NZ624366B2 - Novel purine derivatives and their use in the treatment of disease - Google Patents

Abstract

The disclosure relates to PI3K inhibitors of the formula (I) in which all of the variables are as defined in the specification, to their preparation, to their medical use, in particular to their use in the treatment of cancer and neurodegenerative disorders, and to medicaments comprising them. A representative purine derivative is: 8-(6-Fluoro-1H-indol-4-yl)-2-((S)-3-methylmorpholin-4-yl)-6-((R)-3-methyl-morpholin-4-yl)-9H-purine. resentative purine derivative is: 8-(6-Fluoro-1H-indol-4-yl)-2-((S)-3-methylmorpholin-4-yl)-6-((R)-3-methyl-morpholin-4-yl)-9H-purine.

Description

Novel Purine Derivatives and their Use in the ent of Disease Field of the Invention The invention relates to purine derivatives and ceutically acceptable salts thereof, processes for their preparation, their use in the treatment of diseases, their use, either alone or in combination with at least one additional therapeutic agent and optionally in combination with a pharmaceutically acceptable carrier, for the manufacture of pharmaceutical ations, use of the pharmaceutical preparations for the treatment of diseases, and a method of treatment of said diseases, comprising administering the purine derivatives to a warm-blooded animal, especially a human.

Background of the Invention The phosphatidylinositolkinases superfamily comprises 4 different PI3K d lipid or protein kinases. Class I, II and III are lipid kinases that differ by virtue of their substrate specificities whereas class IV Pl3Ks (also called PlKKs) are protein kinases. Class | phosphatidylinositol—S-kinases comprise a family of lipid kinases that catalyze the er of phosphate to the D'—3' position of inositol lipids to produce phosphoinositolphosphate (PIP), phosphoinositol-3,4-diphosphate (Ple) and oinositol-3,4,5—triphosphate (PIP3) that, in turn, act as second messengers in signaling cascades by docking proteins containing pleckstrin-homology, FYVE, Phox and other phospholipid-binding domains into a variety of signaling complexes often at the plasma membrane ((Vanhaesebroeck et al., Annu. Rev.

Biochem 70:535 (2001); Katso et al., Annu. Rev. Cell Dev. Biol. 172615 (2001)). Of the two Class I Pl3Ks, Class IA Pl3Ks are dimers composed of a catalytic p110 subunit (Cl [3, 6, isoforms) constitutively associated with a regulatory subunit that can be p85d, p55d, p50d, p858 or p55v. The Class IB sub-class has one family member, a dimer composed of a catalytic p110v subunit associated with one of two regulatory subunits, p101 or p84 (Fruman et al., Annu Rev. Biochem. 672481 (1998); Suire et al., Curr. Biol. 15:566 ). The modular domains of the p85/55/50 subunits include Src gy (SH2) domains that bind phosphotyrosine residues in a specific sequence t on activated receptor and cytoplasmic tyrosine kinases, resulting in activation and zation of Class lA Pl3Ks. Class IB PI3K is activated ly by G protein-coupled receptors that bind a diverse repertoire of peptide and non-peptide ligands (Stephens et al., Cell 892105 (1997)); Katso et al., Annu.

Rev. Cell Dev. Biol. 172615-675 (2001)). Consequently, the resultant phospholipid products of class I P|3K link upstream receptors with downstream cellular activities including proliferation, survival, chemotaxis, cellular king, motility, metabolism, inflammatory and allergic responses, transcription and translation (Cantley et al., Cell 642281 (1991); Escobedo and Williams, Nature 335:85 (1988); Fantl et al., Cell 69:413 (1992)).

PCT/1B2012/055929 In many cases, PIP2 and PIP3 recruit Akt, the product of the human homologue of the viral oncogene v-Akt, to the plasma membrane where it acts as a nodal point for many intracellular signaling pathways important for growth and survival (Fantl et al., Cell - 423(1992); Bader et al., Nature Rev. Cancer 5:921 (2005); Vivanco and Sawyer, Nature Rev.

Cancer 2:489 (2002)). Aberrant regulation of PI3K, which often increases survival through Akt activation, is one ofthe most prevalent events in human cancer and has been shown to occur at multiple levels. The tumor suppressor gene PTEN, which dephosphorylates phosphoinositides at the 3' position of the inositol ring and in so doing antagonizes PI3K activity, is functionally deleted in a y of tumors. In other tumors, the genes for the p110q isoform, PIK3CA, and for Akt are amplified and increased protein expression of their gene products has been demonstrated in several human s. Furthermore, mutations and translocation of p850! that serve to up—regulate the p85-p110 x have been described in human cancers. Also, somatic missense mutations in PIK3CA that activate downstream signaling pathways have been described at icant frequencies in a wide diversity of human cancers (Kang at al., Proc. Natl. Acad. Sci. USA 2 (2005); Samuels et al., e 304:554 (2004); Samuels et al., Cancer Cell 7:561-573 (2005)). These observations show that lation of phosphoinositoI-3 kinase and the am and downstream ents of this signaling y is one of the most common deregulations associated with human cancers and proliferative diseases (Parsons et al., Nature 4362792 (2005); Hennessey at el., Nature Rev. Drug Disc. 42988-1004 (2005)).

The mammalian target of rapamycin (mTOR) is a member of the class IV PI3K. mTOR assembles a signaling network that transduces nutrient signals and various other stimuli to regulate a wide range of cellular functions including cell growth, proliferation, survival, autophagy, various types of differentiation and metabolism. In mammalian cells, the mTOR protein is found xed in two distinct entities called mTORC1 and . The mTORC1 complex, that is to say mTOR associated with raptor, has been the matter of numerous studies. It is mTORC1 that integrates nutrient and growth factor inputs, and is in turn responsible for cell growth regulation, mainly through protein synthesis regulators such as 4EBP1 or RPSG. mTORC1 regulation requires PI3K and Akt activation for activation, meaning that mTORCl is an effector of the PI3K pathway. mTOR when associated in the mTOR complex 2 2) has been shown to be responsible for the activation of Akt by phosphorylation of S473 (Akt 1 numbering) ssov et al., Science 30727098 (2005)). mTORCZ is hence here considered as an upstream activator of Akt. Interestingly mTOR can therefore be considered as being important both upstream and downstream of Akt. mTOR catalytic inhibiton might therefore represent a unique way of addressing a very strong block in the kt pathway, by addressing both upstream and downstream effectors.

A link between mTOR inhibition and autophagy has also been demonstrated (Ravikumar et al., Nat Genet. 36(6):585—95 (2004)). Autophagy is essential for neuronal homeostasis and its dysfunction has been linked to neurodegeneration. Loss of autophagy in neurons causes egenerative disease in mice (Komatsu et al., Nature 441 :880-4 ; Hara et al., Nature 441:885-9 (2006)) suggesting a al role for autophagy to maintain protein tasis in neurons. Neurodegenerative es are characterized by inclusions of misfolded proteins as one of the hallmarks. ion of autophagy enhances nce of misfolded ns and thus is proposed as therapy for neurodegenerative proteinopathies.

Huntington‘s Disease (HD) is an autosomal dominant neurodegenerative disorder where a mutation of IT15 gene encoding the Huntingtin (Htt) protein leads to Polyglutamine expansion in Exon1 of Htt. Intracellular aggregation of this mutant Htt protein and brain y (in particular cortex and striatum) are the main hallmarks of HD. It clinically leads to movement disturbance and cognitive dysfunction besides psychiatric bances and weight loss.

Inhibition of mTOR induces autophagy and reduces mutant Htt aggregation and mutant Htt- mediated cell death in in vitro and in vivo models of HD (Ravikumar et al., Nat Genet. 36(6):585—95 (2004)). mTOR inhibition ore provides an opportunity for pharmaceutical intervention and modulation of the disrupted cellular processes characteristic of HD.

In view of the above, mTOR inhibitors are considered to be of value in the treatment of proliferative diseases, such as cancer, and other disorders, in particular, HD.

The present invention relates to novel purine derivatives having mTOR inhibitory activity, their preparation, medical use and to medicaments comprising them.

Summag of the Invention In a first aspect, the invention relates to a compound of formula (I), or a pharmaceutically able salt thereof, PCT/IBZOlZ/055929 \1R1o R11R12 N R13 R17 Y R1‘; R15 R14 wherein R1 is selected from the group ting of (R18)m / \ _N HZNQ—EN— ”ZN—(wN— 7 , [M3N HN/N\ N R H R R18 on each ence independently represents fluoro or methyl; m represents 0, 1, 2 or 3; R19 and R20 independently represent hydrogen or fluoro; R21 ents fluoro; R22 on each occurrence independently represents fluoro, methoxy, hydroxymethyl or methoxycarbonyl; q represents 0, 1 or 2 and rrepresents 0, 1, 2 or 3 provided that q + r is not 0; R2, R3, R4, R5, R6, R7, R8 and R9 independently represent hydrogen, C1_3alky| orfluoro—C1. salkyl; or R3 and R6 together form a methylene bridge; or R3 and R8 together form an ethylene ; or R5 and R6 together form an ethylene bridge; n and p independently represent 0, 1 or 2; R10, R“, R12, R13, R14, R15, R16 and R17 on each occurrence independently represent hydrogen, C1_3alkyl, fluoro-C1_3alky| or hydroxy—C1_3alkyl; or R11 and R16 together form an PCT/132012/055929 ethylene bridge; or R13 and R14 together form an ethylene bridge; or R14 and R15, together with the carbon atom to which they are attached, are linked to form a tetrahydropyranyl ring; Y represents 0, CHRza, CRZ’J'R25 or NRZS, wherein R23 represents hydroxyl or fiuoro-C1.3alkyl; or R23 and R13, together with the carbon atoms to which they are attached, are linked to form a fused ydrofuranyl ring; R24 and R25 independently represent en or halogen; or R24 and R25, together with the carbon atom to which they are attached, are linked to form a tetrahydropyranyl ring; R26 represents C1_3alkyl or oxetanyl; a compound, or a pharmaceutically acceptable salt thereof, selected from the following list of compounds: 8—(1H-Indol-4—yl)(3-methyl-morpholinyl)[1 ,4]oxazepanyl-9H-purine; 8—(1H-lndolyl)(3-methyl—morpholinyI)(3-propyl-morpholinyl)—9H-purine; 8—[8-(1H-lndolyl)(3-methyl-morpholinyl)—9H-purinyl]-8—aza-bicyclo[3.2.1]octanol; 8-[8-(1H-|ndolyl)—6-(3-methyl-morpholin-4—yl)—9H-purinyl]—8-aza-bicyclo[3.2.1]octanol; 2—(3-Ethyl-morpholinyl)—8—(1H-indoI—4-y|)(3-methyl-morpholinyl)—9H-purine; 8-(1H-lndolyl)(3-methyl-morpho|inyl)(4-methyl-piperazin-‘l-y|)-9H-pu rine; lndol—4-yl)—6-(3—methyl-morpholinyl)(6-oxaaza—spiro[3.5]nonyl)-9H-purine; 8—(1H-lndolyl)(3-methyl-morpholin-4~yl)(4-oxetan-3—yl—piperazinyl)-9H-purine; 8-(1 H-lndolyl)(3-methyl-morpho|inyl)(tetrahydro-furo[3,4-c]pyrrolyl)-9H-purine; 2-(Hexahydro-furo[3,4-c]pyridin-5—yl)~8-(1 H-indolyl)(3-methyl-morpholin-4—yl)—9H-purine; 8—(1H-lndol—4-yl)(3-isopropyl-morpho|inyl)(3—methyl-morpholin-4—yl)—9H-purine; 8—(1H-lndolyl)(3-methyl—morpho|inyl)—2—(4—trifluoromethyl-piperidin—1—yl)-9H-purine; -Dimethyl-morpholinyl)(1H—indolyl)(3-methyl-morpholinyl)—9H-purine; lndolyl)(3-methyl-morpholinyl)(7-oxaaza-spiro[3.5]nony|)-9H-purine; {4-[8-(1 H-lndol-4—yl)(3-methyl-morpholinyl)—9H-purinyl]-morpholiny|}-methanol; {4-[8—(1H-lndoI—4—yl)—6—(3-methyl-morpholin—4—yl)—9H—purinyl]-morpholin—2—yl}-methanol.

Definitions As used herein, the term “halogen" or “halo” refers to fluoro, chloro, bromo, and iodo.

WO 61305 As used herein, the term “C1_3alkyl” refers to a fully saturated branched or unbranched hydrocarbon moiety having up to 3 carbon atoms. Representative examples of C1_3a|ky| include methyl, ethyl, n-propyl and iso—propyl.

As used herein, the term xy-C1_3alkyl" refers to a C1_3alkyl group as defined herein above, substituted by one hydroxy radical. Representative examples of hydroxy-C1_3alkyl include, but are not limited to, hydroxyl-methyl, 2—hydroxy-ethyl, 2—hydroxy—propyl and 3- y-propyl.

As used herein, the term "fluoro-C1.aalkyl" refers to a C1.3a|ky| radical, as defined above, substituted by one or more fluoro radicals. Examples of fluoro-C1-3alkyl include trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 1-f|uoromethylfluoroethyl and fluoropropyl.

As used herein, the term "a,” "an,” "the” and similar terms used in the context of the present invention (especially in the context of the claims) are to be construed to cover both the ar and plural unless otherwise indicated herein or clearly contradicted by the context.

The use ofany and all examples, or exemplary language (e.g. "such as”) provided herein is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention othenivise claimed.

The term "compounds of the present invention" (unless specifically identified othen/vise) refer to nds of formula (l), compounds of the Examples, pharmaceutically acceptable salts of such compounds, and/or hydrates or solvates of such compounds, as well as, all stereoisomers ding diastereoisomers and enantiomers), tautomers and isotopically labeled compounds (including deuterium). The term s of the ion” is intended to have the same meaning as “compounds of the present invention".

As used herein, the term “inhibit”, "inhibition" or “inhibiting" refers to the reduction or suppression of a given condition, symptom, or disorder, or disease, or a icant decrease in the baseline activity of a biological activity or process.

As used , the term “isomers” refers to different compounds that have the same molecular formula but differ in arrangement and configuration of the atoms. Also as used , the term “an optical isomer” or “a stereoisomer" refers to any of the s stereo isomeric rations which may exist for a given nd of the present invention and includes geometric isomers. It is understood that a substituent may be attached at a chiral center of a carbon atom. The term "chiral'l refers to molecules which have the property of non—superimposability on their mirror image partner, while the term "achiral" refers to molecules which are superimposable on their mirror image partner. Therefore, the invention W0 2013/061305 includes enantiomers, diastereomers or racemates of the compound. “Enantiomers” are a pair of stereoisomers that are non- superimposable mirror images of each other. A 1:1 mixture of a pair of omers is a "racemic” mixture. The term is used to designate a racemic mixture where appropriate. "Diastereoisomers" are stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other. The absolute stereochemistry is specified according to the Cahn— lngold- Prelog R-S system. When a compound is a pure enantiomer the chemistry at each chiral carbon may be specified by either R or 8. Resolved compounds whose absolute configuration is unknown can be designated (+) or (-) depending on the ion (dextro- or levorotatory) which they rotate plane polarized light at the wavelength of the sodium D line. Certain nds described herein contain one or more asymmetric centers or axes and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute chemistry, as (R)— or (S)-.

As used herein, the term aceutically acceptable carrier" includes any and all solvents, dispersion media, gs, surfactants, antioxidants, preservatives (e.g., cterial agents, antifungal agents), isotonic agents, absorption delaying agents, salts, preservatives, drugs, drug stabilizers, binders, excipients, disintegration agents, lubricants, sweetening agents, flavoring agents, dyes, and the like and combinations thereof, as would be known to those d in the art (see, for example, Remington's Pharmaceutical es, 18th Ed.

Mack Printing Company, 1990, pp. 1289- 1329). Except insofar as any conventional carrier is incompatible with the active ingredient, its use in the therapeutic or pharmaceutical compositions is contemplated.

As used herein, the term “prevention” of any particular disease or er refers to the administration of a compound of the invention to a subject before any symptoms of that e or disorder are apparent.

As used herein, the terms “salt” or “salts” refers to an acid addition salt of a compound of the ion. “Salts” include in particular “pharmaceutically acceptable salts”. The term “pharmaceutically acceptable salts" refers to salts that retain the biological effectiveness and properties of the compounds of this ion and, which typically are not biologically or othenNise undesirable.

As used herein, the term “subject" refers to an animal. Typically the animal is a mammal. A subject also refers to for example, primates (e.g., humans, male or female), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds and the like. in certain embodiments, the subject is a primate. In yet other embodiments, the subject is a human.

As used herein, a subject is “in need of’ a treatment if such subject would benefit biologically, medically or in quality of life from such treatment.

The term "a eutically effective amount" of a compound of the present invention refers to an amount of the compound of the present invention that will elicit the ical or l se of a subject, for example, reduction or inhibition of an enzyme or a protein activity, or ameliorate symptoms, alleviate conditions, slow or delay disease progression, or prevent a disease, etc. In one non-limiting ment, the term “a therapeutically effective amount" refers to the amount of the compound of the present invention that, when administered to a subject, is effective to (1) at least partially alleviating, inhibiting, preventing and/or ameliorating a condition, or a disorder or a disease (i) mediated by mTOR or (ii) associated with mTOR activity, or (iii) characterized by activity (normal or abnormal) of mTOR; (2) reducing or inhibiting the activity of mTOR. In another non-limiting embodiment, the term “a therapeutically effective amount” refers to the amount of the compound of the present invention that, when administered to a cell, or a tissue, or a non-cellular biological material, or a medium, is effective to at least lly reduce or inhibit the activity of mTOR. The meaning of the term “a therapeutically effective amount" as illustrated in the above embodiments for mTOR also applies by the same means to any other relevant proteins/peptides/enzymes, such as class IV PI3Ks.

As used , the term “treat", “treating" or "treatment" of any e or disorder refers in one embodiment, to ameliorating the disease or disorder (i.e., slowing or arresting or reducing the development of the disease or at least one of the clinical symptoms thereof). In another embodiment, “treat", "treating" or "treatment" refers to modulating the disease or disorder, either physically, (e,g., ization of a discernible symptom), physiologically, (e.g., ization of a physical parameter), or both.

Detailed Description of the ion The present invention provides compounds and pharmaceutical formulations thereof that may be useful in the treatment or prevention of diseases, conditions and/or disorders modulated by the inhibition of mTOR.

Embodiment 1: a nd of formula (I), or a pharmaceutically acceptable salt thereof, as described hereinbefore.

Embodiment 2: a nd of formula (I), or a pharmaceutically able salt thereof, PCT/lBZ012/055929 R N 9 N \ N 1“ R1—</fiR 11 R R12 {:1 N N R13 R15 14 wherein R1 is selected from the group ting of (R18)m / \ HNW HN />—E (R )q E \ \ N R19 22 H R (R and )' , ; wherein R18 on each occurrence independently represents fluoro or methyl; m represents 0, 1, 2 or 3; R19 and R20 independently represent hydrogen or fluoro; R21 represents fluoro; R22 on each occurrence independently ents , methoxy, hydroxymethyl or methoxycarbonyl; q represents 0, 1 or 2 and r represents 0, 1, 2 or 3 provided that q + r is not 0; R2, R3, R4, R5, R6, R7, R8 and R9 independently represent hydrogen, C1_3alkyl or fluoro-C1. 3alkyl; or R3 and R6 together form a methylene bridge; or R3 and R3 together form an ethylene bridge; or R5 and R6 together form an ethylene bridge; n and p ndently represent 0, 1 or 2; R10, R11, R12, R13, R14, R15, R16 and R17 on each occurrence independently represent hydrogen, C1-3alkyl, fluoro-C1.3alky| or hydroxy-C1_3alkyl; or R11 and R16 together form an WO 61305 ethylene ; or R13 and R” together form an ethylene bridge; or R14 and R15, er with the carbon atom to which they are attached, are linked to form a tetrahydropyranyl ring; Y represents 0, CHR23, CR24R25 or NR”, wherein R23 represents hydroxyl or fluoro-C1.3alkyl; or R23 and R13, together with the carbon atoms to which they are attached, are linked to form a fused tetrahydrofuranyl ring; R24 and R25 independently represent hydrogen or halogen; or R24 and R25, together with the carbon atom to which they are attached, are linked to form a tetrahydropyranyl ring; R26 represents C1_3alky| or oxetanyl.

Embodiment 3: a compound according to Embodiment 1 or Embodiment 2, or a pharmaceutically acceptable salt thereof, wherein R1 represents m")m / \ ment 4: a compound according to Embodiment 3, or a pharmaceutically acceptable salt thereof, wherein m represents 0.

Embodiment 5: a compound according to Embodiment 1 or Embodiment 2, or a pharmaceutically able salt thereof, wherein R1 represents HN/ \ Embodiment 6: a compound according to Embodiment 5, or a pharmaceutically acceptable salt thereof, n R19 and R20 both represent hydrogen.

Embodiment 7: a compound according to Embodiment 1 or Embodiment 2, or a pharmaceutically acceptable salt thereof, wherein R1 represents W0 2013/061305 (R21) (Rn)r Embodiment 8: a nd according to Embodiment 7, or a pharmaceutically acceptable salt thereof, wherein q represents 0 or 1 and r represents 0, 1 or 2.

Embodiment 9: a compound ing to any one of Embodiments 1 to 8, or a pharmaceutically acceptable salt thereof, wherein R2, R3, R4, R5, R6, R7, R8 and R9 independently represent hydrogen or methyl; or R3 and R6 together form a methylene bridge; or R3 and R8 together form an ethylene ; or R5 and R6 together form an ethylene bridge.

Embodiment 10: a compound according to any one of Embodiments 1 to 9, or a ceutically acceptable salt thereof, wherein Y ents 0.

Embodiment 11: a compound according to any one of Embodiments 1 to 9, or a pharmaceutically acceptable salt thereof, wherein Y represents CHR” or CR24R25.

Embodiment 12: a compound, or a pharmaceutically acceptable salt thereof, according to Embodiment 1 which is selected from: 2,6-Bis—(3-methyl-morpholinyl)pyridin-2—yl-9H-purine; ethyl—morpholinyl)(3-methyl-morpholinyl)—8—(1H-pyrazolyI)-9H—purine; 8—(1H-|ndoIy|)(3-methyl-morpholinyl)[1,4]oxazepanyI-9H-purine; 8-[4-(1H-Imidazol—Z-y|)-phenyl]-2,6-bis-(3-methyI-morpholin-4—yl)—9H-purine; 8—(6-FIuoro-1H-indol-4—yl)—2-(3-methyl-morpholiny|)(3-methyl—morpholin-4—yl)-9H—purine; {4-[2,6-Bis-(3-methyl-morpholin-4—yl)—9H-purin-8—yl]-1H—indol—6-yl}-methanol; 2—(3-Methyl—morpholinyl)—6-(3-methyl-morpholinyl)pyridinyl-9H-purine; 2,6-Bis-(3-methyl-morpho|iny|)pyridin-2—yl—9H-purine; 2,6-Di-morpholin-4—yl-8—pyridinyl-9H-purine; 2,6—Bis-(3-methy|-morpho|in—4—yl)—8—(1H-pyrazol—3-yl)—9H-purine; 2,6-Bis-(3-methyl-morpholin-4—yl)(1H-pyrazoIyl)-9H-purine; 8—(1H-lndol-4—yl)(3-methyl-morphoIinyl)(3-propyl-morpho|in—4-y|)-9H-purine; 8-[8-(1H-IndoIyl)(3-methyl-morpholinyl)—9H-purinyl]aza-bicyclo[3.2.1]octanol; 1H-lndol-4—yl)(3-methyl-morpholinyI)-9H-purin—2-yl]—8—aza-bicyclo[3.2.1]octanol; 2—(3—EthyI-morpholin-4—yl)—8—(1H—indol—4-y|)(3—methy|—morpholin-4—yl)—9H—purine; PCT/lBZOlZ/055929 IndoIyl)(3-methyl—morpholinyl)(4-methyl-piperaziny|)-9H-purine; 8—(1H-lndol-4—yl)(3-methyl-morpholinyl)(6—oxaaza-spiro[3.5]nonyI)-9 H-pu rine; 8—(1H-lndolyl)(3-methyl-morpholinyI)(4-oxetanyl-piperazinyl)-9H-purine; 8-(1H-lndoIyl)(3-methyl-morpho|iny|)(tetrahydro-furo[3,4-c]pyrro|yl)-9H-purine; 2—(Hexahydro-furo[3,4—c]pyridin-5—yl)—8—(1H-indol—4-yl)(3-methyl-morpholinyl)—9H—purine; 8—(1H-lndolyl)(3-isopropyl-morpholinyl)(3-methyl-morpho|iny|)-9H-purine; lndo|-4—y|)(3-methyl-morpholin~4-yI)(4-trifluoromethyl-piperidinyl)-9H-pu rine; 2-(2,6-Dimethyl-morpholinyI)(1 H-indoly|)-6—(3-methyl-morpholinyl)—9 ne; 8-(1H-lndoIyl)(3-methyl-morpholinyl)(7-oxaaza-spiro[3.5]nonyl)-9H-purine; {4-[8-(1 H-lndolyl)(3-methyl—morpholinyl)-9H-purin—2—yl]—morpholiny|}-methanol ; {4-[8-(1 H-I ndolyl)(3-methyl—morpho|inyl)-9H-purin—2-yl]—morpholinyl}-methanol; -[2,6—Bis-(3-methyl-morpholin—4-y|)-9H-purinyl]-pyridinylamine; -[2,6—Bis-(3-methyl-morpholin—4—yl)—9 H-purinyl]-pyridin—2-ylamine; —[2,6-Bis—(3-methyl—morpholin—4-y|)- 9H-purin-8—yl]—pyrimidinyl-amine; 8-[4-(1H-lmidazolyl)—phenyI]-2,6-bis-(3-methyl—morpholinyl)—9H-purine; 8-(6-Methoxy-1H—indolyl)(3-methyl—morpholinyl)(3-methyl-morpholinyl)-9H— purine; 4-[2,6-Bis-(3-methyl-morpholin-4—y|)-9H-purinyl]-1H-indole—G—carboxylic acid methyl ester; and pharmaceutically acceptable salts thereof.

Embodiment 12: a compound, or a pharmaceutically acceptable salt thereof, according to Embodiment 1 which is selected from: 2,6-Bis—((R)—3-methyI-morpho|inyl)pyridinyl—9H-purine; 2—((S)Methyl—morpholin—4-yl)—6-((R)—3-methyl—morpholinyl)—8—(1 zol-S-yl)—9H— purine; 8-(1H-IndoIyl)((R)methyl-morpholiny|)[1 ,4]oxazepanyI-9H-purine; 8-[4—(1H-Imidazol-2—yl)-phenyl]—2,6~bis—((R)—3-methyl-morpholinyl)—9H—purine; 8—(6-Fluoro-1 H-indol-4—yl)((S)—3-methyl-morph0linyl)((R)—3-methyl-morpholinyl)- 9H—purine; {4-[2,6-Bis-((R)—3-methyl-morpholinyl)-9H-purin—8-yl]-1H-indol—6-y|}-methanol; 2—((S)Methyl-morpholinyl)—6-((R)methyl-morpholiny|)pyridin-2—yI-9H-purine; 2,6-Bis-((S)—3-methyI-morpholiny|)pyridinyl—9H-purine; 2,6-Di-morpho|inylpyridinyl-9H-purine; s—((S)—3—methyl-morpholinyl)—8—(1H-pyrazol-3—yl)-9H-purine; 2,6-Bis-((R)—3-methyl-morpholinyl)-8—(1H-pyrazolyl)-9H-pu ri ne; 8—(1H-|ndoIyl)((R)methyl-morphoIinyl)((R)—3-propy|—morpholinyl)—9H-pu rine; 8-[8-(1 H-Indolyl)—6-((R)—3-methyl-morpholinyl)-9H-purinyl]—8-aza-bicyclo[3.2.1]octan- 3-ol; 1H-lndo|y|)—6-((R)—3-methyl-morpholin—4-yl)-9H-purinyl]aza-bicyclo[3.2.1]octan- 3-ol; 2—((R)—3-Ethyl-morpholin—4—yl)—8—(1H-indolyl)((R)methyl-morpholinyl)-9H-purine; 8-(1H-lndolyl)((R)methyl-morpholinyl)(4-methyl-piperazinyl)-9H-purine; 8-(1H-lndol—4—yl)—6-((R)methyl-morpholinyl)(6-oxaaza—spiro[3.5]nonyl)-9H- purine; 8—(1H-lndolyl)((R)—3-methyl-morpholin—4-yl)-2—(4-oxetanyl-piperaziny|)-9H-purine; 8-(1H-lndolyl)((R)methyl-morpholin-4~yl)—2-(tetrahydro-furo[3,4-c]pyrrol-5—yl)-9H- purine; 2—(Hexahyd ro-furo[3,4-c] pyridin—5—yl )(1 H-indolyl)((R)methyl-morpholin—4—yl)—9H- purine; 8—(1H-lndolyl)—2-((R)isopropyl-morpholinyl)—6-((R)—3-methyl-morpholin-4—yl)—9H- purine; &(1H—lndol—4—yl)—6-((R)methyl—morpholinyl)(4—trifluoromethyl—piperidin—1-yl)-9H- purine; ,6R)-2,6-Dimethyl-morpholin-4—yl)—8—(1H-indolyl)—6—((R)—3-methyl—morpholinyl)-9H- purine; 8—(1H-|ndolyl)((R)methyl-morpholinyI)(7-oxa-1—aza-spiro[3.5]non—1-y|)—9H- purine; {(S)—4-[8-(1 H-lndolyl)—6-((R)methyl-morpholin—4-yI)-9H-purinyl]-morpholinyl}- {(R)[8-(1H-lndolyl)((R)methyl-morpholinyl)—9H-pu rinyl]-morpholinyl}— methanol; -[2,6-Bis-((S)methyl—morpholin-4—yl)—9H—purin—8—yl]—pyridin—2-ylamine; -[2,6-Bis-((R)—3-methyl-morpholinyl)-9H-purin-8—yl]-pyridinylamine; -[2,6-Bis—((R)methyl-morpholin—4-yl)— 9H-purinyl]-pyrimidinyI-amine; 8-[4-(1H-lmidazol-2—yl)—phenyl]—2,6-bis-((S)methy|—morpholin-4—yl)-9H-purine; 8—(6-Methoxy—1 l—4-yl)((S)methyl—morpholin-4—yl)—6—((R)methyl-morpholinyl)- 9H—purine; 4-[2,6-Bis—((R)—3-methyl-morpholinyl)-9H-purin-B-yl]-1H-indole—G-carboxylic acid methyl ester; and pharmaceutically acceptable salts thereof.

On account of one or more than one asymmetrical carbon atom, which may be present in a compound of the formula (I), a corresponding nd of the formula (I) may exist in pure optically active form or in the form of a mixture of optical isomers, e. g. in the form of a race- mic mixture. All of such pure optical isomers and all of their mixtures, including the racemic es, are part of the present invention.

Depending on the choice of the starting materials and procedures, the nds can be present in the form of one of the le isomers or as mixtures thereof, for example as pure optical isomers, or as isomer mixtures, such as tes and diastereoisomer mixtures, depending on the number of asymmetric carbon atoms. The present invention is meant to e all such possible isomers, including racemic mixtures, diasteriomeric es and optically pure forms. Optically active (R)- and (S)- isomers may be ed using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituent may be E or 2 configuration. If the compound contains a disubstituted cycloalkyl, the cycloalkyl substituent may have a cis- or trans-configuration. Where a compound comprising one or more chiral centers is drawn herein with the stereochemistry indicated in the drawn structure, then the individual optical isomer is intended. Where a compound comprising one or more chiral centers is drawn herein without the stereochemistry indicated in the drawn structure, then no one specific optical isomer is intended and the drawn chemical structure may represent any optical isomer or mixture of isomers having that structure, for example a racemic or diasteriomeric mixture.

In one ment, there is provided a compound of the Examples as an isolated stereoisomer wherein the compound has one stereocenter and the isomer is in the R configuration.

In one embodiment, there is provided a compound of the Examples as an isolated stereoisomer wherein the compound has one stereocenter and the stereoisomer is in the S uration.

In one embodiment, there is provided a nd of the Examples as an isolated stereoisomer wherein the compound has two stereocenters and the stereoisomer is in the R R configuration.

In one embodiment, there is provided a compound of the es as an isolated stereoisomer n the compound has two stereocenters and the stereoisomer is in the R S configuration.

In one embodiment, there is provided a compound of the Examples as an isolated stereoisomer n the compound has two stereocenters and the stereoisomer is in the S R configuration.

In one embodiment, there is provided a compound of the Examples as an ed stereoisomer wherein the compound has two stereocenters and the stereoisomer is in the S S configuration.

In one embodiment, there is provided a compound of the Examples, wherein the nd has one or two centers, as a racemic mixture.

It is also possible that the intermediates and nds of the present invention may exist in different eric forms, and all such forms are embraced within the scope of the invention. The term "tautomer" or "tautomeric form" refers to ural isomers of different energies which are interconvertible via a low energy barrier. For e, proton tautomers (also known as prototropic tautomers) include interconversions via ion of a proton, such as keto-enol and imine-enamine isomerizations. A specific example of a proton tautomer is the imidazole moiety where the proton may migrate between the two ring nitrogens. Valence tautomers include interconversions by reorganization of some of the bonding electrons.

The compounds of the present invention may be capable of forming acid salts by virtue of the presence of amino groups or groups similar thereto.

In one embodiment, the invention relates to a compound of the formula (I) as defined , in free form. In another embodiment, the invention relates to a compound of the formula (I) as defined herein, in salt form. In another embodiment, the ion relates to a compound of the formula (I) as defined herein, in acid addition salt form. In a further embodiment, the invention relates to a compound of the formula (I) as defined herein, in pharmaceutically acceptable salt form. In yet a further embodiment, the invention relates to a compound of the formula (I) as defined herein, in pharmaceutically acceptable acid addition salt form. In yet a further embodiment, the ion relates to any one of the compounds of the Examples in free form. In yet a further embodiment, the invention relates to any one of the nds of the Examples in salt form. In yet a further embodiment, the invention relates to any one of the compounds of the Examples in acid addition salt form. In yet a further ment, the invention relates to any one of the compounds of the Examples in pharmaceutically able salt form. In still another embodiment, the invention relates to any one of the nds of the Examples in pharmaceutically acceptable acid addition salt form.

Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids, e.g., acetate, aspartate, te, besylate, bromide/hydrobromide, bicarbonate/carbonate, bisulfate/sulfate, oamphorsulfonate, chloride/hydrochloride, chIortheophyIIonate, citrate, isulfonate, fumarate, gluceptate, gluconate, glucuronate, hippurate, hydroiodide/iodide, isethionate, e, Iactobionate, Iaurylsulfate, malate, maleate, malonate, mandelate, mesylate, methylsulphate, naphthoate, napsylate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, e, phosphate/hydrogen PCT/132012/055929 phosphate/dihydrogen phosphate, polygalacturonate, propionate, te, succinate, sulfosalicylate, tartrate, tosylate and trifluoroacetate salts.

Inorganic acids from which salts may be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.

Organic acids from which salts may be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, c acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, sulfosalicylic acid, and the like.

The ceutically able salts of the present invention can be synthesized from an acidic moiety, by conventional chemical methods. Generally, such salts can be prepared by reacting free base forms of these compounds with a stoichiometric amount of the appropriate acid. Such reactions are typically carried out in water or in an organic solvent, or in a mixture of the two. Generally, use of non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or itrile is desirable, where practicable. Lists of additional suitable salts can be found, e.g., in “Remington's ceutical Sciences", 20th ed., Mack Publishing Company, Easton, Pa., (1985); and in “Handbook of Pharmaceutical Salts: Properties, ion, and Use” by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002). rmore, the nds of the present invention, ing their salts, may also be obtained in the form of their hydrates, or include other solvents used for their crystallization.

The compounds of the present invention may inherently or by design form solvates with pharmaceutically acceptable solvents (including water); therefore, it is intended that the ion embrace both solvated and unsolvated forms. The term "solvate" refers to a molecular complex of a compound of the present invention (including pharmaceutically acceptable salts thereof) with one or more solvent molecules. Such solvent molecules are those commonly used in the pharmaceutical art, which are known to be innocuous to the recipient, e.g., water, ethanol, and the like. The term "hydrate" refers to the x where the solvent molecule is water.

Compounds of the invention, i.e. compounds of formula (I) that contain groups capable of acting as donors and/or acceptors for hydrogen bonds may be e of forming co-crystals with suitable co-crystal formers. These co-crystals may be prepared from nds of formula (I) by known co-crystal forming ures. Such procedures include grinding, heating, co-subliming, co-melting, or contacting in solution compounds of formula (I) with the co-crystal former under crystallization conditions and isolating co-crystals thereby formed.

PCT/IBZOIZ/055929 Suitable co-crystal formers include those bed in . Hence the invention further provides co-crystals comprising a compound of formula (I).

The compounds of the present invention, including salts, hydrates and es thereof, may inherently or by design form polymorphs.

Any formula given herein is also intended to represent unlabeled forms as well as ically labeled forms of the compounds. lsotopically labeled compounds have ures depicted by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be orated into compounds of the invention include isotopes of en, carbon, nitrogen, oxygen, phosphorous, fluorine, and chlorine, such as 2H, 3H, 11C, 130, 14C, 15N, 18F 31F, 32F, 358, 36Cl, 125l respectively. The invention includes various isotopically labeled compounds as defined herein, for example those into which ctive isotopes, such as 3H and 14C, or those into which non—radioactive es, such as 2H and 13C3 are t. Such isotopically labelled compounds are useful in metabolic studies (with 14C), reaction kinetic studies (with, for example 2H or 3H), detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) ing drug or substrate tissue distribution assays, or in radioactive treatment of patients. In particular, an 18F or labeled compound may be particularly desirable for PET or SPECT studies. lsotopically- labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and ations using an appropriate isotopically-labeled reagents in place of the non—labeled reagent previously employed.

Further, substitution with heavier isotopes, particularly deuterium (i.e., 2H or D) may afford certain eutic ages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements or an improvement in therapeutic index. It is understood that deuterium in this context is ed as a tuent of a compound of the formula (I). The concentration of such a heavier isotope, specifically deuterium, may be defined by the ic enrichment factor. The term "isotopic enrichment factor" as used herein means the ratio between the ic abundance and the natural abundance of a specified isotope. If a tuent in a compound of this invention is denoted deuterium, such compound has an isotopic enrichment factorfor each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium oration), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation).

Pharmaceutically acceptable solvates in accordance with the invention include those wherein the solvent of crystallization may be isotopically substituted, e.g. D20, de-acetone, de-DMSO.

Compounds of the present invention may be synthesized by synthetic routes that include processes analogous to those well-known in the chemical arts, particularly in light of the description contained . The starting materials are generally available from cial sources such as Sig ma-Aldrich or are readily prepared using methods well known to those skilled in the art (e.g., prepared by methods generally described in Louis F. Fieser and Mary Fieser, Reagents for Organic Synthesis, v. 1-19, Wiley, New York (1967-1999 ed.), or Beilsteins Handbuch der organischen Chemie, 4, Aufl. ed. Springer-Verlag, Berlin, including supplements (also available via the ein online database».

In a further aspect, the invention relates to a s for the preparation of a compound of the a (I), in free form or in ceutically acceptable salt form, comprising (a) the reaction of a compound of formula (II) (II) in which Y, R2, R3, R4, R5, R6, R7, R8, R9, R”, R", R12, R13, R14, R15, R16, R”, n and p are as defined for formula (I), with a compound of formula (III), (IV) or (V) H o\B,o \/\/S I1 I1 i (III) (IV) (V) in which R1 is as defined for formula (I), or (b) the reaction of a compound of formula (VI) W0 2013/061305 (VI) in which R‘, R2, R3, R4, R5, R6, R7, R3 and R9 are as defined for formula (I) and Hal represents halogen, for example chloro, with a compound of formula (VII) R10 R11 HN R13 R17 Y R R15 R14 (VII) in which Y, R10, R“, R12, R13, R14, R15, R16, R", n and p are as defined for formula (I), and (c) the optional reduction, oxidation or other functionalisation of the resulting nd, (d) the cleavage of any protecting group(s) present, (e) the recovery of the so obtainable nd of the a (I) in free form or in pharmaceutically able salt form, (f) the optional separation of mixtures of optically active s into their individual optically active isomeric forms.

The reactions can be effected according to conventional methods. For example, the reaction described in step (a) above may be carried out in the presence of a suitable metal catalyst, for example Pd(PPh3)4 or PdC|2(dppf), optionally a suitable base, for example cesium fluoride, a suitable solvent, for example toluene or NEta, acetonitrile/water, and at a suitable temperature, for example 90 to 150 °C.

The reaction described in step (b) above may be carried out in the presence of suitable base, for example DIPEA, a suitable solvent, for example 1-butanol, and at a suitable temperature, for example 70 to 90 °C.

The further optional reduction, oxidation or other onalisation of compounds of formula (I) may be carried out ing to methods well know to those skilled in the art.

Within the scope of this text, only a y removable group that is not a constituent of the particular desired end product of the compounds of the present invention is designated a W0 2013/061305 "protecting group", unless the context indicates otherwise. The protection of functional groups by such ting , the protecting groups themselves, and their cleavage reactions are described for example in standard reference works, such as J. F. W. McOmie, "Protective Groups in Organic Chemistry", Plenum Press, London and New York 1973, in T. .

W. Greene and P. G. M. Wuts, "Protective Groups in Organic Synthesis", Third edition, Wiley, New York 1999, in "The Peptides"; Volume 3 (editors: E. Gross and J. Meienhofer), Academic Press, London and New York 1981, in "Methoden der organischen Chemie" (Methods of Organic Chemistry), Houben Weyl, 4th n, Volume 15/l, Georg Thieme Verlag, Stuttgart 1974, and in H.—D. Jakubke and H. Jeschkeit, "Aminoséuren, Peptide, Proteine" (Amino acids, Peptides, Proteins), Verlag Chemie, Weinheim, Deerfield Beach, and Basel 1982. A characteristic of protecting groups is that they can be removed readily (i.e. without the ence of red secondary reactions) for example by solvolysis, reduction, photolysis or alternatively under logical conditions (e.g. by enzymatic cleavage).

Salts of compounds of the present invention having at least one salt-forming group may be prepared in a manner known to those skilled in the art. For example, acid addition salts of compounds of the present invention are ed in customary manner, e.g. by treating the compounds with an acid or a suitable anion exchange reagent.

Salts can be converted into the free compounds in accordance with methods known to those skilled in the art. Acid addition salts can be converted, for example, by treatment with a suitable basic agent.

Any ing mixtures of isomers can be separated on the basis of the physicochemical differences of the constituents, into the pure or ntially pure geometric or l isomers, diastereomers, racemates, for example, by tography and/or fractional crystallization.

For those compounds containing an asymmetric carbon atom, the nds exist in individual optically active isomeric forms or as mixtures thereof, eg. as racemic or diastereomeric mixtures. Diastereomeric mixtures can be separated into their individual diastereoisomers on the basis of their physical al differences by methods well known to those skilled in the art, such as by tography and/or fractional crystallization.

Enantiomers can be ted by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereoisomers and converting (e.g., hydrolyzing) the individual reoisomers to the corresponding pure WO 61305 omers. Enantiomers can also be separated by use of a commercially available chiral HPLC column.

The invention further includes any t of the present processes, in which the reaction components are used in the form of their salts or optically pure material. Compounds of the invention and intermediates can also be converted into each other according to s generally known to those d in the art.

For illustrative purposes, the reaction schemes depicted below provide potential routes for synthesizing the compounds of the present invention as well as key intermediates. For a more detailed description of the individual reaction steps, see the Examples section below.

Those skilled in the art will appreciate that other synthetic routes may be used to synthesize the inventive compounds. Although specific ng materials and reagents are depicted in the schemes and discussed below, other starting materials and reagents can be easily substituted to provide a variety of derivatives and/or on conditions. In addition, many of the compounds prepared by the methods described below can be further modified in light of this disclosure using conventional chemistry well known to those skilled in the art.

PCT/IBZOIZ/055929 Scheme 1. General Procedure 1 for synthesis of purine compounds R 10 O R11R12 HN R13 E R9 R17 Y N R16 R15 (VII) H—'</ \N (IX) R14 I k —> —> H N/ CI Base, Solvent Base, t Heat (VIII) R11R12 R R11R12 R13 Base, Solvent R13 WY Y 16 R16 R15 R14 R14 W R7 R‘\ R8 I1 I N R 1 \ (III). R (IV) or M R” R1 / N | /J\ :2"er N N R13 . u Coupling Agent Base, Solvent R17 Y (I) R16 R15 R14 Generally, the nds of formula (I) can be ed according to Scheme 1 in four steps, starting from commercially available material (VlIl). As to the individual steps in the scheme shown above, step one involves preparation of the intermediate (X) by chlorine displacement with a nucleophile such as functionalized morpholino intermediate (IX).

Intermediate (XI) can be prepared by on of intermediate (X) with intermediate (VII) in the presence of adequate base such as diisopropylethyl amine, solvent such as dimethyl acetamide and heat. Step three involves bromination of intermediate (XI) to intermediate (II) utilizing bromine in an appropriate t such as dichloromethane. Target compounds of formula (I) can be prepared by coupling intermediate (II) with a variety of cially available or synthesized boronic acids or esters of structures (III) or (IV), or tributylstannyl derivatives of formula (V), using metal catalysts most often exemplified by commercially available palladium complexes.

Scheme 2. General Procedure 2 for synthesis of purine compounds R6 R R7 R7 R“ R8 CI R9 R9 N (IX) N \ \ Br2 N N/ Base, Solvent Cl H N/ Base, Solvent (VIII) (X) HO\ /OH 0\ /o R‘\ /\/\ IB ? W3“ R 1 (In), R (IV) or (V) Coupling Agent Base, t (XII) R10 11 R R12 R R7 R R HM R13 RWWY 9 R16 R15 N 14 IV") 11 R R1—</ l R R12 R1 1R")/ 13 Base, Solvent u N N R Heat R17WY (XIII) (I) R16 R15 R14 Generally, the compounds of formula (I) can be prepared according to Scheme 2 in four steps, starting from commercially available material (VIII). As to the individual steps in the scheme shown above, step one involves preparation of the intermediate (X) by chlorine displacement with a nucleophile such as a onalized lino intermediate of a (IX). Intermediate (XII) can be prepared by bromination of intermediate (X) in the presence of PCT/I32012/055929 an appropriate solvent such as dichloromethane. Step three es the coupling of intermediate (XII) with a variety of commercially available or synthesized boronic acids or esters of structures (III) or (IV), or tributylstannyl derivatives of formula (V), using metal catalysts most often exemplified by commercially available palladium complexes. Target nds of formula (I) can be prepared by treatment of the intermediate (XIII) with a functionalized morpholino intermediate (VII) in the presence of adequate base such as diisopropylethyl amine, solvent such as dimethyl acetamide and heat or under microwave irradiation.

Scheme 3. General Procedure for synthesis of boronic esters. o o \ / / \ o o 1 1 R—Br _———» R—-B XIV catalyst, solvent, base IV heat Boronic esters of formula (IV) can be prepared according to Scheme 3 in one step where R1 is as described in a (I). The step involves reacting substituted arylbromide or heteroarylbromide of formula (XIV) with nacolato)diboron in the presence of a commercially available palladium catalyst, a t such as dioxane, and at a temperature g from 80°C to 120°C.

The invention further es any variant of the present processes, in which the reaction components are used in the form of their salts or optically pure material. Compounds of the invention and intermediates can also be converted into each other according to methods lly known to those skilled in the art.

Compounds of the formula (I), in free form or in pharmaceutically acceptable salt form, hereinafter often referred to as “agents of the invention”, exhibit valuable pharmacological properties, when tested in vitro, and may, therefore, be useful in medicaments, in therapy or for use as ch als, for example as tool compounds.

The agents of the invention are inhibitors of mTOR. The inhibiting properties of a compound of the invention towards mTOR can be evaluated in tests as described hereinafter.

Biological Assays Test 1: mTOR nding assay based on TR—FRET for recombinant human mTOR PCT/IBZOlZ/055929 1. 8-point serial dilutions of compounds (10 mM stock) are performed in 90% DMSO in a 384-well "masterplate” and 50 nL is erred onto 384-well assay plates (white polystyrene small volume; Matrix/Thermo Scientific Cat. No. . 2. The final volume of the assay is 10 pL and the order of addition is as follows: 50 nL of compounds on; uL of a mixture of GST-mTOR and Europium anti-GST antibody with or without the Pl3K/mTOR inhibitor Pl-103 (3-(4—(4-morpholinyl)pyrido[3’,2' :4,5]furo[3,2-d]pyrimidin-2— yl)phenol, Calbiochem); uL of tracer-314. incubated for 60 minutes at room temperature.

TR—FRET measured in Biotek Synergy2 reader at: Excitation 340nm/emission 665nm Excitation 340nm/emission 620nm The assay buffer ts of 50 mM HEPES pH 7.5, 5 mM MgCl2, 1 mM EGTA, 0.01% Pluronic F-127. Tracer-314 (Alexa Fluor® 647-labeled mpetitive kinase inhibitor; Cat.

No. PV6087), Europium anti-GST antibody (Cat. No PV5594) and N-terminally GST-tagged truncated human mTOR (FRAP1) (Cat. No PV4754) are ble from Invitrogen.

The following final concentrations are used: 3 nM GST—mTOR; 1 nM Europium anti-GST antibody; +/— 10 pM PI-103; and nM tracer-314.

The final concentrations of d compounds are 9091; 2730; 910; 273; 91; 27; 9; and 3 nM. The final tration of DMSO is 0.45% The following controls are used: High signal: solvent vehicule, GST—mTOR, Eu—anti-GST antibody, tracer-314; Low signal: solvent vehicule, GST—mTOR, Eu-anti—GST antibody, , -314. 3. leo determinations may be performed as follows: Raw signal at 340/665 is divided by the raw signal at 340/620 to give an emission ratio.

The Emission ratio is converted to percentage of inhibition for each compound concentration.

IC50 values are calculated by fitting a dal dose-response curve to a plot of assay readout over compound concentration. All fits and analysis are performed with the program XLfit4 (ID Business Solutions, Guildford, UK).

Test 2: Cellular mTOR assay A cell based assay (384-well ) was developed for determination of compound effects on cellular mTOR kinase activity in MEFs (mouse embryo rasts) cells derived from mice lacking TSC1 (Tuberosclerosis Complex1) a potent suppressor of mTOR kinase activity. Due to lack of TSC1 the mTOR kinase is constitutively activated resulting in permanently ed phosphorylation of Thr 389 of 86 kinase 1 (86K1) which is one of the downstream targets of mTOR (Kwiatkowski D.J., Zhang H., Bandura J.L. et al. (2002)] A mouse model of TSC1 reveals sex—dependent lethality from liver hemangiomas, and up- regulation of p7086 kinase activity in T80 null cells. Hum.Mol.Gen. 11: 525-534).

Day 0 : Cell seeding .' Subconfluent TSC1-/— MEFs are cultured in DMEM High glucose supplemented with 10 % Heat Inactivated FCS and 2 % Hepes. mTOR is constitutively active in these cells leading to permanently enhanced phosphorylation of p7086 kinase. The cells are harvested by trypsinization, resuspended in growth medium, counted and adjusted to 133,333 cells/ml. 30 pl are added per well to a 384 well-plate using a Multidrop instrument (Thermo scientific), resulting in 4000 well. The plates are incubated at 37°C / 5% 002 for 20 hours (to allow for settling and adherance to the surface).

Day 1 : Compound treatment: Eight 3-fold serial dilutions of test-compounds (beginning at 1.8 mM) are prepared in 90 % DMSO and compiled on 384 well master plates (Greiner). A pan- pPl3K/mTOR tor (0.8 mM of 8-(6-methoxy—pyridinyl)methy|—1-(4—plperaziny| trifluoromethyl-phenyl)—1,3-dihydro-imidazo[4,5—c]quinolinone in 90 % DMSO) is added to the wells for the low control. 90% DMSO is added to the wells for the high controls. nds are ed as 250 nl shots (Hummingbird) in 384 well-polypropylene microplates (compound plates). 50 pl of growth medium is added to the compound plates (dilution 1:200)with the Multidrop. After shaking (1 min at 2000 rpm), 10 pl of the first dilution is then transferred to the cell plate with a Matrix Plate Mate 2x3 pipettor (final dilution 1:4).

After 1 hour of treatment, medium is removed from the plate and 20 pl of Surefire lysis buffer is added per well with the rop.

Surefire assay: Cell lysates are frozen for 15 minutes, thawed with shaking and transferred to the experimental 384 well—Proxiplate (5 l) for the P-P7086K (T389) Surefire assay (Perkin Elmer #TGR7OS50). The fist mix is ed of the reaction buffer (containing the specific antibody), the activation buffer and the acceptor beads (40 vol, 10 vol and 1 vol respectively). 5 pl per well is added to the s with a Zephyr® SPE Workstation (Caliper Life Sciences) and incubated for 2 hours with shaking at room temperature. After this PCT/lBZOlZ/055929 incubation time, the second mix of dilution buffer and donor beads (20 vol and 1 vol respectively) is added to the plate with the same instrument (2 pl/well). After 2 hours, the plate can be read with an EnVision® Multilabel Reader (Perkin Elmer). Since the beads are light sensitive, their transfer and incubation is executed in a dark room (greenlight).

Day 2 : Data analysis .' The raw data is used to generate dose response curves for test compounds and leo values calculated therefrom.

Test 3: Autophagy assay Autophagy is a lic pathway that degrades bulk cytosol in lysosomal compartments enabling amino acids and fatty acids to be recycled. One of the key regulators of agy is the mammalian target of rapamycin , a conserved serine/threonine kinase which suppresses the initiation of the autophagic process when nutrients, growth factors and energy are available. To quantify autophagy induction by mTOR inhibitors, we use a y-GFP-LC3 reporter which is le to retroviral delivery into mammalian cells, stable expression and analysis by scence microscopy. mCherry-GFP-LCB Reporter The amino acid sequence of the mCherry-GFP-LC3 construct is shown below (SEQ ID NO: 1). The mCherry ce is underlined, GFP sequence is in bold and LC3A sequence is boxed.

MVSKGEEDNMAI|KEFMRFKVHMEGSVNGHEFEIEGEGEGRPYEGTQTAK LKVTKGGPLPFAWDlLSPQFMYGSKAYVKHPADiPDYLKLSFPEGFKWER VMNFEDGGVVTVTQDSSLQDGEFIYKVKLRGTNFPSDGPVMQKKTMGWEA SSERMYPEDGALKGElKQRLKLKDGGHYDAEVKTTYKAKKPVQLPGAYNV NI KLDITS HN EDYTIVEQYERAEGRHSTGGMDELYKPVATMVSKGEELFT GWPILVELDGDVNGHKFSVSGEGEGDATYGKLTLKFICTTGKLPVPWPT LVTTLTYGVQCFSRYPDHMKQHDFFKSAMPEGYVQERTlFFKDDGNYKTR AEVKFEGDTLVNRIELKGIDFKEDGNlLGHKLEYNYNSHNWIMADKQKN GIKVNFKIRHNlEDGSVQLADHYQQNTPlGDGPVLLPDNHYLSTQSALSK DPNEKRDHMVLLEFVTAAGlTLGMDELYKSGLRSRAQASNSAVD- FKQRRSFADRCKEVQQlRDQHPSKlPVllERYKGEKQLPVLDKTKFLVPD LVKl |RRRLQLNPTQAFFLLVNQHSMVSVSTPIADIYEQEKDED GFLYMVYASQETFGF Described hereinafter is an imaging protocol and image recognition algorithm to visualize and e changes in the autophagic pathway.

Quantification of autoghagy using hig h-content imaging and analysis 1. Day 0: Cell plating. Subconfluent H4 mCherry—GFP—LC3 cells are harvested by trypsinization, resuspended in growth medium, and counted (H4 cells: Human neuroglioma cell line (ATCC)). A cell suspension of 66‘000 cells/mL is prepared and 30 uL are added into the wells of a 384-well plate using an electronic hannel pipette.

This results in 2000 cells/well being plated. The cell plates are briefly spun down and placed at 37°C and 5% C02.

N. Day 1: Compound treatment. nd dose responses are prepared in DMSO. The dose ses are then diluted 1:50 in medium. 10u| of the diluted compound is added to 30ul of cells, yielding a final 1:200 dilution of the al compound and final of 0.5% DMSO. Compound-treatments are performed in triplicates. The 384-well plates are placed at 37°C and 5% 002. Compound treatment is performed for 16-18 h (see Note 1). 3. Day 2: Cell on. Cells are fixed by adding 10 uL/well 5x concentrated Mirsky‘s fixative supplemented with L Hoechst33342. This results in a total volume of 50|JL per well and a concentration of 1x ‘s fixative and 5 pg/mL Hoechst33342.

The 384-well plate is briefly spun down and incubated for 1 h at room temperature. Cells are then washed using a 384~we|l plate washer using a ol which aspirates the volume down to 10 pL/well before dispensing 100 pL/well 1X TBS. Aspiration and dispensing steps are repeated 4 times and a final volume of 100 uL/well is left. The plate is sealed using an adhesive PCR foil. 4. Imaging. The bottom of the plate is cleaned with 70% ethanol and then imaged using the InCell 1000 automated epifluorescence microscope. 20x ication is used and 4 ent areas (fields) are imaged per well, this typically captures a total of around 400 cells per well. Hoechst33342 images are acquired using an excitation of 360 nm 40x filter), an emission of 460 nM (HQ460_40M filter) and an exposure time of 150 ms. GFP images are acquired using an excitation of 475 nm (S475_20x filter), an emission of 535 nM (HQ535_50M filter) and an exposure time of 1 s. mCherry images are acquired using an excitation of 535 nm (HQ535_50X filter), an emission of 620 nM (H0620_60M filter) and an exposure time of 1 s. A quadruple band pass mirror is used for all images.

. Image analysis. The InCell Analysis software is used to analyze the images using the Multi Target Analysis algorithm. First, nuclei are detected in the Hoechst33342 image using top-hat segmentation and a minimal nuclear area of 50pm2. Cells are defined using a collar of 10 um around the nuclei. Second, puncta (organelles) are identified in the mCherry image inside the cells using multi-top-hat segmentation. Third, the mask of the mCherry pu ncta is transferred onto the GFP image. Fourth, the GFP fluorescence intensity inside the mCherry puncta mask is measured (reference intensity). 6. The ‘organelles‘ ter reflects mCherry-positive puncta of the mCherry-GFP-LC3 reporter and is used to calculate ‘LC3 puncta/cell’. For this e, the number of organelles is calculated per cell and averaged over all the cells in a given well ge per cell basis). y-positive L03 puncta s (y-axis) are plotted against the compound dose se values (x-axis) and EC50 values are calculated for each compound. EC50 values represent compound potency in terms of autophagy activation (e.g. increase in mCherry-positive LC3 puncta count).

Notes 1. Autophagy—modulation and redistribution of mCherry-GFP-LC3 can be already observed after a compound treatment time of 3-4 h. r, more robust effects are seen with 16—18 h treatment times.

The compounds of the Examples showed the values presented in Table 1 below when tested in the above assays.

Table 1 Test 2: T389 cellular Test 3: Autophagy assay IC50 (nM) E050 (nM) 1010 351 296 471 727 484 319 1682 4743 n.d. = not determined; n.m.— not measurable As indicated by the test s described before, compounds of the present invention may be useful for treating diseases, ions and disorders modulated by the inhibition of the mTOR ; consequently, the compounds of the present invention (including the compositions and processes used therein) may be used in the manufacture of a medicament for the therapeutic applications described herein. Hence, another embodiment of the present invention is a pharmaceutical composition sing a compound of the t invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, diluent or carrier.

A typical formulation is prepared by mixing a compound of the present invention and a carrier, diluent or excipient. Suitable carriers, diluents and ents are well known to those skilled in the art and include materials such as carbohydrates, waxes, water soluble and/or ble polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and the like. The particular carrier, diluent or excipient used will depend upon the means and purpose for which the compound of the present invention is being applied. Solvents are generally selected based on solvents recognized by persons skilled in the art as safe to be administered to a mammal. In l, safe solvents are non-toxic aqueous solvents such as water and other non-toxic ts that are soluble or miscible in water. Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycols (e.g., PEG400, PEG300), etc. and mixtures thereof. The formulations may also include one or more buffers, stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents and other known additives to e an elegant presentation of the drug (Le, a compound of the present invention or pharmaceutical composition thereof) or aid in the manufacturing of the pharmaceutical product (i.e., medicament).

The formulations may be prepared using tional dissolution and mixing procedures.

For example, the bulk drug substance (i.e., compound of the present ion or stabilized form of the compound (e.g., complex with a cyclodextrin derivative or other known xation agent)) is dissolved in a suitable solvent in the presence of one or more of the W0 2013/061305 PCT/1B2012/055929 excipients. The compound of the present invention is typically ated into pharmaceutical dosage forms to provide an easily controllable dosage of the drug and to give the patient an elegant and easily handleable product.

The pharmaceutical composition (or formulation) for application may be packaged in a variety of ways depending upon the method used for administering the drug. Generally, an article for distribution es a container having deposited therein the pharmaceutical formulation in an appropriate form. Suitable containers are well-known to those d in the art and include materials such as bottles (plastic and , sachets, ampoules, plastic bags, metal cylinders, and the like. The container may also include a tamper-proof assemblage to prevent indiscreet access to the contents of the package. In addition, the container has deposited thereon a label that describes the ts of the container. The label may also include appropriate warnings.

In one embodiment, the invention relates to the treatment of cellular proliferative diseases such as tumor and/or cancerous cell growth mediated by mTOR. Diseases may include those showing overexpression or amplification of PI3K alpha, Rheb, somatic mutation of PIKSCA or germline mutations or somatic mutation of PTEN, T801, T802, or ons and translocation of p85d that serve to up—regulate the p85-p110 complex. In particular, the nds are useful in the treatment of human or animal (e.g., murine) cancers, including, for example, sarcoma; lung; bronchus; prostate; breast (including sporadic breast cancers and sufferers of Cowden e); as; gastrointestinal cancer; colon; rectum; colon carcinoma; colorectal adenoma; thyroid; liver; intrahepatic bile duct; hepatocellular; adrenal gland; stomach; gastric; glioma; glioblastoma; endometrial; melanoma; ; renal pelvis; y bladder; uterine oorpus; uterine ; vagina; ovary; le myeloma; esophagus; a leukaemia; acute myelogenous leukemia; chronic myelogenous leukemia; lymphocytic leukemia; myeloid leukemia; brain; a carcinoma of the brain; oral cavity and pharynx; larynx; small intestine; non-Hodgkin lymphoma; ma; villous colon adenoma; a neoplasia; a neoplasia of epithelial character; lymphomas; a y oma; basal cell carcinoma; squamous cell carcinoma; actinic keratosis; tumor diseases, ing solid tumors; a tumor of the neck or head; polycythemia vera; essential thrombocythemia; myelofibrosis with myeloid metaplasia; and Walden stroem disease.

In other ments, the condition or disorder is selected from the group consisting of: polycythemia vera, essential thrombocythemia, myelofibrosis with myeloid metaplasia, asthma, COPD, ARDS, Loffler's syndrome, eosinophilic pneumonia, tic (in particular metazoan) infestation (including tropical eosinophilia), bronchopulmonary aspergillosis, polyarteritis nodosa (including Churg—Strauss syndrome), eosinophilic granuloma, eosinophil- PCT/132012/055929 d disorders affecting the airways occasioned by drug-reaction, psoriasis, contact itis, atopic itis, alopecia areata, erythema multiforme, dermatitis herpetiformis, scleroderma, vitiligo, hypersensitivity is, urticaria, bullous pemphigoid, lupus erythematosus, pemphisus, epidermolysis bullosa ita, autoimmune haematogical disorders (e.g. haemolytic anaemia, aplastic anaemia, pure red cell anaemia and idiopathic thrombocytopenia), systemic lupus erythematosus, ondritis, scleroderma, Wegener omatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, Steven- Johnson syndrome, idiopathic sprue, autoimmune inflammatory bowel disease (e.g. ulcerative colitis and s disease), endocrine mopathy, Grave's disease, sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis, primary biliary cirrhosis, uveitis (anterior and posterior), interstitial lung fibrosis, psoriatic arthritis, glomerulonephritis, vascular diseases, atherosclerosis, hypertension, deep venous thrombosis, stroke, dial infarction, unstable angina, thromboembolism, pulmonary embolism, thrombolytic diseases, acute arterial ischemia, peripheral thrombotic ions, and coronary artery disease, reperfusion injuries, pathy, such as ic retinopathy or hyperbaric oxygen-induced retinopathy, and conditions characterized by elevated intraocular pressure or secretion of ocular aqueous humor, such as glaucoma. onal syndromes with an ished or potential molecular link to dysregulation of mTOR kinase activity are, for instance, described in “K. Inoki et al. ; Disregulation of the TSC-mTOR pathway in human disease, Nature Genetics, vol 37, ; “D.M. Sabatini; mTOR and cancer: insights into a complex relationship, Nature Reviews, vol. 6, 729-734”; and in “B.T. sy et al.; Exploiting the Pl3K/Akt pathway for cancer drug discovery, Nature Reviews, vol. 4, 988—1004”, and are as follows: 0 Organ or tissue transplant rejection, e.g. for the treatment of recipients of eg. heart, lung, combined heart-lung, liver, kidney, pancreatic, skin or corneal transplants; graft-versus- host disease, such as following bone marrow transplantation; 0 Restenosis o Tuberous sclerosis o Lymphangioleiomyomatosis o Retinitis pigmentosis and other retinal degenerative disorders 0 Autoimmune diseases including encephalomyelitis, insulin-dependent diabetes mellitus, lupus, dermatomyositis, tis and tic diseases . Steroid-resistant acute Lymphoblastic Leukaemia o Fibrotic diseases including scleroderma, pulmonary fibrosis, renal fibrosis, cystic fibrosis o Pulmonary hypertension . lmmunomodulation . Multiple sclerosis . VHL syndrome 0 Carney complex 0 Familial adenonamtous polyposis 0 Juvenile polyposis syndrome . Birt-Hogg-Duke syndrome 0 al hypertrophic cardiomyopathy o Wolf-Parkinson-White syndrome . Neurodegenerative disorders such as Parkinson's Disease, Huntington’s Disease, Alzheimer's Disease and dementias caused by tau mutations, spinocerebellar ataxia type 3, motor neuron disease caused by SOD1 mutations, neuronal ceroid lipofucinoses/Batten disease (pediatric neurodegeneration) . Ophthalmological diseases such as wet and dry macular degeneration, uveitis, including autoimmune uveitis, retinopathy, such as ic retinopathy or hyperbaric oxygen- induced retinopathy, and glaucoma . muscle g (atrophy, cachexia) and myopathies such as Danon's disease. . bacterial and viral infections including M. tuberculosis, group A streptococcus, HSV type |, HIV infection 0 Neurofibromatosis ing Neurofibromatosis type 1, and o Peutz-Jeghers syndrome, Cowden's disease.

Compounds with an inhibitory activity on mTORC1 have shown benefit in immunomodulation and in treating proliferative diseases such as advance renal cell carcinoma or Tubero- Sclerosis (TSC) germ line mutation ated disorders.

For the above uses the required dosage will of course vary ing on the mode of administration, the particular ion to be d and the effect desired. In general, satisfactory results are indicated to be obtained systemically at daily dosages of from about 0.03 to about 100.0 mg/kg per body weight, e.g. about 0.03 to about 10.0 mg/kg per body . An indicated daily dosage in the larger , e.g. humans, is in the range from about 0.5 mg to about 3 g, e.g. about 5 mg to about 1.5 g, iently administered, for example, in divided doses up to four times a day or in retard form. Suitable unit dosage forms for oral administration comprise from ca. 0.1 to about 500 mg, e.g. about 1.0 to about 500 mg active ingredient.

In general, compounds of the present invention will be administered as pharmaceutical compositions by any one of the following routes: oral, systemic (e.g., transdermal, intranasal or by suppository), or parenteral (e.g., intramuscular, enous or subcutaneous) administration. The preferred manner of administration is oral using a convenient daily dosage regimen that can be ed according to the degree of affliction. Compositions can take the form of tablets, pills, capsules, semisolids, powders, sustained release formulations, solutions, suspensions, s, aerosols, or any other appropriate compositions. Another preferred manner for administering compounds of the present invention is inhalation. This is an effective method for delivering a therapeutic agent directly to the respiratory tract.

Consequently, the invention also provides: - a method for preventing or treating conditions, ers or diseases mediated by the activation of the PI3K (e.g. Pl3 kinase alpha) and/or mTOR enzymes e.g. such as ted above, in a subject in need of such treatment, which method comprises administering to said subject an ive amount of a compound of the present ion or a pharmaceutically acceptable salt thereof. In one embodiment, there is provided a method for preventing or treating cancer, a neurodegenerative disorder or an lmological e, in a subject in need of such treatment, which method comprises administering to said subject an effective amount of a nd of the present invention or a pharmaceutically acceptable salt thereof. In another embodiment, the neurodegenerative disorder is Parkinson's, Huntington’s or Alzheimer's Disease. In yet another embodiment, the neurodegenerative disorder is Huntington’s Disease. - a compound of the present invention, or a pharmaceutically acceptable salt thereof, for use as a medicament, e.g. in any of the ions, ers or diseases indicated , in particular for the use in one or more phosphatidylinositol 3-kinase mediated diseases. In one embodiment, there is provided a compound of the present invention, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of cancer, a neurodegenerative disorder or an ophthalmological e. In another embodiment, the egenerative disorder is Parkinson's, Huntington's or Alzheimer's Disease. In yet another embodiment, the neurodegenerative disorder is Huntington’s Disease. - the use of a compound of the present invention, or a pharmaceutically acceptable salt f, as an active pharmaceutical ingredient in a medicament, e.g. for the ent or prevention of any of the conditions, disorders or diseases indicated herein, in particular for the treatment or prevention of one or more phosphatidylinositol 3-kinase mediated diseases. In one embodiment, there is provided the use of a compound of the present invention, or a pharmaceutically acceptable salt thereof, as an active pharmaceutical ient in a medicament for the treatment or prevention of , a neurodegenerative disorder or an ophthalmological disease. In another embodiment, 2012/055929 the neurodegenerative disorder is Parkinson's, Huntington’s or Alzheimer's Disease. In yet another embodiment, the neurodegenerative disorder is Huntington’s Disease. - the use of a compound of the present invention, or a pharmaceutically acceptable salt thereof, for the cture of a medicament for the treatment or prevention of one or more phosphatidylinositol se mediated diseases. In one embodiment, there is provided the use of a compound of the present invention, or a pharmaceutically acceptable salt f, for the manufacture of a medicament for the treatment or prevention of cancer, a neurodegenerative disorder or an ophthalmological disease. In another embodiment, the egenerative disorder is Parkinson's, Huntington's or Alzheimer's e. In yet another embodiment, the neurodegenerative disorder is Huntington’s Disease.

An agent of the invention can be administered as sole active pharmaceutical ingredient or as a combination with at least one other active pharmaceutical ingredient effective, e. g., in the treatment or prevention of cancer or a neurodegenerative disorder. Such a pharmaceutical ation may be in the form of a unit dosage form, which unit dosage form comprises a predetermined quantity of each of the at least two active ents in association with at least one pharmaceutically acceptable excipient, diluent or carrier. Alternatively, the pharmaceutical combination may be in the form of a package comprising the at least two active components separately, e. g. a pack or ser-device adapted for the itant or separate administration of the at least two active components, in which these active components are separately arranged. In a further aspect, the invention relates to such pharmaceutical combinations.

In a further aspect, the invention therefore s to a combination product comprising an agent of the invention, or a ceutically acceptable salt thereof, and another eutic agent In one embodiment, the combination product is a pharmaceutical composition comprising an agent of the invention, or a pharmaceutically acceptable salt thereof, and another therapeutic agent, and a pharmaceutically acceptable excipient, diluent or carrier.

In one ment, the combination product is a kit comprising two or more separate pharmaceutical compositions, at least one of which contains an agent of the invention. In one embodiment, the kit ses means for separately ing said compositions, such as a container, divided bottle, or divided foil packet. An example of such a kit is a blister pack, as typically used for the packaging of tablets, capsules and the like. The kit of the invention may be used for administering different dosage forms, for example, oral and eral, for administering the separate compositions at different dosage intervals, or for titrating the separate compositions against one another. To assist compliance, the kit of the invention typically comprises directions for administration.

In view of their mTOR inhibitory activity, nds of the invention, either alone or combination, may be useful in the treatment of cancer. In one embodiment, the invention therefore relates to a compound of the invention, or a pharmaceutically acceptable salt thereof, in combination with another therapeutic agent wherein the other therapeutic agent is selected from the group of anticancer agents set forth below: (a) Kinase Inhibitors: for example inhibitors of Epidermal Growth Factor Receptor (EGFR) kinases such as small molecule quinazolines, including gefitinib (US 5457105, US 5616582, and US 5770599), ZD-6474 (WO 51), erlotinib (Tarceva®, US 498 and WO 96/30347), and Iapatinib (US 6,727,256 and WO 02/02552); Vascular Endothelial Growth Factor Reoeptor ) kinase tors, including SU-11248 (WO 01/60814), SU 5416 (US 5,883,113 and WO 99/61422), SU 6668 (US 113 and WO 99/61422), CHlR-258 (US 6,605,617 and US 6,774,237), vatalanib or PTK—787 (US 6,258,812), VEGF-Trap (WO 02/57423), B43-Genistein (WC-09606116), fenretinide (retinoic acid p—hydroxyphenylamine) (US 4,323,581 ), IM—862 (WO 02/62826), bevacizumab or Avastin® (W0 94/10202), KRN- 951, 3—[5—(methylsulfonylpiperadine methyl)—indolyl]-quinolone, AG-13736 and AG-13925, pyrrolo[2,1-t][1,2,4]triazines, ZK-304709, Veglin®, 601, EG-004, CEP-701 (US ,621,100), Cand5 (WO 04/09769); Erb2 ne kinase inhibitors such as umab (WO 01/00245), trastuzumab, and rituximab; Akt protein kinase inhibitors, such as RX-0201; Protein Kinase C (PKC) tors, such as LY-317615 (WO 95/17182), and perifosine (US 2003171303); Raf/Map/MEK/Ras kinase inhibitors including sorafenib (BAY 43-9006), ARQ- 350RP, LErafAON, BMS-354825 AMG-548, and others disclosed in WO 72; Fibroblast Growth Factor Receptor (FGFR) kinase inhibitors; Cell Dependent Kinase (CDK) inhibitors, including CYC-202 or roscovitine (WO 97/20842 and WO 99/02162); Platelet- Derived Growth Factor Receptor (PDGFR) kinase inhibitors such as CHlR-258, 3G3 mAb, AG—13736, SU-11248 and SU6668; and Bcr-Abl kinase tors and fusion proteins such as STI-571 or Gleevec® (imatinib). (b) Anti-Estrogens: such as Selective Estrogen Receptor Modulators (SERMs) including tamoxifen, toremifene, fene; aromatase inhibitors ing Arimidex® or anastrozole; Estrogen Receptor Downregulators (ERDs) including Faslodex® or trant. (c) ndrogens: such as flutamide, bicalutamide, finasteride, aminoglutethamide, ketoconazole, and corticosteroids. (d) Other Inhibitors: such as protein farnesyl transferase inhibitors including tipifarnib or R- 115777 (US 2003134846 and WO 97/21701), BMS-214662. AZD-3409, and 7; topoisomerase tors including merbarone and difiomotecan (BM-80915); mitotic kinesin spindle n (KSP) inhibitors including SB—743921 and MKl-833; proteasome modulators such as bortezomib or e® (US 5,780,454), XL-784; and cyclooxygenase 2 (COX-2) inhibitors including non-steroidal antiinflammatory drugs I (NSAle). (e) Cancer Chemotherapeutic Drugs: such as anastrozole (Arimidex®), bicalutamide (Casodex®), bleomycin sulfate (Blenoxane®), busulfan (Myleran®), busulfan injection fex®), capecitabine (Xeloda®), N4—pentoxycarbonyldeoxyfluorocytidine, carboplatin (Paraplatin®), carmustine (BiCNU®), chlorambucil (Leukeran®), cisplatin (Platinol®), bine (Leustatin®), hosphamide (Cytoxan® or Neosar®), cytarabine, cytosine arabinoside ar-U®), cytarabine liposome injection (DepoCyt®), dacarbazine (DTlC—Dome®), omycin (Actinomycin D, Cosmegan), daunorubicin hydrochloride (Cerubidine®), daunorubicin citrate liposome injection Xome®), dexamethasone, docetaxel (Taxotere®), doxorubicin hydrochloride (Adriamycin®, Rubex®), etoposide (Vepesid®), fludarabine phosphate (Fludara®), 5-fluorouracil (Adrucil®, Efudex®), flutamide (Eulexin®), tezacitibine, Gemcitabine (difluorodeoxycitidine), hydroxyurea (Hydrea®), ldarubicin (ldamycin®), ifosfamide (IFEX®), irinotecan (Camptosar®), L—asparaginase (ELSPAR®), orin calcium, melphalan (Alkeran®), 6-mercaptopurine (Purinethol®), methotrexate (Folex®), mitoxantrone (Novantrone®), rg, paclitaxel (Taxol®), phoenix (Yttrium90/MX-DTPA), pentostatin, polifeprosan 20 with carmustine implant (Gliadel®), tamoxifen citrate (Nolvadex®), teniposide (Vumon®), 6-thioguanine, thiotepa, tirapazamine (Tirazone®), topotecan hydrochloride for injection (Hycamptin®), vinblastine (Velban®), stine (Oncovin®), and vinorelbine bine®). (f) Alkylating Agents: such as VNP-40101 M or izine, latin (US 4,169,846, WO 03/24978 and WO 03/04505), glufosfamide, mafosfamide, etopophos (US 5,041,424), prednimustine; lfan; busulfan; irofluven (acylfulvene); penclomedine; pyrazoloacridine (PD-115934); OG-benzylguanine; decitabine (5-azadeoxycytidine); brostallicin; mitomycin C (MitoExtra); TLK—286 (Telcyta®); lomide; trabectedin (US 5,478,932); AP-5280 (Platinate formulation of Cisplatin); porfiromycin; and clearazide (meclorethamine). (g) ing : such as tetrathiomolybdate (WO 01/60814); RP—697; Chimeric T8466 (cT84.66); gadofosveset (Vasovist®); deferoxamine; and cin optionally in combination with electorporation (EPT). (h) Biological Response Modifiers: such as immune modulators, including staurosprine and macrocyclic analogs thereof, including , CEP-701 and midostaurin (see WO 02/30941, WO 81, WO 89/07105, US 5,621,100, WO 93/07153, WO 01/04125, WO 02/30941, WO 93/08809, WO 94/06799, WO 00/27422, WO 96/13506 and WO 88/07045); mine (WO 55); DA—9601 (WO 98/04541 and US 6,025,387); alemtuzumab; interferons (e.g. lFN-a, IFN-b etc.); interleukins, specifically lL-2 or aldesleukin as well as IL- 1, lL-3, IL-4, |L-5, |L-6, |L-7, lL-8, |L-9, |L-10, |L-11, |L-12, and active biological variants thereof having amino acid sequences greater than 70% of the native human sequence; amine (Hexalen®); SU 101 or leflunomide (WO 04/06834 and US 6,331,555); imidazoquinolines such as resiquimod and imiquimod (US 4,689,338, 5,389,640, 5,268,376, 4,929,624, 5,266,575, 5,352,784, 5,494,916, 5,482,936, 5,346,905, 5,395,937, 5,238,944, and 5,525,612); and SMlPs, ing benzazoles, anthraquinones, thiosemicarbazones, and Itryptanthrins (WO 04/87153, WO 04/64759, and WO 04/60308). (i) Cancer Vaccines: including Avicine® (Tetrahedron Lett. 26:2269-70 (1974)); oregovomab (OvaRex®); Theratope® (STn—KLH); Melanoma Vaccines; Gl—4000 series (GI-4014, Gl- 4015, and Gl-4016), which are directed to five ons in the Ras protein; GlioVax-1; MelaVaX; Advexin® or |NGN-201 (WO 95/12660); Sig/E7/LAMP-1, encoding HPV-16 E7; MAGE-3 Vaccine or M3TK (WO 94/05304); HER-2VAX; ACTIVE, which stimulates T-cells specific for tumors; GM-CSF cancer vaccine; and Listeria monocytogenes-based vaccines. (j) Antisense y: including antisense itions, such as AEG-35156 40); AP-12009 and AP-11014 (TGF-beta2-specific antisense ucleotides); AVI-4126; AVI— 4557; 72; oblimersen (Genasense®); JFSZ; aprinocarsen (WO 97/29780); GTI-2040 (R2 ribonucleotide reductase mRNA antisense oligo) (WO 98/05769); GTl-2501 (WO 98l05769); liposome—encapsulated c-Raf antisense oligodeoxynucleotides (LErafAON) (WO 98/43095); and Sirna-027 (RNAi-based therapeutic targeting VEGFR—1 mRNA).

Thus, in another embodiment, the invention provides a pharmaceutical composition comprising; i) a compound of the invention, or a pharmaceutically acceptable salt thereof, and ii) at least one compound selected from (a) kinase inhibitors, (b) anti-estrog ens, (c) ndrogens, (e) cancer herapeutic drugs, (f) alkylating agents, (9) chelating agents, (h) ical response modifiers, and ii) one or more pharmaceutically acceptable ent, diluent or carrier.

WO 61305 In one embodiment, the invention provides a pharmaceutical composition comprising a compound of the invention, or a pharmaceutically acceptable salt thereof, and everolimus (Afinitor®).

In view of their mTOR inhibitory activity, compounds of the invention, either alone or combination, may be useful in the treatment of neurodegenerative disorders. in one embodiment, the invention therefore relates to a compound of the invention, or a pharmaceutically able salt thereof, in combination with another therapeutic agent n the other therapeutic agent is selected from: (a) cholinesterase inhibitors: such as donepezil (AriceptT’V'), rivastigmine (ExelonTM) and galantamine yneTM); (b) glutamate antagonists: such as memantine daTM); (c) antidepressant medications: for low mood and irritability such as citalopram (Celexa TM), fluoxetine (ProzacTM), paroxeine (PaxilTM), sertraline (ZoloftT'V‘) and trazodone (DesyrelTM); (d) anxiolytics: for anxiety, restlessness, verbally disruptive behavior and resistance, such as lorazepam (AtivanTM) and oxazepam (SeraxTM); (e) antipsychotic medications: for hallucinations, ons, aggression, agitation, hostility and uncooperativeness, such as aripiprazole (AbilifyTM), clozapine (ClozarilT'V'), ridol (HaldolTM), olanzapine (ZyprexaTM), quetiapine (SeroquelTM), risperidone rdalTM) and ziprasidone nTM); (f) mood stabilizers: such as carbamazepine (TegretolTM) and divalproex (DepakoteTM); (g) nicotinic apha — 7 agonists; (h) mGluR5 antagonists; (i) H3 agonists; and (j) amyloid therapy vaccines.

Thus, in another embodiment, the invention provides a pharmaceutical composition comprising; i) a compound of the invention, or a pharmaceutically acceptable salt thereof, and ii) at least one compound selected from (a) acetylcholinesterase inhibitors, (b) glutamate antagonists, W0 2013/061305 PCT/1B2012/055929 (c) antidepressant medications, (d) anxiolytics, (e) ychotic medications, (f) mood stabilizers, (g) nicotinic apha — 7 agonists, (h) mGIuR5 antagonists, (i) H3 agonists, and ii) one or more pharmaceutically acceptable excipient, diluent or carrier.

Consequently, the invention provides in further aspects - a pharmaceutical combination, e.g. for use in any of the methods described , comprising a therapeutically effective amount of a compound of the present ion, or a pharmaceutically able salt thereof, and another therapeutic agent, for simultaneous or sequential administration. - a combination product comprising a compound of the present invention, or a pharmaceutically acceptable salt thereof, and another therapeutic agent. - a combination product comprising a compound of the present invention, or a pharmaceutically acceptable salt thereof, and another therapeutic agent as a combined preparation for use in therapy, e.g. for use in any of the therapies described herein. In one embodiment, the therapy is the ent or prevention of cancer or a neurodegenerative disorder. In another embodiment, the therapy is the treatment or prevention of Parkinson's, Huntington's or Alzheimer's Disease. in yet another embodiment, the therapy is the treatment or prevention of Huntington’s e. - a ceutical ition comprising a compound of the present invention, or a pharmaceutically acceptable salt thereof, another therapeutic agent, and a ceutically able excipient, diluent or carrier. - a method as defined above sing co-administration, e.g. concomitantly or in sequence, of a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, and another therapeutic agent, e.g. as ted above. - a pharmaceutical combination, e.g. a kit, comprising a) a first agent which is a compound of the present invention as disclosed herein, or a pharmaceutically acceptable salt thereof, and b) another therapeutic agent, e.g. as indicated above; whereby such kit may comprise ctions for its administration.

The following examples of compounds of the present ion illustrate the invention.

Methods for preparing such nds are described hereinafter.

PCT/lB2012/055929 EXAMPLES Abbreviations EtOAc ethyl acetate AcOH acetic acid brs broad singlet CDCI; deuterated form CsF cesium fluoride d doublet CHZClg dichloromethane DIPEA di-isopropylethyl amine DMSO dimethylsulfoxide DMSO—da deuterated dimethylsulfoxide dppf 1,1'-Bis(diphenylphosphino)ferrocene EtOH ethanol LC—MS liquid chromatography-mass spectrometry MeOH methanol m multiplet MS mass ometry NEta triethylamine NMR nuclear magnetic resonance 1HNMR proton nuclear magnetic resonance 3)4 tetrakis(triphenylphosphine)palladium PPh3 triphenyl phosphine s singlet TFA trifluoroacetic acid THF tetrahydrofu ran UV ultraviolet EtOH ethanol CDCIa deuterated chloroform Si02 silica gel M9804 magnesium sulfate Na2804 sodium sulfate Pd palladium aq aqueous TBME tertbutylmethylether mL milliliter PCT/lBZOlZ/055929 LDA mdiisopropylamine Raney—Ni Raney—nickel ax axial eq rial MHz megahertz Rt retention time Na23203 sodium thiosulfate ANALYTICAL METHODS NMR: proton spectra are recorded on a Bruker Avancespectrometer or Varian Oxford 400 spectrometer unless otherwise noted. Chemical shifts are reported in ppm relative to dimethyl sulfoxide (6 2.50), or chloroform (6 7.26). A small amount of the dry sample (2-5 mg) is dissolved in an riate deuterated solvent (1 mL).

LC/MS: The sample is dissolved in suitable solvent such as MeCN, DMSO or MeOH and is injected directly into the column using an automated sample handler. The analysis is performed using one of the following methods: LC-MS-Method 1 Column: Acquity HSS T3, 1.8pm, 2.1 x 50 mm; Eluent: Water (+ 0.05% formic acid + 3.75 mM ammonium acetate) : acetonitrile (+ 0.04% formic acid), from 98:2 to 2:98 in 1.4 min, hold 98% for 0.75 min; Flow rate/Temperature: 1.2 ml/min at 50°C.

LC-MS-Method 2 Column: Machery—Nagel Nucleosil 100-3 C18 (70 x 4.6 mm); Solvents/Gradient: A: 0.05% TFA in water; B: 0.05% TFA in acetonitrile; from 95% A/ 5% B to 5% A / 95% B in 8min.

Flow emperature: 1.4 ml/min at 45°C.

Synthesis of amine intermediates The amine intermediates are either commercially available or may be ed as described in the literature, or in an analogous , or can be prepared as described hereafter, or in an analogous manner.

Synthesis of ic amine intermediates W0 2013/061305 ic amine 1: 3-Hydroxyaza-bicyclo[3.2.1Joctane-S-carboxylic acid tert-butyl ester w< Av WK Am.

RT,——>24h . \f3%“ O O 0 To a solution of 3-oxoaza-bicyclo[3.2.1]octanecarboxylic acid tert—butyl ester (1.03 g, 4.57 mmol) in EtOH (20 mL) was added NaBH4 dropwise. The e was stirred for 4.5 hours at room temperature under nitrogen, followed by a second addition of NaBH4 (0.36 g, 9.60 mmol). The reaction was stirred at room ature for 17.5 hours and a last addition of NaBH4 (0.36 g, 9.60 mmol) was performed. The solution was stirred at room temperature for 2 hours. then a saturated solution of ammonium chloride was added and the aqueous phase was extracted with EtOAc. The combined organic fractions were dried over NaZSO4, filtered and concentrated. The crude was purified by flash chromatography on silica gel using cyclohexane/EtOAc as eluent to yield, after evaporation, to the axial and rial isomers (186 mg, 17.9%) and (205 mg, 19.7%) as white solids. 1H NMR (600 MHZ, CDCI3): 4.57 (d, 1H), 4.02 (m, 2H), 3.89 (d, 1Hax), 1.89- 1.71 (m, 5H), 1.65 - 1.54 (m, 1H), 1.47 - 1.28 (m, 11H)and 4.60 (d, 1H) 3.99 (m, 2H), 3.91 (m, 1Heq), 2.18 -2.03 (m, 2H), 1.92 - 1.72 (m, 4H), 1.67 — 1.56 (m, 2H), 1.39 (s, 9H) Bicclic amine 2: 8-Aza-bicyclo[3.2.1]octanol \l< NM HCI 4M in dioxane ”A: CH3CN,70°C, 1h ; 0H A solution of HCI (4N in dioxane,0.82 mL, 3.27 mmol) was added to a suspension of 3- hydroxyaza-bicyclo[3.2.1]octane-8—carboxylic acid tert—butyl ester in acetonitrile. The mixture was stirred at 70°C for 1 hour, cooled down and concentrated. The product (138 mg, 93%) was isolated as a hydrochloric acid salt. 1H NMR (600 MHz, : 9.07 —- 8.49 (m, 1H), 3.94 (m, 2H), 3.85 (m, 1H), 1.97 — 1.74 (m 6H), 1.60 (t, 2H) The axial isomer (137 mg, 93%) was ed in the same way. 1H NMR (600 MHz, CDCIa): 9.01 — 8.44 (m, 1H), 3.89 (m, 3H), 2.29 (d, 2H), 2.07 (dt, 2H), 1.96 - 1.84 (m, 2H), 1.83 -1.71 (m, 2H) 012/055929 Synthesis of indole intermediates The indole ediates are either commercially available or may be prepared as described in the literature, or in an analogous manner, or can be prepared as described hereafter, or in an analogous manner. lndole 1: 4-Bromomethoxy-1H-indole \o :2 (a) N-(3-Bromomethoxy-phenyl)-N-hydroxy-acetamide 3-Bromonitroanisole (1.5 g, 6.46 mmol) was dissolved in 20 mL of 1,2—dichloroethane and mL of ethanol, and the mixture was cooled to 0 °C. Ni (30 mg) and ine e (0.79 mL, 12.9 mmol) were added within 10 minutes, and the reaction was stirred for 4 hours at room temperature, when 50 mg of Raney-Ni were added. After stirring for 16 hours, another 50 mg of Raney—Ni were added, and after further ng for 4 hours, r 50 mg of Raney—Ni were added. Stirring was continued for 4 hours at room temperature, when the starting material had completely disappeared. The reaction mixture was filtered through celite. and the solvent was removed under reduced pressure to provide N-(3-bromo- -methoxy-pheny|)-N-hydroxylamine as a solid, which was dissolved in 80 ml of toluene.

Sodium bicarbonate (597 mg, 7.11 mmol) was added, followed by acetyl chloride (0.51 mL, 7.11 mol). Stirring at room temperature was continued for 20 hours. The reaction e was then filtered and concentrated under reduced pressure. The residue was purified by column chromatography (40 gSiO2; EtOAc/heptane in a gradient from 5/95 to 1/3) to yield the title compound as a solid (360 mg, 21% over 2 steps). LC-MS at 254 nm; [M+H] 2600/2621; Rt 0.82 min; (LCMS method 1). 1H-NMR (600 MHz; DMSO-ds):10.85 (brs, 1H), 7.50 (dd, 1H), 7.26 (dd, 1H), 6.94 (dd, 1H), 3.77 (s, 3H), 2.22 (s, 3H). (b) 4-Bromomethoxy-1H-indole N-(3-Bromomethoxy—phenyl)—N-hydroxy-acetamide (360 mg, 1.384 mmol) was dissolved in vinyl acetate (1.92 mL, 20.8 mmol), and LideCl4 (18.2 mg, 69 umol) was added. The reaction mixture was stirred for 3 hours at 60 °C. The reaction mixture was diluted with EtOAc and brine; the organic layer was separated and concentrated under reduced pressure to give a solid, which was dissolved in 20 mL of MeOH. 1N aqueous NaOH (2.61 mL, 2.61 mmol) was added, and the reaction was stirred for two hours at room temperature. The reaction mixture was quenched by addition of2 N s HCI (1.3 mL, 2.6 mmol), followed by addition of 500 mg of N32003. After addition of 50 mL of EtOAc, the organic layers were separated, dried over NaZSO4, filtered, and concentrated. The e was purified by column chromatography (20 g Si02, EtOAc/heptane in a gradient from 0/100 to 1/4) to yield the title compound as a liquid (145 mg, 46% over 2 steps). 1H-NMR (600 MHz; DMSO-de): 11.26 (hrs, 1H), 7.31 (dd, 1H), 6.93 (d, 1H), 6.90 (d, 1H), 6.29 (dd, 1H), 3.78 (s, 3H). lndole 2: 4-Chlorofluoro-1H-indole 11 :2 (a) 1-Chlorofluoronitro-benzene Sodium perborate tetrahydrate (7.699, 50.0 mmol) was suspended in 30 mL of acetic acid, and this suspension was warmed to 55 °C. rofluoroaniline (1.469, 10 mmol) was dissolved in 20 mL of acetic acid and added within one hour. The reaction was stirred for 1 hour at 55 °C and then cooled to room temperature. 300 mL of TBME was added, and the reaction mixture was filtered. The organic layer was washed with brine, followed by 20 mL of aqueous Nazszoa, followed by brine. The organic layer was dried over NaZSO4 and concentrated under reduced pressure to give a residue, which was purified by column tography (40 g SiOz; cyclohexane) to yield the title compound as a solid (320 mg, 18%). 1H—NMR (400 MHz; DMSO—d6)28.20 (s, 1H), 8.18 (d, 1H), 8.07 (d, 1H). (b) hlorofluoro-phenyl)-N-hydroxy-acetamide 1-Chlorofluoronitro-benzene (320 mg, 1.82 mmol) was dissolved in 5 mL of 1,2- dichloroethane and 5 mL of ethanol, and the mixture was cooled to 0 °C. Raney-Ni (30 mg, 2.0 mmol) and hydrazine hydrate (0.11 mL, 1.82 mmol) were added within 10 minutes, and the reaction was stirred for 4 hours at room temperature, when 50 mg of Raney—Ni were added. After stirring for 16 hours, another 50 mg of Raney—Ni were added, and after further stirring for 4 hours, another 50 mg of Raney—Ni were added. ng was continued for 4 hours at room temperature, when the starting material had completely disappeared. The reaction mixture was filtered through celite, and the t was removed under reduced pressure to provide N-(3-bromofluoro-phenyl)-N-hydroxylamine as a solid, which was dissolved in 15 ml of toluene. Sodium bicarbonate (160 mg, 1.91 mmol) was added, followed by acetyl chloride (136 uL, 1.91 mmol) in 0.5 mL of toluene. Stirring at room ature was ued for 20 hours. The reaction mixture was then filtered and concentrated under reduced re. The residue was d by column chromatography (4O gSiOz; EtOAc/ heptane in a gradient from 5/95 to 1/3) to yield the title compound as a solid (214 mg, 53% over 2 steps). LC-MS at 254nm; [M+H] 204.1; Rt 0.83 min; (LCMS method 1). 1H-NMR (DMSO-de): 10.95 (s, 1H), 7.62 (s, 1H), 7.51 (dd, 1H), 7.19 (d, 1H), 2.24 (s, 3H). (c) 4-Chlorofluoro-1H-indole N-(3-Chlorofluoro-phenyl)-N-hydroxy-acetamide (200 mg, 982 umol) was dissolved in vinyl acetate (1.81 mL, 19.6 mmol), and LigPdCl4 (25.7 mg, 98 umol) was added. The reaction mixture was stirred for 3 hr at 60 °C. The reaction mixture was diluted with EtOAc and brine; the organic layer was separated and concentrated under reduced pressure to give a solid, which was dissolved in 8 mL of MeOH. 1N aqueous NaOH (1.89 mL, 1.89 mmol) was added, and the reaction was stirred for two hours at room temperature. The reaction mixture was quenched by addition of 2 N aqueous HCI (0.95 mL, 1.9 mmol), followed by addition of 300 mg of NaZCO3. After addition of 50 mL of EtOAc, the organic layers were separated, dried over NaZSO4, filtered, and concentrated. The residue was purified by column tography (12 gSiOZ; EtOAc /heptane in a gradient from 0/100 to 1/4) to yield the title nd as a liquid (72 mg, 45% over 2 steps). 1H-NMR (DMSO-ds): 11.52 (brs, 1H), 7.45 (d, 1H), 7.20 (d, 1H), 7.05 (d, 1H), 6.45 (d, 1H).

Synthesis of boronic ester intermediates The boronic ester intermediates used in the preparation of compounds of the present invention are either commercially available or may be prepared as described in the literature, or in an ous manner, or can be prepared as described ter, or in an analogous Boronic ester 1: 6-Methoxy(4,4,5,5-tetramethyI-[1,3,2]dioxaborolanyl)-1H-indole To a on of 4-bromomethoxy-1H-indole (200 mg, 885 umol) in dioxane (5 mL) was added under argon bis(pinacolato)diboron (247 mg, 973 pmol)followed by tricyclohexylphosphine (14.9 mg, 53 umol), bis(dibenzylideneacetone)Pd (15.3 mg, 27 pmol) and potassium e (130 mg, 1.33 mmol). The reaction mixture was stirred for 18 hours at 65 °C under argon. The reaction mixture was then diluted by addition of 30 ml of EtOAc and ml of brine. The organic solvents were separated, dried over , filtered, and concentrated under d pressure. The residue was purified by column chromatography (20 g of SiOz, tertbutylmethylether/heptane in a ratio of 3/7) to give the product (190 mg, 79%). 1H-NMR (DMSO-de): 10.89 (brs, 1H), 7.22 (dd, 1H), 7.03 (dd, 1H), 7.00 (d, 1H), 6.64 (dd, 1H), 3.77 (s, 3H), 1.33 (s, 12H).

Examgle 1: 2,6-Bis-((R)methyl-morpholinyl)pyridinyl-9H-purine W0 2013/061305 a) 2-Chloro((R)methyl-morpholinyl)-9H-purine 2,6-Dichloro-9H-purine (2.36 g, 12.5 mmol), (R)—3-methylmorpholin hydrochloride (1.89 g, 13.8 mmol), and diisopropylethylamine (5.46 mL, 31.3 mmol) were dissolved in 15 mL of panol, and the reaction mixture was stirred for 18 hours at 75 °C. The on mixture was then diluted with 200 mL of CHZCIZ. The organic solvents were washed with aqueous Nagcoa, followed by water and brine. Drying over Na2804, filtering and concentration under reduced pressure gave a residue, which was purified by column chromatography (150 g Si02, CchlzlEtOH/aq NH3 in a ratio of 96/4/01) to give the product as a solid (2.87 g, 91%).

LC-MS at 254 nm; [M+H] 2541/2561; Rt 0.72 min; (LCMS method 1). 1H NMR (DMSO—de): 13.25 (1H, brs), 8.17 (1H, s), 6.0—4.5 (brs, 2H), 4.0—3.0 (brs, 1H), 3.96 (dd, 1H), 3.76 (d, 1H), 3.67 (dd, 1H), 3.51 (ddd,1H), 1.31 (d, 3H) b) 2,6-Bis-((R)methyl-morpholinyl)-9H-purine 2-ChIoro((R)—3-methy|—morpholinyl)-9H-purine (1.02 g, 4 mmol), ropylethylamine (1.40 mL, 8 mmol), and (R)—3-methylmorpholin hydrochloride (826 mg, 6 mmol) were stirred in 2-butanol (5 mL) in a closed microwave tube under argon at 50 °C, until all ingredients were dissolved. The reaction was then stirred at 180 °C for 100 hours. The reaction mixture was then cooled to room temperature and diluted with 200 mL of CHQCIQ.

The organic layer was washed with aqueous Na2003 and brine. Drying over NaZSO4, filtering and tration under reduced pressure gave a residue, which was purified by column chromatography (120 g SiOz, CH2Cl2/EtOHlaqueous NHa in a gradient with a ratio from 100/0/0.1 to 1) to give the t as a foam (1.11 g, 87%).

LC—MS at 254nm; [M+H] 319.0; Rt 0.71 min; (LCMS method 1). 1H NMR(DMSO—d6): 12.44 (s, 1H), 7.77 (s, 1H), 6.0-4.5 (brs, 2H), 4.51 (dd, 1H), 4.15 (dd, 1H), 0 (brs, 1H), 3.94 (dd, 1H), 3.89 (dd, 1H), 3.73 (d, 1H), 3.69 (d, 1H), 3.65 (dd, 1H), 3.58 (dd, 1H), 3.50 (ddd, 1H), 3.42 (dd, 1H), 3.07 (ddd, 1H), 1.27 (d, 3 H) 1.15 (d, 3 H). c) 2,6-Bis-((R)methy|-morphoIinyl)(tetrahydro-pyranyl)-9H-purine 2,6-Bis-((R)—3-methyI-morpho|iny|)-9H-purine (600 mg, 1.89 mmol) was dissolved in EtOAc (25 mL) under argon. After addition of 3,4-dihydro—2H-pyrane (172 pl, 1.89 mmol), trifluoro acetic acid anhydride (27 pl, 188 umol), and trifluoro acetic acid (319 pl, 4.15 mmol), the reaction mixture was heated to 70 °C. After 6 hours, 3,4-dihydro-2H-pyrane (1.44 mL, .7 mmol) was added. The reaction was then stirred for 22 hours at 70 °C and then cooled to room temperature. 500 mg of solid Na2C03 was added and stirring continued for 10 s. The reaction mixture was diluted with EtOAc, the organic layer was separated, dried over , filtered and concentrated under reduced pressure to give a residue, which was ed by column chromatography (40 g SiOz, heptane/EtOAc in a gradient from 9/1 to 2/3) to give the product as a foam (600 mg, 79%).

LC—MS at 254nm; [M+H] 403.3; Rt 1.11 min; (LCMS method 1). d) 8-Bromo-2,6-bis-((R)methyl-morpholinyI)(tetrahydro-pyran-Z-yl)-9H-purine ropylamine (290 pl, 2.04 mmol) was dissolved in 4 mL of THF at -60 °C, when butyllithium in hexane was added (1.27 mL, 2.04 mmol) to form LDA. 2,6-Bis-((R)methyl- morpholinyI)—9—(tetrahydro-pyran—2—yI)—9H—purine (585 mg, 1.45 mmol) was dissolved in 8 mL of THF and added to the reaction e at — 78°C within 10 minutes. The on was stirred for 1 hour at — 78 °C. Dibromotetrachloroethane (947 mg, 2.91 mmol) in 4 mL of THF was added within 10 minutes. The reaction was stirred for 2 hours at — 78°C. The reaction was quenched by addition of saturated aqueous NH4Cl and warmed to room ature.

The mixture was diluted with 80 mL of EtOAc and 50 mL of brine. The organic layers were separated, dried over Na2804, filtered, and concentrated to give a residue, which was purified by column chromatography (30 g SiOg, heptane/TBME in a ratio 7/3) to give the product as a foam (546 mg, 78%).

LC-MS at 254nm; [M+H] 481.3/4832; Rt 1.37 min; (LCMS method 1). 1H NMR(DMSO—d6): 5.50 (dd, 1H), 5.4—4.5 (brs, 2H), 4.48 (brs, 1H), 4.13 (dd, 1H), 4.01 (d, 1H), 3.93-3.87 (m, 2H), 3.74-3.66 (m, 2H), 3.64-3.55 (m, 3H), 3.5-3.0 (brs, 1H), 3.46 (ddd, 1H), 3.40 (dd, 1H), 3.11-3.03 (m, 1H), 3.00-2.90 (m, 1H), 1.96 (d, 1H), 1.78 (d, 1H), 1.70- 1.48 (m, 3H), 1.24 (d, 3H), 1.14 (d, 3H). e) 2,6-Bis-((R)methyl-morpholinyl)pyridinyI(tetrahydro-pyranyl)-9H- pufine 8-Bromo-2,6-bis-((R)-3—methyl-morpholinyl)—9-(tetrahydro-pyranyl)-9H-purine (40 mg, 83 pmol) was dissolved in 2 mL of toluene under argon in a microwave vial, and 2- (tributylstannyl)—pyridine (36 mg, 83 umol) and Pd(PPh3)4 (4.8 mg, 4.2 pmol) were added.

The microwave vial was capped, and the reaction mixture was stirred for 3 hours at 120 °C.

The vial was cooled to room temperature and opened. The mixture was diluted with EtOAc (20 mL) and brine. The organic layer was ted, dried over Na2SO4, d and concentrated under reduced pressure. The residue was purified by column chromatography PCT/lBZOlZ/055929 (12 g SiOg, heptane/TBME in a gradient from 4/1 to 2/3) to give the t as a solid (35 mg, 88%).

LC-MS at 254nm; [M+H] 480.3; Rt 1.34 min; (LCMS method 1). 1H NMR (DMSO-de): 8.68 (d, 1H), 8.06 (d, 1H), 7.94 (dd, 1H), 7.46 (dd, 1H), 6.53 (dd, 1H), 6.0-4.5 (brs, 2H), 4.58-4.48 (m, 1H), 4.18 (dd, 1H), 3.99-3.86 (m, 3H), 3.78-3.69 (m, 2H), 3.69—3.64 (m, 1H), 3.64-3.56 (m, 1H), 3.5-3.0 (brs, 1H), 3.55-3.39 (m, 3H), 3.28-3.17 (m, 1H), 3.15-3.05 (m, 1H), 2.00-1.92 (m, 1H), 1.85 (dd, 1H), 1.65-1.45 (m, 3H), 1.28 (d, 3H), 1.18 (d, 3H). f) 2,6-Bis-((R)methyl-morpholinyl)pyridinyI-9H-purine s-((R)—3-methyI-morpholin-4—yl)pyridin-Z-yI(tetrahydro-pyranyl)-9H-purine (33 mg, 69 umol) was dissolved in 3 mL of THF. 2N s HCI (344 pl, 688 umol) was added, and the reaction was stirred for 2 hours at room temperature. 100 mg of NaZCO3 and 10 mL of CHZCIZ were added, and the reaction mixture was stirred for 20 minutes. The organic layer was separated, dried over Na2804, filtered, and concentrated under reduced pressure. The residue was ed by column chromatography (12 g SiOg, heptane/EtOAc in a gradient from 100/0 to 3/2) to give the product as a solid (24 mg, 88%).

LC-MS at 254nm; [M+H] 396.3; Rt 1.03 min; (LCMS method 1). 1H NMR(DMSO-d6): 12.98 (s, 1 H), 8.62 (d, 1 H), 8.12 (d, 1H), 7.89 (ddd, 1H), 7.40 (ddd, 1H), 6.0-4.5 (brs, 2H), 4.57 (dd, 1H), 4.20 (d, 1H), 4.0-3.0 (brs, 1H), 3.97 (dd, 1H), 3.89 (dd, 1H), 3.76 (d, 1H), 3.71-3.66 (m, 2H), 3.57 (dd, 1H), 3.53 (ddd, 1H), 3.41 (ddd, 1H), 3.09 (ddd, 1H), 1.30 (d, 3 H) 1.17 (d, 3 H) e 2: 2-((S)Methyl-morpholinyI)((R)methyl-morpholinyl)(1H- pyrazolyl)-9H-purine Eo.k HN / N N NAN ” O0 a) 2-((S)Methyl-morpholinyl)((R)methyl-morpholinyl)-9H-purine 2-Chloro((R)—3-methyl-morpholinyl)—9H-purine (712 mg, 2.81 mmol), diisopropylethylamine (0.98 mL, 5.61 mmol), and (S)—3-methy|morpholin hydrochloride (579 mg, 4.21 mmol) were stirred in 2-butanol (3 mL) in a closed 5 mL microwave tube under argon at 50 0C, until all ingredients were ved. The reaction was then stirred at 175 °C for 48 hours. The organic layer was diluted with 200 mL of CH2C|2 and washed with brine.

Drying over NaZSO4, filtering and concentration under reduced pressure gave a residue, which was purified by column chromatography (40 g SiOz, CHQCl2/EtOH/aq NH3 in a nt from 100/0/0.1 to 01) to give the product as a solid (588 mg, 66%).

LC-MS at 254nm; [M+H] 319.2; Rt 0.70 min; (LCMS method 1). 1H NMR(DMSO-d6): 12.42 (s, 1H), 7.75 (s, 1H), 6.0-4.5 (brs, 2H), 4.50 (dd, 1H), 4.09 (d, 1H), 4.0-3.0 (brs, 1H), 3.92 (dd, 1H), 3.87 (d, 1H), 3.71 (d, 1H), 3.67 (d, 1H), 3.64 (dd, 1H), 3.56 (dd, 1H), 3.48 (ddd, 1H), 3.40 (dd, 1H), 3.05 (ddd, 1H), 1.24 (d, 3 H) 1.12 (d, 3 H). b) 8-Bromo((S)methyl-morpholinyl)((R)methyl-morpholinyl)-9H-purine 2-((S)Methyl-morpholinyl)((R)methyl-morpholiny|)-9H-purine (786 mg, 2.47 mmol) were dissolved in CH2CI2 (25 mL). Bromine (0.16 mL, 3.09 mmol) diluted in 2 mL of CH20I2 was added slowly within 2 minutes. The reaction mixture was stirred for 6 hours at room temperature. Aqueous Na28203 (10 mL) was added to the reaction mixture, and ng was continued for 15 minutes. The organic layer was washed with brine and aqueous NaHCOa. Drying over , filtering and concentration under reduced pressure gave a residue, which was purified by column chromatography (40 g SiOz, heptane/EtOAc in a gradient from 2/3 to 4/1) to give the product as a foam (455 mg, 46%).

LC-MS at 254nm; [M+H] 3991/3972; Rt 0.94 min; (LCMS method 1). c) 2-((S)Methyl-morpholinyl)((R)-methyl-morpholinyl)(1H-pyrazolyI)-9H- pufine 8-Bromo—2-((S)-3—methyl-morpholinyl)((R)methyl—morpholinyl)—9H-purine (50 mg, 126 umol) was dissolved in oxyethane (2 mL) and water (0.2 mL), followed by addition of 1H-pyrazoIeylboronic acid (21.1 mg, 189 pmol), PdCl2(dppf) (9.21 mg, 13 umol) and NEt3 (53 pl, 378 umol) under argon. The on mixture was heated to 85 °C for 23 hours.

The reaction mixture was then diluted with EtOAc, the organic layer was separated, washed with brine, dried over M9804, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (12 g SiOz, EtOAc) to give the product (19 mg, 39% yield).

LC—MS at 254nm; [M+H] 385.3; Rt 0.81 min; (LCMS method 1). 1H NMR(DMSO—d6): 13.13 (s, 1H), 12.72 (s, 1 H), 7.82 (s, 1 H), 6.73 (s, 1H), 5 (brs, 2H), 4.54 (d, 1H), 4.13 (d, 1H), 4.0-3.0 (brs, 1H), 3.95 (d, 1H), 3.89 (d, 1H), 3.74 (d, 1H), 3.71-3.64 (m, 2H). 3.57 (d, 1H), 3.51 (dd, 1H), 3.41 (dd, 1H), 3.07 (dd, 1H), 1.26 (d, 3 H) 1.15 (d, 3 H) Example 3: 8-(1 H-lndolyl)((R)methyl-morpholinyl)[1,4]oxazepanyl-9H- pufine PCT/IBZOIZ/055929 a) 8-Bromochloro((R)methyl-morpholiny|)-9H-purine To a solution of 2-chloro((R)methyl-morpholinyl)-9H-purine (950 mg, 3.74 mmol) in CH2C|2( 19 mL )was added bromine (0.23 mL, 4.49 mmol). The e was stirred at ambient temperature for 19 hours. Saturated sodium thiosulfate was added. The aqueous layer was extracted with dichloromethane two times. Organic layers were combined and dried over Na2804 and solvent was d under reduced pressure. The crude was purified by flash column chromatography (0—70% EtOAc/cyclohexane gradient) to furnish product as a white solid (495 mg, 39%). LC—MS at 254 nm; [M+H] 334.1; Rt 0.89 min; (LCMS method 1). 1H NMR (400 MHz, DMSO-de): 14.09 (br. s., 1H), 5.4-4.9 (m, 2H) 3.96 (d, 1H) 3.75 (d, 1H) 3.65 (dd, 1H) 3.42 - 3.57 (m, 1H), 3.41-3.37 (m, 1H), 1.29 (d, 3H) b) 2-Chloro(1H-indolyl)((R)methyI-morpho|inyl)—9H-purine In a sealed tube, to a solution of ochloro((R)methyl-morpholin—4-yl)-9H-purine (495 mg, 1.49 mmol) in H20 (11 / 1.1 mL) was added cesium fluoride (452 mg, 2.98 mmol), indoleboronic acid (266 mg, 1.64 mmol), and is(tripheny|phosphine)palladium (172 mg, 0.15 mmol). Then the reaction was conducted under microwave irradiation at 160°C for 30 min. The ts were removed under reduced pressure and the crude was purified by flash column chromatography (20-100% EtOAc/cyclohexane gradient) to e 2-chloro(1H-indolyl)((R)methyl-morpholinyl)-9H-purine (350 mg, 63.8%) as a pale yellow solid. LC-MS at 254nm; [M+H] 369.2; Rt 1.00 min; (LCMS method 1). (400 MHz, DMSO—de): 13.59 (s, 1H), 11.41 (s, 1H), 7.73 (dd, 1H), 7.58 - 7.49 (m, 2H), 7.38 - 7.20 (m, 2H), 5.14 (s, 1H), 4.05-4.01 (m, 1H), 3.79 — 3.88 (m, 1H), 3.69 — 3.79 (m, 1H), 3.57 (s, 1H), 3.60 (s, 1H), 1.41 (d, 3H) c) 8-(1 H-Indolyl)((R)methyl-morpholinyl)[1,4]oxazepanyl-9H-purine To the solution of 2-chloro(1H-indol—4-yl)((R)methyl-morpholinyl)—9H-purine (50 mg, 0.14 mmol) in 1-butanol (300 pL) was added 1,4-oxazepane (20.6 mg, 0.20 mmol), followed by DIPEA (47.4 uL, 0.27 mmol). The mixture was stirred at 120°C for 24 hours.

Upon completion of the reaction, the solution was poured into water. The aqueous layer was extracted with CH20|2 three times. The combined organic layers were dried over Na2804, filtered, concentrated under reduced pressure and the crude was purified by flash column chromatography (30-100% EtOAc/cyclohexane gradient) to provide 2-((28,6R)-2,6-dimethyl— linyl)morpholin—4—yl-9H-purine (35 mg, 59%) as a beige solid. LC-MS at 254nm; [M+H] 432.3; Rt 1.00 min; (LCMS method 1). 1H NMR (400 MHz, DMSO-de) 12.47 (br. s., 1H), 11.00 (br. s., 1H), 7.67 (d, 1H), 7.43 - 7.39 (m, 2H), 7.28 (br. s., 1H), 7.16 (t, 1H), 5.45 (d, 1H), 5.08 (d, 1H), 4.10 — 3.95 (m, 1H), 3.91 - 3.85 (m, 4H), 3.82 - 3.75 (m, 4H), 3.69-3.65 (m, 2H), 3.63-3.57 (m, 1H), 3.48-3.40 (m, 1H), .90 (m, 2H), 1.23 - 1.18 (m, 3H)u Example 4: 8-[4-(1H-lmidazolyl)-phenyll-Z,6-bis-((R)methyl-morpholinyl)-9H- pufine H H a a) 8-Bromo-2,6-bis-((R)methyl-morpholinyl)—9H-purine 2,6-Bis-((R)—3-methyl-morpholin—4-yl)-9H-purine (637 mg, 2 mmol) was dissolved in 50 mL of CHQCI2 and stirred under argon. Bromine (124 pl, 2.4 mmol) was dissolved in 2 mL of CHZClz and added within 2 minutes. The reaction was d for 6 hours at room temperature. 5 mL of aqueous Na28203 were added, the mixture was stirred for 15 minutes, and the c solvents were separated, washed with brine and aqueous , dried over , filtered, and concentrated. The residue was purified by column chromatography (40 g SiOg, heptane/EtOAc in a gradient from 2/3 to 4/1) to give a foam (422 mg, 53%). 1H NMR(DMSO—d6): 13.20 (1H, brs), 54-45 (brs, 2H), 4.48 (d, 1H), 4.12 (d, 1H), 3.93 (d, 1H), 3.89 (dd, 1H), 3.73 (d, 1H), 3.68 (d, 1H), 3.64 (d, 1H), 3.56 (dd, 1H), 3.48 (ddd, 1H), 3.41 (ddd, 1H), 3.4-3.1 (brs, 1H), 3.07 (ddd, 1H), 1.26 (d, 3H), 1.15 (d, 3H) b) 8-[4-(1 H-lmidazoIy|)-phenyl]-2,6-bis-((R)methyl-morpholinyl)-9H-purine 8—Bromo-2,6-bis—((R)-3—methyl-morpholinyl)-9H-purlne (99 mg, 250 umol) was dissolved in 2 mL of acetonitrile and 0.2 mL of water under argon. 4-(1H-imidazol-2—yl)phenyl boronic acid (58.7 mg, 313 umol), CsF (57 mg, 375 umol), and Pd(PPh3)4 (28.9 mg, 25 umol) were added.

The suspension was stirred at 50 °C for 10 minutes in a closed microwave vial. Then it was irradiated for 40 minutes in a microwave apparatus at 150 °C. The vial was cooled and uncapped, and the reaction mixture was diluted with 50 mL of CHZCIZ and 10 mL of isopropanol. The organic solvents were washed with brine and aqueous NaHCO3, dried over Na2304, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (40 g SiOz, CH20l2/EtOH/aqueous NH3 in a nt from 100/0/0.1 to 90/10/0.1) to give the product as a solid (58 mg, 48%).

LC-MS at 254nm; [M+H] 461.3; Rt 0.76 min; (LCMS method 1). 1H NMR (600 MHz, DMSO-de):13.03 (s, 1 H), 12.62 (s, 1H), 8.10 (d, 2H), 8.02 (d, 2 H), 7.31 (s, 1H), 7.07 (s, 1H), 6.0-4.5 (brs, 2H), 4.55 (dd, 1H), 4.20 (d, 1H), 4.0-3.0 (brs, 1H), 3.99 (dd, 1H), 3.92 (dd, 1H), 3.79 (d, 1H). 3.74-3.68 (m, 2H), 3.61 (dd, 1H), 3.55 (ddd, 1H), 3.45 (ddd, 1H), 3.12 (ddd, 1H), 1.32 (d, 3 H), 1.19 (d, 3 H) Example 5: 8-(6-Fluoro-1 H-indolyl)((S)methyI-morpholinyl)((R)methyl- morpholinyl)-9H-purine 4-Chloro-6—fluoro-1H-indole (72 mg, 0.42 mmol) was dissolved in 4 mL of dioxane under argon. Bis(pinacolato)diboron (198 mg, 778 umol), tricyclohexylphospine (19.8 mg, 71 pmol), bis(dibenzylidenacetone)palladium (20.3 mg, 35 pmol), and potassium acetate (104 mg, 1.06 mmol) were added under argon. The reaction was stirred for 24 hours at 80 °C. The reaction mixture was cooled to room temperature and diluted with 30 mL of EtOAc. The organic layer was washed with 20 mL of brine, dried over NaZSO4, filtered, and concentrated under reduced pressure. The residue was filtered h a column (40 9 SD; EtOAc/ heptane in a gradient from 0/100 to 12/88) to yield a mixture, which was concentrated under d pressure, and then ved in 2 mL of acetonitrile and 0.2 mL of water under argon. 8- Bromo((S)—3-methylmorpholinyl-)((R)—3-methyl-morpholinyl)-9H-purine (100 mg, 153 umol) was added, followed by cesium fluoride (25.8 mg, 170 umol) and tetrakis(triphenylphospine)pa|ladium (26 mg, 23 umol). The reaction mixture was stirred at 135 °C for 2 hours in a sealed vial. The reaction mixture was cooled to room temperature and diluted with 40 mL of EtOAc. The organic layer was washed with brine, dried over Na2304, filtered, and concentrated. The e was purified by column chromatography (10 g SiO2; tertbutylmethylether) to give the title nd as a foam (36 mg, 19% over 2 steps).

LC-MS at 254 nm; [M+H] 452.3; Rt 1.06 min; (LCMS method 1). 1H-NMR (400 MHz; DMSO—de): 12.95 (s, 1 H), 11.33 (s, 1H), 7.57 (d, 1H), 7.45 (s, 1H), 7.25 (s, 1H), 7.23 (d, 1H), 5 (brs, 2H), 4.56 (d, 1H), 4.17 (d, 1H), 4.0-3.0 (brs, 1H), 4.00 (d, 1H), 3.91 (d, 1H), 3.30 (d, 1H), .68 (m, 2H), 3.60 (d, 1H), 3.57 (dd, 1H), 3.44 (dd, 1H), 3.11 (ddd, 1H), 1.35 (d, 3H), 1.18 (d, 3H).

Example 6: {4-[2,6-Bis-((R)methyl-morpholiny|)-9H-purinyI]-1H-indolyl}- methanol [ClN N \ N / l A 4-[2,6-Bis—((R)methyl—morpho|inyI)-9H-purinyl]-1H-indole-6—carboxylic acid methyl ester (example 32, 72 mg, 146 umol) was dissolved in 10 ml THF under argon. 1N LiAlH4 in THF (0.22 mL, 0.22 mmol) was added at 5 °C, and the reaction was stirred for 2 hours at room temperature. The reaction was quenched by addition of aqueous saturated Na2804 (1 mL). The mixture was diluted with 30 mL of CH20|2 and 3 mL of isopropanol. The organic phases were separated, dried over , filtered, and concentrated. The residue was purified by column chromatography (12 g SiOz, CH2Cl2/EtOH in a gradient from 100/0 to 88/12) to give the product as a solid (58 mg, 84%).

LC-MS at 254nm; [M+H] 464.3; Rt 0.88 min; (LCMS method 1). 1H NMR (600 MHZ, DMSO-de): 12.83 (s, 1 H), 11.22 (s, 1H),7.63 (d, 1 H), 7.44 (s, 1H), 7.40 (dd, 1H), 7.18 (dd, 1H), 5 (brs, 2H), 5.16 (t, 1H), 4.61 (d, 2H), 4.55 (dd, 1H), 4.19 (d, 1H), 4.0-3.0 (brs, 1H), 3.99 (dd, 1H), 3.90 (dd, 1H), 3.79 (d, 1H), 3.74-3.68 (m, 2H), 3.59 (dd, 1H), 3.56 (ddd, 1H), 3.44 (ddd, 1H), 3.10 (ddd, 1H), 1.35 (d, 3 H), 1.17 (d, 3 H) Examgles 7 to 32 Examples 7 to 9 in Table 2 below can be made using procedures analogous to those described in Example 1 using the appropriate boronic acid or boronic ester intermediate.

Examples 10 to 11 in Table 2 below can be made using procedures analogous to those described in Example 2 using the appropriate boronic acid or boronic ester intermediate.

Examples 12 to 26 in Table 2 below can be made using procedures analogous to those described in e 3 using the riate boronic acid or boronic ester intermediate.

Examples 27 to 32 in Table 2 below can be made using procedures analogous to those described in Example 4 using the appropriate c acid or boronic ester intermediate.

Structure and Name m Number 1H NMR (600 MHz, DMSO-dg): 1300 (s 1 )864(d1H),8.14(d, 1H), 7.91 (ddd, 1H), 7.42 (ddd, 1H), 5 (brs, 2H), 4.59 (dd, 1H), 4.19 Retention Time: (d, 1H), 40-30 (brs, 1H), 1.06 min 3.99 (dd, 1H), 3.91 (dd, Mass (ES+): 1H), 3.79 (d, 1H), 3.73- 396.4 3.68 (m, 2H), 3.59 (dd, 2—(—(S)——3--Methyl—morpholin---yl)6—((R)- 1H), 3.56 (ddd, 1H), 3.43 3-m—ethyl-morpholin-y|)-8—pyridin (ddd, 1H), 3.11 (ddd, yI-9H-purine 1H), 1.31 (d, 3H)1.18 1H NMR (600 MHz, DMSO-de): 12.99 (s, 1 H), 8.62 (d, 1 H), 8.12 (d, 1H), 7.89 (ddd, 1H), 7.40 (ddd, 1H), 6.0-4.5 (brs, 2H), 4.56 (dd, 1H), 4.19 Retention Time: (d, 1H), 4.0-3.0 (brs, 1H), 1.04 min 3.96 (dd, 1H), 3.89 (dd, Mass (ES+): 1H), 3.76 (d, 1H), 3.71- 396.4 3.66 (m, 2H), 3.57 (dd, 1H), 3.53 (ddd, 1H), 3.41 2,6-Bis-((S)—3-methyl-morpholin—4-yl)- (ddd, 1H), 3.09 (ddd, dinyl-9H-purine 1H), 1.30 (d, 3 H) 1.16 Retention Time: 4.38 min Mass (ES+): 367.95 1H NMR (400 MHz, DMSO-de): 13.13 (s, 1H), 12.72 (s, 1 H), 7.84 (dd, Method 1 1 H), 6.75 (dd, 1H), 6.0- Retention Time: 4.5 (brs, 2H), 4.6-4.47 0.81 min (m, 1H), 4.16 (dd, 1H), Mass (ES+): 40-30 (hrs, 1H), 3.96 385.3 (dd, 1H), 3.90 (dd, 1H), 3.76 (d, 1H), 3.73-3.64 W0 2013/061305 PCT/lBZOlZ/055929 2,6-Bis-((S)methyl-morpholin—4—yl)— (m, 2H), 3.59 (dd, 1H), 8-(1H-pyrazolyI)-9H-purine 3.52 (dd, 1H), 3.43 (dd, 1H), 3.09 (dd, 1H), 1.29 d,3H 1.17 d,3H 1H NMR (600 MHz, DMSO-d6):13.12 (s, 1H), 12.71 (s, 1 H), 7.82 (d, 1 H), 6.74 (d, 1H), 6.0-4.5 (brs, 2H), 4.52 (d, 1H), Mew 4.16 (d, 1H), 40-30 (hrs, Retention Time: 1H), 3.95 (d, 1H), 3.88 0.81 min (d, 1H), 3.74 (d, 1H), Mass (ES+): 3.71-3.63 (m, 2H), 3.57 385.3 (d, 1H), 3.51 (dd, 1H), 3.41 (dd, 1H), 3.08 (ddd, 2,6-Bis—((R)—3-methyl-morpholin—4—yl)- 1H), 1.27 (d, 3 H), 1.15 8-(1H-pyrazolyl)-9H-purine d, 3 H H NMR (600 MHZ.

DMSO-ds): 12.77 (br. s., 1 H), 11.28 (br. s., 1 H), 7.66 (d, 1 H), 7.46 - 7.43 (m, 2 H), 7.25 (t, 1 H), 7.15 (t, 1 H), 5.6-5.4 (s, 1 Method 1 H), 5.1-4.8 (m, 1H), 4.49 ion Time: (t, 1H), 4.27 (d, 1H), 3.98 1.17 min (dd, 1H), 3.85 (dd, 1H), Mass (ES+): 3.79 (d, 2H), 3.72 (d, 462.3 1H), 3.59 - 3.48 (m, 2H), 3.45 - 3.35 (m, 1H), 3.31 8-(1 H-I ndoiy|)((R)methyl- morpholinyl)((R)propyl- (br. s., 1H), 3.10 (td, 1H), 1.75- 1.68 (m, 1H), 1.60 morpholin-4—yl)—9H-purine - 1.53 (m, 1H), 1.37 - 1.20 m, 5H 0.89 , t, 3H 1H NMR (400 MHz, e): 12.93 (s, 1H), 11.28 (br. s., 1H), 7.67 (d, 1H), 7.56 - 7.44 (m, 2H), 7.28 (br. s., 1H), Mail 7.16 (t, 1H), 5.5—5.0 (m, Retention Time: 1H), 4.56 (br. s., 2H), 0.85 min 4.36 (d, 1H), 4.07 - 3.95 Mass (ES+): (m, 3H), 3.84 - 3.71 (m, 460.4 2H), 3.62-3.55 (m, 1H), 8—[8—(1H-IndoIyl)—6-((R)methyl- 1.94 (d, 2H), 1.82 - 1.66 morpholin—4-yI)-9H-purinyl]-8—aza- (m, 4H), 1.66 - 1.49 (m, bic clo 3.2.1 octano! 2H), 1.45 - 1.31 (m, 3H) 1H NMR (400 MHz, DMSO—de): 12.87 (s, 1H), 11.28 (br. s., 1H), 7.66 (d, 1H), 7.50 - 7.40 (m, 2H), 7.30—7.25 (m, 1H), 7.16 (t, 1H), 5.6-5.0 (m, M 1H), 4.58-4.46 (m, 3H), Retention Time: 4.07 - 3.94 (m, 2H), 3.88 0.86 min (br. s., 1H), 3.85 - 3.68 Mass (ES+): (m, 2H), 3.58 (t, 1H), 460.3 3.44-3.40 (m, 1H), 2.26 (d, 2H), 2.14-2.06 (d, 8-[8-(1H-IndoIy|)((R)methyl- 2H), 2.94 — 1.79 (m, 2H), morpholinyl)-9H—purin-2—yl]aza- 155-157 ( m, 2H )1 1.36 bicyclo[3.2.1]octan—3-ol d, 3H H NMR (600 MHz, DMSO-ds): 12.79 (s, 1H), 11.27 (br. s., 1H), 7.66 (d, 1H), 7.48 - 7.42 (m, 2H), 7.25 (br. s., 1H), 7.14 (t, 1H), 5.7-4.7 (m, Method 1 2H), 4.37 (t, 1H), 4.27 (d, Retention Time: 1H), 3.99 (dd, 1H), 3.88 - 1.07 min 3.77 (m, 3H), 3.72 (d, Mass (ES+): 1H), 3.62 - 3.47 (m, 2H), 448.3 3.42 (td, 2H), 3.12 - 3.06 2—((R)Ethyl—morpho|in—4-y|)(1H- (m, 1H), 1,79 - 1,72 (m, indoIyl)((R)methyl-morpholin- 1H), 1.63 - 1.56 (m, 1H), 9H-purine 1.40 — 1.29 (m, 3H), 0.87 t, 3H H NMR (600 MHz, DMSO-de) 12.81 (s, 1H), 11.28 (br. s., 1H), 7.65 (d, 1H), 7.53 — 7.43 (m, 2H), 7.25 (t, 1H), 7.15 (t, Method 1 1H), 5.6-5.0 (m, 2H), Retention Time: 3.99 (dd, 1H), 3.82 - 3.76 0.69 min (m, 1H), 3.75 - 3.65 (m, Mass (ES+): 3H), 3.58-3.53 (m, 1H), 433.3 3.49-3.46 (m, 1H), 3.40 Indolyl)((R)methyl- (t, 1H), 3.34-3.29 (m, morpholinyl)(4-methyl-piperazin— 1H), 2.39 - 2.27 (m, 4H), 9H—purine 2.26 - 2.10 (m, 3H), 1.34 d, 3H H NMR (600 MHz, DMSO—de): 12.95 (s, 1H), 11.28 (br. s., 1H), 7.63 - 7.60 (m, 1H), 7.46 - 7.40 Method 1 (m, 2H), 7.25 (t, 1H), Retention Time: 7.14 (t, 1H), 5.65-4.85 0.97 min (m, 2H), 4.00 — 3.95 (m, Mass (ES+): 1H), 3.81 - 3.75 (m, 1H), 460.3 3.73 - 3.66 (m, 3H), 3.65 - 3.59 (m, 4H), 3.57 - 3.44 (m, 3H), 3.42—3.38 m,1H,1.83-1.68 m, morpho|inyi)(6-oxaaza- 2H), 1.55 - 1.43 (m, 2H),_ siro[3.5]non | -9H—ourine 1.34 d, 3H 1H NMR (600 MHz, g): 12.83 (s, 1H), 11.28 (br. s., 1H), 7.64 (d, 1H), 7.50 - 7.42 (m, 2H), 7.25 (br. s., 1H), Method 1 7.15 (t, 1H), 5.75-4.70 Retention Time: (m, 2H), 4.55 (t, 2H), 0.72 min 4.47 (t, 2H), 3.99 (dd, 1 Mass (ES+): H), 3.81 - 3.76 (m, 1 H), 475.3 3.75 - 3. 64 (m, 5 H), 8—(1 H-lndolyl)((R)methyl- 3.62 -3. 51 (m, 1 H), morpholinyl)(4-oxetan—3-yl— 3.46 - 3.38 (m, 2H), 2.30 nierazin l -9H-urine (t, 4H), 1.34 (d, 3H) 1H NMR (400 MHz, DMSO-de): 12.89 (s, 1H), 11.28 (br. s., 1H), 7.68- 7.64 (m, 1H), 7.48 - 7.44 (m, 2H), 7.28 (t, 1H), Meflm 7.18 (t, 1H), 5.7—4.2 (m, Retention Time: 2H), 4.01 (dd, 1 H), 3.89 0.88 min - 3.79 (m, 3H), 3.77 - Mass (ES+): 3.66 (m, 3H), 3.62 - 3.55 446.3 (m, 3H), 3.54 - 3.42 (m, 8—(1 H-IndoI—4-yl)—6-((R)—3-methyl- 2H), 3.32 (s, 1H), 3.02 - morpholin-4—yl)—2-(tetrahydro-furo[3,4- 2.91 (m, 2H), 1.37 (d, H NMR (400 MHz, DMSO—de):12.81 (s, 1H), 11.29 (br. s., 1H), 7.69 — 7.84 (m, 1H), 7.49 - 7.44 (m, 2H), 7.27 (br. s., 1H), 7.18 m1 (t, 1H), 5.6-4.8 (m, Retention Time: 2H), 3.98 - 3.90 (m, 1H), 0.95 min 3.84 - 3.71 (m, 8H), 3.62 Mass (ES+): - 3.54 (m, 2H), 3.48 — 460.3 3.39 (m, 3H), 3.33 — 3.30 2-(Hexahydro-furo[3,4-c]pyridin-5—yl)— (m, 1H), 2.49 -2.33 (m, 8-(1 H-indolyl)—6-((R)—3—methyl- 2H), 1.77 (br. s., 1H), morpholin-4—yl)-9H-purine 1.52 (br. s., 1H), 1.38 (d.

H NMR (600 MHz, e): 12.75 (s, 1H), 11.27 (br. s., 1H), 7.64 (d, 1H), 7.38 - 7.45 (m, 2H), 7.24 (t, 1H), 7.14 (t, Method 1 1H), 5.2-4.7 (m, 2H), Retention Time: 4.45 (d, 1H), 4.29 (d, 1.12 min 1H), 3.98 -3.92 (m, 2H), Mass (ES+): 3.84 - 3.78 (m, 2H), 3.74 462.3 - 3.69 (m, 1H), 3.60 - 8-(1H-Indoiyl)((R)isopropy|- 3.53 (m, 1H), 3.43 — 3.35 morphoiin-4—yl)((R)—3-methyl- (m, 2H), 3.32 — 3.21 (m, morpholin—4-y|)-9H-purine 1H ,3.09 td, 1H ,2.48- WO 61305 2.30 (m, 1H), 1.34 (d, 3H), 1.00 (d, 3H), 0.77 d, 3H H NMR (600 MHz, DMSO-de): 12.84 (br. s., 1H),11.28(br.s.,1H), 7.65 (d, 1H), 7.47 - 7.43 (m, 2H), 7.25 (br. s., 1H), Method 1 7.15 (t, 1H), 5.7-5.3 (m, Retention Time: 1H), 4.75 (d, 2H), 4.00 1.24 min (d, 1H), 3. 82 - 3. 77 (m, Mass (ES+): 1H), 3.76 — 3.70 (m, 1H), 486.3 3.57 (t, 1H), 3.37 (br. s., 1H), 2.86 (t, 2H), 2. 64 — 8—( 1 H-l ndoIyl)((R)—3—methyl- 2. 56 (m, 1H), 1.83 (d, morpholinyl)(4-trifluoromethyl- 2H), 1.43-1.36 (m, 3H), piperidinyl)—9H-pu rine 1H NMR (600 MHz, DMSO-ds): 12.83 (br. s., 1H), 11.28 (br. s., 1H), 7.65 (d, 1H), 7.53 - 7.42 Method 1 (m, 2H), 7.25 (br. s., 1H), Retention Time: 7.15 (t, 1H), 5.5-5.0 (m, 1.1 min 2H), 4.42 (d, 2H), 4.00 Mass (ES+): (d, 1H), 3.80 (d, 1H), 448.3 3.73 (d, 1H), 3.60 - 3.52 (m, 3H), 3.3 (m, 1H), 2-((2S,6R)—2,6-Dimethyl—morpholin-4— 2.48-2.43 (m, 2H), 1.35 y|)(1H-indolyl)—6-((R)methyl- (d, 3H), 1.15 (d, 6H) morpholin 1H NMR (600 MHz, CHLOROFORM-d): 8.42 (br. s., 1H), 7.55 (d, 1H), 7.49 (d, 1H) 7.38 (br. s., Method 1 1H), 7.31 - 7.26 (m, 2H), ion Time: 4.17 - 4.07 (m, 3H), 4.01 0.92 min (dd, 3H), 3.88 (d, 2H), Mass (ES+): 3.77-3.64 (m, 3H), 3.43 460.3 (t, 3 H), 2.73 (br. s., 2 H), 2.25 (t, 2H), 1.76 (d, 2H), 1.51 (br. s., 3H) 1H NMR (600 MHz, DMSO—de): 12.87 (s, 1H), 11.28 (br. s., 1H), 7.65 (d, 1H), 7.45 (d, 2H), 7.25 (br. s., 1H), 7.15 (t, Method 1 1H), 5.7-4.9 (m, 2H), Retention Time: 4.80 (t, 1H), 4.53 (d, 1H), 0.82 min 4.38 (d, 1H), 4.00 (d, Mass (ES+): 1H), 3.91 (d, 1H), 3.80 450.3 (d, 1H), 3.73 (d, 1H), 3.60 - 3.46 (m, 3H), 3.44 {(S)[8-(1H-lndolyl)((R)—3— — 3.38 (m, 3H), 2.90 (t, methyl-morpholinyl)-9H-purinyl]- 1H), 2.58 - 2.84 (m, 1H), 1.35 (d, 3H) H NMR (600 MHz, DMSO-de): 12.86 (s, 1H), 11.28 (br. s., 1H), 7.65 (d, 1H), 7.55 - 7.43 (m, 2H), 7.27-7.23 (m, 1H), 7.15 (t, 1H), 5.7-5.0 (m, Method 1 2H), 4.81 (t, 1H), 4.52 (d, Retention Time: 1H), 4.42 - 4.32 (m, 1H), 0.83 min 3.99 (d, 1H), 3.91 (d, Mass (ES+): 1H), 3.80 (d, 1H), 3.73 450.3 (d, 1H), 3.56 - 3.38 (m, 6H), 2.93 - 2.86 (m, 1H), -[8-(1H-Indolyl)((R) 2.64 - 2.58 (m, 1H), 1.33 methyl-morpholin-4—yl)-9H-purin—2-yl]— (d, 3H) morpholin-Z-yl}-methanol 1H NMR (600 MHz, DMSO—de):12.72 (s, 1 H), 8.58 (d, 1 H), 7.97 (dd, 1H), 6.51 (d, 1H), 6.36 (s, 2H), 6.0-4.5 (brs, 2H), Method 1 4.52 (dd, 1H), 4.16 (dd, Retention Time: 1H), 4.0—3.0 (brs, 1H), 0.73 min 3.96 (dd, 1H), 3.90 (dd, Mass (ES+): 1H), 3.76 (d, 1H), 3.72- 411.3 3.64 (m, 2H), 3.60 (dd, 1H), 3.52 (ddd, 1H), 3.44 -[2,6-Bis-((S)methyl-morpholin (ddd, 1H), 3.09 (ddd, y|)-9H-purin-8—yl]—pyridinylamine 1H), 1.29 (d, 3 H) 1.17 1H NMR (600 MHz, DMSO-de): 12.72 (s, 1 H), 8.58 (d, 1 H), 7.97 (dd, 1H), 6.51 (d, 1H), 6.36 Method 1 (s, 2H), 5 (brs, 2H), Retention Time: 4.52 (dd, 1H), 4.16 (dd, 0.73 min 1H), 4.0-3.0 (brs, 1H), Mass (ES+): 3.96 (dd, 1H), 3.90 (dd, 411.3 1H), 3.76 (d, 1H), 3.72- 3.64 (m, 2H), 3.60 (dd, -[2,6-Bis-((R)—3—methy|—morpholin—4— 1H), 3,52 (ddd, 1H), 3_44 yl)-9H-purinyl]—pyridinyiamine PCT/IBZOlZ/055929 H NMR 6(00 MHz, DMSO-d6): , 1 H), 8.80(s, 2H), 7.s,08( 2H), 6.0-4.5 (brs, 2H), 4.49 (dd, 1H), 4.14 (d, Method 1 1H), 0 (brs, 1H), Retention Time: 3.94 (dd, 1H), 3.88 (dd, 0.78 min 1H), 3.74 (d, 1H), 3.71- Mass (ES+): 3.63 (m, 2H), 3.58 (dd, 412.3 1H), 3.50 (ddd, 1H), 3.42 (ddd, 1H), 3.07 (ddd, -[2,6-BIs—((R)—3—methyl-morpholin~4— 1H) 1.27 (d 3 H) 1.15 yl')- 9H-purinyl]-pyrimidin—2-yl-amine 1H NMR (600 MHz, DMSO-de): 13.82 (brs, 1H), 13.11 (s, 1 H), 8.17 (d, 2H), 8.05 (d, 2 H), 7.47 (s, 2H), 6.0-4.5 Method 1 (brs, 2H), 4.55 (dd, 1H), Retention Time: 4.20 (d, 1H), 4.0-3.0 (brs, 0.76 min 1H), 3.99 (dd, 1H), 3.92 Mass (ES+): (dd, 1H), 3.79 (d, 1H), 461.3 3.74-3.66 (m, 2H), 3.61 8—[4-(1H-lmidazol—2-yi)-phenyl]—2,6— (dd, 1H), 3.55 (ddd, 1H), bis-((S)—3-methyI-morpholin-4—yl)—9H— 3.45 (ddd, 1H), 3.12 purine (ddd, 1H), 1.33 (d, 3 H), 1H NMR (600 MHz, DMSO-d6): 12.87 (s, 1 H), 11.04 (s, 1H), 7.39 (d, 1H), 7.29 (dd, 1H), 7.14 (s, 1H), 6.96 (s. 1H), 6.0-4.5 (brs, 2H), Method 1 4.56 (d, 1H), 4.16 (d, ion Time: 1H), 4.0-3.0 (brs, 1H), 1.02 min 3.99 (d, 1H), 3.90 (dd, Mass (ES+): HN 1H), 3.82 (s, 3H), 3.79 464.3 (d, 1H), 3.75-3.67 (m, 8-(6-Methoxy-1H-indol—4—yi)((S)—3- 2H), 3.60 (dd, 1H), 3.56 methyl—morpholin—4—yl)—6—((R)—3— (dd, 1H), 3.44 (dd, 1H), methyl-morpholin-4—yi)—9H—purine 3.10 (ddd, 1H), 1.34 (d, 3H 1.17 d,3H. 1H NMR (400 MHz, DMSO-ds) :13.11 (s, 1 H), 11.70 (s, 1H), 8.34 (d, 1 H), 8.09 (s, 1H), Method 1 7.71 (dd, 1H), 7.32 (dd, Retention Time: 1H), 6.0-4.5 (brs, 2H), 1.05 min 4.56 (dd, 1H), 4.19 (d, Mass (ES+): 1H), 4.0-3.0 (brs, 1H), 492.3 3.99 (dd, 1H), 3.90 (dd, 1H), 3.89 (s, 3H), 3.79 4-[2,6-Bis-((R)—3-methyl-morpholin (d, 1H), 375-368 (m, yI)—9H-purin—8-yI]—1H-indole—6- - ylic acid methyl ester (ddd, 1H), 3.44 (ddd, 1H), 3.11 (ddd, 1H), 1.36 d,3H,1.18 d,3H

Claims (17)

1. Claims 1. A compound of formula (I), or a pharmaceutically acceptable salt thereof, R1 is ed from the group consisting of (R18)m _N N— N— , a (R )q p \ n R20 (R22)r a and ; wherein R18 on each occurrence independently represents fluoro or methyl; m represents 0, 1, 2 or 3; R19 and R20 ndently represent hydrogen or ; R21 represents fluoro; R22 on each occurrence independently represents fluoro, methoxy, hydroxymethyl or methoxycarbonyl; q represents 0, 1 or 2 and r represents 0, 1, 2 or 3 provided that q + r is not 0; R2, R3, R4, R5, R6, R7, R8 and R9 independently represent hydrogen, C1_3alky|orfluoro-C1. 3alkyl; or R3 and R6 together form a methylene bridge; or R3 and R8 together form an ethylene bridge; or R5 and R6 together form an ethylene bridge; n and p independently represent 0, 1 or 2; R“, R“, R12, R13, R14, R15, R16 and R17 on each occurrence independently represent hydrogen, C1_3alkyl, fluoro-C1_3alkyl or hydroxy—C1_3alkyl; or R11 and R16 together form an ethylene bridge; or R13 and R14 together form an ethylene ; or R14 and R15, together with the carbon atom to which they are ed, are linked to form a tetrahydropyranyl ring; Y represents 0, CHR23, CR24R25 or NR26, wherein R23 represents hydroxyl or fluoro-C1.3alkyl; or R23 and R13, together with the carbon atoms to which they are attached, are linked to form a fused tetrahydrofuranyl ring; R24 and R25 independently ent en or halogen; or R24 and R25, together with the carbon atom to which they are attached, are linked to form a tetrahydropyranyl ring; R26 represents kyl or oxetanyl; a compound, or a pharmaceutically acceptable salt f, selected from the following list of compounds: 8—(1H-lndolyl)(3-methyl-morpholinyl)[1,4]oxazepanyl-9H-purine; 8—(1H—lndol—4-yl)(3-methyl-morpholinyl)—2—(3—propyl-morpholin—4-yl)-9H-purine; 8—[8-(1 H-lndoI-4—yl)(3-methyl-morpholinyl)-9H-purinyl]aza-bicyclo[3.2.1]octan—3-ol; 8—[8-(1H-lndolyl)(3-methyl-morpholinyl)-9H-purinyl]-8—aza—bicyclo[3.2.1]octanol; 2—(3-Ethyl-morpholin—4—yl)—8—(1H-indolyl)-6—(3-methyl-morpholin—4—yl)—9H-purine; 8-(1H-lndol-4—yl)(3-methyl-morphoIinyl)—2-(4-methyl-piperazinyl)-9H-pu rine; 8-(1H-Indolyl)-6—(3-methyl-morpholinyl)(6-oxaaza-spiro[3.5]nonyl)-9H-purine; 8-(1H-lndolyl)(3-methyl-morpholinyl)(4-oxetanyl-piperaziny|)-9H-purine; 8—(1H-lndolyl)(3—methyl-morpholinyI)-2—(tetrahyd ro-furo[3,4-c]pyrrolyl)—9H-purine; ahydro—furo[3,4-c]pyridin-5—yl)—8—(1H-indo|yl)—6-(3-methyl-morpholinyl)-9H-purine; 8—(1H-lndolyl)(3-isopropyl-morpholin—4—yl)—6-(3-methyl-morpholinyl)-9H-purine; 8-(1H-|ndolyl)(3-methyl-morpholin—4—yl)(4-trifluoromethyl-piperidiny|)-9H-pu rine; 2-(2,6-Dimethyl—morpholinyl)-8—(1H-indolyl)(3-methyl-morpholinyl)-9H-purine; 8-(1H-lndolyl)(3-methyl-morpholin—4-y[)(7-oxaaza-spiro[3.5]nonyl)-9H-purine; {4-[8—(1 H-lndolyl)—6-(3-methyI-morpholin-4—yl)—9H—puriny|]-morpholinyl}—methanol; {4-[8-(1H-lndol-4—yl)(3-methyl-morpholin-4—yl)-9H-purinyl]-morpholinyl}-methanol.
2. 2. A compound according to Claim 1, or a pharmaceutically acceptable salt thereof, wherein R1 represents mm)". / \
3. 3. A compound according to Claim 1, or a pharmaceutically acceptable salt thereof, wherein R1 represents HN \
4. 4. A compound according to Claim 1, or a pharmaceutically acceptable salt f, wherein R1 represents 02“), (R22),
5. 5. A compound according to any one of Claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R2, R3, R4, R5, R6, R7, R8 and R9 independently represent hydrogen or methyl; or R3 and R6 together form a methylene bridge; or R3 and R8 together form an ethylene bridge; or R5 and R6 together form an ne bridge.
6. 6. A compound according to any one of Claims 1 to 5, or a pharmaceutically acceptable salt f, wherein Y represents 0.
7. 7. A compound ing to any one of Claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein Y represents CHR23 or CR24R25.
8. 8. A nd, or a pharmaceutically acceptable salt thereof, according to Claim 1 which is selected from: 2,6-Bis-((R)—3-methyl-morpholinyl)—8—pyridin-2—yl-9H-purine; Methyl-morpholinyl)((R)methyl-morpholinyl)(1 H-pyrazolyl)-9H- purine; 8—(1H-lndolyl)((R)—3-methyl-morpholin-4—yl)—2-[1,4]oxazepan-4—yl-9H-purine; 1H-lmidazol—2-yl)—phenyl]-2,6-bis-((R)—3-methyl-morpholinyl)—9H-purine; Iuoro—1 H-indolyl)((S)methyl-morphoiinyl)((R)—3-methyl-morpholin—4-y|)- 9H-purine; {4-[2,6-Bis-((R)—3-methyl-morpholinyl)-9H-purin-8—yl]-1H-indol—6-y|}—methanol; 2-((S)Methy|-morpholinyl)((R)—3-methyl-morpholin-4—yl)—8—pyridinyI-9H-pu rine; 2,6-Bis-((S)methyI-morpholinyl)pyridin—Z-yl—QH-purine; 2,6-Di-morpholinylpyridinyi-9 H-purine; 2,6-Bis-((S)—3-methyl—morpho|in-4—y|)(1H-pyrazol-3—yI)-9H-purine; 2.6-Bis-((R)—3-methyl-morpholinyl)(1H-pyrazoIyI)-9H-purine; 8—(1H-lndoI—4-yl)((R)~3-methyl-morpholinyl)((R)propy|—morpholiny|)-9H-purine; 8-[8-(1 H—lndol-4—yI)((R)—3—methyi—morpholinyI)-9H-purin-2—yl]—8—aza-bicyclo [3 .2. 1 - 3-ol; 8—[8-(1H-indolyl)((R)—3-methyl-morpholin—4-yl)—9H-purin-2—yl]—8-aza-bicyclo[3.2.1]octan- 3-ol; 2-((R)-3—Ethyl-morpholinyi)(1H-indo|yl)((R)methyi-morpholin-4—yl)—9H—purine; 8—(1H-lndoIyl)((R)methy|—morpho|in—4—yl)—2—(4—methyl—piperaziny|)-9H-pu rine; 8-(1H-lndo|yi)((R)methyl-m0rpholin—4-yl)(6-oxaaza—spiro[3.5]nonyl)—9H- purine; 8-(1H—|ndoI-4—yi)—6—((R)methyl—morpholinyl)—2-(4-oxetan-3—yl-piperazin—1-y|)-9H—purine; 8-(1H-lndol-4—yl)—6-((R)methyl-morpholinyl)—2-(tetra hyd ro-fu ro[3 ,4-c]pyrro|—5-y|)—9H- purine; 2-(Hexahydro-fu ro[3,4-c] pyridin-5—yl )(1 H-indol—4—yl)((R)methyI-morpholinyl)-9H— purine; 8—(1H-Indolyl)—2—((R)—3—isopropyl-morphoiin—4—yi)—6—((R)—3—methyl-morpholin—4—yl)—9H- purine; 8-(1H-IndoIyl)((R)methy|~morpholinyl)(4-trifluoromethyl-piperidinyl)-9H- 2-((28,6R)-2,6-Dimethyl-morpholin—4~yl)—8—(1H-indoIyl)((R)—3—methyl-morpho|inyl)-9H- purine; 8-(1H-lndolyl)—6-((R)methyl-morpholinyl)(7-oxaaza-spiro[3.5]non—1-y|)-9H- purine; {(S)[8-(1 H-Indolyl)—6—((R)methyl-morpholin-4—yl)—9H-purinyll-morpholinyl}- methanol; {(R)—4—[8—(1H-Indolyl)((R)—3-methyl-morpholin-.4-y|)-9H-purin—2—y|]-morpholinyl}- methanol; 5-[2,6-Bis-((S)methyl-morpholinyl)—9H-purinyI]-pyridinylamine; 5-[2,6-Bis-((R)—3-methyl-morpholinyi)-9H-purinyl]-pyridinylamine; 5-[2,6-Bis-((R)—3-methyl-morpholin-4—yl)— 9H-purinyl]-pyrimidinyl-amine; 8-[4-(1H-lmidazolyl)-phenyl]-2,6-bis-((S)methyl-morpholinyl)-9H—purine; 8-(6-Methoxy—1 H-indol-4—yl)((S)methyl-morpho|in-4—yl)((R)—3-methyl-morpholin-4—yl)- ine; 5 4-[2,6-Bis-((R)—3-methyl-morpho|in-4—yl)—9H-purinyl]-1H-indolecarboxylic acid methyl ester; and pharmaceutically acceptable salts thereof.
9. 9. A compound according to claim 1 which is 2,6-Bis-((R)methyl—morpholinyl)pyridin- 10 2-yl-9H-purine having the following formula [0ML WN \ . i ; or a pharmaceutically acceptable salt f.
10. 10. A compound according to claim 1 which is luoro-1H-indolyl)((S)—3-methyl- morpho|in-4—yl)((R)—3-methyl-morpho|in—4—yl)—9H-purine having the following formula ; or a pharmaceutically acceptable salt thereof.
11. 11. A compound according to claim 1 which is 2-((S)—3-Methyl-morpholin-4—yl)—6-((R) methyl-morpholin—4-yl)pyridinyl-9H-purine having the following formula Q—<n/ \ /N \N l NAN/H “9‘“ ‘\/ ; or a pharmaceutically acceptable salt thereof.
12. 12. A compound according to claim 1 which is 2,6—Bis-((S)—3-methyl-morpholin-4—yl)(1 H- pyrazol-3—yl)—9H-purine having the following formula ; or a pharmaceutically acceptable salt thereof.
13. 13. A compound according to any one of Claims 1 to 12, or a pharmaceutically acceptable salt thereof, for use as a ment.
14. 14. A compound according to any one of Claims 1 to 12, or a pharmaceutically acceptable 10 salt thereof, for use in the treatment or prevention of cancer, a neurodegenerative disorder or an ophthalmological disease.
15. 15. A pharmaceutical composition comprising a compound according to any one of Claims 1 to 12, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable 15 excipient, diluent or carrier.
16. 16. The use of a compound according to any one of Claims 1 to 12, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the ent or prevention of cancer, a neurodegenerative er or an ophthalmological disease.
17. 17. A combination product comprising a nd according to any one of Claims 1 to 12, or a ceutically acceptable salt f, and another therapeutic agent.