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WO2009066084A1 - 2-morpholinopyrimidines et leur utilisation en tant qu'inhibiteurs de kinase pi3 - Google Patents

2-morpholinopyrimidines et leur utilisation en tant qu'inhibiteurs de kinase pi3 Download PDF

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Publication number
WO2009066084A1
WO2009066084A1 PCT/GB2008/003910 GB2008003910W WO2009066084A1 WO 2009066084 A1 WO2009066084 A1 WO 2009066084A1 GB 2008003910 W GB2008003910 W GB 2008003910W WO 2009066084 A1 WO2009066084 A1 WO 2009066084A1
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bipyrimidinyl
moφholin
amino
ylamine
morpholin
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PCT/GB2008/003910
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English (en)
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Irina Chuckowree
Adrian Folkes
Sally Oxenford
Alan Olivero
Daniel P. Sutherlin
Bing-Yan Zhu
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F. Hoffmann-La Roche Ag
Genentech, Inc.
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Publication of WO2009066084A1 publication Critical patent/WO2009066084A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • 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
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/48—Two nitrogen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • 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
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/42—One nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • 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
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/47—One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the present invention relates to pyrimidine derivatives and their use as inhibitors of phosphatidylinositol 3-kinase (PI3K).
  • PI3K phosphatidylinositol 3-kinase
  • Phosphatidylinositol (hereinafter abbreviated as "PI") is one of a number of phospholipids found in cell membranes. In recent years it has become clear that PI plays an important role in intracellular signal transduction. In the late 1980s, a PB kinase (PI3K) was found to be an enzyme which phosphorylates the 3-position of the inositol ring of phosphatidylinositol (M.Whitman et ah, 1988, Nature, 332, 644-646).
  • PI3K was originally considered to be a single enzyme, but it has now been clarified that a plurality of subtypes are present in PI3K. Each subtype has its own mechanism for regulating activity.
  • Three major classes of PI3Ks have been identified on the basis of their in vitro substrate specificity (B. Vanhaesebroeck et al, 1997, Trends in Biochemical Sciences, 22, 267-272).
  • Substrates for class I PBKs are PI, PI 4-phosphate (PI4P) and PI 4,5-biphosphate (PI (4,5)P2).
  • Class I PBKs are further divided into two groups, class Ia and class Ib, in terms of their activation mechanism.
  • Class Ia PBKs include PBK p 11 Oa, p 11 O ⁇ and p 11 O ⁇ subtypes, which transmit signals from tyrosine kinase-coupled receptors.
  • Class Ib PBK includes a pi lO ⁇ subtype activated by a G protein-coupled receptor.
  • PI and PI(4)P are known as substrates for class II PBKs.
  • Class II PBKs include PBK C2 ⁇ , C2 ⁇ and C2 ⁇ subtypes, which are characterized by containing C2 domains at the C terminus.
  • the substrate for class III PBKs is PI only. In the PBK subtypes, the class Ia subtype has been most extensively investigated to date.
  • the three subtypes of class Ia are heterodimers of a catalytic 110 kDa subunit and regulatory subunits of 85 kDa or 55 kDa.
  • the regulatory subunits contain SH2 domains and bind to tyrosine residues phosphorylated by growth factor receptors with a tyrosine kinase activity or oncogene products, thereby inducing the PBK activity of the pi 10 catalytic subunit which phosphorylates its lipid substrate.
  • the class Ia subtypes are considered to be associated with cell proliferation and carcinogenesis.
  • the present invention provides a compound which is a morpholino pyrimidine of formula (I):
  • R 1 is selected from -Y-R 6 and -NR 4 R 5 ;
  • R 3 is selected from H, C 1 -C 6 alkyl and C 1 -C 6 alkoxy;
  • Y is selected from a direct bond, -(CR 2 ) m -, C 2 -C 6 alkenylene, C 2 -C 6 alkynylene, -(CR 2 ) P -O-(CR 2 ) r, -(CR 2 ) P -NR-(CR 2 ) r, -(CR 2 ) p -NR-(CR 2 ) n -C(O)-, -(CR 2 ) P -NR-C(O)- (CR 2 V, -(CR 2 ) P -C(O)-NR-(CR 2 ) ,-, -(CR 2 ) p -C(O)-(CR 2 ) n -NR-(CR 2 ),- and -(CR 2 ) P - C(O)-(CR 2 ) ⁇ -;
  • R 6 is selected from an unsaturated 5- to 12-membered carbocyclic or heterocyclic ring, a saturated 5-, 6- or 7- membered N-containing heterocyclic group which is unsubstituted or substituted, C 1 -C 6 alkyl, -NR 2 , -OR, -NR(CO)R and - C(O)NR 2 ;
  • R and R 5 which are the same or different, are both C 1 -C 6 alkyl which is unsubstituted or substituted, or R 4 and R 5 together form, with the nitrogen atom to which they are attached, a saturated 5-, 6- or 7- membered N-containing heterocyclic group which is unsubstituted or substituted; each R, which are the same or different when more than one is present in a given group, is independently H, C 1 -C 6 alkyl which is unsubstituted or substituted or a 5- to 12-membered aryl or heteroaryl group which is unsubstituted or substituted; R 10 and R 11 , which are the same or different, are independently selected from H,
  • R 6 is linked to Y through a constituent O or N atom of R 6 ; or a pharmaceutically acceptable salt thereof; with the provisos that:
  • R 1 is other than a phenyl group which is unsubstituted or substituted;
  • R 1 when R 2 is a pyridyl group and R 3 is H then R 1 is other than a dimethylamino group, a morpholine group or a piperazinyl group which is unsubstituted or substituted by Ci-C 6 alkyl, phenyl or heteroaryl; (iii) when R 2 is a thiazole group, R 1 is -Y-R 6 in which Y is a direct bond and R 3 is H, then R 6 is other than a 5 - 12 membered aryl group; and
  • R 1 is -Y-R 6 in which Y is a group -C(O)-NH- , R 3 is H and R 6 is an a 5 - 12 membered aryl group, then R is other than an unsubstituted pyrazole ring.
  • the invention provides a compound which is a morpholino pyrimidine of formula (I' ) :
  • R' is selected from -Y-R 0 and -NR 4 4 rR>5 3 .
  • R 3 is selected from H, Ci-C 6 alkyl and C]-C 6 alkoxy;
  • Y is selected from a direct bond, -(CR 2 ) m -, C 2 -C 6 alkenylene, C 2 -C 6 alkynylene, -(CR 2 ) P -O-(CR 2 ) r, -(CR 2 ) P -NR-(CR 2 ) r , -(CR 2 ) p -NR-(CR 2 ) n -C(O)-, -(CR 2 ) P -NR-C(O)- (CR 2 ) n -, -(CR 2 ) P -C(O)-NR-(CR 2 ) r, -(CR 2 ) p -C(O)-(CR 2 ) n -NR-(CR 2 ) t - and -(CR 2 ) P - C(O)-(CR 2 ) n -;
  • R 6 is selected from Ci-C 6 alkyl, -NR 2 , -OR, -NR(CO)R, -C(O)NR 2 , an unsaturated 5- to 12-membered carbocyclic or heterocyclic ring which is unsubstituted or substituted and a saturated 5-, 6- or 7- membered N-containing heterocyclic group which is unsubstituted or substituted by a group Z';
  • R 4 and R 5 which are the same or different, are both Cj-C 6 alkyl which is unsubstituted or substituted, or R 4 and R 5 together form, with the nitrogen atom to which they are attached, a saturated 5-, 6- or 7- membered N-containing heterocyclic group which is unsubstituted or substituted by a group Z'; each R, which are the same or different when more than one is present in a given group, is independently H or C 1 -C 6 alkyl which is unsubstituted or substituted;
  • R 10 and R 11 which are the same or different, are independently selected from H, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl and C 3 -C 3 cycloalkyl;
  • Z' is selected from unsubstituted C 1 -C 6 alkyl, -(alk) v -OR, -(alk) v -NR 2 , -(alk) v -
  • alk is C 1 -C 8 alkylene, v is O or 1
  • R is selected from H, C]-C 6 alkyl and Ar
  • Ar is 5- to 12-membered aryl as defined above
  • Het is 5- to 12-membered heteroaryl as defined above
  • R 4a and R 5a form together, with the N atom to which they are attached, a saturated 5-, 6-, or 7-membered N- containing heterocyclic group which is unsubstituted or substituted
  • n is 0 or an integer of 1 to 6
  • m is an integer of 1 to 6
  • p is 0 or
  • R 6 is linked to Y through a constituent O or N atom of R 6 ; or a pharmaceutically acceptable salt thereof.
  • the invention provides a compound which is a morpholino pyrimidine of formula (I"):
  • R 2 is a N-containing monocyclic heteroaryl group which is selected from pyridyl, isoxazolyl, imidazolyl, pyrazolyl, pyrrolyl, thiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, oxazolyl, furanyl, thienyl, triazolyl and tetrazolyl and which is substituted by -NR 10 R 11 , -OR 10 , -C(O)R 10 , -NR 10 C(O)R 11 , -N(C(O)R n ) 2 , -NR 10 C(O)NR 10 R 11 , - SO 2 R 10 R 11 , -SO 2 NR 10 R 11 , -C(O)OR 1 °, -C(O)NR 1 V 1 , halo-d -C 6 alkyl and unsubstituted C 1 -C 12 alkyl;
  • R 3 is selected from H, Ci-C 6 alkyl and C 1 -C 6 alkoxy; Y is C 2 -C 6 alkynylene or -0-(CR 2 ) ,- ;
  • R 6 is selected from C 1 -C 6 alkyl, -NR 2 , -OR, -NR(CO)R, -C(O)NR 2 , an unsaturated 5- to 12-membered carbocyclic or heterocyclic ring which is unsubstituted or substituted and a saturated 5-, 6- or 7- membered N-containing heterocyclic group which is unsubstituted or substituted, said saturated N-containing heterocyclic group being C-linked to Y when Y is -0-(CR 2 ) t - ;
  • R 4 and R 5 which are the same or different, are both C 1 -C 6 alkyl which is unsubstituted or substituted, or R 4 and R 5 together form, with the nitrogen atom to which they are attached, a saturated 5-, 6- or 7- membered N-containing heterocyclic group which is unsubstituted or substituted; each R, which are the same or different when more than one is present in a given group, is independently H or C 1 -C 6 alkyl which is unsubstituted or substituted;
  • R 10 and R 11 which are the same or different, are independently selected from H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl and C 3 -C 8 cycloalkyl; and t is O or an integer of 1 to 6; or a pharmaceutically acceptable salt thereof.
  • R 6 when t is O then R 6 is not an unsubstituted 5- to 12-membered heterocyclic ring which is unsubstituted or substituted or a saturated 5-, 6- or 7-membered N-containing heterocyclic group which is unsubstituted or substituted.
  • R 6 when, in formula (I") an atom or group is substituted, it is typically substituted by a group Z'as defined above.
  • the invention provides a compound which is a morpholino pyrimidine of formula (Ia):
  • R 1 and R 3 are as defined above for formula (I), (F) or (I");
  • W is CR or N
  • R is H or Cj -C 6 alkyl which is unsubstituted or substituted
  • R 7 is selected from -NR 10 R 11 , -OR 10 , -C(O)R 10 , -NR 10 C(O)R 11 , -N(C(O)R n ) 2 , -NR 10 C(O)NR 10 R 11 , SO 2 R 10 R 11 , -SO 2 NR 10 R 11 , -C(O)OR 10 , -C(O)NR 10 R 1 ⁇ halo-d -C 6 alkyl and unsubstituted C]-Ci 2 alkyl, wherein R 1 and R 11 are as defined above; or a pharmaceutically acceptable salt thereof; with the proviso that, when W is CR, R 1 is other than a piperazinyl group which is substituted by a phenyl or heteroaryl group.
  • R is typically H or unsubstituted Cj -C 6 alkyl. More typically W is CH.
  • the invention provides a compound which is a morpholino pyrimidine of formula (Ib):
  • R 1 and R 3 are as defined above for formula (I), (U) or (F ');
  • an alkyl group is a straight or branched chain saturated hydrocarbon radical which is unsubstituted or substituted. Typically it is C 1 -C 20 alkyl, for instance C 1 -C 10 alkyl, such as C 1 -C 6 alkyl group. C 1 -C 6 alkyl is typically Ci-C 4 alkyl.
  • Analkyl group is unsubstituted or substituted, typically by one or more groups Z or R 9 as defined below. Typically it is C 1 -C 4 alkyl, for example methyl, ethyl, i-propyl, n-propyl, t-butyl, s-butyl or n-butyl
  • Z is selected from H, unsubstituted C 1 -C 6 alkyl, halo, -OR', -SR', CH 2 OR', -CF 3 , -(haIo)-Ci-C 6 alkyl, -(CR 8 2 ) q O-(halo)-d-C 6 alkyl, -CO 2 R', -(CR 8 2 ) q CO 2 R', - (CR 8 2 ) q COR ⁇ -CF 2 OH, -CH(CF 3 )OH, -C(CF 3 ) 2 OH, -(CH 2 ) q OR ⁇ -(CR 8 2 ) q OR ⁇ -(CH 2 ) q NR' 2 , -(CR 8 2 ) q NR' 2 , -(CR 8 2 ) S -NR'-(CR 8 2 )-R', -C(0)NR' 2 ,
  • R 9 is selected from C 1 -C 6 alkoxy, OR 8 , SR 8 , S(O) m R 8 , nitro, CN, halogen, - C(O)R 8 , - CO 2 R 8 , -C(O)N(R 8 ) 2 and -N(R 8 ) 2 .
  • R 8 each of which is the same or different when more than one is present in a given substituent, is selected from H, C 1 -C 6 alkyl and C 3 -CiO cycloalkyl., and m is 1 or 2.
  • a halogen or halo group is F, Cl, Br or I. Preferably it is F, Cl or Br.
  • a C 1 -C 6 alkyl group substituted by halogen may be denoted by the term "halo-Ci-C 6 alkyl", which means an alkyl group in which one or more hydrogens is replaced by halo.
  • a halo-d-C 6 alkyl group preferably contains one, two or three halo groups. A preferred example of such a group is trifluoromethyl.
  • a C 1 -C 6 alkoxy group is linear or branched.
  • Ci-C 4 alkoxy group for example a methoxy, ethoxy, propoxy, i-propoxy, n-propoxy, n-butoxy, sec- butoxy or tert-butoxy group.
  • a C 1 -C 6 alkoxy group is unsubstituted or substituted, typically by one or more groups Z or R 9 as defined above.
  • a C 3 -C 10 cycloalkyl group may be, for instance, C 3 -C 8 cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. Typically it is C 3 -C 6 cycloalkyl.
  • a C 3 -C 10 cycloalkyl group is unsubstituted or substituted, typically by one or more groups Z or R 9 as defined above.
  • alkylene group is unsubstituted or substituted, straight or branched chain saturated divalent hydrocarbon group.
  • alk denotes such an alkylene group.
  • alkylene or “alk” is C 1 -C 8 alkylene, for instance C 1 -C 6 alkylene.
  • it is C 1 -C 4 alkylene, for example C 2 -C 4 alkylene, such as methylene, ethylene, i-propylene, n-propylene, t-butylene, s-butylene or n-butylene. It may also be pentylene, hexylene, heptylene, octylene and the various branched chain isomers thereof.
  • the alkylene group is substituted it is typically substituted by a group R 20 as defined above.
  • each of the constituent units CR 2 or CR 8 2 may be the same or different when m, n, p, q or t is greater than 1.
  • An alkenyl group is an unsubstituted or substituted, straight or branched chain hydrocarbon radical having one or more double bonds.
  • alkenyl typically C 2 -C 8 alkenyl, for instance C 2 -C 6 alkenyl, such as allyl, butenyl, butadienyl, pentenyl or hexenyl.
  • alkenyl group is substituted it is typically substituted by a group Z or R 9 as defined above or by alkyl which is unsubstituted or substituted by a group Z or R 9 as defined above.
  • alkenylene group is a divalent alkenyl group as defined above.
  • alkynyl group is an unsubstituted or substituted, straight or branched chain hydrocarbon radical having one or more triple bonds. Typically it is C 2 -C 8 alkynyl, for instance C 2 -C 6 alkynyl, such as ethynyl, propynyl or butynyl.
  • alkynyl group is substituted it is typically substituted by a group R 20 as defined above or by alkyl which is unsubstituted or substituted by a group R 20 as defined above.
  • An alkynylene group is a divalent alkynyl group as defined above.
  • a saturated 5-, 6-, or 7-membered N-containing heterocyclic group typically contains one nitrogen atom and either an additional N atom or an O or S atom, or no additional heteroatoms. It may be C-linked or N-linked. It may alternatively be O- or S- linked when an additional O or S atom is present.
  • the group may be, for example, piperidine, piperazine, morpholine, thiomorpholine, pyrrolidine or homopiperazine.
  • the saturated 5-, 6-, or 7-membered N-containing heterocyclic group is unsubstituted or substituted on one or more ring carbon atoms and/or on any additional N atom present in the ring.
  • suitable substituents include one or more groups Z or R 9 as defined above, and a C 1 -C 6 alkyl group which is unsubstituted or substituted by a group Z or R 9 as defined above.
  • the ring When the ring is piperazine it is typically unsubstituted or substituted, typically on the second ring nitrogen atom, by - C(O)R 8 , -C(O)N(R 8 ) 2 or -S(O) 1n R 8 , or by C r C 6 alkyl which is unsubstituted or substituted by C 1 -C 6 alkoxy or OH.
  • An unsaturated 5- to 12-membered carbocyclic group is a 5-, 6-, 7-, 8-, 9-, 10, 11- or 12-membered carbocyclic ring containing at least one unsaturated bond. It is a monocyclic or fused bicyclic ring system.
  • the group is non-aromatic or aromatic, for instance a 5- to 12-membered aryl group. Examples include phenyl, naphthyl, indanyl, indenyl and tetrahydronaphthyl groups.
  • the group is unsubstituted or substituted, typically by one or more groups Z or R 9 as defined above.
  • An aryl group is a 5- to 12-membered aromatic carbocyclic group. It is monocyclic or bicyclic. Examples include phenyl and naphthyl groups. The group is unsubstituted or substituted, for instance by a group Z or R 9 as defined above.
  • An unsaturated 5- to 12-membered heterocyclic group is a 5-, 6-, 7-, 8-, 9-, 10, 11- or 12-membered heterocyclic ring containing at least one unsaturated bond and at least one heteroatom selected from O, N and S. It is C-linked or heteroatom-linked. It is a monocyclic or fused bicyclic ring system. The group is non-aromatic or aromatic, for instance heteroaryl.
  • the group may be, for example, furan, thiophene, pyrrole, pyrrolopyrazine, pyrrolopyrimidine, pyrrolopyridine, pyrrolopyridazine, indole, isoindole, pyrazole, pyrazolopyrazine, pyrazolopyrimidine, pyrazolopyridine, pyrazolopyridazine, imidazole, imidazopyrazine, imidazopyrimidine, imidazopyridine, imidazopyridazine, benzimidazole, benzodioxole, benzodioxine, benzoxazole, benzothiophene, benzothiazole, benzofuran, indole, indolizinyl, isoxazole, oxazole, oxadiazole, thiazole, isothiazole, thiadiazole, dihydroimidazole, dihydrobenzofur
  • Heteroaryl is a 5- to 12-membered aromatic heterocyclic group which contains 1, 2, 3, or 4 heteroatoms selected from O, N and S. It is monocyclic or bicyclic. Typically it contains one N atom and 0, 1, 2 or 3 addditional heteroatoms selected from O, S and N. It may be, for example, selected from the heteroaryl groups in the above list of options for a 5 to 12-membered heterocyclic group.
  • heteroaryl is selected from pyridyl, isoxazolyl, imidazolyl, pyrazolyl, pyrrolyl, thiazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, oxazolyl, furanyl, thienyl, triazolyl, tetrazolyl, indolyl, quinolinyl, isoquinolinyl, quinazolinyl and indazolyl.
  • R 6 is an unsaturated 5- to 12-membered carbocyclic ring, for instance an aryl group as defined above, it is unsubstituted or substituted by a group Z or R 9 as defined above. When it is substituted it is typically substituted by one or more, typically 1 or 2, substituents selected from -(alk) v -OR, -SO 2 R, -SO 2 NR 2 , -SO 2 NR 4a R 5a , -NRSO 2 R, -(alk) v -NRC(O)R, -(alk) v -C(O)NR 2 , -CO 2 R, halo, unsubstituted Ci-C 6 alkyl, -(alk) v -NR 2 , -C(O)-NR-alk-NR 2 , -(alk) v -C(O)NR 4a R 5a , -alk-NR 4a R 5a , -alk-
  • R 6 is a saturated 5-, 6- or 7- membered N-containing heterocyclic group which is unsubstituted or substituted, it is unsubstituted or substituted by a group Z or R 9 as defined above.
  • linker Y is -(CR 2 ) P -O-(CR 2 ) t -,it may, for example, be selected from -0-, - alk-O-alk-, -alk-O- and -O-alk- wherein alk is alkylene as defined above.
  • -(CR 2 ) P -O-(CR 2 ) t - is -0-(CR 2 ) t - , of which -O-alk- is an example.
  • Examples of -O-alk- include -0-(CH 2 )-, -0- ⁇ CHMe)-, -0-(CMe 2 )-, -O-(CH 2 ) 2 - and - O-(CH 2 ) 3 -.
  • Examples of -alk-O- include -(CH 2 )-O-, -(CHMe)-O-, -(CMe 2 )-0-, - (CH 2 ) 2 -O- and -(CH 2 ) 3 -O-.
  • linker Y is -(CR 2 ) P -NR-(CR 2 ) t - it may, for example, be selected from -NR-, alk-NR-alk, -alk-NR- and -NR-alk- wherein alk is alkylene as defined above.
  • Examples of -alk-NR- include -(CH2)-NH-, -(CH 2 )-NMe- -(CHMe)-NH-, -(CHMe)-NMe-, -(CMe 2 )-NH-, -(CMe 2 )-NMe-, -(CH 2 ) 2 -NH-, - (CH 2 ) 2 -NMe-, -(CH 2 ) 3 -NH- and -(CH 2 ) 3 -NMe-.
  • Examples of -NR-alk- include -NH- (CH 2 )-, -NMe-(CH 2 )-, -NH-(CHMe)-, -NMe-(CHMe)-, -NH-(CMe 2 )-, -NMe-(CMe 2 )-, -NH-(CH 2 ) 2 -, -NMe-(CH 2 ) 2 -, -NH-(CH 2 ) 3 - and -NMe-(CH 2 ) 3 .
  • linker Y When linker Y is -(CR 2 ) p -NR-(CR 2 ) n -C(O)- it may, for example, be selected from -NR-C(O)-, -alk-NR-alk-C(O)-, -alk-NR-C(O)- and -NR-alk-C(O)- wherein alk is alkylene as defined above.
  • Examples of -NR-C(O)- include -NH-C(O)- and -NMe-C(O).
  • Examples of -alk-NR-alk-C(O)- include -(CH 2 )-NH-(CH 2 )-C(O)- , -(CH 2 )- NMe-(CH 2 )-C(0)-, -(CHMe)-NH-(CH2)-C(0)-, -(CHMe)-NMe-(CH2)-C(0)-, - (CH 2 )-NH-(CHMe)-C(O)-, -(CH 2 )-NMe-(CHMe)-C(0)-, -(CMe 2 )-NH-(CH2)-C(O)-, -(CMe 2 )-NMe-(CH 2 )-C(0)-, -(CH 2 )-NH-(CMe 2 )-C(O)-, -(CMe 2 )-NMe-
  • Examples of -alk-NR-C(O)- include -(CH 2 )-NH-C(O)-, - ⁇ CH 2 )-NMe-C(O)-, - (CHMe)-NH-C(O)-, -(CHMe)-NMe-C(O)-, -(CMe 2 )-NH-C(O)-, -(CMe 2 )-NMe-C(0)- , - ⁇ CH 2 ) 2 -NH-C(O)-, -(CH 2 ) 2 -NMe-C(O)-, - ⁇ CH 2 ) 3 -NH-C(O)- and -(CH 2 ) 3 -NMe- C(O)-.
  • Examples of -NR-alk-C(O)- include -NH-(CH 2 )-C(0)- , -NMe-(CH 2 )-C(0)- , -
  • linker Y When linker Y is -(CR 2 ) p -NR-C(O)-(CR 2 ) n - it may, for example, be selected from -alk-NR-C(O)-alk- , -alk-NR-C(O)- and -NR-C(O)-alk-.
  • Examples of -alk-NR-C(O)-alk- include -(CH 2 )-NH-C(O)-(CR' ' 2 )-, -(CH 2 )-
  • Examples of -NR-C(O)-alk- include -NH-C(O)-(CH 2 )-, -NMe-C(O)-(CH 2 )-, -NH-C(OHCHMe)-, -NMe-C(O)-(CHMe)-, -NH-C(O)-(CMe 2 )-, -NMe-C(O)- (CMe 2 )-, -NH-C(OHCH 2 ) 2 -, NMe-C(O)-(CH 2 ) 2 -, -NH-C(OMCH 2 ) 3 - and -NMe- C(OHCH 2 ) 3 -.
  • linker Y is -(CR 2 ) p -C(O)-NR-(CR 2 ) t - it may, for example, be selected from -alk-C(O)-NR-alk, -alk-C(0)-NR- and -C(O)-NR-alk-.
  • alk-C(O)-NR-alk- examples include -(CH 2 )-C(O)-NH-(CR" 2 )-, -(CH 2 )- C(0)-NMe-(CR" 2 )-, -(CHMe)-C(0)-NH-(CR" 2 )-, -(CHMe)-C(O)-NMe-(CR" 2 )-, - (CMe 2 )-C(O)-NH-(CR 5 ' 2 )-, -(CMe 2 )-C(O)-NMe-(CR' '2)-, -(CH 2 ) 2 -C(O)-NH-(CR' ⁇ )-, -(CH 2 ) 2 -C(O)-NMe-(CR' ' 2 >, -(CH 2 ) 3 -C(O)- NH-(CR' ' 2 )- and -(CH 2 ) 3 - C(O)-NMe- (
  • Examples of -alk-C(O)-NR- include -(CH 2 )-C(0) NH-, -(CH 2 )-C(O) NMe-, - (CHMe)-C(O)-NH-, -(CHMe)-C(O)-NMe-, -(CMe 2 )-C(0)-NH-, -(CMe 2 )-C(O)- NMe-, -(CH 2 ) 2 -C(O)-NH-, -(CH 2 ) 2 -C(O)-NMe-, -(CH 2 ) 3 -C(O)-NH- and -(CH 2 ) 3 - C(O)-NMe-.
  • linker Y is -(CR 2 ) p -C(O)-(CR 2 ) n -NR-(CR 2 ) t -it may, for example, be -alk- C(0)-alk-NR-, -C(O)-alk-NR-, -alk-C(O)-NR- or -alk-C(O)-NR-alk-.
  • Examples of-alk-C(O)-alk-NR- include include - ⁇ CH 2 )-C(O)-(CR" 2 )-NH-, - (CH 2 )-C(O)-(CR' ' 2 )-NMe- -(CHMe)-C(O)-(CR' ' 2 )-NH-, -(CHMe)-C(O)-(CR' ' 2 )- NMe, -(CMe 2 )- C(O)-(CR" 2 )-NH-, -(CMe 2 )-C(O)-(CR" 2 )-NMe-, -(CH 2 ) 2 -C(O)- (CR" 2 )-NH, - ⁇ CH 2 ) 2 -C(O)-(CR" 2 )-NMe-, -(CH 2 ) 3 -C(O)-(CR" 2 )-NH- and- ⁇ CH 2 ) 3 - C(O)
  • Examples of -C(O)-alk-NR- include -C(0)-(CH 2 )-NH-, -C(0)-(CH 2 )-NMe-, - C(O)-(CHMe)-NH-, -C(O)-(CHMe)-NMe-, -C(0)-(CMe 2 )-NH-, -C(0)-(CMe 2 )-NMe, - C(O)-(CH 2 ) 2 -NH, -(C(O)-(CH 2 ) 2 -NMe-, -C(O)- (CH 2 ) 3 -NH- and -C(O)-(CH 2 ) 3 -NMe-
  • alk-C(O)-NR-alk- examples include -(CH 2 )-C(O)-NH-(CH 2 )-, -(CH 2 )-C(0)-
  • alk-C(O)- examples include -(CH 2 )-C(O)-, -(CH 2 ) 2 -C(O)-, -(CHMe)-C(O)- and -(CMe 2 )-C(0)-.
  • Examples of -C(O)-alk- include -C(O)-(CH 2 )-, -C(O)- ⁇ CH 2 ) 2 -. -C(O)- (CHMe)- and -C(O)-(CMe 2 )-.
  • Examples of alk-C(O)-alk- include -(CH 2 )-C(O)-(CH 2 )-, -(CHMe)-C(O)-(CH 2 )-, -(CMe 2 )-C(O)-(CH 2 )-, -(CH 2 )-C(0)-(CHMe)- and -(CH 2 )- C(O)-(CMe 2 )-.
  • the monocyclic heteroaryl group R 2 in formulae (I) and (F) as defined above is typically a C-linked monocyclic heteroaryl group. When it is substituted, it is typically substituted by -NR 10 R 1 ', -OR 10 or C 1 -C 6 alkyl.
  • R 7 in formulae (Ia) and (Ib) as defined above is typically selected from -NR 10 R 11 , -OR 10 and C 1 -C 6 alkyl.
  • Y is typically C 2 -C 6 alkynylene or -0-(CR 2 ) t - wherein t is as defined above.
  • R 6 is typically selected from OR, -NR 2 ,an unsaturated 5- to 12-membered carbocyclic or heterocyclic ring which is unsubstituted or substituted and a saturated 5-, 6- or 7- membered N-containing heterocyclic group which is unsubstituted or substituted, said saturated N-containing heterocyclic group being C-linked to Y when Y is -0-(CR 2 ) r .
  • R 6 is selected from -NR 2 , -OR, an aryl group as defined above, a heteroaryl group as defined above and a C-linked saturated 5-, 6- or 7- membered N-containing heterocyclic group, each said group being unsubstituted or substituted, for instance by a group Z or R 9 as defined above.
  • Y is C 2 -C 6 alkynylene or -0-(CR 2 ) t- wherein t is as defined above and R 6 is selected from -NR 2 , -OR, an aryl group as defined above and a heteroaryl group as defined above.
  • the aryl or heteroaryl group is unsubstituted or substituted by a group Z or R 9 as defined above, for instance by a group -SO 2 R, -COR, -CONR 2 or -CN wherein each R is, independently, H or C 1 - C 6 alkyl.
  • the aryl group is typically phenyl and the heteroaryl group is typically pyridyl, imidazolyl or quinolinyl.
  • Morpholino pyrimidines of the invention may be produced by a process which comprises a palladium-mediated (Suzuki-type) cross-coupling reaction as the last step.
  • a morpholino pyrimidine of formula (I) may be produced by a process which comprises treating a compound of formula (II):
  • R 1 and R 3 are as defined above, with a boronic acid or ester thereof of formula R 2 B(OR 15 ) 2 , in which R 2 is as defined above and each R 15 is H or C 1 -C 6 alkyl or the two groups OR 15 form, together with the boron atom to which they are attached, a pinacolato boronate ester group, in the presence of a suitable base and a Pd catalyst.
  • a suitable solvent is acetonitrile.
  • a suitable temperature range for this reaction is room temperature to 80-180°C. This reaction may be performed thermally or in a microwave reactor.
  • a compound of formula (II) wherein R 1 is a group -Y-R 6 in which Y is -O-(CR 2 ) n - and R 6 is as defined above may be produced by a process which comprises treating a compound of the following formula (III):
  • R is as defined above, with a compound of formula HO-(CR 2 ) n -R in the presence of a base.
  • a suitable base is sodium hydride or potassium carbonate.
  • a suitable solvent is N,N-dimethylformamide or acetonitrile.
  • a suitable temperature range for this reaction is room temperature to 100°C.
  • a compound of formula (II) wherein R 1 is a group -Y-R 6 in which Y is -NR-(CR 2 ) n - may be prepared by treating a compound of formula (III) as defined above with an amine of formula HNR-(CR 2 ) ⁇ -R 6 in the presence of a base.
  • a suitable base is sodium hydride or potassium carbonate.
  • a suitable solvent is N,N-dimethylforaiamide, tetrahydrofuran or acetonitrile.
  • a suitable temperature range for this reaction is room temperature to 100°C.
  • a compound of formula (II) wherein R 1 is a group -Y-R 6 in which Y is a direct bond and R is an unsaturated 5- to 12-membered carbocyclic or heterocyclic ring which is aromatic may be prepared by treating a compound of formula (III) as defined above with a boronic acid or ester thereof of formula R 1 B(OR ⁇ ) 2 , in which R 1 is as defined above and each R 15 is H or C 1 -C 6 alkyl or the two groups OR 15 form, together with the boron atom to which they are attached, a pinacolato boronate ester group, in the presence of a suitable base and a Pd catalyst.
  • a suitable solvent is acetonitrile.
  • a suitable temperature range for this reaction is room temperature to 80-180°C. This reaction may be performed thermally or in a microwave reactor.
  • a compound of formula (II) wherein R 1 is a group -Y-R 6 in which Y is a linker group -(CR 2 ) p -NR-(CR 2 ) n - in which p is 0 may be produced by a process which comprises treating a compound of formula (VI):
  • a compound of formula (VI) may be produced by a process which comprises treating 2,4,6-trichloropyrimidine with an amine of formula R 6 -(CR 2 ) P -NRH in the presence of a base in an appropriate solvent.
  • a morpholino pyrimidine of formula (I) may also be produced by a process which comprises treating a compound of formula (IV):
  • R 2 and R 3 are as defined above, with a boronic acid or ester thereof of formula R 1 B(OR 15 ) 2 , in which R 1 is -Y-R 6 in which Y is a direct bond and R 6 is a 5- to 12- membered aryl or heteroaryl group and each R 15 is H or Ci-C 6 alkyl or the two groups OR 15 form, together with the boron atom to which they are attached, a pinacolato boronate ester group, in the presence of a suitable base and a Pd catalyst.
  • a suitable solvent is acetonitrile.
  • a suitable temperature range for this reaction is room temperature to 80- 18O 0 C. This reaction may be performed thermally or in a microwave reactor.
  • a morpholino pyrimidine of formula (I) in which R 1 is a group -Y-R wherein Y is an alkynylene group and R 6 is as defined above may be produced by a process which comprises submitting a compound of formula (IV) as defined above to Sonogashira coupling with a compound of formula HC ⁇ C-(CR 2 ) n -R 6 in the presence of a palladiaum catalyst, a copper (I) cocatalyst and an amine base.
  • a compound of formula (IV) as defined above may be produced by a process which comprises by treating a compound of formula (III) as defined above with a boronic acid or ester thereof of formula R 2 B(OR 15 )2, in which R 2 is as defined above and each R 15 is H or C 1 -C 6 alkyl or the two groups OR 15 form, together with the boron atom to which they are attached, a pinacolato boronate ester group, in the presence of a suitable base and a Pd catalyst.
  • a suitable solvent is acetonitrile.
  • a suitable temperature range for this reaction is room temperature to 80-180 0 C. This reaction may be performed thermally or in a microwave reactor.
  • a compound of formula (I) in which R 1 is a group -Y-R 6 in which Y is a linker group -(CR 2 ) p -NH-(CR 2 ) n - as defined above in which p is 0, may be produced by a process which comprises treating a compound of formula (Ha):
  • R 3 , R 6 , R and p are as defined above for formula (I), with a boronic acid or ester thereof of formula R 2 B(OR 15 ) 2 , in which R 2 is as defined above and each R 15 is H or C 1 -C 6 alkyl or the two groups OR 15 form, together with the boron atom to which they are attached, a pinacolato boronate ester group, in the presence of a suitable base and a Pd catalyst.
  • a suitable solvent is acetonitrile.
  • a suitable temperature range for this reaction is room temperature to 80- 180°C. This reaction may be performed thermally or in a microwave reactor.
  • a compound of formula (Ha) may be prepared by a process which comprises treating a compound of formula (V):
  • a compound of formula (V) may be prepared by treatment of a compound of formula (VTa):
  • a compound of formula (VI) may be prepared by a process which comprises treating 2,4,6-trichloropyrimidine with an amine of formula R 6 -(CR 2 ) P -NH 2 in the presence of a base in an appropriate solvent.
  • a morpholino pyrimidine of the invention may be converted into a pharmaceutically acceptable salt, and a salt may be converted into the free compound, by conventional methods.
  • salts include salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulphuric acid, nitric acid and phosphoric acid; and organic acids such as methanesulfonic acid, benzenesulphonic acid, formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, ethanesulfonic acid, aspartic acid and glutamic acid.
  • the salt is a mesylate, a hydrochloride, a phosphate, a benzenesulphonate or a sulphate.
  • the salt is a mesylate or a hydrochloride.
  • the salts for instance salts with any of the inorganic or organic acids mentioned above, may be mono-salts, bis-salts or tris-salts.
  • the mesylate salt may be the mono-mesylate or the bis-mesylate.
  • the morpholino pyrimidines of the invention and their salts may exist as hydrates or solvates.
  • Compounds of the present invention have been found in biological tests to be inhibitors of PB kinase.
  • the compounds are inhibitors of the pi 10a isoform of PI3 kinase.
  • the compounds may show selectivity for the pi 10a isoform over one or more of the other isoforms of PB kinase, i.e. selectivity over one or more of the pi lO ⁇ , pi lO ⁇ and pi lO ⁇ isoforms.
  • a compound of the present invention may thus be used as an inhibitor of PI3 kinase, in particular of a class Ia PO kinase. Accordingly, a compound of the present invention can be used to treat a disease or disorder arising from abnormal cell growth, function or behaviour. Such abnormal cell growth, function or behaviour is typically associated with PD kinase. Examples of such diseases and disorders are discussed by Drees et al in Expert Opin. Ther. Patents (2004) 14(5):703 - 732. These include cancer, immune disorders, cardiovascular disease, viral infection, inflammation, metabolism/endocrine disorders and neurological disorders. Examples of metabolism/endocrine disorders include diabetes and obesity.
  • cancers which the present compounds can be used to treat include leukaemia, brain tumours, renal cancer, gastric cancer and cancer of the skin, bladder, breast, uterus, lung, colon, prostate, ovary and pancreas.
  • a human or animal patient suffering from an immune disorder, cancer, cardiovascular disease, viral infection, inflammation, a metabolism/endocrine disorder or a neurological disorders may thus be treated by a method comprising the administration thereto of a compound of the present invention as defined above. The condition of the patient may thereby be improved or ameliorated.
  • Diseases and conditions treatable according to the methods of this invention include, but are not limited to, cancer, stroke, diabetes, hepatomegaly, cardiovascular disease, Alzheimer's disease, cystic fibrosis, viral disease, autoimmune diseases, atherosclerosis, restenosis, psoriasis, allergic disorders, inflammation, neurological disorders, a hormone-related disease, conditions associated with organ transplantation, immunodeficiency disorders, destructive bone disorders, proliferative disorders, infectious diseases, conditions associated with cell death, thrombin-induced platelet aggregation, chronic myelogenous leukemia (CML), liver disease, pathologic immune conditions involving T cell activation, and CNS disorders in a patient.
  • CML chronic myelogenous leukemia
  • a human patient is treated with a compound of the invention and a pharmaceutically acceptable carrier, adjuvant, or vehicle, wherein said compound is present in an amount to detectably inhibit PI3 kinase activity.
  • Cancers which can be treated according to the methods of this invention include, but are not limited to, breast, ovary, cervix, prostate, testis, genitourinary tract, esophagus, larynx, glioblastoma, neuroblastoma, stomach, skin, keratoacanthoma, lung, epidermoid carcinoma, large cell carcinoma, non-small cell lung carcinoma (NSCLC), small cell carcinoma, lung adenocarcinoma, bone, colon, adenoma, pancreas, adenocarcinoma, thyroid, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, sarcoma, bladder carcinoma, liver carcinoma and biliary passages, kidney carcinoma, myeloid
  • Cardiovascular diseases which can be treated according to the methods of this invention include, but are not limited to, restenosis, cardiomegaly, atherosclerosis, myocardial infarction, and congestive heart failure.
  • Neurodegenerative disease which can be treated according to the methods of this invention include, but are not limited to, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, and cerebral ischemia, and neurodegenerative disease caused by traumatic injury, glutamate neurotoxicity and hypoxia.
  • Inflammatory diseases which can be treated according to the methods of this invention include, but are not limited to, rheumatoid arthritis, psoriasis, contact dermatitis, and delayed hypersensitivity reactions.
  • a compound of the present invention can be administered in a variety of dosage forms, for example orally such as in the form of tablets, capsules, sugar- or film-coated tablets, liquid solutions or suspensions or parenterally, for example intramuscularly, intravenously or subcutaneously.
  • the compound may therefore be given by injection or infusion.
  • the dosage depends on a variety of factors including the age, weight and condition of the patient and the route of administration. Daily dosages can vary within wide limits and will be adjusted to the individual requirements in each particular case. Typically, however, the dosage adopted for each route of administration when a compound is administered alone to adult humans is 0.0001 to 50 mg/kg, most commonly in the range of 0.001 to 10 mg/kg, body weight, for instance 0.01 to 1 mg/kg. Such a dosage may be given, for example, from 1 to 5 times daily. For intravenous injection a suitable daily dose is from 0.0001 to 1 mg/kg body weight, preferably from 0.0001 to 0.1 mg/kg body weight. A daily dosage can be administered as a single dosage or according to a divided dose schedule.
  • a dose to treat human patients may range from about 10 mg to about 1000 mg of a compound of the invention.
  • a typical dose may be about 100 mg to about 300 mg of the compound.
  • a dose may be administered once a day (QID), twice per day (BID), or more frequently, depending on the pharmacokinetic and pharmacodynamic properties, including absorption, distribution, metabolism, and excretion of the particular compound.
  • toxicity factors may influence the dosage and administration regimen.
  • the pill, capsule, or tablet may be ingested daily or less frequently for a specified period of time. The regimen may be repeated for a number of cycles of therapy.
  • a compound is formulated for use as a pharmaceutical or veterinary composition also comprising a pharmaceutically or veterinarily acceptable carrier or diluent.
  • compositions are typically prepared following conventional methods and are administered in a pharmaceutically or veterinarily suitable form.
  • the compound may be administered in any conventional form, for instance as follows: A) Orally, for example, as tablets, coated tablets, dragees, troches, lozenges, aqueous or oily suspensions, liquid solutions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs.
  • Compositions intended for oral use may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavouring agents, colouring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations.
  • Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
  • excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, dextrose, saccharose, cellulose, corn starch, potato starch, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, maize starch, alginic acid, alginates or sodium starch glycolate; binding agents, for example starch, gelatin or acacia; lubricating agents, for example silica, magnesium or calcium stearate, stearic acid or talc; effervescing mixtures; dyestuffs, sweeteners, wetting agents such as lecithin, polysorbates or lauryl sulphate.
  • inert diluents such as calcium carbonate, sodium carbonate, lactose, dextrose, saccharose, cellulose
  • the tablets may be uncoated or they may be coated by known techniques to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl monostearate or glyceryl distearate may be employed.
  • Such preparations may be manufactured in a known manner, for example by means of mixing, granulating, tableting, sugar coating or film coating processes.
  • Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is present as such, or mixed with water or an oil medium, for example, peanut oil, liquid paraffin, or olive oil.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
  • water or an oil medium for example, peanut oil, liquid paraffin, or olive oil.
  • Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients are suspending agents, for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethyl-cellulose, sodium alginate, polyvinylpyrrolidone gum tragacanth and gum acacia; dispersing or wetting agents may be naturally-occurring phosphatides, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides for example polyoxyethylene sorbitan monooleate.
  • the said aqueous suspensions may also contain one or more preservatives, for example, ethyl or n-propyl p-hydroxybenzoate, one or more colouring agents, such as sucrose or saccharin.
  • preservatives for example, ethyl or n-propyl p-hydroxybenzoate
  • colouring agents such as sucrose or saccharin.
  • Oily suspension may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.
  • the oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol.
  • Sweetening agents such as those set forth above, and flavouring agents may be added to provide a palatable oral preparation. These compositions may be preserved by this addition of an antioxidant such as ascorbic acid.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavouring and colouring agents, may also be present.
  • the pharmaceutical compositions of the invention may also be in the form of oil-in- water emulsions.
  • the oily phase may be a vegetable oil, for example olive oil or arachis oils, or a mineral oil, for example liquid paraffin or mixtures of these.
  • Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally occuring phosphatides, for example soy bean lecithin, and esters or partial esters derived from fatty acids an hexitol anhydrides, for example sorbitan mono-oleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate.
  • the emulsion may also contain sweetening and flavouring agents.
  • Syrups and elixirs may be formulated with sweetening agents, for example glycerol, sorbitol or sucrose.
  • sweetening agents for example glycerol, sorbitol or sucrose.
  • a syrup for diabetic patients can contain as carriers only products, for example sorbitol, which do not metabolise to glucose or which only metabolise a very small amount to glucose.
  • Such formulations may also contain a demulcent, a preservative and flavouring and coloring agents.
  • This suspension may be formulated according to the known art using those suitable dispersing of wetting agents and suspending agents which have been mentioned above.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic paternally-acceptable diluent or solvent, for example as a solution in 1,3-butane diol.
  • Suitable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • SCX-2 cartridges were also used in the purification of some compounds.
  • Method B A mixture of morpholinoformamidine hydrobromide (3.38g), methanol ( 1 OmL) and sodium methoxide in methanol (25% wt, 7.35ml) was heated to reflux for 30 minutes. Diethyl malonate (2.69ml) was then added and the reaction mixture was heated for a further 5 hours. The reaction mixture was then cooled and poured onto ice/water ( ⁇ 50ml) and acidified using 2N HCl to give a white precipitate. This was collected by filtration and air-dried to give 2-morpholin-4-yl-pyrimidine-4,6-diol (2.38g).
  • Methyl-[5-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-pyridin-2-yl]-carbamic acid tert-butyl ester was prepared from tert-butyl 5-bromopyridin-2- yl(methyl)carbamate according to J. Label Compd. Radiopharm., (2003), 46, 1055- 1065, Kumar et al.
  • 6-(4-Methyl-piperazin- 1 -yl)-2-morpholin-4-yl-[4,5']bipyrimidinyl-2'-ylamine (5) was prepared using N-methylpiperazine.
  • N-6-Benzyl-2-mo ⁇ holin-4-yl-[4,5']bipyrimidinyl-6,2'-diamine (16) was prepared using benzylamine.
  • N-6-Benzyl-N-6-methyl-2-morpholin-4-yl-[4,5']bipyrimidinyl-6,2'-diamine (18) was prepared using N-benzylmethylamine IH NMR (400MHz, CDCl 3 )
  • N-6-[2-(3,4-Dimethoxy-phenyl)-ethyl]-N-6-methyl-2-morpholin-4-yl- ⁇ 'Jbipyrimidinyl- ⁇ '-diamine (23) was prepared using 2-(3,4-dimethoxyphenyl)-N- methylethylamine.
  • N-6-(2-Dimethylamino-ethyl)-2-morpholin-4-yl-[4,5']bipyrimidinyl-6,2'-diamine was prepared using N,N-dimethylethylenediamine; NMR (CDC13): 2.29 (6H, s), 2.55 (2H, t), 3.44-3.47 (2H, m), 3.77-3.80 (4H, m), 3.84- 3.87 (4H, m), 5.20 (2H, br), 5.32 (IH, br), 6.03 (IH, s), 8.89 (2H, s) MS (ESI+): MH+ 345.21 (30%) N-6-(3-Dimethylamino-propyl)-2-morpholin-4-yl-[4,5']bipyrimidinyl-6,2 l -diamine (67) was prepared using 3-dimethylaminopropylamine.
  • N-6,N-6-Bis-(2-methoxy-ethyl)-2-morpholin-4-yl-[4,5']bipyrimidinyl-6,2'-diamine was prepared using bis-(2-methoxy-ethyl)-amine.
  • N-6-(3-Fluoro-benzyl)-2-mo ⁇ holin-4-yl-[4,5']bipyrimidinyl-6,2'-diamine (70) was prepared using 3-fluorobenzylamine.
  • N-6-(2-Methoxy-ethyl)-N-6-methyl-2-mo ⁇ holin-4-yl-[4,5']bipyrimidinyl-6,2'-diamine (111) was prepared using (2-methoxyethyl)methylamine.
  • 2-Morpholin-4-yl-N-6-(2-pyridin-2-yl-ethyl)-[4,5']bipyrimidinyl-6,2'-diamine (92) was prepared using2-(2-aminoethyl)pyridine.
  • N-6-[2-(lH-Imidazol-4-yl)-ethyl]-2-mo ⁇ holin-4-yl-[4,5']bipyrimidinyl-6,2 1 -diamine (101) was prepared using histamine.
  • N-6-[2-(lH-Indol-3-yl)-ethyl]-2-morpholin-4-yl-[4,5 f ]bipyrimidinyl-6,2'-diamine (102) was prepared using tryptamine
  • N-[4-(6-Chloro-2-morpholin-4-yl-pyrimidin-4-yl)-phenyl]-ethane-sulfonamide (69mg) and 2-aminopyrimidine-5-boronic acid pinacol ester (1.8 equiv., 47mg) were taken up in acetonitrile (2ml).
  • sodium carbonate (3 equiv., 60mg) as a solution in water (0.5ml) and PdCl 2 (PPh 3 ) 2 (0.05 equiv.).
  • the reaction mixture was heated in microwave at 14O 0 C for 30 min.
  • 6-(3-Methanesulfonyl-phenyl)-2-mo ⁇ holin-4-yl-[4,5 l ]bipyrimidinyl-2'-ylamine (6) was prepared using 3-methoxysulphonylphenyl boronic acid.
  • N-[4-(2'-Amino-2-mo ⁇ holin-4-yl-[4,5']bipyrimidinyl-6-yl)-phenyl]-acetamide (13) was prepared using 4'-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)acetamide.
  • N-[2-(2'-Amino-2-m ⁇ holin-4-yl-[4,5']bipyrimidinyl-6-yl)-phenyl]- methanesulfonamide (57) was prepared using N-[2-(4,4,5,5-tetramethyl- 1,3,2- dioxaborolan-2-yl)phenyl]methanesulfonamide.
  • N- [3 -(T- Amino-2-morpholin-4-yl- [4, 5 ']bipyrimidinyl-6-yl)-phenyl] -acetamide (62) was prepared using 3-acetamidobenzeneboronic acid.
  • N- [3 -(2'- Amino-2-morpholin-4-yl- [4,5 ']bipyrimidinyl-6-yl)-pheny 1] - methanesulfonamide (79) was prepared using N-[3-(4,4,5,5-tetramethyl- 1,3,2- dioxaborolan-2-yl)phenyl]methanesulfonamide.
  • 6-(4-Methanesulfonyl-phenyl)-2-morpholin-4-yl-[4,5']bipyrimidinyl-2'-ylamine (58) was prepared using 4-(methanesulfonyl)benzeneboronic acid.
  • 6-(2-Methanesulfonyl-phenyl)-2-morpholin-4-yl-[4,5']bipyrimidinyl-2'-ylamine (74) was prepared using (2-methylsulfonyl)phenylboronic acid.
  • 6-[4-(4-Methanesulfonyl-piperazin- 1 -ylmethyl)-phenyl]-2-morpholin-4-yl- [4,5']bipyrimidinyl-2'-ylamine (39) was prepared using Intermedaite G.
  • N-I *-(6-Chloro-2-morpholin-4-yl-pyrimidin-4-yl)-ethane- 1 ,2-diamine hydrochloride 150mg, 0.51mmol was dissolved in pyridine (ImI), to this was added methanesulfonyl chloride (1.2 equiv., 47ul) and the reaction mixture was stirred at room temperature overnight.
  • Example 9 4-(2'-Amino-2-morpholin-4-vI-r4,5'lbipyrimidinyI-6-vD-2- methyl-but-3-vn-2-ol (114)
  • 2-methyl-3-butyn-2-ol 1.2 equiv., 12ul
  • copper (I) iodide 0.022 equiv., 0.5mg
  • triethylamine 2 equiv., 29ul
  • PdCl 2 (PPh 3 ) 2 0.05 equiv., 3.5mg.
  • the reaction mixture was heated in microwave at 18O 0 C for 10 min.
  • 6-(3-Dimethylamino-prop-l-ynyl)-2-morpholin-4-yl-[4,5']bipyrimidinyl-2'-ylamine (124) was prepared from l-dimethylamino-2-propyne.
  • 6-(3,5-Difluoro-phenoxy)-2-morpholin-4-yl-[4,5']bipyrimidinyl-2'-ylamine (34) was prepared from 3,5-difluorophenol.
  • 6-(2,6-Dimethyl-phenoxy)-2-morpholin-4-yl-[4,5']bipyrimidinyl-2'-ylamine (35) was prepared from 2,6-dimethylphenol.
  • 6-(4-Methanesulfonyl-phenoxy)-2-mo ⁇ holin-4-yl-[4,5']bipyrirnidinyl-2'-ylamine (82) was prepared from 4-methylsulphonylphenol.
  • N,N-dimethyl-benzamide ( 26) To a solution of Intermediate Dl (70mg) in dry N,N-dimethylformamide (2mL) was added 1,1-carbonyldiimidazole (42mg). After 2 hours dimethylamine hydrochloride (25mg) and triethylamine (41 ⁇ L) were added. The reaction mixture was stirred overnight before water was added to yield a precipitate. This was collected by filtration and air-dried to yield 4-(6-chloro-2-mo ⁇ holin-4-yl-pyrimidin-4-yloxy)-N,N-dimethyl- benzamide (76mg).
  • Example 12 2-MorphoKn-4-vI-N-6-phenvI-r4,5Mbipyrimidinyl-6,2'- diamine (49) To a solution of N-BOC-aniline( 171 mg) in dry N,N-dimethy lformamide (was added sodium hydride (60% dispersion in mineral oil, 59mg). After stirring for 15 minutes, Intermediate Al (197mg) was added and the reaction mixture was heated to
  • 6-(3-Methanesulfonyl-ben2yloxy)-2-morpholin-4-yl-[4,5 l ]bipyrimidinyl-2'-ylarnine (116) was prepared from (3-methanesulfonyl-phenyl)-methanol.
  • (3-Methanesulfonyl-phenyl)-methanol was prepared as follows: To 3- Methanesulfonyl-benzoic acid in THF at O 0 C was added dropwise a borane-THF complex and the reaction mixture stirred at room temperature overnight. Excess hydride was destroyed by slow addition of a water/THF mixture. The aqueous phase was saturated with potassium carbonate then extracted with ether. The organics were dried with MgSO 4 and the solvent reduced in vacuo to yield (3-methanesulfonyl-phenyl)- methanol as a clear oil.
  • 3-Hydroxymethyl-benzonitrile was prepared as follows: To 3- cyanobenzaldehyde in dry MeOH at O 0 C was added NaBH 4 and the reaction stirred at room temperature for 2hours. The mixture was quenched with 50:50 H 2 O:sat. aq.NaHCO 3 then extracted into MeOH-EtOAc to yield 3-hydroxymethyl-benzonitrile.
  • 6-(3-Methyl-3H-imidazol-4-ylmethoxy)-2-morpholin-4-yl-[4,5']bipyrimidinyl-2'- ylamine 120 was prepared from (l-methyl-lH-imidazol-5-yl)methanol.
  • 2-Morpholin-4-yl-6-(quinolin-3-ylmethoxy)-[4,5']bipyrimidinyl-2'-ylamine (121) was prepared from quinolin-3-yl-methanol.
  • 3-Hydroxymethyl-N,N-dimethyl-benzamide was prepared as follows: To 3- carboxybezaldehyde in DMF was added carbonyldiimidazole. After stirring for 4 hours, triethylamine and dimethylamine.HCl were added and the mixture stirred at room temperature for a weekend. The mixture was quenched with water, extracted into DCM and washed with brine. Drying with MgSO 4 and removal of the solvent in vacuo yielded crude material which was purified on silica to give 3-Formyl-N,N-dimethyl-benzamide as a yellow oil.
  • 6-(4-Methanesulfonyl-benzyloxy)-2-morpholin-4-yl-[4,5 l ]bipyrimidinyl-2'-ylamine (127) was prepared from/>-(methylsulfonyl)benzylalcohol.
  • 6-(l-Methyl-l-phenyl-ethoxy)-2-mo ⁇ holin-4-yl-[4,5']bipyrimidinyl-2'-ylamine (135) was prepared from 2-phenyl-2-propanol.
  • 2-(3-methanesulfonyl-phenyl)-ethanol was prepared as follows: To a solution of 3-methylsulphonylphenylacetic acid (200mg, 0.93mmol) in dry THF (3ml) at O 0 C was added borane-tetrahydrofuran complex ( 1.0M solution in THF, 1.4 equiv, 1.31 ml) dropwise. The reaction was allowed to warm up to room temperature overnight and then quenched with water. DCM/brine extraction gave 2-(3-methanesulfonyl-phenyl)-ethanol as a clear oil (184mg).
  • 2-(3-cyanol-phenyl)-ethanol was prepared as follows: To a solution of 3- cyanophenylacetic acid (250mg, 1.55mmol) in dry THF (3ml) at O 0 C was added borane- tetrahydrofuran complex (LOM solution in THF, 1.4 equiv, 2.17ml) dropwise. The reaction was allowed to warm up to room temperature overnight and then quenched with water. DCM/brine extraction gave 2-(3-cyanol-phenyl)-ethanol as a yellow oil (170mg).
  • LOM solution in THF 1.4 equiv, 2.17ml
  • 6-[2-(lH-Indol-3-yl)-ethoxy]-2-morpholin-4-yl-[4,5']bipyrimidinyl-2'-ylamine (144) was prepared from 3-(2-hydroxy-ethyl)-indole-l-carboxylic acid tert-butyl ester.
  • 3-(2-Hydroxy-ethyl)-indole-l-carboxylic acid tert-butyl ester was prepared as follows: To a solution of tryptophol (200mg, 1.25mmol) in DCM (5ml) were added di- tert-butyldicarbonate (1.5equiv, 410mg) and dimethylaminopyridine (0.05equiv, 8mg) and the reaction mixture was stirred at room temperature overnight. DCM/brine extraction afforded 3-(2-hydroxy-ethyl)-indole-l-carboxylic acid tert-butyl ester as an oil (348mg).
  • 6-(4-Benzenesulfonyl-piperazin-l-yl)-2-morpholin-4-yl-[4,5']bipyrimidinyl-2'-ylamine (9) was prepared in an analogous manner using Intermediate H and benzene sulphonyl chloride.
  • 6-(4-Dimethylaminomethyl-phenoxy)-2-mo ⁇ holin-4-yl-[4,5']bipyrimidinyl-2'-ylamine was prepared in a similar manner using Intermediate E2 and dimethylamine hydrochloride.
  • N-6-(3-Methanesulfonyl-phenyl)-5-methyl-2-morpholin-4-yl-[4,5']bipyrimidinyl-6,2'- diamine (150) was prepared in an analogous manner using Intermediate A2.
  • N-6-(4-Methanesulfonyl-phenyl)-2-morpholin-4-yl-[4,5']bipyrimidinyl-6,2'-diamine (103) was prepared using 4-methylsulphonyl aniline.
  • N-6-Methyl-6-morpholin-4-yl-N-6-phenyl-[4,5']bipyrimidinyl-6,2'-diamine (106) was prepared using N-methylaniline.
  • N-6-[3-(4-Methyl-piperazine-l-sulfonyl)-phenyl]-2-morpholin-4-yl-[4,5']bipyrimidinyl- 6,2'-diamine (105) was prepared in a similar manner by replacing dimethylamine with N-methylpiperazine
  • 6-(6-Amino-pyridin-3-yl)-2-morpholin-4-yl-pyrimidin-4-yl]-[3-(4-methyl-piperazine-l- sulfonyl)-phenyl]-amine (133) was prepared in a similar manner using 2-aminopyridine- 5-boronic acid pinacol ester for the last step
  • Example 23 3-f2-(2 > -Amino-2-morphoIin-4-vI-r4,5'lbipyrimidinyl-6- yloxy)-ethvU-benzamide (143) To 3-[2-(2'-amino-2-morpholin-4-yl-[4,5']bipyrimidinyl-6-yloxy)-ethyl]- benzonitrile 96mg, 0.24mmol) (described above) in MeOH (5ml) was added sodium hydroxide (1 equiv, 9.5mg) in water (0.5ml) and hydrogen peroxide (30% solution in water, 5 equiv., 0.12ml).
  • PI3K Compound inhibition of PI3K was determined in a radiometric assay using purified, recombinant enzyme and ATP at a concentration of lmicromole All compounds were serially diluted in 100% DMSO. The kinase reaction was incubated for 1 hour at room temperature, and the reaction was terminated by the addition of PBS. ICso values were subsequently determined using sigmoidal dose-response curve fit (variable slope). All of the compounds tested had an IC 50 against PBK of 10 micromole or less.
  • EC 50 values were calculated using a sigmoidal dose response curve fit. All the compounds tested had an EC 50 S of 10 micromole or less in the range of cell lines utilized.
  • Tablets each weighing 0.15 g and containing 25 mg of a compound of the invention are manufactured as follows:
  • the active compound, lactose and half of the corn starch are mixed. The mixture is then forced through a sieve 0.5 mm mesh size. Corn starch (10 g) is suspended in warm water (90 ml). The resulting paste is used to granulate the powder.
  • Example 28 Injectable Formulation
  • the compound of the invention is dissolved in most of the water (35° 40° C) and the pH adjusted to between 4.0 and 7.0 with the hydrochloric acid or the sodium hydroxide as appropriate.
  • the batch is then made up to volume with water and filtered through a sterile micropore filter into a sterile 10 ml amber glass vial (type 1) and sealed with sterile closures and overseals.
  • the active compound is dissolved in the glycofurol.
  • the benzyl alcohol is then added and dissolved, and water added to 3 ml.
  • the mixture is then filtered through a sterile micropore filter and sealed in sterile 3 ml glass vials (type 1).
  • the compound of the invention is dissolved in a mixture of the glycerol and most of the purified water.
  • An aqueous solution of the sodium benzoate is then added to the solution, followed by addition of the sorbitol solution and finally the flavour.
  • the volume is made up with purified water and mixed well.

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Abstract

L'invention concerne des morpholinopyrimidines de formule (I) : dans laquelle R1 est choisi parmi -Y-R6 et -NR4R5 ; R2 est un groupe hétéroaryle monocyclique contenant N qui est choisi parmi pyridyle, isoxazolyle, imidazolyle, pyrazolyle, pyrrolyle, thiazolyle, pyridazinyle, pyrimidinyle, pyrazinyle, oxazolyle, furanyle, thiényle, triazolyle et tétrazolyle et qui est non substitué ou substitué par halogéno, -CN, -NR10R11, -OR10, -C(O)R10, -NR10C(O)R11, -N(C(O)R11)2, -NR10C(O)NR10R11, -SO2R10R11, -SO2NR10R11, -C(=O)OR10, -C(=O)NR10R11, halogénoalkyle en C1-C6 et alkyle en C1-C12 non substitué ; R3 est choisi parmi H, alkyle en C1-C6 et alcoxy en C1-C6 ; Y est choisi parmi une liaison directe, -(CR2)m-, alcénylène en C2-C6, alcynylène en C2-C6, -(CR2)p-O-(CR2)t-, -(CR2)p-NR-(CR2)t, -(CR2)p-NR-(CR2)n-C(O)-, -(CR2)p-NR-C(O)-(CR2)n-, -(CR2)p-C(O)-NR-(CR2)t, -(CR2)p-C(O)-(CR2)n-NR-(CR2)t-, et -(CR2)p-C(O)-(CR2)n- ; R6 est choisi parmi un cycle carbocyclique ou hétérocyclique insaturé ayant 5 à 12 éléments, un groupe hétérocyclique saturé contenant N à 5, 6 ou 7 éléments qui est non substitué ou substitué, un alkyle en C1-C6, -NR2, -OR, -NR(CO)R et -C(O)NR2 ; R4 et R5, qui sont identiques ou différents, sont tous les deux un alkyle en C1-C6 qui est substitué ou non substitué, ou R4 et R5 forment ensemble, avec l'atome d'azote auquel ils sont attachés, un groupe hétérocyclique saturé contenant N à 5, 6 ou 7 éléments qui est substitué ou non substitué ; chacun des R, qui sont identiques ou différents lorsque plus d'un est présent dans un groupe donné, est indépendamment H, alkyle en C1-C6 qui est substitué ou non substitué ou un groupe aryle ou hétéroaryle ayant 5 à 12 éléments qui est substitué ou non substitué ; R10 et R11, qui sont identiques ou différents, sont indépendamment choisis parmi H, alkyle en C1-C6, alcényle en C2-C6, alcynyle en C2-C6 et cycloalkyle en C3-C8 ; n est 0 ou un entier de 1 à 6 ; m est un entier de 1 à 6 ; p est 0 ou un entier de 1 à 6 ; et t est 0 ou un entier de 1 à 6, à condition que t soit un entier de 2 à 6 lorsque R6 est relié à Y par un atome O ou N constitutif de R6 ; et leurs sels pharmaceutiquement acceptables, soumis à diverses conditions, qui présentent une activité en tant qu'inhibiteurs de PI3K et peuvent ainsi être utilisés pour traiter des maladies et des troubles causés par une croissance, un fonctionnement ou un comportement cellulaire anormal, notamment associé avec la kinase PI3, tel que le cancer, les troubles immunitaires, les maladies cardiovasculaires, les infections virales, l'inflammation, les troubles métaboliques/endocriniens et les troubles neurologiques. L'invention concerne également des procédés de synthèse des composés.
PCT/GB2008/003910 2007-11-21 2008-11-21 2-morpholinopyrimidines et leur utilisation en tant qu'inhibiteurs de kinase pi3 WO2009066084A1 (fr)

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