WO2016134668A1 - Composés d'aminopyrimidine substituée et procédés d'utilisation - Google Patents

Composés d'aminopyrimidine substituée et procédés d'utilisation Download PDF

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WO2016134668A1
WO2016134668A1 PCT/CN2016/074666 CN2016074666W WO2016134668A1 WO 2016134668 A1 WO2016134668 A1 WO 2016134668A1 CN 2016074666 W CN2016074666 W CN 2016074666W WO 2016134668 A1 WO2016134668 A1 WO 2016134668A1
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alkylene
cycloalkyl
membered
alkyl
membered heterocyclyl
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Ning Xi
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Sunshine Lake Pharma Co., Ltd.
Calitor Sciences, Llc
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Definitions

  • the present invention is directed to certain novel compounds which are inhibitors of kinase activity, processes for their preparation, pharmaceutical compositions comprising the compounds, and the use of the compounds or the compositions in the treatment of various disorders. More specifically, the compounds disclosed herein are inhibitors of the activity or function of the phosphatidylinositol 3-kinase kinase family (hereinafter PI3-kinases, PI3Ks) , for example PI3K ⁇ , PI3K ⁇ , PI3K ⁇ and/or PI3K ⁇ .
  • PI3-kinases phosphatidylinositol 3-kinase kinase family
  • PI3 kinases The phosphoinositide 3-kinases (PI3 kinases or PI3Ks) , a family of lipid kinases, have been found to have key regulatory roles in many cellular processes including cell survival, proliferation and differentiation.
  • RTKs receptor tyrosine kinases
  • GPCRs G protein-coupled receptors
  • PI3Ks transduce signals from various growth factors and cytokines into intracellular massages by generating phospholipids, which activate the serine-threonine protein kinase AKT (also known as protein kinase B (PKB) ) and other downstream effector pathways.
  • AKT serine-threonine protein kinase AKT
  • PBB protein kinase B
  • the tumor suppressor or PTEN (phosphatase and tensin homologue) is the most important negative regulator of the PI3K signaling pathway ( “Small-molecule inhibitors of the PI3K signaling network. ” Future Med. Chem., 2011, 3, 5, 549-565) .
  • PI3Ks have been identified, divided into three main classes (I, II and III) on the basis of their genetic sequence, structure, adapter molecules, expression, mode of activation, and preferred substrate. Among them, Class I PI3Ks are further divided based on signaling pathways and regulatory proteins into class IA and class IB.
  • the class IA PI3Ks comprise three closely related kinases, PI3K ⁇ , PI3K ⁇ , and PI3K ⁇ , which exist as heterodimers composed of a catalytic subunit (p110 ⁇ , p110 ⁇ , and p110 ⁇ respectively) and a p85 regulatory adapter subunits (i.e., p85 ⁇ , p85 ⁇ , p55 ⁇ , p55 ⁇ and p50 ⁇ ) .
  • the catalytic p110 subunit uses ATP to phosphorylate phosphatidylinositol (PI, PtdIns) , PI4P and PI (4, 5) P2. These signal responses are generally transducted through receptor tyrosine kinases (RTKs) .
  • the class IB PI3K ⁇ signals are transduced through G-protein-coupled receptors (GPCRs) , and are composed of a p110 ⁇ catalytic domain that can associate with regulatory subunits distinct from the class IA
  • class I PI3-kinases (e.g. PI3K ⁇ , PI3Kdelta) generate second messengers from the membrane phospholipid pools.
  • Class I PI3Ks convert the membrane phospholipid PI (4, 5) P2 into PI (3, 4, 5) P3, which functions as a second messenger.
  • PI and PI (4) P are also substrates of PI3K and can be phosphorylated and converted into PI3P and PI (3, 4) P2, respectively.
  • these phosphoinositides can be converted into other phosphoinositides by 5'-specific and 3'-specific phophatases.
  • PI3K enzymatic activity results either directly or indirectly in the generation of two 3'-phosphoinositide subtypes which function as second messengers in intracellular signal transduction pathways (Nature Reviews Molecular Cell Biology, 2010, 11, 329) .
  • PI3K ⁇ and PI3K ⁇ isoforms are ubiquitous, while the expression pattern of PI3K ⁇ and PI3K ⁇ seems more restricted, with both isoforms found primarily in leukocytes.
  • the relatively restricted expression pattern of PI3K ⁇ and PI3K ⁇ in addition to data accumulated from studies in mice suggests that these two isoforms play a major role in the adaptive and innate immune systems (J. Med. Chem., 2012, 55, 20, 8559-8581) .
  • PI3Ks In B and T cells, PI3Ks have an important role through activation of the Tec family of protein tyrosine kinases which include Bruton's tyrosine kinase (BTK) in B cells and lnterleukin-2-inducible T-cell kinase (ITK) in T cells.
  • BTK Bruton's tyrosine kinase
  • ITK lnterleukin-2-inducible T-cell kinase
  • PLC ⁇ 1 phospholipase C-gamma
  • DAG diacylglycerol
  • PI3K ⁇ kinase dead knock-in mice are viable and their phenotype is restricted to defects in immune signaling (Okkenhaug et al., Science, 2002, 297, p. 1031-4) .
  • These transgenic mice have offered insight into the function of PI3K ⁇ in B-cell and T-cell signaling.
  • PI3K ⁇ is required for PI (3, 4, 5) P3 formation downstream of CD28 and/or T cell Receptor (TCR) signaling.
  • TCR T cell Receptor
  • T cells with inactive PI3K ⁇ have defects in proliferation and Th1 and Th2 cytokine secretion.
  • Activation of T cells through CD28 lowers the threshold for TCR activation by antigen and increases the magnitude and duration of the proliferative response.
  • PI3K inhibitors are anticipated to provide therapeutic benefit via its role in modulating T-cell mediated inflammatory responses associated to respiratory diseases such as asthma, COPD and cystic fibrosis.
  • T-cell directed therapies may provide corticosteroid sparing properties (Lancet, 1992, 339, p. 324-8) suggesting that it may provide a useful therapy either as a standalone or in combination with inhaled or oral glucocorticosteroids in respiratory diseases.
  • a PI3K inhibitor might also be used alongside other conventional therapies such as long acting beta-agonists (LABA) in asthma.
  • PI3K ⁇ is expressed by endothelial cells and participates in neutrophil trafficking by modulating the proadhesive state of these cells in response to TNF-alpha (Blood, 2004, 103, 9, p. 3448) .
  • a role for PI3K ⁇ in TNFalpha-induced signaling of endothelial cells is demonstrated by the pharmacological inhibition of Akt phosphorylation and PDK1 activity.
  • PI3K ⁇ is implicated in vascular permeability and airway tissue edema through the VEGF pathway (Allergy Clin. Immunol., 2006, 118, 2, p. 403) .
  • PI3K ⁇ inhibition in asthma by the combined reduction of leukocyte extravasation and vascular permeability associated with asthma.
  • PI3K ⁇ activity is required for mast cell function both in vitro and in vivo (Nature, 2004, 431, p. 1007; J. Immunol., 2008, 180, 4, p. 2538) further suggesting that PI3K inhibition should be of therapeutic benefit for allergic indications such asthma, allergic rhinitis and atopic dermatitis.
  • PI3K ⁇ in B cell proliferation, antibody secretion, B-cell antigen and IL-4 receptor signaling, B-cell antigen presenting function is also well established (J. Immunol., 2007, 178, 4, p. 2328-35; Blood, 2006, 107, 2, p. 642-50) and indicates a role in autoimmune diseases such as rheumatoid arthritis or systemic lupus erythematosus. Therefore PI3K inhibitors may also be of benefit for these indications.
  • PI3K ⁇ Pharmacological inhibition of PI3K ⁇ inhibits fMLP-dependent neutrophil chemotaxis on an ICAM coated agarose matrix integrin-dependent biased system (J. Immunol., 2003, 170, 5, p. 2647-54) . Inhibition of PI3K ⁇ regulates neutrophil activation, adhesion and migration without affecting neutrophil mediated phagocytosis and bactericidal activity over Staphylococcus aureus (Biochem. Biophys. Res. Commun., 2003, 308, 4, p. 764-9) . Overall, the data suggest that PI3K ⁇ inhibition should not globally inhibit neutrophil functions required for innate immune defense. PI3K ⁇ 's role in neutrophils offers further scope for treating inflammatory diseases involving tissue remodeling such as COPD or rheumatoid arthritis.
  • PI3K ⁇ has been identified as a mediator of G beta-gamma-dependent regulation of JNK activity, and G beta-gamma are subunits of heterotrimeric G proteins (J. Biol. Chem., 1998, 273, 5, p. 2505-8) . It has been described that PI3K ⁇ relays inflammatory signals through various G (i) -coupled receptors and is central to mast cell function, stimuli in the context of leukocytes, and immunology including cytokines, chemokines, adenosines, antibodies, integrins, aggregation factors, growth factors, viruses or hormones for example (Immunity, 2002, 16, 3, p. 441-51; J. Cell Sci., 2001, 114 (Pt 16) , p. 2903-10 and Curr. Opinion Cell Biol., 2002, 14, 2, p. 203-13) .
  • PI3K enzymes contribute to tumourigenesis in a wide variety of human cancers, either directly or indirectly (Nature Reviews Cancer, 2002, 2, 7, p. 489-501) .
  • inhibition of PI3K ⁇ may have a therapeutic role for the treatment of malignant haematological disorders such as acute myeloid leukaemia (Oncogene, 2006, 25, 50, p. 6648-59) .
  • activating mutations within p110 ⁇ have been associated with various other tumors such as those of the colon and of the breast and lung (Science, 2004, 304, 5670, p. 554; Nature Reviews Cancer, 2009, 9, 551) .
  • PI3K inhibitors may have anti-viral properties in addition to more established oncolytic and anti-inflammatory indications. These antiviral effects raise interesting prospects in viral induced inflammatory exacerbations.
  • HRV common cold human rhinovirus
  • COPD chronic obstruction pulmonary disease
  • Rhinoviral infection of epithelial cells leads to a PI3K dependent cytokine and chemokine secretion (J. Biol. Chem., 2005, 280, 44, p. 36952) .
  • This inflammatory response correlates with worsening of respiratory symptoms during infection. Therefore PI3K inhibitors may dampen an exaggerated immune response to an otherwise benign virus.
  • the majority of HRV strains infect bronchial epithelial cells by initially binding to the ICAM-1 receptor.
  • the HRV-ICAM-1 complex is then further internalised by endocytosis and it has been shown that this event requires PI3K activity (J. Immunol., 2008, 180, 2, p. 870-880) . Therefore, PI3K inhibitors may also block viral infections by inhibiting viral entry into host cells.
  • PI3K inhibitors may be useful in reducing other types of respiratory infections including the fungal infection aspergillosis (Mucosal Immunol., 2010, 3, 2, p. 193-205) .
  • PI3K ⁇ deficient mice are more resistant towards infections by the protozoan parasite Leishmania major (J. Immunol., 2009, 183, 3, p. 1921-1933) .
  • these reports suggest that PI3K inhibitors may be useful for the treatment of a wide variety of infections.
  • PI3K inhibition has also been shown to promote regulatory T cell differentiation (Proc. Natl. Acad. Sci. USA, 2008, 105, 22, p. 7797-7802) suggesting that PI3K inhibitors may serve therapeutic purposes in auto-immune or allergic indications by inducing immuno-tolerance towards self-antigen or allergen.
  • PI3K ⁇ isoform has also been linked to smoke induced glucocorticoid insensitivity (Am. J. Respir. Crit. Care Med., 2009, 179, 7, p. 542-548) . This observation suggests that COPD patients, which otherwise respond poorly to corticosteroids, may benefit from the combination of a PI3K inhibitor with a corticosteroid.
  • IPF idiopathic pulmonary fibrosis
  • IPF idiopathic pulmonary fibrosis
  • IPF is a fibrotic disease with progressive decline of lung function and increased mortality due to respiratory failure.
  • circulating fibrocytes are directed to the lung via the chemokine receptor CXCR4.
  • PI3K is required for both signaling and expression of CXCR4 (Int. J. Biochem. and Cell Biol., 2009, 41, p. 1708-1718) . Therefore, by reducing CXCR4 expression and blocking its effector function, a PI3K inhibitor should inhibit the recruitment of fibrocytes to the lung and consequently slow down the fibrotic process underlying IPF, a disease with high unmet need.
  • PI3K ⁇ and ⁇ 3 ⁇ play an essential role in maintaining homeostasis and pharmacological inhibition of these molecular targets has been associated with cancer therapy (Maira et al., Expert Opin. Ther. Targets, 2008, 12, 223) .
  • PI3K ⁇ is involved in insulin signaling and cellular growth pathways (Nature, 2006, 441, 366) .
  • ⁇ 3 ⁇ isoform-selective inhibition is expected to avoid potential side effects such as hyperglycemia, and metabolic or growth disregulation.
  • PI3K ⁇ -selective inhibitors have also been described recently.
  • the most selective compounds include the quinazolinone purine inhibitors (PIK39 and IC87114) .
  • IC87114 inhibits PI3K ⁇ in the high nanomolar range (triple digit) and has greater than 100-fold selectivity against PI3K ⁇ , is 52 fold selective against PI3K ⁇ but lacks selectivity against PI3K ⁇ (approx. 8-fold) . It shows no activity against any protein kinases tested (Cell, 2006, 125, 733-747) .
  • PI3K ⁇ D910A delta-selective compounds or genetically manipulated mice
  • PI3K inhibitors that are good drug candidates.
  • compounds disclosed herein should bind potently to PI3K whilst showing little affinity for other receptors and show functional activity as inhibitors. They should be well absorbed from the gastrointestinal tract, be metabolically stable and possess favorable pharmacokinetic properties. When targeted against receptors in the central nervous system they should cross the blood brain barrier freely and when targeted selectively against receptors in the peripheral nervous system they should not cross the blood brain barrier. They should be non- toxic and demonstrate few side-effects.
  • the ideal drug candidate will exist in a physical form that is stable, non-hygroscopic and easily formulated.
  • the compounds disclosed herein show a certain level of selectivity against the different paralogs PI3K ⁇ , ⁇ , ⁇ and ⁇ . In particular, show a certain level of selectivity for the isoform ⁇ 3 ⁇ .
  • the compounds disclosed herein are therefore potentially useful in the treatment of a wide range of disorders, particularly disorders including but not limited to autoimmune disorders, inflammatory diseases, allergic diseases, disease or infection associated immunopathologies, airway diseases, transplant rejection, cancers of hematopoietic origin or solid tumors.
  • the invention also relates to the treatment, either alone or in combination, with one or more other pharmacologically active compounds, includes methods of treating conditions, diseases or disorders in respiratory diseases including asthma, chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF) ; viral infections including viral respiratory tract infections and viral exacerbation 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 (Future Med.
  • respiratory diseases including asthma, chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF)
  • viral infections including viral respiratory tract infections and viral exacerbation of respiratory diseases such as asthma and COPD
  • non-viral respiratory infections including
  • hematologic malignancies such as Acute Myeloid leukaemia (AML) Myelo-dysplastic syndrome (MDS) myelo-proliferative diseases (MPD) Chronic Myeloid Leukemia (CML) T-cell acute lymphoblastic leukaemia (T-ALL) B-cell Acute Lymphoblastic leukaemia (B-ALL) Non Hodgkins Lymphoma (AML) Myeloid leukaemia (AML) Myelo-dysplastic syndrome (MDS) myelo-proliferative diseases (MPD) Chronic Myeloid Leukemia (CML) T-cell acute lymphoblastic leukaemia (T-ALL) B-cell Acute Lymphoblastic leukaemia (B-ALL) Non Hodgkins Lymphoma (AML) Myeloid leukaemia (MDS) myelo-proliferative diseases (MPD) Chronic Myeloid Leukemia (CML) T-cell acute lymphoblastic le
  • the present inventors have discovered novel compounds which are inhibitors of kinase activity, in particular PI3-kinase activity.
  • Compounds which are PI3-kinase inhibitors may be useful in the treatment of disorders associated with inappropriate kinase activity, in particular 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 exacerbation 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; hematologic malignancies; neurodegenerative diseases; pancreatitis; multiorgan failure; kidney diseases; platelet aggregation; cancer; sperm motility; transplantation rejection; graft rejection; lung injuries; and pain including pain associated with rheumatoid arthritis or osteoarthritis, back pain, general inflammatory pain, post hepatic neuralgia, diabetic neuropathy, inflammatory neuropathic pain (trauma)
  • compounds disclosed herein may show selectivity for PI3-kinases over other kinases.
  • compounds disclosed herein may be potent inhibitors of PI3K ⁇ .
  • compounds disclosed herein may show selectivity for PI3K ⁇ over other PI3-kinases.
  • X is
  • W is N or CH, and Y is optionally substituted by one, two, three, or four R 2 groups;
  • each of R a , R b , R c , R d , R e and R f is independently H, (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, (C 3 -C 6 ) cycloalkyl, - (C 1 -C 4 ) alkylene- (C 3 -C 6 ) cycloalkyl, 3-6 membered heterocyclyl, - (C 1 -C 4 ) alkylene- (3-6 membered heterocyclyl) , (C 6 -C 10 ) aryl, - (C 1 -C 4 ) alkylene- (C 6 -C 10 ) aryl, 5-10 membered heteroaryl, - (C 1 -C 4 ) alkylene- (5-10 membered heteroaryl) , or R c and R d are taken together with the nitrogen atom to which they
  • R 1 is as defined herein.
  • each of R a , R b , R c , R d , R e and R f is independently H, (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, (C 3 -C 6 ) cycloalkyl, - (C 1 -C 2 ) alkylene- (C 3 -C 6 ) cycloalkyl, 5-6 membered heterocyclyl, - (C 1 -C 2 ) alkylene- (5-6 membered heterocyclyl) , 5-6 membered heteroaryl, or R c and R d are taken together with the nitrogen atom to which they are attached to form a 3-6 membered heterocyclic ring, wherein each of the (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl,
  • Y is
  • each of R 3 and R 4 is independently H, F, CN, methyl, ethyl, n-propyl, (C 3 -C 6 ) cycloalkyl, 5-6 membered heterocyclyl, - (C 1 -C 2 ) alkylene- (5-6 membered heterocyclyl) , or R 3 and R 4 are taken together with the carbon atom to which they are attached to form a 5-6 membered carbocyclic or heterocyclic ring, wherein each of the methyl, ethyl, n-propyl, (C 3 -C 6 ) cycloalkyl, 5-6 membered heterocyclyl, - (C 1 -C 2 ) alkylene- (5-6 membered heterocyclyl) , 5-6 membered carbocyclic ring and 5-6 membered heterocyclic ring is optionally substituted with one, two, three, or four substituents independently selected from F, Cl, Br, CN, OR
  • each of R a , R b , R c , R d , R e and R f is independently H, (C 1 -C 3 ) alkyl, (C 2 -C 4 ) alkenyl, (C 2 -C 4 ) alkynyl, (C 3 -C 6 ) cycloalkyl, 5-6 membered heterocyclyl, 5-6 membered heteroaryl, or R c and R d are taken together with the nitrogen atom to which they are attached to form a 5-6 membered heterocyclic ring, wherein each of the (C 1 -C 3 ) alkyl, (C 2 -C 4 ) alkenyl, (C 2 -C 4 ) alkynyl, (C 3 -C 6 ) cycloalkyl, 5-6 membered heterocyclyl, 5-6 membered heteroaryl and 5-6 membered heterocyclic ring is optionally substituted with one, two, three, or
  • the compound disclosed herein, or the pharmaceutically acceptable salt disclosed herein is provided for use as a medicament.
  • a pharmaceutical composition which comprises a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle or a combination thereof, and a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • the composition comprising one or more therapeutic agents.
  • the composition is a liquid, solid, semi-solid, gel, or an aerosol form.
  • provided here is the compound disclosed herein or the pharmaceutical composition disclosed herein for use in preventing, managing, treating or lessening the severity of a disorder mediated by inappropriate PI3-kinase activity in a patient.
  • the disorder is asthma, chronic obstructive pulmonary disease (COPD) , viral respiratory tract infections, viral exacerbation of respiratory diseases, aspergillosis, leishmaniasis, allergic rhinitis, atopic dermatitis, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, thrombosis, atherosclerosis, hematologic malignancy, neurodegenerative disease, pancreatitis, multiorgan failure, kidney disease, platelet aggregation, cancer, sperm motility, transplantation rejection, graft rejection, lung injury, pain associated with rheumatoid arthritis or osteoarthritis, back pain, general inflammatory pain, post hepatic neuralgia, diabetic neuropathy, inflammatory neuropathic pain (trauma) , trigeminal neuralgia, or central pain.
  • COPD chronic obstructive pulmonary disease
  • a disorder or a disease selected from asthma, chronic obstructive pulmonary disease (COPD) , viral respiratory tract infections, viral exacerbation of respiratory diseases, aspergillosis, leishmaniasis, allergic rhinitis, atopic dermatitis, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, thrombosis, atherosclerosis, hematologic malignancy, neurodegenerative disease, pancreatitis, multiorgan failure, kidney disease, platelet aggregation, cancer, sperm motility, transplantation rejection, graft rejection, lung injury, pain associated with rheumatoid arthritis or osteoarthritis, back pain, general inflammatory pain, post hepatic neuralgia, diabetic neuropathy, inflammatory neuropathic pain (trauma) , trigeminal neuralgia, or
  • Another aspect of the invention provides a method of modulating the activity of the PI3K enzymes, preferably of the ⁇ 3 ⁇ isoform, in a subject, which comprises administering to the subject a therapeutically effective amount of the compound disclosed herein, the pharmaceutically acceptable salt thereof, or the pharmaceutical composition disclosed herein.
  • Another aspect of the invention provides a method of treating a disorder mediated by inappropriate PI3-kinase activity comprising administering a safe and effective amount of the compound disclosed herein, the pharmaceutically acceptable salt thereof, or the pharmaceutical composition disclosed herein to a patient in need thereof.
  • Another aspect of the invention provides a method of treating a disorder mediated by inappropriate PI3-kinase activity comprising administering a therapeutically effective amount of the compound disclosed herein or the pharmaceutical composition disclosed herein, to a patient in need thereof.
  • the disorder mediated by inappropriate PI3-kinase activity is a respiratory disease, a viral infection, a non-viral respiratory infection, an allergic disease, an autoimmune disease, an inflammatory disorder, a cardiovascular disease, a hematologic malignancy, a neurodegenerative disease, pancreatitis, multiorgan failure, kidney disease, platelet aggregation, cancer, sperm motility, transplantation rejection, graft rejection, lung injury, or pain.
  • the disorder mediated by inappropriate PI3-kinase activity is asthma, chronic obstructive pulmonary disease (COPD) , viral respiratory tract infections, viral exacerbation of respiratory diseases, aspergillosis, leishmaniasis, allergic rhinitis, atopic dermatitis, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, thrombosis, atherosclerosis, hematologic malignancy, neurodegenerative disease, pancreatitis, multiorgan failure, kidney disease, platelet aggregation, cancer, sperm motility, transplantation rejection, graft rejection, lung injury, pain associated with rheumatoid arthritis or osteoarthritis, back pain, general inflammatory pain, post hepatic neuralgia, diabetic neuropathy, inflammatory neuropathic pain (trauma) , trigeminal neuralgia or central pain.
  • COPD chronic obstructive pulmonary disease
  • a method of inhibiting a phosphatidyl inositol-3 kinase comprising: contacting the PI3 kinase with an effective amount of a compound disclosed herein.
  • the step of contacting comprises contacting a cell that contains said PI3 kinase.
  • the inhibition takes place in a subject suffering from a disorder associated with malfunctioning of one or more types of PI3 kinase.
  • Some exemplary diseases involving malfunctioning of one or more types of PI3 kinases are selected from the group consisting of autoimmune diseases, rheumatoid arthritis, respiratory disease, allergic reactions, and various types of cancers.
  • the method comprises administering a second therapeutic agent to the subject.
  • the PI3K-mediated condition or disorder is selected from rheumatoid arthritis, ankylosing spondylitis, osteoarthritis, psoriatic arthritis, psoriasis, inflammatory diseases, and autoimmune diseases.
  • the PI3K-mediated condition or disorder is selected from cardiovascular diseases, atherosclerosis, hypertension, deep venous thrombosis, stroke, myocardial infarction, unstable angina, thromboembolism, pulmonary embolism, thrombolytic diseases, acute arterial ischemia, peripheral thrombotic occlusions, and coronary artery disease.
  • the PI3K-mediated condition or disorder is selected from cancer, colon cancer, glioblastoma, endometrial carcinoma, hepatocellular cancer, lung cancer, melanoma, renal cell carcinoma, thyroid carcinoma, cell lymphoma, lymphoproliferative disorders, small cell lung cancer, squamous cell lung carcinoma, glioma, breast cancer, prostate cancer, ovarian cancer, cervical cancer, and leukemia.
  • the PI3K-mediated condition or disorder is selected from type II diabetes.
  • the PI3K-mediated condition or disorder is selected from respiratory diseases, bronchitis, asthma, and chronic obstructive pulmonary disease.
  • the subject is a human.
  • Another aspect of the invention relates to the treatment of PI3K-mediated condition or disorder in a patient comprising the step of administering a compound according to any of the above embodiments.
  • Another aspect of the invention relates to the treatment of rheumatoid arthritis, ankylosing spondylitis, osteoarthritis, psoriatic arthritis, psoriasis, infiammatory diseases or autoimmune diseases in a patient comprising the step of administering a compound according to any of the above embodiments.
  • Another aspect of the invention relates to the treatment of respiratory diseases including asthma, chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF) in a patient comprising the step of administering a compound according to any of the above embodiments.
  • respiratory diseases including asthma, chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF)
  • COPD chronic obstructive pulmonary disease
  • IPF idiopathic pulmonary fibrosis
  • Another aspect of the invention relates to the treatment of inflammatory bowel disorders, inflammatory eye disorders, inflammatory or unstable bladder disorders, skin complaints with inflammatory components, chronic inflammatory conditions, systemic lupus erythematosis (SLE) , myestenia gravis, acute disseminated encephalomyelitis, idiopathic thrombocytopenic purpura, multiples sclerosis, Sjoegren's syndrome and autoimmune hemolytic anemia, allergic conditions and hypersensitivity in a patient, comprising the step of administering a compound according to any of the above or below embodiments.
  • SLE systemic lupus erythematosis
  • Another aspect of the invention relates to the treatment of cancers in a patient that are mediated, dependent on or associated with PI3K activity, particularly PI3K delta activity, comprising the step of administering a compound according to any of the above or below embodiments.
  • Another aspect of the invention relates to the treatment of cancers are selected from acute myeloid leukaemia, myelo-dysplastic syndrome, myeloproliferative diseases, chronic myeloid leukaemia, T-cell acute lymphoblastic leukaemia, B-cell acute lymphoblastic leukaemia, non-hodgkins lymphoma, B-cell lymphoma, solid tumors and breast cancer, comprising the step of administering a compound according to any of the above or below embodiments.
  • Another aspect of the invention relates to use of the compound according to any of the above embodiments or the composition according to any of the above embodiments as a medicament.
  • Another aspect of the invention relates to use of the compound according to any of the above embodiments or the composition according to any of the above embodiments in the manufacture of a medicament for the treatment of PI3K-mediated condition or disorder in a patient.
  • Another aspect of the invention relates to use of the compound according to any of the above embodiments or the composition according to any of the above embodiments in the manufacture of a medicament for the treatment of rheumatoid arthritis, ankylosing spondylitis, osteoarthritis, psoriatic arthritis, psoriasis, inflammatory diseases, respiratory diseases including asthma, chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF) , autoimmune diseases, and cancers.
  • COPD chronic obstructive pulmonary disease
  • IPF idiopathic pulmonary fibrosis
  • the salt is a pharmaceutically acceptable salt.
  • pharmaceutically acceptable indicates that the substance or composition must be compatible chemically and/or toxicologically, with the other ingredients comprising a formulation, and/or the mammal being treated therewith.
  • the compounds disclosed herein also include salts of such compounds which are not necessarily pharmaceutically acceptable salts, and which may be useful as intermediates for preparing and/or purifying compounds of Formula (I) and/or for separating enantiomers of compounds of Formula (I) .
  • the compounds disclosed herein, including their salts, can also be obtained in the form of their hydrates, or include other solvents used for their crystallization.
  • the compounds disclosed herein may inherently or by design form solvates with pharmaceutically acceptable solvents (including water) ; therefore, it is intended that the invention embrace both solvated and unsolvated forms.
  • the compounds disclosed herein may have in general several asymmetric centers and are typically depicted in the form of racemic mixtures. This invention is intended to encompass racemic mixtures, partially racemic mixtures and separate enantiomers and diasteromers.
  • Compounds disclosed herein can be in the form of one of the possible isomers, rotamers, atropisomers, tautomers or mixtures thereof.
  • This invention is intended to encompass mixtures of isomers, rotamers, atropisomers, tautomers, partially mixed isomers, rotamers, atropisomers, or tautomers, and separated isomers, rotamers, atropisomers, tautomers.
  • the compounds disclosed herein include isotopically labeled compounds as defined herein, for example those into which radioactive isotopes, such as 3 H, 14 C and 18 F, or those into which non-radioactive isotopes, such as 2 H and 13 C are present.
  • provided herein are methods of preparing, methods of separating, and methods of purifying compounds of Formula (I) .
  • the term "subject" refers to an animal. Typically the animal is a mammal. A subject also refers to for example, primates (e.g., humans) , cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds and the like. In certain embodiments, the subject is a primate. In yet other embodiments, the subject is a human.
  • primates e.g., humans
  • the subject is a primate.
  • the subject is a human.
  • patient refers to a human (including adults and children) or other animal. In one embodiment, “patient” refers to a human.
  • the present invention also includes isotopically-labelled compounds, which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes that can be incorporated into compounds disclosed herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as 2 H, 3 H, 13 C, 14 C, 15 N, 16 O, 17 O, 18 O, 31 P, 32 P, 36 S, 18 F, and 37 Cl.
  • isotopically-labeled compounds of the present invention for example those into which radioactive isotopes such as 3 H and 14 C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3 H, and carbon-14, i.e., 14 C, isotopes are particularly preferred for their ease of preparation and detection. Further, substitution with heavier isotopes such as deuterium, i.e., 2 H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances.
  • the compounds disclosed herein may contain asymmetric or chiral centers, and therefore exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds disclosed herein, including but not limited to, diastereomers, enantiomers, atropisomers, and geometric (or conformational) isomers as well as mixtures thereof such as racemic mixtures, form part of the present invention.
  • a specific stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture.
  • a 50: 50 mixture of enantiomers is referred to as a racemic mixture or a racemate, which may occur where there has been no stereoselection or stereospecificity in a chemical reaction or process.
  • the compounds can be present in the form of one of the possible isomers or as mixtures thereof, for example as pure optical isomers, or as isomer mixtures, such as racemates and diastereoisomer mixtures, depending on the number of asymmetric carbon atoms.
  • Optically active (R) -and (S) -isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituent may be E or Z configuration. If the compound contains a disubstituted cycloalkyl, the cycloalkyl substituent may have a cis-or trans-configuration.
  • structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, atropisomeric and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers.
  • tautomer or "tautomeric form” refers to structural isomers of different energies which are interconvertible via a low energy barrier. Where tautomerization is possible (e.g. in solution) , a chemical equilibrium of tautomers can be reached.
  • proton tautomers also known as prototropic tautomers
  • Valence tautomers include interconversions by reorganization of some of the bonding electrons.
  • keto-enol tautomerization is the interconversion of pentane-2, 4-dione and 4-hydroxypent-3-en-2-one tautomers.
  • tautomerization is phenol-keto tautomerization.
  • a specific example of phenol-keto tautomerization is the interconversion of pyridin-4-ol and pyridin-4 (1H) -one tautomers. Unless otherwise stated, all tautomeric forms of the compounds disclosed herein are within the scope of the invention.
  • N-oxide refers to one or more than one nitrogen atoms oxidised to form an N-oxide, where a compound contains several amine functions.
  • Particular examples of N-oxides are the N-oxides of a tertiary amine or a nitrogen atom of a nitrogen-containing heterocycle.
  • N-oxides can be formed by treatment of the corresponding amine with an oxidizing agent such as hydrogen peroxide or a per-acid (e.g. a peroxycarboxylic acid) (See, Advanced Organic Chemistiy, by Jerry March, 4 th Edition, Wiley Interscience, pages) . More particularly, N-oxides can be made by the procedure of L. W. Deady (Syn. Comm. 1977, 7, 509-514) in which the amine compound is reacted with m-chloroperoxybenzoic acid (MCPBA) , for example, in an inert solvent such as dichloromethane.
  • MCPBA m-chlor
  • a “solvate” refers to an association or complex of one or more solvent molecules and a compound disclosed herein.
  • solvents that form solvates include water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine.
  • hydrate refers to the complex where the solvent molecule is water.
  • a “metabolite” is a product produced through metabolism in the body of a specified compound or salt thereof.
  • the metabolite of a compound may be identified using routine techniques known in the art and their activities determined using tests such as those described herein. Such products may result for example from the oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzymatic cleavage, and the like, of the administered compound.
  • the invention includes metabolites of compounds disclosed herein, including compounds produced by a process comprising contacting a compound disclosed herein with a mammal for a period of time sufficient to yield a metabolic product thereof.
  • a “pharmaceutically acceptable salt” refers to organic or inorganic salts of a compound disclosed herein.
  • the pharmaceutically acceptable salts are well known in the art. For example, Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharm. Sci., 1977, 66, 1-19, which is incorporated herein by reference.
  • Some non-limiting examples of the pharmaceutically acceptable salt include salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • the pharmaceutically acceptable salt include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pect
  • Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C 1-4 alkyl) 4 salts.
  • This invention also envisions the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Water or oil-soluble or dispersible products may be obtained by such quaternization.
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • compositions include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, C 1-8 sulfonate and aryl sulfonate.
  • counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, C 1-8 sulfonate and aryl sulfonate.
  • prodrug represents a compound that is transformed in vivo into a compound of formula (I) . Such a transformation can be affected, for example, by hydrolysis in blood or enzymatic transformation of the prodrug form to the parent form in blood or tissue.
  • Prodrugs of the compounds disclosed herein may be, for example, esters. Esters that may be utilized as prodrugs in the present invention are phenyl esters, aliphatic (C 1 -C 24 ) esters, acyloxymethyl esters, carbonates, carbamates, and amino acid esters. For example, a compound disclosed herein that contains an OH group may be acylated at this position in its prodrug form.
  • prodrug forms include phosphates, such as, for example those phosphates resulting from the phosphonation of an OH group on the parent compound.
  • phosphates such as, for example those phosphates resulting from the phosphonation of an OH group on the parent compound.
  • a thorough discussion of prodrugs is provided in Higuchi et al., Pro-drugs as Novel Delivery Systems, Vol. 14, A.C.S. Symposium Series; Roche et al., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987; Rautio et al., Prodrugs: Design and Clinical Applications, Nat. Rev. Drug Discovery, 2008, 7, 255-270, and Hecker et al., Prodrugs of Phosphates and Phosphonates, J. Med. Chem., 2008, 51, 2328-2345, all of which are incorporated herein by reference.
  • any asymmetric atom (e.g., carbon or the like) of the compound (s) disclosed herein can be present in racemic or enantiomerically enriched, for example the (R) -, (S) -or (R, S) -configuration.
  • each asymmetric atom has at least 50 %enantiomeric excess, at least 60%enantiomeric excess, at least 70%enantiomeric excess, at least 80%enantiomeric excess, at least 90%enantiomeric excess, at least 95%enantiomeric excess, or at least 99%enantiomeric excess in the (R) -or (S) -configuration.
  • Substituents at atoms with unsaturated double bonds may, if possible, be present in cis- (Z) -or trans- (E) -form.
  • a compound disclosed herein can be in the form of one of the possible isomers, rotamers, atropisomers, tautomers or mixtures thereof, for example, as substantially pure geometric (cis or trans) isomers, diastereomers, optical isomers (antipodes) , racemates or mixtures thereof.
  • Any resulting mixtures of isomers can be separated on the basis of the physicochemical differences of the constituents, into the pure or substantially pure geometric or optical isomers, diastereomers, racemates, for example, by chromatography and/or fractional crystallization.
  • racemates of final products or intermediates can be resolved into the optical antipodes by methods known to those skilled in the art, e.g., by separation of the diastereomeric salts thereof.
  • Racemic products can also be resolved by chiral chromatography, e.g., high performance liquid chromatography (HPLC) using a chiral adsorbent.
  • HPLC high performance liquid chromatography
  • Preferred enantiomers can also be prepared by asymmetric syntheses. See, for example, Jacques, et al., “Enantiomers, Racemates and Resolutions, ” Wiley Interscience, New York, 1981; Gawley et al., “Principles of Asymmetric Synthesis, ” 2 nd Ed.
  • compounds disclosed herein may optionally be substituted with one or more substituents, such as are illustrated generally below, or as exemplified by particular classes, subclasses, and species of the invention.
  • substituents such as are illustrated generally below, or as exemplified by particular classes, subclasses, and species of the invention.
  • the phrase “optionally substituted” is used interchangeably with the phrase “substituted or unsubstituted” .
  • substituted refers to the replacement of one or more hydrogen radicals in a given structure with the radical of a specified substituent.
  • the term “optional” or “optionally” means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not.
  • Y is
  • W is N or CH
  • Y is optionally substituted by 1, 2, 3, or 4 R 2 groups
  • Y is optionally substituted by 1, 2, 3, or 4 R 2 groups
  • any hydrogen radical of the structure Y can be replaced by R 2 .
  • “Y is substituted by 1 R 2 group” can be represented as Structure Y-1 ⁇ Y-7 below.
  • an optionally substituted group may have a substituent at each substitutable position of the group.
  • the substituent may be either the same or different at each position.
  • substituents of the compounds disclosed herein are disclosed in groups or in ranges. It is specifically intended that the invention includes each and every individual subcombination of the members of such groups and ranges.
  • C 1 -C 6 alkyl is specifically intended to individually disclose methyl, ethyl, C 3 alkyl, C 4 alkyl, C 5 alkyl and C 6 alkyl.
  • linking substituents are described. Where the structure clearly requires a linking group, the Markush variables listed for that group are understood to be linking groups. For example, if the structure requires a linking group and the Markush group definition for that variable lists “alkyl” or “aryl” then it is understood that the “alkyl” or “aryl” represents a linking alkylene group or arylene group, respectively.
  • alkyl refers to a saturated linear or branched-chain monovalent hydrocarbon radical of 1 to 20 carbon atoms, wherein the alkyl radical may be optionally substituted independently with one or more substituents described herein. Unless otherwise specified, the alkyl group contains 1-20 carbon atoms. In some embodiments, the alkyl group contains 1-12 carbon atoms. In other embodiments, the alkyl group contains 1-10 carbon atoms. In other embodiments, the alkyl group contains 1-8 carbon atoms. In other embodiments, the alkyl group contains 1-6 carbon atoms. In still other embodiments, the alkyl group contains 1-4 carbon atoms, and in yet other embodiments, the alkyl group contains 1-3 carbon atoms.
  • alkyl group examples include methyl (Me, -CH 3 ) , ethyl (Et, -CH 2 CH 3 ) , 1-propyl (n-Pr, n-propyl, -CH 2 CH 2 CH 3 ) , 2-propyl (i-Pr, i-propyl, -CH (CH 3 ) 2 ) , 1-butyl (n-Bu, n-butyl, -CH 2 CH 2 CH 2 CH 3 ) , 2-methyl-l-propyl (i-Bu, i-butyl, -CH 2 CH (CH 3 ) 2 ) , 2-butyl (s-Bu, s-butyl, -CH (CH 3 ) CH 2 CH 3 ) , 2-methyl-2-propyl (t-Bu, t-butyl, -C (CH 3 ) 3 ) , 1-pentyl (n-pentyl, -CH 2 CH 2 CH 2 CH 3 ) ,
  • alk- is inclusive of both straight chain and branched saturated carbon chain.
  • alkylene refers to a saturated divalent hydrocarbon group derived from a straight or branched chain saturated hydrocarbon by the removal of two hydrogen atoms. Unless otherwise specified, the alkylene group contains 1-6 carbon atoms. In some embodiments, the alkylene group contains 1-4 carbon atoms. In other embodiments, the alkylene group contains 1-2 carbon atoms. Examples of the alkylene group include, but are not limited to, methylene (-CH 2 -) , ethylidene (-CH 2 CH 2 -) , isopropylidene (-CH (CH 3 ) CH 2 -) , and the like.
  • alkenyl refers to linear or branched-chain monovalent hydrocarbon radical of 2 to 12 carbon atoms with at least one site of unsaturation, i.e., a carbon-carbon, sp 2 double bond, wherein the alkenyl radical may be optionally substituted independently with one or more substituents described herein, and includes radicals having "cis” and “trans” orientations, or alternatively, "E” and “Z” orientations.
  • the alkenyl group contains 2 to 8 carbon atoms, more preferably, 2 to 6 carbon atoms, and most preferably 2 to 4 carbon atoms.
  • alkynyl refers to a linear or branched monovalent hydrocarbon radical of 2 to 12 carbon atoms with at least one site of unsaturation, i.e., a carbon-carbon, sp triple bond, wherein the alkynyl radical may be optionally substituted independently with one or more substituents described herein.
  • the alkynyl group contains 2 to 8 carbon atoms, more preferably 2 to 6 carbon atoms, and most preferably 2 to 4 carbon atoms.
  • alkynyl group examples include ethynyl (-C ⁇ CH) , propynyl (propargyl, -CH 2 C ⁇ CH) , -C ⁇ C-CH 3 , and the like.
  • alkoxy refers to an alkyl group, as previously defined, attached to the principal carbon atom through an oxygen atom. Unless otherwise specified, the alkoxy group contains 1-20 carbon atoms. In some embodiments, the alkoxy group contains 1-10 carbon atoms. In other embodiments, the alkoxy group contains 1-8 carbon atoms. In still other embodiments, the alkoxy group contains 1-6 carbon atoms, and in yet other embodiments, the alkoxy group contains 1-4 carbon atoms. In further embodiments, the alkoxy group contains 1-3 carbon atoms.
  • alkoxy group examples include methoxy (MeO, -OCH 3 ) , ethoxy (EtO, -OCH 2 CH 3 ) , 1-propoxy (n-PrO, n-propoxy, -OCH 2 CH 2 CH 3 ) , 2-propoxy (i-PrO, i-propoxy, -OCH (CH 3 ) 2 ) , 1-butoxy (n-BuO, n-butoxy, -OCH 2 CH 2 CH 2 CH 3 ) , 2-methyl-l-propoxy (i-BuO, i-butoxy, -OCH 2 CH (CH 3 ) 2 ) , 2-butoxy (s-BuO, s-butoxy, -OCH (CH 3 ) CH 2 CH 3 ) , 2-methyl-2-propoxy (t-BuO, t-butoxy, -OC (CH 3 ) 3 ) , 1-pentoxy (n-pentoxy, -OCH 2 CH 2 CH 3 ) ,
  • haloalkyl refers to alkyl, alkenyl, or alkoxy, as the case may be, substituted with one or more halogen atoms.
  • haloalkyl, haloalkenyl and haloalkoxy group include trifluoromethyl, trifluoromethoxy, and the like.
  • carbocycle refers to a monovalent or multivalent non-aromatic, saturated or partially unsaturated ring having 3 to 12 carbon atoms as a monocyclic, bicyclic, or tricyclic ring system, preferably, 3 to 6 carbon atoms, and more preferably 5 to 6 carbon atoms.
  • the carbobicyclyl system includes a spiro carbobicyclyl or a fused carbobicyclyl. In some embodiments, the carbocyclic ring group contains 3 to 8 carbon atoms.
  • carbocyclyl group examples include cycloalkyl, cycloalkenyl, and cycloalkynyl. Further non-limiting examples of the carbocyclyl group include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-l-enyl, l-cyclopent-2-enyl, l-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-l-enyl, l-cyclohex-2-enyl, l-cyclohex-3-enyl, cyclohexadienyl, and the like.
  • cycloalkyl refers to a monovalent or multivalent saturated ring having 3 to 12 carbon atoms as a monocyclic, bicyclic, or tricyclic ring system.
  • a bicyclic ring system includes a spiro bicyclyl or a fused bicyclyl.
  • the cycloalkyl group contains 3 to 10 carbon atoms.
  • the cycloalkyl group contains 3 to 8 carbon atoms.
  • the cycloalkyl group contains 3 to 6 carbon atoms, and in yet other embodiments, the cycloalkyl group contains 5 to 6 carbon atoms.
  • the cycloalkyl group is optionally substituted independently with one or more substituents described herein.
  • Ring sulfur atoms may be optionally oxidized to form S-oxides.
  • Ring nitrogen atoms maybe optionally oxidized to form N-oxides.
  • heterocyclyl examples include oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1, 3-dioxolanyl, dithiolanyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, thioxanyl, dithianyl, homopiperazinyl, homopiperidinyl, oxe
  • heterocyclyl wherein the ring sulfur atom is oxidized are sulfolanyl and 1, 1-dioxo-thiomorpholinyl.
  • the heterocyclyl group may be optionally substituted with one or more substituents described herein.
  • Ring sulfur atoms may be optionally oxidized to form S-oxides.
  • Ring nitrogen atoms maybe optionally oxidized to form N-oxides.
  • 3-8 membered heterocyclyl examples include oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1, 3-dioxolanyl, dithiolanyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, thioxanyl, dithianyl, homopiperazinyl, homopiperidinyl,
  • heterocyclyl wherein the ring sulfur atom is oxidized are sulfolanyl and 1, 1-dioxo-thiomorpholinyl.
  • the 3-8 membered heterocyclyl group may be optionally substituted with one or more substituents described herein.
  • Ring sulfur atoms may be optionally oxidized to form S-oxides.
  • Ring nitrogen atoms maybe optionally oxidized to form N-oxides.
  • Some non-limiting examples of the 3-6 membered heterocyclyl include oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1, 3-dioxolanyl, dithiolanyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, thioxanyl, and dithianyl.
  • heterocyclyl wherein the ring sulfur atom is oxidized are sulfolanyl and 1, 1-dioxo-thiomorpholinyl.
  • the 3-6 membered heterocyclyl group may be optionally substituted with one or more substituents described herein.
  • Ring sulfur atoms may be optionally oxidized to form S-oxides.
  • Ring nitrogen atoms maybe optionally oxidized to form N-oxides.
  • 5-6 membered heterocyclyl examples include pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1, 3-dioxolanyl, dithiolanyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, thioxanyl, and dithianyl.
  • heterocyclyl wherein the ring sulfur atom is oxidized are sulfolanyl and 1, 1-dioxo-thiomorpholinyl.
  • the 5-6 membered heterocyclyl group may be optionally substituted with one or more substituents described herein.
  • Ring sulfur atoms may be optionally oxidized to form S-oxides.
  • Ring nitrogen atoms maybe optionally oxidized to form N-oxides.
  • Some non-limiting examples of the 4-membered heterocyclyl include azetidinyl, oxetanyl, and thietanyl.
  • the 4-membered heterocyclyl group may be optionally substituted with one or more substituents described herein.
  • Ring sulfur atoms may be optionally oxidized to form S-oxides.
  • Ring nitrogen atoms maybe optionally oxidized to form N-oxides.
  • the 5-membered heterocyclyl include pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1, 3-dioxolanyl, and dithiolanyl.
  • the heterocyclyl wherein the ring sulfur atom is oxidized is sulfolanyl.
  • the 5-membered heterocyclyl group may be optionally substituted with one or more substituents described herein.
  • Ring sulfur atoms may be optionally oxidized to form S-oxides.
  • Ring nitrogen atoms maybe optionally oxidized to form N-oxides.
  • 6-membered heterocyclyl examples include tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, thioxanyl, and dithianyl.
  • heterocyclyl wherein the ring sulfur atom is oxidized is 1, 1-dioxo-thiomorpholinyl.
  • the 6-membered heterocyclyl group is optionally substituted with one or more substituents described herein.
  • n membered where n is an integer typically describes the number of ring-forming atoms in a moiety where the number of ring-forming atoms is n.
  • piperidinyl is an example of a 6 membered heterocycloalkyl
  • 1, 2, 3, 4-tetrahydronaphthalenyl is an example of a 10 membered carbocyclyl group.
  • heteroatom refers to one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon, including any oxidized form of nitrogen, sulfur, or phosphorus; the quaternized form of any basic nitrogen; or a substitutable nitrogen of a heterocyclic ring, for example N (as in 3, 4-dihydro-2H-pyrrolyl) , NH (as in pyrrolidinyl) or NR (as in N-substituted pyrrolidinyl) .
  • halogen refers to Fluoro (F) , Chloro (Cl) , Bromo (Br) , or Iodo (I) .
  • azido or “N 3 " refers to an azide moiety. This radical may be attached, for example, to a methyl group to form azidomethane (methyl azide, MeN 3 ) ; or attached to a phenyl group to form phenyl azide (PhN 3 ) .
  • aryl used alone or as part of a larger moiety as in “aralkyl” , “aralkoxy” or “aryloxyalkyl” refers to monocyclic, bicyclic, and tricyclic carbocyclic ring systems having a total of 6 to 14 ring members, preferably, 6 to 12 ring members, and more preferably 6 to 10 ring members, wherein at least one ring in the system is aromatic, wherein each ring in the system contains 3 to 7 ring members and that has one or more points of attachment to the rest of the molecule.
  • aryl may be used interchangeably with the term “aryl ring” or “aromatic. " Some non-limiting examples of the aryl ring would include phenyl, naphthyl, and anthracenyl.
  • the aryl radical is optionally substituted independently with one or more substituents described herein.
  • heteroaryl used alone or as part of a larger moiety as in “heteroaralkyl” or “heteroarylalkoxy” refers to monocyclic, bicyclic, and tricyclic ring systems having a total of 5 to 14 ring members, preferably, 5 to 12 ring members, and more preferably 5 to 10 ring members, wherein at least one ring in the system is aromatic, at least one ring in the system contains one or more heteroatoms, wherein each ring in the system contains 5 to 7 ring members and that has one or more points of attachment to the rest of the molecule.
  • heteroaryl may be a 5-10 membered heteroaryl comprises 1, 2, 3 or 4 heteroatoms independently selected from O, S and N.
  • heteroaryl may be a 5-6 membered heteroaryl comprises 1, 2, 3 or 4 heteroatoms independently selected from O, S and N.
  • heteroaryl may be a 5-membered heteroaryl comprises 1, 2, 3 or 4 heteroatoms independently selected from O, S and N.
  • heteroaryl may be used interchangeably with the term “heteroaryl ring” or the term “heteroaromatic” .
  • the heteroaryl radicals are optionally substituted independently with one or more substituents described herein.
  • heteroaryl ring examples include the following monocycles: 2-furanyl, 3-furanyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (e.g., 3-pyridazinyl) , 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (e.g., 5H-tetrazolyl and 2H-tetrazolyl) , triazolyl (e.g., 2-triazo
  • Carboxy or “carboxyl” , whether used alone or with other terms, such as “carboxyalkyl” , refers to -CO 2 H.
  • alkylamino embraces “N-alkylamino” and "N, N-dialkylamino” where amino groups are independently substituted with one alkyl radical or with two alkyl radicals, respectively.
  • alkylamino radicals are “lower alkylamino” radicals having one or two alkyl radicals of one to six carbon atoms, attached to a nitrogen atom.
  • Suitable alkylamino radicals may be mono or dialkylamino such as N-methylamino, N-ethylamino, N, N-dimethylamino, N, N-diethylamino and the like.
  • arylamino refers to amino groups, which have been substituted with one or two aryl radicals, such as N-phenylamino.
  • the arylamino radicals may be further substituted on the aryl ring portion of the radical.
  • aminoalkyl refers to linear or branched alkyl radicals having one to about ten carbon atoms any one of which may be substituted with one or more amino radicals. More preferred aminoalkyl radicals are "lower aminoalkyl” radicals having one to six carbon atoms and one or more amino radicals. Examples of such radicals include aminomethyl, aminoethyl, aminopropyl, aminobutyl and aminohexyl.
  • a bond drawn from a substituent to the center of one ring within a ring system represents substitution of the substituent at any substitutable position on the ring to which it is attached.
  • Structure a represents possible substitution in any of the positions on the A ring shown in Structure b-1, b-2 and b-3.
  • a bond drawn attachment to the center of one ring within a ring system represents connection of the bond to the rest of the molecule at any attachable position on the ring system.
  • Structure c represents possible connection to the rest of the molecule at any attachable position on the C ring shown in Structure d-1 and d-2.
  • unsaturated refers to a moiety having one or more units of unsaturation.
  • the term "pharmaceutically acceptable carrier” includes any and all solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungal agents) , isotonic agents, absorption delaying agents, salts, preservatives, drug stabilizers, binders, excipients, disintegration agents, lubricants, sweetening agents, flavoring agents, dyes, and the like and combinations thereof, as would be known to those skilled in the art (see, for example, Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, p. 1289-1329) . Except insofar as any conventional carrier is incompatible with the active ingredient, its use in the therapeutic or pharmaceutical compositions is contemplated.
  • a therapeutically effective amount of a compound disclosed herein refers to an amount of the compound disclosed herein that will elicit the biological or medical response of a subject, for example, reduction or inhibition of an enzyme or a protein activity, or ameliorate symptoms, alleviate conditions, slow or delay disease progression, or prevent a disease, etc.
  • a therapeutically effective amount refers to the amount of the compound disclosed herein that, when administered to a subject, is effective to (1) at least partially alleviate, inhibit, prevent and/or ameliorate a condition, or a disorder or a disease (i) mediated by PI3K or (ii) associated with PI3K activity, or (iii) characterized by activity (normal or abnormal) of PI3K or (2) reduce or inhibit the activity of PI3K or (3) reduce or inhibit the expression of PI3K.
  • a therapeutically effective amount refers to the amount of the compound disclosed herein that, when administered to a cell, or a tissue, or a non-cellular biological material, or a medium, is effective to at least partially reducing or inhibiting the activity of PI3K; or at least partially reducing or inhibiting the expression of PI3K.
  • the meaning of the term "a therapeutically effective amount” as illustrated in the above embodiment for PI3K also applies by the same means to any other relevant proteins/peptides/enzymes.
  • the term “treat” , “treating” or “treatment” of any disease or disorder refers in one embodiment, to ameliorating the disease or disorder (i.e., slowing or arresting or reducing the development of the disease or at least one of the clinical symptoms thereof) .
  • the term “treat” , “treating” or “treatment” refers to alleviating or ameliorating at least one physical parameter including those which may not be discernible by the patient.
  • the term “treat” , “treating” or “treatment” refers to modulating the disease or disorder, either physically, (e.g., stabilization of a discernible symptom) , physiologically, (e.g., stabilization of a physical parameter) , or both.
  • the term “treat” , “treating” or “treatment” refers to preventing or delaying the onset or development or progression of the disease or disorder.
  • protecting group refers to a substituent that is commonly employed to block or protect a particular functionality while reacting other functional groups on the compound.
  • an "amino-protecting group” is a substituent attached to an amino group that blocks or protects the amino functionality in the compound. Suitable amino-protecting groups include acetyl, trifluoroacetyl, tert-butoxy-carbonyl (BOC, Boc) , benzyloxycarbonyl (CBZ, Cbz) and 9-fluorenylmethylenoxy-carbonyl (Fmoc) .
  • a "hydroxy-protecting group” refers to a substituent of a hydroxy group that blocks or protects the hydroxy functionality.
  • Suitable protecting groups include acetyl and silyl.
  • a "carboxy-protecting group” refers to a substituent of the carboxy group that blocks or protects the carboxy functionality. Common carboxy-protecting groups include -CH 2 CH 2 SO 2 Ph, cyanoethyl, 2- (trimethylsilyl) ethyl, 2- (trimethylsilyl) ethoxy-methy-l, 2- (p-toluenesulfonyl) ethyl, 2- (p-nitrophenylsulfenyl) -ethyl, 2- (diphenylphosphino) -ethyl, nitroethyl and the like.
  • the present inventors have discovered novel compounds which are inhibitors of kinase activity, in particular PI3-kinase activity.
  • Compounds which are PI3-kinase inhibitors may be useful in the treatment of disorders associated with inappropriate kinase activity, in particular 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 exacerbation 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; hematologic malignancies; neurodegenerative diseases; pancreatitis; multiorgan failure; kidney diseases; platelet aggregation; cancer; sperm motility; transplantation rejection; graft rejection; lung injuries; and pain including pain associated with rheumatoid arthritis or osteoarthritis, back pain, general inflammatory pain, post hepatic neuralgia, diabetic neuropathy, inflammatory neuropathic pain (trauma)
  • compounds disclosed herein may show selectivity for PI3-kinases over other kinases.
  • compounds disclosed herein may be potent inhibitors of PI3K ⁇ .
  • compounds disclosed herein may show selectivity for PI3K ⁇ over other PI3-kinases.
  • X is
  • W is N or CH, and Y is optionally substituted by one, two, three, or four R 2 groups;
  • each of R a , R b , R c , R d , R e and R f is independently H, (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, (C 3 -C 6 ) cycloalkyl, - (C 1 -C 4 ) alkylene- (C 3 -C 6 ) cycloalkyl, 3-6 membered heterocyclyl, - (C 1 -C 4 ) alkylene- (3-6 membered heterocyclyl) , (C 6 -C 10 ) aryl, - (C 1 -C 4 ) alkylene- (C 6 -C 10 ) aryl, 5-10 membered heteroaryl, - (C 1 -C 4 ) alkylene- (5-10 membered heteroaryl) , or R c and R d are taken together with the nitrogen atom to which they
  • R 1 is as defined herein.
  • each of R a , R b , R c , R d , R e and R f is independently H, (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, (C 3 -C 6 ) cycloalkyl, - (C 1 -C 2 ) alkylene- (C 3 -C 6 ) cycloalkyl, 5-6 membered heterocyclyl, - (C 1 -C 2 ) alkylene- (5-6 membered heterocyclyl) , 5-6 membered heteroaryl, or R c and R d are taken together with the nitrogen atom to which they are attached to form a 3-6 membered heterocyclic ring, wherein each of the (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl,
  • Y is
  • each of R 3 and R 4 is independently H, F, CN, methyl, ethyl, n-propyl, (C 3 -C 6 ) cycloalkyl, 5-6 membered heterocyclyl, - (C 1 -C 2 ) alkylene- (5-6 membered heterocyclyl) , or R 3 and R 4 are taken together with the carbon atom to which they are attached to form a 5-6 membered carbocyclic or heterocyclic ring, wherein each of the methyl, ethyl, n-propyl, (C 3 -C 6 ) cycloalkyl, 5-6 membered heterocyclyl, - (C 1 -C 2 ) alkylene- (5-6 membered heterocyclyl) , 5-6 membered carbocyclic ring and 5-6 membered heterocyclic ring is optionally substituted with one, two, three, or four substituents independently selected from F, Cl, Br, CN, OR
  • each of R a , R b , R c , R d , R e and R f is independently H, (C 1 -C 3 ) alkyl, (C 2 -C 4 ) alkenyl, (C 2 -C 4 ) alkynyl, (C 3 -C 6 ) cycloalkyl, 5-6 membered heterocyclyl, 5-6 membered heteroaryl, or R c and R d are taken together with the nitrogen atom to which they are attached to form a 5-6 membered heterocyclic ring, wherein each of the (C 1 -C 3 ) alkyl, (C 2 -C 4 ) alkenyl, (C 2 -C 4 ) alkynyl, (C 3 -C 6 ) cycloalkyl, 5-6 membered heterocyclyl, 5-6 membered heteroaryl and 5-6 membered heterocyclic ring is optionally substituted with one, two, three, or
  • a pharmaceutical composition which comprises a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle or a combination thereof, and a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • the composition is a liquid, solid, semi-solid, gel, or an aerosol form.
  • a method of inhibiting a phosphatidyl inositol-3 kinase comprising: contacting the PI3 kinase with an effective amount of a compound disclosed herein.
  • the step of contacting comprises contacting a cell that contains said PI3 kinase.
  • the inhibition takes place in a subject suffering from a disorder associated with malfunctioning of one or more types of PI3 kinase.
  • Some exemplary diseases involving malfunctioning of one or more types of PI3 kinases are selected from the group consisting of autoimmune diseases, rheumatoid arthritis, respiratory disease, allergic reactions, and various types of cancers.
  • the method comprises administering a second therapeutic agent to the subject.
  • the PI3K-mediated condition or disorder is selected from rheumatoid arthritis, ankylosing spondylitis, osteoarthritis, psoriatic arthritis, psoriasis, inflammatory diseases, and autoimmune diseases.
  • the PI3K-mediated condition or disorder is selected from cardiovascular diseases, atherosclerosis, hypertension, deep venous thrombosis, stroke, myocardial infarction, unstable angina, thromboembolism, pulmonary embolism, thrombolytic diseases, acute arterial ischemia, peripheral thrombotic occlusions, and coronary artery disease.
  • the PI3K-mediated condition or disorder is selected from cancer, colon cancer, glioblastoma, endometrial carcinoma, hepatocellular cancer, lung cancer, melanoma, renal cell carcinoma, thyroid carcinoma, cell lymphoma, lymphoproliferative disorders, small cell lung cancer, squamous cell lung carcinoma, glioma, breast cancer, prostate cancer, ovarian cancer, cervical cancer, and leukemia.
  • the PI3K-mediated condition or disorder is selected from type II diabetes.
  • the PI3K-mediated condition or disorder is selected from respiratory diseases, bronchitis, asthma, and chronic obstructive pulmonary disease.
  • the subject is a human.
  • Another aspect of the invention relates to the treatment of PI3K-mediated condition or disorder in a patient comprising the step of administering a compound according to any of the above embodiments.
  • Another aspect of the invention relates to the treatment of rheumatoid arthritis, ankylosing spondylitis, osteoarthritis, psoriatic arthritis, psoriasis, infiammatory diseases or autoimmune diseases in a patient comprising the step of administering a compound according to any of the above embodiments.
  • Another aspect of the invention relates to the treatment of respiratory diseases including asthma, chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF) in a patient comprising the step of administering a compound according to any of the above embodiments.
  • respiratory diseases including asthma, chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF)
  • COPD chronic obstructive pulmonary disease
  • IPF idiopathic pulmonary fibrosis
  • Another aspect of the invention relates to the treatment of inflammatory bowel disorders, inflammatory eye disorders, inflammatory or unstable bladder disorders, skin complaints with inflammatory components, chronic inflammatory conditions, systemic lupus erythematosis (SLE) , myestenia gravis, acute disseminated encephalomyelitis, idiopathic thrombocytopenic purpura, multiples sclerosis, Sjoegren's syndrome and autoimmune hemolytic anemia, allergic conditions and hypersensitivity in a patient, comprising the step of administering a compound according to any of the above or below embodiments.
  • SLE systemic lupus erythematosis
  • Another aspect of the invention relates to the treatment of cancers in a patient that are mediated, dependent on or associated with PI3K activity, particularly PI3K delta activity, comprising the step of administering a compound according to any of the above or below embodiments.
  • Another aspect of the invention relates to the treatment of cancers are selected from acute myeloid leukaemia, myelo-dysplastic syndrome, myeloproliferative diseases, chronic myeloid leukaemia, T-cell acute lymphoblastic leukaemia, B-cell acute lymphoblastic leukaemia, non-hodgkins lymphoma, B-cell lymphoma, solid tumors and breast cancer, comprising the step of administering a compound according to any of the above or below embodiments.
  • Another aspect of the invention relates to the use of a compound according to any of the above embodiments as a medicament.
  • Another aspect of the invention relates to the use of a compound according to any of the above embodiments in the manufacture of a medicament for the treatment of PI3K-mediated condition or disorder in a patient.
  • Another aspect of the invention relates to the use of a compound according to any of the above embodiments in the manufacture of a medicament for the treatment of rheumatoid arthritis, ankylosing spondylitis, osteoarthritis, psoriatic arthritis, psoriasis, inflammatory diseases, respiratory diseases including asthma, chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF) , autoimmune diseases, and cancers.
  • COPD chronic obstructive pulmonary disease
  • IPF idiopathic pulmonary fibrosis
  • the salt is a pharmaceutically acceptable salt.
  • pharmaceutically acceptable indicates that the substance or composition must be compatible chemically and/or toxicologically, with the other ingredients comprising a formulation, and/or the mammal being treated therewith.
  • the compounds disclosed herein also include salts of such compounds which are not necessarily pharmaceutically acceptable salts, and which may be useful as intermediates for preparing and/or purifying compounds of Formula (I) and/or for separating enantiomers of compounds of Formula (I) .
  • Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids, e.g., acetate, aspartate, benzoate, besylate, bromide/hydrobromide, bicarbonate/carbonate, bisulfate/sulfate, camphorsulfonate, chloride/hydrochloride, chlortheophyllonate, citrate, ethandisulfonate, fumarate, gluceptate, gluconate, glucuronate, hippurate, hydroiodide/iodide, isethionate, lactate, lactobionate, laurylsulfate, malate, maleate, malonate, mandelate, mesylate, methylsulphate, naphthoate, napsylate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen
  • Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
  • Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, sulfosalicylic acid, and the like.
  • Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.
  • Inorganic bases from which salts can be derived include, for example, ammonium salts and metals from columns I to XII of the periodic table.
  • the salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include ammonium, potassium, sodium, calcium and magnesium salts.
  • Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like.
  • Certain organic amines include isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine and tromethamine.
  • the pharmaceutically acceptable salts disclosed herein can be synthesized from a basic or acidic moiety, by conventional chemical methods.
  • such salts can be prepared by reacting free acid forms of these compounds with a stoichiometric amount of the appropriate base (such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate or the like) , or by reacting free base forms of these compounds with a stoichiometric amount of the appropriate acid.
  • a stoichiometric amount of the appropriate base such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate or the like
  • Such reactions are typically carried out in water or in an organic solvent, or in a mixture of the two.
  • use of non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile is desirable, where practicable.
  • the compounds disclosed herein can also be obtained in the form of their hydrates, or include other solvents used for their crystallization.
  • the compounds disclosed herein may inherently or by design form solvates with pharmaceutically acceptable solvents (including water) ; therefore, it is intended that the invention embrace both solvated and unsolvated forms.
  • provided herein are methods of preparing, methods of separating, and methods of purifying compounds of Formula (I) .
  • the compounds disclosed herein may have in general several asymmetric centers and are typically depicted in the form of racemic mixtures. This invention is intended to encompass racemic mixtures, partially racemic mixtures and separate enantiomers and diasteromers.
  • Compounds disclosed herein can be in the form of one of the possible isomers, rotamers, atropisomers, tautomers or mixtures thereof.
  • This invention is intended to encompass mixtures of isomers, rotamers, atropisomers, tautomers, partially mixed isomers, rotamers, atropisomers, or tautomers, and separated isomers, rotamers, atropisomers, tautomers.
  • any formula given herein is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds.
  • Isotopically labeled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number.
  • isotopes that can be incorporated into compounds disclosed herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 18 F, 31 P, 32 P, 35 S, 36 Cl, and 125 I respectively.
  • the compounds disclosed herein include isotopically labeled compounds as defined herein, for example those into which radioactive isotopes, such as 3 H, 14 C and 18 F, or those into which non-radioactive isotopes, such as 2 H and 13 C are present.
  • isotopically labelled compounds are useful in metabolic studies (with 14 C) , reaction kinetic studies (with, for example 2 H or 3 H) , detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays, or in radioactive treatment of patients.
  • PET positron emission tomography
  • SPECT single-photon emission computed tomography
  • an 18 F or labeled compound may be particularly desirable for PET or SPECT studies.
  • Isotopically-labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using an appropriate isotopically-labeled reagent in place of the non-labeled reagent previously employed.
  • isotopic enrichment factor means the ratio between the isotopic abundance and the natural abundance of a specified isotope.
  • a substituent in a compound disclosed herein is denoted deuterium, such compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5%deuterium incorporation at each designated deuterium atom) , at least 4000 (60%deuterium incorporation) , at least 4500 (67.5%deuterium incorporation) , at least 5000 (75%deuterium incorporation) , at least 5500 (82.5%deuterium incorporation) , at least 6000 (90%deuterium incorporation) , at least 6333.3 (95%deuterium incorporation) , at least 6466.7 (97%deuterium incorporation) , at least 6600 (99%deuterium incorporation) , or at least 6633.3 (99.5%deuterium incorporation) .
  • Pharmaceutically acceptable solvates in accordance with the invention include those wherein the solvent of crystallization may be isotopically substituted, e.g. D 2 O, acetone-d 6 , or DMSO-d
  • compositions that include a compound of formula (I) , or a compound listed in Table 1; and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
  • the amount of compound in the pharmaceutical compositions disclosed herein is such that is effective to detectably inhibit a protein kinase in a biological sample or in a patient.
  • compositions disclosed herein can exist in free form for treatment, or where appropriate, as a pharmaceutically acceptable derivative thereof.
  • pharmaceutically acceptable derivative include pharmaceutically acceptable prodrugs, salts, esters, salts of such esters, or any other adduct or derivative which upon administration to a patient in need is capable of providing, directly or indirectly, a compound as otherwise described herein, or a metabolite or residue thereof.
  • compositions or pharmaceutically acceptable compositions disclosed herein additionally comprise a pharmaceutically acceptable carrier, adjuvant, or vehicle, which, as used herein, includes any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired.
  • a pharmaceutically acceptable carrier, adjuvant, or vehicle which, as used herein, includes any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired.
  • compositions disclosed herein may be prepared and packaged in bulk form wherein a safe and effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof can be extracted and then given to the patient such as with powders or syrups.
  • the pharmaceutical compositions disclosed herein may be prepared and packaged in unit dosage form wherein each physically discrete unit contains a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical compositions disclosed herein typically may contain, for example, from 0.5 mg to 1 g, or from 1 mg to 700 mg, or from 5 mg to 100 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • compositions disclosed herein typically contain one compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • pharmaceutically acceptable excipient means a pharmaceutically acceptable material, composition or vehicle involved in giving form or consistency to the pharmaceutical composition.
  • Each excipient must be compatible with the other ingredients of the pharmaceutical composition when commingled such that interactions which would substantially reduce the efficacy of the compound of formula (I) or a pharmaceutically acceptable salt thereof when administered to a patient and interactions which would result in pharmaceutical compositions that are not pharmaceutically acceptable are avoided.
  • each excipient must of course be pharmaceutically-acceptable eg of sufficiently high purity.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof and the pharmaceutically acceptable excipient or excipients will typically be formulated into a dosage form adapted for administration to the patient by the desired route of administration.
  • dosage forms include those adapted for (1) oral administration such as tablets, capsules, caplets, pills, troches, powders, syrups, elixers, suspensions, solutions, emulsions, sachets, and cachets; (2) parenteral administration such as sterile solutions, suspensions, and powders for reconstitution; (3) transdermal administration such as transdermal patches; (4) rectal administration such as suppositories; (5) inhalation such as aerosols, solutions, and dry powders; and (6) topical administration such as creams, ointments, lotions, solutions, pastes, sprays, foams, and gels.
  • oral administration such as tablets, capsules, caplets, pills, troches, powders, syrups, elixers, suspensions, solutions, emulsions, sachets, and cachets
  • parenteral administration such as sterile solutions, suspensions, and powders for reconstitution
  • transdermal administration such as transdermal patches
  • rectal administration such as sup
  • Suitable pharmaceutically acceptable excipients will vary depending upon the particular dosage form chosen.
  • suitable pharmaceutically acceptable excipients may be chosen for a particular function that they may serve in the composition.
  • certain pharmaceutically acceptable excipients may be chosen for their ability to facilitate the production of uniform dosage forms.
  • Certain pharmaceutically acceptable excipients may be chosen for their ability to facilitate the production of stable dosage forms.
  • Certain pharmaceutically acceptable excipients may be chosen for their ability to facilitate the carrying or transporting of the compound or compounds of formula (I) or pharmaceutically acceptable salts thereof once administered to the patient from one organ, or portion of the body, to another organ, or portion of the body.
  • Certain pharmaceutically acceptable excipients may be chosen for their ability to enhance patient compliance.
  • 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, emulsifiers, sweetners, flavoring agents, flavor masking agents, coloring agents, anticaking agents, hemectants, chelating agents, plasticizers, viscosity increasing agents, antioxidants, preservatives, stabilizers, surfactants, and buffering agents.
  • excipients include the following types of excipients: diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifiers, sweetners, flavoring agents, flavor masking agents, coloring agents, anticaking agents, hemectants, chelating agents
  • Skilled artisans possess the knowledge and skill in the art to enable them to select suitable pharmaceutically-acceptable excipients in appropriate amounts for use in the invention.
  • resources that are available to the skilled artisan which 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) .
  • compositions disclosed herein 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) .
  • the invention is directed to process for the preparation of a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients which comprises mixing the ingredients.
  • a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof may be prepared by, for example, admixture at ambient temperature and atmospheric pressure.
  • the compounds of formula (I) or pharmaceutically acceptable salts thereof will be formulated for oral administration. In another embodiment, the compounds of formula (I) or pharmaceutically acceptable salts thereof will be formulated for inhaled administration. In a further embodiment, the compounds of formula (I) or pharmaceutically acceptable salts thereof will be formulated for intranasal administration.
  • the invention is directed to a solid oral dosage form such as a tablet or capsule comprising a safe and effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof and a diluent or filler.
  • Suitable diluents and fillers include lactose, sucrose, dextrose, mannitol, sorbitol, starch (e.g. corn starch, potato starch, and pre-gelatinized starch) , cellulose and its derivatives (e.g. microcrystalline cellulose) , calcium sulfate, and dibasic calcium phosphate.
  • the oral solid dosage form may further comprise a binder.
  • Suitable binders include starch (e.g.
  • the oral solid dosage form may further comprise a disintegrant. Suitable disintegrants include crospovidone, sodium starch glycolate, croscarmelose, alginic acid, and sodium carboxymethyl cellulose.
  • the oral solid dosage form may further comprise a lubricant. Suitable lubricants include stearic acid, magnesuim stearate, calcium stearate, and talc.
  • dosage unit formulations for oral administration can be microencapsulated.
  • the composition can also be prepared to prolong or sustain the release as for example by coating or embedding particulate material in polymers, wax or the like.
  • the compounds of formula (I) or pharmaceutically acceptable salts thereof may also be coupled with soluble polymers as targetable drug carriers.
  • soluble polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide -phenol, polyhydroxyethylaspartamidephenol, or polyethyleneoxidepolylysine substituted with palmitoyl residues.
  • the compounds of formula (I) or pharmaceutically acceptable salts thereof may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.
  • biodegradable polymers useful in achieving controlled release of a drug
  • a drug for example, polylactic acid, polepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.
  • the invention is directed to a liquid oral dosage form.
  • Oral liquids such as solution, syrups and elixirs can be prepared in dosage unit form so that a given quantity contains a predetermined amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • Syrups can be prepared by dissolving the compound of formula (I) or a pharmaceutically acceptable salt thereof in a suitably flavored aqueous solution, while elixirs are prepared through the use of a non-toxic alcoholic vehicle.
  • Suspensions can be formulated by dispersing the compound of formula (I) or a pharmaceutically acceptable salt thereof in a non-toxic vehicle.
  • Solubilizers and emulsifiers such as ethoxylated isostearyl alcohols and polyoxy ethylene sorbitol ethers, preservatives, flavor additive such as peppermint oil or natural sweeteners or saccharin or other artificial sweeteners, and the like can also be added.
  • the invention is directed to a dosage form adapted for administration to a patient by inhalation, for example as a dry powder, an aerosol, a suspension, or a solution composition.
  • the invention is directed to a dosage form adapted for administration to a patient by inhalation as a dry powder.
  • the invention is directed to a dosage form adapted for administration to a patient by inhalation via a nebulizer.
  • Dry powder compositions for delivery to the lung by inhalation typically comprise a compound of formula (I) or a pharmaceutically acceptable salt thereof as a finely divided powder together with one or more pharmaceutically-acceptable excipients as finely divided powders.
  • compositions particularly suited 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 may be prepared by, for example, micronisation and milling.
  • the size-reduced (eg micronised) compound can be defined by a D 50 value of about 1 to about 10 microns (for example as measured using laser diffraction) .
  • the dry powder may be administered to the patient via a reservoir dry powder inhaler (RDPI) having a reservoir suitable for storing multiple (un-metered doses) of medicament in dry powder form.
  • RDPIs typically include a means for metering each medicament dose from the reservoir to a delivery position.
  • the metering means may comprise a metering cup, which is movable from a first position where the cup may be filled with medicament from the reservoir to a second position where the metered medicament dose is made available to the patient for inhalation.
  • 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) .
  • MDPIs are inhalers wherein the medicament is comprised within a multi-dose pack containing (or otherwise carrying) multiple defined doses (or parts thereof) of medicament.
  • the dry powder is presented as a blister pack, it comprises multiple blisters for containment of the medicament in dry powder form.
  • the blisters are typically arranged in regular fashion for ease of release of the medicament therefrom.
  • the blisters may be arranged in a generally circular fashion on a disc-form blister pack, or the blisters may be elongate in form, for example comprising a strip or a tape.
  • Each capsule, cartridge, or blister may, for example, contain between 20 ⁇ g-10 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • Aerosols may be formed by suspending or dissolving a compound of formula (I) or a pharmaceutically acceptable salt thereof in a liquified propellant.
  • Suitable propellants include halocarbons, hydrocarbons, and other liquified gases.
  • propellants include: trichlorofluoromethane (propellant 11) , dichlorofluoromethane (propellant 12) , dichlorotetrafluoroethane (propellant 114) , tetrafluoroethane (HFA-134a) , 1, 1-difluoroethane (HFA-152a) , difluoromethane (HFA-32) , pentafluoroethane (HFA-12) , heptafluoropropane (HFA-227a) , perfluoropropane, perfluorobutane, perfluoropentane, butane, isobutane, and pentane.
  • Aerosols comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof will typically be administered to a patient via a metered dose inhaler (MDI) .
  • MDI metered dose inhaler
  • the aerosol may contain additional pharmaceutically-acceptable excipients typically used with MDIs such as surfactants, lubricants, cosolvents and other excipients to improve the physical stability of the formulation, to improve valve performance, to improve solubility, or to improve taste.
  • additional pharmaceutically-acceptable excipients typically used with MDIs such as surfactants, lubricants, cosolvents and other excipients to improve the physical stability of the formulation, to improve valve performance, to improve solubility, or to improve taste.
  • a pharmaceutical aerosol formulation comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a fluorocarbon or hydrogen-containing chlorofluorocarbon as propellant, optionally in combination with a surfactant and/or a cosolvent.
  • 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 mixtures thereof.
  • compositions disclosed herein may be buffered by the addition of suitable buffering agents.
  • Capsules and cartridges for use in an inhaler or insufflator may be formulated containing a powder mix for inhalation of a compound of formula (I) or a pharmaceutically acceptable salt thereof and a suitable powder base such as lactose or starch.
  • a powder mix for inhalation of a compound of formula (I) or a pharmaceutically acceptable salt thereof and a suitable powder base such as lactose or starch.
  • Each capsule or cartridge may generally contain from 20 ⁇ g to 10 mg of the compound of formula (I) or pharmaceutically acceptable salt thereof.
  • the compound of formula (I) or pharmaceutically acceptable salt thereof may be presented without excipients such as lactose.
  • the proportion of the active compound of formula (I) or pharmaceutically acceptable salt thereof in the local compositions according to the invention depends on the precise type of formulation to be prepared but will generally be within the range of from 0.001 to 10%by weight. Generally, for most types of preparations, the proportion used will be within the range of from 0.005 to 1 %, for example from 0.01 to 0.5%. However, in powders for inhalation or insufflation the proportion used will normally be within the range of from 0.1%to 5%.
  • Aerosol formulations are preferably arranged so that each metered dose or "puff" of aerosol contains from 20 ⁇ g to 10mg, preferably from 20 ⁇ g to 2000 ⁇ g, more preferably from about 20 ⁇ g to 500 ⁇ g of a compound of formula (I) .
  • Administration may be once daily or several times daily, for example 2, 3, 4 or 8 times, giving for example 1, 2 or 3 doses each time.
  • the overall daily dose with an aerosol will be within the range from 100 ⁇ g to 10 mg, preferably from 200 ⁇ g to 2000 ⁇ g.
  • the overall daily dose and the metered dose delivered by capsules and cartridges in an inhaler or insufflator will generally be double that delivered with aerosol formulations.
  • the particle size of the particulate (e.g., micronised) drug should be such as to permit inhalation of substantially all the drug into the lungs upon administration of the aerosol formulation and will thus be less than 100 microns, desirably less than 20 microns, and in particular in the range of from 1 to 10 microns, such as from 1 to 5 microns, more preferably from 2 to 3 microns.
  • formulations disclosed herein may be prepared by dispersal or dissolution of the medicament and a compound of formula (I) or a pharmaceutically acceptable salt thereof in the selected propellant in an appropriate container, for example, with the aid of sonication or a high-shear mixer.
  • the process is desirably carried out under controlled humidity conditions.
  • the chemical and physical stability and the pharmaceutical acceptability of the aerosol formulations according to the invention may be determined by techniques well known to those skilled in the art.
  • the chemical stability of the components may be determined by HPLC assay, for example, after prolonged storage of the product.
  • Physical stability data may be gained from other conventional analytical techniques such as, for example, by leak testing, by valve delivery assay (average shot weights per actuation) , by dose reproducibility assay (active ingredient per actuation) and spray distribution analysis.
  • the stability of the suspension aerosol formulations according to the invention may be measured by conventional techniques, for example, by measuring flocculation size distribution using a back light scattering instrument or by measuring particle size distribution by cascade impaction or by the "twin impinger” analytical process.
  • twin impinger assay means "Determination of the deposition of the emitted dose in pressurised inhalations using apparatus A” as defined in British Pharmacopaeia 1988, pages A204-207, Appendix XVII C.
  • Such techniques enable the "respirable fraction" of the aerosol formulations to be calculated.
  • MDI means a unit comprising a can, a secured cap covering the can and a formulation metering valve situated in the cap.
  • MDI system includes a suitable channelling device. Suitable channelling devices comprise for example, a valve actuator and a cylindrical or cone-like passage through which medicament may be delivered from the filled canister via the metering valve to the nose or mouth of a patient such as a mouthpiece actuator.
  • MDI canisters generally comprise a container capable of withstanding the vapour pressure of the propellant used such as a plastic or plastic-coated glass bottle or preferably a metal can, for example, aluminium or an alloy thereof which may optionally be anodised, lacquer-coated and/or plastic-coated (for example incorporated herein by reference WO 96/32099 wherein part or all of the internal surfaces are coated with one or more fluorocarbon polymers optionally in combination with one or more non-fluorocarbon polymers) , which container is closed with a metering valve.
  • the cap may be secured onto the can via ultrasonic welding, screw fitting or crimping.
  • MDIs taught herein may be prepared by methods of the art (e.g. see Byron, above and WO 96/32099) .
  • the canister is fitted with a cap assembly, wherein a drug-metering valve is situated in the cap, and said cap is crimped in place.
  • the metallic internal surface of the can is coated with a fluoropolymer, more preferably blended with a non-fluoropolymer.
  • the metallic internal surface of the can is coated with a polymer blend of polytetrafluoroethylene (PTFE) and polyethersulfone (PES) .
  • the whole of the metallic internal surface of the can is coated with a polymer blend of polytetrafluoroethylene (PTFE) and polyethersulfone (PES) .
  • the metering valves are designed to deliver a metered amount of the formulation per actuation and incorporate a gasket to prevent leakage of propellant through the valve.
  • the gasket may comprise any suitable elastomeric material such as, for example, low density polyethylene, chlorobutyl, bromobutyl, EPDM, black and white butadiene-acrylonitrile rubbers, butyl rubber and neoprene.
  • suitable valves are commercially available from manufacturers well known in the aerosol industry, for example, from Valois, France (e.g. DF10, DF30, DF60) , Bespak pic, UK (e.g. BK300, BK357) and 3M-TM Neotechnic Ltd, UK (e.g. Spraymiser) .
  • the MDIs may also be used in conjunction with other structures such as, without limitation, overwrap packages for storing and containing the MDIs, including those described in U.S. Patent Nos. 6,119,853; 6,179,118; 6,315,112; 6,352,152; 6,390,291; and 6,679,374, as well as dose counter units such as, but not limited to, those described in U.S. Patent Nos. 6,360,739 and 6,431,168.
  • overwrap packages for storing and containing the MDIs, including those described in U.S. Patent Nos. 6,119,853; 6,179,118; 6,315,112; 6,352,152; 6,390,291; and 6,679,374, as well as dose counter units such as, but not limited to, those described in U.S. Patent Nos. 6,360,739 and 6,431,168.
  • a metering valve is crimped onto an aluminium can to form an empty canister.
  • the particulate medicament is added to a charge vessel and liquefied propellant together with the optional excipients is pressure filled through the charge vessel into a manufacturing vessel.
  • the drug suspension is mixed before recirculation to a filling machine and an aliquot of the drug suspension is then filled through the metering valve into the canister.
  • a metering valve is crimped onto an aluminium can to form an empty canister.
  • the liquefied propellant together with the optional excipients and the dissolved medicament is pressure filled through the charge vessel into a manufacturing vessel.
  • an aliquot of the liquefied formulation is added to an open canister under conditions which are sufficiently cold to ensure the formulation does not vaporise, and then a metering valve crimped onto the canister.
  • each filled canister is check-weighed, coded with a batch number and packed into a tray for storage before release testing.
  • Suspensions and solutions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof may also be administered to a patient via a nebulizer.
  • the solvent or suspension agent utilized for nebulization may be any pharmaceutically-acceptable liquid such as water, aqueous saline, alcohols or glycols, e.g., ethanol, isopropylalcohol, glycerol, propylene glycol, polyethylene glycol, etc. or mixtures thereof.
  • Saline solutions utilize salts which display little or no pharmacological activity after administration.
  • organic salts such as alkali metal or ammonium halogen salts, e.g., sodium chloride, potassium chloride or organic salts, such as potassium, sodium and ammonium salts or organic acids, e.g., ascorbic acid, citric acid, acetic acid, tartaric acid, etc. may be used for this purpose.
  • alkali metal or ammonium halogen salts e.g., sodium chloride, potassium chloride or organic salts, such as potassium, sodium and ammonium salts or organic acids, e.g., ascorbic acid, citric acid, acetic acid, tartaric acid, etc.
  • organic acids e.g., ascorbic acid, citric acid, acetic acid, tartaric acid, etc.
  • the compound of formula (I) or pharmaceutically acceptable salt thereof may be stabilized by the addition of an inorganic acid, e.g., hydrochloric acid, nitric acid, sulphuric acid and/or phosphoric acid; an organic acid, e.g., ascorbic acid, citric acid, acetic acid, and tartaric acid, etc., a complexing agent such as EDTA or citric acid and salts thereof; or an antioxidant such as antioxidant such as vitamin E or ascorbic acid. These may be used alone or together to stabilize the compound of formula (I) or pharmaceutically acceptable salt thereof.
  • an inorganic acid e.g., hydrochloric acid, nitric acid, sulphuric acid and/or phosphoric acid
  • an organic acid e.g., ascorbic acid, citric acid, acetic acid, and tartaric acid, etc.
  • a complexing agent such as EDTA or citric acid and salts thereof
  • an antioxidant such as antioxidant such as vitamin E or as
  • Preservatives may be added such as benzalkonium chloride or benzoic acid and salts thereof.
  • Surfactant may be added particularly to improve the physical stability of suspensions. These include lecithin, disodium dioctylsulphosuccinate, oleic acid and sorbitan esters.
  • the invention is directed to a dosage form adapted for intranasal administration.
  • Formulations for administration to the nose may include pressurised aerosol formulations and aqueous formulations administered to the nose by pressurised pump. Formulations which are non-pressurised and adapted to be administered topically to the nasal cavity are of particular interest. Suitable formulations contain water as the diluent or carrier for this purpose. Aqueous formulations for administration to the lung or nose may be provided with conventional excipients such as buffering agents, tonicity modifying agents and the like. Aqueous formulations may also be administered to the nose by nebulisation.
  • the compounds of formula (I) or pharmaceutically acceptable salts thereof may be formulated as a fluid formulation for delivery from a fluid dispenser, for example a fluid dispenser having a dispensing nozzle or dispensing orifice through which a metered dose of the fluid formulation is dispensed upon the application of a user-applied force to a pump mechanism of the fluid dispenser.
  • a fluid dispenser for example a fluid dispenser having a dispensing nozzle or dispensing orifice through which a metered dose of the fluid formulation is dispensed upon the application of a user-applied force to a pump mechanism of the fluid dispenser.
  • Such fluid dispensers are generally provided with a reservoir of multiple metered doses of the fluid formulation, the doses being dispensable upon sequential pump actuations.
  • the dispensing nozzle or orifice may be configured for insertion into the nostrils of the user for spray dispensing of the fluid formulation into the nasal cavity.
  • a fluid dispenser of the aforementioned type is described and illustrated in WO 05/044354, the entire content of which is hereby incorporated herein by reference.
  • the dispenser has a housing which houses a fluid discharge device having a compression pump mounted on a container for containing a fluid formulation.
  • the housing has at least one finger-operable side lever which is movable inwardly with respect to the housing to cam the container upwardly in the housing to cause the pump to compress and pump a metered dose of the formulation out of a pump stem through a nasal nozzle of the housing.
  • the fluid dispenser is of the general type illustrated in Figures 30-40 of WO 05/044354.
  • compositions adapted for intranasal administration wherein the carrier is a solid include a coarse powder having a particle size for example in the range 20 to 500 microns which is administered by rapid inhalation through the nasal passage from a container of the powder held close up to the nose.
  • suitable compositions wherein the carrier is a liquid, for administration as a nasal spray or as nasal drops include aqueous or oil solutions of the compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • compositions adapted for transdermal administration may be presented as discrete patches intended to remain in intimate contact with the epidermis of the patient for a prolonged period of time.
  • the active ingredient may be delivered from the patch by iontophoresis as generally described in Pharmaceutical Research, 3 (6) , 318 (1986) .
  • compositions adapted for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils.
  • Ointments, creams and gels may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agent and/or solvents.
  • 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 according to the nature of the base include soft paraffin, aluminium stearate, cetostearyl alcohol, polyethylene glycols, woolfat, beeswax, carboxypolymethylene and cellulose derivatives, and/or glyceryl monostearate and/or non-ionic emulsifying agents.
  • Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilising agents, dispersing agents, suspending agents or thickening agents.
  • Powders for external application may be formed with the aid of any suitable powder base, for example, talc, lactose or starch.
  • Drops may be formulated with an aqueous or nonaqueous base also comprising one or more dispersing agents, solubilising agents, suspending agents or preservatives.
  • Topical preparations may be administered by one or more applications per day to the affected area; over skin areas occlusive dressings may advantageously be used. Continuous or prolonged delivery may be achieved by an adhesive reservoir system.
  • compositions may be applied as a topical ointment or cream.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof may be employed with either a paraffinic or a water-miscible ointment base.
  • the compound of formula (I) or pharmaceutically acceptable salt thereof may be formulated in a cream with an oil-in-water cream base or a water-in-oil base.
  • compositions adapted for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
  • the compositions may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use.
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets.
  • the compound and pharmaceutical formulations according to the invention may be used in combination with or include one or more other therapeutic agents, for example selected from anti-inflammatory agents, anticholinergic agents (particularly an M 1 /M 2 /M 3 receptor antagonist) , ⁇ 2 -adrenoreceptor agonists, antiinfective agents, such as antibiotics or antivirals, or antihistamines.
  • other therapeutic agents for example selected from anti-inflammatory agents, anticholinergic agents (particularly an M 1 /M 2 /M 3 receptor antagonist) , ⁇ 2 -adrenoreceptor agonists, antiinfective agents, such as antibiotics or antivirals, or antihistamines.
  • the invention thus provides, in a further aspect, 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 an NSAID, an anticholinergic agent, a ⁇ 2 -adrenoreceptor agonist, an antiinfective agent, such as an antibiotic or an antiviral, or an antihistamine.
  • an anti-inflammatory agent such as a corticosteroid or an NSAID
  • an anticholinergic agent such as a corticosteroid or an NSAID
  • an anticholinergic agent such as a corticosteroid or an NSAID
  • an anticholinergic agent such as an antibiotic or an antiviral
  • an antiinfective agent such as an antibiotic or an antiviral
  • an antihistamine an antihistamine.
  • the invention encompasses a method of treating a disorder mediated by inappropriate PI3-kinase activity comprising administering a safe and effective amount of a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof together with one or more therapeutically active agents.
  • Certain compounds disclosed herein may show selectivity for PI3K ⁇ over other PI3-kinases.
  • the invention thus provides, in a further aspect, a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof which is selective for PI3K ⁇ together with a compound or pharmaceutically acceptable salt thereof which is selective for another PI3-kinase, for example PI3K ⁇ .
  • One embodiment of the invention encompasses combinations comprising one or two other therapeutic agents.
  • the other therapeutic ingredient (s) may be used in the form of salts, for example as alkali metal or amine salts or as acid addition salts, or prodrugs, or as esters, for example lower alkyl esters, or as solvates, for example hydrates to optimise the activity and/or stability and/or physical characteristics, such as solubility, of the therapeutic ingredient. It will be clear also that, where appropriate, the therapeutic ingredients may be used in optically pure form.
  • the invention provides a product comprising a compound of formula (I) and at least one other therapeutic agent as a combined preparation for simultaneous, separate or sequential use in therapy.
  • the therapy is the treatment of a disease or condition mediated by the activity of the PI3K enzymes.
  • Products provided as a combined preparation include a composition comprising the compound of formula (I) and the other therapeutic agent (s) together in the same pharmaceutical composition, or the compound of formula (I) and the other therapeutic agent (s) in separate form, e.g. in the form of a kit.
  • the invention provides a pharmaceutical composition comprising a compound of formula (I) and another therapeutic agent (s) .
  • the pharmaceutical composition may comprise a pharmaceutically acceptable carrier, as described above.
  • the invention provides a kit comprising two or more separate pharmaceutical compositions, at least one of which contains a compound of formula (I) .
  • the kit comprises means for separately retaining said compositions, such as a container, divided bottle, or divided foil packet.
  • An example of such a kit is a blister pack, as typically used for the packaging of tablets, capsules and the like.
  • the kit of the invention may be used for administering different dosage forms, for example, oral and parenteral, for administering the separate compositions at different dosage intervals, or for titrating the separate compositions against one another.
  • the kit of the invention typically comprises directions for administration.
  • the compound disclosed herein and the other therapeutic agent may be manufactured and/or formulated by the same or different manufacturers. Moreover, the compound disclosed herein and the other therapeutic may be brought together into a combination therapy: (i) prior to release of the combination product to physicians (e.g. in the case of a kit comprising the compound disclosed herein and the other therapeutic agent) ; (ii) by the physician themselves (or under the guidance of the physician) shortly before administration; (iii) in the patient themselves, e.g. during sequential administration of the compound disclosed herein and the other therapeutic agent.
  • the invention provides the use of a compound of formula (I) for treating a disease or condition mediated by the activity of the PI3K enzymes, wherein the medicament is prepared for administration with another therapeutic agent.
  • the invention also provides the use of another therapeutic agent for treating a disease or condition mediated by the activity of the PI3K enzymes, wherein the medicament is administered with a compound of formula (I) .
  • the invention also provides a compound of formula (I) for use in a method of treating a disease or condition mediated by the activity of the PI3K enzymes, wherein the compound of formula (I) is prepared for administration with another therapeutic agent.
  • the invention also provides another therapeutic agent for use in a method of treating a disease or condition mediated by the activity of the PI3K enzymes, wherein the other therapeutic agent is prepared for administration with a compound of formula (I) .
  • the invention also provides a compound of formula (I) for use in a method of treating a disease or condition mediated by the activity of the PI3K enzymes wherein the compound of formula (I) is administered with another therapeutic agent.
  • the invention also provides another therapeutic agent for use in a method of treating a disease or condition mediated by the activity of the PI3K enzymes wherein the other therapeutic agent is administered with a compound of formula (I) .
  • the invention also provides the use of a compound of formula (I) for treating a disease or condition mediated by the activity of the PI3K enzymes, wherein the patient has previously (e.g. within 24 hours) been treated with another therapeutic agent.
  • the invention also provides the use of another therapeutic agent for treating a disease or condition mediated by the activity of the PI3K enzymes, wherein the patient has previously (e.g. within 24 hours) been treated with a compound of formula (I) .
  • the compounds of formula I may be administered as the sole active ingredient or in conjunction with, e.g. as an adjuvant to, other drugs e.g. immunosuppressive or immunomodulating agents or other anti-inflammatory agents, e.g.
  • the compounds of formula I may be used in combination with a calcineurin inhibitor, e.g. cyclosporin A or FK 506; a mTOR inhibitor, e.g. rapamycin, 40-O- (2-hydroxyethyl) rapamycin, CCI779, ABT578, AP23573, TAFA-93, biolimus-7 or biolimus-9; an ascomycin having immuno-suppressive properties, e.g.
  • a calcineurin inhibitor e.g. cyclosporin A or FK 506
  • a mTOR inhibitor e.g. rapamycin, 40-O- (2-hydroxyethyl) rapamycin, CCI779, ABT578, AP23573, TAFA-93, biolimus-7 or biolimus-9
  • an ascomycin having immuno-suppressive properties e.g.
  • ABT-281, ASM981, etc. corticosteroids; cyclophosphamide; azathioprene; methotrexate; leflunomide; mizoribine; mycophenolic acid or salt; mycophenolate mofetil; 15-deoxyspergualine or an immunosuppressive homologue, analogue or derivative thereof; a PKC inhibitor, e.g. as disclosed in WO 02/38561 or WO 03/82859, e.g. the compound of Example 56 or 70; a JAK3 kinase inhibitor, e.g.
  • mono-citrate also called CP-690, 550
  • CP-690, 550 mono-citrate
  • immunosuppressive monoclonal antibodies e.g., monoclonal antibodies to leukocyte receptors, e.g., MHC, CD2, CD3, CD4, CD7, CD8, CD25, CD28, CD40, CD45, CD52, CD58, CD80, CD86 or their ligands
  • other immunomodulatory compounds e.g. a recombinant binding molecule having at least a portion of the extracellular domain of CTLA4 or a mutant thereof, e.g.
  • CTLA4 an at least extracellular portion of CTLA4 or a mutant thereof joined to a non-CTLA4 protein sequence, e.g. CTLA4lg (for ex. designated ATCC 68629) or a mutant thereof, e.g. LEA29Y; adhesion molecule inhibitors, e.g. LFA-1 antagonists, ICAM-1 or -3 antagonists, VCAM-4 antagonists or VLA-4 antagonists; or antihistamines; or antitussives, or a bronchodilatory agent; or an angiotensin receptor blockers; or an anti-infectious agent.
  • CTLA4lg for ex. designated ATCC 68629
  • adhesion molecule inhibitors e.g. LFA-1 antagonists, ICAM-1 or -3 antagonists, VCAM-4 antagonists or VLA-4 antagonists
  • antihistamines or antitussives, or a bronchodilatory agent
  • an angiotensin receptor blockers or an anti-infectious agent.
  • dosages of the co-administered immunosuppressant, immunomodulatory, anti-inflammatory, chemotherapeutic or anti-infectious compound will of course vary depending on the type of co-drug employed, e.g. whether it is a steroid or a calcineurin inhibitor, on the specific drug employed, on the condition being treated and so forth.
  • the invention encompasses a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof together with a ⁇ 2 -adrenoreceptor agonist.
  • ⁇ 2 -adrenoreceptor agonists examples include salmeterol (which may be a racemate or a single enantiomer such as the R-enantiomer) , salbutamol (which may be a racemate or a single enantiomer such as the R-enantiomer) , formoterol (which may be a racemate or a single duastereomer such as the R, R-diastereomer) , salmefamol, fenoterol, carmoterol, etanterol, naminterol, clenbuterol, pirbuterol, flerbuterol, reproterol, bambuterol, indacaterol, terbutaline and salts thereof, for example the xinafoate (1-hydroxy-2-naphthalenecarboxylate) salt of salmeterol, the sulphate salt or free base of salbutamol or the fumarate salt of formoterol.
  • the ⁇ 2 -adrenoreceptor agonist may be in the form of a salt formed with a pharmaceutically acceptable acid selected from sulphuric, hydrochloric, fumaric, hydroxynaphthoic (for example 1-or 3-hydroxy-2-naphthoic) , cinnamic, substituted cinnamic, triphenylacetic, sulphamic, sulphanilic, naphthaleneacrylic, benzoic, 4-methoxybenzoic, 2-or 4-hydroxybenzoic, 4-chlorobenzoic and 4-phenylbenzoic acid.
  • a pharmaceutically acceptable acid selected from sulphuric, hydrochloric, fumaric, hydroxynaphthoic (for example 1-or 3-hydroxy-2-naphthoic) , cinnamic, substituted cinnamic, triphenylacetic, sulphamic, sulphanilic, naphthaleneacrylic, be
  • Suitable anti-inflammatory agents include corticosteroids.
  • Suitable corticosteroids which may be used in combination with the compounds of formula (I) or pharmaceutically acceptable salts thereof are those oral and inhaled corticosteroids and their pro-drugs which have anti-inflammatory activity.
  • Examples include methyl prednisolone, prednisolone, dexamethasone, fluticasone propionate, 6 ⁇ , 9 ⁇ -difluoro-11 ⁇ -hydroxy-16 ⁇ -methyl-17 ⁇ - [ (4-methyl-1, 3-thiazole-5-carbonyl) oxy] -3-oxo-androsta-1, 4-diene-17 ⁇ -carbothioic acid S-fluoromethyl ester, 6 ⁇ , 9 ⁇ -difluoro-17 ⁇ - [ (2-furanylcarbonyl) oxy] -11 ⁇ -hydroxy-16 ⁇ -methyl-3-oxo-androsta-1, 4-diene-17 ⁇ - carbothioic acid S-fluoromethyl ester (fluticasone furoate) , 6 ⁇ , 9 ⁇ -difluoro-11 ⁇ -hydroxy-16 ⁇ -methyl-3-oxo-17 ⁇ -propionyloxy-androsta-1, 4-diene-17 ⁇ -carbothioic acid S- (2-oxo-tetrahydro-furan-3S-
  • Preferred corticosteroids include fluticasone propionate, 6 ⁇ , 9 ⁇ -difluoro-11 ⁇ -hydroxy-16 ⁇ -methyl-17 ⁇ - [ (4-methyl-1, 3-thiazole-5-carbonyl) oxy] -3-oxo-androsta-1, 4-diene-17 ⁇ -carbothioic acid S-fluoromethyl ester, 6 ⁇ , 9 ⁇ -difluoro-17 ⁇ - [ (2-furanylcarbonyl) oxy] -11 ⁇ -hydroxy-16 ⁇ -methyl-3-oxo-androsta-1, 4-diene-17 ⁇ -carbothioic acid S-fluoromethyl ester, 6 ⁇ , 9 ⁇ -difluoro-11 ⁇ -hydroxy-16 ⁇ -methyl-3-oxo-17 ⁇ - (2, 2, 3, 3-tetramethycyclopropylcarbonyl) oxy-androsta-1, 4-diene-17 ⁇ -carbothioic acid S-cyanomethyl ester and 6 ⁇ , 9 ⁇ -difluoro-11 ⁇ -hydroxy-16 ⁇ -methyl-17 ⁇
  • the corticosteroid is 6 ⁇ , 9 ⁇ -difluoro-17 ⁇ - [ (2-furanylcarbonyl) oxy] -11 ⁇ -hydroxy-16 ⁇ -methyl-3-oxo-androsta-1, 4-diene-17 ⁇ -carbothioic acid S-fluoromethyl ester.
  • Non-steroidal compounds having glucocorticoid agonism that may possess selectivity for transrepression over transactivation and that may be useful in combination therapy include those covered in the following patents: WO 03/082827, WO 98/54159, WO 04/005229, WO 04/009017, WO 04/018429, WO 03/104195, WO 03/082787, WO 03/082280, WO 03/059899, WO 03/101932, WO 02/02565, WO 01/16128, WO 00/66590, WO 03/086294, WO 04/026248, WO 03/061651 and WO 03/08277. Further non-steroidal compounds are covered in: WO 2006/000401, WO 2006/000398 and WO 2006/015870.
  • anti-inflammatory agents examples include non-steroidal anti-inflammatory drugs (NSAID's ) .
  • NSAID's non-steroidal anti-inflammatory drugs
  • NSAID's examples include sodium cromoglycate, nedocromil sodium, phosphodiesterase (PDE) inhibitors (for example, theophylline, PDE4 inhibitors or mixed PDE3/PDE4 inhibitors) , leukotriene antagonists, inhibitors of leukotriene synthesis (for example montelukast) , iNOS inhibitors, tryptase and elastase inhibitors, beta-2 integrin antagonists and adenosine receptor agonists or antagonists (e.g.
  • adenosine 2a agonists for example chemokine antagonists, such as a CCR3 antagonist
  • cytokine antagonists for example chemokine antagonists, such as a CCR3 antagonist
  • An iNOS inducible nitric oxide synthase inhibitor
  • iNOS inhibitors include those disclosed in WO 93/13055, WO 98/30537, WO 02/50021, WO 95/34534 and WO 99/62875.
  • CCR3 inhibitors include those disclosed in WO 02/26722.
  • the invention provides the use of the compounds of formula (I) in combination with a phosphodiesterase 4 (PDE4) inhibitor, especially in the case of a formulation adapted for inhalation.
  • PDE4-specific inhibitor useful in this aspect of the invention may be any compound that is known to inhibit the PDE4 enzyme or which is discovered to act as a PDE4 inhibitor, and which are only PDE4 inhibitors, not compounds which inhibit other members of the PDE family, such as PDE3 and PDE5, as well as PDE4.
  • Compounds include cis-4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) cyclohexan-1-carboxylic acid, 2-carbomethoxy-4-cyano-4- (3-cyclopropylmethoxy-4-difluoromethoxyphenyl) cyclohexan-1-one and cis- [4-cyano-4- (3-cyclopropylmethoxy-4-difluoromethoxyphenyl) cyclohexan-1-ol] .
  • cis-4-cyano-4- [3- (cyclopentyloxy) -4-methoxyphenyl] cyclohexane-1-carboxylic acid also known as cilomilast
  • salts, esters, pro-drugs or physical forms which is described in U.S. patent 5,552,438 issued 03 September, 1996; this patent and the compounds it discloses are incorporated herein in full by reference.
  • anticholinergic agents are those compounds that act as antagonists at the muscarinic receptors, in particular those compounds which are antagonists of the M 1 or M 3 receptors, dual antagonists of the M 1 /M 3 or M 2 /M 3 , receptors or pan-antagonists of the M 1 /M 2 /M 3 receptors.
  • exemplary compounds for administration via inhalation include ipratropium (for example, as the bromide, CAS 22254-24-6, sold under the name Atrovent) , oxitropium (for example, as the bromide, CAS 30286-75-0) and tiotropium (for example, as the bromide, CAS 136310-93-5, sold under the name Spiriva) .
  • revatropate for example, as the hydrobromide, CAS 262586-79-8) and LAS-34273 which is disclosed in WO 01/04118.
  • Exemplary compounds for oral administration include pirenzepine (CAS 28797-61-7) , darifenacin (CAS 133099-04-4, or CAS 133099-07-7 for the hydrobromide sold under the name Enablex) , oxybutynin (CAS 5633-20-5, sold under the name Ditropan) , terodiline (CAS 15793-40-5) , tolterodine (CAS 124937-51-5, or CAS 124937-52-6 for the tartrate, sold under the name Detrol) , otilonium (for example, as the bromide, CAS 26095-59-0, sold under the name Spasmomen) , trospium chloride (CAS 10405-02-4) and solifenacin (CAS 242478-37-1, or CAS 242478-
  • the invention provides a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof together with an H1 antagonist.
  • H1 antagonist include amelexanox, astemizole, azatadine, azelastine, acrivastine, brompheniramine, cetirizine, levocetirizine, efletirizine, chlorpheniramine, clemastine, cyclizine, carebastine, cyproheptadine, carbinoxamine, descarboethoxyloratadine, doxylamine, dimethindene, ebastine, epinastine, efletirizine, fexofenadine, hydroxyzine, ketotifen, loratadine, levocabastine, mizolastine, mequitazine, mianserin, noberastine, meclizine, norastemizole, olopatad
  • 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) .
  • H3 antagonists include, for example, those compounds disclosed in WO 2004/035556 and in WO 2006/045416.
  • Other histamine receptor antagonists which may be used in combination with the compounds disclosed herein include antagonists (and/or inverse agonists) of the H4 receptor, for example, the compounds disclosed in Jablonowski et al., J. Med. Chem., 2003, 46, 3957-3960.
  • the invention thus provides, in a further aspect, a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof together with a PDE4 inhibitor.
  • the invention thus provides, in a further aspect, a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof together with a ⁇ 2 -adrenoreceptor agonist.
  • the invention thus provides, in a further aspect, a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof together with a corticosteroid.
  • the invention thus provides, in a further aspect, a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof together with a non-steroidal GR agonist.
  • the invention thus provides, in a further aspect, a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof together with an anticholinergic.
  • the invention thus provides, in a further aspect, a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof together with an antihistamine.
  • the invention thus provides, in a further aspect, a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof together with a PDE4 inhibitor and a ⁇ 2 -adrenoreceptor agonist.
  • the invention thus provides, in a further aspect, a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof together with an anticholinergic and a PDE-4 inhibitor.
  • compositions comprising a combination as defined above together with a pharmaceutically acceptable diluent or carrier represent a further aspect of the invention.
  • the individual compounds of such combinations may be administered either sequentially or simultaneously in separate or combined pharmaceutical formulations.
  • the individual compounds will be administered simultaneously in a combined pharmaceutical formulation.
  • Appropriate doses of known therapeutic agents will readily be appreciated by those skilled in the art.
  • the invention thus provides, in a further aspect, a pharmaceutical composition
  • a pharmaceutical composition comprising a combination of a compound of formula (I) or a pharmaceutically acceptable salt thereof together with another therapeutically active agent.
  • the invention thus provides, in a further aspect, a pharmaceutical composition
  • a pharmaceutical composition comprising a combination of a compound of formula (I) or a pharmaceutically acceptable salt thereof together with a PDE4 inhibitor.
  • the invention thus provides, in a further aspect, a pharmaceutical composition
  • a pharmaceutical composition comprising a combination of a compound of formula (I) or a pharmaceutically acceptable salt thereof together with a ⁇ 2 -adrenoreceptor agonist.
  • the invention thus provides, in a further aspect, a pharmaceutical composition
  • a pharmaceutical composition comprising a combination of a compound of formula (I) or a pharmaceutically acceptable salt thereof together with a corticosteroid.
  • the invention thus provides, in a further aspect, a pharmaceutical composition
  • a pharmaceutical composition comprising a combination of a compound of formula (I) or a pharmaceutically acceptable salt thereof together with a non-steroidal GR agonist.
  • the invention thus provides, in a further aspect, a pharmaceutical composition
  • a pharmaceutical composition comprising a combination of a compound of formula (I) or a pharmaceutically acceptable salt thereof together with an anticholinergic.
  • the invention thus provides, in a further aspect, a pharmaceutical composition
  • a pharmaceutical composition comprising a combination of a compound of formula (I) or a pharmaceutically acceptable salt thereof together with an antihistamine.
  • the invention thus provides, in a further aspect, a pharmaceutical composition
  • a pharmaceutical composition comprising a combination of a compound of formula (I) or a pharmaceutically acceptable salt thereof together with a PDE4 inhibitor and a ⁇ 2 -adrenoreceptor agonist.
  • the invention thus provides, in a further aspect, a pharmaceutical composition
  • a pharmaceutical composition comprising a combination of a compound of formula (I) or a pharmaceutically acceptable salt thereof together with an anticholinergic and a PDE4 inhibitor.
  • a compound of the formula (I) may also be used to advantage in combination with each other or in combination with other therapeutic agents, especially other antiproliferative agents.
  • antiproliferative agents include, but are not limited to, aromatase inhibitors; antiestrogens; topoisomerase I inhibitors; topoisomerase II inhibitors; microtubule active agents; alkylating agents; histone deacetylase inhibitors; compounds, which induce cell differentiation processes; cyclooxygenase inhibitors; MMP inhibitors; mTOR inhibitors; antineoplastic antimetabolites; platin compounds; compounds targeting/decreasing a protein or lipid kinase activity and further anti-angiogenic compounds; compounds which target, decrease or inhibit the activity of a protein or lipid phosphatase; gonadorelin agonists; anti-androgens; methionine aminopeptidase inhibitors; bisphosphonates; biological response modifiers; antiproliferative antibodies; heparanase inhibitors
  • aromatase inhibitor relates to a compound which inhibits the estrogen production, i.e., the conversion of the substrates androstenedione and testosterone to estrone and estradiol, respectively.
  • the term includes, but is not limited to, steroids, especially atamestane, exemestane and formestane; and, in particular, nonsteroids, especially aminoglutethimide, roglethimide, pyridoglutethimide, trilostane, testolactone, ketoconazole, vorozole, fadrozole, anastrozole and letrozole.
  • Exemestane can be administered, e.g., in the form as it is marketed, e.g., under the trademark AROMASIN.
  • Formestane can be administered, e.g., in the form as it is marketed, e.g., under the trademark LENTARON.
  • Fadrozole can be administered, e.g., in the form as it is marketed, e.g., under the trademark AFEMA.
  • Anastrozole can be administered, e.g., in the form as it is marketed, e.g., under the trademark ARIMIDEX.
  • Letrozole can be administered, e.g., in the form as it is marketed, e.g., under the trademark FEMARA or FEMAR.
  • Aminoglutethimide can be administered, e.g., in the form as it is marketed, e.g., under the trademark ORIMETEN.
  • a combination of the invention comprising a chemotherapeutic agent which is an aromatase inhibitor is particularly useful for the treatment of hormone receptor positive tumors, e.g., breast tumors.
  • anti-estrogen relates to a compound which antagonizes the effect of estrogens at the estrogen receptor level.
  • the term includes, but is not limited to, tamoxifen, fulvestrant, raloxifene and raloxifene hydrochloride.
  • Tamoxifen can be administered, e.g., in the form as it is marketed, e.g., under the trademark NOLVADEX.
  • Raloxifene hydrochloride can be administered, e.g., in the form as it is marketed, e.g., under the trademark EVISTA.
  • Fulvestrant can be formulated as disclosed in U.S. Patent No.
  • 4,659,516 or it can be administered, e.g., in the form as it is marketed, e.g., under the trademark FASLODEX.
  • a combination of the invention comprising a chemotherapeutic agent which is an antiestrogen is particularly useful for the treatment of estrogen receptor positive tumors, e.g., breast tumors.
  • anti-androgen relates to any substance which is capable of inhibiting the biological effects of androgenic hormones and includes, but is not limited to, bicalutamide (CASODEX) , which can be formulated, e.g., as disclosed in U.S. Patent No. 4,636,505.
  • CASODEX bicalutamide
  • gonadorelin agonist includes, but is not limited to, abarelix, goserelin and goserelin acetate.
  • Goserelin is disclosed in U.S. Patent No. 4,100,274 and can be administered, e.g., in the form as it is marketed, e.g., under the trademark ZOLADEX.
  • Abarelix can be formulated, e.g., as disclosed in U.S. Patent No. 5,843,901.
  • topoisomerase I inhibitor includes, but is not limited to, topotecan, gimatecan, irinotecan, camptothecian and its analogues, 9-nitrocamptothecin and the macromolecular camptothecin conjugate PNU-166148 (compound A1 in WO 99/17804) .
  • Irinotecan can be administered, e.g., in the form as it is marketed, e.g., under the trademark CAMPTOSAR.
  • Topotecan can be administered, e.g., in the form as it is marketed, e.g., under the trademark HYCAMTIN.
  • topoisomerase II inhibitor includes, but is not limited to, the anthracyclines, such as doxorubicin, including liposomal formulation, e.g., CAELYX; daunorubicin; epirubicin; idarubicin; nemorubicin; the anthraquinones mitoxantrone and losoxantrone; and the podophillotoxines etoposide and teniposide.
  • Etoposide can be administered, e.g., in the form as it is marketed, e.g., under the trademark ETOPOPHOS.
  • Teniposide can be administered, e.g., in the form as it is marketed, e.g., under the trademark VM 26-BRISTOL.
  • Doxorubicin can be administered, e.g., in the form as it is marketed, e.g., under the trademark ADRIBLASTIN or ADRIAMYCIN.
  • Epirubicin can be administered, e.g., in the form as it is marketed, e.g., under the trademark FARMORUBICIN.
  • Idarubicin can be administered, e.g., in the form as it is marketed, e.g., under the trademark ZAVEDOS.
  • Mitoxantrone can be administered, e.g., in the form as it is marketed, e.g., under the trademark NOVANTRON.
  • microtubule active agent relates to microtubule stabilizing, microtubule destabilizing agents and microtublin polymerization inhibitors including, but not limited to, taxanes, e.g., paclitaxel and docetaxel; vinca alkaloids, e.g., vinblastine, especially vinblastine sulfate; vincristine, especially vincristine sulfate and vinorelbine; discodermolides; cochicine; and epothilones and derivatives thereof, e.g., epothilone B or D or derivatives thereof.
  • Paclitaxel may be administered, e.g., in the form as it is marketed, e.g., TAXOL.
  • Docetaxel can be administered, e.g., in the form as it is marketed, e.g., under the trademark TAXOTERE.
  • Vinblastine sulfate can be administered, e.g., in the form as it is marketed, e.g., under the trademark VINBLASTIN R.
  • Vincristine sulfate can be administered, e.g., in the form as it is marketed, e.g., under the trademark FARMISTIN.
  • Discodermolide can be obtained, e.g., as disclosed in U.S. Patent No. 5,010,099.
  • epothilone derivatives which are disclosed in WO 98/10121, U.S. Patent No. 6,194,181, WO 98/25929, WO 98/08849, WO 99/43653, WO 98/22461 and WO 00/31247.
  • epothilone A and/or B are particularly preferred.
  • alkylating agent includes, but is not limited to, cyclophosphamide, ifosfamide, melphalan or nitrosourea (BCNU or Gliadel) .
  • Cyclophosphamide can be administered, e.g., in the form as it is marketed, e.g., under the trademark CYCLOSTIN.
  • Ifosfamide can be administered, e.g., in the form as it is marketed, e.g., under the trademark HOLOXAN.
  • histone deacetylase inhibitors or "HDAC inhibitors” relates to compounds which inhibit the histone deacetylase and which possess antiproliferative activity.
  • SAHA suberoylanilide hydroxamic acid
  • anti-plastic antimetabolite includes, but is not limited to, 5-fluorouracil or 5-FU; capecitabine; gemcitabine; DNA demethylating agents, such as 5-azacytidine and decitabine; methotrexate and edatrexate; and folic acid antagonists, such as pemetrexed.
  • Capecitabine can be administered, e.g., in the form as it is marketed, e.g., under the trademark XELODA.
  • Gemcitabine can be administered, e.g., in the form as it is marketed, e.g., under the trademark GEMZAR.
  • the monoclonal antibody trastuzumab which can be administered, e.g., in the form as it is marketed, e.g., under the trademark HERCEPTIN.
  • platinum compound includes, but is not limited to, carboplatin, cis-platin, cisplatinum and oxaliplatin.
  • Carboplatin can be administered, e.g., in the form as it is marketed, e.g., under the trademark CARBOPLAT.
  • Oxaliplatin can be administered, e.g., in the form as it is marketed, e.g., under the trademark ELOXATIN.
  • compounds targeting/decreasing a protein or lipid kinase activity; or a protein or lipid phosphatase activity; or further anti-angiogenic compounds includes, but is not limited to, protein tyrosine kinase and/or serine and/or threonine kinase inhibitors or lipid kinase inhibitors, e.g.,
  • PDGFR platelet-derived growth factor-receptors
  • compounds targeting, decreasing or inhibiting the activity of the platelet-derived growth factor-receptors such as compounds which target, decrease or inhibit the activity of PDGFR, especially compounds which inhibit the PDGF receptor, e.g., a N-phenyl-2-pyrimidine-amine derivative, e.g., imatinib, SU101, SU6668 and GFB-111;
  • FGFR fibroblast growth factor-receptors
  • IGF-IR insulin-like growth factor receptor I
  • compounds targeting, decreasing or inhibiting the activity of the insulin-like growth factor receptor I such as compounds which target, decrease or inhibit the activity of IGF-IR, especially compounds which inhibit the IGF-IR receptor, such as those compounds disclosed in WO 02/092599;
  • compounds targeting, decreasing or inhibiting the activity of the C-kit receptor tyrosine kinases- such as compounds which target, decrease or inhibit the activity of the c-Kit receptor tyrosine kinase family, especially compounds which inhibit the c-Kit receptor, e.g., imatinib;
  • Patent No. 5,093,330 e.g., midostaurin
  • examples of further compounds include, e.g., UCN-01 ; safingol; BAY 43-9006; Bryostatin 1 ; Perifosine; llmofosine; RO 318220 and RO 320432; GO 6976; Isis 3521 ; LY333531/LY379196; isochinoline compounds, such as those disclosed in WO 00/09495; FTIs; PD184352; or QAN697 (aP13K inhibitor) ;
  • k) compounds targeting, decreasing or inhibiting the activity of protein-tyrosine kinase inhibitors include imatinib mesylate (GLEEVEC) or tyrphostin.
  • a tyrphostin is preferably a low molecular weight (Mr ⁇ 1500) compound, or a pharmaceutically acceptable salt thereof, especially a compound selected from the benzylidenemalonitrile class or the S-arylbenzenemalonirile or bisubstrate quinoline class of compounds, more especially any compound selected from the group consisting of Tyrphostin A23/RG-50810, AG 99, Tyrphostin AG 213, Tyrphostin AG 1748, Tyrphostin AG 490, Tyrphostin B44, Tyrphostin B44 (+) enantiomer, Tyrphostin AG 555, AG 494, Tyrphostin AG 556, AG 957 and adaphostin (4- ⁇ [ (2, 5-dihydroxyphenyl) methyl] amino ⁇ -benzoic acid adamantyl ester, NSC 680410, adaphostin; and
  • compounds targeting, decreasing or inhibiting the activity of the epidermal growth factor family of receptor tyrosine kinases are especially compounds, proteins or antibodies which inhibit members of the EGF receptor tyrosine kinase family, e.g., EGF receptor, ErbB2, ErbB3 and ErbB4 or bind to EGF or EGF related ligands, and are in particular those compounds, proteins or monoclonal antibodies generically and specifically disclosed in WO 97/02266, e.g., the compound of Example 39, or in EP 0 564 409; WO 99/03854; EP 0520722; EP 0 566 226; EP 0 787 722; EP 0 837 063; U.S.
  • trastuzumab HERCEPTIN
  • cetuximab cetuximab
  • Iressa Tarceva
  • anti-angiogenic compounds include compounds having another mechanism for their activity, e.g., unrelated to protein or lipid kinase inhibition, e.g., thalidomide (THALOMID) and TNP-470.
  • Compounds which target, decrease or inhibit the activity of a protein or lipid phosphatase are, e.g., inhibitors of phosphatase 1, phosphatase 2A, PTEN or CDC25, e.g., okadaic acid or a derivative thereof.
  • Compounds which induce cell differentiation processes are e.g. retinoic acid, ⁇ - ⁇ -or ⁇ -tocopherol or a- ⁇ -or ⁇ -tocotrienol.
  • cyclooxygenase inhibitor includes, but is not limited to, e.g., Cox-2 inhibitors, 5-alkyl substituted 2-arylaminophenylacetic acid and derivatives, such as celecoxib (CELEBREX) , rofecoxib (VIOXX) , etoricoxib, valdecoxib or a 5-alkyl-2-arylaminophenylacetic acid, e.g., 5-methyl-2- (2'-chloro-6'-fluoroanilino) phenyl acetic acid or lumiracoxib.
  • Cox-2 inhibitors such as celecoxib (CELEBREX) , rofecoxib (VIOXX) , etoricoxib, valdecoxib or a 5-alkyl-2-arylaminophenylacetic acid, e.g., 5-methyl-2- (2'-chloro-6'-fluoroanilino) phenyl acetic acid
  • bisphosphonates includes, but is not limited to, etridonic, clodronic, tiludronic, pamidronic, alendronic, ibandronic, risedronic and zoledronic acid.
  • Etridonic acid can be administered, e.g., in the form as it is marketed, e.g., under the trademark DIDRONEL.
  • Clodronic acid can be administered, e.g., in the form as it is marketed, e.g., under the trademark BONEFOS.
  • titaniumudronic acid can be administered, e.g., in the form as it is marketed, e.g., under the trademark SKELID.
  • “Pamidronic acid” can be administered, e.g., in the form as it is marketed, e.g., under the trademark AREDIA TM .
  • “Alendronic acid” can be administered, e.g., in the form as it is marketed, e.g., under the trademark FOSAMAX.
  • "Ibandronic acid” can be administered, e.g., in the form as it is marketed, e.g., under the trademark BONDRANAT.
  • “Risedronic acid” can be administered, e.g., in the form as it is marketed, e.g., under the trademark ACTONEL.
  • "Zoledronic acid” can be administered, e.g., in the form as it is marketed, e.g., under the trademark ZOMETA.
  • mTOR inhibitors relates to compounds which inhibit the mammalian target of rapamycin (mTOR) and which possess antiproliferative activity, such as sirolimus everolimus (CERTICAN TM ) , CCI-779 and ABT578.
  • heparanase inhibitor refers to compounds which target, decrease or inhibit heparin sulphate degradation.
  • the term includes, but is not limited to, PI-88.
  • biological response modifier refers to a lymphokine or interferons, e.g., interferon ⁇ .
  • inhibitor of Ras oncogenic isoforms refers to compounds which target, decrease or inhibit the oncogenic activity of Ras, e.g., a "farnesyl transferase inhibitor” , e.g., L-744832, DK8G557 or R1 15777 (Zarnestra) .
  • telomerase inhibitor refers to compounds which target, decrease or inhibit the activity of telomerase.
  • Compounds which target, decrease or inhibit the activity of telomerase are especially compounds which inhibit the telomerase receptor, e.g., telomestatin.
  • methionine aminopeptidase inhibitor refers to compounds which target, decrease or inhibit the activity of methionine aminopeptidase.
  • Compounds which target, decrease or inhibit the activity of methionine aminopeptidase are, e.g., bengamide or a derivative thereof.
  • proteasome inhibitor refers to compounds which target, decrease or inhibit the activity of the proteasome.
  • Compounds which target, decrease or inhibit the activity of the proteasome include, e.g., PS-341 and MLN 341.
  • matrix metalloproteinase inhibitor or "MMP inhibitor” , as used herein, includes, but is not limited to, collagen peptidomimetic and nonpeptidomimetic inhibitors, tetracycline derivatives, e.g., hydroxamate peptidomimetic inhibitor batimastat and its orally bioavailable analogue marimastat (BB-2516) , prinomastat (AG3340) , metastat (NSC 683551) BMS-279251, BAY 12-9566, TAA211, MMI270B or AAJ996.
  • MMP inhibitor matrix metalloproteinase inhibitor
  • agents used in the treatment of hematologic malignancies includes, but is not limited to, FMS-like tyrosine kinase inhibitors, e.g., compounds targeting, decreasing or inhibiting the activity of FMS-like tyrosine kinase receptors (Flt-3R) ; interferon, 1-b-D-arabinofuransylcytosine (ara-c) and bisulfan; and ALK inhibitors, e.g., compounds which target, decrease or inhibit anaplastic lymphoma kinase.
  • FMS-like tyrosine kinase inhibitors e.g., compounds targeting, decreasing or inhibiting the activity of FMS-like tyrosine kinase receptors (Flt-3R) ; interferon, 1-b-D-arabinofuransylcytosine (ara-c) and bisulfan; and ALK inhibitors, e.g., compounds which target, decrease or inhibit anaplastic lymphoma
  • FMS-like tyrosine kinase receptors are especially compounds, proteins or antibodies which inhibit members of the Flt-3R receptor kinase family, e.g., PKC412, midostaurin, a staurosporine derivative, SU1 1248 and MLN518.
  • HSP90 inhibitors includes, but is not limited to, compounds targeting, decreasing or inhibiting the intrinsic ATPase activity of HSP90; degrading, targeting, decreasing or inhibiting the HSP90 client proteins via the ubiquitin proteasome pathway.
  • Compounds targeting, decreasing or inhibiting the intrinsic ATPase activity of HSP90 are especially compounds, proteins or antibodies which inhibit the ATPase activity of HSP90, e.g., 17-allylamino, 17-demethoxygeldanamycin (17AAG) , a geldanamycin derivative, other geldanamycin related compounds, radicicol and HDAC inhibitors.
  • antiproliferative antibodies includes, but is not limited to, trastuzumab (Herceptin TM ) , Trastuzumab-DM1, erlotinib (Tarceva TM ) , bevacizumab (Avastin TM ) , rituximab PR064553 (anti-CD40) and 2C4 antibody.
  • trastuzumab Herceptin TM
  • Trastuzumab-DM1 erlotinib
  • Bevacizumab Avastin TM
  • rituximab PR064553 anti-CD40
  • compounds of formula (I) can be used in combination with standard leukemia therapies, especially in combination with therapies used for the treatment of AML.
  • compounds of formula (I) can be administered in combination with, e.g., farnesyl transferase inhibitors and/or other drugs useful for the treatment of AML, such as Daunorubicin, Adriamycin, Ara-C, VP-16, Teniposide, Mitoxantrone, Idarubicin, Carboplatinum and PKC412.
  • a compound of the formula (I) may also be used to advantage in combination with each other or in combination with other therapeutic agents, especially other anti-malarial agents.
  • anti-malarial agents include, but are not limited to proguanil, chlorproguanil, trimethoprim, chloroquine, mefloquine, lumefantrine, atovaquone, pyrimethamine-sulfadoxine, pyrimethamine-dapsone, halofantrine, quinine, quinidine, amodiaquine, amopyroquine, sulphonamides, artemisinin, arteflene, artemether, artesunate, primaquine, inhaled NO, L-arginine, Dipropylenetri-amine NONOate (NO donor) , Rosiglitzone (PPARy agonist) , activated charcoal, Erythropoietin, Levamisole, and pyronaridine.
  • anti-malarial agents include, but are not limited to
  • a compound of the formula (I) may also be used to advantage in combination with each other or in combination with other therapeutic agents, such as used for the treatment of Leishmaniosis, Trypanosomiasis, Toxoplasmosis and Neurocysticercosis.
  • Such agents include, but are not limited to chloroquine sulfate, atovaquone-proguanil, artemether-lumefantrine, quinine-sulfate, artesunate, quinine, doxycycline, clindamycin, meglumine antimoniate, sodium stibogluconate, miltefosine, ketoconazole, pentamidine, amphotericin B (AmB) , liposomal-AmB, paromomycine, eflornithine, nifurtimox, suramin, melarsoprol, prednisolone, benznidazole, sulfadiazine, pyrimethamine, clindamycin, trimetropim, sulfamethoxazole, azitromycin, atovaquone, dexamethasone, praziquantel, albendazole, beta-lactams, fluoroquinol
  • a compound of the formula (I) may also be used to advantage in combination with known therapeutic processes, e.g., the administration of hormones or especially radiation.
  • a compound of formula (I) may in particular be used as a radiosensitizer, especially for the treatment of tumors which exhibit poor sensitivity to radiotherapy.
  • ком ⁇ онент there is meant either a fixed combination in one dosage unit form, or a kit of parts for the combined administration where a compound of the formula (I) and a combination partner may be administered independently at the same time or separately within time intervals that especially allow that the combination partners show a cooperative, e.g., synergistic, effect or any combination thereof.
  • coadministration or “combined administration” or the like as utilized herein are meant to encompass administration of the selected combination partner to a single subject in need thereof (e.g. a patient) , and are intended to include treatment regimens in which the agents are not necessarily administered by the same route of administration or at the same time.
  • pharmaceutical combination means a product that results from the mixing or combining of more than one active ingredient and includes both fixed and non-fixed combinations of the active ingredients.
  • fixed combination means that the active ingredients, e.g. a compound of formula I and a combination partner, are both administered to a patient simultaneously in the form of a single entity or dosage.
  • non-fixed combination means that the active ingredients, e.g. a compound of formula (I) and a combination partner, are both administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific time limits, wherein such administration provides therapeutically effective levels of the two compounds in the body of the patient.
  • cocktail therapy e.g. the administration of three or more active ingredients.
  • the compounds disclosed herein are inhibitors of kinase activity, in particular PI3-kinase activity.
  • Compounds which are PI3-kinase inhibitors may be useful in the treatment of disorders wherein the underlying pathology is (at least in part) attributable to inappropriate PI3-kinase activity, such as asthma and chronic obstructive pulmonary disease (COPD) .
  • inappropriate PI3-kinase activity refers to any PI3-kinase activity that deviates from the normal PI3-kinase activity expected in a particular patient.
  • Inappropriate PI3-kinase may take the form of, for instance, an abnormal increase in activity, or an aberration in the timing and or control of PI3-kinase activity. Such inappropriate activity may result then, for example, from overexpression or mutation of the protein kinase leading to inappropriate or uncontrolled activation. Accordingly, in another aspect the invention is directed to methods of treating such disorders.
  • Such disorders include, but not limited to, respiratory diseases including asthma, chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF) ; viral infections including viral respiratory tract infections and viral exacerbation 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; hematologic malignancies; neurodegenerative diseases; pancreatitis; multiorgan failure; kidney diseases; platelet aggregation; cancer; sperm motility; transplantation rejection; graft rejection; lung injuries; and pain including pain associated with rheumatoid arthritis or osteoarthritis, back pain, general inflammatory pain, post hepatic neuralgia, diabetic neuropathy, inflammatory neuropathic pain
  • 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; hematologic malignancies; neurodegenerative diseases; pancreatitis; multiorgan failure; kidney diseases; platelet aggregation; cancer; sperm motility; transplantation rejection; graft rejection; lung injuries; and pain including pain associated with rheumatoid arthritis or osteoarthritis, back pain, general inflammatory pain, post hepatic neuralgia, diabetic neuropathy, inflammatory neuropathic pain (trauma) , trigeminal neuralgia and Central pain.
  • COPD chronic obstructive pulmonary disease
  • allergic diseases including allergic rhinitis and atopic dermatitis
  • autoimmune diseases including rheumatoid arthritis
  • the methods of treatment of the invention comprise administering a safe and effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to a patient in need thereof.
  • Individual embodiments of the invention include methods of treating any one of the above-mentioned disorders by administering a safe and effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to a patient in need thereof.
  • the compounds of formula (I) or pharmaceutically acceptable salts thereof may be administered by any suitable route of administration, including both systemic administration and topical administration.
  • Systemic administration includes oral administration, parenteral administration, transdermal administration and rectal administration.
  • Parenteral administration refers to routes of administration other than enteral or transdermal, and is typically by injection or infusion.
  • Parenteral administration includes intravenous, intramuscular, and subcutaneous injection or infusion.
  • Topical administration includes application to the skin as well as intraocular, otic, intravaginal, inhaled and intranasal administration.
  • Inhalation refers to administration into the patient's lungs whether inhaled through the mouth or through the nasal passages.
  • the compounds of formula (I) or pharmaceutically acceptable salts thereof may be administered orally.
  • the compounds of formula (I) or pharmaceutically acceptable salts thereof may be administered by inhalation.
  • the compounds of formula (I) or pharmaceutically acceptable salts thereof may be administered intranasally.
  • the compounds of formula (I) or pharmaceutically acceptable salts thereof may be administered once or according to a dosing regimen wherein a number of doses are administered at varying intervals of time for a given period of time. For example, doses may be administered one, two, three, or four times per day. In one embodiment, a dose is administered once per day. In a further embodiment, a dose is administered twice per day. Doses may be administered until the desired therapeutic effect is achieved or indefinitely 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 that compound, such as absorption, distribution, and half-life, which can be determined by the skilled artisan.
  • suitable dosing regimens including the duration such regimens are administered, for a compound of formula (I) or a pharmaceutically acceptable salt thereof depend on the disorder being treated, the severity of the disorder being treated, the age and physical condition of the patient being treated, the medical history of the patient to be treated, the nature of concurrent therapy, the desired therapeutic effect, and like factors within the knowledge and expertise of the skilled artisan. It will be further understood by such skilled artisans that suitable dosing regimens may require adjustment given an individual patient's response to the dosing regimen or over time as individual patient needs change.
  • the compound disclosed herein may be administered either simultaneously with, or before or after, one or more other therapeutic agent.
  • the compound disclosed herein may be administered separately, by the same or different route of administration, or together in the same pharmaceutical composition as the other agents.
  • the pharmaceutical composition or combination disclosed herein can be in unit dosage of about 1-1000 mg of active ingredient (s) for a subject of about 50-70 kg, or about 1- 500 mg or about 1-250 mg or about 1-150 mg or about 0.5-100 mg, or about 1-50 mg of active ingredients.
  • the therapeutically effective dosage of a compound, the pharmaceutical composition, or the combinations thereof is dependent on the species of the subject, the body weight, age and individual condition, the disorder or disease or the severity thereof being treated. A physician, clinician or veterinarian of ordinary skill can readily determine the effective amount of each of the active ingredients necessary to prevent, treat or inhibit the progress of the disorder or disease.
  • the above-cited dosage properties are demonstrable in vitro and in vivo tests using advantageously mammals, e.g., mice, rats, dogs, monkeys or isolated organs, tissues and preparations thereof.
  • the compounds disclosed herein can be applied in vitro in the form of solutions, e.g., aqueous solutions, and in vivo either enterally, parenterally, advantageously intravenously, e.g., as a suspension or in aqueous solution.
  • a therapeutically effective amount in vivo may range depending on the route of administration, between about 0.01-500 mg/kg, or between about 1 -100 mg/kg.
  • a prodrug of a compound of formula (I) is a functional derivative of the compound which, upon administration to a patient, eventually liberates 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 the activity of the compound in vivo; (b) modify the duration of action of the compound in vivo; (c) modify the transportation or distribution of the compound in vivo; (d) modify the solubility of the compound in vivo; and (e) overcome a side effect or other difficulty encountered with the compound.
  • Typical functional derivatives used to prepare prodrugs include modifications of the compound that are chemically or enzymatically cleavable in vivo. Such modifications, which include the preparation of phosphates, amides, esters, thioesters, carbonates, and carbamates, are well known to those skilled in the art.
  • the invention provides a method of treating a disorder mediated by inappropriate PI3-kinase activity comprising administering a safe and effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to a patient in need thereof.
  • the conditions, diseases or disorders mediated by inappropriate PI3-kinase activity is selected from the group consisting of asthma, chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF) ; viral infections including viral respiratory tract infections and viral exacerbation 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; hematologic malignancies; neurodegenerative diseases; pancreatitis; multiorgan failure; kidney diseases; platelet aggregation; cancer; sperm motility; transplantation rejection; graft rejection; lung injuries; and pain including pain associated with rheumatoid arthritis or osteoarthritis, back pain, general inflammatory pain, post hepati
  • Compounds disclosed herein may be useful in the treatment of conditions, diseases or disorders including disease or infection associated immunopathology in which one or more of the functions of B cells such as antibody production, antigen presentation, cytokine production or lymphoid organogenesis are abnormal or are undesirable including rheumatoid arthritis, pemphigus vulgaris and related diseases, idiopathic thrombocytopenia purpura, systemic lupus erythematosus, multiple sclerosis, myasthenia gravis, Sjogren's syndrome, autoimmune hemolytic anemia, ANCA-associated vasculitides, cryoglobulinemia, thrombotic thrombocytopenic purpura, chronic autoimmune urticaria, allergy (atopic dermatitis, contact dermatitis, allergic rhinitis) , goodpasture's syndrome, AMR (antibody-mediated transplant rejection) , B cell-mediated hyperacute, acute and chronic transplant rejection and cancers of haematopoietic origin including but not
  • the invention includes methods of treating conditions, diseases or disorders in which one or more of the functions of neutrophils, such as superoxide release, stimulated exocytosis, or chemoatractic migration are abnormal or are undesirable including rheumatoid arthritis, sepsis, pulmonary or resporatory disorders such as asthma, inflammatory dermatoses such as psoriasis as well as in disease or infection associated immunopathology and others.
  • the invention includes methods of treating conditions, diseases or disorders in which one or more of the functions of basophil and mast cells such as chemoatractic migration or allergen-lgE-mediated degranulation are abnormal or are undesirable including allergic diseases (atopic dermatitis, contact dermatitis, allergic rhinitis) as well as other disorders such as COPD, asthma or emphysema.
  • the invention includes methods of treating conditions, diseases or disorders in which one or more of the functions of T cells such as cytokine production or cell-mediated cytotoxicity abnormal or are undesirable including rheumatoid arthritis, multiple sclerosis, acute or chronic rejection of cell tissue or organ grafts or cancers of haematopoietic origin as well as in disease or infection associated immunopathology.
  • T cells such as cytokine production or cell-mediated cytotoxicity abnormal or are undesirable including rheumatoid arthritis, multiple sclerosis, acute or chronic rejection of cell tissue or organ grafts or cancers of haematopoietic origin as well as in disease or infection associated immunopathology.
  • the invention includes methods of treating neurodegenerative diseases, cardiovascular diseases and platelet aggregation.
  • the invention includes methods of treating skin diseases such as porphyria cutanea tarda, polymorphous light eruption, dermatomyositis, solar urticaria, oral lichen planus, panniculitis, scleroderma, urticarial vasculitis.
  • skin diseases such as porphyria cutanea tarda, polymorphous light eruption, dermatomyositis, solar urticaria, oral lichen planus, panniculitis, scleroderma, urticarial vasculitis.
  • the invention includes methods of treating chronic inflammatory diseases such as sarcoidosis, granuloma annulare.
  • the condition or disorder is selected from the group consisting of: polycythemia vera, essential thrombocythemia, myelofibrosis with myeloid metaplasia, asthma, COPD, ARDS, Loffler's syndrome, eosinophilic pneumonia, parasitic (in particular metazoan) infestation (including tropical eosinophilia) , bronchopulmonary aspergillosis, polyarteritis nodosa (including Churg-Strauss syndrome) , eosinophilic granuloma, eosinophil-related disorders affecting the airways occasioned by drug-reaction, psoriasis, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforme, dermatitis herpetiformis, scleroderma, vitiligo, hypersensitivity angiitis, ur
  • haemolytic anaemia haemolytic anaemia, aplastic anaemia, pure red cell anaemia and idiopathic thrombocytopenia) , systemic lupus erythematosus, polychondritis, scleroderma, Wegener granulomatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, Steven-Johnson syndrome, idiopathic sprue, autoimmune inflammatory bowel disease (e.g.
  • ulcerative colitis and Crohn's disease endocrine opthalmopathy, Grave's disease, sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis, primary biliary cirrhosis, uveitis (anterior and posterior) , interstitial lung fibrosis, psoriatic arthritis, glomerulonephritis, cardiovascular diseases, atherosclerosis, hypertension, deep venous thrombosis, stroke, myocardial infarction, unstable angina, thromboembolism, pulmonary embolism, thrombolytic diseases, acute arterial ischemia, peripheral thrombotic occlusions, and coronary artery disease, reperfusion injuries, retinopathy, such as diabetic retinopathy or hyperbaric oxygen-induced retinopathy, and conditions characterized by elevated intraocular pressure or secretion of ocular aqueous humor, such as glaucoma.
  • Grave's disease sarcoidosis,
  • the disorder mediated by inappropriate PI3-kinase activity is pain.
  • the compounds disclosed herein are useful in the treatment of conditions or disorders selected from the group consisting of, primary cutaneous B-cell lymphoma, immunobullous disease, pemphigus vulgaris, pemphigus foliaceus, endemic form of Brazilian pemphigus (Fogo selvagem) , paraneoplastic pemphigus, bullous pemphigoid, mucous membrane pemphigoid, epidermolysis bullosa acquisita, chronic graft versus host disease, dermatomyositis, systemic lupus erythematosus, vasculitis, small vessel vasculitis, hypocomplementemic urticarial vasculitis, antineutrophil cytoplasmic antibody-vasculitis, cryoglobulinemia, Schnitzler syndrome, Waldenstrom's macroglobulinemia, angioedema, vitiligo, systemic lupus erythematosus, idiopathic thro
  • the compounds disclosed herein are useful in the treatment, prevention, or amelioration of autoimmune disease and of inflammatory conditions, in particular inflammatory conditions with an aetiology including an autoimmune component such as arthritis (for example rheumatoid arthritis, arthritis chronica progrediente and arthritis deformans) and rheumatic diseases, including inflammatory conditions and rheumatic diseases involving bone loss, inflammatory pain, spondyloarhropathies including ankolsing spondylitis, Reiter syndrome, reactive arthritis, psoriatic arthritis, and enterophathics arthritis, hypersensitivity (including both airways hypersensitivity and dermal hypersensitivity) and allergies.
  • arthritis for example rheumatoid arthritis, arthritis chronica progrediente and arthritis deformans
  • rheumatic diseases including inflammatory conditions and rheumatic diseases involving bone loss, inflammatory pain, spondyloarhropathies including ankolsing spondylitis, Reiter syndrome, reactive arthritis, p
  • autoimmune haematological disorders including e.g. hemolytic anaemia, aplastic anaemia, pure red cell anaemia and idiopa-thic thrombocytopenia
  • acquired hemophilia A cold agglutinin disease, cryoglobulinemia, thrombotic thrombocytopenic purpura, Sjogren's syndrome, systemic lupus erythematosus, inflammatory muscle disorders, polychondritis, sclerodoma, anti-neutrophil cytoplasmic antibody-associated vasculitis, IgM mediated neuropathy, opsoclonus myoclonus syndrome, Wegener granulomatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, psoriasis, Steven-Johnson syndrome, pemphigus vulgaris, pemphigus foliacius, idio-pathic s
  • autoimmune haematological disorders including e.g. hemolytic ana
  • ulcerative colitis Crohn's disease and Irritable Bowel Syndrome
  • endocrine ophthalmopathy Graves'disease, sarcoidosis, multiple sclerosis, neuromyelitis optica, primary biliary cirrhosis, juvenile diabetes (diabetes mellitus type I) , uveitis (anterior, intermediate and posterior as well as panuveitis) , keratoconjunctivitis sicca and vernal keratoconjunctivitis, interstitial lung fibrosis, psoriatic arthritis and glomerulonephritis (with and without nephrotic syndrome, e.g.
  • idiopathic nephro-tic syndrome or minimal change nephropathy including idiopathic nephro-tic syndrome or minimal change nephropathy) , tumors, inflammatory disease of skin and cornea, myositis, loosening of bone implants, metabolic disorders, such as atherosclerosis, diabetes, and dislipidemia.
  • the present invention provides the use of a compound of formula (I) in therapy.
  • the therapy is selected from a disease which may be treated by inhibition of PI3K.
  • the disease is selected from the afore-mentioned list, suitably from autoimmune disorders, inflammatory diseases, allergic diseases, airway diseases, such as asthma and COPD, transplant rejection; antibody production, antigen presentation, cytokine production or lymphoid organogenesis are abnormal or are undesirable including rheumatoid arthritis, pemphigus vulgaris, idiopathic thrombocytopenia purpura, systemic lupus erythematosus, multiple sclerosis, myasthenia gravis, Sjogren's syndrome, autoimmune hemolytic anemia, ANCA-associated vasculitides, cryoglobulinemia, thrombotic thrombocytopenic purpura, chronic autoimmune urticaria, allergy (atopic dermatitis, contact dermatitis, allergic r
  • the present invention provides the use of a compound of formula (I) for the manufacture of a medicament.
  • the medicament is for treatment of a disease which may be treated inhibition of PI3K.
  • the disease is selected from the afore-mentioned list, suitably from autoimmune disorders, inflammatory diseases, allergic diseases, airway diseases, such as asthma and COPD, transplant rejection; antibody production, antigen presentation, cytokine production or lymphoid organogenesis are abnormal or are undesirable including rheumatoid arthritis, pemphigus vulgaris, idiopathic thrombocytopenia purpura, systemic lupus erythematosus, multiple sclerosis, myasthenia gravis, Sjogren's syndrome, autoimmune hemolytic anemia, ANCA-associated vasculitides, cryoglobulinemia, thrombotic thrombocytopenic purpura, chronic autoimmune urticaria, allergy (atopic dermatitis,
  • the compounds disclosed herein may be prepared by methods described herein, wherein the substituents are as defined for formula (I) , above, except where further noted.
  • the following non-limiting schemes and examples are presented to further exemplify the invention.
  • Persons skilled in the art will recognize that the chemical reactions described herein may be readily adapted to prepare a number of other compounds disclosed herein, and alternative methods for preparing the compounds disclosed herein are deemed to be within the scope of this invention.
  • the synthesis of non-exemplified compounds according to the invention may be successfully performed by modifications apparent to those skilled in the art, e.g., by appropriately protecting interfering groups, by utilizing other suitable reagents known in the art other than those described, and/or by making routine modifications of reaction conditions.
  • other reactions disclosed herein or known in the art will be recognized as having applicability for preparing other compounds disclosed herein.
  • Anhydrous THF, dioxane, toluene, and ether were obtained by refluxing the solvent with sodium.
  • Anhydrous CH 2 Cl 2 and CHCl 3 were obtained by refluxing the solvent with CaH 2 .
  • EtOAc, PE, hexanes, DMA and DMF were treated with anhydrous Na 2 SO 4 prior use.
  • reaction flasks were typically fitted with rubber septa for the introduction of substrates and reagents via syringe. Glassware was oven dried and/or heat dried.
  • MS data were generally determined on an Agilent 6120 Quadrupole HPLC-MS (Zorbax SB-C18, 2.1 ⁇ 30 mm, 3.5 micron, 6 minutes run, 0.6 mL/min flow rate, 5%to 95% (0.1%formic acid in CH 3 CN) in (0.1%formic acid in H 2 O)) with UV detection at 210 nm/254 nm and electrospray ionization mode (ESI) .
  • Agilent 6120 Quadrupole HPLC-MS Zorbax SB-C18, 2.1 ⁇ 30 mm, 3.5 micron, 6 minutes run, 0.6 mL/min flow rate, 5%to 95% (0.1%formic acid in CH 3 CN) in (0.1%formic acid in H 2 O)
  • UV detection at 210 nm/254 nm
  • ESI electrospray ionization mode
  • LiHMDS lithium bis (trimethylsilyl) -amide
  • R 1 , R 2 , R 3 , R 4 and W carry the definitions set forth above in connection with formula (I) .
  • R h is Cl, Br or I.
  • the intermediate (9) can be prepared in a general method illustrated in Scheme 1. Benzoic acid (1) is firstly reacted with SOCl 2 at refluxed temperature in a nonpolar solvent such as toluene, followed by treating with amino compound (2) to provide amide (3) . Compound (3) is firstly reacted with SOCl 2 at refluxed temperature in a nonpolar solvent such as toluene, followed by treating with compound (4) to provide compound (5) . The reduction and cyclization of the nitro compound (5) in the presence of Zn powder and an acid (such as acetic acid) provides compound (6) . Compound (6) is then coupled with boronic ester (7) in the presence of an appropriate Pd catalyst to give compound (8) . Deprotection of the amino group of compound (8) under standard conditions known to those skilled in the art such as, but not limited to, treatment with an acid to give the intermediate (9) .
  • Scheme 2 shows another method to prepare the intermediate (9) .
  • the reduction of compound (3) affords compound (10) .
  • Compound (10) is then treated with a Boc-protected acid (4) in the presence of a coupling reagent such as EDCI or HATU furnishes compound (11) .
  • a coupling reagent such as EDCI or HATU
  • the cyclization of compound (11) in the presence of N, O-bis (trimethylsilyl) acetamide, DMAP and a base affords compound (6) .
  • Compound (6) is then coupled with boronic ester (7) in the presence of an appropriate Pd catalyst to give compound (8) .
  • Deprotection of the amino group of compound (8) under standard conditions known to those skilled in the art such as, but not limited to, treatment with an acid to give the intermediate (9) .
  • the intermediate (22) can be prepared in a general method illustrated in Scheme 3.
  • Benzoic acid (13) is firstly reacted with SOCl 2 or (COCl) 2 at an elevated temperature in a nonpolar solvent such as toluene, followed by treating with amino compound (2) to provide amide (14) .
  • Compound (16) is then reacted with compound (17) under N 2 atmosphere to give mixture A.
  • Compound (14) is reacted with a base, such as n-BuLi under N 2 atmosphere to give mixture B.
  • mixture A is firstly treated with mixture B, followed by treating with an acid to give compound (18) .
  • the desired kinase inhibitor disclosed herein can also be prepared in a general method illustrated in Scheme 4.
  • Compound (23) is firstly treated with an alcohol derivative (24) in the presence of an acid to give compound (25) .
  • Compound (25) is then reacted with (n-Bu) 3 SnCl to provide compound (26) .
  • compound (26) is coupled with compound (27) to give compound (28) .
  • Compound (28) is then treated with an acid to provide compound (29) .
  • Compound (29) is firstly converted to compound (30) using a chlorinating agent such as POCl 3 or SOCl 2 under heating conditions, then compound (30) is treated with NH 3 to form compound (31) substituted with amine.
  • Compound (31) is finally reacted with the intermediate (32) in the presence of a base such as DIPEA to afford the desired kinase inhibitor (33) .
  • Scheme 5 shows another method to prepare the desired kinase inhibitor.
  • the iodination of compound (34) with N-iodosuccinimide at an elevated temperature affords compound (35) .
  • Bromo compound (36) is reacted with (n-Bu) 3 SnCl with the help of a base, such as n-butyllithium to give compound (37) .
  • Compound (37) is then coupled with compound (35) using an appropriate Pd complex as catalyst such as Pd (PPh 3 ) 2 Cl 2 to provide compound (38) .
  • Compound (38) is finally reacted with the intermediate (32) in the presence of a base (such as DIPEA) to afford the desired kinase inhibitor (39) .
  • a base such as DIPEA
  • the intermediate (I-1) to (I-4) were prepared according to the procedures as described in the patent application of WO 2013012915.
  • Step 1) (S) -tert-butyl (1- (5- (1-methyl-1H-pyrazol-4-yl) -4-oxo-3-phenyl-3, 4-dihydroquinazolin- 2-yl) ethyl) carbamate
  • the reaction mixture was stirred at 120 °C for 3 hours, then cooled to rt, and then DCM (20 mL) was added. The resulted mixture was filtered through a pad, and the filtrate was concentrated in vacuo to give the crude product.
  • Step 2) (S) -2- (1-aminoethyl) -5- (1-methyl-1H-pyrazol-4-yl) -3-phenylquinazolin-4 (3H) -one
  • Step 2) (S) -tert-butyl (1- (2-chloro-N-cyclopropyl-6-nitrobenzamido) -1-oxobutan-2-yl) carbamate
  • Step 1) (S) -tert-butyl (1- (8-chloro-1-oxo-2-phenyl-1, 2-dihydroisoquinolin-3-yl) ethyl) carbamate
  • Step 2) (S) -tert-butyl (1- (8- (1-methyl-1H-pyrazol-4-yl) -1-oxo-2-phenyl-1, 2-dihydroisoquinolin- 3-yl) ethyl) carbamate
  • step 4) (S) -3- (1- ( (6-amino-5- (2-methyl-2H-tetrazol-5-yl) pyrimidin-4-yl) amino) ethyl) -8- (1- methyl-1H-pyrazol-4-yl) -2-phenylisoquinolin-1 (2H) -one
  • Step 1) (S) -tert-butyl (1- (8-chloro-2-cyclopropyl-1-oxo-1, 2-dihydroisoquinolin-3-yl) ethyl) carbamate
  • Step 2) (S) -tert-butyl (1- (2-cyclopropyl-8- (1-methyl-1H-pyrazol-4-yl) -1-oxo-1, 2- dihydroisoquinolin-3-yl) ethyl) carbamate
  • the combined organic phases was washed with saturated brine (30 mL) , dried over anhydrous Na 2 SO 4 , and concentrated in vacuo to give the title compound as a white solid (800 mg, 75.7%) .
  • the LC/MS/MS system used in the analysis consists of an Agilent 1200 Series vacuum degasser, binary pump, well-plate autosampler, thermostatted column compartment, the Agilent G6430 Triple Quadrupole Mass Spectrometer with an electrosprayionization (ESI) source. Quantitative analysis was carried out using MRM mode. The parameters for MRM transitions are in the Table A.
  • an Agilent 6330 series LC/MS/MS spectrometer equipped with G1312A binary pumps, a G1367A autosampler and a G1314C UV detector were used in the analysis.
  • An ESI source was used on the LC/MS/MS spectrometer.
  • the analysis was done in positive ion mode as appropriate and the MRM transition for each analyte was optimized using standard solution.
  • the mobile phase was 5 mM ammonia acetate, 0.1%MeOH in water (A) : 5 mM ammonia acetate, 0.1%MeOH in acetonitrile (B) (70/30, v/v) .
  • the flow rate was 0.6 mL/min. Column was maintained at ambient temperature. 20 ⁇ L of the samples were injected.
  • Human or rat liver microsomes incubations were conducted in duplicate in polypropylene tubes.
  • the typical incubation mixtures consisted of human or rat liver microsomes (0.5 mg protein/mL) , compounds of interest (5 ⁇ M) and NADPH (1.0 mM) in a total volume of 200 ⁇ L potassium phosphate buffer (PBS, 100 mM, pH 7.4) .
  • PBS potassium phosphate buffer
  • Compounds were dissolved in DMSO and diluted with PBS such that the final concentration of DMSO was 0.05%.
  • the enzymatic reactions were commenced with the addition of protein after a 3-min preincubation and incubated in a water bath open to the air at 37 °C. Reactions were terminated at various time points (0, 5, 10, 15, 30, 60 min) by adding equal volume of ice-cold acetonitrile.
  • the samples were stored at -80 °C until LC/MS/MS assays.
  • the concentrations of compounds in the incubation mixtures of human or rat liver microsomes were determined by a LC/MS/MS method.
  • the ranges of the linearity in the concentration range were determined for each tested compounds.
  • Dextromethorphan 70 ⁇ M was selected as the positive control, and reactions were terminated at various time points (0, 5, 10, 15, 30, 60 min) after incubation at 37 °C. Both positive and negative control samples were included in each assay to ensure the integrity of the microsomal incubation system.
  • the concentrations of compounds in human or rat liver microsome incubations were plotted as a percentage of the relevant zero time point control for each reaction.
  • the in vivo CL int were extrapolated (ref. : Naritomi, Y.; Terashita, S.; Kimura, S.; Suzuki, A.; Kagayama, A.; and Sugiyama, Y.; Prediction of human hepatic clearance from in vivo animal experiments and in vitro metabolic studies with liver microsomes from animals and humans. Drug Metab. Dispos., 2001, 29: 1316-1324) .
  • Example B Evaluation of Pharmacokinetics After Intravenous or Oral Administration of The Compounds Disclosed Herein In Mice, Rats, Dogs and Monkeys
  • mice and rats are administered as a water solution, 2%HPMC + 1% in water solution, 5%DMSO + 5%solutol in saline, 4%MC suspension or capsule.
  • the animals are generally given at 1 or 2 mg/kg dose.
  • mice and rats are generally given 5 or 10 mg/kg dose
  • dogs and monkeys are generally given 10 mg/kg dose.
  • the blood samples (0.3 mL) are drawn at 0.25, 0.5, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0, 12 and 24 h time points or 0.083, 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0 and 24 h time points and centrifuged at 3,000 or 4000 rpm for 2 to 10 min.
  • the plasma solutions are collected, stored at -20 °C or -70 °C until analyzed by LC/MS/MS as described above.
  • Kinase assays can be performed by measurement of incorporation of ⁇ - 33 P ATP into immobilized myelin basic protein (MBP) .
  • MBP myelin basic protein
  • High binding white 384 well plates (Greiner) are coated with MBP (Sigma #M-1891) by incubation of 60 ⁇ L/well of 20 ⁇ g/mL MBP in Tris-buffered saline (TBS; 50 mM Tris pH 8.0, 138 mM NaCl, 2.7 mM KCl) for 24 hours at 4 °C. Plates are washed 3 ⁇ with 100 ⁇ L TBS.
  • TBS Tris-buffered saline
  • Kinase reactions are carried out in a total volume of 34 ⁇ L in kinase buffer (5 mM Hepes pH 7.6, 15 mM NaCl, 0.01%bovine gamma globulin (Sigma #I-5506) , 10 mM MgCl 2 , 1 mM DTT, 0.02%TritonX-100) .
  • Compound dilutions are performed in DMSO and added to assay wells to a final DMSO concentration of 1%. Each data point is measured in duplicate, and at least two duplicate assays are performed for each individual compound determination.
  • Enzyme is added to final concentrations of 10 nM or 20 nM, for example.
  • a mixture of unlabeled ATP and ⁇ - 33 P ATP is added to start the reaction (2 ⁇ 10 6 cpm of ⁇ - 33 P ATP per well (3000 Ci/mmole) and 10 ⁇ M unlabeled ATP, typically.
  • the reactions are carried out for 1 hour at rt with shaking. Plates are washed 7 ⁇ with TBS, followed by the addition of 50 ⁇ L/well scintillation fluid (Wallac) . Plates are read using a Wallac Trilux counter. This is only one format of such assays; various other formats are possible, as known to one skilled in the art.
  • the above assay procedure can be used to determine the IC 50 for inhibition and/or the inhibition constant, K i .
  • the IC 50 is defined as the concentration of compound required to reduce the enzyme activity by 50%under the condition of the assay.
  • the IC 50 value is estimated by preparing a 10 point curve using a 1/2 log dilution series (for example, a typical curve may be prepared using the following compound concentrations: 10 ⁇ M, 3 ⁇ M, 1 ⁇ M, 0.3 ⁇ M, 0.1 ⁇ M, 0.03 ⁇ M, 0.01 ⁇ M, 0.003 ⁇ M, 0.001 ⁇ M and 0 ⁇ M) .
  • PI3K (p110 ⁇ /p85 ⁇ ) (h) is incubated in assay buffer containing 10 ⁇ M phosphatidylinositol 4, 5-bisphosphate and MgATP (concentration as required) .
  • the reaction is initiated by the addition of the ATP solution.
  • stop solution containing EDTA and biotinylated phosphatidylinositol-3, 4, 5-trisphosphate.
  • detection buffer is added, which contains europium-labelled anti-GST monoclonal antibody, GST-tagged GRP1 PH domain and streptavidin allophycocyanin.
  • HTRF homogenous time-resolved fluorescence
  • PI3K (p110 ⁇ /p85 ⁇ ) (h) is incubated in assay buffer containing 10 ⁇ M phosphatidylinositol-4, 5-bisphosphate and MgATP (concentration as required) .
  • the reaction is initiated by the addition of the MgATP mix.
  • stop solution containing EDTA and biotinylated phosphatidylinositol-3, 4, 5-trisphosphate.
  • detection buffer is added, which contains europium-labelled anti-GST monoclonal antibody, GST-tagged GRP1 PH domain and streptavidin-allophycocyanin.
  • HTRF homogenous time-resolved fluorescence
  • PI3K (p110 ⁇ /p85 ⁇ ) (h) is incubated in assay buffer containing 10 ⁇ M phosphatidylinositol-4, 5-bisphosphate and MgATP (concentration as required) .
  • the reaction is initiated by the addition of the MgATP mix.
  • stop solution containing EDTA and biotinylated phosphatidylinositol-3, 4, 5-trisphosphate.
  • detection buffer is added, which contains europium-labelled anti-GST monoclonal antibody, GST-tagged GRP1 PH domain and streptavidin-allophycocyanin.
  • HTRF homogenous time-resolved fluorescence
  • PI3K (p120 ⁇ ) (h) is incubated in assay buffer containing 10 ⁇ M phosphatidylinositol-4, 5-bisphosphate and MgATP (concentration as required) .
  • the reaction is initiated by the addition of the MgATP mix.
  • stop solution containing EDTA and biotinylated phosphatidylinositol-3, 4, 5-trisphosphate.
  • detection buffer is added, which contains europium-labelled anti-GST monoclonal antibody, GST-tagged GRP1 PH domain and streptavidin-allophycocyanin.
  • HTRF homogenous time-resolved fluorescence
  • mTOR (h) is incubated with 50 mM HEPES pH 7.5, 1 mM EDTA, 0.01% 2 mg/mL substrate, 3 mM Manganese Chloride and [ ⁇ - 33 P-ATP] (specific activity approx. 500 cpm/pmol, concentration as required) .
  • the reaction is initiated by the addition of the MnATP mix. After incubation for 40 minutes at room temperature, the reaction is stopped by the addition of 3%phosphoric acid solution. 10 ⁇ L of the reaction is then spotted onto a P30 filtermat and washed three times for 5 minutes in 75 mM phosphoric acid and once in methanol prior to drying and scintillation counting.
  • kinase assays described herein were performed at Millipore UK Ltd, Dundee Technology Park, Dundee DD2 1SW, UK.
  • the compounds disclosed herein exhibited potent activities in the PI3K ⁇ (h) assays.
  • the kinase activities of the compounds can be measured using KINOMEscan TM , which is based on a competition binding assay that quantitatively measures the ability of a compound to compete with an immobilized, active-site directed ligand.
  • the assay was performed by combining three components: DNA-tagged kinase; immobilized ligand; and a test compound. The ability of the test compound to compete with the immobilized ligand was measured via quantitative PCR of the DNA tag.
  • kinase-tagged T7 phage strains were prepared in an E. coli host derived from the BL21 strain. E. coli were grown to log-phase and infected with T7 phage and incubated with shaking at 32 °C until lysis. The lysates were centrifuged and filtered to remove cell debris. The remaining kinases were produced in HEK-293 cells and subsequently tagged with DNA for qPCR detection. Streptavidin-coated magnetic beads were treated with biotinylated small molecule ligands for 30 minutes at room temperature to generate affinity resins for kinase assays.
  • the liganded beads were blocked with excess biotin and washed with blocking buffer (SEABLOCK TM (Pierce) , 1%BSA, 0.05% 1 mM DTT) to remove unbound ligand and to reduce nonspecific binding.
  • Binding reactions were assembled by combining kinases, liganded affinity beads, and test compounds in 1x binding buffer (20%SEABLOCK TM , 0.17x PBS, 0.05% 6 mM DTT) . All reactions were performed in polystyrene 96-well plates in a final volume of 0.135 mL. The assay plates were incubated at room temperature with shaking for 1 hour and the affinity beads were washed with wash buffer (1x PBS, 0.05% ) .
  • the beads were then re-suspended in elution buffer (1x PBS, 0.05% 0.5 ⁇ M non-biotinylated affinity ligand) and incubated at room temperature with shaking for 30 minutes.
  • elution buffer (1x PBS, 0.05% 0.5 ⁇ M non-biotinylated affinity ligand
  • kinase assays described herein were performed using KINOMEscan TM Profiling Service at DiscoveRx Corporation, 42501 Albrae St. Fremont, CA 94538, USA.

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Abstract

L'invention concerne la préparation et l'utilisation de nouveaux dérivés d'aminopyrimidine en tant que médicaments candidats sous forme libre ou sous forme de sel pharmaceutiquement acceptable et leurs formulations pour la modulation d'un trouble ou d'une maladie qui est médiée par l'activité des enzymes PI3K. L'invention concerne également des compositions pharmaceutiquement acceptables comprenant de tels composés et des procédés d'utilisation des compositions dans le traitement de troubles ou de maladies, comme des troubles d'immunité et d'inflammation dans lesquels les enzymes PI3K jouent un rôle dans la fonction leucocytaire, et des troubles hyperprolifératifs associés à l'activité de PI3K,y compris mais pas exclusivement, les leucémies et les tumeurs solides, chez les mammifères, en particulier les humains.
PCT/CN2016/074666 2015-02-28 2016-02-26 Composés d'aminopyrimidine substituée et procédés d'utilisation WO2016134668A1 (fr)

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CN115785084B (zh) * 2022-08-26 2024-01-16 广东东阳光药业股份有限公司 嘧啶衍生物及其在药物中的应用

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WO2005095382A1 (fr) * 2004-03-30 2005-10-13 Kyowa Hakko Kogyo Co., Ltd. Agent anti tumoral
WO2013032591A1 (fr) * 2011-08-29 2013-03-07 Infinity Pharmaceuticals Inc. Composés hétérocycliques et leurs utilisations
WO2013116562A1 (fr) * 2012-02-03 2013-08-08 Gilead Calistoga Llc Compositions et procédés de traitement d'une maladie avec (s)-4 amino-6-((1-(5-chloro-4-oxo-3-phényl-3,4-dihydroquinazoline-2-yl)éthyl)amino)pyrimidine-5-carbonitrile
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US10751339B2 (en) 2018-01-20 2020-08-25 Sunshine Lake Pharma Co., Ltd. Substituted aminopyrimidine compounds and methods of use

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