US 20120329780A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2012/0329780 A1 Thormann et al. (43) Pub. Date: Dec. 27, 2012

(54) NOVEL KINASE INHIBITORS (52) U.S. Cl...... 514/212.07: 544/262:544/118: 514/252.16; 540/523: 514/262.1; 514/234.2: (75) Inventors: Michael Thormann, Martinsried (DE); 544/61; 544/58.2: 514/228.5 Andreas Treml, Martinsried (DE); Michael Almstetter, Martinsried (DE); Nadine Traube, Martinsried (DE) (57) ABSTRACT (73) Assignee: Origenis GmbH, Martinsried (DE) The present invention relates to novel compounds of formula (I) (21) Appl. No.: 13/506.510 (22) Filed: Apr. 23, 2012 (I) RS Related U.S. Application Data A. (60) Provisional application No. 61/517,582, filed on Apr. 21 N 21, 2011. N 2 \ Publication Classification R2 lsN S. NH R3 (51) Int. C. A 6LX3/59 (2006.01) A 6LX3/5377 (2006.01) that are capable of inhibiting one or more kinases, especially A6 IK3I/55 (2006.01) SYK (Spleen Tyrosine Kinase). LRRK2 (Leucine-rich repeat A6 IK3I/54 (2006.01) kinase 2) and/or MYLK (Myosin light chain kinase) or A6 IP II/06 (2006.01) mutants thereof. The compounds find applications in the A6IP37/00 (2006.01) treatment of a variety of diseases. These diseases include A6IP37/08 (2006.01) autoimmune diseases, inflammatory diseases, bone diseases, A6IP27/02 (2006.01) metabolic diseases, neurological and neurodegenerative dis A6IP 7/04 (2006.01) eases, cancer, cardiovascular diseases, allergies, asthma, CO7D 487/04 (2006.01) alzheimer's disease, parkinson's disease, skin disorders, eye A6IP 29/00 (2006.01) diseases, infectious diseases and hormone-related diseases. Patent Application Publication Dec. 27, 2012 US 2012/032978.0 A1

Correlation of SYK and LAD2 inhibition

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NOVEL KNASE INHIBITORS 0006 Immunoreceptor tyrosine activation motif (ITAM)- mediated signaling has emerged as a primary event in signal 0001. This application claims benefit of priority to U.S. ing pathways responsible for human pathologies. ITAM-me Provisional Application 61/517,582 filed Apr. 21, 2011, the diated and hemlTAM-mediated signaling is responsible for contents of which are incorporated herein by reference in relaying activation signals initiated at classical immune their entirety. receptors such as T-cell receptors, B-cell receptors, Fc recep 0002 The present invention relates to novel compounds tors in immune cells and at GPVI and FcgammaRIIa in plate that are capable of inhibiting one or more kinases, especially lets to downstream intracellular molecules such as Syk and SYK (Spleen Tyrosine Kinase). LRRK2 (Leucine-rich repeat ZAP-70 (Underhill, D. M and Goodridge, H. S., Trends kinase 2) and/or MYLK (Myosin light chain kinase) or Immunol., 28:66-73, 2007) but also furthermore with hemI mutants thereof. The compounds find applications in the TAM-containing factors as CLEC7A and other C-type lec treatment of a variety of diseases. These diseases include tins. autoimmune diseases, inflammatory diseases, bone diseases, 0007. The binding of a ligand to an ITAM-containing metabolic diseases, neurological and neurodegenerative dis receptor triggers signaling events which allows for the eases, cancer, cardiovascular diseases, allergies, asthma, recruitment of proteins from a family of nonreceptor tyrosine alzheimer's disease, parkinson's disease, skin disorders, eye kinases called the Src family. These kinases phosphorylate diseases, infectious diseases and hormone-related diseases. tyrosine residues within the ITAM sequence, a region with which the tandem SH2 domains on either Syk or ZAP-70 BACKGROUND OF THE INVENTION interact. 0003 Protein kinases constitute a large family of structur 0008 Syk, along with Zap-70, is a member of the Syk ally related enzymes that are responsible for the control of a family of protein tyrosine kinases. The interaction of Syk or variety of signal transduction processes within cells (see, e.g., ZAP-70 with diphosphorylated ITAM sequences induces a Hardie and Hanks, The Protein Kinase Facts Book, I and II, conformation change in the kinases that allows for tyrosine Academic Press, San Diego, Calif., 1995). Protein kinases are phosphorylation of the kinase itself. Phosphorylated Syk thought to have evolved from a common ancestral gene due to family members activate a multitude of downstream signal the conservation of their structure and catalytic function. ing pathway proteins which include Src homology 2 (SH2) Almost all kinases contain a similar 250-300 amino acid domains. Direct binding partners of Syk are VAV family catalytic domain. The kinases can be categorized into fami members, phospholipase C gamma (PLCgamma, lies by the substrates they phosphorylate (e.g., protein-ty PLCgamma 2), phosphoinositide 3-kinases (PI3Ks), SH2 rosine, protein-Serine/threonine, lipids, etc.). Sequence domain-containing leukocyte protein family members (SLP motifs have been identified that generally correspond to each 76 or SLP-65). Other signaling intermediates are p38, Janus of these families (see, e.g., Hanks & Hunter, (1995), FASEB kinase (JNK), RAS homologue (RHO) family, Ca++, dia J. 9:576-596: Knighton et al., (1991), Science 253:407-414: cylglycerol DAG, TEC family, caspase-recruitment Hiles et al., (1992), Cell 70:419-429; Kunzet al., (1993), Cell domain-B cell lymphoma 10-mucosa-associated lym 73:585-596; Garcia-Bustos et al., (1994), EMBO.J. 13:2352 phoid tissue lymphoma translocation protein 1 (CARD-BCL 2361). 10-MALT1) complex, protein tyrosine kinase 2 (PYK2), 0004. Many diseases are associated with abnormal cellu nuclear factor of activated T cells (NFAT), protein kinase C lar responses triggered by protein kinase-mediated events. (PKC), RAS guanyl-releasing protein (RASGRP), extracel These diseases include autoimmune diseases, inflammatory lular signal-regulated kinase (ERK), AKT, NLR family, pyrin diseases, bone diseases, metabolic diseases, neurological and domain-containing 3 (NLRP3) inflammasome, NLR family neurodegenerative diseases, cancer, cardiovascular diseases, and nuclear factor kappaB (NFkappaB) and factors in the allergies, asthma, alzheimer's disease, parkinson's disease canonical and non-canonical signaling pathways. These con skin disorders, infectious diseases and hormone-related dis tribute to a variety of cellular responses as cytoskelletal eases. As a consequence, there has been Substantial effort in changes, ROS production, differentiation, proliferation, Sur medicinal chemistry to find inhibitors of protein kinases for vival of cells and cytokine release. use as therapeutic agents. 0009 Syk as a key mediator of immunoreceptor and non immuno receptor signaling in a host of inflammatory cells is SYK Spleen Tyrosine Kinase identified as a key player in the pathogenesis of a variety of diseases and disorders attributed to dysfunctional signaling 0005 Syk is known to play an essential role in adaptive including autoimmune diseases Such as rheumatoid arthritis, immune response and immune cell signaling. Recent findings systemic lupus, multiple Sclerosis, hemolytic anemia, impressively demonstrate a variety of further biological func immune-thrombocytopenia purpura, and heparin-induced tions as cellular adhesion, innate immune recognition, osteo thrombocytopenia, functional gastrointestinal disorders, clast maturation, platelet activation and vascular develop asthma, allergic disorders, anaphylactic shock and arterio ment (Moscai, A. et al., Nat Rev Immunol, 10:387-402. sclerosis (Riccaboni, M. et al., DDT, 15:517-529, 2010). 2010). Syk associates with a variety of receptors of immune Interestingly, many of the above mentioned diseases are cells (mast cells, B cells, macrophages and neutrophils) and thought to occur through crosslinking of Fc receptors by non-immune cells (osteoclasts, breast cancer cells) and antibodies which, via Syk, activate a signaling cascade in orchestrates various different cellular processes including mast, basophil and other immune cells that result in the cytokine production, bone resorption and phagocytosis. Due release of cell mediators responsible for inflammatory reac to the interaction with immunoreceptors and G-coupled tions. The release of mediators and the production of cytok receptors Syk not only functions as a protein kinase but also ines in IgE stimulation-dependent allergic and inflammatory as a true protein adaptor and therefore became a central para reactions from mast cells and basophiles can be controlled by digm in immune cell signaling. inhibiting the kinase activity of Syk (Rossi, A. B. et al., J US 2012/032978.0 A1 Dec. 27, 2012

Allergy Clin Immunol. 118:749-755, 2006). In immune Willebrand factor which tethers platelets through binding thrombocytopenia, antibody bound platelets are cleared by platelet membrane GPIb. Collagen functions secondarily by the spleen by an Fc receptor/ITAM/Syk-mediated process engaging the two collagen receptors on platelets, GPVI and (Crow, A. R. et al., Blood, 106:abstract 2165, 2005). Drug integrin alpha2beta1. induced thrombocytopenia, caused by heparin-platelet factor 0014 GPVI exists in platelet membranes as a complex 4 immune complexes that activate platelet FcgammaRIIa, with FcRgamma, an interaction required for the expression of also involve Syk signaling downstream of receptor engage GPVI. Activation of FcgammaRIIa on platelets results in ment (Reilly, M. P. Blood, 98:2442-2447, 2001). platelet shape change, secretion and thrombosis. Signaling by 0010) Syk has also been shown to mediate signaling by the GPVI/FcRgamma complex is initiated by tyrosine phos classes of receptors that do not contain conventional ITAM phorylation of the ITAM domain of FCRgamma followed by motifs as integrins and lectins (Kerrigan, A. M. et al., Immu the recruitment of Syk. Activation of GPVI leads to induction nol. Rev. 234:335-352, 2010). Furthermore Syk plays an of multiple platelet functions including: activation of inte important role in pathogen recognition like fungi, bacteria grins alpha2beta1 to achieve firm platelet adhesion, and GP and viruses (Hughes, C. E., et al., Blood, 115:2947-2955, IIb-IIIa which mediates platelet aggregation and thrombosis 2010; Geitenbeek, T. B. et al., Nat Rev Immunol, 9:465-479, growth; platelet secretion, allowing for the delivery of inflam 2009) The mechanism of Syk activation by integrins-medi matory proteins such as CD40L, RANTES and TGFbeta to ated Platelet agonists induce inside-out integrin signaling the vessel wall; and the expression of P-selectin which allows resulting in fibrinogen binding and platelet aggregation. This for the recruitment of leukocytes. Therefore, it is believed that initiates outside-in signaling which produces further stimu Syk inhibitors can inhibit thrombotic events mediated by lation of platelets. Syk is activated during both phases of platelet adhesion, activation and aggregation. integrin signaling, and inhibition of Syk is shown to inhibit 0015. It has been reported that the tyrosine phosphoryla platelet adhesion to immobilized proteins (Law, D. A. et al., tion of intracellular protein (activation) induced by stimula Blood,93:2645-2652, 1999). Release of arachidonic acid and tion of a receptor for IgG antibody, FcgammaRI, and the serotonin and platelet aggregation induced by collagen are phagocytosis mediated by FcgammaR are considerably markedly inhibited in platelets derived from Syk deficient inhibited in macrophages derived from Syk deficient mouse mouse (Poole, A. et al., EMBO.J., 16:2333-2341, 1997). Thus (Crowley, M. T. et al., J. Exp. Med., 186:1027-1039, 1997). Syk inhibitors may also possess anticoagulation action. This suggests that Syk has a markedly important role in the 0011 Because of the role Syk plays in Ig-induced platelet FcgammaR-mediated phagocytosis of macrophages. activations, it is of interest in arteriosclerosis and restenosis. 0016. It has also been reported that an antisense oligo Arteriosclerosis is a class of diseases characterized by the nucleotide of Syk Suppresses the apoptosis inhibition of eosi thickening and hardening of the arterial walls of blood ves nophils induced by GM-CSF (Yousefi, S. et al., J. E. Med., sels. Although all blood vessels are susceptible to this serious 183: 1407-1414, 1996), showing that Syk is essential for the degenerative condition, the aorta and the coronary arteries life extending signal of eosinophils caused by GM-CSF and serving the heart are most often affected. Arteriosclerosis is of the like. Since life extension of eosinophils is closely related profound clinical importance since it can increase the risk of to the transition of diseases into a chronic state in allergic heart attacks, myocardial infarctions, strokes, and aneurysms. disorders, such as asthma, Syk inhibitors can also serve as 0012. The traditional treatment for arteriosclerosis therapeutic agents for chronic eosinophilic inflammation. includes vascular recanalization procedures for less-serious 0017 Syk is important for the activation of B-cells via a blockages and coronary bypass Surgery for major blockages. B-cell antigen receptor and is involved in the phosphatidyli A serious shortcoming of intravascular procedures is that, in nositol metabolism and increase in the intracellular calcium a significant number of treated individuals, some or all of the concentration caused by the antigen receptor stimulation treated vessels restenose (i.e., re-narrow). While the exact (Hutchcroft, J. E. et al., J. Biol. Chem., 267:8613-8619, 1992: hormonal and cellular processes promoting restenosis have and Takata, M. et al., EMBO J., 13:1341-1349, 1994). Thus, not been determined, restenosis is thought to be due in part to Syk inhibitors may be used to control the function of B-cells mechanical injury to the walls of the blood vessels caused by and are, therefore, expected to serve as therapeutic agents for the balloon catheter or other intravascular device. In response antibody-related diseases. to this injury, adhering platelets, infiltrating macrophages, 0018 Syk binds to a T-cell antigen receptor, quickly leukocytes, or the Smooth muscle cells themselves release undergoes tyrosine phosphorylation through crosslinking of cell-derived growth factors such as platelet-derived growth the receptor and synergistically acts upon intracellular signals factor (PDGF), with subsequent proliferation and migration mediated by Src tyrosine kinases such as Lck (Couture, C. et of medial smooth muscle cells (SMCs) through the internal al., Proc. Natl. Acad. Sci. USA, 91:5301-5305, 1994; and elastic lamina to the area of the vessel intima. Further prolif Couture, C. et al., Mol. Cell. Biol., 14:5249-5258, 1994). Syk eration and hyperplasia of intimal SMCs and, most signifi is present in mature T-cell populations, such as intraepithelial cantly, production of large amounts of extracellular matrix gammadelta T-cells and naive alphabeta T-cells, and has been over a period of three to six months results in the filling in and reported to be capable of phosphorylation of multiple com narrowing of the vascular space Sufficient to significantly ponents of the TCR signaling cascade (Latour, S. et. al., Mol obstruct blood flow. Cell Biol., 17:4434-4441, 1997). As a consequence, Syk 0013. In addition to the role Syk plays in Ig-induced plate inhibitors may serve as agents for inhibiting cellular immu let activations, Syk plays a very important role in collagen nity mediated by T-cell antigen receptor. mediated signaling. The primary adhesive protein respon 0019 Recent comparative genomic hybridization studies sible for platelet adhesion and activation is collagen. have identified Syk as another gene important in the patho Collagen is a filamentous protein contained within the fibrotic genesis of Mantle Cell Lymphoma (MCL) (Chen, R. et al. caps of atheromas which becomes exposed to blood during Journal of Clinical Oncology, 2007 ASCO Annual Meeting plaque rupture. Collagen functions initially by binding Von Proceedings (Post-Meeting Edition), Vol 25, No 18S (June 20 US 2012/032978.0 A1 Dec. 27, 2012

Supplement), 2007: 8056). MCL represents 5-10% of all immuno-tyrosine based activation motif (ITAM) (Jumaa, non-Hodgkins lymphomas and it is a difficult form of lym Hendriks et al. Annu Rev Immunol 23: 415-45 (2005). The phoma to treat. It has the worst prognosis among the B cell ITAM domain is directly phosphorylated by Src family lymphomas with median survival of three years. It has been kinases in response to BCR engagement. Syk docks with and reported that Syk is overexpressed in MCL (Rinaldi, A, et. al. phosphorylates the ITAM, a process that enhances its kinase Br. J. Haematol, 2006: 132:303-316) and that Syk mediates activity, resulting in Syk autophosphorylation and tyrosine mTOR (mammalian target of Rapamycin) Survival signals in phosphorylation of multiple downstream substrates (Rolli, follicular, mantel cell, Burkitt's, and diffuse large B-cell non Gallwitzetal. Mol Cell 10(5): 1057-69 (2002). This signaling Hodgkin’s lymphomas (Leseux, L., et. al. Blood, 2006; 108: pathway is active in B cells beginning at the transition from 4156-4162). pro- to pre-B cell stage of development, when the newly 0020 Several lines of evidence suggest that many B-cell formed pre-BCR is expressed. In fact, B cell development lymphomas depend upon B-cell receptor (BCR)-mediated arrests at the pro-B cell stage in Syk knockout mice (Cheng, Survival signals. BCR signaling induces receptor oligomer Rowley et al. 1995: Turner, Mee et al. Nature 378(6554): ization and phosphorylation of Igalpha and beta immunore 303-6 (1995). Inducible loss of the B cell receptor (Lam, ceptor tyrosine-based activated motifs by SRC family Kuhn et al. Cell 90(6): 1073-83 (1997) or Igalpha (Kraus, kinases. ITAM phosphorylation results in the recruitment and Alimzhanov et al. Cell 117(6): 787-800 (2004) results in loss activation of Syk that initiates downstream events and ampli of peripheral B cells in mice. Human B cells also appear to fies the original BCR signal. Given the role of tonic BCR require Syk for proliferation and survival. Over-expression of signaling in normal B cell and Syk-dependent Survival of the protein tyrosine phosphatase PTP-RO, a negative regula non-Hodgkins lymphoma cell lines in vitro (Chen, L., et. al. tor of Syk activity, inhibits proliferation and induces apopto Blood, 2006; 108:3428-3433), Syk inhibition is a promising sis in cell lines derived from non-Hodgkin’s lymphomas rational treatment target for certain B-cell lymphomas and (NHL) (Chen, Juszczynski et al. Blood 108(10): 3428 chronic lymphocytic leukemia (CLL) (Stefania Gobessi, (2006). Knock down of Syk by siRNA in the NHL line Luca Laurenti, Pablo Longo, Laura Carsetti, Giuseppe SUDHL-4 led to a block in the G1/S transition of the cell Leone, Dimitar G. Efremov, Constitutive activation of the cycle (Gururajan, Dasu et al. J. Immunol 178(1): 111-21 protein tyrosine kinase Syk in Chronic Lymphocytic Leuke (2007). Together, these data Suggest that Syk signaling is mia B-cells, Blood, 2007, 110, Abstract 1123). Recent data required for the development, proliferation, and even survival shows that administration of a multikinase inhibitor which of human and mouse B cells. inhibits Syk, may have significant clinical activity in CLL 0024 Conversely, the oncogenic potential of Syk has been patients (Friedberg JW et al, Blood 2008; 112(11), Abstract described in a number of different settings. Clinically, Syk 3). over-expression is reported in Mantle Cell Lymphoma 0021. The oncogenic potential of Syk has been described (Rinaldi, Kwee et al. Br J Haematol 132(3): 303-16 (2006) in a number of different settings. Clinically, Syk over-expres and the TEL-Syk fusion protein (Translocated ETS Leuke sion is reported in Mantle Cell Lymphoma (Rinaldi, A, et. al. mia) generated by a chromosomal translocation (t(9:12)(cq22; Br. J. Haematol., 2006: 132:303-316) and the TEL-Syk p12)) leads to increased Syk activity and is associated with fusion protein (Translocated ETS Leukemia) generated by a myelodysplastic syndrome (Kuno, Abe et al. Blood 97(4): chromosomal translocation (t(9:12)(q22p12)) leads to 1050-5 (2001). Leukemia is induced in mice by the adoptive increased Syk activity and is associated with myelodysplastic transfer of bone marrow cells that express human TEL-Syk syndrome (Kuno.Y., et. al., Blood, 2001;97:1050-1055). Leu (Wossining, Herzog et al. J Exp Med 203(13): 2829-40 kemia is induced in mice by adoptively transferring bone (2006). Further, in mouse primary bone marrow cells, over marrow cells that express human TEL-Syk (Wossining, T., expression of Syk results in IL-7 independent growth in cul JEM, 2006; 203:2829-2840). Further, in mouse primary bone ture (Wossining, Herzog et al. 2006). Consistently, Syk was marrow cells, over-expression of Syk results in IL-7 indepen reported to mediate mTOR (mammalian target of Rapamy dent growth in culture (Wossining, T., et. al., JEM, 2006; cin) Survival signals in follicular, mantle cell, Burkitt's, and 203:2829-2840). diffuse large B-cell NHL (Leseux, Hamdi et al. Blood 108 0022 Interestingly, Syk signaling appears to be required (13): 4156-62 (2006). Additional recent studies also suggest for B-cell development and Survival in humans and mouse. that Syk-dependant Survival signals may play a role in B-cell Inducible loss of the B-cell receptor (Lam, K., et. al. Cell, malignancies, including DLBCL, mantle cell lymphoma and 1997: 90:1073-1083) or Igalpha (Kraus, M., et.al, Cell, 2004; follicular lymphoma (Gururajan, Jennings et al. 2006; Irish, 117:787-800) results in loss of peripheral B-cells in mice. Czerwinski et al. JImmunol 176(10): 5715-9 (2006)). Given Over-expression of the protein tyrosine phosphatase PTP the role of tonic BCR signaling in normal B cells and Syk RO, which is known to negatively regulate Sykactivity, inhib dependent survival of NHL cell lines in vitro, the specific its proliferation and induces apoptosis in cell lines derived inhibition of Syk may prove promising for the treatment of from non-Hodgkin’s lymphomas (Chen, L., et. al. Blood, certain B-cell lymphomas. 2006: 108:3428-3433). Finally, B-cell lymphomas rarely 0025 Recently, R406 (Rigel Pharmaceuticals) was exhibit loss of BCR expression, and anti-idiotype therapy reported to inhibit ITAM signaling in response to various rarely leads to resistance (Kuppers, R. Nat Rev Cancer, 2005; stimuli, including Fcepsilon R1 and BCR induced Syk acti 5:251-262). vation (Braselmann, Taylor et al. J Pharmacol Exp Ther 319 0023 Engagement of the antigen-specific B cell receptor (3): 998-1008 (2006). Interestingly, this ATP-competitive (BCR) activates multiple signaling pathways that ultimately inhibitor of Syk was also active against Flt3, cKit, and JAK regulate the cells activation status, promoting Survival and kinases, but not against Src kinsase (Braselmann, Taylor et al. clonal expansion. Signaling through the BCR is made pos 2006). Activating mutations to Flt3 are associated with AML sible by its association with two other members of the immu and inhibition of this kinase is currently under clinical devel noglobulin Super-family; Igalpha and Igbeta, each bearing an opment (Burnett and Knapper Hematology AmSoc. Hematol US 2012/032978.0 A1 Dec. 27, 2012

Educ Program 2007: 429-34 (2007). Over-activation of the LRRK2-Leucine-Rich Repeat Kinase 2 tyrosine kinase cKit is also associated with hematologic malignancies, and a target for cancer therapy (Heinrich, Grif 0032. There has been much interest raised by the discov fith et al. Blood 96(3): 925-32 (2000). Similarly, JAK3 sig ery that different autosomal dominant point mutations within naling is implicated in leukemias and lymphomas, and is the gene encoding for LRRK2 predispose humans to develop currently exploited as a potential therapeutic target (Heinrich, late-onset Parkinson's disease (PD), with a clinical appear Griffith et al. 2000). Importantly, the multi-kinase inhibitory ance indistinguishable from idiopathic PD (see Paisan-Ruiz, activity of R406 attenuates BCR signaling in lymphoma cell C, Jain, S., Evans, E.W. Gilks, W. P. Simon, J., van der Brug, lines and primary human lymphoma samples, resulting in M., Lopez de Munain, A., Aparicio, S. Gill A. M., Khan, N., apoptosis of the former (Chen, Monti et al. Blood 111(4): Johnson, J., Martinez, J. R., Nicholl, D., Carrera, I.M., Pena, 2230-7 (2008). Further, a phase II clinical trial reported favor A. S., de Silva, R., Lees, A., Marti-Masso, J. F., Perez-Tur, J., able results by this compound in refractory NHL and chronic Wood, N.W. and Singleton, A.B. (2004) Cloning of the gene lymphocytic leukemia (Friedberg J W et al. Blood 2008: containing mutations that cause PARK8-linked Parkinson's 112(11), Abstract 3). Although the precise mechanism of disease. Neuron. 44, 595-600; Mata, I. F., Wedemeyer, W.J., action is unclear for R406, the data suggest that inhibition of Farrer, M.J., Taylor, J. P. and Gallo, K. A. (2006) LRRK2 in kinases that mediate Survival signaling in lymphocytes is Parkinson's disease: protein domains and functional insights. clinically beneficial. Trends Neurosci. 29, 286-293; Taylor, J. P. Mata, I. F. and Farrer, M.J. (2006) LRRK2: a common pathway for parkin 0026. Additional recent studies also suggest that Syk-de sonism, pathogenesis and prevention? Trends MoI Med. 12, pendant Survival signals may play a role in B-cell malignan 76-82). The genetic analysis undertaken to date indicates that cies, including DLBCL, mantle cell lymphoma and follicular mutations in LRRK2 are relatively frequent, not only lymphoma (see e.g., S. Linfengshen et al. Blood, February accounting for 5-10% of familial PD, but also being found in 2008: 111: 2230-2237; J. M. Irish et al. Blood, 2006; 108: a significant proportion of sporadic PD cases (see Farrer, M., 3135-3142; A. Renaldietal. Brit J. Haematology, 2006; 132: Stone, J., Mata, I.F., Lincoln, S. Kachergus, J., Hulihan, M., 303-316; M. Guruoajan et al. J. Immunol, 2006; 176: 5715 Strain, K. J. and Maraganore, D. M. (2005) LRRK2 muta 57.19; L. Laseux et al. Blood, 2006; 108: 4156-4162. tions in Parkinson disease. Neurology. 65,738-740; Zabetian, 0027. A recent publication summarizes the frequent find C. P. Sami, A., Mosley, A. D. Roberts, J. W., Leis, B. C. ing of eye involvement with rheumatoid arthritis and other Yearout, D., Raskind, W. H. and Griffith, A. (2005) A clinic autoimmune diseases. Scleritis, episcleritis and keratocon based study of the LRRK2 gene in Parkinson disease yields junctivitis sicca may represent the leading clinical manifes new mutations. Neurology. 65, 741-744. Little is known tation of these autoimmune diseases. All components of the about how LRRK2 is regulated in cells, what its physiological visual organ might be affected. Autoimmune reactions based substrates are and how mutations cause or increase risk of PD. on the patients genetic predisposition are assumed to be of 0033 Genomewide-wide association studies show a pos significance in pathogenesis of eye diseases. sible involvement in further neurodegenerative diseases like 0028. This manifests Syk as relevant therapeutic target in Alzheimer furthermore leprosy but also revealed a higher occular diseases. (Feist, E., Pleyer, U., Z Rheumatol, 69: probability of cancer occurrence for carriers of LRRK2 403-410, 2010). mutants and may indicate an involvement of this kinase and mutants in cancer development. Inzelberg, et al. The LRRK2 0029. Furthermore SYK is also a relevant target in the G2019S mutation is associated with Parkinson disease and treatment of fungal, viral and bacterial infections of the eye concomitant non-skin cancers. Neurology, 2012, 78, 781 e.g. fungal keratitis. Dectin-1 mediated activation of p-Syk, 786. Zhao, Y., Ho, P., Yih, Y., Chen, C., Lee, W. L., & Tan, E. and further factors as p-IkB or NFkB lead to the production of K. (2011). LRRK2 variant associated with Alzheimer's dis IL-1b and CXCL1/KC that are important for neutrophiland ease. Neurobiology of aging, 32(11), 1990-1993. Lewis, P. mononuclear cell recruitment to the corneal stroma. Leal, S. A., & Manzoni, C. (2012). LRRK2 and Human Disease: A M. Cowden, S., Hsia, Y.-C., Ghannoum, M.A., Momany, M., Complicated Question or a Question of Complexes? Science & Pearlman, E. (2010). Distinct roles for Dectin-1 and TLR4 Signaling, 5(207). in the pathogenesis of Aspergillus fumigatus keratitis. PLoS Pathogens, 6. 0034. An unexpected finding was the involvement of LRRK2 as a major susceptibility gene for Crohn's disease 0030. In general recent evidence shows that SYK is a (CD) and other related inflammatory diseases. LRRK2 defi essential target for treatment of PRR and CLR mediated ciency in mice confers enhanced Susceptibility to experimen adaptive immune response. Kingeter, L.M., & Lin, X. (2012). tal colitis. The complex nature of the multidomain LRRK2 C-type lectin receptor-induced NF-kB activation in innate protein makes it plausible that LRRK2 may also regulate immune and inflammatory responses. Cellular & molecular different pathways in immune reactions through its involve immunology, 9(2), 105-112. Drummond, R. A., Saijo, S., ment in NFAT1 regulation in participating in the NRON com Iwakura, Y., & Brown, G. D. (2011). The role of Syk/CARD9 plex in immune cells. Liu, Z. & Lenardo, M.J. (2012) “The coupled C-type lectins in antifungal immunity. European role of LRRK2 in inflammatory bowel disease’. Cell journal of immunology, 41(2), 276-281. Lee, H.-M., Yuk, research; “LRRK2 as a negative regulator of NFAT: implica J.-M., Kim, K.-H., Jang, J., Kang, G., Park, J. B., Son, J.-W., tions for the pathogenesis of inflammatory bowel disease' et al. (2011). Mycobacterium abscessus activates the NLRP3 Puja Vora, Dermot P B McGovern. Expert Review of Clinical inflammasome via Dectin-1-Syk and p62/SQSTM1. Immu Immunology, March 2012, Vol. 8, No. 3, Pages 227-229. nology and cell biology. 0035. According to one embodiment, the present inven 0031. According to one embodiment, the present inven tion provides compounds that are capable of inhibiting one or tion provides compounds that are capable of inhibiting one or more kinases, more particularly, LRRK, even more prefer more kinases, more particularly SYK and mutants thereof. ably LRRK2. US 2012/032978.0 A1 Dec. 27, 2012

Myosin Light Chain Kinase (MLCK or MYLK) N. Wangensteen R, Ohlmann P. Loichot C, Tesse A, Cha lupsky K, Lobysheva I, Haiech J. Watterson D M and Andri 0036. Inhibitors of MYLK (or MLCK) are of interest in antsitohaina R (2007) Protection against endotoxic shock as a the treatment and/or prevention of any disorder where tissue consequence of reduced nitrosative stress in MLCK210-null barrier dysfunction or changes in cell motility are part of the mice. Am J Pathol 170:439-446: Reynoso R, Perrin RM, disease mechanism or progression of pathophysiology. These Breslin JW, Daines DA, Watson KD, Watterson DM, Wu M include a large number of diseases in a variety of categories, Hand Yuan SA role for long chain myosin light chain kinase including but not limited to skin disorders: including ichthyo (MLCK-2 10) in microvascular hyperpermeability during sis Vulgaris, atopic dermatitis, psoriasis, eczema, allergic skin severe burns. Shock, June 14 epub; Rossi J. Bayram M. Udel disease, and hypersensitivity reactions; intestinal disorders: son JE, Lloyd-Jones D, Adams K F. Oconnor CM, Stough W including inflammatory bowel disease, Crohn's disease, G, Ouyang J, Shin D D, Orlandi Cand Gheorghiade M (2007) ulcers, bacterial infections hemorrhagic shock, diarrhea, coli Improvement in hyponatremia during hospitalization for tis, viral and alcoholic liver disease, pancreatitis; lung disor worsening heart failure is associated with improved out ders: including acute lung injury after infection, mechanical comes: insights from the Acute and Chronic Therapeutic ventilation-induced injury, sepsis, thrombin-induced lung Impact of a Vasopressin Antagonist in Chronic Heart Failure injury, lung injury after reperfusion; interstitial cystitis of the (ACTIV in CHF) trial. Acute Card Care 9:82-86: Scott KG, bladder, coronary disease after ischemia-reperfusion injury, Meddings J. B. Kirk D R, Lees-Miller S P and Buret AG flow-induced injury, aortic aneurysm, hypertension; burn (2002) Intestinal infection with Giardia spp. reduces epithe induced injury; chorioretinal vascular disease; neurologic lial barrier function in a myosin light chain kinase-dependent disorders: including multiple Sclerosis, Alzheimer's disease, fashion. Gastroenterology 123: 1179-1190; Tohtong R, Phat vascular dementia, traumatic brain injury, ALS, Parkinson's tarasakul K, Jiraviriyakul A and Sutthiphongchai T (2003) disease, stroke, meningoencephalitis, cerebral hemorrhage, Dependence of metastatic cancer cell invasion on MLCK Guillain-Barre syndrome, Vasogenic brain edema, hypoxia catalyzed phosphorylation of myosin regulatory light chain. induced injury and bloodbrain barrier compromise after etha Prostate Cancer Prostatic Dis 6: 212-216; Yuan SY (2002) nol toxicity; and cancers, including metastatic cancers such as Protein kinase signaling in the modulation of microvascular non-Small cell lung cancers, pancreatic cancer, adenocarci permeability. Vascul Pharmacol 39:213-223;Yuan SY. Wu M noma and prostate cancer. See, e.g., Behanna H A, Watterson H, Ustinova EE, Guo M, Tinsley J. H. De Lanerolle P and Xu D M and Ralay Ranaivo H (2006) Development of a novel W (2002) Myosin light chain phosphorylation in neutrophil bioavailable inhibitor of the calmodulin-regulated protein stimulated coronary microvascular leakage. Circ Res 90: kinase MLCK: a lead compound that attenuates vascular leak. 1214-1221; Zolotarevsky Y. Hecht G. Koutsouris A. Gonza Biochim Biophys Acta 1763: 1266-1274; Behanna H A, Ber lez, DE, Quan C, Tom J, Mrsny RJ and Turner J R (2002) A gan Rand Watterson DM (2007), unpublished observations: membrane-permeant peptide that inhibits MLC kinase Bratcher J M and Korelitz BI (2006) Toxicity of infliximab in restores barrier function in in vitro models of intestinal dis the course of Crohn's disease. Expert Opin Drug Saf 5:9-16; ease. Gastroenterology 123 (2002) 163-172. Role of myosin Clayburgh D R. Shen L and Turner J R (2004) A porous light chain kinase in regulation of basal blood pressure and defense: the leaky epithelial barrier in intestinal disease. Lab maintenance of salt-induced hypertension. (2011). Role of Invest 84: 282-291; Clayburgh D R, Barrett T A, Tang Y. myosin light chain kinase in regulation of basal blood pres Meddings JB, Van Eldik L. J. Watterson DM, Clarke L. L. Sure and maintenance of salt-induced hypertension. Ameri Mrsny RJ and Turner J R (2005) Epithelial myosin light chain can journal of physiology. Heart and circulatory physiology, kinase-dependent barrier dysfunction mediates T cell activa 301(2). tion-induced diarrhea in vivo. J. Clin Invest 11.5: 2702-2715; 0037 According to one embodiment, the present inven Demling R H (2005) The burn edema process: current con tion provides compounds that are capable of inhibiting one or cepts. J Burn Care Rehabil 26: 207-227: Dreyfuss D and Saumon G (1998) Ventilator-induced lung injury: lessons more kinases, especially MYLK (or MLCK). from experimental studies. Am J Respir Crit. Care Med 157: STATEMENT OF INVENTION 294-323; Haorah J. Heilman D. Knipe B, Chrastil J, Leibhart 0038. The present invention provides one or more com J. Ghorpade A, Miller DW and Persidsky Y (2005) Ethanol pounds of formula (I) induced activation of myosin light chain kinase leads to dys function of tight junctions and blood-brain barrier compro mise. Alcohol Clin Exp Res 29: 999-1009: Huang Q, Xu W. (I) Ustinova E, Wu M, Childs E. Hunter F and Yuan S (2003) Myosin light chain kinase-dependent microvascular hyper permeability in thermal injury. Shock 20:363-368; Kaneko K. Satoh K, Masamune A, Satoh A and Shimosegawa T (2002) Myosin light chain kinase inhibitors can block inva sion and adhesion of human pancreatic cancer cell lines. Pancreas 24:34-41; Ma TY, Boivin MA, Ye D, Pedram Aand Said H M (2005) Mechanism of TNFalpha modulation of Caco-2 intestinal epithelial tight junction barrier: role of myosin light-chain kinase protein expression. Am J Physiol wherein Gastrointest Liver Physiol 288: G422-G430; Minamiya Y. A is O, S, C-O, NR or CRR (especially NH); Nakagawa T. Saito H. Matsuzaki I, Taguchi K, Ito M and R" is an optionally substituted alkyl, alkenyl, alkynyl, het Ogawa J (2005) Increased expression of myosin light chain eroalkyl, aryl, heteroaryl, cycloalkyl, alkylcycloalkyl, het kinase mRNA is related to metastasis in non-Small cell lung eroalkylcycloalkyl, heterocycloalkyl, aralkyl or hetero cancer. Tumour Biol 26: 153-157; Ralay Ranaivo H. Carusio aralkyl group; US 2012/032978.0 A1 Dec. 27, 2012

R’ is an optionally substituted alkyl, alkenyl, alkynyl, het from O, S and/or N (especially O and/or N). The term C-C, eroalkyl, aryl, heteroaryl, cycloalkyl, alkylcycloalkyl, het heteroalkyl refers to a heteroalkyl group containing from 1 to eroalkylcycloalkyl, heterocycloalkyl, aralkyl or hetero 4 carbon atoms and 1, 2 or 3 heteroatoms selected from O, S aralkyl group, wherein R is preferably bound to the and/or N (especially 0 and/or N). Furthermore, the term het pyrimidine ring of formula (I) via a carbon-carbon bond; eroalkyl refers to groups in which one or more hydrogen R is a hydrogen atom, a halogen atom, NO, N, OH, SH, atoms have been replaced by a halogenatom (preferably For NH2 or an alkyl, alkenyl, alkynyl, heteroalkyl, aryl, het Cl). eroaryl, cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, hetero-cycloalkyl, aralkyl or heteroaralkyl group; 0043. Examples of heteroalkyl groups are groups of for R" is a hydrogen atom or an alkyl, alkenyl, alkynyl, hetero mulae: R O Y" . R. S. Y. , R. N(R) Y. , alkyl, aryl, heteroaryl, cycloalkyl, alkylcycloalkyl, hetero R CO Y , R O CO. Y. , R. CO O alkylcycloalkyl, heterocycloalkyl, aralkyl or heteroaralkyl Y , R. CO N(R) Y. , R. N(R) CO Y , group; R O CO. N(R) Y. , R" N(R) CO. O. R is a hydrogen atom, NO, N, OH, SH, NH, or an alkyl, Y , R. N(R) CO N(R) Y. , R O CO alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, O Y , R" N(R) C(-NR) N(R) Y. , R. CS Y , R O CS Y , R. CS O Y , alkylcycloalkyl, heteroalkylcycloalkyl, heterocycloalkyl, R. CS N(R) Y. , R. N(R) CS Y , aralkyl or heteroaralkyl group; and R O CS N(R) Y. , R. N(R) CS O Y R is a hydrogen atom, NO, N, OH, SH, NH, or an alkyl, R. N(R) CS N(R) Y. , R. O CS O Y alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, R. S. CO Y , R. CO S. Y. , R S CO N alkylcycloalkyl, heteroalkylcycloalkyl, heterocycloalkyl, (R) Y. , R. N(R) CO S. Yi , R S CO aralkyl or heteroaralkyl group; O Y , R O CO. S. Y' R S CO S ora pharmaceutically acceptable salt, ester, Solvate or hydrate Y , R S CS Y , R. CS S Y , R. S or a pharmaceutically acceptable formulation thereof. CS N(R) Y. , R. N(R) CS S Y , R. S 0039. The expression alkyl refers to a saturated, straight CS O Y" . R O CS S Y“ , wherein R being a chain or branched hydrocarbon group that contains from 1 to hydrogen atom, a C-C alkyl, a C-C alkenyl or a C-C, 20 carbon atoms, preferably from 1 to 12 carbon atoms, alkynyl group; R being a hydrogen atom, a C-C alkyl, a especially from 1 to 6 (e.g. 1, 2, 3 or 4) carbon atoms, for C-C alkenyl or a C-C alkynyl group; R being a hydrogen example a methyl, ethyl, propyl, iso-propyl. n-butyl, iso atom, a C-C alkyl, a C-C alkenyl or a C-C alkynyl butyl, sec-butyl, tert-butyl, n-pentyl, iso-pentyl, n-hexyl, 2.2- group; R being a hydrogen atom, a C-C alkyl, a C-C, dimethylbutyl or n-octyl group. Furthermore, the term alkyl alkenyl or a C-C alkynyl group and Y being a direct bond, refers to groups in which one or more hydrogen atoms have a C-C alkylene, a C-C alkenylene or a C-C alky been replaced by a halogenatom (preferably For Cl) such as, nylene group, wherein each heteroalkyl group contains at for example, a 2.2.2-trichloroethyl or a trifluoromethyl group. least one carbon atom and one or more hydrogen atoms may 0040. The expressions alkenyl and alkynyl refer to at least be replaced by fluorine or chlorine atoms. partially unsaturated, straight-chain or branched hydrocarbon groups that contain from 2 to 20 carbon atoms, preferably 0044 Specific examples of heteroalkyl groups are meth from 2 to 12 carbonatoms, especially from 2 to 6 (e.g. 2, 3 or oxy, trifluoromethoxy, ethoxy, n-propyloxy, isopropyloxy, 4) carbon atoms, for example an ethenyl (vinyl), propenyl butoxy, tert-butyloxy, methoxymethyl, ethoxymethyl, (allyl), iso-propenyl, butenyl, ethinyl, propinyl, butinyl, —CH2CH2OH. —CH2OH. methoxyethyl, 1-methoxyethyl, acetylenyl, propargyl, isoprenyl or hex-2-enyl group. Pre 1-ethoxyethyl, 2-methoxyethyl or 2-ethoxyethyl, methy ferably, alkenyl groups have one or two (especially preferably lamino, ethylamino, propylamino, isopropylamino, dimethy one) double bond(s), and alkynyl groups have one or two lamino, diethylamino, isopropyl-ethylamino, methylamino (especially preferably one) triple bond(s). Furthermore, the methyl, ethylamino methyl, diiso-propylamino ethyl, meth terms alkenyl and alkynyl refer to groups in which one or ylthio, ethylthio, isopropylthio, enol ether, dimethylamino more hydrogen atoms have been replaced by a halogenatom methyl, dimethylamino ethyl, acetyl, propionyl, butyryloxy, (preferably For Cl). acetyloxy, methoxycarbonyl, ethoxy-carbonyl, propiony 0041. The expression heteroalkyl refers to an alkyl, alk loxy, acetylamino or propionylamino, carboxymethyl, car enyl or alkynyl group in which one or more (preferably 1, 2 or boxyethyl or carboxypropyl. N-ethyl-N-methylcarbamoyl or 3) carbon atoms have been replaced by an oxygen, nitrogen, N-methylcarbamoyl. Further examples of heteroalkyl groups phosphorus, boron, selenium, silicon or Sulfur atom (prefer are nitrile, isonitrile, cyanate, thio-cyanate, isocyanate, ably by an oxygen, Sulfur or nitrogen atom). The expression isothiocyanate and alkylnitrile groups. heteroalkyl furthermore refers to a carboxylic acid or to a 0045. The expression cycloalkyl refers to a saturated or group derived from a carboxylic acid, such as, for example, partially unsaturated (for example, a cycloalkenyl group) acyl, acylalkyl, alkoxycarbonyl, acyloxy, acyloxyalkyl, car cyclic group that contains one or more rings (preferably 1 or boxyalkylamide or alkoxycarbonyloxy. 2), and contains from 3 to 14 ring carbon atoms, preferably 0042 Preferably, a heteroalkyl group contains from 1 to from 3 to 10 (especially 3, 4, 5, 6 or 7) ring carbonatoms. The 12 carbon atoms and from 1 to 4 hetero atoms selected from expression cycloalkyl refers furthermore to groups in which oxygen, nitrogen and Sulphur (especially oxygen and nitro one or more hydrogen atoms have been replaced by fluorine, gen). Especially preferably, a heteroalkyl group contains chlorine, bromine or iodine atoms or by OH, =O, SH, =S. from 1 to 6 (e.g. 1, 2, 3 or 4) carbon atoms and 1, 2 or 3 NH =NH, N, or NO. groups, thus, for example, cyclic (especially 1 or 2) hetero atoms selected from oxygen, nitro ketones such as, for example, cyclohexanone, 2-cyclohex gen and Sulphur (especially oxygen and nitrogen). The term enone or cyclopenta-none. Further specific examples of C-C heteroalkyl refers to a heteroalkyl group containing cycloalkyl groups are a cyclopropyl, cyclobutyl, cyclopentyl, from 1 to 6 carbon atoms and 1, 2 or 3 heteroatoms selected spiro4.5 decanyl, norbornyl, cyclohexyl, cyclopentenyl, US 2012/032978.0 A1 Dec. 27, 2012 cyclohexadienyl, decalinyl, bicyclo4.3.0nonyl, tetraline, Zolyl, tetrazolyl pyrazinyl, pyrimidinyl, pyridazinyl, cyclopentylcyclohexyl, fluorocyclohexyl or cyclohex-2-enyl oxazolyl, isoxazolyl, triazolyl, tetrazolyl, isoxazolyl, inda group. Zolyl, indolyl, benzimidazolyl, benzoxazolyl, benzisoX 0046. The expression heterocycloalkyl refers to a azolyl, benzthiazolyl pyridazinyl, quinolinyl, isoquinolinyl, cycloalkyl group as defined above in which one or more pyrrolyl, purinyl, carbazolyl, acridinyl, pyrimidyl, 2,3-bifu (preferably 1, 2 or 3) ring carbonatoms have been replaced by ryl, pyrazolyl (e.g. 3-pyrazolyl) and isoquinolinyl groups. an oxygen, nitrogen, silicon, selenium, phosphorus or Sulfur 0051. The expression aralkyl refers to groups containing atom (preferably by an oxygen, Sulfur or nitrogen atom). A both aryl and also alkyl, alkenyl, alkynyl and/or cycloalkyl heterocycloalkyl group has preferably 1 or 2 ring(s) contain groups in accordance with the above definitions, such as, for ing from 3 to 10 (especially 3, 4, 5, 6 or 7) ring atoms example, arylalkyl, arylalkenyl, arylalkynyl, arylcycloalkyl, (preferably selected from C, O, N and S). The expression aryl-cycloalkenyl, alkylarylcycloalkyl and alkylarylcy heterocycloalkyl refers furthermore to groups in which one or cloalkenyl groups. Specific examples of aralkyls are toluene, more hydrogen atoms have been replaced by fluorine, chlo Xylene, mesitylene, styrene, benzyl chloride, o-fluorotoluene, rine, bromine or iodine atoms or by OH, =O, SH, =S, NH, 1H-indene, tetraline, dihydronaphthalene, indanone, phenyl —NH, N, or NO groups. Examples area piperidyl, prolinyl, cyclopentyl, cumene, cyclohexylphenyl, fluorene and indane. imidazolidinyl, piperazinyl, morpholinyl, urotro-pinyl, pyr Anaralkyl group preferably contains one or two aromatic ring rolidinyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahy systems (1 or 2 rings) containing from 6 to 10 carbon atoms drofuryl or 2-pyrazolinyl group and also lactames, lactones, and one or two alkyl, alkenyl and/or alkynyl groups contain cyclic imides and cyclic anhydrides. ing from 1 or 2 to 6 carbon atoms and/or a cycloalkyl group 0047. The expression alkylcycloalkyl refers to groups that containing 5 or 6 ring carbon atoms. contain both cycloalkyl and also alkyl, alkenyl or alkynyl groups in accordance with the above definitions, for example 0.052 The expression heteroaralkyl refers to an aralkyl alkylcyclo-alkyl, cycloalkylalkyl, alkylcycloalkenyl, alk group as defined above in which one or more (preferably 1, 2, enylcycloalkyl and alkynylcycloalkyl groups. An alkylcy 3 or 4) carbon atoms have been replaced by an oxygen, cloalkyl group preferably contains a cycloalkyl group that nitrogen, silicon, selenium, phosphorus, boron or Sulfur atom contains one or two rings having from 3 to 10 (especially 3, 4, (preferably oxygen, Sulfur or nitrogen), that is to say to groups 5, 6 or 7) ring carbon atoms, and one or two alkyl, alkenyl or containing both aryl or heteroaryl, respectively, and also alkynyl groups (especially alkyl groups) having 1 or 2 to 6 alkyl, alkenyl, alkynyl and/or heteroalkyl and/or cycloalkyl carbon atoms. and/or heterocycloalkyl groups in accordance with the above 0048. The expression heteroalkylcycloalkyl refers to alky definitions. A heteroaralkyl group preferably contains one or lcycloalkyl groups as defined above in which one or more two aromatic ring systems (1 or 2 rings) containing from 5 or (preferably 1, 2 or 3) carbon atoms have been replaced by an 6 to 10 ring carbonatoms and one or two alkyl, alkenyland/or oxygen, nitrogen, silicon, selenium, phosphorus or Sulfur alkynyl groups containing 1 or 2 to 6 carbon atoms and/or a atom (preferably by an oxygen, Sulfur or nitrogen atom). A cycloalkyl group containing 5 or 6 ring carbon atoms, heteroalkylcycloalkyl group preferably contains 1 or 2 rings wherein 1, 2, 3 or 4 of these carbon atoms have been replaced having from 3 to 10 (especially 3, 4, 5, 6 or 7) ring atoms, and by oxygen, Sulfur or nitrogen atoms. one or two alkyl, alkenyl, alkynyl or heteroalkyl groups (espe 0053 Examples are arylheteroalkyl, arylheterocy cially alkyl or heteroalkyl groups) having from 1 or 2 to 6 cloalkyl, aryl-heterocycloalkenyl, arylalkylheterocycloalkyl, carbon atoms. Examples of Such groups are alkylheterocy arylalkenyl-heterocycloalkyl, arylalkynylheterocycloalkyl, cloalkyl, alkylheterocycloalkenyl, alkenylheterocycloalkyl, arylalkyl-heterocycloalkenyl, heteroarylalkyl, heteroarylalk alkynylheterocycloalkyl, heteroalkylcycloalkyl, heteroalkyl enyl, heteroarylalkynyl, heteroarylheteroalkyl, heteroaryl heterocycloalkyl and heteroalkylheterocycloalkenyl, the cycloalkyl, heteroarylcycloalkenyl, heteroarylhetero-cy cyclic groups being Saturated or mono-, di- or tri-unsaturated. cloalkyl, heteroarylheterocycloalkenyl, heteroarylalkyl 0049. The expression aryl refers to an aromatic group that cycloalkyl, heteroarylalkylheterocycloalkenyl, heteroaryl contains one or more rings containing from 6 to 14 ring heteroalkylcycloalkyl, heteroarylheteroalkylcycloalkenyl carbon atoms, preferably from 6 to 10 (especially 6) ring and heteroarylheteroalkylheterocycloalkyl groups, the cyclic carbon atoms. The expression aryl refers furthermore to groups being Saturated or mono-, di- or tri-unsaturated. Spe groups in which one or more hydrogen atoms have been cific examples are a tetrahydroisoquinolinyl, benzoyl, 2- or replaced by fluorine, chlorine, bromine or iodine atoms or by 3-ethylindolyl, 4-methylpyridino, 2-, 3- or 4-methoxyphenyl, OH, SH, NH, N, or NO, groups. Examples are the phenyl, 4-ethoxyphenyl, 2-, 3- or 4-carboxy-phenylalkyl group. naphthyl, biphenyl, 2-fluorophenyl, anilinyl, 3-nitrophenyl or 0054 The expression “optionally substituted especially 4-hydroxyphenyl group. refers to groups in which one, two, three or more hydrogen 0050. The expression heteroaryl refers to an aromatic atoms may have been replaced by fluorine, chlorine, bromine group that contains one or more rings containing from 5 to 14 or iodine atoms or by OH, =O, SH, =S, NH, —NH, N, or ring atoms, preferably from 5 to 10 (especially 5 or 6 or 9 or NO groups. This expression refers furthermore to groups 10) ring atoms, and contains one or more (preferably 1, 2, 3 or that may be substituted by one, two, three or more unsubsti 4) oxygen, nitrogen, phosphorus or Sulfur ring atoms (pref tuted C-Co alkyl, C-Co alkenyl, C-Co alkynyl, het erably O, S or N). The expression heteroaryl refers further eroalkyl, C-C cycloalkyl, C-C, heterocycloalkyl, Ca-Co more to groups in which one or more hydrogen atoms have alkylcycloalkyl, C-Co heteroalkylcycloalkyl, C-Cs aryl, been replaced by fluorine, chlorine, bromine or iodine atoms C-C, heteroaryl, C7-Caralkyl or C-C heteroaralkyl or by OH, SH, N, NH or NO groups. Examples are pyridyl groups. This expression refers furthermore especially to (e.g. 4-pyridyl), imidazolyl (e.g. 2-imidazolyl), phenylpyrro groups that may be substituted by one, two, three or more lyl (e.g. 3-phenylpyrrolyl), thiazolyl, isothiazolyl, 1,2,3-tria unsubstituted C-C alkyl, C-C alkenyl, C-C alkynyl, Zolyl, 1,2,4-triazolyl, oxadiazolyl, thiadiazolyl, indolyl, inda C-C heteroalkyl, C-Co cycloalkyl, C-C heterocy US 2012/032978.0 A1 Dec. 27, 2012 cloalkyl, C7-C alkylcycloalkyl, C-C heteroalkylcy ing one or two rings containing 5, 6, 7, 8, 9 or 10 ring atoms, cloalkyl, Co-Co aryl, C-C heteroaryl, C7-Caralkyl or or an optionally substituted arylheterocycloalkyl, heteroaryl C-C heteroaralkyl groups. cycloalkyl or heteroarylheterocycloalkyl group containing 0055 Preferred substituents are F, Cl, Br, OH, =O, NH, two or three (especially two) rings and from 9 to 20 (espe C. alkyl (e.g. methyl, ethyl, t-butyl), NMe2, CONH2, cially 9 or 10) ring atoms. Preferably, the heteroatoms are CHNMe, NHSOMe, C(CH)CN, COMe, OMe, S.Me, selected from S. O and N. Further preferably, the number of COOMe, COOEt, CHCOOH, OCHCOOH, COOH, heteroatoms is from 1 to 6 (especially 1, 2, 3 or 4). SOMe, SOMe, cyclopropyl, SONH, SONHMe, SOCHCH-OH, SF, SONMe, OCF, SOCF, COMe, 0067. As already mentioned above, according to a pre CN or CF. ferred embodiment of the present invention, R is bound to the 0056 Especially preferred substituents are F, Cl, Br, OH, pyrimidine ring of formula (I) or (Ia) via a carbon-carbon NH, Me, Ethyl, NMe, CONHOMe, CN or CF. bond. In other words, R is bound to the pyrimidine moiety of 0057 According to a preferred embodiment, all alkyl, alk formula (I) or (Ia) via a carbon atom, i.e. a carbon atom of enyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, het group R is bound to the pyrimidine moiety. erocycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, aralkyl and heteroaralkyl groups described herein may 0068. Especially preferred are compounds of formula (I) optionally be substituted. or (Ia) wherein, R is selected from the following groups: 0058 When an aryl, heteroaryl, cycloalkyl, alkylcy phenyl: 3-anisyl, 4-anisyl: 2-anisyli; 4.5 dimethoxyphenyl: cloalkyl, hetero-alkylcycloalkyl, heterocycloalkyl, aralkyl or 6-hydroxyphenyl: 4-pyridyl; 6-pyrrolidinyl-3-pyridinyl: heteroaralkyl group contains more than one ring, these rings 3-pyrid-3-ylphenyl: 3-morpholinophenyl: 1-methyl-4-pip may be bonded to each other via a single or double bond or eridyl: 2-thienyl: 3-thienyl: 3-pyrazolyl: 2-benzthiazolyl: these rings may be annulated. imidazol-2-alpyridin-2-yl: 3.6 dimethoxyphenyl; benzimi 0059. Further preferred are compounds of formula (I) or daZ-2-yl and 1-methyl-2-benzimidazolyl. (Ia) wherein R' is an optionally substituted aryl, heteroaryl, 0069. Especially preferably, R is selected from the fol cycloalkyl, heterocycloalkyl, alkylcycloalkyl, heteroalkylcy lowing groups: cloalkyl, aralkyl or heteroaralkyl group. 0060 Morover preferred are compounds of formula (I) or (Ia) wherein R' is an optionally substituted phenyl or naph thyl group or an optionally substituted heteroaryl group hav ing one or two rings containing 5, 6, 7, 8, 9 or 10 ring atoms, or an optionally substituted arylheterocycloalkyl or het eroaryl-heterocycloalkyl group containing two or three (es pecially two) rings and from 9 to 20 (especially 9 or 10) ring atoms. Preferably, the heteroatoms are selected from S. Oand N, especially from NandO. Further preferably, the number of heteroatoms is from 1 to 6 (especially 1, 2, 3 or 4). 0061 Preferred are compounds of formula (I) wherein A is NH. 0062. Further preferred are compounds of formula (I) wherein R is H, F, Cl, CH, CF, NO, cyclopropyl, CN, N. OH, SH, OMe, SMe, NHMe, NMe, or NH, 0063 Moreover preferred are compounds of formula (I) wherein R is a hydrogenatom. 0064. Especially preferred are compounds of formula (I) wherein A is NH and R is H, i.e. compounds of formula (Ia):

(Ia) R n NH

N 21 2N NH Sa S. wherein R' and Rare as defined above. 0065. Further preferred are compounds of formula (I) or (Ia) wherein R is an optionally substituted aryl, heteroaryl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl, heteroalkylcy cloalkyl, aralkyl or heteroaralkyl group. 0066. Moreover preferred are compounds of formula (I) or (Ia) wherein R is an optionally substituted phenyl or naph thyl group or an optionally Substituted heteroaryl group hav US 2012/032978.0 A1 Dec. 27, 2012

S d - hi - O - () --O" ( ) US 2012/032978.0 A1 Dec. 27, 2012 10

-continued 0072 Further preferred are compounds of formula (Ic):

(Ic)

R11 0070 Moreover preferably, R is derived from the follow ing aldehydes: benzaldehyde; isonicotinaldehyde; 6-(pyrro wherein R'' and R'' together are part of an optionally sub lidin-1-yl)nicotinaldehyde; 3,4-dimethoxybenzaldehyde: stituted cycloalkyl or heterocycloalkyl group and R' is as 1-methylpiperidine-4-carbaldehyde; 1 H-pyrazole-3-carbal defined above. dehyde: 4-methoxybenzaldehyde: 3-methoxybenzaldehyde: 0073. Further preferred are compounds of formula (I), thiophene-2-carbaldehyde; thiophene-3-carbaldehyde; (Ia), (Ib)and (Ic) wherein R' is an aryl, heteroaryl, cycloalkyl, benzodthiazole-2-carbaldehyde: 3-(pyridin-3-yl)benzalde heterocycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, hyde: 2-hydroxybenzaldehyde: 3-morpholinobenzaldehyde; aralkyl or heteroaralkyl group, all of which may optionally be 2-methoxybenzaldehyde; 2,5-dimethoxybenzaldehyde; substituted. N-(2-aminoethyl)-3-formylbenzamide; imidazo 1,2-alpyri 0074. Further preferred are compounds of formula (I), dine-2-carbaldehyde; 1 H-benzodimidazole-2-carbalde (Ia), (Ib) and (Ic) wherein R' is an aryl, heteroaryl, CH2-aryl hyde; 1-methyl-1H-benzodimidazole-2-carbaldehyde; or CH-heteroaryl group, all of which may optionally be 1H-imidazole-5-carbaldehyde: 1H-imidazole-2-carbalde substituted. hyde: 3-(2H-tetrazol-5-yl)benzaldehyde: 2-oxo-2-phenylac 0075 Moreover preferred are compounds of formula (I), etaldehyde: 3-formylbenzoic acid: 2-(3-formylphenoxy)ace (Ia), (Ib) and (Ic) wherein R' is an optionally substituted tic acid; 5-formylthiophene-3-carboxylic acid: 2-(3- phenyl or naphthyl group or an optionally Substituted het formylphenyl)acetic acid; 6-formylpicolinic acid; thiazole-2- eroaryl group having one or two rings containing 5, 6, 7, 8, 9 carbaldehyde; 3-(((4-methylbenzyl)amino)methyl) or 10 ring atoms, or an optionally Substituted arylheterocy benzaldehyde; 3-(3-(dimethylamino)propoxy) cloalkyl, heteroarylcycloalkyl or heteroarylheterocycloalkyl group containing two or three (especially two) rings and from benzaldehyde; 3-formylbenzenesulfonamide: N-(3- 9 to (especially 9 or 10) ring atoms. Preferably, the heteroa formylphenyl)methanesulfonamide; thiazole-4- toms are selected from S. O and N, especially from N and O. carbaldehyde; oxazole-4-carbaldehyde; oxazole-2- Further preferably, the number of heteroatoms is from 1 to 6 carbaldehyde; methyl 3-formylbenzoate: methyl (especially 1, 2, 3 or 4). 4-formylbenzoate: 3-(pentafluorosulfanyl)benzaldehyde: I0076 Especially preferably, R is an optionally substi 3-(methylthio)benzaldehyde: 3-(trifluoromethoxy)benzalde tuted phenyl group or an optionally Substituted heteroaryl hyde: 3-(trifluoromethyl)benzaldehyde: 3-chlorobenzalde group having one ring containing 5 or 6 ring atoms. Prefer hyde; 2-fluorobenzaldehyde; 3-fluorobenzaldehyde: ably this phenyl or heteroaryl group is substituted by one or 4-formylbenzoic acid; 3-(methylsulfonyl)benzaldehyde: more (especially one) C-C alkyl, C-C alkenyl, C-Co 1H-indazole-6-carbaldehyde; 1H-pyrrolo3.2-bipyridine-6- alkynyl, C-Cohetero-alkyl, C-Cs cycloalkyl, C-C, het carbaldehyde: 4-fluorobenzaldehyde; 3,4-difluorobenzalde erocycloalkyl, Ca-Coalkylcycloalkyl, C-Cls heteroalkylcy hyde; 3,5-difluorobenzaldehyde; 2,6-difluorobenzaldehyde; cloalkyl, C-Cs aryl, heteroaryl, C7-Co aralkyl or C-Co 2,4-difluorobenzaldehyde: 3-oxo-3,4-dihydro-2H-benzob. heteroaralkyl group(s). Preferably, the heteroatoms are 1,4-oxazine-6-carbaldehyde; selected from S. Oand N, especially from NandO. Especially preferably the phenyl or heteroaryl group is substituted by 0071. Further preferred are compounds of formula (Ib): one or more (especially one) C-C alkyl, C-C alkenyl, C-C alkynyl, C-C heteroalkyl, C-C cycloalkyl, C-Co heterocycloalkyl, C7-C alkylcycloalkyl, C-C heteroalky (Ib) lcycloalkyl, C-C aryl, C-C heteroaryl, C7-Caralkyl or C-C heteroaralkyl group(s). Preferably, the heteroatoms are selected from S. O and N, especially from N and O. 0077. Further preferred are compounds of formula (I), (Ia), (Ib) and (Ic) wherein R' is a group of formula—CH2— Arwherein Aris an optionally substituted phenyl or naphthyl group or an optionally Substituted heteroaryl group having one or two rings containing 5, 6, 7, 8, 9 or 10 ring atoms, oran optionally substituted arylheterocycloalkyl, heteroarylcyclo alkyl or heteroarylheterocycloalkyl group containing two or three (especially two) rings and from 9 to 20 (especially 9 or wherein R and R together are part of an optionally substi 10) ring atoms. Preferably, the heteroatoms are selected from tuted cycloalkyl, heterocycloalkyl, aryl or heteroaryl group S, O and N, especially from N and O. Further preferably, the and R' is as defined above. number of heteroatoms is from 1 to 6 (especially 1, 2, 3 or 4). US 2012/032978.0 A1 Dec. 27, 2012

0078 Especially preferably, Ar is an optionally substi L is a bond or a group of formula —CH2—, —C(=O)—, tuted phenyl group or an optionally Substituted heteroaryl SO— —SO —NH CO O)— —C(=O)—NH : group having one ring containing 5 or 6 ring atoms. Prefer C(=O)—O— —O—C(=O)— —NH CO O)—O—, ably this phenyl or heteroaryl group is substituted by one or O C(=O) NH , NH-SO. NH-, CH, more (especially one) C-Co alkyl, C-Coalkenyl, C-Co NH-CH , -NH SO , -SO. NH or -NH C alkynyl, C-Cohetero-alkyl, C-C cycloalkyl, C-C, het (=O) NH (preferably, L is a bond or a group of formula erocycloalkyl, Ca-Coalkylcycloalkyl, C-Coheteroalkylcy CH , —C(=O)— —SO or —NH CO O) cloalkyl, C-Cs aryl, heteroaryl, C7-Co aralkyl or C-Co NH ); heteroaralkyl group(s). Preferably, the heteroatoms are Y is an optionally substituted phenyl group, an optionally selected from S. Oand N, especially from NandO. Especially Substituted heteroaryl group containing 5 or 6 ring atoms and preferably the phenyl or heteroaryl group is substituted by 1, 2, 3 or 4 heteroatoms selected from O, S and N, an option one or more (especially one) C-C alkyl, C-C alkenyl, ally substituted C-C cycloalkyl group or an optionally Sub C-C alkynyl, C-C heteroalkyl, C-C cycloalkyl, C-C, stituted heterocycloalkyl group containing 3, 4, 5, 6 or 7 ring heterocycloalkyl, C7-C alkylcycloalkyl, C-C heteroalky atoms and 1, 2, 3 or 4 heteroatoms selected from O, S and N lcycloalkyl, Co-Co aryl, C-Coheteroaryl, C7-Caralkyl or (preferably, Y is an optionally substituted C-C, cycloalkyl C-C heteroaralkyl group(s). Preferably, the heteroatoms group or an optionally Substituted heterocycloalkyl group are selected from S. O and N, especially from N and O. containing 3, 4, 5, 6 or 7 ring atoms and 1, 2, 3 or 4 heteroa 0079. Further preferably, R is a group of formula X-L'- toms selected from O, S and N); Y' or a group of formula X-L'-Y-L-Z' wherein L' is a bond or a group of formula —CH2—, —C(=O)—, X' is an optionally substituted phenyl group or an optionally SO— —SO —NH CO O)— —C(=O)—NH : Substituted heteroaryl group containing 5 or 6 ring atoms and C(=O)—O— —O—C(=O)— —NH CO O)—O—, 1, 2, 3 or 4 heteroatoms selected from O, S and N: O C(=O) NH , NH-SO. NH-, CH L' is a bond or a group of formula —CH2—, —C(=O)—, NH-CH , -NH SO , -SO. NH or -NH C SO— —SO —NH CO O)— —C(=O)—NH : (=O) NH (preferably, L' is a bond or a group of formula C(=O)—O— —O—C(=O)— —NH CO =O)—O—, CH , —C(=O)— —SO or —NH CO O) O C(=O) NH-, NH-SO. NH , CH NH ; especially preferably, L' is a bond); and NH-CH , -NH SO, , -SO. NH- or -NH C Z is an optionally substituted phenyl group, an optionally (=O) NH (preferably, L' is a bondora group of formula Substituted heteroaryl group containing 5 or 6 ring atoms and CH2—, —CGEO)— —SO - or NH CO O) 1, 2, 3 or 4 heteroatoms selected from O, S and N, an option NH ); ally substituted C-C cycloalkyl group or an optionally Sub Y' is an optionally substituted phenyl group, an optionally stituted heterocycloalkyl group containing 3, 4, 5, 6 or 7 ring Substituted heteroaryl group containing 5 or 6 ring atoms and atoms and 1, 2, 3 or 4 heteroatoms selected from O, S and N 1, 2, 3 or 4 heteroatoms selected from O, S and N, an option (preferably, Z is an optionally substituted C-C, cycloalkyl ally substituted C-C cycloalkyl group or an optionally Sub group or an optionally Substituted heterocycloalkyl group stituted heterocycloalkyl group containing 3, 4, 5, 6 or 7 ring containing 3, 4, 5, 6 or 7 ring atoms and 1, 2, 3 or 4 heteroa atoms and 1, 2, 3 or 4 heteroatoms selected from O, S and N toms selected from O, S and N). (preferably, Y is an optionally substituted C-C, cycloalkyl I0081. Especially preferred are compounds of formula (I), (Ia), (Ib) and/or (Ic) wherein, R' is selected from the follow group or an optionally Substituted heterocycloalkyl group ing groups: 4-morpholinophenyl: 4-(4-methylpiperazino) containing 3, 4, 5, 6 or 7 ring atoms and 1, 2, 3 or 4 heteroa phenyl; 6-(4-methylpiperazino)-3-pyridyl, 4-piperidinophe toms selected from O, S and N); nyl: 4-pyrrolidinophenyl: 4-carboxyphenyl: 4-(di L is a bond or a group of formula —CH2—, —C(=O)—, methylamino)phenyl: p-amino-carbonylphenyl; SO— —SO —NH CO O)— —C(=O)—NH : 4-cyanophenyl; 4.5 dimethoxyphenyl: 3-hydroxyphenyl: C(=O)—O— —O—C(=O)— —NH CO =O)—O—, 3-aminophenyl: 3-anisyl: 1,6-benzomorpholinylene; 6-inda O C(=O) NH-, NH-SO. NH , CH Zolyl; 2H-1,4-benzoxazin-3-on-6-yl: 2-methyl-benzimida NH-CH , -NH SO, , -SO. NH- or -NH C Zol-6-yl; 6-benzotriazolyl; 5-cyclopropylpyrazol-3-yl: (=O) NH (preferably, L is a bondora group of formula 3-pyrazolyl: 2-aminocyclohexyl, 4-chlorphenyl: 3-dimethy CH2—, —C(=O)— —SO - or NH CO O) laminophenyl: 3-(aminocarbonyl)phenyl: 2-(aminocarbo NH ; especially preferably, L is a bond); and nyl)phenyl: 4-(N-ethylpiperazino)phenyl, 4-(4-cyclopropyl Z' is an optionally substituted phenyl group, an optionally 1-piperazinyl)phenyl: 4-dimethylaminomethyl-phenyl, 4-(4- Substituted heteroaryl group containing 5 or 6 ring atoms and methylpiperazinomethyl)phenyl and 4-pyrrolidinomethyl 1, 2, 3 or 4 heteroatoms selected from O, S and N, an option phenyl. ally substituted C-C cycloalkyl group or an optionally Sub I0082) Especially preferably, R is selected from the fol stituted heterocycloalkyl group containing 3, 4, 5, 6 or 7 ring lowing groups: atoms and 1, 2, 3 or 4 heteroatoms selected from O, S and N (preferably, Z' is an optionally substituted C-C, cycloalkyl group or an optionally Substituted heterocycloalkyl group containing 3, 4, 5, 6 or 7 ring atoms and 1, 2, 3 or 4 heteroa toms selected from O, S and N). N O 0080. Further preferably, R is a group of formula X-L- Y’ or a group of formula X-L-Y-L-Z wherein X is an optionally substituted phenyl group or an optionally N Substituted heteroaryl group containing 5 or 6 ring atoms and 1, 2, 3 or 4 heteroatoms selected from O, S and N: US 2012/032978.0 A1 Dec. 27, 2012 12

-continued -continued N / \ CONH, X CONH,

--O-(-)-\ ()-O-\

CN c)OH C co US 2012/032978.0 A1 Dec. 27, 2012 13

-continued -continued N%O D s^so F : C : ( ) | /\ . C / . . . . - { } { : S -i ( ) He / \-O Os/ N SS is M-7 ——{ s - ( )-( X- / \ N- O s.(Sa ( ) O o N ( N CF so so

- { } { OH () 's ( y-NH So NH to c) --O-O. N N s/ No ( ) SFs C N/ \NH

US 2012/032978.0 A1 Dec. 27, 2012

6-yl)-N-(3,4-dimethoxyphenyl)-1H-pyrazolo 4.3-d I0089. The pharmaceutical composition optionally com pyrimidin-7-amine; 5-(3,4-dihydro-2H-benzob.14 prises one or more of the following compounds or is admin oxazin-6-yl)-N-(4-morpholinophenyl)-1H-pyrazolo 4.3-d istered in combination with one or more of these compounds: pyrimidin-7-amine; 5-(3,4-dihydro-2H-benzob.14 oxazin-6-yl)-N-(2-methyl-1H-benzodimidazol-5-yl)-1H Chlorhexidine; polynoxylin; domiphen; oxyquinoline; neo pyrazolo 4,3-dipyrimidin-7-amine; N-(2-methylisoindolin mycin; miconazole; natamycin; various; hexetidine; tetracy 5-yl)-5-(thiophen-2-yl)-1H-pyrazolo 4,3-dipyrimidin-7- cline; mepartricin; metronidazole; clotrimazole; chlortetra amine; N-(1,3-dihydroisobenzofuran-5-yl)-5-(thiophen-2- cycline, doxycycline; minocycline; triamcinolone; yl)-1H-pyrazolo 4,3-dipyrimidin-7-amine; N-(3-(tert-butyl) dexamethasone; hydrocortisone; epinephrine; benzydamine; phenyl)-5-(thiophen-2-yl)-1H-pyrazolo 4,3-dipyrimidin-7- adrenalone; amlexanox; becaplermin; algeldrate; alogluta amine; methyl 3-(7-((4-(4-acetylpiperazin-1-yl)phenyl) mol; magaldrate; almagate; hydrotalcite; almasilate; cimeti amino)-1H-pyrazolo 4,3-dipyrimidin-5-yl)benzoate; methyl dine, ranitidine; famotidine; nizatidine; niperotidine; roXati 3-(7-((1H-indazol-6-yl)amino)-1H-pyrazolo4.3-dpyrimi dine; lafutidine; misoprostol; enprostil, omeprazole; din-5-yl)benzoate; methyl 3-(7-((4-morpholinophenyl) pantoprazole; lanSoprazole; rabeprazole; esomeprazole; car amino)-1H-pyrazolo 4,3-dipyrimidin-5-yl)benzoate, 5-(3- benoXolone; Sucralfate; pirenzepine; proglumide; gefarnate; aminophenyl)-N-(4-(dimethylamino)methyl)phenyl)-1H Sulglicotide; acetoxolone; Zolimidine; troXipide; oxyphen pyrazolo 4,3-dipyrimidin-7-amine; 5-(2-fluorophenyl)-N- cyclimine; camylofin, mebeverine; trimebutine; rociverine; (2-methylisoindolin-5-yl)-1H-pyrazolo 4.3-dpyrimidin-7- dicycloverine; dihexy verine; difemerine; piperidolate; ben amine; N-(4-(dimethylamino)methyl)phenyl)-5-(2- Zilone; glycopyrronium; oxyphenonium; penthienate; pro fluorophenyl)-1H-pyrazolo 4.3-dpyrimidin-7-amine; N-(3- pantheline; methantheline; tridihexethyl; isopropamide; ((dimethylamino)methyl)phenyl)-5-(2-fluorophenyl)-1H hexocyclium; poldine; mepenZolate; bevonium; pipenZolate; pyrazolo 4.3-dpyrimidin-7-amine. diphemanil; fempiverinium; dimethylaminopropionylphe nothiazine; nicofetamide; tiropramide; papaverine; drotaver I0086 Preferably, the following compounds are excluded ine; moXaverine; alosetron, tegaserod; cilansetron; prucalo from the scope of the present application: pride; fenpiprane; diisopromine; chlorbenzoxamine; pinaverium; fenoverine; idanpramine; proxazole; alverine;

trepibutone; isometheptene; caroverine: phloroglucinol; sili cones; trimethyldiphenylpropylamine; atropine; hyos cyamine; butylscopolamine; methylatropine; methylscopola mine; fentonium; metoclopramide: cisapride; domperidone: bromopride; allizapride; clebopride; ondansetron; granis etron; tropisetron; dolasetron; palonosetron; Scopolamine; chlorobutanol; metopimazine; dronabinol; nabilone: aprepi tant; casopitant; piproZolin; hymecromone; cyclobutyrol; silymarin; citiolone; epomediol; oxyphenisatine; bisacodyl; dantron; phenolphthalein; cascara; bisoxatin; ethulose; ster culia; linseed; methylcellulose; lactulose; lactitol; pentaer ithrityl; macrogol; mannitol; Sorbitol; glycerol; oil; alvimo pan, lubiprostone; nystatin; Streptomycin; paromomycin; kanamycin; Vancomycin; colistin: rifaximin, phthalylsul fathiazole; Sulfaguanidine; Succinylsulfathiazole; broX ycuinoline; acetarSol; nifuroxazide, nifurzide; pectin; kaolin; crospovidone; attapulgite; dioSmectite; diphenoxylate; opium; loperamide; difenoxin; prednisolone; prednisone; betamethasone; tixocortol; budesonide; beclometasone; Sul fasalazine; mesalazine; olsalazine; balsalazide; ceratonia; racecadotril; phentermine; fenfluramine; amfepramone; dexfenfluramine; mazindol; etilamfetamine; cathine; cloben Zorex, mefenorex: Sibutramine; orlistat; rimonabant, dia Stase; pepsin, tilactase; phenformin; metformin; buformin; glibenclamide; chlorpropamide; tolbutamide; glibornuride; tolaZamide; carbutamide; glipizide; gliquidone; gliclaZide; metahexamide; glisoxepide; glimepiride; acetohexamide; glymidine; acarbose, miglitol; Voglibose; troglitaZone; rosiglitaZone, pioglitaZone; Sitagliptin; Vildagliptin; saxa gliptin; alogliptin; repaglinide; nateglinide; exenatide; pram 0087. Especially preferably, the compounds disclosed in lintide; benfluorex: liraglutide; mitiglinide; tolrestat; betac WO 98/29413 are excluded from the scope of the present arotene; ergocalciferol, dihydrotachysterol; alfacalcidol; application. calcitriol; collecalciferol; calcifediol; Sulbutiamine; benfo 0088. The present invention further provides pharmaceu tiamine; nicotinamide; biotin; inositol; tocofersolan; dexpan tical compositions comprising one or more compounds of thenol; pantethine; androstanolone; stanozolol, metandi formula (I), (Ia), (Ib) and/or (Ic) as defined herein or a phar enone; metenolone; oxymetholone; quinbolone; prasterone; maceutically acceptable ester, prodrug, hydrate, Solvate or Oxandrolone; norethandrolone; nandrolone; ethylestrenol; salt thereof, optionally in combination with a pharmaceuti levocarnitine; ademetionine; glutamine; mercaptamine; cally acceptable carrier. betaine; alglucerase; imiglucerase; laronidase; sacrosidase; US 2012/032978.0 A1 Dec. 27, 2012 26 galsulfase; idursulfase; initisinone; miglustat; Sapropterin; lamine; Visnadine; cetiedil; cinepazide; ifenprodil, azapetine; dicoumarol; phenindione; warfarin; phenprocoumon; aceno fasudil; fluorometholone; fluocortolone; fluocinonide; tetra coumarol; clorindione; diphenadione, tioclomarol; heparin; caine; benzocaine; cinchocaine; procaine; oxetacaine; dalteparin; enoxaparin; nadroparin; parnaparin; reviparin; pramocaine; tribenoside; organo-heparinoid; polidocanol: danaparoid; tinzaparin; Sulodexide; bemiparin; ditazole; clo phenol; rutoside; monoxerutin; dioSmin; troXerutin; ricromen; picotamide; clopidogrel, ticlopidine; dipy hidrosmin, alprenolol; oXprenolol; pindolol; propranolol; ridamole: epoprostenol; indobufen, iloprost; abciximab; timolol; so talol; nadolol; mepindolol; carteolol; tertatolol; aloxiprin; eptifibatide; tirofiban; triflusal; beraprost; trepros bopindolol; bupranolol; penbutolol; cloranolol; practolol; tinil; prasugrel, streptokinase; alteplase; anistreplase; uroki metoprolol; atenolol; acebutolol; betaxolol; bevantolol; biso nase; fibrinolysin; brinase; reteplase; Saruplase; ancrod; prolol; celiprolol; esmolol; epanolol; s-atenolol; nebivolol; tenecteplase; desirudin; lepirudin; argatroban; melagatran; talinolol; labetalol; carvedilol; amlodipine; felodipine; israd Ximelagatran; bivalirudin; defibrotide; fondaparinux; rivar ipine; nicardipine; nifedipine; nimodipine; nisoldipine; Oxaban; camo.stat; phytomenadione; menadione; thrombin; nitrendipine; lacidipine; nilvadipine; manidipine; barnid collagen; etamsylate; carbazochrome; batroXobin; romi ipine; lercanidipine; cilnidipine; benidipine; mibefradil; ploStim, eltrombopag; dextriferron; cyanocobalamin; Verapamil; gallopamil; diltiazem; fendiline; bepridil; lidofla hydroxocobalamin; cobamamide; mecobalamin; erythropoi Zine; perhexyline; captopril; enalapril; lisinopril; perindopril; etin; albumin; dextran; hydroxyethylstarch; erythrocytes; ramipril; quinapril; benazepril; cilaZapril; fosinopril; tran thrombocytes; carbohydrates; electrolytes; trometamol; car dollapril; spirapril; delapril; moexipril; temocapril; Zolfeno bamide; cetylpyridinium; nitrofural; sulfamethizole; tauroli pril; imidapril; losartan, eprosartan; Valsartan; irbesartan; dine; noxytiolin; glucose: glycine; lysine: hyaluronidase; tasosartan; candesartan; telmisartan; remikiren; alliskiren; chymotrypsin, trypsin; desoxyribonuclease; bromelains; simvastatin; lovastatin; pravastatin: fluvastatin; atorvastatin: hematin; acetyldigitoxin; acetyldigoxin; digitoxin; digoxin; cerivastatin; rosuvastatin: pitavastatin: clofibrate; beZafi deslanoside; metildigoxin; gitoformate; proscillaridin; brate; gemfibrozil; fenofibrate; simfibrate; ronifibrate; g-strophanthin; cymarin; peruvoside; quinidine; procaina ciprofibrate; etofibrate; clofibride; colestyramine; colestipol: mide; disopyramide: Sparteine; ajmaline; prajmaline; colextran; colesevelam, niceritrol; nicofuranose; acipimox; lorajmine; lidocaine; mexiletine; tocamide: aprindine; pro dextrothyroxine; probucol; tiadenol; meglutol; policosanol: pafenone; flecamide; lorcamide; encamide; amiodarone; eZetimibe; hachimycin; pecilocin, pyrrolnitrin; griseofulvin; bunaftine; dolfetilide; ibutilide; tedisamil; moracizine; ciben econazole; chlormidazole; isoconazole; tiabendazole; tio Zoline; etillefrine; isoprenaline; norepinephrine: dopamine: conazole; ketoconazole; sulconazole; bifonazole; oxicona norfenefrine; phenylephrine; dobutamine; oxedrine; met Zole; fenticonazole; omoconazole; Sertaconazole; flucona araminol; methoxamine; mephentermine; dimetofrine; pren Zole; flutrimazole; bromochlorosalicylanilide; alterol: dopexamine; gepefrine; ibopamine; midodrine; octo methylrosaniline; tribromometacresol; chlorphenesin, ticla pamine; fenoldopam, cafedrine; arbutamine; theodrenaline; tone; Sulbentine; haloprogin, ciclopirox, terbinafine; amo aminone; milrinone; enoXimone; bucladesine; angiotensina rolfine; dimazole; tolnaftate; tolciclate; flucytosine; naftifine; mide; Xamoterol; levosimendan; propatylnitrate; troInitrate; butenafine; Octinoxate; dextranomer; crilanomer, enoXolone; tenitramine; floseduinan; prenylamine; oxyfedrine; benzio collagenase; thonZylamine; mepyramine; thenalidine; tripe darone; carbocromen; hexobendine; etafenone; heptaminol; lennamine; chloropyramine; promethazine; tolpropamine; imolamine; dilazep; trapidil; molsidomine; efloxate; dimetindene; clemastine; bamipine; isothipendyl; diphenhy cinepazet; cloridarol; nicorandil; linsidomine; nesiritide; dramine; chlorphenoxamine; oxybuprocaine; quinisocaine; alprostadil; camphora; indometacin; creatinolfosfate; fosfo dithranol; trioxysalen; methoXSalen; calcipotriol; tacalcitol; creatine; ubidecarenone; adenosine; tiracizine; acadesine; tri tazarotene; bergapten, etretinate; acitretin; demeclocycline; metazidine, ibuprofen; ivabradine, ranolazine; icatibant; oxytetracycline; chloramphenicol; bacitracin; gentamicin; regadenoson; rescinnamine; reserpine; deserpidine; meth tyrothricin; mupirocin, Virginiamycin; amikacin; retapamu oserpidine; bietaserpine; clonidine; guanfacine; tolonidine; lin; Sulfathiazole; mafenide; Sulfanilamide; Sulfamerazine; moXonidine, rilmenidine; trimetaphan; mecamylamine; pra idoxuridine; tromantadine; aciclovir, podophyllotoxin; Zosin; indoramin; trimaZosin: doxazosin: urapidil; betani inosine; penciclovir, lysozyme; ibacitabine, edoxudine; imi dine:guanethidine:guanoxan; debrisoquine:guanoclor, gua quimod; docosanol; methylprednisolone; clobetaSone; flu naZodine; guanoxabenz; diazoxide; dihydralazine; metaSone; fluocortin; fluperolone; fluprednidene; desonide; hydralazine; endralazine; cadralazine; minoxidil; nitroprus alclometaSone; clocortolone; fluclorolone; desoximetaSone; side; pinacidil; Veratrum; metirosine; pargyline; ketanserin; diflucortolone; fludroxycortide; diflorasone; amcinonide; bosentan; ambrisentan; sitaxentan; bendroflumethiazide; halometaSone; mometaSone; fluticaSone; prednicarbate; dif hydroflumethiazide; hydrochlorothiazide; chlorothiazide: luprednate; ulobetasol; clobetasol; halcinonide; aminoacri polythiazide; trichlormethiazide; cyclopenthiazide; methy dine; euflavine; dibrompropamidine; propamidine; hexami clothiazide, cyclothiazide; mebutizide; quinethaZone; clopa dine; polihexanide; hexachlorophene; policresulen; mide; chlortalidone; mefruside; clofenamide; metolaZone; triclosan; chloroxylenol; biphenylol; iodine/octylphenoxy meticrane; Xipamide; indapamide; clorexolone; fenduizone; polyglycolether, povidone-iodine; iodine; diiodohydrox mersalyl; theobromine; cicletanine; furosemide; bumetanide; ypropane; dequalinium; chlorquinaldol; clioquinol; benza piretanide; torasemide; muZolimine: etoZolin; spironolac Ikonium; cetrimonium, cetrimide; mercurochrome; tone; canrenone; eplerenone; amiloride; triamterene; tolvap thiomersal; silver, eosin; propanol; isopropanol; ethanol; fra tan; conivaptan; isoxSuprine; buphenine; bamethan; phento mycetin; benzododecinium; iodoform; bithionol; sulfur, lamine; tolaZoline; ciclonicate; pentifylline; pentoxifylline; tioxolone; mesulfen, tretinoin, retinol; adapalene; isotretin nicergoline; dihydroergocristine; kallidinogenase; cyclande oin; motretinide; clindamycin; erythromycin; meclocycline; late; phenoxybenzamine; Vincamine; moxisylyte; bency resorcinol, dapsone; ichtasol, Xenysalate; others; tacrolimus; clane; vinburnine; Suloctidil; buflomedil; naftidrofuryl; buta pimecrolimus; meduinol; tiratricol; oxaceprol; finasteride; US 2012/032978.0 A1 Dec. 27, 2012 27 hydroquinone; monobenzone; eflornithine; diclofenac; ali quinupristin?dalfopristin; streptoduocin, tobramycin; tretinoin, candicidin; carfecillin; pentamycin; diiodohydrox netilmicin; sisomicin; dibekacin: ribostamycin; isepamicin; yduinoline; Sulfonamides: Sulfatolamide; ornidazole; aza arbekacin; ofloxacin; ciprofloxacin; pefloxacin; enoxacin; nidazole; propenidazole; butoconazole; terconazole; temafloxacin; norfloxacin, lomefloxacin; fleroxacin; spar clodantoin: nifuratel; furazolidone; protiofate; methylergo floxacin, rufloxacin; grepafloxacin; levofloxacin; trovafloxa metrine; ergometrine; dinoprost, dinoprostone; gemeprost; cin; moxifloxacin, gemifloxacin; gatifloxacin; prulifloxacin; carboprost; Sulprostone; ritodrine; fenoterol; bromocriptine; paZufloxacin, garenoxacin; roSoxacin; cinoxacin; flume lisuride; cabergoline; quinagolide; metergoline; terguride; quine; teicoplanin; telavancin; dalbavancin; oritavancin; naproxen; flunoxaprofen; atosiban; norethisterone; lynestre timidazole; nitrofurantoin: nifurtoinol; fosfomycin; Xibornol: nol; levonorgestrel; quingestanol; megestrol; medroX clofoctol; spectinomycin; methenamine; nitroxoline; lin yprogesterone; norgestrienone; etonogestrel; desogestrel; eZolid; daptomycin; itraconazole; Voriconazole; posacona fluoxymesterone; methyltestosterone; testosterone; mester Zole; caspofungin: micafungin; anidulafungin; cycloserine; olone; ethinylestradiol; estradiol; estriol: chlorotrianisene: rifampicin: rifamycin; rifabutin: rifapentine; capreomycin; estrone; promestriene; dienestrol; diethylstilbestrol; methal isoniazid; protionamide; tiocarlide; ethionamide; pyraZina lenestril; moxestrol; tibolone; gestonorone; hydroxyprogest mide; ethambutol; terizidone; morinamide; clofazimine; erone; progesterone; dydrogesterone; medrogestone; nome metisaZone; Vidarabine; ribavirin; ganciclovir; famciclovir, gestrol; demegestone; chlormadinone; promegestone; Valaciclovir, cidofovir, Valganciclovir, brivudine, rimanta allylestrenol; ethisterone; etynodiol; methylestrenolone; uro dine; foscarnet; foSfonet, Saquinavir, indinavir, ritonavir, follitropin; cyclofenil; clomifene, epimestrol; cyproterone; nelfinavir, amprenavir, lopinavir, foSamprenavir, atazanavir, danazol; gestrinone; mifepristone; raloxifene; baZedoxifene; tipranavir, darunavir, Zidovudine; didanosine; Zalcitabine; emepronium; flavoxate; meladrazine; oxybutynin, terodiline; stavudine; lamivudine; abacavir, emitricitabine; entecavir, propiverine; tolterodine; Solifenacin; trospium; darifenacin; telbivudine; clevudine; nevirapine; delavirdine; efavirenz; fesoterodine; sildenafil; yohimbine; apomorphine; tadalafil; etravirine; Zanamivir; oseltamivir; moroxydine; pleconaril; Vardenafil; phenazopyridine. Succinimide; dapoxetine; alfu enfuVirtide; raltegravir, maraviroc; maribavir, palivizumab; Zosin; tamsulosin; teraZosin; silodosin; dutasteride; corti nebacumab, diphtheria-poliomyelitis-tetanus; diphtheria cotropin, tetracosactide; thyrotropin; Somatropin; somatrem: pertussis-poliomyelitis-tetanus; diphtheria-rubella-tetanus; mecasermin; sermorelin: pegvisomant; vasopressin; desmo cyclophosphamide; chlorambucil; melphalan; chlormethine; pressin; lypressin; terlipressin; ornipressin, argipressin; ifosfamide; trofosfamide; prednimustine; bendamustine; demoxytocin; oxytocin; carbetocin; gonadorelin; nafarelin; busulfan; treosulfan; mannosulfan; thiotepa; triaziquone; car histrelin; Somatostatin; octreotide; lanreotide; vapreotide; boduone; carmustine; lomustine; Semustine; streptozocin, ganirelix; cetrorelix; aldosterone; fludrocortisone; desoxy fotemustine; nimustine; ranimustine; etoglucid, mitobroni cortone; paramethasone; cortisone; prednylidene; rimex tol; pipobroman; temozolomide, dacarbazine; methotrexate; olone; deflazacort; cloprednol; meprednisone; cortivaZol; raltitrexed; pemetrexed; pralatrexate; mercaptopurine; trilostane; methylthiouracil; propylthiouracil; benzylthiou tioguanine; cladribine; fludarabine; clofarabine; nelarabine; racil; carbimazole; thiamazole; diiodotyrosine; dibromoty cytarabine; fluorouracil; tegafur, carmofur, gemcitabine; rosine; glucagon; teriparatide; elcatonin; cinacalcet; parical capecitabine; azacitidine, decitabine; vinblastine; Vincris citol; doxercalciferol; lymecycline; metacycline; tine; Vindesine; Vinorelbine; Vinflunine; etoposide; tenipo rolitetracycline; penimepicycline; clomocycline; tigecycline; side; demecolcine; paclitaxel, docetaxel; trabectedin, dacti thiamphenicol; amplicillin; pivampicillin; carbenicillin; nomycin; doxorubicin; daunorubicin; epirubicin; amoxicillin; carindacillin; bacampicillin; epicillin; pivmecil aclarubicin; Zorubicinidarubicin; mitoxantrone, pirarubicin; linam, azlocillin; mezlocillin; mecillinam, piperacillin, ticar valrubicin; bleomycin; plicamycin; mitomycin; ixabepilone; cillin; metampicillin; talampicillin; Sulbenicillin, temocillin; cisplatin; carboplatin, oxaliplatin; Satraplatin: procarbazine; hetacillin; benzylpenicillin; phenoxymethylpenicillin; propi edrecolomab, rituximab, trastuzumab; alemtuzumab, gemtu cillin; azidocillin; pheneticillin; penamecillin; clometocillin; Zumab, cetuximab; bevacizumab: panitumumab, catumax dicloxacillin; cloxacillin; meticillin; oxacillin; flucloxacillin; omab. ofatumumab; temoporfin; efaproxiral; imatinib, gefi Sulbactam, taZobactam, Sultamicillin, cefalexin, cefaloridine; tinib; erlotinib; Sunitinib: sorafenib, dasatinib; lapatinib; cefalotin; cefazolin; cefadroxil, cefazedone; cefatrizine; nilotinib; temsirolimus; everolimus; paZopanib, amsacrine; cefapirin; cefradine, cefacetrile; cefroxadine; ceftezole; asparaginase; altretamine; hydroxycarbamide; lonidamine; cefoxitin, cefuroxime; cefamandole; cefaclor, cefotetan: pentostatin: miltefosine; masoprocol; estramustine, mitogua cefonicid; cefotiam; loracarbef, cefinetazole; cefprozil; cefo Zone; topotecan; tiazofurine; irinotecan; mitotane; pegaspar ranide; cefotaxime; ceftazidime; cefsulodin, ceftriaxone; gase; bexarotene; bortezomib; celecoxib; anagrelide; cefinenoXime; latamoxef, ceftizoxime; cefixime, cefodizime; oblimersen; vorinostat; romidepsin; fosfestrol; buserelin; cefetamet; ce?piramide; cefoperaZone; cefpodoxime; ceftib leuprorelin; goserelin; triptorelin; tamoxifen; toremifene; uten, cefdinir, cefditoren, cefcapene; cefepime; ce?pirome; fulvestrant; flutamide; nilutamide; bicalutamide; aminoglu cefoZopran; meropenem, ertapenem; doripenem; biapenem: tethimide; formestane; anastroZole; letrozole; Vorozole; trimethoprim; brodimoprim; iclaprim; Sulfaisodimidine; Sul exemestane; abarelix; degarelix; filgrastim; molgramoStim; fadimidine: sulfapyridine: sulfafurazole; sulfathiourea; sul SargramoStim; lenograstim; ancestim; pegfilgrastim; famethoxazole; Sulfadiazine; Sulfamoxole; sulfadimethox aldesleukin; oprelvekin; lentinan, roquinimex: pegademase; ine; Sulfalene; Sulfametomidine; Sulfametoxydiazine; pidotimod; thymopentin; immunocyanin; tasonermin; mifa Sulfamethoxypyridazine; Sulfaperin; Sulfaphenazole, Sulfa murtide; plerixafor; muromonab-CD3; sirolimus; lefluno maZone; spiramycin; midecamycin; oleandomycin; roXithro mide; alefacept, gusperimus; efalizumab; abetimus; natali mycin; josamycin; troleandomycin; clarithromycin; azithro Zumab, abatacept; eculizumab; etanercept, infliximab; mycin, miocamycin; rokitamycin; dirithromycin; afelimomab; adalimumab; golimumab, daclizumab, basilix flurithromycin; tellithromycin; lincomycin; pristinamycin; imab; anakinra, rilonacept, ustekinumab; mepolizumab; US 2012/032978.0 A1 Dec. 27, 2012 28 tocilizumab; canakinumab, ciclosporin; azathioprine; thali Zine; fluiphenazine; perphenazine; prochlorperazine; thiopro domide; lenalidomide; phenylbutaZone; mofebutaZone; pazate; trifluoperazine; acetophenazine; thioproperazine; oxyphenbutaZone; clofeZone; kebuZone; Sulindac; tolmetin: butaperazine; perazine; periciazine; thioridazine; Zomepirac, alclofenac; bumadizone: etodolac, lonazolac, mesoridazine; pipotiazine; haloperidol; trifluperidol; melper fentiaZac; acemetacin; difenpiramide; oxametacin; proglu one; moperone; pipamperone; bromperidol; benperidol; flu metacin; ketorolac; aceclofenac; bufexamac, piroxicam, anisone; oxypertine; molindone; sertindole; Ziprasidone; flu tenoxicam, droxicam, lornoxicam, meloxicam, ketoprofen; pentixol; clopenthixol; chlorprothixene; tiotixene; fenoprofen; fenbufen, benoxaprofen; Suprofen; pirprofen; Zuclopenthixol; fluspirilene; pimozide; penfluridol; loxapine; flurbiprofen; indoprofen; Oxaprozin, ibuproxam; dexibupro clozapine, olanzapine; quetiapine; asenapine; clotiapine; fen; alminoprofen; dexketoprofen; rofecoxib; Valdecoxib; #Sulpiride; Sultopride; tiapride; remoxipride; amisulpride; parecoxib: etoricoxib; lumiracoxib: nabumetone; azapropa veralipride; levosulpiride; lithium; prothipendyl; risperidone; Zone; glucosamine; produaZone; orgotein; nimeSulide; fepra mosapramine; Zotepine; aripiprazole; paliperidone; diaz Zone; diacerein; morniflumate; tenidap; oxycinchophen; epam, chlordiazepoxide; medazepam, oxazepam, auranofin; aurothioglucose; aurotioprol; penicillamine; buci lorazepam, adinazolam; bromazepam, clobazam, ketazolam; llamine; etofenamate; felbinac; bendaZac; SuxibuZone; prazepam, alprazolam; halazepam, pinazepam, camazepam, nifenaZone; capsaicin; Zucapsaicin; alcuronium; tub nordazepam, fludiazepam, etizolam; clotiazepam, clox ocurarine; dimethyltubocurarine; suxamethonium; pancuro aZolam, tofisopam; hydroxyzine; captodiame; meprobamate; nium; gallamine; vecuronium; atracurium; hexafluoronium; emylcamate; mebutamate; benzoctamine; buspirone; mephe cisatracurium; phenprobamate; carisoprodol; methocar noxalone; gedocarnil; etifoxine; pentobarbital; amobarbital; bamol, styramate; febarbamate; chlormeZanone; chlorZOX butobarbital; barbital; aprobarbital; secobarbital; talbutal; aZone; baclofen; tizanidine; pridinol; tolperisone; thiocolchi vinylbital; vinbarbital; cyclobarbital; heptabarbital; reposal; coside; mephenesin, tetrazepam, cyclobenzaprine; etallobarbital; allobarbital; proxibarbal: chloralodol; dichlo eperisone; femyramidol; dantrolene; allopurinol; tisopurine; ralphenaZone; paraldehyde; flurazepam, nitrazepam; fluni febuXostat; probenecid; Sulfinpyrazone; benzbromarone; iso trazepam, estazolam; triazolam; lormetazepam, temazepam, bromindione; colchicine; cinchophen; pegloticase; iprifla midazolam; brotizolam; quazepam; loprazolam, dox Vone; denosumab; hydroquinine; chymopapain; halothane; efazepam, cinolazepam, glutethimide; methyprylon; pyrith chloroform; enflurane; trichloroethylene; isoflurane; desflu yldione; Zopiclone; Zolpidem; Zaleplon; esZopiclone; mela rane; sevoflurane; methohexital; hexobarbital; thiopental; tonin; ramelteon; methaqualone; clomethiazole; bromisoval; narcobarbital; fentanyl; alfentanil; sufentanil; phenoperidine: carbromal; propiomazine; triclofos; ethchlorvynol; valerian; anileridine; remifentanil; droperidol, ketamine; propanidid; hexapropymate; bromides; apronal; Valnoctamide; methyl alfaxalone; etomidate; propofol; esketamine; Xenon; pentynol; niaprazine; dexmedetomidine; desipramine; imi metabutethamine; chloroprocaine; bupivacaine; mepiv pramine; clomipramine; opipramol; trimipramine; acaine; prilocalne; butanilicaine; etidocaine; articaine; ropi lofepramine; dibenzepin; amitriptyline; nortriptyline; prot vacaine; levobupivacaine; cocaine: dyclonine; morphine; riptyline: doxepin; iprindole; melitracen; butriptyline; dosul hydromorphone; nicomorphine; oxycodone; dihydroco epin; amoxapine; dimetacrine; amineptine; maprotiline; deine; diamorphine; papavereturn, ketobemidone; pethidine; quinupramine; Zimeldine; fluoxetine; citalopram; paroxetine; dextromoramide: piritramide; dextropropoxyphene; bezitra Sertraline; alaproclate; fluvoxamine; etoperidone; escitalo mide; pentazocine; phenazocine; buprenorphine; butorpha pram; isocarboxazid; nialamide; phenelzine; tranylcyprom nol; nalbuphine; tilidine; tramadol; dezocine; meptazinol; ine; iproniazide, iproclozide; moclobemide; toloxatone; tapentadol; salicylamide; Salsalate; ethenZamide; dipyro oxitriptan; tryptophan; mianserin; nomifensine; traZodone; cetyl; benorilate; diflunisal; guacetisal; phenaZone; ami nefazodone; minaprine; bifemelane; Viloxazine; oxafloZane; nophenaZone; propyphenaZone; paracetamol; phenacetin: mirtazapine; bupropion; medifoxamine; tianeptine; pivagab bucetin; propacetamol, rimazolium; glafenine; floctafenine; ine; Venlafaxine; milnacipran; reboxetine; gepirone; dulloxet Viminol; nefopam; flupirtine; Ziconotide; methoxyflurane; ine; agomelatine; desvenlafaxine, amfetamine; dexamfe nabiximols; dihydroergotamine; ergotamine; methysergide; tamine; metamfetamine; methylphenidate; pemoline; flumedroxone; Sumatriptan; naratriptan; Zolmitriptan; riza fencamfamin; modafinil; fenozolone; atomoxetine; fenetyl triptan; almotriptan; eletriptan; froVatriptan; pizotifen, ipra line; dexmethylphenidate; caffeine; propentofylline: Zochrome; dimetotiazine; oxetorone; methylphenobarbital; meclofenoxate, pyritinol; piracetam; deanol; fipexide; citi phenobarbital; primidone; barbexaclone; metharbital; etho coline; oxiracetam; pirisudanol; linopirdine; niZofenone; toin: phenyloin, mephenyloin, fosphenyloin, paramethadi aniracetam; acetylcarnitine; idebenone; prolintane; one; trimethadione; ethadione; ethoSuximide: phensuximide; pipradrol; pramiracetam; adrafinil; vinpocetine; tacrine; meSuximide; clonazepam, carbamazepine; oXcarbazepine; donepezil; rivastigmine; galantamine; memantine; neostig rufinamide; eslicarbazepine; valpromide; vigabatrin; proga mine; pyridostigmine; distigmine; ambenonium; carbachol; bide; tiagabine; Sultiame; phenacemide; lamotrigine; felbam bethanechol; pilocarpine, cevimeline; nicotine; Varenicline; ate; topiramate; gabapentin; pheneturide; levetiracetam; disulfuram; acamprosate; naltrexone; methadone; levacetyl Zonisamide; pregabalin; Stiripentol; lacosamide; carisbam methadol; lofexidine; betahistine: cinnarizine; flunarizine; ate; beclamide; trihexyphenidyl; biperiden; metixene; procy acetylleucine; tirilazad, riluzole; Xaliproden; amifampiridine; clidine; profenamine; dexetimide: phenglutarimide; mazati tetrabenazine; tilbroquinol; nimorazole; secnidazole; dilox col; bornaprine; tropatepine; etanautine; benZatropine; anide; clefamide: etofamide; teclozan, arsthinol; difetarSone; etybenzatropine; levodopa; melevodopa; amantadine; per glycobiarsol, chiniofon, emetine; phanquinone; mepacrine; golide; ropinirole; pramipexole, piribedil; rotigotine; sel atovaquone; trimetrexate; tenonitroZole; dihydroemetine; egiline; rasagiline; tolcapone; entacapone; budipine; chlor fumagillin: nitazoxanide; chloroquine; hydroxychloroquine; promazine; levomepromazine; promazine; acepromazine; primaquine; amodiaquine; proguanil; quinine; mefloquine; triflupromazine; cyamemazine; chlorproethazine; dixyra pyrimethamine; artemisinin; artemether, artesunate; artemo US 2012/032978.0 A1 Dec. 27, 2012 29 til; artenimol; halofantrine; benznidazole; nifurtimox; melar thiosulfate; dimercaprol; obidoxime; protamine; naloxone; Soprol; praziquantel, oxamniquine; metrifonate: niridazole; flumazenil; methionine; cholinesterase; glutathione; fomepi stilbophen; triclabendazole; mebendazole; albendazole; Zole; Sugammadex; deferoxamine; deferiprone; deferasiroX; ciclobendazole; flubendazole; fenbendazole; piperazine: sevelamer, dexraZOxane; amifostine; rasburicase; palifermin; diethylcarbamazine; pyrantel, oxantel; levamisole; ivermec glucarpidase; oxygen; helium; nitrogen; nalfurafine; sin tin, pyrvinium; bephenium; niclosamide; desaspidin; dichlo calide; ceruletide; metyrapone; corticorelin; somatorelin; rophen; dixanthogen; thiram; clofenotane; lindane; pyre galactose; Sulfobromophtlialein; tuberculin; betazole; penta thrum; bioallethrin; phenothrin; permethrin; malathion; gastrin; phenolsulfonphthalein; alsactide; protirelin; secretin: quassia: cyfluthrin; cypermethrin; decamethrin, tetramethrin; bentiromide; iodamide; methiodal; diodone; metrizamide; diethyltoluamide; dimethylphthalate: dibutylphthalate: dibu iohexyl, iopamidol; iopromide; iotrolan; ioVersol, iopentol; iodixanol; iomeprol; iobitridol; ioxilan; adipiodone; iopydol; tylsuccinate; dimethylcarbate; etohexadiol; cyclopentamine; propyliodone; iofendylate; gadodiamide: gadoteridol; man ephedrine; oxymetazoline; tetry Zoline; Xylometazoline; nap gafodipir, gadoversetamide, gadobutrol, gadofosveset; feru haZoline; tramaZoline; metizoline; tuaminoheptane; fenox moxsil; ferristene; perflubron; perflenapent. aZoline; tymazoline; levocabastine; azelastine; antazoline; nedocromil, olopatadine; flunisolide; ritiometan: phenylpro 0090. It is a further object of the present invention to panolamine; pseudoephedrine; ambazone; benzethonium; provide a compound of formula (I), (Ia), (Ib) and/or (Ic) as myristyl-benzalkonium; hexylresorcinol; fusafungine; defined herein or a pharmaceutical composition as defined gramicidin; orciprenaline; salbutamol; terbutaline; rimiterol; herein for the preparation of a medicament for the treatment hexoprenaline; isoetarine;pirbuterol; tretoquinol; carbuterol; of one or more diseases mentioned herein. tulobuterol; salmeterol; formoterol; clenbuterol; reproterol: 0091 Preferably the compounds of the present invention procaterol; bitolterol; indacaterol; ciclesonide; fenspiride; may be used for the treatment and/or prevention of the fol methoxyphenamine; bambuterol, diprophylline; proxyphyl lowing conditions: line; theophylline; aminophylline; etamiphylline; bamifyl respiratory tract/obstructive airways diseases and disorders line; bufylline: doxofylline; Zafirlukast; pranlukast; mon including: telukast, ibudilast, eproZinol; omalizumab; seratrodast; rhinorrhea, tracheal constriction, airway contraction, acute-, roflumilast; tyloxapol: guaifenesin: ipecacuanha; Senega; allergic, atrophic rhinitis or chronic rhinitis (such as rhinitis creosote; guaiacolsulfonate; levoVerbenone; acetylcysteine; caseosa, hypertrophic rhinitis, rhinitis purulenta, rhinitis bromhexine, carbocisteine; eprazinone; mesna; ambroXol; sicca), rhinitis medicamentosa, membranous rhinitis (includ sobrerol: domiodol; letosteine; stepronin; tiopronin; nelten ing croupous, fibrinous and pseudomembranous rhinitis), exine; erdosteine; ethylmorphine; hydrocodone; codeine; scrofulous rhinitis, perennial allergic rhinitis, seasonal rhini normethadone; noscapine; pholcodine; dextromethorphan; tis (including rhinitis nervosa (hay fever) and vasomotor thebacon; dimemorfan; acetyldihydrocodeine; benzonatate; rhinitis), pollinosis, asthma (such as bronchial, atopic, aller benproperine; clobutinol; isoaminile; pentoxyverine; oxola gic, intrinsic, extrinsic, exercise-induced, cold air-induced, mine; oxeladin; clo?edanol; pipaZetate; butamirate; fedrilate; occupational, bacterial infection-induced, and dust asthma Zipeprol: dibunate; droxypropine; prenoxdiazine; dro particularly chronic or inveterate asthma (e.g. late asthma and propizine; cloperastine; meprotixol; piperidione; tipepidine; airways hyper-responsiveness)), bronchitis (including morclofone; nepinalone; levodropropizine; dimethoxanate; chronic, acute, arachidic, catarrhal, croupus, phthinoid and bromazine; diphenylpyraline; carbinoxamine, doxylamine; eosinophilic bronchitis), cardiobronchitis, pneumoconiosis, brompheniramine; dexchlorpheniramine; chlorphenamine; chronic inflammatory disease of the lung which result in pheniramine; dexbrompheniramine; talastine; histapyrrod interstitial fibrosis, such as interstitial lung disease (ILD) ine; methapyrilene; alimemazine; thiethylperazine; methdi (e.g., idiopathic pulmonary fibrosis, or ILD associated with lazine; hydroxyethylpromethazine; thiazinam; meduitazine; rheumatoid arthritis, or other autoimmune conditions), acute oXomemazine; buclizine; cyclizine; chlorcyclizine; mecloz lung injury (ALI), adult respiratory distress syndrome ine; oxatomide; cetirizine; levocetirizine; cyproheptadine; (ARDS), chronic obstructive pulmonary, airways or lung dis phenindamine; triprolidine; pyrrobutamine; azatadine; ease (CORD, COAD, COLD or COPD, such as irreversible astemizole; terfenadine, loratadine; mebhydrolin; dep COPD), chronic sinusitis, conjunctivitis (e.g. allergic con tropine; ketotifen; acrivastine; tritoqualine; ebastine; pime junctivitis), cystic fibrosis, extrinsic allergic alveolitis (like thixene; epinastine; mizolastine; fexofenadine; deslorata farmer's lung and related diseases), fibroid lung, hypersensi dine; rupatadine: doxapram; nikethamide; pentetraZol; tivity lung diseases, hyperSensitivity pneumonitis, idiopathic etamivan; bemegride; prethcamide; almitrine; dimefline; interstitial pneumonia, nasal congestion, nasal polyposis, oti mepixanox, dihydrostreptomycin; micronomicin; azidam tis media, and cough (chronic cough associated with inflam fenicol; sulfadicramide; sulfacetamide; sulfafenazol; trifluri mation or iatrogenic induced), pleurisy, pulmonary conges dine; interferon; fomivirsen; bibrocathol; picloxydine: tion, emphysema, bronchiectasis, sarcoidosis, lung fibrosis, medry Sone; formocortal; loteprednol; pranoprofen; including cryptogenic fibrosing alveolitis, fibrosis complicat nepafenac; bromfenac; diplivefrine; apraclonidine; brimoni ing anti-neoplastic therapy and chronic infection, including dine; ecothiopate; demecarium; physostigmine; fluostig tuberculosis and aspergillosis and other fungal infections, mine; aceclidine; acetylcholine; paraoxon; acetazolamide; vasculitic and thrombotic disorders of the lung vasculature, diclofenamide; dorzolamide; brinzolamide; methazolamide: and pulmonary hypertension, acute viral infection including levobunolol; metipranolol; befunolol; latanoprost; unopros the common cold, and infection due to respiratory syncytial tone; bimatoprost; travoprost, tafluprost, dapiprazole; cyclo virus, influenza, coronavirus (including SARS) and adenovi pentolate; homatropine; tropicamide: lodoxamide; emedas rus, allergic bronchopulmonary mycosis, emphysema, dif tine; proxymetacaine; fluorescein; hypromellose; fuse panbronchiolitis, systemic anaphylaxis or hypersensitiv Verteporfin; anecortave; pegaptainib, ranibizumab; guaiaZu ity responses, drug allergies (e.g., to penicillin, len; alum; iodoheparinate; nalorphine, edetates; pralidoxime; cephalosporins), insect sting allergies, and food related aller US 2012/032978.0 A1 Dec. 27, 2012 30 gies which may have effects remote from the gut (such as degenerative or inflammatory disorders affecting the retina, migraine, rhinitis and eczema), anaphylactic shock, Vascular ophthalmitis including sympathetic ophthalmitis, sarcoido Spasms; sis, Xerosis infections including viral, fungal, and bacterial, bone and joint related diseases and disorders including: allergic conjunctivitis, increased fibrosis, keloids, keloplasty, osteoporosis, arthritis (including rheumatic, infectious, post-Surgical Scars, epidermolysis bullosa, dry eye, ocular autoimmune, chronic, malignant), seronegative spondyloar inflammation, allergic conjunctivitis, Vernal conjunctivitis, thropathies (such as ankylosing spondylitis, rheumatoid Vernal keratoconjunctivitis, and giant papillary conjunctivi spondylitis, psoriatic arthritis, enthesopathy, Bechet's dis tis, ocular angiogenesis, cornea damage and scar, all forms of ease, Marie-Strümpell arthritis, arthritis of inflammatory macular degeneration, macular edema, macular dystrophy, bowel disease, and Reiter's disease), systemic sclerosis, abnormal wound healing, Scleritis, episcleritis, pachydermia, osteoarthritis, osteoarthrosis, both primary and secondary to peripheral ulcerative keratitis, fungal keratitis, herpetic e.g. congenital hip dysplasia, cervical and lumbar spondylitis, keratitis, invasive aspergillosis; conical cornea, dystorphia and low back and neck pain, Still's disease, reactive arthritis epithelialis corneae, severe intraocular inflammation; and undifferentiated spondarthropathy, septic arthritis and gastrointestinal tract and abdominal related diseases and dis other infection-related arthropathies and bone disorders such orders including: as tuberculosis, including Pott's disease and Poncet's Syn celiac/coeliac disease (e.g. celiac sprue), cholecystitis, enteri drome, acute and chronic crystal-induced synovitis including tis (including infectious, ischemic, radiation, drug-induced, urate gout, calcium pyrophosphate deposition disease, and and eosinophilic gastroenteritis), eosinophilic esophagitis, calcium apatite related tendon, bursar and synovial inflam eosinophilic gastrointestinal inflammation, allergen induced mation, primary and secondary Sjogren's syndrome, sys diarrhea, enteropathy associated with seronegative arthropa temic Sclerosis and limited Scleroderma, mixed connective thies, gastritis, autoimmune atrophic gastritis, ischemic tissue disease, and undifferentiated connective tissue disease, bowel disease, inflammatory bowel disease (Crohn's disease inflammatory myopathies including, polymalgia rheumatica, and ulcerative colitis), colitis, Mooren’s ulcer, irritable bowel juvenile arthritis including idiopathic inflammatory arthriti syndrome, necrotizing enterocolitis, gut ischemia, glossitis, des of whatever joint distribution and associated syndromes, gingivitis, periodontitis, oesophagitis, including reflex, proc other joint disease (such as intervertebral disc degeneration or titis, fibrosis and cirrhosis of the liver, pancreatitis, both acute temporomandibular joint degeneration), rheumatic fever and and chronic, pancreatic fibrosis, pancreatic Sclerosis, pan its systemic complications, vasculitides including giant cell creatolithiasis, hepatic cirrhosis, hepatitis (congestive, arteritis, Takayasu’s arteritis, polyarteritis nodosa, micro autoimmune, acute, fulminant, chronic, drug-induced, alco scopic polyarteritis, and vasculitides to associated with viral holic, lupoid, Steatohepatitis and chronic viral), fatty liver, infection, hypersensitivity reactions, cryoglobulins, parapro primary biliary cirrhosis, hepatic porphyria, and gastrointes teins, low back pain, Familial Mediterranean fever, Muckle tinal related allergic disorders, spastic colon, diverticulitis, Wells syndrome, and Familial Hibenian Fever, Kikuchi dis gastroenteric bleeding, Behcet’s disease; partial liver resec ease, drug-induced arthalgias, tendonititides, polychondritis, tion, acute liver necrosis (e.g. necrosis caused by toxins, viral and myopathies, osteoporosis, osteomalacia like osteoporo hepatitis, shock or anoxia), hemolytic uremic syndrome; sis, osteopenia, osteogenesis imperfects, osteopetrosis, hematological disorders including: osteofibrosis, osteonecrosis, Paget’s disease of bone, hypo anemias, coagulation, myeloproliferative disorders, hemor phosphatemia, Felty's syndrome, Still's disease, slack of arti rhagic disorders, leukopenia, eosinophilic disorders, leuke ficial joint implant, sprain or strain of muscle or joint, ten mias (e.g. myelogenous, lymphomas, plasma cell dyscrasias, dinitis, fasciitis, periarthritis humeroScapularis, cervico disorders of the spleen, Banti’s disease, hemophilia, purpura omo-brachial syndrome, tenosynovitis; (including idiopathic thrombocytopenic purpura), Wiskott Skin and eye related diseases and disorders including: Aldrich syndrome; glaucoma, ocular hypertension, cataract, retinal detachment, metabolic disorders including: psoriasis (including psoriasis Vulgaris, pustular psoriasis, obesity, amyloidosis, disturbances of the amino and acid arthritic psoriasis, erythroderma psoriaticum), palmoplantar metabolism like branched chain disease, hyperaminoaci pustulosis, Xerodoma, eczematous diseases (like atopic der demia, hyperaminoaciduria, disturbances of the metabolism matitis, ultraviolet radiation dermatitis, contact dermatitis, of urea, hyperammonemia, mucopolysaccharidoses e.g. and seborrheic dermatitis), phytodermatitis, photodermatitis, Maroteaux-Lamy syndrome, storage disease like glycogen cutaneous eosinophilias, chronic skin ulcers, cutaneous lupus storage diseases and lipid storage diseases, glycogenosis I erythematosus, contact hypersensitivity/allergic contact der diseases like Cori's disease, malabsorption diseases like matitis (including sensitivity to poison ivy, Sumac, or oak), intestinal carbohydrate malabsorption, oligosaccharidase and eosinophilic folliculitis (Ofuji's disease), pruritus, drug deficiency like maltase-, lactase-, Sucrase-insufficiency, dis eruptions, urticaria (acute or chronic, allergic or non-aller orders of the metabolism of fructose, disorders of the metabo gic), acne, erythema, dermatitis herpetiformis, Scleroderma, lism of galactose, galactosaemia, disturbances of carbohy vitiligo, lichen planus, lichen Sclerosus et atrophica, pyo drate utilization like diabetes, hypoglycemia, disturbances of denna gangrenosum, skin Sarcoid, pemphigus, ocular pem pyruvate metabolism, hypolipidemia, hypolipoproteinemia, phigus, pemphigoid, epidennolysis bullosa, angioedema, hyperlipidemia, hyperlipoproteinemia, carnitine or carnitine vasculitides, toxic erythemas, cutaneous eosinophilias, acyltransferase deficiency, disturbances of the porphyrin alopecia greata, male-pattern baldness, Sweet's syndrome, metabolism, porphyrins, disturbances of the purine metabo Stevens-Johnson syndrome, Weber-Christian syndrome, lism, lysosomal diseases, metabolic diseases of nerves and erythema multiforme, cellulitis, botl, infective and non infec nervous systems like gangliosidoses, sphingolipidoses, Sul tive, panniculitis, cutaneous Lymphomas, non-melanoma fatidoses, leucodystrophies, Lesch-Nyhan syndrome; skin cancer and other dysplastic lesions, blepharitis, iritis, cerebellar dysfunction, disturbances of brain metabolism anterior and posterior uveitis, choroiditis, autoimmune, like: US 2012/032978.0 A1 Dec. 27, 2012

dementia, Alzheimer's disease, Huntington's chores, Parkin cobasal degeneration, motor neuron disease, dementia, son's disease, Pick's disease, toxic encepha-lopathy, demy including ALS (Amyotrophic lateral Sclerosis), multiple scle elinating neuropathies like inflammatory neuropathy, Guil rosis, traumatic brain injury, stroke, post-stroke, post-trau lain-Barre Syndrome; Meniere's disease and radiculopathy, matic brain injury, and Small-vessel cerebrovascular disease, primary and secondary metabolic disorders associated with dementias, vascular dementia, dementia with Lewy bodies, hormonal defects like any disorder Stemming from either an frontotemporal dementia and Parkinsonism linked 1 to chro hyperfunction or hypofunction of some hormone-secreting mosome 17, frontotemporal dementias, including Pick's dis endocrine gland and any combination thereof. Sipple's Syn ease, progressive Supranuclear palsy, corticobasal degenera drome, pituitary gland dysfunction and its effects on other tion, Huntington's disease, thalamic degeneration, HIV endocrine glands. Such as the thyroid, adrenals, ovaries, and dementia, Schizophrenia with dementia, and Korsakoff's psy testes, acromegaly, hyper- and hypothyroidism, euthyroid chosis, within the meaning of the definition are also consid goiter, euthyroid sick syndrome, thyroiditis, and thyroid can ered to be CNS disorders central and peripheral nervous cer, over or underproduction of the adrenal steroid hormones, system complications of malignant, infectious or autoim adrenogenital syndrome, Cushing's syndrome. Addison's mune processes, algesia, cerebral infarction, attack, cerebral disease of the adrenal cortex. Addison's pernicious anemia, ischemia, head injury, spinal cord injury, myelopathic mus primary and secondary aldosteronism, diabetes insipidus, cular atrophy, Shy-Drager syndrome, Reye's syndrome, pro diabetes mellitus, carcinoid syndrome, disturbances caused gressive multifocal leukoencephalopathy, normal pressure by the dysfunction of the parathyroid glands, pancreatic islet hydrocephalus, Sclerosing panencephalitis, frontal lobe type cell dysfunction, diabetes, disturbances of the endocrine sys dementia, acute anterior poliomyelitis (poliomyelitis), polio tem of the female like estrogen deficiency, resistant ovary myelitis neurosis, viral encephalitis, allergic encephalomy syndrome; muscle weakness, myotonia. Duchenne's and elitis, epileptic encephalopathies, Creutzfeldt-Jakob disease, other muscular dystrophies, dystrophia myotonica of Stein Kuru disease, bovine spongiform encephalopathy (mad cow ert, mitochondrial myopathies like I disturbances of the cata disease), Scrapie, epilepsy, cerebral amyloid angiopathy, bolic metabolism in the muscle, carbohydrate and lipid stor depression, mania, manic-depressive psychosis, hereditary age myopathies, glycogenoses, myoglobinuria, malignant cerebellar ataxia, peripheral neuropathy, Nasu-Hakola Syn hyperthermia, polymyalgia rheumatics, dermatomyositis, drome, Machado-Joseph disease; multiple myositis, primary myocardial disease, cardiomy inflammatory or immunological diseases or disorders includ opathy; disorders of the ectoderm, neurofibromatosis, Sclero ing: derma and polyar teritis, Louis-Bar Syndrome, Von Hippel general inflammation (of the ocular, nasal, pulmonary, and Lindau disease, Sturge-Weber syndrome, tuberous sclerosis, gastrointestinal passages), mastocytosis/mast cell disorders amyloidosis, porphyria; sexual dysfunction of the male and (cutaneous, systemic, mast cell activation syndrome, and female; confused States and seizures due to inappropriate pediatric mast cell diseases), mastitis (mammary gland), secretion of antidiuretic hormone from the pituitary gland, vaginitis, vasculitis (e.g., necrotizing, cutaneous, and hyper Liddle's syndrome, Bartter's syndrome, Fanconi's I syn sensitivity vasculitis), Wegener granulamatosis, myyositis drome, and renal electrolyte wasting; (including polyinyositis, dermatomyositis), basophil related transplant rejection related conditions including: diseases including basophilic leukemia and basophilic leuko acute and chronic allograft rejection following Solid organ cytosis, and eosinophil related diseases such as Churg transplant, for example, transplantation of kidney, heart, liver, Strauss syndrome, eosinophilic granuloma, lupus erythema lung, and cornea, chronic graft versus host disease, skin graft tosus (such as, systemic lupus erythematosus, Subacute rejection, and bone marrow transplant rejection, immunosup cutaneous lupus erythematosus, and discoid lupus erythema presion; tosus), chronic thyroiditis, Hashimoto's thyroiditis, Grave's genitourinary related conditions including: disease, type I diabetes, complications arising from diabetes nephritis (interstitial, acute interstitial (allergic), and glom mellitus, other immune disorders, eosinophilia fasciitis, erulonephritis), nephrotic syndrome, cystitis including acute hyper IgE syndrome. Addison's disease, antiphospholipid and chronic (interstitial) cystitis and Hunner's ulcer, acute syndrome, immunodeficiency disease, acquired immune and chronic urethritis, prostatitis, epididymitis, oophoritis, deficiency syndrome (AIDS), leprosy, Sezary syndrome, salpingitis, Vulvo Vaginitis, Vulvovaginal candidiasis, Peyro paraneoplastic syndromes, and other autoimmune disorders, nie's disease, and erectile dysfunction, renal disease, renal fervescence, myositis, nervous diseases selected from mul fibrosis, nephropyelitis, secondary contracted kidney, Steroid tiple myositis, bursitis, Evans syndrome, leukotriene B4-me dependent and steroid-resistant nephrosis, Goodpasture's diated diseases, idiopathic hypoparathyroidism, nephrotic syndrome; syndrome lupus, immunosuppression; CNS related diseases and disorders including: cardiovascular diseases and disorders including: neurodegenerative diseases, Alzheimer's disease and other congestive heart failure, myocardial infarction, ischemic dis cementing disorders including CJD and nVCJD., amyloidosis, eases of the heart, all kinds of atrial and ventricular arrhyth and other demyelinating syndromes, cerebral atherosclerosis mias, hypertension, cerebral trauma, occlusive vascular dis and vasculitis, temporal arteritis, myasthenia gravis, acute ease, stroke, cerebrovascular disorder, atherosclerosis, and chronic so pain (acute, intermittent or persistent, whether restenosis, affecting the coronary and peripheral is circula of central or peripheral origin) including post-operative, vis tion, pericarditis, myocarditis, inflammatory and auto-im ceral pain, headache, migraine, neuralgia (including trigemi mune cardiomyopathies including myocardial sarcoid, nal), atypical facial pain, joint and bone pain, pain arising endocarditis, valvulitis, and aortitis including infective (e.g. from cancer and tumor invasion, neuropathic pain syndromes syphilitic), hypertensive vascular diseases, peripheral vascu including diabetic, post-herpetic, and HIV-associated neuro lar diseases, and atherosclerosis, vasculitides, disorders of the pathies, neurosarcoidosis, to brain injuries, cerebrovascular proximal and peripheral veins including phlebitis and throm diseases and their consequences, Parkinson's disease, corti bosis, including deep vein thrombosis and complications of US 2012/032978.0 A1 Dec. 27, 2012 32

Varicose veins, aortic aneurism, periarteritis nodosa, cardiac administered, the route of administration, the condition being fibrosis, post-myocardial infarction, idiopathic cardiomyopa treated, as well as the patient being treated. thy; angioplasty; 0094. Examples of pharmacologically acceptable salts of oncological diseases and disorders including: sufficiently basic compounds of formula (I), (Ia), (Ib) and (Ic) common cancers (prostrate, breast, lung, ovarian, pancreatic, are salts of physiologically acceptable mineral acids like bowel and colon, abdomen, stomach (and any other digestive hydrochloric, hydrobromic, Sulfuric and phosphoric acid; or system cancers), liver, pancreas, peritoneum, endocrine salts of organic acids like methanesulfonic, p-toluene glands (adrenal, parathyroid, pituitary, testicles, ovary, thy Sulfonic, lactic, acetic, trifluoroacetic, citric, succinic, mus, thyroid), eye, head, neck, nervous system (central and fumaric, maleic and Salicylic acid. Further, a Sufficiently peripheral), lymphatic system, blood, pelvic, skin, bone, soft acidic compound of formula (I), (Ia). (Ib) and (Ic) may form tissue, spleen, thoracic, urogenital, and brain tumors), breast alkali or earth alkali metal salts, for example Sodium, potas cancer, genitourinary cancer, lung cancer, gastrointestinal sium, lithium, calcium or magnesium salts; ammonium salts; cancer, epidermoid cancer, melanoma, ovarian cancer, pan or organic base salts, for example methylamine, dimethy creas cancer, neuroblastoma, malignancies affecting the bone lamine, trimethylamine, triethylamine, ethylenediamine, marrow (including the leukaemias) and lymphoproliferative ethanolamine, choline hydroxide, meglumin, piperidine, systems, such as Hodgkin’s and non-Hodgkin’s lymphoma, morpholine, tris-(2-hydroxyethyl)amine, lysine or arginine B-cell lymphoma, follicular lymphoma, metastatic disease salts; all of which are also further examples of salts of formula and tumour recurrences, and paraneoplastic syndromes, as (I), (Ia), (Ib) and (Ic). Compounds of formula (I), (Ia), (Ib) and well as hypergammaglobulinemia, lymphoproliferative dis (Ic) may be solvated, especially hydrated. The hydratization/ eases, disorders, and/or conditions, paraproteinemias, pur hydration may occur during the process of production or as a pura (including idiopathic thrombocytopenic purpura), consequence of the hygroscopic nature of the initially water Waldenstron’s Macroglobulinemia, Gaucher's Disease, his free compounds of formula (I), (Ia), (Ib) and (Ic). The solvates tiocytosis, retinoblastoma and any other hyperproliferative and/or hydrates may e.g. be present in Solid or liquid form. disease, sarcomata, cachexia, tumor growth, tumor invasion, 0095. It should be appreciated that certain compounds of metastasis, AIDS-related lymphomas, malignant immuno formula (I), (Ia), (Ib) and (IC) may have tautomeric forms proliferative diseases, multiple myeloma and malignant from which only one might be specifically mentioned or plasma cell neoplasms, lymphoid leukemia, acute or chronic depicted in the following description, different geometrical myeloid leukemia, acute or chronic lymphocytic leukemia, isomers (which are usually denoted as cis/trans isomers or monocytic leukemia, other leukemias of specified cell type, more generally as (E) and (Z) isomers) or different optical leukemia of unspecified cell type, other and unspecified isomers as a result of one or more chiral carbon atoms (which malignant neoplasms of lymphoid, haematopoietic and are usually nomenclatured under the Cahn-Ingold-Prelog or related tissues, for example diffuse large cell lymphoma, R/S system). All these tautomeric forms, geometrical or opti T-cell lymphoma or cutaneous T-cell lymphoma). Myeloid cal isomers (as well as racemates and diastereomers) and cancer includes e.g. acute or chronic myeloid leukaemia, polymorphous forms are included in the invention. Since the keratoleukoma and compounds of formula (I), (Ia), (Ib) and (Ic) may contain asymmetric C-atoms, they may be present either as achiral other diseases and disorders including: compounds, mixtures of diastereomers, mixtures of enanti pain, migraine, sleep disorders, fever, sepsis, idiopathic omers or as optically pure compounds. The present invention thrombocytopenia pupura, post-operative adhesions, flush comprises both all pure enan-tiomers and all pure diastere ing, ischemic/reperfusion injury in the heart, brain, peripheral omers, and also the mixtures thereof in any mixing ratio. limbs, bacterial infection, viral infection, fungal infection, 0096. According to a further embodiment of the present thrombosis, endotoxin shock, septic shock, thermal regula invention, one or more hydrogenatoms of the compounds of tion including fever, Raynaud's disease, gangrene, diseases the present invention may be replaced by deuterium. Deute requiring anti-coagulation therapy, congestive heart failure, rium modification improves the metabolic properties of a mucus secretion disorders, pulmonary hypotension, pros drug with little or no change in its intrinsic pharmacology. tanoid-induced Smooth muscle contract associated with dys Deuterium Substitution at specific molecular positions menorrhea and premature labor, premature delivery, reperfu improves metabolic stability, reduces formation of toxic sion injury, burn, thermal injury, hemorrhage or traumatic metabolites and/or increases the formation of desired active shock, menstrual pain, menstrual cramp, dysmenorrhea, peri metabolites. Accordingly, the present invention also encom odontosis, rickettsial infectious disease, protozoal disease, passes the partially and fully deuterated compounds of for reproduction disease, toothache, pain after tooth extraction, mula (I), (Ia), (Ib) and (Ic). The term hydrogen also encom Herpes Zoster, Herpes simplex, retroperitoneal fibrosis, vari passes deuterium. ous radiation injuries and the like. 0097. The therapeutic use of compounds according to for 0092. A therapeutically effective amount of a compound mula (I), (Ia), (Ib) and (Ic), their pharmacologically accept in accordance with this invention means an amount of com able salts, Solvates and hydrates, respectively, as well as for pound that is effective to prevent, alleviate or ameliorate mulations and pharmaceutical compositions also lie within symptoms of disease or prolong the Survival of the Subject the scope of the present invention. being treated. Determination of a therapeutically effective 0098. The pharmaceutical compositions according to the amount is within the skill in the art. present invention comprise at least one compound of formula 0093. The therapeutically effective amount or dosage of a (I), (Ia), (Ib) and (Ic) as an active ingredient and, optionally, compound according to this invention can vary within wide carrier Substances and/or adjuvants. limits and may be determined in a manner known in the art. 0099. The present invention also relates to pro-drugs Such dosage may be adjusted to the individual requirements which are composed of a compound of formula (I), (Ia), (Ib) in each particular case including the specific compound being and/or (Ic) and at least one pharmacologically acceptable US 2012/032978.0 A1 Dec. 27, 2012 protective group which will be cleaved off under physiologi especially preferred with a particle size between 300 to 350 cal conditions, such as an alkoxy-, arylalkyloxy-, acyl-, acy nm) preferred in phosphate buffered saline (pH-7 to 8, pre loxymethyl group (e.g. pivaloyloxymethyl), an 2-alkyl-, ferred 7.4). For Suppositories one may use excipients as are 2-aryl- or 2-arylalkyl-oxycarbonyl-2-alkylidene ethyl group e.g. Vegetable, petroleum, animal or synthetic oils, wax, fat oran acyloxy group as defined herein, e.g. ethoxy, benzyloxy, and polyols. For aerosol formulations one may use com acetyl or acetyloxy or, especially for a compound of formula pressed gases Suitable for this purpose, as are e.g. oxygen, (I), (Ia), (Ib) and/or (Ic), carrying a hydroxy group (-OH): a nitrogen and carbon dioxide. The pharmaceutically useful sulfate, a phosphate (—OPO or—OCHOPO) or an ester of agents may also contain additives for conservation, stabiliza an amino acid. Especially preferred are pro-drugs of the tion, e.g. UV stabilizers, emulsifiers, Sweetener, aromatizers, hydroxy group of a compound of formula (I), (Ia), (Ib) and/or salts to change the osmotic pressure, buffers, coating addi (Ic). tives and antioxidants. 0100 Preferably, the present invention also relates to a 0104. In general, in the case of oral or parenteral admin prodrug, a biohydrolyzable ester, a biohydrolyzable amide, a istration to adult humans weighing approximately 80 kg, a polymorph, tautomer, Stereoisomer, metabolite, N-oxide, daily dosage of about 10 mg to about 10,000 mg, preferably biohydrolyzable carbamate, biohydrolyzable ether, physi from about 20 mg to about 1,000 mg, should be appropriate, ologically functional derivative, atropisomer, or in vivo-hy although the upper limit may be exceeded when indicated. drolysable precursor, diastereomer or mixture of diastere The daily dosage can be administered as a single dose or in omers, chemically protected form, affinity reagent, complex, divided doses, or for parenteral administration, it may be chelate and a stereoisomer of the compounds of formula (I), given as continuous infusion or Subcutaneous injection. (Ia), (Ib) and/or (Ic). 0105. The present invention refers furthermore to com 0101. As used herein, the term pharmaceutically accept pounds of formulas (II), (IIIA) and/or (IIIb) wherein R and able ester especially refers to esters which hydrolyze in vivo Rare defined as above and PG is a protecting group. and include those that break down readily in the human body to leave the parent compound or a salt thereof. Suitable ester groups include, for example, those derived from pharmaceu (II) tically acceptable aliphatic carboxylic acids, particularly alkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which each alkyl or alkenyl moiety advantageously has not more than 6 carbon atoms. Examples of particular esters include, but are not limited to, formates, acetates, propi onates, butyrates, acrylates and ethylsuccinates. 0102. As mentioned above, therapeutically useful agents (IIIa) that contain compounds of formula (I), (Ia), (Ib) and/or (Ic), their solvates, salts or formulations are also comprised in the Scope of the present invention. In general, compounds of formula (I), (Ia), (Ib) and/or (Ic) will be administered by using the known and acceptable modes known in the art, either alone or in combination with any other therapeutic agent. 0103 For oral administration such therapeutically useful agents can be administered by one of the following routes: (IIIb) oral, e.g. as tablets, dragees, coated tablets, pills, semisolids, Soft or hard capsules, for example soft and hard gelatine capsules, aqueous or oily solutions, emulsions, Suspensions or syrups, parenteral including intravenous, intramuscular and Subcutaneous injection, e.g. as an injectable solution or Suspension, rectal as Suppositories, by inhalation or insuffla tion, e.g. as a powder formulation, as microcrystals or as a spray (e.g. liquid aerosol), transdermal, for example via an transdermal delivery system (TDS) Such as a plaster contain 0106 Protecting groups are known to a person skilled in ing the active ingredient or intranasal. For the production of the art and e.g. described in P. J. Kocienski, Protecting Such tablets, pills, semisolids, coated tablets, dragees and Groups, Georg Thieme Verlag, Stuttgart, 1994 and in T. W. hard, e.g. gelatine, capsules the therapeutically useful product Greene, P. G. M. Wuts, Protective Groups in Organic Synthe may be mixed with pharmaceutically inert, inorganic or sis, John Wiley & Sons, New York, 1999. organic excipients as are e.g. lactose. Sucrose, glucose, 0107 Preferably, PG is a 4-methoxybenzyl group or a gelatine, malt, silica gel, starch or derivatives thereof, talc, carboxybenzyl (Cbz or Z) group; especially preferably, PG is stearinic acid or their salts, dried skim milk, and the like. For a 4-methoxybenzyl group. the production of soft capsules one may use excipients as are 0.108 Preferred compounds of formula (II) are: e.g. Vegetable, petroleum, animal or synthetic oils, wax, fat, 7-chloro-5-phenyl-2H-pyrazolo4.3-dpyrimidine: 7-chloro polyols. For the production of liquid solutions, emulsions or 5-(pyridin-4-yl)-2H-pyrazolo 4.3-dpyrimidine; 7-chloro-5- Suspensions or syrups one may use as excipients e.g. water, (6-(pyrrolidin-1-yl)pyridin-3-yl)-2H-pyrazolo 4,3-dipyri alcohols, aqueous saline, aqueous dextrose, polyols, glycerin, midine: 7-chloro-5-(3,4-dimethoxyphenyl)-2H-pyrazolo4. lipids, phospholipids, cyclodextrins, vegetable, petroleum, 3-dipyrimidine: 7-chloro-5-(1-methylpiperidin-4-yl)-2H animal or synthetic oils. Especially preferred are lipids and pyrazolo 4,3-dipyrimidine: 7-chloro-5-(1H-pyrazol-3-yl)- more preferred are phospholipids (preferred of natural origin; 2H-pyrazolo 4,3-dipyrimidine: 7-chloro-5-(4-

US 2012/032978.0 A1 Dec. 27, 2012

dpyrimidine; 7-chloro-5-(3-chlorophenyl)-2-(4- -continued methoxybenzyl)-2H-pyrazolo 4,3-dipyrimidine; 7-chloro-5- - O (2-fluorophenyl)-2-(4-methoxybenzyl)-2H-pyrazolo 4.3-d pyrimidine; 7-chloro-5-(3-fluorophenyl)-2-(4- methoxybenzyl)-2H-pyrazolo 4,3-dipyrimidine: 4-(7- chloro-2-(4-methoxybenzyl)-2H-pyrazolo 4,3-dipyrimidin 5-yl)benzoic acid; 7-chloro-2-(4-methoxybenzyl)-5-(3- (methylsulfonyl)phenyl)-2H-pyrazolo 4.3-dpyrimidine: - . N -- 7-chloro-5-(1H-indazol-6-yl)-2-(4-methoxybenzyl)-2H pyrazolo 4,3-dipyrimidine: 7-chloro-2-(4-methoxybenzyl)- - 5-(1H-pyrrolo3.2-bipyridin-6-yl)-2H-pyrazolo 4,3-dipyri midine: 7-chloro-5-(4-fluorophenyl)-2-(4-methoxybenzyl)- R2 2H-pyrazolo4.3-dpyrimidine: 7-chloro-5-(3,4- difluorophenyl)-2-(4-methoxybenzyl)-2H-pyrazolo 4,3-d pyrimidine; 7-chloro-5-(3,5-difluorophenyl)-2-(4- methoxybenzyl)-2H-pyrazolo 4,3-dipyrimidine; 7-chloro-5- (2,6-difluorophenyl)-2-(4-methoxybenzyl)-2H-pyrazolo4. 3-dipyrimidine: 7-chloro-5-(2,4-difluorophenyl)-2-(4- O methoxybenzyl)-2H-pyrazolo 4,3-dipyrimidine: 6-(7- chloro-2-(4-methoxybenzyl)-2H-pyrazolo 4,3-dipyrimidin & 5-yl)-2H-benzob 14oxazin-3 (4H)-one. General Synthesis O - 0110. The procedures shown in the following synthesis schemes may be used to provide chloride intermediates. The chloride intermediates may then be used in an amination 0114. The pyrazole is protected e.g. with a para-methoxy reaction with various amines and a Subsequent deprotection benzyl protection group. This step results in the formation of to provide the final products. two isomers—5-substituted 1-(4-Methoxy-benzyl)-1,6-di hydro-pyrazolo 4,3-dipyrimidin-7-one and 5-substituted 2-(4-Methoxy-benzyl)-2,6-dihydro-pyrazolo 4,3-dipyrimi Step 1: din-7-one. Both isomers can be used in the following steps. 0111 Step 3:

N /N / N 0115 HN O HN le NH l -e- e f R2 O O - NH2 H R2

0112 4-Amino-2H-pyrazole-3-carboxylic acid amide is reacted with an aldehyde in the presence of an oxidant esp. 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone to result in the formation of 5-substituted 1,6-dihydro-pyrazolo 4,3-dipyri midin-7-one. Step 2: 0113

C

N -- + NaI + US 2012/032978.0 A1 Dec. 27, 2012 36

-continued -continued

N /N -- N^ NS -- N e e N N Cl-N l HN-N l N I N 2 R2 RI R \, O

N NCN N

C N-lN R2

0116 5-substituted 1-(4-Methoxy-benzyl)-1,6-dihydro- 0118 5 -substituted 7-Chloro-1 -(4-methoxy-benzyl)- 1H pyrazolo 4,3-dipyrimidin-7-one and 5-substituted 2-(4- pyrazolo 4.3-dipyrimidine and 5 substituted 7-Chloro -2-(4- Methoxy-benzyl)-2,6-dihydro-pyrazolo 4.3-dpyrimidin-7- methoxy-benzyl) -2H-pyrazolo 4.3-d pyrimidine a reacted one are chlorinated e.g. with POCl resulting in the formation 8 with the corresponding amine to result in the formation of of 5-substituted 7-Chloro-1-(4-methoxy-benzyl)-1H-pyra- the protected final products. Zolo4.3-dpyrimidine and 5-substituted 7-Chloro-2-(4- methoxy-benzyl)-2H-pyrazolo4.3-dpyrimidine. Step 5: Step 4: 0119)

0117 - O

- O N N/ S --

e /N -- N

N HN-NN l e N R2 Cl-N l, \

N O R2

HN I N R

R2 I0120 In a final step the para-methoxy-benzyl protection group is removed e.g. with trifluoroacetic acid to provide the final product for biological characterisation. US 2012/032978.0 A1 Dec. 27, 2012 37

EXAMPLES 0.126 To the wells of an 384 well small volume plate (Greiner, Frickenhausen) are added (i) the compound under Materials and Methods test in 5% DMSO/distilled water (5ul), (ii) 5ul of the kinase antibody mixture resulting in a final concentration 5 nM Biological Assays—Protein Kinase Assays LRRK2 or their mutants, 2 nM EU-Anti-GST antibody in 1x kinase buffer A. The reaction was started with addition of (iii) SYK Assay 5ul resulting in a final concentration of 10 nM tracer 236. The assay plate was incubated at RT for 1 h and fluorescence 0121. In the assay OMNIAR, KINASE ASSAY by Invit intensitiy readings were collected using a TECAN M1000 at rogen Corporation (Carlsbad) the effect of invention of a two wavelengthes of Wex 340/Wem 615 nm and Wex 340/um compound on the phosphorylation is determined by measure 665 nm with a delay time of 100 us and an integration time of ment of fluorescence intensity of a chelation-enhanced fluo rophore called SOX. Upon phosphorylation of the peptide by 200 us after 60 minutes. The emission ratio was calculated by the kinase of interest, Mg2+ is chelated to form a bridge division of the acceptor/tracer emission (665 nM) by the between the SOX moiety and the phosphate group that is antibody/donor emission (615 nM). The inhibitor concentra transferred to the specific tyrosine on the peptide. The fluo tion was plotted versus the emission ratio to determine the rescence intensity is directly proportional to the amount of IC50 using XLFit 5.0 (IDBS, Guildford) to fit to a sigmoidal peptide phosphorylation. dose response curve with a variable slope. 0122) To the wells of an 384 well small volume plate MYLK Assay (Greiner, Frickenhausen) are added (i) the compound under test in 5% DMSO/distilled water (2 Jul), (ii) 16 ul of the master I0127. In the assay LanthaScreenTM Eu Kinase Binding mix containing ATP, DTT, Kinase Reaction Buffer, Omina Assay by Invitrogen Corporation (Carlsbad) the effect of Peptide Substrate Tyr 7 resulting in a final concentration of 1 invention of a compound on the phosphorylation is deter mM ATP, 0.2 mM DTT and 10 uM Peptide Substrate. mined by measurement of fluorescence intensity emission 0123. The Master Mix and the assay plate was incubated to ratio based on the binding and displacement of a proprietary, reaction temperature before the measurement (30° C.). The Alexa Fluor 647-labeled, ATP-competitive kinase inhibitor reaction was started with addition of (iii) 2 Jul 4 g/ml SYK scaffold (kinase tracer) to the kinase of interest as described kinase (Invitrogen, Carlsbad). During measurement fluores above. cence intensitiy readings were collected using a TECAN I0128. To the wells of an 384 well small volume plate M1000 at a wavelength of ex360/em 485 nm every 30s for (Greiner, Frickenhausen) are added (i) the compound under 30 minutes. The reaction velocity was plotted versus the test in 5% is DMSO/distilled water (5 ul), (ii) 5 ul of the inhibitor concentration to determine the 1050 using XLFit 5.0 kinase antibody mixture resulting in a final concentration 5 (IDBS, Guildford) to fit to a sigmoidal dose response curve, nMMYLK, 2nMEU-Anti-GST antibody in 1x kinase buffer and the apparent Ki values were calculated from the IC50 A. The reaction was started with addition of (iii) 5ul resulting using the Cheng-Prusoff equation (Cheng, Y.; Prusoff, W. H. in a final concentration of 30 nM tracer 236. The assay plate Biochem. Pharmacol. 22, 3099-3108, 1973). was incubated at RT for 1 h and fluorescence intensity read 0.124. The ATP dependency was determined according to ings were collected using a TECAN M1000 at two wave Lai C-J-, Wu JCA Simple Kinetic Method for Rapid Mecha lengths of Wex 340/Wem 615 nm and Wex 340/Wem 665 nm. nistic Analysis of Reversible Enzyme Inhibitors. Assays and with a delay time of 100 us and an integration time of 200 us Drug Dev. Technologies. 2003: 1(4):527-535. To demon after 60 minutes. The emission ratio was calculated by divi strate a competition effect of the test compounds towards ATP sion of the acceptor/tracer emission (665 nM) by the anti the corresponding test compound was used at the 50% inhibi body/donor emission (615 nM). The inhibitor concentration tory concentration. Assay conditions as described previously was plotted versus the emission ratio to determine the IC50 were maintained. ATP concentrations used was 1000, 333, using XLFit 5.0 (IDBS, Guildford) to fit to a sigmoidal dose 100, 33.3, 10, 3.3, 1 uM. response curve with a variable slope. LRRK2-LRRK2 G2019S-Assay Biological Assays—Cellular Assay 0.125. In the assay LanthaScreenTM Eu Kinase Binding Assay by Invitrogen Corporation (Carlsbad) the effect of LAD2 Assay invention of a compound on the phosphorylation is deter I0129. The inhibition of Syk may also be determined by mined by measurement of fluorescence intensity emission examining IgE mediated release of histamine in vitro using ratio based on the binding and displacement of a proprietary, human conjunctival tissue mast cells or in LAD2 mast cells Alexa Fluorr) 647-labeled, ATP-competitive kinase inhibitor (Leuk Res. 2003 Aug. 27(8):677-82). Human conjunctival scaffold (kinase tracer) to the kinase of interest. Binding of tissue mast cells (HCTMCs) are obtained using the method the tracer to the kinase is detected using a europium-labeled ology outlined in U.S. Pat. No. 5,360,720, for example. anti-tag antibody, which binds to the kinase of interest. Simul Briefly, HCTMCs are enzymatically released from human taneous binding of both the tracer and antibody to the kinase conjunctival tissues and then partially enriched by density results in a high degree of FRET (fluorescence resonance centrifugation over a PERCOLL(R) cushion. A monodispersed energy transfer) from the europium (Eu) donor fluorophore to cell Suspension is obtained from the resulting pellet, and these the Alexa Fluor(R) 647 acceptor fluorophore on the kinase cells are used for a histamine release assay. Cells are exposed tracer. Binding of an inhibitor to the kinase competes for to drug or control prior to stimulation with anti-human IgE, binding with the tracer, resulting in a loss of FRET. The which triggers mast cell degranulation and histamine release fluorescence intensity ratio is directly proportional to the to the Supernatant. Histamine is then measured in the Super amount of peptide phosphorylation. natant by EIA (Beckman Coulter), RIA (Beckman Coulter) or US 2012/032978.0 A1 Dec. 27, 2012

other method known to one of skill in the art. A decrease in Gradient: histamine release drug treated cells indicates that the com pound has potential for further investigation. 0.138 0130. The LAD2 mast cell line is used in much the same way with the exception that the cells are passively sensitized with human IgE myeloma prior to stimulation with anti Time min % B % C %D Flow mL/min human IgE to cross-link receptor bound IgE and trigger O 90 5 O 1.3 degranulation. 2.5 10 5 O 1.3 4 10 5 O 1.3 General Procedures for Synthesis of Compounds 4.5 90 5 O 1.3 6 90 5 O 1.3 Chromatography 0131 The compound verification via analytical HPLC Stop time (a 7 min MS was done after purification using the following instru MS: ESI positive, Mass scan from 100 to 800 mentation, column and method: gradient fragmentation: 50 to 125V Analytical method for compound purity UV: detection (a 220 and 254 nm

Instrumentation: Method C I0139 Column ODS-AQ from YMC 2.1x50 mm 3 um Agilent MSD 1100 particle size, Analytical Methods: thermostated (a 40°C. Gradient: Solvents: 0140 (0132 A:acetonitrile B: H2O Time min % B % C %D Flow mL/min 0.133 C: 2% HCOOH in acetonitrile O 90 5 O O6 D: 0.1% NEt3 in acetonitrile 2.5 10 5 O O6 0134. The following analytical methods were used: 4 10 5 O O6 4.5 90 5 O O6 6 90 5 O O6 Method A 0135 Column SunFire C18 from Waters 2.1 x50 mm 2.5 Stop time (a 7 min um particle size, MS: ESI positive, Mass scan from 100 to 800 thermostated (a 40° gradient fragmentation: 50 to 125V UV: detection (a 220 and 254 nm Gradient: Method D 0136 0141 Column ODS-AQ from YMC 2.1x50 mm 3 um particle size, incl. GuardCol 2.1 x 10 mm, 3 um particle size thermostated 40°C. Time min % B % C %D Flow mL/min O 90 5 O O.6 Gradient: 2.5 10 5 O O.6 4 10 5 O O.6 4.5 90 5 O O.6 0142 6 90 5 O O.6

Stop time (a 7 min Time min % B % C %D Flow mL/min MS: ESI positive, Mass scan from 100 to 800 O 90 5 O O6 1O.O 10 5 O O6 gradient fragmentation: 50 to 125V 13.0 10 5 O O6 UV: detection (a) 220 and 254 nm 14.O 90 5 O O6

Method B Stop time (a 15 min 0137 Column ODS-AQ from YMC 4.0x50 mm 2.5 um MS: ESI positive, Mass scan from 100 to 800 particle size, gradient fragmentation: 50 to 125V thermostated (a) RT UV: detection (a 220 and 254 nm US 2012/032978.0 A1 Dec. 27, 2012 39

Method E Method H 0143 Column ODS-AQ from YMC 2.1x50 mm 3 um 0149 Column Waters XBridge C18 2.1 x50 mm 2.5 um particle size, particle size, thermostated (a 40°C. thermostated (a 40° Gradient: Gradient: 0144) O150

Time min % B % C % D Flow mL/min Time min % B % C % D Flow mL/min

O 90 5 O O.6 O 90 5 O 0.55 S.O 10 5 O O.6 2.5 10 5 O 0.55 8 3. g 8. 4.0 10 5 O 0.55 4.5 90 5 O 0.55 6.O 90 5 O 0.55 Stop time (a) 10 min MS: ESI positive, Mass scan from 100 to 800 Stop time (a 6 min gradient fragmentation: 50 to 125V MS: ESI positive, Mass scan from 100 to 800 UV: detection (a) 220 and 254 nm gradient fragmentation: 50 to 125V Method F UV: detection (a 220 and 254 nm (0145 Column SunFire C18 from Waters 2.1 x50 mm 2.5 Method I um particle size, thermostated (a 40° 0151. Column Waters XBridge C18 2.1 x50 mm 2.5 um particle size, Gradient: thermostated (a 40° O146 Gradient: 0152 Time min % B % C %D Flow mL/min O 90 5 O 1.2 7.0 10 5 O 1.2 Time min % B % C %D Flow mL/min 8.5 10 5 O 1.2 9.0 90 5 O 1.2 O 90 O 5 0.55 11.0 90 5 O 1.2 2.5 10 O 5 0.55 4.0 10 O 5 0.55 4.5 90 O 5 0.55 Stop time (a 12 min 6.O 90 O 5 0.55 MS: ESI positive, Mass scan from 100 to 800 gradient fragmentation: 50 to 125V Stop time (a 6 min UV: detection (a) 220 and 254 nm MS: ESI positive, Mass scan from 100 to 800 Method G gradient fragmentation: 50 to 125V UV: detection (a 220 and 254 nm 0147 ColumnYMCC8 OS 4.0x50mm 4 um particle size, thermostated (a 40° Method J Gradient: (O153 Column Waters SunFire C18 2.1x50 mm, 2.5 um 0148 particle size thermostated(a)40°C. Gradient: Time min % B % C %D Flow mL/min 0154) O 90 5 O 1.5 2.5 10 5 O 1.5 4.0 10 5 O 1.5 4.5 90 5 O 1.5 6.O 90 5 O 1.5 Timemin % B % C %D Flow mL/min O 90 5 O O6 Stop time (a 6 min g g 9. MS: ESI positive, Mass scan from 100 to 800 14 90 5 O 0.6 gradient fragmentation: 50 to 125V UV: detection (a) 220 and 254 nm US 2012/032978.0 A1 Dec. 27, 2012 40

Stop time(a)15 min Purification Via Semi-Preparative HPLC-MS MS: ESI positive, Mass scan from 100 to 800 gradient fragmentation: 50 to 125V Instrumentation: UV: detection (a) 220 and 254 nm 2x Varian PrepStar SD-1 Method K 1x Dionex P580 Pump 1 Channel (MakeUPI) 0155 Column YMCODS-AQ 2.1x50mm, 3 um particle size 1x Dionex AXP-MS (MakeUP II) incl. GuardCol 2.1 x 10 mm, 3 um particle size thermostated(a)40°C. 1x Dionex MSQ

Gradient: 1x Dionex UVD 340V-Prep Flow Cell 0156 Gilson 215 Liquid Handler

Column: Timemin % B % C %D FlowmL/min O 99 5 O O.6 SunFire Prep C18 OBD 5um 19x50mm 2.5 10 5 O O.6 4 10 5 O O.6 Method: 4.5 99 5 O O.6 6 99 5 O O.6 (0160 Column Flow: 30 ml/min Solvent A: methanol, 0.3% acetic acid Stop time(a).7 min Solvent B: water, 0.3% acetic acid MS: ESI positive, Mass scan from 100 to 800 gradient fragmentation: 50 to 125V Time Table for Gradient: UV: detection (a) 220 and 254 nm (0161 Method L Column YMC TriArt C18 2.0x50 mm, 1.9 um, Time (min) Solv. A Solv. B HTA 12SP90502WT O.O 30.00 7O.OO 1O.O 100.00 O.OO (O157 thermostated(a)40° C. 14.0 100.00 O.OO 14.4 30.00 7O.OO 16.4 30.00 7O.OO Gradient: 0158 Detection: (0162 UV 254 nm, Mass Spectrometer Detector (API-ES, Timemin % B % C %D FlowmL/min positive) O 90 5 O O45 O.S 90 5 O O45 4.5 10 5 O O45 Compound Preparation 5.5 10 5 O O45 S.6 90 5 O O45 0163 Where the preparation of starting materials is not described, these are commercially available, known in the literature, or readily obtainable by those skilled in the art Stop time(a) 10 min using standard procedures. Where it is stated that compounds MS: ESI positive, Mass scan from 100 to 800 were prepared analogously to earlier examples or intermedi ates, it will be appreciated by the skilled person that the gradient fragmentation: 50 to 125V reaction time, number of equivalents of reagents and tempera UV: detection (a) 220 and 254 nm ture can be modified for each specific reaction and that it may be necessary or desirable to employ different workup or puri Purification and Characterisation: fication techniques. Where reactions are carried out using microwave irradiation, the microwave used is an Initiator 60 0159. The resulting crude reaction products were purified Supplied by Biotage. The actual power Supplied varies during in an automatic process using a semi-preparative HPLC-MS the course of the reaction in order to maintain a constant with mass-triggered sampling of the desired peak: temperature. US 2012/032978.0 A1 Dec. 27, 2012

Abbreviations (0176) Both isomers can be used for the next steps. 0.177 Yield: 47% DCM=Dichloromethane 0178 Mexact=332,149 0179 HPLC-MS method: A DMF=N,N-Dimethylformamide 0180 Retention time: 2.96 min/3.2 min (Isomers) 0164 DDQ-2,3-Dichloro-5,6-dicyano-1,4-benzo 0181 Mass found (m+H): 333.1 quinone Step 3: Chlorination THF=Tetrahydrofuran 0182. The mixture of 1-(4-Methoxy-benzyl)-5-phenyl-1, 6-dihydro-pyrazolo 4.3-dpyrimidin-7-one and 2-(4-Meth MeOH=Methanol oxy-benzyl)-5-phenyl-2,6-dihydro-pyrazolo 4.3-dpyrimi (016.5 TFA=Trifluoroacetic acid din-7-one (0.18 mmol) was suspended in POCl3. The mixture was heated to 100° C. in a reaction vessel. After 0.5 h-24h TEA-Triethylamine LC-MS showed reaction completion. The mixture was cooled to rt. The mixture was concentrated to dryness, cooled to 0° 0166 rm-Reaction mixture C., and quenched with ice/water. The mixture was extracted rt=Room temperature with DCM. The organic layer was washed with NaHCO3 sat. AcOH-Acetic acid aq. and water, dried (Na2SO4) filtered and concentrated. 0183 The product was used without further purification. MeCN=Acetonitrile 0.184 The product is an isomeric mixture of 7-Chloro-1- (4-methoxy-benzyl)-5-phenyl-1H-pyrazolo 4,3-dipyrimi EtOH=Ethanol dine and 7-Chloro-2-(4-methoxy-benzyl)-5-phenyl-2H pyrazolo 4.3-dipyrimidine EtOAc=Ethyl Acetate 0185. Both isomers can be used for the next steps. 0167 LCMS-Mass spectrometry directed high pressure 0186 Mexact=350,113 liquid chromatography 0187. HPLC-MS method: A 0188 Retention time: 3.98 min/4.3 min UV=Ultraviolet (0189 Mass found (m+H): 351.1 (0190. The following Chlorides and Isomers were synthe DMSO–Dimethylsulphoxide sized according the above mentioned procedure: 7-chloro-2-(4-methoxybenzyl)-5-phenyl-2H-pyrazolo 4.3- Intermediates dpyrimidine: 7-chloro-2-(4-methoxybenzyl)-5-(pyridin-4- yl)-2H-pyrazolo 4,3-dipyrimidine; 7-chloro-2-(4-methoxy Preparation of 7-chloro-2-(4-methoxybenzyl)-5-phe benzyl)-5-(6-(pyrrolidin-1-yl)pyridin-3-yl)-2H-pyrazolo4. nyl-2H-pyrazolo 4,3-dipyrimidine 3-dipyrimidine: 7-chloro-5-(3,4-dimethoxyphenyl)-2-(4- methoxybenzyl)-2H-pyrazolo 4,3-dipyrimidine: 7-chloro-2- Step 1: 5-Phenyl-1,6-dihydro-pyrazolo4.3-dpyrimi (4-methoxybenzyl)-5-(1-methylpiperidin-4-yl)-2H din-7-one pyrazolo 4,3-dipyrimidine: 7-chloro-2-(4-methoxybenzyl)- 0168 4-Amino-2H-pyrazole-3-carboxylic acid amide (5 5-(1H-pyrazol-3-yl)-2H-pyrazolo 4,3-dipyrimidine: mmol) and benzaldehyde (5 mmol) were dissolved in acetic 7-chloro-2-(4-methoxybenzyl)-5-(4-methoxyphenyl)-2H acid (14 ml). Subsequently DDQ (3.75 mmol) were added pyrazolo 4,3-dipyrimidine: 7-chloro-2-(4-methoxybenzyl)- and the reaction mixture is heated in the microwave to 180°C. 5-(3-methoxyphenyl)-2H-pyrazolo 4,3-dipyrimidine: for 30 minutes. The precipitate was filtered and washed with 7-chloro-2-(4-methoxybenzyl)-5-(thiophen-2-yl)-2H-pyra Et2O. Zolo 4,3-dipyrimidine: 7-chloro-2-(4-methoxybenzyl)-5- (0169 Mexact=212,079 (thiophen-3-yl)-2H-pyrazolo 4.3-dpyrimidine: 2-(7-chloro Yield 80% 2-(4-methoxybenzyl)-2H-pyrazolo 4,3-dipyrimidin-5-yl) 0170 benzodthiazole; 7-chloro-2-(4-methoxybenzyl)-5-(3- 0171 HPLC-MS method: A (pyridin-3-yl)phenyl)-2H-pyrazolo 4,3-dipyrimidine: 2-(7- 0172 Retention Time: 2.1 min chloro-2-(4-methoxybenzyl)-2H-pyrazolo 4,3-dipyrimidin 0173 mass found (m+H): 213.1 5-yl)phenol; 4-(3-(7-chloro-2-(4-methoxybenzyl)-2H pyrazolo 4.3-dipyrimidin-5-yl)phenyl)morpholine; Step 2: Protection of Pyrazole with 7-chloro-2-(4-methoxybenzyl)-5-(2-methoxyphenyl)-2H 1-Chloromethyl-4-methoxy-benzene pyrazolo 4,3-dipyrimidine: 7-chloro-5-(2,5-dimethoxyphe 0.174 5-Phenyl-1,6-dihydro-pyrazolo 4.3-dpyrimidin-7- nyl)-2-(4-methoxybenzyl)-2H-pyrazolo 4,3-dipyrimidine: one (3.9 mmol) was dissolved in 14 ml acetonitrile. 1-Chlo N-(2-aminoethyl)-3-(7-chloro-2-(4-methoxybenzyl)-2H romethyl-4-methoxy-benzene (4.7 mmol), 1.2 eq triethy pyrazolo 4,3-dipyrimidin-5-yl)benzamide; 7-chloro-5-(imi lamine (4.7 mmol) and sodiumiodide (0.39 mmol) was added dazol-2-alpyridin-2-yl)-2-(4-methoxybenzyl)-2H-pyrazolo Subsequently. The reaction mixture was heated in the micro 4.3-dpyrimidine; 5-(1H-benzodimidazol-2-yl)-7-chloro wave for 30 min at 160° C. After cooling down the reaction 2-(4-methoxybenzyl)-2H-pyrazolo 4,3-dipyrimidine: the resulting precipitate was filtered and washed with Et2O. 7-chloro-2-(4-methoxybenzyl)-5-(1-methyl-1H-benzod 0.175. The reaction is leading to two isomers (1-(4-Meth imidazol-2-yl)-2H-pyrazolo 4,3-dipyrimidine: 7-chloro-5- oxy-benzyl)-5-phenyl-1,6-dihydro-pyrazolo 4.3-dpyrimi (1H-imidazol-5-yl)-2-(4-methoxybenzyl)-2H-pyrazolo 4.3- din-7-one and 2-(4-Methoxy-benzyl)-5-phenyl-2,6-dihydro dpyrimidine; 7-chloro-5-(1H-imidazol-2-yl)-2-(4- pyrazolo 4.3-dpyrimidin-7-one). methoxybenzyl)-2H-pyrazolo 4,3-dipyrimidine; 5-(3-(2H

US 2012/032978.0 A1 Dec. 27, 2012

The residue was dissolved in TFA (3 mL). The reaction mix 0216) exact mass: 372.199 g/mol ture was irradiated in a microwave reactor for 5 minat 140°C. 0217. HPLC-MS: analytical method A The reaction mixture was concentrated and purified by semi 0218 rt: 2.546 min-found mass: 373 (m/z+H) preparative HPLC-MS and freeze dried from water/t-BuOH 4f1. Example #8 0204 exact mass: 330.1856 g/mol 0205 HPLC-MS: analytical method I Preparation of N-(3-methoxyphenyl)-5-phenyl-1H 0206 rt: 3.175 min-found mass: 331 (m/z+H) pyrazolo 4.3-dpyrimidin-7-amine Example #5 0219) 7-chloro-2-(4-methoxybenzyl)-5-phenyl-2H-pyra Zolo 4,3-dipyrimidine (0.16 mmol) and 3-methoxyaniline Preparation of 3-((5-phenyl-1H-pyrazolo4.3-dpyri (0.3 mmol 2 eq.) were suspended in MeOH (dry, 3 mL) in a midin-7-yl)amino)benzamide microwave vial (2-5 mL), HCl in dioxane (4M, 3 drops) was added. The reaction mixture was irradiated in a microwave 0207 7-chloro-2-(4-methoxybenzyl)-5-phenyl-2H-pyra reactor for 5 min at 140°C. The reaction mixture was evapo Zolo4.3-dpyrimidine (0.16 mmol) and 3-aminobenzamide rated and used without further purification. The residue was (0.3 mmol 2 eq.) were suspended in MeOH (dry, 3 mL) in a dissolved in TFA (3 mL). The reaction mixture was irradiated microwave vial (2-5 mL), HCl in dioxane (4M, 3 drops) was in a microwave reactor for min at 140°C. The reaction mix added. The reaction mixture was irradiated in a microwave ture was concentrated and purified by semi-preparative reactor for 5 min at 140°C. The reaction mixture was evapo HPLC-MS and freeze dried from waterft-BuOH 4/1. rated and used without further purification. The residue was 0220 exact mass: 317.1479 g/mol dissolved in TFA (3 mL). The reaction mixture was irradiated 0221) HPLC-MS: analytical method A in a microwave reactor for 5 min at 140° C. The reaction mixture was concentrated and purified by semi-preparative 0222 rt: 2.867 min-found mass: 318 (m/z+H) HPLC-MS and freeze dried from waterft-BuOH 4/1. Example #9 0208 exact mass: 330.1405 g/mol 0209 HPLC-MS: analytical method A Preparation of N-(2-methyl-1H-benzodimidazol-5- 0210 rt: 2.290 min-found mass: 331 (m/z+H) yl)-5-phenyl-1H-pyrazolo 4,3-dipyrimidin-7-amine Example #6 0223 7-chloro-2-(4-methoxybenzyl)-5-phenyl-2H-pyra Zolo 4,3-dipyrimidine (0.16 mmol) and 2-methyl-1H-benzo Preparation of N-(3,4-dimethoxyphenyl)-5-phenyl dimidazol-5-amine (0.3 mmol 2 eq.) were Suspended in 1H-pyrazolo 4,3-dipyrimidin-7-amine MeOH (dry, 3 mL) in a microwave vial (2-5 mL), HCl in dioxane (4M, 3 drops) was added. The reaction mixture was 0211 7-chloro-2-(4-methoxybenzyl)-5-phenyl-2H-pyra irradiated in a microwave reactor for 5 min at 140°C. The Zolo4.3-dpyrimidine (0.16 mmol) and 3,4-dimethoxya reaction mixture was evaporated and used without further niline (0.3 mmol 2 eq.) were suspended in MeOH (dry, 3 mL) purification. The residue was dissolved in TFA (3 mL). The in a microwave vial (2-5 mL), HCl in dioxane (4M, 3 drops) reaction mixture was irradiated in a microwave reactor for 5 was added. The reaction mixture was irradiated in a micro min at 140° C. The reaction mixture was concentrated and wave reactor for 5 min at 140°C. The reaction mixture was purified by semi-preparative HPLC-MS and freeze dried evaporated and used without further purification. The residue from waterft-BuOH 4/1. was dissolved in TFA (3 mL). The reaction mixture was irradiated in a microwave reactor for min at 140° C. The 0224 exact mass: 341.1581 g/mol reaction mixture was concentrated and purified by semi-pre 0225 HPLC-MS: analytical method I parative HPLC-MS and freeze dried from water/t-BuOH4/1. 0226 rt: 2.576 min-found mass: 342 (m/z+H) 0212 exact mass: 347.1618 g/mol 0213 HPLC-MS: analytical method A Example #10 0214 rt: 2.544 min-found mass: 348 (m/z+H) Preparation of 4-((5-phenyl-1H-pyrazolo 4,3-dipyri Example #7 midin-7-yl)amino)benzoic-acid 0227 7-chloro-2-(4-methoxybenzyl)-5-phenyl-2H-pyra Preparation of N-(4-morpholinophenyl)-5-phenyl Zolo 4,3-dipyrimidine (0.16 mmol) and 4-aminobenzoic 1H-pyrazolo 4,3-dipyrimidin-7-amine acid (0.3 mmol 2 eq.) were suspended in MeCH (dry, 3 mL) 0215 7-chloro-2-(4-methoxybenzyl)-5-phenyl-2H-pyra in a microwave vial (2-5 mL), HCl in dioxane (4M, 3 drops) Zolo4.3-dpyrimidine (0.16 mmol) and 4-morpholinoaniline was added. The reaction mixture was irradiated in a micro (0.3 mmol 2 eq.) were suspended in MeOH (dry, 3 mL) in a wave reactor for 5 min at 140°C. The reaction mixture was microwave vial (2-5 mL), HCl in dioxane (4M, 3 drops) was evaporated and used without further purification. The residue added. The reaction mixture was irradiated in a microwave was dissolved in TFA (3 mL). The reaction mixture was reactor for 5 min at 140°C. The reaction mixture was evapo irradiated in a microwave reactor for min at 140° C. The rated and used without further purification. The residue was reaction mixture was concentrated and purified by semi-pre dissolved in TFA (3 mL). The reaction mixture was irradiated parative HPLC-MS and freeze dried from water/t-BuOH4/1. in a microwave reactor for min at 140°C. The reaction mix 0228 exact mass: 331.1224 g/mol ture was concentrated and purified by semi-preparative 0229 HPLC-MS: analytical method A HPLC-MS and freeze dried from waterft-BuOH 4/1. 0230 rt: 2.581 min-found mass: 332 (m/z+H) US 2012/032978.0 A1 Dec. 27, 2012 44

Example #11 Example #14 Preparation of 4-((5-phenyl-1H-pyrazolo4.3-dpyri Preparation of N-(1H-indazol-5-yl)-5-(6-(pyrrolidin midin-7-yl)amino)benzamide 1-yl)pyridin-3-yl)-1H-pyrazolo 4,3-dipyrimidin-7- amine 0231 7-chloro-2-(4-methoxybenzyl)-5-phenyl-2H-pyra Zolo4.3-dpyrimidine (0.16 mmol) and 4-aminobenzamide 0243 7-chloro-2-(4-methoxybenzyl)-5-(6-(pyrrolidin-1- (0.3 mmol 2 eq.) were suspended in MeOH (dry, 3 mL) in a yl)pyridin-3-yl)-2H-pyrazolo 4.3-dpyrimidine (0.16 mmol) microwave vial (2-5 mL), HCl in dioxane (4M, 3 drops) was and 1H-indazol-5-amine (0.3 mmol 2 eq.) were suspended in added. The reaction mixture was irradiated in a microwave MeOH (dry, 3 mL) in a microwave vial (2-5 mL), HCl in reactor for 5 min at 140°C. The reaction mixture was evapo dioxane (4M, 3 drops) was added. The reaction mixture was rated and used without further purification. The residue was irradiated in a microwave reactor for 5 min at 140°C. The dissolved in TFA (3 mL). The reaction mixture was irradiated reaction mixture was evaporated and used without further in a microwave reactor for min at 140°C. The reaction mix purification. The residue was dissolved in TFA (3 mL). The ture was concentrated and purified by semi-preparative reaction mixture was irradiated in a microwave reactor for 5 HPLC-MS and freeze dried from waterft-BuOH 4/1. min at 140° C. The reaction mixture was concentrated and purified by semi-preparative HPLC-MS and freeze dried 0232 exact mass: 330.1405 g/mol from waterft-BuOH 4/1. 0233 HPLC-MS: analytical method A 0244 exact mass: 397.2021 g/mol 0234 rt: 2.287 min-found mass: 331 (m/z+H) 0245 HPLC-MS: analytical method A 0246 rt: 2.011 min-found mass: 398 (m/z+H) Example #12 Example #15 Preparation of 4-((5-phenyl-1H-pyrazolo4.3-dpyri midin-7-yl)amino)benzonitrile Preparation of 2-((5-(3,4-dimethoxyphenyl)-1H pyrazolo 4.3-dpyrimidin-7-yl)amino)benzamide 0235) 7-chloro-2-(4-methoxybenzyl)-5-phenyl-2H-pyra 0247 7-chloro-5-(3,4-dimethoxyphenyl)-2-(4-methoxy Zolo4.3-dipyrimidine (0.16 mmol) and 4-aminobenzonitrile benzyl)-2H-pyrazolo 4.3-dpyrimidine (0.16 mmol) and (0.3 mmol 2 eq.) were suspended in MeOH (dry, 3 mL) in a 2-aminobenzamide (0.3 mmol 2 eq.) were suspended in microwave vial (2-5 mL), HCl in dioxane (4M, 3 drops) was MeOH (dry, 3 mL) in a microwave vial (2-5 mL), HCl in added. The reaction mixture was irradiated in a microwave dioxane (4M, 3 drops) was added. The reaction mixture was reactor for 5 min at 140°C. The reaction mixture was evapo irradiated in a microwave reactor for 5 min at 140°C. The rated and used without further purification. The residue was reaction mixture was evaporated and used without further dissolved in TFA (3 mL). The reaction mixture was irradiated purification. The residue was dissolved in TFA (3 mL). The in a microwave reactor for min at 140°C. The reaction mix reaction mixture was irradiated in a microwave reactor for 5 ture was concentrated and purified by semi-preparative min at 140° C. The reaction mixture was concentrated and HPLC-MS and freeze dried from waterft-BuOH 4/1. purified by semi-preparative HPLC-MS and freeze dried 0236 exact mass: 312.126 g/mol from waterft-BuOH 4/1. 0237 HPLC-MS: analytical method A 0248 exact mass: 390.1682 g/mol 0238 rt: 3.081 min-found mass: 313 (m/z+H) 0249 HPLC-MS: analytical method A (0250 rt: 1.960 min-found mass: 391 (m/z+H) Example #13 Example #16 Preparation of N-(1H-indazol-5-yl)-5-(pyridin-4-yl)- Preparation of N-(1H-indazol-6-yl)-5-(pyridin-4-yl)- 1H-pyrazolo 4,3-dipyrimidin-7-amine 1H-pyrazolo 4,3-dipyrimidin-7-amine 0239) 7-chloro-2-(4-methoxybenzyl)-5-(pyridin-4-yl)- 0251 7-chloro-2-(4-methoxybenzyl)-5-(pyridin-4-yl)- 2H-pyrazolo4.3-dpyrimidine (0.16 mmol) and 1H-indazol 2H-pyrazolo 4,3-dipyrimidine (0.16 mmol) and 1H-indazol 5-amine (0.3 mmol 2 eq.) were suspended in MeCH (dry, 3 6-amine (0.3 mmol 2 eq.) were suspended in MeOH (dry, 3 mL) in a microwave vial (2-5 mL), HCl in dioxane (4M, 3 mL) in a microwave vial (2-5 mL), HCl in dioxane (4M, 3 drops) was added. The reaction mixture was irradiated in a drops) was added. The reaction mixture was irradiated in a microwave reactor for 5 min at 140°C. The reaction mixture microwave reactor for 5 min at 140°C. The reaction mixture was evaporated and used without further purification. The was evaporated and used without further purification. The residue was dissolved in TFA (3 mL). The reaction mixture residue was dissolved in TFA (3 mL). The reaction mixture was irradiated in a microwave reactor for 5 minat 140°C. The was irradiated in a microwave reactor for min at 140°C. The reaction mixture was concentrated and purified by semi-pre reaction mixture was concentrated and purified by semi-pre parative HPLC-MS and freeze dried from water/t-BuOH4/1. parative HPLC-MS and freeze dried from water/t-BuOH4/1. 0240 exact mass: 328.1316 g/mol 0252) exact mass: 328.1316 g/mol 0241 HPLC-MS: analytical method A 0253 HPLC-MS: analytical method A 0242 rt: 1.850 min-found mass: 329 (m/z+H) 0254 rt: 1.935 min-found mass: 329 (m/z+H) US 2012/032978.0 A1 Dec. 27, 2012 45

Example #17 Example #20 Preparation of N1,N1-dimethyl-N4-(5-(pyridin-4- Preparation of N-(4-(4-methylpiperazin-1-yl)phe yl)-1H-pyrazolo 4,3-dipyrimidin-7-yl)benzene-1,4- nyl)-5-(pyridin-4-yl)-1H-pyrazolo 4.3-dpyrimidin diamine 7-amine 0255) 7-chloro-2-(4-methoxybenzyl)-5-(pyridin-4-yl)- 0267 7-chloro-2-(4-methoxybenzyl)-5-(pyridin-4-yl)- 2H-pyrazolo4.3-dpyrimidine (0.16 mmol) and N1,N1-dim 2H-pyrazolo 4,3-dipyrimidine (0.16 mmol) and 4-(4-meth ethylbenzene-1,4-diamine (0.3 mmol 2 eq.) were suspended ylpiperazin-1-yl)aniline (0.3 mmol 2 eq.) were suspended in in MeCH (dry, 3 mL) in a microwave vial (2-5 mL), HCl in MeOH (dry, 3 mL) in a microwave vial (2-5 mL), HCl in dioxane (4M, 3 drops) was added. The reaction mixture was dioxane (4M, 3 drops) was added. The reaction mixture was irradiated in a microwave reactor for 5 min at 140°C. The irradiated in a microwave reactor for 5 min at 140°C. The reaction mixture was evaporated and used without further reaction mixture was evaporated and used without further purification. The residue was dissolved in TFA (3 mL). The purification. The residue was dissolved in TFA (3 mL). The reaction mixture was irradiated in a microwave reactor for 5 reaction mixture was irradiated in a microwave reactor for 5 min at 140° C. The reaction mixture was concentrated and min at 140° C. The reaction mixture was concentrated and purified by semi-preparative HPLC-MS and freeze dried purified by semi-preparative HPLC-MS and freeze dried from waterft-BuOH 4/1. from waterft-BuOH 4/1. 0256 exact mass: 331.1786 g/mol 0268 exact mass: 386.2296 g/mol 0257 HPLC-MS: analytical method A 0269. HPLC-MS: analytical method A 0258 rt: 0.678 min-found mass: 332 (m/z+H) (0270 rt: 0.504 min-found mass: 387 (im/z+H) Example #18 Example #21 Preparation of 6-((5-(pyridin-4-yl)-1H-pyrazolo 4.3- Preparation of N-(3,4-dimethoxyphenyl)-5-(pyridin dpyrimidin-7-yl)amino)-2H-benzob 14oxazin-3 4-yl)-1H-pyrazolo 4.3-dpyrimidin-7-amine (4H)-one 0259 7-chloro-2-(4-methoxybenzyl)-5-(pyridin-4-yl)- 0271 7-chloro-2-(4-methoxybenzyl)-5-(pyridin-4-yl)- 2H-pyrazolo 4.3-dpyrimidine (0.16 mmol) and 3,4- 2H-pyrazolo 4,3-dipyrimidine (0.16 mmol) and 6-amino dimethoxyaniline (0.3 mmol 2 eq.) were suspended in MeOH 2H-benzob 14oxazin-3 (4H)-one (0.3 mmol 2 eq.) were (dry, 3 mL) in a microwave vial (2-5 mL), HCl in dioxane suspended in MeCH (dry, 3 mL) in a microwave vial (2-5 (4M, 3 drops) was added. The reaction mixture was irradiated mL), HCl in dioxane (4M, 3 drops) was added. The reaction in a microwave reactor for 5 min at 140° C. The reaction mixture was irradiated in a microwave reactor for 5 min at mixture was evaporated and used without further purification. 140°C. The reaction mixture was evaporated and used with The residue was dissolved in TFA (3 mL). The reaction mix out further purification. The residue was dissolved in TFA (3 ture was irradiated in a microwave reactor for min at 140°C. mL). The reaction mixture was irradiated in a microwave The reaction mixture was concentrated and purified by semi reactor for 5 min at 140°C. The reaction mixture was con preparative HPLC-MS and freeze dried from water/t-BuOH centrated and purified by semi-preparative HPLC-MS and 4f1. freeze dried from waterft-BuOH 4/1. 0260 exact mass: 348.1548 g/mol (0272 exact mass: 359.1274 g/mol 0261 HPLC-MS: analytical method A (0273 HPLC-MS: analytical method A 0262 rt: 2.013 min-found mass: 349 (m/z+H) (0274 rt: 1.930 min-found mass: 360 (m/z+H) Example #19 Example #22 Preparation of N-(4-morpholinophenyl)-5-(pyridin Preparation of 5-(3,4-dimethoxyphenyl)-N-(1H-in 4-yl)-1H-pyrazolo 4.3-dpyrimidin-7-amine dazol-6-yl)-1H-pyrazolo 4,3-dipyrimidin-7-amine 0275) 7-chloro-5-(3,4-dimethoxyphenyl)-2-(4-methoxy 0263) 7-chloro-2-(4-methoxybenzyl)-5-(pyridin-4-yl)- benzyl)-2H-pyrazolo 4.3-dpyrimidine (0.16 mmol) and 2H-pyrazolo4.3-dpyrimidine (0.16 mmol) and 4-morpholi 1H-indazol-6-amine (0.3 mmol 2 eq.) were suspended in noaniline (0.3 mmol 2 eq.) were suspended in MeCH (dry, 3 MeOH (dry, 3 mL) in a microwave vial (2-5 mL), HCl in mL) in a microwave vial (2-5 mL), HCl in dioxane (4M, 3 dioxane (4M, 3 drops) was added. The reaction mixture was drops) was added. The reaction mixture was irradiated in a irradiated in a microwave reactor for 5 min at 140°C. The microwave reactor for 5 min at 140°C. The reaction mixture reaction mixture was evaporated and used without further was evaporated and used without further purification. The purification. The residue was dissolved in TFA (3 mL). The residue was dissolved in TFA (3 mL). The reaction mixture reaction mixture was irradiated in a microwave reactor for 5 was irradiated in a microwave reactor for min at 140°C. The min at 140° C. The reaction mixture was concentrated and reaction mixture was concentrated and purified by semi-pre purified by semi-preparative HPLC-MS and freeze dried parative HPLC-MS and freeze dried from water/t-BuOH4/1. from waterft-BuOH 4/1. 0264 exact mass: 373.192 g/mol (0276 exact mass: 387.1664 g/mol 0265 HPLC-MS: analytical method A (0277. HPLC-MS: analytical method A 0266 rt: 1.974 min-found mass: 374 (m/z+H) (0278 rt: 2.233 min-found mass: 388 (m/z+H) US 2012/032978.0 A1 Dec. 27, 2012 46

Example #23 Example #26 Preparation of N1-(5-(3,4-dimethoxyphenyl)-1H Preparation of 6-((5-(3,4-dimethoxyphenyl)-1H pyrazolo 4,3-dipyrimidin-7-yl)-N4.N4-dimethylben pyrazolo4.3-dpyrimidin-7-yl)amino)-2H-benzob. Zene-1,4-diamine 1,4-oxazin-3 (4H)-one 0279 7-chloro-5-(3,4-dimethoxyphenyl)-2-(4-methoxy 0291) 7-chloro-5-(3,4-dimethoxyphenyl)-2-(4-methoxy benzyl)-2H-pyrazolo 4.3-dpyrimidine (0.16 mmol) and benzyl)-2H-pyrazolo 4.3-dpyrimidine (0.16 mmol) and N1,N1-dimethylbenzene-1,4-diamine (0.3 mmol 2 eq.) were 6-amino-2H-benzob 14oxazin-3 (4H)-one (0.3 mmol 2 suspended in MeCH (dry, 3 mL) in a microwave vial (2-5 eq.) were suspended in MeCH (dry, 3 mL) in a microwave mL), HCl in dioxane (4M, 3 drops) was added. The reaction vial (2-5 mL), HCl in dioxane (4M, 3 drops) was added. The mixture was irradiated in a microwave reactor for 5 min at reaction mixture was irradiated in a microwave reactor for 5 140°C. The reaction mixture was evaporated and used with min at 140°C. The reaction mixture was evaporated and used out further purification. The residue was dissolved in TFA (3 without further purification. The residue was dissolved in mL). The reaction mixture was irradiated in a microwave TFA (3 mL). The reaction mixture was irradiated in a micro reactor for 5 min at 140°C. The reaction mixture was con wave reactor for 5 min at 140°C. The reaction mixture was centrated and purified by semi-preparative HPLC-MS and concentrated and purified by semi-preparative HPLC-MS freeze dried from waterft-BuOH 4/1. and freeze dried from waterft-BuOH 471. 0280 exact mass: 390.2133 g/mol 0292 exact mass: 418.1621 g/mol (0281 HPLC-MS: analytical method A 0293 HPLC-MS: analytical method A 0282) rt: 2.173 min-found mass: 391 (m/z+H) 0294 rt: 2.218 min-found mass: 419 (m/z+H) Example #24 Example #27 Preparation of N,5-bis(3,4-dimethoxyphenyl)-1H Preparation of N-(1H-indazol-6-yl)-5-(1-methylpip pyrazolo 4.3-dpyrimidin-7-amine eridin-4-yl)-1H-pyrazolo 4,3-dipyrimidin-7-amine 0283) 7-chloro-5-(3,4-dimethoxyphenyl)-2-(4-methoxy 0295) 7-chloro-2-(4-methoxybenzyl)-5-(1-methylpiperi benzyl)-2H-pyrazolo 4.3-dpyrimidine (0.16 mmol) and 3,4- din-4-yl)-2H-pyrazolo 4,3-dipyrimidine (0.16 mmol) and dimethoxyaniline (0.3 mmol 2 eq.) were suspended in MeOH 1H-indazol-6-amine (0.3 mmol 2 eq.) were suspended in (dry, 3 mL) in a microwave vial (2-5 mL), HCl in dioxane MeOH (dry, 3 mL) in a microwave vial (2-5 mL), HCl in (4M, 3 drops) was added. The reaction mixture was irradiated dioxane (4M, 3 drops) was added. The reaction mixture was in a microwave reactor for 5 min at 140° C. The reaction irradiated in a microwave reactor for 5 min at 140°C. The mixture was evaporated and used without further purification. reaction mixture was evaporated and used without further The residue was dissolved in TFA (3 mL). The reaction mix purification. The residue was dissolved in TFA (3 mL). The ture was irradiated in a microwave reactor for 5 minat 140°C. reaction mixture was irradiated in a microwave reactor for 5 The reaction mixture was concentrated and purified by semi min at 140° C. The reaction mixture was concentrated and preparative HPLC-MS and freeze dried from water/t-BuOH purified by semi-preparative HPLC-MS and freeze dried 4f1. from waterft-BuOH 4/1. 0284 exact mass: 407.1896 g/mol 0296 exact mass: 348.211 g/mol 0285 HPLC-MS: analytical method A 0297 HPLC-MS: analytical method A 0286 rt: 2.303 min-found mass: 408 (m/z+H) 0298 rt: 0.486 min-found mass: 349 (m/z+H) Example #25 Example #28 Preparation of 5-(3,4-dimethoxyphenyl)-N-(4-mor Preparation of N1,N1-dimethyl-N4-(5-(1-methylpip pholinophenyl)-1H-pyrazolo 4,3-dipyrimidin-7- eridin-4-yl)-1H-pyrazolo 4,3-dipyrimidin-7-yl)ben amine Zene-1,4-diamine 0287 7-chloro-5-(3,4-dimethoxyphenyl)-2-(4-methoxy 0299 7-chloro-2-(4-methoxybenzyl)-5-(1-methylpiperi benzyl)-2H-pyrazolo 4.3-dpyrimidine (0.16 mmol) and din-4-yl)-2H-pyrazolo 4,3-dipyrimidine (0.16 mmol) and 4-morpholinoaniline (0.3 mmol 2 eq.) were Suspended in N1,N1-dimethylbenzene-1,4-diamine (0.3 mmol 2 eq.) were MeOH (dry, 3 mL) in a microwave vial (2-5 mL), HCl in suspended in MeCH (dry, 3 mL) in a microwave vial (2-5 dioxane (4M, 3 drops) was added. The reaction mixture was mL), HCl in dioxane (4M, 3 drops) was added. The reaction irradiated in a microwave reactor for 5 min at 140°C. The mixture was irradiated in a microwave reactor for 5 min at reaction mixture was evaporated and used without further 140°C. The reaction mixture was evaporated and used with purification. The residue was dissolved in TFA (3 mL). The out further purification. The residue was dissolved in TFA (3 reaction mixture was irradiated in a microwave reactor for 5 mL). The reaction mixture was irradiated in a microwave min at 140° C. The reaction mixture was concentrated and reactor for 5 min at 140°C. The reaction mixture was con purified by semi-preparative HPLC-MS and freeze dried centrated and purified by semi-preparative HPLC-MS and from waterft-BuOH 4/1. freeze dried from waterft-BuOH 4/1. 0288 exact mass: 432.2267 g/mol (0300 exact mass: 351.258 g/mol 0289 HPLC-MS: analytical method A (0301 HPLC-MS: analytical method A 0290 rt: 2.282 min-found mass: 433 (m/z+H) (0302 rt: 0.293 min-found mass: 352 (m/z+H) US 2012/032978.0 A1 Dec. 27, 2012 47

Example #29 Example #32 Preparation of N-(4-chlorophenyl)-5-(1-methylpip Preparation of N-(3,4-dimethoxyphenyl)-5-(6-(pyr eridin-4-yl)-1H-pyrazolo 4,3-dipyrimidin-7-amine rolidin-1-yl)pyridin-3-yl)-1H-pyrazolo 4,3-dipyrimi din-7-amine 0303) 7-chloro-2-(4-methoxybenzyl)-5-(1-methylpiperi din-4-yl)-2H-pyrazolo 4,3-dipyrimidine (0.16 mmol) and 0315) 7-chloro-2-(4-methoxybenzyl)-5-(6-(pyrrolidin-1- 4-chloroaniline (0.3 mmol 2 eq.) were suspended in MeOH yl)pyridin-3-yl)-2H-pyrazolo 4.3-dpyrimidine (0.16 mmol) (dry, 3 mL) in a microwave vial (2-5 mL), HCl in dioxane and 3,4-dimethoxyaniline (0.3 mmol 2 eq.) were suspended (4M, 3 drops) was added. The reaction mixture was irradiated in MeCH (dry, 3 mL) in a microwave vial (2-5 mL), HCl in in a microwave reactor for 5 min at 140° C. The reaction dioxane (4M, 3 drops) was added. The reaction mixture was mixture was evaporated and used without further purification. irradiated in a microwave reactor for 5 min at 140°C. The The residue was dissolved in TFA (3 mL). The reaction mix reaction mixture was evaporated and used without further ture was irradiated in a microwave reactor for 5 minat 140°C. purification. The residue was dissolved in TFA (3 mL). The The reaction mixture was concentrated and purified by semi reaction mixture was irradiated in a microwave reactor for 5 preparative HPLC-MS and freeze dried from water/t-BuOH min at 140° C. The reaction mixture was concentrated and 4f1. purified by semi-preparative HPLC-MS and freeze dried 0304 exact mass: 342.1648 g/mol from waterft-BuOH 4/1. 0305 HPLC-MS: analytical method A 0316 exact mass: 417.2253 g/mol (0306 rt: 0.935 min-found mass: 343 (m/z+H) 0317 HPLC-MS: analytical method I 0318 rt: 2.551 min-found mass: 418 (m/z+H) Example #30 Example #33 Preparation of N-(1H-indazol-6-yl)-5-(6-(pyrrolidin 1-yl)pyridin-3-yl)-1H-pyrazolo 4,3-dipyrimidin-7- Preparation of N-(4-morpholinophenyl)-5-(6-(pyrro amine lidin-1-yl)pyridin-3-yl)-1H-pyrazolo 4,3-dipyrimi din-7-amine 0307 7-chloro-2-(4-methoxybenzyl)-5-(6-(pyrrolidin-1- yl)pyridin-3-yl)-2H-pyrazolo 4.3-dpyrimidine (0.16 mmol) 0319 7-chloro-2-(4-methoxybenzyl)-5-(6-(pyrrolidin-1- and 1H-indazol-6-amine (0.3 mmol 2 eq.) were Suspended in yl)pyridin-3-yl)-2H-pyrazolo 4.3-dipyrimidine (0.16 mmol) MeOH (dry, 3 mL) in a microwave vial (2-5 mL), HCl in and 4-morpholinoaniline (0.3 mmol 2 eq.) were suspended in dioxane (4M, 3 drops) was added. The reaction mixture was MeOH (dry, 3 mL) in a microwave vial (2-5 mL), HCl in irradiated in a microwave reactor for 5 min at 140°C. The dioxane (4M, 3 drops) was added. The reaction mixture was irradiated in a microwave reactor for 5 min at 140°C. The reaction mixture was evaporated and used without further reaction mixture was evaporated and used without further purification. The residue was dissolved in TFA (3 mL). The purification. The residue was dissolved in TFA (3 mL). The reaction mixture was irradiated in a microwave reactor for 5 reaction mixture was irradiated in a microwave reactor for 5 min at 140° C. The reaction mixture was concentrated and purified by semi-preparative HPLC-MS and freeze dried min at 140° C. The reaction mixture was concentrated and from waterft-BuOH 4/1. purified by semi-preparative HPLC-MS and freeze dried from waterft-BuOH 4/1. 0308) exact mass: 397.2021 g/mol 0320 exact mass: 442.2624 g/mol 0309 HPLC-MS: analytical method A 0321) HPLC-MS: analytical method I 0310 rt: 2.060 min-found mass: 398 (m/z+H) 0322 rt: 2.553 min-found mass: 443 (m/z+H) Example #31 Example #34 Preparation of N1,N1-dimethyl-N4-(5-(6-(pyrroli Preparation of 5-(3,4-dimethoxyphenyl)-N-(4-(4- din-1-yl)pyridin-3-yl)-1H-pyrazolo 4,3-dipyrimidin methylpiperazin-1-yl)phenyl)-1H-pyrazolo 4,3-d 7-yl)benzene-1,4-diamine pyrimidin-7-amine 0311 7-chloro-2-(4-methoxybenzyl)-5-(6-(pyrrolidin-1- 0323) 7-chloro-5-(3,4-dimethoxyphenyl)-2-(4-methoxy yl)pyridin-3-yl)-2H-pyrazolo 4.3-dpyrimidine (0.16 mmol) benzyl)-2H-pyrazolo 4.3-dpyrimidine (0.16 mmol) and and N1,N1-dimethylbenzene-1,4-diamine (0.3 mmol 2 eq.) 4-(4-methylpiperazin-1-yl)aniline (0.3 mmol 2 eq.) were sus were suspended in MeOH (dry, 3 mL) in a microwave vial pended in MeOH (dry, 3 mL) in a microwave vial (2-5 mL), (2-5 mL), HCl in dioxane (4M, 3 drops) was added. The HCl in dioxane (4M, 3 drops) was added. The reaction mix reaction mixture was irradiated in a microwave reactor for 5 ture was irradiated in a microwave reactor for 5 minat 140°C. min at 140°C. The reaction mixture was evaporated and used The reaction mixture was evaporated and used without fur without further purification. The residue was dissolved in ther purification. The residue was dissolved in TFA (3 mL). TFA (3 mL). The reaction mixture was irradiated in a micro The reaction mixture was irradiated in a microwave reactor wave reactor for 5 min at 140°C. The reaction mixture was for 5 min at 140°C. The reaction mixture was concentrated concentrated and purified by semi-preparative HPLC-MS and purified by semi-preparative HPLC-MS and freeze dried and freeze dried from waterft-BuOH 471. from waterft-BuOH 4/1. 0312 exact mass: 400.2491 g/mol 0324 exact mass: 445.2643 g/mol 0313 HPLC-MS: analytical method A 0325 HPLC-MS: analytical method A 0314 rt: 1.890 min-found mass: 401 (m/z+H) 0326 rt: 1.761 min-found mass: 446 (m/z+H) US 2012/032978.0 A1 Dec. 27, 2012 48

Example #35 Example #38 Preparation of N-(4-(4-methylpiperazin-1-yl)phe Preparation of 5-phenyl-N-(1H-pyrazol-3-yl)-1H nyl)-5-phenyl-1H-pyrazolo 4,3-dipyrimidin-7-amine pyrazolo 4.3-dpyrimidin-7-amine 0327 7-chloro-2-(4-methoxybenzyl)-5-phenyl-2H-pyra 0339) 7-chloro-2-(4-methoxybenzyl)-5-phenyl-2H-pyra Zolo4.3-dpyrimidine (0.16 mmol) and 4-(4-methylpiper Zolo 4,3-dipyrimidine (0.16 mmol) and 1H-pyrazol-3-amine azin-1-yl)aniline (0.3 mmol 2 eq.) were suspended in MeOH (0.3 mmol 2 eq.) were suspended in MeOH (dry, 3 mL) in a (dry, 3 mL) in a microwave vial (2-5 mL), HCl in dioxane microwave vial (2-5 mL), HCl in dioxane (4M, 3 drops) was (4M, 3 drops) was added. The reaction mixture was irradiated added. The reaction mixture was irradiated in a microwave in a microwave reactor for 5 min at 140° C. The reaction reactor for 5 min at 140°C. The reaction mixture was evapo mixture was evaporated and used without further purification. rated and used without further purification. The residue was The residue was dissolved in TFA (3 mL). The reaction mix dissolved in TFA (3 mL). The reaction mixture was irradiated ture was irradiated in a microwave reactor for 5 minat 140°C. in a microwave reactor for min at 140°C. The reaction mix The reaction mixture was concentrated and purified by semi ture was concentrated and purified by semi-preparative preparative HPLC-MS and freeze dried from water/t-BuOH HPLC-MS and freeze dried from waterft-BuOH 4/1. 4f1. (0340 exact mass: 277.1205 g/mol 0328 exact mass: 385.2366 g/mol 0329. HPLC-MS: analytical method I (0341 HPLC-MS: analytical method A 0330 rt: 2.028 min-found mass: 386 (m/z+H) 0342 rt: 2.202 min-found mass: 278 (m/z+H) Example #36 Example #39 Preparation of N-(1H-indazol-6-yl)-5-phenyl-1H Preparation of 5-phenyl-N-(4-(pyrrolidin-1-yl)phe pyrazolo 4.3-dpyrimidin-7-amine nyl)-1H-pyrazolo4.3-dpyrimidin-7-amine 0331 7-chloro-2-(4-methoxybenzyl)-5-phenyl-2H-pyra 0343 7-chloro-2-(4-methoxybenzyl)-5-phenyl-2H-pyra Zolo4.3-dpyrimidine (0.16 mmol) and 1H-indazol-6-amine Zolo 4,3-dipyrimidine (0.16 mmol) and 4-(pyrrolidin-1-yl) (0.3 mmol 2 eq.) were suspended in MeOH (dry, 3 mL) in a aniline (0.3 mmol 2 eq.) were suspended in MeOH (dry, 3 microwave vial (2-5 mL), HCl in dioxane (4M, 3 drops) was mL) in a microwave vial (2-5 mL), HCl in dioxane (4M, 3 added. The reaction mixture was irradiated in a microwave drops) was added. The reaction mixture was irradiated in a reactor for 5 min at 140°C. The reaction mixture was evapo microwave reactor for 5 min at 140°C. The reaction mixture rated and used without further purification. The residue was was evaporated and used without further purification. The dissolved in TFA (3 mL). The reaction mixture was irradiated residue was dissolved in TFA (3 mL). The reaction mixture in a microwave reactor for 5 min at 140° C. The reaction was irradiated in a microwave reactor for 5 minat 140°C. The mixture was concentrated and purified by semi-preparative reaction mixture was concentrated and purified by semi-pre HPLC-MS and freeze dried from waterft-BuOH 4/1. parative HPLC-MS and freeze dried from water/t-BuOH4/1. 0332 exact mass: 327.1386 g/mol 0344 exact mass: 356.2046 g/mol 0333 HPLC-MS: analytical method A (0345 HPLC-MS: analytical method A 0334 rt: 2.428 min-found mass: 328 (m/z+H) 0346 rt: 2.714 min-found mass: 357 (m/z+H) Example #37 Example #40 Preparation of 6-((5-phenyl-1H-pyrazolo4.3-dpyri midin-7-yl)amino)-2H-benzob 14oxazin-3 (4H)- Preparation of 5-(3,4-dimethoxyphenyl)-N-(1H-in O dazol-5-yl)-1H-pyrazolo 4,3-dipyrimidin-7-amine 0335) 7-chloro-2-(4-methoxybenzyl)-5-phenyl-2H-pyra 0347 7-chloro-5-(3,4-dimethoxyphenyl)-2-(4-methoxy Zolo4.3-dpyrimidine (0.16 mmol) and 6-amino-2H-benzo benzyl)-2H-pyrazolo 4.3-dpyrimidine (0.16 mmol) and b1,4-oxazin-3 (4H)-one (0.3 mmol 2 eq.) were suspended 1H-indazol-5-amine (0.3 mmol 2 eq.) were suspended in in MeCH (dry, 3 mL) in a microwave vial (2-5 mL), HCl in MeOH (dry, 3 mL) in a microwave vial (2-5 mL), HCl in dioxane (4M, 3 drops) was added. The reaction mixture was dioxane (4M, 3 drops) was added. The reaction mixture was irradiated in a microwave reactor for 5 min at 140°C. The irradiated in a microwave reactor for 5 min at 140°C. The reaction mixture was evaporated and used without further reaction mixture was evaporated and used without further purification. The residue was dissolved in TFA (3 mL). The purification. The residue was dissolved in TFA (3 mL). The reaction mixture was irradiated in a microwave reactor for 5 reaction mixture was irradiated in a microwave reactor for 5 min at 140° C. The reaction mixture was concentrated and min at 140° C. The reaction mixture was concentrated and purified by semi-preparative HPLC-MS and freeze dried purified by semi-preparative HPLC-MS and freeze dried from waterft-BuOH 4/1. from waterft-BuOH 4/1. 0336 exact mass: 358.1344 g/mol 0348 exact mass: 387.1664 g/mol 0337 HPLC-MS: analytical method A (0349 HPLC-MS: analytical method A 0338 rt: 2.390 min-found mass: 359 (m/z+H) 0350 rt: 2.102 min-found mass: 388 (m/z+H) US 2012/032978.0 A1 Dec. 27, 2012 49

Example #41 Example #44 Preparation of 5-(3,4-dimethoxyphenyl)-N-(1H Preparation of 5-(pyridin-4-yl)-N-(4-(pyrrolidin-1- pyrazol-3-yl)-1H-pyrazolo 4,3-dipyrimidin-7-amine yl)phenyl)-1H-pyrazolo 4,3-dipyrimidin-7-amine 0351) 7-chloro-5-(3,4-dimethoxyphenyl)-2-(4-methoxy 0363 7-chloro-2-(4-methoxybenzyl)-5-(pyridin-4-yl)- benzyl)-2H-pyrazolo 4.3-dpyrimidine (0.16 mmol) and 2H-pyrazolo 4,3-dipyrimidine (0.16 mmol) and 4-(pyrroli 1H-pyrazol-3-amine (0.3 mmol 2 eq.) were suspended in din-1-yl)aniline (0.3 mmol 2 eq.) were suspended in MeCH MeOH (dry, 3 mL) in a microwave vial (2-5 mL), HCl in (dry, 3 mL) in a microwave vial (2-5 mL), HCl in dioxane dioxane (4M, 3 drops) was added. The reaction mixture was (4M, 3 drops) was added. The reaction mixture was irradiated irradiated in a microwave reactor for 5 min at 140°C. The in a microwave reactor for 5 min at 140° C. The reaction reaction mixture was evaporated and used without further mixture was evaporated and used without further purification. purification. The residue was dissolved in TFA (3 mL). The The residue was dissolved in TFA (3 mL). The reaction mix reaction mixture was irradiated in a microwave reactor for 5 ture was irradiated in a microwave reactor for 5 minat 140°C. min at 140° C. The reaction mixture was concentrated and The reaction mixture was concentrated and purified by semi purified by semi-preparative HPLC-MS and freeze dried preparative HPLC-MS and freeze dried from water/t-BuOH from waterft-BuOH 4/1. 4f1. 0352 exact mass: 337.1483 g/mol 0364 exact mass: 357.1976 g/mol 0353 HPLC-MS: analytical method A 0365 HPLC-MS: analytical method A 0354 rt: 2.046 min-found mass: 338 (m/z+H) 0366 rt: 2.138 min-found mass: 358 (m/z+H) Example #42 Example #45 Preparation of 5-(3,4-dimethoxyphenyl)-N-(4-(pyr Preparation of N,5-di(1H-pyrazol-3-yl)-1H-pyrazolo rolidin-1-yl)phenyl)-1H-pyrazolo 4.3-dpyrimidin-7- 4.3-dipyrimidin-7-amine amine 0367 7-chloro-2-(4-methoxybenzyl)-5-(1H-pyrazol-3- 0355) 7-chloro-5-(3,4-dimethoxyphenyl)-2-(4-methoxy yl)-2H-pyrazolo 4,3-dipyrimidine (0.16 mmol) and benzyl)-2H-pyrazolo 4.3-dpyrimidine (0.16 mmol) and 1H-pyrazol-3-amine (0.3 mmol 2 eq.) were suspended in 4-(pyrrolidin-1-yl)aniline (0.3 mmol 2 eq.) were suspended MeOH (dry, 3 mL) in a microwave vial (2-5 mL), HCl in in MeCH (dry, 3 mL) in a microwave vial (2-5 mL), HCl in dioxane (4M, 3 drops) was added. The reaction mixture was dioxane (4M, 3 drops) was added. The reaction mixture was irradiated in a microwave reactor for 5 min at 140°C. The irradiated in a microwave reactor for 5 min at 140°C. The reaction mixture was evaporated and used without further reaction mixture was evaporated and used without further purification. The residue was dissolved in TFA (3 mL). The purification. The residue was dissolved in TFA (3 mL). The reaction mixture was irradiated in a microwave reactor for 5 reaction mixture was irradiated in a microwave reactor for 5 min at 140° C. The reaction mixture was concentrated and min at 140° C. The reaction mixture was concentrated and purified by semi-preparative HPLC-MS and freeze dried purified by semi-preparative HPLC-MS and freeze dried from waterft-BuOH 4/1. from waterft-BuOH 4/1. 0368 exact mass: 267.1069 g/mol 0356) exact mass: 416.2323 g/mol 0369 HPLC-MS: analytical method A 0357 HPLC-MS: analytical method A 0370 rt: 0.817 min-found mass: 268 (m/z+H) 0358 rt: 2.560 min-found mass: 417 (m/z+H) Example #46 Example #43 Preparation of N-(4-(4-methylpiperazin-1-yl)phe nyl)-5-(6-(pyrrolidin-1-yl)pyridin-3-yl)-1H-pyrazolo Preparation of N-(1H-pyrazol-3-yl)-5-(pyridin-4-yl)- 4.3-dipyrimidin-7-amine 1H-pyrazolo 4,3-dipyrimidin-7-amine 0371 7-chloro-2-(4-methoxybenzyl)-5-(6-(pyrrolidin-1- 0359 7-chloro-2-(4-methoxybenzyl)-5-(pyridin-4-yl)- yl)pyridin-3-yl)-2H-pyrazolo 4.3-dpyrimidine (0.16 mmol) 2H-pyrazolo4.3-dpyrimidine (0.16 mmol) and 1H-pyrazol and 4-(4-methylpiperazin-1-yl)aniline (0.3 mmol 2 eq.) were 3-amine (0.3 mmol 2 eq.) were suspended in MeOH (dry, 3 suspended in MeCH (dry, 3 mL) in a microwave vial (2-5 mL) in a microwave vial (2-5 mL), HCl in dioxane (4M, 3 mL), HCl in dioxane (4M, 3 drops) was added. The reaction drops) was added. The reaction mixture was irradiated in a mixture was irradiated in a microwave reactor for 5 min at microwave reactor for 5 min at 140°C. The reaction mixture 140°C. The reaction mixture was evaporated and used with was evaporated and used without further purification. The out further purification. The residue was dissolved in TFA (3 residue was dissolved in TFA (3 mL). The reaction mixture mL). The reaction mixture was irradiated in a microwave was irradiated in a microwave reactor for 5 minat 140°C. The reactor for 5 min at 140°C. The reaction mixture was con reaction mixture was concentrated and purified by semi-pre centrated and purified by semi-preparative HPLC-MS and parative HPLC-MS and freeze dried from water/t-BuOH4/1. freeze dried from waterft-BuOH 4/1. 0360 exact mass: 278.1135 g/mol 0372 exact mass: 455.3001 g/mol 0361 HPLC-MS: analytical method A 0373 HPLC-MS: analytical method A 0362 rt: 0.823 min-found mass: 279 (m/z+H) 0374 rt: 1.038 min-found mass: 456 (m/z+H) US 2012/032978.0 A1 Dec. 27, 2012 50

Example #47 Example #50 Preparation of 6-((5-(6-(pyrrolidin-1-yl)pyridin-3- Preparation of N-(1H-indazol-5-yl)-5-(1-methylpip yl)-1H-pyrazolo 4,3-dipyrimidin-7-yl)amino)-2H eridin-4-yl)-1H-pyrazolo 4,3-dipyrimidin-7-amine benzob 14oxazin-3 (4H)-one 0387 7-chloro-2-(4-methoxybenzyl)-5-(1-methylpiperi 0375 7-chloro-2-(4-methoxybenzyl)-5-(6-(pyrrolidin-1- din-4-yl)-2H-pyrazolo 4,3-dipyrimidine (0.16 mmol) and yl)pyridin-3-yl)-2H-pyrazolo 4.3-dpyrimidine (0.16 mmol) 1H-indazol-5-amine (0.3 mmol 2 eq.) were suspended in and 6-amino-2H-benzob 14oxazin-3 (4H)-one (0.3 mmol MeOH (dry, 3 mL) in a microwave vial (2-5 mL), HCl in 2 eq.) were suspended in MeCH (dry, 3 mL) in a microwave dioxane (4M, 3 drops) was added. The reaction mixture was vial (2-5 mL), HCl in dioxane (4M, 3 drops) was added. The irradiated in a microwave reactor for 5 min at 140°C. The reaction mixture was irradiated in a microwave reactor for 5 reaction mixture was evaporated and used without further min at 140°C. The reaction mixture was evaporated and used purification. The residue was dissolved in TFA (3 mL). The without further purification. The residue was dissolved in reaction mixture was irradiated in a microwave reactor for 5 TFA (3 mL). The reaction mixture was irradiated in a micro min at 140° C. The reaction mixture was concentrated and wave reactor for 5 min at 140°C. The reaction mixture was purified by semi-preparative HPLC-MS and freeze dried concentrated and purified by semi-preparative HPLC-MS from waterft-BuOH 4/1. and freeze dried from waterft-BuOH 471. 0388 exact mass: 348.211 g/mol 0376 exact mass: 428.1979 g/mol (0389 HPLC-MS: analytical method I 0377 HPLC-MS: analytical method A 0390 rt: 0.465 min-found mass: 349 (m/z+H) 0378 rt: 2.047 min-found mass: 429 (m/z+H) Example #48 Example #51 Preparation of N-(3,4-dimethoxyphenyl)-5-(1-meth Preparation of N-(1H-pyrazol-3-yl)-5-(6-(pyrrolidin ylpiperidin-4-yl)-1H-pyrazolo 4,3-dipyrimidin-7- 1-yl)pyridin-3-yl)-1H-pyrazolo 4,3-dipyrimidin-7- amine amine 0391) 7-chloro-2-(4-methoxybenzyl)-5-(1-methylpiperi 0379 7-chloro-2-(4-methoxybenzyl)-5-(6-(pyrrolidin-1- din-4-yl)-2H-pyrazolo 4,3-dipyrimidine (0.16 mmol) and yl)pyridin-3-yl)-2H-pyrazolo 4.3-dipyrimidine (0.16 mmol) 3,4-dimethoxyaniline (0.3 mmol 2 eq.) were suspended in and 1H-pyrazol-3-amine (0.3 mmol 2 eq.) were Suspended in MeOH (dry, 3 mL) in a microwave vial (2-5 mL), HCl in MeOH (dry, 3 mL) in a microwave vial (2-5 mL), HCl in dioxane (4M, 3 drops) was added. The reaction mixture was dioxane (4M, 3 drops) was added. The reaction mixture was irradiated in a microwave reactor for 5 min at 140°C. The irradiated in a microwave reactor for 5 min at 140°C. The reaction mixture was evaporated and used without further reaction mixture was evaporated and used without further purification. The residue was dissolved in TFA (3 mL). The purification. The residue was dissolved in TFA (3 mL). The reaction mixture was irradiated in a microwave reactor for 5 reaction mixture was irradiated in a microwave reactor for 5 min at 140° C. The reaction mixture was concentrated and min at 140° C. The reaction mixture was concentrated and purified by semi-preparative HPLC-MS and freeze dried purified by semi-preparative HPLC-MS and freeze dried from waterft-BuOH 4/1. from waterft-BuOH 4/1. 0380 exact mass: 347.184 g/mol 0392 exact mass: 368.2343 g/mol 0381 HPLC-MS: analytical method A 0393 HPLC-MS: analytical method I 0382 rt: 1.867 min-found mass: 348 (m/z+H) 0394 rt: 0.331 min-found mass: 369 (m/z+H) Example #49 Example #52 Preparation of N-(4-(pyrrolidin-1-yl)phenyl)-5-(6- Preparation of 5-(1-methylpiperidin-4-yl)-N-(4-mor (pyrrolidin-1-yl)pyridin-3-yl)-1H-pyrazolo 4.3-d pholinophenyl)-1H-pyrazolo 4,3-dipyrimidin-7- pyrimidin-7-amine amine 0383) 7-chloro-2-(4-methoxybenzyl)-5-(6-(pyrrolidin-1- 0395 7-chloro-2-(4-methoxybenzyl)-5-(1-methylpiperi yl)pyridin-3-yl)-2H-pyrazolo 4.3-dpyrimidine (0.16 mmol) din-4-yl)-2H-pyrazolo 4,3-dipyrimidine (0.16 mmol) and and 4-(pyrrolidin-1-yl)aniline (0.3 mmol 2 eq.) were sus 4-morpholinoaniline (0.3 mmol 2 eq.) were suspended in pended in MeOH (dry, 3 mL) in a microwave vial (2-5 mL), MeOH (dry, 3 mL) in a microwave vial (2-5 mL), HCl in HCl in dioxane (4M, 3 drops) was added. The reaction mix dioxane (4M, 3 drops) was added. The reaction mixture was ture was irradiated in a microwave reactor for 5 minat 140°C. irradiated in a microwave reactor for 5 min at 140°C. The The reaction mixture was evaporated and used without fur reaction mixture was evaporated and used without further ther purification. The residue was dissolved in TFA (3 mL). purification. The residue was dissolved in TFA (3 mL). The The reaction mixture was irradiated in a microwave reactor reaction mixture was irradiated in a microwave reactor for 5 for 5 min at 140°C. The reaction mixture was concentrated min at 140° C. The reaction mixture was concentrated and and purified by semi-preparative HPLC-MS and freeze dried purified by semi-preparative HPLC-MS and freeze dried from waterft-BuOH 4/1. from waterft-BuOH 4/1. 0384 exact mass: 426.2681 g/mol 0396 exact mass: 393.2714 g/mol 0385 HPLC-MS: analytical method A 0397. HPLC-MS: analytical method I 0386 rt: 2.326 min-found mass: 427 (m/z+H) 0398 rt: 0.331 min-found mass: 394 (m/z+H) US 2012/032978.0 A1 Dec. 27, 2012 51

Example #53 Example #56 Preparation of N-(4-(4-methylpiperazin-1-yl)phe Preparation of 5-(1-methylpiperidin-4-yl)-N-(4-(pyr nyl)-5-(1-methylpiperidin-4-yl)-1H-pyrazolo 4.3-d rolidin-1-yl)phenyl)-1H-pyrazolo 4,3-dipyrimidin-7- pyrimidin-7-amine amine 0399 7-chloro-2-(4-methoxybenzyl)-5-(1-methylpiperi 0411 7-chloro-2-(4-methoxybenzyl)-5-(1-methylpiperi din-4-yl)-2H-pyrazolo 4,3-dipyrimidine (0.16 mmol) and din-4-yl)-2H-pyrazolo 4,3-dipyrimidine (0.16 mmol) and 4-(4-methylpiperazin-1-yl)aniline (0.3 mmol 2 eq.) were sus 4-(pyrrolidin-1-yl)aniline (0.3 mmol 2 eq.) were suspended pended in MeOH (dry, 3 mL) in a microwave vial (2-5 mL), in MeCH (dry, 3 mL) in a microwave vial (2-5 mL), HCl in HCl in dioxane (4M, 3 drops) was added. The reaction mix dioxane (4M, 3 drops) was added. The reaction mixture was ture was irradiated in a microwave reactor for 5 minat 140°C. irradiated in a microwave reactor for 5 min at 140°C. The The reaction mixture was evaporated and used without fur reaction mixture was evaporated and used without further ther purification. The residue was dissolved in TFA (3 mL). purification. The residue was dissolved in TFA (3 mL). The The reaction mixture was irradiated in a microwave reactor reaction mixture was irradiated in a microwave reactor for 5 for 5 min at 140°C. The reaction mixture was concentrated min at 140° C. The reaction mixture was concentrated and and purified by semi-preparative HPLC-MS and freeze dried purified by semi-preparative HPLC-MS and freeze dried from waterft-BuOH 4/1. from waterft-BuOH 4/1. (0400 exact mass: 406.309 g/mol 0412 exact mass: 377.277 g/mol 0401 HPLC-MS: analytical method I 0413 HPLC-MS: analytical method I 0402 rt: 0.326 min-found mass: 407 (m/z+H) 0414 rt: 2.282 min-found mass: 378 (m/z+H) Example #54 Example #57 Preparation of 6-((5-(1-methylpiperidin-4-yl)-1H Preparation of N-(5-cyclopropyl-1H-pyrazol-3-yl)-5- pyrazolo 4,3-dipyrimidin-7-yl)amino)-2H-benzob. phenyl-1H-pyrazolo 4,3-dipyrimidin-7-amine 1,4-oxazin-3 (4H)-one 0415) 7-chloro-2-(4-methoxybenzyl)-5-phenyl-2H-pyra 0403) 7-chloro-2-(4-methoxybenzyl)-5-(1-methylpiperi Zolo4,3-dipyrimidine (0.16 mmol) and 5-cyclopropyl-1H din-4-yl)-2H-pyrazolo 4,3-dipyrimidine (0.16 mmol) and pyrazol-3-amine (0.3 mmol 2 eq.) were suspended in MeOH 6-amino-2H-benzob 14oxazin-3 (4H)-one (0.3 mmol 2 (dry, 3 mL) in a microwave vial (2-5 mL), HCl in dioxane eq.) were suspended in MeCH (dry, 3 mL) in a microwave (4M, 3 drops) was added. The reaction mixture was irradiated vial (2-5 mL), HCl in dioxane (4M, 3 drops) was added. The in a microwave reactor for 5 min at 140° C. The reaction reaction mixture was irradiated in a microwave reactor for 5 mixture was evaporated and used without further purification. min at 140°C. The reaction mixture was evaporated and used The residue was dissolved in TFA (3 mL). The reaction mix without further purification. The residue was dissolved in ture was irradiated in a microwave reactor for 5 minat 140°C. TFA (3 mL). The reaction mixture was irradiated in a micro The reaction mixture was concentrated and purified by semi wave reactor for 5 min at 140°C. The reaction mixture was preparative HPLC-MS and freeze dried from water/t-BuOH concentrated and purified by semi-preparative HPLC-MS 4f1. and freeze dried from waterft-BuOH 471. 0404 exact mass: 379.2068 g/mol 0416) exact mass: 317.159 g/mol 04.05 HPLC-MS: analytical method I 0417. HPLC-MS: analytical method A 04.06 rt: 0.331 min-found mass: 380 (m/z+H) 0418 rt: 2.540 min-found mass: 318 (m/z+H) Example #55 Example #58 Preparation of 5-(1-methylpiperidin-4-yl)-N-(1H Preparation of N-(3,4-dimethoxyphenyl)-5-(4-meth pyrazol-3-yl)-1H-pyrazolo 4,3-dipyrimidin-7-amine oxyphenyl)-1H-pyrazolo 4.3-dpyrimidin-7-amine 04.07 7-chloro-2-(4-methoxybenzyl)-5-(1-methylpiperi 0419 7-chloro-2-(4-methoxybenzyl)-5-(4-methoxyphe din-4-yl)-2H-pyrazolo 4,3-dipyrimidine (0.16 mmol) and nyl)-2H-pyrazolo4.3-dpyrimidine (0.16 mmol) and 3,4- 1H-pyrazol-3-amine (0.3 mmol 2 eq.) were suspended in dimethoxyaniline (0.3 mmol 2 eq.) were suspended in MeCH MeOH (dry, 3 mL) in a microwave vial (2-5 mL), HCl in (dry, 3 mL) in a microwave vial (2-5 mL), HCl in dioxane dioxane (4M, 3 drops) was added. The reaction mixture was (4M, 3 drops) was added. The reaction mixture was irradiated irradiated in a microwave reactor for 5 min at 140°C. The in a microwave reactor for 5 min at 140° C. The reaction reaction mixture was evaporated and used without further mixture was evaporated and used without further purification. purification. The residue was dissolved in TFA (3 mL). The The residue was dissolved in TFA (3 mL). The reaction mix reaction mixture was irradiated in a microwave reactor for 5 ture was irradiated in a microwave reactor for 5 minat 140°C. min at 140° C. The reaction mixture was concentrated and The reaction mixture was concentrated and purified by semi purified by semi-preparative HPLC-MS and freeze dried preparative HPLC-MS and freeze dried from water/t-BuOH from waterft-BuOH 4/1. 4f1. 04.08 exact mass: 298.193 g/mol 0420 exact mass: 377.1757 g/mol 04.09 HPLC-MS: analytical method I 0421 HPLC-MS: analytical method A 0410 rt: 0.344 min-found mass: 299 (m/z+H) 0422 rt: 2.386 min-found mass: 378 (m/z+H) US 2012/032978.0 A1 Dec. 27, 2012 52

Example #59 Example #62 Preparation of 5-(4-methoxyphenyl)-N-(4-morpholi Preparation of 5-(3-methoxyphenyl)-N-(4-(4-meth nophenyl)-1H-pyrazolo 4.3-dipyrimidin-7-amine ylpiperazin-1-yl)phenyl)-1H-pyrazolo 4.3-dipyrimi din-7-amine 0423) 7-chloro-2-(4-methoxybenzyl)-5-(4-methoxyphe nyl)-2H-pyrazolo 4,3-dipyrimidine (0.16 mmol) and 4-mor 0435 7-chloro-2-(4-methoxybenzyl)-5-(3-methoxyphe pholinoaniline (0.3 mmol 2 eq.) were suspended in MeOH nyl)-2H-pyrazolo4.3-dpyrimidine (0.16 mmol) and 4-(4- (dry, 3 mL) in a microwave vial (2-5 mL), HCl in dioxane methylpiperazin-1-yl)aniline (0.3 mmol 2 eq.) were Sus (4M, 3 drops) was added. The reaction mixture was irradiated pended in MeOH (dry, 3 mL) in a microwave vial (2-5 mL), in a microwave reactor for 5 min at 140° C. The reaction HCl in dioxane (4M, 3 drops) was added. The reaction mix mixture was evaporated and used without further purification. ture was irradiated in a microwave reactor for 5 minat 140°C. The residue was dissolved in TFA (3 mL). The reaction mix The reaction mixture was evaporated and used without fur ture was irradiated in a microwave reactor for 5 minat 140°C. ther purification. The residue was dissolved in TFA (3 mL). The reaction mixture was concentrated and purified by semi The reaction mixture was irradiated in a microwave reactor preparative HPLC-MS and freeze dried from water/t-BuOH for 5 min at 140°C. The reaction mixture was concentrated 4f1. and purified by semi-preparative HPLC-MS and freeze dried from waterft-BuOH 4/1. 0424 exact mass: 402.2128 g/mol 0436 exact mass: 415.2504 g/mol 0425 HPLC-MS: analytical method A 0437. HPLC-MS: analytical method B 0426 rt: 2.336 min-found mass: 403 (m/z+H) 0438 rt: 1.631 min-found mass: 416 (m/z+H) Example #60 Example #63 Preparation of N-(3,4-dimethoxyphenyl)-5-(3-meth Preparation of N1-(5-(3-methoxyphenyl)-1H-pyra oxyphenyl)-1H-pyrazolo 4.3-dipyrimidin-7-amine Zolo4.3-dpyrimidin-7-yl)-N4.N4-dimethylbenzene 1,4-diamine 0427 7-chloro-2-(4-methoxybenzyl)-5-(3-methoxyphe nyl)-2H-pyrazolo 4,3-dipyrimidine (0.16 mmol) and 3,4- 0439 7-chloro-2-(4-methoxybenzyl)-5-(3-methoxyphe dimethoxyaniline (0.3 mmol 2 eq.) were suspended in MeOH nyl)-2H-pyrazolo 4,3-dipyrimidine (0.16 mmol) and N1,N1 (dry, 3 mL) in a microwave vial (2-5 mL), HCl in dioxane dimethylbenzene-1,4-diamine (0.3 mmol 2 eq.) were Sus (4M, 3 drops) was added. The reaction mixture was irradiated pended in MeOH (dry, 3 mL) in a microwave vial (2-5 mL), in a microwave reactor for 5 min at 140° C. The reaction HCl in dioxane (4M, 3 drops) was added. The reaction mix mixture was evaporated and used without further purification. ture was irradiated in a microwave reactor for 5 minat 140°C. The residue was dissolved in TFA (3 mL). The reaction mix The reaction mixture was evaporated and used without fur ture was irradiated in a microwave reactor for 5 minat 140°C. ther purification. The residue was dissolved in TFA (3 mL). The reaction mixture was concentrated and purified by semi The reaction mixture was irradiated in a microwave reactor preparative HPLC-MS and freeze dried from water/t-BuOH for 5 min at 140°C. The reaction mixture was concentrated 4f1. and purified by semi-preparative HPLC-MS and freeze dried from waterft-BuOH 4/1. 0428 exact mass: 377.1757 g/mol 0440 exact mass: 360.1994 g/mol 0429 HPLC-MS: analytical method A 0441 HPLC-MS: analytical method A 0430 rt: 2.561 min-found mass: 378 (m/z+H) 0442 rt: 2.312 min-found mass: 361 (m/z+H) Example #61 Example #64 Preparation of 5-(3-methoxyphenyl)-N-(4-morpholi Preparation of N-(5-phenyl-1H-pyrazolo 4,3-dipyri nophenyl)-1H-pyrazolo 4.3-dipyrimidin-7-amine midin-7-yl)-3,4-dihydro-2H-benzob 14oxazin-6- amine 0431 7-chloro-2-(4-methoxybenzyl)-5-(3-methoxyphe nyl)-2H-pyrazolo 4,3-dipyrimidine (0.16 mmol) and 4-mor 0443) 7-chloro-2-(4-methoxybenzyl)-5-phenyl-2H-pyra pholinoaniline (0.3 mmol 2 eq.) were suspended in MeOH Zolo 4,3-dipyrimidine (0.16 mmol) and 3,4-dihydro-2H (dry, 3 mL) in a microwave vial (2-5 mL), HCl in dioxane benzob 14oxazin-6-amine (0.3 mmol 2 eq.) were Sus (4M, 3 drops) was added. The reaction mixture was irradiated pended in MeOH (dry, 3 mL) in a microwave vial (2-5 mL), in a microwave reactor for 5 min at 140° C. The reaction HCl in dioxane (4M, 3 drops) was added. The reaction mix mixture was evaporated and used without further purification. ture was irradiated in a microwave reactor for 5 minat 140°C. The residue was dissolved in TFA (3 mL). The reaction mix The reaction mixture was evaporated and used without fur ture was irradiated in a microwave reactor for 5 minat 140°C. ther purification. The residue was dissolved in TFA (3 mL). The reaction mixture was concentrated and purified by semi The reaction mixture was irradiated in a microwave reactor preparative HPLC-MS and freeze dried from water/t-BuOH for 5 min at 140°C. The reaction mixture was concentrated 4f1. and purified by semi-preparative HPLC-MS and freeze dried from waterft-BuOH 4/1. 0432 exact mass: 402.2128 g/mol 0444 exact mass: 344.16 g/mol 0433 HPLC-MS: analytical method A 0445 HPLC-MS: analytical method A 0434 rt: 2.487 min-found mass: 403 (m/z+H) 0446 rt: 2.358 min-found mass: 345 (m/z+H) US 2012/032978.0 A1 Dec. 27, 2012 53

Example #65 Example #68 Preparation of 3-((5-phenyl-1H-pyrazolo4.3-dpyri Preparation of N-(3,4-dimethoxyphenyl)-5- midin-7-yl)amino)phenol (thiophen-2-yl)-1H-pyrazolo 4,3-dipyrimidin-7- amine 0447 7-chloro-2-(4-methoxybenzyl)-5-phenyl-2H-pyra Zolo4.3-dpyrimidine (0.16 mmol) and 3-aminophenol (0.3 0459 7-chloro-2-(4-methoxybenzyl)-5-(thiophen-2-yl)- mmol 2 eq.) were suspended in MeOH (dry, 3 mL) in a 2H-pyrazolo 4,3-dipyrimidine (0.16 mmol) and 3,4- microwave vial (2-5 mL), HCl in dioxane (4M, 3 drops) was dimethoxyaniline (0.3 mmol 2 eq.) were suspended in MeCH added. The reaction mixture was irradiated in a microwave (dry, 3 mL) in a microwave vial (2-5 mL), HCl in dioxane reactor for 5 min at 140°C. The reaction mixture was evapo (4M, 3 drops) was added. The reaction mixture was irradiated rated and used without further purification. The residue was in a microwave reactor for 5 min at 140° C. The reaction dissolved in TFA (3 mL). The reaction mixture was irradiated mixture was evaporated and used without further purification. in a microwave reactor for 5 min at 140° C. The reaction The residue was dissolved in TFA (3 mL). The reaction mix mixture was concentrated and purified by semi-preparative ture was irradiated in a microwave reactor for 5 minat 140°C. HPLC-MS and freeze dried from waterft-BuOH 4/1. The reaction mixture was concentrated and purified by semi preparative HPLC-MS and freeze dried from water/t-BuOH 0448 exact mass: 303.1284 g/mol 4f1. 0449 HPLC-MS: analytical method A 0460 exact mass: 353.1143 g/mol 0450 rt: 2.408 min-found mass: 304 (m/z+H) 0461 HPLC-MS: analytical method A Example #66 0462 rt: 2.541 min-found mass: 354 (m/z+H) Preparation of 5-(4-methoxyphenyl)-N-(4-(4-meth Example #69 ylpiperazin-1-yl)phenyl)-1H-pyrazolo 4,3-dipyrimi Preparation of N-(4-morpholinophenyl)-5-(thiophen din-7-amine 2-yl)-1H-pyrazolo 4,3-dipyrimidin-7-amine 0451 7-chloro-2-(4-methoxybenzyl)-5-(4-methoxyphe nyl)-2H-pyrazolo 4,3-dipyrimidine (0.16 mmol) and 4-(4- 0463) 7-chloro-2-(4-methoxybenzyl)-5-(thiophen-2-yl)- methylpiperazin-1-yl)aniline (0.3 mmol 2 eq.) were sus 2H-pyrazolo 4,3-dipyrimidine (0.16 mmol) and 4-morpholi pended in MeOH (dry, 3 mL) in a microwave vial (2-5 mL), noaniline (0.3 mmol 2 eq.) were suspended in MeCH (dry, 3 HCl in dioxane (4M, 3 drops) was added. The reaction mix mL) in a microwave vial (2-5 mL), HCl in dioxane (4M, 3 ture was irradiated in a microwave reactor for 5 minat 140°C. drops) was added. The reaction mixture was irradiated in a The reaction mixture was evaporated and used without fur microwave reactor for 5 min at 140°C. The reaction mixture ther purification. The residue was dissolved in TFA (3 mL). was evaporated and used without further purification. The The reaction mixture was irradiated in a microwave reactor residue was dissolved in TFA (3 mL). The reaction mixture for 5 min at 140°C. The reaction mixture was concentrated was irradiated in a microwave reactor for 5 minat 140°C. The and purified by semi-preparative HPLC-MS and freeze dried reaction mixture was concentrated and purified by semi-pre from waterft-BuOH 4/1. parative HPLC-MS and freeze dried from water/t-BuOH4/1. 0452 exact mass: 415.2504 g/mol 0464 exact mass: 378.1515 g/mol 0453 HPLC-MS: analytical method B 0465 HPLC-MS: analytical method A 0454 rt: 1.540 min-found mass: 416 (m/z+H) 0466 rt: 2.497 min-found mass: 379 (m/z+H) Example #70 Example #67 Preparation of N-(4-(4-methylpiperazin-1-yl)phe Preparation of N-(1H-indazol-6-yl)-5-(3-methox nyl)-5-(thiophen-2-yl)-1H-pyrazolo 4.3-dpyrimidin yphenyl)-1H-pyrazolo 4,3-dipyrimidin-7-amine 7-amine 0455 7-chloro-2-(4-methoxybenzyl)-5-(3-methoxyphe 0467 7-chloro-2-(4-methoxybenzyl)-5-(thiophen-2-yl)- nyl)-2H-pyrazolo 4,3-dipyrimidine (0.16 mmol) and 1H-in 2H-pyrazolo 4,3-dipyrimidine (0.16 mmol) and 4-(4-meth dazol-6-amine (0.3 mmol 2 eq.) were suspended in MeOH ylpiperazin-1-yl)aniline (0.3 mmol 2 eq.) were suspended in (dry, 3 mL) in a microwave vial (2-5 mL), HCl in dioxane MeOH (dry, 3 mL) in a microwave vial (2-5 mL), HCl in (4M, 3 drops) was added. The reaction mixture was irradiated dioxane (4M, 3 drops) was added. The reaction mixture was in a microwave reactor for 5 min at 140° C. The reaction irradiated in a microwave reactor for 5 min at 140°C. The mixture was evaporated and used without further purification. reaction mixture was evaporated and used without further The residue was dissolved in TFA (3 mL). The reaction mix purification. The residue was dissolved in TFA (3 mL). The ture was irradiated in a microwave reactor for 5 minat 140°C. reaction mixture was irradiated in a microwave reactor for 5 The reaction mixture was concentrated and purified by semi min at 140° C. The reaction mixture was concentrated and preparative HPLC-MS and freeze dried from water/t-BuOH purified by semi-preparative HPLC-MS and freeze dried 4f1. from waterft-BuOH 4/1. 0456 exact mass: 357.1524 g/mol 0468 exact mass: 391.1891 g/mol 0457. HPLC-MS: analytical method A 0469 HPLC-MS: analytical method B 0458 rt: 2.485 min-found mass: 358 (m/z+H) 0470 rt: 1.587 min-found mass: 392 (m/z+H) US 2012/032978.0 A1 Dec. 27, 2012 54

Example #71 Example #74 Preparation of N1,N1-dimethyl-N4-(5-(thiophen-2- Preparation of N-(4-(4-methylpiperazin-1-yl)phe yl)-1H-pyrazolo 4,3-dipyrimidin-7-yl)benzene-1,4- nyl)-5-(thiophen-3-yl)-1H-pyrazolo 4.3-dpyrimidin diamine 7-amine 0471) 7-chloro-2-(4-methoxybenzyl)-5-(thiophen-2-yl)- 0483 7-chloro-2-(4-methoxybenzyl)-5-(thiophen-3-yl)- 2H-pyrazolo4.3-dpyrimidine (0.16 mmol) and N1,N1-dim 2H-pyrazolo 4,3-dipyrimidine (0.16 mmol) and 4-(4-meth ethylbenzene-1,4-diamine (0.3 mmol 2 eq.) were suspended ylpiperazin-1-yl)aniline (0.3 mmol 2 eq.) were suspended in in MeCH (dry, 3 mL) in a microwave vial (2-5 mL), HCl in MeOH (dry, 3 mL) in a microwave vial (2-5 mL), HCl in dioxane (4M, 3 drops) was added. The reaction mixture was dioxane (4M, 3 drops) was added. The reaction mixture was irradiated in a microwave reactor for 5 min at 140°C. The irradiated in a microwave reactor for 5 min at 140°C. The reaction mixture was evaporated and used without further reaction mixture was evaporated and used without further purification. The residue was dissolved in TFA (3 mL). The purification. The residue was dissolved in TFA (3 mL). The reaction mixture was irradiated in a microwave reactor for 5 reaction mixture was irradiated in a microwave reactor for 5 min at 140° C. The reaction mixture was concentrated and min at 140° C. The reaction mixture was concentrated and purified by semi-preparative HPLC-MS and freeze dried purified by semi-preparative HPLC-MS and freeze dried from waterft-BuOH 4/1. from waterft-BuOH 4/1. 0472 exact mass: 336.138 g/mol 0484 exact mass: 391.1891 g/mol 0473 HPLC-MS: analytical method A 0485 HPLC-MS: analytical method B 0474 rt: 2.230 min-found mass: 337 (m/z+H) 0486 rt: 1.478 min-found mass: 392 (m/z+H) Example #72 Example #75 Preparation of N-(3,4-dimethoxyphenyl)-5- Preparation of N1,N1-dimethyl-N4-(5-(thiophen-3- (thiophen-3-yl)-1H-pyrazolo 4,3-dipyrimidin-7- yl)-1H-pyrazolo 4,3-dipyrimidin-7-yl)benzene-1,4- amine diamine 0475) 7-chloro-2-(4-methoxybenzyl)-5-(thiophen-3-yl)- 0487 7-chloro-2-(4-methoxybenzyl)-5-(thiophen-3-yl)- 2H-pyrazolo4.3-dpyrimidine (0.16 mmol) and 3,4- 2H-pyrazolo 4,3-dipyrimidine (0.16 mmol) and N1,N1-dim dimethoxyaniline (0.3 mmol 2 eq.) were suspended in MeOH ethylbenzene-1,4-diamine (0.3 mmol 2 eq.) were suspended (dry, 3 mL) in a microwave vial (2-5 mL), HCl in dioxane in MeCH (dry, 3 mL) in a microwave vial (2-5 mL), HCl in (4M, 3 drops) was added. The reaction mixture was irradiated dioxane (4M, 3 drops) was added. The reaction mixture was in a microwave reactor for 5 min at 140° C. The reaction irradiated in a microwave reactor for 5 min at 140°C. The mixture was evaporated and used without further purification. reaction mixture was evaporated and used without further The residue was dissolved in TFA (3 mL). The reaction mix purification. The residue was dissolved in TFA (3 mL). The ture was irradiated in a microwave reactor for 5 minat 140°C. reaction mixture was irradiated in a microwave reactor for 5 The reaction mixture was concentrated and purified by semi min at 140° C. The reaction mixture was concentrated and preparative HPLC-MS and freeze dried from water/t-BuOH purified by semi-preparative HPLC-MS and freeze dried 4f1. from waterft-BuOH 4/1. 0476 exact mass: 353.1143 g/mol 0488 exact mass: 336.138 g/mol 0477. HPLC-MS: analytical method A 0489 HPLC-MS: analytical method A 0478 rt: 2.319 min-found mass: 354 (m/z+H) 0490 rt: 2.121 min-found mass: 337 (m/z+H) Example #73 Example #76 Preparation of N-(4-morpholinophenyl)-5-(thiophen Preparation of N-(1H-indazol-6-yl)-5-(thiophen-3- 3-yl)-1H-pyrazolo 4.3-dpyrimidin-7-amine yl)-1H-pyrazolo 4,3-dipyrimidin-7-amine 0479 7-chloro-2-(4-methoxybenzyl)-5-(thiophen-3-yl)- 0491) 7-chloro-2-(4-methoxybenzyl)-5-(thiophen-3-yl)- 2H-pyrazolo4.3-dpyrimidine (0.16 mmol) and 4-morpholi 2H-pyrazolo 4,3-dipyrimidine (0.16 mmol) and 1H-indazol noaniline (0.3 mmol 2 eq.) were suspended in MeCH (dry, 3 6-amine (0.3 mmol 2 eq.) were suspended in MeOH (dry, 3 mL) in a microwave vial (2-5 mL), HCl in dioxane (4M, 3 mL) in a microwave vial (2-5 mL), HCl in dioxane (4M, 3 drops) was added. The reaction mixture was irradiated in a drops) was added. The reaction mixture was irradiated in a microwave reactor for 5 min at 140°C. The reaction mixture microwave reactor for 5 min at 140°C. The reaction mixture was evaporated and used without further purification. The was evaporated and used without further purification. The residue was dissolved in TFA (3 mL). The reaction mixture residue was dissolved in TFA (3 mL). The reaction mixture was irradiated in a microwave reactor for 5 minat 140°C. The was irradiated in a microwave reactor for 5 minat 140°C. The reaction mixture was concentrated and purified by semi-pre reaction mixture was concentrated and purified by semi-pre parative HPLC-MS and freeze dried from water/t-BuOH4/1. parative HPLC-MS and freeze dried from water/t-BuOH4/1. 0480 exact mass: 378.1515 g/mol 0492 exact mass: 333.091 g/mol 0481 HPLC-MS: analytical method A 0493 HPLC-MS: analytical method A 0482 rt: 2.288 min-found mass: 379 (m/z+H) 0494 rt: 2.242 min-found mass: 334 (m/z+H) US 2012/032978.0 A1 Dec. 27, 2012

Example #77 Example #80 Preparation of N-(5-cyclopropyl-1H-pyrazol-3-yl)-5- Preparation of 3-((5-(4-methoxyphenyl)-1H-pyra (thiophen-3-yl)-1H-pyrazolo 4,3-dipyrimidin-7- Zolo4.3-dpyrimidin-7-yl)amino)phenol amine 0507 7-chloro-2-(4-methoxybenzyl)-5-(4-methoxyphe 0495 7-chloro-2-(4-methoxybenzyl)-5-(thiophen-3-yl)- nyl)-2H-pyrazolo4.3-dpyrimidine (0.16 mmol) and 3-ami 2H-pyrazolo4.3-dpyrimidine (0.16 mmol) and 5-cyclopro nophenol (0.3 mmol 2 eq.) were suspended in MeCH (dry, 3 pyl-1H-pyrazol-3-amine (0.3 mmol 2 eq.) were Suspended in mL) in a microwave vial (2-5 mL), HCl in dioxane (4M, 3 MeOH (dry, 3 mL) in a microwave vial (2-5 mL), HCl in drops) was added. The reaction mixture was irradiated in a dioxane (4M, 3 drops) was added. The reaction mixture was microwave reactor for 5 min at 140°C. The reaction mixture irradiated in a microwave reactor for 5 min at 140°C. The was evaporated and used without further purification. The reaction mixture was evaporated and used without further residue was dissolved in TFA (3 mL). The reaction mixture purification. The residue was dissolved in TFA (3 mL). The was irradiated in a microwave reactor for 5 minat 140°C. The reaction mixture was irradiated in a microwave reactor for 5 reaction mixture was concentrated and purified by semi-pre min at 140° C. The reaction mixture was concentrated and parative HPLC-MS and freeze dried from water/t-BuOH4/1. purified by semi-preparative HPLC-MS and freeze dried (0508) exact mass: 333.1423 g/mol from waterft-BuOH 4/1. (0509 HPLC-MS: analytical method A 0496 exact mass: 323.1115 g/mol 0510 rt: 2.253 min-found mass: 334 (m/z+H) 0497. HPLC-MS: analytical method A Example #81 0498 rt: 2.379 min-found mass: 324 (m/z+H) Preparation of 3-((5-(3-methoxyphenyl)-1H-pyra Example #78 Zolo4.3-dpyrimidin-7-yl)amino)phenol 0511 7-chloro-2-(4-methoxybenzyl)-5-(3-methoxyphe Preparation of N1-(5-(4-methoxyphenyl)-1H-pyra nyl)-2H-pyrazolo4.3-dpyrimidine (0.16 mmol) and 3-ami Zolo4.3-dpyrimidin-7-yl)-N4N4-dimethylbenzene nophenol (0.3 mmol 2 eq.) were suspended in MeCH (dry, 3 1,4-diamine mL) in a microwave vial (2-5 mL), HCl in dioxane (4M, 3 0499 7-chloro-2-(4-methoxybenzyl)-5-(4-methoxyphe drops) was added. The reaction mixture was irradiated in a nyl)-2H-pyrazolo 4,3-dipyrimidine (0.16 mmol) and N1,N1 microwave reactor for 5 min at 140°C. The reaction mixture dimethylbenzene-1,4-diamine (0.3 mmol 2 eq.) were sus was evaporated and used without further purification. The pended in MeOH (dry, 3 mL) in a microwave vial (2-5 mL), residue was dissolved in TFA (3 mL). The reaction mixture HCl in dioxane (4M, 3 drops) was added. The reaction mix was irradiated in a microwave reactor for 5 minat 140°C. The ture was irradiated in a microwave reactor for 5 minat 140°C. reaction mixture was concentrated and purified by semi-pre The reaction mixture was evaporated and used without fur parative HPLC-MS and freeze dried from water/t-BuOH4/1. ther purification. The residue was dissolved in TFA (3 mL). 0512 exact mass: 333.1423 g/mol The reaction mixture was irradiated in a microwave reactor 0513 HPLC-MS: analytical method A for 5 min at 140°C. The reaction mixture was concentrated 0514 rt: 2.486 min-found mass: 334 (m/z+H) and purified by semi-preparative HPLC-MS and freeze dried from waterft-BuOH 4/1. Example #82 (0500 exact mass: 360.1994 g/mol Preparation of N-(1H-indazol-6-yl)-5-(thiophen-2- 0501 HPLC-MS: analytical method A yl)-1H-pyrazolo 4,3-dipyrimidin-7-amine 0502 rt: 2.244 min-found mass: 361 (m/z+H) 0515 7-chloro-2-(4-methoxybenzyl)-5-(thiophen-2-yl)- Example #79 2H-pyrazolo 4,3-dipyrimidine (0.16 mmol) and 1H-indazol 6-amine (0.3 mmol 2 eq.) were suspended in MeOH (dry, 3 Preparation of N-(1H-indazol-6-yl)-5-(4-methox mL) in a microwave vial (2-5 mL), HCl in dioxane (4M, 3 yphenyl)-1H-pyrazolo 4,3-dipyrimidin-7-amine drops) was added. The reaction mixture was irradiated in a microwave reactor for 5 min at 140°C. The reaction mixture 0503) 7-chloro-2-(4-methoxybenzyl)-5-(4-methoxyphe was evaporated and used without further purification. The nyl)-2H-pyrazolo 4,3-dipyrimidine (0.16 mmol) and 1H-in residue was dissolved in TFA (3 mL). The reaction mixture dazol-6-amine (0.3 mmol 2 eq.) were suspended in MeOH was irradiated in a microwave reactor for 5 minat 140°C. The (dry, 3 mL) in a microwave vial (2-5 mL), HCl in dioxane reaction mixture was concentrated and purified by semi-pre (4M, 3 drops) was added. The reaction mixture was irradiated parative HPLC-MS and freeze dried from water/t-BuOH4/1. in a microwave reactor for 5 min at 140° C. The reaction 0516 exact mass: 333.091 g/mol mixture was evaporated and used without further purification. 0517. HPLC-MS: analytical method A The residue was dissolved in TFA (3 mL). The reaction mix 0518 rt: 2.463 min-found mass: 334 (m/z+H) ture was irradiated in a microwave reactor for 5 minat 140°C. The reaction mixture was concentrated and purified by semi Example #83 preparative HPLC-MS and freeze dried from water/t-BuOH 4f1. Preparation of 3-((5-(thiophen-2-yl)-1H-pyrazolo4. 0504 exact mass: 357.1524 g/mol 3-dipyrimidin-7-yl)amino)phenol 0505 HPLC-MS: analytical method A 0519) 7-chloro-2-(4-methoxybenzyl)-5-(thiophen-2-yl)- 0506 rt: 2.294 min-found mass: 358 (m/z+H) 2H-pyrazolo 4,3-dipyrimidine (0.16 mmol) and 3-ami US 2012/032978.0 A1 Dec. 27, 2012 56 nophenol (0.3 mmol 2 eq.) were suspended in MeCH (dry, 3 ture was irradiated in a microwave reactor for 5 minat 140°C. mL) in a microwave vial (2-5 mL), HCl in dioxane (4M, 3 The reaction mixture was evaporated and used without fur drops) was added. The reaction mixture was irradiated in a ther purification. The residue was dissolved in TFA (3 mL). microwave reactor for 5 min at 140°C. The reaction mixture The reaction mixture was irradiated in a microwave reactor was evaporated and used without further purification. The for 5 min at 140°C. The reaction mixture was concentrated residue was dissolved in TFA (3 mL). The reaction mixture and purified by semi-preparative HPLC-MS and freeze dried was irradiated in a microwave reactor for 5 minat 140°C. The from waterft-BuOH 4/1. reaction mixture was concentrated and purified by semi-pre 0532 exact mass: 347.1729 g/mol parative HPLC-MS and freeze dried from water/t-BuOH4/1. 0533 HPLC-MS: analytical method A 0520 exact mass: 3.09.08.09 g/mol 0534 rt: 2.412 min-found mass: 348 (m/z+H) 0521 HPLC-MS: analytical method A 0522 rt: 2.441 min-found mass: 310 (m/z+H) Example #87 Example #84 Preparation of N-(5-(4-methoxyphenyl)-1H-pyrazolo 4,3-dipyrimidin-7-yl)-3,4-dihydro-2H-benzob.1, Preparation of N-(5-(thiophen-3-yl)-1H-pyrazolo4. 4oxazin-6-amine 3-dipyrimidin-7-yl)-3,4-dihydro-2H-benzob.14 0535) 7-chloro-2-(4-methoxybenzyl)-5-(4-methoxyphe oxazin-6-amine nyl)-2H-pyrazolo4.3-dpyrimidine (0.16 mmol) and 3,4-di 0523) 7-chloro-2-(4-methoxybenzyl)-5-(thiophen-3-yl)- hydro-2H-benzob 14oxazin-6-amine (0.3 mmol 2 eq.) 2H-pyrazolo4.3-dpyrimidine (0.16 mmol) and 3,4-dihydro were suspended in MeOH (dry, 3 mL) in a microwave vial 2H-benzob 14oxazin-6-amine (0.3 mmol 2 eq.) were sus (2-5 mL), HCl in dioxane (4M, 3 drops) was added. The pended in MeOH (dry, 3 mL) in a microwave vial (2-5 mL), reaction mixture was irradiated in a microwave reactor for 5 HCl in dioxane (4M, 3 drops) was added. The reaction mix min at 140°C. The reaction mixture was evaporated and used ture was irradiated in a microwave reactor for 5 minat 140°C. without further purification. The residue was dissolved in The reaction mixture was evaporated and used without fur TFA (3 mL). The reaction mixture was irradiated in a micro ther purification. The residue was dissolved in TFA (3 mL). wave reactor for 5 min at 140°C. The reaction mixture was The reaction mixture was irradiated in a microwave reactor concentrated and purified by semi-preparative HPLC-MS for 5 min at 140°C. The reaction mixture was concentrated and freeze dried from waterft-BuOH 471. and purified by semi-preparative HPLC-MS and freeze dried 0536 exact mass: 374.1738 g/mol from waterft-BuOH 4/1. 0537 HPLC-MS: analytical method A 0524 exact mass: 350.1124 g/mol 0538 rt: 2.296 min-found mass: 375 (m/z+H) 0525 HPLC-MS: analytical method A 0526 rt: 2.255 min-found mass: 351 (m/z+H) Example #88 Example #85 Preparation of N-(5-cyclopropyl-1H-pyrazol-3-yl)-5- (3-methoxyphenyl)-1H-pyrazolo 4,3-dipyrimidin-7- Preparation of 3-((5-(thiophen-3-yl)-1H-pyrazolo4. amine 3-dipyrimidin-7-yl)amino)phenol 0539 7-chloro-2-(4-methoxybenzyl)-5-(3-methoxyphe 0527 7-chloro-2-(4-methoxybenzyl)-5-(thiophen-3-yl)- nyl)-2H-pyrazolo4.3-dpyrimidine (0.16 mmol) and 5-cy 2H-pyrazolo4.3-dpyrimidine (0.16 mmol) and 3-ami clopropyl-1H-pyrazol-3-amine (0.3 mmol 2 eq.) were Sus nophenol (0.3 mmol 2 eq.) were suspended in MeCH (dry, 3 pended in MeOH (dry, 3 mL) in a microwave vial (2-5 mL), mL) in a microwave vial (2-5 mL), HCl in dioxane (4M, 3 HCl in dioxane (4M, 3 drops) was added. The reaction mix drops) was added. The reaction mixture was irradiated in a ture was irradiated in a microwave reactor for 5 minat 140°C. microwave reactor for 5 min at 140°C. The reaction mixture The reaction mixture was evaporated and used without fur was evaporated and used without further purification. The ther purification. The residue was dissolved in TFA (3 mL). residue was dissolved in TFA (3 mL). The reaction mixture The reaction mixture was irradiated in a microwave reactor was irradiated in a microwave reactor for 5 minat 140°C. The for 5 min at 140°C. The reaction mixture was concentrated reaction mixture was concentrated and purified by semi-pre and purified by semi-preparative HPLC-MS and freeze dried parative HPLC-MS and freeze dried from water/t-BuOH4/1. from waterft-BuOH 4/1. 0528 exact mass: 3.09.08.09 g/mol (0540 exact mass: 347.1729 g/mol 0529 HPLC-MS: analytical method A (0541 HPLC-MS: analytical method A 0530 rt: 2.255 min-found mass: 310 (m/z+H) 0542 rt: 2.604 min-found mass: 348 (m/z+H) Example #86 Example #89 Preparation of N-(5-cyclopropyl-1H-pyrazol-3-yl)-5- Preparation of N-(5-(3-methoxyphenyl)-1H-pyrazolo (4-methoxyphenyl)-1H-pyrazolo 4,3-dipyrimidin-7- 4,3-dipyrimidin-7-yl)-3,4-dihydro-2H-benzob.1, amine 4oxazin-6-amine 0531 7-chloro-2-(4-methoxybenzyl)-5-(4-methoxyphe 0543) 7-chloro-2-(4-methoxybenzyl)-5-(3-methoxyphe nyl)-2H-pyrazolo 4,3-dipyrimidine (0.16 mmol) and 5-cy nyl)-2H-pyrazolo4.3-dpyrimidine (0.16 mmol) and 3,4-di clopropyl-1H-pyrazol-3-amine (0.3 mmol 2 eq.) were sus hydro-2H-benzob 14oxazin-6-amine (0.3 mmol 2 eq.) pended in MeOH (dry, 3 mL) in a microwave vial (2-5 mL), were suspended in MeOH (dry, 3 mL) in a microwave vial HCl in dioxane (4M, 3 drops) was added. The reaction mix (2-5 mL), HCl in dioxane (4M, 3 drops) was added. The US 2012/032978.0 A1 Dec. 27, 2012 57 reaction mixture was irradiated in a microwave reactor for 5 mixture was irradiated in a microwave reactor for 5 min at min at 140°C. The reaction mixture was evaporated and used 140°C. The reaction mixture was evaporated and used with without further purification. The residue was dissolved in out further purification. The residue was dissolved in TFA (3 TFA (3 mL). The reaction mixture was irradiated in a micro mL). The reaction mixture was irradiated in a microwave wave reactor for 5 min at 140°C. The reaction mixture was reactor for 5 min at 140°C. The reaction mixture was con concentrated and purified by semi-preparative HPLC-MS centrated and purified by semi-preparative HPLC-MS and and freeze dried from waterft-BuOH 471. freeze dried from waterft-BuOH 4/1. (0544 exact mass: 374.1738 g/mol 0556 exact mass: 338.2315 g/mol (0545 HPLC-MS: analytical method A 0557. HPLC-MS: analytical method A 0546 rt: 2.434 min-found mass: 375 (m/z+H) 0558 rt: 0.330 min-found mass: 339 (m/z+H) Example #90 Example #93 Preparation of N-(5-cyclopropyl-1H-pyrazol-3-yl)-5- Preparation of N-(5-(1-methylpiperidin-4-yl)-1H (thiophen-2-yl)-1H-pyrazolo 4,3-dipyrimidin-7- pyrazolo 4,3-dipyrimidin-7-yl)-3,4-dihydro-2H amine benzob 14oxazin-6-amine 0547 7-chloro-2-(4-methoxybenzyl)-5-(thiophen-2-yl)- 0559) 7-chloro-2-(4-methoxybenzyl)-5-(1-methylpiperi 2H-pyrazolo4.3-dpyrimidine (0.16 mmol) and 5-cyclopro din-4-yl)-2H-pyrazolo 4,3-dipyrimidine (0.16 mmol) and pyl-1H-pyrazol-3-amine (0.3 mmol 2 eq.) were Suspended in 3,4-dihydro-2H-benzob 14oxazin-6-amine (0.3 mmol 2 MeOH (dry, 3 mL) in a microwave vial (2-5 mL), HCl in eq.) were suspended in MeCH (dry, 3 mL) in a microwave dioxane (4M, 3 drops) was added. The reaction mixture was vial (2-5 mL), HCl in dioxane (4M, 3 drops) was added. The irradiated in a microwave reactor for 5 min at 140°C. The reaction mixture was irradiated in a microwave reactor for 5 reaction mixture was evaporated and used without further min at 140°C. The reaction mixture was evaporated and used purification. The residue was dissolved in TFA (3 mL). The without further purification. The residue was dissolved in reaction mixture was irradiated in a microwave reactor for 5 TFA (3 mL). The reaction mixture was irradiated in a micro min at 140° C. The reaction mixture was concentrated and wave reactor for 5 min at 140°C. The reaction mixture was purified by semi-preparative HPLC-MS and freeze dried concentrated and purified by semi-preparative HPLC-MS from waterft-BuOH 4/1. and freeze dried from waterft-BuOH 471. (0548 exact mass: 323.1115 g/mol 0560 exact mass: 365.2325 g/mol (0549. HPLC-MS: analytical method F 0561 HPLC-MS: analytical method A 0550 rt: 5.010 min-found mass: 324 (m/z+H) 0562 rt: 0.321 min-found mass: 366 (m/z+H) Example #91 Example #94 Preparation of N-(5-(thiophen-2-yl)-1H-pyrazolo4. Preparation of 3-((5-(1-methylpiperidin-4-yl)-1H 3-dipyrimidin-7-yl)-3,4-dihydro-2H-benzob.14 pyrazolo 4.3-dpyrimidin-7-yl)amino)phenol oxazin-6-amine 0563) 7-chloro-2-(4-methoxybenzyl)-5-(1-methylpiperi 0551 7-chloro-2-(4-methoxybenzyl)-5-(thiophen-2-yl)- din-4-yl)-2H-pyrazolo 4,3-dipyrimidine (0.16 mmol) and 2H-pyrazolo4.3-dpyrimidine (0.16 mmol) and 3,4-dihydro 3-aminophenol (0.3 mmol 2 eq.) were suspended in MeCH 2H-benzob 14oxazin-6-amine (0.3 mmol 2 eq.) were sus (dry, 3 mL) in a microwave vial (2-5 mL), HCl in dioxane pended in MeOH (dry, 3 mL) in a microwave vial (2-5 mL), (4M, 3 drops) was added. The reaction mixture was irradiated HCl in dioxane (4M, 3 drops) was added. The reaction mix in a microwave reactor for 5 min at 140° C. The reaction ture was irradiated in a microwave reactor for 5 minat 140°C. mixture was evaporated and used without further purification. The reaction mixture was evaporated and used without fur The residue was dissolved in TFA (3 mL). The reaction mix ther purification. The residue was dissolved in TFA (3 mL). ture was irradiated in a microwave reactor for 5 minat 140°C. The reaction mixture was irradiated in a microwave reactor The reaction mixture was concentrated and purified by semi for 5 min at 140°C. The reaction mixture was concentrated preparative HPLC-MS and freeze dried from water/t-BuOH and purified by semi-preparative HPLC-MS and freeze dried 4f1. from waterft-BuOH 4/1. 0564) exact mass: 324.2009 g/mol 0552 exact mass: 350.1124 g/mol 0565 HPLC-MS: analytical method A 0553 HPLC-MS: analytical method A 0566 rt: 0.308 min-found mass: 325 (m/z+H) 0554 rt: 2.425 min-found mass: 351 (m/z+H) Example #95 Example #92 Preparation of 5-(benzodthiazol-2-yl)-N-(4-(4- Preparation of N-(5-cyclopropyl-1H-pyrazol-3-yl)-5- methylpiperazin-1-yl)phenyl)-1H-pyrazolo 4,3-d (1-methylpiperidin-4-yl)-1H-pyrazolo 4,3-dipyrimi pyrimidin-7-amine din-7-amine 0567 2-(7-chloro-2-(4-methoxybenzyl)-2H-pyrazolo.4, 0555) 7-chloro-2-(4-methoxybenzyl)-5-(1-methylpiperi 3-dipyrimidin-5-yl)benzodthiazole (0.16 mmol) and 4-(4- din-4-yl)-2H-pyrazolo 4,3-dipyrimidine (0.16 mmol) and methylpiperazin-1-yl)aniline (0.3 mmol 2 eq.) were Sus 5-cyclopropyl-1H-pyrazol-3-amine (0.3 mmol 2 eq.) were pended in MeOH (dry, 3 mL) in a microwave vial (2-5 mL), suspended in MeCH (dry, 3 mL) in a microwave vial (2-5 HCl in dioxane (4M, 3 drops) was added. The reaction mix mL), HCl in dioxane (4M, 3 drops) was added. The reaction ture was irradiated in a microwave reactor for 5 minat 140°C. US 2012/032978.0 A1 Dec. 27, 2012

The reaction mixture was evaporated and used without fur purification. The residue was dissolved in TFA (3 mL). The ther purification. The residue was dissolved in TFA (3 mL). reaction mixture was irradiated in a microwave reactor for 5 The reaction mixture was irradiated in a microwave reactor min at 140° C. The reaction mixture was concentrated and for 5 min at 140°C. The reaction mixture was concentrated purified by semi-preparative HPLC-MS and freeze dried and purified by semi-preparative HPLC-MS and freeze dried from waterft-BuOH 4/1. from waterft-BuOH 4/1. 0580 exact mass: 384.1021 g/mol 0568 exact mass: 442.2001 g/mol 0581 HPLC-MS: analytical method C 0569. HPLC-MS: analytical method A 0582 rt: 2.360 min-found mass: 385 (m/z+H) 0570 rt: 2.111 min-found mass: 443 (m/z+H) Example #99 Example #96 Preparation of N-(4-(4-methylpiperazin-1-yl)phe Preparation of 5-(benzodthiazol-2-yl)-N-(3,4- nyl)-5-(3-(pyridin-3-yl)phenyl)-1H-pyrazolo 4,3-d dimethoxyphenyl)-1H-pyrazolo 4,3-dipyrimidin-7- pyrimidin-7-amine amine 0583) 7-chloro-2-(4-methoxybenzyl)-5-(3-(pyridin-3-yl) 0571 2-(7-chloro-2-(4-methoxybenzyl)-2H-pyrazolo.4, phenyl)-2H-pyrazolo 4,3-dipyrimidine (0.16 mmol) and 3-dipyrimidin-5-yl)benzodthiazole (0.16 mmol) and 3,4- 4-(4-methylpiperazin-1-yl)aniline (0.3 mmol 2 eq.) were sus dimethoxyaniline (0.3 mmol 2 eq.) were suspended in MeOH pended in MeOH (dry, 3 mL) in a microwave vial (2-5 mL), (dry, 3 mL) in a microwave vial (2-5 mL), HCl in dioxane HCl in dioxane (4M, 3 drops) was added. The reaction mix (4M, 3 drops) was added. The reaction mixture was irradiated ture was irradiated in a microwave reactor for 5 minat 140°C. in a microwave reactor for 5 min at 140° C. The reaction The reaction mixture was evaporated and used without fur mixture was evaporated and used without further purification. ther purification. The residue was dissolved in TFA (3 mL). The residue was dissolved in TFA (3 mL). The reaction mix The reaction mixture was irradiated in a microwave reactor ture was irradiated in a microwave reactor for 5 minat 140°C. for 5 min at 140°C. The reaction mixture was concentrated The reaction mixture was concentrated and purified by semi and purified by semi-preparative HPLC-MS and freeze dried preparative HPLC-MS and freeze dried from water/t-BuOH from waterft-BuOH 4/1. 4f1. 0584) exact mass: 462.2667 g/mol 0572 exact mass: 404.1254 g/mol 0585 HPLC-MS: analytical method A 0573 HPLC-MS: analytical method A 0586 rt: 1.861 min-found mass: 463 (m/z+H) 0574 rt: 3.058 min-found mass: 405 (m/z+H) Example #100 Example #97 Preparation of N-(5-cyclopropyl-1H-pyrazol-3-yl)-5- Preparation of N-(5-(benzodthiazol-2-yl)-1H-pyra (3-(pyridin-3-yl)phenyl)-1H-pyrazolo4.3-dpyrimi Zolo4,3-dipyrimidin-7-yl)-3,4-dihydro-2H-benzob din-7-amine 1.4 oxazin-6-amine 0587 7-chloro-2-(4-methoxybenzyl)-5-(3-(pyridin-3-yl) 0575 2-(7-chloro-2-(4-methoxybenzyl)-2H-pyrazolo.4, phenyl)-2H-pyrazolo 4,3-dipyrimidine (0.16 mmol) and 3-dipyrimidin-5-yl)benzodthiazole (0.16 mmol) and 3,4- 5-cyclopropyl-1H-pyrazol-3-amine (0.3 mmol 2 eq.) were dihydro-2H-benzob 14oxazin-6-amine (0.3 mmol 2 eq.) suspended in MeCH (dry, 3 mL) in a microwave vial (2-5 were suspended in MeOH (dry, 3 mL) in a microwave vial mL), HCl in dioxane (4M, 3 drops) was added. The reaction (2-5 mL), HCl in dioxane (4M, 3 drops) was added. The mixture was irradiated in a microwave reactor for 5 min at reaction mixture was irradiated in a microwave reactor for 5 140°C. The reaction mixture was evaporated and used with min at 140°C. The reaction mixture was evaporated and used out further purification. The residue was dissolved in TFA (3 without further purification. The residue was dissolved in mL). The reaction mixture was irradiated in a microwave TFA (3 mL). The reaction mixture was irradiated in a micro reactor for 5 min at 140°C. The reaction mixture was con wave reactor for 5 min at 140°C. The reaction mixture was centrated and purified by semi-preparative HPLC-MS and concentrated and purified by semi-preparative HPLC-MS freeze dried from waterft-BuOH 4/1. and freeze dried from waterft-BuOH 471. 0588 exact mass: 394.1891 g/mol 0576 exact mass: 401.1235 g/mol 0589 HPLC-MS: analytical method A 0577. HPLC-MS: analytical method A 0590 rt: 2.318 min-found mass: 395 (m/z+H) 0578 rt: 2.909 min-found mass: 402 (m/z+H) Example #101 Example #98 Preparation of N-(3,4-dimethoxyphenyl)-5-(3-(pyri Preparation of 5-(benzodthiazol-2-yl)-N-(1H-inda din-3-yl)phenyl)-1H-pyrazolo 4,3-dipyrimidin-7- Zol-6-yl)-1H-pyrazolo 4,3-dipyrimidin-7-amine amine 0579. 2-(7-chloro-2-(4-methoxybenzyl)-2H-pyrazolo.4, 0591) 7-chloro-2-(4-methoxybenzyl)-5-(3-(pyridin-3-yl) 3-dipyrimidin-5-yl)benzodthiazole (0.16 mmol) and phenyl)-2H-pyrazolo 4,3-dipyrimidine (0.16 mmol) and 3,4- 1H-indazol-6-amine (0.3 mmol 2 eq.) were suspended in dimethoxyaniline (0.3 mmol 2 eq.) were suspended in MeCH MeOH (dry, 3 mL) in a microwave vial (2-5 mL), HCl in (dry, 3 mL) in a microwave vial (2-5 mL), HCl in dioxane dioxane (4M, 3 drops) was added. The reaction mixture was (4M, 3 drops) was added. The reaction mixture was irradiated irradiated in a microwave reactor for 5 min at 140°C. The in a microwave reactor for 5 min at 140° C. The reaction reaction mixture was evaporated and used without further mixture was evaporated and used without further purification. US 2012/032978.0 A1 Dec. 27, 2012 59

The residue was dissolved in TFA (3 mL). The reaction mix reaction mixture was irradiated in a microwave reactor for 5 ture was irradiated in a microwave reactor for 5 minat 140°C. min at 140° C. The reaction mixture was concentrated and The reaction mixture was concentrated and purified by semi purified by semi-preparative HPLC-MS and freeze dried preparative HPLC-MS and freeze dried from water/t-BuOH from waterft-BuOH 4/1. 4f1. 0604 exact mass: 404.1687 g/mol 0592 exact mass: 424.1919 g/mol 0605 HPLC-MS: analytical method A 0593 HPLC-MS: analytical method A 0606 rt: 2.238 min-found mass: 405 (m/z+H) 0594) rt: 2.349 min-found mass: 425 (m/z+H) Example #105 Example #102 Preparation of 2-(7-((4-(4-methylpiperazin-1-yl) Preparation of N-(4-morpholinophenyl)-5-(3-(pyri phenyl)amino)-1H-pyrazolo 4,3-dipyrimidin-5-yl) din-3-yl)phenyl)-1H-pyrazolo 4,3-dipyrimidin-7- phenol amine 0607 2-(7-chloro-2-(4-methoxybenzyl)-2H-pyrazolo.4, 0595) 7-chloro-2-(4-methoxybenzyl)-5-(3-(pyridin-3-yl) 3-dipyrimidin-5-yl)phenol (0.16 mmol) and 4-(4-methylpip phenyl)-2H-pyrazolo 4,3-dipyrimidine (0.16 mmol) and erazin-1-yl)aniline (0.3 mmol 2 eq.) were suspended in 4-morpholinoaniline (0.3 mmol 2 eq.) were Suspended in MeOH (dry, 3 mL) in a microwave vial (2-5 mL), HCl in MeOH (dry, 3 mL) in a microwave vial (2-5 mL), HCl in dioxane (4M, 3 drops) was added. The reaction mixture was dioxane (4M, 3 drops) was added. The reaction mixture was irradiated in a microwave reactor for 5 min at 140°C. The irradiated in a microwave reactor for 5 min at 140°C. The reaction mixture was evaporated and used without further reaction mixture was evaporated and used without further purification. The residue was dissolved in TFA (3 mL). The purification. The residue was dissolved in TFA (3 mL). The reaction mixture was irradiated in a microwave reactor for 5 reaction mixture was irradiated in a microwave reactor for 5 min at 140° C. The reaction mixture was concentrated and min at 140° C. The reaction mixture was concentrated and purified by semi-preparative HPLC-MS and freeze dried purified by semi-preparative HPLC-MS and freeze dried from waterft-BuOH 4/1. from waterft-BuOH 4/1. 0608 exact mass: 401.231 g/mol 0596 exact mass: 449.2291 g/mol 0609 HPLC-MS: analytical method A 0597. HPLC-MS: analytical method A 0610 rt: 2.011 min-found mass: 402 (m/z+H) 0598 rt: 2.299 min-found mass: 450 (m/z+H) Example #106 Example #103 Preparation of N-(4-(4-methylpiperazin-1-yl)phe Preparation of N-(5-(3-(pyridin-3-yl)phenyl)-1H nyl)-5-(3-morpholinophenyl)-1H-pyrazolo 4,3-d pyrazolo 4,3-dipyrimidin-7-yl)-3,4-dihydro-2H pyrimidin-7-amine benzob 14oxazin-6-amine 0611) 4-(3-(7-chloro-2-(4-methoxybenzyl)-2H-pyrazolo 0599 7-chloro-2-(4-methoxybenzyl)-5-(3-(pyridin-3-yl) 4.3-dpyrimidin-5-yl)phenyl)morpholine (0.16 mmol) and phenyl)-2H-pyrazolo 4,3-dipyrimidine (0.16 mmol) and 3,4- 4-(4-methylpiperazin-1-yl)aniline (0.3 mmol 2 eq.) were sus dihydro-2H-benzob 14oxazin-6-amine (0.3 mmol 2 eq.) pended in MeOH (dry, 3 mL) in a microwave vial (2-5 mL), were suspended in MeOH (dry, 3 mL) in a microwave vial HCl in dioxane (4M, 3 drops) was added. The reaction mix (2-5 mL), HCl in dioxane (4M, 3 drops) was added. The ture was irradiated in a microwave reactor for 5 minat 140°C. reaction mixture was irradiated in a microwave reactor for 5 The reaction mixture was evaporated and used without fur min at 140°C. The reaction mixture was evaporated and used ther purification. The residue was dissolved in TFA (3 mL). without further purification. The residue was dissolved in The reaction mixture was irradiated in a microwave reactor TFA (3 mL). The reaction mixture was irradiated in a micro for 5 min at 140°C. The reaction mixture was concentrated wave reactor for 5 min at 140°C. The reaction mixture was and purified by semi-preparative HPLC-MS and freeze dried concentrated and purified by semi-preparative HPLC-MS from waterft-BuOH 4/1. and freeze dried from waterft-BuOH 471. 0612 exact mass: 470.3015 g/mol 0600 exact mass: 421.1901 g/mol 0613 HPLC-MS: analytical method A 0601 HPLC-MS: analytical method A 0614 rt: 1.793 min-found mass: 471 (m/z+H) 0602 rt: 2.218 min-found mass: 422 (m/z+H) Example #107 Example #104 Preparation of N-(3,4-dimethoxyphenyl)-5-(3-mor Preparation of N-(1H-indazol-6-yl)-5-(3-(pyridin-3- pholinophenyl)-1H-pyrazolo 4,3-dipyrimidin-7- yl)phenyl)-1H-pyrazolo 4,3-dipyrimidin-7-amine amine 0603) 7-chloro-2-(4-methoxybenzyl)-5-(3-(pyridin-3-yl) 0615) 4-(3-(7-chloro-2-(4-methoxybenzyl)-2H-pyrazolo phenyl)-2H-pyrazolo 4,3-dipyrimidine (0.16 mmol) and 4.3-dpyrimidin-5-yl)phenyl)morpholine (0.16 mmol) and 1H-indazol-6-amine (0.3 mmol 2 eq.) were suspended in 3,4-dimethoxyaniline (0.3 mmol 2 eq.) were suspended in MeOH (dry, 3 mL) in a microwave vial (2-5 mL), HCl in MeOH (dry, 3 mL) in a microwave vial (2-5 mL), HCl in dioxane (4M, 3 drops) was added. The reaction mixture was dioxane (4M, 3 drops) was added. The reaction mixture was irradiated in a microwave reactor for 5 min at 140°C. The irradiated in a microwave reactor for 5 min at 140°C. The reaction mixture was evaporated and used without further reaction mixture was evaporated and used without further purification. The residue was dissolved in TFA (3 mL). The purification. The residue was dissolved in TFA (3 mL). The US 2012/032978.0 A1 Dec. 27, 2012 60 reaction mixture was irradiated in a microwave reactor for 5 wave reactor for 5 min at 140°C. The reaction mixture was min at 140° C. The reaction mixture was concentrated and concentrated and purified by semi-preparative HPLC-MS purified by semi-preparative HPLC-MS and freeze dried and freeze dried from waterft-BuOH 471. from waterft-BuOH 4/1. (0628 exact mass: 374.1738 g/mol 0616) exact mass: 432.2267 g/mol 0629 HPLC-MS: analytical method A 0617. HPLC-MS: analytical method A 0618 rt: 2.410 min-found mass: 433 (m/z+H) 0630 rt: 2.227 min-found mass: 375 (m/z+H) Example #108 Example #111 Preparation of 5-(2-methoxyphenyl)-N-(4-(4-meth Preparation of N-(1H-indazol-6-yl)-5-(2-methox ylpiperazin-1-yl)phenyl)-1H-pyrazolo 4,3-dipyrimi yphenyl)-1H-pyrazolo 4,3-dipyrimidin-7-amine din-7-amine 0631 7-chloro-2-(4-methoxybenzyl)-5-(2-methoxyphe 0619 7-chloro-2-(4-methoxybenzyl)-5-(2-methoxyphe nyl)-2H-pyrazolo4.3-dpyrimidine (0.16 mmol) and 1H-in nyl)-2H-pyrazolo 4,3-dipyrimidine (0.16 mmol) and 4-(4- dazol-6-amine (0.3 mmol 2 eq.) were suspended in MeOH methylpiperazin-1-yl)aniline (0.3 mmol 2 eq.) were sus (dry, 3 mL) in a microwave vial (2-5 mL), HCl in dioxane pended in MeOH (dry, 3 mL) in a microwave vial (2-5 mL), (4M, 3 drops) was added. The reaction mixture was irradiated HCl in dioxane (4M, 3 drops) was added. The reaction mix in a microwave reactor for 5 min at 140° C. The reaction ture was irradiated in a microwave reactor for 5 minat 140°C. mixture was evaporated and used without further purification. The reaction mixture was evaporated and used without fur The residue was dissolved in TFA (3 mL). The reaction mix ther purification. The residue was dissolved in TFA (3 mL). ture was irradiated in a microwave reactor for 5 minat 140°C. The reaction mixture was irradiated in a microwave reactor The reaction mixture was concentrated and purified by semi for 5 min at 140°C. The reaction mixture was concentrated preparative HPLC-MS and freeze dried from water/t-BuOH and purified by semi-preparative HPLC-MS and freeze dried 4f1. from waterft-BuOH 4/1. 0632 exact mass: 357.1524 g/mol 0620 exact mass: 415.2504 g/mol 0633 HPLC-MS: analytical method A 0621 HPLC-MS: analytical method A 0634 rt: 2.125 min-found mass: 358 (m/z+H) 0622 rt: 1.338 min-found mass: 416 (m/z+H) Example #112 Example #109 Preparation of 5-(2-methoxyphenyl)-N-(4-morpholi Preparation of N-(3,4-dimethoxyphenyl)-5-(2-meth nophenyl)-1H-pyrazolo 4.3-dipyrimidin-7-amine oxyphenyl)-1H-pyrazolo 4.3-dipyrimidin-7-amine 0635) 7-chloro-2-(4-methoxybenzyl)-5-(2-methoxyphe 0623) 7-chloro-2-(4-methoxybenzyl)-5-(2-methoxyphe nyl)-2H-pyrazolo4.3-dpyrimidine (0.16 mmol) and 4-mor nyl)-2H-pyrazolo 4,3-dipyrimidine (0.16 mmol) and 3,4- pholinoaniline (0.3 mmol 2 eq.) were suspended in MeCH dimethoxyaniline (0.3 mmol 2 eq.) were suspended in MeOH (dry, 3 mL) in a microwave vial (2-5 mL), HCl in dioxane (dry, 3 mL) in a microwave vial (2-5 mL), HCl in dioxane (4M, 3 drops) was added. The reaction mixture was irradiated (4M, 3 drops) was added. The reaction mixture was irradiated in a microwave reactor for 5 min at 140° C. The reaction in a microwave reactor for 5 min at 140° C. The reaction mixture was evaporated and used without further purification. mixture was evaporated and used without further purification. The residue was dissolved in TFA (3 mL). The reaction mix The residue was dissolved in TFA (3 mL). The reaction mix ture was irradiated in a microwave reactor for 5 minat 140°C. ture was irradiated in a microwave reactor for 5 minat 140°C. The reaction mixture was concentrated and purified by semi The reaction mixture was concentrated and purified by semi preparative HPLC-MS and freeze dried from water/t-BuOH preparative HPLC-MS and freeze dried from water/t-BuOH 4f1. 4f1. 0624 exact mass: 377.1757 g/mol 0636 exact mass: 402.2128 g/mol 0625 HPLC-MS: analytical method A 0637 HPLC-MS: analytical method A 0626 rt: 2.215 min-found mass: 378 (m/z+H) 0638 rt: 2.252 min-found mass: 403 (m/z+H) Example #110 Example #113 Preparation of N-(5-(2-methoxyphenyl)-1H-pyrazolo Preparation of N-(5-cyclopropyl-1H-pyrazol-3-yl)-5- 4.3-dpyrimidin-7-yl)-3,4-dihydro-2H-benzob.1, (2-methoxyphenyl)-1H-pyrazolo 4,3-dipyrimidin-7- 4oxazin-6-amine amine 0627 7-chloro-2-(4-methoxybenzyl)-5-(2-methoxyphe 0639 7-chloro-2-(4-methoxybenzyl)-5-(2-methoxyphe nyl)-2H-pyrazolo 4,3-dipyrimidine (0.16 mmol) and 3,4-di nyl)-2H-pyrazolo4.3-dpyrimidine (0.16 mmol) and 5-cy hydro-2H-benzob 14oxazin-6-amine (0.3 mmol 2 eq.) clopropyl-1H-pyrazol-3-amine (0.3 mmol 2 eq.) were Sus were suspended in MeOH (dry, 3 mL) in a microwave vial pended in MeOH (dry, 3 mL) in a microwave vial (2-5 mL), (2-5 mL), HCl in dioxane (4M, 3 drops) was added. The HCl in dioxane (4M, 3 drops) was added. The reaction mix reaction mixture was irradiated in a microwave reactor for 5 ture was irradiated in a microwave reactor for 5 minat 140°C. min at 140°C. The reaction mixture was evaporated and used The reaction mixture was evaporated and used without fur without further purification. The residue was dissolved in ther purification. The residue was dissolved in TFA (3 mL). TFA (3 mL). The reaction mixture was irradiated in a micro The reaction mixture was irradiated in a microwave reactor US 2012/032978.0 A1 Dec. 27, 2012

for 5 min at 140°C. The reaction mixture was concentrated wave reactor for 5 min at 140°C. The reaction mixture was and purified by semi-preparative HPLC-MS and freeze dried concentrated and purified by semi-preparative HPLC-MS from waterft-BuOH 4/1. and freeze dried from waterft-BuOH 471. (0640 exact mass: 347.1729 g/mol 0652 exact mass: 3.14.159 g/mol (0641 HPLC-MS: analytical method A 0653 HPLC-MS: analytical method C 0642 rt: 2.242 min-found mass: 348 (m/z+H) 0654) rt: 1.388 min-found mass: 315 (m/z+H) Example #114 Example #117 Preparation of N1,N1-dimethyl-N-3-(5-(thiophen-3- Preparation of N1-(5-(thiophen-3-yl)-1H-pyrazolo4. yl)-1H-pyrazolo 4,3-dipyrimidin-7-yl)benzene-1,3- 3-dipyrimidin-7-yl)benzene-1,3-diamine diamine 0655 7-chloro-2-(4-methoxybenzyl)-5-(thiophen-3-yl)- 0643) 7-chloro-2-(4-methoxybenzyl)-5-(thiophen-3-yl)- 2H-pyrazolo 4,3-dipyrimidine (0.16 mmol) and benzene-1, 2H-pyrazolo4.3-dpyrimidine (0.16 mmol) and N1,N1-dim 3-diamine (0.3 mmol 2 eq.) were suspended in MeOH (dry, 3 ethylbenzene-1,3-diamine (0.3 mmol 2 eq.) were suspended mL) in a microwave vial (2-5 mL), HCl in dioxane (4M, 3 in MeCH (dry, 3 mL) in a microwave vial (2-5 mL), HCl in drops) was added. The reaction mixture was irradiated in a dioxane (4M, 3 drops) was added. The reaction mixture was microwave reactor for 5 min at 140°C. The reaction mixture irradiated in a microwave reactor for 5 min at 140°C. The was evaporated and used without further purification. The reaction mixture was evaporated and used without further residue was dissolved in TFA (3 mL). The reaction mixture purification. The residue was dissolved in TFA (3 mL). The was irradiated in a microwave reactor for 5 minat 140°C. The reaction mixture was irradiated in a microwave reactor for 5 min at 140° C. The reaction mixture was concentrated and reaction mixture was concentrated and purified by semi-pre purified by semi-preparative HPLC-MS and freeze dried parative HPLC-MS and freeze dried from water/t-BuOH4/1. from waterft-BuOH 4/1. 0656 exact mass: 308.099 g/mol 0644 exact mass: 336.138 g/mol 0657 HPLC-MS: analytical method A (0645 HPLC-MS: analytical method C 0658 rt: 1.937 min-found mass: 309 (m/z+H) (0646 rt: 2.085 min-found mass: 337 (m/z+H) Example #118 Example #115 Preparation of N-(6-(4-methylpiperazin-1-yl)pyridin Preparation of (1R,2R)- N-(5-Thiophen-3-yl-1H 3-yl)-5-(thiophen-3-yl)-1H-pyrazolo 4,3-dipyrimi pyrazolo 4.3-dpyrimidin-7-yl)-cyclohexane-1,2- din-7-amine diamine 0659 7-chloro-2-(4-methoxybenzyl)-5-(thiophen-3-yl)- 0647 7-chloro-2-(4-methoxybenzyl)-5-(thiophen-3-yl)- 2H-pyrazolo 4,3-dipyrimidine (0.16 mmol) and 6-(4-meth 2H-pyrazolo4.3-dpyrimidine (0.16 mmol) and ((1R,2R)-2- ylpiperazin-1-yl)pyridin-3-amine (0.3 mmol 2 eq.) were sus Amino-cyclohexyl)-carbamic acid tert-butyl ester (0.3 mmol pended in MeOH (dry, 3 mL) in a microwave vial (2-5 mL), 2 eq.) were suspended in MeCH (dry, 3 mL) in a microwave HCl in dioxane (4M, 3 drops) was added. The reaction mix vial (2-5 mL), HCl in dioxane (4M, 3 drops) was added. The ture was irradiated in a microwave reactor for 5 minat 140°C. reaction mixture was irradiated in a microwave reactor for 5 The reaction mixture was evaporated and used without fur min at 140°C. The reaction mixture was evaporated and used ther purification. The residue was dissolved in TFA (3 mL). without further purification. The residue was dissolved in The reaction mixture was irradiated in a microwave reactor TFA (3 mL). The reaction mixture was irradiated in a micro for 5 min at 140°C. The reaction mixture was concentrated wave reactor for 5 min at 140°C. The reaction mixture was and purified by semi-preparative HPLC-MS and freeze dried concentrated and purified by semi-preparative HPLC-MS from waterft-BuOH 4/1. and freeze dried from waterft-BuOH 471. 0660 exact mass: 392.1821 g/mol 0648 exact mass: 3.14.159 g/mol 0661 HPLC-MS: analytical method C (0649. HPLC-MS: analytical method C 0662 rt: 1.428 min-found mass: 393 (m/z+H) 0650 rt: 1.411 min-found mass: 315 (m/z+H) Example #119 Example #116 Preparation of N-(4-(4-ethylpiperazin-1-yl)phenyl)- Preparation of (1S,2R)-N-(5-Thiophen-3-yl-1H 5-phenyl-1H-pyrazolo 4,3-dipyrimidin-7-amine pyrazolo 4.3-dpyrimidin-7-yl)-cyclohexane-1,2- 0663 7-chloro-2-(4-methoxybenzyl)-5-phenyl-2H-pyra diamine Zolo 4,3-dipyrimidine (0.16 mmol) and 4-(4-ethylpiperazin 0651) 7-chloro-2-(4-methoxybenzyl)-5-(thiophen-3-yl)- 1-yl)aniline (0.3 mmol 2 eq.) were suspended in MeCH (dry, 2H-pyrazolo4.3-dpyrimidine (0.16 mmol) and (1S,2R)-2- 3 mL) in a microwave vial (2-5 mL), HCl in dioxane (4M, 3 Amino-cyclohexyl)-carbamic acid tert-butyl ester (0.3 mmol drops) was added. The reaction mixture was irradiated in a 2 eq.) were suspended in MeCH (dry, 3 mL) in a microwave microwave reactor for 5 min at 140°C. The reaction mixture vial (2-5 mL), HCl in dioxane (4M, 3 drops) was added. The was evaporated and used without further purification. The reaction mixture was irradiated in a microwave reactor for 5 residue was dissolved in TFA (3 mL). The reaction mixture min at 140°C. The reaction mixture was evaporated and used was irradiated in a microwave reactor for 5 minat 140°C. The without further purification. The residue was dissolved in reaction mixture was concentrated and purified by semi-pre TFA (3 mL). The reaction mixture was irradiated in a micro parative HPLC-MS and freeze dried from water/t-BuOH4/1. US 2012/032978.0 A1 Dec. 27, 2012 62

0664 exact mass: 399.2561 g/mol 0676 exact mass: 459.2839 g/mol 0665 HPLC-MS: analytical method C 0677. HPLC-MS: analytical method A 0666 rt: 1.586 min-found mass: 400 (m/z+H) 0678 rt: 1.848 min-found mass: 460 (m/z+H) Example #120 Example #123 Preparation of N-(4-(dimethylamino)methyl)phe Preparation of N-(4-(4-cyclopropylpiperazin-1-yl) nyl)-5-phenyl-1H-pyrazolo 4,3-dipyrimidin-7-amine phenyl)-5-(2,5-dimethoxyphenyl)-1H-pyrazolo 4.3- dpyrimidin-7-amine 0667 7-chloro-2-(4-methoxybenzyl)-5-phenyl-2H-pyra Zolo4.3-dpyrimidine (0.16 mmol) and 4-(dimethylamino) 0679 7-chloro-5-(2,5-dimethoxyphenyl)-2-(4-methoxy methyl)aniline (0.3 mmol 2 eq.) were suspended in MeOH benzyl)-2H-pyrazolo 4.3-dpyrimidine (0.16 mmol) and (dry, 3 mL) in a microwave vial (2-5 mL), HCl in dioxane 4-(4-cyclopropylpiperazin-1-yl)aniline (0.3 mmol 2 eq.) (4M, 3 drops) was added. The reaction mixture was irradiated were suspended in MeOH (dry, 3 mL) in a microwave vial in a microwave reactor for 5 min at 140° C. The reaction (2-5 mL), HCl in dioxane (4M, 3 drops) was added. The mixture was evaporated and used without further purification. reaction mixture was irradiated in a microwave reactor for 5 The residue was dissolved in TFA (3 mL). The reaction mix min at 140°C. The reaction mixture was evaporated and used ture was irradiated in a microwave reactor for 5 minat 140°C. without further purification. The residue was dissolved in The reaction mixture was concentrated and purified by semi TFA (3 mL). The reaction mixture was irradiated in a micro preparative HPLC-MS and freeze dried from water/t-BuOH wave reactor for 5 min at 140°C. The reaction mixture was 4f1. concentrated and purified by semi-preparative HPLC-MS and freeze dried from waterft-BuOH 471. 0668 exact mass: 344.2051 g/mol 0680 exact mass: 471.2833 g/mol 0669 HPLC-MS: analytical method C 0681 HPLC-MS: analytical method A 0670 rt: 1.601 min-found mass: 345 (m/z+H) 0682 rt: 1.976 min-found mass: 472 (m/z+H) Example #121 Example #124 Preparation of 5-(2,5-dimethoxyphenyl)-N-(3,4- Preparation of N-(3,4-dimethoxyphenyl)-5-(imidazo dimethoxyphenyl)-1H-pyrazolo 4.3-dipyrimidin-7- 1.2-alpyridin-2-yl)-1H-pyrazolo 4.3-dpyrimidin-7- amine amine 0671 7-chloro-5-(2,5-dimethoxyphenyl)-2-(4-methoxy 0683) 7-chloro-5-(imidazo[1,2-alpyridin-2-yl)-2-(4- benzyl)-2H-pyrazolo 4.3-dpyrimidine (0.16 mmol) and 3,4- methoxybenzyl)-2H-pyrazolo 4,3-dipyrimidine (0.16 dimethoxyaniline (0.3 mmol 2 eq.) were suspended in MeOH mmol) and 3,4-dimethoxyaniline (0.3 mmol 2 eq.) were Sus (dry, 3 mL) in a microwave vial (2-5 mL), HCl in dioxane pended in MeOH (dry, 3 mL) in a microwave vial (2-5 mL), (4M, 3 drops) was added. The reaction mixture was irradiated HCl in dioxane (4M, 3 drops) was added. The reaction mix in a microwave reactor for 5 min at 140° C. The reaction ture was irradiated in a microwave reactor for 5 minat 140°C. mixture was evaporated and used without further purification. The reaction mixture was evaporated and used without fur The residue was dissolved in TFA (3 mL). The reaction mix ther purification. The residue was dissolved in TFA (3 mL). ture was irradiated in a microwave reactor for 5 minat 140°C. The reaction mixture was irradiated in a microwave reactor The reaction mixture was concentrated and purified by semi for 5 min at 140°C. The reaction mixture was concentrated preparative HPLC-MS and freeze dried from water/t-BuOH and purified by semi-preparative HPLC-MS and freeze dried 4f1. from waterft-BuOH 4/1. 0672 exact mass: 407.1896 g/mol 0684 exact mass: 387.1664 g/mol 0673 HPLC-MS: analytical method A 0685 HPLC-MS: analytical method A 0674 rt: 2.363 min-found mass: 408 (m/z+H) 0686 rt: 1.962 min-found mass: 388 (m/z+H) Example #122 Example #125 Preparation of 5-(2,5-dimethoxyphenyl)-N-(4-(4- Preparation of N-(4-(4-ethylpiperazin-1-yl)phenyl)- ethylpiperazin-1-yl)phenyl)-1H-pyrazolo 4.3-dpyri 5-(imidazo 1,2-alpyridin-2-yl)-1H-pyrazolo 4,3-d midin-7-amine pyrimidin-7-amine 0675) 7-chloro-5-(2,5-dimethoxyphenyl)-2-(4-methoxy 0687 7-chloro-5-(imidazo[1,2-alpyridin-2-yl)-2-(4- benzyl)-2H-pyrazolo 4.3-dpyrimidine (0.16 mmol) and methoxybenzyl)-2H-pyrazolo 4,3-dipyrimidine (0.16 4-(4-ethylpiperazin-1-yl)aniline (0.3 mmol 2 eq.) were sus mmol) and 4-(4-ethylpiperazin-1-yl)aniline (0.3 mmol 2 eq.) pended in MeOH (dry, 3 mL) in a microwave vial (2-5 mL), were suspended in MeOH (dry, 3 mL) in a microwave vial HCl in dioxane (4M, 3 drops) was added. The reaction mix (2-5 mL), HCl in dioxane (4M, 3 drops) was added. The ture was irradiated in a microwave reactor for 5 minat 140°C. reaction mixture was irradiated in a microwave reactor for 5 The reaction mixture was evaporated and used without fur min at 140°C. The reaction mixture was evaporated and used ther purification. The residue was dissolved in TFA (3 mL). without further purification. The residue was dissolved in The reaction mixture was irradiated in a microwave reactor TFA (3 mL). The reaction mixture was irradiated in a micro for 5 min at 140°C. The reaction mixture was concentrated wave reactor for 5 min at 140°C. The reaction mixture was and purified by semi-preparative HPLC-MS and freeze dried concentrated and purified by semi-preparative HPLC-MS from waterft-BuOH 4/1. and freeze dried from waterft-BuOH 471. US 2012/032978.0 A1 Dec. 27, 2012 63

0688 exact mass: 439.2607 g/mol (0700 exact mass: 371.1269 g/mol 0689 HPLC-MS: analytical method C (0701 HPLC-MS: analytical method C (0690 rt: 1.787 min-found mass: 440 (m/z+H) (0702 rt: 2.104 min-found mass: 372 (m/z+H) Example #126 Example #129 Preparation of 5-(imidazo 1,2-alpyridin-2-yl)-N- Preparation of 5-(1H-benzodimidazol-2-yl)-N-(3,4- (1H-indazol-5-yl)-1H-pyrazolo4.3-dpyrimidin-7- dimethoxyphenyl)-1H-pyrazolo 4,3-dipyrimidin-7- amine amine 0691) 7-chloro-5-(imidazo[1,2-alpyridin-2-yl)-2-(4- 0703 5-(1H-benzodimidazol-2-yl)-7-chloro-2-(4- methoxybenzyl)-2H-pyrazolo 4,3-dipyrimidine (0.16 methoxybenzyl)-2H-pyrazolo 4,3-dipyrimidine (0.16 mmol) and 1H-indazol-5-amine (0.3 mmol 2 eq.) were sus mmol) and 3,4-dimethoxyaniline (0.3 mmol 2 eq.) were Sus pended in MeOH (dry, 3 mL) in a microwave vial (2-5 mL), pended in MeOH (dry, 3 mL) in a microwave vial (2-5 mL), HCl in dioxane (4M, 3 drops) was added. The reaction mix HCl in dioxane (4M, 3 drops) was added. The reaction mix ture was irradiated in a microwave reactor for 5 minat 140°C. ture was irradiated in a microwave reactor for 5 minat 140°C. The reaction mixture was evaporated and used without fur The reaction mixture was evaporated and used without fur ther purification. The residue was dissolved in TFA (3 mL). ther purification. The residue was dissolved in TFA (3 mL). The reaction mixture was irradiated in a microwave reactor The reaction mixture was irradiated in a microwave reactor for 5 min at 140°C. The reaction mixture was concentrated for 5 min at 140°C. The reaction mixture was concentrated and purified by semi-preparative HPLC-MS and freeze dried and purified by semi-preparative HPLC-MS and freeze dried from waterft-BuOH 4/1. from waterft-BuOH 4/1. (0692 exact mass: 367.1431 g/mol (0704) exact mass: 387.1664 g/mol (0693 HPLC-MS: analytical method A (0705 HPLC-MS: analytical method A (0694 rt: 1.835 min-found mass: 368 (m/z+H) (0706 rt: 2.255 min-found mass: 388 (m/z+H) Example #127 Example #130 Preparation of 5-(imidazo 1,2-alpyridin-2-yl)-N- Preparation of N-(3,4-dimethoxyphenyl)-5-(1-me (1H-indazol-6-yl)-1H-pyrazolo 4,3-dipyrimidin-7- thyl-1H-benzodimidazol-2-yl)-1H-pyrazolo 4.3-d amine pyrimidin-7-amine 0695) 7-chloro-5-(imidazo[1,2-alpyridin-2-yl)-2-(4- 0707 7-chloro-2-(4-methoxybenzyl)-5-(1-methyl-1H methoxybenzyl)-2H-pyrazolo 4,3-dipyrimidine (0.16 benzodimidazol-2-yl)-2H-pyrazolo 4,3-dipyrimidine mmol) and 1H-indazol-6-amine (0.3 mmol 2 eq.) were sus (0.16 mmol) and 3,4-dimethoxyaniline (0.3 mmol 2 eq.) were pended in MeOH (dry, 3 mL) in a microwave vial (2-5 mL), suspended in MeCH (dry, 3 mL) in a microwave vial (2-5 HCl in dioxane (4M, 3 drops) was added. The reaction mix mL), HCl in dioxane (4M, 3 drops) was added. The reaction ture was irradiated in a microwave reactor for 5 minat 140°C. mixture was irradiated in a microwave reactor for 5 min at The reaction mixture was evaporated and used without fur 140°C. The reaction mixture was evaporated and used with ther purification. The residue was dissolved in TFA (3 mL). out further purification. The residue was dissolved in TFA (3 The reaction mixture was irradiated in a microwave reactor mL). The reaction mixture was irradiated in a microwave for 5 min at 140°C. The reaction mixture was concentrated reactor for 5 min at 140°C. The reaction mixture was con and purified by semi-preparative HPLC-MS and freeze dried centrated and purified by semi-preparative HPLC-MS and from waterft-BuOH 4/1. freeze dried from waterft-BuOH 4/1. (0696 exact mass: 367.1431 g/mol (0708 exact mass: 401.1859 g/mol (0697. HPLC-MS: analytical method A (0709 HPLC-MS: analytical method A (0698 rt: 1.900 min-found mass: 368 (m/z+H) 0710 rt: 2.267 min-found mass: 402 (m/z+H) Example #128 Example #131 Preparation of 4-((5-(imidazo 1,2-alpyridin-2-yl)- Preparation of 5-(3-methoxyphenyl)-N-(4-(4-meth 1H-pyrazolo 4,3-dipyrimidin-7-yl)amino)benzoic ylpiperazin-1-yl)methyl)phenyl)-1H-pyrazolo 4,3-d acid pyrimidin-7-amine 0699) 7-chloro-5-(imidazo[1,2-alpyridin-2-yl)-2-(4- 0711 7-chloro-2-(4-methoxybenzyl)-5-(3-methoxyphe methoxybenzyl)-2H-pyrazolo 4,3-dipyrimidine (0.16 nyl)-2H-pyrazolo4.3-dpyrimidine (0.16 mmol) and mmol) and 4-aminobenzoic-acid (0.3 mmol 2 eq.) were sus 4-Amino-phenyl)-(4-methyl-piperazin-1-yl)-methanone pended in MeOH (dry, 3 mL) in a microwave vial (2-5 mL), (0.3 mmol 2 eq.) were suspended in MeOH (dry, 3 mL) in a HCl in dioxane (4M, 3 drops) was added. The reaction mix microwave vial (2-5 mL), HCl in dioxane (4M, 3 drops) was ture was irradiated in a microwave reactor for 5 minat 140°C. added. The reaction mixture was irradiated in a microwave The reaction mixture was evaporated and used without fur reactor for 5 min at 140°C. The reaction mixture was evapo ther purification. The residue was dissolved in TFA (3 mL). rated and used without further purification. The residue was The reaction mixture was irradiated in a microwave reactor dissolved in TFA (3 mL). The reaction mixture was irradiated for 5 min at 140°C. The reaction mixture was concentrated in a microwave reactor for 5 min at 140° C. The reaction and purified by semi-preparative HPLC-MS and freeze dried mixture was concentrated and dissolved in THF (dry) LiAlH4 from waterft-BuOH 4/1. powder was added (excess, 2 by 2 eq) until completion of US 2012/032978.0 A1 Dec. 27, 2012 64 reaction is observed (by LCMS). The reaction was quenched Example #134 with water (1 mL per gram LiAlH4), then NaOH (ca. 15% aq. 1 mL per g LiAlH4), water (3 mL per gram LiAlH4). The Preparation of (4-methylpiperazin-1-yl)(4-((5- mixture was filtered, washed with THF, MeOH, MeCN (ca. (thiophen-2-yl)-1H-pyrazolo 4.3-dpyrimidin-7-yl) 10 mL each). The reaction mixture was concentrated and amino)phenyl)methanone purified by semi-preparative HPLC-MS and freeze dried 0723) 7-chloro-2-(4-methoxybenzyl)-5-(thiophen-2-yl)- from waterft-BuOH 4/1. 2H-pyrazolo 4,3-dipyrimidine (0.16 mmol) and (4-ami 0712 exact mass: 429.27 g/mol nophenyl)(4-methylpiperazin-1-yl)methanone (0.3 mmol 2 0713 HPLC-MS: analytical method A eq.) were suspended in MeCH (dry, 3 mL) in a microwave vial (2-5 mL), HCl in dioxane (4M, 3 drops) was added. The 0714 rt: 2.239 min-found mass: 430 (m/z+H) reaction mixture was irradiated in a microwave reactor for 5 min at 140°C. The reaction mixture was evaporated and used Example #132 without further purification. The residue was dissolved in TFA (3 mL). The reaction mixture was irradiated in a micro Preparation of 5-(3-methoxyphenyl)-N-(4-(pyrroli wave reactor for 5 min at 140°C. The reaction mixture was din-1-ylmethyl)phenyl)-1H-pyrazolo 4,3-dipyrimi concentrated and purified by semi-preparative HPLC-MS din-7-amine and freeze dried from waterft-BuOH 471. 0724 exact mass: 419.1830 g/mol 0715 7-chloro-2-(4-methoxybenzyl)-5-(3-methoxyphe 0725 HPLC-MS: analytical method C nyl)-2H-pyrazolo 4,3-dipyrimidine (0.16 mmol) and 0726 rt: 1.97 min-found mass: 420 (m/z+H) (4-Amino-phenyl)-pyrrolidin-1-yl-methanone (0.3 mmol 2 eq.) were suspended in MeCH (dry, 3 mL) in a microwave Example #135 vial (2-5 mL), HCl in dioxane (4M, 3 drops) was added. The reaction mixture was irradiated in a microwave reactor for 5 Preparation of pyrrolidin-1-yl(4-((5-(thiophen-2-yl)- min at 140°C. The reaction mixture was evaporated and used 1H-pyrazolo 4,3-dipyrimidin-7-yl)amino)phenyl) without further purification. The residue was dissolved in methanone TFA (3 mL). The reaction mixture was irradiated in a micro wave reactor for 5 min at 140°C. The reaction mixture was 0727 7-chloro-2-(4-methoxybenzyl)-5-(thiophen-2-yl)- concentrated and dissolved in THF (dry) LiAlH4 powder was 2H-pyrazolo 4,3-dipyrimidine (0.16 mmol) and (4-ami added (excess, 2 by 2 eq) until completion of reaction is nophenyl)(pyrrolidin-1-yl)methanone (0.3 mmol 2 eq.) were observed (by LCMS). The reaction was quenched with water suspended in MeCH (dry, 3 mL) in a microwave vial (2-5 (1 mL per gram LiAlH4), then NaOH (ca. 15% aq., 1 mL per mL), HCl in dioxane (4M, 3 drops) was added. The reaction g LiAlH4), water (3 mL per gram LiAlH4). The mixture was mixture was irradiated in a microwave reactor for 5 min at filtered, washed with THF, MeOH, MeCN (ca. 10 mL each). 140°C. The reaction mixture was evaporated and used with The reaction mixture was concentrated and purified by semi out further purification. The residue was dissolved in TFA (3 preparative HPLC-MS and freeze dried from water/t-BuOH mL). The reaction mixture was irradiated in a microwave 4f1. reactor for 5 min at 140°C. The reaction mixture was con centrated and purified by semi-preparative HPLC-MS and 0716) exact mass: 400.238 g/mol freeze dried from waterft-BuOH 4/1. 0717 HPLC-MS: analytical method A 0728 exact mass: 390.1510 g/mol 0718 rt: 2.021 min-found mass: 401 (m/z+H) 0729 HPLC-MS: analytical method J (0730 rt: 5.14 min-found mass: 391 (m/z+H) Example #133 Example #136 Preparation of 1-(4-((5-(thiophen-3-yl)-1H-pyrazolo Preparation of N-(4-thiomorpholinophenyl)-5- 4,3-dipyrimidin-7-yl)amino)phenyl)-3-(m-tolyl)urea (thiophen-2-yl)-1H-pyrazolo 4,3-dipyrimidin-7- amine 0719 7-chloro-2-(4-methoxybenzyl)-5-(thiophen-3-yl)- 2H-pyrazolo4.3-dpyrimidine (0.16 mmol) and 1-(4-ami 0731 7-chloro-2-(4-methoxybenzyl)-5-(thiophen-2-yl)- nophenyl)-3-(m-tolyl)urea (0.3 mmol 2 eq.) were suspended 2H-pyrazolo 4,3-dipyrimidine (0.16 mmol) and 4-thiomor in MeCH (dry, 3 mL) in a microwave vial (2-5 mL), HCl in pholinoaniline (0.3 mmol 2 eq.) were suspended in MeCH dioxane (4M, 3 drops) was added. The reaction mixture was (dry, 3 mL) in a microwave vial (2-5 mL), HCl in dioxane irradiated in a microwave reactor for 5 min at 140°C. The (4M, 3 drops) was added. The reaction mixture was irradiated reaction mixture was evaporated and used without further in a microwave reactor for 5 min at 140° C. The reaction purification. The residue was dissolved in TFA (3 mL). The mixture was evaporated and used without further purification. reaction mixture was irradiated in a microwave reactor for 5 The residue was dissolved in TFA (3 mL). The reaction mix min at 140° C. The reaction mixture was concentrated and ture was irradiated in a microwave reactor for 5 minat 140°C. purified by semi-preparative HPLC-MS and freeze dried The reaction mixture was concentrated and purified by semi from waterft-BuOH 4/1. preparative HPLC-MS and freeze dried from water/t-BuOH 4f1. 0720 exact mass: 441.1620 g/mol (0732 exact mass: 394.1286 g/mol 0721 HPLC-MS: analytical method C (0733 HPLC-MS: analytical method C 0722 rt: 2.74 min-found mass: 442 (m/z+H) (0734 rt: 2.81 min-found mass: 395 (m/z+H) US 2012/032978.0 A1 Dec. 27, 2012 65

Example #137 Example #140 Preparation of 4-(4-((5-(thiophen-2-yl)-1H-pyrazolo Preparation of 5-(1H-imidazol-5-yl)-N-(4-(4-meth 4,3-dipyrimidin-7-yl)amino)phenyl)thiomorpholine ylpiperazin-1-yl)phenyl)-1H-pyrazolo 4.3-dipyrimi 1,1-dioxide din-7-amine 0735) 7-chloro-2-(4-methoxybenzyl)-5-(thiophen-2-yl)- 0747 7-chloro-5-(1H-imidazol-5-yl)-2-(4-methoxyben 2H-pyrazolo4.3-dpyrimidine (0.16 mmol) and 4-(4-ami Zyl)-2H-pyrazolo 4,3-dipyrimidine (0.16 mmol) and 4-(4- nophenyl)thiomorpholine 1,1-dioxide (0.3 mmol 2 eq.) were methylpiperazin-1-yl)aniline (0.3 mmol 2 eq.) were Sus suspended in MeCH (dry, 3 mL) in a microwave vial (2-5 pended in MeOH (dry, 3 mL) in a microwave vial (2-5 mL), mL), HCl in dioxane (4M, 3 drops) was added. The reaction HCl in dioxane (4M, 3 drops) was added. The reaction mix mixture was irradiated in a microwave reactor for 5 min at ture was irradiated in a microwave reactor for 5 minat 140°C. 140°C. The reaction mixture was evaporated and used with The reaction mixture was evaporated and used without fur out further purification. The residue was dissolved in TFA (3 ther purification. The residue was dissolved in TFA (3 mL). mL). The reaction mixture was irradiated in a microwave The reaction mixture was irradiated in a microwave reactor reactor for 5 min at 140°C. The reaction mixture was con for 5 min at 140°C. The reaction mixture was concentrated centrated and purified by semi-preparative HPLC-MS and and purified by semi-preparative HPLC-MS and freeze dried freeze dried from waterft-BuOH 4/1. from waterft-BuOH 4/1. 0736 exact mass: 426.1174 g/mol 0748 exact mass: 375.2231 g/mol (0737. HPLC-MS: analytical method A 0749 HPLC-MS: analytical method A (0738 rt: 2.32 min-found mass: 427 (m/z+H) (0750 rt: 0.47 min-found mass: 376 (m/z+H) Example #138 Example #141 Preparation of 1-(4-(4-((5-(thiophen-2-yl)-1H-pyra Preparation of 5-(1H-imidazol-2-yl)-N-(4-(4-meth Zolo 4,3-dipyrimidin-7-yl)amino)phenyl)piperazin ylpiperazin-1-yl)phenyl)-1H-pyrazolo 4.3-dipyrimi 1-yl)ethan-1-one din-7-amine 0739 7-chloro-2-(4-methoxybenzyl)-5-(thiophen-2-yl)- 0751) 7-chloro-5-(1H-imidazol-2-yl)-2-(4-methoxyben 2H-pyrazolo 4,3-dipyrimidine (0.16 mmol) and 1-(4-(4-ami Zyl)-2H-pyrazolo 4,3-dipyrimidine (0.16 mmol) and 4-(4- nophenyl)piperazin-1-yl)ethan-1-one (0.3 mmol 2 eq.) were methylpiperazin-1-yl)aniline (0.3 mmol 2 eq.) were Sus suspended in MeCH (dry, 3 mL) in a microwave vial (2-5 pended in MeOH (dry, 3 mL) in a microwave vial (2-5 mL), mL), HCl in dioxane (4M, 3 drops) was added. The reaction HCl in dioxane (4M, 3 drops) was added. The reaction mix mixture was irradiated in a microwave reactor for 5 min at ture was irradiated in a microwave reactor for 5 minat 140°C. 140°C. The reaction mixture was evaporated and used with The reaction mixture was evaporated and used without fur out further purification. The residue was dissolved in TFA (3 ther purification. The residue was dissolved in TFA (3 mL). mL). The reaction mixture was irradiated in a microwave The reaction mixture was irradiated in a microwave reactor reactor for 5 min at 140°C. The reaction mixture was con for 5 min at 140°C. The reaction mixture was concentrated centrated and purified by semi-preparative HPLC-MS and and purified by semi-preparative HPLC-MS and freeze dried freeze dried from waterft-BuOH 4/1. from waterft-BuOH 4/1. 0740 exact mass: 419.1830 g/mol (0752 exact mass: 375.2231 g/mol 0741 HPLC-MS: analytical method J (0753 HPLC-MS: analytical method A 0742 rt: 4.21 min-found mass: 420 (m/z+H) (0754) rt: 0.41 min-found mass: 376 (m/z+H) Example #139 Example #142 Preparation of (3-methoxy-4-((5-(thiophen-2-yl)-1H Preparation of pyrrolidin-1-yl(4-((5-(thiophen-3-yl)- pyrazolo 4.3-dipyrimidin-7-yl)amino)phenyl)(4-(4- 1H-pyrazolo 4,3-dipyrimidin-7-yl)amino)phenyl) methylpiperazin-1-yl)piperidin-1-yl)methanone methanone 0743) 7-chloro-2-(4-methoxybenzyl)-5-(thiophen-2-yl)- 0755) 7-chloro-2-(4-methoxybenzyl)-5-(thiophen-3-yl)- 2H-pyrazolo4.3-dpyrimidine (0.16 mmol) and (4-amino-3- 2H-pyrazolo 4,3-dipyrimidine (0.16 mmol) and (4-ami methoxyphenyl)(4-(4-methylpiperazin-1-yl)piperidin-1-yl) nophenyl)(pyrrolidin-1-yl)methanone (0.3 mmol 2 eq.) were methanone (0.3 mmol 2 eq.) were suspended in MeCH (dry, suspended in MeCH (dry, 3 mL) in a microwave vial (2-5 3 mL) in a microwave vial (2-5 mL), HCl in dioxane (4M, 3 mL), HCl in dioxane (4M, 3 drops) was added. The reaction drops) was added. The reaction mixture was irradiated in a mixture was irradiated in a microwave reactor for 5 min at microwave reactor for 5 min at 140°C. The reaction mixture 140°C. The reaction mixture was evaporated and used with was evaporated and used without further purification. The out further purification. The residue was dissolved in TFA (3 residue was dissolved in TFA (3 mL). The reaction mixture mL). The reaction mixture was irradiated in a microwave was irradiated in a microwave reactor for 5 minat 140°C. The reactor for 5 min at 140°C. The reaction mixture was con reaction mixture was concentrated and purified by semi-pre centrated and purified by semi-preparative HPLC-MS and parative HPLC-MS and freeze dried from water/t-BuOH4/1. freeze dried from waterft-BuOH 4/1. 0744 exact mass: 532.2869 g/mol (0756 exact mass: 390.1510 g/mol 0745 HPLC-MS: analytical method A (0757. HPLC-MS: analytical method A 0746 rt: 1.91 min-found mass: 533 (m/z+H) (0758 rt: 2.40 min-found mass: 391 (m/z+H) US 2012/032978.0 A1 Dec. 27, 2012 66

Example #143 Example #146 Preparation of 4-(4-((5-(thiophen-3-yl)-1H-pyrazolo Preparation of 6-((5-(thiophen-3-yl)-1H-pyrazolo4. 4,3-dipyrimidin-7-yl)amino)phenyl)thiomorpholine 3-dipyrimidin-7-yl)amino)-2H-benzob 14oxazin 1,1-dioxide 3(4H)-one 0759 7-chloro-2-(4-methoxybenzyl)-5-(thiophen-3-yl)- 0771) 7-chloro-2-(4-methoxybenzyl)-5-(thiophen-3-yl)- 2H-pyrazolo4.3-dpyrimidine (0.16 mmol) and 4-(4-ami 2H-pyrazolo 4,3-dipyrimidine (0.16 mmol) and 6-amino nophenyl)thiomorpholine 1,1-dioxide (0.3 mmol 2 eq.) were 2H-benzob 14oxazin-3 (4H)-one (0.3 mmol 2 eq.) were suspended in MeCH (dry, 3 mL) in a microwave vial (2-5 suspended in MeCH (dry, 3 mL) in a microwave vial (2-5 mL), HCl in dioxane (4M, 3 drops) was added. The reaction mL), HCl in dioxane (4M, 3 drops) was added. The reaction mixture was irradiated in a microwave reactor for 5 min at mixture was irradiated in a microwave reactor for 5 min at 140°C. The reaction mixture was evaporated and used with 140°C. The reaction mixture was evaporated and used with out further purification. The residue was dissolved in TFA (3 out further purification. The residue was dissolved in TFA (3 mL). The reaction mixture was irradiated in a microwave mL). The reaction mixture was irradiated in a microwave reactor for 5 min at 140°C. The reaction mixture was con reactor for 5 min at 140°C. The reaction mixture was con centrated and purified by semi-preparative HPLC-MS and centrated and purified by semi-preparative HPLC-MS and freeze dried from waterft-BuOH 4/1. freeze dried from waterft-BuOH 4/1. 0760 exact mass: 426.1174 g/mol (0772 exact mass: 364,0869 g/mol 0761 HPLC-MS: analytical method A (0773 HPLC-MS: analytical method A 0762 rt: 2.14 min-found mass: 427 (m/z+H) (0774 rt: 2.17 min-found mass: 365 (m/z+H) Example #144 Example #147 Preparation of 1-(4-(4-((5-(thiophen-3-yl)-1H-pyra Preparation of (4-methylpiperazin-1-yl)(4-((5- Zolo 4,3-dipyrimidin-7-yl)amino)phenyl)piperazin (thiophen-3-yl)-1H-pyrazolo 4.3-dpyrimidin-7-yl) 1-yl)ethan-1-one amino)phenyl)methanone 0763) 7-chloro-2-(4-methoxybenzyl)-5-(thiophen-3-yl)- 0775) 7-chloro-2-(4-methoxybenzyl)-5-(thiophen-3-yl)- 2H-pyrazolo 4,3-dipyrimidine (0.16 mmol) and 1-(4-(4-ami 2H-pyrazolo 4,3-dipyrimidine (0.16 mmol) and (4-ami nophenyl)piperazin-1-yl)ethan-1-one (0.3 mmol 2 eq.) were nophenyl)(4-methylpiperazin-1-yl)methanone (0.3 mmol 2 suspended in MeCH (dry, 3 mL) in a microwave vial (2-5 eq.) were suspended in MeCH (dry, 3 mL) in a microwave mL), HCl in dioxane (4M, 3 drops) was added. The reaction vial (2-5 mL), HCl in dioxane (4M, 3 drops) was added. The mixture was irradiated in a microwave reactor for 5 min at reaction mixture was irradiated in a microwave reactor for 5 140°C. The reaction mixture was evaporated and used with min at 140°C. The reaction mixture was evaporated and used out further purification. The residue was dissolved in TFA (3 without further purification. The residue was dissolved in mL). The reaction mixture was irradiated in a microwave TFA (3 mL). The reaction mixture was irradiated in a micro reactor for 5 min at 140°C. The reaction mixture was con wave reactor for 5 min at 140°C. The reaction mixture was centrated and purified by semi-preparative HPLC-MS and concentrated and purified by semi-preparative HPLC-MS freeze dried from waterft-BuOH 4/1. and freeze dried from waterft-BuOH 471. 0764 exact mass: 419.1830 g/mol (0776 exact mass: 419.1830 g/mol 0765 HPLC-MS: analytical method A (0777. HPLC-MS: analytical method A 0766 rt: 2.11 min-found mass: 420 (m/z+H) (0778 rt: 0.29 min-found mass: 420 (m/z+H) Example #145 Example #148 Preparation of N-(4-thiomorpholinophenyl)-5- Preparation of 2,2-dimethyl-N-(5-(thiophen-3-yl)- (thiophen-3-yl)-1H-pyrazolo 4,3-dipyrimidin-7- 1H-pyrazolo 4,3-dipyrimidin-7-yl)-3,4-dihydro-2H amine benzob 14thiazin-6-amine 0767 7-chloro-2-(4-methoxybenzyl)-5-(thiophen-3-yl)- 0779) 7-chloro-2-(4-methoxybenzyl)-5-(thiophen-3-yl)- 2H-pyrazolo4.3-dpyrimidine (0.16 mmol) and 4-thiomor 2H-pyrazolo 4,3-dipyrimidine (0.16 mmol) and 2,2-dim pholinoaniline (0.3 mmol 2 eq.) were suspended in MeOH ethyl-3,4-dihydro-2H-benzob 14thiazin-6-amine (0.3 (dry, 3 mL) in a microwave vial (2-5 mL), HCl in dioxane mmol 2 eq.) were suspended in MeOH (dry, 3 mL) in a (4M, 3 drops) was added. The reaction mixture was irradiated microwave vial (2-5 mL), HCl in dioxane (4M, 3 drops) was in a microwave reactor for 5 min at 140° C. The reaction added. The reaction mixture was irradiated in a microwave mixture was evaporated and used without further purification. reactor for 5 min at 140°C. The reaction mixture was evapo The residue was dissolved in TFA (3 mL). The reaction mix rated and used without further purification. The residue was ture was irradiated in a microwave reactor for 5 minat 140°C. dissolved in TFA (3 mL). The reaction mixture was irradiated The reaction mixture was concentrated and purified by semi in a microwave reactor for 5 min at 140° C. The reaction preparative HPLC-MS and freeze dried from water/t-BuOH mixture was concentrated and purified by semi-preparative 4f1. HPLC-MS and freeze dried from waterft-BuOH 4/1. 0768 exact mass: 394.1286 g/mol 0780 exact mass: 394.1286 g/mol 0769 HPLC-MS: analytical method A 0781 HPLC-MS: analytical method C (0770 rt: 2.50 min-found mass: 395 (m/z+H) 0782 rt: 2.95 min-found mass: 395 (m/z+H) US 2012/032978.0 A1 Dec. 27, 2012 67

Example #149 Example #152 Preparation of 5-(3-(2H-tetrazol-5-yl)phenyl)-N-(4- Preparation of (7-((4-(4-methylpiperazin-1-yl)phe (4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo 4,3-d nyl)amino)-1H-pyrazolo 4.3-dpyrimidin-5-yl)(phe pyrimidin-7-amine nyl)methanone 0783 5-(3-(2H-tetrazol-5-yl)phenyl)-7-chloro-2-(4- 0795 (7-chloro-2-(4-methoxybenzyl)-2H-pyrazolo 4,3- methoxybenzyl)-2H-pyrazolo 4,3-dipyrimidine (0.16 dpyrimidin-5-yl)(phenyl)methanone (0.16 mmol) and 4-(4- mmol) and 4-(4-methylpiperazin-1-yl)aniline (0.3 mmol 2 methylpiperazin-1-yl)aniline (0.3 mmol 2 eq.) were Sus eq.) were suspended in MeCH (dry, 3 mL) in a microwave pended in MeOH (dry, 3 mL) in a microwave vial (2-5 mL), vial (2-5 mL), HCl in dioxane (4M, 3 drops) was added. The HCl in dioxane (4M, 3 drops) was added. The reaction mix reaction mixture was irradiated in a microwave reactor for 5 ture was irradiated in a microwave reactor for 5 minat 140°C. min at 140°C. The reaction mixture was evaporated and used The reaction mixture was evaporated and used without fur without further purification. The residue was dissolved in ther purification. The residue was dissolved in TFA (3 mL). TFA (3 mL). The reaction mixture was irradiated in a micro The reaction mixture was irradiated in a microwave reactor wave reactor for 5 min at 140°C. The reaction mixture was for 5 min at 140°C. The reaction mixture was concentrated concentrated and purified by semi-preparative HPLC-MS and purified by semi-preparative HPLC-MS and freeze dried and freeze dried from waterft-BuOH 471. from waterft-BuOH 4/1. 0784 exact mass: 453.2462 g/mol 0796 exact mass: 413.2305 g/mol 0785 HPLC-MS: analytical method L 0797. HPLC-MS: analytical method L 0786 rt: 3.29 min-found mass: 454 (m/z+H) 0798 rt: 3.50 min-found mass: 414 (m/z+H) Example #150 Example #153 Preparation of (7-((2-(dimethylamino)ethyl)amino)- Preparation of (7-((3,4-dimethoxyphenyl)amino)- 1H-pyrazolo 4,3-dipyrimidin-5-yl)(phenyl)metha 1H-pyrazolo 4,3-dipyrimidin-5-yl)(phenyl)metha O O 0787 (7-chloro-2-(4-methoxybenzyl)-2H-pyrazolo 4,3- 0799 (7-chloro-2-(4-methoxybenzyl)-2H-pyrazolo 4,3- dpyrimidin-5-yl)(phenyl)methanone (0.16 mmol) and dpyrimidin-5-yl)(phenyl)methanone (0.16 mmol) and 3,4- N1,N1-dimethylethane-1,2-diamine (0.3 mmol 2 eq.) were dimethoxyaniline (0.3 mmol 2 eq.) were suspended in MeCH suspended in MeCH (dry, 3 mL) in a microwave vial (2-5 (dry, 3 mL) in a microwave vial (2-5 mL), HCl in dioxane mL), HCl in dioxane (4M, 3 drops) was added. The reaction (4M, 3 drops) was added. The reaction mixture was irradiated mixture was irradiated in a microwave reactor for 5 min at in a microwave reactor for 5 min at 140° C. The reaction 140°C. The reaction mixture was evaporated and used with mixture was evaporated and used without further purification. out further purification. The residue was dissolved in TFA (3 The residue was dissolved in TFA (3 mL). The reaction mix mL). The reaction mixture was irradiated in a microwave ture was irradiated in a microwave reactor for 5 minat 140°C. reactor for 5 min at 140°C. The reaction mixture was con The reaction mixture was concentrated and purified by semi centrated and purified by semi-preparative HPLC-MS and preparative HPLC-MS and freeze dried from water/t-BuOH freeze dried from waterft-BuOH 4/1. 4f1. 0788 exact mass: 310.1815 g/mol (0800 exact mass: 375.1558 g/mol 0789 HPLC-MS: analytical method L (0801 HPLC-MS: analytical method L 0790 rt: 3.17 min-found mass: 311 (m/z+H) 0802 rt: 4.51 min-found mass: 376 (m/z+H) Example #151 Example #154 Preparation of (7-(((1-methylpiperidin-4-yl)methyl) Preparation of (4-((5-benzoyl-1H-pyrazolo 4.3-d amino)-1H-pyrazolo 4,3-dipyrimidin-5-yl)(phenyl) pyrimidin-7-yl)amino)phenyl)(pyrrolidin-1-yl) methanone methanone 0791 (7-chloro-2-(4-methoxybenzyl)-2H-pyrazolo 4,3- 0803 (7-chloro-2-(4-methoxybenzyl)-2H-pyrazolo 4,3- dpyrimidin-5-yl)(phenyl)methanone (0.16 mmol) and dpyrimidin-5-yl)(phenyl)methanone (0.16 mmol) and (1-methylpiperidin-4-yl)methanamine (0.3 mmol 2 eq.) were (4-aminophenyl)(pyrrolidin-1-yl)methanone (0.3 mmol 2 suspended in MeCH (dry, 3 mL) in a microwave vial (2-5 eq.) were suspended in MeCH (dry, 3 mL) in a microwave mL), HCl in dioxane (4M, 3 drops) was added. The reaction vial (2-5 mL), HCl in dioxane (4M, 3 drops) was added. The mixture was irradiated in a microwave reactor for 5 min at reaction mixture was irradiated in a microwave reactor for 5 140°C. The reaction mixture was evaporated and used with min at 140°C. The reaction mixture was evaporated and used out further purification. The residue was dissolved in TFA (3 without further purification. The residue was dissolved in mL). The reaction mixture was irradiated in a microwave TFA (3 mL). The reaction mixture was irradiated in a micro reactor for 5 min at 140°C. The reaction mixture was con wave reactor for 5 min at 140°C. The reaction mixture was centrated and purified by semi-preparative HPLC-MS and concentrated and purified by semi-preparative HPLC-MS freeze dried from waterft-BuOH 4/1. and freeze dried from waterft-BuOH 471. 0792 exact mass: 350.2200 g/mol 0804 exact mass: 412.1924 g/mol 0793 HPLC-MS: analytical method L (0805 HPLC-MS: analytical method L 0794 rt: 2.92 min-found mass: 351 (m/z+H) 0806 rt: 4.42 min-found mass: 413 (m/z+H) US 2012/032978.0 A1 Dec. 27, 2012 68

Example #155 0816 exact mass: 406.1454 g/mol 0817. HPLC-MS: analytical method A Preparation of 7-((5-benzoyl-1H-pyrazolo 4,3-d 0818 rt: 2.44 min-found mass: 407 (m/z+H) pyrimidin-7-yl)amino)-3,4-dihydroquinolin-2(1H)- O Example #158 0807 (7-chloro-2-(4-methoxybenzyl)-2H-pyrazolo 4,3- Preparation of 6-((5-(thiophen-3-yl)-1H-pyrazolo4. dpyrimidin-5-yl)(phenyl)methanone (0.16 mmol) and 3-dipyrimidin-7-yl)amino)-2H-benzob 14thiazin 7-amino-3,4-dihydroquinolin-2(1H)-one (0.3 mmol 2 eq.) 3(4H)-one were suspended in MeOH (dry, 3 mL) in a microwave vial (2-5 mL), HCl in dioxane (4M, 3 drops) was added. The 0819 7-chloro-2-(4-methoxybenzyl)-5-(thiophen-3-yl)- reaction mixture was irradiated in a microwave reactor for 5 2H-pyrazolo 4,3-dipyrimidine (0.16 mmol) and 6-amino min at 140°C. The reaction mixture was evaporated and used 2H-benzob 14thiazin-3 (4H)-one (0.3 mmol 2 eq.) were without further purification. The residue was dissolved in suspended in MeCH (dry, 3 mL) in a microwave vial (2-5 TFA (3 mL). The reaction mixture was irradiated in a micro mL), HCl in dioxane (4M, 3 drops) was added. The reaction wave reactor for 5 min at 140°C. The reaction mixture was mixture was irradiated in a microwave reactor for 5 min at concentrated and purified by semi-preparative HPLC-MS 140°C. The reaction mixture was evaporated and used with and freeze dried from waterft-BuOH 471. out further purification. The residue was dissolved in TFA (3 (0808 exact mass: 384.1534 g/mol mL). The reaction mixture was irradiated in a microwave reactor for 5 min at 140°C. The reaction mixture was con (0809 HPLC-MS: analytical method L centrated and purified by semi-preparative HPLC-MS and 0810 rt: 4.22 min-found mass: 385 (m/z+H) freeze dried from waterft-BuOH 4/1. Example #156 0820 exact mass: 380.0640 g/mol 0821 HPLC-MS: analytical method A Preparation of 3-(7-(4-morpholinophenyl)amino)- 0822 rt: 2.58 min-found mass: 381 (m/z+H) 1H-pyrazolo 4,3-dipyrimidin-5-yl)benzoic acid Example #159 0811 Methyl 3-(7-chloro-2-(4-methoxybenzyl)-2H pyrazolo 4,3-dipyrimidin-5-yl)benzoate (0.16 mmol) and Preparation of 7-((5-(4-methoxyphenyl)-1H-pyra 4-morpholinoaniline (0.3 mmol 2 eq.) were suspended in Zolo 4,3-dipyrimidin-7-yl)amino)-3,4-dihydroquino MeOH (dry, 3 mL) in a microwave vial (2-5 mL), HCl in lin-2(1H)-one dioxane (4M, 3 drops) was added. The reaction mixture was irradiated in a microwave reactor for 5 min at 140°C. The 0823) 7-chloro-2-(4-methoxybenzyl)-5-(4-methoxyphe reaction mixture was evaporated and used without further nyl)-2H-pyrazolo4.3-dpyrimidine (0.16 mmol) and purification. The residue was dissolved in TFA (3 mL). The 7-amino-3,4-dihydroquinolin-2(1H)-one (0.3 mmol 2 eq.) reaction mixture was irradiated in a microwave reactor for 5 were suspended in MeOH (dry, 3 mL) in a microwave vial min at 140°C. The reaction mixture was evaporated and used (2-5 mL), HCl in dioxane (4M, 3 drops) was added. The without further purification. For the saponification the residue reaction mixture was irradiated in a microwave reactor for 5 was dissolved in methanol. 2Maqueous NaOH-solution was min at 140°C. The reaction mixture was evaporated and used added to ensure basic conditions. The mixture was irradiated without further purification. The residue was dissolved in in a microwave reactor for 10 min at 120° C. The reaction TFA (3 mL). The reaction mixture was irradiated in a micro mixture was concentrated and purified by semi-preparative wave reactor for 5 min at 140°C. The reaction mixture was HPLC-MS and freeze dried from waterft-BuOH 4/1. concentrated and purified by semi-preparative HPLC-MS and freeze dried from waterft-BuOH 471. 0812 exact mass: 416.1872 g/mol 0824) exact mass: 386.1733 g/mol 0813 HPLC-MS: analytical method A 0825 HPLC-MS: analytical method A 0814 rt: 2.39 min-found mass: 417 (m/z+H) 0826 rt: 2.30 min-found mass: 387 (im/z+H) Example #157 Example #160 Preparation of morpholino(4-((5-(thiophen-3-yl)-1H Preparation of (4-((5-(4-methoxyphenyl)-1H-pyra pyrazolo 4,3-dipyrimidin-7-yl)amino)phenyl)metha Zolo4.3-dpyrimidin-7-yl)amino)phenyl)(pyrrolidin O 1-yl)methanone 0815) 7-chloro-2-(4-methoxybenzyl)-5-(thiophen-3-yl)- 0827) 7-chloro-2-(4-methoxybenzyl)-5-(4-methoxyphe 2H-pyrazolo4.3-dpyrimidine (0.16 mmol) and (4-ami nyl)-2H-pyrazolo4.3-dpyrimidine (0.16 mmol) and (4-ami nophenyl)(morpholino)methanone (0.3 mmol 2 eq.) were nophenyl)(pyrrolidin-1-yl)methanone (0.3 mmol 2 eq.) were suspended in MeCH (dry, 3 mL) in a microwave vial (2-5 suspended in MeCH (dry, 3 mL) in a microwave vial (2-5 mL), HCl in dioxane (4M, 3 drops) was added. The reaction mL), HCl in dioxane (4M, 3 drops) was added. The reaction mixture was irradiated in a microwave reactor for 5 min at mixture was irradiated in a microwave reactor for 5 min at 140°C. The reaction mixture was evaporated and used with 140°C. The reaction mixture was evaporated and used with out further purification. The residue was dissolved in TFA (3 out further purification. The residue was dissolved in TFA (3 mL). The reaction mixture was irradiated in a microwave mL). The reaction mixture was irradiated in a microwave reactor for 5 min at 140°C. The reaction mixture was con reactor for 5 min at 140°C. The reaction mixture was con centrated and purified by semi-preparative HPLC-MS and centrated and purified by semi-preparative HPLC-MS and freeze dried from waterft-BuOH 4/1. freeze dried from waterft-BuOH 4/1. US 2012/032978.0 A1 Dec. 27, 2012 69

0828 exact mass: 414.2123 g/mol 0840 exact mass: 433.2476 g/mol 0829 HPLC-MS: analytical method A 0841 HPLC-MS: analytical method A 0830 rt: 2.44 min-found mass: 415 (m/z+H) 0842 rt: 1.94 min-found mass: 434 (m/z+H) Example #161 Example #164 Preparation of N-(4-(4-(tert-butyl)piperazin-1-yl) Preparation of 8-((5-(4-methoxyphenyl)-1H-pyra phenyl)-5-(thiophen-3-yl)-1H-pyrazolo 4,3-dipyri Zolo 4,3-dipyrimidin-7-yl)amino)-4,5-dihydro-1H midin-7-amine benzoblazepin-2(3H)-one 0831 7-chloro-2-(4-methoxybenzyl)-5-(thiophen-3-yl)- 0843) 7-chloro-2-(4-methoxybenzyl)-5-(4-methoxyphe 2H-pyrazolo4.3-dpyrimidine (0.16 mmol) and 4-(4-(tert nyl)-2H-pyrazolo4.3-dpyrimidine (0.16 mmol) and butyl)piperazin-1-yl)aniline (0.3 mmol 2 eq.) were sus 8-amino-4,5-dihydro-1H-benzoblazepin-2(3H)-one (0.3 pended in MeOH (dry, 3 mL) in a microwave vial (2-5 mL), mmol 2 eq.) were suspended in MeOH (dry, 3 mL) in a HCl in dioxane (4M, 3 drops) was added. The reaction mix microwave vial (2-5 mL), HCl in dioxane (4M, 3 drops) was ture was irradiated in a microwave reactor for 5 minat 140°C. added. The reaction mixture was irradiated in a microwave The reaction mixture was evaporated and used without fur reactor for 5 min at 140°C. The reaction mixture was evapo ther purification. The residue was dissolved in TFA (3 mL). rated and used without further purification. The residue was The reaction mixture was irradiated in a microwave reactor dissolved in TFA (3 mL). The reaction mixture was irradiated for 5 min at 140°C. The reaction mixture was concentrated in a microwave reactor for 5 min at 140° C. The reaction and purified by semi-preparative HPLC-MS and freeze dried mixture was concentrated and purified by semi-preparative from waterft-BuOH 4/1. HPLC-MS and freeze dried from waterft-BuOH 4/1. 0832 exact mass: 433.2476 g/mol 0844 exact mass: 400. 1928 g/mol 0833 HPLC-MS: analytical method L 0845 HPLC-MS: analytical method A 0834 rt: 3.23 min-found mass: 434 (m/z+H) 0846 rt: 2.33 min-found mass: 401 (m/z+H) Example #162 Example #165 Preparation of 6-((5-(thiophen-2-yl)-1H-pyrazolo4. Preparation of 6-((5-(thiophen-2-yl)-1H-pyrazolo4. 3-dipyrimidin-7-yl)amino)-2H-benzob 14oxazin 3-dipyrimidin-7-yl)amino)-2H-benzob 14thiazin 3(4H)-one 3(4H)-one 0835) 7-chloro-2-(4-methoxybenzyl)-5-(thiophen-2-yl)- 0847 7-chloro-2-(4-methoxybenzyl)-5-(thiophen-2-yl)- 2H-pyrazolo4.3-dpyrimidine (0.16 mmol) and 6-amino 2H-pyrazolo 4,3-dipyrimidine (0.16 mmol) and 6-amino 2H-benzob 14oxazin-3 (4H)-one (0.3 mmol 2 eq.) were 2H-benzob 14thiazin-3 (4H)-one (0.3 mmol 2 eq.) were suspended in MeCH (dry, 3 mL) in a microwave vial (2-5 suspended in MeCH (dry, 3 mL) in a microwave vial (2-5 mL), HCl in dioxane (4M, 3 drops) was added. The reaction mL), HCl in dioxane (4M, 3 drops) was added. The reaction mixture was irradiated in a microwave reactor for 5 min at mixture was irradiated in a microwave reactor for 5 min at 140°C. The reaction mixture was evaporated and used with 140°C. The reaction mixture was evaporated and used with out further purification. The residue was dissolved in TFA (3 out further purification. The residue was dissolved in TFA (3 mL). The reaction mixture was irradiated in a microwave mL). The reaction mixture was irradiated in a microwave reactor for 5 min at 140°C. The reaction mixture was con reactor for 5 min at 140°C. The reaction mixture was con centrated and purified by semi-preparative HPLC-MS and centrated and purified by semi-preparative HPLC-MS and freeze dried from waterft-BuOH 4/1. freeze dried from waterft-BuOH 4/1. 0836) exact mass: 364,0869 g/mol 0848 exact mass: 380.0640 g/mol 0837 HPLC-MS: analytical method A 0849 HPLC-MS: analytical method A 0838 rt: 2.40 min-found mass: 365 (m/z+H) 0850 rt: 2.63 min-found mass: 381 (m/z+H) Example #163 Example #166 Preparation of N-(4-(4-(tert-butyl)piperazin-1-yl) Preparation of 1-methyl-N-(5-(thiophen-2-yl)-1H phenyl)-5-(thiophen-2-yl)-1H-pyrazolo 4,3-dipyri pyrazolo 4,3-dipyrimidin-7-yl)-1,2,3,4-tetrahydro midin-7-amine quinolin-7-amine 0839 7-chloro-2-(4-methoxybenzyl)-5-(thiophen-2-yl)- 0851) 7-chloro-2-(4-methoxybenzyl)-5-(thiophen-2-yl)- 2H-pyrazolo4.3-dpyrimidine (0.16 mmol) and 4-(4-(tert 2H-pyrazolo 4,3-dipyrimidine (0.16 mmol) and 1-methyl-1, butyl)piperazin-1-yl)aniline (0.3 mmol 2 eq.) were sus 2,3,4-tetrahydroquinolin-7-amine (0.3 mmol 2 eq.) were Sus pended in MeOH (dry, 3 mL) in a microwave vial (2-5 mL), pended in MeOH (dry, 3 mL) in a microwave vial (2-5 mL), HCl in dioxane (4M, 3 drops) was added. The reaction mix HCl in dioxane (4M, 3 drops) was added. The reaction mix ture was irradiated in a microwave reactor for 5 minat 140°C. ture was irradiated in a microwave reactor for 5 minat 140°C. The reaction mixture was evaporated and used without fur The reaction mixture was evaporated and used without fur ther purification. The residue was dissolved in TFA (3 mL). ther purification. The residue was dissolved in TFA (3 mL). The reaction mixture was irradiated in a microwave reactor The reaction mixture was irradiated in a microwave reactor for 5 min at 140°C. The reaction mixture was concentrated for 5 min at 140°C. The reaction mixture was concentrated and purified by semi-preparative HPLC-MS and freeze dried and purified by semi-preparative HPLC-MS and freeze dried from waterft-BuOH 4/1. from waterft-BuOH 4/1. US 2012/032978.0 A1 Dec. 27, 2012 70

0852 exact mass: 362.1571 g/mol 0864 exact mass: 450.1787 g/mol 0853 HPLC-MS: analytical method L 0865 HPLC-MS: analytical method A 0854 rt: 4.78 min-found mass: 363 (m/z+H) 0866 rt: 2.23 min-found mass: 451 (m/z+H) Example #167 Example #170 Preparation of 2-methyl-2-(4-((5-(thiophen-2-yl)- Preparation of 1-(4-(4-((5-(4-methoxyphenyl)-1H 1H-pyrazolo 4,3-dipyrimidin-7-yl)amino)phenyl) pyrazolo 4.3-dipyrimidin-7-yl)amino)phenyl)piper propanenitrile azin-1-yl)ethan-1-one 0855) 7-chloro-2-(4-methoxybenzyl)-5-(thiophen-2-yl)- 0867 7-chloro-2-(4-methoxybenzyl)-5-(4-methoxyphe 2H-pyrazolo4.3-dpyrimidine (0.16 mmol) and 2-(4-ami nyl)-2H-pyrazolo4.3-dpyrimidine (0.16 mmol) and 1-(4- nophenyl)-2-methylpropanenitrile (0.3 mmol2 eq.) were sus (4-aminophenyl)piperazin-1-yl)ethan-1-one (0.3 mmol 2 pended in MeOH (dry, 3 mL) in a microwave vial (2-5 mL), eq.) were suspended in MeCH (dry, 3 mL) in a microwave HCl in dioxane (4M, 3 drops) was added. The reaction mix vial (2-5 mL), HCl in dioxane (4M, 3 drops) was added. The ture was irradiated in a microwave reactor for 5 minat 140°C. reaction mixture was irradiated in a microwave reactor for 5 The reaction mixture was evaporated and used without fur min at 140°C. The reaction mixture was evaporated and used ther purification. The residue was dissolved in TFA (3 mL). without further purification. The residue was dissolved in The reaction mixture was irradiated in a microwave reactor TFA (3 mL). The reaction mixture was irradiated in a micro for 5 min at 140°C. The reaction mixture was concentrated wave reactor for 5 min at 140°C. The reaction mixture was and purified by semi-preparative HPLC-MS and freeze dried concentrated and purified by semi-preparative HPLC-MS from waterft-BuOH 4/1. and freeze dried from waterft-BuOH 471. 0856 exact mass: 360.1371 g/mol 0868 exact mass: 443.2443 g/mol 0857. HPLC-MS: analytical method A 0869 HPLC-MS: analytical method A 0858 rt: 3.12 min-found mass: 361 (m/z+H) 0870 rt: 2.21 min-found mass: 444 (m/z+H) Example #168 Example #171 Preparation of 5-(4-methoxyphenyl)-N-(4-thiomor Preparation of 6-((5-(4-methoxyphenyl)-1H-pyra pholinophenyl)-1H-pyrazolo 4,3-dipyrimidin-7- Zolo 4,3-dipyrimidin-7-yl)amino)-2H-benzob 1.4 amine oxazin-3 (4H)-one 0859 7-chloro-2-(4-methoxybenzyl)-5-(4-methoxyphe 0871 7-chloro-2-(4-methoxybenzyl)-5-(4-methoxyphe nyl)-2H-pyrazolo 4,3-dipyrimidine (0.16 mmol) and 4-thio nyl)-2H-pyrazolo4.3-dpyrimidine (0.16 mmol) and morpholinoaniline (0.3 mmol 2 eq.) were suspended in 6-amino-2H-benzob 14oxazin-3 (4H)-one (0.3 mmol 2 MeOH (dry, 3 mL) in a microwave vial (2-5 mL), HCl in eq.) were suspended in MeCH (dry, 3 mL) in a microwave dioxane (4M, 3 drops) was added. The reaction mixture was vial (2-5 mL), HCl in dioxane (4M, 3 drops) was added. The irradiated in a microwave reactor for 5 min at 140°C. The reaction mixture was irradiated in a microwave reactor for 5 reaction mixture was evaporated and used without further min at 140°C. The reaction mixture was evaporated and used purification. The residue was dissolved in TFA (3 mL). The without further purification. The residue was dissolved in reaction mixture was irradiated in a microwave reactor for 5 TFA (3 mL). The reaction mixture was irradiated in a micro min at 140° C. The reaction mixture was concentrated and wave reactor for 5 min at 140°C. The reaction mixture was purified by semi-preparative HPLC-MS and freeze dried concentrated and purified by semi-preparative HPLC-MS from waterft-BuOH 4/1. and freeze dried from waterft-BuOH 471. 0860 exact mass: 418.1899 g/mol 0872 exact mass: 388.1483 g/mol 0861 HPLC-MS: analytical method A 0873. HPLC-MS: analytical method A 0862 rt: 2.57 min-found mass: 419 (m/z+H) 0874 rt: 2.26 min-found mass: 389 (m/z+H) Example #169 Example #172 Preparation of 4-(4-((5-(4-methoxyphenyl)-1H-pyra Preparation of N-(4-(4-(tert-butyl)piperazin-1-yl) Zolo4.3-dpyrimidin-7-yl)amino)phenyl)thiomor phenyl)-5-(4-methoxyphenyl)-1H-pyrazolo 4.3-d pholine 1,1-dioxide pyrimidin-7-amine 0863) 7-chloro-2-(4-methoxybenzyl)-5-(4-methoxyphe 0875) 7-chloro-2-(4-methoxybenzyl)-5-(4-methoxyphe nyl)-2H-pyrazolo 4,3-dipyrimidine (0.16 mmol) and 4-(4- nyl)-2H-pyrazolo4.3-dpyrimidine (0.16 mmol) and 4-(4- aminophenyl)thiomorpholine 1,1-dioxide (0.3 mmol 2 eq.) (tert-butyl)piperazin-1-yl)aniline (0.3 mmol 2 eq.) were sus were suspended in MeOH (dry, 3 mL) in a microwave vial pended in MeOH (dry, 3 mL) in a microwave vial (2-5 mL), (2-5 mL), HCl in dioxane (4M, 3 drops) was added. The HCl in dioxane (4M, 3 drops) was added. The reaction mix reaction mixture was irradiated in a microwave reactor for 5 ture was irradiated in a microwave reactor for 5 minat 140°C. min at 140°C. The reaction mixture was evaporated and used The reaction mixture was evaporated and used without fur without further purification. The residue was dissolved in ther purification. The residue was dissolved in TFA (3 mL). TFA (3 mL). The reaction mixture was irradiated in a micro The reaction mixture was irradiated in a microwave reactor wave reactor for 5 min at 140°C. The reaction mixture was for 5 min at 140°C. The reaction mixture was concentrated concentrated and purified by semi-preparative HPLC-MS and purified by semi-preparative HPLC-MS and freeze dried and freeze dried from waterft-BuOH 471. from waterft-BuOH 4/1. US 2012/032978.0 A1 Dec. 27, 2012 71

0876 exact mass: 457.3090 g/mol rated and used without further purification. The residue was 0877. HPLC-MS: analytical method C dissolved in TFA (3 mL). The reaction mixture was irradiated 0878 rt: 2.13 min-found mass: 458 (m/z+H) in a microwave reactor for 5 min at 140° C. The reaction mixture was evaporated and used without further purification. Example #173 For the saponification the residue was dissolved in methanol. 2Maqueous NaOH-solution was added to ensure basic con Preparation of 2,2-dimethyl-N-(5-(thiophen-2-yl)- ditions. The mixture was irradiated in a microwave reactor for 1H-pyrazolo 4,3-dipyrimidin-7-yl)-3,4-dihydro-2H 10 min at 120°C. The reaction mixture was concentrated and benzob 14thiazin-6-amine purified by semi-preparative HPLC-MS and freeze dried 0879 7-chloro-2-(4-methoxybenzyl)-5-(thiophen-2-yl)- from waterft-BuOH 4/1. 2H-pyrazolo4.3-dpyrimidine (0.16 mmol) and 2,2-dim 0888 exact mass: 435.1774 g/mol ethyl-3,4-dihydro-2H-benzob 14thiazin-6-amine (0.3 0889 HPLC-MS: analytical method L mmol 2 eq.) were suspended in MeOH (dry, 3 mL) in a (0890 rt: 3.19 min-found mass: 436 (m/z+H) microwave vial (2-5 mL), HCl in dioxane (4M, 3 drops) was added. The reaction mixture was irradiated in a microwave Example #176 reactor for 5 min at 140°C. The reaction mixture was evapo rated and used without further purification. The residue was Preparation of 2-(3-(7-((4-(4-methylpiperazin-1-yl) dissolved in TFA (3 mL). The reaction mixture was irradiated phenyl)amino)-1H-pyrazolo 4,3-dipyrimidin-5-yl) in a microwave reactor for 5 min at 140° C. The reaction phenyl)acetic acid mixture was concentrated and purified by semi-preparative HPLC-MS and freeze dried from waterft-BuOH 4/1. 0891 2-(3-(7-chloro-2-(4-methoxybenzyl)-2H-pyrazolo 0880 exact mass: 394.1286 g/mol 4.3-dpyrimidin-5-yl)phenyl)acetic acid methyl ester (0.16 0881 HPLC-MS: analytical method A mmol) and 4-(4-methylpiperazin-1-yl)aniline (0.3 mmol 2 0882 rt: 3.18 min-found mass: 395 (m/z+H) eq.) were suspended in MeCH (dry, 3 mL) in a microwave vial (2-5 mL), HCl in dioxane (4M, 3 drops) was added. The Example #174 reaction mixture was irradiated in a microwave reactor for 5 min at 140°C. The reaction mixture was evaporated and used Preparation of 2-(3-(7-((4-(4-methylpiperazin-1-yl) without further purification. The residue was dissolved in phenyl)amino)-1H-pyrazolo 4,3-dipyrimidin-5-yl) TFA (3 mL). The reaction mixture was irradiated in a micro phenoxy)acetic acid wave reactor for 5 min at 140°C. The reaction mixture was evaporated and used without further purification. For the 0883 2-(3-(7-chloro-2-(4-methoxybenzyl)-2H-pyrazolo saponification the residue was dissolved in methanol. 2M 4,3-dipyrimidin-5-yl)phenoxy)acetic acid methyl ester aqueous NaOH-solution was added to ensure basic condi (0.16 mmol) and 4-(4-methylpiperazin-1-yl)aniline (0.3 tions. The mixture was irradiated in a microwave reactor for mmol 2 eq.) were suspended in MeOH (dry, 3 mL) in a 10 min at 120°C. The reaction mixture was concentrated and microwave vial (2-5 mL), HCl in dioxane (4M, 3 drops) was purified by semi-preparative HPLC-MS and freeze dried added. The reaction mixture was irradiated in a microwave from waterft-BuOH 4/1. reactor for 5 min at 140°C. The reaction mixture was evapo 0892 exact mass: 443.2444 g/mol rated and used without further purification. The residue was dissolved in TFA (3 mL). The reaction mixture was irradiated (0893 HPLC-MS: analytical method L in a microwave reactor for 5 min at 140° C. The reaction 0894 rt: 3.06 min-found mass: 444 (m/z+H) mixture was evaporated and used without further purification. For the saponification the residue was dissolved in methanol. Example #177 2Maqueous NaOH-solution was added to ensure basic con ditions. The mixture was irradiated in a microwave reactor for Preparation of 6-(7-((4-(4-methylpiperazin-1-yl) 10 min at 120°C. The reaction mixture was concentrated and phenyl)amino)-1H-pyrazolo 4,3-dipyrimidin-5-yl) purified by semi-preparative HPLC-MS and freeze dried picolinic acid from waterft-BuOH 4/1. 0895 6-(7-chloro-2-(4-methoxybenzyl)-2H-pyrazolo.4, 0884 exact mass: 459.2388 g/mol 3-dipyrimidin-5-yl)picolinic acid methyl ester (0.16 mmol) 0885 HPLC-MS: analytical method L and 4-(4-methylpiperazin-1-yl)aniline (0.3 mmol 2 eq.) were 0886 rt: 3.04 min-found mass: 460 (m/z+H) suspended in MeCH (dry, 3 mL) in a microwave vial (2-5 mL), HCl in dioxane (4M, 3 drops) was added. The reaction Example #175 mixture was irradiated in a microwave reactor for 5 min at Preparation of 5-(7-((4-(4-methylpiperazin-1-yl) 140°C. The reaction mixture was evaporated and used with phenyl)amino)-1H-pyrazolo 4,3-dipyrimidin-5-yl) out further purification. The residue was dissolved in TFA (3 thiophene-3-carboxylic acid mL). The reaction mixture was irradiated in a microwave reactor for 5 min at 140°C. The reaction mixture was evapo 0887 5-(7-chloro-2-(4-methoxybenzyl)-2H-pyrazolo.4, rated and used without further purification. For the saponifi 3-dipyrimidin-5-yl)thiophene-3-carboxylic acid methyl ester cation the residue was dissolved in methanol. 2M aqueous (0.16 mmol) and 4-(4-methylpiperazin-1-yl)aniline (0.3 NaOH-solution was added to ensure basic conditions. The mmol 2 eq.) were suspended in MeOH (dry, 3 mL) in a mixture was irradiated in a microwave reactor for 10 min at microwave vial (2-5 mL), HCl in dioxane (4M, 3 drops) was 120° C. The reaction mixture was concentrated and purified added. The reaction mixture was irradiated in a microwave by semi-preparative HPLC-MS and freeze dried from water/ reactor for 5 min at 140°C. The reaction mixture was evapo t-BuOH 471. US 2012/032978.0 A1 Dec. 27, 2012 72

(0896 exact mass: 430.2179 g/mol (0908 exact mass: 518.3447 g/mol (0897 HPLC-MS: analytical method L (0909 HPLC-MS: analytical method L (0898 rt: 2.70 min-found mass: 431 (m/z+H) (0910 rt: 3.20 min-found mass: 519 (m/z+H) Example #178 Example #181 Preparation of N-(4-(pentafluorosulfanyl)phenyl)-5- Preparation of 5-(3-(3-(dimethylamino)propoxy) (thiophen-3-yl)-1H-pyrazolo 4,3-dipyrimidin-7- phenyl)-N-(4-(4-methylpiperazin-1-yl)phenyl)-1H amine pyrazolo 4.3-dpyrimidin-7-amine 0899) 7-chloro-2-(4-methoxybenzyl)-5-(thiophen-3-yl)- 0911 3-(3-(7-chloro-2-(4-methoxybenzyl)-2H-pyrazolo 2H-pyrazolo4.3-dpyrimidine (0.16 mmol) and 4-Ami 4.3-dpyrimidin-5-yl)phenoxy)-N,N-dimethylpropan-1- nophenylsulphur pentafluoride (0.3 mmol 2 eq.) were sus amine (0.16 mmol) and 4-(4-methylpiperazin-1-yl)aniline pended in MeOH (dry, 3 mL) in a microwave vial (2-5 mL), (0.3 mmol 2 eq.) were suspended in MeOH (dry, 3 mL) in a HCl in dioxane (4M, 3 drops) was added. The reaction mix microwave vial (2-5 mL), HCl in dioxane (4M, 3 drops) was ture was irradiated in a microwave reactor for 5 minat 140°C. added. The reaction mixture was irradiated in a microwave The reaction mixture was evaporated and used without fur reactor for 5 min at 140°C. The reaction mixture was evapo ther purification. The residue was dissolved in TFA (3 mL). rated and used without further purification. The residue was The reaction mixture was irradiated in a microwave reactor dissolved in TFA (3 mL). The reaction mixture was irradiated for 5 min at 140°C. The reaction mixture was concentrated in a microwave reactor for 5 min at 140° C. The reaction and purified by semi-preparative HPLC-MS and freeze dried mixture was concentrated and purified by semi-preparative from waterft-BuOH 4/1. HPLC-MS and freeze dried from waterft-BuOH 4/1. 0900 exact mass: 419.0376 g/mol 0912 exact mass: 486.3410 g/mol (0901 HPLC-MS: analytical method C (0913 HPLC-MS: analytical method L (0902 rt: 3.40 min-found mass: 420 (m/z+H) 0914 rt: 3.21 min-found mass: 487 (n/Z+H) Example #179 Example #182 Preparation of N-(4-(4-methylpiperazin-1-yl)phe Preparation of 3-(7-((4-(4-methylpiperazin-1-yl) nyl)-5-(thiazol-2-yl)-1H-pyrazolo 4,3-dipyrimidin-7- phenyl)amino)-1H-pyrazolo 4.3-dipyrimidin-5-yl) amine benzenesulfonamide 0903 2-(7-chloro-2-(4-methoxybenzyl)-2H-pyrazolo.4, 0915. 3-(7-chloro-2-(4-methoxybenzyl)-2H-pyrazolo.4, 3-dipyrimidin-5-yl)thiazole (0.16 mmol) and 4-(4-meth 3-dipyrimidin-5-yl)benzenesulfonamide (0.16 mmol) and ylpiperazin-1-yl)aniline (0.3 mmol 2 eq.) were suspended in 4-(4-methylpiperazin-1-yl)aniline (0.3 mmol 2 eq.) were sus MeOH (dry, 3 mL) in a microwave vial (2-5 mL), HCl in pended in MeOH (dry, 3 mL) in a microwave vial (2-5 mL), dioxane (4M, 3 drops) was added. The reaction mixture was HCl in dioxane (4M, 3 drops) was added. The reaction mix irradiated in a microwave reactor for 5 min at 140°C. The ture was irradiated in a microwave reactor for 5 minat 140°C. reaction mixture was evaporated and used without further The reaction mixture was evaporated and used without fur purification. The residue was dissolved in TFA (3 mL). The ther purification. The residue was dissolved in TFA (3 mL). reaction mixture was irradiated in a microwave reactor for 5 The reaction mixture was irradiated in a microwave reactor min at 140° C. The reaction mixture was concentrated and for 5 min at 140°C. The reaction mixture was concentrated purified by semi-preparative HPLC-MS and freeze dried and purified by semi-preparative HPLC-MS and freeze dried from waterft-BuOH 4/1. from waterft-BuOH 4/1. (0904) exact mass: 392.1821 g/mol 0916 exact mass: 464.2094 g/mol (0905 HPLC-MS: analytical method D (0917 HPLC-MS: analytical method L (0906) rt: 2.67 min-found mass: 393 (m/z+H) 0918 rt: 0.46 min-found mass: 465 (m/z+H) Example #180 Example #183 Preparation of 5-(3-(((4-methylbenzyl)amino)me Preparation of 3-(7-((3,4-dimethoxyphenyl)amino)- thyl)phenyl)-N-(4-(4-methylpiperazin-1-yl)phenyl)- 1H-pyrazolo 4,3-dipyrimidin-5-yl)benzenesulfona 1H-pyrazolo 4,3-dipyrimidin-7-amine mide 0907 N-(3-(7-chloro-2-(4-methoxybenzyl)-2H-pyrazolo 0919 3-(7-chloro-2-(4-methoxybenzyl)-2H-pyrazolo.4, 4,3-dipyrimidin-5-yl)benzyl)-1-(p-tolyl)methanamine 3-dipyrimidin-5-yl)benzenesulfonamide (0.16 mmol) and (0.16 mmol) and 4-(4-methylpiperazin-1-yl)aniline (0.3 3,4-dimethoxyaniline (0.3 mmol 2 eq.) were suspended in mmol 2 eq.) were suspended in MeOH (dry, 3 mL) in a MeOH (dry, 3 mL) in a microwave vial (2-5 mL), HCl in microwave vial (2-5 mL), HCl in dioxane (4M, 3 drops) was dioxane (4M, 3 drops) was added. The reaction mixture was added. The reaction mixture was irradiated in a microwave irradiated in a microwave reactor for 5 min at 140°C. The reactor for 5 min at 140°C. The reaction mixture was evapo reaction mixture was evaporated and used without further rated and used without further purification. The residue was purification. The residue was dissolved in TFA (3 mL). The dissolved in TFA (3 mL). The reaction mixture was irradiated reaction mixture was irradiated in a microwave reactor for 5 in a microwave reactor for 5 min at 140° C. The reaction min at 140° C. The reaction mixture was concentrated and mixture was concentrated and purified by semi-preparative purified by semi-preparative HPLC-MS and freeze dried HPLC-MS and freeze dried from waterft-BuOH 4/1. from waterft-BuOH 4/1. US 2012/032978.0 A1 Dec. 27, 2012 73

0920 exact mass: 426.1346 g/mol 0932 exact mass: 363.1049 g/mol 0921 HPLC-MS: analytical method L 0933 HPLC-MS: analytical method A 0922 rt: 3.91 min-found mass: 427 (m/z+H) 0934 rt: 2.30 min-found mass: 364 (m/z+H) Example #184 Example #187 Preparation of 1-(4-(4-((5-(thiazol-2-yl)-1H-pyrazolo Preparation of N-(3-(7-((4-(4-methylpiperazin-1-yl) 4.3-dipyrimidin-7-yl)amino)phenyl)piperazin-1-yl) phenyl)amino)-1H-pyrazolo 4,3-dipyrimidin-5-yl) ethan-1-one phenyl)methanesulfonamide 0923 2-(7-chloro-2-(4-methoxybenzyl)-2H-pyrazolo.4, 0935 N-(3-(7-chloro-2-(4-methoxybenzyl)-2H-pyrazolo 3-dipyrimidin-5-yl)thiazole (0.16 mmol) and 1-(4-(4-ami 4.3-dpyrimidin-5-yl)phenyl)methanesulfonamide (0.16 nophenyl)piperazin-1-yl)ethan-1-one (0.3 mmol 2 eq.) were mmol) and 4-(4-methylpiperazin-1-yl)aniline (0.3 mmol 2 suspended in MeCH (dry, 3 mL) in a microwave vial (2-5 eq.) were suspended in MeCH (dry, 3 mL) in a microwave mL), HCl in dioxane (4M, 3 drops) was added. The reaction vial (2-5 mL), HCl in dioxane (4M, 3 drops) was added. The mixture was irradiated in a microwave reactor for 5 min at reaction mixture was irradiated in a microwave reactor for 5 140°C. The reaction mixture was evaporated and used with min at 140°C. The reaction mixture was evaporated and used out further purification. The residue was dissolved in TFA (3 without further purification. The residue was dissolved in mL). The reaction mixture was irradiated in a microwave TFA (3 mL). The reaction mixture was irradiated in a micro reactor for 5 min at 140°C. The reaction mixture was con wave reactor for 5 min at 140°C. The reaction mixture was centrated and purified by semi-preparative HPLC-MS and concentrated and purified by semi-preparative HPLC-MS freeze dried from waterft-BuOH 4/1. and freeze dried from waterft-BuOH 471. 0924 exact mass: 420.1760 g/mol 0936 exact mass: 478.2289 g/mol 0925 HPLC-MS: analytical method L 0937 HPLC-MS: analytical method D 0926 rt: 3.66 min-found mass: 421 (m/z+H) 0938 rt: 3.27 min-found mass: 479 (m/z+H) Example #185 Example #188 Preparation of N-(3-(7-((4-(piperazin-1-yl)phenyl) Preparation of N-(3,4-dimethoxyphenyl)-5-(thiazol amino)-1H-pyrazolo 4,3-dipyrimidin-5-yl)phenyl) 2-yl)-1H-pyrazolo 4.3-dpyrimidin-7-amine methanesulfonamide 0927 2-(7-chloro-2-(4-methoxybenzyl)-2H-pyrazolo.4, 0939 N-(3-(7-chloro-2-(4-methoxybenzyl)-2H-pyrazolo 3-dipyrimidin-5-yl)thiazole (0.16 mmol) and 3,4- 4.3-dpyrimidin-5-yl)phenyl)methanesulfonamide (0.16 dimethoxyaniline (0.3 mmol 2 eq.) were suspended in MeOH mmol) and 4-(piperazin-1-yl)aniline (0.3 mmol 2 eq.) were (dry, 3 mL) in a microwave vial (2-5 mL), HCl in dioxane suspended in MeCH (dry, 3 mL) in a microwave vial (2-5 (4M, 3 drops) was added. The reaction mixture was irradiated mL), HCl in dioxane (4M, 3 drops) was added. The reaction in a microwave reactor for 5 min at 140° C. The reaction mixture was irradiated in a microwave reactor for 5 min at mixture was evaporated and used without further purification. 140°C. The reaction mixture was evaporated and used with The residue was dissolved in TFA (3 mL). The reaction mix out further purification. The residue was dissolved in TFA (3 ture was irradiated in a microwave reactor for min at 140°C. mL). The reaction mixture was irradiated in a microwave The reaction mixture was concentrated and purified by semi reactor for 5 min at 140°C. The reaction mixture was con preparative HPLC-MS and freeze dried from water/t-BuOH centrated and purified by semi-preparative HPLC-MS and 4f1. freeze dried from waterft-BuOH 4/1. 0928 exact mass: 354.1073 g/mol 0940 exact mass: 464.2094 g/mol 0929 HPLC-MS: analytical method L (0941 HPLC-MS: analytical method L 0930 rt: 3.93 min-found mass: 355 (m/z+H) 0942 rt: 2.90 min-found mass: 465 (m/z+H) Example #186 Example #189 Preparation of 7-((5-(thiazol-2-yl)-1H-pyrazolo 4,3- Preparation of N-(3-(7-((3,4-dimethoxyphenyl) dpyrimidin-7-yl)amino)-3,4-dihydroquinolin-2(1H)- amino)-1H-pyrazolo 4,3-dipyrimidin-5-yl)phenyl) O methanesulfonamide 0931 2-(7-chloro-2-(4-methoxybenzyl)-2H-pyrazolo.4, 0943 N-(3-(7-chloro-2-(4-methoxybenzyl)-2H-pyrazolo 3-dipyrimidin-5-yl)thiazole (0.16 mmol) and 7-amino-3,4- 4.3-dpyrimidin-5-yl)phenyl)methanesulfonamide (0.16 dihydroquinolin-2(1H)-one (0.3 mmol 2 eq.) were suspended mmol) and 3,4-dimethoxyaniline (0.3 mmol 2 eq.) were Sus in MeCH (dry, 3 mL) in a microwave vial (2-5 mL), HCl in pended in MeOH (dry, 3 mL) in a microwave vial (2-5 mL), dioxane (4M, 3 drops) was added. The reaction mixture was HCl in dioxane (4M, 3 drops) was added. The reaction mix irradiated in a microwave reactor for 5 min at 140°C. The ture was irradiated in a microwave reactor for 5 minat 140°C. reaction mixture was evaporated and used without further The reaction mixture was evaporated and used without fur purification. The residue was dissolved in TFA (3 mL). The ther purification. The residue was dissolved in TFA (3 mL). reaction mixture was irradiated in a microwave reactor for 5 The reaction mixture was irradiated in a microwave reactor min at 140° C. The reaction mixture was concentrated and for 5 min at 140°C. The reaction mixture was concentrated purified by semi-preparative HPLC-MS and freeze dried and purified by semi-preparative HPLC-MS and freeze dried from waterft-BuOH 4/1. from waterft-BuOH 4/1. US 2012/032978.0 A1 Dec. 27, 2012 74

0944 exact mass: 440.1541 g/mol 0956 exact mass: 481.2401 g/mol (0945 HPLC-MS: analytical method L 0957 HPLC-MS: analytical method A 0946 rt: 4.06 min-found mass: 441 (m/z+H) 0958 rt: 2.34 min-found mass: 482 (m/z+H) Example #190 Example #193 Preparation of N-(3-(7-((2-oxo-1,2,3,4-tetrahydro Preparation of 5-(3-(2H-tetrazol-5-yl)phenyl)-N-(3, quinolin-7-yl)amino)-1H-pyrazolo 4.3-dipyrimidin 4-dimethoxyphenyl)-1H-pyrazolo4.3-dpyrimidin 5-yl)phenyl)methanesulfonamide 7-amine 0947 N-(3-(7-chloro-2-(4-methoxybenzyl)-2H-pyrazolo 0959 5-(3-(2H-tetrazol-5-yl)phenyl)-7-chloro-2-(4- 4,3-dipyrimidin-5-yl)phenyl)methanesulfonamide (0.16 methoxybenzyl)-2H-pyrazolo 4,3-dipyrimidine (0.16 mmol) and 7-amino-3,4-dihydroquinolin-2(1H)-one (0.3 mmol) and 3,4-dimethoxyaniline (0.3 mmol 2 eq.) were Sus mmol 2 eq.) were suspended in MeOH (dry, 3 mL) in a pended in MeOH (dry, 3 mL) in a microwave vial (2-5 mL), microwave vial (2-5 mL), HCl in dioxane (4M, 3 drops) was HCl in dioxane (4M, 3 drops) was added. The reaction mix added. The reaction mixture was irradiated in a microwave ture was irradiated in a microwave reactor for 5 minat 140°C. reactor for 5 min at 140°C. The reaction mixture was evapo The reaction mixture was evaporated and used without fur rated and used without further purification. The residue was ther purification. The residue was dissolved in TFA (3 mL). dissolved in TFA (3 mL). The reaction mixture was irradiated The reaction mixture was irradiated in a microwave reactor in a microwave reactor for 5 min at 140° C. The reaction for 5 min at 140°C. The reaction mixture was concentrated mixture was concentrated and purified by semi-preparative and purified by semi-preparative HPLC-MS and freeze dried HPLC-MS and freeze dried from waterft-BuOH 4/1. from waterft-BuOH 4/1. (0948 exact mass: 449.1518 g/mol 0960 exact mass: 415.1714 g/mol (0949 HPLC-MS: analytical method D 0961 HPLC-MS: analytical method A 0950 rt: 4.65 min-found mass: 450 (m/z+H) 0962 rt: 2.49 min-found mass: 416 (m/z+H) Example #191 Example #194 Preparation of N-(3-(7-((4-(4-acetylpiperazin-1-yl) Preparation of 3-(7-((3,4-dimethoxyphenyl)amino)- phenyl)amino)-1H-pyrazolo 4,3-dipyrimidin-5-yl) 1H-pyrazolo 4.3-dipyrimidin-5-yl)benzoic acid phenyl)methanesulfonamide 0963 3-(7-chloro-2-(4-methoxybenzyl)-2H-pyrazolo.4, 0951 N-(3-(7-chloro-2-(4-methoxybenzyl)-2H-pyrazolo 3-dipyrimidin-5-yl)benzoic acid methyl ester (0.16 mmol) 4,3-dipyrimidin-5-yl)phenyl)methanesulfonamide (0.16 and 3,4-dimethoxyaniline (0.3 mmol 2 eq.) were suspended mmol) and 1-(4-(4-aminophenyl)piperazin-1-yl)ethan-1-one in MeCH (dry, 3 mL) in a microwave vial (2-5 mL), HCl in (0.3 mmol 2 eq.) were suspended in MeOH (dry, 3 mL) in a dioxane (4M, 3 drops) was added. The reaction mixture was microwave vial (2-5 mL), HCl in dioxane (4M, 3 drops) was irradiated in a microwave reactor for 5 min at 140°C. The added. The reaction mixture was irradiated in a microwave reaction mixture was evaporated and used without further reactor for 5 min at 140°C. The reaction mixture was evapo purification. The residue was dissolved in TFA (3 mL). The rated and used without further purification. The residue was reaction mixture was irradiated in a microwave reactor for 5 dissolved in TFA (3 mL). The reaction mixture was irradiated min at 140°C. The reaction mixture was evaporated and used in a microwave reactor for 5 min at 140° C. The reaction without further purification. For the saponification the residue mixture was concentrated and purified by semi-preparative was dissolved in methanol. 2Maqueous NaOH-solution was HPLC-MS and freeze dried from waterft-BuOH 4/1. added to ensure basic conditions. The mixture was irradiated 0952 exact mass: 506.2228 g/mol in a microwave reactor for 10 min at 120° C. The reaction 0953 HPLC-MS: analytical method L mixture was concentrated and purified by semi-preparative 0954 rt: 3.75 min-found mass: 507 (m/z+H) HPLC-MS and freeze dried from waterft-BuOH 4/1. 0964 exact mass: 391.1501 g/mol Example #192 0965 HPLC-MS: analytical method L 0966 rt: 4.04 min-found mass: 392 (m/z+H) Preparation of 1-(4-(4-((5-(3-(2H-tetrazol-5-yl)phe nyl)-1H-pyrazolo4.3-dpyrimidin-7-yl)amino)phe Example #195 nyl)piperazin-1-yl)ethan-1-one 0955 5-(3-(2H-tetrazol-5-yl)phenyl)-7-chloro-2-(4- Preparation of 3-(7-((2-oxo-1,2,3,4-tetrahydroquino methoxybenzyl)-2H-pyrazolo 4,3-dipyrimidine (0.16 lin-7-yl)amino)-1H-pyrazolo 4,3-dipyrimidin-5-yl) mmol) and 1-(4-(4-aminophenyl)piperazin-1-yl)ethan-1-one benzoic acid (0.3 mmol 2 eq.) were suspended in MeOH (dry, 3 mL) in a 0967 3-(7-chloro-2-(4-methoxybenzyl)-2H-pyrazolo.4, microwave vial (2-5 mL), HCl in dioxane (4M, 3 drops) was 3-dipyrimidin-5-yl)benzoic acid methyl ester (0.16 mmol) added. The reaction mixture was irradiated in a microwave and 7-amino-3,4-dihydroquinolin-2(1H)-one (0.3 mmol 2 reactor for 5 min at 140°C. The reaction mixture was evapo eq.) were suspended in MeCH (dry, 3 mL) in a microwave rated and used without further purification. The residue was vial (2-5 mL), HCl in dioxane (4M, 3 drops) was added. The dissolved in TFA (3 mL). The reaction mixture was irradiated reaction mixture was irradiated in a microwave reactor for 5 in a microwave reactor for 5 min at 140° C. The reaction min at 140°C. The reaction mixture was evaporated and used mixture was concentrated and purified by semi-preparative without further purification. The residue was dissolved in HPLC-MS and freeze dried from waterft-BuOH 4/1. TFA (3 mL). The reaction mixture was irradiated in a micro US 2012/032978.0 A1 Dec. 27, 2012

wave reactor for 5 min at 140°C. The reaction mixture was mL), HCl in dioxane (4M, 3 drops) was added. The reaction evaporated and used without further purification. For the mixture was irradiated in a microwave reactor for 5 min at saponification the residue was dissolved in methanol. 2M 140°C. The reaction mixture was evaporated and used with aqueous NaOH-solution was added to ensure basic condi out further purification. The residue was dissolved in TFA (3 tions. The mixture was irradiated in a microwave reactor for mL). The reaction mixture was irradiated in a microwave 10 min at 120°C. The reaction mixture was concentrated and reactor for 5 min at 140°C. The reaction mixture was con purified by semi-preparative HPLC-MS and freeze dried centrated and purified by semi-preparative HPLC-MS and from waterft-BuOH 4/1. freeze dried from waterft-BuOH 4/1. 0968 exact mass: 400.1478 g/mol 0980 exact mass: 420.1760 g/mol 0969 HPLC-MS: analytical method L 0981 HPLC-MS: analytical method L 0970 rt: 4.02 min-found mass: 401 (m/z+H) 0982) rt: 3.32 min-found mass: 421 (m/z+H) Example #196 Example #199 Preparation of 7-((5-(3-(2H-tetrazol-5-yl)phenyl)- Preparation of N-(3,4-dimethoxyphenyl)-5-(thiazol 1H-pyrazolo 4,3-dipyrimidin-7-yl)amino)-3,4-dihy 4-yl)-1H-pyrazolo 4,3-dipyrimidin-7-amine droquinolin-2(1H)-one 0983 4-(7-chloro-2-(4-methoxybenzyl)-2H-pyrazolo.4, 0971 5-(3-(2H-tetrazol-5-yl)phenyl)-7-chloro-2-(4- 3-dipyrimidin-5-yl)thiazole (0.16 mmol) and 3,4- methoxybenzyl)-2H-pyrazolo 4,3-dipyrimidine (0.16 dimethoxyaniline (0.3 mmol 2 eq.) were suspended in MeCH mmol) and 7-amino-3,4-dihydroquinolin-2(1H)-one (0.3 (dry, 3 mL) in a microwave vial (2-5 mL), HCl in dioxane mmol 2 eq.) were suspended in MeOH (dry, 3 mL) in a (4M, 3 drops) was added. The reaction mixture was irradiated microwave vial (2-5 mL), HCl in dioxane (4M, 3 drops) was in a microwave reactor for 5 min at 140° C. The reaction added. The reaction mixture was irradiated in a microwave mixture was evaporated and used without further purification. reactor for 5 min at 140°C. The reaction mixture was evapo The residue was dissolved in TFA (3 mL). The reaction mix rated and used without further purification. The residue was ture was irradiated in a microwave reactor for min at 140°C. dissolved in TFA (3 mL). The reaction mixture was irradiated The reaction mixture was concentrated and purified by semi in a microwave reactor for 5 min at 140° C. The reaction preparative HPLC-MS and freeze dried from water/t-BuOH mixture was concentrated and purified by semi-preparative 4f1. HPLC-MS and freeze dried from waterft-BuOH 471. 0984 exact mass: 354.1073 g/mol 0972 exact mass: 424.1690 g/mol 0985 HPLC-MS: analytical method L 0973 HPLC-MS: analytical method L 0986 rt: 3.47 min-found mass: 355 (m/z+H) 0974 rt: 3.97 min-found mass: 425 (m/z+H) Example #200 Example #197 Preparation of N-(4-(4-methylpiperazin-1-yl)phe Preparation of N-(4-(4-methylpiperazin-1-yl)phe nyl)-5-(oxazol-4-yl)-1H-pyrazolo 4,3-dipyrimidin-7- nyl)-5-(thiazol-4-yl)-1H-pyrazolo 4,3-dipyrimidin-7- amine amine 0987 4-(7-chloro-2-(4-methoxybenzyl)-2H-pyrazolo.4, 0975 4-(7-chloro-2-(4-methoxybenzyl)-2H-pyrazolo.4, 3-dipyrimidin-5-yl)oxazole (0.16 mmol) and 4-(4-meth 3-dipyrimidin-5-yl)thiazole (0.16 mmol) and 4-(4-meth ylpiperazin-1-yl)aniline (0.3 mmol 2 eq.) were suspended in ylpiperazin-1-yl)aniline (0.3 mmol 2 eq.) were suspended in MeOH (dry, 3 mL) in a microwave vial (2-5 mL), HCl in MeOH (dry, 3 mL) in a microwave vial (2-5 mL), HCl in dioxane (4M, 3 drops) was added. The reaction mixture was dioxane (4M, 3 drops) was added. The reaction mixture was irradiated in a microwave reactor for 5 min at 140°C. The irradiated in a microwave reactor for 5 min at 140°C. The reaction mixture was evaporated and used without further reaction mixture was evaporated and used without further purification. The residue was dissolved in TFA (3 mL). The purification. The residue was dissolved in TFA (3 mL). The reaction mixture was irradiated in a microwave reactor for 5 reaction mixture was irradiated in a microwave reactor for 5 min at 140° C. The reaction mixture was concentrated and min at 140° C. The reaction mixture was concentrated and purified by semi-preparative HPLC-MS and freeze dried purified by semi-preparative HPLC-MS and freeze dried from waterft-BuOH 4/1. from waterft-BuOH 4/1. 0988 exact mass: 376.2050 g/mol 0976 exact mass: 392.1821 g/mol 0989 HPLC-MS: analytical method CP 0977 HPLC-MS: analytical method CP 0990 rt: 2.18 min-found mass: 377 (m/z+H) 0978 rt: 2.13 min-found mass: 393 (m/z+H) Example #201 Example #198 Preparation of 1-(4-(4-((5-(oxazol-4-yl)-1H-pyrazolo Preparation of 1-(4-(4-((5-(thiazol-4-yl)-1H-pyrazolo 4.3-dipyrimidin-7-yl)amino)phenyl)piperazin-1-yl) 4.3-dipyrimidin-7-yl)amino)phenyl)piperazin-1-yl) ethan-1-one ethan-1-one 0991) 4-(7-chloro-2-(4-methoxybenzyl)-2H-pyrazolo.4, 0979 4-(7-chloro-2-(4-methoxybenzyl)-2H-pyrazolo.4, 3-dipyrimidin-5-yl)oxazole (0.16 mmol) and 1-(4-(4-ami 3-dipyrimidin-5-yl)thiazole (0.16 mmol) and 1-(4-(4-ami nophenyl)piperazin-1-yl)ethan-1-one (0.3 mmol 2 eq.) were nophenyl)piperazin-1-yl)ethan-1-one (0.3 mmol 2 eq.) were suspended in MeCH (dry, 3 mL) in a microwave vial (2-5 suspended in MeCH (dry, 3 mL) in a microwave vial (2-5 mL), HCl in dioxane (4M, 3 drops) was added. The reaction US 2012/032978.0 A1 Dec. 27, 2012 76 mixture was irradiated in a microwave reactor for 5 min at 140°C. The reaction mixture was evaporated and used with 140°C. The reaction mixture was evaporated and used with out further purification. The residue was dissolved in TFA (3 out further purification. The residue was dissolved in TFA (3 mL). The reaction mixture was irradiated in a microwave mL). The reaction mixture was irradiated in a microwave reactor for 5 min at 140°C. The reaction mixture was con reactor for 5 min at 140°C. The reaction mixture was con centrated and purified by semi-preparative HPLC-MS and centrated and purified by semi-preparative HPLC-MS and freeze dried from waterft-BuOH 4/1. freeze dried from waterft-BuOH 4/1. 1004 exact mass: 404.1989 g/mol 0992 exact mass: 404.1989 g/mol 1005 HPLC-MS: analytical method L 0993 HPLC-MS: analytical method A 1006 rt: 3.59 min-found mass: 405 (m/z+H) 0994) rt: 2.01 min-found mass: 405 (m/z+H) Example #205 Example #202 Preparation of N-(3,4-dimethoxyphenyl)-5-(oxazol Preparation of N-(3,4-dimethoxyphenyl)-5-(oxazol 2-yl)-1H-pyrazolo 4,3-dipyrimidin-7-amine 4-yl)-1H-pyrazolo 4.3-dpyrimidin-7-amine 1007 2-(7-chloro-2-(4-methoxybenzyl)-2H-pyrazolo.4, 0995 4-(7-chloro-2-(4-methoxybenzyl)-2H-pyrazolo.4, 3-dipyrimidin-5-yl)oxazole (0.16 mmol) and 3,4- 3-dipyrimidin-5-yl)oxazole (0.16 mmol) and 3,4- dimethoxyaniline (0.3 mmol 2 eq.) were suspended in MeCH dimethoxyaniline (0.3 mmol 2 eq.) were suspended in MeOH (dry, 3 mL) in a microwave vial (2-5 mL), HCl in dioxane (dry, 3 mL) in a microwave vial (2-5 mL), HCl in dioxane (4M, 3 drops) was added. The reaction mixture was irradiated (4M, 3 drops) was added. The reaction mixture was irradiated in a microwave reactor for 5 min at 140° C. The reaction in a microwave reactor for 5 min at 140° C. The reaction mixture was evaporated and used without further purification. mixture was evaporated and used without further purification. The residue was dissolved in TFA (3 mL). The reaction mix The residue was dissolved in TFA (3 mL). The reaction mix ture was irradiated in a microwave reactor for min at 140°C. ture was irradiated in a microwave reactor for min at 140°C. The reaction mixture was concentrated and purified by semi The reaction mixture was concentrated and purified by semi preparative HPLC-MS and freeze dried from water/t-BuOH preparative HPLC-MS and freeze dried from water/t-BuOH 4f1. 4f1. 1008 exact mass: 338.1302 g/mol 0996 exact mass: 338.1302 g/mol 1009 HPLC-MS: analytical method L 0997 HPLC-MS: analytical method A 1010 rt: 3.88 min-found mass: 339 (m/z+H) 0998 rt: 2.13 min-found mass: 339 (m/z+H) Example #206 Example #203 Preparation of 7-((5-(thiazol-4-yl)-1H-pyrazolo 4,3- Preparation of N-(4-(4-methylpiperazin-1-yl)phe dpyrimidin-7-yl)amino)-3,4-dihydroquinolin-2(1H)- nyl)-5-(oxazol-2-yl)-1H-pyrazolo 4,3-dipyrimidin-7- O amine 1011 4-(7-chloro-2-(4-methoxybenzyl)-2H-pyrazolo.4, 0999 2-(7-chloro-2-(4-methoxybenzyl)-2H-pyrazolo.4, 3-dipyrimidin-5-yl)thiazole (0.16 mmol) and 7-amino-3,4- 3-dipyrimidin-5-yl)oxazole (0.16 mmol) and 4-(4-meth dihydroquinolin-2(1H)-one (0.3 mmol 2 eq.) were suspended ylpiperazin-1-yl)aniline (0.3 mmol 2 eq.) were suspended in in MeCH (dry, 3 mL) in a microwave vial (2-5 mL), HCl in MeOH (dry, 3 mL) in a microwave vial (2-5 mL), HCl in dioxane (4M, 3 drops) was added. The reaction mixture was dioxane (4M, 3 drops) was added. The reaction mixture was irradiated in a microwave reactor for 5 min at 140°C. The irradiated in a microwave reactor for 5 min at 140°C. The reaction mixture was evaporated and used without further reaction mixture was evaporated and used without further purification. The residue was dissolved in TFA (3 mL). The purification. The residue was dissolved in TFA (3 mL). The reaction mixture was irradiated in a microwave reactor for 5 reaction mixture was irradiated in a microwave reactor for 5 min at 140° C. The reaction mixture was concentrated and min at 140° C. The reaction mixture was concentrated and purified by semi-preparative HPLC-MS and freeze dried purified by semi-preparative HPLC-MS and freeze dried from waterft-BuOH 4/1. from waterft-BuOH 4/1. 1012 exact mass: 363.1049 g/mol 1000 exact mass: 376.2050 g/mol 1013 HPLC-MS: analytical method L 1001 HPLC-MS: analytical method CP 1014 rt: 3.42 min-found mass: 364 (m/z+H) 1002 rt: 2.23 min-found mass: 377 (m/z+H) Example #207 Example #204 Preparation of 7-((5-(oxazol-4-yl)-1H-pyrazolo 4.3- Preparation of 1-(4-(4-((5-(oxazol-2-yl)-1H-pyrazolo dpyrimidin-7-yl)amino)-3,4-dihydroquinolin-2(1H)- 4.3-dipyrimidin-7-yl)amino)phenyl)piperazin-1-yl) O ethan-1-one 1015) 4-(7-chloro-2-(4-methoxybenzyl)-2H-pyrazolo.4, 1003 2-(7-chloro-2-(4-methoxybenzyl)-2H-pyrazolo.4, 3-dipyrimidin-5-yl)oxazole (0.16 mmol) and 7-amino-3,4- 3-dipyrimidin-5-yl)oxazole (0.16 mmol) and 1-(4-(4-ami dihydroquinolin-2(1H)-one (0.3 mmol 2 eq.) were suspended nophenyl)piperazin-1-yl)ethan-1-one (0.3 mmol 2 eq.) were in MeCH (dry, 3 mL) in a microwave vial (2-5 mL), HCl in suspended in MeCH (dry, 3 mL) in a microwave vial (2-5 dioxane (4M, 3 drops) was added. The reaction mixture was mL), HCl in dioxane (4M, 3 drops) was added. The reaction irradiated in a microwave reactor for 5 min at 140°C. The mixture was irradiated in a microwave reactor for 5 min at reaction mixture was evaporated and used without further US 2012/032978.0 A1 Dec. 27, 2012 77 purification. The residue was dissolved in TFA (3 mL). The without further purification. The residue was dissolved in reaction mixture was irradiated in a microwave reactor for 5 TFA (3 mL). The reaction mixture was irradiated in a micro min at 140° C. The reaction mixture was concentrated and wave reactor for 5 min at 140°C. The reaction mixture was purified by semi-preparative HPLC-MS and freeze dried concentrated and purified by semi-preparative HPLC-MS from waterft-BuOH 4/1. and freeze dried from waterft-BuOH 471. 1016 exact mass: 347.1278 g/mol 1028) exact mass: 414.1673 g/mol 1017 HPLC-MS: analytical method L 1029 HPLC-MS: analytical method L 1018 rt: 3.47 min-found mass: 348 (m/z+H) 1030 rt: 4.53 min-found mass: 415 (m/z+H) Example #208 Example #211 Preparation of 7-((5-(oxazol-2-yl)-1H-pyrazolo 4.3- Preparation of methyl 3-(7-((3-oxo-3,4-dihydro-2H dpyrimidin-7-yl)amino)-3,4-dihydroquinolin-2(1H)- benzob 14oxazin-6-yl)amino)-1H-pyrazolo 4.3- O dpyrimidin-5-yl)benzoate 1019 2-(7-chloro-2-(4-methoxybenzyl)-2H-pyrazolo.4, 1031 methyl 3-(7-chloro-2-(4-methoxybenzyl)-2H-pyra 3-dipyrimidin-5-yl)oxazole (0.16 mmol) and 7-amino-3,4- Zolo 4,3-dipyrimidin-5-yl)benzoate (0.16 mmol) and dihydroquinolin-2(1H)-one (0.3 mmol 2 eq.) were suspended 6-amino-2H-benzob 14oxazin-3 (4H)-one (0.3 mmol 2 in MeCH (dry, 3 mL) in a microwave vial (2-5 mL), HCl in eq.) were suspended in MeCH (dry, 3 mL) in a microwave dioxane (4M, 3 drops) was added. The reaction mixture was vial (2-5 mL), HCl in dioxane (4M, 3 drops) was added. The irradiated in a microwave reactor for 5 min at 140°C. The reaction mixture was irradiated in a microwave reactor for 5 reaction mixture was evaporated and used without further min at 140°C. The reaction mixture was evaporated and used purification. The residue was dissolved in TFA (3 mL). The without further purification. The residue was dissolved in reaction mixture was irradiated in a microwave reactor for 5 TFA (3 mL). The reaction mixture was irradiated in a micro min at 140° C. The reaction mixture was concentrated and wave reactor for 5 min at 140°C. The reaction mixture was purified by semi-preparative HPLC-MS and freeze dried concentrated and purified by semi-preparative HPLC-MS from waterft-BuOH 4/1. and freeze dried from waterft-BuOH 471. 1020 exact mass: 347.1278 g/mol 1032 exact mass: 416.1422 g/mol 1021 HPLC-MS: analytical method L 1033 HPLC-MS: analytical method L 1022 rt: 3.68 min-found mass: 348 (m/z+H) 1034 rt: 4.50 min-found mass: 417 (m/z+H) Example #209 Example #212 Preparation of N-(4-(1-methylpiperidin-4-yl)phe Preparation of 3-(7-((3-oxo-3,4-dihydro-2H-benzo nyl)-5-(thiophen-2-yl)-1H-pyrazolo 4.3-dpyrimidin b 14oxazin-6-yl)amino)-1H-pyrazolo 4,3-dipyri 7-amine midin-5-yl)benzoic acid 1023) 7-chloro-2-(4-methoxybenzyl)-5-(thiophen-2-yl)- 1035 3-(7-chloro-2-(4-methoxybenzyl)-2H-pyrazolo.4, 2H-pyrazolo4.3-dpyrimidine (0.16 mmol) and 4-(1-meth 3-dipyrimidin-5-yl)benzoic acid methyl ester (0.16 mmol) ylpiperidin-4-yl)aniline (0.3 mmol 2 eq.) were Suspended in and 6-amino-2H-benzob 14oxazin-3 (4H)-one (0.3 mmol MeOH (dry, 3 mL) in a microwave vial (2-5 mL), HCl in 2 eq.) were suspended in MeOH (dry, 3 mL) in a microwave dioxane (4M, 3 drops) was added. The reaction mixture was vial (2-5 mL), HCl in dioxane (4M, 3 drops) was added. The irradiated in a microwave reactor for 5 min at 140°C. The reaction mixture was irradiated in a microwave reactor for 5 reaction mixture was evaporated and used without further min at 140°C. The reaction mixture was evaporated and used purification. The residue was dissolved in TFA (3 mL). The without further purification. The residue was dissolved in reaction mixture was irradiated in a microwave reactor for 5 TFA (3 mL). The reaction mixture was irradiated in a micro min at 140° C. The reaction mixture was concentrated and wave reactor for 5 min at 140°C. The reaction mixture was purified by semi-preparative HPLC-MS and freeze dried evaporated and used without further purification. For the from waterft-BuOH 4/1. saponification the residue was dissolved in methanol. 2M 1024 exact mass: 390.1961 g/mol aqueous NaOH-solution was added to ensure basic condi 1025 HPLC-MS: analytical method L tions. The mixture was irradiated in a microwave reactor for 1026 rt: 4.22 min-found mass: 391 (m/z+H) 10 min at 120°C. The reaction mixture was concentrated and purified by semi-preparative HPLC-MS and freeze dried Example #210 from waterft-BuOH 4/1. 1036 exact mass: 402.1227 g/mol Preparation of methyl 3-(7-((2-oxo-1,2,3,4-tetrahyd 1037. HPLC-MS: analytical method D roquinolin-7-yl)amino)-1H-pyrazolo 4.3-dpyrimi 1038 rt: 4.69 min-found mass: 403 (m/z+H) din-5-yl)benzoate 1027 methyl 3-(7-chloro-2-(4-methoxybenzyl)-2H-pyra Example #213 Zolo4.3-dpyrimidin-5-yl)benzoate (0.16 mmol) and Preparation of methyl 4-(7-((4-(4-methylpiperazin-1- 7-amino-3,4-dihydroquinolin-2(1H)-one (0.3 mmol 2 eq.) yl)phenyl)amino)-1H-pyrazolo 4,3-dipyrimidin-5-yl) were suspended in MeOH (dry, 3 mL) in a microwave vial benzoate (2-5 mL), HCl in dioxane (4M, 3 drops) was added. The reaction mixture was irradiated in a microwave reactor for 5 1039 methyl 4-(7-chloro-2-(4-methoxybenzyl)-2H-pyra min at 140°C. The reaction mixture was evaporated and used Zolo 4,3-dipyrimidin-5-yl)benzoate (0.16 mmol) and 4-(4- US 2012/032978.0 A1 Dec. 27, 2012 methylpiperazin-1-yl)aniline (0.3 mmol 2 eq.) were sus eq.) were suspended in MeCH (dry, 3 mL) in a microwave pended in MeOH (dry, 3 mL) in a microwave vial (2-5 mL), vial (2-5 mL), HCl in dioxane (4M, 3 drops) was added. The HCl in dioxane (4M, 3 drops) was added. The reaction mix reaction mixture was irradiated in a microwave reactor for 5 ture was irradiated in a microwave reactor for 5 minat 140°C. min at 140°C. The reaction mixture was evaporated and used The reaction mixture was evaporated and used without fur without further purification. The residue was dissolved in ther purification. The residue was dissolved in TFA (3 mL). TFA (3 mL). The reaction mixture was irradiated in a micro The reaction mixture was irradiated in a microwave reactor wave reactor for 5 min at 140°C. The reaction mixture was for 5 min at 140°C. The reaction mixture was concentrated concentrated and purified by semi-preparative HPLC-MS and purified by semi-preparative HPLC-MS and freeze dried and freeze dried from waterft-BuOH 471. from waterft-BuOH 4/1. 1052 exact mass: 432.1193 g/mol 1040 exact mass: 443.2443 g/mol 1041 HPLC-MS: analytical method L 1053 HPLC-MS: analytical method L 1042 rt: 3.54 min-found mass: 444 (m/z+H) 1054 rt: 4.81 min-found mass: 433 (m/z+H) Example #214 Example #217 Preparation of methyl 4-(7-((3,4-dimethoxyphenyl) Preparation of methyl 3-(7-((2-oxo-2,3,4,5-tetrahy amino)-1H-pyrazolo 4,3-dipyrimidin-5-yl)benzoate dro-1H-benzoblazepin-8-yl)amino)-1H-pyrazolo4. 1043 methyl 4-(7-chloro-2-(4-methoxybenzyl)-2H-pyra 3-dipyrimidin-5-yl)benzoate Zolo4.3-dpyrimidin-5-yl)benzoate (0.16 mmol) and 3,4- dimethoxyaniline (0.3 mmol 2 eq.) were suspended in MeOH 1055 methyl 3-(7-chloro-2-(4-methoxybenzyl)-2H-pyra (dry, 3 mL) in a microwave vial (2-5 mL), HCl in dioxane Zolo 4,3-dipyrimidin-5-yl)benzoate (0.16 mmol) and (4M, 3 drops) was added. The reaction mixture was irradiated 8-amino-4,5-dihydro-1H-benzoblazepin-2(3H)-one (0.3 in a microwave reactor for 5 min at 140° C. The reaction mmol 2 eq.) were suspended in MeOH (dry, 3 mL) in a mixture was evaporated and used without further purification. microwave vial (2-5 mL), HCl in dioxane (4M, 3 drops) was The residue was dissolved in TFA (3 mL). The reaction mix added. The reaction mixture was irradiated in a microwave ture was irradiated in a microwave reactor for 5 minat 140°C. reactor for 5 min at 140°C. The reaction mixture was evapo The reaction mixture was concentrated and purified by semi rated and used without further purification. The residue was preparative HPLC-MS and freeze dried from water/t-BuOH dissolved in TFA (3 mL). The reaction mixture was irradiated 4f1. in a microwave reactor for 5 min at 140° C. The reaction 1044 exact mass: 405. 1697 g/mol mixture was concentrated and purified by semi-preparative 1045 HPLC-MS: analytical method L HPLC-MS and freeze dried from waterft-BuOH 4/1. 1046 rt: 4.81 min-found mass: 406 (m/z+H) 1056 exact mass: 428.1868 g/mol Example #215 1057. HPLC-MS: analytical method L 1058 rt: 4.65 min-found mass: 429 (m/z+H) Preparation of methyl 4-(7-((2-oxo-1,2,3,4-tetrahyd roquinolin-7-yl)amino)-1H-pyrazolo 4.3-dpyrimi Example #218 din-5-yl)benzoate 1047 methyl 4-(7-chloro-2-(4-methoxybenzyl)-2H-pyra Preparation of 3-(7-((2-oxo-2,3,4,5-tetrahydro-1H Zolo4.3-dpyrimidin-5-yl)benzoate (0.16 mmol) and benzoblazepin-8-yl)amino)-1H-pyrazolo 4,3-d 7-amino-3,4-dihydroquinolin-2(1H)-one (0.3 mmol 2 eq.) pyrimidin-5-yl)benzoic acid were suspended in MeOH (dry, 3 mL) in a microwave vial (2-5 mL), HCl in dioxane (4M, 3 drops) was added. The 1059 3-(7-chloro-2-(4-methoxybenzyl)-2H-pyrazolo.4, reaction mixture was irradiated in a microwave reactor for 5 3-dipyrimidin-5-yl)benzoic acid methyl ester (0.16 mmol) min at 140°C. The reaction mixture was evaporated and used and 8-amino-4,5-dihydro-1H-benzoblazepin-2(3H)-one without further purification. The residue was dissolved in (0.3 mmol 2 eq.) were suspended in MeOH (dry, 3 mL) in a TFA (3 mL). The reaction mixture was irradiated in a micro microwave vial (2-5 mL), HCl in dioxane (4M, 3 drops) was wave reactor for 5 min at 140°C. The reaction mixture was added. The reaction mixture was irradiated in a microwave concentrated and purified by semi-preparative HPLC-MS reactor for 5 min at 140°C. The reaction mixture was evapo and freeze dried from waterft-BuOH 471. rated and used without further purification. The residue was dissolved in TFA (3 mL). The reaction mixture was irradiated 1048 exact mass: 414.1673 g/mol in a microwave reactor for 5 min at 140° C. The reaction 1049 HPLC-MS: analytical method L mixture was evaporated and used without further purification. 1050 rt: 4.54 min-found mass: 415 (m/z+H) For the saponification the residue was dissolved in methanol. 2Maqueous NaOH-solution was added to ensure basic con Example #216 ditions. The mixture was irradiated in a microwave reactor for Preparation of methyl 3-(7-((3-oxo-3,4-dihydro-2H 10 min at 120°C. The reaction mixture was concentrated and benzob 14thiazin-6-yl)amino)-1H-pyrazolo 4.3- purified by semi-preparative HPLC-MS and freeze dried dpyrimidin-5-yl)benzoate from waterft-BuOH 4/1. 1051 methyl 3-(7-chloro-2-(4-methoxybenzyl)-2H-pyra 1060 exact mass: 414.1673 g/mol Zolo4.3-dpyrimidin-5-yl)benzoate (0.16 mmol) and 1061 HPLC-MS: analytical method L 6-amino-2H-benzob 14thiazin-3 (4H)-one (0.3 mmol 2 1062 rt: 4.04 min-found mass: 415 (m/z+H) US 2012/032978.0 A1 Dec. 27, 2012 79

Example #219 Example #222 Preparation of N-(3,4-dimethoxyphenyl)-5-(3-(pen Preparation of 7-((5-(3-(pentafluorosulfanyl)phenyl)- tafluorosulfanyl)phenyl)-1H-pyrazolo 4.3-dpyrimi 1H-pyrazolo 4,3-dipyrimidin-7-yl)amino)-3,4-dihy din-7-amine droquinolin-2(1H)-one 1063) 7-chloro-5-(3-(pentafluorosulfanyl)phenyl)-2-(4- 1075) 7-chloro-5-(3-(pentafluorosulfanyl)phenyl)-2-(4- methoxybenzyl)-2H-pyrazolo 4,3-dipyrimidine (0.16 methoxybenzyl)-2H-pyrazolo 4,3-dipyrimidine (0.16 mmol) and 3,4-dimethoxyaniline (0.3 mmol 2 eq.) were sus mmol) and 7-amino-3,4-dihydroquinolin-2(1H)-one (0.3 pended in MeOH (dry, 3 mL) in a microwave vial (2-5 mL), mmol 2 eq.) were suspended in MeOH (dry, 3 mL) in a HCl in dioxane (4M, 3 drops) was added. The reaction mix microwave vial (2-5 mL), HCl in dioxane (4M, 3 drops) was ture was irradiated in a microwave reactor for 5 minat 140°C. added. The reaction mixture was irradiated in a microwave The reaction mixture was evaporated and used without fur reactor for 5 min at 140°C. The reaction mixture was evapo ther purification. The residue was dissolved in TFA (3 mL). rated and used without further purification. The residue was The reaction mixture was irradiated in a microwave reactor dissolved in TFA (3 mL). The reaction mixture was irradiated for 5 min at 140°C. The reaction mixture was concentrated in a microwave reactor for 5 min at 140° C. The reaction and purified by semi-preparative HPLC-MS and freeze dried mixture was concentrated and purified by semi-preparative from waterft-BuOH 4/1. HPLC-MS and freeze dried from waterft-BuOH 4/1. 1064 exact mass: 473.1128 g/mol 1076 exact mass: 482.1105 g/mol 1065 HPLC-MS: analytical method D 1077. HPLC-MS: analytical method D 1066 rt: 7.77 min-found mass: 474 (m/z+H) 1078 rt: 7.25 min-found mass: 483 (m/z+H) Example #220 Example #223 Preparation of 5-(3-(pentafluorosulfanyl)phenyl)-N- Preparation of N-(3,4-dimethoxyphenyl)-5-(3-(meth (4-morpholinophenyl)-1H-pyrazolo 4.3-dipyrimidin ylthio)phenyl)-1H-pyrazolo4.3-dpyrimidin-7- 7-amine amine 1067 7-chloro-5-(3-(pentafluorosulfanyl)phenyl)-2-(4- 1079 7-chloro-2-(4-methoxybenzyl)-5-(3-(methylthio) methoxybenzyl)-2H-pyrazolo 4.3-dipyrimidine (0.16 phenyl)-2H-pyrazolo 4.3-dipyrimidine (0.16 mmol) and 3,4- mmol) and 4-morpholinoaniline (0.3 mmol 2 eq.) were sus dimethoxyaniline (0.3 mmol 2 eq.) were suspended in MeCH pended in MeOH (dry, 3 mL) in a microwave vial (2-5 mL), (dry, 3 mL) in a microwave vial (2-5 mL), HCl in dioxane HCl in dioxane (4M, 3 drops) was added. The reaction mix (4M, 3 drops) was added. The reaction mixture was irradiated ture was irradiated in a microwave reactor for 5 minat 140°C. in a microwave reactor for 5 min at 140° C. The reaction The reaction mixture was evaporated and used without fur mixture was evaporated and used without further purification. ther purification. The residue was dissolved in TFA (3 mL). The residue was dissolved in TFA (3 mL). The reaction mix The reaction mixture was irradiated in a microwave reactor ture was irradiated in a microwave reactor for 5 minat 140°C. for 5 min at 140°C. The reaction mixture was concentrated The reaction mixture was concentrated and purified by semi and purified by semi-preparative HPLC-MS and freeze dried preparative HPLC-MS and freeze dried from water/t-BuOH from waterft-BuOH 4/1. 4f1. 1068 exact mass: 498.1500 g/mol 1080 exact mass: 393.1528 g/mol 1069 HPLC-MS: analytical method D 1081 HPLC-MS: analytical method D 1070 rt: 7.74 min-found mass: 499 (m/z+H) 1082 rt: 6.18 min-found mass: 394 (m/z+H) Example #221 Example #224 Preparation of N-(4-(4-methylpiperazin-1-yl)phe Preparation of 5-(3-(methylthio)phenyl)-N-(4-mor nyl)-5-(3-(pentafluorosulfanyl)phenyl)-1H-pyrazolo pholinophenyl)-1H-pyrazolo 4,3-dipyrimidin-7- 4.3-dipyrimidin-7-amine amine 1071 7-chloro-5-(3-(pentafluorosulfanyl)phenyl)-2-(4- 1083) 7-chloro-2-(4-methoxybenzyl)-5-(3-(methylthio) methoxybenzyl)-2H-pyrazolo 4,3-dipyrimidine (0.16 phenyl)-2H-pyrazolo 4,3-dipyrimidine (0.16 mmol) and mmol) and 4-(4-methylpiperazin-1-yl)aniline (0.3 mmol 2 4-morpholinoaniline (0.3 mmol 2 eq.) were suspended in eq.) were suspended in MeCH (dry, 3 mL) in a microwave MeOH (dry, 3 mL) in a microwave vial (2-5 mL), HCl in vial (2-5 mL), HCl in dioxane (4M, 3 drops) was added. The dioxane (4M, 3 drops) was added. The reaction mixture was reaction mixture was irradiated in a microwave reactor for 5 irradiated in a microwave reactor for 5 min at 140°C. The min at 140°C. The reaction mixture was evaporated and used reaction mixture was evaporated and used without further without further purification. The residue was dissolved in purification. The residue was dissolved in TFA (3 mL). The TFA (3 mL). The reaction mixture was irradiated in a micro reaction mixture was irradiated in a microwave reactor for 5 wave reactor for 5 min at 140°C. The reaction mixture was min at 140° C. The reaction mixture was concentrated and concentrated and purified by semi-preparative HPLC-MS purified by semi-preparative HPLC-MS and freeze dried and freeze dried from waterft-BuOH 471. from waterft-BuOH 4/1. 1072 exact mass: 511.1876 g/mol 1084 exact mass: 418.1899 g/mol 1073 HPLC-MS: analytical method D 1085 HPLC-MS: analytical method D 1074 rt: 5.24 min-found mass: 512 (m/z+H) 1086 rt: 6.11 min-found mass: 419 (m/z+H) US 2012/032978.0 A1 Dec. 27, 2012 80

Example #225 Example #228 Preparation of N-(4-(4-methylpiperazin-1-yl)phe Preparation of N-(3,4-dimethoxyphenyl)-5-(3-(trif nyl)-5-(3-(methylthio)phenyl)-1H-pyrazolo 4,3-d luoromethyl)phenyl)-1H-pyrazolo 4.3-dpyrimidin pyrimidin-7-amine 7-amine 1087 7-chloro-2-(4-methoxybenzyl)-5-(3-(methylthio) 1099) 7-chloro-2-(4-methoxybenzyl)-5-(3-(trifluorom phenyl)-2H-pyrazolo 4,3-dipyrimidine (0.16 mmol) and ethyl)phenyl)-2H-pyrazolo 4,3-dipyrimidine (0.16 mmol) 4-(4-methylpiperazin-1-yl)aniline (0.3 mmol 2 eq.) were sus and 3,4-dimethoxyaniline (0.3 mmol 2 eq.) were suspended pended in MeOH (dry, 3 mL) in a microwave vial (2-5 mL), in MeCH (dry, 3 mL) in a microwave vial (2-5 mL), HCl in HCl in dioxane (4M, 3 drops) was added. The reaction mix dioxane (4M, 3 drops) was added. The reaction mixture was ture was irradiated in a microwave reactor for 5 minat 140°C. irradiated in a microwave reactor for 5 min at 140°C. The The reaction mixture was evaporated and used without fur reaction mixture was evaporated and used without further ther purification. The residue was dissolved in TFA (3 mL). purification. The residue was dissolved in TFA (3 mL). The The reaction mixture was irradiated in a microwave reactor reaction mixture was irradiated in a microwave reactor for 5 for 5 min at 140°C. The reaction mixture was concentrated min at 140° C. The reaction mixture was concentrated and and purified by semi-preparative HPLC-MS and freeze dried purified by semi-preparative HPLC-MS and freeze dried from waterft-BuOH 4/1. from waterft-BuOH 4/1. 1088 exact mass: 431.2275 g/mol 1100 exact mass: 415.1450 g/mol 1089 HPLC-MS: analytical method D 1101 HPLC-MS: analytical method A 1090 rt: 3.80 min-found mass: 432 (m/z+H) 1102 rt: 3.30 min-found mass: 416 (m/z+H) Example #226 Example #229 Preparation of N-(3,4-dimethoxyphenyl)-5-(3-(trif Preparation of N-(4-morpholinophenyl)-5-(3-(trif luoromethoxy)phenyl)-1H-pyrazolo 4,3-dipyrimi luoromethyl)phenyl)-1H-pyrazolo 4.3-dpyrimidin din-7-amine 7-amine 1091) 7-chloro-2-(4-methoxybenzyl)-5-(3-(trifluo romethoxy)phenyl)-2H-pyrazolo 4,3-dipyrimidine (0.16 1103) 7-chloro-2-(4-methoxybenzyl)-5-(3-(trifluorom mmol) and 3,4-dimethoxyaniline (0.3 mmol 2 eq.) were sus ethyl)phenyl)-2H-pyrazolo 4,3-dipyrimidine (0.16 mmol) pended in MeOH (dry, 3 mL) in a microwave vial (2-5 mL), and 4-morpholinoaniline (0.3 mmol 2 eq.) were suspended in HCl in dioxane (4M, 3 drops) was added. The reaction mix MeOH (dry, 3 mL) in a microwave vial (2-5 mL), HCl in ture was irradiated in a microwave reactor for 5 minat 140°C. dioxane (4M, 3 drops) was added. The reaction mixture was The reaction mixture was evaporated and used without fur irradiated in a microwave reactor for 5 min at 140°C. The ther purification. The residue was dissolved in TFA (3 mL). reaction mixture was evaporated and used without further The reaction mixture was irradiated in a microwave reactor purification. The residue was dissolved in TFA (3 mL). The reaction mixture was irradiated in a microwave reactor for 5 for 5 min at 140°C. The reaction mixture was concentrated and purified by semi-preparative HPLC-MS and freeze dried min at 140° C. The reaction mixture was concentrated and from waterft-BuOH 4/1. purified by semi-preparative HPLC-MS and freeze dried from waterft-BuOH 4/1. 1092 exact mass: 431. 1394 g/mol 1093 HPLC-MS: analytical method A 1104 exact mass: 440.1821 g/mol 1094 rt: 3.35 min-found mass: 432 (m/z+H) 1105 HPLC-MS: analytical method A 1106 rt: 3.28 min-found mass: 441 (m/z+H) Example #227 Example #230 Preparation of N-(4-morpholinophenyl)-5-(3-(trif luoromethoxy)phenyl)-1H-pyrazolo 4,3-dipyrimi Preparation of 5-(3-chlorophenyl)-N-(3,4-dimethox din-7-amine yphenyl)-1H-pyrazolo 4,3-dipyrimidin-7-amine 1095) 7-chloro-2-(4-methoxybenzyl)-5-(3-(trifluo 1107 7-chloro-5-(3-chlorophenyl)-2-(4-methoxyben romethoxy)phenyl)-2H-pyrazolo 4,3-dipyrimidine (0.16 Zyl)-2H-pyrazolo 4,3-dipyrimidine (0.16 mmol) and 3,4- mmol) and 4-morpholinoaniline (0.3 mmol 2 eq.) were sus dimethoxyaniline (0.3 mmol 2 eq.) were suspended in MeCH pended in MeOH (dry, 3 mL) in a microwave vial (2-5 mL), (dry, 3 mL) in a microwave vial (2-5 mL), HCl in dioxane HCl in dioxane (4M, 3 drops) was added. The reaction mix (4M, 3 drops) was added. The reaction mixture was irradiated ture was irradiated in a microwave reactor for 5 minat 140°C. in a microwave reactor for 5 min at 140° C. The reaction The reaction mixture was evaporated and used without fur mixture was evaporated and used without further purification. ther purification. The residue was dissolved in TFA (3 mL). The residue was dissolved in TFA (3 mL). The reaction mix The reaction mixture was irradiated in a microwave reactor ture was irradiated in a microwave reactor for 5 minat 140°C. for 5 min at 140°C. The reaction mixture was concentrated The reaction mixture was concentrated and purified by semi and purified by semi-preparative HPLC-MS and freeze dried preparative HPLC-MS and freeze dried from water/t-BuOH from waterft-BuOH 4/1. 4f1. 1096 exact mass: 456.1765 g/mol 1108 exact mass: 381.1201 g/mol 1097 HPLC-MS: analytical method A 1109 HPLC-MS: analytical method A 1098 rt: 3.31 min-found mass: 457 (m/z+H) 1110 rt: 3.23 min-found mass: 382 (m/z+H) US 2012/032978.0 A1 Dec. 27, 2012 81

Example #231 Example #234 Preparation of 5-(3-chlorophenyl)-N-(4-morpholi Preparation of N-(3,4-dimethoxyphenyl)-5-(3-fluo nophenyl)-1H-pyrazolo 4.3-dipyrimidin-7-amine rophenyl)-1H-pyrazolo 4.3-dpyrimidin-7-amine 1111 7-chloro-5-(3-chlorophenyl)-2-(4-methoxyben 1123) 7-chloro-5-(3-fluorophenyl)-2-(4-methoxyben Zyl)-2H-pyrazolo 4,3-dipyrimidine (0.16 mmol) and 4-mor Zyl)-2H-pyrazolo 4,3-dipyrimidine (0.16 mmol) and 3,4- pholinoaniline (0.3 mmol 2 eq.) were suspended in MeOH dimethoxyaniline (0.3 mmol 2 eq.) were suspended in MeCH (dry, 3 mL) in a microwave vial (2-5 mL), HCl in dioxane (dry, 3 mL) in a microwave vial (2-5 mL), HCl in dioxane (4M, 3 drops) was added. The reaction mixture was irradiated (4M, 3 drops) was added. The reaction mixture was irradiated in a microwave reactor for 5 min at 140° C. The reaction in a microwave reactor for 5 min at 140° C. The reaction mixture was evaporated and used without further purification. mixture was evaporated and used without further purification. The residue was dissolved in TFA (3 mL). The reaction mix The residue was dissolved in TFA (3 mL). The reaction mix ture was irradiated in a microwave reactor for 5 minat 140°C. ture was irradiated in a microwave reactor for 5 minat 140°C. The reaction mixture was concentrated and purified by semi The reaction mixture was concentrated and purified by semi preparative HPLC-MS and freeze dried from water/t-BuOH preparative HPLC-MS and freeze dried from water/t-BuOH 4f1. 4f1. 1112 exact mass: 406.1572 g mol 1124 exact mass: 365.1497 g/mol 1113 HPLC-MS: analytical method A 1125 HPLC-MS: analytical method A 1114 rt: 3.20 min-found mass: 407 (m/z+H) 1126 rt: 3.01 min-found mass: 366 (m/z+H) Example #232 Example #235 Preparation of N-(3,4-dimethoxyphenyl)-5-(2-fluo Preparation of 5-(3-fluorophenyl)-N-(4-morpholi rophenyl)-1H-pyrazolo 4.3-dpyrimidin-7-amine nophenyl)-1H-pyrazolo 4.3-dipyrimidin-7-amine 1115) 7-chloro-5-(2-fluorophenyl)-2-(4-methoxyben 1127 7-chloro-5-(3-fluorophenyl)-2-(4-methoxyben Zyl)-2H-pyrazolo 4,3-dipyrimidine (0.16 mmol) and 3,4- Zyl)-2H-pyrazolo 4,3-dipyrimidine (0.16 mmol) and 4-mor dimethoxyaniline (0.3 mmol 2 eq.) were suspended in MeOH pholinoaniline (0.3 mmol 2 eq.) were suspended in MeOH (dry, 3 mL) in a microwave vial (2-5 mL), HCl in dioxane (dry, 3 mL) in a microwave vial (2-5 mL), HCl in dioxane (4M, 3 drops) was added. The reaction mixture was irradiated (4M, 3 drops) was added. The reaction mixture was irradiated in a microwave reactor for 5 min at 140° C. The reaction in a microwave reactor for 5 min at 140° C. The reaction mixture was evaporated and used without further purification. mixture was evaporated and used without further purification. The residue was dissolved in TFA (3 mL). The reaction mix The residue was dissolved in TFA (3 mL). The reaction mix ture was irradiated in a microwave reactor for 5 minat 140°C. ture was irradiated in a microwave reactor for 5 minat 140°C. The reaction mixture was concentrated and purified by semi The reaction mixture was concentrated and purified by semi preparative HPLC-MS and freeze dried from water/t-BuOH preparative HPLC-MS and freeze dried from water/t-BuOH 4f1. 4f1. 1116 exact mass: 365.1497 g/mol 1128 exact mass: 390.1868 g/mol 1117 HPLC-MS: analytical method A 1129 HPLC-MS: analytical method A 1118 rt: 2.64 min-found mass: 366 (m/z+H) 1130 rt: 2.97 min-found mass: 391 (m/z+H) Example #236 Example #233 Preparation of 7-((5-(3-(methylthio)phenyl)-1H Preparation of 5-(2-fluorophenyl)-N-(4-morpholi pyrazolo 4,3-dipyrimidin-7-yl)amino)-3,4-dihydro nophenyl)-1H-pyrazolo 4.3-dipyrimidin-7-amine quinolin-2(1H)-one 1119) 7-chloro-5-(2-fluorophenyl)-2-(4-methoxyben 1131) 7-chloro-2-(4-methoxybenzyl)-5-(3-(methylthio) Zyl)-2H-pyrazolo 4,3-dipyrimidine (0.16 mmol) and 4-mor phenyl)-2H-pyrazolo 4,3-dipyrimidine (0.16 mmol) and pholinoaniline (0.3 mmol 2 eq.) were suspended in MeOH 7-amino-3,4-dihydroquinolin-2(1H)-one (0.3 mmol 2 eq.) (dry, 3 mL) in a microwave vial (2-5 mL), HCl in dioxane were suspended in MeOH (dry, 3 mL) in a microwave vial (4M, 3 drops) was added. The reaction mixture was irradiated (2-5 mL), HCl in dioxane (4M, 3 drops) was added. The in a microwave reactor for 5 min at 140° C. The reaction reaction mixture was irradiated in a microwave reactor for 5 mixture was evaporated and used without further purification. min at 140°C. The reaction mixture was evaporated and used The residue was dissolved in TFA (3 mL). The reaction mix without further purification. The residue was dissolved in ture was irradiated in a microwave reactor for 5 minat 140°C. TFA (3 mL). The reaction mixture was irradiated in a micro The reaction mixture was concentrated and purified by semi wave reactor for 5 min at 140°C. The reaction mixture was preparative HPLC-MS and freeze dried from water/t-BuOH concentrated and purified by semi-preparative HPLC-MS 4f1. and freeze dried from waterft-BuOH 471. 1120 exact mass: 390.1868 g/mol 1132 exact mass: 402.1505 g/mol 1121 HPLC-MS: analytical method A 1133 HPLC-MS: analytical method D 1122 rt: 2.59 min-found mass: 391 (m/z+H) 1134 rt: 5.89 min-found mass: 403 (m/z+H) US 2012/032978.0 A1 Dec. 27, 2012 82

Example #237 Example #240 Preparation of 3-(7-((4-(4-acetylpiperazin-1-yl)phe Preparation of 3-(7-((3-methoxy-4-morpholinophe nyl)amino)-1H-pyrazolo4.3-dpyrimidin-5-yl)ben nyl)amino)-1H-pyrazolo4.3-dpyrimidin-5-yl)ben Zenesulfonamide Zenesulfonamide 1135 3-(7-chloro-2-(4-methoxybenzyl)-2H-pyrazolo.4, 1147 3-(7-chloro-2-(4-methoxybenzyl)-2H-pyrazolo.4, 3-dipyrimidin-5-yl)benzenesulfonamide (0.16 mmol) and 3-dipyrimidin-5-yl)benzenesulfonamide (0.16 mmol) and 1-(4-(4-aminophenyl)piperazin-1-yl)ethan-1-one (0.3 mmol 3-methoxy-4-morpholinoaniline (0.3 mmol 2 eq.) were Sus 2 eq.) were suspended in MeCH (dry, 3 mL) in a microwave pended in MeOH (dry, 3 mL) in a microwave vial (2-5 mL), vial (2-5 mL), HCl in dioxane (4M, 3 drops) was added. The HCl in dioxane (4M, 3 drops) was added. The reaction mix reaction mixture was irradiated in a microwave reactor for 5 ture was irradiated in a microwave reactor for 5 minat 140°C. min at 140°C. The reaction mixture was evaporated and used The reaction mixture was evaporated and used without fur without further purification. The residue was dissolved in ther purification. The residue was dissolved in TFA (3 mL). TFA (3 mL). The reaction mixture was irradiated in a micro The reaction mixture was irradiated in a microwave reactor wave reactor for 5 min at 140°C. The reaction mixture was for 5 min at 140°C. The reaction mixture was concentrated concentrated and purified by semi-preparative HPLC-MS and purified by semi-preparative HPLC-MS and freeze dried and freeze dried from waterft-BuOH 471. from waterft-BuOH 4/1. 1136 exact mass: 492.2033 g/mol 1148 exact mass: 481.1856 g/mol 1137 HPLC-MS: analytical method L 1149 HPLC-MS: analytical method L 1138 rt: 3.83 min-found mass: 493 (m/z+H) 1150 rt: 3.99 min-found mass: 482 (m/z+H) Example #238 Example #241 Preparation of 3-(7-((2-oxo-1,2,3,4-tetrahydroquino Preparation of 4-(7-((4-(4-methylpiperazin-1-yl) lin-7-yl)amino)-1H-pyrazolo 4,3-dipyrimidin-5-yl) phenyl)amino)-1H-pyrazolo 4,3-dipyrimidin-5-yl) benzenesulfonamide benzoic acid 1139 3-(7-chloro-2-(4-methoxybenzyl)-2H-pyrazolo.4, 1151 4-(7-chloro-2-(4-methoxybenzyl)-2H-pyrazolo.4, 3-dipyrimidin-5-yl)benzenesulfonamide (0.16 mmol) and 3-dipyrimidin-5-yl)benzoic acid methyl ester (0.16 mmol) 7-amino-3,4-dihydroquinolin-2(1H)-one (0.3 mmol 2 eq.) and 4-(4-methylpiperazin-1-yl)aniline (0.3 mmol 2 eq.) were were suspended in MeOH (dry, 3 mL) in a microwave vial suspended in MeCH (dry, 3 mL) in a microwave vial (2-5 (2-5 mL), HCl in dioxane (4M, 3 drops) was added. The mL), HCl in dioxane (4M, 3 drops) was added. The reaction reaction mixture was irradiated in a microwave reactor for 5 mixture was irradiated in a microwave reactor for 5 min at min at 140°C. The reaction mixture was evaporated and used 140°C. The reaction mixture was evaporated and used with without further purification. The residue was dissolved in out further purification. The residue was dissolved in TFA (3 TFA (3 mL). The reaction mixture was irradiated in a micro mL). The reaction mixture was irradiated in a microwave wave reactor for 5 min at 140°C. The reaction mixture was reactor for 5 min at 140°C. The reaction mixture was evapo concentrated and purified by semi-preparative HPLC-MS rated and used without further purification. For the saponifi and freeze dried from waterft-BuOH 471. cation the residue was dissolved in methanol. 2M aqueous NaOH-solution was added to ensure basic conditions. The 1140 exact mass: 435.1323 g/mol mixture was irradiated in a microwave reactor for 10 min at 1141 HPLC-MS: analytical method L 120° C. The reaction mixture was concentrated and purified 1142 rt: 3.91 min-found mass: 436 (m/z+H) by semi-preparative HPLC-MS and freeze dried from water/ t-BuOH 471. Example #239 1152 exact mass: 429.2249 g/mol Preparation of 3-(7-(4-morpholinophenyl)amino)- 1153 HPLC-MS: analytical method L 1H-pyrazolo 4,3-dipyrimidin-5-yl)benzenesulfona 1154 rt: 3.12 min-found mass: 430 (m/z+H) mide Example #242 1143) 3-(7-chloro-2-(4-methoxybenzyl)-2H-pyrazolo.4, 3-dipyrimidin-5-yl)benzenesulfonamide (0.16 mmol) and Preparation of methyl 4-(7-(4-morpholinophenyl) 4-morpholinoaniline (0.3 mmol 2 eq.) were Suspended in amino)-1H-pyrazolo 4,3-dipyrimidin-5-yl)benzoate MeOH (dry, 3 mL) in a microwave vial (2-5 mL), HCl in 1155 methyl 4-(7-chloro-2-(4-methoxybenzyl)-2H-pyra dioxane (4M, 3 drops) was added. The reaction mixture was Zolo 4,3-dipyrimidin-5-yl)benzoate (0.16 mmol) and 4-mor irradiated in a microwave reactor for 5 min at 140°C. The pholinoaniline (0.3 mmol 2 eq.) were suspended in MeCH reaction mixture was evaporated and used without further (dry, 3 mL) in a microwave vial (2-5 mL), HCl in dioxane purification. The residue was dissolved in TFA (3 mL). The (4M, 3 drops) was added. The reaction mixture was irradiated reaction mixture was irradiated in a microwave reactor for 5 in a microwave reactor for 5 min at 140° C. The reaction min at 140° C. The reaction mixture was concentrated and mixture was evaporated and used without further purification. purified by semi-preparative HPLC-MS and freeze dried The residue was dissolved in TFA (3 mL). The reaction mix from waterft-BuOH 4/1. ture was irradiated in a microwave reactor for 5 minat 140°C. 1144 exact mass: 451.1718 g/mol The reaction mixture was concentrated and purified by semi 1145 HPLC-MS: analytical method L preparative HPLC-MS and freeze dried from water/t-BuOH 1146 rt: 4.03 min-found mass: 452 (m/z+H) 4f1. US 2012/032978.0 A1 Dec. 27, 2012 83

1156 exact mass: 430.2067 g/mol The reaction mixture was evaporated and used without fur 1157 HPLC-MS: analytical method L ther purification. The residue was dissolved in TFA (3 mL). 1158 rt: 4.83 min-found mass: 431 (m/z+H) The reaction mixture was irradiated in a microwave reactor for 5 min at 140°C. The reaction mixture was concentrated Example #243 and purified by semi-preparative HPLC-MS and freeze dried from waterft-BuOH 4/1. Preparation of 4-(7-(4-morpholinophenyl)amino)- 1168 exact mass: 347.1105 g/mol 1H-pyrazolo 4,3-dipyrimidin-5-yl)benzoic acid 1169 HPLC-MS: analytical method D 1159 4-(7-chloro-2-(4-methoxybenzyl)-2H-pyrazolo.4, 1170 rt: 3.80 min-found mass: 348 (m/z+H) 3-dipyrimidin-5-yl)benzoic acid methyl ester (0.16 mmol) and 4-morpholinoaniline (0.3 mmol 2 eq.) were suspended in Example #246 MeOH (dry, 3 mL) in a microwave vial (2-5 mL), HCl in Preparation of 1-(4-(4-((5-(3-(methylsulfonyl)phe dioxane (4M, 3 drops) was added. The reaction mixture was nyl)-1H-pyrazolo4.3-dpyrimidin-7-yl)amino)phe irradiated in a microwave reactor for 5 min at 140°C. The nyl)piperazin-1-yl)ethan-1-one reaction mixture was evaporated and used without further purification. The residue was dissolved in TFA (3 mL). The 1171 7-chloro-2-(4-methoxybenzyl)-5-(3-(methylsulfo reaction mixture was irradiated in a microwave reactor for 5 nyl)phenyl)-2H-pyrazolo4.3-dpyrimidine (0.16 mmol) and min at 140°C. The reaction mixture was evaporated and used 1-(4-(4-aminophenyl)piperazin-1-yl)ethan-1-one (0.3 mmol without further purification. For the saponification the residue 2 eq.) were suspended in MeOH (dry, 3 mL) in a microwave was dissolved in methanol. 2Maqueous NaOH-solution was vial (2-5 mL), HCl in dioxane (4M, 3 drops) was added. The added to ensure basic conditions. The mixture was irradiated reaction mixture was irradiated in a microwave reactor for 5 in a microwave reactor for 10 min at 120° C. The reaction min at 140°C. The reaction mixture was evaporated and used mixture was concentrated and purified by semi-preparative without further purification. The residue was dissolved in HPLC-MS and freeze dried from waterft-BuOH 4/1. TFA (3 mL). The reaction mixture was irradiated in a micro 1160 exact mass: 416.1872 g/mol wave reactor for 5 min at 140°C. The reaction mixture was 1161 HPLC-MS: analytical method L concentrated and purified by semi-preparative HPLC-MS 1162 rt: 4.07 min-found mass: 417 (m/z+H) and freeze dried from waterft-BuOH 471. 1172 exact mass: 491.2103 g/mol Example #244 1173 HPLC-MS: analytical method L 1174 rt: 4.09 min-found mass: 492 (m/z+H) Preparation of 4-(7-((3,4-dimethoxyphenyl)amino)- 1H-pyrazolo 4,3-dipyrimidin-5-yl)benzoic acid Example #247 1163 4-(7-chloro-2-(4-methoxybenzyl)-2H-pyrazolo.4, Preparation of 5-(1H-indazol-6-yl)-N-(4-morpholi 3-dipyrimidin-5-yl)benzoic acid methyl ester (0.16 mmol) nophenyl)-1H-pyrazolo 4.3-dipyrimidin-7-amine and 3,4-dimethoxyaniline (0.3 mmol 2 eq.) were suspended in MeCH (dry, 3 mL) in a microwave vial (2-5 mL), HCl in 1175 7-chloro-5-(1H-indazol-6-yl)-2-(4-methoxyben dioxane (4M, 3 drops) was added. The reaction mixture was Zyl)-2H-pyrazolo 4,3-dipyrimidine (0.16 mmol) and 4-mor irradiated in a microwave reactor for 5 min at 140°C. The pholinoaniline (0.3 mmol 2 eq.) were suspended in MeCH reaction mixture was evaporated and used without further (dry, 3 mL) in a microwave vial (2-5 mL), HCl in dioxane purification. The residue was dissolved in TFA (3 mL). The (4M, 3 drops) was added. The reaction mixture was irradiated reaction mixture was irradiated in a microwave reactor for 5 in a microwave reactor for 5 min at 140° C. The reaction min at 140°C. The reaction mixture was evaporated and used mixture was evaporated and used without further purification. without further purification. For the saponification the residue The residue was dissolved in TFA (3 mL). The reaction mix was dissolved in methanol. 2Maqueous NaOH-solution was ture was irradiated in a microwave reactor for 5 minat 140°C. added to ensure basic conditions. The mixture was irradiated The reaction mixture was concentrated and purified by semi in a microwave reactor for 10 min at 120° C. The reaction preparative HPLC-MS and freeze dried from water/t-BuOH mixture was concentrated and purified by semi-preparative 4f1. HPLC-MS and freeze dried from waterft-BuOH 4/1. 1176 exact mass: 412.2036 g/mol 1164 exact mass: 391.1501 g/mol 1177. HPLC-MS: analytical method D 1165 HPLC-MS: analytical method L 1178 rt: 4.88 min-found mass: 413 (m/z+H) 1166 rt: 4.14 min-found mass: 392 (m/z+H) Example #248 Example #245 Preparation of 5-(1H-indazol-6-yl)-N-(4-(4-meth Preparation of N-(2-methyl-1H-benzodimidazol-5- ylpiperazin-1-yl)phenyl)-1H-pyrazolo 4.3-dipyrimi yl)-5-(thiophen-2-yl)-1H-pyrazolo 4.3-dpyrimidin din-7-amine 7-amine 1179 7-chloro-5-(1H-indazol-6-yl)-2-(4-methoxyben 1167 7-chloro-2-(4-methoxybenzyl)-5-(thiophen-2-yl)- Zyl)-2H-pyrazolo 4,3-dipyrimidine (0.16 mmol) and 4-(4- 2H-pyrazolo4.3-dpyrimidine (0.16 mmol) and 2-methyl methylpiperazin-1-yl)aniline (0.3 mmol 2 eq.) were Sus 1H-benzodimidazol-5-amine (0.3 mmol 2 eq.) were sus pended in MeOH (dry, 3 mL) in a microwave vial (2-5 mL), pended in MeOH (dry, 3 mL) in a microwave vial (2-5 mL), HCl in dioxane (4M, 3 drops) was added. The reaction mix HCl in dioxane (4M, 3 drops) was added. The reaction mix ture was irradiated in a microwave reactor for 5 minat 140°C. ture was irradiated in a microwave reactor for 5 minat 140°C. The reaction mixture was evaporated and used without fur US 2012/032978.0 A1 Dec. 27, 2012

ther purification. The residue was dissolved in TFA (3 mL). purification. The residue was dissolved in TFA (3 mL). The The reaction mixture was irradiated in a microwave reactor reaction mixture was irradiated in a microwave reactor for 5 for 5 min at 140°C. The reaction mixture was concentrated min at 140° C. The reaction mixture was concentrated and and purified by semi-preparative HPLC-MS and freeze dried purified by semi-preparative HPLC-MS and freeze dried from waterft-BuOH 4/1. from waterft-BuOH 4/1. 1180 exact mass: 425.2411 g/mol 1192 exact mass: 450.1787 g/mol 1181 HPLC-MS: analytical method D 1193 HPLC-MS: analytical method L 1182 rt: 3.53 min-found mass: 426 (m/z+H) 1194 rt: 4.35 min-found mass: 451 (m/z+H) Example #249 Example #252 Preparation of N-(3,4-dimethoxyphenyl)-5-(3-(meth Preparation of N-(2-methyl-1H-benzodimidazol-5- ylsulfonyl)phenyl)-1H-pyrazolo 4,3-dipyrimidin-7- yl)-5-(3-(methylsulfonyl)phenyl)-1H-pyrazolo 4.3-d amine pyrimidin-7-amine 1183 7-chloro-2-(4-methoxybenzyl)-5-(3-(methylsulfo 1195 7-chloro-2-(4-methoxybenzyl)-5-(3-(methylsulfo nyl)phenyl)-2H-pyrazolo4.3-dpyrimidine (0.16 mmol) and nyl)phenyl)-2H-pyrazolo4.3-dpyrimidine (0.16 mmol) and 3,4-dimethoxyaniline (0.3 mmol 2 eq.) were suspended in 2-methyl-1H-benzodimidazol-5-amine (0.3 mmol 2 eq.) MeOH (dry, 3 mL) in a microwave vial (2-5 mL), HCl in were suspended in MeOH (dry, 3 mL) in a microwave vial dioxane (4M, 3 drops) was added. The reaction mixture was (2-5 mL), HCl in dioxane (4M, 3 drops) was added. The irradiated in a microwave reactor for 5 min at 140°C. The reaction mixture was irradiated in a microwave reactor for 5 reaction mixture was evaporated and used without further min at 140°C. The reaction mixture was evaporated and used purification. The residue was dissolved in TFA (3 mL). The without further purification. The residue was dissolved in reaction mixture was irradiated in a microwave reactor for 5 TFA (3 mL). The reaction mixture was irradiated in a micro min at 140° C. The reaction mixture was concentrated and wave reactor for 5 min at 140°C. The reaction mixture was purified by semi-preparative HPLC-MS and freeze dried concentrated and purified by semi-preparative HPLC-MS from waterft-BuOH 4/1. and freeze dried from waterft-BuOH 471. 1184 exact mass: 425.1416 g/mol 1196 exact mass: 419.1378 g/mol 1185 HPLC-MS: analytical method L 1197. HPLC-MS: analytical method L 1186 rt: 4.38 min-found mass: 426 (m/z+H) 1198 rt: 3.21 min-found mass: 420 (m/z+H) Example #250 Example #253 Preparation of 7-((5-(3-(methylsulfonyl)phenyl)-1H Preparation of N,5-bis(3-(methylsulfonyl)phenyl)- pyrazolo 4,3-dipyrimidin-7-yl)amino)-3,4-dihydro 1H-pyrazolo 4,3-dipyrimidin-7-amine quinolin-2(1H)-one 1199) 7-chloro-2-(4-methoxybenzyl)-5-(3-(methylsulfo 1187 7-chloro-2-(4-methoxybenzyl)-5-(3-(methylsulfo nyl)phenyl)-2H-pyrazolo4.3-dpyrimidine (0.16 mmol) and nyl)phenyl)-2H-pyrazolo4.3-dpyrimidine (0.16 mmol) and 3-(methylsulfonyl)aniline (0.3 mmol 2 eq.) were suspended 7-amino-3,4-dihydroquinolin-2(1H)-one (0.3 mmol 2 eq.) in MeCH (dry, 3 mL) in a microwave vial (2-5 mL), HCl in were suspended in MeOH (dry, 3 mL) in a microwave vial dioxane (4M, 3 drops) was added. The reaction mixture was (2-5 mL), HCl in dioxane (4M, 3 drops) was added. The irradiated in a microwave reactor for 5 min at 140°C. The reaction mixture was irradiated in a microwave reactor for 5 reaction mixture was evaporated and used without further min at 140°C. The reaction mixture was evaporated and used purification. The residue was dissolved in TFA (3 mL). The without further purification. The residue was dissolved in reaction mixture was irradiated in a microwave reactor for 5 TFA (3 mL). The reaction mixture was irradiated in a micro min at 140° C. The reaction mixture was concentrated and wave reactor for 5 min at 140°C. The reaction mixture was purified by semi-preparative HPLC-MS and freeze dried concentrated and purified by semi-preparative HPLC-MS from waterft-BuOH 4/1. and freeze dried from waterft-BuOH 471. 1200 exact mass: 443.0937 g/mol 1188 exact mass: 434.1393 g/mol 1201 HPLC-MS: analytical method L 1189 HPLC-MS: analytical method L 1202 rt: 4.29 min-found mass: 444 (m/z+H) 1190 rt: 4.04 min-found mass: 435 (m/z+H) Example #254 Example #251 Preparation of N-(3-(methylsulfonyl)phenyl)-5- Preparation of 5-(3-(methylsulfonyl)phenyl)-N-(4- (thiophen-2-yl)-1H-pyrazolo 4,3-dipyrimidin-7- morpholinophenyl)-1H-pyrazolo 4,3-dipyrimidin-7- amine amine 1203) 7-chloro-2-(4-methoxybenzyl)-5-(thiophen-2-yl)- 1191) 7-chloro-2-(4-methoxybenzyl)-5-(3-(methylsulfo 2H-pyrazolo 4,3-dipyrimidine (0.16 mmol) and 3-(methyl nyl)phenyl)-2H-pyrazolo4.3-dpyrimidine (0.16 mmol) and sulfonyl)aniline (0.3 mmol 2 eq.) were suspended in MeOH 4-morpholinoaniline (0.3 mmol 2 eq.) were Suspended in (dry, 3 mL) in a microwave vial (2-5 mL), HCl in dioxane MeOH (dry, 3 mL) in a microwave vial (2-5 mL), HCl in (4M, 3 drops) was added. The reaction mixture was irradiated dioxane (4M, 3 drops) was added. The reaction mixture was in a microwave reactor for 5 min at 140° C. The reaction irradiated in a microwave reactor for 5 min at 140°C. The mixture was evaporated and used without further purification. reaction mixture was evaporated and used without further The residue was dissolved in TFA (3 mL). The reaction mix US 2012/032978.0 A1 Dec. 27, 2012

ture was irradiated in a microwave reactor for 5 minat 140°C. TFA (3 mL). The reaction mixture was irradiated in a micro The reaction mixture was concentrated and purified by semi wave reactor for 5 min at 140°C. The reaction mixture was preparative HPLC-MS and freeze dried from water/t-BuOH concentrated and purified by semi-preparative HPLC-MS 4f1. and freeze dried from waterft-BuOH 471. 1204 exact mass: 371.0664 g/mol 1216 exact mass: 396.1640 g/mol 1205 HPLC-MS: analytical method L 1217. HPLC-MS: analytical method CP 1206 rt: 4.43 min-found mass: 372 (m/z+H) 1218 rt: 2.46 min-found mass: 397 (m/z+H) Example #255 Example #258 Preparation of 2-((3-((5-(thiophen-2-yl)-1H-pyrazolo Preparation of N-(4-morpholinophenyl)-5-(1H-pyr 4.3-dpyrimidin-7-yl)amino)phenyl)sulfonyl)ethan rolo3.2-bipyridin-6-yl)-1H-pyrazolo 4.3-dpyrimi 1-ol din-7-amine 1207 7-chloro-2-(4-methoxybenzyl)-5-(thiophen-2-yl)- 1219 7-chloro-2-(4-methoxybenzyl)-5-(1H-pyrrolo3.2- 2H-pyrazolo4.3-dpyrimidine (0.16 mmol) and 2-((3-ami bipyridin-6-yl)-2H-pyrazolo 4,3-dipyrimidine (0.16 mmol) nophenyl)sulfonyl)ethan-1-ol (0.3 mmol 2 eq.) were sus and 4-morpholinoaniline (0.3 mmol 2 eq.) were suspended in pended in MeOH (dry, 3 mL) in a microwave vial (2-5 mL), MeOH (dry, 3 mL) in a microwave vial (2-5 mL), HCl in HCl in dioxane (4M, 3 drops) was added. The reaction mix dioxane (4M, 3 drops) was added. The reaction mixture was ture was irradiated in a microwave reactor for 5 minat 140°C. irradiated in a microwave reactor for 5 min at 140°C. The The reaction mixture was evaporated and used without fur reaction mixture was evaporated and used without further ther purification. The residue was dissolved in TFA (3 mL). purification. The residue was dissolved in TFA (3 mL). The The reaction mixture was irradiated in a microwave reactor reaction mixture was irradiated in a microwave reactor for 5 for 5 min at 140°C. The reaction mixture was concentrated min at 140° C. The reaction mixture was concentrated and and purified by semi-preparative HPLC-MS and freeze dried purified by semi-preparative HPLC-MS and freeze dried from waterft-BuOH 4/1. from waterft-BuOH 4/1. 1208 exact mass: 401.0803 g/mol 1220 exact mass: 412.2036 g/mol 1209 HPLC-MS: analytical method L 1221 HPLC-MS: analytical method L 1210 rt: 4.12 min-found mass: 402 (m/z+H) 1222 rt: 3.40 min-found mass: 413 (m/z+H) Example #256 Example #259 Preparation of 1-(4-(4-((5-(1H-pyrrolo3.2-bipyri Preparation of N-(2-methyl-1H-benzodimidazol-5- din-6-yl)-1H-pyrazolo4.3-dpyrimidin-7-yl)amino) yl)-5-(1H-pyrrolo3.2-bipyridin-6-yl)-1H-pyrazolo phenyl)piperazin-1-yl)ethan-1-one 4.3-dipyrimidin-7-amine 1211 7-chloro-2-(4-methoxybenzyl)-5-(1H-pyrrolo3.2- 1223 7-chloro-2-(4-methoxybenzyl)-5-(1H-pyrrolo3.2- bipyridin-6-yl)-2H-pyrazolo 4.3-dpyrimidine (0.16 mmol) bipyridin-6-yl)-2H-pyrazolo 4,3-dipyrimidine (0.16 mmol) and 1-(4-(4-aminophenyl)piperazin-1-yl)ethan-1-one (0.3 and 2-methyl-1H-benzodimidazol-5-amine (0.3 mmol 2 mmol 2 eq.) were suspended in MeOH (dry, 3 mL) in a eq.) were suspended in MeCH (dry, 3 mL) in a microwave microwave vial (2-5 mL), HCl in dioxane (4M, 3 drops) was vial (2-5 mL), HCl in dioxane (4M, 3 drops) was added. The added. The reaction mixture was irradiated in a microwave reaction mixture was irradiated in a microwave reactor for 5 reactor for 5 min at 140°C. The reaction mixture was evapo min at 140°C. The reaction mixture was evaporated and used rated and used without further purification. The residue was without further purification. The residue was dissolved in dissolved in TFA (3 mL). The reaction mixture was irradiated TFA (3 mL). The reaction mixture was irradiated in a micro in a microwave reactor for 5 min at 140° C. The reaction wave reactor for 5 min at 140°C. The reaction mixture was mixture was concentrated and purified by semi-preparative concentrated and purified by semi-preparative HPLC-MS HPLC-MS and freeze dried from waterft-BuOH 4/1. and freeze dried from waterft-BuOH 471. 1212 exact mass: 453.2351 g/mol 1224) exact mass: 381.1626 g/mol 1213 HPLC-MS: analytical method L 1225 HPLC-MS: analytical method L 1214 rt: 3.32 min-found mass: 454 (m/z+H) 1226 rt: 3.20 min-found mass: 382 (m/z+H) Example #257 Example #260 Preparation of 7-((5-(1H-pyrrolo3.2-bipyridin-6-yl)- Preparation of N,N-dimethyl-4-((5-(thiophen-2-yl)- 1H-pyrazolo 4,3-dipyrimidin-7-yl)amino)-3,4-dihy 1H-pyrazolo 4,3-dipyrimidin-7-yl)amino)benzene droquinolin-2(1H)-one Sulfonamide 1215) 7-chloro-2-(4-methoxybenzyl)-5-(1H-pyrrolo3.2- 1227 7-chloro-2-(4-methoxybenzyl)-5-(thiophen-2-yl)- bipyridin-6-yl)-2H-pyrazolo 4.3-dpyrimidine (0.16 mmol) 2H-pyrazolo 4,3-dipyrimidine (0.16 mmol) and 4-amino-N. and 7-amino-3,4-dihydroquinolin-2(1H)-one (0.3 mmol 2 N-dimethylbenzenesulfonamide (0.3 mmol 2 eq.) were sus eq.) were suspended in MeCH (dry, 3 mL) in a microwave pended in MeOH (dry, 3 mL) in a microwave vial (2-5 mL), vial (2-5 mL), HCl in dioxane (4M, 3 drops) was added. The HCl in dioxane (4M, 3 drops) was added. The reaction mix reaction mixture was irradiated in a microwave reactor for 5 ture was irradiated in a microwave reactor for 5 minat 140°C. min at 140°C. The reaction mixture was evaporated and used The reaction mixture was evaporated and used without fur without further purification. The residue was dissolved in ther purification. The residue was dissolved in TFA (3 mL). US 2012/032978.0 A1 Dec. 27, 2012

The reaction mixture was irradiated in a microwave reactor reaction mixture was irradiated in a microwave reactor for 5 for 5 min at 140°C. The reaction mixture was concentrated min at 140° C. The reaction mixture was concentrated and and purified by semi-preparative HPLC-MS and freeze dried purified by semi-preparative HPLC-MS and freeze dried from waterft-BuOH 4/1. from waterft-BuOH 4/1. 1228 exact mass: 400.0984 g/mol 1240 exact mass: 360.1031 g/mol 1229 HPLC-MS: analytical method L 1241 HPLC-MS: analytical method L 1230 rt: 4.90 min-found mass: 401 (m/z+H) 1242 rt: 5.10 min-found mass: 361 (m/z+H) Example #261 Example #264 Preparation of N-cyclopropyl-3-((5-(thiophen-2-yl)- Preparation of N,N-dimethyl-3-((5-(thiophen-2-yl)- 1H-pyrazolo 4,3-dipyrimidin-7-yl)amino)benzene 1H-pyrazolo 4,3-dipyrimidin-7-yl)amino)benzene Sulfonamide Sulfonamide 1231 7-chloro-2-(4-methoxybenzyl)-5-(thiophen-2-yl)- 1243) 7-chloro-2-(4-methoxybenzyl)-5-(thiophen-2-yl)- 2H-pyrazolo4.3-dpyrimidine (0.16 mmol) and 3-amino-N- 2H-pyrazolo 4,3-dipyrimidine (0.16 mmol) and 3-amino-N. cyclopropylbenzenesulfonamide (0.3 mmol 2 eq.) were sus N-dimethylbenzenesulfonamide (0.3 mmol 2 eq.) were sus pended in MeOH (dry, 3 mL) in a microwave vial (2-5 mL), pended in MeOH (dry, 3 mL) in a microwave vial (2-5 mL), HCl in dioxane (4M, 3 drops) was added. The reaction mix HCl in dioxane (4M, 3 drops) was added. The reaction mix ture was irradiated in a microwave reactor for 5 minat 140°C. ture was irradiated in a microwave reactor for 5 minat 140°C. The reaction mixture was evaporated and used without fur The reaction mixture was evaporated and used without fur ther purification. The residue was dissolved in TFA (3 mL). ther purification. The residue was dissolved in TFA (3 mL). The reaction mixture was irradiated in a microwave reactor The reaction mixture was irradiated in a microwave reactor for 5 min at 140°C. The reaction mixture was concentrated for 5 min at 140°C. The reaction mixture was concentrated and purified by semi-preparative HPLC-MS and freeze dried and purified by semi-preparative HPLC-MS and freeze dried from waterft-BuOH 4/1. from waterft-BuOH 4/1. 1232 exact mass: 412.0979 g/mol 1244 exact mass: 400.0984 g/mol 1233 HPLC-MS: analytical method L 1245 HPLC-MS: analytical method A 1234 rt: 4.74 min-found mass: 413 (m/z+H) 1246 rt: 2.93 min-found mass: 401 (m/z+H) Example #262 Example #265 Preparation of N-(3-(2H-1,2,3-triazol-2-yl)phenyl)- Preparation of N-methyl-3-((5-(thiophen-2-yl)-1H 5-(thiophen-2-yl)-1H-pyrazolo 4.3-dpyrimidin-7- pyrazolo 4,3-dipyrimidin-7-yl)amino)benzene amine Sulfonamide 1235) 7-chloro-2-(4-methoxybenzyl)-5-(thiophen-2-yl)- 1247 7-chloro-2-(4-methoxybenzyl)-5-(thiophen-2-yl)- 2H-pyrazolo4.3-dpyrimidine (0.16 mmol) and 3-(2H-1.2. 2H-pyrazolo 4,3-dipyrimidine (0.16 mmol) and 3-amino-N- 3-triazol-2-yl)aniline (0.3 mmol 2 eq.) were suspended in methylbenzenesulfonamide (0.3 mmol 2 eq.) were suspended MeOH (dry, 3 mL) in a microwave vial (2-5 mL), HCl in in MeCH (dry, 3 mL) in a microwave vial (2-5 mL), HCl in dioxane (4M, 3 drops) was added. The reaction mixture was dioxane (4M, 3 drops) was added. The reaction mixture was irradiated in a microwave reactor for 5 min at 140°C. The irradiated in a microwave reactor for 5 min at 140°C. The reaction mixture was evaporated and used without further reaction mixture was evaporated and used without further purification. The residue was dissolved in TFA (3 mL). The purification. The residue was dissolved in TFA (3 mL). The reaction mixture was irradiated in a microwave reactor for 5 reaction mixture was irradiated in a microwave reactor for 5 min at 140° C. The reaction mixture was concentrated and min at 140° C. The reaction mixture was concentrated and purified by semi-preparative HPLC-MS and freeze dried purified by semi-preparative HPLC-MS and freeze dried from waterft-BuOH 4/1. from waterft-BuOH 4/1. 1236 exact mass: 360.1031 g/mol 1248 exact mass: 386.0789 g/mol 1237 HPLC-MS: analytical method D 1249 HPLC-MS: analytical method A 1238 rt: 6.78 min-found mass: 361 (m/z+H) 1250 rt: 2.68 min-found mass: 387 (im/z+H) Example #263 Example #266 Preparation of N-(4-(2H-1,2,3-triazol-2-yl)phenyl)- Preparation of N-(3-(morpholinosulfonyl)phenyl)-5- 5-(thiophen-2-yl)-1H-pyrazolo 4.3-dpyrimidin-7- (thiophen-2-yl)-1H-pyrazolo 4,3-dipyrimidin-7- amine amine 1239 7-chloro-2-(4-methoxybenzyl)-5-(thiophen-2-yl)- 1251) 7-chloro-2-(4-methoxybenzyl)-5-(thiophen-2-yl)- 2H-pyrazolo4.3-dpyrimidine (0.16 mmol) and 4-(2H-1.2. 2H-pyrazolo 4,3-dipyrimidine (0.16 mmol) and 3-(mor 3-triazol-2-yl)aniline (0.3 mmol 2 eq.) were suspended in pholinosulfonyl)aniline (0.3 mmol 2 eq.) were suspended in MeOH (dry, 3 mL) in a microwave vial (2-5 mL), HCl in MeOH (dry, 3 mL) in a microwave vial (2-5 mL), HCl in dioxane (4M, 3 drops) was added. The reaction mixture was dioxane (4M, 3 drops) was added. The reaction mixture was irradiated in a microwave reactor for 5 min at 140°C. The irradiated in a microwave reactor for 5 min at 140°C. The reaction mixture was evaporated and used without further reaction mixture was evaporated and used without further purification. The residue was dissolved in TFA (3 mL). The purification. The residue was dissolved in TFA (3 mL). The US 2012/032978.0 A1 Dec. 27, 2012

reaction mixture was irradiated in a microwave reactor for 5 TFA (3 mL). The reaction mixture was irradiated in a micro min at 140° C. The reaction mixture was concentrated and wave reactor for 5 min at 140°C. The reaction mixture was purified by semi-preparative HPLC-MS and freeze dried concentrated and purified by semi-preparative HPLC-MS from waterft-BuOH 4/1. and freeze dried from waterft-BuOH 471. 1252 exact mass: 442.1118 g/mol 1264 exact mass: 396.1640 g/mol 1253 HPLC-MS: analytical method A 1265 HPLC-MS: analytical method D 1254 rt: 2.87 min-found mass: 443 (m/z+H) 1266 rt: 4.76 min-found mass: 397 (m/z+H) Example #267 Example #270 Preparation of 5-(thiophen-2-yl)-N-(3-((trifluorom Preparation of N-(3,4-dimethoxyphenyl)-5-(4-fluo ethyl)sulfonyl)phenyl)-1H-pyrazolo 4,3-dipyrimi rophenyl)-1H-pyrazolo 4.3-dpyrimidin-7-amine din-7-amine 1267 7-chloro-5-(4-fluorophenyl)-2-(4-methoxyben 1255) 7-chloro-2-(4-methoxybenzyl)-5-(thiophen-2-yl)- Zyl)-2H-pyrazolo 4,3-dipyrimidine (0.16 mmol) and 3,4- 2H-pyrazolo4.3-dpyrimidine (0.16 mmol) and 3-((trifluo dimethoxyaniline (0.3 mmol 2 eq.) were suspended in MeCH romethyl)sulfonyl)aniline (0.3 mmol 2 eq.) were suspended (dry, 3 mL) in a microwave vial (2-5 mL), HCl in dioxane in MeCH (dry, 3 mL) in a microwave vial (2-5 mL), HCl in (4M, 3 drops) was added. The reaction mixture was irradiated dioxane (4M, 3 drops) was added. The reaction mixture was in a microwave reactor for 5 min at 140° C. The reaction irradiated in a microwave reactor for 5 min at 140°C. The mixture was evaporated and used without further purification. reaction mixture was evaporated and used without further The residue was dissolved in TFA (3 mL). The reaction mix purification. The residue was dissolved in TFA (3 mL). The ture was irradiated in a microwave reactor for 5 minat 140°C. reaction mixture was irradiated in a microwave reactor for 5 The reaction mixture was concentrated and purified by semi min at 140° C. The reaction mixture was concentrated and preparative HPLC-MS and freeze dried from water/t-BuOH purified by semi-preparative HPLC-MS and freeze dried 4f1. from waterft-BuOH 4/1. 1256 exact mass: 425.0301 g/mol 1268 exact mass: 365.1497 g/mol 1257. HPLC-MS: analytical method A 1269 HPLC-MS: analytical method A 1258 rt: 3.37 min-found mass: 426 (m/z+H) 1270 rt: 2.88 min-found mass: 366 (m/z+H) Example #268 Example #271 Preparation of N-(3-(methylsulfinyl)phenyl)-5- Preparation of 5-(4-fluorophenyl)-N-(4-morpholi (thiophen-2-yl)-1H-pyrazolo 4,3-dipyrimidin-7- nophenyl)-1H-pyrazolo 4.3-dipyrimidin-7-amine amine 1271 7-chloro-5-(4-fluorophenyl)-2-(4-methoxyben 1259) 7-chloro-2-(4-methoxybenzyl)-5-(thiophen-2-yl)- Zyl)-2H-pyrazolo 4,3-dipyrimidine (0.16 mmol) and 4-mor 2H-pyrazolo4.3-dpyrimidine (0.16 mmol) and 3-(methyl pholinoaniline (0.3 mmol 2 eq.) were suspended in MeCH sulfinyl)aniline (0.3 mmol 2 eq.) were suspended in MeOH (dry, 3 mL) in a microwave vial (2-5 mL), HCl in dioxane (dry, 3 mL) in a microwave vial (2-5 mL), HCl in dioxane (4M, 3 drops) was added. The reaction mixture was irradiated (4M, 3 drops) was added. The reaction mixture was irradiated in a microwave reactor for 5 min at 140° C. The reaction in a microwave reactor for 5 min at 140° C. The reaction mixture was evaporated and used without further purification. mixture was evaporated and used without further purification. The residue was dissolved in TFA (3 mL). The reaction mix The residue was dissolved in TFA (3 mL). The reaction mix ture was irradiated in a microwave reactor for 5 minat 140°C. ture was irradiated in a microwave reactor for 5 minat 140°C. The reaction mixture was concentrated and purified by semi The reaction mixture was concentrated and purified by semi preparative HPLC-MS and freeze dried from water/t-BuOH preparative HPLC-MS and freeze dried from water/t-BuOH 4f1. 4f1. 1272 exact mass: 390.1868 g/mol 1260 exact mass: 355.0720 g/mol 1273 HPLC-MS: analytical method A 1261 HPLC-MS: analytical method A 1274 rt: 2.83 min-found mass: 391 (m/z+H) 1262 rt: 2.51 min-found mass: 356 (m/z+H) Example #272 Example #269 Preparation of 5-(3,4-difluorophenyl)-N-(3,4- Preparation of 7-((5-(1H-indazol-6-yl)-1H-pyrazolo dimethoxyphenyl)-1H-pyrazolo 4,3-dipyrimidin-7- 4.3-dpyrimidin-7-yl)amino)-3,4-dihydroquinolin-2 amine (1H)-one 1275) 7-chloro-5-(3,4-difluorophenyl)-2-(4-methoxy 1263) 7-chloro-5-(1H-indazol-6-yl)-2-(4-methoxyben benzyl)-2H-pyrazolo 4.3-dpyrimidine (0.16 mmol) and 3,4- Zyl)-2H-pyrazolo 4,3-dipyrimidine (0.16 mmol) and dimethoxyaniline (0.3 mmol 2 eq.) were suspended in MeCH 7-amino-3,4-dihydroquinolin-2(1H)-one (0.3 mmol 2 eq.) (dry, 3 mL) in a microwave vial (2-5 mL), HCl in dioxane were suspended in MeOH (dry, 3 mL) in a microwave vial (4M, 3 drops) was added. The reaction mixture was irradiated (2-5 mL), HCl in dioxane (4M, 3 drops) was added. The in a microwave reactor for 5 min at 140° C. The reaction reaction mixture was irradiated in a microwave reactor for 5 mixture was evaporated and used without further purification. min at 140°C. The reaction mixture was evaporated and used The residue was dissolved in TFA (3 mL). The reaction mix without further purification. The residue was dissolved in ture was irradiated in a microwave reactor for 5 minat 140°C. US 2012/032978.0 A1 Dec. 27, 2012

The reaction mixture was concentrated and purified by semi for 5 min at 140°C. The reaction mixture was concentrated preparative HPLC-MS and freeze dried from water/t-BuOH and purified by semi-preparative HPLC-MS and freeze dried 4f1. from waterft-BuOH 4/1. 1276 exact mass: 383.1376 g/mol 1288 exact mass: 403.224.5 g/mol 1277. HPLC-MS: analytical method A 1289 HPLC-MS: analytical method A 1278 rt: 3.15 min-found mass: 384 (m/z+H) 1290 rt: 1.84 min-found mass: 404 (m/z+H) Example #273 Example #276 Preparation of 5-(3,4-difluorophenyl)-N-(4-mor Preparation of 5-(2-fluorophenyl)-N-(3-(methylsul pholinophenyl)-1H-pyrazolo 4,3-dipyrimidin-7- fonyl)phenyl)-1H-pyrazolo 4,3-dipyrimidin-7-amine amine 1291) 7-chloro-5-(2-fluorophenyl)-2-(4-methoxyben 1279 7-chloro-5-(3,4-difluorophenyl)-2-(4-methoxy Zyl)-2H-pyrazolo 4,3-dipyrimidine (0.16 mmol) and 3-(me benzyl)-2H-pyrazolo 4.3-dpyrimidine (0.16 mmol) and thylsulfonyl)aniline (0.3 mmol 2 eq.) were suspended in 4-morpholinoaniline (0.3 mmol 2 eq.) were Suspended in MeOH (dry, 3 mL) in a microwave vial (2-5 mL), HCl in MeOH (dry, 3 mL) in a microwave vial (2-5 mL), HCl in dioxane (4M, 3 drops) was added. The reaction mixture was dioxane (4M, 3 drops) was added. The reaction mixture was irradiated in a microwave reactor for 5 min at 140°C. The irradiated in a microwave reactor for 5 min at 140°C. The reaction mixture was evaporated and used without further reaction mixture was evaporated and used without further purification. The residue was dissolved in TFA (3 mL). The purification. The residue was dissolved in TFA (3 mL). The reaction mixture was irradiated in a microwave reactor for 5 reaction mixture was irradiated in a microwave reactor for 5 min at 140° C. The reaction mixture was concentrated and min at 140° C. The reaction mixture was concentrated and purified by semi-preparative HPLC-MS and freeze dried purified by semi-preparative HPLC-MS and freeze dried from waterft-BuOH 4/1. from waterft-BuOH 4/1. 1280 exact mass: 408.1747 g/mol 1292 exact mass: 383.1018 g/mol 1281 HPLC-MS: analytical method A 1293 HPLC-MS: analytical method A 1282 rt: 3.13 min-found mass: 409 (m/z+H) 1294 rt: 2.63 min-found mass: 384 (m/z+H) Example #274 Example #277 Preparation of 5-(3,5-difluorophenyl)-N-(3,4- Preparation of 5-(2-fluorophenyl)-N-(2-(methylsul dimethoxyphenyl)-1H-pyrazolo 4,3-dipyrimidin-7- fonyl)phenyl)-1H-pyrazolo 4,3-dipyrimidin-7-amine amine 1295 7-chloro-5-(2-fluorophenyl)-2-(4-methoxyben 1283) 7-chloro-5-(3,5-difluorophenyl)-2-(4-methoxy Zyl)-2H-pyrazolo 4,3-dipyrimidine (0.16 mmol) and 2-(me benzyl)-2H-pyrazolo 4.3-dpyrimidine (0.16 mmol) and 3,4- thylsulfonyl)aniline (0.3 mmol 2 eq.) were suspended in dimethoxyaniline (0.3 mmol 2 eq.) were suspended in MeOH MeOH (dry, 3 mL) in a microwave vial (2-5 mL), HCl in (dry, 3 mL) in a microwave vial (2-5 mL), HCl in dioxane dioxane (4M, 3 drops) was added. The reaction mixture was (4M, 3 drops) was added. The reaction mixture was irradiated irradiated in a microwave reactor for 5 min at 140°C. The in a microwave reactor for 5 min at 140° C. The reaction reaction mixture was evaporated and used without further mixture was evaporated and used without further purification. purification. The residue was dissolved in TFA (3 mL). The The residue was dissolved in TFA (3 mL). The reaction mix reaction mixture was irradiated in a microwave reactor for 5 ture was irradiated in a microwave reactor for 5 minat 140°C. min at 140° C. The reaction mixture was concentrated and The reaction mixture was concentrated and purified by semi purified by semi-preparative HPLC-MS and freeze dried preparative HPLC-MS and freeze dried from water/t-BuOH from waterft-BuOH 4/1. 4f1. 1296 exact mass: 383.1018 g/mol 1284 exact mass: 383.1376 g/mol 1297 HPLC-MS: analytical method A 1285 HPLC-MS: analytical method A 1298 rt: 2.89 min-found mass: 384 (m/z+H) 1286 rt: 3.24 min-found mass: 384 (m/z+H) Example #278 Example #275 Preparation of 5-(2-fluorophenyl)-N-(4-(4-(4-meth Preparation of 5-(2-fluorophenyl)-N-(4-(4-meth ylpiperazin-1-yl)piperidin-1-yl)phenyl)-1H-pyrazolo ylpiperazin-1-yl)phenyl)-1H-pyrazolo 4,3-dipyrimi 4.3-dipyrimidin-7-amine din-7-amine 1299) 7-chloro-5-(2-fluorophenyl)-2-(4-methoxyben 1287 7-chloro-5-(2-fluorophenyl)-2-(4-methoxyben Zyl)-2H-pyrazolo 4,3-dipyrimidine (0.16 mmol) and 4-(4- Zyl)-2H-pyrazolo 4,3-dipyrimidine (0.16 mmol) and 4-(4- (4-methylpiperazin-1-yl)piperidin-1-yl)aniline (0.3 mmol 2 methylpiperazin-1-yl)aniline (0.3 mmol 2 eq.) were sus eq.) were suspended in MeCH (dry, 3 mL) in a microwave pended in MeOH (dry, 3 mL) in a microwave vial (2-5 mL), vial (2-5 mL), HCl in dioxane (4M, 3 drops) was added. The HCl in dioxane (4M, 3 drops) was added. The reaction mix reaction mixture was irradiated in a microwave reactor for 5 ture was irradiated in a microwave reactor for 5 minat 140°C. min at 140°C. The reaction mixture was evaporated and used The reaction mixture was evaporated and used without fur without further purification. The residue was dissolved in ther purification. The residue was dissolved in TFA (3 mL). TFA (3 mL). The reaction mixture was irradiated in a micro The reaction mixture was irradiated in a microwave reactor wave reactor for 5 min at 140°C. The reaction mixture was US 2012/032978.0 A1 Dec. 27, 2012 89 concentrated and purified by semi-preparative HPLC-MS The reaction mixture was concentrated and purified by semi and freeze dried from waterft-BuOH 471. preparative HPLC-MS and freeze dried from water/t-BuOH 1300 exact mass: 486.3146 g/mol 4f1. 1301 HPLC-MS: analytical method A 1312 exact mass: 383.1377 g/mol 1313 HPLC-MS: analytical method A 1302 rt: 2.00 min-found mass: 487 (n/Z+H) 1314 rt: 2.71 min-found mass: 384 (m/z+H) Example #279 Example #282 Preparation of N-(4-(4-cyclopropylpiperazin-1-yl) Preparation of 5-(2,6-difluorophenyl)-N-(4-mor phenyl)-5-(2-fluorophenyl)-1H-pyrazolo 4,3-dipyri pholinophenyl)-1H-pyrazolo 4,3-dipyrimidin-7- midin-7-amine amine 1303) 7-chloro-5-(2-fluorophenyl)-2-(4-methoxyben 1315) 7-chloro-5-(2,6-difluorophenyl)-2-(4-methoxy Zyl)-2H-pyrazolo 4,3-dipyrimidine (0.16 mmol) and 4-(4- benzyl)-2H-pyrazolo 4.3-dpyrimidine (0.16 mmol) and cyclopropylpiperazin-1-yl)aniline (0.3 mmol 2 eq.) were sus 4-morpholinoaniline (0.3 mmol 2 eq.) were suspended in pended in MeOH (dry, 3 mL) in a microwave vial (2-5 mL), MeOH (dry, 3 mL) in a microwave vial (2-5 mL), HCl in HCl in dioxane (4M, 3 drops) was added. The reaction mix dioxane (4M, 3 drops) was added. The reaction mixture was ture was irradiated in a microwave reactor for 5 minat 140°C. irradiated in a microwave reactor for 5 min at 140°C. The The reaction mixture was evaporated and used without fur reaction mixture was evaporated and used without further ther purification. The residue was dissolved in TFA (3 mL). purification. The residue was dissolved in TFA (3 mL). The The reaction mixture was irradiated in a microwave reactor reaction mixture was irradiated in a microwave reactor for 5 for 5 min at 140°C. The reaction mixture was concentrated min at 140° C. The reaction mixture was concentrated and and purified by semi-preparative HPLC-MS and freeze dried purified by semi-preparative HPLC-MS and freeze dried from waterft-BuOH 4/1. from waterft-BuOH 4/1. 1304 exact mass: 429.2434 g/mol 1316 exact mass: 408.1747 g/mol 1305 HPLC-MS: analytical method A 1317 HPLC-MS: analytical method A 1306 rt: 2.03 min-found mass: 430 (m/z+H) 1318 rt: 2.71 min-found mass: 409 (m/z+H) Example #280 Example #283 Preparation of N-(3,4-dimethoxyphenyl)-5-(1H-in Preparation of N-(4-(4-cyclopropylpiperazin-1-yl) dazol-6-yl)-1H-pyrazolo 4,3-dipyrimidin-7-amine phenyl)-5-(2,6-difluorophenyl)-1H-pyrazolo 4.3-d pyrimidin-7-amine 1307) 7-chloro-5-(1H-indazol-6-yl)-2-(4-methoxyben Zyl)-2H-pyrazolo 4,3-dipyrimidine (0.16 mmol) and 3,4- 1319) 7-chloro-5-(2,6-difluorophenyl)-2-(4-methoxy dimethoxyaniline (0.3 mmol 2 eq.) were suspended in MeOH benzyl)-2H-pyrazolo 4.3-dpyrimidine (0.16 mmol) and (dry, 3 mL) in a microwave vial (2-5 mL), HCl in dioxane 4-(4-cyclopropylpiperazin-1-yl)aniline (0.3 mmol 2 eq.) (4M, 3 drops) was added. The reaction mixture was irradiated were suspended in MeOH (dry, 3 mL) in a microwave vial in a microwave reactor for 5 min at 140° C. The reaction (2-5 mL), HCl in dioxane (4M, 3 drops) was added. The mixture was evaporated and used without further purification. reaction mixture was irradiated in a microwave reactor for 5 The residue was dissolved in TFA (3 mL). The reaction mix min at 140°C. The reaction mixture was evaporated and used ture was irradiated in a microwave reactor for 5 minat 140°C. without further purification. The residue was dissolved in The reaction mixture was concentrated and purified by semi TFA (3 mL). The reaction mixture was irradiated in a micro preparative HPLC-MS and freeze dried from water/t-BuOH wave reactor for 5 min at 140°C. The reaction mixture was 4f1. concentrated and purified by semi-preparative HPLC-MS and freeze dried from waterft-BuOH 471. 1308 exact mass: 387.1664 g/mol 1320 exact mass: 447.2313 g/mol 1309 HPLC-MS: analytical method D 1321 HPLC-MS: analytical method A 1310 rt: 4.93 min-found mass: 388 (m/z+H) 1322 rt: 2.07 min-found mass: 448 (m/z+H) Example #281 Example #284 Preparation of 5-(2,6-difluorophenyl)-N-(3,4- Preparation of 5-(2,6-difluorophenyl)-N-(4-(4-(4- dimethoxyphenyl)-1H-pyrazolo 4,3-dipyrimidin-7- methylpiperazin-1-yl)piperidin-1-yl)phenyl)-1H amine pyrazolo 4.3-dpyrimidin-7-amine 1311 7-chloro-5-(2,6-difluorophenyl)-2-(4-methoxy 1323 7-chloro-5-(2,6-difluorophenyl)-2-(4-methoxy benzyl)-2H-pyrazolo 4.3-dpyrimidine (0.16 mmol) and 3,4- benzyl)-2H-pyrazolo 4.3-dpyrimidine (0.16 mmol) and dimethoxyaniline (0.3 mmol 2 eq.) were suspended in MeOH 4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline (0.3 (dry, 3 mL) in a microwave vial (2-5 mL), HCl in dioxane mmol 2 eq.) were suspended in MeOH (dry, 3 mL) in a (4M, 3 drops) was added. The reaction mixture was irradiated microwave vial (2-5 mL), HCl in dioxane (4M, 3 drops) was in a microwave reactor for 5 min at 140° C. The reaction added. The reaction mixture was irradiated in a microwave mixture was evaporated and used without further purification. reactor for 5 min at 140°C. The reaction mixture was evapo The residue was dissolved in TFA (3 mL). The reaction mix rated and used without further purification. The residue was ture was irradiated in a microwave reactor for 5 minat 140°C. dissolved in TFA (3 mL). The reaction mixture was irradiated US 2012/032978.0 A1 Dec. 27, 2012 90 in a microwave reactor for 5 min at 140° C. The reaction in a microwave reactor for 5 min at 140° C. The reaction mixture was concentrated and purified by semi-preparative mixture was concentrated and purified by semi-preparative HPLC-MS and freeze dried from waterft-BuOH 4/1. HPLC-MS and freeze dried from waterft-BuOH 4/1. 1324) exact mass: 504.3025 g/mol 1336 exact mass: 427.1598 g/mol 1325 HPLC-MS: analytical method A 1337 HPLC-MS: analytical method D 1326 rt: 1.97 min-found mass: 505 (m/z+H) 1338 rt: 4.82 min-found mass: 428 (m/z+H) Example #285 Example #288 Preparation of 5-(2,4-difluorophenyl)-N-(3,4- Preparation of 6-(7-(4-morpholinophenyl)amino)- dimethoxyphenyl)-1H-pyrazolo 4,3-dipyrimidin-7- 1H-pyrazolo 4,3-dipyrimidin-5-yl)-2H-benzob.1, amine 4-oxazin-3(4H)-one 1327 7-chloro-5-(2,4-difluorophenyl)-2-(4-methoxy 1339) 6-(7-chloro-2-(4-methoxybenzyl)-2H-pyrazolo.4, benzyl)-2H-pyrazolo 4.3-dpyrimidine (0.16 mmol) and 3,4- 3-dipyrimidin-5-yl)-2H-benzob 14oxazin-3 (4H)-one dimethoxyaniline (0.3 mmol 2 eq.) were suspended in MeOH (0.16 mmol) and 4-morpholinoaniline (0.3 mmol 2 eq.) were (dry, 3 mL) in a microwave vial (2-5 mL), HCl in dioxane suspended in MeCH (dry, 3 mL) in a microwave vial (2-5 (4M, 3 drops) was added. The reaction mixture was irradiated mL), HCl in dioxane (4M, 3 drops) was added. The reaction in a microwave reactor for 5 min at 140° C. The reaction mixture was irradiated in a microwave reactor for 5 min at mixture was evaporated and used without further purification. 140°C. The reaction mixture was evaporated and used with The residue was dissolved in TFA (3 mL). The reaction mix out further purification. The residue was dissolved in TFA (3 ture was irradiated in a microwave reactor for 5 minat 140°C. mL). The reaction mixture was irradiated in a microwave The reaction mixture was concentrated and purified by semi reactor for 5 min at 140°C. The reaction mixture was con preparative HPLC-MS and freeze dried from water/t-BuOH centrated and purified by semi-preparative HPLC-MS and 4f1. freeze dried from waterft-BuOH 4/1. 1328) exact mass: 383.1376 g/mol 1340 exact mass: 443.1992 g/mol 1329 HPLC-MS: analytical method A 1341 HPLC-MS: analytical method D 1330 rt: 2.83 min-found mass: 384 (m/z+H) 1342 rt: 4.96 min-found mass: 444 (m/z+H) Example #286 Example #289 Preparation of 5-(2,4-difluorophenyl)-N-(4-mor Preparation of 6-(7-((2-methyl-1H-benzodimida pholinophenyl)-1H-pyrazolo 4,3-dipyrimidin-7- Zol-5-yl)amino)-1H-pyrazolo 4,3-dipyrimidin-5-yl)- amine 2H-benzob 14oxazin-3 (4H)-one 1331 7-chloro-5-(2,4-difluorophenyl)-2-(4-methoxy 1343 6-(7-chloro-2-(4-methoxybenzyl)-2H-pyrazolo.4, benzyl)-2H-pyrazolo 4.3-dpyrimidine (0.16 mmol) and 3-dipyrimidin-5-yl)-2H-benzob 14oxazin-3 (4H)-one 4-morpholinoaniline (0.3 mmol 2 eq.) were Suspended in (0.16 mmol) and 2-methyl-1H-benzodimidazol-5-amine MeOH (dry, 3 mL) in a microwave vial (2-5 mL), HCl in (0.3 mmol 2 eq.) were suspended in MeOH (dry, 3 mL) in a dioxane (4M, 3 drops) was added. The reaction mixture was microwave vial (2-5 mL), HCl in dioxane (4M, 3 drops) was irradiated in a microwave reactor for 5 min at 140°C. The added. The reaction mixture was irradiated in a microwave reaction mixture was evaporated and used without further reactor for 5 min at 140°C. The reaction mixture was evapo purification. The residue was dissolved in TFA (3 mL). The rated and used without further purification. The residue was reaction mixture was irradiated in a microwave reactor for 5 dissolved in TFA (3 mL). The reaction mixture was irradiated min at 140° C. The reaction mixture was concentrated and in a microwave reactor for 5 min at 140° C. The reaction purified by semi-preparative HPLC-MS and freeze dried mixture was concentrated and purified by semi-preparative from waterft-BuOH 4/1. HPLC-MS and freeze dried from waterft-BuOH 4/1. 1332 exact mass: 408.1747 g/mol 1344 exact mass: 412.1584 g/mol 1333 HPLC-MS: analytical method A 1345 HPLC-MS: analytical method D 1334 rt: 2.79 min-found mass: 409 (m/z+H) 1346 rt: 3.81 min-found mass: 413 (m/z+H) Example #287 Example #290 Preparation of 6-(7-((2-oxo-1,2,3,4-tetrahydroquino Preparation of N-(4-(4-(4-methylpiperazin-1-yl)pip lin-7-yl)amino)-1H-pyrazolo 4,3-dipyrimidin-5-yl)- eridin-1-yl)phenyl)-5-(thiophen-2-yl)-1H-pyrazolo 2H-benzob 14oxazin-3 (4H)-one 4.3-dipyrimidin-7-amine 1335 6-(7-chloro-2-(4-methoxybenzyl)-2H-pyrazolo.4, 1347 7-chloro-2-(4-methoxybenzyl)-5-(thiophen-2-yl)- 3-dipyrimidin-5-yl)-2H-benzob 14oxazin-3 (4H)-one 2H-pyrazolo 4,3-dipyrimidine (0.16 mmol) and 4-(4-(4-me (0.16 mmol) and 7-amino-3,4-dihydroquinolin-2(1H)-one thylpiperazin-1-yl)piperidin-1-yl)aniline (0.3 mmol 2 eq.) (0.3 mmol 2 eq.) were suspended in MeOH (dry, 3 mL) in a were suspended in MeOH (dry, 3 mL) in a microwave vial microwave vial (2-5 mL), HCl in dioxane (4M, 3 drops) was (2-5 mL), HCl in dioxane (4M, 3 drops) was added. The added. The reaction mixture was irradiated in a microwave reaction mixture was irradiated in a microwave reactor for 5 reactor for 5 min at 140°C. The reaction mixture was evapo min at 140°C. The reaction mixture was evaporated and used rated and used without further purification. The residue was without further purification. The residue was dissolved in dissolved in TFA (3 mL). The reaction mixture was irradiated TFA (3 mL). The reaction mixture was irradiated in a micro US 2012/032978.0 A1 Dec. 27, 2012

wave reactor for 5 min at 140°C. The reaction mixture was for 5 min at 140°C. The reaction mixture was concentrated concentrated and purified by semi-preparative HPLC-MS and purified by semi-preparative HPLC-MS and freeze dried and freeze dried from waterft-BuOH 471. from waterft-BuOH 4/1. 1348 exact mass: 474.2791 g/mol 1349 HPLC-MS: analytical method L 1360 exact mass: 417.2081 g/mol 1350 rt: 3.08 min-found mass: 475 (m/z+H) 1361 HPLC-MS: analytical method L Example #291 1362 rt: 3.40 min-found mass: 418 (m/z+H) Preparation of N-(2-(methylsulfonyl)phenyl)-5- Example #294 (thiophen-2-yl)-1H-pyrazolo 4,3-dipyrimidin-7- amine Preparation of morpholino(4-((5-(thiophen-2-yl)-1H 1351 7-chloro-2-(4-methoxybenzyl)-5-(thiophen-2-yl)- pyrazolo 4.3-dpyrimidin-7-yl)amino)phenyl)metha 2H-pyrazolo4.3-dpyrimidine (0.16 and 2-mmol) (methyl O sulfonyl)aniline (0.3 mmol 2 eq.) were suspended in MeOH 1363) 7-chloro-2-(4-methoxybenzyl)-5-(thiophen-2-yl)- (dry, 3 mL) in a microwave vial (2-5 mL), HCl in dioxane 2H-pyrazolo 4,3-dipyrimidine (0.16 mmol) and (4-ami (4M, 3 drops) was added. The reaction mixture was irradiated nophenyl)(morpholino)methanone (0.3 mmol 2 eq.) were in a microwave reactor for 5 min at 140° C. The reaction suspended in MeCH (dry, 3 mL) in a microwave vial (2-5 mixture was evaporated and used without further purification. mL), HCl in dioxane (4M, 3 drops) was added. The reaction The residue was dissolved in TFA (3 mL). The reaction mix mixture was irradiated in a microwave reactor for 5 min at ture was irradiated in a microwave reactor for 5 minat 140°C. 140°C. The reaction mixture was evaporated and used with The reaction mixture was concentrated and purified by semi out further purification. The residue was dissolved in TFA (3 preparative HPLC-MS and freeze dried from water/t-BuOH mL). The reaction mixture was irradiated in a microwave 4f1. reactor for 5 min at 140°C. The reaction mixture was con 1352 exact mass: 371.0663 g/mol centrated and purified by semi-preparative HPLC-MS and 1353 HPLC-MS: analytical method L freeze dried from waterft-BuOH 4/1. 1354 rt: 4.94 min-found mass: 372 (m/z+H) 1364 exact mass: 406.1454 g/mol Example #292 1365 HPLC-MS: analytical method L Preparation of N-(3-((dimethylamino)methyl)phe 1366 rt: 4.29 min-found mass: 407 (m/z+H) nyl)-5-(thiophen-2-yl)-1H-pyrazolo 4.3-dpyrimidin 7-amine Example #295 1355) 7-chloro-2-(4-methoxybenzyl)-5-(thiophen-2-yl)- 2H-pyrazolo4.3-dpyrimidine (0.16 mmol) and 3-((dim Preparation of N-(4-(morpholinomethyl)phenyl)-5- ethylamino)methyl)aniline (0.3 mmol 2 eq.) were suspended (thiophen-2-yl)-1H-pyrazolo 4,3-dipyrimidin-7- in MeCH (dry, 3 mL) in a microwave vial (2-5 mL), HCl in amine dioxane (4M, 3 drops) was added. The reaction mixture was 1367 7-chloro-2-(4-methoxybenzyl)-5-(thiophen-2-yl)- irradiated in a microwave reactor for 5 min at 140°C. The 2H-pyrazolo 4,3-dipyrimidine (0.16 mmol) and (4-Amino reaction mixture was evaporated and used without further phenyl)-morpholin-4-yl-methanone (0.3 mmol 2 eq.) were purification. The residue was dissolved in TFA (3 mL). The suspended in MeCH (dry, 3 mL) in a microwave vial (2-5 reaction mixture was irradiated in a microwave reactor for 5 mL), HCl in dioxane (4M, 3 drops) was added. The reaction min at 140° C. The reaction mixture was concentrated and mixture was irradiated in a microwave reactor for 5 min at purified by semi-preparative HPLC-MS and freeze dried 140°C. The reaction mixture was evaporated and used with from waterft-BuOH 4/1. out further purification. The residue was dissolved in TFA (3 1356 exact mass: 350.1576 g/mol mL). The reaction mixture was irradiated in a microwave 1357. HPLC-MS: analytical method L reactor for 5 min at 140°C. The reaction mixture was evapo 1358 rt: 3.33 min-found mass: 351 (m/z+H) rated and used without further purification. The residue was dissolved in TFA (3 mL). The reaction mixture was irradiated Example #293 in a microwave reactor for 5 min at 140° C. The reaction mixture was concentrated and dissolved in THF (dry) LiAlH4 Preparation of N-(4-(4-cyclopropylpiperazin-1-yl) powder was added (excess, 2 by 2 eq) until completion of phenyl)-5-(thiophen-2-yl)-1H-pyrazolo 4,3-dipyri reaction is observed (by LCMS). The reaction was quenched midin-7-amine with water (1 mL per gram LiAlH4), then NaOH (ca. 15% aq., 1359 7-chloro-2-(4-methoxybenzyl)-5-(thiophen-2-yl)- 1 mL per g LiAlH4), water (3 mL per gram LiAlH4). The 2H-pyrazolo4.3-dpyrimidine (0.16 mmol) and 4-(4-cyclo mixture was filtered, washed with THF, MeOH, MeCN (ca. propylpiperazin-1-yl)aniline (0.3 mmol 2 eq.) were sus 10 mL each). The reaction mixture was concentrated and pended in MeOH (dry, 3 mL) in a microwave vial (2-5 mL), purified by semi-preparative HPLC-MS and freeze dried HCl in dioxane (4M, 3 drops) was added. The reaction mix from waterft-BuOH 4/1. ture was irradiated in a microwave reactor for 5 minat 140°C. 1368 exact mass: 392.1710 g/mol The reaction mixture was evaporated and used without fur ther purification. The residue was dissolved in TFA (3 mL). 1369 HPLC-MS: analytical method L The reaction mixture was irradiated in a microwave reactor 1370 rt: 3.20 min-found mass: 393 (m/z+H) US 2012/032978.0 A1 Dec. 27, 2012 92

Example #296 Example #299 Preparation of N-(3-fluoro-4-morpholinophenyl)-5- Preparation of 6-(7-((3,4-dimethoxyphenyl)amino)- (thiophen-2-yl)-1H-pyrazolo 4,3-dipyrimidin-7- 1H-pyrazolo 4,3-dipyrimidin-5-yl)-2H-benzob.1, amine 4-oxazin-3(4H)-one 1371) 7-chloro-2-(4-methoxybenzyl)-5-(thiophen-2-yl)- 1383 6-(7-chloro-2-(4-methoxybenzyl)-2H-pyrazolo.4, 2H-pyrazolo4.3-dpyrimidine (0.16 mmol) and 3-fluoro-4- 3-dipyrimidin-5-yl)-2H-benzob 14oxazin-3 (4H)-one morpholinoaniline (0.3 mmol 2 eq.) were suspended in (0.16 mmol) and 3,4-dimethoxyaniline (0.3 mmol 2 eq.) were MeOH (dry, 3 mL) in a microwave vial (2-5 mL), HCl in suspended in MeCH (dry, 3 mL) in a microwave vial (2-5 dioxane (4M, 3 drops) was added. The reaction mixture was mL), HCl in dioxane (4M, 3 drops) was added. The reaction irradiated in a microwave reactor for 5 min at 140°C. The mixture was irradiated in a microwave reactor for 5 min at reaction mixture was evaporated and used without further 140°C. The reaction mixture was evaporated and used with purification. The residue was dissolved in TFA (3 mL). The out further purification. The residue was dissolved in TFA (3 reaction mixture was irradiated in a microwave reactor for 5 mL). The reaction mixture was irradiated in a microwave min at 140° C. The reaction mixture was concentrated and reactor for 5 min at 140°C. The reaction mixture was con purified by semi-preparative HPLC-MS and freeze dried centrated and purified by semi-preparative HPLC-MS and from waterft-BuOH 4/1. freeze dried from waterft-BuOH 4/1. 1372 exact mass: 396.1393 g/mol 1384 exact mass: 418.1621 g/mol 1373 HPLC-MS: analytical method L 1385 HPLC-MS: analytical method A 1374 rt: 4.90 min-found mass: 397 (m/z+H) 1386 rt: 2.41 min-found mass: 419 (m/z+H) Example #297 Example #300 Preparation of (4-(4-methylpiperazin-1-yl)piperidin Preparation of 5-(3,4-dihydro-2H-benzob 14ox 1-yl)(4-((5-(thiophen-2-yl)-1H-pyrazolo 4.3-dpyri azin-6-yl)-N-(3,4-dimethoxyphenyl)-1H-pyrazolo4. midin-7-yl)amino)phenyl)methanone 3-dipyrimidin-7-amine 1375) 7-chloro-2-(4-methoxybenzyl)-5-(thiophen-2-yl)- 1387 6-(7-chloro-2-(4-methoxybenzyl)-2H-pyrazolo.4, 2H-pyrazolo 4,3-dipyrimidine (0.16 mmol) and (4-ami 3-dipyrimidin-5-yl)-2H-benzob 14oxazin-3 (4H)-one nophenyl)(4-(4-methylpiperazin-1-yl)piperidin-1-yl)metha (0.16 mmol) and 3,4-dimethoxyaniline (0.3 mmol 2 eq.) were none (0.3 mmol 2 eq.) were suspended in MeCH (dry, 3 mL) suspended in MeCH (dry, 3 mL) in a microwave vial (2-5 in a microwave vial (2-5 mL), HCl in dioxane (4M, 3 drops) mL), HCl in dioxane (4M, 3 drops) was added. The reaction was added. The reaction mixture was irradiated in a micro mixture was irradiated in a microwave reactor for 5 min at wave reactor for 5 min at 140°C. The reaction mixture was 140°C. The reaction mixture was evaporated and used with evaporated and used without further purification. The residue out further purification. The reaction mixture was dissolved was dissolved in TFA (3 mL). The reaction mixture was in THF (dry) LiAlH4 powder was added (excess, 2 by 2 eq) irradiated in a microwave reactor for min at 140° C. The until completion of reaction is observed (by LCMS). The reaction mixture was concentrated and purified by semi-pre reaction was quenched with water (1 mL per gram LiAlH4), then NaOH (ca. 15% aq., 1 mL perg LiAlH4), water (3 mL parative HPLC-MS and freeze dried from water/t-BuOH4/1. per gram LiAlH4). The mixture was filtered, washed with 1376 exact mass: 502.2731 g/mol THF, MeOH, MeCN (ca. 10 mL each). The residue was 1377. HPLC-MS: analytical method L dissolved in TFA (3 mL). The reaction mixture was irradiated 1378 rt: 3.25 min-found mass: 503 (m/z+H) in a microwave reactor for 5 min at 140° C. The reaction mixture was concentrated and purified by semi-preparative Example #298 HPLC-MS and freeze dried from waterft-BuOH 4/1. Preparation of 6-(7-((4-(4-acetylpiperazin-1-yl)phe 1388 exact mass: 404.1877 g/mol nyl)amino)-1H-pyrazolo4.3-dpyrimidin-5-yl)-2H 1389 HPLC-MS: analytical method L benzob 14oxazin-3 (4H)-one 1390 rt: 3.84 min-found mass: 405 (m/z+H) 1379) 6-(7-chloro-2-(4-methoxybenzyl)-2H-pyrazolo.4, Example #301 3-dipyrimidin-5-yl)-2H-benzob 14oxazin-3 (4H)-one (0.16 mmol) and 1-(4-(4-aminophenyl)piperazin-1-yl)ethan Preparation of 5-(3,4-dihydro-2H-benzob 14ox 1-one (0.3 mmol 2 eq.) were suspended in MeCH (dry, 3 mL) azin-6-yl)-N-(4-morpholinophenyl)-1H-pyrazolo 4, in a microwave vial (2-5 mL), HCl in dioxane (4M, 3 drops) 3-dipyrimidin-7-amine was added. The reaction mixture was irradiated in a micro 1391 6-(7-chloro-2-(4-methoxybenzyl)-2H-pyrazolo.4, wave reactor for 5 min at 140°C. The reaction mixture was 3-dipyrimidin-5-yl)-2H-benzob 14oxazin-3 (4H)-one evaporated and used without further purification. The residue (0.16 mmol) and 4-morpholinoaniline (0.3 mmol 2 eq.) were was dissolved in TFA (3 mL). The reaction mixture was suspended in MeCH (dry, 3 mL) in a microwave vial (2-5 irradiated in a microwave reactor for 5 min at 140°C. The mL), HCl in dioxane (4M, 3 drops) was added. The reaction reaction mixture was concentrated and purified by semi-pre mixture was irradiated in a microwave reactor for 5 min at parative HPLC-MS and freeze dried from water/t-BuOH4/1. 140°C. The reaction mixture was evaporated and used with 1380 exact mass: 484.2308 g/mol out further purification. The reaction mixture was dissolved 1381 HPLC-MS: analytical method A in THF (dry) LiAlH4 powder was added (excess, 2 by 2 eq) 1382 rt: 2.22 min-found mass: 485 (m/z+H) until completion of reaction is observed (by LCMS). The US 2012/032978.0 A1 Dec. 27, 2012 reaction was quenched with water (1 mL per gram LiAlH4), Example #304 then NaOH (ca. 15% aq., 1 mL perg LiAlH4), water (3 mL per gram LiAlH4). The mixture was filtered, washed with Preparation of N-(1,3-dihydroisobenzofuran-5-yl)-5- THF, MeOH, MeCN (ca. 10 mL each). The residue was (thiophen-2-yl)-1H-pyrazolo 4,3-dipyrimidin-7- dissolved in TFA (3 mL). The reaction mixture was irradiated amine in a microwave reactor for 5 min at 140° C. The reaction mixture was concentrated and purified by semi-preparative 1403) 7-chloro-2-(4-methoxybenzyl)-5-(thiophen-2-yl)- HPLC-MS and freeze dried from waterft-BuOH 4/1. 2H-pyrazolo 4,3-dipyrimidine (0.16 mmol) and 1,3-dihy droisobenzofuran-5-amine (0.3 mmol 2 eq.) were suspended 1392 exact mass: 429.2248 g/mol in MeCH (dry, 3 mL) in a microwave vial (2-5 mL), HCl in 1393 HPLC-MS: analytical method L dioxane (4M, 3 drops) was added. The reaction mixture was 1394 rt: 3.81 min-found mass: 430 (m/z+H) irradiated in a microwave reactor for 5 min at 140°C. The reaction mixture was evaporated and used without further Example #302 purification. The residue was dissolved in TFA (3 mL). The reaction mixture was irradiated in a microwave reactor for 5 Preparation of 5-(3,4-dihydro-2H-benzob 14ox min at 140° C. The reaction mixture was concentrated and azin-6-yl)-N-(2-methyl-1H-benzodimidazol-5-yl)- purified by semi-preparative HPLC-MS and freeze dried 1H-pyrazolo 4,3-dipyrimidin-7-amine from waterft-BuOH 4/1. 1404 exact mass: 335.0999 g/mol 1395 6-(7-chloro-2-(4-methoxybenzyl)-2H-pyrazolo.4, 1405 HPLC-MS: analytical method L 3-dipyrimidin-5-yl)-2H-benzob 14oxazin-3 (4H)-one (0.16 mmol) and 2-methyl-1H-benzodimidazol-5-amine 1406 rt: 4.61 min-found mass: 336 (m/z+H) (0.3 mmol 2 eq.) were suspended in MeOH (dry, 3 mL) in a Example #305 microwave vial (2-5 mL), HCl in dioxane (4M, 3 drops) was added. The reaction mixture was irradiated in a microwave Preparation of N-(3-(tert-butyl)phenyl)-5-(thiophen reactor for 5 min at 140°C. The reaction mixture was evapo 2-yl)-1H-pyrazolo 4,3-dipyrimidin-7-amine rated and used without further purification. The reaction mix ture was dissolved in THF (dry) LiAlH4 powder was added 1407 7-chloro-2-(4-methoxybenzyl)-5-(thiophen-2-yl)- (excess, 2 by 2 eq) until completion of reaction is observed 2H-pyrazolo 4,3-dipyrimidine (0.16 mmol) and 3-(tert-bu (by LCMS). The reaction was quenched with water (1 mL per tyl)aniline (0.3 mmol 2 eq.) were suspended in MeCH (dry, 3 gram LiAlH4), then NaOH (ca. 15% aq., 1 mL perg LiAlH4), mL) in a microwave vial (2-5 mL), HCl in dioxane (4M, 3 water (3 mL per gram LiAlH4). The mixture was filtered, drops) was added. The reaction mixture was irradiated in a washed with THF, MeOH, MeCN (ca. 10 mL each). The microwave reactor for 5 min at 140°C. The reaction mixture residue was dissolved in TFA (3 mL). The reaction mixture was evaporated and used without further purification. The was irradiated in a microwave reactor for 5 minat 140°C. The residue was dissolved in TFA (3 mL). The reaction mixture reaction mixture was concentrated and purified by semi-pre was irradiated in a microwave reactor for 5 minat 140°C. The parative HPLC-MS and freeze dried from water/t-BuOH4/1. reaction mixture was concentrated and purified by semi-pre 1396 exact mass: 398.1840 g/mol parative HPLC-MS and freeze dried from water/t-BuOH4/1. 1397) HPLC-MS: analytical method L 1408) exact mass: 349.1646 g/mol 1398 rt: 3.09 min-found mass: 399 (m/z+H) 1409 HPLC-MS: analytical method L 1410 rt: 5.75 min-found mass: 350 (m/z+H) Example #303 Example #306 Preparation of N-(2-methylisoindolin-5-yl)-5- Preparation of methyl 3-(7-((4-(4-acetylpiperazin-1- (thiophen-2-yl)-1H-pyrazolo 4,3-dipyrimidin-7- yl)phenyl)amino)-1H-pyrazolo 4,3-dipyrimidin-5-yl) amine benzoate 1399 7-chloro-2-(4-methoxybenzyl)-5-(thiophen-2-yl)- 1411 methyl 3-(7-chloro-2-(4-methoxybenzyl)-2H-pyra 2H-pyrazolo4.3-dpyrimidine (0.16 mmol) and 2-methyl Zolo 4,3-dipyrimidin-5-yl)benzoate (0.16 mmol) and 1-(4- isoindolin-5-amine (0.3 mmol 2 eq.) were suspended in (4-aminophenyl)piperazin-1-yl)ethan-1-one (0.3 mmol 2 MeOH (dry, 3 mL) in a microwave vial (2-5 mL), HCl in eq.) were suspended in MeCH (dry, 3 mL) in a microwave dioxane (4M, 3 drops) was added. The reaction mixture was vial (2-5 mL), HCl in dioxane (4M, 3 drops) was added. The irradiated in a microwave reactor for 5 min at 140°C. The reaction mixture was irradiated in a microwave reactor for 5 reaction mixture was evaporated and used without further min at 140°C. The reaction mixture was evaporated and used purification. The residue was dissolved in TFA (3 mL). The without further purification. The residue was dissolved in reaction mixture was irradiated in a microwave reactor for 5 TFA (3 mL). The reaction mixture was irradiated in a micro min at 140° C. The reaction mixture was concentrated and wave reactor for 5 min at 140°C. The reaction mixture was purified by semi-preparative HPLC-MS and freeze dried concentrated and purified by semi-preparative HPLC-MS from waterft-BuOH 4/1. and freeze dried from waterft-BuOH 471. 1400 exact mass: 348.1375 g/mol 1412 exact mass: 471.2382 g/mol 1401 HPLC-MS: analytical method L 1413 HPLC-MS: analytical method D 1402 rt: 3.03 min-found mass: 349 (m/z+H) 1414 rt: 5.83 min-found mass: 482 (m/z+H) US 2012/032978.0 A1 Dec. 27, 2012 94

Example #307 1424) exact mass: 359.2176 g/mol 1425 HPLC-MS: analytical method D Preparation of methyl 3-(7-((1H-indazol-6-yl) 1426 rt: 0.63 min-found mass: 360 (m/z+H) amino)-1H-pyrazolo 4,3-dipyrimidin-5-yl)benzoate 1415 methyl 3-(7-chloro-2-(4-methoxybenzyl)-2H-pyra Example #310 Zolo4.3-dpyrimidin-5-yl)benzoate (0.16 mmol) and 1H-in Preparation of 5-(2-fluorophenyl)-N-(2-methylisoin dazol-6-amine (0.3 mmol 2 eq.) were suspended in MeOH dolin-5-yl)-1H-pyrazolo 4,3-dipyrimidin-7-amine (dry, 3 mL) in a microwave vial (2-5 mL), HCl in dioxane (4M, 3 drops) was added. The reaction mixture was irradiated 1427 7-chloro-5-(2-fluorophenyl)-2-(4-methoxyben in a microwave reactor for 5 min at 140° C. The reaction Zyl)-2H-pyrazolo 4,3-dipyrimidine (0.16 mmol) and 2-me mixture was evaporated and used without further purification. thylisoindolin-5-amine (0.3 mmol 2 eq.) were suspended in The residue was dissolved in TFA (3 mL). The reaction mix MeOH (dry, 3 mL) in a microwave vial (2-5 mL), HCl in ture was irradiated in a microwave reactor for 5 minat 140°C. dioxane (4M, 3 drops) was added. The reaction mixture was The reaction mixture was concentrated and purified by semi irradiated in a microwave reactor for 5 min at 140°C. The preparative HPLC-MS and freeze dried from water/t-BuOH reaction mixture was evaporated and used without further 4f1. purification. The residue was dissolved in TFA (3 mL). The 1416 exact mass: 385.1464 g/mol reaction mixture was irradiated in a microwave reactor for 5 1417. HPLC-MS: analytical method D min at 140° C. The reaction mixture was concentrated and purified by semi-preparative HPLC-MS and freeze dried 1418 rt: 5.91 min-found mass: 386 (m/z+H) from waterft-BuOH 4/1. Example #308 1428 exact mass: 360.1729 g/mol 1429 HPLC-MS: analytical method C Preparation of methyl 3-(7-(4-morpholinophenyl) 1430 rt: 2.00 min-found mass: 409 (m/z+H) amino)-1H-pyrazolo 4,3-dipyrimidin-5-yl)benzoate Example #311 1419 methyl 3-(7-chloro-2-(4-methoxybenzyl)-2H-pyra Zolo4.3-dpyrimidin-5-yl)benzoate (0.16 mmol) and 4-mor Preparation of N-(4-(dimethylamino)methyl)phe pholinoaniline (0.3 mmol 2 eq.) were suspended in MeOH nyl)-5-(2-fluorophenyl)-1H-pyrazolo 4.3-dipyrimi (dry, 3 mL) in a microwave vial (2-5 mL), HCl in dioxane din-7-amine (4M, 3 drops) was added. The reaction mixture was irradiated in a microwave reactor for 5 min at 140° C. The reaction 1431) 7-chloro-5-(2-fluorophenyl)-2-(4-methoxyben mixture was evaporated and used without further purification. Zyl)-2H-pyrazolo 4,3-dipyrimidine (0.16 mmol) and The residue was dissolved in TFA (3 mL). The reaction mix 4-(dimethylamino)methyl)aniline (0.3 mmol 2 eq.) were ture was irradiated in a microwave reactor for 5 minat 140°C. suspended in MeCH (dry, 3 mL) in a microwave vial (2-5 The reaction mixture was concentrated and purified by semi mL), HCl in dioxane (4M, 3 drops) was added. The reaction preparative HPLC-MS and freeze dried from water/t-BuOH mixture was irradiated in a microwave reactor for 5 min at 4f1. 140°C. The reaction mixture was evaporated and used with out further purification. The residue was dissolved in TFA (3 1420 exact mass: 430.2067 g/mol mL). The reaction mixture was irradiated in a microwave 1421 HPLC-MS: analytical method D reactor for 5 min at 140°C. The reaction mixture was con 1422 rt: 6.26 min-found mass: 431 (m/z+H) centrated and purified by semi-preparative HPLC-MS and freeze dried from waterft-BuOH 4/1. Example #309 1432 exact mass: 362. 1930 g/mol 1433 HPLC-MS: analytical method C Preparation of 5-(3-aminophenyl)-N-(4-(dimethy 1434 rt: 2.17 min-found mass: 361 (m/z+H) lamino)methyl)phenyl)-1H-pyrazolo 4.3-dpyrimi din-7-amine Example #312 1423 7-Chloro-2-(4-methoxy-benzyl)-5-(3-nitro-phe Preparation of N-(3-((dimethylamino)methyl)phe nyl)-2H-pyrazolo 4,3-dipyrimidine (0.16 mmol) and nyl)-5-(2-fluorophenyl)-1H-pyrazolo 4,3-dipyrimi 4-(dimethylamino)methyl)aniline (0.3 mmol 2 eq.) were din-7-amine suspended in MeCH (dry, 3 mL) in a microwave vial (2-5 mL), HCl in dioxane (4M, 3 drops) was added. The reaction 1435) 7-chloro-5-(2-fluorophenyl)-2-(4-methoxyben mixture was irradiated in a microwave reactor for 5 min at Zyl)-2H-pyrazolo 4,3-dipyrimidine (0.16 mmol) and 140°C. The reaction mixture was evaporated and used with 3-((dimethylamino)methyl)aniline (0.3 mmol 2 eq.) were out further purification. The residue was dissolved in TFA (3 suspended in MeCH (dry, 3 mL) in a microwave vial (2-5 mL). The reaction mixture was irradiated in a microwave mL), HCl in dioxane (4M, 3 drops) was added. The reaction reactor for 5 min at 140°C. The reaction mixture was evapo mixture was irradiated in a microwave reactor for 5 min at rated and used without further purification. The reaction mix 140°C. The reaction mixture was evaporated and used with ture was dissolved in methanol (3 mL). Pd/C was added (20 out further purification. The residue was dissolved in TFA (3 mg) and the reaction was stirred overnight under N2 at room mL). The reaction mixture was irradiated in a microwave temperature. After filtration with celite the reaction mixture reactor for 5 min at 140°C. The reaction mixture was con was concentrated and purified by semi-preparative HPLC centrated and purified by semi-preparative HPLC-MS and MS and freeze dried from waterft-BuOH 4/1. freeze dried from waterft-BuOH 4/1. US 2012/032978.0 A1 Dec. 27, 2012

1436 exact mass: 362. 1930 g/mol #156: Example #157: Example #158: Example #159; 1437 HPLC-MS: analytical method C Example #165; Example #166; Example #167; Example 1438 rt: 2.18 min-found mass: 363 (m/z+H) #168: Example #171; Example #173: Example #176: Example #177; Example #180: Example #181; Example Biological Data #185; Example #199: Example #202: Example #209; Example #210; Example #211; Example #212; Example SYKActivities: #216; Example #218: Example #220; Example #221; 1439 Kilower than 10 nM: Example #223; Example #226; Example #227: Example Example #1; Example #2; Example #4: Example #5; #228: Example #229; Example #230; Example #231; Example #6; Example #7: Example #10; Example #11; Example #236. Example #242; Example #249. Example Example #16; Example #20; Example #23; Example #25; #252: Example #253: Example #254; Example #258: Example #30; Example #31: Example #33; Example #34; Example #260; Example #268: Example #270; Example Example #35; Example #36; Example #46; Example #54; #271; Example #273: Example #276: Example #279; Example #58: Example #59; Example #60; Example #61; Example #282; Example #283: Example #284; Example Example #62; Example #63; Example #64; Example #66: #286: Example #287; Example #288: Example #289; Example #67: Example #68: Example #69; Example #70; Example #291; Example #294; Example #299; Example Example #71; Example #72; Example #73: Example #74; #301; Example #306; Example #309; Example #310; Example #75; Example #76: Example #78; Example #79; Example #311; Example #82; Example #84; Example #87: Example #91; Ki between 100 nM and 1000 nM: Example #95; Example #98: Example #99; Example #117: Example #13; Example #21; Example #39; Example #45; Example #118: Example #119. Example #128; Example Example #48; Example #55; Example #56. Example #88: #131; Example #132: Example #134; Example #137; Example #113: Example #115; Example #121; Example Example #138; Example #143: Example #144; Example #130; Example #133; Example #148; Example #150; #149; Example #151; Example #160; Example #161; Example #153; Example #174; Example #178; Example Example #162; Example #163; Example #164; Example #215; Example #217: Example #219; Example #222: #169; Example #170; Example #172: Example #175: Example #224; Example #255; Example #259; Example Example #179; Example #182; Example #183; Example #262; Example #263: Example #264; Example #265; #184: Example #186: Example #187: Example #188: Example #266; Example #267: Example #272; Example Example #189; Example #190. Example #191. Example #274; Example #277; Example #292; Example #305; #192: Example #193: Example #194; Example #195; Example #307: Example #312: Example #196: Example #197. Example #198: Example #200; Example #201: Example #203: Example #204: LRRK2 Activities: Example #205; Example #206: Example #207: Example 1440 IC50 lower than 10 nM: #208: Example #213: Example #225; Example #232: Example #233; Example #234; Example #235; Example Example #36; Example #82; Example #135; Example #144: #237: Example #238; Example #239; Example #240: Example #247; Example #269; Example #241; Example #243; Example #244; Example #245; Example #246; Example #247; Example #248: 1441 IC50 between 10 nM and 100 nM: Example #251; Example #256. Example #257; Example Example #23; Example #26: Example #37; Example #46; #269; Example #275; Example #278; Example #280; Example #59; Example #62; Example #64; Example #69; Example #281; Example #285; Example #290; Example Example #70; Example #71; Example #72: Example #73: #293: Example #295; Example #296: Example #297: Example #75; Example #76: Example #77: Example #79; Example #298; Example #300; Example #302; Example Example #84; Example #87: Example #89; Example #91; #303: Example #304; Example #95; Example #117: Example #118: Example #136; Ki between 10 nM and 100 nM: Example #137: Example #139; Example #143: Example Example #3: Example #8; Example #9; Example #12; #145; Example #147: Example #158: Example #161; Example #14: Example #17; Example #18. Example #19; Example #164: Example #166; Example #182; Example Example #22; Example #24; Example #26: Example #27; #183: Example #184: Example #185; Example #190; Example #28. Example #29; Example #32; Example #37; Example #195; Example #199: Example #206: Example Example #38; Example #40. Example #47; Example #50: #235; Example #238; Example #280: Example #297: Example #51; Example #52; Example #53: Example #57: IC50 between 100 nM and 1000 nM: Example #65; Example #77: Example #80: Example #81; Example #1; Example #2; Example #4: Example #5; Example #83: Example #85; Example #86: Example #89; Example #6; Example if7; Example #9; Example #10; Example #90; Example #92: Example #93; Example #94; Example #14: Example #16: Example #17; Example #18; Example #96: Example #97: Example #100; Example #101; Example #20. Example #21; Example #22; Example #24; Example #102; Example #103: Example #104; Example Example #25; Example #27: Example #28. Example #32; #105; Example #106; Example #107: Example #108; Example #33; Example #34; Example #35; Example #40; Example #109; Example #110. Example #111; Example Example #41; Example #47: Example #48; Example #50: #112: Example #114: Example #116; Example #120; Example #51; Example #58: Example #60; Example #61; Example #122; Example #123; Example #124; Example Example #63; Example #65; Example #66; Example #67; #125; Example #126; Example #127: Example #129: Example #68; Example #74; Example #78; Example #80; Example #135; Example #136. Example #139; Example Example #81; Example #83. Example #85; Example #86: #140; Example #141; Example #142: Example #145; Example #88: Example #93; Example #96: Example #97: Example #146; Example #147: Example #152; Example Example #99: Example #101; Example #108: Example #109: US 2012/032978.0 A1 Dec. 27, 2012 96

Example #110. Example #111; Example #114; Example R’ is an alkyl, alkenyl, alkynyl, heteroalkyl, aryl, het #119; Example #120; Example #126; Example #127: eroaryl, cycloalkyl, alkylcycloalkyl, heteroalkylcy Example #131; Example #132; Example #134; Example cloalkyl, heterocycloalkyl, aralkyl or heteroaralkyl #138; Example #140; Example #142: Example #146; group, wherein R is bound to the pyrimidine ring of Example #156: Example #157: Example #159; Example formula (I) via a carbon-carbon bond; #162: Example #163; Example #169; Example #170: R is a hydrogenatom, a halogenatom, NO, N, OH, SH, Example #171; Example #172; Example #173: Example NH oran alkyl, alkenyl, alkynyl, heteroalkyl, aryl, het #179; Example #186: Example #187: Example #188: eroaryl, cycloalkyl, alkylcycloalkyl, heteroalkylcy Example #189; Example #191. Example #193: Example cloalkyl, heterocycloalkyl, aralkyl or heteroaralkyl #194; Example #196: Example #197: Example #198: group; Example #200; Example #201: Example #202; Example R" is an alkyl, alkenyl, alkynyl, heteroalkyl, aryl, hetero #203: Example #204; Example #205; Example #207: aryl, cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, Example #208: Example #209; Example #218: Example heterocycloalkyl, aralkyl or heteroaralkyl group; #225; Example #232; Example #233; Example #234: R is a hydrogenatom, NO, N, OH, SH, NH, or an alkyl, Example #237: Example #239; Example #240; Example alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, #248: Example #251; Example #254; Example #257; cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, het Example #261; Example #265; Example #268; Example erocycloalkyl, aralkyl or heteroaralkyl group; and #271; Example #275; Example #278; Example #279; R is a hydrogenatom, NO, N, OH, SH, NH, or an alkyl, Example #281; Example #282; Example #283; Example alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, #284; Example #290; Example #293: Example #294; cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, het Example #295; Example #296: Example #300; Example erocycloalkyl, aralkyl or heteroaralkyl group; #301; Example #302; Example #303: Example #304; or a pharmaceutically acceptable salt, ester, Solvate or Example #310. Example #311; hydrate or a pharmaceutically acceptable formulation MYLKActivities: thereof. 2. A compound according to claim 1, wherein A is NH. 1442 IC50 lower than 5000 nM: 3. A compound according to claim 1, wherein R is H.F, Cl, Example #5. Example #8; Example #20. Example #21; Example #34; Example #35; Example #45; Example #46; CH, CF, NO cyclopropyl, CN, N, OH, SH, OMe, S.Me, Example #57: Example #58: Example #62. Example #68; NHMe, NMe, or NH. Example #70; Example #74; Example #83: Example #91; 4. A compound according to claim 1, wherein R is a Example #95; Example #97: Example #99; Example #114; hydrogen atom. Example #117: Example #118; Example #120; Example 5. A compound according to claim 1, wherein A is NH and #127: Example #131; Example #132: Example #134; R is H. Example #138; Example #139; Example #143: Example 6. A compound according to claim 1, wherein R' is an #144; Example #147: Example #160; Example #161 ; optionally Substituted aryl, heteroaryl, cycloalkyl, heterocy Example #163; Example #172; Example #175. Example cloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, aralkyl or #179; Example #182: Example #187: Example #188: heteroaralkyl group. Example #189; Example #190. Example #191. Example 7. A compound according to claim 1, wherein R is an #225; Example #238; Example #240; Example #241; optionally substituted phenyl or naphthyl group or an option Example #247; Example #248; Example #252; Example ally Substituted heteroaryl group having one or two rings #254; Example #255; Example #268: Example #275: containing 5, 6, 7, 8, 9 or 10 ring atoms, or an optionally Example #276: Example #277; Example #279; Example substituted arylheterocycloalkyl, heteroarylcycloalkyl or het #280: Example #284; Example #286: Example #288: eroarylhetero-cycloalkyl group containing two or three rings Example #289; Example #290; Example #293: Example and 9 to 20 ring atoms. #294; Example #295; 8. A compound according to claim 1, wherein R' is a group 1443 FIG. 1 shows the LAD2-SYK Correlation of formula or a group of formula X'-L'-Y' or a group of formula X'-L-Y-L-Z" wherein 1. A compound of formula (I) X is an optionally substituted phenyl group or an option ally Substituted heteroaryl group containing 5 or 6 ring (I) atoms and 1,2,3 or 4 heteroatoms selected from O, Sand N: L' is a bond or a group of formula —CH2—, —C(=O)—,

Y' is an optionally substituted phenyl group, an optionally Substituted heteroaryl group containing 5 or 6 ring atoms wherein and 1,2,3 or 4 heteroatoms selected from O, Sand N, an A is NH, O, S, C-O, NR or CRR: optionally Substituted C-C, cycloalkyl group or an R" is an alkyl, alkenyl, alkynyl, heteroalkyl, aryl, hetero optionally Substituted heterocycloalkyl group contain aryl, cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, ing 3, 4, 5, 6 or 7 ring atoms and 1, 2, 3 or 4 heteroatoms heterocycloalkyl, aralkyl or heteroaralkyl group; selected from O, S and N: US 2012/032978.0 A1 Dec. 27, 2012 97

L is a bond or a group of formula —CH2—, —C(=O)—, -continued SO , —SO. , NH C(=O)— —C(=O) NH-; C(=O)-O-, - O C(=O)-, -NH C (=O)-O-, - O C(=O) NH-, -NH SO NH CH NH-CH , NH SO , SO. NH or -NH C(=O) NH-; and Z' is an optionally substituted phenyl group, an optionally Substituted heteroaryl group containing 5 or 6 ring atoms and 1,2,3 or 4 heteroatoms selected from O, Sand N, an optionally substituted C-C, cycloalkyl group or an optionally Substituted heterocycloalkyl group contain ing 3, 4, 5, 6 or 7 ring atoms and 1, 2, 3 or 4 heteroatoms selected from O, S and N. 9. A compound according to claim 1, wherein R' is selected from the following groups:

-(

O US 2012/032978.0 A1 Dec. 27, 2012 98