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AssigneeGlaxoSmithKline Intellecutual Property Development
InventorsJulie Nicole Hamblin, Zoe Alicia Harrison, Paul Spencer Jones, Suzanne Elaine Keeling, Joelle Le, Christopher James Lunniss, Nigel James Parr
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The invention is directed to certain novel compounds. Specifically, the invention is directed to compounds of formula (I): and salts thereof. The compounds of the invention are inhibitors of kinase activity, in particular PI3-kinase activity.
A compound of formula (I):
A compound which is selected from the group consisting of:
A compound which is selected from the group consisting of:
Dependencies are inferred from the claim text.
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Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms:…
Drugs for disorders of the alimentary tract or the digestive system
Drugs for disorders of the alimentary tract or the digestive system: for pancreatic disorders, e.g. pancreatic enzymes
Drugs for disorders of the blood or the extracellular fluid: antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
About 3 years 4 months of term left · ends 10 Mar 2030 (estimated)
The present invention is directed to certain novel compounds which are inhibitors of activity or function of the phosphoinositide 3′OH kinase family (hereinafter PI3-kinases), 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 of the invention are inhibitors of the activity or function of, for example, PI3Kδ, PI3Kα, PI3Kβ and/or PI3Kγ. Compounds which are inhibitors of the activity or function of PI3-kinases may be useful in the treatment of disorders such as 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; cystic fibrosis; 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 (trama), trigeminal neuralgia and central pain.
Cellular membranes represent a large store of second messengers that can be enlisted in a variety of signal transduction pathways. In relation to function and regulation of effector enzymes in phospholipids signaling pathways, class I PI3-kinases (e.g. PI3 Kdelta) 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. In addition, these phosphoinositides can be converted into other phosphoinositides by 5′-specific and 3′-specific phophatases. Thus, 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 (Trends Biochem. Sci. 22(7) p. 267-72 (1997) by Vanhaesebroeck et al.; Chem. Rev. 101(8) p. 2365-80 (2001) by Leslie et al.; Annu. Rev. Cell Dev. Biol. 17 p. 615-75 (2001) by Katso et al.; and Cell. Mol. Life. Sci. 59(5) p. 761-79 (2002) by Toker). To date, eight mammalian PI3Ks have been identified, divided into three main classes (I, II, and III) on the basis of sequence homology, structure, binding partners, mode of activation, and substrate preference. In vitro, class I PI3Ks can phosphorylate phosphatidylinositol (PI), phosphatidylinositol-4-phosphate (PI4P), and phosphatidylinositol-4,5-bisphosphate (PI(4,5)P2) to produce phosphatidylinositol-3-phosphate (PI3P), phosphatidylinositol-3,4-bisphosphate (PI(3,4)P2, and phosphatidylinositol-3,4,5-trisphosphate (PI(3,4,5)P3, respectively. Class II PI3Ks can phosphorylate PI and PI4P. Class III PI3Ks can only phosphorylate PI (Vanhaesebrokeck et al. (1997), above; Vanhaesebroeck et al., Exp. Cell Res. 253(1) p. 239-54 (1999); and Leslie et al. (2001), above).
Class I PI3K is a heterodimer consisting of a p110 catalytic subunit and a regulatory subunit, and the family is further divided into class Ia and class Ib enzymes on the basis of regulatory partners and mechanism of regulation. Class Ia enzymes consist of three distinct catalytic subunits (p110α, p110β, and p110δ) that dimerise with five distinct regulatory subunits (p85α, p55α, p50α, p85β, and p55γ), with all catalytic subunits being able to interact with all regulatory subunits to form a variety of heterodimers. Class Ia PI3K are generally activated in response to growth factor-stimulation of receptor tyrosine kinases, via interaction of the regulatory subunit SH2 domains with specific phospho-tyrosine residues of the activated receptor or adaptor proteins such as IRS-1. Small GTPases (ras as an example) are also involved in the activation of PI3K in conjunction with receptor tyrosine kinase activation. Both p110α and p110β are constitutively expressed in all cell types, whereas p110δ expression is more restricted to leukocyte populations and some epithelial cells. In contrast, the single Class Ib enzyme consists of a p110γ catalytic subunit that interacts with a p101 regulatory subunit. Furthermore, the class Ib enzyme is activated in response to G-protein coupled receptor (GPCR) systems and its expression appears to be limited to leukocytes.
In one embodiment, the invention is directed to compounds of formula (I)
wherein R1 is 9- or 10-membered bicyclic heteroaryl wherein the 9- or 10-membered bicyclic heteroaryl contains from one to three heteroatoms independently selected from oxygen and nitrogen and is optionally substituted by C1-6alkyl, C3-6cycloalkyl, halo, —CN or —NHSO2R5, or pyridinyl optionally substituted by one or two substituents independently selected from C1-6alkyl, —OR6, halo and —NHSO2R7; X is —CH2NR2R3, C1-6alkyl, —CH2phenyl, —(CH2)nOR10, —CH2SO2R11 or —(CH2)pC3-6cycloalkyl; R2 and R3, together with the nitrogen atom to which they are attached, are linked to form a 6- or 7-membered heterocyclyl or a 9- or 10-membered bicyclic heterocyclyl wherein the 6- or 7-membered heterocyclyl or the 9- or 10-membered bicyclic heterocyclyl optionally contains an oxygen atom, a sulphur atom or a further nitrogen atom and is optionally substituted by from one to three substituents independently selected from oxo, C1-6alkyl, —(CH2)mNR8R6, phenyl optionally substituted by halo, and 6-membered heteroaryl wherein the 6-membered heteroaryl contains one or two nitrogen atoms, a 7-membered bridged heterocyclyl wherein the 7-membered bridged heterocyclyl optionally contains a further nitrogen atom and is optionally substituted by from one to three substituents independently selected from C1-6alkyl, or a 10-membered spiro bicyclic heterocyclyl wherein the 10-membered spiro bicyclic heterocyclyl optionally contains an oxygen atom, or R2 is hydrogen and R3 is C1-6alkyl optionally substituted by one or two substituents independently selected from —OR12 and —NR13R14; R4 is hydrogen or methyl; R6, R12 and R15 are each independently hydrogen or C1-4alkyl; R5 and R7 are each independently C1-6alkyl or phenyl wherein the phenyl is optionally substituted by one or two substituents independently selected from halo and —OR15; R8 and R9, together with the nitrogen atom to which they are attached, are linked to form a 5- or 6-membered heterocyclyl optionally containing an oxygen atom; R10 is hydrogen, C1-6alkyl, —(CH2)qphenyl or C3-6cycloalkyl wherein the C3-6cycloalkyl is optionally substituted by one or two substituents independently selected from C1-6alkyl; R11 is C1-6alkyl or phenyl; R13 and R14, together with the nitrogen atom to which they are attached, are linked to form a 6-membered heterocyclyl optionally containing an oxygen atom; m, p and q are each independently 0, 1 or 2; and n is 1 or 2; and salts thereof (hereinafter “compounds of the invention”).
In another embodiment, the invention is directed to compounds of formula (IA)