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WO2012069852A1 - Composés pharmaceutiques en tant qu'inhibiteurs de la sphingosine kinase - Google Patents

Composés pharmaceutiques en tant qu'inhibiteurs de la sphingosine kinase Download PDF

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WO2012069852A1
WO2012069852A1 PCT/GB2011/052334 GB2011052334W WO2012069852A1 WO 2012069852 A1 WO2012069852 A1 WO 2012069852A1 GB 2011052334 W GB2011052334 W GB 2011052334W WO 2012069852 A1 WO2012069852 A1 WO 2012069852A1
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tetramethyl
tetrahydronaphthalen
pyridin
butyl
tert
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Timothy Harrison
Frank Burkamp
Linda Jordan
Mark Bell
Dominic Janssen
Hugues Miel
Mary Mcfarland
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Almac Discovery Ltd
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Almac Discovery Ltd
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/26—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
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    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
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    • C07D401/04—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 directly linked by a ring-member-to-ring-member bond
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    • 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
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    • C07D403/04—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 directly linked by a ring-member-to-ring-member bond
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    • 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
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    • 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
    • C07D471/10—Spiro-condensed systems
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    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to compounds that are useful as inhibitors of the activity of one or more isoforms of sphingosine kinase. Particularly, although not exclusively, the present invention also relates to pharmaceutical compositions comprising these compounds and to the use of these compounds in the treatment and/or prevention of cancers, hyperproliferative, inflammatory, angiogenic, immune and viral infectious diseases. BACKGROUND TO THE INVENTION
  • Sphingolipids not only represent the major component of the cellular membrane but also serve as a reservoir for important signaling molecules with pleiotropic effects on important cellular processes.
  • Sphingolipid metabolites including ceramide, sphingosine and sphingosine-1 phosphate (S1 P) have emerged as a new class of potent bioactive messengers directly involved in numerous pathological conditions and disorders including cancer, hyperproliferative, inflammatory and immune disorders, angiogenesis, and viral infectious diseases. Consequently, the possibilities of harnessing the sphingolipid metabolic pathways represent a new avenue for the treatment and prevention of a variety of diseases related to undesirable sphingosine kinase (SphK) activity and S1 P homeostasis.
  • SphK undesirable sphingosine kinase
  • Ceramide results from the hydrolysis of sphingomyelin in response to various stimuli including inflammatory cytokines, chemokines, growth factors and hormones. Ceramide is further hydrolysed by ceramidase to produce sphingosine. Sphingosine in turn is rapidly phosphorylated by sphingosine kinase to produce S1 P.
  • ceramide and sphingosine exert antiproliferative effects such as cell growth inhibition, apoptosis induction and/or modulation of senescence.
  • S1 P is a growth promoter and survival factor, acting by up-regulating several anti-apoptotic pathways including PI3K/AKT or nuclear factor- ⁇ (NF-KB).
  • PI3K/AKT PI3K/AKT
  • NF-KB nuclear factor- ⁇
  • SphK sphingosine kinase
  • Both enzymes phosphorylate sphingosine to produce S1 P.
  • the functions of SphK1 and 2 are at least partly redundant as mice lacking either isoforms maintain nearly normal levels of S1 P and lack severe phenotypes.
  • the SphK1 and 2 double knock-out mouse is embryonic lethal due to incomplete maturation of the vascular system and brain.
  • Overexpression of mice SphK1 in NHI-3T3 fibroblasts induces transformation via a Ras-dependant signaling pathway, hence demonstrating the oncogenic function of the enzyme.
  • sphingosine kinases are ubiquitously expressed in cells with increased expression of SphK1 commonly reported in tumor tissues.
  • SphK may be activated by a variety of proliferative factors including Tumor Necrosis Factor-alpha (TNFoc), protein kinase C (PKC), serum or Platelet-Derived Growth Factors (PDGF).
  • TNFoc Tumor Necrosis Factor-alpha
  • PKC protein kinase C
  • PDGF Platelet-Derived Growth Factors
  • S1 P can then act as an intramolecular messenger and/or extracellular ligand for specific G-protein coupled receptors; namely S1 PR1 , S1 PR2, S1 PR3, S1 PR4, S1 PR5.
  • S1 P The intracellular action of S1 P is pro-survival and pro-growth whilst signaling through the S1 P receptors elicits various cellular processes important to tumorigenesis and cancer progression including proliferation, survival, differentiation, transformation and vascularization / angiogenesis.
  • SphK activity SphK1 , SphK2
  • SphK up-regulation correlates in the clinical setting with higher clinical grades and poor patient outcome.
  • down-regulation of SphK (SphK1 , SphK2) by siRNA, inhibition by a dominant-negative SphK mutant or treatment with small molecule inhibitors has demonstrated strong anti-proliferative effects and has been shown to block
  • Cancers that can be treated, managed and/or ameliorated include, but are not restricted to, benign, pre- malignant, metastatic and malignant cancers. Such cancers may include, without limitations, solid tumors as well as hematopoietic cancers.
  • SphK1 overexpression typically impairs treatment efficacy by decreasing the ceramide / S1 P ratio.
  • SphK1 , SphK2 down- regulation of SphK (SphK1 , SphK2) by siRNA or pharmacologic inhibition induces ceramide elevation with concomitant loss of S1 P and apoptosis induction hence overcoming the resistance phenotype.
  • MDR-associated protein MDR-associated protein
  • Pgp P-gylcoprotein
  • SphK inhibitors alone or in combination therapies could provide a new strategy for the treatment and management of therapeutic-resistant cancers. While maintaining and/or enhancing efficacy of current single agent treatment or combination therapies, combinations with SphK (SphK1 , SphK2) inhibitors may provide a better therapeutic profile by improving efficacy and/or reducing unwanted, adverse effects.
  • Treatments that can be used in combination with SphK (SphK1 , SphK2) inhibitors include, but or not restricted to, chemo- and radiotherapy, cancer vaccines, cytokines, immunotherapeutics (including antibodies or immunomodulators), anti- angiogenic agents, hormone therapies and gene therapies.
  • hypoxia Another condition known to promote tumor progression and treatment failure in which the SphK / S1 P pathway is involved is hypoxia. Hypoxia exists in 50-60% of solid tumors. To circumvent periods of insufficient nutrient and oxygen supply, cells evolve
  • hypoxia-inducible factor HIF-1 oc
  • the SphK/S1 P pathway is a strong modulator of HIF- 1 a activity under hypoxic conditions.
  • HIF-1 a positively regulates the expression of SphK1 under hypoxia.
  • Increased expression and activation of SphK1 and S1 P signaling through the S1 P receptors has been correlated with
  • SphK1 SphK2 activity may therefore provide a novel approach to treat hypoxic tumors.
  • Angiogenesis refers to a state in the body whereby various stimuli including growth factors promote the formation of new blood vessels. Excessive angiogenesis is commonly associated with disease progression and/or the production of undesirable effects. For instance, signaling of S1 P through the S1 P1 receptor stimulates NFKB production and promotes the formation of vascular endothelial growth factor (VEGF), COX-2, cytokines and adhesion molecules, all known contributors to VEGF (VEGF), COX-2, cytokines and adhesion molecules, all known contributors to VEGF.
  • VEGF vascular endothelial growth factor
  • angiogenesis In addition, SphK regulates the expression of endothelial isoforms of nitric oxide synthase which have also been implicated in modulating angiogenesis.
  • treatment of mice with anti-S1 P mAb blocked endothelial cell migration, capillary formation, inhibited VEGF- and FGF-induced blood vessel formation and arrested tumor- associated angiogenesis.
  • the S1 P mAb also prevented the release of pro-angiogenic cytokines (IL-8, IL-6) from tumor cells.
  • SphK SphK1 , SphK2
  • S1 P production in vascular endothelial cells can lead to reduction of angiogenesis and provide a novel strategy to treat and/or prevent disorders arising from abnormal angiogenesis.
  • disorders include, but are not limited to, cancer, hemangiomas, arthritis, psoriasis, atherosclerosis, myocardial angiogenesis, diabetic retinopathy and/or macular degeneration.
  • Sphk SphK1 , SphK2
  • S1 P are also emerging as important mediators in
  • SphK1 has been shown to be activated by cytokines including tumors necrosis factor-alpha (TNF-alpha) and interleukinl -beta (IL1 -beta).
  • TNF-alpha tumors necrosis factor-alpha
  • IL1 -beta interleukinl -beta
  • the activation of SphK1 in this pathway has been shown to be, at least in part, required for mediating TNF-alpha and IL1 -beta inflammatory responses in cells, including induction of cyclo-oxygenease 2 (COX2).
  • COX2 cyclo-oxygenease 2
  • SphKs and S1 P have also been implicated in various immune cell functions including mast cell degranulation, migration of neutrophils, maturation and migration of lymphocytes, and T-cell development.
  • Sphingosine kinase (SphK1 , SphK2) inhibitors may be used as single agent or administered in conjunction with known immunomodulators or anti- inflammatory agents.
  • immune disorders include, but are not restricted to ankylosing spondylitis, chronic fatigue immune dysfunction syndrome, Crohn's disease, multiple sclerosis, rheumatoid arthritis, autoimmune hepatitis, polyglandular syndromes, organ transplantation, post-surgical organ failure.
  • inflammatory diseases include, but are not limited to, inflammatory bowel disease, asthma, allergy, septic shock, inflammatory kidney disease, post-surgical organ failure, organ transplantation, multiple sclerosis, skin inflammation and chronic inflammation as a result of viral or bacteria infections.
  • SphK SphK1 , SphK2
  • S1 P are involved in various other pathological states such as diabetes, viral infections including HIV and Hepatitis C as well as diverse hyperproliferative disorders in addition to cancer including, but not limited to, psoriasis which is characterised by local keratinocyte hyperproliferation, mesangial disorders resulting from the abnormal proliferation of mesangial cells in the kidney as well as various vascular disorders such as atherosclerosis and restenosis both characterised by hyperproliferation of vascular smooth muscle cells.
  • psoriasis which is characterised by local keratinocyte hyperproliferation
  • mesangial disorders resulting from the abnormal proliferation of mesangial cells in the kidney well as various vascular disorders such as atherosclerosis and restenosis both characterised by hyperproliferation of vascular smooth muscle cells.
  • vascular disorders such as atherosclerosis and restenosis
  • SphK inhibitors are expected to be of use in the prevention, therapy and/or management of these diseases.
  • Examples of SphK1 inhibitors are provided in WO 2009/156041 and DE 10 2008/029734. These documents provide specific thiazolo-piperidine compounds. It would be useful if there were compounds available that showed improved activity, differential activity between different types of enzymes, differential activity between the sphingosine isoforms, better stability, greater ease of formulation, and an improved side- effect profile. It is an object of the present invention to address these needs in the art, to address the shortcomings of the prior art compounds, or to at least provide the public with a useful alternative.
  • the present invention provides a compound according to formula I
  • RrR 8 are independently hydrogen, lower alkyl, phenyl or benzyl and where X is O, CRR', or NR' where R and R' are independently hydrogen or lower alkyl and where for structures c and d Ri and R 2 may together form an optionally lower alkyl substituted 5 or 6 membered ring and where R 3 is optionally OR" where R" is alkyl or aryl;
  • X 1 , X 2 , X 3 , X 4 , X 5 , and X 6 are independently selected from nitrogen atom or carbon atom optionally substituted with halogen, oxo, cyano, amino, aryl, heteroaryl, optionally substituted lower alkoxyl and optionally substituted lower alkyl,
  • X 1 , X 2 , X 3 , X 4 , X 5 , and X 6 is an oxo-substituted carbon atom at least one of the others is a nitrogen atom;
  • X 1 , X 2 , X 3 , X 4 , X 5 , and X 6 are nitrogen atoms; and wherein Q is a heteroatom-containing alkyl, substituted alkyl, optionally substituted cycloalkyi, optionally substituted aryl, or optionally substituted heterocyclyl containing side chain bound through a heteroatom or directly through a carbon atom; and pharmaceutically acceptable salts, stereoisomers and tautomers thereof.
  • Ri , R 2 , R 5 and R 6 are independently hydrogen, lower alkyl or lower cycloalkyi. More preferably Ri , R 2 , R5 and R 6 are each methyl, or and R 2 are both methyl and R 5 and R 6 are both hydrogen, or R 5 and R 6 are both methyl and Ri and R 2 are both hydrogen. In preferred embodiments where substructure 'a' is present R 3 is benzyloxy and R 4 is hydrogen. In preferred embodiments where substructure 'b' is present, Ri , R 2 , R 7 and R 8 are independently hydrogen, lower alkyl or lower cycloalkyi.
  • Ri , R 2 , R 7 and R 8 are each methyl, or R 7 and R 8 are both methyl and Ri and R 2 are both hydrogen. In particularly preferred compounds R 7 and R 8 are both methyl. In these preferred embodiments, R 3 , R 4 , R 5 and R 6 are each hydrogen.
  • the preferred gem-dimethyl groups may be joined to form a cyclopropyl group or other lower cycloalkyi group.
  • Ri , R 3 , and R 4 are independently hydrogen, lower alkyl or lower cycloalkyi, Ri and R 4 may cooperate to form a lower cycloalkyi group, and R 2 is lower alkyl or lower cycloalkyi; where X is preferably O or NR' where R' is H, lower alkyl or lower cycloalkyi and where R 3 and R 2 may cooperate to form a 5 or 6 membered heterocyclic ring.
  • R 2 is a branched lower alkyl group.
  • substructure 'c' wherein Ri R 2 , R 3 , and R 4 are defined as above.
  • the compound is not morpholine-2-carboxylic acid [6-(5,5,8,8- tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-pyridin-2-yl]-amide or a compound selected from compounds of formula (I I)
  • R 9 and R ⁇ R and R 2 , R 2 and R 3 , R 3 and R 4 , R 4 and R 5 , R 5 and R 6 , R 6 and R 7 , R 7 and R 8 , R 0 and R , R and R 2 , R 2 and R 3 , R 4 and R 5 , R 5 and R 6 , R 6 and R 7 may also in each case together form a cycloalkyl having 3, 4, 5, 6 or 7 C atoms or Het having 3, 4, 5, 6 or 7 ring atoms,
  • R 8 , R 8' represent H, Dor A;
  • R 9 , R 9' represent H, D, A, OR 18 , NR 8 R 18 , F, CI, Br, CN or Het;
  • Mi, M 2 , M 3 , M 4 represent CR 19 or N;
  • Yi, Y 2 represent CR 19 or N;
  • V represents C(R 9 )(R 19' ), NR 9 or is absent;
  • W represents [C(R 9 )(R 9' )] P Z, CO-[C(R 9 )(R 9' )] p Z, [C(R 9 )(R 9' )] P N(R 9 )-Z, CO-N(R 19 ) [C(R 9 )(R 9' )] p Z, N(R 9 )-CO-[C(R 9 )(R 9' )] p Z, CO-0-[C(R 9 )(R 9' )] p Z, C(0)OR 18 , OR 18 , H or D;
  • V, W and Y 2 may also in each case together form a cycloalkyl having 3, 4, 5, 6 or 7 C atoms, in which preferably 1 , 2, 3, 4, 5, 6 or 7 H atoms can be replaced with F, CI, Br, CN and/or OH, OR 19 , OC(0)R 19 , NR 9 C(0)OZ, C(0)OR 19 , C(0)N(R 9 )(R 19' ) or N(R 9 )(R 19' ), or form Het having 3, 4, 5, 6 or 7 ring atoms, wherein Het is preferably a saturated, unsaturated or aromatic heterocycle having 1 to 4 N, O and/or S atoms which can be unsubstituted or singly, doubly or triply substituted with Hal, F, CI, Br, CN, A, OR 18 , W, SR 8 , N0 2 , N(R 9 )(R 19' ),
  • Z represents Het, Ar or A
  • A represents unbranched or branched alkyl having 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10 C atoms, in which 1 , 2, 3, 4, 5, 6 or 7 H atoms can be replaced with F, CI, Br, CN and/or OH, OR 19 , OC(0)R 19 , NR 9 C(0)OZ, C(0)OR 19 , C(0)N(R 9 )(R 19' ) or N(R 9 )(R 19' );
  • Ar represents phenyl, naphthyl or biphenyl substituted singly, doubly or triply with Hal, F, CI, Br, CN, A, OR 18 , W, SR 8 , N0 2 , N(R 9 )(R 19' ), NR 8 COOZ, OCONHZ, NR 8 S0 2 Z,
  • Het represents, in each case independently of one another, a mononuclear, binuclear or trinuclear saturated, unsaturated or aromatic heterocycle having 1 to 4 N, O and/or S atoms which can be unsubstituted or singly, doubly or triply substituted with Hal, F, CI, Br, CN, A, OR 18 , W, SR 18 , N0 2 , N(R 9 )(R 19' ), NR 8 COOZ, OCONHZ, NR 8 S0 2 Z,
  • n 1 , 2 or 3
  • n, o are 0, 1 or 2
  • p 0, 1 , 2, 3 or 4
  • the compound is not a compound selected from the group: morpholine-2-carboxylic acid [6-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)- pyridin-2-yl]-amide
  • Q is not a heteroatom-containing optionally substituted aryl.
  • one or more of X 1 , X 2 , X 3 , X 4 , X 5 , and X 6 is an oxo- substituted carbon atom, methyl substituted carbon atom, or fluorine substituted carbon atom.
  • one or more of X 1 , X 2 , X 3 , X 4 , X 5 , and X 6 is a carbon atom or nitrogen atom.
  • X 1 , X 2 , X 3 , X 4 , X 5 , and X 6 are carbon atoms or nitrogen atoms.
  • the ring formed by X 1 , X 2 , X 3 , X 4 , X 5 , and X 6 is aromatic or doubly unsaturated, more preferably the ring is aromatic.
  • the groups X 1 , X 2 , X 3 , X 4 , X 5 , and X 6 are selected so as to form, together with the atoms to which they are bonded, the following ring structures:
  • the groups X 1 , X 2 , X 3 , X 4 , X 5 , and X 6 are selected so as to form, together with the atoms to which they are bonded, a pyrimidine ring.
  • a pyrimidine ring is selected so as to form, together with the atoms to which they are bonded, a pyrimidine ring.
  • the Inventors have found that surprisingly the presence of a pyrimidine group at this position combines good inhibition activity with improved physical properties of the compounds of the invention, such as their solubility, and that certain compounds having the pyrimidine ring present therefore have good pharmacokinetic properties, and are preferred.
  • at least one of the heteroatoms in Q is a nitrogen atom.
  • Q contains at least two heteroatoms, more preferably two nitrogen atoms.
  • Q may be selected from:
  • R10- 14 are selected from hydrogen or optionally substituted lower alkyl, or may combine with other R groups in Q to form optionally substituted cycloalkyl or optionally substituted heterocycloalkyl rings which may be aromatic or non-aromatic.
  • R 0 may, together with a nitrogen atom to which it is bound, form a guanidino group. In other preferred embodiments R 0 may be a double bonded nitrogen atom and any other R x moiety bound to the same atom is absent.
  • one or more aromatic carbon atoms of the benzylamino group may be replaced with N, for example to give those two pyridines shown in the structures above. Where two aromatic carbon atoms are replaced by nitrogen they are preferably arranged to give a pyridazine ring, although pyrimidine and pyrazine arrangements are also available in certain embodiments of the invention.
  • Particulary preferred are compounds of the invention having optionally substituted guanidino or amidino moiety containing Q groups.
  • the compounds of the invention have a guanidine or amidino group forming part of the side-chain 'Q' moiety.
  • the guanidine or amidino group forming part of the side-chain 'Q' moiety may be optionally substituted, preferably with cyano, OH or OR" where R" is optionally substituted lower alkyl.
  • alkyi group refers to an aliphatic group containing at least carbon and hydrogen and containing 1 to 15 carbon atoms, such as 1 to 10 carbon atoms.
  • Attachment to the alkyi group occurs through a carbon atom.
  • Cn alkyi refers to an aliphatic group containing n carbon atoms.
  • a C1 -C10 alkyi group contains 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms.
  • An alkyi group may be straight chained or it may be branched.
  • An alkyi group may contain no ring structures or it may contain one or more rings.
  • the alkyi group is a lower alkyi group, that is one having between 1 and 6 carbon atoms whether branched or straight chain.
  • a "cycloalkyi" group contains at least one ring. It is understood that attachment to a cycloalkyi group is via a ring of the cycloalkyi group.
  • Each ring may contain 3 to 10 atoms, such as 4 to 8 or 5 to 7 atoms.
  • Each ring may be independently selected to contain just carbon atoms or to contain both carbon atoms and from 1 to 4 heteroatoms selected from O, N and S.
  • cyclo-heteroalkyl groups i.e.
  • cycloalkyi groups that contain one or more heteroatoms
  • attachment to the cycloalkyi group may occur either through a carbon atom or, if one or more heteroatoms are contained in a ring, attachment may also occur through a heteroatom contained in a ring.
  • a cycloalkyi group may be mono-cyclic or bi-cyclic.
  • a "C n cycloalkyi" group contains n carbon atoms. All n carbon atoms may be contained in the ring(s) of the cycloalkyi group or one or more of the carbons may not be contained in the ring(s) and may instead form one or more chains branching from the ring.
  • a Cn alkyl group is joined to a separate C m alkyl group containing m carbon atoms to form, for example, a heterocycle, the two alkyl groups contain a total number of m + n carbon atoms.
  • an alkyl group may be saturated or unsaturated.
  • the alkyl group may be an alkenyl group (i.e. contain a carbon-carbon double bond) and / or an alkynyl group (i.e. contain a carbon-carbon triple bond). If the alkyl group is unsaturated, it may contain at least 2 carbon atoms. It is understood that any unsaturated portions of an alkyl group are non-aromatic (aromatic groups fall within the scope of the definition of "aryl'). Any part of the alkyl group may be unsaturated, for example the straight, branched or cyclic portion of an alkyl group may contain a carbon-carbon double bond or a carbon-carbon triple bond. Attachment to an unsaturated alky group may occur through the unsaturated part of the alkyl group or may occur through the unsaturated part of the group.
  • an unsaturated alkyl group may contain 1 to 4 carbon-carbon double bonds or 1 to 3 carbon-carbon triple bonds or 1 to 4 of a combination of carbon-carbon double bonds and carbon-carbon triple bonds.
  • An alkyl group may be substituted with one or more heteroatoms or it may be
  • the substituents are independently selected from one another unless they form a part of a particular functional group (e.g. an amide, amidino, or guanidino group).
  • the heteroatom substituents may in turn be substituted with further carbon-containing groups.
  • the C n or C m prefix that defines the substituted alkyl group refers to the total number of carbons contained in the group, i.e. including the carbon atoms contained in any substituted heteroatomic groups, and the total alkyl group contains 1 to 15 carbon atoms as defined previously.
  • the alkyl group may, for example, contain one or more of CN, C0 2 H, CONH 2 , CONHR, CONR a R b , C0 2 R, NH 2 , NHR, NR a R b , OH, OR, SH, SR, F, CI, Br and I, wherein each R, R a and R b are independently selected groups (e.g. alkyl / aryl groups) attached to the atom to which the group joins through a carbon atom of each group, including wherein R a and R b form a heterocycle that includes the heteroatom to which they are attached.
  • a group containing two C m -C n alkyl moieties that form a cycle that includes, for example, the heteroatom to which they are attached may contain from C 2m to C 2n carbon atoms.
  • unsubstituted saturated alkyl groups containing no cyclic structures include methyl, ethyl, n-propyl, sec-propyl, n-butyl, sec-butyl, te/t-butyl, pentyl (branched or unbranched), hexyl (branched or unbranched), heptyl (branched or unbranched), octyl (branched or unbranched), nonyl (branched or unbranched), and decyl (branched or unbranched).
  • Examples of unsubstitued saturated cyclic alkyl groups include cyclopropyl, cylcobutyl, cyclopentyl and cyclohexyl.
  • Examples of unsaturated alkyl groups include ethenyl, propenyl, butenyl, 2-methybutenyl and cyclohexenyl.
  • aryl group refers to a group containing at least one ring that is aromatic.
  • aryl group is stated as being substituted at a particular position, attachment of the position to the aryl group is onto the aromatic ring of the aryl group itself rather than the position being joined to the aryl group through any non-aromatic side-chain of the aryl group.
  • R is an aryl group in CR
  • the C is attached to the aromatic part of the aryl group.
  • Each ring may be independently selected to contain only carbon atoms or to contain both carbon atoms and from 1 to 4 heteroatoms selected from O, N and S.
  • heteroaryl groups i.e. aryl groups that contain one or more heteroatoms
  • attachment to the aryl group may occur either through a carbon atom or, if one or more heteroatoms are contained in a ring, attachment may also occur through a heteroatom contained in a ring.
  • heteroatoms contained in a ring of a heteroaryl group may be substituted, for example forming an /V-oxide.
  • the aromatic group may be mono-cyclic or bi-cyclic, wherein one or both of the rings of a bi-cyclic system is aromatic.
  • aryl groups include acridinyl, phenyl, carbazolyl, cinnolinyl, quinoxalinyl, pyrrazolyl, benzotriazolyl, furanyl, naphthyl, thienyl, thiazolyl, benzothienyl, benzofuranyl, quinolinyl, isoquinolinyl, oxazolyl, isoxazolyl, indolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetrahydroquinolinyl, benzimidazolyl and melaminyl.
  • heterocycle includes within its scope both cycloalkyl groups containing one or more heteroatoms within the ring system and aryl groups containing one or more heteroatoms within the ring system.
  • halo refers to a group selected from chlorine, fluorine, bromine and iodine.
  • each tautomeric form is intended to fall within the scope of the invention.
  • each enantiomer or diastereoisomer is intended to fall within the scope of the invention.
  • one enantiomer or diasterioisomer has more desirable characteristics than the related molecule(s)
  • the one having desirable characteristics is preferred.
  • the compounds of the present invention may be provided as a pro-drug.
  • Prodrugs are transformed, generally in vivo, from one form to the active forms of the drugs described herein.
  • a prodrug may be formed by protecting an amine as a physiological hydrolyzable amide.
  • the compounds of the present invention may be provided in the form of their pharmaceutically acceptable salts or as co-crystals.
  • the compounds may be provided having protonated amine groups.
  • pharmaceutically acceptable salt refers to ionic compounds formed by the addition of an acid to a base. The term refers to such salts that are considered in the art as being suitable for use in contact with a patient, for example in vivo and
  • compositions are generally chosen for their non-toxic, non-irritant characteristics.
  • co-crystal refers to a multi- component molecular crystal, which may comprise non-ionic interactions.
  • salts and co-crystals may be prepared by ion exchange chromatography or by reacting the free base or acidic form of a compound with stoichiometric amounts or with an excess of the desired salt-forming inorganic or organic acid or base in one or more suitable solvents.
  • Salts known in the art to be generally suitable for use in contact with a patient include salts derived from inorganic and / or organic acids, including the hydrobromide, hydrochloride, sulphate, bisulphate, nitrate, acetate, oxalate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate and tartrate. These may include cations based on the alkali and alkaline earth metals, such as sodium, potassium, calcium and magnesium, as well as ammonium,
  • the compounds of the present invention may sometimes exist as zwitterions, which are considered as part of the invention.
  • the compounds of the present invention are useful in the treatment of medical conditions associated with undesirable SphK activity and S1 P homeostasis and to treat a wide range of diseases where SphK acitivity and S1 P has been shown to play a key role including cancers, hyperproliferative, inflammatory, angiogenic, immune and viral infectious diseases.
  • the present invention provides compounds according to the invention for the treatment of a disease or disorder involving associated with SphK activity and S1 P homeostasis.
  • the present invention provides the use of those compounds of the invention having selectivity for Sphkl over Sphk2 for the treatment of a disease or disorder involving or associated with SphK1 activity and S1 P homeostasis.
  • the present invention provides the use of those compounds of the invention having selectivity for Sphk2 over Sphkl for the treatment of a disease or disorder involving or associated with SphK2 activity and S1 P homeostasis.
  • the compounds of the invention are for the treatment of cancers including benign, pre-malignant, metastatic and malignant cancers.
  • the cancers to be treated may include solid tumors as well as hematopoietic cancers.
  • the compounds of the invention are for the treatment of solid cancers.
  • the Inventors have found that surprisingly certain of the compounds developed in the work detailed herein demonstrate an effect not only in inhibiting Sphkl but also a marked inhibition of Sphk2.
  • Such 'dual active' compounds are preferred compounds of the invention and preferred compounds in this regard are detailed below as Examples 39, 41 , 47, 90 and 96.
  • Some compounds of the invention in general show Sphk2 activity and these compounds are also preferred in certain embodiments of the invention.
  • the compounds of the present invention may be administered separately, sequentially, simultaneously, concurrently or may be chronologically staggered with one or more standard therapeutics..
  • the present invention also provides a pharmaceutical composition suitable for clinical use.
  • a pharmaceutical composition may comprise a pharmaceutical carrier and, dispersed therein, a therapeutically effective amount of the compounds of the invention.
  • the composition may be solid or liquid.
  • the pharmaceutical carrier is generally chosen based on the type of administration being used and the pharmaceutical carrier may for example be solid or liquid.
  • the compounds of the invention may be in the same phase or in a different phase than the pharmaceutical carrier.
  • compositions may be formulated according to their particular use and purpose by mixing, for example, excipient, binding agent, lubricant, disintegrating agent, coating material, emulsifier, suspending agent, solvent, stabilizer, absorption enhancer and / or ointment base.
  • the composition may be suitable for oral, injectable, rectal or topical administration.
  • the pharmaceutical composition may be administered orally, such as in the form of tablets, coated tablets, hard or soft gelatine capsules, solutions, emulsions, or suspensions.
  • Administration can also be carried out rectally, for example using suppositories, locally or percutaneously, for example using ointments, creams, gels or solution, or parenterally, for example using injectable solutions.
  • the compounds of the present invention may be admixed with pharmaceutically inert, inorganic or organic excipients.
  • suitable excipients include lactose, mize starch or derivatives thereof, talc or stearic acid or salts thereof.
  • suitable excipients for use with soft gelatine capsules include, for example, vegetable oils, waxes, fats and semi-solid or liquid polyols.
  • excipients include, for example, water, polyols, saccharose, invert sugar and glucose.
  • excipients include, for example, water, alcohols, polyols, glycerine and vegetable oil.
  • excipients include, for example, natural or hardened oils, waxes, fats and semi-solid or liquid polyols.
  • compositions may also contain preserving agents, solublizing agents, stabilizing agents, wetting agents, emulsifiers, sweeteners, colorants, odorants, buffers, coating agents and / or antioxidants.
  • the second drug may be provided in pharmaceutical composition with the present invention or may be provided separately.
  • a pharmaceutical formulation for oral administration may, for example, be granule, tablet, sugar coated tablet, capsule, pill, suspension or emulsion.
  • a sterile aqueous solution may be provided that may contain other substances including, for example, salts and / or glucose to make to solution isotonic.
  • the therapeutic agent may also be administered in the form of a suppository or pessary, or may be applied topically in the form of a lotion, solution, cream, ointment or dusting powder.
  • Sphkl /Sphk2 of greater than 10 ie the activity in inhibiting Sphkl is 10-fold greater than the inhibition of Sphk2.
  • those compounds where the selectivity is much higher than 10, eg 50 or higher are also preferred.
  • those compounds that demonstrate selectivity for Sphk2 over Sphkl of around 10 times or greater are also preferred.
  • the present invention provides the use of the preferred compounds having selectivity as described herein for inhibiting Sphkl or Sphk2.
  • these enzymes are inhibited by the use of a compound of the invention having specificity for that subtype such that the other subtype is relatively less inhibited.
  • DCM Dichloromethane
  • DIPEA Diisopropylethylamine
  • DMA N,N- Dim ethyl acetamide
  • DMAP 4-Dimethylaminopyridine
  • DME Dimethyl ether
  • DMF /V,/V-Dimethylformamide
  • DMSO Dimethylsulfoxide
  • EDCI 1 -Ethyl-3-(3'-dimethylaminopropyl)carbodiimide
  • EtOAc Ethyl acetate
  • h Hour: HATU: 0-(7-Azabenzotriazol-1 -yl)-A/,/V,/V',/V- tetramethyluronium hexafluorophosphate
  • HCI Hydrochloric acid
  • HOBt 1 -
  • THF Tetrahydrofuran
  • TMSCI Trimethylsilyl chloride
  • H NMR spectra were recorded at ambient temperature using a Varian Unity Inova (400MHz) spectrometer with a triple resonance 5mm probe, a Bruker Avance DRX (400MHz) with a 5mm inverse detection triple resonance TXI probe, a Bruker Avance (500MHz) spectrometer with a 5mm QNP probe or a Bruker Avance DPX (300MHz) spectrometer with a standard 5mm dual frequency probe. Chemical shifts are expressed in ppm relative to tetramethylsilane.
  • Method A The system consists of a Agilent Technologies 6120 single quadrupole mass spectrometer linked to a Agilent Technologies 1200 Preparative LC system with Multiple Wavelength detector and autosampler.
  • the spectrometer has a multimode ionization source (electrospray and atmospheric pressure chemical ionizations) operating in positive and negative ion mode. Fraction collection is mass-triggered.
  • a purification experiment is performed on each sample submitted using the following conditions: LC Column - Waters XBridgeTM Prep C18 5 ⁇ OBDTM 19 x 50mm column at room temperature. Mobile phase - A) Water 0.1 % ammonium hydroxide B) Acetonitrile/Water 95: 5 with 0.1 % ammonium hydroxide.
  • Method B The system consists of a Agilent Technologies 6120 single quadrupole mass spectrometer linked to a Agilent Technologies 1200 Preparative LC system with Multiple Wavelength detector and autosampler.
  • the spectrometer has a multimode ionization source (electrospray and atmospheric pressure chemical ionizations) operating in positive and negative ion mode. Fraction collection is mass-triggered.
  • a purification experiment is performed on each sample submitted using the following conditions: LC Column - Waters XBridgeTM Prep C18 5 ⁇ OBDTM 19 x 50mm column at room temperature. Mobile phase - A) Water 0.1 % ammonium hydroxide B) Acetonitrile/Water 95: 5 with 0.1 % ammonium hydroxide.
  • Method C The system consists of a Agilent Technologies 6120 single quadrupole mass spectrometer linked to a Agilent Technologies 1200 Preparative LC system with Multiple Wavelength detector and autosampler.
  • the spectrometer has a multimode ionization source (electrospray and atmospheric pressure chemical ionizations) operating in positive and negative ion mode. Fraction collection is mass-triggered. A purification experiment is performed on each sample submitted using the following conditions: LC Column - Waters XBridgeTM Prep C18 5 ⁇ OBDTM 30 x 100mm column at room temperature. Mobile phase - A) Water 0.1 % ammonium hydroxide B) Acetonitrile/Water 95: 5 with 0.1 % ammonium hydroxide.
  • Method D The system consists of a Agilent Technologies 6120 single quadrupole mass spectrometer linked to a Agilent Technologies 1200 Preparative LC system with Multiple Wavelength detector and autosampler.
  • the spectrometer has a multimode ionization source (electrospray and atmospheric pressure chemical ionizations) operating in positive and negative ion mode. Fraction collection is mass-triggered.
  • a purification experiment is performed on each sample submitted using the following conditions: LC Column - Waters XBridgeTM Prep C18 5 ⁇ OBDTM 30 x 100mm column at room temperature. Mobile phase - A) Water 0.1 % ammonium hydroxide B) Acetonitrile/Water 95: 5 with 0.1 % ammonium hydroxide. Gradient - Time Flow ml/min %A %B
  • Method E The system consists of a Agilent Technologies 6120 single quadrupole mass spectrometer linked to a Agilent Technologies 1200 Preparative LC system with Multiple Wavelength detector and autosampler.
  • the spectrometer has a multimode ionization source (electrospray and atmospheric pressure chemical ionizations) operating in positive and negative ion mode. Fraction collection is mass-triggered.
  • a purification experiment is performed on each sample submitted using the following conditions: LC Column - Waters XBridgeTM Prep C18 5 ⁇ OBDTM 30 x 100mm column at room temperature. Mobile phase - A) Water 0.1 % ammonium hydroxide B) Acetonitrile/Water 95: 5 with 0.1 % ammonium hydroxide.
  • Method H The system consists of a Agilent Technologies 6120 single quadrupole mass spectrometer linked to a Agilent Technologies 1200 Preparative LC system with Multiple Wavelength detector and autosampler.
  • the spectrometer has a multimode ionization source (electrospray and atmospheric pressure chemical ionizations) operating in positive and negative ion mode. Fraction collection is mass-triggered.
  • a purification experiment is performed on each sample submitted using the following conditions: LC Column - Waters XBridgeTM Prep C18 5 ⁇ OBDTM 19 x 50mm column at room temperature. Mobile phase - A) Water 0.1 % formic acid B) Acetonitrile/Water 95: 5 with 0.1 % formic acid.
  • LCMS High Pressure Liquid Chromatography Mass Spectrometry
  • Method F The system consists of an Agilent Technologies 6140 single quadrupole mass spectrometer linked to an Agilent Technologies 1290 Infinity LC system with UV diode array detector and autosampler.
  • the spectrometer has a multimode ionization source (electrospray and atmospheric pressure chemical ionizations) operating in positive and negative ion mode.
  • An LCMS experiment is performed on each sample submitted using the following conditions: LC Column - Zorbax Eclipse Plus C18 RRHD 1 .8micron 50 x 2.1 mm maintained at 40 ⁇ .
  • the system consists of ThermoFinnigan LCQ Advantage Mass Spectrometer with the Surveyor LC system and 200 position autosampler.
  • the spectrometer has an electrospray source operating in positive and negative ion mode.
  • An LC-MS experiment is performed on each sample submitted using the following conditions: LC Column - Luna 3micron Ci 8 50 x 2 mm; Mobile phase -A) Water 0.1 % Formic Acid B) Acetonitrile 0.1 % Formic Acid
  • microwave experiments were carried out using a Biotage InitiatorTM Sixty, which uses a single-mode resonator and dynamic field tuning, both of which give reproducibility and control. Temperature from 60-250 °C can be achieved, and pressures of up to 20bar can be reached.
  • Sphingosine kinase 1 (SPHK1 ) or 2 (SPHK2) were purchased from Invitrogen (lot number 417324B and 683074A respectively). Unless otherwise indicated, all other reagents were purchased from Sigma.
  • the kinase reaction was performed in white polystyrene 384-well plates in 1 x reaction buffer containing 40 mM Tris (pH 7.5), 20 mM MgCI 2 , 0.1 img/mL BSA and 1 mM DTT.
  • SPHK1 (0.26 units) or SPHK2 (0.53 units) were incubated in the presence or absence of the appropriate concentration of the inhibitor (5 ⁇ ) for 30min at room temperature.
  • Inhibitors were dissolved in a 10 mM DMSO stock solution and serially diluted prior the assay to give a fourteen point half log dose response.
  • the Kinase reaction was then initiated by the addition of Ultrapure ATP (20 ⁇ ) (Promega) and Sphingosine (75 ⁇ ) (Echelon) and allowed to incubate at room temperature for 1 hour (total reaction volume of 15 ⁇ ). Sphingosine kinase inhibition was subsequently determined using the ADP-GloTM Kinase Assay as described by the manufacturer (Promega). Curve fitting was performed using the GraphPad Prism software and IC 5 o values determined using the non-linear regression curve fitting model. IC 50 values for the inhibitors of the invention represent the average of at least duplicate experiments.
  • Example 1 1 -(3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahvdronaphthalen-2- vDphenvDpiperazine di(trifluoroacetate)
  • Step 1 6-(3-bromophenyl)- 1 , 1 ,4,4-tetramethyl-1 ,2,3,4-tetrahydronaphthalene:
  • Step 2 tert-butyl 4-(3-(5,5,8,8-tetramethyl-5,6, 7,8-tetrahydronaphthalen-2- yl)phenyl)piperazine- 1 -carboxylate:
  • Step 3 1 -(3-(5,5,8,8-tetramethyl-5,6, 7,8-tetrahydronaphthalen-2-yl)phenyl)piperazine di( trifluoroacetate):
  • Example 2 1 -(2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahvdronaphthalen-2-yl)pyridin-4- yl)piperidin-4-amine di(trifluoroacetate)
  • reaction mixture was heated at 100 °C for 18 h, cooled to room temperature, poured onto brine (100 ml), extracted with ethyl acetate, dried over magnesium sulphate, filtered and concentrated in vacuo to afford the title compound as a clear oil, which was used without further purification.
  • Step 3 1-(2-(5,5,8,8-tetramethyl-5fi ,8-tetrahydronaphthalen-2-yl)pyridin-4-yl)pfa 4-amine di(trifluoroacetate): Following the procedure for 1 -(3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2- yl)phenyl)piperazine di(trifluoroacetate), te/t-butyl (1 -(2-(5,5,8,8-tetramethyl-5, 6,7,8- tetrahydronaphthalen-2-yl)pyridin-4-yl)piperidin-4-yl)carbamate (105 mg, 0.23 mmol) was reacted to afford the title compound as a white solid (68 mg, 83%).
  • Example 3 1 -(3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahvdronaphthalen-2-yl)pyridin-4- vDpiperazine di(trifluoroacetate)
  • Step 1 tert-butyl 4-(2-chloropyridin-4-yl)piperazine-1-carboxylate:
  • Step 1 tert-butyl 8-(2-chloropyridin-4-yl)-2,8-diazaspiro[4.5]decane-2-carboxylate:
  • Step 2 tert-butyl 8-(2-(5A8,8-tetramethyl-5A 7,8-tetrahydronaphthalen-2-yl)pyrid ⁇ yl) -2, 8-diazaspiro[4.5]decane-2-carboxylate:
  • Example 5 1 -(4-(2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahvdronaphthalen-2-yl)pyridin-4- vDphenvDcvclobutanamine di(trifluoroacetate)
  • Step 1 tert-butyl (1-(4-(2-chloropyridin-4-yl)phenyl)cyclobutyl)carbamate:
  • Step 2 tert-butyl (1-(4-(2-(5,5A8-tetramethyl-5A 7,8-tetrahydronaphthalen-2 ⁇
  • Step 1 tert-butyl 2'-chloro-5,6-dihydro-[4,4'-bipyridine]- 1(2H)-carboxylate:
  • Step 2 tert-butyl 2'-(5,5,8,8-tetramethyl-5,6, 7,8-tetrahydronaphthalen-2-yl)-5,6-dihydro- [4,4'-bipyridine]-1(2H)-carboxylate:
  • Step 1 3-bromo-5-(5,5,8,8-tetramethyl-5,6, 7,8-tetrahydronaphthalen-2-yl)pyridine:
  • Step 2 tert-butyl 5-(5A8,8-tetramethyl-5A 7,8-tetrahydronaphthalen-2-yl)- ⁇
  • Step 3 5-(5,5,8,8-tetramethyl-5,6, 7,8-tetrahydronaphthalen-2-yl)- 1 ',2',3',6'-tetrahydro- 3,4'-bipyridine di(trifluoroacetate):
  • Step 1 tert-butyl 4-(6-(5 ! 5 ! 8 ! 8-tetramethyl-5 ⁇ ,8-tetrahydronaphthalen-2-yl)pyrffl ⁇ yl)benzylcarbamate:
  • Step 2 (4-(6-(5,5,8,8-tetramethyl-5,6, 7,8-tetrahydronaphthalen-2-yl)pyridin-2- yl)phenyl)methanamine di(trifluoroacetate):
  • Step 1 tert-butyl 4-(4-(5 ! 5 ! 8 ! 8-tetramethyl-5 ⁇ ,8-tetrahydronaphthalen-2-yl)pyrid ⁇ yl)benzylcarbamate:
  • Step 2 (4-(6-(5,5,8,8-tetramethyl-5,6, 7,8-tetrahydronaphthalen-2-yl)pyridin-2- yl)phenyl)methanamine di(trifluoroacetate):
  • Example 10 1 -(6-(5,5,8,8-tetramethyl-5,6 J,8-tetrahvdronaphthalen-2-yl)pyridin-2- yl)piperidin-4-amine
  • Step 1 4,4,5,5-Tetramethyl-2-(5,5,8,8-tetramethyl-5,6, 7,8-tetrahydronaphthalen-2-yl)- 1 , 3, 2-dioxaborolane:
  • Step 2 2-bromo-6-(5,5,8,8-tetramethyl-5,6, 7,8-tetrahydronaphthalen-2-yl)pyridine:
  • Example 1 1 -(6-(5,5,8,8-tetramethyl-5,6,7,8-tetrahvdronaphthalen-2-yl)pyridin-2-yl) piperazine
  • Example 12 6-(5,5,8,8-tetramethyl-5,6,7,8-tetrahvdronaphthalen-2-yl)-1 '.2'.3'.6'- tetrahvdro-2,4'-bipyridine
  • Step 1 tert-butyl 6-(5,5 ⁇ -tetramethyl-5 ⁇ ⁇ -tetrahydronaphthalen-2-yl)-5 6'-dihydro- [2,4'-bipyridine]- 1 '(2'H)-carboxylate:
  • Example 13 1 -(4-(6-(5,5,8,8-tetramethyl-5,6,7,8-tetrahvdronaDhthalen-2-yl)Dyridin-2- yl)phenyl)cvclobutanamine dihydrochloride
  • Step 1 tert-butyl 1-(4-(6-(5,5 ⁇ -tetramethyl-5 ⁇ J ⁇ -tetrahydronaphthalen-2-yl)pyridin-2- yl)phenyl)cyclobutylcarbamate:
  • Step 2 1-(4-(6-(5,5,8,8-tetramethyl-5,6, 7,8-tetrahydronaphthalen-2-yl)pyridin-2-yl) phenyl)cyclobutanamine hydrochloride:
  • Step 1 tert-butyl 8-(6-(5,5 ⁇ etra et y ⁇ -5 ⁇ etra ydronap t a ⁇ en-2-y ⁇ )pyridin-2- yl) -2, 8-diazaspiro[4.5]decane-2-carboxylate:
  • the reaction mixture was heated at 90 °C for 18 h under nitrogen. After cooling to RT, the mixture was filtered through celite and washed with EtOAc. The combined filtrates were concentrated in vacuo. The resultant residue was subjected to flash chromatography (Si0 2 , gradient 0 to 25 % EtOAc in cyclohexane) to afford the title compound as a yellow foam (34.2 mg, 31 %).
  • Step 2 8-(6-(5,5,8,8-tetramethyl-5,6, 7,8-tetrahydronaphthalen-2-yl)pyridin-2-yl)-2,8- diazaspiro[4.5]decane dihydrochloride:
  • Example 15 1 -(4-(5,5,8,8-tetramethyl-5,67,8-tetrahvdronaphthalen-2-yl)pyridin-2- yl)piperidin-4-amine
  • Step 1 2-chloro-4-(5,5,8,8-tetramethyl-5,6, 7,8-tetrahydronaphthalen-2-yl)pyridine:
  • Step 2 1-(4-(5,5,8,8-tetramethyl-5fi ,8-tetrahydronaphthalen-2-yl)pyridin
  • Example 16 1 -(4-(5,5,8,8-tetramethyl-5,6 J,8-tetrahvdronaphthalen-2-yl)pyridin-2-yl) piperazine
  • Step 1 1-(4-(5,5,8,8-tetramethyl-5,6, 7,8-tetrahydronaphthalen-2-yl)pyridin-2-yl) piperazine:
  • Example 17 4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahvdronaphthalen-2-yl)-1 ',2',3',6'- tetrahvdro-2,4'-bipyridine dihydrochloride
  • Step 1 tert-butyl 4-(5 ! 5A8-tetramethyl-5 ! 6 ! 8-tetrahydronaphthalen-2-yl)-5' ! 6'-dihydro- [2,4'-bipyridine]- 1 '(2'H)-carboxylate:
  • Step 2 4-(5,5,8,8-tetramethyl-5,6, 7,8-tetrahydronaphthalen-2-yl)- 1 ',2',3',6'-tetrahydro- 2, 4 '-bipyridine dihydrochloride:
  • Example 18 1 -(4-(4-(5,5,8,8-tetramethyl-5,6 J,8-tetrahvdronaphthalen-2-yl)pyridin-2- vDphenvDcvclobutanamine dihvdrochloride
  • Step 1 tert-butyl (1-(4-(4-(5,5A8-tetramethyl-5A7,8-tetrahydronaphthalen-2-y ⁇
  • Step 2 1-(4-(4-(5,5,8,8-tetramethyl-5,6, 7,8-tetrahydronaphthalen-2-yl)pyridin-2-yl) phenyl)cyclobutanamine dihydrochloride:
  • Example 21 1 -(4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahvdronaphthalen-2-yl)pyrimidin-2- yl)piperidin-4-amine dihydrochloride
  • Step 1 2-chloro-4-(5,5,8,8-tetramethyl-5,6, 7,8-tetrahydronaphthalen-2-yl)pyrimidine: To a solution of 2,4-dichloropyrimidine (0.603 g, 4.05 mmol) and 4,4,5, 5-tetramethyl-2- (5,5,8, 8-tetramethyl-5, 6,7, 8-tetrahydronaphthalen-2-yl)-1 ,3,2-dioxaborolane (1 .4 g, 4.45 mmol) in DMF (12 ml) was added 2M Na 2 C0 3 (aq) (8.10 ml, 16.20 mmol). Nitrogen was bubbled through the mixture for 5 min.
  • Step 2 tert-butyl (1-(4-(5,5,8,8-tetramethyl-5 ⁇ ,8-tetrahydronaphthalen-2-yl)pyrimidin- 2-yl)piperidin-4-yl)carbamate:
  • tert-butyl 8-(6-(5,5,8,8-tetramethyl-5, 6,7,8- tetrahydronaphthalen-2-yl)pyridin-2-yl)-2,8-diazaspiro[4.5]decane-2-carboxylate tert- butyl piperidin-4-ylcarbamate (59.9 mg, 0.299 mmol) and 2-chloro-4-(5,5,8,8-tetramethyl- 5,6,7,8-tetrahydronaphthalen-2-yl)pyrimidine (75 mg, 0.249 mmol) were reacted to afford the title compound (55.4 mg, 48 %).
  • Step 3 1 -(4-(5,5,8,8-tetramethyl-5,6, 7,8-tetrahydronaphthalen-2-yl)pyrimidin-2- yl)piperidin-4-amine dihydrochloride: Following the procedure for 8-(6-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2- yl)pyridin-2-yl)-2,8-diazaspiro[4.5]decane dihydrochloride, tert-butyl (1 -(4-(5, 5,8,8- tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)pyr
  • Step 1 tert-butyl 4-(4-(5,5,8,8-tetramethyl-5 ⁇ ,8-tetrahydronaphthalen-2-yl)pyrimidin-2- yl)piperazine- 1 -carboxylate:
  • tert-butyl 8-(6-(5,5,8,8-tetramethyl-5, 6,7,8- tetrahydronaphthalen-2-yl)pyridin-2-yl)-2,8-diazaspiro[4.5]decane-2-carboxylate tert- butyl piperazine-1 -carboxylate (55.7 mg, 0.299 mmol) and 2-chloro-4-(5,5,8,8- tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)pyrimidine (75 mg, 0.249 mmol) were reacted to afford the title compound (40.5 mg, 36 %).
  • Step 2 2-(piperazin- 1 -yl) -4-(5, 5, 8, 8-tetramethyl-5, 6, 7, 8-tetrahydronaphthalen-2-yl) pyrimidine dihydrochloride:
  • Example 24 2-(1 -methyl-1 ,2.3.6-tetrahvdropyridin-4-yl)-4-(5.5.8.8-tetramethyl-5.6.7.8- tetrahvdronaphthalen-2-yl)pyrimidine
  • Example 25 1 -(4-(4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahvdronaDhthalen-2-yl)Dyrimidin-2- vDphenvDcyclobutanamine dihydrochloride
  • Step 1 tert-butyl (1-(4-(4-(5,5A8-tetramethyl-5,6 ,8-tetrahydronaphthalen-2- yl)pyrimidin-2-yl)phenyl)cyclobutyl)carbamate:
  • Step 2 1-(4-(4-(5,5,8,8-tetramethyl-5,6, 7,8-tetrahydronaphthalen-2-yl)pyrimidin-2- yl)phenyl)cyclobutanamine dihydrochloride:
  • Step 1 tert-butyl 8-(4-(5,5,8,8-tetramethyl-5 ⁇ ,8-tetrahydronaphthalen-2-yl)pyrimidin yl) -2, 8-diazaspiro[4.5]decane-2-carboxylate:
  • Step 2 8-(4-(5,5,8,8-tetramethyl-5,6, 7,8-tetrahydronaphthalen-2-yl)pyrimidin-2-yl)-2,8- diazaspiro[4.5]decane dihydrochloride:
  • Example 30 1 -(2-(5,5,8,8-tetramethyl-5,67,8-tetrahvdronaphthalen-2-yl)pyrimidin-4- yl)piperidin-4-amine dihydrochloride
  • Step 1 tert-butyl (1 -(2-chloropyrimidin-4-yl)piperidin-4-yl)carbamate:
  • Step 2 tert-butyl (1-(2-(5,5A8-tetramethyl-5A 7,8-tetrahydronaphthalen-2-yl)pyr ⁇ 4-yl)piperidin-4-yl)carbamate:
  • Step 1 tert-butyl 4-(2-chloropyrimidin-4-yl)piperazine- 1-carboxylate:
  • Step 2 tert-butyl (1-(2-(5,5 ⁇ -tetramethyl-5 ⁇ ⁇ -tetrahydronaphthalen-2-yl)pyr ⁇ 4-yl)piperidin-4-yl)carbamate:
  • Step 2 2-(4-Bromo-2-isopropoxyphenyl)propan-2-ol: To a solution of methylmagnesium chloride (3M in THF, 4.88 ml, 14.65 mmol) in THF (4 ml) was slowly added a solution of methyl 4-bromo-2-isopropoxybenzoate (1 g, 3.66 mmol) in THF (4 ml). After stirring at 60 °C for 7 h, the mixture was added to 2N HCI (10 ml) and then partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc, and the combined organic extracts were dried (MgS0 4 ) and concentrated in vacuo to afford the title compound as a brown oil (1 .0 g, 100%).
  • Step 4 1-(6-(3-isopropoxy-4-isopropylphenyl)pyridin-2-yl)piperazine dihydrochloride: To a solution of tert-butyl 4-(6-(4-(2-hydroxypropan-2-yl)-3-isopropoxyphenyl)pyridin-2- yl)piperazine-1 -carboxylate (0.1 g, 0.219 mmol) in DCM (1 ml) at 0 °C, was added triethylsilane (0.1 15 ml, 0.720 mmol) and borontrifluoride diethyletherate (0.088 ml, 0.713 mmol).
  • Step 3 tert-butyl 4-(6-(3-(2-hydroxypropan-2-yl)-4-isopropoxyphenyl)pyridin-2- yl)piperazine- 1 -carboxylate: Following the procedure for tert-butyl 4-(6-(4-(2-hydroxypropan-2-yl)-3- isopropoxyphenyl)pyridin-2-yl)piperazine-1 -carboxylate, 2-(5-bromo-2- isopropoxyphenyl)propan-2-ol (250 mg, 0.915 mmol) was reacted to afford the title compound as an off-white foam (139 mg, 50%).
  • Step 4 1-(6-(4-isopropoxy-3-isopropylphenyl)pyridin-2-yl)piperazine dihydrochloride: Following the procedure for 1 -(6-(3-isopropoxy-4-isopropylphenyl)pyridin-2-yl)piperazine dihydrochloride, tert-butyl 4-(6-(3-(2-hydroxypropan-2-yl)-4-isopropoxyphenyl)pyridin-2- yl)piperazine-1 -carboxylate (0.1 1 g, 0.241 mmol) was reacted to afford the title compound as a yellow solid (78 mg, 78%).
  • Step 1 tert-butyl 4-(6-chloropyrazin-2-yl)piperazine-1 -carboxylate;
  • Te -butyl 4-(6-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)pyrazin-2- yl)piperazine-1 -carboxylate (0.15 g, 0.33 mmol) was added to a solution of 4N HCI in dioxane (2 ml). The resulting solution was heated at 40 °C for 30 min then cooled to room temperature. The resulting precipitate was filtered and dried at ambient to give the title compound (0.1 18 g, 84%).
  • Example 35 1 -(5-(5,5,8,8-tetramethyl-5,6 ,7,8-tetrahvdronaphthalen-2-yl)pyridin-3- vDpiperazine trihvdrochloride
  • Step 1 tert-butyl 4-(5-bromopyridin-3-yl)piperazine-1 -carboxylate: A solution of 3,5-dibromopyridine (0.6 g, 2.53 mmol), tert-butyl piperazine-1 -carboxylate (0.71 g, 3.8 mmol), Pd 2 dba 3 (0.07 g, 0.076 mmol), cesium carbonate (0.82 g, 2.53 mmol) and xantphos (0.132 g, 0.228 mmol) in dioxane (10 ml) was heated at 1 15 °C for 15 h. The solution was cooled to room temperature and concentrated in vacuo.
  • Step 2 tert-butyl 4-(5-(5,5 ⁇ etra et y ⁇ -5 ⁇ etra ydronap t a ⁇ en-2-y ⁇ )pyridin-3- yl)piperazine- 1 -carboxylate:
  • tert-butyl 4-(6-(5,5,8,8-tetramethyl-5, 6,7,8- tetrahydronaphthalen-2-yl)pyrazin-2-yl)piperazine-1 -carboxylate tert-butyl 4-(5- bromopyridin-3-yl)piperazine-1 -carboxylate (0.2 g, 0.58 mmol) was reacted to give the title compound (0.15 g, 57%).
  • Step 3 ⁇ -(5-(5,5 ⁇ etra et y ⁇ -5 ⁇ etra ydronap t a ⁇ en-2-y ⁇ )pyridin-3- yl)piperazine trihydrochloride:
  • Example 36 1 -(5-(5,5,8,8-tetramethyl-5,6,7,8-tetrahvdronaphthalen-2-yl)pyridin-3- yl)piperidin-4-amine trihydrochloride
  • Step 1 tert-butyl 1-(5-bromopyridin-3-yl)piperidin-4-ylcarbamate:
  • Step 2 tert-butyl 1-(5-(5 -tetramethyl-5fi -tetrahydronaphthalen-2-yl)pyrM ⁇ yl)piperidin-4-ylcarbamate:
  • tert-butyl 4-(6-(5,5,8,8-tetramethyl-5, 6,7,8- tetrahydronaphthalen-2-yl)pyrazin-2-yl)piperazine-1 -carboxylate tert-butyl 1-(5- bromopyridin-3-yl)piperidin-4-ylcarbamate (0.2 g, 0.56 mmol) was reacted to give the title compound (0.125 g, 48%).
  • Step 3 1-(5-(5 -tetramethyl-5fi -tetrahydronaphthalen-2-yl)pyrti ⁇
  • Example 37 4-(piperazin-1 -yl)-6-(5,5,8,8-tetramethyl-5,6,7,8-tetrahvdronaphthalen-2- vDpyrimidine dihydrochloride
  • Step 1 tert-butyl 4-(6-chloropyrimidin-4-yl)piperazine- 1-carboxylate:
  • Step 2 tert-butyl 4-(6-(5,5,8,8-tetramethyl-5,6, 7,8-tetrahydronaphthalen-2-yl)pyrimidin-4- yl)piperazine- 1 -carboxylate:
  • tert-butyl 4-(6-(5,5,8,8-tetramethyl-5, 6,7,8- tetrahydronaphthalen-2-yl)pyrazin-2-yl)piperazine-1 -carboxylate tert-butyl 4-(6- chloropyrimidin-4-yl)piperazine-1 -carboxylate (0.19 g, 0.63 mmol) was reacted to give the title compound (0.20 g, 72%).
  • Step 3 4-(piperazin-1-yl)-6-(5,5,8,8-tetramethyl-5,6, 7,8-tetrahydronaphthalen-2- yl)pyrimidine dihydrochloride:
  • Step 1 tert-butyl 1-(6-chloropyrimidin-4-yl)piperidin-4-ylcarbamate:
  • Step 2 tert-butyl 1-(6-(5,5,8,8-tetramethyl-5fi ,8-tetrahydronaphthalen-2-yl)pyrimidin-4- yl)piperidin-4-ylcarbamate:
  • Step 3 1-(6-(5,5,8,8-tetramethyl-5fi ,8-tetrahydronaphthalen-2-yl)pyrimidin-4- yl)piperidin-4-amine dihydrochloride:
  • Step 1 tert-butyl 1-(6-chloropyrazin-2-yl)piperidin-4-ylcarbamate:
  • Step 2 tert-butyl 1-(6-(5 ⁇ -tetramethyl-5 ⁇ ⁇ -tetrahydronaphthalen-2-yl)pyrazin-2- yl)piperidin -4 -ylcarbamate
  • tert-butyl 4-(6-(5,5,8,8-tetramethyl-5, 6,7,8- tetrahydronaphthalen-2-yl)pyrazin-2-yl)piperazine-1 -carboxylate tert-butyl 1 -(6- chloropyrazin-2-yl)piperidin-4-ylcarbamate (0.15g, 0.48mmol) was reacted to give the title compound (0.15 g, 71 %).
  • Step 3 1-(6-(5 ⁇ -tetramethyl-5 ⁇ ⁇ -tetrahydronaphthalen-2-yl)pyrazin-2- yl)piperidin-4-amine dihydrochloride:
  • Example 40 1 -(2-methoxyethyl)-4-(6-(5,5,8,8-tetramethyl-5,67,8-tetrahydronaphthalen- 2-yl)pyridin-2-yl)piperazine dihydrochloride
  • the product was extracted with ethyl acetate, the combined organic phases were dried over magnesium sulphate, filtered and concentrated in vacuo.
  • the resultant residue was subjected to flash chromatography (KP-NH, Si0 2 , gradient 0 to 50 % ethyl acetate in cyclohexane) to afford the title compound as a yellow oil.
  • the oil was dissolved in dioxane and 4M HCI in dioxane was added. The solution was stirred at room temperature for 5 min. before being concentrated in vacuo.
  • the residue was triturated with diethyl ether to give the target compound as a yellow solid (121 mg, 52%).
  • Example 42 A/,A/-dimethyl-2-(4-(6-(5,5,8,8-tetramethyl-5,6,7,8-tetrahvdronaDhthalen-2- yl)pyridin-2-yl)piperazin-1 -yl)acetamide
  • Example 44 A/.A/-dimethyl-2-(4-(6-(5.5.8.8-tetramethyl-5.6.7.8-tetrahvdronaphthalen-2- yl)pyridin-2-yl)piperazin-1 -vDethanamine trihydrochloride
  • the product was extracted with ethyl acetate, the combined organic phases were dried over magnesium sulphate, filtered and concentrated in vacuo.
  • the resultant residue was subjected to flash chromatography (KP-NH, Si0 2 , gradient 0 to 50 % ethyl acetate in cyclohexane) to afford the title compound as a clear oil.
  • the oil was dissolved in dioxane and 4M HCI in dioxane was added. The solution was stirred at room temperature for 5 min. before being concentrated in vacuo.
  • the residue was triturated with diethyl ether to give the target compound as a yellow solid (24 mg, 34%).
  • Example 45 3-hvdroxy-2-(hvdroxymethyl)-2-methyl-1 -(4-(6-(5,5,8,8-tetramethyl-5,6,7,8- tetrahvdronaphthalen-2-yl)pyridin-2-yl)piperazin-1 -yl)propan-1 -one hydrochloride
  • Example 46 4-(piperidin-4-yloxy)-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahvdronaphthalen-2- vDpyrimidine di(trifluoroacetate)
  • Step 1 tert-butyl 4-((2-chloropyrimidin-4-yl)oxy)piperidine- 1-carboxylate:
  • Step 2 tert-butyl 4-((2-(5 ! 5A8-tetramethyl-5 ⁇ ! 8-tetrahydronaphthalen-2-yl)pyrim 4-yl)oxy)piperidine- 1 -carboxylate:
  • Step 3 4-(piperidin-4-yloxy)-2-(5,5,8,8-tetramethyl-5,6, 7,8-tetrahydronaphthalen-2- yl)pyrimidine di(trifluoroacetate):
  • Step 1 tert-butyl 4-((4-chloropyrimidin-2-yl)oxy)piperidine- 1 -carboxylate:
  • Step 2 tert-butyl 4-((4-(5,5,8,8-tetramethyl-5,6, 7,8-tetrahydronaphthalen-2-yl)pyrimidin- 2-yl)oxy)piperidine- 1 -carboxylate:
  • Example 48 2-methyl-4-(piperazin-1 -yl)-6-(5,5, 8,8-tetramethyl-5, 6,7,8- tetrahvdronaphthalen-2-yl)pyrimidine di(trifluoroacetate)
  • Step 1 tert-butyl 4-(6-chloro-2-methylpyrimidin-4-yl)piperazine-1-carboxylate:
  • Step 2 tert-butyl 4-(2-methyl-6-(5,5,8,8-tetramethyl-5,6, 7,8-tetrahydronaphthalen-2- yl)pyrimidin-4-yl)piperazine- 1 -carboxylate:
  • Step 3 2-(piperidin-4-yloxy)-4-(5,5,8,8-tetramethyl-5,6, 7,8-tetrahydronaphthalen-2- yl)pyrimidine di(trifluoroacetate): Following the procedure for 1 -(3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2- yl)phenyl)piperazine di(trifluoroacetate), te/t-butyl 4-(2-methyl-6-(5,5,8,8-tetramethyl- 5,6,7,8-tetrahydronaphthalen-2-yl)pyrimidin-4-yl)piperazine-1 -carboxylate (120 mg , 0.26 mmol) was reacted to afford the title compound as a white solid (82 mg, 87%).
  • Step 2 tert-butyl 4-(6-(4-hydroxy-3-isopropylphenyl)pyridin-2-yl)piperazine-1- carboxylate:
  • Step 3 tert-butyl 4-(6-(4-isobutoxy-3-isopropylphenyl)pyridin-2-yl)piperazine-1- carboxylate: Following the procedure for Methyl 4-bromo-2-isopropoxybenzoate, tert-butyl 4-(6-(4- hydroxy-3-isopropylphenyl)pyridin-2-yl)piperazine-1 -carboxylate (150 mg, 0.377 mmol) and 1 -bromo-2-methylpropane (0.062 ml, 0.566 mmol) were reacted to afford the title compound as a yellow solid (37.7 mg, 22%).
  • Step 4 1-(6-(4-isobutoxy-3-isopropylphenyl)pyridin-2-yl)piperazine dihydrochloride: Following the procedure for 8-(6-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2- yl)pyridin-2-yl)-2,8-diazaspiro[4.5]decane dihydrochloride, tert-butyl 4-(6-(4-isobutoxy-3- isopropylphenyl)pyridin-2-yl)piperazine-1 -carboxylate (37.7 mg, 0.083 mmol) was reacted to afford the title compound as a yellow solid (20.9 mg, 59%).
  • Step 2 tert-butyl 4-(6-(3-(tert-butyl)-4-hydroxyphenyl)pyridin-2-yl)piperazine- 1- carboxylate:
  • Step 3 tert-butyl 4-(6-(3-(tert-butyl)-4-isopropoxyphenyl)pyridin-2-yl)piperazine- 1- carboxylate:
  • Step 4 1-(6-(3-(tert-butyl)-4-isopropoxyphenyl)pyridin-2-yl)piperazine dihydrochloride: Following the procedure for 8-(6-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2- yl)pyridin-2-yl)-2,8-diazaspiro[4.5]decane dihydrochloride, tert-butyl 4-(6-(3-(tert-butyl)-4- isopropoxyphenyl)pyridin-2-yl)piperazine-1 -carboxylate (60 mg, 0.132 mmol) was reacted to afford the title compound as a yellow solid (35.6 mg, 63%).
  • Step 1 tert-butyl 4-(6-(3-(tert-butyl)-4-isobutoxyphenyl)pyridin-2-yl)piperazine- 1- carboxylate:
  • Step 2 1-(6-(3-(tert-butyl)-4-isobutoxyphenyl)pyridin-2-yl)piperazine dihydrochloride: Following the procedure for 8-(6-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2- yl)pyridin-2-yl)-2,8-diazaspiro[4.5]decane dihydrochloride, tert-butyl 4-(6-(3-(tert-butyl)-4- isobutoxyphenyl)pyridin-2-yl)piperazine-1 -carboxylate (43.6 mg, 0.093 mmol) was reacted to afford the title compound as a yellow solid (25.0 mg, 61 %).
  • Example 52 1 -(6-(2-(benzyloxy)-1 .1 ,3,3-tetramethyl-2,3-dihvdro-1 H-inden-5-yl)pyridin-
  • Step 1 1 , 1 ,3,3-tetramethyl- 1H-inden-2(3H)-one:
  • Step 3 5-bromo- 1, 1,3,3-tetramethyl-2,3-dihydro-1H-inden-2-ol:
  • Step 4 2-(benzyloxy)-5-bromo- 1 , 1 ,3,3-tetramethyl-2,3-dihydro- 1 H-indene:
  • Step 5 2-(2-(benzyloxy)- 1, 1 ,3,3-tetramethyl-2,3-dihydro-1 H-inden-5-yl)-4,4,5,5- tetramethyl- 1,3,2-dioxaborolane:
  • Nitrogen was bubbled through a suspension of 2-(benzyloxy)-5-bromo-1 ,1 ,3,3- tetramethyl-2,3-dihydro-1 H-indene (1 .1 g, 3.06 mmol), PdCI 2 (dppf) CH 2 CI 2 (0.250 g, 0.306 mmol), potassium acetate (0.9 g, 9.18 mmol) and 4,4,4',4', 5,5,5', 5'-octamethyl- 2,2'-bi(1 ,3,2-dioxaborolane) (1 .166 g, 4.59 mmol) in DMF (10 ml) for 10 minutes. The mixture was heated at 100 ' ⁇ for 15h.
  • Step 6 tert-butyl 1-(6-(2-(benzyloxy)-1 , 1,3,3-tetramethyl-2,3-dihydro- 1H-inden-5- yl)pyridin-2-yl)piperidin-4-ylcarbamate:
  • Step 7 1-(6-(2-(benzyloxy)-1, 1 ,3 etramethyl-2,3-dihydro-1H-inden-5-yl)pyridin-2- yl)piperidin-4-amine 1 -(6-(2-(benzyloxy)-1 ,1 ,3,3-tetramethyl-2,3- dihydro-1 H-inden-5-yl)pyridin-2-yl)piperidin-4-ylcarbamate (50 mg, 0.09 mmol) was added to a 4N HCI solution in dioxane (2ml_, 8mmol). The resulting solution was stirrred at 50 °C for 15 min then concentrated in vacuo to afford the title compound (48 mg, 100%).
  • Step 1 4-bromo-2-(tert-butyl)- 1-isopropoxybenzene:
  • Step 2 2-(3-(tert-butyl)-4-isopropoxyphenyl)-4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolane: To a solution of 4-bromo-2-(tert-butyl)-1 -isopropoxybenzene (1 1 .8 g, 43.5 mmol) in DMF (150 ml) was added 4,4,4',4', 5,5, 5', 5'-octamethyl-2,2'-bi(1 ,3,2-dioxaborolane) (16.57 g, 65.3 mmol) and potassium acetate (12.81 g, 131 mmol).
  • Step 4 2-(4-(4-(3-(tert-butyl)-4-isopropoxyphenyl)pyrimidin-2-yl)piperazin- 1 -yl)ethanol: To a solution of 2-(piperazin-1 -yl)ethanol (42.7mg, 0.328 mmol) in THF (0.5 ml), in a sealable vial, was added DIPEA (0.086 ml, 0.492 mmol). A solution of 4-(3-(tert-butyl)-4- isopropoxyphenyl)-2-chloropyrimidine (50 mg, 0.164 mmol) in THF (0.500 ml) was added and the vial was sealed.
  • Example 54 cis-A/ l -(4-(3-(tert-butyl)-4-isopropoxyphenyl)pyrimidin-2-yl)cvclohexane-1 ,4- diamine
  • Example 58 1 -(4-(3-(tert-butyl)-4-isopropoxyphenyl)pyrimidin-2-yl)-4-methyl-1 A- diazepane
  • Step 1 2-(4-isopropoxy-3-isopropylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane: Following the procedure for 2-(3-(tert-butyl)-4-isopropoxyphenyl)-4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolane, 4-bromo-1 -isopropoxy-2-isopropylbenzene (1 .67 g, 6.49 mmol) was reacted to afford the title compound (686 mg, 35%).
  • Step 3 tert-butyl 4-(4-(4-isopropoxy-3-isopropylphenyl)pyrimidin-2-yl)piperazine-1- carboxylate:
  • Step 4 4-(4-isopropoxy-3-isopropylphenyl)-2-(piperazin- 1-yl)pyrimidine dihydrochloride: To a solution of tert-butyl 4-(4-(4-isopropoxy-3-isopropylphenyl)pyrimidin-2-yl)piperazine- 1 -carboxylate (56.3 mg, 0.128 mmol) in dioxane (0.5 ml) was added HCI (4M in dioxane, 1 ml, 4.00 mmol). The mixture was stirred at room temperature for 1 h, and then further HCI (4M in dioxane, 0.5 ml, 2.00 mmol) was added. After 1 h at room temperature the mixture was concentrated in vacuo . The resultant solid was slurried in Et 2 0, then lyophilized o/n to afford the title compound as a white solid (19 mg, 36%).
  • Step 1 tert-butyl 4-(4-(3-(tert-butyl)-4-isopropoxyphenyl)pyrimidin-2-yl)piperazine- 1- carboxylate:
  • Step 2 4-(3-(tert-butyl)-4-isopropoxyphenyl)-2-(piperazin- 1 -yl)pyrimidine dihydrochloride: Following the procedure for 4-(4-isopropoxy-3-isopropylphenyl)-2-(piperazin-1 - yl)pyrimidine dihydrochloride, tert-butyl 4-(4-(3-(tert-butyl)-4-isopropoxyphenyl)pyrimidin- 2-yl)piperazine-1 -carboxylate (39.4 mg, 0.087 mmol) was reacted to afford the title compound as a white solid (16 mg, 44%).
  • Example 66 1 -(4-(3-(tert-butyl)-4-isopropoxyphenyl)pyrimidin-2-yl)piperidin-4-amine dihydrochloride
  • Step 1 tert-butyl 4-(4-(3-(tert-butyl)-4-isopropoxyphenyl)pyrimidin-2-yl)piperazine- 1- carboxylate:
  • Step 1 4-bromo-2-(tert-butyl)- 1-(cyclopentyloxy)benzene:
  • Step 2 2-(3-(tert-butyl)-4-(cyclopentyloxy)phenyl)-4,4,5,5-tetramethyl- 1,3,2- dioxaborolane:
  • Step 3 4-(3-(tert-butyl)-4-(cyclopentyloxy)phenyl)-2-chloropyrimidine:
  • Step 4 1-(4-(3-(tert-butyl)-4-(cyclopentyloxy)phenyl)pyrimidin-2-yl)piperidin-4-am dihydrochloride:
  • Example 68 1 -(2-(3-isopropoxy-4-isopropylphenyl)pyrimidin-4-yl)piperidin-4-amine dihydrochloride
  • Step 1 tert-butyl (1 -(2-chloropyrimidin-4-yl)piperidin-4-yl)carbamate:
  • Step 2 tert-butyl (1-(2-(3-isopropoxy-4-isopropylphenyl)pyrimidin-4-yl)piperidin-4- yl) carbarn ate:
  • Step 3 1 -(2-(3-isopropoxy-4-isopropylphenyl)pyrimidin-4-yl)piperidin
  • Step 1 tert-butyl 4-(6-(3-hydroxy-4-isopropylphenyl)pyridin-2-yl)piperazine-1- carboxylate:
  • Step 2 tert-butyl 4-(6-(3-isobutoxy-4-isopropylphenyl)pyridin-2-yl)piperazine-1- carboxylate:
  • Example 70 1 -(6-(4-isopropyl-3-propoxyphenyl)pyridin-2-yl)piperazine dihydrochloride
  • Step 1 tert-butyl 4-(6-(4-isopropyl-3-propoxyphenyl)pyridin-2-yl)piperazine- 1- carboxylate:
  • Step 1 tert-butyl 4-(6-(3-(cyclopentyloxy)-4-isopropylphenyl)pyridin-2-yl)piperazine- 1- carboxylate:
  • Example 72 1 -(6-(4-isopropyl-3-(prop-1 -en-2-yl)phenyl)pyridin-2-yl)piperazine dihydrochloride
  • Step 1 tert-butyl 4-(6-(4-isopropyl-3-(((trifluoromethyl)sulfonyl)oxy)phenyl)pyridin-2- yl)piperazine- 1 -carboxylate:
  • Step 1 tert-butyl 4-(6-(3,4-diisopropylphenyl)pyridin-2-yl)piperazine- 1 -carboxylate:
  • Step 1 tert-butyl 4-(6-(3-isopropyl-4-propoxyphenyl)pyridin-2-yl)piperazine- 1- carboxylate:
  • Example 75 1 -(6-(4-(cvclopentyloxy)-3-isopropylphenyl)pyridin-2-yl)piperazine dihydrochloride
  • Step 1 tert-butyl 4-(6-(4-(cyclopentyloxy)-3-isopropylphenyl)pyridin-2-yl)piperazine- 1- carboxylate:
  • Example 76 (rac)-1 -(6-(3-isopropyl-4-((1 .1 ,1 -trifluoropropan-2-yl)oxy)phenyl)pyridin-2- vDpiperazine dihydrochloride
  • Step 1 (rac)-tert-butyl 4-(6-(3-isopropyl-4-((1 , 1, 1-trifluoropropan-2-yl)oxy)phenyl)pyridin- 2-yl)piperazine- 1 -carboxylate:
  • Step 2 (rac)-1 -(6-(3-isopropyl-4-((1 , 1, 1-trifluoropropan-2-yl)oxy)phenyl)pyridin-2- yl)piperazine dihydrochloride:
  • Step 1 (rac)-tert-butyl 4-(6-(4-(sec-butoxy)-3-isopropylphenyl)pyridin-2-yl)piperazine- 1- carboxylate:
  • Step 2 (rac)-1-(6-(4-(sec-butoxy)-3-isopropylphenyl)pyridin-2-yl)piperazine
  • Step 1 tert-butyl 4-(6-(3-isopropyl-4-(2,2,2-trifluoroethoxy)phenyl)pyridin-2-yl)piperazin 1-carboxylate:
  • Example 82 1 -(6-(3-(tert-butyl)-4-(2.2.2-trifluoroethoxy)phenyl)pyridin-2-yl)piperazine dihydrochloride
  • Step 1 tert-butyl 4-(6-(3-(ten-butyl)-4-(2,2,2-trifluoroethoxy)phenyl)pyridin-2- yl)piperazine- 1 -carboxylate:
  • tert-butyl 4-(6-(3-isobutoxy-4-isopropylphenyl)pyridin-2- yl)piperazine-1 -carboxylate tert-butyl 4-(6-(3-(tert-butyl)-4-hydroxyphenyl)pyridin-2- yl)piperazine-1 -carboxylate (120 mg, 0.292 mmol) and 1 ,1 ,1 -trifluoro-2-iodoethane (0.043 ml, 0.437 mmol) were reacted to afford the title compound as a yellow oil (51 .2 mg, 36%).
  • Step 2 1 -(6-(3-(ten-butyl)-4-(2,2,2-trifluoroethoxy)phenyl)pyrid ⁇
  • Example 83 1 -(2-(4-isopropoxy-3-isopropylphenyl)pyrimidin-4-yl)piperidin-4-amine dihydrochloride
  • Step 1 tert-butyl (1-(2-(4-isopropoxy-3-isopropylphenyl)pyrimidin-4-yl)piperidin-4- yl) carbarn ate:

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des composés qui sont utiles en tant qu'inhibiteurs de l'activité d'une ou de plusieurs isoformes de la sphingosine kinase. En particulier, bien que non exclusivement, la présente invention concerne aussi des compositions pharmaceutiques comprenant ces composés et l'utilisation de ces composés dans le traitement et/ou la prévention des cancers, de maladies hyperprolifératives, inflammatoires, angiogéniques, immunes et virales infectieuses.
PCT/GB2011/052334 2010-11-26 2011-11-25 Composés pharmaceutiques en tant qu'inhibiteurs de la sphingosine kinase Ceased WO2012069852A1 (fr)

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JP2013513628A (ja) * 2009-12-14 2013-04-22 メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフツング スフィンゴシンキナーゼの阻害薬
JP2016540824A (ja) * 2013-12-20 2016-12-28 インスティテュート オブ ファーマコロジー アンド トキシコロジー アカデミー オブ ミリタリー メディカル サイエンシズ ピー．エル．エー．チャイナ 新規ピペリジンカルボキサミド化合物、その調製方法及び使用
WO2017129769A1 (fr) 2016-01-28 2017-08-03 INSERM (Institut National de la Santé et de la Recherche Médicale) Méthodes permettant d'améliorer la puissance d'inhibiteurs de points de contrôle immunitaires
WO2019162325A1 (fr) 2018-02-21 2019-08-29 INSERM (Institut National de la Santé et de la Recherche Médicale) Utilisation de sk1 en tant que biomarqueur pour prédire la réponse à des inhibiteurs de point de contrôle immunitaire
US10858359B2 (en) 2016-06-07 2020-12-08 Jacobio Pharmaceuticals Co., Ltd. Heterocyclic ring derivatives useful as SHP2 inhibitors
US10988466B2 (en) 2017-03-23 2021-04-27 Jacobio Pharmaceuticals Co., Ltd. Heterocyclic derivatives useful as SHP2 inhibitors
US11046658B2 (en) 2018-07-02 2021-06-29 Incyte Corporation Aminopyrazine derivatives as PI3K-γ inhibitors
US11926616B2 (en) 2018-03-08 2024-03-12 Incyte Corporation Aminopyrazine diol compounds as PI3K-γ inhibitors
US12233062B2 (en) 2018-09-26 2025-02-25 Jacobio Pharmaceuticals Co., Ltd. Heterocyclic derivatives useful as SHP2 inhibitors

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Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2013513628A (ja) * 2009-12-14 2013-04-22 メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフツング スフィンゴシンキナーゼの阻害薬
JP2016540824A (ja) * 2013-12-20 2016-12-28 インスティテュート オブ ファーマコロジー アンド トキシコロジー アカデミー オブ ミリタリー メディカル サイエンシズ ピー．エル．エー．チャイナ 新規ピペリジンカルボキサミド化合物、その調製方法及び使用
WO2017129769A1 (fr) 2016-01-28 2017-08-03 INSERM (Institut National de la Santé et de la Recherche Médicale) Méthodes permettant d'améliorer la puissance d'inhibiteurs de points de contrôle immunitaires
US10858359B2 (en) 2016-06-07 2020-12-08 Jacobio Pharmaceuticals Co., Ltd. Heterocyclic ring derivatives useful as SHP2 inhibitors
US10988466B2 (en) 2017-03-23 2021-04-27 Jacobio Pharmaceuticals Co., Ltd. Heterocyclic derivatives useful as SHP2 inhibitors
WO2019162325A1 (fr) 2018-02-21 2019-08-29 INSERM (Institut National de la Santé et de la Recherche Médicale) Utilisation de sk1 en tant que biomarqueur pour prédire la réponse à des inhibiteurs de point de contrôle immunitaire
US11926616B2 (en) 2018-03-08 2024-03-12 Incyte Corporation Aminopyrazine diol compounds as PI3K-γ inhibitors
US12365668B2 (en) 2018-03-08 2025-07-22 Incyte Corporation Aminopyrazine diol compounds as PI3K-y inhibitors
US11046658B2 (en) 2018-07-02 2021-06-29 Incyte Corporation Aminopyrazine derivatives as PI3K-γ inhibitors
US12421197B2 (en) 2018-07-02 2025-09-23 Incyte Corporation Aminopyrazine derivatives as PI3K-γ inhibitors
US12233062B2 (en) 2018-09-26 2025-02-25 Jacobio Pharmaceuticals Co., Ltd. Heterocyclic derivatives useful as SHP2 inhibitors

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