WO2020212697A1 - Composés à titre d'inhibiteurs - Google Patents

Composés à titre d'inhibiteurs Download PDF

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WO2020212697A1
WO2020212697A1 PCT/GB2020/050957 GB2020050957W WO2020212697A1 WO 2020212697 A1 WO2020212697 A1 WO 2020212697A1 GB 2020050957 W GB2020050957 W GB 2020050957W WO 2020212697 A1 WO2020212697 A1 WO 2020212697A1
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amino
pyrazol
carboxamide
pyrazine
benzyl
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PCT/GB2020/050957
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Julie Nicole Hamblin
Benjamin Martin SUTTON
Arwel LEWIS
Michael Daniel Goldsmith
Christopher Alan Brown
Isabelle Anne LEMASSON
Alicia HIGUERUELO
Jonathon Richard Anthony ROFFEY
Julian Blagg
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Azeria Therapeutics Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the present invention relates to certain compounds that are pharmacologically active compounds which modulate protein kinase activity, specifically the activity of serum and glucocorticoid regulated kinase (SGK) proteins, in particular: serum and glucocorticoid regulated kinase isoform 1 (SGK1); serum and glucocorticoid regulated kinase isoform 2 (SGK2); and serum and glucocorticoid regulated kinase isoform 3 (SGK3).
  • SGK serum and glucocorticoid regulated kinase
  • the compounds of the present invention may be used to treat disease or conditions mediated, at least in part, by inappropriate SGK activity, for example hyperproliferative diseases, including cancer, and regulation of electrolyte balance in renal and cardiovascular disease.
  • the invention furthermore relates to processes for the preparation of these compounds, their use as pharmaceuticals, and pharmaceutical compositions comprising them.
  • the serum and glucocorticoid kinase (SGK) family are a subfamily of serine/threonine kinases which consist of three isoforms: SGK1 (Serum/Glucocorticoid Regulated Kinase 1 , SGK, Serum/Glucocorticoid-Regulated Kinase 1 , Serum/Glucocorticoid Regulated Kinase, Serine/Threonine-Protein Kinase Sgk1 , Serine/Threonine Protein Kinase SGK, Sgk1 Variant I3, EC 2.7.11.1 , Uniprot ID 000141); SGK2 (Serine/Threonine Kinase 2, Serum/Glucocorticoid Regulated Kinase 2, Serum/Glucocorticoid-Regulated Kinase 2, Serine/Threonine-Protein Kinase Sgk2, EC
  • the SGKs are post-translationally modified and activated by phosphorylation in response to signals that stimulate PI3K, this is mediated in part by PDK1 [Lang 2001 , Kobayashi 2003, Tessier 2006]
  • the activation of SGK1 through the PI3K signalling pathway is known to be in response to insulin, IGF and growth factors.
  • SGK3 is distinguished by an N-terminal PX (phox) domain and in contrast to regulation of SGK1 gene transcription, the gene encoding SGK3 is not induced by serum or glucocorticoids [Kobayashi 2003, Tessier 2006] Whereas a distinguishing feature of SGK1 is stimulus- dependent regulation of transcription, cellular localisation and enzymatic activation [Firestone 2003]
  • the PX domain preferentially binds to Ptdlns(3)P, thereby localizing a pool of the kinase to endosomal membranes rather than to the plasma membrane and this has been shown to be essential for activation [Kobayashi 2003, Virbasius 2001]
  • FOXOs are involved in a number of pathologic and physiologic processes that include proliferation, apoptosis, autophagy, metabolism, inflammation, cytokine expression, immunity, differentiation, and resistance to oxidative stress.
  • the activity of FOXOs is tightly regulated by posttranslational modification, including phosphorylation, acetylation, and ubiquitylation.
  • AKT and SGK1 can phosphorylate FOX01 and FOX03 at well-defined sites, however as AKT is able to phosphorylate FOXO at the same sites as SGK1 , it may be able to compensate for SGK1 function [Wang and Liu. 2017]
  • in vitro experiments have shown that is able to modulate a range of ion channels [Lang 2006]
  • Protein kinases control and modulate a wide variety of biological processes through the catalytic transfer of a phosphate group from adenosine triphosphate (ATP) to their protein substrates [Manning, 2002] Since the ATP binding site is similar in different kinases and the majority of small-molecule inhibitors of kinases target the ATP binding site, a challenge in kinase inhibitor discovery is the optimization of selectivity [Huang 2009] Full length sequence alignment of the three human SGK isoforms reveals high sequence identity (> 60%). The sequence identity is even higher in the protein kinase domain (>75%) and very high for those residues defining the putative ATP binding site.
  • ATP adenosine triphosphate
  • the amino acid residue sequence identity in the ATP binding sites between SGK3 and the other SGK family members is 93% and 90% for SGK1 and SGK2 respectively.
  • This striking degree of amino acid sequence similarity for the SGK isoforms in their ATP binding sites suggests an inhibitor with an ATP- competitive mechanism of inhibition would not be expected to exhibit significant SGK isoform selectivity. Therefore, given the high degree of amino acid sequence similarity for the SGK isoforms in their ATP binding sites, the development of an SGK-isoform selective ATP binding site inhibitor would represent a daunting challenge.
  • SGK1 mRNA is ubiquitously expressed in almost all human tissues, with highest levels in the pancreas, followed by placenta, kidney and lung [Raikwar 2008] In addition, SGK1 mRNA is found in several embryonic tissues and is detectable during organogenesis [Lee 2001] On a protein level SGK1 expression was concentrated in the intestine, brain, eyes, kidney, ovaries, breast, rectum, adrenal cortical cells, nasopharynx, neuronal cells and bone marrow poietic cells, gastric superficial mucosa, gallbladder and alveolar macrophages.
  • SGK1 can be found throughout the cell (cytoplasm, nucleus, mitochondria, endoplasmic reticulum and cell membranes). The subcellular localization is controlled by the cell cycle, exposure to specific hormones, and environmental stress stimuli [Lang 2006] In proliferating cells, SGK1 shuttles between the nucleus and cytoplasm in synchrony with the cell cycle, and in serum/growth factor-stimulated cells it resides in the nucleus. SGK2 mRNA is highly expressed in liver, kidney and pancreas, and at lower levels in brain [Kobayashi 1999] The protein was found localized to the cytoplasm and nucleus of cells (uniprot.org).
  • SGK3 mRNA is expressed in most tissues with highest levels in pancreas, kidney liver, heart and brain and lower levels in lung, placenta and skeletal muscle [Kobayashi 1999] SGK3 protein is expressed in most tissues and is particularly high in the heart, breast, testis, intestinal glands, gall bladder, exocrine pancreas, placenta and immune cells. Intracellularly SGK3 is localized to cytoplasmic vesicles and the nucleus.
  • the SGK1 gene has been amplified and overexpression has been observed in breast cancer a proportion of patients [Di Cristofano 2017]
  • SGK3 expression has been linked to the oestrogen receptor both in breast cancer cell lines and in primary tumour samples [Xu 2012]
  • a study of hepatocellular carcinoma specimens has found an amplification and overexpression of SGK3 and SGK2 were frequently detected and that their genomic activation was significantly associated with poor outcome in patients [Liu 2012; Liu 2017]
  • the most notable role of the SGK family is their regulation of ion channel activity, transport, and transcription. They can regulate ion channels and carrier proteins directly by phosphorylating the serine or threonine residues on the target protein, modulating their activity [Lang 2006]
  • the SGK kinases participate in the regulation of a wide variety of ion channels and membrane transporters, for example Na+/K+-ATPase activity [Henke 2002]; K + channel activation [Gamper 2002]; regulation of cardiac Na + channels [Boehmer 2003]; regulation of the epithelial Ca2+ channel TRPV5 (ECaC1) [Embark 2004], regulation of Na + -dependent neutral amino acid transporter type 2 (hASCT2/SLC1A5) [Palmada 2005], regulation of the excitatory amino acid transporter EAAT5 [Boehmer 2005] , regulation of the epithelial calcium channel TRPV6 [Boehmer 2007], the neutral amino acid transporter SLC6A
  • ENaC is the channel that controls Na+ reabsorption across epithelial tissues including the colon, sweat glands, salivary ducts, airway and the distal kidney nephron.
  • Sodium reabsorption is a major determinant of extracellular fluid volume and consequently is involved in the regulation of blood pressure.
  • SKG1 -knockout mice are viable and seemingly normal when fed a standard diet but demonstrate a defect in sodium homeostasis in which dietary salt deficiency leads to marked decrease of glomerular filtration rate and blood pressure
  • Enhanced SGK1 expression has been observed in the salt-sensitive Dahl rat [Farjah 2003], and moderately enhanced blood pressure is observed in individuals carrying a gain of function variant of the SGK1 gene, affecting as many as 5% of unselected Caucasians [Busjahn 2002]
  • One study highlighted that individuals who are carrying a polymorphism of the SGK1 gene had hypertension.
  • SGK3 knockout mice are viable, fertile, healthy and of normal size and weight but they display distinctly abnormal whiskers and hair coats [Alonso 2005, Ciprian 2005]
  • the SGK3 null mice also show a decrease in intestinal glucose transport mediated through the sodium-dependent glucose transporter SGLT1 [Dieter 2004, Sandu 2005]
  • SGK1/SGK3 double knockout mice sg ⁇ -/-/sgk3-/ ⁇ ) are viable and display a phenotype reflecting properties of sgk1-l- and sgk3-/ ⁇ mice.
  • SGK1 plays a critical role in the induction of pathogenic Th17 cells and interacts with environmental factors such as a high salt diet to trigger Th17 development and promote tissue inflammation.
  • Th17 cells are potent proinflam matory cells critical for clearing extracellular pathogens and for induction of multiple autoimmune diseases.
  • IL-23 plays a critical role in stabilizing and reinforcing the Th17 phenotype by increasing expression of IL-23 receptor [Wu 2013]
  • SGK1 is not thought not to play a role in Th17 cell differentiation, however it does promote TH2 differentiation upon activation by mTORC2, but it is not essential for TH 1 differentiation.
  • mice with a selective deletion of SGK1 in T cells were also resistant to experimentally induced asthma, generated robust amounts of IFN-g in response to viral infections and more readily rejected tumours. Together this shows the importance of SGK1 on driving TH2 cell differentiation and identifies SGK1 as a potential target for the treatment of TH2-mediated autoimmune and allergic diseases [Heikamp 2014] Conversely, SGK1 has been shown to be a potent negative regulator of toll-like receptor (TLR) induced inflammation. Suppression of SGK1 by siRNA in vitro, enhanced proinflammatory cytokine production in tolllike receptor engaged monocytes.
  • TLR toll-like receptor
  • SGK1 inhibition was shown to aggravate the severity of multiple organ damage and enhance the inflammatory response by heightening both proinflammatory cytokine levels and neutrophil infiltration [Zhou e2015]. This supports that SGK1 activity is key in down regulating TLR-medicated inflammation and protects against endotoxin driven failure.
  • PI3K phosphatidylinositol 3-kinase
  • Classl phosphoinositide3-kinase (PI3K) generates phosphatidylinositol3,4,5-trisphosphate (Ptdlns(3,4,5)P3) at the plasma membrane in response to growth factors, activating a signalling cascade that regulates many cellular functions.
  • the PI3K pathway is commonly dysregulated in human cancer and drives tumorigenesis by promoting aberrant cell growth and transformation.
  • Ptdlns(3,4,5)P3 signalling is degraded and terminated by phosphoinositide phosphatases such as phosphatase and tensin homologue (PTEN), proline-rich inositol polyphosphate 5- phosphatase (PIPP) (INPP5J) and inositol polyphosphate 4-phosphatase type ll(INPP4B).
  • PTEN phosphatase and tensin homologue
  • PTEN proline-rich inositol polyphosphate 5- phosphatase
  • PIPP5J proline-rich inositol polyphosphate 5- phosphatase
  • the serum and glucocorticoid inducible protein kinase (SGK) family signals downstream of the PI3K pathway as members of the AGC kinase family, the SGK sub-family proteins phosphorylate a variety of proteins, including core components of signal pathways that play important roles in multiple cellular processes, such as cell growth, proliferation, survival and apoptosis [Basnet 2008, Bruhn 2010]
  • SGK1 has been reported to be essential for several cancers: prostate, human melanoma and kidney cancer cells [Basnet 2008] SGK1 was highly expressed in colonic tumour samples from CRC patients, and it was shown to be essential for CRC development via the promotion of tumour cell proliferation, migration and survival [Liang 2017] SGK1 plays a critical role in promoting epithelial cell survival under conditions of cellular stress such as serum-deprivation and chemotherapy treatment [Mitkosz 2001] SGK1 is able to directly phosphorylate F0X01 at residues T32 and S315 [Brunet 2001] and has been correlated with resistance to AKT inhibition as AKT-inhibitor-resistant breast cancer possess elevated levels of SGK1 and are dependent on SGK1 for proliferation [Sommer 2013] SGK1 has been identified as a substrate of mTOR kinase activity and in breast cancer cells the dependence of SGK1 Ser422 phosphorylation on mTORCI activity associates with ER-alpha expression
  • SGK1 prevents mTORCI activation, restoring the antitumoral effects of PI3Ka inhibition in resistant cells [Castel 2016]
  • SGK1 interferes with the signaling of membrane androgen receptors, to trigger down regulation on the PI3K pathway to induce apoptosis of prostate tumour cells and protect against tumour growth [Papadopoulou 2008] and promoted cell growth of prostate cancer cell lines [Sherk 2008]
  • the expression of SGK3 is not regulated by glucocorticoids.
  • SGK3 also promotes estrogen-mediated cell survival of ER-positive breast cancer cells and activated SGK3 can promote estrogen/ER-dependent transcription and cell survival [Xu 2012], supporting a model in which SGK3 and ER form a feedback loop [Wang 2006]
  • SGK3 was highly expressed in breast invasive ductal carcinoma tissues, and positively correlated with the pathological grade of tumour and the ER expression [Xu 2012]
  • SGK3 has been shown to enhance ERa transactivation activity through phosphorylation of coactivator Flightless-I [Xu 2009]
  • SGK3 expression is higher in ER-positive breast tumors than ER-negative breast tumours [Wang 2011]
  • SGK3 has been found to sustain ERa signaling and
  • INPP4B shRNA knockdown attenuated melanoma cell proliferation and xenograft tumour growth whereas INPP4B overexpression enhanced cell proliferation and promoted melanocyte anchorage-independent cell growth, driven by INPP4B-mediated activation of SGK3 in an AKT-independent manner [Chi 2015]
  • inhibitors of the SGK family proteins such as the compounds of the present invention can be used in the treatment of various disease states in which SGK activity plays a role or which are associated with inappropriate SGK activity, or in which inhibition, regulation or modulation of signal transduction by SGK family proteins is desired.
  • SGK activity plays a role or which are associated with inappropriate SGK activity, or in which inhibition, regulation or modulation of signal transduction by SGK family proteins is desired.
  • 3-amino-N-(1-benzyl-1 H-pyrazol-4-yl) pyrazine-2-carboxamide and 2-amino-N-(1- benzyl-1 H-pyrazol-4-yl)nicotinamide (CAS 1311914-47-2 and 1851812-22-0) are known compounds but no pharmacological activity, and in particular no SGK inhibitory activity, has been previously disclosed for these two compounds.
  • a pharmaceutical composition comprising a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in admixture with a pharmaceutically acceptable diluent or carrier.
  • a method of inhibiting SGK activity comprising contacting a cell with an effective amount of a compound or a pharmaceutically acceptable salt, hydrate or solvate thereof as defined herein.
  • a method of inhibiting cell proliferation or regulating electrolyte balance in renal and/or cardiovascular disease, in vitro or in vivo comprising contacting a cell with an effective amount of a compound or a pharmaceutically acceptable salt, hydrate or solvate thereof as defined herein, or a pharmaceutical composition as defined herein.
  • a method of treating a disease or disorder in which SGK activity is implicated in a patient in need of such treatment comprising administering to said patient a therapeutically effective amount of a compound or a pharmaceutically acceptable salt, hydrate or solvate thereof as defined herein, or a pharmaceutical composition as defined herein.
  • a method of treating a proliferative disorder or regulating electrolyte balance in renal and/or cardiovascular disease in a patient in need of such treatment comprising administering to said patient a therapeutically effective amount of a compound or a pharmaceutically acceptable salt, hydrate or solvate thereof as defined herein, or a pharmaceutical composition as defined herein.
  • a method of treating cancer or regulating electrolyte balance in renal and/or cardiovascular disease in a patient in need of such treatment comprising administering to said patient a therapeutically effective amount of a compound or a pharmaceutically acceptable salt, hydrate or solvate thereof as defined herein, or a pharmaceutical composition as defined herein.
  • a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein for use in therapy is provided.
  • the cancer is human cancer, in particular oestrogen positive cancers, such as breast cancer, or androgen receptor positive cancers, such as prostate cancer.
  • a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein for use in the inhibition of SGK activity is provided.
  • a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof as defined herein for use in the treatment of a disease or disorder in which SGK activity is implicated.
  • a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof as defined herein in the manufacture of a medicament for the treatment of a proliferative condition or in regulating electrolyte balance in renal and/or cardiovascular disease.
  • the proliferative disorder is cancer, suitably a human cancer (for example haematological cancers such as lymphomas (including diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), Burkitt lymphoma (BL) and angioimmunoblastic T-cell lymphoma (AITL)), leukaemias (including acute lymphoblastic leukaemia (ALL) and chronic myeloid leukaemia (CML)) and multiple myeloma, and solid tumours (including glioma, breast cancer, non-small cell lung cancer (NSCLC) and squamous cell carcinomas (SCC) (including SCC of the head and neck, oesophagus, lung and ovary)).
  • haematological cancers such as lymphomas (including diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), Burkitt lymphoma (BL) and angioimmunoblastic T-
  • a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof obtainable by, or obtained by, or directly obtained by a process of preparing a compound as defined herein.
  • references to“treating” or“treatment” include prophylaxis as well as the alleviation of established symptoms of a condition.“Treating” or“treatment” of a state, disorder or condition therefore includes: (1) preventing or delaying the appearance of clinical symptoms of the state, disorder or condition developing in a human that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition, (2) inhibiting the state, disorder or condition, i.e., arresting, reducing or delaying the development of the disease or a relapse thereof (in case of maintenance treatment) or at least one clinical or subclinical symptom thereof, or (3) relieving or attenuating the disease, i.e., causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms.
  • A“therapeutically effective amount” means the amount of a compound that, when administered to a mammal for treating a disease, is sufficient to effect such treatment for the disease.
  • the “therapeutically effective amount” will vary depending on the compound, the disease and its severity and the age, weight, etc., of the mammal to be treated.
  • alkyl includes both straight and branched chain alkyl groups. References to individual alkyl groups such as“propyl” are specific for the straight chain version only and references to individual branched chain alkyl groups such as“isopropyl” are specific for the branched chain version only.
  • (1-6C)alkyl includes (1- 4C)alkyl, (1-3C)alkyl, propyl, isopropyl and f-butyl.
  • (m-nC) or "(m-nC) group” used alone or as a prefix, refers to any group having m to n carbon atoms.
  • An“alkylene” group is an alkyl group that is positioned between and serves to connect two other chemical groups.
  • “(1-6C)alkylene” means a linear saturated divalent hydrocarbon radical of one to six carbon atoms or a branched saturated divalent hydrocarbon radical of three to six carbon atoms, for example, methylene (-CH 2 -), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), 2-methylpropylene (-CH 2 CH(CH 3 )CH 2 -), pentylene (- CH2CH2CH2CH2CH2-), and the like.
  • alkyenyl refers to straight and branched chain alkyl groups comprising 2 or more carbon atoms, wherein at least one carbon-carbon double bond is present within the group.
  • alkenyl groups include ethenyl, propenyl and but-2,3-enyl and includes all possible geometric (E/Z) isomers.
  • alkynyl refers to straight and branched chain alkyl groups comprising 2 or more carbon atoms, wherein at least one carbon-carbon triple bond is present within the group.
  • alkynyl groups include acetylenyl and propynyl.
  • (3-10C)cycloalkyl means a hydrocarbon ring containing from 3 to 10 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and bicyclo[2.2.1]heptyl.
  • alkoxy refers to O-linked straight and branched chain alkyl groups. Examples of alkoxy groups include methoxy, ethoxy and f-butoxy.
  • haloalkyl is used herein to refer to an alkyl group in which one or more hydrogen atoms have been replaced by halogen (e.g. fluorine) atoms.
  • halogen e.g. fluorine
  • alkyl groups include -CH 2 F, -CHF 2 and -CF3.
  • halo or“halogeno” refers to fluoro, chloro, bromo and iodo, suitably fluoro, chloro and bromo, more suitably, fluoro and chloro.
  • “carbocyclyl”,“carbocyclic” or“carbocycle” means a non-aromatic saturated or partially saturated monocyclic, fused, bridged, or spiro bicyclic carbon-containing ring system(s).
  • Monocyclic carbocyclic rings contain from about 3 to 12 (suitably from 3 to 7) ring atoms.
  • Bicyclic carbocycles contain from 6 to 17 member atoms, suitably 7 to 12 member atoms, in the ring.
  • Bicyclic carbocyclic(s) rings may be fused, spiro, or bridged ring systems. Examples of carbocyclic groups include cyclopropyl, cyclobutyl, cyclohexyl, cyclohexenyl and spiro[3.3]heptanyl.
  • heterocyclyl means a non-aromatic saturated or partially saturated monocyclic, fused, bridged, or spiro bicyclic heterocyclic ring system(s).
  • Monocyclic heterocyclic rings contain from about 3 to 12 (suitably from 3 to 7) ring atoms, with from 1 to 5 (suitably 1 , 2 or 3) heteroatoms selected from nitrogen, oxygen or sulfur in the ring.
  • Bicyclic heterocycles contain from 7 to 17 member atoms, suitably 7 to 12 member atoms, in the ring.
  • Bicyclic heterocyclic(s) rings may be fused, spiro, or bridged ring systems.
  • heterocyclic groups include cyclic ethers such as oxiranyl, oxetanyl, tetrahydrofuranyl, dioxanyl, and substituted cyclic ethers.
  • Heterocycles containing nitrogen include, for example, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydrotriazinyl, tetrahydropyrazolyl, and the like.
  • Typical sulfur containing heterocycles include tetrahydrothienyl, dihydro-1 , 3-dithiol, tetrahydro-2/-/-thiopyran, and hexahydrothiepine.
  • heterocycles include dihydro-oxathiolyl, tetrahydro-oxazolyl, tetrahydro-oxadiazolyl, tetrahydrodioxazolyl, tetrahydro-oxathiazolyl, hexahydrotriazinyl, tetrahydro-oxazinyl, morpholinyl, thiomorpholinyl, tetrahydropyrimidinyl, dioxolinyl, octahydrobenzofuranyl, octahydrobenzimidazolyl, and octahydrobenzothiazolyl.
  • heterocycles containing sulfur the oxidized sulfur heterocycles containing SO or SO2 groups are also included.
  • examples include the sulfoxide and sulfone forms of tetrahydrothienyl and thiomorpholinyl such as tetrahydrothiene 1 , 1-dioxide and thiomorpholinyl 1 , 1-dioxide.
  • heterocyclyl groups are saturated monocyclic 3 to 7 membered heterocyclyls containing 1 , 2 or 3 heteroatoms selected from nitrogen, oxygen or sulfur, for example azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, morpholinyl, tetrahydrothienyl, tetrahydrothienyl 1 , 1-dioxide, thiomorpholinyl, thiomorpholinyl 1 , 1-dioxide, piperidinyl, homopiperidinyl, piperazinyl or homopiperazinyl.
  • any heterocycle may be linked to another group via any suitable atom, such as via a carbon or nitrogen atom.
  • reference herein to piperidino or morpholino refers to a piperidin-1- yl or morpholin-4-yl ring that is linked via the ring nitrogen.
  • bridged ring systems is meant ring systems in which two rings share more than two atoms, see for example Advanced Organic Chemistry, by Jerry March, 4 th Edition, Wiley Interscience, pages 131-133, 1992.
  • bridged heterocyclyl ring systems include, aza-bicyclo[2.2.1]heptane, 2-oxa-5-azabicyclo[2.2.1]heptane, aza-bicyclo[2.2.2]octane, aza- bicyclo[3.2.1]octane and quinuclidine.
  • spiro bi-cyclic ring systems we mean that the two ring systems share one common spiro carbon atom, i.e. the heterocyclic ring is linked to a further carbocyclic or heterocyclic ring through a single common spiro carbon atom.
  • spiro ring systems include 6-azaspiro[3.4]octane, 2-oxa-6-azaspiro[3.4]octane, 2-azaspiro[3.3]heptanes, 2-oxa-
  • heteroaryl or“heteroaromatic” means an aromatic mono-, bi-, or polycyclic ring incorporating one or more (for example 1-4, particularly 1 , 2 or 3) heteroatoms selected from nitrogen, oxygen or sulfur.
  • heteroaryl includes both monovalent species and divalent species. Examples of heteroaryl groups are monocyclic and bicyclic groups containing from five to twelve ring members, and more usually from five to ten ring members.
  • the heteroaryl group can be, for example, a 5- or 6-membered monocyclic ring or a 9- or 10- membered bicyclic ring, for example a bicyclic structure formed from fused five and six membered rings or two fused six membered rings.
  • Each ring may contain up to about four heteroatoms typically selected from nitrogen, sulfur and oxygen.
  • the heteroaryl ring will contain up to 3 heteroatoms, more usually up to 2, for example a single heteroatom.
  • the heteroaryl ring contains at least one ring nitrogen atom.
  • the nitrogen atoms in the heteroaryl rings can be basic, as in the case of an imidazole or pyridine, or essentially non-basic as in the case of an indole or pyrrole nitrogen. In general the number of basic nitrogen atoms present in the heteroaryl group, including any amino group substituents of the ring, will be less than five.
  • heteroaryl examples include furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1 ,3,5-triazenyl, benzofuranyl, indolyl, isoindolyl, benzothienyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, benzothiazolyl, indazolyl, purinyl, benzofurazanyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, cinnolinyl, pteridinyl, naphthy
  • Examples of five membered heteroaryl groups include but are not limited to pyrrolyl, furanyl, thienyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl and tetrazolyl groups.
  • heteroaryl groups include but are not limited to pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl and triazinyl.
  • a bicyclic heteroaryl group may be, for example, a group selected from:
  • thiazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms
  • bicyclic heteroaryl groups containing a six membered ring fused to a five membered ring include but are not limited to benzfuranyl, benzthiophenyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzthiazolyl, benzisothiazolyl, isobenzofuranyl, indolyl, isoindolyl, indolizinyl, indolinyl, isoindolinyl, purinyl (e.g., adeninyl, guaninyl), indazolyl, benzodioxolyl and pyrazolopyridinyl groups.
  • bicyclic heteroaryl groups containing two fused six membered rings include but are not limited to quinolinyl, isoquinolinyl, chromanyl, thiochromanyl, chromenyl, isochromenyl, chromanyl, isochromanyl, benzodioxanyl, quinolizinyl, benzoxazinyl, benzodiazinyl, pyridopyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, naphthyridinyl and pteridinyl groups.
  • aryl means a cyclic or polycyclic aromatic ring having from 5 to 12 carbon atoms.
  • aryl includes both monovalent species and divalent species. Examples of aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl and the like. In a particular embodiment, an aryl is phenyl.
  • optionally substituted refers to either groups, structures, or molecules that are substituted and those that are not substituted.
  • the term“wherein a/any CH, Chb, CH 3 group or heteroatom (i.e. NH) within a R 1 group is optionally substituted” suitably means that (any) one of the hydrogen radicals of the R 1 group is substituted by a relevant stipulated group.
  • the present invention relates to compounds, or pharmaceutically acceptable salts, hydrates or solvates thereof, having the structural Formula (I), shown below:
  • Xi is N or CH
  • X 2 is N or C-Ri ;
  • Ri is selected from hydrogen, halo, cyano, amino, hydroxy, (1-2C)alkyl or (1-2C)alkoxy; either:
  • Yi and Y2 are N and Y3 is C-RY3 and Y4 is C-RY 4 ; or
  • Yi is C, Y2 and Y3 are both N and Y4 is O;
  • R 2 is selected from hydrogen, halo, cyano or a group of the formula:
  • l_2 is absent or a (1-3C)alkylene
  • M is absent, N(R e ) or C(0)N(R e ), wherein R e is selected from hydrogen or (1-4C)alkyl
  • Q 2 is hydrogen, (1-6C)alkyl, (3-6C)cycloalkyl, (2-6C)alkenyl, (2-6C)alkynyl, aryl, heterocyclyl or heteroaryl;
  • Q 2 is optionally substituted by one or more substituents selected from (1-4C)alkyl, (3-6C) cycloalkyl, halo, trifluorom ethyl, trifluoromethoxy, cyano, NR g R h , OR g , C(0)R g , C(0)0R g , 0C(0)R g , C(0)N(R g )R h , N(R g )C(0)R h , S(0) y R g (where y is 0, 1 or 2), S0 2 N(R g )R h , N(R g )S0 2 R h or (CH 2 ) z NR g R h (where z is 1 , 2 or 3), wherein R g and R h are each independently selected from hydrogen or (1-4C)alkyl, (1-4C)haloalkyl or aryl(1-2C)alkyl;
  • R 3 is selected from hydrogen, (1-4C)alkyl, (1-6C)alkoxy(1-2C)alkyl or hydroxy(1-2C)alkyl; or R 2 and R 3 may be linked such that, together with the carbon atom to which they are attached, they form a (3-7C)cycloalkyl or a 3 to 7-membered heterocyclic ring comprising one, two or three heteroatoms selected from N, O or S, wherein the (3-7C)cycloalkyl or the 3 to 7- membered heterocyclic ring is optionally substituted by one or more substituents selected from halo, cyano, (1-4C)alkyl, NRMR2B, OR2A, C(0)R2A, C(0)0R2A, 0C(0)R2A, C(0)N(R 2 A)R2B, N(R 2 A)C(0)R 2 B, S(0)yR2A (where y is 0, 1 or 2), S0 2 N(R 2 A)R2B, N(R 2
  • Y is absent or -CR j R k -, wherein Rj and Rk are each independently selected from hydrogen or (1-4C)alkyl;
  • Z is a group of the formula:
  • Zi is N or CRzi
  • Z 2 is N or CR z2 ;
  • Z 3 is N or CR z3 ;
  • Z 4 is N or CR Z4 ;
  • Z 5 is N or CR Z5 ;
  • ⁇ 6 is N, O, S or CRzs;
  • ⁇ 7 is N, O, S or CR Z 7;
  • ⁇ 8 is N, O, S or CRzs
  • ⁇ 9 is N, O, S or CR zg ;
  • R zi , R Z 3, R z 4, R z s, R z6 , R z e and R Z 9 are each independently selected from hydrogen, halo, methyl, methoxy, -CF 3 , -OCF 3 , -NH 2 , -NHMe, -NMe 2 , cyano, and
  • R z2 and R Z 7 are selected from hydrogen, halo, cyano or a group of the formula:
  • l_3 is absent or a (1-3C)alkylene optionally substituted by one or more substituents selected from (1-2C)alkyl, halo, hydroxy or oxo;
  • M3 is absent or selected from O, S, SO, S0 2 , N(R k ), C(O), C(0)0, OC(O), C(0)N(R k ), N(R k )C(0), N(R k )C(0)N(Ri), S(0) 2 N(R k ), or N(R k )S0 2 , wherein R k and Ri are each independently selected from hydrogen or (1-4C)alkyl; and
  • Q 3 is hydrogen, (1-6C)alkyl, (3-8C)cycloalkyl, (3-8C)cycloalkyl(1-2C)alkyl, (2- 6C)alkenyl, (2-6C)alkynyl, aryl, heterocyclyl or heteroaryl;
  • Q 3 is optionally substituted by one or more substituents selected from (1-4C)alkyl, halo, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, carboxy, carbamoyl, sulphamoyl, NR m Rn, OR m , C(0)R m , C(0)0R m , 0C(0)R m , C(0)N(R m )Rn, N(R m )C(0)Rn, S(0) y R m (where y is 0, 1 or 2), S0 2 N(R m )R n , N(R m )S0 2 R n , (CH 2 ) z NR m R n (where z is 1 , 2 or 3), aryl, heterocyclyl or heteroaryl,
  • R m and R n are each independently selected from hydrogen or (1- 4C)alkyl or
  • R m and R n when R m and R n are both attached to a N atom, R m and R n may be linked such that, together with the N atom to which they are attached, they form a 4 to 12 membered heterocyclic ring which is optionally substituted by (1-4C).
  • Particular compounds of the invention include, for example, compounds of the Formula (I), or pharmaceutically acceptable salts, hydrates and/or solvates thereof, wherein, unless otherwise stated, each of Xi, X 2 , Yi , Y 2 , Y 3 , Y 4 , R 2 , R 3 , Y and Z and any associated substituent groups has any of the meanings defined hereinbefore or in any of paragraphs (1) to (34) hereinafter:
  • Xi is CH
  • Xi is N and X 2 is CH;
  • Xi is N and X 2 is C-Ri;
  • Xi is CH and X 2 is N;
  • Ri is selected from hydrogen, halo, or (1-2C)alkyl
  • (10) Ri is selected from hydrogen or halo
  • Yi is C, Y2 and Y 3 are both N and Y 4 is O;
  • R is selected from hydrogen or a group of the formula:
  • M2 is absent or C(0)N(R e ), wherein R e is independently selected from hydrogen or (1- 4C)alkyl;
  • Q2 is hydrogen, (1-6C)alkyl, (3-6C)cycloalkyl, (2-6C)alkenyl, (2-6C)alkynyl, aryl, heterocyclyl or heteroaryl;
  • Q2 is optionally substituted by one or more substituents selected from (1-4C)alkyl, (3-6C)cycloalkyl, halo, trifluoromethyl, trifluoromethoxy, cyano, NR g R h , ORg, C(0)Rg, C(0)ORg, OC(0)R g , C(0)N(Rg)R h , N(Rg)C(0)R h , S(0) y Rg (where y is 0,
  • R g and R h are each independently selected from hydrogen or (1-4C)alkyl, (1- 4C)haloalkyl, or aryl(1-2C)alkyl; (14) R is selected from hydrogen or a group of the formula:
  • M2 is absent or C(0)N(R e ), wherein R e is independently selected from hydrogen or (1- 4C)alkyl;
  • Q2 is hydrogen, (1-6C)alkyl or heterocyclyl
  • Q2 is optionally substituted by one or more substituents selected from (1-4C)alkyl, halo, NR g R h and OR g , wherein R g and R h are each independently selected from hydrogen, (1-4C)alkyl or aryl(1-2C)alkyl;
  • R 2 is hydrogen
  • R 2 is a group of the formula:
  • Q2 is (1-6C)alkyl or heterocyclyl
  • Q 2 is optionally substituted by one or more substituents selected from (1-4C)alkyl, halo, NR g R h and OR g , wherein R g and R h are each independently selected from hydrogen, (1-4C)alkyl or benzyl;
  • R 2 is a group of the formula:
  • Q 2 is (1-6C)alkyl
  • Q 2 is substituted by one or more substituents selected from halo, NR g R h and OR g , wherein R g and R h are each independently selected from hydrogen, (1- 4C)alkyl or benzyl;
  • R 2 is a group of the formula:
  • Q 2 is (1-6C)alkyl; and wherein Q is substituted by NR g R h , wherein R g and R h are each independently selected from hydrogen or (1-4C)alkyl;
  • R 2 is a group of the formula:
  • Q 2 is heterocyclyl
  • Q 2 is optionally substituted by one or more substituents selected from (1-4C)alkyl, halo and OR g , wherein R g is hydrogen, (1-4C)alkyl or benzyl;
  • R 2 is a group of the formula:
  • Q 2 is heterocyclyl
  • Q 2 is optionally substituted by one or more substituents selected from methyl and fluoro;
  • R 2 is a group of the formula:
  • Q 2 is selected from one of the following heterocyclyl groups:
  • Q2 is selected from one of the following heterocyclyl groups:
  • LLL ⁇ represents the point of attachment of the heterocyclyl group to the rest of the compound of formula I and wherein Q 2 is optionally substituted by one or more substituents selected from (1-4C)alkyl, fluoro and OR a , wherein R g is hydrogen, (1-2C)alkyl or benzyl;
  • R 3 is hydrogen, methyl or hydroxymethyl
  • R3 is hydrogen
  • R j is hydrogen
  • R k is hydrogen
  • Z is a group of the formula: wherein vrv/w* represents the point of attachment to the rest of the compound of formula I and wherein:
  • Zi is N or CR zi ;
  • Z2 is N or CRz2i
  • Z 3 is N or CR z3 ;
  • Z4 is N or CR z ;
  • Z5 is N or CR Z5 ;
  • R zi , R Z 3, R ⁇ 4 and R z s are each independently selected from hydrogen, halo, methyl, methoxy, -CF 3 , -OCF3, -INH2, -NHMe, -NMe2, cyano, and
  • R Z 2 is selected from hydrogen, halo, cyano or a group of the formula:
  • l_3 is absent or a (1-3C)alkylene optionally substituted by one or more substituents selected from (1-2C)alkyl, halo, hydroxy or oxo;
  • M3 is absent or selected from O, S, SO, S0 2 , N(R k ), C(O), C(0)0, OC(O), C(0)N(R k ), N(R k )C(0), N(R K )C(0)N(R I ), S(0) 2 N(R k ), or N(R k )S0 2 , wherein R k and Ri are each independently selected from hydrogen or (1-4C)alkyl; and Q3 is hydrogen, (1-6C)alkyl, (3-8C)cycloalkyl, (3-8C)cycloalkyl(1-2C)alkyl, (2- 6C)alkenyl, (2-6C)alkynyl, aryl, heterocyclyl or heteroaryl;
  • Q 3 is optionally substituted by one or more substituents selected from (1-4C)alkyl, halo, trifluoromethyl, trifluoromethoxy, cyano, NR m R n , OR m , C(0)R m , C(0)0R m , 0C(0)R m , C(0)N(R m )R discipline, N(R m )C(0)Rtask, S(0) y R m (where y is 0, 1 or 2), S0 2 N(R m )R n , N(R m )S0 2 R n , (CH 2 ) z NR m R n (where z is 1 , 2 or 3), aryl, heterocyclyl or heteroaryl,
  • R m and R n are each independently selected from hydrogen or (1- 4C)alkyl or
  • R m and R n when R m and R n are both attached to a N atom, R m and R n may be linked such that, together with the N atom to which they are attached, they form a 4 to 12 membered heterocyclic ring which is optionally substituted by (1-4C)alkyl, halo, trifluoromethyl, trifluoromethoxy, amino, cyano, hydroxy, carboxy, carbamoyl, sulphamoyl, NR 0 R P , OR 0 , wherein R 0 and R p are hydrogen or (1-2C)alkyl;
  • ⁇ LL represents the point of attachment to the rest of the compound of formula I and wherein:
  • Zi is CRzi
  • Z 2 is CR z2 ;
  • Z 3 is CR z3 ;
  • Z4 is CR z ,
  • Z5 is CR z5 ;
  • R zi , R z3 , R ⁇ 4 and R z5 are each independently selected from hydrogen, halo, methyl, methoxy, -CF 3 , cyano, and -C(0)NH 2 ;
  • R z2 is selected from hydrogen, halo or a group of the formula:
  • l_ 3 is absent or (1-3C)alkylene
  • M 3 is absent or selected from O, S0 2 , N(R k ), C(0)0, C(0)N(R k ), N(R k )C(0) or N(R k )S0 2 , wherein R k is selected from hydrogen or (1-4C)alkyl;
  • Q 3 is hydrogen, (1-6C)alkyl, (3-6C) cycloalkyl, (3-6C)cycloalkyl(1-2C)alkyl, (2- 6C)alkenyl, heterocyclyl;
  • Q 3 is optionally substituted by one or more substituents selected from (1-4C)alkyl, halo, trifluoromethyl, cyano, NR m R n , OR m , C(0)N(R m )R n , aryl or heterocyclyl, wherein R m and R n are each independently selected from hydrogen or (1-4C)alkyl or
  • R m and R n when R m and R n are both attached to a N atom, R m and R n may be linked such that, together with the N atom to which they are attached, they form a 4 to 12 membered heterocyclic ring;
  • Z is a group of the formula: wherein ww « represents the point of attachment to the rest of the compound of formula I and wherein:
  • Zi is CRzi
  • Z 2 is CR z2 ;
  • Z 3 is CR z3 ;
  • Z 4 is CR Z4
  • Z 5 is CR z5 ;
  • R zi , R Z3 , R z4 and R z5 are each independently selected from hydrogen, fluoro, chloro, and methoxy;
  • R Z2 is selected from (1-4C)alkyl, halo, trifluoromethyl, trifluoromethoxy, cyano,
  • NR m Rn OR m , C(0)Rm, C(0)0R m , 0C(0)R m , C(0)N(R m )R n , N(R m )C(0)R n , S(0) y R m (where y is 0, 1 or 2), S0 2 N(R m )Rn, N(R m )S0 2 R n , (CH 2 ) z NR m Rn (where z is 1 , 2 or 3), aryl, heterocyclyl or heteroaryl and wherein R m and R n are each independently selected from hydrogen or (1-4C)alkyl;
  • R z2 is selected from hydrogen, halo or a group of the formula:
  • l_ 3 is absent or (1-3C)alkylene
  • M 3 is absent or selected from O, S0 2 , N(R k ), C(0)0, C(0)N(R k ), N(R k )C(0) or N(R k )S0 2 , wherein R k is selected from hydrogen or (1-4C)alkyl;
  • Q 3 is hydrogen, (1-6C)alkyl, (3-8C)cycloalkyl, (3-8C)cycloalkyl(1-2C)alkyl, (2- 6C)alkenyl, heterocyclyl;
  • Q 3 is optionally substituted by one or more substituents selected from (1-4C)alkyl, halo, trifluoromethyl, cyano, NR m Rn, OR m , C(0)N(R m )Rn, aryl or heterocyclyl, wherein R m and R n are each independently selected from hydrogen or (1-4C)alkyl or
  • R m and R n when R m and R n are both attached to a N atom, R m and R n may be linked such that, together with the N atom to which they are attached, they form a 4 to 12 membered heterocyclic ring;
  • R z is fluoro, chloro or methyl
  • n 0 or 1 ;
  • R Z 2 is selected from hydrogen, halo or a group of the formula:
  • l_3 is absent or (1-3C)alkylene
  • Ms is absent or selected from O, S0 2 , N(R k ), C(0)0, C(0)N(R k ), N(R k )C(0) or N(R k )S0 2 , wherein R k is selected from hydrogen or (1-4C)alkyl;
  • Q 3 is hydrogen, (1-6C)alkyl, (3-8C)cycloalkyl, (3-8C)cycloalkyl(1-2C)alkyl, (2- 6C)alkenyl, heterocyclyl;
  • Q 3 is optionally substituted by one or more substituents selected from (1-4C)alkyl, halo, trifluoromethyl, cyano, NR m R n , OR m , C(0)N(R m )R n , aryl or heterocyclyl, wherein R m and R n are each independently selected from hydrogen or (1-4C)alkyl or
  • R m and R n when R m and R n are both attached to a N atom, R m and R n may be linked such that, together with the N atom to which they are attached, they form a 4 to 12 membered heterocyclic ring;
  • R Z 4 is hydrogen, fluoro, chloro or methyl
  • R Z 2 is selected from hydrogen, halo or a group of the formula:
  • l_ 3 is absent or (1-3C)alkylene
  • Ms is absent or selected from O, S0 2 , N(R k ), C(0)0, C(0)N(R k ), N(R k )C(0) or N(R k )SC>2, wherein R k is selected from hydrogen or (1-4C)alkyl; and
  • Q 3 is hydrogen, (1-6C)alkyl, (3-8C)cycloalkyl, (3-8C)cycloalkyl(1-2C)alkyl, (2- 6C)alkenyl, heterocyclyl;
  • Q 3 is optionally substituted by one or more substituents selected from (1-4C)alkyl, halo, trifluoromethyl, cyano, NR m Rn, OR m , C(0)N(R m )Rn, aryl or heterocyclyl, wherein R m and R n are each independently selected from hydrogen or (1-4C)alkyl or
  • R m and R n when Rm and R n are both attached to a N atom, R m and R n may be linked such that, together with the N atom to which they are attached, they form a 4 to 12 membered heterocyclic ring;
  • R Z 2 is selected from (1-4C)alkyl, halo, trifluoromethyl, trifluoromethoxy, cyano, NR m Rn, ORm, C(O) Rm, C(0)0Rm, 0C(0)Rm, C(0)N(Rm)Rn, N(Rm)C(0)R perennial, S(0)yRm (where y is 0, 1 or 2), S0 2 N(Rm)Rn, N(R m )S0 2 Rn, (CH2)zNR m Rn (where z is 1 , 2 or 3), aryl, heterocyclyl or heteroaryl and wherein R m and R n are each independently selected from hydrogen or (1-4C)alkyl.
  • Xi is as defined in any one of paragraphs (1) to (2) above. Most suitably, Xi is as defined in paragraph (2) above.
  • X2 is as defined in any one of paragraphs (3) to (4) above. Most suitably, X2 is as defined in paragraph (4) above.
  • Xi and X 2 are as defined in any one of paragraphs (5) to (8) above. Most suitably, Xi and X 2 are as defined in paragraph (5) above.
  • Ri is as defined in any one of paragraphs (9) to (10) above. Most suitably, Ri is as defined in paragraph (10) above.
  • Yi to Y 4 are as defined in any one of paragraphs (11) to (12) above. Most suitably, Yi to Y 4 are as defined in paragraph (11) above.
  • R 2 is as defined in any one of paragraphs (13) to (22) above. Most suitably, R 2 is as defined in paragraph (16) above.
  • R 3 is as defined in paragraph (23) or (24) above. Most suitably, R 3 is as defined in paragraph (24) above
  • Y is as defined in any one of paragraphs (25) to (26) above. Most suitably, Y is as defined in paragraph (25) above.
  • Z is as defined in any one of paragraphs (27) to (34) above. Most suitably, Z is as defined in paragraph (27), paragraph (32) or paragraph (34) above.
  • an aryl group is phenyl
  • Xi is N and X2 is CH, i.e. the compounds have the structural formula la (a sub-definition of Formula (I)) shown below, or a pharmaceutically acceptable salt, hydrate and/or solvate thereof:
  • R 2 is as defined in any one of paragraphs (13) to (22) above;
  • R 3 is as defined in paragraphs (23) to (24) above;
  • Y is as defined in any one of paragraphs (25) to (26) above; and Z is as defined in any one of paragraphs (27) to (34) above.
  • R 2 is as defined in paragraph (16) above;
  • R 3 is as defined in paragraph (24) above;
  • Y is as defined in paragraph (25) above;
  • the compounds have the structural formula lb (a sub-definition of Formula (I)) shown below, or a pharmaceutically acceptable salt, hydrate and/or solvate thereof:
  • R 2 is as defined in any one of paragraphs (13) to (22) above;
  • R 3 is as defined in paragraph (23) to (24) above;
  • Y is as defined in any one of paragraphs (25) to (26) above;
  • R 2 is as defined in paragraph (16) above;
  • R 3 is as defined in paragraph (24) above;
  • Y is as defined in paragraph (25) above;
  • R 3 is hydrogen and Y is absent, i.e. the compounds have the structural formula lc (a sub-definition of Formula (I)) shown below, or a pharmaceutically acceptable salt, hydrate and/or solvate thereof: Formula lc
  • Xi and X 2 are as defined in any one of paragraphs (5) to (8) above;
  • R 2 is as defined in any one of paragraphs (13) to (22) above;
  • Xi and X 2 are as defined in paragraph (5) above;
  • R 2 is as defined in paragraph (16) above;
  • the compounds have the structural formula Id (a sub-definition of Formula (I)) shown below, or a pharmaceutically acceptable salt, hydrate and/or solvate thereof:
  • Xi and X 2 are as defined in any one of paragraphs (5) to (8) above;
  • R 2 is as defined in any one of paragraphs (13) to (22) above; and Zi to Z 5 are as defined in any one of paragraphs (28) to (30) above.
  • Xi and X 2 are as defined in paragraph (5) above;
  • R 2 is as defined in paragraph (16) above;
  • the compounds have the structural formula le (a sub-definition of Formula (I)) shown below, or a pharmaceutically acceptable salt, hydrate and/or solvate thereof:
  • Xi and X 2 are as defined in any one of paragraphs (5) to (8) above;
  • R 2 is as defined in any one of paragraphs (13) to (22) above;
  • R z2 is as defined in any one of paragraphs (31) to (34) above.
  • Xi and X 2 are as defined in paragraph (5) above;
  • R 2 is as defined in paragraph (16) above;
  • R z2 is as defined in paragraph (34) above.
  • the compounds have the structural formula If (a sub-definition of Formula (I)) shown below, or a pharmaceutically acceptable salt, hydrate and/or solvate thereof: Formula If
  • Xi and X 2 are as defined in any one of paragraphs (5) to (8) above;
  • R 2 is as defined in any one of paragraphs (13) to (22) above;
  • Rz and m are as defined in any one of paragraphs (31) or (32);
  • R z2 is as defined in any one of paragraphs (31) to (34) above.
  • Xi and X 2 are as defined in paragraph (5) above;
  • R 2 is as defined in paragraph (16) above;
  • Rz and m are as defined in any one of paragraphs (31) or (32);
  • R z2 is as defined in paragraph (34) above.
  • the compounds have the structural formula Ig (a sub-definition of Formula (I)) shown below, or a pharmaceutically acceptable salt, hydrate and/or solvate thereof:
  • Xi and X 2 are as defined in any one of paragraphs (5) to (8) above;
  • R 2 is as defined in any one of paragraphs (13) to (22) above;
  • R Z4 is as defined in any one of paragraphs (28) to (30) or (32) above.
  • Xi and X 2 are as defined in paragraph (5) above;
  • R 2 is as defined in paragraph (16) above;
  • R Z4 is as defined in paragraph (32) above.
  • the compounds have the structural formulae Ih, li, Ij or Ik (a sub-definition of Formula (I)) shown below, or a pharmaceutically acceptable salt, hydrate and/or solvate thereof:
  • R z is fluoro, chloro or methyl
  • m is 0 or 1
  • R 4 is hydrogen, fluoro, methyl or hydroxy
  • R 5 is hydrogen or (1- 4C)alkyl
  • R g and R h are each independently selected from hydrogen or (1-4C)alkyl and q is 1 to 3.
  • Xi and X 2 are as defined in any one of paragraphs (5) to (8) above;
  • R Z 2 is as defined in any one of paragraphs (31) to (34) above;
  • R z is fluoro, chloro or methyl
  • n 0 or 1 ;
  • R 4 is hydrogen, hydroxy or fluoro
  • Re is hydrogen or methyl
  • R g and R h are independently selected from hydrogen or methyl
  • q 1 or 2.
  • Xi and X 2 are as defined in paragraph (5) above;
  • R z2 is as defined in defined in paragraph (34) above;
  • R z is fluoro, chloro or methyl
  • n 0 or 1 ;
  • R is hydrogen or fluoro
  • R 5 is hydrogen or methyl
  • R g and R h are independently selected from hydrogen or methyl
  • the compounds have the structural formulae Im or In (a sub-definition of Formula (I)) shown below (preferably formulae Im), or a pharmaceutically acceptable salt, hydrate and/or solvate thereof:
  • R 2 and Z are as defined hereinabove.
  • R is as defined in any one of paragraphs (13) to (22) above; and Z is as defined in any one of paragraphs (27) to (32) above.
  • R 2 is as defined in paragraph (16) above;
  • Particular compounds of the present invention include any of the compounds exemplified in the present application, or a pharmaceutically acceptable salt or solvate thereof, and, in particular, any of the following:
  • the various functional groups and substituents making up the compounds of the Formula (I), or sub-formulae la to In, are typically chosen such that the molecular weight of the compound of the formula (I) does not exceed 1000. More usually, the molecular weight of the compound will be less than 900, for example less than 800, or less than 750, or less than 700, or less than 650. More preferably, the molecular weight is less than 600 and, for example, is 550 or less.
  • a suitable pharmaceutically acceptable salt of a compound of the invention is, for example, an acid-addition salt of a compound of the invention which is sufficiently basic, for example, an acid-addition salt with, for example, an inorganic or organic acid, for example hydrochloric, hydrobromic, sulfuric, phosphoric, trifluoroacetic, formic, citric methane sulfonate or maleic acid.
  • an inorganic or organic acid for example hydrochloric, hydrobromic, sulfuric, phosphoric, trifluoroacetic, formic, citric methane sulfonate or maleic acid.
  • a suitable pharmaceutically acceptable salt of a compound of the invention which is sufficiently acidic is an alkali metal salt, for example a sodium or potassium salt, an alkaline earth metal salt, for example a calcium or magnesium salt, an ammonium salt or a salt with an organic base which affords a pharmaceutically acceptable cation, for example a salt with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.
  • an alkali metal salt for example a sodium or potassium salt
  • an alkaline earth metal salt for example a calcium or magnesium salt
  • an ammonium salt or a salt with an organic base which affords a pharmaceutically acceptable cation, for example a salt with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.
  • An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers respectively).
  • a chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a“racemic mixture”.
  • the compounds of this invention may possess one or more asymmetric centers; such compounds can therefore be produced as individual ( R )- or (S)-stereoisomers or as mixtures thereof. Unless indicated otherwise, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures, racemic or otherwise, thereof.
  • the methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art (see discussion in Chapter 4 of “Advanced Organic Chemistry”, 4th edition J. March, John Wiley and Sons, New York, 2001), for example by synthesis from optically active starting materials or by resolution of a racemic form.
  • Some of the compounds of the invention may have geometric isomeric centres (E- and Z- isomers).
  • the present invention encompasses all optical, diastereoisomers and geometric isomers and mixtures thereof that possess antiproliferative activity and/or activity in regulating electrolyte balance in renal and/or cardiovascular disease.
  • the present invention also encompasses compounds of the invention as defined herein which comprise one or more isotopic substitutions.
  • H may be in any isotopic form, including 1 H, 2H(D), and 3H (T);
  • C may be in any isotopic form, including 12C, 13C, and 14C; and O may be in any isotopic form, including 160 and180; and the like.
  • tautomeric forms include keto-, enol-, and enolate-forms, as in, for example, the following tautomeric pairs: keto/enol (illustrated below), imine/enamine, amide/imino alcohol, amidine/amidine, nitroso/oxime, thioketone/enethiol, and nitro/aci-nitro.
  • N-oxides Compounds of the Formula (I), or sub-formulae la to Im, containing an amine function may also form N-oxides.
  • a reference herein to a compound of the Formula (I), or sub-formulae la to In, that contains an amine function also includes the N-oxide.
  • one or more than one nitrogen atom may be oxidised to form an N-oxide.
  • 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.
  • 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-chloroperoxybenzoic acid
  • the compounds of Formula (I), or sub-formulae la to In may be administered in the form of a pro-drug which is broken down in the human or animal body to release a compound of the invention.
  • a pro-drug may be used to alter the physical properties and/or the pharmacokinetic properties of a compound of the invention.
  • a pro-drug can be formed when the compound of the invention contains a suitable group or substituent to which a propertymodifying group can be attached.
  • pro-drugs examples include in vivo cleavable ester derivatives that may be formed at a carboxy group or a hydroxy group in a compound of the Formula (I), or sub-formulae la to In, and in-vivo cleavable amide derivatives that may be formed at a carboxy group or an amino group in a compound of the Formula (I), or subformulae la to Im.
  • the present invention includes those compounds of the Formula (I), or sub-formulae la to In, as defined hereinbefore, when made available by organic synthesis and when made available within the human or animal body by way of cleavage of a pro-drug thereof. Accordingly, the present invention includes those compounds of the Formula (I), or sub-formulae la to In, that are produced by organic synthetic means and also such compounds that are produced in the human or animal body by way of metabolism of a precursor compound, that is a compound of the Formula (I), or sub-formulae la to In, may be a synthetically-produced compound or a metabolically-produced compound.
  • a suitable pharmaceutically acceptable pro-drug of a compound of the Formula (I), or sub-formulae la to In is one that is based on reasonable medical judgement as being suitable for administration to the human or animal body without undesirable pharmacological activities and without undue toxicity.
  • pro-drug Various forms of pro-drug have been described, for example in the following documents :- a) Methods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et al. (Academic Press, 1985);
  • a suitable pharmaceutically acceptable pro-drug of a compound of the Formula (I), or sub-formulae la to In, that possesses a carboxy group is, for example, an in vivo cleavable ester thereof.
  • An in vivo cleavable ester of a compound of the Formula I, or sub-formulae la to In, containing a carboxy group is, for example, a pharmaceutically acceptable ester which is cleaved in the human or animal body to produce the parent acid.
  • Suitable pharmaceutically acceptable esters for carboxy include (1-6C)alkyl esters such as methyl, ethyl and tert- butyl, (1-6C)alkoxymethyl esters such as methoxymethyl esters, (1-6C)alkanoyloxymethyl esters such as pivaloyloxymethyl esters, 3-phthalidyl esters, (3-8C)cycloalkylcarbonyloxy-(1-6C)alkyl esters such as cyclopentylcarbonyloxymethyl and 1-cyclohexylcarbonyloxyethyl esters, 2- oxo-1 ,3-dioxolenylmethyl esters such as 5-methyl-2-oxo-1 ,3-dioxolen-4-ylmethyl esters and (1-6C)alkoxycarbonyloxy-(1-6C)alkyl esters such as methoxycarbonyloxymethyl and 1- methoxycarbonyloxyethyl esters.
  • a suitable pharmaceutically acceptable pro-drug of a compound of the Formula (I), or sub-formulae la to In, that possesses a hydroxy group is, for example, an in vivo cleavable ester or ether thereof.
  • An in vivo cleavable ester or ether of a compound of the Formula (I), or sub-formulae la to In, containing a hydroxy group is, for example, a pharmaceutically acceptable ester or ether which is cleaved in the human or animal body to produce the parent hydroxy compound.
  • Suitable pharmaceutically acceptable ester forming groups for a hydroxy group include inorganic esters such as phosphate esters (including phosphoramidic cyclic esters).
  • ester forming groups for a hydroxy group include (1-10C)alkanoyl groups such as acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups, (1-10C)alkoxycarbonyl groups such as ethoxycarbonyl, N,N-(1-6C) 2 carbamoyl, 2-dialkylaminoacetyl and 2-carboxyacetyl groups.
  • Suitable pharmaceutically acceptable ether forming groups for a hydroxy group include a-acyloxyalkyl groups such as acetoxymethyl and pivaloyloxymethyl groups.
  • a suitable pharmaceutically acceptable pro-drug of a compound of the Formula (I), or sub-formulae la to In, that possesses a carboxy group is, for example, an in vivo cleavable amide thereof, for example an amide formed with an amine such as ammonia, a (1- 4C)alkylamine such as methylamine, a [(1-4C)alkyl] 2 amine such as dimethylamine, N-ethyl-N- methylamine or diethylamine, a (1-4C)alkoxy-(2-4C)alkylamine such as 2-methoxyethylamine, a phenyl-(1-4C)alkylamine such as benzylamine and amino acids such as glycine or an ester thereof.
  • an amine such as ammonia
  • a (1- 4C)alkylamine such as methylamine
  • a [(1-4C)alkyl] 2 amine such as dimethylamine, N-ethyl-N
  • a suitable pharmaceutically acceptable pro-drug of a compound of the Formula (I), or sub-formulae la to In, that possesses an amino group is, for example, an in vivo cleavable amide derivative thereof.
  • Suitable pharmaceutically acceptable amides from an amino group include, for example an amide formed with (1-10C)alkanoyl groups such as an acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups.
  • Examples of ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N- dialkylaminomethyl, morpholinomethyl, pi perazin-1-yl methyl and
  • the in vivo effects of a compound of the Formula (I), or sub-formulae la to In may be exerted in part by one or more metabolites that are formed within the human or animal body after administration of a compound of the Formula (I), or sub-formulae la to In.
  • the in vivo effects of a compound of the Formula (I), or sub-formulae la to In may also be exerted by way of metabolism of a precursor compound (a pro-drug).
  • the present invention may relate to any compound or particular group of compounds defined herein by way of optional, preferred or suitable features or otherwise in terms of particular embodiments, the present invention may also relate to any compound or particular group of compounds that specifically excludes said optional, preferred or suitable features or particular embodiments.
  • the present invention excludes any individual compounds not possessing the biological activity defined herein.
  • the compounds of the present invention can be prepared by any suitable technique known in the art. Particular processes for the preparation of these compounds are described further in the accompanying examples.
  • protecting groups see one of the many general texts on the subject, for example,‘Protective Groups in Organic Synthesis’ by Theodora Green (publisher: John Wiley & Sons).
  • Protecting groups may be removed by any convenient method described in the literature or known to the skilled chemist as appropriate for the removal of the protecting group in question, such methods being chosen so as to effect removal of the protecting group with the minimum disturbance of groups elsewhere in the molecule.
  • reactants include, for example, groups such as amino, carboxy or hydroxy it may be desirable to protect the group in some of the reactions mentioned herein.
  • a suitable protecting group for an amino or alkylamino group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an alkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl or t-butoxycarbonyl group, an arylmethoxycarbonyl group, for example benzyloxycarbonyl, or an aroyl group, for example benzoyl.
  • the deprotection conditions for the above protecting groups necessarily vary with the choice of protecting group.
  • an acyl group such as an alkanoyl or alkoxycarbonyl group or an aroyl group may be removed by, for example, hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
  • a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
  • an acyl group such as a ferf-butoxycarbonyl group may be removed, for example, by treatment with a suitable acid as hydrochloric, sulfuric or phosphoric acid or trifluoroacetic acid and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon, or by treatment with a Lewis acid for example boron tris(trifluoroacetate).
  • a suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group which may be removed by treatment with an alkylamine, for example dimethylaminopropylamine, or with hydrazine.
  • a suitable protecting group for a hydroxy group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an aroyl group, for example benzoyl, or an arylmethyl group, for example benzyl.
  • the deprotection conditions for the above protecting groups will necessarily vary with the choice of protecting group.
  • an acyl group such as an alkanoyl or an aroyl group may be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium, sodium hydroxide or ammonia.
  • a suitable base such as an alkali metal hydroxide, for example lithium, sodium hydroxide or ammonia.
  • an arylmethyl group such as a benzyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.
  • a suitable protecting group for a carboxy group is, for example, an esterifying group, for example a methyl or an ethyl group which may be removed, for example, by hydrolysis with a base such as sodium hydroxide, or for example a t-butyl group which may be removed, for example, by treatment with an acid, for example an organic acid such as trifluoroacetic acid, or for example a benzyl group which may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.
  • a base such as sodium hydroxide
  • a t-butyl group which may be removed, for example, by treatment with an acid, for example an organic acid such as trifluoroacetic acid, or for example a benzyl group which may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.
  • Resins may also be used as a protecting group.
  • the compounds of Formula (I) may be synthesised by the general synthetic routes shown in Schemes 1 to 12 in the Examples section below, specific examples of which are described in more detail in the Examples.
  • the compounds of the invention demonstrate an ICso of 10 mM or less in the SGK3 TR-FRET assay described in the Examples section.
  • Preferred compounds of the invention demonstrate an IC 50 of 1 mM or less, or an IC 50 of 100 nM or less.
  • the most preferred compounds of the invention demonstrate an IC 50 of 10 nM or less in the SGK3 TR-FRET assay.
  • the compounds of the invention demonstrate an IC 50 of 10 mM or less in the SGK1 TR-FRET assay described in the Examples section.
  • Preferred compounds of the invention demonstrate an IC 50 of 5 mM or less.
  • the most preferred compounds of the invention demonstrate an IC 50 of 1 mM or less in the SGK1 TR-FRET assay.
  • the compounds of the invention demonstrate an IC5 0 of 10 mM or less in the SGK2 Radiometric assay described in the Examples section.
  • Preferred compounds of the invention demonstrate an IC5 0 of 1 mM or less.
  • the most preferred compounds of the invention demonstrate an IC5 0 of 100 nM or less in the SGK2 Radiometric assay.
  • preferred compounds of the invention demonstrate an IC5 0 of 100 nM or less in the SGK2 Radiometric assay and 1 pM or less in the SGK1 and SGK3 Radiometric assays.
  • the compounds of the invention as defined hereinbefore also includes the compounds 3-amino-N-(1 -benzyl-1 H- pyrazol-4-yl)pyrazine-2-carboxamide and 2-amino-N-(1-benzyl-1 H-pyrazol-4-yl)nicotinamide.
  • a pharmaceutical composition which comprises a compound of the invention as defined hereinbefore, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in association with a pharmaceutically acceptable diluent or carrier.
  • compositions of the invention may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular dosing or as a suppository for rectal dosing).
  • oral use for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or
  • compositions of the invention may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art.
  • compositions intended for oral use may contain, for example, one or more colouring, sweetening, flavouring and/or preservative agents.
  • An effective amount of a compound of the present invention for use in therapy is an amount sufficient to treat or prevent a proliferative condition referred to herein, slow its progression and/or reduce the symptoms associated with the condition.
  • a formulation intended for oral administration to humans will generally contain, for example, from 0.5 mg to 0.5 g of active agent (more suitably from 0.5 to 100 mg, for example from 1 to 30 mg) compounded with an appropriate and convenient amount of excipients which may vary from about 5 to about 98 percent by weight of the total composition.
  • the size of the dose for therapeutic or prophylactic purposes of a compound of the formula I will naturally vary according to the nature and severity of the conditions, the age and sex of the animal or patient and the route of administration, according to well-known principles of medicine.
  • a daily dose in the range for example, 0.1 mg/kg to 75 mg/kg body weight is received, given if required in divided doses.
  • a parenteral route is employed.
  • a dose in the range for example, 0.1 mg/kg to 30 mg/kg body weight will generally be used.
  • a dose in the range for example, 0.05 mg/kg to 25 mg/kg body weight will be used.
  • Oral administration may also be suitable, particularly in tablet form.
  • unit dosage forms will contain about 0.5 mg to 0.5 g of a compound of this invention.
  • the compounds of the invention as defined hereinbefore also includes the compounds 3-amino-N-(1 -benzyl-1 H- pyrazol-4-yl) pyrazine-2-carboxamide and 2-amino-N-(1-benzyl-1 H-pyrazol-4-yl)nicotinamide.
  • the present invention provides compounds that function as inhibitors of SGK activity.
  • the present invention therefore provides a method of inhibiting SGK activity in vitro or in vivo, said method comprising contacting a cell with an effective amount of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein.
  • the present invention also provides a method of treating a disease or disorder in which SGK activity is implicated in a patient in need of such treatment, said method comprising administering to said patient a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein.
  • the present invention provides a method of inhibiting cell proliferation or for regulating electrolyte balance in renal and/or cardiovascular disease, in vitro or in vivo, said method comprising contacting a cell with an effective amount of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein.
  • the present invention provides a method of treating a proliferative disorder or for regulating electrolyte balance in renal and/or cardiovascular disease in a patient in need of such treatment, said method comprising administering to said patient a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein.
  • the present invention provides a method of treating cancer or for regulating electrolyte balance in renal and/or cardiovascular disease in a patient in need of such treatment, said method comprising administering to said patient a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein.
  • the present invention provides a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein for use in therapy.
  • the present invention provides a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein for use in the treatment of a proliferative condition or for regulating electrolyte balance in renal and/or cardiovascular disease.
  • the present invention provides a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein for use in the treatment of cancer or for regulating electrolyte balance in renal and/or cardiovascular disease.
  • the cancer is human cancer, in particular oestrogen positive cancers, such as breast cancer, or androgen receptor positive cancers, such as prostate cancer.
  • the present invention provides a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, for use in the inhibition of SGK activity.
  • a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, for use in the inhibition of SGK1 , SGK2 and/or SGK3 activity Preferably, there is provided a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, for use in the inhibition of SGK1 and/or SGK3 activity; most preferably, for use in the inhibition of SGK3 activity.
  • the present invention provides a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein for use in the treatment of a disease or disorder in which SGK activity is implicated.
  • the present invention provides a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein for use in the treatment of a disease or disorder in which SGK3 activity is implicated.
  • the present invention provides a use of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein in the manufacture of a medicament for the treatment of a proliferative condition or for regulating electrolyte balance in renal and/or cardiovascular disease.
  • the present invention provides a use of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein in the manufacture of a medicament for the treatment of cancer or for regulating electrolyte balance in renal and/or cardiovascular disease.
  • the medicament is for use in the treatment of human cancers, in particular oestrogen positive cancers, such as breast cancer, or androgen receptor positive cancers, such as prostate cancer.
  • the present invention provides a use of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein in the manufacture of a medicament for the inhibition of SGK (such as SGK3) activity.
  • the present invention provides a use of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein in the manufacture of a medicament for the treatment of a disease or disorder in which SGK (such as SGK3) activity is implicated.
  • SGK such as SGK3
  • proliferative disorder and “proliferative condition” are used interchangeably herein and pertain to an unwanted or uncontrolled cellular proliferation of excessive or abnormal cells which is undesired, such as, neoplastic or hyperplastic growth, whether in vitro ox in vivo.
  • proliferative conditions include, but are not limited to, pre-malignant and malignant cellular proliferation, including but not limited to, malignant neoplasms and tumours, cancers (including breast cancer, non-small cell lung cancer (NSCLC) and squamous cell carcinomas (SCC) (including SCC of the head and neck, oesophagus, lung and ovary), leukemias (including acute lymphoblastic leukaemia (ALL) and chronic myeloid leukaemia (CML)), lymphomas (including acute lymphoblastic leukaemia (ALL) and chronic myeloid leukaemia (CML)), psoriasis, bone diseases, fibroprol iterative disorders (e.g., of connective tissues), and atherosclerosis.
  • Any type of cell may be treated, including but not limited to, lymphatic, blood, lung, colon, breast, ovarian, prostate, liver, pancreas, brain, and skin.
  • the anti-cancer effect may arise through one or more mechanisms, including but not limited to, the regulation of cell proliferation, the inhibition of angiogenesis (the formation of new blood vessels), the inhibition of metastasis (the spread of a tumour from its origin), the inhibition of invasion (the spread of tumour cells into neighbouring normal structures), or the promotion of apoptosis (programmed cell death).
  • Examples of conditions for regulating electrolyte balance in renal and/or cardiovascular disease include, but are not limited to, high blood pressure or hypertension.
  • the compound of Formula (I), or a pharmaceutically acceptable salt thereof, being an inhibitor of SGK (in particular SGK3), has potential therapeutic uses in a variety of SGK- mediated disease states.
  • a method for treating cancers such as breast cancer and prostate cancer in a warm-blooded animal, such as man, that is in need of such treatment which comprises administering an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as defined hereinbefore.
  • a method for treating oestrogen receptor-positive (ER+) breast cancer or androgen receptor positive (AR+) prostate cancer in a warm-blooded animal, such as man, that is in need of such treatment which comprises administering an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as defined hereinbefore.
  • the compounds of the invention as defined hereinbefore also includes the compounds 3-amino-N-(1 -benzyl-1 H-pyrazol-4- yl)pyrazine-2-carboxamide and 2-amino-N-(1-benzyl-1 H-pyrazol-4-yl)nicotinamide.
  • the compounds of the invention or pharmaceutical compositions comprising these compounds may be administered to a subject by any convenient route of administration, whether systemically, peripherally or topically (i.e., at the site of desired action).
  • Routes of administration include, but are not limited to, oral (e.g, by ingestion); buccal; sublingual; transdermal (including, e.g. , by a patch, plaster, etc.); transmucosal (including, e.g., by a patch, plaster, etc.); intranasal (e.g., by nasal spray); ocular (e.g., by eye drops); pulmonary (e.g., by inhalation or insufflation therapy using, e.g., via an aerosol, e.g., through the mouth or nose); rectal (e.g., by suppository or enema); vaginal (e.g., by pessary); parenteral, for example, by injection, including subcutaneous, intradermal, intramuscular, intravenous, intra-arterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, sub
  • the compounds of the invention as defined hereinbefore also includes the compounds 3-amino-N-(1 -benzyl-1 H-pyrazol-4- yl)pyrazine-2-carboxamide and 2-amino-N-(1-benzyl-1 H-pyrazol-4-yl)nicotinamide.
  • the antiproliferative treatment defined hereinbefore may be applied as a sole therapy or may involve, in addition to the compound of the invention, conventional surgery or radiotherapy or chemotherapy.
  • Such chemotherapy may include one or more of the following categories of anti-tumour agents:-
  • antiproliferative/antineoplastic drugs and combinations thereof as used in medical oncology, such as alkylating agents (for example cis-platin, oxaliplatin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulphan, temozolamide and nitrosoureas); antimetabolites (for example gemcitabine and antifolates such as fluoropyrimidines like 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosine arabinoside, and hydroxyurea); antitumour antibiotics (for example anthracyclines like adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin and mithramycin); antimitotic agents (for example vinca alkaloids like vincristine, vinblast
  • cytostatic agents such as antioestrogens (for example tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene and iodoxyfene), antiandrogens (for example bicalutamide, flutamide, nilutamide and cyproterone acetate), LHRH antagonists or LHRH agonists (for example goserelin, leuprorelin and buserelin), steroid hormones, including progestogens (for example megestrol acetate) and corticosteroids (for example dexamethasone, prednisone and prednisolone), aromatase inhibitors (for example as anastrozole, letrozole, vorazole and exemestane) and inhibitors of 5a-reductase such as finasteride;
  • antioestrogens for example tamoxifen, fulvestrant, toremif
  • anti-invasion agents for example c-Src kinase family inhibitors like 4-(6-chloro-2,3- methylenedioxyanilino)-7-[2-(4-methylpiperazin-1-yl)ethoxy]-5-tetrahydropyran-4- yloxyquinazoline (AZD0530; International Patent Application WO 01/94341), A/-(2-chloro-6- methylphenyl)-2- ⁇ 6-[4-(2-hydroxyethyl)piperazin-1-yl]-2-methylpyrimidin-4-ylamino ⁇ thiazole- 5-carboxamide (dasatinib, BMS-354825; J. Med.
  • anti-invasion agents for example c-Src kinase family inhibitors like 4-(6-chloro-2,3- methylenedioxyanilino)-7-[2-(4-methylpiperazin-1-yl)ethoxy]-5-tetrahydropyran
  • inhibitors of growth factor function include growth factor antibodies and growth factor receptor antibodies (for example the anti-erbB2 antibody trastuzumab [HerceptinTM], the anti-EGFR antibody panitumumab, the anti-erbB1 antibody cetuximab [Erbitux, C225] and any growth factor or growth factor receptor antibodies disclosed by Stern et al. (Critical reviews in oncology/haematology, 2005, Vol.
  • inhibitors also include tyrosine kinase inhibitors, for example inhibitors of the epidermal growth factor family (for example EGFR family tyrosine kinase inhibitors such as /V-(3-chloro-4- fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine (gefitinib, ZD1839), N- (3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine (erlotinib, OSI-774) and 6- acrylamido-/V-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)-quinazolin-4-amine (Cl 1033), erbB2 tyrosine kinase inhibitors such as lapatinib); inhibitors of the hepatocyte growth factor family; inhibitors of the epidermal growth factor family (for
  • antiangiogenic agents such as those which inhibit the effects of vascular endothelial growth factor, [for example the anti-vascular endothelial cell growth factor antibody bevacizumab (AvastinTM) and for example, a VEGF receptor tyrosine kinase inhibitor such as vandetanib (ZD6474), vatalanib (PTK787), sunitinib (SU 11248), axitinib (AG-013736), pazopanib (GW 786034) and 4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(3-pyrrolidin-1- ylpropoxy)quinazoline (AZD2171 ; Example 240 within WO 00/47212), compounds such as those disclosed in International Patent Applications W097/22596, WO 97/30035, WO 97/32856 and WO 98/13354 and compounds that work by other mechanisms (for example linomide
  • vascular damaging agents such as Combretastatin A4 and compounds disclosed in International Patent Applications WO 99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO 02/04434 and WO 02/08213;
  • an endothelin receptor antagonist for example zibotentan (ZD4054) or atrasentan;
  • antisense therapies for example those which are directed to the targets listed above, such as ISIS 2503, an anti-ras antisense;
  • (ix) gene therapy approaches including for example approaches to replace aberrant genes such as aberrant p53 or aberrant BRCA1 or BRCA2, GDEPT (gene-directed enzyme pro-drug therapy) approaches such as those using cytosine deaminase, thymidine kinase or a bacterial nitroreductase enzyme and approaches to increase patient tolerance to chemotherapy or radiotherapy such as multi-drug resistance gene therapy; and
  • GDEPT gene-directed enzyme pro-drug therapy
  • (x) immunotherapy approaches including for example ex-vivo and in-vivo approaches to increase the immunogenicity of patient tumour cells, such as transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor, approaches to decrease T-cell anergy, approaches using transfected immune cells such as cytokine-transfected dendritic cells, approaches using cytokine-transfected tumour cell lines and approaches using anti-idiotypic antibodies.
  • cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor
  • Estrogen binds to the ER with high affinity and specificity and functions through two main types of pathways, the classical (or nuclear) pathway and the alternative (nonnuclear) pathway. Successful targeting of genes within these nuclear and nonnuclear pathways has led to a number of agents for patients with early, advanced, or metastatic BC.
  • serum and glucocorticoid regulated kinase (SGK) inhibitors will, in particular, also have application in combination with agents such as: Selective estrogen receptor modulators (SERMs), such as Tamoxifen and Toremifene; Aromatase inhibitors (Als), such as nonsteroidal aromatase inhibitors: Anastrozole, Fadrozole and Letrozole; and Steroidal aromatase inhibitor such as Exemestane; Selective estrogen receptor degrader (SERDs), such as Fulvestrant, Elacestrant and GDC-0810; Inhibitors of the phosphatidylinositol 3 kinase (PI3K), such as Buparlisib, Apitolisib, AZD8186, Omipalisib, Duvelisib, Gedatolisib, Copanlisib, Pictilisib, Alpelisib, Idelalisib, A
  • AR androgen receptor
  • the AR axis is an essential player in prostate cancer. Blocking AR function directly or indirectly or through targeting of genes within the nuclear and non-nuclear pathways and targeting growth-promoting and survival pathways that interact with AR signaling has led to a number of agents for patients with early, advanced, or metastatic prostate cancer.
  • serum and glucocorticoid regulated kinase (SGK) inhibitors will, in particular, also have application in combination with agents such as: direct AR antagonists such as Bicalutamide, Enzalutamide, Apalutamide, Darolutamide; non-competitive AR antagonists such as ralaniten acetate (EPI-506); Indirect AR blockers such as steroid synthesis inhibitors such as Abiraterone acetate; selective androgen receptor degrader or downregulator (SARDs) and Induced androgen receptor protein degradation such as proteolysis- targeting chimaeras (PROTACs); Signaling Pathway Inhibitors such as Inhibitors of the phosphatidylinositol 3 kinase (PI3K), such as Buparlisib, Apitolisib, AZD8186, Omipalisib, Duvelisib, Gedatolisib, Copanlisib, Pict
  • the antiproliferative treatment defined hereinbefore may involve, in addition to the compound of the invention, conventional surgery or radiotherapy or chemotherapy, wherein the chemotherapy may include one or more anti-tumour agents selected from cyclophosphamide, epirubicin, fluorouracil, methotrexate, mitomycin C, doxorubicin, gemcitabine, docetaxel, carbazitaxel and radium-223 dichloride.
  • the chemotherapy may include one or more anti-tumour agents selected from cyclophosphamide, epirubicin, fluorouracil, methotrexate, mitomycin C, doxorubicin, gemcitabine, docetaxel, carbazitaxel and radium-223 dichloride.
  • the antiproliferative treatment defined hereinbefore may involve, in addition to the compound of the invention, conventional surgery or radiotherapy or chemotherapy, wherein the chemotherapy may include one or more anti- hormonal agents selected from a selective estrogen receptor modulator (SERM) (e.g. tamoxifen or toremifene), a aromatase inhibitor (Al) (e.g. anastrozole, fadrozole, letrozole or exemestane), a selective estrogen receptor degrader (SERD) (e.g. fulvestrant, elacestrant or GDC-0810), a luteinising hormone (LH) blocker (e.g.
  • SERM selective estrogen receptor modulator
  • Al aromatase inhibitor
  • SESD selective estrogen receptor degrader
  • LH luteinising hormone
  • goserelin direct androgen receptor (AR) antagonist
  • AR direct androgen receptor
  • AR direct androgen receptor
  • a non-competitive AR antagonist e.g. ralaniten acetate
  • a androgen steroid synthesis inhibitor e.g. abiraterone acetate
  • GNRH gonadotropin-releasing hormone
  • the antiproliferative treatment defined hereinbefore may involve, in addition to the compound of the invention, conventional surgery or radiotherapy or chemotherapy, wherein the chemotherapy may include one or cell-cycle agents selected from a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor (e.g. palbociclib, ribociclib or abemaciclib).
  • CDK4/6 cyclin-dependent kinase 4/6
  • the antiproliferative treatment defined hereinbefore may involve, in addition to the compound of the invention, conventional surgery or radiotherapy or chemotherapy, wherein the chemotherapy may include one or DNA damage response agents agents selected from a poly ADP ribose polymerase (PARP) inhibitor (e.g. olaparib, veliparib, rucaparib or niraparib).
  • PARP poly ADP ribose polymerase
  • the antiproliferative treatment defined hereinbefore may involve, in addition to the compound of the invention, conventional surgery or radiotherapy or chemotherapy, wherein the chemotherapy may include one or cell signalling agent selected from a phosphatidylinositol 3 kinase (PI3K) inhibitor , (e.g. PI3K) inhibitor , (e.g. PI3K) inhibitor , (e.g. PI3K) inhibitor , (e.g.
  • PI3K phosphatidylinositol 3 kinase
  • buparlisib apitolisib, azd8186, omipalisib, duvelisib, gedatolisib, copanlisib, pictilisib, alpelisib, idelalisib, acalisib, serabelisib, pilaralisib or taselisib
  • an AKT inhibitor e.g. MK2206, AZD5363, afuresertib, AT13148, miransertib or ipatasertib
  • a (mTOR) signaling pathway inhibitor e.g.
  • everolimus sirolimus, temsirolimus, vistusertib, sapanisertib or ridaforolimus
  • FGF Fibroblast growth factor
  • the antiproliferative treatment defined hereinbefore may involve, in addition to the compound of the invention, conventional surgery or radiotherapy or chemotherapy, wherein the chemotherapy may include one or more anti-tumour agents selected from procarbazine, carmustine, lomustine, irinotecan, temozolomide, cisplatin, carboplatin, methotrexate, etoposide, cyclophosphamide, ifosfamide, and vincristine.
  • the chemotherapy may include one or more anti-tumour agents selected from procarbazine, carmustine, lomustine, irinotecan, temozolomide, cisplatin, carboplatin, methotrexate, etoposide, cyclophosphamide, ifosfamide, and vincristine.
  • the antiproliferative treatment defined hereinbefore may involve, in addition to the compound of the invention, conventional surgery or radiotherapy or chemotherapy, wherein the chemotherapy may include one or more chemotherapeutic agents selected from a BCL-2 family inhibitor (e.g. Venetoclax and/or navitoclax), a BTK inhibitor (e.g. Ibrutinib, Acalabrutinib, Tirabrutinib (ONO/GS-4059), BGB- 31 11 or Spebrutinib (CC-292) or a TNF inhibitor (e.g. Lenalidomide).
  • a BCL-2 family inhibitor e.g. Venetoclax and/or navitoclax
  • a BTK inhibitor e.g. Ibrutinib, Acalabrutinib, Tirabrutinib (ONO/GS-4059
  • BGB- 31 11 or Spebrutinib CC-292
  • TNF inhibitor e.g. Lenalidomide
  • Such conjoint treatment may be achieved by way of the simultaneous, sequential or separate dosing of the individual components of the treatment.
  • Such combination products employ the compounds of this invention within the dosage range described hereinbefore and the other pharmaceutical ly-active agent within its approved dosage range.
  • a combination for use in the treatment of a cancer comprising a compound of the invention as defined hereinbefore, or a pharmaceutically acceptable salt, hydrate or solvate thereof, and another anti-tumour agent.
  • a combination for use in the treatment of a proliferative condition such as cancer (for example a cancer involving a solid tumour), comprising a compound of the invention as defined hereinbefore, or a pharmaceutically acceptable salt, hydrate or solvate thereof, and any one of the anti-tumour agents listed herein above.
  • a combination for use in the treatment of a cancer comprising a compound of the invention as defined hereinbefore, or a pharmaceutically acceptable salt, hydrate or solvate thereof, and a tyrosine kinase inhibitor.
  • a combination for use in the treatment of leukaemia comprising a compound of the invention as defined hereinbefore, or a pharmaceutically acceptable salt, hydrate or solvate thereof, and a tyrosine kinase inhibitor.
  • a compound of the invention or a pharmaceutically acceptable salt, hydrate or solvate thereof for use in the treatment of cancer in combination with a tyrosine kinase inhibitor, optionally selected from one listed herein above.
  • a compound of the invention or a pharmaceutically acceptable salt, hydrate or solvate thereof for use in the treatment of leukaemia (such as ALL or CML) in combination with a tyrosine kinase inhibitor, optionally selected from one listed herein above.
  • leukaemia such as ALL or CML
  • tyrosine kinase inhibitor optionally selected from one listed herein above.
  • a pharmaceutical composition which comprises a compound of the invention, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in combination with an anti-tumour agent (optionally selected from one listed herein above), in association with a pharmaceutically acceptable diluent or carrier.
  • Preparative HPLC purification was performed by reverse phase HPLC using a Waters Fractionlynx preparative HPLC system (2525 pump, 2996/2998 UV/VIS detector, 2767 liquid handler) or an equivalent HPLC system such as a Gilson Trilution UV directed system.
  • the Waters 2767 liquid handler acted as both auto-sampler and fraction collector.
  • the columns used for the preparative purification of the compounds were a Waters Sunfire OBD Phenomenex Luna Phenyl Hexyl or Waters Xbridge Phenyl at 10 pm 19 c 150 mm or Waters CSH Phenyl Hexyl, 19 c 150, 5 pm column.
  • Appropriate focused gradients were selected based on acetonitrile and methanol solvent systems under either acidic or basic conditions.
  • the modifiers used under acidic/basic conditions were formic acid or trifluoroacetic acid (0.1 % V/V) and ammonium bicarbonate (10 mM) respectively.
  • the purification was controlled by Waters Fractionlynx software through monitoring at 210-400 nm, and triggered a threshold collection value at 260 nm and, when using the Fractionlynx, the presence of target molecular ion as observed under API conditions. Collected fractions were analysed by LCMS (Waters Acquity systems with Waters SQD).
  • the modifier used under acidic conditions was either formic acid (0.1 % V/V) or trifluoroacetic acid (0.1% V/V).
  • the SFC purification was controlled by Waters Fractionlynx software through monitoring at 210-400 nm and triggered at a threshold collection value, typically 260 nm. Collected fractions were analysed by SFC (Waters/Thar SFC systems with Waters SQD). The fractions that contained the desired product were concentrated by vacuum centrifugation.

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Abstract

La présente invention concerne des composés de formule (I) qui fonctionnent en tant qu'inhibiteurs de l'activité de la kinase sérique et régulée par les glucocorticoïdes (SGK) : formule (I) dans laquelle X1, X2, Y1, Y2, Y3, Y4, R2, R3, Y et Z sont tels que définis dans la description. La présente invention concerne également des procédés de préparation de ces composés, des compositions pharmaceutiques les comprenant et leur utilisation dans le traitement de troubles prolifératifs, tels que le cancer, ainsi que d'autres maladies ou affections dans lesquelles l'activité de SGK est impliquée.
PCT/GB2020/050957 2019-04-15 2020-04-15 Composés à titre d'inhibiteurs WO2020212697A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115819330A (zh) * 2022-12-28 2023-03-21 天津均凯农业科技有限公司 一种连续化制备2-氨基甲基-3-氯-5-三氟甲基吡啶的方法

Citations (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997022596A1 (fr) 1995-12-18 1997-06-26 Zeneca Limited Derives de quinazoline
WO1997030035A1 (fr) 1996-02-13 1997-08-21 Zeneca Limited Derives de la quinazoline utilises comme inhibiteurs du vegf
WO1997032856A1 (fr) 1996-03-05 1997-09-12 Zeneca Limited Derives de 4-anilinoquinazoline
WO1998013354A1 (fr) 1996-09-25 1998-04-02 Zeneca Limited Derives quinazolines et compositions pharmaceutiques les contenant
WO1999002166A1 (fr) 1997-07-08 1999-01-21 Angiogene Pharmaceuticals Ltd. Utilisation de derives de colchinol comme agents de degradation vasculaire
WO2000040529A1 (fr) 1999-01-07 2000-07-13 Angiogene Pharmaceuticals Ltd. Derives de colchinol utilises comme agents de degradation vasculaire
WO2000041669A2 (fr) 1999-01-15 2000-07-20 Angiogene Pharmaceuticals Ltd. Agents de degradation vasculaire aux benzimidazoles
WO2000047212A1 (fr) 1999-02-10 2000-08-17 Astrazeneca Ab Derives de quinazoline utilises comme inhibiteurs de l'angiogenese
WO2001092224A1 (fr) 2000-05-31 2001-12-06 Astrazeneca Ab Derives d'indole possedant une activite endommageant les vaisseaux sanguins
WO2001094341A1 (fr) 2000-06-06 2001-12-13 Astrazeneca Ab Derives de la quinazoline pour le traitement de tumeurs
WO2002004434A1 (fr) 2000-07-07 2002-01-17 Angiogene Pharmaceuticals Limited Derives de colchinol utilises comme agents de degradation vasculaire
WO2002008213A1 (fr) 2000-07-07 2002-01-31 Angiogene Pharmaceuticals Limited Derives de colchinol utiles comme inhibiteurs de l'angiogenese
DE102007002717A1 (de) * 2007-01-18 2008-07-24 Merck Patent Gmbh Heterocyclische Indazolderivate
WO2017039331A1 (fr) * 2015-08-31 2017-03-09 Dong-A Socio Holdings Co., Ltd. Composés hétéroaryle et leur utilisation comme médicaments thérapeutiques

Patent Citations (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997022596A1 (fr) 1995-12-18 1997-06-26 Zeneca Limited Derives de quinazoline
WO1997030035A1 (fr) 1996-02-13 1997-08-21 Zeneca Limited Derives de la quinazoline utilises comme inhibiteurs du vegf
WO1997032856A1 (fr) 1996-03-05 1997-09-12 Zeneca Limited Derives de 4-anilinoquinazoline
WO1998013354A1 (fr) 1996-09-25 1998-04-02 Zeneca Limited Derives quinazolines et compositions pharmaceutiques les contenant
WO1999002166A1 (fr) 1997-07-08 1999-01-21 Angiogene Pharmaceuticals Ltd. Utilisation de derives de colchinol comme agents de degradation vasculaire
WO2000040529A1 (fr) 1999-01-07 2000-07-13 Angiogene Pharmaceuticals Ltd. Derives de colchinol utilises comme agents de degradation vasculaire
WO2000041669A2 (fr) 1999-01-15 2000-07-20 Angiogene Pharmaceuticals Ltd. Agents de degradation vasculaire aux benzimidazoles
WO2000047212A1 (fr) 1999-02-10 2000-08-17 Astrazeneca Ab Derives de quinazoline utilises comme inhibiteurs de l'angiogenese
WO2001092224A1 (fr) 2000-05-31 2001-12-06 Astrazeneca Ab Derives d'indole possedant une activite endommageant les vaisseaux sanguins
WO2001094341A1 (fr) 2000-06-06 2001-12-13 Astrazeneca Ab Derives de la quinazoline pour le traitement de tumeurs
WO2002004434A1 (fr) 2000-07-07 2002-01-17 Angiogene Pharmaceuticals Limited Derives de colchinol utilises comme agents de degradation vasculaire
WO2002008213A1 (fr) 2000-07-07 2002-01-31 Angiogene Pharmaceuticals Limited Derives de colchinol utiles comme inhibiteurs de l'angiogenese
DE102007002717A1 (de) * 2007-01-18 2008-07-24 Merck Patent Gmbh Heterocyclische Indazolderivate
WO2017039331A1 (fr) * 2015-08-31 2017-03-09 Dong-A Socio Holdings Co., Ltd. Composés hétéroaryle et leur utilisation comme médicaments thérapeutiques

Non-Patent Citations (79)

* Cited by examiner, † Cited by third party
Title
"Bioreversible Carriers in Drug Design", 1987, PERGAMON PRESS
"Methods in Enzymology", vol. 42, 1985, ACADEMIC PRESS, pages: 309 - 396
ALONSO, L. ET AL.: "Sgk3 links growth factor signaling to maintenance of progenitor cells in the hair follicle", J CELL BIOL, vol. 170, no. 4, 2005, pages 559 - 70
BAGO, R. ET AL.: "Characterization ofVPS34-IN1, a selective inhibitor of Vps34, reveals that the phosphatidylinositol 3-phosphate-binding S G K3 protein kinase is a downstream target of class III phosphoinositide 3-kinase", BIOCHEMJ, vol. 463, no. 3, 2014, pages 413 - 27, XP055379959, DOI: 10.1042/BJ20140889
BASNET, RAJESH ET AL.: "S erum and glucocorticoid inducible protein kinases (S G Ks): a potential target for cancer intervention", ACTA PHARMACEUTICA SINICA B, 2018
BOEHMER, CHRISTOPH ET AL.: "Regulation of the excitatory amino acid transporter EAAT5 by the serum and glucocorticoid dependent kinases SG K1 and S G K3", BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, vol. 329.2, 2005, pages 738 - 742, XP004767157, DOI: 10.1016/j.bbrc.2005.02.035
BOEHMER, CHRISTOPH ET AL.: "S erum and glucocorticoid inducible kinases in the regulation of the cardiac sodium channel S C N5A", CARDIOVASCULAR RESEARCH, vol. 57.4, 2003, pages 1079 - 1084
BRUFSKY, THE ONCOLOGIST, 2018
BRUHN, MARESSA A. ET AL.: "Second AKT: the rise of SGK in cancer signalling", GROWTH FACTORS, vol. 28.6, 2010, pages 394 - 408
BUSJAHN, ANDREAS ET AL.: "Serum-and glucocorticoid-regulated kinase (SGK1) gene and blood pressure", HYPERTENSION, vol. 40.3, 2002, pages 256 - 260, XP008016812, DOI: 10.1161/01.HYP.0000030153.19366.26
BUTTERWORTH, MICHAEL B.: "Regulation of the epithelial sodium channel (E NaC) by membrane trafficking", BIOCHIMICA ET BIOPHYSICA ACTA (BBA)-MOLECULAR BASIS OF DISEASE, vol. 1802.12, 2010, pages 1166 - 1177, XP027446153, DOI: 10.1016/j.bbadis.2010.03.010
BΓDHMER, C. ET AL.: "Regulation of the epithelial calcium channel TRPV6 by the serum and glucocorticoid inducible kinase isoforms S G K1 and S G K3", F E BS LETTERS, vol. 581.29, 2007, pages 5586 - 5590
BΓDHMER, CHRISTOPH ET AL.: "The serum and glucocorticoid inducible kinases SG K1-3 stimulate the neutral amino acid transporter S LC6A19", CELLULAR PHYSIOLOGY AND BIOCHEMISTRY, vol. 25.6, 2010, pages 723 - 732
CASTEL, PAU ET AL.: "PDK1-SGK1 signaling sustains AKT-independentmTORC1 activation and confers resistance to PI3K inhibition", CANCER CELL, vol. 30.2, 2016, pages 229 - 242, XP029678738, DOI: 10.1016/j.ccell.2016.06.004
CHEMICAL ABSTRACTS, Columbus, Ohio, US; abstract no. 1398705-01 - 5
CHI, MENG NA ET AL.: "NPP4B is upregulated and functions as an oncogenic driver through SG K3 in a subset of melanomas", ONCOTARGET, vol. 6.37, 2015, pages 39891
DAI, FANGYAN ET AL.: "Human serum and glucocorticoid-inducible kinase-like kinase (SG KL) phosphorylates glycogen syntheses kinase 3 beta (GS K-3f ) at serine-9 through direct interaction", BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, vol. 293.4, 2002, pages 1191 - 1196, XP002308179, DOI: 10.1016/S0006-291X(02)00349-2
DATABASE REGISTRY [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; 19 December 2017 (2017-12-19), XP002799698, Database accession no. 2161104-76-1 *
DATABASE REGISTRY [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; 5 February 2016 (2016-02-05), XP002799697, Database accession no. 1860741-53-2 *
DATABASE REGISTRY [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; 7 July 2011 (2011-07-07), XP002799696, Database accession no. 1311628-86-0 *
DI CRISTOFANO, ANTONIO: "Current topics in developmental biology", vol. 123, 2017, ACADEMIC PRESS, article "SGK1: the dark side of PI3K signaling", pages: 49 - 71
DIETER, M. ET AL.: "Regulation of glucose transporter SGLT1 by ubiquitin ligase Nedd4-2 and kinases SGK1, SGK3, and PKB", OBES RES, vol. 12, no. 5, 2004, pages 862 - 70
EMBARK, HAMDY ET AL.: "Regulation of the epithelial Ca2+ channel TRPV5 by the NHE regulating factor NHE R F2 and the serum and glucocorticoid inducible kinase isoforms SG K1 and SGK3 expressed in Xenopus oocytes", CELLULAR PHYSIOLOGY AND BIOCHEMISTRY, vol. 14.4-6, 2004, pages 203 - 212
ENGELMAN, J EFFREY A: "Targeting PI3K signalling in cancer: opportunities, challenges and limitations", NATURE REVIEWS CANCER, vol. 9.8, 2009, pages 550
FARJAH, MARIAM ET AL.: "Dietary salt regulates renal SGK1 abundance: relevance to salt sensitivity in the Dahl rat", HYPERTENSION, vol. 41.4, 2003, pages 874 - 878
FIRESTONE, GARY ET AL.: "Stimulus-dependent regulation of serum and glucocorticoid inducible protein kinase (SGK) transcription, subcellular localization and enzymatic activity", CELLULAR PHYSIOLOGY AND BIOCHEMISTRY, vol. 13.1, 2003, pages 1 - 12
FRIEDRICH, BJORN ET AL.: "The serine/threonine kinases SGK2 and SGK3 are potent stimulators of the epithelial Na+ channel , f, .- E NaC", PFLAGERS ARCHIV, vol. 445.6, 2003, pages 693 - 696
GAMPER, N. ET AL.: "K+ channel activation by all three isoforms of serum-and glucocorticoid-dependent protein kinase S G K", PFLAGERS ARCHIV, vol. 445.1, 2002, pages 60 - 66
GASSER, J ESSICA A. ET AL.: "SGK3 mediates INPP4B-dependent PI3K signaling in breast cancer", MOLECULAR CELL, vol. 56.4, 2014, pages 595 - 607, XP055389816, DOI: 10.1016/j.molcel.2014.09.023
GRAHAMMER, FLORIAN ET AL.: "Renal function of gene-targeted mice lacking both SGK1 and SG K3", AMERICAN J OURNAL OF PHYSIOLOGY-REGULATORY, INTEGRATIVE AND COMPARATIVE PHYSIOLOGY, vol. 290.4, 2006, pages R945 - R950
GUO, S. T. ET AL.: "INPP4B is an oncogenic regulator in human colon cancer", ONCOGENE, vol. 35.23, 2016, pages 3049
H. BUNDGAARD ET AL., J OURNAL OF PHARMACEUTICAL SCIENCES, vol. 77, 1988, pages 285
H. BUNDGAARD, ADVANCED DRUG DELIVERY REVIEWS, vol. 8, 1992, pages 1 - 38
H. BUNDGAARD: "A Textbook of Drug Design and Development", 1991, article "Design and Application of Pro-drugs", pages: 113 - 191
HALL, BEN A. ET AL.: "Serum and glucocorticoid-regulated kinase 1 (SG K1) activation in breast cancer: requirement for mTOR C 1 activity associates with ER-alpha expression", BREAST CANCER RESEARCH AND TREATMENT, vol. 135.2, 2012, pages 469 - 479, XP035104478, DOI: 10.1007/s10549-012-2161-y
HARTMANN, S. ET AL.: "Highly recurrent mutations of SGK1, DUS P2 and J UNB in nodular lymphocyte predominant Hodgkin lymphoma", LEUKEMIA, vol. 30.4, 2016, pages 844
HEIKAMP, EMILY B. ET AL.: "The AGC kinase SGK1 regulates T H 1 and T H 2 differentiation downstream of the mTORC2 complex", NATURE IMMUNOLOGY, vol. 15.5, 2014, pages 457
HENKE, GUIDO ET AL.: "Activation of Na+/K+-ATPase by the serum and glucocorticoid-dependent kinase isoforms", KIDNEY AND BLOOD PRESSURE RESEARCH, vol. 25.6, 2002, pages 370 - 374
HUANG, DANZHI ET AL.: "Kinase selectivity potential for inhibitors targeting the ATP binding site: a network analysis", BIOINFORMATICS, vol. 26.2, 2009, pages 198 - 204
J. MED. CHEM., vol. 47, 2004, pages 6658 - 6661
KOBAYASHI, TAKAYASU ET AL.: "Characterization of the structure and regulation of two novel isoforms of serum-and glucocorticoid-induced protein kinase", BIOCHEMICAL J OURNAL, vol. 344.1, 1999, pages 189 - 197, XP000881885, DOI: 10.1042/0264-6021:3440189
L. W. DEADY, SYN. COMM., vol. 7, 1977, pages 509 - 514
LAI, NATURE REVIEWS DRUG DISCOVERY, vol. 16.2, 2017, pages 1012017
LANG, FLORIANPHILIP COHEN: "Regulation and physiological roles of serum-and glucocorticoid-induced protein kinase isoforms", SCI. STKE, vol. 2001.108, 2001, pages re17 - re17
LANG, UNDINE E. ET AL.: "Reduced locomotion in the serum and glucocorticoid inducible kinase 3 knock out mouse", BEHAVIOURAL BRAIN RESEARCH, vol. 167.1, 2006, pages 75 - 86
LEE, ELSA ET AL.: "Tissue-specific expression of the transcriptionally regulated serum and glucocorticoid-inducible protein kinase (Sgk) during mouse embryogenesis", MECHANISMS OF DEVELOPMENT, vol. 103.1-2, 2001, pages 177 - 181
LIANG, XUCHUN ET AL.: "Therapeutic inhibition ofSGKI suppresses colorectal cancer", EXPERIMENTAL & MOLECULAR MEDICINE, vol. 49.11, 2017, pages e399
LIU, J UNYING ET AL.: "SGK2 promotes hepatocellular carcinoma progression and mediates GS K-3<f/<f-catenin signaling in HCC cells", TUMOR BIOLOGY, vol. 39.6, 2017, pages 1010428317700408
LIU, MING ET AL.: "S erum and glucocorticoid kinase 3 at 8q13. 1 promotes cell proliferation and survival in hepatocellular carcinoma", HEPATOLOGY, vol. 55.6, 2012, pages 1754 - 1765
MANNING, GERARD ET AL.: "The protein kinase complement of the human genome", SCIENCE, vol. 298.5600, 2002, pages 1912 - 1934, XP002422776, DOI: 10.1126/science.1075762
MURRAY, J AMES T. ET AL.: "Identification offilamin C as a new physiological substrate of PKB using KESTREL", BIOCHEMICAL OURNAL, vol. 384.3, 2004, pages 489 - 494
N. KAKEYA ET AL., CHEM. PHARM. BULL., vol. 32, 1984, pages 692
NEVEDOMSKAYA, INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, vol. 19.5, 2018, pages 1359
PALMADA, MONICA ET AL.: "The serine/threonine kinases SGK1, 3 and PKB stimulate the amino acid transporter AS CT2", BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, vol. 331.1, 2005, pages 272 - 277, XP004858647, DOI: 10.1016/j.bbrc.2005.03.159
PAPADOPOULOU, NATALIA ET AL.: "Membrane androgen receptor activation triggers downregulation of PI-3K/Akt/NF-kappaB activity and induces apoptotic responses via Bad, FasL and caspase-3 in DU145 prostate cancer cells", MOLECULAR CANCER, vol. 7.1, 2008, pages 88
PEARCE, DAVID ET AL.: "Salt, sodium channels, and S G K1", THE J OURNAL OF CLINICAL INVESTIGATION, vol. 117.3, 2007, pages 592 - 595
RAIKWAR, NANDITA S. ET AL.: "An evolutionarily conserved N-terminal Sgk1 variant with enhanced stability and improved function", AMERICAN J OURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY, 2008
S HERK, ANDREA B. ET AL.: "Development of a small-molecule serum-and glucocorticoid-regulated kinase-1 antagonist and its evaluation as a prostate cancer therapeutic", CANCER RESEARCH, vol. 68.18, 2008, pages 7475 - 7483, XP002520616, DOI: 10.1158/0008-5472.CAN-08-1047
SANDU, CIPRIAN ET AL.: "Decreased intestinal glucose transport in the sgk3-knockout mouse", PFLAGERS ARCHIV, vol. 451.3, 2005, pages 437 - 444, XP019344100, DOI: 10.1007/s00424-005-1474-7
SCHWAB, MATTHIAS ET AL.: "Association of SGK1 gene polymorphisms with type 2 diabetes", CELLULAR PHYSIOLOGY AND BIOCHEMISTRY, vol. 21.1-3, 2008, pages 151 - 160
SOMMER, EEVA M. ET AL.: "Elevated SGK1 predicts resistance of breast cancer cells to Akt inhibitors", BIOCHEMICAL J OURNAL, vol. 452.3, 2013, pages 499 - 508, XP055350489, DOI: 10.1042/BJ20130342
STERN ET AL., CRITICAL REVIEWS IN ONCOLOGY/HAEMATOLOGY, vol. 54, 2005, pages 11 - 29
T. HIGUCHIV. STELLA: "Pro-Drugs as Novel Delivery Systems", A.C.S. SYMPOSIUM SERIES, vol. 14
TANG, ZHIYUAN ET AL.: "S erum and glucocorticoid-regulated kinase 1 (SGK1) is a predictor of poor prognosis in non-small cell lung cancer, and its dynamic pattern following treatment with S G K1 inhibitor and .--ray irradiation was elucidated", ONCOLOGY REPORTS, vol. 39.3, 2018, pages 1505 - 1515
TESSIER, MAUDE ET AL.: "Role of the Phox homology domain and phosphorylation in activation of serum and glucocorticoid-regulated kinase-3", J OURNAL OF BIOLOGICAL CHEMISTRY, vol. 281.33, 2006, pages 23978 - 23989
TESSIER, MAUDEJ AMES R. WOODGETT: "Serum and glucocorticoid Regulated protein kinases: variations on a theme", J OURNAL OF CELLULAR BIOCHEMISTRY, vol. 98.6, 2006, pages 1391 - 1407
VASUDEVAN, KRISHNA M. ET AL.: "AKT-independent signaling downstream of oncogenic PIK3CA mutations in human cancer", CANCER CELL, vol. 16.1, 2009, pages 21 - 32, XP002693048, DOI: 10.1016/J.CCR.2009.04.012
VIRBASIUS, J OSEPH V. ET AL.: "Activation of the Akt-related cytokine-independent survival kinase requires interaction of its phox domain with endosomal phosphatidylinositol 3-phosphate", PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES, vol. 98.23, 2001, pages 12908 - 12913
WANG, XIANWANGLEI LIU: "Phosphorylation and acetylation modifications of FOX03a: Independently or synergistically?", ONCOLOGY LETTERS, vol. 13.5, 2017, pages 2867 - 2872
WANG, YUANZHONG ET AL.: "SGK3 is an estrogen-inducible kinase promoting estrogen-mediated survival of breast cancer cells", MOLECULAR ENDOCRINOLOGY, vol. 25.1, 2011, pages 72 - 82
WANG, YUANZHONG ET AL.: "SGK3 sustains ER signaling and drives acquired aromatase inhibitor resistance through maintaining endoplasmic reticulum homeostasis", PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES, vol. 114.8, 2017, pages E 1500 - E 1508
WANG, YUANZHONGDUJIN ZHOUSHIUAN CHEN: "SGK3 is an androgen-inducible kinase promoting prostate cancer cell proliferation through activation of p70 S6 kinase and up-regulation of cyclin D1", MOLECULAR E NDOCRINOLOGY, vol. 28.6, 2014, pages 935 - 948, XP055389867, DOI: 10.1210/me.2013-1339
WU, CHUAN ET AL.: "Induction of pathogenic T H 17 cells by inducible salt-sensing kinase S G K1", NATURE, vol. 496.7446, 2013, pages 513
WULFF P ET AL.: "Impaired renal Na+ retention in the sgk1-knockout mouse", J CLIN INVEST, vol. 110, 2002, pages 1263 - 1268
XU, J UN ET AL.: "Identification of Flightless-I as a substrate of the cytokine-independent survival kinase CISK", J OURNAL OF BIOLOGICAL CHEMISTRY, vol. 284.21, 2009, pages 14377 - 14385
XU, J UN ET AL.: "SGK3 is associated with estrogen receptor expression in breast cancer", BREAST CANCER RESEARCH AND TREATMENT, vol. 134.2, 2012, pages 531 - 541
YAO, YONGLIANG ET AL.: "Lnc-SGK1 induced by Helicobacter pylori infection and highsalt diet promote Th2 and Th17 differentiation in human gastric cancer by SG K1/J un B signaling", ONCOTARGET, vol. 7.15, 2016, pages 20549
ZHOU, HUAXIN ET AL.: "Inhibition of serum-and glucocorticoid-inducible kinase 1 enhances TLR-mediated inflammation and promotes endotoxin-driven organ failure", THE FAS E BJ OURNAL, vol. 29.9, 2015, pages 3737 - 3749
ZHOU, RUIFENGPETER M. SNYDER: "Nedd4-2 phosphorylation induces serum and glucocorticoid-regulated kinase (SGK) ubiquitination and degradation.", JOURNAL OF BIOLOGICAL CHEMISTRY, vol. 280.6, 2005, pages 4518 - 4523

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