboxylic acid trifluoroacetate0.8231152

2-(2-aminoethyl)-7-hydroxy-8-(3- nitrophenyl)-4,5-dihydro-2H- benzo[g]indazole-3-carboxylic acid trifluoroacetate0.84540.93

3-hydroxy-2-(3-nitrophenyl)- 5,6,8,9,10,11-hexahydro-7H- benzo[g][1,4]diazepino[1,2- b[indazole-7-one trifluoroacetate1.48>2004

2-(3-aminopropyl)-7-hydroxy-4,5- dihydro-2H-benzo[g]indazole-3- carboxylic acid dihydrochloride2.0937.95

2-(2-aminoethyl)-8-bromo-7- hydroxy-4,5-dihydro-2H- benzo[g]indazole-3-carboxylic acid trifluoroacetate2.14>2006

2-(3-aminopropyl)-8-[2-(4- chlorophenyl)ethyl]-7-hydroxy-4,5- dihydro-2H-benzo[g]indazole-3- carboxylic acid trifluoroacetate2.2938.27

3-hydroxy-2-(3-nitrophenyl) 5,6,9,10- tetrahydrobenzo[g]pyrazino[1,2- b]indazol-7(8H)-one hydrobromide3>2008

2-(3-aminopropyl)-8-bromo-7- hydroxy-4,5-dihydro-2H- benzo[g]indazole-3-carboxylic acid hydrobromide3.75>2009

2-(3-aminopropyl)-7-hydroxy-8-(4- nitrophenyl)-4,5-dihydro-2H- benzo[g]indazole-3-carboxylic acid trifluoroacetate4.9110410

2-(3-aminopropyl)-8-(3- cyanophenyl)-7-hydroxy-4,5- dihydro-2H-benzo[g]indazole-3- carboxylic acid trifluoroacetate5.3516811

2-(3-aminopropyl)-7-hydroxy-8-[3- (trifluoromethyl)phenyl]-4,5-dihydro- 2H-benzo[g]indazole-3-carboxylic acid trifluoroacetate7.5371.712

2-(3-aminopropyl)-7-hydroxy-8- (3,3,3-trifluoropropyl)-4,5-dihydro- 2H-benzo[g]indazole-3-carboxylic acid trifluoroacetate8.1114913

2-(3-aminopropyl)-8-(3- chlorophenyl)-7-hydroxy-4,5- dihydro-2H-benzo[g]indazole-3-carboxylic acid trifluoroacetate10.512114

2-(3-aminopropyl)-7-hydroxy-5- methyl-4,5-dihydro-2H- benzo[g]indazole-3-carboxylic acid trifluoroacetate10.7>20015

2-(3-aminopropyl)-8-(4- chlorophenyl)-7-hydroxy-4,5- dihydro-2H-benzo[g]indazole-3- carboxylic acid trifluoroacetate1110916

2-(3-aminopropyl)-7-hydroxy-8-[3- (methylsulfonyl)phenyl]-4,5-dihydro 2H-benzo[g]indazole-3-carboxylic acid trifluoroacetate12.9>20017

2-(3-aminopropyl)-8-(3,4- difluorophenyl)-7-hydroxy-4,5- dihydro-2H-benzo[g]indazole-3- carboxylic acid trifluoroacetate14.216718

3-hydroxy-5,6,8,9,10,11-hexahydro 7H-benzo[g][1,4]diazepino[1,2- b]indazol-7-one1719

8-(3-aminophenyl)-2-(3- aminopropyl)-7-hydroxy-4,5- dihydro-2H-benzo[g]indazole-3- carboxylic acid trifluoroacetate17.216620

6-bromo-7-hydroxy-4,5-dihydro-2H- benzo[g]indazole-3-carboxamide17.6>20021

2-(3-aminopropyl)-7-hydroxy-8-[4- (methylamino)phenyl]-4,5-dihydro- 2H-benzo[g]indazole-3-carboxylic acid trifluoroacetate17.7>20022

2-(3-aminopropyl)-8-(4-tert- butylphenyl)-7-hydroxy-4,5-dihydro- 2H-benzo[g]indazole-3-carboxylic acid trifluoroacetate18.812023

2-(3-aminopropyl)-7-hydroxy-8- pyridin-4-yl-4,5-dihydro-2H- benzo[g]indazole-3-carboxylic acid trifluoroacetate18.8>20024

7-hydroxy-4,5-dihydro-2H- benzo[g]indazole-3-carboxylic acid19.6>20025

2-(3-aminopropyl)-7-hydroxy-8- isobutyl-4,5-dihydro-2H- benzo[g]indazole-3-carboxylic acid trifluoroacetate20.826

2-(3-aminopropyl)-8-(4-carboxy-3,3 dimethylbutyl)-7-hydroxy-4,5- dihydro-2H-benzo[g]indazole-3- carboxylic acid trifluoroacetate22.213527

8-amino-2-(3-aminopropyl)-7- hydroxy-4,5-dihydro-2H- benzo[g]indazole-3-carboxylic acid26.8>20028

7,8-dihydroxy-4,5-dihydro-2H- benzo[g]indazole-3-carboxylic acid28.3>20029

2-(3-aminopropyl)-8-benzyl-7- hydroxy-4,5-dihydro-2H- benzo[g]indazole-3-carboxyiic acid trifluoroacetate29.630

2-(3-aminopropyl)-8-(2- chlorophenyl)-7-hydroxy-4,5- dihydro-2H-benzo[g]indazole-3- carboxylic acid trifluoroacetate29.860.731

2-allyl-7-hydroxy-4,5-dihydro-2H- benzo[g]indazole-3-carboxylic acid35.6>20032

2-{3-[(tert- butoxycarbonyl)amino]propyl}-7- methoxy-8-(4-nitrophenyl)-4,5- dihydro-2H-benzo[g]indazole-3- carboxylic acid37.411533

39.210734

7-hydroxy-2-methyl-4,5-dihydro-2H benzo[g]indazole-3-carboxylic acid44.4>20035

2-(3-aminopropyl)-8-(sec- butylamino)-7-hydroxy-4,5-dihydro- 2H-benzo[g]indazole-3-carboxylic acid45.936

2-(3-aminopropyl)-8-(3- carboxyphenyl)-7-hydroxy-4,5- dihydro-2H-benzo[g]indazole-3- carboxylic acid trifluoroacetate47.3>20037

2-{3-[(tert- butoxycarbonyl)amino]propyl}-7- methoxy-8-(3-nitrophenyl)-4,5- dihydro-2H-benzo[g]indazole-3- carboxylic acid53.7>20038

2-{3-[(tert- butoxycarbonyl)amino]propyl}-8-(3- cyanophenyl)-7-methoxy-4,5- dihydro-2H-benzo[g]indazole-3- carboxylic acid56.2>20039

7-hydroxy-1-methyl-4,5-dihydro-1H benzo[g]indazole-3-carboxylic acid56.2>20040

2-{3-[(tert- butoxycarbonyl)amino]propyl}-8-[2- (4-chlorophenyl)ethyl]-7-methoxy- 4,5-dihydro-2H-benzo[g]indazole-3- carboxylic acid59.6>20041

2-{3-[(tert- butoxycarbonyl)amino]propyl}-7- methoxy-8-[3- (trifluoromethyl)phenyl]-4,5-dihydro 2H-benzo[g]indazole-3-carboxylic acid63.8>20042

2-{3-[(tert- butoxycarbonyl)amino]propyl}-8-(4- tert-butylphenyl)-7-methoxy-4,5- dihydro-2H-benzo[g]indazole-3- carboxylic acid65.7>20043

2-(3-aminopropyl)-6-chloro-7- hydroxy-8-(3-nitrophenyl)-4,5- dihydro-2H-benzo[g]indazole-3- carboxylic acid74.344

2-{2-[(tert- butoxycarbonyl)amino]ethyl}-7- methoxy-8-(3-nitrophenyl)-4,5- dihydro-2H-benzo[g]indazole-3- carboxylic acid82.2>20045

2-amino-3-hydroxy-5,6,8,9,10,11- hexahydro-7H- benzo[g][1,4]diazepino[1,2- b]indazol-7-one trifluoroacetate88.7>20046

2-{3-[(tert- butoxycarbonyl)amino]propyl}-8- (3,4-difluorophenyl)-7-methoxy-4,5- dihydro-2H-benzo[g]indazole-3- carboxylic acid92.7>20047

methyl 8-[(dimethylamino)sulfonyl]- 7-hydroxy-4,5-dihydro-2H- benzo[g]indazole-3-carboxylate92.848

7-hydroxy-5-methyl-4,5-dihydro-2H benzo[g]indazole-3-carboxylic acid97.1>20049

2-{3-[(tert- butoxycarbonyl)amino]propyl}-8-(4- chlorophenyl)-7-methoxy-4,5- dihydro-2H-benzo[g]indazole-3- carboxylic acid98.116150

2-{3-[(tert- butoxycarbonyl)amino]propyl}-8-(3- chlorophenyl)-7-methoxy-4,5- dihydro-2H-benzo[g]indazole-3- carboxylic acid10451

2-(3-aminophenyl)-3-hydroxy- 5,6,8,9,10,11-hexahydro-7H- benzo[g][1,4]diazepino[1,2- b]indazol-7-one trifluoroacetate10552

2-{3-[(tert- butoxycarbonyl)amino]propyl}-8-(2- chlorophenyl)-7-methoxy-4,5- dihydro-2H-benzo[g]indazole-3- carboxylic acid109>20053

ethyl 6-bromo-7-hydroxy-4,5- dihydro-2H-benzo[g]indazole-3- carboxylate116>20054

2-{3-[(tert- butoxycarbonyl)amino]propyl}-7- methoxy-8-(3,3,3-trifluoropropyl)- 4,5-dihydro-2H-benzo[g]indazole-3- carboxyiic acid134>20055

2-(3-aminopropyl)-8-(3,5- dimethylisoxazol-4-yl)-7-hydroxy- 4,5-dihydro-2H-benzo[g]indazole-3- carboxylic acid trifluoroacetate13616956

5-allyl-7-hydroxy-4,5-dihydro-1H- benzo[g]indazole-3-carboxamide139>20057

100

2-{3-[(tert- butoxycarbonyl)amino]propyl}-7- methoxy-8-[3- (methylsulfonyl)phenyl]-4,5-dihydro 2H-benzo[g]indazole-3-carboxylic acid143>20058

101

2-{3-[(tert- butoxycarbonyl)amino]propyl}-8-[1- N(tert-butoxycarbonyl)-1H-pyrrol-2- yl]-7-methoxy-4,5-dihydro-2H- benzo[g]indazole-3-carboxylic acid148>20059

102

7-hydroxy-4-methyl-4,5-dihydro-2H benzo[g]indazole-3-carboxylic acid148>20060

103

5-allyl-7-hydroxy-4,5-dihydro-1H- benzo[g]indazole-3-carboxylic acid148>20061

104

7-[(2-methoxyethoxy)methoxy]-4,5- dihydro-2H-benzo[g]indazole-3- carboxylic acid150>20062

105

6-bromo-7-hydroxy-4,5-dihydro-2H- benzo[g]indazole-3-carboxylic acid152>20063

106

8-benzyl-2-{3-[(tert- butoxycarbonyl)amino]propyl}-7- methoxy-4,5-dihydro-2H- benzo[g]indazole-3-carboxylic acid15464

107

methyl 7,8-dihydroxy-4,5-dihydro- 2H-benzo[g]indazole-3-carboxylate154>20065

108

7-hydroxy-1-methyl-4,5-dihydro-1H benzo[g]indazole-3-carboxamide158>20066

109

8-bromo-7-hydroxy-4,5-dihydro-2H- benzo[g]indazole-3-carboxylic acid16367

110

2-{3-[(tert- butoxycarbonyl)amino]propyl}-7- methoxy-8-pyridin-4-yl-45-dihydro- 2H-benzo[g]indazole-3-carboxylic acid165>20068

111

7-hydroxy-4-methyl-4,5-dihydro-2H benzo[g]indazole-3-carboxamide17319669

112

7-hydroxy-N-methyl-4,5-dihydro-2H benzo[g]indazole-3-carboxamide176>20070

113

176>20071

114

7-hydroxy-2-methyl-4,5-dihydro-2H benzo[g]indazole-3-carboxamide179>20072

115

2-{3-((tert- butoxycarbonyl)amino]propyl}-7- hydroxy-4,5-dihydro-2H- benzo[g]indazole-3-carboxylic acid181>20073

116

7-hydroxy-N-(2-hydroxyethyl)-4,5- dihydro-2H-benzo[g]indazole-3- carboxamide184>20074

117

2-(3-aminopropyl)-8-(Sec- butylamino)-7-methoxy-4,5-dihydro 2H-benzo[g]indazole-3-carboxylic acid19675

118

ethyl 7-methoxy-4,5-dihydro-2H- benzo[g]indazole-3-carboxylate>200>20076

119

7-methoxy-4,5-dihydro-2H- benzo[g]indazole-3-carboxamide>200>20077

120

ethyl 7-hydroxy-1-phenyl-4,5- dihydro-1H-benzo[g]indazole-3- carboxylate>200>20078

121

ethyl 7-hydroxy-1-(4- methoxyphenyl)-4,5-dihydro-1H- benzo[g]indazole-3-carboxylate>200>20079

122

2-allyl-7-[(2- methoxyethoxy)methoxy]-4,5- dihydro-2H-benzo[g]indazole-3- carboxamide>200>20080

123

2-allyl-7-[(2- methoxyethoxy)methoxy]-4,5- dihydro-2H-benzo[g]indazole-3- carboxylic acid>200>20081

124

ethyl 7-methoxy-5-phenyl-4,5- dihydro-1H-benzo[g]indazole-3- carboxylate>200>20082

125

7-[(2-methoxyethoxy)methoxy]-4,5- dihydro-2H-benzo[g]indazole-3- carboxamide>200>20083

126

6-bromo-7-[(2- methoxyethoxy)methoxy]-4,5- dihydro-2H-benzo[g]indazole-3- carboxamide>200>20084

127

6-bromo-7-[(2- methoxyethoxy)methoxy]-4,5- dihydro-2H-benzo[g]indazole-3- carboxylic acid>200>20085

128

ethyl 6-bromo-7-[(2- methoxyethoxy)methoxy]-4,5- dihydro-2H-benzo[g]indazole-3- carboxylate>200>20086

129

ethyl 2-allyl-7-[(2- ethoxyethoxy)methoxy]-4,5- dihydro-2H-benzo[g]indazole-3- carboxylate>200>20087

130

7-hydroxy-N,N-dimethyl-4,5- dihydro-2H-benzo[g]indazole-3- carboxamide>200>20088

131

8-bromo-2-{2-[(tert- butoxycarbonyl)amino]ethyl}-7- methoxy-4,5-dihydro-2H- benzo[g]indazole-3-carboxylic acid>200>20089

132

ethyl 8-bromo-2-{2-[(tert- butoxycarbonyl)amino]ethyl}-7- methoxy-4,5-dihydro-2H- benzo[g]indazole-3-carboxylate>20090

133

8-bromo-2-{3-[(tert- butoxycarbonyl)amino]propyl}-7- methoxy-4,5-dihydro-2H- benzo[g]indazole-3-carboxylic acid>20091

134

8-[(dimethylamino)sulfonyl]-7- hydroxy-4,5-dihydro-2H- benzo[g]indazole-3-carboxylic acid>20092

135

ethyl 8-bromo-2-{3-[(tert- butoxycarbonyl)amino]propyl}-7- methoxy-4,5-dihydro-2H- benzo[g]indazole-3-carboxylate>20093

136

7-hydroxy-8- [(isopropylamino)sulfonyl]-4,5- dihydro-2H-benzo[g]indazole-3- carboxylic acid>20094

137

methyl 7-hydroxy-8- [(isopropylamino)sulfonyl]-4,5- dihydro-2H-benzo[g]indazole-3- carboxylate>20095

138

ethyl 8-bromo-7-methoxy-4,5- dihydro-2H-benzo[g]indazole-3- carboxylate>20096

139

8-(aminosulfonyl)-7-hydroxy-4,5- dihydro-2H-benzo[g]indazole-3- carboxylic acid>20097

140

methyl 7-hydroxy-5-methyl-4,5- dihydro-2H-benzo[g]indazole-3- carboxylate>20098

141

methyl 7-methoxy-5-methyl-4,5- dihydro-2H-benzo[g]indazole-3- carboxylate>20099

142

methyl 7-methoxy-4-methyl-4,5- dihydro-2H-benzo[g]indazole-3- carboxylate>200100

143

ethyl 8-(aminosulfonyl)-7-methoxy- 4,5-dihydro-2H-benzo[g]indazole-3- carboxylate>200101

144

ethyl 2-(3-aminopropyl)-7-hydroxy- 4,5-dihydro-2H-benzo[g]indazole-3- carboxylate dihydrochloride>200102

145

ethyl 7-[(2- methoxyethoxy)methoxy]-4,5- dihydro-2H-benzo[g]indazole-3- carboxylate>200>200103

146

5-butyl-7-hydroxy-4,5-dihydro-2H- benzo[g]indazole-3-carboxamide>200>200104

147

5-ethyl-7-hydroxy-4,5-dihydro-2H- benzo(g]indazole-3-carboxamide>200>200105

148

5-butyl-7-hydroxy-4,5-dihydro-2H- benzo[g]indazole-3-carboxylic acid>200>200106

149

5-ethyl-7-hydroxy-4,5-dihydro-2H- benzo[g]indazole-3-carboxylic acid>200>200107

150

5-benzyl-7-hydroxy-4,5-dihydro-1H- benzo[g]indazole-3-carboxamide>200>200108

151

7-hydroxy-5-phenyl-4,5-dihydro-1H benzo[g]indazole-3-carboxamide>200>200109

152

5-benzyl-7-hydroxy-4,5-dihydro-1H benzo[g]indazole-3-carboxylic acid>200>200110

153

ethyl 5-allyl-7-methoxy-4,5-dihydro- 1H-benzo[g]indazole-3-carboxylate>200>200111

154

ethyl 5-benzyl-7-methoxy-4,5- dihydro-1H-benzo[g]indazole-3- carboxylate>200>200112

155

7-hydroxy-5-phenyl-4,5-dihydro-1H benzo[g]indazole-3-carboxyIic acid>200>200113

156

>200>200114

157

methyl 2-{3-[(tert- butoxycarbonyl)amino]propyl}-8- (3,4-difluorophenyl)-7-methoxy-4,5- dihydro-2H-benzo[g]indazole-3- carboxylate>200>200115

158

methyl 2-{3-[(tert- butoxycarbonyl)amino]propyl}-7- methoxy-8-[3- (methylsulfonyl)phenyl]-4,5-dihydro 2H-benzo[g]indazole-3-carboxylate>200116

159

methyl 2-{3-[(tert- butoxycarbonyl)amino]propyl}-7- methoxy-8-(4-nitrophenyl)-4,5- dihydro-2H-benzo[g]indazole-3- carboxylate>200117

160

methyl 2-{3-[(tert- butoxycarbonyl)amino]propyl}-7- methoxy-8-(3,3,3-trifluoropropyl)- 4,5-dihydro-2H-benzo[g]indazole-3- carboxylate>200118

161

3-methoxy-2-(3-nitrophenyl)- 5,6,9,10- tetrahydrobenzo[g]pyraziflo[1,2- b]indazol-7(8H)-one>200119

162

methyl 2-{3-[(tert- butoxycarbonyl)amino]propyl}-8-(3- cyanophenyl)-7-methoxy-4,5- dihydro-2H-benzo[g]indazole-3- carboxylate>200120

163

methyl 2-{2-[(tert- butoxycarbonyl)amino]ethyl}-7- methoxy-8-(3-nitrophenyl)-4-5- dihydro-2H-benzo[g]indazole-3- carboxylate>200121

164

2-amino-3-methoxy-5,6,8,9,10,11- hexahydro-7H- benzo[g][1,4]diazepino[1,2- b]indazol-7-one>200122

165

methyl 8-amino-2-(3-aminopropyl)- 7-methoxy-4,5-dihydro-2H- benzo[g]indazole-3-carboxylate hydrochloride>200123

166

2-{3-[(tert- butoxycarbonyl)amino]propyl}-7- methoxy-8-(5-nitropentyl)-4,5- dihydro-2H-benzo[g]indazole-3- carboxylic acid>200124

167

2-{3-[(tert- butoxycarbonyl)amino]propyl}8-(4- carboxy-3,3-dimethylbutyl)-7- methoxy-4,5-dihydro-2H- benzo[g]indazole-3-carboxylic acid>200125

168

2-{3-[(tert- butoxycarbonyl)amino]propyl}8- (3,5-dimethylisoxazol-4-yl)-7- methoxy-4,5-dihydro-2H- benzo-[g]indazoIe-3-carboxyIic acid>200126

169

methyl 2-{3-[(tert- butoxycarbonyl)amino]propyl}-8- (3,5-dimethylisoxazol-4-yl)-7- methoxy-4,5-dihydro-2H- benzo[g]indazole-3-carboxylate>200127

170

2-{3-[(tert- butoxycarbonyl)amino]propyl}-8-(3- carboxyphenyl)-7-methoxy-4,5- dihydro-2H-benzo[g]indazoIe-3- carboxylic acid>200128

171

methyl 2-{3-[(tert- butoxycarbonyl)amino]propyl}-7- methoxy-8-[3- (methoxycarbonyl)phenyl]-4,5- dihydro-2H-benzo[g]indazole-3- carboxylate>200129

172

2-{3-[(tert- butoxycarbonyl)amino]propyl}-8- isobutyl-7-methoxy-4,5-dihydro-2H- benzo[g]indazole-3-carboxylic acid>200130

173

methyl 2-{3-[(tert- butoxycarbonyl)amino]propyll-8-(3- chlorophenyl)-7-methoxy-4,5- dihydro-2H-benzo[g]indazole-3- carboxylate>200131

174

methyl 2-{3-[(tert- butoxycarbonyl)amino]propyl}-8- (sec-butylamino)-7-methoxy-4,5- dihydro-2H-benzo[g]indazole-3- carboxylate>200132

175

methyl 2-{3-[(tert- butoxycarbonyl)amino]propyl}-8- isobutyl-7-methoxy-4,5-dihydro-2H- benzo[g]indazole-3-carboxylate>200133

176

methyl 8-benzyl-2-{3-[(tert- butoxycarbonyl)amino]propyl}-7- methoxy-4,5-dihydro-2H- benzo[g]indazole-3-carboxylate>200134

177

3-methoxy-2-(3-nitrophenyl)- 5,6,8,9,10,11-hexahydro-7H- benzo[g][1,4]diazepino[1,2- b]indazol-7-one>200135

178

2-bromo-3-methoxy-5,6,9,10- tetrahydrobenzol[g]pyrazino[1,2- b]indazol-7(8H)-one>200136

179

methyl 7-methoxy-6,8-dinitro-4,5- dihydro-2H-benzo[g]indazole-3- carboxylate>200137

180

methyl 7-methoxy-8-nitro-4,5- dihydro-2H-benzo[g]indazole-3- carboxylate>200138

181

methyl 2-{3-[(tert- butoxycarbonyl)amino]propyl}-7- methoxy-8-nitro-4,5-dihydro-2H- benzo[g]indazole-3-carboxylate>200139

182

methyl 8-amino-2-{3-[(tert- butoxycarbonyl)amino]propyl}-7- methoxy-4,5-dihydro-2H- benzo[g]indazole-3-carboxylate>200140

183

8-amino-2-(3-aminopropyl)-7- methoxy-4,5-dihydro-2H- benzo[g]indazole-3-carboxylic acid>200141

184

methyl 2-{3-[(tert- butoxycarbonyl)amino]propyl}-8-[2- (4-chlorophenyl)ethyl]-7-methoxy- 4,5-dihydro-2H-benzo[g]indazoIe-3- carboxylate>200142

185

methyl 2-{3-{(tert- butoxycarbonyl)amino]propyl}-8-[1- (tert-butoxycarbonyl)-1H-pyrrol-2- yl]-7-methoxy-4,5-dihydro-2H- benzo[g]indazole-3-carboxylate>200143

186

2-{3-[(tert- butoxycarbonyl)amino]propyl}-7- methoxy-5-methyl-4,5-dihydro-2H- benzo[g]indazole-3-carboxylic acid>200144

187

methyl 2-{3-[(tert- butoxycarbonyl)amino]propyl}-8-(2- chlorophenyl)-7-methoxy-4,5- dihydro-2H-benzo[g]indazole-3- carboxylate>200145

188

2-(3-aminopropyl)-8-(4- chlorophenyl)-7-methoxy-4,5- dihydro-2H-benzo[g]indazole-3- carboxylic acid hydrochloride>200146

189

methyl 2-{3-[(tert- butoxycarbonyl)amino]propyl}-7- methoxy-8-(3-nitrophenyl)-4,5- dihydro-2H-benzo[g]indazole-3- carboxylate>200147

190

methyl 2-{3-[(tert- butoxycarbonyl)amino]propyl}-5-(4- tert-butylphenyl)-7-methoxy-4,5- dihydro-2H-benzo[g]indazole-3- carboxylate>200148

191

methyl 2-{3-[(tert- butoxycarbonyl)amino]propyl}-7- methoxy-8-[3- (trifluoromethyl)phenyll-4,5-dihydro 2H-benzo[g]indazole-3-carboxylate>200149

192

methyl 2-{3-[(tert- butoxycarbonyl)amino]propyl}-8-(4- chlorophenyl)-7-methoxy-4,5- dihydro-2H-benzo[g]indazole-3- carboxylate>200150

193

2-bromo-3-methoxy-9-methyl- 5,6,9,10- tetrahydrobenzo[g]pyrazino[1,2- b]indazol-7(8H)-one>200151

194

2-bromo-3-hydroxy-9-methyl- 5,6,9,10- tetrahydrobenzo[g]pyrazino[1,2- b]indazol-7(8H)-one>200>200152

195

methyl 2-{3-[(tert- butoxycarbonyl)amino]propyl}-8-[4- (dimethylamino)phenyl]-7-methoxy- 4,5-dihydro-2H-benzo[9]indazole-3- carboxylate>200>200153

196

2-(2-aminoethyl)-8-bromo-7- methoxy-4,5-dihydro-2H- benzo[g]indazole-3-carboxylic acid hydrochloride>200154

197

ethyl 7-hydroxy-1-methyl-4,5- dihydro-1H-benzo[g]indazole-3- carboxylate>200155

198

7-hydroxy-1-phenyl-4,5-dihydro-1H benzo[g]indazole-3-carboxamide>200>200156

199

ethyl 7-hydroxy-2-methyl-4,5- dihydro-2H-benzo[g]indazole-3- carboxylate>200>200157

200

>200>200158

201

>200>200159

202

>200>200160

203

>200>200161

204

>200>200162

205

>200>200163

206

>200>200164

207

>200>200165

208

>200>200166

209

>200>200167

210

>200>200168

211

>200>200169

212

>200>200170

213

>200>200171

214

>200>200172

215

>200>200173

216

>200>200174

217

>200>200175

218

>200>200176

219

>200>200177

220

>200>200178

221

>200>200179

222

>200>200180

223

>200>200181

224

>200>200182

225

>200>200183

226

>200>200184

227

>200>200185

228

>200>200186

229

>200>200aThe pyrazolylpyrazole compound may be shown with a solvent, such as, for example, trifluoroacetate, with which it can form a salt. Both the salt and acid forms of the pyrazolylpyrazole compound are included in the present invention. bcompound names generated by ACD/Name software.

[0394]

2

TABLE 2

Pyrazolylpyrazole MK-2 inhibitors

MK-2
MK-3

Avg.
Avg.

IC50
IC50

No.
Structurea
Compound Nameb
(uM)
(uM)

1

230

2-(3-aminopropyl)-8-(methylthio) 2,4,5,6-tetrahydropyrazolo[3,4- e]indazole-3-carboxylic acid dihydrochloride
1.06
47

2

231

2-(3-aminopropyl)-2,4,5,6- tetrahydropyrazolo[3,4- e]indazole-3-carboxylic acid hydrochloride
2.17
35.3

3

232

2-(3-{[2-(4- bromophenyl)ethyl]amino}propyl)- 2,4,5,6-tetrahydropyrazolo[3,4- e]indazole-3-carboxylic acid hydrochloride
2.23
20.8

4

233

2-(2-aminoethyl)-2,4,5,6- tetrahydropyrazolo[3,4- e]indazole-3-carboxylic acid hydrochloride
2.43
63.3

5

234

8-(allylthio)-2-(3-aminopropyl)- 2,4,5,6-tetrahydropyrazolo[3,4- e]indazole-3-carboxylic acid dihydrochloride
2.84
41.4

6

235

2-(3-aminopropyl)-8-(benzylthio) 2,4,5,6-tetrahydropyrazolo[3,4- e]indazole-3-carboxylic acid dihydrochloride
2.89
22.1

7

236

2-{3-[(2-thien-2- ylethyl)amino]propyl}-2,4,5,6- tetrahydropyrazolo[3,4- e]indazole-3-carboxylic acid
3.66
55.2

8

237

2-{3-[(2-thien-3- ylethyl)amino]propyl}-2,4,5,6- tetrahydropyrazolo[3,4- e]indazole-3-carboxylic acid hydrochloride
7.84
48.5

9

238

ethyl 2-(3-{[2-(4- bromophenyl)ethyl]amino}propyl)- 2,4,5,6-tetrahydropyrazolo[3,4- e]indazole-3-carboxylate
8.54
68.1

10

239

2-(2-aminobutyl)-2,4,5,6- tetrahydropyrazolo[3,4- e]indazole-3-carboxylic acid dihydrochloride
10.1
200

11

240

1-(methylthio)-4,5,7,8,9,10- hexahydro[1,4]diazepino[1,2- b]pyrazolo[3,4-g]indazol-6(3H)- one
10.5
200

12

241

1-(allylthio)-4,5,7,8,9,10- hexahydro[1,4]diazepino[1,2- b]pyrazolo[3,4-g]indazol-6(3H)- one
10.8
55.6

13

242

4,5,7,8,9,10- hexahydro[1,4]diazepino[1,2- b]pyrazolo[3,4-g]indazol-6(3H)- one
19.6
144

14

243

4,5,8,9-tetrahydro-3H- pyrazino[1,2-b]pyrazolo[3,4- g]indazol-6(7H)-one
20
137

15

244

2-allyl-2,4,5,6- tetrahydropyrazolo[3,4- e]indazole-3-carboxylic acid hydrochloride
22.7
134

16

245

1-(benzylthio)-4,5,7,8,9,10- hexahydro[1,4]diazepino[1,2- b]pyrazolo[3,4-g]indazol-6(3H)- one
23.8
56

17

246

2,4,5,6-tetrahydropyrazolo[3,4- e]indazole-3-carboxamide
28.4
129

18

247

8-(methylthio)-2,4,5,6- tetrahydropyrazolo[3,4- e]indazole-3-carboxamide
30.3

19

248

1-{1- [(benzyloxy)carbonyl]piperidin-4- yl}-6-trityl-1,4,5,6- tetrahydropyrazolo[3,4- e]indazole-3-carboxylic acid
46.5
200

20

249

ethyl 2-(3-aminopropyl)-8- (methylthio)-2,4,5,6- tetrahydropyrazolo[3,4- e]indazole-3-carboxylate dihydrochloride
55.3
200

21

250

2-piperidin-4-yl-2,4,5,6- tetrahydropyrazolo[3,4- e]indazole-3-carboxylic acid hydrochloride
60.4
200

22

251

1-(2,2,2-trifluoroethyl)-6-trityl- 1,4,5,6-tetrahydropyrazolo[3,4- e]indazole-3-carboxylic acid
68.3
195

23

252

1-(2-hydroxyethyl)-1,4,5,6- tetrahydropyrazolo[3,4- e]indazole-3-carboxamide
72.2
200

24

253

1-[4-(aminocarbonyl)phenyl]- 1,4,5,6-tetrahydropyrazolo[3,4- e]indazole-3-carboxamide or 1- [4-(aminocarbonyl)phenyl]- 1,4,5,6-tetrahydropyrazolo[3,4- e]indazole-3-carboxamide
78.4
200

25

254

8-(benzylthio)-2,4,5,6- tetrahydropyrazolo[3,4- e]indazole-3-carboxamide
80.7

26

255

1-allyl-1,4,5,6- tetrahydropyrazolo[3,4- e]indazole-3-carboxamide
95.1
49.3

27

256

2-(3-hydroxypropyl)-2,4,5,6- tetrahydropyrazolo[3,4- e]indazole-3-carboxylic acid
103
200

28

257

1-(3-aminopropyl)-1,4,5,6- tetrahydropyrazolo[3,4- e]indazole-3-carboxamide dihydrochloride
104

29

258

1-phenyl-1,4,5,6- tetrahydropyrazolo[3,4- e]indazole-3-carboxmide
112
200

30

259

6-(2-hydroxyethyl)-2,4,5,6- tetrahydropyrazolo[3,4- e]indazole-3-carboxylic acid
114
200

31

260

114
200

32

261

2-(3-cyanopropyl)-2,4,5,6- tetrahydropyrazolo[3,4- e]indazole-3-carboxylic acid hydrochloride
116
200

33

262

ethyl 2-(3-aminopropyl)-2,4,5,6- tetrahydropyrazolo[3,4- e]indazole-3-carboxylate dihydrochloride
116
186

34

263

1-benzyl-1,4,5,6- tetrahydropyrazolo[3,4- e]indazole-3-carboxamide
120
200

35

264

1-[4-(methylsulfonyl)phenyl]- 1,4,5,6-tetrahydropyrazolo[3,4- e]indazole-3-carboxamide
124
200

36

265

ethyl 2-{3-[(2-thien-3- ylethyl)amino]propyl}-2,4,5,6- tetrahydropyrazolo[3,4- e]indazole-3-carboxylate dihydrochloride
133
200

37

266

2-(2-hydroxyethyl)-2,4,5,6- tetrahydropyrazolo[3,4- e]indazole-3-carboxylic acid
139
200

38

267

2-{2-[(tert- butoxycarbonyl)amino]ethyl}-6- trityl-2,4,5,6- tetrahydropyrazolo[3,4- e]indazole-3-carboxylic acid
139
200

39

268

N-methoxy-2,4,5,6- tetrahydropyrazolo[3,4- e]indazole-3-carboxamide hydrochloride
141
180

40

269

1-[4-(aminosulfonyl)phenyl]- 1,4,5,6-tetrahydropyrazolo[3,4- e]indazole-3-carboxylic acid
145
200

41

270

2-(2,2,2-trifluoroethyl)-2,4,5,6- tetrahydropyrazolo[3,4- e]indazole-3-carboxylic acid
150
200

42

271

1-(2,2,2-trifluoroethyl)-1,4,5,6- tetrahydropyrazolo[3,4- e]indazole-3-carboxylic acid hydrochloride
180
200

43

272

2-allyl-2,4,5,6- tetrahydropyrazolo[3,4- e]indazole-3-carboxmide
181
200

44

273

ethyl 2-(3-aminopropyl)-8- (benzylthio)-2,4,5,6- tetrahydropyrazolo[3,4- e]indazole-3-carboxylate dihydrochloride
181
200

45

274

2,4,5,6-tetrahydropyrazolo[3,4- e]indazole-3-carboxylic acid hydrochloride
188
200

46

275

6-(ethoxymethyl)-2,4,5,6- tetrahydropyrazolo[3,4- e]indazole-3-carboxamide
200
145

47

276

ethyl 6-phenyl-2,4,5,6- tetrahydropyrazolo[3,4- e]indazole-3-carboxylate
200
200

48

277

1-[4-(aminosulfonyl)phenyl]-6- benzyl-N-methyl-1,4,5,6- tetrahydropyrazolo[3,4- e]indazole-3-carboxamide
200
200

49

278

6-methyl-2,4,5,6- tetrahydropyrazolo[3,4- e]indazole-3-carboxamide
200
200

50

279

ethyl 6-methyl-2,4,5,6- tetrahydropyrazolo[3,4- e]indazole-3-carboxylate
200
200

51

280

6-phenyl-2,4,5,6- tetrahydropyrazolo[3,4- e]indazole-3-carboxamide
200
200

52

281

1-[4-(aminosulfonyl)phenyl]-N- methyl-1,4,5,6- tetrahydropyrazolo[3,4- e]indazole-3-carboxamide
200
200

53

282

6-benzyl-1-phenyl-1,4,5,6- tetrahydropyrazolo[3,4- e]indazole-3-carboxamide
200
200

54

283

ethyl 1-phenyl-1,4,5,6- tetrahydropyrazolo[3,4- e]indazole-3-carboxylate
200
200

55

284

ethyl 6-benzyl-1-phenyl-1,4,5,6- tetrahydropyrazolo[3,4- e]indazole-3-carboxylate
200
200

56

285

1-(3-amino-oxopropyl)-1,4,5,6- tetrahydropyrazolo[3,4- e]indazole-3-carboxamide
200

57

286

1-(2-amino-2-oxoethyl)-1,4,5,6- tetrahydropyrazolo[3,4- e]indazole-3-carboxamide
200

58

287

8-(methylsulfonyl)-2,4,5,6- tetrahydropyrazolo[3,4- e]indazole-3-carboxamide
200

59

288

ethyl 2-{2-[(tert- butoxycarbonyl)amino]ethyl}-6- trityl-2,4,5,6- tetrahydropyrazolo[3,4- e]indazole-3-carboxylate
200
200

60

289

8-(benzylthio)-2,4,5,6- tetrahydropyrazolo[3,4- e]indazole-3-carboxylic acid
200

61

290

ethyl 8-(benzylthio)-2,4,5,6- tetrahydropyrazolo[3,4- e]indazole-3-carboxylate
200

62

291

8-(methylsulfinyl)-2,4,5,6- tetrahydropyrazolo[3,4- e]indazole-3-carboxylic acid
200

63

292

ethyl 8-(methylsulfinyl)-2,4,5,6- tetrahydropyrazolo[3,4- e]indazole-3-carboxylate
200

64

293

8-(methylthio)-2,4,5,6- tetrahydropyrazolo[3,4- e]indazole-3-carboxylic acid
200

65

294

ethyl 8-(methylthio)-2,4,5,6- tetrahydropyrazolo[3,4- e]indazole-3-carboxylate
200

66

295

tert-butyl 3-[3-(aminocarbonyl)- 5,6-dihydropyrazolo[3,4- e]indazol-2(4H)- yl]propylcarbamate
200
200

67

296

1-(2-cyanoethyl)-1,4,5,6- tetrahydropyrazolo[3,4- e]indazole-3-carboxamide
200
200

68

297

6-[(benzyloxy)methyl]-2,4,5,6- tetrahydropyrazolo[3,4- e]indazole-3-carboxamide
200
200

69

298

ethyl 6-(2-hydroxyethyl)-2,4,5,6- tetrahydropyrazolo[3,4- e]indazole-3-carboxylate acetate
200
200

70

299

6-(2-hydroxyethyl)-2,4,5,6- tetrahydropyrazolo[3,4- e]indazole-3-carboxamide
200
200

71

300

1-phenyl-1,4,5,6- tetrahydropyrazolo[3,4- e]indazole-3-carboxylic acid
200
200

72

301

ethyl 2-(2,2,2-trifluoroethyl)- 2,4,5,6-tetrahydropyrazolo[3,4- e]indazole-3-carboxylate hydrochloride
200
200

73

302

ethyl 1-(2,2,2-trifluoroethyl)-6- trityl-1,4,5,6- tetrahydropyrazolo[3,4- e]indazole-3-carboxylate
200
200

74

303

ethyl 2-allyl-6-trityl-2,4,5,6- tetrahydropyrazolo[3,4- e]indazole-3-carboxylate
200
200

75

304

ethyl 7-isobutyl-2,4,5,7- tetrahydropyrazolo[3,4- e]indazole-3-carboxylate
200
200

76

305

6-(4-methylphenyl)-2,4,5,6- tetrahydropyrazolo[3,4- e]indazole-3-carboxylic acid
200
200

77

306

ethyl 6-(4-methylphenyl)-2,4,5,6- tetrahydropyrazolo[3,4- e]indazole-3-carboxylate
200
200

78

307

7-[(benzyloxy)methyl]-2,4,5,7- tetrahydropyrazolo[3,4- e]indazole-3-carboxamide
200
200

79

308

7-isobutyl-2,4,5,7- tetrahydropyrazolo[3,4- e]indazole-3-carboxamide
200
102

80

309

ethyl 1-(2,2,2-trifluoroethyl)- 1,4,5,6-tetrahydropyrazolo[3,4- e]indazole-3-carboxylate hydrochloride
200
124

81

310

1-[4-(methylsulfonyl)phenyl]- 1,4,5,6- tetrahydropyrazolo[3,4- e]indazole-3-carboxylic acid
200
200

82

311

ethyl 1-[4- (methylsulfonyl)phenyl]-1,4,5,6- tetrahydropyrazolo[3,4- e]indazole-3-carboxylate
200
200

83

312

ethyl 6-benzyl-1-[4- (methylsulfonyl)phenyl]-1,4,5,6- tetrahydropyrazolo[3,4- e]indazole-3-carboxylate
200
200

84

313

ethyl 6-[(benzyloxy)methyl]- 2,4,5,6-tetrahydropyrazolo[3,4- e]indazole-3-carboxylate
200
200

85

314

ethyl 7-[(benzyloxy)methyl]- 2,4,5,7-tetrahydropyrazolo[3,4- e]indazole-3-carboxylate
200
200

86

315

1-(2,2,2-trifluoroethyl)-1,4,5,6- tetrahydropyrazolo[3,4- e]indazole-3-carboxamide
200
200

87

316

ethyl 1-(2-cyanoethyl)-1,4,5,6- tetrahydropyrazolo[3,4- e]indazole-3-carboxylate hydrochloride
200
112

88

317

ethyl 1-(3-aminopropyl)-1,4,5,6- tetrahydropyrazolo[3,4- e]indazole-3-carboxylate
200
125

89

318

ethyl 1-{3-[(tert- butoxycarbonyl)amino]propyl}-6- trityl-1,4,5,6- tetrahydropyrazolo[3,4- e]indazole-3-carboxylate
200
200

90

319

1-(3-aminopropyl)-1,4,5,6- tetrahydropyrazolo[3,4- e]indazole-3-carboxylic acid
200
200

91

320

2-(carboxymethyl)-2,4,5,6- tetrahydropyrazolo[3,4- e]indazole-3-carboxylic acid
200
200

92

321

ethyl 1-(2-ethoxy-2-oxoethyl)-6- trityl-1,4,5,6- tetrahydropyrazolo[3,4- e]indazole-3-carboxylate
200
200

93

322

ethyl 1-(2-cyanoethyl)-6-trityl- 1,4,5,6-tetrahydropyrazolo[3,4- e]indazole-3-carboxylate
200
200

94

323

2-(3-aminopropyl)-2,4,5,6- tetrahydropyrazolo[3,4- e]indazole-3-carboxamide
200
200

95

324

1-allyl-1,4,5,6- tetrahydropyrazolo[3,4- e]indazole-3-carboxylic acid hydrochloride
200
200

96

325

6-allyl-2,4,5,6- tetrahydropyrazolo[3,4- e]indazole-3-carboxamide
200
200

97

326

7-allyl-2,4,5,7- tetrahydropyrazolo[3,4- e]indazole-3-carboxamide
200
169

98

327

ethyl 2-(2-ethoxy-2-oxoethyl)-6- trityl-2,4,5,6- tetrahydropyrazolo[3,4- e]indazole-3-carboxylate
200
200

99

328

ethyl 2-(2-hydroxyethyl)-6-trityl- 2,4,5,6-tetrahydropyrazolo[3,4- e]indazole-3-carboxylate
200
200

100

329

1-(2-carboxyethyl)-1,4,5,6-tetrahydropyrazolo[3,4- e]indazole-3-carboxylic acid
200
200

101

330

6-benzyl-1,4,5,6- tetrahydropyrazolo[3,4- e]indazole-3-carboxamide
200
200

102

331

ethyl 2-(3-hydroxypropyl)- 2,4,5,6-tetrahydropyrazolo[3,4- e]indazole-3-carboxylate hydrochloride
200
200

103

332

ethyl 2-[3-(tetrahydro-2H-pyran- 2-yloxy)propyl]-6-trityl-2,4,5,6- tetrahydropyrazolo[3,4- e]indazole-3-carboxylate
200
200

104

333

[3-(ethoxycarbonyl)-5,6- dihydropyrazolo[3,4-e]indazol- 2(4H)-yl]acetic acid
200
200

105

334

[3-(methoxycarbonyl)-5,6- dihydropyrazolo[3,4-e]indazol- 2(4H)-yl]acetic acid
200
200

106

335

1-piperidin-4-yl-1,4,5,6- tetrahydropyrazolo[3,4- e]indazole-3-carboxylic acid dihydrochloride
200
200

107

336

1-piperidin-4-yl-6-trityl-1,4,5,6- tetrahydropyrazolo[3,4- e]indazole-3-carboxylic acid hydrochloride
200
200

108

337

ethyl 1-{1- [(benzyloxy)carbonyl]piperidin-4- yl}-6-trityl-1,4,5,6- tetrahydropyrazolo[3,4- e]indazole-3-carboxylate
200
200

109

338

ethyl 2-(3-cyanopropyl)-6-trityl-2,4, 5,6-tetrahydropyrazolo[3,4- e]indazole-3-carboxylate
200
200

110

339

ethyl 2-(4-aminobutyl)-2,4,5,6- tetrahydropyrazolo[3,4- e]indazole-3-carboxylate hydrochloride
200
200

111

340

1-(3-amino-3-oxopropyl)-1,4,5,6- tetrahydropyrazolo[3,4- e]indazole-3-carboxylic acid
200
200

112

341

[3-(ethoxycarbonyl)-5,6- dihydropyrazolo[3,4-e]indazol- 1(4H)-yl]acetic acid
200
200

113

342

ethyl 2-(2-ethoxy-2-oxoethyl)- 2,4,5,6-tetrahydropyrazolo[3,4- e]indazole-3-carboxylate hydrochloride
200
200

114

343

1-(2-hydroxyethyl)-1,4,5,6- tetrahydropyrazolo[3,4- e]indazole-3-carboxylic acid
200
200

115

344

ethyl 1-(2-hydroxyethyl)-1,4,5,6- tetrahydropyrazolo[3,4- e]indazole-3-carboxylate hydrochloride
200
126

116

345

8-(methylsulfonyl)-2,4,5,6- tetrahydropyrazolo[3,4- e]indazole-3-carboxylic acid
200

117

346

ethyl 8-(methylsulfonyl)-2,4,5,6- tetrahydropyrazolo[3,4- e]indazole-3-carboxylate
200

118

347

ethyl 6-allyl-2,4,5,6- tetrahydropyrazolo[3,4- e]indazole-3-carboxylate
200
200

119

348

ethyl 7-allyl-2,4,5,7- tetrahydropyrazolo[3,4- e]indazole-3-carboxylate
200
200

120

349

ethyl 1-(2-hydroxyethyl)-6-trityl- 1,4,5,6-tetrahydropyrazolo[3,4- e]indazole-3-carboxylate
200
200

121

350

ethyl 1-benzyl-1,4,5,6- tetrahydropyrazolo[3,4- e]indazole-3-carboxylate
200
200

122

351

ethyl 2,4,5,6- tetrahydropyrazolo[3,4- e]indazole-3-carboxylate
200
98.4

123

352

ethyl 6-trityl-2,4,5,6- tetrahydropyrazolo[3,4- e]indazole-3-carboxylate
200
200

124

353

8-amino-2,4,5,6- tetrahydropyrazolo[3,4- e]indazole-3-carboxylic acid dihydrochloride
200

125

354

200

126

355

ethyl 2-{3-[(tert- butoxycarbonyl)amino]propyl}-6- [(4-methylphenyl)sulfonyl]-8- (methylthio)-2,4,5,6- tetrahydropyrazolo[3,4- e]indazole-3-carboxylate
200

127

356

ethyl 8-(tert-butylamino)-2,4,5,6- tetrahydropyrazolo[3,4- e]indazole-3-carboxylate
200

128

357

8-(tert-butylamino)-2,4,5,6- tetrahydropyrazolo[3,4- e]indazole-3-carboxylic acid hydrochloride
200

129

358

ethyl 8-(allylthio)-6-[(4- methylphenyl)sulfonyl]-2,4,5,6- tetrahydropyrazolo[3,4- e]indazole-3-carboxylate
200

130

359

8-Allylsulfanyl-2-(3-tert- butoxycarbonylamino-propyl)-6- (toluene-4-sulfonyl)-2,4,5,6- tetrahydro-1,2,6,7-tetraaza-a s- indacene-3-carboxylic acid ethyl ester
200

131
End MK-2 compounds

132

360

133

361

134

362

135

363

136

364

137

365

138

366

139

367

140

368

141

369

142

370

143

371

144

372

145

373

146

374

147

375

148

376

149

377

150

378

151

379

152

380

153

381

154

382

155

383

156

384

157

385

158

386

159

387

160

388

161

389

162

390

163

391

164

392

165

393

166

394

167

395

168

396

169

397

170

398

171

399

172

400

173

401

174

402

175

403

176

404

177

405

178

406

179

407

180

408

181

409

182

410

183

411

184

412

185

413

186

414

187

415

188

416

189

417

190

418

191

419

192

420

193

421

194

422

195

423

196

424

197

425

198

426

199

427

200

428

201

429

202

430

203

431

204

432

205

433

206

434

207

435

208

436

209

437

210

438

211

439

212

440

213

441

214

442

215

443

216

444

217

445

218

446

219

447

220

448

221

449

222

450

223

451

224

452

225

453

226

454

227

455

228

456

229

457

230

458

231

459

232

460

233

461

234

462

235

463

236

464

237

465

238

466

239

467

240

468

241

469

242

470

243

471

244

472

245

473

246

474

247

475

248

476

249

477

250

478

251

479

252

480

253

481

254

482

255

483

256

484

257

485

258

486

259

487

260

488

261

489

262

490

263

491

a
The pyrazolylpyrazole compound may be shown with a solvent, such as, for example, trifluoroacetate, with which it can form a salt. Both the salt and acid forms of the pyrazolylpyrazole compound are included in the present invention.

b
Compound names generated by ACD/Name software.

[0395]

3

TABLE 3

Pyridylpyrazole MK-2 inhibitors

MK-2
MK-3

Avg.
Avg.

IC50
IC50

No.
Structurea
Chemical Nameb
(uM)
(uM)

1

492

2-(3-amino- propyl)-8-quinoline-3-yl-4,5-di- hydro-2H-pyrazolo[3,4-f]iso- quinolin-3-carboxylic acid trifluoroacetate
0.00946
0.0354

2

493

2-(3-amino- propyl)-8-(3-nitro- phenyl)-4,5-dihydro-2H-py- razolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate
0.018
0.142

3

494

2-(3-aminopropyl)-8-(4-hydroxy- phenyl)-4,5-dihydro-2H-py- razolo[3,4-f]iso- quinoline-3-carboxylic acid hydrobromide
0.0189
0.361

4

495

2-(3-aminopropyl)-8-(3-hydroxy- phenyl)-4,5-dihydro-2H-py- razolo[3,4-f]iso- quinoline-3-carboxylic acid hydrobromide
0.0194
0.55

5

496

2-(3-aminopropyl)-8-(2-naph- thyl)-4,5-dihydro-2H-py- razolo[3,4-f]isoquino- line-3-carboxylic acid trifluoroacetate
0.023
0.0698

6

497

2-(3-aminopropyl)-8-(3,5-di- fluorophenyl)-4,5-dihydro-2H-py- razolo[3,4-f]iso- quinoline-3-carboxylic acid trifluoroacetate
0.028
0.135

7

498

2-(3-aminopropyl)-8-(1,3-benzo- dioxol-5-yl)-4,5-dihydro-2H-py- razolo[3,4-f]isoquinoline-3 carboxylic acid trifluoroacetate
0.0296
0.269

8

499

2-(3-aminopropyl)-8-(3-cyano- phenyl)-4,5-dihydro-2H-py- razolo[3,4-f]iso- quinoline-3-carboxylic acid trifluoroacetate
0.0302
0.226

9

500

9-(hydroxymethyl)-2-quino- lin-3-yl-5,6,9,10-tetra- hydropyrazino[1′,2′:1,5]pyra- zolo[3,4-f]isoquinolin-7(8H)-one trifluoroacetate
0.0313
5.68

10

501

2-(3-aminopropyl)-8-(4-methoxy- phenyl)-4,5-dihydro-2H pyrazolo[3,4-f]iso- quinoline-3-carboxylic acid trifluoroacetate
0.0371
0.995

11

502

2-(3-aminopropyl)-8-[3-(methyl- sulfonyl)phenyl]-4,5-di- hydro-2H-pyrazolo[3,4-f]iso- quinoline-3-carboxylic acid trifluoroacetate
0.0391
0.453

12

503

2-(3-aminopropyl)-8-[3-(tri- fluoromethyl)phenyl]-4,5-di- hydro-2H-pyrazolo[3,4-f]iso- quinoline-3-carboxylic acid trifluoroacetate
0.0433
0.29

13

504

2-(1H-imidazol-1-yl)-5,6,9,10-tetra- hydropyrazino[1′,2′:1,5]pyra- zolo[3,4-f]isoquinolin-7(8H)-one trifluoroacetate
0.0523
5.34

14

505

2-(3-aminopropyl)-8-(3-methoxy- phenyl)-4,5-dihydro-2H pyrazolo[3,4-f]iso- quinoline-3-carboxylic acid trifluoroacetate
0.0558
0.875

15

506

2-(3-aminopropyl)-8-[4-(tri- fluoromethyl)phenyl]-4,5-di- hydro-2H-pyrazolo[3,4-f]iso- quinoline-3-carboxylic acid trifluoroacetate
0.0567
0.209

16

507

2-(3-aminopropyl)-8-anilino-4,5-di- hydro-2H-pyrazolo[3,4-f]iso- quinoline-3-carboxylic acid
0.074
1.15

17

508

2-(3-aminopropyl)-8-(3,4-di- fluorophenyl)-4,5-dihydro-2H-py- razolo[3,4-f]iso- quinoline-3-carboxylic acid trifluoroacetate
0.0786
1.73

18

509

2-(3-{[2-(4′-carboxy-1,1′-bi- phenyl-4-yl)ethyl]a- mino}propyl)-4,5-di- hydro-2H-pyrazolo[3,4-f]iso- quinoline-3-carboxylic acid trifluoroacetate
0.0796
2.18

19

510

2-(4-hydroxyphenyl)-5,6,9,10-tetra- hydropyrazino[1′,2′:1,5]pyra- zolo[3,4-f]isoquinolin-7(8H)-one trifluoroacetate
0.0867
0.861

20

511

2-propyl-8-quinolin-3-yl-4,5-di- hydro-2H-pyrazolo[3,4-f]iso- quinoline-3-carboxylic acid
0.0914

21

512

2-[3-({2-[3′-(trifluoromethyl)-1,1′-bi- phenyl-4-yl]ethyl}amino)pro- pyl]-4,5-dihydro-2H-py- razolo[3,4-f]iso- quinoline-3-carboxylic acid trifluoroacetate
0.103
10.4

22

513

2-(3-aminopropyl)-8-(4-tert-butyl- phenyl)-4,5-dihydro-2H-py- razolo[3,4-f]isoquino- line-3-carboxylic acid trifluoroacetate
0.112
0.426

23

514

2-[3-({2-[4-(3-furyl)phenyl]eth- yl}amino)pro- pyl]-4,5-di- hydro-2H-pyrazolo[3,4-f]iso- quinoline-3-carboxylic acid trifluoroacetate
0.126
2.62

24

515

2-(3-{[2-(3′-chloro-1,1′-bi- phenyl-4-yl)eth- yl]amino}propyl)-4,5-di- hydro-2H-pyrazolo[3,4-f]iso- quinoline-3-carboxylic acid trifluoroacetate
0.13
5.85

25

516

2-(4-methoxy- phenyl)-5,6,8,9,10,11-hexa- hydro-7H-[1,4]diaze- pino[1′,2′:1,5]pyrazolo[3,4-f]iso- quinolin-7-one
0.142
6.52

26

517

2-[3-({2-[4′-(trifluoromethyl)-1,1′-bi- phenyl-4-yl]eth- yl}amino)propyl]-4,5-di- hydro-2H-pyrazolo[3,4-f]iso- quinoline-3-carboxylic acid trifluoroacetate
0.147
9.04

27

518

2-(3-hydroxyphenyl)-5,6,9,10-tetra- hydropyrazino[1′,2′:1,5]pyra- zolo[3,4-f]isoquinolin-7(8H)-one
0.148
2.51

28

519

2-(3-amino- propyl)-N-hydroxy-8-quino- lin-3-yl-4,5-dihydro-2H-py- razolo[3,4-f]isoquinoline-3-carboxa- mide hydrochloride
0.162
4.67

29

520

2-[(E)-2-(4-hydroxy- phenyl)ethenyl]-5,6,9,10 tetrahydropyrazino[1′,2′:1,5]pyra- zolo[3,4-f]isoquinolin-7(8H)-one trifluoroacetate
0.164
27.5

30

521

2-quinolin-3-yl-5,6,8,9,10,11-hexa- hydro-7H-[1,4]diaze- pino[1′,2′:1,5]pyrazolo[3,4-f]iso- quinolin-7-one
0.171
11.9

31

522

2-(4-hydroxy- phenyl)-5,6,8,9,10,11-hexa- hydro-7H-[1,4]diaze- pino[1′,2′:1,5]pyrazolo[3,4-f]iso- quinolin-7-one
0.183
2.56

32

523

2-(3-{[2-(2′-chloro-1,1′-bi- phenyl-4-yl)eth- yl]amino}propyl)-4,5-di- hydro-2H-pyrazolo[3,4-f]iso- quinoline-3-carboxylic acid trifluoroacetate
0.185
9.61

33

524

2-(3-{[2-(4′-tert-butyl-1,1′-bi- phenyl-4-yl)eth- yl]amino}propyl)-4,5-di- hydro-2H-pyrazolo[3,4-f]iso- quinoline-3-carboxylic acid trifluoroacetate
0.201
7.22

34

525

2-(3-{[2-(3,4-di- chlorophenyl)eth- yl]amino}propyl)-4,5-di- hydro-2H-pyrazolo[3,4-f]iso- quinoline-3-carboxylic acid trifluoroacetate
0.201
10.3

35

526

2-(3-{[3-(3-chloro- phenyl)propyl]amino}propyl)-4,5-di- hydro-2H-pyrazolo[3,4-f]iso- quinoline-3-carboxylic acid trifluoroacetate
0.207
8.57

36

527

2-[(E)-2-phenylethenyl]-5,6,9,10 tetrahydropyrazino[1′,2′:1,5]pyra- zolo[3,4-f]isoquinolin-7(8H)-one trifluoroacetate
0.21
11.5

37

528

2-(3-{[2-(4-pyridin-4-ylphen- yl)ethyl]amino}propyl)-4,5 dihydro-2H-pyrazolo[3,4-f]iso- quinoline-3-carboxylic acid trifluoroacetate
0.211
7.71

38

529

2-(3-{[3-(4-bromo- phenyl)propyl]amino}pro- pyl)-4,5-dihydro-2H-py- razolo[3,4-f]iso- quinoline-3-carboxylic acid trifluoroacetate
0.22
10.3

39

530

2-(3-{[3-(4-tert- butylphenyl)propyl]a- mino}propyl)-4,5-di- hydro-2H-pyrazolo[3,4-f]iso- quinoline-3-carboxylic acid trifluoroacetate
0.234
11.6

40

531

2-(3-{[2-(3′-isopropyl-1,1′-bi- phenyl-4-yl)ethyl]amino}pro- pyl)-4,5-dihydro-2H-pyra- zolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate
0.245
16.1

41

532

2-(3-[(2-thien-2-yleth- yl)amino]propyl}-4,5-di- hydro-2H-pyrazolo[3,4-f]iso- quinoline-3-carboxylic acid trifluoroacetate
0.269
15.7

42

533

2-[4-(dimethyl- amino)phenyl]-5,6,9,10-tetra- hydropyrazino[1′,2′:1,5]pyra- zolo[3,4-f]isoquinolin-7(8H)-one
0.272
36

43

534

0.288
15.8

44

535

2-(3-{[2-(1,1′-biphenyl-4-yl)eth- yl]amino}propyl)-4,5-di- hydro-2H-pyrazolo[3,4-f]iso- quinoline-3-carboxylic acid trifluoroacetate
0.316
5.01

45

536

2-(3-methoxyphenyl)-5,6,9,10-tetra- hydropyrazino[1′,2′:1,5]pyra- zolo[3,4-f]isoquinolin-7(8H)-one
0.322
200

46

537

2-(3-{[2-(4-bromo- phenyl)ethyl]amino}propyl)-4,5-di- hydro-2H-pyrazolo[3,4-f]iso- quinoline-3-carboxylic acid trifluoroacetate
0.325
10.7

47

538

2-(3-{[2-(2,4-di- chlorophenyl)ethyl]amino}pro- pyl)-4,5-dihydro-2H-py- razolo[3,4-f]iso- quinoline-3-carboxylic acid trifluoroacetate
0.347
6.59

48

539

2-{3-[(benzyl- sulfonyl)amino]propyl}-8 quinolin-3-yl-4,5-dihydro-2H-py- razolo[3,4-f]isoquino- line-3-carboxylic acid
0.374
4.51

49

540

9-(aminomethyl)-5,6,9,10-tetra- hydropyrazino[1′,2′:1,5]pyra- zolo[3,4-f]isoquinolin-7(8H)-one trifluoroacetate
0.427
45.8

50

541

2-(3-nitrophenyl)-5,6,8,9,10,11-hexa- hydro-7H-[1,4]diaze- pino[1′,2′:1,5]pyrazolo[3,4-f]iso- quinolin-7-one
0.453
200

51

542

2-(3-amino- propyl)-8-quinolin-3-yl-4,5-di- hydro-2H-pyrazolo[3,4-f]iso- quinoline-3-carboxamide hydrochloride
0.473
9.21

52

543

2-(3-{[3-(4-chloro- phenyl)propyl]amino}propyl)-4,5-di- hydro-2H-pyrazolo[3,4-f]iso- quinoline-3-carboxylic acid trifluoroacetate
0.479
34.3

53

544

2-[3-(dimethyl- amino)phenyl]-5,6,8,9,10,11-hexa- hydro-7H-[1,4]diaze- pino[1′,2′:1,5]pyrazolo[3,4-f]iso- quinolin-7-one
0.483
4.92

54

545

2-(3-{[4-chloro- benzyl)sulfonyl]amino}pro- pyl)-8-quino- lin-3-yl-4,5-dihydro-2H-pyra- zolo[3,4-f]isoquinoline-3 carboxylic acid
0.52
6.46

55

546

2-(3-{[2-(4-pyridin-3-ylphen- yl)ethyl]amino}propyl)-4,5 dihydro-2H-pyrazolo[3,4-f]iso- quinoline-3-carboxylic acid trifluoroacetate
0.522
11.2

56

547

2-(3-{[2-(4-chloro- phenyl)ethyl]amino}propyl)-4,5-di- hydro-2H-pyrazolo[3,4-f]iso- quinoline-3-carboxylic acid trifluoroacetate
0.551
7.86

57

548

2-(3-{[2-(5-chlorothien-2-yl)eth- yl]amino}propyl)-4,5-di- hydro-2H-pyrazolo[3,4-f]iso- quinoline-3-carboxylic acid trifluoroacetate
0.559
8.85

58

549

2-(3-{[3-(4-cyano- phenyl)propyl]amino}prop- yl)-4,5-di- hydro-2H-pyrazolo[3,4-f]iso- quinoline-3-carboxylic acid trifluoroacetate
0.561
44.3

59

550

2-(3-{[3-(5-methyl-2-furyl)bu- tyl]amino}propyl)-4,5-di- hydro-2H-pyrazolo[3,4-f]iso- quinoline-3-carboxylic acid trifluoroacetate
0.574
22.5

60

551

2-[3-({2-[4-(1-benzothien-3-yl)phen- yl]ethyl}amino)propyl]-4,5-di- hydro-2H-pyrazolo[3,4-f]iso- quinoline-3-carboxylic acid trifluoroacetate
0.575
15.6

61

552

2-(3-ammoniopropyl)-3-carboxy 4,5-dihydro-2H-pyrazolo[3,4-f]iso- quinolin-7-ium dichloride
0.581
42.6

62

553

2-(4-methoxyphenyl)-5,6,9,10-tetra- hydropyrazino[1′,2′:1,5]pyra- zolo[3,4-f]isoquinolin-7(8H)-one
0.587
200

63

554

2-(3-{[3-(4-acetyl- phenyl)propyl]amino}prop- yl)-4,5-dihydro-2H-pyra- zolo[3,4-f]iso- quinoline-3-carboxylic acid trifluoroacetate
0.603
12.6

64

555

2-(3-amino- propyl)-4,5-dihydro-2H-py- razolo[3,4-f]isoquinoline-3 carboxylic acid trifluoroacetate
0.62
22.8

65

556

2-[3-({3-[4-(methyl- sulfonyl)phenyl]propyl}a- mino)propyl]-4,5-dihydro-2H-py- razolo[3,4-f]iso- quinoline-3-carboxylic acid trifluoroacetate
0.622
26.1

66

557

2-(3-aminopropyl)-8-(2-methoxy- phenyl)-4,5-dihydro-2H pyrazolo[3,4-f]iso- quinoline-3-carboxylic acid trifluoroacetate
0.632
6.87

67

558

2-[3-{(2-[3′-(aminomethyl)-1,1′-bi- phenyl-4-yl]ethyl}amino)pro- pyl]-4,5-dihydro-2H-pyra- zolo[3,4-f]iso- quinoline-3-carboxylic acid trifluoroacetate
0.663
10

68

559

2-(2-aminoethyl)-4,5-dihydro-2H pyrazolo[3,4-f]iso- quinoline-3-carboxylic acid dihydrochloride
0.706
43.1

69

560

2-(3-{[2-(4-nitro- phenyl)ethyl]amino}propyl)-4,5-di- hydro-2H-pyrazolo[3,4-f]iso- quinoline-3-carboxylic acid trifluoroacetate
0.765
11.9

70

561

2-[3-({2-[2′-(trifluoromethyl)-1,1′-bi- phenyl-4-yl]eth- yl}amino)propyl]-4,5-di- hydro-2H-pyrazolo[3,4-f]iso- quinoline-3-carboxylic acid trifluoroacetate
0.801
44.8

71

562

9-(hydroxymethyl)-5,6,9,10-tetra- hydropyrazino[1′,2′:1,5]pyra- zolo[3,4-f]isoquinolin-7(8H)-one
0.825
35

72

563

2-(3-{[2-(4-methyl- phenyl)ethyl]amino}propyl)-4,5-di- hydro-2H-pyrazolo[3,4-f]iso- quinoline-3-carboxylic acid trifluoroacetate
0.89
17.2

73

564

9-{[(2-thien-2-yleth- yl)amino]methyl}-5,6,9,10-tetra- hydropyrazino[1′,2′:1,5]pyra- zolo[3,4-f]isoquinolin-7(8H)-one
0.924
27.8

74

565

2-(3-{[2-(4-ethoxy- phenyl)ethyl]amino}propyl)-4,5-di- hydro-2H-pyrazolo[3,4-f]iso- quinoline-3-carboxylic acid trifluoroacetate
0.931
34.8

75

566

2-(1,3-benzo- dioxol-5-yl)-5,6,8,9,10,11-hexa- hydro-7H-[1,4]diaze- pino[1′,2′:1,5]pyrazolo[3,4-f]iso- quinolin-7-one
0.935
200

76

567

2-(3-{[2-(4-methoxy- phenyl)ethyl]amino}pro- pyl)-4,5-dihydro-2H-pyra- zolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate
0.939
16.1

77

568

3-[3-(1H-tetraazol-5-yl)-4,5-di- hydro-2H-pyrazolo[3,4-f]iso- quinolin-2-yl]propan-1-amine hydrochloride
1.08
72.4

78

569

2-(3-aminopropyl)-8-chloro-4,5-di- hydro-2H-pyrazolo[3,4-f]iso- quinoline-3-carboxylic acid trifluoroacetate
1.1
55.7

79

570

2-(3-{[(1R,2S)-2-phenyl- cyclopropyl]amino}propyl)-4,5-di- hydro-2H-pyrazolo[3,4-f]iso- quinoline-3-carboxylic acid trifluoroacetate
1.15
47.8

80

571

2-{3-[(3,3-di- phenylpropyl)amino]propyl}-4,5-di- hydro-2H-pyrazolo[3,4-f]iso- quinoline-3-carboxylic acid trifluoroacetate
1.18
30.3

81

572

2-(3-{[2-(3-bromo-4-methoxy- phenyl)ethyl]amino}pro- pyl)-4,5-dihydro-2H-pyra- zolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate
1.22
33

82

573

2-{3-[(4-phenyl- butyl)amino]propyl}-4,5-di- hydro-2H-pyrazolo[3,4-f]iso- quinoline-3-carboxylic acid trifluoroacetate
1.26
40.6

83

574

2-[3-(2,3-dihydro-1H-inden-2-yla- mino)propyl]-4,5-dihydro-2H-pyra- zolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate
1.26
31.1

84

575

2-(2-naphthyl)-5,6,8,9,10,11-hexa- hydro-7H-[1,4]diaze- pino[1′,2′:1,5]pyrazolo[3,4-f]iso- quinolin-7-one
1.3
2.13

85

576

2-{3-[(3-phenyl- propyl)amino]propyl}-4,5-di- hydro-2H-pyrazolo[3,4-f]iso- quinoline-3-carboxylic acid trifluoroacetate
1.33
200

86

577

2-(3-{[2-(4-fluoro- phenyl)ethyl]amino}propyl)4,5-di- hydro-2H-pyrazolo[3,4-f]iso- quinoline-3-carboxylic acid trifluoroacetate
1.34
20.2

87

578

2-{3-[(2-thien-3-yleth- yl)amino]propyl}-4,5-di- hydro-2H-pyrazolo[3,4-f]iso- quinoline-3-carboxylic acid dihydrochloride
1.38
34.1

88

579

5,6,9,10-tetra- hydropyrazino[1′,2′:1,5]pyra- zolo[3,4-f]isoquinolin-7(8H)-one
1.45
103

89

580

2-[3-(glycoloyl- amino)propyl]-8-quino- lin-3-yl-4,5-dihydro-2H-pyra- zolo[3,4-f]isoquinoline-3-carboxylic acid hydrochloride
1.48
11.3

90

581

8-quinolin-3-yl-4,5-dihydro-2H-pyra- zolo[3,4-f]isoquinoline-3-carboxylic acid
1.51
11.3

91

582

2-(3-{[2-(4-ethyl- phenyl)ethyl]amino}propyl)-4,5-di- hydro-2H-pyrazolo[3,4-f]iso- quinoline-3-carboxylic acid trifluoroacetate
1.52
44.2

92

583

2-(3-{[2-(2-chloro- phenyl)ethyl]amino}propyl)-4,5-di- hydro-2H-pyrazolo[3,4-f]iso- quinoline-3-carboxylic acid trifluoroacetate
1.53
49.3

93

584

2-{3-[(2-ethyl- butyl)amino]propyl}4,5-di- hydro-2H-pyrazolo[3,4-f]iso- quinoline-3-carboxylic acid trifluoroacetate
1.55
44.1

94

585

8-quinolin-3-yl-4,5-dihydro-2H-pyra- zolo[3,4-f]iso- quinoline-3-carboxamide
1.63
200

95

586

PHA-00767498
1.64
17.3

96

587

2-{3-[(2-pyridin-4-yleth- yl)amino]propyl}-4,5-di- hydro-2H-pyrazolo[3,4-f]iso- quinoline-3-carboxylic acid trifluoroacetate
1.84
35.6

97

588

2-(3-{[2-(4-chloro- phenyl)propyl]amino}prop- yl)-4,5-dihydro-2H-py- razolo[3,4-f]iso- quinoline-3-carboxylic acid trifluoroacetate
1.86
25.4

98

589

2-(3-{[2-(3-chloro- phenyl)ethyl]amino}propyl)-4,5-di- hydro-2H-pyrazolo[3,4-f]iso- quinoline-3-carboxylic acid trifluoroacetate
2.05
48.6

99

590

2-[3-(glycoloylamino)propyl]-4,5 dihydro-2H-pyrazolo[3,4-f]iso- quinoline-3-carboxylic acid trifluoroacetate
2.15
98.6

100

591

2-(3-{[2-(3,4-dimethoxy- phenyl)ethyl]amino}prop- yl)-4,5-dihydro-2H-pyra- zolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate
2.33
48.1

101

592

2-(1-benzo- furan-2-yl)-5,6,8,9,10,11-hexa- hydro-7H-[1,4]diaze- pino[1′,2′:1,5]pyrazolo[3,4-f]iso- quinolin-7-one
2.53
200

102

593

2-(3-{[4-(2-amino- ethyl)phenyl]amino}propyl)-4,5-di- hydro-2H-pyrazolo[3,4-f]iso- quinoline-3-carboxylic acid trifluoroacetate
2.58
34.2

103

594

2-(1-naphthyl)-5,6,9,10-tetra- hydropyrazino[1′,2′:1,5]pyra- zolo[3,4-f]isoquinolin-7(8H)-one
2.59
1.25

104

595

8-(3-aminopropyl)-5,6,8,9,10,11 hexahydro-7H-[1,4]diaze- pino[1′,2′:1,5]pyrazolo[4,5-f]iso- quinolin-7-one dihydrochloride
2.61
122

105

596

2-anilino-5,6,9,10-tetra- hydropyrazino[1′,2′:1,5]pyra- zolo[3,4-f]isoquinolin-7(8H)-one
2.65
2.25

106

597

2-(3-aminopropyl)-8-[2-(tri- fluoromethyl)phenyl]-4,5-di- hydro-2H-pyrazolo[3,4-f]iso- quinoline-3-carboxylic acid trifluoroacetate
2.69
5.26

107

598

9-(azidomethyl)-5,6,9,10-tetra- hydropyrazino[1′,2′:1,5]pyra- zolo[3,4-f]isoquinolin-7(8H)-one
2.72
67.7

108

599

9-({[2-(4-chloro- phenyl)ethyl]amino}meth- yl)-5,6,9,10-tetra- hydropyrazino[1′,2′:1,5]pyra- zolo[3,4-f]isoquinolin-7(8H)-one
2.8
120

109

600

2-phenyl-5,6,8,9,10,11-hexa- hydro-7H-[1,4]diaze- pino[1′,2′:1,5]pyrazolo[3,4-f]iso- quinolin-7-one
2.84
200

110

601

2-[3-(pentylamino)propyl]-4,5-di- hydro-2H-pyrazolo[3,4-f]iso- quinoline-3-carboxylic acid trifluoroacetate
2.86
73.3

111

602

10-(2-aminoethyl)-5,6,9,10-tetra- hydropyrazino[1′,2′:1,5]pyra- zolo[3,4-f]isoquinolin-7(8H)-one
2.94
107

112

603

2-[3-(allylamino)propyl]-4,5-di- hydro-2H-pyrazolo[3,4-f]iso- quinoline-3-carboxylic acid trifluoroacetate
3
86.3

113

604

2-(4-aminobutyl)-4,5-dihydro-2H pyrazolo[3,4-f]iso- quinoline-3-carboxylic acid dihydrochloride
3.01
174

114

605

2-(3-{[2-(4-amino- phenyl)ethyl]amino}propyl)-4,5-di- hydro-2H-pyrazolo[3,4-f]iso- quinoline-3-carboxylic acid trifluoroacetate
3.03
40.3

115

606

2-[(1E)-3,3-dimethyl- but-1-enyl]-5,6,9,10-tetra- hydropyrazino[1′,2′:1,5]pyra- zolo[3,4-f]isoquinolin-7(8H)-one trifluoroacetate
3.21
18.1

116

607

10-(nitromethyl)-5,6,9,10-tetra- hydropyrazino[1′,2′:1,5]pyra- zolo[3,4-f]isoquinolin-7(8H)-one
3.25
110

117

608

3-carboxy-2-[3-(methyl- ammonio)propyl]-4,5-di- hydro-2H-pyrazolo[3,4-f]iso- quinolin-7-ium dichloride
3.3
99

118

609

2-[3-({[(4-butoxy- phenyl)amino]carbonyl}a- mino)propyl]-4,5-dihydro-2H-py- razolo[3,4-f]iso- quinoline-3-carboxylic acid
3.39
174

119

610

2-{3-[(2-pyridin-3-yleth- yl)amino]propyl}-4,5-di- hydro-2H-pyrazolo[3,4-f]iso- quinoline-3-carboxylic acid trifluoroacetate
3.75
64.5

120

611

2-{3-[(2-pyridin-2-yleth- yl)amino]propyl}-4,5-di- hydro-2H-pyrazolo[3,4-f]iso- quinoline-3-carboxylic acid trifluoroacetate
3.75
44.3

121

612

2-{3-[(cyclo- propylmethyl)amino]prop- yl}-4,5-di- hydro-2H-pyrazolo[3,4-f]iso- quinoline-3-carboxylic acid trifluoroacetate
3.94
141

122

613

2-{3-[(2-thien-2-ylprop- yl)amino]propyl}-4,5-di- hydro-2H-pyrazolo[3,4-f]iso- quinoline-3-carboxylic acid trifluoroacetate
4.03
115

123

614

2-methoxy-5,6,9,10-tetra- hydropyrazino[1′,2′:1,5]pyra- zolo[3,4-f]isoquinolin-7(8H)-one
4.05
200

124

615

2-[3-(dimethyl- amino)phenyl]-5,6,9,10-tetra- hydropyrazino[1′,2′:1,5]pyra- zolo[3,4-f]isoquinolin-7(8H)-one
4.08
51.8

125

616

2-(3-{[2-(1H-pyrrol-1-yl)eth- yl]amino}propyl)-4,5-di- hydro-2H-pyrazolo[3,4-f]iso- quinoline-3-carboxylic acid trifluoroacetate
4.26
100

126

617

2-[3-(benzyloxy)propyl]-8-quino- lin-3-yl-4,5-dihydro-2H-py- razolo[3,4-f]iso- quinoline-3-carboxylic acid
4.31
102

127

618

2-{3-[(4-butoxy- benzyl)amino]propyl}-4,5-di- hydro-2H-pyrazolo[3,4-f]iso- quinoline-3-carboxylic acid trifluoroacetate
4.35
148

128

619

2-(1,3-benzo- dioxol-5-yl)-5,6,9,10-tetra- hydropyrazino[1′,2′:1,5]pyra- zolo[3,4-f]isoquinolin-7(8H)-one
4.44
200

129

620

2-[(E)-2-(2-fluoro- phenyl)ethenyl]5,6,9,10-tetra- hydropyrazino[1′,2′:1,5]pyra- zolo[3,4-f]isoquinolin-7(8H)-one
4.46
200

130

621

2-[(1E)-hex-1-enyl]-5,6,9,10-tetra- hydropyrazino[1′,2′:1,5]pyra- zolo[3,4-f]isoquinolin-7(8H)-one trifluoroacetate
4.66
182

131

622

2-anilino-5,6,8,9,10,11-hexa- hydro-7H-[1,4]diaze- pino[1′,2′:1,5]pyrazolo[3,4-f]iso- quinolin-7-one
4.68
25.2

132

623

5,6,8,9,10,11-hexa- hydro-7H-[1,4]diaze- pino[1′,2′:1,5]pyrazolo[3,4-f]iso- quinolin-7-one
4.75
191

133

624

2-chloro-5,6,9,10-tetra- hydropyrazino[1′,2′:1,5]pyra- zolo[3,4-f]isoquinolin-7(8H)-one
4.76
200

134

625

2-[(E)-2-(4-methoxy- phenyl)ethenyl]-5,6,9,10-tetra- hydropyrazino[1′,2′:1,5]pyra- zolo[3,4-f]isoquinolin-7(8H)-one
4.76
200

135

626

2-(methylthio)-5,6,9,10-tetra- hydropyrazino[1′,2′:1,5]pyra- zolo[3,4-f]isoquinolin-7(8H)-one
4.98
200

136

627

2-{3-[(2-furyl- methyl)amino]propyl}-4,5-di- hydro-2H-pyrazolo[3,4-f]iso- quinoline-3-carboxylic acid trifluoroacetate
5.05
57.1

137

628

2-azepan-1-yl-5,6,9,10-tetra- hydropyrazino[1′,2′:1,5]pyra- zolo[3,4-f]isoquinolin-7(8H)-one trifluoroacetate
5.12
200

138

629

2-(3,6-dihydro- pyridin-1(2H)-yl)-5,6,9,10-tetra- hydropyrazino[1′,2′1,5]pyra- zolo[3,4-f]isoquinolin-7(8H)-one trifluoroacetate
5.28
8.73

139

630

9-methyl-5,6,9,10-tetra- hydropyrazino[1′,2′:1,5]pyra- zolo[3,4-f]isoquinolin-7(8H)-one
5.93
200

140

631

2-(piperidin-3-ylmethyl)-4,5-di- hydro-2H-pyrazolo[3,4-f]iso- quinoline-3-carboxylic acid hydrochloride
5.97
200

141

632

9-(chloromethyl)-5,6,9,10-tetra- hydropyrazino[1′,2′:1,5]pyra- zolo[3,4-f]isoquinolin-7(8H)-one
6.28
73.5

142

633

2-[(4-methoxy- benzyl)amino]-5,6,9,10-tetra- hydropyrazino[1′,2′:1,5]pyra- zolo]3,4-f]isoquinolin-7(8H)-one trifluoroacetate
6.37
200

143

634

2-(3-{[2-(1H-imidazol-4-yl)eth- yl]amino}propyl)-4,5-di- hydro-2H-pyrazolo[3,4-f]iso- quinoline-3-carboxylic acid trifluoroacetate
6.62
136

144

635

2-(benzylamino)-5,6,9,10-tetra- hydropyrazino[1′,2′:1,5]pyra- zolo[3,4-f]isoquinolin-7(8H)-one trifluoroacetate
6.72
200

145

636

2-(methylthio)-5,6,8,9,10,11-hexa- hydro-7H-[1,4]diaze- pino[1′,2′:1,5]pyrazolo[3,4-f]iso- quinolin-7-one
6.85
150

146

637

2-{3-[(2-chloro- benzyl)amino]propyl}-4,5-di- hydro-2H-pyrazolo[3,4-f]iso- quinoline-3-carboxylic acid trifluoroacetate
7.02
190

147

638

2-[3-(benzylamino)propyl]-4,5-di- hydro-2H-pyrazolo[3,4-f]iso- quinoline-3-carboxylic acid trifluoroacetate
7.13

148

639

2-[3-({[(4-methoxy- phenyl)amino]carbonyl}a- mino)propyl]-4,5-dihydro-2H-py- razolo[3,4-f]isoquinoline-3-car- boxylic acid
7.32
174

149

640

2-{3-[(2-phenyl- ethyl)amino]propyl}-4,5-di- hydro-2H-pyrazolo[3,4-f]iso- quinoline-3-carboxylic acid trifluoroacetate
7.44
42.1

150

641

2-{3-[(thien-2-ylmeth- yl)amino]propyl}-4,5-di- hydro-2H-pyrazolo[3,4-f]iso- quinoline-3-carboxylic acid trifluoroacetate
7.79
180

151

642

2-benzyl-5,6,9,10-tetra- hydropyrazino[1′,2′:1,5]pyra- zolo[3,4-f]isoquinolin-7(8H)-one
7.86
3.38

152

643

5,6,8,9,10,11-hexa- hydro-7H-[1,4]diaze- pino[1′,2′:1,5]pyrazolo[3,4-f]iso- quinolin-7-one
7.86
200

153

644

2-{3-[(4-chloro- benzyl)amino]propyl}-4,5-di- hydro-2H-pyrazolo[3,4-f]iso- quinoline-3-carboxylic acid trifluoroacetate
7.96
200

154

645

2-{3-[(2-phenyl- propyl)amino]propyl}-4,5-di- hydro-2H-pyrazolo[3,4-f]iso- quinoline-3-carboxylic acid trifluoroacetate
8.28
176

155

646

7-oxo-5,6,7,8,9,10-hexa- hydropyrazino[1′,2′:1,5]pyra- zolo[3,4-f]iso- quinoline-9-carboxamide trifluoroacetate
8.76
200

156

647

2-(3-hydroxypropyl)-4,5-dihydro 2H-pyrazolo[3,4-f]isoquinoline-3 carboxylic acid
9.43
200

157

648

2-(1,3-dihydro-2H-iso- indol-2-yl)-5,6,9,10-tetra- hydropyrazino[1′,2′:1,5]pyra- zolo[3,4-f]isoquinolin-7(8H)-one trifluoroacetate
9.58
45.4

158

649

2-{3-[(4-amino- phenyl)amino]propyl}-4,5-di- hydro-2H-pyrazolo[3,4-f]iso- quinoline-3-carboxylic acid trifluoroacetate
9.73
133

159

650

2-(4-hydroxy- piperidin-1-yl)-5,6,9,10-tetra- hydropyrazino[1′,2′:1,5]pyra- zolo[3,4-f]isoquinolin-7(8H)-one trifluoroacetate
9.84
22.8

160

651

2-{3-[(1H-imidazol-5-ylmeth- yl)amino]propyl}-4,5-di- hydro-2H-pyrazolo[3,4-f]iso- quinoline-3-carboxylic acid trifluoroacetate
10.1
200

161

652

2-{3-[(3-chloro- benzyl)amino]propyl}-4,5-di- hydro-2H-pyrazolo[3,4-f]iso- quinoline-3-carboxylic acid trifluoroacetate
10.3
200

162

653

2-{3-[(pyridin-3-ylcarbo- nyl)amino]propyl}-4,5-di- hydro-2H-pyrazolo[3,4-f]iso- quinoline-3-carboxylic acid trifluoroacetate
10.4
200

163

654

4,5-dihydro-2H-pyrazolo[3,4-f]iso- quinoline-3-carboxamide
10.4
200

164

655

2-[3-(cyclo- pentylamino)propyl]-4,5-di- hydro-2H-pyrazolo[3,4-f]iso- quinoline-3-carboxylic acid dihydrochloride
10.4
200

165

656

2-(3-{[2-(1H-indol-3-yl)eth- yl]amino}propyl)-4,5-di- hydro-2H-pyrazolo[3,4-f]iso- quinoline-3-carboxylic acid
10.7
200

166

657

10-(3-aminopropyl)-5,6,9,10-tetra- hydropyrazino[1′,2′:1,5]pyra- zolo[3,4-f]isoquinolin-7(8H)-one
11
200

167

658

9-(1,2-dihydroxyethyl)-5,6,9,10-tetra- hydropyrazino[1′,2′:1,5]pyra- zolo[3,4-f]isoquinolin-7(8H)-one
11.8
200

168

659

2-morpholin-4-yl-5,6,9,10-tetra- hydropyrazino[1′,2′:1,5]pyra- zolo[3,4-f]isoquinolin-7(8H)-one trifluoroacetate
11.9

169

660

ethyl 2-(2-aminoethyl)-4,5-di- hydro-2H-pyrazolo[3,4-f]iso- quinoline-3-carboxylate dihydrochloride
12.3
200

170

661

2-allyl-4,5-dihydro-2H-py- razolo[3,4-f]iso- quinoline-3-carboxylic acid
12.6
200

171

662

2-quinolin-8-yl-5,6,9,10-tetra- hydropyrazino[1′,2′:1,5]pyra- zolo[3,4-f]isoquinolin-7(8H)-one
14
74.8

172

663

lithium 2-[3-(2,3-dihydro-1H-in- den-2-ylamino)-2-hydroxy- propyl]-4,5-dihydro-2H-py- razolo[3,4-f]isoquinoline-3-car- boxylate
14

173

664

2-(2-hydroxy- ethyl)-4,5-dihydro-2H-py- razolo[3,4-f]isoquinoline-3 carboxylic acid
14.3
200

174

665

2-{3-[(2-pyrrolidin-1-yleth- yl)amino]propyl}-4,5-di- hydro-2H-pyrazolo[3,4-f]iso- quinoline-3-carboxylic acid trifluoroacetate
14.6
200

175

666

2-(3,4-dihydro- isoquinolin-2(1H)-yl)-5,6,9,10-tetra- hydropyrazino[1′,2′:1,5]pyra- zolo[3,4-f]isoquinolin-8(7H)-one trifluoroacetate
15

176

667

2-(3-{[(benzyl- amino)carbonyl]amino}pro- pyl)-4,5-dihydro-2H-py- razolo[3,4-f]iso- quinoline-3-carboxylic acid
15.4
200

177

668

2-[3-(dimethylamino)propyl]-4,5-di- hydro-2H-pyrazolo[3,4-f]iso- quinoline-3-carboxylic acid trifluoroacetate
15.5
200

178

669

10-(3-{[2-(4-chloro- phenyl)ethyl]a- mino}propyl)-5,6,9,10-tetra- hydropyrazino[1′,2′:1,5]pyra- zolo[3,4-f]isoquinolin-7(8H)-one
16.1
40.4

179

670

2-(3-aminopropyl)-6-chloro-4,5-di- hydro-2H-pyrazolo[3,4-f]iso- quinoline-3-carboxylic acid trifluoroacetate
16.5
200

180

671

methyl 7-oxo-5,6,7,8,9,10-hexa- hydropyrazino[1′,2′:1,5]pyra- zolo[3,4-f]isoquinoline-9-car- boxylate
16.5

181

672

2-[2-(glycoloylamino)ethyl]-4,5-di- hydro-2H-pyrazolo[3,4-f]iso- quinoline-3-carboxylic acid hydrochloride
17.4
200

182

673

2-[2-(isopropylamino)ethyl]-4,5-di- hydro-2H-pyrazolo[3,4-f]iso- quinoline-3-carboxylic acid hydrochloride
17.7
200

183

674

2-(3-cyano- propyl)-4,5-dihydro-2H-py- razolo[3,4-f]isoquinoline-3 carboxylic acid
17.9
200

184

675

2-[3-({[(3-cyano- phenyl)amino]carbonyl}a- mino)propyl]-4,5-dihydro-2H-py- razolo[3,4-f]iso- quinoline-3-carboxylic acid
17.9
200

185

676

9-(aminomethyl)-5,6,9,10-tetra- hydro-7H-[1,4]oxa- zino[4′,3′:1,5]pyrazolo[3,4-f]iso- quinolin-7-one trifluoroacetate
19.4

186

677

4-methyl-5,6,8,9,10,11-hexa- hydro-7H-[1,4]diaze- pino[1′,2′:1,5]pyrazolo[3,4-f]iso- quinolin-7-one trifluoroacetate
20

187

678

2-propyl-4,5-dihydro-2H-pyra- zolo[3,4-f]isoquinoline-3-carboxylic acid
20.1

188

679

2-(3-bromo- propyl)-4,5-dihydro-2H-py- razolo[3,4-f]isoquinoline-3 carboxylic acid trifluoroacetate
21.5
200

189

680

2-pyrrolidin-1-yl-5,6,9,10-tetra- hydropyrazino[1′,2′:1,5]pyra- zolo[3,4-f]isoquinolin-7(8H)-one
21.6

190

681

2-[3-(isopropylamino)propyl]-4,5 dihydro-2H-pyrazolo[3,4-f]iso- quinoline-3-carboxylic acid hydrochloride
21.9

191

682

2-(3-amino-3-carboxypropyl)-4,5-di- hydro-2H-pyrazolo[3,4-f]iso- quinoline-3-carboxylic acid trifluoroacetate
25
200

192

683

2-{3-[(amino- carbonyl)amino]propyl}-4,5-di- hydro-2H-pyrazolo[3,4-f]iso- quinoline-3-carboxylic acid
25.3
200

193

684

9-{[(4-chloro- benzyl)amino]methyl}-5,6,9,10-tetra- hydropyrazino[1′,2′:1,5]pyra- zolo[3,4-f]isoquinolin-7(8H)-one
27.3
200

194

685

4-chloro-5,6,9,10-tetra- hydropyrazino[1′,2′:1,5]pyra- zolo[3,4-f]isoquinolin-7(8H)-one
27.7
200

195

686

7-oxo-2-quino- lin-3-yl-5,6,7,8,9,10-hexa- hydropyrazino[1′,2′:1,5]pyra- zolo[3,4-f]iso- quinoline-9-carboxamide
27.9

196

687

2-{3-[(methyl- sulfonyl)amino]propyl}-4,5-di- hydro-2H-pyrazolo[3,4-f]iso- quinoline-3-carboxylic acid trifluoroacetate
28.2
200

197

688

lithium 2-{4-[(2-ethyl- butyl)amino]butyl}-4,5-di- hydro-2H-pyrazolo[3,4-f]iso- quinoline-3-carboxylate
29.4

198

689

2-(3-{[(4-methoxy- phenyl)acetyl]amino}pro- pyl)-4,5-dihydro-2H-pyra- zolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate
30.1

199

690

7-oxo-6,7,8,9,10,11-hexa- hydro-5H-[1,4]diaze- pino[1′,2′:1,5]pyrazolo[3,4-f]iso- quinoline-9-carbonitrile
33.3

200

691

2-{3-[(isopropyl- sulfonyl)amino]propyl}-4,5-di- hydro-2H-pyrazolo[3,4-f]iso- quinoline-3-carboxylic acid trifluoroacetate
33.3
200

201

692

3-[3-(chloro- methyl)-4,5-dihydro-2H-pyra- zolo[3,4-f]isoquinolin-2-yl]pro- pan-1-amine hydrochloride
33.5

202

693

2-(3,3-dimethylbutyl)-5,6,9,10-tetra- hydropyrazino[1′,2′:1,5]pyra- zolo[3,4-f]iso- quinolin-7(8H)-one trifluoroacetate
35.6

203

694

2-thiomorpholin-4-yl-5,6,9,10-tetra- hydropyrazino[1′,2′:1,5]pyra- zolo[3,4-f]iso- quinolin-7(8H)-one trifluoroacetate
35.6
3.3

204

695

ethyl 2-(2-amino- ethyl)-8-chloro-4,5-di- hydro-2H-pyrazolo[3,4-f]iso- quinoline-3-carboxylate
36
200

205

696

2-[4-(benzyl- oxy)phenyl]-5,6,9,10-tetra- hydropyrazino[1′,2′:1,5]pyra- zolo[3,4-f]isoquinolin-7(8H)-one
36.4

206

697

lithium 2-{2-hy- droxy-3-[(thien-2-ylmeth- yl)amino]propyl}-4,5-di- hydro-2H-pyrazolo[3,4-f]iso- quinoline-3-carboxylate
36.8

207

698

2-(3-amino-3-cyanopropyl)-4,5-di- hydro-2H-pyrazolo[3,4-f]iso- quinoline-3-carboxylic acid trifluoroacetate
36.9
186

208

699

2-[3-(pyri- din-3-ylamino)propyl]-4,5-di- hydro-2H-pyrazolo[3,4-f]iso- quinoline-3-carboxylic acid trifluoroacetate
39.4
200

209

700

2-[3-({[(ethoxy- carbonyl)amino]carbo- nyl}amino)propyl]-4,5-di- hydro-2H-py- razolo[3,4-f]isoquinoline-3 carboxylic acid trifluoroacetate
42.5
200

210

701

2-{3-[4-(aminocarbonyl)piperidin 1-yl]propyl}-4,5-dihydro-2H-pyra- zolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate
47.9

211

702

2-(4-amino-4-oxobutyl)-4,5-di- hydro-2H-pyrazolo[3,4-f]iso- quinoline-3-carboxylic acid trifluoroacetate
50.1

212

703

8-quinolin-3-yl-4,5-dihydro-2H-py- razolo[3,4-f]isoquinoline
52

213

704

2-(3-{[(butyl- amino)carbonyl]amino}pro- pyl)-4,5-dihydro-2H-py- razolo[3,4-f]iso- quinoline-3-carboxylic acid trifluoroacetate
53.5
200

214

705

3-(2-furyl)-4,5-dihydro-2H-pyra- zolo[3,4-f]isoquinoline
53.7
200

215

706

4-anilino-5,6,9,10-tetra- hydropyrazino[1′,2′:1,5]pyra- zolo[3,4-f]isoquinolin-7(8H)-one
53.8
200

216

707

8-(3-aminopropyl)-5,6,9,10-tetra- hydropyrazino[1′,2′:1,5]pyra- zolo[3,4-f]isoquinolin-7(8H)-one dihydrochloride
54.8
200

217

708

2-(3-{[(allyl- amino)carbonyl]amino}pro- pyl)-4,5-dihydro-2H-py- razolo[3,4-f]iso- quinoline-3-carboxylic acid trifluoroacetate
55.3
200

218

709

2-{3-[(2,2,2-tri- fluoroethyl)amino]propyl}-4,5-di- hydro-2H-pyrazolo[3,4-f]iso- quinoline-3-carboxylic acid trifluoroacetate
56.3
200

219

710

5,6,9,10-tetra- hydropyrido[1′,2′:1.5]pyra- zolo[3,4-f]isoquinolin-7(8H)-one
59.5

220

711

2-{[2-(dimethyl- amino)ethyl]amino}-5,6,9,10-tetra- hydropyrazino[1′,2′:1.5]pyra- zolo[3,4-f]isoquinolin-7(8H)-one trifluoroacetate
60.7

221

712

2-{2-[(2-ethyl- butyl)amino]ethyl}-4,5-di- hydro-2H-pyrazolo[3,4-f]iso- quinoline-3-carboxylic acid
62.1

222

713

ethyl 2-(2-aminoethyl)-8-ethynyl 4,5-dihydro-2H-pyrazolo[3,4-f]iso- quinoline-3-carboxylate hydrochloride
62.5

223

714

2-[2-(4-chloro- phenyl)ethyl]-5,6,9,10-tetra- hydropyrazino[1′,2′:1.5]pyra- zolo[3,4-f]isoquinolin-7(8H)-one trifluoroacetate
63.2

224

715

4,5-dihydro-2H-pyrazolo[3,4-f]iso- quinoline-3-carboxylic acid
63.4
200

225

716

2-piperazin-1-yl-5,6,9,10-tetra- hydropyrazino[1′,2′:1.5]pyra- zolo[3,4-f]isoquinolin-7(8H)-one trifluoroacetate
64.9

226

717

2-{3-[(thien-2-ylace- yl)amino]propyl}-4,5-di- hydro-2H-pyrazolo[3,4-f]iso- quinoline-3-carboxylic acid trifluoroacetate hydrochloride
66.1
200

227

718

2-[3-(benzoylamino)propyl]-4,5-di- hydro-2H-pyrazolo[3,4-f]iso- quinoline-3-carboxylic acid trifluoroacetate
68
200

228

719

2-[3-(dimethylamino)-2-hydroxy- propyl]-N,N-dimethyl-4,5-di- hydro-2H-pyrazolo[3,4-f]iso- quinoline-3-carboxamide trifluoroacetate
69.3

229

720

2-[(2E)-2-(hydroxy- imino)ethyl]-4,5-di- hydro-2H-pyrazolo[3,4-f]iso- quinoline-3-carboxylic acid
71

230

721

2-allyl-4,5-dihydro-2H-py- razolo[3,4-f]iso- quinoline-3-carboxylic acid 7-oxide
75.4
200

231

722

76.6
200

232

723

78.7

233

724

2-{3-[({[(4-methyl- phenyl)sulfonyl]amino}car- bonyl)amino]propyl}-4,5-di- hydro-2H-pyrazolo[3,4-f]iso- quinoline-3-carboxylic acid trifluoroacetate
80.6
200

234

725

2-(3-aminopropyl)-6-(methyl- thio)-4,5-dihydro-2H-py- razolo[3,4-f]iso- quinoline-3-carboxylic acid trifluoroacetate
83.4
200

235

726

For multi-component charged structures, a total zero charge is required!
84.3

236

727

2-(3-methyl- piperidin-1-yl)-5,6,9,10-tetra- hydropyrazino[1′,2′:1,5]pyra- zolo[3,4-f]isoquinolin-7(8H)-one trifluoroacetate
84.4

237

728

3-(methylthio)-4,5-dihydro-2H-pyra- zolo[3,4-f]isoquinoline
85.2
200

238

729

86.1
200

239

730

2-(3-aminopropyl)-6-phenyl-4,5-di- hydro-2H-pyrazolo[3,4-f]iso- quinoline-3-carboxylic acid trifluoroacetate
87.6
200

240

731

lithium 2-{3-[4-(amino- carbonyl)piperidin-1-yl]-2 hydroxypropyl}-4,5-di- hydro-2H-pyra- zolo[3,4-f]isoquinoline-3-carboxylate
87.6

241

732

2-(3-{bis[3-(5-methyl-2-furyl)bu- tyl]amino}propyl)-4,5-di- hydro-2H-pyrazolo[3,4-f]iso- quinoline-3-carboxylic acid dihydrochloride
87.9
200

242

733

2-[4-(benzyl- oxy)phenyl]-5,6,8,9,10,11-hexa- hydro-7H-[1,4]diaze- pino[1′,2′:1,5]pyrazolo[3,4-f]iso- quinolin-7-one
93.4

243

734

2-(4-chlorobenzyl)-5,6,9,10-tetra- hydropyrazino[1′,2′:1,5]pyra- zolo[3,4-f]isoquinolin-7(8H)-one trifluoroacetate
94.2
200

244

735

3-(difluoro- methyl)-4,5-dihydro-2H-pyra- zolo[3,4-f]isoquinoline
96.5
200

245

736

2-(4-methyl- piperazin-1-yl)-5,6,9,10-tetra- hydropyrazino[1′,2′:1.5]pyra- zolo[3,4-f]isoquinolin-7(8H)-one trifluoroacetate
96.8
108

246

737

2-quinolin-5-yl-5,6,9,10-tetra- hydropyrazino[1′,2′:1.5]pyra- zolo[3,4-f]isoquinolin-7(8H)-one
98.3

247

738

3-[3-(1H-tetraazol-5-yl)-4,5-di- hydro-1H-pyrazolo[3,4-f]iso- quinolin-1-yl]propan-1-amine hydrochloride
100
200

248

739

2-(4-tert-butylphenyl)-5,6,9,10-tetra- hydropyrazino[1′,2′:1.5]pyra- zolo[3,4-f]isoquinolin-7(8H)-one
101

249

740

2-[3-(py- ridin-4-ylamino)propyl]-4,5-di- hydro-2H-pyrazolo[3,4-f]iso- quinoline-3-carboxylic acid
101

250

741

2-[meth- yl(phenyl)amino]-5,6,9,10-tetra- hydropyrazino[1′,2′:1.5]pyra- zolo[3,4-f]isoquinolin-7(8H)-one trifluoroacetate
101

251

742

8-(3-phenylpropyl)-5,6,9,10-tetra- hydropyrazino[1′,2′:1.5]pyra- zolo[3,4-f]isoquinolin-7(8H)-one trifluoroacetate
102
200

252

743

2-propyl-8-quinolin-3-yl-4,5-di- hydro-2H-pyrazolo[3,4-f]iso- quinolin-3-carboxamide
103

253

744

2-[3-(isonicotinoyl- amino)propyl]-4,5-di- hydro-2H-pyrazolo[3,4-f]iso- quinoline-3-carboxylic acid trifluoroacetate
109
200

254

745

2-{3-[(tert- butoxycarbonyl)amino]propyl}-8 chloro-4,5-dihydro-2H-py- razolo[3,4-f]iso- quinoline-3-carboxylic acid
112
200

255

746

2-(3-{[(4-butoxy- phenyl)sulfonyl]amino}pro- pyl)-4,5-dihydro-2H-pyra- zolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate
113
200

256

747

2-(3-{[3-(2-furyl)propan- oyl]amino}propyl)-4,5-di- hydro-2H-pyrazolo[3,4-f]iso- quinoline-3-carboxylic acid trifluoroacetate hydrochloride
116
200

257

748

2-(4-phenoxyphenyl)-5,6,9,10-tetra- hydropyrazino[1′,2′:1,5]pyra- zolo[3,4-f]isoquinolin-7(8H)-one
119

258

749

2-allyl-8-quinolin-3-yl-4,5-di- hydro-2H-pyrazolo[3,4-f]iso- quinolin-3-carboxamide
119

259

750

2-(2-cyclohexylethyl)-5,6,9,10-tetra- hydropyrazino[1′,2′:1,5]pyra- zolo[3,4-f]isoquinolin-7(8H)-one trifluoroacetate
121

260

751

lithium 2-(2-hydroxy-3-morpho- lin-4-ylpropyl)-4,5-di- hydro-2H-pyrazolo[3,4-f]iso- quinoline-3-carboxylate
128

261

752

2-{3-[(pyridin-2-ylcarbo- nyl)amino]propyl}-4,5-di- hydro-2H-pyrazolo[3,4-f]iso- quinoline-3-carboxylic acid trifluoroacetate
129
200

262

753

2-(3-{[(4-cyano- phenyl)sulfonyl]amino}pro- pyl)-4,5-dihydro-2H-pyra- zolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate
130
200

263

754

(7E)-5,6,9,10-tetra- hydropyrido[1′,2′:1,5]pyrazo- lo[3,4-f]isoquinolin-7(8H)-one oxime
131

264

755

2-hexyl-5,6,9,10-tetra- hydropyrazino[1′,2′:1,5]pyra- zolo[3,4-f]isoquinolin-7(8H)-one trifluoroacetate
133

265

756

N-methyl-4,5-dihydro-2H-py- razolo[3,4-f]iso- quinoline-3-carboxamide
135
200

266

757

2-[3-(4-amino- piperidin-1-yl)-2-hydroxy- propyl]-4,5-dihydro-2H-py- razolo[3,4-f]isoquinolin-3-carboxylic acid bis(trifluoroacetate)
136

267

758

2-(3-{[(3-methoxy- phenyl)sulfonyl]amino}pro- pyl)-4,5-dihydro-2H-py- razolo[3,4-f]iso- quinoline-3-carboxylic acid trifluoroacetate
141
200

268

759

2-(3-morpholin-4-ylpropyl)-4,5-di- hydro-2H-pyrazolo[3,4-f]iso- quinoline-3-carboxylic acid
143

269

760

2-(3-{4-[(tert- butoxycarbonyl)a- mino]piperidin-1-yl}pro- pyl)-4,5-dihydro-2H-py- razolo[3,4-f]iso- quinoline-3-carboxylic acid trifluoroacetate
149

270

761

8-methyl-5,6,9,10-tetra- hydropyrazino[1′,2′:1,5]pyra- zolo[3,4-f]isoquinolin-7(8H)-one
156
200

271

762

methyl 2-(2-hydroxyethyl)-4,5-di- hydro-2H-pyrazolo[3,4-f]iso- quinoline-3-carboxylate
161
200

272

763

lithium 2-(2-hydroxy-3-pyrrolidin 1-ylpropyl)-4,5-dihydro-2H-py- razolo[3,4-f]isoquino- line-3-carboxylate
162

273

764

lithium 2-{2-hy- droxy-3-[(2-thien-2-yleth- yl)amino]propyl}-4,5-di- hydro-2H-pyrazolo[3,4-f]iso- quinoline-3-carboxylate
163

274

765

2-(3-{[(1-meth- yl-1H-imidazol-4-yl)sulfo- nyl]amino}propyl)-4,5-di- hydro-2H-pyrazolo[3,4-f]iso- quinoline-3-carboxylic acid trifluoroacetate
164
200

275

766

171
200

276

767

2-[3-({[4-(acetyl- amino)phenyl]sulfonyl}a- mino)propyl]-4,5-dihydro-2H-pyra- zolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate
176
200

277

768

[2-(3-amino- propyl)-4,5-dihydro-2H-py- razolo[3,4-f]iso- quinolin-3-yl]methanol hydrochloride
186

278

769

N-(3-amino- propyl)-4,5-dihydro-2H-py- razolo[3,4-f]isoquinoline-3 carboxamide dihydrochloride
189
200

279

770

2-[3-(2-furoylamino)propyl]-4,5-di- hydro-2H-pyrazolo[3,4-f]iso- quinoline-3-carboxylic acid trifluoroacetate
190
200

280

771

8-[2-(2-chloro- phenyl)ethyl]-5,6,8,9,10,11-hexa- hydro-7H-[1,4]diaze- pino[1′,2′:1,5]pyrazolo[3,4-f]iso- quinolin-7-one trifluoroacetate
190
200

281

772

5,6,10,11,12,13-hexa- hydro-7H,9H-8,12-metha- no[1,4]diazonino[1′,2′:1,5]py- razolo[3,4-f]isoquinolin-7-one dihydrochloride
191

282

773

2-{3-[(1,3-benzodioxol-5-ylcarbo- nyl)amino]propyl}-4,5-di- hydro-2H-pyrazolo[3,4-f]iso- quinoline-3-carboxylic acid trifluoroacetate
194
200

283

774

2-(2-hydroxy-3-piperazin-1-ylpro- pyl)-4,5-dihydro-2H-py- razolo[3,4-f]iso- quinoline-3-carboxylic acid dihydrochloride
198

284

775

2-[3-(7-oxo-5,6,7,8,9,10-hexa- hydropyrazino[1′,2′:1,5]pyra- zolo[3,4-f]isoquinolin-10-yl)pro- pyl]-1H-isoindole-1,3(2H)-dione
200

285

776

2-(3-{4-[3-(di- methylamino)propyl]piperazin 1-yl}propyl)-4,5-dihydro-2H-py- razolo[3,4-f]iso- quinoline-3-carboxylic acid
200

286

777

2-[3-(4-methylpiperazin-1-yl)pro- pyl]-4,5-dihydro-2H-py- razolo[3,4-f]iso- quinoline-3-carboxylic acid
200

287

778

2-(3-piperidin-1-ylpropyl)-4,5-di- hydro-2H-pyrazolo[3,4-f]iso- quinoline-3-carboxylic acid
200

288

779

3-[3-(difluoromethyl)-4,5-di- hydro-1H-pyrazolo[3,4-f]iso- quinolin-1-yl]propan-1-amine hydrochloride
200

289

780

tert-butyl 3-[3-(di- fluoromethyl)-4,5-di- hydro-1H-pyrazolo[3,4-f]iso- quinolin-1-yl]propylcarbamate
200

290

781

3-[3-(difluoromethyl)-4,5-di- hydro-2H-pyrazolo[3,4-f]iso- quinolin-2-yl]propan-1-amine hydrochloride
200

291

782

tert-butyl 3-[3-(di- fluoromethyl)-4,5-di- hydro-2H-pyrazolo[3,4-f]iso- quinolin-2-yl]propylcarbamate
200

292

783

9-(morpho- lin-4-ylmethyl)-5,6,9,10-tetra- hydro-7H-[1,4]oxa- zino[4′,3′:1,5]pyrazolo[3,4-f]iso- quinolin-7-one
200

293

784

ethyl 2-[1-(aminomethyl)-4-(1,3-di- oxo-1,3-dihydro-2H-isoindol-2-yl)bu- tyl]-4,5-dihydro-2H-py- razolo[3,4-f]iso- quinoline-3-carboxylate
200

294

785

8-(3-phenyl- propyl)-5,6,8,9,10,11-hexa- hydro-7H-[1,4]diaze- pino[1′,2′:1,5]pyrazolo[3,4-f]iso- quinolin-7-one hydrochloride
200
200

295

786

ethyl 2-[2-(glycoloyl- amino)ethyl]4,5-di- hydro-2H-pyrazolo[3,4-f]iso- quinoline-3-carboxylate trifluoroacetate
200
200

296

787

2-{3-[(tert- butoxycarbonyl)amino]propyl}-6 chloro-4,5-dihydro-2H-py- razolo[3,4-f]iso- quinoline-3-carboxylic acid
200

297

788

4-chloro-5,6,8,9,10,11-hexa- hydro-7H-[1,4]diaze- pino[1′,2′:1,5]pyrazolo[3,4-f]iso- quinolin-7-one
200

298

789

tert-butyl 3-[3-(1H-tetra- azol-5-yl)-4,5-di- hydro-1H-pyrazolo[3,4-f]iso- quinolin-1-yl]propylcarbamate
200

299

790

tert-butyl 3-[3-(1H-tetra- azol-5-yl)-4,5-di- hydro-2H-pyrazolo[3,4-f]iso- quinolin-2-yl]propylcarbamate
200

300

791

tert-butyl 3-(3-cyano-4,5-di- hydro-2H-pyrazolo[3,4-f]iso- quinolin-2-yl)propylcarbamate
200

301

792

4,5-dihydro-2H-pyrazolo[3,4-f]iso- quinoline-3-carbonitrile
200

302

793

2-[3-(benzyloxy)propyl]-8-quino- lin-3-yl-4,5-dihydro-2H-py- razolo[3,4-f]iso- quinoline-3-carboxamide
200

303

794

3-[3-(amino- methyl)-4,5-dihydro-2H-py- razolo[3,4-f]isoquinolin-2-yl]pro- pan-1-amine hydrochloride
200

304

795

ethyl 2-{2-[(tert- butoxycarbonyl)amino]ethyl}-8-eth- ynyl-4,5-dihydro-2H-py- razolo[3,4-f]isoquinoline-3-car- boxylate
200

305

796

ethyl 2-{2-[(tert- butoxycarbonyl)amino]eth- yl}-8-[(E)-2-(4-methoxy- phenyl)ethenyl]-4,5-di- hydro-2H-pyrazolo[3,4-f]iso- quinoline-3-carboxylate
200

306

797

ethyl 2-{2-[(tert- butoxycarbonyl)amino]eth- yl}-8-[(E)-2-(2-fluoro- phenyl)ethenyl]-4,5-di- hydro-2H-pyrazolo[3,4-f]iso- quinoline-3-carboxylate
200

307

798

ethyl 2-[(2E)-2-(hy- droxyimino)ethyl]-4,5-di- hydro-2H-pyrazolo[3,4-f]iso- quinoline-3-carboxylate
200

308

799

2-(3-amino- propyl)-4,5-dihydro-2H-py- razolo[3,4-f]isoquinoline-3 carbonitrile hydrochloride
200

309

800

2-(2-phenylethyl)-5,6,9,10-tetra- hydropyrazino[1′,2′:1,5]pyra- zolo[3,4-f]isoquinolin-7(8H)-one trifluoroacetate
200

310

801

{2-[(2-methoxy- ethoxy)methyl]-4,5-di- hydro-2H-pyrazolo[3,4-f]iso- quinolin-3-yl}methanol
200

311

802

ethyl 2-{2-[(tert- butoxycarbonyl)amino]eth- yl}-8-[(E)-2-phenyl- ethenyl]-4,5-di- hydro-2H-pyrazolo[3,4-f]iso- quinoline-3-carboxylate
200

312

803

ethyl 8-benzyl-2-{2-[(tert- butoxycarbonyl)amino]ethyl}-4,5 dihydro-2H-pyrazolo[3,4-f]iso- quinoline-3-carboxylate
200

313

804

ethyl 2-[(2-methoxy- ethoxy)methyl]-4,5-di- hydro-2H-pyrazolo[3,4-f]iso- quinoline-3-carboxylate
200

314

805

lithium 2-{2-[(tert-butoxy- carbonyl)amino]ethyl}-4,5 dihydro-2H-pyrazolo[3,4-f]iso- quinoline-3-carboxylate
200

315

806

ethyl 2-{2-[(tert- butoxycarbonyl)amino]ethyl}-4,5 dihydro-2H-pyrazolo[3,4-f]iso- quinoline-3-carboxylate
200

316

807

methyl 2-methyl-4,5-dihydro-2H pyrazolo[3,4-f]isoquinoline-3-car- boxylate
200
200

317

808

methyl 1-methyl-4,5-dihydro-1H pyrazolo[3,4-f]isoquinoline-3-car- boxylate
200
200

318

809

2-[3-(propionylamino)propyl]-4,5 dihydro-2H-pyrazolo[3,4-f]iso- quinoline-3-carboxylic acid trifluoroacetate
200
200

319

810

2-{3-[(cyclo- hexylcarbonyl)amino]pro- pyl}-4,5-dihydro-2H-py- razolo[3,4-f]iso- quinoline-3-carboxylic acid trifluoroacetate
200
200

320

811

2-(3-{[(1-methyl-1H-pyrrol-2-yl)car- bonyl]amino}propyl)-4,5-di- hydro-2H-pyrazolo[3,4-f]iso- quinoline-3-carboxylic acid trifuoroacetate
200
200

321

812

ethyl 2-(3-bromopropyl)-4,5-di- hydro-2H-pyrazolo[3,4-f]iso- quinoline-3-carboxylate
200

322

813

2-allyl-4,5-dihydro-2H-py- razolo[3,4-f]isoquinoline-3-car- boxamide
200
200

323

814

8-(2-oxo-2-thien-3-yleth- yl)-5,6,9,10-tetra- hydropyrazino[1′,2′,1,5]pyra- zolo[3,4-f]isoquinolin-7(8H)-one hydrochloride
200

324

815

methyl 1-(2-hydroxyethyl)-4,5-di- hydro-1H-pyrazolo[3,4-f]iso- quinoline-3-carboxylate
200
200

325

816

tert-butyl 3-[3-(methylthio)-4,5-di- hydro-2H-pyrazolo[3,4-f]iso- quinolin-2-yl]propyl- carbamate
200
200

326

817

3-(4,5-dihydro-2H-pyrazolo[3,4-f]iso- quinolin-2-yl)propan-1-amine hydrochloride
200
200

327

818

200
200

328

819

3-[3-(methylthio)-4,5-dihydro-2H pyrazolo[3,4-f]isoquinolin-2-yl]pro- pan-1-amine hydrochloride
200
200

329

820

ethyl 2-(3-aminopropyl)-4,5-di- hydro-2H-pyrazolo[3,4-f]iso- quinoline-3-carboxylate hydrochloride
200
200

330

821

ethyl 2-{3-[(tert- butoxycarbonyl)a- mino]propyl}-4,5-di- hydro-2H-pyrazolo[3,4-f]iso- quinoline-3-carboxylate
200
200

331

822

tert-butyl 7-oxo-6,7,10,11-tetra- hydro-5H-[1,4]diaze- pino[1′,2′:1,5]pyrazolo[3,4-f]iso- quinoline-8(9H)-carboxylate
200
200

332

823

ethyl 2-(3-cyanopropyl)-4,5-di- hydro-2H-pyrazolo[3,4-f]iso- quinoline-3-carboxylate
200

333

824

3-(methyl- sulfonyl)-4,5-dihydro-2H-py- razolo[3,4-f]isoquinoline
200
200

334

825

2-{4-[bis(2-ethyl- butyl)amino]butyl}-4,5-di- hydro-2H-pyrazolo[3,4-f]iso- quinoline-3-carboxylic acid hydrochloride
200

335

826

ethyl 2-{3-[(4-butoxy- benzyl)amino]propyl}-4,5-di- hydro-2H-pyrazolo[3,4-f]iso- quinoline-3-carboxylate
200

336

827

2-[3-(4-aminopiperidin-1-yl)pro- pyl]-4,5-dihydro-2H-py- razolo[3,4-f]iso- quinoline-3-carboxylic acid trifluoroacetate
200

337

828

lithium 2-[2-hydroxy-3-(3-oxo- piperazin-1-yl)propyl]-4,5-di- hydro-2H-pyrazolo[3,4-f]iso- quinoline-3-carboxylate
200

338

829

lithium 2-(2-hy- droxy-3-piperidin-1-ylpro- pyl)-4,5-dihydro-2H-py- razolo[3,4-f]iso- quinoline-3-carboxylate
200

339

830

2-(3-piperazin-1-ylpropyl)-4,5-di- hydro-2H-pyrazolo[3,4-f]iso- quinoline-3-carboxylic acid trifluoroacetate
200

340

831

2-(3-carboxypropyl)-4,5-dihydro 2H-pyrazolo[3,4-f]isoquinoline-3 carboxylic acid trifluoroacetate
200

341

832

2-(3-pyrrolidin-1-ylpropyl)-4,5-di- hydro-2H-pyrazolo[3,4-f]iso- quinoline-3-carboxylic acid
200

342

833

lithium 2-[2-hydroxy-3-(methyl- amino)propyl]-4,5-di- hydro-2H-pyrazolo[3,4-f]iso- quinoline-3-carboxylate
200

343

834

9-{[(4-amino- cyclohexyl)amino]meth- yl}-5,6,9,10-tetra- hydro-7H-[1,4]oxa- zino[4′,3′:1,5]pyrazolo[3,4-f]iso- quinolin-7-one trifluoroacetate
200

344

835

lithium 2-{3-[(4-amino- cyclohexyl)amino]-2-hydroxy- propyl}-4,5-dihydro-2H-py- razolo[3,4-f]iso- quinoline-3-carboxylate
200

345

836

ethyl2-{3-[(2-thien-2-yleth- yl)amino]propyl}-4,5-di- hydro-2H-pyrazolo[3,4-f]iso- quinoline-3-carboxylate trifluoroacetate
200

346

837

2-{2-[bis(2-ethyl- butyl)amino]ethyl}-4,5-di- hydro-2H-pyrazolo[3,4-f]iso- quinoline-3-carboxylic acid dihydrochloride
200

347

838

9-{[(2-thien-2-yleth- yl)amino]methyl}-5,6,9,10-tetra- hydro-7H-[1,4]oxa- zino[4′,3′:1,5]pyrazolo[3,4-f]iso- quinolin-7-one trifluoroacetate
200

348

839

200

349

840

ethyl 2-[3-amino-4-(benzyl- oxy)-4-oxo- butyl]-4,5-dihydro-2H-py- razolo[3,4-f]iso- quinoline-3-carboxylate bis(trifluoroacetate)
200

350

841

200

351

842

ethyl 2-{4-(benzyloxy)-3-[(tert- butoxycarbonyl)amino]-4-oxo- butyl}-4,5-dihydro-2H-py- razolo[3,4-f]isoquinoline-3-car- boxylate
200

352

843

7-oxo-5,6,7,8,9,10-hexa- hydropyrazino[1′,2′:1,5]py- razolo[3,4-f]isoquinoline-9-car- boxylic acid
200

353

844

4-(7-oxo-6,7,9,10-tetra- hydropyrazino[1′,2′:1,5]pyra- zolo[3,4-f]isoquinolin-8(5H)-yl)bu- tanenitrile
200

354

845

8-(4-aminobutyl)-5,6,9,10-tetra- hydropyrazino[1′,2′:1,5]pyra- zolo[3,4-f]isoquinolin-7(8H)-one dihydrochloride
200

355

846

ethyl 6-chloro-4,5-dihydro-2H-py- razolo[3,4-f]isoquinoline-3-car- boxylate
200

356

847

ethyl 2-{2-[(tert- butoxycarbonyl)amino]eth- yl}-8-chloro-4,5-di- hydro-2H-pyrazolo[3,4-f]iso- quinoline-3-carboxylate
200

357

848

ethyl 8-chloro-2-{2-[(tri- fluoroacetyl)amino]ethyl}-4,5 dihydro-2H-pyrazolo[3,4-f]iso- quinoline-3-carboxylate
200

358

849

ethyl 8-chloro-4,5-dihydro-2H-py- razolo[3,4-f]iso- quinoline-3-carboxylate
200

359

850

8-methyl-5,6,8,9,10,11-hexa- hydro-7H-[1,4]diaze- pino[1′,2′:1,5]pyrazolo[3,4-f]iso- quinolin-7-one
200

360

851

ethyl 2-(3-{[3-(5-methyl-2-furyl)bu- tyl]amino}propyl)-4,5-di- hydro-2H-pyrazolo[3,4-f]iso- quinoline-3-carboxylate trifluoroacetate
200

361

852

N,2-bis(3-aminopropyl)-4,5-di- hydro-2H-pyrazolo[3,4-f]iso- quinoline-3-carboxamide dihydrochloride
200
200

362

853

2-[3-(benzyloxy)propyl]-4,5-di- hydro-2H-pyrazolo[3,4-f]iso- quinoline-3-carboxylic acid
200

363

854

4,5-dihydro-2H-pyrazolo[3,4-f]iso- quinolin-3-ylmethanol
200

364

855

ethyl 2-(2-{[3-(2-furyl)propa- noyl]amino}ethyl)-4,5 dihydro-2H-pyrazolo[3,4-f]iso- quinoline-3-carboxylate
200

365

856

2-(2-{[3-(2-furyl)propa- noyl]amino}ethyl)-4,5 dihydro-2H-pyrazolo[3,4-f]iso- quinoline-3-carboxylic acid hydrochloride
200

366

857

5,6,7,8,9,10-hexa- hydropyrazino[1′,2′:1,5]pyra- zolo[3,4-f]isoquinolin-9-ylmethanol
200

367

858

For multi-component charged structures, a total zero charge is required!
200
200

368

859

2-chloro-5,6,8,9,10,11-hexa- hydro-7H-[1,4]diaze- pino[1′,2′:1,5]pyrazolo[3,4-f]iso- quinolin-7-one
200

369

860

8-{3-[(2-thien-2-yleth- yl)amino]propyl}-5,6,8,9,10,11-hexa- hydro-7H-[1,4]diaze- pino[1′,2′:1,5]pyrazolo[3,4-f]iso- quinolin-7-one dihydrochloride
200

370

861

9-(aminomethyl)-5,6,8,9,10,11-hexa- hydro-7H-[1,4]diaze- pino[1′,2′:1,5]pyrazolo[3,4-f]iso- quinolin-7-one
200

371

862

9-(hydroxy- methyl)-8-methyl-5,6,9,10-tetra- hydropyrazino[1′,2′:1,5]pyra- zolo[3,4-f]isoquinolin-7(8H)-one
200

372

863

4,5-dihydro-2H-pyrazolo[3,4-f]iso- quinoline-3-carboxylic acid

373

864

374

865

375

866

376

867

377

868

378

869

379

870

1-(4,5-dihydro-2H-pyrazolo[3,4-f]iso- quinolin-3-yl)-2-methoxy- ethanone

380

871

ethyl 2-allyl-4,5-dihydro-2H-py- razolo[3,4-f]isoquinoline-3-car- boxylate

381

872

ethyl 1-allyl-4,5-dihydro-1H-py- razolo[3,4-f]isoquinoline-3-car- boxylate

382

873

383

874

ethyl 4,5-dihydro-2H-py- razolo[3,4-f]isoquinoline-3-car- boxylate

384

875

ethyl 2-(4-aminobutyl)-4,5-di- hydro-2H-pyrazolo[3,4-f]iso- quinoline-3-carboxylate

385

876

ethyl 2-(oxiran-2-ylmethyl)-4,5-di- hydro-2H-pyrazolo[3,4-f]iso- quinoline-3-carboxylate

386

877

2,7-bis(3-cyanopropyl)-3-(ethoxy- carbonyl)-4,5-dihydro-2H-py- razolo[3,4-f]isoquinolin-7-ium

387

878

lithium 2-[2-hydroxy-3-(1H-imi- dazol-1-yl)propyl]-4,5-di- hydro-2H-pyrazolo[3,4-f]iso- quinoline-3-carboxylate

388

879

ethyl 2-(3-{[3-(2-furyl)pro- panoyl]amino}propyl)-4,5-di- hydro-2H-pyrazolo[3,4-f]iso- quinoline-3-carboxylate

389

880

ethyl 2-{3-[(thien-2-ylace- tyl)amino]propyl}-4,5-di- hydro-2H-pyrazolo[3,4-f]iso- quinoline-3-carboxylate trifluoroacetate

390

881

ethyl 2-[3-(cyclo- pentylamino)propyl]-4,5-di- hydro-2H-pyrazolo[3,4-f]iso- quinoline-3-carboxylate

391

882

ethyl 2-(2-amino- ethyl)-8-chloro-4,5-di- hydro-2H-pyrazolo[3,4-f]iso- quinoline-3-carboxylate hydrochloride

392

883

2-(3-{[3-(1,1′-bi- phenyl-4-yl)pro- pyl]amino}propyl)-4,5-di- hydro-2H-pyrazolo[3,4-f]iso- quinoline-3-carboxylic acid trifluoroacetate

393

884

2-(3-{[2-(4′-chloro-1,1′-bi- phenyl-4-yl)eth- yl]amino}propyl)-4,5-di- hydro-2H-pyrazolo[3,4-f]iso- quinoline-3-carboxylic acid trifluoroacetate

394

885

2-(3-{[2-(4-thien-3-ylphen- yl)ethyl]amino}propyl)-4,5 dihydro-2H-pyrazolo[3,4-f]iso- quinoline-3-carboxylic acid trilfuoroacetate

395

886

2-{3-[(2-{4-[(E)-2-phenyl- ethenyl]phenyl}ethyl)a- mino]propyl}-4,5-dihydro-2H-py- razolo[3,4-f]isoquinoline-3-carboxy- lic acid trifluoroacetate

396

887

2-(3-{[2-(4′-cy- ano-1,1′-biphenyl-4-yl)eth- yl]amino}propyl)-4,5-di- hydro-2H-pyrazolo[3,4-f]iso- quinoline-3-carboxylic acid trifluoroacetate

397

888

2-[3-({2-[4-(1,3-benzo- dioxol-5-yl)phen- yl]ethyl}amino)propyl]-4,5-di- hydro-2H-pyrazolo[3,4-f]iso- quinoline-3-carboxylic acid trifluoroacetate

398

889

2-quinolin-3-yl-5,6,9,10-tetra- hydropyrazino[1′,2′:1,5]pyra- zolo[3,4-f]isoquinolin-7(8H)-one

399

890

N-(2-hydroxy- ethyl)-4,5-dihydro-2H-py- razolo[3,4-f]isoquinoline-3 carboxamide

400

891

2-(1,1′-biphenyl-4-yl)-5,6,9,10-tetra- hydropyrazino[1′,2′:1,5]pyra- zolo[3,4-f]isoquinolin-7(8H)-one

401

892

2-[3-({[(4-methoxy- phenyl)amino]carbonyl}a- mino)propyl]-8-quinolin-3-yl-4,5-di- hydro-2H-pyrazolo[3,4-f]iso- quinoline-3-carboxylic acid

402

893

{2-[(2-methoxy- ethoxy)methyl]-4,5-di- hydro-2H-pyrazolo[3,4-f]iso- quinolin-3-yl}acetonitrile

403

894

2-allyl-8-quinolin-3-yl-4,5-di- hydro-2H-pyrazolo[3,4-f]iso- quinoline-3-carboxylic acid

404

895

2-[(4-methyl- phenyl)ethynyl]-5,6,9,10-tetra- hydropyrazino[1′,2′:1,5]pyra- zolo[3,4-f]isoquinolin-7(8H)-one trifluoroacetate

405

896

ethyl 2-(2-aminoethyl)-8-(1H-in- dol-2-yl)-4,5-dihydro-2H-py- razolo[3,4-f]iso- quinoline-3-carboxylate

406

897

2-[(E)-2-(3-methoxy- phenyl)ethenyl]-5,6,9,10-tetra- hydropyrazino[1′,2′:1,5]pyra- zolo[3,4-f]isoquinolin-7(8H)-one trilfuoroacetate

407

898

2-[(E)-2-(3-hydroxy- phenyl)ethenyl]-5,6,9,10 tetrahydropyrazino[1′,2′:1,5]pyra- zolo[3,4-f]isoquinolin-7(8H)-one trifluoroacetate

408

899

12593 or 7-oxo-2-quino- lin-3-yl-5,6,7,8,9,10-hexa- hydropyrazino[1′,2′:1,5]pyra- zolo[3,4-f]isoquinoline-9-carbo- nitrile trifluoroacetate

a
The pyridylpyrazole compound may be shown with a solvent, such as, for example, trifluoroacetate, with which it can form a salt. Both the salt and acid forms of the pyridylpyrazole compound are included in the present invention.

b
Compound names generated by ACD/Name software.

[0396]

4

TABLE 4

Pyrimidylpyrazole MK-2 inhibitors

MK-2
NK-3

Avg. IC50
Avg. IC50

No.
Structurea
Chemical Nameb
(uM)
(uM)

1

900

2-(3-aminopropyl)-8-quinolin-3-yl- 4,5-dihydro-2H-pyrazolo[4,3- h]quinazoline-3-carboxylic acid dihydrochloride
0.0761
1.93

2

901

2-(3-aminopropyl)-8-(1,3- benzodioxol-5-yl)-4,5-dihydro-2H- pyrazolo[4,3-h]quinazoline-3- carboxylic acid hydrochloride
0.295
4.61

3

902

2-(3-aminopropyl)-8-phenyl-4,5- dihydro-2H-pyrazolo[4,3- h]quinazoline-3-carboxylic acid hydrochloride
0.406
10.8

4

903

2-quinolin-3-yl-5,6,8,9,10,11- hexahydro-7H- [1,4]diazepino[1′,2′:1,5]pyrazolo[4, 4-h]quinazolin-7-one
1.47
200

5

904

2-pyridin-3-yl-5,6,8,9,10,11- hexahydro-7H- [1,4]diazepino[1′,2′:1,5]pyrazolo[4, 3-h]quinazolin-7-one
1.58
168

6

905

8-quinolin-3-yl-2-[3- (tritylamino)propyl]-4,5-dihydro-2H- pyrazolo[4,3-h]quinazoline-3- carboxylic acid hydrochloride
2.16
154

7

906

2-(1,3-benzodioxol-5-yl)- 5,6,8,9,10,11-hexahydro-7H- [1,4]diazepino[1′,2′:1,5]pyrazolo[4, 3-h]quinazolin-7-one
3.14
200

8

907

2-(4-methoxyphenyl)-5,6,8,9,10,11- hexahydro-7H- [1,4]diazepino[1′,2′:1,5]pyrazolo[4, 3-h]quinazolin-7-one
4.52
200

9

908

2-pyridin-4-yl-5,6,8,9,10,11- hexahydro-7H- [1,4]diazepino[1′,2′:1,5]pyrazolo[4, 3-h]quinazolin-7-one hydrochloride
8.62
200

10

909

8-phenyl-2-[3-(tritylamino)propyl]- 4,5-dihydro-2H-pyrazolo[4,3- h]quinazoline-3-carboxylic acid
52.2

11

910

2-phenyl-5,6,8,9,10,11-hexahydro- 7H- [1,4]diazepino[1′,2′:1,5]pyrazolo[4, 3-h]quinazolin-7-one
81.4
200

12

911

methyl-2-(3-aminopropyl)-8-pyridin- 4-yl-4,5-dihydro-2H-pyrazolo[4,3- h]quinazoline-3-carboxylate dihydrochloride
142

13

912

methyl 8-phenyl-2-[3- (tritylamino)propyl]-4,5-dihydro-2H- pyrazolo[4,3-h]quinazoline-3- carboxylate
200

14

913

methyl 2-(3-aminopropyl)-8-(4- methoxyphenyl)-4,5-dihydro-2H- pyrazolo[4,3-h]quinazoline-3- carboxylate dihydrochloride
200

15

914

ethyl 2-(3-aminopropyl)-8-quinolin- 3-yl-4,5-dihydro-2H-pyrazolo[4,3- h]quinazoline-3-carboxylate dihydrochloride
200

a
The pyrimidylpyrazole compound may be shown with a solvent, such as, for example, trifluoroacetate, with which it can form a salt. Both the salt and acid forms of the pyrimidylpyrazole compound are included in the present invention.

b
Compound names generated by ACD/Name software.

[0397]

5

TABLE 5

Other cyclic pyrazole MK-2 inhibiting compounds

MK-2
MK-3

No.
Structurea
Compound Name(s)b
Avg. IC50 (uM)
Avg. IC50 (uM)

1

915

2-[(E)-2-(3- hydroxyphenyl)ethenyl]-5,6,9,10- tetrahydropyrazino[1′,2′:1,5]pyra- zolo[3,4-f]isoquinolin-7(8H)-one trifluoroacetate
0.0211
3.62

2

916

2-[(E)-2-phenylethenyl]-5,6,9,10- tetrahydropyrazino[1′,2′:1,5]pyra- zolo[3,4-f]isoquinolin-7(8H)-one trifluoroacetate
0.147
11.5

3

917

2-[(E)-2-(4- hydroxyphenyl)ethenyl]-5,6,9,10- tetrahydropyrazino[1′,2′:1,5]pyra- zolo[3,4-f]isoquinolin-7(8H)-one trifluoroacetate
0.164
27.5

4

918

2-[(E)-2-(1,3-benzodioxol-5- yl)ethenyl]-5,6,9,10- tetrahydropyrazino[1′,2′:1,5]pyra- zolo[3,4-f]isoquinolin-7(8H)-one
0.223
>20.0

5

919

2-[(E)-2-(3- methoxyphenyl)ethenyl]-5,6,9,10- tetrahydropyrazino[1′,2′:1,5]pyra- zolo[3,4-f]isoquinolin-7(8H)-one trifluoroacetate
0.328
11.8

6

920

2-[(E)-2-(4-chlorophenyl)ethenyl]- 5,6,9,10- tetrahydropyrazino[1′,2′:1,5]pyra- zolo[3,4-f]isoquinolin-7(8H)-one hydrochloride
0.536
>20.0

7

921

2-[(E)-2-(3,4- difluorophenyl)ethenyl]-5,6,9,10- tetrahydropyrazino[1′,2′:1,5]pyra- zolo[3,4-f]isoquinolin-7(8H)-one
0.623
>20.0

8

922

2-[(E)-2-(4-fluorophenyl)ethenyl]- 5,6,9,10- tetrahydropyrazino[1′,2′:1,5]pyra- zolo[3,4-f]isoquinolin-7(8H)-one
0.749
>20.0

9

923

2-{(E)-2-[4- (trifluoromethyl)phenyl]ethenyl}- 5,6,9,10- tetrahydropyrazino[1′,2′:1,5]pyra- zolo[3,4-f]isoquinolin-7(8H)-one
2.26
>20.0

10

924

2-[(E)-2-(3-chlorophenyl)ethenyl]- 5,6,9,10- tetrahydropyrazino[1′,2′:1,5-pyra- zolo[3,4-f]isoquinolin-7(8H)-one
2.92
>20.0

11

925

2-[(E)-2-(2-fluorophenyl)ethenyl]- 5,6,9,10- tetrahydropyrazino[1′,2′:1,5]pyra- zolo[3,4-f]isoquinolin-7(8H)-one
4.46
>200

12

926

2-[(E)-2-(4-methoxyphenyl)vinyl]- 5,6,9,10- tetrahydropyrazino[1′,2′:1,5]pyra- zolo[3,4-f]isoquinolin-7(8H)-one
4.76
>200

13

927

2-[(E)-2-phenylethenyl]-5,6,9,10- tetrahydropyrazino[1′,2′:1,5]pyra- zolo[3,4-f]isoquinolin-7(8H)-one

14

928

2-[(E)-2-(4-methoxyphenyl)vinyl]- 5,6,9,10- tetrahydropyrazino[1′,2′:1,5]pyra- zolo[3,4-f]isoquinolin-7(8H)-one trifluoroacetate

15

929

2-[(E)-2-(4-chlorophenyl)ethenyl]- 5,6,9,10- tetrahydropyrazino[1′,2′:1,5]pyra- zolo[3,4-f]isoquinolin-7(8H)-one

16

930

2-[(E)-2-(4-methylphenyl)ethenyl]- 5,6,9,10- tetrahydropyrazino[1′,2′:1,5]pyra- zolo[3,4-f]isoquinolin-7(8H)-one

17

931

2-[(E)-2-(4-methylphenyl)ethenyl]- 5,6,9,10- tetrahydropyrazinop[1′,2′:1,5]pyra- zolo[3,4-f]isoquinolin-7(8H)-one hydrochloride

18

932

ethyl 3-[(E)-2-(7-oxo-5,6,7,8,9,10- hexahydropyrazino[1′,2′:1,5]pyra- zolo[3,4-f]isoquinolin-2- yl)ethyl]benzoate

19

933

9-(hydroxymethyl)-2-[(E)-2- phenylvinyl]-5,6,9,10- tetrahydropyrazino[1′,2′:1,5]pyra- zolo[3,4-f]isoquinolin-7(8H)-one

20

934

3-[(E)-2-(7-oxo-5,6,7,8,9,10- hexahydropyrazino[1′,2′:1,5]pyra- zolo[3,4-f]isoquinolin-2- yl)vinyl]benzoic acid

21

935

lithium 3-[(E)-2-(7-oxo- 5,6,7,8,9,10- hexahydropyrazino[1′,2′:1,5]pyra- zolo[3,4-f]isoquinolin-2- yl)vinyl]benzoate

22

936

methyl 7-oxo-2-[(E)-2-phenylvinyl]5,6,7,8,9,10- hexahydropyrazino[1′,2′:1,5]pyra- zolo[3,4-f]isoquinolin-9- carboxylate

23

937

ethyl 4-[(E)-2-(7-oxo-5,6,7,8,9,10- hexahydropyrazino[1′,2′:1,5]pyra- zolo[3,4-f]isoquinolin-2- yl)vinyl]benzoate

24

938

4-[(E)-2-(7-oxo-5,6,7,8,9,10- hexahydropyrazino[1′,2′:1,5]pyra- zolo[3,4-f]isoquinolin-2- yl)vinyl]benzoic acid

25

939

2-((E)-2-{4-[(4-methylpiperazin-1- yl)carbonyl]phenyl}vinyl)-5,6,9,10- tetrahydropyrazino[1′,2′:1,5]pyra- zolo[3,4-f]isoquinolin-7(8H)-one trifluoroacetate

26

940

2-{(E)-2-[4-(pyrrolidin-1- ylcarbonyl)phenyl]vinyl}-5,6,9,10- tetrahydropyrazino[1′,2′:1,5]pyra- zolo[3,4-f]isoquinolin-7(8H)-one trifluoroacetate

27

941

2-{(E)-2-[4-(morpholin-4- ylcarbonyl)phenyl]vinyl}-5,6,9,10- tetrahydropyrazino[1′,2′:1,5]pyra- zolo[3,4-f]isoquinolin-7(8H)-one trifluoroacetate

28

942

2-[(E)-2-(4-{[(2S)-2-(pyrrolidin-1- ylmethyl)pyrrolidin-1- yl]carbonyl}phenyl)vinyl]-5,6,9,10- tetrahydropyrazino[1′,2′:1,5]pyra- zolo[3,4-f]isoquinolin-7(8H)-one trifluoroacetate

29

943

2-[(E)-2-(3-{[(2R)-2-(pyrrolidin-1- ylmethyl)pyrrolidin-1- yl]carbonyl}phenyl)vinyl]-5,6,9,10- tetrahydropyrazino[1′,2′:1,5]pyra- zolo[3,4-f]isoquinolin-7(8H)-one trifluoroacetate

30

944

2-((E)-2-{3-[(4-methylpiperazin-1- yl)carbonyl]phenyl}vinyl)-5,6,9,10- tetrahydropyrazino[1′,2′:1,5]pyra- zo0lo[3,4-f]isoquinolin-7(8H)-one trifluoroacetate

31

945

N,N-dimethyl-3-[(E)-2-(7-oxo- 5,6,7,8,9,10- hexahydropyrazino[1′,2′:1,5]pyra- zolo[3,4-f]isoquinolin-2- yl)vinyl]benzamide trifluoroacetate

32

946

2-[(E)-2-phenylvinyl]-5,6,8,9,10,11- hexahydro-7H- [1,4]diazepino[1′,2′:1,5]pyrazolo[3,4- g]isoquinolin-7-one

33

947

2-(3-aminopropyl)-8-[(E)-2- phenylvinyl]-4,5-dihydro-2H- pyrazolo[3,4-f]isoquinoline-3- carboxylic acid trifluoroacetate
0.0329
0.528

34

948

2-(3-{[2-(4- bromophenyl)ethyl]amino}propyl)- 8-[(E)-2-phenylvinyl]-4,5-dihydro- 2H-pyrazolo[3,4-f]isoquinoline-3- carboxylic acid trifluoroacetate
0.28
2.02

35

949

8-[(E)-2-phenylvinyl]-2-{3-[(2-{4- [(E)-2- phenylvinyl]phenyl}ethyl)amino]pro- pyl}-4,5-dihydro-2H-pyrazolo[3,4- f]isoquinoline-3-carboxylic acid trifluoroacetate
0.528
>20.0

36

950

ethyl 2-(3-aminopropyl)-8-[(E)-2- phenylvinyl]-4,5-dihydro-2H- pyrazolo[3,4-f]isoquinoline-3- carboxylate hydrochloride

37

951

2-(2-aminoethyl)-8-[(E)-2- phenylethenyl]-4,5-dihydro-2H- pyrazolo[3,4-f]isoquinoline-3- carboxylic acid hydroxhloride
0.0413
1.21

38

952

ethyl 2-(2-aminoethyl)-8-[(E)-2- phenylethenyl]-4,5-dihydro-2H- pyrazolo[3,4-f]isoquinoline-3- carboxylate hydrochloride
3.61
>20.0

a
The cyclic pyrazole compound may be shown with a solvent, such as, for example, trifluoroacetate, with which it can for a salt. Both the salt and acid forms of the cyclic pyrazole compound are included in the present invention.

b
Compound names generated by ACD/Name software.

[0398] In some embodiments of the present invention, it is preferred that the cyclic pyrazole MK-2 inhibiting compounds have IC50 MK-2 values of less than 100, more preferred are those with IC50 MK-2 values of less than 50, even more preferred are those with IC50 MK-2 values of less than 20, yet more preferred are those with IC50 MK-2 values of less than 10, and even more preferred are those having IC50 MK-2 values of less than 1. Examples of cyclic pyrazole MK-2 inhibitors having such IC50MK-2 values can be found in the tables above.

[0399] It should be understood that salts and prodrugs of the compounds that are described herein, as well as isomeric forms, tautomers, racemic mixtures of the compounds, and the like, which have the same or similar activity as the compounds that are described, are to be considered to be included within the description of the compound.

[0400] The MK-2 or MK-3 inhibiting activity of any of the compounds described herein can be determined by any one of several methods that are well known to those having skill in the art of enzyme activity testing. One method of measuring the MK-2 inhibiting activity is described in detail in the general methods section of the examples. A similar method, with appropriate modifications, Can be used to measure MK-3 inhibitory activity. In addition, the efficacy of one of the present MK-2 inhibiting compounds in therapeutic applications can be determined by testing for inhibition of TNFα production in cell culture and in animal model assays. In general, it is preferred that the MK-2 inhibiting compounds of the present invention be capable of inhibiting the production and/or the release of TNFα in cell cultures and in animal models.

[0401] In the present method, the MK-2 inhibiting compounds that are described herein can be used as inhibitors of MAPKAP kinase-2. When this inhibition is for a therapeutic purpose, one or more of the present compounds can be administered to a subject that is in need of MK-2 inhibition. As used herein, a “subject in need of MK-2 inhibition” is a subject who has, or who is at risk of contracting a TNFα mediated disease or disorder. TNFα mediated diseases and disorders are described in more detail below.

[0402] As described above, in an embodiment of the present method, a subject in need of prevention or treatment of a TNFα mediated disease or disorder is treated with one or more of the present MK-2 inhibiting compounds. In one embodiment, the subject is treated with an effective amount of the MK-2 inhibiting compound. The effective amount can be an amount that is sufficient for preventing or treating the TNFα mediated disease or disorder.

[0403] The MK-2 inhibiting compound that is used in the subject method can be any cyclic pyrazole MK-2 inhibiting compound that is described herein.

[0404] In the subject method, the MK-2 inhibiting compound can be used in any amount that is an effective amount. It is preferred, however, that the amount of the MK-2 inhibiting compound that is administered is within a range of about 0.1 mg/day per kilogram of the subject to about 1500 mg/day/kg. It is more preferred that the amount of the compound is within a range of about 1 mg/day/kg to about 500 mg/day/kg. An amount that is within a range of about 10 mg/day/kg to about 400 mg/day/kg, is even more preferred.

[0405] When the term “about” is used herein in relation to a dosage amount of the MK-2 inhibiting compound, it is to be understood to mean an amount that is within ±0.05 mg. By way of example, “about 0.1-10 mg/day” includes all dosages within 0.05 to 10.05 mg/day.

[0406] In another embodiment of the present invention, a pharmaceutical composition that contains one or more of the present cyclic pyrazole MK-2 inhibitors can be administered to a subject for the prevention or treatment of a TNFα mediated disease or disorder. The pharmaceutical composition includes a cyclic pyrazole MK-2 inhibitor of the present invention and a pharmaceutically acceptable carrier.

[0407] In another embodiment, a kit can be produced that is suitable for use in the prevention or treatment of a TNFα mediated disease or disorder. The kit comprises a dosage form comprising a cyclic pyrazole MK-2 inhibitor that is described herein in an amount which comprises a therapeutically effective amount.

[0408] As used herein, an “effective amount” means the dose or effective amount to be administered to a patient and the frequency of administration to the subject which is readily determined by one or ordinary skill in the art, by the use of known techniques and by observing results obtained under analogous circumstances. The dose or effective amount to be administered to a patient and the frequency of administration to the subject can be readily determined by one of ordinary skill in the art by the use of known techniques and by observing results obtained under analogous circumstances. In determining the effective amount or dose, a number of factors are considered by the attending diagnostician, including but not limited to, the potency and duration of action of the compounds used, the nature and severity of the illness to be treated, as well as the sex, age, weight, general health and individual responsiveness of the patient to be treated, and other relevant circumstances.

[0409] The phrase “therapeutically-effective” indicates the capability of an agent to prevent, or improve the severity of, the disorder, while avoiding adverse side effects typically associated with alternative therapies. The phrase “therapeutically-effective” is to be understood to be equivalent to the phrase “effective for the treatment, prevention, or inhibition”, and both are intended to qualify the amount of each agent for use in the combination therapy which will achieve the goal of improvement in the severity of pain and inflammation and the frequency of incidence over treatment of each agent by itself, while avoiding adverse side effects typically associated with alternative therapies.

[0410] Those skilled in the art will appreciate that dosages may also be determined with guidance from Goodman & Goldman's The Pharmacological Basis of Therapeutics, Ninth Edition (1996), Appendix 11, pp. 1707-1711.

[0411] The frequency of dose will depend upon the half-life of the active components of the composition. If the active molecules have a short half life (e.g. from about 2 to 10 hours) it may be necessary to give one or more doses per day. Alternatively, if the active molecules have a long half-life (e.g. from about 2 to about 15 days) it may only be necessary to give a dosage once per day, per week, or even once every 1 or 2 months. A preferred dosage rate is to administer the dosage amounts described above to a subject once per day.

[0412] For the purposes of calculating and expressing a dosage rate, all dosages that are expressed herein are calculated on an average amount-per-day basis irrespective of the dosage rate. For example, one 100 mg dosage of an MK-2 inhibitor taken once every two days would be expressed as a dosage rate of 50 mg/day. Similarly, the dosage rate of an ingredient where 50 mg is taken twice per day would be expressed as a dosage rate of 100 mg/day.

[0413] For purposes of calculation of dosage amounts, the weight of a normal adult human will be assumed to be 70 kg.

[0414] When the MK-2 inhibitor is supplied along with a pharmaceutically acceptable carrier, the pharmaceutical compositions that are described above can be formed. Pharmaceutically acceptable carriers include, but are not limited to, physiological saline, Ringer's, phosphate solution or buffer, buffered saline, and other carriers known in the art. Pharmaceutical compositions may also include stabilizers, anti-oxidants, Colorants, and diluents. Pharmaceutically acceptable carriers and additives are chosen such that side effects from the pharmaceutical compound are minimized and the performance of the compound is not canceled or inhibited to such an extent that treatment is ineffective.

[0415] The term “pharmacologically effective amount” shall mean that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by a researcher or clinician. This amount can be a therapeutically effective amount.

[0416] The term “pharmaceutically acceptable” is used herein to mean that the modified noun is appropriate for use in a pharmaceutical product. Pharmaceutically acceptable cations include metallic ions and organic ions. More preferred metallic ions include, but are not limited to, appropriate alkali metal salts, alkaline earth metal salts and other physiological acceptable metal ions. Exemplary ions include aluminum, Calcium, lithium, magnesium, potassium, sodium and zinc in their usual valences. Preferred organic ions include protonated tertiary amines and quaternary ammonium cations, including in part, trimethylamine, diethylamine, N,N′-dibenzylethylenediamine, chloroprocaine, Choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine. Exemplary pharmaceutically acceptable acids include, without limitation, hydrochloric acid, hydroiodic acid, hydrobromic acid, phosphoric acid, sulfuric acid, methanesulfonic acid, acetic acid, formic acid, tartaric acid, maleic acid, malic acid, citric acid, isocitric acid, succinic acid, lactic acid, gluconic acid, glucuronic acid, pyruvic acid oxalacetic acid, fumaric acid, propionic acid, aspartic acid, glutamic acid, benzoic acid, and the like.

[0417] Also included in the combination of the invention are the isomeric forms and tautomers and the pharmaceutically-acceptable salts of the present MK-2 inhibitors. Illustrative pharmaceutically acceptable salts are prepared from formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, stearic, salicylic, p-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, toluenesulfonic, 2-hydroxyethanesulfonic, sulfanilic, cyclohexylaminosulfonic, algenic, P-hydroxybutyric, galactaric and galacturonic acids.

[0418] Suitable pharmaceutically-acceptable base addition salts of compounds of the present invention include metallic ion salts and organic ion salts. More preferred metallic ion salts include, but are not limited to, appropriate alkali metal (group Ia) salts, alkaline earth metal (group IIa) salts and other physiological acceptable metal ions. Such salts can be made from the ions of aluminum, Calcium, lithium, magnesium, potassium, sodium and zinc. Preferred organic salts can be made from tertiary amines and quaternary ammonium salts, including in part, trifluoroacetate, trimethylamine, diethylamine, N,N′-dibenzylethylenediamine, Chloroprocaine, Choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine. All of the above salts can be prepared by those skilled in the art by conventional means from the corresponding compound of the present invention.

[0419] The method of the present invention is useful for, but not limited to, the prevention and treatment of diseases and disorders that are mediated by TNFα. For example, the MK-2 inhibitors of the present invention could be useful to treat arthritis, including, but not limited to, rheumatoid arthritis, spondyloarthopathies, gouty arthritis, osteoarthritis, systemic lupus erythematosus and juvenile arthritis. Such MK-2 inhibiting compounds of the invention would be useful in the treatment of asthma, bronchitis, menstrual cramps, tendinitis, bursitis, connective tissue injuries or disorders, and skin related conditions such as psoriasis, eczema, burns and dermatitis.

[0420] The MK-2 inhibiting compounds that are useful in the method of the invention also would be useful to treat gastrointestinal conditions such as inflammatory bowel disease, gastric ulcer, gastric varices, Crohn's disease, gastritis, irritable bowel syndrome and ulcerative colitis and for the prevention or treatment of cancer, such as colorectal cancer. Such MK-2 inhibiting compounds would be useful in treating inflammation in diseases and conditions such as 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, and the like.

[0421] The present MK-2 inhibitors would also be useful in the treatment of ophthalmic diseases, such as retinitis, retinopathies, conjunctivitis, uveitis, ocular photophobia, and of acute injury to the eye tissue. These compounds would also be useful in the treatment of pulmonary inflammation, such as that associated with viral infections and cystic fibrosis. The compounds would also be useful for the treatment of certain central nervous system disorders such as cortical dementias including Alzheimer's disease.

[0422] As used herein, the terms “TNFα mediated disease or disorder” are meant to include, without limitation, each of the symptoms or diseases that is mentioned above.

[0423] The terms “treating” or “to treat” mean to alleviate symptoms, eliminate the causation either on a temporary or permanent basis, or to prevent or slow the appearance of symptoms. The term “treatment” includes alleviation, elimination of causation of or prevention of pain and/or inflammation associated with, but not limited to, any of the diseases or disorders described herein. Besides being useful for human treatment, these combinations are also useful for treatment of mammals, including horses, dogs, Cats, rats, mice, sheep, pigs, etc.

[0424] The term “subject” for purposes of treatment includes any human or animal subject who is in need of the prevention of or treatment of any one of the TNFα mediated diseases or disorders. The subject is typically a mammal. “Mammal”, as that term is used herein, refers to any animal classified as a mammal, including-humans, domestic and farm animals, and zoo, sports, or pet animals, such as dogs, horses, Cats, Cattle, etc., Preferably, the mammal is a human.

[0425] For methods of prevention, the subject is any human or animal subject, and preferably is a subject that is in need of prevention and/or treatment of a TNFα mediated diseases or disorders. The subject may be a human subject who is at risk of obtaining a TNFα mediated disease or disorder, such as those described above. The subject may be at risk due to genetic predisposition, sedentary lifestyle, diet, exposure to disorder-causing agents, exposure to pathogenic agents and the like.

[0426] The subject pharmaceutical compositions may be administered enterally and parenterally. Parenteral administration includes subcutaneous, intramuscular, intradermal, intramammary, intravenous, and other administrative methods known in the art. Enteral administration includes solution, tablets, sustained release capsules, enteric coated capsules, and syrups. When administered, the pharmaceutical composition may be at or near body temperature.

[0427] In particular, the pharmaceutical compositions of the present invention can be administered orally, for example, as tablets, Coated tablets, dragees, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, Coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, Calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, maize starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed.

[0428] Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredients are mixed with an inert solid diluent, for example, Calcium carbonate, Calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredients are present as such, or mixed with water or an oil medium, for example, peanut oil, liquid paraffin, or olive oil.

[0429] Aqueous suspensions can be produced that contain the MK-2 inhibitors in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethyl-cellulose, sodium alginate, polyvinylpyrrolidone gum tragacanth and gum acacia; dispersing or wetting agents may be naturally-occurring phosphatides, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols; for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyoxyethylene sorbitan monooleate.

[0430] The aqueous suspensions may also contain one or more preservatives, for example, ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, or one or more sweetening agents, such as sucrose or saccharin.

[0431] Oily suspensions may be formulated by suspending the active ingredients in an omega-3 fatty acid, a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol.

[0432] Sweetening agents, such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an antioxidant such as ascorbic acid.

[0433] Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.

[0434] Syrups and elixirs containing the novel combination may be formulated with sweetening agents, for example glycerol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents.

[0435] The subject compositions can also be administered parenterally, either subcutaneously, or intravenously, or intramuscularly, or intrasternally, or by infusion techniques, in the form of sterile injectable aqueous or olagenous suspensions. Such suspensions may be formulated according to the known art using those suitable dispersing of wetting agents and suspending agents which have been mentioned above, or other acceptable 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 may be employed are water, Ringer's solution and 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 may be employed including synthetic mono-, or di-, glycerides. In addition, n-3 polyunsaturated fatty acids may find use in the preparation of injectables.

[0436] The subject compositions can also be administered by inhalation, in the form of aerosols or solutions for nebulizers, or rectally, in the form of suppositories prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperature but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and poly-ethylene glycols.

[0437] The novel compositions can also be administered topically, in the form of creams, ointments, jellies, collyriums, solutions or suspensions. Daily dosages can vary within wide limits and will be adjusted to the individual requirements in each particular case. In general, for administration to adults, an appropriate daily dosage has been described above, although the limits that were identified as being preferred may be exceeded if expedient. The daily dosage can be administered as a single dosage or in divided dosages.

[0438] Various delivery systems include capsules, tablets, and gelatin capsules, for example.

[0439] The following examples describe preferred embodiments of the invention. Other embodiments within the scope of the claims herein will be apparent to one skilled in the art from consideration of the specification or practice of the invention as disclosed herein. It is intended that the specification, together with the examples, be considered to be exemplary only, with the scope and spirit of the invention being indicated by the claims which follow the examples. In the examples all percentages are given on a weight basis unless otherwise indicated.

General Information for Preparation Methods:

[0440] Unless otherwise noted, reagents and solvents were used as received from commercial suppliers.

[0441] NMR Analysis:

[0442] Proton nuclear magnetic resonance spectra were obtained on a Varian Unity Innova 400, a Varian Unity Innova 300 a Varian Unity 300, a Bruker AMX 500 or a Bruker AV-300 spectrometer. Chemical shifts are given in ppm (δ) and coupling constants, J, are reported in Hertz. Tetramethylsilane was used as an internal standard for proton spectra and the solvent peak was used as the reference peak for carbon spectra. Mass spectra were obtained on a Perkin Elmer Sciex 100 atmospheric pressure ionization (APCI) mass spectrometer, a Finnigan LCQ Duo LCMS ion trap electrospray ionization (ES I) mass spectrometer, a PerSeptive Biosystems Mariner TOF HPLC-MS (ESI), or a Waters ZQ mass spectrometer (ESI).

[0443] Determination of MK-2 IC50:

[0444] Recombinant MAPKAPK2 was phosphorylated at a concentration of 42-78 μM by incubation with 0.23 μM of active p38α in 50 mM HEPES, 0.1 mM EDTA, 10 mM magnesium acetate, and 0.25 mM ATP, pH 7.5 for one hour at 30° C.

[0445] The phosphorylation of HSP-peptide (KKKALSRQLSVAA) by MAPKAPK2 was measured using an anion exchange resin capture assay method. The reaction was carried out in 50 mM β-glycerolphosphate, 0.04% BSA, 10 mM magnesium acetate, 2% DMSO and 0.8 mM dithiotheritol, pH 7.5 in the presence of the HSP-peptide with 0.2 μCi [γ33P]ATP and 0.03 mM ATP. The reaction was initiated by the addition of 15 nM MAPKAPK2 and was allowed to incubate at 30° C. for 30 min. The reaction was terminated and [γ33P]ATP was removed from solution by the addition of 150 μl of AG 1×8 ion exchange resin in 900 mM sodium formate pH 3.0. A 50 μl aliquot of head volume was removed from the quenched reaction mixture and added to a 96-well plate, 150 μl of Microscint-40 (Packard) was added and the amount of phosphorylated-peptide was determined. Allow the Microscint to sit in the plates for 60 minutes prior to counting.

[0446] Compounds are evaluated as potential inhibitors of the MK-2 kinase by measuring their effects on MK-2 phosphorylation of the peptide substrate. Compounds may be screened initially at two concentrations prior to determination of IC50 values. Screening results are expressed as percent inhibition at the concentrations of compound tested. For IC50 value determinations, Compounds are tested at six concentrations in ten-fold serial dilutions with each concentration tested in triplicate. Results are expressed as IC50 values in micromolar. The assay is performed at a final concentration of 2% DMSO.

[0447] U937 Cell TNFα Release Assay

[0448] The human monocyte-like cell line, U937 (ATCC #CRL-1593.2), is cultured in RPMI1640 media with 10% heat-inactivated fetal calf serum (GIBCO), glutamine and pen/strep at 37° C. and 5% CO2. Differentiation of U937 to monocytic/macrophage-like cells is induced by the addition of phorbol12-myristate 13-acetate (Sigma) at final concentration of 20 ng/ml to a culture of U937 cells at ˜0.5 million cells/ml and incubated for 24 hrs. The cells are centrifuged, washed with PBS and resuspended in fresh media without PMA and incubated for 24 hrs. Cells adherent to the culture flask are harvested by scraping, Centrifugation, and resuspended in fresh media to 2 million cells/ml, and 0.2 ml is aliquoted to each of 96 wells in flat-bottom plate. Cells are then incubated for an additional 24 hrs to allow for recovery. The media is removed from the cells, and 0.1 ml of fresh media is added per well. 0.05 ml of serially diluted compound or control vehicle (Media with DMSO) is added to the cells. The final DMSO concentration does not exceed 1%. After 1 hr incubation, 0.05 ml of 400 ng/ml LPS (E Coli serotype 0111:B4, Sigma) in media is added for final concentration of 100 ng/ml. Cells are incubated at 37° C. for 4 hrs. After 4 hrs incubation, supernatants are harvest and assayed by ELISA for the presence of TNFα.

[0449] U937 Cell TNFα ELISA

[0450] ELISA plates (NUNC-Immuno™ Plate Maxisorb™ Surface) were coated with purified mouse monoclonal IgG1 anti-human TNFα antibody (R&D Systems #MAB610; 1.25 ug/ml in sodium bicarbonate pH 8.0, 0.1 ml/well) and incubated at 4° C. Coating solution was aspirated the following day and wells were blocked with 1 mg/ml gelatin in PBS (plus 1× thimerasol) for 2 days at 4° C. Prior to using, wells were washed 3× with wash buffer (PBS with 0.05% Tween). Cultured media samples were diluted in EIA buffer (5 mg/ml bovine γ-globulin, 1 mg/ml gelatin, 1 ml/l Tween-20, 1 mg/ml thimerasol in PBS), added to wells (0.1 ml/well) in triplicate and allowed to incubate for 1.5 hr at 37° C. in a humidified chamber. Plates were again washed and 0.1 ml/well of a mixture of rabbit anti-human TNFα polyclonal antibodies in EIA buffer (1:400 dilution of Sigma #T8300, and 1:400 dilution of Calbiochem #654250) was added for 1 hr at 37° C. Plates were washed as before and peroxidase-conjugated goat anti-rabbit IgG (H+L) antibody (Jackson ImmunoResearch #111-035-144, 1 ug/ml in EIA buffer, 0.1 ml/well) was added for 45 min. After final washing, plates were developed with peroxidase-ABTS solution (Kirkegaard/Perry #50-66-01, 0.1 ml/well). Enzymatic conversion of ABTS to colored product was measured after 5-30 minutes using a SpectroMax 340 spectrophotometer (Molecular Devices) at 405 nm. TNF levels were quantitated from a recombinant human TNFα (R&D Systems #210-TA-010) standard curve using a quadratic parameter fit generated by SoftMaxPRO software. ELISA sensitivity was approximately 30 pg TNF/ml. IC50 values for compounds were generated using BioAssay Solver.

[0451] Lipopolysaccharide (LPS)-Induced TNFα Production.

[0452] Adult male 225-250 gram Lewis rats (Harlan Sprague-Dawley) were used. Rats were fasted 18 hr prior to oral dosing, and allowed free access to water throughout the experiment. Each treatment group consisted of 5 animals.

[0453] Compounds were prepared as a suspension in a vehicle consisting of 0.5% methylcellulose, 0.025% Tween-20 in PBS. Compounds or vehicle were orally administered in a volume of 1 ml using an 18 gauge gavage needle. LPS (E. coli serotype 0111:B4, Lot #39H4103, Cat. # L-2630, Sigma) was administered 1-4 hr later by injection into the penile vein at a dose of 1 mg/kg in 0.5 ml sterile saline. Blood was collected in serum separator tubes via cardiac puncture 1.5 hr after LPS injection, a time point corresponding to maximal TNFα production. After clotting, serum was withdrawn and stored at −20° C. until assay by ELISA (described below).

[0454] Rat LPS TNFα ELISA

[0455] ELISA plates (NUNC-Immuno™ Plate Maxisorb™ Surface) were coated with 0.1 ml per well of an Protein G purified fraction of a 2.5 ug/ml of hamster anti-mouse/rat TNFα monoclonal antibody TN19.12 (2.5 ug/ml in PBS, 0.1 ml/well). The hybridoma cell line was kindly provided by Dr. Robert Schreiber, Washington University. Wells were blocked the following day with 1 mg/ml gelatin in PBS. Serum samples were diluted in a buffer consisting of 5 mg/ml bovine γ-globulin, 1 mg/ml gelatin, 1 ml/l Tween-20, 1 mg/ml thimerasol in PBS, and 0.1 ml of diluted serum was added wells in duplicate and allowed to incubate for 2 hr at 37° C. Plates were washed with PBS-Tween, and 0.1 ml per well of a 1:300 dilution of rabbit anti-mouse/rat TNFα antibody (BioSource International, Cat. #AMC3012) was added for 1.5 hr at 37° C. Plates were washed, and a 1:1000 fold dilution of peroxidase-conjugated donkey anti-rabbit IgG antibody (Jackson ImmunoResearch, Cat. #711-035-152) was added for 45 min. After washing, plates were developed with 0.1 ml of ABTS-peroxide solution (Kirkegaard/Perry, Cat. #50-66-01). Enzymatic conversion of ABTS to colored product was measured after 30 minutes using a SpectroMax 340 spectrophotometer (Molecular Devices corp.) at 405 nm. TNF levels in serum were quantitated from a recombinant rat TNFα (BioSource International, Cat. #PRC3014.) standard curve using a quadratic parameter fit generated by SoftMaxPRO software. ELISA sensitivity was approximately 30 pg TNF/ml. Results are expressed in percent inhibition of the production of TNFα as compared to blood collected from control animals dosed only with vehicle.

Synthesis of MK-2 Inhibiting Compounds of the Present Invention

EXAMPLE 1

[0456] This example illustrates the production of 6-hydroxy-2,4-dihydroindeno[1,2-c]pyrazole-3-carboxylic acid.

953

[0457] Step 1: The Preparation of Methyl (5-methoxy-1-oxo-2,3-dihydro-1H-inden-2-yl)(oxo)acetate:

[0458] 5-methoxyindan-1-one (30 mmol, 4.86 g), ether (150 mL), sodium methoxide (25%/methanol, 33 mmol, 7.13 g), and dimethyl oxalate (33 mmol, 3.90 g) were stirred at room temperature for 16 h. Hydrochloric acid (1 N) was added until the mixture was acidic to pH paper. The mixture was extracted with hot ethyl acetate (3×100 mL). The combined organic extracts were washed with brine 2×, dried over magnesium sulfate, and concentrated. This material was used in the next step without further purification or characterization.

[0459] Step 2: The Preparation of Methyl 6-methoxy-2,4-dihydroindeno[1,2-c]pyrazole-3-carboxylate.

[0460] To methyl (5-methoxy-1-oxo-2,3-dihydro-1H-inden-2-yl)(oxo)acetate from step 1 was added hydrazine hydrochloride, the material from the previous step, (33 mmol, 2.26 g) and methanol (100 mL). This mixture was stirred at reflux for 1 h. After cooling to room temperature, water was added until the mixture became cloudy. After standing for 2 h a yellow solid was filtered (3.75 g). 1H NMR (DMSO-d6/300 MHz) 13.6 (brs, 1H), 7.5 (d, 1H), 7.14 (s, 1H), 6.9 (d, 1H), 3.84 (s, 2H), 3.76 (s, 3H) 3.70 (s, 3H). ESHRMS m/z 245.090 (M+H, C13H12N2O3 requires 307.130).

[0461] Step 3: The Preparation of Methyl 6-hydroxy-2,4-dihydroindeno[1,2-c]pyrazole-3-carboxylate.

[0462] Methyl 6-methoxy-2,4-dihydroindeno[1,2-c]pyrazole-3-carboxylate (1 mmol, 244 Mg) and dichloromethane (10 mL) were stirred at −78° under nitrogen. Boron tribromide (1.0 N/dichloromethane, 5 mmol, 5 mL) was added drop wise and the mixture was allowed to slowly warm to room temperature. The mixture was re-cooled to −78° and boron tribromide (1.0 N/dichloromethane, 5 mmol, 5 mL) was added. This sequence was repeated a third time and the mixture was stirred at room temperature 16 h. Methanol (25 mL) was added drop wise with a large exotherm. The mixture was then concentrated to 10 mL, diluted with methanol and re-concentrated three times. Ethyl acetate (100 mL) was added followed by the slow addition of saturated aqueous sodium bicarbonate to neutral pH. Citric acid (1 N) was added to adjust the pH to 4 and the layers were separated. The aqueous layer was then extracted with ethyl acetate (3×30 mL). The combined organics were washed with brine 2×, dried over magnesium sulfate, and concentrated. The product was recrystallized from ethyl acetate/hexanes to yield a tan solid (140 Mg). 1H NMR (DMSO-d6/400 MHz) 13.5 (brs, 1H), 7.41 (m, 1H), 6.94 (s, 1H), 6.72 (dd, 1H), 3.82 (s, 3H), 3.64 (s, 2H). ESHRMS m/z 231.076 (M+H, C12H10N2O3 requires 231.076).

[0463] Step 4: The Preparation of 6-hydroxy-2,4-dihydroindeno[1,2-c]pyrazole-3-carboxylic Acid.

[0464] Methyl 6-hydroxy-2,4-dihydroindeno[1,2-c]pyrazole-3-carboxylate (110 Mg), methanol (5 mL), water (1 mL), and sodium hydroxide (2.5 N, 1 mL) were stirred at room temperature overnight. The mixture was then concentrated to 4 mL and citric acid (1 N) was added to adjust the pH to 4. A white solid was filtered (97 Mg). 1H NMR (DMSO-d6/400 MHz) 13.2 (brs, 1H), 9.48 (s, 1H), 7.39 (m, 1H), 6.92 (s, 1H), 6.72 (dd, 1H), 3.30 (s, 2H). ESHRMS m/z 217.064 (M+H, C11H8N2O3 requires m.w. 217.061).

EXAMPLE 2

[0465] This example illustrates the production of 2-(3-aminopropyl)-6-hydroxy-2,4-dihydroindeno[1,2-c]pyrazole-3-carboxylic acid hydrobromide.

954

[0466] Step 1: The Preparation of tert-butyl 2-{3-[(tert-butoxycarbonyl)amino]propyl}-6-methoxy-2,4-dihydroindeno[1,2-c]pyrazole-3-carboxylate.

[0467] Methyl 6-methoxy-2,4-dihydroindeno[1,2-c]pyrazole-3-carboxylate (10 mmol, 2.44 g) and N,N′-dimethylformamide (100 mL) were stirred at 0° under nitrogen. Lithium t-butoxide (1.0 N/tetrahydrofuran, 20 mmol, 20 mL) was slowly added. After 30 min., tert-butyl 3-bromopropylcarbamate (15 mmol, 3.57 g) was added and the mixture was stirred at room temperature for 16 h. Saturated ammonium chloride solution was added and the mixture was extracted with ethyl acetate (3×75 mL). The combined organics were washed with brine 2×, dried over magnesium sulfate, and concentrated. Purification was by flash column chromatography. The appropriate fractions were concentrated to a viscous yellow oil (0.86 g). 1H NMR (acetone-d6/400 MHz) 7.55 (d, 1H), 7.14 (d, 1H), 6.92 (dd, 1H), 5.96 (brs, 1H), 4.61 (t, 2H), 3.83 (s, 3H), 3.72 (s, 2H), 3.11 (dd, 2H), 2.03 (m, 2H), 1.62 (s, 9H), 1.38 (s, 9H). ESHRMS m/z 444.250 (M+H, C24H33N3O5 requires m.w. 444.249).

[0468] Step 2: The Preparation of 2-(3-aminopropyl)-6-hydroxy-2,4-dihydroindeno[1,2-c]pyrazole-3-carboxylic Acid Hydrobromide.

[0469] Tert-butyl 2-{3-[(tert-butoxycarbonyl)amino]propyl}-6-methoxy-2,4-dihydroindeno[1,2-c]pyrazole-3-carboxylate (1 mmol, 444 Mg) and dichloromethane (15 mL) were stirred at −78° under nitrogen. Boron tribromide (1.0 N/dichloromethane, 20 mmol, 20 mL) was added drop wise and the mixture was allowed to stir at room temperature for 16 h. Methanol (10 mL) was added drop wise. The mixture was concentrated to 5 mL, diluted with methanol, and re-concentrated 2×. Anhydrous ethyl ether was added to precipitate a white solid, which was rinsed with ether/methanol (340 Mg). 1H NMR (DMSO-d6/400 MHz) 7.66 (brs, 2H), 7.39 (d, 1H), 6.94 (d, 1H), 6.73 (dd, 1H), 4.56 (t, 2H), 3.65 (s, 2H), 2.75 (m, 2H), 2.05 (q, 2H). ESHRMS m/z 274.119 (M+H, C14H15N3O3 requires 274.119).

EXAMPLE 3

[0470] This example illustrates the production of 2-(3-aminopropyl)-7-hydroxy-2,4-dihydroindeno[1,2-c]pyrazole-3-carboxylic acid hydrobromide.

955

[0471] Step 1: The Preparation of Methyl (2Z)-hydroxy(6-methoxy-1-oxo-1,3-dihydro-2H-inden-2-ylidene)ethanoate.

[0472] 6-methoxyindanone (60 mmol, 9.73 g), ether (200 mL), sodium methoxide (25%/methanol, 66 mmol, 14.26 g), and dimethyl oxalate (66 mmol, 7.79 g) were stirred at room temperature overnight. Hydrochloric acid (1 N, 75 ml) was added and the mixture was extracted with hot ethyl acetate (3×100 mL). The heated organics were washed with brine 2×, dried over magnesium sulfate, concentrated, and recrystallized from ether/hexanes. A yellow solid was collected by filtration (11.6 g). 1H NMR (acetone-d6/400 MHz) 7.55 (dd, 1H), 7.29 (dd, 1H), 7.25 (d, 1H), 3.90 (s, 3H), 3.88 (s, 3H), 3.86 (s, 2H) ESHRMS m/z 249.074 (M+H, C13H12O5 requires m.w. 249.076).

[0473] Step 2: The Preparation of Methyl 7-methoxy-2,4-dihydroindeno[1,2-c]pyrazole-3-carboxylate.

[0474] Methyl (2Z)-hydroxy(6-methoxy-1-oxo-1,3-dihydro-2H-inden-2-ylidene)ethanoate (46 mmol, 11.5 g), methanol (150 mL), and hydrazine mono hydrochloride (51 mmol, 3.49 g) were heated to reflux for one hour. After cooling to room temperature, saturated aqueous sodium bicarbonate solution was added to neutral pH followed by water (100 mL). A dark yellow solid was collected by filtration (10.9 g). 1H NMR (acetone-d6/400 MHz) 12.85 (brs, 1H), 7.43 (d, 1H), 7.25 (d, 1H), 6.87 (dd, 1H), 3.90 (s, 3H), 3.85 (s, 3H), 3.69 (s, 2H). ESHRMS m/z 245.091 (M+H, C13H12N2O3 requires m.w. 245.092).

[0475] Step 3: The Preparation of tert-butyl 2-{3-[(tert-butoxycarbonyl)amino]propyl}-7-methoxy-2,4-dihydroindeno[1,2-c]pyrazole-3-carboxylate.

[0476] Methyl 7-methoxy-2,4-dihydroindeno[1,2-c]pyrazole-3-carboxylate (30 mmol, 7.33 g) and N,N′-dimethylformamide (100 mL) were stirred at 0° under nitrogen. Lithium t-butoxide (1.0 N/tetrahydrofuran, 66 mmol, 66 mL) was slowly added. After 30 min., tert-butyl 3-bromopropylcarbamate (15 mmol, 3.57 g) was added and the mixture was stirred at room temperature for 16 h. Saturated ammonium chloride solution was added and the mixture was extracted with ethyl acetate (3×50 mL). The combined organics were washed with brine 2×, dried over magnesium sulfate, and concentrated. Purification was by flash column chromatography eluting with ethyl acetate/hexanes. The appropriate fractions were concentrated to a viscous yellow oil (4.2 g). 1H NMR (acetone-d6/400 MHz) 7.41 (d, 1H), 7.22 (d, 1H), 6.85 (dd, 1H), 5.96 (brs, 1H), 4.64 (t, 2H), 3.85 (s, 3H), 3.67 (s, 2H), 3.12 (dd, 2H), 2.05 (m, 2H), 1.62 (s, 9H), 1.38 (s, 9H). ESHRMS m/z 444.248 (M+H, C24H33N3O5 requires m.w. 444.249).

[0477] Step 4: The Preparation of 2-(3-aminopropyl)-7-hydroxy-2,4-dihydroindeno[1,2-c]pyrazole-3-carboxylic Acid Hydrobromide.

[0478] Tert-butyl 2-{3-[(tert-butoxycarbonyl)amino]propyl}-7-methoxy-2,4-dihydroindeno[1,2-c]pyrazole-3-carboxylate (1 mmol, 444 Mg) and dichloromethane (10 mL) were stirred at −78° under nitrogen. Boron tribromide (1.0 N/dichloromethane, 15 mmol, 15 mL) was added drop wise and the mixture was allowed to stir at room temperature for 6 h when it was cooled to −40° and methanol (20 mL) was added drop wise. The mixture was concentrated to 5 mL, diluted with methanol, and re-concentrated 2×. Anhydrous ethyl ether was added to precipitate a white solid, which was rinsed with ether and air-dried (350 Mg). 1H NMR (DMSO-d6/400 MHz) 7.68 (brs, 2H), 7.29 (d, 1H), 6.99 (d, 1H), 6.68 (dd, 1H), 4.59 (t, 2H), 3.60 (s, 2H), 2.76 (m, 2H), 2.07 (q, 2H). ESHRMS m/z 274.118 (M+H, C14H15N3O3 requires m.w. 274.119).

EXAMPLE 4

[0479] This example illustrates the production of 2-(3-aminopropyl)-7-hydroxy-2,5-dihydroisothiochromeno[4,3-c]pyrazole-3-carboxylic acid hydrochloride.

956

[0480] Step 1: The Preparation of [(3-methoxybenzyl)thio]acetic Acid.

[0481] 3-methoxybenzyl chloride (100 mmol, 15.66 g), methanol (40 mL), and thiourea (100 mmol, 7.61 g) were stirred at reflux for 16 h. After cooling to room temperature, water (300 mL) and saturated aqueous sodium bicarbonate solution was added until neutral to pH paper. This mixture was allowed to stand at room temperature for 16 h. and a white solid was collected by filtration (15.0 g). To the resultant white solid was added sodium chloroacetate (115 mmol, 13.4 g), sodium hydroxide (2.5 N, 306 mmol, 122 mL), and methanol (150 mL). After heating to reflux for 16 h. and cooling to room temperature, concentrated hydrochloric acid was carefully added until the mixture was acidic to pH paper. The mixture was then extracted with ether (3×100 mL). The combined ethereal extracts were washed with brine 2×, dried over magnesium sulfate, and concentrated to a light brown oil (17.3 g). 1H NMR (acetone-d6/400 MHz) 7.22 (t, 1H), 6.92 (m, 2H), 6.81 (m, 1H), 3.83 (s, 2H), 3.78 (s, 3H), 3.13 (s, 2H).

[0482] Step 2: The Preparation of 7-methoxy-1H-isothiochromen-4(3H)-one.

[0483] [(3-methoxybenzyl)thio]acetic acid (81 mmol, 17.3 g) and trifluoroacetic acid (20 mL) were cooled to 0° with stirring. Trifluoroacetic anhydride (40 mL) was carefully added. After stirring for 3 h. at 00, water (100 mL) was added. The mixture was extracted with ethyl acetate (3×65 mL). The combined organics were washed with brine, saturated aqueous sodium bicarbonate, and brine 2×, maintaining an acidic pH throughout the process. The mixture was then dried over magnesium sulfate and concentrated under high vacuum to dryness. Purification was via re-crystallization from ether/ethyl acetate/hexanes to yield a black solid (4.23 g).

[0484] Step 3: The Preparation of Methyl 7-methoxy-2,5-dihydroisothiochromeno[4,3-c]pyrazole-3-carboxylate.

[0485] 7-methoxy-1H-isothiochromen-4(3H)-one (the crude material from step 2, 22 mmol, 4.23), ether (100 mL), sodium methoxide (25%/methanol, 24 mmol, 5.18 g), and dimethyl oxalate (24 mmol, 2.83 g) were stirred at room temperature for 16 h. Hydrochloric acid (1 N) was added to pH 1 and the ethereal layers were separated. The aqueous layer was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine 2×, concentrated and recrystalized from ethyl acetate/hexanes to yield a black solid (3.46 g). To this crude material was added hydrazine mono hydrochloride (13.2 mmol, 0.9 g) and methanol (75 mL). The mixture was heated to reflux with stirring for 16 h. After cooling to room temperature, saturated aqueous sodium bicarbonate solution was added to neutral pH followed by water until the mixture became cloudy. After standing, a brown solid was obtained by filtration (2.92 g). 1H NMR (acetone-d6/400 MHz) 12.95 (brs, 1H), 7.75 (s, 1H), 6.95 (m, 2H), 4.00 (s, 2H), 3.87 (s, 3H), 3.83 (s, 3H). ESHRMS m/z 277.064 (M+H, C13H12N2O3S requires m.w. 277.064).

[0486] Step 4: The Preparation of Methyl 2-{3-[(tert-butoxycarbonyl)amino]propyl}-7-methoxy-2,5-dihydroisothiochromeno[4,3-c]pyrazole-3-carboxylate.

[0487] Methyl 7-methoxy-2,5-dihydroisothiochromeno[4,3-c]pyrazole-3-carboxylate (8 mmol, 2.21 g) and N,N′-dimethylformamide (50 mL) were stirred at 0° under nitrogen. Lithium t-butoxide (1.0 N/tetrahydrofuran, 16 mmol, 16 mL) was slowly added. After 30 min., tert-butyl 3-bromopropylcarbamate (16 mmol, 3.81 g) was added and the mixture was stirred at room temperature for 16 h. Saturated ammonium chloride solution was added and the mixture was extracted with ethyl acetate (3×50 mL). The combined organics were washed with brine 2×, dried over magnesium sulfate, and concentrated. Purification was by flash column chromatography eluting with ethyl acetate/hexanes. The appropriate fractions were concentrated to a clear oil (190 Mg). This material was used in the next step without further purification or characterization.

[0488] Step 5: The Preparation of 2-(3-aminopropyl)-7-hydroxy-2,5-dihydroisothiochromeno[4,3-c]pyrazole-3-carboxylic Acid Hydrochloride.

[0489] Methyl 2-{3-[(tert-butoxycarbonyl)amino]propyl}-7-methoxy-2,5-dihydroisothiochromeno[4,3-c]pyrazole-3-carboxylate, the crude material from the previous step, (0.4 mmol, 173 Mg) and dichloromethane (5 mL) were stirred at −78° under nitrogen. Boron tribromide (1.0 M/dichloromethane, 4 mmol, 4 mL) was slowly added. After stirring at room temperature for 3 h., the mixture was cooled to −10° and methanol was added drop wise to a total volume of 30 mL. This dilute mixture was concentrated to 5 mL, diluted with methanol, and re-concentrated 2×. Sodium hydroxide (2.5 N) was added to adjust the pH to 14. After stirring at room temperature for 16 h., hydrochloric acid (1 N) was to adjust the pH to 1. This dilute mixture was concentrated until a white solid appeared which was collected by filtration (95 Mg). 1H NMR (DMSO-d6/300 MHz) 9.79 (brs, 1H), 7.85 (brs, 2H), 7.57 (d, 1H), 6.77 (m, 2H), 4.58 (m, 2H), 3.95 (s, 2H), 2.82 (m, 2H), 2.10 (m, 2H). ESHRMS m/z 306.090 (M+H, C14H15N3O3S requires m.w. 306.091).

EXAMPLE 5

[0490] This example illustrates the production of 2-(3-aminopropyl)-8-(sec-butylamino)-7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid.

957

[0491] Step 1: The Preparation of Methyl 7-methoxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate.

[0492] 6-methoxytetralone (0.5 mol, 89.12 g) was placed in a 3-neck 5 L roundbottom flask equipped with an overhead stirrer, under nitrogen. Ether (1 L) was added followed by dimethyloxylate (0.55 mol, 64.95 g). The mixture was stirred for 10 min. when sodium methoxide (25%/methanol, 0.55 mol, 118.84 g) was slowly added. Ether (500 mL) was used when rinsing reagents into the flask. The mixture was stirred for 1 h., stirring was stopped for 16 h., and continued for an additional 4 h. when a greenish solid was collected by filtration and air-dried. A stream of nitrogen was passed through the flask to remove the remaining ether. The previously filtered green solid material was returned to the flask using methanol (200 mL) to rinse the filter. Methanol (800 mL) was added followed by methanesulfonic acid (0.55 mol, 52.86 g) and hydrazine mono hydrochloride (0.55 mol, 37.68 g) with a mild exotherm. The mixture was then heated to reflux with stirring for 3 h. After standing for 2 days at room temperature, sodium hydroxide (2.5 N, 200 mL) and water (200 mL) were added slowly. A light pink solid was collected by filtration and dried in vacuo at 80° (117.5 g). 1H NMR (DMSO-d6/400 MHz) 13.8 (brs, 1H), 7.6 (dd, 1H), 6.8 (m, 2H), 3.82 (s, 3H), 3.77 (s, 3H), 2.86 (m, 4H). ESHRMS m/z 259.105 (M+H, C14H14N2O3 requires 259.108).

[0493] Step 2: The Preparation of Methyl 7-methoxy-8-nitro-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate.

[0494] Nitric acid (70%, 300 mL) was cooled to −30° and methyl 7-methoxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate (0.1 mol, 25.8 g) was added in portions over 10 min. The mixture was stirred at 0° for 2 h. and poured into a mixture of ice (1.3 L) and ethyl acetate (600 mL). After stirring for 1 h., a yellow solid was collected by filtration. The filtrate was extracted with ethyl acetate (3×150 mL), Combined, washed with brine 2×, dried over magnesium sulfate, and concentrated to 300 mL. Hexane (100 mL) was added and the mixture was allowed to stand 16 h. A yellow solid was collected and combined with the previously obtained solid material (28.3 g).

[0495]

1
H NMR (acetone-d6/300 MHz) 8.25 (s, 1H), 7.38 (s, 1H), 4.05 (s, 3H), 3.94 (s, 3H), 3.11 (m, 4H). ESHRMS m/z 304.095 (M+H, C14H13N3O5 requires 304.093).

[0496] Step 3: The Preparation of Methyl 2-{3-[(tert-butoxycarbonyl) amino]propyl}-7-methoxy-8-nitro-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate.

[0497] Methyl 7-methoxy-8-nitro-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate (20 mmol, 6.06 g) and N,N′-dimethylformamide (100 mL) were cooled to 0° under nitrogen. Lithium t-butoxide (1.0 N/tetrahydrofuran, 40 mmol, 40 mL) was slowly added. After 30 min., tert-butyl 3-bromopropylcarbamate (16 mmol, 3.81 g) was added and the mixture was stirred at room temperature for 16 h. Hydrochloric acid (1 N, 50 mL) was added and the mixture was extracted with ethyl acetate (3×50 mL). The combined organics were washed with brine 2×, dried over magnesium sulfate, and concentrated. Purification was by flash column chromatography eluting with ethyl acetate/hexanes. The appropriate fractions were concentrated to a yellow solid (3.65 g). 1H NMR (acetone-d6/300 MHz) 8.22 (s, 1H), 7.35 (s, 1H), 6.06 (brs, 1H), 4.67 (t, 2H), 4.05 (s, 3H), 3.97 (s, 3H), 3.17 (dd, 2H), 3.09 (m, 4H), 2.0 (m, 2H), 1.44 (s, 9H). ESHRMS m/z 461.201 (M+H, C22H28N4O7 requires 461.203).

[0498] Step 4: The Preparation of Methyl 8-amino-2-{3-[(tert-butoxycarbonyl) amino]propyl}-7-methoxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate.

[0499] Methyl 2-{3-[(tert-butoxycarbonyl)amino]propyl}-7-methoxy-8-nitro-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate (3.55 g), methanol (50 mL), and palladium on carbon (10%, 200 Mg) were placed in a Parr shaker apparatus. The mixture was pressurized to 60 psi of hydrogen gas and agitated for 16 h. After the catalyst was removed by filtration, the mixture was concentrated to a pink/purple solid (2.3 g). 1H NMR (acetone-d6/300 MHz) 7.21 (s, 1H), 6.78 (s, 1H), 6.0 (brs, 1H), 4.61 (t, 2H), 3.94 (s, 3H), 3.88 (s, 3H), 3.15 (dd, 2H), 2.86 (m, 4H), 2.84 (brs, 2H), 2.05 (m, 2H), 1.44 (s, 9H). ESHRMS m/z 431.229 (M+H, C22H30N4O5 requires 431.229).

[0500] Step 5: The Preparation of Methyl 2-{3-[(tert-butoxycarbonyl)amino]propyl}-8-(sec-butylamino)-7-methoxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate.

[0501] Methyl 8-amino-2-{3-[(tert-butoxycarbonyl)amino]propyl}-7-methoxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate (1 mmol, 430 Mg), dichloromethane (25 mL), 2-butanone (1.2 mmol, 86 Mg), and acetic acid (2 mL) were stirred at room temperature under nitrogen. Sodium triacetoxyborohydride (2 mmol, 430 Mg) was added and the mixture was allowed to stir for 3 h. After methanol (10 mL) was added, the mixture was concentrated to 5 mL. Purification was by reverse phase HPLC. The appropriate fractions were combined and extracted with ethyl acetate. The combined organic extracts were washed with saturated aqueous sodium bicarbonate solution and brine. After drying over magnesium sulfate, the mixture was concentrated to a brown oil (400 Mg). 1H NMR (acetone-d6/300 MHz) 7.09 (s, 1H), 6.78 (s, 1H), 6.0 (brs, 1H), 4.63 (t, 2H), 3.95 (s, 3H), 3.88 (s, 3H), 3.53 (m, 1H), 3.16 (m, 4H), 3.00-2.82 (m, 4H), 2.1 (m, 2H), 1.64 (M, 2H), 1.45 (s, 9H), 1.23 (d, 3H), 1.01 (t, 3H). ESHRMS m/z 487.288 (M+H, C26H38N4O5 requires 487.291).

[0502] Step 6: The Preparation of 2-(3-aminopropyl)-8-(sec-butylamino)-7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic Acid.

[0503] Methyl 2-{3-[(tert-butoxycarbonyl)amino]propyl}-8-(sec-butylamino)-7-methoxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate (300 Mg) and dichloromethane (5 mL) were stirred at −78° under nitrogen. Boron tribromide (1.0 M/dichloromethane, 10 mL) was added dropwise. The mixture was stirred at room temperature 16 h. Water and methanol (1:5) was added dropwise to a volume of 30 mL. The mixture was concentrated to 10 mL and filtered. The filtrate was purified by reverse phase HPLC. The appropriate fractions were concentrated to produce the trifluoroacetic acid salt of the desired product, which was triturated with acetonitrile to produce a white solid (95 Mg). 1H NMR D2O/300 MHz) 7.54 (s, 1H), 6.91 (s, 1H), 4.52 (t, 2H), 3.57 (m, 1H), 2.92-2.78 (m, 6H), 2.11 (q, 2H), 1.74 (m, 1H), 1.58 (m, 1H), 1.22 (d, 3H), 0.89 (t, 3H). ESHRMS m/z 359.208 (M+H, C19H26N4O3 requires 359.211).

EXAMPLE 6

[0504] This example illustrates the production of 2-(3-aminopropyl)-8-(sec-butylamino)-7-methoxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid.

958

[0505] Methyl 2-{3-[(tert-butoxycarbonyl)amino]propyl}-8-(sec-butylamino)-7-methoxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate (300 Mg) and dichloromethane (5 mL) were stirred at −78° under nitrogen. Boron tribromide (1.0 M/dichloromethane, 10 mL) was added dropwise. The mixture was stirred at room temperature 16 h. Water and methanol (1:5) was added dropwise to a volume of 30 mL. The mixture was concentrated to 10 mL and filtered. The filtrate was purified by reverse phase HPLC. The appropriate fractions were concentrated to produce the trifluoroacetic acid salt of the desired product as a brown oil (65 Mg). 1H NMR D2O/300 MHz) 7.48 (s, 1H), 6.83 (s, 1H), 4.24 (t, 2H), 3.75 (s, 3H), 3.57 (m, 1H), 2.89 (t, 2H), 2.68 (s, 4H), 2.06 (q, 2H), 1.72 (m, 1H), 1.54 (m, 1H), 1.20 (d, 3H), 0.88 (t, 3H). ESHRMS m/z 373.223 (M+H, C20H28N4O3 requires 373.222).

EXAMPLE 7

[0506] This example illustrates the production of 2-(3-aminopropyl)-6-chloro-7-hydroxy-8-(3-nitrophenyl)-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid.

959

[0507] 2-(3-aminopropyl)-7-hydroxy-8-(3-nitrophenyl)-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid trifluoroacetate (0.2 mmol, 100 Mg) and acetic acid (5 mL) were stirred at room temperature. Chlorine (0.63 N/methanol, (0.2 mmol, 0.32 mL) was added and the mixture was allowed to stir at room temperature for three hours. After concentrating, the mixture was purified by reverse phase HPLC. The appropriate fractions were concentrated to a brown oil, the trifluoroacetic acid salt of the desired product (57 Mg). 1H NMR (DMSO-d6/400 MHz) 9.7 (bs, 1H), 8.35 (t, 1H), 8.2 (m, 1H), 7.97 (m, 1H), 7.73 (t, 1H), 7.68 (bs, 2H), 7.61, (s, 1H), 4.55 (t, 2H), 3.00 (m, 4H), 2.76 (m, 2H), 2.04 (m, 2H). ESHRMS m/z 443.113 (M+H, C21H19N4O5C[requires 443.112).

EXAMPLE 8

[0508] This example illustrates the production of 2-amino-3-hydroxy-5,6,8,9,10,11-hexahydro-7H-benzo[g][1,4]diazepino[1,2-b]indazol-7-one trifluoroacetate.

960

[0509] Step 1: The Preparation of 8-amino-2-(3-aminopropyl)-7-methoxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate hydrochloride.

[0510] Methyl 8-amino-2-{3-[(tert-butoxycarbonyl)amino]propyl}-7-methoxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate (3.7 mmol, 1.6 g), methanol (10 mL), and hydrochloric acid (4 N/dioxane, 30 mL) were stirred at room temperature for 2 h. The mixture was then concentrated and triturated with acetonitrile to produce a white solid. (0.1 g) was collected and characterized, the remaining material was used in the next step without further characterization. 1H NMR (DMSO-d6/300 MHz) 7.87 (bs, 4H), 7.56 (m, 1H), 7.11 (s, 1H), 4.58 (t, 2H), 3.91 (s, 3H), 3.90 (s, 3H), 2.95 (m, 4H), 2.85 (m, 2H), 2.10 (t, 2H). ESHRMS m/z 331.176 (M+H, C17H22N4O3 requires 331.176).

[0511] Step 2: The Preparation of 2-amino-3-hydroxy-5,6,8,9,10,11-hexahydro-7H-benzo[g][1,4]diazepino[1,2-b]indazol-7-one trifluoroacetate.

[0512] 8-amino-2-(3-aminopropyl)-7-methoxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate hydrochloride (1.2 mmol, 0.35 g and dichloromethane (20 mL) were stirred at −20° under nitrogen when boron tribromide (1.0 M/dichloromethane, 10 mL) was added drop wise. After stirring for 16 h at room temperature, methanol (10 mL) was added drop wise. The mixture was then concentrated and purified by reverse phase HPLC. The appropriate fractions were concentrated to produce the trifluoroacetic acid salt. 1H NMR (DMSO-d6/300 MHz) 10.5 (bs, 1H), 8.2 (bs, 1H), 7.50 (s, 1H), 6.87 (s, 1H), 4.39 (t, 2H), 3.18 (m, 2H), 2.82 (s, 4H), 2.13 (m, 2H). ESHRMS m/z 285.136 (M+H, C15H16N4O2 requires 285.135).

EXAMPLE 9

[0513] This example illustrates the production of 7-hydroxy-1-tetralone.

961

[0514] 7-Methoxy-1-tetralone (25.0 g, 0.14 mol) and aluminum chloride (47.3 g, 0.355 mol) were refluxed in toluene (400 mL). Contents were allowed to cool, quenched with water (100 mL), extracted with EtOAc, dried over MgSO4 and concentrated in vacuo leaving a tan solid (15.2 g). Recrystallization from EtOAc gave the desired as tan crystals, 13.9 g (61% yield). 1H NMR (DMSO-d6/300 MHz): 9.60 (s, 1H); 7.25-7.10 (m, 3H); 7.00-6.90 (m, 1H); 2.85-2.75 (m, 2H); 2.55-2.45 (m, 2H); 2.05-1.95 (m, 2H).

[0515] Anal. Calcd for C10H10O2 (0.1H2O): C, 73.24; H, 6.27. Found: C, 73.32; H, 5.88.

EXAMPLE 10

[0516] This example illustrates the production of ethyl 6-bromo-7-[(2 methoxyethoxy)methoxy]-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate.

962

[0517] 5-bromo-6-(methoxyethoxymethoxy)-1-tetralone [Bioorg & Med Chem Lett 7(12) 1573-1576 (1997)] was reacted according to the procedure for the production of ethyl (7-hydroxy-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)(oxo)acetate to give the desired diketo-ester intermediate (86% yield). The diketo-ester intermediate was reacted according to the procedure for the production of ethyl 8-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate to give the desired product as a solid (56% yield). FABHRMS m/z 425.0712, 427.0685 (M+H, C18H21BrN2O5 requires 425.0707, 427.0689). 1H NMR (DMSO-d6/300 MHz): 7.75 (d, 1H); 7.19 (d, 1H); 5.40 (s, 2H); 4.35 (q, 2H); 3.78-3.82 (m, 2H); 3.52-3.48 (m, 2H); 3.25 (s, 3H); 3.15-2.95 (m, 4H); 1.37 (t, 3H).

[0518] Anal. Calcd for C18H21BrN2O5 (0.4H2O): C, 49.99; H, 5.08; N, 6.48. Found: C, 49.64; H, 4.66; N, 6.19.

EXAMPLE 11

[0519] This example illustrates the production of 8-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid.

963

[0520] FABHRMS m/z 231.078 (M+H, C12H11N2O3 requires 231.0770).

EXAMPLE 12

[0521] This example illustrates the production of 6-bromo-7-[(2-methoxyethoxy)methoxy]-4,5-dihydro-2H-benzo[g]indazole-3-carboxamide.

964

[0522] Ethyl 6-bromo-7-[(2-methoxyethoxy)methoxy]-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate was reacted according to the procedure for the production of 8-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxamide to give the desired product as a light amber solid (77% yield). FABHRMS m/z 396.0546, 398.0549 (M+H, C16H19BrN3O4 requires 396.0553, 398.0535).

[0523] Anal. Calcd for C16H18BrN3O4: C, 48.09; H, 4.39; N, 10.31. Found: C, 48.50; H, 4.58; N, 10.60.

EXAMPLE 13

[0524] This example illustrates the production of 6-bromo-7-[(2-methoxyethoxy)methoxy]-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid.

965

[0525] Ethyl 6-bromo-7-[(2-methoxyethoxy)methoxy]-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate was reacted according to the procedure for that of 7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid to give the desired product as a solid (96% yield). FABHRMS m/z 397.0393, 399.0393 (M+H, C16H18BrN2O5 requires 397.0394, 399.0375).

[0526] Anal. Calcd for C16H18BrN2O5 (1.25H2O): C, 45.78; H, 4.68; N, 6.67. Found: C, 45.71; H, 4.28; N, 6.62.

EXAMPLE 14

[0527] This example illustrates the production of 6-bromo-7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid.

966

[0528] To 6-bromo-7-[(2-methoxyethoxy)methoxy]-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid (1.4 g, 0.0035 mol) in CH2Cl2 (10 mL) was added TFA (5 mL) and stirred overnight. Contents were concentrated in vacuo and triturated with EtOAc/MeOH and filtered to give the desired product as an amber solid (88% yield). FABHRMS m/z 308.9845, 310.9813 (M+H, C12H10BrN2O3 requires 308.9869, 310.9850).

[0529] Anal. Calcd for C12H9BrN2O3 (1.1H2O): C, 43.82; H, 3.43; N, 8.52. Found: C, 43.82; H, 3.16; N, 8.25.

EXAMPLE 15

[0530] This example illustrates the production of ethyl 6-bromo-7-hydroxy-2H-benzo[g]indazole-3-carboxylate.

967

[0531] Ethyl 6-bromo-7-[(2-methoxyethoxy)methoxy]-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate (5.0 g, 0.012 mol) and DDQ (2.7 g, 0.012 mol) were refluxed overnight. Contents were allowed to cool and the by-product was filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel chromatography eluting with 50% EtOAc/hexanes to give an amber solid, 5.2 g. The solid was triturated with CH2Cl2 and filtered to give the desired product as a light amber solid, 1.55 g (39% yield). FABHRMS m/z 335.0021, 337.0018 (M+H, C14H12BrN2O3 requires 335.0026, 337.0007). 1H NMR (DMSO-d6+5%TFA/300 MHz): 8.40 (d, 1H); 8.10 (d, 1H); 7.92 (d, 1H); 7.40 (d, 1H); 4.42 (q, 2H); 1.42 (t, 3H).

[0532] Anal. Calcd for C14H11BrN2O3(0.4H2O): C, 49.12; H, 3.47; N, 8.18. Found: C, 49.10; H, 3.36; N, 7.68.

EXAMPLE 16

[0533] This example illustrates the production of 6-bromo-7-hydroxy-2H-benzo[g]indazole-3-carboxylic acid

968

[0534] Ethyl 6-bromo-7-hydroxy-2H-benzo[g]indazole-3-carboxylate was reacted according to the procedure of 7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid to give the desired as a light amber solid (90% yield). FABHRMS m/z 306.9692, 308.9714 (M+H, C12H8BrN2O3 requires 306.9713, 308.9693). 1H NMR (DMSO-d6/300 MHz): 8.42 (d, 1H); 8.13 (d, 1H); 7.92 (d, 1H); 7.43 (d, 1H).

[0535] Anal. Calcd for C12H7BrN2O3 (2.0H2O): C, 42.00; H, 3.23; N, 8.16. Found: C, 42.17; H, 2.96; N, 8.13.

EXAMPLE 17

[0536] This example illustrates the production of ethyl 7-[(2-methoxyethoxy) methoxy]-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate.

969

[0537] To 6-hydroxy-1-tetralone (26.0 g, 0.16 mol) in THF (200 mL) was added dropwise lithium t-butoxide (1M in THF, 170 mL). Contents were stirred a half hour and MEM chloride (19.4 mL, 0.17 mol) in THF (50 mL) was added dropwise. Contents were stirred overnight, partitioned between water and EtOAc. The EtOAc layer was dried over MgSO4 and concentrated in vacuo leaving an oil, 39.9 g. The oil was reacted according to the procedure for the production of ethyl (7-hydroxy-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)(oxo)acetate to give the desired diketo-ester intermediate as a yellow oil (59% yield). The diketo-ester intermediate was reacted according to the procedure for the production of ethyl 8-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate to give the desired product as a light yellow solid (40% yield). FABHRMS m/z 347.1558 (M+H, C18H23N2O5 requires 347.1607). 1H NMR (CDCl3/300 MHz): 7.80 (d, 1H); 7.02 (d, 1H); 7.00 (s, 1H); 5.35 (s, 2H); 4.42 (q, 2H); 3.90-3.85 (m, 2H); 3.65-3.55 (m, 2H); 3.40 (s, 3H); 3.10-2.90 (m, 4H); 1.43 (t, 3H).

[0538] Anal. Calcd for C18H22N2O5: C, 62.42; H, 6.40; N, 8.09. Found: C, 62.20; H, 6.17; N, 7.92.

EXAMPLE 18

[0539] This example illustrates the production of 7-[(2-methoxyethoxy)methoxy]-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid.

970

[0540] Ethyl 7-[(2-methoxyethoxy)methoxy]-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate was reacted according to the procedure for the production of 7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid, to give the desired product (63% yield). FABHRMS m/z 319.1289 (M+H, C16H19N2O5 requires 319.1288).

[0541] Anal. Calcd for C16H18N2O5 (0.3H2O): C, 59.36; H, 5.79; N, 8.65. Found: C, 59.35; H, 5.66; N, 8.55.

EXAMPLE 19

[0542] This example illustrates the production of 7-[(2-methoxyethoxy)methoxy]-4,5-dihydro-2H-benzo[g]indazole-3-carboxamide.

971

[0543] Ethyl 7-[(2-methoxyethoxy)methoxy]-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate was reacted according to the procedure for the production of 8-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxamide to give the desired product (81% yield). FABHRMS m/z 318.1439 (M+H, C16H20N3O4 requires 318.1448).

[0544] Anal. Calcd for C16H19N3O4 (0.7H2O): C, 58.24; H, 6.23; N, 12.73. Found: C, 58.05; H, 6.35; N, 12.55.

EXAMPLE 20

[0545] This example illustrates the production of ethyl 2-allyl-7-[(2-methoxyethoxy)methoxy]-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate.

972

[0546] Ethyl 7-[(2-methoxyethoxy)methoxy]-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate and allyl bromide were reacted according to the procedure for the production of ethyl 2-(3-aminopropyl)-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate dihydrochloride to give the desired product after silica gel chromatography, eluting with 20% EtOAc/hexanes, as a colorless oil (70% yield). FABHRMS m/z 387.1910 (M+H, C21H27N2O5 requires 387.1920).

[0547] Anal. Calcd for C21H26N2O5: C, 65.27; H, 6.78; N, 7.25. Found: C, 66.13; H, 6.49; N, 7.42.

EXAMPLE 21

[0548] This example illustrates the production of 2-allyl-7-[(2-methoxyethoxy)methoxy]-4,5-dihydro-2H-benzo[g]indazole-3-carboxamide.

973

[0549] Ethyl 2-allyl-7-[(2-methoxyethoxy)methoxy]-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate was reacted according to the procedure for the production of 8-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxamide to give the desired as a white solid (40% yield). FABHRMS m/z 358.1756 (M+H, C19H24N3O4 requires 358.1761).

[0550] Anal. Calcd for C19H23N3O4: C, 63.85; H, 6.49; N, 11.76. Found: C, 63.58; H, 6.34; N, 11.65.

EXAMPLE 22

[0551] This example illustrates the production of 2-allyl-7-[(2-methoxyethoxy) methoxy]-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid.

974

[0552] Ethyl 2-allyl-7-[(2-methoxyethoxy)methoxy]-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate was reacted according to the procedure for the production of 7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid to give the desired as a white solid (62% yield). FABHRMS m/z 359.1619 (M+H, C19H23N2O5 requires 359.1601).

[0553] Anal. Calcd for C19H22N2O5 (0.2H2O): C, 63.04; H, 6.24; N, 7.74. Found: C, 62.96; H, 5.79; N, 7.88.

EXAMPLE 23

[0554] This example illustrates the production of 2-allyl-7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid.

975

[0555] 2-allyl-7-[(2-methoxyethoxy)methoxy]-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid was reacted according to the procedure for the production of 6-bromo-7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid to give the desired product as an off-white solid (55% yield). FABHRMS m/z 271.1055 (M+H, C15H15N2O3 requires 271.1077). 1H NMR (DMSO-d6/300 MHz): 9.42 (br s, 1H); 7.50 (d, 2H); 6.65 (s, 2H); 6.10-5.96 (m, 1H); 5.204.95 (m, 4H); 3.00-2.80 (m, 4H).

[0556] Anal. Calcd for C15H14N2O3 (1.0H2O): C, 62.49; H, 5.59; N, 9.72. Found: C, 62.79; H, 5.62; N, 9.65.

EXAMPLE 24

[0557] This example illustrates the production of ethyl (7-hydroxy-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)(oxo)acetate.

976

[0558] To 7-hydroxy-3,4-dihydronaphthalen-1 (2H)-one (13.9 g, 0.086 mol) and diethyl oxalate (27.2 mL, 0.2 mol) in ether (200 mL) was added dropwise lithium bis(trimethylsilyl)amide (1M in THF, 200 mL). Contents were stirred overnight and a solid was filtered. The solid was dissolved in water, which was made acidic to pH 2 with 1N HCl, precipitating a solid, which was filtered. Recrystallization from EtOAc/hexanes gave the desired as yellow crystals, 13.35 g (59% yield). FABHRMS m/z 263.0947 (M+H, C14H15O5 requires 263.0919). 1H NMR (CDCl3/300 MHz): 7.42 (s, 1H); 7.15-7.06 (m, 1H); 7.03-6.98 (m, 1H); 5.80 (br s, 1H); 4.40 (q, 2H); 2.95-2.80 (m, 4H); 1.40 (t, 3H).

[0559] Anal. Calcd for C14H14O5: C, 64.12; H, 5.38. Found: C, 64.04; H, 5.28

EXAMPLE 25

[0560] This example illustrates the production of ethyl 8-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate.

977

[0561] To ethyl (7-hydroxy-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)(oxo)acetate (2.25 g, 0.009 mol) in glacial acetic acid (10 mL) was added dropwise hydrazine monohydrate (0.437 mL, 0.009 mol) in glacial acetic acid (2 mL). Contents were stirred overnight, diluted with water and a white solid was filtered, 1.8 g. The solid was triturated with acetonitrile and filtered to give the desired as a white solid, 1.5 g (68% yield). FABHRMS m/z 259.1091 (M+H, C14H15N2O3 requires 259.1083). 1H NMR (DMSO-d6/300 MHz): 9.43, 9.25 (s, 1H); 7.20-7.00 (m, 2H); 6.65-6.58 (m, 1H); 4.40-4.20 (m, 2H); 2.95-2.70 (m, 4H); 1.4-1.2 (m, 3H).

[0562] Anal. Calcd for C14H14N2O3: C, 65.11; H, 5.46; N, 10.85. Found: C, 64.87; H, 5.24; N, 10.85.

EXAMPLE 26

[0563] This example illustrates the production of 8-Hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxamide.

978

[0564] Ethyl 8-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate (1.3 g, 0.005 mol), conc ammonium hydroxide (40 mL) and methanol (20 mL) were stirred in a stoppered flask for 48 hours. Contents were poured into a beaker to let the volatiles evaporate and a solid was filtered to give the desired as a light amber solid, 1.1 g, (96% yield). FABHRMS m/z 230.0935 (M+H, C12H12N3O2 requires 230.0930). 1H NMR (DMSO-d6/300 MHz): 9.40 (br s, 1H); 7.40 (br s, 1H); 7.20 (br s, 1H); 7.10-7.00 (m, 2H); 6.63-6.58 (m, 1H); 2.90-2.70 (m, 4H).

[0565] Anal. Calcd for C12H11N3O2 (1H2O): C, 58.29; H, 5.30; N, 16.99. Found: C, 58.22; H, 5.54; N, 17.06.

EXAMPLE 27

[0566] This example illustrates the production of ethyl 1-[4-(aminosulfonyl) phenyl]-8-hydroxy-4,5-dihydro-1H-benzo[g]indazole-3-carboxylate.

979

[0567] Ethyl 1-[4-(aminosulfonyl)phenyl]-8-hydroxy-4,5-dihydro-1H-benzo[g]indazole-3-carboxylate was prepared according to the procedure of ethyl 8-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate, using 4-aminosulfonylphenyl hydrazine at 55° C. FABHRMS m/z 414.1143 (M+H, C20H20N3O5S requires 414.1124).

[0568] Anal. Calcd for C20H19N3O5S (0.2H2O): C, 57.60; H, 4.69; N, 10.08. Found: C, 57.69; H, 4.85; N, 10.06.

EXAMPLE 28

[0569] This example illustrates the production of 1-[4(Aminosulfonyl)phenyl]-8-hydroxy-4,5-dihydro-1H-benzo[g]indazole-3-carboxamide.

980

[0570] 1-[4-(aminosulfonyl)phenyl]-8-hydroxy-4,5-dihydro-1H-benzo[g]indazole-3-carboxamide was prepared according to the procedure for the production of 8-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxamide to give the desired as a white solid (88% yield). FABHRMS m/z 385.0985 (M+H, C18H17N4O4S requires 385.0971).

[0571] Anal. Calcd for C18H16N4O4S (0.3H2O): C, 55.46; H, 4.29; N, 14.37. Found: C, 55.27; H, 4.37; N, 14.29.

EXAMPLE 29

[0572] This example illustrates the production of ethyl (6-hydroxy-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)(oxo)acetate.

981

[0573] Ethyl (6-hydroxy-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)(oxo)acetate was prepared according to the procedure for the production of ethyl (7-hydroxy-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)(oxo)acetate to give the desired as a yellow solid (43% yield). FABHRMS m/z 263.0919 (M+H, C14H15O5 requires 263.0925). 1H NMR (CDCl3/300 MHz): 8.02-7.95 (m, 1H); 7.30-7.20 (m, 1H); 6.85-6.70 (m, 1H); 6.65 (s, 1H); 5.40 (br s, 1H); 4.35-4.25 (m, 2H); 3.00-2.80 (m, 4H); 1.45-1.35 (t, 3H).

[0574] Anal. Calcd for C14H14O5: C, 64.12; H, 5.38. Found: C, 63.79; H, 5.35.

EXAMPLE 30

[0575] This example illustrates the production of ethyl 7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate.

982

[0576] Ethyl 7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate was prepared according to the procedure of ethyl 8-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate to give the desired product as a yellow solid (75% yield). FABHRMS m/z 259.1059 (M+H, C14H15N2O3 requires 259.1083). 1H NMR (DMSO-d6+5%TFA/300 MHz): 7.50 (d, 1H); 6.70-6.60 (m, 2H); 4.25 (q, 2H); 2.95-2.75 (m, 4H); 1.30 (t, 3H).

[0577] Anal. Calcd for C14H14N2O3 (0.85H2O): C, 61.46; H, 5.78; N, 10.24. Found: C, 61.56; H, 5.70; N, 9.88.

EXAMPLE 31

[0578] This example illustrates the production of 7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid.

983

[0579] 7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid (717 mg, 0.003 mol), aqueous sodium hydroxide (2.5N, 4 mL), water (5 mL) and methanol (5 mL) were stirred overnight. 1N HCl was added to pH 2, precipitating a solid, which was filtered to give the desired product as a white solid of 575 mg (89% yield). FABHRMS m/z 231.0773 (M+H, C12H11N2O3 requires 231.0770). 1H NMR (DMSO-d6+5%TFA/300 MHz): 7.55 (d, 1H); 6.75-6.65 (m, 2H); 2.90-2.75 (m, 4H).

[0580] Anal. Calcd for C12H10N2O3 (0.9H2O): C, 58.49; H, 4.83; N, 11.37. Found: C, 58.69; H, 4.87; N, 11.49.

EXAMPLE 32

[0581] This example illustrates the production of 7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxamide.

984

[0582] 7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid was reacted according to the procedure for the production of 8-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxamide to give the desired product as a tan solid (67% yield). FABHRMS m/z 230.0914 (M+H, C12H12N3O2 requires 230.0930). 1H NMR (DMSO-d6+TFA/300 MHz): 7.42 (d, 1H); 6.68-6.60 (m, 2H); 2.90-2.70 (m, 4H).

[0583] Anal. Calcd for C12H11N3O2 (0.2H2O): C, 61.90; H, 4.94; N, 18.05. Found: C, 62.07; H, 4.87; N, 18.25.

EXAMPLE 33

[0584] This example illustrates the production of ethyl 7-hydroxy-2-methyl-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate.

985

[0585] To ethyl (6-hydroxy-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)(oxo)acetate (2.6 g, 0.01 mol) in glacial acetic acid (25 mL) was added dropwise methyl hydrazine (0.638 mL, 0.012 mol) in glacial acetic acid (5 mL). Contents were stirred overnight, diluted with water (100 mL) and a yellow solid (2.5 g) was filtered. Analysis of the solid by LC/MS shows two isomers (74:26). The solid was triturated with methanol (75 mL) and filtered to give the desired isomer as light yellow solid, 1.5 g (56% yield). The methanol filtrate was worked up below in Example 12 to obtain the other isomer. FABHRMS m/z 273.1217 (M+H, C15H16N2O3 requires 273.1239).

[0586] Anal. Calcd for C15H16N2O3: C, 66.16; H, 5.92; N, 10.29. Found: C, 65.97; H, 5.78; N, 10.15.

EXAMPLE 34

[0587] This example illustrates the production of 7-hydroxy-2-methyl-4,5-dihydro-2H-benzo[g]indazole-3-carboxamide.

986

[0588] 7-hydroxy-2-methyl-4,5-dihydro-2H-benzo[g]indazole-3-carboxamide was prepared according to the procedure for the production of 8-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxamide FABHRMS m/z 244.1076 (M+H, C13H14N3O2 requires 244.1086).

[0589] Anal. Calcd for C13H13N3O2 (0.4H2O): C, 62.34; H, 5.55; N, 16.78. Found: C, 62.22; H, 4.93; N, 6.74.

EXAMPLE 35

[0590] This example illustrates the production of 7-hydroxy-2-methyl-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid.

987

[0591] 7-hydroxy-2-methyl-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid was prepared according to the procedure of 7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid to give the desired as a white solid (98% yield). FABHRMS m/z 245.0906 (M+H, C13H13N2O3 requires 245.0926). 1H NMR (DMSO-d6/300 MHz): 9.70 (s, 1H); 7.55 (d, 1H); 6.80-6.70 (m, 2H); 2.95-2.75 (m, 4H).

[0592] Anal. Calcd for C13H12N2O3 (0.3H2O): C, 62.54; H, 5.09; N, 11.22. Found: C, 62.37; H, 4.86; N, 11.19.

EXAMPLE 36

[0593] This example illustrates the production of ethyl 7-hydroxy-1-methyl-4,5-dihydro-1H-benzo[g]indazole-3-carboxylate.

988

[0594] The methanol filtrate from ethyl 7-hydroxy-2-methyl-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate was concentrated in vacuo. The residue was filtered through a pad of silica gel, eluting with 25% EtOAc/hexanes to give a solid (450 mg). The solid was recrystallized from EtOAc/MeOH gave the desired isomer as a white solid, 275 mg (10% yield). FABHRMS m/z 273.1216 (M+H, C15H17N2O3 requires 273.1239).

[0595] Anal. Calcd for C15H16N2O3: C, 66.16; H, 5.92; N, 10.29. Found: C, 65.78; H, 6.07; N, 10.30.

EXAMPLE 37

[0596] This example illustrates the production of 7-hydroxy-1-methyl-4,5-dihydro-1H-benzo[g]indazole-3-carboxamide.

989

[0597] 7-hydroxy-1-methyl-4,5-dihydro-1H-benzo[g]indazole-3-carboxamide was prepared according to the procedure for the production of 8-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxamide to give the desired product as a light tan solid (59% yield). FABHRMS m/z 244.1084 (M+H, C13H14N3O2 requires 244.1086).

[0598] Anal. Calcd for C13H13N3O2 (H2O): C, 59.68; H, 5.86; N, 16.34. Found: C, 59.64; H, 5.92; N, 16.35.

EXAMPLE 38

[0599] This example illustrates the production of 7-hydroxy-N-methyl-4,5-dihydro-2H-benzo[g]indazole-3-carboxamide.

990

[0600] 7-hydroxy-N-methyl-4,5-dihydro-2H-benzo[g]indazole-3-carboxamide was prepared according to the procedure for the production of 8-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxamide, using 40% aqueous methyl amine to give the desired as an off-white solid (93% yield). FABHRMS m/z 244.1069 (M+H, C13H14N3O2 requires 244.1086).

[0601] Anal. Calcd for C13H13N3O2 (0.2H2O): C, 63.25; H, 5.47; N, 17.02. Found: C, 63.02; H, 5.79; N, 17.01.

EXAMPLE 39

[0602] This example illustrates the production of 2-amino-3-methoxy-5,6,8,9,10,11-hexahydro-7H-benzo[g][1,4]diazepino[1,2-b]indazol-7-one,

991

[0603] ESHRMS m/z 299.148 (M+H, C16H18N4O2 requires 299.150).

EXAMPLE 40

[0604] This example illustrates the production of 6-methoxy-2,4-dihydroindeno[1,2-c]pyrazole-3-carboxylic acid,

992

[0605] ESHRMS m/z 231.073 (M+H, C12H10N2O3 requires 231.076).

EXAMPLE 41

[0606] This example illustrates the production of, methyl 2-{3-[(tert-butoxycarbonyl)amino]propyl}-6-methoxy-2,4-dihydroindeno[1,2-c]pyrazole-3-carboxylate

993

[0607] ESHRMS m/z 444.250 (M+H, C24H33N3O5 requires 444.249).

EXAMPLE 42

[0608] This example illustrates the production of 7-methoxy-2,4-dihydroindeno[1,2-c]pyrazole-3-carboxylic acid.

994

[0609] ESHRMS m/z 231.078 (M+H, C12H10N2O3 requires 231.076).

EXAMPLE 43

[0610] This example illustrates the production of methyl 7-hydroxy-2,4-dihydroindeno[1,2-c]pyrazole-3-carboxylate.

995

[0611] ESHRMS m/z 231.076 (M+H, C12H10N2O3 requires 231.076).

EXAMPLE 44

[0612] This example illustrates the production of 7-hydroxy-2,4-dihydroindeno[1,2-c]pyrazole-3-carboxylic acid,

996

[0613] ESHRMS m/z 217.062 (M+H, C11H8N2O3 requires 217.061).

EXAMPLE 45

[0614] This example illustrates the production of methyl 2-{3-[(tert-butoxycarbonyl)amino]propyl}-7-methoxy-2,4-dihydroindeno[1,2-c]pyrazole-3-carboxylate,

997

[0615] ESHRMS m/z 402.203 (M+H, C21H27N3O5 requires 402.202).

EXAMPLE 46

[0616] This example illustrates the production of tert-butyl 2-{3-[(tert-butoxycarbonyl)amino]propyl}-7-methoxy-2,4-dihydroindeno[1,2-c]pyrazole-3-carboxylate,

998

[0617] ESHRMS m/z 444.248 (M+H, C24H23N3O5 requires 444.249).

EXAMPLE 47

[0618] This example illustrates the production of 7-methoxy-2,5-dihydroisothiochromeno[4,3-c]pyrazole-3-carboxylic acid,

999

[0619] ESHRMS m/z 263.046 (M+H, C12H10N2O3S requires 263.048).

EXAMPLE 48

[0620] This example illustrates the production of methyl 7-methoxy-5-[(4-methylphenyl)sulfonyl]-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline-3-carboxylate,

1000

[0621] ESHRMS m/z 414.115 (M+H, C20H19N3O5S requires 414.112).

EXAMPLE 49

[0622] This example illustrates the production of 2-bromo-3-methoxy-9-methyl-5,6,9,10-tetrahydrobenzo[g]pyrazino[1,2-b]indazol-7(8H)-one,

1001

[0623] ESHRMS m/z 362.047 (M+H, C16H16N3O2Br requires 362.050).

EXAMPLE 50

[0624] This example illustrates the production of 2-bromo-3-hydroxy-9-methyl-5,6,9,10-tetrahydrobenzo[g]pyrazino[1,2-b]indazol-7(8H)-one,

1002

[0625] ESHRMS m/z 348.033 (M+H, C15H14N3O2Br requires 348.034).

EXAMPLE 51

[0626] This example illustrates the production of methyl 2-{3-[(tert-butoxycarbonyl)amino]propyl}-8-(sec-butylamino)-7-methoxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate,

1003

[0627] ESHRMS m/z 487.288 (M+H, C26H38N4O5 requires 487.291).

EXAMPLE 52

[0628] This example illustrates the production of methyl 8-amino-2-(3-aminopropyl)-7-methoxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate hydrochloride,

1004

[0629] ESHRMS m/z 331.176 (M+H, C17H22N4O3 requires 331.176).

EXAMPLE 53

[0630] This example illustrates the production of (7-methoxy-4,5-dihydro-2H-benzo[g]indazol-3-yl)methanol,

1005

[0631] ESHRMS m/z 231.109 (M+H, C13H14N2O2 requires 231.113).

EXAMPLE 54

[0632] This example illustrates the production of ethyl 7-hydroxy-1-(4-methoxyphenyl)-4,5-dihydro-1H-benzo[g]indazole-3-carboxylate.

1006

[0633] FABHRMS m/z 365.1514 (M+H, C21H21N2O4 requires 365.1496).

EXAMPLE 55

[0634] This example illustrates the production of ethyl 7-hydroxy-1-phenyl-4,5-dihydro-1H-benzo[g]indazole-3-carboxylate,

1007

[0635] FABHRMS m/z 335.1384 (M+H, C20H19N2O3 requires 335.1396).

EXAMPLE 56

[0636] This example illustrates the production of 6-bromo-7-hydroxy-2H-benzo[g]indazole-3-carboxamide,

1008

[0637] FABHRMS m/z 305.9880 (M+H, C12H9BrN3O2 requires 305.9873).

EXAMPLE 57

[0638] This example illustrates the production of 7-hydroxy-1-(4-methoxyphenyl)-4,5-dihydro-1H-benzo[g]indazole-3-carboxamide,

1009

[0639] FABHRMS m/z 336.1347 (M+H, C19H18N3O3 requires 336.1348).

EXAMPLE 58

[0640] This example illustrates the production of 7-hydroxy-1-phenyl-4,5-dihydro-1H-benzo[g]indazole-3-carboxamide,

1010

[0641] FABHRMS m/z 306.1248 (M+H, C18H16N3O2 requires 306.1243).

EXAMPLE 59

[0642] This example illustrates the production of 7-hydroxy-N,N-dimethyl-4,5-dihydro-2H-benzo[g]indazole-3-carboxamide,

1011

[0643] FABHRMS m/z 258.1268 (M+H, C14H16N3O2 requires 258.1243).

EXAMPLE 60

[0644] This example illustrates the production of 7,8-dihydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid.

1012

[0645] To boron tribromide (1.7 mL) in CH2Cl2 (25 mL) at −78° C. was added ethyl 7,8-dimethoxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate (1.8 g, 0.006 mol) in CH2Cl2 (25 mL). Contents were stored at 0° C. overflight and poured into ice water. Contents were heated on a steam bath to evaporate the CH2Cl2 and filtered to give a red solid. Recrystallization from EtOAc/MeOH gave the diketo-acid as an orange solid, 727 mg (49% yield). FABHRMS m/z 249.0425 (M+H, C12H11O6 requires 249.0399). 1H NMR (DMSO-d6+TFA/300 MHz): 7.30 (s, 1H); 6.60 (s, 1H); 2.65 (s, 4H). Anal. Calcd for C12H10O6: C, 57.60; H, 4.03. Found: C, 57.63; H, 4.14. To the diketo-acid (500 mg, 0.002 mol) in glacial acetic acid (20 mL) was added hydrazine monohydrate (0.218 mL, 0.0045 mol). Contents were stirred overnight, added water and filtered a white solid, to give the desired product, 40 mg (8% yield). FABHRMS m/z 247.0729 (M+H, C12H11N2O4 requires 247.0719). 1H NMR (DMSO-d6+TFA/300 MHz): 7.10 (s, 1H); 6.63 (s, 1H); 2.90-2.81 (m, 2H); 2.78-2.65 (m, 2H).

[0646] Anal. Calcd for C12H10N2O4 (0.6H2O): C, 56.08; H, 4.39; N, 10.90. Found: C, 56.03; H, 4.12; N, 10.73.

EXAMPLE 61

[0647] This example illustrates the production of ethyl 6-bromo-7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate,

1013

[0648] 5-bromo-6-hydroxy-1-tetralone [Bioorg & Med Chem Lett 7(12) 1573-1576 (1997)] was reacted according to the procedure for the production of ethyl (7-hydroxy-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)(oxo)acetate to give the desired diketo-ester intermediate (51% yield). The diketo-ester intermediate was reacted according to the procedure for the production of ethyl 8-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate to give the desired product as yellow crystals (38% yield). FABHRMS m/z 337.0175, 339.0169 (M+H, C14H14BrN2O3 requires 337.0188, 339.0169). 1H NMR (DMSO-d6+TFA/300 MHz): 7.58 (d, 1H); 6.90 (d, 1H); 4.30 (q, 2H); 3.05-2.90 (m, 4H); 1.30 (t, 3H).

[0649] Anal. Calcd for C14H13BrN2O3: C, 49.87; H, 3.89; N, 8.31. Found: C, 51.44; H, 4.65; N, 7.28

EXAMPLE 62

[0650] This example illustrates the production of 6-bromo-7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxamide,

1014

[0651] Ethyl 6-bromo-7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate was reacted according to the procedure for the production of 8-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxamide to give the desired product as an off-white solid (62% yield). FABHRMS m/z 310.0020 (M+H, C12H11BrN3O2 requires 310.0010). 1H NMR (DMSO-d6+TFA/300 MHz): 7.55 (d, 1H); 6.92 (d, 1H); 3.10-2.90 (m, 4H).

[0652] Anal. Calcd for C12H10BrN3O2 (0.6H2O): C, 45.19; H, 3.54; N, 13.17. Found: C, 45.00; H, 3.48; N, 13.09.

EXAMPLE 63

[0653] This example illustrates the production of 7-hydroxy-N-(2-hydroxyethyl)-4,5-dihydro-2H-benzo[g]indazole-3-carboxamide,

1015

[0654] 7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid (2.0 g, 0.0077 mol), ethanolamine (5 mL), water (5 mL) and methanol (5 mL) were stirred in a stoppered flask overnight. Contents were concentrated in vacuo and the residue was filtered through a pad of silica gel, eluting with EtOAc to give the desired as an oil. The oil was crystallized under methanol to give white crystals, 664 mg (32% yield). FABHRMS m/z 274.1152 (M+H, C14H16N3O3 requires 274.1186).

[0655] Anal. Calcd for C14H15N3O3: C, 61.53; H, 5.53; N, 15.38. Found: C, 61.45; H, 5.62; N, 15.35.

EXAMPLE 64

[0656] This example illustrates the production of ethyl 2-(3-aminopropyl)-7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate dihydrochloride,

1016

[0657] Ethyl 7-[(2-methoxyethoxy)methoxy]-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate was reacted according to the procedure for the production of ethyl 2-(3-aminopropyl)-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate dihydrochloride to give an oil, which was mixed with 4N HCl in dioxane and filtered to give the desired product as a white solid. FABHRMS m/z 316.1658 (M+H, C17H22N3O3 requires 316.1656). 1H NMR (DMSO-d6+5%TFA/300 MHz): 8.00 (br s, 1H); 7.80 (br s, 2H); 7.5 (d, 1H); 6.62 (s, 1H); 6.60 (d, 1H); 4.60-4.50 (m, 2H); 4.25 (q, 2H); 2.90-2.70 (m, 4H); 2.10-2.00 (m, 2H); 1.30 (t, 3H).

[0658] Anal. Calcd for C17H21N3O3(2H2O): C, 48.12; H, 6.41; N, 9.90. Found: C, 48.00; H, 6.53; N, 10.89.

EXAMPLE 65

[0659] This example illustrates the production of 2-{3-[(tert-butoxycarbonyl) amino]propyl}-7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid,

1017

[0660] To ethyl 2-(3-aminopropyl)-7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate dihydrochloride (15.2 g, 0.04 mol) and di-t-butyl-dicarbonate (24.3 g) in CH2Cl2 was added triethylamine (10 mL) dropwise. Contents were stirred overnight, washed with water and the CH2Cl2 layer was dried over MgSO4 and concentrated in vacuo leaving the intermediate Boc ester as a light yellow oil, 25.4 g. The intermediate Boc ester was reacted according to the procedure of 7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid to give the desired as a white solid (58% yield). FABHRMS m/z 388.1883 (M+H, C20H26N3O5 requires 388.1867). 1H NMR (DMSO-d6+5%TFA/300 MHz): 9.45 (s, 1H); 7.55 (d, 1H); 7.83 (br s, 1H); 6.70 (s, 1H); 6.65 (d, 1H); 4.49 (t, 2H); 3.00-2.80 (m, 6H); 2.00-1.80 (m, 2H); 1.40 (s, 9H).

[0661] Anal. Calcd for C20H25N3O5 (0.2H2O): C, 61.43; H, 6.55; N, 10.75. Found: C, 61.35; H, 6.76; N, 10.47.

EXAMPLE 66

[0662] This example illustrates the production of 2-(3-aminopropyl)-7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid dihydrochloride,

1018

[0663] 2-{3-[(tert-butoxycarbonyl)amino]propyl}-7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid (702 mg, 0.002 mol) and 4N HCl in dioxane (20 mL) were stirred overnight, diluted with EtOAc and filtered to give the desired product as a white solid, 608 mg (94% yield). FABHRMS m/z 288.1367 (M+H, C15H18N3O3 requires 288.1343). 1H NMR (DMSO-d6+5%TFA/300 MHz): 7.90 (br s, 3H); 7.52 (d, 1H); 6.70 (s, 1H); 6.65 (d, 1H); 4.60 (t, 2H); 3.00-2.80 (m, 4H); 2.10 (t, 2H).

[0664] Anal. Calcd for C15H17N3O3 (2.3 HCl): C, 48.54; H, 5.24; N, 11.32. Found: C, 48.53; H, 5.82; N, 11.78.

EXAMPLE 67

[0665] This example illustrates the production of 7-hydroxy-1-methyl-4,5-dihydro-1H-benzo[g]indazole-3-carboxylic acid,

1019

[0666] Ethyl 7-hydroxy-1-methyl-4,5-dihydro-1H-benzo[g]indazole-3-carboxylate was reacted according to the procedure of 7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid to give the desired product as a white solid (95% yield). FABHRMS m/z 245.0896 (M+H, C13H13N2O3 requires 245.0921). 1H NMR (DMSO-d6/300 MHz): 7.50 (d, 1H); 6.70 (s, 1H); 6.68 (d, 1H); 4.10 (s, 3H); 2.95-2.75 (m, 4H).

[0667] Anal. Calcd for C13H12N2O3 (1.3H2O): C, 58.33; H, 5.50; N, 10.47. Found: C, 58.36; H, 5.09; N, 10.41.

EXAMPLE 68

[0668] This example illustrates the production of ethyl 7-hydroxy-2H-benzo[g]indazole-3-carboxylate,

1020

[0669] 7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid (5.0 g, 0.02 mol) and DDQ (5.5 g, 0.025 mol) were stirred in dioxane (30 mL) for 72 hours. A solid was filtered (by-product) and the filtrate was concentrated in vacuo leaving an amber solid. The solid was recrystallized from methanol to give the desired product as a light amber solid, 246 mg. More desired product was recovered from the methanol filtrate, 1.1 g (26% total yield). FABHRMS m/z 257.0891 (M+H, C14H13N2O3 requires 257.0921). 1H NMR (DMSO-d6/300 MHz): 9.98 (s, 1H); 8.38 (d, 1H); 7.95 (d, 1H); 7.55 (d, 1H); 7.35 (s, 1H); 7.22 (d, 1H); 4.40 (q, 2H); 1.40 (t, 3H).

[0670] Anal. Calcd for C14H12N2O3 (0.7H2O): C, 62.54; H, 5.02; N, 10.42. Found: C, 62.84; H, 4.69; N, 10.39.

EXAMPLE 69

[0671] This example illustrates the production of 3-hydroxy-5,6,8,9,10,11-hexahydro-7H-benzo[g][1,4]diazepino[1,2-b]indazol-7-one,

1021

[0672] Ethyl 2-(3-aminopropyl)-7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate dihydrochloride was reacted according to the procedure for the production of 8-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxamide to give the desired product as a light amber solid (46% yield). FABHRMS m/z 270.1209 (M+H, C15H16N3O2 requires 270.1237). 1H NMR (DMSO-d6+5%TFA/300 MHz): 8.19 (br s, 1H); 7.50 (d, 1H); 6.68 (s, 1H); 6.62 (d, 1H); 5.75 (s, 1H); 4.40 (t, 2H); 3.24-3.15 (m, 2H); 2.80 (s, 4H); 2.20-2.05 9 (m, 2H).

[0673] Anal. Calcd for C15H15N3O2 (HCl): C, 58.92; H, 5.27; N, 13.74. Found: C, 59.10; H, 5.18; N, 13.46.

EXAMPLE 70

[0674] This example illustrates the production of 7-hydroxy-2H-benzo[g]indazole-3-carboxylic acid,

1022

[0675] Ethyl 7-hydroxy-2H-benzo[g]indazole-3-carboxylate was reacted according to the procedure of 7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid to give the desired product as a white solid (95% yield). FABHRMS m/z 229.0616 (M+H, C12H9N2O3 requires 229.0608). 1H NMR (DMSO/300 MHz): 9.95 (br s, 1H) 8.35 (d, 1H); 7.95 (d, 1H); 7.50 (d, 1H); 7.30 (s, 1H); 7.22 (d, 1H).

[0676] Anal. Calcd for C12H8N2O3 (H2O): C, 58.54; H, 4.09; N, 11.38. Found: C, 58.07; H, 4.08; N, 11.32.

EXAMPLE 71

[0677] This example illustrates the production of 7-hydroxy-2H-benzo[g]indazole-3-carboxamide,

1023

[0678] Ethyl 7-hydroxy-2H-benzo[g]indazole-3-carboxylate was reacted according to the procedure for the production of 8-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxamide to give the desired product (62% yield). FABHRMS m/z 228.0786 (M+H, C12H10N3O2 requires 228.0768). 1H NMR (DMSO-d6+TFA/300 MHz): 8.32 (d, 1H); 8.03 (d, 1H); 7.40 (d, 1H); 7.28 (s, 1H); 7.20 (d, 1H).

[0679] Anal. Calcd for C12H9N3O2 (0.25H2O): C, 62.20; H, 4.13; N, 18.13. Found: C, 62.67; H, 4.05; N, 17.69.

EXAMPLE 72

[0680] This example illustrates the production of ethyl [6-(acetylamino)-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl](oxo)acetate,

1024

[0681] Ethyl [6-(acetylamino)-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl](oxo)acetate was prepared according to the procedure for the production of ethyl (7-hydroxy-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)(oxo)acetate using 6-(acetylamino)-1-tetralone to give the desired product as yellow crystals (42% yield). FABHRMS m/z 304.1216 (M+H, C16H19NO5 requires 304.1185).

[0682] Anal. Calcd for C16H17NO5: C, 63.36; H, 5.65; N, 4.62. Found: C, 63.47; H, 5.46; N, 4.46.

EXAMPLE 73

[0683] This example illustrates the production of ethyl 7-(acetylamino)-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate,

1025

[0684] Ethyl [6-(acetylamino)-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl](oxo)acetate was reacted according to the procedure for ethyl 8-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate to give the desired product as a yellow solid (41% yield). FABHRMS m/z 300.1347 (M+H, C16H18N3O3 requires 300.1348).

[0685] Anal. Calcd for C16H17N3O3 (0.5H2O): C, 62.31; H, 5.55; N, 13.64. Found: C, 62.31; H, 5.55; N, 13.64.

EXAMPLE 74

[0686] This example illustrates the production of 7-(acetylamino)-4,5-dihydro-2H-benzo[g]indazole-3-carboxamide,

1026

[0687] Ethyl 7-(acetylamino)-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate was reacted according to the procedure for the production of 8-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxamide to give the desired product as a white solid (76% yield). FABHRMS m/z 271.1208 (M+H, C14H15N4O2 requires 271.1195).

[0688] Anal. Calcd for C14H14N4O2: C, 62.21; H, 5.22; N, 20.73. Found: C, 62.27; H, 5.25; N, 20.62.

EXAMPLE 75

[0689] This example illustrates the production of 7-amino-4,5-dihydro-2H-benzo[g]indazole-3-carboxamide,

1027

[0690] 7-(acetylamino)-4,5-dihydro-2H-benzo[g]indazole-3-carboxamide (318 mg, 0.0012 mol) and 1N HCl (20 mL) were refluxed in MeOH (10 mL) overnight giving a mixture of amide and methyl ester. The contents were concentrated in vacuo and mixed with conc ammonium hydroxide (20 mL) and MeOH (5 mL), and stirred in a stoppered flask for 72 hours. Contents were poured into a beaker to let the volatiles evaporate and filtered to give the desired product as a light tan solid, 205 mg (75% yield). FABHRMS m/z 229.1106 (M+H, C12H13N4O requires 229.1089).

[0691] Anal. Calcd for C12H12N4O (0.25H2O): C, 61.92; H, 5.41; N, 24.07. Found: C, 62.24; H, 5.2; N, 23.73.

EXAMPLE 76

[0692] This example illustrates the production of 3-ethyl 7-methyl 4,5-dihydro-2H-benzo[g]indazole-3,7-dicarboxylate.

1028

[0693] 3-ethyl 7-methyl 4,5-dihydro-2H-benzo[g]indazole-3,7-dicarboxylate was prepared according to the procedures for the production for the production of ethyl (7-hydroxy-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)(oxo)acetate and for the production of ethyl 8-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate, starting with 6-carboxymethyltetralone [Tet. Lett 33(38) 5499 1992] to give the desired product as an off-white solid (47% yield). FABHRMS m/z 301.1192 (M+H, C16H17N2O4 requires 301.1188). 1H NMR (CDCl3/300 MHz): 8.20 (brs, 1H); 7.99 (s, 3H); 4.40 (q, 2H); 3.15-3.00 (m, 4H); 1.45 (t, 3H).

[0694] Anal. Calcd for C16H16N2O4: C, 63.99; H, 5.37; N, 9.33. Found: C, 63.73; H, 5.25; N, 9.29.

EXAMPLE 77

[0695] This example illustrates the production of 4,5-dihydro-2H-benzo[g]indazole-3,7-dicarboxamide.

1029

[0696] 3-ethyl 7-methyl 4,5-dihydro-2H-benzo[g]indazole-3,7-dicarboxylate was reacted according to the procedure for the production of 8-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxamide to give the desired product as a pale yellow solid (54% yield). FABHRMS m/z 257.1015 (M+H, C13H13N4O2 requires 257.1039). 1H NMR (DMSO-d6/300 MHz): 7.83-7.68 (m, 3H); 7.30 (br s, 2H); 2.95 (s, 4H).

[0697] Anal. Calcd for C13H13N4O2 (0.1H2O): C, 60.51; H, 4.77; N, 21.71. Found: C, 60.56; H, 4.57; N, 21.35.

EXAMPLE 78

[0698] This example illustrates the production of 7-(aminocarbonyl)-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid.

1030

[0699] 7-(aminocarbonyl)-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid was a side product in the preparation of 4,5-dihydro-2H-benzo[g]indazole-3,7-dicarboxamide obtained as a second crop from the aqueous filtrate to give desired product as a white solid. FABHRMS m/z 258.0883 (M+H, C13H12N3O3 requires 258.0873).

[0700] Anal. Calcd for C13H11N3O3(0.7H2O): C, 57.86; H, 4.63; N, 15.57. Found: C, 57.92; H, 4.71; N, 15.65.

EXAMPLE 79

[0701] This example illustrates the production of 4,5-dihydro-2H-benzo[g]indazole-3,7-dicarboxylic acid.

1031

[0702] 3-ethyl 7-methyl 4,5-dihydro-2H-benzo[g]indazole-3,7-dicarboxylate was reacted according to the procedure of that for the production of 7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid to give the desired product as a white solid (64% yield). FABHRMS m/z 259.0737 (M+H, C13H11N2O4 requires 259.0719).

[0703] Anal. Calcd for C13H10N2O4(0.55H2O): C, 58.23; H, 4.17; N, 10.45. Found: C, 58.54; H, 4.68; N, 10.12.

EXAMPLE 80

[0704] This example illustrates the production of ethyl (6,7-dimethoxy-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)(oxo)acetate.

1032

[0705] 6,7-dimethoxy-1-tetralone was reacted according to the procedure for the production of ethyl (7-hydroxy-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)(oxo)acetate to give the desired product as a yellow solid (86% yield). FABHRMS m/z 307.1185 (M+H, C16H19O6 requires 307.1182). 1H NMR (CDCl3/300 MHz): 7.50 (s, 1H); 6.65 (s, 1H); 4.40 (q, 2H); 3.92 (s, 3H); 3.94 (s, 3H); 3.05-2.80 (m, 4H); 1.4 (t, 3H).

[0706] Anal. Calcd for C16H18O6: C, 62.74; H, 5.92. Found: C, 62.54; H, 5.83.

EXAMPLE 81

[0707] This example illustrates the production of ethyl 7,8-dimethoxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate.

1033

[0708] Ethyl 6,7-dimethoxy-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl](oxo)acetate was reacted according to the procedure for the production of ethyl 8-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate to give the desired product as a light amber solid (67% yield). FABHRMS m/z 303.1334 (M+H, C16H19N2O4 requires 303.1345). 1H NMR (CDCl3/300 MHz): 7.40 (s, 1H); 6.78 (s, 1H); 4.40 (q, 2H); 3.95 (s, 3H); 3.90 (s, 3H); 3.05-2.85 (m, 4H); 1.40 (t, 3H).

[0709] Anal. Calcd for C16H18N2O4: C, 63.56; H, 6.00; N, 9.27. Found: C, 63.63; H, 5.97; N, 9.19.

EXAMPLE 82

[0710] This example illustrates the production of 2-(3-Aminopropyl)-7-hydroxy-4-methyl-2H-benzo[g]indazole-3-carboxylic acid trifluoroacetate.

1034

[0711] Step 1: Preparation of 2-methyl-7-methoxytetralone.

1035

[0712] In a 1L 3-neck flask under Ar, lithium bis(TMS) amide (192 mL, 192 mmol of a 1.0 M solution in THF) was cooled to 0° C. 7-Methoxy tetralone (50.0 g, 284 mmol) dissolved in THF (200 mL) was added via addition funnel over one hour. Stirred at 0° C. for 30 minutes. In a 2L 3-neck flask, iodomethane (109 g, 768 mmol) was cooled to −78° C. The contents of the 1L flask were added to the 2L flask via cannula. Stirred at −78° C. for two hours. The reaction was quenched with NH4Cl (aq.). Extracted with ethyl acetate (2×300 mL). The organic phases were combined, washed with brine, dried over MgSO4, filtered, and evaporated to yield a dark brown oil. Purified by flash column chromatography in 3% ethyl acetate/97% hexane. (30.25 g, 83%): 1H NMR (CDCl3/300 MHz) 7.52 (d, 1H), 7.14 (d, 1H), 7.05 (dd, 1H), 3.83 (s, 3H), 3.01-2.87 (m, 2H), 2.61-2.53 (m, 1H), 2.22-2.14 (m, 1H), 1.92-1.83 (m, 1H), 1.22 (d, 3H). ESHRMS m/z 191.1092 (M+H, C12H14O2 requires 191.1067).

[0713] Step 2: Preparation of 2-ethyl-7-methoxy-1,2,3,4-tetrahydronaphthalene.

1036

[0714] 2-Methyl-7-methoxytetralone (29.14 g, 153 mmol) was dissolved in CH2Cl2 (150 mL). Triethylsilane (35.5 g, 306 mmol was added and the reaction was cooled to 0° C. Trifluoroacetic acid (175 mL, 1.53 mol) was slowly added via addition funnel. The ice bath was removed and the reaction stirred at room temperature overnight. Dichloromethane and trifluoroacetic acid were evaporated. Sodium bicarbonate (aq.) was added to consume any remaining trifluoroacetic acid. Extracted with dichloromethane (2×200 mL). The combined organic phases were washed with brine, dried over MgSO4, filtered, and evaporated. Purified by flash column chromatography in hexane. (14.67 g, 54%): 1H NMR (CDCl3/300 MHz) 6.98 (d, 1H), 6.65 (dd, 1H), 6.59 (s, 1H), 3.76 (s, 3H), 2.82-2.75 (m, 3H), 2.42-2.33 (m, 1H), 1.87-1.76 (m, 2H), 1.42-1.33 (m, 1H), 1.04 (d, 3H). GCHRMS (m/z) 176.1189 (M+H C12H16O, requires 176.1201).

[0715] Step 3: Preparation of 6-methoxy-3-methyl-3,4-dihydronaphthalen-1 (2H)-one.

1037

[0716] 2-Ethyl-7-methoxy-1,2,3,4-tetrahydronaphthalene (10.8 g, 61.3 mmol) was dissolved in acetic acid (200 mL). Chromium trioxide (12.25 g, 122 mmol) was slowly added in small portions over two hours. The reaction mixture was heated to 90° C. for four hours and stirred at room temperature overnight. Acetic acid was evaporated. The remaining residue was neutralized with sodium bicarbonate (aq.). Extracted with ethyl acetate (2×200 mL). The combined organic phases were washed with brine, dried over MgSO4, filtered, and evaporated. Purified by flash column chromatography in 10% ethyl acetate/90% hexane. The resulting solid was recrystallized from hexane (5.00 g 43%): mp 70.5-70.6° C. 1H NMR (CDCl3/300 MHz) 8.00 (d, 1H), 6.82 (dd, 1H), 6.70 (s, 1H), 3.85 (s, 3H), 2.95-2.89 (m, 1H), 2.71-2.61 (m, 2H), 2.30-2.19 (m, 2H), 1.13 (d, 3H). ESHRMS (m/z) 191.1073 (M+H, C12H14O2 requires 191.1067).

[0717] Step 4: Preparation of Methyl (2Z)-hydroxy(6-methoxy-3-methyl-1-oxo-3,4-dihydronaphthalen-2(1H)-ylidene)ethanoate.

1038

[0718] 6-Methoxy-3-methyl-3,4-dihydronaphthalen-1 (2H)-one (3.00 g, 15.8 mmol) was dissolved in ether (50 mL). Dimethyl oxalate (2.05 g, 17.4 mmol) and sodium methoxide (3.98 mL, 3.76 g, 17.4 mmol of a 25%/wt. solution in methanol) were added. Stirred at room temperature overnight and added 1 N HCl to pH=1. The solution was transferred to a separatory funnel and the layers were separated. The aqueous phase was washed with ethyl acetate (2×100 mL). The combined organic phases were washed with brine (200 mL), dried over MgSO4, filtered, and evaporated. The resulting brown solid was filtered through a plug of silica with 20% ethyl acetate/80% hexane to afford a dark yellow solid. (2.34 g, 54%) mp 89.0-89.6° C. 1H NMR (CDCl3/300 MHz) 16.13 (s, 1H), 7.98 (d, 1H), 6.87 (d, 1H), 6.72 (s, 1H), 3.92 (s, 3H), 3.88 (s, 3H), 3.52 (t, 1H), 3.15 (dd, 1H), 2.66-2.60 (m, 1H), 1.09 (d, 3H). ESHRMS (m/z) 277.1048 (M+H, C15H16O5 requires 277.1071).

[0719] Step 5: Preparation of Methyl 7-methoxy-4-methyl-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate.

1039

[0720] Methyl (2Z)-hydroxy(6-methoxy-3-methyl-1-oxo-3,4-dihydronaphthalen-2(1H)-ylidene)ethanoate (2.00 g, 7.34 mmol) was dissolved in methanol (50 mL). Hydrazine hydrochloride (0.553 g, 8.08 mmol was added. Stirred at reflux for two hours. Cooled to room temperature and neutralized with NaHCO3 (aq.). Water was added, resulting in formation of a precipitate. Filtered and washed with H2O. (1.84 g, 92%) mp 162.7-162.8° C.: 1H NMR (CDCl3/300 MHz) 7.73 (d, 1H), 6.84 (d, 1H), 6.82 (s, 1H), 3.95 (s, 3H), 3.83 (s, 3H), 3.53 (t, 1H), 3.20 (dd, 1H), 2.73-2.65 (m, 1H), 1.10 (d, 3H). ESHRMS (m/z) 273.1216 (M+H, C15H16N2O3 requires 273.1234).

[0721] Step 6: Preparation of 2-(3-Aminopropyl)-7-hydroxy-4-methyl-2H-benzo[g]indazole-3-carboxylic Acid Trifluoroacetate.

1040

[0722] Methyl 7-methoxy-4-methyl-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate (2.02 g, 7.42 mmol) was dissolved in CH2Cl2 (100 mL). A mixture of KMnO4/CuSO4.5H2O (1:1 by weight, 15.05 g, 37 mmol) was added. The reaction mixture was heated at reflux for 5 days. An additional 1 g of KMnO4/CuSO4.5H2O was added each day. The heating mantle was removed and ethanol (100 mL) was added to the reaction mixture. Stirred at room temperature for 30 minutes, then filtered through a plug of silica. The solvent was evaporated to yield a yellow solid. 15% of non-oxidized product present by analysis. (0.128 g, 6%). This mixture (0.128 g, 0.474 mmol) was dissolved in DMF (5 mL). Cooled to 0° C. in an ice-water bath. Lithium-t-butoxide (0.6 mL, 0.6 mmol of a 1.0 M solution in THF) was added via syringe. Stirred for one hour. Boc-3-bromopropylamine (0.0.135 g, 0.567 mmol) in DMF (5 mL) was added. The ice-bath was removed and the reaction stirred at room temperature for four hours. Quenched with NH4Cl (aq.) (20 mL), and the mixture was extracted with ethyl acetate (2×50 mL). The combined organic phases were washed with brine, dried over MgSO4, filtered, and evaporated to yield a orange solid, which was taken on with no further purification or isolation.

[0723] The ester (0.203 g, 0.474 mmol) was dissolved in a THF/ethanol/water mixture (10 mL, 7/2/1 respectively). Lithium hydroxide monohydrate (0.040 g, 0.948 mmol was added. Stirred overnight at room temperature. Diluted with ethyl acetate (50 mL) and extracted with 0.1N HCl (2×25 mL), and brine (25 mL). The organic phase was dried over MgSO4, filtered, and evaporated. The orange solid was taken to the next step with no further purfication or isolation.

[0724] The carboxylic acid (0.196 g, 0.474 mmol) was slurried in CH2Cl2 (10 mL). The mixture was cooled to −20° C. Boron tribromide (3 mL, 3 mmol of a 1.0 M solution in CH2Cl2) was added dropwise via syringe. The mixture stirred at room temperature for three hours. H2O was slowly added dropwise to quench the reaction. The solvent was evaporated and the resulting solid was purified by preparative reverse phase HPLC to yield a white solid (0.060 g): 1H NMR (DMSO tfa/300 MHz) 8.21 (d, 1H), 7.72 (s, 2H), 7.17 (s, 1H), 7.09-7.03 (m, 2H), 4.69 (t, 2H), 2.86 (t, 2H), 2.56 (s, 3H) 2.20(qt, 2H). ESHRMS (m/z) 300.1321 (M+H, C16H17N3O3 requires 300.1343).

EXAMPLE 83

[0725] This example illustrates the production of 2-(3-aminopropyl)-7-hydroxy-4-methyl-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid trifluoroacetate.

1041

[0726] Step 1: Preparation of 2-{3-[(tert-butoxycarbonyl)amino]propyl}-7-methoxy-4-methyl-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic Acid.

1042

[0727] Methyl 7-methoxy-4-methyl-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate (0.500 g, 1.84 mmol) was dissolved in DMF (5 mL). Cooled to 0° C. in an ice-water bath. Lithium-t-butoxide (2.2 mL, 2.2 mmol of a 1.0 M solution in THF) was added via syringe. Stirred for one hour. Boc-3-bromopropylamine (0.524 g, 2.2 mmol) in DMF (5 mL) was added. The ice-bath was removed and the reaction stirred at room temperature for four hours. Quenched with NH4Cl (aq.) (20 mL), and the mixture was extracted with ethyl acetate (2×50 mL). The combined organic phases were washed with brine, dried over MgSO4, filtered, and evaporated. Purified by flash column chromatography in 20% ethyl acetate/80% hexane. Obtained a slightly orange oil (0.53 g, 67%). The ester (0.517 g, 1.2 mmol) was dissolved in a THF/ethanol/water mixture (10 mL, 7/2/1 respectively). Lithium hydroxide monohydrate (0.100 g, 2.40 mmol was added. Stirred overnight at room temperature. Diluted with ethyl acetate (50 mL) and extracted with 0.1N HCl (2×25 mL), and brine (25 mL). The organic phase was dried over MgSO4, filtered, and evaporated. Recrystallized from ethyl acetate/hexane (0.345 g, 45%): 1H NMR (DMSO tfa/300 MHz) 7.61 (d, 1H), 6.86 (s, 1H), 6.84 (d, 2H), 4.43 (t, 2H), 3.76 (s, 3H), 3.44 (t, 1H), 3.09-2.92 (m, 3H), 2.72-2.65 (m, 1H), 1.87 (qt, 2H), 1.36 (s, 9H), 0.96 (d, 3H). ESHRMS m/z 416.2197 (M+H, C22H29N3O5 requires 416.2180).

[0728] Step 2: Preparation of 2-(3-aminopropyl)-7-hydroxy-4-methyl-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic Acid Trifluoroacetate.

1043

[0729] 2-{3-[(tert-butoxycarbonyl)amino]propyl}-7-methoxy-4-methyl-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid (0.200 g, 0.480 mmol) was slurried in CH2Cl2 (10 mL). The mixture was cooled to −20° C. Boron tribromide (5 mL, 5 mmol of a 1.0 M solution in CH2Cl2) was added dropwise via syringe. The mixture stirred at room temperature for three hours. Slowly added H2O dropwise to quench the reaction. The solvent was evaporated and the resulting solid was purified by preparative reverse phase HPLC to yield a white solid (0.079 g): 1H NMR (DMSO tfa/300 MHz) 7.72 (s, 2H), 7.50 (d, 1H), 6.68 (s, 1H), 6.65 (d, 1H), 4.52 (t, 2H), 3.42 (t, 1H), 3.04-2.97 (m, 1H), 2.85-2.75 (m, 2H), 2.64-2.49 (m, 1H), 2.05 (qt, 2H), 0.96 (d, 3H). ESHRMS (m/z) 302.1527 (M+H, C16H19N3O3 requires 302.1499).

EXAMPLE 84

[0730] This example illustrates the production of 2-(3-Aminopropyl)-7-hydroxy-5-methyl-2H-benzo[g]indazole-3-carboxylic acid trifluoroacetate.

1044

[0731] Step 1: Preparation of 6-methoxy-4-methyl-3,4-dihydronaphthalen-1 (2H)-one.

1045

[0732] A 2L three-necked round-bottomed flask was equipped with and overhead stirred and two rubber septa. The flask was cooled to 0° C., and charged with anhydrous Cerium (III) chloride 71 g, 288 mmol) and anhydrous THF (500 mL). Stirred overnight at room temperature. The flask was cooled to −78° C. Methyllithium (229 mL, 320 mmol of a 1.4 M solution in ether) was added via cannula. Stirred at −78° C. for 30 minutes, and 7-methoxy tetralone (50.0 g, 288 mmol) in THF (200 mL) was added via addition funnel. The cooling bath was removed and the reaction stirred at room temperature for three hours. Quenched with 5% acetic acid (300 mL). Extracted with ether (2×300 mL). The combined organic phases were washed with brine, dried over MgSO4, filtered, and evaporated. Obtained a pale orange oil, which contained a mixture of both the tertiary alcohol, and the alkene. (54 g). The mixture (52.23 g) was dissolved in dichloromethane (100 mL). Triethylsilane (63 g, 543 mmol) was added, and the solution was cooled to 0° C. Trifluoroacetic acid (208 mL) was slowly added via addition funnel. The ice bath was removed and the reaction stirred at room temperature overnight. Dichloromethane and trifluoroacetic acid were evaporated. Sodium bicarbonate (aq.) was added to consume any remaining trifluoroacetic acid. Extracted with dichloromethane (2×200 mL). The combined organic phases were washed with brine, dried over MgSO4, filtered, and evaporated. Purified by flash column chromatography in hexane. Obtained desired product with non-methylated impurity (20%). (37.43 g).

[0733] The mixture (8.31 g) was dissolved in acetic acid (60 mL). Chromium trioxide (9.43 g, 94.3 mmol) was slowly added in small portions over two hours. The reaction mixture was heated to 90° C. for four hours. Stirred at room temperature overnight and evaporated the acetic acid. The remaining residue was neutralized with sodium bicarbonate (aq.) and then extracted with ethyl acetate (2×200 mL). The combined organic phases were washed with brine, dried over MgSO4, filtered, and evaporated. Purified by flash column chromatography in 5% ethyl acetate/95% hexane. The resulting solid was recrystallized from hexane (3.96 g 44%): mp 57.5-58.5° C. 1H NMR (CDCl3/300 MHz) 8.02 (d, 1H), 6.82 (d, 1H), 6.78 (s, 1H), 3.87 (s, 3H), 3.08-3.02 (m, 1H), 2.77-2.52 (m, 2H), 2.26-2.19 (m, 1H), 1.92-1.86 (m, 1H), 1.39 d, 3H). ESHRMS (m/z) 191.1092 (M+H, C12H14O2 requires 191.1067).

[0734] Step 2: Preparation of Methyl 7-methoxy-5-methyl-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate,

1046

[0735] 6-Methoxy-4-methyl-3,4-dihydronaphthalen-1 (2H)-one (3.00 g, 15.8 mmol) was dissolved in ether (50 mL). Dimethyl oxalate (2.05 g, 17.4 mmol) and sodium methoxide (3.98 mL, 3.76 g, 17.4 mmol of a 25%/wt. solution in methanol) were added. Stirred at room temperature overnight. Added 1 N HCl to pH=1. The solution was transferred to a separatory funnel and the layers were separated. The aqueous phase was washed with ethyl acetate (2×100 mL). The combined organic phases were washed with brine (200 mL), dried over MgSO4, filtered, and evaporated. The resulting oil was filtered through a plug of silica with 20% ethyl acetate/80% hexane. Obtained an orange oil (3.48 g, 80%)

[0736] The oil (3.48 g, 12.6 mmol) was dissolved in methanol (50 mL). Hydrazine hydrochloride (0.95 g, 13.8 mmol was added. Stirred at reflux for two hours. Cooled to room temperature and neutralized with NaHCO3 (aq.). Water was added, resulting in formation of a precipitate. Filtered and washed with H2O. (2.23 g, 65%): 1H NMR (CDCl3/300 MHz) 7.76 (d, 1H), 6.86 (s, 1H), 6.82 (d, 1H), 3.95 (s, 3H), 3.85 (s, 3H), 3.14-3.01 (m, 2H), 2.97-2.84 (m, 2H), 1.25 (d, 3H). ESHRMS (m/z) 273.1215 (M+H, C15H16N2O3 requires 273.1234).

[0737] Step 3: Preparation of Methyl 7-methoxy-5-methyl-2H-benzo[g]indazole-3-carboxylate.

1047

[0738] Methyl 7-methoxy-5-methyl-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate (2.58 g, 9.49 mmol) was dissolved in CH2Cl2 (100 mL). A mixture of KMnO4/CuSO4.5H2O (1:1 by weight, 7.73 g, 19 mmol was added the reaction mixture was heated at reflux for 5 days. An additional 1 g of KMnO4/CuSO4.5H2O was added each day. The heating mantle was removed and ethanol (100 mL) was added to the reaction mixture. Stirred at room temperature for 30 minutes, then filtered through a plug of silica. The solvent was evaporated to yield a yellow solid. Trituration with CH2Cl2 removed any remaining starting material. (0.503 g, 20%): 1H NMR (CDCl3/300 MHz) 8.46 (d, 1H), 7.91 (s, 1H), 7.47-7.40 (m, 2H), 3.97 (s, 3H), 3.96 (s, 3H), 2.69 (s, 3H). ESHRMS (m/z) 271.1082 (M+H, C15H14N2O3 requires 271.1077).

[0739] Step 4: Preparation of Methyl 2-{3-[(tert-butoxy-carbonyl)amino]propyl}-7-methoxy-5-methyl-2H-benzo[g]indazole-3-carboxylate.

1048

[0740] Methyl 7-methoxy-5-methyl-2H-benzo[g]indazole-3-carboxylate (0.401 g, 1.48 mmol) was dissolved in DMF (10 mL). Cooled to 0° C. in an ice-water bath. Lithium-t-butoxide (3 mL, 3 mmol of a 1.0 M solution in THF) was added via syringe. Stirred for one hour. Boc-3-bromopropylamine (0.529 g, 2.22 mmol) in DMF (5 mL) was added. The ice-bath was removed and the reaction stirred at room temperature for four hours. Quenched with NH4Cl (aq.) (20 mL), and the mixture was extracted with ethyl acetate (2×50 mL). The combined organic phases were washed with brine, dried over MgSO4, filtered, and evaporated to yield a brown oil. Purified by flash column chromatography in 15% ethyl acetate/85% hexane. The resulting solid was recrystallized from ethanol/water. (0.350 g, 55%): 1H NMR (CDCl3/300 MHz) 8.55 (d, 1H), 7.73 (s, 1H), 7.35 (d, 1H), 7.28 (m, 1H), 5.14 (s, 1H), 4.94 (t, 2H), 4.06 (s, 3H), 3.97 (s, 3H), 3.12 (t, 2H), 2.66 (s, 3H), 2.16 (qt, 2H). ESHRMS (m/z) 428.2210 (M+H, C23H29N3O5 requires 428.2180).

[0741] Step 5: Preparation of 2-{3-[(tert-butoxy-carbonyl)-amino]propyl}-7-methoxy-5-methyl-2H-benzo[g]indazole-3-carboxylic Acid.

1049

[0742] Methyl 2-{3-[(tert-butoxy-carbonyl)amino]propyl}-7-methoxy-5-methyl-2H-benzo[g]indazole-3-carboxylate (0.320 g, 0.748 mmol was dissolved in a THF/ethanol/water mixture (10 mL, 7/2/1 respectively). Lithium hydroxide monohydrate (0.079 g, 1.9 mmol was added. Stirred overnight at room temperature. Diluted with ethyl acetate (50 mL) and extracted with 0.1N HCl (2×25 mL), and brine (25 mL). The organic phase was dried over MgSO4, filtered, and evaporated. The resulting white solid was recrystallized from ethyl acetate/hexane. (0.220 g, 71%): 1H NMR (DMSO tfa/300 MHz) 8.44 (d, 1H), 7.71 (d, 1H), 7.41 (d, 1H), 7.31 (dd, 1H), 6.95 (s, 1H), 4.84 (t, 2H), 3.94 (s, 3H), 3.00 (t, 2H), 2.63 (s, 3H), 2.04 (qt, 2H). ESHRMS (m/z) 414.2025 (M+H, C23H29N3O5 requires 414.2023).

[0743] Step 6: 2-(3-aminopropyl)-7-hydroxy-5-methyl-2H-benzo[g]indazole-3-carboxylic Acid Trifluoroacetate.

1050

[0744] 2-{3-[(tert-butoxy-carbonyl)amino]propyl}-7-methoxy-5-methyl-2H-benzo[g]indazole-3-carboxylic acid (0.175 g, 0.424 mmol) was slurried in CH2Cl2 (10 mL). The mixture was cooled to −20° C. Boron tribromide (4.5 mL, 4.5 mmol of a 1.0 M solution in CH2Cl2) was added dropwise via syringe. The mixture stirred at room temperature for three hours. Slowly added H2O dropwise to quench the reaction. The solvent was evaporated and the resulting solid was purified by preparative reverse phase HPLC to yield a white solid (0.060 g): 1H NMR (DMSO tfa/300 MHz) 8.35 (d, 1H), 7.73 (d, 3H), 7.31 (d, 1H), 7.18 (dd, 1H), 4.90 (t, 2H), 2.86 (t, 2H), 2.57 (s, 3H), 2.21 (qt, 2H). ESHRMS (m/z) 300.1347 (M+H, C16H17N3O3 requires 300.1343).

EXAMPLE 85

[0745] This example illustrates the production of 2-(3-aminopropyl)-7-hydroxy-5-methyl-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid trifluoroacetate.

1051

[0746] Step 1: Preparation of 2-{3-[(tert-butoxycarbonyl)amino]propyl}-7-methoxy-5-methyl-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic Acid.

1052

[0747] Methyl 7-methoxy-5-methyl-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate (1.00 g, 3.67 mmol) was dissolved in DMF (15 mL). Cooled to 0° C. in an ice-water bath. Lithium-t-butoxide (5.5 mL, 5.5 mmol of a 1.0 M solution in THF) was added via syringe. Stirred for one hour. Boc-3-bromopropylamine (1.31 g, 5.5 mmol) in DMF (15 mL) was added. The ice-bath was removed and the reaction stirred at room temperature for four hours. Quenched with NH4Cl (aq.) (50 mL), and the mixture was extracted with ethyl acetate (2×100 mL). The combined organic phases were washed with brine, dried over MgSO4, filtered, and evaporated. Purified by flash column chromatography in 15% ethyl acetate/85% hexane. Obtained a slightly orange oil. The ester (1.00 g, 2.33 mmol) was dissolved in a THF/ethanol/water mixture (10 mL, 7/2/1 respectively). Lithium hydroxide monohydrate (0.196 g, 4.66 mmol was added. Stirred overnight at room temperature. Diluted with ethyl acetate (50 mL) and extracted with 0.1N HCl (2×25 mL), and brine (25 mL). The organic phase was dried over MgSO4, filtered, and evaporated. Recrystallized from ethanol/water (0.734 g, 48%): 1H NMR (DMSO tfa/300 MHz) 7.65 (d, 1H), 6.90 (s, 1H), 6.87 (d, 1H), 4.49 (t, 2H), 3.79 (s, 3H), 2.99-2.79 (m, 5H), 1.93 (qt, 2H), 1.39 (s, 9H), 1.17 d, 3H). ESHRMS m/z 416.2179 (M+H, C22H29N3O5 requires 416.2180).

[0748] Step 2: Preparation of 2-(3-aminopropyl)-7-hydroxy-5-methyl-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic Acid Trifluoroacetate.

1053

[0749] 2-{3-[(tert-butoxycarbonyl)amino]propyl}-7-methoxy-5-methyl-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid (0.300 g, 0.722 mmol) was slurried in CH2Cl2 (10 mL). The mixture was cooled to −20° C. Boron tribromide (7 mL, 7 mmol of a 1.0 M solution in CH2Cl2) was added dropwise via syringe. The mixture stirred at room temperature for three hours. Slowly added H2O dropwise to quench the reaction. The solvent was evaporated and the resulting solid was purified by preparative reverse phase HPLC to yield a white solid (0.100 g): 1H NMR (DMSO tfa/300 MHz) 7.71 (s, 2H), 7.55 (d, 1H), 6.74 (s, 1H), 6.70 (d, 1H), 4.58 (t, 2H), 3.02-2.85 (m, 5H), 2.08 (qt, 2H), 1.15 (d, 3H). ESHRMS (m/z) 302.1532 (M+H, C16H19N3O3 requires 302.1499).

EXAMPLE 85

[0750] This example illustrates the production of 7-hydroxy-5-methyl-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid.

1054

[0751] Step 1: Preparation of Methyl 7-hydroxy-5-methyl-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate.

1055

[0752] Methyl 7-methoxy-5-methyl-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate (0.400 g, 1.47 mmol) was dissolved in CH2Cl2 (10 mL). The mixture was cooled to −20° C. Boron tribromide (7.5 mL, 7.5 mmol of a 1.0 M solution in CH2Cl2) was added dropwise via syringe. The mixture stirred at room temperature for three hours. Slowly added methanol dropwise to quench the reaction. The solvent was evaporated. Purified by flash column chromatography in 15:1 CH2Cl2:CH3OH to yield a brown solid which was recrystallized from ethanol/water (0.100 g, 26%): 1H NMR (DMSO tfa/300 MHz)7.59 (d, 1H), 6.79 (s, 1H), 6.75 (d, 1H), 3.83 (s, 3H), 3.07-2.98 (m, 2H), 2.90-2.75 (m, 1H), 1.16 (d, 3H). ESHRMS (m/z) 259.1051 (M+H, C14H14N2O3 requires 259.1077).

[0753] Step 2: Preparation of 7-hydroxy-5-methyl-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic Acid.

1056

[0754] Methyl 7-hydroxy-5-methyl-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate (0.050 g, 0.184 mmol) was dissolved in a THF/ethanol/water mixture (10 mL, 7/2/1 respectively). Lithium hydroxide monohydrate (0.025 g 0.60 mmol) was added. Stirred overnight at room temperature. THF was evaporated. 1N HCl was added until solution turned clouldy. The resulting white precipitate was filtered. (0.037 g, 82%): 1H NMR (DMSO tfa/300 MHz) 7.71 (d, 1H), 6.88 (s, 1H), 6.82 (d, 1H), 3.83 (s, 3H), 3.13-2.95 (m, 3H), 1.26 (d, 3H). ESHRMS m/z 245.0917 (M+H, C13H12N2O3 requires 245.0921).

EXAMPLE 86

[0755] This example illustrates the production of 8-bromo-7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid,

1057

[0756] Step 1: Preparation of ethyl 8-bromo-7-methoxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate.

1058

[0757] Ethyl 7-methoxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate (1.0 g, 3.67 mmol) was dissolved in acetic acid (20 mL). Sodium acetate (0.301 g, 3.67 mmol) was added. Cooled to 15° C. in an ice-water bath, and added bromine (0.586 g, 3.67 mmol) in acetic acid (10 mL). The ice bath was removed, and the reaction stirred at room temperature for three hours. The acetic acid was evaporated, and the resulting solid was dissolved in ethyl acetate (100 mL). Extracted with NaHCO3 (aq.) (2×50 mL) and brine (50 mL). The organic phase was dried over MgSO4, filtered, and evaporated. The resulting solid was recrystallized from ethyl acetate/hexane to afford a white solid. (0.5 g, 39%): 1H NMR (CDCl3/300 MHz 8.03 (s, 1H), 6.80 (s, 1H), 4.41 (q, 2H), 3.92 (s, 3H), 3.07-2.91 (m, 4H), 1.42 (t, 3H). ESHRMS m/z 353.0321 (M+H, C15H15BrN2O3 requires 353.0320).

[0758] Step 2: Preparation of 8-bromo-7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic Acid.

1059

[0759] Ethyl 8-bromo-7-methoxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate (0.357 g, 1.02 mmol) was dissolved in CH2Cl2 (20 mL). The mixture was cooled to −20° C. Boron tribromide (5 mL, 5 mmol of a 1.0 M solution in CH2Cl2) was added dropwise via syringe. The mixture stirred at room temperature for three hours. Slowly added ethanol dropwise to quench the reaction. The solvent was evaporated and the resulting solid was washed with water and filtered. The solid was a mixture of ester and carboxylic acid. It was dissolved in a THF/ethanol/water mixture (10 mL, 7/2/1 respectively). Lithium hydroxide monohydrate (0.086 g, 2.04 mmol) was added. Stirred overnight at room temperature. 1N HCl was added to form a white precipitate, which was filtered. (0.250 g, 79%): 1H NMR (DMSO/300 MHz 7.77 (s, 1H), 6.93 (s, 1H), 2.91-2.80 (m, 4H). ESHRMS m/z 310.9875 (M+H, C12H9BrN2O3 requires 310.9850).

1060

[0760] 2-(3-aminopropyl)-8-bromo-7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid hydrobromide

[0761] Step 1: Preparation of ethyl 8-bromo-2-{3-[(tert-butoxycarbonyl)amino]propyl}-7-methoxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate.

1061

[0762] Ethyl 8-bromo-7-methoxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate (1.76 g, 5 mmol) was dissolved in DMF (20 mL). Cooled to 0° C., in an ice-water bath. Lithium t-butoxide (11 mL, 11 mmol of a 1.0 M solution in THF) was added dropwise via syringe. Stirred for 2 hours. N-boc-3-bromopropylamine (2.63 g, 11 mmol) in DMF (20 mL) was added via syringe. The ice bath was removed and the reaction stirred at room temperature overnight. Quenched with NH4Cl (aq.) (50 mL), and the layers were separated. The aqueous phase was extracted with ethyl acetate (2×100 mL). The combined organic phases were washed with brine, (100 mL), dried over MgSO4, filtered, and evaporated. The resulting brown oil solidified upon standing. Recrystallized from ethanol/water to afford a grey solid (1.48 g, 58%): 1H NMR (CDCl3/300 MHz 8.00 (s, 1H), 6.78 (s, 1H), 4.62 (t, 2H) 4.39 (q, 2H), 3.92 (s, 3H), 3.12-2.91 (m, 6H), 2.05 (t, 2H), 1.44 (s, 9H), 1.42 (t, 3H). ESHRMS m/z 508.1469 (M+H, C23H30BrN3O5 requires 508.1442).

[0763] Step 2: Preparation of 8-bromo-2-{3-[(tert-butoxycarbonyl)amino]propyl}-7-methoxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic Acid,

1062

[0764] Ethyl 8-bromo-2-{3-[(tert-butoxycarbonyl)amino]propyl}-7-methoxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate (0.508 g, 1.00 mmol) was dissolved in a THF/ethanol/water mixture (10 mL, 7/2/1 respectively). Lithium hydroxide monohydrate (0.105 g, 2.5 mmol) was added. Stirred overnight at room temperature. Diluted with ethyl acetate (50 mL) and extracted with 0.1N HCl (2×25 mL), and brine (25 mL). The organic phase was dried over MgSO4, filtered, and evaporated. The resulting white solid was recrystallized from ethyl acetate/hexane. (0.433 g, 99%): 1H NMR (DMSO/300 MHz 7.73 (s, 1H), 7.07 (s, 1H), 4.61 (t, 2H), 3.88(s, 3H), 2.95-2.81 (m, 6H), 1.85 (t, 2H), 1.4 (t, 9H). ESHRMS m/z 480.1145 (M+H, C21H26BrN3O5 requires 480.1129).

[0765] Step 3: Preparation of 2-(3-aminopropyl)-8-bromo-7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic Acid Hydrobromide.

1063

[0766] 8-bromo-2-{3-[(tert-butoxycarbonyl)amino]propyl}-7-methoxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid (0.254 g, 0.529 mmol) was slurried in CH2Cl2 (5 mL). The mixture was cooled to −20° C. Boron tribromide (2.5 mL, 2.5 mmol of a 1.0 M solution in CH2Cl2) was added dropwise via syringe. The mixture stirred at room temperature for three hours. Slowly added H2O dropwise to quench the reaction. The solvent was evaporated and the resulting solid was triturated with acetonitrile (0.190 g): 1H NMR (DMSO/300 MHz) 7.75 (s, 1H), 6.91 (s, 1H), 4.59 (t, 2H), 2.94-2.83 (m, 6H), 2.10 (t, 2H). ESHRMS m/z 366.0430 (M+H, C15H16BrN3O3 requires 366.0448).

EXAMPLE 87

[0767] This example illustrates the production of 2-(3-aminopropyl)-8-bromo-7-hydroxy-2H-benzo[g]indazole-3-carboxylic acid trifluoroacetate.

1064

[0768] Step 1: Preparation of ethyl 8-bromo-7-methoxy-2H-benzo[g]indazole-3-carboxylate

1065

[0769] Ethyl 8-bromo-7-methoxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate (0.351 g, 1.00 mmol) was dissolved in anhydrous dioxane (20 mL). DDQ (0.227 g, 1.00 mmol) was added. Stirred at reflux for 10 hours. Stirred at room temperature overnight. The resulting solid was filtered, and washed with ethyl acetate (50 mL). The mother liquor was extracted with 1.0 N NaOH until the yellow color dissipated. Checked combined aqueous extracts by TLC for any product. Back extracted with ethyl acetate until the entire product was in organic extracts. The combined organic phases were washed with brine, dried over MgSO4, filtered and evaporated to yield an orange solid. Recrystallized from ethyl acetate/hexane (0.150 g, 43%). 1H NMR (DMSO/300 MHz) 8.83 (s, 1H) 8.07 (d, 1H), 7.74 (s, 1H), 7.72 (d, 1H), 4.44 (q, 2H), 4.04 (s, 3H) 1.43 (t, 2H). ESHRMS m/z 349.0182 (M+H, C15H13BrN2O3 requires 349.0182).

[0770] Step 2: Preparation of ethyl 8-bromo-2-{3-[(tert-butoxycarbonyl)amino]propyl}-7-methoxy-2H-benzo[g]indazole-3-carboxylate.

1066

[0771] Ethyl 8-bromo-7-methoxy-2H-benzo[g]indazole-3-carboxylate (0.650 g, 1.86 mmol) was dissolved in DMF (20 mL). Cooled to 0° C., in an ice-water bath. Lithium t-butoxide (3.72 mL, 3.72 mmol of a 1.0 M solution in THF) was added dropwise via syringe. Stirred for 2 hours. N-boc-3-bromopropylamine (0.885 g, 3.72 mmol) in DMF (5 mL) was added via syringe. The ice bath was removed and the reaction stirred at room temperature overnight. Quenched with NH4Cl (aq.) (50 mL), and the layers were separated. The aqueous phase was extracted with ethyl acetate (2×50 mL). The combined organic phases were washed with brine, (50 mL), dried over MgSO4, filtered, and evaporated. The resulting yellow oil was purified by flash column chromatography in 20% ethyl acetate/80% hexane. (0.690 g, 73%): 1H NMR (CDCl3/300 MHz) 8.79 (s, 1H), 7.92 (d, 1H), 7.47 (d, 1H), 7.24 (s, 1H), 5.05 (s, 1H), 4.96 (t, 2H), 4.51 (q, 2H), 4.04 (s, 3H), 3.14 (q, 2H), 2.18 (qt, 2H), 1.53 (t, 3H), 1.44 (s, 9H). ESHRMS m/z 506.1259 (M+H, C23H28BrN3O5 requires 506.1296).

[0772] Step 3: Preparation of 8-bromo-2-{3-[(tert-butoxy-carbonyl)amino]propyl}-7-methoxy-2H-benzo[g]indazole-3-carboxylic Acid.

1067

[0773] Ethyl 8-bromo-2-{3-[(tert-butoxycarbonyl)amino]propyl}-7-methoxy-2H-benzo[g]indazole-3-carboxylate (0.506 g, 1.0 mmol) was dissolved in a THF/ethanol/water mixture (10 mL, 7/2/1 respectively). Lithium hydroxide monohydrate (0.105 g, 2.50 mmol) was added. Stirred overnight at room temperature. Diluted with ethyl acetate (50 mL) and extracted with 0.1N HCl (2×25 mL), and brine (25 mL). The organic phase was dried over MgSO4, filtered, and evaporated. The resulting white solid was recrystallized from ethyl acetate/hexane. (0.414 g, 87%): 1H NMR (DMSO/300 MHz) 8.55 (s, 1H), 8.13 (d, 1H), 7.59 (s, 1H), 7.47 (d, 1H), 7.05 (s, 1H), 4.94 (t, 2H), 4.00 (s, 3H), 2.96 (q, 2H), 2.02 (qt, 2H), 1.39 (s, 9H). ESHRMS m/z 478.0988 (M+H, C21H24BrN3O5 requires 478.0983).

[0774] Step 4: Preparation of 2-(3-aminopropyl)-8-bromo-7-hydroxy-2H-benzo[g]indazole-3-carboxylic Acid Trifluoroacetate.

1068

[0775] 8-bromo-2-{3-[(tert-butoxy-carbonyl)amino]propyl}-7-methoxy-2H-benzo[g]indazole-3-carboxylic acid (0.310 g, 0.648 mmol) was slurried in CH2Cl2 (10 mL). The mixture was cooled to −20° C. Boron tribromide (4 mL, 4 mmol of a 1.0 M solution in CH2Cl2) was added dropwise via syringe. The mixture stirred at room temperature for three hours. Slowly added H2O dropwise to quench the reaction. The solvent was evaporated and the resulting solid was purified by preparative reverse phase HPLC to obtain a white solid (0.170 g): 1H NMR (DMSO tfa/300 MHz) 8.56 (s, 1H), 7.88 (d, 1H), 7.44 (s, 2H), 7.53 (d, 1H), 7.44 (s, 1H), 4.93 (t, 2H), 2.87 (q, 2H), 2.24 (qt, 2H). ESHRMS m/z 366.0275 (M+H, C15H14BrN3O3 requires 366.0291).

EXAMPLE 88

[0776] This example illustrates the production of 2-(2-aminoethyl)-8-bromo-7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid trifluoroacetate.

1069

[0777] Step 1: Preparation of ethyl 8-bromo-2-{2-[(tert-butoxycarbonyl)amino]ethyl}-7-methoxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate.

1070

[0778] Ethyl 8-bromo-7-methoxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate (0.710 g, 2.02 mmol) was dissolved in DMF (10 mL). Cooled to 0° C., in an ice-water bath. Lithium t-butoxide (4.45 mL, 4.45 mmol of a 1.0 M solution in THF) was added dropwise via syringe. Stirred for 2 hours. N-boc-2-bromoethylamine (1.08 g, 4.45 mmol) in DMF (10 mL) was added via syringe. The ice bath was removed and the reaction stirred at room temperature overnight. Quenched with NH4Cl (aq.) (50 mL), and the layers were separated. The aqueous phase was extracted with ethyl acetate (2×100 mL). The combined organic phases were washed with brine, (100 mL), dried over MgSO4, filtered, and evaporated to afford a white solid. Recrystallized from ethanol/water. (0.709 g, 72%): 1H NMR (CDCl3/300 MHz) 8.02 (s, 1H), 6.78 (s, 1H) 4.95 (s, 1H) 4.68 (t, 2H), 4.35 q, 2H) 3.92 (s, 3H), 3.61 (t, 2H), 3.04-2.88 (m, 4H), 1.42 (t, 3H), 1.41 (s, 9H). ESHRMS m/z 494.1272 (M+H, C22H28BrN3O5 requires 494.1285).

[0779] Step 2: Preparation of 8-bromo-2-{2-[(tert-butoxy-carbonyl)amino]ethyl}-7-methoxy-4,5-dihydro-2H-benzo-[g]indazole-3-carboxylic Acid.

1071

[0780] 8-bromo-2-{2-[(tert-butoxycarbonyl)amino]ethyl}-7-methoxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate (0.494, 1.0 mmol) was dissolved in a THF/ethanol/water mixture (10 mL, 7/2/1 respectively). Lithium hydroxide monohydrate (0.105 g, 2.50 mmol) was added. Stirred overnight at room temperature. Diluted with ethyl acetate (50 mL) and extracted with 0.1N HCl (2×25 mL), and brine (25 mL). The organic phase was dried over MgSO4, filtered, and evaporated. The resulting white solid was recrystallized from ethyl acetate/hexane. (0.350 g, 75%): 1H NMR (DMSO tfa/300 MHz) 7.82 (s, 1H), 7.11 (s, 1H), 6.92 (s, 1H), 4.55 (t, 2H), 3.90 (s, 3H), 3.36 (t, 2H), 2.93-2.78 (m, 4H), 1.33 (s, 9H). ESHRMS m/z 466.0991 (M+H, C20H24BrN3O5 requires 466.0972).

[0781] Step 3: Preparation of 2-(2-aminoethyl)-8-bromo-7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic Acid Trifluoroacetate.

1072

[0782] 8-bromo-2-{2-[(tert-butoxy-carbonyl)amino]ethyl}-7-methoxy-4,5-dihydro-2H-benzo-[g]indazole-3-carboxylic acid (0.250 g, 0.537 mmol was slurried in CH2Cl2 (10 mL). The mixture was cooled to −20° C. Boron tribromide (3 mL, 3 mmol of a 1.0 M solution in CH2Cl2) was added dropwise via syringe. The mixture stirred at room temperature for three hours. Slowly added H2O dropwise to quench the reaction. The solvent was evaporated and the resulting solid was purified by preparative reverse phase HPLC to obtain a white solid (0.170 g): 1H NMR (DMSO tfa/300 MHz) 7.92 (s, 2H), 7.86 (s, 1H), 6.92 (s, 1H), 4.74 (t, 2H, 3.34 (t, 2H), 2.95-2.83 (m, 4H). ESHRMS m/z 352.0282 (M+H, C14H14BrN3O3 requires 352.0291).

EXAMPLE 89

[0783] This example illustrates the production of methyl 8-[(dimethylamino)sulfonyl]-7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate.

1073

[0784] Step 1: Preparation of Methyl (2Z)-hydroxy[6-[(2-methoxyethoxy)methoxy]-1-oxo-3,4-dihydronaphthalen-2(1H)-ylidene]ethanoate.

1074

[0785] 6-Hydroxy-1-tetralone (15.0 g, 92 mmol) was dissolved in THF (200 mL). Lithium-t-butoxide (92 mL, 92 mmol) was slowly added via addition funnel. Stirred for one hour. MEM chloride (12.1 mL, 92 mmol) was addied via addition funnel. Stirred overnight at room temperature. The reaction mixture was washed with H2O (150 mL), and brine (150 mL). The organic phase was dried over MgSO4, filtered, and evaporated. Purified by flash column chromatography with 15% ethyl acetate/85% hexane. This compound (15.89 g, 63.6 mmol) was dissolved in ether (300 mL) Dimethyl oxalate (7.51 g, 63.6 mmol) was added. Sodium methoxide (14.53 mL, 63.6 mmol of a 25%/wt. solution in methanol) was slowly added via an addition funnel. Stirred overnight at room temperature. The reaction mixture was treated with 1M HCl to pH=1. The solution was then transferred to a separatory funnel, and the layers were separated. The aqueous phase was extracted with ethyl acetate (2×100 mL). The combined organic phases were washed with brine, dried over MgSO4, filtered, and evaporated to yield a brown oil, which solidified upon standing. Filtered through a plug of silica with 20% ethyl acetate/80% hexane. The resulting solid was recrystallized from ethyl acetate/hexane. (19.9 g, 64%): 1H NMR (CDCl3/300 MHz) 15.92 (s, 1H), 7.97 (d, 1H), 7.01 (dd, 1H), 6.90 (d, 1H), 5.33 (s, 2H), 3.92 (s, 3H), 3.83 (t, 2H), 3.56 (t, 2H), 3.38 (s, 3H), 2.99-2.83 (m 4H). ESHRMS m/z 337.1296 (M+H, C17H20O7 requires 337.1282)

[0786] Step 2: Preparation of Methyl 7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate.

1075

[0787] Methyl (2Z)-hydroxy[6-[(2-methoxyethoxy)methoxy]-1-oxo-3,4-dihydronaphthalen-2(1H)-ylidene]ethanoate (19.7 g, 58.6 mmol) was dissolved in methanol (250 mL). Hydrazine monohydrochloride (4.41 g, 64.4 mmol) was added. Heated at reflux for three hours. Cooled to room temperature and neutralized with NaHCO3 (aq.). Water was added, resulting in the formation of a precipitate. Filtered and washed with H2O. (10.47 g, 73%): 1H NMR (acetone/300 MHz) 12.85 (s, 1H), 8.47 (s, 1H), 7.68 (s, 1H), 6.84-6.81 (m 2H), 3.93 (s, 3H), 2.96-2.88 (m 4H). ESHRMS m/z 245.0894 (M+H, C13H12N2O3 requires 245.0921).

[0788] Step 3: Preparation of Methyl 8-[(dimethylamino)sulfonyl]-7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate.

1076

[0789] Chlorosulfonic acid (5 mL) was cooled to 0° C. Methyl 7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate (0.500 g, 2.05 mmol) was added in portions. Stirred at room temperature for two hours. The reaction mixtures was added dropwise to ice. Extracted with ethyl acetate (3×50 mL). The combined organic phases were washed with brine, dried over MgSO4, filtered, and evaporated to 50 mL. Dimethylamine (40% by weight) was added until the reaction mixture was basic. Stirred overnight at room temperature. Neutralized to pH=7 with 1N HCl. The reaction mixture was extracted with water (50 mL) and brine (50 mL). The organic phase was dried over MgSO4, filtered, and evaporated to yield a tan solid. Recrystallized from ethyl acetate/hexane (0.160 g, 22%): 1H NMR (acetone/300 MHz) 12.95 (s, 1H), 9.16 (s, 1H), 8.05 (s, 1H), 7.10 (s 1H), 3.94 (s, 3H), 3.07-3.01 (m 4H) 2.10 (s, 6H). ESHRMS m/z 352.0995 (M+H, C15H17N3O5S requires 352.0296)

EXAMPLE 90

[0790] This example illustrates the production of 2-(3-aminopropyl)-7-hydroxy-2H-benzo[g]indazole-3-carboxylic acid trifluoroacetate.

1077

[0791] Step 1: Preparation of Methyl (2Z)-hydroxy(6-methoxy-1-oxo-3,4-dihydronaphthalen-2(1H)— ylidene)ethanoate.

1078

[0792] 6-Methoxy-1-tetralone (10.0 g, 56.7 mmol) was dissolved in ether (250 mL). Dimethyl oxalate (7.37 g, 62.4 mmol) was added. Sodium methoxide (14.27 mL, 13.48 g, 62.4 mmol of a 25%/wt. solution in methanol) was slowly added via an addition funnel. Stirred overnight at room temperature. The reaction mixture was treated with 1M HCl to pH=1. The solution was then transferred to a separatory funnel, and the layers were separated. The aqueous phase was extracted with ethyl acetate (2×100 mL). The combined organic phases were washed with brine, dried over MgSO4, filtered, and evaporated to yield a brown oil, which solidified upon standing. Filtered through a plug of silica with 20% ethyl acetate/80% hexane. The resulting solid was recrystallized from ethyl acetate/hexane. (10.19 g, 69%): mp 77.3-77.8° C. 1H NMR (CDCl3/300 MHz) 16.02 (s, 1H), 8.03 (d, 1H,), 6.92 (d, 1H), 6.77 (s, 1H), 3.96 (s, 1H), 3.92 (s, 3H), 3.04-2.89 (m, 4H). ESHRMS m/z 263.0907 (M+H, C14H14O5 requires 263.0914).

[0793] Step 2: Preparation of Methyl 7-methoxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate,

1079

[0794] The product from Step 1 (8.77 g, 33.4 mmol) was dissolved in methanol (150 mL). Hydrazine monohydrochloride (2.52 g, 36.8 mmol) was added. Heated at reflux for three hours. Cooled to room temperature and neutralized with NaHCO3 (aq.). Water was added, resulting in the formation of a precipitate. Filtered and washed with H2O. The solid was dried in a vacuum oven. (8.4 g, 98%): 1H NMR (CDCl3/300 MHz) 10.71 (s, 1H), 7.74 (s, 1H), 6.84-6.82 (m, 2H), 3.94 (s, 1H), 3.83 (s, 1H), 3.05-2.95 (m, 4H). ESHRMS m/z 259.1097 (M+H, C14H14N2O3 requires 259.1077).

[0795] Step 3: Preparation of Methyl 2-{3-[(tert-butoxy-carbonyl)amino]propyl}-7-methoxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate,

1080

[0796] Methyl 7-methoxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate (7.00 g, 27 mmol) was dissolved in DMF (100 mL). Cooled to 0° C., in an ice-water bath. Lithium t-butoxide (32 mL, 32 mmol of a 1.0 M solution in THF) was added dropwise via addition funnel. Stirred for 2 hours. N-boc-3-bromopropylamine (7.62 g, 32 mmol) in DMF (20 mL) was added via addition funnel. The ice bath was removed and the reaction stirred at room temperature overnight. Quenched with NH4Cl (aq.) (200 mL), and the layers were separated. The aqueous phase was extracted with ethyl acetate (2×200 mL). The combined organic phases were washed with brine, (200 mL), dried over MgSO4, filtered, and evaporated. The resulting brown oil was purified by flash column chromatography in 20% ethyl acetate/80% hexane. The orange solid was recrytstallized from ether/hexane to afford a white solid (8.11 g, 72%): 1H NMR (CDCl3/300 MHz) 7.75 (d, 1H), 6.83-6.79 (m, 2H), 5.10 (s, 1H), 4.63 (, 2H), 3.91 (s, 3H), 3.83 (s, 3H), 3.13-2.92 (m, 6H), 2.04 (t, 2H), 1.44 (s, 9H). ESHRMS m/z 416.2177 (M+H, C22H29N3O5 requires 416.2180).

[0797] Step 4: Preparation of 1-methyl 2-{3-[(tert-butoxycarbonyl)amino]propyl}-7-methoxy-2H-benzo[g]indazole-3-carboxylate.

1081

[0798] Methyl 2-{3-[(tert-butoxycarbonyl)amino]propyl}-7-methoxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate (3.0 g, 7.22 mmol) was dissolved in anhydrous dioxane (50 mL). DDQ (2.05 g, 9.03 mmol) was added. Stirred at reflux for 10 hours. Stirred at room temperature overnight. The resulting solid was filtered, and washed with ethyl acetate (100 mL). The mother liquor was extracted with 1.0 N NaOH until the yellow color dissipated. Checked combined aqueous extracts by TLC for any product. Back extracted with ethyl acetate until the entire product was in organic extracts. The combined organic phases were washed with brine, dried over MgSO4, filtered and evaporated to yield an orange oil. The oil was filtered through a plug of silica with 20% ethyl acetate/80% hexane. Obtained a clear oil, which solidified upon standing. Recrystallized from ether/hexane (1.94 g, 65%). 1H NMR (CDCl3/300 MHz) 8.50 (d, 1H), 7.88 (d, 1H), 7.50 (d, 1H), 7.28-7.25 (m, 2H), 5.19 (s, 1H), 4.96 (t, 2H), 4.05 (s, 3H), 3.95 (s, 3H), 3.14 (t, 2H), 2.18 (qt, 2H), 1.44 (s, 9H). ESHRMS m/z 414.2003 (M+H, C22H27N3O5 requires 414.2023).

[0799] Step 5: Preparation of 2-{3-[(tert-butoxy-carbonyl)amino]propyl}-7-methoxy-2H-benzo[g]indazole-3-carboxylic Acid.

1082

[0800] 1-methyl 2-{3-[(tert-butoxycarbonyl)amino]propyl}-7-methoxy-2H-benzo[g]indazole-3-carboxylate (0.450 g, 1.09 mmol) was dissolved in a THF/ethanol/water mixture (10 mL, 7/2/1 respectively). Lithium hydroxide monohydrate (0.091 g, 2.18 mmol) was added. Stirred overnight at room temperature. Diluted with ethyl acetate (50 mL) and extracted with 0.1N HCl (2×25 mL), and brine (25 mL). The organic phase was dried over MgSO4, filtered, and evaporated. The resulting white solid was recrystallized from ethyl acetate/hexane. (0.433 g, 99%): 1H NMR (DMSO tfa/300 MHz) 8.36 (d, 1H), 7.88 (d, 1H), 7.58 (d, 1H), 7.45 (s, 1H), 7.26 (d, 1H), 6.86 (s, 1H), 4.83 (t, 2H), 3.88 (s, 3H), 2.99 (t, 2H), 2.01 (qt, 2H), 1.35 (s, 9H). ESHRMS m/z 400.1874 (M+H, C21H25N3O5 requires 400.1867).

[0801] Step 6: Preparation of 2-(3-aminopropyl)-7-hydroxy-2H-benzo[g]indazole-3-carboxylic Acid Trifluoroacetate.

1083

[0802] 2-{3-[(tert-butoxycarbonyl)amino]propyl)-7-methoxy-2H-benzo[g]indazole-3-carboxylic acid (0.200 g, 0.501 mmol) was slurried in CH2Cl2 (5 mL). The mixture was cooled to −20° C. Boron tribromide (5 mL, 5 mmol of a 1.0 M solution in CH2Cl2) was added dropwise via syringe. The mixture stirred at room temperature for three hours. Slowly added H2O dropwise to quench the reaction. The solvent was evaporated and the resulting solid was purified by preparative reverse phase HPLC to obtain a white solid: 1H NMR (DMSO tfa/300 MHz) 8.28 (d, 1H), 7.82 (d, 1H), 7.70 (s, 1H), 7.48 (d, 1H), 7.22 (d, 1H), 7.14 (dd, 1H), 4.92 (t, 2H), 2.84 (t, 2H), 2.20 (qt, 2H), 1.35 (s, 9H). ESHRMS m/z 286.1148 (M+H, C15H15N3O3 requires 286.1186)

EXAMPLE 91

[0803] This example illustrates the production of 2-{3-[(tert-butoxycarbonyl)amino]propyl}-8-(4-chlorophenyl)-7-methoxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid.

1084

[0804] Step 1: Preparation of Methyl 8-bromo-7-methoxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate.

1085

[0805] Methyl 7-methoxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate (5.36 g, 20.8 mmol) was dissolved in glacial acetic acid (100 mL), and sodium acetate (1.88 g, 22.9 mmol was added. Cooled to 15° C. in an ice-water bath, and added bromine (22.9 mL of a 1.0 M solution in acetic acid) was added via addition funnel. The ice bath was removed, and the reaction stirred at room temperature for three hours. The acetic acid was evaporated, and the resulting solid was dissolved in ethyl acetate (300 mL). Extracted with NaHCO3 (aq.) (2×100 mL) and brine (100 mL). The organic phase was dried over MgSO4, filtered, and evaporated. The resulting solid was recrystallized from ethyl acetate/hexane to afford a white solid. (4.7 g, 66%) mp 239.7-241.4° C.: 1H NMR (CDCl3/300 MHz) 8.04 (s, 1H), 6.80 (s, 1H), 3.95 (s, 3H), 3.92 (s, 3H), 3.06-2.94 (m, 4H). ESHRMS m/z 337.0195 (M+H, C14H13BrN2O3 requires 337.0182).

[0806] Step 2: Preparation of Methyl 8-bromo-2-{3-[(tert-butoxycarbonyl)amino]propyl}-7-methoxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate.

1086

[0807] Methyl 8-bromo-7-methoxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate (10.10 g, 30 mmol) was dissolved in DMF (150 mL). Cooled to 0° C., in a ice-water bath. Lithium t-butoxide (50 mL, 50 mmol of a 1.0 M solution in THF) was added dropwise via addition funnel. Stirred for 2 hours. N-boc-3-bromopropylamine (10.69 g, 45 mmol) in DMF (25 mL) was added via addition funnel. The ice bath was removed and the reaction stirred at room temperature overnight. Quenched with NH4Cl (aq.) (200 mL), and the layers were separated. The aqueous phase was extracted with ethyl acetate (2×200 mL). The combined organic phases were washed with brine, (200 mL), dried over MgSO4, filtered, and evaporated. The resulting orange solid was recrystallized from hot ethanol/water to yield a white solid, which was dried under vacuum. (10.57 g, 72%): 1H NMR (CDCl3/300 MHz) 8.00 (s, 1H), 6.78 (s, 1H), 4.99 (s, 1H) 4.63 (t, 2H), 3.92 (s, 3H), 3.12 (t, 2H), 2.99-2.88 (m, 4H), 2.04 (qt, 2H), 1.45 (s, 9H). ESHRMS m/z 494.1267 (M+H, C22H28BrN3O5 requires 494.1285).

[0808] Step 3: Preparatio of Methyl-2-{3-[(tert-butoxycarbonyl)amino]propyl}-8-(4-chlorophenyl)-7-methoxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate.

1087

[0809] Methyl 8-bromo-2-{3-[(tert-butoxycarbonyl)amino]propyl}-7-methoxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate (1.00 g, 2.02 mmol), and 4-chlorophenyl boronic acid (0.632 g, 4.04 mmol) were slurried in 1-propanol (40 mL). Sodium carbonate (0.428 g, 4.06 mmol) in water (2 mL) was added, followed by palladium acetate (0.0136 g, 0.06 mmol), and triphenyl phosphine (0.0477 g, 0.182 mmol). The reaction mixture was heated to reflux for two hours. (Reaction mixture became homogeneous upon heating). The reaction cooled to room temperature, and the propanol was evaporated to approximately 5 mL. The slurry was diluted with ethyl acetate (100 mL). Extracted with H2O (50 mL), and brine (50 mL). The organic phase was dried over MgSO4, filtered and evaporated. Purified by flash column chromatography in 15% ethyl acetate/85% hexane. The resulting solid was recrystallized from ethanol/water. (0.632 g, 60%): 1H NMR (CDCl3/300 MHz) 7.76 (s, 1H), 7.51 (d, 2H), 7.35 (d, 2H), 6.86 (s, 1H), 4.99 (s, 1H), 4.63 (t, 2H), 3.92 (s, 3H), 3.83 (s, 3H), 3.06 (t, 2H), 3.02-2.96 (m, 4H), 2.04 (qt, 2H), 1.42 (s, 9H). ESHRMS m/z 526.2097 (M+H, C28H32ClN3O5 requires 526.2103).

[0810] Step 4: Preparation of 2-{3-[(tert-butoxycarbonyl)amino]propyl}-8-(4-chlorophenyl)-7-methoxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic Acid.

1088

[0811] Methyl-2-{3-[(tert-butoxycarbonyl)amino]propyl}-8-(4-chlorophenyl)-7-methoxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate (0.526 g, 1.00 mmol) was dissolved in a THF/ethanol/water mixture (10 mL, 7/2/1 respectively). Lithium hydroxide monohydrate (0.105 g, 2.5 mmol was added. Stirred overnight at room temperature. Diluted with ethyl acetate (50 mL) and extracted with 0.1N HCl (2×25 mL), and brine (25 mL). The organic phase was dried over MgSO4, filtered, and evaporated. The resulting white solid was recrystallized from ethyl acetate/hexane. (0.409 g, 80%): 1H NMR (CDCl3/300 MHz) 7.77 (s, 1H), 7.51 (d, 2H), 7.36 (d, 2H), 6.87 (s, 1H), 5.01 (s, 1H), 4.65 (t, 2H), 3.84 (s, 3H), 3.17-2.99 (m, 6H), 2.06 (qt, 2H), 1.42 (s, 9H). ESHRMS m/z 512.1971 (M+H, C27H30ClN3O5 requires 512.1947).

[0812] Following the procedure described for the production of 2-{3-[(tert-butoxycarbonyl)amino]propyl}-8-(4-chlorophenyl)-7-methoxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid, the subsequent compounds were prepared.

EXAMPLE 92

[0813] This example illustrates the production of 2-{3-[(tert-butoxycarbonyl) amino]propyl}-7-methoxy-8-(3-nitrophenyl)-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid.

1089

[0814]

1
H NMR (DMSO tfa/300 MHz) 8.33 (s, 1H), 8.22 (d, 1H), 8.00 (d, 1H), 7.76-7.68 (m, 2H), 7.17 (s, 1H), 6.83 (s, 1H), 4.52 (t, 2H), 3.86 (s, 3H), 3.05-2.95 (m, 6H), 1.90 (qt, 2H), 1.37 (s, 9H). ESHRMS m/z 523.2186 (M+H, C27H30N4O7 requires 523.2187)

EXAMPLE 93

[0815] This example illustrates the production of 2-{3-[(tert-butoxycarbonyl) amino]propyl}-8-(2-chlorophenyl)-7-methoxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid.

1090

[0816]

1
H NMR (DMSO tfa/300 MHz) 7.51 (s, 1H), 7.43-7.37 (m, 4H), 7.09 (s, 1H), 6.81 (s, 1H), 4.49 (t, 2H), 3.77 (s, 3H), 2.99-2.93 (m, 6H), 1.88 (qt, 2H), 1.36 (s, 9H). ESHRMS m/z 512.1928 (M+H, C27H30ClN3O5 requires 512.1947)

EXAMPLE 94

[0817] This example illustrates the production of 2-{3-[(tert-butoxycarbonyl) amino]propyl}-8-[1-(tert-butoxycarbonyl)-1H-pyrrol-2-yl]-7-methoxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid.

1091

[0818]

1
H NMR (DMSO tfa/300 MHz) 7.51 (s, 1H), 7.31 (q, 4H), 6.97 (s, 1H), 6.83 (s, 1H), 6.26 (t, 1H), 6.19 (s, 1H), 4.50 (t, 2H), 3.73 (s, 3H), 3.03-2.93 (m, 6H), 1.88 (qt, 2H), 1.38 (s, 9H), 1.32 (s, 9H). ESHRMS m/z 567.2788 (M+H, C30H38N4O7 requires 567.2813)

EXAMPLE 95

[0819] This example illustrates the production of 2-{3-[(tert-butoxycarbonyl)amino]propyl}-8-(3-chlorophenyl)-7-methoxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid,

1092

[0820]

1
H NMR (DMSO tfa/300 MHz) 7.59 (s, 1H), 7.55 (s, 1H), 7.49-7.47 (m, 2H), 7.45-7.40 (m, 1H), 7.12 (s, 1H), 6.83 (s, 1H), 4.51 (t, 2H), 3.83 (s, 3H), 3.03-2.95 (m, 6H), 1.90 (qt, 2H), 1.37 (s, 9H). ESHRMS m/z 512.1933 (M+H, C27H30ClN3O5 requires 567.2813)

EXAMPLE 96

[0821] This example illustrates the production of 2-{3-[(tert-butoxycarbonyl)amino]propyl}-8-(3-cyanophenyl)-7-methoxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid.

1093

[0822]

1
H NMR (DMSO tfa/300 MHz) 7.96 (s, 1H), 7.88-7.80 (m, 2H), 7.67-7.62 (m, 2H), 7.14 (s, 1H), 6.83 (s, 1H), 4.51 (t, 2H), 3.84 (s, 3H), 2.99-2.90 (m, 6H), 1.91 (qt, 2H), 1.37 (s, 9H). ESHRMS m/z 503.2259 (M+H, C28H30ClN4O5 requires 503.2289)

EXAMPLE 97

[0823] This example illustrates the production of 2-{3-[(tert-butoxycarbonyl)amino]propyl}-7-methoxy-8-(4-nitrophenyl)-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid.

1094

[0824]

1
H NMR (DMSO tfa/300 MHz) 8.26 (d, 2H), 7.80 (d, 2H), 7.64(s, 1H), 7.15 (s, 1H), 6.81 (s, 1H), 4.48 (t, 2H), 3.82 (s, 3H), 3.06-2.96 (m, 6H), 1.87 (qt, 2H), 1.34 (s, 9H). ESHRMS m/z 523.2212 (M+H, C27H30N4O7 requires 523.2187).

EXAMPLE 98

[0825] This example illustrates the production of 2-{3-[(tert-butoxycarbonyl) amino]propyl}-7-methoxy-8-[3-(methylsulfonyl)phenyl]-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid.

1095

[0826]

1
H NMR (DMSO tfa/300 MHz) 8.01 (d, 1H), 7.88-7.85(m, 2H), 7.68(d, 1H), 7.64 (s, 1H), 7.11 (s, 1H), 6.81 (s, 1H), 4.49 (t, 2H), 3.81 (s, 3H), 3.25 (s, 3H), 2.96-2.88 (m, 6H), 1.88 (qt, 2H), 1.33 (s, 9H). ESHRMS m/z 556.2137 (M+H, C28H33N3O7S requires 556.2112).

EXAMPLE 99

[0827] This example illustrates the production of 2-{3-[(tert-butoxycarbonyl) amino]propyl}-8-(3,4-difluorophenyl)-7-methoxy-4,5-dihydro-2H-benzo[g]-indazole-3-carboxylic acid

1096

[0828]

1
H NMR (DMSO tfa/300 MHz) 7.57 (s, 1H), 7.55-7.32(m, 2H), 7.09(s, 1H), 6.80 (s, 1H), 4.48 (t, 2H), 3.80 (s, 3H), 2.95-2.82 (m, 6H), 1.85 (qt, 2H), 1.34 (s, 9H). ESHRMS m/z 514.2170 (M+H, C27H29F2N3O5 requires 556.2112)

EXAMPLE 100

[0829] This example illustrates the production of 2-(3-aminopropyl)-8-(4-chlorophenyl)-7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid trifluoroacetate.

1097

[0830] 2-{3-[(tert-butoxycarbonyl)amino]propyl}-8-(4-chlorophenyl)-7-methoxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid (0.300 g, 0.586 mmol) was slurried in CH2Cl2 (15 mL). The mixture was cooled to −20° C. Boron tribromide (6 mL, 6 mmol of a 1.0 M solution in CH2Cl2) was added dropwise via syringe. The mixture was stirred at room temperature for three hours. Then, H2O was slowly added dropwise to quench the reaction. The solvent was evaporated and the resulting solid was purified by preparative reverse phase HPLC to yield a light yellow solid (0.094 g): 1H NMR (DMSO tfa/300 MHz) 7.81 (s, 2H), 7.72 (s, 1H), 7.60 (d, 2H), 7.49 (d, 2H), 6.90 (s, 1H), 4.59 (t, 2H), 2.96-2.84 (m, 6H), 2.11-2.08 (qt, 2H). ESHRMS m/z 398.1262 (M+H, C21H20ClN3O3 requires 398.1266).

[0831] Following the procedure described for 2-(3-aminopropyl)-8-(4-chlorophenyl)-7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid trifluoroacetate, the subsequent 13 compounds were prepared.

EXAMPLE 101

[0832] This example illustrates the production of 2-(3-Aminopropyl)-7-hydroxy-8-[4-(methylamino)phenyl]-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid trifluoroacetate

1098

[0833]

1
H NMR (DMSO tfa/300 MHz) 7.73 (s, 1H), 7.63 (d, 2H), 7.59 (s, 1H), 7.35 (d, 2H), 6.89 (s, 1H), 4.58 (t, 2H), 3.14 (s, 3H) 2.96-2.84 (m, 6H), 2.11-2.08 (qt, 2H). ESHRMS m/z 393.1945 (M+H, C22H24N4O3 requires 393.1921).

EXAMPLE 102

[0834] This example illustrates the production of 2-(3-Aminopropyl)-8-(4-tert-butylphenyl)-7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid trifluoroacetate.

1099

[0835]

1
H NMR (DMSO ffa/300 MHz) 7.70 (s, 2H), 7.59 (s, 1H), 7.50 (d, 2H), 7.44 (d, 2H), 6.88 (s, 1H), 4.59 (t, 2H), 2.96-2.84 (m, 6H), 2.10-2.05 (qt, 2H), 1.34 (s, 9H). ESHRMS m/z 420.2275 (M+H, C25H29N3O3 requires 420.2282).

EXAMPLE 103

[0836] This example illustrates the production of 2-(3-Aminopropyl)-7-hydroxy-8-[3-(trifluoromethyl)phenyl]-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid trifluoroacetate.

1100

[0837]

1
H NMR (DMSO tfa/300 MHz) 7.89 (s, 2H), 7.70-7.57 (m, 5H), 6.93 (s, 1H), 4.59 (t, 2H), 3.00-2.84 (m, 6H), 2.07(qt, 2H). ESHRMS m/z 432.1551 (M+H, C22H2OF3N3O3 requires 432.1530).

EXAMPLE 104

[0838] This example illustrates the production of 2-(3-Aminopropyl)-7-hydroxy-8-pyridin-4-yl-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid trifluoroacetate.

1101

[0839]

1
H NMR (DMSO tfa/300 MHz) 8.92 (d, 2H), 8.37 (d, 2H), 7.86 (s, 1H), 7.74 (s, 2H), 7.04 (s, 1H), 4.60 (t, 2H), 2.98-2.83 (m, 6H), 2.09(qt, 2H). ESHRMS m/z 365.1654 (M+H, C20H20N4O3 requires 365.1608).

EXAMPLE 105

[0840] This example illustrates the production of 2-(3-aminopropyl)-7-hydroxy-8-(3-nitrophenyl)-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid trifluoroacetate.

1102

[0841]

1
H NMR (DMSO tfa/300 MHz) 8.42 (s, 1H), 8.21 (d, 1H), 8.07 (d, 1H), 7.78-7.68 (m, 4H), 6.96 (s, 1H), 4.60 (t, 2H), 2.98-2.82 (m, 6H), 2.09 (qt. 2H). ESHRMS m/z 409.1525 (M+H, C215H2ON4O5 requires 409.1506).

EXAMPLE 106

[0842] This example illustrates the production of 2-(3-Aminopropyl)-8-(2-chlorophenyl)-7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid trifluoroacetate.

1103

[0843]

1
H NMR (DMSO tfa/300 MHz) 7.67 (s, 2H), 7.54 (m, 1H), 7.41-7.37 (m, 4H), 6.87 (s, 1H), 4.56 (t, 2H), 2.97-2.81 (m, 6H), 2.07 (qt, 2H). ESHRMS m/z 398.1276 (M+H, C30H36ClN3O5 requires 398.1266)

EXAMPLE 107

[0844] This example illustrates the production of 2-(3-Aminopropyl)-8-(3-chlorophenyl)-7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid trifluoroacetate,

1104

[0845]

1
H NMR (DMSO tfa/300 MHz) 7.73 (s, 2H), 7.60 (d, 1H) 7.55-7.41 (m, 4H), 6.92 (s, 1H), 4.59 (t, 2H), 2.97-2.85 (m, 6H), 2.09 (qt, 2H). ESHRMS m/z 398.1260 (M+H, C21H20ClN3O3 requires 398.1266)

EXAMPLE 108

[0846] This example illustrates the production of 2-(3-Aminopropyl)-8-(3-carboxyphenyl)-7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid trifluoroacetate.

1105

[0847]

1
H NMR (DMSO ffa/300 MHz) 8.14 (s, 1H), 7.91 (d, 1H) 7.86 (d, 1H), 7.69 (s, 2H), 7.63 (s, 1H), 7.57 (s, 1H), 6.92 (s, 1H), 4.60 (t, 2H), 2.99-2.83 (m, 6H), 2.09 (qt, 2H). ESHRMS m/z 408.1564 (M+H, C22H21N3O5 requires 408.1559)

EXAMPLE 169

[0848] This example illustrates the production of 2-(3-Aminopropyl)-8-(3,5-dimethylisoxazol-4-yl)-7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid trifluoroacetate.

1106

[0849]

1
H NMR (DMSO tfa/300 MHz) 7.69 (s, 2H), 7.41 (s, 1H) 6.91 (s, 1H), 4.58 (t, 2H), 2.99-2.83 (m, 6H), 2.30 (s, 3H), 2.13 (s, 3H), 2.07 (qt, 2H). ESHRMS m/z 383.1687 (M+H, C20H22N4O4 requires 383.1714)

EXAMPLE 110

[0850] This example illustrates the production of 2-(3-Aminopropyl)-8-(3-cyanophenyl)-7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid trifluoroacetate

1107

[0851]

1
H NMR (DMSO tfa/300 MHz) 7.99 (s, 1H), 7.92 (d, 1H) 7.80 (d, 1H), 7.70-7.62 (m, 4H), 6.93 (s, 1H), 4.59 (t, 2H), 2.97-2.82 (m, 6H), 2.08 (qt, 2H). ESHRMS m/z 389.1623 (M+H, C22H20N4O3 requires 389.1608)

EXAMPLE 111

[0852] This example illustrates the production of 2-(3-Aminopropyl)-7-hydroxy-8-(4-nitrophenyl)-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid trifluoroacetate.

1108

[0853]

1
H NMR (DMSO tfa/300 MHz) 8.27 (d, 2H), 7.85 (d, 2H) 7.68-7.64 (m, 3H), 6.93 (s, 1H), 4.57 (t, 2H), 2.94-2.81 (m, 6H), 2.08 (qt, 2H). ESHRMS m/z 409.1506 (M+H, C21H20N4O5 requires 409.1482)

EXAMPLE 112

[0854] This example illustrates the production of 2-(3-Aminopropyl)-7-hydroxy-8-[3-(methylsulfonyl)phenyl]-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid trifluoroacetate.

1109

[0855]

1
H NMR (DMSO tfa/300 MHz) 8.07 (s, 2H), 7.95 (d, 1H) 7.87 (d, 1H), 7.69-7.63 (m, 4H), 6.92 (s, 1H), 4.58 (t, 2H), 3.26 (s, 3H), 2.95-2.82 (m, 6H), 2.06 (qt, 2H). ESHRMS m/z 442.1424 (M+H, C22H23N3O5S requires 442.1431)

EXAMPLE 113

[0856] This example illustrates the production of 2-(3-Aminopropyl)-8-(3,4-difluorophenyl)-7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid trifluoroacetate,

1110

[0857]

1
H NMR (DMSO tfa/300 MHz) 7.70 (s, 2H), 7.63-7.58(m, 1H), 7.56(s, 1H), 7.48-7.38 (m, 2H), 6.88 (s, 1H), 4.56 (t, 2H), 2.95-2.76 (m, 6H), 2.05 (qt, 2H). ESHRMS m/z 400.1473 (M+H, C21H19F2N3O3 requires 400.1467)

EXAMPLE 114

[0858] This example illustrates the production of 2-{3-[(tert-butoxycarbonyl) amino]propyl}-8-[2-(4-chlorophenyl)ethyl]-7-methoxy-4,5-dihydro-2H-benzo[g]-indazole-3-carboxylic acid,

1111

[0859] Step 1: Preparation of Methyl 2-{3-[(tert-butoxycarbonyl)amino]propyl}-8-[2-(4-chlorophenyl)ethyl]-7-methoxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate.

1112

[0860] 9-BBN (8.1 mL, 4.04 mmol of a 0.5M solution in THF) was added to a 100 mL round bottomed flask under Ar. Cooled to 10° C. in an ice/water bath. 4-Chlorostyrene (0.6 g, 4.04 mmol) was added dropwise via syringe. Stirred at room temperature for four hours. Methyl 8-bromo-2-{3-[(tert-butoxycarbonyl)amino]propyl}-7-methoxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate (1.00 g, 2.02 mmol) dissolved into THF (10 mL) was added, followed by Pd{dppf]Cl2CH2Cl2 (0.124 g, 0.101 mmol), and K3PO4 (2.28 mL, 4.54 mmol of a 2M solution in H2O). Heated at 60° C. for 8 hours. Stirred at room temperature overnight. Quenched with NaHCO3 (aq.) (100 mL). Extracted with ethyl acetate (2×100 mL). The combined organic phases were washed with brine, dried over MgSO4, filtered, and evaporated. Purified by flash column chromatography in 15% ethyl acetate/85% hexane. The resulting oil solidified upon standing. Recrystallized from ether/hexane (0.607 g, 54%): 1H NMR (CDCl3/300 MHz) 7.61 (s, 1H), 7.23-7.14 (m 4H), 6.72 (s, 1H), 4.98 (s, 1H), 4.63 (t, 2H), 3.92 (s, 3H), 3.82 (s, 3H), 3.11 (t, 2H), 2.99-2.88 (m, 8H), 2.05 qt, 2H), 1.44 (s, 9H). ESHRMS m/z 554.2389 M+H, C30H36ClN3O5 requires 554.2416).

[0861] Step 2: Preparation of 2-{3-[(tert-butoxycarbonyl)amino]propyl}-8-[2-(4-chlorophenyl)ethyl]-7-methoxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid.

1113

[0862] Methyl 2-{3-[(tert-butoxycarbonyl)amino]propyl}-8-[2-(4-chlorophenyl)-ethyl]-7-methoxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate (0.400 g, 0.722 mmol) was dissolved in a THF/ethanol/water mixture (10 mL, 7/2/1 respectively). Lithium hydroxide monohydrate (0.060 g, 1.44 mmol was added. Stirred overnight at room temperature. Diluted with ethyl acetate (50 mL) and extracted with 0.1N HCl (2×25 mL), and brine (25 mL). The organic phase was dried over MgSO4, filtered, and evaporated. The resulting white solid was recrystallized from ethyl acetate/hexane. (0.352 g, 90%): 1H NMR (DMSO tfa/300 MHz) 7.50 (s, 1H), 7.35-7.26 (m 4H), 6.92 (s, 1H), 6.89 (s, 1H), 4.49 (t, 2H), 3.83 (s, 3H), 3.05-2.91 (m, 10H), 1.89 (qt, 2H), 1.38 (s, 9H). ESHRMS m/z 540.2224 (M+H, C29H34ClN3O5 requires 540.2260).

[0863] Following the procedure described for the production of 2-{3-[(tert-butoxycarbonyl)amino]propyl}-8-[2-(4-chlorophenyl)ethyl]-7-methoxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid, the subsequent 2 compounds were prepared.

EXAMPLE 115

[0864] This example illustrates the production of 8-benzyl-2-{3-[(tert-butoxycarbonyl) amino]propyl}-7-methoxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid.

1114

[0865]

1
H NMR (DMSO tfa/300 MHz) 7.47 (s, 1H), 7.30-7.15 (m 5H), 6.95 (s, 1H), 6.82 (s, 1H), 4.47 (t, 2H), 3.93 (s, 2H), 3.83 (s, 3H), 2.94-2.89 (m, 6H), 1.87 (qt, 2H), 1.39 (s, 9H). ESHRMS m/z 492.2483 (M+H, C28H33N3O5 requires 492.2493).

EXAMPLE 116

[0866] This example illustrates the production of 2-{3-[(tert-butoxycarbonyl) amino]propyl}-7-methoxy-8-(3,3,3-trifluoropropyl)-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid.

1115

[0867]

1
H NMR (DMSO tfa/300 MHz) 7.55 (s, 1H), 6.94 (s, 1H), 6.84 (s, 1H), 4.50 (t, 2H), 3.84 (s, 3H), 2.96-2.80 (m, 8H), 2.60-2.52 (m, 2H), 1.90 (qt, 2H), 1.39 (s, 9H). ESHRMS m/z 498.2233 (M+H, C24H30F3N3O5, requires 498.2210).

EXAMPLE 117

[0868] This example illustrates the production of 2-{3-[(tert-butoxycarbonyl) amino]propyl}-8-[2-(4-chlorophenyl)ethyl]-7-methoxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid (0.275 g, 0.509 mmol) was slurried in CH2Cl2 (10 mL).

1116

[0869] The mixture was cooled to −20° C. Boron tribromide (5 mL, 5 mmol of a 1.0 M solution in CH2Cl2) was added dropwise via syringe. The mixture stirred at room temperature for three hours. Slowly added H2O dropwise to quench the reaction. The solvent was evaporated, and the resulting solid was purified by preparative reverse phase HPLC to yield a white solid (0.170 g): 1H NMR (DMSO tfa/300 MHz) 7.71 (s, 2H), 7.43 (s, 1H), 7.37-7.27 (m 4H), 6.74 (s, 1H), 4.56 (t, 2H), 2.93-2.80 (m, 10H), 2.08 (qt, 2H. ESHRMS m/z 426.1558 (M+H, C23H24ClN3O3 requires 426.1579).

[0870] Following the procedure described for the production of 2-(3-aminopropyl)-8-[2-(4-chlorophenyl)ethyl]-7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid trifluoroacetate, the subsequent 4 compounds were prepared.

EXAMPLE 118

[0871] This example illustrates the production of 2-(3-aminopropyl)-8-benzyl-7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid trifluoroacetate.

1117

[0872]

1
H NMR (DMSO tfa/300 MHz) 7.69 (s, 2H), 7.38 (s, 1H), 7.33-7.20 (m 5H), 6.76 (s, 1H), 4.54 (t, 2H), 3.91 (s, 2H), 2.92-2.78 (m, 6H), 2.05 (qt, 2H). ESHRMS m/z 378.1792 (M+H, C22H23N3O3, requires 378.1812).

EXAMPLE 119

[0873] This example illustrates the production of 2-(3-aminopropyl)-7-hydroxy-8-isobutyl-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid trifluoroacetate

1118

[0874]

1
H NM R (DMSO tfa/300 MHz) 7.70 (s, 2H), 7.36 (s, 1H), 6.71 (s, 1H), 4.57 (t, 2H), 2.91-2.79 (m 6H), 2.42 (d, 2H), 2.07 (qt, 2H), 1.95 (m, 1H), 0.89 (d, 6H). ESHRMS m/z 344.1957 (M+H, C19H25N3O3 requires 344.1969).

EXAMPLE 120

[0875] This example illustrates the production of 2-(3-aminopropyl)-8-(4-carboxy-3,3-dimethylbutyl)-7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid trifluoroacetate.

1119

[0876]

1
H NMR (DMSO tfa/300 MHz) 7.72 (s, 2H), 7.39 (s, 1H), 6.70 (s, 1H), 4.57 (t, 2H), 2.93-2.75 (m, 6H), 2.53-2.49 (m, 2H), 2.20 (s, 2H), 2.08 (qt, 2H), 1.57 (m, 2H), 1.06 (s, 6H). ESHRMS m/z 416.2171 (M+H, C22H29N3O5) requires 416.2180)

EXAMPLE 121

[0877] This example illustrates the production of 2-(3-aminopropyl)-7-hydroxy-8-(3,3,3-trifluoropropyl)-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid trifluoroacetate.

1120

[0878]

1
H NMR (DMSO tfa/300 MHz) 7.71 (s, 2H), 7.43 (s, 1H), 6.72 (s, 1H), 4.54 (t, 2H), 2.88-2.76 (m, 8H), 2.53-2.44 (m, 2H), 2.05 (qt, 2H). ESHRMS m/z 384.1551 (M+H, C18H2OF3N3O3 requires 384.1530).

EXAMPLE 122

[0879] This example illustrates the production of 3-hydroxy-2-(3-nitrophenyl)-5,6,8,9,10,11-hexahydro-7H-benzo[g][1,4]diazepino[1,2-b]indazol-7-one trifluoroacetate.

1121

[0880] Step 1: Preparation of Methyl 2-{3-[(tert-butoxycarbonyl)amino]propyl}-7-methoxy-8-(3-nitrophenyl)-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate.

1122

[0881] Methyl 8-bromo-2-{3-[(tert-butoxycarbonyl)amino]propyl}-7-methoxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate (1.00 g, 2.02 mmol), and 3-nitrophenyl boronic acid (0.674 g, 4.04 mmol) were slurried in 1-propanol (40 mL). Sodium carbonate (0.428 g, 4.06 mmol) in water (2 mL) was added, followed by palladium acetate (0.0136 g, 0.06 mmol), and triphenyl phosphine (0.0477 g, 0.182 mmol). The reaction mixture was heated to reflux for two hours. (Reaction mixture became homogeneous upon heating). The reaction was cooled to room temperature, and the propanol was evaporated to approximately 5 mL. The slurry was diluted with ethyl acetate (100 mL). Extracted with H2O (50 mL), and brine (50 mL). The organic phase was dried over MgSO4, filtered and evaporated. Purified by flash column chromatography in 15% ethyl acetate/85% hexane. The resulting solid was recrystallized from ethyl acetate/hexane. (0.704 g, 65%): 1H NMR (CDCl3/300 MHz) 8.47 (s, 1H), 8.17 (d, 1H), 7.90 (d, 1H), 7.81 (s, 1H), 7.56 (s, 1H), 7.56 (t, 1H), 6.89 (s, 1H), 4.96 (s, 1H), 4.63 (t, 2H), 3.93 (s, 3H), 3.87 (s, 3H), 3.12-2.99 (m, 6H), 2.03 (qt, 2H), 1.42 (s, 9H). ESHRMS m/z 537.2378 (M+H, C28H32N4O7 requires 537.2344.

[0882] Step 2: Preparation of 3-methoxy-2-(3-nitrophenyl)-5,6,8,9,10,11-hexahydro-7H-benzo[g][1,4]diazepino[1,2-b]indazol-7-one.

1123

[0883] 3-Methyl 2-{3-[(tert-butoxycarbonyl)amino]propyl}-7-methoxy-8-(3-nitrophenyl)-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate (0.7 g, 1.3 mmol) was combined with HCl in dioxane (10 mL, of a 4M solution). Stirred at room temperature for two hours. The solvent was then evaporated. A 2:1 mixture of NH4OH/CH3OH (20 mL/10 mL respectively) was added and stirred overnight at room temperature. The resulting solid was filtered and washed with methanol. (0.350, 66%): 1H NMR (CDCl3/300 MHz) 8.47 (s, 1H), 8.17 (d, 1H), 7.90 (d, 1H), 7.81 (s, 1H), 7.56 (s, 1H), 7.56 (t, 1H), 6.91 (s, 1H), 6.14 (s, 1H), 4.51 (t, 2H), 3.86 (s, 3H), 3.41 (q, 2H), 3.04-2.95 (m, 4H), 2.28 (qt, 2H). ESHRMS m/z 405.1573 (M+H, C22H20N4O4 requires 405.1557).

[0884] Step 3: Preparatio of 3-hydroxy-2-(3-nitrophenyl)-5,6,8,9,10,11-hexahydro-7H-benzo[g][1,4]diazepino[1,2-b]indazol-7-one trifluoroacetate.

1124

[0885] 3-methoxy-2-(3-nitrophenyl)-5,6,8,9,10,11-hexahydro-7H-benzo[g][1, 4]diazepino[1,2-b]indazol-7-one (0.300, 0.742 mmol) was slurried in CH2Cl2 (10 mL). The mixture was cooled to −20° C. Boron tribromide (7 mL, 7 mmol of a 1.0 M solution in CH2Cl2) was added dropwise via syringe. The mixture stirred at room temperature for three hours. Slowly added methanol dropwise to quench the reaction. The solvent was evaporated, and the resulting solid was purified by preparative reverse phase HPLC to yield a white solid (0.170 g): 1H NMR (DMSO tfa/300 MHz) 8.45 (s, 1H), 8.20-8.17 (m, 2H), 8.07 (d, 1H), 7.75-7.68 (m, 2H), 6.94 (s, 1H), 4.41 (t, 2H), 3.19 (q, 2H), 2.94-2.85 (m, 4H), 2.10 (qt, 2H). ESHRMS m/z 391.1430 (M+H, C21H18N4O4 requires 426.1579).

EXAMPLE 123

[0886] This example illustrates the production of 2-(3-aminopropyl)-7-hydroxy-8-(3-nitrophenyl)-2H-benzo[g]indazole-3-carboxylic acid trifluoroacetate.

1125

[0887] Step 1: Preparation of Methyl 2-{3-[(tert-butoxycarbonyl)amino]propyl}-7-methoxy-8-(3-nitrophenyl)-2H-benzo[g]indazole-3-carboxylate.

1126

[0888] Methyl 2-{3-[(tert-butoxycarbonyl)amino]propyl}-7-methoxy-8-(3-nitrophenyl)-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate (1.00 g, 1.86 mmol) was dissolved in anhydrous dioxane (30 mL). DDQ (0.423 g, 1.86 mmol) was added. Stirred at reflux for 10 hours. Stirred at room temperature overnight. The resulting solid was filtered, and washed with ethyl acetate (50 mL). The mother liquor was extracted with 1.0 N NaOH until the yellow color dissipated. Checked combined aqueous extracts by TLC for any product. Back extracted with ethyl acetate until the entire product was in organic extracts. The combined organic phases were washed with brine, dried over MgSO4, filtered and evaporated to yield a brown oil. Purified by flash column chromatography with 25% ethyl acetate/75% hexane. Obtained a yellow solid, which was recrystallized from ethanol/water (0.601 g, 61%). 1H NMR (CDCl3MHz) 8.57 (s, 1H), 8.55 (s, 1H), 8.24 (d, 1H), 8.03-7.94 (m, 2H), 7.65-7.54 (m, 2H), 7.36 (s, 1H), 4.97 (m, 3H), 4.07 (s, 3H), 3.98 (s, 3H), 3.15 (q, 2H), 2.19 (qt, 2H), 1.41 (s, 9H). ESHRMS m/z 535.2186 (M+H, C22H27N3O5 requires 535.2187).

[0889] Step 2: Preparation of 2-{3-[(tert-butoxycarbonyl)amino]propyl}-7-methoxy-8-(3-nitrophenyl)-2H-benzo[g]indazole-3-carboxylic Acid.

1127

[0890] Methyl 2-{3-[(tert-butoxycarbonyl)amino]propyl}-7-methoxy-8-(3-nitrophenyl)-2H-benzo[g]indazole-3-carboxylate (0.304 g, 0.569 mmol) was dissolved in a THF/ethanol/water mixture (10 mL, 7/2/1 respectively). Lithium hydroxide monohydrate (0.048 g, 1.15 mmol was added. Stirred overnight at room temperature. Diluted with ethyl acetate (50 mL) and extracted with 0.1N HCl (2×25 mL), and brine (25 mL). The organic phase was dried over MgSO4, filtered, and evaporated. The resulting white solid was recrystallized from ethyl acetate/hexane. (0.203 g, 68%): 1H NMR (DMSO tfa/300 MHz) 8.46 (s, 1H), 8.44 (s, 1H), 8.28 (d, 1H), 8.14 (d, 1H), 7.98 (d, 1H), 7.80 (t, 1H), 7.70-7.60 (m, 2H), 6.88 (s, 1H), 4.87 (t, 2H), 3.98 (s, 3H), 3.01 (q, 2H), 2.03 (qt, 2H), 1.36 (s, 9H). ESHRMS m/z 520.2021 (M+H, C27H28N4O7 requires 521.2031).

[0891] Step 3: Preparation of 2-(3-aminopropyl)-7-hydroxy-8-(3-nitrophenyl)-2H-benzo[g]indazole-3-carboxylic Acid Trifluoroacetate.

1128

[0892] 2-f 3-[(tert-butoxycarbonyl)amino]propyl}-7-methoxy-8-(3-nitrophenyl)-2H-benzo[g]indazole-3-carboxylic acid (0.188 g, 0.463 mmol) was slurried in CH2Cl2 (10 mL). The mixture was cooled to −20° C. Boron tribromide (5 mL, mmol of a 1.0 M solution in CH2Cl2) was added dropwise via syringe. The mixture stirred at room temperature for three hours. Slowly added water dropwise to quench the reaction. The solvent was evaporated, and the resulting solid was purified by preparative reverse phase HPLC to yield a white solid: 1H NMR (DMSO tfa/300 MHz) 8.54 (s, 1H), 8.44 (s, 1H), 8.28 (d, 1H), 8.19 (d, 1H), 7.92 (d, 1H), 7.81 (t, 1H), 7.74-7.57 (m, 3H), 7.48 (s, 1H), 4.94 (t, 2H), 2.88 (q, 2H), 2.21 (qt, 2H). ESHRMS m/z 407.1384 (M+H, C21H18N4O5 requires 407.1350).

EXAMPLE 124

[0893] This example illustrates the production of 3-hydroxy-2-(3-nitrophenyl)-8,9,10,11-tetrahydro-7H-benzo[g][1,4]diazepino[1,2-b]indazol-7-one trifluoroacetate.

1129

[0894] Step 1: Preparation of 3-methoxy-2-(3-nitrophenyl)-8,9,10,11-tetrahydro-7H-benzo[g][1,4]diazepino[1,2-b]indazol-7-one.

1130

[0895] Methyl 2-{3-[(tert-butoxycarbonyl)amino]propyl}-7-methoxy-8-(3-nitrophenyl)-2H-benzo[g]indazole-3-carboxylate (0.270 g, 0.505 mmol) was combined with HCl in dioxane (5 mL, of a 4M solution). Stirred at room temperature for two hours. The solvent was evaporated. A 2:1 mixture of NH4OH/CH3OH (6 mL/3 mL respectively) was added. Stirred overnight at room temperature. The resulting solid was filtered and washed with methanol. (0.196, 97%): 1H NMR (DMSO tfa/300 MHz) 8.46 (s, 1H), 8.42 (s, 1H), 8.26 (d, 1H), 8.13 (d, 1H), 7.91 (d, 1H), 7.78 (t, 1H), 7.66 (s, 1H), 6.60 (d, 1H), 4.80 (t, 2H), 3.97 (s, 3H), 3.28 (q, 2H), 2.31 (qt, 2H). ESHRMS m/z 403.1424 (M+H, C22H18N4O4 requires 403.1406).

[0896] Step 2: Preparation of 3-hydroxy-2-(3-nitrophenyl)-8,9,10,11-tetrahydro-7H-benzo[g][1,4]diazepino[1,2-b]indazol-7-one trifluoroacetate.

1131

[0897] 3-Methoxy-2-(3-nitrophenyl)-8,9,10,11-tetrahydro-7H-benzo[g][1,4]-diazepino[1,2-b]indazol-7-one (0.160 g, 0.398 mmol) was slurried in CH2Cl2 (10 mL). The mixture was cooled to −20° C. Boron tribromide (4 mL, 4 mmol of a 1.0 M solution in CH2Cl2) was added dropwise via syringe. The mixture stirred at room temperature for three hours. Methanol was slowly added dropwise to quench the reaction. The solvent was evaporated, and the resulting solid was purified by preparative reverse phase HPLC to yield a yellow solid: 1H NMR (DMSO tfa/300 MHz) 8.57 (s, 1H), 8.43 (s, 1H), 8.40 (d, 1H), 8.27-8.20 (m, 2H), 7.82-7.77 (m, 2H), 7.48-7.44(m, 2H), 4.76 (t, 2H), 3.27 (q, 2H), 2.27 (qt, 2H). ESHRMS m/z 389.1255 (M+H, C21H16N4O4 requires 389.1250).

EXAMPLE 125

[0898] This example illustrates the production of 2-(2-aminoethyl)-7-hydroxy-8-(3-nitrophenyl)-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid trifluoroacetate.

1132

[0899] Step 1: Preparation of Methyl-8-bromo-2-{2-[(tert-butoxycarbonyl)amino]ethyl}-7-methoxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate.

1133

[0900] Methyl 8-bromo-7-methoxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate (10.0 g, 29.7 mmol) was dissolved in DMF (150 mL). Cooled to 0° C., in a ice-water bath. Lithium t-butoxide (45 mL, 45 mmol of a 1.0 M solution in THF) was added dropwise via addition funnel. Stirred for 2 hours. N-boc-2-bromoethylamine (9.97 g, 44.5 mmol) in DMF (30 mL) was added via addition funnel. The ice bath was removed and the reaction stirred at room temperature overnight. Quenched with NH4Cl (aq.) (200 mL), and the layers were separated. The aqueous phase was extracted with ethyl acetate (2×200 mL). The combined organic phases were washed with brine, (200 mL), dried over MgSO4, filtered, and evaporated. The resulting white solid was recrystallized from hot ethanol/water. (11.95 g, 84%): 1H NMR (CDCl3/300 MHz) 8.01 (s, 1H), 6.78 (s, 1H), 4.93 (s, 1H), 4.68 (t, 2H), 3.91 (s, 6H), 3.60 (t, 2H), 3.02-2.89 (m, 4H), 1.,41 (s, 9H). ESHRMS m/z 480.1120 (M+H, C21H26BrN3O5 requires 480.1134).

[0901] Step 2: Preparation of Methyl 2-{2-[(tert-butoxycarbonyl)amino]ethyl}-7-methoxy-8-(3-nitrophenyl)-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate.

1134

[0902] Methyl-8-bromo-2-{2-[(tert-butoxycarbonyl)amino]ethyl}-7-methoxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate (4.01 g, 8.35 mmol) and 3-nitrophenyl boronic acid (2.78 g, 16.7 mmol) were slurried in 1-propanol (100 mL). Sodium carbonate (1.77 g, 16.7 mmol) in water (8 mL) was added, followed by palladium acetate (0.056 g, 0.25 mmol), and triphenyl phosphine (0.197 g, 0.750 mmol). The reaction mixture was heated to reflux for four hours. (Reaction mixture became homogeneous upon heating). The reaction cooled to room temperature, and the propanol was evaporated to approximately 10 mL. The slurry was diluted with ethyl acetate (200 mL). Extracted with H2O (100 mL), and brine (100 mL). The organic phase was dried over MgSO4, filtered and evaporated. Purified by flash column chromatography in 15% ethyl acetate/85% hexane. The resulting solid was recrystallized from ethyl acetate/hexane. (2.16 g, 50%): 1H NMR (CDCl3/300 MHz) 8.46 (s, 1H), 8.17 (d, 1H), 7.90 (s, 1H), 7.82 (s, 1H), 7.56 (t, 1H), 6.90 (s, 1H), 4.94 (s, 1H), 4.69 (t, 2H), 3.93 (s, 3H), 3.87 (s, 3H), 3.61 (t, 2H), 3.07-2.95 (m, 4H), 1.41 (s, 9H). ESHRMS m/z 523.2220 (M+H, C27H30N4O7 requires 537.2344).

[0903] Step 3: Preparation of 2-{2-[(tert-butoxycarbonyl)amino]ethyl}-7-methoxy-8-(3-nitrophenyl)-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic Acid.

1135

[0904] Methyl 2-{2-[(tert-butoxycarbonyl)amino]ethyl}-7-methoxy-8-(3-nitrophenyl)-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate (0.300 g, 0.547 mmol) was dissolved in a THF/ethanol/water mixture (10 mL, 7/2/1 respectively). Lithium hydroxide monohydrate (0.048 g, 1.15 mmol was added. Stirred overnight at room temperature. Diluted with ethyl acetate (50 mL) and extracted with 0.1N HCl (2×25 mL), and brine (25 mL). The organic phase was dried over MgSO4, filtered, and evaporated. The resulting yellow solid was triturated with hexane. (0.253 g, 87%): 1H NMR (DMSO tfa/300 MHz) 8.32 (s, 1H), 8.22 (d, 1H), 7.99 (s, 1H), 7.75 (t, 1H), 7.68 (s, 1H), 7.16 (s, 1H), 6.86 (s, 1H), 4.55 (t, 2H), 3.86 (s, 3H), 3.33 (t, 2H), 3.05-2.95 (m, 4H), 1.30 (s, 9H). ESHRMS m/z 509.2071 (M+H, C26H28N4O7 requires 509.2031).

[0905] Step 4: Preparation of 2-(2-aminoethyl)-7-hydroxy-8-(3-nitrophenyl)-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic Acid Trifluoroacetate.

1136

[0906] 2-{2-[(tert-butoxycarbonyl)amino]ethyl}-7-methoxy-8-(3-nitrophenyl)-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid (0.200 g, 0.393 mmol)) was slurried in CH2Cl2 (10 mL). The mixture was cooled to −20° C. Boron tribromide (4 mL, 4 mmol of a 1.0 M solution in CH2Cl2) was added dropwise via syringe. The mixture stirred at room temperature for three hours. Slowly added water dropwise to quench the reaction. The solvent was evaporated, and the resulting solid was purified by preparative reverse phase HPLC to yield a yellow solid, which was triturated with acetonitrile: 1H NMR (DMSO tfa/300 MHz) 8.42 (s, 1H), 8.21 (d, 1H), 8.07 (d, 1H), 7.91 (s, 2H), 7.78-7.72 (m, 2H), 6.96 (s, 1H), 4.74 (t, 2H), 3.31 (t, 2H), 2.99-2.90 (m, 4H). ESHRMS m/z 395.1364 (M+H, C20H18N4O5 requires 395.1350).

EXAMPLE 127

[0907] This example illustrates the production of 3-hydroxy-2-(3-nitrophenyl)-5,6,9,10-tetrahydrobenzo[g]pyrazino[1,2-b]indazol-7(8H)-one hydrobromide.

1137

[0908] Step 1: Preparation of 3-methoxy-2-(3-nitrophenyl)-5,6,9,10-tetrahydrobenzo[g]pyrazino[1,2-b]indazol-7(8H)-one.

1138

[0909] Methyl 2-{2-[(tert-butoxycarbonyl)amino]ethyl}-7-methoxy-8-(3-nitrophenyl)-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate (0.507 g, 0.970 mmol) was combined with HCl in dioxane (6 mL, of a 4M solution). Stirred at room temperature for three hours. The solvent was evaporated. A 2:1 mixture of NH4OH/CH3OH (10 mL/5 mL respectively) was added. Stirred overnight at room temperature. The resulting solid was filtered and washed with methanol. (0.330, 87%): 1H NMR (DMSO tfa/300 MHz) 8.35 (s, 1H), 8.24-8.19(m, 2H), 8.01 (d, 1H), 7.74 (t, 1H)), 7.19 (s, 1H), 4.31 (t, 2H), 3.86 (s, 3H), 3.59(t, 2H), 3.01-2.94 (m, 4H). ESHRMS m/z 391.1424 (M+H, C21H18N4O4 requires 391.1401).

[0910] Step 2: Preparation of 3-hydroxy-2-(3-nitrophenyl)-5,6,9,10-tetrahydrobenzo[g]pyrazino[1,2-b]indazol-7(8H)-one hydrobromide.

1139

[0911] 3-Methoxy-2-(3-nitrophenyl)-5,6,9,10-tetrahydro-benzo[g]pyrazino[1,2-b]indazol-7(8H)-one (0.250 g, 0.640 mmol) was slurried in CH2Cl2 (5 mL). The mixture was cooled to −20° C. Boron tribromide (2 mL, 2 mmol of a 1.0 M solution in CH2Cl2) was added dropwise via syringe. The mixture stirred at room temperature for three hours. Slowly added methanol dropwise to quench the reaction. The solvent was evaporated, and the resulting solid was triturated with acetonitrile: (0.222 g) 1H NMR (DMSO tfa/300 MHz) 8.45 (s, 1H), 8.21-8.17 (m, 2H), 8.07 (d, 1H), 7.73 (t, 1H), 7.69 (s, 1H), 6.96 (s, 1H), 4.30 (t, 2H), 3.61 (t, 2H), 2.96-2.89 (m, 4H). ESHRMS m/z 377.1276 (M+H, C20H16N4O4 requires 377.1244).

EXAMPLE 128

[0912] This example illustrates the production of 2-(2-aminoethyl)-7-hydroxy-8-(3-nitrophenyl)-2H-benzo[g]indazole-3-carboxylic acid trifluoroacetate.

1140

[0913] Step 1: Preparation of Methyl 2-{2-[(tert-butoxycarbonyl)amino]ethyl}-7-methoxy-8-(3-nitrophenyl)-2H-benzo[g]indazole-3-carboxylate.

1141

[0914] Methyl 2-{2-[(tert-butoxycarbonyl)amino]ethyl}-7-methoxy-8-(3-nitrophenyl)-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate (1.00 g, 1.91 mmol) was dissolved in anhydrous dioxane (30 mL). DDQ (0.652 g, 2.87 mmol) was added. Stirred at reflux overnight. The resulting solid was filtered, and washed with ethyl acetate (50 mL). The mother liquor was extracted with 1.0 N NaOH until the yellow color dissipated. Checked combined aqueous extracts by TLC for any product. Back extracted with ethyl acetate until the entire product was in organic extracts. The combined organic phases were washed with brine, dried over MgSO4, filtered and evaporated. Purified by flash column chromatography with 20% ethyl acetate/80% hexane. The resulting solid was recrystallized from ethyl acetate/hexane (0.720 g, 72%).

[0915]

1
H NMR (CDCl3/300 MHz) 8.56 (s, 2H), 8.24 (d, 1H), 8.02-7.94 (m, 2H), 7.64-7.54 (m, 2H), 7.36 (s, 1H), 5.03 (t, 2H), 4.94 (s, 1H), 3.98 (s, 3H), 3.76 (s, 3H), 3.75 (t, 2H), 1.35 (s, 9H). ESHRMS m/z 521.2024 (M+H, C27H28N4O7 requires 521.2031).

[0916] Step 2: Preparation of 2-{2-[(tert-butoxycarbonyl)amino]ethyl}-7-methoxy-8-(3-nitrophenyl)-2H-benzo[g]indazole-3-carboxylic Acid.

1142

[0917] Methyl 2-{2-[(tert-butoxycarbonyl)amino]ethyl}-7-methoxy-8-(3-nitrophenyl)-2H-benzo[g]indazole-3-carboxylate (0.282, 0.542 mmol) was dissolved in a THF/ethanol/water mixture (10 mL, 7/2/1 respectively). Lithium hydroxide monohydrate (0.045 g, 1.08 mmol was added. Stirred overnight at room temperature. Diluted with ethyl acetate (50 mL) and extracted with 0.1N HCl (2×25 mL), and brine (25 mL). The organic phase was dried over MgSO4, filtered, and evaporated. The resulting white solid was triturated with hexane. (0.225 g, 82%): 1H NMR (DMSO tfa/300 MHz) 8.44 (s, 2H), 8.29 (d, 1H), 0.812 (d, 1H), 7.98 (d, 1H), 7.80 (t, 1H), 7.69-7.60 (m, 2H), 6.92-(s, 1H); 4:90 (t, 2H), 3.97 (s, 3H), 3.50 (t, 2H), 1.25 (s, 9H). ESHRMS m/z 507.1884 (M+H, C26H26N4O7 requires 507.1874).

[0918] Step 3: Preparation of 2-(2-aminoethyl)-7-hydroxy-8-(3-nitrophenyl)-2H-benzo[g]indazole-3-carboxylic Acid Trifluoroacetate.

1143

[0919] 2-{2-[(tert-butoxycarbonyl)amino]ethyl}-7-methoxy-8-(3-nitrophenyl)-2H-benzo[g]indazole-3-carboxylic acid (0.180 g, 0.355 mmol) was slurried in CH2Cl2 (5 mL). The mixture was cooled to −20° C. Boron tribromide (2 mL, 2 mmol of a 1.0 M solution in CH2Cl2) was added dropwise via syringe. The mixture stirred at room temperature for three hours. Slowly added water dropwise to quench the reaction. The solvent was evaporated, and the resulting solid was purified by preparative reverse phase HPLC to yield a yellow solid triturated with acetonitrile: (0.082 g) 1H NMR (DMSO tfa/300 MHz) 8.51 (s, 1H), 8.48 (s, 1H), 8.25 (d, 1H), 8.17 (d, 1H), 7.96-7.86(m, 3H), 7.80 (t, 1H), 7.58 (s, 1H), 7.45 (s, 1H), 5.08 (t, 2H), 3.47 (t, 3H). ESHRMS m/z 393.1193 (M+H, C20H16N4O5 requires 393.1193).

EXAMPLE 129

[0920] This example illustrates the production of 8-(3-aminophenyl)-2-(3-aminopropyl)-7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid trifluoroacetate.

1144

[0921] 2-(3-aminopropyl)-7-hydroxy-8-(3-nitrophenyl)-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid trifluoroacetate (0.115 g) was dissolved in methanol (2 mL). Palladium on carbon (10%)(5 mg) was added. The reaction vessel was sealed and pressurized with H2 to 40 psi. Heated at 40° C. overnight. The reaction mixture was cooled to room temperature. It was then filtered through celite and evaporated to yield a tan solid, which was triturated with acetonitrile. (0.076 g) 1H NMR (DMSO tfa/300 MHz) 7.81-7.72 (m, 2H), 7.60-7.48 (m, 4H), 7.28 (s, 1H), 6.93 (s, 1H), 4.58 (t, 2H), 2.97-2.83 (m, 6H), 2.08 (qt, 2H). ESHRMS m/z 379.1749 (M+H, C21H22N4O3 requires 379.1765).

EXAMPLE 130

[0922] This example illustrates the production of 2-(3-aminophenyl)-3-hydroxy-8,9,10,1-tetrahydro-7H-benzo[g][1,4]diazepino[1,2-b]indazol-7-one hydrobromide.

1145

[0923] 3-methoxy-2-(3-nitrophenyl)-8,9,10,11-tetrahydro-7H-benzo[g][1,4]-diazepino[1,2-b]indazol-7-one (1.13 g, 2.81 mmol) was slurried in CH2Cl2 (50 mL). The mixture was cooled to −20° C. Boron tribromide (10 mL, 10 mmol of a 1.0 M solution in CH2Cl2) was added dropwise via syringe. The mixture stirred at room temperature for three hours. Slowly added methanol dropwise to quench the reaction. The solvent was evaporated, and the resulting solid was purified by preparative reverse phase HPLC to yield a yellow solid. The solid was dissolved in a THF/methanol mixture (15 mL each). Palladium on carbon (10%)(20 mg) was added. The reaction vessel was sealed and pressurized with H2 to 40 psi. Heated at 40° C. overnight. The reaction mixture was cooled to room temperature. It was filtered through celite and evaporated to yield a yellow solid. (0.7 g): 1H NMR (DMSO tfa/300 MHz) 8.36 (s, 1H), 8.29 (s, 1H), 7.77 (d, 1H), 7.42-7.32 (m, 4H), 7.02 (s, 1H), 4.71 (t, 2H), 3.25 (t, 2H), 2.25 (qt, 2H). ESHRMS m/z 359.1534 (M+H, C21H18N4O2 requires 359.1503).

EXAMPLE 131

[0924] This example illustrates the production of ethyl 2-(3-aminopropyl)-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate.

1146

[0925] To ethyl 6-trityl-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate (5.0 g, 0.01 mol) in DMF (50 mL) at 0° C. was added dropwise lithium t-butoxide (1M in THF, 20 mL). After stirring a half hour at 0° C., added 1-(N-boc-amino)-3-propyl bromide in DMF (10 mL) dropwise. Contents were stirred overnight and partitioned between EtOAc and water. The EtOAc layer was washed with brine, dried over MgSO4 and concentrated in vacuo leaving an amber oil, 8.9 g. The oil was purified by silica gel chromatography, eluting with 15% EtOAc/hexanes to give ethyl 2-{3-[(tert-butoxycarbonyl)-amino]propyl}-7-trityl-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate as a white foam, 2.2 g. The white foam was mixed with 4N HCl in dioxane (20 mL). A white solid was filtered to give the desired product, 2.0 g (61% yield). FABHRMS m/z 290.1617 (M+H, C14H20N5O2 requires 290.1612). 1H NMR (DMSO-d6+TFA/300 MHz): 8.02 (s, 1H); 7.80 (br s, 3H); 4.55 (t, 2H); 4.37 (q, 2H); 3.10-2.90 (m, 4H); 2.90-2.75 (m, 2H); 2.10-2.00 (m, 2H); 1.38 (t, 3H).

[0926] Anal. Calcd for C14H19N5O2 (0.4H2O, 2HCl): C, 45.51; H, 5.95; N, 18.96. Found: C, 45.64; H, 5.89; N, 18.77.

EXAMPLE 132

[0927] This example illustrates the production of ethyl 2-(3-aminopropyl)-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate.

1147

[0928] The protected ester from ethyl 2-(3-aminopropyl)-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate dihydrochloride was reacted according to the procedure for the production of 8-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxamide to give the desired as a light amber solid (75% yield). FABHRMS m/z 361.2012 (M+H, C17H25N6O3 requires 361.1983).

[0929] Anal. Calcd for C17H24N6O3 (0.1H2O): C, 56.37; H. 6.73; N, 23.20. Found: C, 56.03; H, 6.87; N, 22.98.

EXAMPLE 133

[0930] This example illustrates the production of 2-(3-aminopropyl)-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylic acid dihydrochloride.

1148

[0931] The protected ester from ethyl 2-(3-aminopropyl)-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate dihydrochloride was reacted according to the procedure for the production of 7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid to give a white solid which is 2-{3-[(tert-butoxy-carbonyl)amino]propyl}-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylic acid. The solid was triturated with 4N HCl in dioxane, stirred overnight and filtered to give the desired product as a white solid (61% yield). FABHRMS m/z 262.1284 (M+H, C12H16N5O2 requires 262.1299). 1H NMR (DMSO-d6+TFA/300 MHz): 8.20 (s, 1H); 7.95 (br s, 3H); 4.58 (t, 2H); 3.10-2.90 (m, 4H); 2.85-2.75 (m, 2H); 2.20-2.00 (m, 2H).

[0932] Anal. Calcd for C12H15N5O2 (2.5 HCl): C, 40.90; H, 5.00; N, 19.87. Found: C, 40.78; H, 5.15; N, 18.96.

EXAMPLE 134

[0933] This example illustrates the production of 2-(3-aminopropyl)-2,4,5,6-tetrahydro-pyrazolo[3,4-e]indazole-3-carboxamide dihydrochloride.

1149

[0934] ethyl 2-(3-aminopropyl)-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate dihydrochloride was reacted according to the procedure for the production of 8-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxamide to give a white solid (52% yield). FABHRMS m/z 261.1498 (M+H, C12H17N6O requires 261.1464).

[0935] Anal. Calcd for C12H16N6O (2.4 HCl): C, 41.44; H, 5.33; N, 24.16. Found: C, 41.84; H, 5.08; N, 23.87.

EXAMPLE 135

[0936] This example illustrates the production of ethyl 1-{3-[(tert-butoxycarbonyl)amino]propyl}-7-trityl-1,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate.

1150

[0937] Ethyl 1-{3-[(tert-butoxycarbonyl)amino]propyl}-6-trityl-1,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate was prepared according to the procedure for the production of ethyl 2-(3-aminopropyl)-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate dihydrochloride, using THF as the solvent, to give the desired product after silica gel chromatography, eluting with 25% EtOAc/hexanes, as a white solid (30% yield). FABHRMS m/z 632.3209 (M+H, C38H42N5O4 requires 632.3237). 1H NMR (CDCl3/300 MHz): 7.40-7.20 (m, 16H); 4.72 (br, 1H); 4.43 (q, 2H); 4.20 (t, 2H); 3.22-3.15 (m, 2H); 3.10-2.95 (m, 4H); 1.90 (quintet, 2H); 1.45 (t, 3H); 1.40 (s, 9H).

[0938] Anal. Calcd for C38H41N5O4: C, 72.24; H, 6.54; N, 11.09. Found: C, 72.22; H, 6.72; N, 10.66.

EXAMPLE 136

[0939] This example illustrates the production of 1-(3-aminopropyl)-1,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxamide dihydrochloride.

1151

[0940] Ethyl 1-{3-[(tert-butoxycarbonyl)amino]propyl}-6-trityl-1,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate, was reacted according to the procedure for the production of 8-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxamide to give the desired product as a white solid after trituration with 4N HCl in dioxane (70% yield). FABHRMS m/z 261.1434 (M+H, C12H17N6O requires 261.1458). 1H NMR (DMSO-d6+5%TFA/300 MHz): 8.30 (s, 1H); 8.10 (br, 3H); 4.40 (t, 2H); 3.10-3.00 (m, 2H); 3.00-2.80 (m, 4H); 2.20-2.05 (m, 2H).

[0941] Anal. Calcd for C12H16N6O (3 HCl): C, 37.18; —H, 5.46; N, 21.68. Found: C, 37.31; H, 5.88; N, 24.88.

EXAMPLE 137

[0942] This example illustrates the production of ethyl 1-(2,2,2-trifluoroethyl)-7-trityl-1,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate.

1152

[0943] Ethyl oxo(4-oxo-1-trityl-4,5,6,7-tetrahydro-1H-indazol-5-yl)acetate- or ethyl oxo(4-oxo-2-trityl-4,5,6,7-tetrahydro-2H-indazol-5-yl)acetate or ethyl oxo(4-oxo-2-trityl-4,5,6,7-tetrahydro-2H-indazol-5-yl)acetate (12.0 g, 0.025 mol) in glacial acetic acid (100 mL) was added dropwise trifluoroethylhydrazine (70% aqueous, 5.0 g, 0.03 mol). Contents were stirred overnight and diluted with water (100 mL), precipitating a solid, 16.6 g. The solid was triturated with 25% EtOAc/hexanes and filtered to give the desired as a white solid, 5.9 g (42% yield). FABHRMS m/z 557.2186 (M+H, C32H28F3N4O2 requires 557.2159). 1H NMR (CDCl3/300 MHz): 7.40-7.15 (m, 15H); 4.70 (q, 2H); 4.44 (q, 2H); 3.20 (t, 2H); 3.00 (t, 2H); 1.45 (t, 3H).

[0944] Anal. Calcd for C32H27F3N4O2 (0.8H2O): C, 67.31; H, 5.05; N, 9.81. Found: C, 67.26; H, 4.93; N, 9.03.

EXAMPLE 138

[0945] This example illustrates the production of ethyl 2-(2,2,2-trifluoroethyl)-2,4,5,6-tetrahydropyrazolo[34-e]indazole-3-carboxylate hydrochloride.

1153

[0946] The material obtained in the 25% EtOAc/hexanes filtrate of ethyl 1-(2,2,2-trifluoroethyl)-6-trityl-1,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate by concentration in vacuo was a waxy yellow solid, 3.0 g. The waxy solid was purified by silica gel chromatography, eluting with 10% EtOAc/hexanes to give a white foam, 430 mg. The foam was mixed with 4N HCl in dioxane (5 mL), stirred one hour, diluted with EtOAc and filtered to give the desired product as a white solid, 350 mg (4% yield). FABHRMS m/z 315.1077 (M+H, C13H14F3N4O2 requires 315.1063).

[0947] Anal. Calcd for C13H13F3N4O2 (0.9 HCl): C, 44.99; H, 4.04; N, 16.14. Found: C, 45.17; H, 3.86; N, 15.96.

EXAMPLE 139

[0948] This example illustrates the production of ethyl 1-(2,2,2-trifluoroethyl)-1,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate hydrochloride.

1154

[0949] Ethyl 1-(2,2,2-trifluoroethyl)-6-trityl-1,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate (442 mg, 0.8 mmol) was mixed with 4N HCl in dioxane, stirred one hour, diluted with EtOAc and filtered to give the desired product as a white solid, 192 mg (77% yield). FABHRMS m/z 315.1088 (M+H, C13H14F3N4O2 requires 315.1063.

[0950] Anal. Calcd for C13H13F3N4O2 (HCl): C, 44.52; H, 4.02; N, 15.97. Found: C, 44.53; H, 3.93; N, 15.96.

EXAMPLE 140

[0951] This example illustrates the production of 1-(2,2,2-trifluoroethyl)-7-trityl-1,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylic acid.

1155

[0952] Ethyl 1-(2,2,2-trifluoroethyl)-6-trityl-1,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate was reacted according to the procedure for the production of 7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid to give the desired as a white solid (88% yield). FABHRMS m/z 529.1875 (M+H, C30H23F3N4O2 requires 529.1846). 1H NMR (DMSO-d6/300 MHz): 7.85 (s, 1H); 7.42-7.10 (m, 15H); 5.23 (q, 2H); 3.10-2.90 (m, 4H).

[0953] Anal. Calcd for C30H23F3N4O2 (0.5H2O): C, 67.03; H, 4.50; N, 10.42. Found: C, 67.23; H, 4.24; N, 9.92.

EXAMPLE 141

[0954] This example illustrates the production of 1-(2,2,2-trifluoroethyl)-1,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylic acid hydrochloride.

1156

[0955] 1-(2,2,2-trifluoroethyl)-6-trityl-1,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylic acid (1.6 g, 3 mmol) and 4N HCl in dioxane (25 mL) were stirred overnight. Contents were filtered to give the desired product as a white solid, 831 mg (86% yield). FABHRMS m/z 287.0728 (M+H, C11H10F3N4O2 requires 287.0750).

[0956] Anal. Calcd for C11H9F3N4O2 (HCl, 0.2H2O): C, 40.49; H, 3.21; N, 17.17. Found: C, 40.50; H, 3.40; N, 16.62.

EXAMPLE 143

[0957] This example illustrates the production of 2-(2,2,2-trifluoroethyl)-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylic acid.

1157

[0958] Ethyl 2-(2,2,2-trifluoroethyl)-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate hydrochloride was reacted according to the procedure for the production of 7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid to give the desired product as a white solid (93% yield). FABHRMS m/z 287.0745 (M+H, C11H10F3N4O2 requires 287.0750).

[0959] Anal. Calcd for C11H9F3N4O2 (0.4H2O): C, 45.03; H, 3.37; N, 19.09. Found: C, 45.29; H, 3.00; N, 18.83.

EXAMPLE 144

[0960] This example illustrates the production of ethyl 1-(2-hydroxyethyl)-7-trityl-1,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate.

1158

[0961] To 2-hydroxyethylhydrazine (8.5 g, 0.1 mol) in methanol (300 mL) at 0° C. was added drop wise ethyl oxo(4-oxo-1-trityl-4,5,6,7-tetrahydro-1H-indazol-5-yl)acetate- or ethyl oxo(4-oxo-2-trityl-4,5,6,7-tetra hydro-2H-indazol-5-yl)acetate or ethyl oxo(4-oxo-2-trityl-4,5,6,7-tetrahydro-2H-indazol-5-yl)acetate (38.2 g, 0.08 mol) in CH2Cl2/methanol (1:1,100 mL). Contents were stirred overnight and a solid was filtered to give the desired product as a white solid, 6.6 g. The filtrate was concentrated by half and more solid was filtered, 8.5 g, also desired product (36% yield). FABHRMS m/z 519.2380 (M+H, C32H31N4O3 requires 519.2396). 1H NMR (DMSO-d6+TFA/300 MHz): 7.77 (s, 1H); 7.40-7.10 (m, 15H); 4.23 (q, 2H); 4.13-4.10 (m, 2H); 3.70-3.60 (m, 2H); 3.05-2.95 (m, 2H); 2.82-2.75 (m, 2H); 1.30 (t, 3H).

[0962] Anal. Calcd for C32H30N4O3: C, 74.11; H, 5.83; N, 10.80. Found: C, 73.84; H, 5.91; N, 10.85.

EXAMPLE 145

[0963] This example illustrates the production of ethyl 1-(2-hydroxyethyl)-1,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate hydrochloride.

1159

[0964] Ethyl 1-(2-hydroxyethyl)-6-trityl-1,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate (3.0 g, 0.006 mol) and 4N HCl in dioxane (20 mL) were stirred overnight and a solid was filtered to give the desired product as a white solid, 1.13 g (71% yield). FABHRMS m/z 277.1290 (M+H, C13H17N4O3 requires 277.1295).

[0965] Anal. Calcd for C13H17N4O3 (1.2 HCl): C, 48.79; H, 5.42; N, 17.51. Found: C, 48.47; H, 5.83; N, 17.56.

EXAMPLE 146

[0966] This example illustrates the production of 1-(2-hydroxyethyl)-1,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylic acid.

1160

[0967] Ethyl 1-(2-hydroxyethyl)-1,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate hydrochloride was reacted according to the procedure for the production of 7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid (76% yield). FABHRMS m/z 249.1021 (M+H, C11H13N4O3 requires 249.0982).

[0968] Anal. Calcd for C11H12N4O3: C, 52.91; H, 4.77; N, 22.90. Found: C, 53.22; H, 4.87; N, 22.57

EXAMPLE 147

[0969] This example illustrates the production of 1-(2-hydroxyethyl)-1,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxamide.

1161

[0970] Ethyl 1-(2-hydroxyethyl)-6-trityl-1,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate and 4N HCl in dioxane were stirred overnight and filtered to give ethyl 1-(2-hydroxyethyl)-1,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate as a white solid. The white solid was reacted according to the procedure for the production of 8-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxamide to give the desired product as a white solid (59% yield).

[0971] FABHRMS m/z 248.1151 (M+H, C11H14N5O2 requires 248.1147). 1H NMR (DMSO-d6+TFA/300 MHz): 8.10 (s, 1H); 4.25 (t, 2H); 3.80 (t, 2H); 3.02 (t, 2H); 2.80 (t, 2H).

[0972] Anal. Calcd for C11H13N5O2: C, 53.43; H, 5.30; N, 28.32. Found: C, 53.98; H, 5.30; N, 27.99.

EXAMPLE 148

[0973] This example illustrates the production of ethyl 1-benzyl-1,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate.

1162

[0974] Ethyl oxo(4-oxo-1-trityl-4,5,6,7-tetrahydro-1H-indazol-5-yl)acetate- or ethyl oxo(4-oxo-2-trityl-4,5,6,7-tetrahydro-2H-indazol-5-yl)acetate or ethyl oxo(4-oxo-2-trityl-4,5,6,7-tetrahydro-2H-indazol-5-yl)acetate and benzylhydrazine dihydrochloride were reacted according to the procedure for the production of ethyl 8-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate to give the desired product as a white solid (46% yield). FABHRMS m/z 323.1504 (M+H, C18H19N4O2 requires 323.1503).

[0975] Anal. Calcd for C18H18N4O2: C, 67.07; H, 5.63; N, 17.38. Found: C, 66.82; H, 5.48; N, 17.34.

EXAMPLE 149

[0976] This example illustrates the production of 1-benzyl-1,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxamide.

1163

[0977] Ethyl 1-benzyl-1,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate was reacted according to the procedure for the production of 8-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxamide to give the desired product as a tan solid (63% yield). FABHRMS m/z 294.1372 (M+H, C16H16N5O requires 294.1349).

[0978] Anal. Calcd for C16H15N5O: C, 65.52; H, 5.15; N, 23.88. Found: C, 65.27; H, 4.95; N, 23.85.

EXAMPLE 150

[0979] This example illustrates the production of ethyl 7-trityl-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate.

[0980] Ethyl oxo(4-oxo-1-trityl-4,5,6,7-tetrahydro-1H-indazol-5-yl)acetate- or ethyl oxo(4-oxo-2-trityl-4,5,6,7-tetrahydro-2H-indazol-5-yl)acetate or ethyl oxo(4-oxo-2-trityl-4,5,6,7-tetrahydro-2H-indazol-5-yl)acetate was reacted according to the procedure for the production of ethyl 8-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate to give the desired product as a white solid (83% yield). 1H NMR (CDCl3/300 MHz): 7.65 (s, 1H); 7.40-7.20 (m, 15H); 4.41 (q, 2H); 3.20-3.10 (m, 2H); 3.05-2.95 (m, 2H); 1.43 (t, 3H).

[0981] Anal. Calcd for C30H26N4O3(0.8H2O): C, 73.69; H, 5.69; N, 11.46. Found: C, 73.59; H, 6.02; N, 11.03.

EXAMPLE 151

[0982] This example illustrates the production of ethyl 2-{2-[(tert-butoxycarbonyl)amino]ethyl}-7-trityl-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate.

1164

[0983] Ethyl 6-trityl-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate and 2-(N-Boc-aminoethyl) bromide were reacted according to the procedure for the production of ethyl 2-(3-aminopropyl)-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate dihydrochloride to give the desired product as a white solid (60% yield). FABHRMS m/z 618.3076 (M+H, C37H40N5O4 requires 618.3080). 1H NMR (CDCl3/300 MHz): 7.63 (s, 1H); 7.40-7.20 (m, 15H); 4.90 (br s, 1H); 4.69-4.60 (m, 2H); 4.40 (q, 2H); 3.60-3.55 (m, 2H); 3.20-3.10 (m, 2H); 3.00-2.90 (m, 2H); 1.42 (t, 3H); 1.40 (s, 9H).

[0984] Anal. Calcd for C37H39N5O4: C, 71.94; H, 6.36; N, 11.34. Found: C, 71.65; H, 6.07; N, 11.32.

EXAMPLE 152

[0985] This example illustrates the production of 2-{2-[(tert-butoxycarbonyl)amino]ethyl}-7-trityl-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylic acid.

1165

[0986] Ethyl 2-{2-[(tert-butoxycarbonyl)amino]ethyl}-6-trityl-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate was reacted according to the procedure for the production of 7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid to give the desired product as a white solid (90% yield). FABHRMS m/z 590.2748 (M+H, C35H36N5O4 requires 590.2767). 1H NMR (DMSO-d6+5%TFA/300 MHz): 7.45-7.30 (m, 10H); 7.20-7.05 (m, 6H); 6.78 (br s, 1H); 4.50-4.40 (m, 2H); 3.35-3.25 (m, 2H); 3.10-3.00 (m, 2H); 2.90-2.80 (m, 2H); 1.14 (s, 9H).

[0987] Anal. Calcd for C35H35N5O4 (1.0H2O): C, 67.18; H, 6.28; N, 11.19. Found: C, 66.80; H, 5.93; N. 11.06.

EXAMPLE 153

[0988] This example illustrates the production of 2-(2-aminoethyl)-2,4,5,6-tetrahydropyrazolo [3,4-e]indazole-3-carboxylic acid trihydrochloride:

1166

[0989] 2-{2-[(tert-butoxycarbonyl)amino]ethyl}-6-trityl-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylic acid (442 mg, 0.75 mmol) and 4N HCl in dioxane (10 mL) were stirred overnight. Contents were filtered to give the desired product as a white solid, 140 mg (58% yield). FABHRMS m/z 248.1100 (M+H, C11H14N5O2 requires 248.1147). 1H NMR (DMSO-d6/300 MHz): 8.40 (br s, 3H); 8.05 (s, 1H); 4.80-4.70 (m, 2H); 3.30-3.20 (m, 2H); 3.10-3.00 (m, 2H); 2.95-2.85 (m, 2H).

[0990] Anal. Calcd for C11H13N5O2 (3 HCl, 1.0H2O): C, 35.26; H, 4.84; N, 18.69. Found: C, 35.40; H, 4.45; N, 18.81.

EXAMPLE 154

[0991] This example illustrates the production of ethyl 2-(2-hydroxyethyl)-7-trityl-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate.

1167

[0992] To 2-hydroxyethylhydrazine (8.5 g, 0.1 mol) in methanol (300 mL) at 0° C. was added dropwise ethyl oxo(4-oxo-1-trityl-4,5,6,7-tetrahydro-1H-indazol-5-yl)acetate- or ethyl oxo(4-oxo-2-trityl-4,5,6,7-tetrahydro-2H-indazol-5-yl)acetate or ethyl oxo(4-oxo-2-trityl-4,5,6,7-tetrahydro-2H-indazol-5-yl)acetate (38.2 g, 0.08 mol) in CH2Cl2/methanol (1:1,100 mL). Contents were stirred overnight and a solid was filtered to give ethyl 1-(2-hydroxyethyl)-6-trityl-1,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate as a white solid, 6.6 g. The filtrate was concentrated by half and more solid was filtered, 8.5 g, also ethyl 1-(2-hydroxyethyl)-6-trityl-1,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate. The filtrate was purified by silica gel chromatography eluting with 40% EtOAc/hexanes to give the desired product as a white solid, 2.6 g (6% yield). FABHRMS m/z 519.2422 (M+H, C32H31N4O3 requires 519.2396).

[0993] Anal. Calcd for C32H30N4O3 (0.3H2O): C, 73.35; H, 5.89; N, 10.69. Found: C, 73.01; H, 5.52; N, 10.37.

EXAMPLE 155

[0994] This example illustrates the production of 2-(2-hydroxyethyl)-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylic acid.

1168

[0995] Ethyl 2-(2-hydroxyethyl)-6-trityl-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate was reacted according to the procedure for the production of 7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid to give the intermediate carboxylic acid with the trityl group still intact. The intermediate was stirred with 4N HCl in dioxane and stirred overnight, diluted with EtOAc and filtered to give the desired product as a white solid (87% yield).

[0996] FABHRMS m/z 249.0975 (M+H, C11H13N4O3 requires 249.0982).

[0997] Anal. Calcd for C11H12N4O3(2 HCl): C, 41.14; H, 4.39; N, 17.44. Found: C, 41.03; H, 4.56; N, 17.39.

EXAMPLE 156

[0998] This example illustrates the production of 4,5,8,9-tetrahydro-3H-pyrazino[1,2-b]pyrazolo[3,4-g]indazol-6(7H)-one.

1169

[0999] Ethyl 2-{2-[(tert-butoxycarbonyl)amino]ethyl}-6-trityl-2,4,5,6-tetrahydropyrazolo-[3,4-e]indazole-3-carboxylate (1.3 g, 0.002 mol) and 4N HCl in dioxane (20 mL) were stirred overnight and filtered to give a white solid, 630 mg, analysis of which shows deprotection of both the Boc and trityl groups. This solid was reacted according to the procedure for the production of 8-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxamide to give the desired product as a white solid, 377 mg (82% yield). FABHRMS m/z 230.1033 (M+H, C11H12N5O requires 230.1036). 1H NMR (DMSO-d6+5%TFA/300 MHz): 8.15 (br s, 1H); 8.00 (s, 1H); 4.22 (t, 2H); 3.60 (t, 2H); 3.07-2.83 (m, 4H).

[1000] Anal. Calcd for C11H11N5O (0.2H2O): C, 56.74; H, 4.93; N, 30.08. Found: C, 56.92; H, 4.61; N, 29.95.

EXAMPLE 157.

[1001] This example illustrates the production of ethyl 2-[3-(tetrahydro-2H-pyran-2-yloxy)propyl]-7-trityl-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate.

1170

[1002] Ethyl 6-trityl-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate and 2-(3-bromopropoxy)tetrahydro-2H-pyran were reacted according to the procedure for the production of ethyl 2-(3-aminopropyl)-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate dihydrochloride to give the desired product as white crystals, 2.0 g (26% yield). FABHRMS m/z 617.3163 (M+H, C38H41N4O4 requires 617.3122).

[1003] Anal. Calcd for C38H40N4O4: C, 74.00; H, 6.54; N, 9.08. Found: C, 73.60; H, 6.58; N, 9.02.

EXAMPLE 158

[1004] This example illustrates the production of ethyl 2-(3-hydroxypropyl)-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate hydrochloride.

1171

[1005] Ethyl 2-[3-(tetrahydro-2H-pyran-2-yloxy)propyl]-6-trityl-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate (1.8 g, 0.003 mol) and 4N HCl in dioxane were stirred overnight and a solid was filtered to give the desired product as a white solid, 933 mg (98% yield). FABHRMS m/z 291.1444 (M+H, C14H19N4O3 requires 291.1452).

[1006] Anal. Calcd for C14H18N4O3(0.6 HCl): C, 53.86; H, 6.01; N, 17.95. Found: C, 53.74; H, 5.89; N, 18.11.

EXAMPLE 159

[1007] This example illustrates the production of 2-(3-hydroxypropyl)-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylic acid.

1172

[1008] 2-(3-hydroxypropyl)-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylic acid was prepared according to the procedure for the production of 8-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxamide, using ethyl 2-(3-hydroxypropyl)-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate hydrochloride, to give the desired product as a white solid (62% yield). FABHRMS m/z 263.1141 (M+H, C12H15N4O3 requires 263.1139).

[1009] Anal. Calcd for C12H14N4O3: C, 54.58; H, 5.29; N, 21.45. Found: C, 54.96; H, 5.38; N, 21.36.

EXAMPLE 160

[1010] This example illustrates the production of ethyl 2-(3-cyanopropyl)-7-trityl-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate.

1173

[1011] Ethyl 6-trityl-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate and 4-bromobutyronitrile were reacted according to the procedure for the production of ethyl 2-(3-aminopropyl)-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate dihydrochloride to give the desired product as off-white crystals (44% yield). FABHRMS m/z 542.2578 (M+H, C34H32N5O2 requires 542.2551). 1H NMR (CDCl3/300 MHz): 7.67 (s, 1H); 7.40-7.20 (m, 15H); 4.65 (t, 2H); 4.42 (q, 2H); 3.20-3.10 (m, 2H); 3.05-2.95 (m, 2H); 2.45-2.38 (m, 2H); 2.30-2.20 (m, 2H); 1.45 (t, 3H).

[1012] Anal. Calcd for C34H31N5O2 (0.5H2O): C, 74.16; H, 5.86; N, 12.72. Found: C, 74.14; H, 5.98; N, 12.13.

EXAMPLE 161

[1013] This example illustrates the production of 2-(4-aminobutyl)-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylic acid dihydrochloride:

1174

[1014] Ethyl 2-(3-cyanopropyl)-6-trityl-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate (2.0 g, 0.0037 mol), di-t-butyl-dicarbonate (3.3 g, 0.015 mol), platinum oxide (721 mg) and THF (50 mL) were shaken at 55 psi H2 on a Parr hydrogenator overnight. Contents were filtered through clay and the filtrate was concentrated in vacuo leaving a colorless oil. The oil, 2.5 N sodium hydroxide (5 mL), water (50 mL) and methanol (50 mL) were refluxed for 4 hours. Contents were allowed to cool and extracted with EtOAc. The EtOAc extract was concentrated in vacuo and the residue was triturated with 4N HCl in dioxane (25 mL) overnight. Contents were filtered to give the desired product as a white solid, 1.48 g (93% yield). FABHRMS m/z 276.1472 (M+H, C13H18N5O2 requires 276.1455). 1H NMR (DMSO-d6+5%TFA/300 MHz): 8.10 (s, 1H); 7.85 (br s, 3H); 4.50 (t, 2H); 3.10-3.00 (m, 2H); 2.98-2.88 (m 2H); 2.85-2.78 (m, 2H); 1.90-1.80 (m, 2H); 1.60-1.50 (m, 2H).

[1015] Anal. Calcd for C13H17N5O2 (3 HCl, 2.5H2O): C, 36.34; H, 5.86; N, 16.30. Found: C, 36.33; H, 5.75; N, 15.72.

EXAMPLE 162

[1016] This example illustrates the production of 2-(3-cyanopropyl)-2,4,5,6-tetrahydro-pyrazolo[3,4-e]indazole-3-carboxylic acid hydrochloride:

1175

[1017] Ethyl 2-(3-cyanopropyl)-6-trityl-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate (5.8 g, 0.011 mol) and 4N HCl in dioxane (40 mL) were stirred overnight. Contents were concentrated in vacuo and the residue was triturated with EtOAc and filtered to give a white solid, 3.4 g. The white solid was reacted according to the procedure for the production of 7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid to give the desired as a white solid (55% yield). FABHRMS m/z 272.1122 (M+H, C13H14N5O2 requires 272.1142).

[1018] Anal. Calcd for C13H13N5O2 (HCl, 0.2H2O): C, 50.15; H, 4.66; N, 22.49. Found: C, 50.34; H, 4.43; N, 21.95.

EXAMPLE 163

[1019] This example illustrates the production of ethyl 7-[(benzyloxy)methyl]-2,4,5,7-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate:

1176

[1020] To 1,5,6,7-tetrahydro-4H-indazol-4-one (8.9 g, 0.065 mol) and benzyl chloromethyl ether (9.7 mL, 0.07 mol) in CH2Cl2 (500 mL) was added pyridine (10 mL) and DMAP (345 mg). Contents were stirred overnight before filtering through a pad of silica gel, eluting with 50% EtOAc/hexanes to give a mixture of 1-benzyloxymethy-1,5,6,7-tetrahydro-4H-indazol-4-one and 2-benzyloxymethy-1,5,6,7-tetrahydro-4H-indazol-4-one as a colorless oil (55% yield). To the mixture of isomers (9.2 g, 0.036 mol) and diethyl oxalate (4.9 mL, 0.036 mol) in ether (200 mL) was added dropwise lithium bis(trimethylsilyl)amide (1M in THF, 36 mL). Contents were stirred 3 hours and quenched with water. The aqueous layer was made acidic with 1N HCl to pH 2 and extracted with EtOAc, which was dried over MgSO4 and concentrated in vacuo leaving a mixture of ethyl oxo(4-oxo-1-benzyloxymethyl-4,5,6,7-tetrahydro-1H-indazol-5-yl)acetate and ethyl oxo(4-oxo-2-benzyloxy-methyl-4,5,6,7-tetrahydro-1H-indazol-5-yl)acetate as a light amber oil, 12.8 g (100% yield). To the mixture of isomers (12.8 g, 0.036 mol) in glacial acetic acid (100 mL) was added dropwise hydrazine hydrate (1.7 mL, 0.036 mol) in glacial acetic acid (20 mL). Contents were stirred overnight and concentrated in vacuo. The residue was mixed with aqueous methanol, precipitating a solid which was filtered to give a solid (2.5 g). The solid was recrystallized from EtOAc to give the desired product as an off-white solid, 595 mg (5% yield). The aqueous methanolic filtrate was purified in ethyl 6-[(benzyloxy)methyl]-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate below. FABHRMS m/z 353.1619 (M+H, C19H21N4O3 requires 353.1614). 1H NMR (CDCl3/300 MHz): 9.20 (brs, 1H); 7.90 (s, 1H); 7.40-7.20 (m, 5H); 5.50 (s, 2H); 4.60 (s, 2H); 4.40 (q, 2H); 3.20-2.95 (m, 4H); 1.40 (t, 3H).

[1021] Anal. Calcd for C19H20N4O3: C, 64.75; H, 5.64; N, 15.90. Found: C, 64.76; H, 5.72; N, 15.90.

EXAMPLE 164

[1022] This example illustrates the production of ethyl 6-[(benzyloxy)methyl]-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate:

1177

[1023] The aqueous methanolic filtrate from ethyl 7-[(benzyloxy)methyl]-2,4,5,7-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate was purified by silica gel chromatography eluting with 35% EtOAc/hexanes to give after recrystallization from EtOAc/hexanes, the desired product as a white solid, 700 mg (6% yield). FABHRMS m/z 353.1614 (M+H, C19H21N4O3 requires 353.1623). 1H NMR (CDCl3/300 MHz): 9.40 (br s, 1H); 7.92 (s, 1H); 7.40-7.20 (m, 5H); 5.60 (s, 2H); 4.60 (s, 2H); 4.40 (q, 2H); 3.25-3.00 (m, 4H); 1.45 (t, 3H).

[1024] Anal. Calcd for C19H21N4O3: C, 64.76; H, 5.72; N, 15.90. Found: C, 64.49; H, 5.50; N, 15.84.

[1025] EXAMPLE 165.

[1026] This example illustrates the production of 2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylic acid hydrochloride

1178

[1027] A mixture of ethyl 7-[(benzyloxy)methyl]-2,4,5,7-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate and ethyl 6-[(benzyloxy)methyl]-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate (1.1 gm, 0.0032 mol) was heated in 3N HCl overnight. Contents were allowed to cool and evaporated by half under a stream of N2, then filtered to give the desired product as a white solid, 385 mg (50% yield). FABHRMS m/z 205.0704 (M+H, C9H9N4O2 requires 205.0726).

[1028] Anal. Calcd for C9H8N4O2 (1 HCl, 0.4H2O): C, 43.61; H, 3.99; N, 22.60. Found: C, 43.81; H, 4.40; N, 22.75.

EXAMPLE 166

[1029] This example illustrates the production of 2,6-dihydropyrazolo[3,4-e]indazole-3-carboxylic acid hydrochloride:

1179

[1030] A mixture of ethyl 7-[(benzyloxy)methyl]-2,4,5,7-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate and ethyl 6-[(benzyloxy)methyl]-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate (5.3 g, 0.015 mol) and DDQ (3.4 g, 0.015 mol) in dioxane was refluxed 5 hours. Contents were allowed to cool and the by-product was filtered. The filtrate was concentrated in vacuo leaving an amber foam (4.6 g). The amber foam, 3N HCl (50 mL) and methanol (25 mL) were refluxed overnight. Contents were allowed to cool and concentrated in vacuo. The residue was triturated with methanol and filtered to give the desired product as a light amber solid, 1.2 g (41% yield). FABHRMS m/z 203.0578 (M+H, C9H7N4O2 requires 203.0564). 1H NMR (DMSO-d6/300 MHz): 8.30 (s, 1H); 8.00 (d, 1H); 7.43 (d, 1H);

[1031] Anal. Calcd for C9H6N4O2 (0.9 HCl): C, 46.00; H, 2.96; N, 23.84. Found: C, 46.21; H, 3.34; N, 23.94.

EXAMPLE 167

[1032] This example illustrates the production of 1,6-dihydropyrazolo[3,4-e]indazole-3-carboxamide:

1180

[1033] A mixture of ethyl 7-[(benzyloxy)methyl]-2,4,5,7-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate and ethyl 6-[(benzyloxy)methyl]-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate (1.7 g, 0.005 mol) and DDQ (1.1 g, 0.005 mol) in dioxane was refluxed 5 hours. Contents were allowed to cool and the by-product was filtered. The filtrate was concentrated in vacuo leaving an amber foam. The amber foam, TFA (20 mL) and CH2Cl2 (20 mL) were refluxed overnight. Contents were allowed to cool and concentrated in vacuo leaving an amber solid. The residue was triturated with methanol and filtered to give ethyl 2,6-dihydropyrazolo[3,4-e]indazole-3-carboxylate as a light amber solid, 1.3 g (76% yield). The solid (990 mg, 0.003 mol), conc ammonium hydroxide (30 mL) and methanol (15 mL) were stirred in a stoppered flask for 6 days. Contents were poured into a beaker to let the volatiles evaporate and filtered to give a tan solid. The solid was triturated with methanol and filtered to give the desired product as a tan solid, 577 mg (96% yield). (FABHRMS m/z 202.0725 (M+H, C9H8N5O requires 202.0723).

[1034]

1
H NMR (DMSO-d6+TFA/300 MHz): 8.26 (s, 1H); 8.12 (d, 1H); 7.40 (d, 1H).

[1035] Anal. Calcd for C9H7N5O (0.7H2O): C, 50.56; H, 3.96; N, 32.76. Found: C, 50.87; H, 4.11; N, 29.74.

EXAMPLE 168

[1036] This example illustrates the production of 2-allyl-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylic acid hydrochloride:

1181

[1037] To ethyl 7-[(benzyloxy)methyl]-2,4,5,7-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate (1.8 g, 0.005 mol) in DMF (15 mL) was added a 60% dispersion of sodium hydride in mineral oil (204 mg). Contents were stirred 2 hours and allyl bromide (0.512 mL, 0.006 mol) was added. Contents were stirred overnight, quenched with water, extracted with EtOAc, dried over MgSO4 and concentrated in vacuo leaving an oil. The oil was purified by silica gel chromatography eluting with 50% EtOAc/hexanes. Fr 2-3 gave ethyl 2-allyl-2,4,5,6-tetrahydropyrazolo-[3,4-e]indazole-3-carboxylate as a yellow oil (344 mg). Fr 4-6 gave ethyl 1-allyl-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate as a yellow oil (671 mg). Fr 2-3 and 6N HCl were refluxed overnight, allowed to cool and concentrated in vacuo. The residue was triturated with methanol and filtered to give the desired product as a white solid (80% yield). FABHRMS m/z 245.1050 (M+H, C12H13N4O2 requires 245.1033). 1H NMR (DMSO-d6+TFA/300 MHz): 8.15 (s, 1H); 6.10-5.90 (m, 1H); 5.20-4.93 (m, 4H); 3.10-2.90 (m, 4H).

[1038] Anal. Calcd for C12H12N4O2 (HCl, H2O): C, 48.25; H, 5.06; N, 18.75. Found: C, 48.28; H, 4.90; N, 18.67.

EXAMPLE 169

[1039] This example illustrates the production of 2-allyl-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxamide:

1182

[1040] Ethyl 2-allyl-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate, prepared in 2-allyl-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylic acid hydrochloride was reacted according to the procedure for the production of 8-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxamide, to give the desired product as a white solid (60% yield). FABHRMS m/z 244.1159 (M+H, C12H14N5O requires 244.1193).

[1041] Anal. Calcd for C12H13N5O (0.25H2O): C, 58.17; H, 5.49; N, 28.27. Found: C, 58.54; H, 5.86; N, 27.81.

EXAMPLE 170

[1042] This example illustrates the production of ethyl 2-allyl-7-trityl-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate:

1183

[1043] Ethyl 6-trityl-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate was reacted according to the procedure for the production of ethyl 2-(3-aminopropyl)-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate dihydrochloride to give the desired product as a white solid (33% yield).

[1044] Anal. Calcd for C33H30N4O2: C, 77.02; H, 5.88; N, 10.89. Found: C, 76.98; H, 5.88; N, 10.72.

EXAMPLE 171

[1045] This example illustrates the production of 1-allyl-1,4,5,6-tetrahydro-pyrazolo[3,4-e]indazole-3-carboxylic acid hydrochloride:

1184

[1046] Ethyl 1-allyl-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate, obtained from Fr 4-6 of 2-allyl-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylic acid hydrochloride and 6N HCl were refluxed overnight, allowed to cool and concentrated in vacuo. The residue was triturated with methanol and filtered to give the desired product as a white solid (87% yield). FABHRMS m/z 245.1052 (M+H, C12H13N4O2 requires 245.1033).

[1047] Anal. Calcd for C12H12N4O2 (HCl): C, 51.35; H, 4.67; N, 19.96. Found: C, 51.23; H, 4.77; N, 19.52.

EXAMPLE 172

[1048] This example illustrates the production of 1-allyl-1,4,5,6-tetrahydro-pyrazolo[3,4-e]indazole-3-carboxamide:

1185

[1049] Ethyl 1-allyl-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate, prepared in 1-allyl-1,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylic acid hydrochloride was reacted according to the procedure for the production of 8-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxamide, to give the desired product as a white solid (65% yield). FABHRMS m/z 244.1179 (M+H, C12H14N5O requires 244.1193). 1HNMR (DMSO-d6+TFA/300 MHz): 8.00 (s, 1H); 6.10-5.95 (m, 1H); 5.20-4.85 (m, 4H); 3.10-2.80 (m, 4H).

[1050] Anal. Calcd for C12H13N5O (0.3H2O): C, 57.96; H, 5.51; N, 28.16. Found: C, 57.95; H, 5.22; N, 26.32.

EXAMPLE 173

[1051] This example illustrates the production of 4,5-dibromo-2,6-dihydropyrazolo[3,4-e]indazole-3-carboxylic acid:

1186

[1052] To ethyl 6-trityl-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate (1.0 g, 0.002 mol) and sodium acetate (230 mg) in glacial acetic acid was added dropwise, bromine (0.380 mL, 0.0074 mol). Contents were heated at 90° C. for 3 hours, allowed to cool, and filtered to yield a yellow solid. The yellow solid was triturated with CH2Cl2 and filtered to give ethyl 4,5-dibromo-2,6-dihydropyrazolo[3,4-e]indazole-3-carboxylate as a white solid. Ethyl 4,5-dibromo-2,6-dihydropyrazolo[3,4-e]indazole-3-carboxylate, 2.5N sodium hydroxide (0.5 mL), water (0.5 mL) and methanol (5 mL) were stirred overnight. Contents were made acidic to pH 2 with 1N HCl and filtered to give the desired product as a white solid, 310 mg (60% yield). FABHRMS m/z 358.8586 (M+H, C9H5Br2N4O2 requires 358.8597). 1H NMR (DMSO-d6+TFA/300 MHz): 8.20 (s, 1H).

[1053] Anal. Calcd for C9H4Br2N4O2 (0.8H2O): C, 28.87; H, 1.51; N, 14.97. Found: C, 28.96; H, 1.73; N, 14.77.

EXAMPLE 174

[1054] This example illustrates the production of 2-[bis(benzylthio) methylenelcyclohexane-1,3-dione:

1187

[1055] To 1,3-cyclohexanedione (11.2 g, 0.1 mol) in DMF (100 mL) was added CS2 (10 mL, 0.17 mol), and potassium carbonate (41.4 g, 0.3 mol). Contents were stirred for 3 hours and benzyl chloride (23 mL, 0.2 mol) was added dropwise. Contents were stirred overnight. Contents were partitioned between water and EtOAc. The EtOAc layer was dried over MgSO4 and concentrated in vacuo. The residue was filtered through a plug of silica gel, eluting with 25% EtOAc/hexanes. Crystals grew in the filtrate and were filtered to give the desired product as orange flakes, 9.4 g (26% yield). FABHRMS m/z 369.0972 (M+H, C21H21O2S requires 369.0978). 1H NMR (CDCl3/300 MHz): 7.40-7.25 (m, 10H); 4.20 (s, 4H); 2.60 (t, 4H); 1.95 (quintet, 2H).

[1056] Anal. Calcd for C21H20O2S: C, 68.44; H, 5.47. Found: C, 68.29; H, 5.37.

EXAMPLE 175

[1057] This example illustrates the production of 3-(benzylthio)-1-[(4-methylphenyl)sulfonyl]-1,5,6,7-tetrahydro-4H-indazol-4-one:

1188

[1058] 2-[bis(benzylthio)methylene]cyclohexane-1,3-dione (7.0 g, 0.019 mol) and p-toluenesulfonhydrazide (3.9 g, 0.021 mol) in methanol (100 mL) were stirred overnight. Contents were filtered to give the desired product as a white solid, 6.2 g (79% yield). FABHRMS m/z 413.0970 (M+H, C21H21N2O3S2 requires 413.0988). 1H NMR (CDCl3/300 MHz): 7.88 (d, 2H); 7.43-7.27 (m, 7H); 4.35 (s, 3H); 3.24 (t, 2H); 2.45 (s, 3H); 2.43 (t, 2H); 2.20 (quintet, 2H).

[1059] Anal. Calcd for C21H20N2O3S2: C, 60.98; H, 4.75; N, 6.79. Found: C, 61.14; H, 4.89; N, 6.79.

EXAMPLE 176

[1060] This example illustrates the production of ethyl {3-(benzylthio)-1-[(4-methylphenyl)sulfonyl]-4-oxo-4,5,6,7-tetrahydro-1H-indazol-5-yl}(oxo)acetate:

1189

[1061] 3-(benzylthio)-1-[(4-methylphenyl)sulfonyl]-1,5,6,7-tetrahydro-4H-indazol-4-one was reacted according to the procedure for the production of ethyl (7-hydroxy-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)(oxo)acetate to give the desired product as a yellow solid (87% yield). FABHRMS m/z 513.1179 (M+H, C25H25N2O6S2 requires 513.1149). 1H NMR (CDCl3/300 MHz): 7.90 (d, 2H); 7.45-7.25 (m, 7H); 4.42-4.35 (m, 4H); 3.30-3.15 (m, 4H); 2.48 (s, 3H); 1.40 (t, 3H).

[1062] Anal. Calcd for C25H24N2O6S2: C, 58.58; H, 4.72; N, 5.46. Found: C, 58.63; H, 4.51; N, 5.83.

EXAMPLE 177

[1063] This example illustrates the production of ethyl 8-(benzylthio)-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate:

1190

[1064] Ethyl {3-(benzylthio)-1-[(4-methylphenyl)sulfonyl]-4-oxo-4,5,6,7-tetrahydro-1H-indazol-5-yl}(oxo)acetate and hydrazine monohydrochloride were reacted according to the procedure for the production of ethyl 8-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate, refluxing in methanol, to give the desired product as yellow solid (38% yield). FABHRMS m/z 355.1220 (M+H, C18H19N4O2S requires 355.1223). 1H NMR (DMSO-d6+5%TFA/300 MHz): 7.30-7.20 (m, 5H); 4.38 (s, 2H); 4.35 (q, 2H); 3.05 (t, 2H); 2.85 (t, 2H); 1.35 (t, 3H).

[1065] Anal. Calcd for C18H18N4O2S: C, 61.00; H, 5.12; N, 15.81. Found: C, 60.53; H, 4.91; N, 15.38.

EXAMPLE 178

[1066] This example illustrates the production of 8-(benzylthio)-2,4,5,6-tetrahydropyrazolo [3,4-e]indazole-3-carboxamide:

1191

[1067] Ethyl 8-(benzylthio)-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate was reacted according to the procedure for the production of 8-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxamide to give the desired as an off-white solid (60% yield). FABHRMS m/z 326.1065 (M+H, C16H16N5OS requires 326.1070). 1H NMR (DMSO-d6+5%TFA/300 MHz): 7.40 (br, 1H); 7.30-7.15 (m, 5H); 4.35 (s, 2H); 3.05 (t, 2H); 2.80 (t, 2H).

[1068] Anal. Calcd for C16H15N5OS (0.6H2O): C, 57.16; H, 4.86; N, 20.83. Found: C, 57.11; H, 4.73; N, 20.68.

EXAMPLE 179

[1069] This example illustrates the production of 8-(benzylthio)-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylic acid:

1192

[1070] Ethyl 8-(benzylthio)-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate was reacted according to the procedure for the production of 7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid to give the desired as an off-white solid (53% yield). FABHRMS m/z 327.0930 (M+H, C16H15N4O2S requires 327.0910). 1H NMR (CDCl3/300 MHz)

[1071] Anal. Calcd for C16H14N4O2S: C, 58.88; H, 4.32; N, 17.17. Found: C, 58.34; H, 4.62; N, 15.97.

EXAMPLE 180

[1072] This example illustrates the production of 2-(3-t-butoxycarbonylaminopropyl)-8-(benzylthio)-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylic acid:

1193

[1073] Ethyl 8-(benzylthio)-6-[(4-methylphenyl)sulfonyl]-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate was prepared according to the procedure for the production of ethyl 8-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate, using ethyl {3-(benzylthio)-1-[(4-methylphenyl)sulfonyl]-4-oxo-4,5,6,7-tetrahydro-1H-indazol-5-yl}(oxo)acetate and reacted according to the procedure for the production of ethyl 2-(3-aminopropyl)-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate dihydrochloride, to give a red oil. The red oil was reacted according to the procedure for the production of 7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid to give the desired product after trituration with EtOAc, as a white solid (50% yield). FABHRMS m/z 484.1999 (M+H, C24H30N5O4S requires 484.2013). 1H NMR (DMSO-d6+TFA/300 MHz): 7.30-7.15 (m, 5H); 4.60-4.45 (m, 2H); 4.38 (s, 2H); 3.10-2.93 (m, 4H); 2.90-2.80 (m, 2H); 2.00-1.85 (m, 2H); 1.40 (s, 9H).

[1074] Anal. Calcd for C24H29N5O4S: C, 59.61; H, 6.04; N, 14.48. Found: C, 59.34; H, 6.09; N, 14.02.

EXAMPLE 181

[1075] This example illustrates the production of 2-(3-aminopropyl)-8-(benzylthio)-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylic acid dihydrochloride:

1194

[1076] Ethyl 2-{3-[(tert-butoxycarbonyl)amino]propyl}-8-(benzylthio)-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate (171 mg, 0.35 mmol) and 4N HCl in dioxane (10 mL) were stirred overnight, diluted with EtOAc and filtered to give a white solid, 137 mg (86% yield). FABHRMS m/z 384.1457 (M+H, C19H22N5O2S requires 384.1489). 1H NMR (DMSO-d6+TFA/300 MHz): 7.80 (br, 3H); 7.30-7.20 (m, 5H); 4.60 (t, 2H); 4.40 (s, 2H); 3.10-3.00 (m, 2H); 2.90-2.80 (m, 4H); 2.20-2.00 (m, 2H).

[1077] Anal. Calcd for C19H21N5O2S (2HCl): C, 50.00; H, 5.08; N, 15.35. Found: C, 49.66; H, 5.02; N, 15.00.

EXAMPLE 182

[1078] This example illustrates the production of ethyl 2-(3-aminopropyl)-8-(benzylthio)-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate dihydrochloride:

1195

[1079] Ethyl 8-(benzylthio)-6-[(4-methylphenyl)sulfonyl-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate was prepared according to the procedure for the production of ethyl 8-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate using ethyl 2-{3-[(tert-butoxycarbonyl)amino]propyl}-8-(benzylthio)-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate and reacted according to the procedure for the production of ethyl 2-(3-aminopropyl)-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate dihydrochloride, to give a red oil. The red oil was mixed with 4N HCl in dioxane and stirred overnight, then filtered to give the desired product after trituration with EtOAc, as a white solid (80% yield). FABHRMS m/z 412.1796 (M+H, C21H26N5O2S requires 412.1802). 1H NMR (DMSO-d6+TFA/300 MHz): 7.80 (br, 3H); 7.35-7.10 (m, 5H); 4.60-4.50 (m, 2H); 4.35-4.25 (m, 4H); 3.10-3.00 (m, 2H); 2.90-2.80 (m, 4H); 2.20-2.00 (m, 2H); 1.40-1.30 (m, 3H).

[1080] Anal. Calcd for C21H25N5O4S (2HCl): C, 52.06; H, 5.62; N, 14.46. Found: C, 52.22; H, 6.18; N, 14.62.

EXAMPLE 183

[1081] This example illustrates the production of 1-(benzylthio)-4,5,7,8,9,10-hexahydro[1,4]diazepino[1,2-b]pyrazolo[3,4-g]indazol-6(3H)-one:

1196

[1082] Ethyl 2-(3-aminopropyl)-8-(benzylthio)-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate dihydrochloride (1.0 g, 0.0024 mol), conc ammonium hydroxide (30 mL) and methanol (15 mL) were stirred in a stoppered flask for 72 hours. Contents were poured into a beaker to allow volatiles to evaporate and then filtered to give the desired product as a pale green solid, 310 mg (35% yield). FABHRMS m/z 366.1386 (M+H, C19H20N5O2S requires 366.1383). 1H NMR (DMSO-d6+TFA/300 MHz): 8.20 (br s, 1H); 7.35-7.20 (m, 5H); 4.45-4.35 (m, 4H); 3.25-3.15 (m, 2H); 3.00-2.80 (m, 4H); 2.20-2.10 (m, 2H).

[1083] Anal. Calcd for C19H19N5O4S(H2O): C, 59.51; H, 5.52; N, 18.26. Found: C, 59.77; H, 5.19; N, 18.26.

EXAMPLE 184

[1084] This example illustrates the production of 1-[(4-methylphenyl)sulfonyl]-3-(methylthio)-1,5,6,7-tetrahydro-4H-indazol-4-one:

1197

[1085] 2-[bis(methylthio)methylene]cyclohexane-1,3-dione was prepared according to the procedure of 2-[bis(benzylthio)methylene]cyclohexane-1,3-dione, using methyl iodide (28% yield) and reacted according to the procedure of 3-(benzylthio)-1-[(4-methylphenyl)sulfonyl]-1,5,6,7-tetrahydro-4H-indazol-4-one, to give the desired product as a white solid (39% yield). FABHRMS m/z 337.0658 (M+H, C15H17N2O3S2 requires 337.0675). 1H NMR (CDCl3/300 MHz): 7.95 (d, 2H); 7.39 (d, 2H); 3.24 (t, 2H); 2.52 (s, 3H); 2.58-2.44 (m, 2H); 2.46 (s, 3H); 2.23-2.10 (m, 2H).

[1086] Anal. Calcd for C15H16N2O3S2: C, 53.55; H, 4.79; N, 8.33. Found: C, 53.38; H, 4.80; N, 8.48.

EXAMPLE 185

[1087] This example illustrates the production of ethyl [1-[(4-methylphenyl)sulfonyl]-3-(methylthio)-4-oxo-4,5,6,7-tetrahydro-1H-indazol-5-yl](oxo)acetate:

1198

[1088] 1-[(4-methylphenyl)sulfonyl]-3-(methylthio)-1,5,6,7-tetrahydro-4H-indazol-4-one was reacted according to the procedure for the production of ethyl (7-hydroxy-1-oxo-1,2,3,4-tetra hydronaphthalen-2-yl)(oxo)acetate to give the desired as a yellow solid (79% yield). 1H NMR (CDCl3/300 MHz): 7.95 (d, 1H); 7.40 (d, 1H); 4.40 (q, 2H); 3.35-3.20 (m, 4H); 2.55 (s, 3H); 2.50 (s, 3H); 1.44 (t, 3H).

[1089] Anal. Calcd for C19H20N2O6S2 (0.5H2O): C, 51.22; H, 4.75; N, 6.29. Found: C, 51.10; H, 5.08; N, 6.52.

EXAMPLE 186

[1090] This example illustrates the production of ethyl 2-{3-[(tert-butoxycarbonyl) amino]propyl}-6-[(4-methylphenyl)sulfonyl]-8-(methylthio)-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate:

1199

[1091] Ethyl 8-(methylthio)-6-[(4-methylphenyl)sulfonyl]-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate was prepared according to the procedure for the production of ethyl 8-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate, using ethyl [1-[(4-methylphenyl)sulfonyl]-3-(methylthio)-4-oxo-4,5,6,7-tetrahydro-1H-indazol-5-yl](oxo)acetate, and hydrazine monohydrochloride and reacted according to the procedure for the production of ethyl 2-(3-aminopropyl)-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate dihydrochloride to give the desired product as a white solid (31% yield). FABHRMS m/z 590.2120 (M+H, C27H35N5O6S2 requires 590.2102). 1H NMR (DMSO-d6+5%TFA/300 MHz): 7.85 (d, 2H); 7.42 (d, 2H); 6.79 (br, 1H); 4.45-4.40 (m, 2H); 4.30 (q, 2H); 3.35-3.30 (m, 2H); 3.10-3.05 (m, 2H); 2.98-2.85 (m, 2H); 2.40 (s, 3H); 1.85-1.80 (m, 2H); 1.35 (s, 9H); 1.33 (t, 3H).

[1092] Anal. Calcd for C27H35N5O6S2: C, 54.66; H, 5.88; N, 11.69. Found: C, 54.99; H, 5.98; N, 11.88.

EXAMPLE 187

[1093] This example illustrates the production of ethyl 2-(3-aminopropyl)-8-(methylthio)-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate dihydrochloride:

1200

[1094] Ethyl 2-{3-[(tert-butoxycarbonyl)amino]propyl}-6-[(4-methylphenyl)-sulfonyl]-8-(methylthio)-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate (900 mg, 0.0015 mol) and 4 N HCl in dioxane (10 mL) were stirred overnight, diluted with ether (10 mL) and filtered to give the desired as an off-white solid, 628 mg (95% yield). FABHRMS m/z 336.1476 (M+H, C15H22N5O2S requires 336.1489). 1H NMR (DMSO-d6+5%TFA/300 MHz): 4.55 (t, 2H); 4.35 (q, 2H); 3.05-3.00 (m, 2H); 2.90-2.80 (m, 4H); 2.55 (s, 3H); 2.15-2.00 (m, 2H); 1.37 (t, 3H).

[1095] Anal. Calcd for C15H21N5O2S (2HCl): C, 44.12; H, 5.68; N, 17.15. Found: C, 42.97; H, 5.60; N, 16.70.

EXAMPLE 188

[1096] This example illustrates the production of 1-(methylthio)-4,5,7,8,9,10-hexahydro [1,4]diazepino[1,2-b]pyrazolo[3,4-g]indazol-6(3H)-one:

1201

[1097] Ethyl 2-(3-aminopropyl)-8-(methylthio)-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate dihydrochloride (400 mg, 1.0 mmol), conc. ammonium hydroxide (30 mL) and methanol (15 mL) were stirred in a stoppered flask overnight. Contents were poured into a beaker to let the volatiles evaporate and filtered to give the desired product as a light amber solid, 183 mg (63% yield). FABHRMS m/z 290.1074 (M+H, C13H16N5OS requires 290.1070). 1H NMR (DMSO-d6+5%TFA/30O MHz): 8.19 (br, 1H); 4.38 (t, 2H); 3.20 (q, 2H); 2.95-2.80 (m, 4H); 2.55 (s, 3H); 2.10 (quintet, 2H).

[1098] Anal. Calcd for C13H15N5OS: C, 53.96; H, 5.23; N, 24.20. Found: C, 53.72; H, 5.15; N, 24.19.

EXAMPLE 189

[1099] This example illustrates the production of ethyl 8-(methylthio)-2,4,5,6-tetrahydro-pyrazolo[3,4-e]indazole-3-carboxylate:

1202

[1100] Ethyl [1-[(4-methylphenyl)sulfonyl]-3-(methylthio)-4-oxo-4,5,6,7-tetrahydro-1H-indazol-5-yl](oxo)acetate and hydrazine monohydrochloride were reacted according to the procedure for the production of ethyl 8-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate, in refluxing methanol, to give the desired product (90% yield). FABHRMS m/z 279.0881 (M+H, C12H15N4O2S requires 279.0910). 1H NMR (DMSO-d6+5%TFA/300 MHz): 4.36 (q, 2H); 3.05 (t, 2H); 2.90 (t, 2H); 2.55 (s, 3H); 1.38 (t, 3H).

[1101] Anal. Calcd for C12H14N4O2S(HCl): C, 45.79; H, 4.80; N, 17.80. Found: C, 45.70; H, 4.65; N, 17.72.

EXAMPLE 190

[1102] This example illustrates the production of 8-(methylthio)-2,4,5,6-tetrahydro-pyrazolo[3,4-e]indazole-3-carboxamide:

1203

[1103] Ethyl 8-(methylthio)-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate was reacted according to the procedure for the production of 8-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxamide to give the desired product as a white solid (85% yield). FABHRMS m/z 250.0774 (M+H, C10H12N5OS requires 250.0757). 1H NMR (DMSO-d6+5%TFA/300 MHz): 7.40 (br, 2H); 3.05 (t, 2H); 2.85 (t, 2H); 2.55 (s, 3H).

[1104] Anal. Calcd for C10H11N5OS: C, 48.18; H, 4.45; N, 28.09. Found: C, 47.87; H, 4.36; N, 27.78.

EXAMPLE 191

[1105] This example illustrates the production of 8-(methylthio)-2,4,5,6-tetrahydro-pyrazolo[3,4-e]indazole-3-carboxylic acid:

1204

[1106] Ethyl 8-(methylthio)-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate was reacted according to the procedure for the production of 7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid to give the desired as a light amber solid (82% yield). FABHRMS m/z 251.0571 (M+H, C10H11N4O2S requires 251.0597).

[1107] Anal. Calcd for C10H10N4O2S (1.6H2O): C, 43.03; H, 4.77; N, 20.07. Found: C, 42.73; H, 4.46; N, 20.40.

EXAMPLE 192

[1108] This example illustrates the production of ethyl 8-(methylsulfinyl)-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate:

1205

[1109] To a slurry of ethyl 8-(methylthio)-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate (838 mg, 0.003 mol) in THF (20 mL) was added dropwise m-chloroperbenzoic acid (68%, 764 mg, 0.003 mol) in THF (5 mL). Contents were stirred overnight and filtered to give the desired product as a white solid, 455 mg (52% yield). FABHRMS m/z 295.0842 (M+H, C12H15N4O3S requires 295.0859).

[1110] Anal. Calcd for C12H14N4O3S: C, 48.97; H, 4.79; N, 19.04. Found: C, 45.11; H, 4.68; N, 16.96.

EXAMPLE 193

[1111] This example illustrates the production of 8-(methylsulfinyl)-2,4,5,6 tetrahydro-pyrazolo[3,4-e]indazole-3-carboxylic acid:

1206

[1112] Ethyl 8-(methylsulfinyl)-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate was reacted according to the procedure for the production of 7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid to give the desired product as a white solid (71% yield). FABHRMS m/z 267.0541 (M+H, C10H11N4O3S requires 267.0546).

[1113] Anal. Calcd for C10H10N4O3S(H2O): C, 42.25; H, 4.25; N, 19.71. Found: C, 42.36; H, 3.99; N, 19.71.

EXAMPLE 194

[1114] This example illustrates the production of ethyl 8-(methylsulfonyl)-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate:

1207

[1115] Ethyl 8-(methylsulfonyl)-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate was prepared according to the procedure of ethyl 8-(methylsulfinyl)-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate to give the desired product as a white solid (62% yield). FABHRMS m/z 311.0807 (M+H, C12H15N4O4S requires 311.0809).

[1116] Anal. Calcd for C12H14N4O4S (1H2O): C, 43.90; H, 4.91; N, 17.06. Found: C, 43.98; H, 4.62; N, 17.02.

EXAMPLE 195

[1117] This example illustrates the production of 8-(methylsulfonyl)-2,4,5,6-tetrahydro-pyrazolo[3,4-e]indazole-3-carboxylic acid:

1208

[1118] Ethyl 8-(methylsulfonyl)-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate was reacted according to the procedure for the production of 7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid to give the desired product as a white solid (93% yield). FABHRMS m/z 283.0505 (M+H, C10H11N4O4S requires 283.0496).

[1119] Anal. Calcd for C10H10N4O4S (1.3H2O): C, 39.29; H, 4.15; N, 18.33. Found: C, 39.16; H, 3.76; N, 18.29.

EXAMPLE 196

[1120] This example illustrates the production of 8-(methylsulfonyl)-2,4,5,6-tetrahydro-pyrazolo[3,4-e]indazole-3-carboxamide.

1209

[1121] Ethyl 8-(methylsulfonyl)-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate was reacted according to the procedure for the production of 8-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxamide to give the desired product as a white solid (93% yield). FABHRMS m/z 282.0665 (M+H, C10H12N5O3S requires 282.0655).

[1122] Anal. Calcd for C10H11N5O3S(H2O): C, 40.13; H, 4.38; N, 23.40. Found: C, 40.07; H, 4.20; N, 23.53.

EXAMPLE 197

[1123] This example illustrates the production of 2-(3-aminopropyl)-2,6-dihydro-pyrazolo[3,4-e]indazole-3-carboxylic acid dihydrochloride:

1210

[1124] Ethyl 2-{3-[(tert-butoxycarbonyl)amino]propyl}-7-trityl-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate (1.0 g, 0.0016 mol) prepared according to the procedure for the production of ethyl 2-(3-aminopropyl)-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate dihydrochloride and DDQ (360 mg, 0.0016 mol) in dioxane (25 mL) were refluxed 4 hours. Contents were allowed to cool and the by-product was filtered. The filtrate was partitioned between EtOAc and water. The EtOAc layer was dried over MgSO4 and concentrated in vacuo leaving a yellow oil, 900 mg. The oil was reacted according to the procedure for the production of 7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid to give 2-(3-aminopropyl)-7-trityl2,6-dihydropyrazolo[3,4-e]indazole-3-carboxylic acid as a white solid, 870 mg. The white solid was mixed with 4N HCl in dioxane (10 mL) and stirred overnight. Contents were filtered to give the desired product as a white solid, 417 mg (78% yield). FABHRMS m/z 260.1142 (M+H, C12H14N5O2 requires 260.1135). 1H NMR (DMSO-d6+5%TFA/300 MHz): 8.40 (s, 1H); 7.92 (d, 1H); 7.85 (br, 3H); 7.52 (d, 1H); 4.90 (t, 2H); 2.90-2.80 (m, 2H); 2.35-2.20 (m, 2H).

[1125] Anal. Calcd for C12H13N5O2 (2HCl, 2H2O): C, 39.14; H, 5.20; N, 19.02. Found: C, 39.41; H, 4.63; N, 18.75.

EXAMPLE 198

[1126] This example illustrates the production of 7,8,9,10-tetrahydro[1,4]-diazepino[1,2-b]pyrazolo[3,4-g]indazol-6(3H)-one:

1211

[1127] Ethyl 2-{3-[(tert-butoxycarbonyl)amino]propyl}-7-trityl-2,4,5,6-tetrahydropyrazolo-[3,4-e]indazole-3-carboxylate (2.0 g, 0.0032 mol) prepared according to the procedure for the production of ethyl 2-(3-aminopropyl)-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate dihydrochloride and DDQ (720 mg, 0.0032 mol) in dioxane (25 mL) were refluxed 4 hours. Contents were allowed to cool and the by-product was filtered. The filtrate was partitioned between EtOAc and water. The EtOAc layer was dried over MgSO4 and concentrated in vacuo leaving a yellow oil, 1.58 g. The yellow oil was mixed with 4N HCl in dioxane (25 mL) and stirred overnight. Contents were filtered to give a white solid, 530 mg, which is ethyl 2-(3-aminopropyl)-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate dihydrochloride. The white solid was mixed with conc. ammonium hydroxide (30 mL) and methanol (15 mL) and stirred in a stoppered flask overnight. Contents were poured into a beaker to allow volatiles to evaporate and then filtered to give the desired product as a white solid, 384 mg (50% yield). FABHRMS m/z 242.1047 (M+H, C12H12N5O requires 242.1036). 1H NMR (DMSO-d6+5%TFA/300 MHz): 8.40 (br, 1H), 8.35 (s, 1H); 7.80 (d, 1H); 7.40 (d, 1H); 4.73 (t, 2H); 3.30-3.20 (m, 2H); 2.35-2.20 (m, 2H).

[1128] Anal. Calcd for C12H11N5O (0.3H2O): C, 58.43; H, 4.74; N, 28.39. Found: C, 58.05; H, 4.56; N, 28.59.

EXAMPLE 199

[1129] This example illustrates the production of 2-(3-aminopropyl)-8-(methylthio)-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylic acid dihydrochloride:

1212

[1130] Ethyl 2-{3-[(tert-butoxycarbonyl)amino]propyl}-6-[(4-methylphenyl)sulfonyl]-8-(methylthio)-2,4,5,6-tetra hydropyrazolo[3,4-e]indazole-3-carboxylate (260 mg, 0.44 mmol) and 6N HCl (8 mL) were refluxed overnight. Contents were evaporated and the residue was triturated with EtOAc to give the desired product as a white solid, 70 mg (42% yield). FABHRMS m/z 308.1184 (M+H, C13H18N5O2S requires 308.1176). 1H NMR (DMSO-d6+5%TFA/300 MHz): 7.80 (br, 3H); 4.60-4.50 (m, 2H); 3.10-3.00 (m, 2H); 2.90-2.80 (m, 4H); 2.55 (s, 3H); 2.10-2.00 (m, 2H).

[1131] Anal. Calcd for C17H17N5O2S (2HCl, 1H2O): C, 39.20; H, 5.31; N, 17.58. Found: C, 39.23; H, 5.03; N, 17.24.

EXAMPLE 200

[1132] This example illustrates the production of 3-(allylthio)-1-[(4-methylphenyl)-sulfonyl]-1,5,6,7-tetrahydro-4H-indazol-4-one:

1213

[1133] 2-[bis(allylthio)methylene]cyclohexane-1,3-dione was prepared according to the procedure of 2-[bis(benzylthio)methylene]cyclohexane-1,3-dione, using allyl bromide (48% yield) and reacted according to the procedure for the production of 3-(benzylthio)-1-[(4-methylphenyl)sulfonyl]-1,5,6,7-tetrahydro-4H-indazol-4-one, to give the desired product after silica gel chromatography, eluting with 25% EtOAc/hexanes, as a white solid (41% yield). FABHRMS m/z 363.0843 (M+H, C17H19N2O3S2 requires 363.0832). 1H NMR (CDCl3/300 MHz): 7.95 (d, 2H); 7.39 (d, 2H); 6.00-5.85 (m, 1H); 5.27 (d, 1H); 5.10 (d, 1H); 3.80 (d, 2H); 3.25 (t, 2H); 2.55-2.40 (m, 5H); 2.25-2.15 (m, 2H).

[1134] Anal. Calcd for C15H18N2O3S2: C, 56.33; H, 5.01; N, 7.73. Found: C, 56.12; H, 4.57; N, 7.52.

EXAMPLE 201

[1135] This example illustrates the production of ethyl {3-(allylthio)-1-[(4-methylphenyl) sulfonyl]-4-oxo-4,5,6,7-tetrahydro-1H-indazol-5-yl}(oxo)acetate:

1214

[1136] 3-(allylthio)-1-[(4-methylphenyl)sulfonyl]-1,5,6,7-tetrahydro-4H-indazol-4-one was reacted according to the procedure for the production of ethyl (7-hydroxy-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)(oxo)acetate to give the desired as a yellow solid (34% yield). FABHRMS m/z 463.0999 (M+H, C21H23N2O6S2 requires 463.0992). OH NMR (CDCl3/300 MHz): 7.90 (d, 2H); 7.40 (d, 2H); 6.00-5.85 (m, 1H); 5.30 (d, 1H); 5.10 (d, 1H); 4.35-4.24 (m, 2H); 3.80-3.75 (m, 2H) 3.35-3.20 (m, 4H); 2.50 (s, 3H); 1.40 (t, 3H).

[1137] Anal. Calcd for C21H23N2O6S2: C, 54.53; H, 4.79; N, 6.06. Found: C, 54.64; H, 4.55; N, 5.69.

EXAMPLE 202

[1138] This example illustrates the production of ethyl 8-(allylthio)-6-[(4-methylphenyl) sulfonyl]-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate:

1215

[1139] Ethyl {3-(allylthio)-1-[(4-methylphenyl)sulfonyl]-4-oxo-4,5,6,7-tetrahydro-1H-indazol-5-yl}(oxo)acetate was reacted according to the procedure for the production of ethyl 8-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate, to give the desired product, after EtOAc recrystallization as yellow crystals (68% yield). FABHRMS m/z 459.1127 (M+H, C21H23N4O4S2 requires 459.1155). 1H NMR (CDCl3/300 MHz): 7.85 (d, 2H); 7.35 (d, 2H); 6.00-5.85 (m, 1H); 5.25 (d, 2H); 5.05 (d, 2H); 4.40 (q, 2H); 3.80 (d, 2H); 3.40 (t, 2H); 3.20 (t, 2H); 2.45 (s, 3H).

[1140] Anal. Calcd for C21H22N4O4S2: C, 55.00; H, 4.84; N, 12.22. Found: C, 54.93; H, 4.55; N, 12.13.

EXAMPLE 203

[1141] This example illustrates the production of ethyl 8-(allylthio)-2-(3-t-butoxycarbonyl-aminopropyl)-6-[(4-methylphenyl)sulfonyl]-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate:

1216

[1142] Ethyl 8-(allylthio)-6-[(4-methylphenyl)sulfonyl]-2,4,5,6-tetrahydropyrazolo-[3,4-e]indazole-3-carboxylate was reacted according to the procedure for the production of ethyl 2-(3-aminopropyl)-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate dihydrochloride to give the desired product after silica gel chromatography eluting with 25% EtOAc/hexanes, as a white solid (70% yield). FABHRMS m/z 616.2264 (M+H, C29H38N5O6S2 requires 616.2258). 1H NMR (DMSO-d6+TFA/300 M/Hz): 7.82 (d, 2H); 7.42 (d, 2H); 6.78 (br, 1H); 5.85-5.75 (m, 1H); 5.20 (d, 1H); 5.00 (d, 1H); 4.40 (t, 2H); 4.30 (q, 2H); 3.78 (d, 2H); 3.40-3.25 (m, 2H); 3.15-3.00 (m, 1H); 2.95-2.85 (m, 2H); 2.40 (s, 3H); 1.85-1.75 (m, 2H); 1.35 (s, 9H); 1.33 (t, 3H).

[1143] Anal. Calcd for C29H37N5O6S2: C, 56.57; H. 6.06; N. 11.37. Found: C, 56.55; H. 6.21; N. 11.27.

EXAMPLE 204

[1144] This example illustrates the production of 8-(allylthio)-2-(3-aminopropyl)-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylic acid dihydrochloride:

1217

[1145] Ethyl 2-{3-[(tert-butoxycarbonyl)amino]propyl}-6-[(4-methylphenyl)sulfonyl]-8-(allylthio)-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate was reacted according to the procedure for the production of 7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid and after treatment with 4N HCl in dioxane, was filtered to give the desired product as a white solid (33% yield). FABHRMS m/z 334.1336 (M+H, C15H20N5O2S requires 334.1332). 1H NMR (DMSO-d6+TFA/300 MHz): 7.80 (br, 3H); 5.90-5.80 (m, 1H); 5.10-4.95 (m, 2H); 4.60-4.50 (m, 2H); 3.80-3.70 (m, 2H); 3.10-3.00 (m, 2H); 2.90-2.80 (m, 4H); 2.10-2.00 (m, 2H).

[1146] Anal. Calcd for C15H19N5O2S (2HCl): C, 44.34; H, 5.21; N, 17.24. Found: C, 44.37; H, 4.89; N, 17.02.

EXAMPLE 205

[1147] This example illustrates the production of ethyl 2-(3-aminopropyl)-8-(allylthio)-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate dihydrochloride:

1218

[1148] Ethyl 2-{3-[(tert-butoxycarbonyl)amino]propyl}-6-[(4-methylphenyl)sulfonyl]-8-(allylthio)-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate (1.3 g, 0.002 mol) and 4 N HCl in dioxane (10 mL) were stirred overnight. Contents were diluted with EtOAc and filtered to give the desired as a white solid, 870 mg (95% yield). FABHRMS m/z 362.1632 (M+H, C17H24N5O2S requires 362.1645). 1H NMR (DMSO-d6+TFA/300 MHz): 7.80 (br s, 3H); 6.00-5.80 (m, 1H); 5.10-4.95 (m, 2H); 4.60-4.50 (m, 2H); 4.35 (q, 2H); 3.78 (d, 2H); 3.08-3.00 (m, 2H); 2.90-2.80 (m, 4H); 2.20-2.00 (m, 2H); 1.36 (t, 3H).

[1149] Anal. Calcd for C17H23N5O2S (2 HCl): C, 47.00; H, 5.80; N, 16.12. Found: C, 47.28; H, 5.52; N, 15.78.

EXAMPLE 206

[1150] This example illustrates the production of 1-(allylthio)-4,5,7,8,9,10-hexahydro[1,4]diazepino[1,2-b]pyrazolo[3,4-g]indazol-6(3H)-one:

1219

[1151] Ethyl 2-(3-aminopropyl)-8-(allylthio)-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate dihydrochloride (800 mg, 0.002 mol), conc ammonium hydroxide (30 mL) and methanol (15 mL) were stirred in a stoppered flask overnight. Contents were poured into a beaker to let the volatiles evaporate and filtered to give the desired product as a pale green solid, 283 mg (49% yield). FABHRMS m/z 316.1231 (M+H, C15H18N5OS requires 316.1227). 1H NMR (DMSO-d6+TFA/300 MHz): 8.20 (br s, 1H); 6.00-5.80 (m, 1H); 5.15-4.90 (m, 2H); 4.40 (t, 2H); 3.80 (d, 2H); 3.22-3.10 (m, 2H); 2.95-2.80 (m, 4H); 2.20-2.00 (m, 2H).

[1152] Anal. Calcd for C15H17N5OS (0.5H2O): C, 55.54; H, 5.59; N, 21.59. Found: C, 55.28; H, 5.25; N, 21.36.

EXAMPLE 207

[1153] This example illustrates the production of 4,5,7,8,9,10-hexahydro[1,4-diazepino[1,2-b]pyrazolo[3,4-g]indazol-6(3H)-one:

1220

[1154] Ethyl 2-(3-aminopropyl)-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate dihydrochloride (500 mg, 0.0014 mol), conc ammonium hydroxide (30 mL) and methanol (15 mL) were stirred in a stoppered flask overnight. Contents were poured into a beaker to let the volatiles evaporate and filtered to give the desired product as a light amber solid, 325 mg (97% yield). FABHRMS m/z 244.1204 (M+H, C12H14N5O requires 244.1193). 1H NMR (DMSO-d6/300 MHz): 8.20 (br s, 1H); 7.82 (br s, 1H); 4.38 (t, 2H); 3.20 (br s, 2H); 2.98-2.70 (m, 4H); 2.20-2.00 (m, 2H).

[1155] Anal. Calcd for C12H13N5O (0.6H2O): C, 56.73; H, 5.63; N, 27.56. Found: C, 56.56; H, 5.82; N, 27.95.

EXAMPLE 208

[1156] This example illustrates the production of ethyl 2-(3-{[2-(4-bromophenyl) ethyl]amino}propyl)-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate:

1221

[1157] To 4-bromophenethylalcohol (29.5 g, 0.147 mol) and triethylamine (20.9 mL, 0.15 mol) in CH2Cl2 (250 ml) at 0° C. was added dropwise methansulfonylchloride (11.6 mL, 0.15 mol) in CH2Cl2 (50 mL). Contents were stirred overnight, Coming to room temperature, washed with water, dried over MgSO4, and concentrated in vacuo leaving the mesylate intermediate as a white solid, 51.6 g. The mesylate intermediate (51.6 g, 0.185 mol), 3-amino-1-propanol (20.8 g, 0.28 mol) and potassium carbonate (38.7 g, 0.28 mol) in acetonitrile (500 mL) were refluxed for 8 hours. Contents were allowed to cool, quenched with water and extracted with EtOAc. The EtOAc layer was washed with brine, dried over MgSO4, and concentrated in vacuo leaving 4-bromophenethylaminopropanol as a light yellow oil, which solidified, 40.1 g. 4-Bromophenethylaminopropanol (40.1 g, 0.16 mol) and di-t-butyl-dicarbonate (35.0 g, 0.16 mol) in CH2Cl2 (500 mL) were stirred overnight. Contents were washed with water, brine, dried over MgSO4 and concentrated in vacuo leaving 4-bromophenethyl-Boc-aminopropanol as a light yellow oil, 53.7 g. To 4-bromophenethyl-boc-aminopropanol (51.8 g; 0.145 mol) and triethylamine (21 mL, 0.15 mol) in CH2Cl2 (500 mL) at 0° C. was added dropwise methansulfonylchloride (11.6 mL, 0.15 mol) in CH2Cl2 (50 mL). Contents were stirred 5 hours, Coming to room temperature, then washed with water, brine, dried over MgSO4 and concentrated in vacuo leaving 3-[[2-(4-bromophenyl)ethyl](tert-butoxycarbonyl)amino]propyl methanesulfonate as a yellow oil, 48.0 g. To ethyl 6-trityl-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate (11.9 g, 0.025 mol) in DMF (100 mL) at 0° C. was added dropwise lithium t-butoxide (1M in THF, 50 mL). Contents were stirred one hour at 0° C. and added 3-[[2-(4-bromophenyl)ethyl](tert-butoxycarbonyl)amino]propyl methanesulfonate (22.1 g, 0.05 mol) in DMF (25 mL) dropwise. Contents were stirred overnight, Coming to room temperature and partitioned between EtOAc and water. The EtOAc layer was washed with brine, dried over MgSO4 and concentrated in vacuo leaving ethyl 2-(3-{[2-(4-bromophenyl)ethyl]amino}propyl)-7-trityl-2,4,5,6-tetra hydropyrazolo[3,4-e]indazole-3-carboxylate as an amber oil, 26.8 g. Ethyl 2-(3-{[2-(4-bromophenyl)ethyl]amino}propyl)-7-trityl-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate (9.8 g, 0.014 mol) and 4N HCl in dioxane (100 mL) were stirred overnight. Contents were diluted with EtOAc and filtered to give the desired as a white solid, 3.6 g (55% yield). FABHRMS m/z 472.1342 (M+H, C22H27BrN5O2 requires 472.1343). 1H NMR (DMSO-d6+TFA/300 MHz): 9.00 (br, 2H); 8.00 (s, 1H); 7.50 (d, 2H); 7.20 (d, 2H); 4.60-4.50 (m, 2H); 4.35 (q, 2H); 3.20-2.90 (m, 10H); 2.20-2.10 (m, 2H); 1.38 (t, 3H).

[1158] Anal. Calcd for C22H26BrN5O2 (2HCl, H2O): C, 46.99; H, 5.20; N, 12.45. Found: C, 46.93; H, 5.41; N, 12.37.

EXAMPLE 209

[1159] This example illustrates the production of 2-(3-{[2-(4-bromophenyl)ethyl]amino}propyl)-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylic acid hydrochloride:

1222

[1160] Ethyl 2-(3-{[2-(4-bromophenyl)ethyl]amino}propyl)-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate, was reacted according to the procedure for the production of 7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid to give the desired product as a white solid (52% yield). FABHRMS m/z 444.1015 (M+H, C20H23BrN5O2 requires 444.1030). 1H NMR (DMSO-d6+TFA/300 MHz): 8.80 (br, 2H); 8.10 (s, 1H); 7.50 (d, 2H); 7.20 (d, 2H); 4.60-4.55 (m, 2H); 3.20-2.90 (m, 10H); 2.20-2.10 (m, 2H).

[1161] Anal. Calcd for C20H22BrN5O2(2HCl, 2H2O): C, 43.42; H, 5.10; N, 12.66. Found: C, 43.06; H, 5.25; N, 12.68.

EXAMPLE 210

[1162] This example illustrates the production of ethyl 2-{3-[(2-thien-3-ylethyl)amino]propyl}-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate dihydrochloride:

1223

[1163] Ethyl 2-{3-[(2-thien-3-ylethyl)amino]propyl}-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate dihydrochloride was prepared according to the procedure of ethyl 2-(3-{[2-(4-bromophenyl)ethyl]amino}propyl)-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate, using 2-(3-theinyl)ethanol, to give the desired product as a white solid (45% yield). FABHRMS m/z 400.1797 (M+H, C20H26N5O2S requires 400.1802). 1H NMR (DMSO-d6+TFA/300 MHz): 8.80 (br, 2H); 8.10 (s, 1H); 7.50 (s, 1H); 7.30 (s, 1H); 7.00 (d, 1H); 4.60-4.55 (m, 2H); 4.30 (q, 2H); 3.25-2.90 (m, 10H) 2.20-2.10 (m, 2H); 1.35 (t, 3H).

[1164] Anal. Calcd for C20H25N5O2S (2HCl): C, 50.85; H, 5.76; N, 14.82. Found: C, 51.43; H, 6.04; N, 14.48.

EXAMPLE 211

[1165] This example illustrates the production of 2-{3-[(2-thien-3-ylethyl)amino]propyl}-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylic acid hydrochloride:

1224

[1166] Ethyl 2-{3-[(2-thien-3-ylethyl)amino]propyl}-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate dihydrochloride was reacted according to the procedure for the production of 7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid to give the desired as a white solid (28% yield). FABHRMS m/z 372.1451 (M+H, C18H22N5O2S requires 372.1489). 1H NMR (DMSO-d6+TFA/300 MHz): 8.55 (br, 2H); 8.10 (s, 1H); 7.48 (s, 1H); 7.30 (s, 1H); 7.00 (d, 1H); 4.60-4.50 (m, 2H); 3.30-2.90 (m, 10H); 2.20-2.05 (m, 2H).

EXAMPLE 212

[1167] This example illustrates the production of 2-{3-[(2-thien-2-ylethyl)amino]-propyl}-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylic acid:

1225

[1168] 2-{3-[(2-thien-2-ylethyl)amino]propyl}-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylic acid was prepared according to the procedures of ethyl 2-(3-{[2-(4-bromophenyl)ethyl]amino}propyl)-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate and 7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid to give the desired product as a white solid (73% yield). FABHRMS m/z 372.1466 (M+H, C18H22N5O2S requires 372.1489). 1H NMR (DMSO-d6+TFA/300 MHz): 8.55 (br, 2H); 7.95 (s, 1H); 7.40 (d, 2H); 7.00-6.95 (m, 2H); 4.60-4.50 (m, 2H); 3.30-2.90 (m, 10H); 2.20-2.00 (m, 2H).

[1169] Anal. Calcd for C18H21N5O2S (0.3H2O): C, 57.37; H, 5.78; N, 18.58. Found: C, 57.38; H, 5.99; N, 18.55.

EXAMPLE 213

[1170] This example illustrates the production of ethyl 2-{3-[(2-thien-2-ylethyl)amino]propyl}-2,6-dihydropyrazolo[3,4-e]indazole-3-carboxylate:

1226

[1171] Ethyl 6-trityl-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate was reacted with 3-[[2-(2-thienylethyl](tert-butoxycarbonyl)-amino]propyl methanesulfonate according to the procedure for the production of ethyl 2-(3-{[2-(4-bromophenyl)ethyl]amino}propyl)-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate to give ethyl 2-(3-{[2-(2-thienyl)ethyl]amino}propyl)-7-trityl-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate as a yellow oil. The oil (9.9 g, 0.013 mol) and DDQ (3.0 g, 0.013 mol) were refluxed in dioxane (100 mL) for 5 hours. Contents were allowed to cool and a by-product was filtered. The filtrate was concentrated in vacuo and the dark oily residue was filtered through a pad of silica gel, eluting with 25% EtOAc/hexanes to give a pale yellow oil, 4.1 g. The oil was mixed with 4N HCl in dioxane and stirred overnight and filtered to give the desired product as a white solid, 1.4 g (27% yield). FABHRMS m/z 398.1654 (M+H, C20H24N5O2S requires 398.1645). 1H NMR (DMSO-d6+TFA/300 MHz): 8.80 (br, 2H); 8.35 (s, 1H); 7.90 (d, 1H); 7.50 (d, 1H); 7.35 (d, 1H); 7.00-6.95 (m, 2H); 4.92 (t, 2H); 4.43 (q, 2H); 3.25-3.00 (m, 6H); 2.40-2.25 (m, 2H); 1.42 (t, 3H).

[1172] Anal. Calcd for C20H23N5O2S (2HCl): C, 51.07; H, 5.36; N, 14.89. Found: C, 51.29; H, 5.77; N, 14.78.

EXAMPLE 214

[1173] This example illustrates the production of 2-{3-[(2-thien-2-ylethyl)amino]propyl}-2,6-dihydropyrazolo[3,4-e]indazole-3-carboxylic acid.

1227

[1174] Ethyl 2-{3-[(2-thien-2-ylethyl)amino]propyl}-2,6-dihydropyrazolo[3,4-e]indazole-3-carboxylate was reacted according to the procedure for the production of 7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid to give the desired product as a white solid (84% yield). FABHRMS m/z 370.1327 (M+H, C18H20N5O2S requires 370.1332). 1H NMR (DMSO-d6+TFA/300 MHz): 8.60 (br, 2H); 8.35 (s, 1H); 7.90 (d, 1H); 7.50 (d, 1H); 7.40 (s, 1H); 7.00-6.95 (m, 2H); 5.00-4.90 (m, 2H); 3.30-3.00 (m, 6H); 2.40-2.25 (m, 2H).

[1175] Anal. Calcd for C18H19N5O2S (0.25H2O): C, 57.82; H, 5.26; N, 18.73. Found: C, 57.78; H, 5.48; N, 18.87.

EXAMPLE 215

[1176] This example illustrates the production of ethyl 1-{1-[(benzyloxy) carbonyl]piperidin-4-yl}-7-trityl-1,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate.

1228

[1177] Benzyl 4-oxopiperidine carboxylate (29.3 g, 0.126 mol) and t-butyl carbazate (16.6 g, 0.126 mol) in ethanol (180 mL) were stirred overnight. Contents were concentrated in vacuo leaving benzyl 4-[2-t-butoxycarbonyl)hydrazono]-piperidine-1-carboxylate as a colorless oil, 49.3 g. To benzyl 4-[2-t-butoxy-carbonyl)hydrazono]piperidine-1-carboxylate (48 g, 0.14 mole) in THF (150 mL) at 0° C. was added BH3-THF (1M, 200 mL) over 30 minutes. Contents were stirred 2 hours, Coming to room temperature and carefully quenched with methanol (50 mL). Contents were concentrated in vacuo, diluted with EtOAc, washed with 50% aqueous sodium bicarbonate (200 mL), brine, dried over MgSO4, concentrated in vacuo to about 50 mL, and filtered to give benzyl 4-[2-t-butoxycarbonyl)hydrazino]piperidine-1-carboxylate as a white solid, 36.2 g. Benzyl 4-[2-t-butoxycarbonyl)hydrazono]piperidine-1-carboxylate (2.3 g, 0.0066 mol) and 4N HCl in dioxane (5 mL) were stirred for a half hour and concentrated in vacuo leaving a white foam. The white foam was dissolved in methanol (10 mL) and 0.5M sodium methoxide (13 mL) was added dropwise. Contents were stirred a half hour and ethyl oxo(4-oxo-1-trityl-4,5,6,7-tetrahydro-1H-indazol-5-yl)acetate- or ethyl oxo(4-oxo-2-trityl-4,5,6,7-tetrahydro-2H-indazol-5-yl)acetate or ethyl oxo(4-oxo-2-trityl-4,5,6,7-tetrahydro-2H-indazol-5-yl)acetate (3.15 g, 0.0066 mol) in CH2Cl2/methanol (1:1, 10 mL) was added dropwise. Contents were stirred 72 hours and concentrated in vacuo leaving a foam, 5.2 g. The foam was purified by silica gel chromatography, eluting with 15% EtOAc/hexanes. Fractions 5-11 contained a light amber foam, 786 mg used in 2-piperidin-4-yl-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylic acid hydrochloride. Fractions 14-28 were concentrated in vacuo leaving a light amber foam, 2.5 g, which crystallized from methanol to give the desired as a white solid, 1.7 g (74% yield). FABHRMS m/z 692.3237 (M+H, C43H42N5O4 requires 692.3231). 1H NMR (CDCl3/300 MHz): 7.45-7.20 (m, 21H); 5.19 (s, 2H); 4.45 (q, 2H); 4.40-4.30 (m, 2H); 4.05 (m, 1H); 3.25-3.15 (m, 2H); 3.05-2.95 (m, 2H); 2.80-2.55 (m, 2H); 2.35-2.10 (m, 2H); 2.00-1.90 (m, 2H); 1.42 (t, 3H).

[1178] Anal. Calcd for C43H41N5O4: C, 74.65; H, 5.97; N, 10.12. Found: C, 74.39; H, 5.69; N, 9.99.

EXAMPLE 216

[1179] This example illustrates the production of 2-piperidin-4-yl-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylic acid hydrochloride.

1229

[1180] Ethyl 2-{1-[(benzyloxy)carbonyl]piperidin-4-yl}-7-trityl-1,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate was obtained in ethyl 1-{1-[(benzyloxy)carbonyl]piperidin-4-yl}-6-trityl-1,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate in Fractions 5-11 as a light amber foam (17% yield). The foam (786 mg), palladium/carbon (10%, 93 mg) and methanol (20 mL) were shaken at 55 psi H2 on a Parr hydrogenator for 45 minutes. Contents were filtered through clay and the filtrate was concentrated in vacuo. The residue (670 mg), 2.5N sodium hydroxide (4 mL), and methanol (20 mL) were refluxed for 2 hours. Contents were diluted with water (20 mL) and extracted with EtOAc. The aqueous layer was made acidic with 1N HCl to pH 2 and extracted with EtOAc. The EtOAc layer was dried over MgSO4 and concentrated in vacuo leaving a yellow solid (129 mg). The solid was mixed with 4N HCl in dioxane for 3 hours, concentrated in vacuo and the residue triturated with EtOAc and filtered to give the desired product as a light tan solid, 18 mg (6% yield). FABHRMS m/z 288.1489 (M+H, C43H42N5O4 requires 288.1455). 1H NMR (DMSO-d6+5%TFA/300 MHz): 8.80 (brd, 1H); 8.45 (br d, 1H); 8.02 (s, 1H); 5.42-5.35 (m, 1H); 3.50-3.40 (m, 2H); 3.20-2.80 (m, 6H); 2.35-2.05 (m, 4H).

EXAMPLE 217

[1181] This example illustrates the production of 1-{1-[(benzyloxy)carbonyl]-piperidin-4-yl}-7-trityl-1,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylic acid.

1230

[1182] Ethyl 1-{1-[(benzyloxy)carbonyl]piperidin-4-yl}-6-trityl-1,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate was reacted according to the procedure for the production of 7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid to give the desired as a white solid (77% yield). FABHRMS m/z 664.2947 (M+H, C41H38N5O4 requires 664.2918). 1H NMR (DMSO-d6+5%TFA/300 MHz): 7.62 (s, 1H); 7.40-7.10 (m, 20H); 5.12 (s, 2H); 4.47-4.37 (m, 1H); 4.08 (d, 2H); 3.10-3.00 (m, 2H); 2.85-2.80 (m, 4H); 2.00-1.80 (m, 4H).

[1183] Anal. Calcd for C41H37N5O4(1.8H2O): C, 70.73; H, 5.88; N, 10.06. Found: C, 70.70; H, 5.71; N, 9.68.

EXAMPLE 218

[1184] This example illustrates the production of 1-piperidin-4-yl-7-trityl-1,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylic acid.

1231

[1185] Ethyl 1-{1-[(benzyloxy)carbonyl]piperidin-4-yl}-6-trityl-1,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate (1.4 g, 0.002 mol), 10% palladium/carbon (300 mg) and DMF (50 mL) were shaken at 55 psi H2 on a Parr hydrogenator for 45 minutes. Contents were filtered through clay and the filtrate was concentrated in vacuo leaving an oil (1.4 g). The oil, 2.5N sodium hydroxide (4 mL), and methanol (15 mL) were refluxed 3 hours. Contents were concentrated in vacuo to about half and the residue made acidic with 1N HCl to pH 2. Contents were filtered to give the desired product as a white solid, 1.0 g (93% yield). FABHRMS m/z 530.2573 (M+H, C33H32N5O2 requires 530.2551).

[1186] Anal. Calcd for C33H31N5O2(2HCl): C, 65.78; H, 5.52; N, 11.62. Found: C, 65.81; H, 5.81; N, 11.53.

EXAMPLE 219

[1187] This example illustrates the production of 1-piperidin-4-yl-1,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylic acid.

1232

[1188] 1-piperidin-4-yl-6-trityl-1,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylic acid hydrochloride (841 mg, 0.0016 mol) and 4N HCl in dioxane (20 mL) were stirred overnight and filtered to give the desired product as a white solid, 578 mg (96% yield). FABHRMS m/z 288.1437 (M+H, C14H18N5O2 requires 288.1455).

[1189] Anal. Calcd for C14H17N5O2(2HCl, H2O): C, 44.45; H, 5.60; N, 18.51. Found: C, 44.72; H, 5.31; N, 18.28.

EXAMPLE 220

[1190] This example illustrates the production of ethyl 7-oxo-4,5,6,7-tetrahydro-1H-indazole-3-carboxylate.

1233

[1191] Acetyl chloride (50 mL) was added dropwise to ethanol (250 mL) at 0° C. Contents were stirred for 2 hours. 1,2-cyclohexanedione (26.5 g, 0.24 mol) was added and stirred 2 hours. Contents were concentrated in vacuo to about half and diluted with ether and water. Saturated aqueous sodium bicarbonate was added to pH 7. The ether layer was dried over MgSO4 and concentrated in vacuo leaving 2-ethoxy-2-cyclohexene-1-one as an oil, 24.0 g (71% yield). 2-Ethoxy-2-cyclohexene-1-one was reacted according to the procedure for the production of ethyl (7-hydroxy-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)(oxo)acetate to give the diketo-ester as a yellow oil (32% yield). The diketo-ester was reacted according to the procedure for the production of ethyl 8-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate, using hydrazine monohydro-chloride to give the desired product as a yellow solid (95% yield). 1H NMR (CDCl3/300 MHz): 4.40 (q, 2H); 3.05 (t, 2H); 2.61 (t, 2H); 2.18 (quintet, 2H); 1.40 (t, 3H).

EXAMPLE 221

[1192] This example illustrates the production of ethyl (6E)-6-[(dimethylamino)-methylene]-7-oxo-2-[3-(tritylamino)propyl]-4,5,6,7-tetrahydro-2H-indazole-3-carboxylate.

1234

[1193] To 3-aminopropyl bromide hydrobromide (50.0 g, 0.228 mol) and trityl chloride (66.9 g, 0.24 mol) in CH2Cl2 (600 mL) was added dropwise triethylamine (70 mL, 0.5 mol). Contents were stirred overnight, washed with water, brine, dried over MgSO4 and concentrated in vacuo leaving a white solid. The solid was triturated with EtOAc and filtered to give 3-(N-tritylamino)propylbromide as a white solid (91% yield). To ethyl 7-oxo-4,5,6,7-tetrahydro-1H-indazole-3-carboxylate (24.9 g, 0.12 mol) in THF (700 mL) at 0° C. was added dropwise potassium t-butoxide (1M in THF, 0.13 mol) and contents were stirred 3 hours. 3-(N-tritylamino)propyl bromide (49.4 g, 0.13 mol) in DMF (100 mL) was added and refluxed 3 hours. Contents were partitioned between EtOAc and water. The EtOAc layer was washed with brine, dried over MgSO4 and concentrated in vacuo leaving an oil. The oil was purified by silica gel chromatography eluting first with 10% EtOAc/hexanes, then 25% EtOAc/hexanes to give ethyl 7-oxo-2-[3-(tritylamino)propyl]-4,5,6,7-tetrahydro-2H-indazole-3-carboxylate as an oil (19% yield). To ethyl 7-oxo-2-[3-(tritylamino)propyl]-4,5,6,7-tetrahydro-2H-indazole-3-carboxylate (12.3 g, 0.024 mol) in THF (500 mL) was added dropwise Bredereck's reagent (10.0 mL, 0.048 mol) in THF (10 mL). Contents were refluxed for 5 hours, allowed to cool and concentrated in vacuo leaving a dark oil. The oil was purified by silica gel chromatography eluting with 50% EtOAc/hexanes to give the desired product as a yellow solid, 6.5 g (48% yield). 1H NMR (CDCl3/300 MHz): 7.65 (s, 1H); 7.55-7.10 (m, 16H); 4.80-4.70 (m, 2H); 4.30 (q, 2H); 3.12 (s, 6H); 3.00-2.85 (m, 4H); 2.20-2.00 (m, 4H); 1.35 (t, 3H).

[1194] Anal. Calcd for C35H38N4O3(0.2H2O): C, 74.23; H, 6.83; N, 9.89. Found: C, 74.16; H, 6.63; N, 9.77.

EXAMPLE 222

[1195] This example illustrates the production of 2-(3-aminopropyl)-8-(4-methoxyphenyl)-2,4,5,8-tetrahydropyrazolo[4,3-g]indazole-3-carboxylic acid hydrochloride.

1235

[1196] To 4-methoxyphenylhydrazine hydrochloride (786 mg, 0.0045 mol) in methanol (10 mL) was added dropwise 0.5M sodium methoxide (9 mL). Contents were stirred a half hour and added to ethyl (6E)-6-[(dimethylamino)methylene]-7-oxo-2-[3-(tritylamino)propyl]-4,5,6,7-tetrahydro-2H-indazole-3-carboxylate (2.3 g, 0.004 mol) in methanol (25 mL). Contents were refluxed 2 hours, allowed to cool and concentrated in vacuo leaving a red oil. The oil was purified by silica gel chromatography eluting with 25% EtOAc/hexanes, to give ethyl 2-(3-tritylaminopropyl)-8-(4-methoxyphenyl)-2,4,5,8-tetrahydropyrazolo[4,3-g]indazole-3-carboxylate as a red oil (1.5 g). The red oil, 2.5N sodium hydroxide (5 mL), water (5 mL) and methanol (20 mL) were refluxed 2 hours. Contents were partitioned between EtOAc and water. The water layer was made acidic to pH 2.5 with 1N HCl and filtered to give 2-(3-tritylaminopropyl)-8-(4-methoxyphenyl)-2,4,5,8-tetrahydropyrazolo[4,3-g]indazole-3-carboxylic acid as a light tan solid (702 mg). 2-(3-tritylaminopropyl)-8-(4-methoxyphenyl)-2,4,5,8-tetrahydropyrazolo[4,3-g]indazole-3-carboxylic acid (563 mg) and TFA (2 mL) in CH2Cl2 (5 mL) were stirred overnight. Contents were concentrated in vacuo and the residue mixed with 4N HCl in dioxane (5 mL) for 3 hours. Contents were filtered and the amber solid (315 mg) was triturated with acetonitrile/methanol to give the desired product as a light amber solid, 263 mg (15% yield. FABHRMS m/z 368.1696 (M+H, C19H22N5O3 requires 368.1717). 1H NMR (DMSO-d6+TFA/300 MHz): 7.90 (br, 2H); 7.60 (d, 2H); 7.55 (s, 1H); 7.05 (d, 2H); 4.45 (t, 2H); 3.80 (s, 3H); 3.05-2.95 (m, 2H); 2.80-2.70 (m, 4H); 2.10-1.95 (m, 2H).

[1197] Anal. Calcd for C19H21N5O3(1.2H2O): C, 49.40; H, 5.54; N, 15.16. Found: C, 49.70; H, 5.67; N, 14.81.

EXAMPLE 223

[1198] This example illustrates the production of ethyl 7-(acetylamino)-1-[4-(aminosulfonyl)phenyl]-4,5-dihydro-1H-benzo[g]indazole-3-carboxylate.

1236

[1199] FABHRMS m/z 455.1393 (M+H, C22H23N4O5S requires 455.1389).

EXAMPLE 224

[1200] This example illustrates the production of methyl 7-amino-1-[4-(aminosulfonyl) phenyl]-4,5-dihydro-1H-benzo[g]indazole-3-carboxylate hydrochloride.

1237

[1201] FABHRMS m/z 399.1150 (M+H, C19H19N4O4S requires 399.1127).

EXAMPLE 225

[1202] This example illustrates the production of ethyl 6-methyl-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate.

1238

[1203] FABHRMS m/z 247.1208 (M+H, C12H15N4O2 requires 247.1195).

EXAMPLE 226

[1204] This example illustrates the production of 7-amino-1-[4-(aminosulfonyl)phenyl]-4,5-dihydro-1H-benzo[g]indazole-3-carboxamide.

1239

[1205] FABHRMS m/z 384.1135 (M+H, C18H18N5O3S requires 384.1130).

EXAMPLE 227

[1206] This example illustrates the production of 8-amino-1-[4-(aminosulfonyl)phenyl]-4,5-dihydro-1H-benzo[g]indazole-3-carboxylic acid.

1240

[1207] FABHRMS m/z 385.0999 (M+H, C18H17N4O4S requires 385.0965).

EXAMPLE 228

[1208] This example illustrates the production of 1-[4-(aminosulfonyl)phenyl]-6-benzyl-N-methyl-1,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxamide.

1241

[1209] FABHRMS m/z 463.1566 (M+H, C23H23N6O3S requires 463.1552).

EXAMPLE 229

[1210] This example illustrates the production of 8-amino-1-[4-(aminosulfonyl)phenyl]-N-methyl-4,5-dihydro-1H-benzo[g]indazole-3-carboxamide.

1242

[1211] FABHRMS m/z 398.1266 (M+H, C19H20N5O3S requires 398.1287).

EXAMPLE 230

[1212] This example illustrates the production of ethyl 6-phenyl-2,4,5,6-tetrahydro-pyrazolo[3,4-e]indazole-3-carboxylate.

1243

[1213] FABHRMS m/z 309.1330 (M+H, C17H17N4O2 requires 309.1352).

EXAMPLE 231

[1214] This example illustrates the production of 1-[4-(aminosulfonyl)phenyl]-N-methyl-1,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxamide.

1244

[1215] FABHRMS m/z 373.1087 (M+H, C16H17N6O3S requires 373.1083).

EXAMPLE 232

[1216] This example illustrates the production of 6-phenyl-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxamide.

1245

[1217] FABHRMS m/z 280.1166 (M+H, C15H14N5O requires 280.1198).

EXAMPLE 233

[1218] This example illustrates the production of 1-[4-(aminosulfonyl)phenyl]-8-[methyl(methylsulfonyl)amino]-4,5-dihydro-1H-benzo[g]indazole-3-carboxamide.

1246

[1219] FABHRMS m/z 232.1061 (M+H, C12H14N3O2 requires 232.1086).

EXAMPLE 234

[1220] This example illustrates the production of 1-[4-(aminosulfonyl)phenyl]-8-[methyl(methylsulfonyl)amino]-4,5-dihydro-1H-benzo[g]indazole-3-carboxamide.

1247

[1221] FABHRMS m/z 476.1063 (M+H, C20H22N5O5S2 requires 476.1062).

EXAMPLE 235

[1222] This example illustrates the production of 6-benzyl-1-phenyl-1,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxamide.

1248

[1223] FABHRMS m/z 370.1680 (M+H, C22H20N5O requires 370.1668).

EXAMPLE 236

[1224] This example illustrates the production of 7-(acetylamino)-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid.

1249

[1225] FABHRMS m/z 272.1043 (M+H, C14H14N3O3 requires 272.1035).

EXAMPLE 237

[1226] This example illustrates the production of 1-phenyl-1,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylic acid.

1250

[1227] FABHRMS m/z 281.1044 (M+H, C15H13N4O2 requires 281.1039).

EXAMPLE 238

[1228] This example illustrates the production of 6-(2-hydroxyethyl)-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxamide.

1251

[1229] FABHRMS m/z 248.1172 (M+H, C11H14N5O2 requires 248.1147).

EXAMPLE 239

[1230] This example illustrates the production of 7-amino-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid.

1252

[1231] FABHRMS m/z 230.0940 (M+H, C12H12N3O2 requires 230.0930).

EXAMPLE 240

[1232] This example illustrates the production of 1-[4-(methylsulfonyl)phenyl]-1,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylic acid.

1253

[1233] FABHRMS m/z 359.0833 (M+H, C16H15N4O4S requires 359.0814).

EXAMPLE 241

[1234] This example illustrates the production of 6-[(benzyloxy)methyl]-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxamide.

1254

[1235] FABHRMS m/z 324.1460 (M+H, C17H18N5O2 requires 324.1461).

EXAMPLE 242

[1236] This example illustrates the production of 7-[(benzyloxy)methyl]-2,4,5,7-tetrahydro-pyrazolo[3,4-e]indazole-3-carboxamide.

1255

[1237] FABHRMS m/z 324.1460 (M+H, C17H18N5O2 requires 324.1461).

EXAMPLE 243

[1238] This example illustrates the production of ethyl 6-(4-methylphenyl)-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate.

1256

[1239] FABHRMS m/z 323.1539 (M+H, C18H19N4O2 requires 323.1508).

EXAMPLE 244

[1240] This example illustrates the production of 6-(4-methylphenyl)-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylic acid.

1257

[1241] FABHRMS m/z 295.1193 (M+H, C16H15N4O2 requires 295.1195).

EXAMPLE 245

[1242] This example illustrates the production of ethyl 7-allyl-2,4,5,7-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate.

1258

[1243] FABHRMS m/z 273.1340 (M+H, C14H17N4O2 requires 273.1346).

EXAMPLE 246

[1244] This example illustrates the production of 7-allyl-2,4,5,7-tetrahydro-pyrazolo[3,4-e]indazole-3-carboxamide.

1259

[1245] FABHRMS m/z 244.1206 (M+H, C12H14N5O requires 244.1193).

EXAMPLE 247

[1246] This example illustrates the production of ethyl 6-allyl-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate.

1260

[1247] FABHRMS m/z 273.1338 (M+H, C14H17N4O2 requires 273.1346).

EXAMPLE 248

[1248] This example illustrates the production of 6-allyl-2,4,5,6-tetrahydro-pyrazolo[3,4-e]indazole-3-carboxamide.

1261

[1249] FABHRMS m/z 244.1226 (M+H, C12H14N5O requires 244.1193).

EXAMPLE 249

[1250] This example illustrates the production of 6-(ethoxymethyl)-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxamide.

1262

[1251] FABHRMS m/z 262.1282 (M+H, C12H16N5O2 requires 262.1299).

EXAMPLE 250

[1252] This example illustrates the production of ethyl 7-isobutyl-2,4,5,7-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate.

1263

[1253] FABHRMS m/z 289.1624 (M+H, C15H21N4O2 requires 289.1659).

EXAMPLE 251

[1254] This example illustrates the production of 7-isobutyl-2,4,5,7-tetrahydro-pyrazolo[3,4-e]indazole-3-carboxamide.

1264

[1255] FABHRMS m/z 260.1505 (M+H, C13H18N5O requires 260.1506).

EXAMPLE 252

[1256] This example illustrates the production of 1-(2,2,2-trifluoroethyl)-1,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxamide.

1265

[1257] FABHRMS m/z 286.0902 (M+H, C11H11F3N5O requires 286.0910).

EXAMPLE 253

[1258] This example illustrates the production of ethyl 1-(3-aminopropyl)-1,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate.

1266

[1259] FABHRMS m/z 290.1585 (M+H, C14H20N5O2 requires 290.1612).

EXAMPLE 254

[1260] This example illustrates the production of 1-(3-aminopropyl)-1,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylic acid.

1267

[1261] FABHRMS m/z 262.1278 (M+H, C12H16N5O2 requires 262.1299).

EXAMPLE 255

[1262] This example illustrates the production of 1-(2-carboxyethyl)-1,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylic acid.

1268

[1263] FABHRMS m/z 277.0931 (M+H, C12H13N4O4 requires 277.0931).

EXAMPLE 256

[1264] This example illustrates the production of 1-(2-cyanoethyl)-1,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxamide.

1269

[1265] FABHRMS m/z 257.1174 (M+H, C12H13N6O requires 257.1151).

EXAMPLE 257

[1266] This example illustrates the production of ethyl 1-(2-cyanoethyl)-1,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate hydrochloride.

1270

[1267] FABHRMS m/z 286.1304 (M+H, C14H16N5O2 requires 286.1345).

EXAMPLE 258

[1268] This example illustrates the production of ethyl 1-(2-cyanoethyl)-7-trityl-1,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate.

1271

[1269] FABHRMS m/z 550.2219 (M+H, C33H30N5O2 requires 550.2202).

EXAMPLE 259

[1270] This example illustrates the production of ethyl 1-(2-ethoxy-2-oxoethyl)-7-trityl-1,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate.

1272

[1271] FABHRMS m/z 561.2454 (M+H, C34H33N4O4 requires 561.2502).

EXAMPLE 260

[1272] This example illustrates the production of ethyl 2-(2-ethoxy-2-oxoethyl)-7-trityl-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate.

1273

[1273] FABHRMS m/z 561.2495 (M+H, C34H33N4O4 requires 561.2496).

EXAMPLE 261

[1274] This example illustrates the production of 2-(carboxymethyl)-2,4,5,6-tetrahydro-pyrazolo[3,4-e]indazole-3-carboxylic acid.

1274

[1275] FABHRMS m/z 263.0787 (M+H, C11H11N4O4 requires 263.0775).

EXAMPLE 262

[1276] This example illustrates the production of ethyl 2-(2-ethoxy-2-oxoethyl)-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate hydrochloride.

1275

[1277] FABHRMS m/z 319.1422 (M+H, C15H19N4O4 requires 319.1401).

EXAMPLE 263

[1278] This example illustrates the production of 3-(ethoxycarbonyl)-5,6-dihydropyrazolo[3,4-e]indazol-1 (4H)-yl]acetic acid.

1276

[1279] FABHRMS m/z 291.1051 (M+H, C13H15N4O4 requires 291.1088).

EXAMPLE 264

[1280] This example illustrates the production of 1-(3-amino-3-oxopropyl)-1,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylic acid.

1277

[1281] FABHRMS m/z 276.1107 (M+H, C12H14N5O3 requires 276.1091).

EXAMPLE 265

[1282] This example illustrates the production of [3-(methoxycarbonyl)-5,6-dihydropyrazolo[3,4-e]indazol-2(4H)-yl]acetic acid.

1278

[1283] FABHRMS m/z 277.0901 (M+H, C12H13N4O4 requires 277.0931).

EXAMPLE 266

[1284] This example illustrates the production of [3-(ethoxycarbonyl)-5,6-dihydro-pyrazolo[3,4-e]indazol-2(4H)-yl]acetic acid.

1279

[1285] FABHRMS m/z 291.1066 (M+H, C13H15N4O4 requires 291.1088).

EXAMPLE 267

[1286] This example illustrates the production of ethyl 2-(4-aminobutyl)-2,4,5,6-tetrahydro-pyrazolo[3,4-e]indazole-3-carboxylate.

1280

[1287] FABHRMS m/z 304.1785 (M+H, C15H22N5O2 requires 304.1768).

EXAMPLE 268

[1288] This example illustrates the production of 1-(2-amino-2-oxoethyl)-1,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxamide.

1281

[1289] FABHRMS m/z 261.1101 (M+H, C11H13N6O2 requires 261.1095).

EXAMPLE 269

[1290] This example illustrates the production of 1-(3-amino-3-oxopropyl)-1,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxamide.

1282

[1291] FABHRMS m/z 275.1268 (M+H, C12H15N6O2 requires 275.1251).

EXAMPLE 270

[1292] This example illustrates the production of ethyl 8-(tert-butylamino)-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate.

1283

[1293] FABHRMS m/z 304.1739 (M+H, C15H22N5O2 requires 304.1768).

EXAMPLE 271

[1294] This example illustrates the production of 2-(3-aminopropyl)-2,4,5,8-tetrahydropyrazolo[4,3-g]indazole-3-carboxylic acid hydrochloride.

1284

[1295] FABHRMS m/z 262.1304 (M+H, C12H16N5O2 requires 262.1299).

EXAMPLE 272

[1296] This example illustrates the production of 1-(3-aminopropyl)-1,4,5,8-tetrahydro-pyrazolo[4,3-g]indazole-3-carboxylic acid hydrochloride.

1285

[1297] FABHRMS m/z 262.1288 (M+H, C12H16N5O2 requires 262.1299).

EXAMPLE 273

[1298] This example illustrates the production of ethyl 7-trityl-2,4,5,7-tetrahydropyrazolo[4,3-g]indazole-3-carboxylate.

1286

[1299] FABHRMS m/z 497.1899 (M+H, C30H27N4O2 requires 497.1948).

EXAMPLE 274

[1300] This example illustrates the production of ethyl 1-[3-(tritylamino)propyl]-1,4,5,8-tetrahydropyrazolo[4,3-g]indazole-3-carboxylate.

1287

[1301] FABHRMS m/z 532.2707 (M+H, C33H34N5O2 requires 532.2672).

EXAMPLE 275

[1302] This example illustrates the production of 1-(3-aminopropyl)-1,4,5,8-tetrahydropyrazolo[4,3-g]indazole-3-carboxamide.

1288

[1303] FABHRMS m/z 261.1449 (M+H, C12H17N6O requires 261.1458).

EXAMPLE 276 This example illustrates the production of ethyl 6-benzyl-1-[4-(methylsulfonyl)phenyl]-1,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate.

[1304]

1289

[1305] To N,N-dimethylacetamide dimethylacetal (250 mL) was added 1,3-cyclohexanedione (100 g, 0.89 mol). Contents were refluxed 2 hours, allowed to cool and concentrated in vacuo leaving an amber solid. After recrystallizing twice from EtOAc, the desired eneamine intermediate was obtained as light amber crystals, 64.2 g. The eneamine (21.7 g, 0.13 mol) and benzylhydrazine hydrochloride (25.5 g, 0.13 mol) were mixed in glacial acetic acid (200 mL) and stirred overnight. Contents were diluted-with water, extracted with EtOAc, dried over MgSO4, and concentrated in vacuo leaving the desired tetralone intermediate as an amber oil, 37.2 g. The tetralone was reacted with diethyl oxalate according to the procedure for the production of ethyl (7-hydroxy-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)(oxo)acetate, to give the desired diketoester intermediate as an amber oil. The diketoester was reacted with 4-methylsulfonylphenylhydrazine according to the procedure for the production of ethyl 8-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate, to give the desired product as white crystals (53% yield). FABHRMS m/z 477.1587 (M+H, C25H25N4O4S requires 477.1597).

[1306] Anal. Calcd for C24H24N4O4S: C, 63.01; H, 5.08; N, 11.76. Found: C, 62.93; H, 4.92; N, 11.77.

EXAMPLE 277

[1307] This example illustrates the production of ethyl 1-[4-(methylsulfonyl)-phenyl]-1,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate.

1290

[1308] Ethyl 6-benzyl-1-[4-(methylsulfonyl)phenyl]-1,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate (2.5 g, 0.005 mol), Pearleman's catalyst (1.0 g) and glacial acetic acid (30 mL) were shaken at 55 psi H2 and 55° C., overnight. Contents were allowed to cool and filtered through clay. The filtrate was concentrated in vacuo and the residue was triturated with methanol and filtered to give the desired product as a white solid, 609 mg (32% yield). FABHRMS m/z 387.1161 (M+H, C18H19N4O4S requires 387.1127).

[1309] Anal. Calcd for C18H18N4O4S (0.8H2O): C, 53.94; H, 4.93; N, 13.98. Found: C, 53.97; H, 4.71; N, 13.71.

EXAMPLE 278

[1310] This example illustrates the production of 1-[4-(methylsulfonyl)phenyl]-1,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxamide.

1291

[1311] Ethyl 1-[4-(methylsulfonyl)phenyl]-1,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate was reacted according to the procedure for the production of 8-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxamide to give the desired product as a white solid (58% yield).

[1312] Anal. Calcd for C16H15N5O3S (0.5H2O): C, 52.45; H, 4.40; N, 19.11. Found: C, 52.42; H, 4.41; N, 18.63.

EXAMPLE 279

[1313] This example illustrates the production of 1,5,6,7-tetrahydro-4H-indazol-4-one.

1292

[1314] To N,N-dimethylacetamide dimethylacetal (250 mL) was added 1,3-cyclohexanedione (100 g, 0.89 mol). Contents were refluxed 2 hours, allowed to cool and concentrated in vacuo leaving amber solid. After recrystallizing twice from EtOAc, the desired eneamine intermediate was obtained as light amber crystals, 64.2 g. The eneamine (5.0 g, 0.03 mol) and p-tosylhydrazine hydro-chloride (5.6 g, 0.3 mol) were stirred in methanol overnight. 4N HCl in dioxane (100 mL) was added and contents were stirred overnight. A white solid was filtered to give the desired product, 4.5 g (87% yield). FABHRMS m/z 137.0738 (M+H, C7H9N2O requires 137.0715). 1H NMR (DMSO-d6/300 MHz): 7.90 (s, 1H); 2.90-2.80 (m, 2H); 2.40-2.30 (m, 2H); 2.10-2.00 (m, 3H).

[1315] Anal. Calcd for C7H8N2O (0.05H2O): C, 61.35; H, 5.96; N, 20.44. Found: C, 61.25; H, 5.98; N, 20.53.

EXAMPLE 280

[1316] This example illustrates the production of 2-trityl-2,5,6,7-tetrahydro-4H-indazol-4-one.

1293

[1317] To 7-oxo-4,5,6,7-tetrahydro-1H-indazole (2.0 g, 0.012 mol) and triethylamine (4.4 mL, 0.031 mol) in CH2Cl2 (25 mL) was added dropwise trityl chloride (4.3 g, 0.0155 mol) in CH2Cl2 (20 mL). Contents were stirred overnight, washed with water and the CH2Cl2 layer was concentrated in vacuo. The residue was partitioned between ether and water. The ether layer was washed with brine, dried over MgSO4 and concentrated in vacuo leaving an amber oil. Trituration with hexanes gave the desired product as a white solid, 3.6 g (79% yield). FABHRMS m/z 401.1608 (M+H, C26H23N2O requires 401.1630). 1H NMR (CDCl3/300 MHz): 7.90 (s, 1H); 7.40-7.10 (m, 15H); 2.90-2.80 (m, 2H); 2.55-2.45 (m, 2H); 2.20-2.10 (m, 2H).

[1318] Anal. Calcd for C26H22N2O: C, 82.51; H, 5.86; N, 7.4. Found: C, 82.36; H, 6.10; N, 7.32.

EXAMPLE 281

[1319] This example illustrates the production of 6-methyl-2,4,5,6-tetrahydro-pyrazolo[3,4-e]indazole-3-carboxamide.

1294

[1320] FABHRMS m/z 218.1051 (M+H, C10H12N5O requires 218.1042).

EXAMPLE 282

[1321] This example illustrates the production of ethyl 2-trityl-4-oxo-4,5,6,7-tetrahydro-2H-indazol-5-yl](oxo)acetate.

1295

[1322] 1-trityl-1,5,6,7-tetrahydro-4H-indazol-4-one- or 1-trityl-1,5,6,7-tetrahydro-4H-indazol-4-one was reacted according to the procedure for the production of ethyl (7-hydroxy-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)(oxo)acetate to give the desired product as yellow crystals (82% yield). FABHRMS m/z 479.1971 (M+H, C30H27N2O4 requires 479.1965). 1H NMR (CDCl3/300 MHz): 7.97 (s, 1H); 7.40-7.10 (m, 15H); 4.40 (q, 2H); 3.15-3.05 (m, 2H); 2.95-2.85 (m, 2H); 1.45 (t, 3H).

[1323] Anal. Calcd for C30H26N2O4: C, 75.30; H, 5.48; N, 5.85. Found: C, 75.11; H, 5.38; N, 5.73.

EXAMPLE 283

[1324] This example illustrates the production of ethyl 2,4,5,6-tetrahydro-pyrazolo[3,4-e]indazole-3-carboxylate.

1296

[1325] Ethyl oxo(4-oxo-1-trityl-4,5,6,7-tetrahydro-1H-indazol-5-yl)acetate- or ethyl oxo(4-oxo-2-trityl-4,5,6,7-tetrahydro-2H-indazol-5-yl)acetate or ethyl oxo(4-oxo-2-trityl-4,5,6,7-tetrahydro-2H-indazol-5-yl)acetate was reacted according to the procedure for the production of ethyl 8-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate, at 70° C. to give the desired product (67% yield). 1H NMR (DMSO-d6/300 MHz): 7.78 (s, 1H); 4.30 (q, 2H); 3.05-2.95 (m, 2H); 2.90-2.80 (m, 2H); 1.35 (t, 3H).

[1326] Anal. Calcd for C11H13N4O2 (2HOAc): C, 51.13; H, 5.72; N, 15.90. Found: C, 51.09; H, 5.80; N, 16.09.

EXAMPLE 284

[1327] This example illustrates the production of 2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxamide.

1297

[1328] Ethyl 2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate was reacted according to the procedure for the production of 8-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxamide to give the desired as an off-white solid (97% yield). FABHRMS m/z 204.0877 (M+H, C9H10N5O requires 204.0885).

[1329]

1
H NMR (DMSO-d6+TFA/300 MHz): 7.85 (s, 1H); 7.30 (brs, 2H); 3.05-2.95 (m, 2H); 2.90-2.80 (m, 2H).

[1330] Anal. Calcd for C9H9N5O: C, 53.20; H, 4.46; N, 34.47. Found: C, 53.14; H, 4.47; N, 34.57.

EXAMPLE 285

[1331] This example illustrates the production of ethyl [1-(2-hydroxyethyl)-4-oxo-4,5,6,7-tetrahydro-1H-indazol-5-yl](oxo)acetate.

1298

[1332] To N,N-dimethylacetamide dimethylacetal (250 mL) was added 1,3-cyclohexanedione (100 g, 0.89 mol). Contents were refluxed 2 hours, allowed to cool and concentrated in vacuo leaving amber solid. After recrystallizing twice from EtOAc, the desired eneamine intermediate was obtained as light amber crystals, 64.2 g. The eneamine (20.0 g, 0.12 mol) and hydroxyethylhydrazine (7.2 g, 0.12 mol) were mixed in methanol (50 mL) and stirred 72 hours. Contents were concentrated in vacuo leaving an oil, 13.4 g which was purified by silica gel chromatography eluting with 5% MeOH/EtOAc to give the desired tetralone intermediate as a yellow solid, 17.6 g (81% yield). The tetralone was reacted according to the procedure for the production of ethyl (7-hydroxy-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)(oxo)acetate to give the desired product as a white solid (38% yield). FABHRMS m/z 281.1148 (M+H, C13H17N2O5 requires 281.1137).

[1333] Anal. Calcd for C13H16N2O5: C, 55.71; H, 5.75; N, 9.99. Found: C, 55.63; H, 5.67; N, 9.96.

EXAMPLE 286

[1334] This example illustrates the production of ethyl 6-(2-hydroxyethyl)-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate acetate.

1299

[1335] Ethyl 6-(2-hydroxyethyl)-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate acetate was prepared according to the procedure for the production of ethyl 8-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate, to give the desired product as a white solid (80% yield). FABHRMS m/z 277.1296 (M+H, C13H17N4O3 requires 277.1301).

[1336] Anal. Calcd for C13H16N4O3 (HOAc):C, 53.56; H, 5.99; N, 16.66. Found: C, 53.45; H, 5.71; N, 16.60.

EXAMPLE 287

[1337] This example illustrates the production of 6-(2-hydroxyethyl)-2,4,5,6-tetrahydro-pyrazolo[3,4-e]indazole-3-carboxylic acid.

1300

[1338] 6-(2-hydroxyethyl)-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylic acid was prepared according to the procedure for the production of 7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid to give the desired product as a white solid (83% yield). FABHRMS m/z 249.0988 (M+H, C11H13N4O3 requires 249.0988).

[1339] Anal. Calcd for C11H12N4O3: C, 53.22; H, 4.87; N, 22.57. Found: C, 52.86; H, 4.83; N, 22.49.

EXAMPLE 288

[1340] This example illustrates the production of ethyl 1-[4-(aminosulfonyl)-phenyl]-6-benzyl-1,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate.

1301

[1341] Ethyl 1-[4-(aminosulfonyl)phenyl]-6-benzyl-1,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate- or ethyl 1-[4-(aminosulfonyl)phenyl]-6-benzyl-1,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate was prepared according to the procedures for the production of ethyl (7-hydroxy-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)(oxo)acetate and ethyl 1-[4-(aminosulfonyl)phenyl]-8-hydroxy-4,5-dihydro-1H-benzo[g]indazole-3-carboxylate to give the desired as a light tan solid (61% yield). FABHRMS m/z 478.1549 (M+H, C24H24N5O4S requires 478.1551). 1H NMR (DMSO-d6+5%TFA/300 MHz): 7.98 (AB quartet, 4H); 7.38-7.20 (m, 3H); 7.20-7.10 (m, 2H); 5.38 (s, 2H); 4.25 (q, 2H); 3.20-2.90 (m, 4H); 1.25 (t, 3H).

[1342] Anal. Calcd for C24H23N5O4S: C, 60.36; H, 4.85; N, 14.67. Found: C, 60.60; H, 4.86; N, 14.71.

EXAMPLE 289

[1343] This example illustrates the production of ethyl 1-[4-(aminosulfonyl)-phenyl]-1,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate.

1302

[1344] Ethyl 1-[4-(aminosulfonyl)phenyl]-6-benzyl-1,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate- or ethyl 1-[4-(aminosulfonyl)phenyl]-6-benzyl-1,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate (4.2 g, 0.009 mol), Pearleman's catalyst (1.5 g), glacial acetic acid (20 mL) and DMF (40 mL) were shaken at 55 psi H2 for 72 hours. Contents were filtered through clay and the filtrate was concentrated in vacuo leaving a grey solid. The grey solid was triturated with acetonitrile to give an off-white solid, 3.0 g (86% yield). FABHRMS m/z 388.1080 (M+H, C17H18N5O4S requires 388.1124). 1H NMR (DMSO-d6/300 MHz): 7.96 (AB quartet, 4H); 7.55 (br s, 2H); 7.35 (br s, 1H); 4.35 (q, 2H); 3.30 (s, 2H); 3.15-3.05 (m, 2H); 3.00-2.85 (m, 2H); 1.35 (t, 3H).

[1345] Anal. Calcd for C17H17N5O4S: C, 52.70; H, 4.42; N, 18.08. Found: C, 52.47; H, 4.18; N, 17.89.

EXAMPLE 290

[1346] This example illustrates the production of 1-[4-(aminosulfonyl)phenyl]-1,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxamide.

1303

[1347] Ethyl 1-[4-(aminosulfonyl)phenyl]-1,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate- or ethyl 1-[4-(aminosulfonyl)phenyl]-1,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate was reacted according to the procedure for the production of 8-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxamide to give the desired product as a white solid (86% yield). FABHRMS m/z 359.0939 (M+H, C15H15N6O3S requires 359.0926). 1H NMR (DMSO-d6/300 MHz): 7.99 (AB quartet, 4H); 7.58 (s, 1H); 7.50 (s, 1H); 7.35 (s, 1H); 3.35 (s, 2H); 3.10-3.00 (m, 2H); 2.90-2.80 (m, 2H).

[1348] Anal. Calcd for C15H14N6O3S: C, 50.27; H, 3.94; N, 23.45. Found: C, 50.07; H, 3.73; N, 23.08.

EXAMPLE 291

[1349] This example illustrates the production of 1-[4-(aminosulfonyl)phenyl]-1,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylic acid.

1304

[1350] Ethyl 1-[4-(aminosulfonyl)phenyl]-1,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate- or ethyl 1-[4-(aminosulfonyl)phenyl]-1,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate was reacted according to the procedure of 7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid to give the desired product as a white solid (85% yield). FABHRMS m/z 360.0762 (M+H, C15H14N5O4S requires 360.0767).

[1351] Anal. Calcd for C15H13N5O4S: C, 46.03; H, 3.35; N, 17.89. Found: C, 46.67; H, 3.64; N, 17.93.

EXAMPLE 292

[1352] This example illustrates the production of ethyl 6-benzyl-1-phenyl-1,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate.

1305

[1353] To N,N-dimethylacetamide dimethylacetal (250 mL) was added 1,3-cyclohexanedione (100 g, 0.89 mol). Contents were refluxed 2 hours, allowed to cool and concentrated in vacuo leaving an amber solid. After recrystallizing twice from EtOAc, the desired eneamine intermediate was obtained as light amber crystals, 64.2 g. The eneamine (21.7 g, 0.13 mol) and benzylhydrazine hydrochloride (25.5 g, 0.13 mol) were mixed in glacial acetic acid (200 mL) and stirred overnight. Contents were diluted with water, extracted with EtOAc, dried over MgSO4, and concentrated in vacuo leaving the desired tetralone intermediate as an amber oil, 37.2 g. The tetralone was reacted with diethyl oxalate according to the procedure for the production of ethyl (7-hydroxy-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)(oxo)acetate, to give the desired diketoester intermediate as an amber oil. The diketoester was reacted with phenylhydrazine according to the procedure for the production of ethyl 8-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate, to give the desired product as white crystals (14% yield). FABHRMS m/z 399.1826 (M+H, C24H23N4O2 requires 399.1821).

[1354] Anal. Calcd for C24H22N4O2: C, 72.34; H, 5.57; N, 14.06. Found: C, 72.14; H, 5.41; N, 13.98.

EXAMPLE 293

[1355] This example illustrates the production of ethyl 1-phenyl-1,4,5,6-tetrahydro-pyrazolo[3,4-e]indazole-3-carboxylate.

1306

[1356] Ethyl 6-benzyl-1-phenyl-1,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate (3.4 g, 0.009 mol) and Pearleman's catalyst (1.0 g) in ethanol (100 mL) were shaken at 55 psi H2 and 55° C. for 72 hours. Contents were allowed to cool and filtered through clay. The filtrate was concentrated in vacuo leaving a white solid. Triteration of the solid with methanol gave the desired as a white solid, 1.0 g (36% yield). FABHRMS m/z 309.1343 (M+H, C17H17N4O2 requires 309.1352).

[1357] Anal. Calcd for C17H16N4O2: C, 66.22; H, 5.23; N, 18.17. Found: C, 66.06; H, 5.41; N, 17.58.

EXAMPLE 294

[1358] This example illustrates the production of 1-phenyl-1,4,5,6-tetrahydro-pyrazolo[3,4-e]indazole-3-carboxamide.

1307

[1359] 1-phenyl-1,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxamide was prepared according to the procedure for the production of 8-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxamide, at 100° C., to give the desired product as a grey solid (72% yield). FABHRMS m/z 280.1208 (M+H, C15H14N5O requires 280.1198).

[1360] Anal. Calcd for C15H13N5O (0.5H2O): C, 62.49; H, 4.89; N, 24.29. Found: C, 62.94; H, 4.83; N, 23.76.

1308

EXAMPLE 295

[1361] This example illustrates the production of Boc-allyl amine. Boc-anhydride (1M THF, 70 mmol, 70 mL) was added to allyl amine (70 mmol, 4.0 g, 5.26 mL) slowly with stirring. The reaction solution stirred at 23° C. for 16 hours. The THF was removed in vacuo and the residue was reconstituted in dichloromethane (20 mL) and washed with water and brine (1×25 mL). The organic layer was dried (MgSO4) and concentrated in vacuo. The product was isolated as a white low melting solid (10.25 g, 99% yield): 1HNMR (409 MHz, CDCl3) δ 5.853-5.770 (m, 1H), 5.278-5.069 (qm, 2H), 3.723 (bs, 2H), 1.429 (s, 9H).

EXAMPLE 296

[1362] This example illustrates the production of 3-(4-tert-butylphenyl)-propylamine.

[1363] Tert-butyl allylcarbamate (7.0 mmol, 1.10 g) was weighed into a 100 mL flask with-stir bar and 9-BBN solution (0.5M, THF, 7.7 mmol, 15.4 mL) was syringed. Carefully into the neat amine. The reaction stirred at 23° C. for 16 hours. The potassium phosphate (2M, 10.5 mmol, 5.25 mL) was added to the reaction mixture and stirred at 23° C. for 10 minutes. [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II)/DCM complex (0.21 mmol, 171 mg) and the 4-t-butyl-phenylbromide (7.0 mmol, 1.49 g, 1.21 mL) were added to the basic reaction mixture and the slurry was heated to relfux for 16 hours. The crude reaction mixture was purified using a 20 g flash silica plug (eluting with 100% hexane to 50% ethylacetate/hexane). The isolated pale brown oil (2.96 g) was dissolved in 25%TFA/DCM (15 mL) and stirred for 30 minutes at 23° C. The reaction mixture was concentrated in vacuo, reconstituted in dichloromethane (20 mL) and washed with saturated bicarbonate solution (3×30 mL). The organic layer was concentrated in vacuo. The crude product was purified using a 20 g flash silica plug (eluting with 100% hexane to 100% ethyl acetate to 100% methanol). Isolated the product as a light tan solid (1.25 g, 94% yield): 1HNMR (400 MHz, DMSO) δ 7.911 (bs, 2H), 7.200 (q, (a,b), 4H), 2.762 (m, 2H), 2.579 (t, 2H), 1.811 (m, 2H), 1.240 (s, 9H): m/z 192 (M+H).

EXAMPLE 297

[1364] This example illustrates the production of 3-(4-chlorophenyl)propylamine.

[1365] The product was isolated as a tan semi-solid (231 mg, 45% yield): 1HNMR (400 MHz, DMSO) δ 7.300 (q, a,b, 4H), 2.631 (m, 4H), 1.724 (m, 2H): m/z 170 (M+H).

EXAMPLE 298

[1366] This example illustrates the production of 3-(4-bromophenyl)propylamine.

[1367] The product was isolated as a tan semi-solid (310 mg, 48% yield): 1HNMR (400 MHz, DMSO) δ 7.380 (q, a,b, 4H), 2.639 (q, 4H), 1.724 (m, 2H): m/z 216(M+H).

EXAMPLE 299

[1368] This example illustrates the production of 3-(3-chlorophenyl)propylamine.

[1369] The product was isolated as a tan semi-solid (244 mg, 48% yield): 1HNMR (400 MHz, DMSO) δ 7.323 (m, 3H), 7.220 (d, 1H), 2.664 (m, 4H), 1.796 (t, 2H): m/z 170 (M+H).

EXAMPLE 300

[1370] This example illustrates the production of 3-[4-(methylsulfonyl) phenyl]propylamine. The product was isolated as a tan semi-solid (188 mg, 29% yield): 1HNMR (400 MHz, DMSO) δ 7.610 (q, a,b, 4H), 3.220 (s, 3H), 2.783 (m, 4H), 1.873 (m, 2H): m/z 214 (M+H).

EXAMPLE 301

[1371] This example illustrates the production of 3-(1,1′-biphenyl-4-yl)propylamine.

[1372] The product was isolated as a tan semi-solid (485 mg, 76% yield): 1HNMR (400 MHz, DMSO) δ 7.649(m, 4H), 7.483 (t, 2H), 7.374 (m, 3H), 2.842 (t, 2H), 2.686 (t, 2H), 1.894 (t, 2H): m/z 212 (M+H).

[1373] The following compounds were synthesized in the same manner as 2-(3-{[2-(2-chlorophenyl)ethyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate (cyclic pyrazole Bromide alkylation of amines) using the previously described amines.

EXAMPLE 302

[1374] This example illustrates the production-of 2-(3-{[3-(4-tert-butylphenyl)propyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate.

[1375] The product was isolated as a white amorphous solid (148 mg, 30% yield):

[1376]

1
HNMR (400 MHz, DMSO) δ 8.685 (s, 1H), 8.608 (d, 1H), 7.840 (d, 1H), 7.284 (d, 2H), 7.094 (d, 2H), 4.627 (t, 2H), 3.010 (s, 4H), 2.931 (m, 2H), 2.860 (m 2H0, 2.551 (t, 2H), 2.126 (m, 2H), 1.807 (m, 2H), 1.222 (s, 9H): m/z 447 (M+H).

EXAMPLE 303

[1377] This example illustrates the production of 2-(3-{[3-(4-chlorophenyl)propyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate.

[1378] The product was isolated as a white amorphous solid (84 mg, 18% yield):

[1379]

1
HNMR (400 MHz, DMSO) δ 8.726 (bs, 1H), 8.644 (d, 1H), 7.895 (d, 1H), 7.334 (d, 2H), 7.211 (d, 2H), 4.632 (t, 2H), 3.025 (s, 4H), 2.931 (m, 2H), 2.860 (m, 2H), 2.593 (t, 2H), 2.126 (m, 2H), 1.807 (m, 2H): m/z 425 (M+H).

EXAMPLE 304

[1380] This example illustrates the production of 2-(3-{[3-(4-bromophenyl)propyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate.

[1381] The product was isolated as a white amorphous solid (71 mg, 14% yield):

[1382]

1
HNMR (400 MHz, DMSO) δ 8.726 (bs, 1H), 8.644 (d, 1H), 7.895 (d, 1H), 7.449 (d, 2H), 7.154 (d, 2H), 4.632 (t, 2H), 3.006 (s, 4H), 2.931 (m, 2H), 2.860 (m, 2H), 2.593 (t, 2H), 2.126 (m, 2H), 1.807 (m, 2H): m/z 471 (M+H).

EXAMPLE 305

[1383] This example illustrates the production of 2-(3-{[3-(3-chlorophenyl)propyl]-amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate.

[1384] The product was isolated as a white amorphous solid (58 mg, 12% yield):

[1385]

1
HNMR (400 MHz, DMSO) δ 8.727 (s, 1H), 8.644 (d, 1H), 7.899 (d, 1H), 7.268 (m, 3H), 7.156 (d, 1H), 4.634 (t, 2H), 3.027 (s, 4H), 2.931 (m, 2H), 2.862 (m, 2H), 2.613 (t, 2H), 2.153 (m, 2H), 1.830 (m, 2H): m/z 425 (M+H).

EXAMPLE 306

[1386] This example illustrates the production of 2-[3-({3-[4-(methylsulfonyl)phenyl]propyl}amino)propyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate.

[1387] The product was isolated as a white amorphous solid (52 mg, 12% yield):

[1388]

1
HNMR (400 MHz, DMSO) δ 8.662 (bs, 1H), 8.591 (d, 1H), 7.841 (d, 2H), 7.806 (d, 1H), 7.466 (d, 2H), 4.626 (t, 2H), 3.460 (dq, 4H), 3.159 (s, 3H), 2.931 (m, 2H), 2.860 (m, 2H), 2.718 (t, 2H), 2.126 (m, 2H), 1.857 (m, 2H): m/z 469 (M+H).

EXAMPLE 307

[1389] This example illustrates the production of 2-(3-{[3-(1,1′-biphenyl-4-yl)propyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate.

[1390] The product was isolated as a white amorphous solid (52 mg, 12% yield):

[1391]

1
HNMR (400 MHz, DMSO) δ 8.684 (s, 1H), 8.600 (d, 1H), 7.839 (d, 1H), 7.613-7.555 (m, 4H), 7.422 (t, 2H), 7.320 (t, 1H), 7.277 (d, 2H), 4.634 (t, 2H), 3.008 (s, 4H), 2.940 (m, 4H), 2.645 (t, 2H), 2.140 (m, 2H), 1.865 (m, 2H): m/z 467 (M+H).

1309

EXAMPLE 308

[1392] This example illustrates the production of 8-[2-(2-chlorophenyl)ethyl]-5,6,8,9,10,11-hexahydro-7H-[1,4]diazepino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7-one trifluoroacetate.

[1393] 2-(3-{[2-(2-chlorophenyl)ethyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate (0.38 mmol, 200 mg) was dissolved in DMF (5.0 mL) and EDC-HCl (0.57 mmol, 109 mg), and HOBT (0.46 mmol, 62 mg) were added. The reaction mixture stirred at 23° C. for 16 hours. The reaction mixture was diluted with ethyl acetate (20 mL) and washed with water (2×25 mL). The organic layer was concentrated in vacuo, reconstituted in acetonitrile and purified using reverse phase chromatography. The product was isolated as a white amorphous solid (36.0 mg, 24% yield).

[1394]

1
HNMR (400 MHz, DMSO) δ 8.805 (s, 1H), 8.726 (d, 1H), 8.045 (d, 1H), 7.434 (t, 2H), 7.319 (m, 2H), 4.406 (t, 2H), 3.789 (t, 2H), 3.378 (t, 2H), 3.089 (t, 4H), 2.917 (t, 2H), 2.149 (t, 2H): m/z 394 (M+H).

1310

EXAMPLE 309

[1395] This example illustrates the production of ethyl 2-(oxiran-2-ylmethyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylate.

[1396] The pyrazole ester (1.23 mmol, 300 mg) was dissolved in DMF (10 mL) and cooled to −45° C. in a dry ice/acetonitrile bath. Lithium tert-butoxide (1M THF, 1.85 mmol, 1.85 mL) was added slowly being sure to maintain −45° C. The cold solution stirred for 1.5 h. Epibromohydrin (1.85 mmol, 0.253 g, 159 μL) was added via syringe to the cold DMF solution and the ice bath was removed. The reaction was allowed to warm to 23° C. over 16 h. The crude reaction was diluted with ethyl acetate (20 mL) and washed with water (1×10 mL) and brine (1×20 mL). The organic layer was dried (MgSO4) and concentrated in vacuo. The crude oil was purified via gravity feed chromatography using 60% ethyl acetate/hexane. The product was isolated as a clear oil (70 mg, 19% yield):

[1397]

1
HNMR (400 MHz, CDCl3) δ 8.602 (bs, 2H), 7.811(d, 1H), 4.825 (qd, 2H), 4.397 (q, 2H), 3.411 (bs, 1H), 3.035 (qd, 4H), 2.833 (t, 1H), 2.633 (m, 1H), 1.432 (t, 3H): m/z 300 (M+H).

EXAMPLE 310

[1398] This example illustrates the production of 9-(morpholin-4-5,6,9,10-tetrahydro-7H-[1,4]oxazino[4′,3′:1,5]pyrazolo[3,4-f]isoquinolin-7-one.

[1399] Ethyl 2-(oxiran-2-ylmethyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylate (1.34 mmol, 400 mg) was dissolved in acetonitrile (4 mL) and the morpholine (2.0 mmol, 175 mg, 175 μL) and the ytterbium triflate (0.2 mmol, 124 mg) were added. The vial was capped and heated to 70° C. for 4 h with stirring. After four hours of heating, the reaction vessel was allowed to cool and upon cooling the desired product precipitated and was collected via filtration. The product was isolated as a white solid (55 mg, 12% yield):

[1400]

1
HNMR (400 MHz, CDCl3) δ 8.538 (bs, 2H), 7.662 (d, 1H), 4.916 (m, 1H), 4.501(qd, 2H), 3.708 (bs, 4H), 3.178-3.079 (m, 2H), 2.995 (d, 2H), 2.872-2.803 (m, 2H), 2.606 (bs, 4H): m/z 341 (M+H). The following lactones were made (using the appropriate amine) in the same manor as 9-(morpholin-4-ylmethyl)-5,6,9,10-tetrahydro-7H-[1,4]oxazino[4′,3′:1,5] pyrazolo[3,4-f]isoquinolin-7-one:

EXAMPLE 311

[1401] This example illustrates the production of 9-{[(2-thien-2-ylethyl)amino]-methyl}-5,6,9,10-tetrahydro-7H-[1,4]oxazino[4′,3′:1,5]pyrazolo[3,4-f]isoquinolin-7-one trifluoroacetate.

[1402] The product was isolated as a pale yellow solid (129 mg, 23% yield): 1HNMR (400 MHz, DMSO) δ 8.750 (s 1H), 8.655(d, 1H), 7.985 (d, 1H), 7.337 (d, 1H), 6.936 (m, 2H), 4.358 (dd, 2H), 4.220 (dd, 2H), 3.82 (m, 1H), 3.582 (m, 1H), 3.460 (dd, 1H), 3.124 (t, 2H), 3.041 (m, 4H), 2.901 (t, 2H),: m/z 381 (M+H).

EXAMPLE 312

[1403] This example illustrates the production for the production of 9-{[(4-aminocyclohexyl)amino]methyl}-5,6,9,10-tetrahydro-7H-[1,4]oxazino-[4′,3′:1,5]pyrazolo[3,4-f]isoquinolin-7-one trifluoroacetate.

[1404] The product was isolated as a tan solid (338 mg, 61% yield): 1HNMR (400 MHz, DMSO) δ 8.682 (s, 1H), 8.612 (d, 1H), 7.880(d, 1H), 4.502 (dd, 2H), 3.454 (t, 2H), 3.381 (t, 2H), 2.979 (t, 2H), 1.941 (d, 4H), 1.326 (t, 4H): m/z 368 (M+H).

EXAMPLE 313

[1405] This example illustrates the production of 9-(aminomethyl)-5,6,9,10-tetrahydro-7H-[1,4]oxazino[4′,3′:1,5]pyrazolo[3,4-f]isoquinolin-7-one trifluoroacetate.

[1406] The product was isolated as a yellow solid (85.5 mg, 21% yield): 1HNMR (400 MHz, DMSO) δ 8.726 (s, 1H), 8.651 (d, 1-H), 7.968 (d, 1H), 4.588 (dd, 2H), 4.282-4.244 (3H), 3.430 (dd, 4H): m/z 271 (M+H).

EXAMPLE 314

[1407] This example illustrates the production of lithium 2-(2-hydroxy-3-morpholin-4-ylpropyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylate.

[1408] 9-(morpholin-4-ylmethyl)-5,6,9,10-tetrahydro-7H-[1,4]oxazino-[4′,3′:1,5]pyrazolo[3,4-f]isoquinolin-7-one (0.41 mmol, 139.5 mg) was dissolved in 50% THF/water (4.0 mL) and lithium hydroxide (2M, 0.21 mL) was added. The reaction mixture stirred at 23° C. for 3hours. The sample was concentrated under nitrogen stream. The residue was triturated with acetonitrile and sonicated to produce a fine powder. The product was collected via filtration and isolated as a light tan solid (140.4 mg, 95% yield):

[1409]

1
HNMR (400 MHz, DMSO) δ 8.468 (d, 2H), 7.655 (s, 1H), 7.544 (s, 1H), 4.601 (bs, 2H), 3.947 (m, 1H), 3.633 (s, 4H), 2.931-2.88 (d, 4H), 2.555 (m, 6H): m/z 359 (M+H).

[1410] The following compounds were hydrolyzed from the lactone to the acid in the same manner as lithium 2-(2-hydroxy-3-morpholin-4-ylpropyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylate

EXAMPLE 315

[1411] This example illustrates the production of 2-(2-hydroxy-3-piperazin-1-ylpropyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid dihydrochloride.

[1412] The product was isolated as a tan amorphous solid (254 mg, 95% yield):

[1413]

1
HNMR (400 MHz, DMSO) δ 9.055 (d, 1H), 8.941 (s, 1H), 7.211 (d, 1H), 4.742 (m, 1H), 4.421 (dd, 2H), 3.380 (t, 2H), 3.251 (t, 2H), 2.875 (m, 4H), 2.587 (t, 2H), 2.232-2.172 (m, 4H): m/z 358 (M+H).

EXAMPLE 316

[1414] This example illustrates the production of lithium 2-(2-hydroxy-3-piperidin-1-ylpropyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylate.

[1415] The product was isolated as a dark tan solid (120.7 mg, 96% yield): 1HNMR (400 MHz, DMSO) δ 9.068 (d, 1H), 8.946 (s, 1H), 7.222 (d, 1H), 4.499 (m, 2H), 4.321 (t, 1H), 3.661 (t, 2H), 3.551 (t, 2H), 2.553 (t, 2H), 2.321-2.130 (m, 4H), 1.431-1.256 (m, 6H): m/z 357 (M+H).

EXAMPLE 317

[1416] This example illustrates the production of lithium 2-[2-hydroxy-3-(3-oxopiperazin-1-yl)propyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylate.

[1417] The product was isolated as a tan solid (193.7 mg, 98% yield): 1HNMR (400 MHz, DMSO) δ 9.063 (d, 1H), 8.941 (s, 1H), 7.218 (d, 1H), 4.605 (m, 1H), 4.492 (d, 1H), 4.326 (m, 1H), 3.661 (t, 2H), 3.390-3.223 (m, 2H), 3.055 (d, 1H), 2.723-2.500 (m, 5H), 1.921-1.756 (m, 2H): m/z 372 (M+H).

EXAMPLE 318

[1418] This example illustrates the production of lithium 2-(2-hydroxy-3-pyrrolidin-1-ylpropyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylate.

[1419] The product was isolated as a tan solid (104.8 mg, 92% yield): 1HNMR (400 MHz, DMSO) δ 9.063 (d, 1H), 8.941 (s, 1H), 7.218 (d, 1H), 4.661-4.491 (m, 2H), 4.322 (t, 1H), 3.665 (t, 2H), 2.731-2.448 (m, 8H), 1.881-1.664 (m, 4H): m/z 343 (M+H).

EXAMPLES 319-325

[1420]

6

Isolated
Percent
Descrip-
(M + H)

EXAMPLE
Name
Lot #
Amount
Yield
tion
m/z

319
lithium 2-[2-
11934-163-2
124.7 mg
98%
Tan
302

hydroxy-3-

solid

(methylamino

propyl]-4,5-

dihydro-2H-

pyrazolo[3,4-

f]isoquinoline-

3-carboxylate

320
2-[3-(4-
11934-163-4
802.7 mg
98%
Yellow
372

aminopiperidi

oil

n-1-yl)-2-

hydroxypropyl]

-4,5-dihydro-2H-

pyrazolo[3,4-

f]isoquinoline-

3-carboxylic acid

bis(trifluoroac

etate)

321
lithium 2-{3-[4-
11934-163-5
342.6 mg
95%
Tan
399

(aminocarbonyl)

solid

piperidin-1-yl]-2-

hydroxypropyl}-4,5-

dihydro-2H-

pyrazolo[3,4-

f]isoquinoline-

3-carboxylate

322
lithium 2-{3-[(4-
11934-163-6
150.6 mg
70%
Off
385

aminocyclohexyl)

white

amino]-2-

solid

hydroxypropyl}-4,5-

dihydro-2H-

pyrazolo[3,4-

f]isoquinoline

3-carboxylate

323
lithium 2-{2-
11934-163-8
201.5 mg
97%
Off
384

hydroxy-3-

white

[(thien-2-

solid

ylmethyl)amin

o]propyl}-4,5-

dihydro-2H-

pyrazolo[3,4-

f]isoquinoline-

3-carboxylate

324
lithium 2-{2-
11934-163-9
85.0 mg
95%
Off
398

hydroxy-3-[(2-

white

thien-2-

solid

ylethyl)amino]

propyl}-4,5-

dihydro-2H-

pyrazolo[3,4-

f]isoquinoline-

3-carboxylate

325
lithium 2-[3-
11934-163-10
216.5 mg
99%
Tan
404

(2,3-dihydro-

solid

1H-inden-2-

ylamino)-2-

hydroxypropyl]-

4,5-dihydro-2H-

pyrazolo[3,4-

f]isoquinoline-

3-carboxylate

[1421]

1311

[1422] EXAMPLE 326.

[1423] This example illustrates the production of 2-[3-(2-furoylamino)propyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate.

[1424] Ethyl 2-(3-aminopropyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-10 carboxylate hydrochloride (0.54 mmol, 200 mg) was suspended in DMF (3.0 mL) and triethylamine (2.16 mmol, 301 μL) was added. 2-Furoyl chloride (0.65 mmol, 64.1 μL) was added via syringe to the DMF solution in one portion. The reaction stirred at 23° C. for 2 hours. LC/MS indicates starting material is consumed and the desired M+H is seen for the ester. Sodium hydroxide (2.5 mmol, 100 mg) was added to the DMF solution and stirred at 23° C. for 4 hours. The DMF was removed in vacuo and the residue was reconstituted in 50% water/acetonitrile and acidified to pH=3 with trifluoroacetic acid and purified via reverse phase chromatography. The product was isolated as a white amorphous solid (76.9 mg, 49% yield): 1HNMR (400 MHz, DMSO) δ 8.687 (s, 1H), 8.615 (d, 1H), 8.330 (t, 1H), 7.921 (m, 1H), 7.757 (m, 1H), 7.009 (dd, 1H), 6.560 (m, 1H), 4.609 (t, 2H), 3.244 (q, 2H), 2.099 (m, 2H): m/z 367.

1312

EXAMPLE 327

[1425] This example illustrates the production of ethyl 2-allyl-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylate (allyl, ester). The pyrazole ester (1.23 mmol, 300 mg) was dissolved in DMF (10 mL) and cooled to −45° C. in a dry ice/acetonitrile bath. Lithium tert-butoxide (1M THF, 1.85 mmol, 1.85 mL) was added slowly being sure to maintain −45° C. The cold solution stirred for 1.5 h. Allyl bromide (1.85 mmol, 0.224 g) was added via syringe to the cold DMF solution and the ice bath was removed. The reaction was allowed to warm to 23° C. over 16 h. The crude reaction was diluted with ethyl acetate (20 mL) and washed with water (1×10 mL) and brine (1×20 mL). The organic layer was dried (MgSO4) and concentrated in vacuo. The crude oil was purified via gravity feed chromatography using 60% ethyl acetate/hexane. The product was isolated as a clear oil (180 mg, 52% yield): 1HNMR (400 MHz, CDCl3) δ 8.480 (bs, 2H), 7.749 (d, 1H), 6.400-5.990 (m, 1H), 5.207 (dd, 2 h), 4.459-4.338 (m, 3H), 3.060 (t, 2H), 2.942 (t, 2H), 1.397 (t, 3H): m/z 284.

EXAMPLE 328

[1426] Ethyl 2-(oxiran-2-ylmethyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylate (Oxidation)-(ethyl 2-allyl-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylate) (0.64 mmol, 180 mg) was dissolved in dichloromethane (4.0 mL) and meta-chloro-per-benzoic acid (0.96 mmol, 195 mg, 57-86% purity) was added in one portion at 23° C. The reaction stirred for 30 minutes. LC/MS shows starting material is consumed and desired product M+H is evident. The organic layer was washed with water ((1×2 mL), saturated bicarbonate (2×2 mL) and brine (1×2 mL). The organic layer was dried (MgSO4) and concentrated to dryness. Isolated 145 mg (76% yield) of crude product, used without further purification.

EXAMPLE 329

[1427] This example illustrates the production of 2-allyl-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid 7-oxide). (0.50 mmol, 145 mg) was dissolved in 50% THF/water (2.0 mL) and lithium hydroxide (1.0 mmol, 42 mg) was added. The reaction mixture stirred at 23° C. for 2 hours. LC/MS confirms reaction is done. The reaction was concentrated under nitrogen stream, reconstituted in water/acetonitrile and acidified to pH=3 using trifluoroacetic acid, then purified via reverse phase chromatography. The product was isolated as a pale pink solid (84.0 mg, 62% yield): 1HNMR (400 MHz, DMSO) δ 8.209 (bs, 1H), 8.052 (d, 1H), 7.530 (d, 1H), 6.039-5.947 (m, 1H), 5.170 (d, 2H), 5.060 (qd, 2H), 2.950 (q, 2H), 2.850 (q, 2H): m/z 272 (M+H).

1313

EXAMPLE 330

[1428] This example illustrates the production of 2-(3-{[2-(2-chlorophenyl)ethyl]-amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate

[1429] The product was isolated as a white amorphous solid (416.9 mg, 92% yield):

[1430]

1
HNMR (400 MHz, DMSO) δ 8.680 (d, 1H), 8.595 (d, 1H), 7.815 (bs, 1H), 7.430 (dd, 1H), 7.360-7.245 (m, 3H), 4.644 (t, 4H), 3.490 (m, 1H), 3.245 (m, 2H), 2.983 (m, 4H), 2.550 (m, 1H), 2.252 (t, 2H): m/z 411 (M+H).

EXAMPLE 331

[1431] This example illustrates the production of 2-(3-{[2-(3-chlorophenyl)ethyl]-amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate

[1432] The product was isolated as a white amorphous solid (397.8 mg, 88% yield):

[1433]

1
HNMR (400 MHz, DMSO) δ 8.689 (s, 1H), 8.614 (d, 2H), 7.820 (d, 1H), 7.326-7.295 (m, 2H), 7.200 (d, 1H), 4.636 (t, 4H), 3.165 (bs, 2H), 2.983 (m, 4H), 2.868 (t, 2H), 2.160 (t, 2H): m/z 411 (M+H).

EXAMPLE 332

[1434] This example illustrates the production of 2-(3-{[2-(4-chlorophenyl)ethyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate.

[1435] The product was isolated as a white amorphous solid (455.7 mg, 98% yield):

[1436]

1
HNMR (400 MHz, DMSO) δ 8.680 (bs, 2H), 8.635 (d, 1H), 7.889 (d, 1H), 7.359 (d, 2H), 7.257 (d, 2H), 4.638 (t, 4H), 3.140 (m, 2H), 2.991(m, 4H), 2.851 (t, 2H), 2.160 (t, 2H): m/z 411 (M+H).

EXAMPLE 333

[1437] This example illustrates the production of 2-{3-[(2-furylmethyl)amino]-propyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate.

[1438] The product was isolated as an off white amorphous solid (208.5 mg, 54% yield): 1HNMR (400 MHz, DMSO) δ 8.712 (s, 1H), 8.639 (d, 1H), 7.860 (d, 1H), 7.724 (s, 1H), 6.545 (d, 1H), 6.467 (m, 1H), 4.628 (t, 2H), 4.220 (bs, 2H), 3.016 (s, 4H), 2.923 (bs, 2H), 2.139 (m, 2H): m/z 353 (M+H).

EXAMPLE 334

[1439] This example illustrates the production of 2-{3-[(2-chlorobenzyl)amino]-propyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoro-acetate.

[1440] The product was isolated as a white amorphous solid (210.4 mg, 64% yield): —HNMR (400 MHz, DMSO) δ 8.777 (s, 1H), 8.713-(d, 1H), 7.929 (d, 1H), 7.630 (d, 2H), 7.461 (m, 2H), 4.717 (t, 4H), 4.325 (s, 2H), 3.019 (m, 4H), 2.264 (t, 2H): m/z 397 (M+H).

EXAMPLE 335

[1441] This example illustrates the production of 2-{3-[(3-chlorobenzyl)amino]propyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate.

[1442] The product was isolated as a white amorphous solid (259 mg, 79% yield):

[1443]

1
HNMR (400 MHz, DMSO) δ 8.769 (s, 1H), 8.702 (d, 1H), 7.912 (d, 1H), 7.604 (s, 1H), 7.477 (m, 3H), 4.702 (t, 4H), 4.206 (s, 2H), 3.052 (m, 4H), 2.264 (t, 2H): m/z 397 (M+H).

EXAMPLE 336

[1444] This example illustrates the production of 2-{3-[(4-chlorobenzyl)amino]-propyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate.

[1445] The product was isolated as a white amorphous solid (250 mg, 77% yield):

[1446]

1
HNMR (400 MHz, DMSO) δ 8.742 (s, 1H), 8.678 (d, 1H), 7.867(d, 1H), 7.510 (s, 4H), 4.690 (t, 4H), 4.189 (s, 2H), 3.063 (m, 4H), 2.214 (t, 2H): m/z 397 (M+H).

EXAMPLE 337

[1447] This example illustrates the production of 2-(3-{[2-(4-bromophenyl)ethyl]-amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate.

[1448] The product was isolated as a white amorphous solid (345 mg, 92% yield):

[1449]

1
HNMR (400 MHz, DMSO) δ 8.732 (s, 1H), 8.662 (d, 1H), 7.888-(d, 1H), 7:564 (d, 2H), 7.262 (d, 2H), 4.689 (t, 4H), 3.200 (bs, 2H), 3.063 (m, 4H), 2.884 (t, 2H), 2.214 (t, 2H): m/z 456 (M+H).

EXAMPLE 338

[1450] This example illustrates the production of 2-{3-[(2,2,2-trifluoroethyl)amino]-propyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate.

[1451] The product was isolated as a white amorphous solid (213 mg, 73% yield):

[1452]

1
HNMR (400 MHz, DMSO) δ 8.698 (s, 1H), 8.627 (d, 1H), 7.870 (d, 1H), 4.635 (t, 2H), 3.581 (q, 2H), 3.016 (s, 4H), 2.992 (t, 2H), 2.135 (t, 2H): m/z 355 (M+H).

EXAMPLE 339

[1453] This example illustrates the production of 2-(3-{[2-(4-fluorophenyl) ethyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate.

[1454] The product was isolated as a white amorphous solid (118 mg, 36% yield):

[1455]

1
HNMR (400 MHz, DMSO) δ 8.716 (s, 1H), 8.644 (d, 1H), 7.886 (d, 1H), 7.278 (t, 2H), 7.133 (t, 2H), 4.655 (t, 2H), 3.139 (m, 2H), 3.001 (m, 6H), 2.861 (t, 2H), 2.172 (t, 2H): m/z 395 (M+H).

EXAMPLE 340

[1456] This example illustrates the production of 2-(3-{[2-(4-methylphenyl)ethyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate.

[1457] The product was isolated as a white amorphous solid (153 mg, 48% yield):

[1458]

1
HNMR (400 MHz, DMSO) δ 8.715 (s, 1H), 8:642 (d, 1H), 7.886 (d, 1H), 7.110 (s, 4H), 4.655 (t, 2H), 3.129 (m, 2H), 3.031 (m, 6H), 2.816 (t, 2H), 2.249 (s, 3H), 2.171 (t, 2H): m/z 391 (M+H).

EXAMPLE 341

[1459] This example illustrates the production of 2-(3-{[2-(4-ethylphenyl) ethyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate.

[1460] The product was isolated as a white amorphous solid (137 mg, 41% yield):

[1461]

1
HNMR (400 MHz, DMSO) δ 8.706 (s, 1H), 8.635 (d, 1H), 7.875 (d, 1H), 7.137 (s, 4H), 4.655 (t, 2H), 3.120 (m, 2H), 3.028 (m, 6H), 2.825 (t, 2H), 2.536 (q, 2H), 2.199 (t, 2H), 1.133 (t, 3H): m/z 405 (M+H).

EXAMPLE 342

[1462] This example illustrates the production of 2-{3-[(2-phenylpropyl)amino]-propyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate.

[1463] The product was isolated as a white amorphous solid (168 mg, 52% yield):

[1464]

1
HNMR (400 MHz, DMSO) δ 8.707 (s, 1H), 8.636 (d, 1H0, 7.859 (d, 1H), 7.270 (m, 5H), 4.627 (t, 2H), 3.145 (m, 2H), 3.105 (m, 1H), 3.026 (s, 4H), 2.935 (m, 2H), 2.158 (m, 2H0, 1.241 (d, 3H): m/z 391 (M+H).

EXAMPLE 343

[1465] This example illustrates the production of 2-(3-{[2-(4-chlorophenyl)propyl]-amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate.

[1466] The product was isolated as a white amorphous solid (35 mg, 10% yield):

[1467]

1
HNMR (400 MHz, DMSO) δ 8.670 (s, 1H), 8.604 (d, 1H), 7.802 (d, 1H), 7.342 (q (a,b), 4H), 4.618 (t, 2H), 3.140 (m, 2H), 3.087 (m, 1H), 3.011 (s, 4H), 2.930 (m, 2H), 2.142 (t, 2H), 1.220 (d, 3H): m/z 425 (M+H).

EXAMPLE 344

[1468] This example illustrates the production of 2-{3-[(3,3-diphenylpropyl)amino]propyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate.

[1469] The product was isolated as a white amorphous solid (253 mg, 66% yield):

[1470]

1
HNMR (400 MHz, DMSO) δ 8.671 (s, 1H), 8.599 (d, 1H), 7.799 (d, 1H), 7.252 (m, 7H), 7.155(m, 3H), 4.618 (t, 2H), 4.014 (t, 1H), 3.006 (s, 4H), 2.951 (m, 2H), 2.784 (m, 2H), 2.319 (m, 2H), 2.104 (m, 2H): m/z 467 (M+H).

EXAMPLE 345

[1471] This example illustrates the production of ethyl 2-{2-[(tert-butoxycarbonyl)amino]ethyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylate.

1314

[1472] To a cooled (0° C.) solution of ethyl 4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylate (2.00 g, 8.22 mmol) in anhydrous DMF (100 mL) was added lithium t-butoxide (1M in THF, 12.3 mL) dropwise. The reaction stirred for 30 min, then a solution of tert-butyl 2-bromoethylcarbamate [tert-butyl 2-bromoethylcarbamate] (2.75 g, 12.3 mmol,) and sodium iodide (1.84 g, 12.3 mmol) in anhydrous DMF (10 mL) was added dropwise. The reaction was allowed to stir and warm to room temperature for 26 h. The reaction was poured into water and brine, extracted with ethyl acetate, dried over MgSO4, and concentrated. The brown residue was chromatographed (4% ethanol/CH2Cl2). The appropriate fractions were concentrated to a yellow solid, then rinsed with diethyl ether to yield a white powder (0.778 g, 24.6% yield): mp 130.6-131.9° C.; 1H NMR (DMSO-d6/300 MHz) ? 1.32 (s, 9H), 1.39 (t, 3H), 2.94-3.02 (m, 4H), 3.37 (m, 2H), 4.37 (q, 2H), 4.60 (t, 2H), 6.93 (t, 1H), 7.61 (d, 1H), 8.49 (d, 1H), 8.52 (s, 1H); HRMS calcd for (M+H) 387.2027, found 387.2011.

EXAMPLE 346

[1473] This example illustrates the production of lithium 2-{2-[(tert-butoxycarbonyl)amino]ethyl}-4,5-dihydro-2H-pyrazolo[3,4-f]-isoquinoline-3-carboxylate

1315

[1474] A solution of ethyl 2-{2-[(tert-butoxycarbonyl)amino]ethyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylate (0.701 g, 1.81 mmol) and LiOH.H2O (0.235 g, 5.60 mmol) in 40 mL of THF/H2O (1:1) was stirred at room temperature for 1 h. The reaction mixture was concentrated to a white solid which was used in the next step without further purification (0.653 g, quantitative yield): mp>300° C.; 1H NMR (DMSO-d6/300 MHz) ??1.37 (s, 9H), 2.83-2.99 (m, 4H), 3.43 (m, 2H), 4.65 (t, 2H), 7.53 (d, 1H), 7.74 (br s, 1H), 8.41 (d, 1H), 8.45 (s, 1H); HRMS calcd for (M+H) 359.1714, found 359.1700.

EXAMPLE 347

[1475] This example illustrates the production of 2-(2-aminoethyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid dihydrochloride.

1316

[1476] To a flask charged with lithium 2-{2-[(tert-butoxycarbonyl)amino]ethyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylate (0.520 g, 1.43 mmol) was added 4N HCl/dioxane. After 1 h the reaction mixture was concentrated to a white solid (0.457 g, 96.4% yield): mp 266.6-270.9° C.; 1H NMR (DMSO-d6/300 MHz) ? 3.09-3.11 (m, 4H), 3.34 (m, 2H), 4.91 (t, 2H), 8.16 (d, 1H), 8.60 (br s, 3H), 8.74 (d, 1H), 8.86 (s, 1H); HRMS calcd for (M+H) 259.1190, found 259.1173.

EXAMPLE 348

[1477] This example illustrates the production of ethyl 2-(2-aminoethyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylate dihydrochloride.

1317

[1478] To a flask charged with ethyl 2-{2-[(tert-butoxycarbonyl)amino]ethyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylate (3.90 g, 10.09 mmol) was added 4N HCl/dioxane. After 1 h the reaction mixture was concentrated to a white solid (3.580 g, 91.4% yield): mp 220.7-223.7° C.; 1H NMR (DMSO-d6/300 MHz) 1.40 (t, 3H), 3.10-3.19 (m, 4H), 3.41-3.36 (m, 2H), 4.41 (q, 2H), 4.91 (t, 2H), 8.24 (d, 1H), 8.45 (br s, 3H), 8.81 (d, 1H), 8.92 (s, 1H); HRMS calcd for (M+H) 287.1503, found 287.1502.

EXAMPLE 349

[1479] This example illustrates the production of 5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one.

1318

[1480] To a flask charged with ethyl 2-(2-aminoethyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylate dihydrochloride (1.005 g, 2.80 mmol) was added NH4OH (20 mL) and ethanol (10 mL). After 5 min a white precipitate formed. The reaction was filtered, and the white solid rinsed with water, ethanol, and diethyl ether to yield the desired lactam (0.653 g, 97.1% yield): mp>300° C.;

[1481]

1
H NMR (DMSO-d6/300 MHz) 2.94-3.01 (m, 4H), 3.64-3.68 (m, 2H), 4.39 (t, 2H), 7.60 (d, 1H), 8.28 (br s, 1H), 8.49 (d, 1H), 8.53 (s, 1H); HRMS calcd for (M+H) 241.1084, found 241.1082.

EXAMPLE 350

[1482] This example illustrates the production of ethyl 2-(3-cyanopropyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylate

1319

[1483] To a cooled (0° C.) solution of ethyl 4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylate (5.60 g, 23.0 mmol) in anhydrous DMF (200 mL) was added lithium t-butoxide (1M in THF, 34.5 mL) dropwise. The reaction stirred for 30 min, then a solution of 4-bromo-butyronitrile (5.11 g, 34.5 mmol) and sodium iodide (5.18 g, 34.5 mmol) in anhydrous DMF (15 mL) was added dropwise. The reaction was allowed to warm to ambient temperature. After 2.5 h, the reaction was poured into water and brine, extracted with ethyl acetate, dried over MgSO4, and concentrated. The brown residue was passed thru a silica plug, eluting with CH2Cl2. The eluant was concentrated, triturated with diethyl ether, and filtered to give the alkylated product as a tan solid (4.5869, 64.3% yield): mp 100.1-102.5° C.; 1H NMR (DMSO-d6/300 MHz) 1.38 (t, 3H), 2.15 (dd, 2H), 2.59 (t, 2H), 2.94-3.06 (m, 4H), 4.38 (q, 2H), 4.65 (t, 2H), 7.62 (d, 1H), 8.50 (d, 1H), 8.54 (s, 1H); HRMS calcd for (M+H) 311.1503, found 311.1462.

EXAMPLE 351

[1484] This example illustrates the production of 2-(3-cyanopropyl)-4,5-dihydro, 2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid

1320

[1485] A solution of ethyl 2-(3-cyanopropyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylate (0.339 g, 1.09 mmol) and LiOH.H2O (0.056 g, 1.33 mmol) in 25 mL of THF/H2O (1:1) was stirred at room temperature for 1.5 h. The reaction mixture was concentrated to the aqueous layer, and 3N HCl was added until a precipitate was formed (pH=6). The suspension was filtered and the solid dried in a vacuum oven overnight to yield an off-white solid (0.218 g, 70.8% yield): mp 267.7-267.8° C.; 1H NMR (DMSO-d6/300 MHz) 2.15 (dd, 2H), 2.58 (t, 2H), 2.95-3.03 (m, 4H), 4.66 (t, 2H), 7.62 (d, 1H), 8.49 (d, 1H), 8.53 (s, 1H); HRMS calcd for (M+H) 283.1190, found 283.1193.

EXAMPLE 352

[1486] This example illustrates the production of ethyl 2-(4-aminobutyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylate.

1321

[1487] A pressure tube was charged with ethyl 2-(3-cyanopropyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylate (1.001 g, 3.23 mmol) in ethanol (30 mL). The solution was saturated with NH3 (g), and then approximately 1 mL of Raney Ni (50% by weight slurry in water) was added. The system was charged with H2 (55 psi) and stirred for 7 days. The reaction mixture was filtered through Celite, rinsed with ethanol, and the filtrate concentrated to a yellow oil (0.820 g, 80.1% yield) which was used in the next reaction without further purification: 1H NMR (DMSO-d6/300 MHz) 1.34-1.41 (m, 5H), 1.83 (m, 2H), 2.57 (t, 2H), 2.94-3.04 (m, 4H), 4.37 (q, 2H), 4.56 (t, 2H), 7.61 (d, 1H), 8.48 (d, 1H), 8.53 (s, 1H); HRMS calcd for (M+H) 315.1816, found 315.1802.

EXAMPLE 353

[1488] This example illustrates the production of 2-(4-aminobutyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid dihydrochloride.

1322

[1489] A solution of ethyl 2-(4-aminobutyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylate (0.354 g, 1.13 mmol) and LiOH.H2O (0.142 g, 3.38 mmol) in 40 mL of THF/H2O (1:1) was stirred at room temperature for 1 h. The reaction mixture was concentrated to the aqueous layer and purified on a Gilson Reverse Phase High Performance Liquid Chromatography (RP HPLC) apparatus (5-95% acetonitrile/water). The appropriate fractions were concentrated. To this TFA salt residue was added 4N HCl/dioxane and methanol. After 1 h the suspension was filtered and the solid rinsed with diethyl ether to yield a yellow solid (0.0443 g, 10.9% yield): mp 255.2-260.3° C.; 1H NMR (DMSO-d6/300 MHz) 1.59-1.64 (m, 2H), 1.89-1.94 (m, 2H), 2.82 (m, 2H), 3.09-3.13 (m, 4H), 4.67 (t, 2H), 8.12-8.15 (m, 3H), 8.76 (d, 1H), 8.90 (s, 1H); HRMS calcd for (M+H) 287.1503, found 287.1483.

EXAMPLE 354

[1490] This example illustrates the production of 2-(4-amino-4-oxobutyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate.

1323

[1491] 2-(3-cyanopropyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid (0.501 g, 1.77 mmol) was dissolved in conc. H2SO4 (5 mL) and heated on a steam bath for 0.5 h. Ice was then added and the solution brought to pH 3.5, at which point a precipitate formed. The solid was a mixture of the amide and acid. This mixture was purified on the Gilson RP HPLC (5-95% acetonitrile/water). The fractions corresponding to the amide were concentrated to a pale yellow solid (0.201 g, 28.6% yield): mp 201.6-206.7° C.; 1H NMR (DMSO-d6/300 MHz)???2.04-2.17 (m, 4H), 3.09-3.18 (m, 4H), 4.65 (t, 2H), 6.82 (br s, 1H), 7.35 (br s, 1H), 8.19 (d, 1H), 8.79 (d, 1H), 8.89 (s, 1H); HRMS calcd for (M+H) 301.1295, found 301.1274.

EXAMPLE 355

[1492] This example illustrates the production of 2-(3-carboxypropyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate.

1324

[1493] The fractions corresponding to the acid in example 2-(4-amino-4-oxobutyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate were concentrated to a yellow solid. HRMS calcd for (M+H) 302.1135, found 302.1147.

EXAMPLE 356

[1494] This example illustrates the production of 2-{4-[bis(2-ethylbutyl)amino]butyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid hydrochloride.

1325

[1495] 2-{4-[bis(2-ethylbutyl)amino]butyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid hydrochloride was obtained following example lithium 2-{4-[(2-ethylbutyl)amino]butyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylate, but using 12.7 eq of 2-ethylbutyraldehyde. HRMS calcd for (M+H) 455.3381, found 455.3363.

EXAMPLE 357

[1496] This example illustrates the production of 2-{2-[(2-ethylbutyl)amino]ethyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid.

1326

[1497] ethyl 2-(2-aminoethyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylate dihydrochloride (0.502 g, 1.40 mmol) was neutralized by stirring with morpholino-methylpolystyrene resin (2.40 g, ˜3.5 mmol base/g resin) in CH2Cl2/methanol (20:1) for 0.5 h. The resin was filtered, rinsed with methanol, and the filtrates concentrated. The resulting white residue was dissolved in CH2Cl2/methanol (20:1). Six drops of glacial acetic acid were added with stirring, followed by 2-ethylbutyraldehyde (225 uL, 1.68 mmol). After 5 min, sodium triacetoxyborohydride (0.596 g, 2.80 mmol) was added. The reaction stirred overnight, both the mono- and dialkylated products formed. The reaction was quenched with water and extracted with CH2Cl2. The organic layers were concentrated and purified by Gilson RP HPLC (5-95% acetonitrile/water). The fractions corresponding to the monoalkylated product were concentrated. The residue was subjected to hydrolysis conditions [3 eq LiOH.H2O, THF/H2O (1:1)] for 18 h. The resulting product mixture was purified by Gilson RP HPLC (5-95% acetonitrile/water) and the appropriate fractions concentrated to a white solid (0.141 g, 20.6% yield): mp 200.3-202.4° C.; 1H NMR (DMSO-d6/300 MHz) 0.87 (t, 6H), 1.32-1.43 (m, 4H), 1.60-1.64 (m, 1H), 2.93-3.07 (m, 6H), 3.51 (t, 2H), 4.91 (t, 2H), 7.63 (d, 1H), 8.52 (d, 1H), 8.57 (s, 1H), 8.70 (br s, 1H); HRMS calcd for (M+H) 343.2129, found 343.2131.

EXAMPLE 358

[1498] This example illustrates the production of 2-{2-[bis(2-ethylbutyl)amino]ethyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid dihydrochloride

1327

[1499] The fractions corresponding to the dialkylated product in the example which illustrates the production of 2-{2-[(2-ethylbutyl)amino]ethyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid, were concentrated to a white solid. HRMS calcd for (M+H) 427.3068, found 427.3083.

EXAMPLE 359

[1500] This example illustrates the production of lithium 2-{4-[(2-ethylbutyl)amino]butyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylate.

1328

[1501] Synthesis was performed as in the example for the production of 2-{2-[(2-ethylbutyl)amino]ethyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid (omitting the initial neutralization step) using ethyl 2-(4-aminobutyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylate (0.471 g, 1.5 mmol), 2-ethylbutyraldehyde (241 uL, 1.80 mmol), and sodium triacetoxyborohydride (0.636 g, 3.00 mmol). The reaction was monitored by LC-MS and stopped after 2 h. The residue obtained from the chromatographic purification was subjected to hydrolysis conditions [3 eq LiOH.H2O, THF/H2O (1:1)] for 18 h. The reaction mixture was concentrated and triturated with diethyl ether to yield a white solid (0.299 g, 52.7% yield): mp 125.1-128.7° C.; 1H NMR (DMSO-d6/300 MHz) 0.83 (t, 6H), 1.26-1.42 (m, 8H), 1.76-1.80 (m, 3H), 2.35-2.39 (m, 2H), 2.81-2.99 (m, 4H), 4.65 (t, 2H), 7.52 (d, 1H), 8.39 (d, 1H), 8.44 (s, 1H); HRMS calcd for (M+H) 371.2442, found 371.2458.

EXAMPLE 360

[1502] This example illustrates the production of ethyl 6-benzyl-1-[4-(methylsulfonyl)-phenyl]-1,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate.

1329

[1503] To N,N-dimethylacetamide dimethylacetal (250 mL) was added 1,3-cyclohexanedione (100 g, 0.89 mol). Contents were refluxed 2 hours, allowed to cool and concentrated in vacuo leaving an amber solid. After recrystallizing twice from EtOAc, the desired eneamine intermediate was obtained as light amber crystals, 64.2 g. The eneamine (21.7 g, 0.13 mol) and benzylhydrazine hydrochloride (25.5 g, 0.13 mol) were mixed in glacial acetic acid (200 mL) and stirred overnight. Contents were diluted with water, extracted with EtOAc, dried over MgSO4, and concentrated in vacuo leaving the desired tetralone intermediate as an amber oil, 37.2 g. The tetralone was reacted with diethyl oxalate according to the procedure for the production of ethyl (7-hydroxy-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)(oxo)acetate, to give the desired diketoester intermediate as an amber oil. The diketoester was reacted with 4-methylsulfonylphenylhydrazine according to the procedure for the production of ethyl 8-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate, to give the desired product as white crystals (53% yield). FABHRMS m/z 477.1587 (M+H, C25H25N4O4S requires 477.1597).

[1504] Anal. Calcd for C24H24N4O4S: C, 63.01; H, 5.08; N, 11.76. Found: C, 62.93; H, 4.92; N, 11.77.

EXAMPLE 361

[1505] This example illustrates the production of ethyl 1-[4-(methylsulfonyl)phenyl]-1,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate.

1330

[1506] Ethyl 6-benzyl-1-[4-(methylsulfonyl)phenyl]-1,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate (2.5 g, 0.005 mol), Pearleman's catalyst (1.0 g) and glacial acetic acid (30 mL) were shaken at 55 psi H2 and 55° C., overnight. Contents were allowed to cool and filtered through clay. The filtrate was concentrated in vacuo and the residue was triturated with methanol and filtered to give the desired product as a white solid, 609 mg (32% yield). FABHRMS m/z 387.1161 (M+H, C18H19N4O4S requires 387.1127).

[1507] Anal. Calcd for C18H18N4O4S (0.8H2O): C, 53.94; H, 4.93; N, 13.98. Found: C, 53.97; H, 4.71; N, 13.71.

EXAMPLE 362

[1508] This example illustrates the production of 1-[4-(methylsulfonyl)phenyl]-1,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxamide.

1331

[1509] Ethyl 1-[4-(methylsulfonyl)phenyl]-1,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate was reacted according to the procedure for the production of 8-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxamide to give the desired product as a white solid (58% yield).

[1510] Anal. Calcd for C16H15N5O3S (0.5H2O): C, 52.45; H, 4.40; N, 19.11. Found: C, 52.42; H, 4.41; N, 18.63.

EXAMPLE 363

[1511] This example illustrates the production of 1,5,6,7-tetrahydro-4H-indazol-4-one.

1332

[1512] To N,N-dimethylacetamide dimethylacetal (250 mL) was added 1,3-cyclohexanedione (100 g, 0.89 mol). Contents were refluxed 2 hours, allowed to cool and concentrated in vacuo leaving amber solid. After recrystallizing twice from EtOAc, the desired eneamine intermediate was obtained as light amber crystals, 64.2 g. The eneamine (5.0 g, 0.03 mol) and p-tosylhydrazine hydrochloride (5.6 g, 0.3 mol) were stirred in methanol overnight. 4N HCl in dioxane (100 mL) was added and contents were stirred overnight. A white solid was filtered to give the desired product, 4.5 g (87% yield). FABHRMS m/z 137.0738 (M+H, C7H N2O requires 137.0715). 1H NMR (DMSO-d6/300 MHz): 7.90 (s, 1H); 2.90-2.80 (m, 2H); 2.40-2.30 (m, 2H); 2.10-2.00 (m, 3H).

[1513] Anal. Calcd for C7H8N2O (0.05H2O): C, 61.35; H, 5.96; N, 20.44. Found: C, 61.25; H, 5.98; N, 20.53.

EXAMPLE 364

[1514] This example illustrates the production of 2-trityl-2,5,6,7-tetrahydro-4H-indazol-4-one.

1333

[1515] To 1,5,6,7-tetrahydro-4H-indazol-4-one (2.0 g, 0.012 mol) and triethylamine (4.4 mL, 0.031 mol) in CH2Cl2 (25 mL) was added dropwise trityl chloride (4.3 g, 0.0155 mol) in CH2Cl2 (20 mL). Contents were stirred overnight, washed with water and the CH2Cl2 layer was concentrated in vacuo. The residue was partitioned between ether and water. The ether layer was washed with brine, dried over MgSO4 and concentrated in vacuo leaving an amber oil. Trituration with hexanes gave the desired product as a white solid, 3.6 g (79% yield). FABHRMS m/z 401.1608 (M+H, C26H23N2O requires 401.1630). 1H NMR (CDCl3/300 MHz): 7.90 (s, 1H); 7.40-7.10 (m, 15H); 2.90-2.80 (m, 2H); 2.55-2.45 (m, 2H); 2.20-2.10 (m, 2H).

[1516] Anal. Calcd for C26H22N2O: C, 82.51; H, 5.86; N, 7.4. Found: C, 82.36; H, 6.10; N, 7.32.

EXAMPLE 365

[1517] This example illustrates the production of 6-methyl-2,4,5,6-tetrahydropyrazolo-[3,4-e]indazole-3-carboxamide.

1334

[1518] FABHRMS m/z 218.1051 (M+H, C10H12N5O requires 218.1042).

EXAMPLE 366

[1519] This example illustrates the production of ethyl 2-trityl-4-oxo-4,5,6,7-tetrahydro-2H-indazol-5-yl](oxo)acetate.

1335

[1520] 1-trityl-1,5,6,7-tetrahydro-4H-indazol-4-one- or 1-trityl-1,5,6,7-tetrahydro-4H-indazol-4-one was reacted according to the procedure for the production of ethyl (7-hydroxy-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)(oxo)acetate to give the desired product as yellow crystals (82% yield). FABHRMS m/z 479.1971 (M+H, C30H27N2O4 requires 479.1965). 1H NMR (CDCl3/300 MHz): 7.97 (s, 1H); 7.40-7.10 (m, 15H); 4.40 (q, 2H); 3.15-3.05 (m, 2H); 2.95-2.85 (m, 2H); 1.45 (t, 3H).

[1521] Anal. Calcd for C30H26N2O4: C, 75.30; H, 5.48; N, 5.85. Found: C, 75.11; H, 5.38; N, 5.73.

EXAMPLE 367

[1522] This example illustrates the production of ethyl 2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate.

1336

[1523] Ethyl oxo(4-oxo-1-trityl-4,5,6,7-tetrahydro-1H-indazol-5-yl)acetate- or ethyl oxo(4-oxo-2-trityl-4,5,6,7-tetrahydro-2H-indazol-5-yl)acetate or ethyl oxo(4-oxo-2-trityl-4,5,6,7-tetrahydro-2H-indazol-5-yl)acetate was reacted according to the procedure for the production of ethyl 8-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate at 70° C. to give the desired product (67% yield). 1H NMR (DMSO-d6/300 MHz): 7.78 (s, 1H); 4.30 (q, 2H); 3.05-2.95 (m, 2H); 2.90-2.80 (m, 2H); 1.35 (t, 3H).

[1524] Anal. Calcd for C11H13N4O2 (2HOAc): C, 51.13; H, 5.72; N, 15.90. Found: C, 51.09; H, 5.80; N, 16.09.

EXAMPLE 368

[1525] This example illustrates the production of 2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxamide.

1337

[1526] Ethyl 2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate was reacted according to the procedure for the production of 8-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxamide to give the desired as an off-white solid (97% yield). FABHRMS m/z 204.0877 (M+H, C9H10N5O requires 204.0885).

[1527]

1
H NMR (DMSO-d6+TFA/300 MHz): 7.85 (s, 1H); 7.30 (br s, 2H); 3.05-2.95 (m, 2H); 2.90-2.80 (m, 2H).

[1528] Anal. Calcd for C9H9N5O: C, 53.20; H, 4.46; N, 34.47. Found: C, 53.14; H, 4.47; N, 34.57.

EXAMPLE 369

[1529] This example illustrates the production of ethyl [1-(2-hydroxyethyl)-4-oxo-4,5,6,7-tetrahydro-1H-indazol-5-yl](oxo)acetate.

1338

[1530] To N,N-dimethylacetamide dimethylacetal (250 mL) was added 1,3-cyclohexanedione (100 g, 0.89 mol). Contents were refluxed 2 hours, allowed to cool and concentrated in vacuo leaving amber solid. After recrystallizing twice from EtOAc, the desired eneamine intermediate was obtained as light amber crystals, 64.2 g. The eneamine (20.0 g, 0.12 mol) and hydroxyethylhydrazine (7.2 g, 0.12 mol) were mixed in methanol (50 mL) and stirred 72 hours. Contents were concentrated in vacuo leaving an oil, 13.4 g which was purified by silica gel chromatography eluting with 5% MeOH/EtOAc to give the desired tetralone intermediate as a yellow solid, 17.6 g (81% yield). The tetralone was reacted according to the procedure for the production of ethyl (7-hydroxy-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)(oxo)acetate to give the desired product as a white solid (38% yield). FABHRMS m/z 281.1148 (M+H, C13H17N2O5 requires 281.1137).

[1531] Anal. Calcd for C13H16N2O5: C, 55.71; H, 5.75; N, 9.99. Found: C, 55.63; H, 5.67; N, 9.96.

EXAMPLE 370

[1532] This example illustrates the production of ethyl 6-(2-hydroxyethyl)-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate acetate

1339

[1533] Ethyl 6-(2-hydroxyethyl)-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate acetate was prepared according to the procedure for the production of ethyl 8-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate to give the desired product as a white solid (80% yield). FABHRMS m/z 277.1296 (M+H, C13H17N4O3 requires 277.1301).

[1534] Anal. Calcd. for C13H16N4O3 (HOAc):C, 53.56; H, 5.99; N, 16.66. Found: C, 53.45; H, 5.71; N, 16.60.

EXAMPLE 371

[1535] This example illustrates the production of 6-(2-hydroxyethyl)-2,4,5,6-tetrahydro-pyrazolo[3,4-e]indazole-3-carboxylic acid.

1340

[1536] 6-(2-hydroxyethyl)-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylic acid was prepared according to the procedure of 7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid to give the desired product as a white solid (83% yield). FABHRMS m/z 249.0988 (M+H, C11H13N4O3 requires 249.0988).

[1537] Anal. Calcd for C11H12N4O3: C, 53.22; H, 4.87; N, 22.57. Found: C, 52.86; H, 4.83; N, 22.49.

EXAMPLE 372

[1538] This example illustrates the production of ethyl 1-[4-(aminosulfonyl)-phenyl]-6-benzyl-1,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate.

1341

[1539] Ethyl 1-[4-(aminosulfonyl)phenyl]-6-benzyl-1,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate- or ethyl 1-[4-(aminosulfonyl)phenyl]-6-benzyl-1,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate was prepared according to the procedures for the production of ethyl (7-hydroxy-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)(oxo)acetate and ethyl 1-[4-(aminosulfonyl)phenyl]-8-hydroxy-4,5-dihydro-1H-benzo[g]indazole-3-carboxylate to give the desired as a light tan solid (61% yield). FABHRMS m/z 478.1549 (M+H, C24H24N5O4S requires 478.1551). 1H NMR (DMSO-d6+5%TFA/300 MHz): 7.98 (AB quartet, 4H); 7.38-7.20 (m, 3H); 7.20-7.10 (m, 2H); 5.38 (s, 2H); 4.25 (q, 2H); 3.20-2.90 (m, 4H); 1.25 (t, 3H).

[1540] Anal. Calcd. for C24H23N5O4S: C, 60.36; H, 4.85; N, 14.67. Found: C, 60.60; H, 4.86; N, 14.71.

EXAMPLE 373

[1541] This example illustrates the production of ethyl 1-[4-(aminosulfonyl)-phenyl]-1,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate.

1342

[1542] Ethyl 1-[4-(aminosulfonyl)phenyl]-6-benzyl-1,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate- or ethyl 1-[4-(aminosulfonyl)phenyl]-6-benzyl-1,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate (4.2 g, 0.009 mol), Pearleman's catalyst (1.5 g), glacial acetic acid (20 mL) and DMF (40 mL) were shaken at 55 psi H2 for 72 hours. Contents were filtered through clay and the filtrate was concentrated in vacuo leaving a grey solid. The grey solid was triturated with acetonitrile to give an off-white solid, 3.0 g (86% yield). FABHRMS m/z 388.1080 (M+H, C17H18N5O4S requires 388.1124). 1H NMR (DMSO-d6/300 MHz): 7.96 (AB quartet, 4H); 7.55 (br s, 2H); 7.35 (br s, 1H); 4.35 (q, 2H); 3.30 (s, 2H); 3.15-3.05 (m, 2H); 3.00-2.85 (m, 2H); 1.35 (t, 3H).

[1543] Anal. Calcd for C17H17N5O4S: C, 52.70; H, 4.42; N, 18.08. Found: C, 52.47; H, 4.18; N, 17.89.

EXAMPLE 374

[1544] This example illustrates the production of 1-[4-(aminosulfonyl)phenyl]-1,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxamide.

1343

[1545] Ethyl 1-[4-(aminosulfonyl)phenyl]-1,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate- or ethyl 1-[4-(aminosulfonyl)phenyl]-1,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate was reacted according to the procedure for the production of 8-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxamide to give the desired product as a white solid (86% yield). FABHRMS m/z 359.0939 (M+H, C15H15N6O3S requires 359.0926). 1H NMR (DMSO-d6/300 MHz): 7.99 (AB quartet, 4H); 7.58 (s, 1H); 7.50 (s, 1H); 7.35 (s, 1H); 3.35 (s, 2H); 3.10-3.00 (m, 2H); 2.90-2.80 (m, 2H).

[1546] Anal. Calcd for C15H14N6O3S: C, 50.27; H, 3.94; N, 23.45. Found: C, 50.07; H, 3.73; N, 23.08.

EXAMPLE 375

[1547] This example illustrates the production of 1-[4-(aminosulfonyl)phenyl]-1,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylic acid.

1344

[1548] Ethyl 1-[4-(aminosulfonyl)phenyl]-1,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate- or ethyl 1-[4-(aminosulfonyl)phenyl]-1,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate was reacted according to the procedure of 7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid to give the desired product as a white solid (85% yield). FABHRMS m/z 360.0762 (M+H, C15H14N5O4S requires 360.0767).

[1549] Anal. Calcd for C15H13N5O4S: C, 46.03; H, 3.35; N, 17.89. Found: C, 46.67; H, 3.64; N, 17.93.

EXAMPLE 376

[1550] This example illustrates the production of ethyl 6-benzyl-1-phenyl-1,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate.

1345

[1551] To N,N-dimethylacetamide dimethylacetal (250 mL) was added 1,3-cyclohexanedione (100 g, 0.89 mol). Contents were refluxed 2 hours, allowed to cool and concentrated in vacuo leaving an amber solid. After recrystallizing twice from EtOAc, the desired eneamine intermediate was obtained as light amber crystals, 64.2 g. The eneamine (21.7 g, 0.13 mol) and benzylhydrazine hydrochloride (25.5 g, 0.13 mol) were mixed in glacial acetic acid (200 mL) and stirred overnight. Contents were diluted with water, extracted with EtOAc, dried over MgSO4, and concentrated in vacuo leaving the desired tetralone intermediate as an amber oil, 37.2 g. The tetralone was reacted with diethyl oxalate according to the procedure for the production of ethyl (7-hydroxy-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)(oxo)acetate, to give the desired diketoester intermediate as an amber oil. The diketoester was reacted with phenylhydrazine according to the procedure for the production of ethyl 8-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate, to give the desired product as white crystals (14% yield). FABHRMS m/z 399.1826 (M+H, C24H23N4O2 requires 399.1821).

[1552] Anal. Calcd for C24H22N4O2: C, 72.34; H, 5.57; N, 14.06. Found: C, 72.14; H, 5.41; N, 13.98.

EXAMPLE 377

[1553] This example illustrates the production of ethyl 1-phenyl-1,4,5,6-tetrahydro-pyrazolo[3,4-e]indazole-3-carboxylate.

1346

[1554] Ethyl 6-benzyl-1-phenyl-1,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate (3.4 g, 0.009 mol) and Pearleman's catalyst (1.0 g) in ethanol (100 mL) were shaken at 55 psi H2 and 55° C. for 72 hours. Contents were allowed to cool and filtered through clay. The filtrate was concentrated in vacuo leaving a white solid. Triteration of the solid with methanol gave the desired as a white solid, 1.0 g (36% yield). FABHRMS m/z 309.1343 (M+H, C17H17N4O2 requires 309.1352).

[1555] Anal. Calcd for C17H16N4O2: C, 66.22; H, 5.23; N, 18.17. Found: C, 66.06; H, 5.41; N, 17.58.

EXAMPLE 378

[1556] This example illustrates the production of 1-phenyl-1,4,5,6-tetrahydro-pyrazolo[3,4-e]indazole-3-carboxamide.

1347

[1557] 1-phenyl-1,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxamide was prepared according to the procedure for the production of 8-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxamide, at 100° C., to give the desired product as a grey solid (72% yield). FABHRMS m/z 280.1208 (M+H, C15H14N5O requires 280.1198).

[1558] Anal. Calcd for C15H13N5O (0.5H2O): C, 62.49; H, 4.89; N, 24.29. Found: C, 62.94; H, 4.83; N, 23.76.

1348

EXAMPLE 379

[1559] This example illustrates the production of Boc-allyl amine. Boc-anhydride (1M THF, 70 mmol, 70 mL) was added to allyl amine (70 mmol, 4.0 g, 5.26 mL) slowly with stirring. The reaction solution stirred at 23° C. for 16 hours. The THF was removed in vacuo and the residue was reconstituted in dichloromethane (20 mL) and washed with water and brine (1×25 mL). The organic layer was dried (MgSO4) and concentrated in vacuo. The product was isolated as a white low melting solid (10.25 g, 99% yield): 1HNMR (400 MHz, CDCl3) δ 5.853-5.770 (m, 1H), 5.278-5.069 (qm, 2H), 3.723 (bs, 2H), 1.429 (s, 9H).

EXAMPLE 380

[1560] This example illustrates the production of 3-(4-tert-butylphenyl)-propylamine.

[1561] Tert-butyl allylcarbamate (7.0 mmol, 1.10 g) was weighed into a 100 mL flask with stir bar and 9-BBN solution (0.5M, THF, 7.7 mmol, 15.4 mL) was syringed carefully into the neat amine. The reaction stirred at 23° C. for 16 hours. The potassium phosphate (2M, 10.5 mmol, 5.25 mL) was added to the reaction mixture and stirred at 23° C. for 10 minutes. [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II)/DCM complex (0.21 mmol, 171 mg) and the 4-t-butyl-phenylbromide (7.0 mmol, 1.49 g, 1.21 mL) were added to the basic reaction mixture and the slurry was heated to relfux for 16 hours. The crude reaction mixture was purified using a 20 g flash silica plug (eluting with 100% hexane to 50% ethylacetate/hexane). The isolated pale brown oil (2.96 g) was dissolved in 25%TFA/DCM (15 mL) and stirred for 30 minutes at 23° C. The reaction mixture was concentrated in vacuo, reconstituted in dichloromethane (20 mL) and washed with saturated bicarbonate solution (3×30 mL). The organic layer was concentrated in vacuo. The crude product was purified using a 20 g flash silica plug (eluting with 100% hexane to 100% ethyl acetate to 100% methanol). Isolated the product as a light tan solid (1.25 g, 94% yield): 1HNMR (400 MHz, DMSO) δ 7.911 (bs, 2H), 7.200 (q, (a,b), 4H), 2.762 (m, 2H), 2.579 (t, 2H), 1.811 (m, 2H), 1.240 (s, 9H): m/z 192 (M+H).

EXAMPLE 381

[1562] This example illustrates the production of 3-(4-chlorophenyl)propylamine.

[1563] The product was isolated as a tan semi-solid (231 mg, 45% yield): 1HNMR (400 MHz, DMSO) δ 7.300 (q, a,b, 4H), 2.631 (m, 4H), 1.724 (m, 2H): m/z 170 (M+H).

EXAMPLE 382

[1564] This example illustrates the production of 3-(4-bromophenyl)propylamine.

[1565] The product was isolated as a tan semi-solid (310 mg, 48% yield): 1HNMR (400 MHz, DMSO) δ 7.380 (q, a,b, 4H), 2.639 (q, 4H), 1.724 (m, 2H): m/z 216 (M+H).

EXAMPLE 383

[1566] This example illustrates the production of 3-(3-chlorophenyl)propylamine.

[1567] The product was isolated as a tan semi-solid (244 mg, 48% yield): 1HNMR (400 MHz, DMSO) δ 7.323 (m, 3H), 7.220 (d, 1H), 2.664 (m, 4H), 1.796 (t, 2H): m/z 170 (M+H).

EXAMPLE 384

[1568] This example illustrates the production of 3-[4-(methylsulfonyl) phenyl]propylamine. The product was isolated as a tan semi-solid (188 mg, 29% yield): 1HNMR (400 MHz, DMSO) δ 7.610 (q, a,b, 4H), 3.220 (s, 3H), 2.783 (m, 4H), 1.873 (m, 2H): m/z 214 (M+H).

EXAMPLE 385

[1569] This example illustrates the production of 3-(1,1′-biphenyl-4-yl)propylamine.

[1570] The product was isolated as a tan semi-solid (485 mg, 76% yield): 1HNMR (400 MHz, DMSO) δ 7.649(m, 4H), 7.483 (t, 2H), 7.374 (m, 3H), 2.842 (t, 2H), 2.686 (t, 2H), 1.894 (t, 2H): m/z 212 (M+H).

[1571] The following compounds were synthesized in the same manner as 2-(3-{[2-(2-chlorophenyl)ethyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate (cyclic pyrazole Bromide alkylation of amines) using the previously described amines.

EXAMPLE 386

[1572] This example illustrates the production of 2-(3-{[3-(4-tert-butylphenyl)propyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate.

[1573] The product was isolated as a white amorphous solid (148 mg, 30% yield):

[1574]

1
HNMR (400 MHz, DMSO) δ 8.685 (s, 1H), 8.608 (d, 1H), 7.840 (d, 1H), 7.284 (d, 2H), 7.094 (d, 2H), 4.627 (t, 2H), 3.010 (s, 4H), 2.931 (m, 2H), 2.860 (m 2H0, 2.551 (t, 2H), 2.126 (m, 2H), 1.807 (m, 2H), 1.222 (s, 9H): m/z 447 (M+H).

EXAMPLE 387

[1575] This example illustrates the production of 2-(3-{[3-(4-chlorophenyl)propyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate.

[1576] The product was isolated as a white amorphous solid (84 mg, 18% yield):

[1577]

1
HNMR (400 MHz, DMSO) δ 8.726 (bs, 1H), 8.644 (d, 1H), 7.895 (d, 1H), 7.334 (d, 2H), 7.211 (d, 2H), 4.632 (t, 2H), 3.025 (s, 4H), 2.931 (m, 2H), 2.860 (m, 2H), 2.593 (t, 2H), 2.126 (m, 2H), 1.807 (m, 2H): m/z 425 (M+H).

EXAMPLE 388

[1578] This example illustrates the production of 2-(3-{[3-(4-bromophenyl)propyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate.

[1579] The product was isolated as a white amorphous solid (71 mg, 14% yield):

[1580]

1
HNMR (400 MHz, DMSO) δ 8.726 (bs, 1H), 8.644 (d, 1H), 7.895 (d, 1H), 7.449 (d, 2H), 7.154 (d, 2H), 4.632 (t, 2H), 3.006 (s, 4H), 2.931 (m, 2H), 2.860 (m, 2H), 2.593 (t, 2H), 2.126 (m, 2H), 1.807 (m, 2H): m/z 471 (M+H).

EXAMPLE 389

[1581] This example illustrates the production of 2-(3-{[3-(3-chlorophenyl)propyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate.

[1582] The product was isolated as a white amorphous solid (58 mg, 12% yield):

[1583]

1
HNMR (400 MHz, DMSO) δ 8.727 (s, 1H), 8.644 (d, 1H), 7.899 (d, 1H), 7.268 (m, 3H), 7.156 (d, 1H), 4.634 (t, 2H), 3.027 (s, 4H), 2.931 (m, 2H), 2.862 (m, 2H), 2.613 (t, 2H), 2.153 (m, 2H), 1.830 (m, 2H): m/z 425 (M+H).

EXAMPLE 390

[1584] This example illustrates the production of 2-[3-({3-[4-(methylsulfonyl)phenyl]propyl}amino)propyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate.

[1585] The product was isolated as a white amorphous solid (52 mg, 12% yield):

[1586]

1
HNMR (400 MHz, DMSO) δ 8.662 (bs, 1H), 8.591 (d, 1H), 7.841 (d, 2H), 7.806 (d, 1H), 7.466 (d, 2H), 4.626 (t, 2H), 3.460 (dq, 4H), 3.159 (s, 3H), 2.931 (m, 2H), 2.860 (m, 2H), 2.718 (t, 2H), 2.126 (m, 2H), 1.857 (m, 2H): m/z 469 (M+H).

EXAMPLE 391

[1587] This example illustrates the production of 2-(3-{[3-(1,1′-biphenyl-4-yl)propyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate.

[1588] The product was isolated as a white amorphous solid (52 mg, 12% yield):

[1589]

1
HNMR (400 MHz, DMSO) δ 8.684 (s, 1H), 8.600 (d, 1H), 7.839 (d, 1H), 7.613-7.555 (m, 4H), 7.422 (t, 2H), 7.320 (t, 1H), 7.277 (d, 2H), 4.634 (t, 2H), 3.008 (s, 4H), 2.940 (m, 4H), 2.645 (t, 2H), 2.140 (m, 2H), 1.865 (m, 2H): m/z 467 (M+H).

1349

EXAMPLE 392

[1590] This example illustrates the production of 8-[2-(2-chlorophenyl)ethyl]-5,6,8,9,10,11-hexahydro-7H-[1,4]diazepino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7-one trifluoroacetate.

[1591] 2-(3-{[2-(2-chlorophenyl)ethyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate (0.38 mmol, 200 mg) was dissolved in DMF (5.0 mL) and EDC-HCl (0.57 mmol, 109 mg), and HOBT (0.46 mmol, 62 mg) were added. The reaction mixture was stirred at 23° C. for 16 hours. The reaction mixture was diluted with ethyl acetate (20 mL) and washed with water (2×25 mL). The organic layer was concentrated in vacuo, reconstituted in acetonitrile and purified using reverse phase chromatography. The product was isolated as a white amorphous solid (36.0 mg, 24% yield).

[1592]

1
HNMR (400 MHz, DMSO) δ 8.805 (s, 1H), 8.726 (d, 1H), 8.045 (d, 1H), 7.434 (t, 2H), 7.319 (m, 2H), 4.406 (t, 2H), 3.789 (t, 2H), 3.378 (t, 2H), 3.089 (t, 4H), 2.917 (t, 2H), 2.149 (t, 2H): m/z 394 (M+H).

[1593] A general method for the synthesis of pyrazoles described in the following examples are provided below.

1350

EXAMPLE 393

[1594] This example illustrates the production of ethyl 2-(oxiran-2-ylmethyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylate.

[1595] The pyrazole ester (1.23 mmol, 300 mg) was dissolved in DMF (10 mL) and cooled to −45° C. in a dry ice/acetonitrile bath. Lithium tert-butoxide (1M THF, 1.85 mmol, 1.85 mL) was added slowly being sure to maintain −45° C. The cold solution stirred for 1.5 h. Epibromohydrin (1.85 mmol, 0.253 g, 159 μL) was added via syringe to the cold DMF solution and the ice bath was removed. The reaction was allowed to warm to 23° C. over 16 h. The crude reaction was diluted with ethyl acetate (20 mL) and washed with water (1×10 mL) and brine (1×20 mL). The organic layer was dried (MgSO4) and concentrated in vacuo. The crude oil was purified via gravity feed chromatography using 60% ethyl acetate/hexane. The product was isolated as a clear oil (70 mg, 19% yield):

[1596]

1
HNMR (400 MHz, CDCl3) δ 8.602 (bs, 2H), 7.811(d, 1H), 4.825 (qd, 2H), 4.397 (q, 2H), 3.411 (bs, 1H), 3.035 (qd, 4H), 2.833 (t, 1H), 2.633 (m, 1H), 1.432 (t, 3H): m/z 300 (M+H).

EXAMPLE 394

[1597] This example illustrates the production of 9-(morpholin-4-5,6,9,10-tetrahydro-7H-[1,4]oxazino[4′,3′:1,5]pyrazolo[3,4-f]isoquinolin-7-one.

[1598] Ethyl 2-(oxiran-2-ylmethyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylate (1.34 mmol, 400 mg) was dissolved in acetonitrile (4 mL) and the morpholine (2.0 mmol, 175 mg, 175 μL) and the ytterbium triflate (0.2 mmol, 124 mg) were added. The vial was capped and heated to 70° C. for 4 h with stirring. After four hours of heating, the reaction vessel was allowed to cool and upon cooling the desired product precipitated and was collected via filtration. The product was isolated as a white solid (55 mg, 12% yield):

[1599]

1
HNMR (400 MHz, CDCl3) δ 8.538 (bs, 2H), 7.662 (d, 1H), 4.916 (m, 1H), 4.501(qd, 2H), 3.708 (bs, 4H), 3.178-3.079 (m, 2H), 2.995 (d, 2H), 2.872-2.803 (m, 2H), 2.606 (bs, 4H): m/z 341 (M+H). The following lactones were made (using the appropriate amine) in the same manner as 9-(morpholin-4-ylmethyl)-5,6,9,10-tetrahydro-7H-[1,4]oxazino[4′,3′:1,5]pyrazolo[3,4-f]isoquinolin-7-one:

EXAMPLE 395

[1600] This example illustrates the production of 9-{[(2-thien-2-ylethyl)amino]methyl}-5,6,9,10-tetrahydro-7H-[1,4]oxazino[4′,3′:1,5]pyrazolo[3,4-f]isoquinolin-7-one trifluoroacetate.

[1601] The product was isolated as a pale yellow solid (129 mg, 23% yield): 1HNMR (400 MHz, DMSO) δ 8.750 (s 1H), 8.655(d, 1H), 7.985 (d, 1H), 7.337 (d, 1H), 6.936 (m, 2H), 4.358 (dd, 2H), 4.220 (dd, 2H), 3.82 (m, 1H), 3.582 (m, 1H), 3.460 (dd, 1H), 3.124 (t, 2H), 3.041 (m, 4H), 2.901 (t, 2H),: m/z 381 (M+H).

EXAMPLE 396

[1602] This example illustrates the production of 9-{[(4-aminocyclohexyl)amino]methyl}-5,6,9,10-tetrahydro-7H-[1,4]oxazino-[4′,3′:1,5]pyrazolo[3,4-f]isoquinolin-7-one trifluoroacetate.

[1603] The product was isolated as a tan solid (338 mg, 61% yield): 1HNMR (400 MHz, DMSO) δ 8.682 (s, 1H), 8.612 (d, 1H), 7.880(d, 1H), 4.502 (dd, 2H), 3.454 (t, 2H), 3.381 (t, 2H), 2.979 (t, 2H), 1.941 (d, 4H), 1.326 (t, 4H): m/z 368 (M+H).

EXAMPLE 397

[1604] This example illustrates the production of 9-(aminomethyl)-5,6,9,10-tetrahydro-7H-[1,4]oxazino[4′,3′:1,5]pyrazolo[3,4-f]isoquinolin-7-one trifluoroacetate.

[1605] The product was isolated as a yellow solid (85.5 mg, 21% yield): 1HNMR (400 MHz, DMSO) δ 8.726 (s, 1H), 8.651 (d, 1H), 7.968 (d, 1H), 4.588 (dd, 2H), 4.282-4.244 (3H), 3.430 (dd, 4H): m/z 271 (M+H).

EXAMPLE 398

[1606] This example illustrates the production of lithium 2-(2-hydroxy-3-morpholin-4-ylpropyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylate.

[1607] 9-(morpholin-4-ylmethyl)-5,6,9,10-tetrahydro-7H-[1,4]oxazino-[4′,3′:1,5]pyrazolo[3,4-f]isoquinolin-7-one (0.41 mmol, 139.5 mg) was dissolved in 50% THF/water (4.0 mL) and lithium hydroxide (2M, 0.21 mL) was added. The reaction mixture stirred at 23° C. for 3hours. The sample was concentrated under nitrogen stream. The residue was triturated with acetonitrile and sonicated to produce a fine powder. The product was collected via filtration and isolated as a light tan solid (140.4 mg, 95% yield):

[1608]

1
HNMR (400 MHz, DMSO) δ 8.468 (d, 2H), 7.655 (s, 1H), 7.544 (s, 1H), 4.601 (bs, 2H), 3.947 (m, 1H), 3.633 (s, 4H), 2.931-2.88 (d, 4H), 2.555 (m, 6H): m/z 359 (M+H). The following compounds were hydrolyzed from the lactone to the acid in the same manner as lithium 2-(2-hydroxy-3-morpholin-4-ylpropyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylate

EXAMPLE 399

[1609] This example illustrates that MK2 knock-out mice (MK2 (−/−)) are resistant to the formation of K/BN serum-induced arthritis and that compounds that inhibit MK-2 should be effective for the prevention and treatment of TNFα-mediated diseases or disorders.

[1610] A strain of mice has been reported that develops symptoms similar to human rheumatoid arthritis. The mice were designated K/B×N mice. See, Wipke, B. T. and P. M. Allen, J. of Immunology, 167:1601-1608 (2001). Serum from the mice can be injected into host animals to provoke a typical RA response. The progression of the RA symptoms in the mice is measured by measuring paw thickness as a function of time.

[1611] In the present example, host mice having normal MK-2 production (MK2 (+/+)) were genetically altered by disabling the gene encoding MK-2 to produce mice having no capability of endogenous synthesis of active MK-2 (MK2 (−/−)). Normal host mice (MK2 (+/+)) and MK-2 knock-out mice (MK2 (−/−), were separated into four groups with each group containing both male and female mice. All groups of mice were treated similarly, except that one group (Normal), Composed of MK2 (+/+) mice that served as the control group, was not injected with serum from K/B×N mice, while the other three groups were injected with K/B×N serum at day 0. The other three groups of mice were MK2 (+/+), MK2 (−/−), and Anti-TNF. The Anti-TNF group was composed of MK2 (+/+) mice which were also injected at day) with anti-TNF antibody. The paw thickness of all mice was measured immediately after the injections on day 0, and then on each successive day thereafter for 7 days.

[1612]
FIG. 1 is a graph that shows paw thickness as a function of time from day 0 to day 7 for MK2 (+/+) and MK2 (−/−) mice, which have received serum injection. It can be seen that paw thickness increased significantly for MK2(+/+) mice, whereas there was substantially no increase in paw thickness for MK2 knock-out mice. This indicated the requirement for a functioning MK2 regulatory system to the inflammatory response caused by the serum challenge. When anti-TNF antibody was administered to the MK2 (+/+) mice along with the serum injection, the swelling response was significantly reduced. This can be seen in FIG. 2, which is a bar chart showing paw thickness at seven days after injection for normal mice, MK2 (+/+) mice receiving serum, MK2 (−/−) mice receiving serum, and MK2 (+/+) mice receiving serum and anti-TNF antibody.

[1613] This data shows that the MK-2 knock-out mice show no arthritic response to a serum challenge, whereas MK2 (+/+) mice show a normal response. Treatment of MK2 (+/+) mice that receive a serum challenge with anti-TNF antibody reduces the response back to near-normal levels. This illustrates the utility of the MK-2 regulatory system as a potential control point for the modulation of TNFα production, and indicates that such regulation could serve as a treatment for inflammation—such as that caused by arthritis, for example. It further shows that MK-2 inhibition can have a beneficial effect on inflammation, and indicates that administration of an MK-2 inhibitor can be an effective method of preventing or treating TNFα modulated diseases or disorders.

[1614] All references cited in this specification, including without limitation all papers, publications, patents, patent applications, presentations, texts, reports, manuscripts, brochures, books, internet postings, journal articles, periodicals, and the like, are hereby incorporated by reference into this specification in their entireties. The discussion of the references herein is intended merely to summarize the assertions made by their authors and no admission is made that any reference constitutes prior art. Applicants reserve the right to challenge the accuracy and pertinency of the cited references.

[1615] In view of the above, it will be seen that the-several advantages of the invention are achieved and other advantageous results obtained.

[1616] As various changes could be made in the above methods and compositions without departing from the scope of the invention, it is intended that all matter contained in the above description shall be interpreted as illustrative and not in a limiting sense.

Claims

1. A cyclic pyrazole MK-2 inhibiting compound having the structure:
2. A cyclic pyrazole MK-2 inhibiting compound having the structure:
3. A cyclic pyrazole MK-2 inhibiting compound having the structure:
4. A cyclic pyrazole MK-2 inhibiting compound having the structure:
5. A cyclic pyrazole MK-2 inhibiting compound having the structure:
6. A cyclic pyrazole MK-2 inhibiting compound having the structure:
7. A cyclic pyrazole MK-2 inhibiting compound having the structure:
8. A cyclic pyrazole MK-2 inhibiting compound having the structure:
9. A cyclic pyrazole MK-2 inhibiting compound having the structure:
10. A cyclic pyrazole MK-2 inhibiting compound having the structure:
11. A cyclic pyrazole MK-2 inhibiting compound having the structure:
12. A cyclic pyrazole MK-2 inhibiting compound having the structure:
13. A phenoxy pyrazole MK-2 inhibitor that is selected from the group consisting of: 2-(3-aminopropyl)-7-hydroxy-8-(3-nitrophenyl)-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid trifluoroacetate, 2-(2-aminoethyl)-7-hydroxy-8-(3-nitrophenyl)-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid trifluoroacetate, 3-hydroxy-2-(3-nitrophenyl)-5,6,8,9,10,11-hexahydro-7H-benzo[g][1,4]diazepino[1,2-b]indazol-7-one trifluoroacetate, 2-(3-aminopropyl)-7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid dihydrochloride, 2-(2-aminoethyl)-8-bromo-7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid trifluoroacetate, 2-(3-aminopropyl)-8-[2-(4-chlorophenyl)ethyl]-7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid trifluoroacetate, 3-hydroxy-2-(3-nitrophenyl)-5,6,9,10-tetrahydrobenzo[g]pyrazino[1,2-b]indazol-7(8H)-one hydrobromide, 2-(3-aminopropyl)-8-bromo-7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid hydrobromide, 2-(3-aminopropyl)-7-hydroxy-8-(4-nitrophenyl)-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid trifluoroacetate, 2-(3-aminopropyl)-8-(3-cyanophenyl)-7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid trifluoroacetate, 2-(3-aminopropyl)-7-hydroxy-8-[3-(trifluoromethyl) phenyl]-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid trifluoroacetate, 2-(3-aminopropyl)-7-hydroxy-8-(3,3,3-trifluoropropyl)-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid trifluoroacetate, 2-(3-aminopropyl)-8-(3-chlorophenyl)-7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid trifluoroacetate, 2-(3-aminopropyl)-7-hydroxy-5-methyl-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid trifluoroacetate, 2-(3-aminopropyl)-8-(4-chlorophenyl)-7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid trifluoroacetate, 2-(3-aminopropyl)-7-hydroxy-8-[3-(methylsulfonyl)phenyl]-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid trifluoroacetate, 2-(3-aminopropyl)-8-(3,4-difluorophenyl)-7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid trifluoroacetate, 3-hydroxy-5,6,8,9,10,11-hexahydro-7H-benzo[g][1,4]diazepino[1,2-b]indazol-7-one, 8-(3-aminophenyl)-2-(3-aminopropyl)-7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid trifluoroacetate, 6-bromo-7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxamide, 2-(3-aminopropyl)-7-hydroxy-8-[4-(methylamino)phenyl]-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid trifluoroacetate, 2-(3-aminopropyl)-8-(4-tert-butylphenyl)-7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid trifluoroacetate, 2-(3-aminopropyl)-7-hydroxy-8-pyridin-4-yl-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid trifluoroacetate, 7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid, 2-(3-aminopropyl)-7-hydroxy-8-isobutyl-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid trifluoroacetate, 2-(3-aminopropyl)-8-(4-carboxy-3,3-dimethylbutyl)-7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid trifluoroacetate, 8-amino-2-(3-aminopropyl)-7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid, 7,8-dihydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid, 2-(3-aminopropyl)-8-benzyl-7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid trifluoroacetate, 2-(3-aminopropyl)-8-(2-chlorophenyl)-7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid trifluoroacetate, 2-allyl-7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid, 2-{3-[(tert-butoxycarbonyl)amino]propyl}-7-methoxy-8-(4-nitrophenyl)-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid, 7-hydroxy-2-methyl-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid, 2-(3-aminopropyl)-8-(sec-butylamino)-7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid, 2-(3-aminopropyl)-8-(3-carboxyphenyl)-7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid trifluoroacetate, 2-{3-[(tert-butoxycarbonyl)amino]propyl}-7-methoxy-8-(3-nitrophenyl)-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid, 2-{3-[(tert-butoxycarbonyl)amino]propyl}-8-(3-cyanophenyl)-7-methoxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid, 7-hydroxy-1-methyl-4,5-dihydro-1H-benzo[g]indazole-3-carboxylic acid, 2-{3-[(tert-butoxycarbonyl)amino]propyl}-8-[2-(4-chlorophenyl)ethyl]-7-methoxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid, 2-{3-[(tert-butoxycarbonyl)amino]propyl}-7-methoxy-8-[3-(trifluoromethyl)phenyl]-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid, 2-{3-[(tert-butoxycarbonyl)amino]propyl}-8-(4-tert-butylphenyl)-7-methoxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid, 2-(3-aminopropyl)-6-chloro-7-hydroxy-8-(3-nitrophenyl)-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid, 2-{2-[(tert-butoxycarbonyl)amino]ethyl}-7-methoxy-8-(3-nitrophenyl)-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid, 2-amino-3-hydroxy-5,6,8,9,10,11-hexahydro-7H-benzo[g][1,4]diazepino[1,2-b]indazol-7-one trifluoroacetate, 2-{3-[(tert-butoxycarbonyl)amino]propyl}-8-(3,4-difluorophenyl)-7-methoxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid, methyl 8-[(dimethylamino)sulfonyl]-7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate, 7-hydroxy-5-methyl-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid, 2-{3-[(tert-butoxycarbonyl)amino]propyl}-8-(4-chlorophenyl)-7-methoxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid, 2-{3-[(tert-butoxycarbonyl)amino]propyl}-8-(3-chlorophenyl)-7-methoxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid, 2-(3-aminophenyl)-3-hydroxy-5,6,8,9,10,11-hexahydro-7H-benzo[g][1,4]diazepino[1,2-b]indazol-7-one trifluoroacetate, 2-{3-[(tert-butoxycarbonyl)amino]propyl}-8-(2-chlorophenyl)-7-methoxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid, ethyl 6-bromo-7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate, 2-{3-[(tert-butoxycarbonyl)amino]propyl}-7-methoxy-8-(3,3,3-trifluoropropyl)-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid, 2-(3-aminopropyl)-8-(3,5-dimethylisoxazol-4-yl)-7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid trifluoroacetate, 5-allyl-7-hydroxy-4,5-dihydro-1H-benzo[g]indazole-3-carboxamide, 2-{3-[(tert-butoxycarbonyl)amino]propyl}-7-methoxy-8-[3-(methylsulfonyl)phenyl]-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid, 2-{3-[(tert-butoxycarbonyl)amino]propyl}-8-[1-(tert-butoxycarbonyl)-1H-pyrrol-2-yl]-7-methoxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid, 7-hydroxy-4-methyl-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid, 5-allyl-7-hydroxy-4,5-dihydro-1H-benzo[g]indazole-3-carboxylic acid, 7-[(2-methoxyethoxy)methoxy]-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid, 6-bromo-7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid, 8-benzyl-2-{3-[(tert-butoxycarbonyl)amino]propyl}-7-methoxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid, methyl 7,8-dihydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate, 7-hydroxy-1-methyl-4,5-dihydro-1H-benzo[g]indazole-3-carboxamide, 8-bromo-7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid, 2-{3-[(tert-butoxycarbonyl)amino]propyl}-7-methoxy-8-pyridin-4-yl-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid, 7-hydroxy-4-methyl-4,5-dihydro-2H-benzo[g]indazole-3-carboxamide, 7-hydroxy-N-methyl-4,5-dihydro-2H-benzo[g]indazole-3-carboxamide, 7-hydroxy-2-methyl-4,5-dihydro-2H-benzo[g]indazole-3-carboxamide, 2-{3-[(tert-butoxycarbonyl)amino]propyl}-7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid, 7-hydroxy-N-(2-hydroxyethyl)-4,5-dihydro-2H-benzo[g]indazole-3-carboxamide, 2-(3-aminopropyl)-8-(sec-butylamino)-7-methoxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid, ethyl 7-methoxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate, 7-methoxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxamide, ethyl 7-hydroxy-1-phenyl-4,5-dihydro-1H-benzo[g]indazole-3-carboxylate, ethyl 7-hydroxy-1-(4-methoxyphenyl)-4,5-dihydro-1H-benzo[g]indazole-3-carboxylate, 2-allyl-7-[(2-methoxyethoxy)methoxy]-4,5-dihydro-2H-benzo[g]indazole-3-carboxamide, 2-allyl-7-[(2-methoxyethoxy)methoxy]-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid, ethyl 7-methoxy-5-phenyl-4,5-dihydro-1H-benzo[g]indazole-3-carboxylate, 7-[(2-methoxyethoxy)methoxy]-4,5-dihydro-2H-benzo[g]indazole-3-carboxamide, 6-bromo-7-[(2-methoxyethoxy)methoxy]-4,5-dihydro-2H-benzo[g]indazole-3-carboxamide, 6-bromo-7-[(2-methoxyethoxy)methoxy]-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid, ethyl 6-bromo-7-[(2-methoxyethoxy)methoxy]-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate, ethyl 2-allyl-7-[(2-methoxyethoxy)methoxy]-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate, 7-hydroxy-N,N-dimethyl-4,5-dihydro-2H-benzo[g]indazole-3-carboxamide, 8-bromo-2-{2-[(tert-butoxycarbonyl)amino]ethyl}-7-methoxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid, ethyl 8-bromo-2-{2-[(tert-butoxycarbonyl)amino]ethyl}-7-methoxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate, 8-bromo-2-{3-[(tert-butoxycarbonyl)amino]propyl}-7-methoxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid, 8-[(dimethylamino)sulfonyl]-7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid, ethyl 8-bromo-2-{3-[(tert-butoxycarbonyl)amino]propyl}-7-methoxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate, 7-hydroxy-8-[(isopropylamino)sulfonyl]-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid, methyl 7-hydroxy-8-[(isopropylamino)sulfonyl]-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate, ethyl 8-bromo-7-methoxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate, 8-(aminosulfonyl)-7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid, methyl 7-hydroxy-5-methyl-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate, methyl 7-methoxy-5-methyl-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate, methyl 7-methoxy-4-methyl-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate, ethyl 8-(aminosulfonyl)-7-methoxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate, ethyl 2-(3-aminopropyl)-7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate dihydrochloride, ethyl 7-[(2-methoxyethoxy)methoxy]-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate, 5-butyl-7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxamide, 5-ethyl-7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxamide, 5-butyl-7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid, 5-ethyl-7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid, 5-benzyl-7-hydroxy-4,5-dihydro-1H-benzo[g]indazole-3-carboxamide, 7-hydroxy-5-phenyl-4,5-dihydro-1H-benzo[g]indazole-3-carboxamide, 5-benzyl-7-hydroxy-4,5-dihydro-1H-benzo[g]indazole-3-carboxylic acid, ethyl 5-allyl-7-methoxy-4,5-dihydro-1H-benzo[g]indazole-3-carboxylate, ethyl 5-benzyl-7-methoxy-4,5-dihydro-1H-benzo[g]indazole-3-carboxylate, 7-hydroxy-5-phenyl-4,5-dihydro-1H-benzo[g]indazole-3-carboxylic acid, methyl 2-{3-[(tert-butoxycarbonyl)amino]propyl}-8-(3,4-difluorophenyl)-7-methoxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate, methyl 2-{3-[(tert-butoxycarbonyl)amino]propyl}-7-methoxy-8-[3-(methylsulfonyl)phenyl]-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate, methyl 2-{3-[(tert-butoxycarbonyl)amino]propyl}-7-methoxy-8-(4-nitrophenyl)-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate, methyl 2-{3-[(tert-butoxycarbonyl)amino]propyl}-7-methoxy-8-(3,3,3-trifluoropropyl)-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate, 3-methoxy-2-(3-nitrophenyl)-5,6,9,10-tetrahydrobenzo[g]pyrazino[1,2-b]indazol-7(8H)-one, methyl 2-{3-[(tert-butoxycarbonyl)amino]propyl}-8-(3-cyanophenyl)-7-methoxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate, methyl 2-{2-[(tert-butoxycarbonyl)amino]ethyl}-7-methoxy-8-(3-nitrophenyl)-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate, 2-amino-3-methoxy-5,6,8,9,10,11-hexahydro-7H-benzo[g][1,4]diazepino[1,2-b]indazol-7-one, methyl 8-amino-2-(3-aminopropyl)-7-methoxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate hydrochloride, 2-{3-[(tert-butoxycarbonyl)amino]propyl}-7-methoxy-8-(5-nitropentyl)-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid, 2-{3-[(tert-butoxycarbonyl)amino]propyl}-8-(4-carboxy-3,3-dimethylbutyl)-7-methoxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid, 2-{3-[(tert-butoxycarbonyl)amino]propyl}-8-(3,5-dimethylisoxazol-4-yl)-7-methoxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid, methyl 2-{3-[(tert-butoxycarbonyl)amino]propyl}-8-(3,5-dimethylisoxazol-4-yl)-7-methoxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate, 2-{3-[(tert-butoxycarbonyl)amino]propyl}-8-(3-carboxyphenyl)-7-methoxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid, methyl 2-{3-[(tert-butoxycarbonyl)amino]propyl}-7-methoxy-8-[3-(methoxycarbonyl)phenyl]-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate, 2-{3-[(tert-butoxycarbonyl)amino]propyl}-8-isobutyl-7-methoxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid, methyl 2-{3-[(tert-butoxycarbonyl)amino]propyl}-8-(3-chlorophenyl)-7-methoxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate, methyl 2-{3-[(tert-butoxycarbonyl)amino]propyl}-8-(sec-butylamino)-7-methoxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate, methyl 2-{3-[(tert-butoxycarbonyl)amino]propyl}-8-isobutyl-7-methoxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate, methyl 8-benzyl-2-{3-[(tert-butoxycarbonyl)amino]propyl}-7-methoxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate, 3-methoxy-2-(3-nitrophenyl)-5,6,8,9,10,11-hexahydro-7H-benzo[g][1,4]diazepino[1,2-b]indazol-7-one, 2-bromo-3-methoxy-5,6,9,10-tetrahydrobenzo[g]pyrazino[1,2-b]indazol-7(8H)-one, methyl 7-methoxy-6,8-dinitro-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate, methyl 7-methoxy-8-nitro-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate, methyl 2-{3-[(tert-butoxycarbonyl)amino]propyl}-7-methoxy-8-nitro-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate, methyl 8-amino-2-{3-[(tert-butoxycarbonyl)amino]propyl}-7-methoxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate, 8-amino-2-(3-aminopropyl)-7-methoxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid, methyl 2-{3-[(tert-butoxycarbonyl)amino]propyl}-8-[2-(4-chlorophenyl)ethyl]-7-methoxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate, methyl 2-{3-[(tert-butoxycarbonyl)amino]propyl}-8-[1-(tert-butoxycarbonyl)-1H-pyrrol-2-yl]-7-methoxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate, 2-{3-[(tert-butoxycarbonyl)amino]propyl}-7-methoxy-5-methyl-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid, methyl 2-{3-[(tert-butoxycarbonyl)amino]propyl}-8-(2-chlorophenyl)-7-methoxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate, 2-(3-aminopropyl)-8-(4-chlorophenyl)-7-methoxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid hydrochloride, methyl 2-{3-[(tert-butoxycarbonyl)amino]propyl}-7-methoxy-8-(3-nitrophenyl)-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate, methyl 2-{3-[(tert-butoxycarbonyl)amino]propyl}-8-(4-tert-butylphenyl)-7-methoxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate, methyl 2-{3-[(tert-butoxycarbonyl)amino]propyl}-7-methoxy-8-[3-(trifluoromethyl)phenyl]-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate, methyl 2-{3-[(tert-butoxycarbonyl)amino]propyl}-8-(4-chlorophenyl)-7-methoxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate, 2-bromo-3-methoxy-9-methyl-5,6,9,10-tetrahydrobenzo[g]pyrazino[1,2-b]indazol-7(8H)-one, 2-bromo-3-hydroxy-9-methyl-5,6,9,10-tetrahydrobenzo[g]pyrazino[1,2-b]indazol-7(8H)-one, methyl 2-{3-[(tert-butoxycarbonyl)amino]propyl}-8-[4-(dimethylamino)phenyl]-7-methoxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate, 2-(2-aminoethyl)-8-bromo-7-methoxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid hydrochloride, ethyl 7-hydroxy-1-methyl-4,5-dihydro-1H-benzo[g]indazole-3-carboxylate, 7-hydroxy-1-phenyl-4,5-dihydro-1H-benzo[g]indazole-3-carboxamide, ethyl 7-hydroxy-2-methyl-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate.
14. A pyrazolyl pyrazole MK-2 inhibitor that is selected from the group consisting of: 2-(3-aminopropyl)-8-(methylthio)-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylic acid dihydrochloride, 2-(3-aminopropyl)-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylic acid hydrochloride, 2-(3-{[2-(4-bromophenyl)ethyl]amino}propyl)-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylic acid hydrochloride, 2-(2-aminoethyl)-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylic acid hydrochloride, 8-(allylthio)-2-(3-aminopropyl)-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylic acid dihydrochloride, 2-(3-aminopropyl)-8-(benzylthio)-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylic acid dihydrochloride, 2-{3-[(2-thien-2-ylethyl)amino]propyl}-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylic acid, 2-{3-[(2-thien-3-ylethyl)amino]propyl}-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylic acid hydrochloride, ethyl 2-(3-{[2-(4-bromophenyl)ethyl]amino}propyl)-2,4,5,6-tetra hydropyrazolo[3,4-e]indazole-3-carboxylate, 2-(4-aminobutyl)-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylic acid dihydrochloride, 1-(methylthio)-4,5,7,8,9,10-hexahydro[1,4]diazepino[1,2-b]pyrazolo[3,4-g]indazol-6(3H)-one, 1-(allylthio)-4,5,7,8,9,10-hexahydro[1,4]diazepino[1,2-b]pyrazolo[3,4-g]indazol-6(3H)-one, 4,5,7,8,9,10-hexahydro[1,4]diazepino[1.,2-b]pyrazolo[3,4-g]indazol-6(3H)-one, 4,5,8,9-tetrahydro-3H-pyrazino[1,2-b]pyrazolo[3,4-g]indazol-6(7H)-one, 2-allyl-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylic acid hydrochloride, 1-(benzylthio)-4,5,7,8,9,10-hexahydro[1,4]diazepino[1,2-b]pyrazolo[3,4-g]indazol-6(3H)-one, 2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxamide, 8-(methylthio)-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxamide, 1-{1-[(benzyloxy)carbonyl]piperidin-4-yl}-6-trityl-1,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylic acid, ethyl 2-(3-aminopropyl)-8-(methylthio)-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate dihydrochloride, 2-piperidin-4-yl-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylic acid hydrochloride, 1-(2,2,2-trifluoroethyl)-6-trityl-1,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylic acid, 1-(2-hydroxyethyl)-1,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxamide, [4-(aminocarbonyl)phenyl]-1,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxamide or (1-[4-(aminocarbonyl)phenyl]-1,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxamide), 8-(benzylthio)-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxamide, 1-allyl-1,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxamide, 2-(3-hydroxypropyl)-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylic acid, 1-(3-aminopropyl)-1,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxamide dihydrochloride, 1-phenyl-1,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxamide, 6-(2-hydroxyethyl)-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylic acid, 2-(3-cyanopropyl)-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylic acid hydrochloride, ethyl 2-(3-aminopropyl)-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate dihydrochloride, 1-benzyl-1,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxamide, 1-[4-(methylsulfonyl)phenyl]-1,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxamide, ethyl 2-{3-[(2-thien-3-ylethyl)amino]propyl}-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate dihydrochloride, 2-(2-hydroxyethyl)-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylic acid, 2-{2-[(tert-butoxycarbonyl)amino]ethyl}-6-trityl-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylic acid, N-methoxy-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxamide hydrochloride, 1-[4-(aminosulfonyl)phenyl]-1,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylic acid, 2-(2,2,2-trifluoroethyl)-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylic acid, 1-(2,2,2-trifluoroethyl)-1,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylic acid hydrochloride, 2-allyl-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxamide, ethyl 2-(3-aminopropyl)-8-(benzylthio)-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate dihydrochloride, 2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylic acid hydrochloride, 6-(ethoxymethyl)-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxamide, ethyl 6-phenyl-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate, 1-[4-(aminosulfonyl)phenyl]-6-benzyl-N-methyl-1,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxamide, 6-methyl-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxamide, ethyl 6-methyl-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate, 6-phenyl-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxamide, 1-[4-(aminosulfonyl)phenyl]-N-methyl-1,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxamide, 6-benzyl-1-phenyl-1,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxamide, ethyl 1-phenyl-1,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate, ethyl 6-benzyl-1-phenyl-1,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate, 1-(3-amino-3-oxopropyl)-1,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxamide, 1-(2-amino-2-oxoethyl)-1,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxamide, 8-(methylsulfonyl)-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxamide, ethyl 2-{2-[(tert-butoxycarbonyl)amino]ethyl}-6-trityl-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate, 8-(benzylthio)-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylic acid, ethyl 8-(benzylthio)-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate, 8-(methylsulfinyl)-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylic acid, ethyl 8-(methylsulfinyl)-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate, 8-(methylthio)-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylic acid, ethyl 8-(methylthio)-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate, tert-butyl 3-[3-(aminocarbonyl)-5,6-dihydropyrazolo[3,4-e]indazol-2(4H)yl]propylcarbamate, 1-(2-cyanoethyl)-1,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxamide, 6-[(benzyloxy)methyl]-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxamide, ethyl 6-(2-hydroxyethyl)-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate acetate, 6-(2-hydroxyethyl)-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxamide, 1-phenyl-1,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylic acid, ethyl 2-(2,2,2-trifluoroethyl)-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate hydrochloride, ethyl 1-(2,2,2-trifluoroethyl)-6-trityl-1,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate, ethyl 2-allyl-6-trityl-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate, ethyl 7-isobutyl-2,4,5,7-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate, 6-(4-methylphenyl)-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylic acid, ethyl 6-(4-methylphenyl)-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate, 7-[(benzyloxy)methyl]-2,4,5,7-tetrahydropyrazolo[3,4-e]indazole-3-carboxamide, 7-isobutyl-2,4,5,7-tetrahydropyrazolo[3,4-e]indazole-3-carboxamide, ethyl 1-(2,2,2-trifluoroethyl)-1,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate hydrochloride, 1-[4-(methylsulfonyl)phenyl]-1,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylic acid, ethyl 1-[4-(methylsulfonyl)phenyl]-1,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate, ethyl 6-benzyl-1-[4-(methylsulfonyl)phenyl]-1,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate, ethyl 6-[(benzyloxy)methyl]-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate, ethyl 7-[(benzyloxy)methyl]-2,4,5,7-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate, 1-(2,2,2-trifluoroethyl)-1,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxamide, ethyl 1-(2-cyanoethyl)-1,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate hydrochloride, ethyl 1-(3-aminopropyl)-1,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate, ethyl 1-{3-[(tert-butoxycarbonyl)amino]propyl}-6-trityl-1,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate, 1-(3-aminopropyl)-1,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylic acid, 2-(carboxymethyl)-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylic acid, ethyl 1-(2-ethoxy-2-oxoethyl)-6-trityl-1,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate, ethyl 1-(2-cyanoethyl)-6-trityl-1,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate, 2-(3-aminopropyl)-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxamide, 1-allyl-1,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylic acid hydrochloride, 6-allyl-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxamide, 7-allyl-2,4,5,7-tetrahydropyrazolo[3,4-e]indazole-3-carboxamide, ethyl 2-(2-ethoxy-2-oxoethyl)-6-trityl-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate, ethyl 2-(2-hydroxyethyl)-6-trityl-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate, 1-(2-carboxyethyl)-1,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylic acid, 6-benzyl-1,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxamide, ethyl 2-(3-hydroxypropyl)-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate hydrochloride, ethyl 2-[3-(tetrahydro-2H-pyran-2-yloxy)propyl]-6-trityl-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate, [3-(ethoxycarbonyl)-5,6-dihydropyrazolo[3,4-e]indazol-2(4H)-yl]acetic acid, [3-(methoxycarbonyl)-5,6-dihydropyrazolo[3,4-e]indazol-2(4H)-yl]acetic acid, 1-piperidin-4-yl-1,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylic acid dihydrochloride, 1-piperidin-4-yl-6-trityl-1,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylic acid hydrochloride, ethyl 1-{1-[(benzyloxy)carbonyl]piperidin-4-yl}-6-trityl-1,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate, ethyl 2-(3-cyanopropyl)-6-trityl-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate, ethyl 2-(4-aminobutyl)-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate hydrochloride, 1-(3-amino-3-oxopropyl)-1,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylic acid, [3-(ethoxycarbonyl)-5,6-dihydropyrazolo[3,4-e]indazol-[(4H)-yl]acetic acid, ethyl 2-(2-ethoxy-2-oxoethyl)-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate hydrochloride, 1-(2-hydroxyethyl)-1,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylic acid, ethyl 1-(2-hydroxyethyl)-1,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate hydrochloride, 8-(methylsulfonyl)-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylic acid, ethyl 8-(methylsulfonyl)-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate, ethyl 6-allyl-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate, ethyl 7-allyl-2,4,5,7-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate, ethyl 1-(2-hydroxyethyl)-6-trityl-1,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate, ethyl 1-benzyl-1,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate, ethyl 2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate, ethyl 6-trityl-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate, 8-amino-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylic acid dihydrochloride, ethyl 2-{3-[(tert-butoxycarbonyl)amino]propyl}-6-[(4-methylphenyl)sulfonyl]-8-(methylthio)-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate, ethyl 8-(tert-butylamino)-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate, 8-(tert-butylamino)-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylic acid hydrochloride, ethyl 8-(allylthio)-6-[(4-methylphenyl)sulfonyl]-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate, 8-Allylsulfanyl-2-(3-tert-butoxycarbonylamino-propyl)-6-(toluene-4-sulfonyl)-2,4,5,6-tetrahydro-1,2,6,7-tetraaza-a s-indacene-3-carboxylic acid ethyl ester
15. A pyridyl pyrazole MK-2 inhibitor that is selected from the group consisting of: 2-(3-aminopropyl)-8-quinolin-3-yl-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-aminopropyl)-8-(3-nitrophenyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-aminopropyl)-8-(4-hydroxyphenyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid hydrobromide, 2-(3-aminopropyl)-8-(3-hydroxyphenyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid hydrobromide, 2-(3-aminopropyl)-8-(2-naphthyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-aminopropyl)-8-(3,5-difluorophenyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-aminopropyl)-8-(1,3-benzodioxol-5-yl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-aminopropyl)-8-(3-cyanophenyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 9-(hydroxymethyl)-2-quinolin-3-yl-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one trifluoroacetate, 2-(3-aminopropyl)-8-(4-methoxyphenyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-aminopropyl)-8-[3-(methylsulfonyl)phenyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-aminopropyl)-8-[3-(trifluoromethyl)phenyl]-4., 5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(1H-imidazol-1-yl)-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one trifluoroacetate, 2-(3-aminopropyl)-8-(3-methoxyphenyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-aminopropyl)-8-[4-(trifluoromethyl)phenyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-aminopropyl)-8-anilino-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid, 2-(3-aminopropyl)-8-(3,4-difluorophenyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-{[2-(4′-carboxy-1,1′-biphenyl-4-yl)ethyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(4-hydroxyphenyl)-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one trifluoroacetate, 2-propyl-8-quinolin-3-yl-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid, 2-[3-({2-[3′-(trifluoromethyl)-1,1′-biphenyl-4-yl]ethyl}amino)propyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-aminopropyl)-8-(4-tert-butylphenyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-[3-({2-[4-(3-furyl)phenyl]ethyl}amino)propyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-{[2-(3′-chloro-1,1′-biphenyl-4-yl)ethyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(4-methoxyphenyl)-5,6,8,9,10,11-hexahydro-7H-[1,4]diazepino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7-one, 2-[3-({2-[4′-(trifluoromethyl)-1,1′-biphenyl-4-yl]ethyl}amino)propyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-hydroxyphenyl)-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, 2-(3-aminopropyl)-N-hydroxy-8-quinolin-3-yl-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxamide hydrochloride, 2-[(E)-2-(4-hydroxyphenyl)ethenyl]-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one trifluoroacetate, 2-quinolin-3-yl-5,6,8,9,10,11-hexahydro-7H-[1,4]diazepino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7-one, 2-(4-hydroxyphenyl)-5,6,8,9,10,11-hexahydro-7H-[1,4]diazepino[1′,2′:1,5]pyrazolo[3,4-q]isoquinolin-7-one, 2-(3-{[2-(2′-chloro-1,1′-biphenyl-4-yl)ethyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-{[2-(4′-tert-butyl-1,1′-biphenyl-4-yl)ethyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-{[2-(3,4-dichlorophenyl)ethyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-{[3-(3-chlorophenyl)propyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-[(E)-2-phenylethenyl]-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one trifluoroacetate, 2-(3-{[2-(4-pyridin-4-ylphenyl)ethyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-{[3-(4-bromophenyl)propyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-{[3-(4-tert-butylphenyl)propyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-{[2-(3′-isopropyl-1,1′-biphenyl-4-yl)ethyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-{3-[(2-thien-2-ylethyl)amino]propyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-[4-(dimethylamino)phenyl]-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, 2-(3-{[2-(1,1′-biphenyl-4-yl)ethyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-methoxyphenyl)-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, 2-(3-{[2-(4-bromophenyl)ethyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-{[2-(2,4-dichlorophenyl)ethyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-{3-[(benzylsulfonyl)amino]propyl}-8-quinolin-3-yl-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid, 9-(aminomethyl)-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one trifluoroacetate, 2-(3-nitrophenyl)-5,6,8,9,10,11-hexahydro-7H-[1,4]diazepino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7-one, 2-(3-aminopropyl)-8-quinolin-3-yl-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxamide hydrochloride, 2-(3-{[3-(4-chlorophenyl)propyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-[3-(dimethylamino)phenyl]-5,6,8,9,10,11-hexahydro-7H [1,4]diazepino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7-one, 2-(3-{[(4-chlorobenzyl)sulfonyl]amino}propyl)-8-quinolin-3-yl-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid, 2-(3-{[2-(4-pyridin-3-ylphenyl)ethyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-{[2-(4-chlorophenyl)ethyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-{[2-(5-chlorothien-2-yl)ethyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-{[3-(4-cyanophenyl)propyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-{[3-(5-methyl-2-furyl)butyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-[3-({2-[4-(1-benzothien-3-yl)phenyl]ethyl}amino)propyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-ammoniopropyl)-3-carboxy-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinolin-7-ium dichloride, 2-(4-methoxyphenyl)-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, 2-(3-{[3-(4-acetylphenyl)propyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-aminopropyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-[3-({3-[4-(methylsulfonyl)phenyl]propyl}amino)propyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-aminopropyl)-8-(2-methoxyphenyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-[3-({2-[3′-(aminomethyl)-1,1′-biphenyl-4-yl]ethyl}amino)propyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(2-aminoethyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid dihydrochloride, 2-(3-{[2-(4-nitrophenyl)ethyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-[3-({2-[2′-(trifluoromethyl)-1,1′-biphenyl-4-yl]ethyl}amino)propyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 9-(hydroxymethyl)-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, 2-(3-{[2-(4-methylphenyl)ethyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 9-{[(2-thien-2-ylethyl)amino]methyl}-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, 2-(3-{[2-(4-ethoxyphenyl)ethyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(1,3-benzodioxol-5-yl)-5,6,8,9,10,11-hexahydro-7H-[1,4]diazepino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7-one, 2-(3-{[2-(4-methoxyphenyl)ethyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 3-[3-(1H-tetraazol-5-yl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinolin-2-yl]propan-1-amine hydrochloride, 2-(3-aminopropyl)-8-chloro-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-{[(1R,2S)-2-phenylcyclopropyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-{3-[(3,3-diphenylpropyl)amino]propyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-{[2-(3-bromo-4-methoxyphenyl)ethyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-{3-[(4-phenylbutyl)amino]propyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-[3-(2,3-dihydro-1H-inden-2-ylamino)propyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate; 2-(2-naphthyl)-5,6,8,9,10,11-hexahydro-7H-[1,4]diazepino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7-one, 2-{3-[(3-phenylpropyl)amino]propyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-{[2-(4-fluorophenyl)ethyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-{3-[(2-thien-3-ylethyl)amino]propyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid dihydrochloride, 5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, 2-[3-(glycoloylamino)propyl]-8-quinolin-3-yl-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid hydrochloride, 8-quinolin-3-yl-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid, 2-(3-{[2-(4-ethylphenyl)ethyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-{[2-(2-chlorophenyl)ethyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-{3-[(2-ethylbutyl)amino]propyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 8-quinolin-3-yl-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxamide, 2-{3-[(2-pyridin-4-ylethyl)amino]propyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-{[2-(4-chlorophenyl)propyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-{[2-(3-chlorophenyl)ethyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-[3-(glycoloylamino)propyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-{[2-(3,4-dimethoxyphenyl)ethyl]amino}propyl)-4,5-dihydro-2H pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(1-benzofuran-2-yl)-5,6,8,9,10,11-hexahydro-7H-[1,4]diazepino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7-one, 2-(3-{[4-(2-aminoethyl)phenyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(1-naphthyl)-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, 8-(3-aminopropyl)-5,6,8,9,10,11-hexahydro-7H-[1,4]diazepino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7-one dihydrochloride, 2-anilino-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, 2-(3-aminopropyl)-8-[2-(trifluoromethyl)phenyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 9-(azidomethyl)-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, 9-({[2-(4-chlorophenyl)ethyl]amino}methyl)-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, 2-phenyl-5,6,8,9,10,11-hexahydro-7H-[1,4]diazepino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7-one, 2-[3-(pentylamino)propyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 10-(2-aminoethyl)-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, 2-[3-(allylamino)propyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(4-aminobutyl)-4,5-dihydro-2H-pyrazolo[3,4-q]isoquinoline-3-carboxylic acid dihydrochloride, 2-(3-{[2-(4-aminophenyl)ethyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-[(1E)-3,3-dimethylbut-1-enyl]-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one trifluoroacetate, 10-(nitromethyl)-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, 3-carboxy-2-[3-(methylammonio)propyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinolin-7-ium dichloride, 2-[3-({[(4-butoxyphenyl)amino]carbonyl}amino)propyl]-4,5-dihydro-2H-pyrazolo[3,4-q]isoquinoline-3-carboxylic acid, 2-{3-[(2-pyridin-3-ylethyl)amino]propyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-{3-[(2-pyridin-2-ylethyl)amino]propyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-{3-[(cyclopropylmethyl)amino]propyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-{3-[(2-thien-2-ylpropyl)amino]propyl}-4,5-dihydro-2H-pyrazolo[3,4-q]isoquinoline-3-carboxylic acid trifluoroacetate, 2-methoxy-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, 2-[3-(dimethylamino)phenyl]-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, 2-(3-{[2-(1H-pyrrol-1-yl)ethyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-[3-(benzyloxy)propyl]-8-quinolin-3-yl-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid, 2-{3-[(4-butoxybenzyl)amino]propyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(1,3-benzodioxol-5-yl)-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-q]isoquinolin-7(8H)-one, 2-[(E)-2-(2-fluorophenyl)ethenyl]-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, 2-[(1E)-hex-1-enyl]-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-q]isoquinolin-7(8H)-one trifluoroacetate, 2-anilino-5,6,8,9,10,11-hexahydro-7H-[1,4]diazepino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7-one, 5,6,8,9,10,11-hexahydro-7H-[1,4]diazepino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7-one, 2-chloro-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, 2-[(E)-2-(4-methoxyphenyl)ethenyl]-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, 2-(methylthio)-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, 2-{3-[(2-furylmethyl)amino]propyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-azepan-1-yl-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one trifluoroacetate, 2-(3,6-dihydropyridin-1 (2H)-yl)-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one trifluoroacetate, 9-methyl-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, 2-(piperidin-3-ylmethyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid hydrochloride, 9-(chloromethyl)-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, 2-[(4-methoxybenzyl)amino]-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one trifluoroacetate, 2-(3-{[2-(1H-imidazol-4-yl)ethyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(benzylamino)-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one trifluoroacetate, 2-(methylthio)-5,6,8,9,10,11-hexahydro-7H-[1,4]diazepino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7-one, 2-{3-[(2-chlorobenzyl)amino]propyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-[3-(benzylamino)propyl-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-[3-({[(4-methoxyphenyl)amino]carbonyl}amino)propyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid, 2-{3-[(2-phenylethyl)amino]propyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-{3-[(thien-2-ylmethyl)amino]propyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-benzyl-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, 5,6,8,9,10,11-hexahydro-7H-[1,4]diazepino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7-one, 2-{3-[(4-chlorobenzyl)amino]propyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-{3-[(2-phenylpropyl)amino]propyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 7-oxo-5,6,7,8,9,10-hexahydropyrazino[1′,2′:1,5)pyrazolo[3,4-f]isoquinoline-9-carboxamide trifluoroacetate, 2-(3-hydroxypropyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid, 2-(1,3-dihydro-2H-isoindol-2-yl)-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one trifluoroacetate, 2-{3-[(4-aminophenyl)amino]propyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(4-hydroxypiperidin-1-yl)-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one trifluoroacetate, 2-{3-[(1H-imidazol-5-ylmethyl)amino]propyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-{3-[(3-chlorobenzyl)amino]propyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-{3-[(pyridin-3-ylcarbonyl)amino]propyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxamide, 2-[3-(cyclopentylamino)propyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid dihydrochloride, 2-(3-{[2-(1H-indol-3-yl)ethyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid, 10-(3-aminopropyl)-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, 9-(1,2-dihydroxyethyl)-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, 2-morpholin-4-yl-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one trifluoroacetate, ethyl 2-(2-aminoethyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylate dihydrochloride, 2-allyl-4,5-dihydro-2H-pyrazolo[3.,4-f]isoquinoline-3-carboxylic acid, 2-quinolin-8-yl-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, lithium 2-[3-(2,3-dihydro-1H-inden-2-ylamino)-2-hydroxypropyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylate, 2-(2-hydroxyethyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid, 2-{3-[(2-pyrrolidin-1-ylethyl)amino]propyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3,4-dihydroisoquinolin-2(1H)-yl)-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one trifluoroacetate, 2-(3-{[(benzylamino)carbonyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid, 2-[3-(dimethylamino)propyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 10-(3-{[2-(4-chlorophenyl)ethyl]amino}propyl)-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, 2-(3-aminopropyl)-6-chloro-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, methyl 7-oxo-5,6,7,8,9,10-hexahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinoline-9-carboxylate, 2-[2-(glycoloylamino)ethyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid hydrochloride, 2-[2-(isopropylamino)ethyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid hydrochloride, 2-(3-cyanopropyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid, 2-[3-({[(3-cyanophenyl)amino]carbonyl}amino)propyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid, 9-(aminomethyl)-5,6,9,10-tetrahydro-7H-[1,4]oxazino[4′, 3′:1,5]pyrazolo[3,4-f]isoquinolin-7-one trifluoroacetate, 4-methyl-5,6,8,9,10,11-hexahydro-7H-[1,4]diazepino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7-one trifluoroacetate, 2-propyl-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid, 2-(3-bromopropyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-pyrrolidin-1-yl-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, 2-[3-(isopropylamino)propyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid hydrochloride, 2-(3-amino-3-carboxypropyl)-4,5-dihydro-2H-pyrazolo[3,4-q]isoquinoline-3-carboxylic acid trifluoroacetate, 2-{3-[(aminocarbonyl)amino]propyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid, 9-{[(4-chlorobenzyl)amino]methyl}-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, 4-chloro-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, 7-oxo-2-quinolin-3-yl-5,6,7,8,9,10-hexahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinoline-9-carboxamide, 2-{3-[(methylsulfonyl)amino]propyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, lithium 2-{4-[(2-ethylbutyl)amino]butyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylate, 2-(3-{[(4-methoxyphenyl)acetyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 7-oxo-6,7,8,9,10,11-hexahydro-5H-[11,4]diazepino[1′,2′:1,5]pyrazolo[3,4-f]isoquinoline-9-carbonitrile, 2-{3-[(isopropylsulfonyl)amino]propyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 3-[3-(chloromethyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinolin-2-yl]propan-1-amine hydrochloride, 2-(3,3-dimethylbutyl)-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one trifluoroacetate, 2-thiomorpholin-4-yl-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one trifluoroacetate, ethyl 2-(2-aminoethyl)-8-chloro-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylate, 2-[4-(benzyloxy)phenyl]-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, lithium 2-{2-hydroxy-3-[(thien-2-ylmethyl)amino]propyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylate, 2-(3-amino-3-cyanopropyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-[3-(pyridin-3-ylamino)propyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-[3-({[(ethoxycarbonyl)amino]carbonyl}amino)propyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-{3-[4-(aminocarbonyl)piperidin-1-yl]propyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(4-amino-4-oxobutyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 8-quinolin-3-yl-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline, 2-(3-{[(butylamino)carbonyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 3-(2-furyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline, 4-anilino-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, 8-(3-aminopropyl)-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one dihydrochloride, 2-(3-{[(allylamino)carbonyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-{3-[(2,2,2-trifluoroethyl)amino]propyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 5,6,9,10-tetrahydropyrido[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, 2-{[2-(dimethylamino)ethyl]amino}-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one trifluoroacetate, 2-{2-[(2-ethylbutyl)amino]ethyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid, ethyl 2-(2-aminoethyl)-8-ethynyl-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylate hydrochloride, 2-[2-(4-chlorophenyl)ethyl]-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one trifluoroacetate, 4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid, 2-piperazin-1-yl-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one trifluoroacetate, 2-{3-[(thien-2-ylacetyl)amino]propyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate hydrochloride, 2-[3-(benzoylamino)propyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-[3-(dimethylamino)-2-hydroxypropyl]-N,N-dimethyl-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxamide trifluoroacetate, 2-[(2E)-2-(hydroxyimino)ethyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid, 2-allyl-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid 7-oxide, 2-{3-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]propyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-aminopropyl)-6-(methylthio)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-methylpiperidin-1-yl)-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one trifluoroacetate, 3-(methylthio)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline, 2-(3-aminopropyl)-6-phenyl-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, lithium 2-{3-[4-(aminocarbonyl)piperidin-1-yl]-2-hydroxypropyl}-4,5-d hydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylate, 2-(3-{bis[3-(5-methyl-2-furyl)butyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid dihydrochloride, 2-[4-(benzyloxy)phenyl]-5,6,8,9,10,11-hexahydro-7H-[1,4]diazepino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7-one, 2-(4-chlorobenzyl)-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one trifluoroacetate, 3-(difluoromethyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline, 2-(4-methylpiperazin-1-yl)-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one trifluoroacetate, 2-quinolin-5-yl-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, 3-[3-(1H-tetraazol-5-yl)-4,5-dihydro-1H-pyrazolo[3,4-f]isoquinolin-1-yl]propan-1-amine hydrochloride, 2-(4-tert-butylphenyl)-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-q]isoquinolin-7(8H)-one, 2-[3-(pyridin-4-ylamino)propyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid, 2-[methyl(phenyl)amino]-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one trifluoroacetate, 8-(3-phenylpropyl)-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one trifluoroacetate, 2-propyl-8-quinolin-3-yl-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxamide, 2-[3-(isonicotinoylamino)propyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-{3-[(tert-butoxycarbonyl)amino]propyl}-8-chloro-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid, 2-(3-{[(4-butoxyphenyl)sulfonyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-{[3-(2-furyl)propanoyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate hydrochloride, 2-(4-phenoxyphenyl)-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, 2-allyl-8-quinolin-3-yl-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxamide, 2-(2-cyclohexylethyl)-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one trifluoroacetate, lithium 2-(2-hydroxy-3-morpholin-4-ylpropyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylate, 2-{3-[(pyridin-2-ylcarbonyl)amino]propyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-{[(4-cyanophenyl)sulfonyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, (7E)-5,6,9,10-tetrahydropyrido[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one oxime, 2-hexyl-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one trifluoroacetate, N-methyl-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxamide, 2-[3-(4-aminopiperidin-1-yl)-2-hydroxypropyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid bis(trifluoroacetate), 2-(3-{[(3-methoxyphenyl)sulfonyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-morpholin-4-ylpropyl)-4,5-dihydro-2H-pyrazolo[3,4-q]isoquinoline-3-carboxylic acid, 2-(3-{4-[(tert-butoxycarbonyl)amino]piperidin-1-yl}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 8-methyl-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, methyl 2-(2-hydroxyethyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylate, lithium 2-(2-hydroxy-3-pyrrolidin-1-ylpropyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylate, lithium 2-{2-hydroxy-3-[(2-thien-2-ylethyl)amino]propyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylate, 2-(3-{[(1-methyl-1H-imidazol-4-yl)sulfonyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-[3-({[4-(acetylamino)phenyl]sulfonyl}amino)propyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, [2-(3-aminopropyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinolin-3-yl]methanol hydrochloride, N-(3-aminopropyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxamide dihydrochloride, 2-[3-(2-furoylamino)propyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 8-[2-(2-chlorophenyl)ethyl]-5,6,8,9,10,11-hexahydro-7H-[1,4]diazepino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7-one trifluoroacetate, 5,6,10,11,12,13-hexahydro-7H,9H-8,12-methano[1,4]diazonino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7-one dihydrochloride, 2-{3-[(1,3-benzodioxol-5-ylcarbonyl)amino]propyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(2-hydroxy-3-piperazin-1-ylpropyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid dihydrochloride, 2-[3-(7-oxo-5,6,7,8,9,10-hexahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-10-yl)propyl]-1H-isoindole-1,3(2H)-dione, 2-(3-{4-[3-(dimethylamino)propyl]piperazin-1-yl}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid, 2-[3-(4-methylpiperazin-1-yl)propyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid, 2-(3-piperidin-1-ylpropyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid, 3-[3-(difluoromethyl)-4,5-dihydro-1H-pyrazolo[3,4-f]isoquinolin-1-yl]propan-1-amine hydrochloride, tert-butyl 3-[3-(difluoromethyl)-4,5-dihydro-1H-pyrazolo[3,4-f]isoquinolin-1-yl]propylcarbamate, 3-[3-(difluoromethyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinolin-2-yl]propan-1-amine hydrochloride, tert-butyl 3-[3-(difluoromethyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinolin-2-yl]propylcarbamate, 9-(morpholin-4-ylmethyl)-5,6,9,10-tetrahydro-7H-[1,4]oxazino[4′,3′:1,5]pyrazolo[3,4-f]isoquinolin-7-one, ethyl 2-[1-(aminomethyl)-4-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)butyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylate, 8-(3-phenylpropyl)-5,6,8,9,10,11-hexahydro-7H-[1,4]diazepino[1′,2′-1,5]pyrazolo[3,4-f]isoquinolin-7-one hydrochloride, ethyl 2-[2-(glycoloylamino)ethyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylate trifluoroacetate, 2-{3-[(tert-butoxycarbonyl)amino]propyl}-6-chloro-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid, 4-chloro-5,6,8,9,10,11-hexahydro-7H-[1,4]diazepino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7-one, tert-butyl 3-[3-(1H-tetraazol-5-yl)-4,5-dihydro-1H-pyrazolo[3,4-f]isoquinolin-1-yl]propylcarbamate, tert-butyl 3-[3-(1H-tetraazol-5-yl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinolin-2-yl]propylcarbamate, tert-butyl 3-(3-cyano-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinolin-2-yl)propylcarbamate, 4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carbonitrile, 2-[3-(benzyloxy)propyl]-8-quinolin-3-yl-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxamide, 3-[3-(aminomethyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinolin-2-yl]propan-1-amine hydrochloride, ethyl 2-{2-[(tert-butoxycarbonyl)amino]ethyl}-8-ethynyl-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylate, ethyl 2-{2-[(tert-butoxycarbonyl)amino]ethyl}-8-[(E)-2-(4-methoxyphenyl)ethenyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylate, ethyl 2-{2-[(tert-butoxycarbonyl)amino]ethyl}-8-[(E)-2-(2-fluorophenyl)ethenyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylate, ethyl 2-[(2E)-2-(hydroxyimino)ethyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylate, 2-(3-aminopropyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carbonitrile hydrochloride, 2-(2-phenylethyl)-5,6,9,10-tetrahydropyrazino[1′,2′-: 1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one trifluoroacetate, {2-[(2-methoxyethoxy)methyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinolin-3-yl}methanol, ethyl 2-{2-[(tert-butoxycarbonyl)amino]ethyl}-8-[(E)-2-phenylethenyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylate, ethyl 8-benzyl-2-{2-[(tert-butoxycarbonyl)amino]ethyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylate, ethyl 2-[(2-methoxyethoxy)methyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylate, lithium 2-{2-[(tert-butoxycarbonyl)amino]ethyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylate, ethyl 2-{2-[(tert-butoxycarbonyl)amino]ethyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylate, methyl 2-methyl-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylate, methyl 1-methyl-4,5-dihydro-1H-pyrazolo[3,4-f]isoquinoline-3-carboxylate, 2-[3-(propionylamino)propyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-{3-[(cyclohexylcarbonyl)amino]propyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-{[(1-methyl-1H-pyrrol-2-yl)carbonyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, ethyl 2-(3-bromopropyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylate, 2-allyl-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxamide, 8-(2-oxo-2-thien-3-ylethyl)-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one hydrochloride, methyl 1-(2-hydroxyethyl)-4,5-dihydro-1H-pyrazolo[3,4-f]isoquinoline-3-carboxylate, tert-butyl 3-[3-(methylthio)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinolin-2-yl]propylcarbamate, 3-(4,5-dihydro-2H-pyrazolo[3,4-f]isoquinolin-2-yl)propan-1-amine hydrochloride, 3-[3-(methylthio)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinolin-2-yl]propan-1-amine hydrochloride, ethyl 2-(3-aminopropyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylate hydrochloride, ethyl 2-{3-[(tert-butoxycarbonyl)amino]propyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylate, tert-butyl 7-oxo-6,7,10,11-tetrahydro-5H-[1,4]diazepino[1′,2′:1,5]pyrazolo[3,4-f]isoquinoline-8(9H)-carboxylate, ethyl 2-(3-cyanopropyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylate, 3-(methylsulfonyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline, 2-{4-[bis(2-ethylbutyl)amino]butyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid hydrochloride, ethyl 2-{3-[(4-butoxybenzyl)amino]propyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylate, 2-[3-(4-aminopiperidin-1-yl)propyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, lithium 2-[2-hydroxy-3-(3-oxopiperazin-1-yl)propyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylate, lithium 2-(2-hydroxy-3-piperidin-1-ylpropyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylate, 2-(3-piperazin-1-ylpropyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-carboxypropyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-pyrrolidin-1-ylpropyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid, lithium 2-[2-hydroxy-3-(methylamino)propyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylate, 9-{[(4-aminocyclohexyl)amino]methyl}-5,6,9,10-tetrahydro-7H-[1,4]oxazino[4′, 3′:1,5]pyrazolo[3,4-f]isoquinolin-7-one trifluoroacetate, lithium 2-{3-[(4-aminocyclohexyl)amino]-2-hydroxypropyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylate, ethyl 2-{3-[(2-thien-2-ylethyl)amino]propyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylate trifluoroacetate, 2-{2-[bis(2-ethylbutyl)amino]ethyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid dihydrochloride, 9-{[(2-thien-2-ylethyl)amino]methyl}-5,6,9,10-tetrahydro-7H-[1,4]oxazino[4′, 3′:1,5]pyrazolo[3,4-f]isoquinolin-7-one trifluoroacetate, ethyl 2-[3-amino-4-(benzyloxy)-4-oxobutyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylate bis(trifluoroacetate), ethyl 2-{4-(benzyloxy)-3-[(tert-butoxycarbonyl)amino]-4-oxobutyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylate, 7-oxo-5,6,7,8,9,10-hexahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinoline-9-carboxylic acid, 4-(7-oxo-6,7,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-8(5H)-yl)butanenitrile, 8-(4-aminobutyl)-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one dihydrochloride, ethyl 6-chloro-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylate, ethyl 2-{2-[(tert-butoxycarbonyl)amino]ethyl}-8-chloro-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylate, ethyl 8-chloro-2-{2-[(trifluoroacetyl)amino]ethyl}-4,5-dihydro-2H-pyrazolo[3,4-q]isoquinoline-3-carboxylate, ethyl 8-chloro-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylate, 8-methyl-5,6,8,9,10,11-hexahydro-7H-[1,4]diazepino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7-one, ethyl 2-(3-{[3-(5-methyl-2-furyl)butyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylate trifluoroacetate, N,2-bis(3-aminopropyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxamide dihydrochloride, 2-[3-(benzyloxy)propyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid, 4,5-dihydro-2H-pyrazolo[3,4-f]isoquinolin-3-ylmethanol, ethyl 2-(2-{[3-(2-furyl)propanoyl]amino}ethyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylate, 2-(2-{[3-(2-furyl)propanoyl]amino}ethyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid hydrochloride, 5,6,7,8,9,10-hexahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-9-ylmethanol, 2-chloro-5,6,8,9,10,11-hexahydro-7H-[1,4]diazepino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7-one, 8-{3-[(2-thien-2-ylethyl)amino]propyl}-5,6,8,9,10,11-hexahydro-7H-[1,4]diazepino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7-one dihydrochloride, 9-(aminomethyl)-5,6,8,9,10,11-hexahydro-7H-[1,4]diazepino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7-one, 9-(hydroxymethyl)-8-methyl-5,6,9,10-tetrahydropyrazino[1′,2′-11,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, 4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid, 1-(4,5-dihydro-2H-pyrazolo[3,4-f]isoquinolin-3-yl)-2-methoxyethanone, ethyl 2-allyl-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylate, ethyl 1-allyl-4,5-dihydro-1H-pyrazolo[3,4-f]isoquinoline-3-carboxylate, ethyl 4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylate, ethyl 2-(4-aminobutyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylate, ethyl 2-(oxiran-2-ylmethyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylate, 2,7-bis(3-cyanopropyl)-3-(ethoxycarbonyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinolin-7-ium, lithium 2-[2-hydroxy-3-(1H-imidazol-1-yl)propyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylate, ethyl 2-(3-{[3-(2-furyl)propanoyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylate, ethyl 2-{3-[(thien-2-ylacetyl)amino]propyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylate trifluoroacetate, ethyl 2-[3-(cyclopentylamino)propyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylate, ethyl 2-(2-aminoethyl)-8-chloro-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylate hydrochloride, 2-(3-{[3-(1,1′-biphenyl-4-yl)propyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-{[2-(4′-chloro-1,1′-biphenyl-4-yl)ethyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-{[2-(4-thien-3-ylphenyl)ethyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-{3-[(2-{4-[(E)-2-phenylethenyl]phenyl}ethyl)amino]propyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-{[2-(4′-cyano-1,1′-biphenyl-4-yl)ethyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-[3-({2-[4-(1,3-benzodioxol-5-yl)phenyl]ethyl}amino)propyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-quinolin-3-yl-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, N-(2-hydroxyethyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxamide, 2-(1,1′-biphenyl-4-yl)-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, 2-[3-({[(4-methoxyphenyl)amino]carbonyl}amino)propyl]-8-quinolin-3-yl-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid, {2-[(2-methoxyethoxy)methyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinolin-3-yl}acetonitrile, 2-allyl-8-quinolin-3-yl-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid, 2-[(4-methylphenyl)ethynyl]-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one trifluoroacetate, ethyl 2-(2-aminoethyl)-8-(1H-indol-2-yl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylate, 2-[(E)-2-(3-methoxyphenyl)ethenyl]-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one trifluoroacetate, 2-[(E)-2-(3-hydroxyphenyl)ethenyl]-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one trifluoroacetate, 12593 or 7-oxo-2-quinolin-3-yl-5,6,7,8,9,10-hexahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinoline-9-carbonitrile trifluoroacetate.
16. A pyrimidyl pyrazole MK-2 inhibitor that is selected from the group consisting of: 2-(3-aminopropyl)-8-quinolin-3-yl-4,5-dihydro-2H-pyrazolo[4,3-h]quinazoline-3-carboxylic acid dihydrochloride, 2-(3-aminopropyl)-8-(1,3-benzodioxol-5-yl)-4,5-dihydro-2H-pyrazolo[4,3-h]quinazoline-3-carboxylic acid hydrochloride, 2-(3-aminopropyl)-8-phenyl-4,5-dihydro-2H-pyrazolo[4,3-h]quinazoline-3-carboxylic acid hydrochloride, 2-quinolin-3-yl-5,6,8,9,10,11-hexahydro-7H-[1,4]diazepino[1′,2′:1,5]pyrazolo[4,3-h]quinazolin-7-one, 2-pyridin-3-yl-5,6,8,9,10,11-hexahydro-7H-[1,4]diazepino[1′,2′:1,5]pyrazolo[4,3-h]quinazolin-7-one, 8-quinolin-3-yl-2-[3-(tritylamino)propyl]-4,5-dihydro-2H-pyrazolo[4,3-h]quinazoline-3-carboxylic acid hydrochloride, 2-(1,3-benzodioxol-5-yl)-5,6,8,9,10,11-hexahydro-7H-[1,4]diazepino[1′,2′:1,5]pyrazolo[4,3-h]quinazolin-7-one, 2-(4-methoxyphenyl)-5,6,8,9,10,11-hexahydro-7H-[1,4]diazepino[1′,2′:1,5]pyrazolo[4,3-h]quinazolin-7-one, 2-pyridin-4-yl-5,6,8,9,10,11-hexahydro-7H-[1,4]diazepino[1′,2′:1,5]pyrazolo[4,3-h]quinazolin-7-one hydrochloride, 8-phenyl-2-[3-(tritylamino)propyl]-4,5-dihydro-2H-pyrazolo[4,3-h]quinazoline-3-carboxylic acid, 2-phenyl-5,6,8,9,10,11-hexahydro-7H-[1,4]diazepino[1′,2′:1,5]pyrazolo[4,3-h]quinazolin-7-one, methyl 2-(3-aminopropyl)-8-pyridin-4-yl-4,5-dihydro-2H-pyrazolo[4,3-h]quinazoline-3-carboxylate dihydrochloride, methyl 8-phenyl-2-[3-(tritylamino)propyl]-4,5-dihydro-2H-pyrazolo[4,3-h]quinazoline-3-carboxylate, methyl 2-(3-aminopropyl)-8-(4-methoxyphenyl)-4,5-dihydro-2H-pyrazolo[4,3-h]quinazoline-3-carboxylate dihydrochloride, ethyl 2-(3-aminopropyl)-8-quinolin-3-yl-4,5-dihydro-2H-pyrazolo[4,3-h]quinazoline-3-carboxylate dihydrochloride
17. The cyclic pyrazole MK-2 inhibitor according to claim 1, wherein the MK-2 inhibitor has an MK-2 IC50 of less than 100 and is selected from the group consisting of: 2-(3-aminopropyl)-8-(methylthio)-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylic acid dihydrochloride, 2-(3-aminopropyl)-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylic acid hydrochloride, 2-(3-{[2-(4-bromophenyl)ethyl]amino}propyl)-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylic acid hydrochloride, 2-(2-aminoethyl)-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylic acid hydrochloride, 8-(allylthio)-2-(3-aminopropyl)-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylic acid dihydrochloride, 2-(3-aminopropyl)-8-(benzylthio)-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylic acid dihydrochloride, 2-{3-[(2-thien-2-ylethyl)amino]propyl}-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylic acid, 2-{3-[(2-thien-3-ylethyl)amino]propyl}-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylic acid hydrochloride, ethyl 2-(3-{[2-(4-bromophenyl)ethyl]amino}propyl)-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate, 2-(4-aminobutyl)-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylic acid dihydrochloride, 1-(methylthio)-4,5,7,8,9,10-hexahydro[1,4]diazepino[1,2-b]pyrazolo[3.,4-g]indazol-6(3H)-one, 1-(allylthio)-4,5,7,8,9,10-hexahydro[1,4]diazepino[1,2-b]pyrazolo[3,4-g]indazol-6(3H)-one, 4,5,7,8,9,10-hexahydro[1,4]diazepino[1,2-b]pyrazolo[3,4-g]indazol-6(3H)-one 4,5,8,9-tetrahydro-3H-pyrazino[1,2-b]pyrazolo[3,4-g]indazol-6(7H)-one, 2-allyl-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylic acid hydrochloride, 1-(benzylthio)-4,5,7,8,9,10-hexahydro[1,4]diazepino[1,2-b]pyrazolo[3,4-g]indazol-6(3H)-one, 2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxamide, 8-(methylthio)-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxamide, 1-{1-[(benzyloxy)carbonyl]piperidin-4-yl}-6-trityl-1,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylic acid, ethyl 2-(3-aminopropyl)-8-(methylthio)-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate dihydrochloride, 2-piperidin-4-yl-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylic acid hydrochloride, 1-(2,2,2-trifluoroethyl)-6-trityl-1,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylic acid, 1-(2-hydroxyethyl)-1,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxamide, 1-[4-(aminocarbonyl)phenyl]-1,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxamide (or 1-[4-(aminocarbonyl)phenyl]-1,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxamide), 8-(benzylthio)-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxamide, 1-allyl-1,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxamide, 2-(3-aminopropyl)-8-quinolin-3-yl-4,5-dihydro-2H-pyrazolo[4,3-h]quinazoline-3-carboxylic acid dihydrochloride, 2-(3-aminopropyl)-8-(1,3-benzodioxol-5-yl)-4,5-dihydro-2H-pyrazolo[4,3-h]quinazoline-3-carboxylic acid hydrochloride, 2-(3-aminopropyl)-8-phenyl-4,5-dihydro-2H-pyrazolo[4,3-h]quinazoline-3-carboxylic acid hydrochloride, 2-quinolin-3-yl-5,6,8,9,10,11-hexahydro-7H-[1,4]diazepino[1′,2′:1,5]pyrazolo[4,3-h]quinazolin-7-one, 2-pyridin-3-yl-5,6,8,9,10,11-hexahydro-7H-[1,4]diazepino[1′,2′:1,5]pyrazolo[4,3-h]quinazolin-7-one, 8-quinolin-3-yl-2-[3-(tritylamino)propyl]-4,5-dihydro-2H-pyrazolo[4,3-h]quinazoline-3-carboxylic acid hydrochloride, 2-(1,3-benzodioxol-5-yl)-5,6,8,9,10,11-hexahydro-7H-[1,4]diazepino[1′,2′:1,5]pyrazolo[4,3-h]quinazolin-7-one, 2-(4-methoxyphenyl)-5,6,8,9,10,11-hexahydro-7H-[1,4]diazepino[1′,2′:1,5]pyrazolo[4,3-h]quinazolin-7-one, 2-pyridin-4-yl-5,6,8,9,10,11-hexahydro-7H-[1,4]diazepino[1′,2′:1,5]pyrazolo[4,3-h]quinazolin-7-one hydrochloride, 8-phenyl-2-[3-(tritylamino)propyl]-4,5-dihydro-2H-pyrazolo[4,3-h]quinazoline-3-carboxylic acid, 2-phenyl-5,6,8,9,10,11-hexahydro-7H-[1,4]diazepino[1′,2′:1,5]pyrazolo[4,3-h]quinazolin-7-one, 2-(3-aminopropyl)-8-quinolin-3-yl-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-aminopropyl)-8-(3-nitrophenyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-aminopropyl)-8-(4-hydroxyphenyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid hydrobromide, 2-(3-aminopropyl)-8-(3-hydroxyphenyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid hydrobromide, 2-(3-aminopropyl)-8-(2-naphthyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-aminopropyl)-8-(3,5-difluorophenyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-aminopropyl)-8-(1,3-benzodioxol-5-yl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-aminopropyl)-8-(3-cyanophenyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 9-(hydroxymethyl)-2-quinolin-3-yl-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one trifluoroacetate, 2-(3-aminopropyl)-8-(4-methoxyphenyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-aminopropyl)-8-[3-(methylsulfonyl)phenyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-aminopropyl)-8-[3-(trifluoromethyl)phenyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(1H-imidazol-1-yl)-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one trifluoroacetate, 2-(3-aminopropyl)-8-(3-methoxyphenyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-aminopropyl)-8-[4-(trifluoromethyl)phenyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-aminopropyl)-8-anilino-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid, 2-(3-aminopropyl)-8-(3,4-difluorophenyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-{[2-(4′-carboxy-1,1′-biphenyl-4-yl)ethyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(4-hydroxyphenyl)-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one trifluoroacetate, 2-propyl-8-quinolin-3-yl-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid, 2-[3-({2-[3′-(trifluoromethyl)-1,1′-biphenyl-4-yl]ethyl}amino)propyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-aminopropyl)-8-(4-tert-butylphenyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-[3-({2-[4-(3-furyl)phenyl]ethyl}amino)propyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-{[2-(3′-chloro-1,1′-biphenyl-4-yl)ethyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(4-methoxyphenyl)-5,6,8,9,10,11-hexahydro-7H-[1,4]diazepino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7-one, 2-[3-({2-[4′-(trifluoromethyl)-1,1′-biphenyl-4-yl]ethyl}amino)propyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-hydroxyphenyl)-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, 2-(3-aminopropyl)-N-hydroxy-8-quinolin-3-yl-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxamide hydrochloride, 2-[(E)-2-(4-hydroxyphenyl)ethenyl]-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one trifluoroacetate, 2-quinolin-3-yl-5,6,8,9,10,11-hexahydro-7H-[1,4]diazepino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7-one, 2-(4-hydroxyphenyl)-5,6,8,9,10,11-hexahydro-7H-[1,4]diazepino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7-one, 2-(3-{[2-(2′-chloro-1,1′-biphenyl-4-yl)ethyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-{[2-(4′-tert-butyl-1,1′-biphenyl-4-yl)ethyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-{[2-(3,4-dichlorophenyl)ethyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-{[3-(3-chlorophenyl)propyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-[(E)-2-phenylethenyl]-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one trifluoroacetate, 2-(3-{[2-(4-pyridin-4-ylphenyl)ethyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-{[3-(4-bromophenyl)propyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-{[3-(4-tert-butylphenyl)propyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-{[2-(3′-isopropyl-1,1′-biphenyl-4-yl)ethyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-{3-[(2-thien-2-ylethyl)amino]propyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-[4-(dimethylamino)phenyl]-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, 2-(3-{[2-(1,1′-biphenyl-4-yl)ethyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-methoxyphenyl)-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, 2-(3-{[2-(4-bromophenyl)ethyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-{[2-(2,4-dichlorophenyl)ethyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-q]isoquinoline-3-carboxylic acid trifluoroacetate, 2-{3-[(benzylsulfonyl)amino]propyl}-8-quinolin-3-yl-4,5-dihydro-2H--pyrazolo[3,4-f]isoquinoline-3-carboxylic acid, 9-(aminomethyl)-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one trifluoroacetate, 2-(3-nitrophenyl)-5,6,8,9,10,11-hexahydro-7H-[1,4]diazepino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7-one, 2-(3-aminopropyl)-8-quinolin-3-yl-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxamide hydrochloride, 2-(3-{[3-(4-chlorophenyl)propyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-[3-(dimethylamino)phenyl]-5,6,8,9,10,11-hexahydro-7H-[1,4]diazepino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7-one, 2-(3-{[(4-chlorobenzyl)sulfonyl]amino}propyl)-8-quinolin-3-yl-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid, 2-(3-{[2-(4-pyridin-3-ylphenyl)ethyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-{[2-(4-chlorophenyl)ethyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-{[2-(5-chlorothien-2-yl)ethyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-{[3-(4-cyanophenylypropyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-{[3-(5-methyl-2-furyl)butyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-[3-({2-[4-(1-benzothien-3-yl)phenyl]ethyl}amino)propyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-ammoniopropyl)-3-carboxy-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinolin-7-ium dichloride, 2-(4-methoxyphenyl)-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, 2-(3-{[3-(4-acetylphenyl)propyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-aminopropyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-[3-({3-[4-(methylsulfonyl)phenyl]propyl}amino)propyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-aminopropyl)-8-(2-methoxyphenyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-[3-({2-[3′-(aminomethyl)-1,1′-biphenyl-4-yl]ethyl}amino)propyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(2-aminoethyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid dihydrochloride, 2-(3-{[2-(4-nitrophenyl)ethyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-[3-({2-[2′-(trifluoromethyl)-1,1′-biphenyl-4-yl]ethyl}amino)propyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 9-(hydroxymethyl)-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, 2-(3-{[2-(4-methylphenyl)ethyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 9-{[(2-thien-2-ylethyl)amino]methyl}-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, 2-(3-{[2-(4-ethoxyphenyl)ethyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(1,3-benzodioxol-5-yl)-5,6,8,9,10,11-hexahydro-7H-[1,4]diazepino[1′,2′-: 1,5]pyrazolo[3,4-f]isoquinolin-7-one, 2-(3-{[2-(4-methoxyphenyl)ethyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 3-[3-(1H-tetraazol-5-yl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinolin-2-yl]propan-1-amine hydrochloride, 2-(3-aminopropyl)-8-chloro-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-{[(1R,2S)-2-phenylcyclopropyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-{3-[(3,3-diphenylpropyl)amino]propyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-{[2-(3-bromo-4-methoxyphenyl)ethyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-{3-[(4-phenylbutyl)amino]propyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-[3-(2,3-dihydro-1H-inden-2-ylamino)propyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(2-naphthyl)-5,6,8,9,10,11-hexahydro-7H-[1,4]diazepino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7-one, 2-{3-[(3-phenylpropyl)amino]propyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-{[2-(4-fluorophenyl)ethyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-{3-[(2-thien-3-ylethyl)amino]propyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid dihydrochloride, 5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, 2-[3-(glycoloylamino)propyl]-8-quinolin-3-yl-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid hydrochloride, 8-quinolin-3-yl-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid, 2-(3-{[2-(4-ethylphenyl)ethyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-{[2-(2-chlorophenyl)ethyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-{3-[(2-ethylbutyl)amino]propyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 8-quinolin-3-yl-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxamide, 2-{3-[(2-pyridin-4-ylethyl)amino]propyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-{[2-(4-chlorophenyl)propyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-{[2-(3-chlorophenyl)ethyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-[3-(glycoloylamino)propyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-{[2-(3,4-dimethoxyphenyl)ethyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(1-benzofuran-2-yl)-5,6,8,9,0,11-hexahydro-7H-[1,4]diazepino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7-one, 2-(3-{[4-(2-aminoethyl)phenyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(1-naphthyl)-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, 8-(3-aminopropyl)-5,6,8,9,10,11-hexahydro-7H-[1,4]diazepino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7-one dihydrochloride, 2-anilino-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, 2-(3-aminopropyl)-8-[2-(trifluoromethyl)phenyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 9-(azidomethyl)-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, 9-({[2-(4-chlorophenyl)ethyl]amino}methyl)-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, 2-phenyl-5,6,8,9,10,11-hexahydro-7H-[1,4]diazepino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7-one, 2-[3-(pentylamino)propyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 10-(2-aminoethyl)-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, 2-[3-(allylamino)propyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(4-aminobutyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid dihydrochloride, 2-(3-{[2-(4-aminophenyl)ethyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-[(1E)-3,3-dimethylbut-1-enyl]-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one trifluoroacetate, 10-(nitromethyl)-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, 3-carboxy-2-[3-(methylammonio)propyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinolin-7-ium dichloride, 2-[3-({[(4-butoxyphenyl)amino]carbonyl}amino)propyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid, 2-{3-[(2-pyridin-3-ylethyl)amino]propyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-{3-[(2-pyridin-2-ylethyl)amino]propyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-{3-[(cyclopropylmethylamino]propyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-{3-[(2-thien-2-ylpropyl)amino]propyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-methoxy-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, 2-[3-(dimethylamino)phenyl]-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, 2-(3-{[2-(1H-pyrrol-1-yl)ethyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-[3-(benzyloxy)propyl]-8-quinolin-3-yl-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid, 2-{3-[(4-butoxybenzyl)amino]propyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(1,3-benzodioxol-5-yl)-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, 2-[(E)-2-(2-fluorophenyl)ethenyl]-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, 2-[(1E)-hex-1-enyl]-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one trifluoroacetate, 2-anilino-5,6,8,9,10,11-hexahydro-7H-[1,4]diazepino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7-one, 5,6,8,9,10,11-hexahydro-7H-[1,4]diazepino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7-one, 2-chloro-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, 2-[(E)-2-(4-methoxyphenyl)ethenyl]-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, 2-(methylthio)-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, 2-{3-[(2-furylmethyl)amino]propyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-azepan-1-yl-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one trifluoroacetate, 2-(3,6-dihydropyridin-1 (2H)-yl)-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one trifluoroacetate, 9-methyl-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, 2-(piperidin-3-ylmethyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid hydrochloride, 9-(chloromethyl)-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, 2-[(4-methoxybenzyl)amino]-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one trifluoroacetate, 2-(3-{[2-(1H-imidazol-4-yl)ethyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(benzylamino)-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one trifluoroacetate, 2-(methylthio)-5,6,8,9,10,11-hexahydro-7H-[1,4]diazepino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7-one, 2-{3-[(2-chlorobenzyl)amino]propyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-[3-(benzylamino)propyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-[3-({[(4-methoxyphenyl)amino]carbonyl}amino)propyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic-acid, 2-{3-[(2-phenylethyl)amino]propyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-{3-[(thien-2-ylmethyl)amino]propyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-benzyl-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, 5,6,8,9,10,11-hexahydro-7H-[1,4]diazepino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7-one, 2-{3-[(4-chlorobenzyl)amino]propyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-{3-[(2-phenylpropyl)amino]propyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 7-oxo-5,6,7,8,9,10-hexahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinoline-9-carboxamide trifluoroacetate, 2-(3-hydroxypropyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid, 2-(1,3-dihydro-2H-isoindol-2-yl)-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one trifluoroacetate, 2-{3-[(4-aminophenyl)amino]propyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(4-hydroxypiperidin-1-yl)-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one trifluoroacetate, 2-{3-[(1H-imidazol-5-ylmethyl)amino]propyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-{3-[(3-chlorobenzyl)amino]propyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-{3-[(pyridin-3-ylcarbonyl)amino]propyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxamide, 2-[3-(cyclopentylamino)propyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid dihydrochloride, 2-(3-{[2-(1H-indol-3-yl)ethyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid, 10-(3-aminopropyl)-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, 9-(1,2-dihydroxyethyl)-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, 2-morpholin-4-yl-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one trifluoroacetate, ethyl 2-(2-aminoethyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylate dihydrochloride, 2-allyl-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid, 2-quinolin-8-yl-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, lithium 2-[3-(2,3-dihydro-1H-inden-2-ylamino)-2-hydroxypropyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylate, 2-(2-hydroxyethyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid, 2-{3-[(2-pyrrolidin-1-ylethyl)amino]propyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3,4-dihydroisoquinolin-2(1H)-yl)-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one trifluoroacetate, 2-(3-{[(benzylamino)carbonyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid, 2-[3-(dimethylamino)propyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 10-(3-{[2-(4-chlorophenyl)ethyl]amino}propyl)-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, 2-(3-aminopropyl)-6-chloro-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, methyl 7-oxo-5,6,7,8,9,10-hexahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinoline-9-carboxylate, 2-[2-(glycoloylamino)ethyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid hydrochloride, 2-[2-(isopropylamino)ethyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid hydrochloride, 2-(3-cyanopropyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid, 2-[3-({[(3-cyanophenyl)amino]carbonyl}amino)propyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid, 9-(aminomethyl)-5,6,9,10-tetrahydro-7H-[1,4]oxazino[4′,3′:1,5]pyrazolo[3,4-f]isoquinolin-7-one trifluoroacetate, 4-methyl-5,6,8,9,10,11-hexahydro-7H-[1,4]diazepino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7-one trifluoroacetate, 2-propyl-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid, 2-(3-bromopropyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-pyrrolidin-1-yl-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, 2-[3-(isopropylamino)propyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid hydrochloride, 2-(3-amino-3-carboxypropyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-{3-[(aminocarbonyl)amino]propyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid, 9-{[(4-chlorobenzyl)amino]methyl}-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, 4-chloro-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, 7-oxo-2-quinolin-3-yl-5,6,7,8,9,10-hexahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinoline-9-carboxamide, 2-{3-[(methylsulfonyl)amino]propyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, lithium 2-{4-[(2-ethylbutyl)amino]butyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylate, 2-(3-{[(4-methoxyphenyl)acetyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 7-oxo-6,7,8,9,10,11-hexahydro-5H-[1,4]diazepino[1′,2′:1,5]pyrazolo[3,4-f]isoquinoline-9-carbonitrile, 2-{3-[(isopropylsulfonyl)amino]propyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 3-[3-(chloromethyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinolin-2-yl]propan-1-amine hydrochloride, 2-(3,3-dimethylbutyl)-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one trifluoroacetate, 2-thiomorpholin-4-yl-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one trifluoroacetate, ethyl 2-(2-aminoethyl)-8-chloro-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylate, 2-[4-(benzyloxy)phenyl]-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one-lithium 2-{2-hydroxy-3-[(thien-2-ylmethyl)amino]propyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylate, 2-(3-amino-3-cyanopropyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-[3-(pyridin-3-ylamino)propyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-[3-({[(ethoxycarbonyl)amino]carbonyl}amino)propyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-{3-[4-(aminocarbonyl)piperidin-1-yl]propyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(4-amino-4-oxobutyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 8-quinolin-3-yl-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline, 2-(3-{[(butylamino)carbonyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 3-(2-furyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline, 4-anilino-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, 8-(3-aminopropyl)-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one dihydrochloride, 2-(3-{[(allylamino)carbonyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-{3-[(2,2,2-trifluoroethyl)amino]propyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 5,6,9,10-tetrahydropyrido[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, 2-{[2-(dimethylamino)ethyl]amino}-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one trifluoroacetate, 2-{2-[(2-ethylbutyl)amino]ethyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid, ethyl 2-(2-aminoethyl)-8-ethynyl-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylate hydrochloride, 2-[2-(4-chlorophenyl)ethyl]-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one trifluoroacetate, 4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid, 2-piperazin-1-yl-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one trifluoroacetate, 2-{3-[(thien-2-ylacetyl)amino]propyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate hydrochloride, 2-[3-(benzoylamino)propyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-[3-(dimethylamino)-2-hydroxypropyl]-N,N-dimethyl-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxamide trifluoroacetate, 2-[(2E)-2-(hydroxyimino)ethyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid, 2-allyl-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid 7-oxide, 2-{3-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]propyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-aminopropyl)-6-(methylthio)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-methylpiperidin-1-yl)-5,6,9,10-tetrahydropyrazino[1′,2′-: 1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one trifluoroacetate, 3-(methylthio)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline, 2-(3-aminopropyl)-6-phenyl-4,5-dihydro-2H-pyrazolo[3,4-q]isoquinoline-3-carboxylic acid trifluoroacetate, lithium 2-{3-[4-(aminocarbonyl)piperidin-1-yl]-2-hydroxypropyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylate, 2-(3-{bis[3-(5-methyl-2-furyl)butyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid dihydrochloride, 2-[4-(benzyloxy)phenyl]-5,6,8,9,10,11-hexahydro-7H-[1,4]diazepino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7-one, 2-(4-chlorobenzyl)-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one trifluoroacetate, 3-(difluoromethyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline, 2-(4-methylpiperazin-1-yl)-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one trifluoroacetate, 2-quinolin-5-yl-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, 2-(3-aminopropyl)-7-hydroxy-8-(3-nitrophenyl)-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid trifluoroacetate, 2-(2-aminoethyl)-7-hydroxy-8-(3-nitrophenyl)-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid trifluoroacetate, 3-hydroxy-2-(3-nitrophenyl)-5,6,8,9,10,11-hexahydro-7H-benzo[g][1,4]diazepino[1,2-b]indazol-7-one trifluoroacetate, 2-(3-aminopropyl)-7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid dihydrochloride, 2-(2-aminoethyl)-8-bromo-7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid trifluoroacetate, 2-(3-aminopropyl)-8-[2-(4-chlorophenyl)ethyl]-7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid trifluoroacetate, 3-hydroxy-2-(3-nitrophenyl)-5,6,9,10-tetrahydrobenzo[g]pyrazino[1,2-b]indazol-7(8H)-one hydrobromide, 2-(3-aminopropyl)-8-bromo-7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid hydrobromide, 2-(3-aminopropyl)-7-hydroxy-8-(4-nitrophenyl)-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid trifluoroacetate, 2-(3-aminopropyl)-8-(3-cyanophenyl)-7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid trifluoroacetate, 2-(3-aminopropyl)-7-hydroxy-8-[3-(trifluoromethyl)phenyl]-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid trifluoroacetate, 2-(3-aminopropyl)-7-hydroxy-8-(3,3,3-trifluoropropyl)-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid trifluoroacetate, 2-(3-aminopropyl)-8-(3-chlorophenyl)-7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid trifluoroacetate, 2-(3-aminopropyl)-7-hydroxy-5-methyl-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid trifluoroacetate, 2-(3-aminopropyl)-8-(4-chlorophenyl)-7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid trifluoroacetate, 2-(3-aminopropyl)-7-hydroxy-8-[3-(methylsulfonyl)phenyl]-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid trifluoroacetate, 2-(3-aminopropyl)-8-(3,4-difluorophenyl)-7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid trifluoroacetate, 3-hydroxy-5,6,8,9,10,11-hexahydro-7H-benzo[g][1,4]diazepino[1,2-b]indazol-7-one, 8-(3-aminophenyl)-2-(3-aminopropyl)-7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid trifluoroacetate, 6-bromo-7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxamide, 2-(3-aminopropyl)-7-hydroxy-8-[4-(methylamino)phenyl]-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid trifluoroacetate, 2-(3-aminopropyl)-8-(4-tert-butylphenyl)-7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid trifluoroacetate, 2-(3-aminopropyl)-7-hydroxy-8-pyridin-4-yl-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid trifluoroacetate, 7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid, 2-(3-aminopropyl)-7-hydroxy-8-isobutyl-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid trifluoroacetate, 2-(3-aminopropyl)-8-(4-carboxy-3,3-dimethylbutyl)-7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid trifluoroacetate, 8-amino-2-(3-aminopropyl)-7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid, 7,8-dihydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid, 2-(3-aminopropyl)-8-benzyl-7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid trifluoroacetate, 2-(3-aminopropyl)-8-(2-chlorophenyl)-7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid trifluoroacetate, 2-allyl-7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid, 2-{3-[(tert-butoxycarbonyl)amino]propyl}-7-methoxy-8-(4-nitrophenyl)-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid, 7-hydroxy-2-methyl-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid, 2-(3-aminopropyl)-8-(sec-butylamino)-7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid, 2-(3-aminopropyl)-8-(3-carboxyphenyl)-7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid trifluoroacetate, 2-{3-[(tert-butoxycarbonyl)amino]propyl}-7-methoxy-8-(3-nitrophenyl)-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid, 2-{3-[(tert-butoxycarbonyl)amino]propyl}-8-(3-cyanophenyl)-7-methoxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid, 7-hydroxy-1-methyl-4,5-dihydro-1H-benzo[g]indazole-3-carboxylic acid, 2-{3-[(tert-butoxycarbonyl)amino]propyl}-8-[2-(4-chlorophenyl)ethyl]-7-methoxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid, 2-{3-[(tert-butoxycarbonyl)amino]propyl}-7-methoxy-8-[3-(trifluoromethyl)phenyl]-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid, 2-{3-[(tert-butoxycarbonyl)amino]propyl}-8-(4-tert-butylphenyl)-7-methoxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid, 2-(3-aminopropyl)-6-chloro-7-hydroxy-8-(3-nitrophenyl)-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid, 2-{2-[(tert-butoxycarbonyl)amino]ethyl}-7-methoxy-8-(3-nitrophenyl)-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid, 2-amino-3-hydroxy-5,6,8,9,10,11-hexahydro-7H-benzo[g][1,4]diazepino[1,2-b]indazol-7-one trifluoroacetate, 2-{3-[(tert-butoxycarbonyl)amino]propyl}-8-(3,4-difluorophenyl)-7-methoxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid, methyl 8-[(dimethylamino)sulfonyl]-7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylate, 7-hydroxy-5-methyl-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid, and 2-{3-[(tert-butoxycarbonyl)amino]propyl}-8-(4-chlorophenyl)-7-methoxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid.
18. The cyclic pyrazole MK-2 inhibitor according to claim 1, wherein the MK-2 inhibitor has an MK-2 IC50 of less than 50 and is selected from the group consisting of: 2-(3-aminopropyl)-8-(methylthio)-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylic acid dihydrochloride, 2-(3-aminopropyl)-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylic acid hydrochloride, 2-(3-{[2-(4-bromophenyl)ethyl]amino}propyl)-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylic acid hydrochloride, 2-(2-aminoethyl)-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylic acid hydrochloride, 8-(allylthio)-2-(3-aminopropyl)-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylic acid dihydrochloride, 2-(3-aminopropyl)-8-(benzylthio)-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylic acid dihydrochloride, 2-{3-[(2-thien-2-ylethyl)amino]propyl}-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylic acid, 2-{3-[(2-thien-3-ylethyl)amino]propyl}-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylic acid hydrochloride, ethyl 2-(3-{[2-(4-bromophenyl)ethyl]amino}propyl)-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate, 2-(4-aminobutyl)-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylic acid dihydrochloride, 1-(methylthio)-4,5,7,8,9,10-hexahydro[1,4]diazepino[1,2-b]pyrazolo[3,4-g]indazol-6(3H)-one, 1-(allylthio)-4,5,7,8,9,10-hexahydro[1,4]diazepino[1,2-b]pyrazolo[3,4-g]indazol-6(3H)-one, 4,5,7,8,9,10-hexahydro[1,4]diazepino[1,2-b]pyrazolo[3,4-g]indazol-6(3H)-one, 4,5,8,9-tetrahydro-3H-pyrazino[1,2-b]pyrazolo[3,4-g]indazol-6(7H)-one, 2-allyl-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylic acid hydrochloride, 1-(benzylthio)-4,5,7,8,9,10-hexahydro[1,4]diazepino[1,2-b]pyrazolo[3,4-g]indazol-6(3H)-one, 2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxamide, 8-(methylthio)-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxamide, 1-{1-[(benzyloxy)carbonyl]piperidin-4-yl}-6-trityl-1,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylic acid, 2-(3-aminopropyl)-8-quinolin-3-yl-4,5-dihydro-2H-pyrazolo[4,3-h]quinazoline-3-carboxylic acid dihydrochloride, 2-(3-aminopropyl)-8-(1,3-benzodioxol-5-yl)-4,5-dihydro-2H-pyrazolo[4,3-h]quinazoline-3-carboxylic acid hydrochloride, 2-(3-aminopropyl)-8-phenyl-4,5-dihydro-2H-pyrazolo[4,3-h]quinazoline-3-carboxylic acid hydrochloride, 2-quinolin-3-yl-5,6,8,9,10,1-hexahydro-7H-[1,4]diazepino[1′,2′:1,5]pyrazolo[4,3-h]quinazolin-7-one, 2-pyridin-3-yl-5,6,8,9,10,11-hexahydro-7H-[1,4]diazepino[1′,2′:1,5]pyrazolo[4,3-h]quinazolin-7-one, 8-quinolin-3-yl-2-[3-(tritylamino)propyl]-4,5-dihydro-2H-pyrazolo[4,3-h]quinazoline-3-carboxylic acid hydrochloride, 2-(1,3-benzodioxol-5-yl)-5,6,8,9,10,11-hexahydro-7H-[1,4]diazepino[1′,2′:1,5]pyrazolo[4,3-h]quinazolin-7-one, 2-(4-methoxyphenyl)-5,6,8,9,10,11-hexahydro-7H-[1,4]diazepino[1′,2′:1,5]pyrazolo[4,3-h]quinazolin-7-one, 2-pyridin-4-yl-5,6,8,9,10,11-hexahydro-7H-[1,4]diazepino[1′,2′:1,5]pyrazolo[4,3-h]quinazolin-7-one hydrochloride, 2-(3-aminopropyl)-8-quinolin-3-yl-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-aminopropyl)-8-(3-nitrophenyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-aminopropyl)-8-(4-hydroxyphenyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid hydrobromide, 2-(3-aminopropyl)-8-(3-hydroxyphenyl)-4,5-dihydro-2H-pyrazolo[3,4-q]isoquinoline-3-carboxylic acid hydrobromide, 2-(3-aminopropyl)-8-(2-naphthyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-aminopropyl)-8-(3,5-difluorophenyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-aminopropyl)-8-(1,3-benzodioxol-5-yl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-aminopropyl)-8-(3-cyanophenyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 9-(hydroxymethyl)-2-quinolin-3-yl-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one trifluoroacetate, 2-(3-aminopropyl)-8-(4-methoxyphenyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-aminopropyl)-8-[3-(methylsulfonyl)phenyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-aminopropyl)-8-[3-(trifluoromethyl)phenyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(1H-imidazol-1-yl)-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one trifluoroacetate, 2-(3-aminopropyl)-8-(3-methoxyphenyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-aminopropyl)-8-[4-(trifluoromethyl)phenyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-aminopropyl)-8-anilino-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid, 2-(3-aminopropyl)-8-(3,4-difluorophenyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-{[2-(4′-carboxy-1,1′-biphenyl-4-yl)ethyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(4-hydroxyphenyl)-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one trifluoroacetate, 2-propyl-8-quinolin-3-yl-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid, 2-[3-({2-[3′-(trifluoromethyl)-1,1′-biphenyl-4-yl]ethyl}amino)propyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-aminopropyl)-8-(4-tert-butylphenyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-[3-({2-[4-(3-furyl)phenyl]ethyl}amino)propyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-{[2-(3′-chloro-1,1′-biphenyl-4-yl)ethyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(4-methoxyphenyl)-5,6,8,9,10,11-hexahydro-7H-[1,4]diazepino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7-one, 2-[3-({2-[4′-(trifluoromethyl)-1,1′-biphenyl-4-yl]ethyl}amino)propyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-hydroxyphenyl)-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, 2-(3-aminopropyl)-N-hydroxy-8-quinolin-3-yl-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxamide hydrochloride, 2-[(E)-2-(4-hydroxyphenyl)ethenyl]-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one trifluoroacetate, 2-quinolin-3-yl-5,6,8,9,10,11-hexahydro-7H-[1,4]diazepino[1′,2′-: 1,5]pyrazolo[3,4-f]isoquinolin-7-one, 2-(4-hydroxyphenyl)-5,6,8,9,10,11-hexahydro-7H-[1,4]diazepino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7-one, 2-(3-{[2-(2′-chloro-1,1′-biphenyl-4-yl)ethyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-{[2-(4′-tert-butyl-1,1′-biphenyl-4-yl)ethyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-{[2-(3,4-dichlorophenyl)ethyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-25 f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-{[3-(3-chlorophenyl)propyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-[(E)-2-phenylethenyl]-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one trifluoroacetate, 2-(3-{[2-(4-pyridin-4-ylphenyl)ethyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-{[3-(4-bromophenyl)propyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-{[3-(4-tert-butylphenyl)propyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-{[2-(3′-isopropyl-1,1′-biphenyl-4-yl)ethyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-{3-[(2-thien-2-ylethyl)amino]propyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-[4-(dimethylamino)phenyl]-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, 2-(3-{[2-(1,1′-biphenyl-4-yl)ethyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-methoxyphenyl)-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, 2-(3-{[2-(4-bromophenyl)ethyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-{[2-(2,4-dichlorophenyl)ethyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-{3-[(benzylsulfonyl)amino]propyl}-8-quinolin-3-yl-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid, 9-(aminomethyl)-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one trifluoroacetate, 2-(3-nitrophenyl)-5,6,8,9,10,11-hexahydro-7H-[1,4]diazepino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7-one, 2-(3-aminopropyl)-8-quinolin-3-yl-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxamide hydrochloride, 2-(3-{[3-(4-chlorophenyl)propyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-[3-(dimethylamino)phenyl]-5,6,8,9,10,11-hexahydro-7H-[1,4]diazepino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7-one, 2-(3-{[(4-chlorobenzyl)sulfonyl]amino}propyl)-8-quinolin-3-yl-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid, 2-(3-{[2-(4-pyridin-3-ylphenyl)ethyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-{[2-(4-chlorophenyl)ethyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-{[2-(5-chlorothien-2-yl)ethyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-{[3-(4-cyanophenyl)propyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-{[3-(5-methyl-2-furyl)butyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-[3-({2-[4-(1-benzothien-3-yl)phenyl]ethyl}amino)propyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-ammoniopropyl)-3-carboxy-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinolin-7-ium dichloride, 2-(4-methoxyphenyl)-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, 2-(3-{[3-(4-acetylphenyl)propyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-aminopropyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-[3-({3-[4-(methylsulfonyl)phenyl]propyl}amino)propyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-aminopropyl)-8-(2-methoxyphenyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-[3-({2-[3′-(aminomethyl)-1,1′-biphenyl-4-yl]ethyl}amino)propyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(2-aminoethyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid dihydrochloride, 2-(3-{[2-(4-nitrophenyl)ethyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-[3-({2-[2′-(trifluoromethyl)-1,1′-biphenyl-4-yl]ethyl}amino)propyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 9-(hydroxymethyl)-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, 2-(3-{[2-(4-methylphenyl)ethyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 9-{[(2-thien-2-ylethyl)amino]methyl}-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, 2-(3-{[2-(4-ethoxyphenyl)ethyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(1,3-benzodioxol-5-yl)-5,6,8,9,10,11-hexahydro-7H-[1,4]diazepino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7-one, 2-(3-{[2-(4-methoxyphenyl)ethyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 3-[3-(1H-tetraazol-5-yl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinolin-2-yl]propan-1-amine hydrochloride, 2-(3-aminopropyl)-8-chloro-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-{[(1R,2S)-2-phenylcyclopropyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-{3-[(3,3-diphenylpropyl)amino]propyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-{[2-(3-bromo-4-methoxyphenyl)ethyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-{3-[(4-phenylbutyl)amino]propyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-[3-(2,3-dihydro-1H-inden-2-ylamino)propyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(2-naphthyl)-5,6,8,9,10,11-hexahydro-7H-[1,4]diazepino[1′,2′-: 1,5]pyrazolo[3,4-f]isoquinolin-7-one, 2-{3-[(3-phenylpropyl)amino]propyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-{[2-(4-fluorophenyl)ethyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-{3-[(2-thien-3-ylethyl)amino]propyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid dihydrochloride, 5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, 2-[3-(glycoloylamino)propyl]-8-quinolin-3-yl-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid hydrochloride, 8-quinolin-3-yl-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid, 2-(3-{[2-(4-ethylphenyl)ethyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-{[2-(2-chlorophenyl)ethyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-{3-[(2-ethylbutyl)amino]propyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 8-quinolin-3-yl-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxamide, 2-{3-[(2-pyridin-4-ylethyl)amino]propyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-{[2-(4-chlorophenyl)propyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-{[2-(3-chlorophenyl)ethyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-[3-(glycoloylamino)propyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-{[2-(3,4-dimethoxyphenyl)ethyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(1-benzofuran-2-yl)-5,6,8,9,10,11-hexahydro-7H-[1,4]diazepino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7-one, 2-(3-{[4-(2-aminoethyl)phenyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(1-naphthyl)-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, 8-(3-aminopropyl)-5,6,8,9,10,1,1-hexahydro-7H-[1,4]diazepino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7-one dihydrochloride, 2-anilino-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, 2-(3-aminopropyl)-8-[2-(trifluoromethyl)phenyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 9-(azidomethyl)-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, 9-({[2-(4-chlorophenyl)ethyl]amino}methyl)-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, 2-phenyl-5,6,8,9,10,11-hexahydro-7H-[1,4]diazepino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7-one, 2-[3-(pentylamino)propyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 10-(2-aminoethyl)-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, 2-[3-(allylamino)propyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(4-aminobutyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid dihydrochloride, 2-(3-{[2-(4-aminophenyl)ethyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-[(1E)-3,3-dimethylbut-1-enyl]-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one trifluoroacetate, 10-(nitromethyl)-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, 3-carboxy-2-[3-(methylammonio)propyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinolin-7-ium dichloride, 2-[3-({[(4-butoxyphenyl)amino]carbonyl}amino)propyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid, 2-{3-[(2-pyridin-3-ylethyl)amino]propyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-{3-[(2-pyridin-2-ylethyl)amino]propyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-{3-[(cyclopropylmethyl)amino]propyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-{3-[(2-thien-2-ylpropyl)amino]propyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-methoxy-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, 2-[3-(dimethylamino)phenyl]-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, 2-(3-{[2-(1H-pyrrol-1-yl)ethyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-[3-(benzyloxy)propyl]-8-quinolin-3-yl-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid, 2-{3-[(4-butoxybenzyl)amino]propyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(1,3-benzodioxol-5-yl)-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, 2-[(E)-2-(2-fluorophenyl)ethenyl]-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, 2-[(1E)-hex-1-enyl]-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one trifluoroacetate, 2-anilino-5,6,8,9,10,11-hexahydro-7H-[1,4]diazepino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7-one, 5,6,8,9,10,11-hexahydro-7H-[1,4]diazepino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7-one, 2-chloro-5,6,9,10-tetrahydropyrazino[1′,2′:1,]pyrazolo[3,4-f]isoquinolin-7(8H)-one, 2-[(E)-2-(4-methoxyphenyl)ethenyl]-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, 2-(methylthio)-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, 2-{3-[(2-furylmethyl)amino]propyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-azepan-1-yl-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one trifluoroacetate, 2-(3,6-dihydropyridin-1 (2H)-yl)-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one trifluoroacetate, 9-methyl-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, 2-(piperidin-3-ylmethyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid hydrochloride, 9-(chloromethyl)-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, 2-[(4-methoxybenzyl)amino]-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one trifluoroacetate, 2-(3-{[2-(1H-imidazol-4-yl)ethyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(benzylamino)-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one trifluoroacetate, 2-(methylthio)-5,6,8,9,10,11-hexahydro-7H-[1,4]diazepino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7-one, 2-{3-[(2-chlorobenzyl)amino]propyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-[3-(benzylamino)propyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-[3-({[(4-methoxyphenyl)amino]carbonyl}amino)propyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid, 2-{3-[(2-phenylethyl)amino]propyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-{3-[(thien-2-ylmethyl)amino]propyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-benzyl-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, 5,6,8,9,10,11-hexahydro-7H-[1,4]diazepino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7-one, 2-{3-[(4-chlorobenzyl)amino]propyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-{3-[(2-phenylpropyl)amino]propyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 7-oxo-5,6,7,8,9,10-hexahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinoline-9-carboxamide trifluoroacetate, 2-(3-hydroxypropyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid, 2-(1,3-dihydro-2H-isoindol-2-yl)-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one trifluoroacetate, 2-{3-[(4-aminophenyl)amino]propyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(4-hydroxypiperidin-1-yl)-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one trifluoroacetate, 2-{3-[(1H-imidazol-5-ylmethyl)amino]propyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-{3-[(3-chlorobenzyl)amino]propyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-{3-[(pyridin-3-ylcarbonyl)amino]propyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxamide, 2-[3-(cyclopentylamino)propyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid dihydrochloride, 2-(3-{[2-(1H-indol-3-yl)ethyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid, 10-(3-aminopropyl)-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, 9-(1,2-dihydroxyethyl)-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, 2-morpholin-4-yl-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one trifluoroacetate, ethyl 2-(2-aminoethyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylate dihydrochloride, 2-allyl-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid, 2-quinolin-8-yl-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, lithium 2-[3-(2,3-dihydro-1H-inden-2-ylamino)-2-hydroxypropyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylate, 2-(2-hydroxyethyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid, 2-{3-[(2-pyrrolidin-1-ylethyl)amino]propyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3,4-dihydroisoquinolin-2(1H)-yl)-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one trifluoroacetate, 2-(3-{[(benzylamino)carbonyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid, 2-[3-(dimethylamino)propyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 10-(3-{([2-(4-chlorophenyl)ethyl]amino}propyl)-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, 2-(3-aminopropyl)-6-chloro-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, methyl 7-oxo-5,6,7,8,9,10-hexahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinoline-9-carboxylate, 2-[2-(glycoloylamino)ethyl]-45-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid hydrochloride, 2-[2-(isopropylamino)ethyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid hydrochloride, 2-(3-cyanopropyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid, 2-[3-({[(3-cyanophenyl)amino]carbonyl}amino)propyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid, 9-(aminomethyl)-5,6,9,10-tetrahydro-7H-[1,4]oxazino[4′,3′:1,5]pyrazolo[3,4-t]isoquinolin-7-one trifluoroacetate, 4-methyl-5,6,8,9,10,11-hexahydro-7H-[1,4]diazepino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7-one trifluoroacetate, 2-propyl-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid, 2-(3-bromopropyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-pyrrolidin-1-yl-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, 2-[3-(isopropylamino)propyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid hydrochloride, 2-(3-amino-3-carboxypropyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-{3-[(aminocarbonyl)amino]propyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid, 9-{[(4-chlorobenzyl)amino]methyl}-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, 4-chloro-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, 7-oxo-2-quinolin-3-yl-5,6,7,8,9,10-hexahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinoline-9-carboxamide, 2-{3-[(methylsulfonyl)amino]propyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, lithium 2-{4-[(2-ethylbutyl)amino]butyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylate, 2-(3-{[(4-methoxyphenyl)acetyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 7-oxo-6,7,8,9,10,11-hexahydro-5H-[1,4]diazepino[1′,2′:1,5]pyrazolo[3,4-f]isoquinoline-9-carbonitrile, 2-{3-[(isopropylsulfonyl)amino]propyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 3-[3-(chloromethyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinolin-2-yl]propan-1-amine hydrochloride, 2-(3,3-dimethylbutyl)-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one trifluoroacetate, 2-thiomorpholin-4-yl-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one trifluoroacetate, ethyl 2-(2-aminoethyl)-8-chloro-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylate, 2-[4-(benzyloxy)phenyl]-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, lithium 2-{2-hydroxy-3-[(thien-2-ylmethyl)amino]propyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylate, 2-(3-amino-3-cyanopropyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-[3-(pyridin-3-ylamino)propyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-[3-({[(ethoxycarbonyl)amino]carbonyl}amino)propyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-{3-[4-(aminocarbonyl)piperidin-1-yl]propyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-aminopropyl)-7-hydroxy-8-(3-nitrophenyl)-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid trifluoroacetate, 2-(2-aminoethyl)-7-hydroxy-8-(3-nitrophenyl)-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid trifluoroacetate, 3-hydroxy-2-(3-nitrophenyl)-5,6,8,9,10,11-hexahydro-7H-benzo[g][1,4]diazepino[1,2-b]indazol-7-one trifluoroacetate, 2-(3-aminopropyl)-7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid dihydrochloride, 2-(2-aminoethyl)-8-bromo-7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid trifluoroacetate, 2-(3-aminopropyl)-8-[2-(4-chlorophenyl)ethyl]-7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid trifluoroacetate, 3-hydroxy-2-(3-nitrophenyl)-5,6,9,10-tetrahydrobenzo[g]pyrazino[1,2-b]indazol-7(8H)-one hydrobromide, 2-(3-aminopropyl)-8-bromo-7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid hydrobromide, 2-(3-aminopropyl)-7-hydroxy-8-(4-nitrophenyl)-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid trifluoroacetate, 2-(3-aminopropyl)-8-(3-cyanophenyl)-7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid trifluoroacetate, 2-(3-aminopropyl)-7-hydroxy-8-[3-(trifluoromethyl)phenyl]-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid trifluoroacetate, 2-(3-aminopropyl)-7-hydroxy-8-(3,3,3-trifluoropropyl)-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid trifluoroacetate, 2-(3-aminopropyl)-8-(3-chlorophenyl)-7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid trifluoroacetate, 2-(3-aminopropyl)-7-hydroxy-5-methyl-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid trifluoroacetate, 2-(3-aminopropyl)-8-(4-chlorophenyl)-7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid trifluoroacetate, 2-(3-aminopropyl)-7-hydroxy-8-[3-(methylsulfonyl)phenyl]-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid trifluoroacetate, 2-(3-aminopropyl)-8-(3,4-difluorophenyl)-7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid trifluoroacetate, 3-hydroxy-5,6,8,9,10,11-hexahydro-7H-benzo[g][1,4]diazepino[1,2-b]indazol-7-one, 8-(3-aminophenyl)-2-(3-aminopropyl)-7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid trifluoroacetate, 6-bromo-7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxamide, 2-(3-aminopropyl)-7-hydroxy-8-[4-(methylamino)phenyl]-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid trifluoroacetate, 2-(3-aminopropyl)-8-(4-tert-butylphenyl)-7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid trifluoroacetate, 2-(3-aminopropyl)-7-hydroxy-8-pyridin-4-yl-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid trifluoroacetate, 7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid, 2-(3-aminopropyl)-7-hydroxy-8-isobutyl-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid trifluoroacetate, 2-(3-aminopropyl)-8-(4-carboxy-3,3-dimethylbutyl)-7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid trifluoroacetate, 8-amino-2-(3-aminopropyl)-7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid, 7,8-dihydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid, 2-(3-aminopropyl)-8-benzyl-7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid trifluoroacetate, 2-(3-aminopropyl)-8-(2-chlorophenyl)-7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid trifluoroacetate, 2-allyl-7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid, 2-{3-((tert-butoxycarbonyl)amino]propyl}-7-methoxy-8-(4-nitrophenyl)-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid, 7-hydroxy-2-methyl-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid, 2-(3-aminopropyl)-8-(sec-butylamino)-7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid, and 2-(3-aminopropyl)-8-(3-carboxyphenyl)-7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid trifluoroacetate.
19. The cyclic pyrazole MK-2 inhibitor according to claim 1, wherein the MK-2 inhibitor has an MK-2 IC50 of less than 20 and is selected from the group consisting of: 2-(3-aminopropyl)-8-(methylthio)-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylic acid dihydrochloride, 2-(3-aminopropyl)-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylic acid hydrochloride, 2-(3-{[2-(4-bromophenyl)ethyl]amino}propyl)-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylic acid hydrochloride, 2-(2-aminoethyl)-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylic acid hydrochloride, 8-(allylthio)-2-(3-aminopropyl)-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylic acid dihydrochloride, 2-(3-aminopropyl)-8-(benzylthio)-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylic acid dihydrochloride, 2-{3-[(2-thien-2-ylethyl)amino]propyl}-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylic acid, 2-{3-[(2-thien-3-ylethyl)amino]propyl}-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylic acid hydrochloride, ethyl 2-(3-{[2-(4-bromophenyl)ethyl]amino}propyl)-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate, 2-(4-aminobutyl)-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylic acid dihydrochloride, 1-(methylthio)-4,5,7,8,9,10-hexahydro[1,4]diazepino[1,2-b]pyrazolo[3,4-g]indazol-6(3H)-one, 1-(allylthio)-4,5,7,8,9,10-hexahydro[1,4]diazepino[1,2-b]pyrazolo[3,4-g]indazol-6(3H)-one, 4,5,7,8,9,10-hexahydro[1,4]diazepino[1,2-b]pyrazolo[3,4-g]indazol-6(3H)-one, 2-(3-aminopropyl)-8-quinolin-3-yl-4,5-dihydro-2H-pyrazolo[4,3-h]quinazoline-3-carboxylic acid dihydrochloride, 2-(3-aminopropyl)-8-(1,3-benzodioxol-5-yl)-4,5-dihydro-2H-pyrazolo[4,3-h]quinazoline-3-carboxylic acid hydrochloride, 2-(3-aminopropyl)-8-phenyl-4,5-dihydro-2H-pyrazolo[4,3-h]quinazoline-3-carboxylic acid hydrochloride, 2-quinolin-3-yl-5,6,8,9,10,11-hexahydro-7H-[1,4]diazepino[1′,2′:1,5]pyrazolo[4,3-h]quinazolin-7-one, 2-pyridin-3-yl-5,6,8,9,10,11-hexahydro-7H-[1,4]diazepino[1′,2′:1,5]pyrazolo[4,3-h]quinazolin-7-one, 8-quinolin-3-yl-2-[3-(tritylamino)propyl]-4,5-dihydro-2H-pyrazolo[4,3-h]quinazoline-3-carboxylic acid hydrochloride, 2-(1,3-benzodioxol-5-yl)-5,6,8,9,10,11-hexahydro-7H-[1,4]diazepino[1′,2′:1,5]pyrazolo[4,3-h]quinazolin-7-one, 2-(4-methoxyphenyl)-5,6,8,9,10,11-hexahydro-7H-[1,4]diazepino[1′,2′:1,5]pyrazolo[4,3-h]quinazolin-7-one, 2-pyridin-4-yl-5,6,8,9,10,11-hexahydro-7H-[1,4]diazepino[1′,2′:1,5]pyrazolo[4,3-h]quinazolin-7-one hydrochloride, 2-(3-aminopropyl)-8-quinolin-3-yl-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-aminopropyl)-8-(3-nitrophenyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-aminopropyl)-8-(4-hydroxyphenyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid hydrobromide, 2-(3-aminopropyl)-8-(3-hydroxyphenyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid hydrobromide, 2-(3-aminopropyl)-8-(2-naphthyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-aminopropyl)-8-(3,5-difluorophenyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-aminopropyl)-8-(1,3-benzodioxol-5-yl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-aminopropyl)-8-(3-cyanophenyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 9-(hydroxymethyl)-2-quinolin-3-yl-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one trifluoroacetate, 2-(3-aminopropyl)-8-(4-methoxyphenyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-aminopropyl)-8-[3-(methylsulfonyl)phenyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-aminopropyl)-8-[3-(methylsulfonyl)phenyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(1H-imidazol-1-yl)-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one trifluoroacetate, 2-(3-aminopropyl)-8-(3-methoxyphenyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-aminopropyl)-8-[4-(trifluoromethyl)phenyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-aminopropyl)-8-anilino-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid, 2-(3-aminopropyl)-8-(3,4-difluorophenyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-{[2-(4′-carboxy-1,1′-biphenyl-4-yl)ethyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(4-hydroxyphenyl)-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one trifluoroacetate, 2-propyl-8-quinolin-3-yl-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid, 2-[3-({2-[3′-(trifluoromethyl)-1,1′-biphenyl-4-yl]ethyl}amino)propyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-aminopropyl)-8-(4-tert-butylphenyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-[3-({2-(4-(3-furyl)phenyl]ethyl}amino)propyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-{[2-(3′-chloro-1,1′-biphenyl-4-yl)ethyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(4-methoxyphenyl)-5,6,8,9,10,11-hexahydro-7H-[1,4]diazepino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7-one, 2-[3-({2-[4′-(trifluoromethyl)-1,1′-biphenyl-4-yl]ethyl}amino)propyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-hydroxyphenyl)-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, 2-(3-aminopropyl)-N-hydroxy-8-quinolin-3-yl-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxamide hydrochloride, 2-[(E)-2-(4-hydroxyphenyl)ethenyl]-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one trifluoroacetate, 2-quinolin-3-yl-5,6,8,9,10,11-hexahydro-7H-[1,4]diazepino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7-one, 2-(4-hydroxyphenyl)-5,6,8,9,10,11-hexahydro-7H-[1,4]diazepino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7-one, 2-(3-{[2-(2′-chloro-1,1′-biphenyl-4-yl)ethyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-{[2-(4′-tert-butyl-1,1′-biphenyl-4-yl)ethyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-{[2-(3,4-dichlorophenyl)ethyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-{[3-(3-chlorophenyl)propyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-[(E)-2-phenylethenyl]-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one trifluoroacetate, 2-(3-{[2-(4-pyridin-4-ylphenyl)ethyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-{[3-(4-bromophenyl)propyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-{[3-(4-tert-butylphenyl)propyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-{[2-(3′-isopropyl-1,1′-biphenyl-4-yl)ethyl]amino}propyl)-45-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-{3-[(2-thien-2-ylethyl)amino]propyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-[4-(dimethylamino)phenyl]-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, 2-(3-{[2-(1,1′-biphenyl-4-yl)ethyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-methoxyphenyl)-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, 2-(3-{[2-(4-bromophenyl)ethyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-{[2-(2,4-dichlorophenyl)ethyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-{3-[(benzylsulfonyl)amino]propyl}-8-quinolin-3-yl-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid, 9-(aminomethyl)-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one trifluoroacetate, 2-(3-nitrophenyl)-5,6,8,9,10,11-hexahydro-7H-[1,4]diazepino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7-one, 2-(3-aminopropyl)-8-quinolin-3-yl-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxamide hydrochloride, 2-(3-{[3-(4-chlorophenyl)propyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-[3-(dimethylamino)phenyl]-5,6,8,9,10,11-hexahydro-7H-[1,4]diazepino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7-one, 2-(3-{[(4-chlorobenzyl)sulfonyl]amino}propyl)-8-quinolin-3-yl-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid, 2-(3-{[2-(4-pyridin-3-ylphenyl)ethyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-{[2-(4-chlorophenyl)ethyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-{[2-(5-chlorothien-2-yl)ethyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-{[3-(4-cyanophenyl)propyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-{[3-(5-methyl-2-furyl)butyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-[3-({2-[4-(1-benzothien-3-yl)phenyl]ethyl}amino)propyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-ammoniopropyl)-3-carboxy-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinolin-7-ium dichloride, 2-(4-methoxyphenyl)-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, 2-(3-{[3-(4-acetylphenyl)propyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-aminopropyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-[3-({3-[4-(methylsulfonyl)phenyl]propyl}amino)propyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-aminopropyl)-8-(2-methoxyphenyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-[3-({2-[3′-(aminomethyl)-1,1′-biphenyl-4-yl]ethyl}amino)propyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(2-aminoethyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid dihydrochloride, 2-(3-{[2-(4-nitrophenyl)ethyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-[3-({2-[2′-(trifluoromethyl)-1,1′-biphenyl-4-yl]ethyl}amino)propyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 9-(hydroxymethyl)-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, 2-(3-{[2-(4-methylphenyl)ethyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 9-{[(2-thien-2-ylethyl)amino]methyl}-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, 2-(3-{[2-(4-ethoxyphenyl)ethyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(1,3-benzodioxol-5-yl)-5,6,8,9,10,11-hexahydro-7H-[1,4]diazepino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7-one, 2-(3-{[2-(4-methoxyphenyl)ethyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 3-[3-(1H-tetraazol-5-yl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinolin-2-yl]propan-1-amine hydrochloride, 2-(3-aminopropyl)-8-chloro-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-{[(1R,2S)-2-phenylcyclopropyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-{3-[(3,3-diphenylpropyl)amino]propyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-{[2-(3-bromo-4-methoxyphenyl)ethyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-{3-[(4-phenylbutyl)amino]propyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-[3-(2,3-dihydro-1H-inden-2-ylamino)propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(2-naphthyl)-5,6,8,9,10,11-hexahydro-7H-[1,4]diazepino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7-one, 2-{3-[(3-phenylpropyl)amino]propyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-{[2-(4-fluorophenyl)ethyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-{3-[(2-thien-3-ylethyl)amino]propyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid dihydrochloride, 5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, 2-[3-(glycoloylamino)propyl]-8-quinolin-3-yl-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid hydrochloride, 8-quinolin-3-yl-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid, 2-(3-{[2-(4-ethylphenyl)ethyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-{[2-(2-chlorophenyl)ethyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-{3-[(2-ethylbutyl)amino]propyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 8-quinolin-3-yl-4,5-dihydro-2H-pyrazolo[3,4-q]isoquinoline-3-carboxamide, 2-{3-[(2-pyridin-4-ylethyl)amino]propyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-{[2-(4-chlorophenyl)propyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-{[2-(3-chlorophenyl)ethyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-[3-(glycoloylamino)propyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-{[2-(3,4-dimethoxyphenyl)ethyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(1-benzofuran-2-yl)-5,6,8,9,10,11-hexahydro-7H-[1,4]diazepino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7-one, 2-(3-{[4-(2-aminoethyl)phenyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(1-naphthyl)-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, 8-(3-aminopropyl)-5,6,8,9,10,11-hexahydro-7H-[1,4]diazepino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7-one dihydrochloride, 2-anilino-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, 2-(3-aminopropyl)-8-[2-(trifluoromethyl)phenyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 9-(azidomethyl)-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, 9-({[2-(4-chlorophenyl)ethyl]amino}methyl)-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, 2-phenyl-5,6,8,9,10,11-hexahydro-7H-[1,4]diazepino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7-one, 2-[3-(pentylamino)propyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 10-(2-aminoethyl)-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, 2-[3-(allylamino)propyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(4-aminobutyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid dihydrochloride, 2-(3-{[2-(4-aminophenyl)ethyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-[(1E)-3,3-dimethylbut-1-enyl]-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one trifluoroacetate, 10-(nitromethyl)-5,6,9,10-tetrahydropyrazino[1′,2′:1,5)pyrazolo[3,4-f]isoquinolin-7(8H)-one, 3-carboxy-2-[3-(methylammonio)propyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinolin-7-ium dichloride, 2-[3-({[(4-butoxyphenyl)amino)carbonyl}amino)propyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid, 2-{3-[(2-pyridin-3-ylethyl)amino]propyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-{3-[(2-pyridin-2-ylethyl)amino]propyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-{3-[(cyclopropylmethyl)amino]propyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-{3-[(2-thien-2-ylpropyl)amino]propyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-methoxy-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, 2-[3-(dimethylamino)phenyl]-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, 2-(3-{[2-(1H-pyrrol-1-yl)ethyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-[3-(benzyloxy)propyl]-8-quinolin-3-yl-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid, 2-{3-[(4-butoxybenzyl)amino]propyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(1,3-benzodioxol-5-yl)-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, 2-[(E)-2-(2-fluorophenyl)ethenyl]-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, 2-[(1E)-hex-1-enyl]-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one trifluoroacetate, 2-anilino-5,6,8,9,10,11-hexahydro-7H-[1,4]diazepino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7-one, 5,6,8,9,10,11-hexahydro-7H-[1,4]diazepino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7-one, 2-chloro-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, 2-[(E)-2-(4-methoxyphenyl)ethenyl]-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, 2-(methylthio)-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, 2-{3-[(2-furylmethyl)amino]propyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-azepan-1-yl-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one trifluoroacetate, 2-(3,6-dihydropyridin-1 (2H)-yl)-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one trifluoroacetate, 9-methyl-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, 2-(piperidin-3-ylmethyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid hydrochloride, 9-(chloromethyl)-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, 2-[(4-methoxybenzyl)amino]-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one trifluoroacetate, 2-(3-{[2-(1H-imidazol-4-yl)ethyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(benzylamino)-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one trifluoroacetate, 2-(methylthio)-5,6,8,9,10,11-hexahydro-7H-[1,4]diazepino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7-one, 2-{3-[(2-chlorobenzyl)amino]propyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-[3-(benzylamino)propyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-[3-({[(4-methoxyphenyl)amino]carbonyl}amino)propyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid, 2-{3-[(2-phenylethyl)amino]propyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-{3-[(thien-2-ylmethyl)amino]propyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-benzyl-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, 5,6,8,9,10,11-hexahydro-7H-[1,4]diazepino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7-one, 2-{3-[(4-chlorobenzyl)amino]propyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-{3-[(2-phenylpropyl)amino]propyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 7-oxo-5,6,7,8,9,10-hexahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinoline-9-carboxamide trifluoroacetate, 2-(3-hydroxypropyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid, 2-(1,3-dihydro-2H-isoindol-2-yl)-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one trifluoroacetate, 2-{3-[(4-aminophenyl)amino]propyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(4-hydroxypiperidin-1-yl)-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one trifluoroacetate, 2-{3-[(1H-imidazol-5-ylmethyl)amino]propyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-{3-[(3-chlorobenzyl)amino]propyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-{3-[(pyridin-3-ylcarbonyl)amino]propyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxamide, 2-[3-(cyclopentylamino)propyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid dihydrochloride, 2-(3-{[2-(1H-indol-3-yl)ethyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid, 10-(3-aminopropyl)-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, 9-(1,2-dihydroxyethyl)-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, 2-morpholin-4-yl-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one trifluoroacetate, ethyl 2-(2-aminoethyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylate dihydrochloride, 2-allyl-4,5-dihydro-2-H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid, 2-quinolin-8-yl-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, lithium 2-[3-(2,3-dihydro-1H-inden-2-ylamino)-2-hydroxypropyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylate, 2-(2-hydroxyethyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid, 2-{3-[(2-pyrrolidin-1-ylethyl)amino]propyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3,4-dihydroisoquinolin-2(1H)-yl)-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one trifluoroacetate, 2-(3-{[(benzylamino)carbonyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid, 2-[3-(dimethylamino)propyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 10-(3-{[2-(4-chlorophenyl)ethyl]amino}propyl)-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, 2-(3-aminopropyl)-6-chloro-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, methyl 7-oxo-5,6,7,8,9,10-hexahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinoline-9-carboxylate, 2-[2-(glycoloylamino)ethyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid hydrochloride, 2-[2-(isopropylamino)ethyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid hydrochloride, 2-(3-cyanopropyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid, 2-[3-({[(3-cyanophenyl)amino]carbonyl}amino)propyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid, 9-(aminomethyl)-5,6,9,10-tetrahydro-7H-[1,4]oxazino[4′,3′:1,5]pyrazolo[3,4-f]isoquinolin-7-one trifluoroacetate, 2-(3-aminopropyl)-7-hydroxy-8-(3-nitrophenyl)-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid trifluoroacetate, 2-(2-aminoethyl)-7-hydroxy-8-(3-nitrophenyl)-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid trifluoroacetate, 3-hydroxy-2-(3-nitrophenyl)-5,6,8,9,10,11-hexahydro-7H-benzo[g][1,4]diazepino[1,2-b]indazol-7-one trifluoroacetate, 2-(3-aminopropyl)-7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid dihydrochloride, 2-(2-aminoethyl)-8-bromo-7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid trifluoroacetate, 2-(3-aminopropyl)-8-[2-(4-chlorophenyl)ethyl]-7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid trifluoroacetate, 3-hydroxy-2-(3-nitrophenyl)-5,6,9,10-tetrahydrobenzo[g]pyrazino[1,2-b]indazol-7(8H)-one hydrobromide, 2-(3-aminopropyl)-8-bromo-7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid hydrobromide, 2-(3-aminopropyl)-7-hydroxy-8-(4-nitrophenyl)-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid trifluoroacetate, 2-(3-aminopropyl)-8-(3-cyanophenyl)-7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid trifluoroacetate, 2-(3-aminopropyl)-7-hydroxy-8-[3-(trifluoromethyl)phenyl]-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid trifluoroacetate, 2-(3-aminopropyl)-7-hydroxy-8-(3,3,3-trifluoropropyl)-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid trifluoroacetate, 2-(3-aminopropyl)-8-(3-chlorophenyl)-7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid trifluoroacetate, 2-(3-aminopropyl)-7-hydroxy-5-methyl-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid trifluoroacetate, 2-(3-aminopropyl)-8-(4-chlorophenyl)-7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid trifluoroacetate, 2-(3-aminopropyl)-7-hydroxy-8-[3-(methylsulfonyl)phenyl]-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid trifluoroacetate, 2-(3-aminopropyl)-8-(3,4-difluorophenyl)-7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid trifluoroacetate, 3-hydroxy-5,6,8,9,10,11-hexahydro-7H-benzo[g][1,4]diazepino[1,2-b]indazol-7-one, 8-(3-aminophenyl)-2-(3-aminopropyl)-7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid trifluoroacetate, 6-bromo-7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxamide, 2-(3-aminopropyl)-7-hydroxy-8-[4-(methylamino)phenyl]-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid trifluoroacetate, 2-(3-aminopropyl)-8-(4-tert-butylphenyl)-7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid trifluoroacetate, 2-(3-aminopropyl)-7-hydroxy-8-pyridin-4-yl-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid trifluoroacetate, and 7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid.
20. The cyclic pyrazole MK-2 inhibitor according to claim 1, wherein the MK-2 inhibitor has an MK-2 IC50 of less than 10 and is selected from the group consisting of: 2-(3-aminopropyl)-8-(methylthio)-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylic acid dihydrochloride, 2-(3-aminopropyl)-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylic acid hydrochloride, 2-(3-{[2-(4-bromophenyl)ethyl]amino}propyl)-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylic acid hydrochloride, 2-(2-aminoethyl)-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylic acid hydrochloride, 8-(allylthio)-2-(3-aminopropyl)-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylic acid dihydrochloride, 2-(3-aminopropyl)-8-(benzylthio)-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylic acid dihydrochloride, 2-{3-[(2-thien-2-ylethyl)amino]propyl}-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylic acid, 2-{3-[(2-thien-3-ylethyl)amino]propyl}-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylic acid hydrochloride, ethyl 2-(3-{[2-(4-bromophenyl)ethyl]amino}propyl)-2,4,5,6-tetrahydropyrazolo[3,4-e]indazole-3-carboxylate, 2-(3-aminopropyl)-8-quinolin-3-yl-4,5-dihydro-2H-pyrazolo[4,3-h]quinazoline-3-carboxylic acid dihydrochloride, 2-(3-aminopropyl)-8-(1,3-benzodioxol-5-yl)-4,5-dihydro-2H-pyrazolo[4,3-h]quinazoline-3-carboxylic acid hydrochloride, 2-(3-aminopropyl)-8-phenyl-4,5-dihydro-2H-pyrazolo[4,3-h]quinazoline-3-carboxylic acid hydrochloride, 2-quinolin-3-yl-5,6,8,9,10,11-hexahydro-7H-[1,4]diazepino[1′,2′:1,5]pyrazolo[4,3-h]quinazolin-7-one, 2-pyridin-3-yl-5,6,8,9,10,11-hexahydro-7H-(1,4]diazepino[1′,2′:1,5]pyrazolo[4,3-h]quinazolin-7-one, 8-quinolin-3-yl-2-[3-(tritylamino)propyl]-4,5-dihydro-2H-pyrazolo[4,3-h]quinazoline-3-carboxylic acid hydrochloride, 2-(1,3-benzodioxol-5-yl)-5,6,8,9,10,11-hexahydro-7H-[1,4]diazepino[1′,2′:1,5]pyrazolo[4,3-h]quinazolin-7-one, 2-(4-methoxyphenyl)-5,6,8,9,10,11-hexahydro-7H-[1,4]diazepino[1′,2′:1,5]pyrazolo[4,3-h]quinazolin-7-one, 2-pyridin-4-yl-5,6,8,9,10,11-hexahydro-7H-[1,4]diazepino[1′,2′:1,5]pyrazolo[4,3-h]quinazolin-7-one hydrochloride, 2-(3-aminopropyl)-8-quinolin-3-yl-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-aminopropyl)-8-(3-nitrophenyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-aminopropyl)-8-(4-hydroxyphenyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid hydrobromide, 2-(3-aminopropyl)-8-(3-hydroxyphenyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid hydrobromide, 2-(3-aminopropyl)-8-(2-naphthyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-aminopropyl)-8-(3,5-difluorophenyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-aminopropyl)-8-(1,3-benzodioxol-5-yl)-4,5-dihydro-2H-pyrazolo[3,4-q]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-aminopropyl)-8-(3-cyanophenyl)-4,5-dihydro-2H-pyrazolo[3,4-q]isoquinoline-3-carboxylic acid trifluoroacetate, 9-(hydroxymethyl)-2-quinolin-3-yl-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one trifluoroacetate, 2-(3-aminopropyl)-8-(4-methoxyphenyl)-4,5-dihydro-2H-pyrazolo[3,4-q]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-aminopropyl)-8-[3-(methylsulfonyl)phenyl]-4,5-dihydro-2H-pyrazolo[3,4-q]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-aminopropyl)-8-[3-(trifluoromethyl)phenyl]-4,5-dihydro-2H-pyrazolo[3,4-q]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(1H-imidazol-1-yl)-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-q]isoquinolin-7(8H)-one trifluoroacetate, 2-(3-aminopropyl)-8-(3-methoxyphenyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-aminopropyl)-8-[4-(trifluoromethyl)phenyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-aminopropyl)-8-anilino-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid, 2-(3-aminopropyl)-8-(3,4-difluorophenyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-{[2-(4′-carboxy-1,1′-biphenyl-4-yl)ethyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f)isoquinoline-3-carboxylic acid trifluoroacetate, 2-(4-hydroxyphenyl)-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one trifluoroacetate, 2-propyl-8-quinolin-3-yl-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid, 2-[3-({2-[3′-(trifluoromethyl)-1,1′-biphenyl-4-yl]ethyl}amino)propyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-aminopropyl)-8-(4-tert-butylphenyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-[3-({2-[4-(3-furyl)phenyl]ethyl}amino)propyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-{[2-(3′-chloro-1,1′-biphenyl-4-yl)ethyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(4-methoxyphenyl)-5,6,8,9,10,11-hexahydro-7H-[1,4]diazepino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7-one, 2-[3-({2-[4′-(trifluoromethyl)-1,1′-biphenyl-4-yl]ethyl}amino)propyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-hydroxyphenyl)-5,6,9,10-tetrahydropyrazino[1′,2′-:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, 2-(3-aminopropyl)-N-hydroxy-8-quinolin-3-yl-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxamide hydrochloride, 2-[(E)-2-(4-hydroxyphenyl)ethenyl]-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one trifluoroacetate, 2-quinolin-3-yl-5,6,8,9,10,11-hexahydro-7H-[1,4]diazepino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7-one, 2-(4-hydroxyphenyl)-5,6,8,9,10,11-hexahydro-7H-[1,4]diazepino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7-one, 2-(3-{[2-(2′-chloro-1,1′-biphenyl-4-yl)ethyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-{[2-(4′-tert-butyl-1,1′-biphenyl-4-yl)ethyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-{[2-(3,4-dichlorophenyl)ethyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-{[3-(3-chlorophenyl)propyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-[(E)-2-phenylethenyl]-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one trifluoroacetate, 2-(3-{[2-(4-pyridin-4-ylphenyl)ethyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-{[3-(4-bromophenyl)propyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-{[3-(4-tert-butylphenyl)propyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-{[2-(3′-isopropyl-1,1′-biphenyl-4-yl)ethyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-{3-[(2-thien-2-ylethyl)amino]propyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-[4-(dimethylamino)phenyl]-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, 2-(3-{[2-(1,1′-biphenyl-4-yl)ethyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[34-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-methoxyphenyl)-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, 2-(3-{[2-(4-bromophenyl)ethyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-{[2-(2,4-dichlorophenyl)ethyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-{3-[(benzylsulfonyl)amino]propyl}-8-quinolin-3-yl-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid, 9-(aminomethyl)-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one trifluoroacetate, 2-(3-nitrophenyl)-5,6,8,9,10,11-hexahydro-7H-[1,4]diazepino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7-one, 2-(3-aminopropyl)-8-quinolin-3-yl-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxamide hydrochloride, 2-(3-{[3-(4-chlorophenyl)propyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-[3-(dimethylamino)phenyl]-5,6,8,9,10,11-hexahydro-7H-[1,4]diazepino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7-one, 2-(3-{[(4-chlorobenzyl)sulfonyl]amino}propyl)-8-quinolin-3-yl-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid, 2-(3-{[2-(4-pyridin-3-ylphenyl)ethyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-{[2-(4-chlorophenyl)ethyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-{[2-(5-chlorothien-2-yl)ethyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-{[3-(4-cyanophenyl)propyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-{[3-(5-methyl-2-furyl)butyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-[3-({2-[4-(1-benzothien-3-yl)phenyl]ethyl}amino)propyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-ammoniopropyl)-3-carboxy-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinolin-7-ium dichloride, 2-(4-methoxyphenyl)-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, 2-(3-{[3-(4-acetylphenyl)propyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-aminopropyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-[3-({3-[4-(methylsulfonyl)phenyl]propyl}amino)propyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-aminopropyl)-8-(2-methoxyphenyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-[3-({2-[3′-(aminomethyl)-1,1′-biphenyl-4-yl]ethyl}amino)propyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(2-aminoethyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid dihydrochloride, 2-(3-{[2-(4-nitrophenyl)ethyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-[3-({2-[2′-(trifluoromethyl)-1,1′-biphenyl-4-yl]ethyl}amino)propyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 9-(hydroxymethyl)-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, 2-(3-{[2-(4-methylphenyl)ethyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 9-{[(2-thien-2-ylethyl)amino]methyl}-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, 2-(3-{[2-(4-ethoxyphenyl)ethyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(1,3-benzodioxol-5-yl)-5,6,8,9,10,11-hexahydro-7H-[1,4]diazepino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7-one, 2-(3-{[2-(4-methoxyphenyl)ethyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 3-[3-(1H-tetraazol-5-yl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinolin-2-yl]propan-1-amine hydrochloride, 2-(3-aminopropyl)-8-chloro-4,5-dihydro-2H-pyrazolo[3,4-q]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-{[(1R,2S)-2-phenylcyclopropyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-{3-[(3,3-diphenylpropyl)amino]propyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-{[2-(3-bromo-4-methoxyphenyl)ethyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-{3-[(4-phenylbutyl)amino]propyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-[3-(2,3-dihydro-1H-inden-2-ylamino)propyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(2-naphthyl)-5,6,8,9,10,11-hexahydro-7H-[1,4]diazepino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7-one, 2-{3-[(3-phenylpropyl)amino]propyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-{[2-(4-fluorophenyl)ethyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-{3-[(2-thien-3-ylethyl)amino]propyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid dihydrochloride, 5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, 2-[3-(glycoloylamino)propyl]-8-quinolin-3-yl-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid hydrochloride, 8-quinolin-3-yl-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid, 2-(3-{[2-(4-ethylphenyl)ethyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-{[2-(2-chlorophenyl)ethyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-{3-[(2-ethylbutyl)amino]propyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 8-quinolin-3-yl-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxamide, 2-{3-[(2-pyridin-4-ylethyl)amino]propyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-{[2-(4-chlorophenyl)propyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-{[2-(3-chlorophenyl)ethyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-[3-(glycoloylamino)propyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-{[2-(3,4-dimethoxyphenyl)ethyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(1-benzofuran-2-yl)-5,6,8,9,10,1,1-hexahydro-7H-[1,4]diazepino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7-one, 2-(3-{[4-(2-aminoethyl)phenyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(1-naphthyl)-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, 8-(3-aminopropyl)-5,6,8,9,10,11-hexahydro-7H-[1,4]diazepino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7-one dihydrochloride, 2-anilino-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, 2-(3-aminopropyl)-8-[2-(trifluoromethyl)phenyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 9-(azidomethyl)-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, 9-({[2-(4-chlorophenyl)ethyl]amino}methyl)-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, 2-phenyl-5,6,8,9,10,11-hexahydro-7H-[1,4]diazepino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7-one, 2-[3-(pentylamino)propyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 10-(2-aminoethyl)-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, 2-[3-(allylamino)propyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(4-aminobutyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid dihydrochloride, 2-(3-{[2-(4-aminophenyl)ethyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-[(1E)-3,3-dimethylbut-1-enyl]-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one-trifluoroacetate, 10-(nitromethyl)-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, 3-carboxy-2-[3-(methylammonio)propyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinolin-7-ium dichloride, 2-[3-({[(4-butoxyphenyl)amino]carbonyl}amino)propyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid, 2-{3-[(2-pyridin-3-ylethyl)amino]propyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-{3-[(2-pyridin-2-ylethyl)amino]propyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-{3-[(cyclopropylmethyl)amino]propyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-{3-[(2-thien-2-ylpropyl)amino]propyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-methoxy-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, 2-[3-(dimethylamino)phenyl]-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-q]isoquinolin-7(8H)-one, 2-(3-{[2-(1H-pyrrol-1-yl)ethyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-[3-(benzyloxy)propyl]-8-quinolin-3-yl-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid, 2-{3-[(4-butoxybenzyl)amino]propyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(1,3-benzodioxol-5-yl)-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, 2-[(E)-2-(2-fluorophenyl)ethenyl]-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-q]isoquinolin-7(8H)-one, 2-[(1E)-hex-1-enyl]-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one trifluoroacetate, 2-anilino-5,6,8,9,10,11-hexahydro-7H-[1,4]diazepino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7-one, 5,6,8,9,10,11-hexahydro-7H-[1,4]diazepino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7-one, 2-chloro-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, 2-[(E)-2-(4-methoxyphenyl)ethenyl]-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, 2-(methylthio)-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, 2-{3-[(2-furylmethyl)amino]propyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-azepan-1-yl-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one trifluoroacetate, 2-(3,6-dihydropyridin-1 (2H)-yl)-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one trifluoroacetate, 9-methyl-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, 2-(piperidin-3-ylmethyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid hydrochloride, 9-(chloromethyl)-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, 2-[(4-methoxybenzyl)amino]-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one trifluoroacetate, 2-(3-([2-(1H-imidazol-4-yl)ethyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(benzylamino)-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one trifluoroacetate, 2-(methylthio)-5,6,8,9,10,11-hexahydro-7H-[1,4]diazepino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7-one, 2-{3-[(2-chlorobenzyl)amino]propyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-[3-(benzylamino)propyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate; 2-[3-({[(4-methoxyphenyl)amino]carbonyl}amino)propyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid, 2-{3-[(2-phenylethyl)amino]propyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-{3-[(thien-2-ylmethyl)amino]propyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-benzyl-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, 5,6,8,9,10,11-hexahydro-7H-[1,4]diazepino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7-one, 2-{3-[(4-chlorobenzyl)amino]propyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-{3-[(2-phenylpropyl)amino]propyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 7-oxo-5,6,7,8,9,10-hexahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinoline-9-carboxamide trifluoroacetate, 2-(3-hydroxypropyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid, 2-(1,3-dihydro-2H-isoindol-2-yl)-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one trifluoroacetate, 2-{3-[(4-aminophenyl)amino]propyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(4-hydroxypiperidin-1-yl)-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one trifluoroacetate, 2-(3-aminopropyl)-7-hydroxy-8-(3-nitrophenyl)-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid trifluoroacetate, 2-(2-aminoethyl)-7-hydroxy-8-(3-nitrophenyl)-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid trifluoroacetate, 3-hydroxy-2-(3-nitrophenyl)-5,6,8,9,10,11-hexahydro-7H-benzo[g][1,4]diazepino[1,2-b]indazol-7-one trifluoroacetate, 2-(3-aminopropyl)-7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid dihydrochloride, 2-(2-aminoethyl)-8-bromo-7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid trifluoroacetate, 2-(3-aminopropyl)-8-[2-(4-chlorophenyl)ethyl]-7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid trifluoroacetate, 3-hydroxy-2-(3-nitrophenyl)-5,6,9,10-tetrahydrobenzo[g]pyrazino[1,2-b]indazol-7(8H)-one hydrobromide, 2-(3-aminopropyl)-8-bromo-7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid hydrobromide, 2-(3-aminopropyl)-7-hydroxy-8-(4-nitrophenyl)-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid trifluoroacetate, 2-(3-aminopropyl)-8-(3-cyanophenyl)-7-hydroxy-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid trifluoroacetate, 2-(3-aminopropyl)-7-hydroxy-8-[3-(trifluoromethyl)phenyl]-4,5-dihydro-2H--benzo[g]indazole-3-carboxylic acid trifluoroacetate, and 2-(3-aminopropyl)-7-hydroxy-8-(3,3,3-trifluoropropyl)-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid trifluoroacetate.
21. The cyclic pyrazole MK-2 inhibitor according to claim 1, wherein the MK-2 inhibitor has an MK-2 IC50 of less than 1 and is selected from the group consisting of: 2-(3-aminopropyl)-8-quinolin-3-yl-4,5-dihydro-2H-pyrazolo[4,3-h]quinazoline-3-carboxylic acid dihydrochloride, 2-(3-aminopropyl)-8-(1,3-benzodioxol-5-yl)-4,5-dihydro-2H-pyrazolo[4,3-h]quinazoline-3-carboxylic acid hydrochloride, 2-(3-aminopropyl)-8-phenyl-4,5-dihydro-2H-pyrazolo[4,3-h]quinazoline-3-carboxylic acid hydrochloride, 2-(3-aminopropyl)-8-quinolin-3-yl-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-aminopropyl)-8-(3-nitrophenyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-aminopropyl)-8-(4-hydroxyphenyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid hydrobromide, 2-(3-aminopropyl)-8-(3-hydroxyphenyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid hydrobromide, 2-(3-aminopropyl)-8-(2-naphthyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-aminopropyl)-8-(3,5-difluorophenyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-aminopropyl)-8-(1,3-benzodioxol-5-yl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-aminopropyl)-8-(3-cyanophenyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 9-(hydroxymethyl)-2-quinolin-3-yl-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one trifluoroacetate, 2-(3-aminopropyl)-8-(4-methoxyphenyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-aminopropyl)-8-[3-(methylsulfonyl)phenyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-aminopropyl)-8-[3-(trifluoromethyl) phenyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(1H-imidazol-1-yl)-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one trifluoroacetate, 2-(3-aminopropyl)-8-(3-methoxyphenyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-aminopropyl)-8-(4-(trifluoromethyl)phenyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-aminopropyl)-8-anilino-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid, 2-(3-aminopropyl)-8-(3,4-difluorophenyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-{[2-(4′-carboxy-1,1′-biphenyl-4-yl)ethyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(4-hydroxyphenyl)-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one trifluoroacetate, 2-propyl-8-quinolin-3-yl-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid, 2-[3-({2-[3′-(trifluoromethyl)-1,1′-biphenyl-4-yl]ethyl}amino)propyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-aminopropyl)-8-(4-tert-butylphenyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-[3-({2-[4-(3-furyl)phenyl]ethyl}amino)propyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-{[2-(3′-chloro-1,1′-biphenyl-4-yl)ethyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(4-methoxyphenyl)-5,6,8,9,10,11-hexahydro-7H-[1,4]diazepino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7-one, 2-[3-({2-[4′-(trifluoromethyl)-1,1′-biphenyl-4-yl]ethyl}amino)propyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-hydroxyphenyl)-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, 2-(3-aminopropyl)-N-hydroxy-8-quinolin-3-yl-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxamide hydrochloride, 2-[(E)-2-(4-hydroxyphenyl)ethenyl]-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one trifluoroacetate, 2-quinolin-3-yl-5,6,8,9,10,11-hexahydro-7H-[1,4]diazepino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7-one, 2-(4-hydroxyphenyl)-5,6,8,9,10,11-hexahydro-7H-[1,4]diazepino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7-one, 2-(3-{[2-(2′-chloro-1,1′-biphenyl-4-yl)ethyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-{[2-(4′-tert-butyl-1,1′-biphenyl-4-yl)ethyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-{[2-(3,4-dichlorophenyl)ethyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-{[3-(3-chlorophenyl)propyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-[(E)-2-phenylethenyl]-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one trifluoroacetate, 2-(3-{[2-(4-pyridin-4-ylphenyl)ethyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-{([3-(4-bromophenyl)propyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-{[3-(4-tert-butylphenyl)propyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-{[2-(3′-isopropyl-1,1′-biphenyl-4-yl)ethyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-{3-[(2-thien-2-ylethyl)amino]propyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid, 9-(aminomethyl)-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one trifluoroacetate, 2-(3-nitrophenyl)-5,6,8,9,10,11-hexahydro-7H-[1,4]diazepino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7-one, 2-(3-aminopropyl)-8-quinolin-3-yl-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxamide hydrochloride, 2-(3-{[3-(4-chlorophenyl)propyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-[3-(dimethylamino)phenyl]-5,6,8,9,10,11-hexahydro-7H-[1,4]diazepino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7-one, 2-(3-{[(4-chlorobenzyl)sulfonyl]amino}propyl)-8-quinolin-3-yl-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid, 2-(3-{[2-(4-pyridin-3-ylphenyl)ethyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-{[2-(4-chlorophenyl)ethyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-{[2-(5-chlorothien-2-yl)ethyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-{[3-(4-cyanophenyl)propyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-{[3-(5-methyl-2-furyl)butyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-[3-({2-[4-(1-benzothien-3-yl)phenyl]ethyl}amino)propyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-ammoniopropyl)-3-carboxy-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinolin-7-ium dichloride, 2-(4-methoxyphenyl)-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, 2-(3-{[3-(4-acetylphenyl)propyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-aminopropyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-[3-({3-[4-(methylsulfonyl)phenyl]propyl}amino)propyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-aminopropyl)-8-(2-methoxyphenyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-[3-({2-[3′-(aminomethyl)-1,1′-biphenyl-4-yl]ethyl}amino)propyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(2-aminoethyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid dihydrochloride, 2-(3-{[2-(4-nitrophenyl)ethyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-[3-({2-[2′-(trifluoromethyl)-1,1′-biphenyl-4-yl]ethyl}amino)propyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 9-(hydroxymethyl)-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, 2-(3-{[2-(4-methylphenyl)ethyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 9-{[(2-thien-2-ylethyl)amino]methyl}-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, 2-(3-{[2-(4-ethoxyphenyl)ethyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(1,3-benzodioxol-5-yl)-5,6,8,9,10,11-hexahydro-7H-[1,4]diazepino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7-one, 2-(3-{[2-(4-methoxyphenyl)ethyl]amino}propyl)-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-aminopropyl)-7-hydroxy-8-(3-nitrophenyl)-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid trifluoroacetate, and 2-(2-aminoethyl)-7-hydroxy-8-(3-nitrophenyl)-4,5-dihydro-2H-benzo[g]indazole-3-carboxylic acid trifluoroacetate.
22. A method of inhibiting mitogen activated protein kinase-activated protein kinase-2 in a subject in need of such inhibition, the method comprising administering to the subject an MK-2 inhibiting compound having the structure shown in claim 1.
23. The method according to claim 22, wherein the MK-2 inhibiting compound is administered in an effective amount.
24. The method according to claim 22, wherein the MK-2 inhibiting compound has the structure shown in claim 2.
25. A method of preventing or treating a TNFα mediated disease or disorder in a subject in need of such prevention or treatment, the method comprising administering to the subject an effective amount of an MK-2 inhibiting compound having the structure shown in claim 1.
26. The method according to claim 25, wherein the MK-2 inhibiting compound has the structure shown in claim 2.
27. The method according to claim 25, wherein the subject is a mammal.
28. The method according to claim 27, wherein the subject is a human.
29. The method according to claim 25, wherein the TNFα mediated disease or disorder is selected from the group consisting of: 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.
30. The method according to claim 25, wherein the subject is administered an effective amount of the MK-2 inhibiting compound.
31. The method according to claim 22, wherein the MK-2 inhibiting compound provides an MK-2 inhibition IC50 value of below 50 μM.
32. The method according to claim 22, wherein the MK-2 inhibiting compound provides an MK-2 inhibition IC50 value of below 20 μM.
33. The method according to claim 22, wherein the MK-2 inhibiting compound provides an MK-2 inhibition IC50 value of below 10 μM.
34. The method according to claim 22, wherein the MK-2 inhibiting compound provides an MK-2 inhibition IC50 value of below 1 μM.
35. The method according to claim 22, wherein the MK-2 inhibiting compound provides a selectivity ratio (IC50 MK-3/IC50 MK-2) of at least about 1.
36. The method according to claim 22, wherein the MK-2 inhibiting compound provides a selectivity ratio (IC50 MK-3/IC50 MK-2) of at least about 10.
37. The method according to claim 22, wherein the MK-2 inhibiting compound provides a selectivity ratio (IC50 MK-3/IC50 MK-2) of at least about 100.
38. A pharmaceutical composition comprising an MK-2 inhibiting compound comprising a pharmaceutical carrier and an MK-2 inhibiting compound having the structure shown in claim 1.
39. A kit comprising a dosage form that includes an MK-2 inhibiting compound in a therapeutically effective amount, the MK-2 inhibiting compound having the structure shown in claim 1.
40. The cyclic pyrazole MK-2 inhibitor according to claim 1, wherein the compound is selected from the group consisting of: 2-[(E)-2-(3-hydroxyphenyl)ethenyl]-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one trifluoroacetate, 2-[(E)-2-phenylethenyl]-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one trifluoroacetate, 2-[(E)-2-(4-hydroxyphenyl)ethenyl]-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one trifluoroacetate, 2-[(E)-2-(1,3-benzodioxol-5-yl)ethenyl]-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, 2-[(E)-2-(3-methoxyphenyl)ethenyl]-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one trifluoroacetate, 2-[(E)-2-(4-chlorophenyl)ethenyl]-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one hydrochloride, 2-[(E)-2-(3,4-difluorophenyl)ethenyl]-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, 2-[(E)-2-(4-fluorophenyl)ethenyl]-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, 2-{(E)-2-[4-(trifluoromethyl)phenyl]ethenyl}-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, 2-[(E)-2-(3-chlorophenyl)ethenyl]-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, 2-[(E)-2-(2-fluorophenyl)ethenyl]-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, 2-[(E)-2-(4-methoxyphenyl)vinyl]-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, 2-[(E)-2-phenylethenyl]-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one., 2-[(E)-2-(4-methoxyphenyl)vinyl]-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one trifluoroacetate, 2-[(E)-2-(4-chlorophenyl)ethenyl]-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, 2-[(E)-2-(4-methylphenyl)ethenyl]-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, 2-[(E)-2-(4-methylphenyl)ethenyl]-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one hydrochloride, ethyl 3-[(E)-2-(7-oxo-5,6,7,8,9,10-hexahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-2-yl)ethenyl]benzoate, 9-(hydroxymethyl)-2-[(E)-2-phenylvinyl]-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one, 3-[(E)-2-(7-oxo-5,6,7,8,9,10-hexahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-2-yl)vinyl]benzoic acid, lithium 3-[(E)-2-(7-oxo-5,6,7,8,9,10-hexahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-2-yl)vinyl]benzoate, methyl 7-oxo-2-[(E)-2-phenylvinyl]-5,6,7,8,9,10-hexahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinoline-9-carboxylate, ethyl 4-[(E)-2-(7-oxo-5,6,7,8,9,10-hexahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-2-yl)vinyl]benzoate, 4-[(E)-2-(7-oxo-5,6,7,8,9,10-hexahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-2-yl)vinyl]benzoic acid, 2-((E)-2-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}vinyl)-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one trifluoroacetate, 2-{(E)-2-[4-(pyrrolidin-1-ylcarbonyl)phenyl]vinyl}-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one trifluoroacetate, 2-{(E)-2-[4-(morpholin-4-ylcarbonyl)phenyl]vinyl}-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one trifluoroacetate, 2-[(E)-2-(4-{[(2S)-2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl]carbonyl}phenyl)vinyl]-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one trifluoroacetate, 2-[(E)-2-(3-{[(2R)-2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl]carbonyl}phenyl)vinyl]-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one trifluoroacetate, 2-((E)-2-{3-[(4-methylpiperazin-1-yl)carbonyl]phenyl}vinyl)-5,6,9,10-tetrahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7(8H)-one trifluoroacetate, N,N-dimethyl-3-[(E)-2-(7-oxo-5,6,7,8,9,10-hexahydropyrazino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-2-yl)vinyl]benzamide trifluoroacetate, 2-[(E)-2-phenylvinyl]-5,6,8,9,10,11-hexahydro-7H-[1,4]diazepino[1′,2′:1,5]pyrazolo[3,4-f]isoquinolin-7-one, 2-(3-aminopropyl)-8-[(E)-2-phenylvinyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 2-(3-{[2-(4-bromophenyl)ethyl]amino}propyl)-8-[(E)-2-phenylvinyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, 8-[(E)-2-phenylvinyl]-2-{3-[(2-{4-[(E)-2-phenylvinyl]phenyl}ethyl)amino]propyl}-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid trifluoroacetate, ethyl 2-(3-aminopropyl)-8-[(E)-2-phenylvinyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylate hydrochloride, 2-(2-aminoethyl)-8-[(E)-2-phenylethenyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylic acid hydrochloride, and ethyl 2-(2-aminoethyl)-8-[(E)-2-phenylethenyl]-4,5-dihydro-2H-pyrazolo[3,4-f]isoquinoline-3-carboxylate hydrochloride.

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[0001] This application claims priority to U.S. Provisional Application Serial No. 60/357,918, filed Feb. 19, 2002, which is hereby incorporated by reference herein in its entirety.

Provisional Applications (1)

	Number	Date	Country
	60357918	Feb 2002	US

Cyclic pyrazoles for the inhibition of mitogen activated protein kinase-activated protein kinase-2

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