Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/425—Thiazoles
  • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
  • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
  • A61P11/06—Antiasthmatics
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/04—Ortho-condensed systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
  • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
  • C07D487/04—Ortho-condensed systems

Definitions

• the technical field relates to certain novel chemical compounds (including
• phosphatidylinositol 3-kinase delta ( ⁇ ) and phosphatidylinositol 3-kinase gamma ( ⁇ 3 ⁇ ) activity to their utility in treating and/or preventing clinical conditions including respiratory diseases, such as asthma and chronic obstructive pulmonary disease (COPD), to their use in therapy, to pharmaceutical compositions containing them and to processes for preparing such compounds.
• respiratory diseases such as asthma and chronic obstructive pulmonary disease (COPD)
• COPD chronic obstructive pulmonary disease
• PI3K phosphoinositide 3-kinase
• Class I PI3K catalytic subunits can be further subdivided into class 1 A (isoforms ⁇ , ⁇ , ⁇ ) and class IB ( ⁇ isoform) based on their catalytic subunit.
• Class IA PBKs form heterodimers with a regulatory subunit ( ⁇ 85 ⁇ / ⁇ 55 ⁇ / ⁇ 50 ⁇ / ⁇ 85 ⁇ or ⁇ 55 ⁇ ).
• ⁇ is largely restricted to myeloid and lymphoid cells, and can feature downstream of receptor tyrosine kinases, T & B cell receptors, toll-like receptors and co-stimulatory molecules [Okkenhaug, Ann Rev Immunol, 31 (2013), 675-704].
• ⁇ expression is also largely restricted to immune cells (neutrophils, eosinophils, macrophages, dendritic cells, T cells and mast cells), as well as low levels in endothelium, airway smooth muscle cells and the heart [Curr Opin Cell Biol, 17 (2005), 141— 149].
• GPCRs G-protein-coupled receptors
• Class 1 PBKs convert phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2) to form PtdIns(3,4,5)P3 in vivo [Biochim Biophys Acta, 1179 (1993), 27-75 and Science, 296 (2002), 1655-1657].
• the PtdIns(3,4,5)P3 generated at the plasma membrane serves as a docking site for pleckstrin-homology (PH)-domain containing proteins such as protein kinase B (PKB/Akt), which can then influence a broad array of proteins and thereby effect many different cellular responses [Cell, 129 (2007), 1261- 1274].
• PH pleckstrin-homology
• ⁇ kinase dead knock-in mice and ⁇ knockout mouse strains are viable and fertile and have been studied in a wide variety of preclinical models - identifying the ⁇ isoform as having multiple roles in adaptive immunity and the ⁇ isoform as a biochemical compass for migrating cells, particularly those of the innate immune system [Science, 287 (2000), 1049-1052 and Science, 297 (2002), 1031-1034].
• the adaptive immune system relies on the presentation of antigen by professional presenting cells (macrophages, dendritic cells (DCs) and B cells) to T lymphocytes in lymph nodes which drain the site of antigen entry/discovery.
• PI3K5 signaling is key to T lymphocyte stimulation, as demonstrated in kinase-dead knock-in animals which show defective signaling through the antigen complex and also costimulatory molecules [EMBO J. 1999; 18(5): 1292-302] .
• humans with activating PI3K5 mutations are also characterized by defective immunity, indicating the fine balance of PI3K5 signaling necessary for effective functional responses [Clin Exp Immunol. 2016; 183(2) :221 -9] .
• ⁇ 3 ⁇ has been shown to be essential in the lung-specific development of DCs, as well as in effective trafficking to lymph nodes [Immunity 2015, 43, 674-689 and EMBO J. 2004, 23(17), 3505-15].
• CD4 T cell subsets can be broadly dived into Thl, Th2 and Thl7 which help B lymphocyte responses and recruit granulocytes, or T reg cells which dampen the immune response.
• PI3K5 to be essential for cytokine production from T cell subsets - an important feature of subset maturation [Blood. 2010, 115;2203-2213].
• ⁇ 3 ⁇ plays a lesser role in the T cell differentiation process, yet has been shown to be needed for optimal responses [Eur J Immunol. 2013, 43, 3183-3196].
• PI3K5 may contribute through interaction with integrins - evidence supported by our findings of more effective dual inhibition of CD4 T cell movement [J Leuk Biol. 2008, 84;814-823].
• CD4 T cell 'help' for B cells to generate antibody responses is perturbed in the absence of PI3K5, both with respect to reduced cytokine production and signaling via co-stimulatory CD40, though seemingly less so via the B cell receptor itself [J Immunol. 2010. 185;4042-4052].
• a decrease in marginal zone B cells in rodents lacking ⁇ can lead to aberrant control of class switching and paradoxically enhanced IgE production [J Immunol. 2012, 188;3700-3708].
• Dysregulation of the adaptive immune system can result in chronic inflammation or autoimmunity, in which T cell subsets react inappropriately to innocuous antigen sampled from the environment (eg. grass pollen allergy) or from 'self (eg. rheumatoid arthritis).
• ⁇ driving the priming and survival of such populations, particularly in central nervous system (CNS) related inflammatory disorders, such as Multiple Sclerosis (MS) [PLoS One. 2012, 7(9)].
• CNS central nervous system
• MS Multiple Sclerosis
• ⁇ has been shown to feature at the heart of aberrant T/B lymphocyte responses [Biochem Biophys Acta. 2015. 1851;882-897].
• Cells of the innate immune response including neutrophils, eosinophils, macrophages and mast cells, offer the first line of host defense against invading pathogens, yet it is often their extended/perpetual activation via dysregulated T cells which underlie the hallmark chronic inflammation in pulmonary diseases such as asthma and COPD.
• Early responders to damage/infection are neutrophils, where pro -inflammatory mediators and chemotactic factors activate and draw them to the site of injury, where they act to engulf bacteria by phagocytosis, then use a powerful serine protease - neutrophil elastase - to kill the pathogen.
• neutrophil elastase can also cause problems for its host by degrading extracellular matrix proteins and coagulation, complement and immunoglobulin factors.
• neutrophil elastase evades regulation at inflammatory sites to induce further damage and release pro-inflammatory cytokines, such as IL-6 and IL-8.
• cytokines such as IL-6 and IL-8.
• Neutrophil influx/activation is seen in numerous diseases, including hereditary emphysema, chronic obstructive pulmonary disease, cystic fibrosis, adult respiratory distress syndrome, ischemic-reperfusion injury and rheumatoid arthritis. Both ⁇ and ⁇ isoform signaling are important in the generation of reactive oxygen species within neutrophils [Blood.
• Eosinophils also derive from the bone marrow and circulate at low levels in the blood in healthy individuals. Stimulation by IL-5, potentially from activated T cells, innate lymphoid cells (ILC2s) or other eosinophils, will enhance circulating eosinophil numbers [FASEB J. 2006 Mar;20(3), 455-65 and Anderson et al. Allergy.
• Macrophages are found in tissues throughout the body and form one of the first lines of defense to injury and pathogens, and are increased in diseases such as COPD. Since ⁇ - and p2-integrin dependent monocyte adhesion and migration require PI3K5, its inhibition should impair the increased monocyte infiltration observed in COPD [Microcirculation. 2006. 13:6, 439-456]. PI3K5 expression and signaling is increased in the lungs of patients with COPD. Selective inhibition of PI3K5 restored glucocorticoid responsiveness ex vivo [J Allergy Clin Immunol. 2010;125(5), 1146-53]. Early experiments in ⁇ 3 ⁇ knockout mice demonstrated that macrophages derived from mutant animals failed to produce
• Macrophages can be further divided into proinflammatory (Ml) and the "alternatively activated" anti-inflammatory (M2) macrophages, which often play sequential roles in inflammation and repair/remodeling respectively.
• Ml proinflammatory
• M2 anti-inflammatory
• Chemokines are the major mediators of chemotaxis in both subsets, yet the pattern of GPCR expression which control cell movement differ.
• Chemokines CCL19 or CCL21 induced activation of both MEK1-ERK1/2 and PI3K-AKT cascades in Ml but not in M2 macrophages, although pan PI3K inhibition via wortmannin was able to block migration, presumably through lack of ⁇ 3 ⁇ activity [J Leukoc Biol. 2015, 97(1), 61-9]. Furthermore, a skewing toward M2 activated macrophages was sensitive to PI3K5 inhibition when modeled in IL-4-stimulated murine systems [Eur. J. Immunol. 2011. 41, 1742-1753]. Lastly, ⁇ 3 ⁇ knockout mice show abrogated atherosclerosis by reducing macrophage proliferation (but not polarization or apoptosis) in lesions [PLoS One. 2013 Aug 22;8(8):e72674].
• T-type which express only tryptase
• TC-type which express both tryptase and chymase
• the T-type mast cells are located primarily in alveolar tissue and intestinal mucosa while the TC-type cells predominate in skin and conjunctiva. Tryptase and chymase appear to be important mediators of allergic diseases, being involved in processes of inflammation, bronchoconstriction, mucus secretion and tissue remodelling. Mast cell activation by IgE and survival via c-kit stimulation is reliant upon PI3K5 signaling [Nature 2004. 431, 1007-1011].
• Airway smooth muscle cell expression of ⁇ 3 ⁇ has been linked with the desensitization of ⁇ 2 adrenergic receptors following agonism - a common treatment for bronchoconstriction in asthma.
• the mechanism appears to be via the sequestration of internalized receptor in the endoplasmic reticulum, thus inhibition of ⁇ 3 ⁇ may return some efficacy of ⁇ 2 agonists which has been lost through long term use [PLoS One. 2015, 10(5), e0125803].
• Fibrosis is a hallmark of most chronic lung diseases, although location and severity can vary dramatically.
• Fibroblast mesenchymal transition (FMT), in which fibroblasts differentiate in response to TGF into myofibroblasts is key to this pathologic process.
• ⁇ and ⁇ isoforms have been identified as important signaling mediators in cancer.
• ⁇ upregulation has been shown to be oncogenic in cancers such as pancreatic intraepithelial neoplasia and ductal carcinoma [Clin Cancer Res. 2010, 16(20), 4928-37], and has had roles in both tumor growth and metastasis shown in rodent oncology models
• MDSCs are central to said immune evasion, through signaling mechanisms which feature ⁇ 3 ⁇ not only downstream of GPCRs but also cytokine and growth factor receptors [Cancer Cell. 2011, 19(6), 715-27 and Cell Rep. 2015, 11(4), 577-91]. Results indicate that upregulated ⁇ 3 ⁇ conveys the metastatic signal initiated by GPCRs in breast cancer cells, and suggest that ⁇ 3 ⁇ may be a novel therapeutic target for development of
• chemotherapeutic agents to prevent breast cancer metastasis.
• active T reg immunity confers a tumourigenic environment
• recent findings suggest a unique sensitivity to PI3K5 inhibition, and thus the potential for therapeutic inhibition in tumours where T regs are dominant [Nature. 2014. 510;407-411].
• Yet PI3K5 is also reported to be essential for tumour clearance by cytotoxic T lymphocytes (CTLs) [PLoS ONE. 2012. 7;e40852].
• CTLs cytotoxic T lymphocytes
• We and others have shown CTL migration to be sensitive to ⁇ 3 ⁇ inhibition, and thus may impact the killing of cells which present antigen from within (e.g. virus infected cells, cancer) [J Immunol. 2008. 180;2081-2088].
• Pulmonary ⁇ dual inhibition may treat complex multi-cellular diseases characterized by lung tissue adaptive immune T cell activation and consequent granulocyte influx and activation, such as is found in asthma, COPD and beyond [Biochim Biophys Acta. 2015 Jun, 1851(6), 882-97].
• J. Med. Chem. 2012, 55, 8559 - 8581 highlights the roles of PI3K5 and ⁇ 3 ⁇ as targets in autoimmune and inflammatory diseases and summarize the efforts toward the development of small molecule inhibitors of PI3K5 and ⁇ 3 ⁇ as well as dual inhibitors.
• WO2012052753 discloses 6-(2-((4-amino-3-(3-hydroxyphenyl)-lH-pyrazolo[3,4- d]pyrimidin- 1 -yl)methyl)-3-(2-c ⁇
• WO2013052699 disclose compounds capable of selectively inhibiting PI3K5 and ⁇ 3 ⁇ .
• WO2013012915, WO2013012918, WO2013032591, WO2014124757, WO2015001491 and WO2015010641 disclose compounds capable of selectively inhibiting PI3K5 and/or ⁇ 3 ⁇ .
• WO2015198289 disclose substituted chromene derivatives as selective dual inhibitors of PI3K5 and ⁇ 3 ⁇ .
• J. Med. Chem. 2015, 58, 7831 - 7399 discloses selective inhibitors of PI3K5 for the treatment of respiratory indications via inhalation.
• An object is to provide novel dual inhibitors of PI3K5 and ⁇ 3 ⁇ useful in therapy.
• a further object is to provide dual inhibitors of PI3K5 and ⁇ 3 ⁇ displaying selectivity over the PI3K class 1 A isoforms a and ⁇ .
• PI3K5 phosphatidylinositol 3 -kinase delta
• ⁇ 3 ⁇ phosphatidylinositol 3 -kinase gamma
• X is C(O) or SO2
• Y is SO2NHR 5 or SO2R 6 ; selected from C ⁇ _4alkyl, wherein said Ci _4alkyl is optionally substituted by
• R2 is selected from H or CH3;
• R ⁇ is selected from H or C ⁇ _3alkyl; is selected from Ci _3alkyl, wherein said Ci _3alkyl is optionally substituted by OC1 .
• cycloheteroalkylring containing 0 or 1 further heteroatoms selected from N or O, wherein said cycloheteroalkylring is substituted by 0, 1 or 2 substituents independently selected from CH3, OH, CH 2 OH or CH 2 CH 2 OH; or
• R3 and R ⁇ taken together with the N atom and X are selected from
• R ⁇ is selected from Ci _3alkyl or (oxetan-3-yl); R ⁇ is selected from Ci _3alkyl;
• the compounds of formula (I) are inhibitors of ⁇ and ⁇ .
• the compounds of formula (I) can be used as a medicament, in particular for disorders, disease or conditions responsive to inhibition of ⁇ and/or ⁇ , and more specifically respiratory diseases (such as COPD and asthma).
• a pharmaceutical formulation comprising a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt of a compound of formula (I), and a pharmaceutically acceptable diluent, excipient and/or inert carrier.
• a pharmaceutical formulation comprising a compound of formula (I), or a pharmaceutically acceptable salt of a compound of formula (I), for use in the treatment of a condition where inhibition of ⁇ and/or ⁇ would be beneficial.
• administration of a compound of formula (I), or a pharmaceutically acceptable salt of a compound of formula (I) results in a reduction in levels of activity of ⁇ and/or ⁇ in a mammal, particularly a human.
• the compounds of formula (I) also display promising pharmacological profiles by separating desired and undesired effects in vivo.
• Figure 1 shows the X-ray powder diffraction pattern for Example 1, form B: 2-[(15)-l- Cyclopropylethyl] -5 -(4-methyl-2- ⁇ [6-(2-oxopyrrolidin- 1 -yl)pyridin-2-yl] amino ⁇ - 1 ,3 -thiazol- 5-yl)-7-(methylsulfonyl)-2,3-dihydro-lH-isoindol-l-one.
• Figure 2 shows the X-ray powder diffraction pattern for Example 1, form A: 2-[(15)-l- Cyclopropylethyl] -5 -(4-methyl-2- ⁇ [6-(2-oxopyrrolidin- 1 -yl)pyridin-2-yl] amino ⁇ - 1 ,3 -thiazol- 5-yl)-7-(methylsulfonyl)-2,3-dihydro-lH-isoindol-l-one.
• Figure 3 shows the X-ray powder diffraction pattern for Example 10: 5-(4-Methyl-2- ⁇ [6-(2- oxopyrrolidin- 1 -yl)pyridin-2-yl] amino ⁇ - 1 ,3-thiazol-5-yl)-7-(methylsulfonyl)-2-[(25)-l , 1,1- trifluoropropan-2-yl]-2,3 -dihydro- lH-isoindol- 1 -one.
• Figure 4 shows the X-ray powder diffraction pattern for Example 14 N- ⁇ 6-[(5- ⁇ 2-[(15)-l-
• Figure 5 shows the X-ray powder diffraction pattern for Example 20: 2-[(15)-l-
• Figure 6 shows the X-ray powder diffraction pattern for Example 20: 2-[(15)-l-
• Figure 7 shows the X-ray powder diffraction pattern for Example 31: 2-[(15)-l-
• Figure 8 shows the X-ray powder diffraction pattern for Example 32: 2-[(15)-l-
• Ci .4 means a carbon group having 1, 2, 3 or 4 carbon atoms.
• Ci .3 means a carbon group having 1, 2 or 3 carbon atoms.
• alkyl includes both straight and branched chain alkyl groups and may be, but is not limited to, methyl, ethyl, n-propyl, i- propyl, n-butyl, sec-butyl, z ' so-butyl or tert-bvXy ⁇ .
• a pharmaceutically acceptable moiety e.g. a salt, dosage form, or excipient
• a pharmaceutically acceptable moiety has one or more benefits that outweigh any deleterious effect that the moiety may have. Deleterious effects may include, for example, excessive toxicity, irritation, allergic response, and other problems and complications.
• X is C(O) or SO2.
• X is C(O).
• X is SO2.
• Y is SO2NHR 5 or SO2 6 ;
• R5 is selected from C ⁇ ⁇ alkyl or (oxetan-3-yl);
• R ⁇ is selected from C ⁇ _3alkyl.
• Y is SC ⁇ NHR ⁇
• R is selected from Ci _3alkyl or (oxetan-3-yl).
• Y is SC ⁇ R ⁇
• R ⁇ is selected from C ⁇ _3alkyl.
• R1 is selected from Ci _4alkyl, wherein said Ci _4alkyl is optionally substituted by cyclopropyl, 0, 1 or 2 CH3 and 0, 1, 2 or 3 F.
• R1 is selected from tert-butyl, butan-2-yl, 3,3-dimethylbutan-2-yl, 1,1,1 -trifluoropropan-2-yl, 1 -cyclopropylethyl.
• R1 is selected from l,l,l-trifluoropropan-2-yl or 1- cyclopropylethyl .
• R1 is l,l,l-trifluoropropan-2-yl.
• R1 is (25)-l,l,l-trifluoropropan-2-yl.
• R1 is 1 -cyclopropylethyl.
• R1 is (15)-l-cyclopropylethyl.
• R ⁇ is selected from H or CH3.
• R ⁇ is H
• R ⁇ is CH3.
• R ⁇ is selected from H or C ⁇ _3alkyl.
• R ⁇ is CH3.
• R.4 is selected from C ⁇ .3alkyl, wherein said C ⁇ _3alkyl is optionally substituted by OC ⁇ _3alkyl.
• R ⁇ and R ⁇ taken together with the N atom and X form a 5, 6 or 7- membered cycloheteroalkylring containing 0 or 1 further heteroatoms selected from N or O, wherein said cycloheteroalkylring is substituted by 0, 1 or 2 substituents independently selected from CH 3 , OH, CH 2 OH or CH 2 CH 2 OH;
• X is C(0) or S0 2 .
• R ⁇ and R ⁇ taken together with the N atom and X form a 7- membered cycloheteroalkylring containing 1 further N;
• R ⁇ and R ⁇ taken together with the N atom and X form a 6- membered cycloheteroalkylring containing 0 or 1 further heteroatoms selected from N or O, wherein said cycloheteroalkylring is substituted by 0, 1 or 2 substituents independently selected from CH 3 or CH 2 CH 2 OH;
• R ⁇ and R ⁇ taken together with the N atom and X form a 5- membered cycloheteroalkylring containing 0 or 1 further heteroatoms selected from N or O, wherein said cycloheteroalkylring is substituted by 0 or 1 substituents independently selected from CH 3 , OH, or CH 2 OH;
• R ⁇ and R ⁇ taken together with the N atom and X are selected from
• R*> is selected from C ⁇ .3alkyl.
• R ⁇ is CH3.
• the compound of formula (I) is selected from:
• the compounds of formula (I) and their pharmaceutically acceptable salts have activity as pharmaceuticals, in particular as inhibitors of ⁇ and/or ⁇ activity, and thus may be used in the treatment of obstructive diseases of the airways including: asthma, including bronchial, allergic, intrinsic, extrinsic, exercise-induced, drug-induced (including aspirin and NSAID-induced) and dust-induced asthma, both intermittent and persistent and of all severities, and other causes of airway hyper-responsiveness; chronic obstructive pulmonary disease (COPD); bronchitis, including infectious and eosinophilic bronchitis; emphysema; bronchiectasis; cystic fibrosis; sarcoidosis; alpha- 1 antitrypsin deficiency; EGPA
• Eosinophilic Granulocytic with Polyangiitis also known as Churg-Strauss syndrome or allergic granulomatosis
• ABPA Allergic Broncopulmonary Aspergillosis
• CEP Chronic Eosinophilic Pneumonia
• farmer's lung and related diseases hypersensitivity pneumonitis; lung fibrosis, including cryptogenic fibrosing alveolitis, idiopathic interstitial pneumonias, fibrosis complicating anti-neoplastic therapy and chronic infection, including tuberculosis and aspergillosis and other fungal infections; complications of lung transplantation; vasculitic and thrombotic disorders of the lung vasculature, and pulmonary hypertension; antitussive activity including treatment of chronic cough associated with inflammatory and secretory conditions of the airways, and iatrogenic cough; acute and chronic rhinitis including rhinitis
• medicamentosa, and vasomotor rhinitis perennial and seasonal allergic rhinitis including rhinitis nervosa (hay fever); nasal polyposis; acute viral infection including the common cold, and infection due to respiratory syncytial virus, influenza, coronavirus (including SARS) and adenovirus, acute lung injury, adult respiratory distress syndrome (ARDS), as well as exacerbations of each of the foregoing respiratory tract disease states, in particular exacerbations of all types of asthma or COPD.
• perennial and seasonal allergic rhinitis including rhinitis nervosa (hay fever); nasal polyposis
• acute viral infection including the common cold, and infection due to respiratory syncytial virus, influenza, coronavirus (including SARS) and adenovirus, acute lung injury, adult respiratory distress syndrome (ARDS), as well as exacerbations of each of the foregoing respiratory tract disease states, in particular exacerbations of all types of asthma or COPD.
• Prophylaxis is expected to be particularly relevant to the treatment of persons who have suffered a previous episode of, or are otherwise considered to be at increased risk of, the disease or condition in question.
• Persons at risk of developing a particular disease or condition generally include those having a family history of the disease or condition, or those who have been identified by genetic testing or screening to be particularly susceptible to developing the disease or condition.
• the compounds of formula (I), or a pharmaceutically acceptable salt thereof may be used in the treatment of asthma ⁇ such as bronchial, allergic, intrinsic, extrinsic or dust asthma, particularly chronic or inveterate asthma (for example late asthma or airways hyper-responsiveness) ⁇ , chronic obstructive pulmonary disease (COPD) or allergic rhinitis.
• asthma such as bronchial, allergic, intrinsic, extrinsic or dust asthma, particularly chronic or inveterate asthma (for example late asthma or airways hyper-responsiveness) ⁇ , chronic obstructive pulmonary disease (COPD) or allergic rhinitis.
• COPD chronic obstructive pulmonary disease
• an obstructive airways disease or condition e.g. asthma or COPD
• administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as hereinbefore defined.
• a combination therapy wherein a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a second active ingredient are administered concurrently, sequentially or in admixture, for the treatment of one or more of the conditions listed above.
• a combination may be used in combination with one or more further active ingredients.
• Another embodiment relates to the combination of a compound of formula (I), or a pharmaceutically acceptable salt thereof, together with an anti-inflammatory and/or bronchodilatory compound.
• Another embodiment relates to the combination of a compound of formula (I), or a pharmaceutically acceptable salt thereof, together with a glucocorticoid receptor agonist (steroidal or non-steroidal).
• Another embodiment still further relates to the combination of a compound of formula (I), or a pharmaceutically acceptable salt thereof, together with a selective ⁇ 2 adrenoceptor agonist.
• Another embodiment still further relates to the combination of a compound of formula (I), or a pharmaceutically acceptable salt thereof, together with an antimuscarinic agent.
• Another embodiment still further relates to the combination of a compound of formula (I), or a pharmaceutically acceptable salt thereof, together with a dual ⁇ 2
• adrenoceptor agonist/antimuscarinic agent adrenoceptor agonist/antimuscarinic agent.
• Another embodiment still further relates to the combination of a compound of formula (I), or a pharmaceutically acceptable salt thereof, together with a p38 antagonist.
• Another embodiment still further relates to the combination of a compound of formula (I), or a pharmaceutically acceptable salt thereof, together with a xanthine derivative.
• Another embodiment still further relates to the combination of a compound of formula (I), or a pharmaceutically acceptable salt thereof, together with a phosphodiesterase (PDE) inhibitor (including a PDE4 inhibitor or an inhibitor of the isoform PDE4D).
• PDE phosphodiesterase
• a pharmaceutical composition for example, for use as a medicament for the treatment of one of the diseases or conditions listed herein, such as COPD or asthma
• a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and at least one active ingredient selected from:
• glucocorticoid receptor agonist steroidal or non-steroidal
• the compound of formula (I), or a pharmaceutically acceptable salt thereof is administered concurrently or sequentially with one or more further active ingredients selected from those defined above.
• the compound of formula (I), or a pharmaceutically acceptable salt thereof may be administered concurrently or sequentially with a further pharmaceutical composition for use as a medicament for the treatment of one of the diseases or conditions listed herein, such as a respiratory tract condition (e.g. COPD or asthma).
• Said further pharmaceutical composition may be a medicament which the patient may already be prescribed (e.g. an existing standard of care medication), and may itself be a composition comprising one or more active ingredients selected from those defined above.
• the dosage administered will vary with the compound employed, the mode of administration, the treatment desired and the disorder indicated.
• the daily dosage of the compound of formula (I), if inhaled may be in the range from 0.05 micrograms per kilogram body weight ⁇ g/kg) to 100 micrograms per kilogram body weight ⁇ g/kg).
• the daily dosage of the compound of formula (I) may be in the range from 0.01 micrograms per kilogram body weight ⁇ g/kg) to 100 milligrams per kilogram body weight (mg/kg).
• the compounds of formula (I), or pharmaceutically acceptable salts thereof may be used on their own but will generally be administered in the form of a pharmaceutical composition in which the formula (I) compound/salt (active ingredient) is in association with a pharmaceutically acceptable adjuvant(s), diluents(s) or carrier(s).
• a pharmaceutically acceptable adjuvant(s), diluents(s) or carrier(s) Conventional procedures for the selection and preparation of suitable pharmaceutical formulations are described in, for example, "Pharmaceuticals - The Science of Dosage Form Designs", M. E. Aulton, Churchill
• composition(s) comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, as hereinbefore defined in association with pharmaceutically acceptable adjuvant(s), diluent(s) or carrier(s).
• a process for the preparation of a pharmaceutical composition which comprises mixing a compound of formula (I), or a pharmaceutically acceptable salt thereof, as hereinbefore defined with a pharmaceutically acceptable adjuvant(s), diluents(s) or carrier(s).
• the pharmaceutical composition will, for example, comprise from 0.05 to 99%w (per cent by weight), such as from 0.05 to 80%w, for example from 0.10 to 70%w, such as from 0.10 to 50%w, of active ingredient, all percentages by weight being based on total composition.
• compositions may be administered in standard manner for the disease condition that it is desired to treat, for example by topical (such as to the lung and/or airways or to the skin), inhalation, oral, rectal or parenteral administration.
• topical such as to the lung and/or airways or to the skin
• inhalation oral, rectal or parenteral administration.
• the compounds of formula (I) may be formulated by means known in the art.
• a suitable pharmaceutical composition is one suitable for oral administration in unit dosage form, for example a tablet or capsule which contains between 0.1 mg and 1 g of active ingredient.
• Each patient may receive, for example, a dose of 0.0001 mgkg ' l to 10 mgkg ' l, for example in the range of 0.005 mgkg ' l ⁇ 0 5 m gkg-l, of the active ingredient administered, for example, 1 to 4 times per day.
• a pharmaceutical composition comprising a compound of formula (I) in association with a pharmaceutically acceptable adjuvant, diluent or carrier, which is formulated for inhaled administration (including oral and nasal inhalation).
• the compound of formula (I) may be administered using a suitable delivery device, for example from a dry powder inhaler, a metered dose inhaler, a nebuliser or a nasal delivery device.
• a suitable delivery device for example from a dry powder inhaler, a metered dose inhaler, a nebuliser or a nasal delivery device.
• a suitable delivery device for example from a dry powder inhaler, a metered dose inhaler, a nebuliser or a nasal delivery device.
• Dry powder inhalers may be used to administer the compound of formula (I), alone or in combination with a pharmaceutically acceptable carrier, in the latter case either as a finely divided powder or as an ordered mixture.
• the dry powder inhaler may be single dose or multi-dose and may utilise a dry powder or a powder-containing capsule.
• the compound of formula (I), or a pharmaceutical composition containing a compound of formula (I), is administered by means of a dry powder inhaler (DPI).
• DPI dry powder inhaler
• the DPI may be "passive" or breath-actuated, or “active” where the powder is dispersed by some mechanism other than the patient's inhalation, for instance, an internal supply of compressed air.
• passive dry powder inhalers are available: single- dose, multiple unit dose or multidose (reservoir) inhalers.
• single-dose devices individual doses are provided, usually in gelatine capsules, and have to be loaded into the inhaler before use, examples of which include Spinhaler ® (Aventis), Rotahaler ® (GlaxoSmithKline), AeroliserTM (Novartis), Inhalator ® (Boehringer) and Eclipse (Aventis) devices.
• Multiple unit dose inhalers contain a number of individually packaged doses, either as multiple gelatine capsules or in blisters, examples of which include Diskhaler ® (GlaxoSmithKline), Diskus ® (GlaxoSmithKline), Nexthaler ® (Chiesi) and Aerohaler ® (Boehringer) devices.
• An inhalable pharmaceutical composition for use in a DPI can be prepared by mixing finely divided active ingredient (having an aerodynamic diameter generally equal to or less than 10 ⁇ , such as equal to or less than 5 ⁇ , e.g. from 1 to 5 ⁇ ) with a carrier substance, for example, a mono-, di- or polysaccharide, a sugar alcohol, or another polyol.
• a carrier substance for example, a mono-, di- or polysaccharide, a sugar alcohol, or another polyol.
• Suitable carriers are sugars, for example, lactose, glucose, raffinose, melezitose, lactitol, maltitol, trehalose, sucrose, mannitol; and starch.
• the particles of the active ingredient adhere to the carrier particles to form an ordered (interactive) powder mixture.
• the carrier particles may have a mass median diameter of from 20 to 1000 ⁇ , more usually from 50 to 500 ⁇ .
• an inhalable pharmaceutical composition may be prepared by processing a finely divided powder (e.g. consisting of finely divided active ingredient and finely divided carrier particles) into spheres that break up during the inhalation procedure.
• a finely divided powder e.g. consisting of finely divided active ingredient and finely divided carrier particles
• the powder mixture may then, as required, be dispensed into hard gelatine capsules, each containing the desired dose of the active ingredient.
• the powder mixture may be loaded into the reservoir of a multidose inhaler for example, the Genuair ® , or the Turbuhaler ® .
• the compound of formula (I) is administered by means of a metered dose inhaler, particularly a pressurized metered dose inhaler (pMDI).
• pMDI contains the active as a suitable solution or suspension in a pressurized container.
• the active is delivered by actuating a valve on the pMDI device. Actuation may be manual or breath actuated. In manually actuated pMDIs the device is actuated by the user as they inhale, for example by pressing a suitable release mechanism on the pMDI device. Breath actuated pMDIs are actuated when the patient inhales through the mouthpiece of the pMDI. This can be advantageous as the actuation of the device is timed with the patients' inhalation and can result in a more consistent dosing of the active. Examples of pMDI devices include for example Rapihaler® (AstraZeneca).
• An inhalable pharmaceutical composition for use in a pMDI can be prepared by dissolving or dispersing the compound of formula (I) in a suitable propellant and with or without additional excipients such as solvents (for example ethanol), surfactants, lubricants or stabilising agents.
• suitable propellants include hydrocarbon, chlorofluorocarbon and hydro fluoroalkane (e.g. heptafluoroalkane) propellants, or mixtures of any such propellants.
• Preferred propellants are PI 34a and P227, each of which may be used alone or in combination with other propellants and/or surfactant and/or other excipients.
• the compound of formula (I) is administered by means of a metered dose inhaler in combination with a spacer.
• Suitable spacers are well known and include Nebuchamber® (AstraZeneca) or Volumatic® (Glaxo SmithKline).
• the compound of formula (I) is administered by means of a nebuliser.
• Suitable nebulisers are well known and include eFlow® (PARI GmbH).
• An inhalable pharmaceutical composition for use in a nebuliser can be prepared by dispersing or dissolving the compound of formula (I) in a suitable aqueous medium.
• the composition may also include for example suitable pH and/or tonicity adjustment, surfactants and preservatives.
• a suitable composition for inhalation from a nebuliser comprises a compound of formula (I) dispersed in an aqueous medium (mg/g in highly purified water, e.g. Milli-Q water) comprising sodium chloride (9 mg/g); citric acid dried (0.0735 mg/g); sodium citrate (0.19 mg/g); benzalkonium chloride (0.1 mg/g), EDTA
• the compound of formula (I) is administered nasally as a spray from a suitable nasal delivery device, for example a spray pump or an MDI.
• a suitable nasal delivery device for example a spray pump or an MDI.
• the compound could be administered nasally as a powder using a suitable DPI device e.g. Rhinocort®, Turbuhaler® (AstraZeneca).
• An inhalable pharmaceutical composition for use in a spray pump or MDI nasal delivery device can be prepared by dispersing or dissolving the compound of formula (I) in a suitable aqueous medium.
• the composition may also include for example suitable pH and/or tonicity adjustment, surfactants, preservatives, lubricants flavourings or viscosity modifiers. If required additives to enhance absorption from the nasal cavity can be included, such as a suitable bioadhesive polymer.
• Suitable dry powder compositions for nasal delivery are as hereinbefore described in relation to DPI delivery.
• the compound may be necessary to use the compound as larger particle sizes, for example with an average particle diameter greater than about 10 ⁇ , e.g. from 10 ⁇ to 50 ⁇ .
• an inhaler device for example a dry powder inhaler, in particular a multiple unit dose dry powder inhaler, or a pMDI inhaler
• a dry powder inhaler for example a dry powder inhaler, in particular a multiple unit dose dry powder inhaler, or a pMDI inhaler
• an inhalable pharmaceutical composition of the invention for example a dry powder inhaler, in particular a multiple unit dose dry powder inhaler, or a pMDI inhaler
• a process for preparing a compound of the formula (I), or a pharmaceutically acceptable salt thereof comprises: a) Reaction of a compound of the formula (II) with a compound of the formula (III),
• R1, R 2 , R3, R4 ⁇ and Y are as defined in formula (I), Hal is halogen, and under conditions such that a displacement of the halogen of the compound of formula (III) by the amino group of the compound of formula (II) occurs, and, where desired, separating the resultant compound of formula (I) into its individual optical isomers, and where necessary converting the resultant compound of formula (I) into a pharmaceutically acceptable salt thereof and, where necessary converting the resultant compound of formula (I) into a preferred polymorph; or
• R 1 , R 2 , R 3 , R 4 , X and Y are as defined in formula (I) and under conditions such that a bond is formed between the carbon atom bearing the chlorine or bromine atom of formula (IV) and C-5 of the thiazole, and, where desired, separating the resultant compound of formula (I) into its individual optical isomers, and where necessary converting the resultant compound of formula (I) into a pharmaceutically acceptable salt thereof and, where necessary converting the resultant compound of formula (I) into a preferred polymorph.
• the compounds of formula (II) and (III) react under conditions promoting nucleophilic aromatic
• the reaction is typically performed in a polar aprotic solvent, such as DMF or THF, with heating, typically in a range from 60 - 140 °C. Heating can be by conventional or microwave means and the use of pressurised systems to enable reactions to run above the boiling point of the solvent may be advantageous.
• the reaction may be catalysed by a transition metal, for example palladium, in the presence of suitable ligands, such as bidentate trisubstituted phosphines, for example xantphos, and a base such as an alkali metal carbonate, for example sodium carbonate.
• suitable ligands such as bidentate trisubstituted phosphines, for example xantphos
• a base such as an alkali metal carbonate, for example sodium carbonate.
• the compounds of formula (IV) and (V) react under conditions promoting the activation of aryl bromides and their reaction with activated double bonds ("Heck reaction").
• the reaction is typically performed in a polar aprotic solvent, such as DMF or THF, with heating, typically in a range from 60 - 140 °C. Heating can be by conventional or microwave means and the use of pressurised systems to enable reactions to run above the boiling point of the solvent may be advantageous.
• a catalytic amount of a transition metal such as palladium in the presence of a suitable ligand, such as a sterically hindered trialkylphosphine, for example tri t-butylphosphine in the presence of a suitable base such as an alkali metal carbonate, for example cesium carbonate.
• R.1, and Y are as defined in formula (I) and under conditions promoting the activation of aryl bromides and their reaction with activated double bonds ("Heck reaction").
• the reaction is typically performed in a polar aprotic solvent, such as DMF or THF, with heating, typically in a range from 60 - 140 °C. Heating can be by conventional or microwave means and the use of pressurised systems to enable reactions to run above the boiling point of the solvent may be advantageous.
• trialkylphosphine for example tri t-butylphosphine
• a suitable base such as an alkali metal carbonate, for example cesium carbonate.
• Compounds of formula (VI) may be optionally protected during the reaction with a compound of formula (II), for example with an acetyl or BOC group. Such protecting groups may be removed by methods known in the art, for example acid or base treatment.
• a suitable agent for example a peracid such as mCPBA in a suitable solvent, such as dichloromethane or chloroform at a temperature of typically -20 - 25 °C.
• a suitable agent for example a peracid such as mCPBA in a suitable solvent, such as dichloromethane or chloroform at a temperature of typically -20 - 25 °C.
• a suitable agent for example a peracid such as mCPBA in a suitable solvent, such as dichloromethane or chloroform at a temperature of typically -20 - 25 °C.
• the oxidant can be potassium
• Oxone peroxymonosulfate
• a suitable solvent such as an alcohol, for example ethanol, optionally containing water, at a temperature between ambient and reflux, for example 50 °C.
• R1 and R ⁇ are as defined in formula (I), by oxidation with a suitable agent, for example a peracid such as mCPBA in a suitable solvent, such as dichloromethane or chloroform at a temperature of typically -20 - 25 °C.
• a suitable agent for example a peracid such as mCPBA in a suitable solvent, such as dichloromethane or chloroform at a temperature of typically -20 - 25 °C.
• the oxidant can be potassium peroxymonosulfate ("Oxone") in a suitable solvent such as an alcohol, for example ethanol, optionally containing water, at a temperature between ambient and reflux, for example 50 °C.
• reaction is typically carried out in the presence of a base, which may be an excess of the compound of formula (X), or an amine base such as triethylamine or 4-dimethylaminopyridine, in a suitable solvent, such as dichloromethane or THF, at a suitable temperature, for example between 0 °C and ambient temperature.
• a base which may be an excess of the compound of formula (X), or an amine base such as triethylamine or 4-dimethylaminopyridine
• a suitable solvent such as dichloromethane or THF
• R1 and R ⁇ are as defined in formula (I).
• the reaction is typically carried out in the presence of a base, which may be an excess of the compound of formula (X), or an amine base such as triethylamine or 4-dimethylaminopyridine, in a suitable solvent, such as dichloromethane or THF, at a suitable temperature, for example between 0 °C and ambient temperature.
• a base which may be an excess of the compound of formula (X), or an amine base such as triethylamine or 4-dimethylaminopyridine
• a suitable solvent such as dichloromethane or THF
• a compound of formula (IX or XI) may be prepared from a compound of formula (VII or
• R*> represents benzyl, optionally suitably protected, with a suitable chlorinating and oxidising agent, for example sulfuryl chloride or l,3-dichloro-5,5- dimethylimidazolidine-2,4-dione;
• a suitable chlorinating and oxidising agent for example sulfuryl chloride or l,3-dichloro-5,5- dimethylimidazolidine-2,4-dione
• the reaction can be carried out in a suitable solvent mixture, for example a mixture of water and acetonitrile containing acetic acid at a suitable
• a compound of formula (VII), optionally protected, may be prepared from a compound of formula (XII), optionall protected, by reaction with a compound of formula (XIII),
• R.1, and R ⁇ are as defined in formula (I)
• a suitable base for example a sodium alkoxide such as sodium 2-methylbutan-2-olate or sodium t-butoxide; alternatively a preformed thiolate, such as sodium methanethiolate, may be used; the reaction can be run in a suitable solvent, for example DMF or dioxan at a suitable temperature, typically between 80 and 120 °C.
• a compound of formula (VIII), optionally protected, may be prepared from a compound of formula (XIV) by reaction with a com ound of formula (XIII),
• R1 and R ⁇ are as defined in formula (I), in the presence a suitable base, for example a sodium alkoxide such as sodium 2-methylbutan-2-olate or sodium t-butoxide; alternatively a preformed thiolate, such as sodium methanethiolate, may be used; the reaction can be run in a suitable solvent, for example DMF or dioxan at a suitable temperature, typically between 80 and 120 °C.
• a suitable base for example a sodium alkoxide such as sodium 2-methylbutan-2-olate or sodium t-butoxide
• a preformed thiolate such as sodium methanethiolate
• Compounds of formula (XII) may be prepared from a compound of formula (XIV) and a compound of formula (VI) under conditions promoting the activation of aryl bromides and their reaction with activated double bonds ("Heck reaction").
• the reaction is typically performed in a polar aprotic solvent, such as DMF or THF, with heating, typically in a range from 60 - 140 °C. Heating can be by conventional or microwave means and the use of pressurised systems to enable reactions to run above the boiling point of the solvent may be advantageous.
• a suitable ligand such as a sterically hindered trialkylphosphine, for example tri t- butylphosphine
• a suitable base such as an alkali metal carbonate, for example cesium carbonate.
• a compound of formula (V) may be prepared by reaction of a compound of formula (III) with a compound of formula (VI) and under conditions such that a displacement of the halogen of the compound of formula (III) by the amino group of the compound of formula (V) occurs; the reaction is typically performed in a polar aprotic solvent, such as DMF or THF, with heating, typically in a range from 60 - 140 °C. Heating can be by conventional or microwave means and the use of pressurised systems to enable reactions to run above the boiling point of the solvent may be advantageous.
• a polar aprotic solvent such as DMF or THF
• the reaction may be catalysed by a transition metal, for example palladium, in the presence of suitable ligands, such as bidentate trisubstituted phosphines, for example xantphos, and a base such as an alkali metal carbonate, for example sodium carbonate.
• suitable ligands such as bidentate trisubstituted phosphines, for example xantphos
• a base such as an alkali metal carbonate, for example sodium carbonate.
• a compound of formula (III) may be prepared from a compound of formula (XV) and a compound of formula (XVI),
• X, R.3 and are as defined in formula (I) and Hal is a halogen, under conditions promoting nucleophilic aromatic displacement.
• the reaction is typically performed in a polar aprotic solvent, such as dioxan, with heating, typically in a range from 60 - 100 °C. Heating can be by conventional or microwave means and the use of pressurised systems to enable reactions to run above the boiling point of the solvent may be advantageous.
• the reaction may be catalysed by a transition metal, for example palladium, in the presence of suitable ligands, such as bidentate trisubstituted phosphines, for example xantphos, and a base such as an alkali metal carbonate, for example cesium carbonate.
• a compound of formula (III) may be prepared from a compound of formula (XVII) and a compound of formula (XVIII),
• a compound of formula (III) may be prepared by reaction of a compound of formula (XIX) with a compound of formula (XX),
• a compound of formula (XVII) may be prepared by reaction of a compound of formula
• mixtures of isomers e.g. racemates
• a single stereoisomer may be obtained by isolating it from a mixture of isomers (e.g., a racemate) using, for example, chiral chromatographic separation.
• a further embodiment encompasses pharmaceutically acceptable salts of the compounds of formula (I).
• a salt of a compound of formula (I) may be advantageous due to one or more of its chemical or physical properties, such as stability in differing temperatures and humidities, or a desirable solubility in ⁇ 3 ⁇ 40, oil, or other solvent.
• a salt may be used to aid in the isolation or purification of the compound.
• the salt is pharmaceutically acceptable.
• pharmaceutically acceptable salts include, but are not limited to, an alkali metal salt, e.g. Na or K, an alkali earth metal salt, e.g. Ca or Mg, or an organic amine salt.
• pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid addition salts.
• an acid or base co-former is a solid at rt and there is no or only partial proton transfer between the compound of formula (I) and such an acid or base co-former, a co-crystal of the co-former and compound of formula (I) may result rather than a salt. All such co- crystal forms of the compound of formula (I) are encompassed.
• the compounds of formula (I) may form mixtures of its salt and co-crystal forms. It is also to be understood that salt/co-crystal mixtures of the compound of formula (I) are encompassed
• Salts and co-crystals may be characterized using well known techniques, for example X-ray powder diffraction, single crystal X-ray diffraction (for example to evaluate proton position, bond lengths or bond angles), solid state NMR, (to evaluate for example C, N or P chemical shifts) or spectroscopic techniques (to measure for example, O-H, N-H or COOH signals and IR peak shifts resulting from hydrogen bonding).
• X-ray powder diffraction for example to evaluate proton position, bond lengths or bond angles
• solid state NMR to evaluate for example C, N or P chemical shifts
• spectroscopic techniques to measure for example, O-H, N-H or COOH signals and IR peak shifts resulting from hydrogen bonding.
• certain compounds of formula (I) may exist as racemates and racemic mixtures, single enantiomers, individual diastereomers and diastereomeric mixtures. It is to be understood that all such isomeric forms are encompassed. Certain compounds of formula (I) may also contain linkages (e.g. carbon-carbon bonds, carbon-nitrogen bonds such as amide bonds) wherein bond rotation is restricted about that particular linkage, e.g.
• a derivative is a derivative of a compound of formula (I) wherein one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature.
• isotopes examples include 3 ⁇ 4 (also written as "D" for deuterium).
• the compounds of formula (I) may be administered in the form of a prodrug which is broken down in the human or animal body to give a compound of the formula (I).
• prodrugs include in vivo hydro lysable esters of a compound of the formula (I).
• An in vivo hydrolysable (or cleavable) ester of a compound of the formula (I) that contains a carboxy or a hydroxy group is, for example, a pharmaceutically acceptable ester which is hydrolyzed in the human or animal body to produce the parent acid or alcohol.
• ester prodrugs derivatives see: Curr. Drug. Metab. 2003, 4, 461.
• prodrug derivatives see: Nature Reviews Drug Discovery 2008, 7, 255 and references cited therein.
• LCMS was run in two set ups: 1) BEH C18 column (1.7 ⁇ 2.1x50 mm) in combination with a gradient (2-95% B in 5 min) of aqueous 46 mM NH4HCO3/NH3 buffer at pH 10 (A) and MeCN (B) at a flow rate of 1.0 mL/min or in combination with a gradient (5-95% B in 2 min) of water and TFA (0.05%) (A) and MeCN and TFA (0.05%) at a flow rate of 1.0 mL/min (B).
• Preparative SCF was performed with a Waters Prep 100 SCF system with integrated MS detection, equipped with Waters Viridis 2-EP or Phenomenex Luna Hilic, 30 x 250 mm, 5 ⁇ .
• Samples were mounted on single silicon crystal (SSC) wafer mounts and powder X-ray diffraction was recorded with a PANalytical X'Pert PRO (reflection geometry, wavelength of X-rays 1.5418 A nickel-filtered Cu radiation, Voltage 45 kV, filament emission 40 niA). Automatic variable divergence and anti scatter slits were used and the samples were rotated during measurement. Samples were scanned from 2 - 50 °2Theta or 2 - 40 °2Theta using a 0.013° step width and between 44 and 233 seconds count time using a PIXCEL detector (active length 3.35 °2Theta).
• SSC single silicon crystal
• an X-ray powder diffraction pattern may be obtained which has one or more measurement errors depending on measurement conditions (such as equipment, sample preparation or machine used).
• intensities in an X-ray powder diffraction pattern may fluctuate depending on measurement conditions and sample preparation.
• persons skilled in the art of X-ray powder diffraction will realise that the relative intensities of peaks may vary according to the orientation of the sample under test and on the type and setting of the instrument used.
• the position of reflections can be affected by the precise height at which the sample sits in the diffractometer and the zero calibration of the diffractometer.
• the surface planarity of the sample may also have a small effect.
• a measurement error of a diffraction angle in an X-ray powder diffractogram may be approximately plus or minus 0.1° 2-theta, and such a degree of a measurement error should be taken into account when considering the X-ray powder diffraction data.
• intensities might fluctuate depending on experimental conditions and sample preparation (e.g. preferred orientation).
• the following definitions have been used for the relative intensity (%): 81 - 100%, vs (very strong); 41 - 80%, str (strong); 21 - 40%, med (medium); 10 - 20%, w (weak); 1 - 9%, vw (very weak).
• Mobile Phase A: Water/6.5 mM ammonium hydrogen carbonate + 40mM ammonia; B:95% MeCN, 5% (v/v) water 16.5 mM ammonium hydrogen carbonate + 40mM ammonia
• N-(5- ⁇ 7-chloro-2-[(15)-l-cyclopropylethyl]-l- oxo-2,3-dihydro-lH-isoindol-5-yl ⁇ -4-methyl-l,3-thiazol-2-yl)acetamide (Intermediate 6, 20 g, 51.30 mmol), phenylmethanethiol (12.74 g, 102.59 mmol), and sodium 2-methylbutan-2- olate (11.30 g, 102.59 mmol) in DMF (500 mL)
• the reaction mixture was stirred for a further 2 h at l lO °C .
• the reaction mixture was filtered through celite. The solvent was removed under reduced pressure.
• the crude product was purified by flash silica chromatography, elution gradient 0 to 25% EtOAc in DCM. Pure fractions were evaporated to dryness to afford the title compound (18.00 g) as a yellow solid,
• Methanamine (2M in THF, 22.0 mL, 44.0 mmol) was added dropwise to 6-[2-(acetylamino)- 4-methyl-l,3-thiazol-5-yl]-2-[(15)-l-cyclopropylethyl]-3-oxo-2,3-dihydro-lH-isoindole-4- sulfonyl chloride (Intermediate 14, 2 g, 4.41 mmol), in DCM (40 mL) at 25°C over a period of 30 min under nitrogen. The resulting mixture was stirred at 25 °C for 12 h. The solvent was removed under reduced pressure. The crude product was purified by flash silica
• Xantphos (1.145 g, 1.98 mmol) was added to 2,6-dibromopyridine (3.51 g, 14.84 mmol), morpholin-3-one (1 g, 9.89 mmol), PdOAc 2 (0.111 g, 0.49 mmol) and Cs 2 C0 3 (6.45 g, 19.78 mmol) in 1,4-dioxane (100 mL) at 25 °C under nitrogen. The resulting mixture was stirred at 80 °C for 12 h. The reaction mixture was filtered through celite, evaporated to dryness and redissolved in DCM (75 mL), and washed sequentially with water (50 mLx2) and saturated brine (50 mLx2).
• Lactam starting material Intermediate 44.
• Lactam starting material Intermediate 49.
• Lactam starting material Intermediate 47.
• Lactam starting material Intermediate 48.
• Lactam starting material J. Med. Chem., 2015, 58, 9179.
• Lactam starting material Intermediate 46.
• Lactam starting material Intermediate 45.
• Lactam starting material Angewandte Chemie - Int. Ed., 2006, 45, 1463.
• Lactam starting material Helv. Chim. Acta, 1990, 73, 122.
• Lactam starting material Tetrahedron, 2000, 56, 7705.
• Lactam starting material Org. Lett., 2005, 7, 553.
• Lactam starting material WO2014008285A1.
• 6-Bromopyridin-2-amine (5.09 g, 29.42 mmol) and 4-bromobutanoyl chloride (6.55 g, 35.30 mmol) were added to MeCN (50 mL) at 0 °C in a 250 ml flask. Then pyridine (3.56 mL, 44.13 mmol) was added dropwise to the mixture. The reaction mixture was allowed to reach rt and was stirred for 2 h. LCMS showed product formation. The reaction mixture was stirred at rt overnight. The MeCN was concentrated and then the mixture was diluted with 200 ml of EtOAc, washed twice with 2x 100ml of 0.4 M HC1 and once with brine.
• the residue was purified by automated flash chromatography on a Biotage® KP-SIL 340 g column. A gradient from 0% to 75% of EtOAc in heptane over 15 CV was used as mobile phase. The product was collected using the wavelength 254 nm; (5.22 g) was obtained as a yellow glass solid.
• the reaction mixture was diluted with DCM (200 mL), and washed sequentially with saturated NaHCC”3 (2x150 mL), and saturated brine (150 mL).
• the organic layer was dried over Na2SC"4, filtered and evaporated to afford the crude product.
• the crude product was purified by flash silica chromatography, elution gradient 0 to 5% MeOH in DCM. Pure fractions were evaporated to dryness to afford the title compound (3.10 g) as a yellow solid.
• 6-(2-Amino-4-methyl-l,3-thiazol-5-yl)-2-[(15)-l-cyclopropylethyl]-N-methyl-3-oxo-2,3- dihydro-lH-isoindole-4-sulfonamide (Intermediate 32, 150 mg, 0.37 mmol), benzyl 4-(6- bromopyridin-2-yl)-3-oxopiperazine-l-carboxylate (Intermediate 53, 288 mg, 0.74 mmol), Xantphos (64.1 mg, 0.11 mmol), 2nd Generation XantPhos precatalyst (65.6 mg, 0.07 mmol) and Na2CC"3 (117 mg, 1.11 mmol) were mixed in DMF (5 mL) and sealed into a microwave tube.
• the reaction was heated to 130 °C for 2.5 h in the microwave reactor and cooled to rt.
• the crude product was purified by flash silica chromatography, elution gradient 0 to 3% MeOH in DCM. Pure fractions were evaporated to dryness to afford the title compound (160 mg) as a pale yellow solid.
• reaction mixture was diluted with DCM (25 mL).
• the aqueous layer was separated and re-extracted with DCM (25 mL).
• the organic layers were combined, dried over Na2SC>4, filtered and evaporated to afford crude product that was purified by flash silica
• the reaction was heated to 125 °C for 1 h in the microwave reactor and cooled to RT. The solvent was removed under reduced pressure. The crude product was purified by flash silica chromatography, elution gradient 0 to 4% MeOH in CH2CI2 and then by preparative
• the pure solid residue (69 mg) was suspended in a mixture of ethanol and water (3: 1, 1.4 mL) and this suspension was slurried at a range of tempeatures as follows : 110 °C (4 x 30 min allowing to cool to ambient temperature inbetween each time); 110 °C (60 min), 90 °C (60 min), 80 °C (60 min) and then left to cool to ambient temperature overnight.
• the resultant solid was collected and dried to give the title compound (64 mg) which was found to be crystalline by XRPD and a typical diffractogram is displayed in Figure 1. Characteristic peak positions are listed below in Tables 1 and 2.
• the mixture was filtered through a pad of silica (eluted with 200 mL DCM:MeOH 9: 1) and evaporated to dryness.
• the resulting solid was suspended in methanol (120 mL) and the suspension was heated to 50 °C overnight.
• the solid was collected and then suspended in methanol (120 mL) at 50 °C overnight.
• the solid was collected, washed with methanol (50 mL) and then heptane (50 mL) and was then dissolved in methanol : DCM (1 :9, 120 mL).
• Methanol (120 mL) was added and the volume was reduced to ca 120 mL; the resulting suspension was stirred for 24 h at 50 °C.
• the solid was collected, washed with methanol (50 mL) and dried to give the title compound (10.0 g) as a yellow solid.
• the solid product was found to be crystalline by XRPD and a typical diffractogram is displayed in Figure 2. Characteristic peak positions are listed below in Tables 3 and 4.
• Example 1 Alternative preparation 2 Cesium carbonate (0.56 g), l-(6-((4-methylthiazol-2-yl)amino)pyridin-2-yl)pyrrolidin-2-one (Intermediate 115, 0.22 g), 5-Chloro-2-[(lS)-l-cyclopropylethyl]-7-(methylsulfonyl)-2,3- dihydro-lH-isoindol-l-one (Intermediate 120, 0.25 g) and Pd-118 (0.015 g) were combined in DMF (2.5 mL) and the mixture was degassed thoroughly. The mixture was heated to 85 °C for 140 min and then allowed to cool. Water (5 mL) was added and the mixture was stirred for 75 min before the precipitated solid was collected to give the title compound as a yellow solid.

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