Oxazole substituted indazoles as pi3-kinase inhibitors

Description

FIELD OF THE INVENTION

[0001] The present invention relates to certain combinations of new compounds that are inhibitors of kinase activity, pharmaceutical compositions containing the combinations, and the use of the combinations for the treatment of various disorders. More particularly, the compounds of the combination according to the invention are inhibitors of the activity or function of the phosphatidylinositol 3'OH family of kinases (henceforth PI3 kinases), for example ΡΙ3ΡΙδ, ΡΙ3Κα, ΡΙ3Κβ and / or ΡΙ3Κγ. Compounds that are inhibitors of the activity or function of PI3 kinases 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 mobility; transplant rejection; transplant rejection; lung damage; and pain including rheumatoid arthritis or osteoarthritis pain, back pain, general inflammatory pain, hepatic disease-induced neuralgia, diabetic neuropathy, inflammatory neuropathic (traumatic) pain, trigeminal neuralgia, and central pain.

BACKGROUND OF THE INVENTION

[0002] Cell membranes are a large body of secondary messengers that may be involved in a variety of signal transduction pathways. Due to the function and regulation of effector enzymes in phospholipid-mediated signaling pathways, PI3 class I kinases (e.g., PI3Kdelta) generate secondary transmitters from membrane phospholipid pools. Class I PI3Ks convert the membrane phospholipid PI (4.5) P₂ in PI (3,4,5) P3, which acts as a secondary relay. PI and PI (4) P are also substrates of PI3K and can be phosphorylated and converted to PI3P and PI (3,4) P, respectively₂. Moreover, these phosphatidylinositols can be converted to other phosphatidylinositols by 5'-specific and 3'specific phosphatases. Thus, the enzymatic activity of PI3K leads both directly and indirectly to the generation of two subtypes of 3'-phosphatidylinositols 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). Eight mammalian PI3Ks have now been identified and classified into three major classes (I, II and III) based on sequence homology, structure, binding partners, mode of activation and substrate preference. In vitro, class I PI3Ks can phosphorylate phosphatidylinositol (PI), phosphatidylinositol-4-phosphate (PI4P) and phosphatidylinositol-4,5-bisphosphate (PI (4,5) P₂) with the formation of phosphatidylinositol-3-phosphate (PI3P), phosphatidylinositol-3,4-bisphosphate (PI (3,4) P₂ and phosphatidylinositol-3,4,5-triphosphate (PI (3,4,5) P3. Class II PI3Ks can phosphorylate PI and PI4P. Class III PI3Ks can only phosphorylate PI (Vanhaesebroeck et al. (1997) supra; Vanhaesebroeck and 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 a pl10 catalytic subunit and a regulatory subunit, and the family is further subdivided into class Ia and class Ib enzymes based on regulatory partners and a regulatory mechanism. Class la enzymes are composed of three different catalytic subunits (pl 10α, pl 10β and pl 10δ) that dimerize with five different regulatory subunits (ρ85α, ρ55α, ρ50α, ρ85β and ρ55γ), all catalytic subunits are capable of interacting with all regulatory subunits to form various heterodimers. Class Ia PI3Ks are generally activated in response to growth factor stimulation of receptor tyrosine kinases through the interaction of 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 receptor tyrosine kinase activation. Both pl 10α and pl 10β are constitutively expressed in all cell types, and ρδδ expression is more restricted to the leukocyte population and some epithelial cells. In contrast, a single class Ib enzyme is composed of the p10γ catalytic unit, which interacts with the p101 regulatory subunit. Moreover, the class Ib enzyme is activated in response to G protein-coupled receptor (GPCR) systems and its expression appears to be limited to leukocytes. .

Scheme A: Transformation of PI (4,5) P2 into PI (3,4,5) P3

[0004]

<img file="PL2899191T3_D0001.tif" />

<img file="PL2899191T3_D0002.tif" />

As illustrated above in Scheme A, phosphatidylinositol 3-kinases (PI3Ks) phosphorylate the hydroxyl at the third carbon of the inositol ring. Phosphatidylinositol phosphorylation to form PtdIns (3,4,5) P3, PtdIns (3,4) P2 and PtdIns (3) P produces secondary messengers for various signal transduction pathways, including those important for cell proliferation, differentiation and cell, cell growth, cell size, cell survival, apoptosis, adhesion, cell motility, cell migration, chemotaxis, invasion, cytoskeleton rearrangement, cell shape changes, vesicular transport, and metabolic pathways (Katso et al. (2001) supra; and Mol. Med. Today 6 (9) pp. 347-57 (2000), Stein et al.).

The activity of PI3 kinases responsible for the production of these phosphorylated signal transduction products was originally identified to be associated with viral oncoproteins and tyrosine kinases that are growth factor receptors, which phosphorylate phosphatidylinositol (PI) and its phosphorylated derivatives at the 3'-hydroxyl ring ( Panayotou et al., Trends Cell Biol. 2 pp. 358-60 (1992)). However, recent biochemical studies have revealed that class I PI3 kinases (e.g. class IA ΡΙ3Kδ isoforms) are bi-specific kinase enzymes, meaning that they exhibit both lipid kinase activity (phosphatidylinositol phosphorylation) and protein kinase activity that has been shown to be that it enables the 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.). The cellular processes in which PI3Ks play a pivotal role include inhibition of apoptosis, reorganization of the actin skeleton, proliferation of cardiac muscle fibers, insulin stimulation of glycogen synthase, TNFα-mediated neutrophil stimulation and superoxide production, and leukocyte migration and adhesion to endothelial cells.

[0006] PI3 kinase activation is believed 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)). PI3 kinase appears to be involved in many aspects of leukocyte activation. P85-related PI3 kinase has been shown to be physically associated with the cytoplasmic domain of CD28, which is an important costimulatory molecule for antigen-response T cell activation (Pages et al. Nature 369 pp. 327-29 (1994); and Rudd, Immunity 4 pp. 527-34 (1996)). Activation of T cells by CD28 lowers the threshold for activation by the antigen and increases the magnitude and duration of the proliferative response. These effects are related to the 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)).

[0007] ΡΙ3Κγ has been identified as a mediator of beta-gamma protein G subunit 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)). More recently (Laffargue et al. Immunity 16 (3) p. 441-51 (2002)) that ΡΙ3Κγ transmits inflammatory signals through various G (i) coupled receptors and is essential for mast cell function, leukocyte-related stimuli and immunology, including for example cytokines, chemokines, adenosines, 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), supra; and Curr. Opinion Cell. Biol. 14 (2) pp. 203-13 (2002), Stephens et al.).

[0008] Specific inhibitors to individual members of the enzyme family provide valuable tools for recognizing the function of each enzyme. Two compounds, LY294002 and wortmannin (henceforth) have been widely used as PI3 kinase inhibitors. These compounds are nonspecific PI3K inhibitors as they do not discriminate among the four members of class I PI3 kinases. For example, the IC50 values ​​for wortmannin against each of the various 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 approximately 15-20 μΜ (Fruman et al. Ann. Rev. Biochem. 67 pp. 481-507 (1998)), also 5-10 microM for the kinase. CK2 protein and some inhibitory activity on phospholipases. Wortmannin is a fungal metabolite that irreversibly inhibits the activity of PI3K by 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 Ptdlns (3,4,5) P3. This synthesis correlates with the activation of an oxygen burst leading to destruction by neutrophils of the invading microbes. Treatment of neutrophils with wortmannin prevents the fMLP-induced oxygen burst response (Thelen et al. Proc. Natl. Acad. Sci. USA 91 pp. 4960-64 (1994)). Indeed, these experiments with wortmannin, as well as other experimental evidence show that PI3K activity in hematopoietic cells, especially neutrophils, monocytes and other leukocytes, is involved in many immune responses other than memory cells associated with acute acute. and chronic inflammation.

<img file="PL2899191T3_D0003.tif" />

<img file="PL2899191T3_D0004.tif" />

LY294002 WORTMANINE

[0009] Based on studies using wortmannin, there is evidence that PI3 kinase function is also required for certain aspects of leukocyte signaling through G-protein coupled receptors (Thelen et al. (1994) supra). In addition, wortmannin and LY294002 have been shown to block neutrophil migration and the release of peroxides.

[0010] It is now fully understood that dysregulation of oncogenes and tumor suppressor genes contributes to the formation of malignant neoplasms, for example by increasing cell growth and proliferation or increasing cell survival. It is now also known that PI3K family-mediated signaling pathways play a major role in many cellular processes including proliferation and survival, and disregulation of these pathways is a contributing factor to a wide range of human cancer 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). The PI3K effector proteins initiate signaling pathways and networks by translocation to cell membranes through a conserved plextrin homology (PH) domain that specifically interacts with Ptdlns (3,4,5) P3 (Vanhaesebroeck et al. Annu Rev. Biochem. (2001) 70 pp. 535-602). Effector proteins signaling through 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).

[0011] In B and T cells, PI3Ks play an important role by activating the Tec family of protein tyrosine kinases, which include Bruton's tyrosine kinase (BTK) in B cells and T cell kinase inducible by interleukin-2 (ITK) in T cells. 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 the C-gamma phospholipase (PLCyl), 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 kinases C in activated T cells

[0012] Contrary to the class IA p110α and p110β, p110δ 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. Knock-in pI-kinase inactivated mice are also viable and their phenotype is limited to defects in signaling in the immune system (Okkenhaug et al. Science (2002) 297 pp. 1031-4). These transgenic mice offer the possibility to observe the function of ΡΙ3Kδ in signaling in B cells and T cells. ). A key effect of PI3K downstream signaling downstream of the TCR is the activation of Akt, which phosphorylates anti-apoptotic factors as well as various transcription factors for cytokine production. Consequently, T cells with a defective p110δ show defects in the proliferation and secretion of Thl and Th2 cytokines. Activation of T cells by CD28 lowers the threshold of TCR activation by the antigen and increases the size and duration of the proliferative response. These effects are mediated by the ΡΙ3Kδ-dependent increase in transcription of many genes including IL2, an important T cell growth factor.

[0013] Thus, PI3K inhibitors are predicted to provide therapeutic benefit through their roles 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-targeting therapies may provide corticosteroid dose reduction properties (Alexander et al. Lancet (1992) 339 p. 324-8), suggesting that they can provide a useful therapy as monotherapy or in combination with inhaled or oral glucocorticosteroids for respiratory disease. The PI3K inhibitor may also be used with other conventional therapies such as long-acting beta-agonists (LABA) in asthma.

[0014] In the vascular system, PI is expressed by endothelial cells and is involved in neutrophil transport by modulating the pro-adhesion state of these cells in response to TNFalpha (Puri et al. Blood (2004) 103 (9) pp. 3448-56.). The role of ΡΙ3Kδ in TNFalpha-induced signaling in endothelial cells was demonstrated by pharmacological inhibition of Akt phosphorylation and PDK1 activity. Moreover, ΡΙ3Kδ is involved in vascular permeability and edema of airway tissues via the VEGF pathway (Lee et al. J. Alergia Clin. Immunol. (2006) 118 (2) p. 4039). These observations suggest an additional benefit of inhibiting PI3Kδ in asthma through the combined reduction of leukocyte extravasation and vascular permeability associated with asthma. Moreover, aktywność3Kδ activity is required for mast cell function both in vitro and in vivo (Ali et al. Nature (2004) 431 pp. 1007-11; and Ali et al. J. Immunol. (2008) 180 (4) pp. 2538-44) further suggesting that inhibition of PI3K should have a therapeutic benefit for allergic indications such as asthma, allergic rhinitis and atopic dermatitis.

[0015] The role of P3Kδ in B cell proliferation, antibody secretion, B cell antigen and IL-4 receptor signaling, B cell antigen presentation function is also well recognized in Okkenhaug et al. (2002) supra; AlAlwan et al. J. Immunol. (2007) 178 (4) pp. 2328-35; and Bilancio et al. Blood (2006) 107 (2) pp. 642-50) and points to a role in autoimmune diseases such as rheumatoid arthritis or systemic lupus erythematosus. Thus, PI3K inhibitors may be of benefit for these indications.

[0016] Pharmacological inhibition of P3Kδ inhibits fMLP-dependent neutrophil chemotaxis in an agarose matrix in a disturbed integrin-dependent ICAM coated system (Sadhu et al., J. Immunol. (2003) 170 (5) pp. 2647-54.). PI inhibition regulates activation, adhesion and migration of neutrophils without affecting neutrophil-mediated phagocytosis and bactericidal activity against Staphylococcus aureus (Sadhu et al. Biochem. Biophys. Res. Commun. (2003) 308 (4) pp. 764-9). Overall, these data suggest that PI3K5 inhibition should not globally suppress neutrophil functions required for innate immune defense. The role of PI3K5 in neutrophils offers a further range in the treatment of inflammatory diseases including tissue remodeling such as COPD or rheumatoid arthritis.

Additionally, there is also strong evidence that the class Ia PI3K 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) p. . 489-501). For example, inhibition of PI 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 pl10a (the PIK3CA gene) has been linked to various other cancers such as colon, breast and lung cancer (Samuels et al. Science (2004) 304 (5670) p. 554).

[0018] PI3K has also been shown to be involved in the formation of central sensitization in painful inflammation (Pezet et al. The J. of Neuroscience (2008) 28 (16), pp. 4261-4270).

[0019] A wide variety of retroviruses and DNA-based viruses activate the PI3K pathway as a means of preventing host cell death during viral infection and ultimately use the synthesis machinery in the host cell 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, PI3K inhibitors may have antiviral properties in addition to well-established oncolytic and anti-inflammatory indications. These antiviral activities offer interesting prospects for virus-induced exacerbations in inflammation. For example, human cold rhinovirus (HRV) is responsible for more than 50% of respiratory tract infections, but the complications from these infections can be significant in some populations. This is especially true of respiratory diseases such as asthma or chronic obstructive pulmonary disease (COPD). Infection by rhinoviruses of epithelial cells leads to PI3K-dependent secretion of cytokines and chemokines (J. Biol. Chem. (2005) 280 (44) p. 36952, Newcomb et al.). These inflammatory responses correlate with worsening of respiratory symptoms during infection. Thus, PI3K inhibitors can suppress an exaggerated immune response to an otherwise mild virus. Most HRV strains infect bronchial epithelial cells by initially binding to the ICAM-1 receptor. The HRV-ICAM-1 complex is then further internalized by endocytosis, and it has been shown that this process requires PI3K activity (J. Immunol. (2008) 180 (2) pp. 870-880, Lau et al.). Thus, PI3K inhibitors can also block viral infections by inhibiting viral entry into host cells.

[0020] PI3K inhibitors may be useful in reducing other types of respiratory infections including the fungal infection of aspergillosis (Mucosal Immunol. (2010) 3 (2) pp. 193-205, Bonifazi et al.). In addition, the ΡΙ3Kδ deficient mice are more resistant to infection by the protozoan Leishmania major (J. Immunol. (2009) 183 (3) pp. 1921-1933, Liu et al.). Given these effects on viral infections, these reports suggest that PI3K inhibitors may be useful in the treatment of a wide variety of infections.

[0021] It has also been shown that PI3K inhibition promotes regulatory T cell differentiation (Proc. Natl. Acad. Sci. USA (2008) 105 (22) pp. 7797-7802, Sauer et al.), Suggesting that PI3K inhibitors may be used for therapeutic targets in case of autoimmune or allergic indications by inducing immunological tolerance towards self antigen or allergen. Recently, the ΡΙ3Kδ 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 otherwise poorly responding COPD patients to corticosteroids may benefit from combining a PI3K inhibitor with a corticosteroid.

[0022] 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 from respiratory failure. In IPF, circulating fibrocytes are targeted to the lungs through the CXCR4 chemokine receptor. PI3K is required for both signaling and expression of CXCR4 (Int. J. Biochem. And Cell Biol. (2009) 41 pp. 1708-1718, Mehrad et al.). Thus, by reducing the expression of CXCR4 and blocking its effector function, a PI3K inhibitor should inhibit the recruitment of fibrocytes into the lungs and consequently slow down the process of fibrosis underlying IPF, a disease causing high unmet need.

[0023] 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 aberrant responses that are mediated by PI3 kinases, there is a continuing need for PI3 kinase inhibitors that can be used to treat a variety of conditions.

[0024] The present inventors have developed new compounds that are inhibitors of kinase activity, especially PI3 kinase activity. Compounds that are inhibitors of PI3 kinase may be useful in the treatment of disorders associated with inappropriate kinase activity, especially 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 mobility; transplant rejection; transplant rejection; lung damage; and pain including rheumatoid arthritis pain or osteoarthritis, back pain, general inflammatory pain, hepatic disease-induced neuralgia, diabetic neuropathy, inflammatory neuropathic (traumatic) pain, trigeminal neuralgia, and central pain.

[0025] In one embodiment, the compounds of the combination of the invention may exhibit selectivity for PI3 kinases over other kinases.

[0026] In another embodiment, the compounds of the combination of the invention may be potent PI3Kδ inhibitors.

[0027] In a further embodiment, the compounds of the combination according to the invention may show selectivity for PI3K5 over other PI3 kinases.

SUMMARY OF THE INVENTION

[0028] The invention relates to certain combinations of novel compounds. More particularly, the invention relates to combinations comprising a compound of formula (I)

<img file="PL2899191T3_D0005.tif" />

(i) in which R.¹, R², R³ and r⁴ are as defined below, and a pharmaceutically acceptable salt thereof together with one or more other therapeutically active agents.

[0029] The compounds are inhibitors of kinase activity, especially 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 combination of a compound of formula (I) or a pharmaceutically acceptable salt thereof together with another therapeutically active agent. Still further, the invention relates to a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof together with one or more other therapeutically active agents for use in inhibiting PI3 kinase activity and treating disorders related thereto. Still further, the disclosure relates to methods of making the combination compounds of the invention.

DETAILED DESCRIPTION OF THE INVENTION

[0030] In one embodiment, the invention relates to combinations comprising a compound of formula (I)

<img file="PL2899191T3_D0006.tif" />

(l) in which

R¹ is a 9- or 10-membered bicyclic heteroaryl, the 9- or 10-membered bicyclic heteroaryl containing from one to three heteroatoms independently selected from oxygen and nitrogen, and is optionally substituted with C1-6alkyl, C8-ecycloalkyl, or halogen , -CN or - NHSO2R⁵or pyridinyl optionally substituted with one or two substituents independently selected from Ci_ealkyl, -OR⁶, halogen and -NHSO2R⁷;

R² and r³, together with the nitrogen atom to which they are attached, are attached to form a 6 or 7-membered heterocyclyl, the 6- or 7-membered heterocyclyl optionally containing an oxygen atom or an additional nitrogen atom and optionally substituted with one or two substituents independently selected from Ci_6alkyl;

R⁴ is hydrogen or methyl;

R⁶ is hydrogen or C1-4alkyl; and each of R.⁵ and r⁷ is independently Ci-ealkyl or phenyl optionally substituted with one or two substituents independently selected from halogen or a pharmaceutically acceptable salt thereof together with one or more other therapeutically active agents.

[0031] 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, R.¹ is a 9- or 10-membered bicyclic heteroaryl, the 9- or 10-membered bicyclic heteroaryl containing 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, R.¹ is a 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, R.¹ is a 9-membered bicyclic heteroaryl, the 9-membered bicyclic heteroaryl contains one or two nitrogen atoms. In another embodiment, R.¹ is indolyl e.g. 1Hindol-4-yl. In another embodiment, R.¹ is pyridinyl optionally substituted with one or two substituents independently selected from Ci_6alkyl, -OR⁶, halogen and -NHSO2R⁷. In another embodiment, R.¹ is pyridinyl optionally substituted with one or two substituents independently selected from -OR⁶ and -NHSO2R⁷. In a further form, R.¹ represents pyridinyl substituted -OR⁶ and -NHSO2R⁷

[0032] In one embodiment, R² and r³, taken together with the nitrogen atom to which they are attached are attached to form a 6-membered heterocyclyl, the 6-membered heterocyclyl optionally containing an oxygen atom or an additional nitrogen atom and optionally substituted with one or two substituents independently selected from C 1-6 alkyl. In another embodiment, R.² and r³, taken together with the nitrogen atom to which they are attached are attached to form a 6-membered heterocyclyl, the 6-membered heterocyclyl optionally containing an oxygen atom or an additional nitrogen atom and is substituted with one or two substituents independently selected from C 1-4 alkyl, on methyl example. In another embodiment, R.² and r³, taken together with the nitrogen atom to which they are attached are attached to 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 C 1-4 alkyl, for example methyl. In another embodiment, R.² and r³, taken together with the nitrogen atom to which they are attached are attached to form a 6-membered heterocyclyl, said 6-membered heterocyclyl containing an oxygen atom and substituted with one or two substituents independently selected from C 1-6 alkyl. In another embodiment, R.² and r³, together with the nitrogen atom to which they are attached are attached to form a 6-membered heterocyclyl, the 6-membered heterocyclyl containing an additional nitrogen atom and is optionally substituted with C 1-4 alkyl, for example isopropyl. In a further form, R.² and r³, together with the nitrogen atom to which they are attached, are attached to form a 6-membered heterocyclyl, said 6-membered heterocyclyl containing an additional nitrogen atom and substituted with C 1-4 alkyl, for example isopropyl.

[0033] In one embodiment, R⁴ is hydrogen.

[0034] In one embodiment, R⁵ is C1-4alkyl such as methyl.

[0035] In one embodiment, R⁶ is C1-4alkyl such as methyl.

[0036] In one embodiment, R⁷ is C 1-6 alkyl. In another embodiment, R.⁷ is C1-4alkyl such as methyl. In a further form, R.⁷ is phenyl optionally substituted with one or two substituents independently selected from halogen, for example fluoro.

[0037] It is to be understood that the present invention includes all combinations of the substituent groups described above.

[0038] In one embodiment, the invention relates to combinations comprising a compound of formula (IA)

<img file="PL2899191T3_D0007.tif" />

(ΙΑ) in which

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 attached to form a 6-membered heterocyclyl, said 6-membered heterocyclyl containing oxygen and optionally substituted with one or two substituents independently selected from C 1-4 alkyl;

R⁴ is a hydrogen atom;

R⁶ is C 1-4 alkyl; and

R⁷ is C 1-4 alkyl;

or a pharmaceutically acceptable salt thereof together with one or more other therapeutically active agents.

[0039] In a further embodiment, the invention relates to combinations comprising a compound of formula (IB)

<img file="PL2899191T3_D0008.tif" />

(IA) in which

R¹ is indolyl;

R² and r³, together with the nitrogen atom to which they are attached, are attached to form a 6-membered heterocyclyl, said 6-membered heterocyclyl containing an additional nitrogen atom and is optionally substituted with C 1-4 alkyl; and

R⁴ is a hydrogen atom;

and their salts, or a pharmaceutically acceptable salt thereof, together with one or more other therapeutically active agents.

[0040] The compounds of the combination according to the invention include the compounds of Examples 1 to 9 and their pharmaceutically acceptable salts.

[0041] In one embodiment, the combination compound of the invention is:

A- [5- [4- (5 - {[(27 ', 6S) -2,6-dimethyl-4-morpholinyl] methyl} -1,3-oxazol-2-yl) -1H-indazol-6 -yl] -2- (methyloxy) -3-pyridinyl] methanesulfonamide;

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

7V- [5- [4- (5 - {[(27 ', 6S) -2,6-dimethyl-4-morpholinyl] methyl} -1,3-oxazol-2-yl) -1 / 7-indazole- 6-yl] -2- (methyloxy) -3-pyridinyl] -2,4-difluorobenzenesulfonamide;

2,4-difluoro-N - [5- [4- (5 - {[4- (1-methylethyl) -1-piperazinyl] methyl} -1,3-oxazol-211-yl) -1 H -indazole- 6-yl] -2- (methyloxy) -3-pyridinyl] benzenesulfonamide;

4- (5 - {[(2J?, 65) -2,6-dimethyl-4-morpholinyl] methyl} -1,3-oxazol-2-yl) -6- (1H-indol-4-yl) - l // - indazole;

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

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

/ V- [5- [4- (5- {[(2J ', 6J') - 2,6-dimethyl-4-morpholinyl] methyl} -1,3-oxazol-2-yl) -1 H - 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 a pharmaceutically acceptable salt thereof.

[0042] In another embodiment, the combination compound of the invention is:

/ V- [5- [4- (5- {[(2 / ?, 65) -2,6-dimethyl-4-morpholinyl] methyl} -1,3-oxazol -2-yl) -1 H - indazol-6-yl] -2- (methyloxy) -3-pyridinyl] methanesulfonamide;

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

/ V- [5- [4- (5- {[(2 / ?, 65) -2,6-dimethyl-4-morpholinyl] methyl} -1,3-oxazol -2-yl) -1 H - indazol-6-yl] -2- (methyloxy) -3-pyridinyl] -2,4-difluorobenzenesulfonamide;

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

4- (5 - {[(2J ?, 65) -2,6-dimethyl-4-morpholinyl] methyl} - 1,3-oxazol-2-yl) -6- (1 H -indol-4-yl) - l // - indazole;

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

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

or a pharmaceutically acceptable salt thereof.

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

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

or a salt thereof.

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

/ V- [5- [4- (5- {[(2 / ?, 65) -2,6-dimethyl-4-morpholinyl] methyl} -1,3-oxazol -2-yl) -1 H - indazol-6-yl] -2- (methyloxy) -3-pyridinyl] methanesulfonamide;

or a pharmaceutically acceptable salt thereof.

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

(J?) - Migdalan jV- [5- [4- (5 - {[(2J?, 65) -2,6-dimethyl-4-morpholinyl] methyl} -1,3-oxazol-2-yl) -1 / n -indazol-6-yl] -2- (methyloxy) -3-pyridinyl] methanesulfonamide.

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

/ V- [5- [4- (5- {[(2 / ?, 65) -2,6-dimethyl-4-morpholinyl] methyl} -1,3-oxazol -2-yl) -1 H - indazol-6-yl] -2- (methyloxy) -3-pyridinyl] methanesulfonamide.

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

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

or a pharmaceutically acceptable salt thereof.

In another embodiment, the combination compound of the invention is: 6- (1H-indol-4-yl) -4- (5 - {[4- (1-methylethyl) -1-piperazinyl] methyl} hydrochloride. , 3-oxazol-2-yl) -1H-indazou.

[0049] In a further embodiment, the combination compound of the invention is:

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

Terms and definitions

[0050] "Alkyl" means a saturated hydrocarbon chain containing the specified number of member atoms. For example, C 1-6 alkyl means an alkyl group having 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.

[0051] "Cycloalkyl" means a saturated hydrocarbon ring containing the specified number of member atoms. Cycloalkyl groups are monocyclic ring systems. For example, C8-cycloalkyl is a cycloalkyl group having 3 to 6 membered atoms. In one embodiment, cycloalkyl groups have 3 or 4 membered atoms. In a further embodiment, cycloalkyl groups contain 5 or 6 membered atoms. Cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

[0052] "Enantiomerically enriched" refers to products whose enantiomeric excess is greater than zero. For example, the term enantiomerically enriched refers to products where the enantiomeric excess is greater than 50% ee, greater than 75% ee, and greater than 90% ee.

[0053] "Enantiomeric excess" or "ee" means the excess of one enantiomer over the other expressed as a percentage. As a result, since both enantiomers are present in equal amounts in the racemic mixture, the enantiomeric excess is zero (0% ee). However, if one enantiomer was enriched to represent 95% of the product, then the enantiomeric excess would be 90% ee (enantiomer enriched 95% minus the other enantiomer 5%).

[0054] "Enantiomerically pure" refers to products whose enantiomeric excess is 99% ee or more.

[0055] "Half-life" (or "half-lives") refers to the time required to convert half the amount of a substance to other chemically distinct molecules in vitro or in vivo.

[0056] "Halogen" means a halogen atom, a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.

[0057] "Heteroaryl", unless otherwise specified, means an aromatic group having 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. Heteroaryl groups herein 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, quinazinilinyl, benzopyridinyl, benzopyridinyl, benzopyrinazolyl.

[0058] "Heteroatom" means a nitrogen atom, a sulfur atom or an oxygen atom.

[0059] "Heterocyclyl", unless otherwise specified, means a saturated or unsaturated ring having 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 of 6 or 7 membered atoms. Monocyclic heterocyclyl includes piperidinyl, piperazinyl, morpholinyl, and hexahydro-1,4-oxazepinyl.

[0060] "Membership atoms" means the atom or atoms that form (s) a 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 of the chain or ring. The atoms that make up the substituent group on the chain or ring are not members of the chain or ring.

[0061] "Optionally substituted" indicates that a group such as heteroaryl may be unsubstituted or substituted with one or more substituents as defined herein.

[0062] "Substituted" in relation to a group indicates that the hydrogen attached to a membered atom in the group is replaced. It is understood that the term "substituted (s)" includes the implied disclaimer that such substitution conforms to the allowed valency of the substituted atom and substituent, and that the result of the substitution yields a stable compound (i.e., a compound that does not spontaneously undergo a 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 valency of the atom. Suitable substituents are defined herein for each substituted or optionally substituted group.

[0063] "Pharmaceutically acceptable" refers to those compounds, salts, materials, compositions, and dosage forms which are, within the reasonable medical judgment, suitable for use in contact with human and animal tissues without undue delay. toxic effects, irritation, or any other problem or complication, commensurate with a reasonable risk-benefit ratio.

[0064] As used herein, the symbols and conventions used in these processes, schemes, and examples are in accordance with those used in current scientific literature, for example, the Journal of the American Chemical Society or the Journal of Biological Chemistry. The standard one-letter or three-letter abbreviations are generally used to indicate amino acid residues 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 may be used in the examples and throughout the description:

DCM Dichloromethane

DMF Dimethylformamide

DMPU 1,3-Dimethyl-3,4,5,6-tetrahydo-2- (1H) -pyrimidinone

DMSO Dimethyl sulfoxide

EtOAc Ethyl acetate g Grams h Hour (hours)

HPLC High performance liquid chromatography

LCMS Liquid chromatography-mass spectroscopy

Liter

M Molar

MDAP Mass directed automated preparative HPLC

Me Methyl

MeCN Acetonitrile

MeOH Methanol mg Milligrams min Minutes ml Milliliters mmol Millimoles

Rt Retention time

RT Room temperature

SCX Exchange of strong cations

SPE Solid phase extraction

TFA Trifluoroacetic acid

THF Tetrahydrofuran

UPLC Ultra high performance liquid chromatography

UV Ultraviolet

[0065] All references to brine are saturated aqueous NaCl.

[0066] Included within the scope of "compounds of the combination according to the invention" are all solvates (including hydrates), complexes, polymorphs, prodrugs, radiolabelled derivatives, stereoisomers and optical isomers of the compounds of formula (I) and pharmaceutically acceptable salts thereof.

[0067] The compounds of the combination according to the invention may be in solid or liquid form. In the solid state, the compounds of the combination according to the invention may be crystalline or non-crystalline, or a mixture thereof. For the compounds of the combination according to the invention which are in crystalline form, the skilled person will appreciate that pharmaceutically acceptable solvates can be formed where solvent molecules are incorporated into the crystal lattice during crystallization. Solvates can include non-aqueous solvents such as ethanol, isopropanol, DMSO, acetic acid, ethanolamine, and EtOAc, or they can contain water as a solvent that is built into the crystal lattice. Solvates where the solvent incorporated into the crystal lattice is water are usually referred to as "hydrates". Hydrates include stoichiometric hydrates as well as compositions involving various amounts of water. The invention includes all such solvates.

[0068] One skilled in the art will further appreciate that certain compounds of the combination according to the invention that exist in crystalline form, including different solvates thereof, may exhibit polymorphism (ie, the ability to exist 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 crystal state. Thus, polymorphs can have different physical properties such as shape, density, hardness, deformability, stability, and dissolution properties. Polymorphs typically exhibit different melting points, IR spectra, and X-ray powder diffraction patterns that can be used for identification. One skilled in the art will recognize that different polymorphs can be produced, for example, by changing or adjusting the reaction conditions or the reagents used in preparing the compound. For example, changes in temperature, pressure or solvent can lead to polymorphs. Moreover, one polymorph may spontaneously transform into another polymorph under certain conditions.

[0069] In one aspect, the present invention provides a combination comprising A- [5 [4- (5 - {[(27 ', 6S) -2,6-dimethyl-4-morpholinyl] methyl} -1,3-oxazole- 2-yl) -1 H -indazol-6-yl] 2- (methyloxy) -3-pyridinyl] methanesulfonamide or a pharmaceutically acceptable salt thereof in crystalline form.

[0070] In one embodiment, the present invention provides a combination comprising A- [5- [4- (5 {[(27 ', 6S) -2,6-dimethyl-4-morpholinyl] methyl} -1,3-oxazol-2 -yl) -1 H -indazol-6-yl] -2 (methyloxy) -3-pyridinyl] methanesulfonamide in crystalline form.

[0071] In another embodiment, the present invention provides a combination comprising crystalline A- [5- [4- (5 - {[(27 ', 6S) -2,6-dimethyl-4-morpholinyl] methyl} -1,3-oxazole -2-yl) -1 H -indazol-6-yl] -2- (methyloxy) -3-pyridinyl] methanesulfonamide, characterized in that it provides an XRPD (X-ray powder diffraction) diffractogram having peaks (° 20) at about 4 , 5, about 11.7, and / or about 12.9.

[0072] In another embodiment, the present invention provides a combination comprising the crystalline / V- [5- [4- (5 - {[(27 ', 6S) -2,6-dimethyl-4-morpholinyl] methyl} -1,3- oxazol-2-yl) -1 H -indazol-6-yl] -2- (methyloxy) -3-pyridinyl] methanesulfonamide, characterized in that it provides an XRPD diffractogram containing the peaks essentially as set forth in Table 2.

[0073] In another embodiment, the present invention provides a combination comprising the crystalline / V- [5- [4- (5 - {[(27 ', 6S) -2,6-dimethyl-4-morpholinyl] methyl} -1,3- oxazol-2-yl) -1 H -indazol-6-yl] -2- (methyloxy) -3-pyridinyl] methanesulfonamide, characterized in that it provides the XRPD pattern essentially according to Figure 2.

[0074] In a further aspect, the present invention provides a combination comprising 6- (1 H indol-4-yl) -4- (5 - {[4- (1-methylethyl) -1-piperazinyl] methyl} -1,3 -oxazol-2-yl) -1 H indazole or a pharmaceutically acceptable salt thereof in crystalline form.

In one embodiment, the present invention provides a combination comprising 6- (1 H -indol-4-yl) -4- (5 - {[4- (1-methylethyl) -1-piperazinyl] methyl} -1 hydrochloride. Crystalline 3-oxazol-2-yl) -1 H -indazole.

[0076] In another embodiment, the present invention provides a combination comprising crystalline 6- (1H-indol-4-yl) -4- (5- {[4- (1-methylethyl) -1-piperazinyl] methyl] -1 hydrochloride. , 3oxazol-2-yl) -1 H -indazole, characterized in that it provides an XRPD (X-ray Powder Diffraction) diffractogram having peaks (° 20) at about 5.2, about 10.3 and / or about 12. 8.

[0077] In another embodiment, the present invention provides a combination comprising the crystalline 6- (1H-indol-4-yl) -4- (5- {[4- (1-methylethyl) -1-piperazinyl] methyl] -1 hydrochloride. , 3-oxazol-2-yl) -1 H -indazole, characterized in that it provides an XRPD pattern containing peaks essentially as set forth in Table 1.

[0078] In a further embodiment, the present invention provides a combination comprising the crystalline 6- (1H-indol-4-yl) -4- (5 - {[4- (1-methylethyl) -1-piperazinyl] methyl} -1 hydrochloride. , 3-Oxazol-2-yl) -1 H -indazole, characterized in that it provides an XRPD pattern substantially consistent with Figure 1.

[0079] When it is indicated herein that there is a peak in the XRPD pattern at a given value, it typically means that the peak is ± 0.2 of the stated value.

The invention also includes a combination comprising isotopically labeled compounds which are identical to the compounds of formula (I) and their pharmaceutically acceptable salts, but because one or more atoms are replaced with an atom of atomic weight or mass number of a different species. than the atomic mass or mass number most commonly found in nature. Examples of isotopes that can be incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, and fluorine, such as²H, ³H, ^hC, ¹⁴C i ¹⁸F.

[0081] The 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, diastereoisomers or other stereoisomeric forms, or as mixtures thereof. Chiral centers such as chiral carbon atoms may also be present on a substituent such as an alkyl group. Where the stereochemistry of the chiral center present in formula (I) or in any chemical structure illustrated herein is not given, it is intended that any stereoisomer and all mixtures thereof are meant to be included. 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.

[0082] Individual stereoisomers of a compound according to formula (I) which contain one or more asymmetric centers can be separated by methods known to those skilled in the art. For example, such resolution may be carried out (1) by formation of diastereomeric salts, complexes or other derivatives; (2) selectively reacting 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 an attached chiral ligand or in the presence of a chiral solvent. As the skilled artisan will appreciate, an additional release step of the desired form is required when a desired stereoisomer is converted to another chemical molecule by one of the separation procedures described above. Alternatively, certain stereoisomers may be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer to another by asymmetric conversion.

The compounds according to formula (I) may also contain centers of geometric asymmetry. Where stereochemistry is not given, the geometric asymmetry centers present in formula (I) or in any chemical structure illustrated herein are intended to include the trans geometric isomer, the cis geometric isomer, and all mixtures thereof. Likewise, all tautomeric forms are also encompassed by formula (I) regardless of whether such tautomers are in equilibrium or one form predominates.

[0084] It is to be understood that reference herein to the compounds of formula (I) and their salts includes compounds of formula (I) in the form of the free acids or free bases or their salts, e.g. in the form of their pharmaceutically acceptable salts. Thus, in one embodiment, the invention relates to combinations comprising a compound of formula (I) in free acid or free base form. In another embodiment, the disclosure relates to compounds of formula (I) and salts thereof. In a further embodiment, the invention relates to combinations comprising a compound of formula (I) and pharmaceutically acceptable salts thereof.

[0085] The skilled artisan will appreciate that pharmaceutically acceptable salts of the compounds according to formula (I) can be prepared. Indeed, in certain embodiments of the invention, pharmaceutically acceptable salts of the compounds according to formula (I) may be advantageous over the corresponding free acid or free base in that such salts may impart greater stability or solubility to the molecule thereby facilitating formulation into the molecule. dosage form. Accordingly, the invention further relates to combinations comprising the compounds of formula (I) and their pharmaceutically acceptable salts.

[0086] 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.

[0087] Salts and solvates having pharmaceutically unacceptable counterions or associated solvents are, for example, for use as intermediates in the preparation of other compounds of formula (I) and their pharmaceutically acceptable salts. Thus, one embodiment of the disclosure includes compounds of formula (I) and salts thereof.

[0088] In certain embodiments, compounds according to formula (I) may contain an acid functional group. Suitable pharmaceutically acceptable salts include salts of such acid functional groups. 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.

[0089] 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, citrate, salicylate, /? - aminosalicylate, glycolate, lactate, heptanoate, phthalate, oxalate, succinate, benzoate, o-acetoxybenzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, naphthoate, hydroxynaphthoate, mandelate, tannate, formate, stearate, ascorbate, palmitate, oleate, pyruvate, pamoate, malonate, laurate, glutarate, ethosulfate, estersulfate (glutanate, mesylate, ester) hydroxyethanesulfonate, benzenesulfonate (besylate), (β-aminobenzenesulfonate), β-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 an almondate, such as (7 ') - mandelate.

[0090] In one embodiment, the invention provides a combination comprising a compound which is:

jV- [5- [4- (5- {[(27 ', 60) -2,6-dimethyl-4-morpholinyl] methyl} -1,3-oxazol-2-yl) -1 / 7-indazole- 6-yl] -2- (methyloxy) -3-pyridinyl] methanesulfonamide;

or a pharmaceutically acceptable salt thereof.

[0091] In another embodiment, the invention provides a combination comprising a compound which is: 6- (177-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

[0092] The combination compounds of the invention can be made in a variety of ways, including standard chemical reactions. Any previously defined variable will continue to have the previously defined meaning unless otherwise indicated. Illustrative synthetic methods are provided below, and then specific combination compounds of the invention are prepared in the Examples section.

Method A

[0093] Compounds of formula (I), wherein R¹, R², R³ and r⁴ are as defined above, or their salts can be prepared from compounds of formula (II)

<img file="PL2899191T3_D0009.tif" />

(H) where R.² and r³ are as defined above, and R.^4a is methyl or a suitable protecting group such as benzenesulfonyl by treatment with an appropriate 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 (17 ', 4S) -bicyclo [2.2.1] hept-2-yl [(lS, 47') bicyclo [2.2.1] hept-2-yl ] chloro [2 '- (dimethylamino) -2-biphenylyl] palladium phosphate, in a suitable solvent, such as a mixture of 1,4-dioxane and water in a suitable ratio, for example 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.

[0094] The R group¹ introduced via a boronic acid or boronate ester may be protected with a suitable protecting group such as a t-butyldimethylsilyl group and an additional deprotection step may be required, for example 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.

[0095] If necessary, for compounds of formula (II), wherein R^4a represents a suitable protecting group, the protecting group such as benzenesulfonyl may 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 for example around 20 ° C.

[0096] Compounds of formula (II), wherein R², R³ and r^4a are as defined above, can be prepared from compounds of formula (III)

Z ζ — χ '

N. O

JO3ⁿ

R^4a (HI) where R.^4a has the meaning as above, and X¹ is a suitable leaving group, such as Br, by treatment with an amine of formula HNR²R³where R.² and r³ are as above, in a suitable solvent such as dichloromethane and at a suitable temperature such as room temperature, for example about 20 ° C.

[0097] Compounds of formula (III), wherein R^4a has the meaning as above, and X¹ is Br, can be prepared from compounds of formula (IV)

<img file="PL2899191T3_D0010.tif" />

(IV) in which R.^4a is 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 at example at about 0 ° C while heating to about 20 ° C after the addition.

[0098] Relatively, alternatively compounds of formula (III) wherein R^4a has the meaning as 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.

[0099] Compounds of formula (IV), wherein R^4a is as defined above, it can be prepared from compounds of formula (V)

<img file="PL2899191T3_D0011.tif" />

(V) 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.

[0100] Compounds of formula (V), wherein R^4a is as defined above, can be prepared from compounds of formula (VI)

SnMe₃

R⁴³ (VI) in which R.^4a is as defined above, by treatment with a suitable 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) palladium (0) in in a suitable solvent, such as V, V-dimethylformamide, in the presence of a suitable iodide, such as sodium iodide, and under microwave irradiation at a suitable temperature such as from about 80 ° C to about 150 ° C. for example about 100 ° C.

[0101] Or, alternatively, compounds of formula (V) wherein R^4a is as defined above, can be prepared from compounds of formula (VII) as defined below by treatment with a suitable 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, for example 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, for example about 85 ° C.

[0102] Compounds of formula (VI), wherein R^4a is as defined above, it can be prepared from compounds of formula (VII)

<img file="PL2899191T3_D0012.tif" />

(VII) in which R.^4a is as defined above by treatment with a suitable 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.

[0103] Compounds of formula (VII) wherein R^4a is methyl, can be prepared from compounds such as a compound of formula (VIII)

AND

<img file="PL2899191T3_D0013.tif" />

(VIII) by methylation with 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 addition of an alkylating agent such as iodomethane and stirring at a suitable temperature such as room temperature, for example about 20 ° C.

[0104] The compound of formula (VIII) is commercially available.

[0105] Compounds of formula (VII) wherein 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 hydride in a suitable solvent such as V, 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, such as about 0 ° C by heating to about 20 ° C after the addition.

[0106] Or, alternatively, compounds of formula (VII) wherein 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 bisulfate 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

[0107] Compounds of formula (I), wherein R¹, R² and r³ are as defined above, and R.⁴ represents a hydrogen atom, or a salt thereof, can be prepared from compounds of formula (IX)

<img file="PL2899191T3_D0014.tif" />

<img file="PL2899191T3_D0015.tif" />

(IX) in which R.¹, R², R³ are as defined above, and R.^4b represents 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, for example about 20 ° C.

[0108] Compounds of formula (IX), wherein R¹, R², R³ and r^4b are as defined above, can be prepared from compounds of formula (X)

<img file="PL2899191T3_D0016.tif" />

<img file="PL2899191T3_D0017.tif" />

(X) in which R.¹ and r^4b are as defined above and X² is a suitable leaving group, such as Br, by treatment with an amine of formula HNR²R³where R.²and 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.

[0109] Compounds of formula (X), wherein R¹ and r^4b are as defined above and X²is Br, can be prepared from compounds of formula (XI)

<img file="PL2899191T3_D0018.tif" />

<img file="PL2899191T3_D0019.tif" />

(XI) in which R.¹ 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 at example around 0 ° C warming to room temperature after addition.

[0110] Compounds of formula (XI), wherein R¹ and r^4b are as defined above, can be prepared from compounds of formula (XII)

<img file="PL2899191T3_D0020.tif" />

<img file="PL2899191T3_D0021.tif" />

(XII) in which R.¹ and r^4b are 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. .

[0111] Compounds of formula (XII) wherein R¹ and r^4b are as defined above, can be prepared from compounds of formula (XIII)

<img file="PL2899191T3_D0022.tif" />

<img file="PL2899191T3_D0023.tif" />

(ΧΙΗ) where R.^4b is as defined above, by treatment with a suitable boronic acid or boronate ester such as {1 - [(1,1-dimethylethyl) (dimethyl) silyl] -1 / f-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 [2 'phosphate - (dimethylamino) -2-biphenylyl] 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 trobasic potassium phosphate, and at a suitable temperature such as about 80 ° C to about 150 ° C, for example about 100 ° C. Alternatively, this method may be performed under microwave irradiation, and at a suitable temperature, such as from about 80 ° C to about 150 ° C, for example about 120 ° C.

<img file="PL2899191T3_D0024.tif" />

(XIV)

[0112] Boronate esters of formula (XIV), wherein R⁷ has the meaning defined above, R.⁸ is C 1-6 alkyl, -OR⁶ or a halogen atom, wherein R⁶ is as defined above, and n = 0 or 1, may be prepared from compounds of formula (XV)

<img file="PL2899191T3_D0025.tif" />

(XV) in which R.⁸ is as defined 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 for example about 20 ° C.

[0113] Compounds of formula (XV) wherein R⁸ is as defined above, and n = 0 or 1, may be prepared from compounds of formula (XVI)

H.₂Nx ^ .Br (XVI) in which R.⁸ is as defined above where a number of analogs are commercially available, by treatment with a suitable borolate such as 4,4,4 ', 4', 5.5,5 ', 5'octamethyl-2,2'-bi- 1,3,2-dioxaborolane, in the presence of a suitable palladium catalyst such as dichloro [1,1'-bis (diphenylphosphino) ferrocene] palladium (II) dichloromethane adduct in the presence of a suitable base such as potassium acetate in a suitable solvent , such as 1,4-dioxane, and at an appropriate temperature, such as from about 50 ° C to about 120 ° C, such as about 80 ° C.

[0114] Thus, in one embodiment, the disclosure provides a method of making a combination compound of the invention, comprising:

a) reacting the compound of formula (II)

With no²r³

N ^ O

JOT^N

R^4a (U) in which R.² and r³ are as defined above, and R.^4a is methyl or an appropriate 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 R.⁴ represents a hydrogen atom, a compound of formula (IX) is reacted

Z —No²R³^N^/°

R^4b (IX) in which R.¹, R², R³ and r^4b are as defined above, with the appropriate aqueous inorganic base.

Application methods

[0115] The compounds of the combination 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 an 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 PI3 kinase activity expected for an individual patient. Inadequate PI3 kinase activity may take the form of, for example, an abnormal increase in activity or a deviation from the level of normal PI3 kinase activity synchronization and / or regulation. Such inappropriate activity may then result, for example, from overexpression or mutation of the protein kinase leading to inappropriate or uncontrolled activation. Thus, in another aspect, the invention relates to use for the treatment of such disorders.

[0116] 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 mobility; transplant rejection; transplant rejection; lung damage; and pain, including rheumatoid arthritis or osteoarthritis pain, back pain, general inflammatory pain, hepatic disease-induced 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 mobility; transplant rejection; transplant rejection; lung damage; and pain including rheumatoid arthritis or osteoarthritis pain, back pain, general inflammatory pain, liver disease-induced neuralgia, diabetic neuropathy, inflammatory neuropathic (traumatic) pain, trigeminal neuralgia, and central pain.

[0117] The uses of the disclosure 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 disclosure include the use in treating any of the above-mentioned 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.

[0118] The term "treat" as used herein in reference 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 the biological cascade that lead to or responsible for the disorder, or affecting (b) one or more biological signs of the disorder, (3) alleviation of 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.

[0119] As indicated above, "treating" a disorder includes preventing the disorder. As one skilled in the art will recognize, "prevention" is not an absolute must. 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 onset of such a disorder or its biological sign.

[0120] As used herein, "safe and effective amount" in reference 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 treat the condition in a patient, but small enough to avoid serious harm to the patient. side effects (with a reasonable risk-benefit ratio) in terms of rational medical judgment. The safe and effective amount of a compound will vary with the particular compound selected (e.g. including compound potency, efficacy and half-life); 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 to be treated; the medical history of the treated patient; duration of treatment; the nature of the co-therapy; the desired therapeutic effect; and the like, but nevertheless can be determined by a person skilled in the art on a routine basis.

[0121] As used herein, the term "patient" refers to a human (including adults and children) or other animal. In one embodiment, "patient" refers to a human.

[0122] The compounds of formula (I), or pharmaceutically acceptable salts thereof, may be administered by any suitable route of administration, including both systemic and local 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 by injection or infusion. Parenteral administration includes injection or infusion intravenously, intramuscularly, and subcutaneously. Topical administration includes application to the skin as well as ocular, aural, vaginal, inhalation and intranasal administration. Inhalation refers to administration into the lungs of a patient, whether inhalation is via the oral cavity 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, compounds of formula (I) or pharmaceutically acceptable salts thereof can be administered intranasally.

[0123] The compounds of formula (I), or pharmaceutically acceptable salts thereof, may be administered at once or according to a dosage regimen in which the number of doses is administered at varying 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 a day. In a further embodiment, the dose is administered twice daily. Dosages can be administered until the desired therapeutic effect is achieved or indefinitely in order to maintain the desired therapeutic effect. Suitable dosing regimens for a compound of formula (I) or a pharmaceutically acceptable salt thereof depend on the pharmacokinetic properties of such compound such as absorption, distribution, and half-life, which can be determined by one skilled in the art. In addition, suitable dosing regimens, including the duration of such regimens, are employed with the compound of formula (I) or a pharmaceutically acceptable salt thereof depending on the disorder treated, the severity of the disorder being treated, the age and physical condition of the patient to be treated, the medical history of the patient being treated, simultaneous therapy, the desired therapeutic effect, and similar factors within the knowledge and experience of the specialist. Furthermore, it will be understood by those skilled in the art that appropriate dosing regimens may need to be adjusted either with the particular patient's response to the dosing regimen or over time as it may vary from patient to patient.

[0124] Typical daily doses may vary depending upon the particular route of administration selected. Typical daily doses for oral administration are in the 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 be from 0.5 mg to 2 g per patient, such as 10 mg to 1 g per patient.

[0125] In addition, the compounds of formula (I) can be administered as prodrugs. The term "prodrug" of a compound of formula (I) as used herein is a functional derivative of the compound which, 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 artisan to do one or more of the following: (a) modify the onset of in vivo activity of the compound; (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 solubility of the compound in vivo; and (e) overcoming a side effect or other relationship difficulty. Typical functional derivatives used to prepare prodrugs include modified forms of the compound that can be chemically or enzymatically cleaved in vivo. Such modified forms, which include the preparation of phosphates, amides, esters, thioesters, carbonates, and carbamates, are well known to those skilled in the art.

[0126] In one aspect, the disclosure therefore provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in treating a disorder mediated by inappropriate PI3 kinase activity, comprising administering to a patient in need thereof a safe and effective amount. In one embodiment, the disclosure provides A- [5- [4 (5 - {[(27 ', 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 use in the treatment of a disorder mediated by inappropriate PI3 kinase activity, comprising administering to a patient in need thereof a safe and effective amount. In another embodiment, the disclosure provides (7 ') - mandelate A- [5- [4- (5 - {[(27', 6S) 2,6-dimethyl-4-morpholinyl] methyl} -1,3-oxazol-2 -yl) -1 H -indazol-6-yl] -2- (methyloxy) 3-pyridinyl] methanesulfonamide for use in the treatment of a disorder mediated by inappropriate PI3 kinase activity, comprising administering to a patient in need thereof a safe and effective amount. In another embodiment, the disclosure provides 6- (1 H indol-4-yl) -4- (5 - {[4- (1-methylethyl) -1-piperazinyl] methyl} -1,3-oxazol-2-yl) Indazole or a pharmaceutically acceptable salt thereof for use in the treatment of a disorder mediated by inappropriate PI3 kinase activity comprising administering to a patient in need thereof a safe and effective amount. In a further embodiment, the invention provides 6- (1H-indol-4-yl) -4- (5 - {[4- (1-methylethyl) -1piperazinyl] methyl} -1,3-oxazol-2-yl) hydrochloride -1 H -indazole for use in treating a disorder mediated by inappropriate PI3 kinase activity, comprising administering to a patient in need thereof a safe and effective amount.

[0127] 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 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); gastrointestinal diseases (including thrombosis and atherosclerosis); hematological malignancies; neurodegenerative diseases; inflammation of the pancreas; multi- organ failure; kidney disease; platelet aggregation; tumor; sperm mobility; transplant rejection; transplant rejection; lung damage; and pain (including rheumatoid arthritis or osteoarthritis pain, back pain, general inflammatory pain, liver disease-induced neuralgia, diabetic neuropathy, inflammatory neuropathic (traumatic) pain, trigeminal neuralgia, and central pain).

[0128] 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).

[0129] In one embodiment, the disorder mediated by inappropriate PI3 kinase activity is pain.

[0130] In another embodiment, the present disclosure provides A- [5- [4- (5 - {[(2J ', 6S) -2,6-dimethyl-4-morpholinyl] methyl} -1,3-oxazol-2-yl) - l / 7-indazol-6-yl] -2- (methyloxy) -3-pyridinyl] methanesulfonamide or a pharmaceutically acceptable salt thereof for use in the treatment of a respiratory disease comprising administering to a patient in need thereof a safe and effective amount.

[0131] In another embodiment, the present disclosure provides A- [5- [4- (5 - {[(2J ', 6S) -2,6-dimethyl-4-morpholinyl] methyl} -1,3-oxazol-2-yl) - l / 7-indazol-6-yl] -2- (methyloxy) -3-pyridinyl] methanesulfonamide or a pharmaceutically acceptable salt thereof for use in the treatment of asthma comprising administering to a patient in need thereof a safe and effective amount.

[0132] In another embodiment, the present disclosure provides (J ') - manddalate A- [5- [4- (5 - {[(2J', 6S) 2,6-dimethyl-4-morpholinyl] methyl} -1,3 -oxazol-2-yl) -1 / 7-indazol-6-yl] -2- (methyloxy) 3-pyridinyl] methanesulfonamide or a pharmaceutically acceptable salt thereof for use in the treatment of a respiratory disease comprising administering to a patient in need thereof a safe and effective amount .

[0133] In another embodiment, the present disclosure provides (J ') - mandelate A- [5- [4- (5 - {[(2J', 6S) 2,6-dimethyl-4-morpholinyl] methyl} -1,3 -oxazol-2-yl) -1 / 7-indazol-6-yl] -2- (methyloxy) 3-pyridinyl] methanesulfonamide or a pharmaceutically acceptable salt thereof for use in the treatment of asthma comprising administering to a patient in need thereof a safe and effective amount.

[0134] In another embodiment, the present disclosure provides 6- (1/7-indol-4-yl) -4- (5 - {[4- (1-methylethyl) -1-piperazinyl] methyl} -1,3-oxazol-2. -yl) -1 / 7-indazole or a pharmaceutically acceptable salt thereof for use in the treatment of a respiratory disease comprising administering to a patient in need thereof a safe and effective amount.

[0135] In another embodiment, the present disclosure provides 6- (1/7-indol-4-yl) -4- (5 - {[4- (1-methylethyl) -1-piperazinyl] methyl} -1,3-oxazol-2. -yl) -1 / 7-indazole or a pharmaceutically acceptable salt thereof for use in the treatment of asthma comprising administering to a patient in need thereof a safe and effective amount.

[0136] In another embodiment, the present disclosure provides 6- (177-indol-4-yl) 4- (5 - {[4- (1-methylethyl) -1-piperazinyl] methyl} -1,3-oxazol-2 hydrochloride. -yl) -1 / 7-indazole for use in treating a respiratory disease comprising administering to a patient in need thereof a safe and effective amount.

In a further embodiment, the present disclosure provides 6- (1-7-indol-4-yl) -4- (5 - {[4- (1-methylethyl) -1-piperazinyl] methyl} -1,3-oxazole- hydrochloride 2-yl) -1 / 7-indazole for use in treating asthma comprising administering to a patient in need thereof a safe and effective amount.

[0138] In one aspect, the disclosure provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in medical therapy. In one embodiment, the disclosure provides A- [5- [4- (5 - {[(2J ', 6S) -2,6-dimethyl-4-morpholinyl] methyl} -1,3-oxazol-2-yl) l / 7-indazol-6-yl] -2- (methyloxy) -3-pyridinyl] methanesulfonamide or a pharmaceutically acceptable salt thereof for use in medical therapy. In another embodiment, the disclosure provides A- [5- [4- (5 - {[(2J ', 6S) -2,6-dimethyl-4-morpholinyl] methyl} -1,3-oxazole- 2-yl) -1 / 7-indazol-6-yl] -2- (methyloxy) -3-pyridinyl] methanesulfonamide for use in medical therapy. In another embodiment, the disclosure provides 6- (1/7-indol-4-yl) -4- (5 {[4- (1-methylethyl) -1-piperazinyl] methyl} -1,3-oxazol-2-yl) -1 / 7-indazole or a pharmaceutically acceptable salt thereof for use in medical therapy. In a further embodiment, the disclosure provides 6- (1/7-indol-4-yl) -4- (5 - {[4- (1-methylethyl) -1piperazinyl] methyl} -1,3-oxazol-2-yl) hydrochloride. -1 / 7-indazole for use in medical therapy.

[0139] In another aspect, the disclosure 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 disclosure provides A- [5- [4- (5 {[(27 ', 6S) -2,6-dimethyl-4-morpholinyl] methyl} -1,3-oxazol-2-yl) -1 / 7-indazol-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 disclosure provides A- [5- [4- (5 - {[(27 ', 6S) -2,6-dimethyl-4-morpholinyl] methyl} -1,3-oxazol-2- yl) -1 / 7-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 disclosure provides 6- (1 / 7indol-4-yl) -4- (5 - {[4- (1-methylethyl) -1-piperazinyl] methyl} -1,3-oxazol-2-yl) - 1 H -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 disclosure provides 6- (1H-indol-4-yl) -4- (5 - {[4- (1-methylethyl) -1-piperazinyl] methyl} -1,3-oxazol-2- hydrochloride. ilo) -1 H -indazole for use in the treatment of a disorder mediated by inappropriate PI3 kinase activity.

[0140] In a further aspect, the disclosure 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 disclosure provides the use of A- [5- [4- (5 - {[(27 ', 6S) -2,6-dimethyl-4-morpholinyl] methyl} -1,3-oxazol-2-yl) - 1 H -indazol-6-yl] -2- (methyloxy) -3-pyridinyl] methanesulfonamide 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 another embodiment, the disclosure provides the use of (7 ') - almonds A- [5- [4- (5 - {[(27', 6S) -2,6-dimethyl-4-morpholinyl] methyl} -1,3-oxazol-2 -yl) -1 / 7-indazol-6-yl] -2- (methyloxy) -3-pyridinyl] methanesulfonamide in the manufacture of a medicament for use in the treatment of a disorder mediated by inappropriate PI3 kinase activity. In another embodiment, the disclosure provides the use of 6- (1H-indol-4-yl) -4- (5- {[4- (1-methylethyl) -1-piperazinyl] methyl} -1,3-oxazol-2- il) -1 H -indazole 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 a further embodiment, the disclosure provides the use of 6- (1H-indol-4-yl) -4- (5- {[4- (1-methylethyl) -1-piperazinyl] methyl} -1,3-oxazol-2 hydrochloride. -yl) 1/7-indazole in the manufacture of a medicament for use in the treatment of a disorder mediated by inappropriate PI3 kinase activity.

Compositions

[0141] The compounds of formula (I) and their pharmaceutically acceptable salts will typically, but not necessarily, be formulated into a pharmaceutical composition prior to administration to a patient.

[0142] Accordingly, in one aspect, the disclosure relates to pharmaceutical compositions comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

[0143] In one embodiment, the present disclosure provides a pharmaceutical composition comprising 7V- [5- [4- (5 - {[(27 ', 6X) -2,6-dimethyl-4-morpholinyl] methyl} -1,3-oxazole -2-yl) -1 / 7-indazol-6-yl] -2- (methyloxy) -3-pyridinyl] methanesulfonamide or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients. [0144] In another embodiment, the present disclosure provides a pharmaceutical composition comprising A- [5- [4- (5 - {[(27 ', 6S) -2,6-dimethyl-4-morpholinyl] methyl} (7') mandelate. -1,3-oxazol-2-yl) -1 / 7-indazol-6-yl] -2- (methyloxy) -3-pyridinyl] methanesulfonamide, and one or more pharmaceutically acceptable excipients.

In another embodiment, the present disclosure provides a pharmaceutical composition comprising 6- (1H-indol-4-yl) -4- (5 - {[4- (1-methylethyl) -1-piperazinyl] methyl} -1, 3-oxazol-2-yl) -1 / 7-indazole or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

[0146] In a further embodiment, the present disclosure provides a pharmaceutical composition comprising 6- (1H-indol-4-yl) -4- (5 - {[4- (1-methylethyl) -1-piperazinyl] methyl} -1 hydrochloride. , 3-oxazol-2-yl) -1 H -indazole, and one or more pharmaceutically acceptable excipients.

[0147] In another aspect, the disclosure relates to pharmaceutical compositions containing 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.

[0148] In a further aspect, the disclosure 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.

[0149] In one embodiment, the present disclosure provides a pharmaceutical composition comprising A- [5- [4- (5 - {[(2J ', 65) -2,6-dimethyl-4-morpholinyl] methyl} -1, 3- oxazol-2-yl) -1 Hindazol-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.

[0150] In one embodiment, the present disclosure provides a pharmaceutical composition comprising A- [5- [4- (5 - {[(2J ', 6S) -2,6-dimethyl-4-morpholinyl] methyl) - mandelate. } -1,3-oxazol-2-yl) -1 H -indazol-6-yl] -2- (methyloxy) -3-pyridinyl] methanesulfonamide, for the treatment or prophylaxis of a disorder mediated by inappropriate PI3 kinase activity.

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

[0152] In a further embodiment, the present disclosure provides a pharmaceutical composition comprising 6- (lH-indol-4-yl) -4- (5 - {[4- (l-methylethyl) -1-piperazinyl] methyl} - hydrochloride. 1,3-oxazol-2-yl) -1 H -indazole, for the treatment or prevention of a disorder mediated by inappropriate PI3 kinase activity.

[0153] The pharmaceutical compositions of the disclosure can 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 disclosure 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 prepared in a unit dosage form, the pharmaceutical compositions of this disclosure can 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 pharmaceutical thereof. acceptable salt.

[0154] The pharmaceutical compositions of the disclosure typically contain one compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0155] The term "pharmaceutically acceptable excipient" as used herein means a pharmaceutically acceptable substance, composition, or vehicle involved in giving the pharmaceutical composition form or cohesiveness. Each excipient must be compatible with the other ingredients of the pharmaceutical composition when mixed with them, thus avoiding interactions which, upon administration to a patient of the compound of formula (I) or a pharmaceutically acceptable salt thereof, would significantly reduce its effectiveness and result in pharmaceutical compositions which would would be pharmaceutically unacceptable. Furthermore, any excipient must of course be pharmaceutically acceptable, e.g. of sufficiently high purity.

[0156] The compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or excipients will typically be formulated into dosage forms adapted for administration to a 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 wafers; (2) parenteral administration, such as sterile solutions, suspensions, and reconstitution powders; (3) transdermal administration, such as transdermal patches; (4) rectal administration, such as suppositories; (5) inhalation, such as aerosols, solutions, and dry powders; and (6) topical administration, such as creams, ointments, lotions, solutions, pastes, sprays, foams, and gels.

[0157] Suitable pharmaceutically acceptable excipients will vary depending on the particular dosage form selected. Moreover, suitable pharmaceutically acceptable excipients may be selected for the particular function they may perform in the composition. For example, certain pharmaceutically acceptable excipients may be selected for their ability to facilitate the manufacture of unitary dosage forms. Certain pharmaceutically acceptable excipients may be selected for their ability to facilitate the manufacture of stable dosage forms. Certain pharmaceutically acceptable excipients may be selected for their ability to facilitate the transfer or transport of a compound or compounds of formula (I), or pharmaceutically acceptable salts thereof, from one organ or part of the body to a patient, into another organ or part of the body. Certain pharmaceutically acceptable excipients may be selected for their ability to increase patient compliance.

[0158] Suitable pharmaceutically acceptable excipients include the following types of excipients: diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifying agents, sweetening agents, flavoring agents, flavor masking agents , colorants, anti-caking agents, humectants, chelating agents, plasticizers, viscosity-increasing agents, antioxidants, preservatives, stabilizing agents, surfactants and buffering agents. One skilled in the art will recognize that certain pharmaceutically acceptable excipients may serve more than one function and may have alternative functions depending on what amount of the excipient is present in the formulation and what other ingredients are present in the formulation.

[0159] Those skilled in the art are knowledgeable and skilled in the art to select suitable pharmaceutically acceptable excipients in appropriate amounts for use in this invention. Furthermore, there are many sources available to the skilled artisan 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).

[0160] 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).

[0161] Thus, in another aspect, the disclosure relates to a method of 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 admixing the ingredients. A pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt thereof can be prepared, for example, by preparing a mixture at ambient temperature and atmospheric pressure.

[0162] In one embodiment, the compounds of formula (I) or a pharmaceutically acceptable salt 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.

[0163] In one aspect, the disclosure relates to a solid oral dosage form, such as a tablet or capsule, containing a safe and effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof and a diluent or filler. Suitable diluents and fillers 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 can further include a binding agent. 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 further include a disintegrant. Suitable disintegrants include crospovidone, sodium starch glycolate, croscarmellose, alginic acid, and sodium carboxymethyl cellulose. The oral solid dosage form may further include a lubricant. Suitable lubricants include stearic acid, magnesium stearate, calcium stearate and talc.

[0164] Where appropriate, dosage unit formulations for oral administration may be microencapsulated. The composition can also be prepared to release in a sustained or sustained release manner such as by coating or embedding the particulate compound in polymers, wax, and the like.

[0165] The compounds of formula (I) or their pharmaceutically acceptable salts can also be coupled with soluble polymers as drug carriers capable of targeting a drug. Such polymers may include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropyl methacrylamide-phenol, polyhydroxyethylaspartamide-phenol, or polyethylene-polylysine substituted with palimitoyl moieties. In addition, the compounds of formula (I) or pharmaceutically acceptable salts thereof can be coupled with a class of biodegradable polymers useful for achieving controlled drug release, for example poly (lactic acid), poly (epsilon-caprolactone), poly (hydroxybutyric acid), polyorthoesters, polyacetals. , polydihydropyranes, polycyanoacrylates, and cross-linked or amphipathic block copolymers of hydrogels.

[0166] In another aspect, the disclosure 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 aliquot contains a predetermined amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. Syrups can be prepared by dissolving a compound of formula (I) or a pharmaceutically acceptable salt thereof in a suitable aromatized aqueous solution, and elixirs are prepared by using a non-toxic alcoholic vehicle. Suspensions may be formulated by dispersing a compound of formula (I) or a pharmaceutically acceptable salt thereof in a non-toxic vehicle. Solubilizers and emulsifying agents, such as ethoxylated isostearyl alcohols and polyoxyethylene sorbitan ethers, preservatives, a flavoring agent such as peppermint oil or natural sweeteners or saccharin or other artificial sweeteners, and the like may also be added.

[0167] In another aspect, the disclosure provides 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 disclosure relates to a dosage form adapted for administration to a patient by inhalation as a dry powder. In a further embodiment, the disclosure relates to a dosage form adapted for administration to a patient by inhalation through a nebulizer.

[0168] Dry powder compositions for pulmonary delivery by inhalation typically contain the 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 produced, for example, by micronization and grinding. Generally, the 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).

[0169] The dry powder may be administered to a patient via a reservoir-type dry powder inhaler (RDPI) having a reservoir suitable for holding multiple doses of the drug (unmeasured doses) as a dry powder. RDPI inhalers typically include means for measuring each dose of drug from the reservoir to the delivery position. For example, the measuring means may include a dosing cup that is movable from a first position where the cup can be filled with drug from a reservoir to a second position where a metered dose of drug becomes available to the patient by inhalation.

[0170] 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 medicament is contained in a multi-dose package containing (or otherwise containing) multiple defined doses of medicament (or fractions thereof). When the dry powder is presented as a blister pack, it includes a plurality of sheets for storing the dry powder medicament. The leaves are usually arranged in a regular pattern for easy release of the medicine. For example, the flaps can be arranged typically circularly on a disc-shaped blister pack, or the flaps can be oblong-shaped, for example include a strip or tape. Each capsule, cartridge or blister may contain, for example, between 20 µg - 10 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0171] 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 halogenated hydrocarbons, 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), pentafluoroethane (HFA-32) -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 typically be administered to the patient via a metered dose inhaler (MDI). Such devices are well known to those skilled in the art.

[0172] The aerosol may contain additional pharmaceutically acceptable excipients conventionally used in MDI inhalers, such as surfactants, lubricants, cosolvents, and other excipients to improve the physical stability of the formulation, improve valve performance, improve solubility, or improve taste.

[0173] Thus, as a further aspect of the disclosure, there is provided a pharmaceutical aerosol formulation comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and, as a propellant, a hydrogen-containing hydrofluorocarbon or chlorofluorocarbon, optionally in combination with a surfactant and / or cosolvents. em.

[0174] According to another aspect of the disclosure, there is provided a pharmaceutical aerosol formulation wherein the propellant is selected from 1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoro-n -propane and their mixtures.

[0175] The formulations of the disclosure may be buffered by the addition of appropriate buffering agents.

[0176] Capsules and cartridges of, for example, gelatin for use in an inhaler and insufflator may be formulated containing 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 each cartridge may generally contain from 20 µg to 10 mg of the 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.

[0177] The proportion of the active compound of formula (I) or a pharmaceutically acceptable salt thereof in the topical compositions of this disclosure will depend on the exact type of formulation being prepared, but will generally be in the range from 0.001 to 10% by weight. Typically, however, for most types of preparation the proportion used will be in the range from 0.005 to 1%, for example from 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%.

[0178] Aerosol formulations are prepared such that each metered dose or "puff" of the aerosol contains from 20 pg - 10 mg, preferably from 20 pg to 2000 pg, more preferably from about 20 pg to 500 pg of a compound of formula (I). Administration may be once or several times a day, for example 2, 3, 4 or 8 times, for example giving 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 the metered dose delivered by capsules or cartridges in an inhaler or insufflator will usually be twice the dose given by aerosol formulations.

[0179] For suspension aerosol formulations, the particle size of the particulate (e.g., micronized) drug should be such that substantially all of the drug may be inhaled into the lungs following administration of the aerosol formulation and will therefore be less than 100 microns, preferably less than 20 microns, and especially in the range of 1 to 10 microns, such as 1 to 5 microns, more preferably 2 to 3 microns.

[0180] The formulations of the disclosure can be prepared by dispersing or dissolving the drug and a compound of formula (I) or a pharmaceutically acceptable salt thereof in a selected propellant in a suitable container, for example, by use of ultrasound or a high shear mixer. The process is conveniently carried out under controlled humidity conditions.

[0181] The chemical and physical stability and pharmaceutical acceptability of the aerosol formulations of the present 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 an HPLC method, for example, after prolonged storage of the product. [0182] Physical stability data can be obtained from other common analytical techniques such as, for example, leakage testing, valve delivery test (average weight of dose per actuation), dose repeatability test (active ingredient per actuation), or distribution analysis. spray.

[0183] The stability of the suspension aerosol formulations according to the invention can be measured by conventional techniques, for example by measuring the flocculation size distribution using a backscattering apparatus or by measuring the particle size distribution by cascading collisions or by using a double impactor analytical procedure ( "Twin impinger"). Reference herein to "twin impinger" test means "Determination of release dose deposition in pressure inhalations using apparatus A" as defined in British Pharmacopaeia 1988, pages A204-207, Annex XVII C. Such techniques allow the calculation of the "inhaled fraction" of aerosol formulations. One method used to calculate the respirable fraction refers to the "fine fraction", which is the amount of active ingredient collected in the lower impactor chamber during one actuation as a percentage of the total amount of active ingredient delivered during one actuation determined using the twin impinger method described above. ".

[0184] The term "metered dose inhaler" or MDI means a unit comprising a can, an attached closure protecting the can, and a metering valve within the closure. The MDI system includes an appropriate targeting device. Suitable orienting devices include, for example, a valve actuator and a cylindrical or conical passage through which medication can be delivered from a filled cartridge via a metering valve to a patient's nose or mouth, such as a mouthpiece actuator.

[0185] MDI canisters typically consist of a container that is capable of withstanding the vapor pressure of the propellant used, such as a plastic-coated or plastic-coated glass bottle, or preferably a metal, for example, aluminum or aluminum alloy can, which may optionally be anodized. coated with varnish and / or plastic (for example, incorporated herein by reference WO96 / 32099, wherein some or all of the interior surfaces are coated with one or more fluorocarbon polymers, optionally in combination with one or more polymers of compounds other than fluorocarbons), the container closed by a metering valve. The closure can be securely attached to the can by ultrasonic welding, bolted connection, or crimping. MDI cartridges discussed herein can be made by methods in the art (e.g., see Byron, supra and WO96 / 32099). Preferably, the cartridge is mated with a closure assembly wherein the drug metering valve is within the closure and said closure is clamped into place.

[0186] 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 polyethersulfone (PES) polymers. In a further embodiment of the invention, the metal inner surface of the can is completely covered with a blend of polytetrafluoroethylene (PTFE) and polyethersulfone (PES) polymers.

[0187] The metering valves are designed to deliver a metered amount of the formulation per actuation and to apply 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 Valois, France (e.g. DF10, DF30, DF60), Bespak pic, UK (e.g. BK300, BK357) and 3M-Neotechnic Ltd, UK (e.g. Spraymiser ™).

[0188] In various embodiments, MDIs may also be used in conjunction with other components such as, but not limited to, wrapping packages for storage and containing MDI devices, including those described in US Patent Nos. 6,119,853; 6179118; 6315112; 6352152; 6,390,291; and 6,679,374, as well as dose counting devices such as, but not limited to, those described in US Patent Nos. 6,360,739 and 6431168.

[0189] Conventional bulk manufacturing methods and machines known to those skilled in the art of pharmaceutical aerosol preparation may be used to produce large batches for the commercial production of filled canisters. Thus, for example, in one mass production process for aerosol suspension formulations in the form of a suspension, the metering valve is crimped onto the aluminum can to form an empty reservoir. The particulate drug is added to the charging vessel and the production vessel is pressurized through the charging vessel with liquefied propellant along with any excipients. The drug suspension is mixed prior to circulation into the filling machine and then a metering valve is filled into the reservoir with a portion of the drug suspension. In one example of mass production of solution aerosol formulations, a metering valve is crimped on an aluminum can to form an empty reservoir. The production vessel is filled under pressure with the liquefied propellant along with any excipients and dissolved drug through the batch vessel.

[0190] In an alternative method, an aliquot of the condensed formulation is added to an open reservoir at a temperature low enough that the formulation does not evaporate, and then the metering valve on the reservoir is tightened.

[0191] Typically, in batches made for pharmaceutical use, each filled cartridge is weight checked, coded with a batch number code, and packed on a pallet for storage prior to performing a release test.

[0192] 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 the nebulization may be any pharmaceutically acceptable liquid such as water, saline, alcohols or glycols, e.g. ethanol, isopropyl alcohol, glycerol, propylene glycol, polyethylene glycol and the like or mixtures thereof. Saline solutions use salts which, after administration, show little or no pharmacological activity. For this purpose, both organic salts, such as alkali metal or ammonium halide salts, e.g. sodium chloride, potassium chloride, and organic salts, such as potassium, sodium and ammonium / ammonium salts, and organic acids, e.g. acid, can be used. ascorbic acid, citric acid, acetic acid, tartaric acid, etc.

[0193] Other pharmaceutically acceptable excipients can be added to the suspension or solution. The compound of formula (I) or a pharmaceutically acceptable salt thereof may 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 a 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 the suspensions. These include lecithin, disodium dioctylsulfosuccinate, oleic acid, and sorbitan esters.

[0194] In a further aspect, the disclosure relates to a dosage form adapted for nasal administration.

[0195] Formulations for topical nasal administration may include pressurized aerosol formulations and aqueous nasal formulations via a pressurized pump. Formulations which are not pressurized and adapted to be administered topically to the nasal cavity are of particular interest. For this purpose, suitable formulations contain water as diluent or carrier. Aqueous formulations for lung or nasal administration can be delivered using conventional excipients such as buffering agents, tonicity modifying agents, and the like. Aqueous preparations can also be administered intranasally by nebulization.

[0196] 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 a metering orifice through which a measured dose of the fluid formulation is delivered after dosing. application of a force applied by a user to the pump mechanism of the fluid-dispensing device. Such fluid dispensing devices typically include a reservoir containing a plurality of metered doses of the fluid formulation, the doses being dispensable by successive actuation of the pump. The dispensing nozzle or orifice may be configured to introduce a spray of liquid into the nostrils of a user to dispense the liquid formulation into the nasal cavity. A fluid dispensing device of the type mentioned is described and illustrated in WO05 / 044354, the entire contents of which is hereby incorporated by reference. The dosing device has a housing that houses a fluid discharge device with a compression pump mounted on a container for storing a liquid preparation. The housing includes at least one finger-actuated side lever that can move toward the inside of the housing to move the container upward in the housing causing the pump to compress and pump a metered dose out of the pump passage through the nose nozzle of the housing. In one embodiment, the fluid dispensing device is generally of the type illustrated in Figures 30-40 of WO05 / 044354.

[0197] Pharmaceutical compositions adapted for nasal administration in which the carrier is solid and comprises a coarse powder with a particle size for example in the range of 20 to 500 microns which is administered by quick inhalation through the nasal passage from a powder-containing container held close to the nose. Suitable compositions where the carrier is a liquid for administration as a nasal spray or nasal drops include aqueous or oily solutions of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0198] Pharmaceutical compositions adapted for transdermal administration can be presented as independent patches designed to be in close contact with the epidermis of a patient for an extended period of time. For example, the active ingredient may be delivered from the patch by iontophoresis as generally described in Pharmaceutical Research, 3 (6), 318 (1986).

[0199] Pharmaceutical compositions adapted for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils.

[0200] Ointments, creams and gels, for example, may be formulated with an aqueous or oily base with the addition of a suitable thickening and / or gelling agent and / or solvents. Such bases may thus, for example, include water and / or an oil, such as liquid paraffin or a vegetable oil, such as arachis oil or castor oil, or a solvent such as polyethylene glycol. Thickening agents and gelling agents which may be used depending on the nature of the base include petroleum jelly, aluminum stearate, cetostearyl alcohol, polyethylene glycols, wool grease, beeswax, carboxypolymethylene and cellulose derivatives, and / or glyceryl monostearate and / or nonionic emulsifiers.

[0201] Lotions may be formulated with an aqueous or oily base and will generally contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents or thickening agents.

[0202] Powders for external use may be formulated with any suitable powder base, for example talc, lactose or starch. Drops may be formulated with an aqueous or non-aqueous vehicle also containing one or more dispersing agents, solubilizers, suspending agents or preservatives.

[0203] Formulations for topical administration may be administered at one or more treatments per day to the affected areas; occlusive dressings can be advantageously applied to the skin surface. Continuous or sustained delivery can be achieved through a pressure-sensitive tank type system.

[0204] For the treatment of the eye or other external tissues, for example the mouth and skin, the compositions may be applied as a topical ointment or cream. Thus, when formulated into an ointment, a compound of formula (I) or a pharmaceutically acceptable salt thereof may be used with a paraffinic or water-miscible ointment base. Alternatively, a compound of formula (I) or a pharmaceutically acceptable salt thereof may thus be formulated in a cream with an oil-in-water cream base or a water-in-oil base.

[0205] Pharmaceutical compositions adapted for parenteral administration include aqueous and non-aqueous sterile injectable solutions, which may contain antioxidants, buffers, bacteriostatic agents, and solutes that make the preparation isotonic with blood to the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The compositions may be presented in single-dose or multi-dose containers, for example sealed ampoules or vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of a sterile liquid carrier, for example water for injection, immediately prior to use. Solutions and suspensions for injection made immediately before use can be prepared from sterile powders, granules and tablets.

[0206] The compound and pharmaceutical formulations of the disclosure may be used in conjunction with or include one or more other therapeutic agents, for example selected from anti-inflammatory agents, anti-cholinergic agents (especially M1 / ​​M2 / M3 receptor antagonists), β2 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 anticholinergic agent, a receptor agonist P2-adrenergic agent, anti-infective agent such as an antibiotic or antiviral agent, or antihistamines. One embodiment of the invention comprises combinations comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof together with a β2 adrenoceptor agonist and / or an anticholinergic and / or PDE-4 inhibitor and / or an antihistamine.

[0207] In one embodiment, the invention includes a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof together with one or more therapeutically active agents for use in a method of treating a disorder mediated by inappropriate PI3 kinase activity, comprising administering a safe and effective amount.

[0208] Certain compounds of the combination of the invention may show selectivity for ΡΙ3Kδ 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 is selective for ΡΙ3Kδ, together with the compound or a pharmaceutically acceptable salt thereof, which is selective for another PI3 kinase, for example ΡΙ3Κγ.

[0209] One embodiment of the invention includes combinations comprising one or more other therapeutic agents.

[0210] It will be clear to the person skilled in the art that the other therapeutic ingredient (s) may be used in salt form, for example as alkali metal or amine salts, if appropriate. either as acid addition salts, or prodrugs, or esters, for example lower alkyl esters, or as salts of watts, for example hydrates in order 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 can be used in optically pure form.

[0211] In one embodiment, the invention includes a combination comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, with a β2 adrenergic receptor agonist.

[0212] Examples of P2-adrenergic receptor agonists include salmeterol (which may be a racemate or a single enantiomer such as the R enantiomer), mol salbut (which may be a racemate or a single enantiomer such as enantiomer A), formoterol (which may be a racemate or a single diastereoisomer, such as the R, R diastereomer, salmefamol, fenoterol, carmoterol, ethanterol, naminterol, clenbuterol, pirbuterol, flerbuterol, reproterol, bambuterol, indacaterol, terbutaline and salts thereof, for example salmeterol xinafoate salt (1-hydroxy-2-naphthalene carboxylate), salbutamol sulfate salt or free base, or formoterol fumarate salt. In one embodiment, long-acting β2 adrenergic agonists are preferred, for example compounds that provide effective bronchodilation for about 12 h or more.

[0213] Other P2-adrenergic receptor agonists include those 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.

[0214] Examples of β2 adrenoceptor agonists include:

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

3- (3 - {[7 - ({(2J ') - 2-hydroxy-2- [4-hydroxy-3-hydroxymethyl) phenyl] ethyl} amino) heptyl] oxy} propyl o-benzenesulphonoami d;

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

4 - {(1J?) - 2 - [(6- {4- [3- (cyclopentylsulfonyl) phenyl] butoxy} hexyl) amino] -1-hydroxyethyl} -2- (hydroxymethylphenol;

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

[0215] The β-adrenoceptor agonist may be in the form of a salt formed with a pharmaceutically acceptable acid selected from sulfuric acid, hydrochloric acid, fumaric acid, hydroxynaphthoic acid (e.g. 1- or 3-hydroxy-2-naphthoic acid), cinnamic acid, substituted cinnamic acid, triphenylacetic, sulfamic, sulfanilic, naphthalene acrylate, benzoic, 4-methoxybenzoic, 2- or 4-hydroxybenzoic, 4-chlorobenzoic and 4-phenylbenzoic.

[0216] Suitable anti-inflammatory agents include corticosteroids. Suitable corticosteroids that can be used in combination with the compounds of formula (I) or their pharmaceutically acceptable salts are oral or inhaled corticosteroids and prodrugs thereof, which have anti-inflammatory activity. Examples include methylprednisolone, prednisolone, dexamethasone, fluticasone propionate, 6α, 9α-difluoro-1β-hydroxy-16α-methyl-17a - [(4-methyl-1,3-thiazole-5-carbonyl) oxy-S-fluoromethyl ester ] -3-oxoandrosta-1,4-diene-173-thiocarboxylic acid, 5-fluoromethyl ester 6a, 9a-difluoro-17a - [(2-furanylcarbonyl) oxy] -11 β-hydroxy-16a-methyl-3- oxoandrosta-1,4-diene-17β-thiocarboxylic acid (fluticasone furoate), 6a, 9a-difluoro-11β-hydroxy-16a-methyl-3-oxo-17a-propionyloxyandrosta-1,4-diene-17β-thiocarboxylic acid 5- (2-oxotetrahydrofuran-3S-yl) ester, 5- ester 6α, 9αdifluoro-11 β-hydroxy-16a-methyl-3-oxo-17a- (2,2,3,3-tetramethylcyclopropylcarbonyl) oxyandrosta-1,4-diene-17β-thiocarboxylic acid cyanomethyl and 6a-S-fluoromethyl ester , 9a-difluoro-11 β-hydroxy-16a-methyl-17α- (1-methylcyclopropylcarbonyl) oxy-3oxoandrosta-1,4-diene-17β-thiocarboxylic acid, beclometasone esters (for example 17-propionate ester or 17.21-dipropionate ester), budesonide, flunisolide, mometasone esters (for example mometasone furoate), triamcinolone acetonide, rofleponide, ciclesonide (16α, 17 - [[(J?) - cyclohexylmethylene ] bis (oxy)] - 11β, 21-dihydroxypregna-1,4-dieno-3.20 dione), butixocort propionate, RPR-106541 and ST-126. Preferred corticosteroids include fluticasone propionate, 6a, 9a-difluoro-1β-hydroxy-16a-methyl-17a - [(4-methyl-1,3-thiazole-5-carbonyl) oxy] -3-oxoandrosta-1, 5-fluoromethyl ester. , 4-diene-17βthiocarboxylic acid, 6a, 9a-difluoro-17a - [(2-furanylcarbonyloxy] -11 β-hydroxy-16a-methyl-3-oxoandrosta-1,4-diene-17β-thiocarboxylic acid 5-fluoromethyl ester , 6a, 9a-difluoro-1'-hydroxy-16a-methyl-3-oxo-17a (2,2,3,3-tetramethylcyclopropylcarbonyl) oxy-androsta-1,4-diene-17β-thiocarboxylic acid 5-cyanomethyl ester and 6α, 9a-difluoro-11 β-hydroxy-16a-methyl-17a- (1-methylcyclopropylcarbonyl) oxy-3-oxoandrosta-1,4-diene-17β-thiocarboxylic acid 5-fluoromethyl ester. In one embodiment, the corticosteroid is 6a, 9a-difluoro-17a - [(2-furanylcarbonyloxy] -11β-hydroxy-16a-methyl-3-oxoandrosta-1,4-diene-17β-thiocarboxylic acid S-fluoromethyl ester.

[0217] 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.

[0218] Non-steroidal glucocorticoid agonism compounds that may exhibit selectivity for transrepression over 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 non-steroidal compounds are included in: WO2006 / 000401, WO2006 / 000398 and WO2006 / 015870.

[0219] Examples of anti-inflammatory agents include non-steroidal anti-inflammatory agents (NSAIDs).

Examples of NSAIDs include sodium cromoglycate, sodium nedocromil, phosphodiesterase (PDE) inhibitors (e.g., theophylline, PDE4 inhibitors, or mixed PDE3 / PDE4 inhibitors), leukotriene antagonists, leukotriene synthesis inhibitors (e.g., montelukast), iNOS inhibitors, and iNOS inhibitors, and elastase, beta-2 integrin antagonists, and adenosine receptor agonists or antagonists (e.g. adenosine 2a agonists), cytokine antagonists (e.g. chemokine antagonists such as a CCR3 antagonist) or cytokine synthesis inhibitors or 5-lipoxygenase inhibitors. iNOS (Inducible Nitric Oxide Synthase Inhibitor) 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.

[0221] In one embodiment, the invention provides the use of compounds of formula (I) in combination with a phosphodiesterase 4 (PDE4) inhibitor, especially when formulated for inhalation. A PDE4-specific inhibitor useful in this aspect of the invention can be any compound that is known to inhibit the PDE4 enzyme or that has been found to function as a PDE4 inhibitor and that 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.

[0222] These compounds include c / s-4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) cyclohexane-1-carboxylic acid, 2-carbomethoxy-4-cyano-4- (3-cyclopropylmethoxy-4-difluoromethoxyphenyl) ) cyclohexan-1-one and ic (5- [4-cyano-4- (3-cyclopropylmethoxy-4-difluoromethoxyphenyl) cyclohexan-1-ol]. Also, c / s-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 the patent specification US 5,552,438 issued September 3, 1996; this patent and the compounds it discloses are fully incorporated herein by reference.

[0223] Other compounds include AWD-12-281 from Elbion (Hofgen, N. et al. 15th EFMC Int

Symp Med Chem (Sep 6-10, Edinburgh) 1998, Abst P.98; CAS reference number 247584020-9); a 9-benzyladenine derivative named NCS-613 (INSERM); D-4418 from Chiroscience and Schering-Plow; a PDE4 benzodiazepine 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; Pumafentrin, (-) - p - [(4aR *, 10Z&gt; S *) - 9-ethoxy-1,2,3,4,4a, 10b-hexahydro-8-methoxy-2-methylbenzo [c] [l, 6] naphthyridin-6-yl] -N, N-diisopropylbenzamide, which is a mixed PDE3 / PDE4 inhibitor prepared and reported 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.

[0224] 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.

[0225] Examples of anticholinergic agents are those compounds which act as antagonists at muscarinic receptors, in particular those compounds which are Mi or M3 antagonists, dual M1 / ​​M3 or M2 / M3 receptor antagonists, or pan-M1 / M2 receptor antagonists. / 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 of interest are revatropate (e.g. 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 hydrobromide sold as Enablex), Oxybutynin (CAS 5633-20-5, sold as Ditropan), Theodiline (CAS 15793-40-5), tolterodine (CAS 124937-51-5 or CAS 124937-52-6 as tartrate, sold under the name Detrol), otylonium (for example, as CAS 26095-59-0 bromide, 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).

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

(3-erato) -3- (2,2-di-2-thienylethenyl) -8,8-dimethyl-8-azoniabicyclo [3.2. l] octane; (3-erato) -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 (1J ', 5S) -3- (2-cyano-2,2-diphenylethyl) -8-methyl-8- {2 - [(phenylmethyl) oxy] ethyl] -8-azoniabicyclo [3.2.1] octane bromide .

[0227] Other anticholinergic agents include compounds that are disclosed in US Patent Application 60/487981, including, for example:

(3-erato) -3- (2,2-di-2-thienylethenyl) -8,8-dimethyl-8-azoniabicyclo [3.2.1] octane bromide; (3-erato) -3- (2,2-diphenylethenyl) -8,8-dimethyl-8-azoniabicyclo [3.2. l] octane; (3-c / α-cfo) -3- (2,2-diphenylethenyl) -8,8-dimethyl-8-azoniabicyclo [3.2.1] octane 4-methylbenzenesulfonate;

(3-erato) -8,8-dimethyl-3- [2-phenyl-2- (2-thienyl) ethenyl] -8-azoniabicyclo bromide 41

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

[0228] Further anticholinergic agents include compounds which are disclosed in US patent application 60/511009, including, for example:

(entto) -3- (2-methoxy-2,2-dithiophen-2-ylethyl) -8,8-dimethyl-8-azoniabicyclo [3.2. l] octane;

3 - ((erato) -8-methyl-8-azabicyclo [3.2.1] oct-3-yl) -2,2-diphenylpropionitrile;

(entto) -8-methyl-3- (2,2,2-triphenylethyl) -8-azabicyclo [3.2.1] octane;

3 - ((erato) -8-methyl-8-azabicyclo [3.2.1] oct-3-yl) -2,2-diphenylpropionamide;

3 - ((erato) -8-methyl-8-azabicyclo [3.2.1] oct-3-yl) -2,2-diphenylpropionic acid;

(entto) -3- (2-cyano-2,2-diphenylethyl) -8,8-dimethyl-8-azoniabicyclo [3.2. l] octane;

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

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

A-benzyl-3 - ((entto) -8-methyl-8-azabicyclo [3.2.1] oct-3-yl) -2,2-diphenylpropionamide;

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

1-benzyl-3- [3 - ((entto) -8-methyl-8-azabicyclo [3.2.1] oct-3-yl) -2,2-diphenylpropyl] urea;

1-ethyl-3- [3 - ((erato) -8-methyl-8-azabicyclo [3.2.1] oct-3-yl) -2,2-diphenylpropyl] urea;

A- [3 - ((entto) -8-methyl-8-azabicyclo [3.2.1] oct-3-yl) -2,2-diphenylpropyl] acetamide;

A- [3 - ((entto) -8-methyl-8-azabicyclo [3.2.1] oct-3-yl) -2,2-diphenylpropyl] benzamide;

3 - ((entto) -8-methyl-8-azabicyclo [3.2.1] oct-3-yl) -2,2-dithiophen-2-ylpropionitrile;

(entto) -3- (2-cyano-2,2-dithiophen-2-ylethyl) -8,8-dimethyl-8-azoniabicyclo [3.2. l] octane;

A- [3 - ((entto) -8-methyl-8-azabicyclo [3.2.1] oct-3-yl) -2,2-diphenylpropyl] benzenesulfonamide;

[3 - ((entto) -8-methyl-8-azabicyclo [3.2.1] oct-3-yl) -2,2-diphenylpropyl] urea;

A- [3 - ((entto) -8-methyl-8-azabicyclo [3.2.1] oct-3-yl) -2,2-diphenylpropyl] methanesulfonamide; and / or (entto) -3- {2,2-diphenyl-3 - [(1-phenylmethanoyl) amino] propyl} -8,8-dimethyl-8-azoniabicyclo [3.2.1] octane bromide.

[0229] Further compounds include:

(entto) -3- (2-methoxy-2,2-dithiophen-2-ylethyl) -8,8-dimethyl-8-azoniabicyclo [3.2. l] octane;

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

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

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

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

[0230] In one embodiment, the invention provides a combination comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, together with an HI antagonist. Examples of HI antagonists include, without limitation, amelexanox, astemizole, azatadine, azelastine, acrivastine, brompheniramine, cetirizine, levocetirizine, efletirizine, chlorpheniramine, clemastine, cyclizine, carbastine, cypaminroheoxetilinetin, eepamininheoxadetylsin, eepamininheoxetilorin, epa- rabastine, eepaminheoxetilinadine, fexofenadine, hydroxyzine, ketotifen, loratadine, levocabastine, mizolastine, mequitazine, mianserin, noberastine, meclizine, norastemizole, olopatadine, picumast, pyrrylamine, 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 can be used in combination with compounds of the present invention include H4 receptor antagonists (and / or inverse agonists), for example the compounds disclosed in Jabłonowski et al., J. Med. Chem. 46: 3957-3960 (2003).

[0231] Therefore, 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.

[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 beta-adrenergic receptor agonist.

[0233] Therefore, 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.

[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 non-steroidal GR agonist.

[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 an anticholinergic agent.

[0236] Therefore, 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.

[0237] Therefore, 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 a beta-adrenergic receptor agonist.

[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 an anticholinergic agent and a PDE-4 inhibitor.

[0239] The combinations as defined above may conveniently be presented for use in the form of a pharmaceutical composition, and therefore, pharmaceutical compositions comprising the combination as defined above together with a pharmaceutically acceptable diluent or carrier form a further aspect of the invention.

[0240] The individual compounds of such combinations may be administered either sequentially or simultaneously in separate or combined pharmaceutical formulations. In one embodiment, the individual compounds will be administered simultaneously in a combined pharmaceutical formulation. Those skilled in the art will readily know the appropriate dosages of known therapeutic agents.

[0241] Thus, in a further aspect, the invention provides a pharmaceutical composition comprising the combination of a compound of formula (I) or a pharmaceutically acceptable salt thereof together with another therapeutically active agent.

[0242] Thus, in a further aspect, the invention provides a pharmaceutical composition comprising the combination of a compound of formula (I) or a pharmaceutically acceptable salt thereof together with a PDE4 inhibitor.

[0243] Thus, in a further aspect, the invention provides a pharmaceutical composition comprising the combination of a compound of formula (I) or a pharmaceutically acceptable salt thereof together with a β2 adrenergic receptor agonist.

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

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

[0246] Thus, in a further aspect, the invention provides a pharmaceutical composition comprising the combination of a compound of formula (I) or a pharmaceutically acceptable salt thereof together with an anticholinergic agent.

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

[0248] Thus, in a further aspect, the invention provides a pharmaceutical composition comprising the combination of a compound of formula (I) or a pharmaceutically acceptable salt thereof together with a PDE4 inhibitor and a 32-adrenergic receptor agonist.

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

[0250] The disclosure will now be illustrated by the following non-limiting examples.

EXAMPLES

[0251] The following examples illustrate the disclosure. It is not intended that these examples limit the scope of the present invention, but rather to provide guidance to those skilled in the art regarding the preparation and use of the compounds, compositions and uses of the present invention. While particular embodiments of the present invention have been described, it will be appreciated by those skilled in the art that various changes and modifications can be made without departing from the spirit and scope of the invention.

[0252] When the name of a commercial supplier is given after the name of the compound or reagent, such as "compound X (Aldrich)" or "compound X / Aldrich", this means that compound X can be obtained from a commercial supplier such as the listed commercial supplier. If not referred to herein, the compound or reagent can be purchased from a conventional supplier such as Sigma Aldrich, Lancaster, Fluorochem, TCI etc.

[0253] The compound names of the examples were obtained using a compound naming program that matches the structure to the name (e.g., ACD / Name Batch v 9.0).

General details of the experiments Methods - Liquid Chromatography-Mass Spectroscopy (LCMS)

[0254] LCMS analysis was performed using one of the methods listed below.

Method A:

[0255] The LCMS equipment consists of the following:

Column: Acquity UPLC BEH C 18 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

The volume of the injected portion: 0.5 pl

Injection technique: overflow and feeding part of the loop volume

<td>UV detection:</td><td>220 to 330 nm</td>

<td>UV sampling rate:</td><td>40 points per second</td>

<td>MS scan range:</td><td>100 to 1000 amu</td>

<td>MS Scanning Rate:</td><td>0.2 second scan with 0.1 second inter-scan delay</td>

<td>MS scan function:</td><td>electrospray in positive and negative ion mode, with switching</td>

<td>Cycle time:</td><td>2 minutes and 30 seconds</td>

Gradient:

<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> 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:

[0256] HPLC analysis was performed on a Sunfire C18 column (30mm x 4.6mm ID 3.5 µm packing average) at 30 degrees Celsius.

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

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

[0257] 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>

[0258] For UV detection, the average signal at a wavelength of 210 nm to 350 nm was taken and the mass spectrum was recorded on a mass spectrometer using electrospray ionization in positive and negative ion mode with alternating scanning.

Method C:

[0259] HPLC analysis was performed on a Phenomenex Luma C18 (2) (50 mm x 2 mm ID 3 pm packing diameter, or validated equivalent) at 40 degrees Celsius.

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

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

[0260] 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 for UV detection was analyte dependent and the mass spectrum was recorded on a mass spectrometer using electrospray in positive ion mode.

Method D:

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

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

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

[0263] 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>

[0264] The wavelength for UV detection was analyte dependent and the mass spectrum was recorded on a mass spectrometer using electrospray in positive ion mode.

Mass-controlled, automated preparative and HPLC methods

[0265] The mass-directed automated preparative HPLC methods used to purify compounds are described below:

Method A - high pH

Column Details: Waters_XBRIDGE Prep C18 5um OBD Column (30 x 150mm)

[0267] The solvents used were:

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

B = acetonitrile + 0.1% aq. ammonia

[0268] Collection was triggered based on uv, ms, or a combination thereof. For UV detection, the average signal from 210 nm to 350 nm was taken. Mass spectra were recorded on a mass spectrometer using positive and negative electrospray ionization with alternating scanning.

Method B - low pH

Column Details: SUNFIRE C18 column (30 x 150 mm ID 5 µM packing diameter)

[0270] The solvents used were:

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

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

[0271] Harvesting was triggered on the basis of uv, ms, or a combination thereof. For UV detection, the average signal from 210 nm to 350 nm was taken. The mass spectrum was recorded on a mass spectrometer using positive and negative electrospray ionization with alternating scanning.

Method C

Column Details: XBRIDGE Shield RP18 Column (100 x 19mm, 5 µM packing diameter)

[0273] The solvents used were:

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

B = Methanol

[0274] Collection was triggered on the basis of uv, ms, or a combination thereof. For UV detection, the average signal from 210 nm to 350 nm was taken. The mass spectrum was recorded on a mass spectrometer using positive and negative electrospray ionization with alternating scanning.

Intermediates and examples

Intermediate link 1

6-Chloro-4-iodo-1- (phenylsulfonyl) -1-indazole

[0275] i

<img file="PL2899191T3_D0026.tif" />

<img file="PL2899191T3_D0027.tif" />

Method A

6-Chloro-4-iodo-177-indazole (30 g, 108 mmol, available from Sinova) was dissolved in V, H -dimethylformamide (300 mL) and cooled in an ice / water bath under a stream of nitrogen. Sodium hydride (5.17 g, 129 mmol) was added in portions keeping the temperature below 10 ° C. After everything was added, 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 (ca. 400 ml) and dried in a vacuum oven overnight to give the title compound (43.3 g).

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

Method B

[0277] Sodium hydroxide (227.4 g) was added to a stirred solution of 6-chloro-4-iodo-1H-indazole (633.6 g) in THF (5.7 L) followed by tetra-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 with 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 a rate 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 1.9L), dried under suction then further dried under vacuum with nitrogen leak at 40 ° C ± 3 ° C overnight to give the title compound (780.8 g).

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

Intermediate link 2

6-Chloro-1- (phenylsilphonyl) -4- (trimethylostannanyIo) -1 H -indazoI

[0278]

-L yo ₀+ ° O

[0279] 6-Chloro-4-iodo-1- (phenylsulfonyl) -177-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) was heated at 150 ° C for 2 h. The reaction mixture was filtered hot through celite, washed further with xylene and the solvent was evaporated off 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): R t 1.51 min, MH⁺ 457.

Intermediate 3a

Ethyl 2- [6-Chloro-1- (phenylsulfonyl) -177-indazol-4-yl] -1,3-oxazole-5-carboxylate [0280] ____.

/ ° / □ O⁴°⁼t ° O

In 4 batches, to a solution of 6-chloro-1- (phenylsulfonyl) -4- (trimethylstannanyl) 177-indazole (13.28 g, 29.2 mmol) in N, H -dimethylformamide (52 mL) was added tetrakis (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, to a solution of 6-chloro-1- (phenylsulfonyl) -4- (trimethylstannanyl) -1 / 7-indazole (4.06 g, 8.91 mmol) in N, H - dimethylformamide (16 ml ) added tetrakis (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 iodide (I) (0.34 g, 1.78 mmol). In the fourth batch, tetrakis (4 mL) was added to a solution of 6-chloro-1- (phenylsulfonyl) -4- (trimethylstannanyl) -177-indazole (1.10 g, 2.42 mmol) in H. triphenylphosphine) 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 followed by 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): R t 1.38 min, MH⁺ 432.

Intermediate 3b

Methyl 2- [6-Chloro-1- (phenylsulfonyl) -17 H -indazol-4-yl] -1,3-oxazole-5-carboxylate [0282]

<img file="PL2899191T3_D0028.tif" />

To a stirred solution of 6-chloro-4-iodo-1- (phenylsulfonyl) -17H-indazole (549.8 g) in toluene (1.43 L) was added triethylamine (380 ml) in 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 µm inline Dominiek hunter, washing with additional toluene (550 ml). The batch was then washed with 50% aq. KF (5.5 L), the aqueous suspension was filtered and the filtrate was recombined with the organic phase. The aqueous phase was separated and the organic layers were washed sequentially with 50% aqueous KF (5.5 L) then with 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 was added copper (I) iodide (25.5 g) 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 a vacuum and a 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 approx. 1 vol. within approx. 15 min until crystallization begins. The resulting slurry was aged at 20 ° C ± 3 ° C for 1.5 h. The solids were collected by vacuum filtration, washed with water (2x 2.75 L), dried with suction then further dried under vacuum with a nitrogen leak at 45 ° 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. ^NV ° crn -S = O Ć)

Method A

[0285] 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 toluene solution) 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 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 (3 x 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): R t 1.09 min, MH⁺ 390.

[0286] The remaining filtrate was mostly concentrated in vacuo and the residue was partitioned between ethyl acetate (500 ml) and water (500 ml). The layers were separated and the aqueous layer was extracted with additional ethyl acetate (3 x 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): R t 1.09 min, MH⁺ 390.

Method B

[0287] 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), While stirring under 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): R t 2.20 min, MH⁺ 390.

Intermediate 5

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

[0288] ci

<img file="PL2899191T3_D0029.tif" />

Method A

{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 purified directly by chromatography on silica gel, 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): R t 3.70 min, MH⁺ 454.

Method B

[0290] Triphenylphosphine dibromide (20.60 g, 48.8 mmol) was added to the suspension of {2- [6-chloro-1- (phenylsulfonyl) -1H-indazol-4-yl] -1,3-oxazole- 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 the reaction was complete. 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- {| (27 ', 6A) -2,6-diniethyl-4-rpholinyl] methyl] -1,3-oxazol-2-yl) - 1- (phenylsulfonyl) - lH-indazole

<img file="PL2899191T3_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 (27 A, 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 0.86min, MH⁺ 487.

Ή 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 = 7.5Hz, 2H), 7.15 (s, 1H), 3.67 (s, 2H), 3.75 - 3.66 (m , 2 H), 2.79 - 2.72 (m, 2H), 1.86 (dd, J = 10.5, 11.0 Hz, 2H), 1.16 (d, J = 6, 5Hz, 6H).

[0293] In a similar manner using the appropriate amine, the following was prepared:

<td>Intermediate number</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} -1,3oxazol-2-yl) -1 - (phenylsulfonyl) -1H-indazole</td><td> 0</td><td>1- (1-methylethyl) piperazine</td><td> 0,77</td><td> 500</td>

Intermediate 7 2- (Methyloxy) -5- (4.4_?5,5-tetramethyl-1,3_?2-dioxaborolan-2-yl) -3-pyridinamine [0294]

<img file="PL2899191T3_D0031.tif" />

[0295] 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 1,4-dioxane (500 mL) after purging with nitrogen. then 4,4,4 ', 4', 5,5,5 ', 5'-octamethyl-2,2'-bi-1,2-dioxaborolate (47.4 g, 186 mmol), potassium acetate ( 27.5 g, 280 mmol) and adduct of di chloro {1,1'-bis (diphenylphosphino) ferrocene] palladium (II) with dichloromethane (7.61 g, 9.32 mmol). The mixture was then stirred at 80 ° C under nitrogen 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 chromatography on silica gel, eluting with 0-50% ethyl acetate / dichloromethane. Appropriate fractions were combined and evaporated to dryness and the residue was triturated with cyclohexane. The resulting solid was filtered and dried in vacuo to give the title compound as a light pink solid (11.1 g).

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

Intermediate 8

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

[0296]

<img file="PL2899191T3_D0032.tif" />

[0297] To a solution of 2- (methyloxy) -5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -3-pyridinamine (0.5g, 1.999mmol) 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 (10ml) and dichloromethane (20ml), partitioned 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 (0.1 46 g).

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

Intermediate 9

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

[0298]

<img file="PL2899191T3_D0033.tif" />

[0299] While stirring into a solution of 2- (methyloxy) -5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -3-pyridinamine (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. 2N hydrogen chloride (aq) (20 ml) and dichloromethane (20 ml) were added. ), 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 leave a brown oil. There was still some pyridine 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): R t 1.20 min, MH⁺ 427 [Note: also observed Rt 0.73 min, MH⁺ 345 compatible with boronic acid (hydrolysis product caused by HPLC eluent)].

Intermediate 10

N- [5- [4- (5- {[(27 ', 6A) -2,6-dimethyl-4-morpholinyl] methyl} - 1,3-oxazol-2-yl) -1- (phenylsulfonyl) - 1Ff-indazol-6-10] -2- (methyloxy) -3-pyridinyl] -2,4-difluorobenzenesulfonamide

[0300]

<img file="PL2899191T3_D0034.tif" />

[0301] To a solution of 6-chloro-4- (5 - {[(27 ', 6S) -2,6-dimethyl-4-morpholinyl] methyl} -1,3-oxazol-2-yl) -1- ( phenylsulfonyl) -177-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) was added 1 (1R, 4S) -bicyclo [2.2.1] hept-2-yl [(1S , 4J ') - bicyclo [2.2.1] hept-2-yl] chloro- [2' - (dimethylamino) -2-biphenylyl] 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 to 120 ° C with stirring for 3 h under microwave irradiation then filtered over silica SPE, 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 2.5ml). The combined organic layers were concentrated under a stream of nitrogen and the residue was dissolved in DMSO and 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.

Intermediate 11

2,4-Difhioro -. / V- [5- [4- (5 - {[4- (1-methylethyl) -1-piperazinyl] eetyl} -1,3-oxazoI-2-10) 1- (phenylsulfonyl ) -17 H -indazol-6-yl] -2- (methyloxy) -3-pyridinyl] benzenesulfonamide

[0302]

<img file="PL2899191T3_D0035.tif" />

To a solution of 6-chloro-4- (5 - {[4- (1-methylethyl) -1-piperazinyl] methyl} -1,3-oxazol-2-yl) -1- (phenylsulfonyl) -1) f-indazole (0.2 g, 0.40 mmol) and 2,4-difluoro-N- [2- (methoxy) -5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolate -2-yl) -3-pyridinyl] benzenesulfonamide (0.222 g, 0.52 mmol) in 1,4-dioxane (2 ml) was added 1 (1R, 4S) -bicyclo [2.2.1] hept-2yl [(1S , 47 ') - bicyclo [2.2.1] hept-2-yl] chloro [2' - (dimethylamino) -2-biphenylyl] palladium phosphate (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 with stirring for 3 h under microwave irradiation then filtered over silica SPE, eluting with methanol. The solvent was removed in vacuo and the residue was partitioned between dichloromethane (5ml) and water (5ml). The layers were separated and the aqueous layer was further extracted with dichloromethane (2x 2ml). The combined organic layers were concentrated under a stream of nitrogen and the residue was purified by chromatography on silica gel, 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 0.85min, MH⁺ 764.

Intermediate 12

2- [6- {1- | (1,1-Dimethylethyl) (dimethyl) silyl | -1 H -indol-4-yl! -1- (phenylsulfonyl) -1Hindazol-4-yl] -1,3-3 ethyl oxazole-5-carboxylate

[0304]

<img file="PL2899191T3_D0036.tif" />

N o ^ r °

[0305] To a solution of ethyl 2- [6-chloro-1- (phenylsulfonyl) -1H-indazol-4-o] -1,3-oxazole-5-carboxylate (1.5 g, 3.47 mmol) in 1,4-dioxane (15 ml) and water (1.5 ml) were added {l - [(l, l-dimethylethyl) (dimethyl) silyl] -177-indol-4-yl} boronic acid (1.243 g, 4 , 52mmol, available from Combi-Blocks Inc.), l (U ', 4S) -bicyclo [2.2.1] hept-2-yl [(lS, 4R) -bicyclo [2.2.1] hept-2-yl ] chloro [2 '- (dimethylamino) -2-biphenylyl] palladium phosphate (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 was removed in vacuo and the residue was partitioned between dichloromethane (20 ml) and water (10 ml). A 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 chromatography on silica gel, 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 contained some unreacted starting material by LCMS.

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

Intermediate 13 {2- [6- {1 - [(1,1-Dimethylethyl) (dimethyl) silyl] -1 / 7-indol-4-yl} -1- (phenylsulfbnyl) -17 / indazol-4-yl ] -1,3-oxazol-5-yl} methanol

[0306]

<img file="PL2899191T3_D0037.tif" />

To a solution of 2- [6- {1 - [(1,1-dimethylethyl) (dimethyl) silyl] -177-indol-4-yl} -1- (phenylsulfonyl) -177-indazol-4-yl] Ethyl -1,3-oxazole-5-carboxylate (containing an impurity compatible with ethyl 2- [6-chloro-1- (phenylsulfonyl) -1H-indazol-4-yl] -1,3-oxazole-5-carboxylate) ( 0.84 g) in dichloromethane (10 ml) and 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 10% ammonium chlorine solution (10 ml) was added. The mixture was stirred for 5 min, then extracted with dichloromethane (10 ml), the layers were 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 by LCMS contained 2- [6-chloro-1- (phenylsulfonyl) -177-indazol-4-yl] 1,3-oxazole- 5-yl} methanol as an impurity. LCMS (method A): R t 1.55 min, MH⁺585 (and Rt 1.11 min, MH⁺ 390 compatible with {2- [6-chloro-1- (phenylsulfonyl) -1 / 7-indazol-4-yl] -1₅3-oxazol-5-yl} methanol as an impurity).

Intermediate 14

6-Chloro-4- (5 - {[(21 ', 6 /') - 2,6-dimethyl-4-morpholinyl] methyl} -1,3-oxazol-2-yl) -1- (phenylsulfonyl) - l / Z-indazole

[0308]

<img file="PL2899191T3_D0038.tif" />

[0309] To a solution of 4- [5- (bromomethyl) -1,3-oxazol-2-yl] -6-chloro-1- (phenylsulfonyl) 1H-indazole (750mg, 1.657mmol) in dichloromethane (50ml) while stirring in air at room temperature, neat 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 preabsorbed onto Fluorosil ™ and purified by silica column chromatography (100 g) using a 0-100% ethyl acetate-cyclohexane gradient over 60 min. Two diastereoisomers were isolated. The appropriate fractions were combined and evaporated in vacuo to give the title compound as a yellow oil (226 mg).

1 H NMR confirmed the structure as the 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, 6.5Hz, 2H), 3.66 (d, J = 14.5Hz, 1H), 3.61 (d, J = 14.5Hz, 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, 6H).

Intermediate 15

1,1-Dimethylethyl 4 - ({2- [6-chloro-1- (phenylsulfonyl) -1Z / -indazol-4-yl] -1,3-oxazol-5-yl} methyl) -1-piperazinecarboxylate

[0310]

<img file="PL2899191T3_D0039.tif" />

[0311] 1,1-Dimethylethyl 1-piperazinecarboxylate (185mg, 0.994mmol) was dissolved in 1ml of DCM and triethylamine (0.185ml, 1.325mmol) 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

7V- [5- [4- (5- {[(2 R, 65) -2,6-dimethyl-4-morpholinyl] methyl] -1,3-oxazol-2-yl) -1 H - in dazol-6-yl] -2- (methyloxy) -3-pyridinyl] methanesulfonamide

<img file="PL2899191T3_D0040.tif" />

<img file="PL2899191T3_D0041.tif" />

[0312]

Method A

[0313] To a solution of 6-chloro-4- (5 - {[(27 ', 6S) -2,6-dimethyl-4-morpholinyl] methyl} -1,3-oxazol-2-yl) -1- ( phenylsulfonyl) -1 / 7-indazole (0.20 g, 0.411 mmol) and A- [2- (methoxy) -5 (4,4,5,5-tetramethyl-1,2,2-dioxaborolan-2-yl ) -3-pyridyl] methanesulfonamide (0.175 g, 0.534 mmol) in 1,4-dioxane (2 mL) was added 1 (17 ', 45) -bicyclo [2.2.1] hept-2-yl [(IS, 47' ) bicyclo [2.2.1] hept-2-yl] chloro [2 '- (dimethylamino) -2-biphenylyl] 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 aliquots of l (17 ", 4S) -bicyclo [2.2.1] hept-2-yl [(lS, 47") bicyclo [2.2. 1] hept-2-yl] palladium chloro [2 '- (dimethylamino) -2-biphenylyl] phosphate (11.5 mg, 0.021 mmol) and potassium phosphate tri-base (80 mg) and the reaction mixture was heated to 120 ° C at microwave irradiation for 1 h. An additional portion of and tri-base potassium phosphate (80 mg) was added and the reaction mixture was heated under the same conditions for a further 1 h. The reaction mixture was filtered through silica SPE and eluted with methanol. The solvent was removed in vacuo and the residue was partitioned between dichloromethane (5ml) and water (5ml). The layers were separated and the aqueous layer was further extracted with dichloromethane (2x 2ml). 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 nitrogen flow at 40 ° C for 3 h to give the title compound as a white solid (26 mg).

LCMS (method A): Rt 0.53min, MH⁺513.

Method B

[0314] 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 slurried in 1,4-dioxane (1840 ml) and water (460 ml) under a stream of nitrogen and heated to 80 ° C . 1 (1J ', 4S) bicyclo [2.2.1] hept-2-yl [(15.4') bicyclo [2.2.1] hept-2-yl] chloro [2 '- (dimethylamino) - phosphate was added 2-biphenylyl] palladium (8.63 g, 15.40 mmol) and the mixture was stirred overnight at 80 ° C.

[0315] 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 with 1,4-dioxane / DCM 2: 1 (1 L) then 1,4-dioxane / DCM 1: 1 (2x500ml). The organics 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:

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

Batch 2: 30g 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, solid sample injection module) eluting with toluene / ethanol / ammonia 80: 20: 2 to give the title compound as an off-white solid ( 9.44 g).

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

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

[0316] Mixed fractions from 4 columns were combined and evaporated to give 19 g which was dissolved in 200 ml of toluene / ethanol / ammonia 80: 20: 2 (+ additional 4 ml 0.88 NH3 to improve solubility) then purified. column chromatography (1.5 kg silica column) eluting with toluene / ethanol / ammonia 80: 20: 2 to give the title compound as an off-white solid (6.1g).

[0317] 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 sparingly with ethanol and dried in vacuo to give the title compound as an off-white solid (56 g). This material was recrystallized again from ethanol (1100 ml). The suspension was heated to reflux and a solution formed. The resulting solution was then cooled to room temperature overnight with stirring. The resulting solid was collected by filtration and washed sparingly with ethanol. The solid was dried under vacuum at 60 ° C for 5 h and gave the title compound as an off-white solid (45.51 g)

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

[0318] 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 0.88 NH3 to improve solubility), then purified by column chromatography (1.5 kg silica column), 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 in vacuo 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 V- [5- [4- (5 - {[4- (1-Methylethyl) -1-piperazinyl] methyl J-L3-oxazol-2-yl) -1 H -indazol-6-yl] -2- ( methyloxy) -3-pyridinyl] methanesulfonamide

[0319]

<img file="PL2899191T3_D0042.tif" />

To a solution of 6-chloro-4- (5 - {[4- (1-methylethyl) -1-piperazinyl] methyl} -1,3-oxazol-2-yl) -1- (phenylsulfonyl) -17 / -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) was added 1 (17 ", 4S) -bicyclo [2.2.1] hept-2-yl [(lS, 4J ') bicyclo [2.2.1] hept -2-yl] chloro [2 '- (dimethylamino) -2-biphenylyl] 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 through silica SPE and eluted with methanol. The solvent was removed in vacuo and the residue was partitioned between dichloromethane (5ml) and water (5ml). 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): R t 0.51 min, MH⁺526.

Example 3

A- [5- [4- (5 - {[(2R, 6S) -2,6-dimethyl-4-inorpholinyl] methyl} -1,3-oxazol-2-yl) -1H-indazol-6-yl ] -2- (methyloxy) -3-pyridinyl] -2,4-difluorobenzenesulfonamide [0321]

<img file="PL2899191T3_D0043.tif" />

[0322] A- [5- [4- (5 - {[(27 ', 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 (105 mg, 0.140 mmol) was suspended in isopropanol (2 mL) and 2M was added 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 addition of 2M hydrogen chloride (aq) (black precipitate formed). The slurry was extracted with dichloromethane (3 x 2 mL) and the combined organic layers were dried to give a brown solid. This material was combined with the black solid that 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-A^L.[5- [4- (5- {f4- (1-methylethyl) -1-piperazinyl] methyl} -1,3-oxazol-2-yl) -1H-indazol-6-yl] -2- (methyloxy ) -3-pyridinyl] benzenesulfonamide

[0323]

<img file="PL2899191T3_D0044.tif" />

2,4-Difluoro-N- [5- [4- (5 - {[4- (1-methylethyl) -1-piperazinyl] methyl} -1,3-oxazol-2-yl) -1 - (phenyl osulfonyl) -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) (0 , 53 mL, 1.060 mmol). The reaction mixture was stirred at RT for 2 h, the solvent was removed and the residue was dissolved in water (1 ml) and acidified to pH ~ 6 by adding 2M hydrogen chloride (aq). The resulting slurry was extracted with dichloromethane (3 x 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): R t 0.65 min, MH⁺624.

Example 5

4- (5- {[(2Λ, 65) -2,6-dimethyl-4-morpholinyl] methyl} -1,3-oxazol-2-yl) -6- (1H-indol-4-yl) -TH -indazole

[0325]

<img file="PL2899191T3_D0045.tif" />

[0326] To a solution of 6-chloro-4- (5 - {[(27 ', 65) -2,6-dimethyl-4-morpholinyl] methyl} -1,3-oxazol-2-yl) -1- ( phenylsulfonyl) -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] lH-indol-4yl] boronic acid (37 mg, 0.133 mmol), (17 ', 45) -bicyclo [2.2.1] hept-2-yl [(15.4J') - bicyclo [2.2.1] hept- 2-yl] chloro [2 '- (dimethylamino) -2-biphenylyl] palladium phosphate (5.75 mg, 10.27 pmol) and tribasic potassium phosphate (65 mg, 0.308 mmol). The reaction mixture was heated under microwave irradiation 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 chromatography on silica gel, 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. Solvent was removed and residue was removed. 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 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 (1g) eluting with 0 , 5M ammonia in 1,4-dioxane.

The solvent was removed and the residue was further purified by MDAP to give 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) IH-indazole

[0327]

<img file="PL2899191T3_D0046.tif" />

<img file="PL2899191T3_D0047.tif" />

Method A

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 ), (U ', 4S) -bicyclo [2.2.1] hept-2-yl [(1S, 47') - bicyclo [2.2.1] hept-2-yl] chloro [2 '- (dimethylamino) - phosphate 2-biphenylyl] 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 heated in the 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 (17 ', 45) -bicyclo was added. [2.2.1] hept-2-yl [(1S, 4J ') - bicyclo [2.2.1] hept-2-yl] chloro [2' - (dimethylamino) -2-biphenylyl] palladium phosphate (5 mg) and the reaction mixture was 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 chromatography on silica gel, eluting with 0-25% methanol in dichloromethane. The appropriate fractions were combined and concentrated 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 (30 mg). LCMS (method A): R t 0.57 min, MH⁺441.

Method B

[0329] 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, 47 ') bicyclo [2.2.1] hept-2-yl] chloro [ 2 '- (dimethylamino) -2-biphenylyl] palladium (8.43 g, 15.03 mmol) was slurried in 1,4-dioxane (1200 mL) and water (300 mL) under a nitrogen purge. The reaction vessel was placed alternately under vacuum and nitrogen atmosphere 5 times with an overhead stirrer, then finally placed under nitrogen and heated to 120 ° C for 2.5 h.

[0330] The reaction mixture was cooled to 45 ° C 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 was 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 (1000 ml) was added to the organic layer. The mixture was filtered again through celite washing with 500 mL 2M HCl keeping the washes separate. The layers of the filtrate were then separated and the organic layer was washed with acidic celite washes. The layers were separated and the acidic water layer was combined. This layer was then washed again with 2x500 ml of DCM; each washing required filtration through celite. The acidic aqueous layer was then subjected to a final celite filtration, washing the celite pad with 150 mL of 2M HCl.

[0331] The acidic water layer was transferred to a beaker (5000 mL) and 2M NaOH was added with vigorous stirring to basify the mixture 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 vacuo at 50 ° C overnight.

[0332] This material was separated into three batches and each purified by reverse phase column chromatography (3x 1.9 kg Cl8 column) loaded in DMF / TFA (1: 1, 30 ml) followed by 3-40 elution. % MeCN in water + 0.25% TFA (Note: Columns 2 and 3 use a different gradient starting from 10% MeCN).

[0333] The appropriate fractions were combined, the acetonitrile was removed in vacuo and the acidic aqueous layer was basified to pH 10 by adding saturated aqueous sodium carbonate to the stirring solution. The resulting solid was collected by filtration, washed with water, then dried in vacuo 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.

Ή NMR (400 MHz, DMSO-d₆) d = 13.41 (br. s, 1H), 11.35 (br. s, 1H), 8.59 (br. s, 1H), 8.07 (d, J = 1.5 Hz, 1H), 7.90 (br. S, 1H), 7.51 - 7.44 (m, 2H), 7.32 (s, 1H), 7.27 7 , 21 (m, 2H), 6.61 - 6.58 (m, 1H), 3.73 (br.s "2H), 2.64 - 2.36 (m, 9H), 0 , 97 - 0.90 (m, 6H).

Example 7

6- (l / 7-Indol-4-yl) -4- [5- (4-morpholinylmethyl) -1,3-oxazol-2-yl] -1 / 7-indazole trifluoroacetate

[0334]

<img file="PL2899191T3_D0048.tif" />

<img file="PL2899191T3_D0049.tif" />

[0335] To the solution of {2- [6- {1 - [(1,1-dimethylethyl) (dimethyl) silyl] -177-indol-4-yl} -1- (phenylsulfonyl) -! H-indazol-4- yl] -1,3-oxazol-5-yl} methanol (containing an impurity compatible with 2- [6-chloro-1- (phenylsulfonyl) -1H-indazol-4-yl] -1,3-oxazol-5-yl } methanol) (350 mg) in dichloromethane (10 ml) was added carbon tetrabromide (397 mg, 1.197 mmol). The reaction mixture was cooled to 0 ° C and triphenylphosphine (314 mg, 1.197 mmol) as a solution in dichloromethane (2 mL) was added dropwise. The reaction mixture was allowed to warm to RT, then the solvent was partially removed and the solution was directly purified by chromatography on silica gel, eluting with a gradient of dichloromethane and ethyl acetate. The desired fractions were concentrated to give a brown solid (37 mg).

[0336] 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 chromatography on silica gel, 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): R t 0.65 min, MH⁺400.

Example 8 \ - | 5- | 4- (5-11 (2 / ?, 6 /?) - 2,6-dimethyl-4-morpholinyl | methyl} -1,3-oxazol-2-yl) -1Hindazol- 6-yl] -2- (methyloxy) -3-pyridinyl] methanesulfonamide

[0337]

<img file="PL2899191T3_D0050.tif" />

[0338] To a solution of 6-chloro-4- (5 - {[(2R, 6R) -2,6-dimethyl-4-morpholinyl] methyl} -1,3-oxazol-2-yl) -1- (phenylsulfonyl ) -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), while stirring with air at room temperature, was 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) R t 0.63 min, MH⁺ 513.

Example 9

6- (1ZMndol-4-yl) -4- [5- (1-piperazinylmethyl) -1,3-oxazol-2-yl] -1 H -indazole [0339]

<img file="PL2899191T3_D0051.tif" />

1,1-Dimethylethyl 4 - ({2- [6-Chloro-1- (phenylsulfonyl) -1H-indazol-4-yl] -1,3-oxazol-5-yl} methyl) 1-piperazinecarboxylate ( 303mg, 0.543mmol), 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-indole (172mg, 0.706mmol, available from Frontier Scientific), ( 17 ', 4S) -bicyclo [2.2.1] hept-2-yl [(1S, 47') - bicyclo [2.2.1] hept-2-yl] chloro [2 '- (dimethylamino) -2- phosphate biphenylyl] palladium (1: 1) (30 mg, 0.054 mmol, available from Fluka) and tripotassium phosphate (346 mg, 1.629 mmol) was dissolved in 1,4-dioxane (10 ml) and water (2.5 ml). The reaction vessel was sealed and heated in a Biotage Initiator microwave oven at 150 ° C for 30 min. 2M aq. NaOH (5 ml) was then added and the mixture was stirred for 2 hours. Additional 2M aq. NaOH (3 mL) was added and stirring was continued until deprotection was complete 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 re-extracted 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 was 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 of DMSO / MeOH (1: 1) and purified by MDAP (method A). The title compound was obtained by combining the appropriate fractions and concentration by blowing down under a stream of nitrogen at 40 ° C. The title compound was obtained (43 mg).

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

Example 10

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

[0341]

<img file="PL2899191T3_D0052.tif" />

[0342] A solution of 6- (1H-indol-4-yl) -4- (5- {[4- (1-methylethyl) -1-piperazinyl] methyl} -1,3oxazol-2-yl) -1H- indazole in tetrahydrofuran (THF) (7.5 mL) was heated to 60 ° C under a nitrogen stream. 2M hydrochloric acid in diethyl ether (0.567 mL, 1.135 mmol) and tetrahydrofuran (THF) (0.5 mL) were mixed and added via an addition funnel. The solution was stirred at 60 ° C for 30 min before it was slowly cooled to RT. After stirring at RT for a further 30 min, the solid was filtered off, then re-combined with aqueous solutions and evaporated to dryness. THF (10 ml) was added and the suspension was cycled from RT to reflux for 3 times (30 min hold at higher / lower temp). The suspension was stirred at RT for one hour then vacuum filtered and the resulting solid was dried in a vacuum oven at 50 ° C overnight to give the title compound as an off-white solid (322mg).

LCMS (method A): Rt 0.66 min, MH⁺ 441. 1 H NMR (400 MHz, DMSO-d6) d = 13.53 (s, 1H), 11.44 (br. S, "1H), 10.20 (br. S," 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.s "1H), 3.87 (s, 2H), 3.41 3.32 (m, 3 H +, obscured by H 2 O), 3.10 - 2.93 (m, 4H), 2.71 - 2.58 (m, 2H), 1.23 (d, J = 6.5 Hz, 6H).

Example 11

6- (17 H -indol-4-yl) -4- (5 - {[4- (1-methylethyl) -1-piperazinyl] methyl} 1,3-oxazol-2-yl) -1 H - hydrochloride indazole

[0343]

<img file="PL2899191T3_D0053.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 formed 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): R t 0.65 min, MH⁺ 441.

1 H NMR (600 MHz, DMSO-d₆) d = 13.47 (br. s, 1H), 11.38 (br. s, 1H), 10.17 (br. s, 1H), 8.66 (s, 1H) ), 8.13 (s, 1H), 7.93 (s, 1H), 7.51 (br. S, 1H), 7.49 (dt, J = 1.0, 7.5Hz , 1H), 7.47 (t, J = 3.0Hz, 1H), 7.25 (t, J = 7.0Hz, 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.s., 2H), 3, 50 - 3.39 (m, 3H), 3.35 - 3.25 (m, 2H), 3.22 - 3.11 (m, 2H), 2.99 - 2.76 (m, 2 H), 1.24 (d, J = 6.5 Hz, 6H).

Example 12 (If) -Mygdalate 7V- [5- [4- (5 - {[(21 ', 65) -2,6-dimethyl-4-morpholinyl] methyl} -1,3-oxazol-2-yl) -1H -indazol-6-yl] -2- (methyloxy) -3-pyridinyl] methanesulfonamide

[0345]

<img file="PL2899191T3_D0054.tif" />

Method A

[0346] A- [5- [4- (5 - {[(27 ', 65) -2,6-dimethyl-4-morpholinyl] methyl} -1,3-oxazol-2-yl) -1 / 7-indazole -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 µΐ, 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.

Ή NMR (400 MHz, DMSO-d6) d = 13.53 (br. S, 1H), 9.43 (s, 1H), 8.58 (s, 1H), 8.43 (d, J = 2.5Hz, 1H), 7.99 (d, J = 2.5Hz, 1H), 7.93 (d, J = 1.5Hz, 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 = 10.5Hz, 2H), 1.78 (t, J = 10.5 Hz, 2H), 1.04 (d, J = 6.5 Hz, 6H).

Note - almond is only present in a molar ratio of 0.8.

Method B

[0347] A- [5- [4- (5 - {[(27 ', 65) -2,6-dimethyl-4-morpholinyl] methyl} -1,3-oxazol-2-yl) -177indazol-6 -yl] -2- (methyloxy) -3-pyridinyl] methanesulfonamide (3.17 mg) was suspended in 5% dextrose / water (3 mL). 100 mg / ml of an aqueous solution of (7µ) - mandelic acid (10 µΐ) 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 were acquired on a PANalytical X'Pert Pro powder diffractometer, model PW3040 / 60, serial number DY1850 using an X'Celerator detector. The data acquisition conditions were: radiation: Cu Ka, generator current: 40 kV, generator current: 45 mA, angle at the start: 2.0 ° 20, angle at the end: 40.0 ° 20, step size: 0.0167 ° 20 time per step: 31.75 seconds. The samples were prepared by depositing a few milligrams of the sample on silicon wafers (zero background) to form a thin layer of powder.

[0349] X-ray powder diffraction (XRPD) data are shown in Figure 1.

[0350] The peaks characteristic of the solid state are summarized in Table 1 with the calculated lattice interplanar distances. Peak positions were measured using Highscore software.

Table 1

<td> 20/°</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> 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] The data was acquired using a similar method to the one described above.

[0352] X-ray Powder Diffraction (XRPD) data are shown in Figure 2.

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

Table 2

<td> 20/°</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> 20/°</td><td>distance d / A</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> 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

Trials with PI3K Alpha, Beta, Delta and Gamma kinases

Principle of trial

[0354] The reading in the assay uses the specific and high affinity binding of PIP3 to the isolated plextrin (PH) homology domain in signal generation. Briefly, the PIP3 product is detected by displacing biotinylated PIP3 from the energy transfer complex of Europium (Eu) labeled anti-GST monoclonal antibody, GST labeled PH domain, biotin-PIP3 and streptavidin APC. Excitation of Eu leads to energy transfer to the APC and sensitized fluent emission at 665nm. The PIP3 generated by the activity of PI3 kinase competes for a binding site in the PH domain, leading to a loss of energy transfer and a reduction in signal.

Test protocol

[0355] Solid compounds are typically applied in 0.1 μΐ 100% DMSO to all wells (except columns 6 and 18) of a low volume, 384-well V-bottom Greiner plate. Compounds are 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, yielding 11 concentrations for each test compound.

[0356] The assay is carried out with a kit with the defined PI3 kinase from Millipore (cat no. 33-001)

The test kit consists of:

• 4x PI3K reaction buffer (containing 200 mM Hepes pH 7, 600 mM NaCl, 40 mM MgCl 2, &lt;1% cholate (w / v), &lt;1% Chaps (w / v), 0.05% sodium azide (w / v)). PIP2 (1 mM) • 3xBiotin-PIP3 (50 μΜ) • detection mixture C (containing 267 mM KF) • detection mixture A (containing 60 μβ / ττιΐ streptavadin-APC) • detection mixture B (containing 36 μg / ml Europium-antibody anti-GST (Anti-GST-K) and 90 pg / ml GST-GRP1-PH domain and 1 mM DTT) • stop solution (containing 150 mM EDTA)

[0357] Manually add 3 μΐ reaction buffer (contains 1 mM DTT) to column 18 for 100% inhibition (no activity) control only

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

Manually add 3 μΐ of 2X Substrate Solution to all wells (Column 6 is 0% inhibition control)

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

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

The sample is read on the BMG Rubystar and the ratio data is used to calculate 11 point curves.

Note: Substrate solution (concentration) is different 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 µM ATP, 10 µM PIP2, and 0.030 µM 3X Biotin-PIP3.

Gamma

[0361] 2X substrate solution containing 30 µM ATP, 16 µM PIP2, and 0.030 µM 3X Biotin-PIP3.

Analysis method

[0362] Data was processed using the 4-parameter XC50 logistic curve fitting algorithm in the Activity Base.

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

Primary module fit: slope, asymptotes min. and max, variable

Secondary modulus fits: (1) Find the min asymptote, (2) Find the max asymptote, (3) Find the min asymptote and max

Curve fit quality control: 95% confidence limits 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 Alpha, Beta, Delta and / or Gamma PI3Ks or similar assays and were found to exhibit a mean pIC50 against PI3K Delta of at least 7 or bigger.

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