Cdk inhibitors

Field of the Invention

0001The invention relates to compounds useful for inhibiting cyclin-dependent kinase ("CDK").

Background

0002Cancer continues to be a challenge for modem medicine. At a basic level, cancer occurs when there is uncontrollable cell division. The uncontrollable cell division is an effect of a break down in the natural life cycle of cells. CDK is a family of kinases involved in the cell life cycle. Abnormally high CDK activity is one characteristic of several cancers. There are naturally occurring CDK-inhibiting proteins and the abnormally high CDK activity maybe due to a malfunction of the naturally occurring CDK inhibitors or due to an overabundance of CDK. CDK inhibitors are known in the art but there remains a need for additional CDK inhibitors.

Summary

0003The invention is directed to compounds as defined in the claims wherein R, R¹, R², X, and y are as defined herein and to pharmaceutically acceptable salts thereof.

0004The disclosed compounds are useful as CDK inhibitors and could be useful in the treatment of diseases and disorders mediated by CDK such as cancer. Pharmaceutical compositions comprising the compounds and pharmaceutically acceptable salts of the compounds are also disclosed.

Brief Description of the Drawings

0005<ul id="ul0001" list-style="none"><li><figref idref="f0001 f0002 f0003">FIGS. 1-3</figref> illustrate embodiments of R² of the compounds of the invention.</li><li><figref idref="f0004 f0005 f0006">FIGS. 4-6</figref> illustrate embodiments of the core structure of the compounds of the invention.</li></ul>

Detailed Description

0006In one embodiment, compounds are provided wherein: <ul id="ul0002" list-style="none" compact="compact"><li>each X is independently CH or N;</li><li>R is H, C₁-C₃ alkyl or haloalkyl;</li><li>each R¹ is independently aryl, alkyl, cycloalkyl or haloalkyl, wherein each of said alkyl, cycloalkyl and haloalkyl groups optionally includes O or N heteroatoms in place of a carbon in the chain and two R¹' s on adjacent ring atoms or on the same ring atom together with the ring atom(s) to which they are attached optionally form a 3-8-membered cycle;</li><li>y is 0, 1, 2, 3 or 4;</li></ul> or a pharmaceutically acceptable salt thereof.

0007In some aspects, R is hydrogen or C₁-C₃ alkyl.

0008In some aspects, R² is selected from the structures depicted in <figref idref="f0001 f0002 f0003">FIGS. 1-3</figref>.

0009In some aspects, the compound has one of the general structures in <figref idref="f0004 f0005 f0006">FIGS. 4-6</figref> wherein the variables are as previously defined.

0010In some aspects, the compound has general formula Ia: <chemistry id="chem0001" num="0001"><img file="EP2632467B1_D0001.tif" /></chemistry> wherein R¹, R², R and y are as previously defined.

0011In some embodiments, the compound has formula Ia and R is alkyl.

0012In some embodiments, the compound has formula Ia and R is H.

0013In some embodiments, the compound has formula Ib: <chemistry id="chem0002" num="0002"><img file="EP2632467B1_D0002.tif" /></chemistry> wherein R² and R are as previously defined.

0014In some embodiments, the compound has formula Ib and R is alkyl.

0015In some embodiments, the compound has formula Ib and R is H.

0016In some embodiments, the compound has formula Ic: <chemistry id="chem0003" num="0003"><img file="EP2632467B1_D0003.tif" /></chemistry> wherein R² and R are as previously defined.

0017In some embodiments, the compound has formula Ic and R is alkyl.

0018In some embodiments, the compound has formula Ic and R is H.

0019In some embodiments, the compound has formula Id: <chemistry id="chem0004" num="0004"><img file="EP2632467B1_D0004.tif" /></chemistry> wherein R² and R are as previously defined.

0020In some embodiments, the compound has formula Id and R is alkyl.

0021In some embodiments, the compound has formula Id and R is H.

0022In some embodiments, the compound has formula Ie: <chemistry id="chem0005" num="0005"><img file="EP2632467B1_D0005.tif" /></chemistry>

0023In some embodiments, the compound has formula Ie and R is alkyl.

0024In some embodiments, the compound has formula Ie and R is H.

0025In some embodiments, the compound has formula If: <chemistry id="chem0006" num="0006"><img file="EP2632467B1_D0006.tif" /></chemistry>

0026In some embodiments, the compound has formula If and R is alkyl.

0027In some embodiments, the compound has formula If and R is H.

0028In some embodiments, the compound has formula Ig: <chemistry id="chem0007" num="0007"><img file="EP2632467B1_D0007.tif" /></chemistry>

0029In some embodiments, the compound has formula Ig and R is alkyl.

0030In some embodiments, the compound has formula Ig and R is H.

0031In some embodiments, the compound has formula Ih: <chemistry id="chem0008" num="0008"><img file="EP2632467B1_D0008.tif" /></chemistry>

0032In some embodiments, the compound has formula Ih and R is alkyl.

0033In some embodiments, the compound has formula Ih and R is H.

0034In some embodiments, the compound has formula Ii: <chemistry id="chem0009" num="0009"><img file="EP2632467B1_D0009.tif" /></chemistry>

0035In some embodiments, the compound has formula Ii and R is alkyl.

0036In some embodiments, the compound has formula Ii and R is H.

0037In some embodiments, the compound has formula Ij: <chemistry id="chem0010" num="0010"><img file="EP2632467B1_D0010.tif" /></chemistry>

0038In some embodiments, the compound has formula Ij and R is alkyl.

0039In some embodiments, the compound has formula Ij and R is H.

0040In some embodiments, the compound has formula Ij and R is H, and both X are N.

0041In some embodiments, the compound has formula Ik: <chemistry id="chem0011" num="0011"><img file="EP2632467B1_D0011.tif" /></chemistry>

Definitions

0042Unless otherwise stated, the following terms used in this application, including the specification and claims, have the definitions given below. Definition of standard chemistry terms may be found in reference works, including <nplcit id="ncit0001" npl-type="b"><text>Carey and Sundberg (2007) Advanced Organic Chemistry 5th Ed. Vols. A and B, Springer Science+Business Media LLC, New York</text></nplcit>. The practice of the present invention will employ, unless otherwise indicated, conventional methods of synthetic organic chemistry, mass spectroscopy, preparative and analytical methods of chromatography, protein chemistry, biochemistry, recombinant DNA techniques and pharmacology. Conventional methods of organic chemistry include those included in <nplcit id="ncit0002" npl-type="b"><text>March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 6th Edition, M.B. Smith and J. March, John Wiley &amp; Sons, Inc., Hoboken, NJ, 2007</text></nplcit>.

0043The term "alkyl," either alone or within other terms such as "haloalkyl" and "alkylamino," embraces linear or branched radicals having one to about twelve carbon atoms.

0044"Lower alkyl" radicals have one to about six carbon atoms. Examples of such radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, <i>tert-butyl,</i> pentyl, isoamyl, hexyl and the like. The term "alkylene" embraces bridging divalent linear and branched alkyl radicals. Examples include methylene, ethylene, propylene, isopropylene and the like.

0045The term "alkenyl" embraces linear or branched radicals having at least one carbon-carbon double bond of two to about twelve carbon atoms. "Lower alkenyl" radicals having two to about six carbon atoms. Examples of alkenyl radicals include ethenyl, propenyl, allyl, propenyl, butenyl and 4-methylbutenyl. The terms "alkenyl" and "lower alkenyl," embrace radicals having "cis" and "trans" orientations, or alternatively, "E" and "Z" orientations.

0046The term "alkynyl" denotes linear or branched radicals having at least one carbon-carbon triple bond and having two to about twelve carbon atoms. "Lower alkynyl" radicals having two to about six carbon atoms. Examples of such radicals include propargyl, butynyl, and the like.

0047Alkyl, alkenyl, and alkynyl radicals may be optionally substituted with one or more functional groups such as halo, hydroxy, nitro, amino, cyano, haloalkyl, aryl, heteroaryl, heterocyclo and the like.

0048The term "alkylamino" embraces "N-alkylamino" and "N,N-dialkylamino" where amino groups are independently substituted with one alkyl radical and with two alkyl radicals, respectively. "Lower alkylamino" radicals have one or two alkyl radicals of one to six carbon atoms attached to a nitrogen atom. Suitable alkylamino radicals may be mono or dialkylamino such as N-methylamino, N-ethylamino, N.N-dimethylamino, N,N-diethylamino and the like.

0049The term "halo" means halogens such as fluorine, chlorine, bromine or iodine atoms.

0050The term "haloalkyl" embraces radicals wherein any one or more of the alkyl carbon atoms is substituted with one or more halo as defined above. Examples include monohaloalkyl, dihaloalkyl and polyhaloalkyl radicals including perhaloalkyl. A monohaloalkyl radical, for one example, may have an iodo, bromo, chloro or fluoro atom within the radical. Dihalo and polyhaloalkyl radicals may have two or more of the same halo atoms or a combination of different halo radicals. "Lower haloalkyl" embraces radicals having 1-6 carbon atoms. Examples of haloalkyl radicals include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl. "Perfluoroalkyl" means an alkyl radical having all hydrogen atoms replaced with fluoro atoms. Examples include trifluoromethyl and pentafluoroethyl.

0051The term "aryl", alone or in combination, means a carbocyclic aromatic system containing one or two rings wherein such rings may be attached together in a fused manner. The term "aryl" embraces aromatic radicals such as phenyl, naphthyl, indenyl, tetrahydronaphthyl, and indanyl. More preferred aryl is phenyl. Said "aryl" group may have 1 or more substituents such as lower alkyl, hydroxyl, halo, haloalkyl, nitro, cyano, alkoxy, lower alkylamino, and the like. An aryl group may be optionally substituted with one or more functional groups such as halo, hydroxy, nitro, amino, cyano, haloalkyl, aryl, heteroaryl, heterocyclo and the like.

0052The term "heterocyclyl" (or "heterocyclo") embraces saturated, and partially saturated heteroatom-containing ring radicals, where the heteroatoms may be selected from nitrogen, sulfur and oxygen. Heterocyclic rings comprise monocyclic 6-8 membered rings, as well as 5-16 membered bicyclic ring systems (which can include bridged fused and spiro-fused bicyclic ring systems). It does not include rings containing -O-O-.-O-S- or -S-S-portions. Said "heterocyclyl" group may have 1 to 3 substituents such as hydroxyl, Boc, halo, haloalkyl, cyano, lower alkyl, lower aralkyl, oxo, lower alkoxy, amino, lower alkylamino, and the like.

0053Examples of saturated heterocyclo groups include saturated 3- to 6-membered heteromonocyclic groups containing 1 to 4 nitrogen atoms [e.g. pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl, piperazinyl]; saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g. morpholinyl]; saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g., thiazolidinyl]. Examples of partially saturated heterocyclyl radicals include dihydrothienyl, dihydropyranyl, dihydrofuryl, dihydrothiazolyl, and the like.

0054Particular examples of partially saturated and saturated heterocyclo groups include pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl, pyrazolidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, thiazolidinyl, dihydrothienyl, 2,3-dihydro-benzo[1,4]dioxanyl, indolinyl, isoindolinyl, dihydrobenzothienyl, dihydrobenzofuryl, isochromanyl, chromanyl, 1,2-dihydroquinolyl, 1,2,3,4-tetrahydro-isoquinolyl, 1 ,2,3,4-tetrahydro-quinolyl, 2,3,4,4a,9,9a-hexahydro-1H-3-aza-fluorenyl, 5,6,7- trihydro-1,2,4-triazolo[3,4-a]isoquinolyl, 3,4-dihydro-2H-benzo[1,4]oxazinyl, benzo[1,4]dioxanyl, 2,3- dihydro-1H-1λ'-benzo[d]isothiazol-6-yl, dihydropyranyl, dihydrofuryl and dihydrothiazolyl, and the like.

0055Heterocyclo groups also includes radicals where heterocyclic radicals are fused/condensed with aryl radicals: unsaturated condensed heterocyclic group containing 1 to 5 nitrogen atoms, for example, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridazinyl [e.g., tetrazolo [1,5-b]pyridazinyl]; unsaturated condensed heterocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g. benzoxazolyl, benzoxadiazolyl]; unsaturated condensed heterocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g., benzothiazolyl, benzothiadiazolyl]; and saturated, partially unsaturated and unsaturated condensed heterocyclic group containing 1 to 2 oxygen or sulfur atoms [e.g. benzofuryl, benzothienyl, 2,3-dihydro-benzo[1,4]dioxinyl and dihydrobenzofuryl].

0056The term "heteroaryl" denotes aryl ring systems that contain one or more heteroatoms selected from the group O, N and S, wherein the ring nitrogen and sulfur atom(s) are optionally oxidized, and nitrogen atom(s) are optionally quarternized. Examples include unsaturated 5 to 6 membered heteromonocyclyl group containing 1 to 4 nitrogen atoms, for example, pyrrolyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl [e.g., 4H-1,2,4-triazolyl, IH-1 ,2,3-triazolyl, 2H-1,2,3-triazolyl]; unsaturated 5- to 6-membered heteromonocyclic group containing an oxygen atom, for example, pyranyl, 2-furyl, 3-furyl, etc.; unsaturated 5 to 6-membered heteromonocyclic group containing a sulfur atom, for example, 2-thienyl, 3-thienyl, etc.; unsaturated 5- to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example, oxazolyl, isoxazolyl, oxadiazolyl [e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5- oxadiazolyl]; unsaturated 5 to 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, thiazolyl, thiadiazolyl [e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl].

0057The term "heteroarylalkyl" denotes alkyl radicals substituted with a heteroaryl group. Examples include pyridylmethyl and thienylethyl.

0058The term "sulfonyl", whether used alone or linked to other terms such as alkylsulfonyl, denotes respectively divalent radicals -SO₂-.

0059The terms "carboxy" or "carboxyl", whether used alone or with other terms, such as "carboxyalkyl", denotes -C(O)-OH.

0060The term "carbonyl", whether used alone or with other terms, such as "aminocarbonyl", denotes -C(O)-.

0061The term "aminocarbonyl" denotes an amide group of the formula -C(O)-NH₂.

0062The terms "heterocycloalkyl" embrace heterocyclic-substituted alkyl radicals. Examples include piperidylmethyl and morpholinylethyl.

0063The term "arylalkyl" embraces aryl-substituted alkyl radicals. Examples include benzyl, diphenylmethyl and phenylethyl. The aryl in said aralkyl may be additionally substituted with halo, alkyl, alkoxy, halkoalkyl and haloalkoxy.

0064The term "cycloalkyl" includes saturated carbocyclic groups of 3 to 10 carbons. Lower cycloalkyl groups include C₃-C₆ rings. Examples include cyclopentyl, cyclopropyl, and cyclohexyl. Cycloalkyl groups may be optionally substituted with one or more functional groups such as halo, hydroxy, nitro, amino, cyano, haloalkyl, aryl, heteroaryl, heterocyclo and the like.

0065The term "cycloalkylalkyl" embraces cycloalkyl-substituted alkyl radicals. "Lower cycloalkylalkyl" radicals are cycloalkyl radicals attached to alkyl radicals having one to six carbon atoms. Examples of include cyclohexylmethyl. The cycloalkyl in said radicals may be additionally substituted with halo, alkyl, alkoxy and hydroxy.

0066The term "cycloalkenyl" includes carbocyclic groups having one or more carbon-carbon double bonds including "cycloalkyldienyl" compounds. Examples include cyclopentenyl, cyclopentadienyl, cyclohexenyl and cycloheptadienyl.

0067The term "comprising" is meant to be open ended, including the indicated component but not excluding other elements.

0068The term "oxo" as used herein contemplates an oxygen atom attached with a double bond.

0069The term "nitro" as used herein contemplates -NO₂.

0070The term "cyano" as used herein contemplates -CN.

<u>Synthesis</u>

0071The disclosed compounds can be made by the following general schemes: <chemistry id="chem0012" num="0012"><img file="EP2632467B1_D0012.tif" /></chemistry>

0072In Scheme 1, Ref-1 is <patcit id="pcit0001" dnum="WO2010020675A1"><text>WO 2010/020675 A1</text></patcit>; Ref-2 is <nplcit id="ncit0003" npl-type="s"><text>White, J. D.; et al J. Org. Chem. 1995, 60, 3600</text></nplcit>; and Ref-3 <nplcit id="ncit0004" npl-type="s"><text>Presser, A. and Hufner, A. Monatshefte fur Chemie 2004, 135, 1015</text></nplcit>. <chemistry id="chem0013" num="0013"><img file="EP2632467B1_D0013.tif" /></chemistry>

0073In Scheme 2, Ref-1 is <patcit id="pcit0002" dnum="WO2010020675A1"><text>WO 2010/020675 A1</text></patcit>; Ref-4 is <patcit id="pcit0003" dnum="WO2005040166A1"><text>WO 2005/040166 A1</text></patcit>; and Ref-5 is <nplcit id="ncit0005" npl-type="s"><text>Schoenauer, K and Zbiral, E. Tetrahedron Letters 1983, 24, 573</text></nplcit>. <chemistry id="chem0014" num="0014"><img file="EP2632467B1_D0014.tif" /></chemistry>

0074In Scheme 3, Ref - 1 is <patcit id="pcit0004" dnum="WO2010020675A1"><text>WO 2010/020675 A1</text></patcit>. <chemistry id="chem0015" num="0015"><img file="EP2632467B1_D0015.tif" /></chemistry><chemistry id="chem0016" num="0016"><img file="EP2632467B1_D0016.tif" /></chemistry>

0075Scheme 5 illustrates a scheme useful for the synthesis of compounds of formula II.

<u>EXAMPLES</u>

<b>Example</b> 1

<i>tert-butyl</i>

N-

[2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]

ethyl] carbamate

0076<chemistry id="chem0017" num="0017"><img file="EP2632467B1_D0017.tif" /></chemistry>

0077To a solution of 5-bromo-2,4-dichloropyrimidine 3.2 g (0.0135 mole) in ethanol 80 mL was added Hunig's base 3.0 mL followed by the addition of a solution of N-(<i>tert-</i>butoxycarbonyl)-1,2-diaminoethane 2.5 g (0.0156 mole) in 20 mL ethanol. The contents were stirred overnight for 20 hrs. The solvent was evaporated under vacuum. Ethyl acetate (200 mL) and water (100 mL) was added and the layers separated. The organic layer was dried with magnesium sulfate and then concentrated under vacuum. Column chromatography on silica gel using hexane/ethyl acetate (0- 60%) afforded <i>tert</i>-butyl N-[2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]ethyl]carbamate. ¹HNMR (d6-DMSO) 8.21 (s, 1H), 7.62 (brs, 1H), 7.27 (brs, 1H), 3.39 (m, 2H), 3.12 (m, 2H), 1.34 (s, 9H). LCMS (ESI) 351 (M + H)

<i>tert</i>-butyl N-[2-[[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl] amino] ethyl] carbamate

0078<chemistry id="chem0018" num="0018"><img file="EP2632467B1_D0018.tif" /></chemistry>

0079To 3.6 mmole (1.265 g) of <i>tert</i>-butyl N-[2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]ethyl]carbamate in THF (10 mL) was added 0.778 mL of the acetal (5.43 mmol), 148 mg of Pd(dppf)CH₂Cl₂, triethylamine 0.757 mL (5.43 mmol. The contents were degassed and then purged with nitrogen. To this was then added 29 mg of CuI. The reaction mixture was heated under reflux for 48 hrs. After cooling, the contents were filtered over CELITE^TM and concentrated. Column chromatography of the resulting residue using hexane/ethyl acetate (0- 30%) afforded <i>tert</i>-butyl N-[2-[[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl]amino]ethyl]carbamate. ¹HNMR (d6-DMSO) 8.18 (s, 1H), 7.63 (brs, 1H), 7.40 (brs, 1H), 5.55 (s, 1H), 3.70 (m, 2H), 3.60 (m, 2H), 3.42 (m, 2H), 3.15 (m, 2H), 1.19 - 1.16 (m, 15H). LCMS (ESI) 399 (M + H)

<i>tert</i>-butyl N-[2-[2-chloro-6-(diethoxymethyl)pyrrolo[2,3-d]pyrimidin-7-yl] ethyl] carbamate

0080<chemistry id="chem0019" num="0019"><img file="EP2632467B1_D0019.tif" /></chemistry>

0081To a solution of the coupled product 2.1 g (0.00526 mole) in THF (30 mL) was added 7.0 g of TBAF solid. The contents were heated to 65 degrees for 2 hrs. Concentration followed by column chromatography using ethyl acetate/hexane (0-50%) afforded <i>tert</i>-butyl N-[2-[2-chloro-6-(diethoxymethyl)pyrrolo[2,3-d]pyrimidin-7-yl]ethyl]carbamate as a pale brown liquid (1.1 g). ¹HNMR (d6-DMSO) 8.88 (s, 1H), 6.95 (brs, 1H), 6.69 (s, 1H), 5.79 (s, 1H), 4.29 (m, 2H), 3.59 (m, 4H), 3.34 (m, 1H), 3.18 (m, 1H), 1.19 (m, 9H), 1.17 (m, 6H). LCMS (ESI) 399 (M + H).

<i>tert</i>-butyl N-[2-(2-chloro-6-formyl-pyrrolo[2,3-d]pyrimidin-7-yl)ethyl]carbamate

0082<chemistry id="chem0020" num="0020"><img file="EP2632467B1_D0020.tif" /></chemistry>

0083To 900 mg of the acetal was added 8.0 mL AcOH and 1.0 mL water. This was stirred at room temperature for 16 hrs. Conc. and column ethyl acetate/hexanes (0- 60%) afforded 0.510 g of <i>tert</i>-butyl N-[2-(2-chloro-6-formyl-pyrrolo[2,3-d]pyrimidin-7-yl)ethyl]carbamate as a foam. ¹HNMR (d6-DMSO) 9.98 (s, 1H), 9.18 (s, 1H), 7.66 (s, 1H), 6.80 (brs, 1H), 4.52 (m, 2H), 4.36 (m, 2H), 1.14 (s, 9H). LCMS (ESI) 325 (M + H)

7-[2-(<i>tert</i>-butoxycarbonylamino)ethyl]-2-chloro-pyrrolo[2,3-d]pyrimidine-6-carboxylic

acid

0084<chemistry id="chem0021" num="0021"><img file="EP2632467B1_D0021.tif" /></chemistry>

0085To the aldehyde 0.940 g in DMF (4 mL) was added oxone (1.95 g, 1.1 eq). The contents were stirred at room temp for 7 hrs. Column hexane/ethyl acetate (0- 100%) afforded 0.545 g of 7-[2-(<i>tert</i>-butoxycarbonylamino)ethyl]-2-chloro-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid. ¹HNMR (d6-DMSO) 9.11 (s, 1H), 7.39 (s, 1H), 4.38 (m, 2H), 4.15 (m, 2H), 1.48 (m, 9H). LCMS (ESI) 341(M + H)

methyl 7-[2-(<i>tert</i>-butoxycarbonylamino)ethyl]-2-chloro-pyrrolo[2,3-d]pyrimidine-6-carboxylate

0086<chemistry id="chem0022" num="0022"><img file="EP2632467B1_D0022.tif" /></chemistry>

0087To a solution of 2-chloro-7-propyl-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid 0.545 g (0.00156 mole) in toluene (3.5 mL) and MeOH (1 mL) was added TMS-diazomethane (1.2 mL). After stirring overnight at room temperature excess of TMS-diazomethane was quenched with acetic acid (3 mL) and then concentrated under vacuum. The residue was columned with hexane/ethyl acetate (0- 70%) to afford methyl 7-[2-(<i>tert-</i>butoxycarbonylamino)ethyl]-2-chloro-pyrrolo[2,3-d]pyrimidine-6-carboxylate as a off white solid (0.52 g). ¹HNMR (d6-DMSO) 9.10 (s, 1H), 7.45 (s, 1H), 6.81 (brs, 1H) 4.60 (m, 2H), 3.91 (s, 3H), 3.29 (m, 2H), 1.18 (m, 9H) LCMS (ESI) 355 (M + H)

Chloro tricyclic amide

0088<chemistry id="chem0023" num="0023"><img file="EP2632467B1_D0023.tif" /></chemistry>

0089To methyl 7-[2-(<i>tert</i>-butoxycarbonylamino)ethyl]-2-chloro-pyrrolo[2,3-d]pyrimidine-6-carboxylate 0.50 g (0.0014 mole) in dichloromethane (2.0 mL) was added TFA 0.830 mL. The contents were stirred at room temperature for 1 hr. Concentration under vacuum afforded the crude amino ester which was suspended in toluene (5 mL) and Hunig's base (0.5 mL). The contents were heated under reflux for 2 hrs. Concentration followed by column chromatography using hexane/ethyl acetate (0- 50%) afforded the desired chloro tricyclic amide (0.260 g). ¹HNMR (d6-DMSO) 9.08 (s, 1H), 8.48 (brs, 1H), 7.21 (s, 1H) 4.33 (m, 2H), 3.64 (m, 2H). LCMS (ESI) 223 (M + H)

chloro-N-methyltricyclic amide

0090<chemistry id="chem0024" num="0024"><img file="EP2632467B1_D0024.tif" /></chemistry>

0091To a solution of the chloro tricycliclactam (185 mg, 0.00083 mole) in DMF (2.0 mL) was added sodium hydride (55% dispersion in oil, 52 mg). After stirring for 15 mins, methyl iodide (62 µL, 1.2 eq). The contents were stirred at room temperature for 30 mins. After the addition of methanol (5 mL), sat NaHCO₃ was added followed by the addition of ethyl acetate. Separation of the organic layer followed by drying with magnesium sulfate and concentration under vacuum afforded the N-methylated amide in quantitative yield. ¹HNMR (d6-DMSO) 9.05 (s, 1H), 7.17 (s, 1H) 4.38 (m, 2H), 3.80 (m, 2H), 3.05 (s, 3H). LCMS (ESI) 237 (M + H)

1-methyl-4-(6-nitro-3-pyridyl)piperazine

0092<chemistry id="chem0025" num="0025"><img file="EP2632467B1_D0025.tif" /></chemistry>

0093To 5-bromo-2-nitropyridine (4.93 g, 24.3 mmole) in DMF (20 mL) was added N-methylpiperazine (2.96 g, 1.1 eq) followed by the addition of DIPEA (4.65 mL, 26.7 mmole). The contents were heated at 90 degrees for 24 hrs. After addition of ethyl acetate (200 mL) water 100 mL was added and the layers separated. Drying followed by concentration afforded the crude product which was columned using (0-10%) DCM/Methanol. ¹HNMR (δ6-DMSO) 8.26 (s, 1H), 8.15 (1H, d, J = 9.3 Hz), 7.49 (1H, d, J = 9.4 Hz), 3.50 (m, 4H), 2.49 (m, 4H), 2.22 (s, 3H).

5-(4-methylpiperazin-1-yl)pyridin-2-amine

0094<chemistry id="chem0026" num="0026"><img file="EP2632467B1_D0026.tif" /></chemistry>

0095To 1-methyl-4-(6-nitro-3-pyridyl)piperazine 3.4 g in ethyl acetate (100 mL) and ethanol (100 mL) was added 10% Pd/c (400 mg) and then contents stirred under hydrogen (10 psi) overnight. After filtration through CELITE^TM, the solvents were evaporated and the crude product was purified over silica gel using DCM/ 7N Ammonia in MeOH (0- 5%) to afford 5-(4-methylpiperazin-1-yl)pyridin-2-amine (2.2 g). ¹HNMR (d6-DMSO) 7.56 (1H, d, J = 3 Hz), 7.13 (1H, m), 6.36 (1H, d, J = 8.8 Hz), 5.33 (brs, 2H), 2.88 (m, 4H), 2.47 (m, 4H), 2.16 (s, 3H).

<i>tert</i>-butyl 4-(6-amino-3-pyridyl)piperazine-1-carboxylate

0096<chemistry id="chem0027" num="0027"><img file="EP2632467B1_D0027.tif" /></chemistry>

0097This compound was prepared as described in <patcit id="pcit0005" dnum="WO2010020675A1"><text>WO 2010/020675 A1</text></patcit>.

<u>Example 2 - Synthesis of Additional Intermediates</u>

0098<chemistry id="chem0028" num="0028"><img file="EP2632467B1_D0028.tif" /></chemistry>

Intermediate A: <i>tert</i>-butyl N-[2-(benzyloxycarbonylamino)-3-methyl-butyl] carbamate

0099<chemistry id="chem0029" num="0029"><img file="EP2632467B1_D0029.tif" /></chemistry>

0100To 11.0 g (0.0464 mole) of benzyl N-[1-(hydroxymethyl)-2-methyl-propyl]carbamate in dioxane (100 mL) cooled to 0°C was added diphenylphosphoryl azide 10.99 mL (1.1 eq) followed by the addition of DBU 8.32 mL (1.2 eq). The contents were allowed to warm to room temperature and stirred for 16 hrs. After the addition of ethyl acetate (300 mL) and water (100 mL), the organic layer was separated and then washed with satd. NaHCO₃ (100 mL). The organic layer was then dried (magnesium sulfate) and then concentrated under vacuum. To this intermediate in DMSO (100 mL) was added sodium azide 7.54 g and the contents then heated to 90 degrees for 2 hrs. After addition of ethyl acetate and water the layers were separated. The organic layer was dried with magnesium sulfate followed by concentration under vacuum to afford an oil that was columned using hexane/ethyl acetate (0- 70%) to afford benzyl N-[1-(azidomethyl)-2-methyl-propyl] carbamate 6.9 g as a colorless oil.

0101To benzyl N-[1-(azidomethyl)-2-methyl-propyl] carbamate 6.9 g (0.0263 mole) in THF (100 mL) was added triphenyl phosphine 7.59 g (1.1 eq). The contents were stirred for 20 hrs. After addition of water (10 mL), and stirring for an additional 6 hrs, ethyl acetate was added and the layers separated. After drying with magnesium sulfate and concentration under vacuum, the crude product was columned using DCM/MeOH (0 - 10%) to afford benzyl N-[1-(aminomethyl)-2-methyl-propyl] carbamate as a yellow oil.

0102To benzyl N-[1-(aminomethyl)-2-methyl-propyl] carbamate 4.65 g (0.019 mole) in THF (70 mL) was added 2N NaOH (20 mL) followed by the addition of di-<i>tert</i>-butyl dicarbonate 5.15 g (1.2 eq). After stirring for 16 hrs, ethyl acetate was added and the layers separated. After drying with magnesium sulfate and concentration under vacuum, the crude product was purified using hexane/ethyl acetate (0- 40%) over a silica gel column to afford intermediate A, <i>tert</i>-butyl N-[2-(benzyloxycarbonylamino)-3-methyl-butyl] carbamate, (6.1 g). 1H NMR (600 MHz, CHLOROFORM-<i>d</i>) δ ppm 0.89 (d, <i>J</i>=6.73 Hz, 3 H) 0.92 (d, <i>J</i>=6.73 Hz, 3 H) 1.38 (s, 9 H) 1.70 - 1.81 (m, 1 H) 3.18 (d, <i>J</i>=5.56 Hz, 2 H) 3.47 - 3.60 (m, 1 H) 4.76 (s, 1 H) 4.89 (d, <i>J</i>=7.90 Hz, 1 H) 5.07 (s, 2 H) 7.25 - 7.36 (m, 5 H). LCMS (ESI) 337 (M + H).

Intermediate B: <i>tert</i>-butyl N-[2-(benzyloxycarbonylamino)-4-methyl-pentyl] carbamate

0103<chemistry id="chem0030" num="0030"><img file="EP2632467B1_D0030.tif" /></chemistry>

0104To a solution of benzyl N-[1-(hydroxymethyl)-3-methyl-butyl]carbamate 6.3 g (0.025 mole) in DCM (100 mL) was added diisopropylethyl amine 5.25 mL (1.2 eq) followed by the addition of methane sulfonylchloride 2.13 mL (1.1 eq) at 0 degrees. After stirring for 3 hrs, water (100 mL) was added and the organic layer separated. After drying with magnesium sulfate and concentration under vacuum, the crude [2-(benzyloxycarbonylamino)-4-methyl-pentyl] methanesulfonate which was taken directly to the next step.

0105To the crude [2-(benzyloxycarbonylamino)-4-methyl-pentyl] methanesulfonate from the above reaction in DMF (50 mL), was added sodium azide 2.43 g. The reaction mixture was then heated to 85 degrees for 3 hrs. After cooling, ethyl acetate (300 mL) and water was added. The organic layer was separated, dried with magnesium sulfate and then concentrated under vacuum to afford the crude benzyl N-[1-(azidomethyl)-3-methyl-butyl] carbamate. To this crude intermediate was added THF (100 mL) followed by triphenylphosphine 7.21 g and stirred under nitrogen for 16 hrs. After addition of water (10 mL), and stirring for an additional 6 hrs, ethyl acetate was added and the layers separated. After drying with magnesium sulfate and concentration under vacuum, the crude product was columned using DCM/MeOH (0 - 10%) to afford benzyl N-[1-(aminomethyl)-3-methyl-butyl] carbamate (4.5 g).

0106To benzyl N-[1-(aminomethyl)-3-methyl-butyl] carbamate 4.5 g (0.018 mole) in THF (60 mL) was added 2N NaOH (18 mL) followed by the addition of di-<i>tert</i>-butyl dicarbonate 4.19 g (1.07 eq). After stirring for 16 hrs, ethyl acetate was added and the layers separated. After drying with magnesium sulfate and concentration under vacuum, the crude product was taken to the next step. 1H NMR (600 MHz, CHLOROFORM-<i>d</i>) δ ppm 0.89 (d, <i>J</i>=6.73 Hz, 6 H) 1.25 - 1.34 (m, 1 H) 1.39 (s, 9 H) 1.57 - 1.71 (m, 2 H) 3.04 - 3.26 (m, 2 H) 3.68 - 3.80 (m, 1 H) 4.72 - 4.89 (m, 2 H) 5.06 (s, 2 H) 7.25 - 7.38 (m, 5 H). LCMS (ESI) 351 (M + H).

Intermediate C: <i>tert</i>-butyl N-[(2R)-2-(benzyloxycarbonylamino)-3-methyl-butyl]

carbamate

0107<chemistry id="chem0031" num="0031"><img file="EP2632467B1_D0031.tif" /></chemistry>

0108Intermediate C was synthesized from benzyl N-[(1R)-1-(hydroxymethyl)-2-methyl-propyl] carbamate using similar synthetic steps as that described for intermediate B. The analytical data (NMR and mass spec) was consistent with that for intermediate A.

Intermediate D: - <i>tert</i>-butyl N-[(2S)-2-(benzyloxycarbonylamino)-3-methyl-butyl] carbamate

0109<chemistry id="chem0032" num="0032"><img file="EP2632467B1_D0032.tif" /></chemistry>

0110Intermediate D was synthesized from benzyl N-[(1S)-1-(hydroxymethyl)-2-methyl-propyl] carbamate using similar synthetic steps as that described for intermediate B. The analytical data (NMR and mass spec) was consistent with that for intermediate A.

Intermediate E: <i>tert</i>-butyl N-[(1S)-1-(aminomethyl)-2-methyl-propyl]carbamate

0111<chemistry id="chem0033" num="0033"><img file="EP2632467B1_D0033.tif" /></chemistry>

0112To a solution of <i>tert</i>-butyl N-[(1S)-1-(hydroxymethyl)-2-methyl-propyl]carbamate carbamate 6.3 g (0.025 mole) in THF (100 mL) was added diisopropylethyl amine 5.25 mL (1.2 eq) followed by the addition of methane sulfonylchloride 2.13 mL (1.1 eq) at 0 degrees. After stirring for 3 hrs, water (100 mL) was added and the organic layer separated. After drying with magnesium sulfate and concentration under vacuum, the crude [(2S)-2-(<i>tert-</i>butoxycarbonylamino)-3-methyl-butyl] methanesulfonate which was taken directly to the next step.

0113To the crude [(2S)-2-(<i>tert</i>-butoxycarbonylamino)-3-methyl-butyl] methanesulfonate from the above reaction in DMSO (50 mL), was added sodium azide 2.43 g. The reaction mixture was then heated to 85 degrees for 3 hrs. After cooling, ethyl acetate (300 mL) and water was added. The organic layer was separated, dried with magnesium sulfate and then concentrated under vacuum to afford the crude benzyl N-[1-(azidomethyl)-3-methyl-butyl] carbamate. To this crude intermediate was added THF (100 mL) followed by triphenylphosphine 7.21 g and stirred under nitrogen for 16 hrs. After addition of water (10 mL), and stirring for an additional 6 hrs, ethyl acetate was added and the layers separated. After drying with magnesium sulfate and concentration under vacuum, the crude product was columned using DCM/MeOH (0 - 10%) to afford benzyl N-[1-(aminomethyl)-3-methyl-butyl] carbamate (4.5 g). LCMS (ESI) 203 (M + H).

Intermediate F: <i>tert</i>-butyl N-[(1R)-1-(aminomethyl)-2-methyl-propyl]carbamate

0114<chemistry id="chem0034" num="0034"><img file="EP2632467B1_D0034.tif" /></chemistry>

0115Intermediate F was synthesized from <i>tert</i>-butyl N-[(1R)-1-(hydroxymethyl)-2-methyl-propyl] carbamate using a similar synthetic sequence as described for intermediate E. The analytical data (NMR and mass spec) was consistent with intermediate E.

Intermediate G: <i>tert</i>-butyl N-[(2S)-2-(benzyloxycarbonylamino)-4-methyl-pentyl] carbamate

0116<chemistry id="chem0035" num="0035"><img file="EP2632467B1_D0035.tif" /></chemistry>

0117Intermediate G was synthesized from benzyl N-[(1S)-1-(hydroxymethyl)-3-methyl-butyl]carbamate using a similar synthetic sequence as described for intermediate B. The analytical data (NMR and mass spec) was consistent with intermediate B.

Intermediate H: <i>tert</i>-butyl N-[(2S)-2-(benzyloxycarbonylamino)-2-phenyl-ethyl] carbamate

0118<chemistry id="chem0036" num="0036"><img file="EP2632467B1_D0036.tif" /></chemistry>

0119Intermediate H was synthesized from benzyl N-[(1S)-2-hydroxy-1-phenyl-ethyl] carbamate using a similar synthetic sequence as described for intermediate B. 1H NMR (600 MHz, DMSO-<i>d</i>₆) δ ppm 1.20 - 1.33 (m, 9 H) 3.11 (t, <i>J</i>=6.29 Hz, 2 H) 4.59 - 4.68 (m, 1 H) 4.88 - 5.01 (m, 2 H) 6.81 (t, <i>J</i>=5.42 Hz, 1 H) 7.14 - 7.35 (m, 10 H) 7.69 (d, <i>J</i>=8.49 Hz, 1 H). LCMS (ESI) 371 (M + H).

Intermediate I: <i>tert</i>-butyl N-[(2S)-2-(benzyloxycarbonylamino)-3-methyl-pentyl] carbamate

0120<chemistry id="chem0037" num="0037"><img file="EP2632467B1_D0037.tif" /></chemistry>

0121Intermediate I was synthesized from benzyl N-[(1S)-1-(hydroxymethyl)-2-methyl-butyl] carbamate using a similar synthetic sequence as described for intermediate B. 1H NMR (600 MHz, CHLOROFORM-<i>d</i>) δ ppm 0.85 - 0.92 (m, 6 H) 1.05 - 1.15 (m, 1 H) 1.35 - 1.41 (m, 9 H) 1.45 - 1.56 (m, 2 H) 3.14 - 3.24 (m, 2 H) 3.54 - 3.64 (m, 1 H) 4.78 (s, 1 H) 4.96 (d, <i>J</i>=7.91 Hz, 1 H) 5.06 (s, 2 H) 7.27 - 7.37 (m, 5 H). LCMS (ESI) 351 (M + H).

Intermediate J: <i>tert</i>-butyl N-[(2S)-2-(benzyloxycarbonylamino)-3,3-dimethyl-butyl] carbamate

0122<chemistry id="chem0038" num="0038"><img file="EP2632467B1_D0038.tif" /></chemistry>

0123Intermediate J was synthesized from benzyl N-[(1S)-1-(hydroxymethyl)-2,2-dimethyl-propyl]carbamate using a similar synthetic sequence as described for intermediate B. LCMS (ESI) 351.

Intermediate K: <i>tert</i>-butyl N-[[1-(benzyloxycarbonylamino)cyclohexyl]methyl] carbamate

0124<chemistry id="chem0039" num="0039"><img file="EP2632467B1_D0039.tif" /></chemistry>

0125To a solution of benzyl N-[1-(aminomethyl)cyclohexyl]carbamate 10.0 g (0.0381 mole) in THF (150 mL) was added di-<i>tert</i>-butyl dicarbonate (9.15 g, 1.1 eq) and the contents stirred at room temperature for 16 hrs. Ethyl acetate and water was then added. The organic layer was separated, dried over magnesium sulfate and then concentrated under vacuum to afford <i>tert</i>-butyl N-[[1-(benzyloxycarbonylamino)cyclohexyl]methyl] carbamate (13.1 g). 1H NMR (600 MHz, DMSO-<i>d</i>₆) δ ppm 0.92 - 1.54 (m, 17 H) 1.76 - 2.06 (m, 2 H) 3.09 (d, <i>J</i>=6.15 Hz, 2 H) 4.92 (s, 2 H) 6.63 (d, <i>J</i>=17.27 Hz, 1 H) 7.16 - 7.49 (m, 6 H). LCMS (ESI) 363 (M + H).

Intermediate L: <i>tert</i>-butyl N-[[1-(benzyloxycarbonylamino)cyclopentyl]methyl] carbamate

0126<chemistry id="chem0040" num="0040"><img file="EP2632467B1_D0040.tif" /></chemistry>

0127<i>tert</i>-butyl N-[[1-(benzyloxycarbonylamino)cyclopentyl]methyl]carbamate was synthesized in an analogous manner to <i>tert</i>-butyl N-[[1-(benzyloxycarbonylamino) cyclohexyl]methyl] carbamate. LCMS (ESI) 349 (M + H).

<b>Example 3 - Synthesis of Substituted 2</b>-<b>aminopyridines</b>

0128<chemistry id="chem0041" num="0041"><img file="EP2632467B1_D0041.tif" /></chemistry>

0129To 5-bromo-2-nitropyridine (1.2 g, 5.9 mmol) in DMSO (4 mL) was added 1-(4-piperidyl)piperidine (1.0 g, 5.9 mmole) and triethyl amine (0.99 mL, 7.1 mmole). The contents were heated to 120 degrees in a CEM Discovery microwave system for 3 hours. The crude reaction was then loaded over a silica gel column and eluted with DCM/methanol (0-20%) to afford 2-nitro-5-[4-(1-piperidyl)-1-piperidyl]pyridine as an oil (457 mg). 1H NMR (600 MHz, DMSO-<i>d</i>₆) δ ppm 1.26 - 1.36 (m, 2 H) 1.43 (m, 6 H) 1.76 (m, 2 H) 2.37 (m, 5 H) 2.94 (t, <i>J</i>=12.74 Hz, 2 H) 4.06 (d, <i>J</i>=13.47 Hz, 2 H) 7.41 (dd, <i>J</i>=9.37, 2.64 Hz, 1 H) 8.08 (d, <i>J</i>=9.37 Hz, 1 H) 8.20 (d, <i>J</i>=2.64 Hz, 1 H).

.

5-[4-(1-piperidyl)-1-piperidyl] pyridin-2-amine

0130<chemistry id="chem0042" num="0042"><img file="EP2632467B1_D0042.tif" /></chemistry>

01315-[4-(1-piperidyl)-1-piperidyl]pyridin-2-amine was prepared in a manner similar to that used in the synthesis of 5-(4-methylpiperazin-1-yl)pyridin-2-amine. 1H NMR (600 MHz, DMSO-<i>d</i>₆) δ ppm 1.13 - 1.37 (m, 6 H) 1.40 - 1.63 (m, 6 H) 1.71 (m, 2 H), 2.24 (m, 1H) 2.43 (m, 2 H) 3.33 (d, J=12.30 Hz, 2 H) 5.31 (s, 2 H) 6.33 (d, <i>J</i>=8.78 Hz, 1 H) 7.10 (dd, <i>J</i>=8.78, 2.93 Hz, 1 H) 7.55 (d, <i>J</i>=2.64 Hz, 1 H). LCMS (ESI) 261 (M + H).

4-[1-(6-nitro-3-pyridyl)-4-piperidyl] morpholine

0132<chemistry id="chem0043" num="0043"><img file="EP2632467B1_D0043.tif" /></chemistry>

01334-[1-(6-nitro-3-pyridyl)-4-piperidyl]morpholine was synthesized in a manner similar to that used in the synthesis of 2-nitro-5-[4-(1-piperidyl)-1-piperidyl]pyridine. 1H NMR (600 MHz, DMSO-<i>d</i>₆) δ ppm 1.41 (m, 2 H) 1.82 (m, 2 H) 2.42 (m, 5 H) 2.98 (t, <i>J</i>=12.44 Hz, 2 H) 3.52 (s, 4 H) 4.04 (d, <i>J</i>=12.88 Hz, 2 H) 7.42 (d, <i>J</i>=9.37 Hz, 1 H) 8.08 (d, J=9.08 Hz, 1 H) 8.21 (s, 1 H).

5-(4-morpholino-1-piperidyl) pyridin-2-amine

0134<chemistry id="chem0044" num="0044"><img file="EP2632467B1_D0044.tif" /></chemistry>

01355-(4-morpholino-1-piperidyl)pyridin-2-amine was prepared in a manner similar to that used in the synthesis of 5-(4-methylpiperazin-1-yl)pyridin-2-amine. 1H NMR (600 MHz, DMSO-<i>d</i>₆) δ ppm 1.34 - 1.52 (m, 2 H) 1.78 (m, 2 H) 2.14 (m, 1 H) 2.43 (m, 4 H) 3.32 (d, J=12.30 Hz, 4 H) 3.47 - 3.59 (m, 4 H) 5.32 (s, 2 H) 6.34 (d, J=8.78 Hz, 1 H) 7.11 (dd, <i>J</i>=8.93, 2.78 Hz, 1 H) 7.47 - 7.62 (m, 1 H). LCMS (ESI) 263 (M + H).

4-[1-(6-nitro-3-pyridyl)-4-piperidyl] thiomorpholine

0136<chemistry id="chem0045" num="0045"><img file="EP2632467B1_D0045.tif" /></chemistry>

01374-[1-(6-nitro-3-pyridyl)-4-piperidyl] thiomorpholine was synthesized in a manner similar to that used in the synthesis of 2-nitro-5-[4-(1-piperidyl)-1-piperidyl]pyridine. 1H NMR (600 MHz, DMSO-<i>d</i>₆) δ ppm 1.40 - 1.52 (m, 2 H) 1.71 (m, 2 H) 2.49 - 2.55 (m, 4 H) 2.56 - 2.63 (m, 1 H) 2.68 - 2.75 (m, 4 H) 2.88 - 2.98 (m, 2 H) 4.09 (d, <i>J</i>=13.18 Hz, 2 H) 7.42 (dd, J=9.22, 3.07 Hz, 1 H) 8.08 (d, J=9.37 Hz, 1 H) 8.20 (d, <i>J</i>=3.22 Hz, 1 H).

5-(4-thiomorpholino-1-piperidyl) pyridin-2-amine

0138<chemistry id="chem0046" num="0046"><img file="EP2632467B1_D0046.tif" /></chemistry>

01395-(4-thiomorpholino-1-piperidyl) pyridin-2-amine was prepared in a manner similar to that used in the synthesis of 5-(4-methylpiperazin-1-yl)pyridin-2-amine. 1H NMR (600 MHz, DMSO-<i>d</i>₆) δ ppm 1.47 - 1.59 (m, 2 H) 1.65 (m, 2 H) 2.22 - 2.38 (m, 1 H) 2.50 - 2.59 (m, 6 H) 2.68 - 2.82 (m, 4 H) 3.33 (d, <i>J</i>=12.00 Hz, 2 H) 5.31 (s, 2 H) 6.33 (d, <i>J</i>=9.08 Hz, 1 H) 7.10 (dd, <i>J</i>=8.78, 2.93 Hz, 1 H) 7.55 (d, <i>J</i>=2.64 Hz, 1 H). LCMS (ESI) 279 (M + H).

2-nitro-5-(1-piperidyl)pyridine

0140<chemistry id="chem0047" num="0047"><img file="EP2632467B1_D0047.tif" /></chemistry>

01412-nitro-5-(1-piperidyl) pyridine was synthesized in a manner similar to that used in the synthesis of 2-nitro-5-[4-(1-piperidyl)-1-piperidyl]pyridine. 1H NMR (600 MHz, DMSO-<i>d</i>₆) δ ppm 1.56 (m, 6 H) 3.49 (d, <i>J</i>=4.39 Hz, 4 H) 7.30 - 7.47 (m, 1 H) 8.02 - 8.12 (m, 1 H) 8.15 - 8.26 (m, 1 H).

5-(1-piperidyl)pyridin-2-amine

0142<chemistry id="chem0048" num="0048"><img file="EP2632467B1_D0048.tif" /></chemistry>

01435-(1-piperidyl) pyridin-2-amine was prepared in a manner similar to that used in the synthesis of 5-(4-methylpiperazin-1-yl)pyridin-2-amine. 1H NMR (600 MHz, DMSO-<i>d</i>₆) δ ppm 1.39 - 1.46 (m, 2 H) 1.51 - 1.62 (m, 4 H) 2.75 - 2.92 (m, 4 H) 5.30 (s, 2 H) 6.34 (d, <i>J</i>=8.78 Hz, 1 H) 7.09 (dd, J=8.78, 2.93 Hz, 1 H) 7.54 (d, <i>J</i>=2.93 Hz, 1 H). LCMS (ESI) 178 (M + H).

4-(6-nitro-3-pyridyl) thiomorpholine

0144<chemistry id="chem0049" num="0049"><img file="EP2632467B1_D0049.tif" /></chemistry>

01454-(6-nitro-3-pyridyl) thiomorpholine was synthesized in a manner similar to that used in the synthesis of 2-nitro-5-[4-(1-piperidyl)-1-piperidyl]pyridine. 1H NMR (600 MHz, DMSO-<i>d</i>₆) δ ppm 2.56 - 2.69 (m, 4 H) 3.79 - 3.92 (m, 4 H) 7.43 (dd, <i>J</i>=9.22, 3.07 Hz, 1 H) 8.10 (d, <i>J</i>=9.37 Hz, 1 H) 8.20 (d, <i>J</i>=2.93 Hz, 1 H).

5-thiomorpholinopyridin-2-amine

0146<chemistry id="chem0050" num="0050"><img file="EP2632467B1_D0050.tif" /></chemistry>

01475-thiomorpholinopyridin-2-amine was prepared in a manner similar to that used in the synthesis of 5-(4-methylpiperazin-1-yl) pyridin-2-amine. 1H NMR (600 MHz, DMSO-<i>d</i>₆) δ ppm 2.59 - 2.73 (m, 4 H) 3.04 - 3.20 (m, 4 H) 5.41 (s, 2 H) 6.35 (d, <i>J</i>=8.78 Hz, 1 H) 7.10 (dd, <i>J</i>=8.78, 2.93 Hz, 1 H) 7.57 (d, <i>J</i>=2.64 Hz, 1 H). LCMS (ESI) 196 (M + H).

<i>tert</i>-butyl (4R)-5-(6-nitro-3-pyridyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate

0148<chemistry id="chem0051" num="0051"><img file="EP2632467B1_D0051.tif" /></chemistry>

0149<i>tert</i>-butyl (4R)-5-(6-nitro-3-pyridyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate was synthesized in a manner similar to that used in the synthesis of 2-nitro-5-[4-(1-piperidyl)-1-piperidyl]pyridine. 1H NMR (600 MHz, DMSO-<i>d</i>₆) δ ppm 1.33 (d, <i>J</i>=32.21 Hz, 11 H) 1.91 (m, 2 H) 3.15 (d, <i>J</i>=10.25 Hz, 1 H) 3.58 (m, 1 H) 4.46 (m, 1 H) 4.83 (s, 1 H) 7.16 (s, 1 H) 7.94 (s, 1 H) 8.05 - 8.16 (m, 1 H).

<i>tert</i>-butyl (4R)-5-(6-amino-3-pyridyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate

0150<chemistry id="chem0052" num="0052"><img file="EP2632467B1_D0052.tif" /></chemistry>

0151<i>tert</i>-butyl (4R)-5-(6-amino-3-pyridyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate was prepared in a manner similar to that used in the synthesis of 5-(4-methylpiperazin-1-yl)pyridin-2-amine. 1H NMR (600 MHz, DMSO-<i>d</i>₆) δ ppm 1.31 (d, <i>J</i>=31.91 Hz, 11 H) 1.83 (m, 2 H) 2.71 - 2.82 (m, 1 H) 3.44 (m,1 H) 4.30 (d, 2H) 5.08 (s, 2 H) 6.35 (d, <i>J</i>=8.78 Hz, 1 H) 6.77 - 6.91 (m, 1 H) 7.33 (s, 1 H). LCMS (ESI) 291 (M + H).

N,N-dimethyl-1-(6-nitro-3-pyridyl) piperidin-4-amine

0152<chemistry id="chem0053" num="0053"><img file="EP2632467B1_D0053.tif" /></chemistry>

0153N,N-dimethyl-1-(6-nitro-3-pyridyl)piperidin-4-amine was synthesized in a manner similar to that used in the synthesis of 2-nitro-5-[4-(1-piperidyl)-1-piperidyl]pyridine. 1H NMR (600 MHz, DMSO-<i>d</i>₆) δ ppm 1.30 - 1.45 (m, 2 H) 1.79 (m, 2 H) 2.14 (s, 6 H) 2.33 (m, 1 H) 2.92 - 3.04 (m, 2 H) 4.03 (d, <i>J</i>=13.76 Hz, 2 H) 7.42 (dd, <i>J</i>=9.22, 3.07 Hz, 1 H) 8.04 - 8.11 (m, 1 H) 8.21 (d, <i>J</i>=2.93 Hz, 1 H).

5-[4-(dimethylamino)-1-piperidyl] pyridin-2-amine

0154<chemistry id="chem0054" num="0054"><img file="EP2632467B1_D0054.tif" /></chemistry>

01555-[4-(dimethylamino)-1-piperidyl]pyridin-2-amine was prepared in a manner similar to that used in the synthesis of 5-(4-methylpiperazin-1-yl)pyridin-2-amine. 1H NMR (600 MHz, DMSO-<i>d</i>₆) δ ppm 1.35 - 1.50 (m, 2 H) 1.69 - 1.81 (m, 2 H) 2.00 - 2.10 (m, 1 H) 2.11 - 2.22 (s, 6 H) 3.17 - 3.36 (m, 4 H) 5.19 - 5.38 (s, 2 H) 6.34 (d, <i>J</i>=8.78 Hz, 1 H) 7.10 (dd, <i>J</i>=8.78, 2.93 Hz, 1 H) 7.55 (d, <i>J</i>=2.63 Hz, 1 H). LCMS (ESI) 221 (M + H).

4-(6-nitro-3-pyridyl) morpholine

0156<chemistry id="chem0055" num="0055"><img file="EP2632467B1_D0055.tif" /></chemistry>

01574-(6-nitro-3-pyridyl) morpholine was synthesized in a manner similar to that used in the synthesis of 2-nitro-5-[4-(1-piperidyl)-1-piperidyl] pyridine.

5-morpholinopyridin-2-amine

0158<chemistry id="chem0056" num="0056"><img file="EP2632467B1_D0056.tif" /></chemistry>

01595-morpholinopyridin-2-amine was prepared in a manner similar to that used in the synthesis of 5-(4-methylpiperazin-1-yl) pyridin-2-amine. 1H NMR (600 MHz, CHLOROFORM-<i>d</i>) δ ppm 2.91 - 3.00 (m, 4 H) 3.76 - 3.84 (m, 4 H) 4.19 (br. s., 2 H) 6.45 (d, <i>J</i>=8.78 Hz, 1 H) 7.12 (dd, <i>J</i>=8.78, 2.93 Hz, 1 H) 7.72 (d, <i>J</i>=2.93 Hz, 1 H).

5-(4-isobutylpiperazin-1-yl) pyridin-2-amine

0160<chemistry id="chem0057" num="0057"><img file="EP2632467B1_D0057.tif" /></chemistry>

01611-isobutyl-4-(6-nitro-3-pyridyl)piperazine was synthesized in a manner similar to that used in the synthesis of 2-nitro-5-[4-(1-piperidyl)-1-piperidyl]pyridine which was then converted 5-(4-isobutylpiperazin-1-yl)pyridin-2-amine in a manner similar to that used in the synthesis of 5-(4-methylpiperazin-1-yl)pyridin-2-amine. 1H NMR (600 MHz, CHLOROFORM-<i>d</i>) δ ppm 0.88 (d, <i>J</i>=6.73 Hz, 6 H) 1.71 - 1.84 (m, 1 H) 2.10 (d, <i>J</i>=7.32 Hz, 2 H) 2.46 - 2.58 (m, 4 H) 2.97 - 3.07 (m, 4 H) 4.12 (s, 2 H) 6.45 (d, <i>J</i>=8.78 Hz, 1 H) 7.14 (dd, <i>J</i>=8.78, 2.93 Hz, 1 H) 7.75 (d, <i>J</i>=2.93 Hz, 1 H). LCMS (ESI) 235 (M + H).

5-(4-isopropylpiperazin-1-yl) pyridin-2-amine

0162<chemistry id="chem0058" num="0058"><img file="EP2632467B1_D0058.tif" /></chemistry>

01631-isopropyl-4-(6-nitro-3-pyridyl)piperazine was synthesized in a manner similar to that used in the synthesis of 2-nitro-5-[4-(1-piperidyl)-1-piperidyl]pyridine which was then converted to 5-(4-isopropylpiperazin-1-yl)pyridin-2-amine in a manner similar to that used in the synthesis of 5-(4-methylpiperazin-1-yl)pyridin-2-amine. 1H NMR (600 MHz, CHLOROFORM-<i>d</i>) δ ppm 1.06 (d, <i>J</i>=6.44 Hz, 6 H) 2.59 - 2.75 (m, 5 H) 2.97 - 3.10 (m, 4 H) 4.13 (s, 2 H) 6.45 (d, <i>J</i>=8.78 Hz, 1 H) 7.15 (dd, <i>J</i>=9.08, 2.93 Hz, 1 H) 7.76 (d, <i>J</i>=2.93 Hz, 1 H). LCMS (ESI) 221 (M + H).

5-[(2R,6S)-2,6-dimethylmorpholin-4-yl]pyridin-2-amine

0164<chemistry id="chem0059" num="0059"><img file="EP2632467B1_D0059.tif" /></chemistry>

0165(2S,6R)-2,6-dimethyl-4-(6-nitro-3-pyridyl)morpholine was synthesized in a manner similar to that used in the synthesis of 2-nitro-5-[4-(1-piperidyl)-1-piperidyl]pyridine which was then converted to 5-[(2R,6S)-2,6-dimethylmorpholin-4-yl]pyridin-2-amine in a manner similar to that used in the synthesis of 5-(4-methylpiperazin-1-yl)pyridin-2-amine. 1H NMR (600 MHz, CHLOROFORM-<i>d</i>) δ ppm 1.20 (d, <i>J</i>=6.44 Hz, 6 H) 2.27 - 2.39 (m, 2 H) 3.11 - 3.21 (m, 2 H) 3.70 - 3.84 (m, 2 H) 4.15 (s, 2 H) 6.45 (d, <i>J</i>=8.78 Hz, 1 H) 7.12 (dd, <i>J</i>=8.78, 2.93 Hz, 1 H) 7.72 (d, <i>J</i>=2.63 Hz, 1 H). LCMS (ESI) 208 (M + H).

5-[(3R,5S)-3,5-dimethylpiperazin-1-yl]pyridin-2-amine

0166<chemistry id="chem0060" num="0060"><img file="EP2632467B1_D0060.tif" /></chemistry>

0167(3S,5R)-3,5-dimethyl-1-(6-nitro-3-pyridyl)piperazine was synthesized in a manner similar to that used in the synthesis of 2-nitro-5-[4-(1-piperidyl)-1-piperidyl]pyridine which was then converted to 5-[(3R,5S)-3,5-dimethylpiperazin-1-yl]pyridin-2-amine in a manner similar to that used in the synthesis of 5-(4-methylpiperazin-1-yl)pyridin-2-amine. 1H NMR (600 MHz, CHLOROFORM-<i>d</i>) δ ppm 1.09 (d, <i>J</i>=6.44 Hz, 6 H) 2.20 (t, <i>J</i>=10.83 Hz, 2 H) 2.95 - 3.08 (m, 2 H) 3.23 (dd, <i>J</i>=11.71, 2.05 Hz, 2 H) 4.13 (s, 2 H) 6.45 (d, <i>J</i>=8.78 Hz, 1 H) 7.14 (dd, <i>J</i>=8.78, 2.93 Hz, 1 H) 7.73 (d, <i>J</i>=2.63 Hz, 1 H). LCMS (ESI) 207 (M + H).

Intermediate

1A:

0168<chemistry id="chem0061" num="0061"><img file="EP2632467B1_D0061.tif" /></chemistry>

<i>tert</i>-butyl N-[2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]-3-methyl-butyl] carbamate

0169<chemistry id="chem0062" num="0062"><img file="EP2632467B1_D0062.tif" /></chemistry>

0170A solution of intermediate A in ethanol (100 mL) was hydrogenated under 30 psi of hydrogen using 10% Pd/C (0.7 g) in a pressure bomb for 7 hrs. After filtration of the reaction mixture through CELITE^TM, the organic layer was concentrated under vacuum to afford <i>tert</i>-butyl N-(2-amino-3-methyl-butyl) carbamate (3.8 g).

0171To a solution of 5-bromo-2,4-dichloro-pyrimidine 7.11 g (0.0312 mole) in ethanol (100 mL) was added diisopropylethyl amine 5.45 mL (1.0 eq) and <i>tert</i>-butyl N-(2-amino-3-methyl-butyl) carbamate 6.31 g (0.0312 mole). The reaction mixture was stirred at room temperature for 20 hrs. After concentration under vacuum, ethyl acetate and water was added. The organic layer was separated, dried with magnesium sulfate and then concentrated under vacuum. The crude product was purified by column chromatography using hexane/ethyl acetate (0- 30%) over silica gel to afford <i>tert</i>-butyl N-[2-[(5-bromo-2-chloropyrimidin-4-yl)amino]-3-methyl-butyl] carbamate. 1H NMR (600 MHz, DMSO-<i>d</i>₆) δ ppm 0.77 - 0.85 (d, <i>J</i>=6.5 Hz, 3 H) 0.87 (d, <i>J</i>=6.73 Hz, 3 H) 1.31 - 1.39 (m, 9 H) 1.82 - 1.93 (m, 1 H) 2.94 (d, <i>J</i>=5.56 Hz, 1 H) 3.08 - 3.22 (m, 2 H) 3.98 (d, <i>J</i>=8.20 Hz, 1 H) 6.96 (d, <i>J</i>=8.78 Hz, 1 H) 8.21 (s, 1 H). LCMS (ESI) 393 (M + H).

<i>tert</i>-butyl N-[2-[2-chloro-6-(diethoxymethyl)pyrrolo[2,3-d]pyrimidin-7-yl]-3-methyl-butyl]carbamate

0172<chemistry id="chem0063" num="0063"><img file="EP2632467B1_D0063.tif" /></chemistry>

0173<i>tert</i>-butyl N-[2-[2-chloro-6-(diethoxymethyl)pyrrolo[2,3-d]pyrimidin-7-yl]-3-methyl-butyl]carbamate was synthesized by subjecting <i>tert</i>-butyl N-[2-[(5-bromo-2-chloropyrimidin-4-yl)amino]-3-methyl-butyl]carbamate to Sonogoshira conditions as described for <i>tert</i>-butyl N-[2-[[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl]amino]ethyl]carbamate followed by subsequent treatment with TBAF as described in the synthesis of <i>tert</i>-butyl N-[2-[2-chloro-6-(diethoxymethyl)pyrrolo[2,3-d]pyrimidin-7-yl]ethyl]carbamate. 1H NMR (600 MHz, DMSO-<i>d</i>₆) δ ppm 1.11 (d, <i>J</i>=6.44 Hz, 3 H) 1.18 (t, <i>J</i>=7.03 Hz, 6 H) 1.21 - 1.26 (m, 12 H) 2.88 (br. s., 1 H) 3.43 - 3.78 (m, 6 H) 3.97 - 4.08 (m, 1 H) 5.61 (s, 1 H) 6.65 (s, 1 H) 6.71 - 6.78 (m, 1 H) 8.87 (s, 1 H). LCMS (ESI) 441 (M + H).

7-[1-[(<i>tert</i>-butoxycarbonylamino)methyl]-2-methyl-propyl]-2-chloro-pyrrolo[23-d]pyrimidine-6-carboxylic acid

0174<chemistry id="chem0064" num="0064"><img file="EP2632467B1_D0064.tif" /></chemistry>

0175To a solution <i>tert</i>-butyl N-[2-[[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl]amino]ethyl]carbamate in THF was added TBAF and the contents refluxed for 3 hrs. Ethyl acetate and water was then added and the organic layer separated, dried with magnesium sulfate and then concentrated under vacuum. To this crude reaction was added acetic acid/water (9:1) and then contents stirred for 12 hrs at room temperature. After concentration under vacuum, sat NaHCO₃ and ethyl acetate was then added. The organic layer was separated, dried and then concentrated under vacuum. The crude reaction product thus obtained was dissolved in DMF, oxone was then added and the contents stirred for 3 hrs. After addition of ethyl acetate, the reaction mixture was filtered through CELITE^TM and concentrated under vacuum. Column chromatography of the crude product over silica gel using hexane/ethyl acetate (0- 100%) afforded 7-[1-[(<i>tert</i>-butoxycarbonylamino)methyl]-2-methyl-propyl]-2-chloro-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid. 1H NMR (600 MHz, DMSO-<i>d</i>₆) δ ppm 0.85 (d, <i>J</i>=7.03 Hz, 3 H) 0.97 (d, <i>J</i>=6.73 Hz, 3 H) 1.52 (s, 9 H) 1.99 - 2.23 (m, 1 H) 3.98 (dd, <i>J</i>=14.05, 3.51 Hz, 1 H) 4.47 - 4.71 (m, 2 H) 7.47 (s, 1 H) 9.17 (s, 1 H). LCMS (ESI) 383 (M + H).

Intermediate 1A

0176To 7-[1-[(<i>tert</i>-butoxycarbonylamino)methyl]-2-methyl-propyl]-2-chloropyrrolo[2,3-d]pyrimidine-6-carboxylic acid 0.050 g (0.00013 mole) in DCM (1.5 mL) was added DIC (32.7 mg) and DMAP (10 mg). The contents were stirred for 2 hrs. Trifluoroacetic acid (0.4 mL) was then added and stirring continued for an additional 30 minutes. After addition of satd NaHCO3 to neutralize the excess acid, ethyl acetate was then added and the organic layer separated, dried using magnesium sulfate and then concentrated under vacuum. The crude product was column chromatographed over silica gel using hexane/ethyl acetate (0- 100%) to afford Intermediate 1A. 1H NMR (600 MHz, DMSO-<i>d</i>₆) δ ppm 0.72 (d, <i>J</i>=6.73 Hz, 3 H) 0.97 (d, <i>J</i>=6.73 Hz, 3 H) 2.09 - 2.22 (m, 1 H) 3.57 (dd, <i>J</i>=13.18, 4.98 Hz, 1 H) 3.72 (dd, <i>J</i>=13.61, 4.25 Hz, 1 H) 4.53 (dd, <i>J</i>=8.05, 3.95 Hz, 1 H) 7.20 (s, 1 H) 8.34 (d, <i>J</i>=4.98 Hz, 1 H) 9.08 (s, 1 H). LCMS (ESI) 265 (M + H).

Intermediate 1B:

0177<chemistry id="chem0065" num="0065"><img file="EP2632467B1_D0065.tif" /></chemistry>

0178Intermediate C was hydrogenated with 10% Pd/C to afford the intermediate <i>tert-</i>butyl N-[(2R)-2-amino-3-methyl-butyl] carbamate, which was then treated with 5-bromo-2,4-dichloro-pyrimidine using analogous reaction conditions as described for Intermediate 1A to afford intermediate 1B. The analytical data is consistent with that reported for the racemate (Intermediate 1A).

Intermediate 1C:

0179<chemistry id="chem0066" num="0066"><img file="EP2632467B1_D0066.tif" /></chemistry>

0180Intermediate D was hydrogenated with 10% Pd/C to afford the intermediate <i>tert-</i>butyl N-[(2S)-2-amino-3-methyl-butyl]carbamate, which was then treated with 5-bromo-2,4-dichloro-pyrimidine using analogous reaction conditions as described for Intermediate 1A to afford intermediate 1C. The analytical data (NMR and LCMS) was consistent with that reported for the racemate (intermediate 1A).

Intermediate 1CA:

0181<chemistry id="chem0067" num="0067"><img file="EP2632467B1_D0067.tif" /></chemistry>

0182To a solution of Intermediate 1A (80 mg, 0.00030 mole) in DMF (3 mL) was added a 60% dispersion of sodium hydride in oil (40 mg). After stirring for 15 minutes, methyl iodide (37 µL, 2eq) was added. The contents were stirred at room temperature for 30 minutes. Satd NaHCO3 was then added followed by ethyl acetate. The organic layer was dried with magnesium sulfate and then concentrated under vacuum to afford intermediate 1AA. 1H NMR (600 MHz, DMSO-<i>d</i>₆) δ ppm 0.74 (d, <i>J</i>=6.73 Hz, 3 H) 0.91 (d, <i>J</i>=6.73 Hz, 3 H) 2.04 - 2.20 (m, 1 H) 3.04 (s, 3 H) 3.69 (dd, <i>J</i>=13.76, 1.17 Hz, 1 H) 3.96 (dd, <i>J</i>=13.76, 4.68 Hz, 1 H) 4.58 (dd, <i>J</i>=7.32, 3.51 Hz, 1 H) 7.16 (s, 1 H) 9.05 (s, 1 H). LCMS (ESI) 279 (M + H).

Intermediate 1D

0183<chemistry id="chem0068" num="0068"><img file="EP2632467B1_D0068.tif" /></chemistry>

<i>tert</i>-butyl N-[(2S)-2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]-4-methl-pentyl]carbamate

0184<chemistry id="chem0069" num="0069"><img file="EP2632467B1_D0069.tif" /></chemistry>

0185Intermediate G was hydrogenated with 10% Pd/C in ethanol under a blanket of hydrogen at 50 psi in a pressure bomb to afford <i>tert</i>-butyl N-[(2S)-2-amino-4-methylpentyl]carbamate which was then reacted with 5-bromo-2,4-dichloro-pyrimidine using analogous reaction conditions as described for <i>tert</i>-butyl N-[2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]-3-methyl-butyl]carbamate to afford <i>tert</i>-butyl N-[(2S)-2-[(5-bromo-2-chloropyrimidin-4-yl)amino]-4-methyl-pentyl]carbamate. 1H NMR (600 MHz, CHLOROFORM-<i>d</i>) δ ppm 0.91 (d, <i>J</i>=6.44 Hz, 3 H) 0.94 (d, <i>J</i>=6.44 Hz, 3 H) 1.32 - 1.51 (m, 11 H) 1.55 - 1.67 (m, 1 H) 3.28 (t, <i>J</i>=5.86 Hz, 2 H) 4.21 - 4.42 (m, 1 H) 4.84 (s, 1 H) 5.84 (d, <i>J</i>=7.32 Hz, 1 H) 8.07 (s, 1 H). LCMS (ESI) 407 (M + H). <chemistry id="chem0070" num="0070"><img file="EP2632467B1_D0070.tif" /></chemistry>

0186To a solution of <i>tert</i>-butyl N-[(2S)-2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]-4-methyl-pentyl]carbamate 5.0 g (12.3 mmole) in tolune (36 mL) and triethyl amine (7.2 mL) was added under nitrogen, 3,3-diethoxyprop-1-yne 2.8 mL (19.7 mmole), Pd₂(dba)₃ 1.1g (1.23 mmole), and triphenylarsine 3.8 g (12.3 mmole). The contents were heated to 70 degrees for 24 hrs. After cooling to room temperature, the reaction mixture was filtered through CELITE^TM and then concentrated under vacuum. The crude product was columned over silica gel using hexane/ethyl acetate (0- 30%) to afford (2S)-N2-[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl]-4-methyl-pentane-1,2-diamine. LCMS (ESI) 455 (M + H). <chemistry id="chem0071" num="0071"><img file="EP2632467B1_D0071.tif" /></chemistry>

01877-[(1S)-1-[(<i>tert</i>-butoxycarbonylamino)methyl]-3-methyl-butyl]-2-chloropyrrolo[2,3-d]pyrimidine-6-carboxylic acid was synthesized using analogous synthetic sequence as that described for 7-[1-[(<i>tert</i>-butoxycarbonylamino)methyl]-2-methyl-propyl]-2-chloro-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid. 1H NMR (600 MHz, DMSO-<i>d</i>₆) δ ppm 0.88 (d, <i>J</i>=6.44 Hz, 3 H) 0.97 (d, <i>J</i>=6.44 Hz, 3 H) 1.47 (s, 9 H) 1.49 - 1.54 (m, 1 H) 1.56 (t, <i>J</i>=7.17 Hz, 2 H) 3.98 (dd, <i>J</i>=13.91, 3.07 Hz, 1 H) 3.76 (dd, <i>J</i>=13.31, 4.13 Hz, 1 H) 4.38 (d, <i>J</i>=14.05 Hz, 1 H) 4.90 (t, <i>J</i>=7.17 Hz, 1 H) 7.41 (s, 1 H) 9.11 (s, 1 H). LCMS (M + H) 397.

0188Intermediate 1D was synthesized using an analogous synthetic sequence as that described for intermediate 1A. 1H NMR (600 MHz, DMSO-<i>d</i>₆) δ ppm 0.82 (d, <i>J</i>=6.73 Hz, 3 H) 0.97 (d, <i>J</i>=6.44 Hz, 3 H) 1.34 - 1.46 (m, 1 H) 1.48 - 1.65 (m, 2 H) 3.40 (dd, <i>J</i>=13.32, 5.42 Hz, 1 H) 3.76 (dd, <i>J</i>=13.47, 4.10 Hz, 1 H) 4.76 - 4.92 (m, 1 H) 7.17 (s, 1 H) 8.34 (d, <i>J</i>=5.27 Hz, 1 H) 9.04 (s, 1 H). LCMS (ESI) 279 (M + H).

Intermediate 1DA:

0189<chemistry id="chem0072" num="0072"><img file="EP2632467B1_D0072.tif" /></chemistry>

0190Intermediate 1DA was synthesized in a manner similar to that described for 1CA. 1H NMR (600 MHz, DMSO-<i>d</i>₆) δ ppm 0.82 (d, <i>J</i>=6.44 Hz, 3 H) 0.97 (d, <i>J</i>=6.44 Hz, 3 H) 1.37 - 1.68 (m, 3 H) 3.04 (s, 3 H) 3.56 (d, <i>J</i>=13.47 Hz, 1 H) 4.00 (dd, <i>J</i>=13.32, 4.25 Hz, 1 H) 4.82 - 4.94 (m, 1 H) 7.16 (s, 1 H) 9.03 (s, 1 H). LCMS (ESI) 293 (M + H)

Intermediate 1E:

0191<chemistry id="chem0073" num="0073"><img file="EP2632467B1_D0073.tif" /></chemistry>

<i>tert</i>-butyl N-[(2S)-2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]-3-methyl-pentyl]carbamate

0192<chemistry id="chem0074" num="0074"><img file="EP2632467B1_D0074.tif" /></chemistry>

0193Intermediate I was hydrogenated using 10% Pd/C under hydrogen at 50 psi in a pressure vessel to afford <i>tert</i>-butyl N-[(2S)-2-amino-3-methyl-pentyl]carbamate which was reacted with 5-bromo-2,4-dichloro-pyrimidine using analogous reaction conditions as described for <i>tert</i>-butyl N-[2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]-3-methyl-butyl]carbamate to afford <i>tert</i>-butyl N-[(2S)-2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]-3-methyl-pentyl]carbamate. 1H NMR (600 MHz, CHLOROFORM-<i>d</i>) δ ppm 0.88 - 0.95 (m, 6 H) 1.11 - 1.20 (m, 1 H) 1.34 (s, 9 H) 1.44 - 1.54 (m, 1 H) 1.64 - 1.72 (m, 1 H) 3.17 - 3.27 (m, 1 H) 3.33 - 3.43 (m, 1 H) 4.11 - 4.21 (m, 1 H) 4.81 (s, 1 H) 5.92 (d, <i>J</i>=8.20 Hz, 1 H) 8.05 (s, 1 H). LCMS (ESI) 407.

<i>tert</i>-butyl N-[(2S)-2-[[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl]amino]-3-methylpentyl]carbamate

0194<chemistry id="chem0075" num="0075"><img file="EP2632467B1_D0075.tif" /></chemistry>

0195<i>tert</i>-butyl N-[(2S)-2-[[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl]amino]-3-methyl-pentyl]carbamate was synthesized using similar experimental conditions to that used in the synthesis of (2S)-N2-[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl]-4-methyl-pentane-1,2-diamine. 1H NMR (600 MHz, DMSO-<i>d</i>₆) δ ppm 0.76 - 0.89 (m, 6 H) 1.03 (q, <i>J</i>=7.22 Hz, 3 H) 1.10 - 1.17 (m, 3 H) 1.25 - 1.42 (m, 11 H) 1.59 - 1.73 (m, 1 H) 3.35 - 3.47 (m, 4 H) 3.51 - 3.73 (m, 2 H) 3.99 - 4.11 (m, 1 H) 5.52 - 5.56 (m, 1 H) 6.76 - 7.03 (m, 2 H) 8.12 - 8.23 (m, 1 H). LCMS (ESI) 455 (M + H).

7-[(1S)-1-[(<i>tert</i>-butoxycarbonylamino)methyl]-2-methyl-butyl]-2-chloro-pyrrolo[23-d]pyrimidine-6-carboxylic acid

0196<chemistry id="chem0076" num="0076"><img file="EP2632467B1_D0076.tif" /></chemistry>

01977-[(1S)-1-[(<i>tert</i>-butoxycarbonylamino)methyl]-2-methyl-butyl]-2-chloropyrrolo[2,3-d]pyrimidine-6-carboxylic acid was synthesized using analogous synthetic sequence as that described for 7-[1-[(<i>tert</i>-butoxycarbonylamino)methyl]-2-methyl-propyl]-2-chloro-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid. 1H NMR (600 MHz, DMSO-<i>d</i>₆) δ ppm 0.80 (t, <i>J</i>=7.47 Hz, 3 H) 0.86 (d, J=7.03 Hz, 3 H) 1.06 - 1.30 (m, 2 H) 1.48 (s, 9 H) 1.79 - 1.96 (m, 1 H) 3.95 (dd, <i>J</i>=14.05, 3.22 Hz, 1 H) 4.52 (d, <i>J</i>=14.35 Hz, 1 H) 4.61 - 4.73 (m, 1 H) 7.43 (s, 1 H) 9.13 (s, 1 H). LCMS (ESI) 397 (M + H).

0198Intermediate 1E was synthesized using an analogous synthetic sequence as that described for intermediate 1A. 1H NMR (600 MHz, DMSO-<i>d</i>₆) δ ppm 0.74 (t, <i>J</i>=7.32 Hz, 3 H) 0.89 (d, J=6.73 Hz, 3 H) 1.00 - 1.12 (m, 2 H) 1.82 - 1.94 (m, 1 H) 3.55 (dd, <i>J</i>=13.91, 4.83 Hz, 1 H) 3.70 (dd, <i>J</i>=13.61, 4.25 Hz, 1 H) 4.57 (dd, <i>J</i>=7.91, 4.10 Hz, 1 H) 7.17 (s, 1 H) 8.31 (d, <i>J</i>=5.27 Hz, 1 H) 9.05 (s, 1 H). LCMS (ESI) 279 (M + H).

Intermediate 1EA:

0199<chemistry id="chem0077" num="0077"><img file="EP2632467B1_D0077.tif" /></chemistry>

0200Intermediate 1EA was synthesized in a manner similar to Intermediate 1CA. 1H NMR (600 MHz, DMSO-<i>d</i>₆) δ ppm 0.77 (t, <i>J</i>=7.47 Hz, 3 H) 0.84 (d, <i>J</i>=6.73 Hz, 3 H) 1.07 - 1.16 (m, 2 H) 1.82 - 1.95 (m, 1 H) 3.03 (s, 3 H) 3.68 (d, <i>J</i>=13.76 Hz, 1 H) 3.96 (dd, <i>J</i>=13.76, 4.39 Hz, 1 H) 4.59 - 4.70 (m, 1 H) 7.16 (s, 1 H) 9.04 (s, 1 H). LCMS (ESI) 293 (M + H).

Intermediate 1F

0201<chemistry id="chem0078" num="0078"><img file="EP2632467B1_D0078.tif" /></chemistry>

<i>tert</i>-butyl N-[(2S)-2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]-3,3-dimethyl-butyl] carbamate

0202<chemistry id="chem0079" num="0079"><img file="EP2632467B1_D0079.tif" /></chemistry>

0203Intermediate J was hydrogenated using 10% Pd/C under hydrogen at 50 psi in a pressure vessel to afford <i>tert</i>-butyl N-[(2S)-2-amino-3,3-dimethyl-butyl]carbamate which was then reacted with 5-bromo-2,4-dichloro-pyrimidine using analogous reaction conditions as described using analogous reaction conditions as described for <i>tert</i>-butyl N-[2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]-3-methyl-butyl]carbamate to afford <i>tert</i>-butyl N-[(2S)-2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]-3,3-dimethyl-butyl]carbamate. LCMS (ESI) 407 (M + H).

<i>tert</i>-butyl N-[(2S)-2-[[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl]amino]-3,3-dimethyl-butyl] carbamate

0204<chemistry id="chem0080" num="0080"><img file="EP2632467B1_D0080.tif" /></chemistry>

0205<i>tert</i>-butyl N-[(2S)-2-[[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl]amino]-3,3-dimethyl-butyl]carbamate was synthesized using similar experimental conditions to that used in the synthesis of (2S)-N2-[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl]-4-methyl-pentane-1,2-diamine. LCMS (ESI) 455 (M + H).

7-[(1S)-1-[(<i>tert</i>-butoxycarbonylamino)methyl]-2,2-dimethyl-propyl]-2-chloro-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid

0206<chemistry id="chem0081" num="0081"><img file="EP2632467B1_D0081.tif" /></chemistry>

02077-[(1S)-1-[(<i>tert</i>-butoxycarbonylamino)methyl]-2,2-dimethyl-propyl]-2-chloro-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid was synthesized using analogous synthetic sequence as that described for 7-[1-[(<i>tert</i>-butoxycarbonylamino)methyl]-2-methyl-propyl]-2-chloro-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid. LCMS (ESI) 397 (M + H).

0208Intermediate 1F was synthesized using an analogous synthetic sequence as that described for intermediate 1A. LCMS (ESI) 279 (M + H).

Intermediate 1FA

0209<chemistry id="chem0082" num="0082"><img file="EP2632467B1_D0082.tif" /></chemistry>

0210Intermediate 1FA was synthesized in a manner similar to that described for Intermediate 1CA. LCMS (ESI) 293 (M + H).

Intermediate 1G

0211<chemistry id="chem0083" num="0083"><img file="EP2632467B1_D0083.tif" /></chemistry>

<i>tert</i>-butyl N-[(2S)-2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]-2-phenyl-ethyl] carbamate

0212<chemistry id="chem0084" num="0084"><img file="EP2632467B1_D0084.tif" /></chemistry>

0213Intermediate J was hydrogenated using 10% Pd/C under hydrogen at 50 psi in a pressure vessel to afford <i>tert</i>-butyl N-[(2S)-2-amino-2-phenyl-ethyl]carbamate which was then reacted with 5-bromo-2,4-dichloro-pyrimidine using analogous reaction conditions as described using analogous reaction conditions as described for <i>tert</i>-butyl N-[2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]-3-methyl-butyl]carbamate to afford <i>tert</i>-butyl N-[(2S)-2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]-2-phenyl-ethyl]carbamate. 1H NMR (600 MHz, DMSO-<i>d</i>₆) δ ppm 1.32 (s, 9 H) 3.29 - 3.50 (m, 2 H) 5.12 - 5.24 (m, 1 H) 7.10 (t, <i>J</i>=5.27 Hz, 1 H) 7.21 (t, <i>J</i>=6.88 Hz, 1 H) 7.26 - 7.34 (m, 4 H) 7.89 (d, <i>J</i>=7.32 Hz, 1 H) 8.24 (s, 1 H). LCMS (ESI) 427 (M + H).

<i>tert</i>-butyl N-[(2S)-2-[[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl]amino]-2-phenyl-ethyl]carbamate

0214<chemistry id="chem0085" num="0085"><img file="EP2632467B1_D0085.tif" /></chemistry>

0215<i>tert</i>-butyl N-[(2S)-2-[[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl]amino]-2-phenyl-ethyl]carbamate was synthesized using similar experimental conditions to that used in the synthesis of (2S)-N2-[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl]-4-methyl-pentane-1,2-diamine. 1H NMR (600 MHz, DMSO-<i>d</i>₆) δ ppm 1.14 (t, <i>J</i>=7.03 Hz, 6 H) 1.32 (s, 9 H) 3.39 (s, 2 H) 3.52 - 3.61 (m, 2 H) 3.64 - 3.73 (m, 2 H) 5.17 - 5.26 (m, 1 H) 5.57 (s, 1 H) 7.07 - 7.14 (m, 1 H) 7.20 - 7.25 (m, 1 H) 7.26 - 7.33 (m, 4 H) 7.90 (d, <i>J</i>=7.61 Hz, 1 H) 8.19 (s, 1 H). LCMS (ESI) 475 (M + H).

7-[(1S)-2-(<i>tert</i>-butoxycarbonylamino)-1-phenyl-2-chloro-pyrrolo[2,3-d]pyrimidine-6-carboxylic

acid

0216<chemistry id="chem0086" num="0086"><img file="EP2632467B1_D0086.tif" /></chemistry>

02177-[(1S)-2-(<i>tert</i>-butoxycarbonylamino)-1-phenyl-ethyl]-2-chloro-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid was synthesized using analogous synthetic sequence as that described for 7-[1-[(<i>tert</i>-butoxycarbonylamino)methyl]-2-methyl-propyl]-2-chloropyrrolo[2,3-d]pyrimidine-6-carboxylic acid. LCMS (ESI) 417 (M + H).

Intermediate 1G

0218Intermediate 1G was synthesized using an analogous synthetic sequence as that described for intermediate 1A. 1H NMR (600 MHz, DMSO-<i>d</i>₆) δ ppm 3.58 - 3.69 (m, 1 H) 4.13 (dd, <i>J</i>=13.47, 4.39 Hz, 1 H) 6.07 (d, <i>J</i>=3.81 Hz, 1 H) 6.85 (d, <i>J</i>=7.32 Hz, 2 H) 7.19-7.31 (m, 3 H) 7.34 (s, 1 H) 8.27 (d, <i>J</i>=5.27 Hz, 1 H) 9.13 (s, 1 H). LCMS (ESI) 299 (M + H).

Intermediate 1H

0219<chemistry id="chem0087" num="0087"><img file="EP2632467B1_D0087.tif" /></chemistry>

<i>tert</i>-butyl N-[(1S)-1-[[(5-bromo-2-chloro-pyrimidin-4-yl)amino]methyl]-2-methyl-propyl] carbamate

0220<chemistry id="chem0088" num="0088"><img file="EP2632467B1_D0088.tif" /></chemistry>

0221<i>tert</i>-butyl N-[(1S)-1-[[(5-bromo-2-chloro-pyrimidin-4-yl)amino]methyl]-2-methyl-propyl]carbamate was synthesized using 5-bromo-2,4-dichloro-pyrimidine and Intermediate E using analogous reaction conditions as described for <i>tert</i>-butyl N-[2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]-3-methyl-butyl]carbamate. 1H NMR (600 MHz, CHLOROFORM-<i>d</i>) δ ppm 0.95 - 1.02 (m, 6 H) 1.35 - 1.45 (m, 9 H) 1.75 - 1.90 (m, 1 H) 3.35 - 3.48 (m, 1 H) 3.52 - 3.61 (m, 1 H) 3.64 - 3.76 (m, 1 H) 4.56 (d, <i>J</i>=8.49 Hz, 1 H) 6.47 (s, 1 H) 8.07 (s, 1 H). LCMS (ESI) 393 (M + H).

<i>tert</i>-butyl N-[(1S)-1-[[[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl]amino]methl] 2-methyl-propyl] carbamate

0222<chemistry id="chem0089" num="0089"><img file="EP2632467B1_D0089.tif" /></chemistry>

0223<i>tert</i>-butyl N-[(1S)-1-[[[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl]amino]methyl]-2-methyl-propyl]carbamate was synthesized using similar experimental conditions to that used in the synthesis (2S)-N2-[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl]-4-methyl-pentane-1,2-diamine. 1H NMR (600 MHz, CHLOROFORM-<i>d</i>) δ ppm 0.90 - 1.00 (m, 6 H) 1.18 - 1.25 (m, 6 H) 1.34 - 1.36 (m, 9 H) 1.69 - 1.90 (m, 1 H) 3.34 - 3.82 (m, 6 H) 4.53 - 4.77 (m, 1 H) 5.45 - 5.55 (m, 1 H) 6.37 (dd, <i>J</i>=15.37, 6.59 Hz, 1 H) 6.56 (s, 1 H) 8.05 (s, 1 H). LCMS (ESI) 441 (M + H).

7-[(2S)-2-(<i>tert</i>-butoxycarbonylamino)-3-methyl-butyl-2-chloro-pyrrolo[2,3-d]pyrimidine-6-carboxylic

acid

0224<chemistry id="chem0090" num="0090"><img file="EP2632467B1_D0090.tif" /></chemistry>

02257-[(2S)-2-(<i>tert</i>-butoxycarbonylamino)-3-methyl-butyl]-2-chloro-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid was synthesized using analogous synthetic sequence as that described for 7-[1-[(<i>tert</i>-butoxycarbonylamino)methyl]-2-methyl-propyl]-2-chloropyrrolo[2,3-d]pyrimidine-6-carboxylic acid. 1H NMR (600 MHz, CHLOROFORM-<i>d</i>) δ ppm 0.90 (d, <i>J</i>=6.73 Hz, 3 H) 0.96 (d, <i>J</i>=7.03 Hz, 3 H) 1.55 - 1.66 (m, 10 H) 4.14 (dd, <i>J</i>=13.61, 3.95 Hz, 1 H) 4.52 - 4.63 (m, 1 H) 4.84 (dd, <i>J</i>=13.61, 1.32 Hz, 1 H) 7.37 (s, 1 H) 8.95 (s, 1 H). LCMS (ESI) 383 (M + H).

Intermediate H

0226Intermediate 1H was synthesized using an analogous synthetic sequence as that described for intermediate 1A. LCMS (ESI) 265 (M + H).

Intermediate 1I

0227<chemistry id="chem0091" num="0091"><img file="EP2632467B1_D0091.tif" /></chemistry>

0228Intermediate 1I was synthesized using 5-bromo-2,4-dichloro-pyrimidine and Intermediate F as starting materials, and following a similar sequence of synthetic steps as for intermediate 1H. The analytical data was consistent with that described for its antipode (intermediate 1H). 1H NMR (600 MHz, DMSO-<i>d</i>₆) δ ppm 0.88 (d, <i>J</i>=6.44 Hz, 6 H) 1.73-1.86 (m, 1 H) 3.67 - 3.76 (m, 2 H) 4.11 - 4.21 (m, 1 H) 7.13 - 7.19 (m, 1 H) 8.56 (s, 1 H) 9.05 (s, 1 H). LCMS (ESI) 265 (M + H).

Intermediate 1J

0229<chemistry id="chem0092" num="0092"><img file="EP2632467B1_D0092.tif" /></chemistry>

<i>tert</i>-butyl N-[2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]-2-methyl-propyl]carbamate

0230<chemistry id="chem0093" num="0093"><img file="EP2632467B1_D0093.tif" /></chemistry>

0231<i>tert</i>-butyl N-[2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]-2-methyl-propyl]carbamate was synthesized using 5-bromo-2,4-dichloro-pyrimidine and <i>tert</i>-butyl N-(2-amino-2-methyl-propyl)carbamate using analogous reaction conditions as described for <i>tert</i>-butyl N-[2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]-3-methyl-butyl]carbamate. LCMS (ESI) 379 (M + H).

<i>tert</i>-butyl N-[2-[[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl]amino]-2-methylpropyl

]

carbamate

0232<chemistry id="chem0094" num="0094"><img file="EP2632467B1_D0094.tif" /></chemistry>

0233<i>tert</i>-butyl N-[2-[[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl]amino]-2-methyl-propyl]carbamate was synthesized using similar experimental conditions to that used in the synthesis of (2S)-N2-[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl]-4-methylpentane-1,2-diamine. 1H NMR (600 MHz, DMSO-<i>d</i>₆) d ppm 1.11 - 1.22 (m, 6 H) 1.31-1.45 (m, 15 H) 3.10 - 3.24 (m, 2 H) 3.51 - 3.76 (m, 4 H) 5.60 (s, 1 H) 6.94 (s, 1 H) 7.33 (t, <i>J</i>=6.44 Hz, 1 H) 8.18 (s, 1 H). LCMS (ESI) 427 (M + H).

7-[2-(<i>tert</i>-butoxycarbonylamino)-1,1-dimethyl-ethyl]-2-chloro-pyrrolo[2,3-d]pyrimidine-6-carboxylic

acid

0234<chemistry id="chem0095" num="0095"><img file="EP2632467B1_D0095.tif" /></chemistry>

02357-[2-(<i>tert</i>-butoxycarbonylamino)-1,1-dimethyl-ethyl]-2-chloro-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid using analogous synthetic sequence as that described for 7-[1-[(<i>tert</i>-butoxycarbonylamino)methyl]-2-methyl-propyl]-2-chloro-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid. 1H NMR (600 MHz, DMSO-<i>d</i>₆) δ ppm 1.43 (s, 9H) 1.73 (s, 6 H) 4.06 (s, 2 H) 7.46 (s, 1 H) 9.23 (s, 1H). LCMS (ESI) 369 (M + H).

Intermediate 1J

0236Intermediate 1J was synthesized using an analogous synthetic sequence as that described for intermediate 1A. 1H NMR (600 MHz, DMSO-<i>d</i>₆) δ ppm 1.73 (s, 6 H) 3.50 (d, <i>J</i>=2.93 Hz, 2 H) 7.25 (s, 1 H) 8.46 - 8.55 (m, 1 H) 9.07 (s, 1 H). LCMS (ESI) 251 (M + H).

Intermediate 1K

0237<chemistry id="chem0096" num="0096"><img file="EP2632467B1_D0096.tif" /></chemistry>

<i>tert</i>-butyl N-[[1-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]cyclohexyl]methyl]carbamate

0238<chemistry id="chem0097" num="0097"><img file="EP2632467B1_D0097.tif" /></chemistry>

0239<i>tert</i>-butyl N-[[1-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]cyclohexyl]methyl] carbamate was synthesized using 5-bromo-2,4-dichloro-pyrimidine and Intermediate K using analogous reaction conditions as described for <i>tert</i>-butyl N-[2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]-3-methyl-butyl] carbamate. 1H NMR (600 MHz, DMSO-<i>d</i>₆) δ ppm 1.18 - 1.54 (m, 17 H) 2.23 (d, <i>J</i>=14.35 Hz, 2 H) 3.36 (d, <i>J</i>=6.44 Hz, 2 H) 5.82 (s, 1 H) 6.93 (s, 1 H) 8.22 (s, 1 H). LCMS (ESI) 419 (M + H).

<i>t</i>e<i>rt</i>-butyl N-[[1-[[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl]amino]cyclohexl] methyl]carbamate

0240<chemistry id="chem0098" num="0098"><img file="EP2632467B1_D0098.tif" /></chemistry>

0241<i>tert</i>-butyl N-[[1-[[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl]amino]cyclohexyl]methyl] carbamate was synthesized using similar experimental conditions to that used in the synthesis of (2S)-N2-[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl]-4-methyl-pentane-1,2-diamine. 1H NMR (600 MHz, DMSO-<i>d</i>₆) d ppm 1.08 - 1.16 (m, 6 H) 1.17 - 1.54 (m, 17 H) 2.13 (br. s., 2 H) 3.36 (d, <i>J</i>=6.73 Hz, 2 H) 3.50-3.69 (m, 4 H) 5.72 (s, 1 H) 6.94 (s, 1 H) 5.72 (br. s., 1H) 8.17 (s, 1 H). LCMS (ESI) 467 (M + H).

7-[1-[(<i>tert</i>-butoxycarbonylamino)methyl]cyclohexyl]-2-chloro-pyrrolo[2,3-d]pyrimidine-6-carboxylic

acid

0242<chemistry id="chem0099" num="0099"><img file="EP2632467B1_D0099.tif" /></chemistry>

02437-[-[(<i>tert</i>-butoxycarbonylamino)methyl]cyclohexyl]-2-chloro-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid was synthesized using analogous synthetic sequence as that described for 7-[1-[(<i>tert</i>-butoxycarbonylamino)methyl]-2-methyl-propyl]-2-chloropyrrolo[2,3-d]pyrimidine-6-carboxylic acid. 1H NMR (600 MHz, DMSO-<i>d</i>₆) δ ppm 1.37-1.54 (m, 13 H) 1.75 (br. s., 4 H) 2.74 (br. s., 2 H) 3.78 - 3.84 (m, 2 H) 7.44 - 7.51 (m, 1 H) 8.23 (s, 1 H) 9.11 (s, 1 H). LCMS (ESI) 409 (M + H).

Intermediate K

0244Intermediate 1K was synthesized using an analogous synthetic sequence as that described for intermediate 1A. 1H NMR (600 MHz, DMSO-<i>d</i>₆) δ ppm 1.28 (br. s., 2 H) 1.42 (br. s., 2 H) 1.70 (br. s., 4 H) 1.85 - 1.95 (m, 2 H) 2.69 (m, 2 H) 7.16 - 7.25 (m, 1 H) 8.41 (br. s., 1 H) 9.04 (s, 1 H). LCMS 291 (M + H).

Intermediate 1L

0245<chemistry id="chem0100" num="0100"><img file="EP2632467B1_D0100.tif" /></chemistry>

<i>tert-</i>butyl N-[[1-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]cyclopentyl]methyl]carbamate

0246<chemistry id="chem0101" num="0101"><img file="EP2632467B1_D0101.tif" /></chemistry>

0247<i>tert</i>-butyl N-[[1-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]cyclopentyl]methyl] carbamate was synthesized using 5-bromo-2,4-dichloro-pyrimidine and Intermediate L using analogous reaction conditions as described for <i>tert</i>-butyl N-[2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]-3-methyl-butyl]carbamate. 1H NMR (600 MHz, DMSO-<i>d</i>₆) δ ppm 1.34 (s, 9 H) 1.50 - 1.58 (m, 2 H) 1.63 - 1.78 (m, 4 H) 1.96 - 2.06 (m, 2 H) 3.25 (d, <i>J</i>=6.15 Hz, 2 H) 6.71 (s, 1 H) 7.18 (t, <i>J</i>=6.29 Hz, 1 H) 8.20 (s, 1 H). LCMS (ESI) 405 (M + H).

<i>tert</i>-butyl N-[[1-[[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl]amino]cyclopentyl] methyl]carbamate

0248<chemistry id="chem0102" num="0102"><img file="EP2632467B1_D0102.tif" /></chemistry>

0249<i>tert</i>-butyl N-[[1-[[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl]amino]cyclopentyl]methyl]carbamate was synthesized using similar experimental conditions to that used in the synthesis of (2S)-N2-[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl]-4-methyl-pentane-1,2-diamine. LCMS (ESI) 453 (M + H).

7-[1-[(<i>tert</i>-butoxycarbonylamino)methyl]cyclopentyl]-2-chloro-pyrrolo[2,3-d]pyrimidine-6-carboxylic

acid

0250<chemistry id="chem0103" num="0103"><img file="EP2632467B1_D0103.tif" /></chemistry>

02517-[1-[(<i>tert</i>-butoxycarbonylamino)methyl]cyclopentyl]-2-chloro-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid was synthesized using analogous synthetic sequence as that described for 7-[1-[(<i>tert</i>-butoxycarbonylamino)methyl]-2-methyl-propyl]-2-chloropyrrolo[2,3-d]pyrimidine-6-carboxylic acid. 1H NMR (600 MHz, DMSO-<i>d</i>₆) δ ppm 1.47 (s, 9 H) 1.74 (br. s., 2 H) 1.88 (br. s., 2 H) 2.04 (br. s., 2 H) 2.41 - 2.45 (m, 2 H) 4.06 (s, 2 H) 7.45 (s, 1 H) 9.11 (s, 1 H). LCMS (ESI) 395 (M + H).

Intermediate 1L

0252Intermediate 1L was synthesized using an analogous synthetic sequence as that described for intermediate 1A. 1H NMR (600 MHz, DMSO-<i>d</i>₆) δ ppm 1.72 (br. s., 2 H) 1.86 - 1.93 (m, 2 H) 1.99 (d, <i>J</i>=3.81 Hz, 2 H) 2.40 (br. s., 2 H) 3.48 (d, <i>J</i>=2.34 Hz, 2 H) 7.22 (s, 1 H) 8.53 (br. s., 1 H) 9.05 (s, 1 H). LCMS (ESI) 277 (M + H).

Intermediate 1M

0253<chemistry id="chem0104" num="0104"><img file="EP2632467B1_D0104.tif" /></chemistry>

<i>tert</i>-butyl N-[2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]-4-methyl-pentyl]carbamate

0254<chemistry id="chem0105" num="0105"><img file="EP2632467B1_D0105.tif" /></chemistry>

0255<i>tert</i>-butyl N-[2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]-4-methylpentyl]carbamate was synthesized using 5-bromo-2,4-dichloro-pyrimidine and Intermediate B using analogous reaction conditions as described for <i>tert</i>-butyl N-[2-[(5-bromo-2-chloropyrimidin-4-yl)amino]-3-methyl-butyl]carbamate. The analytical data is consistent with that described for the L-enantiomer.

<i>tert</i>-butyl N-[2-[[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl]amino]-4-methyl-pentyl]carbamate

0256<chemistry id="chem0106" num="0106"><img file="EP2632467B1_D0106.tif" /></chemistry>

0257<i>tert</i>-butyl N-[2-[[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl]amino]-4-methyl-pentyl]carbamate was synthesized using similar experimental conditions to that used in the synthesis of <i>tert</i>-butyl N-[2-[[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl]amino]ethyl]carbamate. 1H NMR (600 MHz, CHLOROFORM-<i>d</i>) δ ppm 1.21 - 1.31 (m, 12 H) 1.38 - 1.46 (m, 11 H) 1.70 (m, 1H) 3.24 (m, 2 H) 3.65 - 3.82 (m, 4 H) 4.86 (br s., 1H), 5.65 (s, 1 H) 5.85 (br s., 1H) 6.94 (s, 1 H) 8.21 (s, 1 H). LCMS (ESI) 455 (M + H).

7-[1-[(<i>tert</i>-butoxycarbonylamino)methyl-3-methyl-butyl]-2-chloro-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid

0258<chemistry id="chem0107" num="0107"><img file="EP2632467B1_D0107.tif" /></chemistry>

02597-[1-[(<i>tert</i>-butoxycarbonylamino)methyl]-3-methyl-butyl]-2-chloro-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid was synthesized using analogous synthetic sequence as that described for 7-[1-[(<i>tert</i>-butoxycarbonylamino)methyl]-2-methyl-propyl]-2-chloropyrrolo[2,3-d]pyrimidine-6-carboxylic acid. The analytical data was consistent with that described for the L-isomer.

Intermediate 1M

0260Intermediate 1M was synthesized using an analogous synthetic sequence as that described for intermediate 1A. The analytical data was consistent with that described for the L-isomer.

Intermediate 1MA

0261<chemistry id="chem0108" num="0108"><img file="EP2632467B1_D0108.tif" /></chemistry>

0262To a solution of Intermediate 1M (100 mg, 0.00024 mole) in DMF (3.0 mL) was added sodium hydride (60 % dispersion in oil), (27.6 mg, 3 eq). After stirring for 15 mins, methyl iodide (30, 2 eq) was added. The contents were stirred at room temperature for 30 mins. After the addition of sat NaHCO₃, ethyl acetate was added. Separation of the organic layer followed by drying with magnesium sulfate and concentration under vacuum afforded the intermediate 1MA. Analytical data was similar to the Intermediate 1DA.

Intermediate 1N

0263<chemistry id="chem0109" num="0109"><img file="EP2632467B1_D0109.tif" /></chemistry>

<i>tert-</i>butyl N-[(1S,2S)-2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]cyclopentyl]carbamate

0264<chemistry id="chem0110" num="0110"><img file="EP2632467B1_D0110.tif" /></chemistry>

0265<i>tert</i>-butyl N-[(1S,2S)-2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]cyclopentyl]carbamate was synthesized by treating <i>tert</i>-butyl N-[(1S,2S)-2-aminocyclopentyl]carbamate with 5-bromo-2,4-dichloro-pyrimidine using analogous reaction conditions as described for <i>tert</i>-butyl N-[2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]-3-methyl-butyl]carbamate. 1H NMR (600 MHz, DMSO-<i>d</i>₆) δ ppm 1.27 (s, 9 H) 1.42 - 1.54 (m, 2 H) 1.56 - 1.65 (m, 2 H) 1.80 - 1.88 (m, 1 H) 1.96 - 2.01 (m, 1 H) 3.88 - 3.96 (m, 1 H) 4.03 - 4.09 (m, 1 H) 6.91 (d, <i>J</i>=8.20 Hz, 1 H) 7.41 (d, <i>J</i>=7.32 Hz, 1 H) 8.18 (s, 1 H). LCMS (ESI) 391 (M + H).

<i>tert</i>-butylN-[(1S,2S)-2-[[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl]amino]cyclopentyl]carbamate

0266<chemistry id="chem0111" num="0111"><img file="EP2632467B1_D0111.tif" /></chemistry>

0267<i>tert</i>-butylN-[(1S,2S)-2-[[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl]amino]cyclopentyl]carbamate was synthesized using similar experimental conditions to that used in the synthesis of (2S)-N2-[2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl]-4-methyl-pentane-1,2-diamine. 1H NMR (600 MHz, DMSO-<i>d</i>₆) δ ppm 1.13 (t, 6 H) 1.28 (s, 9 H) 1.42 - 1.52 (m, 2 H) 1.58 - 1.65 (m, 2 H) 1.81 - 1.90 (m, 1 H) 1.99 - 2.08 (m, 1 H) 3.49 - 3.60 (m, 2 H) 3.63 - 3.71 (m, 2 H) 3.84 - 3.93 (m, 1 H) 3.96 - 4.04 (m, 1 H) 5.53 (s, 1 H) 6.96 (d, <i>J</i>=7.90 Hz, 1 H) 7.34 (d, <i>J</i>=7.03 Hz, 1 H) 8.14 (s, 1 H). LCMS (ESI) 439 (M + H).

7-[(1S,2S)-2-(<i>tert</i>-butoxycarbonylamino)cyclopentyl]-2-chloro-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid

0268<chemistry id="chem0112" num="0112"><img file="EP2632467B1_D0112.tif" /></chemistry>

02697-[(1S,2S)-2-(<i>tert</i>-butoxycarbonylamino)cyclopentyl]-2-chloro-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid was synthesized using analogous synthetic sequence as that described for 7-[1-[(<i>tert</i>-butoxycarbonylamino)methyl]-2-methyl-propyl]-2-chloro-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid. 1H NMR (600 MHz, DMSO-<i>d</i>₆) δ ppm 1.41 - 1.52 (m, 9 H) 1.55 - 1.68 (m, 1 H) 1.88 - 2.00 (m, 2 H) 2.05 - 2.15 (m, 1 H) 2.26 - 2.35 (m, 1 H) 2.71 - 2.89 (m, 1 H) 4.01 - 4.16 (m, 1 H) 4.28 - 4.45 (m, 1 H) 7.41 (s, 1 H) 9.11 (s, 1 H). LCMS (ESI) 381 (M + H).

Intermediate 1N

0270Intermediate 1N was synthesized using an analogous synthetic sequence as that described for intermediate 1A. 1H NMR (600 MHz, DMSO-<i>d</i>₆) δ ppm 1.48 - 1.60 (m, 1 H) 1.88 - 1.98 (m, 3 H) 1.99 - 2.08 (m, 1 H) 2.66 - 2.75 (m, 1 H) 3.63 - 3.74 (m, 1 H) 3.99 - 4.12 (m, 1 H) 7.21 (s, 1 H) 8.89 (s, 1 H) 9.04 (s, 1 H). LCMS (ESI) 263 (M + H).

<u>Example 3 - Example Compounds</u>

Compound 1

0271<chemistry id="chem0113" num="0113"><img file="EP2632467B1_D0113.tif" /></chemistry>

0272To 0.050 g (0.225 mmole) chloro tricycliclactam in dioxane (2.0 mL) under nitrogen was added 5-(4-methylpiperazin-1-yl)pyridin-2-amine 0.052 g (1.2 eq, 0.270 mmole) followed by the addition ofPd₂(dba)₃ (18.5 mg), BINAP (25 mg) and sodium-<i>tert-</i>butoxide (31 mg , 0.324 mmole). The contents of the flask are degassed for 10 minutes and then heated to 100 degrees for 12 hours. The crude reaction was loaded on a silica gel column and eluted with DCM/MeOH (0- 15%) to afford the desired product (26 mg). To this compound dissolved in DCM/MeOH (10%) was added 3N HCl in iso-propanol (2 eq) and stirred overnight. Concentration under vacuum afforded the hydrochloride salt. ¹HNMR (d6-DMSO) 11.13 (brs, 1H), 9.07 (s, 1H), 8.42 (s, 1H), 8.03 (br m 1H), 7.99 (s, 1H), 7.67 (brm, 1H), 7.18 (s, 1H), 4.33 (m, 2H), 3.79 (m, 2H), 3.64 (m, 2H), 3.50 (m, 2H), 3.16 (m, 4H), 2.79 (s, 3H). LCMS (ESI) 379 (M + H)

Compound 2

0273<chemistry id="chem0114" num="0114"><img file="EP2632467B1_D0114.tif" /></chemistry>

0274To chloro tricycliclactam 0.075 g (0.338 mmole) in dioxane 3.5 mL under nitrogen was added <i>tert</i>-butyl 4-(6-amino-3-pyridyl)piperazine-1-carboxylate 0.098 g (1.05 eq) followed by the addition of Pd₂(dba)₃ (27 mg) and BINAP (36 mg) and sodium- <i>tert-</i>butoxide (45 mg). The contents were refluxed for 11 hrs. The crude reaction was loaded on a silica gel column and eluted with DCM/MeOH (0- 10 %) to afford the desired product (32 mg). ¹HNMR (d6-DMSO) 9.48 (s, 1H), 8.84 (s, 1H), 8.29 (s, 1H), 8.18 (s, 1H), 7.99 (s, 1H), 7.42 (m, 1H), 6.98 (s, 1H), 4.23 (m, 2H), 3.59 (m, 2H), 3.45 (m, 4H), 3.50 (m, 2H), 3.05 (m, 4H). LCMS (ESI) 465 (M + H)

Compound 3

0275<chemistry id="chem0115" num="0115"><img file="EP2632467B1_D0115.tif" /></chemistry>

0276To a solution of Compound 2 (23 mg) in 10% DCM/MeOH was added 10 mL of a 3M solution of HCl in iso-propanol. The contents were stirred overnight for 16 hrs. Concentration of the reaction mixture afforded the hydrochloride salt. ¹HNMR (d6-DMSO) 9.01 (s, 1H), 7.94 (m, 1H), 7.86 (m, 1H), 7.23 (s, 1H), 4.30 (m, 2H), 3.64 (m, 2H), 3.36 (m, 4H), 3.25 (m, 4H). LCMS (ESI) 465 (M + H)

Compound 4

0277<chemistry id="chem0116" num="0116"><img file="EP2632467B1_D0116.tif" /></chemistry>

0278To chloro-N-methyltricyclic amide 0.080 g (0.338 mmole) in dioxane 3.5 mL under nitrogen was added <i>tert</i>-butyl 4-(6-amino-3-pyridyl)piperazine-1-carboxylate 0.102 g (1.1 eq) followed by the addition ofPd₂(dba)₃ (27 mg), BINAP (36 mg) and sodium- <i>tert-</i>butoxide (45 mg). The contents were refluxed for 11 hrs. The crude product was purified using column chromatography with an eluent of dichloromethane/methanol (0- 5%) to afford the desired product (44 mg). ¹HNMR (d6-DMSO) 9.49 (s, 1H), 8.85 (s, 1H), 8.32 (m, 1H), 8.02 (s, 1H), 7.44 (m, 1H), 7.00 (s, 1H), 4.33 (m, 2H), 3.80 (m, 2H), 3.48 (m, 4H), 3.07 (m, 4H), 3.05 (s, 3H), 1.42 (s, 9H). LCMS (ESI) 479 (M + H)

Compound 5

0279<chemistry id="chem0117" num="0117"><img file="EP2632467B1_D0117.tif" /></chemistry>

0280To 32 mg of Compound 4 was added 10 mL 3N HCL in isopropanol and the contents stirred at room temperature overnight for 16 hrs. Concentration afforded the hydrochloride salt. ¹HNMR (d6-DMSO) 9.13 (m, 2H), 8.11 (m, 1H), 8.10 (s, 1H), 7.62 (m, 1H), 7.21 (s, 1H), 4.43 (m, 2H), 3.85 (m, 2H), 3.41 (m, 4H), 3.28 (m, 4H), 3.08 (s, 3H). LCMS (ESI) 379 (M + H)

Compound 6

0281<chemistry id="chem0118" num="0118"><img file="EP2632467B1_D0118.tif" /></chemistry> Compound 6 was synthesized using similar experimental conditions to that described for compound 2. 1H NMR (600 MHz, DMSO-<i>d</i>₆) δ ppm 0.79 (d, <i>J</i>=7.03 Hz, 3 H) 1.01 (d, <i>J</i>=6.73 Hz, 3 H) 1.35 - 1.48 (m, 9 H) 2.16 (dd, <i>J</i>=14.64, 6.73 Hz, 1 H) 3.00 - 3.14 (m, 4 H) 3.40 - 3.51 (m, 4 H) 3.51 - 3.60 (m, 1 H) 3.63 - 3.74 (m, 1 H) 4.44 (dd, <i>J</i>=7.90, 3.81 Hz, 1 H) 6.99 (s, 1 H) 7.46 (dd, <i>J</i>=8.93, 2.78 Hz, 1 H) 7.94 - 8.09 (m, 2 H) 8.31 (dd, <i>J</i>=9.08, 1.46 Hz, 1 H) 8.85 (s, 1 H) 9.46 (s, 1 H). LCMS (ESI) 507 (M + H).

Compound 7

0282<chemistry id="chem0119" num="0119"><img file="EP2632467B1_D0119.tif" /></chemistry>

0283Compound 7 was synthesized using similar experimental conditions to that described for compound 1 and was recovered as an HCl salt. 1H NMR (600 MHz, DMSO-<i>d</i>₆) δ ppm 0.77 - 0.86 (m, 3 H) 0.96 (d, <i>J</i>=7.03 Hz, 3 H) 2.10 - 2.24 (m, 1 H) 3.07 (s, 3 H) 3.37 - 3.79 (m, 8 H) 4.00 (dd, <i>J</i>=13.61, 4.54 Hz, 2 H) 4.63 - 4.73 (m, 1 H) 7.20 (s, 1 H) 7.58 - 7.71 (m, 1 H) 7.99 (d, <i>J</i>=2.34 Hz, 1 H) 8.12 (d, <i>J</i>=9.37 Hz, 1 H) 9.11 (s, 1 H) 9.41 (br. s., 2 H) 11.76 (br. s., 1 H). LCMS (ESI) 421 (M + H).

Compound 8

0284<chemistry id="chem0120" num="0120"><img file="EP2632467B1_D0120.tif" /></chemistry>

0285Compound 8 was synthesized using similar experimental conditions to that described for compounds 2 and 3 and was recovered as an HCl salt. The characterization data (NMR and LCMS) was consistent with that reported for compound 9.

Compound 9

0286<chemistry id="chem0121" num="0121"><img file="EP2632467B1_D0121.tif" /></chemistry>

0287Compound 9 was synthesized using similar experimental conditions to that described for compounds 2 and 3 and was recovered as an HCl salt. 1H NMR (600 MHz, DMSO-<i>d</i>₆) δ ppm 0.79 (d, <i>J</i>=6.73 Hz, 3 H) 1.01 (d, <i>J</i>=6.73 Hz, 3 H) 2.18 (dd, <i>J</i>=14.49, 7.17 Hz, 1 H) 3.18 - 3.84 (m, 10 H) 4.53 - 4.71 (m, 1 H) 7.24 (s, 1 H) 7.65 (d, <i>J</i>=9.37 Hz, 1 H) 8.01 (d, <i>J</i>=2.64 Hz, 1 H) 8.14 (d, <i>J</i>=1.46 Hz, 1 H) 8.35 (d, <i>J</i>=5.27 Hz, 1 H) 9.14 (s, 1 H) 9.46 (s, 2 H) 11.80 (s, 1 H) LCMS (ESI) 407 (M+H).

Compound 10

0288<chemistry id="chem0122" num="0122"><img file="EP2632467B1_D0122.tif" /></chemistry>

0289Compound 10 was synthesized using similar experimental conditions to that described for compounds 2 and 3 and was recovered as an HCl salt. 1H NMR (600 MHz, DMSO-<i>d</i>₆) δ ppm 0.77 (d, <i>J</i>=7.03 Hz, 3 H) 0.99 (d, <i>J</i>=6.73 Hz, 3 H) 2.10 - 2.24 (m, 1 H) 3.18 - 3.81 (m, 10 H) 4.54 - 4.69 (m, 1 H) 7.22 (s, 1 H) 7.63 (d, <i>J</i>=9.08 Hz, 1 H) 7.99 (d, <i>J</i>=2.63 Hz, 1 H) 8.11 (s, 1 H) 8.33 (d, <i>J</i>=5.27 Hz, 1 H) 9.12 (s, 1 H) 9.43 (s, 2 H) 11.77 (s, 1 H). LCMS (ESI) 407 (M+H).

Compound 11

0290<chemistry id="chem0123" num="0123"><img file="EP2632467B1_D0123.tif" /></chemistry>

0291Compound 11 was synthesized using similar experimental conditions to that described for compounds 2 and 3 and was recovered as an HCl salt. 1H NMR (600 MHz, DMSO-<i>d</i>₆) δ ppm 0.84 (d, <i>J</i>=6.73 Hz, 3 H) 0.98 (d, <i>J</i>=6.73 Hz, 3 H) 2.12 - 2.26 (m, 1 H) 3.09 (s, 3 H) 3.22 - 3.81 (m, 8 H) 4.01 (dd, <i>J</i>=13.61, 4.25 Hz, 2 H) 4.59 - 4.72 (m, 1 H) 7.19 (s, 1 H) 7.74 (s, 1 H) 7.96 - 8.10 (m, 2 H) 9.08 (s, 1 H) 9.22 (s, 2 H). LCMS (ESI) 421 (M+H).

Compound 12

0292<chemistry id="chem0124" num="0124"><img file="EP2632467B1_D0124.tif" /></chemistry>

0293Compound 12 was synthesized using similar experimental conditions to that described for compound 1 and was recovered as an HCl salt. 1H NMR (600 MHz, DMSO-<i>d</i>₆) δ ppm 0.85 (d, <i>J</i>=4.98 Hz, 3 H) 0.95 (d, <i>J</i>=4.98 Hz, 3 H) 1.42 - 1.70 (m, 3 H) 2.77 (d, <i>J</i>=2.93 Hz, 3 H) 3.07 - 4.14 (m, 10 H) 4.95 (s, 1 H) 7.20 (s, 1 H) 7.66 (d, <i>J</i>=9.66 Hz, 1 H) 7.94 (s, 1 H) 8.08 - 8.16 (m, 1 H) 8.33 (d, <i>J</i>=4.68 Hz, 1 H) 9.09 (s, 1 H) 11.38 (s, 1 H) 11.71 (s, 1 H). LCMS (ESI) 435 (M+H).

Compound 13

0294<chemistry id="chem0125" num="0125"><img file="EP2632467B1_D0125.tif" /></chemistry>

0295Compound 13 was synthesized using similar experimental conditions to that described for compounds 2 and 3 and was recovered as an HCl salt. 1H NMR (600 MHz, DMSO-<i>d</i>₆) δ ppm 0.87 (d, <i>J</i>=6.15 Hz, 3 H) 0.94 (d, <i>J</i>=6.15 Hz, 3 H) 1.57 (d, <i>J</i>=84.61 Hz, 3 H) 3.05 (s, 3 H) 3.13 - 3.55 (m, 8 H) 3.69 (d, <i>J</i>=78.17 Hz, 2 H) 4.90 (s, 1 H) 7.15 (s, 1 H) 7.63 - 7.85 (m, 1 H) 7.93 (s, 1 H) 8.26 (s, 1 H) 9.03 (s, 1 H) 9.20 (s, 2 H). LCMS (ESI) 421 (M+H).

Compound 14

0296<chemistry id="chem0126" num="0126"><img file="EP2632467B1_D0126.tif" /></chemistry>

0297Compound 14 was synthesized using similar experimental conditions to that described for compound 1 and was recovered as an HCl salt. 1H NMR (600 MHz, DMSO-<i>d</i>₆) δ ppm 0.85 (d, <i>J</i>=6.44 Hz, 3 H) 0.95 (d, <i>J</i>=6.44 Hz, 3 H) 1.43 - 1.70 (m, 3 H) 2.78 (d, <i>J</i>=2.93 Hz, 3 H) 3.05 (s, 3 H) 3.24 - 3.84 (m, 8 H) 4.01 (d, <i>J</i>=9.66 Hz, 2 H) 4.89 - 5.01 (m, 1 H) 7.15 (s, 1 H) 7.77 (s, 1 H) 7.91 - 8.05 (m, 2 H) 9.03 (s, 1 H) 10.96 - 11.55 (m, 2 H). LCMS (ESI) 449 (M+H).

Compound 15

0298<chemistry id="chem0127" num="0127"><img file="EP2632467B1_D0127.tif" /></chemistry>

0299Compound 15 was synthesized using similar experimental conditions to that described for compounds 2 and 3 and was recovered as an HCl salt. 1H NMR (600 MHz, DMSO-<i>d</i>₆) δ ppm 0.83 - 0.88 (d, <i>J</i>=6.15 Hz, 3 H) 0.95 (d, <i>J</i>=6.15 Hz, 3 H) 1.40 - 1.71 (m, 3 H) 3.28 - 3.83 (m, 8 H) 4.00 (d, <i>J</i>=3.22 Hz, 2 H) 4.91 - 5.08 (m, 1 H) 7.17 (s, 1 H) 7.68 (d, <i>J</i>=9.66 Hz, 1 H) 7.93 (s, 1 H) 8.07 (s, 1 H) 9.06 (s, 1 H) 9.40 (s, 2 H) 11.59 (s, 1 H). LCMS (ESI) 435 (M+H).

Compound 16

0300<chemistry id="chem0128" num="0128"><img file="EP2632467B1_D0128.tif" /></chemistry>

0301To intermediate IE 0.060 g (0.205 mmole) was added 5-(4-methylpiperazin-1-yl)pyridin-2-amine 35.42 mg (0.9 eq) followed by the addition of 1,4-dioxane (3 mL). After degassing with nitrogen, Pd₂dba₃ (12 mg), BINAP (16 mg) and sodium <i>tert</i>-butoxide (24 mg) were added. The contents were then heated at 90 degrees in a CEM Discovery microwave for 3 hrs. The reaction is then loaded over a silica gel column and purified by eluting with DCM/MeOH (0- 15%) to afford compound 16. 1H NMR (600 MHz, DMSO-<i>d</i>₆) δ ppm 0.75 (t, <i>J</i>=7.47 Hz, 3 H) 0.91 (d, <i>J</i>=6.73 Hz, 3 H) 1.04 - 1.20 (m, 2 H) 1.80 - 1.98 (m, 1 H) 2.77 (d, <i>J</i>=3.81 Hz, 3 H) 2.94 - 3.90 (m, 10 H) 4.54 - 4.68 (m, 1 H) 7.06 - 7.23 (m, 2 H) 7.56 - 7.75 (m, 1 H) 7.90 - 8.12 (m, 2 H) 8.29 (s, 1 H) 9.07 (s, 1 H) 10.98 - 11.74 (m, 2 H). LCMS (ESI) 435 (M + H).

Compound 17

0302<chemistry id="chem0129" num="0129"><img file="EP2632467B1_D0129.tif" /></chemistry>

0303Compound 17 was synthesized in a similar manner to that described for compound 16 followed by the deblocking step described for compound 3 and was converted to an HCl salt. 1H NMR (600 MHz, DMSO-<i>d</i>₆) δ ppm 0.75 (t, <i>J</i>=7.32 Hz, 3 H) 0.90 (d, <i>J</i>=6.73 Hz, 3 H) 1.07 - 1.15 (m, 2 H) 1.85 - 1.94 (m, 1 H) 3.17 - 3.75 (m, 10 H) 4.58 - 4.67 (m, 1 H) 7.17 (s, 1 H) 7.71 (s, 1 H) 7.96 (s, 1 H) 7.98 - 8.05 (m, 1 H) 8.28 (d, <i>J</i>=4.10 Hz, 1 H) 9.06 (s, 1 H) 9.39 (s, 2 H). LCMS (ESI) 421 (M+H).

Compound 18

0304<chemistry id="chem0130" num="0130"><img file="EP2632467B1_D0130.tif" /></chemistry>

0305Compound 18 was synthesized in a similar manner to that described for compound 16. 1H NMR (600 MHz, DMSO-<i>d</i>₆) δ ppm 0.78 (t, <i>J</i>=7.32 Hz, 3 H) 0.86 (d, J=6.73 Hz, 3 H) 1.13 - 1.21 (m, 2 H) 1.84 - 1.96 (m, 1 H) 2.77 (d, <i>J</i>=4.39 Hz, 3 H) 3.04 (s, 3 H) 3.11 - 3.84 (m, 8 H) 3.98 (dd, <i>J</i>=13.61, 4.25 Hz, 2 H) 4.66 - 4.74 (m, 1 H) 7.17 (s, 1 H) 7.64 (s, 1 H) 7.96 (d, <i>J</i>=2.34 Hz, 1 H) 8.03 - 8.13 (m, 1 H) 9.08 (s, 1 H) 11.26 (s, 1 H) 11.66 (s, 1 H). LCMS (ESI) 449 (M+H).

Compound 19

0306<chemistry id="chem0131" num="0131"><img file="EP2632467B1_D0131.tif" /></chemistry>

0307Compound 19 was synthesized in a similar manner to that described for compound 16 followed by the deblocking step described for compound 3 and was converted to an HCl salt. 1H NMR (600 MHz, DMSO-<i>d</i>₆) δ ppm 0.78 (t, <i>J</i>=7.32 Hz, 3 H) 0.85 (d, <i>J</i>=6.73 Hz, 3 H) 1.10 - 1.27 (m, 2 H) 1.82 - 1.99 (m, 1 H) 3.04 (s, 3 H) 3.28 - 3.77 (m, 8 H) 3.97 (dd, <i>J</i>=13.91, 4.54 Hz, 2 H) 4.62 - 4.75 (m, 1 H) 7.07 - 7.24 (m, 1 H) 7.62 - 7.75 (m, 1 H) 7.94 (d, <i>J</i>=2.34 Hz, 1 H) 7.97 - 8.08 (m, 1 H) 9.05 (s, 1 H) 9.29 (s, 2 H). LCMS (ESI) 435 (M+H).

Compound 20

0308<chemistry id="chem0132" num="0132"><img file="EP2632467B1_D0132.tif" /></chemistry>

0309Compound 20 was synthesized in a similar manner to that described for compound 16 followed by the deblocking step described for compound 3 and was converted to an HCl salt. 1H NMR (600 MHz, DMSO-<i>d</i>₆) δ ppm 0.96 (s, 9 H) 3.15 - 3.87 (m, 10 H) 4.42 - 4.53 (m, 1 H) 6.99 (s, 1 H) 7.24 (s, 1 H) 8.06 (s, 1 H) 8.11 - 8.21 (m, 1 H) 8.79 - 8.98 (m, 2 H) 9.25 (s, 2 H) 9.88 (s, 1 H). LCMS (ESI) 421 (M+H).

Compound 21

0310<chemistry id="chem0133" num="0133"><img file="EP2632467B1_D0133.tif" /></chemistry>

0311Compound 21 was synthesized in a similar manner to that described for compound 16 followed by the deblocking step described for compound 3 and was converted to an HCl salt. 1H NMR (600 MHz, DMSO-<i>d</i>₆) δ ppm 0.95 (s, 9 H) 2.79 (d, <i>J</i>=4.10 Hz, 3 H) 3.06 - 3.86 (m, 10 H) 4.56 - 4.67 (m, 1 H) 7.17 (s, 1 H) 7.70 (s, 1 H) 7.96 (d, <i>J</i>=2.63 Hz, 1 H) 7.99 - 8.08 (m, 1 H) 8.26 (s, 1 H) 9.06 (s, 1 H) 10.80 (s, 1 H). LCMS (ESI) 435 (M+H).

Compound 22

0312<chemistry id="chem0134" num="0134"><img file="EP2632467B1_D0134.tif" /></chemistry>

0313Compound 22 was synthesized in a similar manner to that described for compound 16 and was converted to an HCl salt. 1H NMR (600 MHz, DMSO-<i>d</i>₆) δ ppm 2.75 - 2.81 (m, 3 H) 3.12 - 3.16 (m, 2 H) 3.46 - 3.54 (m, 4 H) 3.60 - 3.69 (m, 2 H) 3.72 - 3.79 (m, 1 H) 4.07 - 4.18 (m, 2 H) 6.06 - 6.09 (m, 1 H) 6.90 (d, <i>J</i>=7.61 Hz, 2 H) 7.20 - 7.31 (m, 3 H) 7.33 (s, 1 H) 7.49 - 7.55 (m, 1 H) 7.62 - 7.70 (m, 1 H) 7.92 (d, <i>J</i>=2.93 Hz, 1 H) 8.22 (s, 1 H) 9.14 (s, 1 H). LCMS (ESI) 455 (M + H).

Compound 23

0314<chemistry id="chem0135" num="0135"><img file="EP2632467B1_D0135.tif" /></chemistry>

0315Compound 23 was synthesized in a similar manner to that described for compound 16 followed by the deblocking step described for compound 3 and was converted to an HCl salt. 1H NMR (600 MHz, DMSO-<i>d</i>₆) δ ppm 3.21 (s, 4 H) 3.35 - 3.67 (m, 5 H) 4.07 - 4.20 (m, 2 H) 6.13 (s, 1 H) 6.90 (d, <i>J</i>=7.32 Hz, 2 H) 7.22 - 7.31 (m, 3 H) 7.36 (s, 1 H) 7.48 (d, <i>J</i>=9.37 Hz, 1 H) 7.93 (d, <i>J</i>=2.34 Hz, 1 H) 8.04 - 8.11 (m, 1 H) 8.25 (d, <i>J</i>=4.98 Hz, 1 H) 9.17 (s, 1 H) 11.77 (br, s., 1H). LCMS (ESI) 441 (M + H).

Compound 24

0316<chemistry id="chem0136" num="0136"><img file="EP2632467B1_D0136.tif" /></chemistry>

0317Compound 24 was synthesized in a similar manner to that described for compound 16 followed by the deblocking step described for compound 3 and was converted to an HCl salt. 1H NMR (600 MHz, DMSO-<i>d</i>₆) δ ppm 0.90 (d, <i>J</i>=6.15 Hz, 6 H) 1.72 - 1.89 (m, 1 H) 3.15 - 3.92 (m, 9 H) 4.10 - 4.46 (m, 2 H) 7.18 (s, 1 H) 7.59 (d, <i>J</i>=8.78 Hz, 1 H) 8.00 (s, 1 H) 8.13 (d, <i>J</i>=9.37 Hz, 1 H) 8.55 (s, 1 H) 9.09 (s, 1 H) 9.67 (s, 2 H) 11.91 (s, 1 H). LCMS (ESI) 407 (ESI).

Compound 25

0318<chemistry id="chem0137" num="0137"><img file="EP2632467B1_D0137.tif" /></chemistry>

0319Compound 25 was synthesized in a manner similar to compound 24 and was converted to an HCl salt. The characterization data (NMR and LCMS) was similar to that obtained for the antipode compound 24.

Compound 26

0320<chemistry id="chem0138" num="0138"><img file="EP2632467B1_D0138.tif" /></chemistry>

0321Compound 26 was synthesized in a similar manner to that described for compound 16 followed by the deblocking step described for compound 3 and was converted to an HCl salt. 1H NMR (600 MHz, DMSO-<i>d</i>₆) δ ppm 1.78 (s, 6 H) 3.40 - 3.53 (m, 6 H) 3.64 - 3.73 (m, 4 H) 7.27 (s, 1 H) 7.66 (d, <i>J</i>=9.37 Hz, 1 H) 7.98 (d, <i>J</i>=2.34 Hz, 1 H) 8.12 (br. s., 1 H) 8.47 (br. s., 1 H) 9.11 (s, 1 H) 9.45 (br. s., 2 H) 11.62 (br. s., 1 H). LCMS (ESI) 393 (M + H).

Compound 27

0322<chemistry id="chem0139" num="0139"><img file="EP2632467B1_D0139.tif" /></chemistry>

0323Compound 27 was synthesized in a similar manner to that described for compound 16 and was converted to an HCl salt. 1H NMR (600 MHz, DMSO-<i>d</i>₆) δ ppm 1.47 (br. s., 6 H) 1.72 (br. s., 2 H) 1.92 (br. s., 2 H) 2.77 (br. s., 3 H) 3.18 (br. s., 2 H) 3.46 (br. s., 2 H) 3.63 (br. s., 2 H) 3.66 (d, <i>J</i>=6.15 Hz, 2 H) 3.80 (br. s., 2 H) 7.25 (s, 1 H) 7.63 (br. s., 2 H) 7.94 (br. s., 1 H) 8.10 (br. s., 1 H) 8.39 (br. s., 1 H) 9.08 (br. s., 1 H) 11.59 (br. s., 1 H). LCMS (ESI) 447 (M + H).

Compound 28

0324<chemistry id="chem0140" num="0140"><img file="EP2632467B1_D0140.tif" /></chemistry>

0325Compound 28 was synthesized in a similar manner to that described for compound 16 followed by the deblocking step described for compound 3 and was converted to an HCl salt. 1H NMR (600 MHz, DMSO-<i>d</i>₆) δ ppm 1.27 - 1.64 (m, 6 H) 1.71 (br. s., 2 H) 1.91 (br. s., 2 H) 2.80 (br. s., 1 H) 3.17 - 3.24 (m, 2 H) 3.41 (br. s., 4 H) 3.65 (br. s., 4 H) 7.26 (br. s., 1 H) 7.63 (br. s., 1 H) 7.94 (br. s., 1 H) 8.13 (br. s., 1 H) 8.40 (br. s., 1 H) 9.09 (br. s., 1 H) 9.62 (br. s., 1 H) 11.71 (br. s., 1 H). LCMS (ESI) 433 (M + H).

Compound 29

0326<chemistry id="chem0141" num="0141"><img file="EP2632467B1_D0141.tif" /></chemistry>

0327Compound 29 was synthesized using similar conditions to that described for compound 16 and was converted to an HCl salt. 1H NMR (600 MHz, DMSO-<i>d</i>₆) δ ppm 1.64 - 1.75 (m, 2 H) 1.83 - 1.92 (m, 2 H) 1.96 - 2.06 (m, 2 H) 2.49 - 2.58 (m, 2 H) 2.79 (d, <i>J</i>=3.81 Hz, 3 H) 3.06 - 3.18 (m, 4 H) 3.59 - 3.69 (m, 2 H) 3.73 - 3.83 (m, 2 H) 4.04 - 4.12 (m, 2 H) 7.17 (br. s., 1 H) 7.60 - 7.70 (m, 2 H) 7.70 - 7.92 (m, 2 H) 7.96 (br. s., 1 H) 8.41 (br. s., 1 H) 8.98 (br. s., 1 H) 10.77 (br. s., 1 H). LCMS (ESI) 433 (M + H).

Compound 30

0328<chemistry id="chem0142" num="0142"><img file="EP2632467B1_D0142.tif" /></chemistry>

0329Compound 30 was synthesized in a similar manner to that described for compound 16 followed by the deblocking step described for compound 3 and was converted to an HCl salt. 1H NMR (600 MHz, DMSO-<i>d</i>₆) δ ppm 1.64 - 1.75 (m, 2 H) 1.84 - 1.92 (m, 2 H) 1.96 - 2.05 (m, 2 H) 2.48 - 2.56 (m, 2 H) 3.22 (br. s., 4 H) 3.42 - 3.48 (m, 4 H) 3.60 - 3.69 (m, 2 H) 4.05 - 4.13 (m, 1 H) 7.18 (s, 1 H) 7.65 (d, <i>J</i>=13.47 Hz, 1 H) 7.70 - 7.77 (m, 1 H) 7.94 (d, <i>J</i>=1.76 Hz, 1 H) 8.42 (br. s., 1 H) 9.00 (s, 1 H) 9.15 (br. s., 2 H). LCMS (ESI) 419 (M + H).

Compound 31

0330<chemistry id="chem0143" num="0143"><img file="EP2632467B1_D0143.tif" /></chemistry>

0331Compound 31 was synthesized in a similar manner to that described for compound 16 followed by the deblocking step described for compound 3 and was converted to an HCl salt. 1H NMR (600 MHz, DMSO-<i>d</i>₆) δ ppm 1.76 (br. s., 2 H) 1.89 (br. s., 2 H) 2.03 (br. s., 2 H) 2.47 - 2.58 (m, 2 H) 3.04 (s, 3 H) 3.22 (br. s., 4 H) 3.39 (br. s., 4 H) 3.66 (s, 2 H) 7.21 (s, 1 H) 7.67 (d, <i>J</i>=9.37 Hz, 1 H) 7.93 (br. s., 1 H) 7.98 - 8.09 (m, 1 H) 9.04 (s, 1 H) 9.34 (br. s., 2 H) 11.31 (br. s., 1 H). LCMS (ESI) 433 (M + H).

Compound 32

0332<chemistry id="chem0144" num="0144"><img file="EP2632467B1_D0144.tif" /></chemistry>

0333Compound 32 was synthesized using similar conditions to that described for compound 16 and was converted to an HCl salt. 1H NMR (600 MHz, DMSO-<i>d</i>₆) δ ppm 1.66 - 1.77 (m, 2 H) 1.84 - 1.94 (m, 2 H) 1.96 - 2.08 (m, 2 H) 2.48 - 2.57 (m, 2 H) 3.36 - 3.52 (m, 4 H) 3.60 - 3.80 (m, 6 H) 7.21 (s, 1 H) 7.53 - 7.74 (m, 2 H) 7.86 (s, 1 H) 8.02 (s, 1 H) 8.45 (s, 1 H) 9.03 (s, 1 H) 11.19 (br. s., 1 H). LCMS (ESI) 420 (M+H).

Compound 33

0334<chemistry id="chem0145" num="0145"><img file="EP2632467B1_D0145.tif" /></chemistry>

0335Compound 33 was synthesized using similar conditions to that described for compound 16 and was converted to an HCl salt. 1H NMR (600 MHz, DMSO-<i>d</i>₆) δ ppm 1.65 - 1.79 (m, 2 H) 1.85 - 1.95 (m, 2 H) 1.97 - 2.08 (m, 2 H) 2.47 - 2.54 (m, 2 H) 3.40 - 3.58 (m, 5 H) 3.65 (dd, <i>J</i>=21.67, 5.56 Hz, 1 H) 3.69 - 3.78 (m, 4 H) 7.24 (s, 1 H) 7.97 - 8.17 (m, 2 H) 8.48 (s, 1 H) 9.08 (s, 1 H) 11.81 (s, 1 H). LCMS (ESI) 421 (M+H).

Compound 34

0336<chemistry id="chem0146" num="0146"><img file="EP2632467B1_D0146.tif" /></chemistry>

0337Compound 34 was synthesized using similar conditions to that described for compound 16 and was converted to an HCl salt. 1H NMR (600 MHz, DMSO-<i>d</i>₆) δ ppm 1.55 - 1.74 (m, 2 H) 1.80 - 1.98 (m, 4 H) 2.48 - 2.60 (m, 2 H) 3.40 - 3.50 (m, 4 H) 3.57 - 3.72 (m, 2 H) 3.90 - 4.20 (m, 4 H) 7.08 (s, 1 H) 7.37 - 7.57 (m, 2 H) 7.70 (m, 2 H) 8.32 (s, 1 H) 8.88 (s, 1 H) 9.98 (s, 1 H). LCMS (ESI) 419 (M+H).

Compound 35

0338<chemistry id="chem0147" num="0147"><img file="EP2632467B1_D0147.tif" /></chemistry>

0339Compound 35 was synthesized using similar conditions to that described for compound 16 and was converted to an HCl salt. 1H NMR (600 MHz, DMSO-<i>d</i>₆) δ ppm 1.30 (d, <i>J</i>=5.27 Hz, 6 H) 1.65 - 1.78 (m, 2 H) 1.83 - 1.95 (m, 2 H) 1.97 - 2.10 (m, 2 H) 2.45 - 2.55 (m, 2H) 3.25 - 3.36 (m, 1 H) 3.39 - 3.48 (m, 4 H) 3.60 - 3.70 (m, 4 H) 3.75 - 4.15 (m, 2 H) 7.24 (s, 1 H) 7.54 - 7.75 (m, 2 H) 7.95 (s, 1 H) 8.10 (s, 1 H) 8.49 (s, 1 H) 9.07 (s, 1 H) 11.25 (s, 1 H) 11.48 (s, 1 H). LCMS (ESI) 461 (M+H).

Compound 36

0340<chemistry id="chem0148" num="0148"><img file="EP2632467B1_D0148.tif" /></chemistry>

0341Compound 36 was synthesized using similar conditions to that described for compound 16 and was converted to an HCl salt. 1H NMR (600 MHz, DMSO-<i>d</i>₆) δ ppm 0.99 (d, <i>J</i>=6.15 Hz, 6 H) 1.65 - 1.78 (m, 2 H) 1.90 (m, 2 H) 1.97 - 2.08 (m, 2 H) 2.08 - 2.17 (m, 1 H) 2.45 - 2.55 (m, 2H) 2.88 - 3.02 (m, 2 H) 3.33 - 3.48 (m, 4 H) 3.50 - 3.90 (m, 6 H) 7.24 (s, 1 H) 7.67 (s, 2 H) 7.94 (s, 1 H) 8.12 (s, 1 H) 8.49 (s, 1 H) 9.07 (s, 1 H) 10.77 (s, 1 H) 11.51 (s, 1 H). LCMS (ESI) 475 (M+H).

Compound 37

0342<chemistry id="chem0149" num="0149"><img file="EP2632467B1_D0149.tif" /></chemistry>

0343Compound 37 was synthesized using similar conditions to that described for compound 16 and was converted to an HCl salt. 1H NMR (600 MHz, DMSO-<i>d</i>₆) δ ppm 1.13 (d, <i>J</i>=5.86 Hz, 6 H) 1.66 - 1.77 (m, 2 H) 1.84 - 1.94 (m, 2 H) 1.97 - 2.09 (m, 2 H) 2.40 - 2.53 (m, 2 H) 3.37 - 3.49 (m, 2 H) 3.50 - 3.59 (m, 2 H) 3.59 - 3.73 (m, 4 H) 7.23 (s, 1 H) 7.64 (m, 3 H) 7.85 (s, 1 H) 8.11 (s, 1 H) 8.47 (s, 1 H) 9.05 (s, 1 H). 11.35 (br s., 1H). LCMS (ESI) 448 (M+H).

Compound 38

0344<chemistry id="chem0150" num="0150"><img file="EP2632467B1_D0150.tif" /></chemistry>

0345Compound 38 was synthesized using similar conditions to that described for compound 16 and was converted to an HCl salt. 1H NMR (600 MHz, DMSO-<i>d</i>₆) δ ppm 1.50 - 1.57 (m, 2 H) 1.62 - 1.68 (m, 3 H) 1.68 - 1.75 (m, 2 H) 1.84 - 1.92 (m, 2 H) 1.97 - 2.08 (m, 2 H) 2.48 - 2.53 (m, 2 H) 3.14 - 3.23 (m, 4 H) 3.43 - 3.47 (m, 2 H) 3.58 - 3.70 (m, 2 H) 7.22 (s, 1 H) 7.58 - 7.70 (m, 2 H) 7.85 - 8.00 (m, 1 H) 8.16 (d, 1 H) 8.46 (s, 1 H) 9.04 (s, 1 H) 11.37 (br s., 1H). LCMS (ESI) 418 (M + H).

Compound 39

0346<chemistry id="chem0151" num="0151"><img file="EP2632467B1_D0151.tif" /></chemistry>

0347Compound 39 was synthesized using similar conditions to that described for compound 16 and was converted to an HCl salt. 1H NMR (600 MHz, DMSO-<i>d</i>₆) δ ppm 1.72 (s, 2 H) 1.90 (s, 4 H) 2.03 (s, 2 H) 2.21 (s, 2 H) 2.48 - 2.54 (m, 2 H) 2.73 (s, 2 H) 3.03 (s, 2 H) 3.25 - 3.35 (m, 1 H) 3.38 - 3.48 (m, 4 H) 3.65 - 3.99 (m, 5 H) 7.23 (s, 1 H) 7.63 (d, <i>J</i>=9.66 Hz, 1 H) 7.90 (s, 1 H) 8.13 (s, 1 H) 8.47 (s, 1 H) 9.06 (s, 1 H) 10.50 (br s., 1H). LCMS (ESI) 503 (M + H).

Compound 40

0348<chemistry id="chem0152" num="0152"><img file="EP2632467B1_D0152.tif" /></chemistry>

0349Compound 40 was synthesized using similar conditions to that described for compound 16 and was converted to an HCl salt. 1H NMR (600 MHz, DMSO-<i>d</i>₆) δ ppm 1.63 - 1.85 (m, 6 H) 1.87 - 1.92 (m, 2 H) 1.99 - 2.06 (m, 2 H) 2.15 - 2.23 (m, 2 H) 2.47 - 2.53 (m, 1 H) 2.69 - 2.79 (m, 2 H) 2.81 - 2.91 (m, 2 H) 2.98 - 3.08 (m, 2 H) 3.32 - 3.48 (m, 4 H) 3.57 - 3.72 (m, 4 H) 3.77 - 3.85 (m, 2 H) 7.22 (s, 1 H) 7.60 - 7.68 (m, 2 H) 7.90 (s, 1 H) 8.07 (s, 1 H) 8.46 (s, 1 H) 9.04 (s, 1 H). 11.41 (br s., 1H). LCMS (ESI) 501 (M + H).

Compound 41

0350<chemistry id="chem0153" num="0153"><img file="EP2632467B1_D0153.tif" /></chemistry>

0351Compound 41 was synthesized using similar conditions to that described for compound 16 and was converted to an HCl salt. 1H NMR (600 MHz, DMSO-<i>d</i>₆) δ ppm 1.64 - 1.76 (m, 2 H) 1.87 - 1.93 (m, 2 H) 2.00 - 2.07 (m, 2 H) 2.48 - 2.53 (m, 2 H) 2.67 - 2.72 (m, 4 H) 3.44 - 3.47 (m, 2 H) 3.50 - 3.55 (m, 4 H) 7.24 (s, 1 H) 7.61 (d, <i>J</i>=9.37 Hz, 2 H) 7.86 (d, <i>J</i>=2.63 Hz, 1 H) 8.09 (d, <i>J</i>=12.88 Hz, 1 H) 8.48 (s, 1 H) 9.06 (s, 1 H) 11.41 (br s., 1H). LCMS (ESI) 436 (M + H).

Compound 42

0352<chemistry id="chem0154" num="0154"><img file="EP2632467B1_D0154.tif" /></chemistry>

0353Compound 42 was synthesized using similar conditions to that described for compound 16 and was converted to an HCl salt. 1H NMR (600 MHz, DMSO-<i>d</i>₆) δ ppm 1.29 (d, <i>J</i>=6.73 Hz, 6 H) 1.66 - 1.79 (m, 2 H) 1.84 - 1.95 (m, 2 H) 1.98 - 2.09 (m, 2 H) 2.46 - 2.55 (m, 2 H) 3.29 - 3.39 (m, 2H) 3.58 - 3.70 (m, 4H) 3.77 - 3.86 (m, 4H) 7.24 (s, 1 H) 7.66 (d, J=9.37 Hz, 1 H) 7.96 (d, <i>J=</i>2.93 Hz, 1 H) 8.08 (s, 1 H) 8.48 (s, 1 H) 9.06 (s, 1 H) 9.28 (s, 1 H) 9.67 (s, 1 H) 11.36 (s, 1H). LCMS (ESI) 447 (M + H).

Compound 43

0354<chemistry id="chem0155" num="0155"><img file="EP2632467B1_D0155.tif" /></chemistry>

0355Compound 43 was synthesized using similar conditions to that described for compound 16 and was converted to an HCl salt. 1H NMR (600 MHz, DMSO-<i>d</i>₆) δ ppm 1.73 (s, 2 H) 1.76 - 1.85 (m, 2 H) 1.85 - 1.94 (m, 2 H) 1.98 - 2.07 (m, 2 H) 2.19 - 2.26 (m, 2 H) 2.48 - 2.52 (m, 1 H) 2.70 - 2.81 (m, 4 H) 3.13 - 3.20 (m, 1 H) 3.30 - 3.48 (m, 3 H) 3.58 - 3.71 (m, 4 H) 3.78 - 3.84 (m, 4 H) 7.24 (s, 1 H) 7.62 (d, <i>J</i>=9.37 Hz, 2 H) 7.89 (d, <i>J</i>=1.17 Hz, 1 H) 8.09 - 8.18 (m, 1 H) 8.48 (s, 1 H) 9.06 (s, 1 H) 11.46 (br s., 1H). LCMS (ESI) 519 (M + H).

Compound 44

0356<chemistry id="chem0156" num="0156"><img file="EP2632467B1_D0156.tif" /></chemistry>

0357Compound 44 was synthesized using similar conditions to that described for compound 16 followed by the deblocking step described for compound 3 and was converted to an HCl salt. 1H NMR (600 MHz, DMSO-<i>d</i>₆) δ ppm 1.65 - 1.75 (m, 2 H) 1.85 - 1.93 (m, 2 H) 1.93 - 1.99 (m, 1 H) 2.00 - 2.06 (m, 2 H) 2.08 - 2.14 (m, 1 H) 2.47 - 2.55 (m, 2 H) 3.07 - 3.25 (m, 2 H) 3.25 - 3.69 (m, 5 H) 4.46 (s, 1 H) 4.67 (s, 1 H) 7.22 (s, 1 H) 7.58 - 7.69 (m, 2 H) 8.46 (s, 1 H) 9.02 (s, 1 H) 9.34 (s, 1 H) 9.65 (s, 1 H). LCMS (ESI) 431 (M + H).

Compound 45

0358<chemistry id="chem0157" num="0157"><img file="EP2632467B1_D0157.tif" /></chemistry>

0359Compound 45 was synthesized using similar conditions to that described for compound 16 and was converted to an HCl salt. 1H NMR (600 MHz, DMSO-<i>d</i>₆) δ ppm 1.65 - 1.82 (m, 3 H) 1.89 (br. s., 2 H) 1.98 - 2.08 (m, 2 H) 2.13 (br. s., 2 H) 2.47 - 2.55 (m, 2 H) 2.68 (d, <i>J</i>=4.98 Hz, 6 H) 2.71 - 2.80 (m, 2 H) 3.29 - 3.71 (m, 10 H) 7.16 - 7.26 (m, 1 H) 7.67 (d, <i>J</i>=9.66 Hz, 2 H) 7.91 (d, <i>J</i>=2.05 Hz, 1 H) 8.14 (br. s., 1 H) 8.48 (br. s., 1 H) 9.05 (s, 1 H) 11.14 (br. s., 1 H) 11.43 (br. s., 1 H). LCMS (ESI) 461 (M + H).

Compound 46

0360<chemistry id="chem0158" num="0158"><img file="EP2632467B1_D0158.tif" /></chemistry>

0361Compound 46 was synthesized in a manner similar to that described for compounds 2 and 3 and was recovered as an HCl salt. The analytical data was consistent with that described for the antipode compound 13.

Compound 47

0362<chemistry id="chem0159" num="0159"><img file="EP2632467B1_D0159.tif" /></chemistry>

0363Compound 47 was synthesized in a manner similar to that described for compounds 2 and 3 and was recovered as an HCl salt. The analytical data was consistent with that described for the antipode compound 15.

Compound 48

0364<chemistry id="chem0160" num="0160"><img file="EP2632467B1_D0160.tif" /></chemistry>

0365Compound 48 was synthesized in a similar manner to that described for compound 16 and then converted to its hydrochloride salt. 1H NMR (600 MHz, DMSO-<i>d</i>₆) δ ppm 1.50 - 1.65 (m, 1 H) 1.92 - 2.02 (m, 3 H) 2.06 - 2.15 (m, 1 H) 2.78 (d, <i>J</i>=3.81 Hz, 4 H) 3.10 - 3.20 (m, 4 H) 3.47 - 3.51 (m, 2 H) 3.64 - 3.71 (m, 1 H) 3.76 - 3.83 (m, 2 H) 3.98 - 4.14 (m, 1 H) 7.20 (s, 2 H) 7.77 (s, 1 H) 7.97 (s, 2 H) 8.81 (s, 1 H) 9.03 (s, 1 H) 10.97 (br s., 1H). LCMS (ESI) 419 (M + H).

Compound 49

0366<chemistry id="chem0161" num="0161"><img file="EP2632467B1_D0161.tif" /></chemistry> Compound 49 was synthesized in a similar manner to that described for compound 16 and then converted to its hydrochloride salt. 1H NMR (600 MHz, DMSO-<i>d</i>₆) δ ppm 1.54 - 1.59 (m, 1 H) 1.92 - 2.01 (m, 3 H) 2.06 - 2.15 (m, 1 H) 2.76 - 2.84 (m, 1 H) 3.17 - 3.24 (m, 6 H) 3.64 - 3.71 (m, 2 H) 4.02 - 4.11 (m, 2 H) 7.22 (s, 2 H) 7.64 (s, 1 H) 7.97 (s, 2 H) 8.75 (s, 1 H) 8.97 (s, 1 H) 9.21 (s, 1 H). LCMS (ESI) 405 (M + H).

Compound 50

0367<chemistry id="chem0162" num="0162"><img file="EP2632467B1_D0162.tif" /></chemistry>

<u>Biological Activity</u>

0368Kinase enzymatic reactions were performed in 384-well microplates using a 12-channel Caliper LabChip instrument as a detection device. The enzymatic phosphorylation of a peptide results in a change in net charge, enabling electrophoretic separation of product from substrate. As substrate and product are separated, two peaks of fluorescence are observed. Change in the relative fluorescence intensity of the substrate and product peaks is the parameter measured, reflecting enzyme activity. In the presence of an inhibitor, the ratio between product and substrate is altered. The signal of the product decreases, while the signal of the substrate increases.

0369For the measurement of CDK2/cyclinE activity, enzyme (0.22 nM) was incubated with 100 mM ATP and the phosphoacceptor substrate peptide (1 mM) for one hour. For the measurement of CDK4/CyclinD activity, enzyme (0.85 nM) was incubated with 200 mM ATP and the phosphoacceptor substrate peptide (1 mM) for three hours. Potential inhibitor compounds (as HCl salts) were tested using 12-point dose response curves in single point at the K_m for ATP. The IC₅₀ of each compound was determined using GraphPad Prism. Results from the IC₅₀ values demonstrate 200 and 100 fold selectivity for compounds Compound 1 and Compound 3 for Cdk4/CycD1 over Cdk2/CycE respectively. Results are provided in Table 1. <tables id="tabl0001" num="0001"><table frame="all"><title><b>Table 1.</b></title><tgroup cols="5"><colspec colnum="1" colname="col1" colwidth="27mm" /><colspec colnum="2" colname="col2" colwidth="19mm" /><colspec colnum="3" colname="col3" colwidth="41mm" /><colspec colnum="4" colname="col4" colwidth="20mm" /><colspec colnum="5" colname="col5" colwidth="41mm" /><thead><row><entry valign="top"><b>Compound</b></entry><entry namest="col2" nameend="col3" align="center" valign="top"><b>CDK2</b>/<b>cyclinE</b></entry><entry namest="col4" nameend="col5" align="center" valign="top"><b>CDK4</b>/<b>cyclinD</b></entry></row><row><entry align="center" valign="top" /><entry align="center" valign="top"><b>IC₅₀ (µM)</b></entry><entry align="center" valign="top"><b>Confidence Interval 95%</b></entry><entry align="center" valign="top"><b>IC₅₀ (µM</b>)</entry><entry align="center" valign="top"><b>Confidence Interval 95%</b></entry></row></thead><tbody><row><entry><b>staurosporine</b></entry><entry>0.00393</entry><entry>0.000706</entry><entry>0.0375</entry><entry>0.99</entry></row><row><entry><b>Compound 1</b></entry><entry>>100</entry><entry /><entry>0.453</entry><entry>0.85</entry></row><row><entry><b>Compound 3</b></entry><entry>>100</entry><entry /><entry>1.05</entry><entry>0.78</entry></row></tbody></tgroup></table></tables>

0370Additional CDK2/cyclinE data is provided in Table 2. IC₅₀ data is as follows: A - 0.001-0.010 µM; B - 0.010-0.100 µM; C - 0.100-1 µM; D - 1-100 µM; and E - >100 µM. Data is also shown for known CDK4/6 inhibitor, PD0332991. <tables id="tabl0002" num="0002"><img file="EP2632467B1_D0163.tif" /></tables><tables id="tabl0003" num="0003"><img file="EP2632467B1_D0164.tif" /></tables>

<u>Pharmaceutical Compositions</u>

0371In one embodiment a pharmaceutical composition comprising compounds of the invention is provided. In a first aspect, the pharmaceutical composition further comprises one or more pharmaceutically acceptable excipients or vehicles, and optionally other therapeutic and/or prophylactic ingredients. Such excipients are known to those of skill in the art. The compounds of the present invention include, without limitation, basic compounds such as free bases. A thorough discussion of pharmaceutically acceptable excipients and salts is available in Remington's Pharmaceutical Sciences, 18th Edition (Easton, Pennsylvania: Mack Publishing Company, 1990).

0372Depending on the intended mode of administration, the pharmaceutical compositions may be in the form of solid, semi-solid or liquid dosage forms, such as, for example, tablets, suppositories, pills, capsules, powders, liquids, suspensions, creams, ointments, lotions or the like, preferably in unit dosage form suitable for single administration of a precise dosage. The compositions will include an effective amount of the selected drug in combination with a pharmaceutically acceptable carrier and, in addition, may include other pharmaceutical agents, adjuvants, diluents, buffers, etc.

0373The invention includes a pharmaceutical composition comprising a compound of the present invention including isomers, racemic or non-racemic mixtures of isomers, or pharmaceutically acceptable salts or solvates thereof together with one or more pharmaceutically acceptable carriers and optionally other therapeutic and/or prophylactic ingredients.

0374For solid compositions, conventional nontoxic solid carriers include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose, magnesium carbonate and the like.

0375For oral administration, the composition will generally take the form of a tablet, capsule, a softgel capsule nonaqueous solution, suspension or syrup. Tablets and capsules are preferred oral administration forms. Tablets and capsules for oral use will generally include one or more commonly used carriers such as lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. When liquid suspensions are used, the active agent may be combined with emulsifying and suspending agents. If desired, flavoring, coloring and/or sweetening agents may be added as well. Other optional components for incorporation into an oral formulation herein include, but are not limited to, preservatives, suspending agents, thickening agents and the like.

0376The pharmaceutical composition or combination of the present invention can be in unit dosage of about 1-1000 mg of active ingredient(s) for a subject of about 50-70 kg, or about 1-500 mg or about 1-250 mg or about 1-150 mg or about 0.5-100 mg, or about 1-50 mg of active ingredients. The therapeutically effective dosage of a compound, the pharmaceutical composition, or the combinations thereof, is dependent on the species of the subject, the body weight, age and individual condition, the disorder or disease or the severity thereof being treated. A physician, clinician or veterinarian of ordinary skill can readily determine the effective amount of each of the active ingredients necessary to prevent, treat or inhibit the progress of the disorder or disease.