WO2006091737A1

WO2006091737A1 - Modulators of gsk-3 activity

Info

Publication number: WO2006091737A1
Application number: PCT/US2006/006447
Authority: WO
Inventors: Lubomir Sebo; Jeffrey Kahl; Christopher Lum; Yazhong Pei; Kent E. Pryor; Jan Urban; Bryan Jones; Robert Sullivan
Original assignee: Kemia, Inc.
Priority date: 2005-02-24
Filing date: 2006-02-23
Publication date: 2006-08-31

Abstract

In various aspects, the present invention relates to novel compounds, which modulate GSK-3 activity; to processes for the preparation of such compounds; and to compositions including such compounds. Compounds of the invention are useful as GSK-3 modulators and in the treatment of CNS diseases, such as Alzheimer's disease and mood disorders, and metabolic diseases, such as insulin requiring states.

Description

MODULATORS OF GSK-3 ACTIVITY

FIELD OF THE INVENTION

[0001] The present invention relates to low molecular weight compounds and compositions thereof, useful as modulators of GSK-3 activity. In particular, 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.

BACKGROUND OF THE INVENTION

[0002] Glycogen synthase kinase-3 (GSK-3) is a proline-directed, serine/threonine kinase, for which two isoforms, GSK-3 α and GSK-3 β, 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- 3α and GSK-3β are highly expressed in the body [Woodgett, et al., EMBO, 9, 2431- 2438 (1990); Loy, et al., J. Peptide Res., 54, 85-91 (1999)]. In addition to GS, a number of other GSK-3 substrates have been identified, including metabolic, signaling, and structural proteins. Among the signaling proteins regulated by GSK-3 are 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; β-catenin; c-Jun; c-Myc; c-Myb; and NFKB [C. A. Grimes, et al., Prog. NeurobioL, 65, 391-426 (2001), H. Eldar-Finkelman, Trends in Molecular Medicine, 8, 126-132 (2002); P. Cohen, et al., Nature, 2, 1-8, (2001)].

[0003] 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. Sci., 695, 209-216 (1993); Mulot et al., FEBS Lett., 349, 359-364 (1994)]. Further evidence came from studies of cells overexpressing GSK-3 and from transgenic mice that specifically expressed GSK-3 in brain. In both cases GSK-3 led to generation of the PHF like epitope tau [Lucas et al., EMBO Journal, 20, 27-29 (2001)].

[0005] 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)]. The discovery has led to a series of studies that were undertaken to determine if lithium can mimic the loss of GSK-3 activity in cellular processes. Indeed, lithium was shown to cause activation of glycogen synthesis [Cheng et al., MoI. Chem. Biochem., 56, 183-189 (1983)], stabilization and accumulation of β- catenin [Stambolic et al., Curr. Biol. 6, 1664-1668 (1996)], induction of axis duplication in Xenopus embryo [Klein et al., Proc. Natl. Acad. Sci. USA, 93, 8455- 8459 (1996)], and protection from neuronal death [Bijur et al., J. Biol. Chem., 275, 7583-7590 (2000)]. Altogether, these studies indicated that GSK-3 is a major in vivo target of lithium and thus has important implications in novel therapeutic treatment of affective disorders.

[0006] Recently, 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)].

[0007] Because of the foregoing, targeting the activity of 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. Cell Biol., 11, 233 (1999)]; diabetes and its related conditions, for example, Syndrome X and obesity [S. E. Nikoulina, et al., Diabetes, 51, 2190-2198 (2002); Orena, et al., J. Biol. Chem., 15765-15772 (2000); Summers, et al., J. Biol. Chem., 274, 17934-17940 (1999)]; hair loss [S. E. Millar, et al., Dev. Biol., 207, 133-149 (1999); E. Fuchs, et al., Dev. Cell, 1, 13-25 (2001)]; inflammation [P. Cohen, Eur. J. Biochem., 268, 5001-5010 (2001)]; mood disorders, such as depression [A. Adnan, et al., Chem. Rev., 101, 2527-2540 (2001); R. S. B. Williams, et al., Trends Phamacol. Sci., 21, 61-64 (2000)]; neuronal cell death and stroke [D. A. E. Cross, et al., J. Neurochem., 77, 94-102 (2001); C. Sasaki, et al., Neurol. Res., 23, 588-592 (2001)]; bipolar disorder [Klein, et al., PNAS, 93, 8455-8459 (1996)]; skeletal muscle atrophy [G. J. Brunn, et al., Science, 277, 99- 101 (1997); R. E. Rhoads, J. Biol. Chem., 274, 30337-30340 (1999); V. R. Dharmesh, et al., Am. J. Physiol. Cell Physiol. 283, C545-551 (2002); K. Baar, et al., A. J. Physiol., 276, C120-C127 (1999)]; decreased sperm motility [Vijayaraghavan, et al., Biol. Reproduction, 54, 709-718 (1996)]; and in cardio-protection (C. Badorff, et al., J. Clin. Invest, 109, 373-381 (2002); S. Haq, et al., J. Cell Biol., 151, 117-129 (2000); H. Tong, et al., Circulation Res., 90, 377-379 (2002)].

[0008] In addition, GSK-3 β 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. These include, in a non-limiting manner, 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.

SUMMARY OF THE INVENTION

[0009] The present invention provides low molecular weight compounds useful as GSK-3 modulators, and compositions thereof. In one aspect, 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.

[0010] Thus, in one aspect there are provided compounds having Formula I:

Formula I, wherein

A is a substituted or unsubstituted C_1-3 alkyl group, -F, -Cl, -Br, -CN, -NO₂, or -NH₂;

B and D are independently -NH-, -CH₂-, or -C(O)-;

R¹ is a substituted or unsubstituted cycloalkyl or cycloalkenyl group;

R² is CHR^2aR^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 R¹ and R² 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 R¹ or R² is a cyclohexyl group, the cyclohexyl group is not substituted with -(CH₂)_nCOR^x, wherein n is 0 or 1 and R^x is OH, OR^y or NR^ZR^Z, wherein R^y is a C_1-5 alkyl or phenyl group, optionally halogenated, and each R^z is independently H, or a Ci_-5 alkyl or aryl group, optionally halogenated.

[0011] In some embodiments of compounds of Formula I, the compound at a concentration of 10 μM inhibits glycogen synthase kinase-3α, glycogen synthase kinase-3β or both.

[0012] In some embodiments of compounds of Formula I, R¹ is a substituted or unsubstituted cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclohexenyl group. In other embodiments, R² is a substituted or unsubstituted pyrrolidinyl, pyrroliiiyl, imidazolinyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl, tetrahydropyranyl, piperazinyl, morpholinyl, thiomorpholinyl, or piperidin-3-yl group.

[0013] In some embodiments of compounds of Formula I, R¹ is a substituted or unsubstituted, bridged cycloalkyl group. In some such embodiments of compounds of Formula I, R¹ 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, R² is substituted or unsubstituted pyrrolidinyl, pyrrolinyl, imidazolinyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl, tetrahydropyranyl, piperidinyl, morpholinyl, thiomorpholinyl, or piperazinyl group.

[0014] In yet other embodiments of compounds of Formula I, R¹ is a substituted or unsubstituted bridged Cg_-12 cycloalkyl group. In some such embodiments, R¹ 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, R² is a substituted or unsubstituted pyrrolidinyl, pyrrolinyl, imidazolinyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl, tetrahydropyranyl, piperidinyl, morpholinyl, thiomorpholinyl, or piperazinyl group.

[0015]- - —In some -embodiments of compQunds_^of Formula I, R¹ is a substitutec or unsubstituted adamantyl or noradamantyl group. For example, R¹ can be a substituted or unsubstituted adamantan-1-yl or adamantan-2-yl group. In some other embodiments, R¹ is substituted with -OH, -0(Ci_-3 alkyl), -NH₂, halogen, or a C_1-3 alkyl group, optionally partially or fully halogenated. In still other embodiments, R¹ is substituted with -OH. For example, R¹ may be adamantan-1-yl substituted at the 2- and/or 3-position.

[0016] In further embodiments of compounds of Formula I, A is a substituted or unsubstituted C_1-3 alkyl group, -Br, or -NO₂. For example, A is -CF₃.

[0017] Contemplated are all of the following compounds of Formula I:

[0018] In some embodiments of compounds of Formula I, B is -NH-. In other embodiments, D is -NH-. In yet other embodiments, B and D are -NH-.

[0019] In some embodiments of compounds of Formula I, R² is a cycloalkyl or cycloalkenyl group, for example, R² 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. In other embodiments, R² is a substituted or unsubstituted cyclohexyl, cyclohexenyl, adamantyl or tetrahydropyranyl group. In some embodiments, R² is substituted with -OH, -0(Ci_-3 alkyl), -NH₂, halogen, or a C_1-3 alkyl group, optionally partially or fully halogenated. For example, R² can be substituted with -OH.

[0020] In some embodiments of compounds of Formula I, R¹ is a substituted or unsubstituted adamantyl or cyclohexyl group, and R² is a substituted or unsubstituted cyclohexyl, cyclohexenyl, adamantyl or tetf ahydropyf aήyl group: [0021] Where features or aspects of the invention are described in terms of

Markush groups or other grouping of alternatives, those skilled in the art will recognize that the invention is also thereby described in terms of any individual member or subgroup of members of the Markush group or other group. By way of illustration and not limitation, Table 1 sets forth various combinations of substituents of Formula I as described herein. Thus, e.g., combination 1580 describes those embodiments in which R¹ is adamantyl and R² is cyclohexyl.

[0022] Table 2 sets forth various combinations of substituents A and B of

Formula I. Thus, e.g., combination 2004 describes those embodiments in which A is -F and B is -NH-. Further, those skilled in the art will understand that 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 R¹ and R², may be combined with any combination from Table 2, describing A and B. For example, combination 1580 from Table 1 and combination 2004 from Table 2 describe those embodiments of Formula I in which R¹ is adamantyl, R² is cyclohexyl, A is -F, and B is -NH-. Each R¹, R² and A group in the tables is understood to be optionally substituted as described herein. Moreover, each value of D (-NH-, -CH₂-, -C(O)-) may be combined with any combination from Table 1 or Table 2 or any pair of combinations from the two tables. Thus, e.g., it will be understood that combination 1582 describes those embodiments in which D is -C(O)-, R¹ is adamantyl and R² is cyclohexenyl, as well as those where D is -CH₂-, R¹ is adamantyl and R is cyclohexenyl, etc. In some embodiments, certain combinations of substituents are excluded, as described herein. For example, R¹ and R² are not simultaneously unsubstituted adamantyl, simultaneously unsubstituted cyclopropyl, simultaneously unsubstituted cyclobutyl or simultaneously unsubstituted cyclohexyl.

Table 1 - Exemplary Combinations of RWd R² for Formula I.

Table 1 (Continued).

Table 1 (Continued).

Table 2.

[0023] In another aspect of the invention, there are provided compounds having Formula II:

Formula II

wherein

R , 1 is a substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, aralkyl, or heterocyclylalkyl group;

R² is CHR^2aR^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 R¹ is unsubstituted phenyl, R² 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.

[0024] In certain embodiments of compounds of Formula II, the compound at a concentration of lOμM inhibits glycogen synthase kinase-3α, glycogen synthase kinase-3β or both.

[0025] In some embodiments of compounds of Formula II, R¹ is a substituted or unsubstituted alkyl group, such as a substituted or unsubstituted methyl, ethyl, or isopropyl group. In other embodiments, R¹ is a substituted or unsubstituted aryl, heterocyclyl, or a cycloalkyl group. In some such embodiments, R¹ is an unsubstituted phenyl, 1-naphthyl, 2-naphthyl, indanyl, indenyl, adamantyl, bicyclo[2.2.1]heptanyl, cyclopentyl or cyclohexyl group. In yet other embodiments, R¹ is substituted with one or more F, Cl, Br, I, -OR³, -C(O)R⁴, substituted or unsubstituted alkyl group, -NR⁵R⁶, -CN, or -C(O)OH, wherein R³ is H, or a substituted or unsubstituted alkyl group; R⁴ is a substituted or unsubstituted alkyl or aryl group; and R⁵ and R⁶, at each occurrence, are independently H, a substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, aralkyl, heterocyclyl, or heterocyclylalkyl group; or R⁵ and R⁶, together with the N to which they are attached, form a substituted or unsubstituted heterocyclyl group. For example R¹ 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. In yet other such embodiments, R¹ 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. For example, R¹ can be a substituted or unsubstituted phenyl, naphthyl, indanyl, adamantyl, bicyclo[2.2.1]heptanyl, cyclopentyl or cyclohexyl group.

[0026] In some embodiments of compounds of Formula II, R² 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. In some other embodiments, R² is substituted with one or more F, Cl, Br, I, a substituted or unsubstituted alkyl group, -OR³, -O(CH₂)_nC(O)OR, -O(CH₂)_nC(O)NR⁵R⁶, -(CH₂VNR⁵R⁶, -C(O)OR⁷, -(CH₂)_n-C(O)OR⁷, -C(O)C(O)OR⁷, -C(O)C(O)NR⁵R⁶, -CN, -C(O)R⁷, -C(O)NR⁵R⁶, -NR⁵R⁶, -NR⁵C(O)R⁷, -NR⁵C(O)OR⁷, -NR⁵C(O)NR⁵R⁶, -NR⁵SO₂R⁶, or -SO₂NR⁵R⁶, wherein R³ and R, at each occurrence, are independently H, or a substituted or unsubstituted alkyl group; R⁵ and R⁶, at each occurrence, are independently H, a substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, aralkyl, heterocyclyl, or heterocyclylalkyl group; or R⁵ and R⁶, together with the N to which they are attached, form a substituted or unsubstituted heterocyclyl group; R⁷, at each occurrence, is independently a substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, aralkyl, heterocyclyl, or heterocyclylalkyl group; and each n is independently 1-4. For example, R² 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; -OCH₂C(O)OR, -O(CH₂)₂C(O)OR, -OCH₂C(O)NR⁵R⁶, -O(CH₂)₂C(O)NR⁵R⁶; -C(O)NR⁵R⁶; -C(O)OH, -(CH₂)-C(O)OR⁷, -(CH₂)₂-C(O)OR⁷,-C(O)C(O)O(d_-6 alkyl), -C(O)C(O)NH₂, -CN; -C(O)R⁷, -NHC(O)R⁷, or C_3-10 alkyl, optionally substituted with one or more F or -OH. Alternatively, R² is a cyclohexyl group, substituted with -OH, or -NR⁵C(O)R⁷. In some such embodiments, 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. In some embodiments, wherein R² 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, dihydroisoindolonyl, isobenzofuranonyl, pyrrolidinyl, piperidinyl, morpholinyl, tetrahydropyranyl, benzyl, phenethyl, -(CH₂)-cyclopentyl, -(CH₂)₂-cyclopentyl, -(CH₂)-cyclohexyl, -(CH₂)₂- cyclohexyl, -(CH₂)-cycloheptyl, -(CH₂)₂-cycloheρtyl, -(CH₂)-morpholinyl, -(CH₂)₂- morpholinyl, -(CH₂)₃ -morpholinyl, -(CH₂)-tetrahydropyranyl, or -(CH₂)₂- tetrahydropyranyl group. In other embodiments, R² is a substituted or unsubstituted cyclohexyl, tetrahydropyranyl, benzyl, phenethyl, -(CH₂)-tetrahydropyranyl, isobenzofuranonyl, benzotriazolyl, dihydrobenzodioxinyl, phthalyl, indazolyl, piperidinyl, or dihydroisoindolonyl group. In yet other embodiments, R² is a substituted or unsubstituted N-ethyl-pyridine-2,6-diamine group.

[0027] In some embodiments of compounds of Formula II, R¹ is a substituted or unsubstituted phenyl or indanyl group, and R² is a substituted or unsubstituted cycloalkyl, bicyclic aryl, bicyclic heterocyclyl, 5-membered heterocyclyl, saturated 6- membered heterocyclyl, aralkyl, or heterocyclylalkyl group. In some such embodiments, R¹ is substituted with one or more F, Cl, Br, I, -OR³, -C(O)R⁴, substituted or unsubstituted alkyl group, -NR⁵R⁶, -CN, or -C(O)OH, wherein R³, R⁴, R⁵ and R⁶ are as defined above. For example, R¹ 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. In some other such embodiments R² is substituted with one or more F, Cl, Br, I, a substituted or unsubstituted alkyl group, -OR³, -O(CH₂)_nC(O)OR, -O(CH₂)_nC(O)NR⁵R⁶, -(CH₂)_n-NR⁵R⁶, -C(O)OR⁷, -(CH₂)_n-C(O)OR⁷, -C(O)C(O)OR⁷, -C(O)C(O)NR⁵R⁶, -CN, -C(O)R⁷, -C(O)NR⁵R⁶, -NR⁵R⁶, -NR⁵C(O)R⁷, -NR⁵C(O)OR⁷, -NR⁵C(O)NR⁵R⁶, -NR⁵SO₂R⁶, or -SO₂NR⁵R⁶, wherein R, R³, R⁵, R⁶, R⁷ and n are as defined herein. For example, R² 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; - -OCH₂C(O)OR, -O(CH₂)₂C(O)OR, -OCH₂C(O)NR⁵R⁶Γ-O(CH₂)₂C(O)NR⁵R⁶; ^" -C(O)NR⁵R⁶; -C(O)OH, -C(O)C(O)O(C_1-6 alkyl), -C(O)C(O)NH₂, -CN; -C(O)R⁷, -NHC(O)R⁷, or C_3-10 alkyl, optionally substituted with one or more F or OH. In yet other such embodiments, 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, -(CH₂)-cyclopentyl, -(CH₂)₂-cyclopentyl, -(CH₂)-cyclohexyl, -(CHa)₂- cyclohexyl, -(CH₂)-cycloheptyl, -(CH₂)₂-cycloheptyl, -(CH₂)-morpholinyl, -(CH₂)₂- morpholinyl, -(CH₂)₃-morpholinyl, -(CH₂)-tetrahydropyranyl, -(CH₂)₂- tetrahydropyranyl group or N-ethyl-pyridine-2,6-diamine group. For example, R² can be a substituted or unsubstituted cyclohexyl, tetrahydropyranyl, benzyl, phenethyl, -(CH₂)-tetrahydropyranyl, isobenzofuranonyl, benzotriazolyl, dihydrobenzodioxinyl, phthalyl, indazolyl, piperidinyl, or dihydroisoindolonyl group.

[0028] Similar to Table 1 above, Table 3 illustrates combinations of R¹ and R² contemplated for compounds having Formula II. In some embodiments of Formula II, R¹ is unsubstituted when R¹ is phenyl, 1 -naphthyl, 2-naphthyl, indanyl, indenyl, adamantyl, bicyclo[2.2.1]heptyl, cyclopentyl or cyclohexyl.

Table 3.

Table 3 (Continued).

Table 3 (Continued).

[0029] In another aspect of the invention, there are also provided compounds having Formula III:

Formula III

wherein

G is

R¹ is a substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, aralkyl, or heterocyclylalkyl group;

R⁸ is CHR^8aR^8b; or a substituted or unsubstituted aryl, cycloalkyl, heterocyclyl, aralkyl, or heterocyclylalkyl group;

R^8a, R^8b, R¹², R¹³ and R are at each occurrence each independently H, or a substituted or unsubstituted alkyl group;

R⁹ is H, an alkyl or C_3-5 cycloalkyl group, optionally substituted with one or more F, Cl, Br, I or -OR¹³;

R¹⁰ is 4-pyridyl, -C(O)OR, -(CH₂)_nC(O)OR, or aryl group, substituted with one or more -OR¹³;

R¹¹ is -OR¹³ or F, Cl, Br, I, provided that when R¹¹ is present, R¹ 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;

provided however, that 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.

[0030] In certain embodiments of compounds of Formula III, the compound at a concentration of lOμM inhibits glycogen synthase kinase-3α, glycogen synthase kinase-3β or both.

[0031] As indicated in Formula III, compounds of the invention include bicyclic heterocycles of the following structures:

Formula IIIA Formula UIB Formula IIIC Formula HID

[0032] In some embodiments of compounds of Formula III, G is

[0033] In some other embodiments of compounds of Formula III, R¹ is a substituted or unsubstituted aryl, heterocyclyl, or a cycloalkyl group. For example, R¹ can be an unsubstituted phenyl, 1-naphthyl, 2-naphthyl or cyclohexyl group. In some other embodiments of compounds of Formula III, R¹ is substituted with one or more F, Cl, Bf, I, -OR^lθ, -C(O)R¹⁴, substituted or unsubstituted alkyl group, -NR¹⁵R¹⁶, -CN._. or -C(O)OH, wherein R¹⁴ is a substituted or unsubstituted alkyl or aryl group; and R 15 and R¹⁶, at each occurrence, are independently H, a substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, aralkyl, heterocyclyl, or heterocyclylalkyl group; or R¹⁵ and R¹⁶, together with the N to which they are attached, form a substituted or unsubstituted heterocyclyl group. For example, R¹ can be substituted with F, Cl, Br, I; -OH; -0-C₁-_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. In yet other embodiments of compounds of Formula III, R¹ is a substituted or unsubstituted phenyl, naphthyl, indanyl, indenyl, pyridyl, thiophenyl, quinolyl, cyclopentyl, cyclohexyl, cycloheptyl, morpholinyl or tetrahydropyranyl group. For example, R¹ can be a substituted or unsubstituted phenyl, naphthyl, or cyclohexyl group.

[0034] In other embodiments of compounds of Formula III, R⁸ is a substituted or unsubstituted aryl, cycloalkyl, heterocyclyl, aralkyl, or heterocyclylalkyl group. In other embodiments, R⁸ is substituted with one or more F, Cl, Br, I, -OR¹³, -C(O)OH, -CN, -NR¹⁵R¹⁶, -C(O)NR¹⁵R¹⁶, -O(CH₂)_nC(O)OR, -O(CH₂)_nC(O)NR¹⁵R¹⁶, substituted or unsubstituted alkyl group, or -SO₂NR¹⁵R¹⁶, wherein R¹⁵ and R¹⁶, at each occurrence, are independently H, a substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, aralkyl, heterocyclyl, or heterocyclylalkyl group; or R¹⁵ and R¹⁶, together with the N to which they are attached, form a substituted or unsubstituted heterocyclyl group. For example, R⁸ 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)NR¹⁵R¹⁶; -OCH₂C(O)OR, -O(CH₂)₂C(O)OR, -OCH₂C(O)NR¹⁵R¹⁶, -O(CH₂)₂C(O)NR¹⁵R¹⁶; or C_3-10 alkyl, optionally substituted with one or more F or OH. In some embodiments, R⁸ is a substituted or unsubstituted phenyl, pyridyl, thiophenyl, quinolyl, cyclopentyl, cyclohexyl, cycloheptyl, morpholinyl, tetrahydropyranyl, benzyl, phenethyl, -(CH₂)-cyclopentyl, -(CH₂)₂-cylcopentyl, - (CH₂)-cyclohexyl, -(CH₂)₂-cyclohexyl, -(CH₂)-cylcoheρtyl, -(CH₂)₂-cycloheptyl, - (CH₂)-morpholinyl, -(CH₂)₂-morpholinyl, -(CH₂)-tetrahydropyranyl, or -(CH₂)₂- tetrahydropyranyl group. For example, R⁸ can be a substituted or unsubstituted phenyl, cyclohexyl, tetrahydropyranyl, benzyl, phenethyl, or -(CH₂)- tetrahydropyranyl group. [0035] Similar to Table 1 above, Table 4 illustrates combinations of R¹ and R for compounds having Formula III. It will be understood that each value of R⁹, R¹⁰, R¹¹, and R¹² maybe combined with any combination from Table 4. Thus, e.g., combination 4002 and R⁹ describes embodiments in which R⁹ is H, R¹ is alkyl, R⁸ is aryl, as well as those in which R⁹ is a C_3-5 cycloalkyl group, R¹ is alkyl, R⁸ is aryl, and so forth.

Table 4.

[0036] In yet another aspect of the invention, there are provided compounds of

Formula IV:

Formula IV

wherein

R¹⁷ is a substituted or unsubstituted C_3-I0 alkyl, alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, aralkyl, or heterocyclylalkyl group; R¹⁸ is CHR¹⁸³R^18b; or a substituted or unsubstituted aiyl, cycloalkyl, aralkyl, or heterocyclylalkyl group;

R^18a, R^18b, R^18c, and R^18d, 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.

[0037] In some embodiments of compounds of Formula IV, the compound at a concentration of lOμM inhibits glycogen synthase kinase-3α, glycogen synthase kinase-3β or both.

[0038] In some embodiments of compounds of Formula IV, R¹⁷ is a substituted or unsubstituted aryl, heterocyclyl, or a cycloalkyl group. In other embodiments, R¹⁷ is substituted with one or more F, Cl, Br, I, -OR¹⁹, -C(O)R²⁰, substituted or unsubstituted alkyl group, -NR²¹R²², -CN, or -C(O)OH, wherein R¹⁹ is H, or a substituted or unsubstituted alkyl group; R²⁰ is a substituted or unsubstituted alkyl or aryl group; and R²¹ and R²², at each occurrence, are independently H, a substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, aralkyl, heterocyclyl, or heterocyclylalkyl group; or R²¹ and R²², together with the N to which they are attached, form a substituted or unsubstituted heterocyclyl group. For example, R¹⁷ 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. In other embodiments, R¹⁷ is a substituted or unsubstituted phenyl, naphthyl, indenyl, pyridyl, thiophenyl, quinolyl, cyclopentyl, cyclohexyl, cycloheptyl, morpholinyl or tetrahydropyranyl group. For example, R¹⁷ can be a substituted or unsubstituted phenyl, naphthyl, or cyclohexyl group.

[0039] In some embodiments of compounds of Formula IV, R¹⁸ is a substituted or unsubstituted aryl, cycloalkyl, heterocyclyl, aralkyl, or heterocyclylalkyl group. In other embodiments, R¹⁸ is substituted with one or more F, Cl, Br, I, -OR¹⁹, -C(O)OH, -CN, -NR²¹R²², -C(O)NR²¹R²²,_, -θχCH₂)_nC(O)_OR, _._ -O(CH₂)_nC(O)NR²¹R²², substituted or unsubstituted alkyl group, or -SO₂NR²¹R²², wherein R¹⁹ and R, at each occurrence, are independently H, or a substituted or unsubstituted alkyl group; R²¹ and R²², at each occurrence, are independently H, a substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, aralkyl, heterocyclyl, or heterocyclylalkyl group; or R²¹ and R²², together with the N to which they are attached, form a substituted or unsubstituted heterocyclyl group; and each n is independently 1-4. For example, R¹⁸ 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)NR²¹R²²; -OCH₂C(O)OR₅ -O(CH₂)₂C(O)OR, -OCH₂C(O)NR²¹R²², -O(CH₂)₂C(O)NR²¹R²²; or C_1-10 alkyl, optionally substituted with one or more F or OH. In other embodiments of compounds of Formula IV, R¹⁸ is a substituted or unsubstituted phenyl, pyridyl, thiophenyl, quinolyl, cyclopentyl, cyclohexyl, cycloheptyl, morpholinyl, tetrahydropyranyl, benzyl, phenethyl, -(CH₂)-cyclopentyl, - (CH₂)₂-cyclopentyl, -(CH₂)-cyclohexyl, -(CH₂)₂-cyclohexyl, -(CH₂)-cycloheptyl, - (CH₂)₂-cylcoheptyl, -(CH₂)-morpholinyl, -(CH₂)₂~morpholinyl, -(CH₂)- tetrahydropyranyl, or -(CH₂)₂-tetrahydropyranyl group. For example, R¹⁸ can be a substituted or unsubstituted phenyl, cyclohexyl, tetrahydropyranyl, benzyl, phenethyl, or -(CH₂)-tetrahydropyranyl group.

[0040] Similar to Table 1 above, Table 5 illustrates combinations of R¹⁷ and

R¹⁸ 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.

Table 5.

[0041] In accordance with yet another aspect of the invention there are provided the following compounds, including representative examples of compounds of Formula I-IV:

N⁴-Cyclohexyl-5-nitro-N²-(tetrahydro-pyran-4-yl)-pyrimidine-2₅4-diamine;

N -Cyclohexyl-N -morpholin-4-yl-5-nitro-pyrimidine-2,4-diamine;

4-[2-(4-hydroxy-cyclohexylamino)-5-nitro-pyrimidin-4-ylamino]-cyclohexanol;

N⁴-Cyclohexyl-5-nitro-N²-piperidin-4-yl-pyrimidine-2,4-diamine;

N²,N⁴-Di-cyclohex-3-enyl-5-nitro-ρyrimidine-2,4-diamine;

4-[4-(Adamantan-l-ylamino)-5-nitro-pyrimidin-2-ylamino]-cyclohexanol;

4-[4-(l-Benzyl-piperidin-4-ylamino)-5-nitro-pyrimidin-2-ylamino]-cyclohexanol;

4-(4-Cyclopentylamino-5-nitro-pyrimidin-2-ylamino)-cyclohexanol;

3-[2-(4-Hydroxy-cyclohexylamino)-5-nitro-ρyrimidin-4-ylamino]-adamantan-l-ol;

3-[4-(4-Hydroxy-cyclohexylamino)-5-trifluoromethyl-pyrimidin-2-ylamino]- adamantan-1-ol;

3-[2-(4-Hydroxy-cyclohexylammo)-5-trifluoromethyl-pyrimidin-4-ylamino]- adamaϊitan-1-όl; 3-[2-(3-hydroxy-adamantan-l-ylamino)-5-nitro-pyriniidin-4-ylaniino]-adamantan-l- ol;

3-[5-Fluoro-2-(4-hydroxy-cyclohexylammo)-pyrimidin-4-ylamino]-adaniantan-l-ol;

3-[5-Bromo-2-(4-hydroxy-cyclohexylamino)-pyrimidin-4-ylamino]-adamantan-l-ol;

3-[5-Chloro-2-(4-hydroxy-cyclohexylamino)-pyrimidin-4-ylamino]-adamantan-l-ol;

4-[2-(4-Hydroxy-cyclohexylamino)-5-trifluoromethyl-pyriniidin-4-ylamino]- cyclohexanol;

4-(3-Phenyl-3H-[l,2,3]triazolo[4,5-d]pyrimidin-5-ylamino)-cyclohexanol;

(lH-Benzotriazol-5-yl)-(3-ρhenyl-3H-[l,2,3]triazolo[4,5-d]pyrimidin-5-yl)-amine;

(2-Moφholin-4-yl-ethyl)-(3-phenyl-3H-[l,2,3]triazolo[4,5-d]pyrimidin-5-yl)-amine;

(3-Morpholin-4-yl-propyl)-(3-phenyl-3H-[l,2,3]triazolo[4,5-d]pyrimidin-5-yl)-amine;

4-(3-Phenyl-3H-[l,2,3]triazolo[4,5-d]pyrimidin-5-ylamino)-butan-l-ol;

(R)-4-Phenyl-3-(3-phenyl-3H-[ 1 ,2,3]triazolo[4,5-d]pyrimidin~5-ylaniino)-butyric acid tert-butyl ester;

4-[3-(4-Fluoro-phenyl)-3H-[l,2,3]triazolo[4,5-d]pyrimidin-5-ylamino]-cyclohexanol;

4-{2-[3-(4-Fluoro-ρhenyl)-3H-[l,2,3]triazolo[4,5-d]ρyrimidin-5-ylamino]-ethyl}- phenol;

(2,3-Dihydro-benzo[l,4]dioxin-6-yl)-(3-ρhenyl-3H-[l_;2,3]triazolo[4,5-d]ρyrimidin-5- yl)-amine;

Benzo[l,3]dioxol-5-yl-(3-phenyl-3H-[l,2,3]triazolo[4,5-d]pyrimidin-5-yl)-amine;

N-[4-(3-Phenyl-3H-[l,2₃3]triazolo[4,5-d]pyrimidin-5-ylamino)-cyclohexyl]- acetamide;

Furan-2-carboxylic acid [4-(3-phenyl-3H-[ 1 ,2,3]triazolo[4,5-d]pyrimidin-5-ylamino)- cyclohexyl]-amide;

3-Methoxy-N-[4-(3-ρhenyl-3H-[l,2,3]triazolo[4,5-d]ρyrimidin-5-ylamino)- cyclohexyl] -benzamide;

5-(3-Phenyl-3H-[l,2₅3]triazolo[4,5-d]pyrimidin-5-ylamino)-isoindole-l,3-dione;

4-{2-[3-(4-tert-Butyl-phenyl)-3H-[l,2,3]triazolo[4,5-d]pyrimidin-5-ylamino]-ethyl}- phenol;

4-[3-(4-Methoxy-phenyl)-3H-[l,2,3]triazolo[4,5-d]pyrimidin-5-ylamino]- cyclohexanol;

4- {2-[3-(4-Methoxy-phenyl)-3H-[l ₅2,3]triazolo[4,5-d]pyrimidin-5-ylaniino]rethyL}- . phenol;

(lH-Indazol-6-yl)-(3-phenyl-3H-[l,2,3]triazolo[4,5-d]pyrimidin-5-yl)-amine; 4-[2-(3-Adamantan-l-yl-3H-[l,2,3]triazolo[4,5-d]pyrimidin-5-ylamino)-ethyl]- phenol;

4-(3-Adamantan-l -yl-3H-[ 1 ,2,3]Mazolo[4,5-d]pyrimidm-5-ylamino)-cyclohexanol;

N_[4_(3.phenyl-3H-[l₅2,3]triazolo[4,5-d]pyrimidin-5-ylaniino)-cyclohexyl]- nicotinamide; N.[4.(3-Phenyl-3H-[l₅2,3]triazolo[4,5-d]pyrimidin-5-ylamino)-cyclohexyl]- isonicotinamide;

2-Methoxy-N-[4-(3-phenyl-3H-[l,2,3]triazolo[4,5-d]pyrimidin-5-ylamino)- cyclohexylj-acetamide;

5-[3-(4-tert-Butyl-ρhenyl)-3H-[l,2,3]triazolo[4,5-d]pyrimidin-5-ylamino]-3H- isobenzofuran- 1 -one;

4-(3-p-Tolyl-3H-[l,2,3]triazolo[4,5-d]pyrimidin-5-ylamino)-cyclohexanol;

4-[2-(3-ρ-Tolyl-3H-[l,2,3]triazolo[4,5-d]ρyrimidin-5-ylamino)-ethyl]-ρhenol;

5-(3-o-Tolyl-3H-[l,2,3]triazolo[4,5-d]pyrimidin-5-ylamino)-3H-isobenzoforan-l-one;

(lR₅2S)-4-(3-Phenyl-3H-[l,2₅3]triazolo[4,5-d]ρyrimidm-5-ylamino)-cyclohexane-l,2- diol;

4-[3-(2-Methoxy-phenyl)-3H-[l,2,3]triazolo[4,5-d]pyrimidin-5-ylamino]- cyclohexanol;

5-[3-(2-Methoxy-phenyl)-3H-[l,2,3]triazolo[4,5-d]pyrimidin-5-ylamino]-3H- isobenzofuran- 1 -one;

4-(3-o-Tolyl-3H-[l,2,3]triazolo[4,5-d]pyrimidin-5-ylamino)-cyclohexanol;

4-[3-(2-Chloro-phenyl)-3H-[l,2,3]triazolo[4,5-d]pyrimidin-5-ylamino]-cyclohexanol;

5-[3-(2-Chloro-phenyl)-3H-[l₅2,3]triazolo[4,5-d]pyrimidin-5-ylamino]-3H- isobenzofuran- 1 -one;

4-[3-(4-Trifluoromethyl-phenyl)-3H-[l,2,3]triazolo[4,5-d]ρyrimidin-5-ylamino]- cyclohexanol;

5-[3-(4-Trifluoromethyl-phenyl)-3H-[l,2,3]triazolo[4,5-d]ρyrimidin-5-ylamino]-3H- isobenzofuran- 1 -one; ό-(3-Phenyl-3H-[l,2,3]triazolo[4,5-d]pyrimidin-5-ylamino)-3H-isobenzofuran-l-one;

(3-Phenyl-3H-[l,2,3]triazolo[4,5-d]pyrimidin-5-yl)-pyrrolidin-3-yl-aniine;

4-(3-Indan-5-yl-3H-[l,2,3]triazolo[4,5-d]pyrimidin-5-ylaniino)-cyclohexanol;

4-(3-Isopropyl-3H-[l,2,3]Mazolo[4_J5-d]pyrimidin-5-γlaminq)-cyclohexanol; - ϊ-[3-(2,4-Dichloro-phenyl)-3H-[l,2,3]triazolo[4,5-d]pyrimidin-5-ylamino]- oyclohexanol; [3-(4-tert-Butyl-ρhenyl)-3H-[l,2,3]triazolo[4,5-d]pyrimidin-5-yl]-piperidin-3-yl- amine; {3_[3_(44_ert-Butyl-ρhenyl)-3H-[l,2,3]triazolo[4,5-d]pyrimidin-5-ylamino]-ρiperidin- l-yl}-oxo-acetic acid methyl ester; {3_[3_(44e_rt-Butyl-phenyl)-3H-[l,2_J3]1iiazolo[4,5-d]ρyiimidin-5-ylammo]-piρeridin-

1 -yl } -plienyl-methanone; l-{3-[3-(4-tert-Butyl-phenyl)-3H-[l,2₅3]triazolo[4,5-d]pyrimidin-5-ylamino]- piperidin- 1 -yl} -ethanone; {3.[3.(4-tert-Butyl-phenyl)-3H-[l,2,3]triazolo[4,5-d]pyrimidin-5-ylamino]-piperidin-

1 -yl} -pyridin-4-yl-methanone;

{3-[3-(4-tert-Butyl-phenyl)-3H-[l,2,3]triazolo[4,5-d]pyrimidin-5-ylamino]-piperidin-

1 -yl } -pyridin-2-yl-methanone;

{3-[3-(4-tert-Butyl-plienyl)-3H-[l,2,3]triazolo[4,5-d]pyrimidin-5-ylamino]-piperidin-

1 -yl} -pyridin-3-yl-methanone;

1 -yl} -furan-2-yl-methanone;

[3-(4-tert-Butyl-phenyl)-3H-[l,2,3]triazolo[4,5-d]ρyrimidin-5-yl]-pyrrolidin-3-yl- amine;

1 - {3-[3-(4-tert-Butyl-phenyl)-3H-[l ,2,3]triazolo[4,5-d]ρyrimidin-5-ylamino]- pyrrolidin- 1 -yl } -ethanone;

{3-[3-(4-tert-Butyl-phenyl)-3H-[l,2,3]triazolo[4,5-d]ρyrimidin-5-ylamino]- pyrrolidin-l-yl}-oxo-acetic acid methyl ester;

{3-[3-(4-tert-Butyl-phenyl)-3H-[l,2,3]triazolo[4,5-d]pyrimidin-5-ylamino]- pyrrolidin-l-yl}-furan-2-yl-methanone;

{3-[3-(4-tert-Butyl-phenyl)-3H-[l,2,3]triazolo[4,5-d]ρyrimidin-5-ylamino]- pyrrolidin-1 -yl} -pyridin-2-yl-methanone;

{3-[3-(4-tert-Butyl-phenyl)-3H-[l,2,3]triazolo[4,5-d]pyrimidin-5-ylamino]- pyrrolidin-l-yl}-pyridin-3-yl-methanone;

4-[2-(3-Phenyl-3H-[l,2,3]triazolo[4,5-d]pyrimidin-5-ylamino)-ethyl]-ρhenol;

{3-[3-(4-tert-Butyl-phenyl)-3H-[l,2,3]triazolo[4,5-d]pyrimidin-5-ylamino]- pyrrolidin- 1 -yl } -pyridin-4-yl-methanone;

5-(3-p-Tolyl-3H-[l,2,3]triazolo[4,5-d]pyrimidin-5-ylamino)-2,3-dihydro-ispindol-l-., one; 5-[3-(4-tert-Butyl-ρhenyl)-3H-[l,2,3]triazolo[4,5-d]ρyrimidin-5-ylamino]-2,3- dihydro-isoindol- 1 -one; 3-Nitro-N^δ-[2-(3-ρ-tolyl-3H-[l,2,3]triazolo[4,5-d]ρyrimidin-5-ylamino)-ethyl]- pyridine-2, 6-diamine; N⁶-{2-[3-(4-tert-Butyl-ρhenyl)-3H-[l,2,3]triazolo[4,5-d]pyrimidin-5-ylamino]-ethyl}-

3 -nitro-pyridine-2,6-diamine; 5-(3-Isoρropyl-3H-[l,2,3]triazolo[4,5-d]pyrimidin-5-ylamino)-3H-isobenzofuran-l- one;

[3-(4-tert-Butyl-phenyl)-3H-[l,2₅3]triazolo[4,5-d]pyrimidin-5-yl]-(2-trifluoromethyl-

1 H-benzoimidazol-5-yl)-amine;

3-[3-(4-tert-Butyl-phenyl)-3H-[l,2,3]triazolo[4₅5-d]pyrimidin-5-ylamino]-adamantan- l-ol;

4-(3-Cyclopentyl-3H-[l,2,3]triazolo[4,5-d]pyrimidin-5-ylamino)-cyclohexanol;

5-(3-Cycloρentyl-3H-[l,2,3]triazolo[4,5-d]pyrimidin-5-ylamino)-3H-isobenzoftιran-

1-one;

4-(3-Bicyclo[2.2.1]hept-2-yl-3H-[l,2,3]triazolo[4,5-d]ρyrimidin-5-ylamino)- cyclohexanol;

2-{3-[3-(4-tert-Butyl-phenyl)-3H-[l₅2,3]triazolo[4,5-d]pyrimidin-5-ylamino]- pyrrolidin- 1 -yl} -2-oxo-acetamide;

N-{3-[3-(4-tert-Butyl-phenyl)-3H-[l,2,3]triazolo[4,5-d]pyrimidin-5-ylamino]- cyclohexyl } -acetamide;

{3-[3-(4-tert-Butyl-phenyl)-3H-[l,2₅3]triazolo[4₅5-d]pyrimidin-5-ylamino]- cyclohexyl}-carbamic acid methyl ester;

N-{3-[3-(4-tert-Butyl-phenyl)-3H-[l,2,3]triazolo[4,5-d]pyrimidin-5-ylamino]- cyclohexyl}-oxalamic acid methyl ester;

N-{3-[3-(4-tert-Butyl-phenyl)-3H-[l,2,3]triazolo[4,5-d]pyrimidin-5-ylamino]- cyclohexyl } -oxalamide;

(3-Adamantan-l-yl-3H-[l,2,3]triazolo[4,5-d]pyrimidin-5-yl)-(lH-indazol-6-yl)- amine;

(3-Adamantan-l-yl-3H-[l,2,3]triazolo[4,5-d]pyrimidin-5-yl)-flιran-2-ylmethyl-amine;

(3-Adamantan-l-yl-3H-[l,2,3]triazolo[4,5-d]pyrimidin-5-yl)-pyridin-3-ylmethyl- amine;

(3^"-Xdamantan-ϊ-yl-3H-[l,2,3]triazolo[4,5-d]pyrimidin-5-yl)-(2-methoxy-ethyl)- amine; 4-(3-Phenyl-3H-[l,2,3]triazolo[4,5-d]pyrimidin-5-ylamino)-cyclohexanone;

Furan-2-carboxylic acid {3-[3-(4-tert-butyl-phenyl)-3H-[l ,2,3]triazolo[4,5- d]pyrimidin-5-ylamino]-cyclohexyl}-amide;

N-{3-[3-(4-tert-Butyl-phenyl)-3H-[l,2,3]triazolo[4,5-d]pyrimidin-5-ylamino]- cyclohexyl}-2-methoxy-acetamide;

4-[(3-Phenyl-3H-[l,2,3]triazolo[4,5-d]ρyriniidin-5-ylamino)-methyl]-benzene-l,2- diol;

(3,4-Dimethoxy-benzyl)-(3-phenyl-3H-[l,2,3]triazolo[4,5-d]pyrimidin-5-yl)-amine;

(3-Phenyl-3H-[l,2,3]triazolo[4,5-d]pyrimidin-5-yl)-(tetrahydro-ρyran-4-ylinethyl)- amine;

(3-Phenyl-3H-[l,2,3]triazolo[4,5-d]pyrimidin-5-yl)-(tetrahydro-pyran-4-yl)-amine;

(3-Methoxy-propyl)-(3-phenyl-3H-[l,2,3]triazolo[4,5-d]pyrimidin-5-yl)-amine;

4-(3-Methyl-3H-[l,2,3]triazolo[4₅5-d]pyrimidm-5-ylamino)-cyclohexanol;

[2-(3-Methoxy-ρhenyl)-ethyl]-(3-ρhenyl-3H-[l,2,3]triazolo[4,5-d]ρyrimidin-5-yl)- amine;

[2-(4-Methoxy-ρhenyl)-ethyl]-(3-phenyl-3H-[l,2,3]triazolo[4,5-d]pyrimidin-5-yl)- amine;

[2-(3,4-Dimetlioxy-phenyl)-ethyl]-(3-phenyl-3H-[l,2,3]triazolo[4,5-d]ρyrimidin-5- yl)-amine;

N-(3-Phenyl-3H-[l,2,3]triazolo[4,5-d]pyrimidin-5-yl)-cyclohexane-l,4-diamine;

Phenethyl-(3-phenyl-3H-[l,2,3]triazolo[4,5-d]ρyrimidin-5-yl)-amine;

[2-(3,4-Dichloro-phenyl)-ethyl]-(3-phenyl-3H-[l,2,3]triazolo[4,5-d]ρyrimidin-5-yl)- amine;

3-[2-(3-Phenyl-3H-[l_J2,3]triazolo[4,5-d]ρyrimidin-5-ylamino)-ethyl]-ρhenol;

4-[2-(3-Phenyl-3H-[l,2,3]triazolo[4,5-d]ρyrimidin-5-ylamino)-ethyl]-benzene-l,2- diol;

Cyclohex-3-enyl-(3-phenyl-3H-[l,2,3]triazolo[4,5-d]pyrimidin-5-yl)-amine;

4-[3-(4-tert-Butyl-ρhenyl)-3H-[l,2,3]triazolo[4,5-d]pyrimidin-5-ylamino]- cyclohexanol;

5-(3 -Phenyl-3 H-[1 ,2,3 ]triazolo [4,5-d]pyrimidin-5-ylamino)-3 H-isobenzofuran- 1 -one;

(4-Morpholin-4-ylmethyl-benzyl)-(3-phenyl-3H-[l,2,3]triazolo[4,5-d]pyrimidin-5- yl)-amine; _._. . l-Phenyl-2-(3-phenyl-3H-[l,2,3]triazolo[4,5-d]pyrimidin-5-ylamino)-ethanol; (R)-3-Phenyl-2-(3-ρhenyl-3H-[l,2_J3]triazolo[4,5-d]pyrimidin-5-ylamino)-proρan-l- ol; (S)-3-Phenyl-2-(3-ρhenyl-3H-[l,2₅3]triazolo[4,5-d]ρyrimidin-5-ylamino)-proρan-l- ol; 4-[(R)-3-Hydroxy-2-(3-ρhenyl-3H-[l,2,3]triazolo[4,5-d]pyrimidin-5-ylamino)- ρropyl]-phenol;

Phenyl-(9-phenyl-8-pyridin-4-yl-9H-purin-2-yl)-amine;

3-(9-Phenyl-2-phenylamino-9H-purin-8-yl)-phenol;

4-[(9-Phenyl-8-pyridin-4-yl-9H-ρurin-2-ylamino)-methyl]-benzenesulfonamide;

N-(3-Methoxy-benzoyl)-4-{[8-(3-methoxy-phenyl)-9-phenyl-9H-purin-2-ylamino]- methyl} -benzenesulfonamide;

3-[9-Phenyl-2-(4-sulfamoyl-benzylamino)-9H-purin-8-yl]-propionic acid ethyl ester;

9-(3-Methoxy-phenyl)-2-(3-methoxy-phenylamino)-9H-purine-8-carboxylic acid ethyl ester;

4-[2-(9-Phenyl-9H-purin-2-ylamino)-ethyl]-phenol;

2-(4-Carboxymethoxy-phenylamino)-9-ρhenyl-9H-ρurine-8-carboxylic acid ethyl ester;

4-(3-Methoxy-l-phenyl-lH-pyrazolo[3,4-d]pyrimidin-6-ylamino)-benzoic acid;

4-(3 -Chloro- 1 -phenyl- 1 H-pyrazolo [3 ,4-d]pyrimidin-6-ylamino)-benzoic acid;

4-(3 -Chloro- 1 -phenyl- 1 H-pyrazolo[3 ,4-d]pyrimidin-6-ylamino)-benzamide;

4-(3 -Chloro- 1 -phenyl- 1 H-pyrazolo[3 ,4-d]pyrimidin-6-ylamino)-cyclohexanol;

2-Methyl- 1 -phenyl-6-phenylamino- 1 ,2-dihydro-pyrazolo[3 ,4-d]pyrimidin-3 -one;

4-(3-Oxo-l-phenyl-2₅3-dihydro-lH-pyrazolo[3₅4-d]pyrimidin-6-ylamino)-benzoic acid methyl ester;

4-(2-Methyl-3 -oxo- 1 -phenyl-2,3 -dihydro- 1 H-pyrazolo[3 ,4-d]pyrimidin-6-ylamino)- benzoic acid methyl ester;

4-(3 -Oxo- 1 -phenyl-2,3 -dihydro- 1 H-pyrazolo[3 ,4-d]pyrimidin-6-ylamino)-benzoic acid;

4-(2-Methyl-3-oxo- 1 -phenyl-2,3 -dihydro- 1 H-pyrazolo[3 ,4-d]pyrimidin-6-ylamino)- benzoic acid;

2-[2-(4-Hydroxy-phenyl)-ethylamino]-8-phenyl-7,8-dihydro-5H-pteridin-6-one;

[4-(6-Oxo-8-phenyl-5,6,7,8-tetrahydro-pteridin-2-ylamino)-phenpxyJ-acetiC-.acid; . _

4-(6-Oxo-8-phenyl-5,6,7,8-tetrahydro-pteridin-2-ylamino)-benzoic acid;

4-(7-Methyl-6-oxo-8-ρhenyl-5,6,7,8-tetrahydro-pteridin-2-ylamino)-benzoic acid; {4-[4-(6-Oxo-8-phenyl-5,6,7,8-tetrahydro-pteridin-2-ylamino)-ρhenyl]-[l,2,3]triazol-

1-yl} -acetic acid;

4-(8-Oxo-9-phenyl-8,9-dihydro-7H-purin-2-ylamino)-benzenesulfonamide;

4-(8-Oxo-9-phenyl-8,9-dihydro-7H-purin-2-ylamino)-benzoic acid;

7-Memyl-9-phenyl-2-phenylamino-7,9-dihydro-purin-8-one;

7-tert-Butyl-9-phenyl-2-phenylamino-7,9-dihydro-purin-8-one;

7-Ethyl-9-phenyl-2-phenylamino-7,9-dihydro-purin-8-one;

2-(3-Methoxy-phenylamino)-7-methyl-9-phenyl-7,9-dihydro-purin-8-one;

3-(7-Methyl-8-oxo-9-phenyl-8,9-dihydro-7H-purin-2-ylamino)-benzoic acid;

5-(3-Indan-5-yl-3H-[l,2,3]triazolo[4,5-d]pyrimidin-5-ylamino)-3H-isobenzofuran-l- one;

5-(3-Phenyl-3H-[l,2,3]triazolo[4,5-d]pyrimidin-5-ylamino)-indan-l-one;

^(S-Indan-S-yl-SH-tl^^Jtriazolo^jS-dlpyrimidin-S-y^-cyclohexane-l^-diamine;

N-[(lS_J3R)-3-(3-Indan-5-yl-3H-[l,2,3]triazolo[4,5-d]pyrimidin-5-ylamino)- cyclohexyl] -acetamide;

5-(3-Indan-5-yl-3H-[l,2,3]triazolo[4,5-d]pyrimidin-5-ylammo)-isoindole-l,3-dione; and

(3-Indan-5-yl-3H-[l,2,3]triazolo[4,5-d]ρyriniidin-5-yl)-(lH-indazol-6-yl)-amine.

[0042] In another aspect, there is provided a method of preparing compounds of Formula IA,

Formula IA,

the method comprising reacting a compound of Formula IAa

Formula IAa with R²NH₂, in a suitable solvent, under conditions suitable to form a compound of Formula I, wherein Hal is F, Cl₅ Br, I , or S(O)_mR^a, R^a is a substituted or unsubstituted alkyl or aryl group, R¹, R² and A are as defined herein for Formula I, and m is 1-2. Typically, the reaction is carried out at elevated temperature and optionally can be carried out in a solvent or in the presence of a base.

[0043] In another aspect, there is provided a method of preparing compounds of Formula IAa,

Formula IAa,

the method comprising reacting a compound of Formula IAb

with R¹NH₂, 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)_mR^a, R^a is a substituted or unsubstituted alkyl or aryl group, R¹ 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.

[0044] In another aspect, the present invention provides a method of preparing compounds of Formula II,

Formula II

the method comprising reacting a compound ofFormula Ua,

Foπnula Ha

with H₂NR², in a suitable solvent, under conditions suitable to form a compound of Formula II, wherein A is F, Cl, Br, I , or S(O)_mR^a, R^a is a substituted or unsubstituted alkyl or aryl group, R¹ and R² are as defined herein for Formula II, and m is 1-2. Typically, the reaction is carried out at a temperature in the range of about 25°C to about 15O⁰C, more typically at about 9O⁰C. 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.

[0045] A compound of Foπnula Ha wherein A is S(O)_mR^a can be prepared by oxidizing a compound of Formula lib,

Formula TIb

in the presence of an oxidizing agent such as mCPBA, NaIO₄, peroxides, dimethyl dioxirane, in a solvent, to form a compound of Formula Ha, wherein A is S(O)_mR^a. Typically the solvent is DCM, water, methanol, EtOH, THF, dioxane and the like, or mixtures thereof.

[0046] 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, NaNO₂/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.

[0047] Compounds of Formula Ha, wherein A is F, Cl, Br, or I can be prepared by cyclizing a compound of Formula Vb

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.

[0048] Alternatively, compounds of Formula II can be prepared by cyclizing a compound of Formula Vc₅

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 R¹ and R² are as defined herein.

[0049] 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 -20⁰C to about 25°C, more typically at about -1O⁰C. [0050] In another aspect, the invention provides methods of preparing compounds of Formula IIIA,

Formula IIIA

the method comprising reacting a compound of Formula IIIAa

Formula IIIAa

with R⁹-X in the presence of a base, in a solvent, under conditions suitable to form a compound of Formula IIIA, wherein R ₅ R , and R are as defined herein and X is Cl, Br, I, OMs, OTos, or OTf. Suitable bases include organic bases such as DIEA, TEA, DBU and the like, while inorganic bases include Cs₂CO₃, K₂CO₃, NaHCO₃ and the like. Typical solvents are DMF, DCM, THF, dioxane, and the like and mixtures thereof.

[0051] Compounds of Formula IIIAa can be prepared by cyclizing a compound of Formula Vc

Formula Vc

with a carbonylating agent, such as N,N'-disuccinimidyl carbonate, phosgene or lj'-carbonyldiimidazole, in a solvent, under conditions suitable to form a compound of Formula IIIAa, wherein R¹, R² and R⁹ 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 16O⁰C, usually about 80°C under standard heating conditions, or about 160°C under microwave irradiation conditions.

[0052] In yet another aspect, the present invention provides methods of preparing compounds of Formula IHB

Formula IHB

the method comprising reacting a compound of Formula Vc

Formula Vc

with R¹⁰C(O)R", in a solvent, to form a compound of Formula IHB, wherein R¹, R² and R¹⁰ 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. When R^x is a halogen, suitable solvents include DMF, NMP, DME, dioxane and the like, while suitable bases include organic bases, such as DIEA, TEA, DBU, pyridine and the like. Typically, the reaction is performed at a temperature in the range of about 8O⁰C to about 200°C, more typically at about 15O⁰C. When 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 80⁰C to about 150⁰C, more typically at about 120⁰C.

[0053] In yet another aspect of the invention, a method is provided for preparing a compound of Formula HIC,

the method comprising reacting a compound of Formula VI,

Formula VI

wherein A is S(O)_mR^a, with H₂NR², in a solvent, optionally in the presence of an acid, to form a compound of Formula UIC, wherein R¹, R² and R¹¹ are as defined herein, R^a is a substituted or unsubstituted alkyl or aryl group, and m is 1-2. Typically, the reaction is carried out at a temperature in the range of about 90⁰C to about 150⁰C, more typically at about 120⁰C. Suitable solvents include dioxane, THF, DMSO, DMF, DME, or mixtures thereof, while suitable acids include TFA.

[0054] Compounds of Formula VI wherein A is S(O)_mR^a can be prepared by oxidizing a compound of Formula Via,

Formula Via

in the presence of an oxidizing agent such as mCPB A, NaIO₄, peroxides, or dimethyl dioxirane in a solvent, to form a compound of Formula VI, wherein A is S(O)_mR^a. Typically the solvent is DCM, THF, dioxane, DCE, DME or the like, or mixtures thereof.

[0055] In yet another aspect of the invention, a method is provided for preparing compounds of Formula HID,

- Formula HID the method comprising reacting a compound of Formula VII,

Formula VII wherein A is is S(O)_mR^a, with H₂NR², in a solvent, to form a compound of Formula HID wherein R¹, R² and R¹² are as defined herein, R^a is a substituted or unsubstituted alkyl or aryl group, and m is 1-2. Typically, the reaction is carried out at a temperature in the range of about 9O⁰C to about 120°C, more typically at about 110⁰C. Suitable solvents include dioxane, DMF, DMSO, NMP, DME or the like, or mixtures thereof.

[0056] Compounds of Formula VII, wherein A is S(O)_mR^a can be prepared by oxidizing a compound of Formula Vila,

Formula Vila

in the presence of an oxidizing agent such as mCPBA, NaIO₄, peroxides, or dimethyl dioxirane, in a solvent, to form a compound of Formula VII, wherein A is S(O)_mR^a. Typically the solvent is DCM, THF, dioxane, DCE, DME or the like, or mixtures thereof.

[0057] In yet another aspect of the invention, a method is provided for preparing a compound of Formula IV,

Formula IV

the method comprising treating a compound of Formula VIII

Formula VIII

wherein 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 SnCl₂, Na₂S₂O₄, Zn/ AcOH or Fe, in a solvent, to form a compound of Formula IV₃ wherein R¹⁷, R¹⁸, 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.

[0058] The invention further provides compositions comprising a compound as described herein and a pharmaceutically acceptable carrier.

[0059] In a further aspect, 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. In some such embodiments, 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 disorder, lung disease, cancer, such as multiple myeloma, and optionally its associated osteolytic lesions, digestive system cancer, neuroblastoma, intestinal cancer, colorectal cancer, hepatoma, breast cancer, adenoma (for example, basal cell adenoma, follicular adenoma, microcystic adenoma, monomorphic adenoma, or papillary adenoma), prostate cancer, lymphoma, carcinomatosis, or lung cancer; hair loss; inflammation; stroke; myocardial infarction; skeletal muscle atrophy; decreased sperm motility; or cardiovascular disease (for example, cardiac hypertrophy or heart failure).

DETAILED DESCRIPTION OF THE INVENTION

[0060] The following definitions are used throughout this specification.

[0061] Generally, reference to a certain element such as hydrogen or H is meant to include all isotopes of that element. For example, if an R group is defined to include hydrogen or H, it also includes deuterium and tritium. Hence, isotopically labeled compounds are within the scope of the invention.

[0062] In general, "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. In some embodiments, substituted groups have 1, 2, 3, 4, 5, or 6 substituents. Examples of 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; isocyanates; isothiocyanates; cyanates; thiocyanates; imines; and nitriles.

[0063] 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.

[0064] 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. Examples of 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. Examples of 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 F₅ Cl, Br, I groups.

[0065] Cycloalkyl groups are cyclic alkyl groups such as, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups. In some embodiments, 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.

[0066] 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_Λ3_..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.

[0067] 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.

[0068] 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. Thus, 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. Examples include, but are not limited to vinyl, -CH=CH(CH₃), -CH=C(CH₃)₂, -C(CH₃)=CH₂, -C(CH₃)=CH(CH₃), -C(CH₂CH₃)=CH₂, cyclohexenyl, cyclopentenyl, cyclohexadienyl, butadienyl, pentadienyl, and hexadienyl, among others.

[0069] Cycloalkenyl groups include cycloalkyl groups having at least one double bond between 2 carbons. Thus for example, cycloalkenyl groups include but are not limited to cyclohexenyl, cyclopentenyl, and cyclohexadienylgroups.

[0070] 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.

[0071] Alkynyl groups include straight and branched chain alkyl groups, except that at least one triple bond exists between two carbon atoms. Thus, 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(CH₃), -C≡C(CH₂CH₃), -CH₂C≡CH, -CH₂C≡C(CH₃), and -CH₂C≡C(CH₂CH₃), among others.

[0072] ^{' ~} Aryl groups are cyclic aromatic hydrocarbons that do not contain heteroatoms. Aryl groups include monocyclic, bicyclic and polycyclic ring systems. Thus, 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. In some embodiments, 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. Although the phrase "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. For example, 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.

[0073] 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.

[0074] 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. In some embodiments, the heterocyclyl group contains 1, 2, 3, or 4 heteroatoms. In some embodiments, 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. The phrase "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. However, 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

"substituted heterocyclyl groups." Heterocyclyl groups include, but are not limited t< _. pyrrolidinyl, pyrrolinyl, imidazolyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, pyrazolyl, pyrazolidinyl, tetrahydropyranyl, thiomorpholinyl, pyranyl, triazolyl, tetrazolyl, furanyl, tetrahydrofuranyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, thioplienyl, benzothiophenyl, benzofuranyl, dihydrobenzofuranyl, indolyl, dihydroindolyl, azaindolyl, indazolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridinyl, isoxazolopyridinyl, thianaphthalenyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinoxalinyl, quinazolinyl, benzotriazolyl, 2,3- dihydrobenzo[l,4]dioxinyl, and benzo[l,3]dioxolyl groups. 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.

[0075] 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. In some embodiments, 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, isoquinolinyl, tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl groups. Although the phrase "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^" όxδ, alkoxy, alkyl, cyand, and/or halo.^{" " " ~} [0076] 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.

[0077] 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.

[0078] 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. Examples of linear alkoxy groups include but are not limited to methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, and the like. Examples of branched alkoxy include but are not limited to isopropoxy, sec-butoxy, tert-butoxy, isopentoxy, isohexoxy, and the like. Examples of cyclic alkoxy include but are not limited to cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like.

[0079] The terms "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.

[0080] The term "carboxylate" as used herein refers to a -COOH group.

[0081] The term "carboxylic ester" as used herein refers to -COOR³⁰ groups.

R³⁰ is a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heterocyclylalkyl or heterocyclyl group as defined herein.

[0082] The term "amide" (or "amido") includes C- and N-amide groups, i.e.,

-C(O)NR³¹R³², and -NR³¹C(O)R³² groups, respectively. R³¹ and R³² 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)NH₂) and formamide groups (-NHC(Θ)H). [0083] Urethane groups include N- and O-urethane groups, i.e.,

-NR³³C(O)OR³⁴ and -OC(O)NR³³R³⁴ groups, respectively. R³³ and R³⁴ are independently hydrogen, or a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl, or heterocyclyl group as defined herein.

[0084] The term "amine" as used herein refers to -NHR³⁵ and -NR³⁶R³⁷ groups, wherein R³⁵, R³⁶ and R³⁷ are independently hydrogen, or a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl or heterocyclyl group as defined herein.

[0085] The term "sulfonamido" includes S- and N-sulfonamide groups, i.e.,

-SO₂NR³⁸R³⁹ and -NR³⁸SO₂R³⁹ groups, respectively. R³⁸ and R³⁹ 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 (-SO₂NH₂).

[0086] The term "thiol" refers to -SH groups, while sulfides include -SR⁴⁰ groups, sulfoxides include — S(O)R⁴¹, sulfones include -SO₂R⁴² groups, and sulfonyls include -SO₂OR⁴³. R⁴⁰, R⁴¹, R⁴², and R⁴³ are each independently a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl aralkyl, heterocyclyl or heterocyclylalkyl group as defined herein.

[0087] The term "urea" refers to -NR⁴⁴-C(O)-NR⁴⁵R⁴⁶ groups. R⁴⁴, R⁴⁵, and

R⁴⁶ groups are independently hydrogen, or a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclyl, or heterocyclylalkyl group as defined herein.

[0088] The term "amidine" refers to -C(NR⁴⁷)NR⁴⁸R⁴⁹ and -NR⁴⁷C(NR⁴⁸)R⁴⁹ groups, wherein R⁴⁷, R⁴⁸, and R⁴⁹ are each independently hydrogen, or a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl aralkyl, heterocyclyl or heterocyclylalkyl group as defined herein.

[0089] The term "guanidine" refers to -NR⁵⁰C(NR^{5 !})NR⁵²R⁵³ groups, wherein R⁵⁰, R⁵¹, R⁵² and R⁵³ are each independently hydrogen, or a substituted or - unsubstituted alkyl-, cycloalkyl, alkenyl; alkynyl, aryharalkyl, heterocyclyl or ^{~ ~ ~} heterocyclylalkyl group as defined herein. [0090] The term "enamine" refers to -C(R⁵⁴)=C(R⁵⁵)NR⁵⁶R⁵⁷ and

-NR⁵⁴C(R^S5)=C(R⁵⁶)R⁵⁷ groups, wherein R⁵⁴, R⁵⁵, R⁵⁶ and R⁵⁷ are each independently hydrogen, a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl aralkyl, heterocyclyl or heterocyclylalkyl group as defined herein.

[0091] The term "imide" refers to -C(O)NR⁵⁸C(O)R⁵⁹ groups, wherein R⁵⁸ and R⁵⁹ are each independently hydrogen, or a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl aralkyl, heterocyclyl or heterocyclylalkyl group as defined herein.

[0092] The term "imine" refers to -CR⁶⁰(NR⁶¹) and -N(CR⁶⁰R⁶¹) groups, wherein R⁶⁰ and R⁶¹ 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 R⁶⁰ and R⁶¹ are H simultaneously.

[0093] The term "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.

[0094] 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,

4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, and the like; sulfonyl groups such as benzenesulfonyl, p-toluenesulfonyl and the like; carbamate forming groups such as benzyloxycarbonyl, p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitro-4,5- dimethoxybenzyloxycarbonyl, 3,4,5-trimethoxybenzyloxycarbonyl, 1 -(p-biphenylyl)- 1 -methyl ethoxycarbonyl, α,θ!-dimethyl-3,5-dimethoxybenzyloxycarbonyl, benzhydryloxycarbonyl, t-butyloxycarbonyl, diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl, 2,2,2,-trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxycarbonyl, fiuorenyl- 9-methoxycarbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, phenylthiocarbonyl and the like; alkyl groups such as benzyl, triphenylmethyl, benzyloxymethyl and the like; and silyl groups such as trimethylsilyl and the like. Typical N-protecting groups are formyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, phenylsulfonyl, benzyl, 9-fluorenylmethyloxycarbonyl (Fmoc), t-butyloxycarbonyl (Boc) and benzyloxycarbonyl (Cbz).

[0095] 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.

[0096] Representative carboxy protecting groups are C₁ to C₈ 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 acetoxymethyl, butyryloxymethyl, valerytoxymethyl, isobutyryloxymethyl, isovaleryloxymethyl, 1 -(propionylrøy)-l -ethyl, l-(piyaloyjoxyl)-l -ethyl, 1 -methyl- l-(propipnyloxy)-l.-_ _ ethyl, pivaloyloxymethyl, propionyloxymethyl and the like; cycloalkanoyloxyalkyl groups such as cyclopropylcarbonyloxymethyl, cyclobutylcarbonyloxymethyl, cyclopentylcarbonyloxymethyl, cyclohexylcarbonyloxymethyl and the like; aroyloxyalkyl, such as benzoyloxymethyl, benzoyloxyethyl and the like; arylalkylcarbonyloxyalkyl, such as benzylcarbonyloxymethyl, 2-benzylcarbonyloxyethyl and the like; alkoxycarbonylalkyl, such as methoxycarbonylmethyl, cyclohexyloxycarbonylmethyl, 1 -methoxycarbonyl-1 -ethyl, and the like; alkoxycarbonyloxyalkyl, such as methoxycarbonyloxymethyl, t-butyloxycarbonyloxymethyl, 1 -ethoxycarbonyloxy- 1 -ethyl, 1-cyclohexyloxycarbonyloxy-l -ethyl and the like; alkoxycarbonylaminoalkyl, such as t-butyloxycarbonylaminomethyl and the like; alkylaminocarbonylaminoalkyl, such as methylaminocarbonylaminomethyl and the like; alkanoylaminoalkyl, such as acetylaminomethyl and the like; heterocycliccarbonyloxyalkyl, such as 4-methylpiperazinylcarbonyloxymethyl and the like; dialkylaminocarbonylalkyl, such as dimethylaminocarbonylmethyl, diethylaminocarbonylmethyl and the like; (5-(alkyl)-2-oxo-l,3-dioxolen-4-yl)alkyl, such as (5-t-butyl-2-oxo-l,3-dioxolen- 4-yl)methyl and the like; and (5-phenyl-2-oxo-l,3-dioxolen-4-yl)alkyl, such as (5-phenyl-2-oxo-l,3-dioxolen-4-yl)methyl and the like.

[0097] "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:

As readily understood by one skilled in the art, a wide variety of functional groups and other structures may exhibit tautomerism, and all tautomers of compounds having Formula I are within the scope of the present invention.

[0098] All chiral, diastereomeric, racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomeric foπ is specifically indicated. Compounds used in the present invention include enriched or resolved optical isomers at any or all asymmetric atoms as are apparent from the depictions. Both raceniic and diastereomeric mixtures, as well as the individual optical isomers can be isolated or synthesized so as to be substantially free of their enantiomeric or diastereomeric partners, and these are all within the scope of the invention.

[0099] 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 -NO₂, are readily prepared as shown in Scheme 1.

Scheme 1

[00100] In a first step, a dihalo pyrimidine, such as 2,4-dichloro-5-nitro- pyrimidine, or a trihalo pyrimidine, such as 2,4-dichloro-5-bromopyrimidine, is derivatized by treatment with alkylamines. The reaction is carried out with about 1 equivalent of amine, and in the presence of a suitable base, such as N₃N'- diisopropylethylamine. In the case where R¹ and R² are identical, the 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 R²NH₂, optionally in the presence of a base and at elevated temperature to generate a compound of Formula IA. To obtain compounds of Formula IA wherein A is -NH₂, the -NO₂ derivative obtained as above is reduced by known methods, such as for example, hydrogenation or reduction by SnCl₂. [00101] Compounds of Formula I, wherein B is -CO- and D is -NH- (Formula

IB), or B is -CH₂- and D is -NH- (Formula IC) can be prepared as shown in Scheme 2.

Scheme 2

[00102] 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. Reaction of the ylide with a dihalo pyrimidine, such as 2,4-dichloro-5-nitro- pyrimidine in the presence of N,O-bis(trimethylsilyl)acetamide, followed by displacement of the halide by R²NH₂ as before, leads to intermediate (c). 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, Bu₄N/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.

Scheme 3

[00103] Similarly, compounds of Formula I, wherein B is -NH- and D is either

-CO- (Formula ID) or -CH₂- (Formula IE) can be prepared as shown in Scheme 3.

[00104] Using the methods as described above, compounds of Formula IF, IG,

IH, and IJ can also be synthesized.

[00105] Compounds of Formula II are readily prepared as shown in Scheme 4, for example. In a first step, a dihalo pyrimidine, such as 2,4-dichloro-5-nitro- pyrimidine, is derivatized by treatment with 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. In the case where R¹ and R² are identical, the 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 ΛζTV-diisopropylethylamine, with or without heating, depending on the reactivity of the amine used. In a first route, a second amine derivative is introduced, by reaction with R²NH₂, optionally in the presence of a base and at elevated temperature (compound a). Reduction of the nitro group by known methods (e.g. hydrogenation or reduction by SnCl₂) provides a precursor b that is readily cyclized to the triazole moiety, by reaction with a nitrite, such as n-butylnitrite, isoamyl nitrite, NaNO₂/AcOH and the like.

Scheme 4

[00106] In a second route, 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 R²NH₂.

[00107] In a third approach, 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. Oxidation of the thioether, to either the sulfone (n=l) or sulfoxide (n=2), provides a leaving group for displacement with the amine component R²NH₂, again leading to the target compounds of Formula II.

IIIA

Scheme 5

[00108] Compounds of Formula III, wherein G is imidazolonyl (Formula IIIA), can be synthesized as shown in Scheme 5. The 2,4,5-triaminopyrimidine derivative b, obtained as in Scheme 4, is cyclized in the presence of a carbonylating agent, such as N,N'-disuccinimidyl carbonate, phosgene or l,r-carbonyldiimidazole. Suitable solvents for this cyclization include, for example, dioxahe, DMF, THF7DME,^"bf ^" NMP. The reaction is typically performed under heating, optionally under microwave irradiation, to a temperature of from about 6O⁰C to about 16O⁰C or more. The reaction is conveniently carried out at about 8O⁰C under standard heating conditions, or at about 16O⁰C under microwave irradiation conditions. The resulting compound is alkylated by treatment with R⁹X, 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 Cs₂CO₃, K₂CO₃, NaHCO₃ and the like. Typical solvents are DMF, DCM, THF, dioxane and the like and mixtures thereof.

Scheme 6

[00109] Similarly, compounds of Formula III, wherein G is imidazolyl

(Formula 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. When acid halides are used, suitable solvents include DMF, while 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 8O⁰C to about 200⁰C, more typically at about 150⁰C. For reaction with aldehydes, 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 150⁰C, more typically at about 12O⁰C.

Scheme 7

[00110] Compounds of Formula III, wherein G is pyrazolyl (Formula IIIC) and pyrazolonyl (Formula HID) can be obtained as exemplified in Scheme 7, Treatment of 4-chloro-2-sulfanyl-pyrimidine-5-carboxylic acid ethyl ester with hydrazines R¹NHNH₂ affords the l,2-dihydro-pyrazolo[3,4-d]pyrirnidin-3-one-l-yl derivative. In a first route, alkylation of this intermediate with alkyl halides in the presence of a base, such as Cs₂CO₃, yields the N and O-alkylated products (Compounds i and k, respectively), which can be separated. As before, the thioether moiety of the O- alkylated product is oxidized to either the sulfone (n=l) or sulfoxide (n=2), to provide a leaving group for displacement with the amine component R NH₂, leading to the target compounds of Formula IIIC. Similarly, the thioether moiety of the N-alkylated derivatives can be oxidized and the sulfone (n=l) or sulfoxide (n=2) moiety displaced with amines R⁸NH₂ to provide compounds of Formula HID. Alternatively, 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 R⁸NH₂ again provides the target compounds of Formula IIIC.

rv

Scheme 8

[00111] Compounds of Formula IV are obtained as shown in Scheme 8. 2,4-

Dichloro-5-nitro-ρyrimidine is treated with amino acids in the presence of a base such as DIEA at room temperature. Reaction with a second amine R¹⁸NH₂ 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 SnCl₂, Zn/ AcOH or Fe, in a solvent such as methanol, ethanol, THF, dioxane or mixtures thereof.

[00112] As used herein, "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. For example, GSK-3 modulators include GSK-3 inhibitors. As used herein, 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.

[00113] "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. Similarly, as used herein, 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. For example, 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. For example, 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.

[00114] 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. Bundgaard, ed.), Elsevier, New York (1985), Goodman and Gilmans, The Pharmacological Basis of Therapeutics, 8th ed., McGraw-Hill, Int. Ed. 1992. The preceding references are hereby incorporated by reference in their entirety.

[00115] Pharmaceutically acceptable salts of the invention compounds are considered within the scope of the present invention. When the compound of the invention has a basic group, such as, for example, an amino group, 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. formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, lactic acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid) or acidic amino acids (such as aspartic acid and glutamic acid). When the compound of the invention has an acidic, group, such as for example, a carboxylic acid group, it can form salts with metals, such as alkali and earth alkali metals (e.g. Na⁺, Li⁺, K⁺, Ca²⁺, Mg²⁺, Zn²⁺), organic amines (e.g. ammonia, trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine) or basic amino acids (e.g. arginine, lysine and ornithine).

[00116] The instant invention also provides for pharmaceutical 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. The instant 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. The following dosage forms are given by way of example and should not be construed as limiting the instant invention.

[00117] For oral, buccal, and sublingual administration, 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. Optionally, 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. [00118] 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. Pharmaceutical formulations 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. Pharmaceutically suitable surfactants, suspending agents, emulsifying agents, may be added for oral or parenteral administration.

[00119] As noted above, suspensions may include oils. Such 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.

[00120] For nasal administration, 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.

[00121] 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.

.[.00.122] For injection, the pharmaceutical, formulation and/or medicament ma) also be a powder suitable for reconstitution with an appropriate solution as described above. Examples of these include, but are not limited to, freeze dried, rotary dried or spray dried powders, amorphous powders, granules, precipitates, or particulates. For injection, the formulations may optionally contain stabilizers, pH modifiers, surfactants, bioavailability modifiers and combinations of these.

[00123] For rectal administration, 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.

[00124] Besides those representative dosage forms described above, pharmaceutically acceptable 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.

[00125] The formulations of the invention may be designed to be short-acting, fast-releasing, long-acting, and sustained-releasing as described below. Thus, the pharmaceutical formulations may also be formulated for controlled release or for slow release.

[00126] The instant compositions may also comprise, for example, micelles or liposomes, or some other encapsulated form, or may be administered in an extended

_rele.ase formixx provide a prolonged storage -and/or delivery effect. Therefore, 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.

[00127] 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.

[00128] 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 LD₅₀ and ED₅₀. The LD₅₀ is the dose lethal to 50% of the population and the ED₅₀ is the dose therapeutically effective in 50% of the population. The LD₅₀ and ED₅₀ are determined by standard pharmaceutical procedures in animal cell cultures or experimental animals.

[00129] As will be understood by one skilled in the art, for any and all purposes, particularly in terms of providing a written description, all ranges disclosed herein also encompass any and all possible subranges and combinations of subranges thereof. Any listed range can be easily recognized as sufficiently describing and enabling the same range being broken down into at least equal halves, thirds, quarters, fifths, tenths, etc. As a non-limiting example, each range discussed herein can be readily broken down into a lower third, middle third and upper third, etc. As will also be understood by one skilled in the art all language such as "up to," "at least," "greater than," "less than," and the like include the number recited and refer to ranges which can be subsequently broken down into subranges as discussed above. Finally, as will be understood by one skilled in the art, a range includes each individual member. Thus, for example, a group having 1-3 atoms refers to groups having 1, 2, or 3 atoms. Similarly, a group having 1-5 atoms refers to groups having 1, 2, 3, 4, oi 5 atoms, and so forth. [00130] All publications, patent applications, issued patents, and other documents referred to in this specification are herein incorporated by reference as if each individual publication, patent application, issued patent, or other document was specifically and individually indicated to be incorporated by reference in its entirety. Definitions that are contained in text incorporated by reference are excluded to the extent that they contradict definitions in this disclosure.

[00131] The present invention, thus generally described, will be understood more readily by reference to the following examples, which are provided by way of illustration and are not intended to be limiting of the present invention.

EXAMPLES

[00132] The following abbreviations are used throughout the discli

AcN Acetonitrile

ACOH: Acetic acid aq. Aqueous

ATP Adenosine triphosphate

DBU l,8-Diazabicyclo[5.4.0]undec-7-ene

DCE Dichloroethane

DCM Dichloromethane

DIEA iV,iV-Diisoproylethylamine

DME Dimethoxyethane

DMF Af,N-Dimethylformamide

DMSO Dimethylsulfoxide eq. Equivalent(s)

EtOAc Ethyl acetate

EtOH Ethanol

FRET Fluorescense Resonance Energy Transfer

Hex Hexanes

Hr Hour

LC-MS Liquid chromatography mass spectroscopy mCPBA Meta-chloroperbenzoic acid

MeOH Methanol min. Minute(s) NMP 1 -Methyl -2-pyrrolidinone

OMs Mesylate, 0-SO₂-CH₃

OTos Tosylate, O-SO₂-Toluene

OTf Triflate, -OSO₂-CF₃

RP-HPLC Reverse phase high performance liquid chromatography

RT Room temperature

TEA Triethylamine

TES Triethylsilane

TFA Trifluoroacetic acid

THF Tetrahydrofuran

[00133] Compounds are named according to standard IUPAC nomenclature using the software program Autonom2000 (Elsevier MDL₅ San Leandro, CA).

Example 1: Synthesis of 2,4-diaminopyrimidine derivatives.

1 2 3

[00134] Synthesis of 2-chloro-4-(7V-phenyl)amino-5-nitropyrimidine (2a).

Aniline (4.55 ml, 50 mmol) was added dropwise to a vigorously stirred solution of 2,4-dichloro-5-nitropyrirnidine (1) (4.85 g, 25 mmol) in dioxane (125 ml) at room temperature. Precipitate was formed immediately. The mixture was stirred at room temperature for 1.5 hrs. The solid was removed by filtration, and washed with dioxane (2 x 100 ml). The combined filtrate was concentrated under vacuum to give an orange solid (6.26 g, 99%). LC-MS: calcd. mass: 250; found: 250.6.

[00135] Synthesis of 2-[iV-(4-butoxycarbonyl)phenyl] amino-4-(iV- phenyl)amino-5-nitropyrimidine (3a). To a solution of 2a (0.502 g, 2.0 mmol) in dioxane (5 ml) was added n-butyl 4-aminobenzoate (1.933 g, 10 mmol). The mixture was stirred at 8O⁰C for 18 hrs. A yellow solid was formed during the reaction. The mixture was cooled to room temperature. The solid was collected by filtration, washed with methanol and dried to give the title compound as a yellow solid (0.763 j ^" 94%J.^~LC-MSrcalcd.lnassr407; ; found: 407.6. ^' [00136] Other examples: In the cases of alkyl amines, step 1 was carried out at

O⁰C with 1.0 equivalent of amine and 2-3 equivalents of DIEA. In some cases, step 2 was carried out using 1 equivalent of amine in the presence of 2-3 equivalents of DIEA. In the cases where R¹ = R², the reactions were carried out in one pot with 2.2 equivalents of amine and 3 equivalents of DIEA with or without heating depending on the reactivity of the amine used.

[00137] Synthesis of carboxylic acids. Carboxylic acid derivatives were prepared by hydrolysis of their corresponding esters using aqueous 6N HCl/dioxane (1/1) at HO⁰C.

[00138] Synthesis of amide derivatives. Amide derivatives were synthesized from their corresponding esters by treatment with 7 N methanolic ammonia at room temperature.

[00139] N²-(4-Methanesulfonyl-phenyI)-5-nitro-N⁴-phenyl-pyrimidine-2,4- diamine (3c). Sodium metaperiodate (400 mg) was added to a solution of 3b (0.056 g) in DMF (2 ml). The mixture was stirred at 100⁰C. The progress of the reaction was monitored using LC-MS. The reaction was complete in 5 hours. The mixture was diluted with water. The product was collected by filtration, washed with water and methanol, and dried to give the title compound. LC-MS: calcd. mass: 385; found: 385.6.

[00140] (lR,2S)-4-(5-Nitro-4-plienylamino-pyrimidinr2-ylamino)= cyclohexane-l,2-diol Qe). A solution of osmium tetraoxide (2.5%) in t-butanol (0.030 ml) and N-methylmorpholine N-oxide (0.053 g) were added to a solution of 3d (0.067 g) in dichloromethane (3 ml) and trace amount of water. The mixture was shaken at room temperature for 17 hours. The solvent was removed under vacuum. The residue was washed with IN HCl (aq.) (2 x 2 ml), water (3 x 2 ml) and methanol (1 x 2 ml), and dried to give the title compound (0.036 g). LC-MS: calcd. mass: 345; found: 345.6.

[00141] N⁴-Cyclohexyl-5-nitro-N²-piperidin-4-yl-pyrimidine-2,4-diamine

(4).A solution of 3f in TFA/DCM (1/1, 10 ml) was stirred at room temperature for 1 hour. The solvent was removed under vacuum. The residue was dried under vacuum to give the title compound. LC-MS: calcd. mass: 320; found: 320.6.

[00142] 3-[2-Chloro-5-nitro-pyrimidin-4-ylamino]-adamantan-l-ol (2b). 3-

Amino-1-adamantanol (836 mg, 5 mmol, 1 eq.) was added to a solution of 2,4- dichloro-5-nitropyrimidine 1 (970 mg, 5 mmol, 1 eq.) in chloroform (25 mL), followed by addition of DIEA (1.75 mL, 10 mmol, 2 eq.) and the mixture was stirred at RT for 6 days. The mixture was washed with 1 M aq. HCl, the aqueous layer was extracted with dichloromethane, the combined organic layers were dried over Na₂SO₄ and concentrated in vacuo. Trituration with diethyl ether gave pure product as an orange solid (763 mg, calc. mass: 324, obs. mass: 324/365). The diethyl ether filtrate gave additional amount of less pure product (751 mg, 95% purity, calc. mass: 324, obs. mass: 324/365). - [00143] 3-[2-(4-trans-Hydroxycyclohexylamino)-5-nitro-pyrimidin-4- ylamino]-adamantan-l-ol (S). A mixture of 2b (65 mg, 0.2 mmol, 1 eq.), trans-4- aminocyclohexanol (92 mg, 0.8 mmol, 4 eq.) and dioxane (0.6 mL) was heated to 100°C for 3.5 hr. Water (2 mL) was added, the precipitated solid was filtered, washed with water and 1 M aq. HCl. The solid is partially soluble in 1 M aq. HCl. The solid was dried under high vacuum, yielding 3 (28.1 mg, observed mass: 403, calc. mass: 403). The acidic filtrate was concentrated in vacuo, and 0.5 M aq. potassium carbonate solution (3 mL) was added. The precipitated solid was washed with water, dried under high vacuum to give another portion of 3 (64.8 mg, calc. mass: 403, obs. mass: 403).

2c 6

[00144] l-Benzyl-piperidin-4-yl)-(2-chloro-5-nitro-pyrimidin-4-yl)-amine

(2c). 2,4-Dichloro-5-nitropyrimidine 1 (415 mg, 2.14 mmol) was dissolved in dioxane (1 mL) and 4-amino-l-benzylpiperidine (440 μl, 2.14 mmol) was added at room temperature, followed by DIEA (160 μl, 0.92 mmol). The reaction mixture was stirred overnight at RT, and evaporated. Part of the crude mixture (220 mg) was partitioned between DCM and saturated aq. NaHCO₃. The organic layer was purified via silica gel chromatography, using a gradient of 0 to 5% of MeOH in DCM, affording 100 mg of desired product as an inseparable mixture of regioisomeres. (Calc. mass: 347, obs. mass: 348).

[00145] 4-[4-(l-Benzyl-piperidin-4-ylamino)-5-nitro-pyrimidin-2-ylamino]- transcyclohexanol (6). 1 -Benzyl-piperidin-4-yl)-(2-chloro-5-nitro-pvrimidm-4-yl)- amine 2c (70 mg, 0.20 mmol) was dissolved in dioxane (1 mL) and trans-4-hydroxy cyclohexylamine (45 mg, 0.40 mmol) was added. The reaction mixture was heated at HO⁰C for 30 minutes, evaporated and the crude product was purified via reverse phase chromatography, using a gradient of acetonitrile in water, affording the title compound. (Calc. mass: 427, obs. mass: 428).

2d

[00146] (2-Chloro-5-nitro-pyrimidin-4-yI)-cyclopentyI-amine (2d). To a scintillation vial were added 2,4-dichloro-5-nitropyrimidine 1 (868 mg, 4 mmol) and dioxane (1.5 mL). After the solids were completely dissolved, the solution was chilled in an ice bath, and a cold solution of cyclopentylamine (341 mg, 4 mmol) was added, followed by DIEA (160 μl, 0.92 mmol). The reaction mixture was allowed to warm up to RT and stirred 1.5 hr at RT. The solvent was evaporated and the residue was dissolved in chloroform. The crude mixture was purified via silica gel chromatography, using a gradient of 0 to 30% of EtOAc in Hex, affording 768 mg of desired product. (CaIc. mass: 242, obs. mass: 283 (+AcN)).

[00147] 4-(4-Cyclopentylamino-5-nitro-pyrimidin-2-ylamino)-trans cyclohexanol (7). To a reaction tube were added (2-chloro-5-nitro-pyrimidin-4-yl)- cyclopentyl-amine (36 mg, 0.15 mmol) 2d, dioxane (750 μL) and trans-4-hydroxy cyclohexylamine (69 mg, 0.60 mmol). The reaction mixture was heated at 100°C for 3 hrs, and diluted with MeOHZH₂O. The resulting solid was isolated by filtration, washed with MeOH/H₂O and dried in vacuo to afford the target compound (CaIc. mass: 321, obs. mass: 322).

Example 2: Synthesis of non-nitro adamantan-1-ol derivatives.

X= F (8a) X= F (9a)

X= Cl (8b) X= Cl (9b)

X= Br (8c) X= Br (9c)

X= CF₃ (8d) X= CF₃ (9d)

[00148] [00149] 3-(2-Chloro-5-fluoro-pyrimidin-4-ylamino)-adamantan-l-ol (8a).

2,4-Dichloro-5-fluoropyrimidine 1 (X=F; 375 mg, 2.25 mmol) was dissolved in dioxane (1 mL) and 3 -hydroxy adamantylamine (300 mg, 1.79 mmol) was added at room temperature, followed by DIEA (500 μl, 2.87 mmol). The reaction mixture was heated overnight at 110⁰C, cooled to RT, and diluted with 1 M aq. HCl. The solid material was filtered off and washed sequentially with 1 M aq. HCl, water and diethyl ether, and dried. The product obtained is a single isomer (430 mg, calc. mass: 297, obs. mass: 298).

[00150] 3-(2-Chloro-5-chIoro-pyrimidin-4-ylamino)-adamantan-l-ol (8b).

2,4,5-trichloropyrimidine 1 (X=Cl; 160 mg, 0.87 mmol) was dissolved in dioxane (1 mL) and 3 -hydroxy adamantylamine (146 mg, 0.87 mmol) was added at room temperature, followed by DIEA (160 μl, 0.92 mmol). The reaction mixture was heated overnight at HO⁰C, evaporated and purified via silica gel chromatography, using a gradient of 0 to 3% MeOH in DCM, affording 130 mg of the desired product as an inseparable mixture of regioisomers. (Calc. mass: 313, obs. mass: 314).

[00151] 3-(2-Chloro-5-bromo-pyrimidin-4-ylamino)-adamantan-l-ol (8c).

2,4-Dichloro~5-bromopyrimidine 1 (X=Br; 141 mg, 0.62 mmol) was dissolved in dioxane (1 mL) and 3-hydroxy adamantylamine (103 mg, 0.62 mmol) was added at room temperature, followed by DIEA (160 μl, 0.92 mmol). The reaction mixture was heated overnight at HO⁰C, evaporated and purified via silica gel chromatography, using a gradient of 0 to 3% of MeOH in DCM, affording 99 mg of the desired product as an inseparable mixture of regioisomeres. (Calc. mass: 357, obs. mass: 3558/360).

[00152] 3-(2-Chloro-5-trifluoromethyl-pyrimidin-4-ylamino)-adamantan- l-ol (8d). 2,4-Dichloro-5-trifluoromethylpyrimidine 1 (X=CF₃; 175 mg, 0.81 mmol) was dissolved in DCM and 3-hydroxy adamantylamine (135 mg, 0.81 mmol) was added at room temperature, followed by DIEA (200 μl, 1.15 mmol). After 5 hours at RT, the reaction mixture was purified via silica gel chromatography, using a gradient of 0 to 3% of MeOH in DCM, affording the desired product as an inseparable mixture of regioisomeres. (Calc. mass: 347, obs. mass: 348). [00153] Step 2:

[00154] 3-[5-Fluoro-2-(trans-4-hydroxy-cyclohexylamino)-pyrimidin-4- ylamino]-adamantan-l-ol (9a). 4-(3-Hydroxyadamantyl)amino-2 -chloro-5- fluoropyrimidine 8a (25 mg, 0.08 mmol) was dissolved in DMSO (0.3 mL) and trans- 4-hydroxy cyclohexylamine (44 mg, 0.38 mmol) was added. The reaction mixture was heated at 180°C for 45 minutes. The reaction mixture was purified via reverse phase chromatography using a gradient of acetonitrile in water, affording the title product. (CaIc mass: 376, obs. mass: 377).

[00155] 3-[5-Chloro-2-(trans-4-hydroxy-cycIohexylamino)-pyrimidin-4- ylamino]-adamantan-l-ol (9b). 4-(3-Hydroxyadamantyl)amino-2,5- dichloropyrimidine 8b (72 mg, 0.23 mmol) was dissolved in dioxane (1 mL) and trans-4-hydroxy cyclohexylamine (60 mg, 0.52 mmol) was added. The reaction mixture was heated at 110°C for 3 hours, EtOH was added (0.2 mL) and heating was continued for another 24 hours. The reaction mixture was evaporated and the crude product was purified via reverse phase chromatography using a gradient of acetonitrile in water, affording the title product along with a small amount of the other regioisomer. (CaIc. mass: 392, obs. mass: 393).

[00156] 3-[5-Bromo-2-(trans-4-hydroxy-cyclohexylamino)-pyrimidin-4- ylamino]-adamantan-l-ol (9c). 4-(3-Hydroxyadamantyl)amino-2 -chloro-5- bromopyrimidine 8c (53 mg, 0.15 mmol) was dissolved in dioxane (1 mL) and trans- 4-hydroxy cyclohexylamine (38 mg, 0.33 mmol) was added. The reaction mixture was heated at 110⁰C for 3 hours, EtOH was added (0.2 mL) and heating was continued for another 24 hours. The reaction mixture was evaporated and the crude product was purified via reverse phase chromatography using a gradient of acetonitrile in water, affording the title product along with a small amount of the other regioisomer. (CaIc. mass: 436, obs. mass: 437/439).

[00157] 3-[5-Trifluoromethyl-2-(trans-4-hydroxy-cyclohexylamino)- pyrimidin-4-ylamino]-adamantan-l-ol (9d). 4-(3-Hydroxyadamantyl)amino-2 - chloro-5-trifluoromethylpyrimidine 8d (38 mg, 0.11 mmol) was dissolved in dioxane (1 mL) and trans-4-hydroxy cyclohexylamine (25 mg, 0.22 mmol) was added. The reaction mixture was heated at 110°C for 4 hours and then purified via reverse phase chromatography using a gradient of acetonitrile in water, affording two regioisomers (CaIc. mass: 426, obs. mass: 427).

Example 3: General synthesis of azapurines 10.

3 8e 10

[00158] Method A: 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.

[00159] Step 2: π-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.

10 14 13

[00160] Method B: Stepl : 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. [00161] 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.

[00162] Step 3: To a solution of 12 (1.0 eq.) in acetic acid at 1O⁰C 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.

[00163] 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.

[00164] Step 5: To a solution of 14 (1.0 eq.) in dioxane was added corresponding amine (R⁸ -NH₂, 4.0 eq.). The mixture was stirred at 9O⁰C 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.

[00165] Method C: Step 1 : To a solution of tin dichloride dihydrate (6 eq.) in concentrated HCl (aq.) at O⁰C 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.

[00166] 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.

[00167] Step 3 : ^"To^" a^bsolution ^~of the azapurine chloride (1.0 eq.) in dioxane was added corresponding amine (R⁸ -NH₂, 5.0 eq.). The mixture was stirred at 90⁰C 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.

[00168] Using these general procedures, the azapurine derivatives listed in

Table 6 were prepared. In some cases, under LC-MS conditions, the azapurines exhibited a fragmentation pattern of [M-N₂ (28) + H (1)]⁺, or an adduct with AcN [M+41]⁺.

Table 6 Cmpd. No. Compd. Name CaIc. MW Obs. MW

IQa 4-(3-Phenyl-3H-[l,2,3]triazolo[4,5- 310 283 d]pyrimidin-5-ylamino)-cyclohexanol

IQb (lR,2S)-4-(3-Phenyl-3H- 326 299

[l,2,3]triazolo[4,5-d]pyrimidin-5- ylamino)-cyclohexane- 1 ,2-diol

10c 4-[2-(3-Phenyl-3H-[l,2,3]triazolo[4,5- 332 305 d]pyrimidin-5-ylamino)-ethyl]-phenol

IQd 4-[(3-Phenyl-3H-[l,2,3]triazolo[4,5- 334 334 d]pyrimidin-5-ylamino)-methyl]-benzene- 1,2-diol

IQe (3,4-Dimethoxy-benzyl)-(3-phenyl-3H- 362 362

[l,2,3]triazolo[4,5-d]pyrimidin-5-yl)- amine

1Of (3-Phenyl-3H-[l,2,3]triazolo[4,5- 310 282 d]pyrimidin-5-yl)-(tetrahydro-pyran-4- ylmethyl)-amine

1Og (3-Phenyl-3H-[l,2,3]triazolo[4,5- 296 269 d]pyrimidin-5-yl)-(tetrahydro-pyran-4-yl)- amine

IQh (3-Methoxy-proρyl)-(3-phenyl-3H- 284 257

[ 1 ,2,3]triazolo[4,5-d]pyrimidin-5-yl)- amine

1Oi 4-(3-Methyl-3H-[l,2,3]triazolo[4,5- 248 290 d]pyrimidin-5-ylamino)-cyclohexanol

1Oi [2-(3-Methoxy-phenyl)-ethyl]-(3-phenyl- 346 318

3H-[l,2,3]triazolo[4,5-d]pyrimidin-5-yl)- amine

IQk [2-(4-Methoxy-phenyl)-ethyl]-(3-phenyl- 346 319

3H-[l,2,3]triazolo[4,5-d]pyrimidin-5-yl)- amine

101 [2-(3,4-Dimethoxy-pheiiyl)-ethyl]-(3_r 376 377.. phenyl-3H-[l ,2,3]triazolo[4,5- d]pyrimidin-5-yl)-amine Cmpd. No. Compd. Name CaIc. MW Obs. MW

10m N-(3-Phenyl-3H-[l,2,3]triazolo[4,5- 309 310 d]pyrimidin-5-yl)-cyclohexane~l,4- diamine

IQn Phenethyl-(3-phenyl-3H- 316 289

[l,2,3]triazolo[4,5-d]pyrimidin-5-yl)- atnine 1Oo [2-(3,4-Dichloro-phenyl)-ethyl]-(3- 385 357 phenyl-3H-[l ,2,3]triazolo[4,5- d]pyrimidin-5-yl)-amine

IQp 3-[2-(3-Phenyl-3H-[l,2,3]triazolo[4,5- 332 304 d]pyrimidin-5-ylamino)-ethyl]-phenol

IQq 4-[2-(3-Phenyl-3H-[l,2,3]triazolo[4,5- 348 349 d]pyrimidin-5-ylamino)-ethyl]-benzene- 1,2-diol

IQr Cyclohex-S-enyl-^-phenyl-SH- 292 334

[ 1 ,2,3]triazolo[4,5-d]pyrimidin-5-yl)- amine

10s 4-[3-(4-tert-Butyl-ρhenyl)-3H- 366 408

[l,2,3]triazolo[4,5-d]pyrimidin-5- ylamino]-cyclohexanol

1Ot 5-(3-Phenyl-3H-[l,2,3]triazolo[4,5- 344 316 d]pyrimidin-5-ylamino)-3H- isobenzofuran- 1 -one

IQu (4-Morpholin-4-ylmethyl-benzyl)-(3- 401 402 phenyl-3H-[l ,2,3]triazolo[4,5- d]pyrimidin-5-yl)-amine

IQv l-Phenyl-2-(3-phenyl-3H- 332 315

[1 ,2,3]triazolo[4,5-d]pyrimidin-5- ylamino)-ethanol

IQw (R)-3-Phenyl-2-(3-phenyl-3H- 346 319

[l,2,3]triazolo[4,5-d]pyrimidin-5- ylamino)-propan- 1 -ol

IQx (S)-3-Phenyl-2-(3-phenyl-3H- 346 347

[1 ,2,3]triazolo[4,5-d]pyrimidin-5- ylamino)-propan-l -ol

IQy 4-[(R)-3-Hydroxy-2-(3-phenyl-3H- 362 363

[l,2,3]triazolo[4,5-d]pyrimidin-5- ylamino)-propyl]-phenol

IQz (lH-Benzotriazol-5-yl)-(3-phenyl-3H- 329 301

[l,2,3]triazolo[4,5-d]pyrimidin-5-yl)- amine lOaa (2-Morpholin-4-yl-ethyl)-(3-phenyl-3H- 325 326

[ 1 ,2,3]triazolo[4,5-d]pyrimidin-5-yl)- - amine Cmpd. No. Compd. Name CaIc. MW Obs. MW lOab (3-Morpholin-4-yl-propyl)-(3-phenyl-3H- 339 340

[l,2,3]triazolo[4,5-d]ρyrimidin-5-yl)- araine lOac 4-(3-Phenyl-3H-[l,2,3]triazolo[4,5~ 284 256 d]pyrimidin-5-ylamino)-butan- 1 -ol lOad (R)-4-Phenyl-3-(3-phenyl-3H- 431 375

[1 ,2,3]triazolo[4,5-d]ρyrimidin-5- ylamino)-butyric acid tert-butyl ester lOae 4-[3-(4-Fluoro-phenyl)-3H- 328 370

[ 1 ,2,3]triazolo[4,5-d]pyrimidin-5- ylamino] -cyclohexanol lOaf 4. {2-[3-(4-Fluoro-phenyl)-3H- 350 323

[l,2,3]triazolo[4,5-d]pyrimidin-5- ylamino]-ethyl}-phenol lOag (2,3-Dihydro-benzo[l,4]dioxin-6-yl)-(3- 346 318 phenyl-3H-[l ,2,3]triazolo[4,5- d]pyrimidin-5-yl)-amine lOah Benzo[l,3]dioxol-5-yl-(3-ρhenyl-3H- 332 304

[ 1 ,2,3 ]triazolo[4,5-d]pyrimidin-5-yl)- amine lOai N-[4-(3-Phenyl-3H-[l,2,3]triazolo[4,5- 351 352 d]pyrimidin-5-ylamino)-cyclohexyl]- acetamide lOai Furan-2-carboxylic acid [4-(3-ρhenyl-3H- 403 404

[ 1 ,2,3]triazolo[4,5-d]pyrimidin-5- ylamino)-cyclohexyl3-amide lOak 3-Methoxy-N-[4-(3-phenyl-3H- 444 444

[1₅2,3]triazolo[4,5-d]pyrimidm-5- ylamino)-cyclohexyl] -benzamide

IQaI 5-(3-Phenyl-3H-[l,2,3]triazolo[4,5- 357 399 d]pyrimidin-5-ylamino)-isoindole-l,3- dione

10am 4-{2-[3-(4-tert-Butyl-phenyl)-3H- 388 389

[l,2,3]triazolo[4,5-d]pyrimidin-5- ylamino]-ethyl} -phenol I Pan 4-[3-(4-Methoxy-ρhenyl)-3H- 340 382

[ 1 ,2,3]triazolo[4,5-d]pyrimidin-5- ylaminoj-cyclohexanol lOao 4-{2-[3-(4-Methoxy-phenyl)-3H- 362 363

[ 1 ,2,3]triazolo[4,5-d]pyrimidm-5- yl amino] -ethyl } -phenol lOap (lH-Indazol-6-yl)-(3-phenyl-3H- 328 300

[1 ,2,3]triazolo[4,5-d]pyrimidin-5-yl> - amine Cmpd. No. Compd. Name CaIc. MW Obs. MW

10-,Ki 4-[2-(3-Adamantan-l-yl-3H- 390 391

[1 ,2,3]triazolo[4,5-d]pyrimidm-5- ylamino)-ethyl]-ρhenol lOar 4-(3-Adamantan- 1 -yl-3H- 368 369, 410

[1 ,2,3]triazolo[4,5-d]ρyrimidin-5- ylamino)-cyclohexanol lOas N-[4-(3-Phenyl-3H-[l,2,3]triazolo[4,5- 414 415 d]pyrimidin-5-ylamino)-cyclohexyl]- nicotinamide lOat N-[4-(3-Phenyl-3H-[l,2,3]triazolo[4,5- 414 415 d]pyrimidin-5-ylamino)-cyclohexyl]- isonicotinamide lOau 2-Methoxy-N-[4-(3-phenyl-3H- 381 382

[1 ,2,3]triazolo[4,5-d]pyrimidin-5- ylamino)-cyclohexyl]-acetamide

10av 5-[3-(4-tert-Butyl-phenyl)-3H- 400 442

[l,2,3]triazolo[4,5-d]pyrimidin-5- ylamino]-3H-isobenzofuran-l -one

4-(3-p-Tolyl-3H-[l,2,3]triazolo[4,5- 324 366 d]pyrimidin-5-ylainino)-cyclohexanol

4-[2-(3-p-Tolyl-3H-[l,2,3]triazolo[4,5- 346 347 d]pyrimidin-5-ylamino)-ethyl]-phenol

5-(3-o-Tolyl-3H-[l,2,3]triazolo[4,5- 358 400 d]pyrimidin-5-ylamino)-3 H- isobenzofuran- 1 -one lOaz 4-[3-(2-Methoxy-phenyl)-3H- 340 341

[1 ,2,3]triazolo[4₅5-d]pyrimidin-5- ylamino] -cyclohexanol lOba 5-[3-(2-Methoxy-phenyl)-3H- 374 346

[1 ,2,3]triazolo[4,5-d]pyrimidin-5- ylamino]-3H-isobenzofuran-l -one lObb 4-(3-o-Tolyl-3H-[l,2,3]triazolo[4,5- 324 366 d]pyrimidin-5-ylamino)-cyclohexanol lObc 4-[3-(2-Chloro-phenyl)-3H- 345 316

[l,2,3]triazolo[4,5-d]pyrimidin-5- ylamino]-cyclohexanol lObd 5-[3-(2-Chloro-phenyl)-3H- 379 350

[1 ,2,3]triazolo[4,5-d]pyrimidin-5- ylamino]-3H-isobenzofuran-l-one lQbe 4-[3-(4-Trifluoromethyl-phenyl)-3H- 378 420

[ 1 ,2,3]triazolo[4₅5-d]pyrimidin-5- ylamino]-cyclohexanol lObf 5-[3-(4-Trifluoromethyl-ptienyl)-3H- 412 453

[ 1 ,2,3]triazolo[4,5-d]pyrimidin-5- ylamino]-3H-isobenzofuran-l -one Cmpd. No. Compd. Name CaIc. MW Obs. MW lObg 6-(3-Phenyl-3H-[l,2,3]triazolo[4,5- 344 385 djpyrimidm- 5-ylamino)- 3 H- isobenzofuran-1 -one lObh (3-Phenyl-3H-[l,2,3]triazolo[4,5- 281 282 d]pyrimidm-5-yl)-pyrrolidin-3-yl-amine lObi 4-(3-Indan-5-yl-3H-[l,2,3]triazolo[4,5- 350 392 d]pyrimidin-5-ylamino)-cyclohexanol lObi 4-(3-Isoρroρyl-3H-[l,2,3]triazolo[4,5- 276 277 d]ρyrimidin-5-ylamino)-cyclohexanol lObk 4-[3-(2,4-Dichloro-phenyl)-3H- 379 350 [ 1 ,2,3]triazolo[4,5-d]pyrimidin-5- ylamino]-cyclohexanol lObi [3 -(4-tert-Butyl-ρhenyl)-3H- 351 352 [l,2,3]triazolo[4,5-d]pyriniidin-5-yl]- piperidin- 3 -y 1- amine lObm {3-[3-(4-tert-Butyl-phenyl)-3H- 438 438 [l,2,3]triazolo[4,5-d]ρyrimidin-5- ylamino]-piperidin- 1 -yl } -oxo-acetic acid methyl ester lObn {3-[3-(4-tert-Butyl-phenyl)-3H- 456 456 [l,2,3]triazolo[4,5-d]pyrimidin-5- ylamino]-piperidin-l -yl} -phenyl- methanone lObo 1 - {3-[3-(4-tert-Butyl-phenyl)-3H- 393 394 [l,2,3]triazolo[4,5-d]pyrimidin-5- ylamino]-piperidin-l -yl} -ethanone lObp {3-[3-(4-tert-Butyl-phenyl)-3H- 457 457 [l,2,3]triazolo[4,5-d]pyrimidin-5- ylamino]-piperidin- 1 -yl} -pyridin-4-yl- methanone lObg {3-[3-(4-tert-Butyl-phenyl)-3H- 457 457 [l,2,3]triazolo[4,5-d]pyrimidin-5- ylamino]-piperidin- 1 -yl} -pyridin-2-yl- methanone lObr {3-[3-(4-tert-Butyl-ρhenyl)-3H- 457 457 [l,2,3]triazolo[4,5-d]pyrimidin-5- ylamino]-ρiperidin-l-yl}-pyridin-3-yl- methanone lObs {3-[3-(4-tert-Butyl-ρhenyl)-3H- 446 446

[ 1 _?2,3]triazolo[4_;5-d]pyrimidin-5- ylamino]-piperidin-l -yl} -furan-2-yl- methanone lObt, . „ [3-(4-tert-B.utyl-plienyL)-3iI- . -337 _ 338

[l,2,3]triazolo[4,5-d]pyrimidin-5-yl]- pyrrolidin-3 -yl-amine Cmpd. No. Compd. Name CaIc. MW Obs. MW lObu l-{3-[3-(4-tert-Butyl-phenyl)-3H- 379 380

[ 1,2,3 ]triazolo[4,5-d]pyrimidin-5- yl amino] -pyrrolidin- 1 -yl } -ethanone lObv {3-[3-(4-tert-Butyl-ρhenyl)-3H- 423 424

[ 1,2,3 ]triazolo[4,5-d]ρyrimidin-5- ylamino] -pyrrolidin- 1 -yl } -oxo-acetic acid methyl ester lObw {3-[3-(4-tert-Butyl-phenyl)-3H- 431 432

[1 ,2,3]triazolo[4,5-d]pyrimidin-5- ylamino]-pyrrolidin- 1 -yl } -furan-2-yl- methanone lObx {3-[3-(4-tert-Butyl-phenyl)-3H- 443 443

[ 1 ,2,3]triazolo[4,5-d]pyrimidin-5- ylamino] -pyrrolidin- 1 -yl } -pyridin-2-yl- methanone lObv {3-[3-(4-tert-Butyl-phenyl)-3H- 443 443

[l,2,3]triazolo[4,5-d]pyrimidin-5- ylamino] -pyrrolidin- 1 -yl } -pyridin-3 -yl- methanone lObz {3-[3-(4-tert-Butyl-phenyl)-3H- 443 443

[l,2,3]triazolo[4,5-d]pyrimidin-5- ylamino]-pyrrolidin-l-yl}-pyridin-4-yl- methanone lOca 5-(3-ρ-Tolyl-3H-[l,2,3]triazolo[4,5- 357 358 d]pyrimidin-5-ylamino)-2,3-dihydro- isoindol-1-one lOcb 5-[3-(4-tert-Butyl-phenyl)-3H- 399 400

[l,2,3]triazolo[4,5-d]pyrimidin-5- ylamino]-2,3-dihydro-isoindol-l-one lOcc 3-Nitro-N⁶-[2-(3-p-tolyl-3H- 406 407

[ 1 ,2,3]triazolo[4,5-d]pyrimidin-5- ylamino)-ethyl]-pyridine-2,6-diamine lOcd N⁶-{2-[3-(4-tert-Butyl-ρhenyl)-3H- 448 449

[1₅2,3]triazolo[4,5-d]ρyrimidm-5- ylamino] -ethyl } -3 -nitro-pyridine-2, 6- diamine lOce 5-(3-Isopropyl-3H-[l,2,3]triazolo[4,5- 310 352 d]pyrimidin-5-ylamino)-3H- isobenzofuran- 1 -one lOcf [3-(4-tert-Butyl-phenyl)-3H- 452 494

[l,2,3]triazolo[4,5-d]pyrimidin-5-yl]-(2- trifluoromethyl-lH-benzoimidazol-5-yl)- amine Crapd. No. Compd. Name CaIc. MW Obs. MW lOcg 3-[3-(4-tert-Butyl-ρhenyl)-3H- 419 460 [1 ,2,3]triazolo[4,5-d]pyrimidin-5- ylarnino]~adarnantan-l-ol lOch 4-(3-Cycloρentyl-3H-[l,2,3]triazolo[4,5- 302 344 d]pyrimidm~5-ylarnino)-cyclohexanol lOci 5-(3-Cyclopentyl-3H-[l,2,3]triazolo[4,5- 336 378 d]pyrimidin-5-ylamino)-3H- isobenzofuran- 1 -one lOci 4-(3-Bicyclo[2.2.1 ]hept-2-yl-3H- 328 328.6 [l,2,3]triazolo[4,5-d]ρyrimidin-5- ylamino)-cyclohexanol lOck 2-{3-[3-(4-tert-Butyl-phenyl)-3H- 408 409 [1 ,2,3]triazolo[4,5-d]pyrirnidin-5- ylamino] -pyrrolidin- 1 -yl } -2-oxo- acetamide lOci N-{3-[3-(4-tert-Butyl-phenyl)-3H- 408 408

[1 ,2,3]triazolo[4,5-d]pyrimidin-5- ylamino]-cyclohexyl}-acetamide

10cm {3-[3-(4-tert-Butyl-phenyl)-3H- 424 424

[1 ,2,3]triazolo[4,5-d]pyrimidin-5- ylamino]-cyclohexyl} -carbamic acid methyl ester lOcn N-{3-[3-(4-tert-Butyl-phenyl)-3H- 452 452

[l,2,3]triazolo[4,5-d]pyrimidin-5- ylamino]-cyclohexyl} -oxalamic acid methyl ester lOco N-{3-[3-(4-tert-Butyl-phenyl)-3H- 437 437

[1 ,2,3]triazolo[4₅5-d]pyrimidin-5- ylamino]-cyclohexyl}~oxalarnide lOcp (3-Adamantan-l-yl-3H- 386 387

[l,2,3]triazolo[4,5-d]pyrimidin-5-yl)-(lH- indazol-6-yl)-amine lOcq (3-Adamantan-l-yl-3H- 350 351

[l,2,3]triazolo[4,5-d]pyrimidin-5-yl)- furan-2-ylmethyl-amine lOcr (3-Adamantan-l-yl-3H- 361 403

[l,2,3]triazolo[4,5-d]pyrimidin-5-yl)- pyridin-3 -ylmethyl-amine lOcs (3-Adamantan-l-yl-3H- 328 329

[l₅2_J3]triazolo[4,5-d]ρyrimidin-5-yl)-(2- methoxy-ethyl)-amine lOct 4-(3-Phenyl-3H-[l,2,3]triazolo[4,5- 308 309 d]pyrimidin-5-ylamino)-cyclohexanone Cmpd. No. Compd. Name CaIc. MW Obs. MW lOcu Furan-2-carboxylic acid {3-[3-(4-tert- 460 460 butyl-phenyl)-3H-[l,2,3]triazolo[4,5- d]pvrimidm-5-ylarnino]-cyclohexyl}- amide lOcv N-{3-[3-(4-tert-Butyl-phenyl)-3H- 438 438

[1₃2,3]triazolo[4,5-dJρvrirnidin-5- ylamino]-cyclohexyl } -2-methoxy- acetamide lOcw 5-(3-Indan-5-yl-3H-[l,2,3]triazolo[4,5- 384 426 d]pyrimidin-5-ylamino)~3H- isobenzofuran- 1 -one lOcx 5-(3-Phenyl-3H-[l,2,3]triazolo[4,5- 342 343 d]pyrimidin-5-ylamino)-indan- 1 -one lOcv N-(3-Indan-5-yl-3H-[l,2,3]triazolo[4,5- 349 350 d]pyrimidin-5-yl)-cyclohexane- 1 ,3- diamine lOcz N-[(lS,3R)-3-(3-Indan-5-yl-3H- 391 392

[ 1 ,2,3]triazolo[4,5-d]pyrirnidin-5- ylamino)-cyclohexyl]-acetamide

IOda 5-(3-Indan-5-yl-3H-[l,2,3]triazolo[4,5- 397 370 d]pyrimidin-5-ylamino)-isoindole-l,3- dione

IOdb (3-Indan-5-yl-3H-[l,2,3]triazolo[4,5- 368 369 d]pyrimidin-5-yl)-(lH-indazol-6-yl)- amine

Example 4: Syntheses of purines 15

§e 15

[00169] Purine derivatives (Table 7) were synthesized using the following general procedure: To a solution of 9 (1 eq.) in DMF was added DIEA (10 eq.) and corresponding acid chloride (3 eq.) The mixture was stirred at room temperature for 1 hour and then at 15O⁰C for 18 hours. The solvent was removed under vacuum. The residue was purified using preparative RP-HPLC to give purine derivatives.

Table 7 Compd # Compound Name Cakd. Mass Obs. Mass

15a Phenyl-(9-ρhenyl-8-pyridin-4-yl-9H- 481 481 purin-2-yl)-amine

15b 3 -(9-Phenyl-2-ρhenylamino-9H-purin-8- 621 621 yl)-phenol

15c 4-[(9-Phenyl-8-ρyridin-4-yl-9H-ρurin-2- 458 458 ylamino)-methyl]-benzenesulfonamide

15d N-(3-Methoxy-benzoyl)-4- {[8-(3- 379 380 methoxy-phenyl)~9~phenyl-9H-purin-2- ylamino]-methyl}-benzenesulfonamide

15e 3-[9-Phenyl-2-(4-sulfamoyl- 364 365 benzylamino)-9H-purin-8-yl]-ρropionic acid ethyl ester

[00170] Method B. Additional purine derivatives (Table 8) were prepared using the following procedure: To a solution of 9 (1.0 eq.) in ethanol was added corresponding aldehyde (2.0 eq.). The mixture was heated at 15O⁰C using a microwave in 10 min. increments. The progress of the reaction was monitored using TLC or LC-MS. The solvent was removed under vacuum. The residue was purified using preparative RP-HPLC to give the desired product.

Table 8 Compd # Compound Name Calcd. Mass Obs. Mass

15e 3-[9-Phenyl-2-(4-sulfamoyl- 481 482 benzylamino)-9H-purin-8-yl]-propionic acid ethyl ester

15f 9-Phenyl-2-phenylamino-9H-purine-8- 359 360 carboxylic acid ethyl ester

15s; N-[4-(9~Phenyl-2-phenylamino-9H-purin- 420 421 8-yl)-phenyl]-acetamide

15h (9-Phenyl-2-phenylamino-9H-purin-8- 416 417 ylrnethyl)-carbamic acid tert-butyl ester

15i 9-(3-Methoxyphenyl)-2-(3- 419

— methoxyphenylamino)=9H-purine-8- ^{" "} carboxylic acid ethyl ester Compd # Compound Name Calcd. Mass Obs. Mass

15i 2-(4-Carboxymethoxy-ρhenylamino)-9- 433 434 phenyl-9H-purine~8-carboxylic acid ethyl ester

[00171] During the synthesis of 15f and 15i, pteridinones 16a and 16b were also isolated from the reaction mixture, respectively.

16a: R^# = H; LC-MS: calcd: 359; found:360 16b: R* = -OCH₃; LC-MS: calcd: 419; found:420

[00172] Method C: Stepl: A solution of 12 (1.0 eq., free base) in DMF was stirred at at 5O⁰C for 2h. The solvent was removed under reduced pressure. The residue was purified on a silica gel column to give the cyclized product.

[00173] Step 2: To a solution of the intermediate obtained above (1.0 eq.) in

DCM at room temperature was added m-chloroperbenzoic acid (77%, 4 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 and extracted with DCM. The combined organic layers were concentrated under vacuum to give the oxidized product.

[00174] Step 3 : To a solution of compound obtained in step 2 (1.0 eq.) in dioxane was added the corresponding amine (R⁸-NH₂, 5.0 eq.). The mixture was stirred at 13O⁰C 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-^uήn-2^'-y\smmoy^hy\y≠ιeΩor(Cal^MW: 331^~ Obs.^" MW: 332) Example 5: Synthesis of isopurine derivatives.

22 21

[00175] 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.

[00176] 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.

[00177] 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.

[00178] 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 12O⁰C 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 HO⁰C 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.

[00180] Using the above procedures, the isopurine derivatives listed in Table 9 were prepared.

Table 9

Compd # Compound Name CaIc. Mass Obs. Mass

22a (3 -Methoxy- 1 -phenyl- 1 H-pyrazolo [3 ,4- 317 318 d]pyrimidin-6-yl)-phenyl-amine

22b 4-(3 -Methoxy- 1 -phenyl- 1 H-pyrazolo [3 ,4- 375 376 d]pyrimidin-6-ylamino)-benzoic acid methyl ester

22c 4-(3-Methoxy-l-phenyl-lH-pyrazolo[3,4- 361 362 d]pyrimidin-6-ylamino)-benzoic acid

Example 6: Syntheses of 7-chloroisopurines 25

18 23 24 25

[00181] Step 1 : A solution of 18 in phosphorus oxychloride was stirred at

140⁰C for 18 hours. The solvent was removed under vacuum. The residue was mixed with ice-water. The solid was collected by filtration and purified on a silica gel column to give 23.

[00182] Step 2: To a solution of 23 (1.0 eq.) in DCM at room temperature wa; added 3-chloroρerbenzoate (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.

[00183] Step 3: To a solution of 24 (1.0 eq.) in dioxane was added an amine (5 eq.). The mixture was stirred at 12O⁰C 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.

[00184] Using the above procedures, the isopurine derivatives listed in Table

10 were prepared. Compound 25d was prepared by hydrolysis of 25c using a similar procedure as illustrated above.

Table 10 Compd # Compound Name Calcd. Mass Obs. Mass

25a 4-(3-Chloro-l-phenyl-lH-pyrazolo[3,4- 365 366 d]pyrimidin-6-ylamino)-benzamide

25b 4-(3-Chloro-l-phenyl-lH-pyrazolo[3,4- 344 345 d]pyrimidin-6-ylamino)-cyclohexanol

25c 4-(3-Chloro-l-phenyl-lH-pyrazolo[3,4- 380 381 d]pyrimidin-6-ylarnino)-benzoic acid methyl ester

25d 4-(3-Chloro-l-phenyl-lH-pyrazolo[3,4- 366 367 d]pyrimidin-6-ylamino)-benzoic acid

Example 7: Syntheses of isopurinone derivatives 27

18 or 20 26 27

[00185] Stepl : To a solution of 18 or 20 (1.0 eq.) in DCM at room temperatui was added-3-chloroperbenzoate (3.0-eqτ).- 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.

[00186] Step 2: To a solution of 26 (1.0 eq.) in dioxane was added the amine

(5 eq.). The mixture was stirred at HO⁰C 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 27.

[00187] Using the above procedure, the isopurinone derivatives listed in Table

11 were prepared. Compounds 27e and 27f were prepared by hydrolysis of 27c and 27d, respectively, using aqueous 6N HCl/dioxane (1/1) at 110⁰C.

Table 11

Compd # Compound Name Calcd. Mass Obs. Mass

27a 1 -Phenyl-6-phenylamino- 1 ,2-dihydro- 303 304 pyrazolo[3 ,4-d]pyrimidin-3-one

27b 2-Methyl- 1 -phenyl-6-phenylamino- 1 ,2- 317 318 dihydro-pyrazolo[3,4-d]pyrimidin-3-one

27c 4-(3 -Oxo- 1 -ρhenyl-2,3 -dihydro- 1 H- 361 362 pyrazolo [3 ,4-d]pyrimidin-6-ylamino)- benzoic acid methyl ester

27d 4-(2-Methyl-3-oxo-l-phenyl-2,3-dihydro- 375 376

1 H-pyrazolo [3 ,4-d]pyrimidin-6-ylamino)- benzoic acid methyl ester

27e 4-(3-Oxo-l-phenyl-2,3-dihydro-lH- 347 348 ρyrazolo[3,4-d]pyrimidin-6-ylamino)- benzoic acid

27f 4-(2-Methyl-3-oxo-l-phenyl-2,3-dihydro- 361 362 lH-pyrazolo[3,4-d]pyrimidin-6~ylamino)- benzoic acid Example 8: Syntheses of pteridinone derivative 29

[00188] 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.

[00189] Step 2: To a solution of 28 (1.0 eq.) were added an appropriate amine

(1.2 eq.) and DIEA (2.0 eq.). The mixture was stirred at HO⁰C 48 hours. The solvent was removed under vacuum. The residue was washed with water and methanol, and dried to give the target product.

[00190] 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. For R^18c = R^l&d— H, the reduction of nitro group and subsequent intramolecular cyclization completed in 1 hour to give 29. For R^1Sc = CH₃, R^18d= H, the reaction took several days to give corresponding 29.

[00191] Compound 29c was obtained by hydrolysis of the corresponding ester using a similar method as illustrated for the isopurine derivatives. Compounds 29d and 29e were prepared from their corresponding tert-butyl ester by treatment with TF A/water (19/1) at room temperature. [00192] Using the above procedure, the pteridinones listed in Table 12 were prepared.

Table 12

Compd # Compound Name Calcd Mass Obs. Mass

29a 2-[2-(4-Hydroxy-phenyl)-ethylamino]-8- 361 362 phenyl-7,8-dihydro-5H-pteridin-6-one

29b 2-(4-Hydroxy-cyclohexylamino)-8-phenyl- 339 340

7,8-dihydro-5H-pteridin-6-one

29c [4-(6-Oxo-8-phenyl-5,6,7,8-tetrahydro- 391 392 pteridin-2-ylamino)-phenoxy] -acetic acid

29d 4-(6-Oxo-8-phenyl-5,6,7,8-tetrahydro- 361 362 pteridin-2-ylamino)-benzoic acid

29e 4-(7-Methyl-6-oxo-8-phenyl-5,6,7,8- 375 376 tetrahydro-pteridin-2-ylamino)-benzoic acid

29f {4-[4-(6-Oxo-8-phenyl-5,6,7,8-tetrahydro- 442 442.7 pteridin-2-ylamino)-phenyl]-[l,2,3]triazol-l- yl} -acetic acid

Example 9: Synthesis of purinones 30 and 31

30 31

[00193] Step 1 : To a solution of 9 (1.0 eq.) in dioxane was added N₁N'- disuccinimidyl carbonate (1.5 eq.). The mixture was stirred at 16O⁰C 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.

[00194] 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 5O⁰C for 18 hours. The solvent was removed under vacuum. The residue was purified on a silica gel column to give 31.

[00195] Using the above procedures, the following purinone derivatives (Table

13) were prepared. 30c, 31k and 311 were prepared by hydrolysis of their corresponding esters using aqueous 6N HCl/dioxane (1/1) at HO⁰C.

Table 13 Compd # Compound Name Calcd. Mass Obs. Mass

30a 9-Phenyl-2-phenylamino-7,9-dihydro-ρurin- 303 304

8 -one

30b 4-(8-Oxo-9-phenyl-8,9-dihydro-7H-purin-2- 382 383 ylamino)-benzenesulfonamide

30c 4-(8-Oxo-9-ρhenyl-8,9-dihydro-7H-purin-2- 347 348 ylamino)-benzoic acid

31a 7-Methyl-9-ρhenyl-2-phenylamino-7,9- 317 318 dihydro-purin-8-one

31b 7-tert-Butyl-9-phenyl-2-phenylamino-7,9- 359 360 dihydro-purin-8-one

31c 7-Ethyl-9-phenyl-2-phenylamino-7,9- 331 332 dihydro-purin-8-one

31d 7-Benzyl-9-ρhenyl-2-phenylamino-7,9- 393 394 dihydro-purin-8-one

31e 7-Cyclohexylmethyl-9-ρhenyl-2- 399 400 ρhenylamino-7,9-dihydro-purin-8-one

31f 7-Bicyclo[2.2.1]hept-2-yl-9-phenyl-2- 397 398 phenylamino-7,9-dihydro-purin-8-one

31g 7-Isopropyl-9-phenyl-2-phenylamino-7,9- 345 346 dihydro-purin-8-one

31h 2-(3-Methoxy-phenylamino)-7-methyl-9- 347 348 phenyl-7,9-dihydro-purin-8-one

31i 4-(7-Methyl-8-oxo-9-phenyl-8,9-dihydro- 375 376

7H-purin-2-ylamino)-benzoic acid methyl ester Compd # Compound Name Calcd. Mass Obs. Mass

Hi 7-Bicyclo[2.2.1]hept-2-yl-9-ρ-tolyl-2-ρ- 426 426 tolylamino-7,9-dihydro-purin-8-one

31k 4-(7-Methyl-8-oxo-9-phenyl-8,9-dihydro- 361 362

7H-purin-2-ylamino)-benzoic acid

311 3-(7-Methyl-8-oxo-9-phenyl-8,9-dihydro- 361 362

7H-purin-2-ylamino)-benzoic acid

Example 10: GSK-3 kinase assay

[00196] Inhibition of the kinases GSK-3 α and GSK-3 β was measured with an in vitro biochemical assay. The individual kinases were purchased from Upstate Cell Signaling Solutions (Waltham, MA). The assay was developed using a Z'LYTE™ ser/thr 9 Peptide Kit available from Invitrogen (Carlsbad, CA). This assay employs a FRET-based, coupled-enzyme format and is based on the differential sensitivity of phosphorylated and unphosphorylated peptides to proteolytic cleavage. This kit supplies a synthetic peptide substrate with 2 fluorophores -one at each end- which GSK-3 actively phosphorylates. In the kinase reaction 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.

[00197] All screening was done in low volume 384-well black plates. The reactions were done with 10 μM ATP, and 2% DMSO. Both the kinase reaction and development reactions were incubated at 25°C for one hour. After the reaction was stopped by addition of the stop-reagent supplied with the kit, the coumarin (excitation 40OnM, emission 445) and fluorescein (excitation 40OnM, emission 445nM) signals were read on a fluorescence plate reader. Using the emission ratio, the % inhibition was calculated versus the positive (supplied phospho-peptide substrate) and negative controls_(kinase reaction_without.ATP).__The^point where the ^compound inhibited _ 50% of GSK-3 activity was calculated using Graphpad Prism. Example 11.

[00198] Compounds listed in the following Table were synthesized and assayed using the above procedures. Compound identity was verified by mass spectroscopy, with all molecules showing the expected mass ion. All compounds in Table 14 exhibited >40% inhibition in either the GSK-3α or GSK-3β assay or both at 10 μM.

-

Cmpd Structure Cmpd name

No. lOai Furan-2-carboxylic acid [4-(3-phenyl- 3H-[l,2,3]triazolo[4,5-d]ρyrimidm-5- ylamino)-cyclohexyl]-amide

lOak 3-Methoxy-N-[4-(3-phenyl-3H~ [ 1 ,2,3 Jtriazolo[4,5-d]pyrimidin~5- ylamino)-cyclohexyl]-benzamide

lOal 5-(3-Phenyl-3H-[l,2,3]triazolo[4,5- d]pyrimidin-5-ylamino)-isoindole-l,3- dione

10am 4-{2-[3-(4-tert-Butyl-phenyl)-3H-

NH ,OH [l,2,3]triazolo[4,5-d]pyrimidin-5- ylamino]-ethyl} -phenol

lOan 4-[3-(4-Methoxy-phenyl)-3H- [l,2,3]triazolo[4_s5-d]pyrimidin-5- ylamino] -cyclohexanol

lOao 4- {2-[3-(4-Methoxy-phenyl)-3H- [l,2,3]triazolo[4,5-d]pyrimidin-5- ylamino] -ethyl } -phenol

lOap Λfϊ rn (lH-Indazol-6-yl)-(3-phenyl-3H- [ 1 ,2,3]triazolo[4,5-d]pyrimidin-5-yl)- J! ^N f amine

U Cmpd Structure Cmpd name

No.

IPaq 4-[2-(3-Adamantan-l -yl-3H- [l,2,3]triazolo[4,5-d]pyrimidin-5- ylamino)-ethyl] -phenol

lOar 4-(3-Adamantan-l-yl-3H-

[l,2,3]triazolo[4,5-d]pyrimidin-5- ylamino)-cyclohexanol

lOas N-[4-(3-Phenyl-3H-[l,2,3]triazolo[4,5- d]pyriniidin-5-ylamino)-cyclohexyl]- nicotinamide

lOat N-[4-(3-Phenyl-3H-[l,2,3]triazolo[4,5- d]pyrimidin-5-ylamino)-cyclohexyl]- isonicotinamide

lOau 2-Methoxy-N-[4-(3-phenyl-3H- [l,2,3]triazolo[4,5-d]pyrimidin-5- ylamino)-cyclohexyl] -acetamide

10av 5-[3-(4-tert-Butyl-phenyl)-3H- [l,2,3]triazolo[4,5-d]pyrimidin-5- ylamino] -SH-isobenzoforan- 1 -one

10aw 4-(3-p-Tolyl-3H-[l,2,3]triazolo[4,5-

-CC tfi d]pyrimidin-5-ylamino)-cyclohexanol

OH

Cmpd Structure Cmpd name

No. lOce 5-(3-Isopropyl-3H-[l,2,3]triazolo[4,5- d]pyrimidin-5-ylamino)-3H- isobenzofuran- 1 -one

lOcf [3-(4-tert-Butyl-ρhenyl)-3H- [l,2,3]triazolo[4,5-d]ρyrimidin-5-yl]-(2- trifluoromethyl- 1 H-benzoimidazol-5- yl)-amine

lOcg 3-[3_(4._tert-Butyl-phenyl)-3H- [l,2,3]triazolo[4,5-d]pyrimidin-5- ylamino]-adamantan- 1 -ol

lOch 4-(3-Cyclopentyl-3H-

[l,2,3]triazolo[4,5-d]pyrimidin-5- ylamino)-cyclohexanol

lOci 5-(3-Cyclopentyl-3H-

[1 ,2,3]triazolo[4,5-d]pyrimidin-5- ylamino)-3 H-isobenzofuran- 1 -one

lOci 4-(3-Bicyclo[2.2.1]hept-2-yl-3H-

[l,2,3]triazolo[4,5-d]pyrimidin-5- ylamino)-cyclohexanol

lOck 2-{3-[3-(4-tert-Butyl-phenyl)-3H- [ 1 ,2,3]triazolo[4,5-d]pyrimidin-5- ylaminoj-pyrrolidin- 1 -yl } -2-oxo- acetamide

Cmpd Structure Cmpd name

No. lOcs (3-Adamantan- 1 -yl-3H-

NH [l,2,3]triazolo[4,5-d]ρyrimidin-5-yl)-(2- methoxy-ethyl)-amine

lOct 4-(3-Phenyl-3H-[l,2,3]triazolo[4,5-

OC NX NH d]pyrimidin-5-ylamino)-cyclohexanone

lOcu Furan-2-carboxylic acid {3-[3-(4-tert- butyl-phenyl)-3H-[l,2,3]triazolo[4,5- d]pyrimidin-5-ylamino] -cyclohexyl } - amide

lOcv N-{3-[3-(4-tert-Butyl-phenyl)-3H- [1 ,2,3]triazolo[4,5-d]pyrimidin-5- ylamino]-cyclohexyl}-2-methoxy- acetamide

lOcw ^■cα 5-(3-Indan-5-yl-3H-[l,2,3]triazolo[4,5-

N NH d]pyrimidin-5-ylamino)-3H- isobenzofuran- 1 -one

lOcx 5-(3-Phenyl-3H-[l,2,3]triazolo[4,5- d]pyrimidin-5-ylamino)-indan- 1 -one

lOcv N-(3-Indan-5-yl-3H-[l,2,3]triazolo[4,5- d]pyrimidin-5-yl)-cyclohexane- 1 ,3 - diamine

Cmpd Structure Cmpd name

No.

1Oh (3-Methoxy~propyl)-(3-phenyl-3H-

[l,2,3]triazolo[4,5-d]ρyrimidin-5-yl)-

amine

1Oi N - OH 4-(3-Methyl-3H-[l,2,3]triazolo[4,5- d]pyrimidin-5-ylaniino)-cyclohexanol

1Oi [2-(3-Methoxy-phenyl)-ethyl]-(3- phenyl-3H-[l,2,3]triazolo[4,5-

H d]pyrimidin-5-yl)-amine

10k [2-(4-Methoxy-phenyl)-ethyl]-(3-

1. phenyl-3H-[l,2,3]triazolo[4,5- d]pyrimidin-5-yl)-amine

101 [2-(3,4-Dimethoxy-ρhenyl)-ethyl]-(3- phenyl-3H-[l,2,3]triazolo[4,5- d]pyrimidin-5-yl)-amine

10m N-(3-Phenyl-3H-[l,2,3]triazolo[4,5- d]pyrimidin-5-yl)-cyclohexane- 1 ,4- diamine

1On Phenethyl-(3-ρhenyl-3H-

[l,2,3]triazolo[4,5-d]pyrimidin-5-yl)- amine

Cmpd Structure Cmpd name

No.

1Ov 1 -Phenyl-2-(3-phenyl-3H-

[l,2,3]triazolo[4,5-d]ρyrimidin-5- ylamino)-ethanol

1Ow Chlral (R)-3-Phenyl-2-(3-phenyl-3H- [1 ,2,3]triazolo[4,5-d]ρyrimidin-5- ylamino)-proρan- 1 -ol

1Ox Chlral (S)-3-Phenyl-2-(3-phenyl-3H- [l,2,3]triazolo[4,5-d]ρyrimidin-5- ylamino)-propan- 1 -ol

IQy ,OHchlral 4-[(R)-3-Hydroxy-2-(3-phenyl-3H-

[l,2,3]triazolo[4,5-d]pyrimidin-5-

H ylamino)-propyl]-phenol

1Oz (lH-Benzotriazol-5-yl)-(3-ρhenyl-3H- [ 1 ,2,3]triazolo[4,5-d]pyrimidin-5-yl)- amine

15a Phenyl-(9-phenyl-8-pyridin-4-yl-9H- purin-2-yl)-amine

15b 3 -(9-Phenyl-2-phenylamino-9H-purin- 8 - yl)-phenol

Cmpd Structure Cmpd name

No.

15c 4-[(9-Phenyl-8-ρyridin-4-yl-9H-purin-2- ylamino)-methyl]-benzenesulfonamide

15d N-(3 -Methoxy-benzoyl)-4- { [8-(3 - methoxy-phenyl)-9-phenyl-9H-purin-2- ylamino]-methyl}-benzenesulfonamide

15e 3-[9-Phenyl-2-(4-sulfamoyl- benzylamino)-9H-purin-8-yl]-propionic acid ethyl ester

15i 9-(3-Methoxyphenyl)-2-(3- methoxyphenylamino)-9H-purine-8- carboxylic acid ethyl ester

m .oJL 2-(4-Carboxymethoxy-phenylamino)-9-

U phenyl-9H-purine-8-carboxylic acid r° XX ethyl ester

15k 4-[2-(9-Phenyl-9H-purin-2-ylamino)- ethyl] -phenol

22c 4-(3 -Methoxy- 1 -phenyl- 1 H- pyrazolo[3,4-d]pyrimidin-6-ylamino)- benzoic acid

,4-

[00199] While typical embodiments have been illustrated and described, it should be understood that changes and modifications can be made therein in accordance with ordinary skill in the art without departing from the invention in its broader aspects as defined in the following claims.

Claims

CLAIMSWhat is claimed is:

1. A compound having Formula I:

Formula I, wherein

A is a substituted or unsubstituted Ci_-3 alkyl group, -F, -Cl, -Br, -CN, -NO₂, or -NH₂;

B and D are independently -NH-, -CH₂-, or -C(O)-;

R is a substituted or unsubstituted cycloalkyl or cycloalkenyl 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 R¹ and R² are not simultaneously unsubstituted adamantyl, or simultaneously unsubstituted cyclopropyl, or simultaneously unsubstituted cyclobutyl or simultaneously unsubstituted cyclohexyl; that the compound is not N-[4-(4-cycloρropylamino-5-methyl-pyrimidin-2-ylamino)- cyclohexyl]-3,4-difluoro-benzamide; and that when R¹ or R² is a cyclohexyl group, the cyclohexyl group is not substituted with -(CH₂)_nCOR^x, wherein n is O or 1 and R^x is OH, 0R^y or NR^ZR^Z, wherein R^y is a Ci_-5 alkyl or phenyl group, optionally halogenated, and each R^z is independently H, or a C_1-5 alkyl or aryl group, optionally halogenated.

2. The compound of claim 1 , wherein the compound at a concentration^" OfTO pM inhibits glycogeiTsyritKase kinase^~-3 ά, glycogen synthase kinase-3β or both.

3. The compound of claim 1, wherein R¹ is a substituted or unsubstituted cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclohexenyl group.

4. The compound of claim 1 , wherein R² is a substituted or unsubstituted pyrrolidinyl, pyrrolinyl, imidazolinyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl, tetrahydropyranyl, piperazinyl, morpholinyl, thiomorpholinyl, or piped din-3-yl group.

5. The compound of claim 1, wherein R¹ is a substituted or unsubstituted bridged cycloalkyl group.

6. The compound of claim 5, wherein R¹ is a substituted or unsubstituted 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.

7. The compound of claim 5, wherein R² is a substituted or unsubstituted pyrrolidinyl, pyrrolinyl, imidazolinyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl, tetrahydropyranyl, piperidinyl, morpholinyl, thiomorpholinyl, or piperazinyl group.

8. The compound of claim 1, wherein R¹ is a substituted or unsubstituted, bridged C_9-12 cycloalkyl group.

9. The compound of claim 8, wherein R¹ is a substituted or unsubstituted bicyclo[3.2.2]nonyl, bicyclo[3.3.1]nonyl, bicyclo[3.3.2]decanyl, adamantyl or noradamantyl group.

10. The compound of claim 8, wherein R² is a substituted or unsubstituted pyrrolidinyl, pyrrolinyl, imidazolinyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl, tetrahydropyranyl, piperidinyl, morpholinyl, thiomorpholinyl, or piperazinyl group.

11. The compound of claim 1 , 5, or 8, wherein R¹ is a substituted or unsubstituted-adamantyl-ornoradamantyhgroup. ^""

12. The compound of claim 11 , wherein R¹ is a substituted or unsubstituted adamantan-1-yl or adamantan-2-yl group.

13. The compound of claim 1, 5 or 8, wherein R¹ is substituted with -OH, -0(C_1-3 alkyl), -NH₂, halogen, or a C_1-3 alkyl group, optionally partially or fully halogenated.

14. The compound of claim 13, wherein R¹ is substituted with OH.

15. The compound of claim 1 , 5 or 8, wherein A is a substituted or unsubstituted C_1-3 alkyl group, -Br, or -NO₂.

16. The compound of claim 15, wherein A is -CF₃.

17. The compound of claim 1, 5, or 8, wherein B is -NH-.

18. The compound of claim 1 , 5 or 8, wherein D is -NH-.

19. The compound of claim 1, 5 or 8, wherein B and D are -NH-.

20. The compound of claim 1, 5 or 8, wherein R² is a cycloalkyl or cycloalkenyl group.

21. The compound of claim 20, wherein R² is a substituted or unsubstituted cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclohexenyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heρtyl, 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.

22. The compound of claim 1, 5 or 8, wherein R² is a substituted or unsubstituted cyclohexyl, cyclohexenyl, adamantyl or tetrahydropyranyl group.

23. The compound of claim 1, 5 or 8, wherein R² is substituted with -OH, -0(C_1-3 alkyl), -NH₂, halogen, or a C_1-3 alkyl group, optionally partially or fully halogenated.

24. The compound of claim 1, 5 or 8, wherein R¹ is a substituted or unsubstituted adamantyl or cyclohexyl group, and R² is a substituted or unsubstituted cyclohexyl, cyclohexenyl, adamantyl or tetrahydropyranyl group.

25. A composition comprising a compound of Formula I and a pharmaceutically acceptable carrier.

26. A method of treating a biological condition mediated by GSK- 3, the method comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound of Formula I.

27. The method according to claim 26, wherein the GSK-3- mediated biological condition is a metabolic disease, neurodegenerative disorder, affective disorder, central nervous system disorder, endocrine disorder, gastrointestinal disorder, liver disease, immune system disorder, lymphatic disorder, cerebrovascular disorder, lung disease, cancer, hair loss, inflammation, stroke, myocardial infarction, skeletal muscle atrophy, decreased sperm motility, or cardiovascular disease.

28. The method of claim 27, wherein the metabolic disease is type I or II diabetes, obesity, insulin resistance, or Syndrome X.

29. The method of claim 27, wherein the cancer is multiple myeloma, digestive system cancer, neuroblastoma, intestinal cancer, colorectal cancer, hepatoma, breast cancer, adenoma, prostate cancer, lymphoma, carcinomatosis, or lung cancer.

30. The method of claim 29, wherein the adenoma is basal cell adenoma, follicular adenoma, microcystic adenoma, monomorphic adenoma, or papillary adenoma.

31. The method of claim 27, wherein the affective disorder is bipolar disorder or manic depression.

32. The method of claim 27, wherein the neurodegenerative disorder is Alzheimer's disease, Parkinson's disease, a tauopathy, dementia; acute stroke; a cerebrovascular accident; a brain or spinal cord trauma; a peripheral neuropathy; retinopathy, or glaucoma.

33. The method of claim 32, wherein the tauopathy is frontotemporoparietal dementia, corticobasal degeneration, Pick's disease, or progressive supranuclear palsy.

34. The method of claim 32, wherein the dementia is vascular dementia or acute confusional senile dementia.

35. The method of claim 32, wherein the cerebrovascular accident is age-related macular degeneration.

36. The method of claim 27, wherein the cardiovascular disease is cardiac hypertrophy or heart failure.

37. The compound of claim 1, wherein the compound is selected from

N⁴-Cyclohexyl-5-nitro-N²-(tetrahydro-pyran-4-yl)-pyrimidine-2,4-diamine; N⁴-Cyclohexyl-N²-morpholin-4-yl-5-nitro-pyrimidine-2,4-diamine; 4-[2-(4-hydroxy-cyclohexylamino)-5-nitro-pyrimidin-4-ylamino]-cyclohexanol; N⁴-Cyclohexyl-5-nitro-N²-piperidin-4-yl-pyrimidine-2,4-diamine; N²,N⁴-Di-cyclohex-3-enyl-5-nitro-pyrimidine-2,4-diamine; 4-[4-(Adamantan-l-ylamino)-5-nitro-pyrimidin-2-ylamino]-cyclohexanol; 4-[4-(l-Benzyl-piperidin-4-ylamino)-5-nitro-pyrimidin-2-ylamino]-cyclohexanol; 4-(4-Cyclopentylamino-5-nitro-pyrimidin-2-ylamino)-cyclohexanol; 3-[2-(4-Hydroxy-cyclohexylamino)-5-nitro-pyrimidin-4-ylamino]-adamantan-l-ol; 3-[4-(4-Hydroxy-cyclohexylamino)-5-trifluoromethyl-pyrimidin-2-ylamino]- adamantan-1-ol;

3-[2-(4-Hydroxy-cyclohexylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]- adamantan-1-ol;

3-[2-(3-hydroxy-adamantan-l-ylamino)-5-nitro-pyrimidin-4-ylamino]-adamantan-l- ol;

3-[5-Fluoro-2-(4-hydroxy-cyclohexylamino)-pyrimidin-4-ylamino]-adamantan-l-ol; 3-[5-Bromo-2-(4-hydroxy-cyclohexylamino)-pyrimidin-4-ylamino]-adamantan-l-ol; 3-[5-Chloro-2-(4-hydroxy-cyclohexylamino)-pyrimidin-4-ylamino]-adamantan-l-ol; or 4-[2-(4-Hydroxy-cyclohexylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]- cyclohexanol.