Oxazole substituted indazoles as pi3-kinase inhibitors

The present invention relates to certain new compounds that are inhibitors of kinase activity, methods for their preparation, pharmaceutical compositions containing the compounds and the use of the compounds or compositions for the treatment of various disorders.

More specifically, the compounds of the invention are inhibitors of family activity or function

3'OH-phosphatidylinositol kinases (henceforth PI3 kinases), for example ΡΙ3Κδ, PI3Ka, ΡΙ3Κβ and / or ΡΙ3Κγ. Compounds that are inhibitors of PI3 kinase activity or function may be useful in the treatment of disorders such as respiratory diseases, including asthma, chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF); viral infections including viral respiratory tract infections and viral exacerbations of respiratory diseases such as asthma and COPD; non-viral respiratory infections including aspergillosis and leishmaniasis; allergic diseases, including allergic rhinitis and atopic dermatitis; autoimmune diseases including rheumatoid arthritis and multiple sclerosis; inflammatory disorders including inflammatory bowel disease; cardiovascular diseases including thrombosis and atherosclerosis; hematological malignancies; neurodegenerative diseases; inflammation of the pancreas; multi-organ failure; kidney disease; platelet aggregation; tumor; sperm motility; rejection of transplantation; transplant rejection; lung damage; and pain including pain associated with rheumatoid arthritis or osteoarthritis, back pain, general pain associated with inflammation, liver neuralgia, diabetic neuropathy, inflammatory neuropathic (traumatic) pain, trigeminal neuralgia and central pain.

BACKGROUND OF THE INVENTION [0002] Cell membranes are a large composition of secondary messengers that can be involved in various signal transduction pathways. Due to the function and regulation of effector enzymes in phospholipid signaling pathways, class I PI3 kinase (e.g. PI3Kdelta) produces secondary messengers from membrane phospholipid pools. Class I PI3Ks transform the membrane phospholipid PI (4,5) P2 into PI (3,4,5) P3, which acts as a secondary messenger. PI and PI (4) P are also PI3K substrates and can be phosphorylated and converted to PI3P and PI (3,4) P2, respectively. In addition, these phosphatidylinositols can be converted to other phosphatidylinositols by 5'-specific and 3'-specific phosphatases. Thus, PI3K enzymatic activity leads both directly and indirectly to the production of two 3'-phosphatidylinositol subtypes that act as secondary messengers in intracellular signal transduction pathways (Trends Biochem. Sci. 22 (7) pp. 267-72 (1997), Vanhaesebroeck et al .; Chem. Rev. 101 (8) pp. 2365-80 (2001), Leslie et al .; Annu. Rev. Cell dev. Biol. 17 pp. 615-75 (2001), Katso et al .; and Cell. Moth. Life Sci. 59 (5) pp. 761-79 (2002), Toker). Currently, eight mammalian PI3Ks have been identified, divided into three main classes (I, II and III) based on sequence homology, structure, binding partners, activation method, and substrate preferences. In vitro, PI3K class I can phosphorylate phosphatidylinositol (PI), phosphatidylinositol-4-phosphate (PI4P) and phosphatidylinositol-4,5-bisphosphate (PI (4,5) P2) to form phosphatidylinositol-3-phosphate (PI3P), respectively, phosphatidylinositol-3,4-bisphosphate (PI (3,4) P2 and phosphatidylinositol-3,4,5-trisphosphate (PI (3,4,5) P3. Class II PI3K can phosphorylate PI and PI4P. Class III PI3K can only phosphorylate PI (Vanhaesebroeck et al. (1997), supra; Vanhaesebroeck et al. Exp. Cell Res. 253 (1) pp. 239-54 (1999); and Leslie et al. (2001), supra).

[0003] Class I PI3K is a heterodimer composed of the p110 catalytic subunit and regulatory subunit, and the family is further divided into class Ia and class Ib enzymes based on regulatory partners and a regulatory mechanism. Class Ia enzymes are composed of three different catalytic subunits (ρ110α, ρ110β and ρ110δ) which dimerize with five different regulatory subunits (p85a, p55a, p50a, p85e and p55y), all catalytic subunits being capable of interacting with all sub5 units regulatory, forming various heterodimers. Class Ia PI3Ks are generally activated in response to stimulation of receptor tyrosine kinases by growth factor by interacting the SH2 regulatory subunit domains with specific phospho-tyrosine residues of the activated receptor or adapter proteins such as IRS-1. Small GTPases (ras as an example) are also involved in PI3K activation in conjunction with activation of receptor tyrosine kinase. Both p110a and p110e ​​are constitutively expressed in all cell types, and p110δ expression is more limited to leukocyte populations and some epithelial cells. In contrast, a single class Ib enzyme is composed of the p110Y catalytic unit that interacts with the p101 regulatory subunit. In addition, the class Ib enzyme is activated in response to G-protein coupled receptor (GPCR) systems and its expression appears to be restricted to leukocytes.

Scheme A: Conversion of PI (4,5) P2 to PI (3,4,5) P3

<img file="PL2424864T3_D0001.tif" />

[0005] As illustrated above in Scheme A, phosphatidylinositol 3-kinases (PI3K kinases) phosphorylate hydroxyl at the third carbon atom of the inositol ring. By phosphorylation of phosphatidylinositols, forming PtdIns (3,4,5) P3, PtdIns (3,4) P2 and

PtdIns (3) P, secondary messengers are produced for various signal transduction pathways, including those important for cell proliferation, cell differentiation, cell growth, cell size, cell survival, apoptosis, adhesion, cell motility, cell migration, chemotaxis, invasion. rearrangement of the cytoskeleton, cell shape changes, follicular transport and metabolic pathways (Katso et al. (2001) above; and Mol. Med. Today 6 (9) pp. 347-57 (2000), Stein et al.).

[0006] PI3 kinase activity responsible for producing these phosphorylated products involved in signal transduction was originally identified as associated with viral oncoproteins and tyrosine kinases that are growth factor receptors that phosphorylate phosphatidylinositol (PI) and its phosphorylated derivatives at the 3'-hydroxyl inositol ring ( Panayotou et al., Trends Cell Biol. 2 p.

358-60 (1992)). However, recent biochemical studies have revealed that class I PI3 kinases (e.g., class ΡΙ3Κδ isoforms) are bispecific kinase enzymes, which means that they exhibit both lipid kinase activity (phosphatylation of phosphatidylinositols) and protein kinase activity, in which has been shown to allow phosphorylation of another protein as substrates, including auto-phosphorylation as an intramolecular regulatory mechanism (EMBO J. 18 (5) p. 1292-302 (1999), Vanhaesebroeck et al.). Cellular processes in which PI3Ks play a central role include inhibition of apoptosis, reorganization of the actin skeleton, hypertrophy of the heart muscle fibers, insulin glycogen synthase stimulation, TNFα-mediated neutrophil stimulation and superoxide production, and leukocyte migration and adhesion to endothelial cells.

[0007] PI3 kinase activation is thought to be involved in a wide range of cellular responses, including cell growth, differentiation and apoptosis (Parker, Current Biology 5 (6) pp. 577-79 (1995); and Yao et al., Science 267 (5206) pp. 2003-06 (1995)). It turns out that PI3 kinase is involved in many aspects of leukocyte activation. P85-related PI3 kinase has been shown to be physically bound to the CD28 cytoplasmic domain, which is an important costimulatory molecule for T cell activation in response to antigen (Pages et al. Nature 369 pp. 327-29 (1994); and Rudd, Immunity 4 pp. 527-34 (1996)). Activation of T cells through CD28 lowers the threshold for antigen activation and increases the size and duration of the proliferative response. These effects are associated with increased transcription of many genes, including interleukin-2 (IL2), an important T cell growth factor (Fraser et al. Science 251 (4991), pp. 313-16 (1991)).

[0008] Κ3Κγ has been identified as a mediator of the beta-gamma G protein-dependent regulation of JNK activity and beta-gamma G protein subunits are subunits of heterotrimeric G proteins (Lopez-Ilasaca et al. J. Biol. Chem. 273 (5) p. 2505 -8 (1998)). Recently described (Laffargue et al. Immunity 16 (3) p. 441-51 (2002)) that ΡΙ3Κγ transmits inflammatory signals through various G (i) coupled receptors and is crucial for mast cell function, leukocyte stimuli and immunology, including, for example, cytokines, chemokines, adenosine, antibodies, integrins , aggregation factors, growth factors, viruses or hormones (J. Cell Sci. 114 (part 16) pp. 2903-10 (2001), Lawlor et al .; Laffargue et al (2002) above; and Curr. Opinion Cell Biol. 14 (2) pp. 203-13 (2002), Stephens et al.).

[0009] Specific inhibitors for individual members of the enzyme family provide valuable tools to recognize the function of each enzyme. Two compounds, LY294002 and wortmannin (henceforth) have been widely used as PI3 kinase inhibitors. These compounds are non-specific PI3K inhibitors as they do not distinguish among the four members of class I PI3 kinases. For example, IC50 values ​​for wortmannin for each of the different class I PI3 kinases are in the range of 1-10 nM. Similarly, the IC50 values ​​for LY294002 for each of these PI3 kinases are about 15-20 μΜ (Fruman et al. Ann. Rev. Biochem. 67 pp. 481-507 (1998)), also 5-10 microM for kinase CK2 protein and some inhibitory activity against phospholipases. Wortmannin is a fungal metabolite that irreversibly inhibits PI3K activity, covalently binding to the catalytic domain of this enzyme. Inhibition of PI3K activity by wortmannin eliminates the subsequent cellular response to the extracellular factor. For example, neutrophils respond to the chemokine fMet-Leu-Phe (fMLP) by stimulating PI3K and synthesizing PtdIns (3,4,5) P3. This synthesis correlates with the activation of an oxygen explosion leading to the destruction by neutrophils of invading microbes. Treatment of neutrophils with wortmannin prevents fMLP-induced oxygen burst response (Thelen et al. Proc. Natl. Acad. Sci. USA 91 pp. 4960-64 (1994)). In fact, these wortmannin experiments as well as other experimental evidence show that PI3K activity in cells of the hematopoietic line, especially in neutrophils, monocytes and other types of leukocytes, is involved in many immune responses other than those involving acute memory cells and chronic inflammation.

<img file="PL2424864T3_D0002.tif" />

[0010] Based on studies with wortmannin, there is evidence that PI3 kinase function is also required for certain aspects of leukocyte signal transduction via G-protein coupled receptors (Thelen et al (1994), above). In addition, wortmannin and LY294002 have been shown to block neutrophil migration and peroxide release.

[0011] It is now fully understood that dysregulation of oncogenes and tumor suppressor genes contributes to the formation of malignant tumors, for example by increasing cell growth and proliferation or increased cell survival. It is also now known that PI3K-mediated signal transduction pathways play a major role in many cellular processes including proliferation and survival, and the dysregulation of these pathways is a contributor to a wide range of human cancers and other diseases (Katso et al. Annual Rev. Cell Dev Biol. (2001) 17 pp. 615-675 and Foster et al. J. Cell Science (2003) 116 (15) pp. 30373040). PI3K effector proteins initiate signal transduction pathways and networks as a result of translocation to cell membranes via a conserved domain homologous to the Pleckstrin Homology (PH) domain, which specifically interacts with PtdIns (3,4,5) P3 (Vanhaesebroeck et al. Annu Rev. Biochem. (2001) 70 pp. 535-602). Signal effector proteins via PtdIns (3,4,5) P3 and PH domains include serine / threonine kinases (Ser / Thr), tyrosine kinases, Rac or Arf GEF (guanine nucleotide exchange factors) and Arf GAP (GTPase activating proteins).

[0012] In B and T cells, PI3Ks play an important role by activating the Tec protein tyrosine kinase family, which includes Bruton tyrosine kinase (BTK) in B cells and interleukin-2 inducible T cell kinase (ITK) in T cells. After activation PI3K, BTK or ITK are translocated to the cell membrane, where they are then phosphorylated by Src kinases. One of the main targets of activated ITK is C-gamma phospholipase (PLCy1), which hydrolyzes PtdIns (4,5) P2 to Ins (3,4,5) P3 and initiates intracellular increased levels of calcium and diacylglycerol (DAG) that can activate protein C kinases in activated T cells.

[0013] Contrary to class IA p110 α and p110 β, p110 δ is expressed in a tissue-restricted manner. Its high level of expression in lymphocytes and lymphoid tissues suggests a role in PI3K-mediated signaling in the immune system. Mice inactivated with kinase ρ110δ using knock-in technology are also viable and their phenotype is limited to defects in signal transduction in the immune system (Okkenhaug et al. Science (2002) 297 pp. 1031-4). These transgenic mice offer the opportunity to observe the function of ΡΙ3Κδ in B-cell and T-cell signaling. In particular, p110δ is required to form PtdIns (3,4,5) P3 as a further stage of CD28 and / or T cell receptor (TCR) signaling. ). The key effect of further PI3K signaling downstream of TCR is activation of Akt, which phosphorylates anti-apoptotic factors as well as various transcription factors for cytokine production. Consequently, T cells with inactive p110δ show defects in the proliferation and secretion of Th1 and Th2 cytokines. Activation of T cells through CD28 lowers the threshold for TCR activation by antigen and increases the size and duration of the proliferative response. These effects are mediated by a ΙΊ3Ι &lt;δ-dependent transcription increase in many genes including IL2, an important T cell growth factor.

[0014] Thus, PI3K inhibitors are anticipated to provide therapeutic benefit through their role in modulating T cell-mediated inflammatory responses associated with respiratory diseases such as asthma, COPD and cystic fibrosis. In addition, there are indications that T-cell therapies may provide corticosteroid dose reduction properties (Alexander et al. Lancet (1992) 339 p. 324-8), suggesting that they may provide useful therapy as monotherapy or in combination with inhaled or oral glucocorticosteroids for respiratory diseases. The PI3K inhibitor may also be used along with other common therapies such as long-acting beta-agonists (LABA) in asthma.

[0015] In the vascular system, PI3KiS is expressed by endothelial cells and is involved in neutrophil transport by modulating the proadhesive state of these cells in response to TNFalpha (Puri et al. Blood (2004) 103 (9) pp. 3448-56.) The role of PI3KiS in TNFalpha-induced signaling in endothelial cells was demonstrated by pharmacological inhibition of Akt phosphorylation and PDK1 activity. In addition, PI3KiS is involved in vascular permeability and swelling of the airway tissues via the VEGF pathway (Lee et al. J. Alergia Clin. Immunol. (2006) 118 (2) p. 4039). These observations suggest additional benefits of PI3KiS inhibition in asthma by a combined reduction of leukocyte extravasation and asthma-related vascular permeability. In addition, PI3KiS activity is required for mast cell function both in vitro and in vivo (Ali et al. Nature (2004) 431 p. 1007-1011; and Ali et al. J. Immunol. (2008) 180 (4) pp. 2538-44) which further suggests that PI3K inhibition should have therapeutic benefit in allergic indications such as asthma, allergic rhinitis and atopic dermatitis.

[0016] The role of PI3K δ in B cell proliferation, antibody secretion, B cell antigen and IL-4 receptor signaling, and B cell antigen presentation function is also well recognized in Okkenhaug et al. (2002), above; AlAlwan et al. J. Immunol. (2007) 178 (4) pp. 2328-35; and Bilancio et al. Blood (2006) 107 (2) pp. 642-50) and indicates a role in autoimmune diseases such as rheumatoid arthritis or systemic lupus erythematosus. Thus, PI3K inhibitors may be beneficial for these indications.

[0017] Pharmacological inhibition of PI3KiS inhibits fMLP-dependent chemotaxis of neutrophils in the agarose matrix in the disturbed integrin-dependent ICAM coated system (Sadhu et al, J. Immunol. (2003) 170 (5) pp. 2647-54.). Inhibition of PI3KiS regulates neutrophil activation, adhesion and migration without affecting neutrophil-mediated phagocytosis and bactericidal activity against Staphylococcus aureus (Sadhu et al. Biochem. Biophys. Res. Commun. (2003) 308 (4) pp. 764-9). In general, these data suggest that PI3KS inhibition should not globally inhibit neutrophil function required for innate immune defense. The role of Κ3Κδ in neutrophils offers a further range of treatment for inflammatory diseases, including tissue remodeling such as COPD or rheumatoid arthritis.

[0018] In addition, there is also strong evidence that PI3 &lt;class Ia enzymes also contribute, both directly and indirectly, to oncogenesis in a wide variety of human cancers (Vivanco and Sawyers, Nature Reviews Cancer (2002) 2 (7 ) pp. 489-501). For example, inhibition of Κ3Κδ may have a therapeutic role in the treatment of a malignant hematological disorder such as acute myeloid leukemia (Billottet et al. Oncogene (2006) 25 (50) pp. 6648-59). In addition, activation of mutations in p110a (PI gene &lt;3CA) has been associated with various other cancers such as colon, breast and lung cancers (Samuels et al. Science (2004) 304 (5670) p. 554).

[0019] PI3 &lt;has also been shown to be involved in the development of central sensitization in painful inflammation (Pezet et al. The J. of Neuroscience (2008) 28 (16), pp. 4261-4270).

[0020] A wide range of retroviruses and DNA-based viruses activates the PI3 &lt;pathway as a means of preventing host cell death during viral infection and ultimately uses host cell synthesis machinery for its replication (Virology 344 (1) pp. 131-8 (2006), Vogt et al .; and Nat. Rev. Microbiol. 6 (4) pp. 265-75 (2008), Buchkovich et al.). Thus, PI3 &lt;inhibitors may have antiviral properties in addition to well-established oncolytic and anti-inflammatory indications. These antiviral activities provide interesting perspectives on viral exacerbations in inflammation. For example, human cold rhinovirus (HRV) is responsible for more than 50% of respiratory infections, but complications from these infections may be significant in some populations. This is especially true for respiratory diseases such as asthma or chronic obstructive pulmonary disease (COPD). Infection with epithelial cell rhinoviruses leads to PI3-dependent &lt;cytokine and chemokine secretion (J. Biol. Chem. (2005) 280 (44) p. 36952, Newcomb et al.). These inflammatory responses correlate with worsening respiratory symptoms during infection. Thus, PI3 &lt;inhibitors may suppress the exaggerated immune response to otherwise a mild virus. Most HRV strains infect bronchial epithelial cells by initially binding to the ICAM-1 receptor. &lt;HRV-ICAM-1 complex is then further internalized by endocytosis and this process has been shown to require PI3 activity &lt;(J. Immunol. (2008) 180 (2) pp. 870-880, Lau et al.). Thus, PI3 &lt;inhibitors may also block viral infections by inhibiting the entry of the virus into host cells.

[0021] PI3 &lt;inhibitors may be useful in limiting other types of respiratory infections including fungal infection aspergillosis (Mucosal Immunol. (2010) 3 (2) pp. 193-205, Bonifazi et al.). In addition, myszy3ΡΙδ deficient mice are more resistant to infection by the protozoan parasite Leishmania major (J. Immunol. (2009) 183 (3) pp. 1921-1933, Liu et al.). Given these effects on viral infections, these reports suggest that PI3 &lt;inhibitors may be useful in the treatment of a variety of different infections.

[0022] Inhibition of PI3 &lt;has also been shown to promote differentiation of regulatory T cells (Proc. Natl. Acad. Sci. USA (2008) 105 (22) pp. 7797-7802, Sauer et al.) Suggesting that PI3 &lt;inhibitors may serve for therapeutic purposes in the case of autoimmune or allergic indications by inducing immune tolerance towards one's own antigen or allergen. Recently, PI3K isoform has also been associated with smoking-induced glucocorticoid insensitivity (Am. J. Respir. Crit. Care Med.

(2009) 179 (7) pp. 542-548, Marwick et al.). This observation suggests that COPD patients who otherwise responded poorly to corticosteroids may benefit from a combination of a PI3K inhibitor and a corticosteroid.

[0023] PI3K is also involved in other respiratory conditions such as idiopathic pulmonary fibrosis (IPF). IPF is a fibrotic disease with progressive decline in lung function and increased mortality due to respiratory failure. In IPF, circulating fibrocytes are directed to the lungs via the chemokine receptor CXCR4. PI3K is required for both signal transduction and CXCR4 expression (Int. J. Biochem. And Cell Biol. (2009) 41 pp. 1708-1718, Mehrad et al.). Thus, by reducing CXCR4 expression and blocking its effector function, the PI3K inhibitor should inhibit the recruitment of fibrocytes to the lungs and, consequently, slow down the fibrosis process underlying IPF, a disease causing a great unmet need. [0024] Attempts have been made to prepare compounds that inhibit PI3 kinase activity and many such compounds have been disclosed in the art. However, in view of the many abnormal responses that are mediated by PI3 kinases, there is a continuing need for PI3 kinase inhibitors that can be used to treat various conditions.

[0025] The inventors of the present invention have developed new compounds that are inhibitors of kinase activity, in particular PI3 kinase activity. Compounds that are PI3 kinase inhibitors may be useful in the treatment of disorders associated with inappropriate kinase activity, especially with inappropriate PI3 kinase activity, for example in the treatment and prevention of disorders mediated by PI3 kinase mechanisms. Such disorders include respiratory diseases, including asthma, chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF); viral infections including viral respiratory tract infections and viral exacerbations of respiratory diseases such as asthma and COPD; non-viral respiratory infections including aspergillosis and leishmaniasis; allergic diseases including allergic rhinitis and atopic dermatitis; autoimmune diseases including rheumatoid arthritis and multiple sclerosis; inflammatory disorders including inflammatory bowel disease; cardiovascular diseases including thrombosis and atherosclerosis; hematological malignancies; neurodegenerative diseases; inflammation of the pancreas; multi-organ failure; kidney disease; platelet aggregation; tumor; sperm motility; rejection of transplantation; transplant rejection; lung damage; and pain including pain associated with rheumatoid arthritis or osteoarthritis, back pain, general pain associated with inflammation, liver neuralgia, diabetic neuropathy, inflammatory neuropathic (traumatic) pain, trigeminal neuralgia and central pain.

[0026] In one embodiment, the compounds of the invention may show selectivity for PI3 kinases over other kinases.

[0027] In another embodiment, the compounds of the invention may be potent PI3K inhibitors (5. In a further embodiment, the compounds of the invention may exhibit selectivity for PI3K (5 over other PI3 kinases).

SUMMARY OF THE INVENTION [0029] The invention relates to certain new compounds. More specifically, the invention relates to compounds of formula (I)

<img file="PL2424864T3_D0003.tif" />

in which R¹, R², R³ and R⁴ have the meanings given below, and their salts.

[0030] The compounds are inhibitors of kinase activity, in particular PI3 kinase activity. Compounds that are PI3 kinase inhibitors may be useful in the treatment of disorders associated with inappropriate PI3 kinase activity, such as asthma and chronic obstructive pulmonary disease (COPD). Accordingly, the invention further relates to pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof. Still further, the invention relates to methods of inhibiting PI3 kinase activity and treating related disorders using a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof. Still further, the invention relates to methods of making the compounds of the invention.

DETAILED DESCRIPTION OF THE INVENTION [0031] In one embodiment, the invention relates to compounds of formula (I)

<img file="PL2424864T3_D0004.tif" />

wherein

R¹ is 9- or 10-membered bicyclic heteroaryl, wherein the 9- or 10-membered bicyclic heteroaryl contains from one to three heteroatoms independently selected from oxygen and nitrogen, and is optionally substituted with C1-6alkyl, C3-6cycloalkyl, halogen , -CN or - NHSO2R⁵, or pyridinyl optionally substituted with one or two substituents independently selected from C 1-6 alkyl, -OR⁶, halogen and -NHSO2R⁷;

R² and R³, together with the nitrogen atom to which they are attached, are joined to form a 6 or 7-membered heterocyclyl, said 6- or 7-membered heterocyclyl optionally containing an oxygen atom or an additional nitrogen atom and is optionally substituted with one or two substituents independently selected from C 1-6;

R⁴ is hydrogen or methyl;

R⁶ is hydrogen or C1-4alkyl; and each of R⁵ and R⁷ independently represents C1-6alkyl or phenyl optionally substituted with one or two substituents independently selected from halogen and salts thereof (hereinafter "the compounds of the invention").

[0032] In one embodiment, R¹ is a 9-membered bicyclic heteroaryl, wherein the 9-membered bicyclic heteroaryl contains one or two nitrogen atoms, or pyridinyl optionally substituted with one or two substituents independently selected from -OR⁶ and -NHSO2R⁷. In another embodiment, R¹ is 9- or 10-membered bicyclic heteroaryl, wherein said 9- or 10-membered bicyclic heteroaryl contains from one to three heteroatoms independently selected from oxygen and nitrogen, and is optionally substituted with C1-6alkyl, C3-6cycloalkyl, halogen , -CN or -NHSO2R⁵. In another embodiment, R¹ is 9- or 10-membered bicyclic heteroaryl, wherein the 9- or 10-membered bicyclic heteroaryl contains one or two nitrogen atoms and is optionally substituted with C1-6alkyl or halogen. In another embodiment, R¹ is 9-membered bicyclic heteroaryl, said 9-membered bicyclic heteroaryl having one or two nitrogen atoms. In another embodiment, R¹ is indolyl, for example 1H9 indol-4-yl. In another embodiment, R¹ is pyridinyl optionally substituted with one or two substituents independently selected from C1-6alkyl, -OR⁶, halogen and -NHSO2R⁷. In another embodiment, R¹ is pyridinyl optionally substituted with one or two substituents independently selected from -OR⁶ and -NHSO2R⁷. In a further embodiment R¹ is pyridinyl substituted with -OR⁶ and -NHSO2R⁷.

[0033] In one embodiment, R² and R³, together with the nitrogen atom to which they are attached, are joined to form a 6-membered heterocyclyl, the 6-membered heterocyclyl optionally containing an oxygen atom or an additional nitrogen atom and is optionally substituted with one or two substituents independently selected from C1-6alkyl. In another embodiment, R² and R³, together with the nitrogen atom to which they are attached, are joined and form a 6-membered heterocyclyl, said 6-membered heterocyclyl optionally containing an oxygen atom or an additional nitrogen atom and is substituted with one or two substituents independently selected from C1-4alkyl, on methyl example. In another embodiment, R² and R³, together with the nitrogen atom to which they are attached, are joined and form a 6-membered heterocyclyl wherein the 6-membered heterocyclyl contains an oxygen atom and is optionally substituted with one or two substituents independently selected from C1-4alkyl, for example methyl. In another embodiment, R² and R³, together with the nitrogen atom to which they are attached, are joined to form a 6-membered heterocyclyl, wherein the 6-membered heterocyclyl contains an oxygen atom and is substituted with one or two substituents independently selected from C1-6alkyl. In another embodiment, R² and R³, together with the nitrogen atom to which they are attached, are joined to form a 6-membered heterocyclyl, wherein the 6-membered heterocyclyl contains an additional nitrogen atom and is optionally substituted with C1-4alkyl, for example isopropyl. In a further embodiment R² and R³, together with the nitrogen atom to which they are attached, are joined to form a 6-membered heterocyclyl, wherein the 6-membered heterocyclyl contains an additional nitrogen atom and is substituted with C1-4alkyl, for example isopropyl.

[0034] In one embodiment, R⁴ is hydrogen.

[0035] In one embodiment, R⁵ is C1-4alkyl such as methyl.

In one embodiment, R⁶ is C1-4alkyl such as methyl.

[0037] In one embodiment, R⁷ is C1-6alkyl. In another embodiment, R⁷ is C1-4alkyl such as methyl. In a further embodiment R⁷ is phenyl optionally substituted with one or two substituents independently selected from halogen, e.g. fluoro.

[0038] It should be understood that the present invention includes all combinations of substituent groups described above.

[0039] In one embodiment, the invention relates to compounds of formula (IA)

<img file="PL2424864T3_D0005.tif" />

wherein

R¹ is pyridinyl optionally substituted with one or two substituents independently selected from -OR⁶ and -NHSO2R⁷;

R² and R³, together with the nitrogen atom to which they are attached, are joined to form a 6-membered heterocyclyl, the 6-membered heterocyclyl containing an oxygen atom and is optionally substituted with one or two substituents independently selected from C1-4alkyl;

R⁴ is hydrogen;

R⁶ is C1-4alkyl; and R⁷ is C1-4alkyl; and their salts.

[0040] In a further embodiment, the invention relates to compounds of formula (IB)

<img file="PL2424864T3_D0006.tif" />

wherein

R¹ is indolyl;

R² and R³, together with the nitrogen atom to which they are attached, are joined to form a 6-membered heterocyclyl, said 6-membered heterocyclyl having an additional nitrogen atom and is optionally substituted with C1-4alkyl; and

R⁴ is hydrogen; and their salts.

[0041] The compounds of the invention include the compounds of Examples 1 to 9 and their salts. In one embodiment, the compound of the invention is:

N- [5- [4- (5 - {[(2R, 6S) -2,6-dimethyl-4-morpholinyl] methyl} -1,3-oxazol-2-yl) -1H-indazol-6-yl ] -2- (methyloxy) -3-pyridinyl] methanesulfonamide;

N- [5- [4- (5 - {[4- (1-methylethyl) -1-piperazinyl] methyl} -1,3-oxazol-2-yl) -1H-indazol-6-yl] -2- (methyloxy) -3-pyridinyl] methanesulfonamide;

N- [5- [4- (5 - {[(2R, 6S) -2,6-dimethyl-4-morpholinyl] methyl} -1,3-oxazol-2-yl) -1H-indazol-6-yl ] -2- (methyloxy) -3-pyridinyl] -2,4-difluoro-benzenesulfonamide;

2,4-difluoro-N- [5- [4- (5 - {[4- (1-methylethyl) -1-piperazinyl] methyl} -1,3-oxazol-2-yl) -1H-indazol-6-yl ] -2- (methyloxy) -3-pyridinyl] benzenesulfonamide;

4- (5 - {[(2R, 6S) -2,6-dimethyl-4-morpholinyl] methyl} -1,3-oxazol-2-yl) -6- (1H-indol-4-yl) -1H-indazole ;

6- (1H-indol-4-yl) -4- (5 - {[4- (1-methylethyl) -1-piperazinyl] methyl} -1,3-oxazol-2-yl) -1H-indazole;

6- (1H-indol-4-yl) -4- [5- (4-morpholinylmethyl) -1,3-oxazol-2-yl] -1H-indazole; N- [5- [4- (5 - {[(2R, 6R) -2,6-dimethyl-4-morpholinyl] methyl} -1,3-oxazol-2-yl) -1H-indazol-6-yl ] -2- (methyloxy) -3-pyridinyl] methanesulfonamide; 6- (1H-indol-4-yl) -4- [5- (1-piperazinylmethyl) -1,3-oxazol-2-yl] -1H-indazole; or its salt.

[0043] In another embodiment, the compound of the invention is:

N- [5- [4- (5 - {[(2R, 6S) -2,6-dimethyl-4-morpholinyl] methyl} -1,3-oxazol-2-yl) -1H-indazol-6-yl ] -2- (methyloxy) -3-pyridinyl] methanesulfonamide;

N- [5- [4- (5 - {[4- (1-methylethyl) -1-piperazinyl] methyl} -1,3-oxazol-2-yl) -1H-indazol-6-yl] -2- (methyloxy) -3-pyridinyl] methanesulfonamide;

N- [5- [4- (5 - {[(2R, 6S) -2,6-dimethyl-4-morpholinyl] methyl} -1,3-oxazol-2-yl) -1H-indazol-6-yl ] -2- (methyloxy) -3-pyridinyl] -2,4-difluoro-benzenesulfonamide;

2,4-difluoro-N- [5- [4- (5 - {[4- (1-methylethyl) -1-piperazinyl] methyl} -1,3-oxazol-2-yl) -1H-indazol-6-yl ] -2- (methyloxy) -3-pyridinyl] benzenesulfonamide;

4- (5 - {[(2R, 6S) -2,6-dimethyl-4-morpholinyl] methyl} -1,3-oxazol-2-yl) -6- (1H-indol-411 yl) -1H- indazole;

6- (1H-indol-4-yl) -4- (5 - {[4- (1-methylethyl) -1-piperazinyl] methyl} -1,3-oxazol-2-yl) -1H-indazole;

6- (1H-indol-4-yl) -4- [5- (4-morpholinylmethyl) -1,3-oxazol-2-yl] -1H-indazole; or its salt.

[0044] In another embodiment, the compound of the invention is:

N- [5- [4- (5 - {[2,6-dimethyl-4-morpholinyl] methyl} -1,3-oxazol-2-yl) -1H-indazol-6-yl] -2- (methyloxy) - 3-pyridinyl] methanesulfonamide;

or its salt.

[0045] In another embodiment, the compound of the invention is:

N- [5- [4- (5 - {[(2R, 6S) -2,6-dimethyl-4-morpholinyl] methyl} -1,3-oxazol-2-yl) -1H-indazol-6-yl ] -2- (methyloxy) -3-pyridinyl] methanesulfonamide;

or its salt.

[0046] In another embodiment, the compound of the invention is:

(R) -Nigdalane N- [5- [4- (5 - {[(2R, 6S) -2,6-dimethyl-4-morpholinyl] methyl} -1,3-oxazol2-yl) -1H-indazol- 6-yl] -2- (methyloxy) -3-pyridinyl] methanesulfonamide.

[0047] In another embodiment, the compound of the invention is:

N- [5- [4- (5 - {[(2R, 6S) -2,6-dimethyl-4-morpholinyl] methyl} -1,3-oxazol-2-yl) -1H-indazol-6-yl ] -2- (methyloxy) -3-pyridinyl] methanesulfonamide.

[0048] In another embodiment, the compound of the invention is:

6- (1H-indol-4-yl) -4- (5 - {[4- (1-methylethyl) -1-piperazinyl] methyl} -1,3-oxazol-2-yl) -1H-indazole;

or its salt.

[0049] In another embodiment, the compound of the invention is:

6- (1H-indol-4-yl) -4- (5 - {[4- (1-methylethyl) -1-piperazinyl] methyl} 1,3-oxazol-2-yl) -1H-indazou hydrochloride.

[0050] In a further embodiment, the compound of the invention is:

6- (1H-indol-4-yl) -4- (5 - {[4- (1-methylethyl) -1-piperazinyl] methyl} -1,3-oxazol-2-yl) -1H-indazole.

Terms and definitions [0051] "Alkyl" means a saturated hydrocarbon chain containing the specified number of member atoms. For example, C 1-6 alkyl means an alkyl group having from 1 to 6 membered atoms, for example 1 to 4 membered atoms. Alkyl groups can be straight or branched. Representative branched alkyl groups have one, two or three branches. Alkyl includes methyl, ethyl, propyl (n-propyl and isopropyl), butyl (n-butyl, isobutyl and t-butyl), pentyl (n-pentyl, isopentyl and neopentyl) and hexyl.

[0052] "Cycloalkyl" means a saturated hydrocarbon ring containing the specified number of member atoms. Cycloalkyl groups are monocyclic ring systems. For example, C 3-6 cycloalkyl means a cycloalkyl group containing from 3 to 6 membered atoms. In one embodiment, the cycloalkyl groups have 3 or 4 membered atoms. In a further embodiment, the cycloalkyl groups contain 5 or 6 member atoms. Cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

[0053] "Enantiomerically enriched" refers to products whose enantiomeric excess is greater than zero. For example, the term enantiomerically enriched refers to products whose enantiomeric excess is greater than 50% ee, greater than 75% ee, and greater than 90% ee.

[0054] "Enantiomeric excess" or "ee" means the excess of one enantiomer relative to another expressed as a percentage. As a result, due to the fact that both enantiomers are present in equal amounts in the racemic mixture, the enantiomeric excess is zero (0% ee). However, if one enantiomer is enriched so that it constitutes 95% of the product, then the enantiomeric excess would be 90% ee (amount of enriched enantiomer, 95%, minus the amount of the other enantiomer, 5%).

[0055] "Enantiomerically pure" refers to products that have an enantiomeric excess of 99% ee or more.

[0056] "Half-life" (or "half-lives") refers to the time required to convert half of the substance into other chemically distinct molecules in vitro or in vivo.

[0057] "Halogen" means a halogen radical, a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

[0058] "Heteroaryl", unless otherwise specified, means an aromatic group containing from 1 to 3 heteroatoms as member atoms. Heteroaryl groups containing more than one heteroatom may contain different heteroatoms. Heteroaryl groups may be optionally substituted as defined herein. The heteroaryl groups here are fused bicyclic ring systems. Bicyclic heteroaryl rings have 9 or 10 membered atoms. Bicyclic heteroaryl includes indolyl, isoindolyl, indolizinyl, benzofuranyl, isobenzofuranyl, indazolyl, benzimidazolyl, pyrrolopyridinyl, pyrazolopyridinyl, pyrrolopyrimidinyl, quinolyl, isoquinolinyl, quinoxalinyl, quinazinyl, benzinyl benzyl

[0059] "Heteroatom" means a nitrogen atom, a sulfur atom or an oxygen atom.

[0060] "Heterocyclyl", unless otherwise specified, means a saturated or unsaturated ring containing 1 or 2 heteroatoms as ring member atoms. However, heterocyclyl rings are not aromatic. In some embodiments, the heterocyclyl is saturated. In other embodiments, the heterocyclyl is unsaturated but not aromatic. Heterocyclyl groups containing more than one heteroatom may contain different heteroatoms. Heterocyclyl groups may be optionally substituted with one or more substituents as defined herein. Heterocyclyl groups herein are monocyclic ring systems having 6 or 7 member atoms. Monocyclic heterocyclyl includes piperidinyl, piperazinyl, morpholinyl and hexahydro-1,4-oxazepinyl.

[0061] "Member atoms" means the atom or atoms that form the chain or ring. When more than one member atom is present in a chain or ring, each member atom is covalently attached to an adjacent member atom in the chain or ring. Atoms that form a substituent group on a chain or ring are not member atoms on the chain or ring.

[0062] "Optionally substituted (s) -" indicates that a group such as heteroaryl may be unsubstituted or substituted with one or more substituents as defined herein.

[0063] "Substituted (s)" when referring to a group indicates that the hydrogen atom attached to the member atom in the group is replaced. It should be understood that the term "substituted (s)" includes the implied claim that such substitution is consistent with the allowed valence of the substituted atom and substituent, and that the substitution results in a stable compound (i.e., a compound that does not spontaneously transformation, such as rearrangement, cyclization or elimination). In some embodiments, a single atom may be substituted with more than one substituent as long as such substitution is in accordance with the allowed valence of the atom. Suitable substituents are defined herein for each substituted or optionally substituted group.

[0064] "Pharmaceutically acceptable" refers to those compounds, salts, materials, compositions and dosage forms that are, in the field of rational medical evaluation, suitable for use in contact with human and animal tissues without undue toxic effects, irritation or other problem or complication commensurate with a reasonable risk-benefit ratio.

[0065] As used herein, the symbols and conventions used in these processes, schemes and examples are consistent with those used in current scientific literature, for example,

Journal of the American Chemical Society or Journal of Biological Chemistry. Standard one or three letter abbreviations are generally used to indicate amino acid residues that are assumed to be in the L configuration, unless otherwise stated. Unless otherwise stated, all starting materials were obtained from commercial suppliers and used without further purification. Specifically, the following abbreviations can be used in the examples and throughout the description:

<td>DCM</td><td>dichloromethane</td>

<td>DMF</td><td>dimethylformamide</td>

<td>DMPU</td><td>1,3-dimethyl-3,4,5,6-tetrahydo-2 (1H) -pyrimidinone</td>

<td>DMSO</td><td>dimethyl sulfoxide</td>

<td>EtOAc</td><td>Ethyl acetate</td>

<td>^g</td><td>Grams</td>

<td>h</td><td>Hour (hours)</td>

<td>HPLC</td><td>High performance liquid chromatography</td>

<td>LCMS</td><td>Liquid chromatography-mass spectroscopy</td>

<td>l</td><td>Liter</td>

<td>M</td><td>Molar</td>

<td>MDAP</td><td>Mass directed automated preparative HPLC (Mass controlled automated preparative HPLC)</td>

<td>Me</td><td>Methyl</td>

<td>MeCN</td><td>acetonitrile</td>

<td>MeOH</td><td>methanol</td>

<td>mg</td><td>milligrams</td>

<td>min</td><td>minutes</td>

<td>ml</td><td>milliliters</td>

<td>mmol</td><td>mmol</td>

<td>rt</td><td>Retention time</td>

<td>RT</td><td>Room temperature</td>

<td>SCX</td><td>Exchange of strong cations</td>

<td>SPE</td><td>Solid phase extraction</td>

<td>TFA</td><td>Trifluoroacetic acid</td>

<td>THF</td><td>tetrahydrofuran</td>

<td>UPLC</td><td>Ultra high performance liquid chromatography</td>

<td>UV</td><td>ultraviolet</td>

[0066] All references to brine mean saturated aqueous NaCl solution.

[0067] The scope of the "compounds of the invention" includes all solvates (including hydrates), complexes, polymorphs, prodrugs, radiolabeled derivatives, stereoisomers and optical isomers of the compounds of formula (I) and their salts.

[0068] The compounds of the invention may exist in solid or liquid form. In the solid state, the compounds of the invention may exist in crystalline or non-crystalline form, or as a mixture thereof. For compounds of the invention that are in crystalline form, one of ordinary skill in the art will be aware that pharmaceutically acceptable solvates may be formed, where solvent molecules are incorporated into the crystal lattice during crystallization. Solvates may include non-aqueous solvents such as ethanol, isopropanol, DMSO, acetic acid, ethanolamine and EtOAc, or they may contain water as a solvent that is embedded in the crystal lattice. Solvates in which the solvent embedded in the crystal lattice is water are usually referred to as "hydrates". Hydrates include stoichiometric hydrates as well as compositions containing various amounts of water. The invention includes all such solvates.

[0069] The skilled person will additionally be aware that certain compounds of the invention that exist in crystalline form, including different solvates thereof, may exhibit polymorphism (i.e., the ability to occur in different crystal structures). These different crystal forms are usually known as "polymorphs". The invention includes all such polymorphs. Polymorphs have the same chemical composition but differ in packing, geometric arrangement and other descriptive properties of the solid crystalline state. Thus, polymorphs may have different physical properties, such as shape, density, hardness, deformability, stability and dissolution properties. Polymorphs usually show different melting points, IR spectra and X-ray powder diffraction patterns that can be used for identification. The skilled person will be aware that various polymorphs can be produced, for example, by varying or adapting the reaction conditions or reagents used in the preparation of the compound. For example, changes in temperature, pressure or solvent may lead to polymorphs. In addition, one polymorph may self-transform into another polymorph under certain conditions.

[0070] In one aspect, the present invention provides N- [5- [4- (5 - {[(2R, 6S) -2,6-dimethyl-4-morpholinyl] methyl} -1,3-oxazol-2- yl) -1H-indazol-6-yl] -2- (methyloxy) -3-pyridinyl] methanesulfonamide or its salt in crystalline form.

In one embodiment, the present invention provides N- [5- [4- (5 - {[(2R, 6S) -2,6-dimethyl-4-morpholinyl] methyl} -1,3-oxazol-2-yl ) -1H-indazol-6-yl] -2- (methyloxy) -3-pyridinyl] methanesulfonamide in crystalline form.

[0072] In another embodiment, the present invention provides crystalline N- [5- [4- (5 - {[(2R, 6S) 2,6-dimethyl-4-morpholinyl] methyl} -1,3-oxazol-2-yl ) -1H-indazol-6-yl] -2- (methyloxy) 3-pyridinyl] methanesulfonamide, characterized in that it provides an XRPD (X-ray powder diffraction) diffraction pattern having peaks (° 2θ) at about 4.5, about 11.7 and / or about 12.9.

[0073] In another embodiment, the present invention provides crystalline N- [5- [4- (5 - {[(2R, 6S) 2,6-dimethyl-4-morpholinyl] methyl} -1,3-oxazol-2-yl ) -1H-indazol-6-yl] -2- (methyloxy) 3-pyridinyl] methanesulfonamide, characterized in that it provides an XRPD pattern comprising peaks essentially as given in Table 2.

[0074] In another embodiment, the present invention provides crystalline N- [5- [4- (5 - {[(2R, 6S) 2,6-dimethyl-4-morpholinyl] methyl} -1,3-oxazol-2-yl ) -1H-indazol-6-yl] -2- (methyloxy) 3-pyridinyl] methanesulfonamide, characterized in that it provides an XRPD pattern substantially in accordance with Figure 2.

[0075] In a further aspect, the present invention provides 6- (1H-indol-4-yl) -4- (5 - {[4- (1-methylethyl) -1-piperazinyl] methyl} -1,3-oxazol-2 -yl) -1H-indazole or its salt in crystalline form.

[0076] In one embodiment, the present invention provides 6- (1H-indol-4-yl) 4- (5 - {[4- (1-methylethyl) -1-piperazinyl] methyl} -1,3-oxazol-2 hydrochloride -yl) -1H-indazole in crystalline form.

[0077] In another embodiment, the present invention provides crystalline 6- (1Hindol-4-yl) -4- (5 - {[4- (1-methylethyl) -1-piperazinyl] methyl} -1,3-oxazol-2 hydrochloride -yl) -1H-indazole, characterized in that it provides an XRPD (X-ray powder diffraction) diffraction pattern having peaks (° 2θ) at about 5.2, about 10.3 and / or about 12.8.

[0078] In another embodiment, the present invention provides crystalline 6- (1Hindol-4-yl) -4- (5 - {[4- (1-methylethyl) -1-piperazinyl] methyl} -1,3-oxazol-2 hydrochloride -yl) -1H-indazole, characterized in that it provides an XRPD pattern comprising peaks essentially as given in Table 1.

In a further embodiment, the present invention provides crystalline 6- (1H-indol-4-yl) -4- (5 - {[4- (1-methylethyl) -1-piperazinyl] methyl} -1,3-oxazole hydrochloride -2-yl) 1H-indazole, characterized in that it provides an XRPD diffraction pattern substantially in accordance with Figure 1.

[0080] When it is indicated here that a peak exists in the XRPD pattern at a given value, it usually means that the peak is ± 0.2 of the specified value.

[0081] The invention also includes isotopically labeled compounds that are identical to the compounds of formula (I) and their salts, but due to the fact that one or more atoms are replaced with an atom of atomic mass or mass number other than atomic mass or mass number most commonly found in nature. Examples of isotopes that can be incorporated into compounds of the invention include hydrogen, carbon, nitrogen, oxygen and fluorine isotopes such as²H ³H ¹¹C ¹⁴C and ¹⁸F.

[0082] Compounds according to formula (I) may contain one or more asymmetric centers (also referred to as chiral centers) and may therefore exist as individual enantiomers, diastereomers or other stereoisomeric forms, or as mixtures thereof. Chiral centers, such as chiral carbon atoms, may also be present in a substituent, such as an alkyl group. In the absence of the stereochemistry of the chiral center present in formula (I) or any of the chemical structures illustrated herein, by definition this structure includes any stereoisomer and all mixtures thereof. Thus, compounds according to formula (I) containing one or more chiral centers can be used as racemic mixtures, enantiomerically enriched mixtures or as enantiomerically pure individual stereoisomers.

[0083] Individual stereoisomers of a compound according to formula (I) which contains one or more asymmetric centers may be separated by methods known to those skilled in the art. For example, such separation can be carried out (1) by forming diastereomeric salts, complexes or other derivatives; (2) selective reaction with a stereoisomer-specific reagent, for example by enzymatic oxidation or reduction; or (3) by gas-liquid or liquid chromatography in a chiral environment, for example, on a chiral support, such as silica with a chiral ligand attached, or in the presence of a chiral solvent. The skilled person will be aware that when the desired stereoisomer is converted to another chemical molecule by one of the separation procedures described above, an additional step of releasing the desired form is required. Alternatively, specific stereoisomers can be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer to another by asymmetric transformation.

[0084] Compounds according to formula (I) may also contain centers of geometric asymmetry. Where no stereochemistry is given, the geometric asymmetry centers present in formula (I) or any of the chemical structures illustrated herein are intended to include the trans geometric isomer, the cis geometric isomer, and all mixtures thereof. Similarly, all tautomeric forms are also encompassed by formula (I) regardless of whether such tautomers are in equilibrium or one form predominates.

[0085] It is to be understood that reference herein to compounds of formula (I) and salts thereof includes compounds of formula (I) in the form of free acids or free bases or their salts, for example in the form of their pharmaceutically acceptable salts. Thus, in one embodiment, the invention relates to compounds of formula (I) in the form of the free acid or free base. In another embodiment, the invention relates to compounds of formula (I) and salts thereof. In a further embodiment, the invention relates to compounds of formula (I) and pharmaceutically acceptable salts thereof.

[0086] The skilled person will be aware that pharmaceutically acceptable salts of compounds according to formula (I) may be prepared. Indeed, in some embodiments of the invention, the pharmaceutically acceptable salts of the compounds according to formula (I) may be advantageous compared to the corresponding free acid or free base due to the fact that such salts can confer greater stability or solubility to the molecule thereby facilitating formulation in dosage form. Accordingly, the invention further relates to compounds of formula (I) and pharmaceutically acceptable salts thereof.

[0087] The term "pharmaceutically acceptable salts" as used herein means salts that retain the desired biological activity of the subject compound and exhibit minimal undesirable toxicological effects. These pharmaceutically acceptable salts can be prepared in situ during the final isolation and purification of the compound either by separately reacting the purified compound in the form of its free acid or free base, or a pharmaceutically unacceptable salt with the appropriate base or acid, respectively.

[0088] Salts and solvates having pharmaceutically unacceptable counterions or bound solvents are within the scope of this invention, for example, for use as intermediates in the preparation of other compounds of formula (I) and pharmaceutically acceptable salts thereof. Thus, one embodiment of the invention includes compounds of formula (I) and salts thereof.

[0089] In some embodiments, compounds according to formula (I) may contain an acid functional group. Suitable pharmaceutically acceptable salts include those of such acid functions. Representative salts include pharmaceutically acceptable metal salts such as sodium, potassium, lithium, calcium, magnesium, aluminum and zinc salts; carbonates and bicarbonates of a pharmaceutically acceptable metal cation such as sodium, potassium, lithium, calcium, magnesium, aluminum and zinc; pharmaceutically acceptable organic primary, secondary and tertiary amines, including aliphatic amines, aromatic amines, aliphatic diamines and hydroxyalkylamines such as methylamine, ethylamine, 2-hydroxyethylamine, diethylamine, TEA, ethylenediamine, ethanolamine, diethanolamine and cyclohexylamine.

[0090] In certain embodiments, compounds according to formula (I) may contain a basic functional group and are therefore capable of forming pharmaceutically acceptable acid addition salts by treatment with an appropriate acid. Suitable acids include pharmaceutically acceptable inorganic acids and pharmaceutically acceptable organic acids. Representative pharmaceutically acceptable acid addition salts include hydrochloride, hydrobromide, nitrate, methyl nitrate, sulfate, bisulfate, sulfamate, phosphate, acetate, hydroxyacetate, phenylacetate, propionate, butyrate, isobutyrate, valerate, maleate, hydroxymaleate, acrylate, fumarate, malate citrate, salicylate, p-aminosalicylate, glycolate, lactate, heptanoate, phthalate, oxalate, succinate, benzoate, o-acetoxybenzoate, chlorobenzoate, methyl benzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, naphthoate, hydroxynaphthoate, mandelate, tannin, formate, stearate, ascorbate, palmitate, oleate, pyruvate, pamoate, malonate, laurate, glutarate, glutamate, esterate, mesylate hydroxyethanesulfonate, benzenesulfonate (besylate), p-aminobenzenesulfonate, p-toluenesulfonate (tosylate) and naphthalene-2-sulfonate. In one embodiment, the pharmaceutically acceptable addition salt is the hydrochloride salt. In a further embodiment, the pharmaceutically acceptable addition salt is mandelate, such as (R) -migdalane.

[0091] In one embodiment, the invention provides a compound which is:

N- [5- [4- (5 - {[(2R, 6S) -2,6-dimethyl-4-morpholinyl] methyl} -1,3-oxazol-2-yl) -1H-indazol-6-yl ] -2- (methyloxy) -3-pyridinyl] methanesulfonamide;

or a pharmaceutically acceptable salt thereof.

In another embodiment, the invention provides a compound which is:

6- (1H-indol-4-yl) -4- (5 - {[4- (1-methylethyl) -1-piperazinyl] methyl} -1,3-oxazol-2-yl) -1H-indazole;

or a pharmaceutically acceptable salt thereof.

Preparation of compounds [0093] The compounds of the invention can be prepared by a variety of methods, including standard chemical reactions. Any predefined variable will continue to have a predetermined meaning, unless otherwise indicated. The following are illustrative synthetic methods, and then specific compounds of the invention are prepared in the Examples section.

Method A [0094] Compounds of formula (I) wherein R¹, R², R³ and R⁴ have the meaning as defined above, or salts thereof, can be prepared from compounds of formula (II)

<img file="PL2424864T3_D0007.tif" />

in which R² and R³ have the meanings specified above and R^4a is methyl or a suitable protecting group, such as benzenesulfonyl, by treatment with a suitable boronic acid or boronate ester, such as 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-indole (commercially available), in the presence of a suitable palladium catalyst such as (1R, 4S) -bicyclo [2.2.1] hept-2-yl [(1S, 4R) -bicyclo [2.2.1] hept-2-yl] chloro [2 '- (dimethylamino) -2-biphenyl] palladium phosphate, in a suitable solvent, such as a mixture of 1,4-dioxane and water, in a suitable ratio, e.g., about 4: 1, in the presence of a suitable base, such as sodium bicarbonate, and at a suitable temperature, such as from about 80 ° C to about 150 ° C, for example about 120 ° C.

[0095] Group R¹ introduced via boronic acid or boronate ester can be protected with a suitable protecting group such as t-butyldimethylsilyl and an additional deprotection step may be required, e.g. by treatment with a suitable fluoride such as tetra-n-butylammonium fluoride in a suitable solvent such as tetrahydrofuran, and at a suitable temperature, such as room temperature, for example about 20 ° C.

[0096] If necessary, in the case of compounds of formula (II) in which R^4a is a suitable protecting group, the protecting group such as benzenesulfonyl can then be removed by treatment with a suitable aqueous inorganic base, such as aqueous sodium hydroxide, in a suitable solvent such as isopropanol, and at a suitable temperature such as room temperature, example around 20 ° C.

[0097] Compounds of formula (II) in which R², R³ and R^4a are as defined above, can be prepared from compounds of formula (III)

<img file="PL2424864T3_D0008.tif" />

in which R^4a has the meaning set out above and X¹ is a suitable leaving group such as Br by treatment with an amine of formula HNR²R³in which R² and R³ it has the meaning as above, in a suitable solvent such as dichloromethane and at a suitable temperature such as room temperature, e.g. around 20 ° C.

[0098] Compounds of formula (III) in which R^4a has the meaning set out above and X¹ is Br, can be prepared from compounds of formula (IV)

<img file="PL2424864T3_D0009.tif" />

in which R^4a has the meaning set out above by treating with a suitable brominating agent such as carbon tetrabromide and a suitable phosphine such as triphenylphosphine in a suitable solvent such as dichloromethane and at a suitable temperature such as from about 0 ° C to about 50 ° C on example about 0 ° C by heating to about 20 ° C after addition.

[0099] Relatively, alternatively, compounds of formula (III) wherein R^4a has the meaning set out above and X¹ is Br, can be prepared from compounds of formula (IV) in which R^4a is as defined above, by treatment with a suitable brominating agent, such as triphenylphosphine dibromide, in a suitable solvent such as dichloromethane, and at a suitable temperature, such as from about 0 ° C to about 50 ° C, for example about 0 ° C.

[0100] Compounds of formula (IV) wherein R^4a has the meaning specified above, you can

<img file="PL2424864T3_D0010.tif" />

in which R^4a is as defined above, by treatment with a suitable reducing agent such as diisobutylaluminum hydride in a suitable solvent such as tetrahydrofuran and at a suitable temperature such as from about

-50 ° C to about 0 ° C, for example about 0 ° C.

[0101] Compounds of formula (V) wherein R^4a has the meaning as defined above, can be prepared from compounds of formula (VI)

<img file="PL2424864T3_D0011.tif" />

in which R^4a has the meaning set out above by treatment with an appropriate halide such as ethyl 2-chloro-1,3-oxazole-5-carboxylate (commercially available) in the presence of a suitable palladium catalyst such as tetrakis (triphenylphosphine) 19 palladium (0), in a suitable solvent such as N, N-dimethylformamide, in the presence of a suitable iodide, such as sodium iodide, and under microwave conditions at a suitable temperature, such as from about 80 ° C to about 150 ° C, for example about 100 ° C.

[0102] Relatively, alternatively, compounds of formula (V) wherein R^4a has the meaning as defined above, can be prepared from compounds of formula (VII) as defined below, by treatment with an appropriate stannane, such as hexamethyldicine, in the presence of a suitable palladium catalyst such as tetrakis (triphenylphosphine) palladium (0) and a suitable base such as triethylamine , in a suitable solvent such as toluene, and at a suitable temperature such as from about 100 ° C to about 200 ° C, e.g. about 120 ° C, then by treatment with a suitable halogen compound such as methyl 2-chloro-1,3-oxazole-5-carboxylate (commercially available) in the presence of a suitable iodide such as copper (I) iodide and a suitable palladium catalyst such as tetrakis (triphenylphosphine) palladium (0), in a suitable solvent such as 1,3-dimethyl-3,4,5,6-tetrahydro-2 (1H) -pyrimidinone, and at a suitable temperature such as from about 50 ° C to about 150 ° C, e.g. about 85 ° C.

[0103] Compounds of formula (VI) in which R^4a has the meaning as defined above, can be prepared from compounds of formula (VII)

<img file="PL2424864T3_D0012.tif" />

in which R^4a has the meaning set out above by treatment with an appropriate stannane such as hexamethyldicine in the presence of a suitable palladium catalyst such as tetrakis (triphenylphosphine) palladium (0) in a suitable solvent such as xylene in the presence of a suitable base such as triethylamine, and a suitable temperature, such as from about 100 ° C to about 200 ° C, for example about 150 ° C.

[0104] Compounds of formula (VII) in which R^4a is methyl, can be prepared from compounds such as compound of formula (VIII)

<img file="PL2424864T3_D0013.tif" />

[0105] by methylation using a suitable base such as sodium hydride in a suitable solvent such as tetrahydrofuran and at a suitable temperature such as about 0 ° C followed by the addition of an alkylating agent such as iodomethane and stirring at the appropriate temperature such as room temperature, e.g. around 20 ° C.

[0106] The compound of formula (VIII) is commercially available.

[0107] Compounds of formula (VII) in which R^4a is a suitable protecting group such as benzenesulfonyl can be prepared from the compound of formula (VIII) as defined above by treatment with a suitable base such as sodium hydride in a suitable solvent such as N, N-dimethylformamide and at a suitable temperature , such as from about 0 ° C to about 20 ° C, for example about 0 ° C, followed by treatment with a suitable sulfonating agent such as benzenesulfonyl chloride at a suitable temperature, such as from about 0 ° C to about 50 ° C, for example about 0 ° C by heating to about 20 ° C after addition.

[0108] Relatively, alternatively, compounds of formula (VII) in which R^4a is a suitable protecting group such as benzenesulfonyl can be prepared from a compound of formula (VIII) as defined above by treatment with a suitable base such as sodium hydroxide and a suitable phase transfer catalyst such as tetra-n-butylammonium hydrogen sulfate in a suitable solvent such as tetrahydrofuran and at a suitable temperature such as from about 0 ° C to about 20 ° C, for example about 20 ° C, then by treatment with a suitable sulfonating agent, such as benzenesulfonyl chloride, at a suitable temperature, such as from about 0 ° C to about 50 ° C, for example about 25 ° C.

Method B [0109] Compounds of formula (I) wherein R¹, R² and R³ have the meanings specified above, and

R⁴ is hydrogen, or their salts, can be prepared from compounds of formula (IX)

<img file="PL2424864T3_D0014.tif" />

in which R¹, R², R³ have the meanings specified above and R^4b is a suitable protecting group, such as benzenesulfonyl, by treatment with a suitable aqueous inorganic base, such as aqueous sodium hydroxide, in a suitable solvent such as 1,4-dioxane and at a suitable temperature such as room temperature, e.g. ° C.

[0110] Compounds of formula (IX) wherein R¹, R², R³ and R^4b have the meaning as defined above, can be prepared from compounds of formula (X)

<img file="PL2424864T3_D0015.tif" />

in which R¹ and R^4b have the meanings specified above and X² is a suitable leaving group such as Br by treatment with an amine of formula HNR²R³in which R²and R³ are as defined above, in a suitable solvent, such as dichloromethane, and at a suitable temperature, such as room temperature, for example about 20 ° C.

[0111] Compounds of formula (X) wherein R¹ and R^4b have the meanings specified above and X² is Br, can be prepared from compounds of formula (XI)

<img file="PL2424864T3_D0016.tif" />

in which R¹ and R^4b are as defined above, by treatment with a suitable brominating agent such as carbon tetrabromide and a suitable phosphine such as triphenylphosphine in a suitable solvent such as dichloromethane and at a suitable temperature such as from about 0 ° C to about 50 ° C on example around 0 ° C warming to room temperature after addition.

[0112] Compounds of formula (XI) wherein R¹ and R^4b have the meaning as defined above, can be prepared from compounds of formula (XII)

<img file="PL2424864T3_D0017.tif" />

in which R¹ and R^4b have the meanings as defined above, by treatment with a suitable reducing agent such as diisobutylaluminum hydride, in a suitable solvent such as dichloromethane, and at a suitable temperature such as from about

-50 ° C to about 0 ° C, for example about -20 ° C.

[0113] Compounds of formula (XII) wherein R¹ and R^4b have the meaning as defined above, can be prepared from compounds of formula (XIII)

<img file="PL2424864T3_D0018.tif" />

in which R^4b has the meaning set out above by treatment with an appropriate boronic acid or boronate ester such as {1 - [(1,1-dimethylethyl) (dimethyl) silyl] -1H-indol-4-yl} boronic acid (commercially available), in the presence of a suitable palladium catalyst such as (1R, 4S) -bicyclo [2.2.1] hept-2-yl [(1S, 4R) -bicyclo [2.2.1] hept-2-yl] chloro phosphate [2'- (dimethylamino) -2-biphenyl] palladium, in a suitable solvent, such as a mixture of 1,4-dioxane and water in a suitable ratio, for example about 10: 1, in the presence of a suitable base, such as tribasic potassium phosphate, and at a suitable temperature, such as about 80 ° C to about 150 ° C, for example about 100 ° C. Alternatively, this method can be carried out under microwave conditions, and at a suitable temperature, such as from about 80 ° C to about 150 ° C, for example about 120 ° C.

<img file="PL2424864T3_D0019.tif" />

[0114] Boronate esters of formula (XIV) in which R⁷ has the meaning specified above, R⁸ is C1-6alkyl, -OR⁶ or halogen in which R⁶ has the meaning given above, and n = 0 or 1, can be prepared from compounds of formula (XV)

<img file="PL2424864T3_D0020.tif" />

in which R⁸ has the meaning specified above, and n = 0 or 1, by treatment with an appropriate sulfonyl chloride of formula R⁷SO2Cl, such as methanesulfonyl chloride, in a suitable solvent such as pyridine and at a suitable temperature such as room temperature, e.g. about 20 ° C.

[0115] Compounds of formula (XV) in which R⁸ has the meaning given above, and n = 0 or 1, can be prepared from compounds of formula (XVI)

<img file="PL2424864T3_D0021.tif" />

in which R⁸ has the meaning set out above, for which a number of analogues are commercially available, by treatment with the appropriate borolate, such as 4,4,4 ', 4', 5,5,5 ', 5'octamethyl-2,2'-bi- 1,3,2-dioxaborolate, in the presence of a suitable palladium catalyst such as dichloro [1,1'-bis (diphenylphosphino) ferrocene] palladium (II) adduct with dichloromethane in the presence of a suitable base such as potassium acetate in a suitable solvent such as 1,4-dioxane, and at the right temperature, such as from about 50 ° C to about 120 ° C, for example about 80 ° C.

[0116] Thus, in one embodiment, the invention provides a method of producing a compound of the invention, comprising:

a) reacting a compound of formula (II)

<img file="PL2424864T3_D0022.tif" />

in which R² and R³ are as defined above and R^4a is methyl or a suitable protecting group, with the appropriate boronic acid or boronate ester, followed by deprotection if necessary; or

b) in the case of a compound of formula (I) wherein R¹, R² and R³ are as defined above and R⁴ is hydrogen, a compound of formula (IX) is reacted

<img file="PL2424864T3_D0023.tif" />

in which R¹, R², R³ and R^4b have the meanings as defined above, with the appropriate aqueous inorganic base.

Methods of use [0117] The compounds of the invention are inhibitors of kinase activity, especially PI3 kinase activity. Compounds that are PI3 kinase inhibitors may be useful in the treatment of disorders in which the underlying pathological condition is (at least in part) attributed to inappropriate PI3 kinase activity, such as asthma and chronic obstructive pulmonary disease (COPD). "Inadequate PI3 kinase activity" refers to any PI3 kinase activity that deviates from the normal patient PI3 kinase activity. Inappropriate PI3 kinase activity may take the form of, for example, an abnormal increase in activity or a deviation from the level of normal synchronization and / or regulation of PI3 kinase activity. Such inappropriate activity may then result, for example, from excessive expression or mutation of the protein kinase leading to inappropriate or uncontrolled activation. Thus, in another aspect, the invention relates to methods of treating such disorders.

[0118] Such disorders include respiratory diseases, including asthma, chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF); viral infections, including viral respiratory tract infections and viral exacerbations of respiratory diseases such as asthma and COPD; non-viral respiratory infections, including aspergillosis and leishmaniasis; allergic diseases, including allergic rhinitis and atopic dermatitis; autoimmune diseases, including rheumatoid arthritis and multiple sclerosis; inflammatory disorders, including inflammatory bowel disease; cardiovascular diseases, including thrombosis and atherosclerosis; hematological malignancies; neurodegenerative diseases; inflammation of the pancreas; multi-organ failure; kidney disease; platelet aggregation; tumor; sperm motility; rejection of transplantation; transplant rejection; lung damage; and pain, including pain associated with rheumatoid arthritis or osteoarthritis, back pain, general pain associated with inflammation, liver neuralgia, diabetic neuropathy, inflammatory neuropathic (traumatic) pain, trigeminal neuralgia and central pain. In one embodiment, such disorders include respiratory diseases, including asthma and chronic obstructive pulmonary disease (COPD); allergic diseases, including allergic rhinitis and atopic dermatitis; autoimmune diseases, including rheumatoid arthritis and multiple sclerosis; inflammatory disorders, including inflammatory bowel disease; cardiovascular diseases including thrombosis and atherosclerosis; hematological malignancies; neurodegenerative diseases; inflammation of the pancreas; multi-organ failure; kidney disease; platelet aggregation; tumor; sperm motility; rejection of transplantation; transplant rejection; lung damage; and pain including pain associated with rheumatoid arthritis or osteoarthritis, back pain, general pain associated with inflammation, liver neuralgia, diabetic neuropathy, inflammatory neuropathic (traumatic) pain, trigeminal neuralgia and central pain.

[0119] Methods of treatment according to the invention include administering to a patient in need thereof a safe and effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. Particular embodiments of the invention include methods of treating any of the aforementioned disorders by administering to a patient in need thereof a safe and effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0120] As used herein, the term "treat" in relation to a disorder means: (1) ameliorating or preventing a disorder or one or more biological signs of the disorder, (2) affecting (a) one or more points in a biological cascade that leads to or is responsible for that disorder or affecting (b) one or more biological signs of the disorder, (3) alleviating one or more symptoms or effects associated with the disorder, or (4) slowing the progression of the disorder or one or more biological signs of the disorder. [0121] As indicated above, "treating" the disorder includes preventing the disorder. The skilled person will be aware that "prevention" is not an absolute term. In medicine, "prevention" is understood to refer to the administration of a prophylactic drug to substantially reduce the likelihood or severity of a disorder or its biological sign, or to delay the occurrence of such disorder or its biological sign.

[0122] As used herein, the term "safe and effective amount" when referring to a compound of formula (I) or a pharmaceutically acceptable salt or other pharmaceutically active agent thereof means an amount of the compound sufficient to cure the condition of the patient but small enough to avoid serious effects side effects (with a reasonable risk-benefit ratio) in rational medical evaluation. A safe and effective amount of a compound will vary with the particular compound selected (e.g. including potency, efficacy and half-life of the compound); the chosen route of administration; the disorder being treated; the severity of the disorder being treated; the age, height, weight and physical condition of the patient being treated; medical history of the patient being treated; duration of treatment; the nature of co-administered therapy; the desired therapeutic effect; and similar factors, but nevertheless it can be routinely determined by a skilled person.

[0123] As used herein, the term "patient" refers to a human (including adults and children) or to another animal. In one embodiment, "patient" refers to a human.

[0124] The compounds of formula (I) or pharmaceutically acceptable salts thereof can be administered by any suitable route of administration, including both systemic and topical administration. Systemic administration includes oral administration, parenteral administration, transdermal administration and rectal administration. Parenteral administration refers to routes of administration other than enteral or transdermal administration, and is usually done by injection or infusion. Parenteral administration includes intravenous, intramuscular and subcutaneous injection or infusion. Topical administration includes application to the skin as well as ocular, in-ear, vaginal, inhalation and intranasal administration. Inhalation refers to administration into the patient's lungs, regardless of whether inhalation is through the mouth or nasal passages. In one embodiment, the compounds of formula (I) or pharmaceutically acceptable salts thereof can be administered orally. In another embodiment, the compounds of formula (I) or pharmaceutically acceptable salts thereof can be administered by inhalation. In a further embodiment, the compounds of formula (I) or a pharmaceutically acceptable salt thereof can be administered intranasally.

[0125] The compounds of formula (I) or pharmaceutically acceptable salts thereof can be administered once or according to a dosing schedule in which a number of doses are administered at different time intervals for a given period of time. For example, doses may be administered once, twice, three or four times daily. In one embodiment, the dose is administered once daily. In a further embodiment, the dose is administered twice a day. Doses can be administered until the desired therapeutic effect is achieved or endless to maintain the desired therapeutic effect. Suitable dosage regimens for a compound of formula (I) or a pharmaceutically acceptable salt thereof depend on the pharmacokinetic properties of such a compound, such as absorption, distribution and half-life, which can be determined by one of ordinary skill in the art. In addition, appropriate dosage regimens, including the duration of such regimens, are used for the compound of formula (I) or a pharmaceutically acceptable salt thereof depending on the disorder being treated, the severity of the disorder being treated, the age and physical condition of the patient being treated, and the patient's medical history. the nature of simultaneous therapy, the desired therapeutic effect and similar factors within the knowledge and experience of a specialist. In addition, it will be understood by those skilled in the art that appropriate dosage regimens may need to be adjusted in accordance with the particular patient's response to the dosage regimen or over time with the need to change for the individual patient.

[0126] Typical daily doses may vary depending on the particular route of administration chosen. Typical daily oral dosages range from 0.001 mg to 50 mg per kg of total body weight, for example from 1 mg to 10 mg per kg of total body weight. For example, daily doses for oral administration may range from 0.5 mg to 2 g per patient, such as 10 mg to 1 g per patient.

[0127] In addition, the compounds of formula (I) may be administered as prodrugs. The term "prodrug" of the compound of formula (I) as used herein is a functional derivative of a compound that, when administered to a patient, ultimately releases the compound of formula (I) in vivo. Administration of a compound of formula (I) as a prodrug may enable the skilled person to perform one or more of the following: (a) modifying the onset of compound activity in vivo; (b) modifying the duration of action of the compound in vivo; (c) modifying the transport or distribution of the compound in vivo; (d) modifying the in vivo solubility of the compound; and (e) overcoming a side effect or other difficulty associated with the relationship. Typical functional derivatives used to produce prodrugs include modified forms of the compound that can be chemically or enzymatically cleaved in vivo. Such modified forms, which include the production of phosphates, amides, esters, thioesters, carbonates and carbamates, are well known to those skilled in the art.

[0128] In one aspect, the invention therefore provides a method of treating a disorder mediated by inappropriate PI3 kinase activity, comprising administering to a patient in need a safe and effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In one embodiment, the invention provides a method of treating a disorder mediated by inappropriate PI3 kinase activity, comprising administering to a patient in need thereof a safe and effective amount of N- [5- [4- (526 {[(2R, 6S) -2,6-dimethyl-4- morpholinyl] methyl} -1,3-oxazol-2-yl) -1H-indazol-6-yl] -2- (methyloxy) -3-pyridinyl] methanesulfonamide or a pharmaceutically acceptable salt thereof. In another embodiment, the invention provides a method of treating a disorder mediated by inappropriate PI3 kinase activity, comprising administering to a patient in need thereof a safe and effective amount of N- [5- [4- (5 - {[(2R, 6S) -2 (R) -magdalane, 6-dimethyl-4-morpholinyl] methyl} -1,3-oxazol-2-yl) -1H-indazol-6-yl] -2- (methyloxy) -3-pyridinyl] methanesulfonamide. In another embodiment, the invention provides a method of treating a disorder mediated by inappropriate PI3 kinase activity comprising administering to a patient in need thereof a safe and effective amount of 6- (1H-indol-4-yl) -4- (5 - {[4 (1-methylethyl) -1 -piperazinyl] methyl} -1,3-oxazol-2-yl) -1H-indazole or a pharmaceutically acceptable salt thereof. In a further embodiment, the invention provides a method of treating a disorder mediated by inappropriate PI3 kinase activity, comprising administering to a patient in need thereof a safe and effective amount of 6- (1H-indol-4-yl) -4- (5 - {[4- (1-methylethyl) hydrochloride ) -1-piperazinyl] methyl} -1,3-oxazol-2-yl) -1H-indazole.

[0129] In one embodiment, the disorder mediated by inappropriate PI3 kinase activity is selected from the group consisting of respiratory diseases (including asthma, chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF)); viral infections (including viral respiratory tract infections and viral exacerbations of respiratory diseases such as asthma and COPD); non-viral respiratory tract infections (including aspergillosis and leishmaniasis); allergic diseases (including allergic rhinitis and atopic dermatitis); autoimmune diseases (including rheumatoid arthritis and multiple sclerosis); inflammatory disorders (including inflammatory bowel disease); gastrointestinal diseases (including thrombosis and atherosclerosis); hematological malignancies; neurodegenerative diseases; inflammation of the pancreas; multi-organ failure; kidney disease; platelet aggregation; tumor; sperm motility; rejection of transplantation; transplant rejection; lung damage; and pain (including pain associated with rheumatoid arthritis or osteoarthritis, back pain, general inflammatory pain, liver disease neuralgia, diabetic neuropathy, inflammatory neuropathic (traumatic) pain, trigeminal neuralgia and central pain).

[0130] In one embodiment, the disorder mediated by inappropriate PI3 kinase activity is a respiratory disease. In another embodiment, the disorder mediated by inappropriate PI3 kinase activity is asthma. In another embodiment, the disorder mediated by inappropriate PI3 kinase activity is chronic obstructive pulmonary disease (COPD). In a further embodiment, the disorder mediated by inappropriate PI3 kinase activity is idiopathic pulmonary fibrosis (IPF).

[0131] In one embodiment, the disorder mediated by inappropriate PI3 kinase activity is pain.

[0132] In one embodiment, the present invention provides a method of treating a respiratory disease comprising administering to a patient in need thereof a safe and effective amount of N- [5- [4- (5 - {[(2R, 6S) -2,6-dimethyl-4- morpholinyl] methyl} -1,3-oxazol-2-yl) 1H-indazol-6-yl] -2- (methyloxy) -3-pyridinyl] methanesulfonamide or a pharmaceutically acceptable salt thereof.

[0133] In another embodiment, the present invention provides a method of treating asthma comprising administering to a patient in need thereof a safe and effective amount of N- [5- [4- (5 {[(2R, 6S) -2,6-dimethyl-4-morpholinyl] methyl } -1,3-oxazol-2-yl) -1H-indazol-6-yl] -2 (methyloxy) -3-pyridinyl] methanesulfonamide or a pharmaceutically acceptable salt thereof.

[0134] In another embodiment, the present invention provides a method of treating a respiratory disease comprising administering to a patient in need thereof a safe and effective amount of N- [5- [4- (5 - {[(2R, 6S) -2.6 -dimethyl-4-morpholinyl] methyl} 27

1,3-oxazol-2-yl) -1H-indazol-6-yl] -2- (methyloxy) -3-pyridinyl] methanesulfonamide. [0135] In another embodiment, the present invention provides a method of treating asthma comprising administering to a patient in need thereof a safe and effective amount of N- [5- [4- (5 - {[(2R, 6S) -2,6-dimethyl (R) -migdalane -4-morpholinyl] methyl} -1,3-oxazol-2-yl) -1H-indazol6-yl] -2- (methyloxy) -3-pyridinyl] methanesulfonamide.

[0136] In another embodiment, the present invention provides a method of treating a respiratory disease comprising administering to a patient in need thereof a safe and effective amount of 6- (1H-indol-4-yl) -4- (5 - {[4- (1-methylethyl) - 1-piperazinyl] methyl} -1,3-oxazol-2-yl) -1H-indazole or a pharmaceutically acceptable salt thereof.

[0137] In another embodiment, the present invention provides a method of treating asthma comprising administering to a patient in need thereof a safe and effective amount of 6- (1H-indol-4-yl) -4- (5 - {[4- (1-methylethyl) -1-piperazinyl] methyl} -1,3-oxazol-2-yl) -1H-indazole or a pharmaceutically acceptable salt thereof.

[0138] In another embodiment, the present invention provides a method of treating a respiratory disease comprising administering to a patient in need thereof a safe and effective amount of 6- (1H-indol-4-yl) -4- (5 - {[4- (1-methylethyl) hydrochloride -1-piperazinyl] methyl} -1,3-oxazol-2-yl) -1H-indazole.

[0139] In a further embodiment, the present invention provides a method of treating asthma comprising administering to a patient in need thereof a safe and effective amount of 6- (1H-indol-4-yl) -4- (5 - {[4- (1-methylethyl) -1 hydrochloride piperazinyl] methyl} -1,3-oxazol-2-yl) -1H-indazole.

[0140] In one aspect, the invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in medical therapy. In one embodiment, the invention provides N- [5- [4- (5 - {[(2R, 6S) -2,6-dimethyl-4-morpholinyl] methyl} -1,3-oxazol-2-yl) 1H-indazole -6-yl] -2- (methyloxy) -3-pyridinyl] methanesulfonamide or a pharmaceutically acceptable salt thereof for use in medical therapy. In another embodiment, the invention provides N- [5- [4- (5 - {[(2R, 6S) -2,6-dimethyl-4-morpholinyl] methyl} -1,3-oxazol-2- (R) -migdalate yl) -1H-indazol-6-yl] -2- (methyloxy) -3-pyridinyl] methanesulfonamide for use in medical therapy. In another embodiment, the invention provides 6- (1H-indol-4-yl) -4- (5 {[4- (1-methylethyl) -1-piperazinyl] methyl} -1,3-oxazol-2-yl) -1H -indazole or a pharmaceutically acceptable salt thereof for use in medical therapy. In a further embodiment, the invention provides 6- (1H-indol-4-yl) -4- (5 - {[4- (1-methylethyl) -1-piperazinyl] methyl} -1,3-oxazol-2-yl hydrochloride) -1H-indazole for use in medical therapy.

[0141] In another aspect, the invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of a disorder mediated by inappropriate PI3 kinase activity. In one embodiment, the invention provides N- [5- [4- (5 {[(2R, 6S) -2,6-dimethyl-4-morpholinyl] methyl} -1,3-oxazol-2-yl) -1H-indazole -6-yl] -2 (methyloxy) -3-pyridinyl] methanesulfonamide or a pharmaceutically acceptable salt thereof for use in the treatment of a disorder mediated by inappropriate PI3 kinase activity. In another embodiment, the invention provides N- [5- [4- (5 - {[(2R, 6S) -2,6-dimethyl-4-morpholinyl] methyl} -1,3-oxazol-2-yl) (R) -migdalate. -1H-indazol-6-yl] -2- (methyloxy) -3-pyridinyl] methanesulfonamide for use in the treatment of a disorder mediated by inappropriate PI3 kinase activity. In another embodiment, the invention provides 6- (1Hindol-4-yl) -4- (5 - {[4- (1-methylethyl) -1-piperazinyl] methyl} -1,3-oxazol-2-yl) -1H- indazole or a pharmaceutically acceptable salt thereof for use in the treatment of a disorder mediated by inappropriate PI3 kinase activity. In a further embodiment, the invention provides 6- (1H-indol-4-yl) -4- (5 - {[4- (1-methylethyl) -1-piperazinyl] methyl} -1,3-oxazol-2-yl hydrochloride) -1H-indazole for use in the treatment of a disorder mediated by inappropriate PI3 kinase activity.

[0142] In a further aspect, the invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in the treatment of a disorder mediated by inappropriate PI3 kinase activity. In one embodiment, the invention provides the use of N- [5- [4- (5 - {[(2R, 6S) -2,6-dimethyl-4-morpholinyl] methyl} -1,3-oxazol-2-yl) - 1H-indazol-6-yl] -2- (methyloxy) -3-pyridinyl] methanesulfonamide or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for use in the treatment of a disorder mediated by inappropriate PI3 kinase activity. In another embodiment, the invention provides the use of N- [5- [4- (5 - {[(2R, 6S) -2,6-dimethyl-4-morpholinyl] methyl} -1,3-oxazol-2-yl (R) -daldalane ) -1H-indazol-6-yl] -2- (methyloxy) -3-pyridinyl] methanesulfonamide for the manufacture of a medicament for use in the treatment of a disorder mediated by inappropriate PI3 kinase activity. In another embodiment, the invention provides the use of 6- (1H-indol-4-yl) -4- (5 - {[4- (1-methylethyl) -1-piperazinyl] methyl} -1,3-oxazol-2-yl) -1H-indazole or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for use in the treatment of a disorder mediated by inappropriate PI3 kinase activity. In a further embodiment, the invention provides the use of 6- (1H-indol-4-yl) -4- (5 - {[4- (1-methylethyl) -1-piperazinyl] methyl} -1,3-oxazol-2-yl hydrochloride ) 1H-indazole for the manufacture of a medicament for use in the treatment of a disorder mediated by inappropriate PI3 kinase activity.

Compositions [0143] The compounds of formula (I) and pharmaceutically acceptable salts thereof will usually, but not necessarily, be formulated into pharmaceutical compositions prior to administration to a patient.

[0144] Accordingly, in one aspect, the invention relates to pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

[0145] In one embodiment, the present invention provides a pharmaceutical composition comprising N- [5- [4- (5 - {[(2R, 6S) -2,6-dimethyl-4-morpholinyl] methyl} -1,3-oxazol- 2-yl) -1Hindazol-6-yl] -2- (methyloxy) -3-pyridinyl] methanesulfonamide or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients. [0146] In another embodiment, the present invention provides a pharmaceutical composition comprising N- [5- [4- (5 - {[(2R, 6S) -2,6-dimethyl-4-morpholinyl] methyl} -1 (R) -daldalane , 3-oxazol-2-yl) -1H-indazol-6-yl] -2- (methyloxy) -3-pyridinyl] methanesulfonamide, and one or more pharmaceutically acceptable excipients.

[0147] In another embodiment, the present invention provides a pharmaceutical composition comprising 6- (1H-indol-4-yl) -4- (5 - {[4- (1-methylethyl) -1-piperazinyl] methyl} -1.3 -oxazol-2-yl) -1H-indazole or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

[0148] In a further embodiment, the present invention provides a pharmaceutical composition comprising 6- (1H-indol-4-yl) -4- (5 - {[4- (1-methylethyl) -1-piperazinyl] methyl} -1 hydrochloride, 3-oxazol-2-yl) -1H-indazole, and one or more pharmaceutically acceptable excipients.

[0149] In another aspect, the invention relates to pharmaceutical compositions comprising 0.05 to 1000 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof, and 0.1 to 2 g of one or more pharmaceutically acceptable excipients.

[0150] In a further aspect, the invention relates to a pharmaceutical composition, comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, for the treatment or prevention of a disorder mediated by inappropriate PI3 kinase activity.

[0151] In one embodiment, the present invention provides a pharmaceutical composition comprising N- [5- [4- (5 - {[(2R, 6S) -2,6-dimethyl-4-morpholinyl] methyl} -1,3- oxazol-2-yl) -1H-indazol-6-yl] -2- (methyloxy) -3-pyridinyl] methanesulfonamide or a pharmaceutically acceptable salt thereof, for the treatment or prevention of a disorder mediated by inappropriate PI3 kinase activity.

[0152] In one embodiment, the present invention provides a pharmaceutical composition comprising N- [5- [4- (5 - {[(2R, 6S) -2,6-dimethyl-4-morpholinyl] methyl} (R) -daldalate -1,3-oxazol-2-yl) -1H-indazol-6-yl] -2- (methyloxy) -3-pyridinyl] methanesulfonamide, for the treatment or prevention of a disorder mediated by inappropriate PI3 kinase activity.

[0153] In one embodiment, the present invention provides a pharmaceutical composition comprising 6- (1H-indol-4-yl) -4- (5 - {[4- (1-methylethyl) -1-piperazinyl] methyl} -1.3 -oxazol-2-yl) -1H-indazole or a pharmaceutically acceptable salt thereof, for the treatment or prevention of a disorder mediated by inappropriate PI3 kinase activity.

[0154] In a further embodiment, the present invention provides a pharmaceutical composition comprising 6- (1H-indol-4-yl) -4- (5 - {[4- (1-methylethyl) -1-piperazinyl] methyl} -1 hydrochloride, 3-oxazol-2-yl) -1H-indazole, for the treatment or prevention of a disorder mediated by inappropriate PI3 kinase activity.

[0155] The pharmaceutical compositions of the invention may be prepared and packaged in bulk forms, such as powder and syrup forms, in which a safe and effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof can be obtained and then administered to a patient. Alternatively, the pharmaceutical compositions of the invention may be prepared and packaged in unit dosage form, each physically discrete unit containing a compound of formula (I) or a pharmaceutically acceptable salt thereof. When preparing a unit dosage form, the pharmaceutical compositions of the invention may typically contain, for example, from 0.5 mg to 1 g, or from 1 mg to 700 mg, or from 5 mg to 100 mg of a compound of formula (I) or a pharmaceutically acceptable compound thereof acceptable salt.

[0156] The pharmaceutical compositions of the invention typically contain one compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0157] The term "pharmaceutically acceptable excipient," as used herein, means a pharmaceutically acceptable substance, composition or vehicle contributing to the formulation of the pharmaceutical composition or consistency. Each excipient must be compatible with the other ingredients of the pharmaceutical composition when mixed with them, thus avoiding interactions that, when administered to a patient of the compound of formula (I) or a pharmaceutically acceptable salt thereof, would significantly reduce its effectiveness and result in the formation of pharmaceutical compositions that would be pharmaceutically unacceptable. In addition, each excipient must of course be pharmaceutically acceptable, e.g. of sufficiently high purity.

[0158] The compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or excipients will usually be formulated into dosage forms adapted for administration to the patient by the desired route of administration. For example, dosage forms include those adapted for (1) oral administration, such as tablets, capsules, caplets, pills, troches, powders, syrups, elixirs, suspensions, solutions, emulsions, sachets and cachets; (2) parenteral administration, such as sterile solutions, suspensions and powders for reconstitution; (3) transdermal administration, such as transdermal patches; (4) rectal administration, such as suppositories; (5) inhalations such as aerosols, solutions and dry powders; and (6) topical administration, such as creams, ointments, lotions, solutions, pastes, sprays, foams and gels.

[0159] Suitable pharmaceutically acceptable excipients will vary depending on the particular dosage form selected. In addition, suitable pharmaceutically acceptable excipients may be selected for the particular function they may perform in the composition. For example, some pharmaceutically acceptable excipients may be selected for their ability to facilitate the production of uniform dosage forms. Certain pharmaceutically acceptable excipients can be selected for their ability to facilitate the production of stable dosage forms. Certain pharmaceutically acceptable excipients may be chosen for their ability to facilitate the transfer or transport of a compound or compounds of formula (I) or its / their pharmaceutically acceptable salts administered to a patient from one organ or body part to another organ or body part. Certain pharmaceutically acceptable excipients can be chosen because of their ability to increase patient compliance. [0160] Suitable pharmaceutically acceptable excipients include the following types of excipients: diluents, bulking agents, binders, disintegrating agents, lubricants, glidants, granulating agents, coating agents, wetting agents, solvents, cosolvents, suspending agents, emulsifying agents, sweeteners, flavors, taste masking agents , coloring agents, anti-caking agents, humectants, chelating agents, plasticizers, viscosifiers, antioxidants, preservatives, stabilizing agents, surfactants and buffering agents. The skilled person will be aware that certain pharmaceutically acceptable excipients may have more than one function and may perform alternative functions depending on the amount of excipient present in the formulation and what other ingredients are present in the formulation.

[0161] Those skilled in the art possess knowledge and qualifications in the art to enable them to select suitable pharmaceutically acceptable excipients in the right amounts for use according to this invention. In addition, there are many sources available to those skilled in the art that describe pharmaceutically acceptable excipients and may be useful in selecting suitable pharmaceutically acceptable excipients. Examples include Remington's Pharmaceutical Sciences (Mack Publishing Company), The Handbook of Pharmaceutical Additives (Gower Publishing Limited) and The Handbook of Pharmaceutical Excipients (the American Pharmaceutical Association and the Pharmaceutical Press).

[0162] The pharmaceutical compositions of the invention are prepared using techniques and methods known to those skilled in the art. Some of the methods commonly used in the art are described in Remington's Pharmaceutical Sciences (Mack Publishing Company).

[0163] Thus, in another aspect, the invention relates to a process for preparing a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients, which comprises mixing the ingredients. A pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt thereof can be prepared, for example, by preparing the mixture at ambient temperature and atmospheric pressure.

[0164] In one embodiment, the compounds of formula (I) or pharmaceutically acceptable salts thereof will be formulated for oral administration. In another embodiment, the compounds of formula (I) or pharmaceutically acceptable salts thereof will be formulated for administration by inhalation. In a further embodiment, the compounds of formula (I) or pharmaceutically acceptable salts thereof will be formulated for nasal administration.

[0165] In one aspect, the invention relates to a solid oral dosage form, such as a tablet or capsule, comprising a safe and effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a diluent or bulking agent. Suitable diluents and bulking agents include lactose, sucrose, dextrose, mannitol, sorbitol, starch (e.g., corn starch, potato starch and pregelatinized starch), cellulose and its derivatives (e.g. microcrystalline cellulose), calcium sulfate and dibasic calcium phosphate. Oral solid dosage forms may further include a binder. Suitable binders include starch (e.g. corn starch, potato starch and pregelatinized starch), gelatin, acacia, sodium alginate, alginic acid, tragacanth, guar gum, povidone and cellulose and its derivatives (e.g. microcrystalline cellulose). The oral solid dosage form may also contain a disintegrant. Suitable disintegrants include crospovidone, sodium starch glycolate, croscarmellose, alginic acid and sodium carboxymethyl cellulose. The oral solid dosage form may further comprise a glidant. Suitable lubricants include stearic acid, magnesium stearate, calcium stearate and talc.

[0166] Where appropriate, dosage unit formulations for oral administration may be microencapsulated. The composition can also be prepared to release in a sustained or long-lasting manner, such as by coating or embedding a compound in particulate form in polymers, wax and the like.

[0167] The compounds of formula (I) or pharmaceutically acceptable salts thereof can also be coupled with soluble polymers as drug carriers capable of directing the drug. Such polymers may include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspartamide-phenol or polyethylene oxide poly substituted with palimitooyl residues. In addition, the compounds of formula (I) or their pharmaceutically acceptable salts can be coupled with a class of biodegradable polymers useful for obtaining controlled drug release, e.g. poly (lactic acid), poly (epsilon-caprolactone), poly (hydroxybutyric acid), polyorthoesters, polyacetals , polydihydropyrans, policanoacrylates and cross-linked or amphipathic hydrogel block copolymers.

[0168] In another aspect, the invention relates to a liquid oral dosage form. Oral liquids, such as solution, syrups and elixirs, can be prepared in the form of a dosage unit, such that a given portion contains a predetermined amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof. Syrups can be prepared by dissolving the compound of formula (I) or a pharmaceutically acceptable salt thereof in a suitable aqueous flavored solution, and elixirs are prepared by using a non-toxic alcoholic base. Suspensions may be formulated by dispersing the compound of formula (I) or a pharmaceutically acceptable salt thereof in a non-toxic vehicle. Solubilizing and emulsifying agents such as ethoxylated isostearyl alcohols and polyoxyethylene sorbitol ethers, preservatives, flavor additive such as peppermint oil or natural sweeteners or saccharin or other artificial sweeteners and the like may also be added.

[0169] In another aspect, the invention relates to a dosage form adapted for administration to a patient by inhalation, for example as a dry powder, aerosol, suspension or solution composition. In one embodiment, the invention relates to a dosage form adapted for administration to a patient by inhalation as a dry powder. In a further embodiment, the invention relates to a dosage form adapted for administration to a patient by inhalation via a nebulizer.

[0170] &lt;inhalable dry powder compositions for pulmonary delivery typically contain a compound of formula (I) or a pharmaceutically acceptable salt thereof as a finely divided powder together with one or more pharmaceutically acceptable excipients as finely divided powders. Pharmaceutically acceptable excipients particularly suitable for use in dry powders are known to those skilled in the art and include lactose, starch, mannitol and mono-, di- and polysaccharides. The finely divided powder can be made, for example, by micronization and milling. Generally, a particulate compound (e.g., micronized) can be determined by a D50 value of about 1 to about 10 microns (e.g., as measured by laser diffraction).

[0171] The dry powder can be administered to a patient through a reservoir-type dry powder inhaler (RDPI) having a reservoir suitable for storing multiple doses of drug (unmeasured doses) as a dry powder. RDPI inhalers typically include means for measuring each dose of drug from the reservoir to the administration position. For example, metering means may include a dispensing vessel that is movable from a first position in which the vessel can be filled with drug from the reservoir to a second position in which the measured dose of drug becomes available to the patient by inhalation.

[0172] Alternatively, the dry powder may be presented in capsules (e.g., gelatin or plastic), cartridges or blister packs for use in a multi-dose dry powder inhaler (MDPI). MDPI inhalers are inhalers in which the medicine is contained in a multi-dose pack containing (or otherwise containing) multiple defined doses of the drug (or parts thereof). When a dry powder is presented as a blister pack, it contains many blisters for storing the drug in the form of a dry powder. The leaflets are usually arranged regularly for easy release of the drug from them. For example, the leaves may typically be arranged in a circular manner on the blister pack in the form of a disc, or the leaves may have an elongated form, e.g. Each capsule, cartridge or blister may contain, for example between 20 μg - 10 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0173] Aerosols can be formed by suspending or dissolving a compound of formula (I) or a pharmaceutically acceptable salt thereof in a liquefied propellant. Suitable propellants include halohydrocarbons, hydrocarbons and other liquefied gases. Representative propellants include: trichlorofluoromethane (propellant 11), dichlorofluoromethane (propellant 12), dichlorotetrafluoroethane (propellant 114), tetrafluoroethane (HFA-134a), 1,1-difluoroethane (HFA-152a), difluoromethane (HFA-32), pf HFA-12), heptafluoropropane (HFA-227a), perfluoropropane, perfluorobutane, perfluoropentane, butane, isobutane and pentane. Aerosols containing a compound of formula (I) or a pharmaceutically acceptable salt thereof will usually be administered to a patient via a metered dose inhaler (MDI). Such devices are well known to those skilled in the art.

[0174] The aerosol may contain additional pharmaceutically acceptable excipients commonly used in MDI inhalers, such as surfactants, glidants, cosolvents and other excipients to improve the physical stability of the formulation, to improve valve function, to improve solubility or to improve taste.

[0175] As a further aspect of the invention, therefore, there is provided a pharmaceutical formulation in the form of an aerosol containing a compound of formula (I) or a pharmaceutically acceptable salt thereof and, as a propellant, a fluorocarbon or a hydrogen containing chlorofluorocarbon, optionally in combination with a surfactant and / or cosolvent.

[0176] According to another aspect of the invention, there is provided a pharmaceutical formulation in the form of an aerosol wherein the propellant is selected from 1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoro-n - propane and mixtures thereof.

[0177] The formulations of the invention can be buffered by the addition of appropriate buffering agents.

[0178] Capsules and cartridges of, for example, gelatin, for use in an inhaler and insufflator, can be formulated that they contain a powder mixture for administration by inhalation, containing a compound of formula (I) or a pharmaceutically acceptable salt thereof and a suitable powder base, such as lactose or starch. Each capsule or cartridge may typically contain from 20 μg to 10 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof. Alternatively, the compound of formula (I) or a pharmaceutically acceptable salt thereof may be provided without excipients such as lactose.

[0179] The proportion of active compound of formula (I) or a pharmaceutically acceptable salt thereof in the topical compositions of the invention depends on the exact type of preparation being prepared, but will generally be in the range of 0.001 to 10% by weight. Usually, however, for most types of preparations the proportion used will be in the range of 0.005 to 1%, for example 0.01 to 0.5%. However, in powders for administration by inhalation or insufflation, the proportion used will generally be in the range of 0.1 to 5%.

[0180] Aerosol formulations are prepared in such a way that each metered dose or 'inhalation / blow' of the aerosol contains from 20 μg - 10 mg, preferably from 20 μg to 2000 μg, more preferably from about 20 μg to 500 μg of formula (I). Administration can be carried out once or several times a day, for example 2, 3, 4 or 8 times, for example by administering 1, 2 or 3 doses each time. The total daily dose administered by aerosol will be in the range from 100 μg to 10 mg, preferably from 200 μg to 2000 μg. The total daily dose and metered dose delivered with capsules or cartridges in the inhaler or insufflator will usually be twice the dose administered in aerosol formulations.

[0181] In the case of aerosol preparations in the form of a suspension, the particle size of the drug in the form of particles (e.g. micronized) should be such as to allow inhalation of substantially all of the drug into the lungs after administration of the aerosol formulation and will therefore be below 100 microns, desirability below 20 microns, and especially in the range from 1 to 10 microns, such as from 1 to 5 microns, more preferably from 2 to 3 microns.

[0182] The formulations of the invention can be prepared by dispersing or dissolving the drug and the compound of formula (I) or a pharmaceutically acceptable salt thereof in a selected propellant in a suitable container, for example by using ultrasound or a high shear mixer. The process is conveniently carried out under controlled humidity conditions.

[0183] The chemical and physical stability and pharmaceutical acceptability of the aerosol formulations of the invention can be determined by techniques well known to those skilled in the art. Thus, for example, the chemical stability of the ingredients can be determined by HPLC, for example, after prolonged storage of the product. Data on physical stability can be obtained from other common analytical techniques, such as, for example, by leakage testing, valve delivery test (average dose weight per actuation), dose repeatability test (active ingredient per actuation) or spray distribution analysis.

[0184] The stability of aerosol suspensions according to the invention can be measured by conventional techniques, for example, by measuring the flocculation size distribution using a backscatter measuring device or by measuring the particle size distribution by cascade collision or by using a dual impact impactor analytical procedure ( "Twin impinger"). Reference to the "twin impinger" trial here means "Determination of release dose deposition in pressurized inhalations using apparatus A" as defined in British Pharmacopaeia 1988, pages A204-207, Annex XVII C. Such techniques allow the calculation of the "inhalable fraction" of aerosol formulations. One method used to calculate the "inhalable fraction" refers to the "fine particle fraction", which is the amount of active ingredient collected in the lower chamber of the impactor during one run expressed as a percentage of the total amount of active ingredient delivered during one run determined using the "twin impinger" method described above ".

[0185] The term "metered dose inhaler" or MDI means a unit comprising a can, a fixed closure covering the can, and a metering valve for the formulation placed in the closure. The MDI system includes an appropriate orientation device. Suitable targeting devices include, for example, a valve actuator and a cylindrical or conical passage through which the drug can be delivered from a filled reservoir through a metering valve to the patient's nose or mouth, such as an actuator with a mouthpiece.

[0186] MDI reservoirs usually consist of a container that is able to withstand the vapor pressure of the propellant used, such as a plastic or glass-coated plastic bottle, or, preferably, a metal can, for example, aluminum or aluminum alloy, which can optionally be anodized , coated with varnish and / or plastic (for example incorporated herein by reference WO96 / 32099, wherein some or all of the inner surfaces are coated with one or more polymers of fluorinated hydrocarbons, optionally in combination with one or more polymers of compounds other than fluorocarbons), which container is closed by means of a metering valve. The closure can be securely attached to the can by ultrasonic welding, bolted connection or crimping. The MDI reservoirs discussed herein can be made by methods of the prior art (e.g., see Byron, above and WO96 / 32099). Preferably the reservoir is fitted with a closure assembly in which the drug metering valve is located inside the closure and said closure is clamped in place.

[0187] In one embodiment of the invention, the metal inner surface of the can is coated with a fluoropolymer, preferably mixed with a polymer other than the fluoropolymer. In another embodiment of the invention, the metal inner surface of the can is coated with a blend of polytetrafluoroethylene (PTFE) and polyether sulfone (PES) polymers. In a further embodiment of the invention, the metal inner surface of the can is entirely covered with a blend of polytetrafluoroethylene (PTFE) and polyether sulfone (PES) polymers.

[0188] The metering valves are designed to deliver a metered amount of formulation per actuation and to introduce a seal to prevent leakage of propellant through the valve. The seal may consist of any elastomeric material such as low density polyethylene, chlorobutyl, bromobutyl, EPDM, black and white acrylonitrile butadiene rubbers, butyl rubber and neoprene. Suitable valves are commercially available from manufacturers well known in the aerosol industry, for example from Valois, France (e.g. DF10, DF30, DF60), Bespak plc, UK (e.g. BK300, BK357) and 3M-Neotechnic Ltd, UK (e.g. Spraymiser^™).

[0189] In various embodiments, MDI inhalers can also be used in conjunction with other components such as, but not limited to, wrapping packages for storage and containing MDI inhalers, including those described in US Patent Nos. 6,119,853; 6179118; 6315112; 6352152; 6390291; and 6,679374, as well as such dose counting devices such as, but not limited to, those described in US Patent Nos. 6,360,739 and 6,431,168.

[0190] For the production of large batches for the commercial production of filled storage tanks, conventional mass production methods and machines known to those skilled in the art of pharmaceutical aerosols can be used. Thus, for example, in one massive method of producing aerosol formulations in the form of a slurry, the metering valve is clamped onto an aluminum can to form an empty reservoir. The drug in the form of particles is added to the batch vessel and the production vessel is filled under pressure with the liquefied propellant together with any excipients under pressure. The drug suspension is mixed prior to circulation into the filling machine and then filled into the reservoir via a metering valve with a portion of the drug suspension. In one example of a massive method of producing aerosol formulations in solution, a metering valve is clamped onto an aluminum can to form an empty reservoir. The production vessel is filled under pressure with liquefied propellant together with any excipients and dissolved drug under pressure.

[0191] In an alternative method, a portion of the liquefied formulation is added to the open reservoir at a low enough temperature so that the formulation does not evaporate, and then the metering valve on the reservoir is clamped.

[0192] Typically, in batches made for pharmaceutical use, each filled reservoir is checked for weight, marked with a batch number code and packed on a pallet for storage before carrying out the release test.

[0193] Suspensions and solutions containing a compound of formula (I) or a pharmaceutically acceptable salt thereof can also be administered to a patient via a nebulizer. The solvent or suspending agent used for nebulization may be any pharmaceutically acceptable liquid, such as water, aqueous saline, alcohols or glycols, e.g., ethanol, isopropyl alcohol, glycerol, propylene glycol, polyethylene glycol, etc., or mixtures thereof. Saline solutions use salts that show little or no pharmacological activity after administration. For this purpose, organic salts such as alkali or ammonium metal halide salts, e.g. sodium chloride, potassium chloride, as well as organic salts such as potassium, sodium and ammonium / ammonium salts, and organic acids, e.g. acid ascorbic, citric acid, acetic acid, tartaric acid, etc.

[0194] Other pharmaceutically acceptable excipients may be added to the suspension or solution. The compound of formula (I) or a pharmaceutically acceptable salt thereof can be stabilized by the addition of an inorganic acid, e.g. hydrochloric acid, nitric acid, sulfuric acid and / or phosphoric acid; organic acid, e.g. ascorbic acid, citric acid, acetic acid and tartaric acid, etc .; a complexing agent such as EDTA or citric acid and their salts; or an antioxidant such as vitamin E or ascorbic acid. These compounds can be used alone or together to stabilize the compound of formula (I) or a pharmaceutically acceptable salt thereof. Preservatives such as benzalkonium chloride or benzoic acid and its salts can be added. Surfactants can be added in particular to improve the physical stability of suspensions. These include lecithin, disodium dioctyl sulfosuccinate, oleic acid and sorbitan esters.

[0195] In a further aspect, the invention relates to a dosage form adapted for nasal administration.

[0196] Formulations for topical nasal administration may include pressurized aerosol formulations and aqueous formulations administered to the nose by means of a pressure pump. Of particular interest are preparations that are not under pressure and are adapted for topical administration to the nasal cavity. To this end, appropriate formulations contain water as the diluent or carrier. Aqueous formulations for pulmonary or nasal administration may be delivered using conventional excipients such as buffering agents, tonicity modifying agents and the like. Aqueous preparations can also be administered through the nose by nebulization.

[0197] The compounds of formula (I) or pharmaceutically acceptable salts thereof may be formulated in a liquid preparation for administration from a fluid delivery device, for example a fluid delivery device having a dispensing nozzle or dispensing orifice through which a measured dose is administered liquid formulation after applying a force applied by the user to the pump mechanism of the fluid dispensing device. Such fluid dosing devices are usually equipped with a reservoir containing a plurality of metered doses of the liquid formulation, these doses being possible to release after subsequent pump starts. The dispensing nozzle or orifice can be configured to introduce sprayed liquid into the user's nostrils by dispensing a liquid formulation into the nasal cavity. A fluid dispensing device of the said type is described and illustrated in WO05 / 044354, the content of which is fully incorporated herein by reference. The dosing device has a housing that houses a fluid release device with a compression pump mounted on a container for storing the liquid formulation. The housing has at least one finger-operated side lever that can move toward the interior of the housing to move the container up in the housing, causing the pump to compress and pump the metered dose outside the pump channel through the housing's nasal nozzle. In one embodiment, the fluid dispensing device is generally of the type as illustrated in Figures 30-40 in WO05 / 044354.

[0198] Pharmaceutical compositions adapted for nasal administration, in which the carrier is solid and includes a coarse powder with a particle size in the range of, for example, 20 to 500 microns, which is administered by rapid inhalation through the nasal passage from a container containing the powder held close to the nose. Suitable compositions in which the carrier is a liquid for administration as a nasal spray or nasal drops include aqueous or oily solutions of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0199] Pharmaceutical compositions adapted for transdermal administration may be presented as independent patches intended to be in close contact with the patient's epidermis for a prolonged period of time. For example, the active ingredient may be delivered from the patch by iontophoresis as described generally in Pharmaceutical Research, 3 (6), 318 (1986).

[0200] Pharmaceutical compositions adapted for topical administration can be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils.

[0201] Ointments, creams and gels may for example be formulated using an aqueous or oily base with the addition of a suitable thickening and / or gelling agent and / or solvents. Such substrates may thus, for example, include water and / or oil, such as liquid paraffin or vegetable oil, such as peanut oil or castor oil, or a solvent such as polyethylene glycol. Thickening agents and gelling agents that can be used depending on the nature of the substrate include petrolatum, aluminum stearate, cetostearyl alcohol, polyethylene glycols, wool fat, beeswax, carboxypolymethylene and cellulose derivatives, and / or glyceryl monostearate and / or nonionic emulsifiers.

[0202] Lotions may be formulated using an aqueous or oily base and will generally contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents or thickening agents.

[0203] Powders for external use may be formed using any suitable powder base, for example talc, lactose or starch. Drops can be formulated with an aqueous or non-aqueous base also containing one or more dispersants, solubilizers, suspending agents or preservatives.

[0204] Formulations for topical administration may be administered in one or more treatments per day to the occupied surfaces; occlusive dressings can be advantageously applied to skin surfaces. Continuous or extended delivery can be achieved through a tank type adhesive system.

[0205] For treatment of the eye or other external tissues, for example mouth and skin, the compositions may be applied as a topical ointment or cream. When formulating in an ointment, the compound of formula (I) or a pharmaceutically acceptable salt thereof can therefore be used with a paraffinic or water-miscible ointment base. Alternatively, the compound of formula (I) or a pharmaceutically acceptable salt thereof may therefore be formulated in an oil-in-water cream or water-in-oil cream base.

[0206] Pharmaceutical compositions adapted for parenteral administration include aqueous and non-aqueous sterile injectable solutions that may contain antioxidants, buffers, bacteriostatic agents and solutes that make the preparation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may contain suspending agents and thickening agents. The compositions can be presented in single-dose or multi-dose containers, for example, sealed ampoules or vials, and can be stored in a freeze-dried (lyophilized) state and only require the addition of a sterile liquid carrier, e.g. water for injection, immediately before use. Injectable solutions and suspensions prepared immediately before use can be prepared from sterile powders, granules and tablets.

[0207] The compound and pharmaceutical preparations of the invention may be used in combination with or include one or more other therapeutic agents, e.g. selected from anti-inflammatory agents, anti-cholinergic agents (especially M1 / ​​M2 / M3 receptor antagonists), e2-adrenergic receptor agonists, anti-infective agents such as antibiotics or anti-viral agents, or antihistamines. Thus, in a further aspect, the invention provides a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof together with one or more other therapeutically active agents, for example selected from an anti-inflammatory agent such as a corticosteroid or NSAID, an anti-cholinergic agent, a receptor agonist e2-adrenergic, anti-infective agent such as an antibiotic or anti-viral agent, or antihistamines. One embodiment of the invention includes combinations comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof together with an e2-adrenoceptor agonist and / or an anti-cholinergic agent and / or a PDE-4 inhibitor and / or an antihistamine.

[0208] In one embodiment, the invention includes a method of treating a disorder mediated by inappropriate PI3 kinase activity, comprising administering a safe and effective amount of a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof together with one or more therapeutically active agents. [0209] Some compounds of the invention may exhibit PI3KiS selectivity over other PI3 kinases. Thus, in a further aspect, the invention provides a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof which (s) is selective for PI3KiS, together with the compound or a pharmaceutically acceptable salt thereof which (s) is selective for other PI3 kinase, e.g. PI3Ky.

[0210] One embodiment of the invention includes combinations comprising one or more other therapeutic agents.

[0211] It will be clear to a person skilled in the art that, if appropriate, the other therapeutic component (s) may be used in the form of salts, for example as salts with alkali metals or with amines or as acid addition salts, or prodrugs or esters, e.g. lower alkyl esters, or slowates, e.g. hydrates to optimize the activity and / or stability and / or physical properties such as solubility of the therapeutic component. It will also be clear that, if appropriate, the therapeutic ingredients may be used in optically pure form.

[0212] In one embodiment, the invention includes a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof with an e2-adrenoceptor agonist.

[0213] Examples of e2-adrenoreceptor agonists include salmeterol (which may be a racemate or single enantiomer, such as the R enantiomer), salbutamol (which may be a racemate or single enantiomer, such as the R enantiomer), formoterol (which may be a racemate or a single diastereomer, such as the R, R) diastereomer, salmefamol, phenoterol, carmoterol, etanterol, naminterol, clenbuterol, pirbuterol, flerbuterol, reproterol, bamboouterol, indacaterol, terbutaline and their salts, e.g. salmeterol xinafoate (1-hydroxy-2-naphthalenecarboxylate) salt, salbutamol sulfate or free base, or formoterol fumarate salt. In one embodiment, long-acting e2-adrenoceptor agonists are preferred, for example compounds that provide effective bronchodilation for about 12 hours or more.

[0214] Other e2-adrenoreceptor agonists include those agonists described in WO 02/066422, WO 02/070490, WO 02/076933, WO 03/024439, WO 03/072539, WO 03/091204, WO 04/016578, WO 2004/022547, WO 2004/037807, WO 2004/037773, WO 2004/037768, WO 2004/039762, WO 2004/039766, WO01 / 42193 and WO03 / 042160.

[0215] Examples of e2-adrenoreceptor agonists include:

- (4 - {[6 - ({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) hexyl] oxy} butyl) benzenesulfonamide;

- (3 - {[7 - ({(2R) -2-hydroxy-2- [4-hydroxy-3-hydroxymethyl) phenyl] ethyl} amino) heptyl] oxy} propyl) benzenesulfonamide;

4- {1 R) -2 - [(6- {2 - [(2,6-dichlorobenzyl) oxy] ethoxy} hexyl) amino] -1-hydroxyethyl} 2- (hydroxymethyl) phenol;

4- {(1R) -2 - [(6- {4- [3- (cyclopentylsulfonyl) phenyl] butoxy} hexyl) amino] -1-hydroxyethyl} -2- (hydroxymethyl) phenol;

N- [2-hydroxy-5 - [(1R) -1-hydroxy-2 - [[2-4 - [[(2R) -2-hydroxy-2-phenylethyl] amino] phenyl] ethyl] amino] ethyl] phenyl] formamide;

N-2- {2- [4- (3-phenyl-4-methoxyphenyl) aminophenyl] ethyl} -2-hydroxy-2- (8-hydroxy-2 (1H) -quinolinone-5-yl) ethylamine; and

5- [(R) -2- (2- {4- [4- (2-amino-2-methylpropoxy) phenylamino] phenyl} ethylamino) -1-hydroxyethyl] -8-hydroxy-1H-quinolin-2-one.

[0216] The e2-adrenoceptor agonist may be in the form of a salt formed with a pharmaceutically acceptable acid selected from sulfuric, hydrochloric, fumaric, hydroxynaphthoic acid (e.g., 1- or 3-hydroxy-2-naphthoic acid), cinnamic, substituted cinnamic acid, triphenylacetic, sulfamic, sulfanil, naphthaleneacrylate, benzoic, 4-methoxybenzoic, 2- or 4-hydroxybenzoic, 4-chlorobenzoic and 4-phenylbenzoic.

[0217] Suitable anti-inflammatory agents include corticosteroids. Suitable corticosteroids that can be used in conjunction with compounds of formula (I) or pharmaceutically acceptable salts thereof are oral or inhaled corticosteroids and their prodrugs that have anti-inflammatory activity. Examples include methylprednisolone, prednisolone, dexamethasone, fluticasone propionate, 6a, 9a-difluoro -11e-hydroxy-16a-methyl-17a - S-fluoromethyl ester - [(4-methyl-1,3-thiazole-5-carbonyl) oxy] -3-oxoandrosta-1,4-diene-17e-thiocarboxylic acid, 6a, 9a-difluoro-17a acid 5-fluoromethyl ester - [(2-furanylcarbonyl) oxy] -11e-hydroxy-16a-methyl-3-oxoandrost -1.4-diene-17e-thiocarboxylic (fluticasone furoate), 5- (2-oxotetrahydrofuran-3S-yl) ester of 6a, 9a-difluoro-11e-hydroxy-16a-methyl-3-oxo-17a-propionyloxyandrosta-1,4-diene-17e-thiocarboxylic acid, 5-cyanomethyl acid ester 6α, 9αdifluoro-11e-hydroxy-16a-methyl-3-oxo-17- (2,2,3,3-tetramethylcyclopropylcarbonyl) oxyandrost-1,4-diene-17e-thiocarboxylic acid and S-fluoromethyl ester 6a, 9a- difluoro-11 β-hydroxy-16a-methyl-17α- (1-methylcyclopropylcarbonyl) oxo-3 oxoandrost-1,4-diene-17e-thiocarboxylic acid, beclometasone esters (e.g. 17-propionate ester or 17,21-dipropionate ester), budesonide, flunizolide, mometasone esters (e.g. mometasone furonate), triamcinolone acetonide, rofleponide, ciclesonide (16α, 17 - [[(R) -cyclohexylmethylene]] bis (oxy)] - 11 β, 21-dihydroxypregna-1,4-diene-3,20-dione), butoxocort propionate, RPR-106541 and ST-126. Preferred corticosteroids include fluticasone propionate, 6a, 9a-difluoro-11e-hydroxy16a-methyl-17a - 5 (fluoromethyl ester) - [(4-methyl-1,3-thiazole-5-carbonyl) oxy] -3-oxoandrosta-1, 4-diene-17-ethiocarboxylic acid, 6a, 9a-difluoro-17a - [(2-furanylcarbonyl) oxy] -11e-hydroxy-16a-methyl-3-oxoandrosta-1,4-diene-17e-thiocarboxylic acid 5-fluoromethyl ester, 6a, 9a-difluoro-11e-hydroxy-16a-methyl-3-oxo-17a (2,2,3,3-tetramethylcyclopropylcarbonyl) oxy-androsta-1,4-diene-17e-thiocarboxylic acid 5-cyanomethyl ester and ester 6a, 9a-difluoro-11e-hydroxy-16a-methyl-17- (1-methylcyclopropylcarbonyl) oxy-3-oxoandrosta-1,4-diene-17e-thiocarboxylic acid 5-fluoromethyl. In one embodiment, the corticosteroid is 6a, 9a-difluoro-17a - [(2-furanylcarbonyl) oxy] -11 β-hydroxy-16a-methyl-3-oxoandrosta-1,4-diene-17e-thiocarboxylic acid S-fluoromethyl ester.

[0218] Examples of corticosteroids may include those described in WO2002 / 088167, WO2002 / 100879, WO2002 / 12265, WO2002 / 12266, WO2005 / 005451, WO2005 / 005452, WO2006 / 072599 and WO2006 / 072600.

[0219] Nonsteroidal glucocorticoid agonism compounds that may exhibit transrepression selectivity for transactivation and which may be useful in combination therapy include agents covered by the following patents: WO03 / 082827, WO98 / 54159, WO04 / 005229, WO04 / 009017, WO04 / 018429, WO03 / 104195,

WO03 / 082787, WO03 / 082280, WO03 / 059899, ​​WO03 / 101932, WO02 / 02565,

WO01 / 16128, WO00 / 66590, WO03 / 086294, WO04 / 026248, WO03 / 061651 and

WO03 / 08277. Further nonsteroidal compounds are included: WO2006 / 000401, WO2006 / 000398 and WO2006 / 015870.

[0220] Examples of anti-inflammatory agents include nonsteroidal anti-inflammatory agents (NSAIDs).

[0221] Examples of NSAIDs include sodium cromoglycate, nedocromil sodium, phosphodiesterase (PDE) inhibitors (e.g. theophylline, PDE4 inhibitors or mixed PDE3 / PDE4 inhibitors), leukotriene antagonists, leukotriene synthesis inhibitors (e.g. montelukast), tryptase inhibitors and elastases, beta-2 integrin antagonists and adenosine receptor agonists or antagonists (e.g., adenosine 2a agonists), cytokine antagonists (e.g. chemokine antagonists (such as CCR3 antagonist) or cytokine synthesis inhibitors, or 5-lipoxygenase inhibitors. iNOS (inhibitor of induced nitric oxide synthase) is preferably intended for oral administration. Examples of iNOS inhibitors include those inhibitors disclosed in WO93 / 13055, WO98 / 30537, WO02 / 50021, WO95 / 34534 and WO99 / ​​62875. Examples of CCR3 inhibitors include those inhibitors disclosed in WO02 / 26722.

[0222] In one embodiment, the invention provides the use of compounds of formula (I) in combination with a phosphodiesterase 4 (PDE4) inhibitor, especially in the case of a formulation adapted for inhalation. The PDE4-specific inhibitor useful in this aspect of the invention may be any compound that is known to inhibit the PDE4 enzyme or which has been found to act as a PDE4 inhibitor and which is only a PDE4 inhibitor and not a compound that inhibits other members of the PDE family. such as PDE3 and PDE5 as well as PDE4.

[0223] These compounds include cis-4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) cyclohexane-1-carboxylic acid, 2-carbomethoxy-4-cyano-4- (3-cyclopropylmethoxy-4-difluoromethoxyphenyl) cyclohexane -1-one and cis- [4-cyano-4- (3-cyclopropylmethoxy-4-difluoromethoxyphenyl) cyclohexan-1-ol]. Also cis-4-cyano-4- [3- (cyclopentyloxy) 4-methoxyphenyl] cyclohexane-1-carboxylic acid (also known as kilomilast) and its salts, esters, prodrugs or physical forms, which are described in US Patent No. 5,552,388 issued on September 3, 1996; this patent and the compounds it discloses is incorporated herein by reference in their entirety.

[0224] Other compounds include AWD-12-281 from Elbion (Hofgen, N. et al. 15th EFMC Int Symp Med Chem (September 6-10, Edinburgh) 1998, Abst P.98; CAS reference number 247584020-9) ; a 9-benzyloadenine derivative named NCS-613 (INSERM); D-4418 from Chiroscience and Schering-Plow; a benzodiazepine PDE4 inhibitor identified as Cl1018 (PD-168787) and assigned to Pfizer; a benzodioxole derivative disclosed by Kyowa Hakko in WO99 / ​​16766; K-34 from Kyowa Hakko; V-11294A from Napp (Landells, LJ et al. Eur Resp J [Annu Cong Eur Resp Soc (September 19-23, Geneva) 1998] 1998, 12 (Suppl. 28): Abst P2393); roflumilast (CAS reference number 162401-32-3) and phthalazinone (WO99 / ​​47505, the disclosure of which is incorporated herein by reference) from Byk-Gulden; Pumafenthrin, (-) - p - [(4aR *, 10bS *) - 9-ethoxy-1,2,3,4,4a, 10b-hexahydro-8-methoxy-2-methylbenzo [c] [1,6] naphthyridin-6-yl] -N, N-diisopropylbenzamide, which is a mixed PDE3 / PDE4 inhibitor, manufactured and described by Byk-Gulden, now Altana; arophylline developed by Almirall-Prodesfarma; VM554 / UM565 from Vernalis; or T-440 (Tanabe Seiyaku; Fuji, K. et al. J Pharmacol Exp Ther, 1998, 284 (1): 162), and T2585.

[0225] Further compounds are disclosed in published international patent application WO04 / 024728 (Glaxo Group Ltd), WO04 / 056823 (Glaxo Group Ltd) and WO04 / 103998 (Glaxo Group Ltd) (e.g. Example 399 or 544 disclosed therein). Further compounds are also disclosed in WO2005 / 058892, WO2005 / 090348, WO2005 / 090353 and WO2005 / 090354, all on behalf of Glaxo Group Limited.

[0226] Examples of anticholinergics are those compounds that act as muscarinic receptor antagonists, in particular those compounds that are M1 or M3 receptor antagonists, dual M1 / ​​M3 or M2 / M3 receptor antagonists, or pan-M1 / antagonists. M2 / M3. Exemplary compounds for administration by inhalation include ipratropium (e.g. as bromide, CAS 22254-24-6, sold under the name Atrovent), oxitropium (e.g. as bromide, CAS 30286-75-0) and tiotropium (e.g. as bromide, CAS 136310-93-5, sold under the name Spiriva). Also interesting are revatropate (for example as bromide, CAS 262586-79-8) and LAS-34273, which is disclosed in WO01 / 04118. Exemplary compounds for oral administration include pirenzepine (e.g. CAS 28797-61-7), darifenacin (CAS 133099-04-4 or CAS 133099-07-7 in the form of the hydrobromide sold under the name Enablex), oxybutynin (CAS 5633-20-5, sold under the name Ditropan), terodiline (CAS 15793-40-5), tolterodine (CAS 124937-51-5 or CAS 124937-52-6 in the form of tartrate, sold under the name Detrol), otylonium (for example as bromide CAS 26095-59-0, sold under the name Spasmomen) , trospium chloride (CAS 10405-02-4) and solifenacin (CAS 242478-37-1 or CAS 242478-38-2, in succinate form, also known as YM-905 and sold under the name Vesicare).

[227] Additional compounds are disclosed in WO 2005/037280, WO 2005/046586 and WO 2005/104745, which are incorporated herein by reference. The connections of the invention include, but are not limited to:

(3-endo) -3- (2,2-di-2-thienylethyl) -8,8-dimethyl-8-azoniabicyclo [3.2.1] octane iodide; (3-endo) -3- (2-cyano-2,2-diphenylethyl) -8,8-dimethyl-8-azoniabicyclo [3.2.1] octane bromide;

4- [hydroxy (diphenyl) methyl] -1- {2 - [(phenylmethyl) oxy] ethyl} -1-azoniabicyclo [2.2.2] octane bromide; and (1R, 5S) -3- (2-cyano-2,2-diphenylethyl) -8-methyl-8- {2 - [(phenylmethyl) oxy] ethyl} -8-azoniabicyclo [3.2.1] octane bromide.

[0228] Other anticholinergic agents include compounds that are disclosed in US Patent Application 60/487981, including, for example:

(3-endo) -3- (2,2-di-2-thienylethyl) -8,8-dimethyl-8-azoniabicyclo [3.2.1] octane bromide; (3-endo) -3- (2,2-diphenylethenyl) -8,8-dimethyl-8-azoniabicyclo bromide [3.2. 1] octane bromide; (3-endo) -3- (2,2-diphenylethenyl) -8,8-dimethyl-8-azoniabicyclo [3.2.1] octane 4-methylbenzenesulfonate;

(3-ene) -8,8-dimethyl-3- [2-phenyl-2- (2-thienyl) ethenyl] -8-azoniabicyclo [3.2.1] octane bromide; and / or (3 -endo) -8,8-dimethyl-3- [2-phenyl-2- (2-pyridinyl) ethenyl] -8-azoniabicyclo [3.2.1] octane bromide.

[0229] Further anticholinergic agents include compounds that are disclosed in US Patent Application 60/511009, including, for example:

(endo) -3- (2-methoxy-2,2-dithiophen-2-ylethyl) -8,8-dimethyl-8-azoniabicyclo [3.2.1] octane iodide;

3 - ((endo) -8-methyl-8-azabicyclo [3.2.1] oct-3-yl) -2,2-diphenyl-propionitrile; (Endo) -8-methyl-3- (2,2,2-triphenyl) -8-azabicyclo [3.2.1] octane; 3 - ((endo) -8-methyl-8-azabicyclo [3.2.1] oct-3-yl) -2,2-diphenyl-propionamide; 3 - ((endo) -8-methyl-8-azabicyclo [3.2.1] oct-3-yl) -2,2-diphenylpropionic acid; (endo) -3- (2-cyano-2,2-diphenylethyl) -8,8-dimethyl-8-azoniabicyclo [3.2.1] octane iodide;

(endo) -3- (2-cyano-2,2-diphenylethyl) -8,8-dimethyl-8-azoniabicyclo [3.2.1] octane bromide;

3 - ((endo) -8-methyl-8-azabicyclo [3.2.1] oct-3-yl) -2,2-diphenyl-1-ol;

N-benzyl-3 - ((endo) -8-methyl-8-azabicyclo [3.2.1] oct-3-yl) -2,2-diphenyl-propionamide;

(endo) -3- (2-carbamoyl-2,2-diphenylethyl) -8,8-dimethyl-8-azoniabicyclo [3.2.1] 41 octane iodide;

1-benzyl-3- [3 - ((endo) -8-methyl-8-azabicyclo [3.2.1] oct-3-yl) -2,2-diphenyl-propyl] -urea;

1-ethyl-3- [3 - ((endo) -8-methyl-8-azabicyclo [3.2.1] oct-3-yl) -2,2-diphenyl-propyl] -urea;

N- [3 - ((endo) -8-methyl-8-azabicyclo [3.2.1] oct-3-yl) -2,2-diphenyl-propyl] -acetamide; N- [3 - ((endo) -8-methyl-8-azabicyclo [3.2.1] oct-3-yl) -2,2-diphenyl-propyl] -benzamide; 3 - ((endo) -8-methyl-8-azabicyclo [3.2.1] oct-3-yl) -2,2-di-thiophen-2-yl-propionitrile; (endo) -3- (2-cyano-2,2-dithiophen-2-ylethyl) -8,8-dimethyl-8-azoniabicyclo [3.2.1] octane iodide;

N- [3 - ((endo) -8-methyl-8-azabicyclo [3.2.1] oct-3-yl) -2,2-diphenyl-propyl] -benzenesulfonamide;

[3 - ((endo) -8-methyl-8-azabicyclo [3.2.1] oct-3-yl) -2,2-diphenyl-propyl] -urea; N- [3 - ((endo) -8-methyl-8-azabicyclo [3.2.1] oct-3-yl) -2,2-diphenyl-propyl] -methanesulfonamide; and / or (endo) -3- {2,2-diphenyl-3 - [(1-phenylmethanoyl) amino] propyl} -8,8-dimethyl8-azoniabicyclo [3.2.1] octane bromide.

[0230] Further compounds include:

(endo) -3- (2-methoxy-2,2-dithiophen-2-ylethyl) -8,8-dimethyl-8-azoniabicyclo [3.2.1] octane iodide;

(endo) -3- (2-cyano-2,2-diphenylethyl) -8,8-dimethyl-8-azoniabicyclo [3.2.1] octane iodide;

(endo) -3- (2-cyano-2,2-diphenylethyl) -8,8-dimethyl-8-azoniabicyclo [3.2.1] octane bromide;

(endo) -3- (2-carbamoyl-2,2-diphenylethyl) -8,8-dimethyl-8-azoniabicyclo [3.2.1] octane iodide;

(endo) -3- (2-cyano-2,2-dithiophen-2-ylethyl) -8,8-dimethyl-8-azoniabicyclo [3.2.1] octane iodide; and / or (endo) -3- {2,2-diphenyl-3 - [(1-phenylmethanoyl) amino] propyl} -8,8-dimethyl8-azoniabicyclo [3.2.1] octane bromide.

[0231] In one embodiment, the invention provides a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof together with an H1 antagonist. Examples of H1 antagonists include, without limitation, amelexanox, astemizole, azatadine, azelastine, acrivastine, bromfeniramine, cetirizine, levocetirizine, efletirizine, chlorfeniramine, epilatinetin, corticillin, fenestinine , fexofenadine, hydroxyzine, ketotifen, loratadine, levocabastine, mizolastine, mecvazine, mencserine, noberastine, meclysine, norastemizole, olopatadine, picumast, pyrilamine, promethazine, terfenadine, tripelenamine, temelastine, trimeprazine and triprolidine, especially cetirizine, levocetirizine, efletirizine and fexofenadine. In a further embodiment, the invention provides a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof together with an H3 antagonist (and / or inverse agonist). Examples of H3 antagonists include, for example, those compounds disclosed in WO2004 / 035556 and in WO2006 / 045416. Other histamine receptor antagonists that may be used in conjunction with compounds of the present invention include the H4 receptor antagonists (and / or inverse agonists), for example the compounds disclosed in Jablonowski et al., J. Med. Chem. 46: 3957-3960 (2003).

[0232] Thus, in a further aspect, the invention provides a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof together with a PDE4 inhibitor.

[0233] Thus, in a further aspect, the invention provides a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof together with an e2-adrenoceptor agonist.

[0234] Thus, in a further aspect, the invention provides a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof together with a corticosteroid.

[0235] Thus, in a further aspect, the invention provides a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof together with a non-steroidal GR agonist.

[0236] Thus, in a further aspect, the invention provides a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof together with an anticholinergic agent.

[0237] Thus, in a further aspect, the invention provides a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof together with an antihistamine.

[0238] Thus, in a further aspect, the invention provides a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof together with a PDE4 inhibitor and an e2-adrenoreceptor agonist.

[0239] Thus, in a further aspect, the invention provides a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof together with an anticholinergic agent and a PDE-4 inhibitor.

[0240] The combinations referred to above may conveniently be presented for use in the form of a pharmaceutical composition, and thus pharmaceutical compositions comprising the above-mentioned combination together with a pharmaceutically acceptable diluent or carrier constitute a further aspect of the invention.

[0241] Individual compounds from such combinations can be administered sequentially or simultaneously in separate or complex pharmaceutical preparations. In one embodiment, the individual compounds will be administered simultaneously in a combined pharmaceutical preparation. Appropriate doses of known therapeutic agents will be readily known to those skilled in the art.

[0242] Thus, in a further aspect, the invention provides a pharmaceutical composition comprising a combination of a compound of formula (I) or a pharmaceutically acceptable salt thereof together with another therapeutic agent.

[0243] Thus, in a further aspect, the invention provides a pharmaceutical composition comprising a combination of a compound of formula (I) or a pharmaceutically acceptable salt thereof together with a PDE4 inhibitor.

[0244] Thus, in a further aspect, the invention provides a pharmaceutical composition comprising a combination of a compound of formula (I) or a pharmaceutically acceptable salt thereof together with an e2-adrenoreceptor agonist.

[0245] Thus, in a further aspect, the invention provides a pharmaceutical composition comprising a combination of a compound of formula (I) or a pharmaceutically acceptable salt thereof together with a corticosteroid.

[0246] Thus, in a further aspect, the invention provides a pharmaceutical composition comprising a combination of a compound of formula (I) or a pharmaceutically acceptable salt thereof together with a non-steroidal GR agonist.

[0247] Thus, in a further aspect, the invention provides a pharmaceutical composition comprising a combination of a compound of formula (I) or a pharmaceutically acceptable salt thereof together with an anti-cholinergic agent.

[0248] Thus, in a further aspect, the invention provides a pharmaceutical composition comprising a combination of a compound of formula (I) or a pharmaceutically acceptable salt thereof together with an antihistamine.

[0249] Thus, in a further aspect, the invention provides a pharmaceutical composition comprising a combination of a compound of formula (I) or a pharmaceutically acceptable salt thereof together with a PDE4 inhibitor and an e2-adrenoreceptor agonist.

[0250] Thus, in a further aspect, the invention provides a pharmaceutical composition comprising a combination of a compound of formula (I) or a pharmaceutically acceptable salt thereof together with an anticholinergic agent and a PDE4 inhibitor.

[0251] The invention will now be illustrated by the following non-limiting examples.

EXAMPLES [0252] The following examples illustrate the invention. It is not intended that these examples limit the scope of the present invention, but rather that they provide guidance to the skilled person regarding the preparation and use of the compounds, compositions and methods of the present invention. Although particular embodiments of the present invention have been described, one of ordinary skill in the art will recognize that various changes and modifications can be made without departing from the spirit and scope of the invention.

[0253] When the name of the commercial supplier is given after the name of the compound or reagent, for example "compound X (Aldrich)" or "compound X / Aldrich", this means that compound X can be obtained from a commercial supplier, such as said commercial supplier. If there is no reference here, the compound or reagent can be purchased from a typical supplier such as Sigma Aldrich, Lancaster, Fluorochem, TCI etc.

[0254] The names of the compounds of the examples were obtained using a compound naming program that matches structure to name (eg, ACD / Name Batch v 9.0).

General details about the experiments

Methods - Liquid Chromatography-Mass Spectroscopy (LCMS) [0255] LCMS analysis was performed using one of the following methods.

Method A:

[0256] LCMS equipment consists of the following:

Column: Acquity UPLC BEH C18 1.7 μm 2.1 mm x 50 mm. The oven for the column was set at 40 degrees Celsius

Solvent A: Water 0.1% formic acid + 10 mM ammonium acetate Solvent B: MeCN: water 95: 5 + 0.05% formic acid

Injection volume: Injection technique:

UV detection:

Sampling rate UV Scanning range MS: MS scanning speed: MS scanning function:

Cycle time:

0.5 gl overflow and feeding part of the volume of the loop

220 up to 330 nm points per second

100 up to 1000 amu

0.2 second scanning with 0.1 second inter-scan delay electrospray in positive and negative ion mode, with 2 minutes and 30 seconds switching

Gradient:

[0257]

<td>Time</td><td>Flow ml / min</td><td>%AND</td><td>% B</td>

<td> 0</td><td> 1</td><td> 97</td><td> 3</td>

<td> 0,1</td><td> 1</td><td> 97</td><td> 3</td>

<td> 1,4</td><td> 1</td><td> 0</td><td> 100</td>

<td>Time</td><td>Flow ml / min</td><td>%AND</td><td>% B</td>

<td> 1,9</td><td> 1</td><td> 0</td><td> 100</td>

<td> 2</td><td> 1</td><td> 97</td><td> 3</td>

Method B:

[0258] HPLC analysis was performed on a Sunfire C18 column (30 mm x 4.6 mm ID 3.5 Pm average packing) at 30 degrees Celsius.

Solvent A = 0.1% v / v solution of formic acid in water.

Solvent B = 0.1% v / v solution of formic acid in acetonitrile. The gradient used was:

<td>Time (min)</td><td>Flow rate (ml / min)</td><td>% A</td><td>% B</td>

<td> 0</td><td> 3</td><td> 97</td><td> 3</td>

<td> 0,1</td><td> 3</td><td> 97</td><td> 3</td>

<td> 4,2</td><td> 3</td><td> 0</td><td> 100</td>

<td> 4,8</td><td> 3</td><td> 0</td><td> 100</td>

<td> 4,9</td><td> 3</td><td> 97</td><td> 3</td>

<td> 5,0</td><td> 3</td><td> 97</td><td> 3</td>

[0259] In UV detection, the average signal was taken for a wavelength of 210 nm to 350 nm and the mass spectrum was recorded on a mass spectrometer using electrospray ionization in positive and negative ion mode with alternating scanning.

Method C:

[0260] HPLC analysis was performed on Phenomenex Luma C18 (2) (50 mm x 2 mm ID 3 μm packing diameter, or validated equivalent) at 40 degrees Celsius.

Solvent A = 0.05% v / v TFA solution in water.

Solvent B = 0.05% v / v solution of TFA in acetonitrile.

The gradient used was:

<td>Time (min)</td><td>Flow rate (ml / min)</td><td>% A</td><td>% B</td>

<td> 0</td><td> 1</td><td> 100</td><td> 0</td>

<td> 8</td><td> 1</td><td> 5</td><td> 95</td>

<td> 8,01</td><td> 1</td><td> 100</td><td> 0</td>

[0261] The wavelength in UV detection was dependent on the analyte and the mass spectrum was recorded on a mass spectrometer using electrospray in positive ion mode.

Method D:

[0262] HPLC analysis was performed on Phenomenex Luma C18 (2) (50 mm x 2 mm ID 3 μm packing diameter, or validated equivalent) at 60 degrees Celsius.

Solvent A = 0.05% v / v TFA solution in water.

Solvent B = 0.05% v / v solution of TFA in acetonitrile.

The gradient used was:

<td>Time (min)</td><td>Flow rate (ml / min)</td><td>% A</td><td>% B</td>

<td> 0</td><td> 1,5</td><td> 100</td><td> 0</td>

<td> 2,5</td><td> 1,5</td><td> 5</td><td> 95</td>

<td> 2,7</td><td> 1,5</td><td> 5</td><td> 95</td>

<td> 2,9</td><td> 1,5</td><td> 100</td><td> 0</td>

[0263] The wavelength in UV detection was dependent on the analyte and the mass spectrum was recorded on a mass spectrometer using electrospray in positive ion mode.

Mass-controlled automated preparative HPLC methods [0264] Mass-controlled automated preparative HPLC methods used for purifying compounds are described below:

Method A - high pH [0265] Column details: Waters_XBRIDGE Prep C18 5um OBD column (30 x 150 mm) [0266] The solvents used were:

A = 10 mM ammonium bicarbonate in water adjusted to pH 10 using aq. ammonia solution

B = acetonitrile + 0.1% aq. ammonia [0267] Harvesting was started based on uv, ms or combinations thereof. For UV detection, an average signal of 210 nm to 350 nm was used. Mass spectra were recorded on a mass spectrometer using ionization by electrospray in a positive and negative ion mode with alternating scanning.

Method B - low pH [0268] Column details: SUNFIRE C18 column (30 x 150 mm ID 5 [mu] m internal diameter) [0269] The solvents used were:

A = 0.1% v / v solution of formic acid in water.

B = 0.1% v / v solution of formic acid in acetontryl.

[0270] Collection was started based on uv, ms or combinations thereof. For UV detection, an average signal of 210 nm to 350 nm was used. Mass spectra were recorded on a mass spectrometer using ionization by electrospray in positive and negative ion mode with alternating scanning.

Method C [0271] Column details: XBRIDGE Shield RP18 column (100 x 19 mm, filling diameter 5 [mu] M) [0272] The solvents used were:

A = 10 mM ammonium bicarbonate in water adjusted to pH 10 using aq. ammonia solution B = Methanol [0273] Collection was started based on uv, ms measurements or a combination thereof. For UV detection, an average signal of 210 nm to 350 nm was used. Mass spectra were recorded on a mass spectrometer using ionization by electrospray in positive and negative ion mode with alternating scanning.

Intermediates and examples

Indirect relationship 1

6-Chloro-4-iodo-1- (phenylsulfonyl) -1H-indazole [0274]

<img file="PL2424864T3_D0024.tif" />

Method A [0275] 6-Chloro-4-iodo-1H-indazole (30 g, 108 mmol, available from Sinova) was dissolved in N, N-dimethylformamide (300 mL) and cooled in an ice and water bath under a nitrogen stream. Sodium hydride (5.17 g, 129 mmol) was added in portions, keeping the temperature below 10 ° C. After adding everything, the reaction mixture was stirred for 20 min, then benzenesulfonyl chloride (16.5 mL, 129 mmol) was added dropwise over 15 min. The reaction mixture was allowed to warm to RT overnight, then poured into ice water (2 L). The precipitated product was collected by filtration, washed with water (approx. 400 ml) and dried in a vacuum oven overnight to give the title compound (43.3 g).

LCMS (method A): Rt 1.38 min, MH⁺ 419.

Method B [0276] While stirring, sodium hydroxide (227.4 g) was added to a solution of 6-chloro-4-iodo-1H-indazole (633.6 g) in THF (5.7 L), followed by tetrahydrogen bisulfate n-butylammonium (38.0 g) at 20 ± 3 ° C, under nitrogen. The mixture was stirred at 20 ± 3 ° C for 1 h 3 min, then benzenesulfonyl chloride (319 ml) was added at such a rate as to keep the temperature inside the vessel &lt;25 ° C. The benzenesulfonyl chloride residue was washed into the vessel using THF (630 ml), then the mixture was stirred for 1 h 10 min. The mixture was cooled to &lt;5 ° C and water (12.7 L) was added at such a rate as to keep the temperature inside the vessel below 5 ± 3 ° C, then the mixture was stirred at 0-5 ° C for 1 h 20 min. The solids were collected by vacuum filtration, washed with water (2x 1.9 L), dried by suction, then further dried under vacuum with a nitrogen leak at 40 ° C ± 3 ° C overnight to afford the title compound (780.8 g).

LCMS (method C): Rt 6.28 min, MH + 419.

Indirect relationship 2

6-Chloro-1- (phenylsulfonyl) -4- (trimethylstannanyl) -1H-indazole [0277]

<img file="PL2424864T3_D0025.tif" />

6-Chloro-4-iodo-1- (phenylsulfonyl) -1H-indazole (30 g, 71.7 mmol), tetrakis (triphenylphosphine) palladium (0) (8.1 g, 7.01 mmol), xylene (200 ml), triethylamine (19.98 ml, 143 mmol) and hexamethyldicine (21.8 ml, 105 mmol) were heated at 150 ° C for 2 h. The reaction mixture was filtered hot through celite, washed with additional xylene and the solvent was evaporated under vacuum. The residue was triturated with cyclohexane and the precipitate was collected by filtration and dried in a vacuum oven to give the title compound (14.4 g).

LCMS (method A): Rt 1.51 min, MH + 457.

Intermediate 3a

Ethyl 2- [6-chloro-1- (phenylsulfonyl) -1H-indazol-4-yl] -1,3-oxazole-5-carboxylate [0279]

<img file="PL2424864T3_D0026.tif" />

[0280] In 4 batches, tetrakis was added to a solution of 6-chloro-1- (phenylsulfonyl) -4- (trimethylstannanyl) 1H-indazole (13.28 g, 29.2 mmol) in N, N-dimethylformamide (52 ml) (triphenylphosphine) palladium (0) (3.37 g, 2.92 mmol), ethyl 2-chloro-1,3-oxazole-5-carboxylate (6.65 g, 37.9 mmol, available from Apollo Scientific) and copper (I) iodide (1.11 g, 5.83 mmol). In 3 of these batches, tetrakis was added to a solution of 6-chloro-1- (phenylsulfonyl) -4- (trimethylstannanyl) -1H-indazole (4.06 g, 8.91 mmol) in N, N-dimethylformamide (16 mL). (triphenylphosphine) palladium (0) (1.03 g, 0.89 mmol), ethyl 2-chloro-1,3-oxazole-5-carboxylate (2.03 g, 11.59 mmol) and copper (I) iodide (0.34 g, 1.78 mmol). In the fourth batch, tetrakis (triphenylphosphine) was added to a solution of 6-chloro-1- (phenylsulfonyl) -4- (trimethylstannanyl) -1H-indazole (1.10 g, 2.42 mmol) in N, N-dimethylformamide (4 mL). ) palladium (0) (0.28 g, 0.24 mmol), ethyl 2-chloro-1,3-oxazole-5-carboxylate (0.55 g, 3.14 mmol) and copper (I) iodide (0 , 09 g, 0.48 mmol). Each batch was washed and stirred at 100 ° C under microwave irradiation for 30 min. The mixtures were allowed to cool to RT and the combined precipitated product was suspended in diethyl ether and collected by filtration, washing with additional diethyl ether, then drying in a vacuum oven for 72 h. Approximately 5.2 g of the resulting solid was dissolved in dichloromethane and passed through celite, eluting with additional dichloromethane. The solvent was evaporated in vacuo to give the title compound as a pale orange solid (4.95 g).

LCMS (method A): Rt 1.38 min, MH + 432.

Intermediate 3b

Methyl 2- [6-chloro-1- (phenylsulfonyl) -1H-indazol-4-yl] -1,3-oxazole-5-carboxylate [0281]

<img file="PL2424864T3_D0027.tif" />

[0282] While stirring, a solution of 6-chloro-4-iodo-1- (phenylsulfonyl) -1H-indazole (549.8 g) in toluene (1.43 L) was added triethylamine (380 ml) at 20 ± 3 ° C under nitrogen atmosphere. Hexamethyldicine (385 mL) in toluene (825 mL) was added, followed by toluene (275 mL) followed by tetrakis (triphenylphosphine) palladium (0) (154.7 g). The reaction mixture was heated to 120 ° C and stirred at this temperature for 3 h. The mixture was allowed to cool to 20 ± 3 ° C, filtered, then washed with toluene (4.95 L). The filtrate was transferred to a clean vessel through a 5 [mu] m built-in Dominick hunter filter, washing with additional toluene (550 ml). The batch was then washed with 50% aqueous KF (5.5 L), the aqueous suspension filtered and the filtrate combined again with the organic phase. The aqueous phase was separated and the organic layers were washed successively with 50% aqueous KF (5.5 L), then water (5.5 L). The organic layer was diluted with DMPU (2.75 L), then concentrated by vacuum distillation to ca. 5.4 vol. To the resulting solution, copper (I) iodide (25.5 g) was added, followed by methyl 2-chloro-1,3-oxazole-5-carboxylate (279 g, available from Apollo Scientific) at 20 ± 3 ° C. The solution was degassed by applying vacuum and nitrogen purge (x3). Tetrakis (triphenylphosphine) palladium (0) (78 g) was added, the mixture was degassed (x3) then heated to 85-90 ° C for 10 h. The mixture was diluted with DMSO (13.75 L) and cooled to 20 ± 3 ° C then water (2.75 L) was added in portions of approx. 1 vol. within approx. 15 min until crystallization begins. The resulting suspension was aged at 20 ° C ± 3 ° C for 1.5 h. The solids were collected by suction filtration, washed with water (2x 2.75 L), dried by suction, and then further dried under vacuum with a nitrogen leakage ° C ± 5 ° C overnight to give the title compound (341.1 g).

LCMS (method C): Rt 6.08 min, MH⁺ 418.

Intermediate 4 {2- [6-Chloro-1- (phenylsulfonyl) -1H-indazol-4-yl] -1,3-oxazol-5-yl} methanol [0283]

<img file="PL2424864T3_D0028.tif" />

Method A [0284] A solution of ethyl 2- [6-chloro-1- (phenylsulfonyl) -1H-indazol-4-yl] -1,3-oxazole-5-carboxylate (5.11 g, 11.8 mmol) in dichloromethane (80 ml) was cooled to -25 ° C in an oven dried round bottom flask. Diisobutylaluminum hydride (25 mL, 37.5 mmol, 1.5M solution in toluene) was added dropwise and the reaction mixture was stirred at -20 ° C for 3 h. A 10% aqueous solution of potassium sodium tartrate (80 mL) was added and the reaction mixture was stirred for 5 min The precipitated solid was filtered off and partitioned between ethyl acetate (500 ml) and water (500 ml). The layers were separated and the aqueous layer was washed further with ethyl acetate (3x 150 mL). The combined organic layers were dried and evaporated in vacuo to give the title compound as a yellow solid (1.1 g).

LCMS (method A): Rt 1.09 min, MH⁺ 390.

[0285] The remaining filtrate was mostly concentrated in vacuo and the residue partitioned between ethyl acetate (500 mL) and water (500 mL). The layers were separated and the aqueous layer was extracted with additional ethyl acetate (3x 150 mL). The combined organic layers were washed with water (2x 150 mL), dried over anhydrous sodium sulfate and evaporated to give the title compound as a yellow solid (1.9 g).

LCMS (method A): Rt 1.09 min, MH + 390.

Method B [0286] To a solution of ethyl 2- [6-chloro-1- (phenylsulfonyl) -1H-indazol-4-yl] -1,3-oxazole-5-carboxylate (1.15 g) in THF (17.25 ml) ), mixed under a stream of nitrogen in an ice bath, a solution of diisobutylaluminum hydride (5.08 mL, 5.64 mmol) in toluene was added. The reaction mixture was stirred at 0 ° C for 2 h. Sodium sulfate decahydrate (2.5 g) was added, the mixture was stirred at RT for 1 h, then filtered, washed with THF (2x 5 vol) and concentrated under reduced pressure to give the title compound (0.98 g).

LCMS (method D): Rt 2.20 min, MH⁺ 390.

Indirect relationship 5

4- [5- (Bromomethyl) -1,3-oxazol-2-yl] -6-chloro-1- (phenylsulfonyl) -1H-indazole [0287]

<img file="PL2424864T3_D0029.tif" />

Method A [0288] {2- [6-Chloro-1- (phenylsulfonyl) -1H-indazol-4-yl] -1,3-oxazol-5-yl} methanol (1.626 g, 4.17 mmol) was dissolved in anhydrous dichloromethane (20 mL) and carbon tetrabromide (2.77 g, 8.34 mmol) was added. The reaction mixture was cooled to 0 ° C and a solution of triphenylphosphine (2.188 g, 8.34 mmol) in dichloromethane (20 mL) was added dropwise. After allowing to warm to RT and stirring for a further 3 h, the solvent was partially removed in vacuo and the solution was purified directly by silica gel chromatography, eluting with 0-100% ethyl acetate in dichloromethane. The appropriate fractions were combined to give the title compound as a cream solid (1.16 g). LCMS (method B): Rt 3.70 min, MH + 454.

Method B [0289] Triphenylphosphine dibromide (20.60 g, 48.8 mmol) was added to the {2- [6-chloro-1- (phenylsulfonyl) -1H-indazol-4-yl] -1,3-oxazol- suspension 5-yl} methanol (9.06 g, 23.2 mmol) in dichloromethane (181 mL) at 0 ° C. The reaction mixture was stirred at 0 ° C until completion of the reaction. Water (91 ml) and saturated sodium bicarbonate solution (91 ml) were added and the mixture was stirred, then separated. The aqueous layer was further extracted with dichloromethane (45 mL) and the organic layers were combined and washed with water (91 mL). The layers were separated and the organic layer was concentrated to dryness, then redissolved in methanol (136 ml). After stirring for 30 min, the resulting white suspension was filtered and the solid was dried in vacuo to give the title compound as an off-white solid (9.58 g).

LCMS (method D): Rt 2.57min, MH + 452/454.

Intermediate 6a

6-Chloro-4- (5 - {[(2R, 6S) -2,6-dimethyl-4-morpholinyl] methyl} -1,3-oxazol-2-yl) -1- (phenylsulfonyl) -1H-indazole [0290]

<img file="PL2424864T3_D0030.tif" />

[0291] 4- [5- (Bromomethyl) -1,3-oxazol-2-yl] -6-chloro-1- (phenylsulfonyl) -1H-indazole (0.580 g, 1.28 mmol) was dissolved in dichloromethane (5 ml) and (2R, 6S) -2,6-dimethylmorpholine (0.317 ml, 2.56 mmol) was added. The reaction mixture was stirred at RT for 3 h, then the solvent was removed under a stream of nitrogen. The resulting yellow solid was dissolved in dichloromethane (5 mL) and washed with water (2x 2.5 mL). The layers were separated (using a hydrophobic frit) and the organic layer was evaporated in vacuo to give the title compound as a pale yellow solid (0.60 g). LCMS (method A): Rt 0.86 min, MH + 487.

¹H NMR (400 MHz, Chloroform-d) δ (ppm) 8.93 (d, J = 1.0 Hz, 1H), 8.33 (dd, J = 1.0, 1.5 Hz, 1H ), 8.04 - 8.00 (m, 2H), 7.98 (d, J = 1.5 Hz, 1H), 7.62 (tt, J = 1.5, 7.5 Hz, 1H), 7.51 (t, J = 7.5 Hz, 2H), 7.15 (s, 1H), 3.67 (s, 2H), 3.75 - 3.66 (m , 2H), 2.79 - 2.72 (m, 2H), 1.86 (dd, J = 10.5, 11.0 Hz, 2H), 1.16 (d, J = 6, 5 Hz, 6 H).

[0292] In a similar manner, a suitable amine was prepared using:

<td>Number Relationship intermediate</td><td>Name</td><td>Structure</td><td>Amine</td><td>LC / MS Rt min</td><td>LC / MS MH⁺</td>

<td>6b</td><td>6-chloro-4- (5 - {[4- (1-methylethyl) -1-piperazinyl] methyl} -1,3oksazol-2-yl) -1- (phenylsulfonyl) -1H-indazole</td><td>t'k O Λ ^ ο about</td><td>1- (1-methylethyl) piperazine</td><td> 0,77</td><td> 500</td>

Indirect relationship 7

2- (Methyloxy) -5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -3-pyridinamine [0293]

<img file="PL2424864T3_D0031.tif" />

[0294] To 5-bromo-2- (methyloxy) -3-pyridinamine (18.93 g, 93 mmol, available from Asymchem International) in a 1 L round bottom flask was added after purging with nitrogen

1,4-dioxane (500 ml), then 4,4,4 ', 4', 5,5,5 ', 5'-octamethyl-2,2'-bi-1,3,2-dioxaborolane (47, 4 g, 186 mmol), potassium acetate (27.5 g, 280 mmol) and dichloro {1,1'-bis (diphenylphosphino) ferrocene] palladium (II) adduct with dichloromethane (7.61 g, 9.32 mmol) . The mixture was then stirred at 80 ° C under a nitrogen atmosphere for 2 h. The reaction mixture was allowed to cool, then partitioned between ethyl acetate and water, and filtered through a pad of celite. The aqueous layer was extracted with additional ethyl acetate (2X) and the combined organic layers were washed with water, brine and dried over magnesium sulfate overnight. The mixture was filtered and the filtrate concentrated in vacuo to give a dark brown solid. The residue was purified by silica gel chromatography, eluting with 0-50% ethyl acetate / dichloromethane. The appropriate fractions were combined and evaporated to dryness, and the residue was triturated with cyclohexane. The resulting solid was filtered off and dried in vacuo to give the title compound as a light pink solid (11.1 g).

LCMS (method A) Rt 0.91 min, MH + 251.

Indirect relationship 8

N- [2- (Methyloxy) -5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -3-pyridinyl] methanesulfonamide [0295]

<img file="PL2424864T3_D0032.tif" />

To a solution of 2- (methyloxy) -5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -3-pyridinamine (0.5 g, 1.999 mmol) in pyridine ( 5 ml) methanesulfonyl chloride (0.309 ml, 4.00 mmol) was added and the mixture was stirred at 20 ° C for 18 h, then the solvent was removed in vacuo. The residue was partitioned between saturated sodium bicarbonate (10 mL) and dichloromethane (20 mL), separated using a hydrophobic frit and purified by silica gel chromatography, eluting with a gradient of dichloromethane and methanol, to give the title compound as a brown solid (0 , 46 g).

LCMS (method A): Rt 0.98 min, MH⁺ 329.

Indirect relationship 9

2,4-Difluoro-N- [2- (methyloxy) -5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -3-pyridinyl] benzenesulfonamide [0297]

<img file="PL2424864T3_D0033.tif" />

[0298] While stirring, into 2- (methyloxy) -5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -3-pyridinamine solution (3 g, 12.00 mmol) in pyridine (12 ml) 2,4-difluorobenzenesulfonyl chloride (1.774 ml, 13.19 mmol) was added and the reaction mixture was stirred at RT for 2 h. 2 N hydrogen chloride (aq) (20 ml) and dichloromethane (20 ml) ), and the layers were separated. The aqueous layer was washed with additional dichloromethane (2x 15 mL) and the organic layers were combined, dried (using a hydrophobic frit) and evaporated in vacuo to give a brown oil. Some pyridine was still present in the reaction mixture, so 2M hydrogen chloride (aq) and dichloromethane (15 mL) were added for one more extraction. The solvent was removed in vacuo to give the title compound as an orange solid (4.3 g).

LCMS (method A): Rt 1.20 min, MH + 427 [Note: Rt 0.73 min, MH was also observed⁺ 345 compatible with boronic acid (hydrolysis product caused by the HPLC eluent)].

Intermediate relationship 10

N- [5- [4- (5 - {[(2R, 6S) -2,6-dimethyl-4-morpholinyl] methyl} -1,3-oxazol-2-yl) -1- (phenylsulfonyl) -1 H -indazol-6-yl] -2- (methyloxy) -3-pyridinyl] -2,4-difluorobenzenesulfonamide [0299]

<img file="PL2424864T3_D0034.tif" />

[0300] For 6-chloro-4- (5 - {[(2R, 6S) -2,6-dimethyl-4-morpholinyl] methyl} -1,3-oxazol-2-yl) -1- (phenylsulfonyl) solution ) -1H-indazole (0.2 g, 0.411 mmol) and 2,4-difluoro-N- [2 (methoxy) -5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-yl) -3-pyridinyl] benzenesulfonamide (0.228 mg, 0.534 mmol) in 1,4-dioxane (2 mL) added 1 (1R, 4S) -bicyclo [2.2.1] hept-2-yl [(1S, 4R) -bicyclo [2.2.1] hept-2-yl] phosphate, chloro [2 '- (dimethylamino) -2-biphenyl] palladium (11.5 mg, 0.021 mmol), tribasic potassium phosphate (0.262 g, 1.23 mmol) and water (0.2 ml). The reaction mixture was heated to 120 ° C under stirring for 3 h under microwave conditions, then filtered using SPE silica, eluting with methanol. The solvent was removed and the residue was partitioned between dichloromethane (5 mL) and water (5 mL). The layers were separated and the aqueous layer was further extracted with dichloromethane (2x 2.5 mL). The combined organic layers were concentrated under a stream of nitrogen and the residue was dissolved in DMSO and in a few drops of dichloromethane (3 mL) and purified by MDAP (method A) in 3 injections. The appropriate fractions were evaporated in vacuo to give the title compound as a pale brown solid (0.105 g).

LCMS (method A): Rt 0.93 min, MH⁺ 751.

Indirect relationship 11

2,4-Difluoro-N- [5- [4- (5 - {[4- (1-methylethyl) -1-piperazinyl] methyl} -1,3-oxazol-2-yl) -1- (phenylsulfonyl) - 1H-indazol-6-yl] -2- (methyloxy) -3-pyridinyl] benzenesulfonamide [0301]

<img file="PL2424864T3_D0035.tif" />

[0302] To the solution of 6-chloro-4- (5 - {[4- (1-methylethyl) -1-piperazinyl] methyl} -1,3-oxazol-2-yl) -1- (phenylsulfonyl) -1H- indazole (0.2 g, 0.40 mmol) and 2,4-difluoro-N- [2- (methoxy) -5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2 -yl) -3-pyridinyl] benzenesulfonamide (0.222 g, 0.52 mmol) in 1,4-dioxane (2 mL) added 1 (1R, 4S) -bicyclo [2.2.1] hept-2yl [(1S, 4R ) -bicyclo [2.2.1] hept-2-yl] phosphate, chloro [2 '- (dimethylamino) -2-biphenyl] palladium (11.2 g, 0.020 mmol), tribasic potassium phosphate (0.255 g, 1.20 mmol) and water (0.2 ml). The reaction mixture was heated to 120 ° C under stirring for 3 h under microwave conditions then filtered using SPE silica, eluting with methanol. The solvent was removed in vacuo and the residue was partitioned between dichloromethane (5 ml) and water (5 ml). The layers were separated and the aqueous layer was further extracted with dichloromethane (2x 2 mL). The combined organic layers were concentrated under a stream of nitrogen and the residue was purified by silica gel chromatography, eluting with 0-25% methanol in dichloromethane. The appropriate fractions were evaporated in vacuo to give the title compound as a brown solid (0.081 g). LCMS (method A): Rt 0.85 min, MH + 764.

Indirect relationship 12

2- [6- {1 - [(1,1-dimethylethyl) (dimethyl) silyl] -1H-indol-4-yl} -1- (phenylsulfonyl) -1Hindazol-4-yl] -1,3-oxazole Ethyl 5-carboxylate [0303]

<img file="PL2424864T3_D0036.tif" />

[0304] To a solution of ethyl 2- [6-chloro-1- (phenylsulfonyl) -1H-indazol-4-yl] -1,3-oxazole-5-carboxylate (1.5 g, 3.47 mmol) in 1.4 dioxane (15 ml) and water (1.5 ml) added {1 - [(1,1-dimethylethyl) (dimethyl) silyl] -1H-indol-4-yl} boronic acid (1.243 g, 4.52 mmol , available from Combi-Blocks Inc.), 1 (1R, 4S) -bicyclo [2.2.1] hept-2-yl [(1S, 4R) -bicyclo [2.2.1] hept-2-yl] chloro phosphate [ 2 '- (dimethylamino) -2-biphenyl] palladium (0.097 g, 0.174 mmol) and tribasic potassium phosphate (2.212 g, 10.42 mmol). The reaction mixture was heated to 100 ° C for 3 h, the solvent removed in vacuo and the residue partitioned between dichloromethane (20 mL) and water (10 mL). Saturated sodium chloride solution (100 ml) was added and the organic phase was separated and dried over anhydrous sodium sulfate. The crude product was purified by silica gel chromatography, eluting with a gradient of cyclohexane and ethyl acetate. The desired fractions were concentrated to give the title compound as a white solid (0.846 g), which according to LCMS contained some unreacted starting material.

LCMS (method A): Rt 1.71 min, MH⁺ 627 (and Rt 1.39 min, MH⁺ 432 compatible with 2- [6-] 1 [(1,1-dimethylethyl) (dimethyl) silyl] -1H-indol-4-yl} -1- (phenylsulfonyl) -1H-indazol-4-yl] -1,3- oxazole-5-carboxylate).

Intermediate 13 {2- [6- {1 - [(1,1-Dimethylethyl) (dimethyl) silyl] -1H-indol-4-yl} -1- (phenylsulfonyl) -1Hindazol-4-yl] -1, 3-oxazol-5-yl} methanol [0305]

<img file="PL2424864T3_D0037.tif" />

[0306] To a solution of 2- [6- {1 - [(1,1-dimethylethyl) (dimethyl) silyl] -1H-indol-4-yl} -1- (phenylsulfonyl) -1H-indazol-4-yl] Ethyl-1,3-oxazole-5-carboxylate (containing impurity according to ethyl 2- [6-chloro-1- (phenylsulfonyl) -1H-indazol-4-yl] -1,3-oxazole-5-carboxylate) (0, 84 g) in dichloromethane (10 mL) at -20 ° C, diisobutylaluminum hydride (2.68 mL, 2.68 mmol, 1M in hexanes) was added. The reaction mixture was stirred at -20 ° C for 2 h, then a 10% ammonium chlorine solution (10 mL) was added. The mixture was stirred for 5 min, then extracted with dichloromethane (10 mL), the layers separated (using a hydrophobic frit) and the organic layer was purified by silica gel chromatography, eluting with a gradient of cyclohexane and ethyl acetate. The desired fractions were concentrated to give the title compound as a pale yellow solid (0.36 g) which according to LCMS contained 2- [6-chloro-1- (phenylsulfonyl) -1H-indazol-4-yl] 1,3-oxazol 5-yl} methanol as an impurity. LCMS (method A): Rt 1.55 min, MH⁺585 (and Rt 1.11 min, MH⁺ 390 compatible with {2- [6-chloro-1- (phenylsulfonyl) -1H-indazol-4-yl] -1,3-oxazol-5-yl} methanol as impurity).

Indirect relationship 14

6- Chloro-4- (5 - {[(2R, 6R) -2,6-dimethyl-4-morpholinyl] methyl} -1,3-oxazol-2-yl) -1- (phenylsulfonyl) -1H-indazole [0307]

<img file="PL2424864T3_D0038.tif" />

[0308] To a solution of 4- [5- (bromomethyl) -1,3-oxazol-2-yl] -6-chloro-1- (phenylsulfonyl) 1H-indazole (750 mg, 1.657 mmol) in dichloromethane (50 ml) stirred in air at room temperature, pure 2,6-dimethylmorpholine (191 mg, 1.657 mmol, available from Aldrich as a mixture of isomers) was added. The reaction mixture was stirred at 20 ° C for 20 h. Volatiles were removed using a rotary evaporator, then the crude material was pre-absorbed onto Fluorosil ™ and purified by silica column chromatography (100 g) using a 0-100% ethyl acetate-cyclohexane gradient over 60 min. Two diastereomers were isolated. The appropriate fractions were combined and evaporated in vacuo to give the title compound as a yellow oil (226 mg).

¹H NMR confirmed the structure as a trans isomer. ¹H NMR (400 MHz, chloroform-d) δ (ppm) 8.92 (d, J = 1.0 Hz, 1H), 8.32 (dd, J = 1.0, 1.5 Hz, 1H ), 8.04 - 8.00 (m, 2H), 7.97 (d, J = 1.5 Hz, 1H), 7.62 (tt, J = 1.5, 7.5 Hz, 1H), 7.54 - 7.48 (m, 2H), 7.13 (s, 1H), 4.08 - 3.99 (m, J = 3.5, 6.0, 6, 5, 6.5, 6.5 Hz, 2H), 3.66 (d, J = 14.5 Hz, 1H), 3.61 (d, J = 14.5 Hz, 1H), 2 , 56 (dd, J = 3.0, 10.5 Hz, 2H), 2.23 (dd, J = 6.0, 10.5 Hz, 2H), 1.24 (d, J = 6 , 5 Hz, 6 H).

Intermediate relationship 15

1,1-dimethylethyl 4 - ({2- [6-Chloro-1- (phenylsulfonyl) -1H-indazol-4-yl] -1,3-oxazol-5-yl} methyl) -1-piperazinecarboxylate [0309]

<img file="PL2424864T3_D0039.tif" />

1,1-Dimethylethyl 1-piperazinecarboxylate (185 mg, 0.994 mmol) was dissolved in 1 mL DCM and triethylamine (0.185 mL, 1.325 mmol) was added dropwise. The mixture was stirred for 1 h then concentrated in vacuo to give a yellow solid. This material was dissolved in water / DCM (1: 1, 50 mL) and the organic phase was collected, then concentrated in vacuo to give the title compound as a yellow gum (347 mg). LCMS (method A) Rt 1.16 min (weak ionization, observed (M + MeCN) + 599).

Example 1

N- [5- [4- (5 - {[(2R, 6S) -2,6-dimethyl-4-morpholinyl] methyl} -1,3-oxazol-2-yl) -1H-indazol-6-yl ] -2- (methyloxy) -3-pyridinyl] methanesulfonamide [0311]

<img file="PL2424864T3_D0040.tif" />

Method A [0312] To the solution of 6-chloro-4- (5 - {[(2R, 6S) -2,6-dimethyl-4-morpholinyl] methyl} -1,3-oxazol-2-yl) -1- (phenylsulfonyl) -1H-indazole (0.20 g, 0.411 mmol) and N- [2- (methoxy) -5 (4,4,5,5-tetramethyl-1,2,3-dioxaborolan-2-yl) -3-pyridyl] methanesulfonamide (0.175 g, 0.534 mmol) in 1,4-dioxane (2 mL) added 1 (1R, 4S) -bicyclo [2.2.1] hept-2-yl [(1S, 4R) bicyclo [ 2.2.1] hept-2-yl] chloro [2 '- (dimethylamino) -2-biphenyl] palladium phosphate (11.5 mg, 0.021 mmol), tribasic potassium phosphate (0.262 g, 1.23 mmol) and water (0.2 ml). The reaction mixture was heated and stirred at 120 ° C under microwave irradiation for 1 h. Additional portions of 1 (1R, 4S) -bicyclo [2.2.1] hept-2-yl [(1S, 4R) bicyclo [2.2.1] were added hept-2-yl] phosphate chloro [2 '- (dimethylamino) -2-biphenyl] palladium (11.5 mg, 0.021 mmol) and tribasic potassium phosphate (80 mg) and the reaction mixture was heated to 120 ° C under microwave irradiation for 1 h An additional portion and tribasic potassium phosphate (80 mg) were added and the reaction mixture was heated under the same conditions for a further 1 h. The reaction mixture was filtered using silica SPE and eluted with methanol. The solvent was removed in vacuo and the residue was partitioned between dichloromethane (5 ml) and water (5 ml). The layers were separated and the aqueous layer was further extracted with dichloromethane (2x 2 mL). The combined organic layers were concentrated under a stream of nitrogen and the residue was dissolved in MeOH: DMSO (3 mL, 1: 1, v / v) and purified by MDAP (method A) in 3 injections. The appropriate fractions were combined and concentrated to give a white solid which was dissolved in MeOH: DMSO (1 mL, 1: 1, v / v) and further purified by MDAP (method B). The appropriate fractions were basified to pH 6 with sodium bicarbonate solution and extracted with ethyl acetate (2x 25 mL). The combined organic layers were dried and evaporated in vacuo to give a white solid which was further dried under a nitrogen stream at 40 ° C for 3 h and the title compound was obtained as a white solid (26 mg).

LCMS (method A): Rt 0.53 min, MH⁺513.

Method B [0313] N- [2- (Methyloxy) -5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -3-pyridinyl] methanesulfonamide (101 g, 308 mmol), 6-chloro-4- (5 - {[(2R, 6S) -2,6-dimethyl-4-morpholinyl] methyl} -1,3-oxazol-2-yl) -1- (phenylsulfonyl) - 1H-indazole (83.3 g, 154 mmol) and sodium bicarbonate (38.8 g, 462 mmol) were suspended in 1,4-dioxane (1840 mL) and water (460 mL) under a stream of nitrogen and heated to 80 ° C. Added 1 (1R, 4S) bicyclo [2.2.1] hept-2-yl [(1S, 4R) -bicyclo [2.2.1] hept-2-yl] chloro [2 '- (dimethylamino) -2-biphenyl) phosphate ] palladium (8.63 g, 15.40 mmol) and the mixture was stirred overnight at 80 ° C. [0314] The reaction mixture was cooled to 45 ° C, sodium hydride 2M aq was added. (770 mL, 1540 mmol) and the reaction mixture was heated to 45 ° C for 4 hours. The mixture was cooled to RT and diluted with water (610 mL). Dichloromethane (920 mL) was added and the mixture was filtered twice through celite (washed with 200 mL 1,4-dioxane / DCM 2: 1 each time). The phases were separated and the aqueous phase was washed with 1,4-dioxane / DCM 2: 1 (500 ml). The aqueous phase was neutralized with hydrochloric acid to pH ~ 7 and extracted

1,4-dioxane / DCM 2: 1 (1 L), then 1,4 dioxane / DCM 1: 1 (2x500 ml). The organic layers were washed with brine (500 mL) and filtered through celite (washed with 200 mL 1.4 dioxane / DCM 2: 1) and evaporated to give a dark black solid which was purified in 4 batches:

A 1: 28 g batch was dissolved in toluene / ethanol / ammonia 80: 20: 2 (100 ml) and purified by column chromatography (column with 1.5 kg silica), eluting with toluene / ethanol / ammonia 80: 20: 2 and the title compound was obtained as an off-white solid (14.78 g).

Batch 2: 30 g was dissolved in methanol and mixed with Fluorisil. The solvent was then removed by evaporation and the solid was purified by column chromatography (1.5 kg silica column, injection module with solid sample), eluting with 80: 20: 2 toluene / ethanol / ammonia to give the title compound as an off-white solid (9.44 g).

Batch 3: 31 g was dissolved in toluene / ethanol / ammonia 80: 20: 2 (100 ml) and purified by column chromatography (column with 1.5 kg silica), eluting with toluene / ethanol / ammonia 80: 20: 2 and the title compound was obtained as an off-white solid (17 g).

A batch of 4: 29 g was dissolved in toluene / ethanol / ammonia 80: 20: 2 (100 ml) and purified by column chromatography (column with 1.5 kg silica), eluting with toluene / ethanol / ammonia 80: 20: 2 and the title compound was obtained as an off-white solid (21 g).

[0315] The mixed fractions from the 4 columns were combined and evaporated to give 19 g, which were dissolved in 200 ml of toluene / ethanol / ammonia 80: 20: 2 (+ an additional 4 ml of 0.88 NH3 to improve solubility), then purified column chromatography (1.5 kg silica column), eluting with toluene / ethanol / ammonium 80: 20: 2 to give the title compound as an off-white solid (6.1 g). [0316] All pure batches were combined (68 g) and recrystallized from ethanol (1200 ml). The suspension was heated to reflux and a solution formed. The resulting solution was then cooled to room temperature overnight. The resulting solid was then collected by filtration, washed economically with ethanol and dried in vacuo to give the title compound as an off-white solid (56 g). This material was again recrystallized from ethanol (1100 ml). The suspension was heated to reflux and a solution formed. The resulting solution was then cooled to room temperature overnight under stirring. The resulting solid was collected by filtration and washed economically with ethanol. The solid was dried under vacuum at 60 ° C for 5 h and the title compound was obtained as an off-white solid (45.51 g).

LCMS (method A): Rt 0.61 min, MH⁺ 513.

[0317] The filtrate from the two recrystallizations was evaporated to give ~ 23 g of a solid residue, which was dissolved in 200 ml of toluene / ethanol / ammonia 80: 20: 2 (+ additional 4 ml of 0.88 NH3 to improve solubility), then purified by column chromatography (column with 1.5 kg of silica), eluting with toluene / ethanol / ammonia 80: 20: 2, to give a further crop of the title compound as an off-white solid (18.5 g). This solid was then recrystallized from ethanol (370 mL). The suspension was heated to reflux, then the resulting solution was stirred for 20 min before being allowed to cool to room temperature naturally overnight. The solid was then dried under vacuum at 65 ° C overnight to give the title compound as an off-white solid (11.90 g).

LCMS (method A): Rt 0.62 min, MH⁺ 513.

Example 2

N- [5- [4- (5 - {[4- (1-methylethyl) -1-piperazinyl] methyl} -1,3-oxazol-2-yl) -1H-indazol6-yl] -2- (methyloxy ) -3-pyridinyl] methanesulfonamide [0318]

<img file="PL2424864T3_D0041.tif" />

[0319] For 6-chloro-4- (5 - {[4- (1-methylethyl) -1-piperazinyl] methyl} -1,3-oxazol-2-yl) -1- (phenylsulfonyl) -1H- solution indazole (200 mg, 0.400 mmol) and N- [2- (methoxy) -5 (4,4,5, 5-tetramethyl-1,3, 2-dioxaborolan-2-yl) -3-pyridyl] methanesulfonamide (171 mg, 0.520 mmol) in 1,4-dioxane (2 ml) added 1 (1R, 4S) -bicyclo [2.2.1] hept-2-yl [(1S, 4R) bicyclo [2.2.1] hept-2- chloro [2 '- (dimethylamino) -2-biphenyl] palladium phosphate (11.2 mg, 0.020 mmol), tribasic potassium phosphate (255 mg, 1.20 mmol) and water (0.2 ml). The reaction mixture was heated and stirred at 120 ° C under microwave irradiation for 3 h. The reaction mixture was filtered using SPE silica and eluted with methanol. The solvent was removed in vacuo and the residue was partitioned between dichloromethane (5 ml) and water (5 ml). The layers were separated and the aqueous layer was extracted with additional dichloromethane (2x 2 mL). The combined organic layers were concentrated under a stream of nitrogen and the residue was dissolved in MeOH: DMSO (2 mL, 1: 1, v / v) and purified by MDAP (method A) with 2 injections. The appropriate fractions were combined and concentrated, and the residue was dissolved in MeOH: DMSO (1 mL, 1: 1, v / v) and further purified by MDAP (method B). The appropriate fractions were basified to pH 7 with sodium bicarbonate solution and extracted with dichloromethane (2 x 20 mL). The combined organic layers were dried (using a hydrophobic frit) and concentrated to give the title compound as a white solid (22 mg). LCMS (method A): Rt 0.51 min, MH + 526.

Example 3

N- [5- [4- (5 - {[(2R, 6S) -2,6-dimethyl-4-morpholinyl] methyl} -1,3-oxazol-2-yl) -1H-indazol-6-yl ] -2- (methyloxy) -3-pyridinyl] -2,4-difluorobenzenesulfonamide [0320]

<img file="PL2424864T3_D0042.tif" />

[0321] N- [5- [4- (5 - {[(2R, 6S) -2,6-dimethyl-4-morpholinyl] methyl} -1,3-oxazol-2-yl) -1- (phenylsulfonyl) ) -1H-indazol-6-yl] -2- (methyloxy) -3-pyridinyl] -2,4-difluorobenzenesulfonamide (105 mg, 0.140 mmol) was suspended in isopropanol (2 mL) and 2M sodium hydroxide ( aq) (0.699 mL, 1.399 mmol). The reaction mixture was stirred at RT for 2 h, the solvent was removed under a stream of nitrogen and the residue was dissolved in water (1 mL) and acidified to pH ~ 6 by the addition of 2M hydrogen chloride (aq) (a black precipitate formed). The suspension was extracted with dichloromethane (3x 2 mL) and the combined organic layers were dried to give a brown solid. This material was combined with a black solid which remained insoluble during extraction, dissolved in MeOH: DMSO (1 mL, 1: 1, v / v) and purified by MDAP (method A). The appropriate fractions were concentrated in vacuo to give the title compound as a white solid (20 mg).

LCMS (method A): Rt 0.69 min, MH + 611.

Example 4

2,4-Difluoro-N- [5- [4- (5 - {[4- (1-methylethyl) -1-piperazinyl] methyl} -1,3-oxazol-2-yl) -1H-indazol-6- yl] -2- (methyloxy) -3-pyridinyl] benzenesulfonamide [0322]

<img file="PL2424864T3_D0043.tif" />

[0323] 2,4 -Difluoro-N- [5- [4- (5 - {[4- (1-methylethyl) -1-piperazinyl] methyl} -1,3-oxazol2-yl) -1- (phenylsulfonyl) ) -1H-indazol-6-yl] -2- (methyloxy) -3-pyridinyl] benzenesulfonamide (81 mg, 0.106 mmol) was suspended in isopropanol (2 mL) and 2M sodium hydroxide (aq) was added (0, 53 ml, 1.060 mmol). The reaction mixture was stirred at RT for 2 h, the solvent removed and the residue dissolved in water (1 mL) and acidified to pH ~ 6 by the addition of 2M hydrogen chloride (aq). The resulting suspension was extracted with dichloromethane (3x 2 mL), the organic layer was separated (using a hydrophobic frit) and concentrated in vacuo to give a brown solid which was dissolved in MeOH: DMSO (1 mL, 1: 1, v / v) .) and purified by MDAP (method A). The appropriate fractions were concentrated in vacuo to give the title compound as a white solid (45 mg).

LCMS (method A): Rt 0.65 min, MH + 624.

Example 5

4- (5 - {[(2R, 6S) -2,6-dimethyl-4-morpholinyl] methyl} -1,3-oxazol-2-yl) -6- (1H-indol-4-yl) -1H-indazole [0324]

<img file="PL2424864T3_D0044.tif" />

[0325] For 6-chloro-4- (5 - {[(2R, 6S) -2,6-dimethyl-4-morpholinyl] methyl} -1,3-oxazol-2-yl) -1- (phenylsulfonyl) solution ) -1 H-indazole (50 mg, 0.103 mmol) in 1,4-dioxane (1.5 ml) and water (0.15 ml) {1- [1,1-dimethylethyl) (dimethyl) silyl acid ] 1-H-indol-4-yl} boronic (37 mg, 0.133 mmol), (1R, 4S) -bicyclo [2.2.1] hept-2-yl [(1S, 4R) -bicyclo [2.2.1] hept- Chloro [2 '- (dimethylamino) -2-biphenyl] palladium 2-yl] phosphate (5.75 mg, 10.27 μmol) and tribasic potassium phosphate (65 mg, 0.308 mmol). The reaction mixture was heated under microwave conditions at 100 ° C for 40 min. The solvent was removed and the residue was dissolved in 10% methanol in dichloromethane (2 mL) and purified by silica gel chromatography, eluting with a gradient of cyclohexane and ethyl acetate. The appropriate fractions were concentrated to give a brown gum which was treated directly with tetra-n-butylammonium fluoride (0.2 mL, 0.2 mmol, 1M in tetrahydrofuran) and allowed to stand at 20 ° C for 18 h. The solvent was removed and the residue dissolved in 1,4-dioxane (1 ml) and treated with 2M sodium hydride (1 ml) and allowed to stand at 20 ° C for 48 h. The solvent was removed and the residue was triturated with 10% methanol in dichloromethane and then purified by silica gel chromatography, eluting with a gradient of dichloromethane and methanol, to give a pale brown solid, which was further purified by SCX SPE (1 g), eluting 0.5M ammonia in 1,4-dioxane. The solvent was removed and the residue was further purified by MDAP to afford the title compound as a white solid (14 mg).

LCMS (method A): Rt 0.70 min, MH + 428.

Example 6

6- (1H-Indol-4-yl) -4- (5 - {[4- (1-methylethyl) -1-piperazinyl] methyl} -1,3-oxazol-2-yl) 1H-indazole [0326]

<img file="PL2424864T3_D0045.tif" />

Method A [0327] 6-Chloro-4- (5 - {[4- (1-methylethyl) -1-piperazinyl] methyl} -1,3-oxazol-2-yl) -1- (phenylsulfonyl) -1H- indazole (97 mg, 0.194 mmol), 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-indole (61.3 mg, 0.252 mmol, available from Frontier Scientific Europe), (1R, 4S) -bicyclo [2.2.1] hept-2-yl [(1S, 4R) -bicyclo [2.2.1] hept-2-yl] chloro [2 '- (dimethylamino) - phosphate 2-biphenyl] palladium (10.87 mg, 0.019 mmol) and tribasic potassium phosphate (124 mg, 0.582 mmol) was dissolved in 1,4-dioxane (1 mL) and water (0.1 mL), and the whole was heated in a Biotage Initiator microwave at 100 ° C for 30 min. An additional amount of 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-indole (61.3 mg, 0.252 mmol) and (1R, 4S) -bicyclo were added [ 2.2.1] hept-2-yl [(1S, 4R) -bicyclo [2.2.1] hept-2-yl] phosphate chloro [2 '- (dimethylamino) -2-biphenyl] palladium (5 mg) and the reaction mixture heated at 110 ° C for 30 min and then at 140 ° C for 30 min. The solvent was removed in vacuo and the residue was purified by silica gel chromatography, eluting with 0-25% methanol in dichloromethane. The appropriate fractions were combined and concentrated to give a brown solid that was dissolved in MeOH: DMSO (1 mL, 1: 1, v / v) and purified by MDAP (method A). The appropriate fractions were concentrated in vacuo to give the title compound as a white solid (30 mg). LCMS (method A): Rt 0.57 min, MH + 441.

Method B [0328] 6-Chloro-4- (5 - {[4- (1-methylethyl) -1-piperazinyl] methyl} -1,3-oxazol-2-yl) -1- (phenylsulfonyl) -1H- indazole (75.17 g, 150 mmol), 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-indole (73.1 g, 301 mmol), sodium bicarbonate (37.9 g, 451 mmol) and (1R, 4S) -bicyclo [2.2.1] hept-2-yl [(1S, 4R) -bicyclo [2.2.1] hept-2-yl] chloro phosphate [2 '- (dimethylamino) -2-biphenyl] palladium (8.43 g, 15.03 mmol) was suspended in 1,4-dioxane (1200 mL) and water (300 mL), with nitrogen purge. The reaction vessel was alternately placed under vacuum and under nitrogen with an overhead stirrer, then finally placed under a nitrogen atmosphere and heated to 120 ° C for 2.5 h.

[0329] The reaction mixture was cooled to 45 ° C and then treated with 2M aqueous sodium hydroxide solution (376 mL, 752 mmol). After stirring at 45 ° C overnight (~ 13h), the mixture was cooled to RT and DCM (600 mL) and water (400 mL) were added. The layers were separated and the aqueous layer re-extracted with DCM: 1,4-dioxane (1: 1). Brine was added and the mixture was filtered through celite, washing with DCM: 1,4-dioxane (1: 1). The layers were separated and 2M HCl (100 mL) was added to the organic layer. The mixture was again filtered through celite washing with 500 ml 2M HCl holding the washing liquids separately. The filtrate layers were then separated and the organic layer was washed with acidic celite wash liquids. The layers were separated and the acidic layer combined. This layer was then washed again with 2x500 ml DCM; each wash required filtration through celite. The acidic aqueous layer was then subjected to final filtration through celite washing the celite pad with 150 ml 2M HCl. [0330] The acidic water layer was transferred to a beaker (5000 ml) and 2M NaOH was added under vigorous stirring to make the mixture alkaline to pH 10-11. The mixture was then extracted with 1,4-dioxane: DCM (1: 1) (5 x 500 mL). The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and evaporated to give a brown foam which was dried in vacuum at 50 ° C overnight.

[0331] This material was separated into three batches and each purified by reverse phase column chromatography (3x 1.9 kg C18 column), applied in DMF / TFA (1: 1, 30 ml), then eluting 3-40 % MeCN in water + 0.25% TFA (Note: Columns 2 and 3 use a different gradient starting from 10% MeCN).

[0332] The appropriate fractions were combined, acetonitrile was removed in vacuo and the acidic aqueous layer was basified to pH 10 by adding saturated aqueous sodium carbonate solution to the solution with stirring. The resulting solid was collected by filtration, washed with water, then dried under vacuum at 65 ° C overnight to give the title compound (28.82 g) as a pale brown foam.

LCMS (method A): Rt 0.68 min, MH + 441.

¹H NMR (400 MHz, DMSO-d6) d = 13.41 (br. P., 1H), 11.35 (br. P., 1H), 8.59 (br. P., 1H) , 8.07 (d, J = 1.5 Hz, 1H), 7.90 (br. P., 1H), 7.51 - 7.44 (m, 2H), 7.32 (s , 1 h), 7.27 7.21 (m, 2H), 6.61 - 6.58 (m, 1H), 3.73 (br. P., 2H), 2.64 - 2 , 36 (m, 9H), 0.97 - 0.90 (m, 6H).

Example 7

6- (1H-Indol-4-yl) -4- [5- (4-morpholinylmethyl) -1,3-oxazol-2-yl] -1H-indazole trifluoroacetate [0333]

<img file="PL2424864T3_D0046.tif" />

[0334] To the {2- [6- {1 - [(1,1-dimethylethyl) (dimethyl) silyl] -1H-indol-4-yl} -1- (phenylsulfonyl) -1H-indazol-4-yl solution ] -1,3-oxazol-5-yl} methanol (containing impurity according to 2- [6-chloro-1- (phenylsulfonyl) -1H-indazol-4-yl] -1,3-oxazol-5-yl} methanol) (350 mg) in dichloromethane (10 mL) carbon tetrabromide (397 mg, 1.197 mmol) was added. The reaction mixture was cooled to 0 ° C and triphenylphosphine (314 mg, 1.197 mmol) was added dropwise as a solution in dichloromethane (2 mL). The reaction mixture was allowed to warm to RT, then the solvent was partially removed and the solution was purified directly by silica gel chromatography, eluting with a gradient of dichloromethane and ethyl acetate. The desired fractions were concentrated to give a brown solid (37 mg).

[0335] To a solution of this solid (30 mg, 0.056 mmol) in dichloromethane (5 mL) was added morpholine (9.8 mg, 0.112 mmol) and the mixture was stirred at 20 ° C for 18 h. The solvent was removed and the residue was dissolved in 1 , 4-dioxane (2 mL) and 2M sodium hydroxide solution (1 mL, 2.0 mmol) was added. The reaction mixture was stirred at 20 ° C for 18 h, then the solvent was removed and the residue was triturated with 10% methanol in dichloromethane (1 mL) and purified by silica gel chromatography, eluting with a gradient of dichloromethane and dichloromethane + 1% ammonia in methanol. The desired fractions were concentrated and purified by MDAP to give the title compound as a brown solid (3 mg).

LCMS (method A): Rt 0.65 min, MH⁺400.

Example 8

N- [5- [4- (5 - {[(2R, 6R) -2,6-dimethyl-4-morpholinyl] methyl} -1,3-oxazol-2-yl) -1Hindazol-6-yl] - 2- (methyloxy) -3-pyridinyl] methanesulfonamide [0336]

<img file="PL2424864T3_D0047.tif" />

[0337] To the 6-chloro-4- (5 - {[(2R, 6R) -2,6-dimethyl-4-morpholinyl] methyl} -1,3-oxazol-2-yl) -1- (phenylsulfonyl) solution ) -1H-indazole (109.5 mg, 0.225 mmol), N- [2- (methyloxy) 5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -3 -pyridinyl] methanesulfonamide (148 mg, 0.450 mmol) and sodium bicarbonate (56.7 mg, 0.675 mmol) in 1,4-dioxane (5 mL) and water (1.5 mL), stirred in air at room temperature, added solid Solvias catalyst (12.60 mg, 0.022 mmol). The reaction mixture was stirred at 120 ° C for 2 h. After this time, sodium hydroxide solution (2N, 0.5 mL) was added and the reaction mixture was allowed to stir at room temperature for two hours. After cooling, the reaction mixture was passed through a celite pad (10 g) and washed with ethyl acetate. The resulting solution was evaporated and the crude residue was purified by MDAP (method C). The appropriate fractions were combined and concentrated in vacuo to give the title compound (43 mg).

LCMS (method A) Rt 0.63 min, MH + 513.

Example 9

6- (1H-Indol-4-yl) -4- [5- (1-piperazinylmethyl) -1,3-oxazol-2-yl] -1H-indazole [0338]

<img file="PL2424864T3_D0048.tif" />

4 - ({2- [6-Chloro-1- (phenylsulfonyl) -1H-indazol-4-ylol] -1,3-oxazol-5-yl} methyl) 1,1-dimethylethyl 1-piperazinecarboxylate ( 303 mg, 0.543 mmol), 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-indole (172 mg, 0.706 mmol, available from Frontier Scientific), (1R, 4S) -bicyclo [2.2. 1] hept-2-yl [(1S, 4R) -bicyclo [2.2. 1] hept-2-yl] phosphate, chloro [2 '- (dimethylamino) -2-biphenyl] palladium (1: 1) (30 mg, 0.054 mmol, available from Fluka) and tripotassium phosphate (346 mg, 1.629 mmol) were dissolved in 1,4-dioxane (10 ml) and water (2.5 ml). The reaction vessel was sealed and heated in a Biotage Initiator at 150 ° C for 30 min. A 2M aqueous NaOH solution (5 ml) was then added and the mixture was stirred for 2 hours. An additional portion of 2M aqueous NaOH (3 mL) was added and stirring continued until deprotection was complete as determined by LCMS analysis. Then DCM was added and the mixture was passed through a phase separator. The organic phase was collected. The aqueous phase was extracted again with DCM, then the organic phases were combined and evaporated to give a brown oil. The oil was dissolved in 5 mL of 4M HCl in 1.4 dioxane and allowed to stir. The mixture was concentrated in vacuo and the resulting solid partitioned between DCM and 2M aqueous HCl. The aqueous phase was basified with 2M aqueous NaOH, then washed with DCM. The organic phase was concentrated in vacuo, then the residue was dissolved in 2 ml DMSO / MeOH (1: 1) and purified by MDAP (method A). Combining the appropriate fractions and concentration by blowing under a stream of nitrogen at 40 ° C gave the title compound (43 mg).

LCMS (method A) Rt 0.62 min, MH + 399.

Example 10

6- (1H-indol-4-yl) -4- (5 - {[4- (1-methylethyl) -1-piperazinyl] methyl} 1,3-oxazol-2-yl) -1H-indazole hydrochloride [0340 ]

<img file="PL2424864T3_D0049.tif" />

[0341] Solution 6- (1H-indol-4-yl) -4- (5 - {[4- (1-methylethyl) -1-piperazinyl] methyl} -1,3-oxazol-2-yl) -1H-indazole in tetrahydrofuran (THF) (7.5 mL) was heated to 60 ° C under a stream of nitrogen. 2M Hydrochloric acid in diethyl ether (0.567 mL, 1.135 mmol) and tetrahydrofuran (THF) (0.5 mL) were mixed and added via a dropping funnel. The solution was stirred at 60 ° C for 30 min before being slowly cooled to RT. After stirring at RT for a further 30 min, the solid was filtered off, then combined with aqueous solutions again and evaporated to dryness. THF (10 ml) was added and the suspension was cycled from RT to reflux 3 times (kept for 30 min at higher / lower temperature). The suspension was stirred at RT for one hour, then filtered under vacuum and the resulting solid was dried in a vacuum oven at 50 ° C overnight to give the title compound as an off-white solid (322 mg).

[0342] LCMS (method A): Rt 0.66 min, MH⁺ 441. ¹H NMR (400 MHz, DMSO-d6) d = 13.53 (s, 1H), 11.44 (br. P., 1H), 10.20 (br. P., 1H), 8, 61 (s, 1H), 8.08 (s, 1H), 7.92 (s, 1H), 7.52 - 7.46 (m, 2H), 7.41 (s, 1H) ), 7.28 - 7.19 (m, 2H), 6.60 (br. P., 1H), 3.87 (s, 2H), 3.41 - 3.32 (m, 3 H +, obscured by H2O), 3.10 - 2.93 (m, 4 H), 2.71 - 2.58 (m, 2 H),

1.23 (d, J = 6.5 Hz, 6H).

Example 11

6- (1H-indol-4-yl) -4- (5 - {[4- (1-methylethyl) -1-piperazinyl] methyl} 1,3-oxazol-2-yl) -1H-indazole hydrochloride [0343 ]

<img file="PL2424864T3_D0050.tif" />

6- (1H-Indol-4-yl) -4- (5 - {[4- (1-methylethyl) -1-piperazinyl] methyl} -1,3-oxazol-2-yl) -1H-indazole ( 19.4 mg, 0.044 mmol) was dissolved in tetrahydrofuran (THF) (0.5 mL) and 4M HCl in dioxane (0.022 mL, 0.088 mmol) was added. The mixture was stirred at RT for 2 h, then the resulting cream precipitate was filtered off and dried in a vacuum oven overnight to give the title compound as a beige solid (15.5 mg).

LCMS (method A): Rt 0.65 min, MH⁺ 441.

¹H NMR (600 MHz, DMSO-d6) d = 13.47 (br. P., 1H), 11.38 (br. P., 1H), 10.17 (br. P., 1H) , 8.66 (s, 1H), 8.13 (s, 1H), 7.93 (s, 1H), 7.51 (br. P., 1H), 7.49 (dt, J = 1.0, 7.5 Hz, 1H), 7.47 (t, J = 3.0 Hz, 1H), 7.25 (t, J = 7.0 Hz, 1H), 7 , 23 (dd, J = 1.5, 7.0 Hz, 1H), 6.60 (ddd, J = 1.0, 2.0, 3.0 Hz, 1H), 4.17 (br p., 2H), 3.50 - 3.39 (m, 3H), 3.35 - 3.25 (m, 2H), 3.22 - 3.11 (m, 2H), 2.99 - 2.76 (m, 2H), 1.24 (d, J = 6.5 Hz, 6H).

Example 12 (R) -Nigdalane N- [5- [4- (5 - {[(2R, 6S) -2,6-dimethyl-4-morpholinyl] methyl} -1,3-oxazol-2-yl) -1H- indazol-6-yl] -2- (methyloxy) -3-pyridinyl] methanesulfonamide [0345]

<img file="PL2424864T3_D0051.tif" />

Method A [0346] N- [5- [4- (5 - {[(2R, 6S) -2,6-dimethyl-4-morpholinyl] methyl} -1,3-oxazol-2-yl) -1H indazol- 6-yl] -2- (methyloxy) -3-pyridinyl] methanesulfonamide (113 mg, 0.220 mmol) was suspended in water (18 mL) and (R) mandelic acid (0.33 M solution in water was added), 735 gl, 0.242 mmol). The mixture was stirred at RT overnight, then concentrated and dried in a vacuum oven at 50 ° C overnight to give the title compound as a white solid (133 mg).

LCMS (method A): Rt 0.60 min, MH + 513.

¹H NMR (400 MHz, DMSO-d6) d = 13.53 (br. P., 1H), 9.43 (s, 1H), 8.58 (s, 1H), 8.43 (d , J = 2.5 Hz, 1H), 7.99 (d, J = 2.5 Hz, 1H), 7.93 (d, J = 1.5 Hz, 1H), 7.89 ( s, 1H), 7.36 (s, 1H), 7.43 - 7.24 (m, 5H), 5.01 (s, 1H), 3.99 (s, 3H), 3.75 (s, 2H), 3.63 - 3.52 (m, 2H), 3.11 (s, 3H), 2.81 (d, J = 10.5 Hz, 2H) , 1.78 (t, J = 10.5 Hz, 2H), 1.04 (d, J = 6.5 Hz, 6H).

Note - mandelate is only present in a 0.8 molar ratio.

Method B [0347] A- [5- [4- (5 - {[(2-R, 65) -2,6-dimethyl-4-morpholinyl] methyl} -1,3-oxazol-2-yl) - 1 Hindazol-6-yl] -2- (methyloxy) -3-pyridinyl] methanesulfonamide (3.17 mg) was suspended in 5% dextrose / water (3 mL). 100 mg / ml aqueous (A) mandelic acid (10 μθ) was added and the mixture was stirred for 45 min to give the title compound as a clear solution.

Experiments with polymorphs

Example 10

X-ray powder diffraction (XRPD) [0348] Data was obtained using a PANalytical X'Pert Pro powder diffractometer, model PW3040 / 60, serial number DY1850 using an X'Celerator detector. Data acquisition conditions were: radiation: Cu Ka, current generator: 40 kV, current generator: 45 mA, start angle: 2.0 ° 2θ, end angle: 40.0 ° 2θ, step size: 0.0167 ° 2θ , time per step: 31.75 seconds. Samples were prepared by depositing a few milligrams of sample on silicon wafers (zero background) to obtain a thin powder film.

[0349] X-ray powder diffraction (XRPD) data are shown in Figure 1. [0350] Peaks characteristic of the solid state form are summarized in Table 1 with the calculated interplanar distances of the crystal lattice. Peak positions were measured using Highscore software.

Table 1

<td>2Θ / °</td><td>distance d / A</td>

<td> 5,2</td><td> 17,0</td>

<td> 10,3</td><td> 8,6</td>

<td> 12,8</td><td> 6,9</td>

<td> 14,8</td><td> 6,0</td>

<td> 15,1</td><td> 5,9</td>

<td> 15,6</td><td> 5,7</td>

<td> 16,8</td><td> 5,3</td>

<td> 17,2</td><td> 5,2</td>

<td> 18,3</td><td> 4,9</td>

<td> 19,6</td><td> 4,5</td>

<td> 20,9</td><td> 4,2</td>

<td>2θ / °</td><td>distance d / A</td>

<td> 21,3</td><td> 4,2</td>

<td> 21,7</td><td> 4,1</td>

<td> 23,2</td><td> 3,8</td>

<td> 24,0</td><td> 3,7</td>

<td> 24,9</td><td> 3,6</td>

<td> 26,0</td><td> 3,4</td>

<td> 27,1</td><td> 3,3</td>

<td> 27,5</td><td> 3,2</td>

<td> 28,2</td><td> 3,2</td>

<td> 28,5</td><td> 3,1</td>

Example 1

X-ray powder diffraction (XRPD) [0351] Data was obtained using a similar method to that described above.

[0352] Data from X-ray powder diffraction (XRPD) are shown in Figure 2.

[0353] Peaks characteristic of the solid state form are summarized in Table 2 with the calculated interplanar distances of the crystal lattice. Peak positions were measured using Highscore software.

Table 2

<td>2θ / °</td><td>distance d / A</td>

<td> 4,5</td><td> 19,8</td>

<td> 6,3</td><td> 13,9</td>

<td> 7,8</td><td> 11,3</td>

<td> 8,8</td><td> 10,1</td>

<td> 9,9</td><td> 8,9</td>

<td> 10,4</td><td> 8,5</td>

<td> 10,7</td><td> 8,3</td>

<td> 11,3</td><td> 7,8</td>

<td> 11,7</td><td> 7,5</td>

<td> 12,2</td><td> 7,3</td>

<td> 12,9</td><td> 6,9</td>

<td> 14,0</td><td> 6,3</td>

<td> 14,5</td><td> 6,1</td>

<td> 15,2</td><td> 5,8</td>

<td> 15,4</td><td> 5,7</td>

<td> 16,1</td><td> 5,5</td>

<td> 16,5</td><td> 5,4</td>

<td> 16,8</td><td> 5,3</td>

<td>2Θ / °</td><td>distance d / A</td>

<td> 17,7</td><td> 5,0</td>

<td> 17,9</td><td> 5,0</td>

<td> 18,5</td><td> 4,8</td>

<td> 19,0</td><td> 4,7</td>

<td> 20,7</td><td> 4,3</td>

<td> 21,4</td><td> 4,1</td>

<td> 22,4</td><td> 4,0</td>

<td> 22,6</td><td> 3,9</td>

<td> 23,4</td><td> 3,8</td>

<td> 23,7</td><td> 3,8</td>

<td> 24,9</td><td> 3,6</td>

<td> 25,4</td><td> 3,5</td>

<td> 25,7</td><td> 3,5</td>

BIOLOGICAL DATA

Samples with PI3K Alfa, Beta, Delta and Gamma kinases

Principle of the assay [0354] The assay reading uses the specific and high affinity binding of PIP3 to an isolated domain homologous to the plexstrin (PH) domain in signal production. Briefly, the PIP3 product is detected by displacing biotinylated PIP3 from an energy transfer complex composed of Europium (Eu) labeled anti-GST monoclonal antibody, GST labeled PH domain, biotin-PIP3 and streptavidinAPC. Eu excitation leads to energy transfer to APC and sensitized emission of fluorescence at 665nm. PIP3 formed as a result of PI3 kinase activity competes for a binding site in the PH domain, which leads to a loss of energy transfer and reduced signal.

Test protocol [0355] Compounds in the form of solids are typically applied in 0.1 μl 100% DMSO 15 to all wells (except columns 6 and 18) of a 384-well low volume Greiner plate with a V-shaped bottom. Compounds serially diluted (4 times in

100% DMSO) across the plate from column 1 to column 12 and from column 13 to column 24 and leaving columns 6 and 18 as containing only DMSO, resulting in 11 concentrations for each test compound.

[0356] The assay is performed using a specific PI3 kinase kit from Millipore (cat. No.

33-001)

The test kit consists of:

4x reaction buffer for PI3K (containing 200 mM Hepes pH 7, 600 mM NaCl, 40 mM MgCl2, &lt;1% cholate (w / v), &lt;1% Chaps (w / v), 0.05% sodium azide (w / v)) · PIP2 (1 mM) · 3x Biotin-PIP3 (50 μΜ) · detection mixture C (containing 267 mM KF) · detection mixture A (containing 60 μg / ml streptavadin -APC) · detection mixture B (containing 36 μg / ml Europium anti-GST antibody (Anti-GST-K) and 90 μg / ml GST-GRP1-PH domain and 1 mM DTT) · stop solution (containing 150 mM EDTA ) [0357] Manually add 3 μl reaction buffer (contains 1 mM DTT) to column 18 only for 100% control inhibition (inactivity)

Manually add 3 μl of 2X enzyme solution to all wells except column 8. Pre-incubate with compound for 15 minutes.

Manually add 3 μl of 2X substrate solution to all wells (column 6 is a control with 0% inhibition)

Leave the plate for 1 h (protect from light) (For gamma only incubation for 50 min)

Manually add 3 μl stop / detection solution to all wells. Leave plate for 1 hour (protect from light)

The sample is read on BMG Rubystar and the ratios are used to calculate 11-point curves.

Note: Substrate solution (concentration) differs for each isoform (see below)

Alpha [0358] 2x substrate solution containing 500 μM ATP, 16 μM PIP2 and 0.030 μM 3X biotin-PIP3.

Beta [0359] 2x substrate solution containing 800 μM ATP, 16 μM PIP2 and 0.030 μM 3X biotin-PIP3.

Delta [0360] 2X substrate solution containing 160 mM ATP, 10 mM PIP2 and 0.030 mM 3X biotin-PIP3.

Gamma [0361] 2X substrate solution containing 30 mM ATP, 16 mM PIP2 and 0.030 mM 3X biotin-PIP3.

Analysis method [0362] Data was processed using a 4-parameter XC50 logistic curve fit algorithm at Activity Base.

[0363] Normalize to% inhibition between control samples with high and low inhibition (0% and 100% inhibition, respectively)

First-class module fit: slope, asymptotes min. and max variables. Secondary module matches: (1) Determine the min. asymptote, (2) Determine the max. asymptote, (3) Determine. asymptotes min. and max

Curve fitting quality control: 95% confidence interval ratio for pXC50&gt; 10

-20 &lt;min. Asymptote &lt;20 &lt;max. Asymptote &lt;120 [0364] The compounds and salts of Examples 1 to 10 and 12 were tested in the above assays with the PI3K Alfa, Beta, Delta and / or Gamma kinases or similar assays and found, that they show a mean pIC50 of PI3K Delta assay of at least 7 or greater.

[0365] The compounds and salts of at least Examples 1, 2, 5 to 10 and 12 were found to exhibit at least 10-fold selectivity for PI3K Delta compared to PI3K Alpha, Beta and / or Gamma.