PT2632467T

Cdk inhibitors

Abstract

This record has no abstract on file.

PT2632467T, drawing sheet 1 — Sheet 1 of 171

Term

5.1 yearsto projected expiry

Projected expiry 25 October 2031, counted from filing; an application has no term until it is granted.

16 claims: 9 independent, 7 dependent

1
REIVINDICAÇÕES Um composto possuindo fórmula Ia:ou possuindo ou possuindo fórmula Id Ou possuindo fórmula If: Ou possuindo fórmula lg: Ou possuindo fórmula Ij: ou um sal farmaceuticamente aceitável relacionado onde R é H, C1-C3 alquilo ou haloalquilo;cada R 1 é independentemente arilo, alquilo, cicloalquilo ou haloalquilo, onde cada um dos referidos grupos alquilo, cicloalquilo e haloalquilo inclui opcionalmente heteroátomos 0 ou N no lugar de um átomo de carbono na cadeia e dois R 1 ' s em átomos do anel adjacentes ou no mesmo átomo do anel conjuntamente com os átomos do anel aos quais se encontram ligados, opcionalmente formando um composto carbocíclico e 3- a 8-membros;y é 0, 1, 2, 3 ou 4;cada X é independentemente CH ou N;e R 2 é selecionado das estruturas: Γ”χ. 'χ, X-·Η Ν' k χ” ,Ν-Od ΐ Ί y Axx •·Ν·' X.·· Η s x·' y k Α Α xy xy ·\χ k ζ»Χ· · Χ ^ΟΗ ,ΖΧ ? Ί Α Χ 5 y μ X, ». ν Αχ X χχ,/χ χ h Χ· xy „ΝΚ \Ζ ΑΧ Xy* ^ χ νΆΧ C C*' V X í?*x, wC AT x x $*· kx My 'aiqaikí X z^ K r „ NK xy x.y x ,'x X' 9 'Χ-' X Ν $ χ κϊ Η Λ , X V s* 7 X X XX XX χ τ $ ! ί Ο ¢- Η Η i I ^ΧΧ ?χ χ χ-··' 'χ X χ.~χ ·*Λ ^ ν ζ\ -Ά Ν X- \ Χ^Χλ Μ χ/ ? Γχ χχ Ν X \χ\ζ\/ Η xk χ*%. • W* Χ/Χ ,Ν XX ΟΝ -^χχ'Χ,Χ Γχ Μ χ\ Ν \ 1 / / Ν Χχ XX ί Α.,.,-'-χ CX ^'χ ι* Ύ\ χ X 1 Χχ. Ν 'Ν X/ Ν' V ,ΧΗ 5 Χχ* ,ΝΗ XX ν .$4 ν. ..χ'-χ Χχ » $ :η X ,-Χ...χ X ,,Χ Ο'μ ζ\ ,0Η Χ. χχ Ν \χ' X •X,.. ΡΓ χ ~Λ Η ,Ν Λ 'Νμ^’Χ ίκ Λ Ν' Η ί ,Ν ,Χ k Χ.Χ X.. ,χ ο Χ^Ζ X 'vqq Χ4;Γχ .-χ - Χ\ϊ · X XX fc ς * Χ \ Η V X. Ά X. / V ΟΗ Ν' I ζ χ-χ Γχ χχ^ ν \κ : \4 .·;.· · %. \ ΜΗ· Η ,Χ'Ύ-Χ - s. ? \\ V X JX XX. ί Η X μ Lx\ ΧΧΊ χχχ XX, ,. ό·’\ χΆ X \,ζ X \ Αχ iH ’\Z xx ÒH X 1 f\ xx V 6T X Xwl·/ $\È \v Z ** rx N - Xx. x X. x' XX x Xy ,, x X A O onde o termo arilo, seja usado isoladamente ou em combinação, designa um sistema aromático carbocíclico contendo um ou dois anéis onde os referidos anéis se podem encontrar ligados um ao outro através de um modo fundido e onde qualquer arilo pode apresentar 1 ou mais substituintes selecionados independentemente de C z -C6 alquilo, hidroxilo, halo, haloalquilo, nitro, ciano, alcoxi e C z -C6 alguilamino.
2
0 composto da reivindicação 1 possuindo a fórmula li:LA.AAAv ou um sal farmaceuticamente aceitável relacionado
3
0 composto da reivindicação 1 ou 2 onde ambos os X são N.
4
0 composto de qualquer uma das reivindicações anteriores onde R é hidrogénio ou C1-C3 alquilo.
5
0 composto de qualquer uma das reivindicações 1 a 4 onde R 2 é:
6
O composto das reivindicações 1 ou 2 possuindo a fórmula:ou um sal farmaceuticamente aceitável relacionado.
7
O composto das reivindicações 1 ou 2 possuindo a fórmula:ou um sal farmaceuticamente aceitável relacionado.
8
O composto das reivindicações 1 ou 2 possuindo a fórmula li:onde R é H ou um sal f armaceuticamente aceitável relacionado.
9
0 composto da reivindicação 8 possuindo a fórmula:ou um sal farmaceuticamente aceitável relacionado.
10
0 composto da reivindicação 8 possuindo a fórmula:ou um sal farmaceuticamente aceitável relacionado.
11
0 composto da reivindicação 1 selecionado das estruturas:reivindicação
12
0 composto da 1 selecionado das estruturas:
13
0 composto da reivindicação 1 selecionado das estruturas:
14
0 composto da reivindicação 1 selecionado das estruturas:N N X .O NH X Ν' ΧΧχ^Χχ ρ/χ-Α ο kx/ Λ ΝΗ Ζ% .0 X. χΧ X* Μ V Ν Ν G Ν— Η Χχ *Χ,Χ-χ 'ú-g Ο ΝΗ ί+ΧΧ XX \κ% Ν Ν Χ..Ζ J3 X %Χ~Ν ÍÍ-ÍY.Í Ϊ*Γ Χχ,,χ p §MH \/\/% ΧΧ I l· | l| -f XjgjííX. ..--XXX\/ \ X/
15
Um composto de qualquer uma das reivindicações 1 a 14, onde o composto ou sal farmaceuticamente aceitável relacionado se encontra na forma de uma forma de dosagem sólida, semi-sólida, ou líquida.
16
Uma composição farmacêutica compreendendo uma quantidade eficaz de um composto de qualquer uma das reivindicações 1 a 14 ou um sal farmaceuticamente aceitável relacionado. Lisboa, 18 de agosto de 2016

Independent claims16

1,139 paragraphs in 11 sections, as filed

DESCRIPTION

CDK INHIBITORS

Technical Field of the Invention

The invention relates to compounds useful for the inhibition of cyclin dependent kinases (CDK).

Technical Background of the Invention Cancer remains a challenge in the field of modern medicine. At a basic level, cancer occurs when there is uncontrollable cell division. Uncontrollable cell division is an effect of a disruption in the natural life cycle of cells. CDK is a family of kinases involved in the life cycle of cells. Abnormally high CDK activity is a feature of many cancers. Naturally occurring CDK inhibitor proteins exist and the abnormally high CDK activity may be due to a dysfunction of naturally occurring CDK inhibitors or due to excessive CDK abundance. CDK inhibitors are known in the prior art but a need for additional CDK inhibitors still remains.

Summary of the Invention

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

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

Brief Description of the Figures

FIGS. 1-3 illustrate embodiments of R2 of the compounds of the invention.

FIGS. 4-6 illustrate embodiments of the basic structure of the compounds of the invention.

Detailed Description of the Invention

In one embodiment, the compounds are as provided herein where:

each X is independently CH or N;

R is H, C1 -C3 alkyl or haloalkyl;

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 one carbon atom in the chain and two R1 are at adjacent ring atoms or at the same ring atom together with the ring atoms to which they are attached, optionally forming a 3- to 8-membered cyclic compound;

y is 0, 1, 2, 3 or 4;

or a related pharmaceutically acceptable salt.

In some aspects of the invention R is hydrogen or C 1 -C 3 alkyl.

In some aspects of the invention R2 is selected from the structures depicted in FIGS. 1-3.

In some aspects of the invention, the compound has one of the generic structures shown in FIGS. 4-6 where the variables are as previously defined.

In some aspects of the invention, the compound has the generic formula Ia:

where R1, R2, R and y are as previously defined.

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

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

In some forms of Ib:

embodiment, compound presents formula

where R2 and R are as previously defined.

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

In some embodiments, Ib and R is H.

the compound has formula

formula where R2 and R are as previously defined.

In some embodiments, the compound has Ic and R is something.

formula

In some embodiments, Ic and R is H.

the compound has formula

formula where R2 and R are as previously defined.

In some embodiments, the compound has Id and R is something.

formula

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

In some embodiments, the compound has:

In some embodiments, the compound has le and R is some.

In some embodiments, the compound has 1 and R is H.

In some embodiments, the compound has If:

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

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

formula formula formula formula formula formula formula

In some embodiments, the compound has formula Ig:

<td>Some Ig and R is</td><td>forms alkyl</td><td>in</td><td>realization,</td><td>O</td><td>compound</td><td>features</td><td>formula</td>

<td>Some</td><td>forms</td><td>in</td><td>realization,</td><td>O</td><td>compound</td><td>features</td><td>formula</td>

<td>Some</td><td>forms</td><td>in</td><td>realization,</td><td>O</td><td>compound</td><td>features</td><td>formula</td>

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

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

In some embodiments formula II:

compound presents

In some li and R is

In some Ij:

In some R1 and R4 embodiments, the compound has alkyl.

embodiments, the compound has

In embodiments, the compound has embodiments, the compound has alkyl.

formula formula formula formula

In some Ij and R is

In some Ij and R are embodiments, the compound has

In embodiments, the compound has H, and both X are N.

formula formula

Definitions

Except as otherwise indicated, the following terms used in this international patent application, including the description and claims, set forth the standardized definitions given below, including Carey Organic Chemistry.th Ed Science + Business Media LLC,

Definition of chemical terms to be found in papers by Sundberg (2007) Advanced

Vol. THE

New York.

B,

Springer

The practice of the present invention will employ, unless otherwise indicated, connective methods of organic synthesis chemistry, mass spectroscopy, chromatographic analytical and preparative methods, protein chemistry, biochemistry, recombinant DNA techniques and pharmacology. Conventional methods of organic chemistry those included in March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 6th Edition, MB Smith and J. March, John Wiley & Sons, Inc., Hoboken, NJ, 2007.

The term alkyl, whether used alone or included in other terms such as haloalkyl and alkylamino, embraces straight or branched radicals having one to twelve carbon atoms.

Lower alkyl radicals have one to six carbon atoms. Examples of such radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isoamyl, hexyl and the like. The term alkylene embraces bonded divalent branched and straight alkyl radicals. Examples include methylene, ethylene, propylene, isopropylene and the like.

The term alkenyl embraces straight or branched radicals having at least one carbon-carbon double bond of two to 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.

The term alkynyl denotes branched or straight radicals having at least one carbonocarbon 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.

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

The term alkylamino encompasses N-alkylamino and N, N-dialkylamino where amino groups are independently substituted with one alkyl radical or two alkyl radicals, respectively. Lower alkylamino radicals have from one to two alkyl radicals to one to six carbon atoms attached to one 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.

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

The term haloalkyl embraces radicals wherein one or more of the alkyl carbon atoms is substituted by one or more halogen atoms as defined above. Examples include monohaloalkyl, dihaloalkyl and polyhaloalkyl radicals including perhaloalkyl. A monohaloalkyl radical, for example, may have an iodine, bromine, chlorine or fluorine atom included in the radical. Dihalo and polyhaloalkyl radicals may have two or more of the same halogen atoms or a combination of different halogen 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, dichloropropyl and dichloropropyl. Perfluoroalkyl means an alkyl radical having all hydrogen atoms substituted with fluorine atoms. Examples include trifluoromethyl and pentafluoroethyl.

The term aryl, whether used alone or in combination, means a carbocyclic aromatic system containing one or two rings wherein said rings may be fused together. The term aryl embraces aromatic radicals such as phenyl, naphthyl, indenyl, tetrahydronaphthyl, and indanyl. A more preferred aryl is phenyl. 0 said aryl group may have 1 or more substituents such as lower alkyl, hydroxy, 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, heterocycle and the like.

The term heterocyclyl (or heterocycle) embraces ring radicals containing saturated, and partially saturated heteroatoms, where heteroatoms may be selected from nitrogen, sulfur and oxygen. Heterocyclic rings comprise 6-8 membered monocyclic rings as well as 5-16 membered bicyclic ring systems (which may include bridged and fused bicyclic ring systems). This designation does not include rings containing -0-0-, -0-S- or -SS- portions. 0 said heterocycle 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.

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

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

Heterocycle groups also include radicals where heterocyclic radicals are fused / fused to any aryl radicals: unsaturated fused heterocyclic groups containing 1 to 5 nitrogen atoms, for example indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, tetrazolyrid [e.g. tetrazolo [1,5-b] pyridazinyl]; unsaturated condensed heterocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g. benzoxazolyl, benzoxadiazolyl]; unsaturated condensed heterocyclic groups containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g. benzothiazolyl, benzothiadiazolyl];

unsaturated condensed heterocyclic, and partially unsaturated, saturated groups containing 1 to 2 oxygen or sulfur atoms [e.g., benzofuryl, benzothienyl, 2,3-dihydrobenzo [1,4] dioxinyl and dihydrobenzofuryl].

The term heteroaryl denotes aryl ring systems containing one or more heteroatoms selected from the group of 0, N and S, where nitrogen and sulfur atoms are optionally oxidized, and nitrogen atoms are optionally quaternized.

Examples include 5- to 6-membered unsaturated heteromonocyclyl groups containing 1 to 4 nitrogen atoms, for example pyrrolyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl [p 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3triazolyl]; 5- to 6-membered unsaturated heteromonocyclic groups containing one oxygen atom, for example pyranyl, 2-furyl, 3-furyl, etc .; 5- to 6-membered unsaturated heteromonocyclic groups containing a sulfur atom, for example 2-thienyl, 3-thienyl, etc .; 5- to 6-membered unsaturated heteromonocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, eg oxazolyl, oxadiazolyl [e.g. 1,2,4-oxadiazolyl, oxadiazolyl, 1,2,5 oxadiazolyl];

5- to 6-membered unsaturated heteromonocyclics containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example thiazolyl, thiadiazolyl [e.g. 1,2,4thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl].

isoxazolyl,

1,3,4groups term heteroarylalkyl denotes alkyl radicals substituted with a heteroaryl group. Examples include pyridylmethyl and thienylethyl.

The term sulfonyl, whether used alone or in connection with other terms such as alkylsulfonyl, respectively denotes divalent -SCg-radicals.

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

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

aminocarbonyl denotes an amide group of the formula C (O) -NH2.

The terms heterocycloalkyl embrace radicals

<td>replaced</td><td colspan="2">with heterocycles.</td><td>Examples</td><td>include</td>

<td colspan="3">piperidylmethyl and morpholinylethyl.</td><td></td><td></td>

<td>0 term </td><td>arylalkyl</td><td>includes</td><td>radicals</td><td>alkyl</td>

<td>replaced</td><td>with arils.</td><td>Examples</td><td>include</td><td>benzyl,</td>

<td>diphenylmethyl</td><td>and phenylethyl.</td><td>0 group</td><td>aryl in</td><td>referred</td>

aralkyl may be further substituted with halo, alkyl, alkoxy, haloalkyl and haloalkoxy.

carbon carbocyclic groups. Term cycloalkyl groups include saturated 3 to 10 lower cycloalkyl atoms 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, heterocycle and the like.

The term cycloalkylalkyl embraces cycloalkyl-substituted alkyl radicals. Lower cycloalkylalkyl radicals are cycloalkyl radicals attached to alkyl radicals having one to six carbon atoms. Examples include cyclohexylmethyl. The cycloalkyl group in said radicals may be further substituted with halo, alkyl, alkoxy and hydroxyl.

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

The term comprising is intended to be open character, including the indicated component but not excluding other components.

The term oxo as used herein contemplates an oxygen atom bonded through a double bond.

term nitro as used herein contemplates —N02.

The term cyano as used herein contemplates -CN.

Synthesis

The compounds disclosed herein may be produced by the following generic schemes:

? »E- Μ '' '*

ν .., · - ·Λ\, - · '' · χ(.:Χ '·', ... · - »· ti * V- / ο ^ · <* • *>: '\ · .................

'> vl

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/ ··, ¢ ,, • ο ί; >;

\% χ «<s A;? s? s

X Λ 'W, ί ·: · “?>. , ·; \ ···· • 'Ãv. χ ^ · \ / ΛΜ

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Ys. z

Esqaesss 1

In Scheme 1, Ref-1 is White, JD, et al. J. Ref-3 is Presser, A. and Chemie 2004, 135, 1015.

WO 2010/020675 Al; Ref-2 is Org. Chem. 1995, 60, 3600; and

Hufner, A. Monatsheftefiir

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: <SufcOíVfc? F '' Y 'X'' ¢5 >

. . ·? · V%^ X \> .- \,.

SF <3 \ &

Os.'Otl

A> - <'· τ * \ & rF: Β> ·' 1 r fd '' 7 '·' · '&, ..- F' '7 W.

right here ..

f • \ s'\

W ' x\ -C> • Λχ%. ^ χ ··ν

Fr 'Wl .s.xFFxÚ-FL í $ 'vK·'^;

<- 'Ç. <..................................... X' · Ή, '' \: SISIS-SSSÍKtB \ \ pS-SITIS

6: fe-i: ./

SSsi <5 ·: <'S «

-Α, -W 7-® 1.,. «··:

Scheme

In Scheme 2, Ref-1 is WO 2010/020675 A1; Ref-4 is WO 2005/040166 A1; and Ref-5 is Schoenauer, K. and Zbiral, E. Tetrahedron Letters 1983, 24, 573.

Scheme 3

In Scheme 3, Ref-1 is WO 2010/020675 Al.

'W'

LOL;

Si s Siiss;

asthma 4

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

synthesis of

EXAMPLES

Example 1

Tert-Butyl N- [2 - [(5-bromo-2-chloro-pyrimidin-4-yl) amino] ethyl] carbamate

To a solution of 5-bromo-2,4-dichloropyrimidine 3.2 g (0.0135 moles) in ethanol 80 mL was added Hunig base 3.0 mL followed by the addition of a solution of N (tert-butoxycarbonyl) - 1,2-diaminoethane 2.5 g (0.0156 moles) 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) were added and the layers separated. The organic layer was dried with magnesium sulfate and then concentrated under vacuum. Silica gel column chromatography using hexane / ethyl acetate (0-60%) yielded tert-butyl N- [2 - [(5-bromo-2-chloro-pyrimidin-4-yl) amino] ethyl] carbamate.

NMR (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 (Μ + H).

Tert-Butyl N- [2 - [[2-chloro-5- (3,3-diethoxyprop-1-ynyl) pyrimidin-4yl] amino] ethyl] carbamate

To 3.6 mmoles (1.265 g) of tert-Butyl N - [2 - [(5-bromo-2-chloropyrimidin-4-yl) amino] ethyl] carbamate in THF (10 mL) was added 0.788 mL of acetal (5.43 mmol), 148 mg Pd (dppf) CH 2 Cl 2, triethylamine 0.757 mL (5.43 mmol. The contents were deaerated and then purged with nitrogen. To this mixture was added 29 mg of Cul. heated at reflux for 48 hrs.After cooling, the contents were filtered through CELITE ™ and concentrated. Column chromatography of the resulting residue using hexane / ethyl acetate (0-30%) afforded

Tert-Butyl N- [2 - [[2-chloro-5- (3,3-diethoxyprop-1-ynyl) pyrimidin-4yl] 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 (Μ + H)

Tert-Butyl N- [2- [2-chloro-6- (diethoxymethyl) pyrrolo [2,3-d] pyrimidin-7yl] ethyl] carbamate

To a solution of the binding product 2.1 g (0.00526 moles) in THF (30 mL) was added 7.0 g solid TBAF. The contents were heated to 65 degrees centigrade for 2 hrs. Concentration followed by column chromatography using ethyl acetate / hexane (0-50%) afforded tert-N- [2- [2-chloro-6- (diethoxymethyl) pyrrolo [2,3-d] pyrimidin-7yl] ethyl] carbamate. butyl in the form of a liquid

<td>brown</td><td>clear (1.1</td><td>g). 1HNMR</td><td>(d6-DMSO)</td><td> 8,88</td><td>(s,</td><td>1H),</td><td> 6, 95</td>

(m, 6H). LCMS (ESI) 399 (δ + H).

Tert-Butyl N- [2- (2-chloro-6-formyl-pyrrolo [2,3-d] pyrimidin-7yl) ethyl] carbamate

To 900 mg of acetal was added 8.0 mL AcOH and 1.0 mL water. This mixture was stirred at room temperature for 16 hrs. Concentration and column chromatography with ethyl acetate / hexanes (0-60%) gave 0.510 g of N [2- (2-chloro-6-formyl-pyrrolo [2,3-d] pyrimidin-7yl) ethyl] carbamate. tert-butyl in the form of a foam. 1 H NMR (d 6 -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 (Μ + H)

7- [2- (tert-Butoxycarbonylamino) ethyl] -2-chloropyrrolo [2,3-d] pyrimidine-6-carboxylic acid

To aldehyde 0.940 g in DMF (4 mL) was added oxone (1.95 g, 1.1 eq). The contents were stirred at room temperature for 7 hrs. Column chromatography with hexane / ethyl acetate (0-100%) yielded 0.545 g of 7- [2- (tert-butoxycarbonylamino) ethyl] -2-chloropyrrolo [2,3d] 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 (Μ + H)

Methyl 7- [2- (tert-butoxycarbonylamino) ethyl] -2-chloro-pyrrolo [2,3d] pyrimidine-6-carboxylate /

X χ \ χ α ν. ο

To a solution of 2-chloro-7-propyl-pyrrolo [2,3d] pyrimidine-6-carboxylic acid 0.545 g (0.00156 moles) in toluene (3.5 mL) and MeOH (1 mL) was added TMSdiazomethane ( 1.2 mL). After stirring overnight at room temperature, excess TMS-diazomethane was neutralized with acetic acid (3 mL) and then concentrated under vacuum.

The residue was subjected to column chromatography with hexane / ethyl acetate (0-70%) to give methyl 7- [2- (tert-butoxycarbonylamino) ethyl] -2-chloro-pyrrolo [2,3d] pyrimidine-6-carboxylate as an 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 (δ + H)

Tricyclic Chloride Amide •• Ο · .. x

... / cr n

To methyl 7- [2- (tert-butoxycarbonylamino) ethyl] -2-chloropyrrolo [2, 3d] pyrimidine-6-carboxylate 0.50 g (0.0014 moles) 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 amine ester which was resuspended 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 (050%) afforded the desired tricyclic chloroamide (0.260 g). XNMR (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 (Μ + H)

Tricyclic chloro-N-methylamide

To a solution of the tricyclic chloro-lactam (185 mg, 0.00083 moles) in DMF (2.0 mL) was added sodium hydroxide (55% oil dispersion, 52 mg). After stirring for 15 mins, methyl iodide (62 µl, 1.2 eq) was added. The contents were stirred at room temperature for 30 mins. After addition of methanol (5 mL), saturated NaHCO 3 was added followed by the addition of ethyl acetate. Separation of the organic layer followed by drying with magnesium sulfate and concentration under vacuum gave the N-methylated amide in substantial yield. 1 HNMR (d 6 -DMSO) 9.05 (s, 1H), 7.17 (s, 1H) 4.38 (m, 2H), 3.80 (m, 2H), 3.05 (s, 3H). LCMS (ESI) 23 7 (Μ + H) 1-methyl-4- (6-nitro-3-pyridyl) piperazine

5-Bromo-2-nitropyridine (4.93 g, 24.3 mmol) in

DMF (20 mL) was added N-methylpiperazine (2.96 g, 1.1 eg) followed by the addition of DIPEA (4.65 mL, 26.7 mmol). Contents were honed at 90 degrees centigrade for 24 hrs. After addition of ethyl acetate (200 mL), 100 mL water was added and the layers separated. Drying followed by concentration afforded the crude product which was subjected to column chromatography using (0-10%) DCM / Methanol.1HNMR (86-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

To 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 the contents stirred under hydrogen flow (10 psi) overnight. After filtration through CELITE ™, the solvents were evaporated and the crude product was purified with silica gel using DCM / 7N Ammonia in MeOH (0-5%) to give 5- (4-methylpiperazin-1-yl) pyridin-2amine. (2.2 g). 1 H NMR (d 6 -DMSO) 7.56 (1H, d, J = 3 Hz),

7.13 (1Η, 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).

Tert-Butyl 4- (6--Amino-3-pyridyl) piperazine-1-carboxylate

This compound was prepared as described in WO 2010/020675

Example 2

Additional Intermediates Overview

Intermediate A: tert-Butyl N- [2- (Benzyloxycarbonylamino) -3-methylbutyl] carbamate fS

To 11.0 g (0.0464 moles) of benzyl N- [1- (hydroxymethyl) -2methylpropyl] carbamate in dioxane (100 mL) cooled to 0 ° C was added 10.99 mL diphenylphosphoryl azide (1.1 eq ) followed by the addition of 8.32 mL DBU (1.2 eq). The contents were allowed to warm to room temperature and stirred for 16 hrs. After addition of ethyl acetate (300 mL) and water (100 mL), the organic layer was separated and then washed with saturated aqueous NaHCO 3.3 (100ml) . 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 were then heated to 90 degrees centigrade 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 give an oil which was column chromatographed using hexane / ethyl acetate (0-70%) to give N- [1- (azidomethyl) -2-methyl. benzyl propyl] carbamate 6.9 g as a colorless oil.

Benzyl N- [1- (Azidomethyl) -2-methyl-propyl] carbamate was added after addition of water (10 mL), and

6.9 g (0.0263 moles) in THF (100 mL triphenylphosphine 7.59 g (1.1 eq).) Stirring for 20 hrs 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 subjected to column chromatography using DCM / MeOH (0-10%) to give benzyl N- [1- (aminomethyl) -2methylpropyl] carbamate in the form of a yellow oil.

To benzyl N- [1- (aminomethyl) -2-methylpropyl] carbamate 4.65 g (0.019 moles) in THF (70 mL) was added 2N NaOH (20 mL) followed by the addition of diterc-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 in vacuo, the crude product was purified using hexane / ethyl acetate (0-40%) through a silica gel column to afford intermediate A, N- [2- (benzyloxycarbonylamino) - Tert-Butyl 3-methyl butyl] carbamate, (6.1 g). :Η NMR (600 MHz, Chloroform-d) δ ppm 0.89 (d, J = 6.73 Hz, 3 H) 0.92 (d, J = 6.73 Hz, 3 H) 1.38 (s, 9 H) 1.70 - 1.81 (m, 1 H) 3.18 (d, J = 5.56 Hz, 2 H) 3.47 - 3.60 (m, 1 H) 4.76 (s , 1 H) 4.89 (d, J = 7.90 Hz,

H) 5.07 (s, 2 H) 7.25 - 7.36 (m, 5 H). LCMS (ESI) 337 (δ + H).

Intermediate B: tert-Butyl N- [2- (benzyloxycarbonylamino) -4-methylpentyl] carbamate

To a solution of benzyl N- [1- (hydroxymethyl) -3-methylbutyl] carbamate 6.3 g (0.025 moles) in DCM (100 mL) was added 5.25 mL diisopropylethylamine (1.2 eq) followed by addition of methanesulfonyl chloride 2.13 mL (1.1 eq) at 0 degrees centigrade. 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 product [2- (benzyloxycarbonylamino) -4-methylpentyl] methanesulfonate was obtained which was used directly in the next step.

To the crude product [2- (benzyloxycarbonylamino) -4-methylpentyl] 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 centigrade for 3 hrs. After cooling, ethyl acetate (300 mL) and water were added. The organic layer was separated, dried with magnesium sulfate and then concentrated under vacuum to give crude benzyl N- [1- (azidomethyl) -3-methylbutyl] carbamate. To this crude intermediate was added THF (100 mL) followed by triphenylphosphine 7.21 g and stirred under nitrogen atmosphere 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 column chromatographed using DCM / MeOH (0-10%) to give benzyl N- [1- (aminomethyl) -3-methylbutyl] carbamate (4 , 5 g).

To benzyl N- [1- (aminomethyl) -3-methylbutyl] carbamate 4.5 g (0.018 moles) in THF (60 mL) was added 2N NaOH (18 mL) followed by the addition of di-tert-butyl dicarbonate. 4.19 g (1.07 eg). 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 used for the next reaction step.21 H NMR (600 MHz, Chloroform-d) δ ppm 0.89 (d, J = 6.73 Hz, 6 H) 1.25 - 1.34 (m, 1 H) 1.39 (s, 9 H ) 1.57 30

1.71 (m, 2) 3, 04 - 3.26 (m, 2) 3, 68 - 3, 80 (m, 1)

4.72 - 4.89 (m, 2 Η) 5.06 (s, 2 Η) 7.25 - 7.38 (m, 5 Η). LCMS (ESI) 351 (δ + H).

Intermediate C: tert-Butyl N - [(2R) -2- (benzyloxycarbonylamino) -3-methyl butyl] carbamate

Intermediate C was synthesized from benzyl N - [(1R) -1 (hydroxymethyl) -2methylpropyl] carbamate using synthetic steps similar to those described for intermediate B.

The analytical data (NMR and mass spectroscopy) were consistent with the data presented for intermediate A.

Intermediate D: tert-Butyl N - [(2S) -2- (benzyloxycarbonylamino) 3-methylbutyl] carbamate

intermediate D was synthesized from benzyl N - [(1S) -1 (hydroxymethyl) -2methyl-propyl] carbamate using synthetic steps similar to those described for intermediate B. Analytical data (NMR and mass spectroscopy) were shown. consistent with the data presented for intermediate A.

Intermediate E: tert-Butyl N - [(IS) -1- (aminomethyl) -2-methylpropyl] carbamate

To a solution of tert-butyl N - [(IS) -1- (hydroxymethyl) -2-methylpropyl] carbamate 6.3 g (0.025 moles) in THF (100 mL) was added 5.25 mL diisopropylethylamine (1, 2 eq) followed by the addition of 2.13 mL (1.1 eq) methanesulfonyl chloride at 0 degrees centigrade. 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 product ((2S) -2- (tert-butoxycarbonylamino) -3-methyl-butyl] methanesulfonate was obtained, which was used directly in the next step.

To the crude product ((2S) -2- (tert-butoxycarbonylamino) -3methyl-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 centigrade for 3 hrs. After cooling, ethyl acetate (300 mL) and water were added. The organic layer was separated, dried with magnesium sulfate and then concentrated under vacuum to give crude benzyl N- [1- (azidomethyl) -3-methylbutyl] carbamate. To this crude intermediate was added THF (100 mL) followed by triphenylphosphine 7.21 g and stirred under nitrogen atmosphere 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 subjected to column chromatography using DCM / MeOH (0 - 10%) to give benzyl N- [1- (aminomethyl) -3-methylbutyl] carbamate (4, 5 g). LCMS (ESI)

203 (Μ + H).

Intermediate F: tert-butyl N - [(IR) -1- (aminomethyl) -2methylpropyl] carbamate

..... V

Intermediate F was synthesized from tert-butyl N - [(1R) -1 (hydroxymethyl) -2methylpropyl] carbamate using a synthetic sequence similar to that described for intermediate E.

Analytical data (NMR and mass spectroscopy) were consistent with the data presented for intermediate E.

Intermediate G: tert-Butyl N - [(2S) -2- (benzyloxycarbonylamino) -4-methylpentyl] carbamate

Intermediate G was synthesized from benzyl N - [(1S) -1 (hydroxymethyl) -3methyl butyl] carbamate using a synthetic sequence similar to that described for intermediate B. Analytical data (NMR and mass spectroscopy) revealed consistent with the data presented for intermediate B.

Intermediate Η: tert-Butyl N - [(2S) -2- (benzyloxycarbonylamino) -2-phenyl] carbamate

Intermediate H was synthesized similar sequence synthetic hydroxy-1-phenyl] carbamate intermediate B. X NMR (600 MHz, from N - [(1S) -2benzyl) using one as described for DMSO-dg) δ ppm 1 , 2 0 34

+ Η).

Intermediate I: tert-Butyl Ν - [(2S) -2- (benzyloxycarbonylamino) -3-methylpentyl] carbamate

Intermediate I was synthesized from benzyl N - [(1S) -1- (hydroxymethyl) -2-methylbutyl] carbamate using a synthetic sequence similar to that described for intermediate B. :1 H NMR (600 MHz, Chloroform-d) 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,

H) 4.78 (s, 1 H) 4.96 (d, J = 7.91 Hz, 1 H) 5.06 (s, 2 H) 7.27 - 7.37 (m, 5 H). LCMS (ESI) 351 (δ + H).

Intermediate J: tert-Butyl N - [(2S) -2- (benzyloxycarbonylamino) -3.3-dimethyl butyl] carbamate

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

Intermediate Κ: tert-Butyl N - [[1 (benzyloxycarbonylamino) cyclohexyl] methyl] carbamate

To a solution of benzyl N- [1- (aminomethyl) cyclohexyl] carbamate 10.0 g (0.0381 moles) in THF (150 mL) was added di-tert-butyl dicarbonate (9.15 g, 1, 1 eq) and the contents stirred at room temperature for 16 hrs. Ethyl acetate and water were then added. The organic layer was separated, dried with magnesium sulfate and then concentrated under vacuum to give tert-butyl N - [[[1- (benzyloxycarbonylamino) cyclohexyl] methyl] carbamate (13.1 g).:1H NMR (600 MHz, DMSO-d6> δ ppm

0.92 - 1.54 (m, 17 H) 1.76 - 2.06 (m, 2 H) 3.09 (d, J = 6.15 Hz, 2 H) 4.92 (s, 2 H) 6 .63 (d, J = 7.27 Hz, 1H) 7.16 7.49 (m, 6H). LCMS (ESI) 363 (δ + H).

Intermediate I: tert-butyl n - [[1- (benzyloxycarbonylamino) cyclopentyl] methyl] carbamate

Tert-Butyl Î ± - [[1- (benzyloxycarbonylamino) cyclopentyl] methyl] carbamate was synthesized in a manner analogous to that described for tert-butyl N - [[[1- (benzyloxycarbonylamino) cyclohexyl] methyl] carbamate. LCMS (ESI) 349 (δ + H).

Example 3 - Synthesis of Substituted 2-Aminopyridines

To 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 mmol) and triethylamine (0 mL). 99 mL, 7.1 mmol). The contents were heated to 120 degrees centigrade in a CEM Discovery microwave system for 3 hours. The crude reaction product was then loaded onto a silica gel column and eluted with DCM / methanol (0-20%) mixture to give 2-nitro-5- [4- (1-piperidyl) -1piperidyl] pyridine as a solid. an oil (457 mg).:1 H NMR (600 MHz, DMSO-d 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, J = 12.74 Hz, 2 H) 4.06 (d, J = 13.47 Hz, 2 H) 7.41 (dd, J = 5.37, 2.64 Hz , 1 H) 8.08 (d, J = 9.37 Hz, 1 H) 8.20 (d, J = 2.64 Hz, 1 H).

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

5- [4- (1-piperidyl) -1-piperidyl] pyridin-2-amine was prepared in a similar manner to that used in the synthesis of 5- (4-methylpiperazin-1-yl) pyridin-2-amine. :1 H NMR (600 MHz,

DMSO-d6) 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, J = 8.78 Hz, 1 H) 7.10 (dd,

J = 8.78, 2.93 Hz, 1 H) 7.55 (d, J = 2.64 Hz, 1 H). LCMS (ESI)

261 (Μ + H).

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

•AT THE-,

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

«2

5- (4-morpholin-1-piperidyl) pyridin-2-amine was prepared in a similar manner to that used in the synthesis of 5- (4-methylpiperazin-1-yl) pyridin-2-amine. :1 H NMR (600 MHz,

DMSO-cU) δ ppm 1.34 - 1.52 (m, 2 H) 1.78 (m,

H) 2.43 (m, 4 H) 3.32 (d, J = 12.30 Hz, 4 (m, 4 H) 5.32 (s, 2 H) 6.34 (d, J = 8, 78 Hz,

J = 8.93, 2.78 Hz, 1H) 7.47 - 7.62 (m, 1H).

H) 2.14 (m,

H) 3.47 - 3.59 1 H) 7.11 (dd, LCMS (ESI) 263 (δ + H).

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

-4-piperidyl]

N ......

4- [1- (6-nitro-3-pyridyl) -4-piperidyl] thiomorpholine was synthesized in a similar manner to that used in the synthesis of 2nitro-5- [4- (1-piperidyl) -1-piperidyl] pyridine. :1 H NMR (600 MHz, DMSO-d 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)

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

5- (4-Thiomorpholino-1-piperidyl) pyridin-2-amine was prepared in a similar manner to that used in the synthesis of 5- (4-methylpiperazin-1-yl) pyridin-2-amine. :1 H NMR (600 MHz, DMSO-d 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, J = 12.00 Hz, 2 H) 5.31 (s, 2 H) 6.33 ( d, J = 9.08 Hz, 1H) 7.10 (dd, J = 8.78, 2.93 Hz, 1H) 7.55 (d, J = 2.64 Hz, 1H). LCMS (ESI) 279 (δ + H).

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

2-nitro-5- (1-piperidyl) pyridine was synthesized in a similar manner to that used in the synthesis of 2-nitro-5- [4- (1piperidyl) -1-piperidyl] pyridine. :1 H NMR (600 MHz, DMSO-d 6) δ ppm 1.56 (m, 6 H) 3.49 (d, J = 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

<td>5- (1-piperidyl</td><td>) pyridin-2-amine</td><td>was</td>

<td colspan="2">similar to that used in synthesis</td><td>in</td>

<td colspan="2">il) pyridin-2-amine. :H NMR (600</td><td>MHz,</td>

prepared 5- (4-methylpiperazin-1DMSO-d6) δ ppm 1.39 2.75 - 2.92 (m, 4 H)

H) 7.09 (dd, J = 8.78, H). LCMS (ESI) 178 (M

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

4- (6-nitro-3-pyridyl) thiomorpholine was synthesized in a similar manner to that used in the synthesis of 2-nitro-5- [4- (1-piperidyl) -1-piperidyl] pyridine. :1 H NMR (600 MHz, DMSO-d 6) δ ppm 2.56 - 2.69 (m, 4 H) 3.79 - 3.92 (m, 4 H) 7.43 (dd,

23.22, 3.07 Hz, 1 H) 8.10 (d, 23.3.3 Hz, 1 H) 8.20 (d,

2.92 Hz, 1H).

5-thiomorpholinopyridin-2-amine

5-Thiomorpholinopyridin-2-amine was prepared in a similar manner to that used in the synthesis of 5- (4-methylpiperazin-1-yl) pyridin-2-amine. :1 H NMR (600 MHz, DMSO-d 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, J=8.78 Hz, 1 H) 7.10 (dd, J=8.78, 2.93 Hz, 1H) 7.57 (d, 3T2.64 Hz, 1H). LCMS (ESI) 196 (δ + H).

Tert-butyl (4R) -5- (6-nitro-3-pyridyl) -2,5diazabicyclo [2,2,1] heptane-2-carboxylate

Tert-Butyl (4R) -5- (6-nitro-3-pyridyl) -2,5-diazabicyclo [2,2,1] heptane 2-carboxylate was synthesized in a similar manner to that used in the synthesis of 2-nitro 5- [4- (1-piperidyl) 1-piperidyl] pyridine. 31 H NMR (600 MHz, DMSO-d 6) δ ppm 1.33 (d, J = 32.21 Hz, 11 H) 1.91 (m, 2 H) 3.15 (d, 1Γ10.25 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, 1H).

Tert-Butyl (4R) -5- (6-amino-3-pyridyl) -2,5-diazabicyclo [2,2,1] heptane2-carboxylate

Tert-Butyl (4R) -5- (6-amino-3-pyridyl) -2,5-diazabicyclo [2,2,1] heptane 2-carboxylate was prepared in a similar manner to that used in the synthesis of 5- (4 -methylpiperazin-lil) pyridin-2-amine. :1 H NMR (600 MHz, DMSO-d 6) δ ppm 1.31

291 (Μ + H).

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

N, N-Dimethyl-1- (6-nitro-3-pyridyl) piperidin-4-amine was synthesized in a similar manner to that used in the synthesis of 242 nitro-5- [4- (1-piperidyl) -1-piperidyl. ] pyridine. 21 H NMR (600 MHz, DMSO-d 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, J = 13.76 Hz, 2 H) 7.42 (dd, J = 9.22, 3.07 Hz, 1 H ) 8.04 8.11 (m, 1 H) 8.21 (d, J = 2.93 Hz, 1 H).

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

5- [4- (Dimethylamino) -1-piperidyl] pyridin-2-amine was prepared in a similar manner to that used in the synthesis of 5- (4-methylpiperazin-1-yl) pyridin-2-amine. 21 H NMR (600 MHz, DMSO-d 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, J = 8, 78 Hz, 1H) 7.10 (dd, J=8.78, 2.93 Hz, 1H) 7.55 (d, J = 2.63 Hz, 1H). LCMS (ESI) 221 (δ + H).

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

50·;

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

5-morpholinopyridin-2-amine

5-morpholinopyridin-2-amine was prepared similarly to that used in the synthesis of 5- (4-methylpiperazin-1-yl)

<td>pyridin-2-amine.</td><td>:H NMR</td><td>(600 MHz, Chloroform</td><td>-d) δ</td><td>ppm</td><td> 2,</td><td> 91</td>

7.72 (d, J = 2.93 Hz, 1 H)

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

........-

1-Isobutyl-4- (6-nitro-3-pyridyl) piperazine was synthesized in a similar manner to that used in the synthesis of 2-nitro-5- [4- (1piperidyl) -1-piperidyl] pyridine which was then converted to 5- (4-Isobutylpiperazin-1-yl) pyridin-2-amine in a similar manner to that used in the synthesis of 5- (4-methylpiperazin-lil) pyridin-2-amine. 21 H NMR (600 MHz, Chloroform-d) δ ppm 0.88 (d, J = 6.73 Hz, 6 H) 1.71 - 1.84 (m, 1 H) 2.10 (d, J = 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, J = 8.78 Hz, 1 H) 7.14 (dd, J = 8.78, 2.93 Hz, 1 H) 7.75 (d, J = 2.93 Hz, 1 H). LCMS (ESI) 235 (M + H).

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

1-Isopropyl-4- (6-nitro-3-pyridyl) piperazine was synthesized in a similar manner to that used in the synthesis of 2nitro-5- [4- (1-piperidyl) -1-piperidyl] pyridine which was then converted to 5- (4-Isopropylpiperazin-1-yl) pyridin2-amine in a similar manner to that used in the synthesis of 5- (4-

<td>methylpiperazin-1-yl) pyridin-2-amine.</td><td>NMR</td><td> (</td><td> 600</td><td>MHz,</td>

<td>Chloroform-d) δ ppm 1.06 (d, J = 6f44 Hz</td><td>.6H)</td><td> 2,</td><td> 59 -</td><td> 2,75</td>

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

(2S, 6R) -2,6-Dimethyl-4- (6-nitro-3-pyridyl) morpholine was synthesized in a similar manner to that used in the synthesis of 2nitro-5- [4- (1-piperidyl) -1- piperidyl] pyridine which was then converted to 5 - [(2R, 6S) -2,6-dimethylmorpholin-4yl] pyridin-2-amine in a similar manner as used in the synthesis of 5- (4-methylpiperazin-1-yl) pyridin-2-amine. :H NMR (600

<td>MHz,</td><td>Chloroform-d)</td><td>δ ppm 1.20</td><td>(d,</td><td>J = 6.44 Hz,</td><td>6 H) 2.27 -</td>

(3S, 5R) -3,5-Dimethyl-1- (6-nitro-3-pyridyl) piperazine was synthesized in a similar manner to that used in the synthesis of 2nitro-5- [4- (1-piperidyl) -1- piperidyl] pyridine which was then converted to 5 - [(3R, 5S) -3,5-dimethylpiperazin-lil] pyridin-2-amine in a similar manner to that used in the synthesis of 5- (4-methylpiperazin-1-yl) pyridin-2-amine. NMR (600

<td>MHz, Chloroform-d) δ ppm</td><td>1.09 (d,</td><td>J = 6,</td><td> 44</td><td>Hz, 6</td><td>H) 2.20</td>

Intermediate IA:

Tert-Butyl N- [2 - [(5-bromo-2-chloro-pyrimidin-4-yl) amino] -3-methylbutyl] carbamate

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

To a solution of 5-bromo-2,4-dichloro-pyrimidine 7.11 g (0.0312 mol) in diisopropylethylamine methyl butyl) carbamate was added and N- (2-amino-36.31 g (0.0312 mol)). ethanol temperature (100 mL)

5.45 mL (1.0 eq) of tert-butyl moles). The reaction mixture was stirred at room temperature for 20 hrs. After concentration under vacuum, ethyl acetate and water were added. The organic layer was separated, dried with magnesium sulfate and then concentrated under vacuum. The crude product was purified by hexane / ethyl acetate (0-30% column chromatography using silica gel to give N- [2 - [(5-bromo-2-chloropyrimidin-4-yl) amino] -3 -

<td>methyl butyl] carbamate</td><td>in</td><td>tert-butyl.</td><td>:H</td><td>NMR</td><td> (600</td><td>MHz,</td>

LCMS (ESI) 393 (δ + H).

Tert-Butyl N- [2- [2-chloro-6- (diethoxymethyl) pyrrolo [2,3-d] pyrimidin-7yl] -3-methylbutyl] carbamate

ι ιι y

“-V

Tert-Butyl [- [2- [2-chloro-6- (diethoxymethyl) pyrrolo [2,3-d] pyrimidin-7yl] -3-methyl-butyl] carbamate was synthesized by subjecting N- [2 - [(5 tert-Butyl-bromo-2-chloropyrimidin-4-yl) amino] -3-methyl-butyl] carbamate under Sonogoshira conditions as described for N- [2 - [[2-chloro-5- (3,3-ethoxyprop-1-ynyl tert-Butyl) pyrimidin-4-yl] amino] ethyl] carbamate followed by subsequent treatment with TBAF as described in the synthesis of N- [2- [2-chloro-6- (diethoxymethyl) pyrrolo [2,3-d] pyrimidin -7-yl] ethyl] carbamate from tert-butyl. 21 H NMR (600 MHz, DMSO-d 6 δ ppm 1.11 (d,

7- [1 - [(tert-Butoxycarbonylamino) methyl] -2-methylpropyl] -2-chloro-pyrrolo [2,3d] pyrimidine-6-carboxylic acid

To a solution of tert-butyl N- [2 - [[2-chloro-5- (3,3-diethoxyprop-linyl) pyrimidin-4-yl] amino] ethyl] carbamate in THF was added TBAF and the contents subjected to at reflux for 3 hrs. Ethyl acetate and water were then added and the organic layer separated, dried with magnesium sulfate and then concentrated under vacuum. To this crude reaction mixture was added acetic acid / water mixture (9: 1) and then the contents were stirred for 12 hrs at room temperature. After concentration under vacuum, saturated NaHCO 3 and ethyl acetate were 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 ™ and concentrated under vacuum. Column chromatography of the crude product over silica gel using hexane / ethyl acetate (0 - 100%) yielded 7- [1 - [(tert-butoxycarbonylamino) methyl] -

<td colspan="4">2-methyl-propyl] -2-chloro-pyrrolo [2,</td><td colspan="4">3-d] pyrimidine-6-</td>

<td>carboxylic acid.</td><td>:H</td><td>NMR</td><td>(600 MHz,</td><td>DMSO-dg) δ</td><td>ppm</td><td> 0,85</td><td>(d,</td>

(ESI) 383 (δ + H).

Intermediate IA

7- [1 - [(tert-Butoxycarbonylamino) methyl] -2-methylpropyl] -2-chloropyrrolo [2,3-d] pyrimidine-6-carboxylic acid 0.050 g (0.00013 moles) 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 stirred continuously for an additional 30 minutes. After addition of saturated NaHCO 3 to neutralize 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 subjected to silica gel column chromatography using hexane / ethyl acetate (0100%) to give intermediate ΙΑ.:Η NMR (600 MHz, DMSO-d6) δ ppm 0.72 (d, J = 6.73 Hz, 3 H) 0.97 (d, J = 6.73 Hz,

H) 2.09 - 2.22 (m, 1 H) 3.57 (dd, J = 13.18, 4.98 Hz, 1 H) 3.72 (dd, J = 13.61, 4.25 Hz, 1 H) 4.53 (dd, J = 8.05, 3.95 Hz, 1 H) 7.20 (s, 1 H) 8.34 (d, J = 4.98 Hz, 1 H) 9.08 (s, 1H). LCMS (ESI) 265 (δ + H).

Intermediate IB:

Intermediate C was hydrogenated with 10% Pd / C to give tert-butyl N - [(2R) -2-amino-3-methyl-butyl] carbamate intermediate, which was then treated with 5-bromo-2,4dichloro -pyrimidine using reaction conditions analogous to those described for Intermediate IA to generate intermediate IB. The analytical data were consistent with those reported for racemate (Intermediate IA).

Intermediate IC:

Intermediate D was hydrogenated with 10% Pd / C to give tert-butyl N - [(2S) -2-amino-3-methyl-butyl] carbamate intermediate which was then treated with 5-bromo-2,4dichloro -pyrimidine using reaction conditions analogous to those described for Intermediate IA to generate intermediate IC. Analytical data (NMR and LCMS) were consistent with those reported for racemate (intermediate IA).

ICA Intermediate:

To a solution of Intermediate IA (80 mg, 0.00030 moles) in DMF (3 mL) was added a 60% dispersion of sodium hydroxide in oil (40 mg). After stirring for 15 minutes, methyl iodide (37 µL, 2eg) was added. The contents were stirred at room temperature for 30 minutes. Saturated NaHCO 3 was then added followed by ethyl acetate. The organic layer was dried with magnesium sulfate and then concentrated under vacuum to give intermediate IAA. NMR (600 MHz, DMSO-d 6) δ ppm 0.74 (d, J = 6.73 Hz, 3 H) 0.91 (d, J = 6.73 Hz, 3 H) 2.04 2.20 ( m, 1 H) 3.04 (s, 3 H) 3.69 (dd, J = 13.76, 1.17 Hz, 1

Δ) 3.96 (dd, J = 13.76, 4.68 Hz, 1 H) 4.58 (dd, J = 7.32, 3.51 Hz, 1 H) 7.16 (s, 1 H ) 9.05 (s, 1H). LCMS (ESI) 279 (δ + H).

Intermediate ID

Tert-Butyl N - [(2S) -2 - [(5-bromo-2-chloro-pyrimidin-4-yl) amino] -4-methylpentyl] carbamate

Intermediate G was hydrogenated with 10% Pd / C in ethanol under a 50 psi hydrogen atmosphere with a pressure pump to generate tert-butyl N - [(2S) -2-amino-4-methylpentyl] carbamate which was then reacted with 5-bromo-2,4-dichloro-pyrimidine using reaction conditions analogous to those described for N- [2 - [(5-bromo-2-chloro-pyrimidin-4-yl) amino] -3-methyl-butyl] carbamate tert-butyl to generate tert-butyl N - [(2S) -2 - [(5-bromo-2-chloropyrimidin-4-yl) amino] -4-methylpentyl] carbamate. :1 H NMR (600 MHz, Chloroform-d / δ ppm 0.91 (d, J = 6.44 Hz, 3 H) 0.94 (d, J = 6.44 Hz, 3 H) 1.32 - 1, 51 (m, 11 H) 1.55 - 1.67 (m, 1 H) 3.28 (t, J = 5.86 Hz, 2 H)

4.21 - 4.42 (m, 1 Η) 4.84 (s, 1 Η) 5.84 (d, J = 7.32 Hz, 1

H) 8.07 (s, 1H). LCMS (ESI) 407 (δ + H).

To a solution of tert-Butyl N - [(2S) -2 - [(5-bromo-2-chloro-pyrimidin-4yl) amino] 4-methylpentyl] carbamate 5.0 g (12.3 mmol) in toluene (36 mL) and triethylamine (7.2 mL) was added under nitrogen, 3,3-diethoxypropoline 2.8 mL (19.7 mmol), Pd2 (dba) 3 1.1 g (1.23 mmol), and triphenylarsine 3.8 g (12.3 mmol). The contents were heated to 70 degrees centigrade for 24 hrs. After cooling to room temperature, the reaction mixture was filtered through CELITE ™ and then concentrated under vacuum. The crude product was subjected to silica gel column chromatography using hexane / ethyl acetate (0-30%) to give (2S) -N2- [2-chloro-5- (3,3diethoxyprop-1-ynyl) pyrimidin -4-yl] -4-methylpentane1,2-diamine. LCMS (ESI) 455 (δ + H).

7 - [(IS) -1 - [(tert-Butoxycarbonylamino) methyl] -3-methylbutyl] -2-chloropyrrolo [2,3-d] pyrimidine-6-carboxylic acid was synthesized using a synthetic sequence similar to that described for 7 - [1 - [(tert-butoxycarbonylamino) methyl] -2-methyl-propyl] -2-chloropyrrolo [2,3-d] pyrimidine-6-carboxylic acid compound. 21 H NMR (600 MHz, DMSO-d 6) δ ppm 0.88 (d, J = 6.44 Hz, 3 H) 0.97 (d, J = 6.44

Hz, 3 H) 1.47 (s, 9 H) 1.49 - 1.54 (m, 1 H) 1.56 (t, J = 7.1

Hz, 2 H) 3.98 (dd, J = 13.91, 3.07 Hz, 1 H) 3.76 (dd,

J = 13.31, 4.13 Hz, 1 H) 4.38 (d, J = 14.05 Hz, 1 H) 4.90 (t,

J = 7.17 Hz, 1H) 7.41 (s, 1H) 9.11 (s, 1H). LCMS (Μ + H)

397 .

Intermediate ID was synthesized using a synthetic sequence analogous to that described for intermediate IA. 21H NMR (600 MHz, DMSO-d6) δ ppm 0.82 (d, J = 6.73 Hz, 3 H) 0.97 (d, J = 6.44 Hz, 3 H) 1.34 - 1.46 (m, 1 H) 1.48 - 1.65 (m, 2 H) 3.40 (dd, J = 13.32, 5.42 Hz, 1 H) 3.76 (dd, J = 13.47, 4.10 Hz, 1 H) 4.76 - 4.92 (m, 1 H) 7.17 (s, 1 H) 8.34 (d, J = 5.27 Hz, 1 H) 9.04 (s, 1 H). LCMS (ESI) 279 (δ + H).

IDA Intermediate:

Intermediate IDA was synthesized in a similar way.

<td>the one described for</td><td>ICA compound. 3H</td><td>NMR</td><td> (600</td><td>MHz,</td>

(Μ + H)

Intermediate IE:

Tert-Butyl N - [(2S) -2 - [(5-bromo-2-chloro-pyrimidin-4-yl) amino] -3-methylpentyl] carbamate

Intermediate I was hydrogenated using 10% Pd / C under a 50 psi hydrogen atmosphere in a pressurized reaction vessel to generate tert-butyl N - [(2S) -2-amino-3-methylpentyl] carbamate which was reacted with 5bromo -2,4-dichloro-pyrimidine using reaction conditions analogous to those described for tert-butyl N- [2 - [(5-bromo-2-chloropyrimidin-4-yl) amino] -3-methyl-butyl] carbamate to generate N Tert-Butyl - [(2S) -2 - [(5-bromo-2-chloro-pyrimidin-4-yl) amino] -3-methyl-pentyl] carbamate.

NMR (600 MHz, Chloroform-d) 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, 1H) 5.92 (d, J =8.20 Hz, 1 H) 8.05 (s, 1 H). LCMS (ESI) 407.

Tert-Butyl N - [(2S) -2 - [[2-chloro-5- (3,3-diethoxyprop-1-ynyl) pyrimidin-4yl] amino] -3-methylpentyl] carbamate

Tert-Butyl N - [(2 S) -2 - [[2-chloro-5- (3,3-diethoxyprop-1-ynyl) pyrimidin-4yl] amino] -3-methylpentyl] carbamate was synthesized using experimental conditions similar to those used in the synthesis of (2S) -N2- [2-chloro-5- (3,3-diethoxypropl-ynyl) pyrimidin-4-yl] -4-methylpentan-1,2-diamine. :1 H NMR (600 MHz, DMSO-d 6 δ ppm 0.76 - 0.89 (m, 6 H) 1.03 (q, J = 7.22 Hz, 3 H) 1.10 - 1.17 (m 1.3 H) 1.25 - 1.42 (m, 11

<td>Acid</td><td colspan="4">7 - [(IS) -1 - [(tert-butoxycarbonylamino) methyl]</td><td>-2-methyl-</td>

butyl] -2-chloro-pyrrolo [2,3d] pyrimidine-6-carboxylic

7 - [(IS) -1 - [(tert-Butoxycarbonylamino) methyl] -2-methylbutyl] -2-chloro-pyrrolo [2,3-d] pyrimidine-6-carboxylic acid was synthesized using a synthetic sequence similar to that described for 7— [1 - [(tert-butoxycarbonylamino) methyl] -2-methyl-propyl] -2-chloropyrrolo [2,3-d] pyrimidine-6-carboxylic acid compound. :1 H NMR (600 MHz, DMSO-d 6 δ ppm 0.80 (t, J = 7.47 Hz, 3 H) 0.86 (d, J = 7.03 Hz,

(ESI) 397 (δ + H).

Intermediate IE was synthesized using a synthetic sequence analogous to that described for intermediate IA. :1H NMR (600 MHz, DMSO-d6) δ ppm 0.74 (t, J = 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, 1H) 3.55 (dd, J = 13.91, 4.83 Hz, 1H) 3.70 (dd, J = 13.61, 4.25 Hz, 1H) 4.57 (dd, J = 7.91, 4.10 Hz, 1 H) 7.17 (s, 1 H) 8.31 (d, 3.25.27 Hz, 1 H) 9.05 (s, 1 H) . LCMS (ESI) 279 (δ + H).

IEA Intermediate:

Intermediate IEA was summarized in a similar way to Intermediate ICA. :1 H NMR (600 MHz, DMSO-d 6) δ ppm 0.77 (t, J = 7.47 Hz, 3 H) 0.84 (d, J = 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, <T13, 76 Hz, 1 H) 3.96 (dd, J=13.76, 4.39 Hz, 1H) 4.59 - 4.70 (m, 1H) 7.16 (s, 1H) 9.04 (s, 1H). LCMS (ESI) 293 (δ + H).

IF Intermediate

Tert-Butyl N - [(2S) -2 - [(5-bromo-2-chloro-pyrimidin-4-yl) amino] -3,3-dimethyl butyl] carbamate

Intermediate J was hydrogenated using 10% Pd / C under a 50 psi hydrogen atmosphere in a pressurized reaction vessel to give tert-butyl N - [(2S) -2-amino-3,3-dimethylbutyl] carbamate which was then reacted with 5-bromo-2,4-dichloro-pyrimidine using reaction conditions analogous to those described for N- [2 - [(5-bromo-2-chloropyrimidin-4-yl) amino] -3-methylbutyl] tert-butyl carbamate to generate tert-butyl N - [(2S) -2 - [(5-bromo-2-chloro-pyrimidin-4yl) amino] -3,3-dimethyl-butyl] carbamate. LCMS (ESI) 407 (M + H +)

Tert-Butyl N - [(2S) -2 - [[2-chloro-5- (3,3-diethoxyprop-1-ynyl) pyrimidin-4yl] amino] -3,3-dimethyl-butyl] carbamate

Tert-Butyl N - [(2S) -2 - [[2-chloro-5- (3,3-diethoxyprop-1-ynyl) pyrimidin-4yl] amino] -3,3-dimethyl-butyl] carbamate was synthesized using experimental conditions similar to those used in the synthesis of (2S) -N2- [2-chloro-5- (3,3-diethoxypropl-ynyl) pyrimidin-4-yl] -4-methylpentan-1,2-diamine. LCMS (ESI) 455 (δ + H).

7 - [(IS) -1 - [(tert-butoxycarbonylamino) methyl] -2,2-dimethyl-propyl] -2-chloro-pyrrolo [2,3d] pyrimidine-6-carboxylic acid

7 - [(1S) —1 - [(tert-butoxycarbonylamino) methyl] -2,2-dimethyl-propyl] -2-chloropyrrolo [2,3-d] pyrimidine-6-carboxylic acid was synthesized using a synthetic sequence analogous to that described for 7- [1 - [(tert-butoxycarbonylamino) methyl] -2-methyl-propyl] -2-chloropyrrolo [2,3-d] pyrimidine-6-carboxylic acid compound. LCMS (ESI) 397 (M + H).

Intermediate IF was synthesized using a synthetic sequence analogous to that described for intermediate IA. LCMS (ESI) 279 (δ + H).

IFA Intermediate

Intermediate IFA was synthesized in a similar manner to that described for Intermediate ICA. LCMS (ESI) 293 (δ + H).

Intermediate IG

Tert-Butyl Ν - [(2S) -2 - [(5-bromo-2-chloro-pyrimidin-4-yl) amino] -2-phenylethyl] carbamate

Intermediate J was hydrogenated using 10% Pd / C under a 50 psi hydrogen atmosphere in a pressurized reaction vessel to generate tert-butyl N - [(2S) -2-amino-2-phenylethyl] carbamate which was then reacted. with 5-bromo-2,4-dichloro-pyrimidine using reaction conditions analogous to those described for N- [2 - [(5-bromo-2-chloro-pyrimidin-4-yl) amino] -3-methyl-butyl] carbamate tert-butyl to generate tert-butyl N - [(2S) -2 - [(5-bromo-2-chloropyrimidin-4-yl) amino] -2-phenyl] carbamate. NMR (600 MHz, DMSO-d6) δ ppm 1.32 (s, 9 H) 3.29 - 3.50 (m, 2 H) 5.12 - 5.24 (m, 1 H) 7.10 (t, J = 5.27 Hz, 1 H) 7.21 (t, J = 6.88 Hz, 1 H) 7.26 - 7.34 (m, 4 H) 7.89 (d, J = 7.32 Hz, 1 H) 8, 24 (s, 1H). LCMS (ESI) 427 (δ + H).

Tert-Butyl Ν - [(2S) -2 - [[2-chloro-5- (3,3-diethoxyprop-1-ynyl) pyrimidin-4yl] amino] -2-phenylethyl] carbamate

Tert-Butyl N - [(2S) -2 - [[2-chloro-5- (3,3-diethoxyprop-1-ynyl) pyrimidin4-yl] amino] -2-phenyl-ethyl] carbamate was synthesized using conditions similar to those used in the synthesis of (2S) -N2- [2-chloro-5- (3,3-ethoxyprop-1-ynyl) pyrimidin-4-yl] -4-methylpentan-1,2-one

<td>diamine</td><td>:1H NMR (600 MHz, DMSO-d6) δ ppm 1.14</td><td>(t,</td><td>J = 7.03</td>

7 - [(IS) -2- (tert-butoxycarbonylamino) -1-phenylethyl] 2-chloro-pyrrolo [2,3-d] pyrimidine-6-carboxylic acid

7 - [(IS) -2- (tert-Butoxycarbonylamino) -1-phenylethyl] 2-chloro-pyrrolo [2,3d] pyrimidine-6-carboxylic acid was synthesized using a synthetic sequence similar to that described for compound 7 - [1 - [(tert-butoxycarbonylamino) methyl] -2-methyl-propyl] -2-chloropyrrolo [2,3-d] pyrimidine-6-carboxylic acid. LCMS (ESI) 417 (δ + H).

Intermediate IG

Intermediate IG was synthesized using a synthetic sequence analogous to that described for intermediate IA.

IH Intermediate

Tert-Butyl N - [(IS) -1 - [[(5-bromo-2-chloro-pyrimidin-4-yl) amino] methyl] 2-methyl-propyl] carbamate

Tert-Butyl β - [(IS) -1 - [[(5-bromo-2-chloro-pyrimidin-4yl) amino] methyl] -2-methyl-propyl] carbamate was synthesized using 5-bromo-2,4 -dichloro-pyrimidine and Intermediate E using reaction conditions analogous to those described for tert-butyl N- [2 - [(5-bromo-2-chloro-pyrimidin-4yl) amino] -3-methyl-butyl] carbamate. 1 H NMR (600 MHz, Chloroform-d) δ ppm 0.95 - 1.02 (m, 6 H) 1.35

393 (Μ + H).

Tert-Butyl N - [(IS) -1 - [[[2-chloro-5- (3,3-diethoxyprop-1-ynyl) pyrimidin4-11] amino] methyl] 2-methylpropyl] carbamate

Tert-Butyl β - [(IS) -1 - [[[2-chloro-5- (3,3-diethoxyprop-1-ynyl) pyrimidin4-yl] amino] methyl] -2-methylpropyl] carbamate was It is synthesized using experimental conditions similar to those used in the synthesis of (2S) -N2- [2-chloro-5- (3,3diethoxyprop-1-ynyl) pyrimidin-4-yl] -4-methylpentan-1,2-diamine. :1 H NMR (600 MHz, Chloroform-d) 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, J = 15.37, 6.59 Hz, 1H) 6.56 (s, 1H) 8.05 (s, 1H). LCMS (ESI) 441 (δ + H).

7 - [(2S) -2- (tert-Butoxycarbonylamino) -3-methyl-butyl] 2-chloro-pyrrolo [2,3-d] pyrimidine-6-carboxylic acid

7 - [(2S) -2- (tert-Butoxycarbonylamino) -3-methyl-butyl] 2-chloro-pyrrolo [2,3d] pyrimidine-6-carboxylic acid was synthesized using a synthetic sequence similar to that described for compound 7 - [1 - [(tert-butoxycarbonylamino) methyl] -2-methyl-propyl] -2-chloro-pyrrolo [2,3-d] pyrimidine-6-carboxylic acid. :H NMR (600

<td>MHz,</td><td colspan="2">Chloroform-d) δ ppm 0.90</td><td>(d,</td><td>J = 6.73</td><td>Hz,</td><td>3 h)</td><td> 0, 96</td>

Intermediate Η

Intermediate IH was synthesized using a synthetic sequence analogous to that described for intermediate IA. LCMS (ESI) 265 (δ + H).

Intermediate II

Intermediate II was synthesized using 5-bromo-2,4dichloro-pyrimidine and Intermediate F as starting materials, and following a synthetic sequence of steps similar to that used for intermediate IH. The analytical data were consistent with those described for its antipode (intermediate IH).:1 H NMR (600 MHz, DMSO-d 6) δ ppm 0.88 (d, J = 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 (δ + H).

IJ Intermediate

LM —7—

Tert-Butyl N- [2 - [(5-bromo-2-chloro-pyrimidin-4-yl) amino] -2-methylpropyl] carbamate

Tert-Butyl Ν- [2 - [2 - [(5-bromo-2-chloro-pyrimidin-4-yl) amino] -2-methylpropyl] carbamate was synthesized using 5-bromo-2,4-dichloro-pyrimidine and N (2- tert-butyl amino-2-methyl-propyl) carbamate using reaction conditions analogous to those described for tert-butyl N- [2 - [(5-bromo-2-chloropyrimidin-4-yl) amino] -3-methyl-butyl] carbamate .

LCMS (ESI) 379 (δ + H).

Tert-Butyl N- [2 - [[2-chloro-5- (3,3-diethoxyprop-1-ynyl) pyrimidin-4yl] amino] -2-methylpropyl] carbamate

Tert-Butyl N- [2 - [[2-chloro-5- (3,3-diethoxyprop-1-ynyl) pyrimidin-4yl] amino] -2-methyl-propyl] carbamate was synthesized using experimental conditions similar to those used in the synthesis of (2S) -N2- [2-chloro-5- (3,3-diethoxyproplinyl) pyrimidin-4-yl] -4-methylpentane-1,2-diamine. X1 H NMR (600 MHz, DMSO-d 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

Δ) 6.94 (s, 1 δ) 7.33 (t, J = 6.44 Hz, 1 H) 8.18 (s, 1 H).

LCMS (ESI) 427 (δ + H).

7- [2- (tert-Butoxycarbonylamino) -1,1-dimethyl-ethyl] -2-chloro-pyrrolo [2,3-d] pyrimidine-6-carboxylic acid

7- [2- (tert-Butoxycarbonylamino) -1,1-dimethyl-ethyl] -2-chloro-pyrrolo [2,3d] pyrimidine-6-carboxylic acid was obtained using synthetic methods analogous to those described for 7- [1 [ (tert-butoxycarbonylamino) methyl] -2-methylpropyl] -2-chloro-pyrrolo [2,3-d] pyrimidine-6-carboxylic acid. :H

<td>IJ Intermediate</td><td></td><td></td>

<td>0 Intermediate IJ was</td><td>synthesized using</td><td>a sequence</td>

<td colspan="3">synthetic compound analogous to that described for intermediate IA. :H</td>

H). LCMS (ESI) 251 (δ + H).

IK Intermediate

Tert-butyl tert-butyl [- [[1 - [(5-bromo-2-chloro-pyrimidin-4yl) amino] cyclohexyl] methyl] carbamate

Tert-Butyl N - [[1 - [(5-bromo-2-chloro-pyrimidin-4yl) amino] cyclohexyl] methyl] carbamate was synthesized using 5-bromo-2,4-dichloro-pyrimidine and Intermediate K using conditions analogous to those described for tert-butyl N - [2 - [(5-bromo-2-chloro-pyrimidin-4yl) amino] -3-methyl-butyl] carbamate. NMR (600 MHz, DMSO-d 6 δ ppm 1.18 - 1.54 (m, 17 H) 2.23 (d,

J = 14.35 Hz, 2 H) 3.36 (d, J = 6.44 Hz, 2 H) 5.82 (s, 1 H)

6.93 (s, 1H) 8.22 (s, 1H). LCMS (ESI) 419 (δ + H).

Tert-Butyl N - [[1 - [[2-chloro-5- (3,3-diethoxyprop-1-ynyl) pyrimidin-4yl] amino] cyclohexyl] methyl] carbamate:

Tert-Butyl N - [[1 - [[2-chloro-5- (3,3-diethoxyprop-1-ynyl) pyrimidin-4yl] amino] cyclohexyl] methyl] carbamate was synthesized using experimental conditions similar to those used in synthesis of (2S) -N2- [2-chloro-5- (3,3diethoxyprop-1-ynyl) pyrimidin-4-yl] -4-methylpentan-1,2-diamine. 21 H NMR (600 MHz, DMSO-d 6) d ppm 1.08 - 1.16 (m,

H) 1.17 - 1.54 (m, 17 H) 2.13 (br. S., 2 H) 3.36 (d, J = 6.73 Hz, 2 H) 3.50 3.69 ( m, 4 H) 5.72 (s, 1H) 6.94 (s, 1H) 5.72 (br. s., 1H) 8.17 (s, 1H). LCMS (ESI)

467 (Μ + H).

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

7- [1 - [(tertbutoxycarbonylamino) methyl] cyclohexyl] -2-chloropyrrolo [2, 3d] pyrimidine-6-carboxylic acid was synthesized using a synthetic sequence similar to that described for 7- [1 - [(tert. -butoxycarbonylamino) methyl] -2methyl-propyl] -2-chloropyrrolo [2,3-d] pyrimidine-670 carboxylic acid. :1 H NMR (600 MHz, DMSO-cb) 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 (δ + H).

Intermediate K

Intermediate IK was synthesized using a synthetic sequence analogous to that described for intermediate IA. :1H NMR (600 MHz, DMSO-d6) 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 (δ + H).

Intermediate IL

Tert-Butyl N - [[1 - [(5-bromo-2-chloro-pyrimidin-4yl) amino] cyclopentyl] methyl] carbamate

Tert-Butyl N - [[1 - [(5-bromo-2-chloro-pyrimidin-4yl) amino] cyclopentyl] methyl] carbamate was synthesized using 5-bromo-2,4-dichloro-pyrimidine and Intermediate I using conditions analogous to those described for tert-butyl N - [2 - [(5-bromo-2-chloro-pyrimidin-4-yl) amino] -3-methyl-butyl] carbamate. NMR (600 MHz, DMSO-d 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, J = 6.15

Hz, 2 H) 6.71 (s, 1 H) 7.18 (t, J = 6.29 Hz, 1 H) 8.20 (s, 1

H) . LCMS (ESI) 405 (δ + H).

Tert-Butyl N - [[1 - [[2-chloro-5- (3,3-diethoxyprop-1-ynyl) pyrimidin-4yl] amino] cyclopentyl] methyl] carbamate

Tert-Butyl N - [[1- [[2-chloro-5- (3,3-diethoxyprop-linyl) pyrimidin-4-yl] amino] cyclopentyl] methyl] carbamate was synthesized using experimental conditions similar to those used in the synthesis of (2S) -N2- [2-chloro-5- (3,3-ethoxyprop-1-ynyl) pyrimidin-4-yl] -4-methylpentane1,2-diamine. LCMS (ESI) 453 (δ + H).

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

7- [1 - [(tert-Butoxycarbonylamino) methyl] cyclopentyl] 2-chloro-pyrrolo [2,3d] pyrimidine-6-carboxylic acid was synthesized using a synthetic sequence analogous to that described for the compound 7— [1— [ (tert-butoxycarbonylamino) methyl] -2-methyl-propyl] -2-chloropyrrolo [2,3-d] pyrimidine-6-carboxylic acid. :1 H NMR (600 MHz, DMSO-d 6 δ ppm 1.47 (s, 9 H) 1.74 (br. S, 2 H) 1.88 (br. S, 2 H) 2.04 (br 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 IL

Intermediate IL was synthesized using a synthetic sequence analogous to that described for intermediate IA. :H

Intermediate IM

Tert-Butyl Ν- [2 - [(5-bromo-2-chloro-pyrimidin-4-yl) amino] -4-methylpentyl] carbamate

Tert-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 conditions analogous to those described for tert-butyl N [2 - [(5-bromo-2-chloropyrimidin-4-yl) amino] -3-methylbutyl] carbamate. Analytical data were consistent with those described for L-enantiomer.

Tert-Butyl N- [2 - [[2-chloro-5- (3,3-diethoxyprop-1-ynyl) pyrimidin-4yl] amino] -4-methylpentyl] carbamate

Tert-Butyl β- [2 - [[2-chloro-5- (3,3-diethoxyprop-1-ynyl) pyrimidin-4yl] amino] -4-methylpentyl] carbamate was synthesized using similar experimental conditions to those used in the synthesis of N- [2 - [[2-chloro-5- (3,3-diethoxyprop-linyl) pyrimidin-4-one

<td>yl] amino] ethyl]</td><td>carbamate</td><td>of tert-butyl.</td><td>2H</td><td>NMR</td><td> (600</td><td>MHz,</td>

<td>Chloroform-d)</td><td colspan="2">δ ppm 1.21 - 1.31 (m, 12</td><td>Η) 1</td><td> ,38 -</td><td> 1,46</td><td>(m,</td>

7- [1 - [(tert-Butoxycarbonylamino) methyl] -3-methylbutyl] -2-chloro-pyrrolo [2,3d] pyrimidine-6-carboxylic acid

7- [1 - [(tert-Butoxycarbonylamino) methyl] -3-methylbutyl] -2-chloro-pyrrolo [2,3d] pyrimidine-6-carboxylic acid was synthesized using a synthetic sequence analogous to that described for 7- [1 - [(tert-butoxycarbonylamino) methyl] -2-methyl-propyl] -2-chloropyrrolo [2,3-d] pyrimidine-6-carboxylic acid. The analytical data were consistent with those described for the L-isomer.

Intermediate IM

Intermediate IM was synthesized using a synthetic sequence analogous to that described for intermediate IA. The analytical data were consistent with those described for the L-isomer.

IMA Intermediate

To a solution of Intermediate IM (100 mg, 0.00024 moles) in DMF (3.0 mL) was added sodium hydroxide (60% oil dispersion), (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 addition of saturated NaHCO3, ethyl acetate was added. Separation of the organic layer followed by drying with magnesium sulfate and concentration under vacuum gave intermediate IMA. Analytical data were similar to those of intermediate IDA.

IN Intermediate

Tert-Butyl N - [(1S, 2S) -2 - [(5-bromo-2-chloro-pyrimidin-4yl) amino] cyclopentyl] carbamate

Tert-Butyl N - [(1S, 2S) -2 - [(5-bromo-2-chloro-pyrimidin-4yl) amino] cyclopentyl] carbamate was synthesized by treating N- [(IS, 2S) -2aminocyclopentyl ] tert-Butyl carbamate with 5-bromo-2,4dichloro-pyrimidine using reaction conditions analogous to those described for N- [2 - [(5-bromo-2-chloro-pyrimidin-4yl) amino] -3-methyl- butyl] tert-butyl carbamate. :1 H NMR (600 MHz, DMSO-d 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,

H) 3.88 - 3.96 (m, 1H) 4.03 - 4.09 (m, 1H) 6.91 (d,

J=8.20 Hz, 1 H) 7.41 (d, <δ 7.32 Hz, 1 H) 8.18 (s, 1 H).

LCMS (ESI) 391 (δ + H).

Tert-Butyl N - [(1S, 2S) -2 - [[2-chloro-5- (3,3-diethoxyprop-linyl) pyrimidin-4-yl] amino] cyclopentyl] carbamate

Tert-Butyl β - [(IS, 2S) -2 - [[2-chloro-5- (3,3-diethoxyprop-linyl) pyrimidin-4-yl] amino] cyclopentyl] carbamate was synthesized using experimental conditions similar to those used in synthesis of (2S) -N2- [2-chloro-5- (3,3-ethoxyprop-1-ynyl) pyrimidin-4-yl] 4-methylpentan-1,2-diamine. NMR (600 MHz, DMSO-d6) 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, J = 7.90 Hz, 1 H) 7.34 (d, J = 7.03 Hz,

H) 8.14 (s, 1H). LCMS (ESI) 439 (δ + H).

7 - [(1S, 2S) -2- (tert-Butoxycarbonylamino) cyclopentyl] 2-chloro-pyrrolo [2,3-d] pyrimidine-6-carboxylic acid

7 - [(1S, 2S) -2- (tert-Butoxycarbonylamino) cyclopentyl] 2-chloro-pyrrolo [2,3d] pyrimidine-6-carboxylic acid was synthesized using a synthetic sequence similar to that described for 7— [acidic compound 1 - [(tert-butoxycarbonylamino) methyl] -2-methyl-propyl] -2-chloro-pyrrolo [2,3-d] pyrimidine-6-carboxylic acid. :1 H NMR (600 MHz, DMSO-d 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,

<td>Intermediate</td><td>IN</td><td></td><td></td><td></td><td></td>

<td>Intermediate</td><td>IN</td><td>was</td><td>synthesized using</td><td>an</td><td>sequence</td>

synthetic compound analogous to that described for intermediate IA. :H

Example 3 - Exemplary Compounds

Compound 1

To 0.050 g (0.225 mmol) of tricyclic chloro-lactam in dioxane (2.0 mL) under a nitrogen atmosphere was added 5- (4-methylpiperazin-1-yl) pyridin-2-amine 0.052 g (1.2 eq, 0.270 mmoles) followed by the addition of Pd2(dba)3 (18.5 mg), BINAP (25 mg) and sodium tert-butoxide (31 mg, 0.324 mmol). The contents of the vial were deaerated for 10 minutes and then heated to 100 degrees centigrade for 12 hours. The crude reaction product was loaded onto a silica gel column and eluted with DCM / MeOH (0-15%) mixture to give the desired product (26 mg). To this compound dissolved in DCM / MeOH (10%) was added 3N HCL in isopropanol (2 eq) and stirred overnight. Concentration under vacuum gave the hydrochloric acid salt. 1 HNMR (d6-DMSO) 11.13 (brs, 1H), 9.07 (s, 1H), 8.42 (s, 1H), 8.03 (br m

Compound 2

To the tricyclic chloro lactam 0.075 g (0.338 mmol) in dioxane 3.5 mL under nitrogen atmosphere was added tert-butyl 4- (6-amino-3-pyridyl) piperazine-1-carboxylate 0.098 g (1.05 eq) followed by addition of Pd 2 (dba) 3 (27 mg) and BINAP (36 mg) and sodium tert-butoxide (45 mg). The contents were refluxed for 11 hrs. The crude reaction product was loaded onto a silica gel column and eluted with DCM / MeOH (0-10%) mixture to give the desired product (32 mg). 1 H NMR (d 6 -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),

LCMS (ESI) 465 (Μ + H)

3.05 (m, 4H).

Compound 3

To a solution of Compound 2 (23 mg) in 10% DCM / MeOH was added 10 mL of a 3M solution of HCl in isopropanol. The contents were stirred overnight for 16 hrs. Concentration of the reaction mixture generated the hydrochloric acid 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 (Μ + H)

Compound 4

To tricyclic chloro-N-methylamide 0.080 g (0.338 mmol) in dioxane 3.5 mL under nitrogen atmosphere was added tert-butyl 4- (6-amino-3-pyridyl) piperazine-1-carboxylate 0.102 g (1.1 eq) followed by the addition of Pd 2 (dba) 3 (27 mg), BINAP (36 mg) and sodium tert-butoxide (45 mg). The contents were refluxed for 11 hrs. The crude product was purified using column chromatography with an eluent mixture of dichloromethane / methanol (0-5%) to give the desired product (44 mg).1HNMR (d6-

To 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 generated the

<td>salt</td><td>in</td><td>acid</td><td>hydrochloric.</td><td>:HNMR</td><td>(d6-DMSO) 9.13</td><td>(m,</td><td>2H),</td>

Compound 6

Compound 6 was synthesized using experimental conditions similar to those described for compound

Compound 7 was synthesized using similar experimental conditions to those described for compound 1 and was recovered as a HCl salt. :H NMR (600

<td colspan="2">MHz,</td><td>DMSOd6) δ</td><td>ppm</td><td> 0,77 -</td><td>0.86 (m,</td><td> 3</td><td>H)</td><td>0.96 (d,</td><td>J = 7.03</td>

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

Experimental Compounds 2 and

was synthesized using conditions similar to those described for 3 and was r <;

(d, J = 1.46 Hz, 1 H) 8.35 (d, J = 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).

Experimental compound 2 and was synthesized using conditions similar to those described for it was recovered as a salt of

Experimental compound 2 and was synthesized using conditions similar to those described for it was recovered as a salt of

HCl. NMR (600 MHz, DMSO-d6) δ ppm 0.84 (d, J = 6.73 Hz, 3

(Μ + Η).

Compound 12 •• -X

Ί Ί \ Ζ \ 'χ.

*s·

Compound 12 was synthesized using experimental conditions similar to those described for compound. 1 H NMR (600 H) 0.95 (d, and was recovered as a HCl MHz salt, DMSOd6) δ ppm 0.85 (d, J = 4.98 Hz, 3

J = 4.98 Hz, 3 H) 1.42 - 1.70 (m, 3 H) 2.77 (d, J = 2.93 Hz, 3 H) 3.07 - 4.14 (m, 10 H) 4.95 (s, 1 H) 7.20 (s, 1 H) 7.66 1 H) 7.94 (s, 1 H) 8.08 - 8.16 (m,

H) 9.09 (s, 1H) 11.38 (s, (d, J 9.66 Hz,

8.33 (d, J = 4.68 Hz,

H) 1 H)

11.71 (s, 1H). LCMS (ESI) 435 (M + H)

JU> íH

Compound 13 was synthesized using experimental conditions similar to those described for compounds 2 and 3 and was recovered as a HCl salt. NMR (600 MHz, DMSO-d6) δ ppm 0.87 (d, J = 6.15 Hz, 3 H) 0.94 (d, J = 6.15 Hz, 3 H) 1.57 (d, J = 84.61 Hz, 3 H) 3.05 (s, 3 H) 3.13 - 3.55 (m, 8 H) 3.69 (d, J = 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, 2H). LCMS (ESI) 421 (M + H).

Compound 14 was synthesized using experimental conditions similar to those described for the compound and was recovered as an HCl salt. 2H NMR (600

MHz, DMSOd 6) δ ppm 0.85 (d, J = 6.44 Hz, 3 H) 0.95 (d,

J = 6.44 Hz, 3 H) 1.43 - 1.70 (m, 3 H) 2.78 (d, J = 2.93 Hz, 3

H) 3.05 (s, 3 H) 3.24 - 3.84 (m, 8 H) 4.01 (d, J = 9.66 Hz,

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).

Experimental compound 2 HCl compounds. NMR was synthesized using s similar to those described and 3 and was recovered as (600 MHz, DMSO-d6) δ ppm 0.83 - 0.88 conditions for a salt of (d, J = 6.15

<td>Compound</td><td> 16</td><td></td><td></td><td></td>

To Intermediate IE 0.060 g (0.205 mmol) 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 deaeration with nitrogen, Pd2dba3 (12 mg), BINAP (16 mg) and sodium tert-butoxide (24 mg) were added. The contents were then heated to 90 degrees centigrade in a CEM Discovery microwave system for 3 hrs. The reaction mixture was then charged through a silica gel column and purified by elution with DCM / MeOH (0-15%).

<td>for</td><td>generate compound 16. :H NMR (600</td><td>MHz, DMSO-dg)</td><td>δ ppm</td>

similar mode to by the step of and was converted 6) δ ppm 0.7 5 (t,

1.07 - 1.15 (m, 2

Compound 17 was synthesized from one described for compound 16 followed by unblocking described for compound 3 in an HCl salt. :1 H NMR (60 MHz, DMSO-d J = 7.32 Hz, 3 H) 0.90 (d, J = 6.73 Hz, 3 H)

Compound 18 was synthesized in a similar manner as described for compound 16. :1 H NMR (600 MHz, DMSO-d 6) δ ppm 0.78 (t, J = 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, J = 4.39 Hz, 3

H) 3.04 (s, 3 H) 3.11 - 3.84 (m, 8 H) 3.98 (dd, J = 13.61,

4.25 Hz, 2 H) 4.66 - 4.74 (m, 1 H) 7.17 (s, 1 H) 7.64 (s,

H) 7.96 (d, J = 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, 1H). LCMS (ESI) 449 (M + H).

Compound 19 was synthesized in a similar manner as described for compound 16 followed by the unlocking step described for compound 3 and was converted to an HCl salt. 31 H NMR (600 MHz, DMSO-d 6) δ ppm 0.78 (t,

J = 7.32 Hz, 3 H) 0.85 (d, J = 6.73 Hz, 3 H) 1.10 - 1.27 (m,

H) 1.82 - 1.99 (m, 1 H) 3.04 (s, 3 H) 3.28 - 3.77 (m, 8

H) 3.97 (dd, J = 13.91, 4.54 Hz, 2 H) 4.62 - 4.75 (m, 1 H)

7.07 - 7.24 (m, 1H) 7.62 - 7.75 (m, 1H) 7.94 (d, J = 2.34 Hz, 1H) 7.97 - 8.08 ( m, 1 H) 9.05 (s, 1 H) 9.29 (s, 2 H). LCMS (ESI) 435 (M + H).

Compound 20 described for was similarly synthesized Compound 16 followed by the unlocking step described for Compound 3 to was converted

(M + H).

Compound 21 was synthesized in a similar manner as described for compound 16 followed by the unlocking step described for compound 3 and was converted to an HCl salt. :1 H NMR (60 MHz, DMSO-d 6 δ ppm 0.95 (s, 9

H) 2.79 (d, J = 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, J = 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, 1H). LCMS (ESI) 435 (M + H).

Compound 22 was synthesized in a similar manner as described for compound 16 and was converted to a salt of

(ESI) 455 (δ + H).

Compound 23 was synthesized in a similar manner as described for compound 16 followed by the unlocking step described for compound 3 and was converted to an HCl salt. 31 H NMR (60 MHz, DMSO-d 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, J = 7.32 Hz, 2 H) 7.22 - 7.31 (m, 3 H) 7.36 (s, 1 H) 7.48 (d , Γ9.37 Hz, 1 H) 7.93 (d, J = 2.34 Hz, 1 H) 8.04 8.11 (m, 1 H) 8.25 (d, J = 4.98 Hz , 1 H) 9.17 (s, 1 H) 11.77 (br, s., 1H) LCMS (ESI) 441 (M + H).

24 \

X • r

Compound 24 was synthesized in a similar manner as described for compound 16 followed by the unlocking step described for compound 3 and was converted to an HCl salt. :Η NMR (600 MHz, DMSO-d 6) δ ppm 0.90 (d,

J = 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, J = 8.78 Hz, 1 H) 8.00 (s, 1 H) 8.13 (d, J = 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 was synthesized in a similar manner to compound 24 and was converted to a HCl salt. The characterization data (NMR and LCMS) were similar to those obtained for compound antipode 24.

Compound 26 was synthesized in a similar manner as described for compound 16 followed by the unlocking step described for compound 3 and was converted

Compound 27 was synthesized in a similar manner to that described for compound 16 and was converted to a salt of

Compound 28 was synthesized in a similar manner as described for compound 16 followed by the unlocking step described for compound 3 and was converted to an HCl salt. :1 H NMR (600 MHz, DMSO-d 6) δ ppm 1.27 - 1.64

(ESI) 433 (δ + H).

Experimental compounds similar to those described for compound 16

<td>has been converted</td><td>in a salt of</td><td>HCl. XH NMR</td><td>(600 MHz,</td><td>DMSO-dg) δ</td>

Compound 30 was synthesized in a similar manner to

<td>described</td><td>for the compound</td><td> 16</td><td>followed</td><td>fur</td><td>step</td><td>in</td>

<td colspan="2">unlock described for the</td><td colspan="2">compound 3 and</td><td>was</td><td colspan="2">converted</td>

Compound 31 was synthesized in a similar manner as described for compound 16 followed by the unlocking step described for compound 3 and was converted to an HCl salt. 21 H NMR (600 MHz, DMSO-d 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

Compound 32 was synthesized using experimental conditions similar to those described for compound 16 and

<td>was</td><td>converted</td><td>in a HCl salt.</td><td>:H NMR</td><td> (600</td><td>MHz, DMSO-dg) δ</td>

Compound 33 was synthesized using experimental conditions similar to those described for compound 16 and was converted to an HCl salt. :1 H NMR (600 MHz, DMSO-d 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, J = 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, 1H). LCMS (ESI) 421 (M + H).

Compound 34 was synthesized using experimental conditions similar to those described for compound 16 and

<td>was</td><td>converted to a salt</td><td>. of HCl.:H NMR</td><td> (600</td><td>MHz, DMSO-d6) δ</td>

419 (M + H).

Compound 35 was synthesized using experimental conditions similar to those described for compound 16 and was converted to an HCl salt. :1 H NMR (600 MHz, DMSO-d 6) δ

Compound 36 was synthesized using experimental conditions similar to those described for compound 16 and

100

<td>was</td><td>converted into a salt of</td><td>HCl. :H NMR</td><td> (600</td><td>MHz, DMSO-dg)</td><td>δ</td>

X

X χ2χ

ZSyj * · ./

X '^ |. |

Μ \ /

Compound 37 was synthesized using experimental conditions similar to those described for compound 16 and was converted to an HCl salt. 21 H NMR (600 MHz, DMSO-d 6) δ ppm 1.13 (d, J=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).

101

Compound 38 was synthesized using experimental conditions similar to those described for compound 16 and

<td>was</td><td>converted into a salt of</td><td>HCl.</td><td>:H NMR (600</td><td>MHz,</td><td>DMSO-dg) δ</td>

H) 11.37 (br s., 1H). LCMS (ESI) 418 (δ + H).

Compound 39 was synthesized using experimental conditions similar to those described for compound 16 and was converted to an HCl salt. NMR (600 MHz, DMSO-d 6) δ ppm 1.72 (s, 2 H) 1.90 (s, 4 H) 2.03 (s, 2 H) 2.21 (s, 2

102

2,4) 2.48 - 2.54 (m, 2 Η) 2.73 (s, 2 Η) 3.03 (s, 2 Η) 3.25 -

X ... 7χ • -γ · - *

Κ Ζ?>

<td> 0</td><td>Compound</td><td>4 0 was</td><td>synthetized</td><td colspan="2">using</td><td>conditions</td>

<td colspan="2">experimental</td><td>similar</td><td>as described</td><td>for</td><td colspan="2">compound 16 and</td>

<td>was</td><td>converted</td><td colspan="2">in a HCl salt. :H NMP</td><td> : (600</td><td>MHz</td><td>, DMSO-dg) δ</td>

3.32 - 3.48 (m, 4 Η) 3.57 - 3.72 (m, 4 Η) 3.77 - 3.85 (m, 2 Η) 7.22 (s, 1 Η) 7, 60 - 7.68 (m, 2) 7.90 (s, 1) 8.07 (s, 1) 8.46 (s, 1) 9.04 (s, 1). 11.41 (br s., 1H).

LCMS (ESI) 501 (Μ + H)

103

Compound 41 was synthesized using experimental conditions similar to those described for compound 16 and

<td>was converted to a HCl salt</td><td> . :H NMR</td><td>(600 MHz, DMSO-dej δ</td>

LCMS (ESI) 436 (δ + H).

Compound 42 was synthesized using experimental conditions similar to those described for compound 16 and was converted to an HCl salt. :1 H NMR (600 MHz, DMSO-d 6) δ ppm 1.29 (d, J = 6.73 Hz, 6 H) 1.66 - 1.79 (m, 2 H) 1.84 -

H) 9.67 (s, 1H) 11.36 (s, 1H). LCMS (ESI) 447 (M + H).

104

Compound 43 was synthesized using experimental conditions similar to those described for compound 16 and was converted to an HCl salt. :1 H NMR (600 MHz, DMSO-d 6) δ

105

Compound 44 was synthesized using experimental conditions similar to those described for compound 16 followed by the unlocking step described for compound

<td>3 and was converted to a salt</td><td>of HCl.</td><td>:H NMR</td><td>(600 MHz,</td><td>DMSO-</td>

Χχ \ XX XX,

Ά ff

X \

X

X. ·

Compound 45 was synthesized using experimental conditions similar to those described for compound 16 and was converted to an HCl salt. 31 H NMR (600 MHz, DMSO-d 6> δ

(ESI) 461 (δ + H).

106

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

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

107

Compound 48 was synthesized in a similar manner as described for compound 16 and then converted to its hydrochloric acid salt. :1 H NMR (600 MHz, DMSO-d 6) δ ppm 1.50 -

419 (Μ + H).

Compound 49 was synthesized in a similar manner as described for compound 16 and then converted to its hydrochloric acid salt. :1 H NMR (600 MHz, DMSO-d 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,

108

4,0) 4.02 - 4.11 (m, 2 Η) 7.22 (s, 2 Η) 7.64 (s, 1 Η) 7.97 (s, 2 Η) 8.75 (s, 1 Η) ) 8.97 (s, 1) 9.21 (s, 1). LCMS (ESI) 405 (M + H).

X1, XNi1H

Biological activity

Enzyme kinase reactions were performed in 384-well culture microplates using the Caliper LabChip 12-channel apparatus as a detection device. Enzymatic phosphorylation of a peptide results in a change in total electrical charge, allowing electrophoretone separation of the product from the substrate. As the substrate and product are separated, two fluorescence peaks are observed. Changes in the relative fluorescence intensity of the substrate and product peaks are the measured parameters, reflecting the enzymatic activity. In the presence of an inhibitor, the ratio of product to substrate is changed. Product signal decreases while substrate signal increases.

For the measurement of CDK2 / cyclin E activity, enzyme (0.22 nM) was incubated with 100 mM ATP and phospho-acceptor peptide (1 mM) for one hour. To the

109 Measurement of CDK4 / Cyclin D activity, enzyme (0.85 nM) was incubated with 200 mM ATP and the phosphoacitating substrate peptide (1 mM) for three hours. Potential inhibitor compounds (in the form of HCl salts) were tested using single-point 12-point dose response curves in Km to ATP. The IC 50 value of each compound was determined using GraphPad Prism software. Results of the IC 50 values demonstrate 200-and 100-fold higher selectivity of Compound 1 and Compound 3 for CDK4 / Cyclin D 1 and CDK2 / Cyclin E respectively. Results are shown in Table 1.

Table 1

<td>Compound</td><td colspan="2">CDK2 / cyclin E</td><td colspan="2">CDK4 / cyclin D</td>

<td></td><td>IC50 (μΜ)</td><td>Interval in confidence 95%</td><td>IC50 (μΜ)</td><td>Interval in confidence 95%</td>

<td>Staurosporine</td><td> 0,00393</td><td> 0,000706</td><td> 0,0375</td><td> 0, 99</td>

<td>Compound 1</td><td> >100</td><td></td><td> 0,453</td><td> 0,85</td>

<td>Compound 3</td><td> >100</td><td></td><td> 1,05</td><td> 0,78</td>

Additional CDK2 / cyclin E data are shown in Table 2. CI data50 are as follows: A - 0.0010.010 μΜ; B - 0.010-0.100 μΜ; C, 0.100-1 μΜ; D 1-100 μΜ; and E -> 100 μΜ.

Data are also represented for the known CDK4 / 6 inhibitor PD0332991.

110

Table 2

<td>Compound #</td><td>CDK2 / Cyclin AND ICso (pM)</td>

<td>Compound #</td><td>CDK2 / Cyclin AND IC50 (μΜ)</td>

Pharmaceutical Compositions

In 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 carriers, and optionally others.

111 therapeutic and / or prophylactic ingredients. Such excipients are known to those skilled in the art. The compounds of the present invention include, without limitation, alkaline compounds such as free bases. A thorough discussion of pharmaceutically acceptable excipients and salts is available from Remington's Pharmaceutical Sciences, 18th Edition (Easton, Pennsylvania: Mack Publishing Company, 1990).

Depending 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, tablets, capsules, powders, liquids, suspensions, creams, ointments, lotions or the like, preferably in unit dosage forms suitable for precise single dose administration. The compositions will include an effective amount of the selected drug in combination with a pharmaceutically acceptable carrier and may additionally comprise other pharmaceutically acceptable agents, adjuvants, diluents, buffering agents, etc.

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

For conventional solid compositions include mannitol pharmaceuticals, non-toxic solid carriers for example lactose, starch, stearate equivalents.

112 magnesium, sodium saccharin, talc, cellulose, glucose, sucrose, magnesium carbonate and the like.

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

The pharmaceutical composition or combination of the present invention may be in a unit dosage of about 1-1000 mg of active ingredients 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. In a therapeutically effective dosage of a compound, the pharmaceutical composition, or related combinations, is dependent upon the subject's species, its body weight, age and individual conditions, the disorder or disease or the related severity to be treated. A routinely skilled health care practitioner, clinician or veterinarian will readily determine the effective amount of each of the active ingredients required for

113 prevent, treat or inhibit the progress of the disorder or disease.

Lisbon, August 18, 2016

Contents11

120 members in 25 offices

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Priority claims
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40649810	United States of America	P	2010-10-25
40649810	United States of America	P	2010-10-25
406498P	–	–	–
US20100406498P	–	–	–

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WO2012061156A1	World Intellectual Property Organization (WIPO)	A1	2012-05-10
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