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WO2008152394A1 - Composés pharmaceutiques - Google Patents

Composés pharmaceutiques Download PDF

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Publication number
WO2008152394A1
WO2008152394A1 PCT/GB2008/002023 GB2008002023W WO2008152394A1 WO 2008152394 A1 WO2008152394 A1 WO 2008152394A1 GB 2008002023 W GB2008002023 W GB 2008002023W WO 2008152394 A1 WO2008152394 A1 WO 2008152394A1
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WO
WIPO (PCT)
Prior art keywords
ring
indol
fluoro
pyrimidine
membered saturated
Prior art date
Application number
PCT/GB2008/002023
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English (en)
Inventor
Timothy Colin Hancox
Neil Anthony Pegg
Alan John Nadin
Stephen Price
Original Assignee
F.Hoffmann-La Roche Ag
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Filing date
Publication date
Priority claimed from GB0711346A external-priority patent/GB0711346D0/en
Priority claimed from GB0715675A external-priority patent/GB0715675D0/en
Application filed by F.Hoffmann-La Roche Ag filed Critical F.Hoffmann-La Roche Ag
Publication of WO2008152394A1 publication Critical patent/WO2008152394A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • 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
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered

Definitions

  • the present invention relates to indolyl furanopyrimidine compounds and to 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 PD kinase (PI3K) was found to be an enzyme which phosphorylates the 3-position of the inositol ring of phosphatidylinositol (D. Whitman et al. 1988, Nature, 332, 664).
  • 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 PBKs have been identified on the basis of their in vitro substrate specificity (B. Vanhaesebroeck,1997, Trend in Biol. Sci, 22, 267).
  • Substrates for class I PDKs are PI, PI 4-phosphate (PI4P) and PI 4,5-biphosphate (PI (4,5)P2).
  • Class I PDKs are further divided into two groups, class Ia and class Ib, in terms of their activation mechanism.
  • Class Ia PDKs include PDK pi 10a, pi lO ⁇ and pi lO ⁇ subtypes, which transmit signals from tyrosine kinase-coupled receptors.
  • Class Ib PDK includes a pi lO ⁇ subtype activated by a G protein-coupled receptor.
  • PI and PI(4)P are known as substrates for class II PDKs.
  • Class II PDKs include PDK C2 ⁇ , C2 ⁇ and C2 ⁇ subtypes, which are characterized by containing C2 domains at the C terminus.
  • the substrate for class III PDKs is PI only.
  • 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 PDK 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, immune disorders and conditions involving inflammation.
  • WO 01/083456 describes a series of condensed heteroaryl derivatives which have activity as inhibitors of PI3 K and which suppress cancer cell growth.
  • the present invention provides a compound which is a furanopyrimidine of formula (I):
  • W represents a furan ring
  • R 1 and R 2 form, together with the N atom to which they are attached, a group of the following formula (Ha):
  • A is selected from:
  • a 4- to 7-membered saturated N-containing heterocyclic ring which includes 0 or 1 additional heteroatoms selected from N, S and O, the ring being fused to a second ring selected from a 4- to 7-membered saturated N- containing heterocyclic ring as defined above, a 5- to 12-membered unsaturated heterocyclic ring, a 5- to 7-membered saturated O-containing heterocyclic ring, a 3- to 12- membered saturated carbocyclic ring and an unsaturated 5- to 12-membered carbocyclic ring to form a heteropoly cyclic ring system, the heteropolycyclic ring system being unsubstituted or substituted;
  • a 4- to 7-membered saturated N-containing heterocyclic ring which includes 0 or 1 additional heteroatoms selected from N, S and O and which further comprises, linking two constituent atoms of the ring, a bridgehead group selected from -(CR' 2 ) n - and -(CR' 2 ) r -O-(CR * 2 ) s - wherein each R' is independently H or C 1 - C 6 alkyl, n is 1, 2 or 3, r is 0 or 1 and s is 0 or 1, the remaining ring positions being unsubstituted or substituted; and (c) a group of formula (lib):
  • ring B is a 4- to 7-membered saturated N-containing heterocyclic ring which includes 0 or 1 additional heteroatoms selected from N, S and O and ring B' is a 3- to 12- membered saturated carbocyclic ring, a 5- to 7- membered saturated O-containing heterocyclic ring or a 4- to 7-membered saturated N-containing heterocyclic ring as defined above, each of B and B' being unsubstituted or substituted; m is 0, 1 or 2; R 3 is H or Ci-C 6 alkyl; R 4 is an indole group which is unsubstituted or substituted; and
  • R a is selected from R, halo, CN, C(O)NR 2 , halo(d-C 6 )alkyl, SO 2 R, SO 2 NR 2 , NRSO 2 R, NRC(O)R, NRC(O)OR and NRC(O)NR 2 wherein each R is independently H or C 1 -C 6 alkyl; and or a pharmaceutically acceptable salt thereof.
  • fusehead denotes a linking group, of one or more atoms in length, which connects two non-adjacent ring atoms. In each of these three cases a polycyclic (typically a bicyclic) structure is the result.
  • a C]-C 6 alkyl group is linear or branched.
  • a C 1 -C 6 alkyl group is typically a C 1 -C 4 alkyl group, for example a methyl, ethyl, n-propyl, i-propyl, n-butyl, sec-butyl or tert-butyl group.
  • a C 1 -C 6 alkyl group is unsubstituted or substituted, typically by one or more groups Z or R 5 as defined below.
  • Ci-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, -(C(R 6 ) 2 ) q R, - CH 2 OR, -CF 3 , -(1IaIo)-C 1 -C 6 alkyl, -(C(R 6 ) 2 ) q O-(halo)-C 1 -C 6 alkyl, -CO 2 R, -(C(R 6 ) 2 ) q CO 2 R, - (C(R 6 ) 2 ) q COR, CF 2 OH, CH(CF 3 )OH, C(CF 3 ) 2 OH, -(CH 2 ) q OR, -(C(R 6 ) 2 ) q OR, -(CH 2 ) q NR 2 , - (C(R 6 ) 2 ) q NR 2 , -C(O)N(R) 2 , -(
  • R 5 is selected from C 1 -C 6 alkoxy, OR 6 , SR 6 , S(O) 15 R 6 , nitro, CN, halogen, -C(O)R 6 , - CO 2 R 6 , -C(O)N(R 6 ) 2 and -N(R 6 ) 2 .
  • R 6 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 -C 10 cycloalkyl. and p 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-d-C ⁇ alkyl", which means an alkyl group in which one or more hydrogens is replaced by halo.
  • a ImIo-C 1 -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. It is typically a C 1 -C 4 alkoxy group, for example a methoxy, ethoxy, propoxy, i-propoxy, n-propoxy, n-butoxy, sec-butoxy or tert- butoxy group.
  • a Ci-C 6 alkoxy group is unsubstituted or substituted, typically by one or more groups Z or R 5 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] 0 cycloalkyl group is unsubstituted or substituted, typically by one or more groups Z or R as defined above.
  • a saturated 4- to 7-membered N-containing heterocyclic ring typically contains one nitrogen atom and either an additional N atom or an O or S atom, or no additional heteroatoms. It may be, for example, azetidine, pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine or homopiperazine.
  • a 4- to 7-membered saturated N-containing heterocyclic ring as defined above is unsubstituted or substituted on one or more ring carbon atoms and/or on any additional N atom present in the ring.
  • substituents include one or more groups Z or R 5 as defined above, and a C 1 -C 6 alkyl group which is unsubstituted or substituted by a group Z or R 5 as defined above.
  • a 5- to 7-membered saturated O-containing heterocyclic ring contains at least one O atom and 0, 1 or 2 additional heteroatoms selected from O, N and S. It is, for instance, tetrahydrofuran, tetrahydropyran or morpholine.
  • a 3- to 12- membered saturated carbocyclic ring is a 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10, 11- or 12-membered carbocyclic ring containing only saturated bonds. It is a monocyclic or fused bicyclic ring system. It is, for instance, a 3- to 7-membered saturated carbocyclic ring.
  • Examples include cyclopropane, cyclobutane, cyclopentane, cyclohexane and cycloheptane, and bicyclic ring systems in which two such rings are fused together.
  • 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 benzene, naphthalene, indane, indene and tetrahydronaphthalene rings, or phenyl, naphthyl, indanyl, indenyl and tetrahydronaphthyl groups.
  • the group is unsubstituted or substituted, typically by one or more groups Z or R 5 as defined above.
  • the unsaturated 5- to 12- membered carbocyclic ring is typically other than benzene.
  • 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 5 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 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, indolizinyl, isoxazole, oxazole, oxadiazole, thiazole, isothiazole, thiadiazole, dihydroimidazole, dihydrobenzofuran, dihydro
  • 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 additional heteroatoms selected from O, S and N. It may be, for example, a 5- to 7-membered heteroaryl group. Typically it is selected from the heteroaryl groups included in the above list of options for a 5 to 12-membered unsaturated heterocyclic group.
  • Examples of a 4- to 7-membered saturated N-containing heterocyclic ring which is fused to a second ring as defined above to form a heteropolycyclic ring system include a group selected from azetidine, pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine and homopiperazine, said group being fused to a second ring as defined above.
  • the second ring is typically a 4- to 7-membered saturated N-containing heterocyclic ring as defined above or a 5- to 12-membered unsaturated heterocyclic group. More typically the second ring is a 5-, 6- or 7-membered saturated N-containing heterocyclic ring or a 5- to 7-membered unsaturated heterocyclic ring.
  • Typical examples of the second ring include azetidine, pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, homopiperazine, pyrrole, imidazole, pyridine, pyridazine, pyrimidine, pyrazine, tetrahydrofuran and tetrahydropyran.
  • Examples of the resulting heteropolycyclic system include octahydro- pyrrolo[l,2-a]pyrazine and octahydro-pyrrolo[3,4-c]pyrrole. Specific examples of the heteropolycyclic system include the following structures:
  • Examples of a 4- to 7-membered saturated N-containing heterocyclic group as defined above which includes a bridgehead group -(CR' 2 ) n - or -(CR' 2 ) r -O-(CR' 2 ) s - as defined above include 3,8-diaza-bicyclo[3.2.1]octane, 2,5-diaza-bicyclo[2.2.1]heptane, 8-aza- bicyclo[3.2.1]octane, 2-aza-bicyclo[2.2.1]heptane, 3,6-diaza-bicyclo[3.1.1]heptane, 6-aza- bicyclo[3.1. l]heptane, 3,9-diaza-bicyclo[4.2. ljnonane and 3-oxa-7,9- diazabicyclo[3.3.1 ]nonane.
  • Examples of a group of formula (lib) as defined above include groups derived from a 4- to 7-membered saturated N-containing heterocyclic group as defined above which is spiro- fused at any available ring carbon atom to a 3 to 12- membered saturated carbocyclic ring, typically to a 3- to 6-membered saturated carbocyclic ring, or to a 4- to 7-membered saturated N-containing heterocyclic group.
  • Examples include a group selected from azetidine, pyrrolidine, piperidine and piperazine which is spiro-fused at a ring carbon atom to a group selected from cyclopropane, cyclobutane, cyclopentane, cyclohexane, azetidine, pyrrolidine, piperidine, piperazine and tetrahydropyran.
  • the group of formula (lib) may, for instance, be a group derived from 3,9- diazaspiro[5.5]undecane, 2,7-diazaspiro[3.5]nonane, 2,8-diazaspiro[4.5]decane or 2,7- diazaspiro[4.4]nonane.
  • Specific examples of a group of formula (lib) include the following structures:
  • R 4 is an indolyl group which is unsubstituted or substituted.
  • the indolyl group may be linked to the furanopyrimidine core via any available ring position. It may, for instance, be an indol-4-yl, indol-5-yl, indol-6-yl or indol-7-yl group. Typically it is indol-4-yl or indol-6-yl, more typically an indol-4-yl group.
  • the indolyl When substituted, the indolyl may be substituted at one or more available ring positions. Typically it bears a substituent on the benzene moiety of the indole group.
  • an indol-4-yl group is typically substituted at the 5- , 6- or 7-position, more typically at the 5- or 6-position.
  • An indol-5-yl group is typically substituted at the 4-, 6- or 7- position, more typically at the 4- or 6-position.
  • An indol-6-yl group is typically substituted at the 4-, 5- or 7-position, more typically at the 4- or 5- position.
  • An indol-7-yl group is typically substituted at the 4-, 5- or 6-position, more typically at the 5- or 6-position.
  • the indolyl group When the. indolyl group is substituted it may be substituted by a group Z or R 5 as defined above.
  • the indolyl group is substituted by a group selected from R, -OR, -SR, -S(O) p R, CH 2 OR, -C(O)R, -CO 2 R, CF 3 , CF 2 OH, CH(CF 3 )OH, C(CF 3 ) 2 OH, -(CH 2 ) q OR, -(CH 2 ) q NR 2 , -C(O)N(R) 2 , -NR 2 , -N(R)C(O)R, -S(O) P N(R) 2 , -OC(O)R, OC(O)N(R) 2 , -N(R)S(O) P R , -NRC(O)N(R) 2 , CN, halo, -NO 2 and a 5-
  • the indolyl group is substituted by a group selected from C 1 - C 6 alkyl, CN, halo, -C(O)NR 2 , halo(C 1 -C 6 )alkyl such as CF 3 , NO 2 , OR, SR, NR 2 , C(O)R, SOR, SO 2 R, SO 2 NR 2 , NRC(O)R, CO 2 R and a 5- membered heteroaryl group as defined above.
  • the indolyl group is substituted by a group selected from CN, halo, -C(O)NR 2 , IwIo(C 1 -C 6 )alkyl such as CF 3 , -SO 2 R, -SO 2 NR 2 , and a 5-membered heteroaryl group containing 1, 2, 3 or 4 heteroatoms selected from O, N and S.
  • R is typically H or C 1 -C 6 alkyl.
  • the substituent on the indolyl group is an electron-withdrawing group.
  • the substituent is a 5-membered heteroaryl group it may be, for example, furan, thiophene, pyrrole, imidazole, pyrazole, triazole, tetrazole, oxazole, isoxazole, oxadiazole, thiazole, isothiazole, or thiadiazole.
  • a substituted indolyl group is an indol-4-yl group substituted at the 5- or 6-position, in particular the 6-position, by CN, halo, -C(O)NH 2 , -CF 3 , -SO 2 Me, - SO 2 NMe 2 or a 5-membered heteroaryl group as defined above.
  • the indol-4-yl group is substituted at the 5- or 6-position by halo, in particular by F. More typically the indol-4-yl group is substituted at the 6-position by halo, in particular by F.
  • the parameter m in formula (I) is O, 1 or 2. Typically m is 1 or 2. More typically m is 1.
  • the furan ring W in formula (I) adopts either of the two available regiochemical orientations.
  • the compounds of the invention may thus be furano[3,2-d]pyrimidines or furano[2,3-d]pyrimidines.
  • the furanopyrimidine is a furano[3,2- djpyrimidine of the following formula (Ia):
  • the furanopyrimidine is a furano[2,3-d]pyrimidine of the following formula (Ib):
  • R 1 , R 2 , R 3 , R 4 , R a and m are as defined above for formula (I).
  • the furanopyrimidine is a furano[2,3-d]pyrimidine of the following formula (Ic):
  • R 1 , R 2 , R 3 , R 4 , R a and and m are as defined above for formula (I).
  • the furanopyrimidine is a furano[3,2-d]pyrimidine of the following formula (Id):
  • R 1 , R 2 , R 3 , R 4 , R a and and m are as defined above for formula (I).
  • a suitable synthetic strategy for producing a furanopyrimidine of formula (I) employs the precursor carboxaldehyde of formula (III):
  • a compound of the invention may thus be produced by a process which comprises treating a compound of formula (III):
  • W, R a , R la and R 2a are as defined above, with a boronic acid or ester thereof of formula R 4 B(OR 15 ) 2 in which R 4 is as defined above 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 Pd catalyst; and, if R la and/or R 2a includes an amine protecting group, removing the protecting group. Any suitable amine protecting groups may be used in R la and/or R 2a , for instance a butoxycarbonyl (BOC) group.
  • BOC butoxycarbonyl
  • a compound of formula (I) may also be produced by treating a compound of formula (III): wherein W and R a are as defined above, with a boronic acid or ester thereof of formula R 4 B(OR 15 ) 2 in which R 4 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 Pd catalyst; and treating the resulting compound of formula (V):
  • the palladium catalyst may be any that is typically used for Suzuki-type cross-couplings, such as PdCl 2 (PPh 3 ) 2 .
  • the reducing agent in the amination step is typically a borohydride, for instance NaBH(OAc) 3 , NaBH 4 or NaCNBH 3 , in particular NaBH(OAc) 3 .
  • a compound of formula (III) as defined above may be produced by a process which comprises treating a compound of formula (VI):
  • W and R a are as defined above with a deprotonating agent and then with dimethylformamide at -78 0 C rising to room temperature.
  • a suitable deprotonating agent is a lithiating agent, for instance an alkyllithium such as n-butyllithium in the presence of trimethylethylenediamine in THF at -78 0 C.
  • a compound of formula (VI) as defined above may be produced by a process which comprises treating a compound of formula (VII):
  • W and R a are as defined above with a chlorinating agent followed by morpholine in a suitable solvent, for instance methanol at room temperature.
  • a suitable chlorinating agent is POCl 3 in PhNMe 2 . This reation is suitably conducted at about 10O 0 C.
  • a compound of formula (VII) may be prepared by known methodologies or by analogy with known methodologies, for instance as shown in scheme 1 which follows. .
  • Furanopyrimidines of formula (I) may be converted into pharmaceutically acceptable salts, and salts may be converted into the free compound, by conventional methods.
  • Pharmaceutically acceptable salts include salts of inorganic acids such as hydrochloric acid, hydrobromic acid and sulfuric acid, and salts of organic acids such as acetic acid, oxalic acid, malic acid, methanesulfonic acid, trifluoroacetic acid, benzoic acid, citric acid and tartaric acid.
  • the salts include both the above-mentioned acid addition salts and the salts of sodium, potassium, calcium and ammonium.
  • the latter are prepared by treating the free furanopyrimidine of formula (I), or an acid addition salt thereof, with the corresponding metal base or ammonia.
  • Compounds of the present invention have been found in biological tests to be inhibitors of PB kinase.
  • the compounds are selective for the pi lO ⁇ isoform, which is a class Ia PB kinase, over other class Ia PB kinases. They are thus selective for the pi lO ⁇ isoform over both the pi 1 Oa isoform and the pi lO ⁇ isoform. In particular they are selective for pi lO ⁇ over pi lO ⁇ .
  • the compounds are also selective for the pi lO ⁇ isoform over pi lO ⁇ , which is a class Ib kinase.
  • the selectivity exhibited by compounds of the invention for pi lO ⁇ over other isoforms of PB kinase is at least 2-fold.
  • the selectivity is 5-fold, or 10-fold, or 20- fold, or 50-fold, rising to 100-fold or higher in many cases.
  • the compounds may be 2- fold, 5-fold, 10-fold, 20-fold, 50-fold or 100-fold selective for pi lO ⁇ over pi lO ⁇ . They may also be 2-fold, 5-fold, 10-fold, 20-fold, 50-fold or 100-fold selective for p 11 O ⁇ over p 11 Oa or over pl lO ⁇ .
  • a compound of the present invention may be used as an inhibitor of PB kinase, in particular of a class Ia PB 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 associated with PB kinase, in particular the pi lO ⁇ isoform of PB 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 proliferative disorders such as cancer, immune disorders, cardiovascular disease, viral infection, inflammation, metabolism/endocrine disorders and neurological disorders. Examples of metabolism/endocrine disorders include diabetes and obesity. Examples of 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 compound of the present invention may be used as an inhibitor of PB kinase.
  • a human or animal patient suffering from a disease or disorder arising from abnormal cell growth, function or behaviour associated with PB kinase, in particular with the pi lO ⁇ isoform of PB kinase such as an immune disorder, cardiovascular disease, viral infection, inflammation, a metabolism/endocrine disorder or a neurological disorder, may thus be treated by a method comprising the administration thereto of a compound of the present invention as defined above.
  • a human or animal patient suffering from cancer may also 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.
  • 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 compound of the invention is formulated for use as a pharmaceutical or veterinary composition also comprising a pharmaceutically or veterinarily acceptable carrier or diluent.
  • the 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:
  • 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, corn starch, potato starch, calcium phosphate or sodium phosphate
  • granulating and disintegrating agents for example, maize
  • 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.
  • 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.
  • dispersing or wetting agents may be naturally-occurring phosphatides, for example lecithin, or condensation products of an
  • 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.
  • 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.
  • sterile injectable aqueous or oleaginous suspensions 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.
  • NMR spectra were obtained on a Varian Unity Inova 400 spectrometer with a 5 mm inverse detection triple resonance probe operating at 400MHz or on a Bruker Avance DRX 400 spectrometer with a 5 mm inverse detection triple resonance TXI probe operating at 400 MHz or on a Bruker Avance DPX 300 spectrometer with a standard 5mm dual frequency probe operating at 300 MHz. Shifts are given in ppm relative to tetramethylsilane.
  • silica gel or Isolute® cartridge or Redisep® cartridge eluting with gradients from 100-0 to 0-100 % of cyclohexane/EtOAc, or from 100-0 to 0-100 % pentane/EtOAc or from 100-0 to 70-30 % DCM/MeOH (with or without the addition OfNH 3 0.1 %).
  • 'Silica gel' refers to silica gel for chromatography, 0.035 to 0.070 mm (220 to 440 mesh) (e.g. Fluka silica gel 60), and an applied pressure of nitrogen up to 10 p.s.i accelerated column elution.
  • TLC thin layer chromatography
  • the free base was liberated by partitioning between EtOAc and a sat. solution of sodium bicarbonate. The organic layer was dried (MgSO 4 ) and concentrated in vacuo. Alternatively, the free base was liberated by passing through an Isolute® SCX-2 cartridge, eluting with NH 3 in methanol.
  • Microwave Reactions Microwave experiments were carried out using either a Personal Chemistry Smith Synthesiser or a Biotage InitiatorTM, which uses a single-mode resonator and dynamic field tuning, both of which give reproducibility and control. Temperatures from 40-250 0 C can be achieved and pressures of up to 20bar can be reached.
  • DIPEA diisopropylethylamine
  • HATU ( ⁇ -(T-Azabenzotriazol-l-y ⁇ - ⁇ yV r /V ⁇ /V-tetramethyluronium hexafluorophosphate
  • mL millilitre
  • NaHCO 3 sodium hydrogen carbonate
  • NaOH sodium hydroxide
  • Na 2 SO 4 sodium sulfate
  • TBAF tetrabutylammonium fluoride
  • TBS tert-butyldimethylsilyl
  • W H, or protecting group, e.g. TBS
  • reaction mixture was loaded onto an Isolute® SCX-2 cartridge, washed with MeOH then eluted with 2 M NH 3 in MeOH. The resulting residue was then purified by either preparative HPLC or column chromatography to give the desired product.
  • reaction mixture was loaded onto an Isolute® SCX-2 cartridge, washed with MeOH then eluted with 2 M NH 3 in MeOH. The resulting residue was then purified by either preparative HPLC or column chromatography to give the desired product.
  • reaction mixture was loaded onto an Isolute® SCX-2 cartridge, washed with MeOH then eluted with 2 M NH 3 in MeOH. The resulting residue was then purified by either preparative HPLC or column chromatography to give the desired product.
  • reaction mixture was loaded onto an Isolute® SCX-2 cartridge, washed with MeOH then eluted with 2 M NH 3 in MeOH. The resulting residue was then purified by either preparative HPLC or column chromatography to give the desired product.
  • reaction mixture was loaded onto an Isolute® SCX-2 cartridge, washed with MeOH then eluted with 2 M NH 3 in MeOH. The resulting residue was then purified by either preparative HPLC or column chromatography to give the desired product.
  • reaction mixture was loaded onto an Isolute® SCX-2 cartridge, washed with MeOH then eluted with 2 M NH 3 in MeOH. The resulting residue was then purified by either preparative HPLC or column chromatography to give the desired product.
  • the reaction mixture was treated with dichloromethane (100 mL) and methanol (5 mL) and the resulting precipitate removed by filtration through celite. The organic layer was separated, washed successively with sodium thiosulfate solution and brine, then dried (MgSO 4 ) and evaporated in vacuo. The resultant material was dissolved in methanol (60 mL) and treated with 40% aqueous NaOH solution (60 mL) then refluxed for 2 h. The reaction mixture was cooled to RT and extracted with DCM/MeOH (ratio 95:5). The organic layer was dried (MgSO 4 ), filtered and concentrated in vacuo.
  • the resultant residue was purified by column chromatography (silica gel, pentane:EtOAc 75:25) to provide 5-fluoro-4-iodo-lH-indole as a pale brown solid (1.05 g, 39 %).
  • the resultant white semi-solid was suspended in DCM and a saturated aqueous solution OfNaHCO 3 was added. The layers were thoroughly mixed, the organic layer isolated and the aqueous layer further extracted with DCM. The combined organic layers were washed with brine, dried (Na 2 SO 4 ) and concentrated in vacuo to give 4-azetidin-l-yl-piperidine-l-carboxylic acid tert-butyl ester as a white solid (2.0 g, 95 %).
  • the compound was produced by using the general coupling method A described in
  • IC 50 values were subsequently determined using sigmoidal dose-response curve fit (variable slope). All of the compounds tested had an IC 50 against PBK of 50 ⁇ M or less. Typically the IC 50 against the pl lO ⁇ isoform of PBK was less than 50OnM.
  • the compound of the invention lactose and half of the corn starch were mixed.
  • the compound of the invention was dissolved in a mixture of the glycerol and most of the purified water. An aqueous solution of the sodium benzoate was then added to the solution, followed by addition of the sorbital solution and finally the flavour. The volume was made up with purified water and mixed well.

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Abstract

La présente invention concerne des furanopyrimidines de formule (I) où W représente un composé cyclique de furanne ; R1 et R2 forment, avec l'atome N auquel ils sont liés, un groupe de formule suivante (IIa) : où A est choisi parmi : (a) un composé hétérocyclique saturé comportant de 4 à 7 chaînons contenant N qui comprend 0 ou 1 hétéroatome supplémentaire choisi parmi N, S et O, ledit composé étant fusionné à un second composé cyclique choisi parmi un composé hétérocyclique saturé comportant de 4 à 7 chaînons contenant N tel que défini précédemment, un composé hétérocyclique insaturé comportant de 5 à 12 chaînons, un composé hétérocyclique saturé comportant de 5 à 7 chaînons contenant O, un composé carbocyclique saturé comportant de 3 à 12 chaînons et un composé carbocyclique insaturé comportant de 5 à 12 chaînons pour former un système de composés hétéropolycycliques, ledit système étant non substitué ou substitué ; (b) un composé hétérocyclique saturé comportant de 4 à 7 chaînons contenant N qui comprend 0 ou 1 hétéroatome supplémentaire choisi parmi N, S et O, et qui comprend également, liant deux atomes constitutifs du composé cyclique, un groupe en tête de pont choisi parmi -(CR'2)n- et -(CR'2)r-O-(CR'2)s- où chaque R' est indépendamment H ou C1 - C6 alkyle, n est 1, 2 ou 3, r est 0 ou 1 et s est 0 ou 1, les positions cycliques restantes étant non substituées ou substituées ; et (c) un groupe de formule (IIb) : où B est un composé hétérocyclique saturé comportant de 4 à 7 chaînons contenant N qui comprend 0 ou 1 hétéroatome supplémentaire choisi parmi N, S et O et B' est un composé carbocyclique saturé comportant de 3 à 12 chaînons, un composé hétérocyclique saturé comportant de 5 à 7 chaînons contenant O ou un composé hétérocyclique saturé comportant de 4 à 7 chaînons contenant N tel que défini précédemment, B et B' étant non substitués ou substitués ; m est 0, 1 ou 2 ; R3 est H ou C1-C6 alkyle ; R4 est un groupe d'indole qui est non substitué ou substitué ; et Ra est choisi parmi R, halo, CN, C(O)NR2, halo(C1-C6)alkyle, SO2R, SO2NR2, NRSO2R, NRC(O)R, NRC(O)OR et NRC(O)NR2 où chaque R est indépendamment H ou C1-C6 alkyle. Les sels pharmaceutiquement acceptables correspondants sont des inhibiteurs de PI3K et sont sélectifs de l'isoforme p110δ, une PI3 kinase de classe Ia, sur les deux autres kinases de classe Ia et de classe Ib. Les composés peuvent être utilisés dans le traitement de maladies et de troubles provoqués par un développement cellulaire, une fonction ou un comportement anormal associé à une kinase PI3, tel qu'un cancer, des désordres immuns, une maladie cardiovasculaire, une infection virale, une inflammation, des troubles fonctionnels du métabolisme/endocriniens et des troubles neurologiques.
PCT/GB2008/002023 2007-06-12 2008-06-12 Composés pharmaceutiques WO2008152394A1 (fr)

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US7893059B2 (en) 2007-09-24 2011-02-22 Genentech, Inc. Thiazolopyrimidine PI3K inhibitor compounds and methods of use
US7893060B2 (en) 2007-06-12 2011-02-22 F. Hoffmann-La Roche Ag Thiazolopyrimidines and their use as inhibitors of phosphatidylinositol-3 kinase
WO2011159726A2 (fr) 2010-06-14 2011-12-22 The Scripps Research Institute Reprogrammation de cellules pour leur conférer un nouveau destin
WO2011162515A2 (fr) 2010-06-23 2011-12-29 Hanmi Holdings Co. , Ltd. Nouveaux dérivés fusionnés de pyrimidine pour l'inhibition de l'activité tyrosine kinase
US8097622B2 (en) 2008-10-14 2012-01-17 Daiichi Sankyo Company, Limited Morpholinopurine derivatives
US8158625B2 (en) 2009-05-27 2012-04-17 Genentech, Inc. Bicyclic indole-pyrimidine PI3K inhibitor compounds selective for P110 delta, and methods of use
US8163763B2 (en) 2008-07-31 2012-04-24 Genentech, Inc. Pyrimidine compounds, compositions and methods of use
US8173650B2 (en) 2009-05-27 2012-05-08 Genentech, Inc. Bicyclic pyrimidine PI3K inhibitor compounds selective for P110 delta, and methods of use
WO2012099581A1 (fr) 2011-01-19 2012-07-26 Takeda Pharmaceutical Company Limited Composés de dihydrofuropyrimidine
WO2012107465A1 (fr) * 2011-02-09 2012-08-16 F. Hoffmann-La Roche Ag Composés hétérocycliques en tant qu'inhibiteurs de pi3 kinase
US8247397B2 (en) 2007-09-12 2012-08-21 Genentech, Inc. Combinations of phosphoinositide 3-kinase inhibitor compounds and chemotherapeutic agents, and methods of use
US8288381B2 (en) 2009-11-12 2012-10-16 Genentech, Inc. N-9 substituted purine compounds, compositions and methods of use
US8333966B2 (en) 2008-04-11 2012-12-18 Emergent Product Development Seattle, Llc CD37 immunotherapeutics and uses thereof
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US8853366B2 (en) 2001-01-17 2014-10-07 Emergent Product Development Seattle, Llc Binding domain-immunoglobulin fusion proteins
US8883799B2 (en) 2010-12-16 2014-11-11 Genentech, Inc. Tricyclic PI3K inhibitor compounds and methods of use
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US9085560B2 (en) 2009-08-17 2015-07-21 Intellikine, Inc. Heterocyclic compounds and uses thereof
US9096590B2 (en) 2010-05-24 2015-08-04 Intellikine Llc Substituted benzoxazoles as PI3 kinase inhibitors
US9127000B2 (en) 2011-02-23 2015-09-08 Intellikine, LLC. Heterocyclic compounds and uses thereof
US9295673B2 (en) 2011-02-23 2016-03-29 Intellikine Llc Combination of mTOR inhibitors and P13-kinase inhibitors, and uses thereof
KR20160082062A (ko) 2014-12-30 2016-07-08 한미약품 주식회사 싸이옥소 퓨로피리미디논 유도체의 제조방법 및 이에 사용되는 중간체
JP2017505343A (ja) * 2014-02-12 2017-02-16 カルス セラピューティクス リミテッド ホスホイノシチド３−キナーゼ阻害剤としての三環式複素環式化合物
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CN113646306A (zh) * 2019-03-29 2021-11-12 阿斯利康(瑞典)有限公司 雌激素受体降解protac
US11352426B2 (en) 2015-09-21 2022-06-07 Aptevo Research And Development Llc CD3 binding polypeptides
US12324807B2 (en) 2018-06-01 2025-06-10 Cornell University Combination therapy for PI3K-associated disease or disorder

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US9005612B2 (en) 2001-01-17 2015-04-14 Emergent Product Development Seattle, Llc Binding domain-immunoglobulin fusion proteins
US10307481B2 (en) 2005-07-25 2019-06-04 Aptevo Research And Development Llc CD37 immunotherapeutics and uses thereof
US10143748B2 (en) 2005-07-25 2018-12-04 Aptevo Research And Development Llc B-cell reduction using CD37-specific and CD20-specific binding molecules
US8409577B2 (en) 2006-06-12 2013-04-02 Emergent Product Development Seattle, Llc Single chain multivalent binding proteins with effector function
US7893060B2 (en) 2007-06-12 2011-02-22 F. Hoffmann-La Roche Ag Thiazolopyrimidines and their use as inhibitors of phosphatidylinositol-3 kinase
US8168633B2 (en) 2007-06-12 2012-05-01 Genentech, Inc. Thiazolopyrimidines and their use as inhibitors of phosphatidylinositol-3 kinase
US8604014B2 (en) 2007-09-12 2013-12-10 Genentech, Inc. Combinations of phosphoinositide 3-kinase inhibitor compounds chemotherapeutic agents, and methods of use
US8247397B2 (en) 2007-09-12 2012-08-21 Genentech, Inc. Combinations of phosphoinositide 3-kinase inhibitor compounds and chemotherapeutic agents, and methods of use
US8158626B2 (en) 2007-09-24 2012-04-17 F. Hoffmann-La Roche Ag Thiazolopyrimidine PI3K inhibitor compounds and methods of use
US7893059B2 (en) 2007-09-24 2011-02-22 Genentech, Inc. Thiazolopyrimidine PI3K inhibitor compounds and methods of use
US8354528B2 (en) 2007-10-25 2013-01-15 Genentech, Inc. Process for making thienopyrimidine compounds
US8431694B1 (en) * 2007-10-25 2013-04-30 Genentech, Inc. Process for making thienopyrimidine compounds
US7820665B2 (en) 2007-12-19 2010-10-26 Amgen Inc. Imidazopyridazine inhibitors of PI3 kinase for cancer treatment
US9101609B2 (en) 2008-04-11 2015-08-11 Emergent Product Development Seattle, Llc CD37 immunotherapeutic and combination with bifunctional chemotherapeutic thereof
US8333966B2 (en) 2008-04-11 2012-12-18 Emergent Product Development Seattle, Llc CD37 immunotherapeutics and uses thereof
US8163763B2 (en) 2008-07-31 2012-04-24 Genentech, Inc. Pyrimidine compounds, compositions and methods of use
US8097622B2 (en) 2008-10-14 2012-01-17 Daiichi Sankyo Company, Limited Morpholinopurine derivatives
US8309546B2 (en) 2008-10-14 2012-11-13 Daiichi Sankyo Company, Limited Morpholinopurine derivatives
US8394796B2 (en) 2009-05-27 2013-03-12 Genentech, Inc. Bicyclic pyrimidine PI3K inhibitor compounds selective for P110 delta, and methods of use
US8158625B2 (en) 2009-05-27 2012-04-17 Genentech, Inc. Bicyclic indole-pyrimidine PI3K inhibitor compounds selective for P110 delta, and methods of use
US8173650B2 (en) 2009-05-27 2012-05-08 Genentech, Inc. Bicyclic pyrimidine PI3K inhibitor compounds selective for P110 delta, and methods of use
US9085560B2 (en) 2009-08-17 2015-07-21 Intellikine, Inc. Heterocyclic compounds and uses thereof
US11547697B2 (en) 2009-08-17 2023-01-10 Millennium Pharmaceuticals, Inc. Heterocyclic compounds and uses thereof
US8288381B2 (en) 2009-11-12 2012-10-16 Genentech, Inc. N-9 substituted purine compounds, compositions and methods of use
US8828990B2 (en) 2009-11-12 2014-09-09 Genentech, Inc. N-7 substituted purine and pyrazolopyrimine compounds, compositions and methods of use
US9359352B2 (en) 2010-05-24 2016-06-07 Intellikine Llc Substituted benzimidazoles as PI3 kinase inhibitors
US9096590B2 (en) 2010-05-24 2015-08-04 Intellikine Llc Substituted benzoxazoles as PI3 kinase inhibitors
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WO2011162515A2 (fr) 2010-06-23 2011-12-29 Hanmi Holdings Co. , Ltd. Nouveaux dérivés fusionnés de pyrimidine pour l'inhibition de l'activité tyrosine kinase
RU2585177C2 (ru) * 2010-06-23 2016-05-27 Ханми Сайенс Ко., Лтд. Новые конденсированные пиримидиновые производные для ингибирования тирозинкиназной активности
RU2598852C2 (ru) * 2010-06-23 2016-09-27 Ханми Сайенс Ко., Лтд. Новые конденсированные пиримидиновые производные для ингибирования тирозинкиназной активности
EP2975042A1 (fr) 2010-06-23 2016-01-20 Boehringer Ingelheim International GmbH Nouveaux dérivés fusionnés de pyrimidine pour l'inhibition de l'activité tyrosine kinase
US8883799B2 (en) 2010-12-16 2014-11-11 Genentech, Inc. Tricyclic PI3K inhibitor compounds and methods of use
US9546182B2 (en) 2010-12-16 2017-01-17 Genentech, Inc. Tricyclic PI3K inhibitor compounds and methods of use
WO2012099581A1 (fr) 2011-01-19 2012-07-26 Takeda Pharmaceutical Company Limited Composés de dihydrofuropyrimidine
CN103476767A (zh) * 2011-02-09 2013-12-25 弗·哈夫曼-拉罗切有限公司 作为pi3激酶抑制剂的杂环化合物
JP2014508145A (ja) * 2011-02-09 2014-04-03 エフ．ホフマン−ラ ロシュ アーゲー Ｐｉ３キナーゼ阻害剤としての複素環化合物
US8653089B2 (en) 2011-02-09 2014-02-18 F. Hoffmann-La Roche Ag Heterocyclic compounds and methods of use
WO2012107465A1 (fr) * 2011-02-09 2012-08-16 F. Hoffmann-La Roche Ag Composés hétérocycliques en tant qu'inhibiteurs de pi3 kinase
US9127000B2 (en) 2011-02-23 2015-09-08 Intellikine, LLC. Heterocyclic compounds and uses thereof
US9295673B2 (en) 2011-02-23 2016-03-29 Intellikine Llc Combination of mTOR inhibitors and P13-kinase inhibitors, and uses thereof
WO2013088404A1 (fr) 2011-12-15 2013-06-20 Novartis Ag Utilisation d'inhibiteurs de l'activité ou de la fonction de pi3k
WO2013174794A1 (fr) 2012-05-23 2013-11-28 F. Hoffmann-La Roche Ag Compositions et procédés d'obtention et d'utilisation de cellules endodermiques et d'hépatocytes
JP2017505343A (ja) * 2014-02-12 2017-02-16 カルス セラピューティクス リミテッド ホスホイノシチド３−キナーゼ阻害剤としての三環式複素環式化合物
KR20160082062A (ko) 2014-12-30 2016-07-08 한미약품 주식회사 싸이옥소 퓨로피리미디논 유도체의 제조방법 및 이에 사용되는 중간체
US11352426B2 (en) 2015-09-21 2022-06-07 Aptevo Research And Development Llc CD3 binding polypeptides
US12324807B2 (en) 2018-06-01 2025-06-10 Cornell University Combination therapy for PI3K-associated disease or disorder
CN113646306A (zh) * 2019-03-29 2021-11-12 阿斯利康(瑞典)有限公司 雌激素受体降解protac

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