MXPA06004245A

MXPA06004245A - Imidazopyrazine tyrosine kinase inhibitors

Info

Publication number: MXPA06004245A
Application number: MXPA/A/2006/004245A
Authority: MX
Inventors: Mark Joseph Mulvihill; Cara Cesario; Patricia Anne Beck; Hanqing Dong; Yingchuan Sun; Matthew Cox; Kenneth Foreman; Anthony Innocenzo Nigro; Lydia Saraglou; Arno G Steinig; Qinghua Weng; Douglas Werner; Robin Wilkes; Jonathan Williams
Original assignee: Patricia Anne Beck; Cara Cesario; Matthew Cox; Hanqing Dong; Kenneth Foreman; Mark Joseph Mulvihill; Anthony Innocenzo Nigro; Osi Pharmaceuticals Inc; Saroglou Lydia; Arno G Steinig; Yingchuan Sun; Qinghua Weng; Douglas Werner; Robin Wilkes; Jonathan Williams
Priority date: 2003-10-15
Filing date: 2006-04-17
Publication date: 2006-10-17

Abstract

Compounds of the formula (I) and pharmaceutically acceptable salts thereof, wherein Q1 and R1 are defined herein, inhibit the IGF-1R enzyme and are useful for the treatment and/or prevention of various diseases and conditions that respond to treatment by inhibition of tyrosine kinases.

Description

INHIBITORS OF IMIDAZOPIRAZINA TIROSINA CINASA BACKGROUND OF THE INVENTION The present invention is directed to novel amidazopyrazines, their salts, and compositions comprising them. In particular, the present invention is directed to imidazopyrazines as novel inhibitors of tyrosine kinase that inhibit tyrosine kinase enzymes in animals, including humans, for the treatment and / or prevention of various diseases and conditions such as cancer. Phosphoryltransferases are a large family of enzymes that transfer phosphorus-containing groups from one substrate to another. Kinases are a class of enzymes that function in the catalysis of phosphoryl transfer. Phosphorylation is usually a transfer reaction of a phosphate group from ATP to the protein substrate. Almost all kinases contain a similar catalytic domain of 250-300 amino acids. Clhanase proteins, with at least 400 identified, constitute the largest subfamily of structurally related phosphoryl transferases and are responsible for the control of a wide variety of signal transduction processes within the cell. Protein kinases can be categorized within families by phosphorylating substrates (eg, protein tyrosine, protein serine / threonine, etc.). It has been identified that the motifs of the protein kinase sequence generally correspond to each of these family kinases. Lipid kinases (for example PI3K) constitute a separate group of kinases with structural similarity to protein kinases. The "kinase domain" appears in numerous polypeptides which serve a variety of functions. Such polypeptides include, for example, transmembrane receptors, polypeptides associated with intracellular receptors, polypeptides located in the cytoplasm, polypeptides located in a nucleus and polypeptides located in subcellular compartments. The activity of protein kinases can be regulated by a variety of mechanisms and any individual protein can be regulated by more than one mechanism. Such mechanisms include, for example, autophosphorylation, transphosphorylation by other kinases, protein-protein interactions, protein-lipid interactions, protein-polynucleotide interactions, ligand binding, and post-translational modification. White protein phosphorylation occurs in response to a variety of extracellular signals (hormones, neurotransmitters, growth factors and differentiation factors, etc.), cell cycle events, environmental or nutrient stress, etc. Proteins and lipid kinases regulate many different cellular processes by adding phosphate groups to targets such as proteins or lipids. Such cellular processes include, for example, proliferation, growth, differentiation, metabolism, cell cycle events, apoptosis, motility, transcription, translation and other signaling processes. Clhanase-catalyzed phosphorylation acts as a molecular on / off regulator to modulate or regulate the biological function of the target protein. Therefore, protein and lipid kinases can function in signaling routes to activate or inactivate, or modulate the activity (either directly or indirectly) of the targets. These targets may include, for example, metabolic enzymes, regulatory proteins, receptors, cytoskeletal proteins, ion channels or pumps, or transcription factors. A partial list of protein kinases includes abl, AKT, bcr-abl, Blk, Brk, Btk, c-kit, c-met, c-src, CDK1, CDK2, CDK3, CDK4, CDKS, CDK6, CDK7, CDK8, CDK9, CDK10, cRafl, CSFir, CSK, EGFR, ErbB2, ErbB3, ErbB4, Erk, Fak, Fes, FGFR1, FGFR2, FGFR3, FGFR4, FGFR5, Fgr, flt-l, Fps, Frk, Fyn, Hck, IGF- 1 R, INS-R, Jak, KDR, Lck, Lyn, MEK, p38, PDGFR, PIK, PKC, PYK2, rum, tie, tie2, TRK, Yes, and Zap70. Therefore, protein kinases represent a large family of proteins that play a central role in regulating a wide variety of cellular processes, maintaining control over cellular function. Uncontrolled signaling due to a defective control of the phosphorylation of the protein has been implicated in numerous diseases and disease conditions, including, for example, inflammation, cancer, allergy / asthma, disease and conditions of the immune system, disease and conditions of the Central nervous system (CNS), cardiovascular disease, dermatology, and angiogenesis.

The initial interest in protein kinases as pharmacological targets was stimulated by the findings that many viral oncogenes encode structurally modified cell kinases with constitutive enzymatic activity. An early example was Rous sarcoma virus (RSV) or avian sarcoma virus (ASV), which causes highly malignant tumors of the same type or sarcomas in infected chickens. Subsequently, the deregulated protein kinase activity, which results from a variety of mechanisms, has been implicated in the pathophysiology of numerous important disorders in humans including, for example, cancer, CNS conditions, and immunologically related diseases. The development of selective inhibitors of the protein kinase that block pathologies and / or symptoms of the disease resulting from the aberrant activity of the protein kinase has therefore become an important therapeutic target. Protein tyrosine kinases (PTKs) are enzymes that catalyze the phosphorylation of specific tyrosine residues in cellular proteins. Such post-translational modification of substrate proteins, often of the enzymes themselves, acts as a molecular switch that regulates cell proliferation, activation or differentiation (review, see Schlessinger and Ulllich, 1992, Neuron 9: 383-391). Aberrant or excessive PTK activity has been observed in many disease states including benign and malignant proliferative disorders as well as diseases resulting from inappropriate activation of the immune system (e.g., autoimmune disorders), allograft rejection, and graft disease. vs. host In addition, endothelial cell-specific receptors PTKs such as KDR and Tie-2 mediate the angiogenic process, and are therefore involved in supporting the progression of cancers and other diseases that involve inappropriate vascularization (eg, diabetic retinopathy). , choroidal neovascularization due to macular degeneration related to age, psoriasis, arthritis, retinopathy of prematurity, infantile hemangiomas). Tyrosine kinases can be of the receptor type (which have extracellular, transmembrane and intracellular domains) or of the non-receptor type (being completely intracellular). Tyrosine kinase receptors (RTKs) comprise a large family of transmembrane receptors with at least nineteen distinct RTK subfamilies that have diverse biological activities. The RTK family includes receptors that are crucial for the growth and differentiation of a wide variety of cell types (Yarden and Ullrich, Ann.Rev. Biochem., 57: 433-478, 1988; Ullrich and Schlessinger, Cell 61: 243-254, 1990). The intrinsic function of the RTKs is activated after ligand binding, which results in phosphorylation of the receptor and of multiple cellular substrates, and subsequently in a variety of cellular responses (Ullrich &Schlessinger, 1990, Cell 61: 203- 212). Therefore, translation of the signal mediated by RTK is initiated by extracellular interaction with a specific growth factor (ligand), typically followed by receptor dimerization, stimulation of intrinsic protein tyrosine kinase activity and trans-phosphorylation of the receiver. The binding sites are thus created by the molecules for transduction of the intracellular signal and lead to the formation of complexes with a spectrum of molecules for cytoplasmic signaling that facilitate the appropriate cellular response such as cell division, differentiation, metabolic effects, and changes in the extracellular microenvironment (see Schlessinger and Ullrich, 1992, Neuron 9: 1-20). Proteins with SH2 binding domains (src homology-2) or phosphotyrosine (PTB) bind to activated tyrosine kinase receptors and their substrates with high affinity to propagate signals within the cell. Both domains recognize phosphotyrosine. (Fantl et al., 1992, Cell 69: 4 13-423; Songyang et al., 1994, Mol. Cell. Biol. 14: 2777-2785; Songyanget al., 1993, Cell 72: 767-778; and Koch et al., 1991, Science 252: 668-678; Shoelson, Curr Opin. Chem. Biol. (1997), 1 (2), 227-234; Cowbum, Curr Opin. Struct. Biol. (1997), 7 (6), 835-838). Several intracellular substrate proteins have been identified that associate with RTKs. These can be divided into two main groups: (1) substrates that have a catalytic domain; and (2) substrates that lack such a domain but serve as adapters and associate with catalytically active molecules (Songyang et al, 1993, Cell 72: 767-778). The specificity of the interactions between the receptors or proteins and the SH2 or PTB domains of their substrates is determined by the amino acid residues that are located immediately around the phosphorylated tyrosine residue. For example, the differences in the binding affinities between the SID domains and the amino acid sequences surrounding the phosphotyrosine residues in particular receptors correlate with the differences observed in their substrate phosphorylation profiles (Songyang et al., 1993, Cell 72: 767-778). The observations suggest that the function of each tyrosine kinase receptor is determined not only by its expression pattern and ligand availability but also by the arrangement of the downstream signal transduction pathways that are activated by a particular receptor as well as for the time and duration of these stimuli. Therefore, phosphorylation provides an important regulatory step which determines the selectivity of the signaling pathways recruited by the specific growth factor receptors, as well as by the differentiation factor receptors. It has been suggested that several tyrosine kinase receptors such as FGFR-1, PDGFR, Tie-2 and c-Met, and growth factors that bind to these, play a role in angiogenesis, although some may indirectly promote angiogenesis ( Mustonen and Alitalo, J. Cell Biol. 129: 895-898, 1995). One such tyrosine kinase receptor, known as "fetal liver kinase 1" (FLK-1), is a member of the subclass of type III RTKs. FLK-1 from human is also known as "receptor containing the kinase insert domain" (KDR) (Terman et al., Oncogene 6: 1677-83, 1991). It is also referred to as "vascular endothelial cell growth factor receptor 2" (VEGFR-2) since it binds to vascular endothelial cell growth factor (VEGF) with high affinity. The murine version of FLK-1 / VEGFR-2 has also been called NYK. (Oelrichs et al, Oncogene 8 (1): 11-15,1993). Numerous studies (such as those reported in Millauer et al, above) suggest that VEGF and FLK-1 / KDR / VEGFR-2 are a ligand-receptor pair that plays an important role in vascular endothelial cell proliferation (vasculogenesis) , and the formation and emergence of blood vessels (angiogenesis). Accordingly, VEGF plays a role in the stimulation of both normal and pathological angiogenesis (Jakeman et al., Endocrinology 133: 848-859, 1993; Kolch et al., Breast Cancer Research and Treatment 36: 139-155, 1995; Ferrara et al., Endocrine Reviews 18 (1), 4-25, 1997, Ferrara et al., Regulation of Angiogenesis (ed. L D. Goldberg and EM Rosen), 209-232, 1997). In addition, VEGF has been implicated in the control and improvement of vascular permeability (Connolly, et al., 1. Viol. Chem. 264: 20017-20024, 1989; Brown et al., Regulation of angiogenesis (ed. and EM Rosen), 233-269, 1997). Another RTK subclass type III related to FLK-1 / KDR (DeVries et al., Science 255: 989-991, 1992; Shibuya et al., Neogene 5: 519-524, 1990) is "tyrosine kinase similar to fms-l" (Flt-1), also referred to as "vascular endothelial cell growth factor receptor 1" (VEGFR-1). The members of the FLK-1 / KDR subfamilies? EGFR-2 and Flt-l / VEGPR-1 are expressed mainly in endothelial cells. These members of the subclass are specifically stimulated by members of the VEGF family of ligands (Klagsbum and D'Amore, Cytokine &; Growth Factor Reviews 7: 259-270, 1996). VEGF binds to Flt-1 with higher affinity than to FLK-1 / KDR and is mitogenic for vascular endothelial cells (Terman et al., 1992, previously mentioned, Mustonen et al., Previously mentioned, DeVries et al., Previously mentioned. ). It is believed that Flt-1 is essential for endothelial organization during vascular development. The expression of Flt-1 is associated with early vascular development in mouse embryos, and with neovascularization during healing (Mustonen and Alitalo, previously mentioned). The expression of Flt-1 in monocytes, osteoclasts, and osteoblasts, as well as in adult tissues such as glomeruli in the kidney suggest an additional function for this receptor that is not related to cell growth (Mustonen and Alitalo, previously mentioned). The placental growth factor (P1GF) has an amino acid sequence that exhibits significant homology to a VEGF sequence (Park et al., 1. Biol. Chem. 269: 25646-54, 1994, Maglione et al., Oncogene 8: 925-31, 1993). As with VEGF, different P1GF species are generated from alternative mRNA processing, and the protein exists in the dimeric form (Park et al., Supra). P1GF-1 and P1GF-2 bind to Flt-1 with high affinity, and P1 GF-2 also binds avidly to neuropilin-1 (Migdal et al., 1. Biol. Chem. 273 (35): 22272- 22278), but none bind to FLK-1 / KDR (Park et al., Supra). It has been reported that P1GF potentiates both vascular permeability and the mitogenic effect of VEGF on endothelial cells when VEGF is present at low concentrations (presumably due to the formation of the heterodimer) (Park et al., Supra). It is thought that VEGF-B plays a role in the regulation of extracellular matrix degradation, cell adhesion, and migration through the modulation of the expression and activation of urokinase-type plasminogen activator and plasminogen activation inhibitor 1 (Pepper et al., Proc. Nati, Acad. Sci. USA (1998), 95 (20): 11709-11714). VEGF-C can also bind to KDR / VEGFR-2 and stimulate the proliferation and migration of endothelial cells in vitro and angiogenesis in in vivo models (Lymboussaki et al., Am. J Pathol. (1998), 153 ( 2): 395-403; Witzenbichler et al., Am. J. Pathol. (1998), 153 (2), 381-394). The transgenic overexpression of VEGF-C causes the proliferation and elongation of only the lymphatic vessels, while the blood vessels are not affected. Unlike VEGF, the expression of VEGF-C is not induced by hypoxia (Ristimaki et al, J. Biol. Chem. (1998), 273 (14), 8413-8418). Structurally similar to VEGF-C, it has been reported that VEGF-D binds and activates at least two VEGFRs, VEGFR-3 / FI.-4 and KDR / VEGFR-2. It was originally cloned as a mitogen for fibroblast inducible by c-fos and is expressed more prominently in the mesenchymal cells of the lung and skin (Achen et al, Proc. Nati. Acad. Sci. U SA (1998), 95 (2 ), 548-553 and references therein). It has been claimed that VEGF, VEGF-C and VEGF-D induce an increase in vascular permeability in vivo in a Miles assay when injected into the skin tissue (PCT / US97 / 14696, WO 98/07832, Witzenbichler et al., previously mentioned). The physiological role and importance of these ligands in the modulation of vascular hyperpermeability and endothelial responses in the tissues where they are expressed remain unknown. Tie-2 (TEK) is a member of a newly discovered family of specific RTKs of endothelial cells involved in critical angiogenic processes such as branching, sprouting, remodeling, maturation and stability of blood vessels. Tie-2 is the first mammalian RTK for which both agonist ligands (eg, Angiopoietin I ("Angl"), which stimulate receptor autophosphorylation and signal transduction), and antagonist ligands (e.g., Angiopoietin 2 ("Ang2")), have been identified. The current model suggests that stimulation of Tie-2 kinase by the Angl ligand is directly involved in the branching, emergence and exocretion of new blood vessels, and the recruitment and interaction of important periendothelial support cells in the maintenance of integrity of the blood vessels and the induction of quiescence. The absence of Tie-2 stimulation by Ang or the inhibition of Tie-2 autophosphorylation by Ang2, which occurs at high levels in the vascular regression sites, can cause a loss in the vascular structure and in the contacts of the matrix resulting in endothelial cell death, especially in the absence of stimuli for growth / survival. Recently, it has been found that significant upregulation of Tie-2 expression within the panus synovial vascular arthritic joints in humans, consistent with a role in inappropriate neovascularization, suggesting that Tie-2 plays a role in the progression of rheumatoid arthritis. We have identified point mutations that constitutively produce activated forms of Tie-2 in association with disorders of venous malformation in humans. Therefore, Tie-2 inhibitors are useful in the treatment of such disorders, and in other situations of inappropriate neovascularization. Non-receptor tyrosine kinases represent a collection of cellular enzymes which lack extracellular and transmembrane sequences (see, Bohlen, 1993, Oncogene 8: 2025-2031). More than twenty-four individual non-receptor tyrosine kinases have been identified, comprising eleven (11) subfamilies (Src, Frk, Btlc, Csk, Abl, Zap70, Fes / Fps, Fak, Jak, Ack and LIMK). The Src subfamily of non-receptor tyrosine kinases is comprised of the largest number of PTKs and includes Src, Yes, Fyn, Lyn, Lck, Blk, Hck, Fgr and Yrk. The Src subfamily of enzymes has been associated with oncogenesis and immune responses. Plk-1 is a serine / threonine kinase which is an important regulator of cell cycle progression. This plays critical roles in the assembly and dynamic function of the mitotic spindle apparatus. It has also been shown that Plk-1 and related kinases are closely involved in the activation and inactivation of other cell cycle regulators, such as cyclin-dependent kinases. High levels of Plk-I expression are associated with cell proliferation activities. It has frequently been found in malignant tumors of various origins. The inhibitors of Plk-1 are expected to block the proliferation of the cancer cell by altering the processes involving the mitotic spindles and inappropriately activated cyclin-dependent kinases. Cdc2 (cdkl) / cyclin B is another serine / threonine kinase enzyme which belongs to the cyclin dependent kinase family (cdks). These enzymes participate in the critical transmission between the various phases of cell cycle progression. It is believed that uncontrolled cell proliferation, the hallmark of cancer, is dependent on the elevated activities of cdk in these cells. Loss of control of cdk regulation is a frequent event in hyperproliferative diseases and cancer (Pines, Current Opinion in Cell Biology, 4: 144-148 (1992); Lees, Current Opinion in Cell Biology, 7: 773-780 (1995); Hunter and Pines, Cell, 79: 573-582 (1994)). The inhibition of cdk activities elevated in cancer cells by inhibitors of cdc2 / cyclin B kinase could suppress proliferation and could re-establish normal control of cell cycle progression. Malignant cells are associated with loss of control over one or more elements of the cell cycle. These elements range from cell surface receptors to transcriptional and translational regulators, including insulin-like growth factors, insulin-1 growth factor (IGF-1), and insulin-like growth factor- 2 (IGF-2). [M. J. Ellis, "The Insulin-Like Growth Factor Network and Breast Cancer," Breast Cancer, Molecular Genetics, Pathogenesis and Therapeutics, Humana Press 1999]. The insulin-like growth factor system consists of ligand families, insulin-like growth factor-binding proteins, and receptors. A major physiological role of the IGF-1 system is the promotion of normal growth and regeneration, and the overexpression of IGF-1 R can initiate mitogenesis and promote neoplastic transformation dependent on the ligand. In addition, IGF-1 R plays an important role in the establishment and maintenance of the malignant phenotype. IGF-1 R exists as a heterodimer, with several disulfide bridges. The catalytic site of tyrosine kinase and the ATP binding site are located on the cytoplasmic portion of the beta subunit. Unlike the epidermal growth factor receptor (EGF), mutant oncogenic forms of IGF-1R have not been identified. However, it has been shown that several oncogenes affect the expression of IGF-1 and IGF-1R. has observed the correlation between a reduction of IGF-1R expression and resistance to transformation. Exposure of the cells to the antisense mRNA to IGF-1 R RNA prevents the growth on soft agar of several human tumor cell lines. Apoptosis is a ubiquitous physiological process used to eliminate damaged or unwanted cells in multicellular organisms. It is believed that the deregulation of apoptosis participates in the pathogenesis of many human diseases. The failure of apoptotic cell death has been implicated in various cancers, as well as in autoimmune disorders. Conversely, increased apoptosis is associated with a variety of diseases that involve the loss of cells such as neurodegenerative disorders and AIDS. As such, the regulators of apoptosis have become an important therapeutic target. It has now been established that a major mode of tumor survival is the escape of apoptosis. IGF-1 R abolishes the progression towards apoptosis, both in vivo and in vitro. It has also been shown that a decrease in the level of IGF-1 R below the levels of the wild type causes apoptosis of tumor cells in vivo. The ability of the alteration of IGF-1 R to cause apoptosis seems to decrease in normal, non-tumorigenic cells. The inappropriately high activity of protein kinase has been implicated in many diseases resulting from abnormal cell function. This could be generated either directly or indirectly, by the failure of the appropriate mechanisms of control for the kinase, related to mutation, over-expression or inappropriate activation of the enzyme; or by over- or underproduction of cytokines or growth factors that also participate in the translation of the upstream or low-current signals of the kinase. In all these cases, it can be expected that the selective inhibition of the action of the kinase has a beneficial effect. The type 1 insulin-like growth factor receptor (IGF-1 R) is a transmembrane RTK that binds primarily to IGF-1 but also to 1GF-II and to insulin with lower affinity. The binding of IGF-1 to its receptor results in oligomerization of its receptor, activation of tyrosine kinase, autophosphorylation of the intermolecular receptor and phosphorylation of cellular substrates (the main substrates are IRS1 and Shc). IGF-1 R activated by ligand induces mitogenic activity in normal cells and plays an important role in abnormal growth. Several clinical reports highlight the important role of the IGF-1 pathway in the development of tumors in humans: 1) the over-expression of IGF-1 R is frequently found in various tumors (breast, colon, lung, sarcoma) and frequently It is associated with an aggressive phenotype. 2) the high circulating concentrations of IGF1 correlate strongly with risk of prostate, lung and breast cancer. In addition, IGF-1 R is required for the establishment and maintenance of the transformed phenotype in vitro and in vivo (Baserga R. Exp. Cell, Res., 1999, 253, 1-6). The kinase activity of IGF-1 R is essential for the transformation activity of several oncogenes: EGFR, PDGFR, SV40 T antigen, Ras, Raf, and activated v-Scr. The expression of IGF-1 R in normal fibroblasts induces neoplastic phenotypes, which can then form tumors in vivo. The expression of IGF-1 R plays an important role in the independent growth of anchorage. IGF-1 R has been shown to protect cells from apoptosis induced by chemotherapy, radiation, and cytokine. In contrast, the inhibition of endogenous IGF-1 R by dominant negative IGF-1 R, triple helix formation or vector for antisense expression have been shown to suppress in vitro transforming activity and tumor growth in animal models. It has been found that many of the tyrosine kinases, either an RTK or a non-receptor tyrosine kinase, participate in the cell signaling pathways involved in numerous pathogenic conditions, including cancer, psoriasis, and other hyperproliferative disorders or hyper-immune responses. Therefore, extensive investigations have been conducted for inhibitors of kinases involved in the mediation or maintenance of disease states to treat such diseases. Examples of such research on kinases include, for example: (1) inhibition of c-Src (Brickell, Critical Reviews in Oncogenesis, 3: 401-406 (1992)); Courtneidge. Seminars in Cancer Biology, 5: 236-246 (1994), raf (Powis, Pharmacology &Therapeutics, 62: 57-95 (1994)) and cyclin-dependent kinases (CDKs) 1, 2, and 4 in cancer (Pines) , Current Opinion in Cell Biology, 4: 144-148 (1992); Lees, Current Opinion in Cell Biology, 7: 773-780 (1995); Hunter and Pines, Cell, 79: 573-582 (1994)), ( 2) inhibition of CDK2 or PDGF-R kinase in restenosis (Buchdunger et al., Proceedings of the National Academy of Science USA, 92: 2258-2262 (1995)), (3) inhibition of CDK5 and GSK3 kinases in Alzheimer's (Hosoi et al., Journal of Biochemistry (Tokyo), 117: 741-749 (1995), Aplin et al., Journal of Neurochemistry, 67: 699-707 (1996), (4) inhibition of c-Src kinase in osteoporosis ( Tanaka et al., Nature, 383: 528-531 (1996), (5) inhibition of GSK-3 kinase in type-2 diabetes (Borthwick et al., Biochemical &Biophysical Research Communications, 210: 738-745 ( 1995), (6) inhibition of p38 kinase in inflammation (Badger et al., The Journal of Phar Macology and Experimental Therapeutics, 279: 1453-1461 (1996)), (7) inhibition of VEGF-R 1-3 and TIE-1 and 2 kinases in diseases involving angiogenesis (Shawver et al., Drug Discovery Today, 2 : 50-63 (1997)), (8) inhibition of UL97 kinase in viral infections (He et al., Journal of Virology, 71: 405-411 (1997)), (9) inhibition of CSF-1 R kinase in bone and hematopoietic diseases (Myerset. al., Biooyganic & Medicinal Chemistry Letters, 7: 421-424 (1997), and (10) inhibition of Lck kinase in autoimmune diseases and graft rejection (Myers et al., Bioorganic &Medicinal Chemistry Letters, 7: 417-420 (1997)). ). Inhibitors of certain kinases may be useful in the treatment of diseases when the kinase is not poorly regulated, but nevertheless it is essential for the maintenance of the disease state. In this case, the inhibition of the kinase activity could act as a cure or palliative for these diseases. For example, many viruses, such as human papillomavirus, altered cell cycle and induction of cells towards the S phase of the cell cycle (Vousden, FASEB Journal, 7: 8720879 (1993)). The prevention of cells from entering the DNA synthesis phase after viral infection by inhibiting the essential activities that start in the S phase such as through CDK2, can alter the life cycle of the virus and prevent the replication of the virus. This same principle can be used to protect normal cells of the body from the toxicity of cycle-specific chemotherapeutic agents (Stone et al., Cancer Research, 56: 3199-3202 (1996); Kohn et al., Journal of Cellular Biochemishy, 54: 44-452 (1994) .Inhibition of CDK 2 or 4 will prevent progression towards the cycle in normal cells and will limit the toxicity of cytotoxics which act in the S, G2 or mitosis phases. , it has also been shown that the activity CDK2 / cyclin E regulates NF-kB.Inhibition of CDK2 activity stimulates the expression of the NF-kB-dependent gene, an event mediated through interactions with the p300 co-activator. (Perkins et al., Science, 275: 523-527 (1997)). NF-kB regulates genes involved in inflammatory responses (such as hematopoietic growth factors, chemokines, and leukocyte adhesion molecules) (Baeuerle et al. Henkel, Annual Review of Immunology, 12 : 141-179 (1994)) and may be involved in the suppression of apoptotic signals within the cell (Beg and Baltimore, Science, 274: 782-784 (1996); Wang et al., Science, 274: 784-787 (1996); Van Antwerp et al., Science, 274: 787-789 (1996). Therefore, inhibition of CDK2 can suppress apoptosis induced by cytotoxic drugs via a mechanism which involves NF-kB and may be useful where regulation of NF-kB plays a role in the etiology of the disease. A further example of the utility of kinase inhibition are fungal infections: Aspergillosis is a common infection in patients who have a compromised immune system (Armstrong, Clinical Infectious Diseases, 16: 1-7 (1993)). Inhibition of aspergillus kinases Cdc2 / CDC28 or Nim A (Osmaniet al., EMBO Journal, 10: 2669-2679 (1991)); Osmani et al., Cell, 67: 283-291 (1991)) can cause growth arrest or death of fungi, effectively treating these infections. It is therefore desirable to identify effective small compounds which specifically inhibit signal transcription and cell proliferation by modulating receptor and non-receptor tyrosine activity and serine / threonine kinases to regulate and modulate the abnormal or inappropriate cell proliferation, differentiation, or metabolism. In particular, the identification of methods and compounds that specifically inhibit the function of a tyrosine kinase which is essential for angiogenic processes or the formation of vascular hyperpermeability leading to edema, ascites, effusions, exudates, and macromolecular extravasation and deposition of matrix as well as associated disorders that could be beneficial. In view of the importance of PTKs for the control, regulation, and modulation of cell proliferation and diseases and disorders associated with abnormal cell proliferation, many attempts have been made to identify inhibitors of receptor and non-receptor tyrosine kinase using a variety of methods, including the use of mutant ligands (U.S. Patent No. 4,966,849), soluble receptors and antibodies (International Patent Publication No. WO94 / 10202; Kendall &Thomas, 1994, Proc. Nati. Acad. Sci 90: 10705-09; Kim et al., 1993, Nature 362: 841-844), RNA ligands (Jellinek, et al., Biochemistry 33: 1045056; Takano, et al., 1993, Mol. Bio. Cell 4: 358A Kinsella, et al., 1992, Exp. Cell Res. 199: 56-62; Wright, et al., 1992.1. Cellular Phys. 152: 448-57) and tyrosine kinase inhibitors (International Patent Publications Nos. WO 94/03427, WO 92/21660, WO 91/15495, WO 94/14808, US Patent No. 5,330, 992, Mariani, et al., 1994 , Froc. Am. Assoc. Cancer Res. 35: 2268). More recently, attempts have been made to identify small molecules which act on tyrosine kinase inhibitors. Bis-, monocyclic, bicyclic or heterocyclic aryl compounds have been generally described (International Patent Publication No. WO 92/20642) and vinylene-azaindole derivatives (International Patent Publication No. WO 94/14808) as tyrosine inhibitors. kinase Styryl compounds have been described (U.S. Patent No. 5,217,999), styryl-substituted pyridyl compounds (U.S. Patent No. 5,302,606), certain quinazoline derivatives (EP Application No. 0566266 A1, Expert Opin. Ther. Pat. 1998), 8 (4): 475-478), selenoindols and selenides (International Patent Publication No. WO 94/03427), tricyclic polyhydroxy compounds (International Patent Publication No. WO 92/21660) and benzylphosphonic acid compounds ( International Patent Publication No. WO 91/15495), compounds for use as tyrosine kinase inhibitors for use in the treatment of cancer. The anillinocinolines compounds (PCT WO 97/34876) and the quinazoline derivative compounds (International Patent Publication No. WO 97/22596; International Patent Publication No.

W097 / 42187) have been described as inhibitors of angiogenesis and vascular permeability. The bis (indolylmaleimide) compounds have been described as particular inhibitors of the PKC serine / threonine kinase isoforms whose function for signal transduction is associated with altered vascular permeability in VEGF-related diseases (International Patent Publications Nos. WO 97/40830 and WO 97/40831). IGF-1 R plays important roles in cell division, development, and metabolism, and in its state of activity, it plays a role in the oncogenesis and suppression of apoptosis. It is known that IGF-1 R is expressed in numerous cancer cell lines (over-expression of IGF-1 R is associated with acromegaly and prostate cancer). In contrast, it has been shown that sub-regulation of IGF-1 R expression results in the inhibition of tumorigenesis and in increased apoptosis of tumor cells. International Patent Publications Nos. WO 03/018021 and WO 03/018022 disclose pyrimidines for the treatment of disorders related to IGF-1 R, International Patent Publications Nos. WO 02/102804 and WO 02/102805 describe cyclolignans and cyclollgnans. as IGF-1 R inhibitors, International Patent Publication No. WO 02/092599 discloses pyrrolopyrimidines for the treatment of a disease which responds to an inhibition of the IGF-1 R tyrosine kinase, International Patent Publication No. WO 01/72751 describes pyrrolopyrimidines as tyrosine kinase inhibitors. International Patent Publication No. WO 00/71129 describes pyrrolotriazine kinase inhibitors. International Patent Publication No. WO 97/28161 discloses pyrrolo [2,3-d] pyrimidines and their use as tyrosine kinase inhibitors. Parrizas, et al. describe tyrphostins with IGF-1 R inhibitory activity in vitro and in vivo (Endocrinology, 138: 1427-1433 (1997)), and International Patent Publication No. WO00 / 35455 discloses heteroaryl aryl ureas as inhibitors of IGF-1R. International Patent Publication No. WO 03/048133 describes pyrimidine derivatives as modulators of IGF-1 R. International Patent Publication No. WO 03/024967 describes chemical compounds with inhibitory effects towards protein kinases. International Patent Publication No. WO 03/068265 describes methods and compositions for the treatment of hyperproliferative conditions. International Patent Publication No. WO 00/17203 discloses pyrrolopyrimidines as protein kinase inhibitors. Japanese Patent Publication No. JP07 / 133280 describes a cephem compound, its production and antimicrobial composition. A. Albert et al., Journal of the Chemical Society, 11: 1540-1547 (1970) describe studies of pteridine and unsubstituted pteridines at position 4, a synthesis from pyrazines via 3,4-dihydropteridines. A. Albert et al., Chem. Biol. Pteridines Proc. Int. Symp .. 4th, 4: 1-5 (1969) describes a synthesis of pteridines (not substituted at position 4) from pyrazines, via 3-4-dihydropteridines.

BRIEF DESCRIPTION OF THE INVENTION The present invention relates to compounds of formula or to a pharmaceutically acceptable salt thereof. The compounds of formula I inhibit the enzyme IGF-1 R and are useful for the treatment and / or prevention of various diseases and conditions that respond to treatment by inhibition of IGF-1R. The compounds of this invention are useful as serine inhibitors. / threonine and tyrosine kinases. In particular, the compounds of this invention are useful as inhibitors of tyrosine kinases that are important in hyperproliferative diseases, especially cancer.

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a compound of formula I: or to a pharmaceutically acceptable salt thereof, wherein: Q1 is aryl1, heteroaryl1, cycloalkyl, heterocyclyl, cycloalkenyl, or heterocycloalkenyl, any of which is optionally substituted by one to five independent G1 substituents; R1 is alkyl, cycloalkyl, bicycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, heterocyclyl, or heterobicycloalkyl, any of which is optionally substituted by one or more independent G1 substituents; G1 and G41 are each independently halo, oxo, -CF3, -OCF3, -OR2, -NR2R3 (R3a) j ?, -C (0) R2, -C02R2, -CONR2R3, -N02, -CN, -SÍO ^ R2, -S02NR2R3, NR2 (C = 0) R3, NR2 (C = 0) 0R3, NR2 (C = 0) NR2R3, NR2S (0) j-, R3, - (C = S) OR2, - (C = 0) SR2, -NR2 (C = NR3) NR2aR3a, NR2 (C = NR3) OR2a, -NR2 (C = NR3) SR3a, -0 (C = 0) OR2, -0 (C = 0) NR2R3, -0 (C = 0) SR2, -S (C = 0) OR2, -S (C = 0) NR2R3, C0-? Oalkyl, C2.10 alkenyl, C2.10 alkynyl, C6alkyl alkoxy of C? -10, C2? alkyloxy of C2. C 1, C 2. 0 alkyloxy, C 1-10 alkyloxy, C 1-10 alkylthio or C.sub.1-10 alkylthio, C.sub.2 -C.ox.alkenyl C.sub.2.sub.0, C.sub.2-10 alkynyl C.sub.2 -C.sub.alkynyl, cycloalkyl. of C3.8, C3_8 cycloalkenyl, C3.8 cycloalkyl of C? .10 cycloalkenyl of C3. d-cycloalkyl, cycloalkyl of C3.8alkenyl of C2-? 0, cycloalkenyl of C3. C2_? 0alkenyl, cycloalkyl of C3.8alkynyl of C2-? 0, cycloalkenyl of C3-8alkynyl of C2-10, heterocyclyl-C0-? alkyl, heterocyclyl-alkenyl of C2.10, or heterocyclyl-alkynyl of C2-? 0, any of which is optionally substituted with one or more independent substituents halo, oxo, -CF3, -OCF3, -OR222, -NR222R333 (R333a) jia, -C (0) R222, -C02R222, -CONR222R333 , -NO2, -CN, -S (0) jiaR222, -S02NR222R333, NR222 (C = 0) R333, NR222 (C = 0) OR333, NR222 (C = 0) NR222R333, NR222S (0) j1aR333, - (C = S) OR222, - (C = 0) SR222, -NR222 (C = NR333) NR222aR333a, -NR222 (C = NR333) OR222a, -NR222 (C = NR333) SR333a, -0 (C = 0) OR222, -0 (C = 0) NR222R333, -0 (C = 0) SR222, -S (C = 0) OR222, or -S (C = 0) ) NR222R333; or - (X1) n- (Y1) m-R4; or aryl-C0-alkyl or, arylalkenyl of C2. 10, or C2- [alpha] arylalkyl, or any of which is optionally substituted with one or more halo, -CF3, -OCF3, -OR222, -NR222R333 (R333a) j2a, -C (0) R222, -C02R222, independent substituents. , -CONR222R333, -NO2, -CN, -S (0) j2aR222, -S02NR222R333, NR222 (C = 0) R333, NR222 (C = 0) OR333, NR222 (C = 0) NR222R333, NR222S (0) j2aR333, - (C = S) OR222, - (C = 0) SR222, -NR222 (C = NR333) NR222aR333a, -NR222 (C = NR333) OR222a, -NR222 (C = NR333) SR333a, -0 (C = 0) OR222, -0 (C = 0) NR222R333, -0 (C = 0) SR222, -S (C = 0) OR222, or -S (C = 0) ) NR222R333; or hetarylalkyl of C0-? or, hetarylalkenyl of C2.10, or hetarylalkynyl of C2-? 0, any of which is optionally substituted with one or more independent substituents halo, -CF3, -OCF3, -OR222, -NR222R333 (R333a ) j3a, -C (0) R222, -C02R222, -CONR222R333, -N02, -CN, -S (0) j3aR222, -S02NR222R333, NR222 (C = 0) R333, NR222 (C = 0) OR333, NR222 (C = 0) NR222R333, NR222S (0) j3aR333, - (C = S) OR222, - (C = 0) SR222, -NR222 (C = NR333) NR222R333a, -NR222 (C = NR333) OR222a, -NR222 (C = NR333) SR333a, -0 (C = 0) OR222, -0 (C = 0) NR222R333, -0 (C = 0) SR222, -S (C = 0) OR222, or -S (C = 0) ) NR222R333; G11 is halo, oxo, -CF3, -OCF3, -OR21, -NR21R31 (R3a1) j4, -C (0) R21, -C02R21, -CONR21R31, -N02, -CN, -S (0) j4R21, -S02NR21R31 , NR21 (C = 0) R31, NR21 (C = 0) OR31, NR21 (C = 0) NR21R31, NR21S (0) j4R31, - (C = S) OR21, - (C = 0) SR21, -NR21 ( C = NR31) NR2a1R3a1, -NR21 (C = NR31) OR2a1, NR21 (C = NR3) SR3a, -0 (C = 0) OR21, -0 (C = O) NR21R31, -0 (C = 0) SR21, -S (C = 0) OR21, -S (C = 0) NR21R31, -P (0) 0R210R31, C0-10 alkyl, C2-10 alkenyl, C2_10 alkynyl, C? _? 0 alkyloxy C1 -10, C 2-10 alkoxy C 2-10 alkoxy, C 2 -C 0 alkyloxykyloxy, C 1-10 alkylthioalkyl CMC, C 2-10 C 2 -C 10 alkylthio, C 2 - C 0 - alkynyl C 2 - alkynyl 10, C3.8 cycloalkyl, C3-8 cycloalkenyl, C3.8 cycloalkylC1-10 alkyl, C3.8 cycloalkenyl C? .10 alkyl, C3-8 cycloalkyl C2-10 alkene, C3-8 alkenyl cycloalkenyl C2-10 cycloalkyl, C3.8alkynyl cycloalkenyl C2-10alkynyl cycloalkenyl C2-10alkynyl, heterocyclylCal-10alkyl, heterocyclyl-C2_alkenyl, or heterocyclic-alkyne C2.o0, any of which is optionally substituted with one or more independent substituents halo, oxo, -CF3, -OCF3, -OR2221, -NR2221R3331 (R333a1) j4a, -C (0) R2221, -C02R2221, -CONR2221R3331, -N02, -CN, -S (0) j4aR2221, -S02NR2221R3331, NR2221 (C = 0) R3331, NR2221 (C = 0) OR3331, NR2221 (C = 0) NR2221R3331, NR2221S (0) j4aR3331, - (C = S) OR2221, - (C = 0) SR2221, -NR2221 (C = NR3331) NR222a1R333a1, NR2221 (C = NR3331) OR222a1, -NR2221 (C = NR3331) SR333a1, -0 (C = 0) OR2221, -0 (C = 0) NR2221R3331, -0 (C = 0) SR2221, -S (C = 0) OR2221, -P (0) OR222 OR3331, or -S (C = 0) NR2221R3331; or aryl-C0-βalkyl, or C2.10 aryl-alkenyl, or C2.10 aryl-alkynyl, any of which is optionally substituted with one or more halo, -CF3, -OCF3, -OR2221, independent substituents. , -NR2221R3331 (R333a1) j5a, -C (0) R2221, -C02R2221, -CONR2221R3331, -N02, -CN, -S (0) j5aR2221, -S02NR2221R3331, NR2221 (C = 0) R3331, NR2221 (C = 0 ) OR3331, NR2221 (C = 0) NR222 R3331, NR2221S (0) j5aR3331, - (C = S) OR2221, - (C = 0) SR2221, -NR2221 (C = NR3331) NR222a1R333a1, -NR2221 (C = NR3331) OR222a1, NR2221 (C = NR3331) SR333a1, -0 (C = 0) OR2221, -0 (C = 0) NR2221R3331, O (C = 0) SR2221, -S (C = 0) OR2221, -P (0) OR2221OR3331, or -S (C = 0) NR2221R3331; or hetaryl-C0-? alkyl, or C2.o0 hetaryl-alkenyl, or C2-? 0 hetaryl-alkynyl, any of which is optionally substituted with one or more halo, -CF3, -OCF3, independent substituents, -OR2221, N R2221 R3331 (R333a.)] 6aj ^ (QJR 21, -C02R2221, -CONR2221R3331, -N02, -CN, -S (0) j6aR2221, -S02NR2221R3331, NR2221 (C = 0) R3331, NR2221 (C = 0) OR3331, NR2221 (C = 0) NR2221R3331, NR2221S (0) j6aR3331, - (C = S) OR2221, - (C = 0) SR2221, -NR2 21 (C = NR3331) NR222a1R333a1, -NR2221 (C = NR3331) OR222a1 , NR2221 (C = NR3331) SR333a1, -0 (C = 0) OR2221, -0 (C = 0) NR2221R3331, 0 (C = 0) SR2221, -S (C = 0) OR2221, -P (0) OR222 OR3331, or -S (C = 0) NR2221R3331; or G11 is taken together with the carbon to which it is attached to form a double bond which is substituted with R5 and G111; r- > 2 o2a D3 I? , I? , I? , R222a1, R3331, and R333a1 are each independently equal to the C0-? Alkyl, C2-? 0 alkenyl, C2-? Alkynyl, C? .10 alkyloxy C1-10alkyl, C? C2_6alkenyl, C2_alkyl 0alkynyl, C2_0alkyl, C1-10alkylthioalkyl, C10-10alkyl, C1_6alkyl, C1_10alkyl, C1_6alkynyl, C2-? O, C3.8 cycloalkyl, C3.8 cycloalkenyl, C3.8 cycloalkyl C1-10 alkyl, C3.8 cycloalkenyl C1-10 alkyl, C3-8 cycloalkyl cycloalkenyl, cycloalkenyl cycloalkenyl, C3.8 C2_6alkenyl, C3.8alkyl cycloalkyl of C2.o.o, C3.8alkynyl cycloalkenyl of C2.10, heterocyclylC0-? Alkyl, C2.10 heterocyclyl-alkenyl, or heterocyclyl- C2. 0 alkynyl, any of which is optionally substituted by one or more substituents G111; or aryl-Co-10 alkyl, C2_? 0 aryl-alkenyl, or C2.10 aryl-alkynyl, hetaryl-C0-? alkyl or > hetaryl-alkenyl of C2_? 0, or hetaryl-alkynyl of C2-10, any of which is optionally substituted by one or more substituents G111; or in the case of -NR2R3 (R3a) J1 or -NR222R333 (R333a) jia or - N R222R333 (R333a) j2a Q _NR2221 R3331 (R333a1) j3a Q _NR2221 R3331 (R333a1) j4a Q.

N R2221 R3331 (R333a1) j5a Q _NR2221 R3331 (R333a1) j6aj R2 and R3 Q R222 and R333 Q R2221 and R333 taken together with the nitrogen atom to which they are attached form a saturated ring, unsaturated ring, saturated heterocyclic ring, or unsaturated heterocyclic ring, of 3-10 members wherein said ring is optionally substituted by one or more substituents G111; X1 and Y1 are each independently -O-, -NR7-, -S (0) j7-, -CR5R6-, -N (C (0) OR7) -, -N (C (0) R7) -, - N (S02R7) -, -CH20-, -CH2S-, -CH2N (R7) -, -CH (NR7) -, -CH2N (C (0) R7) -, -CH2N (C (0) OR7) -, -CH2N (S02R7) -, -CH (NHR7) -, -CH (NHC (0) R7) -, -CH (NHS02R7) -, -CH (NHC (0) OR7) -, -CH (OC (0) R7) -, -CH (OC (0) NHR7) -, -CH = CH-, -C = C-, -C (= NOR7) -, -C (O) -, -CH (OR7) -, - C (0) N (R7) -, -N (R7) C (0) -, -N (R7) S (0) -, -N (R7) S (0) 2- -OC (0) N ( R7) -, -N (R7) C (0) N (R7) -, -NR7C (0) 0-, -S (0) N (R7) -, -S (0) 2N (R7) -, - N (C (0) R7) S (0) -, - N (C (0) R7) S (0) 2-, -N (R7) S (0) N (R7) -, -N (R7) S (0) 2N (R7) -, -C (0) N (R7) C (0) -, -S (0) N (R7) C (0) -, -S (0) 2N (R7) C (0) -, -OS (0) N (R7) -, -OS (0) 2N (R7) -, -N (R7) S (0) 0-, -N (R7) S (0) 20- , -N (R7) S (0) C (0) -, -N (R7) S (0) 2C (0) -, -SON (C (0) R7) -, -S02N (C (0) R7 ) -, -N (R7) SON (R7) -, -N (R7) S02N (R7) -, -C (O) 0-, -N (R7) P (OR8) 0-, -N (R7) P (OR8) -, -N (R7) P (0) (OR8) 0-, -N (R7) P (0) (OR8) -, -N (C (0) R7) P (OR8) 0- , -N (C (0) R7) P (OR8) -, -N (C (0) R7) P (0) (OR8) 0-, N (C (0) R7) P (OR8) -, - CH (R7) S (0) -, -CH (R7) S (0) 2-, -CH (R7) N (C (0) OR7) -, -CH (R7) N (C (0) R7) -, -CH (R7) N (S02R7) '-, -CH (R7) 0-, -CH ( R7) S-, -CH (R7) N (R7) -, -CH (R7) N (C (0) R7) -, -CH (R7) N (C (0) OR7) -, CH (R7) N (S02R7) -, CH (R7) C (= NOR7) -, -CH (R7) C (0) -, -CH (R7) CH (OR7) -, -CH (R7) C (0) N ( R7) -, -CH (R7) N (R7) C (0) -, -CH (R7) N (R7) S (0) -, -CH (R7) N (R7) S (0) 2-, CH (R7) OC (0) N (R7) -, -CH (R7) N (R7) C (0) N (R7) -, -CH (R7) NR7C (0) 0-, -CH (R7) S (0) N (R7) -, -CH (R7) S (0) 2N (R7) -, -CH (R7) N (C (0) R7) S (0) -, CH (R7) N ( C (0) R7) S (0) -, -CH (R7) N (R7) S (0) N (R7) -, -CH (R7) N (R7) S (0) 2N (R7) -, -CH (R7) C (0) N (R7) C (0) -, -CH (R7) S (0) N (R7) C (0) -, -CH (R7) S (0) 2N (R7) ) C (0) -, -CH (R7) OS (0) N (R7) -, -CH (R7) OS (0) 2N (R7) -, -CH (R7) N (R7) S (0) 0-, CH (R7) N (R7) S (0) 20-, -CH (R7) N (R7) S (0) C (0) -, -CH (R7) N (R7) S (0) 2C (0) -, -CH (R7) SON (C (0) R7) -, -CH (R7) S02N (C (0) R7) -, -CH (R7) N (R7) SON (R7) - , -CH (R7) N (R7) S02N (R7) -, -CH (R7) C (0) 0-, -CH (R7) N (R7) P (OR8) 0-, CH (R7) N ( R7) P (OR8) -, -CH (R7) N (R7) P (0) (OR8) 0-, -CH (R7) N (R7) P (0) (OR8) -, -CH (R7) N (C (0) R7) P (OR8) 0-, -CH (R7) N (C (0) R7) P (OR8) -, CH (R7) N (C (0) R7) P (0) (OR8) 0-, or -CH (R7) N (C (0) R7) P (OR8) -; or X1 and Y1 are each independently represented by one of the following structural formulas: R10, taken together with the phosphine or phosphonamide, is a 5-, 6-, or 7-membered aryl, heteroaryl or heterocyclyl ring system; R5, R6, and G111 are each independently an alkyl of Co-?, C2_? alkenyl, C2-? alkynyl, CMC_alkyl, CMC_alkoxy, C2_? Ci_ioalkenyl_alkoxy, or C? -? 0alkynyl C2_alkyl. 0, alkylthio of C |. CMC alkyl, C.sub.2 -C.sub.10 alkyloxy C.sub.2.sub.0 alkyl, C.sub.2 -C.sub.alkynyl C.sub.2-10 alkylthio, C.sub.3.8 cycloalkyl, C.sub.3-8 cycloalkenyl, C.sub.3.8 cycloalkyl C.sub.mole, cycloalkenyl C3.8alkyl CO, C3.8alkyl cycloalkyl C2_6alkyl, cycloalkenyl C3-8alkenyl C2.10, cycloalkyl C3.8alkynyl C2-10, cycloalkenyl C3-8alkynyl C-2-10, heterocyclyl-C0-? alkyl, C2-? 0 heterocyclyl-alkenyl, or C2-0 heterocyclyl-alkynyl, any of which is optionally substituted with one or more halo-independent substituents, -CF3, -OCF3, -OR77 , -NR77R87, -C (0) R77, -C02R77, -CONR77R87, -N02, -CN, -S (0) j5aR77, -S02NR77R87, NR77 (C = 0) R87, NR77 (C = 0) OR87, NR77 (C = 0) NR78R87, NR77S (0) j5aR87, - (C = S) OR77, - (C = 0) SR77, -NR77 (C = NR87) NR78R88, -NR77 (C = NR87) 0R78, -NR77 ( C = NR87) SR78, -O (C = 0) 0R77, -0 (C = 0) NR77R87, -0 (C = 0) SR77, -S (C = 0) OR77, P (0) OR77OR87, or - S (C = 0) NR77R87 substituents; or C 0-10 arylalkyl, C 2. 0 arylalkenyl, or C 2. 0 arylalkynyl, any of which is optionally substituted with one or more halo substituents, -CF 3, -OCF 3, -OR77, -NR77R87, - C (0) R77, -C02R77, -CONR77R87, -N02, -CN, -S (0) j5aR77, -S02NR77R87, NR77 (C = 0) R87, NR77 (C = 0) OR87, NR77 (C = 0) NR78R87, NR77S (0) j5aR87, - (C = S) Or77, - (C = 0) SR77, -NR77 (C = NR87) NR78R88, -NR77 (C = NR87) OR78, -NR77 (C = NR87) SR78 , -0 (C = 0) OR77, -0 (C = 0) NR77R87, -0 (C = 0) SR77, -S (C = 0) OR77, -P (0) OR77OR87, or -S (C = 0) NR77R87; or hetarylalkyl of C0-? or, hetarylalkenyl of C2.o0, or hetarylalkynyl of C2.o0, any of which is optionally substituted with one or more independent substituents halo, -CF3, -OCF3, -OR77, -NR77R87, -C (0) R77, -C02R77, -CONR77R87, -N02, -CN, -S (0) j5aR77, -S02NR77R87, NR77 (C = 0) R87, NR77 (C = 0) OR87, NR77 (C = 0) ) NR78R87, NR77S (0) j5aR87, - (C = S) Or77, - (C = 0) SR77, -NR77 (C = NR87) NR78R88, -NR77 (C = NR87) OR78, -NR77 (C = NR87) SR78, -0 (C = 0) OR77, -0 (C = 0) NR77R87, -0 (C = 0) SR77, -S (C = 0) OR77, P (0) OR77OR87, or -S (C = 0) NR77R87; or R5 with R6 taken together with the respective carbon atom to which they are attached form a saturated or unsaturated ring of 3-10 members, wherein said ring is optionally substituted with R69; or R5 with R6 taken together with the respective carbon atom to which they are attached form a saturated or unsaturated 3-10 membered heterocyclic ring, wherein said ring is optionally substituted with R69; R7 and R8 are each independently H, acyl, alkyl, alkenyl, aryl, heteroaryl, heterocyclyl or cycloalkyl, any of which is optionally substituted by one or more substituents G111; R 4 is H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, cycloalkenyl, or heterocycloalkenyl, any of which is optionally substituted by one or more G41 substituents; R69 is halo, -OR78, -SH, -NR78R88, -C02R78, -CONR78R88, -N02, -CN, -S (0) j8R78, -S02NR78R88, C0-? Alkyl, C2.10 alkenyl, alkynyl, C2-? O, C? -? 0alkyl alkoxy of CMO, C? -? 0alkenyl alkoxy of C2_? 0, C? -10alkynyl alkoxy of C2.o0, alkylthio of C? _? 0alkyl of CMO, alkylthio C |? _ 0alquenilo of C2_ or alquilthlo of C1-10alquinilo of C2- 0, C3-8 cycloalkyl, C3-8 cycloalkenyl, cycloalkyl C3-8alquilo of C 0, cycloalkenyl of C3_ 8alquilo??? of CM0, C3-8alkenyl cycloalkyl of C2-? or > cycloalkenyl C2- C3- 8alquenilo of? 0, cicloalqullo of C3-8alquiniIo of C2-? or cycloalkenyl C3- 8alquinilo of C2.?0, heterocyclyl-alkyl C0? or heterocyclyl-alkenyl C2-? 0 , or C2-10 heterocyclyl-alkynyl, any of which is optionally substituted with one or more substituents independently halo, cyano, nitro, -OR778, -S02NR778R888, or -NR778R888; or aryl-C0-? alkyl, or C2-? aryl, or C2_? 0 aryl-alkynyl, any of which is optionally substituted with one or more halo, cyano, nitro, -OR778, independent substituents, CMC alkyl, C2.10 alkenyl, C2.10 alkynyl, C? 10 haloalkyl, C2-? haloalkenyl, C2-? 0 haloalkynyl, -COOH, C? alkoxycarbonyl. 4, -CONR778R888, -S02NR778R888, or -NR778R888; or hetaryl-C0-? alkyl, or C2-10 -heteroyl-alkenyl, or C2-? hetaryl-alkynyl, any of which is optionally substituted with one or more halo, cyano, nitro, -OR778, independent substituents, CM0 alkyl, alkenyl C2-? or alkynyl C2-? 0, haloalkyl CMO, haloalkenyl C2-? 0, haloalkynyl of C2_? or, -COOH, alkoxycarbonyl C? _4, -CONR778R888, -S02NR778R888, or - NR 5778 RD888; or monoamino (C 1-6 alkyl) C 6 alkyl, diamino (C 1-6 alkyl) C 6 alkyl, monoamino (aryl) C 6 alkyl, diamino (aryl) C alkyl; _6, or -N (C6_6 alkyl) -C1-6alkylaryl-, any of which is optionally substituted with one or more independent substituents halo, cyano, nitro, -OR778, CMO alkyl, C2 alkenyl -? 0, 0 C2_ alkynyl, haloalkyl CMO, C2.?0 haloalkenyl, haloalkynyl of C2- 0, -COOH, CM alkoxycarbonyl, -CONR778R888, -S02NR778R888, or -NR778R888?; or in the case of -NR78R88, R78 and R88 taken together with the nitrogen atom to which they are attached form a saturated ring of 3-10 members, unsaturated ring, saturated heterocyclic ring, or unsaturated heterocyclic ring, wherein said ring is optionally substituted with one or more halo, cyano, hydroxy, nitro, CMO alkoxy, unsubstituted substituents, -S02NR778R888, or -NR778R888; R77, R78, R87, R88, R778 and R888 are each independently C0-? 0 alkyl, C2-? 0 alkenyl, C2-? 0 alkynyl, C? -10 alkyloxy C1-10alkyl, alkoxy C C-α 0-alkenyl of C 2 - 0 0, C ?.10alkynyl alkoxy of C2.o0, Cilt _ ?alkyl alkylthio of CMO. C.sub.2 -C.sub.10 alkenyl of C.sub.2.o.sub.0, C.sub.2 -C.sub.alkynyl of C.sub.2-.sup.-o or C.sup.t. C3-8 cycloalkyl, C3-8 cycloalkenyl, C3.8alkyl cycloalkyl, C3-8 cycloalkenyl CMC alkyl, C3 cycloalkyl. 8 C2-10 alkenyl, C3.8alkyl cycloalkenyl of C2-? 0) C3 cycloalkyl. C2_6alkynyl, C3.8alkynyl cycloalkenyl of C2-? 0, heterocyclyl-C0-? Alkyl, C2-10 heterocyclyl-alkenyl, C2-? 0 heterocyclyl-alkynyl, C1-10-alkylcarbonyl, alkenylcarbonyl of C2.o0, C2_? 0 alkynylcarbonyl, CMO alkoxycarbonyl, C? -? 0alkyl alkoxycarbonyl, C? -6 monoalkylaminocarbonyl, C? .6 dialkylaminocarbonyl, mono (aryl) aminocarbonyl, di (aryl) aminocarbonyl, or C? _ ?alkyl (aryl) aminocarbonyl, any of which is optionally substituted with one or more halo, cyano, hydroxy, nitro, alkoxy, unsubstituted substituents of CO, -S02N (C0- alkyl) (alkyl) of C0-4), or -N (C0-4 alkyl) (C0-4 alkyl); or aryl-C0-10 alkyl. C2-? 0 aryl-alkenyl, or C2_aryl-alkynyl, any of which is optionally substituted with one or more halo, cyano, nitro, -0 (C0-4 alkyl), CMC alkyl, independent substituents, alkenyl of C2_? 0, alkynyl of C2_? 0, haloalkyl of CO, haloalkenyl of C-2-10, haloalkynyl of C2_? 0, -COOH, alkoxycarbonyl of C1-4, -CON (alkyl of C0-4) (alkyl) of C0-10), -S02N (C0.4 alkyl) (C0-4 alkyl), or -N (C0- alkyl) (C0- alkyl); or hetaryl-C0-? alkyl, or C2-?, or C2-?, or hetaryl-alkenyl, any of which is optionally substituted with one or more independent halo, cyano, nitro, -0 substituents (alkyl of Co-4), alkyl of CM0, alkenyl of C2-? 0, alkynyl of C2-10, haloalkyl of CO, haloalkenyl of C2-10, haloalkynyl of C2-10, -COOH, alkoxycarbonyl of C? -4 , -CON (Co-4 alkyl) (C0.4 alkyl), -S02N (C0- alkyl) (C0- alkyl), or -N (C0- alkyl) (C0-4 alkyl) ); or mono (C? -6) aminoalkyl of C? 6, diamino (O. 6 alkyl) aminoalkyl of C? _6, mono (aryl) aminoalkyl of C? -6, di (aryl) aminoalkyl Of C? -6, or -N (C? -6 alkyl) -alkylaryl of C? -6-, any of which is optionally substituted with one or more independent substituents halo, cyano, nitro, -0 ( C0-4 alkyl), CMO alkyl, C2-? o alkenyl, C2-? al alkynyl, CMO haloalkyl, C2.o0 haloalkenyl, C2.o0 haloalkynyl, -COOH, C-alkoxycarbonyl? _4, -CON (C0-4 alkyl) (C0-4 alkyl), -S02N (C0- alkyl) (C0-4 alkyl), or -N (C0- alky1) (C0-4 alkenyl) ); and n, m, j1, j1a, j2a, j3a, j4, j4a, j5a, j6a, j7, and j8 are each independently the same as 0, 1, or 2. In one aspect of the present invention, a compound is represented by Formula I, or a pharmaceutically acceptable salt thereof, wherein R 1 is cycloalkyl, aryl, heteroaryl, aralkyl, or heterocyclyl, any of which is optionally substituted by one or more G 11 substituents and the other variables are described as mentioned above for formula I. In a second aspect of the present invention, a compound is represented by formula I, or by a pharmaceutically acceptable salt thereof, wherein R1 is cycloalkyl, optionally substituted by one or more G11 substituents and the others variables are described as mentioned above for formula I. In one embodiment of this second aspect, a compound is represented by the formula, or by a pharmaceutically acceptable salt thereof, wherein R 1 is cycloalkyl or, optionally substituted by one or more substituents G11; Q1 is aryl1 or heteroaryl, any of which is substituted by one to five independent substituents G1; G1 is halo, -OR2, -NR2R3, -C (0) R2, -C02R2, -CONR2R3, -S02NR2R3, NR2 (C = 0) R3, NR2 (C = 0) OR3, NR2 (C = 0) NR2R3, NR2S (0) jiR3, -0 (C = 0) OR2, -0 (C = 0) NR2R3, C0.10 alkyl, C2-? 0 alkenyl, Ci alkoxy. CMC alkyl, C.sub.50 alkylthio of CMO, C3.8 cycloalkyl, C3.8 cycloalkenyl, or heterocyclylC0-? Alkyl, or C2-? Heterocyclyl-alkenyl, or any of the which is optionally substituted with one or more independent substituents oxo, -CF3, -OCF3, -OR222, -NR222R333, -C (O) R222, -C02R222, -CONR222R333, -S02NR222R333, NR222 (C = 0) R333, NR222 ( C = 0) OR333, NR222 (C = 0) NR222R333, NR222S (0) j1aR333, -NR222 (C = NR333) NR222aR333a, or -0 (C = 0) NR222R333; or - (X1) n- (Y1) m-R4; or aryl-C0-αalkyl or, optionally substituted with one or more halo, -CF3, -OCF3, -OR222, -NR222R333, -C (0) R222, -C02R222, -CONR222R333, -S02NR222R333, NR222 ( C = 0) R333, NR222 (C = 0) OR333, NR222 (C = 0) NR222R333, NR222S (0) j2aR333, -NR222 (C = NR333) NR222aR333a, or -0 (C = 0) NR222R333; or hetaryl-C0-αalkyl or, optionally substituted with one or more halo, -CF3, -OCF3, -OR222, -NR222R333, -C (0) R222, -C02R222, -C0NR222R333, - S02NR222R333, NR222 ( C = 0) R333, NR222 (C = 0) OR333, NR222 (C = 0) NR222R333, NR222S (0) j3aR333, -NR222 (C = NR333) NR222aR333a, or -0 (C = 0) NR222R333; and the other variables are described as mentioned above for formula I. In another embodiment of this second aspect, a compound is represented by formula I, or by a pharmaceutically acceptable salt thereof, wherein R 1 is cycloalkyl, optionally substituted by one or more G11 substituents; Q1 is aryl1 or heteroaryl, any of which is substituted by one to five independent substituents G1; G1 is halo, -OR2, -NR2R3, -C (0) R2, -C02R2, -CONR2R3, -S02NR2R3, NR2 (C = 0) R3, NR2 (C = 0) OR3, NR2 (C = 0) NR2R3, NR2S (0) jiR3, -0 (C = 0) OR2, -0 (C = 0) NR2R3, C0-βalkyl, C2-? 0 alkenyl, Ci.ioalkyl 0alkyloxy, C.sub.0 -C.sub.alkyl of CMO, C3-8 cycloalkyl, C3-8 cycloalkenyl, or C0-? heterocyclyl-alkyl, or C2-? heterocyclyl-alkenyl, or any of which is optionally substituted with one or more independent oxo substituents, -CF3, -OCF3, -OR222, -NR222R333, -C (0) R222, -C02R222, -CONR222R333, -S02NR222R333, NR222 (C = 0) R333, NR222 (C = 0) OR333 , NR222 (C = 0) NR222R333, NR222S (0) jiaR333, -NR 22 (C = NR333) NR222aR333a, or -O (C = 0) NR222R333; or - (X1) n- (Y1) m-R4; and the other variables are described as above for formula I. In another embodiment of this second aspect, a compound is represented by formula I, or by a pharmaceutically acceptable salt thereof, wherein R 1 is cycloalkyl, optionally substituted by one or more G11 substituents; Q1 is aryl1 or heteroaryl, any of which is substituted by one to five independent substituents G1; at least one of said substituents G1 is - (X1) n- (Y1) m-R4; X1 and Y1 are each independently the same as -O-, -NR7-, -CR5-R6-, -S (0) j7-, or -C (O) -; and the other variables are described as mentioned above for formula I. In another embodiment of this second aspect, a compound is represented by formula I, or a pharmaceutically acceptable salt thereof, wherein R 1 is cycloalkyl, optionally substituted by one or more G11 substituents; wherein Q1 is aryl or heteroaryl, any of which is substituted by one to five independent substituents G1; at least one of said substituents G1 is - (X1) n- (Y1) m-R4; X1 and Y1 are each independently the same as -O- or -CR5R6-; and the other variables are described as above for formula I. In another embodiment of this second aspect, a compound is represented by formula I, or by a pharmaceutically acceptable salt thereof, wherein R 1 is cycloalkyl, optionally substituted by one or more G11 substituents; Q1 is aryl1 or heteroaryl, any of which is substituted by one to five independent substituents G1; at least one of said substituents G1 is - (X1) n- (Y1) m-R4; X1 and Y1 are each independently equal to -O- or -CH2-; and the other variables are described as above for formula I. In another embodiment of this second aspect, a compound is represented by formula I, or by a pharmaceutically acceptable salt thereof, wherein R 1 is cycloalkyl, optionally substituted by one or more G11 substituents; Q1 is aryl1 or heteroaryl, any of which is substituted by one to five independent substituents G1; at least one of said substituents G1 is - (X1) n- (Y1) m-R4; R 4 is H, alkyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, cycloalkenyl, or heterocycloalkenyl, any of which is optionally substituted by one or more G41 independent substituents; and the other variables are described as as previously mentioned for formula I. In another embodiment of this second aspect, a compound is represented by formula I, or by a pharmaceutically acceptable salt thereof, wherein R 1 is cycloalkyl, optionally substituted by one or more G11 substituents; Q is aryl1 or heteroaryl, any of which is substituted by one to five independent substituents G1; at least one of said substituents G1 is - (X1) n- (Y1) m-R4; R 4 is aryl or heteroaryl, optionally substituted by one or more G41 independent substituents; and the other variables are described as mentioned above for formula I. In another embodiment of this second aspect, a compound is represented by formula I, or by a pharmaceutically acceptable salt thereof, wherein R is cycloalkyl, optionally substituted by one or more G11 substituents; Q1 is aryl1 or heteroaryl, any of which is substituted by one to five independent substituents G1; at least one of said substituents G1 is - (X1) n- (Y1) m-R4; R 4 is aryl or heteroaryl, optionally substituted by one or more G 11 substituents; and the other variables are described as mentioned above for formula I. In another embodiment of this second aspect, a compound is represented by formula I, or by a pharmaceutically acceptable salt thereof, wherein R 1 is cycloalkyl substituted by one or more independent substituents G11; G11 is -OR21, -NR21R31 (R31a) j4, -C (0) R21-, -C02R21, -CONR21R31, NR21 (C = 0) R31, -NR21 (C = 0) OR31, NR21 (C = 0) NR21R31 , NR21S (0) j4R31, -0 (C = 0) OR21, -0 (C = 0) NR21R31, C0-? Alkyl, C3-8 cycloalkyl, C3-8 cycloalkenyl, heterocyclyl-C0- alkyl or, or C2-C6-heterocyclyl-alkenyl, or any of which is optionally substituted with one or more halo, oxo, -CF3, -OCF3, -OR2221, NR2221R3331 (R333a) j4a, -C (0), independent substituents R2221, -C02R2221, -CONR2221R3331, -N02, -CN, -S (0) j4aR2221, -S02NR2221R3331, NR2221 (C = 0) R3331, NR2221 (C = O) OR3331, NR222 (C = 0) NR222 R3331, NR222 S (0) j4aR3331, - (C = S) OR2221, - (C = 0) SR2221, -NR2221 (C = NR3331) NR222a1R333a1, -NR2221 (C = NR3331) OR222a1, NR2221 (C = NR3331) SR333a1, -0 (C = 0) OR2221, -0 (C = 0) NR2221R3331, 0 (C = 0) SR2221, -S (C = 0) OR2221, or -S (C = 0) NR2221R3331; or arylC0-? alkyl, or C2-? 0 aryl-alkenyl, or C2-? 0 aryl-alkynyl, any of which is optionally substituted with one or more halo, -CF3, -OCF3, independent substituents, -OR2221, -NR2221R333 (R333a1) j5a, -C (0) R2221, -C02R2221, -CONR2221R3331, -N02, -CN, -S (0) j5aR2221, -S02NR2221R3331, NR222 (C = 0) R3331, NR2221 (C = 0) OR3331, NR2221 (C = 0) NR2221R3331, NR2221S (0) j5aR3331, (C = S) OR2221, - (C = 0) SR2221, -NR2221 (C = NR3331) NR222a R333a1, NR2221 (C = NR3331) OR222a1, -NR2221 (C = NR3331) SR333a1, -0 (C = 0) OR2221, -0 (C = 0) NR22 1R3331, -0 (C = 0) SR2221, -S (C = 0) OR2221, or -S (C = 0) NR2221R3331; or hetaryl-C0-? alkyl, or C2-? 0 hetaryl-alkenyl, or C2-? 0 hetaryl-alkynyl, any of which is optionally substituted with one or more halo, -CF3, -OCF3, independent substituents, -OR2221, N R2221 R3331 (R333a1) .6a) _C (0) R2221. -C02R2221, -CONR2221R3331, -N02, -CN, -S (0) j6aR2221, -S02NR2221R3331, NR2221 (C = 0) R3331, NR222 (C = O) OR3331, NR2221 (C = 0) NR2221R3331, NR2221S (0) j6aR3331, - (C = 0) OR2221, - (C = 0) SR2221, -NR2221 (C = NR3331) NR222a1R333a1, -NR2221 (C = NR3331) OR222a1, NR2221 (C = NR3331) SR333a1, -0 (C = 0 ) OR2221, -O (C = 0) NR2221R3331, 0 (C = 0) SR2221, -S (C = 0) OR2221, or -S (C = 0) NR2221R3331; and the other variables are described as mentioned above for formula I. In another embodiment of this second aspect, a compound is represented by formula I, or by a pharmaceutically acceptable salt thereof, wherein R 1 3 s is cycloalkyl substituted by one or more independent substituents G11; G11 is -OR21, -NR21R31, -C02R21, -C (0) R21, -CONR21R31, NR21 (C = 0) R31, NR21 (C = 0) OR31, NR21 (C = 0) NR21R31, NR21S (0) j4R31 , -0 (C = 0) OR21, -0 (C = 0) NR21R31, -alkyl of C0-? O, cycloalkyl of C3-8, cycloalkenyl of C3.8, heterocyclyl-alkyl of C0-? O, or heterocyclyl -alkenyl of C2-? 0, any of which is optionally substituted with one or more halo, oxo, -CF3, -OCF3, -OR2221, -NR22_. R3331 (R333a1) j4a,. ^ p ^ _CQ2R2221 J _CONR2221R3331) ^ Q ^ _QH¡ _ S (0) j4aR2221, -S02NR2221R3331, NR2221 (C = 0) R3331, NR2221 (C = 0) OR3331, NR2221 (C = 0) NR2221R3331, NR2221S (0) j4aR3331, - (C = S) OR2221, - (C = 0) SR2221, -NR2221 (C = NR3331) NR222a1R333a1, -NR2221 (C = NR3331) OR222a1, NR2221 (C = NR3331) SR333a1, -0 (C = 0) OR2221, -0 (C = 0) NR2221R3331, 0 (C = 0) SR2221, -S (C = 0) OR2221, or -S (C = 0) NR2221R3331; and the other variables are described as mentioned above for formula I. In another embodiment of this second aspect, a compound is represented by formula I, or by a pharmaceutically acceptable salt thereof, wherein R1 is cis- or trans- cyclobutyl substituted in the 3-position by G11; G11 is -OH, -NH2, -N (CH3) 2, -NHAc, -NH (CO) NHCH3, -NH (CO) OCH3, -CH2OH, -CH2NH2, -CH2NHAc, C02H, CONH2, -CH2N (CH3) 2, -CH2NH (CO) NHMe, -CH2NH (CO) OCH3, C02CH3, CONHCH3, i and the other variables are described as mentioned above for formula I. In another embodiment of this second aspect, a compound is represented by formula I, or by a pharmaceutically acceptable salt thereof, wherein R1 is cis- or trans- cyclohexyl substituted at the 4 position by G11; G11 is -OH, -NH2, -N (CH3) 2, -NHAc, -NH (CO) NHCH3, -NH (CO) OCH3, -CH2OH, -CH2NH2, -CH2NHAc, C02H, CONH2, -CH2N (CH3) 2, -CH2NH (CO) NHMe, -CH2NH (CO) OCH3, C02CH3, CONHCH3, and the other variables are described as mentioned above for formula I. In another embodiment of this second aspect, a compound is represented by formula I, or by a pharmaceutically acceptable salt thereof, wherein Q1 is aryl1 substituted by a five independent substituents G1; at least one of said G1 is - (X1) n- (Y1) m-R4; n and m are both equal to 1; X1 is -O-; Y1 is -CH2-; R4 is aryl, optionally substituted by one or more G41 substituents; R1 is cis- or trans-cyclohexyl substituted at the 4 position by G11; G11 is -OH, -NH2, -N (CH3) 2, -NHAc, -NH (CO) NHCH3, -NH (CO) OCH3, -CH2OH, -CH2NH2, -CH2NHAc, C02H, CONH2, -CH2N (CH3) 2, -CH2NH (CO) NHMe, -CH2NH (CO) OCH3, C02CH3, CONHCH3, and the other variables are described as mentioned above for formula I. In yet another embodiment of this second aspect, a compound is represented by formula I, or by a pharmaceutically acceptable salt thereof, wherein Q 1 is aryl 1 substituted by one to five independent substituents G1; at least one of said G1 is - (X1) n- (Y1) m-R4; n and m are both equal to 1; X1 is -O-; Y1 is -CH2-; R .4 is aryl, optionally substituted by one or more substituents »41 R1 is cis- or trans-cyclobutyl substituted in the 3-position by G11; G11 is -OH, -NH2, -N (CH3) 2, -NHAc, -NH (CO) NHCH3, NH (CO) OCH3, -CH2OH, -CH2NH2, -CH2NHAc, C02H, CONH2, -CH2N (CH3) 2 , CH2NH (CO) NHMe, -CH2NH (CO) OCH3, C02CH3, CONHCH3, and the other variables are described as mentioned above for formula I. In a third aspect of the present invention, a compound is represented by formula I, or by a salt thereof, wherein R 1 is aryl, optionally substituted by one or more G11 substituents, and the other variables are described as mentioned above for formula I. In one embodiment of this third aspect, a compound is represented by formula I, or by a pharmaceutically acceptable salt thereof, wherein R is aryl, optionally substituted by one or more substituents G11; Q1 is aryl1 or heteroaryl, any of which is substituted by one to five independent substituents G1; G1 is halo, -OR2, -NR2R3, -C (0) R2, -C02R2, -CONR2R3, -S02NR2R3, NR2 (C = 0) R3, NR2 (C = 0) OR3, NR2 (C = 0) NR2R3, NR ^ O ^ R3, -0 (C = 0) OR2, -0 (C = 0) NR2R3, C0-? Alkyl, C2-? O alkenyl, C, alkoxy. ? 0alkyl of CM0, alkylthio of C?.? 0alkyl of CMO, cycloalkyl of C3-8, cycloalkenyl of C3-8, or heterocyclyl-alkyl of C0-? O-, or heterocyclyl-alkenyl of C2-10, any of the which is optionally substituted with one or more independent substituents oxo, -CF3, -OCF3, -OR222, -NR222R333, -C (O) R222, -C02R222, -CONR222R333, -S02NR222R333, NR222 (C = 0) R333, NR222 ( C = 0) OR333, NR222 (C = 0) NR222R333, NR222S (0) ¡? AR333, -NR222 (C = NR333) NR222aR333a, or -O (C = 0) NR222R333; or - (X1) n- (Y1) m-R4; or aryl-C0-? 0 alkyl, optionally substituted with one or more halo, -CF3, -OCF3, -OR222, -NR222R333, -C (0) R222, -C02R222, -CONR222R333, -S02NR222R333, NR222 ( C = 0) R333, NR222 (C = 0) OR333, NR222 (C = 0) NR222R333, NR222S (0) j2aR333, -NR222 (C = NR333) NR222aR333a, or -0 (C = 0) NR222R333; or hetaryl-Co-10 alkyl, optionally substituted with one or more halo, -CF3, -OCF3, -OR222, -NR222R333, -C (0) R222, -C02R222, -CONR222R333, -S02NR222R333, NR222 (C = 0) R333, NR222 (C = 0) OR333, NR222 (C = 0) NR222R333, NR222S (0) j3aR333, -NR222 (C = NR333) NR222aR333a, or -0 (C = 0) NR222R333; and the other variables are described as mentioned above for formula I. In another embodiment of this third aspect, a compound is represented by formula I, or by a pharmaceutically acceptable salt thereof, wherein R1 is aryl, optionally substituted by one or more G11 substituents; Q1 is aryl1 or heteroaryl, any of which is substituted by one to five independent substituents G1; G1 is halo, -OR2, -NR2R3, -C (0) R2, -C02R2, -CONR2R3, -S02NR2R3, NR2 (C = 0) R3, NR2 (C = 0) OR3, NR2 (C = 0) NR2R3, NR ^ O ^ R3, - O (C = 0) 0R2, -0 (C = 0) NR2R3, C0-? Oalkyl, C2-10 alkenyl, C? _? 0alkyl alkoxy of CMO, CTH alkylthio C1.10alkyl, C3-8 cycloalkyl, C3-8 cycloalkenyl, or heterocyclylC0-? alkyl, or C2-? heterocyclyl-alkenyl, or any of which is optionally substituted with one or more substituents independent oxo, CF3) -OCF3, -OR222, -NR222R333, -C (O) R222, -C02R222, -CONR222R333, -S02NR222R333, NR222 (C = 0) R333, NR222 (C = O) 0R333, NR222 (C = 0) NR222R333, NR222S (0) jiaR333, -NR222 (C = NR333) NR222aR333a, or -O (C = 0) NR222R333; or - (X1) n- (Y1) m-R4; and the other variables are described as mentioned above for formula I. In another embodiment of this third aspect, a compound is represented by formula I, or by a pharmaceutically acceptable salt thereof, wherein R1 is aryl, optionally substituted by one or more G11 substituents; Q1 is aryl1 or heteroaryl, any of which is substituted by one to five independent substituents G1; at least one of said substituents G1 is - (X1) p- (Y1) m-R4; X1 and Y1 are each independently the same as -O-, -NR7-, -CR5R6-, - (0) j7-, or -C (O) -; and the other variables are described as mentioned above for formula I. In another embodiment of this third aspect, a compound is represented by formula I, or by a pharmaceutically acceptable salt thereof, wherein R1 is aryl, optionally substituted by one or more G11 substituents; Q1 is aryl1 or heteroaryl, any of which is substituted by one to five independent substituents G1; at least one of said substituents G1 is - (X ^ n-YY ^ m- 4; X1 and Y1 are each independently the same as -O- or -CR5R6-; and the other variables are described as mentioned above for the formula I. In another embodiment of this third aspect, a compound is represented by formula I, or by a pharmaceutically acceptable salt thereof, wherein R1 is aryl, optionally substituted by one or more substituents G11; Q1 is aryl1 or heteroaryl, any of which is replaced by one to five independent substituents G1; at least one of said substituents G1 is - (X1) n- (Y1) m-R4; X1 and Y1 are each independently equal to -O- or -CH2-; and the other variables are described as mentioned above for formula I. In another embodiment of this third aspect, a compound is represented by formula I, or by a pharmaceutically acceptable salt thereof, wherein R1 is aryl, optionally substituted by one or more G11 substituents; Q1 is aryl1 or heteroaryl, any of which is substituted by one to five independent substituents G1; at least one of said substituents G1 is - (X1) n- (Y1) m-R4; R 4 is H, alkyl, aryl, heteroaryl, cycloalkyl, heteroaryl, cycloalkenyl, or heteroaryloalkenyl, any of which is optionally suspended by one or more independents G41; and variable variables are described as mentioned above for formula I. In another embodiment of this third aspect, a compound is represented by formula I, or by a pharmaceutically acceptable salt thereof, wherein R1 is aryl, optionally susíifuido por one or more G11 susíiíuyeníes; Q1 is aryl1 or heteroaryl, any of which is substituted by one to five independent substituents G1; at least one of said subscripts G1 is - (X1) n- (Y) m -R4; R 4 is aryl or heteroaryl, optionally substituted by one or more independents G41; and variable variables are described as mentioned above for formula I. In another embodiment of this aspect, a compound is represented by formula I, or by a pharmaceutically acceptable salt thereof, wherein R1 is aryl, optionally susi fi ed by one or more susíiíuyenles G11; Q1 is aryl1 or heeroaryl1, any of which is susíiuuido by one to five independents G1; at least one of said substituents G1 is - (X1) n- (Y1) m-R4; R 4 is aryl or heteroaryl, optionally susiiuid by one or more G41 susíifuyenfes; and the variables will be described as mentioned above for formula I. In another embodiment of this third aspect, a compound is represented by formula I, or by a pharmaceutically acceptable salt thereof, wherein R 1 is substituted cycloalkyl by one or more independent subscripts G11, G11 is -OR21, -NR21R31 (R31a) j4, -C (0) R21, -C02R21, -CONR21R31, NR21 (C = 0) R31, NR21 (C = 0) OR31, NR21 (C = 0) NR21R31, NR21S (0) j4R31, -O (C = 0) OR21, -0 (C = 0) NR21R31, C0-βalkyl, C3-8 cycloalkyl, C3-8 cycloalkenyl, heyerocyclic-alkyl of C0-? o, or C2-?, or helerocyclyl-alkenyl, any of which is optionally substituted with one or more independent halogen, oxo, -CF3, -OCF3, -OR2221, -N R2221R3331 (R333a) j4aj ^ ^^ 222 ^ _C02R222 -CONR222 R333 \ -N02, -CN -S (0) j4aR2221, -S02NR2221R3331, NR2221 (C = 0) R3331, NR2221 (C = 0) OR3331, NR2221 (C = 0) NR2221R3331, NR2221S ( 0) j4aR3331, - (C = S) OR2221, - (C = 0) SR2221, -NR2221 (C = NR3331) NR222a1R333a1, -NR2221 (C = NR3331) OR222a1, NR2221 (C = NR3331) SR333a1, -0 (C = 0) OR2221, -0 (C = 0) NR2221R3331, 0 (C = 0) SR2221, -S (C = 0) OR2221, OR- S (C = 0) NR2221R3331; or aryl-C0-βalkyl, or C2.oilyl aryl-alkenyl, or C2.oilyl aryl-alkynyl, any of which is optionally susiluted with one or more halo independent halogen, -CF3, -OCF3, -OR2221, -NR222 R3331 (R333a1) j5a, -C (0) R2221, -C02R2221, -CONR2221R3331, -N02, -CN, -S (0) j5aR2221, -S02NR2221R3331, NR2221 (C = 0) R, 33331 ( C = S) OR2221, - (C = 0) SR2221, -NR2221 (C = NR3331) NR222a1R333a1, NR2221 (C = NR3331) OR222a1, -NR2221 (C = NR3331) SR333a1, -0 (C = 0) OR2221, -0 (C = 0) NR222 R3331, -0 (C = 0) SR2221, -S (C = 0) OR2221, or -S (C = 0) NR2221R3331; or hearyl-C0-? -alkyl, C2-? 0 -hearyl-alkenyl, or C2-? hetaryl-alkynyl, or any of which is optionally susiiuuid with one or more haloyl independents, -CF3, -OCF3, -OR2221, N R2221 R3331 (R333a) j6a? ^^^ 222 ^. ^ p ^ _CQN R2221 R3331] ^ Q ^ _CN_ _ S (0) j6aR2221, -S02NR2221R3331, NR2221 (C = 0) R3331, NR2221 (C = 0) OR3331, NR2221 (C = 0) NR2221R3331, NR2221S (0) j6aR3331, - (C = S) OR2221, - (C = 0) SR2221, -NR2221 (C = NR3331) NR222a1R333a1, -NR2221 (C = NR3331) OR222a1, NR2221 (C = NR3331) SR333a1, -0 (C = 0) OR2221, -0 (C = 0) NR2221R3331, 0 (C = 0) SR2221, -S (C = 0) OR2221, or -S (C = 0) NR2221R3331; and variable variables are described as mentioned above for formula I. In another embodiment of this aspect, a compound is represented by formula I, or by a pharmaceutically acceptable salt thereof, wherein R 1 is cycloalkyl subsided by one or more non-dependent G11; G11 is -OR21, -NR2 R31, -C02R21, -C (0) R21, -CONR2 R31, NR21 (C = 0) R31, NR21 (C = 0) OR31, NR21 (C = 0) NR21R31, NR21S (0 ) j4R31, -0 (C = 0) OR21, -0 (C = 0) NR21R31, C0-βalkyl, C3-8 cycloalkyl, C3-8 cycloalkenyl, heterocyclylC0-? alkyl, or, C2-C6-heterocyclyl-alkenyl, or any of which is optionally substituted with one or more halo, oxo, -CF3, -OCF3, -OR2221, independent halogenyl, NR2221 R3331 (R333a1) j4aj. (^ R2221, _C02R2221 f _CONR2 21R3331, ^ Q ^ .Q ^ _ S (0) j4aR2221, -S02NR2221R3331, NR2221 (C = 0) R3331, NR2221 (C = 0) OR3331, NR2221 (C = 0) NR2221R3331, NR2221S (0) j4aR3331, - (C = S) OR2221, - (C = 0) SR2221, -NR2221 (C = NR3331) NR222a1R333a1, -NR2221 (C = NR3331) OR222a1, NR2221 (C = NR3331) SR333a1, -0 (C = 0) OR2221, -0 (C = 0) NR2221R3331, OR (C = 0) SR2221, -S (C = 0) OR2221, or -S (C = 0) NR2221R3331; and variables hear described as mentioned above for formula I. In another embodiment of this third aspect, a compound of formula I represenía, or by a farmacéuíicameníe salt acepfable thereof, wherein R1 is phenyl opcionalmeníe susfiíuido one or more independents G11; and variables hear described as mentioned anferiormeníe for formula I. In yet OLRA embodiment of this third aspect, a compound is represented by formula I, or a pharmaceutically acceptable salt thereof wherein Q1 is aryl1 I sustiíuido one to five susfiíuyeníes G1; at least one of said substituents G1 is - (X1) n- (Y) m -R4; X1 is -0-; Y1 is -CH2-; R4 is aryl, optionally substituted by one or more substituents R1 is phenyl substituted by one or more G11 independent substituents; and the other variables are described as mentioned above for formula I. In a fourth aspect of the present invention, a compound is represented by formula I, or a salt thereof, wherein R 1 is heterocyclyl, optionally substituted by one or G11 more substituents and the other variables are described as above for formula I. in one embodiment of eSie fourth aspect, a compound is represented by formula I, or a pharmaceutically acceptable salt thereof, wherein R1 is heterocyclyl, optionally susíifuido by one or more G11 susíiíuyeníes; Q1 is aryl1 or heeroaryl1, any of which is suspended by one to five independent G1; G1 is halo, -OR2, -NR2R3, -C (0) R2, -C02R2, -CONR2R3, -S02NR2R3, NR2 (C = 0) R3, NR2 (C = 0) OR3, NR2 (C = 0) NR2R3, NR2S (0) jiR3, -0 (C = 0) OR2, -0 (C = 0) NR2R3, C0-? Alkyl, C2-10 alkenyl, C? Alkoxy. loalquilo of C 0j alkylthio C -????? 0alquilo CMO, C3-8 cycloalkyl, C3.8 cycloalkenyl, or heíerociclil-C0 alkyl or, or heterocyclyl-C2-10 alkenyl, any of which is optionally subsituted with one or more independent substituents oxo, -CF3, -OCF3, -OR222, -NR222R333, -C (0) R222, C02R222, -CONR222R333, -S02NR222R333, NR222 (C = 0) R333, NR222 ( C = 0) OR333, NR222 (C = 0) NR222R333, NR222S (0) jiaR333, -NR222 (C = NR333) NR222aR333a, or -O (C = 0) NR222R333; or - (X1) n- (Y1) m-R4; or aryl-Co-10 alkyl, optionally substituted with one or more halo independent halogen, -CF3, -OCF3, -OR222, -NR222R333, -C (0) R222, -C02R222, -CONR222R333, -S02NR222R333, NR222 (C = 0) R333, NR222 (C = 0) OR333, NR222 (C = 0) NR222R333, NR222S (0) j2aR333, -NR222 (C = NR333) NR222aR333a, or -0 (C = 0) NR222R333; or hearyl-C0-βalkyl, or optionally substituted with one or more halo-independent substituents, -CF3, -OCF3, -OR222, -NR222R333, -C (0) R222, -C02R222, -CONR222R333, -S02NR222R333, NR222 ( C = 0) R333, NR222 (C = 0) OR333, NR222 (C = 0) NR222R333, NR222S (0) j3aR333, -NR222 (C = NR333) NR222aR333a, or -0 (C = 0) NR222R333; and variable variables are described as mentioned above for formula I. In another embodiment of this fourth aspect, a compound is represented by formula I, or by a pharmaceuically acceptable salt thereof, wherein R 1 is heteroarycyl, optionally substituted by one or more G11 substituents; Q1 is aryl1 or heteroaryl, any of which is substituted by one to five independents G1; G1 is halo, -OR2, -NR2R3, -C (0) R2, -C02R2, -CONR2R3, -S02NR2R3, NR2 (C = 0) R3, NR2 (C = 0) OR3, NR2 (C = 0) NR2R3, NR2S (0), - R3, -0 (C = 0) OR2, -0 (C = 0) NR2R3, alkyl or C0, C2- 0 alkenyl, alkoxy C .. 0alquilo CMO?? , alkylthio C -? 0alquilo of CM0, C3-8 cycloalkyl, C3-8 cycloalkenyl, or heterocyclyl-C0 alkyl or, or heterocyclyl-C2- alkenyl or, any of which is optionally substituted? with one or more independent oxo substituents, -CF3, -OCF3, -OR222, -NR2 2R333, -C (O) R222, -C02R222, -CONR222R333, -S02NR222R333, NR222 (C = 0) R333, NR222 (C = 0 ) OR333, NR222 (C = 0) NR222R333, -NR222 (C = NR333) NR222aR333a, or -0 (C = 0) NR222R333; or - (X1) n- (Y1) m-R4; and the other variables are described as mentioned above for formula I. In another embodiment of this fourth aspect, a compound is represented by formula I, or by a pharmaceutically acceptable salt thereof, wherein R 1 is heteroaryl, optionally substituted by one or more G11 substituents; Q1 is aryl1 or heeroaryl1, any of which is suspended by one to five independents G1; wherein at least one of said subscripts G1 is - (X1) n- (Y1) m-R4; X1 and Y1 are each independently the same as -O-, -NR7-, -CR5R6-, -S (0) j7-, or -C (O) -; and the variables will be described as mentioned above for formula I. In another embodiment of this fourth aspect, a compound is represented by formula I, or by a pharmaceutically acceptable salt thereof, wherein R 1 is heterocyclyl, optionally substituted by one or more G11 susíiíuyeníes; Q1 is aryl1 or heeroaryl1, any of which is suspended by one to five independent G1; at least one of said subscripts G1 is - (X1) n- (Y1) m-R4; Xi and Yi are each independently equal to -O- or -CR5R6-; and the other variables are described as mentioned above for formula I. In another embodiment of this fourth aspect, a compound is represented by formula I, or by a pharmaceutically acceptable salt thereof, wherein R 1 is heyerocyclyl, optionally susiiluted by one or more G11 susíiíuyeníes; Q1 is aryl1 or heteroaryl, any of which is suspended by one to five independent substituents G1; wherein at least one of said suffixes G1 is - (X1) n- (Y1) m -R4; X1 and Y1 are each independently equal to -O- or -CH2-; and variable variables are described as mentioned above for formula I. In another embodiment of this fourth aspect, a compound is represented by formula I, or by a pharmaceutically acceptable salt thereof, wherein R 1 is heteroaryl, optionally substituted by one or more G11; Q1 is aryl1 or heteroaryl, any of which is substituted by one to five independent substitutes G1; wherein at least one of said substituents G1 is - (X1) n- (Y1) m -R4; R 4 is H, alkyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, cycloalkenyl, or heterocycloalkenyl, any of which is optionally substituted by one or more independent substituents G41; and the variables will be described as mentioned above for formula I. In another embodiment of this fourth aspect, a compound is represented by formula I, or by a pharmaceutically acceptable salt thereof, wherein R 1 is heterocyclyl, optionally substituted by one or more subsitutes G11; Q1 is aryl1 or heteroaryl, any of which is substituted by one to five independent substituents G1; wherein at least one of said substituents G1 is - (X1) n- (Y1) m-R4; R 4 is aryl or heteroaryl, optionally substituted by one or more G41 independent substituents; and the other variables are described as mentioned anteriormeníe for formula I. In ofra mode eSie fourth aspect, a compound of formula I is represented, or a salt farmacéuíicameníe acepíable thereof, wherein Q1 is aryl1 or heferoarilo1, any of which it is subsumed by one to five independent G1; wherein at least one of said substituents G1 is - (X1) n- (Y1) m-R4; is aryl or heteroaryl, optionally substituted by one or more G41 substituents; and the other variables are described as mentioned above for formula I. In another embodiment of this fourth aspect, a compound is represented by formula I, or by a pharmaceutically acceptable salt thereof, wherein R 1 is heterocyclyl represented by the formula structural: and the other variables are described as mentioned above for formula I. In OiRA mode eSie fourth aspect, a compuesío by formula I is represented, or by a farmacéuíicameníe salt acepíable thereof, wherein R1 is heferociclilo represenfado by the formula structural: wherein G11 is equal to -C (0) R2, -C02R2, -CONR2R3, -S02NR2R3, -S (0) jiR3, alkyl C0? or, C2-10 alkenyl, C1-10 alkoxy CM0alquilo, alkylthio C -? 0alquilo CMO, C3-8 cycloalkyl, C3-8 cycloalkenyl, or heterocyclyl-C0 alkyl or alkenyl or C2-10 heterocyclyl, any of which is opcionalmenle I susíituido one? or more independent substituents oxo, -CF3, -OCF3, -OR222, -NR222R333, -C (0) R222, -C02R222, -CONR222R333, -S02NR222R333, NR222 (C = 0) R333, NR222 (C = 0) OR333, NR222 (C = 0) NR222R333, NR222S (0) jiaR333, -NR222 (C = NR333) NR222aR333a, or -O (C = 0) NR222R333; or - (X1) n- (Y1) m-R4; or aryl-C0-? 0alkyl, optionally susiiuid with one or more halo-independent halogen, -CF3, -OCF3, -OR222, -NR222R333, -C (0) R222, -C02R222, -CONR222R333, -S02NR222R333, NR222 ( C = 0) R333, NR222 (C = 0) OR333, NR222 (C = 0) NR222R333, NR222S (0) j2aR333, -NR222 (C = NR333) NR222aR333a, or -0 (C = 0) NR222R333; or hearyl-Co-10 alkyl, optionally susiiuuid with one or more halogen-independent subsides, -CF3, -OCF3, -OR222, -NR222R333, -C (0) R222, -C02R222, -CONR222R333, -S02NR222R333, NR222 (C = 0) R333, NR222 (C = 0) OR333, NR222 (C = 0) NR222R333, NR222S (0) j3aR333, -NR222 (C = NR333) NR222aR333a, or -0 (C = 0) NR222R333; and the variables will be described as mentioned above for formula I. In another embodiment of this fourth aspect, a compound is represented by formula I, or by a pharmaceutically acceptable salt thereof, wherein R 1 is heterocyclyl represented by the formula structural: wherein G11 is equal to -C (0) R2, -C02R2, -CONR2R3, - S02NR2R3, -S (0) jiR3, C0 alkyl or alkenyl C2.?0 alkoxy -10alquilo of C? -10 C, alquilíio Ci-ioalquilo C1-10, C3.8 cycloalkyl, C3-8 cycloalkenyl, or heíerociclil-alkyl C0? o, o-alkenyl heíerociclil C2.?0, any of which it is optionally substituted with one or more independent isocyclines oxo, -CF3, -OCF3, -OR222, -NR222R333, -C (O) R222, -C02R222, -CONR222R333, -S02NR222R333, NR222 (C = 0) R333, NR222 (C = 0) OR333, 0 (C = 0) NR222R333; or - (X1) n- (Y1) m-R4; and the variable ones are described as mentioned above for formula I. In another embodiment of this fourth aspect, a compound is represented by formula I, or by a pharmaceutically acceptable salt thereof, wherein R 1 is heterocyclyl represented by the formula structural: wherein G11 is equal to -C (0) R2, -C02R2, -CONR2R3, -S02NR2R3, -S (0) jiR3, C0-? alkyl, C2-10 alkenyl, CM0alkyl alkoxy of CMO, alkylthio C 1-10 alkylcycloalkyl, C 3-8 cycloalkyl, C 3-8 cycloalkenyl, or heteroaryl-C 0 -α alkyl, or C 2. 0 helerocyclyl-alkenyl, any of which is optionally susi fi ed with one or more independent susphenogens oxo, -CF3, -OCF3, -OR222, -NR222R333, -C (O) R222, -C02R222, -CONR222R333, -S02NR222R333, NR222 (C = 0) R333, NR222 (C = 0) OR333, NR222 (C = 0) NR222R333, NR222S (0) jiaR333, -NR222 (C = NR333) NR222aR333a, or -0 (C = 0) NR222R333; or - (X) n- (Y1) m-R4; or aryl-Co-10 alkyl, optionally substituted with one or more halo-independent substituents, -CF3, -OCF3, -OR222, -NR222R333, -C (0) R222, -C02R222, -CONR222R333, -S02NR222R333, NR222 (C = 0) R333, NR222 (C = 0) OR333, NR222 (C = 0) NR222R333, NR222S (0) j2aR333, -NR222 (C = NR333) NR222aR333a, or -0 (C = 0) NR222R333; or hetaryl-C0-10 alkyl, optionally substituted with one or more halo independent halophi, -CF3, -OCF3, -OR222, -NR222R333, -C (0) R222, -C02R222, -CONR222R333, -S02NR222R333, NR222 (C = 0) R333, NR222 (C = 0) OR333, NR222 (C = 0) NR222R333, NR222S (0) j3aR333, -NR222 (C = NR333) NR222aR333a, or -0 (C = 0) NR222R333; and the variables will be described as mentioned above for formula I. In yet another embodiment of this fourth aspect, a compound is represented by formula I, or by a pharmaceutically acceptable salt thereof, wherein R 1 is heterocyclyl represented by the structural formula: where G11 is equal to -C (0) R2, -C02R2, -CONR2R3, - S02NR2R3, -S (0) jiR3, C0-? alkyl, or C2-10 alkenyl, CO, C.sub.50 alkylthio of CMO, C3-8 cycloalkyl, C3-? Cycloalkenyl, or heterocyclylC0-? Alkyl, or C2-? Heterocyclyl-alkenyl, or any of which is optionally substituted with one or more independent substituents oxo, -CF3, -OCF3, -OR222, -NR222R333, -C (0) R222, -C02R222, - CONR222R333, -S02NR222R333, NR222 (C = 0) R333, NR222 (C = 0) OR333, NR222 (C = 0) NR222R333, NR222S (0) jiaR333, -NR222 (C = NR333) NR222aR333a, or -O (C = 0) NR222R333; or - (X1) n- (Y1) m-R4; and the variable ones are described as mentioned above for formula I. The compounds of the present invention include compounds represented by formula I, or a pharmaceutically acceptable salt thereof, wherein Q 1 is aryl 1 or heteroaryl, any of which is optionally substituted by one or more independent substituents G1; or wherein Q 1 is heteroaryl, any of which is optionally substituted by one or more independent substituents G 1; or wherein Q1 is aryl1, any of which is optionally substituted by one or more independent substituents G1; or wherein G1 is halo, -CF3, -OCF3, -OR2, -NR2R3, -C (O) R2, -C02R2, -CONR2R3, -S (0) jiR2, -S02NR2R3, NR2 (C = 0) R3, NR2 (C = O) OR3, NR2 (C = 0) NR2R3, NR2S (0) j1R3, -0 (C = 0) OR2, -0 (C = 0) NR2R3, C0-? Alkyl, C2 alkenyl -? 0, C2-? 0 alkynyl, C? -? 0alkyl alkoxy of CM0, C? -? 0 alkenyl of C2-? 0, C2_? Alkynyl alkoxy of C2_? 0, alkylthio of Ci-? C10-10alkyl, C2-? 0 Ci-ioalkenylkyloyl, C2-? 0alkynylkyloyl, C3.8 cycloalkyl, C3-8 cycloalkenyl, C3.8 cycloalkyl C- alkyl 10, C3-8 cycloalkenyl of CMO, cycloalkyl of C3-8 alkenyl of C2-? 0, cycloalkenyl of C3-8 alkenyl of C2-? 0, cycloalkyl of C3-8alkynyl of C2.10, cycloalkenyl of C3.8alkynyl of C2 ? 0, heyerocyclyl-CMO alkyl, C 2? 0 hexycyclyl-alkenyl, or C 2 heter 0 heterocyclyl-alkynyl, any of which is optionally substituted with one or more halogen, oxo, -CF 3, -OCF 3 independent halogenylkynes , -OR222, -NR222R333 (R33a), -? A, -C (0) R 222, -C02R222, -CONR222R333, -N02, -CN, -S (0) jiaR222, -S02NR222R333, NR222 (C = 0) R333, NR222 (C = 0) OR333, NR222 (C = 0) NR222R333, NR222S ( 0) jiaR333, - (C = S) OR222, - (C = 0) SR222, -NR222 (C = NR333) NR222aR333a, -NR222 (C = NR333) OR222a, NR222 (C = NR333) SR333a, -0 (C = 0) OR222, -0 (C = 0) NR222R333, -0 (C = 0) SR222, -S (C = 0) OR222, or -S (C = 0) NR222R333; or - (X1) n- (Y1) m-R4; or aryl-C 0 -α alkyl, C 2. 0 arylalkyl, or C2-0 arylalkynyl, any of which is optionally susíiuuido with one or more halo independent substituents, -CF 3) -OCF 3, - OR222, -NR222R333 (R333a) j2a, -C (0) R222, -C02R222, -CONR222R333, -N02, -CN, -S (0)] 2aR222, -S02NR222R333, NR222 (C = 0) R333, NR222 (C = 0) OR333, NR222 (C = 0) NR222R333, NR222S (0) j2aR333, - (C = S) OR222, - (C = 0) SR222, -NR222 (C = NR333) NR222aR333a, -NR222 (C = NR333 ) OR222a, -NR222 (C = NR333) SR333a, -O (C = 0) 0R222, -0 (C = 0) NR222R333, '-0 (C = 0) SR222, -S (C = 0) OR222, or -S (C = 0) NR222R333; or hetaryl-C0-? alkyl, or C2_10 hetaryl-alkenyl, or C2.10 hetaryl-alkynyl, any of which is optionally substituted with one or more independent halo substituents, -CF3) -OCF3, -OR222, -NR222R333 (R333a) j3a, -C (0) R222, -C02R222, -CONR222R333, -N02, -CN, -S (0) j3aR222, -S02NR222R333, NR222 (C = 0) R333, NR222 (C = 0) 0R333, NR222 (C = 0) NR222R333, NR222S (0) j3aR333, - (C = S) OR222, - (C = 0) SR222, -NR222 (C = NR333) NR222aR333a, -NR222 (C = NR333) OR222a, -NR222 (C = NR333) SR333a, -O (C = 0) 0R222, -0 (C = O) NR222R333, -0 (C = 0) SR222, -S (C = 0) OR222, or -S (C = 0) NR222R333; or wherein G1 is halo, -OR2, -NR2R3, -C (0) R2, -C02R2, -CONR2R3, -S02NR2R3, NR2 (C = 0) R3, NR2 (C = 0) OR3, NR2 (C = O ) NR2R3, NR2S (0) jiR3, -0 (C = 0) OR2, -0 (C = 0) NR2R3, C0-? Alkyl, C2-? 0 alkenyl, C? -? 0alkyl alkoxy of CM0 , C 2. 0 alkoxy d, C.sub.50 alkylthio of CMO, C.sub.12 alkyl C.sub.2 alkenyl, C.sub.3-8 cycloalkyl, C.sub.3-8 cycloalkenyl, C.sub.3 cycloalkyl .8 CMC alkyl, C3 cycloalkenyl. 8-C0_alkyl, C3_8alkenyl C2_3alkenyl cycloalkyl, C2_8alkenyl cycloalkenyl, or C6_6 heterocyclyl_alkyl, or C2_2_6_ or C4_6_6-C3-C3-C3-C3-C3-C3-C3-C3_2-C3-C3-C3-C3_2 optionally substituted with one or more independent substituents oxo, -CF3, -OCF3, -OR222, -NR222R333, -C (O) R222, -C02R222, -CONR222R333, -S02NR222R333, NR 22 (C = 0) R333, NR222 (C = 0) OR333, NR222 (C = 0) NR222R333, NR222S (0) jiaR333, -NR222 (C = NR333) NR222aR333a, or -0 (C = 0) NR222R333; or - (X1) n- (Y1) m-R4; or aryl-C0-βalkyl or optionally substituted with one or more halo-independent substituents, -CF3, -OCF3, -OR222, -NR222R333, -C (0) R222, -C02R222, -CONR222R333, -S02NR222R333, NR222 (C = 0) R333, NR222 (C = 0) OR333, NR222 (C = 0) NR222R333, NR222S (0) j2aR333, -NR222 (C = NR333) NR222aR333a, or -0 (C = 0) NR222R333; or hetaryl-C0-αalkyl or, optionally substituted with one or more independent halo substituents, -CF3, -OCF3, -OR222, -NR222R333, -C (0) R222, -C02R222, -CONR222R333, -S02NR222R333, NR222 ( C = 0) R333, NR222 (C = 0) OR333, NR222 (C = 0) NR 22R333, NR222S (0) j3aR333, -NR222 (C = NR333) NR222aR333a, or -0 (C = 0) NR222R333; or wherein G1 is halo, -OR2, -NR2R3, -C (0) R2, -C02R2, -CONR2R3, -S02NR2R3, NR2 (C = 0) R3, NR2 (C = 0) OR3, NR2 (C = O ) NR2R3, NR ^ O ^ R3, -0 (C = 0) OR2, -0 (C = 0) NR2R3, C0-? Alkyl, C2-? 0 alkenyl, C? _? 0alkyl alkoxy of CMO C, C, C, C3, C3.8 cycloalkyl, C3.8 cycloalkenyl, or heterocyclylC0-? alkyl, or C2_? heterocyclyl-alkenyl, any of which is optionally Substituted with one or more independent substituents oxo, -CF3, -OCF3, -OR222, -NR222R333, -C (0) R222, -C02R222, -CONR222R333, -S02NR222R333, NR222 (C = 0) R333, NR222 (C = 0 ) OR333, NR 2 (C = 0) NR222R333, NR222S (0) j1aR333, -NR222 (C = NR333) NR222aR333a, or -0 (C = 0) NR222R333; or - (X1) n- (Y1) m-R4; or C 0 -α arylalkyl, optionally substituted with one or more independent halo substituents, -CF 3, -OCF 3, -OR222, -NR222R333, -C (0) R222, -C02R222, - CONR222R333, -S02NR222R333, NR222 (C = 0) R333, NR222 (C = 0) OR333, NR222 (C = 0) NR222R333, NR222S (0) j2aR333, -NR222 (C = NR333) NR222aR333a, or -O (C = 0) NR222R333; or hearyl-C0-βalkyl or, optionally, susiiuid with one or more independent halogen substrates, -CF3, -OCF3, -OR222, -NR222R333, -C (0) R222, -C02R222, -CONR222R333, -S02NR222R333, NR222 ( C = 0) R333, NR222 (C = 0) OR333, NR222 (C = 0) NR222R333, NR222S (0) j3aR333, NR222 (C = NR333) NR222aR333a, or -0 (C = 0) NR222R333; or wherein G is halo, -OR2, -NR2R3, -C (0) R2, -C02R2, -CONR2R3, -S02NR2R3, NR2 (C = 0) R3, NR2 (C = 0) OR3, NR2 (C = 0) ) NR2R3, NR2S (0) jiR3, -0 (C = 0) OR2, -0 (C = 0) NR2R3, C0-? Alkyl, C2-? 0 alkenyl, CM0alkyl alkoxy of CMO, C-alkylthio or C 0 alkyl, C 3-8 cycloalkyl, C 3-8 cycloalkenyl, or heterocyclyl C 0 -α alkyl, or C 2 -α heterocyclyl-alkenyl, or any of which is optionally sussiíuid with one or more independent substituents oxo, -CF3, -OCF3, -OR222, -NR222R333, -C (0) R222, -C02R222, -CONR222R333, -S02NR222R333, NR222 (C = 0) R333, NR222 (C = 0) OR333, NR222 (C = 0) NR222R333, NR222S (0) jiaR333, -NR222 (C = NR333) NR222aR333a, or -0 (C = 0) NR222R333; or - (X1) n- (Y1) m-R4; or wherein X1 and Y1 are each independently -O-, -NR7-, -S (0) j7-, -CR5R6-, -N (C (0) OR7) -, -N (C (0) R7) -, -N (S02R7) -, -CH20-, -CH2S-, -CH2N (R7) -, -CH (NR7) -, -CH2N (C (0) R7) -, -CH2N (C (0) OR7 ) -, -CH2N (S02R7) -, -CH (NHR7) -, -CH (NHC (0) R7) -, -CH (NHS02R7) -, -CH (NHC (0) OR7) -, -CH (OC (0) R7) -, -CH (OC (0) NHR7) -, -C (O) -, -CH (OR7) -, -C (0) N (R7) -, -N (R7) C ( 0) -, -N (R7) S (0) -, -N (R7) S (0) 2-, -OC (0) N (R7) -, -N (R7) C (0) N (R7) ) -, - NR7C (0) 0-, -S (0) N (R7) -, -S (0) 2N (R7) -, -N (C (0) R7) S (0) -, -N (C (0) R7) S (0) 2-, -N (R7) S (0) N (R7) -, -N (R7) S (0) 2N (R7) -, -C (0) N (R7) C (0) -, -S (0) N (R7) C (0) -, -S (0) 2N (R7) C (0) -, -OS (0) N (R7) -, -OS (0) 2N (R7) -, -N (R7) S (0) 0-, -N (R7) S (0) 20-, -N (R7) S (0) C (0) -, -N (R7) S (0) 2C (0) -, -SON (C (0) R7) -, -S02N (C (0) R7) -, -N (R7) SON (R7) -, -N (R7) S02N (R7) -, -C (0) 0-, -CH (R7) S (0) -, -CH (R7) S (0) 2-, -CH (R7) N (C (0 ) OR7) -, -CH (R7) N (C (0) R7) -, -CH (R7) N (S02R7) -, -CH (R7) 0-, -CH (R7) S-, -CH ( R7) N (R7) -, -CH (R7) N (C (0) R7) -, -CH (R7) N (C (0) OR7) -, -CH (R7) N (S02R7) -, - CH (R7) C (= NOR7) -, -CH (R7) C (0) -, -CH (R7) CH (OR7) -, -CH (R7) C (0) N (R7) -, -CH (R7) N (R7) C (0 ) -, -CH (R7) N (R7) S (0) -, CH (R7) N (R7) S (0) 2-, -CH (R7) OC (0) N (R7) -, -CH (R7) N (R7) C (0) N (R7) -, -CH (R7) NR7C (0) 0-, -CH (R7) S (0) N (R7) -, -CH (R7) S (0) 2N (R7) -, CH (R7) N (C (0) R7) S (0) -, -CH (R7) N (C (0) R7) S (0) -, -CH (R7) N (R7) S (0) (R7) -, -CH (R7) N (R7) S (0) 2N (R7) -, -CH (R7) C (0) N (R7) C (0) -, -CH (R7) S ( 0) N (R7) C (0) -, -CH (R7) S (0) 2N (R7) C (0) -, -CH (R7) OS (0) N (R7) -, -CH (R7) ) OS (0) 2N (R7) -, -CH (R7) N (R7) S (0) 0-, -CH (R7) N (R7) S (0) 20-, -CH (R7) N ( R7) S (0) C (0) -, -CH (R7) N (R7) S (0) 2C (0) -, -CH (R7) SON (C (0) R7) -, -CH (R7) ) S02N (C (0) R7) -, -CH (R7) N (R7) SON (R7) -, -CH (R7) N (R7) S02N (R7) -, or -CH (R7) C (0 ) 0-; or wherein Q1 is substituted by one to five independent subscribers G1 where at least one of said subscribers G1 is - (X1) n- (Y1) m-R4; and wherein X1 and Y1 are each independently equal to -O-, -NR7-, -CR5R6-, -S (0) j7-, or -C (O) -, and where n and m are both equal to 1 and j7 is equal to 1 or 2; or where Q1 is subsumed by said one to five independent subsidiaries G1 where at least one of said substitutions G1 is - (X1) n- (Y1) m-R4, and wherein X1 and Y1 are each independently -O- or -CR5R6-, and where n and m are equal to 1; or wherein R1 is cycloalkyl, bicycloalkyl, aryl, heteroaryl, aralkyl, heteroarylalkyl, heteroalicyclic, or heterobicycloalkyl, any of which is optionally substituted by one or more independent subfifuuides G11; or wherein R1 is cycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, or heterocyclyl, any of which is optionally substituted by one or more independent subunits G11; or wherein R1 is cycloalkyl or heterocyclyl, any of which is optionally substituted by one or more independent substituents G11; or wherein R is cycloalkyl optionally susíiuuido by one or more independent susíiluyeníes G11; or wherein R 1 is heterocyclyl optionally substituted by one or more independent susliuuyeníes G11; or wherein R1 is aryl, hepheroaryl, aralkyl, or heteroaralkyl, any of which is optionally substituted by one or more independent substituents G11; or wherein R1 is aryl or heeroaryl, any of which is optionally suspended by one or more independent subunits G11; or where G11 is -OR21, -NR21R31 (R31a) j4, -C (0) R21, -C02R21, -CONR21R31, NR2 (C = 0) R31, NR21 (C = 0) OR31, NR21 (C = 0) NR21R31, NR21S (0) j4R31, -0 (C = 0) ) OR21, -0 (C = 0) NR21R31, C0-βalkyl, C3.8 cycloalkyl, C3.8 cycloalkenyl, C0-C6 heterocyclyl-, or C2-? any of which is optionally substituted with one or more independent halogen, oxo, -CF3, -OCF3, -OR2221, -NR2221R3331 (R333a) j4a, -C (0) R2221, -C02R2221, -CONR2221R3331, -N02, - CN, -S (0) j4aR2221, -S02NR2221R3331, NR2221 (C = 0) R3331, NR2221 (C = 0) OR3331, NR222 (C = 0) NR2221R3331, NR2221S (0) j4aR3331, - (C = S) OR2221, - (C = 0) SR2221, -NR 221 (C = NR333) NR222a1R333a1, -NR2221 (C = NR3331) OR222a1, NR2221 (C = NR3331) SR333a1, -0 (C = 0) OR2221, -0 (C = 0 ) NR2221R3331, 0 (C = 0) SR2221, -S (C = 0) OR2221, or -S (C = 0) NR2221R3331; or aryl-C0-? alkyl, or C2-? aryl, or C2-? 0 aryl-alkynyl, any of which is optionally substituted with one or more halo, -CF3, -OCF3, independent substituents, -OR2221, -NR2221R3331 (R333a1) j5a, -C (0) R2221, -C02R2221, -CONR2221R3331, -N02, -CN, -S (0) j5aR2221, -S02NR222 R3331, NR2221 (C = 0) R3331, NR2221 ( C = 0) OR3331, NR222 (C = 0) NR2221R3331, NR2221S (0) j5aR3331, (C = S) OR2221, - (C = 0) SR2221, -NR2221 (C = NR3331) NR222a1R333a1, NR2221 (C = NR3331) OR222a1, -NR2221 (C = NR3331) SR333a1, -0 (C = 0) OR2221, -0 (C = 0) NR2221R3331, -0 (C = 0) SR2221, -S (C = 0) OR2221, or -S (C = 0) NR2221R3331; or hetaryl-Co-10 alkyl, C2-? 0 -hearyl-alkenyl, or C2-? hetaryl-alkynyl, any of which is optionally substituted with one or more independent halo substituents, -CF3, -OCF3, - OR2221, NR2221R3331 (R333a1) j6a, -C (0) R2221, -C02R2221, -CONR2221R3331, -N02, -CN, -S (0) j6aR2221, -S02NR2221R3331, NR2221 (C = 0) R3331, NR2221 (C = O ) OR3331, NR2221 (C = 0) NR2221R3331, NR2221S (0) j6aR3331, - (C = S) OR2221, - (C = 0) SR2221, -NR2221 (C = NR3331) NR222a1R333a1, -NR222 (C = NR3331) OR222a1 , NR2221 (C = NR3331) SR333a1, -0 (C = 0) OR2221, -0 (C = 0) NR222 R3331, O (C = 0) SR2221, -S (C = 0) OR2221, or -S (C = 0) NR2221R3331; or wherein G11 is -OR21, -NR21R31, -C02R21, -C (0) R21, -CONR21R31, NR21 (C = 0) R31, NR21 (C = 0) OR31, NR21 (C = 0) NR21R31, NR21S ( 0) j4R31, -0 (C = 0) OR21, -0 (C = 0) NR21R31, C0-βalkyl, C3_s cycloalkyl, C3.8 cycloalkenyl, heterocyclyl-C0-βalkyl, or heterocyclyl C2_alkenyl, or any of which is optionally substituted with one or more independent halo, oxo, -CF3, -OCF3, -OR2221, -NR2221R3331 (R333a1) j4a, -C (0) R2221, -C02R2221 substituents, -CONR2221R3331, -N02, -CN, -S (0) j4aR2221, -S02NR2221R3331, NR2221 (C = 0) R3331, NR2221 (C = 0) OR3331, NR2221 (C = 0) NR2221R3331, NR2221S (0) j4aR3331, - (C = S) OR2221, - (C = 0) SR2221, -NR2221 (C = NR3331) NR222a1R333a1, -NR2221 (C = NR3331) OR222a1, NR2221 (C = NR3331) SR333a1, -0 (C = 0) OR2221, -0 (C = 0) NR 221R3331, 0 (C = 0) SR2221, -S (C = 0) OR2221, or -S (C = 0) NR2221R3331; or wherein R 4 is H, alkyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, cycloalkenyl, or heterocycloalkenyl, any of which is optionally substituted by one or more G41 independent substituents; or wherein R 4 is alkyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, cycloalkenyl, or heterocycloalkenyl, any of which is optionally substituted by one or more independent G41 substituents; or wherein R 4 is alkyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, cycloalkenyl, or heterocycloalkenyl, any of which is optionally substituted by one or more G41 independent substituents; or wherein Q1 is phenyl substituted by said one to five independent substituents G1 wherein at least one of said substituys G1 is - (X1) n- (Y1) m -R4, and wherein n = 1 and X1 is 3- ( -0-), m = 1 and Y1 is - (- CH2-), and R4 is aryl optionally substituted by one or more G41 independent substituents; or wherein R1 is aryl, heteroaryl, cycloalkyl or heterocyclyl, optionally substituted by one or more G11 independent substitutes; or wherein R1 is cycloalkyl or heyerocyclyl, optionally susíifuido by one or more independent susíiluyeníes G11; or wherein R1 is cycloalkyl, optionally substituted by one or more independent G11 substituents; or wherein R1 is cyclo-butyl, cyclo-pentyl or cyclohexyl, optionally substituted by one or more independent G1; or wherein G11 is -OR21, -NR21R31, -C02R21, -C (0) R21, -CONR21R31, NR21 (C = 0) R31, NR21 (C = 0) OR31, NR21 (C = 0) NR21R31, NR21S ( 0) j4R31, -0 (C = 0) OR21, -0 (C = 0) NR21R31, C0-? Alkyl, cycloalkyl of C3.8l cycloalkenyl of C3-s, heteroaryl-alkyl of C0-? Or, or C2-? 0 -aryocyclic alkenyl, any of which is optionally suslides with one or more independent substituents halo, oxo, -CF3, -OCF3, -OR2221, -NR2221 R3331 (R333a1) j4a? _C (0) R222 _ -C02R222 \ -CONR2221R3331, -N02, -CN, -S (0) j4aR2221, -S02NR2221R3331, NR2221 (C = 0) R3331, NR2221 (C = O) OR3331, NR2221 (C = 0) NR2221R3331, NR2221S (0) j4aR3331, - (C = S) OR2221, - (C = 0) SR2221, -NR2221 (C = NR3331) NR222a1R333a1, -NR2221 (C = NR3331) OR222a1, NR2221 (C = NR3331) SR333a1, -0 (C = 0) OR2221, -0 (C = 0) NR222 R3331, 0 (C = 0) SR2221, -S (C = 0) OR2221, or -S (C = 0) NR2221R3331; or wherein Q1 is phenyl substituted by said one to five independent substituents G1 where at least one of said suffixes G1 is - (X1) n- (Y1) m -R4, and wherein n = 1 and X1 is 4- ( -0-), m = 1 and Y1 is - (- CH2-), and R4 is aryl optionally susíifuido by one or more independent susfifuyentes G41; or wherein R1 is aryl, heteroaryl, cycloalkyl or heterocyclyl, optionally substituted by one or more independent agents G11; or wherein R1 is cycloalkyl or heterocyclyl, optionally substituted by one or more independent substituents G11; wherein R1 is cycloalkyl, optionally substituted by one or more G11 independent substituents; or wherein R1 is cyclobufilo, cyclopentyl or cyclohexyl, optionally susiiuuido by one or more independents G11; or wherein G11 is -OR21, -NR21R31, -C02R21, -C (0) R21, - CONR21R31, NR21 (C = 0) R31, NR21 (C = 0) OR31, NR21 (C = 0) NR21R31, NR21S ( 0) j4R31, -0 (C = 0) OR21, -0 (C = 0) NR21R31, C0-? 0 alkyl, C3.8 cycloalkyl, C3-8 cycloalkenyl, hemerocyclyl-alkyl of CM0, or heterocyclyl- C2- [alpha] alkenyl, or any of which is optionally substituted with one or more independent halo, oxo, -CF3, -OCF3, -OR2221, -NR2221R3331 (R333a1) j4a, -C (0) R2221, -C02R2221, -CONR2221R3331, -N02, -CN, -S (0) j4aR2221, -S02NR2221R3331, NR2221 (C = 0) R3331, NR2221 (C = 0) OR3331, NR2221 (C = 0) NR222 R3331, NR2221S (0) j4aR3331, - (C = S) OR2221, - (C = 0) SR2221, -NR2221 (C = NR3331) NR222a1R333a1, -NR2221 (C = NR3331) OR222a1, NR2221 (C = NR3331) SR333a1, -0 (C = 0) OR2221 , -0 (C = 0) NR2221R3331, O (C = 0) SR2221, -S (C = 0) OR2221, or -S (C = 0) NR2221R3331; or wherein Q1 is phenyl sublimed by said one to five independent subsitutes G1 wherein at least one of said substitutes G1 is - (X1) n- (Y) m -R4, and wherein n = 1 and X1 is 3- ( -0-), m = 0, and R4 is (C0-C8) alkyl or cycloalkyl optionally substituted by one or more independent substituents G41; or wherein R1 is aryl, heteroaryl, cycloalkyl or heterocyclyl, optionally substituted by one or more independent G11; or wherein R1 is cycloalkyl or heterocyclyl, optionally substituted by one or more independent substituents G11; or wherein R1 is cycloalkyl, optionally substituted by one or more independent substituents G11; or wherein R1 is cyclobuyyl, cyclopenfilo or ciciohexilo, optionally subsumed by one or more independents G11; or wherein G11 is -OR21, -NR21R31, -C02R21, -C (0) R21, -CONR21R31, NR21 (C = 0) R31, NR21 (C = 0) OR31, NR21 (C = 0) NR21R31, NR21S ( 0) j4R31, -0 (C = 0) OR21, -0 (C = 0) NR21R31, C0.oo alkyl, C3.8 cycloalkyl, C3.8 cycloalkenyl, heyerocyclyl-alkyl of CM0, or heterocyclic- C2_? alkenyl, any of which is optionally substituted with one or more independent halogen, oxo, -CF3, -OCF3, -OR2221, -N R2221R3331 (R333a1) j4a substituents? _C (0) R2221j _C02R2221. -CONR2221R3331, -N02, -CN, -S (0) j4aR2221, -S02NR2221R3331, NR2221 (C = 0) R3331, NR2221 (C = O) OR3331, NR2221 (C = 0) NR2221R3331, NR2221S (0) j4aR3331, - (C = S) OR2221, - (C = 0) SR2221, -NR2221 (C = NR3331) NR222a1R333a1, -NR222 (C = NR3331) OR222a1, NR2221 (C = NR3331) SR333a1, -0 (C = 0) OR2221, -0 (C = 0) NR2221R3331, O (C = 0) SR2221, -S (C = 0) OR2221, or -S (C = 0) NR2221R3331; or wherein R4 is (Co-C6) alkyl; or wherein R 4 is H or melyl; or wherein Q1 is phenyl sub- stituted by said one to five independent substituents wherein at least one of said substituents G1 is - (X1) n- (Y1) m -R4, and wherein n = 1 and X1 is 3 - (- 0-), m = 0, and R4 is aryl optionally susíiuuido by one or more independents G41; or wherein R1 is aryl, heleroaryl, cycloalkyl or heterocyclyl, optionally substituted by one or more independent substituents G11; or wherein R1 is cycloalkyl or heterocyclyl, optionally substituted by one or more independent substituents G11; or wherein R1 is cyclobutyl, cyclopentyl or cyclohexyl, optionally substituted by one or more G11 independent substituents; or wherein G11 is -OR21, -NR21R31, -C02R21, -C (0) R21, -CONR21R31, NR21 (C = 0) R31, NR21 (C = 0) OR31, NR21 (C = 0) NR21R31, NR21S ( 0) j4R31, -0 (C = 0) OR21, -0 (C = 0) NR21R31, Co-yo alkyl, C3.8 cycloalkyl, C3-8 cycloalkenyl, heyerocyclylC0-? O alkyl, or hexy-cyclic-alkenyl of C2-? 0, any of which is optionally substituted with one or more independent halogen, oxo, -CF3, -OCF3, -OR2221 -NR222i R333i (R333ai) j4a. -C (0) R2221, -C02R2221, -CONR2221R3331, -N02, -CN, -S (0) j4aR2221, -S02NR2221R3331, NR2221 (C = 0) R3331, NR2221 (C = 0) OR3331, NR222 (C = 0 ) NR2221R3331, NR2221S (0) j4aR3331, - (C = S) OR2221, - (C = 0) SR2221, -NR2221 (C = NR3331) NR222a1R333a1, -NR2221 (C = NR3331) OR222a1, NR2221 (C = NR3331) SR333a1 , -0 (C = 0) OR2221, -0 (C = 0) NR2221R3331, 0 (C = 0) SR2221, -S (C = 0) OR2221, or -S (C = 0) NR2221R3331; or wherein R 4 is phenyl optionally substituted with G41; or wherein Q1 is phenyl substituted by said one to five independent substituents wherein at least one of said substituents G1 is - (X1) n- (Y1) m -R4, and where n = 1 and X1 is 3- or 4 -NH-), m = 1 and Y1 is - (- S02-), and R4 is aryl optionally subscribed by one or more independent subsidiaries G41; or wherein R1 is aryl, heteroaryl, cycloalkyl or heterocyclyl, optionally substituted by one or more independent G11; or wherein R1 is cycloalkyl or heteroalicyclic, optionally susiIuid by one or more independent substituents G11; or wherein R1 is cyclobuyyl, cyclopenfilo or ciciohexilo, optionally substituted by one or more independents G11; or wherein G11 is -OR21, -NR21R31, -C02R21, -C (0) R21, -CONR21R31, NR2 (C = 0) R31, NR2 (C = 0) OR31, NR21 (C = 0) NR21R31, NR21S ( 0) j4R31, -0 (C = 0) OR21, -0 (C = 0) NR21R31, C0-? O alkyl, C3-8 cycloalkyl, C3.8 cycloalkenyl, heteroaryl-C0-? Alkyl, or C2_? 0 hexycyclyl-alkenyl, any of which is optionally substituted with one or more independent halo, oxo, -CF3, -OCF3, -OR2221, -NR2221R333 (R333a1) j4a, -C (0) R2221, - independent substituents, - C02R2221, -CONR2221R3331, -N02, -CN, -S (0) j4aR2221, -S02NR2221R3331, NR2221 (C = 0) R3331, NR2221 (C = O) OR3331, NR2221 (C = 0) NR2221R3331, NR2221S (0) j4aR3331 , - (C = S) OR2221, - (C = 0) SR2221, -NR2221 (C = NR3331) NR222a1R333a1, -NR2221 (C = NR3331) OR222a1, NR2221 (C = NR3331) SR333a1, -0 (C = 0) OR2221, -0 (C = 0) NR2221R3331, 0 (C = 0) SR2221, -S (C = 0) OR2221, or -S (C = 0) NR2221R3331; or wherein R1 is cis- or trans-cyclobuyl substituted at the 3-position by G11 where G11 is -OH, -NH2, -N (CH3) 2, -NHAc, -NH (CO) NHCH3, -NH (CO) OCH3, -CH2OH, -CH2NH2, -CH2NHAc, C02H, CONH2, -CH2N (CH3) 2, -C02CH3, CONHCH3, wherein R1 is cis- or trans-cyclohexyl substituted at the 4-position by G11 where G11 is -OH, -NH2, -N (CH3) 2, -NHAc, -NH (CO) NHCH3, -NH (CO) OCH3 , -CH2OH, -CH2NH2, -CH2NHAc, C02H, CONH2, -CH2N (CH3) 2, CH2NH (CO) NHMe, -CH2NH (CO) OCH3, C02CH3, CONHCH3, wherein the compound e rmu a is derived from the group consisting of: [1- (3-Benzyloxy-phenyl) -3-cyclobutyl-imidazo [1,5-a] pyrazin-8-ylamine], 1- (3-Benzyloxyphenyl) -3-phenylimidazo [1,5-a] pyrazin-8-ylamine, 3-Benzyl-1- (3-benzyloxyphenyl) -imidazo [1,5-a] pyrazin-8- Iamine, 1- (3-Benzyloxyphenyl) -3-naphthalen-1-yl-imidazo [1,5-a] pyrazin-8-ylamine, 1- (3-benzyloxy-phenyl) -3-naphthalene-2-yl imidazole [1,5-a] pyrazin-8-lamel, 1- (3-benzyl-phenyl) -3-cyclopentenyl-methyldazo [1,5-a] pyrazin-8-ylamine, - (3-Benzyloxy-phenyl) -3-cyclohexyl-imidazole [1, 5-a] pyrazin-8-ylamine, 1- (3-Benzyl-phenyl) -3-cycloheptyl-imidazole [1, 5-a] ] pyrazin-8-ylamine, 1- (3-benzyloxy-phenyl) -3- (tephrahydro-furan-3-yl) -midazole [1,5-a] pyrazin-8-ylamine, frans-3- [8] -Amino-1- (3-benzyloxy-phenyl) -imidazole [1,5-a] prazin-3-yl] -cyclobutanol, 1- (3-benzyloxy-phenyl) -3- (1-methyl-piper) Din-4-yl) -imidazole [1,5-a] pyrazin-8-alamine, cis-3- [8-Amino-1- (3-benzyloxy-phenyl) -imidazole] amide [1, 5] - a] pyrazin-3-yl] -cicl hexancarboxylic acid, trans-4- [8-Amino-1- (3-benzyloxy-phenyl) -midazo [1,5-a] pyrazin-3-yl] -cyclohexanecarboxylic acid amide, cis-4- [8-Amino] -1- (3-benzyloxy-phenyl) -imidazo [1,5-a] pyrazin-3-yl] -cyclohexyl-methanol, trans-4- [8-Amino-1- (3-benzyloxy-phenyl) -imidazo [1, 5-a] pyrazin-3-yl] -cyclohexyl-melanol, cis-2-. { 4- [8-Amino-1- (3-benzyloxy-phenyl) -imidazo [1,5-a] pyrazin-3-yl] -cyclohexylmethyl} -isoindole-1, 3-dione, trans-2-. { 4- [8-Amino-1- (3-benzyloxy-phenyl) -imidazo [1,5-a] pyrazin-3-yl] -cyclohexylmethyl} -isoindole-1, 3-dione, cis-3- (4-Aminomethyl-cyclohexyl) -1- (3-benzyloxy-phenyl) -imidazo [1,5-a] pyrazin-8-ylamine, trans-3- ( 4-Aminomethyl-cyclohexyl) -1- (3-benzyloxy-phenyl) -imidazo [1,5-a] pyrazin-8-ylamine, cis-N-. { 4- [8-Amino-1- (3-benzyloxy-phenyl) -imidazo [1,5-a] p -razin-3-yl] -cyclohexylmethyl} -aceyamide, or frans-N-. { 4- [8-Amino-1- (3-benzyloxy-phenyl) -imidazo [1,5-a] pyrazin-3-yl] -cyclohexylmethyl} -aceiamide; or and the other variables as previously defined by the formula I. The present invention includes a method for the inhibition of protein kinase activity comprising the administration of a compound of formula I or a pharmaceutically acceptable salt thereof. The present invention includes a method for the inhibition of IGF-IR activity comprising the administration of a compound of formula I or a pharmaceutically acceptable salt thereof. The present invention includes a method for the inhibition of protein kinase activity wherein the activity of said protein kinase affects hyperproliferaive transitions comprising administering a compound of formula I or a pharmaceutically acceptable salt thereof. The present invention includes a method for the inhibition of proinin kinase activity wherein the activity of said proinin kinase influences angiogenesis, vascular permeability, immune response, cellular apoptosis, lumoral growth, or inflammation comprising the administration of a compound of Formula I or a pharmaceutically acceptable salt thereof. The present invention includes a method for irradiating a patient that has a condition mediated by the protein kinase activity, said method comprising administering to the patient a therapeutically effective amount of a compound of formula I or a pharmaceutically salt acceptable of it. The present invention includes a method for treating a patient that has a condition that is mediated by the activity of IGF-1 R, said method comprising administering to the patient an effective ferapéuíica quantity of a compound of formula I or a pharmaceutically acceptable salt thereof. The present invention includes a method for the treatment of a patient having a hyperproliferative disorder, said method comprising administering to the patient a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof. The present invention includes a method for the treatment of a patient who has a condition mediated by the activity of protein kinase wherein the activity of said protein kinase influences angiogenesis, vascular permeability, immune response, cellular apoptosis, growth, or inflammation, said method comprising administering to the patient a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof. The present invention includes a method for trafficking a patient having a condition mediated by protein kinase activity wherein the protein kinase is a serine / ireine kinase or protein tyrosine kinase, said method comprises administration to the patient of an idrachemically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof. The present invention includes a method for the treatment of a patient having a condition mediated by protein kinase activity wherein the condition mediated by protein kinase activity is one or more ulcers, said method comprises administering to the patient a Therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof. The present invention includes a method for the treatment of a patient that has a condition mediated by proinin kinase activity wherein the protein kinase-mediated condition is one or more ulcers wherein the ulcer or ulcer is caused by a bacterial or fungal infection; or the ulcer or ulcers are Mooren's ulcers; or the ulcer or ulcers are symptoms of ulcerative colitis, said method comprising the admission to the patient of a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof. The present invention includes a method for treating a patient that has a condition mediated by the activity of a proinin kinase wherein the condition mediated by proine kinase activity is Lyme disease., sepsis or infection by Herpes simplex, Herpes Zoster, human immunodeficiency virus, parapoxvirus, protozoa, or toxoplasmosis, said method comprises administering to the patient a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof . The present invention includes a method for irradiating a patient that has a condition mediated by the protein kinase activity where the protein kinase-mediated condition is Lyme disease, sepsis or infection by Herpes simplex, Herpes Zoster , human immunodeficiency virus, parapoxvirus, proiozoa, or ioxoplasmosis, said method comprises administering to the patient an therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof. The present invention includes a method for the irradiation of a patient having a condition mediated by proine kinase activity wherein the condition mediated by protein kinase activity is von Hippel Lindau disease, pemphigoid, psoriasis, Paget's disease. , or polycystic kidney disease, said method comprises administering to the patient a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof. The present invention includes a method for transporting a patient having a condition mediated by protein kinase activity wherein the protein kinase-mediated condition is fibrosis, sarcoidosis, cirrhosis, thyroiditis, hyperviscosity syndrome, Osler-Weber-Rendu, chronic occlusive pulmonary disease, asthma, exudates, ascites, pleural effusions, pulmonary edema, cerebral edema or edema after burns, trauma, radiation, stroke, hypoxia, or ischemia, said method includes administration to the patient of a therapeutically effective amount of a compound of formula I or of a pharmaceutically acceptable salt thereof. The present invention includes a method for the delivery of a patient having a condition mediated by pro-kinase activity wherein the condition mediated by protein kinase activity is ovarian hyperresponsiveness syndrome, preeclampsia, menometrorrhagia, or endomeíriosis, said method comprises administering to the patient a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof. The present invention includes a method for the treatment of a patient that fills a condition mediated by the activity of proine kinase wherein the condition mediated by the activity of proine kinase is chronic inflammation, systemic lupus, glomerulonephritis, synovitis, bowel disease. inflammatory, Crohn's disease, glomerulonephritis, rheumatoid arthritis and osteoarthritis, multiple sclerosis, or graft rejection, said method comprises administering to the patient a therapeutically effective amount of a compound of formula I or of a sa! pharmaceutically acceptable thereof. The present invention includes a method for the delivery of a patient that has a condition mediated by the activity of proinin kinase wherein the condition mediated by protein kinase activity is sickle cell anemia, said method comprising administering to the patient a Therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof. The present invention includes a method for trapping a patient having a condition mediated by protein kinase activity wherein the condition mediated by protein kinase activity is an ocular condition, said method comprising administering to the patient a canine The effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof. The present invention includes a method for the treatment of a patient having a condition mediated by the activity of proinin kinase wherein the condition mediated by proine kinase activity is an ocular condition wherein the ocular condition is ocular or macular edema., ocular neovascular disease, seleritis, radial keraioimomy, uveiitis, vitritis, myopia, optic fovea, chronic retinal detachment, post-laser complications, conjuncíivifis, Stargardf's disease, Eales disease, reinopathy, or macular degeneration, said period comprises administering to the patient an epistemically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof. The present invention includes a method for transporting a patient that has a condition mediated by protein kinase activity wherein the condition mediated by protein kinase activity is a cardiovascular condition, said method comprising administering to the patient an amount Ierapeuically effective of a compound of formula I or a pharmaceutically acceptable salt thereof. The present invention includes a method for delivery of a patient having a condition mediated by protein kinase activity wherein the condition mediated by protein kinase activity is atherosclerosis, resenosis, ischemic reperfusion injury, vascular occlusion, venous malformation or obstructive disease of the carotid, said method comprising administering to the patient a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof. The present invention includes a method for the delivery of a patient having a condition mediated by protein kinase activity wherein the condition mediated by protein kinase activity is cancer, said method comprising administering to the patient an effective therapeutic amount. of a compound of formula I or a pharmaceutically acceptable salt thereof. The present invention includes a method for fracking a patient having a condition mediated by protein kinase activity wherein the condition mediated by proine kinase activity is cancer wherein the cancer is a solid tumor, a sarcoma, fibrosarcoma , osteoma, melanoma, retinoblasphoma, a rhabdomyosarcoma, glioblasíoma, neuroblasíoma, teratocarcinoma, a hematopoieíica malignancy, or malignant ascites, said method comprises administering to the patient a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof . The present invention includes a method for the irradiation of a patient having a condition mediated by the activity of proine kinase wherein the condition mediated by proine kinase activity is cancer wherein the cancer is Kaposi's sarcoma, Hodgkin's disease, lymphoma, myeloma, or leukemia, said method comprises administering to the patient a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof. The present invention includes a method for derailing a patient who has a condition mediated by proine kinase activity wherein the condition mediated by protein kinase activity is Crow-Fukase Syndrome (POEMS) or a diabetic condition, said method comprises administering to the patient a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof. The present invention includes a method for tracing a patient having a condition mediated by protein kinase activity wherein the condition mediated by protein kinase activity is Crow-Fukase syndrome (POEMS) or a diabetic condition in where the diabetic condition is glaucoma by insulin-dependent diabetes mellitus, diabetic retinopathy, or microangiopay, said method comprises administering to the patient a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof. The present invention includes a method for the treatment of a patient having a condition mediated by protein kinase activity wherein the protein kinase activity participates in the acylation of the T cell, B-cell acyivation, cell degranulation, monocyte acfivation, signal transduction, apopiosis, the enhancement of an inflammatory response or a combination thereof, said method comprises administering to the patient a therapeutically effective amount of a compound of formula I or a pharmaceuically acceptable salt thereof. The present invention includes a composition comprising a compound according to formula I, or a pharmaceutically acceptable salt thereof.; and a pharmaceutically acceptable vehicle. The present invention includes a composition comprising a compound according to formula I, or a pharmaceutically acceptable salt thereof; and an amphi-neoplastic, ani-umoural, anti-angiogenic, or chemotherapeutic agent. The present invention includes a composition comprising a compound according to formula I, or a pharmaceutically acceptable salt thereof; and a cytotoxic therapeutic agent for cancer. The present invention includes a composition comprising a compound according to formula I, or a pharmaceutically acceptable salt thereof; and a therapeutic agent inhibiting angiogenesis in cancer. The present invention includes a method for treating a patient who has a condition mediated by prolein kinase activity, said method comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition comprising a compound in accordance with Formula I, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable vehicle. Unless stated otherwise, the connections of the portions with the name of the compound are the portion that is mentioned further to the right. That is, the name of the substituent starts with a terminal portion, continues with any binding portions, and ends with the connection portion. For example, hephenylthioalkyl of C? - as a heteroaryl group connected through the sulfur thio to a C? -alkyl which connects to the chemical species containing the substituyenfe. As used in the present invention, for example, "Co-4 alkyl" is used to mean an alkyl having 0-4 carbons - that is, 0, 1, 2, 3, or 4 carbons in a configuration of strong or branched chain. An alkyl that has no carbon is hydrogen when the alkyl is a terminal group. An alkyl that has no carbon is a direct bond when the alkyl is a linking group (linker). In all embodiments of this invention, the term "alkyl" includes straight-chain branched alkyl groups. Typical alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-buyl, n-pentyl, isopenlyl, n-hexyl, n-hepyl, isooctyl, nonyl, decyl, undeclyl. , dodecyl, letradecyl, hexadecyl, occydecyl, eicosyl and the like. The term "halo" refers to fluoro, chloro, bromo or iodo.

The term "haloalkyl" refers to an alkyl group substituted with one or more halo groups, for example chloromethyl, 2-bromoethyl, 3-iodopropyl, trifluoromethyl, perfluoropropyl, 8-chlorononyl and the like. The term "cycloalkyl" refers to a cyclic aliphatic ring structure, optionally substituted with alkyl, hydroxy and halo, such as cyclopropyl, methylcyclopropyl, cyclobufyl, cyclopentyl, 2-hydroxycyclopentyl, cyclohexyl, 4-chlorocyclohexyl, cyclohepyl, cycloocyl and the like . The term "alkylcarbonyloxyalkyl" refers to an ester portion, for example, aceioxymethyl, n-butyryloxyfile and the like. The term "alkynylcarbonyl" refers to an alkynylketo functionality, for example propynyl and the like. The term "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxy groups, for example hydroxymethyl, 2,3-dihydroxybutyl and the like. The term "alkylsulfonylalkyl" refers to a substituted alkyl group with an alkylsulfonyl moiety, for example mesylmethyl, isopropylsulfonylethyl, and the like. The term "alkylsulfonyl" refers to a sulfonyl portion substituted with an alkyl group, for example mesyl, n-propylsulfonyl and the like. The term "acetylaminoalkyl" refers to an alkyl group substituted with an amide portion, for example acetylaminomethyl and the like.

The term "acetylaminoalkenyl" refers to an alkenyl group substituted with an amide moiety, for example 2- (acetylamino) vinyl and the like. The term "alkenyl" refers to an ethynylically unsaturated, straight or branched chain hydrocarbon group having 1 or 2 ethylenic bonds, for example vinyl, allyl, 1-buyenyl, 2-butenyl, isopropenyl, 2-pentenyl and the like . The term "haloalkenyl" refers to a substituted alkenyl group with one or more halo groups. The term "cycloalkenyl" refers to a cyclic aliphatic ring structure, optionally substituted with alkyl, hydroxy, and halo, having 1 or 2 general ethylenic bonds such as mephylcyclopropenyl, trifluoromethylcyclopropenyl, cyclopentenyl, cyclohexenyl, 1,4-cyclohexadienyl, and the like. The term "alkynyl" refers to an unsaturated, straight-chain or branched hydrocarbon group having 1 or 2 acetylenic bonds, for example ethynyl, propargyl and the like. The term "haloalkynyl" refers to a substituted alkynyl group with one or more halo groups. The term "alkylcarbonyl" refers to an alkylceio functionality, for example, acetyl, n-bulyryl and the like. The term "alkenylcarbonyl" refers to an alkenylchloride functionality, for example, propenoyl and the like.

The term "aryl" refers to phenyl or naphthyl which may be optionally substituted. Typical aryl sustituyent.es include, but are not limited to, phenyl, 4-chlorophenyl, 4-fluorophenium, 4-bromophenyl, 3-nitrophenyl, 2-methoxyphenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 4- ethylphenylamino, 2-meityl-3-methoxyphenyl, 2,4-dibromophenyl, 3,5-difluorophenyl, 3,5-dimethylphenyl, 2,4,6-trichlorophenyl, 4-methoxyphenyl, naphthyl, 2-chloronaphthyl, 2,4- dimethoxyphenyl, 4- (trifluoromethyl) phenyl and 2-iodo-4-methylphenyl. The term "aryl" refers to phenyl which may optionally be substituted. Aryl aryl substituents include, but are not limited to, phenyl, 4-chlorophenyl, 4-fluorophenyl, 4-bromophenyl, 3-nitrophenyl, 2-methoxyphenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 4-ethylphenyl, 2-methyl-3-methoxyphenyl, 2,4-dibromophenyl, 3,5-difluorophenyl, 3,5-dimethylphenyl, 2,4,6-trichlorophenyl, 4-methoxyphenyl, 2,4-dimethoxyphenyl, 4- (trifluoromethyl) phenyl and 2-iodo-4-methylphenyl. The terms "heteroaryl" or "hepharyl" refer to a unsaturated ring of 5 or 6 members susfifuido or susfiíuido containing one, two, fres or cuafro heferoátomos, preferably one or two heteroáíomos independently selected from oxygen, nitrogen and sulfur or an unsaturated bicyclic ring system containing up to 10 atoms including a selected heterogeneous from oxygen, nitrogen and sulfur. Examples of hetaryls include, but are not limited to, 2-, 3- or 4-pyridinyl, pyrazinyl, 2-, 4-, or 5-pyrimidinyl, pyridazinyl, triazolyl, tefrazolyl, midazolyl, 2- or 3-ynyl , 2- or 3-furyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, quinolyl, isoquinolyl, benzimidazolyl, benzotriazolyl, benzofuranyl, and benzothienyl. The heterocyclic ring may be optionally substituted with up to two substituents. The terms "heteroaryl" or "heteroaryl" refers to an unsubstituted, unsubstituted or unsubstituted 5 or 6-membered ring containing one, two, three or more heteroarylanes, preferably one or two heteroatoms independently selected from oxygen, nitrogen and sulfur. Examples of hetaryls1 include, but are not limited to, 2-, 3- or 4-pyridinyl, pyrazinyl, 2-, 4-, or 5-pyrimidinyl, pyridazinyl, triazolyl, theyrazolyl, imidazolyl, 2-or 3-thienyl, 2- or 3-furyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, and thiadiazolyl. The heterocyclic ring may be optionally substituted with two susiiluyeníes. The terms "aryl-alkyl" or "arylalkyl" are used to describe a group wherein the alkyl chain may be branched or straight chain with the aryl portion, as defined above in the present invention, forming a linking portion of the aryl-alkyl portion. Examples of aryl-alkyl groups include, but are not limited to, optionally substituted benzyl, phenethyl, phenpropyl, and phenbutyl, such as 4-chlorobenzyl, 2,4-dibromobenzyl, 2-methylbenzyl, 2- (3-fluorophenyl) ethyl, - (4-meitylphenyl) ethyl, 2- (4- (trifluoromethyl) phenyl) ethyl, 2- (2-meioxyphenyl) ethyl, 2- (3-nitrophenyl) ethyI, 2- (2,4-dichlorophenyl) ethyI, - (3,5-dimethioxyphenyl) ethylo, 3-phenylpropyl, 3- (3-chlorophenyl) propyl. 3- (2-methylphenyl) propyl, 3- (4-methoxyphenyl) propyl, 3- (4- (1-trifluoromethyl) phenyl) propyl, 3- (2,4-dichlorophenyl) propyl, 4-phenylbutyl, 4- (4- chlorophenyl) butyl, 4- (2-methylyphenyl) bulyl, 4- (2,4-dichlorophenyl) butyl, 4- (2-methoxyphenyl) butyl and 10-phenyldecyl. The terms "aryl-cycloalkyl" or "arylcycloalkyl" are used to describe a group in which the aryl group is attached to a cycloalkyl group, for example phenylcyclopentyl and the like. The terms "aryl-alkenyl" or "arylalkenyl" are used to describe a group in which the alkenyl chain can be branched or straight chain with the aryl portion, as defined above in the present invention, forming a linking portion of the aralkenyl portion, for example styryl (2-phenylvinyl), phenpropenyl and the like. The terms "aryl-alkynyl" or "arylalkynyl" are used to describe a group wherein the alkynyl chain may be branched or straight chain with the aryl portion, as defined above in the present invention, forming a linking portion of the arylalkynyl portion, for example 3-phenyl-1-propynyl and the like. The terms "aryl-oxy" or "aryloxy" are used to describe a terminal aryl group attached to a bonded oxygen atom. Typical aryl-oxy groups include phenoxy, 3,4-dichlorophenoxy and the like. The terms "aryl-oxyalkyl" or "aryloxyalkyl" are used to describe a group in which an alkyl group is substituted with an aryloxy group, for example peniafluorophenoxymethyl and the like. The terms "hetaryl-oxy" or "heleroaryl-oxy" or "heyaryloxy" or "heeroaryloxy" are used to describe a terminal hetaryl group attached to a bonded oxygen atom. Typical hetaryl-oxy groups include 4,6-dimethoxypyrimidin-2-yloxy and the like. The terms "hetarylalkyl" or "heteroarylalkyl" or "hetaryl-alkyl" or "heteroaryl-alkyl" are used to describe a group wherein the alkyl chain may be branched or straight chain with the heteroaryl portion, as defined above in the present invention, forming a linking portion of the heteroaralkyl portion, for example 3-furylmethyl, tenyl, furfuryl and the like. The terms "hetarylalkenyl" or "heeroarylalkenyl" or "hetaryl-alkenyl" or "heteroaryl-alkenyl" are used to describe a group wherein the alkenyl chain may be branched or straight chain with the heeroaryl portion, as defined above in present invention, forming a linking portion of the heeroalkenyl portion, for example 3- (4-pyridyl) -1-propenyl. The terms "hetarylalkyl" or "heteroarylalkynyl" or "hetaryl alkynyl" or "heeroaryl alkynyl" are used to describe a group wherein the alkynyl chain may be branched or straight chain with the heeroaryl portion, as defined above in present invention, forming a linking portion of the heteroaralkynyl moiety, for example 4- (2-ynyl) -1-buyinyl. The term "heterocyclyl" refers to a substituted or unsubstituted 5 or 6-membered saturated ring containing one, two or more hetero-atoms, preferably one or two free-sellers selected from oxygen, nitrogen and sulfur or referred to a system of bicyclic ring containing up to 10 atoms including a hetero-atom selected from oxygen, nitrogen and sulfur wherein the ring containing the hetero-atom is saturated. Examples of heterocyclyls include, but are not limited to, hydrafuranyl, telrahydrofuryl, pyrrolidinyl, piperidinyl, 4-pyranyl, tetrahydropyranyl, thiolanyl, morpholinyl, piperazinyl, dioxolanyl, dioxanyl, indolinyl, 5-methylene-6-chromanyl and the terms "heterocyclylalkyl" or "heterocyclyl-alkyl" are used to describe a group wherein the alkyl chain may be branched or straight chain with the heterocyclyl portion, as defined above in the present invention, forming a linking portion of the heterocyclylalkyl, for example 3-piperidinylmethyl and the like. The terms "heterocyclylalkenyl" or "heterocyclyl-alkenyl" are used to describe a group wherein the alkenyl chain may be straight-chain or branched with the heterocyclyl portion, as defined above in the present invention, forming a linking portion of the heyerocyclylalkenyl portion, for example 2-morpholinyl-1-propenyl. The terms "heterocyclylalkynyl" or "heyerocyclyl-alkynyl" are used to describe a group wherein the alkynyl chain may be branched or straight chain with the heterocyclyl portion, as defined above in the present invention, forming a linking portion of the heterocyclylalkyl portion, for example 2-pyrrolidinyl-1-butinyl.

The term "carboxylalkyl" includes straight chain branched alkyl groups as defined above in the present invention linked to a carboxyl group (-COOH). The term "carboxylalkenyl" includes straight chain as branched alkenyl groups as defined above in the present invention attached to a carboxyl group (-COOH). The term "carboxylalkynyl" includes both straight-chain and branched alkynyl groups as defined above in the present invention attached to a carboxyl group (-COOH). The term "carboxylcycloalkyl" refers to a carboxyl group (-COOH) attached to a cyclic aliphatic ring structure as defined above in the present invention. The term "carboxylcycloalkenyl" refers to a carboxyl group (-COOH) attached to a cyclic aliphatic ring structure having 1 or 2 elylenic bonds as defined above in the present invention. The terms "cycloalkylalkyl" or "cycloalkyl-alkyl" refers to a cycloalkyl group as defined above in the present invention linked to an alkyl group, for example cyclopropylmethyl, cyclohexylenyl and the like. The terms "cycloalkylalkenyl" or "cycloalkyl-alkenyl" refers to a cycloalkyl group as defined above in the present invention linked to an alkenyl group, for example cyclohexylvinyl, cycloheptylalyl and the like.

The terms "cycloalkylalkynyl" or "cycloalkyl alkynyl" refers to a cycloalkyl group as defined above in the present invention linked to an alkynyl group, for example cyclopropylpropargyl, 4-cyclopentyl-2-butynyl and the like. The terms "cycloalkenylalkyl" or "cycloalkenyl-alkyl" refers to a cycloalkenyl group as defined above in the present invention linked to an alkyl group, for example 2- (cyclopenphen-1-yl) ethyl and the like. The terms "cycloalkenylalkenyl" or "cycloalkenyl alkenyl" refers to a cycloalkenyl group as defined above in the present invention linked to an alkenyl group, for example 1- (cyclohexen-3-yl) allyl and the like. The terms "cycloalkenylalkyl" or "cycloalkenyl-alkynyl" refers to a cycloalkenyl group as defined above in the present invention linked to an alkynyl group, for example 1- (cyclohexen-3-yl) propargyl and the like. The term "carboxylcycloalkylalkyl" refers to a carboxyl group (-COOH) attached to the cycloalkyl ring portion of a cycloalkylalkyl group as defined above in the present invention. The term "carboxylcycloalkylalkenyl" refers to a carboxyl group (-COOH) attached to the cycloalkyl ring portion of a cycloalkylalkenyl group as defined above in the present invention. The term "carboxylcycloalkylalkynyl" refers to a carboxyl group (-COOH) attached to the cycloalkyl ring portion of a cycloalkylalkyl group as defined above in the present invention. The term "carboxylcycloalkenylalkyl" refers to a carboxyl group (-COOH) attached to the cycloalkenyl ring portion of a cycloalkenylalkyl group as defined above in the present invention. The term "carboxylcycloalkenylalkenyl" refers to a carboxyl group (-COOH) attached to the cycloalkenyl ring portion of a cycloalkenylalkenyl group as defined above in the present invention. The term "carboxylcycloalkenylalkyl" refers to a carboxyl group (-COOH) attached to the cycloalkenyl ring portion of a cycloalkenylalkyl group as defined above in the present invention. The term "alkoxy" includes straight-chain or branched-chain terminal alkyl groups attached to a bonded oxygen atom. Typical alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, tert-buzoxy and the like. The term "haloalkoxy" refers to a substituted alkoxy group with one or more halo groups, for example chloromethoxy, trifluoromethoxy, difluoromethoxy, perfluoroisobutoxy and the like. The term "alkoxyalkoxyalkyl" refers to an alkyl group substituted with an alkoxy moiety which in turn is substituted with a second alkoxy moiety, for example, mexyloxymethoxymethyl, isopropoxymethyloxy, and the like. The term "alkylthio" includes straight or branched chain alkyl groups attached to a linking sulfur atom, for example methylthio. The term "haloalkylium" refers to a substituted alkylthio group with one or more halo groups, for example, trifluoromethylium. The term "alkoxyalkyl" refers to an alkyl group substituted with an alkoxy group, for example, sopropoxymethyl. The term "alkoxyalkenyl" refers to an alkenyl group substituted with an alkoxy group, for example 3-mefoxyallyl. The term "alkoxyalkynyl" refers to an alkynyl group substituted with an alkoxy group, for example 3-methoxypropargyl. The term "alkoxycarbonylalkyl" refers to a straight or branched chain alkyl substituted with an alkoxycarbonyl, for example, eioxycarbonylmethyl, 2- (methoxycarbonyl) propyl and the like. The term "alkoxycarbonylalkenyl" refers to a straight or branched chain alkenyl as defined above in the present invention substituted with an alkoxycarbonyl, for example 4- (ethoxycarbonyl) -2-butenyl and the like. The term "alkoxycarbonylalkyl" refers to a straight or branched chain alkynyl as defined above in the present invention substituted with an alkoxycarbonyl, for example 4- (ethoxycarbonyl) -2-bujinyl and the like. The term "haloalkoxyalkyl" refers to a straight or branched chain alkyl as defined above in the present invention substituted with a haloalkoxy, for example 2-chloroethoxymethyl, trifluoromethyloxymethyl and the like. The term "haloalkoxyalkenyl" refers to a straight or branched chain alkenyl as defined above in the present invention substituted with a haloalkoxy, for example 4- (chloromeoxy) -2-butenyl and the like. The term "haloalkoxyalkynyl" refers to a straight or branched chain alkynyl as defined above in the present invention substituted with a haloalkoxy, for example 4- (2-fluoroethoxy) -2-butynyl and the like. The term "alkylthioalkyl" refers to a straight or branched chain alkyl as defined above in the present invention substituted with an alkyl group, for example, meilyilyl, 3- (isobuildyl) heptyl, and the like. The term "alkylthioalkenyl" refers to a straight or branched chain alkenyl as defined above in the present invention substituted with an alkylthio group, for example 4- (methylthio) -2-butenyl and the like. The term "alkylthioalkynyl" refers to a straight or branched chain alkynyl as defined above in the present invention susiiluted with an alkyl group, for example 4- (ethyl) -2-buline and the like. The term "haloalkylioalkyl" refers to a straight or branched chain alkyl as defined above in the present invention substituted with a haloalkylthio group, for example 2-chloroethyltiomethyl, trifluoromethylthiometyl and the like. The term "haloalkylioalkenyl" refers to a straight or branched chain alkenyl as defined above in the present invention substituted with a haloalkyl group, for example 4- (chloromethylthio) -2-butenyl and the like. The term "haloalkylthioalkynyl" refers to a straight or branched chain alkynyl as defined above in the present invention substituted with a haloalkylthio group, for example 4- (2-fIuoroethylthio) -2-butynyl and the like. The term "dialkoxyphosphorylalkyl" refers to two straight or branched chain alkoxy groups as defined above in the present invention attached to a pentavalenfe phosphorus atom, which contains an oxo substituent, which in turn is linked to an alkyl, for example diefoxiphosphorylmeryl. The term "oligomer" refers to a low molecular weight polymer, whose average molecular weight number is typically less than about 5000 g / mol, and whose degree of polymerization (average number of monomer units per chain) is greater than one. and typically it is equal to or less than about 50. The compounds disclosed in the present invention contain one or more asymmetric rings and therefore may give rise to diastereomers and optical isomers. The present invention includes all those possible diastereomers as well as their racemic mixtures, their substantially pure resolved enantiomers, all possible geometrical isomers, and pharmaceutically acceptable salts thereof. The aforementioned formula I is shown without a definitive stereochemistry in certain positions. The present invention includes all stereoisomers of formula I and pharmaceutically acceptable salts thereof. In addition, mixtures of stereoisomers as well as the specific isolated stereoisomers are also included. During the course of the synthetic procedures used for the preparation of said compounds, or in the use of the racemization or epimerization methods known to those skilled in the art, the products of said processes may be a mixture of stereoisomers. The invention also encompasses a pharmaceutical composition which is comprised of a compound of formula I in combination with a pharmaceutically acceptable carrier. Preferably the composition is comprised of a pharmaceutically acceptable carrier and a non-toxic therapeutically effective amount of a compound of formula I as described above (or of a pharmaceutically acceptable salt thereof). Furthermore, within this preferred embodiment, the invention encompasses a pharmaceutical composition for disease trafficking by inhibiting kinases, comprising a pharmaceutically acceptable carrier and a non-toxic therapeutically effective amount of the compound of formula I as described above ( or a pharmaceutically acceptable salt thereof). The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids. When the compound of the present invention is acid, its corresponding salt can be conveniently prepared from non-toxic pharmaceutically acceptable bases, including inorganic bases and organic bases. Salts derived from said inorganic bases include aluminum, ammonium, calcium, copper (cupric and cuprous), ferric, ferrous, lithium, magnesium, manganese (manganese and manganese), potassium, sodium, zinc and the like salts. Particularly preferred are the ammonium, calcium, magnesium, potassium and sodium salts. Salts derived from pharmaceutically acceptable non-toxic organic bases include salts of primary, secondary, and tertiary amines, as well as cyclic amines and substituted amines, such as amines which are naturally occurring and syntalyzed. You will hear non-toxic pharmaceutically acceptable organic bases from which the salts can be formed include ion exchange resins such as, for example, arginine, betaine, caffeine, choline, N \ N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, -dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine , tromethamine and the like. When the compound of the present invention is basic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic acids., including inorganic and organic acids. Such acids include, for example, acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanolsulfonic, formic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methane-sulphonic, mucic, nitric, pam, pantothenic , phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid and the like. Preferred are citric, hydrobromic, formic, hydrochloric, maleic, phosphoric, sulfuric and tartaric acids. Particularly preferred are formic and hydrochloric acids. The pharmaceutical compositions of the present invention comprise a compound represented by the formula I (or a pharmaceutically acceptable salt thereof) as an active ingredient, a pharmaceutically acceptable carrier and optionally other ingredients or therapeutic adjuvants. The compositions include compositions suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and in vitro) administration, although the most appropriate in any given case will depend on the particular host, and the nature and severity of the conditions for which the active ingredient is administered. The pharmaceutical compositions can be conveniently presented in unit dosage form and can be prepared by any of the methods well known in the pharmacy art. In practice, the compounds represented by the formula I, or a prodrug, or a metabolite, or by pharmaceutically acceptable salts thereof, of this invention can be combined as the active ingredient in an intimate mixture with a pharmaceutical carrier in accordance with conventional techniques for the formation of pharmaceutical compounds. The vehicle can take a wide variety of forms depending on the form of preparation desired for administration, for example, oral or parenteral (including intravenous). Therefore, the pharmaceutical compositions of the present invention can be presented as discrete units suitable for oral administration such as capsules, seals or tablets each of which contained a predetermined amount of the active ingredient. In addition, the compositions can be presented as a powder, as granules, as a solution, as a suspension in an aqueous liquid, as a non-aqueous liquid, as an emulsion of oil-in-water, or as a water-in-water emulsion. -aceife. In addition to the above-mentioned common dosage forms mentioned above, the compound represented by formula I, or a pharmaceutically acceptable salt thereof, can also be administered by controlled release means and / or devices for administration. The compositions can be prepared by any of the pharmacy methods. In general, said methods include a step of bringing the active ingredient into association with the vehicle that constitutes one or more necessary ingredients. In general, the compositions are prepared by uniform and intimate mixing of the active ingredient with liquid carriers or finely divided solid carriers or both. The product can be conveniently given a shape towards the desired presentation. Therefore, the pharmaceutical compositions of this invention can include a pharmaceutically acceptable carrier and a compound, or a pharmaceutically acceptable salt, of formula I. The compounds of formula I, or pharmaceutically acceptable salts thereof, can be included in pharmaceutical compositions in combination with one or more different therapeutically active compounds. The pharmaceutical carrier employed can be, for example, a solid, liquid, or gas. Examples of solid carriers include lactose, earth alba, sucrose, talc, gelafine, agar, pecíina, acacia, magnesium stearate, and stearic acid. Examples of liquid vehicles are sugar syrup, peanut oil, olive oil, and water. Examples of gaseous vehicles include carbon dioxide and nitrogen. In the preparation of the compositions for oral dosage form, any convenient pharmaceutical medium can be employed. For example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, and the like can be used to form oral liquid preparations such as suspensions, elixirs and solutions.; while vehicles such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, dispersing agents, and the like can be used to form oral solid preparations such as powders, capsules and tablets. Due to their ease of administration, tablets and capsules are the preferred oral dosage units which are used as solid pharmaceutical carriers. Optionally, the tablets can be reversed by standard aqueous or non-aqueous techniques. A tablet containing the composition of this invention can be prepared by compression or molding, optionally with one or more accessory ingredients or adjuvants. Compressed tablets can be prepared by compression, in a suitable machine, of the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active agent or dispersing agent. The molded tablets can be made by molding in a suitable machine, a mixture of the wetted powder compound with inert liquid diluent. The tablet preferably contains from about 0.05 mg to about 5 g of the active ingredient and each seal or capsule preferably contains from about 0.05 mg to about 5 g of the active ingredient. For example, a formulation intended for oral administration to humans may contain from about 0.5 mg to about 5 g of the active agent, compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 95 percent. of the total composition. The unit dosage forms will generally contain from about 1 mg to about 2 g of the active ingredient, typically 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg, or 1000 mg . The pharmaceutical compositions of the present invention suitable for parenteral administration can be prepared as solutions or suspensions of the active compounds in water. A suitable surfactant agent, such as, for example, hydroxypropylcellulose, may be included. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. In addition, a preservative may be included to prevent detrimenal growth of microorganisms. The pharmaceutical compositions of the present invention suitable for injectable use include sterile aqueous solutions or dispersions. In addition, the compositions may be in the form of sterile powders for the extemporaneous preparation of said sterile injectable solutions or dispersions. In all cases, the final injectable form must be sterile and the ease of passage through the syringe must be effectively fluid. The pharmaceutical compositions must be stable under the conditions of processing and storage; therefore, they should preferably be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier may be solvent or dispersion medium containing, for example, water, ethanol, polyol (eg, glycerol, propylene glycol and liquid polyethylene glycol), vegetable oils, and suitable mixtures thereof. The pharmaceutical compositions of the present invention may be in a form suitable for topical use such as, for example, an aerosol, cream, ointment, lotion, fine powder, or the like. In addition, the compositions may be in a form suitable for use in transdermal devices. These formulations can be prepared, using a compound represented by formula I of this invention, or by a pharmaceutically acceptable salt thereof, via conventional methods of processing. As an example, a cream or ointment is prepared by mixing the hydrophilic material and water, together with from about 5% by weight to about 10% by weight of the compound, to produce a cream or ointment having a desired consistency. The pharmaceutical compositions of this invention may be in a form suitable for rectal administration wherein the carrier is a solid. It is preferable that the mixture forms unit dose suppositories. Suitable carriers include cocoa butter and other materials commonly used in the art. The suppositories can be conveniently formed by the initial mixing of the composition with the softened or molten vehicle (s) followed by cooling and molding in molds.

In addition to the aforementioned carrier ingredients, the aforementioned pharmaceutical formulations described above may include, as appropriate, one or more additional vehicle ingredients, such as diluents, pH regulators, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives. (including amphi- oxidants) and the like. In addition, other adjuvants may be included to render the formulation isotonic with the blood of the intended recipient. Compositions containing a compound described by formula I, or pharmaceutically acceptable salts thereof, can also be prepared in powder or in a concentrated liquid form. Generally, dose levels are of the order of about 0.01 mg / kg to about 150 mg / kg of body weight per day are useful in the aforementioned conditions, or alternatively from about 0.5 mg to about 7 g per patient per day. For example, inflammation, cancer, allergy / asthma, diseases and conditions of the immune system, diseases and conditions of the central nervous system (CNS), cardiovascular disease, dermatology, and angiogenesis can effectively be treated by administering approximately 0.01 to 50 mg of the compound per kilogram of body weight per day, or alternatively from about 0.5 mg to about 3.5 g per patient per day. However, it is understood that the specific dose level for any particular patient will depend on a variety of factors including age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, combination of drugs and the severity of the particular disease that undergoes therapy. The compounds described in the present invention contain one or more asymmetric centers and can therefore give rise to diastereomers and optical isomers. The present invention includes all possible diastereomers as well as their racemic mixtures, their substantially pure enantiomers solved, all possible geometrical isomers, and pharmaceutically acceptable salts thereof. The aforementioned formula I is shown without a definitive stereochemistry in certain positions. The present invention includes all stereoisomers of formula I and pharmaceutically acceptable salts thereof. In addition, mixtures of stereoisomers as well as the specific isolated stereoisomers are also included. During the course of the synthetic procedures used to prepare said compounds, or in the use of racemization or epimerization methods known to those skilled in the art, the products of said processes may be a mixture of stereoisomers. The invention also encompasses a pharmaceutical composition comprising a compound of formula I in combination with a pharmaceutically acceptable carrier.

Preferably the composition is comprised of a pharmaceutically acceptable carrier and a therapeutically effective non-toxic amount of a compound of Formula I as described above, or of a pharmaceutically acceptable salt thereof. Furthermore, within this preferred embodiment, the invention encompasses a pharmaceutical composition for the treatment of the disease by the inhibition of the tyrosine kinase enzymes, resulting in cell proliferation, growth, differentiation, metabolism, cell cycle events, apoptosis, motility, transcription , phosphorylation, derivation and other signaling processes, comprising a pharmaceutically acceptable carrier and a therapeutically less effective non-toxic amount of a compound of formula I as described above (or a pharmaceutically acceptable salt thereof). The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids. When the compound of the present invention is acid, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic bases, including inorganic bases and organic bases. Salts derived from said inorganic bases include aluminum, ammonium, calcium, copper or (manganese and manganese), potassium, sodium, zinc and the like salts. Particularly preferred are the ammonium, calcium, magnesium, potassium and sodium salts. Salts derived from pharmaceutically acceptable non-toxic organic bases include salts of primary, secondary, and tertiary amines, as well as cyclic amines and substituted amines, such as amines which are naturally occurring and synleized. Other non-toxic, pharmaceutically acceptable organic bases from which salts can be formed include ion exchange resins such as, for example, arginine, betaine, caffeine, choline, N ', N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol. , 2-dimethylaminoebenol, eiolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, megluclucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, trieylamine, trimethylamine , tripropylamine, tromethamine and the like. When the compound of the present invention is basic, its corresponding salt can conveniently be prepared from non-toxic pharmaceutically acceptable acids, including inorganic and organic acids. Such acids include, for example, acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanolsulfonic, formic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanolsulfonic, mucic, niric, pam, panotenic. , phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid and the like. Preferred are citric, hydrobromic, formic, hydrochloric, maleic, phosphoric, sulfuric and tartaric acids. The pharmaceutical compositions of the present invention comprise a compound represented by formula 1, or a pharmaceutically acceptable salt thereof, as an active ingredient, a pharmaceutically acceptable carrier and optionally other ingredients or adjuvants. The compositions include compositions suitable for oral, partial, topical, and parenteral administration (including subcutaneous, intramuscular, and intravenous), although the most suitable route in any given case will depend on the particular host, and the nature and severity of the conditions for which the active ingredient is administered. The pharmaceutical compositions can conveniently be presented in unit dosage form and can be prepared by any of the methods well known in the art of pharmacy. In practice, the compounds represented by the formula I, or a prodrug, or a metabolite, or by pharmaceutically acceptable salts thereof, of this invention can be combined as the active ingredient in an intimate mixture with a pharmaceutical carrier in accordance with conventional techniques for the formation of pharmaceutical compounds. The vehicle can take a wide variety of forms depending on the form of preparation desired for administration, for example, oral or parenteral (including intravenous). Therefore, the pharmaceutical compositions of the present invention can be presented as discrete units suitable for oral administration such as capsules, seals or tablets each of which contained a predetermined amount of the active ingredient. In addition, the compositions may be presented as a powder, as granules, as a solution, as a suspension in an aqueous liquid, as a non-aqueous liquid, as an emulsion of oil-in-water, or as a water-in-water emulsion. -oil. In addition to the common dosage forms stated above mentioned, the compound represented by the formula I, or by a pharmaceutically acceptable salt thereof, can also be administered by controlled release means and / or devices for administration. The compositions can be prepared by any of the pharmacy methods, in general, said methods include a step of bringing the active ingredient into association with the vehicle which constitutes one or more necessary ingredients. In general, the compositions are prepared by the uniform and intimate mixture of the active ingredient with liquid carriers or finely divided solid carriers or both. The product can be conveniently given a shape towards the desired presentation. Therefore, the pharmaceutical compositions of this invention can include a pharmaceutically acceptable carrier and a compound, or a pharmaceutically acceptable salt, of formula I. The compounds of formula I, or pharmaceutically acceptable salts thereof, can be included in pharmaceutical compositions in combination with one or more different active ferapéuíicameie compounds. The pharmaceutical carrier employed can be, for example, a solid, liquid, or gas. Examples of solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid. Examples of liquid vehicles are sugar syrup, peanut oil, olive oil, and water. Examples of gaseous vehicles include carbon dioxide and nitrogen. In the preparation of the compositions for oral dosage form, any convenient pharmaceutical medium can be employed. For example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, and the like can be used to form oral liquid preparations such as suspensions, elixirs and solutions.; while vehicles such as starches, sugars, microcrystalline cellulose, diluenties, granulating agents, lubricants, binders, dispersing agents, and the like can be used to form solid oral oral preparations such as powders, capsules and blends. Because of their ease of administration, tablets and capsules are the preferred oral dosage units which are used as solid pharmaceutical carriers. Optionally, the tablets can be reversed by standard aqueous or non-aqueous techniques. A tablet containing the composition of this invention can be prepared by compression or molding, optionally with one or more accessory ingredients or adjuvants. The compressed variables can be prepared by compressing, in a suitable machine, the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active agent or agent for dispersion. The molded parts can be made by molding in a suitable machine, a mixture of the wetted powder compound with inert liquid diluent. The tablet preferably contains from about 0.05 mg to about 5 g of the active ingredient and each seal or capsule preferably contains from about 0.05 mg to about 5 g of the active ingredient. For example, a formulation that is intended for oral administration to humans may contain from about 0.5 mg to about 5 g of the active agent, compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 95 per cent. of the total composition. Unit dosage forms will generally contain between about 1 mg to about 2 g of the active ingredient, typically 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg, or 1000 mg . The pharmaceutical compositions of the present invention suitable for parenteral administration can be prepared as solutions or suspensions of the acrylic compounds in water. A suitable surfactant agent such as, for example, hydroxypropylcellulose may be included. The dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. In addition, a preservative may be included to prevent detrimenal growth of microorganisms. The pharmaceutical compositions of the present invention suitable for injectable use include sterile aqueous solutions or dispersions. In addition, the compositions may be in the form of sterile powders for the extemporaneous preparation of said sterile injectable solutions or dispersions. In all cases, the final injectable form must be sterile and the ease of passage through the syringe must be effectively fluid. The pharmaceutical compositions must be stable under the conditions of processing and storage; therefore, they should preferably be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier may be solvent or dispersion medium containing, for example, water, ethanol, polyol (eg, glycerol, propylene glycol and liquid polyethylene glycol), vegetable oils, and suitable mixtures thereof. The pharmaceutical compositions of the present invention may be in a form suitable for topical use such as, for example, an aerosol, cream, ointment, lotion, fine powder, or the like. In addition, the compositions may be in a form suitable for use in transdermal devices. These formulations can be prepared, using a compound represented by formula I of this invention, or by a pharmaceutically acceptable salt thereof, via conventional methods of processing. As an example, a cream or ointment is prepared by mixing the hydrophilic material and water, together with from about 5% by weight to about 10% by weight of the compound, to produce a cream or ointment having a desired consistency. The pharmaceutical compositions of this invention may be in a form suitable for rectal administration wherein the carrier is a solid. It is preferable that the mixture forms unit dose suppositories. Suitable carriers include cocoa butter and other materials commonly used in the art. Suppositories can be conveniently formed by the initial mixing of the composition with the softened or molten vehicle (s) followed by cooling and molding in. In addition to the aforementioned carrier ingredients, the aforementioned pharmaceutical formulations described above may include, as appropriate, one or more additional carrier ingredients such as diluents, pH regulators, flavoring agents, aglifinants, surface-active agents, thickeners, lubricants, preservatives (including anli-oxidants) and the like, In addition, other adjuvants may be included to return isotonic to the formulation with the blood of the intended container Compositions containing a compound described by formula I, or pharmaceutically acceptable salts thereof, may also be prepared in powder or in a concentrated liquid form. they are of the order of approximately 0.01 mg / kg to about 150 mg / kg of body weight per day are useful in the travail of the aforementioned stated conditions, or alternatively from about 0.5 mg to about 7 g per patient per day. For example, inflammation, cancer, allergy / asthma, diseases and conditions of the immune system, diseases and conditions of the central nervous system (CNS), cardiovascular disease, dermatology, and angiogenesis can effectively be treated by administration of about 0.01 to 50 mg of the compound per kilogram of body weight per day, or alternatively of approximately 0.5 mg to approximately 3.5 g per patient per day. However, it is understood that the specific dose level for any particular patient will depend on a variety of factors including age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, combination of drugs and the severity of the particular disease that undergoes therapy.

Biological assays The efficiency of the examples of the invention, the compounds of formula I, as inhibitors of the insulin-like growth factor-1 receptor (IGF-1 R) was demonstrated and confirmed by a number of in vitro pharmacological assays. The following tests and their respective methods have been carried out with the compounds according to the invention. The activity possessed by the compounds of formula I can be demonstrated in vivo.

In vitro tyrosine kinase assays The IGF-1 R inhibitor of a compound of formula I can be displayed in a tyrosine kinase assay using a purified GST fusion protein containing the cytoplasmic kinase domain of IGF-1 RX expressed in cells Sf9. This assay is carried out in a final volume of 90 μL containing 1-100 nM (depending on the specific activity) in a 96-well lmmulon-4 plate (Thermo Labsystems) pre-coated with 1 μg / well of the poly substrate -glu-tyr (ratio 4: 1) the pH regulator for kinase (50 mM Hepes, pH 7.4, 125 mM NaCl, 24 mM MgCl 2, 1 mM MnCl 2, 1% glycerol, 200 μM Na3V04, and 2 mM DTT) . The enzymatic reaction was initiated by the addition of ATP to a final concentration of 100 μM. After incubation at ambient temperature for 30 minutes, the plates were washed with saline with regulated pH of 2 mM Imidazole with 0.02% Tween-20. Subsequently the plate was incubated with mouse anti-phosphotyrosine monoclonal antibody pY-20 conjugated with horseradish peroxidase (HRP) (Calbiochem) at 167 ng / mL diluted in phosphate buffered saline (PBS) containing 3% albumin of bovine serum (BSA), 0.5% Tween-20 and 200 μM Na3V04 for 2 hours at room temperature. Following the 3X250 μL washes, bound anti-phosphotyrosine antibody was detected by incubation with 100 μl / well of ABTS (Kirkegaard &Perry Labs, Inc.) for 30 minutes at room temperature. The reaction was stopped by the addition of 100 μl / well, 1% SDS, and the phosphotyrosine-dependent signal was measured by a plate reader at 405/490 nm.

Examples 1-21 showed the inhibition of IGF-1R. Examples 1-21 showed efficiency and activity by inhibiting IGF-1 R in the biochemical assay with IC 50 values less than 15 μM. Preferably the IC5o value is less than 5 μM. More advantageously, the IC50 value is less than 1 μM. Even more advantageously, the IC50 value is less than 200 nM. The most preferred examples are selected towards IGF-1 R.

Cell-based autophosphotyrosine assay NIH 3T3 cells stably expressing full-length human IGF-1 R were seeded at 1 × 10 4 cells / well in 0.1 ml Dulbecco's minimum essential medium (DMEM) supplemented with 10% serum of fetal calf (FCS) per well in 96-well plates. At day 2, the medium is replaced with spent medium (DMEM containing 0.5% FCS) for 2 hours and a compound was diluted in 100% dimethylsulfoxide (DMSO), added to the cells at six final concentrations in duplicates (20 , 6.6, 2. 2, 0.74, 0.25 and 0.082 μM), and incubated at 37 ° C for 2 additional hours.

After the addition of human recombinant IGF-1 (100 ng / mL) at 37 ° C for 15 minutes, then the medium was removed and the cells were washed once with PBS (phosphate buffered saline), then were lysed with cold TGH pH regulator (10% Triton-100, 10% glycerol, 50 mM Hepes [pH 7.4]) supplemented with 150 mM NaCl, 1.5 mM MgCI, 1 mM EDTA and freshly prepared protease and phosphatase inhibitors [10 μg / ml leupepin, 25 μg / ml aproininin, 1 mM phenyl mephyl sulfonyl fluoride (PMSF ), and Na3V04 200 μM]. The cell lysates were transferred to a 96-well microtiter plate (Corning CoSíar # 3922) coated with 10 ng / well of IGF-1 R antibody (Calbiochem, Cal # GR31 L) and incubated at 4 ° C during the entire night. After washing with pH regulator, the plate was incubated with anti-phosphotyrosine monoclonal antibody pY-20 conjugated with horseradish peroxidase (HRP) for 2 hours at room temperature. However, the autophosphotyrosine was detected by adding the substrate for maximum femto sensitivity for super signal ELISA (Pierce) and the chemiluminescence was read on a Wallac Victor 1420 multimark counter. The IC50 curves of the compounds were plotted using an ExcelFit program. The following examples show the efficiency and activity by inhibition of IGF-1 R in the abovementioned test with IC 50 values ranging from 100 μM to approximately 8 nM, with selecfivity on the insulin receptor that is expected to be in a range of 1-15 times. The selectivity is preferably 5 times, even more preferably the selectivity is 10 times. Preferably the IC50 value is less than 5 μM. More advantageously, the IC50 value is less than 1 μM. Even more advantageously, the IC or value is less than 200 μM. The autophosphotyrosine assays of the insulin receptor are carried out essentially as described above for the cell-based IGF-1 R assays, but use insulin (10 nM) as the activating ligand and an insulin receptor antibody as the capture antibody with HepG2 cells that express the endogenous human insulin receptor.

EXPERIMENTAL Schemes 1-13 below, as well as the examples that follow, will show how to synthesize compounds of this invention and use the following abbreviations: Me by methyl, Ef by ethyl, 'Pr or' Pr by isopropyl, n-Bu by n -bufilo, f-Bu by tert-butyl, Ac by acetyl, Ph by phenyl, 4CI-Ph or (4CI) Ph by 4-chlorophenyl, 4Me-Ph or (4Me) Ph by 4-methylphenyl, (p-CH30) Ph for p-methoxyphenyl, (p-N02) Ph for p-nitrophenyl, 4Br-Ph or (4Br) Ph for 4-bromophenyl, 2-CF3-Ph or (2CF3) Ph for 2-trifluoromethylphenyl, DMAP for 4- ( dimethylamino) pyridine, DCC for 1,3-dicyclohexylcarbodiimide, EDC for 1- (3-dimethylaminopropyl) -3-eylcarbodiimide hydrochloride, HOB for 1-hydroxybenzotriazole, HOAt for 1-hydroxy-7-azabenzoazole, CDI for 1, 1'-carbonyldiimidazole, NMO by N-oxide of 4-mephorylmorpholine, DEAD by diethyl azodicarboxylate, DIAD by diisopropyl azodicarboxylate, DBAD by di-ery-buyl azodicarboxylate, HPLC by high-performance flash chromatography, ta by room temperature, min per minute, h per hour, and Bn by benzyl. Accordingly, the following are compounds which are useful as intermediates in the formation of examples for the inhibition of IGF-1R. The compounds of formula I of this invention and the intermediates used in the synthesis of the compounds of this invention were prepared from compliance with the following methods. Method A was used when the compounds of formula I were prepared as shown below in Scheme 1: Step A: SCHEME 1 wherein Q and R are as previously defined for the compound of formula I. In a typical preparation of compounds of formula I, the compound of formula II was reacted with ammonia in a suitable solvent. Suitable solvents for use in the abovementioned processes include, but are not limited to, ethers such as tetrahydrofuran (THF), glyme, and the like; dimethylformamide (DMF); dimethyl sulfoxide (DMSO); acetonitrile; alcoholics such as methanol, ethanol, isopropanol, trifluoroethanol, and the like; and chlorinated solvents such as methylene chloride (CH2Cl2) or chloroform (CHCl3). If desired, the mixtures of these solvents are used, however, the preferred solvent was isopropanol. The aforementioned process was carried out at temperatures of about -78 ° C and about 120 ° C. Preferably, the reaction was carried out between 80 ° C and about 100 ° C. The aforementioned process for producing the compounds of the present invention was carried out at approximately atmospheric pressure although higher or lower pressures are used if desired. Substantially, equimolar amounts of reagents were preferably used but if desired more or less alias amounts are used. The compounds of formula II of scheme 1 were prepared as shown below in scheme 2.

SCHEME 2 wherein Q1 and R1 are as previously defined for the compound of formula I. In a typical preparation of a compound of formula II, an intermediate of formula III was treated with POCI3 in a suitable solvent at a suitable reaction temperature. Solvents suitable for use in the above-mentioned processes include, but are not limited to, ethers such as telrahydrofuran (THF), glime, and the like; and chlorinated solvents such as methylene chloride (CH2Cl2) or chloroform (CHCl3). If desired, mixtures of these solvents are used. The preferred solvent was methylene chloride. The aforementioned process was carried out at temperatures between about -78 ° C and about 120 ° C.

Preferably, the reaction was carried out between 40 ° C and about 70 ° C. The aforementioned process for producing the compounds of the present invention was preferably carried out at about atmospheric pressure although if desired more or less lower pressures are used. Substantially, equimolar amounts of reactants were preferably used although higher or lower amounts are used if desired.

JV 33 The compounds of formula III of scheme 2 were prepared as shown below in scheme 3: SCHEME 3 wherein Q1 and R1 are as previously defined for the compound of formula I and A-OH, alkoxy, or a residual group such as chloro or imidazole. In a typical preparation, a compound of formula III, a compound of formula IV and a compound of formula V were reacted under suitable amide coupling conditions. Suitable conditions include but are not limited to the bringing of compounds of formula IV and V (when Al = OH) with coupling reagents such as DCC or EDC in conjunction with DMAP, HOBt, HOAt and the like. Solvents suitable for use in the abovementioned processes include, but are not limited to, ethers such as teirahydrofuran (THF), glyme, and the like; dimethylformamide (DMF); dimethyl sulfoxide (DMSO); acetonitrile; halogenated solvents such as chloroform or methylene chloride. If desired, mixtures of these solvents are used, however, the preferred solvent was methylene chloride. The aforementioned process was carried out at temperatures ranging from about 0 ° C to about 80 ° C. Preferably, the reaction was carried out between 22 ° C. The aforementioned process for producing the compounds of the present invention preferably was snowed out at about atmospheric pressure although if desired higher or lower pressures are used. Finally, equimolar amounts of reagents were preferably used, although higher or lower amounts are used if desired. Additionally, other reaction conditions suitable for the conversion of RNH2 to CONHR can be found in Larock, R.C. Comprehensive Organic Transformations, 2nd ed .; Wiley and Sons: New York, 1999, pp 1941-1949. The compounds of formula IV of scheme 3 were prepared as shown below in scheme 4: SCHEME 4 wherein Q1 is as previously defined for the compound of formula I and A2 = phthalimide or N3. In a typical preparation, a compound of formula IV, a compound of formula VI is reacted under suitable reaction conditions in a suitable solvent. When A2 = phthalimide, suitable conditions include the preparation of the compound of formula VI with hydrazine in a suitable solvent. Solvents suitable for use in the aforementioned processes include, but are not limited to, ethers such as tetrahydrofuran (THF), glyme, and the like; dimethylformamide (DMF); dimethyl sulfoxide (DMSO); acetonitrile; halogenated solvents such as chloroform or methylene chloride; alcoholic solvents such as melanol and ethanol. If desired, mixtures of these solvents can be used, however the preferred solvent was ethanol. The aforementioned process was carried out at temperatures between about 0 ° C and about 80 ° C. Preferably, the reaction was carried out at 22 ° C. The aforementioned process for producing the compounds of the present invention was preferably carried out at approximately atmospheric pressure, although if desired more or less pressures are used.

Substantially, equimolar amounts of reagents were preferably used although higher or lower amounts are used if desired. The compounds of formula IV of scheme 3 can alternatively be prepared as shown below in scheme 4a: SCHEME 4a rv wherein Q1 is as previously defined for the compound of formula I. In a typical preparation, of a compound of formula IV, an aldehyde Q1-CHO was reacted under suitable reaction conditions in a suitable solvent with lithium hexamethyldisilazide for produce an N-TMS imine Q1-C = N-Si (CH3) 3. Solvents suitable for use in the aforementioned processes include, but are not limited to, ethers such as tetrahydrofuran (THF), glima, and the like. The preferred solvent was THF. The aforementioned process was carried out at temperatures between about -78 ° C and about 20 ° C. The preferred temperature was about 0 ° C. Subsequently, the imine Q1-C = N-Si (CH3) 3 thus obtained was cooled to approximately -78 ° C and was chased with a lithiated 2-chloropyrazine under suitable reaction conditions in a suitable solvent to produce a compound of formula IV. The lithiated 2-chloropyrazine can be obtained by means of the 2-chloropyrazine treatment with a base such as lithium epifymethylpiperidide (Li-TMP). The methyl tertiary-piperidide can be prepared by the reaction of fetramelylpiperidine with n-butyl-lithium at -78 ° C and warmed to 0 ° C. Suitable solvents for use in the aforementioned processes include, but are not limited to, ethers such as tetrahydrofuran (THF), glyme, and the like. Polar solvents such as hexamethylphosphoramide (HMPA), 1,3-dimethyl-3,4,5,6-tetrahydro-2 (1 H) -pyrimidinone (DMPU), and the like can be added if necessary. If desired, mixtures of these solvents are used, however, the preferred solvent was THF. The above-mentioned process can be carried out at temperatures between about -80 ° C and about 20 ° C. Preferably, the reaction was carried out at -78 ° C to 0 ° C. The aforementioned process for producing the compounds of the present invention was preferably carried out at about atmospheric pressure although higher or lower pressures are used if desired. Substantially, equimolar amounts of reagents were preferably used although higher or lower amounts were used if desired. The compounds of formula VI of scheme 4 were prepared as shown below in scheme 5: SCHEME 5 VK VJ wherein Q1 is as previously defined for the compound of formula I and A2 = phthalimide or N3. In a typical preparation of a compound of formula VI (when A2 = phthalimide), a compound of formula VII was reacted with a phthalimide under Mitsunobu lysic conditions in a suitable solvent in the presence of suitable reagents. Solvents suitable for use in the abovementioned processes include, but are not limited to, ethers such as teirahydrofuran (THF), glyme, and the like; dimethylformamide (DMF); dimethyl sulfoxide (DMSO); acetonitrile (CH3CN); chlorinated solvents such as methylene chloride (CH2Cl2) or chloroform (CHCl3). If desired, mixtures of these solvents are used, however, the preferred solvent was THF. Suitable reactants for use in the aforementioned process include, but are not limited to, triphenylphosphine and the like and an azodicarboxylate (DIAD, DEAD, DBAD). The desired reagents were triphenylphosphine and DIAD. The above-mentioned process can be carried out at temperatures between about -78 ° C and about 100 ° C. Preferably, the reaction was carried out at 22 ° C. The aforementioned process for producing the compounds of the present invention was preferably carried out at about atmospheric pressure although higher or lower pressures are used if desired. Substantially, equimolar amounts of reactants were preferably used although higher or lower amounts may be used if desired. Generally, one equivalent of triphenylphosphine, DIAD and phthalimide was used per equivalent of compound of formula VII. The compounds of formula VII were prepared in accordance with the known procedures (Pie, N .; e., Tetrahedron, 1998, 54, 9701-9710) from aldehydes Q1-CHO. Additionally, the compound of formula VII can be reacted with Ts20, Ms20, Tf20, TsCI, MsCl, or SOCI2 in which the hydroxy group is converted to a residual group such as its tosylates, mesyllapid irides or respective halogens such as chlorine and subsequently they are reacted with an equivalent amine such as NH (Boc) 2, phthalimide, or azide. The conversion of amine equivalents by known methods such as by treatment under acidic conditions (NH: (Boc) 2), with hydrazine (phthalimide) as shown in scheme 4, or with triphenylphosphine / water (azide) will produce the desired amine as shown in scheme 4. Compounds of formula IA (compounds of formula I wherein R1 = Z-CONR2R3) were prepared as shown below in scheme 6: SCHEME 6 wherein Q1, R2, and R3 are as previously defined for the compound of formula I and A3 = hydrogen or alkyl such as methyl or ethyl. In a typical preparation of the compound of formula l-A (compounds of formula I wherein R1 = Z-CONR2R3), when A3 = alkyl and R2 and R3 are both equal to H, the reaction of the compound of formula II-A with ammonia in a suitable solvent gave the compound of formula l-A. Suitable solvents for use in the aforementioned processes include, but are not limited to, ethers such as telrahydrofuran (THF), glyme, and the like; dimethylformamide (DMF); dimethyl sulfoxide (DMSO); acetonitrile; alcoholic substances such as methanol, ethanol, isopropanol, trifluoroethanol, and the like; and chlorinated solvents such as methylene chloride (CH2Cl2) or chloroform (CHCl3). If desired, the mixtures of these solvents are used, however, the preferred solvent was isopropanol. The aforementioned process was carried out at temperatures between about -78 ° C and about 120 ° C. Preferably, the reaction was carried out between 80 ° C and approximately 100 ° C. The aforementioned process for producing the compounds of the present invention was preferably carried out approximately at atmospheric pressure although higher or lower pressures are used if desired. Substantially, equimolar amounts of reagents were preferably used although higher or lower amounts are used if desired. Additionally, in a typical preparation of the compound of formula IA (compounds of formula I wherein R1 = Z-CONR2R3), compound of formula IA (compounds of formula II wherein R1 = Z-C02A3) was reacted with HNR2R3 followed by ammonia in a suitable solvent. When A3 = H, typical coupling procedures are described in Scheme 3 (conversion of C02H to COCÍ via irradiation with SOCI2 or oxalyl chloride followed by reaction with HNR2R3 or tetrahydrofuran of C02H and HNR2R3 with EDC or DCC in conjunction with DMAP , HOBT, or HOAi and the like) were used to produce the conversion of a carboxylic acid to an amide. When A3 = alkyl such as methyl or ethyl, treatment of the ester with AI (NR2R3) resulted in the conversion of C02A3 to CO (NR2R3). Subsequent traction with ammonia produced the compounds of formula l-A. The compounds of formula II-B (compounds of formula II wherein R1 = Z-CH2OH) and l-B (compounds of formula I wherein R1 = Z-CH2OH) were prepared as shown below in scheme 7: SCHEME 7 wherein Q1 is as previously defined for the compound of formula I and A3 = hydrogen or alkyl such as methyl or ethyl. In a typical preparation of the compound of formula lB (compounds of formula I wherein R1 = Z-CH2OH), the compound of formula II-A (compounds of formula II wherein R = Z-C02A3) was borated with was labeled with a suitable reducing agent such as lithium aluminum hydride in a suitable solvent, such as THF to produce the compound of formula II-B (compounds of formula II wherein R1 = Z-CH2OH). Subsequent treatment of the compound of formula II-B (compounds of formula II wherein R1 = Z-CH2OH) with ammonia in a suitable solvent, gave the compound of formula l-B (compounds of formula I wherein R1 = Z-CH2OH). Suitable solvents for use in the aforementioned processes include, but are not limited to, ethers such as teirate id non-break (THF), glyme, and the like; dimethylformamide (DMF); dimethyl sulfoxide (DMSO); Acetonyryl; alcoholic solutions such as meianol, ethanol, sodium propane, trifluoroethanol, and the like; and chlorinated solvents such as methylene chloride (CH2Cl2) or chloroform (CHCl3). If desired, mixtures of these solvents are used. The preferred solvent was isopropanol. The aforementioned process was carried out at temperatures between about -78 ° C and about 120 ° C. Preferably, the reaction was carried out between 80 ° C and about 100 ° C. The aforementioned process for producing the compounds of the present invention was preferably carried out at about atmospheric pressure although higher or lower pressures are used if desired. Substantially, equimolar amounts of reactants were preferably used although higher or lower amounts are used if desired. The compounds of formula II-B (compounds of formula II wherein R1 = Z-CH2OH), ll-C (compounds of formula II wherein R1 = Z-CH2A4), II-D (compounds of formula II wherein R1 = Z-A5 (R2) (R3) d), lB (compounds of formula I wherein R1 = Z-CH OH) and lC (compounds of formula I wherein R1 = Z-A5 (R2) (R3) d) is prepared as shown below in scheme 8: SCHEME 8 wherein Q1, R2, and R3 are as previously defined for the compound of formula I; A4 = suitable residual group such as OTs, OMs, OTf, or halo such as chlorine, bromine, or iodine; d = 0 or 1; and A5 = N, O or S. In a typical preparation of the compound of formula I-C (compounds of formula I wherein R1 = Z-A5 (R2) (R3) d), the hydroxy group of the compound of formula II-B (compounds of formula II wherein R1 = Z-CH2OH) was converted to a residual group suitable, A4, such as Cl or OTs, OMs, or OTf, by reaction with SOCI2 or Ts20, Ms20, or Tf20 to produce the compound of formula II-C (compounds of formula II wherein R1 = Z-CH2A4). The reaction of the compound of formula II-C (compounds of formula II wherein R1 = Z-CH2A4) with HA5 (R2) (R3) d yielded the compound of formula II-D (compounds of formula II wherein R1 = Z- A5 (R2) (R3) d). Subsequent reaction of the compound of formula II-D (compounds of formula II wherein R1 = Z-A5 (R2) (R3)) with ammonia in a suitable solvent such as isopropanol or methanol, produced the compound of formula IC (compounds of Formula I where R1 = Z-A5 (R2) (R3) d). Additionally, the compound of formula II-B (compounds of formula II wherein R1 = Z-CH2OH) was converted to the compound of formula IB (compounds of formula I wherein R1 = Z-CH2OH) as previously described in scheme 7 The additional reaction of the compound of formula lB (compounds of formula I wherein R1 = Z-CH2OH) to the compound of formula IC (compounds of formula I wherein R1 = Z-A5 (R2) (R3)) was following the conditions previously described for the conversion of the compound of formula II-B (compounds of formula II wherein R1 = Z-CH2OH) to the compound of formula II-C (compounds of formula II wherein R1 = Z-CH2A4) and further conversion of the compound of formula II-C (compounds of formula II wherein R1 = Z-CH2A4) to the compound of formula II-D (compounds of formula II wherein R = Z-A5 (R2) (R3) d ) (in the net conversion of OH to A5 (R2) (R3) d). further, the compound of formula II-B (compounds of formula II wherein R1 = Z-CH2OH) can be converted directly to the compound of formula II-D (compound of formula II wherein R1 = Z-A5 (R2) (R3 ) d) by treating the compound of formula II-B with various agents for alkylation or with phenols via the Mitsunobu reaction to produce the compounds of formula II-D (compounds of formula II wherein R1 = Z-A5 (R2) (R3) d) in which A5 = O, d = 0, and R2 = alkyl or aryl. Compounds of formula I C (compounds of formula I wherein R 1 = Z-CH 2 -A 2), I C "(compounds of formula I wherein R 1 = Z-CH 2 -NH 2), and I C" (compounds of formula I wherein R 1 = Z-CH2-N (R2) (R3)), were prepared as shown below in scheme 8a: SCHEME 8a wherein Q1, R2, and R3 are as previously defined for the compound of formula I and A2 = phthalimido. In a typical preparation of compounds of formula IC (compounds of formula I wherein R = Z-CH2-A2), I C "(compounds of formula I wherein R1 = Z-CH2-NH2), and lC" (compounds of formula I wherein R1 = Z-CH2-N (R2) (R3)), the hydroxy group of the compound of formula lB (compounds of formula I wherein R1 = Z-CH2OH) was converted to A2, a phthalimide group, following the procedures as described in scheme 5 for the conversion of the compound of formula VII to the compound of formula VI. Reaction of the compound of formula IC under conditions described in scheme 4 yielded the compound of formula IC "The reaction of the compound of formula IC" with, but is not limited to, various alkylating agents, various aldehydes / ketones under amination conditions reducing, various acylating agents such as acetic anhydride, benzoyl chlorides, or with carboxylic acids in the presence of EDC or DCC with HOBT or HOAT, or with sulfonylating agents such as Ts20 or MeS02CI produced the compounds of formula I-C1". For example, in a typical preparation of the compounds of formula I C "1 (compounds of formula I wherein R 1 = Z-CH 2 -N (R 2) (R 3)), a compound of formula I C" was treated with a suitable acylating agent in the presence of a suitable base in a suitable solvent The solvents suitable for use in the aforementioned processes include, but are not limited to, ethers such as telrahydrofuran (THF), glyme, and the like; and chlorinated solvents such as methylene chloride (CH2Cl2) or chloroform (CHCl3). If desired, the mixtures of these solvents were used, however, the preferred solvent was chloroform. Suitable bases for use in the abovementioned process include, but are not limited to, fryalkylamines such as diisopropylethylamine, triethylamine, or trialkylamines bound to the resin, as PS-DIEA. The preferred base was PS-DIEA. In the case where the suitable acylating agent was acetic anhydride, conversion of the compound of formula I-C "to the compound of formula I-C" where R2 = H and R3 = COCH3 was achieved. The aforementioned process was carried out at temperatures between -78 ° C and about 120 ° C. Preferably, the reaction was carried out between 0 ° C and about 20 ° C. The aforementioned process for producing the compounds of the present invention was preferably carried out at about atmospheric pressure although if desired higher or lower pressures are used. Substantially, equimolar amounts of reactants were preferably used but if desired lower or lower amounts were used. The compounds of formula ID (compounds of formula I wherein R1 = Z2-H and Z2 is a heterocyclyl ring containing a nitrogen atom connected to H) and IE (compounds of formula I wherein R1 = Z2-R2 and Z2 is a heterocyclyl ring containing a nylogen atom connected to R2) were prepared as shown below in scheme 9: SCHEME 9 L-E 61 l-D H I-E R ' wherein Q1 and R2 are as previously defined for the compound of formula I, G1 is C (= 0) A6 or C02A6, and A6 = alkyl, aryl, or aralkyl. In a phytic preparation of the compound of formula IE (compounds of formula I in which R1 = Z2-R2 and Z2 is a heterocyclyl ring containing a nitrogen atom connected to R2), the compound of formula I IE (compounds of formula II in where R1 = Z2-G1 and Z2 is a heterocyclyl ring containing a nitrogen atom connected to G) was treated with suitable reagents capable of deprotecting G1 to H and therefore produced the compound of formula ID (compounds of formula I wherein R1 = Z2-H and Z2 is a heterocyclyl ring containing a halogen atom connected to H). For example, treatment of the compound of formula II-E (compounds of formula II wherein R1 = Z2-G1 and Z2 is a heterocyclyl ring containing a nitrogen atom connected to G) when G1 is equal to C (= 0) CF3 with ammonia in methanol produces the compound of formula ID (compounds of formula I in where R1 = Z2-H and Z2 is a heterocyclyl ring containing a nylrogen atom connected to H). The compound of formula I-D (compounds of formula I wherein R1 = Z2-H and Z2 is a heterocyclyl ring containing a nitrogen atom linked to H) can be subjected to various conditions including but not limited to reductive aminations., alkylations and ar (hetar) ions, and acylations to produce amides, ureas, guanidines, carbamates, thiocarbamates, and nitrogen adducts variablely substituted to produce the net conversion of NH to NR2. The compounds of formula II-G (compounds of formula 11 wherein = Z3-OH), II-H (compounds of formula II wherein R1 = Z3-A5 (R2) (R3) d), I F (compounds of formula I wherein R1 = Z3-OH), and lG (compounds of formula I wherein R1 = Z3-A5 (R2) (R3) d) were prepared as shown below in scheme 10: SCHEME 10 wherein Q1, R2, and R3 are as previously defined for the compound of formula I; d = 0 or 1; and A5 = N, O or S. In a typical preparation of the compound of formula 1-F (compounds of formula I wherein R1 = Z3-OH) and l-G (compounds of formula I where R1 = Z3-A5 (R2) (R3) d), the following transformations occurred: The compound of formula I IF (compounds of formula I wherein R1 = Z3-C = 0) was reduced by treatment with a suitable reducing agent in a suitable solvent, such as sodium borohydride in methanol to produce the compound of formula II-G (compounds of formula II wherein R1 = Z3-OH). The compound of formula II-G (compounds of formula II wherein R1 = Z3-OH) was subjected to ammonia in methanol to yield the compound of formula I-F (compounds of formula I wherein R1 = Z3-OH). Additionally, compounds of formula II-F (compounds of formula I wherein R = Z3-C = 0) can be reacted with various amines under reductive amination conditions (NaBHsCN with HA5 (R2) (R3) d wherein d = 0, A5 = N, and R2 and R3 are as previously described for the compound of formula I) to produce the compounds of formula II-H (compounds of formula II wherein R1 = Z3-A5 (R2) (R3) d) wherein d = 0, A5 = N, and R2 and R3 are as previously described for the compound of formula I. The subsequent reaction of the compounds of formula II-H (compounds of formula II wherein R1 = Z3- A5 (R2) (R3) d wherein d = 0, A5 = N, and R2 and R3 are as previously described for the compound of formula I) with ammonia in methanol yielded the compounds of formula lG (compounds of formula I in where R1 = Z3-A5 (R2) (R3) d). In addition, compounds of formula II-H from ll-G and lG from 1F can be synthesized in accordance with the conditions described in scheme 8 for the transformations of ll-B to ll-D and lB to 1C, respectively. Compounds of formula II-F (compounds of formula II wherein R1 = Z3 = 0) and II-B (compounds of formula II wherein R1 = Z-CH2OH) were prepared as shown below in scheme 11: SCHEME 11 wherein Q1 is as previously defined for the compound of formula I. In a typical preparation of the compound of formula II-F (compounds of formula II wherein R1 = Z3 = 0), the compounds of formula II-J (compounds of formula II wherein R1 = Z3 = CH2) were treated under suitable oxidation conditions to produce the conversion of the methylene moiety exocyclic to its respective ketone (see 3- [1- (3-Benzyloxy-phenyl) -8-chloro-imidazo [1,5-a] pyrazin-3-yl] -cyclobuyenone (compound of formula II-F where Z3 = 3-cyclobutyl and Q1 = Ph- (3-OBn)) in the examples section). Additionally, the compound of formula II-B (compounds of formula II wherein R1 = Z-CH2OH) can be prepared by the reaction of the compounds of formula II-J (compounds of formula II wherein R1 = Z3 = CH2) under suitable hydroboration-oxidation conditions (see. {3- [1- (3-Benzyloxyphenyl) -8-chloro-imidazo [1, 5-a] pyrazin-3-yl] cyclobutyl} methanol in the examples section ). It should be mentioned that the compounds of formula II-B (compounds of formula II in which R1-Z-CH2OH) can be treated under suitable oxidative conditions such as those described in example 65 (a) to produce the compounds of formula II- A (compounds of formula II wherein R1 = Z-C02A3). The compounds of formula 1-H (compounds of formula I wherein R = Z3-OH (CH2OH)), IJ (compounds of formula I wherein R1 = Z3-OH (CH2A4)), and lK (compounds of formula I in where R1 = Z3-OH (CH2A5 (R2) (R3) d), were prepared as shown below in scheme 12: SCHEME 12 wherein Q1, R2, and R3 are as previously defined for the compound of formula 1; A4 = suitable residual group such as OTs, OMs, or OTf; d = 0 or 1; and A5 = N, O or S.

In a typical preparation of the compounds of formula I-H (compounds of formula I wherein R 1 = Z 3 -OH (CH 2 OH)), lJ (compounds of formula I wherein R1 = Z3-OH (CH2A4)) and lK (compounds of formula I wherein R1 = Z3-OH (CH2A5 (R2) (R3) d)), the olefinic exocyclic portion of the compound of formula II-J (compounds of formula II wherein R1 = Z3 = CH2) was reacted with a suitable dihydroxylating agent such as osmium tetraoxide in the presence of NMO in a suitable solvent such as THF to produce the compound of formula II -K (compounds of formula II wherein R1 = Z3-OH (CH2OH)) as a mixture of cis and trans isomers. The compound of formula II-K (compounds of formula II wherein R1 = Z3-OH (CH2OH)) was reacted under ammonolysis conditions in a suitable solvent such as isopropanol in a sealed container under pressure at 110 ° C to produce the composed of formula lH (compounds of formula I wherein R = Z3OH (CH2OH)). The primary hydroxy group of the compound of formula IH (compounds of formula I wherein R1 = Z3-OH (CH2OH)) was converted to a suitable residual group, A4, such as OTs, OMs, or OTf, by reaction with Ts20, Ms20, or Tf20 in the presence of a suitable base such as diisopropylamine or pyridine and solvent such as THF or methylene chloride to produce the compound of formula IJ (compounds of formula I wherein R1 = Z3-OH (CH2A)). The reaction of the compound of formula IJ (compounds of formula I wherein R1 = Z3-OH (CH2A4)) with HA5 (R2) (R3) d in a suitable solvent such as THF or methylene chloride produced the compound of formula IK ( compounds of formula I wherein R1 = Z3-OH (CH2A5 (R2) (R3) d) The compounds of formula IL (compounds of formula I wherein R1 = Z3-OH (G11)) were prepared as shown below in scheme 13: SCHEME 13 II * LY-L wherein Q1 and G1 are as previously defined for the compound of formula I. In a typical preparation of the compounds of formula l-L (compounds of formula I wherein R1 = Z3-OH (G11)), the ketone portion of the compound of formula II-F (compounds of formula II wherein R1 = Z3 = 0) was reacted with a suitable nucleophilic reagent such as MeMgBr or MeLi in a suitable solvent such as THF to produce the compound of formula II-L (compounds of formula II wherein R1 = Z3-OH (G11)) as a mixture of cis and trans isomers. The compound of formula II-L (compounds of formula II wherein R1 = Z3-OH (G11)) was reacted under previously described ammonolysis conditions in a sealed container under pressure at 110 ° C to produce the compound of formula IL ( compounds of formula I wherein R1 = Z3-OH (G11)). It will be appreciated by those skilled in the art that in some situations, a substitution that is identical or having the same reactivity to a functional group which has been modified in one of the aforementioned processes, will have to carry out protection followed by deprotection. to produce the desired product and avoid unwanted side reactions. Alimentarily, other processes described in the present invention may be employed in this invention in order to avoid competition of the functional groups. Examples of suitable protecting groups and methods for their addition and removal can be found in the following reference: "Protecive Groups in Organic Syntheses", TW Green and PGM Wuíz, John Wiley and Sons, 1989. The following examples are intended to be luster and do not limit the scope of the present invention.

CLAR analytical conditions: Unless stated otherwise, all CLAR analyzes were run on a Micromass system with an XTERRA MS C18 5μ 4.6 x 50 mm column and deiection at 254 nm. Table A below lists the mobile phase, flow rate, and pressure.

TABLE A CLAR semipreparative conditions: where indicated as "purified by CLAR Glison", the compounds of interest were purified by a preparative / semipreparative Glaron CLAR workstation with a Fenomenex Luna column 5 μC18 (2) 60 x 21 20MM 5 μ and the Gilson 215 liquid handling instrument (806 manometric module, 811C dynamic mixer, 254 nm detection). Table B lists the gradient, flow rate, time, and pressure.

TABLE B EXAMPLE 1 [1- (3-Benzyloxy-phenyl) -3-cyclobutyl-imidazo [1,5-a] pyrazin-8-ylamine] (compound of formula I wherein R1 = cyclobutyl and Q1 = Ph- (3-OBn)): A methanolic solution (1.0 mL) of 1- (3-benzyloxy-phenyl) -8-chloro-3-cyclobuhyl-imidazo [ 1, 5-a] pyrazine (compound of formula II wherein R 1 = cyclobutyl and Q1 = Ph- (3-OBn)) (47.0 mg, 0.12 mmol) in a sealed tube was charged with 3. 0 mL of 7N NH3 in MeOH and heated at 110 ° C for 48 hours. The reaction was concentrated in vacuo, taken up in CH2CI2 and purified using HPFC with a 2 gm Jones silica gel column (30% EtOAc: Hex) to yield the desired product as an off white solid; 1 H NMR (CDCl 3, 400 MHz) d 1. 99-2.18 (m, 2H), 2.47-2.52 (m, 2H), 2.61-2.66 (m, 2H), 3.81 (q, 1H, J = 8.6 Hz), 5.15 (s, 4H), 7.02-7.05 (m, 2H), 7.10 (d, 1 H, J = 5.0 Hz), 7.24-7.52 (m, 8H); MS (ES) 371.30 (M + 1), 372.31 (M + 2), 373.31 (M + 3). a) 1- (3-Benzyloxy-phenyl) -8-chloro-3-cyclobuyl-imidazo [1, 5a] pyrazine (compound of formula II wherein R1 = cyclobutyl and Q1 = Ph- (3-OBn)): Cyclobutanecarboxylic acid [(3-benzyloxy-phenyl) - (3-chloro-pyrazol-2-yl) -methyl Amide (100.0 mg, 0.25 mmol) was dissolved in POCI3 (0.8 mL) and CH2Ci2 (0.2 mL) and allowed to stir at 45 ° C for 24 hours. The reaction mixture was concentrated in vacuo to a yellow oil, dissolved in EOAc and neutralized with saturated cold NaHC03. The aqueous layer was extracted with EtOAc (3x) and the combined organic layers were dried over Na 2 SO 4, filtered and concentrated in vacuo, to yield the desired product as a yellow gum; 1 H NMR (CDCb, 400 MHz) d 2.18-2.21 (m, 1 H), 2.49-2.53 (m, 2 H), 2.63-2.69 (m, 2 H), 3.82 (q, 1 H, J = 8.5 Hz), 5.14 (s, 2H), 7.03-7.05 (m, 1H), 7.29-7.49 (m, 9H); MS (ES) 390.21 (M + 1), 392.20 (M + 3), 393.21 (M + 4). b) [(3-benzyloxy-phenyl) - (3-chloro-pyrazin-2-yl) -methyl] -amide of the cyclobutanecarboxylic acid (compound of formula III wherein R1 = cyclobutyl and Q1 = Ph- (3-OBn) ): Cyclobutanecarboxylic acid (21.2 mg, 0.2 mmol), EDC (61.0 mg, 0.3) and HOBt (32.5 mg, 0.2 mmol) were dissolved in CH2Cl2 (1.0 mL) and allowed to stir at ambient temperature for 10 min. A solution of CH2Cl2 (1.0 mL) of C- (3-benzyloxy-phenyl) -C- (3-chloro-pyrazin-2-yl) -methylamine (compound of formula IV wherein Q1 = Ph- (3-OBn) ) (69.0 mg, 0.2 mmol) was added to the reaction mixture and allowed to react at room temperature for 24 hours. Purification via HPFC using a Jones silica gel column of 5 g (30% of EOAc: Hex) afforded the desired production as a yellow solid; 1 H NMR (CDCl 3, 400 MHz) d 1.57 (s, 1 H), 1.87-2.13 (m, 1 H), 2.13-2.18 (m, 3 H), 3.06 (q, 1 H, J = 8.5 Hz), 5.05 (s, 2H), 6.54 (d, 1 H, J = 7.9 Hz), 6.86-6.94 (m, 3H), 7.20-7.58 (m, 5H), 8.31 (d, 1 H, J = 2.5 Hz), 8.53 (d, 1 H, J = 2.5 Hz); MS (ES) 408.26 (M + 1), 410.26 (M + 3), 411.27 (M + 4). c) C- (3-Benzyloxy-phenyl) -C- (3-chloro-pyrazin-2-yl) -methylamine (compound of formula IV where Q1 = Ph- (3-OBn)): 2 - [(3-Benzyloxy-phenyl) - (3-chloro-pyrazin-2-yl) -methyl-isoindol-1,3-dione (compound of formula VI where Q1 = Ph- (3-OBn) and A2 = phthalimido) (2.76 g, 6.05 mmol) was dissolved in ElOH (12 mL) and CH2CI2 (4 mL) loaded with N2H4 (0.57 mL, 18.16 millimoles) and allowed to react for 16 hours at room temperature. The white precipitate that formed was filtered and washed with EtOAc. The filtrate and organic washings were concentrated in vacuo, and purified via HPFC using a Jones gel column of 100 g (50% EtOAc: Hex at 5% MeOH: CH 2 Cl 2) to produce the desired product as an oil reddish; 1 H NMR (CDCl 3, 400 MHz) d 5.04 (s, 2 H), 5.52 (s, 1 H), 6.85-6.98 (m, 2 H), 7.21-7.26 (m, 2 H), 7.30-7.41 (m, 5 H) , 8.26 (d, 1 H, J = 2.5 Hz), 8.52 (d, 1 H, J = 2.5 Hz); MS (ES) 326.25 (M + 1), 328.23 (M + 3), 329.24 (M + 4). An alternative preparation of this compound is as follows: To a solution of 3-benzyloxybenzaldehyde (compound of formula Q1-CHO where Q1 = Ph- (3-OBn) (1.00 g, 4.71 mmol) in dry THF (5 mL), cooled by ice / water, LiHMDS (1M solution in THF, 4.8 mL, 4.8 mmol) was added.After 30 minutes at 0 ° C, this solution of (3-Benzyloxybenzylidene) -trimethylsilylamine (compound of formula Q1-C = N-Si (CH3) 3 where Q1 = Ph- (3-OBn) was cooled by CO 2 (s) / acelone to a solution of 2,2,6,6-tephramelylpiperidine (0.90 mL, 0.75 g, 5.3 mmol) ) in dry THF (10 mL), cooled by C02 (s) / aceine, nBuLi (2.5 M in hexanes, 2.2 mL, 5.5 mmol) was added, the cooling bath was replaced with an ice / water bath for 15 minutes. minutes, and then the solution was re-cooled to -78 ° C. After 15 minutes, 2-chloropyrazine (0.39 mL, 0.50 g, 4.4 mmol) was added.The cooled solution of (3-benzyloxybenzylidene) -trimethylsilylamine (cf. previous nte) was transferred into this solution of liiochloropyrazine 2 by cannula 30 minutes later, and the mixture was stirred at -78 ° C for 2.5 hours and at 0 ° C for 0.5 hours. The reaction was quenched by the addition of water and EtOAc. The mixture was filtered through Celite, the layers were separated, the aqueous layer was extracted with EOAc (4x30 mL), and the combined EOAc extracts were washed with water and brine and dried over MgSO4. Unpurified material was adsorbed on a hydromatrix and chromatographed on silica gel [Jones Flashmaster, 50 g / 150 mL cartridge, eluting with hexanes: EtOAc 4: 1 (1-44) 1: 1 (45-64) EOAc (65-97)], producing the white compound as an orange foam. d) 2 - [(3-Benzyloxy-phenyl) - (3-chloro-pyrazin-2-yl) -methyl] -isoindole-1,3-dione (compound of formula VI wherein Q 1 = Ph- (3-OBn ) and A2 = phthalimido): (3-chloro-pyrazin-2-yl) - (3-benzyloxy-phenyl) -methanol (2.00 g, 6.12 mmol), triphenylphosphine (1.80 g, 6.70 mmol), and phthalimide (986 mg, 6.70 mmol) was dissolved in THF (20.0 mL) at ambient temperature. The reaction mixture was charged with DIAD (1.30 mL, 6.70 mmol) dropwise and allowed to react for 24 hours at room temperature (analysis by TLC (20% EtOAc: Hex)). The unpurified product was purified by applying HPFC with a Jones gel column of 100 g (20% EtOAc: Hex) to produce the desired production as a light yellow solid.; 1 H NMR (CDCl 3, 400 MHz) d 5.02 (s, 2 H), 6.41 (brs, 1 H), 6.87-6.97 (m, 3 H), 7.26-7.40 (m, 3 H), 7.72-7.76 (m, 2 H) , 7.83-7.86 (m, 2H), 8.34 (d, 1 H, J = 2.4 Hz), 8.55 (d, 1H, J = 2.4 Hz). e) (3-Chloro-pyrazin-2-yl) - (3-benzyloxy-phenyl) -methanol [compound of formula VII where Q1 = Ph- (3-OBn)]: A THF solution (20 ml) of n -Buü 2M in cyclohexanes was cooled to -78 ° C and charged with 2,2,6,6-tetramethylpperidine (1.8 mL, 10.48 mmol). The reaction vessel was removed from the cooling bath and allowed to warm to 0 ° C for 15 minutes, then cooled back to -78 ° C and charged with 2-chloropyrazine (1.0 g, 8.73 mmol) drop to drop. The reaction was allowed to react for 15 minutes, and was charged with 10.0 mL of THF solution of 3-benzyloxybenzaldehyde (2.0 g, 9.60 mmol) slowly at -78 ° C. The reaction was allowed to react for 2 hours (analysis by TLC (30% EtOAc: Hex)) and was stopped with HCl Concentrate (2.0 mL), and H20 (30.0 mL). The crude product was extracted from the aqueous layer / THF 4x with CH2Cl2. The organic layers were combined and washed with 1x H20, 1x brine, dried over Na2SO and concentrated in vacuo to yield the crude product as a brown oil. Instantaneous resolution chromatography (HPFC) with a Jones silica gel column of 70 g (30% of EOAc: Hex) was applied to produce the desired product as a light yellow solid; 1 H NMR (CDCl 3, 400 MHz) d 5.01 (s, 3 H), 6.00 (s, 2 H), 6.90-6.96 (m, 3 H), 7.23-7.41 (m, 6 H), 8.36 (d, 1 H, J = 2.4 Hz), 8.54 (d, 1 H, J = 2.5 Hz); MS (ES) 327.16 (M + 1), 329.16 (M + 3).

EXAMPLE 2 1- (3-Benzyloxyphenyl) -3-phenyl-imidazole [1,5-a] pyrazin-8-ylamine (compound of formula I wherein R1 = phenyl and Q1 = Ph (3-OBn)) was prepared in accordance with the procedures described for Example 1 mentioned above except for the substitution of 1- (3-benzyloxy-phenyl) -8-chloro-3-cyclobutyl-imidazo [1,5-a] pyrazine (compound of formula II wherein R1 = cyclobutyl and Q 1 = Ph (3-OBn)) with "1- (3-benzyloxy-phenyl) -8-chloro-3-phenylimidazo [1,5-a] pyrazine (compound of formula II wherein R 1 = phenyl and Q = Ph (3-OBn)), white solid, 1H NMR (DMSO-d6, 400 MHz) d 5.12 (s, 2H), 6.12 (bs, 2H), 7.04-7.06 (m, 2H), 7.20 (d, 1 H, J = 7.6 Hz), 7.25-7.55 (m, 10H), 7.70 (d, 1H, J = 4.8 Hz), 7.79 (d, 2H, J = 8.0 Hz). a) 1 - (3-Benzyloxyphenyl) -8-chloro-3-phenylimidazo [1,5-a] pyrazine (compound of formula II wherein R1 = phenyl and Q1 = Ph (3-OBn)) was prepared in accordance with described procedures for 1- (3-benzyloxy-phenyl) -8-chloro-3-cyclobutyl-imidazo [1,5-a] pyrazine (compound of formula II wherein R 1 = cyclobutyl and Q1 = Ph (3-OBn)) mentioned above except for the substitution of [(3-benzyloxy-phenyl) - (3-chloro-pyrazin-2-yl) -methyl] -amide of cyclobutanecarboxylic acid with N - [(3-benzyloxyphenyl) - (3-chloropyrazin-2-yl) methyl] benzamide (compound of formula III wherein R1 = phenyl and Q1 = Ph (3-OBn)); solid yellow, 1H NMR (DMSO-d6, 400 MHz) d 5.12 (s, 2H), 6.98 (ddd, 1 H, J = 1.2, 2.8, 8.2 Hz), 7.21-7.43 (m, 8H), 7.52-7.59 (m, 4H), 7.84-7.87 (m, 2H), 8.37 (d, 1 H, J = 5.2 Hz). b) N - [(3-Benzyloxyphenyl) - (3-chloropyrazin-2-yl) methyl] benzamide (compound of formula III wherein R1 = phenyl and Q1 = Ph- (3-OBn)) was prepared according to the procedures described for the synthesis of [(3-benzyloxy-phenyl) - (3-chloro-pyrazin-2) -cycloalkylcarboxylic acid amide (compound of formula III wherein R1 = cyclobutyl and Q1 = Ph- (3-OBn)) mentioned above except for the substitution of benzoic acid with cyclobutanecarboxylic acid; 1 H NMR (DMSO-d 6, 400 MHz) d 5.02 (s, 2 H), 6.58 (d, 1 H, J = 7.6 Hz), 6.91-6.93 (m, 2 H), 6.99 (s, 1 H), 7.21- 7.49 (m, 9H), 7.85 (d, 2H, J = 7.2 Hz), 8.43 (d, 1 H, J = 2.4 Hz), 8.63 (d, 1 H, J = 2.4 Hz), 9.23 (d, 1 H, J = 7.6 Hz).

EXAMPLE 3 3-Benzyl-1- (3-benzyloxyphenyl) -imidazo [1,5-a] pyrazin-8-ylamine (compound of formula I wherein R 1 = benzyl and Q 1 = Ph- (3-OBn)) was prepared in accordance with the procedures described for the aforementioned Example 1 except for the substitution of 1- (3-benzyloxy-phenyl) -8-chloro-3-cyclobutyl-imidazo [1,5-a] pyrazine (compound of formula II wherein R 1 = cyclobutyl and Q1 = Ph- (3-OBn)) with 3-benzyl-1- (3-benzyloxyphenyl) -8-chloroimidazo [1,5-a] pyrazine (compound of formula II wherein R1 = benzyl and Q1 = Ph (3-OBn)); white solid; 1 H NMR (DMSO-d 6, 400 MHz) d 4.40 (s, 2 H), 5.12 (s, 2 H), 6.08 (bs, 2 H), 7.03 (d, 1 H, J = 4.8 Hz), 7.08 (ddd, 1 H , J = 1.2, 2.8, 8.2 Hz), 7.19-7.49 (m, 13H), 7.57 (d, 1 H, J = 5.2 Hz). a) 3-Benzyl-1- (3-benzyloxyphenyl) -8-chloroimidazo [1,5-a] pyrazine (compound of formula II wherein R1 = benzyl and Q1 = Ph- (3-OBn)) was prepared in accordance with the procedures described by 1- (3-benzyloxy-phenyl) -8-chloro-3-cyclobutyl- imidazo [1, 5-a] p -razine (compound of formula II wherein R1 = cyclobutyl and Q1 = Ph- (3-OBn)) mentioned above except for the substitution of [(3-benzyloxy-phenyl) - ( Cyclobufcarcarboxylic acid 3-chloro-pyrazin-2-yl) -methyl] -amide with N - [(3-benzyloxyphenyl) - (3-chloropyrazin-2-yl-methyl] -2-phenylacetamide (compound of formula III wherein R 1 = benzyl and Q1 = Ph- (3-OBn)), yellow solid, 1 H NMR (DMSO-d6, 400 MHz) d 5.12 (s, 2H), 6.98 (ddd, 1 H, J = 1.2 Hz, 2.8 Hz, 8.2 Hz), 7.21-7.43 (m, 8H), 7.52-7.59 (m, 4H), 7.84-7.87 (m, 2H), 8.37 (d, 1 H, J = 5.2 Hz). b) N - [(3-Benzyloxyphenyl) - (3-chloropyrazin-2-yl-methyl] -2-phenylacetamide (compound of formula III wherein R1 = benzyl and Q1 = Ph- (3-OBn)) is prepared according to the procedures described for the synthesis of [(3-benzyloxy-phenyl) - (3-chloro-pyrazin-2-yl) -methyl-cyclobutanecarboxylic acid amide (compound of formula III wherein R1 = cyclobutyl and Q1 = Ph - (3-OBn)) mentioned above except for the substitution of phenylacetic acid for cyclobufcarcarboxylic acid.

EXAMPLE 4 1 - . 1- (3-Benzyloxyphenyl) -3-naphthalen-1-yl-imidazo [1,5-a] pyrazin-8-ylamine (compound of formula I wherein R 1 = naphthalene-1-yl and Q 1 = Ph- (3-OBn)) was prepared according to the procedures described for the aforementioned Example 1 except for the substitution of 1- (3-benzyloxy-phenyl) -8-chloro-3-cyclobuyl-imidazo [1, 5-a ] pyrazine (compound of formula II wherein R = cyclobutyl and Q1 = Ph- (3-OBn)) with 1- (3-benzyloxy-phenyl) -8-chloro-3-naphthalen-1-yl-imidazo [1, 5-a] pyrazine (compound of formula II wherein R 1 = naphthalen-1-yl and Q 1 = Ph- (3-OBn)); White solid; 1 H NMR (DMSO-d 6, 400 MHz) d 5.20 (s, 2 H), 6.27 (bs, 2 H), 7.05 (d, 1 H, J = 4.8 Hz), 7.13 (m, 1 H), 7.21 (d, 1H, J = 5.2 Hz), 7.33-7.51 (m, 8H), 7.55-7.65 (m, 3H), 7.70-7.72 (m, 1 H), 7.82-7.85 (m, 2H), 8.09 (d, 1 H, J = 7.6 Hz), 8.16 (d, 1 H, J = 8.4 Hz). a) 1 - (3-benzyloxy-phenyl) -8-chloro-3-naphthalen-1-yl-imidazo [1,5-ajpyrazine (compound of formula II wherein R 1 = naphthalen-1-yl and Q 1 = Ph- (3-OBn)) was prepared according to the procedures described for 1- (3-benzyloxy-phenyl) -8-chloro-3-cyclobuyl-imidazo [1,5-aJpyrazine (compound of formula II wherein R1 = cyclobutyl and Q1 = Ph- (3-OBn)) mentioned above except for suspending [(3-benzyloxy-phenyl) - (3-chloro-pyrazin-2-yl) -methyl] -amide of cyclobutanecarboxylic acid with [(3- benzyloxyfenii) - (3-chloropyrazin-2-yl) -methyl] -amide of naphthalene-1-carboxylic acid (compound of formula II wherein R 1 = naphthalen-1-yl and Q 1 = Ph- (3-OBn)); MS (ES) 462.46 (M + 1), 464.46 (M + 3). b) [(3-benzyloxyphenyl) - (3-chloropyrazin-2-yl) -methyl] -amide of naphthalene-1-carboxylic acid (compound of formula II wherein R 1 = naphthalene-1-yl and Q 1 = Ph- ( 3-0Bn)) was prepared according to the procedures described for the synthesis of [(3-benzyloxy-phenyl) - (3-chloro-pyrazin-2-yl) -methyl] -amide of the cyclobutanolcarboxylic acid (compound of formula III in where R1 = cyclobufilo and Q1 = Ph- (3-OBn)) previously mentioned exception by the suslltución of -naphnoic acid for cyclobutanecarboxylic acid; white solid; 1 H NMR (DMSO-de, 400 MHz) d 5.12 (s, 2 H), 6.72 (d, 1 H, J = 7.4 Hz), 6.98 (dd, 1 H, J = 2.4, 8.2 Hz), 7.06 (d, 1 H, J = 7.6 Hz), 7.12 (bs, 1 H), 7.29-7.44 (m, 5H), 7.53- 7.57 (m, 4H), 7.65 (d, 1H, J = 7.0 Hz), 7.97-8.03 (m, 2H), 8.13-8.15 (m, 1H), 8.52 (d, 1 H, J = 2.5 Hz), 8.73 (d, 1 H, J = 2.5 Hz).

EXAMPLE 5 1- (3-benzyloxyphenyl) -3-naphthalen-2-yl-imidazo [1,5-a] pyrazin-8-ylamine 0 (compound of formula I wherein R 1 = naphthalen-2-yl and Q 1 = Ph- ( 3-OBn)) was prepared according to the procedures described by the aforementioned Example 1 except for the suspension of 1- (3-benzyloxy-phenyl) -8-chloro-cyclobutyl-imidazo [1,5-a] pyrazine ( compound of formula II wherein R 1 = cyclobutyl and Q 1 = Ph (3-OBn)) with 1- (3-benzyloxy-phenyl) -8-chloro-3-naphthalen-2-yl-imidazo [1,5-a] pyrazine (compound of formula II wherein R 1 = naphthalen-2-yl and Q 1 = Ph- (3-OBn)); white solid; 1 H NMR (DMSO-d 6; 400 MHz) d 5.18 (s, 2 H), 6.18 (bs, 2 H), 7.11-7.47 (m, 9 H), 7.58-7.61 (m, 2 H), 7.94-8.10 (m, 5 H) ), 8.44 (s, 2H). a) 1 - (3-benzyloxy-phenyl) -8-chloro-3-naphthalen-2-yl-imidazo [1,5-ajpyrazine (compound of formula II wherein R 1 = naphthalene-2-yl and Q 1 = Ph- (3-OBn)) was prepared according to the procedures described for 1- (3-benzyloxy-phenyl) -8-chloro-3-cyclobuyl-imidazo [1,5-a] pyrazine (compound of formula II in where R1 = cyclobutyl and Q1 = Ph- (3-OBn)) mentioned above except by substituting [(3-benzyloxy-phenyl) - (3-chloro-pyrazin-2-yl) -methyl] -amide of the cyclobutanecarboxylic acid with Naphthalene-2-carboxylic acid [(3-benzyl-oxyphenyl) - (3-chloropyrazin-2-yl) -methyl] -amide (compound of formula II wherein R 1 = naphthalene-2-yl and Q 1 = Ph- ( 3-OBn)); MS (ES) 462.49 (M + 1), 464.48 (M + 3). b) [(3-benzyloxyphenyl) - (3-cyoropyrazin-2-yl) -methyl] -amide of naphthalene-2-carboxylic acid (compound of formula II wherein R 1 = naphthalene-2-yl and Q 1 = Ph- ( 3-OBn)) was prepared according to the procedures described for the synthesis of [(3-benzyloxy-phenyl) - (3-chloro-pyrazin-2-yl) -methyl] -amide of the cyclobutanecarboxylic acid (compound of formula III wherein R1 = cyclobuylyl and Q1 = Ph- (3-OBn)) mentioned above except for the substitution of 2-naphthanoic acid for cyclobutanecarboxylic acid; whitish solid, 1 H NMR (DMSO-de, 400 MHz) d 5.12 (s, 2H), 6.70 (d, 1 H, J = 7.5 Hz), 6.89-7.09 (m, 3H), 7.29-7.44 (m, 6H ), 7.60-7.63 (m, 2H), 7.97-8.11 (m, 4H), 8.50 (d, 1 H, J = 2.5 Hz), 8.58 (s, 1 H), 8.72 (d, 1 H, J = 2.5 Hz).

EXAMPLE 6 1- (3-Benzyloxy-phenyl) -3-cyclopenyl-imidazo [1,5-a] pyrazn-8-ylamine (compound of formula I wherein R1 = cyclopenyl and Q1 = Ph- (3-OBn)) was prepared according to the procedures described for Example 1 above except for the suspension of 1- (3-benzyloxy-phenyl) -8-chloro-3-cyclobutyl-imidazo [1,5-a] pyrazine (compound of formula II wherein R1 = cyclobutyl and Q1 = Ph- (3-OBn)) with 1- (3-benzyloxy-phenyl) -8-chloro-3-cyclopentyl-imidazo [1,5-a] pyrazine (compound of formula II wherein R1 = cyclopenyl and Q1 = Ph- (3-OBn)); MS (ES) 385.5 (M + 1). a) 1 - (3-Benzyloxy-phenyl) -8-chloro-3-cyclopentyl-imidazo [1,5-a] pyrazine (compound of formula II wherein R1 = cyclopenyl and Q1 = Ph- (3-OBn)) was prepared according to the procedures described by 1- (3-benzyloxy-phenyl) -8-chloro-3-cyclobutyl-imidazo [1,5-a] pyrazine (compound of formula II wherein R1 = cyclobutyl and Q1 = Ph- (3-OBn)) mentioned above except for the substitution of [(3-benzyloxy-phenyl) - (3-chloro-pyrazin-2-yl) -methyl] -amide of the cyclobutanecarboxylic acid with [(3-benzyloxy- phenyl) - (3-chloro-pyrazin-2-yl) -methyl] -amide of cyclopenancarboxylic acid (compound of formula II wherein R 1 = cyclopentyl and Q 1 = Ph- (3-OBn)); MS (ES) 404.2 (M + 1), 406.2 (M + 3). b) [(3-benzyloxy-phenyl) - (3-chloro-pyrazin-2-yl) -methyl] -amide of the cyclopentanecarboxylic acid (compound of formula II wherein R1 = cyclopentyl and Q1 = Ph- (3-OBn) ) was prepared according to the procedures described for the synthesis of [(3-benzyloxy-phenyl) - (3-chloro-pyrazin-2-yl) -methyl] -amide of the cyclobutanecarboxylic acid (compound of formula III wherein R1 = cyclobutyl and Q1 = Ph- (3-OBn)) mentioned above except for the suspension of the cyclopenianecarboxylic acid by the cyclobutanecarboxylic acid; MS (ES) 422.2 (M + 1), 424.2 (M + 3) EXAMPLE 7 1- (3-benzyloxy-phenyl) -3-cyclohexyl-imidazo [1,5-a] pyrazin-8-ylamine (compound of formula II wherein R1 = cyclohexyl and Q1 = Ph- (3-OBn)) was prepared according to the procedures described for example 1 abovementioned except for the suspension of 1- (3-benzyloxy-phenyl) -8-chloro-3-cyclobutyl-imidazo [1,5-a] pyrazine (compound of formula II wherein R1 = cyclobuyyl and Q1 = Ph- (3-OBn)) with 1- (3-benzyloxy-phenyl) -8-chloro-3-cyclohexyl-imidazo [1,5-a] pyrazine (compound of formula II wherein R1 = cyclohexyl and Q1 = Ph- (3-OBn)); MS (ES) 399.3 (M + 1). a) 1 - (3-Benzyloxy-phenyl) -8-chloro-3-cyclohexyl-imidazo [1,5-a] pyrazine (compound of formula II wherein R1 = cyclohexyl and Q1 = Ph- (3-OBn)) was prepared according to the procedures described by 1- (3-benzyloxy-phenyl) -8-chloro-3-cyclobutyl-imidazo [1, 5-a] pyrazine (compound of formula II wherein R1 = cyclobuylyl and Q1 = Ph- (3-OBn)) mentioned above except by substituting [(3-benzyloxy-phenyl) - (3-chloro-pyrazine) 2-yl) -methyl] amide of the cyclobutanecarboxylic acid with [(3-benzyloxy-phenyl) - (3-chloro-pyrazin-2-yl) -methyl] -amide of the cyclohexylcarboxylic acid (compound of formula II in where R1 cyclohexyl and Q1 = Ph- (3-OBn)); MS (ES) 418.2 (M + 1), 420.2 (M + 3). b) [(3-benzyloxy-phenyl) - (3-cyoro-pyrazin-2-yl) -methyl] -amide of cyclohexanecarboxylic acid (compound of formula II wherein R = cyclohexyl and Q1 = Ph- (3-OBn) ) was prepared according to the procedures described for the synthesis of [(3-benzyloxy-phenyl) - (3-chloro-pyrazin-2-yl) -mef? l] amide of the cyclobutencarboxylic acid (compound of formula III wherein R1 = cyclobutyl and Q1 = Ph- (3-OBn)) mentioned above except for the substitution of cyclohexanecarboxylic acid with cyclobutanecarboxylic acid; MS (ES) 436.2 (M + 1), 438.2 (M + 3) EXAMPLE 8 1- (3-Benzyloxy-phenyl) -3-cycloheptyl-imidazo [1,5-a] pyrazin-8-ylamine (compound of formula I wherein R1 = cycloheptyl and Q1 = Ph- (3-OBn)) was prepared in accordance with the procedures described for the aforementioned Example 1 except for the substitution of 1- (3-benzyloxy-phenyl) -8-chloro-3-cyclobuyl-imidazo [1,5-a] pyrazine (compound of formula II in where R1 = cyclobutyl and Q1 = Ph- (3-OBn)) with 1- (3-benzyloxy-phenyl) -8-chloro-3-cycloheptyl-imidazo [1,5-a] pyrazine (compound of formula II wherein R1 = cycloheptyl and Q1 = Ph- (3-OBn)); MS (ES) 413.3 (M + 1). a) 1 - (3-Benzyloxy-phenyl) -8-cyclo-3-cycloheptyl-imidazo [1,5-a] pyrazine (compound of formula II wherein R 1 = cycloheptyl and Q 1 = Ph- (3-OBn)) was prepared according to the procedures described by 1- (3-benzyloxy-phenyl) -8-chloro-3-cyclobutyl-imidazo [1,5-a] pyrazine (compound of formula II wherein R1 = cyclobutyl and Q1 = Ph - (3-OBn)) mentioned above except for the substitution of [(3-benzyloxy-phenyl) - (3-chloro-pyrazin-2-yl) -methyl] -amide of cyclobutanecarboxylic acid with [(3-benzyloxy-phenyl)] - (3-chloro-pyrazin-2-yl) -methyl] -amide of cycloheptylcarboxylic acid (compound of formula II wherein R 1 cycloheptyl and Q 1 = Ph- (3-OBn)); MS (ES) 432.2 (M + 1), 434.2 (M + 3). b) [(3-benzyloxy-phenyl) - (3-chloro-pyrazin-2-yl) -methyl] -amide of cycloheptanecarboxylic acid (compound of formula II wherein R 1 = cycloheptyl and Q 1 = Ph- (3-OBn) ) was prepared according to the described procedures for the synthesis of [(3-benzyloxy-phenyl) - (3-chloro-pyrazin-2-yl) -methyl] -amide of the cyclobutanecarboxylic acid (compound of formula III wherein R1 = cyclobuyl and Q1 = Ph- (3-OBn)) mentioned above except for the substitution of cycloheplancarboxylic acid for the cyclobutanecarboxylic acid; MS (ES) 450.2 (M + 1), 452.2 (M + 3) EXAMPLE 9 1- (3-Benzyloxy-phenyl) -3- (tetrahydro-furan-3-yl) -imidazo [1,5-a] pyrazin-8-ylamine (compound of formula I wherein R 1 = 1-hydrofuran-3-yl and Q1 = Ph- (3-OBn)) was prepared according to the procedures described for the aforementioned Example 1 except for the substitution of 1- (3-benzyloxy-phenyl) -8-chloro-3-cyclobutyl-imidazo [1 , 5-a] pyrazine (compound of formula II wherein R1 = cyclobutyl and Q1 = Ph- (3-OBn)) with 1- (3-benzyloxy-phenyl) -8-chloro-3- (terahydro-furan-3) -l) -imidazo [1,5-a] pyrazine (compound of formula II wherein R 1 = tetrahydrofuran-3-yl and Q 1 = Ph- (3-OBn)); EM (ES) a) 1- (3-Benzyloxy-phenyl) -8-chloro-3- (tetrahydro-furan-3-yl) -imidazo [1,5-a] pyrazine (compound of formula II wherein R 1 = tetrahydrofuran-3 ilo and Q1 = Ph- (3-OBn)) was prepared according to the procedures described by 1- (3-benzyloxy-phenyl) -8-chloro-3-cyclobutyl-imidazo [1,5-a] pyrazine (compound of formula II wherein R 1 = cyclobutyl and Q 1 = Ph- (3-OBn)) mentioned above except for the substitution of [(3-benzyloxy-phenyl) - (3-cyoro-pyrazin-2-yl) -methyl] amide of cyclobutanecarboxylic acid with tetrahydro-furan-3-carboxylic acid [(3-benzyloxy-phenyl) - (3-chloro-pyrrazin-2-yl) -methyl] -amide (compound of formula II wherein R 1 = telrahydrofuran-3-yl and Q = Ph- (3-OBn)); MS (ES) 406.2 (M + 1), 408.2 (M + 3). b) Tetrahydro-furan-3-carboxylic acid [(3-benzyloxy-phenyl) - (3-chloro-pyrazin-2-yl) -methyl] -amide (compound of formula II wherein R = tetrahydrofuranyl and Q1 = Ph- (3-OBn)) was prepared according to the procedures described for the synthesis of cyclobutanecarboxylic acid [(3-benzyloxy-phenyl) - (3-cyoro-pyrazin-2-yl) -methyl] amide (compound of formula III in where R1 = cyclobutyl and Q1 = Ph- (3-OBn)) above mentioned by the exception of feirahydro-furan-3-carboxylic acid by cyclobutanecarboxylic acid; MS (ES) 424.2 (M + 1), 426.2 (M + 3).

EXAMPLE 10 trans-4- [8-Amino-1- (3-benzyloxy-phenyl) -imidazo [1, 5-a] pyrazin-3-yl] -cidohexancarboxylic acid amide (compound of formula lA wherein Z = cyclohexyl, C ( = 0) NR2R3 = 4-trans-C (= 0) NH2, and Q1 = Ph- (3-OBn)) was prepared as follows: A 0.2 M 2-propanol solution of methyl ester of trans-4- [1] - (3-benzyloxyphenyl) -8-cyoroimidazo [1,5-a] pyrazin-3-yl] cyclohexane carboxylic acid (compound of formula I wherein A = cyclohexyl, C02A3 = 4-trans-C02Me, and Q1 = Ph- (3-0Bn)) (150 mg, 0.32 mmol) in a sealed tube of 15 mL was cooled to -78 ° C and loaded with ammonia for 30 seconds. The reaction was heated at 110 ° C for 4 days, after which time the reaction mixture was charged with EtOAc and saturated NaHCO 3. The EtOAc layer was washed with salted NaHCO 3 (3x) and brine (1x) and the organic layer was dried over Na 2 SO, filtered, and concentrated in vacuo to yield the desired product as an off-white solid. The product was dry-charged and purified by chromatography on silica gel, eluting with 2% MeOH / CH 2 Cl 2 at 5% MeOH / CH 2 Cl 2. The resulting white solid was crystallized with CH2Cl2, CH3CN, and hexanes to yield the title compound as a white powder; 1 H NMR (DMSO-d 6, 400 MHz) d 1.57-1.66 (m, 4H), 1.86-1.88 (m, 2H), 1.98-2.00 (m, 2H), 2.17-2.23 (m, 1 H), 3.07- 3.13 (m, 1 H), 5.17 (s, 1 H), 6.02 (bs, 2H), 6.70 (bs, 2H), 7.03 (d, 1 H, J = 5.2 Hz), 7.07 (ddd, 1 H, J = 0.8, 2.4, 8.4 Hz), 7.18 (d, 1 H, J = 7.6 Hz), 7.21-7.22 (m, 1 H), 7.32-7.37 (m, 1 H), 7.40 (d, 1 H, J = 1.6 Hz), 7.41-7.44 (m, 2H), 7.46 (s, 1H), 7.50 (d, 1 H, J = 1.6 Hz), 7.66 (d, 1H, J = 4.8 Hz); MS (ES) 442.5 (M + 1). a) trans-4- [1 - (3-Benzyloxy-phenyl) -8-chloro-imidazo [1,5-a] pyrazin-3-yl] -cidohexancarboxylic acid methyl (compound of formula II-A wherein Z = cyclohexyl, C02A3 = 4-trans-C02Me, and Q1 = Ph- (3-OBn)) was prepared according to the procedures described by 1- (3-benzyloxy-phenyl) -8-chloro-3-cyclobuyl-imidazo [ 1, 5-a] pyrazine (compound of formula II wherein R1 = cyclobutyl and Q1 = Ph- (3-OBn)) mentioned above except for the substitution of cyclobutanecarboxylic acid [(3-benzyloxy-phenyl) - (3 -chloro-pyrazin-2-yl) -methyl] amide (compound of formula III wherein R1 = cyclobutyl and Q1 = Ph- (3-OBn)) with trans-4-. { [(3-benzyloxy-phenyl) - (3-chloro-pyrazin-2-yl) -methyl] -carbamoyl} - cyclohexanecarboxylic acid methyl ester (compound of formula III wherein R 1 = trans-4-cyclohexane carboxylic acid meilylic ester and Q 1 = Ph- (3-OBn)); MS (ES) 476.2 (M + 1), 478.2 (M + 3). b) frans-4- meitylic acid ester. { [(3-Benzyloxy-phenyl) - (3-chloro-pyrazin-2-yl) -methyl] -carbamoyl} -cyclohexanecarboxylic acid (compound of formula III wherein R1 = trans-4-cyclohexane carboxylic acid methyl ester and Q1 = Ph- (3-OBn)) was prepared according to the procedures described for the synthesis of [(3-benzyloxy- phenyl) - (3-chloro-pyrazin-2-yl) -methyl] -amide of the cyclobutanecarboxylic acid (compound of formula III wherein R1 = cyclobutyl and Q1 = Ph- (3-OBn)) mentioned above except for the monomethyl substitution trans-cyclohexane-1,4-dicarboxylic acid ester by cyclobutanecarboxylic acid; MS (ES) 494.3 (M + 1), 496.3 (M + 3).

EXAMPLE 11 trans-. { 4- [8-Amino-1- (3-benzyloxy-phenyl) -imidazo [1,5-a] pyrazin-3-yl] -cyclohexyl} -methanol (compound of formula lB wherein Z = cyclohexyl and Q1 = Ph- (3-OBn)) was prepared according to the procedures described for the synthesis of 4- [8-amino-1- (3- benzyloxy-phenyl) -imidazo [1,5-a] pyrazin-3-yl] -cyclohexanecarboxylic acid except for the substitution of methyl ester of trans-4- [1- (3-benzyloxyphenyl) -8-chloro-imidazo [1] , 5-a] pyrazin-3-yl-cyclohexane carboxylic acid (compound of formula II-A wherein Z = cyclohexyl, C02A3 = 4-trans-C02Me, and Q1 = Ph- (3-OBn)) with. { 4- [1- (3-benzyloxy-phenyl) -8-chloro-imidazo [1, 5-a] pyrazin-3-yl] -cyclohexyl} -meanol (compound of formula II-B where Z = cyclohexyl and Q1 = Ph- (3-OBn)); 1 H NMR (CDCl 3, 400 MHz) d 1.21 (ddd, 2 H, J = 25.2 Hz, 12.8 Hz, 3.6 Hz), 1.65-1.71 (m, 1 H), 1.91 (ddd, 2 H, J = 29.6 Hz, 13.2 Hz , 3.6 Hz), 2.00-2.05 (m, 2H), 2.12-2.16 (m, 2H), 2.93 (t, 1 H, J = 11.6 Hz, 4.0 Hz), 3.56 (d, 2H, J = 6.0 Hz) , 5.11 (bs, 2H), 5.16 (s, 2H), 7.05 (ddd, 1 H, J = 8.0 Hz, 2.8 Hz, 1.2 Hz), 7.07 (d, 1 H, J = 5.2 Hz), 7.20-7.22 (m, 2H), 7.23-7.24 (m, 2H), 7.31-7.35 (m, 1 H), 7.36-7.41 (m, 2H), 7.42-7.45 (m, 2H); MS (ES) 429.5 (M + 1). a) frans-. { 4- [1 - (3-Benzyloxy-phenyI) -8-chloro-imidazo [1, 5-a] pyrazin-3-yl] -cyclohexyl} -mephanol (compound of formula II-B where Z = cyclohexyl and Q = Ph- (3-OBn)): A 0.2 M THF solution of trans-4- [1- (3-benzyloxyphenyl) -8 methyl ester -chloro-imidazo [1,5-a] pyrazin-3-yl] cyclohexane carboxylic acid (800 mg, 1.68 mmol) was cooled to -78 ° C and loaded with LiAIH4 (63.8 mg, 1.68 mmol) portion by portion; The reaction vessel was removed from the cooling bath at -78 ° C and allowed to warm to ambient temperature. After 2 hours, the reaction mixture was charged with EfOAc, Na2SO'10H2O, and silica gel and concentrated in vacuo to yellow solids. The material was purified by chromatography on silica gel, with EtOAc, to yield the desired product as a yellow solid; MS (ES) 448.2 (M + 1), 450.2 (M + 3).

EXAMPLE 12 cis -3- [8-Amino-1- (3-benzyloxy-phenyl) -imidazo [1,5-a] pyrazin-3-yl] -cyclobutanol (Compound of formula IF wherein Z3 = cis-3- Cyclobuylium and Q1 = Ph- (3-OBn)): 3- [1- (3-Benzyloxy-phenyl) -8-chloro-imidazo [1,5-a] pyrazin-3-yl] -cyclobutanol (compound of formula ll-G wherein Z3 = cis-3-cyclobutyl and Q1 = Ph- (3-OBn)) (84.0 mg, 0.2 mmol) was placed in a sealed tube and charged with 3.0 mL of 7N NH3 in MeOH and heated up to 110 ° C for 60 hours. The reaction was concentrated in vacuo, taken up in CH2CI2 and purified using HPFC with a Jones silica gel column of 5 g (2% MeOH: CH2CI) to produce the desired product as an off white solid; 1 H NMR (CDCl 3, 400 MHz) d 2.45-2.51 (m, 2 H), 2.90-2.97 (m, 2 H), 3.31 (q, 1 H, J = 8.0 Hz), 4.39 (q, 1 H, J = 7.0 Hz), 5.03 (brs, 1 H), 5.15 (s, 2H), 7.03-7.13 (m, 2H), 7.23-7.52 (m, 9H); MS (ES) 387.3 (M + 1), 389.3 (M + 3). a) cis- [1- (3-Benzyloxy-phenyl) -8-chloro-imidazo [1,5-a] pyrazin-3-yl] -cyclobutanol (compound of formula II-G wherein Z3 = cis-3- cyclobutyl and Q1 = Ph- (3-OBn)): A CH2Cl2-methanolic solution (1.0 mL) of 3- [1- (3-benzyloxy-phenyl) -8-chloro-imidazo [1,5-a] pyrazine- 3-yl] -cyclobutanone (compound of formula II-F where Z3 = cis-3-cyclobuyl and Q1 = Ph- (3-OBn)) (80.0 mg, 0.2 mmol) was cooled to 0 ° C and loaded with MP-borohydride (200.0 mg, 2.0 equivalents). The reaction mixture was allowed to warm to room temperature over a period of 24 hours. The reducing agent bound to the resin was filtered and washed with EtOAc. The combined filtrate was concentrated in vacuo to yield the desired production as a light yellow solid; 1 H NMR (CDCl 3, 400 MHz) d 2.61-2.68 (m, 2 H), 2.94-3.01 (m, 2 H), 3.36 (q, 1 H, J = 8.0 Hz), 4.42 (q, 1 H, J = 7.3 Hz), 5.15 (s, 2H), 7.00-7.09 (m, 1 H), 7.30-7.47 (m, 9H), 7.56 (d, 1 H, J = 5.0 Hz); MS (ES) 407.2 (M + 1), 409.2 (M + 3). b) 3- [1 - (3-Benzyloxy-phenyl) -8-chloro-imidazo [1,5-a] pyrazin-3-yl] -cyclobuyenone (compound of formula II-F wherein Z3 = 3-cyclobutyl and Q1 = Ph- (3-OBn)): [3-benzyloxy-phenyl) - (3-chloro-pyrazin-2-yl) -methyl] -amide of 3-oxo-cyclobutanecarboxylic acid (compound of formula III where R1 = 3-cyclobutanone and Q1 = Ph- (3-OBn)) (614.0 mg, 1.5 mmol) was dissolved in POCI3 (8.0 mL) and CH2CI2 (2.0 mL) and allowed to stir at 55 ° C. 24 hours. The reaction mixture was concentrated in vacuo to a yellow solid, dissolved in cold EfOAc and neutralized with cold saturated NaHC03. The aqueous layer was extracted with EtOAc (3x) and the combined organic layers were dried over Na 2 SO, filtered and concentrated in vacuo. Purification via HPFC using a Jones silica gel column of 20 g (50% EtOAc: Hex to 1% MeOH: CH 2 Cl 2) followed by recrystallization from hot EtOH afforded the desired product as a light yellow solid; 1 H NMR (CDCl 3, 400 MHz) d 3.61-3.68 (m, 2 H), 3.86-3.95 (m, 3 H), 5.15 (s, 2 H), 7.00-7.09 (m, 1 H), 7.30-7.47 (m, 9H), 7.61 (d, 1 H, J = 5.0 Hz); MS (ES) 404.2 (M + 1), 406.2 (M + 3). Alternatively, 3- [1- (3-Benzyloxy-phenyl) -8-chloro-imidazo [1,5-a] pyrazin-3-yl] -cyclobutanone can be prepared from 1- (3-benzyloxyphenyl) -8 -chloro-3- (3-methylenecyclobuyl) -imidazo [1, 5-a] pyrazine (Example 44b) as follows: To a solution of 1- (3-benzyloxyphenyl) -8-chloro-3- (3-methylenecyclobutyl) -imidazo [1,5-a] pyrazine (100 mg, 0.25 mmol) in THF (3 mL) and water (1 mL) was added NMO (0.1 mL, 0.5 mmol, 50% aqueous solution) and K20s04? 20 (5 mg, 0.013 mmol). The resulting mixture was stirred at room temperature overnight. The CCF showed that the reaction was complete. The reaction was quenched with Na2SO3 (160 mg, 1.25 mmol), then diluted with EtOAc (40 mL) and water (5 mL), washed with brine (20 mL), and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure to yield 3- [1- (3-benzyloxy-phenyl) -8-chloro-imidazo [1,5-a] pyrazn-3-yl] -1-hydroxymethyl-cyclobutanol as a yellow solid (100 mg). LC-MS (ES, Pos.): M / z 436/438 (3/1) [MH +]. The solution of 3- [1- (3-benzyloxy-phenyl) -8-chloro-imidazo [1,5-a] pyrazin-3-yl] -1-hydroxymethyl-cyclobutanol in THF (3 mL) and water (1 mL) was cooled to 0 ° C and charged with sodium periodate (64 mg, 0.3 mmol). The resulting mixture was slowly warmed to room temperalure in 2 hours. The CCF showed that the reaction had been completed. The mixture was diluted with EOAc (40 mL) and water (5 mL), washed with brine (20 mL), and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure and the crude product was purified by silica gel column chromatography (hexanes: EtOAc = 50:50 - >; -30: 70) to produce the title compound as a yellow solid (70 mg, 70% yield in two steps); LC-MS (ES, Pos.): M / z 404/406 (3/1) [MH +]; 1 H NMR (CDCl 3, 400 MHz) d 3.60-3.67 (m, 2 H), 3.81-3.94 (m, 3 H), 5.14 (s, 2 H), 3.81-3.94 (m, 3 H), 7.06 (m, 1 H) , 7.27-7.47 (m, 9H), 7.59 (d, J = 4.9 Hz, 1 H). c) [3-benzyloxy-phenyl) - 3-oxo-cyclobutanecarboxylic acid [(3-benzyloxy-phenyl) - (3-chloro-p -razin-2-yl) -methyl] -amide (compound of formula III wherein p1 = 3-cyclobuyenone and Q1 = Ph- (3-OBn)): 3-oxo-cyclobutanecarboxylic acid (184.2 mg, 1.8 mmol), EDC (529.1 mg, 2.8 mmol) and HOBi (281.8 mg, 1.8 mmol) were dissolved in CH2Cl2 (18.0 mL) and they were left stirring at room temperature for 10 minutes. A CH2Cl2 solution (1.0 mL) of C- (3-Benzyloxy-phenyl) -C- (3-chloro-pyrazin-2-yl) -methylamine (600.0 mg, 1.8 mmol) was added to the reaction mixture, which it was allowed to stir at room temperature for 24 hours. Purification via HPFC using a Jones gel column of 20 g (30% EtOAc: Hex at 50% EtOAc: Hex) afforded the desired product as a white solid; 1 H NMR (CDCl 3, 400 MHz) d 3.07-3.22 (m, 3 H), 3.42-3.48 (m, 2 H), 5.03 (s, 2 H), 6.55 (d, 1 H, J = 7.8 Hz), 6.89-6.96 (m, 3H), 7.22-7.39 (m, 5H), 8.35 (d, 1 H, J = 2.5 Hz), 8.50 (d, 1 H, J = 2.5 Hz); MS (ES) 422.2 (M + 1), 424.2 (M + 3).

EXAMPLE 13 1- (3-Benzyloxy-phenyl) -3- (1-methyl-piperidin-4-yl) -imidazo [1,5-a] pyrazin-8-ylamine (compound of formula I wherein R1 = 4- N-methylpiperidine and Q1 = Ph- (3-OBn)) was prepared according to the procedures described for the aforementioned Example 1 except for the substitution of 1- (3-benzyloxy-phenyl) -8-chloro-3-cyclobutyl -imidazo [1,5-a] pyrazine (compound of formula II wherein R1 = cyclobutyl and Q1 = Ph- (3-OBn)) with 1- (3-benzyl-phenyl) -8-chloro-3- (1-meityl-pyridin-4-yl) -imidazo [1,5-a] pyrazine (compound of formula II wherein R 1 = 4-N-methylpiperidine and Q = Ph- (3-OBn)); white solid, purified by CLAR Glison to produce the desired product as the formic acid salt as a colorless gum; 1 H NMR (CD 3 OD, 400 MHz) d 2.24-2.27 (m, 4 H), 2.94 (s, 3 H), 3.24 (m, 1 H), 3.55-3.66 (m, 4 H), 5.17 (s, 2 H), 7.05 -7.49 (m, 10H), 7.65 (d, 1 H, J = 5.1 Hz); MS (ES) 414.3 (M + 1). a) 1 - (3-Benzyloxy-phenyl) -8-chloro-3- (1-methyl-piperidin-4-yl) - midazo [1,5-a] pyrazine (compound of formula II wherein R1 = 4 -N-methylpiperidine and Q1 = Ph- (3-OBn)) was prepared according to the procedures described by 1- (3-benzyloxy-phenyl) -8-chloro-3-cyclobutyl-imidazo [1,5-a] pyrazine (compound of formula II where R1 = cyclobutyl and Q1 = Ph- (3-OBn)) mentioned above except for the substitution of [(3-benzyloxy-phenyl) - (3-chloro-pyrazin-2-yl) - methyl] cyclobuylenecarboxylic acid amide with [(3-benzyloxy-phenyl) - (3-cyoro-pyrazin-2-yl) -methyl] -amide of 1-methylethylpiperidine-4-carboxylic acid (compound of formula III wherein R1 = 4-N-metylpiperidine and Q1 = Ph- (3-OBn)); MS (ES) 433.2 (M + 1), 435.2 (M + 3). b) [1- (3-benzyloxy-phenyl) - (3-chloro-pyrazin-2-yl) -methyl] -amide of 1-methyl-piperidin-4-carboxylic acid (compound of formula III wherein R1 = 4 -N-methylpiperidine and Q1 = Ph- (3-OBn)) was prepared in accordance with the procedures described for the synthesis of [(3-benzyloxy-phenyl) - (3-chloro-pyrazin-2-yl) -methyl] cyclobutanecarboxylic acid amide (compound of formula III wherein R1 = cyclobuyl and Q1 = Ph- (3-OBn)) mentioned above by the substitution of 1-meth1-piperidine-4-carboxylic acid for cyclobutanecarboxylic acid; 1 H NMR (CDCl 3, 400 MHz) d 1.25-2.33 (brm, 10 H), 2.95 (brs, 2 H), 5.02 (s, 1 H), 6.50 (d, 1 H, J = 7.8 Hz), 6.87-6.94 ( m, 3H), 7.19-7.38 (m, 5H), 8.33 (d, 1 H, J = 2.5 Hz), 8.50 (d, 1 H, J = 2.5 Hz); MS (ES) 451.2 (M + 1), 453.2 (M + 3).

EXAMPLE 14 cis-4- [8-Amino-1- (3-benzyloxy-phenyl) -imidazo [1,5-a] pyrazin-3-yl] -cyclohexanecarboxylic acid amide (compound of formula IA where Z = cyclohexyl, C (= 0) NR2R3 = 4-cis-C (= 0) NH2, and Q1 = Ph- (3-OBn)) was prepared according to the procedures described for Example 10 except for the substitution of lions -4- [1- (3-benzyloxyphenyl) -8-chloro-imidazo [1,5-a] pyrazn-3-yl] cyclohexane carboxylic acid (compound of formula II-A wherein Z = cyclohexyl, C02A3 = 4 -trans-C02Me, and Q1 = Ph- (3-OBn)) with cis-4- [1- (3-benzyloxyphenyl) -8-chloro-imidazo [1,5-a] pyrazin-3-methyl ester. il] cyclohexane carboxylic (compound of formula II-A wherein Z = cyclohexyl, C02A3 = 4-cis-C02Me, and Q1 = Ph- (3-OBn)); MS (ES) 442.4 (M + 1). a) cis-4- [1- (3-Benzyloxy-phenyl) -8-chloro-imidazo [1,5-a] pyrazin-3-yl] -cyclohexanecarboxylic acid methyl ester (compound of formula II-A where Z = cyclohexyl, C02A3 = 4-cis-C02Me, and Q1 = Ph- (3-OBn)) was prepared according to the procedures described by 1- (3-benzyloxy-phenyl) -8-chloro-3-cyclobulyl- imidazo [1, 5-a] pyrazine (compound of formula II wherein R1 = cyclobutyl and Q1 = Ph- (3-OBn)) mentioned above except for the substitution of [(3-benzyloxy-phenyl) - (3-chloro) Cyclobutanecarboxylic acid (pyrazin-2-yl) -methyl] -amide (compound of formula III wherein R 1 = cyclobuyl and Q 1 = Ph- (3-OBn)) with cis-4-meitylic acid ester. { [(3-benzyloxy-phenyl) - (3-chloro-pyrazin-2-yl) -methyl] -carbamoyl} -cyclohexanecarboxylic acid (compound of formula III wherein R1 = merans ester of rans-4-cyclohexane carboxylic acid and Q1 = Ph- (3-OBn)); MS (ES) 476.2 (M + 1), 478.2 (M + 3). b) cis-4- meitylic acid ester. { [(3-Benzyloxy-phenyl) - (3-chloro-pyrazin-2-yl) -methyl] -carbamoyl} -cyclohexanecarboxylic acid (compound of formula III wherein R1 = cis-4-cyclohexane carboxylic acid methyl ester and Q1 = Ph- (3-OBn)) was prepared in accordance with the procedures described for the synthesis of [(3-benzyloxy- phenyl) - (3-chloro-pyrazin-2-yl) -metliyl] -amide of the cyclobulenecarboxylic acid (compound of formula III wherein R1 = cyclobutyl and Q1 = Ph- (3-OBn)) above mentioned except for the substitution of monomeil cis-cyclohexane-1,4-carboxylic acid ester by cyclobutanecarboxylic acid; MS (ES) 494.3 (M + 1), 496.3 (M + 3).

EXAMPLE 15 cis-. { 4- [8-Amino-1- (3-benzyloxy-phenyl) -imidazo [1,5-a] pyrazin-3-yl] -cyclohexyl-methanol (compound of formula lB wherein Z = cyclohexyl and Q1 = Ph- (3-OBn)) was prepared according to the procedures described for the synthesis of trans-4- [8-amino-1- (3-benzyloxy-phenyl) -imidazo [1,5-a] pyrazine-) amide synthesis. 3-yl] -cyclohexanecarboxylic except for the substitution of cis-4- [1- (3-benzyloxy-phenyl) -8-chloro-imidazo [1,5-a] pyrazin-3-yl] cyclohexane carboxylic acid methyl ester (compound of formula II-A wherein Z = cyclohexyl, C02A3 = 4-cis-C02Me, and Q1 = Ph- (3-OBn)) with. { 4- [1- (3-benzyloxy-phenyl) -8-chloro-imidazo [1,5-a] pyrazn-3-yl] -cyclohexyl} -meanoyl (compound of formula II-B where Z = cyclohexyl and Q1 = Ph- (3-OBn)); MS (ES) 429.2 (M + 1). a) cis-. { 4- [1 - (3-Benzyloxy-phenyl) -8-chloro-imidazo [1, 5-a] pyrazin-3-yl] -cyclohexyl} -melanol (compound of formula II-B wherein Z = cyclohexyl and Q1 = Ph- (3-OBn)) was prepared as described for trans-synthesis. { 4- [1- (3-benzyloxy-phenyl) -8-chloro-imidazo [1, 5-a] pyrazin-3-yl] -cyclohexyl} -mephanol (compound of formula II-B wherein Z = trans-1,4-cyclohexyl and Q1 = Ph- (3-OBn)) except for the substitution of methyl ester of trans-4- [1- (3- benzyloxyphenyl) -8-chloro-imidazo [1, 5-a] pyrazin-3-yl] cyclohexane carboxylic acid ester with cis-4- [1- (3-benzyloxy-phenyl) -8-chloro-imidazo] -methyl ester [1 , 5-a] pyrazin-3-yl] cyclohexane carboxylic acid; MS (ES) 448.2 (M + 1), 450.2 (M + 3). cis-2-. { 4- [8-Amino-1- (3-benzyloxy-phenyl) -imidazo [1,5-a] pyrazin-3-yl] -cyclohexylmethyl} -isoindole-1,3-dione (compound of formula I-C1 wherein Z = cis-1,4-cyclohexyl, A2 = phthalimido and Q1 = Ph- (3-OBn)) was prepared as follows: cis-. { 4- [8-Amino-1- (3-benzyloxy-phenyl) -imidazo [1,5-a] pyrazn-3-yl] -cyclohexyl} -methanol (compound of formula lB where Z = cis-1,4-cyclohexyl and Q1 = Ph- (3-OBn)) (175 mg, 0.41 mmol), phthalimide (72 mg, 0.49 mmol), and triphenylphosphine bound to the resin (PS-Ph3P [Argonaut, 2.33 mmol / g]) (263 mg) was dissolved in 2 mL of THF, evacuated, placed under nitrogen atmosphere and loaded with DIAD (97 μL, 0.49 mmol). After stirring for 16 h, the reaction mixture was filtered through a pipette with a cotton plug, washed with 6X EtOAc, concentrated in vacuo, and purified by silica gel column chromatography (gradient 30). % EOAc / hexanes at 70% ElOAc / hexanes) to yield the desired product as a yellow foamy solid; MS (ES +): m / z 558.5 (M + 1).

EXAMPLE 17 lrans-2-. { 4- [8-Amino-1- (3-benzyloxy-phenyl) -imidazo [1,5-a] pyrazin-3-yl] -cyclohexylmethi} -isoindo I-1, 3-dione (compound of formula IC wherein Z = 4-trans-cyclohexyl, A2 = phthalimido and Q1 = Ph- (3-OBn)) was prepared according to the procedures described in example 16 previously mentioned except for the replacement of cis-. { 4- [8-amino-1- (3-benzyloxy-phenyl) -imidazo [1,5-a] pyrazin-3-yl] -cyclohexyl} -metanol with rans-. { 4- [8-amino-1- (3-benzyloxy-phenyl) -imidazo [1,5- a] plrazin-3-yl] -cyclohexyl} -meanol; MS (ES +): m / z 558.4 [MH +].

EXAMPLE 18 cis -3- (4-Aminomethyl-cyclohexyl) -1- (3-benzyloxy-phenyl) -imidazo [1, 5-a] pyrazin-8-ylamine (compound of formula I C "wherein Z = cis-1, 4 -cyclohexyl and Q1 = Ph- (3-OBn)) was prepared as follows: An ethanolic solution of cis-2- { 4- [8-amino-1 - (3-benzyloxy-phenyl) -imidazo [1, 5-a] pyrazin-3-yl] -cyclohexylmethyl] -isoindole-1,3-dione (compound of formula I C wherein Z = cis-1,4-cyclohexyl, A2 = phthalimide and Q1 = Ph- (3 -OBn)) (490 mg, 0.92 mmol) was charged with an excess of hydrazine (10 μL) and allowed to run at ambient temperature for 16 hours.The solution was filtered through a glass funnel to filter and the solids were filtered through a glass funnel. washed with EtOH (4x) .The filtrate was concentrated in vacuo and the crude product was purified by high pressure flash chromatography (HPFC) (dry loaded, gradient of 2% CH 2 Cl 2 NH 3 ~ 7N in MeOH / CH 2 Cl 2) to produce the desired product as a white foamy solid: 1 H NMR (400 MHz, CDCl 3) d 1.66-1.72 (m, 4H), 1.77-1. 86 (m, 4H), 2.00-2.07 (m, 3H), 2.75 (d, 2H, J = 8.0 Hz), 3.10-3.13 (m, 1 H), 5.10 (bs, 2H), 5.14 (s, 2H) ), 7.00-7.04 (m, 2H), 7.18-7.25 (m, 3H), 7.33-7.46 (m, 6H); MS (ES +): m / z 428.4 [MH +].

EXAMPLE 19 lrans-3- (4-Aminomethyl-cyclohexyl) -1- (3-benzyloxy-phenyl) -imidazo [1, 5-a] pyrazin-8-ylamine (compound of formula I C "wherein Z = trans-1, 4 -cyclohexyl and Q1 = Ph- (3-OBn)) was prepared according to the procedures described for the synthesis of cis-3- (4-aminomeylyl-cyclohexyl) -1- (3-benzyloxy-phenyl) -imidazo [1 , 5-a] pyrazin-8-ylamine (compound of formula I C "wherein Z = cis-1,4-cyclohexyI and Q = Ph- (3-OBn)) mentioned above except for the replacement of cis-2-. { 4- [8-amino-1- (3-benzyloxy-phenyl) -imidazo [1,5-a] pyrazin-3-yl] -cyclohexylmethyl} -isoindole-1, 3-dione (compound of formula I-C wherein Z = cis-1,4-cyclohexyl, A2 = phthalimido and C = Ph- (3-OBn)) with trans-2-. { 4- [8-amino-1- (3-benzyloxy-phenyl) -imidazo [1,5-a] pyrazin-3-yl] -cyclohexylmethyl} -isoindole-1, 3-dione (compound of formula I C "wherein Z = trans-1,4-cyclohexyl, A2 = phthalimide and Q 1 = Ph- (3-OBn)); 1 H NMR (400 MHz, CDCl 3) d 1.13 (ddd, 2H, J = 25.2 Hz, 12.8 Hz, 3.6 Hz), 1.31-1.52 (m, 3H), 1.88 (ddd, 2H, J = 29.6 Hz, 13.2 Hz, 3.6 Hz), 2.00-2.05 (m , 2H), 2.12-2.16 (m, 2H), 2.62 (d, 2H, J = 6.4 Hz), 2.93 (t, 1 H, J = 11.6 Hz, 4.0 Hz), 5.02 (bs, 2H), 5.14 ( s, 2H), 7.01 (ddd, 1 H, J = 8.0 Hz, 2.8 Hz, 1.2 Hz), 7.04 (d, 1 H, J = 5.2 Hz), 7.21-7.22 (m, 2H), 7.23-7.24 ( m, 2H), 7.34-7.36 (m, 1 H), 7.36-7.41 (m, 2H), 7.42-7.45 (m, 2H); MS (ES): 428.5 (M + 1).

EXAMPLE 20 cis-N-. { 4- [8-Amino-1- (3-benzyloxy-phenyl) -imidazo [1,5-a] pyrazin-3-yl] -cyclohexylmethyl} -acelamide (compound of formula I-C "wherein Z = cis-1,4-cyclohexyl, R2 = H, R3 = C (= 0) CH3, and Q1 = Ph- (3-OBn)) was prepared as follows : cis -3- (4-Aminomethyl-cyclohexy () - 1 - (3-benzyloxy-phenyl) -imidazo [1,5-a] pyrazin-8-ylamine (compound of formula I C "where Z = cis-1 , 4-cyclohexyl and Q1 = Ph- (3-OBn)) (10.8 mg, 0.03 mmol) was dissolved in 0.3 mL of chloroform and loaded with PS-DIEA (10 mg, 0.04 mmol) followed by acetic anhydride (2.1 μL , 0.02 millimole) and allowed to stir for 0.5 hours The solution was filtered through a pipette with a cotton plug and the solids were washed with chloroform (4x) .The filtrate was concentrated in vacuo and the crude product was purified. by chromatography on silica gel (2% NH 3 ~ 7N in MeOH / CH 2 Cl 2) to yield the desired product as a white foamy solid: MS (ES) 470.5 (M + 1).

EXAMPLE 21 rans-N-. { 4- [8-Amino-1- (3-benzyloxy-phenyl) -imidazo [1,5-a] pyrazin-3-yl] -cyocohexymethyl} -acefamide (compound of formula IC "where Z = trans-1,4-cyclohexyl, R2 = H, R3 = C (= 0) CH3, and Q1 = Ph- (3-OBn)) was prepared in accordance with procedures described by cis-N-. {4- [8-amino-1- (3-benzyloxy-phenyl) -imidazo [1,5-a] pyrazin-3-yl] -cyclohexylmethyl] -acetam Da (compound of formula l-C1"wherein Z = cis-1,4-cyclohexyl, R2 = H, R3 = C (= 0) CH3, and Q1 = Ph- (3-OBn)) mentioned above except for the replacement of cis-3- (4-aminomethyl-cyclohexyl) -1- (3-benzyloxy-phenyl) -imidazo [1,5-a] pyrazin-8-ylamine (compound of formula IC "where Z = cis- 1,4-cyclohexyl and Q1 = Ph- (3-OBn)) with trans-3- (4-aminomethyl-cyclohexyl) -1- (3-benzyloxy-phenyl) -imidazo [1,5-a] pyrazin-8 -amylamine (compound of formula I C "in which Z = trans-1,4-cyclohexyl and Q 1 = Ph- (3-OBn)); 1 H NMR (400 MHz, CDCl 3) d 1.18 (ddd, 2 H, J = 25.2 Hz, 12.8 Hz, 3.6 Hz), 1.60-1.66 (m, 1 H), 1.85 (ddd, 2H, J = 29.6 Hz, 13.2 Hz , 3.6 Hz), 1.94-1.98 (m, 2H), 2.01 (s, 3H), 2.08- 2.12 (m, 2H), 2.90 (tt, 1 H, J = 11.6 Hz, 4.0 Hz), 3.20 (dd, 2H, J = 6.4 Hz, 6.4 Hz), 5.07 (bs, 2H), 5.14 (s, 2H), 5.49 (m, 1 H), 7.02 (ddd, 1H, J = 8.0 Hz, 2.8 Hz, 1.2 Hz) , 7.04 (d, 1 H, J = 5.2 Hz), 7.19-722 (m, 2H), 7.23-7.24 (m, 2H), 7.31-7.36 (m, 1 H), 7.36-7.41 (m, 2H) , 743-746 (m, 2H); MS (ES) 470.5 (M + 1).

The following examples were synthesized in accordance with the procedures described in Examples 1-22 unless otherwise stated.

EXAMPLE 22 1-B-phenyl-3-yl-3-cyclobutyl-methidazo [1,5-a] pyrazin-8-ylamine: Prepared in accordance with the procedures for 1- (3-benzyloxy-phenyl) -3-cyclobutyl Imidazo [1,5-a] pyrazin-8-ylamine, white solid, MS (ES) 341.38 (M + 1). a) 1-Biphenyl-3-l-8-chloro-3-cyclobutyllimidazo [1,5-a] pyrazine: Prepared according to the procedures for 1- (3-Benzyloxy-phenyl) -8-chloro-3-cyclobuyl-imidazo [1,5-a] pyrazine, yellow solid, MS (ES) 360.36 (M + 1). b) Cyclobufcarcarboxylic acid [biphenyl-3-yl- (3-chloropyrazin-2-yl) -methyl] amide: Prepared in accordance with the procedures for cyclobutanecarboxylic acid [(3-benzyloxy-phenyl) - (3-chloro-pyrazine) 2-yl) -methyl] amide, off-white oil, MS (ES) 378.37 (M + 1). c) C-Biphenyl-3-yl-C- (3-chloropyrazin-2-yl) -methylamine: Prepared in accordance with the procedures for C- (3-benzyloxy-phenyl) -C- (3-chloro- pyrazin-2-yl) -methylamine, orange oil, MS (ES) 296.18 (M + 1), 279. 18 d) 2- [Biphenyl-3-yl- (3-chloropyrazin-2-yl) -methyl] -isoindole-1,3-dione: Prepared according to the procedures for 2 - [(3-Benzyloxy-phenyl) - (3-chloro-pyrazin-2-yl) -methyl] -isoindo-1, 3-dione, orange oil, MS (ES) 426.92 (M + 1). e) Biphenyl-3-yl- (3-chloropyrazin-2-yl) -methanol: Prepared according to the procedures for (3-chloro-pyrazin-2-yl) - (3-benzyloxy-phenyl) -methanol, oil orange, EM (ES) 297.11 (M + 1), 278.13 (M-17). f) Biphenyl-3-carbaldehyde: Prepared from 3-bromo-benzaldehyde and phenylboronic acid using Pd (PPh3) 4, K2C03, DMF: H20 4: 1 (see the detailed description under the general synthesis of the Suzuki analogs in examples 24-26), following the standard procedures for Suzuki coupling as described in the following reference: Strongin, RM; et. to the. Org Lett., 2000, 20, 3201-3204; light anion, 1 H NMR (CDCl 3, 400 MHz) d 7.38-7.51 (m, 3 H), 7.60-7.65 (m, 3 H), 7.87 (dd, 2 H, J = 2.8 Hz, 8.4 Hz), 8.11-8.12 (m , 1 H), 10.0 (s, 1 H); MS (ES) 183.28 (M + 1).

EXAMPLE 23 1- (3-Bromo-phenyl) -3-cyclobuylimidazo [1,5-a] pyrazin-8-ylamine: Prepared according to the procedures for 1- (3-benzyloxy-phenyl) -3-cyclobuyl-imidazo [1 , 5-a] pyrazin-8-ylamine, light pink solids. NMR (CDCl 3, 400 MHz) d 2.02-2.21 (m, 2H), 2.45-2.65 (m, 4H), 3.81 (p, 1 H, J = 8.8 Hz), 5.03 (bs, 2H), 7.07 (d, 1 H, J = 4.8 Hz), 7.13 (d, 1 H, J = 4.8 Hz), 7.33-7.37 (m, 1 H), 7.53 (d, 1 H, J = 7.2 Hz), 7.60 (d, 1 H, J = 7.2 Hz), 7.88 (d, 1 H, J = 1.6 Hz). a) 1 - (3-Bromophenyl) -8-chloro-3-cyclobutylimidazo [1,5-a] pyrazine: Prepared according to the procedures for 1- (3-benzyloxy-phenyl) -8-cyoro-3 -cyclobutyl-imidazo [1,5-a] pyrazine, yellow solid, 1 H NMR (CDCl 3, 400 MHz) d 2.04-2.22 (m, 2H), 2.50-2.67 (m, 4H), 3.84 (p, 1H , J = 8.8 Hz), 7.29-733 (m, 2H), 7.51 (d, 1 H, J = 4.8 Hz), 7.52-7.55 (m, 1 H), 7.61-7.64 (m, 1 H), 7.86 -7.87 (m, 1 H). b) Cyclobutanecarboxylic acid [(3-bromophenyl) - (3-chloropyrazin-2-yl) methyl] amide: Prepared according to the procedures for cyclobutanecarboxylic acid [(3-benzyloxy-phenyl) - (3-chloro-pyrazin-2 -yl) -methyl] amide, white solid, 1 H NMR (CDCl 3, 400 MHz) d 1.83-2.02 (m, 2 H), 2.13-2.29 (m, 4 H), 3.09 (p, 1 H, J = 8.8 Hz) , 6.53 (d, 1 H, J = 8.0 Hz), 7.08 (d, 1 H, J = 8.0 Hz), 7.16-7.20 (m, 1 H), 7.34-7.43 (m, 3H), 7.37 (d, 1 H, J = 2.8 Hz), 8.53 (d, 1 H, J = 2.8 Hz). c) C- (3-Bromophenyl) -C- (3-chloropyrazin-2-yl) -methylamine: Prepared in accordance with the procedures for C- (3-benzyloxy-phenyl) -C- (3-chloro-pyrazine) 2-yl) -methylamine, orange oil, 1 H NMR (CDCl 3, 400 MHz) d 5.54 (s, 1 H), 7.17-7.21 (m, 1 H), 7.31 (d, 1 H, j = 8.0 Hz ), 7.39 (d, 1 H, J = 8.4 Hz), 7.51-7.53 (d, 1 H, J = 8.4 Hz), 8.31 (d, 1 H, J = 2.8 Hz), 8.56 (d, 1 H, J = 2.4 Hz). d) 2 - [(3-Bromophenyl) - (3-chloropyrazin-2-yl) -methyl] -isoindo I-1,3-dione: Prepared according to the procedures for 2 - [(3-benzyloxy-phenyl)] - (3-Chloro-pyrazin-2-yl) -mellyl] -isoindole-1,3-dione, orange-colored oil, 1 H NMR (CDCl 3, 400 MHz) d 6.84 (s, 1 H), 7.47-7.53 (m , 2H), 774-7.86 (m, 6H), 8.37 (dd, 1 H, J = 1.2 Hz, 2.6 Hz), 8.48 (d, 1 H, J = 2.4 Hz). e) (3-Bromophen? l) - (3-chlorop? raz? n-2-? i) -meanol: Prepared according to the procedures for (3-chloro-pyrazin-2-yl) - (3-benzyloxy) phenyl) -methanol, light yellow solid, 1 H NMR (CDCl 3, 400 MHz) d 4.66 (d, 1 H, J = 8.0 Hz), 5.98 (d, 1 H, J = 8.0 Hz), 7.18-7.23 (m, 1 H), 7.29-7.49 (m, 3H), 8.40 (d, 1 H, J = 2.4 Hz), 8.57 (d, 1 H, J = 2.4 Hz).

General synthesis of Suzuki analogs, examples 24-26. A 4: 1 solution of DMF: H20 was purged with N2 for 45 minutes before the reaction. 1- (3-Bromo-phenyl) -3-cyclobutyl-cydazo [1,5-a] p -razn-8-ylamine (1.0 equivalent), the appropriate boronic acid (1.1 equivalents), K2C03 (2.25 equivalents) , and PS-Pd (Ph3) (0.05 equivalents) were processed to a wash paste in sufficient DMF: H20 4: 1 to produce a 0.25 M solution. The reaction mixture was heated at 90 ° C overnight with stirring, it was cooled, diluted with CH2CI2, filtered through Celite, and the resin was washed with additional CH CI. The filtrate was concentrated in vacuo, redissolved in DCM, and purified by chromatography (Jones Flashmaster Personal, 50:50 hexane: 100% EOAc) to produce desired imidazopyrazines, examples 24-26.

EXAMPLE 24 1 - . 1 - (4'-t-Butybiphenyl-3-yl) -3-cyclobutyIimidazo [1, 5a] pyrazin-8-ylamine: light brown solid, 1 H NMR (CDCl 3, 400 MHz) d 1.34 (s, 9 H), 2.02 -2.21 (m, 2H), 2.45-2.68 (m, 4H), 3.83 (p, 1 H, J = 8.8 Hz), 5.18 (bs, 2H), 7.06 (d, 1H, J = 5.2 Hz), 7.13 (d, 1 H, J = 5.2 Hz), 7.50-7.65 (m, 7H), 7.89 (d, 1 H, J = 1.6 Hz).

EXAMPLE 25 3-Cyclobutyl-1- (4, -methylbiphenyl-3-yl) -midazo [1,5-a] pyrraz-8-ylamine: Whitish solid, MS (ES) 355.37 (M + 1).

EXAMPLE 26 3-Cyclobutyl-1- (4'-methoxybiphenyl-3-yl) -imidazo [1,5-a] pyrazin-8-ylamine: White solid, MS (ES) 371.21 (M + 1).

EXAMPLE 27 1- (3-Benzylloxyphenyl) -3-cyclopentylmethylimidazo [1,5-a] pyrazin-8-ylamine: Prepared in accordance with the procedures for 1- (3-benzyloxy-phenyl) -3-cyclobuyl-imidazo [1 , 5-a] p -razin-8-ylamine, light oil, MS (ES) 399.20 (M + 1). a) 1 - (3-Benzyloxyphenyl) -8-chloro-3-cyclopentylmethylimidazo [1,5-Chpyrazine: Prepared according to the procedures for 1- (3-benzyloxy-phenyl) -8-chloro-3-cyclobutyl Imidazo [1,5-a] pyrazine, yellow oil, MS (ES) 418. 37 (M + 1). b) N - [(3-Benzyloxyphenyl) - (3-chloropyrazin-2-yl) -methyl] -2-cyclopenyl-acetamide: Prepared according to the procedures for cyclobutanecarboxylic acid [(3-benzyloxy-phenyl) - (3 -chloro-pyrazin-2-yl) -methyl] amide, white solid, MS (ES) 436.32 (M + 1).

EXAMPLE 28 1- (3-Benzyloxyphenyl) -3-cyclohexylmethylimidazo [1, 5-a] pyrazin-8-ylamine: Prepared according to the procedures for 1- (3-benzyloxy-phenyl) -3-cyclobutyl-imidazo [1, 5 -a] pyrazin-8-alamine, white solid, 1 H NMR (CDCl 3, 400 MHz) d 1.07-1.27 (m, 5H), 1.64-1.73 (m, 5H), 1.83-1.93 (m, 1 H), 2.86 (d , 1 H, J = 6.8 Hz), 5.02 (bs, 2H), 5.15 (s, 2H), 701-7.06 (m, 2H), 7.19 (d, 1 H, J = 2.0 Hz, 4.8 Hz), 7.23 -7.25 (m, 2H), 7.33-7.46 (m, 7H). a) 1 - (3-Benzyloxyphenyl) -8-chloro-3-cyclohexylmethylimidazo [1, 5-ajpyrazine: Prepared according to the procedures for 1- (3-benzyloxy-phenyl) -8-chloro-3-cyclobutyl -imidazo [1,5-a] pyrazine, yellow oil, 1 H NMR (CDCl 3, 400 MHz) d 1.08-1.26 (m, 5H), 1.66-1.73 (m, 5H), 1.85-1.93 (m, 1 H), 2.92 (d, 1 H, J = 7.2 Hz), 5.14 (s, 2H), 7.03 (dd, 1 H, J = 2.0 Hz, 7.8 Hz), 7.29-7.41 (m, 6H), 7.44- 7.46 (m, 2H), 8.32 (d, 1 H, J = 2.0 Hz), 7.59 (d, 1 H, J = 4.8 Hz). b) N - [(3-Benzyloxyphenyl) - (3-chloropyrazin-2-yl) -methyl] -2-cyclohexyl-acetamide: Prepared in accordance with the procedures for [(3-benzyloxy-phenyl) - (3- chloro-pyrazin-2-yl) -methyl] cyclobutanecarboxylic amide, white solid, 1 H NMR (CDCl 3, 400 MHz) d 0.88-0.97 (m, 2H), 1.09-1.29 (m, 3H), 1. 63-1.82 (m, 6H), 2.11 (d, 1 H, J = 7.2 Hz), 5.02 (s, 2H), 6.55 (d, 1 H, J = 7.6 Hz), 6.86-6.94 (m, 3H) , 7.03 (d, 1 H, J = 7.6 Hz), 7.19-7.25 (m, 1 H), 7.30-7.40 (m, 6H), 8.32 (d, 1H, J = 2.0 Hz), 8.49 (d, 1H) , J = 2.0 Hz).

EXAMPLE 29 1- (3-Benzyloxyphenyl) -imidazo [1,5-a] pyrazin-8-ylamine: Prepared according to the procedures for 1- (3-benzyloxy-phenyl) -3-cyclobuyl-imidazo [1,5-a] ] pyrazin-8-ylamine, white solid, 1 H NMR (CDCl 3, 400 MHz) d 5.09 (bs, 2H), 5.15 (s, 2H), 7.05-7.10 (m, 3H), 7.34-7.45 (m, 8H), 8.11 (s, 1 H). a) 1- (3-Benzyloxyphenyl) -8-chloroimidazo [1,5-a] pyrazine: Prepared according to the procedures for 1- (3-benzyloxy-phenyl) -8-chloro-3-cyclobutyl-imidazo [1 , 5-a] pyrazine, yellow oil, MS (ES) 336.06 (M + 1). b) N - [(3-Benzyloxyphenyl) - (3-chloropyrazin-2-yl) -methyl] -formamide: Prepared in accordance with the procedures for cyclobutanecarboxylic acid [(3-benzyloxy-phenyl) - (3-chloro-pyrazin-2-yl) -methyl] amide, white solid, 1 H NMR (CDCl 3, 400 MHz) d 5.03 ( s, 2H), 6.62 (d, 1 H, J = 8.0 Hz), 6.88-6.97 (m, 3H), 7.22-7.24 (m, 1 H), 7.32-7.41 (m, 5H), 8.29 (bs, 1 H), 8.35 (d, 1 H, J = 2.4 Hz), 8.51 (d, 1 H, J = 2.0 Hz).

EXAMPLE 30 1- (3-Benzyloxyphenyl) -3-ylfluoromethylimidazo [1,5-a] p -razin-8-ylamine: Prepared according to the procedures for 1- (3-benzyloxy-phenyl) -3-cyclobutyl-imidazo [1, 5-a] pyrazin-8-yamine, pink solid, 1 H NMR (CDCl 3, 400 MHz) d 5.15 (s, 2 H), 5.25 (bs, 2 H), 7.08-711 (m, 1 H) , 7.23-7.29 (m, 3H), 7.34-7.45 (m, 6H), 7.54 (d, 1 H, J = 4.8 Hz). a) 1 - (3-Benzyloxyphenyl) -8-chloro-3-trifluoromethylimidazo [1,5-a] pyrazine: Prepared according to the procedures for 1- (3-benzyloxy-phenyl) -8-chloro-3 -cyclobutyl-imidazo [1,5-a] pyrazine, yellow oil, 1 H NMR (CDCl 3, 400 MHz) d 5.14 (s, 2 H), 7.08-7.11 (m, 1 H), 7.28-7.46 ( m, 8H), 7.59 (d, 1 H, J = 4.8 Hz), 7.99 (d, 1 H, J = 5.2 Hz). b) N - [(3-Benzyloxyphenyl) - (3-chloropyrazin-2-yl) -methyl] -2,2,2-trifluoroacetamide: Prepared in accordance with the procedures for [(3-benzyloxy-phenyl) - ( 3-chloro-pyrazin-2-yl) -methyl] cyclobutanecarboxylic acid, white solid, 1 H NMR (CDCl 3, 400 MHz) d 5.03 (s, 2H), 6.46 (d, 1 H, J = 7.6 Hz), 6.92- 6.96 (m, 3H), 7.28-7.41 (m, 5H), 8.16 (d, 1 H, J = 6.4 Hz), 8.40 (d, 1 H, J = 2.4 Hz), 8.55 (d, 1 H, J = 2.4 Hz).

EXAMPLE 31 4- [8-Amino-1 - (3-benzyloxyphenyl) -imidazo [1,5-a] pyrazin-3-yl] -benzamide: Prepared according to the procedures for 1- (3-benzyloxy-phenol) -3-Cyclobutyl-imidazo [1, 5-a] pyrazin-8-ylamine, yellow solid, 1 H NMR (DMSO-d 6, 400 MHz) d 5.20 (s, 2 H), 6.23 (bs, 2 H), 7.12 (dd, 1 H, J = 2.4 Hz, 8.2 Hz), 7.16 (d, 1 H, J = 2.4 Hz), 7.27 (d, 1 H, J = 7.6 Hz), 7.32-7.50 (m, 8H), 7.85 (d, 1 H, J = 5.2 Hz), 7.96 (d, 2H, J = 8.8 Hz), 8.07 (d, 2H, J = 8.8 Hz), 8.14 (bs, 1 H). a) 4- [1- (3-Benzyloxyphenyl) -8-chloroimidazo [1, 5-a] pyrazin-3-yl] -benzoic acid methyl ester: Prepared in accordance with the procedures for 1- (3-Benzyloxy) phenyl) -8-cyclo-3-cyclobutyl-imidazo [1,5-ajpyrazine, yellow solid, MS (ES) 469.90 (M + 1). b) N - [(3-Benzyloxyphenyl) - (3-chloropyrazin-2-yl) -methyl] -rephthalamic acid methylester: Prepared in accordance with the procedures for [(3-benzyloxy-phenyl) - (3- chloro-pyrazin-2-yl) -methyl] cyclobutanecarboxylic acid, yellow solid, MS (ES) 490.01 (M + 2).

EXAMPLE 32 3-Cyclobutyl-1-phenylimidazo [1,5-a] pyrazin-8-ylamine: gaseous NH3 was condensed to a cooled solution (-78 ° C) of 8-chloro-3-cyclobutyl-1-phenylimidazo [1.5. -a] prazrazine (602.9 mg, 2.125 mmol) in NH3 / i-PrOH (2M, 15 mL) in a pressurized tube until the volume was doubled. The tube was sealed and heated at 110 ° C for 2 days. After the excess of NH3 / i-PrOH was removed in vacuo, the residue was extracted with CH2Cl2 (3x30 mL), and the combined organic layers were washed with brine (3x30 mL), dried over anhydrous MgSO4, filtered, and dried. Concentrate. The material obtained (670 mg) was crystallized from EOAc, yielding 393.3 mg (70%, 1.488 millimoles) of the compound of the yeast, as light pink crystals. The mother liquor was reduced to almost 50% vacuo and recrystallized again from EtOAc, yielding an additional 38.4 mg (7%, 0.145 mmol) of the title compound, as pink crystals, > 99% pure through CLAR; p.f. 164-166 ° C; 1 H NMR (CDCl 3, 400 MHz) d 1.98-2.09 (m, 1 H), 2.11-2.23 (m, 1 H), 2.44-2.54 (m, 2 H), 2.58-2.70 (m, 2 H), 3.82 (quintet , J = 8.4 Hz, 1 H), 5.02 (s, br, -NH2), 7.05 (d, J = 4.8 Hz, 1 H), 7.12 (d, J = 5.2 Hz, 1 H), 7.38-7.43 ( m, 1 H), 7.46-7.53 (m, 2H), 7.65-770 (m, 2H). 13C NMR (CDCl3, 100.6 MHz, DEPT135): d 18.87 (-), 26.94 (2C, -), 31.48 (+), 106.61 (+), 113.93 (Ccuartet0), 127.43 (+), 128.08 (+), 128.81 (2C, +), 129.67 (2C, +), 134.87 (CCrterteto), 135.32 (Ccuarteto), 143.90 (Ccuarteto), 151.75 (Ccuarteto). MS (ES +): m / z 265.2 (100) [MH +]. a) 8-Chloro-3-cyclobutyl-1-phenylimidazo [1,5-a] pyrazine: A mixture of [(3-chloropyrazin-2-yl) -phenylmethyl] -amido cyclobulenecarboxylic acid (710 mg, 2.35 mmol) and POCI3 (15 mL, 25 g, 163 mmol) was heated to 55 ° C, under N2 atmospheric, for 21 hours. POCI3 was evaporated in vacuo, a cold solution of NH3 in i-PrOH (2M, 15 mL) was added until pH was basic, and rotary evaporation was used to remove excess solvent. The unpurified material was suspended between EtOAc and dH20, the layers were separated, and the aqueous layer was extracted with EOAc (4x50 mL). The combined organic layers were washed with saturated aqueous NaHC03 in solution (2x50 mL) and brine (1x50 mL), dried over anhydrous MgSO4, and filtered. The sample was purified by filtration through a plug of silica gel with 10% EtOAc: CH2Cl2 (250 mL) and the filtrate was concentrated in vacuo, yielding 602.9 mg (90%, 2.125 mmol) of the compound of the extract, which contained "0.5 equivalents of reduced DIAD and < 0.06 equivalents of [(3-chloropyrazin-2-yl) -phenylmethyl] -cyclohexanecarboxylic acid (4), as a gold-colored solid; 1 H NMR (CDCl 3, 400 MHz) d 2.00-2.11 (m, 1 H), 2.13-2.26 (m, 1 H), 2.47-2.57 (m, 2H), 2.60-2.72 (m, 2H), 3.85 (quinite , J = 8.4 Hz, 1 H), 7.30 (d, J = 5.2 Hz, 1 H), 7.38-7.47 (m, 3H), 7.50 (d, J = 5.2 Hz, 1 H), 7.67-7.71 (m , 2H). MS (ES +): m / z 284.1 / 286.1 (100/55) [MH +]. b) [(3-chloropyrazin-2-yl) -phenylmethyl] -cyclobuylenecarboxylic acid: To a solution of C- (3-chloropyrazin-2-yl) -C-phenylmethylamine (610.7 mg, 2780 mmol), DMAP (17) mg, 0.139 mmol), and (Pr) 2 EtN (726 μL, 539 mg, 4.17 mmol) in dry CH2Cl2 (10 mL), cooled to 0 ° C, was added cyclobutanecarbonyl chloride (350 μL, 363 mg, 3.058 millimoles) under N2 atmosphere, the cooling bath was removed, and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with dH20, taken up with CH2Cl2 (3x 20 mL), washed (1 x 30 mL each) with 0.25 M citric acid (pH 2-3), dH20, aqueous saturated NaHCO3 in solution, and brine, dried over anhydrous MgSO 4, and filtered. The sample was purified by filtration through a plug of silica gel with 10% EtOAc: CH2Cl2 (250 mL) and the filtrate was concentrated in vacuo, yielding the crude compound as a gold-colored solid.; H NMR (CDCl 3, 400 MHz) d 1.80-2.02 (m, 2 H), 2.10-2.22 (m, 2 H), 2.22-2.34 (m, 2 H), 3.09 (quintet, J = 8.4 Hz, 1 H), 6.58 (m. d, J = 7.6 Hz, 1 H), 7.01 (d, J = 8.0 Hz, 1 H), 7.24-736 (m, 5H), 8.33 (d, J = 2.4 Hz, 1 H), 8.52 (d, J = 2.0 Hz, 1 H). c) C- (3-Chloropyrazin-2-yl) -C-phenylmethylamine: To a solution of 2 - [(3-chloropyrazin-2-yl) -phenylmethyl] -isoindole-1,3-dione (7.70 g, 22 millimoles), containing "0.77 equivalents of reduced DIAD, in EtOH (10 mL) and CH2CI2 co-solvent (15 mL), was added N2H4 (10 mL, 7.91 g, 0.172 mol) and the reaction solution was stirred at ambient ambience, under N2, for 1 day. The suspension was filtered, the orange solid was washed several times with CH2Cl2, and the filtrate was concentrated in vacuo. The residue was suspended between HCl (2M) / EtOAc and the EtOAc layer was discarded. The aqueous layer was brought to a basic pH using NaOH and extracted with CH2Cl2 (5x60 mL), washed with brine (2x50 mL), dried over MgSO4, filtered, and concentrated, yielding 2.1923 g (45%; 9.9795). millimols) of the title compound, which contained "0.1 equivalents of reduced DIAD, as a brown aceifene; 1 H NMR (CDCl 3, 400 MHz) d 2.24 (s, br, 2 H), 5.56 (s, 1 H), 7.26-7.38 (m, 5 H), 8.27 (s, 1 H), 8.55 (s, 1 H) . MS (ES +): m / z 203.2 / 205.2 (100/73) [MH + -NH3]. C- (3-chloropyrazin-2-yl) -C-phenylmethylamine hydrochloride (2 HCl): To a solution of C- (3-chloropyrazin-2-yl) -C-phenylmethylamine (1582 g, 7.20 mmol) in 1 , 4-dioxane (< 5 mL), HC1 (2 mL, 7.55 mmol, 4M solution in 1,4-dioxane) was added and left for approximately 5 minutes. The reaction mixture was filtered and the solid was washed several times with 1,4-dioxane, yielding the title compound as a tan solid. The sample contained "0.1 equivalents of 1,4-dioxane by 1 H NMR; 1 H NMR (d-MeOH, 400 MHz) d 5.85 (s, 1 H), 7.35 (s, 1 H), 8.44 (d, J = 2.4 Hz, 1 H), 8.65 (d, J = 2.4 Hz, 1 H) . d) 2 - [(3-Chloropyrazin-2-yl) -phenylmethyl] isoindole-1,3-dione: Prepared according to the procedures for 2 - [(3-benzyloxy-phenyl) - (3-chloro-pyrazine) 2-Y) -methyl] -isoindo I-1,3-dione, yellow oil, MS (ES) 350.04 e) (3-Chloropyrazin-2-yl) -phenylmethanol: Prepared according to the procedures for (3-Chloro-pyrazin-2-yl) - (3-benzyloxy-phenyl) -methanol, yellow solid, 1 H NMR (CDCI3, 400 MHz) d 4.62 (d, 1 H, J = 8.0 Hz), 6.04 (d, 1 H, J = 8.0 Hz), 7.29-7.36 (m, 5H), 8.37 (d, 1 H, J = 2.4 Hz), 8.56 (d, 1 H, J = 2.4 Hz).

GENERAL PROCEDURE TO EXAMPLES 33 AND 34 A THF solution (3 mL) of the 4- [8-amino-1- (3-benzyloxy-phenyl) imidazo [1,5-a] pyrazin-3-yl] -cyclohexy-methyl ester of tans-toluene-4- Sulfonic acid (200 mg, 0.34 mmol) in a sealed tube was charged with azetidine (8.92 mmol, 510 mg) and stirred at 50 ° C for 24 hours. The reaction mixture was concentrated in vacuo and partitioned between EtOAc and saturated NaHCO 3. The organic layer was washed with saturated NaHCO 3 (2x), water (1x), brine (1x), dried over Na 2 SO, filtered, and concentrated to a yellow oil. Unpurified material was purified by silica gel column chromatography [Jones Flashmaster, 5 g / 25 mL cartridge, flowing with CH 2 Cl 2 at 2% NH 3 ~ 7 N in MeOH / CH 2 Cl 2] to produce trans-3- (4- azetidin-1-ylmethyl-cyclohexyl) -1- (3-benzyloxy-phenyl) -imidazo [1,5-a] pyrazin-8-ylamine as a white solid (130 mg, 82%).

EXAMPLE 33 (trans-3- (4-Azetidin-1-ylmethyl-cyclohexyl) -1- (3-benzyloxy-phenyl) -imidazo [1,5-a] pyrazin-8-ylamine: MS (ES +): m / z 468.1 . trans-1- (3-Benzyloxy-phenyl) -3- (4-pyrrolidin-1-methyl-cyclohexyl) -imidazo [1,5-a] pyrazin-8-ylamine): MS (ES +): m / z 482.3. a) 4- [8-amino-1- (3-benzyloxy-phenyl) imidazo [1, 5-a] pyrazin-3-yl] -cyclohexylmethyl ester of trans-Ioluene-4-sulfonic acid: A solution of pyridine ( 23 mL) of rans. { 4- [8-amino-1- (3-benzyloxy-phenyl) -imidazo [1,5-a] pyrazin-3-yl] -cyclohexyl} -methanol (2.00 g, 4.67 mmol) was cooled to -20 ° C and charged with Ts20 (1.52 g, 4.67 mmol). The reaction was allowed to warm to room temperature and was stirred for 16 hours. The mixture was concentrated in vacuo to a tan foam and partitioned between CHCl3 and water. The organic layer was washed with 1 M NaOH (2x), water (1x), brine (1x), dried over Na 2 SO 4, filtered, and concentrated to a tan foam. Unpurified material was purified by silica gel column chromatography [Jones Flashmaster, 50 g / 150 mL cartridge, eluting with 50% EtOAc / Hexanes to 5% MeOH / EtOAc] to produce 4- [8-] amino-1- (3-benzyloxy-phenyl) imidazo [1, 5-a] pyrazin-3-yl] -cyclohexylmethyl of rans-loluene-4-sulfonic acid as a tan foam (1.90 g, 70%); MS (ES +): m / z 583.1 EXAMPLE 35 Trans-4- [8-Amino-1- (3-benzyloxy-phenyl) -imidazo [1,5-a] pyrazin-3-yl] -cyclohexanecarboxylic acid methyl ester: A solution of isopropanol (42 mL) of ester methyl trans-4- [1- (3-benzyloxy-phenyl) -8-chloro-imidazo [1,5-a] pyrazin-3-yl] -cyclohexanecarboxylic acid (4.00 g, 8.4 mmol) in a sealed tube was cooled to -78 ° C. Ammonia was bubbled into the solution for 2 minutes; The tube was capped and heated at 110 ° C for 1 day. The reaction mixture was concentrated in vacuo and partitioned between EtOAc and water. The organic layer was washed with water (2x), brine (1x), dried over Na 2 SO, filtered, and concentrated to a yellow oil. Unpurified material was purified by silica gel column chromatography [Jones Flashmaster, 20 g / 70 mL cartridge, eluting with 50% EOAc / 2% Hexanes -NH3 7 N in MeOH / EtOAc] to produce methyl ester of rans-4- [8-amino-1- (3-benzyloxy-phenyl) -imidazo [1,5-a] pyrazin-3-yl] -cyclohexanecarboxylic acid as a tan foam (1.50 g, 39%); recovering carboxylic ester of lrans-4- [1- (3-benzyloxy-phenyl) -8-chloro-imidazo [1, 5-a] pyrazin-3-yl] -cyclohexanmethyl acid (1.20 g, 30%); MS (ES +): m / z 457.1.

EXAMPLE 36 Acid (lrans-4- [8-Amino-1 - (3-benzyloxy-phenyl) -imidazo [1,5-a] pyrazin-3-yl] -cydohexancarboxylic acid): A solution of THF (11 mL) of methyl ester of trans-4- [8-amino-1- (3-benzyloxy-phenyl) -imidazo [1,5-a] pyrazin-3-yl] -cyclohexanecarboxylic acid (1.50 g, 3.28 mmol) was charged with 10 M NaOH (1.64 mL, 16.42 mmol); a minimum amount of mei nol was added to make the reaction mixture homogeneous. The reaction was stirred at room temperature for 2 hours. The reaction mixture was concentrated to solids and acidified to pH 5 with 2M HCl. The resulting precipitate was filtered, washed with water, and dried in a vacuum oven overnight at 50 ° C to produce acid. trans -4- [8-amino-1- (3-benzyloxy-phenyl) -imidazo [1,5-a] pyrazin-3-yl] -cyclohexanecarboxylic acid as an off-white solid (1.10 g, 76%); MS (ES +): GENERAL PROCEDURE FOR EXAMPLES 37 AND 38 A solution of DMF (2 mL) of trans-4- [8-amino-1- (3-benzyloxy-phenyl) -imidazo [1,5-a] pyrazin-3-yl] -cyclohexanecarboxylic acid (100 mg, 0.23 mmol) ) and methylamine hydrochloride (153 mg, 2.26 mmol) in a sealed tube was loaded with DIEA (394 μL, 2.26 mmol), HOAf 0.6 M in DMF (377 μL, 0.23 mmol), and subsequently EDC (65 mg, 0.34 mmol) ). The reaction mixture was stirred at ambient temperature for 16 hours. The reaction mixture was concentrated to solid, taken up in CH 2 Cl 2, charged with silica, and concentrated to obtain brown solids. Unpurified material was purified by silica gel column chromatography [Jones Flashmaster, 20 g / 70 mL cartridge, eluting with 2% NH 3 ~ 7N in MeOH / CH 2 Cl 2 at 5% NH 3 ~ 7N in MeOH / CH 2 Cl 2] produce lrans-4- [8-amino-1- (3-benzyloxy-phenyl) -imidazo [1, 5a] pyrazin-3-yl] -metholamide cyclohexanecarboxylic acid as an off-white solid (60 mg, 57%).

EXAMPLE 37 Acid (trans-4- [8-Amino-1 - (3-benzyloxy-phenyl) imidazo [1,5-a] pyrazin-3-yl] -methylamide cyclohexanecarboxylic acid, MS (ES +): m / z 456.3.

EXAMPLE 38 4- [8-Amino-1 - (3-benzyloxy-phenyl) -imidazo [1,5-a] pyrazin-3-yl] -ethylamide cyclohexanecarboxylic acid: MS (ES +): m / z 470.4.

General procedures of reducing amination: 3- [8-Amino-1- (3-benzyloxy-pheny] -imidazo [1,5-a] pyrazin-3-yl-cyclobutanecarbaldehyde (225 mg, 565 mmol) was dissolved in dichloroethane (DCE) (4.0 mL) followed by the addition of BH (OAc) 3 bound to the resin (562 mg, 1129 mmol), AcOH (70 μL, 1186 mmol) and pyrrolidine (0.14 mL, 1694 mmol). After stirring for 24 hours at room temperature the resin was filtered and washed with CH2Cl2 and the filtrate was combined and concentrated in vacuo. The crude oil was purified by silica gel column chromatography (2-5% 7N NH 3 in MeOH: CH 2 Cl 2) to produce the desired compounds. The most polar point is the cis isomer, which is the main isomer.

EXAMPLE 39 1-rans-1- (3-Benzyloxy-phenyl) -3- (3-pyrrolidin-1-ylmethyl-cyclobutyl) -imidazo [1,5-a] pyrazin-8-ylamine: Following the conditions of reductive amination; 1 H NMR (400 MHz, CDCl 3) d 1.75 (brs, 4H), 2.35 (brs, 2H), 2.66 (brm, 9H), 3.68-3.75 (m, 1 H), 4.94 (brs, 2H), 5.08 (s) , 2H), 6.98-6.99 (m, 3H), 7.20-7.42 (m, 8H); MS (ES +): 454.15 (M + 1), 455.15 (M + 2), 456.17 (M + 3); EXAMPLE 40 cis-1 - (3-Benzyloxy-phenyl) -3- (3-pyrrolidin-1-ylmethyl-cyclobutyl) -imidazo [1,5-a] pyrazin-8-ylamine: Following the conditions of reductive amination; 1 H NMR (400 MHz, CDCl 3) d 1.88-1.91 (m, 4 H), 2.39-2.43 (m, 2 H), 2.64-2.82 (m, 9 H), 3.73-3.90 (m, 1 H), 5.20 (brs, 2H), 5.26 (s, 2H), 7.13-7.15 (m, 1 H), 7.22 (d, 1 H, J = 5.0 Hz), 7.35-7.57 (m, 8H); MS (ES +): 454.11 (M + 1), 455.06 (M + 2), 456.20 (M + 3); EXAMPLE 41 trans-3- (3-Azeidin-1-ylmethylcyclobuityl) -1- (3-benzyloxy-phenyl) -imidazo [1,5-a] pyrazin-8-ylamine: Following the conditions of reductive amination; 1 H NMR (400 MHz, CDCl 3) d 2.07-2.11 (m, 2H), 2.20-44 (m, 2H), 2.51 (brm, 1H), 2.63-2.71 (m, 4H), 3.25 (i, 4H, J = 7.04 Hz), 3.71-3.75 (m, 1H), 5.00 (brs, 2H), 5.11 (s, 2H), 6.98-6.99 (m, 3H), 7.20-7.42 (m, 8H).

EXAMPLE 42 Cis-3- (3-azetidin-1-ylmelyylcyclobuyl) -1 - (3-benzyloxyphenyl) -imidazo [1,5-a] pyrazin-8-ylamine: Following the general conditions of reductive tuning; 1 H NMR (400 MHz, CDCl 3) d 1.98-2.02 (m, 2 H), 2.18-2.21 (m, 2 H), 2.44-2.54 (m, 4 H), 3.12 (t, 4 H, J = 7.0 Hz), 3.52- 3.57 (m, 1 H), 4.98 (brs, 4H), 6.95-6.97 (m, 2H), 7.03 (d, 1 H, J = 5.0 Hz), 7.16-7.45 (m, 8H); MS (ES +): 440.08 (M + 1), 441.08 (M + 2), 442.13 (M + 3). Alfematively, cis-3- (3-azetidin-1-ylmethylcyclobutyl) -1 - (3-benzyloxyphenyl) -imidazo [1,5-a] -pyrazin-8-ylamine could be prepared as follows: A sealed tube containing a 3- [8-amino-1- (3-benzyloxyphenyl) -imidazo [1,5- a] pyrazin-3-yl] cyclobutylmethyl ester of toluene-4-sulfonic acid (15 mg, 0.027 mmol) in THF ( 3 mL) was charged with azetidine (0.04 mL, 0.54 mmol), sealed, and heated at 50 ° C overnight. The mixture was concentrated and the residue was diluted with ethyl acetate (20 mL), washed with saturated aqueous NaHCO3 (2 x 10 mL) and brine (2 x 10 mL), and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure to produce a white solid.

EXAMPLE 43 Ester 3- [8-amino-1 - (3-benzyloxyphenyl) -imidazo [1,5-a] pyrazin-3-yl-cyclobutylmethyl acid of toluene-4-sulfonic acid: A solution of. { 3- [8-amino-1 - (3-benzyloxyphenyl) -imidazo [1,5-a] pyrazin-3-yl] cyclobuyl} Melani (23 mg, 0.057 mmol) in dry methylene chloride (3 mL) was charged with pyridine (0.1 mL) and Ts20 (21 mg, 0.063 mmol) at -20 ° C under the N2 atmosphere. The mixture slowly warmed to ambient temperature during the night. The reaction was quenched with water (1 mL), diluted with ethyl acetate (20 mL), washed with saturated aqueous NaHCO3 (10 mL) and brine (2 x 10 mL), and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure, and the unpurified material was purified by silica gel column chromatography (eluting with EtOAc: MeOH = 98: 2> 96.4), yielding the title compound as a white solid. The partial trans isomer was removed by chromatography and the ratio of the cis and trans isomers was raised to 8: 1; MS (ES, Pos.): M / z 555 [MH +]. 1 H NMR (CDCl 3, 400 MHz) d 2.27-2.35 (m, 2 H), 2.41 (s, 3 H), 2.55-2.62 (m, 2 H), 2.80 (m, 1 H), 3.66 (, 1 H), 4.07 (d, J = 6.7 Hz, 2H), 5.01 (br s, 2H, NH2), 5.15 (s, 2H), 702-7.85 (m, 15H). Analytical calculation for C31H30N4O4S.1 / 3H2O: C, 66.41; H, 5.51; N, 9.99. Found: C, 66.43; H, 5.44; N, 10.07.

EXAMPLE 44 . { 3- [8-Amino-1- (3-benzyloxyphenyl) -imidazo [1,5-a] pyrazin-3-yl] cyclobutyl} methanol: A solution of. { 3- [1- (3-benzyloxyphenyl) -8-chloro-imidazo [1, 5-a] pyrazin-3-yl] cyclobutyl} meianol (40 mg, 0.095 mmol) in 5 mL of 2N NH3 / PrOH was cooled to -78 ° C and charged with NH3 gas for 1 minute. This sealed tube was equipped with an O-ring of Teflon, sealed and heated at 110 ° C during the night. The mixture was cooled to room temperature and the lid removed. The solution was concentrated under reduced pressure and the unpurified material was purified by silica gel column chromatography. (eluting with 100% ethyl acetate * EtOAc: iPrOH = 80:20), yielding the title compound as a white solid, a mixture of cis and trans isomers. MS (ES, Pos.): M / z 401 [MH +]. 1 H NMR (CDCl 3, 400 MHz) d 2.37-2.44 (m, 2 H), 2.61-2.74 (m, 3 H), 3.65-3.82 (m, 3 H), 5.03 (br s, 2 H, NH 2), 5.14 (s, 2H), 7.01-7.46 (m, 11 H). to) . { 3- [1- (3-Benzyloxyphenyl) -8-chloro-imidazo [1,5-a] pyrazin-3-yl] cyclobutyl} methanol: To a solution of 1- (3-benzyloxyphenyl) -8-chloro-3- (3-methylenecyanobutyl) -imidazo [1,5-a] pyrazine (345 mg, 0.86 mmol) in dry THF (5 mL) was added. added 9-BBN (2.6 mL, 1.3 mmol, 0.5 M in THF) grop by drop at 0 ° C under nitrogen atmosphere. The temperature was slowly warmed to room temperature overnight. After that time, the CCF showed what reaction was complete. The mixture was cooled to 0 ° C, and 2 mL of 1N aqueous NaOH and 0.4 mL of 30% aqueous H202 were added, the resulting mixture was stirred at 0 ° C for 10 min., Then at room temperature for 30 minutes. The resulting white solid was filtered, the filtrate was diluted with ethyl acetate (60 mL), washed with brine (3 x 20 mL), and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure, and the unpurified material was purified by column chromatography on silica gel (eluting with 100% ethyl acetate), yielding the title compound as a yellow viscous oil, a mixture of cis and rans isomers. MS (ES, Pos.): MS (ES, Pos.): M / z 420/422 (3/1) [MH +]. 1 H NMR (CDCl 3, 400 MHz) d 2.32 (br s, 1 H), 2.60-2.85 (m, 5 H), 3.88-4.11 (m, 3 H), 5.36 (s, 2 H), 7.27 (m, 1 H) , 7.48-769 (m, 9H), 7.77 (d, J = 5.0 Hz, 1 H). b) 1- (3-Benzyloxyphenyl) -8-chloro-3- (3-methylenecyclobutyl) -imidazo [1,5-a] pyrazine: A mixture of [(3-benzyloxyphenyl) - (3-chloropyrazin-2-yl) ) methyl 3-methylenecyclobuylenecarboxylic acid methyl ester (190 mg, 0.45 mmol) and POCI 3 (2 mL) was heated at 55 ° C under N2 overnight. The mixture was concentrated under reduced pressure, the residue was cooled to 0 ° C, stopped with NH3 2N / 'PrOH to pH > 10, and the solid was filtered and washed with methylene chloride. The filtrate was concentrated and the unpurified material was purified by column chromatography on silica gel (eluting with hexanes: EtOAc = 80:20 or 60:40), producing the title product as a yellow solid; MS (ES, Pos.): M / z 402/404 (3/1) [MH +]; 1 H NMR (CDCl 3, 400 MHz) d 3.26-3.44 (m, 4 H), 3.86 (m, 1 H), 4.94 (m, 2 H), 5.16 (s, 2 H), 7.07 (ddd, J = 8.2, 2.6, 1.1 Hz, 1 H), 7.30-7.50 (m, 9H), 7.54 (d, J = 5.0 Hz, 1 H). c) [3-Methyloxyphenyl] - (3-chloropyrazin-2-yl) -methyl] -amide of 3-methylenecyclobutanecarboxylic acid: To a suspension of hydrochloride of C- (3-benzyloxyphenyl) -C- (3-chloropyrazine) 2-yl) methylamine (724 mg, 2.0 moles) in methylene dichloride (10 mL) was added 'Pr2NEt (1.7 mL, 10.0 mmol), at which time the solid dissolved. The reaction was charged with 3-methylenecyclobutanecarboxylic acid (560 mg, 5.0 mmol), EDC (1.15 g, 6.0 mmol) and HOBt (270 mg, 2.0 mmol) and the resulting mixture was stirred at room temperature overnight. The mixture was diluted with ethyl acetate (50 mL), washed with saturated aqueous NaHCO3 (2 x 20 mL) and brine (2 x 20 mL), and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure, and the unpurified material was purified by silica gel column chromatography (eluting with hexanes: EtOAc = 80:20 * -60: 40), yielding the title product as a viscous oil of light yellow color; MS (ES, Pos.): M / z 420/422 (3/1) [MH]; 1 H NMR (CDCl 3, 400 MHz) d 2.85-3.09 (m, 5 H), 4.78 (m, 2 H), 5.03 (s, 2 H), 6.55 (d, J = 7.9 Hz, 1 H), 6.87-6.95 (m , 3H), 7.08 (br d, 1 H, NH), 7.21-7.41 (m, 6H), 8.33 (d, J = 2.5 Hz, 1H), 8.49 (d, J = 2.5 Hz, 1H). d) 3-Methylenecyclobuylenecarboxylic acid: To a solution of 3-methylenecyclobutanecarbonitrile (10.0 g, 107.4 mmol) in ethanol (100 mL) and water (100 mL) was added potassium hydroxide (28.0 g, 430 mmol, 85% pure); The resulting mixture was refluxed for 8 hours. The ethanol was removed under reduced pressure, then the solution was cooled to 0 ° C and acidified with concentrated HCl until pH = 1. The mixture was extracted with diethyl ether (4 x 100 mL). The combined organic phases were dried over anhydrous sodium sulfate. Concentration in vacuo yielded the desired product as a colorless acefe; 1 H NMR (CDCl 3, 400 MHz) d 2.91-3.18 (m, 4 H), 3.14-3.22 (m, 1 H), 4.83 (m, 2 H); 13 C NMR (CDCl 3, 100 MHz) d 32.95, 35.30, 107.14, 143.77, 181.02 ppm. COOH Procedures for the general Grignard reaction: 3- [1- (3-Benzyloxy-phenyl) -8-chloro-imidazo [1,5-a] pyrazin-3-yl] -cyclobutanone (100 mg, 248 moles) was dissolved in dry THF (1.0 mL) under an inert atmosphere and cooled to -78 ° C. A solution of MeMgBr (40 μL, 322 moles) in toluene: THF (75:25) was slowly added to the cooled solution. After 24 hours at room temperature the reaction was cooled to 0 ° C and quenched with saturated aqueous NH 4 Cl solution and the aqueous layer was washed with EtOAc (2x). The organic layers were combined, dried over sodium sulfate, filtered and concentrated in vacuo. The crude oil was purified by silica gel column chromatography [Jones Flashmaster, 10 g / 70 mL cartridge, eluting with 2-5% ((NH3 7N) in MeOH): CH2Cl2], yielding 3- [1- (3-Benzyloxy-phenyl) -8-chloro-imidazo [1,5-a] pyrazin-3-yl] -1-methyl-cyclobutanol as a brown solid.

EXAMPLE 45 3- [8-Amino-1 - (3-benzyloxy-phenyl) -imidazo [1, 5a] pyrazin-3-yl] -1-methyl-cyclobutanol: Prepared according to the procedures for 1- (3-Benzyloxy- phenyl) -3-cyclobutyl-imidazo [1,5-a] pyrazin-8-ylamine, light brown crystals, H NMR (400 MHz, CDCl 3) d 1.43 (s, 3H), 2.49-2.64 (m, 4H ), 3.27-3.32 (m, 1 H), 5.07 (s, 2H), 6.96-738 (m, 11 H); MS (ES +): 401.34 (M + 1), 402.41 (M + 2), 403.43 (M + 3). a) 3- [1- (3-Benzyloxy-phenyl) -8-chloro-imidazo [1,5-a] pyrazin-3-yl] -1-methyl-cyclobutanol was prepared in accordance with the procedures for the general reaction de Grignárd: MS (ES +): 420.35 (M + 1), 422.35 (M + 3), 423.47 (M + 4). 3- [8-Amino-1- (3-benzyloxy-phenyl) -imidazo [1, 5a] pyrazin-3-yl] -1-ethyl-cyclobutanol: Prepared according to the procedures for 1- (3-Benzyloxy- phenyl) -3-cyclobuyl-imidazo [1,5-a] pyrazin-8-ylamine, light yellow gum (7.9 mg, 22%) light brown cristels, 1 H NMR (400 MHz, CDCl 3) d 0.94 ( t, 3H, J = 7.2 Hz), 1.66 (q, 2H, J = 7.4 Hz), 2.41-2.46 (m, 2H), 2.60-2.65 (m, 2H), 3.26-3.32 (m, 1 H), 5.06 (s, 2H), 6.95-6.97 (m, 2H), 7.05 (d, 1 H, J = 5.1 Hz), 7.26-7.38 (m, 8H); MS (ES +): 415.27 (M + 1), 416.34 (M + 2), 417.40 (M + 3). a) 3- [1- (3-Benzyloxy-phenyl) -8-chloro-imidazo [1,5-a] pyrazin-3-yl] -1-ethyl-cyclobutanol was prepared in accordance with the procedures for the general reaction of Grignard: light yellow gum (38 mg, 36%), 1 H NMR (400 MHz, CDCl 3) d 0.95 (t, 3 H, J = 7.36 Hz), 1.68 (q, 2 H, J = 7.36 Hz), 2.54 -2.69 (m, 4H), 3.31-3.39 (m, 1 H), 5.08 (s, 2H), 6.99-700 (m, 1 H), 7.19-7.40 (m, 9H), 750 (d, 1H, J = 5.0 Hz); MS (ES +): 434.08 (M + 1), 436.09 (M + 3), 437.05 (M + 4).

EXAMPLE 47 1 - . 1 - . 1 -Alyl-3- [8-amino-1 - (3-benzyloxy-phenyl) -imidazo [1,5-a] pyrazin-3-yl] -cyclobutanol: Prepared according to the procedures for 1- (3- Benzyloxy-phenyl) -3-cyclobutyl-imidazo [1,5-a] pyrazin-8-ylamine, light yellow foam (8.2 mg, 34%), 1 H NMR (400 MHz, CDCl 3) d 2.41 (d, 2H , J = 72 Hz), 2.47-2.52 (m, 2H), 2.63-2.68 (m, 2H), 3.29-3.33 (m, 1 H), 5.07 (s, 2H), 5.13-5.18 (m, 2H) , 5.86-5.92 (m, 1H), 6.95-6.97 (m, 2H), 7.05 (d, 1H, J = 5.0 Hz), 7.26-7.38 (m, 8H); MS (ES +): 427.28 (M + 1), 428.34 (M + 2), 429.38 (M + 3). a) 1-Allyl-3- [1- (3-benzyloxy-phenyl) -8-chloro-imidazo [1,5-a] pyrazin-3-yl] -cyclobutanol was prepared in accordance with the procedures for General Grignard reaction: light yellow gum (25 mg, 23%), 1 H NMR (400 MHz, CDCl 3) d 2.40 (d, 2 H, J = 7.2 Hz), 2.49-2.68 (m, 4 H), 3.29- 3.33 (m, 1 H), 5.06 (brs, 4H), 5.84 (m, 1 H), 6.99-7.00 (m, 1 H), 7.19-7.40 (m, 9H), 7.50 (d, 1 H, J = 5.0 Hz); MS (ES +): 446.08 (M + 1), 448.07 (M + 3), 449.05 (M + 4).

EXAMPLE 48 1- (3-Benzyloxyphenyl) -3-yer-buylimidazo [1,5-a] pyrazin-8-ylamine: NH3 gas condensed to a cooled solution (dry ice / acetone) of 1- (3-benzyl) loxyphenyl) -3-tert-buyl-8-chloroimidazo [1, 5-a] pyrrazine (61.8 mg, 0.158 mmol) in PrOH (2 mL) in a pressurized tube until the volume doubled, then the The tube was sealed and heated to 110 ° C (bath temperature) overnight. The seal was filtered during that time, LC indicates «50% conversion; subsequently, the ammonia condensed in and the tube was heated as described above. Unpurified material was purified by preparative TLC (1000 μm silica gel layer, 20 × 20 cm plate), eluting once with 1% MeOH in CH 2 Cl 2 and then three times with hexanes: EtOAc 3: 1. One gets the compound of the title as a light yellow solid, > 95% pure through CLAR; 1 H NMR (CDCl 3, 400 MHz) d 1.57 (s, 9 H), 5.06 (brs, 2 H), 5.14 (s, 2 H), 6.99-7.04 (m, 2 H), 7.22-7.26 (m, 2 H), 7.31- 7.42 (m, 4H), 7.44 (d, J = 8.4 Hz, 2H), 7.46 (d, J = 5.3 Hz, 1 H). MS (ES +): m / z 373.1 (100) [MH +]. a) 1 - (3-Benzyloxyphenyl) -3-yer-butyl-8-chloroimidazo [1,5-a] pyrazine: A mixture of POCI3 (3 mL, 5 g, 33 mmol) and N [(3-benzyloxyphenyl) - (3-chloropyrazin-2-yl) -methyl] -2,2-dimethylpropionamide (109 mg, 0.266 mmol) was heated at 55 ° C for 6 days. POCI3 was evaporated, a cold solution of NH3 in iPrOH (2 M, 5 mL) was added, the suspension was filtered, and the solid was washed with iPrOH. The unpurified material contained in the combined filtrate and in the washings was adsorbed on Hydromatrix and sommelled to silica gel chromatography [Jones Flashmaster, 10 g / 70 mL cartridge, eluting with hexanes: EfOAc 10: 1 (1-22 ) 5: 1 (23-40)], producing the title compound as a yellow oil that slowly solidifies; 1 H NMR (CDCl 3, 400 MHz) d 1.59 (s, 9 H), 5.13 (s, 2 H), 7.03 (d, J = 8.0 Hz, 1 H), 7.27-7.42 (m, 7 H), 7.46 (d, J = 7.2 Hz, 2H), 7.87 (d, J = 4.8 Hz, 1 H). MS (ES +): m / z 392.1 / 394.0 (12/4) [MH +]. b) N - [(3-Benzyloxyphenyl) - (3-chloropyrazin-2-yl) -methyl] -2,2-dimethylpropionamide: To a solution of C- (3-benzyloxyphenyl) -C- (3-chloropyrazine) -2-yl) -methylamine (444 mg, max 1.36 mmol) without purification in CH2CI2 (5 mL), cooled by ice / water, added NEt3 (210 μL, 152 mg, 1. 51 mmol), DMAP (8 mg, 0.07 mmol), and pivaloyl chloride (185 μL, 181 mg, 1.50 mmol), then the bath was removed for cooling, and the reaction solution was stirred at ambient temperature for 4.5 hours. More pivaloyl chloride (90 μL, 88 mg, 0.73 mmol) and NEí3 (100 μL, 73 mg, 0.72 mmol) were added and also after an additional 2.5 hours, and the solution was stirred overnight at ambient temperature. The reaction mixture was taken up in EtOAc (35 mL), washed with dilute HCl, water, NaHCO 3 solution, and brine, dried over MgSO 4, filtered, and concentrated in vacuo. Unpurified material was subjected to silica gel chromatography [Jones Flashmaster, 50 g / 150 mL cartridge, eluting with hexanes: EOAc 10: 1 (1-17-3: 1 (18-41) > -2: 1 (42-56)], yielding the title compound as an orange oil; H NMR (CDCl 3, 400 MHz) d 1.21 (s, 9H), 5.03 (s, 2H), 6.50 (d, J = 8.0 Hz, 1 H), 6.86-6.90 (m, 1 H), 6.93-6.97 (m, 2H), 723 (t, J = 7.8 Hz, 1 H), 7.29-7.43 (m, 6H), 8.32 (d , J = 2. 4 Hz, 2H), 8.50 (d, J = 2.4 Hz, 1 H) MS (ES +): m / z 410.1 / 412.1 (100/36) [MH +], 309.1 / 311.1 (32 / 12) [MH + -íBuCONH2].

EXAMPLE 49 cis-1- [3- (Benzyloxy) phenyl] -3- [3- (dimethylamino) cyclobuyl] imidazo [1,5-a] pyrazin-8-amine: A solution of light yellow isopropanol (5.0 mL) of cis- [3- (8-chloro-1-phenyl-imidazo [1,5-a] pyrazin-3-yl) -cyclobuityl] -dimetholamine (0.21 mmol, 90 mg) in a sealed tube of 15 mL was cooled to -78 ° C. Ammonia was bubbled into the solution for 90 seconds; the lubo was cleaned and heated at 114 ° C for 10 hours. The sealed tube was cooled to room temperature and then to -78 ° C before it was uncovered. The reaction mixture was filtered through a Buchner funnel to remove the NH 4 Cl salt and the remaining solid was washed with EtOAc (15 mL x 2) and MeOH (15 mL x 2). The combined filtrates were concentrated to provide the light yellow fatty compound (90 mg), which was purified by mass directed HPLC (gradient: 5% to 60% CH 3 CN in water at pH 9 in 6 minutes). The title compound was obtained as an off white solid with > 95% purity; 1 H NMR (400 MHz, CDCl 3): d 7.45 (d, J = 8.0 Hz, 2H), 7.41-731 (m, 4H), 726-7.22 (m, 2H), 7.13 (d, J = 5.2 Hz, 1H ), 7.04 (d, J = 4.0 Hz, 1 H), 7.01 (d, J = 2.4 Hz, 1 H), 5.11 (d, J = 24 Hz, 2H), 3.41 (p, J = 8.0 Hz, 1H ), 2.80 (p, J = 8.0 Hz, 1 H), 2.68-2.62 (m, 2H), 2.49-2.41 (m, 2H). MS (ES +): m / z 414 (100) [MH4]. a) cis- [3- (8-Chloro-1-phenyl-imidazo [1,5-a] pyrazin-3-yl) -cyclobutyl] -dimethyl-amine: A solution of DCE of 3-. { 1- [3- (benzyloxy) phenyl] -8-chloroimidazo [1,5-a] pyrazin-3-yl} Cyclobufanone was charged with dimethylamine (0.37 mmol, 0.19 mL) and then the catalytic amount of AcOH (7 μL). The mixture was stirred at room temperature for 30 minutes before the iridium oxide borohydride attached to the resin was added (0.5 mmol.240 mg). The reaction mixture was stirred at ambient temperature for 16 hours before the solution was filtered through a Buchner funnel to remove the resin. The filtrate was concentrated and the oil obtained was dissolved in DCM (15 mL), washed with saturated NaHCO3 solution (2 X 15 mL) and brine (2 X 15 mL). The solvent was dried over sodium sulfate and concentrated under reduced pressure. The title compound was obtained as a yellow fatty oil; MS (ES +): m / z 433 (100) [MH +].

EXAMPLE 50 3- (8-Amino-3-cyclobufil-imidazo [1,5-a] pyrazin-1-yl) -phenol: A solution of 1- (3-benzyloxy-phenyl) -3-cyclobuyl-imidazo [1, 5 a] Pyrazin-8-ylamine (1.82 g, 4.92 mmol) in 4M HCl in dioxane (20 mL) was heated at 75 ° C in a sealed tube, for 1.5 hours. The reaction was allowed to cool to room temperature, the dioxane was decanted and the brown gum residue was cooled to 0 ° C in an ice bath and charged with 7N NH3 in MeOH until basic. The reaction mixture was concentrated in vacuo, dried with EOAc and CHCl3, and the NH4Cl salts were filtered. The filtrate was concentrated in vacuo and purified by flash chromatography on silica (8% MeOH in CHCl3) resulting in a whitish solid; 1 H NMR (DMSO-d 6, 400 MHz) d 1.84-1.99 (m, 1 H), 2.00--2.16 (m, 1 H), 2.34-2.48 (m, 4H), 3.86-4.00 (m, 1 H), 6.08 (brs, 2H), 6.81 (dd, 1 H, J = 8.4 Hz, 8.0 Hz), 6.95-7.06 (m, 3H), 7.30 (i, 1 H, J = 8.4 Hz); 7.41 (d, 1 H, J = 5.2 Hz), 9.63 (brs, 1 H); MS (ES +): m / z 281.39 [MH +].

EXAMPLE 51 3-Cyclobuyyl-1- [3- (4-fluoro-benzyloxy) -phenyl] -imidazo [1,5-a] pyrazin-8-ylamine: A solution of anhydrous DMF (2 mL) of 3- (8-amino) 3-Cyclobutyl-imidazo [1, 5-a] pyrazin-1-yl) -phenol (50 mg, 0.179 mmol) and K2CO3 (27 mg, 0.197 mmol) was charged with 1-bromomethyl-4-fluoro-benzene ( 7) (24 μL, 0.197 mmol) and stirred for 12 hours at 40 ° C. The reaction mixture was partitioned between CHCl3 and H20 and separated. The aqueous layer was reextracted with CHCl3 (3X) and the combined organic fractions were washed with H20 (1X), brine (1X), dried over Na2SO, filtered and concentrated in vacuo. The unpurified mixture was purified by MDP resulting in a clear tan waxy solid; 1 H NMR (CDCl 3, 400 MHz) d 1.99-2.08 (m, 1 H), 2.11-2.25 (m, 1 H), 2.44-2.55 (m, 2 H), 2.58-2.70 (m, 2 H), 3.75-3.88 (m, 1 H), 5.06 (brs, 2H), 5.10 (s, 2H), 6.98-7.15 (m, 5H); 7.20-734 (m, 3H), 7.35-7.47 (m, 3H); MS (ES +): m / z 389.14.

EXAMPLE 52 Trans-4- [8-amino-1- (3-hydroxy-phenyl) -imidazo [1,5-a] pyrazin-3-yl] -cyclohexanecarboxylic acid methyl ester: A solution of methyl ester of trans-4- acid [8-amino-1- (3-benzyloxy-phenyl) -imidazo [1,5-a] pyrazin-3-yl] -cyclohexanecarboxylic acid (50 mg, 0.110 mmol) in 4M HCl in dioxane (2 mL) was heated to 75 ° C in an oil bath for -2 hours. The reaction mixture was allowed to cool to room temperature, the dioxane was decanted and the reaction mixture was quenched with 7N NH3 in MeOH solution (-2 mL). The unpurified mixture was concentrated in vacuo resulting in 79 mg of an off-white solid (which contains NH4Cl salts). Unpurified material was purified by instantaneous chromatography on silica (10% NH3 7N in MeOH in CHCl3) resulting in an off-white solid; 1 H NMR (DMSO-d 6, 400 MHz) d 1.51-1.78 (m, 4 H), 1.95-2.08 (m, 4 H), 2.38-2.48 (m, 1 H), 3.07-3.20 (m, 1 H), 3.63 (s, 3H), 6.06 (brs, 2H), 6.76-6.89 (m, 1 H), 6.95-7.05 (m, 3H), 7.29 (i, 1 H, J = 7.8 Hz), 7.65 (d, 1 H, J = 5.1 Hz), 9.62 (brs, 1 H); MS (ES +): m / z 367.26 [MH +].

EXAMPLE 53 3- [8-Amino-1 - (3-benzyloxyphenyl) -imidazo [1,5-a] pyrazin-3-yl] -benzamide: gaseous NH3 was condensed in a cooled (-78 ° C) methyl ester solution 3- [1- (3-benzyloxyphenyl) -8-chloroimidazo [1, 5-a] pyrazin-3-yl] -benzoic acid (102 mg, 0.216 mmol) in NH3 / i-PrOH (2M, 3 mL) in a pressurized tube, the volume doubled. The tube was sealed and heated at 110 ° C for 2 days. After the excess of NH3 / i-PrOH was removed in vacuo, the unpurified material was taken up in CH2Cl2, adsorbed on Hydromatrix, and purified by chromatography on silica gel [Jones Flashmaster, 5 g / 25 mL cartridge, eluting with MeOH: CH2Cl2 1% - > 5%], yielding the title compound, as a whitish solid; 1 H NMR (d-DMSO, 400 MHz) d 5.18 (s, 2 H), 6.30 (s, br, -NH 2), 7.10-7.18 (m, 2 H), 7.25-7.58 (m, 9 H), 7.67 (m, J = 7.6 Hz, 1 H), 7.81 (d, J = 4.4 Hz, 1 H), 8.00 (d, J = 7.6 Hz, 2H), 8.16 (s, 1 H), 8.31 (s, 1H); MS (ES +): m / z 436.0 (100) [MH +]. a) 3- [1- (3-Benzyloxyphenyl) -8-chloroimidazo [1] methyl ester, 5-a] pyrazin-3-yl] -benzoic acid: To a solution of N - [(3-benzylloxyphenyl) - (3-chloropyrazin-2-yl) -methyl] -isophthalamic acid methyl ester (610 mg , 1.25 mmol) in THF (5 mL), cooled to 0 ° C, KOtBu (1.6 mL, 1 M, 1.6 mmol) was added under N2 atmosphere, the bath was removed for cooling, and the reaction mixture was stirred at ambience for 5 minumens. After the addition, the color of the solution changed from yellow to brown. THF was evaporated under reduced pressure, POCI3 (10 mL, 17 g, 109 mmol) was added, and the reaction mixture was vortexed at 55 ° C for 2 days. POCI3 was removed in vacuo, a cold solution of NH3 / i-PrOH (2M, 10 mL) was added, and the excess solvent was evaporated. The residue was taken up in EtOAc (4x30 mL), washed with saturated aqueous NaHCO3 solution (2x20 mL) and brine (1x20 mL), dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The unpurified material was dissolved in CH2CI2, adsorbed on Hydromatrix, and purified by chromatography on silica gel [Jones Flashmaster, 50 g / 150 mL cartridge, eluting with EtOAc: CH2Cl2 1% 5%], yielding 264 mg ( 45%, 0.562 mmol) of the title compound, as a yellow solid; 1 H NMR (CDCl 3, 400 MHz) d 3.97 (s, 3 H), 5.15 (s, 2 H), 7.08 (ddd, J = 8.0, 2.4, 1.2 Hz, 1 H), 7.30-7.43 (m, 7 H), 7.44 -7.48 (m, 2H), 7.67 (t, J = 7.2 Hz, 1H), 8.04 (d, J = 4.8 Hz, 1H), 8.05-8.09 (m, 1H), 8.19-8.22 (m, 1 H) 8.50-8.52 (m, 1 H); MS (ES +): m / z 469.8 / 471.9 (100/39) [MH +].

EXAMPLE 54 . { 3- [8-Amino-1- (3-benzyloxyphenyl) -imidazo [1, 5-a] pyrazin-3-yl] -phenyl} - methanol: gaseous NH3 was condensed in a cooled solution (-78 ° C) of. { 3- [1- (3-benzyloxyphenyl) -8-chloroimidazo [1, 5-a] pyrazin-3-yl] -phenyl} -methanol (366 mg, 0.829 mmol) in NH3 / i-PrOH (2M, 5 mL) in a pressurized tube until the volume doubled. The tube was sealed and heated at 110 ° C for 19 hours. After the excess of NH3 / i-PrOH was removed in vacuo, the residue was suspended in CH2Cl2 and water, the layers were separated, and the aqueous layer was extracted with CH2Cl2 (3x30 mL). The combined organic layers were washed with brine (3x30 mL), dried over anhydrous MgSO4, and filtered. The unpurified material was purified by filtration through a plug of silica gel, eluting with 5% MeOH: CH2Cl2 (400 mL), concentrated in vacuo, yielding 311.5 mg (89%, 0.737 mmol) of the title compound , as a yellow solid; 1 H NMR (CDCl 3, 400 MHz) d 4.80 (s, 2 H), 5.09 (s, -NH 2), 5.16 (s, 2 H), 7.05-7.09 (m, 1 H), 7.11 (d, J = 4.8 Hz, 1 H), 7.29-7.37 (m, 3H), 7.37-748 (m, 5H), 747-7.51 (m, 1 H), 7.54 (t, J = 7.8 Hz, 1 H), 7.63 (d, J = 4.8 Hz, 1 H), 7.73-778 (m, 1 H), 7.86 (s, 1 H); MS (ES +): m / z 423.0 (100) [MH *]. to) . { 3- [1 - (3-Benzyloxyphenyl) -8-chloroimidazo [1, 5-a] pyrazin-3-yl] -phenyl} - nitrogen: To a solution of methyl ester of 3- [1- (3-benzyloxyphenyl) -8-chloroimidazo [1, 5-a] pyrazin-3-yl] -benzoic acid (552 mg, 1.17 mmol) in THF ( 25 mL), cooled to 0 ° C, 1 M LiAlH 4 (880 μL, 797 mg, 0.880 mmol) was added under N 2, and the reaction solution was vortexed for 2 hours. After the addition, the reaction mixture changed from yellow to dark green. The reaction was quenched with aqueous solution of sodium potassium fartrate (25 mL), extracted with EtOAc (3x20 mL), washed with brine (1x40 mL), dried over MgSO4, and filtered. Unpurified material was purified by filtration through a plug of silica gel [eluting with EfOAc: CH2Cl2 1: 1 (400 mL)] and concentrated, yielding 366.3 mg (71%, 0.829 mmol) of the title compound, as a yellow solid; 1 H NMR (CDCl 3, 400 MHz) d 4.82 (d, J = 6.0 Hz, 2 H), 5.15 (s, 2 H), 7.05-7.11 (m, 1 H), 7.32-7.43 (m, 7 H), 7.44-7.49 (m, 2H), 7.52-7.61 (m, 2H), 7.73-7.78 (m, 1 H), 7.87 (s, 1 H), 8.05 (d, J = 4.8 Hz, 1 H); MS (ES +): m / z 441.9 / 443.9 (100/38) [MH +].

EXAMPLE 55 3- (3-Aminomethylphenyl) -1- (3-benzyloxyphenyl) -imidazo [1,5-a] pyrazin-8-ylamine: To a solution of 2-. { 3- [8-amino-1- (3-benzyloxyphenyl) -imidazo [1, 5-a] pyrazin-3-yl] -benzyl} -isoindole-1,3-dione (328 mg, 0.594 mmol) in CH2Cl2 (4 mL), N2H4 (56 μL, 57 mg, 1.78 mmol) was added and the reaction was subjected to vertex at ambient temperature for 17 hours, under N2 atmosphere. Additional N2H4 (40 μL, 41 mg, 1.27 mmol) and CH2Cl2 (10 mL) were added and vortexing was continued for 3 days. The suspension was filtered, the solid washed extensively with CH2Cl2, and the filtrate was concentrated in vacuo. Unpurified material (273 mg) was purified by chromatography on silica gel [Jones Flashmaster, 5 g / 25 mL cartridge, eluting with MeOH (NH3 7N): CH2Cl2 5% - * 10%], yielding 107.4 mg (43 %, 0.255 millimoles) of the compound of the particle, as a yellow solid, which contains 0.18 equivalents of DMF. The mixed fractions were also collected, yielding an additional 67.4 mg (maximum 16%, 0.159 millimoles) of the title compound, as a yellow solid, containing 0.8 equivalents of DMF; H NMR (CDCl 3, 400 MHz) d 1.88 (s, br, -NH 2), 3.97 (s, 2 H), 5.15 (s, 4 H), 7.05-709 (m, 1 H), 7.10 (d, J = 4.8 Hz, 1H), 7.29-747 (m, 9H), 7.51 (t, J = 7.8 Hz, 1 H), 7.63 (d, J = 5.2 Hz, 1 H), 7.69 (d, J = 7.6 Hz, 1 H), 7.81 (s, 1H); MS (ES +): m / z 422.0 (14) [MH +].

EXAMPLE 56 2-. { 3- [8-Amino-1- (3-benzyloxyphenyl) -imidazo [1,5-a] pyrazn-3-yl] -benzyl} -isoindol-1, 3-dione: To a solution / suspension of. { 3- [8-amino-1- (3-benzyloxy-phenyl) -midazo [1,5-a] p -razin-3-yl] -phenyl} -methane I (312 mg, 0.737 mmol), isoindol-1,3-dione (130 mg, 0.885 mmol), and PS-PPh3 (loading 2. 12 mmol / g; 696 mg, 1.47 mmol) in anhydrous THF (15 mL), was cooled to 0 ° C, DIAD (218 μL, 224 mg, 1.11 mmol) was added dropwise, under N2 atmosphere. After 10 minutes, the cooling bath was removed and the reaction mixture was stirred at room temperature for 3 days.

The resin was filtered on a glass funnel (porosity M) and washed with large volumes of THF and then with CH2Cl2. The filtrate was concentrated, adsorbed on Hydromatrix, and the unpurified material (0.6843 g) was purified by chromatography on silica gel [Jones Flashmaster, g / 70 mL, eluting with MeOH: CH2Cl2 0.5% > 3%], producing the compound of the title as a yellow solid. The sample contains «0.3 equivalents of reduced DIAD by 1H NMR; 1 H NMR (CDCl 3, 400 MHz) d 4.94 (s, 2 H), 5.07 (s, 2 H), 5.16 (s, 2 H), 7.07 (ddd, J = 8.4, 2.8, 1.2 Hz, 1 H), 7.11 (d , J = 5.2 Hz, 1 H), 7.28-7.33 (m, 3H), 7.33-7.36 (m, 1 H), 7.37-7.43 (m, 2H), 7.43-7.47 (m, 2H), 7.50 (t , J = 7.6 Hz, 1 H), 7.53-756 (m, 1 H), 7.62 (d, J = 5.2 Hz, 1 H), 7.72 (dd, J = 5.6, 2.8 Hz, 2H), 7.74-7.77 (m, 1H), 7.86 (dd, J = 5.2, 3.2 Hz, 2H), 7.92 (s, 1 H); MS (ES +): m / z 552.3 (100) [MH +].

EXAMPLE 57 4-8-Amino-1- [3- (2,6-difluoro-benzyloxy) -phenyl] -imidazo [1,5-a] pyrazin-3-yl] -aryl ester} -cyclohexanecarboxylic: The procedures were applied for 3-Cyclobutyl-1 - [3- (4-fluoro-benzyloxy) -phenyl] -imidazo [1, 5a] pyrazin-8-ylamine; MS (ES +): m / z 493.16 [MH4].

EXAMPLE 58 Acid 4-. { 8-Amino-1 - [3- (2,6-difluoro-benzyloxy) -phenyl] -imidazo [1,5-a] pyrazin-3-yl} -cyclohexanecarboxylic acid: The processes for saponification were applied to the synthesis of trans-4- [8-Amino-1- (3-benzyloxy-phenyl) -imidazo [1,5-a] pyrazin-3-yl] -cyclohexanecarboxylic acid it was applied to the 4- methyl acid ester. { 8-Amino-1- [3- (2,6-difluoro-benzyl-oxy) -phenyl] -imidazo [1,5-a] pyrazin-3-yl} -cyclohexanecarboxylic to produce the title compound; MS (ES +): m / z 479.10 [MH +].

EXAMPLE 59 cis-3- (3-Dimethylaminomethyl-cyclobuyl) -1- (3-benzyloxyphenyl) -imidazo [1,5-a] pyrazin-8-ylamine: A sealed tube containing a solution of 3- [8-amino acid] ester. Cis -toluene-4-sulfonic acid 1- (3-benzyloxyphenyl) -imidazo [1,5-a] pyrazin-3-yl] cyclobutylmethyl ester (100 mg, 0.18 mmol) in THF (3 mL) was charged with a solution of dimethylamine (1.8 mL, 3.6 mmol, 2.0 M in THF), sealed, and heated at 50 ° C overnight. The mixture was concentrated and the residue was diluted with ethyl acetate (40 mL), washed with saturated aqueous NaHCO3 (2 x 15 mL) and brine (2 x 15 mL), and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure, and the residue was crystallized to yield a white solid; LC-MS (ES, Pos.): M / z 428 [MH +]; 1 HOUR NMR (CDCl 3, 400 MHz) d 2.23 (s, 6H), 2.24-2.32 (m, 2H), 2.42 (d, J = 6.1 Hz, 2H), 2.61-2.69 (m, 3H), 3.64 (m, 1 H), 4.98 (br s, 2H, NH2), 5.15 (s, 2H), 7.00-7.04 (m, 2H), 7.12 (d, J = 5.0 Hz, 1 H), 7.23-7.27 (m, 2H), 731-7.46 (m, 6H).

EXAMPLE 60 cis -3- (3-Azetidin-1-ylmerylcyclobuyl) -1- (3-benzyloxyphenyl) -imidazo [1,5-a] pyrazin-8-ylamine: The procedures for 3- (3-dimethylaminomethyl-cyclobutyl) were followed -1- (3-benzyloxyphenyl) -imidazo [1,5-a] prazrazin-8-ylamine, replacing dimethylamine with azetidine, LC-MS (ES, Pos.): M / z 440 [MH +]. cs-3- (3-pyrrolidin-1-ylmethylcyclobuyl) -1- (3-benzyl-phenyl) -imidazo [1,5-a] pyrazin-8-ylamine: The procedures for - (3-D-methylaminomeyyl-cyclobutyl) -1- (3-benzyloxyphenyl) -imidazo [1,5-a] pyrazin-8-ylamine, replacing dimethylamine with pyrrolidine, LC-MS (ES, Pos.) : m / z 454 [MH +].

EXAMPLE 62 cis -3- (3-Azidomethyl-cyclobutyl) -1- (3-benzyloxyphenyl) -midazo [1,5-a] pyrazin-8-ylamine: A solution of 3- [8-amino-1-] ester Cis -toluene-4-sulfonic acid (3-benzyloxyphenyl) -imidazo [1,5- a] pyrazin-3-yl] -cyclobutylmethyl ester (100 mg, 0.18 mmol) in DMF (2 mL) was charged with sodium azide ( 35 mg, 0.54 mmol), the resulting mixture was stirred at room temperature overnight. The mixture was diluted with water (5 mL), then extracted with ethyl acetate (3 x 10 mL), the combined organic phases were washed with water (2 x 10 mL) and brine (10 mL), and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluting with 100% ethyl acetate), yielding the compound as a white solid.; LCMS (ES, Pos.): M / z 426 [MH +]; 1 H NMR (CDCl 3, 400 MHz) d 2.36-2.44 (m, 2 H), 2.63-2.79 (m, 3 H), 3.37 (d, J = 6.7 Hz, 2 H), 3.69 (m, 1 H), 5.14 (s) , 4H, -OCH2- and -NH2), 7.02-7.05 (m, 2H), 7.10 (d, J = 5.0 Hz, 1 H), 7.25-7.45 (m, 8H).

EXAMPLE 63 cis -3- (3-aminomethyl-cyclobulyl) -1- (3-benzyloxyphenyl) -imidazo [1,5-a] pyrazin-8-ylamine: cis-3- (3-Azidomethyl-cyclobuyl) -1- (3-benzyloxyphenyl) -imidazo [1,5-a] pyrazin-8-ylamine (35 mg, 0.082 mmol) was dissolved in ethanol (5 mL) after heating, the mixture was cooled to room temperature and charged with catalyst of Lindlar (30 mg). The mixture was hydrogenated at room temperature throughout the night. LC-MS showed that the reaction was complete and pure. The catalyst was removed by filtration through a pad of celite, the filtrate was concentrated and the residue was purified by mass directed purification to produce a white solid; LC-MS (ES, Pos.): M / z 400 [MH +]; 1 H NMR (CD 3 OD, 400 MHz) d 2.17-2.24 (m, 2 H), 2.56-2.67 (m, 3 H), 2.79 (d, J = 6.5 Hz, 2 H), 3.84 (m, 1 H), 5.17 (s) , 2H), 6. 98 (d, J = 5.1 Hz, 1 H), 7.15-7.47 (m, 10H).

EXAMPLE 64 cis -3- [8-Amino-1- (3-benzyloxy-phenyl) -imidazo [1,5-a] pyrazin-3-yl] -cyclobutane-carboxylic acid amide: A solution of cis-acid meitylic acid ester 3- [1 - (3-benzyloxy-phenyl) -8-chloro-imidazo [1,5-a] pyrazin-3-yl] -cyclobunecarboxylic acid (115 mg, 0.26 mmol) in 4 mL of 'PrOH was cooled at -78 ° C and charged with NH3 gas for 2 minutes. This sealed tube was equipped with an O-ring of Teflon, sealed and heated at 110 ° C overnight. The mixture was cooled to -78 ° C and the lid was removed. The mixture was diluted with EtOAc (30 mL) and washed with brine (15 mL), dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure and the unpurified product was purified by mass directed purification to yield an off white solid; LC-MS (ES, Pos.): M / z 414 [MH +]; 1 H NMR (CD 3 OD, 400 MHz) d 2.65-2.73 (m, 4 H), 3.24 (m, 1 H), 3.87 (m, 1 H), 5.17 (s, 2 H), 6.99 (d, J = 5.2 Hz, 1 H), 7.10-7.48 (m, 10H).

EXAMPLE 65 Trans-3- [8-amino-1- (3-benzyloxy-phenyl) -imidazo [1,5-a] pyrazin-3-yl] -cyclobutane-carboxylic acid amide: The title compound was prepared in accordance with the described procedure for cis-3- [8-Amino-1- (3-benzyloxy-phenyl) -imidazo [1,5-a] pyrazin-3-yl] -cyclobutane-carboxylic acid amide, mentioned above, LC-MS (ES, Pos.): M / z 414 [MH +]; 1 H NMR (CD 3 OD, 400 MHz) d 2.70-2.78 (m, 4 H), 3.28 (m, 1 H), 4.03 (m, 1 H), 5.18 (s, 2 H), 6.99 (d, J = 5.1 Hz, 1 H), 710-7.48 (m, 10H).

CONH2 a) cis meylic acid ester and trans-3- [1- (3-Benzyloxy-phenyl) -8-cyoroimidazo [1,5-a] pyrazin-3-yl] -cyclobutane-carboxylic acid: A solution of ( COCI) 2 (3.17 g, 2.2 mL, 25.0 mmol) in dry methylene chloride (20 mL) was charged with a solution of DMSO (3.90 g, 50.0 mmol) in methylene chloride (10 mL) drop by drop to -78. ° C low nilrogen. The resulting mixture was stirred at -78 ° C for 30 minutes, followed by the addition of. { 3- [1- (3-benzyloxyphenyl) -8-chloro-midazo [1,5-a] pyrazin-3-yl] cyclobutyl} methanol in methylene chloride (15 mL). The mixture was stirred at -78 ° C for 30 minutes, then quenched with Et3N (17.5 mL, 125 mmol) and slowly warmed to room temperature. The mixture was diluted with methylene chloride (100 mL), then washed with water (30 mL), saturated aqueous NaHCO 3 (2 x 30 mL) and brine (30 mL), and dried over anhydrous sodium sulfate. The CCF showed that the reaction was complete and produced the desired aldehydes (the trans isomer is less polar than the cis). Evaporation produced the unpurified product as a yellow oil, which was used directly in the next step. The above-mentioned aldehyde solution in anhydrous meianol (50 mL) was charged with NIS (6.75 g, 30 mmol) and potassium carbonate (4.14 g, 30 mmol), The resulting mixture was stirred in the dark at room temperature for the entire night. The CCF showed that the reaction was almost complete. The reaction was quenched with 20 mL of water and diluted with ethyl acetate (150 mL), then washed with saturated aqueous Na2S203 (2 x 30 mL) and brine (50 mL), and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure, and the unpurified material was purified by silica gel column chromatography (eluting with hexanes: EtOAc = 70:30 ^ 60: 40 * 50:50) by means of which the two isomers were separated, cis-3- [1- (3-Benzyloxy-phenyl) -8-chloro-imydazo [1,5-a] pyrazan-3-yl] -cyclobuman-carboxylic acid methylester: acetyl yellow; LC-MS (ES, Pos.): Only 448/450 (3/1) [MH +]; 1 H NMR (CDCl 3, 400 MHz) d 2.73-2.80 (m, 2 H), 2.89-2.97 (m, 2 H), 3.30 (m, 1 H), 3.70 (s, 3 H), 3.78 (m, 1 H), 5.14 (s, 2H), 7.04 (m, 1H), 7.26-7.47 (m, 9H), 7.58 (d, J = 5.0 Hz, 1 H). Irans-3- [1 - (3-Benzyloxy-phenyl) -8-chloro-imidazo [1, 5-a] pyrazin-3-yl] -cyclobutanecarboxylic acid methylester: yellow oil; LC-MS (ES, Pos.): M / z 448/450 (3/1) [MH +]; 1 H NMR (CDCl 3, 400 MHz) d 2.76-2.83 (m, 2 H), 2.88-2.95 (m, 2 H), 3.33 (m, 1 H), 3.77 (s, 3 H), 4.03 (m, 1 H), 5.14 (s, 2H), 7.05 (m, 1 H), 726-7.47 (m, 9H), 7.50 (d, J = 4.9 Hz, 1 H).

EXAMPLE 66 3- [8-Amino-1- (3-benzyloxy-phenyl) -imidazo [1,5-a] pyrazin-3-yl] -1-hydroxymethyl-cyclobutanol: To a solution of 1- (3-benzyloxyphenyl) - 8-Chloro-3- (3-methylenecyclobutyl) -imidazo [1,5-a] pyrrazine (1.0 g, 2.5 mmol) in THF (21 mL) and water (7 mL), NMO (1.0 mL, 5.0 mmol, 50% aqueous solution) and K20s04 * H20 (46 mg, 0.125 mmol). The resulting mixture was stirred at room temperature overnight. The CCF showed that the reaction had been completed. The reaction was quenched with Na2SO3 (1.60 g, 12.5 mmol). Water (15 mL) was added to dissolve the salts and the organic phase was separated. The aqueous phase was extracted with EtOAc (3 x 25 mL), and the combined organic phases were washed with brine (20 mL), and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure to yield a yellow solid, a mixture of two isomers in an almost 3: 2 ratio by 1 H NMR (CDCl 3, 400 MHz). LC-MS (ES, Pos.): M / z 436/438 (3/1) [MH +]. The solution of the aforementioned diol (260 mg, 0.6 mmol) in 5 mL of 'PrOH was cooled to -78 ° C and charged with NH3 gas for 1 minute. This sealed tube was equipped with a Teflon-0 ring, sealed and heated at 110 ° C overnight. The mixture was cooled to -78 ° C and the lid was removed. The mixture was diluted with methylene chloride (30 mL) and the salt filtered. The filtrate was concentrated under reduced pressure and the crude product was purified by silica gel column chromatography (100% ethyl acetate ^ EtOAc: MeOH = 95: 5 to 90:10), the title compound as a color solid pale, a mixture of two isomers in an almost 3: 2 ratio; LC-MS (ES, Pos.): M / z 417 [MH +]; 1 H NMR (CDCl 3, 400 MHz) d 2.54-2.80 (m, 4H), 2.80, 3.85 (2xm, 1 H, ratio 2: 3), 3.67, 3.71 (2xs, 2H, ratio 3: 2), . 06 (br s, 2H), 5.14 (s, 2H), 7.03-7.45 (m, 11 H).

EXAMPLE 67 AND 68 Ester 3- [8-amino-1- (3-benzyloxy-phenyl) -imidazo [1, 5-a] pyrazin-3-yl] -1-hydroxy-cyclobutylmethyl acid of cis- and trans-foluene-4-suphonic acid : A solution of 3- [8-amino-1- (3-benzyloxy-phenyl) -imidazo [1,5-a] pyrazin-3-yl] -1-hydroxymethyl-cyclobuanol (500 mg, 1.2 mmol) in chloride of dry methylene (10 mL) and pyridine (3 mL) was charged with a solution of Ts 0 (470 mg, 1.44 mmol) in methylene chloride (3 mL) at -40 ° C under N2 atmosphere. The mixture was slowly warmed to room temperature overnight. The CCF reported that the reaction had been completed. The reaction was quenched with water (2 mL), diluted with methylene chloride (40 mL), washed with saturated aqueous NaHCO 3 (2 x 15 mL) and brine (15 mL), and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure, and the unpurified material was purified by silica gel column chromatography (eluting with hexanes: EOAc = 50:50 * .30:70> -100% ethyl acetate, then 5%). % MeOH / EOAc) yielding each pure isomer, 3- [8-amino-1- (3-benzyloxy-phenyl) -imidazo [1,5-a] pyrazin-3-yl] -1-hydroxy-cyclobutylmethyl ester cis-toluene-4-sulfonic acid: less polar isomer, light yellow solid, LC-MS (ES, Pos.): m / z 571 [MH +]; 1 H NMR (CDCl 3, 400 MHz) d 2.46 (s, 3 H), 2.50-2.55 (m, 2 H), 2.79-2.84 (m, 2 H), 3.41 (m, 1 H), 4.10 (s, 2 H), 5.06 ( br s, 2H), 5.14 (s, 2H), 703-7.11 (m, 3H), 7.21-723 (m, 2H), 7.33-7.45 (m, 8H), 7.85 (d, J = 8.3 Hz, 2H ). 3- [8-amino-1- (3-benzyloxy-phenyl) -imidazo [1,5-a] pyrazin-3-yl] -1-hydroxy-cyclobutylmethyl ester of trans-Ioluene-4-sulfonic acid: solid light yellow, LC-MS (ES, Pos.): m / z 571 [MH +]; 1 H NMR (CDCl 3, 400 MHz) d 2.37 (s, 3 H), 2.60-2.70 (m, 4 H), 3.85 (m, 1 H), 4.24 (s, 2 H), 5.08 (br s, 2 H), 5.17 ( s, 2H), 6.99-7.08 (m, 3H), 7.20-7.27 (m, 3H), 7.33-7.47 (m, 7H), 7.71 (d, J = 8.3 Hz, 2H).

EXAMPLE 69 lrans-3- [8-Amino-1- (3-benzyloxy-phenyl) -imidazo [1,5-a] pyrazin-3-yl] -1-azetidin-1-ylmethyl-cyclobutanol: A sealed tube containing a solution of 3- (8-amino-1- (3-benzyloxy-phenyl) -imidazo [1, 5-a] pyrazin-3-yl] -1-hydroxy-cyclobuyl-amyl ester of rans-loluene-4-sulfonic acid (100 mg, 0.18 mmol) in THF (5 mL) was charged with azeidine (0.24 mL, 3.6 mmol), sealed, and heated at 50 ° C overnight. The mixture was concentrated and the residue was purified by mass directed purification to yield the title compound as a white solid.; LC-MS (ES, Pos.): M / z 456 [MH +]; 1 H NMR (CDCl 3, 400 MHz) d 2.05-2.12 (m, 2 H), 2.50-2.63 (m, 6 H), 3.30 (t, J = 7.0 Hz, 4 H), 3.96 (m, 1 H), 4.15 (br s, 1 H, -OH), 5.15 (s, 4H, -OCH2- and -NH2), 7.03-7.09 (m, 3H), 7.25-7.46 (m, 8H).

EXAMPLE 70 cis -3- [8-Amino-1 - (3-benzyloxy-phenyl) -imidazo [1,5-a] pyrazin-3-yl] -1-azetidin-1-ylmeryl-cyclobuanol: The compound of the title was prepared according to the procedure described for trans-3- [8-Amino-1- (3-benzyloxy-phenyl) -imidazo [1,5-a] pyrazin-3-yl] -1-azetidin-1-ylmethylamide Cyclobutanol mentioned above, white solid; LC-MS (ES, Pos.): M / z 456 [MH +]; 1 H NMR (CDCl 3, 400 MHz) d 2.05-2.17 (m, 2 H), 2.56-2.68 (m, 4 H), 2.70 (s, 2 H), 3.30 (m, 1 H), 3.39 (,, J = 7.0 Hz , 4H), 4.29 (br s, 1 H, -OH), 5.10 (br s, 2H), 5.14 (s, 2H), 701-7.05 (m, 2H), 7.13 (d, J = 5.0 Hz, 1 H), 722-7.26 (m, 2H), 7.33-7.46 (m, 6H).

EXAMPLE 71 1- [3- (4-Fer-Buzyoxy-benzyloxy) -phenyl] -3-cyclobutyl-imidazo [1,5-a] pyrraz-8-ylamine: A solution of 3- (8-) Amino-3-cyclobutyl-imidazo [1,5-a] pyrazin-1-yl) -phenol (200 mg, 0.71 mmol) in DMF (3.5 mL) was charged with Cs2CO3 (348 mg, 1.07 mmol) and stirred at Femperaíura ambient for 30 minutes. To the reaction mixture was added a solution of 1-bromomethyl-4-yer-butoxy-benzene (162 mg, 0.71 mmol) in 0.5 mL of DMF. After 15 hours, the reaction was completed by LC / MS analysis. The product was an orange / coffee solid. The unpurified product was chromatographed on silica gel [Jones Flashmaster, 5 g cartridge, eluting with 10% ethyl acetate]. The product was then recrystallized with ethyl acetate and hexanes to produce the title compound as a white solid; 1 H NMR (CDCl 3, 400 MHz) d 1.36 (s, 9 H), 2.11-2.23 (m, 2 H), 2.45-2.52 (m, 2 H), 2.59-2.69 (m, 2 H), 3.77-3.85 (m, 1 H), 5.08 (s, 2H), 5.49 (brs, 2H), 7.01-7.04 (m, 3H), 7.05 (dd, J = 4.00 Hz, 1 H), 7.10 (d, J = 5.02 Hz, 1H) , 7.23-7.25 (m, 1H), 7.29 (q, J = 40 Hz, 1 H), 7.34-7.36 (m, 2H), 7.41 (t, J = 16 Hz, 1 H); MS (ES +): m / z 443.04 (100) [MH +] EXAMPLE 72 2- [3- (8-Amyl-3-cyclobutyl-imidazo [1,5-a] pyrazin-1-yl) -phenoxymethyl] -Benzonitryl: A solution of 3- (8-Amino-3-cyclobutylimidazo [1, 5-a] pyrazin-1-yl) -phenol (500 mg, 1.78 mmol) in DMF (8.9 mL) was charged with Cs2CO3 (871 mg, 2.68 mmol) and stirred for 30 minutes at room temperature. A solution of 2-cyanobenzyl bromide (500 mg, 1.78 mmol) in DMF was added to the reaction mixture. After 24 hours at room temperature The reaction mixture was concentrated in vacuo and chromatographed on silica gel [Jones Flashmaster, 10 g cartridge, eluting with 50% EtOAchexanes at 100% EtOAc]. Then the product was recrystallized with CH2Cl2 and hexanes producing the title compound as a light red solid; 1 H NMR (CDCl 3, 400 MHz) d 2.02-2.06 (m, 1 H), 2.11-2.33 (m, 1 H), 2.45-2.53 (m, 2 H), 2.59-2.69 (m, 2 H), 3.77-3.86 (m, 1 H), 5.33 (s, 2H), 7.02- 7.04 (m, 1 H), 7.05 (dd, J = 2.4 Hz, 1 H), 7.10 (d, J = 5.2 Hz, 1 H), 729-730 (m, 1 H), 7.33 (q, J = 3.6, 1H), 7.40-764 (m, 2H), 7.61-766 (m, 1H), 770-772 (m, 2H); MS (ES +): m / z 395.99 (100) [MH +].

EXAMPLE 73 3-Cyclobutyl-1- [3- (2-nitro-benzyloxy) -phenyl] -midazo [1,5-a] pyrazin-8-ylamine: A solution of 3- (8-Amino-3-cyclobutyl-imidazo) [1, 5-a] pyrazin-1-yl) -phenol (2.00 g, 7.13 mmol) in DMF (36.7 mL) was charged with Cs2CO3 (3.48 g, 10.7 mmol) and stirred at room temperature for 30 minutes. Then a DMF solution of 2-nitrobenzyl bromide (1.54 g, 7.13 mmol) was added to the reaction mixture. The reaction was allowed to progress at room temperature under nitrogen for 3.5 hours. The analysis by TLC showed that the reaction was complete. The product was purified using silica gel column chromatography (1-3% NH 3 in MeOH: CH 2 Cl 2). The final product was concentrated to a yellow solid; 1 H NMR (CDCl 3, 400 MHz) d 2.00-2.08 (m, 1 H), 2.11-2.23 (m, 1 H), 2.45-2.53 (m, 2 H), 2.59-2.69 (m, 2 H), 3.77-3.86 (m, 1 H), 5.57 (s, 2H), 7.01-7.05 (m, 2H), 7.11 (d, J = 5.6 HZ, 1 H), 7.27-730 (m, 1 H), 7.32-733 ( m, 1 H), 7.42 (t, J = 16.4 Hz, 1H), 7.48-7.52 (m, 1 H), 7.67-7.71 (m, 1 H), 7.92 (dd, J = 8.0 Hz, 1 H) , 8.17 (d, J = 9.5 Hz, 1 H); MS (ES +): m / z 416.01 (100) [MH +].

EXAMPLE 74 1- [3- (2-Bromo-benzyloxy) -phenyl-3-cyclobutyl-imidazo [1,5-a] pyrazin-8-ylamine: A solution of 3- (8-Amino-3-cyclobuyl-lmidazo [1 , 5-a] pyrazin-1-yl) -phenol (100 mg, 0.36 mmol) in DMF (1.8 mL) was charged with Cs2CO3 (174 mg, 0.54 mmol) and stirred at room temperature for 30 minutes. A solution of 2-bromobenzyl bromide (89.2 mg, 0.36 mmol) in DMF was added to the reaction mixture. The reaction mixture was stirred overnight at room temperature under nitrogen. The unpurified product was left under high vacuum to remove the DMF for 2 hours. The product was then purified by silica gel column chromatography (3% NH 3 in MeOH): CH 2 Cl 2 to yield the title compound as a brown / red solid; 1 H NMR (CDCl 3, 400 MHz) d 2.02-2.08 (m, 1H), 2.14-2.21 (m, 1 H), 2.45-2.53 (m, 2H), 2.59-2.69 (m, 2H), 3.77-3.85 (m, 1 H), 5.21 (s, 2H), 7.00 (d, J = 5.6 Hz, 1 H), 7.04-7.07 (m, 1 H), 7.11 (d, J = 5.2 Hz, 1 H), 718-7.23 (m, 1 H), 7.25-7.30 (m, 2H), 7.33-7.37 (m, 1 H), 7.42 (t, J = 16 Hz, 1 H), 755-761 (m, 2H); MS (ES +): m / z 450.81 (100) [MH +].

EXAMPLE 75 1- [3- (3-Aminomethyl-benzyloxy) -phenyl] -3-cyclobutyl-imidazo [1,5-a] pyrazin-8-ylamine: 2-. { 3- [3- (8-Amino-3-cyclobutyl-imidazo [1,5-a] pyrazin-1-yl) -phenoxymethyl] -benzyl} -isoindole-1,3-dione (100 mg, 0.19 mmol) was dissolved in EtOH (0.76 mL) and charged with hydrazine (60 mg, 1.89 mmol) and stirred overnight at room temperature. The white precipitate was filtered and washed with EtOH. The filtrate was concentrated in vacuo, silica gel in CH2Cl2 was added, and concentrated to a solid. The product was chromatographed on silica gel [Jones Flashmaster, 2 g cartridge, eluting with -2% NH 3 7N MeOH: CH 2 Cl 2] and the title compound was isolated as a yellow solid; 1 H NMR (CDCl 3, 400 MHz) d 1.84-1.92 (m, 1 H), 1.97-2.09 (m, 1 H), 2.34-2.40 (m, 2 H), 2.44-2.46 (m, 2 H), 3.69 (s, 2H), 3.84-3.92 (m, 1 H), 5.10 (s, 2H), 6.96 (d, J = 5.2 Hz, 1 H), 7.01-7.03 (m, 1H), 7.13-716 (m, 1 H ), 7.18-719 (m, 1 H), 7.23-7.32 (m, 3H), 735-740 (m, 3H); MS (ES +): m / z 400.17 (100) [MH +].

EXAMPLE 76 3- [3- (8-Amino-3-cyclobutyl-1-dimetho [1,5-a] pyrazin-1-yl) -phenoxymethyl] -benzoic acid methylester. A solution of 3- (8-Amino-3-cyclobuyl-imidazo [1,5-a] pyrazin-1-yl) -phenol (2.87 g, 10.2 mmol) in DMF was charged with Cs2CO3 (4.98 g, 15.3 mmol). and stirred to lemperaíura ambienie for 30 minutes. A DMF solution of methyl (3-bromomethyl) benzoate (2.33 g, 10.2 mmol) was added to the reaction mixture. The reaction mixture was stirred overnight at room temperature under nitrogen. The unpurified product was placed under high vacuum to remove residual DMF. Then the product was purified using silica gel column chromatography (1% NH 3 in MeOH: CH 2 Cl 2). The product was recrystallized with CH2Cl2 and hexanes to give the title compounds as a white solid; 1 H NMR (CDCl 3, 400 MHz) d 2.00-2.07 (m, 1 H), 2.11-2.22 (m, 1 H), 2.45-2.52 (m, 2H), 2.58-2.68 (m, 2H), 3.76-3.85 (m, 1 H), 3.93 (s, 3H), 5.18 (s, 2H), 701-704 (m, 2H), 710-711 (m, 1 H), 7.24-7.29 (m, 2H), 738 -7.49 (m, 2H), 7.65 (d, J = 7.6 Hz, 1 H), 8.01 (d, J = 8.0 Hz, 1 H), 8.13 (s, 1 H); MS (ES +): m / z 429.18 (100) EXAMPLE 77 3- [3- (8-Amino-3-cyclobuyl-imidazo [1, 5-a] pyrazin-1-yl) -phenoxymethyl] -Benzamide: 3- [3- (8-Amino-3-) methyl ester cyclobutyl-imidazo [1, 5-a] pyrazin-1-yl) -phenoxymethyl] -benzoic acid (150 mg, 0.35 mmol) was dissolved in a sealed tube with 2.0 ml of 7N NH3 in MeOH and heated to 60 ° C. all night. The LC / MS analysis indicated that the reaction was incomplete, therefore the NH3 gas was bubbled in from the solution and the reaction was run at 100 ° C in a Parr vessel at 100 mL pressure. The product was subjected to chromatography on silica gel [Jones Flashmasier, 5 g cartridge, eluting with 2% NH 3 in MeOH: CH 2 Cl 2] to produce the title compound as a white solid; 1 H NMR (CDCl 3, 400 MHz) d 1.99-2.08 (m, 1 H), 2.13-2.25 (m, 1 H), 2.46-2.55 (m, 2 H), 2.55-2.65 (m, 2 H), 3.78-3.87 (m, 1 H), 5.21 (s, 2H), 6.95 (d, J = 5.2 Hz, 1 H), 708-711 (m, 1 H), 7.13 (d, J = 5.6 Hz, 1 H), 7.22-7.24 (m, 2H), 7.42-7.51 (m, 2H), 7.61 (d, J = 8.4 Hz, 1 H), 780-7.83 (m, 1 H), 7.94 (s, 1 H); MS (ES +): m / z 414.21 (100) [MH +].

EXAMPLE 78 . { 3- [3- (8-Amino-3-cyclobutyl-imidazo [1, 5-a] pyrazin-1-yl) -phenoxymethyl] -phenyl} -methane: A solution of 3- [3- (8-Amino-3-cyclobutyl-imidazo [1,5-a] pyrazin-1-yl) -phenoxymethyl] -benzoic acid methylester (600 g, 1.40 mmol) in THF it was cooled to -78 ° C in an acetone / dry ice bath for 5.0 minutes. The reaction was purged with nitrogen and charged dropwise with 1 M lithium aluminum hydride (LAH) (1.40 mL). After all the LAH had been added, the solution was removed from the bath and allowed to warm to room temperature (ía). As the solution warmed up, a solid formed on the sides of the flask. The reaction mixture was then charged with ethyl acetate, Na 2 SO 4 0H 2 O and silica. This solution was then concentrated in vacuo until obtaining a solid, and subjected to chromatography on silica gel [Jones Flashmaster, 50 g cartridge, eluting with 2% NH 3 in MeOH: CH 2 Cl 2] to produce the title compound as a solid. White; 1 H NMR (CDCl 3, 400 MHz) d 1.99-2.07 (m, 1 H), 2.11-2.22 (m, 1 H), 2.44-2.52 (m, 2 H), 2.58-2.68 (m, 2 H), 3.76-3.84 (m, 1H), 4.69 (s, 2H), 5.16 (s, 2H), 6.98 (d, J = 13.2 Hz, 1 H), 7.02-7.05 (m, 1 H), 7.08 (d, J = 4.8) Hz, 1 H), 716-7.17 (m, 2H), 7.25-7.28 (m, 1 H), 7.35-7.43 (m, 5H); MS (ES +): m / z 401.19 (100) [MH +].

EXAMPLE 79 2-. { 3- [3- (8-Amino-3-cyclobuyl-imidazo [1, 5-a] pyrazin-1-yl) -phenoxymethyl] -benzyl} -isoindole-1, 3-dione: Fíalimida (44 mg, 0.25 mmol), PS-triphenylphosphine (169 mg, 0.37 mmol) and. { 3- [3- (8-Amino-3-cyclobutyl-imidazo [1, 5-a] pyrazin-1-yl) -phenoxymethyl] -phenyl} -methanol (100 mg, 0.25 mmol) was added to dry rbf and dissolved with THF (1.25 mL), which was subsequently evacuated and purged three times with nitrogen. DIAD (61 mg, 0.30 mmol) was added slowly to the reaction mixture and allowed to stir slowly for 24 hours at room temperature. The LC / MS analysis indicated that the reaction was almost completed with some residual initial material, but mainly it was a product. Therefore, 0.2 equivalents of DIAD and phthalimide were added and the reaction was allowed to proceed. The reaction mixture was filtered through a glass funnel and washed with CH2Cl2 multiple times. The filtrate was concentrated to a red / brown oil and purified using silica gel column chromatography (1% NH 3 in MeOH: CH 2 Cl 2) to yield the title compound; 1 H NMR (CDCl 3, 400 MHz) d 2.00-2.09 (m, 1 H), 2.11-2.23 (m, 1 H), 2.45-2.53 (m, 2 H), 2.59-2.69 (m, 2 H), 3.77-3.85 ( m, 1 H), 4.87 (s, 2H), 5.11 (s, 2H), 6.99-702 (m, 2H), 7.10 (d, J = 5.2 Hz, 1 H), 7.23-7.26 (m, 2H) , 7.35-7.42 (m, 4H), 7.49 (s, 1 H), 7.69-7.73 (m, 2H), 7.82-7.87 (m, 2H); MS (ES +): m / z 530.14 (100) [MH +].

EXAMPLE 80 3- [3- (8-Amino-3-cyclobutyl-imidazo [1,5-a] pyrazin-1-yl) -phenoxymethyl-benzoic acid: 5 mL of a methanolic solution of 3- [3- methyl ester] (8-Amino-3-cyclobutyl-imidazo [1,5-a] pyrazin-1-yl) -phenoxymethyl] -benzoic acid (600 mg, 1.40 mmol) with 5 mL of THF was charged with 5 mL of 10 N NaOH and The reaction mixture was heated to 60 ° C. After 1 hour, the reaction was allowed to cool to room temperature and the pH of the reaction mixture decreased to 3-4. A white precipitate formed, which was filtered and washed with hexanes to produce the compound of the product as a white powder; 1 H NMR (CDCl 3, 400 MHz) d 1.90-1.97 (m, 1H), 2.04-2.15 (m, 1 H), 2.36-2.56 (m, 4H), 3.60-3.79 (m, 1 H), 5.10 (s) , 2H), 6.84 (d, J = 5.2 Hz, 1 H), 6.97-701 (m, 1 H), 7.07 (d, J = 5.6 Hz, 1 H), 712-715 (m, 2H), 7.32 -7.40 (m, 2H), 7.54 (d, J = 7.2 Hz, 1 H), 7.91 (d, J = 7.6 Hz, 1 H), 8.02 (s, 1 H); MS (ES +): m / z 415.15 (100) [MH4].

EXAMPLE 81 3- [3- (8-Amino-3-cyclobuyl-imidazo [1,5-a] pyrazin-1-yl) -phenoxymethyl] -N-methyl-benzamide: A solution of 3- [3] acid - (8-Amino-3-cyclobutyl-imidazo [1,5-a] pyrazin-1-yl) -phenoxymethyl] -benzoic acid (100 mg, 0.24 mmol) and methylamine HCl (163 mg, 2.41 mmol) in DMF (1.2 mL) was loaded with DIEA (0.42 mL, 2.41 mmol), HOBt (37.0 mg, 0.24 mmol), and EDC (69.0 mg, 0.36 mmol). The brown reaction mixture was allowed to stir for 18 hours. In LC / MS analysis indicated that the reaction was almost complete. The reaction was heated to 50 ° C and allowed to react for an additional 18 hours. The DMF was removed in vacuo and the product was chromatographed on silica gel [Jones Flashmaster, 5 g cartridge, eluting with 2% NH 3 7N MeOH: CH 2 Cl 2] to afford the title compound as a pink solid; 1 H NMR (CDCl 3, 400 MHz) d 1.99-2.07 (m, 1 H), 2.11-2.20 (m, 1 H), 2.44-2.50 (m, 2 H), 2.57-2.67 (m, 2 H), 3.01 (d , J = 5.2 Hz, 3H), 3.76-3.85 (m, 1 H), 5.17 (s, 2H), 6.99-702 (m, 2H), 7.10 (d, J = 5.2 Hz, 1H), 7.24-7.27 (m, 2H), 7.37-7.46 (m, 2H), 7.55 (d, J = 7.6 Hz, 1 H), 7.71 (d, J = 7.6 Hz, 1 H), 7.85 (s, 1 H); MS (ES +): m / z 428.17 (100) [MH4].

EXAMPLE 82 1- (3-Benzyloxy-phenyl) -3- (3-methoxymethylene-cyclobutyl) -imidazo [1,5-a] pyrazin-8-ylamine: Prepared according to the procedures for 1- (3-benzyloxy-phenyl) 3-cyclobutyl imidazo [1, 5-a] prazin-8-ylamine; light brown foam; 1 H NMR (CD 3 OD, 400 MHz) d 3.27-3.29 (m, 4 H), 3.58 (s, 3 H), 3.85 (q, 1 H, J = 7.7 Hz), 5.13 (s, 2 H), 5.93 (s, 1 H), 7.26-7.66 (m, 11 H); MS (ES) 413.15 (M + 1), 414.11 (M + 2), 415.12 (M + 3). a) 1- (3-Benzyloxy-phenyl) -8-chloro-3- (3-methoxymethylene-cyclobutyl) -imidazo [1,5-a] pyrazine: To a solution of Ph3PCH2OMeCI (2.6 g, 7.44 mmol) in benzene (37 mL) was added a solution of sodium urea-amylate (819.0 mg, 7.44 mmol) in benzene (9.0 mL) at room temperature. The dark red solution was allowed to stir at ambient temperature for 10 min. At which point a solution of 3- [1- (3-benzyloxy-phenyl) -8-chloroimidazo [1,5-a] pyrazin was added. -3-yl] -cyclobutanone in benzene (30.0 mL) was good at ambient temperature. Then the reaction mixture was heated at 70 ° C for 4 hours. Subsequently, the reaction was quenched with saturated aqueous NH CI and extracted with diethyl ether (3x). The organic layers were washed with H20 (1x), brine (1x), dried over Na2SO, filtered and concentrated in vacuo. Purification via HPFC using a Jones gel column of 50 g (30% EtOAc: Hex) to produce the desired product as a light yellow solid; 1 H NMR (CDCl 3, 400 MHz) d 3.29-3.33 (m, 4 H), 3.59 (s, 3 H), 3.90 (q, 1 H, J = 8.2 Hz), 5.14 (s, 2 H), 5.93 (s, 1 H), 7.26-766 (m, 11 H); MS (ES) 432.05 (M + 1), 434.01 (M + 3), 435.02 (M + 4).

EXAMPLE 83 3- [8-Amino-1 - (3-benzyloxy-phenyl) -imidazo [1,5-a] pyrazin-3-yl) cyclobutanecarbaldehyde: To a solution of methylene chloride (6.0 mL) of 1- (3-benzyloxy) phenyl) -3- (3-methoxymethylene-cyclobuyl) -imidazo [1,5-a] pyrazin-8-ylamine (287.0 mg, 0.696 mmol), CF3C02H (0.11 mL, 1392 mmol) was added, followed by H20 (0.5 mL). The reaction mixture was allowed to react for 1 hour at ambient temperature. After which an aeolic solution (5.0 mL) of K2CO3 (192.3 mg, 1392 mmol) was added to the reaction and allowed to stir at ambient temperature for an additional 2 hours. The reaction mixture was extracted with water and EOAc. The organic layers were washed with brine (1x), dried over Na 2 SO 4, filled and concentrated in vacuo to yield the desired product as a brown solid; 1 H NMR (CDCl 3, 400 MHz) (mixture of cis and trans isomers) d 2.45-2.84 (m, 4H), 3.25-3.32 (m, 1 H), 3.74-3.79 (m, 1 H), 5.22 (s, 2H), 6.84-6.85 (m, 1 H), 7.00-717 (m, 5H), 7.27-7.39 (m, 6H), 9.69 (s, 1 H), 9.88 (s, 1 H); EM (ES) 399. 07 (M + 1), 400.0 (M + 2), 401.0 (M + 3).

EXAMPLE 84-A AND 84-B cis / trans-1- (3-Benzyloxy-phenyl) -3- (4-meioxy-cyclohexyl) -imidazo [1,5-a] pyrazn-8-ylamine: Prepared in accordance with the procedures for 1- ( 3-Benzyloxy-phenyl) -3-cyclobutyl-imidazo [1,5-a] pyrazin-8-ylamine; 84-A (cis isomer): Whitish solid, 1 H NMR (CDCl 3, 400 MHz) d 1.59-2.11 (m, 5H), 2.12-2.21 (brm, 3H), 3.01 (m, 1 H), 3.35 (s, 3H), 3.56 (brs, 1 H), 5.15 (s, 2H), 6.92 (d, 1 H, J = 5.4 Hz), 7.09 (dd, 1 H, J = 0.9 Hz), 7.20-752 (m, 9H); MS (ES) 430.16 (M + 1), 431.11 (M + 2), 432.12 (M + 3). 84-B (isomer rans): Whitish solid, 1 H NMR (CDCl 3, 400 MHz) d 1.30-1.34 (m, 4 H), 1.80-2.22 (brm, 6 H), 2.85 (t t, 1 H, J = 3.6 Hz) , 3.18-3.31 (m, 1 H), 3.33 (s, 3H), 5.03 (s, 2H), 6.93 (d, 2H, J = 5.4 Hz), 719-738 (m, 9H); a) 1 - (3-Benzyloxy-phenyl) -8-chloro-3- (4-methoxy-cyclohexyl) -imidazo [1,5-a] pyrazine: Prepared according to the procedures for 1- (3-Benzyloxy- phenyl) -8-chloro-3-cyclobuyl-imidazo [1,5-a] pyrazine using [4- (3-benzyloxy-phenyl) - (3-chloro-pyrazin-2-yl) -methyl] -amide meloxy-cyclohexanecarboxylic acid (331.0 mg, 0.71 mmol), POCI3 (3.0 mL); oil yellow; MS (ES) 448.11 (M + 1), 450.13 (M + 3), 451.08 (M + 4). b) [(3-benzyloxy-phenyl) - (3-chloro-pyrazin-2-yl) -methyl] -amide of 4-meioxy-cyclohexanecarboxylic acid: Prepared in accordance with the procedures for [(3-benzyloxy-phenyl)] - (3-Chloro-pyrazin-2-yl) -methyl] -amide of cyclobufcarcarboxylic acid using 4-methoxy-cyclohexanecarboxylic acid (145.7 mg, 0.92 mmol), EDC (264.8 mg, 1.38 mmol), HOBt (141.1 mg, 0.92 mmol) ) and C- (3-Benzyloxy-phenyl) -C- (3-chloro-pyrazin-2-yl) -methylamine (300.0 mg, 0.92 mmol); was purified using a 5 g Jones silica column, (30% EtOAc: Hex) to yield the title compound as a light yellow solid; 1 H NMR (CDCl 3, 400 MHz) d 1.44-2.23 (m, 10 H), 3.29 (s, 3 H), 5.02 (s, 2 H), 6.53 (l, 1 H, J = 8.0 Hz), 6.91-6.94 (m , 3H), 6.86-7.41 (m, 7H), 8.31 (t, 1 H, J = 3.0 Hz), 8.53 (d, 1 H, J = 2.6 Hz); MS (ES) 466.41 (M + 1), 468.38 (M + 3), 469.45 (M + 4).

EXAMPLE 85 cis-ter-BuÍiI ( { 3- [8-amino-1- (3-benzyloxyphenyl) -imidazo [1, 5-a] pyrazin-3-yl] -cyclobuityl} oxy) acetyl: Prepared in accordance with the procedures for 1- (3-Benzyloxy-phenyl) -3-cyclobutyl-imidazo [1,5-a] pyrazin-8-ylamine; 1 H NMR (400 MHz, CD 3 OD) d 7.48-731 (m, 7 H), 7.26 (l, J = 1.6 Hz, 1 H), 7.20 (id, J = 1.2, 6.4 Hz, 1 H), 7.13 (dd, J = 4, 8 Hz, 1 H), 6.99 (d, J = 5.2 Hz, 1 H), 5.18 (s, 2 H), 4.21 (p, J = 6.8 Hz, 1 H), 3.99 (s, 2 H) , 3.43-3.35 (m, 1 H), 2.87-2.81 (m, 2H) 2.49-2.41 (m, 2H), 1.49 (s, 9H). MS (ES +): m / z 501 (100) [MH4]. a) cis-tert-Buil (. {3- [8-chloro-1 - (3-benzyloxyphenyl) imidazo [1,5-a] prazraz-3-yl] cyclobutyl} oxy] acetylation: cis-3- [1- (3-Benzyloxyphenyl) -8-chloroimidazo [1,5-a] pyrazin-3-yl] cyclobuanol (1.58 mmol, 640 mg) was dissolved in THF (8 mL) and cooled at -78 ° C when charged with sodium bis (yrimethyl) amide (2.37 mmol, 2.37 mL), followed by the addition of fer-builoyl bromoacetate (3.15 mmol, 0.47 mL) portion by portion. The reaction mixture was stirred at -20 ° C for 30 minutes and 0 ° C for 1 hour before it was allowed to warm to ambient temperature slowly and stirred for 16 hours. The reaction mixture was concentrated under reduced pressure, dissolved in DCM; it was washed with water (3 X 15 mL) and dried over Na2SO4. The unpurified oil was purified by silica gel column chromatography (Jones Flashmaster, 50 g / 150 mL cartridge, eluting with EtOAc: hexane (2: 3)), yielding the compound of the product as a colorless oil; 1 H NMR (400 MHz, CDCl 3) d 7.53 (d, J = 4.8 Hz, 1 H), 7.46 (d, 1 H, J = 8.0 Hz, 1 H), 7.40-7.27 (m, 7 H), 7.04 (dd) , J = 2.0, 8.0 Hz, 1 H), 5.14 (s, 2H), 4.25 (p, J = 8.0 Hz, 1 H), 3.36-3.27 (m, 1 H), 2.90-2.84 (m, 2H) , 2.70-2.62 (m, 2H), 1.48 (s, 9H).

EXAMPLE 86 cis-2-. { 3- [8-Amino-1- (3-benzyloxyphenyl) imidazo [1,5-a] pyrazin-3-yl] cyclobudoxy} ethanol: cis-ér-Bulil ( { 3- [8-amino-1 - (3-benzyloxyphenyl) -imidazo [1, 5 a] pyrazin-3-yl] cyclobuyl.} oxy) acetamide (0.4 mmol) , 200 mg) was dissolved in THF (2 mL) and charged with LiAIH4 (4 mmol, 4 mL, 1 M in THF) at -78 ° C, and stirred under ambient temperaure for 1 hour before the mixture reaction was heated to 50 ° C for 16 hours. The mixture was charged with EOAc and allowed to stir at ambient temperalure for 10 min, followed by an addition of Na2SOOH2O. The reaction mixture was passed through a pad of Celite and concentrated under reduced pressure. The crude oil was purified by silica gel column chromatography (Jones Flashmaster, 20 g / 70 mL cartridge, eluting with 1-3% MeOH in DCM), yielding the title compound as a colorless oil; NMR 1 H NMR (400 MHz, CD 3 OD) d 7.47 (td, 2H), 7.43-7.42 (m, 1 H), 7.39-7.36 (m, 2H), 7.33-7.29 (m, 1 H), 7.25 (t, J = 2.0 Hz, 1 H), 7.19 (id, J = 1.2 Hz, 8 Hz, 1 H), 7.13 (d, J = 2.4 Hz, 8.0 Hz, 1 H), 6.98 (d, J = 4.8 Hz, 1 H), 5.17 (s, 2H), 4.16 (p, J = 7.2 Hz, 1 H), 3.66-3.65 (m, 2H), 3.51 (f, J = 2.4 Hz, 2H), 3.50-3.43 (m , 1H), 2.88-2.81 (m, 2H), 2.46-2.38 (m, 2H). MS (ES +): m / z 431 (100) [MH4].

EXAMPLE 87 Esther 2-. { 3- [8-amino-1- (3-benzyloxyphenyl) imidazo [1,5-a] pyrazin-3-yl] cyclobudoxy} of cis-to-4-sulfonic acid: Following the described processes of εylation for the ester 3- [8-amino-1- (3-benzyloxyphenyl) -imidazo [1,5-a] pyrazin-3-yl) ] toluene-4-sulfonic acid cyclobutyl methyl previously described; 1 H NMR (400 MHz, CDCl 3) d 7.85-7.76 (m, 2H), 7.47-7.29 (m, 9H), 721-7.06 (m, 4H), 6.81 (d, J = 8.0 Hz, 1H), 5.19 ( s, 2H), 4.20-4.10 (m, 3H), 3.65-3.60 (m, 2H), 3.34-3.27 (m, 1H), 2.84-2.80 (m, 2H), 2.57-2.44 (m, 2H), 2.44-2.41 (m, 4H). MS (ES +): m / z 585 (100) [MH4].

EXAMPLE 88 cis-1- (3-Benzyloxyphenyl) -3- [3- (2-dimethylaminoefoxy) -cyclobutyl] imidazo [1,5-a] pyrazin-8-yl-amine: Following the general procedures described in Examples 33 and 34; 1 H NMR (400 MHz, CD3OD) d 7.47-7.44 (m, 3H), 7.42-7.35 (m, 3H), 7.33-7.28 (m, 1 H), 7.25-7.24 (m, 1 H), 7.19 (td, J = 0.8 Hz, 8.0 Hz, 1 H), 7.12 (ddd, J = 0.8 Hz, 2.8 Hz, 8.0 Hz, 1 H), 6.98 (d, J = 5.2 Hz, 1 H), 5.17 (s, 2 H), 4.12 ( q, J = 8.0 Hz, 1 H), 3.55 (t, J = 5.2 Hz, 2H), 3.49-3.40 (m, 1 H), 2.85-2.82 (m, 2H), 2.61 (t, J = 5.6 Hz , 2H), 2.42-2.39 (m, 2H), 2.32 (s, 6H). MS (ES +): m / z 458 (100) [MH4].

EXAMPLE 89 Cis-acid. { 3- [8-Amino-1- (3-benzyloxy-phenyl) imidazo [1,5-a] pyrazn-3-yl] -cyclobuzoxy} acetic acid: cis-ér-Butyl ( { 3- [8-chloro-1 - (3-benzyloxyphenyl) imidazo [1,5-a] pyrazin-3-yl] cyclobuyl.} oxy) acetylene (0.1 mmol, 50 mg) was dissolved in 1 mL DCM and cooled in an ice bath when charged with Et3SiH (0.1 mmol, 15 μL) and 1 mL of TFA. The reaction mixture was heated to ambient temperature for 1 hour and stirred for another hour at room temperature. The reaction mixture was diluted with 10 mL of DCM and quenched with an aqueous solution of K2C03 (20 mL). The desired product was extracted in an aqueous layer and the impurities from the reaction were left in the organic phase. The aqueous phase was acidified to pH 3 before it was washed with DCM (3 X 15 mL). The DCM solution was dried over Na2SO and concentrated under reduced pressure. The unpurified oil was taken to the next step without purification; 1 H NMR (400 MHz, CD 3 OD) d 7.65 (d, J = 8.0 Hz, 2H), 7.52-7.45 (m, 4H), 7.40-7.36 (m, 2H), 7.34-7.32 (m, 2H), 7.26 ( d, J = 8.0 Hz, 1 H), 7.25-7.19 (m, 2H), 6.96 (d, J = 6.4 Hz, 1 H), 5.18 (s, 2H), 4.25 (p, J = 6.8 Hz, 1 H), 3.50 (p, J = 6.8 Hz, 1 H), 2.90-2.83 (ni, 2H), 2.55-2.46 (m, 2H). MS (ES +): m / z 445 (100) [MH4].

EXAMPLE 90 cis-2-. { 3- [8-Amino-1- (3-benzyloxyphenyl) imidazo [1,5-a] pyrazin-3-yl] cyclobudoxy} -N-meyilaceiamide: Following the general procedures described in Example 37; 1 H NMR (400 MHz, CD 3 OD) d 7.47-7.41 (m, 4 H), 7.37 (l, J = 7.6 Hz, 2 H), 7.32-728 (m, 1 H), 7.25 (t, J = 1.6 Hz, 1 H), 7.20 (d, J = 8 Hz, 1 H), 7.13 (id, J = 1.2 Hz, 8 Hz, 1 H), 6.99 (d, J = 5.2 Hz, 1 H), 5.17 (s, 2 H) ), 4.18 (p, J = 8 Hz, 1 H), 3.91 (s, 2H), 3.46 (p, J = 8 Hz, 1 H), 2.88-2.79 (m, 2H), 2.76 (s, 3H) , 2.50-2.43 (m, 2H). MS (ES +): m / z 458 (100) [MH4].

EXAMPLE 91 cis-2-. { 3- [8-Amino-1- (3-benzyloxy-phenyl) imidazo [1,5-a] pyrazin-3-yl] cyclobutoxy} Aceiamide was prepared from cis-tert -Buyl (. {3- [8-chloro-1- (3-benzyloxyphenyl) imidazo [1,5-a] pyrazin-3-yl] cyclobutyl} oxy) acephate. following the procedures for 1- (3-Benzyloxy-phenyl) -3-cyclobutyl-imidazo [1,5-a] pyrazin-8-ylamine; 1 H NMR (400 MHz, CDCl 3) d 7.34-7.21 (m, 6H), 7.15-7.10 (m, 3H), 6.96-6.93 (m, 1 H), 6.91 (d, J = 4.8 Hz, 1 H) , 6.50 (b, 1 H), 5.74 (b, 1 H), 5.19 (b, 2H), 5.04 (s, 2H), 4.02 (p, J = 0.8 Hz, 1 H), 3.71 (s, 2H) , 3.25 (p, J = 2 Hz, 1 H), 2.72-2.65 (m, 2H), 2.31-2.26 (m, 2H). MS (ES +): m / z 444 (100) [MH4].

EXAMPLE 92 1- (3-benzyloxy-4-methoxy-phenyl) -3-cyclobutyl-imidazo [1,5-a] pyrazin-8-ylamine: A solution jPrOH (5 ml) / DCM (4 ml) of 1- (3 -benzyloxy-4-mexoxyphenyl) -8-chloro-3-cyclobutyl-imidazole [1, 5-a] pyrazine (290 mg, 87%, 0.601 mmol), was cooled to -78 ° C in a dry ice bath. acetone was charged with liquid NH3 for 15 min. The sealed sump was equipped with a Teflon gas scrubber tower, sealed and heated at 110 ° C for 14 hours. After that time, the excess NH3 and the solvent evaporated. The remaining material was purified by chromatography on silica gel to obtain the title compound as a brown oil. Impurities that could not be removed by conventional methods (for example CCF, CLAR, etc.), were removed by SCX column (washed with 7 ml of DCM, 7 ml of MeOH and 7 ml of NH32N in MeOH); 1 H NMR (CDCl 3, 400 MHz) d 2.00-2.24 (m, 2H), 2.42-2.66 (m, 4H), 3.78 (quinite, 1H, J = 8.4 Hz), 3.95 (s, 3H), 4.95 (brs, 2H), 5.23 (s, 2H), 6. 98-702 (m, 2H), 7.07 (d, 1 H, J = 5.2 Hz), 7.17 (d, 1 H, J = 2.0 Hz), 7.23 (dd, 1 H, J = 2.0 and 8.0 Hz), 7.29-7.45 (m, 5H); MS (ES): 401.1 (M + 1). (a) 1 - (3-Benzyloxy-4-mexoxyphenyl) -8-chloro-3-cyclobuylimidazo [1,5-a] pyrazine: [(3-benzyloxy-4-meioxy-phenyl) - (3-chloropyrazine- 2-yl) -methyl] -cyclobufcarcarboxylicamide (308 mg, 0.703 mmol) was dissolved in POCI3 (5 ml) and heated at 55 ° C for 17 hours. After that time, the excess of POCI3 was removed in vacuo and the remaining mixture was basified with NH3 (2 N in 'PrOH). The precipitate formed was filtered and washed with CH2Cl2, and the filtrate was purified by chromatography on silica gel to obtain a yellow-brown solid of the compound of the polymer (87% purity by LC-MS); 1 H NMR (DMSO-de, 400 MHz) d 2.03-2.20 (m, 2H), 2.47-2.67 (m, 4H), 3.95 (s, 3H), 5.22 (s, 2H), 7.00 (d, 1H, J = 8.0 Hz), 7.25-747 (m, 8H); MS (ES): 420.0 / 422.1 (M / M + 2). (b) [(3-benzyloxy-4-methoxyphenyl) - (3-chloropyrazin-2-yl) -methyl] -amide of cyclobutanecarboxylic acid: Within the solution DMF (6 ml) of C- (3-benzyloxycarboxylic acid) 4-mexoxyphenyl) -C- (3-chloropyrazin-2-yl) -methylamine (290 mg, 0.815 mmol), cyclobufcarcarboxylic acid (156 μl, 2 equivalents) and Ef3N (342 μl, 3 equivalents), EDC hydrochloride was added (469 mg, 3 equivalents) and HOBt monohydrate (250 mg, 2 equivalents) at ambient temperature under N 2, after stirring for 24 hours at room temperature, the mixture was poured into saturated Na 2 CO 3 (10 ml) and H 2 O (10 ml ), extracted with EtOAc (3 x 20 ml). The extracts were washed with H20 (20 ml) and brine (20 ml), and dried over MgSO4. After concentration in vacuo, a brown syrup (363 mg) was obtained which was then purified by silica gel chromatography and a brown syrup of [(3-benzyloxy-4-methoxyphenyl) - (3 -chloropyrazin-2-yl) -methyl] -amide of the cyclobutanecarboxylic acid; 1 H NMR (CDCl 3, 400 MHz) d 1.86-1.98 (m, 2 H), 2.11-2.27 (m, 4 H), 3.04 (quintet, 1 H, J = 8.4 Hz), 3.85 (s, 3 H), 5.12 (s) , 2H), 6.43 (d, 1 H, J = 8.0 Hz), 6.79-6.90 (m, 4H), 7.28-7.38 (m, 5H), 8.29 (d, 1 H, J = 2.8 Hz), 8.45 ( d, 1 H, J = 2.4 Hz); MS (ES): 438.1 / 440.1 (M / M + 2). (c) C- (3-Benzyloxy-4-methoxyphenyl) -C- (3-chloropyrazin-2-yl) -methylamine: The mixture of 2 - [(3-benzyloxy-4-methoxyphenyl) - (3-chloropyrazine) 2-yl) -methyl] -isoindole-1,3-dione (400 mg, 0.823 mmol) and H2NNH2 (64.0 μl, 3 equivalents) in EtOH (6 ml) / CH2Cl2 (2 ml) was stirred at room temperature under N2 for 65 hours. After that time, the gray solid was filtered, and the solvent and the excess hydrazine were removed in vacuo to obtain a brown-red oil of C- (3-benzyloxy-4-methoxyphenyl) -C- (3 -chloropyrazin-2-yl) -methylamine; 1 H NMR (CD 3 OD, 400 MHz) d 3.84 (s, 3 H), 4.96 & 5.00 (AB, 2H, J = 12.0 Hz), 5.41 (s, 1 H), 6.94-6.97 (m, 3H), 7.29-7.40 (m, 5H), 8.34 (d, 1H, J = 2.8 Hz), 8.63 (d, 1 H, J = 2.4 Hz); MS (ES): 356.1 / 358.1 (M / M + 2). (d) 2 - [(3-Benzyloxy-4-mexoxyphenyl) - (3-chloropyrazin-2-yl) -methyl] -isoindole-1,3-dione: DIAD (515 μl, 1.1 equivalents) was added drop dropwise into the THF solution (14 ml) of MS-PPh3 (2.12 millimoles / g, 1.24 g, 1.1 equivalents), (3-benzyloxy-4-meioxyphenyl) - (3-chloropyrazin-2-yl) - methanol (849 mg, 2.38 mmol) and phthalimide (385 mg, 1.1 eqivalents) at 0 ° C under N2 lasted 5 minutes. After stirring for 20 hours at room temperature, the mixture was separated by chromatography on silica gel and eluted in increments with 400 ml, 10%, 20%, 30%, 40%, and 50% of EOAc / Hexane, to obtain a light yellow oil of 2 - [(3-benzyloxy-4-methoxyphenyl) - (3-chloropyrazin-2-yl) -methyl] -isoindole-1,3-dione; 1 H NMR (CDCl 3, 400 MHz) d 3.87 (s, 3 H), 5.08 & 5.14 (AB, 2H, J = 12.0 Hz), 6.75 (s, 1 H), 6.85 (d, 1 H, J = 8.0 Hz), 6.88-6.92 (m, 2H), 7.17-7.35 (m, 5H) , 7.72-7.75 (m, 2H), 7.82-7.84 (m, 2H), 8.31 (d, 1H, J = 2.4 Hz), 8.43 (d, 1 H, J = 2.4 Hz); MS (ES): 486.0 / 487.9 (M / M + 2). (e) (3-Benzyloxy-4-methoxyphenyl) - (3-chloropyrazin-2-yl) -methanol-2,2,6,6-Tetramethylpiperidine (1775 μl, 1.2 equivalents) was added dropwise during 5 minutes in vacuo. of the THF solution (20 ml) of n-BuLi (2.5 M in cyclohexane, 4.2 ml, 1.2 equivalents), which was cooled in a dry ice / acetone bath. The reaction vessel was removed from the cooling bath and allowed to warm at 0 ° C for 15 minutes, then cooled back to -78 ° C and charged with chloropyrazine (780 μL, 8.733 mmol) dropwise during 5 minutes. The reaction was allowed to react for 15 min., And was charged with a THF solution (10 ml) of 3-benzyloxy-4-meloxybenzaldehyde (2328 mg, 1.1 equivalents) for 10 min. After 2 hours, the reaction mixture was warmed to room temperature and aqueous HCl (1 N, 15 ml) was added. The mixture was extracted with CH2Cl2 (3 x 50 ml). The combined excretions were washed with water (50 ml) and brine (50 ml), and dried over MgSO4. After concentration in vacuo, a black unpurified oil (3.163 g) was obtained which was further purified by chromatography on silica gel (500 ml at 10%, 30%, 40%, 50%, and 60% strength). EtOAc / hexane) and a brown oil of (3-benzyloxy-4-methoxyphenyl) - (3-chloropyrazin-2-yl) -methanol was obtained; 1 H NMR (DMSO-d 6, 400 MHz) d 3.74 (s, 3 H), 5.04 (s, 2 H), 6.00 (d, 1 H, J = 6.0 Hz), 6.09 (d, 1 H, J = 6.0 Hz), 7.10 (s, 1 H), 731-7.42 (m, 7H), 8.43 (d, 1 H, J = 2.4 Hz), 8.67 (d, 1 H, J = 2.4 Hz); MS (ES): 357.4 / 359.4 (M / M + 2).

EXAMPLE 93 1- (3-Benzyloxy-4-fluorophenyl) -3-cyclobutyl-imidazo [1,5-a] pyrazin-8-ylamine: Following the general ammonolysis described in example 92; 1 H NMR (CDCl 3, 400 MHz) d 1.98-2.24 (m, 2 H), 2.44-2.66 (m, 4 H), 3.78 (quintet, 1 H, J = 8.4 Hz), 5.22 (s, 2 H), 7.01 (d , 1 H, J = 4.8 Hz), 7.10 (d, 1 H, J = 5.2 Hz), 7.20-7.46 (m, 8 H); MS (ES): 389.1 (M + 1). (a) 1- (3-Benzyloxy-4-fluorophenyl) -8-chloro-3-cycloimutilimidazo [1,5-a] pyrazine: Following the general cycle formation described in Example 92- (a); 1 H NMR (CDCl 3, 400 MHz) d 2.05-2.24 (m, 2 H), 2.50-2.69 (m, 4 H), 3.84 (quintet, 1 H, J = 8.4 Hz), 5.21 (s, 2 H), 7.15-7.49 (m, 9H); MS (ES): 408. 0 / 410.0 (M / M + 2). (b) [(3-benzyloxy-4-fluorophenyl) - (3-chloropyrazin-2-yl) -methyl] -amide of the cyclobutanecarboxylic acid: Following the general amide formation described in Example 92- (b); 1 H NMR (CDCl 3, 400 MHz) d 1.82-1.97 (m, 2 H), 2.11-2.34 (m, 4 H), 3.04 (quintet, 1 H, J = 8.0 Hz), 5.10 (s, 2 H), 6.44 (d , 1 H, J = 7.6 Hz), 6.75-6.79 (m, 1H), 6.95-7.02 (m, 3H), 7.27-738 (m, 5H), 8.31 (d, 1H, J = 2.4 Hz), 8.46 (d, 1H, J = 2.4 Hz); MS (ES): 426.0 / 428.0 (M / M + 2) (c) C- (3-Benzyloxy-4-fluorophenyl) -C- (3-chloropyrazin-2-yl) -methylamine: Following the general primary amine formation described in Example 92- (c); ? NMR (CD3OD, 400 MHz) d 5.15 & 5.19 (AB, 2H, J = 12.0 Hz), 5.44 (s, 1 H), 6.90-6.95 (m, 1H), 7.02-7.12 (m, 2H), 7.28-7.38 (m, 5H), 8.33 (d , 1H, J = 2.4 Hz), 8.61 (d, 1 H, J = 2.4 Hz); MS (ES): 327.3 / 329.3 (M-16 / M-16 + 2). (d) 2 - [(3-Benzyloxy-4-fluorophenyl) - (3-chloroplrazin-2-yl) -methyl] -isoindole-1,3-dione: Following the general reaction of Mitsunobu described in example 92 - (d); 1 H NMR (CDCl 3, 400 MHz) d 5.07 & 5.12 (AB, 2H, J = 11.6 Hz), 6.78 (s, 1 H), 6.89-6.92 (m, 1 H), 7.03-7.09 (m, 2H), 7.28-7.37 (m, 2H), 7.74- 7.77 (m, 2H), 7.84-7.86 (m, 2H), 8.35 (d, 1 H, J = 2.4 Hz), 8.45 (d, 1H, J = 2.8 Hz). MS (ES): 474.0 / 476.0 (M / M + 2). (e) (3-Benzyloxy-4-fluorophenyl) - (3-chloropyrazin-2-yl) -methanol: Followed by general lithiation described in example 92- (e); 1 H NMR (CDCl 3, 400 MHz) d 4.58 (d, 1 H, J = 8.0 Hz), 5.00 & 5.04 (AB, 2H, J = 12.0 Hz), 5.94 (d, 1 H, J = 8.0 Hz), 6.85-6.89 (m, 1 H), 6.98-7.06 (m, 2H), 7.26-7.40 (m, 5H), 8.36 (d, 1 H, J = 2.8 Hz), 8.53 (d, 1H, J = 2.4 Hz); MS (ES): 327.1 / 329.1 (M-18 / M-18 + 2). (f) 3-Benzyloxy-4-fluorobenzaldehyde: The mixture of benzyl bromide (1062 μL, 1050 equivalents), potassium carbonate (1500 mg, 1,274 equivalents), 4-fluoro-3-hydroxybenzaldehyde (1193 mg, 8.515 mmol) and acetone (50 ml) was stirred at ambient temperature for 24 hours. After that time, water (40 ml) was added until the inorganic solid dissolved and the acetone was removed in vacuo. The mixture was extracted with ethyl acetate (3 x 50 ml), the combined organic extracts were washed with aqueous acetic acid (5%, 40 ml), water (2 x 40 ml) and brine (40 ml), and dried about MgS0. After concentration in vacuo, a brown oil of 3-benzyloxy-4-fluorobenzaldehyde was obtained; 1 H NMR (CDCl 3, 400 MHz) d 5.20 (s, 2 H), 7.23-7.59 (m, 8 H), 9.89 (s, 1 H). (g) 4-Fluoro-3-hydroxybenzaldehyde: BBr3 (125 ml, 3383 equivalents, 1 M in CH2Cl2) was added into the solution of 4-fluoro-3-methoxybenzaldehyde (5.695 g, 36.95 mmol) in CH2Cl2 (50 ml ) under N2 at 0 ° C about 30 minutes. After stirring at room temperature for 19 hours, the reaction mixture was poured into ice / water (250 ml) slowly. After separation, the oil phase was extracted with aqueous NaOH (2 N, 2 x 150 ml). The basic extracts were acidified by aqueous HCl (37%) until pH < 2, which were then extracted with CH2Cl2 (3 x 200 ml). The organic extracts were washed with brine (100 ml) and dried over MgSO4. After concentration in vacuo, a yellow-brown solid of 4-fluoro-3-hydroxybenzaldehyde was obtained; 1 H NMR (DMSO-d 6, 400 MHz) d 7.43-7.52 (m, 3 H), 9.93 (s, 1 H), 10.55 (brs, 1 H).

EXAMPLE 94 1 - . 1- (3-Benzyloxy-4-isopropoxyphenyl) -3-cycloimutilimidazo [1,5-a] pyrazin-8-ylamine: Following the general ammonolysis described in example 92; 1 H NMR (CDCl 3, 400 MHz) d 1.40 (d, 6 H, J = 6.0 Hz), 1.98-2.21 (m, 2 H), 2.43-2.67 (m, 4 H), 3.77 (quintet, 1 H, J = 8.0 Hz ), 4.60 (septet, 1 H, J = 6.1 Hz), 4.88 (brs, 2H), 5.21 (s, 2H), 700 (d, 1 H, J = 5.2 Hz), 7.04 -7.08 (m, 2H) , 7.17-7.22 (m, 2H), 7.29-7.45 (m, 5H); MS (ES): 429.1 (M + 1). (a) 1 - (3-Benzyloxy-4-isopropoxyphenyl) -8-chloro-3-cyclobutylimidazo [1,5-a] pyrazine: quantitative yield: Following the general cycle formation described in Example 92- (a); 1 H NMR (CDCl 3, 400 MHz) d 1.40 (d, 6 H, J = 6.0 Hz), 1.87-2.09 (m, 2 H), 2.43-2.72 (m, 4 H), 3.82 (quintet, 1 H, J = 8.4 Hz) , 4.61 (septet, 1H, J = 6.1 Hz), 5.19 (s, 2H), 7.03 (d, 1 H, J = 8.4 Hz), 7.24-7.47 (m, 9H); MS (ES): 447.9 / 449.9 (M / M + 2). (b) [(3-benzyloxy-4-isopropoxyphenyl) - (3-chloropyrazin-2-yl) -methyl] -amide of the cyclobutanecarboxylic acid: Following the general amide formation described in Example 92- (b); quantitative performance; 1 H NMR (CDCl 3, 400 MHz) d 1.34 (d, 6 H, J = 6.0 Hz), 1.84-1.98 (m, 2 H), 2.11-2.30 (m, 4 H), 3.05 (quintet, 1 H, J = 8.4 Hz ), 4.48 (septembre, 1 H, J = 5.9 Hz), 5.11 (s, 2H), 6.45 (d, 1 H, J = 7.6 Hz), 6.82-6.90 (m, 4H), 7.28-7.38 (m, 5H), 8.31 (d, 1 H, J = 2.8 Hz), 8.45 (d, 1H, J = 2.8 Hz). MS (ES): 465.9 / 467.9 (M / M + 2). (c) C- (3-Benzyloxy-4-isopropoxyphenyl) -C- (3-chloropyrazin-2-yl) -methylamine: Following the general primary amine formation described in Example 92- (c); 1 H NMR (CDCl 3, 400 MHz) d 1.34 (s, 6 H, J = 6.0 Hz), 4.48 (septerio, 1 H, J = 6.2 Hz), 5.10 (s, 2 H), 5.43 (s, 1 H), 6.33 (brs, 2H), 6.84-6.91 (m, 3H), 7.28-7.40 (m, 5H), 8.24 (d, 1H, J = 2.4 Hz), 8.49 (d, 1H, J = 2.8 Hz); MS (ES): 384.0 / 386.0 (M / M + 2). (d) 2 - [(3-Benzyloxy-4-isopropoxyphenyl) - (3-chloropyrazin-2-yl) -methyl] -isoindole-1,3-dione: Following the general reaction of Mifsunobu described in example 92 - (d); ? NMR (CDCl 3, 400 MHz) d 1.35 (d, 6H, J = 6.0 Hz), 4.53 (septerio, 1 H, J = 6H), 5.05 & 5.10 (AB, 2H, J = 12.0 Hz), 6.75 (s, 1 H), 6.82-6.90 (m, 2H), 6.94 (s, 1 H), 7.19-7.52 (m, 5H), 7.72-7.74 ( m, 2H), 7.82-7.84 (m, 2H), 8.31 (d, 1 H, J = 2.4 Hz), 8.43 (d, 1 H, J = 2.4 Hz); MS (ES): 513.9 / 515.9 (M / M + 2). (e) (3-Benzyloxy-4-isopropoxyphenyl) - (3-chloropyrazin-2-yl) -methanol: Following the general lithiation described in example 92- (e); 1 H NMR (CDCl 3, 400 MHz) d 1.34 (d, 6H, J = 6.4 Hz), 4.50 (septet, 1H, J = 6.0 Hz), 5.10 (AB, 2H, J = 12.4 Hz), 5.91 (d, 1H, J = 8.0 Hz), 6.84-6.86 (m, 4H), 726-739 (m, 5H), 8.34 (d, 1H, J = 2.4 Hz), 8.50 (d, 1 H, J = 2.4 Hz); EM (S): 367.0 / 369.0 (M / M + 2). (f) 3-Benzyloxy-4-isopropoxybenzaldehyde: A mixture of 3-benzyloxy-4-hydroxybenzaldehyde (1297 mg, 5.683 mmol) and Cs2CO3 (2777 mg, 1.5 equivalents) in DMF (5 ml) was stirred at room temperature for 30 minutes. minutes under N2, and then 2-bromopropane (800 μl, 1.5 equivalents) was added and it was heated with stirring at 75 ° C overnight. The reaction mixture was cooled, and H20 (20 ml) was added thereto, and then extracted with EtOAc (4 x 20 ml). The organic extracts were washed with H20 (3 x 20 ml) and brine (20 ml), and dried over MgSO4. After concentration in vacuo, a brown oil of 3-benzyloxy-4-isopropoxybenzaldehyde was obtained, which was used without further purification. 1 H NMR (CDCl 3, 400 MHz) d 1.43 (d, 6 H, J = 6.4 Hz), 4.69 (septerio, 1 H, J = 6.0 Hz), 5.18 (s, 2 H), 7.01 (d, 1 H, J = 8.0 Hz), 726-7.46 (m, 7H), 9.81 (s, 1 H); MS (ES): 271.1 (M + 1). (g) 3-Benzyloxy-4-hydroxybenzaldehyde: A solution of 3-benzyloxy-4- (4-methoxybenzyloxy) -benzaldehyde (2593 mg, 7.443 mmol) in AcOH (20 ml) was heated to reflux (150 ° C) by 27 hours The reaction mixture was concentrated in vacuo and the residue was dissolved in EtOAc (20 ml). The organic solution was washed with H20 (20 ml) and aqueous NaOH (0.5 N, 5 x 20 ml). The basic extracts were combined, acidified to pH = 2-3 with aqueous HCl (2 N) and extracted again with EtOAc (2 x 30 ml). The organic solution was dried over MgSO4, filtered and concentrated to yield 3-benzyloxy-4-hydroxybenzaldehyde as a brown solid. 1 H NMR (CDCl 3, 400 MHz) d 5.18 (s, 2 H), 6.22 (brs, 1 H), 7.08 (d, 1 H, J = 8.0 Hz), 7.39-7.52 (m, 7 H), 9.82 (s) , 1 HOUR); MS (ES): 229.1 (M + 1). (h) 3-Benzyloxy-4- (4-methoxybenzyloxy) -benzaldehyde: Benzyl bromide (5.84 ml, 1.1 equivalents) was added dropwise into the mixture of 3-hydroxy-4- (4-methoxybenzyloxy) -benzaldehyde (11.5 g, 44.6 millimoles) and cesium carbonate (8.73 g, 0.6 equivalents) in DMF (75 ml) at room temperature under N2 for 15 min. After stirring at room temperature for 70 hours, the reaction mixture was poured into water (150 ml) and then extracted with ethyl acetate (200 ml). The organic exiphats were washed with water (100 ml), aqueous NaOH (0.5 M, 100 ml), and brine (100 ml) and dried over MgSO4. After concentration in vacuo, an unpurified, brown solid was made of 3-benzyloxy-4- (4-methoxybenzyloxy) -benzaldehyde; ? NMR (CDCl 3, 400 MHz) d 3.83 (s, 3 H), 5.18 (s, 2 H), 5.20 (s, 2 H), 6.92 (dd, 2 H, J = 2 and 6.8 Hz), 7.04 (d, 2 H, J = 8.0 Hz), 7.33-7.47 (m, 9H), 9.80 (s, 1H). (i) 3-hydroxy-4- (4-meloxybenzyloxy) -benzaldehyde: 4-Meioxybenzyl chloride (11.9 g, 1.05 equivalents) was added dropwise into the mixture of 3,4-dihydrobenzaldehyde (10.0 g, 72.4 mmol) ), (n-C4Hg) 4NI (21.4 g, 0.8 equivalents) and cesium carbonate (17.7 g, 0.75 equivalents) in DMF (100 ml) at room temperature under N2 for 15 minutes. After stirring at ambient temperature for 67 hours, the reaction mixture was poured into water (200 ml) and then extracted with ethyl acetate (3 x 100 ml). The organic exíractos were washed with aqueous HCl (0.5 M, 200 ml), water (4 x 100 ml), and brine (100 ml) and dried over MgSO4. After concentration in vacuo, a yellow-brown unpurified solid was obtained (18.0 g), which was subsequently triturated with ethyl acetate / hexane (75 ml / 150 ml) to yield a yellow-brown solid 3-hydroxy-4- (4-meioxybenzyloxy) -benzaldehyde; 1 H NMR (CDCl 3, 400 MHz) d 3.84 (s, 3 H), 5.13 (s, 2 H), 5.78 (brs, 1 H), 6.96 (d, 2 H, J = 8.0 Hz), 7.06 (d, 2 H, J = 8.0 Hz), 7.37 (d, 2H, J = 8.4 Hz), 7.40-7.45 (m, 2H), 9.84 (s, 1 H); MS (ES): 259.2 (M + 1).

EXAMPLE 95 1- (3-Benzyloxy-4-dioxo-phenyl) -3-cyclobutyl-imidazo [1,5-a] pyrazin-8-ylamine: Following the general ammonolysis described in example 92; 1H NMR (CDCI3, 400 MHz) d 1.50 (t, 3H, J = 7.0 Hz), 1.99-2.19 (m, 2H), 2.42-2.67 (m, 4H), 3.78 (quintet, 1 H, J = 8.4 Hz), 4.19 (q, 2H, J = 6.9 Hz), 4.83 (brs, 2H), . 23 (s, 2H), 6.98-7.47 (m, 10H); MS (ES): 415.1 (M + 1). (a) 1 - (3-Benzyloxy-4-ethoxyphenyl) -8-chloro-3-cyclobutylimidazo [1,5-a] pyrazine: quantifiable yield: Following the general cycle formation described in Example 92- (a); ? NMR (CDCl 3, 400 MHz): 1.49 (i, 3H, J = 7.0 Hz), 2.01-2.22 (m, 2H), 2.48-2.70 (m, 4H), 3.82 (quintet, 1 H, J = 8.4 Hz) , 4.17 (q, 2H, J = 7.0 Hz), 5.21 (s, 2H), 7.00 (d, 1H, J = 8.8 Hz), 7.25-7.47 (m, 9H); MS (ES): 433.9 / 435.9 (M / M + 2). (b) [(3-benzyloxy-4-e-phoxyphenyl) - (3-chloropyrazin-2-yl) -methyl] -amide of cyclobutanecarboxylic acid: A mixture of [(3-benzyloxy-4-hydroxyphenyl) - (3-chloropyrazine -2-yl) -methyl] -amide of cyclobutanecarboxylic acid (162 mg, 0.382 mmol) and Cs2CO3 (187 mg, 0.573 mmol) in DMF (2 mL) was stirred at room temperature for 30 minutes under N2, and then added Eíl (45.9 μL, 0.573 mmol) and heated with stirring at 50 ° C for 5 hours. The reaction mixture was cooled, and H20 (15 ml) was added thereto, and then extracted with EtOAc (3 x 15 ml). The organic extracts were washed with H20 (3 x 15 ml) and brine (15 ml), and dried over MgSO4. After concentration in vacuo, a brown oil was obtained from the [3-benzyloxy-4-ethoxyphenyl] - (3-chloropyrazin-2-yl) -methyl] -amide of 3-cyclobutanecarboxylic acid, which was used without additional purification. A purer sample was obtained by Glaring CLAR purification by LC-MS and CLAR; ? NMR (CDCl 3, 400 MHz) d 1.42 (t, 3 H, J = 7.0 Hz), 1.84-2.11 (m, 2 H), 2.12-2.18 (m, 4 H), 3.04 (quintet, 1 H, J = 8.4 Hz) , 4.04 (q, 2H, J = 6.9 Hz), 5.11 (s, 2H), 6.43 (d, 1 H, J = 7.6 Hz), 6.78-6.88 (m, 4H), 7.25-738 (m, 5H) , 8.29 (d, 1 H, J = 2.4 Hz), 8.44 (d, 1H, J = 2.4 Hz); MS (ES): 451.9 / 453.9 (M / M + 2). (c) [(3-benzyloxy-4-hydroxyphenyl) - (3-chloropyrazin-2-yl) -methyl] -amide of cyclobutanecarboxylic acid: A solution of [[3- benzyloxy-4- (4-methoxybenzyloxy)] -phenyl] - (3-chloropyrazin-2-yl) -methyl] -amide of cyclobutanecarboxylic acid (300 mg, 0.551 mmol) in AcOH (10 ml) was heated to reflux (150 ° C) for 7 hours . The reaction mixture was concentrated in vacuo and the residue was dissolved in EtOAc (15 mL). The organic solution was washed with saturated NaHCO3 (10 mL), H2O (2 x 10 mL) and brine (10 mL), and dried over MgSO4, filtered and concentrated to yield a brown oil. The crude oil was purified by silica gel (eluting with 200 ml of 2%, 4%, 6% MeOH / CH 2 Cl 2) to obtain a light yellow oil of [(3-benzyloxy-4-hydroxyphenyl) - ( Cyclobuylenecarboxylic acid 3-chloropyrazin-2-yl) -methyl] -amide; 1 H NMR (CDCl 3, 400 MHz) d 1.82-1.99 (m, 2 H), 2.13-2.31 (m, 4 H), 3.07 (quintet, 1 H, J = 8.4 Hz), 5.10 (s, 2 H), 5.64 (brs) , 1 H), 6.47 (d, 1 H, J = 8.0 Hz), 6.72 (dd, 1 H, J = 1.6 &8.0 Hz), 6.84 (d, 1 H, J = 8.0 Hz), 6.98 (d , 1 H, J = 7.2 Hz), 7.03 (d, 1 H, J = 1.6 Hz), 7.30-7.38 (m, 5 H), 8.32 (d, 1 H, J = 2.4 Hz), 8.49 (d, 1 H, J = 2.8 Hz); MS (ES): 423.9 / 425.9 (M / M + 2). (d) [[3-benzyloxy-4- (4-meioxybenzyloxy) -phenyl] - (3-chloropyrazin-2-yl) -cyclohexanecarboxylic acid methytic acid: Following the general amide formation described in Example 92 - (b); 1 H NMR (CDCl 3, 400 MHz) d 1.84-1.98 (m, 2 H), 2.11-2.26 (m, 4 H), 3.04 (quintet, 1 H, J = 8.4 Hz), 3.80 (d, 3 H, J = 1.2 Hz ), 5.04 (s, 2H), 5.12 (s, 2H), 6.44 (d, 1 H, J = 8.0 Hz), 6.78-6.89 (m, 6H), 7.26-7.38 (m, 7H), 8.29 (d , 1 H, J = 2.0 Hz), 8.50 (d, 1 H, J = 2.4 Hz); MS (ES): 544.0 / 546.0 (M / M + 2). (e) C- [3-Benzyloxy-4- (4-methoxybenzyloxy) -phenyi] -C- (3-chloropyrazin-2-yl) -methylamine: Following the general primary amine formation described in Example 92- (c) ); quantitative performance; 1 H NMR (CD 3 OD, 400 MHz) d 3.80 (s, 3 H), 5.04 (s, 2 H), 5.12 (m, 2 H), 6.89-6.92 (m, 3 H), 6.98-7.00 (m, 2 H), 7.30 -7.39 (m, 7H), 8.34 (d, 1 H, J = 2.4 Hz), 8.63 (d, 1 H, J = 2.4 Hz); MS (ES): 461.9 / 463.9 (M / M + 2). (f) 2 - [[3-Benzyloxy-4- (4-meloxy-benzyloxy) -phenyl] - (3-chloro-pyrazin-2-yl) -methyl] -isoindole-1,3-dione: Following the general reaction of Miisunobu described in example 92- (d); 1 H NMR (CDCl 3, 400 MHz) d 3.80 (s, 3 H), 4.97-5.14 (m, 4 H), 6.75 (s, 1 H), 6.87-6.91 (m, 4 H), 6.96 (d, 1 H, J = 2.0 Hz), 7.19-7.24 (m, 2H), 7.33-7.36 (m, 5H), 7.72-7.74 (m, 2H), 7.82-7.84 (m, 2H), 8.31 (dd, 1H, J 0.8 and 2.4 Hz), 8.43 (d, 1 H, J = 2.0 Hz); MS (ES): 592.0 / 594.0 (M / M + 2). (g) [3-Benzyloxy-4- (4-meioxybenzyloxy) phenyl] - (3-chloropyrazin-2-yl) -melanol: Following general lithiation, it is described in Example 92- (e); 1 H NMR (CDCl 3, 400 MHz) d 3.80 (s, 4 H), 4.49 (d, 1 H, J = 8.0 Hz), 5.06 (s, 2 H), 5.10 & 5.14 (AB, 2H, J = 12.4 Hz), 5.91 (d, 1 H, J = 8.0 Hz), 6.82-6.88 (m, 5H), 7.27-7.38 (m, 7H), 8.33 (d, 1 H, J = 2.4 Hz), 8.49 (d, 1H, J = 2.8 Hz); MS (ES): 444.9 / 446.9 (M-18 / M-18 + 2).

EXAMPLE 96 4- (8-Amino-3-cyclobuylimidazo [1, 5-a] pyrazin-1-yl) -2-benzyloxyphenol: 2-benzyloxy-4- (8-chloro-3-cyclobutyllimidazo [1, 5-a] pyrazin-1-yl) -pheni isopropyl ester of phosphoramidic acid (300 mg, 0.569 mmol) was dissolved in NH 2 2 N in PrOH (3 ml) and charged with liquid NH 3 (1 ml) in a dry ice / acetone bath. Then the aforementioned mixture was sealed in a sealed tube and heated to 110 ° C. After stirring for 14 hours, excess NH3 and solvent were evaporated. THF (3 mL) was added followed by the addition of LiAIH4 (88.0 mg, 2.28 mmol) at 0 ° C under N2. Then the mixture was stirred at ambient temperature for 26 hours. After that time, the reaction mixture was poured into aqueous AcOH (5%, 15 ml) and exfoliated with EtOAc (3 x 20 ml). The extracts were washed with H20 (3 x 15 ml), brine (15 ml) and dried over MgSO4. After concentrating a vacuum, a brown oil (50 mg) was obtained, which was purified by TLC eluting with 3% MeOH / CH 2 Cl 2 to produce 4- (8-amino-3-cyclobutylimidazo [1, 5 a] pyrazin-1-yl) -2-benzyloxyphenol as a whitish solid; 1 H NMR (CDCl 3, 400 MHz) d 1.96-2.22 (m, 2 H), 2.44-2.68 (m, 4 H), 3.80 (quintet, 1 H, J = 8.6 Hz), 5.06 (brs, 2 H), 5.19 (s) , 2H), 7.01 (d, 1 H, J = 5.2 Hz), 7.05 (d, 1 H, J = 8.0 Hz), 7.09 (d, 1 H, J = 5.2 Hz), 7.17 (dd, 1 H, J = 1.6 &8.4 Hz), 725 (d, 1 H, J = 2.0 Hz), 735-744 (m, 5H); MS (ES): 387.0 (M + 1). (a) 2-benzyloxy-4- (8-chloro-3-cyclobuylimidazo I [1,5-a] pyrazin-1-yl) -phenyl ester isopropyl ester of phosphoramidic acid: Following the general cycle formation described in example 92- (a) by means of which [[3-benzyloxy-4- (4-methoxybenzyloxy) -phenyl] - (3-chloropyrazin-2-yl). methyl] -amide acid was treated with POCI3 and then quenched with 2N NH3 in iPrOH to obtain the title compound; 1 H NMR (CDCl 3, 400 MHz) d 1.31 (d, 3 H, J = 6.0 Hz), 1.35 (d, 3 H, J = 6.4 Hz), 2.01-2.26 (m, 2 H), 2.47-2.69 (m, 4 H) , 3.02 (d, 2H, J = 4.0 Hz), 3.84 (quintet, 1 H, J = 8.4 Hz), 4.78 (septembre, 1 H, J = 6.1 Hz), 5.17 (s, 2H), 7.27-7.53 ( m, 10H): MS (ES): 526.9 / 528.9 (M / M + 2).

EXAMPLE 97 Acid 4-. { 8-amino-1 - [3- (2,6-difluoro-benzyloxy) -phenyl] -imidazo [1,5-a] pyrazin-3-yl} -Cyclohexancarboxylicamide: The procedures for trans-4- [8-amino-1- (3-benzyloxy-phenyl) -midazo [1,5-a] pyrazan-3-yl] -amide cyclohexanecarboxylic acid were applied to 4-methyl ester. { 8-amino-1- [3- (2,6-difluoro-benzyloxy) -phenyl] -imidazo [1,5-a] pyrazin-3-yl} -cyclohexanecarboxylic acid to produce the title compound; MS (ES +): m / z 478.02 [MH].

EXAMPLE 98 Acid 4-. { 8-amino-1- [3- (2,6-d-fluoro-benzyloxy) -phenyl] -imidazo [1,5-a] pyrazin-3-yl} -Cyclohexancarboxylic methylamide: The procedures for coupling the amide were applied to the synthesis of methylamide of the acid (trans-4- [8-amino-1- (3-benzyloxy-phenyl) -imidazo [1,5-a] pyrazine- 3-yl] -cyclohexanecarboxylic acid which was applied to the acid 4-. {8-amino-1- [3- (2,6-difluoro-benzyloxy) -phenyl] -imidazo [1,5-a] pyrazin-3- Figure imgf000025_0001 Figure imgf000018_0001 Figure imgf000025_0001 Figure imgf000018_0001 Figure imgf000018_0001 Figure imgf000018_0001 The following analytical conditions and equipment were used in Examples 99-293: NMR specimens were acquired at 27 ° C on a Varian Mercury 400 spectrometer operating at 400 MHz or on a Bruker AMX2 500 spectrometer operating at 500 MHz. The flow injection samples were processed on a Bruker BEST system comprising the Bruker spectrometer. AMX2 500, a Gilson 215 sample applicator car, a heated transfer line and a Bruker 4 mm Fi-SEI NMR probe. The BEST system was coniroló by means of software XWINNMR V2.6. Analytical LC / MS: Samples were analyzed in a multiple LC / MS system consisting of an LCT mass spectrometer in micromass with a 5-channel MUX interface, a Waters 1525 binary CLAR pump, 4 Jasco Pu-1585 pumps, a auto sample applicator CTC HTS PAL with 4 injection valves, a Waters 2488 UV detector and 4 Walan Atlanis C18 columns (3.1x30 mm, 3 μm). A gradient of water / acetoniiril + 0.1% formic acid with a cycle time of 6 minutes and a flow rate of 0.85 ml / minute was used to elute the compounds. The UV detector was set at 220 nm. The system was established using MassLynx 4.0 software. Mass directed purification: The mass-directed purification system consisted of an LC mass spectrometer with a micromass platform, a CLAR Waíers 600 pump, a Waíers reactive handler, a Waters 2700 auto wand attachment, a Waters 996 detector PDA, a Walers II fraction collector and C18 EM Wafers Xterra Prep columns (19x50 mm). The compounds were eluted with varying water / acetonifrile gradients + 0.1% formic acid processed over a period of 8 minutes. The flow rate was 20 ml / minute. The system was controlled by MassLynx and FractionLynx V3.5 software. UV-directed purification: UV-directed purification was carried out in a 4-channel Biotage Parallex Flex system equipped with 4 C18 Waters Xterra Prep EM columns (19x50 mm). The compounds were eluted by using a gradient of water / acetonifrile + 0.1% formic acid with a cycle formation time of 10 minutes and a flow rate of 20 ml / minute. UV deiction was at 220 nm and 254 nm. The system was controlled by Biotage Parallex Flex V2.9 software. Analytical LC / MS: The compounds were analyzed using a LC / MS method using the following param- eters: CLAR gradient: Solvent A - water grade CLAR + 0.1% formic acid Solvent B - acefoniiril grade CLAR + 0.1% formic acid Flow rate 0.85 ml / minute 0 - 0.3 minutes 100% A 0.3 - 4.25 min. 100% A to 10% of A 4.25-4.40 min. 10% of A to 0% of A 4.40 - 4.90 minutes to 100% of B 4.90 - 5.00 min. 0% of A to 100% of A 5.00 - 6.00 min. keeping to 100% of A for re-equilibration Column: Waters Atlanfis C18 3u 2.1x30 mm with column guard Phenomenex Polar RP 4.0x2.0 mm; UV detection: 220 nm; EM conditions: 80-700 amu records; 30V sample cone; capillarity 3.2 kV; Processing methods using the following types: Pump for binary CLAR Wafers 1525 Pumps 4 x Jasco PU-1585 Device for auto sample CTC HTS Pal with 4 injection valves UV detector Waíers 2488 Micromachining LCT with a 5-channel MUX interface Data acquired using Masslynx V4.0 LC platform for Masslunx V3.5 micromassage CLAR Waíers 600 Waters reactive handpiece Waters 2700 aulomuesíra device Waters II fraction collector Waíers 996 PDA detector Flow rate 20 ml / minute Aceíonitrile / water gradient + 0.1% formic acid with processing during a period of 8 minutes.

Columns C18 Waters Xterra Prep MS 19x50 mm UV-directed purification System Biotage Parallex Flex 4 Channel UV prep. Detection by UV at 220 and 254 nm Columns C18 Waters Xterra Prep MS 19x50 mm Acrylonitrile / water gradient + 0.1% formic acid with processing from 95% aqueous to 100% organic over a period of 10 minutes. Flex Software V2.9 EXAMPLE 99 N-. { 3- [3- (8-Amino-3-cyclobutyl-imidazo [1, 5a] pyrazin-1-yl) -phenoxymethyl] -phenyl} -acetamide Argon was bubbled through a suspension of 1- [3- (3-bromobenzyloxy) -phenyl] -3-cyclobuyl-imidazo [1,5-a] pyrazin-8-ylamine (1.25 mg, 0.056 mmol) ), potassium carbonate (15 mg, 0.109 mmol), copper iodide (I) (10 mg, 0.052 mmol), acetylamide (40 mg, 0.68 mmol) and N, N'-dimethylelylynediamine (5 mg, 0.057 mmol), in dioxane (0.5 ml) in a 5 ml thick-walled microwave tube. The tube was sealed and heated to 170 ° C for 2 hours using the Discover CEM microwave oven at a maximum power of 250W. Then the reaction mixture was partitioned between water (3 ml) and ethyl acetate (3 ml) and the aqueous layer was extracted with additional efyl acetate (2 x 3 ml). The combined organic extracts were washed with water (2 x 3 ml) and brine (3 ml) then evaporated in vacuo. After evaporation the residues were dissolved in methanol and loaded in 1 g SCX cartridges, then eluted with methanol and methanol / ammonia (aqueous ammonia concentrated in meihanol, 3% v / v). The fractions containing the product were combined and evaporated to yield N-3- [3- (8-amino-3-cyclobutyl-imidazo [1,5-a] pyrazin-1-yl) -phenoxymethyl] -phenyl} -acetamide as a whitish solid (10 mg, 0.023 mmol, 42%, 85% pure). This was further purified using preparative HPLC directed by mass purification (conditions) to yield 2 as a whitish solid (6.3 mg, 0.015 mmol, 27%; (M + H) 4 m / z 428.2, retention time, 2.87 minutes; 1 H-NMR (D 4 -MeOH) d 7.72 (1 H, br t), 7.53 (1 H, br d, J = 8 Hz), 7.49 (1 H, t, J = 8 Hz), 7.43 (1 H, d , J = 5.1 Hz), 7.35 (1 H, t, 7.8 Hz), 7.29 (1 H, br t), 725-7.22 (2 H, m), 7.17 (1 H, dd, J = 2.8, 8.2 Hz), 7.01 (1 H, d, J = 5.1 Hz), 5.21 (2 H, s), 4.00 (1 H, p, J = 8.4 Hz), 2.55 (4 H, m), 2.22 (1 H, m), 2.15 ( 3H, s), 2.10-2.02 (1 H, m).

The following examples were synthesized following the method described for -. { 3- [3- (8-Amino-3-cyclobutyl-imidazo [1, 5-a] pyrazin-1-yl) -phenoxymethyl] -phenyl} -acetamide.

The following compounds were synthesized in the same manner using 1- [3- (2-bromobenzyloxy) -phenyl] -3-cyclobutyl-imidazo [1,5-a] pyrazin-8-ylamine isomer as a starting material.

The general procedure for the alkylation reactions of the 4- [8-amino-1- (3-benzyloxy-phenyl) -imidazo [1,5-a] pyrazin-3-yl] -cyclohexylmethyl ester of toluene-4-sulfonic acid and 4- [8-amino-1- (3-benzyloxy-phenyl) -imidazo [1, 5-a] pyrazyl-3-yl] -3-ethyl-3-yl-benzoyl ester sulphonic with amines.

EXAMPLE 124 1- (3-Benzyloxy-phenyl) -3- (4-phenylaminomethyl-cyclohexyl) -imidazo [1,5-a] pyrazin-8-ylamine To a solution of 4- [8-amino-1- (3 methyl-4-sulphonic acid-benzyloxy-phenyl) -imidazo [1,5-a] pyrazyl-3-yl] -cyclohexamethyl ester (29 mg, 0.05 mmol) in DMF (0.5 ml) is added aniline (23 μl, 0.25 mmol). The reaction was irradiated in the microwave (200 W, 150 °, 10 minutes), then evaporated to dryness. The unpurified reaction product was dissolved in MeOH (2 ml) and added to a pre-moistened MX cartridge (6 ml / 500 mg). The cartridge was washed on MeOH (10 ml) and then the product was eluted using 1% NH 3 in MeOH (15 ml). The product was further purified using mass-directed HPLC to produce 1- (3-benzyloxy-phenyl) -3- (4-phenylaminomethyl-cyclohexyl) -imidazo [1,5-a] p -razin-8- acid salt. formic acid (7.8 mg, 31%) as a whitish solid: 1 H NMR (400 MHz, CD 3 OD) d 8.25 (s, 1 H), 7.60 (d, 1 H, J = 5.5 Hz), 748-7.41 ( m, 3H), 7.36 (t, 2H, J = 73 Hz), 733-7.27 (m, 1 H), 7.25-722 (m, 1 H), 7.18 (d, 1 H, J = 7.4 Hz), 7.13 (dd, 1 H, J = 5.5 Hz, 2.3 Hz), 7.08 (t, 2H, J = 7.8 Hz), 6.97 (d, 1 H, J = 5.5 Hz), 6.63 (d, 2H, J = 7.4 Hz), 6.58 (t, 1H, J = 7.4 Hz), 5.16 (s, 2H), 3.12 (m, 1 H), 3.00 (d, 2H, J = 6.7 Hz), 2.06 (br.d, 4H, J = 1 1.7 Hz), 1.88-1.70 (m, 3H), 1.30-1.22 (m, 2H), 3H was not observed (NH2 and NH); MS (ES +) m / z 504.24 [MH +] at a retention time of 3.47 minutes.

General procedure for the coupling of 4- [8-amino-1- (3-benzyloxy-phenyl] -imidazo [1,5-a] p -razin-3-yl] -cyclohexanecarboxylic acid amide with amides.

EXAMPLE 175 4- [8-Amino-1- (3-benzyloxy-phenyl) -imidazo [1, 5a] pyrazin-3-yl] -cyclohexanecarboxylic acid (2-diethylamino-ethyl) -amide To a stirring solution of 2- (dimethylamino) ethylamine (11.6 mg, 0.1 mmol) in MeCN (0.4 mL) was added 4M HCl in 1,4-dioxane (0.1 mL, 0.4 mmol). After stirring for 1 hour at room temperature, a solution of 4- [8-amino-1- (3-benzyloxy-phenyl) -imidazo [1,5-a] pyrazin-3-yl] -cyclohexanecarboxylic acid ( 22 mg, 0.05 mmol) in DMF (1 mL), followed by a solution of EDCI.HCl (14.3 mg, 0.075 mmol), HOAt (10.2 mg, 0.075 mmol) and a catalytic amount of DMAP in DMF (0.5 mL). DIPEA (0.087 ml, 0.5 mmol) was added, and the reaction was stirred at room temperature throughout the nohe. The reaction mixture was poured into saturated aqueous NaHCO3 solution (10 ml) and extracted on ElOA (2 x 10 ml). The combined organic layers were washed with brine (3 x 10 ml), dried (MgSO), filtered and concentrated in vacuo. Unpurified production was purified by using CLAR directed by mass to produce salt of 4- (8-Amino-1- (3-benzyloxy-phenyl) -imidazo [2-diethylamino-eyl] -amide-bis-formic acid] , 5-a] pyrazin-3-yl] -cyclohexanecarboxylic acid (10.8 mg, 40%) as an off-white solid: 1 H NMR (400 MHz, CD 3 OD) d 8.38 (s, 2 H), 7.60 (d, 1 H, J = 5.4 Hz), 747-7.43 (m, 3H), 7.37 (i, 2H, J = 7.4 Hz), 7.33-7.28 (m, 1 H), 7.24 (s, 1 H), 7.19 (d, 1 H, J = 7.4 Hz), 7.15-713 (dd, 1 H, J = 5.3 Hz, 2.4 Hz), 6.99 (d, 1H, 5.5 Hz), 5.17 (s, 2H), 3.56 (f, 2H, J = 6.1 Hz), 3.32-3.24 (m, 6H), 3.18 (t, 1H, J = 10.0 Hz), 2.38 (l, 1H, J = 8.4 Hz), 2.10 (dd, 2H, J = 7.9 Hz, 2.4 Hz) , 2.01 (dd, 2H, J = 6.7 Hz, 2.7 Hz), 1.89-1.66 (m, 4H), 1.34 (f, 6H, J = 7.4 Hz), 3H was not observed (NH2 &NH); LCMS (ES +) m / z 541.01 [MH +] at a retention time of 2.99 minutes.

General procedure for phenolic alkylations of 3- (8-amino-3-cyclobutyl-midazo [1,5-a] pyrazin-1-yl) -phenol with alkyl halides EXAMPLE 211 2- [3- (8-Amino-3-cyclobutyl-imidazo [1,5-a] pyrazin-1-yl) -phenoxy] -ethanol To a solution of 3- (8-amino-3-cyclobutyl-imidazo) [1, 5-a] pyrazin-1-yl) -phenol (28 mg, 0.1 mmol) in anhydrous DMF (1 ml) was added cesium carbonate (49 mg, 0.15 mmol) followed by a solution of 2-bromoethanol (12.5 mg, 0.1 mmol) in DMF (0.5 ml). The reaction was agitated at 60 ° during the night. The reaction was poured into saturated NaHC03 (10 mL) and exuded with EOAc (2 x 10 mL). The combined organic layers were washed with water (10 ml) and aqueous brine solution (3 x 10 ml), dried (MgSO 4), filtered and concentrated in vacuo. Purification by mass-directed HPLC produced salt of 2- [3- (8-Amino-3-cyclobutyl-imidazo [1, 5-a] pyrazin-1-yl) -phenoxy] -enol-formic acid salt (4.0 mg, 12%). %) as a whitish solid: 1 H NMR (400 MHz, CD 3 OD) d 8.54 (s, 1 H), 7.48-7.41 (m, 2 H), 7.13-7.09 (m, 2 H), 7.01 (d, 1 H, J = 10.3 Hz), 6.93 (d, 1 H, J = 5.8 Hz), 4.14 (i, 2H, J = 4.9 Hz), 4. 03-3.97 (m, 1 H), 3.92 (f, 2H, J = 4.9 Hz), 2.61-2.51 (m, 4H), 2.15-2.10 (m, 1 H), 2.06-2.01 (m, 1 H), 3 H was not observed (NH 2 &OH); LMS (ES +) m / z 325.08 [MH +] at a retention time of 2.39 minutes.

General procedure for phenolic alkylations of 3- (8-amino-3-cyclobutyl-imidazo [1, 5-a] pyrazin-1-yl) -phenol with benzyl halides EXAMPLE 236 3-Cyclobutyl-1 - [3- (3-methoxy-benzyloxy) -phenyl] -imidazo [1,5-a] pyrazin-8-ylamine To a solution of 3- (8-amino-3-cyclobutyl-imidazo [ 1,5-a] pyrazin-1-yl) -phenol (28 mg, 0.1 mmol) in anhydrous DMF (1 ml) was added cesium carbonate (49 mg, 0.15 mmol) followed by a solution of 3- bromide. meioxybenzyl (20 mg, 0.1 mmol) in DMF (0.5 ml). The reaction was stirred at room temperature overnight. The reaction was poured into saturated NaHCO3 (10 mL) and extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with water (10 ml) and an aqueous solution of brine (3 x 10 ml)were dried (MgSO), filtered and concentrated in vacuo to yield 3-cyclobuyl-1- [3- (3-meloxy-benzyloxy) -phenyl] -imidazo [1,5-a] pyrazin-8. -amine as a brown solid (24.1 mg, 60%): 1 H NMR (400 MHz, CDCl 3) d 7.42 (1, 1 H, J = 7.8 Hz), 7.35-7.27 (m, 3 H), 7.13 (d , 1 H, J = 5.1 Hz), 7.08-7.03 (m, 4H), 6.90 (d, 1 H, J = 8.6 Hz), 5.17 (s, 2H), 3.84 (s, 3H), 3.86-3.79 ( m, 1 H, darkened), 2.72-2.62 (m, 2H), 2.56-2.47 (m, 2H), 2.25-2.14 (m, 1 H), 2.11-2.02 (m, 1 H), 2H was not observed (NH2); LMS (ES +) m / z 401.34 [MH +] at a hold time of 3.20 minutes.

General procedure for S AG reactions of 1- (3-benzyloxy-phenyl) -8-chloro-3-cyclobutyl-imidazo [1,5-a] pyrazine with amines EXAMPLE 281 [1- (3-Benzyloxy-phenyl) -3-cyclobutyl-midazo [1,5-a] pyrazin-8-yl] -isopropyl-amine To a solution of 1- (3-benzyloxy-phenyl) -8- chloro-3-cyclobutyl-imidazo [1,5-a] pyrazine (30 mg, 0.075 mmol) in NMP (0.4 ml) was added isopropylamine (44 mg, 0.75 mmol). The reaction was irradiated in the microwave (200W, 150 °, 5 minutes.) And then poured into water (10 ml) and extracted with EtOAc (2 x 10 ml). The combined organic layers were washed with brine (3 x 10 ml), dried (MgSO), filtered and evaporated to dryness. Purification by mass-directed HPLC produced [1- (3-benzyloxy-phenyl) -3-cyclobutyl-imidazo [1, 5-a] pyrazin-8-yl] -isopropylamine formic acid salt (11.0 mg, 36%) as a colorless solid: H NMR (400 MHz, CD3OD) d 8.21 (s, 1 H), 7.49 (d, 3H, J = 8.2 Hz), 744-7.31 (m, 4H), 7.29 (s, 1H), 7.24-717 (m, 2H), 7.04 (d, 1 H, J = 5.1 Hz), 5.21 (s, 2H), 4.24-4.11 (m, 1 H), 4.04-3.94 (m, 1 H), 2.64 -2.47 (m, 4H), 2.28-2.17 (m, 1 H), 2.10-2.01 (m, 1 H), 1.14 (d, 6H, J = 6.7 Hz), 1 H was not observed (NH); LMS (ES +) m / z 413.21 [MH +] at a retention time of 3.40 minutes.

EXAMPLE 294 8-Amino-1- (3-benzyloxy-2-fluorophenyl) -3-cyclobutyl-imidazo [1,5-chiroxyazine: 1- (3-benzyloxy-2-fluoro-phenyl) -8-chloro-3-cyclobuyl-imidazo [ 1, 5-ajpyrazine (500 mg, 1.2 mmol) in methylene chloride was placed in a Parr reactor under pressure, cooled in an ice and salt bath and charged with a saline solution of NH3 in 2-propanol (10 mL ). The pressure reactor was heated to 125 ° overnight. The reaction was cooled to ambient temperature and the reaction mixture without purification was evaporated and triturated with methylene chloride and filtered. The filtrate was evaporated to dryness and purified by silica gel column chromatography [eluent CH2Cl2: hexane (70:30)] to afford the title compound (350 mg, 75%); FABMS: m / z 388.9 (M + H) +. a) 1 - (3-Benzyloxy-2-fluorophenyl) -8-chloro-3-cyclobuylimidazo [1,5-a] pyrazine: [(3-benzyloxy-2-fluoro-phenyl) - (3-chloro-p Racein-2-yl) -methyl] -cyclobuylenecarboxylicamide (0.850 g, 2 mmol) was dissolved in POCI3 (6 mL) and heated at 55 ° overnight. The excess of POCI3 was removed in vacuo. The residue was cooled to 0 ° and charged with a saturated solution of NH 3 in 2-propanol (6 mL). The mixture was left overnight at ambient temperature. Then the separated solid was filtered and washed with methylene chloride. The filtrate was evaporated to dryness and purified by silica gel column chromatography using hexane: ethyl acetate (60:40) as the eluent to afford the title compound (615 mg, 75%). FAB-MS: m / z 408.3 (M + H) +. b) N - [(3-benzyloxy-2-fluorophenyl) (3-chloropyrazin-2-yl) -methyl] -cyclobuylcarboxamide: To a solution of C- (3-benzyloxy-2-fluoro-phenyl) -C- (3- chloro-pyrazin-2-yl) -methylamide (1.1 g, 3.2 mmol) in methylene chloride (10 mL) was added diisopropylethylamine (1.1 mL, 6.4 mmol) under a nitrogen atmosphere. The reaction mixture was cooled in an ice bath and cyclobutanecarboxylic acid chloride (0.55 mL, 4.8 mmol) was added in one portion. The reaction mixture was stirred overnight at room temperature then was quenched with water (10 mL). The separated organic layer was washed with 10% aqueous NaHC03, dried over anhydrous Na2SO3, filtered and concentrated. The unpurified product was purified by silica gel column chromatography using hexane: ethyl acetate (60:40) as an eluent to produce the thiful compound (911 mg, 67%). FAB-MS: m / z 426.3 (M + H) +. c) (3-benzyloxy-2-fluorophenyl) (3-chloropyrazin-2-yl) aminomethane: A mixture of 2 - [(3-benzyloxy-2-fluoro-phenyl) - (3-chloro-pyrazin-2-yl) ) -methyl] -isoindole-1, 3-dione (1.63 g, 3.45 mmol) and hydrazine (0.270 mL, 8.6 mmol) in ethanol (30 mL) and methylene chloride (10 mL) was agitated at ambient temperature under nitrile. After 65 hours, the separated solid of phthalazine-1,4-dione was filtered, and the solid concentrate was washed with methylene chloride. The filtrate was concentrated in vacuo to obtain a red oil comprising the desired compound of the product, which solidifies on standing (1.0 g, 85%). d) 2 - [(3-Benzyloxy-2-fluoro-phenyI) - (3-chloro-pyrazin-2-yl) -methyl] -isoindole-1,3-dione: In a flask with three necks of 250 mL, equipped with an N2 inlet and a thermometer, methylfenilphosphine (3.28 g, 12.5 mmol) in THF (30 mL) was placed. The mixture was cooled from 0 to 5 ° and DEAD (1.97 mL, 12. 5 mmol) was added slowly for 15 minutes while maintaining the temperature at 0-3 °. Stirring was continued for an additional 30 minutes at the same temperature. Then to the cold solution was added a solution of (3-benzyloxy-2-fluorophenyl) (3-chloropyrazin-2-yl) carbinol (1.96 g, 5.685 mmol) and phthalimide (§, 1.0 g, 6.8 mmol) in THF (30 mL) at 0-5 ° for 10 minutes. The temperature was allowed to slowly rise to room temperature and then allowed to stir overnight. The reaction mixture was concentrated in vacuo and purified by column chromatography using hexane: ethyl acetate (70:30) as the eluent. The desired pure product was obtained. e) (3-Benzyloxy-2-fluorophenyl) (3-chloropyrazin-2-yl) carbinol: THF (28 mL) was placed in a 100 mL three-necked round bottom flask equipped with an N2 inlet and an ether flask. ). Esio was cooled to -40 ° and to this was added 2.5M n-BuLi solution in hexane (11.52 mL, 28.8 millimoles) followed by 2,2,6,6-eeryamylpiperidine (4.84 mL, 28.8 millimoles). The femperairy of the mixture was allowed to rise to 0 ° and the stirring was continued from -5 to 0 ° for 30 minutes. Then the mixture was cooled to -70 °, and the chloropyrazine (1.28 mL, 14.4 mmol) was added slowly for 15 min. And the stirring was coninuted for 30 min. Then a solution of 3-benzyloxy-2-fluorobenzaIdehyde (3.04 g, 13.2 mmol) in THF (7 mL) was added at -70 ° and the stirring was con- tinuously from -70 to -60 ° for 2 hours. Subsequently the temperature was allowed to rise to room temperature for 1 hour. The reaction mixture was quenched with 2N HCl (6 mL) and stirred overnight at ambient temperature. The mixture was then evaporated on a rotary evaporator to remove most of the THF. Ethyl acetate (20 mL) was added to the residue. The organic layer was separated, washed with water (10 mL), finally with brine (10 mL), dried over Na 2 SO, filtered and concentrated. The unpurified residue obtained was 4.4 g. The aforesaid reaction was repeated four times and the products were combined. The residue was purified by silica gel column chromatography using acetone: hexane (30:70) as the eluent and the title compound was obtained (3.8 g, 21%). f) 3-Benzyloxy-2-fIuorobenzaldehyde: 3-hydroxy-2-fluorobenzaldehyde . { reported by Kirk et. al., J Med. Chem. 1986, 29, 1982.}. (15 g, 107 mmol) was added to an aqueous solution of NaOH. { (5.14 g, 128 mmol in water (50 mL).) And the mixture was stirred for 5 minutes to carry out the complete solution, and a solution of benzyl bromide (16.46 g, 96.3 mmol) was added thereto. methylene chloride (75 mL) followed by tetrabuylylammonium iodide (0.5 g, 1.35 mmol) and vigorous stirring was continued throughout the whole.The organic layer was separated and the aqueous layer was extracted with methylene chloride (100 mL). The combined organic layers were washed with an aqueous solution of 5% NaOH (2 x 25 mL) followed by water (50 mL) and finally with brine (20 mL) .This solution was dried over anhydrous Na2SO4, filtered and evaporated to The resulting pale yellow unpurified solid was crystallized from cyclohexane (150 mL) to yield the title compound (16.5 g, 75%), mp 88-89 °.

Claims

NOVELTY OF THE INVENTION CLAIMS

1. - A compound represented by the formula

or to a pharmaceutically acceptable salt thereof, wherein: Q 1 is aryl 1, heteroaryl 1, cycloalkyl, heterocyclyl, cycloalkenyl, or heteroalkyl alkenyl, any of which is optionally substituted by one to five independent G 1 -substitutes; R1 is alkyl, cycloalkyl, bicycloalkyl, aryl, heeroaryl, aralkyl, heteroaralkyl, helerocyclyl, or heteroalicycloalkyl, any of which is optionally susiiuid by one or more independent G1 susfituyeníes; G and G41 are each independently halo, oxo, -CF3, -OCF3, -OR2, -NR ^ R33) ^, -C (0) R2, -C02R2, -CONR2R3, -N02, -CN, -S (0 ) j-, R2, -S02NR2R3, NR2 (C = 0) R3, NR2 (C = 0) OR3, NR2 (C = 0) NR2R3, NR2S (0) j1R3, - (C = S) OR2, - (C) = 0) SR2, -NR2 (C = NR3) NR2aR3a, -NR2 (C = NR3) OR2a, -NR2 (C = NR3) SR3a, -0 (C = 0) OR2, -0 (C = 0) NR2R3, -0 (C = 0) SR2, -S (C = 0) OR2, -S (C = 0) NR2R3, C0-? O alkyl, C2.10 alkenyl, C2.10 alkynyl, C alkoxy The alkyl of C- | .10, C 2 - C 0 alkenyl alkoxy. C 1 -C 10 alkyloxy-C 2. 10 alkyloxy, C 1-10 alkyl-C 1-10 alkyloxy, C 2 -α alkynyl C 2 -α alkynyl, C 2 -C 1 -alkyl alkynyl .10, C3.8 cycloalkyl, C3.8 cycloalkenyl, C3-8 cycloalkyl C? -? 0 alkyl, C3 cycloalkenyl C-O salicyl, C3-10 cycloalkyl C2-10 alkenyl, C3 cycloalkenyl C2-10-salquenyl, C2-C3-alkynyl cycloalkyl or C3-C3-cycloalkenyl, C2_? 0 -alkynyl, heyerocyclyl-Co-10-alkyl. C2-10 heterocyclyl-alkenyl, or C2-10 heterocyclyl-alkynyl, any of which is optionally substituted with one or more independent halo, oxo, -CF3, -OCF3, -OR222, -NR222R333 (R333a) j1a substituents, -C (0) R222, -C02R222, -CONR222R333, -N02, -CN, -S (0) j1aR222, -S02NR222R333, NR222 (C = 0) R333, NR222 (C = 0) OR333, NR222 (C = 0) ) NR222R333, NR222S (0) j1aR333, - (C = S) OR222, - (C = 0) SR222, -NR222 (C = NR333) NR222aR333a, -NR222 (C = NR333) OR222a, -NR222 (C = NR333) SR333a, -0 (C = 0) OR222, -0 (C = 0) NR222R333, -0 (C = 0) SR222, -S (C = 0) OR222, or -S (C = 0) NR222R333; or - (X1) n- (Y1) m- 4; or aryl-Co-10 alkyl, C2-10 arylalkenyl, or C2-? arylalkynyl, either of which is optionally substituted with one or more halo independent halogen, -CF3, -OCF3, -OR222, -NR222R333 ( R333a) j2a, -C (0) R222, -C02R222, -CONR222R333, -N02, -CN, -S (0) j2aR222, -S02NR222R333, NR222 (C = 0) R333, NR222 (C = 0) OR333,

NR2 2 (C = 0) NR222R333, NR222S (0) j2aR333, - (C = S) OR222, - (C = 0) SR222, -NR222 (C = NR333) NR222aR333a, -NR222 (C = NR333) OR222a, - NR222 (C = NR333) SR333a, -0 (C = 0) OR222, -0 (C = 0) NR222R333, -0 (C = 0) SR222, -S (C = 0) OR222, or -S (C = 0) NR222R333; or hexylalkyl of C0-? or C2-? hetaryllalkyl or C2_? hetarylalkynyl, any of which is optionally substituted with one or more independent halo substituents, -CF3, -OCF3, -OR222, -NR222R333 (R333a ) j3a, -C (0) R222, -C02R222, -CONR222R333, -N02, -CN, -S (0) j3aR222, -S02NR222R333, NR222 (C = 0) R333, NR222 (C = O) OR333,

NR222 (C = 0) NR222R333, NR222S (0) j3aR333, - (C = S) OR222, - (C = 0) SR222, -NR222 (C = NR333) NR222R333a, -NR222 (C = NR333) OR222a, -NR222 (C = NR333) SR333a, -0 (C = 0) OR222, -0 (C = 0) NR222R333, -0 (C = 0) SR222, -S (C = 0) OR222, or -S (C = 0) ) NR222R333; G11 is halo, oxo, -CF3, -OCF3, -OR21, -NR21R31 (R3a1) j4, -C (0) R21, -C02R21, -CONR21R31, -N02, -CN, -S (0) j4R21, -S02NR21R31 , NR21 (C = 0) R31, NR21 (C = 0) OR31, NR21 (C = 0) NR21R31, NR21S (0) j4R31, - (C = S) OR21, - (C = 0) SR21, -NR21 ( C = NR31) NR2a1R3a1, -NR21 (C = NR31) OR2a1, -NR21 (C = NR31) SR3a1, -0 (C = 0) OR21, -0 (C = 0) NR21R31, -0 (C = O) SR21 , -S (C = 0) OR21, -S (C = 0) NR21R31, -P (0) OR21OR31, C0-? 0 alkyl, C2_? Alkenyl, C2-? 0 alkynyl, Ci-alkoxy. C 1 -10alkyl, C 2 -C 10 alkoxy, C 2. 10 alkoxy, C 2 -C 0 alkyloxy, C 2 -α 0 alkyloxy, Cilt-C --C 0 alkyl alkyloxy; , C2-? C? -? 0 alkenyl alkylthio or C2-10 Ci-ioalkynyl alkyl, C3-8 cycloalkyl, C3.8 cycloalkenyl, C3.8 cycloalkyl C-? 10 alkyl, cycloalkenyl C3.8 alkyl of C? .10, cycloalkyl of C3-8 alkenyl of C2.10, cycloalkenyl of C3-8 alkenyl of C2-? Or >; C3-8alkynyl cycloalkyl of C2-? 0, C3-8alkynyl of C2-10alkynyl of C2-10, heterocyclyl-C0-? alkyl, heterocyclyl-alkenyl of C2.o, or heterocyclyl-alkynyl of C2.10, any which is optionally subsumed with one or more independent halogens, oxo, -CF3, -OCF3, -OR2221, -NR2221R3331 (R333a1) j4a, -C (0) R2221, -C02R2221, -CONR2221R3331, -NO2, -CN, -S (0) j4aR2221, -S02NR2221R3331, NR2221 (C = 0) R3331, NR2221 (C = 0) OR3331, NR2221 (C = 0) NR2221R3331, NR2221S (0) j4aR3331, (C = S) OR2221, - (C = 0) SR2221, -NR2221 (C = NR3331) NR222a1R333a1,

NR2221 (C = NR3331) OR222a1, -NR2221 (C = NR3331) SR333a1, -0 (C = 0) OR2221, -0 (C = 0) NR2221R3331, -0 (C = 0) SR2221; -S (C = 0) OR2221, -P (0) OR2221OR3331, or -S (C = 0) NR2221R3331; or aryl-C0-βalkyl or, C2.10 aryl-alkenyl, or C2.o aryl-alkynyl, any of which is optionally substituted with one or more independent halo assistants, -CF3, -OCF3, - OR2221, - NR2221 R333. (R333a1) j5aj .CfOJR2221, _C02R2221, -CONR2221R3331, -NO2, -CN, -S (0) j5aR2221, -S02NR2221R3331, NR2221 (C = 0) R3331, NR2221 (C = 0) OR3331, NR2221 (C = 0) NR2221R3331, NR2221S (0) j5aR3331, - (C = S) OR2221, - (C = 0) SR2221, -NR2221 (C = NR3331) NR222a1R333a1, -NR2221 (C = NR3331) OR222a1, NR2221 (C = NR3331) SR333a1, -0 (C = 0) OR2221, -0 (C = 0) NR2221R3331, OR (C = 0) SR2221, -S (C = 0) OR2221, -P (0) OR2221OR3331, or -S (C = 0) NR2221R3331; or hetaryl-C0-? alkyl, or C2.10 hetaryl-alkenyl, or C2.10 hetaryl-alkynyl, any of which is optionally susíiuid with one or more halogen-independent subsides, -CF3, -OCF3, - OR2221,

NR2221R3331 (R333a1) j6a, -C (0) R2221, -C02R2221, -CONR2221R3331, -N02, -CN, -S (0) j6aR2221, -S02NR2221R3331, NR2221 (C = 0) R3331, NR2221 (C = 0) OR3331 , NR2221 (C = 0) NR2221R3331, NR2221S (0) j6aR3331, - (C = S) OR2221, - (C = 0) SR2221, -NR2221 (C = NR3331) NR222a1R333a1, -NR2221 (C = NR3331) OR222a1, NR2221 (C = NR3331) SR333a1, -0 (C = 0) OR2221, -0 (C = 0) NR2221R3331,

0 (C = 0) SR2221, -S (C = 0) OR2221, -P (0) OR2221OR3331, or -S (C = 0) NR2221R3331; or G11 is juncted with the carbon to which it is bound to form a double bond which is substituted with R5 and G111; R2, R2a, R3, R3a, R222 'R222a, R333, R333a, R21, R2a1, R31, R3a1, R2221, R222a1, R3331, and R333a1 are each independently the same as C0-? Alkyl, C2 alkenyl. 0, C2-C2 alkynyl, C1-10 alkoxy C1-10 alkyl, C2-10 alkenyl C2-10 alkenyl, C2-10 alkynyl C2-10 alkyl, C12 alkylthio; . C-? 10 alkyl, C2_6alkyl, C2_3alkyl, C2-10alkyl, C2-10alkyl, C3-8 cycloalkyl, C3-8 cycloalkenyl, C3_8alkyl cycloalkyl of C1-10, C3 cycloalkenyl. 8alkyl C-O, C3.8alkyl cycloalkyl of C2.10, cycloalkenyl of C3. C2.10 alkenyl, C3-8alkynyl cycloalkyl of C2.10, cycloalkenyl of C3. C2_6alkynyl, heterocyclylC0-? Alkyl, C2-? 0 heterocyclyl-alkenyl, or C2.10 heterocyclyl-alkynyl, any of which is optionally substituted by one or more G111 substituents; or aryl-Co-0alkyl, C2-10 arylalkenyl, or C2-10 arylalkynyl, Caryl-alkyl or C5-10 hetaryl-alkenyl, or C2-hetaryl-alkynyl. 0, any of which is optionally substituted by one or more substituents G111; or in the case of -NR2R3 (R3a) j1 or -NR222R333 (R333a) J1a or -NR222R333 (R333a) j2a or -N R222. R333. (R333a1) j3a Q _N R222l R3331 (R333a1)] 4a Q _N R2221 R3331 (R333a1) j5a Q _

N R2221 R3331 (R333a1) j6a¡ R2 and R3 Q R222 and R333 Q R2221 and R3331 taken together CQn

the nihologen atom to which they are attached form a saturated ring, unsaturated ring, saturated heterocyclic ring, or unsaturated heterocyclic ring, of 3-10 members wherein said ring is optionally substituted by one or more substituents G111; X1 and Y1 are each independently -O-, -NR7-, -S (0), 7-, -CR5R6-, -N (C (0) OR7) -, -N (C (0) R7) -, -N (S02R7) -, -CH20-, -CH2S-, -CH2N (R7) -, -CH (NR7) -, -CH2N (C (0) R7) -, -CH2N (C (0) OR7) - , -CH2N (SO2R7) -, - CH (NHR7) -, -CH (NHC (0) R7) -, -CH (NHS02R7) -, -CH (NHC (0) 0R7) -, -CH (OC (0 ) R7) -, -CH (OC (0) NHR7) -, -CH = CH-, -OC-, -C (= NOR7) -, -C (O) -, -CH (OR7) -, -C (0) N (R7) -, -N (R7) C (0) -, -N (R7) S (0) -, -N (R7) S (0) 2- -OC (0) N (R7) ) -, -N (R7) C (0) N (R7) -, -NR7C (0) 0-, -S (0) N (R7) -, -S (0) 2N (R7) -, -N (C (0) R7) S (0) -, -N (C (0) R7) S (0) 2-, -N (R7) S (0) N (R7) -, -N (R7) S (0) 2N (R7) -, -C (0) N (R7) C (0) -, -S (0) N (R7) C (0) -, -S (0) 2N (R7) C ( 0) -, -OS (0) N (R7) -, -OS (0) 2N (R7) -, -N (R7) S (0) 0-, -N (R7) S (0) 20-, -N (R7) S (0) C (0) -, -N (R7) S (0) 2C (0) -, -SON (C (0) R7) -, -S02N (C (0) R7) -, -N (R7) SON (R7) -, -N (R7) S02N (R7) -, -C (O) 0-, -N (R7) P (OR8) 0-, -N (R7) P (OR8) -, -N (R7) P (0) (OR8) 0-, -N (R7) P (0) (OR8) -, -N (C (0) R7) P (OR8) 0-, -N (C (0) R7) P (OR8) -, -N (C (0) R7) P (0) (OR8) 0-,

N (C (0) R7) P (OR8) -, -CH (R7) S (0) -, -CH (R7) S (0) 2-, -CH (R7) N (C (0) OR7) -, -CH (R7) N (C (0) R7) -, -CH (R7) N (S02R7) -, -CH (R7) 0-, -CH (R7) S-, -CH (R7) N (R7) -, -CH (R7) N (C (0) R7) -, -CH (R7) N (C (0) OR7) -, CH (R7) N (S02R7) -,

CH (R7) C (= NOR7) -, -CH (R7) C (0) -, -CH (R7) CH (OR7) -, -CH (R7) C (0) N (R7) -, -CH (R7) N (R7) C (0) -, -CH (R7) N (R7) S (0) -, -CH (R7) N (R7) S (0) 2-,

CH (R7) OC (0) N (R7) -, -CH (R7) N (R7) C (0) N (R7) -, -CH (R7) NR7C (0) O-, -CH (R7) S (0) N (R7) -, -CH (R7) S (0) 2N (R7) -, -CH (R7) N (C (0) R7) S (0) -, CH (R7) N ( C (0) R7) S (0) -, -CH (R7) N (R7) S (0) N (R7) -, -CH (R7) N (R7) S (0) 2N (R7) -, -CH (R7) C (0) N (R7) C (0) -, -CH (R7) S (0) N (R7) C (0) -, -CH (R7) S (0) 2N (R7) ) C (0) -, -CH (R7) OS (0) N (R7) -, -CH (R7) OS (0) 2N (R7) -, -CH (R7) N (R7) S (0) 0-,

CH (R7) N (R7) S (0) 20-, -CH (R7) N (R7) S (0) C (0) -, -CH (R7) N (R7) S (0) 2C (0 ) -, -CH (R7) SON (C (0) R7) -, -CH (R7) S02N (C (0) R7) -, -CH (R7) N (R7) SON (R7) -, -CH (R7) N (R7) S02N (R7) -, -CH (R7) C (0) 0-, -CH (R7) N (R7) P (OR8) 0-, CH (R7) N (R7) P (0R8) -, -CH (R7) N (R7) P (0) (OR8) 0-, -CH (R7) N (R7) P (0) (OR8) -, -CH (R7) N (C (0) R7) P (OR8) 0-, -CH (R7) N (C (0) R7) P (OR8) -, CH (R7) N (C (0) R7) P (0) (OR8) 0-, or -CH (R7) N (C (0) R7) P (OR8) -; or X1 and Y1 are each independently represented by one of the following sonic formulas:

R10, taken together with the phosphine or phosphonamide, is a 5-, 6-, or 7-membered aryl, heteroaryl or heterocyclyl ring system; R5, R6, and G1 1 are each independently a Co-10 alkyl, C2-10 alkenyl. C2-10 alkynyl, C? - alco alkyloxy C de ?. ?.alkyl, C alco.10 alkyloxycarbonyl alkoxy, C 2-10 C? _ ?alkyloxy alkoxy, C alqu-10 alqu alkyloxy; C?-Α-C o-alkyl, Cilt-C 0-10-alkenyl C2-10alkyl, C2-C Ci-cyanoalkynyl, C3-8 cycloalkyl, C3-cycloalkenyl, C3 cycloalkyl -8 C1-10 alkyl, C3 cycloalkenyl. 8alkyl C-MO, C3.8alkenyl cycloalkyl of C2-10, cycloalkenyl of C3. 8-C2-C0-cycloalkyl, cycloalkyl-C3-C8-alkynyl, C3-cycloalkenyl. C2-? 0alkynyl, heterocyclylCo-10alkyl, C2-? Heterocyclyl-alkenyl, or C2-0 heterocyclyl-alkynyl, any of which is optionally substituted with one or more independent halo substituents, -CF3 , -OCF3, -OR77, -NR77R87, -C (0) R77, -C02R77, -CONR77R87, -N02, -CN, -S (0) j5aR77, -S02NR77R87, NR77 (C = 0) R87, NR77 (C = 0) OR87, NR77 (C = O) NR78R87, NR77S (0) j5aR87, - (C = S) OR77, - (C = 0) SR77, -NR77 (C = NR87) NR78R88, -NR77 (C = NR87 ) OR78, -NR77 (C = NR87) SR78, -0 (C = 0) OR77, -0 (C = 0) NR77R87, -O (C = 0) SR77, -S (C = 0) OR77, -P (0) OR77OR87, or -S (C = 0) NR77R87 substituents; or C2-C2- aryl, C2.10 arylalkenyl, or C2-6 arylalkynyl, either of which is optionally substituted with one or more halo, -CF3, -OCF3, -OR77, -NR77R87, independent substituents, -C (0) R77, -C02R77, -CONR77R87, -N02, -CN, -S (0) j5aR77, -S02NR77R87, NR77 (C = 0) R87, NR77 (C = 0) OR87, NR77 (C = 0) ) NR78R87, NR77S (0) j5aR87, - (C = S) OR77, - (C = 0) SR77, -NR77 (C = NR87) NR78R88, -NR77 (C = NR87) OR78, -NR77 (C = NR87) SR78, -0 (C = 0) OR77, -0 (C = 0) NR77R87, -0 (C = 0) SR77, -S (C = O) 0R77, P (0) OR77OR87, or -S (C = 0) NR77R87; or hetarylalkyl of C0.o0, hetarylalkenyl of C2.o, or hetarylalkynyl of C2_? 0, any of which is optionally substituted with one or more independent substituents halo, -CF3, -OCF3, -OR77, -NR77R87, - C (0) R77, -C02R77, -CONR77R87, -N02, -CN, -S (0) j5aR77, -S02NR77R87, NR77 (C = 0) R87, NR77 (C = 0) OR87, NR77 (C = O) NR78R87, NR77S (0) j5aR87, - (C = S) OR77, - (C = 0) SR77, -NR77 (C = NR87) NR78R88, -NR77 (C = NR87) OR78, -NR77 (C = NR87) SR78 , -0 (C = 0) OR77, -0 (C = 0) NR77R87, -0 (C = 0) SR77, -S (C = 0) OR77, -P (0) OR77OR87, or -S (C = 0) NR77R87; or R5 with R6 taken together with the respecific carbon atom to which they are attached, form a saturated or unsaturated ring of 3-10 members, wherein said rings are optionally susíiuuido with R69; or R5 with R6 taken June with the respective carbon atom to which they are attached, form a saturated or unsaturated heterocyclic ring of 3-10 members, wherein said ring is optionally substituted with R69; R7 and R8 are each independently H, acyl, alkyl, alkenyl, aryl, heleroaryl, heterocyclyl or cycloalkyl, any of which is optionally substituted by one or more substituents G111; R is H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heteroaryl, cycloalkenyl, or heteroaryloalkenyl, any of which is optionally substituted by one or more G41 substituents; R69 is halo, -OR78, -SH, -NR78R88, -C02R78, -CONR78R88, -N02, -CN, -S (0) j8R78, -S02NR78R88, C0-o, alkyl, C2-10 alkenyl, alkynyl, C2-? 0, C1-6 alkoxy, C1-10alkyl, C2-? 0alkenyl alkoxy, C2_? O alkoxy, C2- or C2-? Alkynyl alkoxy, or C? _Oalkyl alkylthio C1-10, C.sub.2 -C.alkylthio C.sub.2.alkyl C.sub.

2, C.sub.2.alkylthio C.sub.2 -C.sub.10 alkynyl, C.sub.3.8 cycloalkyl, C.sub.3.8 cycloalkenyl, C.sub.3.8 cycloalkyl, C.alkyl. -?, C3 cycloalkenyl. C 1-10 alkyl, C 3. 8 alkenyl cycloalkyl, C 3-10 cycloalkenyl, C 2-10 alkenyl, C 3-8 alkynyl cycloalkyl, C 3 - cycloalkenyl, C 3 cycloalkenyl. 8-C2- alkynyl, heterocyclyl-Co-yl alkyl, C2-? 0 heterocyclyl-alkenyl, or C2.10 heterocyclyl-alkynyl, any of which is optionally subsituted with one or more substituents independently halo, cyano , nitro, -OR778, -S02NR778R888, or -NR778R888; or aryl-C0-alkyl or, aryl-C2-alkenyl. or, or aryl-alkynyl of C2-?, or any of which is optionally susíifuido with one or more independent haloyl, cyano, niino, - OR778, CMO alkyl, C2-10 alkenyl. C2.10 alkynyl, C1-10 haloalkyl, C2.10 haloalkenyl, C2-10 haloalkynyl, -COOH, C4-4 alkoxycarbonyl, -CONR778R888, -S02NR778R888, or -NR778R888; or hetaryl-C0-? alkyl, or C2.10 hetaryl-alkenyl, or C2.10 hepharyl-alkynyl, any of which is optionally substituted with one or more halo, cyano, nitro, -OR778, independent substituents, C1-10 alkyl, C2.o.o alkenyl, C2.o0 alkynyl, C1.10 haloalkyl, C2.10 haloalkenyl, C2-10 haloalkynyl, -COOH, C? _4 alkoxycarbonyl, -CONR778R888 , -S02NR778R888, or -NR778R888; or monoamino (C? -6 alkyl) C? -6 alkyl, diamino (C? 6 alkyl) C? -6 alkyl, monoamino (ariI) C? -6 alkyl, diamino (aryl) alkyl of C? -6, or -N (C ^ -alkylaryl of C? -6-, any of which is optionally substituted with one or more independent halogen, cyano, nitro, -OR778 alkyl substituents, C? ? 0, C2-? 0 alkenyl, C2-? 0 alkynyl, C? _10 haloalkyl, C2-10 haloalkenyl, C2-10 haloalkynyl, -COOH, C ^ alkoxycarbonyl, -CONR778R888, -S02NR778R888, or -NR778R888, or in the case of -NR78R88, R78 and R88 taken June with the nitrogen atom to which they are attached they form a saturated ring of 3-10 members, unsaturated ring, sacurated heterocyclic ring, or unsaturated heyerocyclic ring, in wherein said ring is optionally substituted with one or more independent halo, cyano, hydroxy, nitro, C1-10 alkoxy, -S02NR778R888, or -NR778R888.R77J R78J R87J R88j R77ß and R888 are each independently

C 0 -α alkyl, C 2 -α alkenyl or, C 2-10 alkynyl, C 1 - α 0 alkyloxy C 1-10 alkyloxy, C 6-10 alkenyl C 2-10 alkenyl, C 0-0 alkynyl alkoxy C2-10, C alqu _? ?alkyl alkyl of CMO, C? -???? Alkynyl of C 2 - o o, or C alqu alkylfio. C 0 alkynyl. or, C3.8 cycloalkyl, C3.8 cycloalkenyl, C3.8 cycloalkyl C1-10 alkyl, C3.8 cycloalkenyl C1-10 alkyl, C3 cycloalkyl. 8alkenyl of C2.-0. C3-8alkenyl cycloalkenyl of C2.o0, cycloalkyl of C3. C2_? 0alkynyl, C3.8alkynyl of C2_? 0, heterocyclylCal-10alkyl, C2_? Heterocyclyl-alkenyl, C2_? 0 heyerocyclic-alkynyl, C1-10alkylcarbonyl, alkenylcarbonyl C? 0, C2-0 alkynylcarbonyl, C1-10 alkoxycarbonyl, C? -10 alkyloxycarbonyl of C1-10 alkyl, monoalkylaminocarbonyl of C? -6, dialkylaminocarbonyl of C? -6, mono (aryl) aminocarbonyl, di ( aryl) aminocarbonyl, or C1-? alkyl or (aryl) aminocarbonyl, any of which is optionally substituted with one or more halo, cyano, hydroxy, nitro, C1-10 alkoxy, -S02N (C0- 4) (C0-4 alkyl), or -Ñ (C0-4 alkyl) (C0- alkyl); or aryl-C0-10 alkyl, C2.10 aryl-alkenyl, or C2.10 aryl-alkynyl, any of which is optionally substituted with one or more independent halo, cyano, nitro, -0 (alkyl) substituents of C0.), CMO alkyl, C2-? 0 alkenyl, C2-10 alkynyl, C0H haloalkyl, C2.o haloalkenyl, C2_? 0 haloalkynyl, -COOH, C? alkoxycarbonyl. , -CON (C0-4 alkyl) (Co-10 alkyl), -S02N (C0-4 alkyl) (C0- alkyl), or -N (Co-4 alkyl) (C0- alkyl); or hearyl-Co-10 alkyl, C2.o.-hetaryl-alkenyl, or C2-? 0 hetaryl-alkynyl, any of which is optionally substituted with one or more halogen, cyano, ni, -0 ( Co-4 alkyl), C ?.10 alkyl) C2_? alkenyl, C2.o. alkynyl, C1-10 haloalkyl, C2-? 0 haloalkenyl, C2-? o haloalkynyl, -COOH, C4-4 alkoxycarbonyl, -CON (C0-4 alkyl) (C0-4 alkyl), -S02N (C0-4 alkyl) (C0.4 alkyl), or -N (Co-4 alkyl) ) (Co-4 alkyl); or mono (C6-6alkyl) aminoalkyl of C1-6, diamino (C6-6alkyl) aminoalkyl of C6-6, mono (aryl) aminoalkyl of C6-6, di (aryl) aminoalkyl of C -? - 6, or -N (C? -6 alkyl) -alkylaryl of C ^ -, any of which is optionally substituted with one or more independent substituents halo, cyano, niiro, -0 (C0.4 alkyl) ), alkyl of C | -10, alkenyl of C2.10, alkynyl of C2-10, haloalkyl of C1-10, haloalkenyl of C2.o0, haloalkynyl of C2-? o, -COOH, alkoxycarbonyl of C? -4 , -CON (C0- alkyl) (C0- alkyl), -S02N (C0-4 alkyl) (C0-4 alkyl), or -N (C0-4 alkyl) (C0-4 alkenyl); and n, m, j1, j1a, j2a, j3a, j4, j4a, j5a, jda, j7, and j8 are each independently the same as 0, 1, or 2. 2. The compound according to claim 1, characterized in addition because Q1 is aryl1 or heteroaryl, any of which is optionally substituted by one or more independent G1 substituents.

3. The compound according to claim 2, further characterized in that Q1 is heteroaryl, any of which is optionally substituted by one or more independents G.

4. The compound according to claim 3, further characterized in that Q1 is aryl1, any of which is optionally subsumed by one or more independent substituents G.

5. The compound according to claim 1, further characterized in that G1 is halo, -CF3, -OCF3, -OR2, -NR2R3, -C (0) R2, -C02R2, -CONR2R3, -S (0) jiR2, - S02NR2R3, NR2 (C = 0) R3, NR2 (C = 0) OR3, NR2 (C = 0) NR2R3, NR2S (0) jiR3, -0 (C = 0) OR2, -0 (C = 0) NR2R3, C0-.alkyl, C2-? 0 alkenyl, C2-? 0 alkynyl, Ci.ioalkyl alkoxy of C- or C2-10 Ci-alkoxy alkoxy. C2-10 Ci.alkyl alkyloxy. C1-10 alkylthio C1-10 alkyl, C2-10 alkylthio. alkylthio of C |. C 2 -α-0-alkynyl, C 3-8 cycloalkyl, C 3-8 cycloalkenyl, C 3-8 cycloalkyl CMO alkyl, C 3-8 cycloalkenyl C 1-10 alkyl, C 3 cycloalkyl. C2_? 0 salkenyl, C3-8 C2_8 alkenyl cycloalkenyl. 0, C3 cycloalkyl. C2_ [alpha] 0alkynyl, C3.8alkynyl cycloalkenyl of C2_ [alpha] 0, heyerocyclyl-C1_10alkyl, heteroaryl-alkenyl of C2.o0, or heterocyclyl-alkynyl of C2- [beta] 0, any of which is optionally substituted with one or more independent substituents halo, oxo, -CF3, -OCF3, -OR222, NR222R333 (R33a) j1a, -C (0) R222, -C02R222, -CONR222R333, -N02, -CN, -S (0) j1aR222 , -S02NR222R333, NR222 (C = 0) R333, NR222 (C = O) OR333,

NR222 (C = 0) NR222R333, NR222S (0) jiaR333, - (C = S) OR222, - (C = 0) SR222, -NR222 (C = NR333) NR222aR333a, -NR222 (C = NR333) OR 22a, - NR222 (C = NR333) SR333a, -0 (C = 0) OR222, -0 (C = 0) NR222R333, -0 (C = 0) SR222, -S (C = 0) OR222, or -S (C = 0) NR222R333; or - (X) p- (Y1) m-R4; or aryl-Co-10 alkyl, aryl-C2 alkenyl. 10, or C2_? 0 aryl-alkynyl, any of which is optionally substituted with one or more independent halogen substituents, -CF3, -OCF3, -OR222, -NR222R333 (R333a) j2a, -C (0) R222, - C02R222, -CONR222R333, -N02, -CN, -S (0) j2aR222, -S02NR222R333, NR222 (C = 0) R333, NR222 (C = O) OR333,

NR222 (C = 0) NR222R333, NR222S (0) j2aR333, - (C = S) OR222, - (C = 0) SR222, -NR222 (C = NR333) NR222aR333a, -NR222 (C = NR333) OR222a, -NR222 (C = NR333) SR333a, -O (C = 0) 0R222, -0 (C = 0) NR222R333, -0 (C = 0) SR222, -S (C = 0) OR222, or -S (C = 0) ) NR222R333; or hetaryl-C0-oalkyl, C2-C6-hetaryl-alkenyl, or C2-10 -hetanyl-alkynyl, any of which is optionally substituted with one or more halo-free substituents, -CF3, -OCF3, - OR222, -NR222R333 (R333a) j3a, -C (0) R222, -C02R222, -CONR222R333, -N02, -CN, -S (0) j3aR222, -S02NR222R333, NR222 (C = 0) R333, NR222 (C = O) OR333, NR222 (C = 0) NR222R333, NR222S (O) j3aR333, - (C = S) OR222, - (C = 0) SR222, -NR222 (C = NR333) NR222aR333a, -NR222 (C = NR333) OR222a, -NR222 (C = NR333) SR333a, -0 (C = 0) OR222, -0 (C = 0) NR222R333, -0 (C = 0) SR222, -S (C = 0) OR222, or -S (C = 0) NR222R333.

6. The compound according to claim 1, further characterized in that G1 is halo, -OR2, -NR2R3, -C (0) R2, -C02R2, -CONR2R3, -S02NR2R3, NR2 (C = 0) R3, NR2 (C = 0) OR3, NR2 (C = 0) NR2R3, NR2S (0) jiR3, -0 (C = 0) OR2, -0 (C = 0) NR2R3, C0-? Alkyl or C2 alkenyl? 0, C 1-10 alkoxy-C 1-10 alkyloxy, C 1-10 alkylthio, C 1-10 alkyl, C 3-8 cycloalkyl, C 3-8 cycloalkenyl, or heteroaryl-C 1-6 alkyl, or heterocyclic. alkenyl of C2_? 0, any of which is optionally substituted with one or more independent oxo substituents, -CF3, -OCF3, -OR222, -NR222R333, -C (0) R222, -CO2R222, -CONR222R333, -S02NR222R333, NR222 (C = 0) R333, NR222 (C = 0) OR333, NR222 (C = 0) NR222R333, NR222S (0) j1aR333, - NR222 (C = NR333) NR222aR333a, or -0 (C = 0) NR222R333; or - (X1) n- (Y1) m-R4; or Co-10 arylalkyl, optionally substituted with one or more independent halo substituents, -CF3, -OCF3, -OR222, -NR222R333, -C (0) R222, -CO2R222, -CONR222R333, -S02NR222R333, NR222 (C = 0 ) R333, NR222 (C = 0) OR333, NR222 (C = 0) NR222R333, NR222S (0) j2aR333, -NR222 (C = NR333) NR222aR333a, or -0 (C = 0) NR222R333; or hetaryl-C0.oo alkyl, optionally substituted with one or more halo, -CF3, -OCF3, -OR222, -NR222R333, -C (0) R222, -C02R222, -CONR222R333, -S02NR222R333, NR222 ( C = 0) R333, NR222 (C = 0) OR333, NR222 (C = 0) NR222R333, NR222S (0) j3aR333, NR222 (C = NR333) NR222aR333a, or -0 (C = 0) NR222R333.

7. The compound according to claim 1, further characterized in that G1 is halo, -OR2, -NR2R3, -C (0) R2, -C02R2, -CONR2R3, -S02NR2R3, NR2 (C = 0) R3, NR2 (C = 0) OR3, NR2 (C = 0) NR2R3, NR ^ O ^ R3, -0 (C = 0) OR2, -0 (C = 0) NR2R3, C0-? Alkyl, C2 alkenyl. ? 0, C 1-10 alkoxy of C 1-10 alkyl, C? -? 0 alkyl of C ^ o, C3-8 cycloalkyl, C3-scycloalkenyl, or heyerocyclic-Co-10 alkyl, or heterocyclic- C2.o.o alkenyl, any of which is optionally substituted with one or more independent substituents oxo, -CF3, -OCF3, -OR222, -NR222R333, -C (0) R222, -C02R222, -CONR222R333, -S02NR222R333, NR222 (C = 0) R333, NR222 (C = 0) 0R333, NR222 (C = 0) NR222R333, NR222S (0) j1aR333, -NR222 (C = NR333) NR222aR333a, or -0 (C = 0) NR222R333; or - (X1) n- (Y1) m-R4; or Co-arylalkyl, optionally substituted with one or more independent halo substituents, -CF3, -OCF3, -OR222, -NR222R333, -C (0) R222, -CO2R222, - CONR222R333, -S02NR222R333, NR222 (C = 0) R333, NR222 (C = 0) OR333, NR222 (C = 0) NR222R333, NR222S (0) j2aR333, -NR222 (C = NR333) NR222aR333a, or -0 (C = 0) NR222R333; or hetaryl-C0-? alkyl, or optionally substituted with one or more independent halo substituents, -CF3, -OCF3, -OR222, -NR222R333, -C (0) R222, -C02R222, -CONR222R333, -S02NR222R333, NR222 ( C = 0) R333, NR222 (C = 0) OR333, NR222 (C = 0) NR222R333, NR222S (0) j3aR333,

NR222 (C = NR333) NR222aR333a, or -0 (C = 0) NR222R333.

8. The compound according to claim 1, further characterized in that G1 is halo, -OR2, -NR2R3, -C (0) R2, -C02R2, -CONR2R3, -S02NR2R3, NR2 (C = 0) R3, NR2 (C = 0) OR3, NR2 (C = 0) NR2R3, NR2S (0) jiR3, -0 (C = 0) OR2, -0 (C = 0) NR2R3, C0-? Alkyl, C2- alkenyl 10, Ci.ioalkyl-alkyloxy, C? -? 0alkyl of C?.? 0, C3-8 -cycloalkyl, C3-8-cycloalkenyl, or heterocyclyl-Co-10-alkyl, or heterocyclyl -alkenyl of C2.o, any of which is optionally substituted with one or more independent oxo substituents, -CF3, -OCF3, -OR222, -NR222R333. -C (0) R222, -C02R222, -CONR222R333, -S02NR222R333, NR222 (C = 0) R333, NR222 (C = 0) OR333, NR222 (C = 0) NR222R333, NR222S (0) j1aR333, -NR222 (C = NR333) NR222aR333a, or -0 (C = 0) NR222R333; or - (X1) n- (Y1) m-R4.

9. The compound according to claim 1, further characterized in that X1 and Y1 are each independently -O-, -NR7-, -S (0) j7-, -CR5R6-, -N (C (0) OR7 ) -, -N (C (0) R7) -, -N (S02R7) -, -CH20-, -CH2S-, -CH2N (R7) -, -CH (NR7) -, -CH2N (C (0) R7) -, -CH2N (C (0) OR7) -, -CH2N (S02R7) -, -CH (NHR7) -, -CH (NHC (0) R7) -, -CH (NHS02R7) -, CH (NHC) (0) OR7) -, -CH (OC (0) R7) -, -CH (OC (0) NHR7) -, -C (0) -, -CH (OR7) -, -C (0) N ( R7) -, -N (R7) C (0) -, -N (R7) S (0) -, -N (R7) S (0) 2-, -OC (0) N (R7) -, - N (R7) C (0) N (R7) -, -NR7C (0) 0-, -S (0) N (R7) -, -S (0) 2N (R7) -, -N (C (0 ) R7) S (0) -, -N (C (0) R7) S (0) 2-, -N (R7) S (0) N (R7) -, -N (R7) S (0) 2N (R7) -, -C (0) N (R7) C (0) -, -S (0) N (R7) C (0) -, -S (0) 2N (R7) C (0) -, -OS (0) N (R7) -, -OS (0) 2N (R7) -, -N (R7) S (0) 0-, -N (R7) S (0) 2O-, -N (R7) ) S (0) C (0) -, -N (R7) S (0) 2C (0) -, -SON (C (0) R7) -, -S02N (C (0) R7) -, -N (R7) ARE (R7) -, -N (R7) S02N (R7) -, -C (0) 0-, -CH (R7) S (0) -, -CH (R7) S (0) 2- , -CH (R7) N (C (0) OR7) -, -CH (R7) N (C (0) R7) -, -CH (R7) N (S02R7) -, -CH (R7) 0-, -CH (R7) S-, -CH (R7) N (R7) -, -CH (R7) N (C (0) R7) -, -CH (R7) N (C (0) 0R7) -, - CH (R7) N (S02R7) -, -CH (R7) C (= NOR7) -, -CH (R7) C (0) -, -CH (R7) CH (OR7) -, -CH (R7) C (O) N (R7) -, -CH (R7) N (R7) C (0) -, -CH (R7) N (R7) S (0) -, -CH (R7) N (R7) S (0) 2-, -CH (R7) OC (0) N (R7) -, -CH (R7) N (R7) C (0) N (R7) -, -CH (R7) NR7C (0) 0-, -CH (R7) S (0) N (R7) -, -CH (R7) S (0) 2N (R7) -,

CH (R7) N (C (0) R7) S (0) -, -CH (R7) N (C (0) R7) S (0) -, -CH (R7) N (R7) S (0) (R7) -, -CH (R7) N (R7) S (0) 2N (R7) -, -CH (R7) C (0) N (R7) C (0) -, -CH (R7) S ( 0) N (R7) C (0) -, -CH (R7) S (0) 2N (R7) C (0) -, -CH (R7) OS (0) N (R7) -, -CH (R7) ) OS (0) 2N (R7) -, -CH (R7) N (R7) S (0) 0-, -CH (R7) N (R7) S (0) 20-, -CH (R7) N ( R7) S (0) C (0) -, -CH (R7) N (R7) S (0) 2C (0) -, -CH (R7) SON (C (0) R7) -, -CH (R7) ) S02N (C (0) R7) -, -CH (R7) N (R7) SON (R7) -, -CH (R7) N (R7) S02N (R7) -, or -CH (R7) C (0 ) 0-.

10. The compound according to claim 1, further characterized in that Q1 is substituted by said one to five independent substituents G1 wherein at least one of said substituents G1 is - (X1) n- (Y1) m -R4, and where X1 and Y1 are each independently equal to -O-, -NR7-, -CR5R6-, -S (0) j7-, or -C (O) -, and where n and m are both equal to 1 and j7 is equal to 1 or 2.

11. The compound according to claim 1, further characterized in that Q1 is suspended by said one to five independent substituents G1 wherein at least one of said susfiuuyeníes G1 is - (X1) n- ( Y1) m-R4, and wherein X1 and Y1 are each independently -O- or -CR5R6-, and where n and m are equal to 1.

12.- The compound according to claim 1, further characterized in that R1 is cycloalkyl, bicycloalkyl, aryl, heteroaryl, aralkyl, heleroaralkyl, heteroaryl, or hephenobicycloalkyl, any of which is optionally substituted by one or more independent substituents G11.

13. The compound according to claim 1, further characterized in that R1 is cycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, or heterocyclyl, any of which is optionally substituted by one or more independent G11 substituents.

14. The compound according to claim 1, further characterized in that R1 is cycloalkyl or heterocyclyl, any of which is optionally substituted by one or more independent replacers G11.

15. The compound according to claim 1, further characterized in that R1 is cycloalkyl optionally substituted by one or more independent substituents G11.

16. The compound according to claim 1, further characterized in that R1 is optionally substituted by one or more independent G11 substrates.

17. The compound according to claim 1, further characterized in that R1 is aryl, hepheroaryl, aralkyl, or heteroaralkyl, any of which is optionally substituted by one or more independent substituents G11.

18. The compound according to claim 1, further characterized in that R1 is aryl or heteroaryl, any of which is optionally substituted by one or more independent G11 subsitutes.

19. The compound according to claim 1, further characterized in that G11 is -OR21, -NR21R31 (R31a) j4, -C (O) R21, -C02R21, -CONR21R31, NR21 (C = 0) R31, NR21 ( C = 0) OR31, NR21 (C = 0) NR21R31, NR21S (0) j4R31, -0 (C = 0) OR21, -0 (C = 0) NR21R31, C0-? Alkyl, C3-8 cycloalkyl , C3.8 cycloalkenyl, C0-C6 heterocyclyl-, or C2_? 0 heyerocyclyl-alkenyl, any of which is optionally substituted with one or more independent haloyl, oxo, -CF3, -OCF3, -OR2221 , -NR2221R3331 (R333a) j4a, -C (0) R2221, -C02R2221, -CONR2221R3331, -N02, -CN, -S (0) j4aR2221, -S02NR2221R3331, NR2221 (C = 0) R3331, NR2221 (C = 0 ) OR3331, NR2221 (C = 0) NR2221R3331, NR2221S (0) j4aR3331, - (C = S) OR2221, - (C = 0) SR2221, -NR2221 (C = NR3331) NR222a1R333a1, -NR2221 (C = NR3331) OR222a1 , NR2221 (C = NR3331) SR333a1, -0 (C = 0) OR2221, -0 (C = 0) NR2221R3331, 0 (C = 0) SR2221, -S (C = 0) OR2221, or -S (C = 0) NR2221R3331; or aryl-C0-? alkyl or, C2-10 aryl-alkenyl, or C2-10 aryl-alkynyl, any of which is optionally substituted with one or more halo independent halogen, -CF3, -OCF3, -OR2221 , -NR2221R3331 (R333a1) j5a, -C (0) R2221, -C02R2221, -CONR2221R3331, -N02, -CN, -S (0) j5aR2221, -S02NR222 R3331, NR2221 (C = 0) R3331, NR2221 (C = 0) OR3331, NR2221 (C = 0) NR2221R3331, NR2221S (0) j5aR3331, (C = S) OR2221, - (C = 0) SR2221, -NR2221 (C = NR3331) NR222a1R333a1,

NR2221 (C = NR3331) OR222a1, -NR2221 (C = NR3331) SR333a1, -0 (C = 0) OR2221, -0 (C = 0) NR2221R3331, -0 (C = 0) SR2221, -S (C = 0) ) OR2221, or -S (C = 0) NR2221R3331; or hetaryl-C0-? alkyl, or C2_? 0 alkynyl, or C2.10 hetaryl-alkynyl, any of which is optionally substituted with one or more independent halo-substituents, -CF3, -OCF3, -OR2221 , NR222 R3331 (R333a1) j6a, -C (0) R2221, -C02R2221, -CONR2221R3331, -N02, -CN, -S (0) j6aR2221, -S02NR2221R3331, NR2221 (C = 0) R3331, NR2221 (C = 0 ) OR3331, NR2221 (C = 0) NR2221R3331, NR2221S (0) j6aR3331, - (C = S) OR2221, - (C = 0) SR2221, -NR2221 (C = NR3331) NR222a1R333a1, -NR2221 (C = NR3331) OR222a , NR222 (C = NR3331) SR333a1, -0 (C = 0) OR2221, -0 (C = 0) NR2221R3331, 0 (C = 0) SR2221, -S (C = 0) OR2221, or -S (C = 0) NR2221R3331.

20.- The compound of. according to claim 1, further characterized in that G11 is -OR21, -NR21R31, -C02R21, -C (O) R21, -CONR21R31, NR21 (C = 0) R31, NR21 (C = 0) OR31, NR21 (C = 0) NR21R31, NR2 S (0) j4R31, -0 (C = 0) OR21, -0 (C = 0) NR2 R31, C0-? O alkyl, C3-8 cycloalkyl, C3.8 cycloalkenyl, heterocyclic -C0-alkyl, or, or C2.oz heterocyclyl-alkenyl, any of which is optionally substituted with one or more independent subsitutes halo, oxo, -CF3, -OCF3, -OR2221, -NR2221R3331 (R333a1) j4a , -C (0) R2221, -C02R2221, -CONR2221R3331, -N02, -CN, -S (0) j4aR2221, -S02NR2221R3331, NR2221 (C = 0) R3331, NR2221 (C = 0) OR3331, NR2221 (C = 0) NR222 R3331, NR2221S (0) j4aR3331, - (C = S) OR2221, - (C = 0) SR2221, -NR2221 (C = NR3331) NR222a1R333a1, -NR2221 (C = NR3331) OR222a1, NR2221 (C = NR3331 ) SR333a1, -0 (C = 0) OR2221, -0 (C = 0) NR2221R3331, O (C = 0) SR2221, -S (C = 0) OR2221, or -S (C = 0) NR2221R3331.

21. The compound according to claim 1, further characterized in that R4 is H, alkyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, cycloalkenyl, or heterocycloalkenyl, any of which is optionally substituted by one or more independent substituents G41.

22. The compound according to claim 10, further characterized in that R4 is alkyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, cycloalkenyl, or heterocycloalkenyl, any of which is optionally substituted by one or more independent substituents G41.

23. The compound according to claim 11, further characterized in that R4 is alkyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, cycloalkenyloyl or heyerocycloalkenyl, any of which is optionally suspended by one or more independent G1.

24. - The compound according to claim 1, further characterized in that Q1 is phenyl sub- stituted by said one to five independent substituents G1, wherein at least one of said substituents G1 is - (X1) n- (Y1) -R4, and where n = 1 and X1 is 3 - (- 0-), m = 1 and Y1 is - (- CH2-), and R4 is optionally substituted ary by one or more independent substituents G41.

25. The compound according to claim 24, further characterized in that R1 is aryl, heteroaryl, cycloalkyl or heterocyclyl, optionally substituted by one or more independent G11 substituents.

26. The compound according to claim 25, further characterized in that R1 is cycloalkyl or heterocyclyl, optionally substituted by one or more independent substituents G11.

27. The compound according to claim 26, further characterized in that R1 is cycloalkyl, optionally substituted by one or more independent substituents G11.

28. The compound according to claim 27, further characterized in that R1 is cyclobutyl, cyclopentyl or cyclohexyl, optionally susfused by one or more independent substituents G11.

29. The compound according to claim 27, further characterized in that G11 is -OR21, -NR21R31, -C02R21, -C (0) R21, -CONR21R31, NR21 (C = 0) R31, NR21 (C = 0) OR31, NR21 (C = O) NR21R31, NR21S (0) j4R31, -0 (C = 0) OR21, -0 (C = 0) NR21R31, C0-? Alkyl, C3-8 cycloalkyl, C3 cycloalkenyl .8, heterocyclyl-C 0 -α alkyl, or C 2 -α heterocyclyl-alkenyl, or any of which is optionally substituted with one or more halo, oxo, -CF 3, -OCF 3, -OR2221, -NR2221R3331, independent substituents (R333a1) j4a, -C (0) R2221, -C02R2221, -CONR2221R3331, -N02, -CN, -S (0) j4aR2221, -S02NR2221R3331, NR2221 (C = 0) R3331, NR2221 (C = 0) OR3331, NR2221 (C = 0) NR2221R3331, NR2221S (0) j4aR3331, - (C = S) OR2221, - (C = 0) SR2221, -NR2221 (C = NR3331) NR222a1R333a1, -NR2221 (C = NR3331) OR222a1, NR2221 ( C = NR3331) SR333a1, -0 (C = 0) OR2221, -0 (C = 0) NR2221R3331, 0 (C = 0) SR2221, -S (C = 0) 0R2221, or -S (C = 0) NR2221R3331

30. The compound according to claim 1, further characterized in that Q1 is phenyl substituted said one to five independent subsitutes G1 wherein at least one of said substituents G1 is and wherein n = 1 and X1 is 4 - (- 0-), m = 1 and Y1 is - (- CH2-), and R4 is aryl optionally substituted by one or more independent substitutes G41.

31. The compound according to claim 30, further characterized in that R is aryl, heteroaryl, cycloalkyl or heterocyclyl, optionally substituted by one or more independent G11 substituents.

32. The compound according to claim 31, further characterized in that R1 is cycloalkyl or heterocyclyl, optionally substituted by one or more independent substituents G11.

33. - The compound according to claim 32, further characterized in that R1 is cycloalkyl, optionally susfused by one or more independent subunits G11.

34. The compound according to claim 33, further characterized in that R1 is cyclobutyl, cyclopentyl or cyclohexyl, optionally substituted by one or more independent substances G11.

The compound according to claim 33, further characterized in that G11 is -OR21, -NR21R31, -C02R21, -C (0) R21, -CONR21R31, NR21 (C = 0) R31, NR21 (C = 0) OR31, NR21 (C = O) NR21R31, NR21S (0) j4R31, -0 (C = 0) OR21, -0 (C = 0) NR21R31, C0-? Alkyl, C3-8 cycloalkyl, C3 cycloalkenyl -8, heterocyclyl-C0-βalkyl, or C2-β-heterocyclyl-alkenyl, or any of which is optionally substituted with one or more independent haloallers, halo, oxo, -CF3, -OCF3, -OR2221, -NR2221R3331 (R333a1) j4a, -C (0) R2221, -C02R2221, -CONR2221R3331, -NO2, -CN, -S (0) j4aR2221, -S02NR2221R3331, NR2221 (C = 0) R3331, NR2221 (C = 0) OR3331, NR2221 (C = 0) NR2221R3331, NR2221S (0) j4aR3331, - (C = S) OR2221, - (C = 0) SR2221, -NR2221 (C = NR3331) NR222a1R333a1, -NR2221 (C = NR3331) OR222a1, NR2221 (C = NR3331) SR333a1, -0 (C = 0) OR2221, -0 (C = 0) NR2221R3331, 0 (C = 0) SR2221, -S (C = 0) OR2221, or -S (C = 0) NR2221R3331.

36. The compound according to claim 1, further characterized in that Q1 is phenyl substituted by said one to five independent substituents G1 wherein at least one of said substitutes G1 is - (X1) n- (Y1) m-R4, and wherein n = 1 and X1 is 3 - (- 0-), m = 0, and R4 is alkyl or cycloalkyl of (Co-Cs) optionally substituted by one or more independent substituents G41.

37. The compound according to claim 36, further characterized in that R1 is aryl, heteroaryl, cycloalkyl or heterocyclyl, optionally susiiuuido by one or more independents G11.

38. The compound according to claim 37, further characterized in that R1 is cycloalkyl or heterocyclyl, optionally susíiuuido by one or more independent susíiluyentes G11.

39. The compound according to claim 38, further characterized in that R1 is cycloalkyl, optionally substituted by one or more independent substitutes G11.

40. The compound according to claim 39, further characterized in that R1 is cyclobufilo, cyclopenyl or cyclohexyl, optionally substituted by one or more G11 independent subsitutes.

41. The compound according to claim 39, further characterized in that G11 is -OR21, -NR21R31, -C02R21, -C (0) R21, -CONR2 R31, NR2 (C = 0) R31, NR21 (C = 0) ) OR31, NR21 (C = O) NR2 R31, NR21S (0) j4R31, -0 (C = 0) OR21, -0 (C = 0) NR21R31, C0-? Alkyl, C3-8 cycloalkyl, cycloalkenyl of C3_8, heterocyclyl-C0-βalkyl, or C2-? 0 -hearyocyclyl-alkenyl, any of which is optionally susíiuid with one or more independent halogen, oxo, -CF3, -OCF3, -OR2221, -NR2221R3331 (R333a1) j4a, -C (0) R2221, -C02R2221, -CONR2221R3331, -NO2, -CN, -S (0) j4aR2221, -S02NR2221R3331, NR2221 (C = 0) R3331, NR2221 (C = 0) OR3331, NR2221 (C = 0) NR2221R3331, NR2 21S (0) j4aR3331, - (C = S) OR2221, - (C = 0) SR2221, -NR2221 (C = NR3331) NR222a1R333a1, -NR2221 (C = NR3331) OR222a1, NR2221 (C = NR3331) SR333a, -0 (C = 0) OR2221, -0 (C = 0) NR2221R3331, O (C = 0) SR2221, -S (C = 0) OR2221, or -S (C = 0) NR2221R3331.

42. The compounds according to claim 36, further characterized in that R4 is (C0-C6) alkyl.

43. The compound according to claim 41, further characterized in that R4 is (Co-C6) alkyl.

44. The compounds according to claim 36, further characterized in that R4 is H or methyl.

45. The compound according to claim 43, further characterized in that R4 is H or methyl.

46. The compound according to claim 1, further characterized in that Q1 is phenyl substituted by said one to five independent substituents G1 wherein at least one of said substituents G1 is - (X1) n- (Y1) m-R4, and wherein n = 1 and X1 is 3 - (- 0-), m = 0, and R4 is arid optionally substituted by one or more independent substituents G41.

47. The compound according to claim 46, further characterized in that R1 is aryl, heteroaryl, cycloalkyl or heterocyclyl, optionally substituted by one or more independent substituents G11.

48. The compound according to claim 46, further characterized in that R1 is cycloalkyl or heterocyclyl, optionally substituted by one or more independent subunits G11.

49. The compound according to claim 48, further characterized in that R1 is cyclobutyl, cyclopenyl or cyclohexyl, optionally substituted by one or more independent substituents G11.

50.- The compound according to claim 48, further characterized in that G1 is -OR21, -NR21R31, -C02R21, -C (0) R21, -CONR21R31, NR21 (C = 0) R31, NR21 (C = 0) OR31, NR21 (C = 0) NR21R31, NR21S (0) j4R31, -0 (C = 0) OR21, -0 (C = 0) NR21R31, C0-? Alkyl, C3-8 cycloalkyl, C3 cycloalkenyl -8, heterocyclyl-C0-βalkyl, or hexy-cyclic-alkenyl of C2-? 0, any of which is optionally substituted with one or more halo, oxo, -CF3, -OCF3, -OR2221, -NR2221, independent substituents R3331 (R333a.) J4a? _C (0) R22 1. ^ 0 ^ 222 ^ _CONR222 R3331, -N02, -CN, - S (0) j4aR2221, -S02NR2221R3331, NR2221 (C = 0) R3331, NR2221 (C = 0) OR3331, NR2221 (C = 0) NR2221R3331, NR2221S (0) j4aR3331, - (C = S) OR2221, - (C = 0) SR2221, -NR2221 (C = NR3331) NR222a R333a1, -NR2 21 (C = NR3331) OR222a1, NR2221 (C = NR3331) SR333a1, -0 (C = 0) OR2221, -0 (C = 0) NR2221R3331,

0 (C = 0) SR2221, -S (C = 0) OR2221, or -S (C = 0) NR2221R3331.

51. The compounds according to claim 46, further characterized in that R4 is phenyl optionally substituted with G41.

52. The compound according to claim 1, further characterized in that Q1 is phenyl substituted by said one to five independent substituents G wherein at least one of said subscripts G is - (X1) n- (Y1) m-R4, and wherein n = 1 and X1 is 3- or 4 - (- NH-), m = 1 and Y1 is - (- S02-), and R4 is aryl optionally substituted by one or more G41 independent substituents.

53. The compound according to claim 52, further characterized in that R1 is aryl, heteroaryl, cycloalkyl or heterocyclyl, optionally substituted by one or more independent subsitutes G11.

54. The compound according to claim 53, further characterized in that R1 is cycloalkyl or heterocyclyl, optionally substituted by one or more independent susfiluyeníes G11.

55. The compound according to claim 54, further characterized in that R1 is cyclobuyyl, cyclopenyl or cyclohexyl, optionally substituted by one or more independent substrates G1.

56.- The compound according to claim 54, further characterized in that G11 is -OR21, -NR21R31, -C02R21, -C (0) R21, -C0NR21R31, NR21 (C = 0) R31, NR21 (C = 0) OR31, NR21 (C = 0) NR21R31, NR21S (0) j4R31, -0 (C = 0) OR21, -0 (C = 0) NR21R31, C0-? Alkyl, C3-8 cycloalkyl, C3 cycloalkenyl -8, heterocyclyl-C0-? 0 alkyl, or C2-? 0 heterocyclyl-alkenyl, any of which is optionally substituted with one or more independent halogen, oxo, -CF3, -OCF3, -OR2221, -NR222 substituents . R333. (R333a.) J4a. -C (0) R2221, -C02R2221, -CONR2221R3331, -N02, -CN, -S (0) j4aR2221, -S02NR2221R3331, NR2221 (C = 0) R3331, NR2221 (C = 0) OR3331, NR2221 (C = 0 ) NR2221R3331, NR2221S (0) j4aR3331, - (C = S) OR2221, - (C = 0) SR2221, -NR222 (C = NR3331) NR222a1R333a1, -NR2221 (C = NR3331) OR222a1, NR2221 (C = NR3331) SR333a1 , -0 (C = 0) OR2221, -0 (C = 0) NR2221R3331, O (C = 0) SR2221, -S (C = 0) OR2221, or -S (C = 0) NR2221R3331.

57. The compound according to claim 56, further characterized in that R1 is cis- or trans-cyclobutyl substituted in the 3-position by G11 where G11 is -OH, -NH2, -N (CH3) 2, -NHAc , -NH (CO) NHCH3, -NH (CO) OCH3, -CH2OH, -CH2NH2, -CH2NHAc, C02H, CONH2, -CH2N (CH3) 2, -CH2NH (CO) NHMe, -CH2NH (CO) OCH3, C02CH3 , CONHCH3,

58. The compound according to claim 56, further characterized in that R1 is cis- or trans-cyclohexyl substituted at the 4 position by G11 where G11 is -OH, -NH2, -N (CH3) 2, -NHAc, -NH (CO) NHCH3, -NH (CO) OCH3, -CH2OH, -CH2NH2, -CH2NHAc, C02H, CONH2, -CH2N (CH3) 2, -CH2NH (CO) NHMe, -CH2NH (CO) OCH3, C02CH3, CONHCH3,

59. - A compound selected from the group consisting of: [1- (3-Benzyloxy-phenyl) -3-cyclobutyl-imidazole [1, 5-a] pyrazin-8-ylamine], 1- (3-benzyloxyphenyl) -3-phenyl-imidazo [1,5-a] pyrazin-8-ylamine, 3-benzyl-1- (3-benzyloxyphenyl) - imidazole [1,5-a] pyrazin-8-ylamine, 1- (3-benzyloxyphenyl) -3-naphthalen-1-yl-imidazo [1,5-a] pyrazin-8-ylamine, 1- (3-benzyloxyphenyl) ) -3-naphthalen-2-yl-imidazoI [1,5-a] pyrazin-8-ylamine, 1- (3-Benzyloxy-phenyl) -3-cyclopentyl-imidazole [1,5-a] pyrazin-8 -amylamine, 1- (3-benzyloxy-phenyl) -3-cyclohexyl-imidazole [1,5-a] pyrazin-8-alamine, 1- (3-benzyloxy-phenyl) -3-cycloheptyl-imidazole [1 , 5-a] pyrazin-8-ylamine, 1- (3-benzyloxy-phenyl) -3- (1-eryhydro-furan-3-yl) -imidazo [1,5-a] pyrazin-8-ylamine, trans-3 - [8-Amino-1 - (3-benzyloxy-phenyl) -imidazo [1,5-a] pyrazin-3-yl] -cyclobutanol, 1- (3-benzyloxy-phenyl) -3- (1-methyl) piperidin-4-yl) -imidazole [1,5-a] pyrazin-8-ylamine, cis-3- [8-Amino-1- (3-benzyloxy-phenyl) -midazole [1-5]] a] pyrazin-3-yl] -amide cyclohexanecarboxylic acid, rans-4- [8-Amino-1- (3-benzyloxy-phenyl) -imidazo [1,5-a] pyrazin-3-yl] -amide cyclohexanecarboxylic acid, cis-4- [8-Amin o-1- (3-benzyloxy-phenyl) -imidazo [1, 5-a] pyrazin-3-yl] -cyclohexyl} -melanol, lrans-4- [8-Amino-1 - (3-benzyloxy-phenyl) -imidazo [1, 5-a] p -razin-3-yl] -cyclohexyl} -methanol, cis-2-. { 4- [8-Amino-1 - (3-benzyloxy-phenyl) -imidazo [1,5-a] pyrazin-3-yl] -cyclohexylmethyl} -isoindole-1, 3-dione, trans-2-. { 4- [8-Amino-1- (3-benzyloxy-phenyl) -imidazo [1,5-a] pyrazin-3-yl] -cyclohexylmethyl} -isoindole-1, 3-dione, cis-3- (4-Aminomethyl-cyclohexyl) -1 - (3-benzyloxy-phenyl) -imidazo [1,5-a] pyrazin-8-ylamine, trans-3- ( 4-Aminomethyl-cyclohexyl) -1 - (3-benzyloxy-phenyl) -imidazo [1,5-a] pyrazin-8-ylamine, cis-N-. { 4- [8-Amino-1- (3-benzyloxy-phenyl) -imidazo [1,5-a] pyrazin-3-yl] -cyclohexylmethi} -aceyamide, or trans-N-. { 4- [8-Amino-1- (3-benzyloxy-phenyl) -imidazo [1,5-a] pyrazan-3-yl] -cyclohexylmethyl} -aceyamide; or pharmaceutically acceptable salts thereof.

60. The use of a compound according to claim 1 or a pharmaceutically acceptable salt thereof, for preparing a medicament for inhibiting protein kinase activity.

61.- The use claimed in claim 60, wherein said protein kinase is IGF-IR.

62.- The use claimed in claim 60, wherein the aclivity of said protein kinase affects hyperproliferative disorders.

63. The use claimed in claim 60, wherein the activity of said protein kinase influences angiogenesis, vascular permeability, immune response, cellular apoptosis, tumor growth, or inflammation.

The use of a compound according to claim 1 or a pharmaceutically acceptable salt thereof, for preparing a medicament for the treatment of a patient having a condition mediated by the activity of proine kinase.

65.- The use claimed in claim 64, wherein said proinin kinase is IGF-IR.

66. The use claimed in claim 64, wherein the condition mediated by protein kinase activity is a hyperproliferative disorder.

67. The use claimed in claim 64, wherein the activity of said protein kinase influences angiogenesis, vascular permeability, immune response, cellular apoptosis, tumor growth, or inflammation.

68.- The use claimed in claim 64, wherein the protein kinase is a serine / threonine kinase protein or a protein tyrosine kinase.

69. The use claimed in claim 64, wherein the condition mediated by protein kinase activity is one or more ulcers.

70. The use claimed in claim 69, wherein the ulcer or ulcers are caused by a bacterial or fungal infection; or the ulcer or ulcers are Mooren's ulcers; or the ulcer or ulcers are symptoms of ulcerative colitis.

71.- The use claimed in claim 64, wherein the condition mediated by protein kinase activity is Lyme disease, sepsis or infection by Herpes simplex, Herpes Zoster, human immunodeficiency virus, parapoxvirus, protozoa, or ioxoplasmosis.

72. The use claimed in claim 64, wherein the condition mediated by proine kinase activity is the disease of von Hippel Lindau, pemphigoid, psoriasis, disease in Pagei, or polycystic kidney disease.

73.- The use claimed in claim 64, wherein the condition mediated by activity of propin kinase is fibrosis, sarcoidosis, cirrhosis, thyroiditis, hyperviscosity syndrome, Osler-Weber-Rendu disease, chronic occlusive pulmonary disease, asthma. , exudates, ascites, pleural effusions, pulmonary edema, cerebral edema or edema after burns, trauma, radiation, cerebrovascular accident, hypoxia, or ischemia.

74. The use claimed in claim 64, wherein the condition mediated by protein kinase activity is ovarian hyperstimulation syndrome, preeclampsia, menomeorrhagia, or endomeíriosis.

75.- The use claimed in claim 64, wherein the condition mediated by proinin kinase activity is chronic inflammation, sys- temic lupus, glomerulonephritis, synovitis, inflammatory bowel disease, Crohn's disease, glomerulonephritis, rheumatoid arthritis and osteoarthritis. , multiple sclerosis, or graft rejection.

76. The use claimed in claim 64, wherein the condition mediated by proinin kinase activity is sickle cell anemia.

77. The use claimed in claim 64, wherein the condition mediated by protein kinase activity is an ocular condition.

78.- The use claimed in claim 77, wherein the ocular condition is ocular or macular edema, ocular neovascular disease, seleritis, radial keratotomy, uveitis, vitritis, myopia, optic depressions, chronic retinal detachment, post-treatment complications with laser, conjuncfiviíis, Síargardt's disease, Eales disease, retinopathy, or macular degeneration.

79. The use claimed in claim 64, wherein the condition mediated by proine kinase activity is a cardiovascular condition.

80. The use claimed in claim 79, wherein the condition mediated by proine kinase activity is aerosol, resenosis, ischemia / reperfusion injury, vascular occlusion, venous malformation, or obstructive disease of the carotid.

81. The use claimed in claim 64, wherein the protein kinase-mediated condition is cancer.

82. The use claimed in claim 81, wherein the cancer is a solid tumor, a sarcoma, fibrosarcoma, osteoma, melanoma, retinoblasphoma, a rhabdomyosarcoma, glioblastoma, neuroblastoma, teratocarcinoma, a hematopoietic malignancy, or malignant malformations.

83. The use claimed in claim 82, wherein the cancer is Kaposi's sarcoma, Hodgkin's disease, lymphoma, myeloma, or leukemia.

84. The use claimed in claim 64, wherein the condition mediated by proine kinase activity is Crow-Fukase syndrome (POEMS) or a diabetic condition.

85.- The use claimed in claim 84, wherein the diabetic condition glaucoma by diabei melliíus insulinodependienie, diabetic retinopaíía, or microangiopaíía.

86. - The use claimed in claim 64, wherein the activity of protein kinase participates in the acyivation of the T cell, B-cell acyivation, cell degranulation, monocyte acyivation, signal transduction, apoptosis, the potentiation of an inflammatory response or a combination thereof.

87.- A composition comprising a compound according to claim 1, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable vehicle.

88.- A composition comprising a compound according to claim 1, or a pharmaceutically acceptable salt thereof; and an antimicrobial, antimicrobial, antiangiogenic, or chemo-therapeutic agent.

89. A composition comprising a compound according to claim 1, or a pharmaceutically acceptable salt thereof; and a cytotoxic agent for cancer.

90.- A composition comprising a compound according to claim 1, or a pharmaceutically acceptable salt thereof; and a therapeutic agent inhibiting angiogenesis in cancer.

91.- The use of a pharmaceutical composition according to claim 87, for preparing a medicament for the treatment of a patient that has a condition mediated by the protein kinase activity.

92. - A compound selected from the group consisting of: 1-Biphenyl-3-yl-3-cyclobuylimidazo [1,5-a] pyrazin-8-ylamine, 1- (3-Bromo-phenyl) -3- Cyclobutimimidazo [1,5-a] pyrazin-8-ylamine, 1- (4'-t-Bubylbiphenyl-3-yl) -3-cyclobuylimidazo [1,5a] pyrazin-8-ylamine, 3-Cyclobutyl-1- (4'-Melylbiphenyl-3-yl) -imidazo [1,5-a] pyrazin-8-ylamine, 3-Cyclobuhyl-1- (4'-methoxybiphenyl-3-yl) -imidazo [1, 5-a] pyrazin-8-ylamine, 1- (3-benzyloxyphenyl) -3-cyclopenemethylimidazo [1,5-a] pyrazin-8-ylamine, 1- (3-benzyloxyphenyl) -3-cyclohexylmethylimidazo [1,5-a] pyrazine- 8-iAmino, 1- (3-Benzyloxyphenyl) -imidazo [1,5-a] pyrazin-8-ylamine, 1- (3-Benzyloxyphenyl) -3-trifluoromethylimidazo [1,5-a] pyraz-8- Lamin, 4- [8-Amino-1- (3-benzyloxyphenyl) -imidazo [1,5-a] pyrazin-3-yl] -benzamide, 3-cyclobuyl-1-phenylimidazo [1,5-a] pyrazine -8-ylamine, (trans-3- (4-Azetidin-1-ylmethyl-cyclohexyl) -1 - (3-benzyloxy-phenyl) -imidazo [1,5-a] pyrazin-8-ylamine, rans-1 - (3- Benzyloxy-phenyl) -3- (4-pyrrolidin-1-ylmeiyl-cyclohexyl) -imidazo [1, 5 -a] pyrazin-8-ylamine), trans-4- [8-Amino-1- (3-benzyloxy-phenyl) -imidazo [1,5-a] pyrazin-3-yl] - meitylic ester - cyclohexanecarboxylic acid (trans-4- [8-Amino-1- (3-benzyloxy-phenyl) -imidazo [1,5-a] pyrazin-3-yl] -cydohexancarboxylic acid), (trans-4- [8-] Amino-1- (3-benzyloxy-phenyl) imidazo [1,5-a] pyrazin-3-yl] -methyl amide cyclohexanecarboxylic acid), 4- [8-Amino-1- (3-benzyloxy-phenyl) -imidazo [1, 5-a] pyrazin-3-yl] -ethylamine cyclohexanecarboxylic acid, 4- acid. { 8-amino-1- [3- (2,6-difluoro-benzyloxy) -phenyl] -imidazo [1,5-a] pyrazin-3-yl} -cyclohexanecarboxylic acid, cis -3- (3-dimethylaminomethyl-cyclobuyl) -1- (3-benzyloxyphenyl) -midazo [1,5-a] pyrazin-8-ylamine, cis -3- (3-azetidin-1) -ylmethylcyclobuyl) -1- (3-benzyloxyphenyl) -imidazo [1,5-a] pyrazin-8-ylamine, cis -3- (3-pyrrolidin-1-ylmethylcyclobufil) -1 - (3-benzyloxyphenyl) -imidazo [ 1, 5-a] pyrazin-8-ylamine, cis-3- (3-azidomeyyl-cyclobuyl) -1- (3-benzyloxyphenyl) -imidazo [1,5-a] pyrazin-8-ylamine, cis- 3- (3-aminomethyl-cyclobuyl) -1- (3-benzyloxyphenyl) -imidazo [1,5-a] pyrazin-8-ylamine, cis-3- [8-amino-1- (3-benzyloxy-phenyl)] ) -imidazo [1,5-a] pyrazin-3-yl] -cyclobufanamide carboxylic acid, trans-3- [8-amino-1- (3-benzyloxy-phenyl) -imidazo [1,5-a] pyrazin-3-yl] -cyclobuo-amide carboxylic acid, 3- [8-amino-1- (3-benzyloxy-phenyl) -imidazo [1,5-a] pyrazin-3-yl] -1-hydroxymethyl-cyclobutanol, 3- [8-Amino-1- (3-benzyloxy-phenyl) -imidazo [1,5-a] pyrazin-3-yl] -1-hydroxy-cyclobutylmethyl ester of cis-toluene-4-sulfonic acid, ester 3 - [8-amino-1- (3-benzyloxy-phenyl) -imidazo [1,5-a] pyrazin-3-yl] Irans-loluene-4-sulfonic acid-1-hydroxycyclobutylmethyl, trans-3- [8-amino-1- (3-benzyloxy-phenyl) -imidazo [1,5-a] pyrazin-3-yl] -1- azetidin-1-ylmeiyl-cyclobuanol, cis-3- [8-amino-1- (3-benzyloxy-phenyl) -imidazo [1,5-a] pyrazin-3-yl] -1-azetidin-1- ylmethyl-cyclobutanol, 1 - [3- (4-tert-buzoxy-benzyloxy) -phenyl] -3-cyclobuyl-imidazo [1,5-a] pyrazin-8-ylamine, 2- [3- (8- amino-3-cyclobutyl-imidazo [1,5-a] pyrazin-1-yl) -phenoxymethyl] -benzonitrile, 3-cyclobuyl-1- [3- (2-nifro-benzyloxy) -phenyl] -imidazo [1, 5-a] pyrazin-8-ylamine, 1 - [3- (2-bromo-benzyloxy) -phenyl] -3-cyclobutyl-imidazo [1,5-a] pyrazin-8-ylamine, 1- [3- (3-aminomeyiI-benzyloxy) -phenyl] -3-cyclobutyl-imidazo [1,5-a] pyrazin-8-ylamine, 3- [3- (8-amino-3-) methyl ester Cyclobuyl-imidazo [1,5-a] pyrazin-8-yl) -phenoxymethyl] benzoic acid, 3- [3- (8-amino-3-cyclobutyl-imidazo [1,5-a] pyrrazin-1-yl) - phenoxymethyl] -benzamide,. { 3- [3- (8-amino-3-cyclobuyl-imidazo [1, 5-a] pyrazin-1-yl) -phenoxymethyl] -pheni} -methanol, 2-. { 3- [3- (8-amino-3-cyclobutyl-imidazo [1,5-a] pyrazin-1-yl) -phenoxymethyl] -benzyl} -isoindole-1, 3-dione, 3- [3- (8-amino-3-cyclobutoyl-imidazo [1,5-a] pyrazin-1-yl) -phenoxymethyl] -benzoic acid, 3- [3- (8-amino-3-cyclobuyl-imidazo [1,5-a] pyrazin-1-yl) -phenoxymethyl] -N-methyl-benzamide, 1- (3-benzyloxy-phenyl) -3- (3 -methoxymethylene-cyclobutyl) - midazo [1,5-a] pyrazin-8-ylamine, 3- [8-amino-1- (3-benzyloxy-phenyl) -imidazo [1,5-a] pyrazine- 3-yl] cyclobufcarcardehyde, cis-1 - (3-benzyloxy-phenyl) -3- (4-methoxy-cyclohexyl) -imidazo [1,5-a] pyrazin-8-ylamine, Irans-1- (3-benzyloxy) -phenyl) -3- (4-meioxy-cyclohexyl) -imidazo [1,5-a] pyrazin-8-ylamine, cis-eer-builyl- (. {3- [8-amino-1 - (3-benzyloxyphenyl) -imidazo [1,5-a] pyrazin-3-yl] -cyclobuyl.} Oxy) acetyl, cis-2-. { 3- [8-amino-1- (3-benzyloxyphenyl) imidazo [1,5-a] pyrazin-3-yl] cyclobutyl} Ethanol, ester 2-. { 3- [8-amino-1- (3-benzyloxyphenyl) imidazo [1, 5-a] pyrazin-3-yl] cyclobutoxy} Efficacy of cis-toluene-4-sulfonic acid, cis-1- (3-benzyloxyphenyl) -3- [3- (2-dimethylamino-ephoxy) -cyclobuyl] imidazo [1,5-a] pyrazin-8-yl amine, cis- acid. { 3- [8-amino-1- (3-benzyloxyphenyl) imidazo [1,5-a] pyrazin-3-yl] -cyclobutoxy} acéíico, cis-2-. { 3- [8-amino-1- (3-benzyloxyphenyl) midazo [1,5-a] pyrazn-3-yl] cyclobutoxy} -N-meitylacetamide, cis-2-. { 3- [8-amino-1- (3-benzyloxyphenyl) imidazo [1,5-a] pyrazin-3-yl] cyclobudoxy} -N-Aceamide, 1- (3-benzyloxy-4-mexoxyphenyl) -3-cyclobuyl-imidazo [1,5-a] pyrazin-8-ylamine, 1- (3-benzyloxy-4-fluorophenyl) -3- Cyclobutyl-imidazo [1,5-a] pyrazin-8-ylamine, 1- (3-benzyloxy-4-isopropoxyphenyl) -3-cyclobutyl-imidazo [1,5-a] pyrazin-8-ylamine, 1- (3 -benzyloxy-4-dioxyphenyl) -3-cyclobuylimidazo [1,5-a] pyrazin-8-ylamine, 4- (8-amino-3-cyclobuildimidazo [1,5-a] pyrazin-1-yl) -2- benzyloxyphenol, 4- acid. { 8-amino-1- [3- (2,6-difluoro-benzyloxy) -phenyl] -imidazo [1,5-a] pyrazin-3-yl} -Cyclohexancarboxylicamide, 4- acid. { 8-amino-1- [3- (2,6-difluoro-benzyloxy) -pheny] -imidazo [1,5-a] pyrazin-3-yl} cyclohexancarboxylic-methylamide, N-. { 3- [3- (8-amino-3-cyclobuyl-imidazo [1, 5-a] pyrazin-1-yl) -phenoxymethyl] -phenyl} -acetamide, or pharmaceutically acceptable salts thereof. 93.- A compound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof. 94.- A compound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof 95.- A compound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof, wherein * is the point of attachment.

96.- A compound selected from the group consisting of:

97. A compound selected from the group consisting of: or a pharmaceutically acceptable salt thereof, wherein * is the point of attachment.

98. - A compound selected from the group consisting of

from:

99.- A compound selected from the group consisting of:

100. - A compound selected from the group consisting of:

NOVELTY OF THE INVENTION

Compounds of the formula (I)

1 and pharmaceutically acceptable salts thereof, wherein Q1 and R1 are as defined in the present invention, which inhibit the enzyme IGF-1 R and are useful for the treatment and / or prevention of various diseases and conditions that respond to treatment by inhibiting tyrosine kinases.

12B / cgt * P06 / 542F