WO2006091737A1 - Modulateurs de l'activite de gsk-3 - Google Patents

Modulateurs de l'activite de gsk-3 Download PDF

Info

Publication number
WO2006091737A1
WO2006091737A1 PCT/US2006/006447 US2006006447W WO2006091737A1 WO 2006091737 A1 WO2006091737 A1 WO 2006091737A1 US 2006006447 W US2006006447 W US 2006006447W WO 2006091737 A1 WO2006091737 A1 WO 2006091737A1
Authority
WO
WIPO (PCT)
Prior art keywords
ylamino
substituted
pyrimidin
compound
phenyl
Prior art date
Application number
PCT/US2006/006447
Other languages
English (en)
Inventor
Lubomir Sebo
Jeffrey Kahl
Christopher Lum
Yazhong Pei
Kent E. Pryor
Jan Urban
Bryan Jones
Robert Sullivan
Original Assignee
Kemia, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Kemia, Inc. filed Critical Kemia, Inc.
Publication of WO2006091737A1 publication Critical patent/WO2006091737A1/fr

Links

Classifications

    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to low molecular weight compounds and compositions thereof, useful as modulators of GSK-3 activity.
  • the compounds are well suited for use as GSK-3 inhibitors.
  • the invention further relates to methods of preparation and use of such compounds and compositions in treating disorders mediated by GSK-3, such as metabolic and CNS diseases.
  • Glycogen synthase kinase-3 (GSK-3) is a proline-directed, serine/threonine kinase, for which two isoforms, GSK-3 ⁇ and GSK-3 ⁇ , have been identified.
  • GSK-3 phosphorylates the rate-limiting enzyme of glycogen synthesis, glycogen synthase (GS) [Embi, et al., Eur. J. Biochem., 107, 519-527 (1980)].
  • GSK- 3 ⁇ and GSK-3 ⁇ are highly expressed in the body [Woodgett, et al., EMBO, 9, 2431- 2438 (1990); Loy, et al., J.
  • GSK-3 substrates include metabolic, signaling, and structural proteins.
  • signaling proteins regulated by GSK-3 include transcription factors, including activator protein- 1 ; cyclic AMP response element binding protein (CREB); the nuclear factor (NF) of activated T-cells; heat shock factor-1; ⁇ -catenin; c-Jun; c-Myc; c-Myb; and NFKB [C.
  • CREB cyclic AMP response element binding protein
  • NF nuclear factor
  • NFKB nuclear factor
  • GSK-3 Insulin stimulates glycogen synthesis in skeletal muscles via the dephosphorylation and thus activation of glycogen synthase. Under resting conditions GSK-3 phosphorylates and inactivates glycogen synthase. GSK-3 is also over- expressed in muscles from Type II diabetic patients [Nikoulina et al., Diabetes, 49(2), 263-71, 2000]. Inhibition of GSK-3 increases the activity of glycogen synthase, thereby decreasing glucose levels by its conversion to glycogen. GSK-3 inhibition may therefore be of therapeutic relevance in the treatment of Type I and Type II diabetes and diabetic neuropathy. [0004] GSK-3 is also considered to be an important player in the pathogenesis of Alzheimer's disease.
  • GSK-3 was identified as one of the kinases that phosphorylates tau, a microtubule-associated protein, that is responsible for formation of paired helical filaments (PHF), an early characteristics of Alzheimer's disease. Apparently, abnormal hyperphosphorylation of tau is the cause for destabilization of microtubules and PHF formation. Despite the fact that several protein kinases were shown to promote phosphorylation of tau, only GSK-3 phosphorylation directly affected tau ability to promote microtubule self-assembly [Hanger et al., Neurosci. Lett. 147, 58-62, 1992; Mandelkow et al., Ann. NY Acad.
  • GSK-3 Another role of GSK-3 was detected in the context of affective disorders, i.e., bipolar disorder or manic depression. This linkage was based on the findings that lithium, a primary mood stabilizer frequently used in bipolar disease, is a strong and specific inhibitor of GSK-3 at the therapeutic concentration range used in clinics [Klein et al., Proc. Natl. Acad. Sci. USA, 93, 8455-8459 (1996); Stambolic et al., Curr. Biol. 6, 1664-1668 (1996); Phiel et al., Annu. Rev. Pharmacol. Toxicol., 41, 789-813 (2001)].
  • GSK-3 inhibitors have also been shown to have promise for the treatment of osteolytic lesions.in multiple myeloma.patient&.[A. M.JConley,_etal Abs. hit. Soc Cell. Ther., 2004 Annual Meeting]. It has also been suggested recently that GSK-3 inhibitors could promote the generation of new axons after neural injuries [H. Jiang, et al. Cell, 120, 123-135 (2005); T. Yoshimura, et al. Cell, 120, 137-149, (2005)].
  • GSK-3 has significant therapeutic potential in the treatment of many pathologies and conditions, for example, Alzheimer's Disease [A. Castro, et al., Exp. Opin. Ther. Pat., 10, 1519- 1527 (2000)]; asthma [P. J. Barnes, Ann. Rev. Pharmacol. Toxicol., 42, 81-98 (2002)]; cancer [Beals, et al., Science, 275, 1930-1933 (1997); L. Kim, et al., Curr. Opin. Genet. Dev., 10, 508-514 (2000); Q. Eastman, et al., Curr. Opin.
  • GSK-3 ⁇ modulation may find application in the treatment of the neuropathological consequences and the cognitive and attention deficits associated with Alzheimer's disease, as well as other acute and chronic neurodegenerative disorders.
  • Parkinson's disease tauopathies (e.g. frontotemporoparietal dementia, corticobasal degeneratior - .. Pick's disease, progressive supranuclear palsy)_and other dementia including vascul dementia; acute stroke and other traumatic injuries; cerebrovascular accidents (e.g. age related macular degeneration); brain and spinal cord trauma; peripheral neuropathies; retinopathies and glaucoma.
  • the present invention provides low molecular weight compounds useful as GSK-3 modulators, and compositions thereof.
  • the present invention relates in part to compounds having Formulas I-IV; to processes for preparing compounds of Formulas I-IV; to compositions including such compounds; and to methods for their use in treating conditions mediated by GSK-3. More specifically, 2,4,5-trisubstituted-pyrimidine and bicyclic 2-aminopyrimidine derivatives are provided for use in the treatment of disorders mediated by GSK-3.
  • A is a substituted or unsubstituted C 1-3 alkyl group, -F, -Cl, -Br, -CN, -NO 2 , or -NH 2 ;
  • B and D are independently -NH-, -CH 2 -, or -C(O)-;
  • R 1 is a substituted or unsubstituted cycloalkyl or cycloalkenyl group
  • R 2 is CHR 2a R 2b or a substituted or unsubstituted cycloalkyl, cycloalkenyl, saturated or partially saturated heterocyclyl, or a saturated or partially unsaturated heterocyclylalkyl group;
  • R 2a and R 2b are independently H, or a substituted or unsubstituted alkyl group; and stereoisomers thereof, tautomers thereof, solvates thereof, prodrugs thereof, and pharmaceutically acceptable salts thereof; with the provisos that R 1 and R 2 are not simultaneously unsubstituted unsubstituted adamantyl, or simultaneously unsubstituted cyclopropyl, or simultaneously unsubstituted cyclobutyl or simultaneously unsubstituted cycfohexy] that the compound is not N-[4-(4-cyclopropylamino-5-methyl-pyrimidin-2-ylamino)- cyclohexyl]-3,4-difluoro-benzamide; and that when R 1 or R 2 is a cyclohexyl group, the cyclohexyl group is not substituted with -(CH 2 ) n COR x , wherein n is 0 or 1
  • the compound at a concentration of 10 ⁇ M inhibits glycogen synthase kinase-3 ⁇ , glycogen synthase kinase-3 ⁇ or both.
  • R 1 is a substituted or unsubstituted cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclohexenyl group.
  • R 2 is a substituted or unsubstituted pyrrolidinyl, pyrroliiiyl, imidazolinyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl, tetrahydropyranyl, piperazinyl, morpholinyl, thiomorpholinyl, or piperidin-3-yl group.
  • R 1 is a substituted or unsubstituted, bridged cycloalkyl group.
  • R 1 is a substituted or unsubstituted bicyclo[2.1.l]hexyl, bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octyl, bicyclo[3.2.2]nonyl, bicyclo[3.3.1]nonyl, bicyclo[3.3.2]decanyl, adamantyl or noradamantyl group, hi other embodiments, R 2 is substituted or unsubstituted pyrrolidinyl, pyrrolinyl, imidazolinyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl, tetrahydropyranyl, piperidinyl, morpholinyl, thio
  • R 1 is a substituted or unsubstituted bridged Cg -12 cycloalkyl group.
  • R 1 is a substituted or unsubstituted bicyclo[3.2.2]nonyl, bicyclo[3.3.1]nonyl, bicyclo[3.3.2]decanyl, adamantyl or noradamantyl group, hi other embodiments,
  • R 2 is a substituted or unsubstituted pyrrolidinyl, pyrrolinyl, imidazolinyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl, tetrahydropyranyl, piperidinyl, morpholinyl, thiomorpholinyl, or piperazinyl group.
  • R 1 is a substitutec or unsubstituted adamantyl or noradamantyl group.
  • R 1 can be a substituted or unsubstituted adamantan-1-yl or adamantan-2-yl group.
  • R 1 is substituted with -OH, -0(Ci -3 alkyl), -NH 2 , halogen, or a C 1-3 alkyl group, optionally partially or fully halogenated.
  • R 1 is substituted with -OH.
  • R 1 may be adamantan-1-yl substituted at the 2- and/or 3-position.
  • A is a substituted or unsubstituted C 1-3 alkyl group, -Br, or -NO 2 .
  • A is -CF 3 .
  • B is -NH-.
  • D is -NH-.
  • B and D are -NH-.
  • R 2 is a cycloalkyl or cycloalkenyl group
  • R 2 can be a substituted or unsubstituted cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclohexenyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octyl, bicyclo[3.2.2]nonyl, bicyclo[3.3.1]nonyl, bicyclo[3.3.2]decanyl, adamantyl or noradamantyl group.
  • R 2 is a substituted or unsubstituted cyclohexyl, cyclohexenyl, adamantyl or tetrahydropyranyl group.
  • R 2 is substituted with -OH, -0(Ci -3 alkyl), -NH 2 , halogen, or a C 1-3 alkyl group, optionally partially or fully halogenated.
  • R 2 can be substituted with -OH.
  • R 1 is a substituted or unsubstituted adamantyl or cyclohexyl group
  • R 2 is a substituted or unsubstituted cyclohexyl, cyclohexenyl, adamantyl or tetf ahydropyf a ⁇ yl group:
  • combination 2004 describes those embodiments in which A is -F and B is -NH-.
  • a combination of substituents is permissible only if such a combination results in a chemically stable compound, and that any combination from Table 1, describing R 1 and R 2 , may be combined with any combination from Table 2, describing A and B.
  • combination 1580 from Table 1 and combination 2004 from Table 2 describe those embodiments of Formula I in which R 1 is adamantyl, R 2 is cyclohexyl, A is -F, and B is -NH-.
  • R 1 , R 2 and A group in the tables is understood to be optionally substituted as described herein.
  • each value of D may be combined with any combination from Table 1 or Table 2 or any pair of combinations from the two tables.
  • combination 1582 describes those embodiments in which D is -C(O)-, R 1 is adamantyl and R 2 is cyclohexenyl, as well as those where D is -CH 2 -, R 1 is adamantyl and R is cyclohexenyl, etc.
  • certain combinations of substituents are excluded, as described herein.
  • R 1 and R 2 are not simultaneously unsubstituted adamantyl, simultaneously unsubstituted cyclopropyl, simultaneously unsubstituted cyclobutyl or simultaneously unsubstituted cyclohexyl.
  • R , 1 is a substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, aralkyl, or heterocyclylalkyl group;
  • R 2 is CHR 2a R 2b ; a substituted or unsubstituted cycloalkyl, bicyclic aryl, bicyclic heterocyclyl, 5-membered heterocyclyl, saturated or partially saturated 6-membered heterocyclyl, aralkyl, or heterocyclylalkyl group, provided that when R 1 is unsubstituted phenyl, R 2 is not methyl, n-butyl or a benzyl group;
  • R 2a , and R 2b at each occurrence, are independently H, or a substituted or unsubstituted alkyl group; and stereoisomers thereof, tautomers thereof, solvates thereof, prodrugs thereof, and pharmaceutically acceptable salts thereof.
  • the compound at a concentration of lO ⁇ M inhibits glycogen synthase kinase-3 ⁇ , glycogen synthase kinase-3 ⁇ or both.
  • R 1 is a substituted or unsubstituted alkyl group, such as a substituted or unsubstituted methyl, ethyl, or isopropyl group.
  • R 1 is a substituted or unsubstituted aryl, heterocyclyl, or a cycloalkyl group.
  • R 1 is an unsubstituted phenyl, 1-naphthyl, 2-naphthyl, indanyl, indenyl, adamantyl, bicyclo[2.2.1]heptanyl, cyclopentyl or cyclohexyl group.
  • R 1 is substituted with one or more F, Cl, Br, I, -OR 3 , -C(O)R 4 , substituted or unsubstituted alkyl group, -NR 5 R 6 , -CN, or -C(O)OH, wherein R 3 is H, or a substituted or unsubstituted alkyl group; R 4 is a substituted or unsubstituted alkyl or aryl group; and R 5 and R 6 , at each occurrence, are independently H, a substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, aralkyl, heterocyclyl, or heterocyclylalkyl group; or R 5 and R 6 , together with the N to which they are attached, form a substituted or unsubstituted heterocyclyl group.
  • R 1 can be substituted with one or more F, Cl, Br, I; -OH; -0-C 1-10 alkyl, optionally substituted with one or more F; -C(O)C 1-8 alkyl, -C(O)phenyl; C 1-10 alkyl, optionally substituted with one or more F; -CN, or -C(O)OH.
  • R 1 is a substituted or unsubstituted phenyl, naphthyl, indanyl, indenyl, pyridyl, thiophenyl, quinolyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, bicyclo[2.2.1]heptanyl, morpholinyl or tetrahydropyranyl group.
  • R 1 can be a substituted or unsubstituted phenyl, naphthyl, indanyl, adamantyl, bicyclo[2.2.1]heptanyl, cyclopentyl or cyclohexyl group.
  • R 2 is a substituted or unsubstituted cycloalkyl, a bicyclic aryl, a bicyclic heterocyclyl, a 5-membered heterocyclyl, a saturated 6-membered heterocyclyl, an aralkyl, or a heterocyclylalkyl group.
  • R 2 is substituted with one or more F, Cl, Br, I, a substituted or unsubstituted alkyl group, -OR 3 , -O(CH 2 ) n C(O)OR, -O(CH 2 ) n C(O)NR 5 R 6 , -(CH 2 VNR 5 R 6 , -C(O)OR 7 , -(CH 2 ) n -C(O)OR 7 , -C(O)C(O)OR 7 , -C(O)C(O)OR 7 , -C(O)C(O)NR 5 R 6 , -CN, -C(O)R 7 , -C(O)NR 5 R 6 , -NR 5 R 6 , -NR 5 C(O)R 7 , -NR 5 C(O)OR 7 , -NR 5 C(O)NR 5 R 6 , -NR 5 SO 2 R 6 , or -SO 2 NR 5 R 6 ,
  • R 2 can be substituted with one or more F, Cl, Br, I; -OH, -0-C 1-10 alkyl, optionally substituted with one or more F or OH; -OCH 2 C(O)OR, -O(CH 2 ) 2 C(O)OR, -OCH 2 C(O)NR 5 R 6 , -O(CH 2 ) 2 C(O)NR 5 R 6 ; -C(O)NR 5 R 6 ; -C(O)OH, -(CH 2 )-C(O)OR 7 , -(CH 2 ) 2 -C(O)OR 7 ,-C(O)C(O)O(d -6 alkyl), -C(O)C(O)NH 2 , -CN; -C(O)R 7 , -NHC(O)R 7 , or C 3-10 alkyl, optionally substituted with one or more F or -OH.
  • R 2 is a cyclohexyl group, substituted with -OH, or -NR 5 C(O)R 7 .
  • the cyclohexyl is substituted at the 4- - position, in others, it is substituted at the 2- and/or 3-position;
  • the " cyclohexyl may also be disubstituted.
  • R 2 is a substituted or unsubstituted cycloalkyl, a bicyclic aryl, a bicyclic heterocyclyl, a 5-membered heterocyclyl, a saturated 6-membered heterocyclyl, an aralkyl, or a heterocyclylalkyl group
  • R is a substituted or unsubstituted cyclopentyl, cyclohexyl, cycohexenyl, cycloheptyl, adamantyl, naphthyl, tetrahydronaphthyl, indenyl, indanyl, quinolyl, dihydrobenzodioxinyl, benzodioxolyl, phthalyl, benzotriazolyl, indazolyl, benzimidazolyl, indolyl, isoindolyl, indolinyl, dihydroindolyl, dihydr
  • R 2 is a substituted or unsubstituted cyclohexyl, tetrahydropyranyl, benzyl, phenethyl, -(CH 2 )-tetrahydropyranyl, isobenzofuranonyl, benzotriazolyl, dihydrobenzodioxinyl, phthalyl, indazolyl, piperidinyl, or dihydroisoindolonyl group.
  • R 2 is a substituted or unsubstituted N-ethyl-pyridine-2,6-diamine group.
  • R 1 is a substituted or unsubstituted phenyl or indanyl group
  • R 2 is a substituted or unsubstituted cycloalkyl, bicyclic aryl, bicyclic heterocyclyl, 5-membered heterocyclyl, saturated 6- membered heterocyclyl, aralkyl, or heterocyclylalkyl group.
  • R 1 is substituted with one or more F, Cl, Br, I, -OR 3 , -C(O)R 4 , substituted or unsubstituted alkyl group, -NR 5 R 6 , -CN, or -C(O)OH, wherein R 3 , R 4 , R 5 and R 6 are as defined above.
  • R 1 can be substituted with one or more F, Cl, Br, I; -OH; -0-C 1-1O alkyl, optionally substituted with one or more F; -C(O)C 1-8 alkyl, -C(O)phenyl; C 1-10 alkyl, optionally substituted with one or more F; -CN, or -C(O)OH.
  • R 2 is substituted with one or more F, Cl, Br, I, a substituted or unsubstituted alkyl group, -OR 3 , -O(CH 2 ) n C(O)OR, -O(CH 2 ) n C(O)NR 5 R 6 , -(CH 2 ) n -NR 5 R 6 , -C(O)OR 7 , -(CH 2 ) n -C(O)OR 7 , -C(O)C(O)OR 7 , -C(O)C(O)NR 5 R 6 , -CN, -C(O)R 7 , -C(O)NR 5 R 6 , -NR 5 R 6 , -NR 5 C(O)R 7 , -NR 5 C(O)OR 7 , -NR 5 C(O)NR 5 R 6 , -NR 5 SO 2 R 6 , or -SO 2 NR 5 R 6 , wherein R,
  • R 2 can be substituted with one or more F, Cl, Br, I; -OH, -0-C 1-1O alkyl, optionally substituted with one or more F or OH; - -OCH 2 C(O)OR, -O(CH 2 ) 2 C(O)OR, -OCH 2 C(O)NR 5 R 6 ⁇ -O(CH 2 ) 2 C(O)NR 5 R 6 ; " -C(O)NR 5 R 6 ; -C(O)OH, -C(O)C(O)O(C 1-6 alkyl), -C(O)C(O)NH 2 , -CN; -C(O)R 7 , -NHC(O)R 7 , or C 3-10 alkyl, optionally substituted with one or more F or OH.
  • R is a substituted or unsubstituted cyclopentyl, cyclohexyl, cycohexenyl, cycloheptyl, adamantyl, naphthyl, tetrahydronaphthyl, indenyl, indanyl, quinolyl, dihydrobenzodioxinyl, benzodioxolyl, phthalyl, benzotriazolyl, indazolyl, benzimidazolyl, indolyl, isoindolyl, indolinyl, dihydroindolyl, dihydroisoindolonyl, isobenzofuranonyl, pyrrolidinyl, piperidinyl, morpholinyl, tetrahydropyranyl, benzyl, phenethyl, -(CH 2 )-cyclopentyl, -(CH 2 )
  • R 2 can be a substituted or unsubstituted cyclohexyl, tetrahydropyranyl, benzyl, phenethyl, -(CH 2 )-tetrahydropyranyl, isobenzofuranonyl, benzotriazolyl, dihydrobenzodioxinyl, phthalyl, indazolyl, piperidinyl, or dihydroisoindolonyl group.
  • R 1 is unsubstituted when R 1 is phenyl, 1 -naphthyl, 2-naphthyl, indanyl, indenyl, adamantyl, bicyclo[2.2.1]heptyl, cyclopentyl or cyclohexyl.
  • R 1 is a substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, aralkyl, or heterocyclylalkyl group;
  • R 8 is CHR 8a R 8b ; or a substituted or unsubstituted aryl, cycloalkyl, heterocyclyl, aralkyl, or heterocyclylalkyl group;
  • R 8a , R 8b , R 12 , R 13 and R are at each occurrence each independently H, or a substituted or unsubstituted alkyl group;
  • R 9 is H, an alkyl or C 3-5 cycloalkyl group, optionally substituted with one or more F, Cl, Br, I or -OR 13 ;
  • R 10 is 4-pyridyl, -C(O)OR, -(CH 2 ) n C(O)OR, or aryl group, substituted with one or more -OR 13 ;
  • R 11 is -OR 13 or F, Cl, Br, I, provided that when R 11 is present, R 1 is not methyl, isopropyl, or benzyl;
  • each n is independently 1-4; and stereoisomers thereof, tautomers thereof, solvates thereof, prodrugs thereof, and pharmaceutically acceptable salts thereof;
  • the compound is not l-methyl-6-methylamino- l,2-dihydro-pyrazolo[3,4-d]pyrimidin-3-one, l-methyl-6-propylamino-l,2-dihydro- pyrazolo[3,4-d]pyrirnidin-3-one, 7-isopropyl-9-phenyl-2-phenylamino-7,9-dihydro- purin-8-one, or 9-benzyl-2-butylamino-7,9-dihydro-purin-8-one.
  • the compound at a concentration of lO ⁇ M inhibits glycogen synthase kinase-3 ⁇ , glycogen synthase kinase-3 ⁇ or both.
  • compounds of the invention include bicyclic heterocycles of the following structures:
  • G is
  • R 1 is a substituted or unsubstituted aryl, heterocyclyl, or a cycloalkyl group.
  • R 1 can be an unsubstituted phenyl, 1-naphthyl, 2-naphthyl or cyclohexyl group.
  • R 1 is substituted with one or more F, Cl, Bf, I, -OR l ⁇ , -C(O)R 14 , substituted or unsubstituted alkyl group, -NR 15 R 16 , -CN. .
  • R 14 is a substituted or unsubstituted alkyl or aryl group
  • R 15 and R 16 at each occurrence, are independently H, a substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, aralkyl, heterocyclyl, or heterocyclylalkyl group; or R 15 and R 16 , together with the N to which they are attached, form a substituted or unsubstituted heterocyclyl group.
  • R 1 can be substituted with F, Cl, Br, I; -OH; -0-C 1 - I0 alkyl, optionally substituted with one or more F; -C(O)C]- S alkyl, - C(O)phenyl; Ci -I0 alkyl, optionally substituted with one or more F; -CN, or -C(O)OH.
  • R 1 is a substituted or unsubstituted phenyl, naphthyl, indanyl, indenyl, pyridyl, thiophenyl, quinolyl, cyclopentyl, cyclohexyl, cycloheptyl, morpholinyl or tetrahydropyranyl group.
  • R 1 can be a substituted or unsubstituted phenyl, naphthyl, or cyclohexyl group.
  • R 8 is a substituted or unsubstituted aryl, cycloalkyl, heterocyclyl, aralkyl, or heterocyclylalkyl group.
  • R 8 is substituted with one or more F, Cl, Br, I, -OR 13 , -C(O)OH, -CN, -NR 15 R 16 , -C(O)NR 15 R 16 , -O(CH 2 ) n C(O)OR, -O(CH 2 ) n C(O)NR 15 R 16 , substituted or unsubstituted alkyl group, or -SO 2 NR 15 R 16 , wherein R 15 and R 16 , at each occurrence, are independently H, a substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, aralkyl, heterocyclyl, or heterocyclylalkyl group; or R 15 and
  • R 8 can be substituted with one or more F, Cl, Br, I; -OH, -0-C 1-10 alkyl, optionally substituted with one or more F or OH; -C(O)OH, -CN; -C(O)NR 15 R 16 ; -OCH 2 C(O)OR, -O(CH 2 ) 2 C(O)OR, -OCH 2 C(O)NR 15 R 16 , -O(CH 2 ) 2 C(O)NR 15 R 16 ; or C 3-10 alkyl, optionally substituted with one or more F or OH.
  • R 8 is a substituted or unsubstituted phenyl, pyridyl, thiophenyl, quinolyl, cyclopentyl, cyclohexyl, cycloheptyl, morpholinyl, tetrahydropyranyl, benzyl, phenethyl, -(CH 2 )-cyclopentyl, -(CH 2 ) 2 -cylcopentyl, - (CH 2 )-cyclohexyl, -(CH 2 ) 2 -cyclohexyl, -(CH 2 )-cylcohe ⁇ tyl, -(CH 2 ) 2 -cycloheptyl, - (CH 2 )-morpholinyl, -(CH 2 ) 2 -morpholinyl, -(CH 2 )-tetrahydropyranyl, or -(CH 2 ) 2 - tetrahydropyranyl,
  • R 8 can be a substituted or unsubstituted phenyl, cyclohexyl, tetrahydropyranyl, benzyl, phenethyl, or -(CH 2 )- tetrahydropyranyl group.
  • Table 4 illustrates combinations of R 1 and R for compounds having Formula III. It will be understood that each value of R 9 , R 10 , R 11 , and R 12 maybe combined with any combination from Table 4.
  • combination 4002 and R 9 describes embodiments in which R 9 is H, R 1 is alkyl, R 8 is aryl, as well as those in which R 9 is a C 3-5 cycloalkyl group, R 1 is alkyl, R 8 is aryl, and so forth.
  • R 17 is a substituted or unsubstituted C 3-I0 alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, aralkyl, or heterocyclylalkyl group;
  • R 18 is CHR 183 R 18b ; or a substituted or unsubstituted aiyl, cycloalkyl, aralkyl, or heterocyclylalkyl group;
  • R 18a , R 18b , R 18c , and R 18d are independently H, or a substituted or unsubstituted alkyl group;
  • the compound at a concentration of lO ⁇ M inhibits glycogen synthase kinase-3 ⁇ , glycogen synthase kinase-3 ⁇ or both.
  • R 17 is a substituted or unsubstituted aryl, heterocyclyl, or a cycloalkyl group.
  • R 17 is substituted with one or more F, Cl, Br, I, -OR 19 , -C(O)R 20 , substituted or unsubstituted alkyl group, -NR 21 R 22 , -CN, or -C(O)OH, wherein R 19 is H, or a substituted or unsubstituted alkyl group; R 20 is a substituted or unsubstituted alkyl or aryl group; and R 21 and R 22 , at each occurrence, are independently H, a substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, aralkyl, heterocyclyl, or heterocyclylalkyl group; or R 21 and R 22 , together with the N to which they are attached, form
  • R 17 can be substituted with one or more F, Cl, Br, I; -OH; -0-C 1-1O alkyl, optionally substituted with one or more F; -C(O)Ci -8 alkyl, -C(O)phenyl; Ci -I0 alkyl, optionally substituted with one or more F; -CN, or -C(O)OH.
  • R 17 is a substituted or unsubstituted phenyl, naphthyl, indenyl, pyridyl, thiophenyl, quinolyl, cyclopentyl, cyclohexyl, cycloheptyl, morpholinyl or tetrahydropyranyl group.
  • R 17 can be a substituted or unsubstituted phenyl, naphthyl, or cyclohexyl group.
  • R 18 is a substituted or unsubstituted aryl, cycloalkyl, heterocyclyl, aralkyl, or heterocyclylalkyl group.
  • R 18 is substituted with one or more F, Cl, Br, I, -OR 19 , -C(O)OH, -CN, -NR 21 R 22 , -C(O)NR 21 R 22 , , - ⁇ CH 2 ) n C(O)_OR, .
  • R 19 and R are independently H, or a substituted or unsubstituted alkyl group
  • R 21 and R 22 are independently H, a substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, aralkyl, heterocyclyl, or heterocyclylalkyl group
  • R 21 and R 22 together with the N to which they are attached, form a substituted or unsubstituted heterocyclyl group
  • each n is independently 1-4.
  • R 18 can be substituted with one or more F, Cl, Br, I; -OH, -0-C 1-10 alkyl, optionally substituted with one or more F or OH; -C(O)OH, -CN; -C(O)NR 21 R 22 ; -OCH 2 C(O)OR 5 -O(CH 2 ) 2 C(O)OR, -OCH 2 C(O)NR 21 R 22 , -O(CH 2 ) 2 C(O)NR 21 R 22 ; or C 1-10 alkyl, optionally substituted with one or more F or OH.
  • R 18 is a substituted or unsubstituted phenyl, pyridyl, thiophenyl, quinolyl, cyclopentyl, cyclohexyl, cycloheptyl, morpholinyl, tetrahydropyranyl, benzyl, phenethyl, -(CH 2 )-cyclopentyl, - (CH 2 ) 2 -cyclopentyl, -(CH 2 )-cyclohexyl, -(CH 2 ) 2 -cyclohexyl, -(CH 2 )-cycloheptyl, - (CH 2 ) 2 -cylcoheptyl, -(CH 2 )-morpholinyl, -(CH 2 ) 2 ⁇ morpholinyl, -(CH 2 )- tetrahydropyranyl, or -(CH 2 ) 2 -tetrahydropyranyl, or -
  • R 18 can be a substituted or unsubstituted phenyl, cyclohexyl, tetrahydropyranyl, benzyl, phenethyl, or -(CH 2 )-tetrahydropyranyl group.
  • Table 5 illustrates combinations of R 17 and
  • R 18 for compounds having Formula IV. It will be understood that each value of R 18c and R 18d can be combined with any combination of Table 5.
  • Furan-2-carboxylic acid [4-(3-phenyl-3H-[ 1 ,2,3]triazolo[4,5-d]pyrimidin-5-ylamino)- cyclohexyl]-amide;
  • Formula IAa with R 2 NH 2 , in a suitable solvent, under conditions suitable to form a compound of Formula I, wherein Hal is F, Cl 5 Br, I , or S(O) m R a , R a is a substituted or unsubstituted alkyl or aryl group, R 1 , R 2 and A are as defined herein for Formula I, and m is 1-2.
  • the reaction is carried out at elevated temperature and optionally can be carried out in a solvent or in the presence of a base.
  • R 1 NH 2 in a suitable solvent, under conditions suitable to form a compound of Formula IAa, wherein Hal and Hal' are each independently F, Cl, Br, I , or S(O) m R a , R a is a substituted or unsubstituted alkyl or aryl group, R 1 and A are as defined herein for Formula I, and m is 1-2.
  • the reaction is typically carried out in the presence of a suitable base, such as N,N'-diisopropylethylamine.
  • the present invention provides a method of preparing compounds of Formula II,
  • reaction is carried out at a temperature in the range of about 25°C to about 15O 0 C, more typically at about 9O 0 C.
  • suitable solvents include organic solvents such as dioxane, THF, DMF, DMSO, AcOH, NMP, or DME, and mixtures thereof.
  • the reaction can be carried out in the presence of an acid, such as TFA, or a base, such as DIEA, and the like.
  • a compound of Fo ⁇ nula Ha wherein A is S(O) m R a can be prepared by oxidizing a compound of Formula lib,
  • oxidizing agent such as mCPBA, NaIO 4 , peroxides, dimethyl dioxirane
  • solvent is DCM, water, methanol, EtOH, THF, dioxane and the like, or mixtures thereof.
  • a compound of Formula lib can be prepared by cyclizing a compound of Formula Va,
  • Formula Va by reaction with a nitrite, such as n-butylnitrite, isoamyl nitrite, NaNO 2 /AcOH and the like, in the presence of an acid, optionally in a suitable solvent, under conditions suitable to form a compound of Formula lib.
  • a nitrite such as n-butylnitrite, isoamyl nitrite, NaNO 2 /AcOH and the like
  • Formula Vb by reaction with a nitrite, in the presence of an acid, to form a compound of Formula Ha, wherein A is F, Cl, Br, or I.
  • compounds of Formula II can be prepared by cyclizing a compound of Formula Vc 5
  • Formula Vc by reaction with a nitrite, such as n-butylnitrite, isoamyl nitrite, NaN(VAcOH and the like, in the presence of an acid, optionally in a suitable solvent, under conditions suitable to form a compound of Formula II, wherein R 1 and R 2 are as defined herein.
  • a nitrite such as n-butylnitrite, isoamyl nitrite, NaN(VAcOH and the like
  • Suitable acids for the above cyclization reactions include acetic acid or aqueous HCl, optionally with a cosolvent, such as dioxane. Typically the reaction is performed at a temperature in the range of about -20 0 C to about 25°C, more typically at about -1O 0 C.
  • the invention provides methods of preparing compounds of Formula IIIA,
  • Suitable bases include organic bases such as DIEA, TEA, DBU and the like, while inorganic bases include Cs 2 CO 3 , K 2 CO 3 , NaHCO 3 and the like.
  • Typical solvents are DMF, DCM, THF, dioxane, and the like and mixtures thereof.
  • a carbonylating agent such as N,N'-disuccinimidyl carbonate, phosgene or lj'-carbonyldiimidazole
  • a solvent under conditions suitable to form a compound of Formula IIIAa, wherein R 1 , R 2 and R 9 are as defined herein.
  • Suitable solvents include dioxane, DMF, THF, DME, NMP and the like.
  • the reaction is typically-performed underheating; Optionally under microwave irradiation, to a temperature from about 60°C to about 16O 0 C, usually about 80°C under standard heating conditions, or about 160°C under microwave irradiation conditions.
  • the present invention provides methods of preparing compounds of Formula IHB
  • R 10 C(O)R in a solvent, to form a compound of Formula IHB, wherein R 1 , R 2 and R 10 are as defined herein, R x is H or a halogen, such as F, Cl, Br or I, and wherein if R x is halogen the solvent contains a base.
  • suitable solvents include DMF, NMP, DME, dioxane and the like
  • suitable bases include organic bases, such as DIEA, TEA, DBU, pyridine and the like.
  • the reaction is performed at a temperature in the range of about 8O 0 C to about 200°C, more typically at about 15O 0 C.
  • R x is H
  • typical solvents include acetic acid, EtOH, MeOH, DMF, DME, THF, dioxane, and the like, and the reaction is performed under microwave irradiation at a temperature in the range of about 80 0 C to about 150 0 C, more typically at about 120 0 C.
  • A is S(O) m R a , with H 2 NR 2 , in a solvent, optionally in the presence of an acid, to form a compound of Formula UIC, wherein R 1 , R 2 and R 11 are as defined herein, R a is a substituted or unsubstituted alkyl or aryl group, and m is 1-2.
  • the reaction is carried out at a temperature in the range of about 90 0 C to about 150 0 C, more typically at about 120 0 C.
  • Suitable solvents include dioxane, THF, DMSO, DMF, DME, or mixtures thereof, while suitable acids include TFA.
  • oxidizing agent such as mCPB A, NaIO 4 , peroxides, or dimethyl dioxirane in a solvent
  • A is S(O) m R a
  • the solvent is DCM, THF, dioxane, DCE, DME or the like, or mixtures thereof.
  • Formula HID the method comprising reacting a compound of Formula VII, Formula VII wherein A is is S(O) m R a , with H 2 NR 2 , in a solvent, to form a compound of Formula HID wherein R 1 , R 2 and R 12 are as defined herein, R a is a substituted or unsubstituted alkyl or aryl group, and m is 1-2.
  • the reaction is carried out at a temperature in the range of about 9O 0 C to about 120°C, more typically at about 110 0 C.
  • Suitable solvents include dioxane, DMF, DMSO, NMP, DME or the like, or mixtures thereof.
  • oxidizing agent such as mCPBA, NaIO 4 , peroxides, or dimethyl dioxirane
  • solvent Typically the solvent is DCM, THF, dioxane, DCE, DME or the like, or mixtures thereof.
  • R' is a lower alkyl group, with hydrogen in the presence of a catalyst, such as Raney Ni or Pd, or with a reducing agent, such as SnCl 2 , Na 2 S 2 O 4 , Zn/ AcOH or Fe, in a solvent, to form a compound of Formula IV 3 wherein R 17 , R 18 , R 18c and R I8d are as defined herein.
  • Suitable solvents include solvents such as methanol, ethanol, THF, dioxane and the like, and mixtures thereof.
  • compositions comprising a compound as described herein and a pharmaceutically acceptable carrier.
  • the invention provides methods for treating a biological condition mediated by GSK-3, the method comprising administering to a subject in need thereof an effective amount of a compound as described herein.
  • the biological condition can be a metabolic disease, such as type I or II diabetes, obesity, insulin resistance, or Syndrome X; acute or chronic neurodegenerative disorder, such as for example, Alzheimer's disease, Parkinson's disease, tauopathies (including, but not limited to frontotemporoparietal dementia, corticobasal degeneration, Pick's disease, or progressive supranuclear palsy), dementia (for example, vascular dementia or acute confusional senile dementia); acute stroke; cerebrovascular accidents (for example, age-related macular degeneration); brain or spinal cord trauma; peripheral neuropathies; retinopathies or glaucoma; affective disorder, for example bipolar disorder, or manic depression; central nervous system disorder, endocrine disorder, gastrointestinal disorder, liver disease, immune system disorder, lymphatic disorder, cerebrovascular disorders, and the respiratory disorders.
  • central nervous system disorder
  • references to a certain element such as hydrogen or H is meant to include all isotopes of that element.
  • an R group is defined to include hydrogen or H, it also includes deuterium and tritium.
  • isotopically labeled compounds are within the scope of the invention.
  • substituted refers to a functional group as defined below in which one or more bonds to a hydrogen atom contained therein are replaced by a bond to non-hydrogen or non-carbon atoms.
  • Substituted groups also include groups in which one or more bonds to a carbon(s) or hydrogen(s) atom are replaced by one or more bonds, including double or triple bonds, to a heteroatom.
  • substituted groups have 1, 2, 3, 4, 5, or 6 substituents.
  • substituent groups include, but are not limited to: halogens (i.e., F, Cl, Br, and I); hydroxyls; alkoxy, alkenoxy, alkynoxy, aryloxy, aralkyloxy, heterocyclyloxy, and heterocyclylalkoxy groups; carbonyls (oxo); carboxyls; esters; urethanes; oximes; hydroxylamines; alkoxyamines; thiols; alkyl, alkenyl, alkynyl, aryl, aralkyl, heterocyclyl and heterocyclylalkyl sulfide groups; sulfoxides; sulfones; sulfonyls; sulfonamides; amines; N-oxides; hydrazines; hydrazides; hydrazones; azides; amides; ureas; amidines; guanidines; enamines; imides; is
  • Substituted ring groups such as substituted cycloalkyl, aryl, heterocyclyl and heteroaryl groups also include rings and fused ring systems in which a bond to a hydrogen atom is replaced with a bond to a carbon atom. Therefore, substituted cycloalkyl, aryl, heterocyclyl and heteroaryl groups may also be substituted with alkyl, alkenyl, and alkynyl groups as defined below.
  • Alkyl groups include straight chain and branched alkyl groups and cycloalkyl groups having from 1 to about 20 carbon atoms, and typically from 1 to 11 carbons or, in some embodiments, from 1 to 8 carbon atoms.
  • straight chain alkyl groups include those with from 1 to 8 carbon atoms such as methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, and n-octyl groups.
  • branched alkyl groups include, but are not limited to, isopropyl, iso-butyl, sec-butyl, tert-butyl, neopentyl, isopentyl, and 2,2-dimethylpropyl groups.
  • Representative substituted alkyl groups may be substituted one or more times with any of the groups listed above, for example, amino, oxo, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and F 5 Cl, Br, I groups.
  • Cycloalkyl groups are cyclic alkyl groups such as, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups.
  • the cycloalkyl group has 3 to 8 ring members, whereas in other embodiments the number of ring carbon atoms range from 3 to 5, 6, or 7.
  • Cycloalkyl groups further include mono-, bicyclic and polycyclic ring systems, such as, for example bridged cycloalkyl groups as described below, and fused rings, such as, but not limited to, decalinyl, and the like.
  • Substituted cycloalkyl groups may be substituted one or more times with non-hydrogen and non-carbon groups as defined above. However, substituted cycloalkyl groups also include rings that are substituted with straight or branched chain alkyl groups as defined above. Representative substituted cycloalkyl groups may be mono-substituted or substituted more than once, such as, but not limited to, 2,2-, 2,3-, 2,4- 2,5- or 2,6-disubstituted cyclohexyl groups, which may be substituted with any of the groups listed above, for example, methyl, amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and F, Cl, Br, I groups.
  • Bridged cycloalkyl groups are cycloalkyl groups in which two or more hydrogen atoms are replaced by an alkylene bridge, wherein the bridge can contain 2 to 6 carbon atoms if two hydrogen atoms are located on the same carbon atom, or 1 to 5 carbon atoms, if the two hydrogen atoms are located on adjacent carbon atoms, or 1 to 4 carbon atoms if the two hydrogen atoms are located on carbon atoms separated by 2 carbon atoms.
  • Bridged cycloalkyl groups can be bicyclic, such as, for example bicyclo[2.1.1]hexyl, or tricyclic, such as, for example, adamantyl.
  • Representative bridged cycloalkyl groups include bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octyl, bicyclo[3.2.2]nonyl, bicyclo[3.3.1]nonyl, bicyclo[3 ⁇ 3 . .2]decanyl, adamantyl,. noradamantyl, bornyl, or_norbprnyl groups.
  • Substituted bridged cycloalkyl groups may be substituted one or more times with noi hydrogen and non-carbon groups as defined above.
  • Representative substituted bridged cycloalkyl groups may be mono-substituted or substituted more than once, such as, but not limited to, mono-, di- or tri-substituted adamantyl groups, which may be substituted with any of the groups listed above, for example, amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and F, Cl, Br, I groups.
  • Cycloalkylalkyl groups are alkyl groups as defined above in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to a cycloalkyl group as defined above.
  • Alkenyl groups include straight and branched chain alkyl and cycloalkyl groups as defined above, except that at least one double bond exists between two carbon atoms.
  • alkenyl groups have from 2 to about 20 carbon atoms, and typically from 2 to 12 carbons or, in some embodiments, from 2 to 8 carbon atoms.
  • Cycloalkenyl groups include cycloalkyl groups having at least one double bond between 2 carbons.
  • cycloalkenyl groups include but are not limited to cyclohexenyl, cyclopentenyl, and cyclohexadienylgroups.
  • Cycloalkenylalkyl groups are alkyl groups as defined above in which a hydrogen or carbon bond of the alkyl group is replaced with a bond to a cycloalkenyl group as defined above.
  • Alkynyl groups include straight and branched chain alkyl groups, except that at least one triple bond exists between two carbon atoms.
  • alkynyl groups have from 2 to about 20 carbon atoms, and typically from 2 to 12 carbons or, in some embodiments, from 2 to 8 carbon atoms. Examples include, but are not limited to -C ⁇ CH, -C ⁇ C(CH 3 ), -C ⁇ C(CH 2 CH 3 ), -CH 2 C ⁇ CH, -CH 2 C ⁇ C(CH 3 ), and -CH 2 C ⁇ C(CH 2 CH 3 ), among others.
  • Aryl groups are cyclic aromatic hydrocarbons that do not contain heteroatoms.
  • Aryl groups include monocyclic, bicyclic and polycyclic ring systems.
  • aryl groups include, but are not limited to, phenyl, azulenyl, heptalenyl, biphenylenyl, indacenyl, fluorenyl, phenanthrenyl, triphenylenyl, pyrenyl, naphthacenyl, chrysenyl, biphenyl, anthracenyl, indenyl, indanyl, pentalenyl, and naphthyl groups.
  • aryl groups contain 6-14 carbons, and in others from 6 to 12 or even 6-10 carbon atoms in the ring portions of the groups.
  • aryl groups includes groups containing fused rings, such as fused aromatic-aliphatic ring systems (e.g., indanyl, tetrahydronaphthyl, and the like), it does not include aryl groups that have other groups, such as alkyl or halo groups, bonded to one of the ring members. Rather, groups such as tolyl are referred to as substituted aryl groups.
  • Representative substituted aryl groups may be mono- substituted or substituted more than once.
  • monosubstituted aryl groups include, but are not limited to, 2-, 3-, A-, 5-, or 6-substituted phenyl or naphthyl groups, which may be substituted with groups such as those listed above.
  • Aralkyl groups are alkyl groups as defined above in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to an aryl group as defined above.
  • Representative aralkyl groups include but are not limited to benzyl and phenethyl groups and fused (cycloalkylaryl)alkyl groups such as 4-ethyl-indanyl.
  • Heterocyclyl groups include aromatic (also referred to as heteroaryl) and non-aromatic ring compounds containing 3 or more ring members, of which one or more is a heteroatom such as, but not limited to, N, O, and S.
  • the heterocyclyl group contains 1, 2, 3, or 4 heteroatoms.
  • heterocyclyl groups include 3 to 20 ring members, whereas other such groups have 3 to 6, 10, 12, or 15 ring members.
  • Heterocyclyl groups encompass unsaturated, partially saturated and saturated ring systems, such as, for example, imidazolyl, imidazolinyl and imidazolidinyl groups.
  • heterocyclyl group includes fused ring species including those comprising fused aromatic and non- aromatic groups, such as, for example, benzotriazolyl, 2,3-dihydrobenzo[l,4]dioxinyl, and benzo[l,3]dioxolyl.
  • the phrase also includes bridged polycyclic ring systems containing a heteroatom such as, but not limited to, quinuclidyl.
  • the phrase does not include heterocyclyl groups that have other groups, such as alkyl, oxo or hal ⁇ groups, bonded to one of the ring members ⁇ Rather, these are referred to as
  • Heterocyclyl groups include, but are not limited t ⁇ .
  • Representative substituted lieterocyclyl groups may be mono-substituted or substituted more than once, such as, but not limited to, pyridinyl or morpholinyl groups, which are 2-, 3-, 4-, 5-, or 6-substituted, or disubstituted with various groups as defined above, including, but not limited to, alkyl, oxo, carbonyl, amino, alkoxy, cyano, and/or halo.
  • Heteroaryl groups are aromatic ring compounds containing 5 or more ring members, of which, one or more is a heteroatom such as, but not limited to, N, O, and S.
  • the heteroaryl group includes 1, 2, 3, or 4 heteroatoms and has 5 to 20, 5 to 15, or 5 to 10 ring members, hi other embodiments, the heteroaryl groups have 5, 6, 7, 8, or 9 ring members.
  • Heteroaryl groups include, but are not limited to, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiophenyl (thienyl), benzothiophenyl, benzofuranyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, azabenzimidazolyl, benzotriazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridinyl, isoxazolopyridinyl, thianaphthalenyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquino
  • heteroaryl groups includes fused ring compounds such as indolyl and 2,3-dihydro indolyl, the phrase does not include heteroaryl groups that have other groups bonded to one of the ring members, such as alkyl groups. Rather, heteroaryl groups with such substituents are referred to as "substituted heteroaryl groups”. Representative substituted heteroaryl groups may be substituted one or more times with various groups as defined above, “ including, “ but not limited to, amino " ⁇ x ⁇ , alkoxy, alkyl, cyand, and/or halo.
  • Heterocyclylalkyl groups are alkyl groups as defined above in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to a heterocyclyl group as defined above.
  • Representative heterocyclyl alkyl groups include, but are not limited to, 4-ethyl-morpholinyl, 4-propylmorpholinyl, furan-2-yl methyl, furan-3-yl methyl, pyridine-3-yl methyl, tetrahydrofuran-2-yl ethyl, and indol-2-yl propyl.
  • Heteroaralkyl groups are alkyl groups as defined above in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to a heteroaryl group as defined above.
  • Alkoxy groups are hydroxyl groups (-OH) in which the bond to the hydrogen atom is replaced by a bond to a carbon atom of an alkyl group as defined above.
  • linear alkoxy groups include but are not limited to methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, and the like.
  • branched alkoxy include but are not limited to isopropoxy, sec-butoxy, tert-butoxy, isopentoxy, isohexoxy, and the like.
  • cyclic alkoxy include but are not limited to cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like.
  • aryloxy and arylalkoxy refer to, respectively, an aryl group bonded to an oxygen atom and an aralkyl group bonded to the oxygen atom at the alkyl. Examples include but are not limited to phenoxy, naphthyloxy, and benzyloxy.
  • carboxylate refers to a -COOH group.
  • carboxylic ester refers to -COOR 30 groups.
  • R 30 is a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heterocyclylalkyl or heterocyclyl group as defined herein.
  • amide (or “amido”) includes C- and N-amide groups, i.e.,
  • R 31 and R 32 are independently hydrogen, or a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl or heterocyclyl group as defined herein.
  • Amido groups therefore include but are not limited to carbamoyl groups (-C(O)NH 2 ) and formamide groups (-NHC( ⁇ )H).
  • Urethane groups include N- and O-urethane groups, i.e.,
  • R 33 and R 34 are independently hydrogen, or a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl, or heterocyclyl group as defined herein.
  • amine refers to -NHR 35 and -NR 36 R 37 groups, wherein R 35 , R 36 and R 37 are independently hydrogen, or a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl or heterocyclyl group as defined herein.
  • sulfonamido includes S- and N-sulfonamide groups, i.e.,
  • R 38 and R 39 are independently hydrogen, or a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl, or heterocyclyl group as defined herein.
  • Sulfonamido groups therefore include but are not limited to sulfamoyl groups (-SO 2 NH 2 ).
  • thiol refers to -SH groups
  • sulfides include -SR 40 groups
  • sulfoxides include — S(O)R 41
  • sulfones include -SO 2 R 42 groups
  • sulfonyls include -SO 2 OR 43 .
  • R 40 , R 41 , R 42 , and R 43 are each independently a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl aralkyl, heterocyclyl or heterocyclylalkyl group as defined herein.
  • urea refers to -NR 44 -C(O)-NR 45 R 46 groups.
  • R 46 groups are independently hydrogen, or a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclyl, or heterocyclylalkyl group as defined herein.
  • amidine refers to -C(NR 47 )NR 48 R 49 and -NR 47 C(NR 48 )R 49 groups, wherein R 47 , R 48 , and R 49 are each independently hydrogen, or a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl aralkyl, heterocyclyl or heterocyclylalkyl group as defined herein.
  • guanidine refers to -NR 50 C(NR 5 ! )NR 52 R 53 groups, wherein R 50 , R 51 , R 52 and R 53 are each independently hydrogen, or a substituted or - unsubstituted alkyl-, cycloalkyl, alkenyl; alkynyl, aryharalkyl, heterocyclyl or ⁇ ⁇ ⁇ heterocyclylalkyl group as defined herein.
  • R 54 , R 55 , R 56 and R 57 are each independently hydrogen, a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl aralkyl, heterocyclyl or heterocyclylalkyl group as defined herein.
  • imide refers to -C(O)NR 58 C(O)R 59 groups, wherein R 58 and R 59 are each independently hydrogen, or a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl aralkyl, heterocyclyl or heterocyclylalkyl group as defined herein.
  • the term "imine” refers to -CR 60 (NR 61 ) and -N(CR 60 R 61 ) groups, wherein R 60 and R 61 are each independently hydrogen or a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl aralkyl, heterocyclyl or heterocyclylalkyl group as defined herein, with the proviso that not both R 60 and R 61 are H simultaneously.
  • protected with respect to hydroxyl groups, amine groups, carboxy groups, and sulfhydryl groups refers to forms of these functionalities which are protected from undesirable reaction by means of protecting groups.
  • Protecting groups are known to those skilled in the art , and can be added or removed using well- known procedures such as those set forth in Protective Groups in Organic Synthesis, Greene, T.W.; Wuts, P. G. M., John Wiley & Sons, New York, NY, (3rd Edition, 1999).
  • Examples of protected hydroxyl groups include, but are not limited to, silyl ethers such as those obtained by reaction of a hydroxyl group with a reagent such as, but not limited to, t-butyldimethyl-chlorosilane, trimethylchlorosilane, triisopropylchlorosilane, triethylchlorosilane; substituted methyl and ethyl ethers such as, but not limited to methoxymethyl ether, methythiomethyl ether, benzyloxymethyl ether, t-butoxymethyl ether, 2-methoxyethoxymethyl ether, tetrahydropyranyl ethers, 1-ethoxyethyl ether, allyl ether, benzyl ether; esters such as, but not limited to, benzoylformate, formate, acetate, trichloroacetate, and trifluoracetate.
  • a reagent such as, but not limited to
  • N-Protecting groups comprise acyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl j .phthalyl, o-nitrophenoxyacetyl, archlorobutyryl, benzoyl,
  • N-protecting groups are formyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, phenylsulfonyl, benzyl, 9-fluorenylmethyloxycarbonyl (Fmoc), t-butyloxycarbonyl (Boc) and benzyloxycarbonyl (Cbz).
  • Examples of protected sulfhydryl groups include, but are not limited to, thioethers such as S-benzyl thioether, S-t-butylthioether, and S-4-picolyl thioether; substituted S-methyl derivatives such as hemithio, dithio and aminothio acetals; and others.
  • thioethers such as S-benzyl thioether, S-t-butylthioether, and S-4-picolyl thioether
  • substituted S-methyl derivatives such as hemithio, dithio and aminothio acetals
  • Representative carboxy protecting groups are C 1 to C 8 alkyl (e.g., methyl, ethyl or tertiary butyl and the like); haloalkyl; alkenyl; cycloalkyl and substituted derivatives thereof such as cyclohexyl, cyclopentyl and the like; cycloalkylalkyl and substituted derivatives thereof such as cyclohexylmethyl, cyclopentylmethyl and the like; arylalkyl, for example, phenethyl or benzyl and substituted derivatives thereof such as alkoxybenzyl or nitrobenzyl groups and the like; arylalkenyl, for example, phenylethenyl and the like; aryl and substituted derivatives thereof, for example, 5-indanyl and the like; dialkylaminoalkyl (e.g., dimethylaminoethyl and the like); alkanoyloxyalkyl groups such as
  • Tautomers refers to isomeric forms of a compound that are in equilibrium with each other. The concentrations of the isomeric forms will depend on the environment the compound is found in and may be different depending upon, for example, whether the compound is a solid or is in an organic or aqueous solution. For example, triazoles may exhibit the following isomeric forms, which are referred to as tautomers of each other:
  • Compounds of the invention can generally be prepared by methods known in the art.
  • Compounds of Formula I, wherein B and D are -NH- (Formula IA), and A is a substituted or unsubstituted C 1-3 alkyl group, -F, -Cl, -Br, -CN, or -NO 2 , are readily prepared as shown in Scheme 1.
  • a dihalo pyrimidine such as 2,4-dichloro-5-nitro- pyrimidine, or a trihalo pyrimidine, such as 2,4-dichloro-5-bromopyrimidine
  • alkylamines such as 2,4-dichloro-5-nitro- pyrimidine
  • trihalo pyrimidine such as 2,4-dichloro-5-bromopyrimidine
  • reaction is carried out in one pot with an excess of amine reagent, optionally in the presence of an excess of a base, such as but not limited to N,N-diisopropylethylamine, with or without heating, depending on the reactivity of the amine used.
  • a second amine derivative is introduced, by reaction with R 2 NH 2 , optionally in the presence of a base and at elevated temperature to generate a compound of Formula IA.
  • the -NO 2 derivative obtained as above is reduced by known methods, such as for example, hydrogenation or reduction by SnCl 2 .
  • Alkylbromides can be treated with triphenylphosphine to generate triphenylphosphonium salt derivatives (a), which can be converted into their ylides (b) by treatment with a base such as, for example, nBuLi or NaH in THF or DMF.
  • a base such as, for example, nBuLi or NaH in THF or DMF.
  • Intermediate (c) can be oxidized to generate compounds of Formula IB, or reduced to generate compounds of Formula IC.
  • the oxidation can be achieved by treatment with agents such as, for example, Bu 4 N/Oxone, MCPBA, peroxide, or the like.
  • Reduction can be achieved by treatment with Pd reagents in the presence of TES, typically in toluene/DME/EtOH and mixtures thereof.
  • IH, and IJ can also be synthesized.
  • a dihalo pyrimidine such as 2,4-dichloro-5-nitro- pyrimidine
  • anilines or alkylamines In the case of alkyl amines, the reaction is carried out at low temperature with about 1 equivalent of amine, and in the presence of a base, such as N,iV'-diisopropylethylamine.
  • reaction is carried out in one pot with about 2.2 equivalents of amine reagent, in the presence of an excess of a base, such as but not limited to ⁇ TV-diisopropylethylamine, with or without heating, depending on the reactivity of the amine used.
  • a base such as but not limited to ⁇ TV-diisopropylethylamine
  • a second amine derivative is introduced, by reaction with R 2 NH 2 , optionally in the presence of a base and at elevated temperature (compound a). Reduction of the nitro group by known methods (e.g.
  • nitrite such as n-butylnitrite, isoamyl nitrite, NaNO 2 /AcOH and the like.
  • the nitro group is first reduced by the methods described above, providing the precursor amine c for cyclization.
  • the cyclic compound d is obtained as described above, which can then be derivatized with R 2 NH 2 .
  • the 2-chloro-4-amino-5-nitropyrimidine is converted to the 2-thioalkyl or 2-thioaryl derivative e, the nitro group is reduced and the intermediate f obtained is cyclized to the azapurine g as before.
  • the reaction is conveniently carried out at about 8O 0 C under standard heating conditions, or at about 16O 0 C under microwave irradiation conditions.
  • the resulting compound is alkylated by treatment with R 9 X, wherein X is Cl, Br, I, OMs, OTos, or OTf, in a solvent, in the presence of a base.
  • Suitable bases include organic bases such as DIEA, TEA, DBU and the like, while inorganic bases include Cs 2 CO 3 , K 2 CO 3 , NaHCO 3 and the like.
  • Typical solvents are DMF, DCM, THF, dioxane and the like and mixtures thereof.
  • Form IIIB are synthesized as shown in Scheme 6.
  • the 2,4,5-triaminopyrirnidine derivative b, obtained as in Scheme 4, is cyclized by reaction with either acid halides or aldehydes.
  • suitable solvents include DMF
  • suitable bases include organic bases, such as DIEA, TEA, DBU, pyridine and the like.
  • the reaction is typically performed at elevated temperature, usually in the range of about 8O 0 C to about 200 0 C, more typically at about 150 0 C.
  • typical solvents include acetic acid, EtOH, MeOH, DMF, DME, THF, dioxane, and the like, and the reaction can be performed under microwave irradiation at a temperature in the range of about 80°C to about 150 0 C, more typically at about 12O 0 C.
  • 7- chloroisopurine compounds are obtained by treatment of the 4-chloro-2-sulfanyl- pyrimidine-5-carboxylic acid ethyl ester with phosphorous oxychloride or the like to yield compounds m. Oxidation of the thioether and displacement with R 8 NH 2 again provides the target compounds of Formula IIIC. rv
  • Dichloro-5-nitro- ⁇ yrimidine is treated with amino acids in the presence of a base such as DIEA at room temperature. Reaction with a second amine R 18 NH 2 at elevated temperature provides the fully functionalized precursor for cyclization. Reduction of the nitro group and subsequent intramolecular cyclization to compounds of Formula IV is accomplished by treatment with hydrogen gas in the presence of a catalyst, such as Pd or Raney Ni, or by treatment with a reducing agent, such as SnCl 2 , Zn/ AcOH or Fe, in a solvent such as methanol, ethanol, THF, dioxane or mixtures thereof.
  • a catalyst such as Pd or Raney Ni
  • a reducing agent such as SnCl 2 , Zn/ AcOH or Fe
  • GSK-3 modulators denotes compounds that alter the activity of GSK-3 as compared to a control or as compared to expected GSK-3 activity.
  • GSK-3 modulators include GSK-3 inhibitors.
  • GSK-3 inhibitors are compounds that directly or indirectly reduce the level of GSK-3 activity, by competitive or non-competitive enzyme inhibition; by decreasing protein levels, e.g. by a targeted genetic disruption, reducing transcription of the GSK-3 gene, or increasing protein instability, etc.
  • Effective amounts of the compounds of the invention generally include any amount sufficient to detectably inhibit GSK-3 activity by any of the assays described herein, or by other GSK-3 kinase activity assays known to those having ordinary skill in the art.
  • Treating within the context of the instant invention, means an alleviation, in whole or in part, of symptoms associated with a disorder or disease, or halt of further progression or worsening of those symptoms, or prevention or prophylaxis of the disease or disorder.
  • a "therapeutically effective amount" of a compound of the invention refers to an amount of the compound that alleviates, in whole or in part, symptoms associated with a disorder oi -disease, or-halts further- progression or worsening of those symptoms, orprevents-or - provides prophylaxis for the disease or disorder.
  • a therapeutically effective amount of a GSK-3 modulator administered to a subject may produce a reduction in glucose levels in diabetic patients (measured, e.g., as a 0.5% to 2% reduction in hemoglobin AIc, or a 30 mg - 80 mg decrease in fasting glucose levels from a baseline amount), a reduction in the formation of paired helical filaments in Alzheimer's disease, or a reduction in the symptoms of bipolar disorder and manic depression.
  • Treatment may also include administering the pharmaceutical formulations of the present invention in combination with other therapies.
  • the compounds of the invention can also be administered in conjunction with other therapeutic agents against CNS diseases or agents used for the treatment of metabolic disorders.
  • prodrugs Certain compounds within the scope of Formula I are derivatives referred to as prodrugs.
  • the expression "prodrug” denotes a derivative of a known direct acting drug, e.g. esters and amides, which derivative has enhanced delivery characteristics and therapeutic value as compared to the drug, and is transformed into the active drug by an enzymatic or chemical process; see Notari, R.E., "Theory and Practice of Prodrug Kinetics," Methods in Enzymology 112:309-323 (1985); Bodor, N., “Novel Approaches in Prodrug Design," Drugs of the Future (5:165-182 (1981); and Bundgaard, H., “Design of Prodrugs: Bioreversible-Derivatives for Various Functional Groups and Chemical Entities,” in Design of Prodrugs (H.
  • compositions are considered within the scope of the present invention.
  • pharmaceutically acceptable salts can be formed with inorganic acids (such as hydrochloric acid, hydroboric acid, nitric acid, sulfuric acid, and phosphoric acid), organic acids (e.g.
  • the compound of the invention can form salts with metals, such as alkali and earth alkali metals (e.g.
  • organic amines e.g. ammonia, trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine
  • basic amino acids e.g. arginine, lysine and ornithine
  • compositions which may be prepared by mixing one or more compounds of the invention, pharmaceutically acceptable salts thereof, stereoisomers thereof, tautomers thereof, or solvates thereof, with pharmaceutically acceptable carriers, excipients, binders, diluents or the like to treat or ameliorate a variety of biological conditions mediated by GSK-3.
  • the compositions of the invention may be used to create formulations and prevent or treat a variety of disorders mediated by GSK-3, such as CNS and metabolic diseases.
  • Such compositions can be in the form of, for example, granules, powders, tablets, capsules, syrup, suppositories, injections, emulsions, elixirs, suspensions or solutions.
  • compositions can be formulated for various routes of administration, for example, by oral administration, by nasal administration, by rectal administration, subcutaneous injection, intravenous injection, intramuscular injections, or intraperitoneal injection.
  • routes of administration for example, by oral administration, by nasal administration, by rectal administration, subcutaneous injection, intravenous injection, intramuscular injections, or intraperitoneal injection.
  • dosage forms are given by way of example and should not be construed as limiting the instant invention.
  • powders, suspensions, granules, tablets, pills, capsules, gelcaps, and caplets are acceptable as solid dosage forms. These can be prepared, for example, by mixing one or more compounds of the instant invention, or pharmaceutically acceptable salts or tautomers thereof, with at least one additive such as a starch or other additive.
  • Suitable additives are sucrose, lactose, cellulose sugar, mannitol, maltitol, dextran, starch, agar, alginates, chitins, chitosans, pectins, tragacanth gum, gum arabic, gelatins, collagens, casein, albumin, synthetic or semi-synthetic polymers or glycerides.
  • oral dosage forms can contain other ingredients to aid in administration, such as an inactive diluent, or lubricants such as magnesium stearate, or preservatives such as paraben or sorbic acid, or anti-oxidants such as ascorbic acid, tocopherol or cysteine, a disintegrating agent, binders, thickeners, buffers, sweeteners, flavoring agents or perfuming agents. Tablets and pills may be further treated with suitable coating materials known in the. art.
  • Liquid dosage forms for oral administration may be in the form of pharmaceutically acceptable emulsions, syrups, elixirs, suspensions, and solutions, which may contain an inactive diluent, such as water.
  • compositions and medicaments may be prepared as liquid suspensions or solutions using a sterile liquid, such as, but not limited to, an oil, water, an alcohol, and combinations of these.
  • a sterile liquid such as, but not limited to, an oil, water, an alcohol, and combinations of these.
  • Pharmaceutically suitable surfactants, suspending agents, emulsifying agents, may be added for oral or parenteral administration.
  • suspensions may include oils.
  • oils include, but are not limited to, peanut oil, sesame oil, cottonseed oil, corn oil and olive oil.
  • Suspension preparation may also contain esters of fatty acids such as ethyl oleate, isopropyl myristate, fatty acid glycerides and acetylated fatty acid glycerides.
  • Suspension formulations may include alcohols, such as, but not limited to, ethanol, isopropyl alcohol, hexadecyl alcohol, glycerol and propylene glycol.
  • Ethers such as but not limited to, poly(ethyleneglycol), petroleum hydrocarbons such as mineral oil and petrolatum; and water may also be used in suspension formulations.
  • the pharmaceutical formulations and medicaments may be a spray or aerosol containing an appropriate solvent(s) and optionally other compounds such as, but not limited to, stabilizers, antimicrobial agents, antioxidants, pH modifiers, surfactants, bioavailability modifiers and combinations of these.
  • a propellant for an aerosol formulation may include compressed air, nitrogen, carbon dioxide, or a hydrocarbon based low boiling solvent.
  • Injectable dosage forms generally include aqueous suspensions or oil suspensions which may be prepared using a suitable dispersant or wetting agent and a suspending agent. Injectable forms may be in solution phase or in the form of a suspension, which is prepared with a solvent or diluent. Acceptable solvents or vehicles include sterilized water, Ringer's solution, or an isotonic aqueous saline solution. Alternatively, sterile oils may be employed as solvents or suspending agents. Typically, the oil or fatty acid is non-volatile, including natural or synthetic oils, fatty acids, mono-, di- or tri-glycerides.
  • the pharmaceutical, formulation and/or medicament also be a powder suitable for reconstitution with an appropriate solution as described above.
  • these include, but are not limited to, freeze dried, rotary dried or spray dried powders, amorphous powders, granules, precipitates, or particulates.
  • the formulations may optionally contain stabilizers, pH modifiers, surfactants, bioavailability modifiers and combinations of these.
  • the pharmaceutical formulations and medicaments may be in the form of a suppository, an ointment, an enema, a tablet or a cream for release of compound in the intestines, sigmoid flexure and/or rectum.
  • Rectal suppositories are prepared by mixing one or more compounds of the instant invention, or pharmaceutically acceptable salts or tautomers of the compound, with acceptable vehicles, for example, cocoa butter or polyethylene glycol, which is present in a solid phase at normal storing temperatures, and present in a liquid phase at those temperatures suitable to release a drug inside the body, such as in the rectum.
  • Oils may also be employed in the preparation of formulations of the soft gelatin type and suppositories.
  • Water, saline, aqueous dextrose and related sugar solutions, and glycerols may be employed in the preparation of suspension formulations which may also contain suspending agents such as pectins, carbomers, methyl cellulose, hydroxypropyl cellulose or carboxymethyl cellulose, as well as buffers and preservatives.
  • excipients and carriers are generally known to those skilled in the art and are thus included in the instant invention. Such excipients and carriers are described, for example, in "Remingtons Pharmaceutical Sciences” Mack Pub. Co., New Jersey (1991), which is incorporated herein by reference.
  • the formulations of the invention may be designed to be short-acting, fast-releasing, long-acting, and sustained-releasing as described below.
  • the pharmaceutical formulations may also be formulated for controlled release or for slow release.
  • compositions may also comprise, for example, micelles or liposomes, or some other encapsulated form, or may be administered in an extended
  • the pharmaceutical formulations and medicaments may be compressed into pellets or cylinders and implanted intramuscularly or subcutaneously as depot injections or as implants such as stents.
  • Such implants may employ known inert materials such as silicones and biodegradable polymers.
  • Specific dosages may be adjusted depending on conditions of disease, the age, body weight, general health conditions, sex, and diet of the subject, dose intervals, administration routes, excretion rate, and combinations of drugs. Any of the above dosage forms containing effective amounts are well within the bounds of routine experimentation and therefore, well within the scope of the instant invention.
  • a therapeutically effective amount of a compound of the present invention may vary depending upon the route of administration and dosage form.
  • the typical compound or compounds of the instant invention is a formulation that exhibits a high therapeutic index.
  • the therapeutic index is the dose ratio between toxic and therapeutic effects which can be expressed as the ratio between LD 50 and ED 50 .
  • the LD 50 is the dose lethal to 50% of the population and the ED 50 is the dose therapeutically effective in 50% of the population.
  • the LD 50 and ED 50 are determined by standard pharmaceutical procedures in animal cell cultures or experimental animals.
  • a range includes each individual member.
  • a group having 1-3 atoms refers to groups having 1, 2, or 3 atoms.
  • a group having 1-5 atoms refers to groups having 1, 2, 3, 4, oi 5 atoms, and so forth.
  • step 2 was carried out using 1 equivalent of amine in the presence of 2-3 equivalents of DIEA.
  • Carboxylic acid derivatives were prepared by hydrolysis of their corresponding esters using aqueous 6N HCl/dioxane (1/1) at HO 0 C.
  • Step 1 A solution of 3 in THF was stirred at room temperature with a catalytic amount of Raney Ni under hydrogen atmosphere for 18 hours. The catalyst was removed by filtration. The filtrate was concentrated under vacuum to give intermediate 8e which was used immediately in the next step without further purification.
  • Step 2 ⁇ -Butyl nitrite (1.1 eq.) was added to a solution of 8e (1.0 eq.) in acetic acid at room temperature. The mixture was stirred at room temperature for 1 hour. The solvent was removed under vacuum. The residue was suspended in water. The product was collected by filtration, and washed with water (3 x). In some cases, this reaction was carried out with co-solvent such as THF and dioxane.
  • co-solvent such as THF and dioxane.
  • Step 2 To a solution of 2 (1.0 eq.) in dioxane at room temperature were added dropwise a 15% solution of sodium thiomethoxide (1.25 eq.) and sodium hydroxide (1.25 eq., 2 N aqueous solution) in water. The mixture was stirred for 4.5 hours and diluted with cold water. The precipitate was collected via -filtration j washed-with water and dried to -give 11.
  • Step 2 To a suspension of 11 (1.0 eq.) in concentrated HCl (aq.) at room temperature was added tin(II) dichloride dehydrate (6.4 eq.). The mixture was stirred at room temperature for 18 hours. The solid was collected via filtration, washed with water, and dried to give the HCl salt of 12.
  • Step 3 To a solution of 12 (1.0 eq.) in acetic acid at 1O 0 C was added dropwise n-butyl nitrite(1.3 eq.). The mixture was stirred for 3 hours and allowed to warm to room temperature. The solvent was removed under reduced pressure. The residue was dried under high vacuum to give 13.
  • Step 4 To a solution of 13 (1.0 eq.) in DCM at room temperature was added m-chloroperbenzoate (77%, 2.1 eq.). The mixture was stirred at room temperature for 1 hour. The reaction was quenched with 0.5 M potassium carbonate (aq.). The organic layer was separated. The aqueous layer was extracted with DCM. The combined organic layers were concentrated under vacuum to give 14.
  • Step 5 To a solution of 14 (1.0 eq.) in dioxane was added corresponding amine (R 8 -NH 2 , 4.0 eq.). The mixture was stirred at 9O 0 C for 1 hour and cooled to room temperature, and diluted with methanol. The precipitate was collected via filtration, washed with methanol and dried to give 10.
  • Step 1 To a solution of tin dichloride dihydrate (6 eq.) in concentrated HCl (aq.) at O 0 C was added 2 (1.0 eq.). The suspension was stirred for 1 hour. The solid was collected via filtration, washed with cold water and 1 N HCl (aq.) and dried to give the HCl salt of the target intermediate.
  • Step 2 To a solution of the intermediate obtained above (1.0 eq.) in acetic acid at room temperature was added n-butyl nitrite (1.3 eq.). The mixture was stirred for 30 min. The solvent was removed under reduced pressure. The residue was dried under high vacuum to give the cyclized products.
  • Step 3 " To " a b solution ⁇ of the azapurine chloride (1.0 eq.) in dioxane was added corresponding amine (R 8 -NH 2 , 5.0 eq.). The mixture was stirred at 90 0 C for 2 hour and cooled to room temperature, and diluted with methanol. The precipitate was collected via filtration, washed with methanol and dried to give 10.
  • Method C Stepl: A solution of 12 (1.0 eq., free base) in DMF was stirred at at 5O 0 C for 2h. The solvent was removed under reduced pressure. The residue was purified on a silica gel column to give the cyclized product.
  • Step 2 To a solution of the intermediate obtained above (1.0 eq.) in
  • Step 3 To a solution of compound obtained in step 2 (1.0 eq.) in dioxane was added the corresponding amine (R 8 -NH 2 , 5.0 eq.). The mixture was stirred at 13O 0 C for 2 days and cooled to room temperature, and diluted with water. The precipitate was collected via filtration, washed with IM aq. HCl, water or methanol, and dried to give the target purines, such as for example, 4-[2-(9-Phenyl- 9U- ⁇ u ⁇ n-2 ' -y ⁇ smmoy ⁇ hy ⁇ y ⁇ e ⁇ or(Cal ⁇ MW: 331 ⁇ Obs. " MW: 332)
  • Example 5 Synthesis of isopurine derivatives.
  • Step 1 To a solution of 17 (1.0 eq.) in ethanol at room temperature was added dropwise a mono-substituted hydrazine (2.0 eq.). The mixture was stirred at room temperature for 18 hours. Precipitate formed during the reaction. The mixture was poured into 5% aqueous HCl and stirred for 1 hour. The solid was collected via filtration, washed with water and dried to give 18.
  • Step 2 To a solution of 18 (1.0 eq.) in DMF at room temperature were added cesium carbonate (5.0 eq.) and an alkyl halide (5.0 eq.). The mixture was stirred at room temperature for 18 hours. Cesium carbonate was removed via filtration the filtrate was concentrated under vacuum. The residue was purified on a silica gel column to give ⁇ 9_ and 20.
  • Step 3 To a solution of 19 (1.0 eq.) in DCM at room temperature was added 3-chloroperbenzoate (3.0 eq.). The mixture was stirred at room temperature for 1 hour, washed with aqueous sodium bicarbonate and dried over anhydrous sodium sulfate. The sodium sulfate was removed via filtration. The filtrate was concentrated under vacuum to give 21, which was used in the next step without further purification.
  • Step 4 To a solution of 21 (1.0 eq.) in dioxane/TFA (100/1) was added the amine (10 eq.). The mixture was stirred at 12O 0 C for 18 hours. The solver* was removed under vacuum. The residue was purified on a silica gel column to give 22. [00179] Compound 22c was prepared by hydrolysis of 22b using the following procedure. A solution of ester (1.0 eq.) in dioxane/1 N NaOH (aq.)(2/l) was stirred at HO 0 C for 1.5 hours. The mixture was cooled to room temperature and neutralized with 1 N HCl. The precipitate was collected via filtration, washed with water and dried to give the corresponding acid.
  • Step 1 A solution of 18 in phosphorus oxychloride was stirred at
  • Step 2 To a solution of 23 (1.0 eq.) in DCM at room temperature wa; added 3-chloro ⁇ erbenzoate (3.0 eq.). The mixture was stirred at room temperature fc 1.5 hours, washed with 2 M aqueous potassium carbonate and dried over anhydrous sodium sulfate. The sodium sulfate was removed via filtration. The filtrate was concentrated under vacuum to give 24, which was used in the next step without further purification.
  • Step 3 To a solution of 24 (1.0 eq.) in dioxane was added an amine (5 eq.). The mixture was stirred at 12O 0 C for 18 hours. The solvent was removed under vacuum. The residue was suspended in water. The solid was collected via filtration, washed with water and methanol and dried to give 25.
  • Compound 25d was prepared by hydrolysis of 25c using a similar procedure as illustrated above.
  • Stepl To a solution of 18 or 20 (1.0 eq.) in DCM at room temperatui was added-3-chloroperbenzoate (3.0-eq ⁇ ).- The mixture was- stirred at room -— temperature for 1.5 hours, washed with 2 M aqueous potassium carbonate and dried over anhydrous sodium sulfate. The sodium sulfate was removed via filtration. The filtrate was concentrated under vacuum to give 26, which was used in the next step without further purification.
  • Step 2 To a solution of 26 (1.0 eq.) in dioxane was added the amine
  • Compounds 27e and 27f were prepared by hydrolysis of 27c and 27d, respectively, using aqueous 6N HCl/dioxane (1/1) at 110 0 C.
  • Step 1 To a solution of 1 (1.0 eq.) in dioxane at room temperature were added the appropriate alpha-amino ethyl ester (1.0 eq.) and DIEA (1.2 eq.). The mixture was stirred at room temperature for 24 hours. The solvent was removed under vacuum. The residue was purified on a silica gel column to give 28.
  • Step 2 To a solution of 28 (1.0 eq.) were added an appropriate amine
  • Step 3 A solution of the compound obtained in the previous step in methanol was stirred with catalytic amount of Raney Ni under hydrogen atmosphere for 18 hours. The catalyst was removed by filtration. The filtrate was concentrated under vacuum.
  • Step 1 To a solution of 9 (1.0 eq.) in dioxane was added N 1 N'- disuccinimidyl carbonate (1.5 eq.). The mixture was stirred at 16O 0 C for 10 min. using microwave heating, cooled to room temperature and concentrated under vacuum. The residue was purified using preparative RP-HPLC to give 30.
  • Step 2 To a solution of 30 (1.0 eq.) in DMF at room temperature was added-cesium- carbonate (3.0 -eq-.-)-. The mixture was-stirred at 90 ? C for-l-5-min. and- cooled to room temperature. The alkyl halide (2.0 eq.) was added. The mixture was stirred at 5O 0 C for 18 hours. The solvent was removed under vacuum. The residue was purified on a silica gel column to give 31.
  • GSK-3 phosphorylates the synthetic peptide substrate, and then in the secondary reaction a site-specific protease recognizes and cleaves non-phosphorylated peptides.
  • the phosphorylated (uncleaved) substrate allows fluorescence resonance energy transfer between the coumarin and fluorescein fluorophores on the peptide, while the FRET is disrupted with non-phosphorylated (cleaved) substrate.
  • a GSK-3 inhibitor blocks the phosphorylation of the substrate by GSK-3 and hence the subsequent FRET signal.
  • IPaq 4-[2-(3-Adamantan-l -yl-3H- [l,2,3]triazolo[4,5-d]pyrimidin-5- ylamino)-ethyl] -phenol

Abstract

Dans divers aspects, l'invention concerne de nouveaux composés qui modulent l'activité de GSK-3 ; des procédés de préparation de ces composés ; et des compositions comprenant ces composés. Les composés selon l'invention sont utiles en tant que modulateurs de GSK-3 et dans le traitement des maladies du système nerveux central, telles que la maladie d'Alzheimer et les troubles de l'humeur et les maladies métaboliques, telles que les états nécessitant de l'insuline.
PCT/US2006/006447 2005-02-24 2006-02-23 Modulateurs de l'activite de gsk-3 WO2006091737A1 (fr)

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
US65626505P 2005-02-24 2005-02-24
US60/656,265 2005-02-24
US69151905P 2005-06-17 2005-06-17
US60/691,519 2005-06-17
US72536905P 2005-10-11 2005-10-11
US60/725,369 2005-10-11

Publications (1)

Publication Number Publication Date
WO2006091737A1 true WO2006091737A1 (fr) 2006-08-31

Family

ID=36927759

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2006/006447 WO2006091737A1 (fr) 2005-02-24 2006-02-23 Modulateurs de l'activite de gsk-3

Country Status (1)

Country Link
WO (1) WO2006091737A1 (fr)

Cited By (71)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007035873A1 (fr) * 2005-09-21 2007-03-29 Pharmacopeia, Inc. Dérivés de purinone pour le traitement de maladies neurodégénératives
WO2007126128A1 (fr) 2006-04-27 2007-11-08 Banyu Pharmaceutical Co., Ltd. Dérivé de dihydropyrazolopyrimidinones
WO2007140222A2 (fr) * 2006-05-26 2007-12-06 Novartis Ag Composés de pyrrolopyrimidine et leurs utilisations
WO2008051826A2 (fr) * 2006-10-20 2008-05-02 N.V. Organon Purines en tant qu'inhibiteurs de pkc-theta
EP1953163A1 (fr) * 2007-02-01 2008-08-06 Boehringer Ingelheim Pharma GmbH & Co. KG Dérivés de Pteridinone comme inhibiteurs des Kinases PI3
WO2009024824A1 (fr) * 2007-08-23 2009-02-26 Astrazeneca Ab Composés chimiques 1-994
WO2009032194A1 (fr) 2007-08-31 2009-03-12 Whitehead Institute For Biomedical Research Stimulation de la voie wnt dans la reprogrammation de cellules somatiques
WO2009054332A1 (fr) 2007-10-23 2009-04-30 Banyu Pharmaceutical Co., Ltd. Dérivé de dihydropyrazolopyrimidinone substitué par pyridone
EP2090577A3 (fr) * 2006-10-19 2009-08-26 Signal Pharmaceuticals LLC Composés héteroaryliques, compositions les contenant et leur utilisation en tant qu'inhibiteurs des protein kinases
WO2011018518A1 (fr) 2009-08-14 2011-02-17 Boehringer Ingelheim International Gmbh Préparation régiosélective de dérivés de 2-amino-5trifluorométhylpyrimidine
WO2011018517A1 (fr) 2009-08-14 2011-02-17 Boehringer Ingelheim International Gmbh Préparation régiosélective de dérivés de 2-amino-5-trifluorométhylpyrimidine
US7902187B2 (en) 2006-10-04 2011-03-08 Wyeth Llc 6-substituted 2-(benzimidazolyl)purine and purinone derivatives for immunosuppression
US7915268B2 (en) 2006-10-04 2011-03-29 Wyeth Llc 8-substituted 2-(benzimidazolyl)purine derivatives for immunosuppression
US7919490B2 (en) 2006-10-04 2011-04-05 Wyeth Llc 6-substituted 2-(benzimidazolyl)purine and purinone derivatives for immunosuppression
US7989459B2 (en) 2006-02-17 2011-08-02 Pharmacopeia, Llc Purinones and 1H-imidazopyridinones as PKC-theta inhibitors
CN102186856A (zh) * 2008-08-22 2011-09-14 诺瓦提斯公司 作为cdk抑制剂的吡咯并嘧啶化合物
US20110281821A9 (en) * 2007-01-30 2011-11-17 Biogen Idec Ma Inc. Modulators of Mitotic Kinases
US8110578B2 (en) 2008-10-27 2012-02-07 Signal Pharmaceuticals, Llc Pyrazino[2,3-b]pyrazine mTOR kinase inhibitors for oncology indications and diseases associated with the mTOR/PI3K/Akt pathway
WO2012059932A1 (fr) 2010-11-01 2012-05-10 Aurigene Discovery Technologies Limited Dérivés de 2,4-diaminopyrimidine en tant qu'inhibiteurs de protéine kinases
WO2013110309A1 (fr) * 2012-01-28 2013-08-01 Merck Patent Gmbh Dérivés de triazolo[4,5-d]pyrimidine
US8569494B2 (en) 2009-10-26 2013-10-29 Signal Pharmaceuticals, Llc Methods of synthesis and purification of heteroaryl compounds
US8642598B2 (en) 2006-10-21 2014-02-04 Abbvie Inc. Heterocyclic compounds and their use as glycogen synthase kinase 3 inhibitors
WO2014127816A1 (fr) * 2013-02-21 2014-08-28 Boehringer Ingelheim International Gmbh Dihydroptéridinones ii
WO2014130693A1 (fr) * 2013-02-25 2014-08-28 Pharmacyclics, Inc. Inhibiteurs de la tyrosine kinase de bruton
WO2014127815A1 (fr) * 2013-02-21 2014-08-28 Boehringer Ingelheim International Gmbh Dihydroptéridinones i
WO2014135244A1 (fr) * 2013-03-05 2014-09-12 Merck Patent Gmbh Dérivés de triazolo[4,5-d]pyrimidine pour le traitement de maladies telles que le cancer
US8865716B2 (en) 2012-02-23 2014-10-21 Boehringer Ingelheim International Gmbh Dihydropteridinones II
US8957074B2 (en) 2010-02-19 2015-02-17 Novartis Ag Pyrrolopyrimidine compounds as inhibitors of CDK4/6
WO2015038417A1 (fr) * 2013-09-10 2015-03-19 Asana Biosciences, Llc Composés permettant de réguler les voies fak et/ou src
US9006226B2 (en) 2012-02-23 2015-04-14 Boehringer Ingelheim International Gmbh Dihydropteridinones I
US20150126508A1 (en) * 2012-05-14 2015-05-07 East China University Of Science And Technology Pteridine ketone derivative and applications thereof as egfr, blk, and flt3 inhibitor
US9139534B2 (en) 2011-04-22 2015-09-22 Signal Pharmaceuticals, Llc Substituted diaminocarboxamide and diaminocarbonitrile pyrimidines, compositions thereof, and methods of treatment therewith
US9155736B2 (en) 2012-10-18 2015-10-13 Signal Pharmaceuticals, Llc Inhibition of phosphorylation of PRAS40, GSK3-beta or P70S6K1 as a marker for TOR kinase inhibitory activity
CN105111215A (zh) * 2014-12-12 2015-12-02 苏州晶云药物科技有限公司 一种周期蛋白依赖性激酶抑制剂的晶型及其制备方法
CN105399743A (zh) * 2010-11-10 2016-03-16 诺华有限公司 7-环戊基-2-(5-哌嗪-1-基-吡啶-2-基氨基)-7h-吡咯并[2,3-d]嘧啶-6-羧酸二甲酰胺的盐及其制备方法
US9346812B2 (en) 2013-01-16 2016-05-24 Signal Pharmaceuticals, Llc Substituted pyrrolopyrimidine compounds, compositions thereof, and methods of treatment therewith
US9359364B2 (en) 2013-04-17 2016-06-07 Signal Pharmaceuticals, Llc Pharmaceutical formulations, processes, solid forms and methods of use relating to 1-ethyl-7-(2-methyl-6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b] pyrazin-2(1H)-one
US9358232B2 (en) 2013-04-17 2016-06-07 Signal Pharmaceuticals, Llc Methods for treating cancer using TOR kinase inhibitor combination therapy
US9365524B2 (en) 2014-01-30 2016-06-14 Signal Pharmaceuticals, Llc Solid forms of 2-(tert-butylamino)-4-((1R,3R,4R)-3-hydroxy-4-methylcyclohexylamino)-pyrimidine-5-carboxamide, compositions thereof and methods of their use
US9375443B2 (en) 2012-02-24 2016-06-28 Signal Pharmaceuticals, Llc Method for treating advanced non-small cell lung cancer (NSCLC) by administering a combination of a TOR kinase inhibitor and azacitidine or erlotinib
US9403829B2 (en) 2011-12-02 2016-08-02 Signal Pharmaceuticals, Llc Pharmaceutical compositions of 7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-((trans)-4-methoxycyclohexyl)-3,4-dihydropyrazino [2,3-b]pyrazin-2(1H)-one, a solid form thereof and methods of their use
US9416134B2 (en) 2014-04-16 2016-08-16 Signal Pharmaceuticals, Llc Solid forms of 1-ethyl-7-(2-methyl-6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one, as TOR kinase inhibitors
US9434735B2 (en) 2014-07-14 2016-09-06 Signal Pharmaceuticals, Llc Amorphous form of 4-((4-(cyclopentyloxy)-5-(2-methylbenzo[d]oxazol-6-yl)-7h-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-3-methoxy-n-methylbenzamide, compositions thereof and methods of their use
US9474757B2 (en) 2013-04-17 2016-10-25 Signal Pharmaceuticals, Llc Methods for treating cancer using TOR kinase inhibitor combination therapy
US9493466B2 (en) 2011-10-19 2016-11-15 Signal Pharmaceuticals, Llc Treatment of cancer with TOR kinase inhibitors
US9505764B2 (en) 2013-04-17 2016-11-29 Signal Pharmaceuticals, Llc Treatment of cancer with dihydropyrazino-pyrazines
US9512129B2 (en) 2014-04-16 2016-12-06 Signal Pharmaceuticals, Llc Solid forms comprising 1-ethyl-7-(2-methyl-6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one and a coformer
US9513297B2 (en) 2014-12-16 2016-12-06 Signal Pharmaceuticals, Llc Methods for measurement of inhibition of c-Jun N-terminal kinase in skin
US9540370B2 (en) 2010-12-30 2017-01-10 Abbvie Deutschland Gmbh & Co., Kg. Heterocyclic compounds and their use as glycogen synthase kinase-3 inhibitors
US9604939B2 (en) 2013-05-29 2017-03-28 Signal Pharmaceuticals, Llc Pharmaceutical compositions of 7-(6-(2-hydroxypropan-2-YL)pyridin-3-YL)-1-((trans)-4-methoxycyclohexyl)-3,4-dihydropyrazino [2,3-B]pyrazin-2(1H)-one, a solid form thereof and methods of their use
US9623028B2 (en) 2014-07-14 2017-04-18 Signal Pharmaceuticals, Llc Methods of treating a cancer using substituted pyrrolopyrimidine compounds, compositions thereof
US9630966B2 (en) 2013-04-17 2017-04-25 Signal Pharmaceuticals, Llc Treatment of cancer with dihydropyrazino-pyrazines
US9718824B2 (en) 2014-04-16 2017-08-01 Signal Pharmaceuticals, Llc Solid forms comprising 7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-((trans)-4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one, and a coformer, compositions and methods of use thereof
US9737535B2 (en) 2014-04-16 2017-08-22 Signal Pharmaceuticals, Llc Methods for treating cancer using TOR kinase inhibitor combination therapy comprising administering substituted pyrazino[2,3-b]pyrazines
US9782427B2 (en) 2013-04-17 2017-10-10 Signal Pharmaceuticals, Llc Methods for treating cancer using TOR kinase inhibitor combination therapy
US9796685B2 (en) 2014-12-16 2017-10-24 Signal Pharmaceuticals, Llc Formulations of 2-(tert-butylamino)-4-((1R,3R,4R)-3-hydroxy-4-Methylcyclohexylamino)-pyrimidine-5-carboxamide
US9937169B2 (en) 2013-04-17 2018-04-10 Signal Pharmaceuticals, Llc Methods for treating cancer using dihydropyrazino-pyrazine compound combination therapy
US10100048B2 (en) 2010-09-27 2018-10-16 AbbVie Deutschland GmbH & Co. KG Heterocyclic compounds and their use as glycogen synthase kinase-3 inhibitors
US10252981B2 (en) 2015-07-24 2019-04-09 Celgene Corporation Methods of synthesis of (1R,2R,5R)-5-amino-2-methylcyclohexanol hydrochloride and intermediates useful therein
WO2019212256A1 (fr) * 2018-05-02 2019-11-07 제이더블유중외제약 주식회사 Nouveau dérivé hétérocyclique
WO2020027225A1 (fr) 2018-07-31 2020-02-06 ファイメクス株式会社 Composé hétérocyclique
KR20200029949A (ko) * 2018-09-11 2020-03-19 재단법인 대구경북첨단의료산업진흥재단 신규 트리아졸로-피리미딘 유도체, 이의 제조방법 및 이를 유효성분으로 함유하는 단백질 키나아제 관련 질환의 예방 또는 치료용 약학적 조성물
US10689351B2 (en) 2015-01-29 2020-06-23 Signal Pharmaceuticals, Llc Isotopologues of 2-(tert butylamino)-4-((1R,3R,4R)-3-hydroxy-4-methylcyclohexylamino)-pyrimidine-5-carboxamide
WO2020163812A1 (fr) 2019-02-08 2020-08-13 Frequency Therapeutics, Inc. Composés d'acide valproïque et agonistes wnt pour le traitement de troubles de l'oreille
EP3736268A1 (fr) * 2013-12-20 2020-11-11 Signal Pharmaceuticals, LLC Procédé pour la préparation de composés substitués de diaminopyrimidyle
WO2021050688A1 (fr) * 2019-09-10 2021-03-18 X-Chem, Inc. Composés et leurs utilisations
JP2021516231A (ja) * 2018-02-28 2021-07-01 ザ リージェンツ オブ ザ ユニバーシティ オブ コロラド，ア ボディー コーポレイトＴＨＥ ＲＥＧＥＮＴＳ ＯＦ ＴＨＥ ＵＮＩＶＥＲＳＩＴＹ ＯＦ ＣＯＬＯＲＡＤＯ，ａ ｂｏｄｙ ｃｏｒｐｏｒａｔｅ Ｗｅｅ１キナーゼ阻害物質およびそれを使用してがんを処置する方法
WO2021136463A1 (fr) * 2019-12-31 2021-07-08 成都百裕制药股份有限公司 Dérivé purine et son utilisation médicale
US11096940B2 (en) 2017-06-22 2021-08-24 Celgene Corporation Treatment of hepatocellular carcinoma characterized by hepatitis B virus infection
US11529350B2 (en) 2019-07-03 2022-12-20 Sumitomo Pharma Oncology, Inc. Tyrosine kinase non-receptor 1 (TNK1) inhibitors and uses thereof
RU2792163C2 (ru) * 2018-05-02 2023-03-17 ДжейВ ФАРМАСЬЮТИКАЛ КОРПОРЕЙШН Новое гетероциклическое производное

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20020052386A1 (en) * 2000-02-17 2002-05-02 Armistead David M. Kinase inhibitors

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20020052386A1 (en) * 2000-02-17 2002-05-02 Armistead David M. Kinase inhibitors

Cited By (168)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007035873A1 (fr) * 2005-09-21 2007-03-29 Pharmacopeia, Inc. Dérivés de purinone pour le traitement de maladies neurodégénératives
US7989459B2 (en) 2006-02-17 2011-08-02 Pharmacopeia, Llc Purinones and 1H-imidazopyridinones as PKC-theta inhibitors
US20110189130A1 (en) * 2006-04-27 2011-08-04 Takeshi Sagara Dihydropyrazolopyrimidinone derivatives
WO2007126128A1 (fr) 2006-04-27 2007-11-08 Banyu Pharmaceutical Co., Ltd. Dérivé de dihydropyrazolopyrimidinones
WO2007126122A1 (fr) * 2006-04-27 2007-11-08 Banyu Pharmaceutical Co., Ltd. Dérivés de dihydropyrazolopyrimidinones
US7834019B2 (en) 2006-04-27 2010-11-16 Banyu Pharmaceutical Co., Ltd. Substituted pyrazolo[3,4-d]pyrimidinone derivatives
US8791125B2 (en) * 2006-04-27 2014-07-29 Msd K.K. Dihydropyrazolopyrimidinone derivatives
JP2010132689A (ja) * 2006-04-27 2010-06-17 Banyu Pharmaceut Co Ltd ジヒドロピラゾロピリミジノン誘導体
US7935708B2 (en) 2006-04-27 2011-05-03 Msd K.K. Dihydropyrazolopyrimidinone derivatives
EA016301B1 (ru) * 2006-05-26 2012-04-30 Новартис Аг Пирролопиримидины и их применение
WO2007140222A3 (fr) * 2006-05-26 2008-08-07 Novartis Ag Composés de pyrrolopyrimidine et leurs utilisations
US8324225B2 (en) 2006-05-26 2012-12-04 Novartis Ag Pyrrolopyrimidine compounds and their uses
WO2007140222A2 (fr) * 2006-05-26 2007-12-06 Novartis Ag Composés de pyrrolopyrimidine et leurs utilisations
US7902187B2 (en) 2006-10-04 2011-03-08 Wyeth Llc 6-substituted 2-(benzimidazolyl)purine and purinone derivatives for immunosuppression
US7919490B2 (en) 2006-10-04 2011-04-05 Wyeth Llc 6-substituted 2-(benzimidazolyl)purine and purinone derivatives for immunosuppression
US7915268B2 (en) 2006-10-04 2011-03-29 Wyeth Llc 8-substituted 2-(benzimidazolyl)purine derivatives for immunosuppression
EP2457913A3 (fr) * 2006-10-19 2012-08-15 Signal Pharmaceuticals LLC Composés d'hétéroaryle, compositions associées et procédés de traitement
EP2090577A3 (fr) * 2006-10-19 2009-08-26 Signal Pharmaceuticals LLC Composés héteroaryliques, compositions les contenant et leur utilisation en tant qu'inhibiteurs des protein kinases
US8372976B2 (en) 2006-10-19 2013-02-12 Signal Pharmaceuticals, Llc Methods of treatment comprising the administration of heteroaryl compounds
US7981893B2 (en) 2006-10-19 2011-07-19 Signal Pharmaceuticals, Llc Heteroaryl compounds, compositions thereof, and methods of treatment therewith
WO2008051826A2 (fr) * 2006-10-20 2008-05-02 N.V. Organon Purines en tant qu'inhibiteurs de pkc-theta
WO2008051826A3 (fr) * 2006-10-20 2008-10-02 Organon Nv Purines en tant qu'inhibiteurs de pkc-theta
US9856234B2 (en) 2006-10-21 2018-01-02 AbbVie Deutschland GmbH & Co. KG Heterocyclic compounds and their use as glycogen synthase kinase 3 inhibitors
US8642598B2 (en) 2006-10-21 2014-02-04 Abbvie Inc. Heterocyclic compounds and their use as glycogen synthase kinase 3 inhibitors
US20110281821A9 (en) * 2007-01-30 2011-11-17 Biogen Idec Ma Inc. Modulators of Mitotic Kinases
EP1953163A1 (fr) * 2007-02-01 2008-08-06 Boehringer Ingelheim Pharma GmbH & Co. KG Dérivés de Pteridinone comme inhibiteurs des Kinases PI3
WO2008092831A1 (fr) * 2007-02-01 2008-08-07 Boehringer Ingelheim International Gmbh Dérivés de ptéridinone servant d'inhibiteurs des pi3-kinases
US8410100B2 (en) 2007-02-01 2013-04-02 Boehringer Ingelheim International Gmbh Pteridinone derivatives as PI3-kinases inhibitors
WO2009024824A1 (fr) * 2007-08-23 2009-02-26 Astrazeneca Ab Composés chimiques 1-994
US9593311B2 (en) 2007-08-31 2017-03-14 Whitehead Institute For Biomedical Research Wnt pathway stimulation in reprogramming somatic cells with nuclear reprogramming factors
WO2009032194A1 (fr) 2007-08-31 2009-03-12 Whitehead Institute For Biomedical Research Stimulation de la voie wnt dans la reprogrammation de cellules somatiques
USRE49281E1 (en) 2007-08-31 2022-11-08 Whitehead Institute For Biomedical Research Wnt pathway stimulation in reprogramming somatic cells with nuclear reprogramming factors
US9102919B2 (en) 2007-08-31 2015-08-11 Whitehead Institute For Biomedical Research WNT pathway stimulation in reprogramming somatic cells with nuclear reprogramming factors
EP3078738A1 (fr) 2007-08-31 2016-10-12 Whitehead Institute for Biomedical Research Stimulation de la voie wnt dans la reprogrammation de cellules somatiques
US8329711B2 (en) 2007-10-23 2012-12-11 Msd K.K. Pyridone-substituted-dihydropyrazolopyrimidinone derivative
WO2009054332A1 (fr) 2007-10-23 2009-04-30 Banyu Pharmaceutical Co., Ltd. Dérivé de dihydropyrazolopyrimidinone substitué par pyridone
US9416136B2 (en) 2008-08-22 2016-08-16 Novartis Ag Pyrrolopyrimidine compounds and their uses
CN102186856B (zh) * 2008-08-22 2014-09-24 诺华股份有限公司 作为cdk抑制剂的吡咯并嘧啶化合物
US8415355B2 (en) 2008-08-22 2013-04-09 Novartis Ag Pyrrolopyrimidine compounds and their uses
US8962630B2 (en) 2008-08-22 2015-02-24 Novartis Ag Pyrrolopyrimidine compounds and their uses
CN102186856A (zh) * 2008-08-22 2011-09-14 诺瓦提斯公司 作为cdk抑制剂的吡咯并嘧啶化合物
US8685980B2 (en) 2008-08-22 2014-04-01 Novartis Ag Pyrrolopyrimidine compounds and their uses
US8492381B2 (en) 2008-10-27 2013-07-23 Signal Pharmaceuticals, Llc Pyrazino[2,3-b]pyrazine mTOR kinase inhibitor for oncology indications and diseases associated with the mTOR/PI3K/Akt pathway
US9771371B2 (en) 2008-10-27 2017-09-26 Signal Pharmaceuticals, Llc Substituted pyrazino[2,3-b]pyrazines as mTOR kinase inhibitors
US10167290B2 (en) 2008-10-27 2019-01-01 Signal Pharmaceuticals, Llc Substituted pyrazino[2,3-b]pyrazines as mTOR kinase inhibitors
US9193692B2 (en) 2008-10-27 2015-11-24 Signal Pharmaceuticals, Llc Halogen substituted pyrazines as intermediates of mTOR kinase inhibitors
US8507492B2 (en) 2008-10-27 2013-08-13 Signal Pharmaceuticals, Llc Pyrazino[2,3-b]pyrazine mTOR kinase inhibitor for oncology indications and diseases associated with the mTOR/PI3K/AKT pathway
US10683298B2 (en) 2008-10-27 2020-06-16 Signal Pharmaceuticals, Llc Substituted pyrazino[2,3-b]pyrazines as mTOR kinase inhibitors
US8110578B2 (en) 2008-10-27 2012-02-07 Signal Pharmaceuticals, Llc Pyrazino[2,3-b]pyrazine mTOR kinase inhibitors for oncology indications and diseases associated with the mTOR/PI3K/Akt pathway
US11292796B2 (en) 2008-10-27 2022-04-05 Signal Pharmaceuticals, Llc Substituted pyrazino[2,3-b]pyrazines as mTOR kinase inhibitors
US8907087B2 (en) 2008-10-27 2014-12-09 Signal Pharmaceuticals, Llc Substituted pyrazino[2,3-b]pyrazines as mTOR kinase inhibitors
WO2011018517A1 (fr) 2009-08-14 2011-02-17 Boehringer Ingelheim International Gmbh Préparation régiosélective de dérivés de 2-amino-5-trifluorométhylpyrimidine
WO2011018518A1 (fr) 2009-08-14 2011-02-17 Boehringer Ingelheim International Gmbh Préparation régiosélective de dérivés de 2-amino-5trifluorométhylpyrimidine
US9079900B2 (en) 2009-10-26 2015-07-14 Signal Pharmaceuticals, Llc Methods of synthesis and purification of heteroaryl compounds
US8686135B2 (en) 2009-10-26 2014-04-01 Signal Pharmaceuticals, Llc Methods of synthesis and purification of heteroaryl compounds
US8569494B2 (en) 2009-10-26 2013-10-29 Signal Pharmaceuticals, Llc Methods of synthesis and purification of heteroaryl compounds
US8957074B2 (en) 2010-02-19 2015-02-17 Novartis Ag Pyrrolopyrimidine compounds as inhibitors of CDK4/6
US9309252B2 (en) 2010-02-19 2016-04-12 Novartis Ag Pyrrolopyrimidine compounds as inhibitors of CDK4/6
US10100048B2 (en) 2010-09-27 2018-10-16 AbbVie Deutschland GmbH & Co. KG Heterocyclic compounds and their use as glycogen synthase kinase-3 inhibitors
WO2012059932A1 (fr) 2010-11-01 2012-05-10 Aurigene Discovery Technologies Limited Dérivés de 2,4-diaminopyrimidine en tant qu'inhibiteurs de protéine kinases
CN105399743A (zh) * 2010-11-10 2016-03-16 诺华有限公司 7-环戊基-2-(5-哌嗪-1-基-吡啶-2-基氨基)-7h-吡咯并[2,3-d]嘧啶-6-羧酸二甲酰胺的盐及其制备方法
US9540370B2 (en) 2010-12-30 2017-01-10 Abbvie Deutschland Gmbh & Co., Kg. Heterocyclic compounds and their use as glycogen synthase kinase-3 inhibitors
US10919865B2 (en) 2011-04-22 2021-02-16 Signal Pharmaceuticals, Llc Substituted diaminocarboxamide and diaminocarbonitrile pyrimidines, compositions thereof, and methods of treatment therewith
US11325890B2 (en) 2011-04-22 2022-05-10 Signal Pharmaceuticals, Llc Substituted diaminocarboxamide and diaminocarbonitrile pyrimidines, compositions thereof, and methods of treatment therewith
US10266500B2 (en) 2011-04-22 2019-04-23 Signal Pharmaceuticals, Llc Substituted diaminocarboxamide and diaminocarbonitrile pyrimidines, compositions thereof, and methods of treatment therewith
US9139534B2 (en) 2011-04-22 2015-09-22 Signal Pharmaceuticals, Llc Substituted diaminocarboxamide and diaminocarbonitrile pyrimidines, compositions thereof, and methods of treatment therewith
US9701643B2 (en) 2011-04-22 2017-07-11 Signal Pharmaceuticals, Llc Substituted diaminocarboxamide and diaminocarbonitrile pyrimidines, compositions thereof, and methods of treatment therewith
US10040770B2 (en) 2011-04-22 2018-08-07 Signal Pharmaceuticals, Llc Substituted diaminocarboxamide and diaminocarbonitrile pyrimidines, compositions thereof, and methods of treatment therewith
US9493466B2 (en) 2011-10-19 2016-11-15 Signal Pharmaceuticals, Llc Treatment of cancer with TOR kinase inhibitors
US11166950B2 (en) 2011-10-19 2021-11-09 Signal Pharmaceuticals, Llc Treatment of cancer with TOR kinase inhibitors
US9937170B2 (en) 2011-10-19 2018-04-10 Signal Pharmaceuticals, Llc Treatment of cancer with TOR kinase inhibitors
US9403829B2 (en) 2011-12-02 2016-08-02 Signal Pharmaceuticals, Llc Pharmaceutical compositions of 7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-((trans)-4-methoxycyclohexyl)-3,4-dihydropyrazino [2,3-b]pyrazin-2(1H)-one, a solid form thereof and methods of their use
CN104066734A (zh) * 2012-01-28 2014-09-24 默克专利股份公司 ***并[4,5-d]嘧啶衍生物
WO2013110309A1 (fr) * 2012-01-28 2013-08-01 Merck Patent Gmbh Dérivés de triazolo[4,5-d]pyrimidine
JP2015505541A (ja) * 2012-01-28 2015-02-23 メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフツングＭｅｒｃｋ Ｐａｔｅｎｔ Ｇｅｓｅｌｌｓｃｈａｆｔ ｍｉｔ ｂｅｓｃｈｒａｅｎｋｔｅｒ Ｈａｆｔｕｎｇ トリアゾロ［４，５−ｄ］ピリミジン誘導体
US9409914B2 (en) 2012-01-28 2016-08-09 Merck Patent Gmbh Triazolo[4,5-d]pyrimidine derivatives
US8865716B2 (en) 2012-02-23 2014-10-21 Boehringer Ingelheim International Gmbh Dihydropteridinones II
US9006226B2 (en) 2012-02-23 2015-04-14 Boehringer Ingelheim International Gmbh Dihydropteridinones I
US9375443B2 (en) 2012-02-24 2016-06-28 Signal Pharmaceuticals, Llc Method for treating advanced non-small cell lung cancer (NSCLC) by administering a combination of a TOR kinase inhibitor and azacitidine or erlotinib
DE112013002484B4 (de) 2012-05-14 2023-05-04 Shanghai Yidian Pharmaceutical Technology Development Co., Ltd. Pteridinketon-Derivat und Anwendungen desselben als EGFR-, BLK- und FLT3-Inhibitor
JP2015516445A (ja) * 2012-05-14 2015-06-11 イースト チャイナ ユニバーシティ オブ サイエンス アンド テクノロジー プテリジノン誘導体およびｅｇｆｒ、ｂｌｋ、ｆｌｔ３の阻害剤としての応用
CN106008511B (zh) * 2012-05-14 2018-08-14 华东理工大学 蝶啶酮衍生物及其作为egfr、blk、flt3抑制剂的应用
CN106008511A (zh) * 2012-05-14 2016-10-12 华东理工大学 蝶啶酮衍生物及其作为egfr、blk、flt3抑制剂的应用
US9670213B2 (en) * 2012-05-14 2017-06-06 East China University Of Science And Technology Pteridine ketone derivative and applications thereof as EGFR, BLK, and FLT3 inhibitor
US20150126508A1 (en) * 2012-05-14 2015-05-07 East China University Of Science And Technology Pteridine ketone derivative and applications thereof as egfr, blk, and flt3 inhibitor
US9557338B2 (en) 2012-10-18 2017-01-31 Signal Pharmaceuticals, Llc Inhibition of phosphorylation of PRAS40, GSK3-beta or P70S6K1 as a marker for tor kinase inhibitory activity
US9155736B2 (en) 2012-10-18 2015-10-13 Signal Pharmaceuticals, Llc Inhibition of phosphorylation of PRAS40, GSK3-beta or P70S6K1 as a marker for TOR kinase inhibitory activity
US9428509B2 (en) 2013-01-16 2016-08-30 Signal Pharmaceuticals, Llc Substituted pyrrolopyrimidine compounds, compositions thereof, and methods of treatment therewith
US9795607B2 (en) 2013-01-16 2017-10-24 Signal Pharmaceuticals, Llc Substituted pyrrolopyrimidine compounds, compositions thereof, and methods of treatment therewith
US9346812B2 (en) 2013-01-16 2016-05-24 Signal Pharmaceuticals, Llc Substituted pyrrolopyrimidine compounds, compositions thereof, and methods of treatment therewith
WO2014127815A1 (fr) * 2013-02-21 2014-08-28 Boehringer Ingelheim International Gmbh Dihydroptéridinones i
WO2014127816A1 (fr) * 2013-02-21 2014-08-28 Boehringer Ingelheim International Gmbh Dihydroptéridinones ii
JP2016509033A (ja) * 2013-02-21 2016-03-24 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング ジヒドロプテリジノンｉ
JP2016513116A (ja) * 2013-02-21 2016-05-12 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング ジヒドロプテリジノンｉｉ
US9708326B2 (en) 2013-02-25 2017-07-18 Pharmacyclics Llc Inhibitors of bruton's tyrosine kinase
WO2014130693A1 (fr) * 2013-02-25 2014-08-28 Pharmacyclics, Inc. Inhibiteurs de la tyrosine kinase de bruton
WO2014135244A1 (fr) * 2013-03-05 2014-09-12 Merck Patent Gmbh Dérivés de triazolo[4,5-d]pyrimidine pour le traitement de maladies telles que le cancer
JP2016510044A (ja) * 2013-03-05 2016-04-04 メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフツングＭｅｒｃｋ Ｐａｔｅｎｔ Ｇｅｓｅｌｌｓｃｈａｆｔ ｍｉｔ ｂｅｓｃｈｒａｅｎｋｔｅｒ Ｈａｆｔｕｎｇ 癌などの疾患の処置のためのトリアゾロ［４，５−ｄ］ピリミジン誘導体
CN105026398B (zh) * 2013-03-05 2018-05-18 默克专利股份公司 用于治疗疾病诸如癌症的***并[4,5-d]嘧啶衍生物
AU2014224975B2 (en) * 2013-03-05 2017-09-14 Merck Patent Gmbh Triazolo(4,5-d)pyrimidine derivatives for the treatment of diseases such as cancer
CN105026398A (zh) * 2013-03-05 2015-11-04 默克专利股份公司 用于治疗疾病诸如癌症的***并[4,5-d]嘧啶衍生物
US9855268B2 (en) 2013-03-05 2018-01-02 Merck Patent Gmbh Triazolo[4,5-d]pyrimidine derivatives
US9474757B2 (en) 2013-04-17 2016-10-25 Signal Pharmaceuticals, Llc Methods for treating cancer using TOR kinase inhibitor combination therapy
US10183019B2 (en) 2013-04-17 2019-01-22 Signal Pharmaceuticals, Llc Treatment of cancer with dihydropyrazino-pyrazines
US9359364B2 (en) 2013-04-17 2016-06-07 Signal Pharmaceuticals, Llc Pharmaceutical formulations, processes, solid forms and methods of use relating to 1-ethyl-7-(2-methyl-6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b] pyrazin-2(1H)-one
US10391092B2 (en) 2013-04-17 2019-08-27 Signal Pharmaceuticals, Llc Methods for treating cancer using dihydropyrazino-pyrazine compound combination therapy
US9827243B2 (en) 2013-04-17 2017-11-28 Signal Pharmaceuticals, Llc Pharmaceutical formulations, processes, solid forms and methods of use relating to 1-ethyl-7-(2-methyl-6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one
US9782427B2 (en) 2013-04-17 2017-10-10 Signal Pharmaceuticals, Llc Methods for treating cancer using TOR kinase inhibitor combination therapy
US9505764B2 (en) 2013-04-17 2016-11-29 Signal Pharmaceuticals, Llc Treatment of cancer with dihydropyrazino-pyrazines
US9358232B2 (en) 2013-04-17 2016-06-07 Signal Pharmaceuticals, Llc Methods for treating cancer using TOR kinase inhibitor combination therapy
US9937169B2 (en) 2013-04-17 2018-04-10 Signal Pharmaceuticals, Llc Methods for treating cancer using dihydropyrazino-pyrazine compound combination therapy
US9630966B2 (en) 2013-04-17 2017-04-25 Signal Pharmaceuticals, Llc Treatment of cancer with dihydropyrazino-pyrazines
US10052322B2 (en) 2013-04-17 2018-08-21 Signal Pharmaceuticals, Llc Pharmaceutical formulations, processes, solid forms and methods of use relating to 1-ethyl-7-(2-methyl-6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one
US9980963B2 (en) 2013-04-17 2018-05-29 Signal Pharmaceuticals, Llc Treatment of cancer with dihydropyrazino-pyrazines
US10052323B2 (en) 2013-05-29 2018-08-21 Signal Pharmaceuticals, Llc Pharmaceutical compositions of 7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-(trans)-4-methoxycyclohexyl)-3,4-dihydropyrazino [2,3-b]pyrazin-2(1H)-one, a solid form thereof and methods of their use
US9795603B2 (en) 2013-05-29 2017-10-24 Signal Pharmaceuticals, Llc Pharmaceutical compositions of 7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-((trans)-4-methoxycyclohexyl)-3,4-dihydropyrazino [2,3-B]pyrazin-2(1H)-one, a solid form thereof and methods of their use
US9604939B2 (en) 2013-05-29 2017-03-28 Signal Pharmaceuticals, Llc Pharmaceutical compositions of 7-(6-(2-hydroxypropan-2-YL)pyridin-3-YL)-1-((trans)-4-methoxycyclohexyl)-3,4-dihydropyrazino [2,3-B]pyrazin-2(1H)-one, a solid form thereof and methods of their use
US9974786B2 (en) 2013-05-29 2018-05-22 Signal Pharmaceuticals, Llc Pharmaceutical compositions of 7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-((trans)-4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3- B]pyrazin-2(1H)-one, a solid form there of and methods of their use
WO2015038417A1 (fr) * 2013-09-10 2015-03-19 Asana Biosciences, Llc Composés permettant de réguler les voies fak et/ou src
EP3736268A1 (fr) * 2013-12-20 2020-11-11 Signal Pharmaceuticals, LLC Procédé pour la préparation de composés substitués de diaminopyrimidyle
US9814713B2 (en) 2014-01-30 2017-11-14 Signal Pharmaceuticals, Llc Solid forms of 2-(tert-butylamino)-4-((1R,3R,4R)-3-hydroxy-4-methylcyclohexylamino)-pyrimidine-5-carboxamide, compositions thereof and methods of their use
US10226461B2 (en) 2014-01-30 2019-03-12 Signal Pharmaceuticals, Llc Solid forms of 2-(tert-butylamino)-4-((1R,3R,4R)-3-hydroxy-4-methylcyclohexylamino)-pyrimidine-5-carboxamide, compositions thereof and methods of their use
US11241430B2 (en) 2014-01-30 2022-02-08 Signal Pharmaceuticals, Llc Solid forms of 2-(tert-butylamino)-4-((1R,3R,4R)-3-hydroxy-4-methylcyclohexylamino)-pyrimidine-5-carboxamide, compositions thereof and methods of their use
US10517873B2 (en) 2014-01-30 2019-12-31 Signal Pharmaceuticals, Llc Solid forms of 2-(tert-butylamino)-4-((1R,3R,4R)-3-hydroxy-4-methylcyclohexylamino)-pyrimidine-5-carboxamide, compositions thereof and methods of their use
US9365524B2 (en) 2014-01-30 2016-06-14 Signal Pharmaceuticals, Llc Solid forms of 2-(tert-butylamino)-4-((1R,3R,4R)-3-hydroxy-4-methylcyclohexylamino)-pyrimidine-5-carboxamide, compositions thereof and methods of their use
US10004735B2 (en) 2014-04-16 2018-06-26 Signal Pharmaceuticals, Llc Methods for treating cancer using TOR kinase inhibitor combination therapy comprising administering substituted pyrazino[2,3-b]pyrazines
US9718824B2 (en) 2014-04-16 2017-08-01 Signal Pharmaceuticals, Llc Solid forms comprising 7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-((trans)-4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one, and a coformer, compositions and methods of use thereof
US9737535B2 (en) 2014-04-16 2017-08-22 Signal Pharmaceuticals, Llc Methods for treating cancer using TOR kinase inhibitor combination therapy comprising administering substituted pyrazino[2,3-b]pyrazines
US9981971B2 (en) 2014-04-16 2018-05-29 Signal Pharmaceuticals, Llc Solid forms of 1-ethyl-7-(2-methyl-6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one as TOR kinase inhibitors
US9416134B2 (en) 2014-04-16 2016-08-16 Signal Pharmaceuticals, Llc Solid forms of 1-ethyl-7-(2-methyl-6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one, as TOR kinase inhibitors
US9512129B2 (en) 2014-04-16 2016-12-06 Signal Pharmaceuticals, Llc Solid forms comprising 1-ethyl-7-(2-methyl-6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one and a coformer
US9975898B2 (en) 2014-04-16 2018-05-22 Signal Pharmaceuticals, Llc Solid forms of 1-ethyl-7-(2-methyl-6-(1H-1,2,4-triazol-3-yl)pyridin-3-YL)-3,4-dihydropyrazino [2,3-b]pyrazin-2(1H)-one as tor kinase inhibitors
US9623028B2 (en) 2014-07-14 2017-04-18 Signal Pharmaceuticals, Llc Methods of treating a cancer using substituted pyrrolopyrimidine compounds, compositions thereof
US9434735B2 (en) 2014-07-14 2016-09-06 Signal Pharmaceuticals, Llc Amorphous form of 4-((4-(cyclopentyloxy)-5-(2-methylbenzo[d]oxazol-6-yl)-7h-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-3-methoxy-n-methylbenzamide, compositions thereof and methods of their use
CN105111215A (zh) * 2014-12-12 2015-12-02 苏州晶云药物科技有限公司 一种周期蛋白依赖性激酶抑制剂的晶型及其制备方法
US10590089B2 (en) 2014-12-16 2020-03-17 Signal Pharmaceuticals, Llc Formulations of 2-(tert-butylamino)-4-((1R,3R,4R)-3-hydroxy-4-methylcyclohexylamino)-pyrimidine-5-carboxamide
US10197579B2 (en) 2014-12-16 2019-02-05 Signal Pharmaceuticals, Llc Methods for measurement of inhibition of c-Jun N-terminal kinase in skin
US10131639B2 (en) 2014-12-16 2018-11-20 Signal Pharmaceuticals, Llc Formulations of 2-(tert-butylamino)-4-((1R,3R,4R)-3-hydroxy-4methylcyclohexylamino)-pyrimidine-5-carboxamide
US9513297B2 (en) 2014-12-16 2016-12-06 Signal Pharmaceuticals, Llc Methods for measurement of inhibition of c-Jun N-terminal kinase in skin
US9796685B2 (en) 2014-12-16 2017-10-24 Signal Pharmaceuticals, Llc Formulations of 2-(tert-butylamino)-4-((1R,3R,4R)-3-hydroxy-4-Methylcyclohexylamino)-pyrimidine-5-carboxamide
US10689351B2 (en) 2015-01-29 2020-06-23 Signal Pharmaceuticals, Llc Isotopologues of 2-(tert butylamino)-4-((1R,3R,4R)-3-hydroxy-4-methylcyclohexylamino)-pyrimidine-5-carboxamide
US11492332B2 (en) 2015-01-29 2022-11-08 Signal Pharmaceuticals, Llc Isotopologues of 2-(tert-butylamino)-4-((1R,3R,4R)-3-hydroxy-4-methylcyclohexylamino)-pyrimidine-5-carboxamide
US10975039B2 (en) 2015-01-29 2021-04-13 Signal Pharmaceuticals, Llc Isotopologues of 2-(tert-butylamino)-4-((1R,3R,4R)-3-hydroxy-4-methylcyclohexylamino)-pyrimidine-5-carboxamide
US10774033B2 (en) 2015-07-24 2020-09-15 Celgene Corporation Methods of synthesis of (1R, 2R, 5R)-5-amino-2-methylcyclohexanol hydrochloride and intermediates useful therein
US10252981B2 (en) 2015-07-24 2019-04-09 Celgene Corporation Methods of synthesis of (1R,2R,5R)-5-amino-2-methylcyclohexanol hydrochloride and intermediates useful therein
US11780801B2 (en) 2015-07-24 2023-10-10 Celgene Corporation Methods of synthesis of (1R,2R,5R)-5-amino-2-methyl-cyclohexanol hydrochloride and intermediates useful therein
US11192847B2 (en) 2015-07-24 2021-12-07 Celgene Corporation Methods of synthesis of (1R,2R,5R)-5-amino-2-methylcyclohexanol hydrochloride and intermediates useful therein
US11096940B2 (en) 2017-06-22 2021-08-24 Celgene Corporation Treatment of hepatocellular carcinoma characterized by hepatitis B virus infection
JP2021516231A (ja) * 2018-02-28 2021-07-01 ザ リージェンツ オブ ザ ユニバーシティ オブ コロラド，ア ボディー コーポレイトＴＨＥ ＲＥＧＥＮＴＳ ＯＦ ＴＨＥ ＵＮＩＶＥＲＳＩＴＹ ＯＦ ＣＯＬＯＲＡＤＯ，ａ ｂｏｄｙ ｃｏｒｐｏｒａｔｅ Ｗｅｅ１キナーゼ阻害物質およびそれを使用してがんを処置する方法
JP2021522353A (ja) * 2018-05-02 2021-08-30 ジェイダブリュ ファーマシューティカル コーポレーションＪｗ Ｐｈａｒｍａｃｅｕｔｉｃａｌ Ｃｏｒｐｏｒａｔｉｏｎ 新規なヘテロサイクル誘導体
JP7322140B6 (ja) 2018-05-02 2024-02-21 ジェイダブリュ ファーマシューティカル コーポレーション 新規なヘテロサイクル誘導体
CN112313232B (zh) * 2018-05-02 2024-03-08 Jw中外制药公司 新型杂环衍生物
CN112313232A (zh) * 2018-05-02 2021-02-02 Jw中外制药公司 新型杂环衍生物
JP7322140B2 (ja) 2018-05-02 2023-08-07 ジェイダブリュ ファーマシューティカル コーポレーション 新規なヘテロサイクル誘導体
AU2022204211B2 (en) * 2018-05-02 2023-07-20 Jw Pharmaceutical Corporation Novel heterocycle derivative
KR102653799B1 (ko) * 2018-05-02 2024-04-03 제이더블유중외제약 주식회사 신규한 헤테로 사이클 유도체
WO2019212256A1 (fr) * 2018-05-02 2019-11-07 제이더블유중외제약 주식회사 Nouveau dérivé hétérocyclique
KR20200139171A (ko) * 2018-05-02 2020-12-11 제이더블유중외제약 주식회사 신규한 헤테로 사이클 유도체
RU2792163C2 (ru) * 2018-05-02 2023-03-17 ДжейВ ФАРМАСЬЮТИКАЛ КОРПОРЕЙШН Новое гетероциклическое производное
US11639354B2 (en) 2018-07-31 2023-05-02 Fimecs, Inc. Heterocyclic compound
WO2020027225A1 (fr) 2018-07-31 2020-02-06 ファイメクス株式会社 Composé hétérocyclique
KR20200029949A (ko) * 2018-09-11 2020-03-19 재단법인 대구경북첨단의료산업진흥재단 신규 트리아졸로-피리미딘 유도체, 이의 제조방법 및 이를 유효성분으로 함유하는 단백질 키나아제 관련 질환의 예방 또는 치료용 약학적 조성물
KR102328423B1 (ko) 2018-09-11 2021-11-18 재단법인 대구경북첨단의료산업진흥재단 신규 트리아졸로-피리미딘 유도체, 이의 제조방법 및 이를 유효성분으로 함유하는 단백질 키나아제 관련 질환의 예방 또는 치료용 약학적 조성물
WO2020163812A1 (fr) 2019-02-08 2020-08-13 Frequency Therapeutics, Inc. Composés d'acide valproïque et agonistes wnt pour le traitement de troubles de l'oreille
US11529350B2 (en) 2019-07-03 2022-12-20 Sumitomo Pharma Oncology, Inc. Tyrosine kinase non-receptor 1 (TNK1) inhibitors and uses thereof
WO2021050688A1 (fr) * 2019-09-10 2021-03-18 X-Chem, Inc. Composés et leurs utilisations
JP7428806B2 (ja) 2019-12-31 2024-02-06 成都百裕制薬股▲ふん▼有限公司 プリン誘導体および医薬におけるその使用
WO2021136463A1 (fr) * 2019-12-31 2021-07-08 成都百裕制药股份有限公司 Dérivé purine et son utilisation médicale

Similar Documents

Publication Publication Date Title
WO2006091737A1 (fr) Modulateurs de l'activite de gsk-3
EP1641805B1 (fr) Composes a base de thiazolo-, oxazalo et imidazolo-quinazoline capables d'inhibition de proteine-kinases
EP2516405B1 (fr) Dérivés de 4-phénylamino-pyrimidine ayant une activité d'inhibition d'une protéine kinase
JP4426660B2 (ja) ピラゾール誘導体、その製法および医薬としてのその使用
US6001839A (en) Substituted 4-amino-7H-pyrrolo [2,3,-d]-pyrimidines as PTK inhibitors
KR100736012B1 (ko) 벤즈아졸 유도체 및 이의 ｊｎｋ 조절자로의 용도
EP1343782B1 (fr) Composes chimiques
US7157580B2 (en) Aminopyrimidine and aminopyridine anti-inflammation agents
US7816350B2 (en) Substituted [1,2,3] triazolo[4,5-D]pyrimidines as cdk inhibitors
JP2504879B2 (ja) アゾ―ル誘導体
US6153630A (en) Phenylpyridyl compounds for inhibiting phosphodiesterase IV and methods of using same
SK18612001A3 (sk) Deriváty 5-kyano-2-aminopyridínu a farmaceutický prostriedok obsahujúci tieto deriváty
JP2006518381A (ja) プロテインキナーゼのインヒビターとして有用なヘテロアリール置換ピロール
WO2006031806A2 (fr) 2-thiopyrimidinones utilises en tant qu'agents therapeutiques
WO2005007099A2 (fr) Inhibiteurs de la pkb utilises comme agents antitumoraux
AU2005227997A1 (en) Pyrimidine derivatives and methods of treatment related to the use thereof
KR20090040908A (ko) 벤조트리아졸 키나아제 조절제
AU2008229147A1 (en) Chemical compounds
KR20090121399A (ko) 화합물
EP2154967A1 (fr) Dérivés de pyrimidine
KR20110002465A (ko) 세포 보호 작용을 갖는 피리미딘 유도체 및 그 용도
EA024295B1 (ru) N-[4-(1H-ПИРАЗОЛО[3,4-b]ПИРАЗИН-6-ИЛ)ФЕНИЛ]СУЛЬФОНАМИДЫ И ИХ ПРИМЕНЕНИЕ В КАЧЕСТВЕ ЛЕКАРСТВЕННЫХ СРЕДСТВ
CN101506176A (zh) 2-苯胺基-4-氨基亚烷基氨基嘧啶
JP2010526045A (ja) Ｃｄｃ２５ホスファターゼインヒビターとしてのトリアミノピリミジン誘導体
KR20100035711A (ko) 포스파타제 ｃｄｃ25 억제제로서 사용되는 트리아미노피리미딘 시클로부텐디온 유도체

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application
NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 06735918

Country of ref document: EP

Kind code of ref document: A1