Compounds and compositions as inhibitors of mek

COMPOUNDS V COMPOSITIONS C OMO INHIBITORS OF THE MLR

BASIS

FIELD OF THE INVENTION) | 80lH¡ The present invention relates to compounds capable of sectically inhibiting MLR activity. The invention further provides a process for the preparation of compounds of the invention, pharmaceutical preparations comprising such compounds and methods of use of such compounds and compositions in the management of hyperproSííraiívas diseases, such as canceling inhumation.

FOUNDATION OF THE INVENTION

100021 It is known that an increased activation of the cascade of the raitogen-activated protein kinase cascade (MAP) plays an important role in cell proliferation and differentiation. This pathway can be activated when a growth factor binds to its lirosira kinase receptor. This interaction promotes the RAS association with RAE c initiates a phosphorylation cascade through MEK. (MAP kinase) to ERK. The only known substrates for the phosphorylation of MEK are the MAP, FRK1 and ERK2 kinases. The tosylation of Mf.K increases its affinity and the ERK catalytic activity, thus closing its affinity with ATE, the constitutive activation of the pathway ΜΛΡΚ it has been found in a number of diseases, for example, melanoma, cancer of the pancreas, colon, lung, kidney and ovarian; in particular, pancreatic, colon, lung, kidney and ovarian cancers. Therefore, inhibition of this pathway, in particular inhibiting MEN activity, is known to be beneficial in the treatment of hyperpreliferative diseases.

[00031 Therefore, MER represents a very attractive target for the development of a new therapy for the treatment of many cancer tumors. In particular, there is a need for small molecules that inhibit selectively the tic MEK activity. The present invention satisfies this need.

SUMMARY OF THE INVENTION (0004) In one aspect, the present invention provides compounds of the formula

And> ........._...ALffffffffff 1; _:olo o-_:::M _::: ooR or ......... o- 1 .......... if ........ ov i .............. < voioi ....... i ......... _:..................) _α ,, Ο. , ^ χ Λ

Ri V-> · * · Ν -¾ LLK, Α_Χ , ·· ** 'Ε; ϊ; í

F Ν

<td>(GOflSj</td><td>in the euai;</td><td></td>

<td>f »000 |</td><td>n is selected from 0. i, 2 and 3;</td><td></td>

<td> (0007(</td><td>R 'is selected from:</td><td></td>

<td>f Ύ *</td><td>r „m y. O- ^ V f PT p '</td><td>OR..</td>

<td>Y^N</td><td>«Af * 'itp</td><td>R &lt;'</td>

<td>r₇</td><td>R? R,</td><td></td>

r'L

Rj is selected from chlorine and methoxy;

(0009 (R^Ha is selected from damage-methyl, 2- hydroxy-ethyl, i-hydroaipropan-2io, 3- hydroxy-2- (hydroxy-mcti!) propanoyl, 2- methoxy-ethyl, 2- thioopropanolku (3-methyloxetan-3- yl} ~ methyl, mcti-suifonyl, aminocarbonymethyl »dclopropyl-suifonyl. isopropyl-suifonyl, dimelsicarbamciio, 3- hydroxy-2- (hydroxymethyl) propslo, 2- hydroxypropyl, 2- hydroxyacetyl, 2- acetoxlacetyl, 2- methoxyacetyl, (2,2,2-thio -iuiuododotototamide, oxetan-2- uncle, 2- sminoacetjlo, oxetan-3- imimet, (S) -2 * hydroxypropanoyl, 2-hydroxypropanotyl, acetyl, 2-amino-2- oxoetiium and carbamoyl;

(OOUH R '* ss selects between hydrogen, halo, methyl and hydroxymethyl; and.

optionally, two groups R 'together with the carbon atoms to which they are attached, form - (CH ^ te .; (for example, δ- azabiciele 13.2. i (ocian- 3- mess), (00ί I j R &lt; it is selected from hydrogen and methyl;

(00Ϊ2i Rj is selected from hydrogen and halogen;

(08131 R 'is selected from hydrogen, fiuoro, doro, CITE, Ct ílri, € F. &lt;, CH2ÜH, ddopropyl and methyl; and

R * is selected from eiano.

[00151

In another aspect. The invention relates to a compound of the formula I ^ 3 *.

R «

..JL .. &lt;s. ..R *^χ·**’\ /

R,&gt; &lt;Y NY,

...... j,. · id? x x'X. ,. ··&gt;. .. * '^s&lt;x '\ / ^ X^s* · '' &lt;&gt; / “Uc 1/1 (7) 1 /// 1 / ..... 7

F 'Ν' · where n is selected from 0, K 2 and 3, R 'is selected from:

f Ύ

A ^ -N «I h₇

Jf.

_Λ, N „

ReV &lt;Ñ

7

H

S,

OR,.

OR.

ΥΎ .N „^ Ñ mW'w

Ox., - k

Ñ,

Rj is selected from chlorine, methyl, hydrogen, fjuoro and raeioxyl;

R '^s is selected from cyanomethyl. 2- hydroxy ethyl, l-hydroxypropan- 2- ¡k&gt;, 3- hydroxy 2- (hydroxl · inetiOpropanoyl. 2- methoxy-ethyl, '2- fluoroptopanoyl, (3- methylxetan-3- yl) · methyl, methy- suifoniio, amino · carboni-methyl, cycioptopí! ·· scJfbniío, isopropyl-sulforuto dtntedlearbamayl, 3- hydroxt- 2, - (hydroxymethyl) propite, 2- hydroxypropyl, 2 hydroxyxyacetyl, .2-acetyloxyacetyl. 2- methoxyacetyl, '2,2,2-tnfiuoroet' »! O} carbantoHo, 2 amsnoacetio, oxetan- 3- Umeíiio, (S} ~ 2- nidroxspropanoyl, 2 ~ hydroxypropanoyl, acetyl, 2 amino '2- oxoetiium, earbamui, (oxetan-2 · uncle) - mctanoyl, 2- (sylfooxí) aeeliio, 2 fiodyloyanoite, 3- hydroxypropanoiium, and NN-diroethylsulfonantidyl;

every R⁴ it is independently selected from hydrogen, halo, methium and hydroxymethyl; and, operativemertte, two R groups⁴ together with the carbon atoms to which they are attached, they form

Rs is selected from hydrogen and methyl;

R «is selected from hydrogen, methoxy and halogen;

R^: is selected from hydrogen, fluoto, Cf '\ CH * OH, cyclopropyl and methyl; and estuary 'or pharmaceutically acceptable salts thereof, (OOíój In another aspect, the present invention provides a pharmaceutical composition containing a compound of the Formula I or an N-oxide derivative, tautometers, individual isomers and mixture of isomers thereof, or a pharmaceutically acceptable sai thereof, in combination with one or more suitable excipients, ¡80I7J In another aspect. The present invention provides a method of treating a disease in an animal in which the measurement of MEK activity. can prevent, inhibit or improve the pathology and / or symptomatology of the diseases, such a method comprises administering to the animal a therapeutically effective amount of a compound of the formula I "derived from M-oxide, individual isomers and mixture of isomers thereof. , or a pharmaceutically acceptable sai thereof, jOOlSj In another aspect, the present invention provides the use of a compound of Formula I in the manufacture of a medicament for trafficking; A disease in an anima! in that the activity of MEK contributes to the pathology and / or symptoms of the disease. (0019) In another aspect, the present invention provides a process for preparing compounds of the Formula 1 and M-oxide derivatives, prodrug derivatives. protected derivatives, individual isomers and mixture of isomers thereof and the tarmacctnically acceptable salts thereof.

.QiQQC.iones j0S20] The general terms used herein before and afterwards preferably have the following meanings within the context of this disclosure, unless otherwise indicated, where more general terms are used whenever they may be used.

independently, be replaced by more specific definitions, thus defining more detailed embodiments of the invention:

"Halogen (or" halo ") preferably represents chlorine or fluoro, in particular iluoro, but may also be bromine or iodine. The term dimethylcarbamoyl as used herein refers to 3 N, Ν 'dímcnkarbamoyl (ie Me-¿NC í-O)&gt;).

J0021] (00221 Compounds of the formula .1 may have different isomeric forms.

For example, any asymmetric carbon atom may be present in the configuration (Rp (Si- or (R, $), preferably in the configuration (R) - or (Si-. Substituents on a double bond or especially on a Ring may be present in the cis- (~ Z} ~ or trans- (~ Ex- form. Compounds may therefore be present as mixtures of isomers or preferably as pure isomers, preferably as pure diasterophilic or pure enantiomers.

(00231 The compounds of the formula are selective MLR inhibitors. The selectivity of the compounds for MLR is attributed to the compounds of the formula containing a fluorine atom linked directly to the II-imide2o (4, S- ejquinolone as shown in compounds A and B below In the absence of a fiuoto group in this position, selectivity for MEK over other kinases is reduced, for example, by comparing the following compounds;

N $

O (A)

<img file="CU20160020A7_D0001.tif" />

| 0024 | Both compounds inhibit MEK at less than 100 nM and are equipment equivalent.

However, when tested against a qninase panel, the number of kinases in the panel inhibited with an IC '^V less than 100 nM is zero for compound (A) and 4 for compound (B), that is, compound (A) is selective for MEK while compound (β) is less selective for MLK. The compound B) also inhibits ABL!, - LCK, LYN and PDGFR: less than * «&gt; of 20 nM, '7 nM, 30 nM and 50 nM, respectively.

[00251 A selectively MEK and less than i00 nM;

Similar comparison shows that the following compounds inhibit 'do not inhibit other kinases from the kinase panel with an IC-ü of

<img file="CU20160020A7_D0002.tif" />

(€)

<img file="CU20160020A7_D0003.tif" />

[0026] The compounds of the invention are selected, using test conditions known in the art, against some or all of the Kinase Panel comprising ABLl, ABLl (Π1SI), ACVRL AKTL ALK, AURKA, AXL, BTK , CAMK2D, CDKIJ3, CDK2A, CDK4D1. CSK, CSNKIG3, EGFR, EPHA4, EPHB4, ER8B4, FGFRI, FGFR2, FGFR3, FGFR3 (K65OE), FGFR4, FLT3 {£&gt; 83 5 Y), IGFUL GSK3B, INSR. IRAK4, JAKL JAK2. JAKl KDR, KIT, LCK, LYN, MAP3K8, ΜΑΡΚΕ ΜΑΓΚΙΟ, MAPK14, MAPKAPK2, MAPKAFK5, MET, MKNK1, MKNK2, FAK2, PDGFRa, PDPKL P1M2, FKNf, FKN'2, PLKl, RRKACA. PRKCA, PRKCQ, RET, ROCK2, RPSÓKB1, SBC, SYK, TYK2. WNKL ZAP70, PIKSCD, F1K3CG, MTOR, PIK3C3, PIK3CA, P1K3CB and P1K4C8. 0027) When the plural form (for example, compounds, salts) is used, this includes the singular (for example, a single compound, a single salt). A compound does not exclude that (for example, in a pharmaceutical formulation) more than one compound of the formula you (or a same) is present, and 'Mjí' only represents the indefinite article. "And V 'can therefore be read preferably as Master or more", less preferably alternatively as one ".

0020) Whenever a compound or compounds: of the formula I are mentioned, it is also intended to include N-oxides of such compounds and the tautoners thereof.

The term and / or an N-oxide of! same, a tautomer of itself and / or a sai thereof (preferably pharmaceutically acceptable) especially means that a compound of the formula í may be present as such or in admixture with its N-oxide, I take tautomer (for example due to tautoms .-ris.mo keto-enol, lactam-iacima, amide-imfdic acid or enamma-imine. or in (eg "equivalence reaction caused) mixing with its tautomer, or as a salt of compound of the formula (1) and / or any of these forms or mixtures of two or more such forms.

(00301 be present invention also includes all suitable isotopic variations of the compounds of the invention, or pharmaceutically acceptable salts thereof. Lints isotopic variation of a compound of the invention or a pharmaceutically acceptable salt of the misino is defined as common) that at least one atom is replaced by an atom that has the same atomic number but an atomic mass different from the atomic mass usually found in nature. Examples of isotopes that may be incorporated into the compounds of the invention and pharmaceutically acceptable salts thereof include, but are not limited to, hydrogen, carbon, nitrogen and oxygen isotopes, such as copy H, 'IL ^!!C,^! C / X, ^,?N, ^:'O,' * O, '⁵S, ^{! S}r, ⁱ⁶C! Y^{! ii}í. Close isotopic variations of the compounds of the invention and pharmaceutically acceptable salts thereof, for example, those which a radioactive isotope such as * H or 'T is incorporated, are useful in studies of drug and / or substrate distribution in tissues. In particular examples, the isotopes H and '' C can be used for their ease of preparation and dectactability. In other examples, substitution with isotopes such as df can provide certain therapeutic advantages that result from greater metahyoic stability, such as increased life in vivo or reduction in dosage requirements. Isotopic variations of compounds composed of The invention or pharmaceutically acceptable salts thereof can generally be prepared by conventional procedures using appropriate isotopic variations of suitable reagents.

Description of the Preferred Embodiments | 0031 | The present invention MEK activity. In 'an embodiment,;

Composites of íormyla ia:

It refers to compounds capable of inhibiting you from the compounds of Formula 1, they are

<img file="CU20160020A7_D0004.tif" />

10032j in which 'R-; is selected from chloro and methoxy, Re · is selected from 2- · hydroxy-ethyl, 1- hydroxypropan-2- yl, 2- methoxy-ethyl, (3- meloxetan-3-i!) - methyl, methyl- suifbniSo, 2- aethoxyacetyl, 2- finoropropanoyl. 2- hydroxypropyl, eiciopropriosiosilonyl. isoptopüo- su bottom, 3- hydroxy-2- (hydroxymethyl) propylc-3- hydroxy-2- (hydroxymethyl) propane!_: oxetan-2- yl, dimethylearbamoyl, (2.2,2-trifluoroethyl) carbamoyl. ÍSI- 2hydroxypropanoiío, oxetan- 3- ílmetiío. 2- aminoacetyl, 2- methoxyacene, 2- hldroxíacetil. 2-hydroxypropanoyl, acetyl. 2- "mino-2- oxoelyl and carhamoyl; Ri is selected from hydrogen, methyl and hydroxymethyl; R&gt; is selected from hydrogen and methyl: IN is selected from hydrogen and fiuoro: R? is selected from hydrogen, ftuoro, chloro, CH-¡, CHF ;, CF, s. ODOR, eícioproprio and medium; and R¡ &lt;is selected from ciara »; or pharmaceutically acceptable salts thereof, 0033) In one embodiment; Additional are the compounds, or iarmaccmically acceptable salts thereof, selected from:

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- Ν 'jjfei / í (((( ^sÍÉ-ú -&gt;. Íl1 _:::.......... (faith faith,. &lt;Ñ Ά / Α.-fes ífefe

WO, faith--,

DO NOT'\ ,. \.faith\^N- 'Vy⁰¹ Goes _i; w A / N faith // /// faith

............

Λ, x /

F me- -_N.tfe ..O, ..Cf '' -fe / '·' / / fe- N-fe ¿i / i S feS &lt;i | S &lt;&lt;&lt;&lt;&lt;&lt; &lt;'* ^ faith. To faith

A, zx, Á 'n

X fes / z / -z fe / - 'Ν'S. | Ófe_to í \ fe .Ñ mA / feA

V^or

ON ”* 'f

&lt;.-fes.

N ~ faith h _r j faith // ' ^xv ··· —fe, ..'- 'faith / *

X / Λ. Z?

faith / '' faith or

iys tp

Did

S ----- N ''^x

N-faith

faith -χ faith N \ í- m / · -m. · - w

HO

X / • 'θ fe-fe'm ··' 'faith »· ^:·^ ·^{:::! ί:}

Cí ^v--&lt;

N-faith faith / 'faith

TO _ZOr to

O N - \ 'faith ·&gt; ·, N. ... Cfe, .z; s_v ... Ci ^V'Á / - »x / fe /» ·· faith. ·· • sV &lt;/ N faith. faith, faith / // 'faith /' 'x /' faith / Afe

S_: -.¡; ; S &lt;Sis^:

A, / faith faith 'Ν'

........ sil ^: ..........................

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ΖΛ &lt;

., 'or.

Ν- · '\ &lt;&lt; is (1 (111 (((ll (((' ílfe (^:· 'Fefe / faith As fes. , .α '-' 'faith / .- 1 ··, ·' ·; ··&gt; · / ÍSt-í faith:&gt;_: sjs ·}&gt; s faith.- »: mi N

<td>&lt;i</td><td></td><td></td>

<td>A / pAi-sfe * ..... Í (l (li (((</td><td></td><td></td>

N

-Ν., 0 '3' c.74,, - &lt;K, e¡ / 'go ¡ry 7 o Ν' χ ,, χΧχ, X ^ A,

-US 'X «&lt;-y * w

B φ 1 _FAA /

OR

.................................._.........................Your ...............

M - '\ &lt;/

N. „0. ^_VCI_{Ν λ &lt;} &lt; &gt;&gt;

N- \ _XN_X ..Or ..

V and

xN VΝ-_Λ_ΓΛ ./ „• 01 \

NV,

V \\ z XV fV '&lt;.......... lu' 'N-xN' U ....... &lt;^su &lt;_:

0 'r ..... \: · \ U /,.

HO x Cl -yv-y na, zr \ Z; x_x -.Λ \ z x&gt; &lt;sX ^{&gt; A}\&gt; v • &lt;X? X, Λ .N ^sh&gt; · '· XX X /

<td>f &lt;W</td><td></td><td>F</td>

<td>HG F \ -A N ~ - \</td><td></td><td>HG_V</td>

<td>\ j - vy</td><td></td><td>, .X Αχν, uTuu TT · TIjTT il</td>

<td>x ... Á V. Λ,, χ ·._χ , x. Y • XX ^sv X- ··&gt; · &lt;&gt;. · &lt;&gt; xV Η Γ 1 uuuu</td><td></td><td>ΧχΝ - \ ,, a ^: F</td>

<td>..... TT uuuuu ........... f us, ..... and_;&lt;:_:and (Vuu^: uu; F '' 'i' · 'q ··</td><td></td><td>F'</td>

N - \ 'XX X ··

V xl xi 'XXXX “N

Nx \

HO.

X ~ \, N. „0_x z \ Xf /

F ν vy y.pÑ Va,. . xt JF and

H0

... N_{x X}Q_S , CI ^x- 'X' ν \ ZV n- - \ x - N '· ··% í? *.

V \ Z% / V, i

XÁ, V • χ Ή '

<td>HO,</td><td>and HO,</td>

<td></td><td> ( ' ' \..-~·.</td>

<td>and x</td><td>H (1 (1 le ^: l (t '(((fe- (: fe-'fe.</td>

<td>ζ% -θχ_τν-_ν. · Ο ^ -χ; .., faith: --fe- - -: faith: -! ¡- - X &lt;&lt;V. -. : &lt;</td><td>faith_;; , Ν- ... Οχ χχ zOMé'-N '' i ί TY f</td>

<td>And, N A - M ex --X. .,^M &gt;’· ^v'·' '··· y. · Μγ &lt;γ ·</td><td>MY J .....} ί i i. jj</td>

<td>((cit (c ((((^: 1 ((1 - (. L; ((yJx (l: (yi3l (</td><td>:: :( Χ:_: 'faith  1 'faith. faith, '' (To J-Mfe (j. fe fefe</td>

<td>F '' fr '</td><td>l F 'xx Ή</td>

Y - QH

0^\ \ ,/'.^F

And ~ \

N- ~ \

HO, 1.

..OR. , 0.

Xy'í- * Y * '' X

X &lt;, N., / 'Xj' h -.- r- χ _γΧ

, .X XX

F 'N x, N_X ,. &lt;- x .XI ........

'' X./.·· yy ίψ ~: \ j: i (1 ¡c J 1 cl 1 (1, V ',.

, Ñ kvÁ. zxzí \ / ^&gt; \ _ Α · γ /. Ύ · '

„.Á-Á -&gt; '

F '' N

H0 ”\ ¿'

-x.

H0 ~ zO ^ wCiM ₍ /

i. - N hx Jk J ··, N

X. · ..- XX • χΧ. · - 'x \ v

Jl J. J

F

THE.

A ... O., Ζχ A h \ x, .N

MOLD'

N '\ xYAx, &lt;x Y &lt;· \ Ύ ··· &gt;&gt; ·

Μ t

-Neither

Xz '· X.- x&gt;

FY '

Or, /

N

Λ A - &lt;x -zC8 '' b x ': · vX,' r! \ P

I --NY /

<td>Μβ8</td><td>x „. &lt;</td><td>x¡x y.- y</td>

<td></td><td></td><td>faith 'J¡j'&gt; ·;_F- Xfe-</td>

'N'

HO.

Tf 1111 lllll ^ p 11 ji ......... ..... 11 τ&gt;^χ ít V · - x N- *_s\

VpZ &lt;5./kv ¡&lt;χ ·

HO.

N - \ ^T l K; Ν 'X-' V 'V'V „Á_&lt;;A. vi r N

HíN '· \

H · '· x- Rx, ..--- Q x ^F

<td>í 1¡ | η: oplORilpj</td><td>¿V fc • «Λ. ,&gt; 5x&gt; -X. Χ '.. χ ^Χ· Χχ 'ίχ, .χ</td>

<td>:: &lt;&lt;v</td><td>! i . . ρΛρ ·, χ'ί-Κ p &lt;\ pX&gt; '</td>

<td>—— ~ ™ ilssslssl) · ρ 1 lliisssilll^slss 111 ................ i ...............</td><td>\ -.0, s 0 no</td>

<td>χΝ_ν ...0_xf: T '</td><td>^ \. x &amp; T-- ' et Ó - '^KK: t</td>

<td>1 x; Ñ Ύ</td><td>or 1: I l^ζ&gt; χ. ✓ • '' S. χ'ΐϊχ, / FÍ -,_sY</td>

<td></td><td>X'S&gt;. &gt; · &lt;· - \ r 'ΧΟ&gt; ·'</td>

N-Α

N Ί,

OR

VX

HO .H,, 0,, ​​-.- χ,, υι ¡i d- rr tí

V, „.. N '\ í &lt;

xx ,,. 1 HOUR

Χχχ^ζ Ο, χ ”χχν '^ζ'\ γ]} J i, χ, X. ··, - / .- ρ · x&gt;' 'Jp * U

HO

Ν '„Μ&gt; ΧΤν, N, ι ·, x'L

F '- Ορp

H / 4- C * K5

Ι, χθγΑχΌ

HQ \ ~ -l \

Hl χ_τχ · Ov · - 'O / x&gt; &lt;&gt;&gt;' 'M' nifc ~ \, N. 70_x X.-X. , G: ------- r ύ r κ b ϊχ λ -, A^NχΧ-X 'x ^ .x χΧχ, - Χχ, χ, Χ

V i ....... iPOpP x ^ 'N'

ΗΟ

Ο

..... Λί

, .ν-., is

Ύ ν, χ γ

ΝΑ, / Ν

ΡΙΟ

η ..........

Ν- '·.

χ7 r Wv^aVA . ~: -Ρ

NA

Α-_;Α Ty-.-a./A/'S /: /&gt; * &lt;, · &lt;χί- 'ΚΟ \ - · Α hJ r \

-Ν. , 0. , -&gt;. , .C! '-TO . / '' Υ γ / γ N - Í ί ....... '· ή-;^- &lt;ϊ ^Λ·_ν,, Ν fo.

.Λ Ν Ά- '' Ύν '„/ ν Afo.A r' Ν

HC1

V-ο ^ \ _: fob / fú ........ _: γ (η ν-^Ν^ · Θ '._γί&lt;'4γ ···'^&lt;'^! Y-fo; Ν

Υ ../ '· .. / Υ / Α ζ ···&gt; Υγ'. &lt;

'Ν'

ΗΟ

Π

Ν., 0. ./. CI \ / ί'ί Ύ γ. ···, γ Μ · - · ζ \ \ „υ Ñ% Α yfo / p

Λ J. J

F Ό 'Κ'

Η, ΝΆ

Μ

, .Ν, .Ο. ./. Α-. .....

Ί Τ Τ 'Τ'Τ

Α^κ &amp; '^κ: Αγ&gt; fo '^:..... * - &lt;- Ί · - Ο

Ά^{&gt; Ν} γ / - ·. / A- υ, 0 * Λ- \

T.Á fo. J

W'A.

&lt;/ '' χ / foA'xW / Λ. .-J · / 'κΗ-_λΝ

4s ....................... 4^:Τ: ^ 4 &lt;

° V 'ς /

..Ν. Ζ &lt;\ / γ -Ο^νΆ, / if Ύ τ τ ν · τ γ ζ-.Ν k Λ. TO. , τ

Χ · &lt;ν · \ &lt;^ cy \ ίγ ·

44 ':!' '4'4foú | l)' 4Τ: Γ4 440

H¿.N

Η0&gt;, xU'-N '· λ, * Λ, &lt;../ &lt;

ΟΗ

ΝΛ

<td>Ν , 0 | ί ϊ Χ &lt;&gt; Ν</td><td>ζ: χ. .Ci^Χ- \ Τ and Ν- Α&gt; „, ζ-Χ yA /%</td>

<td></td><td>is 1 &lt;px iliépí zfii p- x.zz</td>

Ο

Ζ / η₂νΝ -'- '·&gt; 11 ^:ύΧ) Α1 5 /

-Ο

ΑΧ

Ci Λ χ &lt;. ··? - &lt;&gt; · 'Μ

ΗΟ

Ο

„... ¿?

'--Λ

Ν '- \

FOR

<td>X «YES T it</td><td>Np</td><td>• X^xx .- · χχ „. &lt;, '· ^vx, ........ 1 ...... you ...... Χ · | ΐχζ3ί11ΐδ</td>

<td>&lt;. n</td><td>zú Λ</td><td>í ΑχΑ ^ 8.</td>

V 'Ά' '' '' 'Ύ | 1ί | 1.,&gt; · \. Xr'-χ: ζ'λ ··¹

-ο- _1Γ_:|)))11|......_...........

Ν /). .-χ .CÍ ^ -'- Á / q γ- χ ^ χ, .-_Ν_&lt;

Ας, .Ν Κχ, / Χ ^ · &lt;χ ζ-4 ,,. ^ ^ ··&gt; &lt;ν 'χ) ·. · ^ -Σγ

Ο

ΗΟ ¿T

- ~\

Ν ο Λ F '&gt;:' '' γί '' Ά

Ν \

I ........

Neither

X, .- Ν Μχ ^ Λγ ^Ν .X. .Χ \.-Χ

F χ

Η, Ν x ~~ - &lt;

ΗΟ

Ν-A, - · \, · \ .Ν χγ, '· χ ^ χ x ^ xvy

H'-s λ: 'ν' A /

Ν ~ \ .-.

......^ζ

X._ν .Λ, JV Άχ Χ.Χ 'xy Χίχ: ί 5 ί ι Χχ &lt;&gt;'

F ^ν Ν

Ο

Η₂νΛ

X? 4 · \ '&lt;

χ Ν ,. &lt;χ_ν &gt;- ''.....~&lt;

V'j / X 'Χ. &lt;· -' \ _s

Χ, Ν Αχ ..,.

Ν-'λ '&lt;' χ, ζ χ \ χ &lt;- Χ&gt; .γ '

ΗΟ

Ν- ~ \ ν; χ. „νχ; ^ -Vi,

Α χ _χΡ Ν

Ν-Α xxs Λ, Ν

Χ'Χ ^χ_. sv¿vs Ρ \ /

S .. · '' ν 'Χ, χ ^ *

1^ζιχ^: R 'Η' ¹

HC

\ .., X

N ~ \ í 7?

Μ —-Ί rtyN '

N-'t

XZ · '' \ Z ^&gt; / Ύ. N., 0. xtu, F Γ Ύ γ-- 'and N-γ

XN UV ^ vA?

L

H? N '' V

BQ, hk _x0. , F ^Χ· ~ Λ &lt;“X&gt; &lt;ν, .ζ'ζ · ', 7X .'X

O 'V ,, N

N- «XM

XZ -'Y '· &lt;γ' χ; γ

F γ

ΙίΝΛ

N ~ \

, .N, .0. , &lt;·, .0;

• S \&gt;. X MZ v. * ··

Ν ~ -λ

FN

OR

\ .X

N · ”-, _X.N_X ...OR. , C&gt;^x- \ / &lt;- v vz XN -p

Γ; i :::!, &lt;P &lt;&lt;: ', · &lt;W. ! &lt;? · ¥ 1 í -, 1 1 í ji &lt;: f: SK:^:lft¡ 'Χ'., Β ^;· Χ z · '^ / ¼, .Z \_X. , ^TO

..... Lí íjLl í / X idl!

, ,, * x. .;&gt;_s .

BO

\ .- ~ 4 iBx

TO

, .N \ zO-, &lt;m zCI '-'Á ·, · γ X,., · - Y

XA X.&gt;

'; χ_Λ . N o · · · • \. ·· · &lt;&gt;? · '“Xas ··'&gt; x Z '\ XF' \ z γ '•', 'γ

1-¾. Ν ..0 .. zx, F^VX '\ v ~' yz, γ · N - \ &lt;- M km ik, Λ N ms - '* χ, - ·' -ν, Χ '' Xt ··· m &lt;Z

Í &lt; ^.............. x jf? '' t^::S^: : &lt;'£:

O \ -A

Ν '• Νΐ, Οχ Y_{x eí}\.. -\ /

X η Ϊ 'V Βγ _:faith »ο »: ib íhzbüé &lt;&lt; tim ·^ϊ: &gt; X ·· 'íb mm · · ^x &lt;iz \ z -X..XX \, z&gt; Όχ “\. Zj, vx .. &lt;γ, .γ: · \, ι&gt; zr N&gt; X^{&gt; v}v &lt;&gt;

υ, ν

FSC - \ XN ~ '\

BN * \

........ t ..... iixtitusk / xld π ..., .C!

Z \ .Χ- · »z m .. · γ γ γ • Z'k X'z '^TO'Y •' XF 'X&gt; γ

BQ

OR

\ .χ

ΝΆ

..0. , rm,, 0i z- γ γ γ ¡ψ .._;.

'Xv- ^ Av-'

X. * ÍZ.

OR

HO, \ __ H 'n, N „..O, ..n,, C^iV\, /

-: N n-%.

A / AAJ

FH '

TO.

jaoMj

In another embodiment, compounds of the formula Ib were presented:

<img file="CU20160020A7_D0005.tif" />

ib | 0035 {in which: n is selected from O, l and 2; R¡ is selected from:

OR,

R / rf A, assid

VWv

TO_v

Xs ·· 'Ό,

..one. A JOÍESÓj R? it is selected from chlorine and methoxy; R &amp; is selected from cyanomethyl, 2 * hydroxy ethyl, i-hydroxypropan- 2- 2-, 2- raeloxy-ethyl., (3- methylxetan-3 ~ ib-methyl, methyl-suifonyl, 2- illuoropropanoyl , 2- hydroxypropyl, cyclopropyl-sclfonyl, isopropyl-suifonyl, 3- hydroxy-2- (hydroxymethyljpropyl, 2- aeethoxyacetite, 3- hydroxy-2 (hydroxy-inctihpropanoikx dimerylcarbamoite, (2,2,2-trirtuoroeüí) caiby «wito, (S) ~ 2-hydroxypropanoite, oxetan- 2- iio, oxeían- 3- ilmetito, 2- amirsoaccept, 2 ~ methoxiacstlto, ?. ~ hydroxyaeetite, 2- indroxypropanoxy, acetyl, 2- amino-2- oxoetite and carbamoite; R₄ it is selected from hydrogen, methyl and htdroxymethyl; IN is selected from hydrogen and methyl; and R? it is selected from hydrogen, iluoto, chloro, CiTF, CHFs, CE CHjOH, cielopropyl and methyl; or pharmaceutically acceptable salts thereof. 10037) In a further embodiment are the compounds, or pharmaceutically acceptable ones thereof, selected from:

<img file="CU20160020A7_D0006.tif" />

<td>NS \ ._ / '&gt;</td><td>N,</td><td>**In 1</td>

<td>O-,, 0, -Cl /</td><td></td><td>O, XI '“X / i</td>

<td>Ύ YOU Ύ</td><td>And ¡í</td><td>x 3r 'n- · ?, i</td>

<td>, N .... N X&gt;,, -X: - y χγ xy</td><td></td><td>Y., 'Λ. TO._SNeither í B í or í o i</td>

<td>¿Zk. χΕ-k. Xz F ”X 'Ή</td><td></td><td>&gt; * &lt;/ A XR * FN |</td>

[0038J

<img file="CU20160020A7_D0007.tif" />

[0039 | Where: or so is selected from 0, 1,2 and 3; AND; is selected from doro and methoxy; fU is selected from illuoro; and, optionally, two groups R.¡ together with the carbon atoms to which they are attached, form (CS-Vh. j ~ · í for example, 8itf &amp; bívieto [3.2. Hocían- 3- iloy Rj is selected from hydrogen and methyl; FE is selected from hydrogen, and E? Is selected from hydrogen, fluorine, chlorine, CHjF, CHFj, CFj. CHjOH, Cielopropyl and Rneyl; or pharmaceutically acceptable salts thereof.

(0040) In a further embodiment there are the compounds, or iáíroaecuííeamcnte acceptable salts thereof, selected from:

Ν'Ά \, ·&gt; ρ r ~ \ .._F_{} ί}^·''^Ογ ^ γ^α 'Ά ·· /

: ..... &lt;....... | i¿; .....&gt; \ 4 &lt;Μ ,, · Α. , «· Ύ · * · 'Ν ... · Ζχ &lt;

Ρ ν&gt; · _Ν • ^ -y, wr^Q- '' 'W s &lt;íh &lt;^: ....... JóAp '&lt;&gt; χ ·' \ / V / •?. and and záx. .'í⁷', - · .Ν, N, A zr. ¿'ΛΑ /., - .._ifz _XN„.^

. Z - .. N

Ά; · / V

7- ~ 7- \ ζΝΆ t / yww | 5L, N,, &lt;?. z-í ^ -s.

z; -xv y · r xA

ΆΧ 'Χ., -' Ά ·

N ~, \ ζ N ^xsy

tC '

N '

ΚΪ04Ϊ); t! another embodiment compounds of the tonnuia id are presented;

-YES ~ A

W- “S / O 7f!

~ .··· ·'&gt;

\. / &amp;¿

... , R,^x- \ z ⁵ * N -; \ jS 'O- z «' ** S &lt;.Χγ * 'Vh Ά · Rr id (f042 | in which n is selected from 0, L 2 and 3; R₂ it is selected from chlorine and methoxy; R $ ¡¡is selected from 2- hydroxy ethyl, 1- hydrexfpropan-2- mess, 2- methoxyethyl, (3- medioxeían- 3 ·· il) - methyl, methyl-suiónonil, 2- hydroxypropyl, 2 - aethoxyacetyl, 2fluoropropanoyium, cyclopropyl-suiphoniplo, oxetan-2- yl, isopropyl-suiphonipho, 3- hydroxy-2 (hydroxymethyl) propyl, 3- hydroxy-2-hydroxy-mtrtji) propartoifo. dimeülearbamoyl, f2.2,2trifhjoroeui'jcarbamoiíe, {$) - 2 ~ bídroxipropanollo, oxetan- 3- ilmeíilo, 2- aminoacetyl, 2methoxyacetyl, 2-hydroxyacetyl. 2- hydroxypropanoyl. acetyl. 2- amino-2- oxoetiio and e &amp; rbsmoilo; R., is selected from fiuoro; and, optionally. two groups Rejoined with ices carbon atoms to which they are attached, form - {CH₂} 2- j -; &amp; 5 is selected from hydrogen and methyl; is selected from hydrogen and fluoro; and R; hydrogen is selected from hydrogen, Huero, chloro, CHjF, CHÍA, CF ?, Ci-bOH, cyclopropyl and methyl: or the pharmaceutically acceptable salts thereof.

(0043] In a further embodiment are the compounds, or pharmaceutically acceptable salts thereof, selected from:

<img file="CU20160020A7_D0008.tif" />

[0044] In another embodiment, compounds of the formula le are presented;

<img file="CU20160020A7_D0009.tif" />

le ¡0045] in which: IGa and R-í »are derived from - (R, t)_n; in which n is 2; and Rj of

Summary of the Invention is defined by 1¼ v fiqy, in which R ^ ¡¡is selected from hydrogen and methyl; and ÍGs is selected from hydrogen and ... fluorine; R¡ is selected from:

fV '

Rt

, .N. GARLIC

Rs γ

Rr ν 'Λγ ·'

Ύ

R_?

OR.

. Jsfid sAAJW r

Rf

IOO4é |

Ri is selected from chlorine and methoxy; Ry is selected from 2-hydroxy-ethyl, 1 · hydroxpropyl &amp; n * 2-, 2-methoxy-ethyl, (3- mebioxetan-3-yl) -methyl, methyl 20-alkyl, 2-acetoaiaethyl. 2- fiuoropropanoyl. 2- hydroxypipepipe, cyclopropyl * suU'onyl, isopropyl-tmlforolo, 3- hydroxy-2- (hydroxymethyl) propyl_F 3- hydroxy-2- (hydroxymethylpropanoium. Oxidized-2 "yl, dimedlcarbamoyl, {2,2,2-trinuoroct: 1) carbamoyl, (S) -2h. Hydroxypropanoyne, oxetan-3-ylmethyl, 2-aminoacetyl. 2- methoxyacetyl, 2-hydrox tacen, 2-hydroxypropanoyl, ethyl, 2-amino-2-oxeetil and carbamoyl; is selected from hydrogen, methyl and hydroxymethyl: IT is selected from hydrogen and methyl; R? it is selected from hydrogen and last; Rr 3 is selected from hydrogen, ileus. Chlorine, CH2E. CHfo, CFj, CH&gt; OH, own sky and meóte ;; and is selected from silt, or pharmaceutically acceptable salts thereof.

| {) 047 | In a further embodiment there are the compounds, or a pharmaceutically acceptable one thereof, selected from;

and ° v. ~ 4

N-

<img file="CU20160020A7_D0010.tif" />

&lt;rr h-Vs .x &lt;y. . &lt;&gt;, .- 'S; N_z-'x, _Z&lt;'^TO\

F '-O -_N·

N 'ióE, N_S ... G .._x ,..-_v , G /: \ v rty · \ ξγ ·. :&gt; ψ — and .N, ..O,, C;

\ V 'y' • ¿y '

.. L (7 N t · 7 ^: . rrrrm'p ···· \ V.

<img file="CU20160020A7_D0011.tif" />

Ν '&lt;V'^F , ~, C! &lt;&lt; / r-í- 'V

OR ^: I ••• vN. · -N,

N-í, 'SSb /&gt; -, xÁ&gt; v .----' ^ γ

Additional reactions of the invention: Reaiizadón L A compound of the formula Ϊ:

^l3rd.

R_K

RZ V⁵'V

N - A vv

Λ Λ i

ÍV '' M 'where a is selected from 0.1, 2 and 3; R 'is selected from:

R_? ¡&lt;% A

Re N \ i ^!

R_? Ν V ¡y &lt;&gt; y¿

OR,

OR.

0VW vs

Rz is selected from chlorine, methyl, hydrogen, fluoro and methoxy;

R '^j is selected from eianomethyl, .2-hydroxy ethyl. I- hydroxyprn-2- fio. 3- hydroxy2- (hydroxymethyl) pfopanoiium, 2- methoxy-ethyl, 2- finoropropannife, 3- methyl-axtan-3- ii) methyl, methylsulfonyl. aminocarbonymethyl, eielopropd-sulfenite. Isopropylsulophil dimethyearhamoyl, 3- hydroxy- 2- (.hydroxymethyl) propife, 2- hydroxypropyl, 2-tidroMaceíSSo. 2- acetcxiacetíio, 2- metoxtacetiio, (2.2,2-trinuoroethylofearbamotlo. 2 aminoacetyl, oxeania-3- ioethio, (S) · 2- hydroxypropanoyl, 2- mdroxypropanoyl, acetyl. 2 aromo-2- exceeded, carbamoyl, toxetan-2- lio) -methanoyl, 2- (xulfeosi aeetüo, 2fluoroetanoiks, 3- hydroxypropanoyl, and N, N-dimctylsoifcnamidyl:

each R "is independently selected from hydrogen, halo, methyl and hydroxymethyl; and, optionally, two groups IV together with the carbon atoms to which they are attached, form

<img file="CU20160020A7_D0012.tif" />

Rs laughed, he

R^: be^s Yo lo se

Rs is selected from hydrogen and methyl;

Rí, is selected from hydrogen, methoxy lo and halogen;

R^: is selected from hydrogen, iltt oro. CF '\ C1TOH, eidopropyl and methyl; Y

R is selected from eiano;

or pharmaceutically acceptable salts thereof.

E mbodiment 2. The compound of the formula i according to claim k is where n is selected from 0 or í;

• IV is selected from;

<img file="CU20160020A7_D0013.tif" />

N,, -. N 'i

OR.

<img file="CU20160020A7_D0014.tif" />

<img file="CU20160020A7_D0015.tif" />

R ¿is selected from chlorine, methyl, hydrogen, floor and methoxy:

R^?to is selected from damage-methyl, 2- hydroxy-ethyl, I-hydroxypropyl-2-lio. 3- hydroxy2- ('hydroxymei) propanoib, 2- methylene ethyl; 2- llaoropropanoyl, (3- methyloxetan-3- í!&gt; ​​Methyl, methyldisphonium, amine-earbonylmethyl, ciciopropih sulforsílu, isopraptí-suifonsío, dtmcíilearbamoyl, 3- hydroxy-2- (hydroxy-tnetyl) propyl. 2- hydroxypropyl, 2-hydroxyaethyl, 2- a-yioxyacetyl, 2- methoxyacetyl, (2,2,2-trifluoroethyljcarbamoykx 2-aminoacetyl, oxetane-3-methyl, CS) -2-hydroxypropanoyl, 2-hydroxypropanoyl, acetyl, 2-simino oarbamoyl, ioxetan-2-yl) -methanoyl, 2- (styloloxy) acetyl, 3-fiuoroetanoyl, 3- hydroxypropanoyl, and N, N-dnnetiisulfonamidium:

every R₄ $ e independently selects from halo, methyl and hydroxymethyl;

Rs is selected from hydrogen and methyl;

R &lt;: is selected from hydrogen, methoxy and halogen:

R^? it is selected from hydrogen, rluoro, CF ', CITQH, cyclopropyl and methyl; and R * is selected from eiano; or pharmaceutically acceptable saies of the same.

Embodiment 3, Ei compound of the formula i, according to claim L wherein n is selected from 0 or I;

R¹ is selected from;

l ^r ,

Y

R_?

Rv is selected from chlorine, methyl, hydrogen, Huaro and methoxy;

R^&gt;3 it is selected from cyano-methyl, 2- hydroxy-ethyl, i-hydroxypropan-2-yl. 3- htdroxí2- (hydroxymethylpropanofio, 2- methoxy-ethyl, 2- illuoropfopanoyl, (3- methylxetan-3- ii) methyl, methy! - snifontlo, amino-earbonylmethyl, eieiopropi-suíímlc, isopropyl-suifbnílo, dimstilearbamoyl , 3- hydroxy · 2- (hydroxymethyl) propium, 2- hydroxypropyl, 2 hydroxyacetyl, 2- aethoxyacetyl, 2- methoxyacetyium, (2,2,2-tríí1uoroethio) carbamoi! O, 2-aminoacetyl, oxetan- 3- imimethyl . (2-hydroxypropanoyl, 2- hydroxypropanoyl, acetyl, 2-amino-2- oxoethyl, carbamoyl, (oxetan-.2-yl) ·· methanoyl, 2- (suifooxy) aethyl, 2-fluoroethanoyl, 3- hydroxypropanoyl, and N, N-dimethisúlfonanúdilo;

each IL is independently selected from halo, methyl and hydroxy * methyl; B-5 is selected from hydrogen and methyl;

Rs is selected from hydrogen and halogen; Y

R- 'is ​​selected from hydrogen, fluoro, CP *, CJ-ROH, cyclopropyl and methyl; Or pharmaceutically acceptable salts thereof.

Realization í. The compound of the formula I according to claim t, wherein n is selected from i) or I;

R¹ is selected from:

R_z it is selected from chlorine, methyl, hydrogen, fluoro and methoxy;

R^{? i} so it is selected from mano-methyl, 3- hydroxy-2- (hydroxy-mctyljpropanoyl, 2- meioxyethyl, 2- flooropropanoyl, (3- methioxetan-3- yl) -methyl, methyl-sol, amino-carbonylmethyl, ekdopropyl-sujfontlo , isoproptl-solfonyl, dirnetylcarbamoyl, 2- hydrox lacerated it, 2acetoxyaceolo, 2- methoxyacetiium, (2,2,2-trifluoroethyl) carbamotlo, 2- aminoacetyl, oxetan-3iimethyl, ($) - 2- hydroxtpropanoyl, 2- hsdroxypropaneyl acetyl, 2-amino-2- oxoethyl, carbamollo, (oxetan-2- mess) -methanoyl, 2- (suipkoxy) acetiium, 2- tlnoroetanoyl, 3-hydroxypropylyl, and N, N-dimethylsulfonamidyl;

each R4 is independently selected from halo, methyl and hydroxy 'methyl;

R5 is selected from hydrogen and methyl;

is selected from hydrogen and halogen; and R 'is selected from hydrogen, fluoro. CE, CÍEOH ,. c lefopropyl and methyl;

or the pharmaceutically acceptable salts thereof;

Embodiment 5. The compound of the formula i according to claim I, wherein n is selected from 0 or 1;

R^! is selected from.

R_;. it is selected from chlorine, methyl, hydrogen, Huero and methoxy;

R^J3 is selected from 3- hydroxy-2- (hydroxymethyl!) propane. 2-fluoropiopanoyl, (3-methioxethan-3-yl) -measured, motyl · sulfonium, amino-carbonyl-medium, cyclopropyl-sulfonium, isopropyl-sulfonium, dimethylcarbamoyl, 2-hydroxyacetyl, 2-aceto; iaced lo, 2- methoxyacept, (2,2,2-uro.inuoroethyl) earbamoiio, '2- aminoaeeíjio, oxeían- 3- ilmethyl, (S) - 2-hydroxypropanollo, 2-hydroxypropanoium. acetsio, 2-ambo- 2- oxoctyl, earbamoyl, (oxetan2- i So) ·· methane, 2- (sülfooxí) acetiSo, 2- fluoroethanyl. 3- hydroxyprepanoite. and N, N ~ dimeíik «f fonamidí lo;

every R_;} it is independently selected from halo, methyl and hydroxymethyl;

R $ is selected from hydrogen and methyl;

R &lt;_; is selected from hydrogen and halogen; Y

IV is selected from hydrogen, fluorine », € F \ CH'OH, cielopropyl and methyl; or the fsrmsecutically acceptable salts thereof.

Embodiment or, Ei compound of formula 1, according to claim E wherein n is selected from 0 or i;

Rl is selected according to;

ro

Ry

Ri is selected from chlorine, methyl, hydrogen, fluoro and methoxy;

R- '³ is selected from 3- hydroxy-2- (hydroxy-methyl) pfopaneOo. 2- flnoropropanoyl, methylsulfonyl, cyclopropyl · sulfonium, isopropyl-sulfonium, dimethylcarbamoyl, 2- hydroxylacenne, 2acetoxyacetyl, 2- mctoxyacetyl, (2.2,2-trifluoroethyl'toarbamoite, 2- ammoaeethyl, (S) --hydroxyl, (S) --hydroxyl, (S) --hydroxyl, (S) --hydroxyl, (S) --hydroxy, acetyloxyl, (S) , curbarnolium, 2- fsutfooxyiacetyl, 2fluoruetanoyl, 3- bidroxypropanoium, and N &lt;N-dimethylsulfonamidite;

each Im is independently selected from halo, methyl and hydroxymethyl;

<img file="CU20160020A7_D0016.tif" />

Rj is selected from hydrogen and methyl;

Rt is selected from hydrogen and halogen; Y

R^? it is selected from hydrogen, fluoro, CF '\ OH, cyclopropyte and put it; or pharmaceutically acceptable salts thereof.

Embodiment 7 "The compound of formula 1 according to claim 1.

where n is selected from 0 or i;

R · is selected from ¿

R., 'A, &lt;&gt; and * 75 ,:. ·: ·

,.;&gt; N '

TO

Ry

Ri is selected from chlorine, methyl, hydrogen, illuoro and meioxyl;

R^{3; i} is selected from 3- hydroxy-2- (hydroxymethyl) propanoyl, 2- fluoropropanothiomethylcarbamode, 2- hydroxyactyl, 2- aesiexíaestilo, 2- fnetoxíacefiio, (2,2,2 trifluoroethylolearbamoyl, 2- amino &amp; cctilo, (S) · 2 - hydroxypropanoyio, 2- hydroxiptopaooyl aceíiio, earbamoüo, 2- (suliboxi) acerilo, 2- fuoroetanoiio, 3- hydroxypropanoiio; each K4 is independently selected from halo, methyl and hydroxymethyl;

R $ is selected from hydrogen and methyl;

R &amp; is selected from hydrogen and halogen; Y

R⁷ it is selected from hydrogen, iluoro, CF \ CH'OH, cieiopropyl and methyl; or pharmaceutically acceptable salts thereof,

Embodiment 8. The compound of formula 1, according to claim i, wherein n is selected from 0 or 1 .:

R^! is selected from:

<img file="CU20160020A7_D0017.tif" />

R; it is selected from chlorine and mephóxtio;

R^,:1 Shabby 3- hydroxy-2- (hydroxy-mctyl) propanotium is selected. 2- fluoropropanoyl. dtmetílearbamoüo, 2- hydrixixycyl, 2- aceioxyacctyl, 2- methoxyacetiium, (2.2,2lrínuoroei¡k&gt;} carbamoík ?, 2- aminoacetyl. tSb 3- hydroxypatywiium, 2- hydroxypropannile. acetyl, earbarncyl. 2- (std.t't'flio , 2- fiiRfroetanoik! And 3- htdroxiprofjanoil, each R &lt;is independently selected from halo, c-hydroxymethyl medium;

Rs is selected from hydrogen and methyl;

R&gt;, is selected from hydrogen and halogen; Y

R^; is selected from hydrogen, fluoro »CF '. C1TOI I, cidopropy and half; or pharmaceutically acceptable salts thereof.

Embodiment 9, compound compound of formula 1, according to claim I.

where n was selected from 0 or I;

E: is selected to. from:

R; it is selected from chlorine and methoxy;

R^JS is selected from 3- hydroxy-2- {hydroxymethylpnopanoyl, 2-luoropropanoyl.

dimethylarbamoiium. 2- hydroxktcephyte. 2- acetoxntcetyl. 2- methoxyacetiium, (2.2,2 • rifinoroctíioícmbmnoiIO. 2- armnoacchio, (Yes- 2- hydroxypropanoyl, 2- hydroxypropanoyl, acetyl, carbamoyl, 2- (sulidoxQacetyl, 2- finoroethanoylcite and 3- hydroxypropanoyl; each Ra is independently selected from of balo, methyl and hydroxymethyl;

Ri is selected from hydrogen and methyl;

Re: is hydrogen: and

R: ..hydrogen;

or pharmaceutically acceptable salts of coughs themselves.

Restateaone 30. The compound of the formula I. according to claim I, wherein n is selected from or or i;

R · 'is selected from;

2S λr 'ΐ.

AA 'ν'

Ri is selected from chlorine and methoxy;

R^ia it is selected from 3- hydroxy-2- (hydroxy-medlipropanoyl, 2- yluoropropanoyl »dimethicarbamoyl, 2- hydroxyacetyl, 2- acetoxíaethyl. 2- methoxyacetyl, (2,2,2-tri-etiotearbamoyl, 2- amyrtoacetyl, (S) - 2- hydroxypropanoyl , 2- hydroxypropanoyl, aeetiic, carbamoo, 2- (snifooxOacetiio, 2- phytioroetanoyl and 3- hydroxypropauoyl; each R &lt;is independently selected from halo, methyl and hydroxymethyl;

R $ is me:

R &lt;¡is hydrogen; Y

R? it is hydrogen;

or pharmaceutically acceptable salts thereof.

Carried out Ȓ f, The compound of the formula L according to the claim wherein n is selected from 0 or i;

R 'is selected from:

_XN „\ s' &lt;γ'Ί.

«AV * 7

R ^ is selected from 3- hydroxy-2- (hydroxy-tnetyljpropansyl, 2- -luoropropanoyl. Dimeriicarbamoyl, 2- hydroxyaceiyl, 2- acetoxyacetiium, 2- meioxyacetUo, (2,2,2-trifluoroethyl) carbamoyl, 2- aminoacetiium, ÍS} - 2- hsdroxypropSnoiium, 2-hydrodipipropanoyl, acetyl, carhatnode, .2- (suifooxy) acidic, 2 ~ forooroatao and 3 ~ hydroxypropanoyl; each is independently selected from halo, methyl and hydroxymethyl;

Rs Emery:

Rs is hydrogen; Y

R? it is hydrogen;

or pharmaceutically acceptable salts of the misinos.

Embodiment 12. The compound of the formula according to claim 1, wherein n is selected from 0 or 1, R 'is selected from:

, «U v Ij- · &lt;γΆ ^: R?

: .R¿. escioroc

R^ha is selected from 1- hydroxy-2- (hydroxymethylpropanoyl, 2- fiuoropropanoyl, 2-hydroxyacetyl, 2- aethoxyether »2-methoxyacetyl. 2- aminoacetyl, (S) -2-hydroxypropanium. sulxyboxeacetyl, 2-fruoroethanyl and 3-hydroxypropanolium, each R¡ is independently selected from halo, methyl and hydroxy · 'methyl;

Rs is methyl;

Rs is hydrogen; Y

R? it is hydrogen;

or pharmaceutically acceptable salts thereof.

Embodiment 13, A compound of the formula le;

<img file="CU20160020A7_D0018.tif" />

where

R^! is selected from:

V fr, N

<td>, .N _X V íf U</td><td>will</td><td>WILL &lt;.............. jt ....... TX &lt;.</td><td>) Y</td>

<td>, 4 „Ñ '</td><td>The '</td><td>Ñ ​​J</td><td>Ñ</td>

<td>VT</td><td>Ύ</td><td>-yes- I</td><td></td>

<td>r₇</td><td>R?</td><td>R_?</td><td></td>

Λ

i.

-N

Ύ R

OR.

A, H, A '^A.M ., x^s? * SJÍI ··

OyK .Ñ, J ib is selected from chlorine, methyl, Huero and meioxyl;

R^ha is selected from cyanomethyl, 2- hydroxyl-ethyl, i-hydroxypropan- 2- ib, 3- hydroxy2- (hydroxymethylpropanoyl. 2- methoxy * ethyl, 2- Huoropropanaile, (3- methylxetan-3-11) methyl , ineti-sulfonyl, aminocarbonymethyl, cyclopropyl-sulfonium, isupropyl-sulfbnik), dimethylcarbatnoyl, 3- hydroxy-2- (hydroxymethyl!) propionic, 2- hydroxypropyl. 2-hydroxyaethyl, 2- acetoxlacellyl, 2- methoxyacetyl, (2.2,2-trifiucroet'dojcafbamoifo, 2-arninoacetyl, oxetan- 3- ihneil, (S) ~ 2- hydroxypropro &amp; noylc, 2- hydroxypropaooyl. carbamoyl. (oxetan-2- ito) -methanoio, 2- (stioxyo) acetyl, 2fluc'i'oethanoyl, 3-hydroxypropanoyl. and N, N-dimethisittonamidite;

&amp;&amp; is hydrogen;

fUb is selected from hydrogen and fluorine;

Ib is selected from hydrogen and methyl;

R, s is selected from hydrogen and fluorine;

R⁷ is selected from hydrogen, {lauro, CF³, CÍ.-FOH, cyclopropyl and methyl; Y

Rs is cyano;

or pharmaceutically acceptable salts thereof.

Embodiment 14, £ ¡compound of the formula le, according to claim it, wherein

R^! is selected from;

if'V Λ λ *

Rt

<td>rV R .; '·^N</td><td>k .- '. Ñ T</td><td>V^? ·</td><td>N</td>

<td>R?</td><td>Rt</td><td></td><td></td>

Αγ /! 4

Ύ

or..

° γ · ^ Λ., Hk, &lt;Ν

0._χ .ÁΎ ^χ Η, £! .XÍ

ο. , Χ, γ Α

R₂ it is selected from doro, methyl, ftuoro and methoxy;

R '³ is selected from damage-medium, 2- hydroxy-ethyl, l-mdroxypropan-2-yl, 3- hydroxy 2- (hydroxy-medipropropanoyl, 2- methoxy-ethyl, 2- lluoropropanoyio, (3- methioxeian-3-i) methyl, rneti-sulfonyl, asnin-carbonylmethyl, cyclopropyl-sulfur, isopropyl-odfoniium dlmetiicarbamoyl, 3- hydroxy-2- (hydroxymethyl!) propiic, 2- hydroxypropyl, 2 hydroxyactyl, 2- acetoxyacetyl, 2- Methoxyaceedium, (2,2,2-trifluoroethyl) carbamoyl, 2 aminoacetiium, oxetan-3- I, (S) - 2-hydroxypropanoyl, 2- hydroxypropanoyl, acetyl, 2-amino-2- oxoeido, earbamodo, (oxetan-2- iiotomethanenoio, 2- (sulfooxitacctyl, 2 fluoroetanoyl, 3- hydroxypropanoyl, and NN-dimctiisuifonarnidium:

Rs₃ is not;

Rjí »: it is fluorine;

Rt: is methyl;

R &gt;&gt; is selected from hydrogen and fluoro;

R⁷ it is selected from hydrogen, fluorine », CF ', CH'OH, ctcicpropiio and methyl: and R scian;

or pharmaceutically acceptable salts thereof,

Embodiment 15, The compound of the formula le, according to claim 13, wherein

R 'is selected from;

, Λ J

Re Ύ R_T

Rí is selected from doro, methyl, fluoro and methoxy;

R '^to is selected from cyano methyl, 2-hydroxy ethyl. I- hydroxyprppan-2-yl, .3-hydroxy2- (hydroxymethyl!) Propanoyl, 2- methoxy-ethyl, 2- fiuoropropanoyl, (3- methioxetan-.3-yl} ~ methyl, dipped suiphonium, smtno-carbonyl - methyl, cyclophoplopyl swifonium, isopropylidene, dimethylcarbamoyl, 3-hydroxy-2- (hydroxymethyl) propyl, 2- hydroxypropyl, 2-hydroxyethoxy, 2- steel-acetyl, 2-methoxyacetyl, (2,2.2-tnfluoroethyl ) carbamoyl, 2 aminoacedpho, oxetan-.3 * ümethyl, (S) -2-hydroxypropanoyl, 2- hydroxypropanoyl, hazel. two antino-2- oxoethyl, carbamoyl, (oxetan-2-lio) -methane, 2- (sulfoxyjacetyl, 2-fiuoroetanoyl, 3- hydroxypropanoyl, and N, N-dimethylsulfonarnidyl;

R,_{} i} it is hydrogen;

Ras sphincter:

Rs is methyl:

Re is selected from hydrogen and fluoro; Y

R^? is selected from hydrogen, CP³, CH * OH, and methyl;

or the pharmaceutically acceptable salts of the misinos,

Embodiment 16. The compound of the formula le, according to claim 13, wherein

R^! is selected from;

% 7 «V^KF^N

Rt

R;&gt; is selected from doro, methyl, fluoro and methoxy;

R '”is selected from damage-methyl, 3- hydroxy-2- (hydroxymethylipropanoyl. 2- methoxyethyl, 2- illuoropropanoite, (3- methylxetan-3- it&gt; methyl, methylsulfonyl, amino * carbonyl · rnetyl. Ddopropyl. - sulfonyl, isopropyl sulphite, dimelylcarbantoyl, 2-hydroxyacefue, 2acetoxyaethyl, 2-meioxyacetyl, (2.2,2-trif! uoroethyl) carbamoyio. 2- aminoacedio, oxetan-3-methylmethyl, (S) -2-hydroxypropanoyl, 2- hydroxypropanoyl, acetyl, 2-saline-2- oxenenlo, 33 carbamoyl, {oxetatt- 2- yl) »nethanoyl, 2- (s« lfooxy) aeetyl, 2-fiuoroeianoyl, 3-hydroxypropanoium, and N, N-dimethylsulfonatnidyl; It is hydrogen;

Rat, it's fluorine;

Rs is methyl;

Rs is selected from hydrogen and fluoro; Y

R⁷ is selected from hydrogen, CF^J, C'f ͲOH, and methyl;

or pharmaceutically acceptable salts thereof.

Embodiment 17. The compound of the. formula le according to claim 13, wherein

R 'is selected from:

f. » ^Rs'

R?

Rz is selected from chlorine, methyl, fluoro and methoxy;

R^Jd it is selected from eianomethyl, 3- hydroxy-2- (hydroxymethyl;) propanoxy, 2fluoropropanoyl, methyl · '· sutfoniium, cyclopropyl-suiphonyl. isopropyl-sultonyl, dithnellylcarbamoyl, 2- hydroxyacetyl, 2- aceioxyacetiium, 2- methoxyacetiium, (2,2,2-trifluoroethyl-arbamoiium, 2- aminoacetiium, (S) - .2- hydroxypropanoyl, 2- hydroxypropanoxy, acetylium, earthio, ear-2 - ii) - methanoyl, 2- (sulfooxyjaccyl, 2-fiuoroctanoyl, 3-hydroxypropanoium, and N, N-dimethyl dihydrogenase;

INá is hydrogen;

Rw is fluorine;

Rs is methyl;

Rs is selected from hydrogen and fiuoro; Y

R⁷ is selected from hydrogen, CF * \ CHOH, and methyl;

or pharmaceutically acceptable salts thereof.

Embodiment The compound of the formula ie, according to claim 13, wherein

R * is selected from:

and N, π _: *

R-; it is selected from chlorine, methyl, fluoro and methoxy;

R^3rd is selected from eianomethyl, methylsulfonyl, 2-hydroxyacetyl, 2-aethoxyacetyl, 2-methoxyaethyl, (S) -2-hydroxypropanoyl, acyl, aethylcarbamoyl. {oxetan-2- ii) -methane, 2- (sultboxi) acetiium, 2- fluoroethanoio and 3- hydroxypropanoyl;

Rta is hydrogen;

Fbb is fluorine;

R, is methyl;

R &lt;. it is selected from hydrogen and finoro; Y

R 'is selected from hydrogen, CF^J, CH³OH, and methyl:

or pharmaceutically acceptable salts thereof.

Embodiment 19. The pharmaceutical composition comprising the cost according to any one of embodiments 1 yes 18 or a pharmaceutically acceptable sai thereof and one or three pharmaceutically acceptable carriers.

Embodiment 20. A combination comprising a compound according to any one of claims ia 18 or pharmaceutically acceptable salt thereof and one or more therapeutically active agents, for example selected from;

1) P13K inhibitors, such as BKM120 (i.e. .3 - (2,6-dinsorph Jinopyrimidin- 4- ylj 4 - (trifluoromedi) pyridine-2-asnin] or BYL719 (i.e. - metii-5- (2- (1,1,1Irifluoro-2- mctylpropan-2- iljpiridin-4- yl} thiazol · 2- llipyrrolidine-1,2-dicarboxamidaj: i) compounds which are directed to. reduce or inhibit the activity of the members of protein kinase C (FKC) and the Raí family of felt / threonine kinases, members of the family MFK, íiRK, SRC, JAR, FAK, PDKf, FK8 / There, and Ras 7 MAPK, and / or members of the family of cielina-dependent kinases (CDK): such as Dahrafénib, Encorafenib or LEEbi1 (i.e. 7- eidopeniH- N, N-dimethyl-2- ((5- (piperaxm- 1- iljptridin-2-yljamino) 7H-pyrro! or [2,3-djpirijmidme-o-earboxasnide); and íií&gt; mTOR inhibitors, such as Everolimus,

Embodiment 20a, A combination comprising a compound according to any of embodiments 1 to 18. or a pharmaceutically acceptable salt thereof, and one or more therapeutically active agents. such as ΡΓ3Κ inhibitors, such as 8KM120 (ie. 5 (2,6-dimorpholinopyrimidin-4- ib-4 ~ (tri-luoromethylpyridin-2-aminach or BYE719) (Mr NI- (4- methyl-5- (2- (l, t, I-triftuoro-2- rnetiipropan-2- ilipyridin- 4- ilithiszol- 2iljpí rroíidina- 1,2-dicarboxamídaj.

Accomplishment 20 b. A combination comprising a compound according to any of embodiments ia 18, or a pharmaceutically acceptable sai thereof, and one or more therapeutically active agents, such as compounds that are directed to, reduce or inhibit the activity of protein kulinase C members (PKC) and the Raf family of serine / threonine kinase, members of the family MEK, ERK, SRC,? AK, FAK, RPKi, F.KB and Akt, and Ras / MAFK, and / or members of the family of cyclin-dependent kinases (CDK); coma '' Dabrafenib, Encorafenib or EEEÜί í (i.e.? - cyclopentyl- NN- dimethyl- 2- R5- (piperazin1 - íOpiridui- 2- ibaminoF 7H- plrolo (2,3- djpirimidine- 6- eatboxamide).

20c realization. A combination comprising a compound according to any of claims ia 18 or pharmaceutically acceptable salt thereof and one or more therapeutically active agents, such as mTOR inhibitors, such as Everolimus,

Embodiment 21. A compound according to any of Embodiments ia 18, or a pharmaceutically acceptable sai thereof, for use as a medicament.

Embodiment 22, A compound according to any of embodiments ia 18, or a pharmaceutically acceptable sai thereof, for use in the treatment of a disorder or disease that is mediated by MEK activity, for example a disease or disorder selected from earcinoma ovarian, kidney cancer, prostate cancer, breast carcinoma. Ilnfomas, myeloma, bladder carcinoma, colon cancer, cutaneous melanoma, hepatocclular carcinoma, endometrial cancer, lung cancer, pancreas cancer, gastric cancer and soft tissue sarcomas selected from rhabdomyosarcorna, synovial sarcoma! and Ewing's sarconm; in particular, melanoma, cancer of the pancreas, colon, lung, kidney and ovarian.

Embodiment 23. Use of a compound according to any of the reaiiz.aeior.es 1 to 18. or a pharmaceutically acceptable salt thereof, for use in the treatment of a disorder or disease that is mediated by the activity of MEK, for example a selected disease or disorder of ovarian carcinoma, kidney cancer, prostate cancer, breast carcinoma, myomas, myeloma, bladder carcinoma, colon cancer, cutaneous mebanorn, hepatocellular carcinoma, endometrial cancer. Lung cancer, pancreatic cancer, gastric cancer and soft tissue sarcomas selected from rhabdomyosarcoma, synovial sarcoma! and Ewíng sarcoma; in particular, melanoma, cancer of the pancreas, colon, lung, kidney and ovarian.

Embodiment 24, A pharmaceutical composition according to embodiment 19 for use in the treatment of an disorder or disease that is mediated by MEK activity, for example a disease or disorder selected from ovarian carcinoma, kidney cancer, prostate cancer, carcinoma of blanket, Unfbmas, myeloma, bladder carcinoma, colon cancer, cutaneous melanoma, hepatocellular carcinoma, endometrial cancer, lung cancer, pancreatic cancer, Gastric cancer and soft tissue sarcomas selected from rhabdomy osarcoma. synovial sarcoma and Evvíng sarcoma; in. in particular, melanoma, cancer of the pancreas, colon, lung, kidney and ovarian.

Embodiment 25, A method of treating a MEK-mediated disease comprising the step of administering to a patient in need thereof a therapeutically effective amount of a compound according to any one of embodiments 18 or a pharmaceutically acceptable salt thereof. .

Embodiment 26, The method of embodiment 25 wherein said MEK-mediated disorders are selected from ovarian carcinoma, kidney cancer, prostate cancer, blanket carcinoma, Hnfomas, myeloma, bladder carcinoma, colon cancer, cutaneous mehmotna , hepatocellular carcinoma, endometrial cancer, lung cancer, pancreas cancer, gastric cancer and soft tissue sarcomas selected from rhabdomyosarcoma, synovial sarcoma and Ewing's sarcoma; in particular, melanoma, cancer of the pancreas, colon, lung, kidney and ovarian.

Embodiments add; »;

Preferred substituents present in the compounds of the formula L or the formula (le) are defined below. The definition of the substituents applies to the final products, as well as to the corresponding intermediates. In addition, the definitions of

3?

Substituents, as provided below, may be combined at will, for example, preferred substituents R3a and preferred substituents R, i,

In one embodiment, the compound of the invention provides a compound of formula (Ϊ), wherein n is 0,

In one embodiment, the compound of the invention provides a compound of formula fl), wherein n is I.

In one embodiment, the compound of the invention provides a compound of formula (i), wherein R is

J.

In one embodiment, the compound of the invention provides a compound of formula (1), or of formula (i), as defined herein, wherein R_; it is _XN „A

- .....) 1 - - 4 ........... Yf &amp; Ϊ

In one embodiment, the compound of the invention provides a compound of formula (i), or of formula (le), as defined herein, wherein Ri is

Ύ r₇

In one embodiment, the compound of the invention provides a compound of formula (I), or of formula (íe), as defined herein, wherein R¡ is

or ........ Βόν-'ϊ-Υ7

Ry

In one embodiment, the compound of the invention provides a compound of formula ii). or of the formula &lt;le), as defined herein, where R¡ is

..Ν. λ ¡r vo.

In one embodiment, the compound of the invention provides a compound of formula (i). or of the formula (te), as defined herein, where Ri is ® Α'Αγ-'Υ

In one embodiment, the compound of the invention provides a compound of formula (I), or of formula (le), as defined herein, wherein tfo is vfVW ° vS, N, P

In one embodiment, the compound of the invention provides a compound of formula (1), or of formula (le), as defined herein, wherein R¡ is

or. TO,

Saw

In one embodiment, the compound of the invention provides a compound of formula (I), or of formula (le), as defined in Sa present, wherein R&gt; is chlorine.

In one embodiment, the compound of the invention provides a compound of formula (1), or of formula (le), as defined in Sa present, wherein R_&gt; is methyl.

In one embodiment, the compound of Sa invention provides a compound of formula (1), or of Sa formula (íe), as defined in Sa present, wherein R; is hydrogert

In one embodiment, the compound of the invention provides a compound of formula (1), or of formula (le), as defined herein, wherein R? It is fluoro.

In one embodiment, e! Compound of Sa invention provides a compound of formula (1), or phonnuía (le), as defined in the present. where Rj is methoxy

In one embodiment, the compound of the invention is a compound of formula (1). or of formula (le), as defined herein, in which R^{j: l}_________ is selected from cyancmethyl, 2- hydroxy-ethyl, 1- hydroxypropan-2- yl, 2- methoxy-ethyl, (3- methylxetan-3- i?) methyl, asnin-earbonyl-methyl, 3- hydroxy-2- ( hydroxymethylpropyl, 2- hydroxypropyl, oxetan-2-1-methyl and 2- amino-2- oxoethyl; in particular cyano-medium, 2- methoxy-ethiium, (3mets Ioxetan-3- ii) -methyl, amino- earbonylmethyl, oxetan-3-methyl, and 2- amino-2oxoeíiio; such as cisnemethyl,

In one embodiment, the compound of the invention is a compound of formula (1), or of formula (le), as defined herein, wherein Rj »is selected from 3- 3- hydroxy3 (hydroxymeti) Propanoyl, 2-finoropropanothium, dimethylcarhamoyl, 2-hydroxy acetyl, 2-acetoxyacetyl, 2- mctoxyacetiium, (2,2,2-trifiuoroethyl) carbamoyl, 2-ammoacctyl. sS) - 2-hydroxypropane, 2- hjdtoxypropastoyl, acetyl. carbamoyl, (oxetan-2-si) -methane, 2 (sulfooxt) acer, 2- fluoroethnoyl and .3-hydroxypropanoyl: in particular, 3- hydroxy-2 - '(hydroxymethyl.jpropanosium, 2- hydroxy-acetyl, (S) -2-hydroxypropanoyl, 2-hydroxypropanoyl, and 3- hydroxypropanoyl; such as 2- hydroxy-acetyl,

In one embodiment, the compound of the invention provides a compound of formula (1), or of the formula (les, as defined herein, wherein Rj_dit is selected from methyl sulfonyl, eieiopropyl sulfonyl, isopropyl sulfonyl and N. N-dimethisulonaroidyl.

In this embodiment, the compound of the invention provides a compound of lomuda (1), or of the formula (le), as defined herein, wherein Rj_toit is selected from methylsulfonyl, propium sulfide, isopropyl sulfonyl and N, N-dimethylsulfonamidyl.

In one embodiment, the compound of the invention provides a compound of formula (I), or of formula (le), as defined herein, wherein R34 is selected from dimethicarbamoyl, (2,2,2-tri-uoroethylojearbainoyl) and carbamoyl.

In one embodiment, the compound of the invention provides a compound of formula (I), as defined herein, where it is hydrogen.

In one embodiment, the compound of the invention provides a compound of formula (i), as defined herein, wherein R, is halo, in particular fluoro.

In one embodiment, the compound of the invention provides a compound of formula t), as defined herein, wherein R, is methyl or hydroxymethyl.

In one embodiment, the compound of the invention provides a compound of formula (1), or of formula (le), as defined herein, wherein R&gt; is hydrogen.

In one embodiment, the compound of the invention provides a compound of formula {1), or of the reliable formula), as defined herein, where R_s It is methyl.

In one embodiment, the compound of the invention provides a compound of formula Π), or of the formula fie), as defined herein, wherein R¡¡ is hydrogen.

In one embodiment, the compound of the invention provides a compound of formula fi), or of formula (le), as defined herein, wherein Re is methoxy.

In one embodiment, the compound of the invention provides a compound of formula ('{). or of the formula (le), as defined herein, wherein IN is halo, in particular ftooro.

In one embodiment, e! Compound of the invention provides a compound of formula (1, or of formula (le), as defined herein, wherein R? is selected from fiuoro, cyclopropyl, CFi and CHjOH,

In one embodiment, the compound of the invention provides a compound of formula (i), or of the formula fie), as defined herein, wherein R? it's hydrogen »

In one embodiment, the compound of the invention provides a compound of formula (1), or of the formula fie), as defined herein, wherein R₇ It is methyl.

In one embodiment, the compound of the invention provides a compound of formula fie), as defined herein, wherein Ri_{; í} It is hydrogen.

In one embodiment, the compound of the invention provides a compound of formula fi), as defined herein, wherein 1Ν_Λ It is methyl.

In one embodiment, the compound of the invention provides a compound of formula (1), as defined herein, wherein R_Item&lt;is fluorine.

Additional embodiments;

Embodiment 1 / lm compound of the formula í vsa-vM ·

Λ

".Y"_r«NA./^s i

n is selected from 0, 1, 2 and 3; R 'is selected from:

<td>TO" r7 í- He has.........</td><td>, .tL A: ' í ^Γ</td><td>..... ...... h 1&gt; ·</td><td></td><td>. year 1</td>

<td>: J</td><td>* A &lt;-. n Re Ύ</td><td>-; Μ 3 : : : Μ M and V</td><td></td><td> 8/</td>

<td>r₇</td><td>r₇</td><td>Rt</td><td></td><td></td>

R? it is selected from chlorine and methoxy;

R^ia is selected from cyano-methyl, 2- hydroxy-ethyl, i-htdroxypropan-2- yl, 3- hydroxy2- (hydroxymethylpropanoyio, 2- methoxy-ethyl, 2- Ouoropropanoite, (3- methoxetan-3-l) metho , meth! - sulfonyl, amine-carbonyl · · methyl, sky-propyl sulphnyl, isopropit-sytfbnHo, dimethylcarbamoyl, 3- hicroxt- 2 ~ hydroxymethyl!) propyl, 2- hydroxy-propyl, 2 ~ hydroxyacetyl, 2-aeeloxyacetyl, 2- methoxyacetyl, (2,2,2-tnf1uoroethio) carbatnoyl, oxetan-2yl, 2- aminoacetyl, oxetan-3- ylmethio, ($) -2-hydroxypropanoyl, 2- hydroxypropaphthoxy, acetyl, 2-asnin-2- oxoethyl and carbamoyl;

R * is selected from hydrogen, halo, methyl and hydroxymethyl; And, jpchmahneníe, two groups together with the carbon atoms to which they are attached, form - (CH²h-, r;

R₅ is selected from hydrogen and methyl;

R * is selected from hydrogen and halogen;

R 'is selected from hydrogen, lichloro, chloro, CH ^ F, Cííq, CFu CHjOH, ciciopropiío and methyl; Y

Rv is selected from ethane; or pharmaceutically acceptable salts thereof.

Embodiment 2. The compound of embodiment 1 "of Formula la:

<img file="CU20160020A7_D0019.tif" />

on which one

R: is selected from chlorine and methoxy;

R &amp; is selected from 2- hydroxy-ethyl, i-hydroxypropan- 2- do, 2- mefox-ethyl, (3-meisioxeania- 3- ii} -methyl, medi-sulfonium, 2- acetoxyacetiium, 2- flueroprop &amp; noyl, 2- hydroxypropyl, cyclopropyl-sulfoniium, isopropyl-selfoniíy, 3- hydroxy-2- (hydroxymethyljpropyl, 3htdroxy-2- (hydroxyraethyl) propanophil, oxetan * 2- slo, dimerylbamollo, (2,2,2triíhmroedljc &amp; rbamoito, {$) - 2 - hfdroxypropanoyl, oxetan-3-ylmethyl, 2- ammoacetyl, 2-methoxy &amp; ceiyl, 2-hydroxyethyl, 2- hydroxypropanoyl, acyl, 2- amino-2- oxoetslo and carbamoyl;

R,} is selected from hydrogen, methyl and hydroxymethyl;

Rs is selected from hydrogen and methyl;

1E is selected from hydrogen and fluoro;

R⁷ is selected from hydrogen, ileum, chlorine, CK²f, CHE ?, CFj, CHjÜH, cielopropyl and methyl; Y

Rs is selected from cyano; or pharmaceutically acceptable salts thereof.

Embodiment 3 ", The compound of embodiment 2" selected from;

<img file="CU20160020A7_D0020.tif" />

Ν, 0 θ 'Ν and-Á -. Α Λ VA /

Á -A -rt F '- N' __y

N 'w O .-. C¡ Á - A'xA'X

VV, ÍÑ

N- /. &lt;&gt;

Ntz 'XA XA- / rsrtS: · Ar^:r &lt;&lt;'-^: , A „, .A. &lt;F XA '_NHO xAX, and · 'íí

FX \

N-YOU / 'i, N

Ά '\ XA^Z 'V tl · &lt;' 7: J * rtlM

F '' Ν '

He has? /

N - ^ \ &lt;/ .A¿yV^! W

XAX .- 'X, A

X, N xz · α \. .aC · 'N' \ '- Á / ΝΛ

...... / kórtB:

, TyO, Ar_Y.-Cí i Ί | i,&gt;_x . &lt;Μ Χ_{% Λ} .Á A * X &lt;,. &lt;* ^S\ Z XZ χΧ-Α

N ~ rt _ Αχ A'r

H, N and x rt! Ά '\ Q;

Ν '' ' ⁷ Y ^or and &lt;&gt; »· -

-,&gt; Ñ A, A, and- ». . · X&gt; - 'γ ·' \&gt; γ * Ά

-γ 'Μ

Z¿&gt; 'X

..-TO

NA i

N

HO ..

•---'•\

N ~ \ 'i /' ''., ¿'7 / y' / ·

NxzOs Ax zC! ^X- ~ Á Ά A y

Líí! W • ¿and X'Z XAyAv '“(777 77¡7i

Nx \ v¿&gt;

HO,, N, „0. / 01

- 'Xz', -í 'X

Y-Ñ ^!Aa¹'- to

TO\......

L ............

\ ~ Á ~

M.—;

• Λ &amp;

V ΎΎ AA /

Η O.

Ν- \, ζ Υ · - 'θ, &lt;Ν νζ&gt; ζ

Χχ ..ζΧ, οΑΑ

ΝΗΟ '

Ν \ &lt;¿, ΧΑ ζ&gt; χ. , .. OMek ζΧ. ZX ίι. ' ϊ .Α^ΛΧ

F ^χ'- Ν

Ιττ ϊ &lt;&gt; Ñ kx Α

Ν'V \ z \ A /^N

F '\ ~ -QH οΧ

Ν - * \

ΗΟ

Α \

Ν O --χ O X-Á '' V-_:,

ΧΧΝ .'V &lt;&lt;_:

VXX / V&gt; * · &lt;.Ζ&gt; Υ. &lt;&gt; '

F Ν

X, .-. Ν \ .. · Ό &lt;&gt; ζχ &lt;1x ^ x1 * - Α:.

y; f γ · and ν - χΎ 'χ.ζχ., - γγγ- · ν

X, ιΛ, -J f 'x¿- · ύ ο

Η0- \ or&gt; -χ / Ν

ΒΟ ( _s ζΧ Λ _χθΛΆ , &lt;γ&gt; * Y Ν

ΗΟ

ΗΟ ', Χ \ ^ -ν „-C¡ &lt;Ά' ^X| fx- ^ · &lt;

Ν - '\

OR

ΑΑ

SF \ s.

, ί Ν W χ χ, Ν

Χζ'Χ,, Ζχχ, ΖΚ ζ η- χγ χ ^ ·

.. 'X γχγ- γ&gt; Ζ

ΗΟ

Ο // ~ γ / χ, ο; / '

Ν- '_ΧΛ, 0. ..οΑΆ γ: Τ V jj '^s Νγ „Χ ... Ο, ζ \.

ζ χΝζ 'ν: Ζ Χ &lt;

γ, Ν

ΝΖ -χΖ • xSZ ΧχΖ, Ν μ

Αν π

'XI \ ---- \ / • κζΐ V / ίγ χ ._χ \. · &lt;&gt; Μ. Χζ, ζ&gt;

• Ά ..ΥΎ χ&gt;^!

F '' Ν

HO.

AA 'ΛΝ.Μ'Α · », N.

i '

Í..Z- x_vx Xz ·· 'e, /

HO

X? '

-F-......

AA

N- ~ \

A.MA ... X οι Ύ / '

To&gt;_;zay^N \ z

OR

A * · ΑΎ \ J, N „, 0. zx, or - \ f ·: '-χγ ·' X '&lt;z XZ. H-5

· - γ &lt;γ- -oz

Λ ζ&gt;

X. '..Ζ ./7

Ν '

N. Ό, ZS • z - &lt;x, z xz

And

NX

AN

'.'The X

A .. &lt;- N \ Z

NA. £ N • v / νΎ Ά- _CA &lt;

\.

ugly

HO

M- ~ \ 0- - O \ ^Fr- '· * —Ά

N .............................. Nfe ....... ((W (((ifeÍfe4fe &lt;^:-fel p AY

K₃c you

GOES

HO

, .N. , .0-. • yx y

AA

O yy i / • ,, \ „·· / J - V

H --M χχ. Ζχ Xv -Αχ, χ&gt; · sy * &lt;^. Z '* ΐΆ í h₃nA _{t |}, _ .fejfe fe-ss -............... faith ............ s fesfe, &lt;de &lt;........ .......

i χ ..N,, 0. . ^ x. / iz T {Z n-ó.

i Xx N ¹&lt;X. A Λ zX .N j^vx&gt; - * Yy γΑν / γγ i. ^ A ^ nA ·:! - x · N fX ¿7 zNx z0 .., .. &lt;x. „Cj_F; &lt;and Xzz

ÁJ íf N'A

XZ '' &lt;x, z '

zN XX A z-χ AA

XZ XN ·· XZ X^x 'p li' TT

, .- &lt;, Ή χ MF 'X' '_N~

ΗΟ

- ~ Ύ

ΚΟ,

Υ --- \

Yf

, .Ν._,. &lt;Κ) - &lt;.....

&lt;-Υ, Cf

Ν- &lt;

γγ, Ν. .Ο, γχ .C¡ · - &lt;γ γ '^:ΝΥ, · .Ν

Ύ Ζχ .Ύ,. ••• '.χ .., ·' - '' Χ'χΧ '· ΥΖ

X -χχχ

Ν '

Ο

ALREADY

Ν -'-, ΚΟ; &gt;

ΗΟ,

..Ν ^, Οχ λ, C¡ ΟΥ ύυ Υ * ·

I ί ΥΥ \ -Á /

Υ ^ χγΥ_νΑ&gt; /^Ν

Ν- \, ί

ΗΟ, \

F ^:&lt;.(,

Ν \ χχ χ&gt; „ν.-Λχ ζ

Ύ ^sv ' ^sS&gt; &lt;&lt;\ V&gt; £ ί / ¡wi-4 'Μ Ν'-.

jxgx 4 | s '&lt;&gt; ✓ **' f! I! ί^!&lt;.Υ Υ. &gt;

Ν -_λ\ ^ΛνΥΛ /^Ν

..... ? ................_:Χ £ .......

Λ Υ -&gt;^:

F ''&gt; ¡χ

χ ΑΑζίΎ ν · &lt;&gt;? &lt;·? Γ &lt;

ί {:&gt; ι '”' · ^κ

L Υ 'Αθ &lt;Υ, Ν

Ν- ·;

.1 :

AZ \ /% zY / ί I Ί

Η-Λί-Λ

Ο

Γ \

V4- '^Χ Ν-χ .-- χχ · ^ Υ_ν^Νih ι c. \ χ

Η-Ν ί

Ν - \ ρ Ύ Y yn -á γ-ί ν Ύ Υγ Υν- '^Λ

Η-, Ν

HCX, όΧ

OH ρΜχ ^ 'χζ, Ν r \ \ / X

0ί

ΝΑ X Η 'XV

AND V ^χ'9 ζΝ' \ ΧΧ: &lt;&gt; &lt;&gt; Α &lt;s X. - 'X

i ................... «

F '' 'V' '' ν '¡7

ΗοΝ'-Α

Ν X χ&gt; · Ν. ζθ-, ζχ -01 U'- A γ&gt; 1 γΥ and Ν —Ά 'Ά-Ν ζΧ ΖΧ. ΖΧ ... X 'Χζ Αγ _ A JxJ

F Ν, Ν

ΗΟ

Ν · '\, &lt;Α ,, Ν. , -0 .. ^ íx, ΧΙ^Χ~~ Α '^ · ·' • '¿ν' ^xs-0^x χy “x, ο Ν .Á. &lt;· 'ίχ F' α- Ν

--0. ζ / '-'Λ -: · :.

Ν · - \ &lt;/ „Ν .. Λλ ^ Cl ^x -~\ /

A v XX V

ΗΟ

Η '•&gt; F

Αγ, Α

So ζ \ ζχ zS. χ χχ% ·· 'x&gt;., x^s&lt;v. 11 '

Ζ '' Χ&gt; Ζ- ~ Χ-ίί- 'Χ ~ Ζ

Αζ

C: Ύ

Ν ~ Α χΧ

Ά / V

<td>χ 9 ηθ ??</td><td>! to '' 'Q:' ' &gt; ': i ........... / 1 ​​..........</td>

<td>\ χ</td><td> = ^Η^ Λ- -x</td>

<td>Γ \</td><td>i N \ &lt;χ [Χ :. . · 'Isa /</td>

<td>X -0. , &lt;χ A^XTO / hey XX NA,</td><td>x_rXO_V- z 'XY</td>

<td>YEAR 9 ~ i. N A&gt; - and. /</td><td>or íx Μ ΐχ jl &lt;χ AN j ΧγΧΧχ ^.</td>

<td>r 'Ν</td><td>; -.- X -ΑΧ .. A ¡F '···· N</td>

<td>“~ ™“ 0 t {:</td><td>¡ΗΟ P</td>

<td>H; lK</td><td>1 \ ~ X</td>

<td>NA ÍA sp xaa «pX ....._........ ati ap s</td><td>i N '\</td>

<td>v N. zOs z \ χ ^VTO / X&gt; X XA X Μ ..---</td><td>X XXX / yyyy_{: K} a pa aa^::. ΐ, N-, 0-, zx a</td>

<td>...... axX sfa_:..... and a ............. a ....... &lt;a_:X Y -..... a</td><td rowspan="2">if¡ yvy n-xk : kz-NA IX zx A,^Ni V - 'and χγ χγ</td>

<td>A Μ XX x N 'V^N Azyzíyy</td>

<td>_F- XX</td><td>to ...... j ..... .........to.........^:ia ia; taá aY'ua., to_:........... - zX V'A „P '</td>

<td></td><td>Rx ···</td>

ί ¹ /Role

-A s- Α * Χ A &lt;XA p

Xs

X í \ *:

&lt;z.Ñ Y. .J \ ·. z &lt;x A,. ñ

XY: AA-í ·· Y &lt;X -Οχζ Άχ /

Y*^- Yy^- ΥΎ

.......... Ti 6^:TA ...... I z; N Y.

..ζ-^Jx .z Ά., ζ^χ 6&gt; ^ -. Χ ^ Ύ χ · /^Λ\.,, &lt;A

FN

Y ,, A. 'b Yy h₂nA.

z _N„.

HO.

, F \ -A: N * X ¡, N_X JX X if Y&gt; í [Y .. jq X ¡ii YZX «A * /

ΥΛΥ ^VX,

ΝΑ:

&lt;Ñ Υλ z

<td>A / V 'ΐ</td><td>X&gt; ··</td><td>AX AX</td>

<td>J xl zJ í</td><td></td><td>x '\ xF C * AX</td>

, N 'N'

O h-nA

ΝΑ, \ \ ~ A., Νζ „0. _ζλ _χΧ! —Y. &lt;Γ γ γ Ν'Ά

6. ζ'ζΝ Υ .Υ-γ χχ ζί \ ζ “\ Ζ \ Ζ&gt; γΧ Χ ^ Χ Xj '·'

Ν: Β · ζΑ &lt;z '.- t ζ&gt; λ F' Μ, Χ ζθ- ζ · ^ -CI 'Ά /

Y Ύ Y- '' V Ν —Χ kx. Ñ ​​γ χ * χ χχ ζ&gt; Υ η Υ

Α ** ν

Ν- \ ζ ^ ζθ_χ ζ &lt;χ z-CI&gt; γ- ^χγ&gt; · ': γU, JÑ X Λ, .. χ

ΑΧ &lt;Χ \ / ν

Ο γο-γ. Á Ν- \,

Η N '\

......./: &gt;::1':&lt;_: : Υ

HQ \ Χ Υ / ζ · .. · ϊ&gt; · 'ΝΝ,_χ ζθ , ζ ^ z-CI^χ- / - 'V * γ Ν- · γ \

Υ-Χ ί

F

Ύ Α ζ \\ ζ'-χ ζ - χγ γ. , .Υ ... Ύ. , ρ F χ-&gt; Υ 'z-Ns Υ ·, - &lt;Χ -C1 ---- \, /

Υ γ and · * γ Ν-γ

And, ..Ñ Ύ .Υ ζ &lt;χ. · Υ

ΑΧ \ χ · Άυ Αγ _F- 'Χ.Υ' &lt;η ⁰

HQ ί;

Ν '

Ν ^ · \

ζΝχ .X zYxzCI Α · - \ / γ γ γ- 'Y: Ν-γ

ΧΥ ί * V • 'χΑ χΑ. ΧΆ, Ά^ν'·· .ζ-' 'Ά *' '&gt; \_&gt;Χ · Χ 'Άχ *' j Λ ζ '

F 'χ&gt;' fy

WO, faith /

YV „, x, x £ fe c F s / -_M·

<img file="CU20160020A7_D0021.tif" />

in which;

n is selected from 0.1 and 2; R^: is selected from:

<img file="CU20160020A7_D0022.tif" />

R; it is selected from chlorine and roetoxtlo;

R. «_s is selected from cysto-methyl, 2- hydroxy-ethyl, i-hydroxy propan * 2 * lio, 2- methoxyethyl, (3- methioxetan-3-i) -methyl, methyl-sulfonium, 2- fluoropropanoyl, 2- hydroxy- Propyl, cyclopropyl-suiphonyl, isopropyl-suifonyl, 3- hydroxy-2- (hydroxymethyljpropyl, 2-aethoxyacetiium, 3- hydroxy-2- (hydroxymethylipropanoyl, dhnetHcarbarium). (2,2,2-trifluoroethyljcarbamoyl, (S) ~ 2- hyd .roxypropane.yl, oxetan-3- clean it up. 2- aminoaeetiium, 251 methoxyacetyl, 2- hydrophroxyacetyl, 2- hydroxypropaneslo, oxefan-2- yl, acetyl, 2- amino-2oxoeido and carbarnoslo;

It is selected from hydrogen, methyl and hydroxymethyl;

Rs is selected from hydrogen and methyl;

R^? is selected from hydrogen, (Inoro, chloro, CH²F, CHFj, CFj, CHjOH, cyclopropyl and methyl; Y

Ra is selected from cyano; or pharmaceutically acceptable salts thereof.

Realization S '\

The compound of embodiment 4 selected from;

<img file="CU20160020A7_D0023.tif" />

<img file="CU20160020A7_D0024.tif" />

Embodiment ES composed of embodiment E * of the formula le:

<img file="CU20160020A7_D0025.tif" />

<img file="CU20160020A7_D0026.tif" />

him in which;

n is selected from 0, 1,2 and 3;

is selected from chlorine and methoxy,

R⁴ is selected from fluoro; and, optionally, two R * June groups with the carbon atoms to which they are attached, form - (CH²) ;;, _s-;

R&gt; is selected from hydrogen and methyl;

R &lt;&gt; is selected from hydrogen and fluoro; Y

R 'is selected from hydrogen, fluoro. chlorine, CH^¿F. CHF;

methyl; or pharmaceutically acceptable salts thereof.

X-- I

CHJÜR. skypropyl and

Embodiment T \ The compound of embodiment 6 '' or a pharmaceutically salt thereof, selected from ceptable Ia

Ν ~ \ * K ¿.N

Α-γ-yyAx Aa_nJ

<img file="CU20160020A7_D0027.tif" />

NONE, o. ^ O&gt; A nA - Λ. , N

I .......... E, ......... A ....... _r

Ά 'VAy / y í J, ·

N^? rv * K ζθ - ^^ ci ^VA / &lt;&gt;: · and · and NA

XA&gt;

Ύ

.. &lt;, N

Ύ ·· Y''Y'g /

..A,.-Í? A ·· '' S '* F' - 'N'

Embodiment 8 '\ The compound of embodiment i^!! of the formula Id;

K_3rd , m-. · :.

&amp; í „

NV (7 R »

Y y-γ * y;

_ A * · ^ «a / K x **

RL · * ^xand A * '^^{xz x}&lt;Nz

K₇

AA go on which one:

n is selected from 0, I, 2 and 3;

R ¿is selected from doro and methoxy;

ÍA is selected from 2- hydroxy ethyl, 1- hydroxypropan-2-io, 2- methoxy ethyl, (3-methoxetan-3- yl) -methyl, methyl-suifonyl, 2- hydroxypropyl, 2- aceloxyacetyl, 2-fluoropropanophyl, Eieiopropyl-suifonyl, oxetan-2-yl, isopropyl-suifonyl, 3- hydroxy-2 (hydroxymethyljpropyl, 3- hydroxy-2- (hydroxymethylpropanoyl, dimethylcarbamoyl, (2,2,2-trifluoroethylcarbamyloyl, (S) -2- hydroxylpropanoium, oxetan-3- tlmeite, 2- ammoacetite, 2-methoxyacet, 2-hydroxyacetyl, .2- hydroxyproparsium, acetyl, 2-amine-2-oxoethio and carbamoyl;

IN is selected from fiuoro; and, optionally, two R groups⁴ together with the carbon atoms to which they are attached, they form - (CHA .;

Rs is selected from hydrogen and medium,

Rs is selected from hydrogen and fiuoro; Y

R 'is selected from hydrogen »Hue, chlorine, CH'F, CHIA» CP? »CH_:? üH, middle sky; or pharmaceutically acceptable salts tic the same.

Embodiment 9, The compound of Embodiment X or a same highly acceptable salt, selected from

..... .........

KO

HC

OH

Y

<td>Y*_: ......&gt; μ ~% · ................ .....</td><td></td>

<td>k &lt;..... ¡r ^........ *.&gt;. ............... &lt;N .......... ....................... ...</td><td></td>

<td>^&gt; ·· Nf '-W' '</td><td> ...........</td>

t ··; '

, .Ci

N- &lt;

r ....

Embodiment 10 ", ES composed of embodiment 1" of the formula le

Rj₃

in which:

R 'is selected from:

Re &lt;&gt;

R?

. J9 ...; ft A r₇^x - V r &lt;. TO

Ai

R?

Yes MC

P &lt;&lt; is selected from doro vmetoxiío;

is selected from 2- hydroxy-ethyl, i-hydroxypropan-2- yl, 2- methoxy-ethyl, (3-methylxeian-3- ii) -methyl, medi-sulfbnyl, 2- hydroxypropyl, 2- aceloxyacetyl, 2-fiuoropropanoyl, cyclopropyl - suiphonyl, oxetan-2- io, isopropyl-suiphonyl, 3- hydroxy-2 (hydroxymethyl) propium, 3- hydroxy-2- (hydroxy-mstiljpropanoiio, diraethykarbainoyl, (2,2,2-tri-oxy-eti-cathobamoyl, (S) - 2 - hydroxy prapanoyio, oxetan-3-ylmethyl, 2- aminoacetiium, 2-methoxyaethyl, 2-hydroxyacetyl. 2- hydroxypropanoium, aethyl, 2- amino-2- oxoethio and carbamoyl

IN_to is selected from hydrogen and methyl;

INh is selected from hydrogen and fluorine;

Rs is selected from hydrogen and methyl;

Ré is selected from hydrogen and fluoro;

R⁷ is selected from hydrogen, fluoro, doro, CITE, CHF ?., CFj, CHjOH, cyclopropyl and methyl; Y

Rs is selected from cyano; or pharmaceutically acceptable salts thereof.

Embodiment 11 ", The compound of embodiment 10" or a pharmaceutically acceptable salt thereof, selected from

<img file="CU20160020A7_D0028.tif" />

-N ..., -0 .., Ci f Z^F,

Ύ · 'íi P

-OR.

N-

..N „, 0. , &amp;

&lt;Ύ&gt; r Y · '&lt;4::: &lt;: .....

Ν '*'

F o- '_N á: n

HQ

HQ

Ñ ​​~ '\ r ......., / Χ (..... γφΟΕ 7) αΥά, yy' ❖r '&gt; A,' ........ and

N - A ύ á .Λ .N,^N\&gt; F

M.

CFj

A ·&gt; Ά - &lt;ú

HQ

) &lt;) L&gt; t .-. N

F v '

O._x.. &lt;»JUJ •&gt; F

F₃C .. ..A ..O ,. ..Cl '^ V

N - and νΖηΑ / 's.Ay

Realization 12 ”. A pharmaceutical composition comprising a compound of embodiment i '^! or a pharmaceutically acceptable sai thereof and one or more pharmaceutically acceptable vehicles.

Embodiment 13 ". A pharmaceutical composition according to embodiment 12 "for use in e! treatment of a disorder or disease that is mediated by the activity of MEKRealization 54 ", A method of treating a disease mediated by MEK comprising the step of administering to a patient in need of the misino a therapeutically effective amount of a compound of embodiment P; or a pharmaceutically acceptable salt thereof.

Realization 15 ”. The method of embodiment 14 wherein said MEK-mediated disorders, are selected from prostate cancer, breast carcinoma, lines, mseloma, bladder carcinoma, colon cancer, cutaneous melanoma, hepatocellular carcinoma, endometrial cancer, lung cancer , pancreatic cancer, gastric cancer and soft tissue sarcomas selected from rabdenuosareoma, synovial sarcoma! and Euing's sarcoma.

Pharmacology&gt; Utility ¡0048j Hyperproliferatic diseases such as cancer and inflammation are receiving a lot of attention from the scientific community and there is a strong desire to discover compounds that provide therapeutic benefits in relation to the treatment of hyperproliferative diseases. In this regard, efforts have been made to identify and select the specific mechanisms that play a role in these diseases.

[0049J] A target of interest is the over-activation of the mitogen-activated protein kinase (MAP) cascade that is known to play a role! Itnportanfe in cell proliferation and differentiation. This pathway can be activated when a growth factor binds to its tyrosine kinase receptor. This interaction promotes the RAS association with RAF and initiates a phosphorylation cascade through MEK (MAE kinase) to ERK. Inhibition of this pathway is known to be beneficial in the treatment of hyperproliferative diseases. MEK is an attractive therapeutic target since the well-known substrates for MEK phosphorylation are the MAE, ERKi and ERK2 kinases. The constitutive activation of MEK / ERK has been found in teachers of pancreas, colon, lung, kidney and primary ovarian tumors, 00501 MEK phosphorylation increases its affinity and catalytic activity towards

ERK, as well as its affinity with ATE. This invention describes compounds that inhibit MEK activity by ATE binding modulation and association of MEK with ERK through a mechanism that is ATP-competitive, 0851j Activation of MEK has been demonstrated in many disease models that suggest that MEK inhibition could have a potency! therapeutic benefit in various diseases such as pain (see, for example, evidence of efficacy in pain models described in i. Neúrosci. 22: 478, 2002: Acta Pharmacol Siss. 26: 789 200.5; Expert Opin Ther Targets. 7: 699, 2005; and Mol, Eain. 2: 2 2006); Cerebrovascular accident (see, for example, evidence of efficacy in models of cerebrovascular accident significant neuroprotection against ischemic brain injury due to the inhibition of MEK described in. L Eltarmacoí, .Exp, Ther, 304; i 72, 2003; and Brain Res, 996: 55, 2004); Diabetes (see, eg, Evidence on diabetic complications described in Am. J. Physioí. Renal. 286, F120 2004); Inflammation (Veásc cj., Evidence of efficacy in inflammation models described in Bioehera Bsophy, Res. Com. 268: 647, 2000): and Arthritis (see, for example, 58 evidence of efficacy in osteoarthritis and experimental arthritis as described in,!, Clin, Invest, 116: 163. 2006).

0652] The present invention relates to compounds capable of inhibiting MEK activity. The invention further provides a process for the preparation of compounds of the invention and pharmaceutical preparations comprising compound compounds. Another aspect of the present invention relates to a method of treatment of MEK-mediated disorders comprising the step of administering to a patient in need thereof a therapeutically effective amount of a phonnuide compound Ϊ as defined in the Summary of the Invention .

[00S3 | In certain embodiments, the present invention relates to the above-mentioned method, in e! that said MEK-mediated disorders are selected cancers of, but are not limited to; angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposareoma, myxoma, rhabdomyoma, fibroma, lipoma, teratoma; bronchogenic carcinoma squamous cell carcinoma, undifferentiated small cell carcinoma, undifferentiated large cell carcinoma, alveolar carcinoma (bronchiolesl, bronchial adenoma, lymphoma, erythornorous haniartoma, inesotehoma, squamous cell carcinoma of the esophagus, ileomvosareoma, adenocarcinoma, duodenal carcinoma, duodenal gland , stomach and carcinoid tumors of the small intestine, adenocarcinoma, Kaposi's sarcoma, ileomyoma, hemangioma, lipoma, neurofibroma, fibroma, tubular adenoma, hairy adenoma, bamartoma, Wilm's tumor (nephroblastoma, leukemia, squamous cell carcinoma of the bladder and urethra, Iransitional cell carcinoma, adenocarcinoma, semicoma, teratoma, embryonic carcinoma, teratoeareinoma, chorioarcinoma, interstitial carcinoma fibroadenoma, adenomatoid tumor, bepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, hepatoeelular adenoma. hemangioma, iosieosarcoma osteogenic sarcoma), malignant fibrous histioeltoma, eondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticular cell sarcoma), multiple rnieloma, malignant giant cell chondroma, osteoebronphroma (cartilaginous exostosss, chondromibroma chondromaxoma Osteoid and giant cell tumors, osteoma, granuloma, xamoma, osteitis defornians, meningioma, meningiosarcoma. gl¡ornatosis, astrocytoma, medulloblastoma, gyroma, ependymoma, germinoma ípineaioma], glioblasloma multiforme, oligodendroglioma, neurofibroma, retinoblastoma, eongéniíos tumors, neurofibroma of the spinal cord, meningioma, glioma, cervical carcinoma.

Pre-tumorai cervical dysplasia, ovarian carcinoma, serous senodenocarcinoma, mucosal cystadenocarcinoma, fecal granulose cell tumors, Sertoli- Leydig cell tumors, dysgerminorna. malignant teraíorna, carcinoma intrcepiteliab adenocarcinoma, melawma), carcinoma of vaginal ciaras cells, botryoid sarcoma (embryonic rhabdomyosareoma), carcinoma of the papian tubes, acute and chronic myeloid leukemia, lymphobíástíea leukemia, rheumatoemia, multiple leukemia, chronic leukemia, chronic imbaemia, chronic leukemia, chronic imbaemia, chronic leukemia, chronic imbaemia myelodysplasic syndrome, Hodgkin's disease, non-Hodgkin's lymphoma, malignant lymphoma, malignant melanoma, basal, lunar cell carcinoma, dysplastic nevi, angioma, dennatofibroma, keloids, psoriasis and nenroblastoma; in particular ovarian carcinoma, kidney cancer, prostate cancer, breast carcinoma, lymphomas, mleloma, bladder carcinoma, colon cancer, cutaneous melanoma, hepatocellular carcinoma. Endometrial cancer, lung cancer, pancreatic cancer, gastric cancer and soft tissue sarcomas selected from rhabdomyosareoma, synovial sarcoma! and Rwing's sarcoma: preferably pancreatic cancer, colon cancer, lung cancer, kidney cancer and ovarian carcinoma, [0054] The compounds of the present invention may also be useful in the treatment of other diseases or conditions related to MEK's hyper-life. Therefore, as an additional aspect, the invention relates to a method of treating a disorder selected from; xenograft (cellos), rejection of transplantation of skin, limbs, organs or bone marrow; osteoarthritis; rheumatoid arthritis; Chiric ebrosis; complications of diabetes (including diabetic retinopathy and diabetic nephropathy); hepaiomegaly; cardiomegaite; cerebrovascular accident (such as acute ischemic eercbrovascuiric accident and global cerebral ischemia); heart failure; septic shock; asthma; chronic obstructive pulmonary disease; Alzheimer disease; and chronic or neuropathic pain, [0055) The term chronic pain '^- For the purposes of the present invention includes, but is not limited to, idiopathic pain, and pain associated with chronic alcoholism, vitamin deficiency, uremia, or hypothyroidism. Chronic pain is associated with numerous conditions including, but not limited to, inflammation, and post-operative pain. [0056] As used herein, the term '' neuropathic pain is associated with numerous conditions that include, but are not limited to, inflammation, postoperative pain, phantom limb pain, burn pain, gout, trigeminal neuralgia , acute post-herpene herpeneal pain, causigia, diabetic neuropathy, plexus avulsion, neurorea, vasculltls, viral infection !, Pof crushing session, constriction injury, tissue injury, limb amputation, and nervous festoon between the peripheral nervous system and the central nervous system, 0057] The compounds of the invention may also be useful as antiviral agents for the treatment of viral infections such as HIV, hepatitis (B) (HBV) Human papilloma (HPV cytoegalovjims (CMV), and EpsteinBárr virus (EBV).

I9U5S | The compounds of the invention may also be useful in the treatment of restenosis, psoriasis, allergic contact dermatitis, autoimmune disease, ate rose lerosls and inflammatory bowel diseases, for example, Crohn's disease and ulcerative colitis.

[0QS9 | The MEK inhibitor of the present invention can be usefully combined with another pharmacologically active compound, or with two or more other pharmacologically active compounds, particularly in the treatment of cancer. For example, a compound of the formula &lt;!)., Or a pharmaceutically acceptable salt thereof, choreo defined above, can be administered simultaneously, sequentially or separately in combination with one or more agents selected from chemotherapy agents, for example, mitosis inhibitors such as a taxane, an ia vinca alkaloid, paclitaxvl, doeetaxel, violin, vinina, vinblastine, vinorelbine or vinflimine, and other anticancer agents, for example, cisplatin, 5- fluorcuracyl or 5- fluoro-2- 4 (1IL 3Lf) ~ pyrimidinadione (5EÜ)., Flutamide or gemcitabine.

00601 faies combinations can offer significant advantages, including synergistic activity, in therapy, 0061 In certain embodiments, the present invention relates to the above-mentioned method, wherein said compound is administered parenterally, [0fl62! In certain embodiments, the present invention relates to the aforementioned method, wherein said compound is administered intramuscularly, intravenously, subacute, orally, pulmonary, iptraiecai, topical or üuranasa !, 0063¡ In certain embodiments, the present invention relates to the aforementioned method; wherein said compound is administered systemically.

Yes [0064] In certain embodiments, the present invention refers to the aforementioned burning method, wherein said patient is a mammal.

| O065j In certain embodiments, the present invention relates to the aforementioned method, wherein said patient is a primate.

| 0866) In certain embodiments, the present invention relates to the above-mentioned method, wherein said patient is a human.

(0067j) In another aspect, the present invention relates to a method of treating a disorder mediated by MEK, which comprises the step of administering to a patient in need thereof a therapeutically effective amount of a chemotherapeutic agent in combination with an amount therapeutically Effective of a compound of formula I as defined in the Summary of the Invention.

Pharmaceutical Compositions] 0068j In another aspect, the present invention provides pharmaceutically acceptable compositions comprising a therapeutically effective amount of one or more of the compounds described above, formulated together with one or more pharmaceutically acceptable carriers (additives) and / or diluents. As described in detail below, the pharmaceutical compositions of the present invention can be formulated especially by administration in solid or liquid form, including those adapted to the following: ti) oral administration !, for example, dragees (aqueous or non-aqueous solutions or suspensions aqueous), tablets, eg, those intended for oral absorption »sublingual and systemic, botos, powders,« null, pastes for application to the tongue; (2) parenteral administration, for example, by subcutaneous »intramuscular, intravenous or epjdutal injection, such as, for example, a sterile solution or suspension, or sustained release formulation; (3) topical application, for example as a crettra, ointment, or n controlled-release patch or spray applied to the skin; (4) intravaginal or intrarectai, for example, as a pesarte, cream or foam; (5) sublingually; (6) ocularly; (7) transdermally; (8) Nasally. (9) pulmonary; or (10) intrathecally. In one embodiment, the pharmaceutical formulation comprises a solid dispersion having a compound of the present invention, or a pharmaceutically acceptable sai thereof, as the active ingredient embedded in a polymer or polymer mixture, optionally mixed with at least one excipient. (for example, a surfactant agent). Examples of suitable polymers are PVP K.30, PVP-VA. 64, HPMC F3, MP.MC- FAL.V, HPMC P, Eudragít EPÍ.X Eudragh LIGO, Soíuplus or PEG8O0O. Examples of suitable excipients are SLS. Cremophor EL, vitamin E TPGS, Poloxamer40 ?, PoloxamerlSS or Soluto? HS1S, {0069] The phrase "therapeutically effective amount" as used herein means the amount of a compound, material, or composition comprising a compound of the present invention that is effective in producing any desired therapeutic effect in at least one sub-population of cells in an animal at a reasonable benefit / risk ratio applicable to any medical treatment.

10970] The pharmaceutically acceptable phrase is used herein to refer to those compounds, materials, compositions, and / or dosage forms that are, within the scope of! medical judgment, suitable for use in contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response, or other problem or complication, consistent with a reasonable benefit / risk ratio, {0071.1 The pharmaceutically acceptable vehicle phrase as used at the moment

Means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, manufacturing silence (for example, lubricate me, magnesium talc, calcium or zinc stearate, or stearic acid), or encapsulation material solvent, involved in carrying or transporting the subject compound from an organ, or portion of the body, to another organ, or portion of the body. Each '' vehicle '' must be acceptable in the sense of being compatible with the other ingredients in the formulation and not harmful to the patient, / Some examples of materials that can serve as pharmaceutically acceptable carriers include; (J) sugars, such as lactose, glucose and sucrose .; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) tragacanth powder; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, soybean oil and corn oil; id) glycols, such as propylene glycol; (11) poliols, such as glieeñna, sorbitol, manitoi and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (¡4) buffering agents, such as magnesium hydroxide and aluminum hydroxide; {15) almic acid; (i 6) pyrogen free water; 117) isotonic saline solution; (18) Ringer's solution; (19) ethyl alcohol; (20) pH buffered solutions; (21) pefiésteres, poilearbonaios and / or 63 pobanhldridos, and (22) other compatible non-toxic substances used in the pharmaceutical formulations;

[0072f] As stated above, certain embodiments of the present compounds may contain a basic functional group, such as aniino or alkylamino, and are therefore capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable acids. The term "pharmaceutically acceptable salts in this sense" refers to the relatively non-toxic, inorganic and organic acid addition salts of compounds of the present invention. These salts can be prepared ι / t xñu in the administration vehicle or in the dosage form manufacturing process, or separately react a purified compound of the invention in its free base form with a suitable organic or inorganic acid, and isolating the sai thus formed during subsequent purification. Representative salts include salts of hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, paimitate, stearate, uranium, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, meso ato, glucohepfonate, lactobionate, and ianrylsulfonate and the like, (see, for example, Berge (192?) Pbarmaceutical Salís, / Pharm. Sa. 66: 1-19), 01) 73) Pharmaceutically acceptable salts of the subject compounds include conventional non-toxic salts or quaternary ammonium salts of the compounds, for example, from non-toxic organic or inorganic acids. For example, such conventional non-toxic salts include derivatives of inorganic acids taies; such as bidrocichoride, bronthyrrhic, sulfuric, suifamic, phosphoric, nitric, and the like, and salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, icic-acidic, metallic, tartaric, citric, ascorbic, palmitic , maleic, hydroximaisic, phenylacetic, giutámieo, benzoic, salicfiico, suífaniíico, 2- acetoxjhenzoico, fomáricc, toluenosulfónico, methanosuphonic, ethane disisulfonico, oxálico, isotióníco, and the like.

0074) In other cases, the compounds of the present invention may contain one or more acidic functional groups and, therefore, are capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable bases. The term salts; Pharmaceutically acceptable in this regard, refers to the relatively non-toxic, inorganic and organic acid addition salts of compounds of the present invention. These salts can also be prepared or? yes in s! administration vehicle or the dosage form manufacturing process, or by reacting separately the purified compound 64 in its free acid form with a suitable base, such as htdroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation, with ammonia , or with pharmaceutically acceptable primary secondary or organic tertiary ana amine. Representative alkali metal or alkaline ferrous metal salts include lithium, sodium, potassium, calcium, magnesium, and aluminum salts and the like,. Representative organic amines useful for the formation of base addition salts include diethiamine, ethylenediamine, ethanoamine, diethanolanine, piperazine and similar, (see, for example, Berge, above;

(00? 5 | Wetting, emulsifying and lubricating agents, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweeteners, flavorings and perfumes, preservatives and antioxidants may also be present in the compositions

Examples of pharmaceutically acceptable antioxidants include: (1.1 water-soluble antioxidants, such as ascorbic acid, cistern hydrochloride, sodium bisulfate, sodium metablsuphite, sodium sulfyl and the like; (2) oil-soluble antioxidants, such as ascorhyl pslmitate Hydroxlaniso! hutilado (BHA). butylated hydroxytoluene (BHT), lecithin, propium gallate, alpha-tecool !, and the like, and O) metal complaining agents, such as citric acid, ethylenediamine ethemaceous acid (E.DTA), sorbitol, tartaric acid, phosphoric acid, and the like, (0077) Formulations of the present invention include those suitable for oral, nasal, topical (including oral and sublingual), rectal, vaginal and / or parenterai administration. The formulations can be conveniently presented in unit dosage form and can be prepared by any of the methods well known in the pharmacy technique La. amount of active ingredient that can be combined with nn matter! Carrier to produce a single dosage form will vary depending on the host being treated, and the particular mode of administration. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will generally be the amount of the compound that. It produces a therapeutic effect. Generally, from one hundred percent, this amount will vary from about 0.1 percent to about ninety-nine percent active ingredient, preferably from about 5 percent to about 70 percent, more preferably from about 10 percent to approximately 30 percent.

¡0O7SJ In certain embodiments, a formulation of the present invention comprises an excipient selected from the group consisting of cyclodex trinas, celluloses, liposomes, numbering agents. for example, bile acids and polymorphic carriers, for example, polyesters and polyanhydrides, and a compound of the present invention, for certain embodiments, a formulation mentioned above makes bioavailable via ora! a compound of the present invention, (0079.) Methods for preparing these formulations or compositions include the.

step of associating a compound of the present invention with the vehicle v, optionally, one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately associating a compound of the present invention with liquid vehicles or finely divided solid vehicles, or both, and then, if necessary, shaping the product.

fOflSO] Formulations of the invention suitable for oral administration may be in the form of capsules, dragees, pills, tablets, pills (using a flavored base, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or suspension in an aqueous or non-aqueous liquid, or as a liquid oil-in-water or water-in-oil emulsion, or as an elixir or syrup, or as tablets (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and / or as mouth washes and the like, each containing a predetermined amount of a compound of the present invention as an active ingredient. A compound of the present invention can also be administered as a bolus, electuary or paste.

COQJLIj In solid dosage forms of the invention for oral administration (capsules, tablets, pills, dragees, powders, granules, troches and the like), the active ingredient is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicáldco phosphate, and / or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and / or silicic acid; (2) binders, such as horn, for example, earboximethyletose, aiginates, gelatin, polyvinylpyrrolidons, sucrose and / or acacia; (3) humectants, such as glyceri; (4) disintegrating agents, such as agar agar, calcium carbonate, potato or tapioca starch, algic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (or) absorption accelerators, such as quaternary ammonium compounds and surfactants, such as poloxamer and sodium lauryl sullate; (?) wetting agents, such as, for example, cetyl alcohol, ghceroi monostearate, and non-tonic tertsiocafives; (8) absorbents, such as kaolin and bentomta clay; (9) lubricants. such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, zinc stearate, sodium stearate, stearic acid, and mixtures thereof; (19) coloring agents and (11) controlled release agents, such as crospovidone or ethyl cellulose. In the case of capsules, tablets, and pills, the pharmaceutical compositions may also comprise buffering agents. Solid compositions of a similar type can also be used as fillers in soft and hard gelatin capsules using excipients such as lactose or milk sugar as well as molecular weight polyletylene glycols and the like.

00821 l Jn tablet can be manufactured by compression or molding, optionally with one or more accessory ingredients. Compressed ulcers can be prepared using binder (for example, gelatin or hydroxypropylroerythiculose), lubricant, inert diiuyenie, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surfactant or dispersant. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

f0083 The tablets, and other solid dosage forms of the pharmaceutical compositions of the present invention, such as dragees, capsules, pills and granules, may optionally be labeled or prepared with coatings and covers, such as enteric coatings and other well known coatings in the technique of pharmaceutical formulation. They can also be formulated to provide a slow or controlled release of the active ingredient using, for example, bidroxypropylmethyl ketose in varying proportions to provide the desired release profile, other polymeric matrices, Siposomes and / or microspheres. They can be formulated for rapid release, for example, lyophilized. They can be sterilized by, for example, filtration through a bacterial retention filter, or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved in sterile water, or some other sterile injectable medium immediately before its use. These compositions may also optionally contain opacifying agents and may be of a composition such that they release the active ingredient only, or preferably, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner. Examples of incorporation of 6?

Compositions that can be used include polymeric substances and waxes. The active ingredient may also be in micro-encapsulated form, if appropriate, with one or more of the excipients described above, [0084 (Liquid dosage forms for the oral administration of the compounds of the invention include lannaceatically acceptable emulsions, microemulsions , solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents used in the art, such as, for example, water or other solvents, solubilizing and emulsifying agents such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate , benzyl alcohol, benzyl benzoate. proptlengícol, 1.3 buíiíerigliccl, oils (in particular, cottonseed, peanut, corn, germ, olive, castor, and sesame oils), glieerol, tetrahydrofurfuryl alcohol, polyethering, and sorbitan fatty acid esters, and mixtures thereof.

(11885} In addition to the Inert diluents, oral compositions may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, perfuming and preservative agents, (0086) The suspensions, in addition to the active compounds, may contain suspending agents such as, for example, ethoxytelated ethoxytearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrtstalin cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof, [0087] The formulations of the pharmaceutical compositions of the invention for rectal or vaginal administration may be presented as a suppository, which may be prepared by mixing one or more compounds thereof. invention with one or more suitable non-irritating excipients or vehicles comprising, for example, cocoa butter, polyeti glycol, a suppository wax or a saifcylate, and which is solid at room temperature, but liquid at body temperature and, therefore , it will melt in the rectum or vaginal cavity and release the active compound.

(| 888 [Formulations of the present invention that are suitable for vaginal administration also include weighing, lamellae, creams, gels, pastes, foams or spray formulations containing such vehicles as are known in the art to be appropriate.

[00S9] Dosage forms for the topical or imnsdermal administration of a compound of this invention include powders, aerosols, ointments, pastes, creams, lotions, peels, solutions, patches and inhalers. The active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any of the preservatives, buffets, or propellants that may be required.

} 6090] Ointments, pastes, creams and managers may contain, in addition to an active compound of this invention, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene gheols, Silicon, benonium, silicic acid, talc and zinc oxide, or mixtures thereof, [0091] Powders and aerosols may contain, in addition to a compound of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and poisamide powder, or mixtures of these substances. Aerosols may additionally contain usual propellants, such as eioroí, Tuorohydroearburos and volatile unsubstituted hydrocarbons, such as butane and propane.

[0092] Trans-dynamic patches have the added advantage of providing controlled release of a compound of the present invention to the body. Such dosage forms can be prepared by dissolving or dispersing the compound in the appropriate medium. Absorption enhancers can also be used to increase the flow of the compound through the skin. The rate of such flow can be controlled by either providing a rate controlling membrane or dispersing the active compound in a matrix or ge! polymeric, [0093] Also contemplated, within the scope of this, invention are ophthalmic formulations, eye ointments, powders, solutions and the like.

[0094 | Luis pharmaceutical compositions of this invention suitable for parenteral administration comprise one or more compounds of the invention in combination with one or more pharmaceutically acceptable, sterile, isotonic, aqueous or non-aqueous solutions, dispersions, emulsions, or sterile powders that can be reconstituted in sterile injectable solutions or dispersions just before use, which may contain sugars, alcohols, antioxidants, buffers, bateteriostats, solutes that return the isotome formulation with the blood of the intended receptor or suspending agents or thickeners.

Examples of suitable aqueous and non-aqueous vehicles that may be employed in the pharmaceutical compositions of the description include water, ethane, poliols (such as glycerol, propylene glycol !, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate. Adequate fluidity can be maintained, for example, by the use of tai coating materials as an excitin, by maintaining the required particle size in the case of dispersions and by the use of surfactants, (0096 | Lists compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. The prevention of the action of microorganisms on the subject compounds can be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, cforobuianoi, phenolic sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like in the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be caused by the inclusion of agents that delay absorption such as aluminum monostearate and gelatin.

[0097) In some cases, in order to prolong the effect of a drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This can be achieved by the use of a liquid suspension of crystalline or amorphous material that has Low water solubility. The absorption rate of the drug then depends on its dissolution rate which, in turn, may depend on the size of the crystal and the crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is achieved by dissolving or suspending the drug in an oily vehicle, (00981 Injectable depot forms are made by forming microencapsulated matrices of the subject compounds in biodegradable polymers such as activated peptide). polyglycolide Depending on the ratio of drug to polymer, and the nature of the particular polymer embedded, the drug release rate can be controlled. Examples of other biodegradable polymers include poly (orthoesters) and poly (anhydrides). Injectable depot formulations are also prepared by trapping the drug in liposules or microemulsions that are compatible with body tissue.

| íf099j When the compounds of the present invention are administered as pharmaceuticals, to humans and attimates, ss can be administered per se or as 70 a pharmaceutical composition containing, for example, from 0.1 to 99% (more preferably, from 10 to 30%) of active ingredient in combination with a pharmaceutically acceptable carrier, jOÍHOO) i, as preparations of the present invention can be administered orally, parentera !, topically, or rectally. These, of course, are given in appropriate forms for each route of administration. For example, they are administered in tablets or capsules, by injection, inhalation, eye lotion, ointment, suppository, etc., administration by invention, infusion or inhalation; topical by lotion or ointment, and rectal by suppositories. The administrations orafes are preferred, [001011 As used herein, the terms parenterai administration and '' administered parenterafly refer to modes of administration other than the entire administration! and topically, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial injection and infusion. intraiecaí, intracapsníar, intraorfeital, intracardiaca, iníradérmies, intrsperitoneal, subcutaneous translraqueab, subcuticalar, intraartiealar, subcapsu'ar, subarachnoidc, intraspinal, and intrasiemai.

100102) The phrases systemic administration, administered sstémícame, peripheral administration and peripherally administered as used herein means the administration of a compound, drug or other material that is not directly in the central nervous system), so that it enters the system of the patient and, therefore, is subject to metabolism and other processes such as, for example, subcutaneous administration, [O0103 [These compounds may be administered to humans and other animals for therapy by any suitable route of administration, including orally, nasally, for example, by aerosol, rectally, intravagonal, parenteral! intracisternal and topical, as well as by powders, ointments or drops, including bucaymenie and sublingually, [001Ó4] regardless of the route of administration selected, the compounds of the present invention, which can be used in a suitable hydrated form, and / or Pharmaceutical compositions of the present invention are formulated in pharmaceutically acceptable dosage forms by conventional methods known to those skilled in the art.

[00195) Actual dosage levels of the active ingredients in the pharmaceutical compositions of the present invention can be varied to obtain an amount of the active ingredient that is effective in achieving the desired therapeutic response for a patient in paríieuíar, composition, and mode of administration. , without being toxic to the patient, (601ÍÍÓ) The dosage level selected will depend on a variety of factors that include the activity of the particular compound employed in the present invention, or the esier, sai or amide of the Husmas, the vfe of administration, the time of administration, the rate of excretion or metabolism of the particular compound used, the rate and extent of absorption, the duration of treatment, other drugs, compounds and / or materials used in combination with the particular compound employed, at age, sex, weight, condition, general health and previous medical history of the treated patient, and factors of this type known in the medical technical fields, (60107 (A physician or a veterinarian who has ordinary experience and the technique can easily determine and prescribe the effective amount of the required pharmaceutical composition, for example, The doctor or veterinarian can start with doses of the antibodies of the invention used in the pharmaceutical composition at levels lower than those required to achieve the desired therapeutic effect and gradually increase the dosage, it is sufficient that the desired effect be achieved.

(00188 (In general, a suitable daily dose of a compound of the invention will be that amount of the compound that is the lowest effective dose to produce a therapeutic effect. Such an effective dose will generally depend on the factors described above. Generally, the oral, intravenous, intraeerebroventricular and subcutaneous doses of the compounds of this invention for a patient, when used for the indicated analgesic effects, will vary from about 0.0001 to 100 mg. per kilogram of body weight per day.

(OOíííOj If desired, the effective daily dose of the active compound may be administered as two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms, dosage. Preferred is one administration per day.

(00110) While it is possible for a compound of the present invention to be administered alone, it is preferable to administer the compound as a pharmaceutical formulation (composition).

t¿) 00111) The compounds according to the invention may be formulated for administration in any convenient manner for use in human or veterinary medicine, by analogy with other pharmacists.

[90112] In another aspect »the present invention provides pharmaceutically acceptable compositions comprising a therapeutically effective amount of one or more of the object compounds described above, formulated together with one or more pharmaceutically acceptable carriers (additives) and / or diluents. As described in detail below, the pharmaceutical compositions of the present invention may be specially formulated for administration in solid or liquid form, including those adapted to the following: (1) oral administration, for example, soak (aqueous or non-aqueous solutions or suspensions), tablets, bowling, powders, granules, pastes for application to the tongue; (2) parenteral administration, for example, by subcutaneous, intramuscular or intravenous injection, such as a sterile solution or suspension; (3) topical application, for example, as a cream, ointment or spray applied to the foot !, the lungs, or mucous membranes, or (4) intravaginantly or intrarectally, for example, as a regret, cream or foam; (5) sublguably or buccally; (or) ocularly. (7) intra-transmiently or (S) nasa!

(00113) The term treatment is intended to also cover prophylaxis, treatment and cure,

J0O114J The patient receiving this treatment is any animal that needs it, including primates, particularly humans, and other mammals such as horses, cattle, pigs and sheep, and poultry and domestic animals in general.

| 00JÍ5 | The compound of the invention can be administered as such or in mixtures with pharmaceutically acceptable carriers and amimerobic agents such as penicillins, cephalosporins, aminoglycosides and glycopeptides can also be co-administered. Joint therapy, therefore, includes simultaneous and separate administration of the active compound in a manner that the therapeutic effects of the first administered did not completely disappear when administered the following, (00116) Mieroemuisifieation technology can improve biodispomhílídad of some lipophilic pharmaceutical agents (insoluble in water) Examples include Trimetrina (Dordunoo, 5. K .., et al, Drug Development and Industrial Pharmacy, 17 (12), 1685-1713, 1991 and RLV 5901 (Sheen, E, C. »3 Pbarm Sci 80 (7). 712-714, 1991). Among other cesas, rntcroemulsification can provide improved bioavailability by preferentially directing the absorption to the lymphatic system instead of the circulatory system, which thus deviates from the liver, and prevents destruction of the compounds in the hepatobilian circulation (00117) While all carriers suitable amphiphilic are contemplated, Currently pretermed carriers are generally those that have the Generally Recognized-as-Safe (ORAS) status, and which can both solubilize the compound of the present invention as mieroemulsiíear it at a later stage when the solution comes into contact with a phase. complex water (such as that found in the human gastro-intestinal tract). In general, amphiphilic ingredients that meet these requirements have HLB (lipophilic hydrophilic balance) values ​​of 2-20, and their structures contain straight chain aliphatic radicals in e! range from C-6 to C-20, Examples are fatty glycerides glycolized by polyethylene and glycol depolyethiene, (001ISj Commercially available anti-filial vehicles are particularly contemplated, including Gducira-series, · Labrail, Labrasoi. or Lauroglycol (all manufactured and distributed by Gattefesse Corporation. Saint Priest, Flannel), PEG-monedéate, PEG-diolol, PPG-monolaurate and diurate, leonin, pollsorbate 80, etc. (produced and distributed by a series of companies in the US and worldwide).

(001 19 | Hydrophilic polymers suitable for use in the present invention are those that are readily soluble in water, can be bound in a covalent manner to a vesicle-forming lipid, and that are tolerated in vivo without toxic effects (i.e., they are biocompatible.) Suitable polymers include polyethylene glycol (PEG). lactic acid (also called poiiíácfidoj, polyglycolic acid (also called polyglycoid), a copolymer of polyurethane-polyglycolic acid, and polyvinyl alcohol. Preferred polymers are those having a molecular weight of approximately f00 or 20 daltons up to approximately 5,000 or 10,000 daltons, and more preferably from about 300 daltons to about 5,000 daltons. In a particularly preferred embodiment, the polymer is polyethylene glycol having a molecular weight of about 100 to about 5,000 daltons, and more preferably having a molecular weight of about 300 to about 5,000 daltons. In a particularly preferred embodiment, the polymer is 750 Dalton polyethylene glycol (PEG (750)). The polymers can also be defined by the number of tnonomers therein; A preferred embodiment of the present invention uses polymers of at least about three monomers, such FEG polymers consisting of three monomers (approximately 50 daííons), 00! 20 Other hydrophilic polymers that may be suitable for use in the Present invention include polyvinylpylidone, pohmetoxazoUna, peiíetífox &amp; zoiing. Methyl acrylamide, polyhydroxy Huida trida, polydimethylamide, and derivatized celluloses such as hydroxymethyl cellulose or hydroxyethyl cellulose.

00121) In certain embodiments, a formulation of the present invention comprises a bi-compatible polymer selected from! group consisting of polyamides, polycarbonates, polyalkylenes, polymers of acrylic and methacrylic esters, polyvinyl polymers, polyglyloids, polysiloxanes. poiiurethanes and eopoh'meros thereof, celluloses, polypropylene, polyethylene, polystyrene, polymers of lactic acid and glycolic acid, poltsnhtdridos, poH (orlo) esters., butyric polhydehyde), poly (valeric acid), poly (iaetida ·· cocaprolaetone ), polysaccharides, proteins, pouhiauric acid, polycyanoacnlates. and mixtures, mixtures or copolymers thereof, 00122 Oelodextrins are cyclic oligosaccharides, which consist of or, 7 or 7 glucose units, designated by the Greek Ira. High ... Beta. or. gamma ,, respectively. It is not known that there are cyelodestrins with less than six glucose units. The glucose units are linked by alpha-1,4-giucosidic bonds. As a consequence of the chair conformation of the sugar units, all secondary hydroxyl groups (in C- '2, C-3) are located on one side of the ring, while all primary hydroxyl groups in C-Ó are located on the other side. As a result, the external faces are hydrophilic, making the cyclodextrins water soluble. In contrast, the cavities of the cyclodextrin pathways are hydrophobic, since they are coated by the hydrogen of the C-3 and O 5 atoms, and by ether-type oxygen . These matrices allow the formation of complexes with a variety of relatively hydrophobic compounds, including, for example, steroidal compounds such as 1?, Beta ·· estradiol (see, for example, van Uden, Plant Ce.il Tíss. Org. Culi, 38: 1- 3- 113 (1994)), Complex formation takes place through Van der Waalxy interactions through the formation of hydrogen bonds. For a general review of the chemistry of ckiodextrins, see, Wenz, Agnetv. Chem. Int, Ed. £ ngl „33: 803-822 (1994),) 00123) The Ositochemical properties of cyclodextrin derivatives depend strongly on the type and degree of substitution. For example, its water solubility ranges from unbearable (for example, iaeethyl-beta-cyclodextrin) to 147% soluble (weight Num) (G-2-beta-cyclodextrin). In addition, they are soluble in many organic solvents. The properties of Cielodcxtrins allow control over the solubility of various formulation components by increasing or decreasing their solubility.

{00124} Numerous cielodextrirtas and methods for their preparation have been described.

For example, Farmeter (1), US Pat. No. 3,453,259) and Gramera, (US Patent No. 3,459,731) described electro-neutral skydextrins. Other derivatives include cyclodextrins with catholic properties [Parroeter (1.1), Pal. US No. 3,453,257], crosslinked eidodexlrins soluble (Soims, Pat EE4JU. No. 3,420,788), and cyclodextrins with catholic properties [Parmeter (MI), Pat. USA No, 3,426.01 i], Among the cyclodextrin derivatives with anionic properties, carboxylic acids. phosphorous acids, phosphine acids, phosphonic acids, phosphoric acids, thiophosphonic acids, ileosulfinic acids, and sollameic acids have been annexed to the precursor cyclodextrin see, Parmeter (ii), supra], 4, in addition, the sulfoalkyl ether cyclodextrin derivatives have been described by Stelia. (U.S. Patent No. 5,134,127).

} 00125j Üposomas consist of at least one membrane of bscapa lipidies that encloses an aqueous internal compartment. The üposomas can be characterized by membrane type and size. Small unilamellar vesicles (SUVs) have an arctic membrane and typically range between 0.02 and 0.05 pm in diameter; large unilamellar vesicles (LVVs) are typically larger than 0.05 iun. Large ougoiamellar vesicles and multilamellar vesicles have multiple membrane layers, generally concentric and are typically larger than 0, i pm. Liposomes with several non-concentric membranes, that is, several smaller vesicles contained in a larger vesicle, are called meltivesicular vesicles.

[00126] One aspect of the present invention relates to formulations comprising iposomes containing a compound of the present invention, wherein the liposome membrane is formulated to provide a liposome with a greater loading capacity. Alternatively or in addition, the compound of the present invention may be contained within, or adsorbed on. Ja liposoraal feieaps of the liposome. The compound of the present invention can be added with a lipid surfactant and is carried within the internal space of the liposome; In these cases, the liposome membrane! It is formulated to resist the disruptive effects of! active agent aggregate - surfactant.

Oe according to an embodiment of the present invention, the lipid lipid of a liposome contains lipids derivatized with poitetüengíicol (PEO), so that the PEO chains extend from the internal surface of the bilayer of you to the encapsulated interior space per liposome, and extend from the outside of the lipid bilayer of the surrounding environment.

| ff (H28j The active agents contained within the liposomes of the present invention are in solubilized form. Aggregates of surfactant and active agent (as for example emulsions or micelles that condemn the active agent of interest) can be trapped within the interior space of Jiposomes according to the present invention. A surfactant acts to disperse and solubilize the active agent, and it can be selected from any suitable aiferous, cycloaliphatic or aromatic surfactant, including but not limited to biosocotyne biotinypatis (LPC) of various chain lengths (e.g., from about CI4 to C20) . Lipids derived from polymers such as PEG lipids can also be used for the formation of nodules since they will act to inhibit the truncated and membrane fusion and as the addition of a po.time.ro to surfactant molecules decreases the CMC of the surfactant and helps in mycelia formation. Surfactants with CMCs in the myelomarial range are preferred: CMC surfactanies plus sites can be used to prepare micelles trapped within liposomes of the present invention, however, monomers of! Nerve surfactant could affect the stability of the liposome bilayer and would be a factor in the design of a liposome. of a desired stability. | ÍÍ0129 | Liposomes according to the present invention can be prepared by any of a variety of methods that are known in the art. See, for example, EfoUU Patent, No. 4,2.35,871; Published PCT applications WO 96/14057; New RRC, Liposomes; To practice! approach, IRL Press, Oxford (199C&gt;), pages 33-104; Lasic DD. Liposomes from physiesto applicalions, tlsevier Science Pubiishers RV&gt; Amslerdam, í 995. (Q333 &amp; J For example, the liposomes of the present invention can be prepared by diffusion of an iiptdn derived with a hydrophilic polymer in preformed liposomes, such as the exposure of preformed liposomes to atlases composed of lipid grafted polymers, at concentrations of lipids corresponding to the final molar percentage of the derivitous h'psdo that is desired in the liposome. Liposomes containing a hydrophilic polymer can also be formed by homogenization, hydrolysis of the lipid domain, or extrusion techniques, as are known in the art.

[00131 j In one aspect of the present invention, ilposomss are prepared to have socially homogeneous sizes in a selected size range. An elective method for determining the size involves extrusion of an aqueous suspension of the liposomes through a series of polyurethane membranes having a uniform pore size selected; The pore size of the membrane will correspond approximately to the larger sizes of iiposomes produced by extrusion through that membrane. See, for example, US Pat. Do not. 4,737,323 (Apr, 12, 1988), [00132] The release characteristics of a formulation of the present invention depend on the encapsulation material, the concentration of encapsulated drug, and the presence of release modifiers, for example, is release it can be manipulated to be pH dependent, for example, using a pH sensitive coating that is released only at a low pH, as in e! stomach, c a higher pU, as in the intestine. An enteric coating can be used to prevent the release from occurring just after passing through the stomach. Multiple coatings or mixtures of cyanamide encapsulated in different materials can be used to obtain an initial release! in the stomach, followed by the release later in the intestine. The release can also be manipulated by the inclusion of salts or pore-forming agents, which can increase the absorption of water or the release of the drug by diffusion from the capsule. Excipients that modify the solubility of the drug can also be used to control the rate of release. Agents that improve degradation of the matrix, or release from the matrix, can also be incorporated. They can be added to the drug, added as a separate phase (that is, in the form of particles), or they can be published in the polymeric pit depending on! compound. In all cases the amount must be between 0.1 and 30% (weight ί polymer weight). Types of degradation intensifiers include inorganic salts such as ammonium sulfate and ammonium chloride, organic acids such as citric acid, benzoic acid, and axcorbic acid, organic bases such as sodium carbonate, potassium carbonate, calcium carbonate, zinc carbonate, and zinc bidroxide, and organic bases such as protamin »sulfate, choline, ethanoiainin, diethanolamine, and trictanoiatnine and surfactants such as Tween® and Pluronic®, Pore-forming agents that add ml-structure to the matrices (i.e. water-soluble compounds such as inorganic salts and sugars) are added in the form of particles, the range must be between one and thirty percent (weight 'polymer weight) ,

JOS 133] The uptake can also be manipulated by altering the residence time of the panicuias in the intestine, which can be achieved, for example, by coating the particle with. o seieceíoa &amp; ndc as matter! encapsuiaute. a mucous adhesive polymer Examples include most of the first with free carboxy groups, such as quitusuno, celluloses, and especially polyacrylates (as used herein, "polyacrylates" refers to polymers that include acrylate groups and modified acrylate groups such as eianoacrylates and methacryls).

Cobolbine ^^ (00134} The invention especially relates to the use of a compound of the formula I (or a pharmaceutical composition comprising a Compound of the formula 1) in the treatment of one or more of the emesmedadex mentioned in this document. , where the response to treatment is beneficial as demonstrated, for example, by the partial or complete elimination of one or more of the symptoms of emergency until complete healing or remission, s

1001351 A compound of the formula can also be used in combination with other antiprofiferative compounds. Such amiproliíeratívos compounds include, but are not limited to, inhibitors of archaelas »; anti-estrogen; topoisomerase I inhibitors; topo1 Ja topoisomerase inhibitors; active compounds of mycrobors; alkylating compounds; histone deqcetiiasa inhibitors; compounds that induce cell differentiation processes; cyclooxygenase inhibitors; MMP inhibitors; mTOR inhibitors, such as RAOOOl; antineoplastic amimctaholiíos: platinum compounds; compounds that act on / decrease the activity of a lipidn protein or kinase and other anti-angiogenic compounds; compounds that act on, reduce or inhibit the activity of a protein or phosphates »lipidies; gunadureiin agonists; aíitísmágenox; Nirdriopepiidi'e inhibitors: metienma: bi fus h mattos; Biofogic icspucsta modifers: imipreil'erative antibodies, such as HCD122 ·; heparanase inhibitors: oneogenic isoforms inhibitors of lees; ia tclomerase inhibitors; proieasome inhibitors: compounds used in the. hematcfiógiesa malignancies treatment, such as fKidambina; compounds that &lt;act '-on, reduce or inhibit the activity of I It-L such a PK PK (~ ¡2; Hsp90 inhibitors such as 17- AAG ¢ 17- allylaminogeldanamicin, NSC'3305t&gt; 7)&gt; 17 - DMAÜ (17 - dimethylaminoethinia- i 7 demethoxy-geldanamicine, NSC70754.5). {pp 50- (., CRESO! 0, CNi'2024, C'NEJQlO of Conforma Therapeuiuz 5 · AW922: temuzoiomide ('Temoda!}; inhibitors of the protein uuinesma spindle, such as SB715992 or SB743921 of OiaxoSmíthKIme, or pentamidine i Chlorpromszine from CotnbinaioRx; IT3K inhibitors, such as BEZ233, 8 KM 120 fes say $ - (2,6-dimorfclinopyrimidin- 4- ili - 4 ttrifiuoromef¡1) pjrtdm- 2- amine] or BYi., 719 jm. say iS&gt; - NI- (4- methyl- 5- (2- {sTÍfluoro- 2- methylpropan- 2- Üjpiridm- 4- iipbizol · 2- yltpirrolidine- i, 2- dicurboxamtda]: in particular BE2235; preferably B KM 120 or BYL.719: ia RAF inhibitors, such as LGX8Í8 or RAE265; MEK inhibitors such as ARRYi42836 from .Arrcty PíoPharma, AZD6244 from AstraZeneca. PD18146J from Pfizer, leucovorin, EDO linkers, antilcuccntieov compounds, mbimíors of the ribonucieclide rtxfuctase- inhibitors of ia decarboxylase S-adenosylmetiouin, antiproiiferative antibodies or other chemotherapeutic compounds, In addition, a combination of these can also be used Tumor treatment, including surgery, ionizing radiation, therapeutic therapy. Implants, for example, with eoritcotdea, hormones, or can be used as radiosensitizers. Also, in the ami-inflammatory and / or anupi-positive anti-inflammatory treatment, your combination with anti-inflammatory drugs is included. The combination is also possible with nntihistamimeos drugs, brenccdiiator drugs, ΛΙΝΕ or chemokine receptor antagonists.

001 JÓ] The term inhibited: from ia ammatase * 'tai as used herein, refers to a compound that inhibits the production of estrogens, that is, the conversion of the substrates andrvstcttedione and tvsfosterone -t stoma and estradiol respectively 171 term includes, but is not limited to stetoids, especially atamestane. exemestane and fonnestane and, in particular, non-steroids. especially amtnogiutetírnida, rogleítmida, piridoglutettmida, trilostano., Íestolactona, ketoe &lt;mazo ', vorozol. Fadtozol, anastrozo! and ietrozole. 17 i exemestarm can be administered, for example, in the way it is marketed, for example, based on the trade mark] AROMASIN. Formestane can be administered. pure example ,, in the form as it is marketed, for example, under the merca cotr.ercisi 1, 'ENTARON. Fadrozoi can be administered, for example. in the form as it is marketed, for example, under the trade mark ΑΕΈΜΑ. Anastrozole can be administered, for example, in the form as it is known, for example, under the brand name AiíMiDE.Y. I'.i letrozoi can be administered, for example, in the form as it is marketed. for example, under ia otare at 80 registered FEMARA or FEMAR. Aminoglutetirnide can be administered, for example, in the form as lira is traded, for example, under the trademark ORiMETEM. A combination of the invention comprising a chemotherapeutic agent that is an atomatase inhibitor is useful for the treatment of tumors with positive hormonal receptors, for example »breast tumors, | O0137 | The term "anti-estrogen", as used herein, refers to a compound that threatens the effect of the esophogens on the estrogen receptor level. The term includes, but is not limited to tanmxifcno, fulvestrant, raloxifetto and tatoxifene hydrochloride. Exetnestane can be administered, for example, in which form it is marketed, for example, under the trade brand! AROM.ASÍM. Raloxifene hydrochloride can be administered, for example, in the form as it is marketed, for example, under the trademark EVISTA. Fulvestrant can be formulated as described in the US, 4,659,516 or it can be administered, for example, in tonas as it is marketed, for example, under the commercial tide f / XSLOflFX. A combination of the invention comprising a chemotherapeutic agent that is an anistrogen is particularly üti! for the trait of tumors with positive estrogen receptors, for example, breast tumors.

| 06í38 {E! The term and · - androgynous as used herein refers to any substance that is capable of inhibiting the biological effects of androgenic hormones and includes, but is not limited to. bleaiafamide (CASODEXTM). which can be formulated, for example, as described by the US. 4,636,505.

{CH) Í59 {The term gonadorelin agonist as used herein includes, but is not limited to abarel is. goserelin and goserelin acetate. Goserelin is described in the USA. 4 100.274 and can be administered, for example, in the form as it is marketed, for example, under the commercial tide XOLADFX. Abarclix can be formulated, for example, as described in the US. 5,843.90!

OOHOj The term "topoisotnerase inhibitor" as used herein includes, but is not limited to topotecan, gimatecart »irinotecan» camptothecin and its analogues. 9npecocnmptotecina and the conjugate of camperous maeroinolecuiar RNÍ.1- ióóURt (compound Al in WO99 / ​​17804). The chemotherapy can be administered, for example in the way it is marketed, for example under the trademark CAMPTOSAR. Topolccan can be administered, for example, in the form as it is used, for example - under the tidal wave IIYCA M 'ÍN :.

100143] The term "iopoisomcrase inhibitor" as used herein includes, but is not limited to aiitraciclmss such as doxomibicins {including liposénmca formulation. for example CAELYXt, dauitorubient, eptrublcuta, tdarubiein and nemottibycin. the ardrsquinomiA mití »: antruna and losovantrona, and the podophyllotoxins etoposide and teniposide. The eopóstdo can be administered, for example, in the way it is marketed, for example, son the tide trades! ETOPOFHGS, Tenipósido can be administered, for example in the way it is marketed, for example under the brand VM 26- BRISTOL, Doxorabiema can be administered, for example in the way it is eaten and reed, for example under the commercial tide ADRtSLASTIN o ADRÍAMYCiX Epiburielna can be administered. for example, in the way it is marketed, for example, under the commercial inland f ARMORíLSICIN. Sd &amp; rtibjcina can be administered. for example in the form as it is marketed, for example under commercial mama 2AVEIÚOS. Miioxautrone can be administered, for example in the form as it is marketed, for example under the tide to eat NOV Λ NT RON.

j (SÜÍ42j The term active compound on NERVs refers to stabilizing compounds, of mforotubules, microtubes destabilizers and mtcrotubule polymerization inhibitors that include, but were not intrinsic, for example, paclitaxeJ and docetaxcl. vinca alkaloids, by For example, vinblastine, especially vinblasin sulfate, especially vincristine, vmcrisfin sulfate and vinorelbine, discodermolides. colchimna and epoxyls and their derivatives, for example, epothilone B or D or derivatives thereof: ios themselves. Pacliíaxel can be administered, for example in Is. Form as it is marketed, for example TAXOL^7M. The! docetasel can be administered, for example, in the same way as it is marketed, for example at commercial tide AXOTERE. Vitilblastine sulfate can be administered, for example in the form as it is marketed, for example under the commial brand Υ1ΝΒΕΛ5Τ1Ν RF. ES vincristine sulfate can be administered, for example, in the form as it is marketed, for example, under the commercial seas EARMISTÍN, Discodennofide can be obtained, for example, as described in EEi.CE 5,010,999. Also included are Epoilone derivatives which are disclosed in WOfoEíOtTi, US 6,194.1 SI. WO 98/25929, WO 98/08849. WO 99/41653, WO 98/22461 and WO 000124 ?. Specifically preferred are Epoilone A and / or B 00143] The term "alkylating compound" as used herein includes, but is not limited to, cyclophosi'atnide. ifosfámide, meífáían or nitroaourea (BCNLi or Gliade!). Cryophosphamide can be administered, for example in the form as it is marketed, for example under the commercial tide CYCLOSTIN. Ifosfamide can be administered, for example, in the form as it is marketed, for example, under the ccmetciaí HQLOXAN tide:

06144] The term history inhibitors deacerated lasa or inhibitors of l-ÍDAC or I refer to compounds that inhibit histone deacetyiasis and which have aniproliferative activity. This includes compounds such as LDH589 disclosed in WO 02/22577. especially N- hydroxy '3- ¡4- [[(2- hydroxyethylb 2 - (1H- indol- 3- ill etiijj amirto | methylj fentlj- 2E- 2- propenamide, N- hydroxy- 3- 4-! 2 - &lt;2- motil- Π-i-indole-3¡I) - ctdl-amino] medí] phenylj-2E-2- propenamide and pharmaceutically acceptable salts thereof! Also, it especially includes suberotlanilide hydroxammonium acid ( SARA). 00145] The term antineoplastic amphimotabolite '' includes, but is not limited to, 5 Fluorouracil or 5- FU, capecitabine, gemcitabine. demedial compounds of DNA, such as 5- azacitidma and decitabine, mciolrexate and edaíre.xato, and antagonists · of! foic acid such as pemeirexed. Capecitabine can be administered, for example, in the form as it is marketed, for example, under the registered trademark XELODA. Gemcitabine can be administered, for example, in the form as it is marketed, for example, the garlic brand GEMXAR.

Ι00Ϊ46] The term '' platinum compound as used herein includes, but is not limited to, earbopit-thmo, eysplatin, cisplatin and oxaliplatin. The carboplatin can be administered, for example in the form as it is marketed, for example under the commercial tide CARBOFLA'E, The oxalipyatuto can be admlmstrar.se, for example, in the form as it is marketed, for example, under the trademark ELOXATIN, 00147] The term "compounds that act on / dissolve a protein or Sipida kinase activity; or a protein or lipid phosphatase activity * ': or additional anian-angiogenic compounds "as" filisam herein. Includes, but is not limited to inhibitors of ia proreine tyrosine kinase and / or serine and / or ileum kinase or ia kinase inhibitors. lipid, for example:

00148] a) compounds that act on, decrease or inhibit the activity of platelet derived growth factor receptors (PDGFR). tai as compounds that act on, reduce or inhibit the activity of PDGFR. especially eomposes that inhibit the PDGF receptor, for example, a derivative of N-fensi-2-pyrimidioa-amine, for example UNAattnib, SU! 0i, SU66611 and GFB 1 and 1 -;

[00149] bi compounds that act on, decrease or inhibit the activity of fibroblast growth factor receptor (FGFR) receptors;

[00150 (c) compounds that act on, decrease or inhibit the activity of insulin-like growth tactor receptor 1 (K3F&gt; IR), such as compounds that act on, reduce or inhibit IGF-IR activity, especially compounds that inhibit the activity of! IGF-1 receptor, such as those compounds described in WO 02/092599, or antibodies that act on the exitoeekdar domain of the IGF-í receptor or its growth factors;

(00151 (d) compounds that act on, disseminate or inhibit the activity of the firoxyne quinase family of Trk receptors, iaephrine inhibitors 84;

[00152} e) compounds that act on, decrease or inhibit the activity of the Λ xi receptor family of tyrosio qutnasa;

[00153} í) compounds that act on, decrease or inhibit the activity of the tyrosine receptor qtduase Ret;

(00154} g) compounds that act on, decrease or inhibit the activity of receptors of the resin kinines »e-kit / SCFR, ie receptors of the C-kit tyrosine kinases {part of the FDOFR family). such as compounds that act on, reduce or inhibit the activity of the c-Rif tyrosine kinase receptor family especially compounds that inhibit the c-Kit receptor, for example, imatinib;

[001551 h) compounds that act on, decrease or inhibit the activity of members of ia tamiiia Abl, their fusion products (for example, BCR-There kinasit) and miners, tules as compounds that act on, reduce or inhibit activity of members of the e-Abl family and their gene fusion products, for example, a N-feoyl-2-pyrimidiosamine derivative, for example imatinib or niíotíuib (AMN i07l PD »80970 ·. AG957, N $ C 680410, PaikeOavis PDi73955, or dasatio; b (BMS- 354825) s of [00156 (I) compounds that act on, reduce or inhibit the activity of proteinu kin members * C (PKC) and the Raí family of serious / frsonin kinases. members of ia MEK, ERK, SRC, JAR, FAK, POR], PKB / Akt, and members of the Ras · 'MAPR family. such as members of MtK, SRC, J.AK, FAK, PDR1, PKB / Ákt, and members of the family

Ras / MAPK. and n members of the phyllilia of dependent kinases would decide (CDK) and are mostly the derivatives of staurosponna described in EEA / U. 5,093.3. / 9, for example, midcstaurm »; Examples of other compounds include xx example, VCN-01. satinad. BAY 43-9006, Brlosíatiria 1, Periphosine; ilntofosina, RO 31822.0 and 320432 RO; OO 6976; Luis .3521, 1, Y333S3I / !, Y379596; iaequmoline compounds Ules as Sos discards ”in WO 09/09495; F'Hs; BEZ235 (a P13K inhibitor.) Or AT75I9 (COK inhibitor); in particular, the compounds (pao act on, reduce or inhibit the activity of the members of protein kinase C (PKC) and the physiha Ral 'of serine^s Ireonin kinases, members of the MEK, ERK. SRC, JAK. FAK, PDKK PKB Akt, and members of the Ras / MAPK family, and / or members of the cyclin-dependent kinase (COK) family and especially those staurosporine derivatives disclosed in EEA5U. 5,093.3 39, for example, rnidostaur'ma. Examples of other compounds include, for example, OC \ - 91, snfingoi, BAY 43-9996, Briostaúna i, Pcrifosina; ibneí'osina; RO 3¡ &amp; 220 and 320432 RO; GO 6979; Isis 352 '!; 33'33353 bLY379; 99: isoquoline compounds such as those described in WO 99/09495; Dabraíénib, vemurafenib, Eneorafenib; Flis; BEZ235 (a PI3K inhibitor) or ΛΤ7519 (CDK inhibitor) or NVF- E £ E9i I. that is, 7- oyciapentilY, K- dimeryl- 2- ((5- (pipernzm- 1- iíjptridm- 2- ibamino) -? H- pirro! u [2,3- djp'timidma-6carboxamide); GDC- 0994 (es ticen, | S&gt; - 1 · (1- (4- chloro- 3- finotophenyl) - 2- hydroxyeíüp 4 {2- {{i-methyl · lid- piras®! - 5- iljamino) pinmtdin- 4- ytbpiridin- 2 (114) - one) or SC149O0353 or DVB- 523 (i.e. (S&gt; 4- (5- doro- 2- (isopropyl)) pyridin- 4- ib- N- (1- (3-chlorophenyl) - hydroxyetiite 114-pyrrola-2-earboxannda); preferably Dnbroiemh, NVPLEE01Í (ie. 7- cidopenti-NN- dimer · 2- ((5- (piperazin- 1- iljpindin- 2- ibamino) 754-pi (To5o (2,3-djpirimidma- or- carboxamtdajo Eneorafenib ¡06? 57j j) acting compounds on, decrease or inhibit the activity of ios tyrosine kinase protein inhibitors, such as k) '- compounds that act on, reduce or inhibit the activity of protein tyrosine kinase inhibitors include imatioib mesiate (Gieevec) or irphostma. Thyphosphine tub is preferably a low molecular weight compound (, Mr &lt;1590), or a sa! pharmaceutically acceptable thereof, especially a compound selected from the class of benzylidene-jonitrile compounds or Sarilbeneenomalomtrik) or bbmbstrato quinolimt classes, more especially any compound selected from the group consisting of Thyrostin A23 / RG- $ 0850; AG 99; 'firi'ostin AC »215; Tiríostin AG i 748; firíostin AG 490; Thyrostin 13-14; Tktbstm 13-14 enautíómero {), Tiríostin 85 í \ G 553, AG 494; Thyrostin AG 556, AG957 and adamar / thio ester dd adaphosinic acid &lt;4 (: (2,5-dthydroxriertyl) medi) amino} -benzoic acid; NSC 680410, adaldsine);

[00158} k) compounds that act on, decrease or inhibit the activity of the family of epidermal growth factor of firosine kinase receptors (EGFR, ErbB2. ErbB3, Erbl34 as homo- or heterodirneros) and their walkers, such as compounds that aetíma on, decrease or inhibit the activity of the family of epidermal growth Actor receptors are especially compounds, proteins or antibodies that inhibit members of the EGF family of thyrostna kinase receptors. e}., for example EOF receiver, ErbB¿, FrbB3 v Er'bB4 or are attached to EOF or related eos ligands; EGF and are in particular those compounds, proteins or monoelonal antibodies generically or specifically disclosed in WO 97, 02266, for example, the compound of! example 39, or in EF 0 564 409, MG 99/03854, EF 0520722, EF 0 566 226, EF 0? $? 722, EF 0 83? 063, E? 8 5Y7JO8, ftO 98/10767, WO 97GOO34, WO 97/49688, WO 97/38983 and. especially, WO 96/30347 iet .. compound known as CP 358774), WO 96/13980 (eg, compound ZD i 815?) and WO 95.03283 (eg "compound 2M105180); eg, rrasmxumah (Hercepítn ™), cetuximab (ErbítuxY Jressa, i'arceva, OSÍ- 774, Cl-1033, EK8-569, GW- 2016, El, i. E2.4, E2.5, 66.2, E6.4, E2.1 i, F.ó.3 or E7.6.1, and derivatives of 7-pyrrolo- {2,3-djpirsmidinít which are disclosed in WO 03/01354 ;: and (00150} i) compounds that act on, decrease or inhibit cMet receptor activity, such as compounds that act on, reduce or inhibit c-Met activity, especially compounds that inhibit the kinase activity of c-Met receiver, or antibodies that act on the extracellular domain of e-Met or bind to HOF [00160] Additional amine angiogenic compounds include compounds that have another mechanism for their activity. eg, unrelated to inhibition of protein kinase or lipyria eg, mfidmnin (FIlADGMiü) and TNF-470, [(8) 1.61} Compounds that act on, decrease or inhibit = s activity of a protein or phosphstase tpidfi are for example phosphatase 1 inhibitors, iosfatase 2.A. or CDC25. e ·., akadaic acid or a derivative thereof, [00162} Compounds that induce cell differentiation processes are for example retinoic acid, or.- y- or 5- toenferní or r s- y- 6 6- tocofriennl (00161} The term "cyclooxygenase coma inhibitor" used herein includes, but is not limited to, for example, inhibitors of Co.v 2, 2- ardainemoyleric acid, ethaethyl ether 586 alkyl-derivative&gt; derivatives. such as celecoxib ((Ε.Ι.ΕΒΚΕΧ), rofecuxtb foioXXj, etoricoxib, valdecoxib or an S-alkyl · 2-aryiainin-technical-acetic acid, for example, 5-methyl-2-z-chloro-6 acid^!- Huoraanilinojfenil * acetic, lumiracoxib.

100164 (The term blsphosphonates, as used herein includes, but is not limited to, elrídónico acid, clvdfúniuo, tiludiónico. Pamidrónico. Alendronico. Ibaudronsco. Nsedróruco and zoledronic. The eiridonic acid can be administered, for example, in the form as it is marketed, for example, under the commercial tide DIDRONEL Ei eledtonic acid '' can be administered, for example, in the way it is marketed, for example, under the BOMEFOS tide. Tiluiirónic acid '' can be administered. For example, in the way it is marketed, for example, under the trademark Sfcelío. The p-mudotranic acid can be administered, for example in the form as it is. Marketed, for example under the trademark AREOLA ™, Alleric acid can be administered, for example, in the form as it is marketed, for example, under the EOS AMA X comi-aciai matea. Ibandronic acid ”can be adhered to, for example, in the way it is marketed. for example, under the trademark FiONDRANAT. The "risedronic acid can be administered, for example, in the form as it is marketed, for example, under the trademark ACTONEL. Zoledronic acid can be administered. for example in the way it is marketed, for example under the commercial breast Z0ME7 A.

(00I6YES The term mTOR inhibitors refers to compounds that inhibit the mammalian objective of mpamicirta fmlOR) and that possess tsí antiprolitic activity such as siroismus (Rapamune®), evetoísmtts {Cerdean '”), CCl-779 v ABT578; preferably sverolímus, (0 (1166) The term heparanase inhibitor as used herein, refers to compounds that act on, reduce or inhibit degradation of beparírsa sulfate. The term includes, but is not limited to, PI - 88.

f00I67] The term "biological response modifier" as used herein refers to a hnfoqninn or interféromts, for example, inlerferon and.

100168 (The term inhibitor of Ras oncogenic isophones ”, for example, El · Ras, K ~ Ras, or N-Ras, as used herein refers to compounds that accentuate on, reduce or inhibit the oneogeuic activity of Ras for example, an inhibitor of ia fumesií transforase, for example, t-744.832, DK8G557 or R i 15777 {Zarnestra}.

] U0jp9] H te¡üIüm '' telomerase inhibitor '' as used herein or "removes compounds that act on, reduce or inhibit the activity of fa tefomerase." Compounds that act on, reduce or inhibit the activity of telomersse are especially compounds that inhibit the ileum receptor, for example, telomestahna, [Í&gt; OÍ7Ú | The term ia jnethionine aminopepididium inhibitor as used herein is teiled to compounds that act on, (educate or inhibit ia rne activity; amine peptide tonin ». Compounds that act on, reduce or inhibit the activity of methionine sminopeptidase with, for example, bengamide or a derivative thereof.

[Ú0Í71] The term "proteasome inhibitor" as used herein refers to compounds that act on, reduce or inhibit proteasotna activity. Computers that act on, reduce or inhibit proteasome activity include, for example, Bottezomíd f Ve ¡cade ™} and MLN 34 !.

fOOÍ72 The term "matrix metaioproteinase matrix" or (MMP inhibitor) as used herein includes, but is not limited to pepudomirnciieos and non-peptidomimetic collagen inhibitors, derived from tetracycline, for example, the peptidomimetic inhibitor of hydra «amato, batunastaí and its orally hyponisponibfe analogue, (tuirinmstat ¡ΈΒ- 2516), prinomastaf (AO3340), mephytites (NSC 68355!) 3MS- 279251. BAY 12-9566. IAA211, MMÍ270B or AA.I996.

[00173] Ll ténntno "compounds used in the treatment of bemaymiological malignancies as used herein includes, but is not limited to, tyrosine inhibitors of type l '-' MS for example, compounds acting on,, decrease or inhibit the activity of fa tyrosine quinase receptors; FMS type (El; - 3R); inferred! hi&gt; aiahinofuransileitosine (ara- ej and btsolfísn; and ALK inhibitors, for example, compounds that act on, reduce or inhibit anaplasic finfoma qulnase.

00174] Compounds that act on, reduce or inhibit the activity of tyrosine qninase receptors or FMS (I It-3Rt "are especially compounds, proteins or antibodies that inhibit members of the Eft-3R qm'nase receptor family for example PKf'41 ?. TKÍ258, midostaurma, a derivative of staurosporine, SL11248 and MLN.5Í8.

j00P5] I? j term HSPSO inhibitors as used herein includes, but is not limited to, compounds that act upon, decrease or inhibit the intrinsic ATRase activity of HSE90; degrading, acting on, decreasing or inhibiting the Hsp90 client proteins through the uhiquitin proteasome pathway, Compounds that act 88 on, decrease or inhibit the intrinsic ATPase activity of ÍISP90 are especially compounds, proteins or antibodies that inhibit iSP90 inutnaeca ATPase activity for example, 5 7- aiiiamino, 5 7- dioiethoxyigeldanamieins J7AAG), a derivative of geldanamicin: other related compounds coa geldauaroiein; Rididicot c HÜAC inhibitors. An example IISP90 inhibitor is AUY922 [00176) The term "anti-prophylactic antibodies" as used herein includes, but is not scaled to, trasivozuroab (Werceprin^rMt, írastuzufoab- DME erbítux, bevaciznntab (Avastirt ™}, Riíuximab {Riíuxas ''⁵). PRO64553 (anü-CD40), Antibody 2C4 and antibody HCDI22 (Añil-CD40), Pot antibodies are understood, for example, ios intact monoclonal antibodies, polyclonaic antibodies, muitispecific antibodies panned from ai mentis 2. intact antibodies, and fragments of antibodies provided they have the desired biological activity.

[00177] For the treatment of acute myioid leukemia (SMA), the compounds of the formula (!) Can be used in combination with standard therapies for pandemic therapy, especially in combination with therapies used for the treatment of AVIE In particular, the compounds Fónnuia (1) can be administered in combination with, for example, inhibitors of famesit transferase and / or other titile drugs for the treatment of SMA, such as Oaunorublcma, Adriamtcina, Ara-C, VP-16, Tentposide Mitoxantrone, ídaruhydna, carbopíatino and PKC4S2.

[UO17S [The term anti-succulent compounds includes, for example, Ara-C. A pyrimidine analogue, which is derived from 2'- .alpha-hydroxy-ribose (arabtnoside) from ia dcsoxtcittdtna. Fnmbicti is included in the purine rheumato of hypoxanrinti, 6- rnercaptoputin (6- MPI and ios kilo of tludarabine, [601791 Eos compounds, which act on, reduce or inhibit the activity of inhibitors of ia itistone rieaeetylase (HDACj such as buttrato) sodium and suberot acid andida htdfoxámieoíSAlÍA) inhibit the activity of enzymes known as deacylase bistones, specific HDAC inhibitors include MS275, SAHA, EK22 &amp; (formerly FR901228), Thcostatma A and the compounds described in EEGO. 6,552,065. in particular, .Y- itidroxí- 3 · [4- ¡'[[2- t'2- methyl- H- irtdol- 3- 11) - etiij- aminol inetüí dyed Ij-2E- 2- propenamídn, or a of its acceptable fat-pharmaceutical salts and A- hydroxy3- [4-1 (2- huifoxictií) {2 - (iii- indol-3- tí) eíilj-amino] methyl] phenyl] - 2E-2SS prcípenam-dm or tub salt pharmaceutically acceptable puppet itself, especially the lactate salt, {OOtSOl Antagonists yes sornalostatin receptor as used herein, refers to compounds acting on, treat or inhibit »e! sonostatin receptor. such as octreotldo, and SO.M230 (pasbeotldc).

[dOíSt] Etiibqucs of immoral cell damage refer to approaches such as ionizing radiation. The term ionizing radiation mentioned above and hereafter means ionizing radiation that occurs either as electromagnetic rays (such as x-rays and gamma rays) or particles (such as alpha and beta particles). Ionizing radiation is provided in, but It is not limited to radiation therapy and is known in the art See r-lciiman, Principles of Radiation Dterapy, Cancer, ir. Pí'rec.yvís .red fyocficfc 'oíÜHcoíogp, Devita, Eds., 4^to Edition, Voi. i, pp. 248 «2.75 / i 993).

[001321 The term "linkers of EDO '* tai as used herein, refers to a cynase of inntunosuppressants that modulates the recircuiactón of Itnf'ocitos, as well as (FTV72O). 0 (M83j E! Term '' reduephase ribormclotide inhibitors refers to the pyrimidimt or purine nueteoside analogs including, but not limited to., Hudarabitia and / or cyanosine arabinoside (ara-C¡, 6- thioguanine, 5 - fluorounteyl, eiadríbiuíi, o- ¡rteicaptopurine (especially in combination with ara- C against ALE} and / or pernostatin. The inhibitors, of the reduetase ribofutcleotide are especially hydroxyurea derivatives or 2- bldroxy-1 Hisomdob L3-dions, such as EL-LEL-2,3-EL, PE-4, EL · 5, EL- or, EL- 7 or PE-8 mentioned in Nandy, de / u Owc-o / ogré / z voi. 33, No. S. pp. 953-96 i (i 994).

(00Í84J) The term inhibitors of S-adcnostlmcitonin deearboxtiase as defined herein includes, but is not limited to the compounds described in IJ1J. 5.46Lí¡? 6 [iltlíSSJ Also included, in particular, those compounds, proteins or mono-lorial antibodies disclosed in WO 98 / 3595S, for example, '- t' ~ chloroaninium) - 4 - &lt;4- pyridiimethy) phthalazine or a pharmaceutically acceptable sai thereof, for example, succinate, or in WO 09/09495. WO 00/27820. WO 00/59509, WO 98/11223. WO 00/27819 and EP 0 769 947; those as described by Ereweh, Cancer Ras., vol, 59, pp 5,209-5,2iS (1999); Ynan, Proc Nati Asad Set LSA, val 95, pp 14765 to 14770/1996); 2bu, Caaccr Res ,, vn !. 58. pp 3209-32 and 4 (1999); and Mordemi, Toxico! Eatbol Voi., 27, No. 1, pp} 4- 21/1999); in WO 00/37502 and WO 94/10202; Angiosiatinii, described by CTReilty, Ccil, vol. 79. pp 315-32 / 1: 994); Endostatin, described

SO pot O'Reiíly. Cell, voí 88, pp 277-285 {1997); amides tfe acid smtramiko; ZiMt90; ZD6474; St; S4ib; St 16668: bevac i zuma b; or bind-VEGF antibodies or VEGF antireceptor antibodies, for example, rhuMAb and thuFab, for example VEGF sptñmero Macugmt; FLT- 4. ia FLT-3 inhibitors. VEGFR-2 IgGL antibody Angmzyme iRFÍ 4610) and bevac izumab {Avastin ™).

| {ί01§6) Photodynamic tetapia as used herein refers to ii; therapy that uses certain chemicals known as foiosensitizing compounds to treat or prevent cancers. Examples of íbtedinñnnca therapy include treatment with compounds, such as VtSUDYNE and porfimero sodium.

[00.IS7) Angostharteous lyseroids as used herein, refers to compounds that block or inhibit angiogenesis, such as, for example, anecortave. Triame Molona Hydrocortisone, II-A-Epihydrocotisol. cortexolone i7a- htdroxyprogesterone, caiwosterone. deoxy «orttcosteraia, testosterone, estrone and dexaraetasona.

[{) 0.188) Implants containing corycosyeroids refer to compounds such as ei., Molona fines, dcxarnctasona.

[00189] Other chemotherapeutic compounds include, but are not limited to. vegetable alkaloids, honnonalss? antagonists; biological response modifiers, preferably hníbqoinas or tmet &amp; ronas; antisense oligonucleotides or derivatives of oitponueleotides; shRNA or siRNA; or miscellaneous compounds or compounds with another mechanism of unknown action.

[00190) The structure of active agents identified by code numbers .. generic or commercial names can be dubbed from the current edition of the standard Merck Index or from databases, for example, Fatents International (for example, IMS World Fubiicatioíis).

[0019íj Some combinations may be useful for you! Treatment of certain types of proliferative diseases. I read the following non-exhaustive list indicates some preferred combinations and the respective diseases; a compound of the present invention in combination with an EGFR inhibitor (for example iressn '^M). e »part-ctrlar for the treatment of NSCLC; a compound of the present invention in combination with a PL 3K inhibitor, such as BEZ235 (N^c CAS 415919-65-?) From Novaros, in particular for the treatment of nasolatingso carcinoma (NPC) and some other types of cancer; a compound of the present invention in combination with a nffOrL 91 uti inhibitor compound of the present invention in combination with a protein »kinase of irosine and / or inhibitor of Raf corno sorafémb, in particulate for the treatment of primary kidney cancer { advanced renal cell carcinoma; · and advanced primary liver cancer {hepatocdniar carcinoma); a compound of the present invention in combination with a VEGER inhibitor such as ΡΪΚ787 or urs antibody against the VEGE ligand. such as Avastin®; a compound of the present invention in combination with an FDGFR inhibitor, for example, imatinib (ST157} or Glivec X); a compound of the present invention in combination with an mTOR inhibitor, such as rapanieniein and everolimus í RADOOt). (O0192J In one embodiment, the other therapeutic agent is selected from; an EGFR inhibitor such as JressííTM; Raf inhibitor such as Sorafenib; Fl · 3K inhibitor. As BE7.235 CAS No. 91 5QIO- 65-7); VEGFR tai corno inhibitor FTK787; VEGF antibody, me as Avastin ®; PDGFR inhibitor, tai as STI 571 (Glivec &amp;); mTOR inhibitor, such as tapamiein and everolimus; Atomatase inhibitor such as letrozo. 1 (Femara .Φ) or snssftozole; active compound of micTOhifeuíes. such as paclitaxel or an epothione; antincoplastic anthnetaboite such as gcmcitabine or capecitabine: platinum compounds such as carboplatin or tanplanne; biphosphonates such as AREDIA® or ΖΟΜΕΓΛ®; and HER2 antibodies such as trastuzumab.

00193} None of the citations of references made within the present disclosure will be understood as an admission that Ins cited references are prior art that would adversely affect the patentafility of the present invention.

ibpccsosjrara jTm:&gt; urmJoyCün ^^

Compounds of the invention can be prepared according to Reaction Scheme 1, wherein n, Rt, R2, RS, R4 and R3a are as defined for a compound of formula &lt;.1.S in G herein and E5 is R3a and optionally comprises a hydroxyl or a protective group.

In the present application, the term "nitrogen protecting group" generally comprises any group that is capable of reversibly protecting a nitrogen functionality, preferably an amino and / or arroda functionality. The term "hydroxyl protecting group" generally comprises any group that is capable of protecting hydroxyl tuning from reversible lorrine. Suitable nitrogen protecting groups $ hydroxyl protecting groups are described, for example, in the corresponding chapters 92 of the standard reference works, such as JFW McOtnte, Protective Groups in Organic Chernístry **. Plenary ») Press. London and New York, 1973; TW O reene and PGM Wuis, Protective Qrcmps de Grecos in Organic Synthesís, Coarta Edition, Wíley, New York 2007; in Trie Peptides; Volume 3 (editors: E, Gross and L Msienhofer), Aeadciníc Press, London and New York 1981, and in A / e / horfen «ter orgenjisefeen Cfejwfe (Organic Chemistry Methods). Houben Weyl, fourth edition, Vc-iunie 55/1, Georg T'nieme Verlag, Sintfgart: .1974. Scheme 1 'rr^Laughed ; λ^{: ί}&lt;&lt;

i L^:And V.

'' γ Y,_S'' * '' 'v⁴ⁱ

Y, . : SV. -N -: 'í &lt;si *, - χ, A ·. „N &lt;k r. a ^ r «QOCtttfeftCSg * f» dySC&gt; ¿«⁶'»« * »-; , JuU

1* *

j: | ¡A) í y - $ ?, · '&gt; γ $ * Ύ ··

-A i &lt;% *****

SN A, a&gt; * »:? '* Γ vy γ-jf ijc¡mx¡_and..

1, - '* δδ d »or $ s $ YesOí # &lt;tk&gt;« á.fi aí ^ m

Xv

<img file="CU20160020A7_D0029.tif" />

<img file="CU20160020A7_D0030.tif" />

Lea * $

W Í2

C &lt;Xí &lt;ítCÍ &lt;5ív «$ i3 * .ítí5íiP« tí »Ci &amp; t

P, £ * Í «Í ¿

OÍW ^ s »í&gt; T '&lt;« t * £ ** «-« {

Xfti ^ 'ííi ^ íVfcfr.'íÍÍjt í®í&gt; Síiffí0 #&gt; * S ·, | * Í9 «ΐ * t &lt;® &lt;5 ¡&lt;δ« ί # Κ * δ ^ «&lt;$ * £ &amp; $ € ·?

&lt;5&gt; γ · £ '£ .Φ&gt;^χ* $ 3 $ SOÍ ^ -ÍÍSRÍBC * '

A .Á.

&gt;; ........

1·:&gt;&lt;

JL'L, $ £ *

Or «'\ - faith * · / y- γ -; .-. ·,

V_Y^ z,_v ”J '·' \\ $ '' A &lt;

[00194] The present invention ambiétt includes processes for the preparation of compounds of the invention. In the reactions described, it may be necessary to protect reactive phonemic groups, for example the hydroxyl, omino, iminc, thio or carbony groups, when these are desired in the final product, to avoid their unwanted participation in the reactions Conventional protecting groups may, be used in accordance with standard practice, for example, see TW Greene and R, GM Wuts in "Protective Groups in Ofganic Chemistry", John Wiley and Children. 1991 [Ó0t9S | The compounds of ónnuía 1 can be prepared by proceeding as in the following.

Reaction Scheme 2;

TFA-HN ...... 77 ™^: 77 ./'¿¿A

L&gt; i_ Ai * &lt;· _ / 4v

Ά \ /: S33Í7S

- A Γ'Λ \ -A and · *⁵ ft &lt;A γ ^N- tete ^ 5 = · ^ -A. &lt;A £ -Z fvf

100196] itself which Ri, A Rj_b, &amp; $ and R-. are as defined for Formula I in the

Summary of the invention and X represents a group, also as a leaving group, selected from bromine, elm, or the like.

100197] A compound of Formula i can be prepared by reacting a compound of. Tannyla (2) with a compound of the formula (3) in the presence of a suitable base (such as TEA, Di PEA, K2CO3, or the like), a suitable coupling reagent (such as FDCt, HODt. HATU, or the like), a suitable reagent (tai corno hateros of alkyl, acid chlorides, sulíonslo chlorides, carbamoyl chlorides, suiíamollo chlorides, isodanato or similar, in particular, teles such as hateros de alkyl, acid chlorides, chlorides sulfate) and a suitable solvent (tai as diethomeomene, THF, ACN, DME, or the like). The reaction takes place in a temperature range of approximately 20 "C ai 2O''C and may take up to approximately 24 hours to complete. p.) 0198j 6- Bromo- 4- chloro- 7- fluorine »- 3- niyroqainoin (L3 in Scheme i) be prepared» according to the synthesis described in WO 200505-33, Example 54b The dieterieter of botanical acid used in the Cross coupling Step 4 of Scheme I can be prepared according to general scheme 3 below, either from phenol 3.! or hteroileíer 3.2 comsrciaimetee available.

9S

Scheme 3:

<td rowspan="2">6f R; Y Oh</td><td rowspan="2">Br t fi,</td><td>Step-12</td><td colspan="2">Ef .xRXz Step-I 3 IL í ---</td><td rowspan="2">'3 Λ (Item F %,</td>

<td>conatícoes. 4e burning aropf Ce tuafíleief</td><td>Y %,</td><td>rOTídicsones «te úorcnacién</td>

<td>X1</td><td></td><td></td><td> 3.?</td><td></td><td>X.3</td>

[00199] Detailed examples of the synthesis of the compounds of Formula 1 can be found in the Examples. look. The steps 1 to 12 in Scheme 1 and steps 12 and Í 3 in Scheme 3 refer to the specific reaction conditions described for example in the experimental section in this document and in the standard reference works, such as in the pertinent chapters of Richard C. Larock, Comprehensive Organic Transformattons: Á Ooide to Functional Group Preparatíons, Second Edition, Witey-VCH Verlag GmbH, 2Ó00 and in T. W, Greene and P. G, M, Wats, ^:'Greene's Protecííve Graups in Organic Synthesis ”, Fourth Edition, Wfiiey, New York 2007,

Additional Processes to Prepare the Compounds of the Invention

100200) The compound of the invention can be prepared as a pharmaceutically acceptable acid addition salt by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid. Alternatively, a pharmaceutically acceptable base addition salt of a compound of the invention can be prepared by reacting the free acid form of the compound with a pharmaceutically acceptable inosganic or organic base,

100201 j The compounds of the formula 1 can also be modified by adding appropriate functionalities to improve the selective biological properties. Modifications of this type are known in the technique and include those that increase penetration into a given biological system (for example, blood, lymphatic system, central nervous system, testicles), increase bipodness, increase solubility to allow parenteral administration ( for example, injection, typhusion), alter metabolism and / or alter the secretion rate. Examples of such modifications 96 include but are not intended for esterification, for example, with polygienics. dcrivatiíactón with phaloüoxi or substituents of fatty acids, conversion 3 carbamates, tudroxilacioo of: aromatic amitos and substitution of hetetoátomos in the aromatic united. Wherever compounds of the formula I, and / or N-oxides, methods and salts are preferable as well as physically acceptable, are mentioned, does this comprise such formula? modified, while reference is preferably made to the molecules of the formula I, their bioxides. its taulomers and / or its salts.

00202) Alternatively, the salt forms of the compounds of the invention can be prepared using salts of the intermediates or starting materials In view of the close relationship between the new compounds laughs in the free form 1 and those in the form of their salts, including those salts that can be used as imersneíúos. for example in the purification or identification of the new compounds, any reference to the compounds or a compound of the formula (1) above and hereafter referred to as a reference to the compound in free form and^zor also to one or more salts thereof, as appropriate and convenient, as well as to one or more solvates. for example, hydrates, | 0 (2020Jj The salts are formed, for example, as acid addition salts, (preferably with organic or inorganic acids, n part of compounds of the oimuia ib with an alkaline nitrogen atom, especially salts pharmaceutically acceptable. Suitable inorganic acids are, for example, halogen acids, such as hydrochloric acid, sulfuric acid, or phosphoric acid. Suitable organic acids are, for example, carboalitic, fasfonic, sulírtic or sulfámlca acid, jxrr, for example, acetic acid, proprioid acid, octanoic acid, decanoic acid, dodecanoic acid, gbeoic acid, lacheo acid, fumuric acid, succinic acid, malic acid, adipic acid, piniéllco acid. Sberic acid, aelic acid, mabeic acid, tartaric acid, citric acid, amino acids, such as giümámleo acid or aspartic acid, maloic acid, hydroxyleleic acid. Nietifondeic acid. cyclobexanoeacbnxitieo acid, adamantaneearhosilieo acid, benzoic acid, sidieilieo acid, 4- aminosalicylic acid, italic acid, phenylacetic acid, mandelic acid. cinnamic acid, methano- or eianesultanic acid »2- hydroxyethanesulfonic acid, cuinot, 2disonic phonic, heneenosuifomeric acid, 4- toluenesidomatic acid, 2-naiphoieno-disulfonic acid, 1,5-naphthalene-disuifonic acid, acid 2 or 3- methylbcncenosuphonic acid, metlisulturieo acid, ettlsuliurtco acid, dodeoibuiidite acid, N-cyclobexiisu'fáfntco acid, &lt;V&gt; · o /

N- meth? -, Ν- mil- ο Ν- propyl-suifamic. ts other organic protonic acids, like corneal ascorfetic acid.

fo02O4 [Pure isolation or purification purposes it is also possible to use acceptable chemical salts, for example picrates or periorates. For therapeutic use, pharmaceutically acceptable salts or free compounds are used emphatically (when applicable in the form of pharmaceutical preparations), and these are therefore preferred. [08205 (The free acid or free base forms of the compounds of the invention can be prepared from the corresponding base addition salt or avid addition sai, respectively. For example a compound of the invention in a sai form Acid addition can be converted into the corresponding free base by treatment with a base adeeuadtt tej .. solution of ammonium hydroxide, a sodium bldroxide, and the like). The compound purpose of the invention in a form of base addition salt can be converted to the corresponding free acid by treating with a suitable acid (the ,, hydrochloric acid, etc,}. (8028b) S. The compounds of the invention in non-oxidized form can be prepared from N-oxides of the compounds of the invention by treating with a reducing agent (e., Sulfur, sulfur dioxide, trifcnylphosphine, yttrium borohydride, sodium borohydride, phosphorus trichloride, tribromide, or the like) in an appropriate inert organic solvent tej ,, aeeforturiio, ethanol. aqueous dioxane, or the like) between 0 and 88 "C.

(00207 (Proannae derivatives of the compounds of the invention can be prepared by methods known to those skilled in the art (for example, for more details see Saulniet »(1994). Btoorgomc and Medicinal Cbcmislry i etters, vol 4, p 1985). For example, suitable prodrugs can be prepared by reacting a non-derivatized compound of the invention with a suitable carbamination agent (for example, 1,1-aethyloxyalkylhanocyotidate, pata-nitrophenyl carbonate, or the like). [00208 (Protected derivatives of the compounds of the invention may be prepared by means known to those of ordinary skill in the art, (..a detailed description of the techniques applicable to the creation of protective groups and their 'disposal can be found in TW Greene, Protectíng Gtaups in Organte Chemisttytercera edition, .¡ohn. W iicy and Sons, inc., (999.

1 (10209 (i. Compounds of the present invention may conveniently be prepared, or during the process of the invention, as solvate? (Ei ,, hydrates). Hydrates of the compounds of the present invention are conveniently prepared by recrystallization from a mixture of aetKiso / otganic solvent, using organic solvents such as dioxin, tetrahydrophirane or methane!

(002101 The compounds of the invention can be prepared as their individual stereoisomers; reaecionat "a racemic mixture" imposed with an optically active resoiiicton agent to form a pair of diastereomeric compounds, separating the diastereophilic and recovering the optically pure enantiorneros. While resolution of the enantiomers can be carried out using envalent diastereomeric derivatives of the compounds of the invention, dtsociable complexes are preferred (eg, diastereomeric Cfistaline salts). they have different physical properties (for example, melting points, boiling points, solubilities, reactivity, etc.) and are easily separated by taking advantage of these differences. The dlastereoisomers can be separated by chromatography, or by separation techniques based on diferencins in solubility. Then the optically pure enantiomer is recovered, together with the resolution agent, by any practical means that does not give rise to racemizaeion. A more detailed description of the techniques applicable to the resolution of ios is Ureoisomers of the compounds of their racial mixture can be found in lean-Jacques, Arsdre Coilef. Samuel H, Wilen. Enantiomem, Racemates and Resoluíions ”, John Wiley and Sons, inc., 1981 d

100211 In rest, the compounds of the formula (1) can be prepared by a process, which:

ta) those of! reaction scheme L and (b) optionally converting a compound of the invention into an acceptable pharmaceutically acceptable sai;

te) optionally converting a salt form of a compound of the invention to "na fonna de no sai;

id '} optionally agree an un-oxidized form of a compound of the invention in a pharmaceutically acceptable N-oxide;

fe) opc tona lineóte convert an N-oxide photnip of the invention into its non-oxidized form:

(t) optionally solve individual isomer tub! of a compound of the invention from the mixture of isomers;

(g) opclonally converting a compound not derived from the invention into a pharmaceutically acceptable prodrug derivative; and fifi opeionaime / rte convert a profannaceous derivative of a compound of the invention cm its non-evacuated form;

100212 (as long as the production of the start materials nc · is particularly described, the compounds are known or can be prepared analogously to the methods known in the art or as disclosed in the Examples below)

100213} One skilled in the art will appreciate that the above transformations are only representative of methods for the preparation of the compounds of the present invention, and that other known methods can be used in a similar manner.

Eíppppjps 002.S4J The following examples and intermediates serve to illustrate the invention without limitation the scope thereof. Some abbreviations used in the examples are as follows; acetic acid (AcOH); tríf lamina (TEA); teirahydroforan (THF); aqueous tac.); atmosphere (atmi; 2,2-bis-diethyl-phosphoryl-ii, i '| bsnaphthaienyl (BINAP); 4-dimethyl ammonium-pyrilyl (DMAFy. tere-butoxycarbony (Roe): 1,1-earbonyldiimiazole idi; di-tert-butyl dicarbonate (BOC? O); bcnzotriazol-i-oxytris (dimethylamino) -phosphonium hexafluorophosphate (BOP); dichloromethane (DCM); diethyl ether (EtzO); ptoluene suiiómee acid (PYSA); ethyl acetate (EtOAc); ethane! (EtOlf); lithium bis ítrimetiisili?) amide (LrlMDS); azodio &amp; tboxihtte diisopropy (DIAD); N, bi-diisopropyl-eiiiamine (DJEa or DIÍ-ΈΑ); N, N-dimethiimormamide (DMF); dimethyl sulfoxide (DMSO), difemilhsforii azide ÍOPPA); hour (s) (bí; hexatluorophosía of 2 - {1H-? - smbemmtríazuL i-;!) - i, 1,3,3-telrametiiuroni »(HAYO); High performance liquid chromatography (BPLQ: liter aluminum hydride (LAUp liquid chromatography coupled with mass spectrometry). (If'MS); lithium diisoproprlamide (LOA); methanol (MeOH); milliliter (s) (mi); mmt (s) ttnín); microwave (MW); n-butyllithium (n-BuLi),!,! - bis (dtismylphosim}} phenoeenodieloropaiadium (H) (PdCl; dppf)); tris (díbeneiíjdenaeetona) dipaladio (di &lt;Pdj f'dba? dichlorobis (trífentbbsftna) palladium fí) fFdCL (PPÍ53) rF ambient temperature &lt;RT&gt;; acid

SriOuoroacetieo (f'FAF teír &amp; bidro forano (THF), tub layer chromatography (TLC); retention time (fo); and 4,5-bis (dimethyl) - 9,9-dimethyl-x-phene (Xamophosj.

100 (092LSI The LCMS data for the compounds below were generated on a Mercury Synergi 2.5 U MAX-RF i 60A column with the mobile phase: A - 0.1% foic acid, 8 ACM, applying a gradient 0 / 30, 0.5 / 30, i. 5/95, 2.4 / 95, 3.0 / 30 at a flow of 2.0 mi / min and a temperature of 50.0 ^cC.

Five different HPLC methods were used and the method used was given purely each individual compound in Labia 1 below. Unless otherwise indicated, the method used for the detailed examples is Method-L The conditions were as follows:

Method information- i: Column: Zorbax XDB Cí 8 5u C6 X150 mm

Mobile phase: A - TFA ai 0.01% in water. 8 = MeOH: ACN í Li)

Gradient tk-mpo /% B: 0/30, 1 '70, 6Ί 00. 8 / WO, 19/59, 12/30 Flow: 1.0 mi / tnin

Temperature: 40.0 ° C luidrinadon of the method- 2: Column: AG / C18 / 15- 91 ti Mobile phase; A® Agita, 8® ACN {I: í&gt;

Gíadiente: 70/30

Loose: 4.0 ml / min

Temperature: 49.9 Í'C

Htíórmaeíótt of the method- 3: Column: Kdenetex 5u Cl8 100A 159x4.60mm

Mobile phase: A - Tf A ai 9.01% in water, f ® MeOH: ACN f 1: 1}

Iron gradient /% 8: 0/5. 1/5, 6/109, 8/100, 10/5, i 2/5 Flow: 1.0 mi / min

Temperature: 40.0 C

Information of method- 4: Column. Zorbax Eclipse Flus CI8 RR HD 2,1-lOOmm 1.8: .t Mobile phase, A TFA at 0.01% in water, 8 - MeOH: ACN i;: lj Gradient time ^ 8: 0/10. 5/30, 1.5 / 100, 3 / iOO, 4 / i0, 509 Flow: 0.5 ntlúnin

Temperature: 40.0 'C métuüa- 5 information: Column: Kteneíex 2.0a Cl 8

Mobile phase: A = TFA ai 0.01% in water, 8 ~ MeOH: ACN (1: 1)

Gradient time / ^ 8: 0 / 1.0, 0.509, 1.5000.3 / 100 »4/10, 5/10

Fh.no: 1.4 ml / tttin í empetatara: 40.0? C

W1

Intermediate 5.1

5- Bromo-4- fluoro-2- ((2- nitrovinii} amine) benzoic acid and -^;'· .Α' · yYi&gt; FQ_F | ί) 0246 | Step 1.1: Synthesis of! intermediate! .i; Acid 5- bromo- · + · finroro- 2- ¡(2nurovmil) amisto »Ixmzoic:

00217) Part-a; WCi gas was porgasj through mine 2- mriino-5brosno-4- Huorobenzotco acid solution (38 g, 0.162 mol) in 570 n »l of 1,4-dloxane for ί 5- 2 -iotas at 0ⁿ C. The mezeia was stirred for 2 hours and it was said to rest overnight at room temperature. The solid was filtered, washed with methyl ether and dried at! empty to provide a lid salt (44.5 e: 2-amine-5-bromo-4-yluoroberizofco acid.

¡0 &amp; ÍI8) Part-b: To a stirred solution of NaOH (22 g. 0.1 ¿&gt; 2 mol) in water (44 ml). cooled to 0-5'C, nlírotneian drip (2x8.5 ml) was added in order to maintain an internal entjxrramra of 25-ffL C. After completing the addition, the cooling bath was removed, causing an increase spontaneously at a temperature of '70 'Y ?, and a red color developed. Despees, the mixture was cooled to 25- SO' C. t..a residual red-orange solution was carefully poured onto ice 48 g and HC! concentrate 48 me »to provide the metazonium acid.

00219) Part-c; To a suspension of the salt, WO (44g&gt; of 2- anuno-5brorno-4-luorobenzoic acid (Part-to-solid? In EiCl (140 ml) and water (800 ml) is used by meíazonieo acid (Part b), The resulting mixture was stirred for 30 minutes. The solid that precipitated was allowed to stand overnight before filtration, washing with excess water and methane! (60 ml) and drying if vacuum for 3 ~ 4 hours to provide 5- bromo-4fluoro-2- ((2-nitrovioi!) Amino) benzoic acid 44 g, 88.5% yield.^{HNMR (DMSO &lt;4 300MHz): S 13.0 (d, IH), 8.20 (d, 1H), 8.0 (m, 1H), 7.95 (d, 5H), 6.90 (d, 1H): LCMS: 77.7%, m / z- 304.9 (M &lt;t).

Intermediate Lí bromo- 7- fluoro- 3- nitroquinoiin- 4- oi

402

OH r '^: n (() 9220 (Step 1.2: 'Yes thesis of intermediate compound 1.2; 6- bromo- ⁷- íluoro- 3nttroqtjínolíri ·· 4- I heard. 5- bromo ·· 4- fluoro-2-1 (2-niírovinii) asnin) benzoic acid (44 g, i) was heated. Í44 rolls ») in acetic anhydride, (220 ml) at 510 ° C it is enough that the dissolution was achieved, and cooled to 4IP C. Potassium acetate-o (16.9 e) was added and the resulting mixture was heated at (40 C for 4.5 min. The reaction mixture was cooled to room temperature. The resulting solid was filtered and washed with acetic acid (25 mL). , water, methane! (30 ml) and dried in the pipeline to provide bromo- 7- Fluoro- 3- oitroqoíriolln · 4 · oi IS g 43.4% yield ^!H NMR (DMSO-Y. 300MHz) · OR 13.i tbs, 1H), 9.25 (s, 1H). 841 (d. IH), 7.61 (d, i'Hp LCMS; 98.2%, m / z - 286.9 (Μ * i I

Intermediate L3 ó- bromo- 4. doto- 7- fluoro- 3- «itroquinoline

Yxxx γ ^: γ

YY) 00221) Step L3: Synthesis of intermediate 1.3: o- bromo- 4- chloro- 'i-fluoro- 3nltrequinoSma: Heated to reflux 6- bromo- 7- fluoro- 3- nitroquinoin- 4- e ·} (20 g.,&gt; 069 moles) in POCE (180 mL) and PEA (1 1.8 mL, 9,083 moles) for 24 hours at i29 'C The reaction mixture was cooled to room temperature, slowly poured onto ice water. The precipitated solid was filtered and washed with ice water. The solid was dissolved in cycloomethane and washed with cold brine solution. The organic layer was seeded on sodium sulfate and evaporated in vacuo. The residue was buckled by column chromatography on silica gel (10% EiOAe-Resano) to provide 6- bromo-4- chloro-7- illuoro-3-lymphoqutnulma (19 g; 89.6% yield). 'flKMR tDMSO- Y 300MHz): 3 9 * (s. IB),

8.76 (d, | Hi, 8.22 (d, ί 10; LCMS-. 96.5%, m / z ~ 304.9 tM (1),

Intermediate 1.4 (00222) Step-I in Scheme 1 above; General Procedure for the Summary of Intermediate 1.4:

100223) Method A; 6- Bromo-4- chloro-7- fluoro-3- uitroquinolints (4 mmol) and desired aryl amine, 1 mmol) in AcOH was stirred for 2-3 hours at temperature

103 environment. After finishing the TLC reaction (2 &lt;i% EtOAc-Líexanp), the reaction mixture was diluted with water. ES Highlighted yellow precipitate was filtered and washed with stirring, solid Ei was dissolved in EtOAc ΓίΙΓ (El) and washed with saturated NaliCOj solution. The crustacean layer was dried over NujSí.L, and evaporated to provide intermediate L4. The matter! crude was purified by H.F1..C prepa! iva.

(00224} Method-B: 6- Bromo-4- chloro-7- {Inoro-&gt; -thioquinnin (t mmol) and desired alkyl amines (i mmol) were dissolved in DMF and DIFEA was added at room temperature. The reaction was stirred at room temperature for o-4 hours. The reaction was monitored by TLC (20% LtOAc- Bexanol, After completion, water was added to the reaction and the resulting yellow precipitate was filtered off, curagua was washed and dried in vacuo for 1-2 hours to provide Intermediate 1.4.

Intermediate 1.5 (00225 (Step-2 in Scheme i above: General Procedure for the Synthesis of Intermediate I, or:_: (00226 (Method C: Intermediate 1.4 obtained from any of the methods

A or B was reduced with Ni Raney under pressure of gas Hj (balloon) in a solvent mixture MeOH; THE (2: 1) for 5- or boots. After completion of the reaction jxv TLC i'óü% EtOAc-Hexane), the reaction mass was filtered through a bed of ceiite and washed with ethyl acetate. The filtrate was evaporated to! empty to provide intermediate i .5.

(00227} Method D: Intermediate 1.4 (i mol) obtained from any of methods A or B was treated with sodium dithiomuo (5 moles) in diosano for i- or iteras.After the end of the pot reaction TLC (60% EtOAc-Hexane) The reaction mixture was partitioned between EtOAc and water The separated organic layer was washed with water, brine, dried over Na ^ SO.-, and evaporated to dryness to get the desired LS Intermediate.

Intermediate í, 6 (00.228 (Step-3 in Scheme 1 above. General procedure for the test of intermediate 1.6:

(00220} Intermediate i, 5 wafer gone in Step 1.5 was heated in irieiyl orthophonnia for 4 hours at td.5^s C. After completion of the reaction by TLC r60% EtOAc104

Hexane), the solvent was evaporated completely under reduced pressure and the constraint was purified tnedtanie crontalograíia in column on ge! of sibee (MeGH 'DCMt to provide intermediate 1. (&gt;.

JET Intermediate 00259) Step-4 in Scheme i above: General Procedure for Synthesis of Intermediate 1.7: To a stirred solution of intermediate Lo in a mixture of toluene: ethanol (8: 2) in a sedated tube, alluded to PdíPPhyh (0.05 eq). The reaction mixture was purged with Otgan gas for 10 minutes before tic aryl / heteroaryl baronic acids / esters and 2M Na ^ CO solution .; (2 eq). Organ gas purging was continued for 15 minutes before sealing the reaction vial. The reaction mass was heated to 95 "C brown me 4-16 hours, t, the reaction was monitored by TLC (109% ElOAc). After completion of the reaction, the reaction was partitioned between EtOAc and water. The organic layers were separated, washed with water and brine, dried over NioSCq and evaporated in vacuo. The crude residue was purified by column chromatography on silica gel &lt;MeOH · DCMj to provide intermediate L7.

(H1231J

Example LA i - QS, 4S) ~ 4- 18- (2- doro-4- tpyrimidin- 2- ik&gt; xi) tenyl) - 7- fiuoro- 2- methyl- IBtm'uiazo! 4,5- cyquinoline- 1- you ') - 2- fiuoropiperidin- i - ti i- 2- hydroxyetanone

<img file="CU20160020A7_D0031.tif" />

105 tXewíia 4

7χΧ '

<img file="CU20160020A7_D0032.tif" />

;&gt; ·} '&gt; -A ·&gt; ^ΛΛ S \ - \ .X '

*..Oh

<img file="CU20160020A7_D0033.tif" />

Jdfi »f t &lt;&gt; C.á &lt;5:

»\ V '

<img file="CU20160020A7_D0034.tif" />

<img file="CU20160020A7_D0035.tif" />

<img file="CU20160020A7_D0036.tif" />

'Xy ^&gt; &lt;- X. to .....

..... 7; ai^x·' .....

.

^orró] 00232 Step- 5, Acid 4 - ((6- bromo- 7- fluoro- 3- nifroqumolin- 4- ií) ammo) - 3nuoropíperiífin- - · carbiwnlaío tic (33. 4S) - tereboryl,!;

<img file="CU20160020A7_D0037.tif" />

[00233] 6- bromo- 4- chloro- 7- fluoro- 3- nichrochenoin (47.S g, 0.005? Moi) was placed in dry D.MP (200 mfj under the atmosphere of bb, DIPEA (14.8 g, 0.1 1-lmof) and 4-amino-3-fluoropiperidium-1- carboxylate of (3S, 4S.t- erected) (12.5 g, 0.057 mol j in dry DMP (50 ml) was seouenc added at room temperature. The resulting mixture was stirred overnight at room temperature. The reaction was memotereo by TLC (30% EtOAc bexane), after the end of the reaction, the reaction n3cz was poured into ice water and extracted with EtOAc (3x200 ral). The combined EtOAc layers were washed with brine solution and water, dried over sodium sulfate. The organic layer was evaporated hypo vacuum and the residue was purified by column chromatography on silica gel (10-50% EtO.Ac06

Ik-xano) to provide 4 - "o- bromo-? - fiaoro - 3- nitroquinolyr" - 4- i!) Aroinoj- 3-fluoropipendin- 1- carboxylate of (3S, 4S&gt; - terrobuido, i (27 g, 956% yield), 'HNMR (CDCb. 400MHz): or 9.37 (a, .IB) 8.83-8.81 (d. Ul) 8.48- 8.46 id, IH) 7.74 · 7.71 (d. IB), 4 $ 8- 4.40 («i, 2H), 4.19-412 (m, 2.H), 2.95-287 im, 2H.) 2.2? · 2.23 (m. 1H) i .79- i, 69 &lt; ro. IB), 1.4? ú,? H); LCMS: 98.84%. ÍM + 2) 488.7; HPLC: 90.47%.

002341 Step-2, Synthesis of 4 - ((3-aromo-6- bromine? - Huotoquinalm- 4- iljamaro3-fiuoropipcrtdine-carboxylate of (3S, 451-tere-butyl. 2;

<img file="CU20160020A7_D0038.tif" />

(902.35} 4 - «o- bromo- 7- fluoro- 3-« ilroqainolin- 4- ii) amino) - 5Fiuoropiperidifta- i-carboxylate of 3S, 4S&gt; tere-butyl (2? G. O. OSotnol) was taken in L 4dioxane (150 mi). Sodium dhioniro solution (29 g, O.dotnol in water and 50 ml) was added at room temperature and the result mixture was stirred for 5 1&gt; at room temperature. The reaction was monitored by TLC ($ 0% LtOAc / besano), after finishing the reaction, the reaction mixture was poured into ice water and extracted with EtOAc (.3x200 ml). The combined organic "layers" were washed with brine and water, dried over partner sulfate. The organic layer was evaporated under vacuum to provide 4-í (3- gromo- 6- btoroo- 7fluoroquinolin- 4-? H aroi.no) - 3- fiuoropipehdin- 1- carboxylate of (35, 4S) -tere-butyl . 2 (27 g). This material was used directly in the next step without purification, LCMS; 99.5% nvz ~ 456.7 fM-r I), 00236} Puso- 3, Synthesis cte 4 - (8- bromo · 7- fluoro- '2- methyl- IB- midazo 4.5- cj quino! in- 1- il) -3 -luoropipendma -i-carboxylate of (35, 4S) -terebutyl, 3:

<img file="CU20160020A7_D0039.tif" />

(00237] Heated 4 - ((3- antí® · 6- bromo- 7- fluorequinolin- 4- you) arninoj- 3fluonapipendin- I-cat box Hato de (3S, 4S} -tere-butyl (27 g, 8 , S59mol&gt; in tttedio orthoacetate (150 nd) under N atmosphere; for; hours at 120^to C. The reaction was monitored by measuring TLC (5% MeOH / DCM). The volatiles were concentrated in vacuo, and the crude product obtained was purified by column chromatography on silica gel (0-3% MeOH / DCM) to provide 4- (8-bromo-7- fluoro-2- mefib IH - imidazo (4.5- cj quinoÜ »1- ib- 3- fiuoropiperidine- i-carboxylic acid from US, 4S) - tere-butyl (i 5 g, two-step yield), * HNMR &lt;CDC1_?, 400MHz): or 9.28 (s, IH) 8.43-8.34 id, 1H1 8.01 - 7.99 (d, IH) 5.60- 5.35 (d, 1Ií), 5.25- 4.85- *, 40 (m, 2H) , 4.75-4.35 (m, 2H), 3.I 5- 2.95 ith. 2H) 2,792.23 (tn, IH) 2.40-2.05 &lt;m. IH), i .57 (s, 9H); LCMS: 100%, tmb - 480.8 (Mt-1}. 97.31%. (00238} Laso- 4. Synthesis of 4- (yes- (2- chloro- 4- (pyrimidin- 2- íloxiífeul) - 7- ímoro2- medí- IH- ímídsuu [4,5- vjquinoíút- i- ilp 3- fiuoroptperidma- 1- carboxylate of (3S.4S) tetc-butyl

<img file="CU20160020A7_D0040.tif" />

fOfr'uta Qa-fftta, 01-, 44) - ^ ,, - 0. M3: eci¡: $ ?. í) p? OS (00239] 4 - (8- Bromo- 7- fluoro- 2- irtetti- IH- imidazo 4, S- the quinoimi- i-i!) - 3- isopropylpendiRit- 1- tere-butyl carboxylate ( 9 g, 0.0i8mot) in toluene: ethanol! 8.2.50 ml) in a 250 ml sealed tube and the precautionary mixture was begassed with argon gas for 15 minutes. Ítrakis (2.1 g, 0.001 Sntol) was added and the reaction mixture was degassed with argon gas for 5 minutes, 2 - (3- chloro-4- (4, -1,5,5-tetramethyl-1. 3 , 2-dioxaborolan-2-&gt;!) Ileoxt) pyrintidine (8 g, or.24.mob. Followed by NffiC (.fi 2 MD me) and finally the reaction mixture was degassed with argon gas for IO minutes. resulting heated 5 hours at 90 ° C. The reaction was tnonttoreo by TLC {% MeOH · 'DCM), after finishing the reaction by' Π-C the reaction mixture was poured into ice water and extracted with EtO.Ae (3x100 tnfi, the combined organic layers were washed, water, brine solution, dried over sodium sulfate and evaporated in vacuo.The residue was purified by column chromatography on silica gel (0-3% MeOH

108

DCMy psuh provide 4- (8- (2- doto- 4- (pyrimidiu- 2- doxtííml) - 7- of Í5S, 4S&gt; - torofcuiikx 4 {10.2 g, 95% yield). ^:H ~ NMR &lt;400 MHz. CDCh. 400MHz.) · Ύ 9.28 td. IH), 8.68-8.60 im. 2H). 8.34-8.3.1 (d. 0.8H). 8J? (D, 0.2 H). 8.09-8.02 (m, IHl, 7.5S- 7.44 (tn. 2H&gt;, 7.30 (dd. Í H), 7. i6- 7, ¡0 (m, tH), 5.62- 5.04 (m_; IH), 4.89-4.25 (m. 3H », 3.10-2.75 (m, 5H), 2.49-2.20 (ft's, 2HL 1.51 (s, 9H): LCMS: 98.99%, ro / x- 607.45 (Mt | p HPLC : 96.89%, rt: 4.32 min, [00240] (-'aso- 5, ​​Synthesis of 8- (2- eioro- 4- (ptrímidin- 2 · ítoxt) phenyl&gt; - 7- fluoro- · t (( 3S, 4S) - (- 3- Πυοταρϊρρπάίη- 4- il) - 2- methyl- i H- Ímidazo [4..5- cjouloolina salt from Ή A, 5:

HN \

1.

, \. V-&gt; «&lt;AV '' 'V'

N ~ t&gt;

[09241] TFA (20 ml) was added to a solution of (3S, 4S) - terebordo- 4 (8- (2- otoro- 4- (pifiniidin- 2- yloxy) femi) - 7- fluoro - 2- mei-IH ~ imtdazo4,5- cjqmtiolin-tifb 3- SluorophxnkÍsní! - 1- carboxylate (10 g, (fOtó-Anei) in dry DCM (i50 thousand at 0® C under N2 atmosphere. After completing the addition, the reaction mixture was left at room temperature and stirred for 5 it- The reaction was cootroic by TIA. ' {5% MeOH? DCM), after the completion of the reaction according to TLC, the voladles were emptied in vacuo. The residue obtained was triturated with eier dieritico. Ll sotido leaked and dried to! empty to provide ia sai of TFA of 8- (2- chloro-4- ipyrimidin- 2- iioxy) &amp; mL- 7- illuoro- I ({3S, 4S&gt; - 3- ftuoropiperidine- 4- ii) - 2- methyl- tH- imidazo [4,5- cjqyinoiína íítg, ciiantirativoi. LCMS- 99.4%, mú?^::: 507. i (M-¡) (ba.se libre): HPLC; 96.43%, 6,002 trun. [0Ü242] Step- 6, acetate synthesis of 2.- ((38., 48) - 4- (8- (2- chloro- 4- (pyrimidin- 2 «iioxDíemi} - 7- (Inoro-2-meo i- IH- itoidazo [^;L5- c] chitio! In-! - Π) - 3- fluDropiperidin- i - iit2- osoetiio, 6;

WS

<img file="CU20160020A7_D0041.tif" />

? (- !, &lt;! Mbíí't lS3r 39 Γ.9 1 [002431

HOBT (5.4.g. 0.040 mol) and EDCÍ.HCÍ ¡7.64 «were added sequentially,

0.04O mol) to a solution of 2-acetoxyacetic acid (4.3, g, 0.036¡ no)) in dry DMF (00 ml) in N aimóslsra? at O * C. The resulting mixture was stirred at room temperature for 30 mm. A solution of 8- (2-chloro-4-pyrimidin-2 »iloxyXemi) -7-fluoro-H 03S4S) -3fluoropiperidine-4-i)) -2- medi-IH-umda? .O {4,5- (fiqainohna. Salt of ΊΤΛ (1 i .0 g, 0.01? ísmc4i in dry DMF (59 ml) and ASD (5.4 g, fl.053mot) was added to the tcaection mixture. The resulting reaction mixture was left at room temperature and stirred for 3 h. The reaction is monitored »by TLC (5% MeOH / DCM). After completion of the reaction, the reaction mixture was poured onto a saturated saturated NaHCOj solution and extracted with EtOAe (3x290 roll). The combined organic traps tic EtÜAc They were washed with brine solution and water, dried over sodium sulfate and evaporated in vacuo. The residue was purified by silica gel column chromatography (O-3% MeOH 7 DCM) to provide 2 · f acetate (3S, 4S} · 4- (8- (2- chloro-4- (pyrimidin-2) - iioxijiémí&gt; - 7- fluoro2-methyl-imidazo [4,5- c] quiróoí¡n- .1-il) - 3- fuorop&gt; peridutg-I-yl) - 2- oxoethyl, or (Sg 85% yield). 'HNMR and COCI,;. 400MHz): δ 9 3! (d, IH), 8.68-8.60 (m, 214), 8.34 (d, 0.5.14), 8.12-8.01 (m . 1,514), 7.59 (d, 0.YES4), 7.54- 7.45 (m, ESH), 7.37-7.30 (m, U4}_;7.18-7.11 (m. 1 Ht, 5.69-516 (m_s 210, 4.99-4.61 (rn, 314), 4.3 ?. 4.25 (m, 0..5Í4), 4.01- 3.8b (m, 0.5Í4), 3.50 (d,! Í4), 3.03-2.90 (m, 20). 2.88 (s, 1.5H). 2.8! (s. ESH), 2.50-2.33 (m, 114). 2.22 (s, 1,514). 2.07 ís, t, 5H); LCMS: 98.0%, m / z- 607.45 (M + lj; HPLC: 96.89%, rt: 4.32 min.

[00244)

Step- 7, Synthesis of! - ((3S..4S) - 4- (ít- (2- chloro- 4- pyrimiditi- 2iioxi jiánií i- 7- fluoro-2- methyl- i Sl- imidazo [4,5 - clquinolin-I-i!) - 3- finoropiperidin-í- ií&gt; ~ 2- hn.írcxíetanone.

110

<img file="CU20160020A7_D0042.tif" />

<img file="CU20160020A7_D0043.tif" />

fermtUS S9 f. ., M, ¡; j&gt; A \ &lt;í&gt; Píse Mo »í &lt;« jS *, - C £ 4 &amp; S

NaHCO¿ (i 1 g, fl.l309moi) was added to a stirred solution of 2- ({3S, 4St- 4- (8- (2- cyoto4- (pyrimidin- 2- ylox;) feniiH 7- fluoro-2) - methyl- SH- imidazbí4,5- clquinolin-! - ií&gt; - 3fluoropiperidirt- I- il) - 2- oxoothiiacetate i 8 g, 0.0! 3 tnel) in MeOH (300 trd »at room temperature and stirred for 24 h The reaction was monitored by TLC (5% EtOAc / hexane) After tetuating the reaction, the reaction mixture was poured into berated water and extracted with EfOAc (3x300 ml). The filtrate was concentrated to remove methane! and the residue was dissolved in IX. M (200 ml) and washed with water »brine solution, dried over sodium sulfate and evaporated in vacuo, Et residue was purified by column chromatography on silica get (0-4% MeOH / fX? M) to provide!. ((3S, $ 4) - 4- (8- (2 * doro- 4, (pitintidin- 2- íloxijfcníl) ·· 7- fluoro- 2- rnetií-) H- imidazo [4,5- cjqtJtrtolin- 1 ~ ilj-3fluoropiperidium-i-til-2- hodroxyetanone, f.flg, yield 81%), The solid obtained was teerisitized in EtOH (alternatively in MeOH) ^!HNMR (CDCl · ,, 400MHz): δ 9.33 (s, IK). 8.65-8.64 (d. 2H), 8.08-8.05 (d, Hi). 8.00- 7.85 end, IH), 7.S1- 7.30 (m, 2HL 7 30. 7.28 (dd. Hlb 7.15- 7.13 Un, HI), 5.65- 5.23 (m. ÍH¡, 4.96- 4.75 (m, Un. 4.35-4.15 end. 2H) 3.92 · 3.74 (m, 2H), 3.35-3.15 (m, ÍHk 3.05-285 (tn, 2H), 2.80 (s, 3H ), 2.45-2.15 (m, 2H); LCMS: 100% m / z- 565.1 (MM): HPLC (Method-3): 99.80%, chiral HPLC: 99.48%, rt20.38 min., Column : AG / CHI PALPAR AD- ΗΌ3.

Free flush

A free form of I - &lt;(3S, 4S} - 4- (8- (2- doro- 4- (pinmtdin- 2- iioxijfenii) - 7- ffuoro- 2¡netil- HI- imtdazofiR? - c tejuino Un í - il) - 3- fiueropiperidin- 1- if) - 2- btdroxyetanone in crystalline form (Form A of the free form) was produced from the crystallization by cooling of a supersaturated solution of the enmol compound at concentrations of i ti ) mg / me approximately. ! 7.6 g of compound j A was heated in 500 ml of ethanol under a nitrogen atmosphere at reflux temperature. Approx. 100 ml of ethanol was added dropwise at tem.pemture &lt;reflux, it is enough that all the solid dissolved and a miara solution was obtained. The ciara solution was cooled to room temperature and kept under slow stirring for 48 h. The precipitated solid was filtered and washed with ethanol Wt: 16.1 &amp; HPLC: 99.20%, NMR and II showing residual ethanol was trapped. Crystalline solid CI obtained from! Example IA (16 g) was refluxed with 266 ml of. «HPLC grade oltrene (compound not soluble in toluene) for 2 h. To commonclub. The reaction mixture was slowly cooled to room temperature, the solid was filtered and washed with toluene and dried under vacuum Weight: 1.5. &amp;. HPLC: 99.89%, LCMS: LCMS '99.39%, IHRMlv was cleaned and showed no residual EtüH peaks. The &lt;! E XRPD pattern of a sample prepared according to a method is shown in Figure I. The measurements were carried out at a temperature of approximately 22 C and a wavelength of rays χ, λ. of 1,590,906.Λ (CuRa 1 .5-¹ i 8Ai .. The following radiography method was used:

<td>Instrument</td><td>D8 Bruker spectrometer (Advantage)</td>

<td>Geometry</td><td>Reflection</td>

<td>Detector:</td><td>Hold</td>

<td>Parameter Generator</td><td>30 IV: 40 mA</td>

<td>San Rank</td><td>2 - 40 T-2 * Theta</td>

<td>San rate</td><td>107.1 s</td>

<td>Pass or ia size stage</td><td> 0,0170</td>

<td>slits (from left to</td><td> ..... .............</td>

<td>right)</td><td></td>

XRPD Pattern Summary:

<td>Grades 2- Theta (s. ...............................</td><td>Relative Intensity ^</td>

<td>(LLL ,,; ti7,324jy_:and (yj:</td><td>Half</td>

<td>..............'(you</td><td>Low</td>

<td> 51,285</td><td>Bsja</td>

<td>12.i $ 6</td><td>Low</td>

<td> 18,073</td><td>Half</td>

<td> 58.845</td><td>high</td>

<td> 19,569</td><td>Half</td>

<td> 21.219</td><td>Half</td>

<td> 22.564</td><td>Half</td>

112

In one embodiment, Form Λ of the free form of i - &lt;(3S.4 $} - 4- fo- (2- chloro-4-pyrimim- 2- íiosijienil) -? - fluoro- 2- motil- IH- imidazoi ' 4,5- ejqulnolin-1- HE 3fluoropiperldin-1- &lt;!) -2-hydroxyetanone in crystalline form is characterized by an XRPD pattern with at least four, more preferably five. Typically, iodes of the following peaks at a refractive angle of 2 theta (2 * 3) of 7.3, 1S. 1, i 8.8, 19.6, 21.2 and 22.6 ± 8.L resjxxtivamentei

In one embodiment, Form A of the free form of I- ((3S.4S) -4- fo- (2- chloro-4 {psrimidtrv- 2- yloxy jfeniiy 7- tluoro- 2- medi- Ϊ iL inudazole ' 4,5- ojquinolln-t-íl) · 3 · fluoropipertdir-i-ti) - 2- hydroxyethimone in crystalline form is characterized by a substrictive XRPD tic pattern the same as the XRPD pattern shown in Figure 1,

The melting point of Form A of the free form was determined by heating to 10 ^fJ C · 'minute tt 238 ^v C approximately.

The following are additional embodiments of the invention:

Carrying out a free form of i - (foSfoSE 4- fofochloro- 4- fosir imidut- 2- duxi; -f in d) 7- fluoro- 2- methyi II- ioudazo.fofo-clquinolin- 11 ) - 3-fluoropiperidin-í-I 2-hydroxyeiaoone in solid form.

2nd realization; The free form according to the embodiment i a. where the free form is in crystalline form.

Embodiment 3a: The free form according to the 2nd embodiment, wherein the free form is characterized by an XRPD sustanetuimenie pattern the same as the XRPD pattern shown in Figure i.

Embodiment 4a: The free form according to the 2nd or 3rd embodiment, wherein the free form is a substantially pure form.

Realization .Sa: The free form according to the ·; 2nd or 3rd embodiments, where going * free form has a purity greater than 90% by weight.

LÍ3

Example 2

8- (2- doro- 4- (pinmidio- 2- doxijíend} - Huero- Ϊ- 0- (2- metoxiefiijpjpetidin- 4- üi- 2metí! - IH- isnidazof4,5- c] Qu »noltna

<img file="CU20160020A7_D0044.tif" />

To a stirred solution of 7- Huaro-8- (2- f1uo.ro- 4- (pyrimidin-2-linoxyjienyl) -2-merii- (piperidífi-4- ili-H- imidazo {4,5 ~ c juuinoiona Sai 7FA (0.2 g, 0.408mm;) with dry DMF (2 trd) at 0^tJ C, HIPEA was added (d.2 r&gt; 1, i.2 tnmolj. Followed by 1- bromo-2- me-oxethane (0.08 g, 0.6 µmol). The reaction mixture was stirred at room temperature for 48 h and was controlled by i..C (10% MeOH eti DCM) The reaction mixture was poured into crippled water and extracted with ethyl acetate (3x25mL) .The combined organic layers were washed with ice water, a brine solution, dried over Na; .SOa and concentrated. were purified by ge! chromatography of silica using 2% MeOH at 1&gt; CM as ¡Flee me to provide 8- (2- chloro-4- (pyrirmdm- 2- iioxs) ieml&gt; 7- illuoro- I- (1- (2metuxietdipiperidiTi- 4- Ü} - 2- methyl- 111- imidazo! - + / - cjtj »inclines, (0.1 g, 46%) IH NMR &lt;I&gt; MSO- ús- 400MHz !; § 9.21 (s, IH !, 8.73 (d_: 2H), 8.42-8.35 (m, IH), 8.07 id,! H), 7.73 (d, ÍHx 7.67 (d, IH), 7.43 (dd, IH). 7.3? (T. IH), 4.85- 4.65 a, IH), 3.16 (s, 3H), 3. s 5- 3.02 (ni, 311), 2/7 (s, 311}, 2.68 (ΐ, 2H) 2.34 (t, 2H¡, 2.32- 2.22 (m, 31.1¡, 2.10-1.95 (m, 211); LCMS: 90.41%, trdz ~ 547.10 (M + l); HPLC; 96.15%, ri: 3.0! Min.

Examples

8- (2-Chloro-4- (pyrimidm-2--ioxüphenyl) -7-Huero-2-methyl-1- (1- (methylsnlfonihpiperidin-4-ti) -111-imidaxo (4,5-cjquinoline)

<img file="CU20160020A7_D0045.tif" />

114

Λ an agitated solution of? -Fluoro- 8- (2- fiuoro- 4- (ptrimidm- 2- iloxijfenií} · 2- methyl- (piperidin- 4- yl} - ¡14-imidazo (4,5-cjqutnolone. LEA salt (0.O5 &amp; 0, i02mmoi, s in dry D.MF {2 mi) to Cr C. DIPEÁ was added 0 2 mi.) Followed by mefauosuifoniium chloride {0.08 g, 0.6! Mtnoi). The reaction mixture was stirred at room temperature for 4 h and was controlled by TLC 1.5% MeOH at 1&gt; CM.) The reaction mixture was poured into ice water »and extracted with ethyl acetate f3xl5wL&gt;. The combined organic layers were washed with ice water, a brine solution, dried over NajSCL and concentrated, purified by silica gel chromatography using 2% MeOEl in DCM as a eiudent to provide 8- (2- chlorine). - 4- (pyrimidin-2--yloxy-lcnyl) - 7- fluoro-2- methyl- 1- &lt;1 (snetilsulibnil'ipiperidin-4- il} - 1H- imidazopiA 'cyano lino, (0.O25g, 46%), 1H NMR. (DMSO-; .c, 400MHz); or 9.20 (&gt;, 111), S. 71 (d, 2H}, S.55- 8.47 (m, 114), 8.06 id. one Hi, 7.74 (d, .114), 7.61 (s, i H), 7.4L- 7.32 (m, 2H)_; 5.45-5.33 (m,!. 14), 3.85- 3.7? (ro, 2H), 3.09-292 (ro, 2H). 2.89 {$ »3H). 2.79 (s, 3H), 2.35-2.17 (m. 4H); LCMS: 98.33%, m / sre- 567.4 (ΜΉ): HPLC: 94.22%, rt: 6.80 min.

AL example

Synthesis of 4- (8- 2- doro- 4- ((4- mefilpirimidln- 2- i!) Oxf) fend) - 7- fluoro- 2- methyl- 1Himldazoí + .S-c'jqdnoim- 1- iljptpendma - 1- carboxamide

<img file="CU20160020A7_D0046.tif" />

To a stirred solution of 8- (2- doro- 4- ((4- methylpinmidin- 2- ii) oxy) fenii} ~ 7- fluoro-2met.il · i- (piperidin- 4- 11) -! H- imidazopí.S- cjonínoiona. Sai of TEA (0.25g, 0.49immol) in dry DMF 5mi) at ü * C, TEA (0.276 mL, 1.964 mmol} was added followed by t: imetiií.iiílo IÓ.085 my., 0.744 nmoi). The reaction mixture was stirred at room temperature for 4 h and was monitored by TLC (10% measured in DCM). The reaction mixture was poured into ice water and extracted with ethyl acetate &lt;3x15mL), Las. Combined organic layers were washed with drinking water, a brine solution, dried over Na? SO? and concentrated, purified by silica gel chromatography using 8% MeOH at t&gt; CM as an invention to provide 4- {8- chloro- 4- p4- methypyrimidin- 2 i!) O- \ ipemil? - 7115 i doro- 2- molií- i H- ím: da / .otf'4,5- c¡quinolin- i- jpiperidine - earboxttmids (líTíSg. ¡6%) Ή NMR «DMSO- ¿L, M'iOMHO 6 9.Í9 (s, IH), 8.51 (d. IH). 8/19 (m, IH). 3.95 (d. Di !, 7.72-7.54 (m, 2111. 7.42-7.36n, íH), 7.22 (d, LH), 6.19-5.50 &lt;m. 3H), 5.10- 4.89 (m. 1F¡}_: 4.20 (m, 2H} „2.92 (t, 2H), 2.77 (s. 3Hi._: 2.46 (s „3H), 2.10- ¿90 (m, 3H); LCMS; 90.6%, m / z546.5 im-m); HPLC; 96.6%, rt: 6.26 snin.

190246j Repeating the procedure¹? described in the previous examples, using the appropriate starting materials, the following compounds of Formula 1 are obtained, as identified by their chemical name in Table SL. Examples 55 and 56 can be prepared attaloga from there. commercial synthesis precursors 1,1-4- ammelerrahydro-2H-thioptran dioxide (CAS 210249-29-3) and 3- tluorotetrahydro-2H-pyran-4atnttta (CAS 141637; -97-5).

U table

Eg Steps

<td>TO</td><td>Step O 5.6</td>

<td>IB</td><td>Step t- 5.6</td>

<td>Y</td><td>Step OR 5.8</td>

<td> 3</td><td>Step 1- 5.8</td>

<td> 4</td><td>Pus·? i-5.8</td>

<td>Y§/</td><td>He passed .5.1 d</td>

<td> 6</td><td>Step i · 5.6</td>

<td> 7</td><td>Step i - 5.8</td>

<td> 8</td><td>He passed one- 5 &lt;9</td>

<td> 9</td><td>He passed ; T-7^K 7;^:</td>

Chemical name

1- ((3S, 4S) - 4- (8- &lt;2- chloro- 4- (pyrimidin ·· 2- sloxi.ifeníi) - 7- flvoto- 2- methylIH- jnsidazopbS- cfqninolin- i - ¡b-3 -nuoropipetítiin- 1 ~ iiV 2bsdroxieísnooa

I - (Í3R, 4Rl- 4- (S- (2- chloro-4- (pyrimidin- 2- iloxijfentlp 7- Huero- 2- methyliH · irnidnzoM.S ·· clquinotin ·· 1-: 1) -3- t - 3-il&gt; - 2 · bidroxteíanone

8- (2- doro- 4- (pyrimidin · - 2- üoxíjícniít- 7- Huero- i- (1- (2fnetoxierihpiperidin- 4- ií) - 2- methyl- IH- irnidazof4,5- cjqotuoiina

2- (4- / §- (2- chloro- 4- (piriíniditi- 2- tloxsjíerdJ) - 7- Huoro- 2- rodil- iHímídazof4,5- ejqninonn- i - il&gt; p¡pe &lt;¡rfhi- 1- iljetauol

8 -. (2- chloro- 4- fpyrimidin- 2- ílnxhienií&gt; - 7- fluoro- 2- methyl- 1 - · i- &lt;(7meiiioxetan-3- il ¡metí! Tpipertdin- 4- ii) - H- jmidazoí'4,5- cjquiuolitta

8- (2- doto- 4- (pyrimidin- 2- üox i) íon i i7- -'Inoro- 2- metí ί- i - (1 · (mctilsulfonihpiperidin- 4-11) · SH- imídi¡zo | M , 5-cjquinolirta i- &lt;4- (8- (2-citoro-4- (pyriroidírt-2- ilo \ i&gt; tenil)) - 7 -ilustro-2- methyl- Hiimirtazd4,5- cjquroolm- 1- iPpiperidin- 1 - -i) - 2- hidrosripropan- 1- a 1-01- ¢ 8- ¡2 doro- 4 - O llpropan- 2- oí

8- (2- doro- 4- (pyrimidin- 2- iloxyiphenii) - i- (1- (cidopropiLtíiiónií) piperid-n4- ií) -? - finóte? - 2- rodil-! H - imidazcqd.S- cichinoisnís 8 - (2- doro- 4- tpirimidin- 2- uncleshiero '!) - iluoro- ¡fí (! &lt;. Opfopi.tsnifonií} piperidm- 4- ih- 2- rneíil- IH- irmdaze (4,5- c' jquinoíirta

11S

5,10

<td> 10</td><td>He passed ) 27 5.10</td>

<td>you</td><td>He passed 7) 25.1</td>

<td> 12</td><td>Píi'ií! i - 5, (?</td>

<td> 13</td><td>He passed 1 - 5.8</td>

<td>¹⁴</td><td>Step i- 5.6</td>

<td> 15</td><td>Step i-5.8</td>

<td> 16</td><td>Faso 1- 5.8</td>

<td></td><td>Faso</td>

<td> 17</td><td> 5 - 5,8</td>

<td> ¡8</td><td>Faso: - 5.8</td>

<td> ¡9</td><td>Pica- : - 5.8</td>

<td> 20</td><td>He passed di-il</td>

<td> 21</td><td>He passed 1- 5.6</td>

<td> 71·^</td><td>Step i-5.8</td>

<td> 23</td><td>He passed lili-</td>

<td> 24</td><td>He passed 1- 5.6</td>

<td> 25</td><td>Faso 1 - 5.8</td>

<td> 26</td><td>Faso i - 5.6</td>

<td> 27</td><td>Faso 1 - 5.6</td>

<td> 28</td><td>He passed 1-5.6</td>

<td> 29</td><td>Step i- 5.6</td>

<td> 30</td><td>Step i - 5.6</td>

4- (8- (2- Chloro- 4- (pyrimidin- 2- iioxilfenii) - fluoro- 2- methyl- 1Hmida2of4,5- cjquínoHn- t- íl) -N_tN-tiúnetíipiperidtna- 5- sitltonamide

4- (8- (2- chloro- 4- ipiriroidin- 2- í! Or&gt; .i}! Erot) - 7- fluoro- 2- methyl- 111 ¡nidazo'4.5- ejqoinolin- 5- you) - NN - dimetiiplperidine- 1 - earboxatn id »

1-; 4 ~ (8- (2- chloro-4- (pnimidro- 2- i oxi) fetjii i- 7- fluoro- 2- me! Il ·:! Midazofa 5- c | quinoiro- i- iftpípcridin - 1 - iijet &amp; norsa

2- (4- (8- (2- chloro- 4- (pinroidm- 2- iloxQfeml) - Huaro- 2- medi- ^; H¡: nida? .O (4,5- ejqutnoim- 1- dípipetidin- 1- iljacetaroide

- (4- (8- (2- chloro ·· 4- (pirirn¡din ·· 2- iloxi) ténii} · 7- íluoro- 2- meíü-; 11imidazo (4.5- ejquinolin- 1- iijpiperidin- i- ¡ !) ~ 2 ~ hydroxyethane

2- (4- ¡8- &lt;2- doro- 4. ¢ (4- rnetiSpirimidin- 2- i!} Oxy) feni) - 7- ílt¡or¡&gt; - Himidazold.S- cjqumoim- 1- iii- 4- methypiperidin- i - iijetanoi

2- (4- í8- ¡2- doro- 4- (pyriroidin- 2- ílo&gt; .i) feníi) -? - fluoro- 2- medí-; íiisnida2O: 4,5- · ojqnmolin- ·! ÍDpiperidio- 1- Bpropan-l-ol

2- (4- (8- (2- chloro- 4- (pyrimidin- 2- yloxBfentB- 7- fluoro- 1H- imidazo} 4,5Cjqn.iííírír

2- {4- (7- (inoro- S- (2- methoxy-4- ¢ (4- roeliipinroiám- 2- iljoxijlditi¡- i H; midazo [4,5- cjquínoHn- 1- íí) - 4- methylpiperidm - i- íí) oíartd 2- (4- (? - (inoro- 8- (2- methoxy-4- ipirimidin- 2- ilc&gt; x¡) (er¡í ') - iíliraidctzo [4,5-cjquínclm- 1- il) - 4- methylpiperidin- i - íQeítmol S (4- (7- fluoto- 8- (2- methoxy-4- ((4- methylpyrimid-2- illoxiliemh- 1Himidazoj-LÓ- cjquíodm- i-íi) - 4-methylpiperidine - i - il) - 2- hxiroxiprep &amp; n · 1o.na ................................. ................. ........

5- (4- ¡8- (2- doro- 4- ((4- meiylpyrimidin- 2- ¡í) oxy) phenyl} - 7- íluoro- Π1iratdazc- (4,5-e] quneim- I - il) - 4- metiSpiperidm- 1- il) -2-hydroxypropan- 1on: ·; '

1- (4- (8- (2-doro- 4- (pyrimidin- 2- ¡ioxijiénií) - 7- íluoro- 2- methyl- I Himidazo [-1.5- e-lichenin- 1- il) p ¡pendí » ·· I- il) - I- hydroxy-2 (Sridroxymethyl ¡propan- 1- a

2- ((4- (8- (2- doro- 4- (pyrimidin- 2- iloxilfei ') - 7- íluoro- 2- rnetii- 1 i-1imidazo [4,5' ejquinolin-! - i! Ipiperidin- i-il) methyl) propane-!, 3-d¡ol i - (4. (? '- fluoro- 8- (2- methoxy-4- i (4 ~ methylpyrimidin- 2- yl&gt; oxy} íGiií) - 1 ΙΪimidazo [4,5- clqnitrolíts- i- il) - 4- rne! Iípiperidíti- · i- il) - 2- hydroxyethanotia 8- (2- doro- 4- (pyrimidin- 2- iioxijienií) - 7- (inoro - 2- motil- 1- (i- (oxefan3- iitnedLpíperidin- 4- j¡; ~ i? - ;. · mid &lt;ux) [4,5- ejquiuojina

;. pt_ (g. (2- doro- 4-1 (4- roelilpirimidin- 2- ¡lósi) 'enceí!) - 7- I smoke- 1 YES imidazoid.p- ejquiriolin- I -; l&gt; - 4- methypiperidtn-i-il ) - 2- hydroxidarmin i - ¡4- (8- (2- doro- 4- pyrimidin- 2- yloxy-jfénil) - 7- fluoro-1.H- imide:? Or | 4,5cjquinoíin- 1- il} - 4- methylpipeñdm-1- ii) - 2- hydroxypropan- i-one 1 - (4- (8 ·· (2- doro- 4- ((4- mdilpsrisr.idin- 2- il) oxy) (eni¡) - 7- íluoro- 2- roeiis i 14- imídazc [4.5-cjqi¡inoiin- 1- ilipiperidin- 1- 11) 2-hydroxyeianonn I - (4- (8- (2- chloro- 4- ((4 · Meiylpyrimidin- 2- yl) oxisfeoyl) - 7- Iluoro- 2- methyl liidacide [4.5- clquinoiin- I- Hpiperidin- 1-yl} · 2-hydroxypropan t-on »

4- (8- (2-chloro- 4- (pyrimidin- 2- Soxillem!} - 7- (Inoro- 2- methyl- 1Himidazopi.d- clquinonn- 1-ylipiperidirus- I- eafboxsmide)

...... .......... Ilscll) 47 () - 7^......

<td> 31</td><td>Favo 1 - 5.6</td>

<td> 52</td><td>Base one- 5, t0</td>

<td> 55</td><td>He passed 1-5.6</td>

<td>ülli.</td><td>Faso i- 5.6</td>

<td> 35</td><td>Ρηχό i - 5.6</td>

<td> 36</td><td>Faso 1- 5.8</td>

<td> 3</td><td>Pass 1 - 5.0</td>

<td> 38</td><td>He passed 1 - 5.6</td>

<td> 39</td><td>He passed i - 5.6</td>

<td> 40</td><td>He passed 1-5.6</td>

<td> 41</td><td>He passed 1-5.6</td>

<td> 42</td><td>Faso 1-5.6</td>

<td>4.3Λ</td><td>Faso 1- 5.6</td>

<td>43fí</td><td>Fixo 1-5.6</td>

<td> 44</td><td>Pa. \ O í - 5.6</td>

<td> 45</td><td>He passed 1- 5.6</td>

<td> 46</td><td>He passed 1- 5.6</td>

<td>j'Aíg</td><td>He passed 1- 5.6</td>

<td> ¿8</td><td>Step: -?, 6</td>

<td> 49</td><td>He passed 1- 5.6</td>

{8- (2- chloro ·· 4- ((-! - methylpyrimkiii- 3- 11ioxíHenil) - 7- (Inoro- 2- rne'JÍ1H- imi¡jazo [4, $ - ejqimíohri- i - íi) pjpend »A-! -Carboxatnide

8- (2- chloro 4- ((4- methylptnmklin- 2- iBoxijícntl) - 7- Huero- 2- metis- i -1 1 (methyisibnillipiporidin-4- iB- iil-tmidazo (4,5- ejquirtoílna

1- (4- (8- (2- cinto- 4- (pitiipíílin- 2- lexiltenis} - 7- fluero- 1H- imidaz.Í&gt; | 4.5 · cjquinolitv l · íl) - 4- mvfilpípcridm- i- íl ) - 2- hydroxytetanoaa (5) - i - (4- (8- (2- chloro- 4- (pyrimldin- 2 «iloxOfcstil) -? - fluoro- 2- urafií- 1HimklazoMó cjquinolin- 1- iipepiperidin-! - 4 ) - 2- hydroxypropan- 1- one (S) - 1- (4- (8- (2- chloro-4- ((4- methylpiritrddín- 3- iOoxjífenilb 7- fluera- 2jneíl- IB- iaitdazol4,5- cjquinoün - i-it) pipcridin- i-ii) -2-fiídrexiprapaii-) · one

7- (4- (8- (2- doro- 4 - ((- 4- methylphirnidírt- 2- Í!) Oxy) fentJ) - 7- Huero- 2- methyl1B- imidazo i 4,5- ejquinúhn- i - iltpiperidin- 1- íDetanoí 4- (7- Huero- 8- (2- rosioxi- 4- (U ·· mctilpifimidin- 2- íl) oxi) feru'l) - i Himtdazo! 4, S-cjquinolin- 1- iB - 4- methylpiperidm ·· i - carboxandda 4- (7- Huero- 8- (2- methoxy- 4- (pyrintidin- 2- í¡o, \ i) in il) - BÍ- imídazop,? · &lt;-. ' jqtbí) üÍ! i ~ 1- iB- 4- mstiípipenoiua- i - earboxurnida

2- amibo- 1- (4- (8- (2- chlora- 4- (pirinddin- 2- ilexj) fcníi) - 7- fluore- 2- tnettl · 114- imidazo¡4,5- cjqulnelin-1- iBpiperídín -1- iftetanone

2- «Mino- 1- (4- (8- (2- Chloro- 4- ((4- Methyl Pyrímkou- 2- Il) Oxy) Pheny) - 7ilyore- 2- Methyl- Bl-- im» dazo¡'4.5 . eiquinolin- 1- iltpiperidin- I - iftetsnoua 1- (4- ¡8- (2- chlora- 4- ((4- raeí ilpfrirmdin- 2- d) oxt) fen) i) - 7- Boom- t Bimidazo { 4.5 * cjquinolin-1-l) - 4- (hydroxymethylpiperidin- 1- ifi- 2-hydroxyetanone

1- (4- (8- (2- chloro- 4- (ptrunidln- 2- iloxstieniI) - 7- Duero- 2- mefii- i Bi! Rddazo (4,5- cjtpiineitn- 1- iltpiperidin- 1- Il) - 2- ntetoxteiancna (R or St- 1- (4- (8- (2- clergy- 4- (piritnidim 2- itoxOfenií) · 7- Smoke- 2- rsieí hIB- ítmd &amp; zoí4, $ ~ cjquinoikt- 1- dlpipetidin- 1- il, t- 2- fuoropropan- 'i- o: ¡at Pico 4) (R or $) 1 - {4 - (8- (2, - chloro - 4- (prnmkiin- 2- ii oxi Henil}) - 7- Huero- 2-- mei'tb IB- go »idazof4,5- cjquinoiie- 1 - ülpíperidin- B i!) - 2- fluoroprepan- 1-one (Peak 2) í- (4- {8- {2-chloro- 4- ((6- (hk'roximc-tiltpiridin · 2- íBoxitíéníl) - 7- Duero- 2mesii- BI- imiduzoj'4,5- cjquinehtt- 1- ilipíperidm- 1- i} ) - 2- hydrastelárteos 4- (8- (2- chloro- 4- (pirimidiu- 2- tloxt) íenilF 7- Huero- 2- roetü- i Bimtdazo¡4,5- eiquinolin- 1- ib- N- (2 , 2,2- triDuoroethylOpiperidine- 1eaíboxamide

1- 14- (8- (2- chlore- 4- &lt;(4- Duorepirtmidin- 2- iBoxi) phenyl) - 7- ílaoro- 2mclií- IB · iíuíditzo¡4,5- cjqmnoiirt- 1-íBpipcridin- i-il ) - 2- hydroxyctauone b- (4- (8- (2- dore- 4- &lt;(6- fluoropyridin- 2- illoa BiéniD- 7- fiaore- 2- met-i114- imídaao (4.5- clqnmolim 1 iSlpiperidin- 1 - 11) - 2- hydroxycctanone

- Í4- 18- {2- chloro- 4-1 (5- .Hero- 4- methylpyridiidi 2- ijoxijfcnii) - 7S'luoro- 2- methyl- í H- imidazoí4,5- cjquinolin- i- lOpiperidin- i - di- 2bidroxtetanonu.

run it from 2 - ((3S.4S) · 4- (8- Γ2- chloro- 4- (pit imidin- 2- iloxí tfíoiB- 7- fiuoro2- rneítS- IB- tmidazoi4.S-ejqaiRoíln- i- db 4- Ruompipendim i - db 2oxoctilo

148

He passed

4-7-7:

<td> 50</td><td>yM)</td>

<td> 51</td><td>Step i - 5.6</td>

<td> 52</td><td>He passed 1-5.6</td>

<td> 53</td><td>Satin 77-: 5.6</td>

<td> 547</td><td>He passed¹ - 5,6</td>

<td> 55</td><td>NA</td>

<td> 56</td><td></td>

<td> 57</td><td>Step i - 5.8</td>

<td> 58</td><td>Step i · 5.8</td>

<td> 59</td><td>He passed 1- 5.8</td>

<td> 60</td><td>He passed 1-5.8</td>

<td>i heard</td><td>Step i-.5,8</td>

<td> 02</td><td>Pa »o 1 - 5.8</td>

<td> 03</td><td>He passed 1-5.6</td>

<td> 64</td><td>Step i-5.6</td>

<td> 65</td><td>He passed 1-5.6</td>

<td> 66</td><td>He passed I- 5.6</td>

<td> 67</td><td>Step i-5, or</td>

<td> 68</td><td>P% .o 1- 5.6</td>

8- (2- chloro- 4- (pyrurddin- 2- ¡ÍoxÍíícbíi) - 7. (note ·· I- Í {3S, 4 $} · 5- finoro · IOnvílRuiíoniSlpipendin- 4- tí) - 2- tnefii- IH- inndazo [4,5- cjquinolirta I- {{3S, 4 $} - ¿- (8- (2- chloro · 4- {(4- (tnñuorornetÍÍ) piriniidín- 2- il) oxi) fenís} 7- lluoro- 2- nettí · IB- imidazo! 4,5- e¡qusnofin- i - i!) - 3- llnoropiperidin-! ii) ~ 2. hydroxieieieofia

1- ((5S, 4 $ i- 4- (8- (2- chloro- 4- (pyriondin- 2- yloxOtenyl) - 7- ííoorn · 2- methylÍH- ífródasof-'l, 5- cj &lt;juíf! Oi (or · I- ii} -3- fíuoropípvndín- 1- ¡I) - 2oiotoxieinncnia

I - ((3S, 4S) - 4- (8- (2- chloro- 4- {{'5- íktoto- 4- mabípirimidin- 2- d} oxy) íenii} 7- illuoro- 2- trictd- IH- ítnidazo [4,5- cjquinoiin- i- ií) ~ 3- flooropiperidin- Iyli- 2- hydroxytin

I - (4- {8- (2- chloro- 4- (74- cyclopropylpyrnidrn- 2- íl) oxy) f'cní!} - 7- íluoro- 2meil-imil-imidazo [4,5- cjquinolin- i- ü) piperidin- I - ¢ 1) -2- hydroxycysrione 4- (8- (2- chloro- 4- ({4- methylpinmidíñ- 2- ii'ioxi'ifentlj- 7- {Inoro- 2- nielil iíl · ¡ irddazof4.5 · c) quínrd (n- I- ilpeimhldro- 2H- dopyran 1,1-dioxide

8- (2- chloro- 4- (pirinildm- 2- üoxi) ícrdí) - 7- íluoro- I- (3- íluorottírahidro2H- piran- 4- il} - 2- medí-! H- rtnídazo {4.5-ciqnirtoiiní ·

7- {(3R, 4R ./- 4- t, S- {2- chloro- 4- (¢ 4- meplpirímirlín- 2- il) ositfeniJ) - 7- {inoro2- íoctll- IB- imldnzo¡4,5 -clqulnolin- 1- i?) - 3- ÍSuoropipcridin- Iliiacoioídirdo

2- ¢ (38/18) - 4- (8- (2- chloro- 4- {(4- methylpyrimidin- 2- yl) oxy) fenih- 7- lluoro2- noli! - IH- imidaxol4,5-clqmnoliu - 1-yl} -3-ilooropiperidin- iibacet.ordtríia

4- (3- chloro- 4- {I- (I- (etafiomedOpiperidin · - 4- i!} - 7- fúuoro- 2- medí- ¡IIimidazo [4, S- cjquinolin- 8-ylpenoxy) - 6- meyrlpirtmidine - 2- Carbonyrrile 2- (4- {8- (2- Chloro- 4- (¢ 1- Medi- o- Bear- 1,6- Diiddiriritníd¡n- 4¡ioxíiienilj- 7- Hooro- 2- Nicyl- IH - imidazo¡4,5- clqnioolm- I - illpiper.dinI - ii {action

2- Í (3R, 4R} - 3- (Inoro- 4- (7- iluoro- 8- (2- methoxs- 4- (pudmidin-2yloxyHenyl) - 2- rrtení- IH-i; nidazoi4,5-cjquinolin- 1 - ii) piperi.dm- Iil race ion ii rilo

2- ¢ (35,48) - 3- flnoro- A- (7- ítuoro- 8- (2- methoxy-4- (ptrimidin-2-xyloxyHenii) - 2- triethyl- IH- ñnn?, Oí4.5- cjquinoirn- t- iltpiperidin- Iíhacetonitriío

3- ('3- Chloro- 4- {Inoro- I- (I- (2- Hydroxyaceíi Dippiperium- 4- II} -' 2- Methyll-H-imktazo [4,5- cjquinolin-8-ylifcnoxy) - I- meiipyridm- 2¡ 1 Η) - οπ · ι

4- ¢ 8- (2- chloro- 4- (pyrimidin- 2- HoxOfobi) - 7- illuoro- IH- irnidazoi4 &lt;5c quiísolin-i-il} - 4- merylpiperidine- I-carboxamide

4- (8- (2- chloro- 4- «4- medipirifnidin- 2- il) oxi lleniij-? - íluoro- IHurddazo [4.S- c jquinolin · i-il) - 4- mesylpiperidinu- i - carboxamide

I- (4- (8- (2- chloro- 4- ¢ END 4- rnetoxi- or- merylpyrmidin- 2- ii} oxy · ίεηϋ) · 7-lluoro- IH- lmidazo¡4,5- c'-qmnolin - i-yl) - 4- medipiperidin- 1- ii) -.

1- (4- í8- (2- chloro- 4 - ((4- methylpyrimidin- 2- yl) oxy) fenit) - 7-yluoro- 2- merylIH- itr.idazof4,5-c) quinoim- i-il } piperidin-I-yl} -2-methoxyeonia

5- í {3S, 4 $ ¡- 4- (8- (2- chloro- 4- ((4- medlpirimidin- 2- i!) Ox.i) ft? Nil7- Huero2- medí- IH- imidazo 14, 5- clquInoSin- I- si) -, 7- flnoropipcrdin- i - i!) - 2bidroxietanone

119

<td> 69</td><td>He passed -5.6</td><td>6- (5 - doro- 4- (7- Huero- 1 - (. 1- í'2- hidrexiacenl) - 4- metiipipendm- 4- íl) 1 H- irnkiazo¡4,5- ejquinehn- 8- ihf ' enoxb- 3- methyipinmidin- 4 &lt;3H} - ana</td>

<td> 70</td><td>Biso</td><td>4- (7- Huero- 8- (2- fluoro- 4- ((4- motilpirtmídin- 2- íljosijíénih- 2- inctiiIH- trnidazo [4.5- ejquindin- t- Opíperidine- I- earboxamide</td>

<td> 7^:ίί</td><td>Step i-5.6</td><td>i- (- + - (? - Huaro- 8- (2- Huota- 4- (&lt;4- methylpyrinsidin- 5- iijoxtjienii} - 2medl- S H- imidazo [4, $ - üjquinoiin- i-tbpipendirs-1- ilp 2- hydroxyetanone</td>

<td> 72</td><td>He passed I- 5.6</td><td>6- (5- doro- 4- (7- Huero- i - (.1- (2- liidraxÍacedlípiperidin- 4- H) ~ 2- me-tüΓΗ- irt) id3zo¡4,5- cjqüfnoiin- 8- i! Sídioxh- 5- Metypyrhnidi »- 4 {5H} - Ona</td>

<td> 75</td><td>He passed I - 5.6</td><td>4- {8- (2-doro- 4- {(! -Ruefii- 2- oso- 1,2- dihydtopindin- .5- ihoxhíedi) ^?fluoro- 2- motil · - 114- imidazo [4.5- cjqumolin- '- ihpiperidine- 1csdsoxam'id;}</td>

<td> 74</td><td>He passed I- 5.6</td><td>4- (8- (2- clear- 4- ¡: S- rneíil- 6- oxai-, 6- dihydropyrimidin- 4- ii) a&gt; .i} tertí¡1- 7 Huero- 2- metí; - Π .1- ürúdaza (4.5 · ejquinoli »- 1- ihpiperídiua-! Earboxamida</td>

<td> 75</td><td>He passed i- 5.6</td><td>4- (8- 62- doro- 4- ((! - mefil- 2- oxo- L2- dihydropyridin- 3- iyloxyhydride) - 7fluoro- IH- iniidazoí4,5-i'jquifiaü !! - 1- ih- 4- nseiüpiperidine- lcarboxam one way</td>

<td> 76</td><td>He passed : -5.6</td><td>4- ¢ 7- Huoro- 2- medí- 8- (2- roeHS- 4- í {4- methylpinmidm- 2- ihoxht'enib ·· ¡L · im¡da2a [4.5 ~ e quincho- I- illpiperidina- í-carboxairnda</td>

<td> 77</td><td>He passed</td><td>1- (4- (7- Huaro- 2- mutih 8- (2- rnetil-4- {(4- mciilpírinHdin- 2- Go ledhIH- ¡nddazof4,5- cjquinolin- 1- illpiperidin- i- il&gt; 2 - hydroxyotonone</td>

<td> 78</td><td>He passed</td><td>i - (4- (7- Huaro- 2- motil- 8- (4- (¡4- methylpirim¡din- 2- UJoxbfeuif} - 1 HmHdazo (4,5- cjquinolin-1- ibpipendm-1- ib- 2 - hydroxieíanone</td>

<td> ;&lt;&gt;</td><td>He passed / 401 &lt;</td><td>4- {? - fluoro- 8- (2- Huero- 4- (¡4- Meíiipirimidín- 2- iíJoxhfeniB- ΐ Hímidazo¡4,5- ¿(quinolin- 1- ih- 4- ntetÜpiperídiua- i - carboxatruda</td>

<td> 80</td><td>He passed / Nslóc</td><td>4- ¡7- Fluorescent- 8- (2- Huaro- 4- (pñimidm- 2- ilaxbfenü) - 1 imide?? Or {4.s.</td>

<td> 8¡</td><td>He put i-5.6</td><td>(Sj- 3- (3- dora- 4- ¡7- Huota- i- (h (2- hydroxypropaneibpipendirf- 4- q). 2rnafií- IH- »» idazo (4_s5- e (quino! Ín- 8- ihfenoxi) - I-rnuhipiridiu- 2 (ií i) - ana</td>

<td> 82</td><td>He passed 1 - 5.6</td><td>4- (8 ·· {? .- clergy- 4- (¡, 4 ·· metí! - 3-oxa- 3,4- dihydropyrazin- 2- chi) e. \ :) tenii) - ⁷fluoro-2-ntetii- IH- imide ?, or [4,5-cjqtiínoiiu- 1- ibpiperidine-Icitrboxamide</td>

<td> 83</td><td>Step i · 5.6</td><td>1- (4- (7- Huaro- 8- (2- fiuoro- 4- ((4- íuetilpirúBidín- 2- ÍOoxi'ífent)} - ​​1Hú «idazaf4,5- cjqainoiin-1- i () - 4- methylpiperidiu - 1 - ih- 2- hydroxyethartone</td>

<td> 64</td><td>He passed 1- 5J</td><td>2- (4- (8- (2- dora- 4- (pyrimidin- 2- iioxí jfeod) - 7- fiuoro-2- rnetií- i Himldazo (+, 5-ejqtilndin- - iíipípetidin- i - ibacetouitníe</td>

<td> 85</td><td>Step ¡- 5.8</td><td>2- 03S_s4S &gt;&gt; 4- (8- (2- clear- 4- (pinmidd- 2- iioxilferhi) - 7- Huaro- 2- metii; H- im id a / .0 (4,5- cjqdnolirí- i- ih- 3- Huoropiperídin- 1- íhuccton itrio</td>

<td> 86</td><td>Step í - 5.6</td><td>ί ί 3S,; S) ~ &lt;4- (8- (2- doro- 4- (pyrirnidin- 2- iiaxi / feriiíj- f- fluoro- 2- mtiil · ÍH- irnidazo [4,5- tjqoinolin-! -ih-3-Huoropipehdin- 1- ihfoxetnn- 2ihnieHmona</td>

<td> 37</td><td>He passed 1-5.6</td><td>i - ¢ (35,43) - 4- í'8- (2- daré- 4- ¢ (5- Huaro- 4- methylpínmidin- 2- iboxilién i h7- Huera- 2- medí- IB- im! dií2o ( 4 „5- dquínoím- i - íi) - 3- iloaropiperídin- I!) - 2- Jbdroxietóuena</td>

<td>H.H</td><td>He passed 1-5.6</td><td>J - (s3S, 4 $ '¡- 3- Huoro- 4- (7- Huaro- 8- (2- mefoxi- 4- (pyrimidin-2yloxy} íend} -2- methy-; H- imid3zo [4,5 - aíquindín- 1- ií5pijxr.iídi »- 5- ih- 3« idRwdafioríii</td>

120

<td> 89</td><td>He passed 1-5.5</td><td>1- ¢: 38.48) - 4- (8- (2-cioro- 4- ¢ (4- (bidroxínetíi) plrimidín- 2- ilíoxideoílv 7- fluoro- 2- muflí- 1H- immidaz.uí4,5- c quínolÍR- 1- ií} - 3- fluorapíperidln-ii! ') - 2- hydroxyeaniaorite</td>

<td> 90</td><td>He passed 1-5.6</td><td>i- ¢ (35,45) - 3- fluoro- 4- (7- fluofo- 2- medí- 8- (2- uredo 4- ípñíddin- 2¡losi&gt; ténii 1- ífl - »:« ída ?. « í4,5-cjqutnobf! - 1- »bpípefid? n- 1- il&gt; - 2h.idroxí.cfanons</td>

<td> 9;</td><td>He passed 1- 5.6</td><td>h id ro genos or data of 2- ((36,48) - 4- (8- (2- chloro-4- (oiriroidit; - 2- Soxijfenil) 7- fluoro- 2- meti! - 114- imidazo [ 4,5- clquinolin-i-ti) - fluoropipendin · 1ib-2 * oxoctíler</td>

<td> 92</td><td>He passed</td><td>1- ((3S.4S) - 3- fluoro- 4- (7- fluoro- 8- {2- fluoro- 4- (pyrintidium-2doxy) fcnii} -2-mycyl- JH- tratd &amp; 20 [4,5- ciquioodn - 1- iflpiperídio- 1- ií} - 2hidroxíetanone</td>

<td> 93</td><td>He passed 1- 5.6</td><td>I- í (3S, 4S) - 4- (8- (2- chloro- 4- (ssrimidm- 2- iloxflientl} - 7- fluoro- 2- mcfii1H ~ íruidazoflflS- cjqumolini- í- il} - 3- fluoropiperidin- 1- djefanena</td>

<td> 94</td><td>Step '· - 5.6</td><td>(38,45) - 4- (8- (2- chloro-4- (pyreimidin-2-ioxy) faith »ií) - 7- fluoro- 2- medí- 1Himidazo {4.5- cjquínofln- í-; S} - 3- fluoropiperidin-1-carbox amide</td>

<td> 95</td><td>He passed i - 5.6</td><td>&lt;S&gt; - í- &lt;(3S, 4S) - 4- (8- (2- chloro- 4- (pa-soiidin- 2- yloxy) fcnil) - 7- fluoro- 2nreíii- 1H- ímídazol4,5- cjquinolíu - 1- «i&gt; - 3- fluoropperidin- 1-: 1) -2droxipropan- í-one</td>

<td> 96</td><td>Step - 5_xb</td><td>í4 „(g, (2- chloro-4- (prstnídln- 2- ijoxijfcniíi- 7- fluoro- 2- muid- iHlfiiidazo (4,5- ejqumodn- 1- iljpipcndin- i - il) - 2- fluoroetarrenu</td>

<td> 97</td><td>Step i-5.6</td><td>! - ((35,45) - 4- (8- (2- chloro- 4 ~ (pirinsIdin- 2- sioxflfenfl) - 7- fluoro- 2- rrretd111- ínbdazn [4,5-cjouiitolín- 1- d) - 3-fluoropiperidin- 1- il} - 2- fluoioethanone</td>

<td> 98</td><td>He passed 1-5.6</td><td>1- {(3S, 45¡- 4- (8- (2- chloro- 4- (pyrpyrphiditi- 2- ifoxílfcrtd) - 7- fluoro- 2- rcciü1H- ittndazoi-LS- cjquinolm- 1- ilh 3- fluoropiperidin- i - il) - 3hydroxypropan- 1- ona</td>

<td> 99</td><td>He passed 1-5.6</td><td>i - ((35,45) - 4- (8- (2- chloro- 4- (i 4- areas? - 1.3,5- Iriazkj- 2- 11 joxsfl'ew 1) - 7fluoro- 2- medi- 'H-imidazo} 4,5-cjquinolm- 1-11) -3- fluoropiperidin- 1-: D2- Iridroxietíiijooí</td>

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V «£ € í&gt; ií £: £ - &gt;&gt; · $ (-¾¾ (00246} Step * 2.1: Synthesis of 4 - ((írtmetílsdit) oxi) - 5.6- dihydropyridins- i (2H) carfcoxiian» de tere - butyl, 2, 2;

Q-^w' £

OR

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J0Ü247] 4- tere-butyl osopiperidine-i-carboxylate, 1.! (2 50 gi256mo!) Was taken in dry DMF (150 tul) under 1% atmosphere and TEA (230 g, 2.27 mmol at room temperature was added. The reaction mixture was cooled to 0 * C, total drip was added Irimetíisi Siio (i? 8g. I. marble) for 30 min. After the addition of the reaction mixture was heated to 80 '¹ C for 16 h. The reaction was monitored by TLC (20% EtOAc hexane), and the reaction mixture was allowed to cool to room temperature, poured into ice water and extracted with EtOAc (3x200 ml). The combined organic layers were washed with water, brine solution, dried over Na;&gt; SOi and evaporated «3 empty. The residue was purified by c rom ai to make a column based on silica gei (EtOAc ai 5-10% ·· itexane) to provide 4 - ((tri mctiisiHl) oxy) - 5,6-dihydropyridine-i (2H&gt; terebutyl earboxtite, 2.2 (300g, 87.79%). 'HNMR (CDCb, 400MHz): δ 4.78 (s, 1H), 3.S7-3.80 (ra, 2H), 3.55 (i, 2H), 2.15-2.05 (m, 2H),!, 45 (s, 9H), 0, i9 (s, 911).

00248) Step 2.2: Synthesis of 3- fluoro-4- oxopipertdine-S-carboxylate terchutyl, 2, 3:

OR

AP .....

<img file="CU20160020A7_D0049.tif" />

'V,. ·. · * ^: N Soc ¡00249¡ 4 - ((trimcíiisiiilt oxi) - 5.6- dihydropyrididoa- 1 (2H} - terebutyl carboxylate, 2.2 (300 g, L02mo¡) was dissolved in dry air (300 ndj and cooled λ 0^and C and seieetfiuor (430g, E2lmoí) was added portionwise over a period of 45 minutes under N ?. After completing the addition. The reaction mixture was left at room temperature and stirred for 2 b. The reaction was monitored by TLC (50% EtOAe / hexane). After completion of the reaction by TLC, the reaction mixture was poured into saturated sainmera solution cooled 300 ml) and extracted with EtOAc (2x200 ml). The combined organic layers of EtOAc were washed with brine solution, water, dried over NasSQa and evaporated in vacuo. The residue was purified by chromatography. in column on silica gel. {10-40% EtOAc-Hexane) to provide 3- fluoro-4-oxopiperidma- and carboxylate 2.3 (J70g; 70.7%). 'HNMR (CDCIj, 400MHz): 6 4.3 "(dd. 0.5H), 4.77 (dd, 0.5 H), 4.47 (brs, i H), 4.17 (ddd, 1K), 3.2.5 (brs. 1 H). 3.23 (ddd, i H). 2.58 m. H). 2.5 í (m, ί H), 1.49 (s. 9H).

002501 Step-2.3; Synthesis of 3- fitmro-4-biroxypiperimid-i-carboxylate d? Terebuti, 2,4;

Oh

<img file="CU20160020A7_D0050.tif" />

Scc 00251) Can 3-fluoro-4-oxopiperidine-t-carboxylate solution of re-butyl,

2.3 (80 a. OJóSntoi) in THE (890 mi) dealt with i, - Seleeíridc (405mi, 0.405moi, drip) a - 78^to C under nitrogen atmosphere. The resulting reaction mixture was stirred for 39

123 min. at the same temperature, he added MeOH (45.1 mE .. í. ΐ () 5rool j of NaOB ί M t! I 04mL, E 105wgI) and the reaction was allowed to warm to Q^and C, And reaction was quenched by the drip addition of ERO: (125.1mL, l, 843.moi), your vedábks were removed in vacuo and diluted with water (500 ml) and raehkno chloride (500 mi). After separation. Id cap »organic washed with brine, seeded on Na_;SOs and concentrated in vacuo to provide the desired product 3- illuoro-4-bidroxtpiperidine-I-tereuthium carboxylate_; 2.4 (63g, 78%). 'HNMR (CDCÍ ;, 400MHzi: or 4.70-4.65 (m, O.SH). 4.58-4.52 (m, 0.511). 3.99-3.84 &lt;m, 2H), 3.82- 3.58 (rn. IB) , 3.55-3-27 im, IH). 3.IS (Oís. IB), 2.06 (brs_t IB), 1.89- I 70 fm, 2H). 1.47 (s ;. 9H).

(00252 | Step- 2.4: Synthesis of 3- lloro-4- ((methylisulfonyl oxy) pipe; idlna-tere-butyl tere-butyl, '2.5:

<img file="CU20160020A7_D0051.tif" />

tí) 0253j One solution of 3- fluoro-4- hjdroxipjperidine-tert-butyl carboxylate, 2.4 (63g, 0.287moi) in anhydrous methane chloride iol Orn Et se. trotted with trietdnmb-a (60 ml, (1.43 i mol) followed by methane sulfon chloride (26.7mL, 0.345mol) or 0'C under N2 atmosphere. The solution was allowed to warm to room temperature and stirred for 4 hours The mixture was partitioned between saturated NaHCO.i (400 ntl) and netylene chloride 1400 ml). The aqueous layer was extracted with methylene chloride (2x500mL). The combined organic phases were washed with HCII, brine, dried over NajSG », filtered and concentrated under reduced pressure. The residue was purified by silica gel cu chromatography, eitjyersdo with 20-30% EtOAc and Itexano to provide.) Fiuoio-4 ((meriisuifenti) osi) piperidine-I-butyl carboxylate. 2.5 (78 g. 91% 't HNMR (CDCB, 400MHz): 6 4.98-4.86 (tn, IH), 4.80-4.74 S.:m „0.5H), 4.67-4.63 (rn, 0.5H), 3.923.45 (m 3H), 3.44-3.25 (m, IH), 3.08 (s, 3H)_; 2 20-2.0? (m, IB), i.93-1.80 (m. Π1). 1.45 (S59M),

100254J Step- 2.5: Synthesis of 4- aggregate- 3- fluoropiperidine- 1- terebutyl carboxylate, 2.6:

124

<img file="CU20160020A7_D0052.tif" />

0Ü255¡ s sodium azirla (or 8.2g. Ϊ́ .050moi) was added to the solution of 3- (Inoro- · + ((methisulfoniifoxylpipendin-1- tere-butyl carboxy, 2.5-78g., OR, 262rnoi ) N DMF (or 20mt) The reaction mixture was heated at 100 * C overnight, the mixture was cooled and diluted with 500 ml of water and roeólena chloride (500 ml). After separation, the organic layer was washed with brine, dried over NthSCL, filtered and concentrated in vacuo to give the desired product 4- azulo-3-fiuoropiperidine-1-carboxylic acid terebutyl. 2.6 (62 g, yield 96%). and which was used for the next reaction without ttmetina purifeaeióív ¡00256¡ Poso-2.6: Synthesis of 4- aromo- 3- Oueropípendina- 5- carboxylate of iercbufíio. 2.7;

MH,

Boc ¡00257J Pd ¡C ai 10% (i2 g) was added to a solution of 4-azido-3fiuoropiperjdiua-i-tere-butyl carboxylate, 2.6.62 g, 0.254tno!) In EtOH (600 mL ), The reaction was stirred under an atmosphere of hydrogen (balloon pressure) for 48 years. The mixture was liter to ships made from. edit and concentrate under reduced pressure to obtain the title compound 4- t-amirot&gt; -5-teorobuido-fiuoropiperidine-i-carboxylate, 2.⁷ (42 g. 75% yield). LCMS: m / z 2 'SS (Mr 1 i 0025O¡ Step- 2.7; Synthesis of 4 (bertciSatuino) - 3- fiuotüpjperidró · 1-tere-butyl carboxylate, 2. S:

VHBn

<img file="CU20160020A7_D0053.tif" />

éoc {0O259¡ So added benzitidchtdo (34.0 g, 0.321 mol) to a solution of 4- amino-? ·· fluoroptperidine-1- carboxylate of terebutyl, 2.7 (70 g. t) j2 mol) and acetic acid (10 my) in | 00261!

butyl, 2.9 Pfiito 'sp

Fi 'fií!:?

1002621 ethanol ´500 ml&gt; and stirred brown me 50 min at room temperature. Sodium aanoborohydroxy (2.23g, OdiTitiol) was added and stirred brown for 3 hours. The reaction was quenched with saturated sodium bicarbonate solution (200 ml) and extracted with dichloromethane (2x250ml). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was dissolved in a minimum amount of dichloroinetary (200 µL) and the pH was adjusted to 3-4 measured by the aqueous oiifieo acid (i 24 g, C, 645moi in 10 (10 ml) water). The layers were separated and the aqueous layer was washed with dseJororoetairo {3x259mb}, then the aqueous py layer was separated, adjusted to 9-10 by using saturated NeaCCL and extracted with diction dichloride (2x5ó0trd ... t . The combined organic layers were washed with brine, dried over anhydrous sodium subate, fixed and concentrated to obtain the crude product that was purified as a light yellow oil. The residue was purified by silica gel chromatography eluting with 19- 1 5% EiOAc and hexane to provide the desired product 4 - (beneüammoL 3fiuoropiperidroa- I-terebutyl carboxylate, 2.8 tale, Si.52% yield) iiNMP (400MH®, CIXT) δ 7.39- 7.29 anger, 5Hj, 4.44-4.35 Im, 0.514), 4.32- 4- 10 (m, 1.5H), 3,985.85 (tu, 2H&gt;, 7 S0 (d, 1HL 2.97-2 L&gt;&gt; ( m, 411) 2 04-1 1.93 (m,: H&gt;, 1.46 (s, 9H); L.CMS. 92.34%. RMZ- 399 2 (M + U; HPLC. 95.40%; HPLC quirab 47.2% at 9.50 mine and 48 3% at 12.34 min. Column; AG / Chiral Pak AD- Η.Ό3, n- Hexí¡rso.EtOH (80:20), (00260! Eriamiomeric messes were separated by preparative HPLC from the

Compound- 2.8. Camidtid: 42.5g (load: SOmg'rnl Conditions: Column: CHIRALPAK AD- H (250x50} m.Smteron; Esse mobile: ACN 'EiOK (05:35): Parameters: SOml / mln refinement rate, column temperature $ 2⁹ C.

Pico- 1: 4- (hene and lamino) - 3- fúoropipersdina- 1- carboxylate of íerc2.0 í! 9.3g, yield of J 45%) 'HNMR. (CÍ9CE 400MHz) 3 7.35- 7.25 (ro,

5Hk 4.37-4.28 (m. 2Hj, 3.91-3.79 (dd, 3H \ 2.8b- 2.82 un, 3H). 1.99-1.9m. 1H), i .45 (s, 9H}, 1.37- Ϊ.34 ( m, 1 H); LCMS: 99.43% m / 2 ~ 309 (Mm); HPLC; 99.9%, «= 10.0 min., {Column: CH1RALPAR AD- H {250x4.0) mm.dmicron, Mobile phase; u-MexímofiHQHOPA

126

80/20 / Oi, Parameters, Ιτπΐ / ιηΐη flow rate. column temperature of 25 * C. Detection 'DAD22Üíirí L (00263} P (co 2: 4 - (benzidourous) - 3- fiuoropiperiáína- 1- carboxylate of GR.

4R) tstc-butyl, 2.10:

NHBn

...................................

f / U («k J ......................... &lt;; &lt;..... / ssssssssssssssssssssssssssssssssssssssssssss .í¿.,; i ^: Sní.fi &lt;Z^: / Μ '

..........

} U0264j tl9,3g, 46% withdrawal). HNMR (CÍXI'h 400MHz.}; Or 7.35-⁷-25 (ro,

5H), 4.3? - 4.23 (m, 2H), 3.9C 3.70 {dd, 3H). 2 36-232 (m. 3H), i.09-1.77 (m, IR), 1.43 ts, 9Hi. ! 3? 1.34 (m, i H); 99.64% m / z- 309 (M --- 1g HPLC: 99.5%, rt ~ 12.8 trun. {Column 'CHIRALPAK ΛΓ.) - H (250x4.6) roíu, 5miero? T, Mobile phase- n- Hexa.no/FiOH/DE.A 80/20, · 0.i, Parameters: mldnín tase, de {luxury, column temperature of 25¹'C, Detection: DAD220nro), (00265} Step-2.8: Srote-xis of 4- amino- 3- ñuor "pyreid" ia- 1- carboxylate of (3S,

Shouted-hut uncle. 2.11:.:

NH?

i

N t &lt;BOC

2 / B (00266}

10% Pd / C (4.5g) was added to a solution

4- tbetieílamino) 3 íluDfopiperidina-l - carboxylate of i.3s, 4 $ itere-butyl, 2.9 (i9, lg, d.062ntoi) in LtOR (500 rolls ..). The reaction was stirred under a hydrogen atmosphere (balloon pressure) for 16 hours. After completing the reaction by TLC, the mixture was filtered through a bed of edite and concentrated under reduced pressure to obtain the title compound 3- (3S, 4S} tert-butyl tert-butyl-3-carboxylate-I-carboxylate, 2.11 (12.og, yield 793%).^!HNMR (CDCL 400MHz): δ 4.33-4.14 (m, IH), 4.13-4.02 (ro, 2H), 2.94-273 (rn, 3H), 1.89-1.86 (ro. IH). 1.48 (s, 9H), 1.42-1.34 (ro, IH}; LCMS: 100% .ro / z 163.1 (M- 55, íercButílo): HPLC: 99.17%, rt ~ 5,146 ruin. (Column:

} (í0267j Synthesis of 4- antino- 3- fluoropiperidine- 1- carboxylate of (3R, 4R) tercbntiin. 2.12 ·

127

Γ²

Η oc

2.) 2 | bO268] 10% Fd / C (- '+. Sg) was added to a solution of 4- (benzyllamino) -3fluoropiperidine · i-carboxylate of (3R, 4R) terebutyl, 2.10 { '9.6g, 0.063mal) in EtOH {.500 mi.). The reaction was stirred under a hydrogen atmosphere (balloon pressure} Fleeing for 16 hours. After completing the reaction by TLC, the mixture was filtered through a bed of cebte and concentrated under reduced pressure to obtain the compound of the 4-antino-3-phyoropiperidma-1-carboxylate (3R, 4R) tere-butyl, 2 , 1.2 (! 3, óg, 92% yield). '' NMR (COCi ^ 400MHz): or 4.33-4.14 (ra, 1H), 4, i 3- 4.02 (ra, 2H), 2.94-2.7S (m, 3H), 1.89-1.86 (ra , 1H), 1.48 &lt;s&gt; 9H&gt;, 1.42-1.34 (ra, 1H), LCMS. 10055, m / z 163.1 (M-55, tereButyl); HPLC: 99.62%, rt «5,214 min.

100269]

Alternative Synthesis of (3S, 4S | - 4- atntno- 3- ftnornpiperidiiM- 1- carboxylate of tere £ ssjütamn- &amp;

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Step- 6.1; Synthesis of (3S, 4S) - 3 * fluoro- 4- (tosyloxy) ptpendlua- 1- tvrebond carboxylate. 4.3-1. 4

128

3- fluoro- 4-hityroxipsperidirta- I-car box and tere-butyl tin, 2.4 (6 g, 0.02? 3mcl) in anhydrous OCM (100 roi) was treated with írietilamitia (5.6 g, 0.055mol) and DMA? (0.35 g, 0.029 mol) followed by sulibnii p-toiuer chloride or (5-7 g, 0.03 moja) (Γ C under nitrogen atmosphere. The residual mixture was left slowly at room temperature and stirred for 16 h. The reaction mixture was poured into ice water, the organic layer was separated, washed with saturated NaiCO-, brine solution, dried over NtfiSO ^, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (10-30% EtOAe and hexane), as the second product eiuido 4 2- 2, 4, ig (main product, mezeia of two enantiomers). HPLC (ZORBAX XJ3B): $ 8.35% at rt S.3 mine. HPLC removes !: [(LUX .AMALOSE Smtcron 2 (2S0x4.60mm), Hexane: EtOH (50:50)] shows two peaks in 7.2 minutes (Peak-i: 49.5 9% at rt) already! 1,406 min (Peak- 2: 49.61% at rt),

1.6 g of the 4.2.2 isomer was separated by quirai HPLC (LUX column AMÓ'LOSE-2, refining rate: 20m / mln, solvent: n-hexane / ethane! (60:40)) and 0.7 was obtained g of 3S. 4R- isomer 4,3-! and 0.75 g of 3R, 4 $ - isomer 4.3-2.

Peak-L 4.3- l: 'HNMR (400MHz, CDCb): 6 7.8i - 7.79 (d, 2H), 7.35-7.33 &lt;d, 2H), 4.83 4.52 (ro, 2.H.), 4.05- 3 , 55 (m. 2H), 3.50-3.05 (ro, 2H), 2.44 (s, 3H), 2.07-25 fin, IH), 1,711.68 (ro, IH), L43 &lt;s, 9H); LCMS: 96.00%, m / z 274.1 (M- &amp; oc + l}; HPLC; 99.62%.

Peak- 2 ,. 4.3-2:^!H NMR (400MHz, CDCE): S 7.85-7.79 (d, 2Hj, 7.35-7.33 (d, 2H), 4.83 4.52 end, 2.H). 4.05-3, S5 (ro, 2H), 3.50-3.5.5 end, 211), 2.44 (s, 3H&gt;, 2.07-2.55 (m, IH), i.?t1 68 end, IH), i .43 (s, 9H); LCMS: 94.48.0%, m / z 274 (M- Boc-í-i ?; HPLC: 97.64%.

Fas »- 6.2; Synthesis of (3S, 4SL 4- azido- 3- fiuoropipendma- 1- terebutyl carboxylate. 4.4:

..

.F ργ fi · '

Sor

4,4

Sodium azide (0.48 g, O. O073roid) was added to a solution of I3S, 4R) -3-fluoro-4 (tosyloxy) piperidine-I-carboxylate tere-butyl, 4.3-L Peak-1 (0.7 g, 0,005S? Moí) dissolved in DMF (15 mi). The reaction mixture was heated at 100 * C for 4h. The mixture was cooled and diluted with water and methane chloride. After separation, the organic layer was dried over Na ^ SO ,? and concentrated in vacuo to provide the desired product, 4.4 (0.4g,). The product obtained was taken for the next reaction without any purification.

129

Faso- 6.3: Synthesis of (38, 4S) - 4- amino- 3- fiuoropiperidiua- 1- tert-carbon carboxylate »4.6:

NMj ,, -. / FW í J .....

8th «

4.8

10% Pd '' C (OJgt «a solution of (3S. 4S) ~ 4- aztdu-3-fluoropipefidinn · -terebutyl t-carboxylate, 4.4 (fl.4g, 0.00163 moLí in EíÜH (600) was added mL), The reaction was placed under a tic hydrogen atom (40 psi pressure) for 16 h. The mixture was filtered through an edit bed and concentrated down, reduced pressure to obtain the title compound (3 $, 4SP 4- arnroo-3- fluoropiperidine-i-reneburyl carboxylate, 4.6 (d.4g, crude).

The product obtained was taken for the following reaction without any purification., After conversion of 4.6 with 6- bromo-4- chloro-7- iluoro-3- nirroquinoisae according to the procedure detailed above in Step-1 , 4 - ((6- bromo- 7- (profit-3-nitroquinobu-4- ii) amino) -3-fiuoroptpettdifta-I-carboxylate of (3S, 4S) - tetragonium with identical analytical data to those indicated above was obtained (for example, HPLC, quino HPLC and tCMSj;

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Table L2

.......... τ

Ejenrp what

Structure

IH NMR, LCMS, HPLC, rt and fnétod

ICSOpM and Cascade; &lt;* BPL MEK1 i

LA, N. .,OR,. ! Í ”Ύ ''

<td></td><td>i Ή NMR (CDCfi, 400MH2):</td>

<td>OR</td><td>6 9.33 (s. IH), 8.65- 8.64 (d, i</td>

<td colspan="2">......... í ^: .....&gt; í</td>

<td>, .r</td><td>2M). 8.08-8.05 id. 1W), i</td>

<td colspan="2">X ..... riLeWLLyyyyó and ' _:...... ...............................</td>

<td>.. ... Ci v / 6: W 5¡w</td><td>! 8.00- 7.8? im, IH), 7.5L j</td>

<td>, XA&gt; and · 'Vy ·' · · \, ν</td><td>! 7 30 (m, 2H), 7.30- 7.28 |</td>

<td></td><td>i (dd, iHi, Ti5-7. i 3 (ro, ii Hi), 5.65-5.25 (ro, IH), |</td>

130 do not.

IB '-Wi

.. · * χ. · 'Ί *^Λ,&lt;. ·: £ * '.! ·. s »· x« ¡4.96-4.75 (m, IH), 4.35- i | 4.15 (ni, 2H). 3.92-3.74 (m, [¡2H). 3.35- 3.i5 (m, 1H)&gt;

[3.95-2.85 &lt;¡r ». 2H), 2.80 (s,

3H). 2.45-2.15 (ni, 2H); LCMS: 97.59%, m / z- 565, í (Mil): HPLC: 98.80%, rt: 3.61 min. Column: ZORBAX XDB C1S, nor icro (4.6x 150mm); Chira! HPLC; 95.97%, rt21.3;

Roni

Column: ADΛΗ CHIRA 1 ΒΛΚ

H / 03.

^TH''ÑMRfCDCh ”400MHz):

9.52 (3. IH), 8.65-8.64 (d,

2H), 8.98-8.05 (d,! H),

7.95 · 7.86 ith, IH), 7.50p, 40 (tn, 2H), 7.31- 7.28 j (m, IH), 7.15- 7.13 (m.

| IH), 5.65- $ .20 (m, IH),; 4.95-4.70 (m, IH), 4.25i 4 15 (m, 2H). 3.90-3.70 (tn,

2H). 3.35-3.15 (m, ÍH) J 0.138 3.01-2.85 im, 2H), 2.80 (s,

3H), 2.45-2.15 (ni. 2H);

LCMS; 99.77 '%, m / z ~ $ 64.90 (MM); HPLC:

97.14%, rt: 3.6 5 ruin., Column: ZORBAX XDB Ci8, 5micro í4.6xi50niín);

Chira! HPLC: 97.23%, rt8.53 min .. Column:

^:L

131

<td></td><td></td><td>ACLCÍ-Ü PALPAR. ΑΓΑ H / 0.3,</td><td></td><td></td>

<td>; &lt;ssssss: s one...... It; -....... I :. eleven</td><td> ; _:ll ^: llu22211111 llll^{H H}^ (1 1 &amp; '1, 2 i:^:: · :) 1 i</td><td>Ή NMR (DMSO- A „ 400MHz) 6 9.21 (s, IH), 8,? 3 id, 2Hk 8.42-8.35 (ni. H), 8.0? (d, IH), 7.73 (d, OD, 7.67 (d, IH), 7 43 (dd, 113.), 7.31 (t. 1H), 4.85-4.65 go to. IH), 3.16 (s, 3.HL 335- 3.02 (ra, 3H)_F 2.77 (s, 3H), 2.68 (t, 2H), 2.34 (t. 2H), 2.32-2.22 (ra, 3H), 2. ¡ΟΙ. 95 (ra, 211): LCMS: 90.4.1%, m / z- 547.10 (MM): HPLC: 96.15%. rt: 3.01 rain.</td><td> 0.726</td><td>7 P /))_:) ^: 7 / (A //) i '(lili: _:</td>

<td> 3</td><td>do not_: the,_FV "_T- * r “V &lt; , s A I! and!</td><td>'H ÑMR (CDCL,' 4Ó0MHz): or 9.26 (s. IH), 8.63 (d, 2H), 8.35- 8.2? anger, 1H), 8.04 &lt;d, IH). 7.56 id, IH). 7.50 (d, IH). 7.30 (dd, IH), 7.14 (i, LH'k 5.13-4.90 (ra, IH). 3.71-3.52 (ra, 2H), 3.25- 336 im, 2H), 2 83 ís, 3H), 2.69-2.50 (ra, 4H), 2.41- 2.29 (m, 2H), 2.32-199 2H): LCMS: 100%, ra / z- 533.4 (MM); HPLC: 97.69%, I laughed: 5.54 mi ».</td><td> 0.104</td><td>(lililí)</td>

<td> 4</td><td>\\-X ΐ ........ &lt;....... :%_: N-'/W-'V ........................... &lt; ' O%_:^:| o ^........Ί .« ¡~ ,e -—\ / í ? r i na A-V</td><td>&gt;H ÑMR (CDCS,, 400MHz): 6 9,26 ís, í H), 8,64 (d, 2Ht, 8 04 (d. IH). 7,55 (d, !H). 7..50 (s. IH), 7.29 (d, 2H),</td><td> 0.309</td><td>)%) )/3333 ) &lt;AA-A™AA^:&lt; 3:</td>

132

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4Ηι, 2.99- 2.79 (m, 6Η), 2.6* Η. 3Η), 234- 2,22 (m,

S 2Η). 2.58- ¡.85 áte 2Η), | i.45~ 0.90 (m, 4Hi: LCMS: ΐ 97,45%, m/z- 573.6 (ΜΉ); | HPLC: 96.81%, rt: 3.58 mín.

’ΪΓ NMR’“(DMSO- í4 400MHz): δ 9.20 ís. Hí), 8,71 (d, 2H), 8,55- 8,4? (ni, Hí), 8.06 (d. IH), 7.74 (d, IH), 7.61 (s, 3Hí, 7.4 i7.32 áte 2H), 5,45- 53.3 (m, iíi), 3,85- 3.7? ím, 2H), 3.09- 2.92 (m, 2H), 2.89 (s, 3H), 2.79 (s, 3H), 2.35-2.17 áte 4H) ; LCMS; 98.33%, m.ré~ 567.4 (M+i); HPLC: 94,22%, te 6.80 min. H'NMR'(C^b”4Ó0MI-k); δ 9.27 {s, l.H), 8.64 (d, 2H), 8.26 (d, IH), 8.06 (d, IH), 7,6 i - 7,48 (m, 2H), 730 (d, Hí), 7.13 (L LH), 535- 5.22 (m, IH), 5.02- 4,92 fm, 1H), 4,59- 4.50 (m, IH), 4,093.98 (ni, IH), 3.81- 3.72 (m, 1HL 3,38- 3.2.5 áte IH\ 2.92- 2.82 &lt;m, 3H), 2,80 (s, 3H), 2.41- 2.2.2 áte 2H), 1.34 (s, 3H); LCMS:

j 96,69%, m/ZF 56L5 (ΜΉ);

0.04

0,062

133 ^SV' -X;- ' Sí, · ν' \_.P \9-S · . _x»· V \ X; . ,/W¿ jv

HPLC: 95.29%, «; 3.37 min.

Ή NMR (DMSO- 4. 400MHz): ó 9.20 &lt;s, IH), 8,74 id, 2H). 8.06 id, IH). 7.75- 7.68 (m, 1HL 7.67'/.62 (in, I H)„ 7.43- 7.3:3 (m, 3H). 4.30- 4,59 (m, IH), 3.67- 3,48 (m, iíí), 3.25i 2.99 (nt, 4H), vx

3H),

12.35- 2,18 ím, 6H), L30.2 i (m, 3H): LCMS:

ΐ 92.41%, m/z- 547.2 (MH):

HPLC: 96.85%, ft: mi».

3.43

0,468

H NMR {CDCb, 400MHz};

^! 6 9,2? (s, i H), 8.64 (d, 2121, | 8.26 &lt;%, IH), 8.Ü6 (d, IH), i 7.59 (d, i tí), 7.49 (s, IH), ⁵ 7,33- 7.3C (dd, IH), 7,16723 (m, IH), 5.20 (m, IH), 423 (d, 2H.i, 3 15 (m, 2H)&gt; 2,84 (s₍ 3H) 2.58 (bs, 212), 2,30 (bs, 3H), 1.03 un, 4H); LCMS· 99.23%, m/z592.95 (M 4-1); HPLC:

9722%, ri. 3.84 min.

^Ύΰ.......iolDM^rx

400MHz): 8 9.20 ($, 1H), i 8.72 (d, 21-1), 8.46 (d, 3H).

¡ 8.06 (dJH), 7,73 id, ÍH), 7.63 (s, IH), 7.36- 7.3O (dd, 2HX 5,3 U ro.lH), 3.85 (d, í

0.0 i 5

0.103

134

--Á P

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..οΛ.-'X pH;733T(^2Hy¿2yí(s7| .......

I 3H), 2.19(tn, 2H), 2 30 (bs, | ¡ 3H), 5.35 (s, 6H); LCMS:

96.70%, iw’z-- 595.00 (M+L); HPLC. 92,43%, rt: | ί 3.99 min.

(CBCb^dOOMBzjr]..............

S 9.27 (s, i H&gt;, 8.64 (d, 2H),

8,31 (bs, HTí 8.06 (d, IB), i 2.57 (d, !H), 7.50 (s, 1H), ¡7.32- 7.30 (dd, IB), 7.16 | i (dd, IB) 5.23 (m, IB), 3.99 | 0.213 I (d, 21-1), 3.07 (bs, 2H), 2 84 ί (s, 8H), 2.20 (dd, 2H), 2.30 i (bs. 3H.K LCMS: 99.20%. i m/&gt;= 595.95 (MU): HPLC:

Lj ) j 98.14%, rt: 4,104 mi», ] M NMR (CDCIj, 4O0MBz): ί δ 0.28 (s, I H). 8.64 (d, 2B», ¡ 8.46 (bs. 1H), 8.06 (d, 111), i 7,52 (m, 1H\ 7.49 (s, IB), | 7.30 (d, IH), 7,13 &lt;m, 1H), ¡ 4.83 íro. 1H), 3.91 (s, 2H&gt;, í ' 2 35 ί 2.91 (bs, 4H), 2.85 (m, 5H), ¡ 2.58 (bs, 3H), 2.16 (bs, 2H).

¡ 1.25 (s, 1H), LCMS; ί 98.22%, m/z- 560.35 i (ΜΉ); HPLC; 97.56%, rt: 2,594 mm.

<img file="CU20160020A7_D0057.tif" />

H NMR (CDCh, 400MHz):

S 9.27 (s, IH), 8.63 (d, 2H), 8.27 (d, IB), 8.06 (d, IB), i 7.61- 7.53 tro, IH), 7,49 (s,

0.212

135

Η-Ν

ν.ί.Ν— Q 'ÍN'-W:

ΗΟ,

P~\ i .μ. .o. ,,. ,ςΑ--\ / ί &lt; Ϊ ^: Τ | : Α\ &lt; ,. Χλ &amp;, &lt;*.·· Λ Ν i ÍH), 7.32 id, 1Η), 7,12 (t I I Η). 5-33- 5.15 ím. i Η), | 4.99 id., ΗΤ&gt;, 411 (d, 1 Η), i 3.39- 3,26 (m, 2Η), 2.81 (s, ^! 3H,k 2.80- 2.69 Cm, 2H),

2.41- 2.25 2.18 (m,

3H); ÍXMS, 93.09%, (m'z~ ,531.4 (M-H); HPLC:

95.6?%, rt: 3.55 min.

Ti NMR (CDCb, 400MHar $ 9.51 (s, 1H), 8.89 id, IH). 8,8í (d, SH), 8.06 (d, ÍH), 7.58 id, 1H), 7.47 id, IH), 7.30 {d, H-b, 7.28 (d, IH), 7 19 (t, 1 H)_: 4.62- 4.5 i (m, IH), 3.21- 3.07 im. 2H), 3,05- 2.9? ¡m, 2H), 2.822.96 (m, 2H&gt;, 2.78 (s, 3H), 2,62- 2.46 (m, 2Ht. 2.051,92 (sn. 2H); LCMS: 99.57%, m/z- 546.6 (ΜΗ); HPLC: 96.97%, rt: 3.03 min.

VÑmFcCüc1₃. 400MH2): &lt;5 9.28 is, IH), 8.6? (d, 2H),

8.25 (d, IH), 8,05 (d, IH), 7,51 id, 2H), 7.32- 7.30 (m, IH), 7.15- 7.13 fm. ÍH},.5.6 (bs, ÍB), 4,98- 4.95 (m, IH) 4,22- 4.19 (m, 2H), 3.83 id, 2H), 3.50 id, IB),

3.26 &lt;d, ÍH), 2.90 is, ÍH), 2,81 (s, 4H), 2,34 (dd., 2H);

0.515

0.0071

136

LCMS: 99.8%, m/Y 547.4 (MH); HPLC: 95.8%. ri; 3,36 min.

VNA^CDCOWMÍfe):r hq:

<td></td><td>δ 9.39 (s, IH), 9.15 G, IH), 8.42 (d, IH), 8.33 (d, IH), I</td>

<td>.., γ$Χ\·ζ f f</td><td>8.06 |d, ÍH), 7.53 (d, iH), | 7.46 (m, ÍH), 7.2.6- 7.24 (dd. IB), 7.01 id, IH), 3.49</td>

<td>z». ’ ^4-** ,Í4 \,„</td><td>(s, 2HX 3.32 (m, 2H), 2.95 0,016</td>

<td>..i.. ¡1¿. '•.ZW^v·'’</td><td>(s, 3H), 2.8i (hs, ÍH), 2.57</td>

<td> Z''</td><td>(s, 3H), 2,50- 2.4? (m, 3H),</td>

<td></td><td>2.08 (d, 2H). 2.0 ís, 3H);</td>

HO,

A''', η

X. ,&gt; ** ,1

KO.

*·'* \

Y '}

X\:..&lt;h %·«Α.' Ζ3$&lt;

li 'I

LCMS: 97.08%, mY 547.2 (M-H); HPLC: 99 6%, rt:

3,61 min.

“ÍH NMR ÍCDCh, 400MHz):

9,27 (s, IH), 8,64 (d, ¿H),

8,33- 8.25 (m. i H), 8.05 (ti, ’H), 7.57 (d, ÍH), 7,52 (d,

1H)_? 7.32 «id, ÍH), 7.i4 (t,

IB), 3.89' 3.82 (m. IH),

3.50- 3.45 (tn, IH), 3.29 (d, ! 0.059 ÍH), 3.10 (d, .iH), .2,84 (s,

3H), 2,61- 2.50 (m, 2H), _f2.43- 2.i3 (m, 6H), i .14 (s,

3H) ; LCMS: 99,31%, nCz547.05 (M+i); HPLC:

90.33%, rr 5.89 mi».

^TH NMR (DMSÓ-” ΐξ ,400MHz): 6 9.33 ís, iH),

9.29 fbs, 5H), 8.73 (m, 3H),

8.08 (d, ÍH), 7.64 (dJH),

0,093 &lt;*7

7.46 (dd, IH), 7.26- 7.34 (dd, 2H), 4.32 (ro, IH), 3.ÍS- 3.14 (q, IH), 2.88 (ro, 4B,¡. 2.SO (:&gt;, M-l), 2.42- 2 30 (ro, 2Hs. í.99 id, 2H)„ 1.92 (ro, 2H): LCMS: 99.71%, ro/z- 533.7 (MH); HPLC: 98,32%,rt: 5.77 min. VHMR (CDCb, 400MHz):

δ 9.37 is. IHs, 9.0Í (s, ÍH), 8.42 (d, IH). 8.32 (s, IH), 8.03 (d., IH), 7.43 (d&gt; ÍH), 7.00- 6.95 (ro, 3H), 3.83 {% 3H). 3 38 (t, 2H), 2.96 (r, 2H), 2.71 (ro, IH), 2,58 (s, 3H), 2.56- 2.48 (ro, 5H), »¡o.

,5 -·νγ· &gt;&gt;:· _κγ χ \«-ΐ&lt;. .Χχ, γ ‘^r -γ 'Ν'

<td></td><td></td><td>**· ·· .-.· &gt;*♦*·/&gt; y * ' *·/&gt; LCMS: 99 41%, «Lz- ¿43.W+H, HPLC: 90.90%, rt: 5.7 i mi».</td>

<td>hPPP........1|(</td><td>^¡o</td><td>ΪΙ ÑMR (CÓCk 400MHz): δ 9.37 (a, IH), 8.95 (s, IH), 8.64 (d, ÍH), 8.32 (s, IH), 8.03 (d, IH), 7.45 (d, IH), 7.2? (s, !H), 7.i4 (t, IH),</td>

<td></td><td rowspan="2">^:: 7YY PP · ( : ......... .......................... ,Ρ·^^ΥΡ_:. JP A IB iiii. .....O-X........., O</td><td>7.01- 6.91 (ro. 2H), 3 83 ($, 3H). 3.49- 3.39 (ro, 2Π).</td>

<td>ppp........... P</td><td>2.99- 2.88 (ro. 2H), 2.79- 2.55 (ro, 4K). 2.55 (í, 2H),</td>

j 2.25- 2.15 (ro. 2H), L99 &lt;s, ¡ ' 3H&gt;; LCMS: 90.51%, m/z- | $29.4(M9-H; HPLC; ¡

98.02%, rt; 5,66 min. '

138

Htí

ÍN·* &lt;

Ά,'^Ν : ,JLX,J ⁷HNMR (CDCIj,dOOMih): 5 9.37 (s, IH), 8.50- 8.4S (m, 1H), 8,43 A iH), 8.28 I (d, IH), 8.05 A IH), 7.43 A IH), 1.01- 6.95 (ni, 3H), 4.46-4,39 (re, IH), 3.82 ('$, i 3H), 3.71 A 1.H), 3.523.43 (tn, 3H), 2.92- 2.69 {tn, 2H), 2.57 (s, 3H), 2.552,50 (in, 2H), 2.06 (s, JH), 1.34 A L5H), 1.17 A i.5 tí):; LCMS: 94,08%, m/z- 571.7 (M+ί); HPLC: 99.42%, rt: 4 03 min,

15?

'ÍjA' _:,,.o

O

\....&lt; HÓ fCC í -íí,

F

- Π ''f'' Vy··' '-^C

1A J

x.:·· ·χ&lt;

Ή NMR (CDClj, 400MHz): S 9.4i {$, IH), 8.46· 8.39 {tn, 2H), 8.29 (s, IH), 8.10 A HH, 7.53- 7,49 (m, 2H), 7,30 (d, IH), 7.01 (d. íH), 4,49- 4,40 A&gt; IH), 3.813.80 {m, 1H), 3.79- 3.69 (re, )Hi, 3.S9-- 3.45 (tn, 2H), 2.83- 2 67 (re, 2H), 2.57 ($, 3H), 2.43- 2,35 (re, 2H't, 2.50 (s, 3H), 1,39- 1.28 (re, 3H); LCMS: 95.93%, re/z 575.4(MfJ); HPLC:

97.48%, rv 4.42 min.

0.028 o

¡ííi- % no9 -\ .8 ,0, -·. ,0^—'^J ' í-AAf &lt;........^. ..

Sí , i g- U λ . .. a n s ..&lt;‘9 K-X' '•-a ..••'•N .'.Av/

H NMR (CDCh, 400MHz): ί δ 9.2? (s, f H), 8.65 (d, 2H&gt;,

8,28 (s, IH), 8.05 A ΠΙ), 7.60- 7.46 A, 2H), 7.30 (d, IH), 7.16 (s, 1H)_: 5,48-5.23

1.346

139

<img file="CU20160020A7_D0058.tif" />

nor'\

ΗΟ''

<img file="CU20160020A7_D0059.tif" />

(ra, 111), 5.12-4.97(10, 1Η), 4,88- 4.65 (ra, 1 11), 4.40» 4.24 (ra. 111). 4.10- 3.71 (ra, 3Η), 5.48- 3.00 (ηι, 511), 2.80 (s, 4Η), 2.48- 2.29 (ra, 3H); LCMS: 99.45%, ra/r= 591.05 (MM); HPLC:

98.66%, rt: 3.13 rain.

Ίϊ ÑMR(CDC^ 4Ó9MRZ):’ δ 9.28 (s, 1.H), 8.66 (d, 211), 8.05 id, 1H¡, 7,69- 7.57 (ra, ÍH), 7.52- ?.48 (ra, !H),

7.32- 7.26 (ra, 2H», 7.217.15 (ra, IH), 4Jó- 4,10 (ra, 1H), 3.79- 3.62 (ra, 411), 3.56- 3.44 (ra, 3H), 3,343, .15 ira, 5H), 2.89 (s, 411),

2.32- 2,18 (ra, 411); LCMS: 98.29%, m/z= 576.85 (MM); HPLC: 98.61%, ± 5.56 rain ⁷HÑMR (CDCL, 490MHz): δ 9.38 ís, 5 H), 8.48 id, Π1), i 8.43 id, IH), 8 39 (s, ÍH), | 8.95 (d, ÍH), 7,40 (d, IH), | 6.99- 6.95 (ra, 311), 4.20- i 4.10 (ra, 211),4,01-3.94 (ra, | IH), 3.81 &lt;s, 3H), 3.73 (t, IH), 3.63- 3.52 (ra, IH), 3.45- 3,32 ira, 2H). 2.93- j '2.82 (ra, 2H), 2.57 (s, 3H), ¡ 2,35- 2.25 (ra, IH), 2,252 16 (ra, IH), 2.97 (s, 3H);

0.31

<img file="CU20160020A7_D0060.tif" />

0.021

140 ’Χ.. : .

%/' m-\ : / 7 ' X ,N_S ..Ó_x ,.Cl -Ά / í r .) n

- N , |·ψ ζi . ..-,. ,í,: *-C.

γ }{ V &gt;, *-~

W*' '' SíS -χΑ

LCMS: 97.44%, nv¿ - 557.3 (M-t-h; HPLC: 94.48%, rt: 3 .90 min.

^NMRCCDCb^dOOMHz); 6 9.24 (s, iH), 8.63 (d, 2H), 8.32- 8.18 ím, IH), 8,01 (A !H), 7.58- 7.48 (¡n, 2H), 7.3{- 7.2? (nú iH), 7,i2 (í, sHi, 5.03- 4.85 (ro, Bí), 4,84- 4.68 {πι, 2H), 4.444,26 (m, 2H), 3.30- 3,32 ím, iH), 3.06- 2.84 (m, 2HL 2,88- 2.67 (m, 6H), 2.582,32 ¡m. iH), 2.39- 2,02 (m. 4HL LCMS: 53.64%, m/z559.35 (M-M); HPLC:

98.77%, rt: 3,39 min.

Ή NMR tCDCh, 400MHz): 6 9,41 (s, iH), 8,47- 8.40 (m, 2H), 8.32 (5, IB), 8.09 (d, H-j), 7,49 (A IH), 7.46 (s_t iH). 7.29 (dd, IH), 6.99 (d, IH). 4.30- 4.20 (m, IH), 4,16 (d, iH). 4.03 id, iH), 3.73 (6s, Í .H.), 3.56- 3,30 &lt;m, 3H&gt;, 2.90- 2.79 (m. 2H), 2.57 (s, 3H), 2,32- 2,19 (m, 2H), 2.08 (s, 3H); LCMS: 99.11%, m/z- 56i.2 &lt;M+i); HPLC: 99.47%, rt; 3.83 min.

0,655

0.0043

2(3 /1/

141 _X,..N

Ν'*’* ' S. ·· '' ·,ζ··' % ^N '

Jl,

Λ®

9\ «Βγ %,·Ν

................................ ....... 7ÉBI' ηό 9\ ^: ’Η NMR. (CDC1.;, 400MHz.);

§ 9.42 (&gt;, 1 Η), 8.6x6- 8.65 {&lt;!, 2Η), 8.45- S.40 Cd, 1Η&gt;. 83 lis,Π·ί), 8.15- 8.1 OiJH), } 7,55- '7.50 id, 2Hs, 7.35i 7,30 Id. iH). 7.20- 7.10 (i.

Hí), 4.50- 4.40 (t, !H),

3,90- 3/0 (m, 2H), 3.643.45 ím, 2H), 2/0- 2.0 (m,

2H¡, 2.45- 2.30 (bs, 2H),

2.09 is, 3.H), 1.40- LIS (dd,

3H); LCMS; 93.23%,

561.4 (M-H); HPLC:

98.04%, rt: 3,07 min.

H NMR (CHCÍqΙΟΟΜΪϊζ): δ 9.26 (s, ΗΪ), 8.43 (d, IH), 8.?A (d, IH), 8.04 id, IH), 7,48 (d_t 5 H), 7,30- 7.25 {m, 2H), 6.98 (d, IH), 4.994.90 (m, IH), 4.i9 (d, SH), .3/6 (d, SH), 3.31- 3.! 9 (ro, 2H), 2,95- 2.79 («i, 4.H), 2/9 (s&gt; 3H), 2.55 (s, 3H), i.89- 1,70 (rn, 2H); LCMS; 87,67%, m/s- 561.) (M+d); HPLC: 99.2986. ri; 2.57 mit).

Ύί NLÍR/O'HCís, 400MHz)⁷δ 9.26 (s, SH), 8.43 (d, 1H), 8.26 id, IH). 8.05 Id, iH), 7,50 (s, 2H). 7.30- 7 26 (m, iH), 7.98 (d, SH), $.35. 5.20 (ro, i H), 4.98 (d. ÍH),

0.073

0.003

0.0 i 9

142 η_?ηN--\ i 30 íb«··

N ,fi, .:- ,C¡ -.- ;/ ,-.-' /

j.:

,N f ^s-^'' 'fi* ! 4,60- 4.49 (W.ÍHX 4,113.93 (m, IH), 3.85- 3.69 (m, ÍH), 3.39- 3.20 (m, IH), 2.95- .2.82 {jn. SH&gt;, 2.80 (s, 3H), 2.56 {$, 3H), 2.-42- 2,22 (m, 2B). 5,72- 1,59 (m, 2H), 1,42- 1.29 (m, 3H); LCMS: | 90.37%, m/z- 575,03 | (M+5); HPLC: 95.0434, rt: | 3.74 min. i ⁷h ”NMR (DMSO- ¿o 30054Hz): 6 9.20 &lt;s, 1 H)_s j 8.71 td, 2H). 8.40 (d, 1 H). [ 8.05 id, IH), 7.75- 7,59 (m, j 2H), 7.4i (d, 111), 7.36 (í, ( IB). 6.i9- 5.92 fm, IH), 5.90- 5.65 (m, IH), 5.41! 5.15 (m, iHt, 5.10- A79 (m, IH), 4,19 (d, 2.H), 3.012.85 (m, 2H), 2.77 (s, 3H), 2.22- 1.85 (m. 3H); LCMS: | 99.43%, tn/z=“ 532,3 (MH): j HPLC: 96.63%, n: 3.16( //:::/(7/:/1

HíífL |

Γ^;η“““νμε“75μ8ο“”£Π ' 400MHz): 6 9.39 (s, IH), | 8.51 (d, IB), 8.40 (m, IH)

8,05 (d, i H), .54 (m.

0.011

<td>: 2B).</td><td> 7,.</td>

<td>J 7 ·79</td><td>Id-</td>

<td>¡ 3B),</td><td></td>

<td> 1 4.20</td><td>(m</td>

<td>i ? ?7</td><td>(s.</td>

0.005

B), 5.10- 4.80 &lt;m, IH),

143 ¿ΤηV

-Λ.

”&lt;\4 &amp;Τ~',

y. ..........j &lt;Υ _Á..-s-k

2,50- 5.90 (rn, 3H); LCMS: I 99.6%. m/z ~ 546.5 (Mt-l); HPLC: 96.6%, :1: 6.26 rntn. ^ΜΜδηαΓ4(Μ)ΜΗ2);· δ 9,52 (s, IH). 8.64 (tí, IH), 8.55 (tí, ÍH), 8.22 (tí, IH), 7.78 td, IH), 7.63 (s, L4). 7.40 (s, IH), 7.26 (d, IH), 3.89- 3.85 (m, Hi), 3,793.50 (m, 4H), 316- 3.02 (m, 2H)_S 2.99- 2.80 (m, 2H), 2.88 (x, 3H), 2,48 (s, 3H)« 2.45- 2.20 (ai, 3B&gt;; LCMS: 96,64%. ro/z= 58LI(MH); HPLC: 96.81%. rt. 2.68 m·

VÑMR ÍCDCb, 400MHz):

............. ' ¡ δ 9.43 (s. IH), 8.67- 8 66 (d, ) 2H|, 8.44- 8,42 (d, IH), 1 8.33 (s,lH). 8,52- 8.) | (d,SH), ?,Si- 7.49 (in,2H), 7.32- 7.27 (dd, IH), 7,177,15 ¡L ¡H), 4.21- 4.56 (m, 2H), 4.08- 4.04 (d, 5H), 3.71 ís, IH), 3,60- 3.S0 (

0.03;

0.028

1.H), 3.44- 3.35 (m, 2H), 2.86- 2.83 (fes, 2H), 2.282.24 (t, 2H.t, 2.09 (_s, 3H); LCMS: 99.69%, m/z- S47.0 LM+5); HPLC: 99.06%, rt:

't') m m.

444

<td></td><td colspan="2">í Ó'LNMR (CDCL, 400MHZ); ¡</td><td></td>

<td></td><td>| d 9.27 (s, IB), 8.64 (d, 2H),</td><td></td><td></td>

<td></td><td>ί 8.27 (d, Bf), 8.06 (d, IB),</td><td></td><td></td>

<td></td><td>| 7.59- 7.49 (ro, 2H}&gt; 7.31 (d,</td><td></td><td></td>

<td></td><td>| IH), 7,14 (5; 1H), 5.45- 5.33</td><td></td><td></td>

<td>o</td><td>i (ro, IHi, 5.03- 4.93 (ro, IH),</td><td>, ls ;||7 :</td><td></td>

<td> •^4·.</td><td colspan="2">¡4.61- 4.52 (ro. IB), 4.12-¡</td><td></td>

<td>^Bv í /</td><td>| 3.98 tro, IH), 3.79 (d, IB),</td><td> 0.088</td><td> 1</td>

<img file="CU20160020A7_D0061.tif" />

-&gt;

:!- -‘ fS

XX •ί \·-\

ΗΟ ’ \ , _πχχ ’&lt;' ΐί ?&lt;

··&gt;_.· ίχχ &gt; .........7;.........7;......... ......7 7 Χ*\ ........

: )' ^: £ : Β ^:WteS^Si^;7^:7; W· N Λ. ·-&lt; .Λ ·&amp;:

νυΰ

3.40- 3.25 (;r, IB), 2,952,83 (m. ¿H). 2.81 (s, 3H}„ 2,¿5- 2.33 (ro, 2B), 1.491.31 (ro, 3H). LCMS; 98,63%, m/z“ 561.4 (Mi l); HPLC: 96.79%, rt: 3.38 rom.

ΊΪNMR fCíX' b, 400M1 &amp;):

S 9,2? (s, IB), 8.43 id, IH), 8,0? (d, IB). 8.06 {d, Bí), 7.60· 7.51 (ro, 2H}, 7.307.26 O;n, IH), 7.00 id, IH), 5.59- 5,29 (ro, IB), 4.104.00 (ni, IB), 3.80- 3 30 &lt;tn, 2H), 2.90- 2.60 (ro, 2H), 2.81 (s, 3H), 2.56 ís, .?H), ¡

2.40- 2.10 (ro. 3B). 1.351.33 On. 4H): LCMS: 98.74%, ro.'z^ 575,60 (M+l); HPLC: 90.71%, rt: 3.50 min.

IH ÑMR íCOCÍs, 400MHz): δ 9,25 (s, IH), 8,41 id, IB), 8.02 (d, IH), 7.54 (d, IH), 7,48 (d, IH),

145

,.'&lt; ,·&lt;;·χ. ·:ί·' ? χ-·· '#

Ο

Ηΐ^ί ^fcr~\

..u. ,ο,. . ,ο?-·'\7 !i % ϊ·' Y ' ^-¾ ,¿ .X·· .·.-s, .-Λ,. .fl

7.39- 7.24 im, 2H\ 6.98 (d, !H), 3.75- 3.30 ím, 3H), 3.25- 32 5 (m, 2H), 2.82 (s, 3H), 2.70- 2.59 ím, 4H), 2.55 (s, 3Hi, 2.42- 2.30 (m, 2H), 2.25- L90 ím, 2H); LCMS: 98.76%, 547.2 (M+i); HPLC: 95.40%, rt: 3,02 min,

H NMR {CDCb, 400MHz): S 9.39 (s, ÍH), 8.73 id, IH), 8.40 id, IH), 8.35 (s, IH), 8,05 (d, ÍH), 7.40 (d, IH), 728 (d, ÍH), 6.99-6.9! (m, 2H), 4.74 (s, 2H); 3.97 (tí, 2H). 3.81 (s, 3H), 3.25-2.98 (m, 4H), 2.56 &lt;s. 3HL 2.08 (s, 3H), i.94 (d, 2H); LCMS: 99,54%, r»/z= 542,4 ÍM2); HPLC: 982 5%, n: 3.30 min.

H NMR (CDCij, 400MHz): δ 9.38 ís, ÍH), 8,70 (d, IH), 8.61 (d, 2H), 8.34 (S, ÍH), ; 8.04 (d, IH), 7.4í (dd, IH), i 72 i (L IH), 6,95 - 6.90 (m, j 2H). 4.73 (a, 2H), 3,95 (d, | 2H), 3.81 (s, 3H), 3.20 (i, 2H), 32 ! - 2.94 (m, 2H), 2.07 (s, 3H), 1.96 (ti. 2Hg ; LCMS: 98,83%, «ν&gt; 528,3 1 (Mtl); HPLC: 98.7254. rt:

i 3.96 min.

0.0027

0,0046

146 ilg-j

0---.

jíN,

N~\

-s, ··'

V X Vhi·:.·

A ,x. ,J : -- 'fü

Mj!-y

0-4,

N'\ ,Ü, -O, ,C; / í y y v w-y, N 4 ·&gt;,/%,. ^íj^:·' y T η

HO ·.

on ií t sfX y-% ’U'v-ax/' e, Α-Λ J r '- «'

Ή NMR (CDCs₃, 400MJfe):

Ó 9,27 (s, IH), 8,64 (d, 2H),

8,27 id, 1 H), 8.06 (d, IH),

7,61-7.52 (ra, Π-í), 7.51(6,

IH), 7.32 (d. iH), 7.14 (t ¡

ÍH), S.3S- 5.16 (ra, 1H), j 5.15- 4,92 (ra, IH), 4,09-] 0.455 3.99 (ni, IH). 3.61 - 3.51 (rn, i 2H). 3.33- 3.20 ¡ra, 2HL |

2,81 (s, 3H), 2.41- 2.19 (ra, ¡

4H); LCMS: 95.70%, mfe~ |

546.1 (MM): HPLC; |

92.16%, ri: 3.39 rain. ;

•tf NMR (CDCIj, 400MHz): ¡ * 9.24 (s, IH), 8.42 (d, IH), ¡

8.25 (d, IH), 8.02 (d. IH), | 7,60- 7.40 (m, 2H). 7,30- ¡

7.26 (ra, !H), 6.97 (s, IH), i

25 is. Hí), 4.97 cd, IH), i

4.01 (d. IH), 3.52- 3.24 (ra, j 411), 2.78 (s, 3H), 2.54 (s, | 3H), 2.28- 2.02 (ra, 6H): | LCMS: 97,47%, rafe- 560.1 ¡ (M+I); HPLC; 95,25%, rt: ¡ 2.94 rain. ί i O.Í86

<td colspan="2">Ή NMR (DMSO- &lt;4</td>

<td>400MHz): 6 9.34</td><td>(s, IH),</td>

<td>8.68 fs, IH), 8.53</td><td>(6, IH),</td>

<td>8,44 (d, IH), 8,11</td><td>(d, IH),</td>

<td>7.67 (d, IH), 7.60</td><td>ís, ÍH),</td>

<td>7.3? (d, IH), 7.23</td><td>(d, IH),</td>

<td>5 58- 5.48 (ra, i i-</td><td>I), 4.49-</td>

<td>4.38 (rn, IH), 4,15</td><td>(6, 2H&gt;,</td>

í 0 022

147

A ,Ν. ..Ο, γ

j, Ύ

S^'Sfíiíí

ÍT”\ te-te p -·- N

Pico I

4.12- 4.Oí im, IH), 3,983.87 (tn, ÍH&gt;, 3.82- 3.69 ?m, IH), 3.58- 3.43 Ote 2H), 3,23- 3.Í0 (m, IH). 2.812.63 Ote 2H&gt;, 2.47 ts. 3H}, 2,35- 2.15 0». 2H); LCMS: 97.48%, «-Áte 577 4 (ΜΉ): HPLC: 96.69%, rt: 3.55 mite

Ή NMR {.COCO, 400MHz):

S 9.25 ís, 1H), 8.62 (te 21.0, 8,29 te, IH), 8.24 id, IH), j 7.6Í- 7.46 áte 2H). 7.30 (d, IH), 7.13 (í, ÍH), 5,35- 5.16 Ote ΪΗ), 4.99-4.87 Ote IH), 4.30- 4.5 9 &lt;ro, 2H). 3,523.38 (m. 2H). 2.26 (s, 3H&gt;, 2.80 (δ, 3HK 2.41- L89 im, 5H); LCMS: 93.59%, nVz= 565.5 (ΜΉ): HPLC:

98.48%, rt; 3.63 jnin.

0.085 ’HNMR (CDCij, 400MHz): S 9.30 (S, IH), 8,06 (O, 2H),

8.31 id, !H), 8.10 Oí, !H&gt;, 7.55- 7,48 (m, 2H), 7.33 (dd, IH). 7.160, IK), 5.485.31 Ου, !H), 5.10- 4.95 (ι«_Λ!Hi. 4.52- 4.3í 0% Π-Ϊ), 3.38- 3.24 (m, Π4), 2.952.85 On, 2H), 2.83 Ύ 3Π), 2.50- 2.18 (ro, 3H), 1,701.49 Ote 4H); LCMS: 94.03%. máte 563.2 (M'^:);

0.06

748

HPLC: 97,94%, rt: 28,93

43B (S tfí sf/'d·' ;;;;

; .....^:C;.pY;

,W .0, .C: ---'·. /

ΡΪ........ _.................

C. .&amp; X. ,Y .·&gt;,. ..·&lt;·, .4

C,· ’ y -y -y «^Α·^:&gt;·A^:

Pico 2 mar,

WNírVCTXLYiOMHz)· δ 9.31 (s, IH), 8.65 (d₅ 2H), 8,33 (d, 1H), 8.i2 (tí, IH), ¡ 7.61- 7.49 (ro. 2H), 7.32 (dd, IK), 7.16 rt, IH), 5.455.17 un, IH), 5.04- 4.88 ítn, I i H), 4.50- 4.31 ítn, IH), 3,40- 3,22 fro. ÍH), 2.952.85 (sn, 2H ), 2,84 (s, 3H&gt;, 2.56- 2,19 (ro, 3.H) 1,721.S2 (m, 4H); LCMS:

98,75%, ro/z= 563,2 (ML HPLC: 94.64%, rt: 32.55 min.

0.541

i............I

<img file="CU20160020A7_D0062.tif" />

^:HNMR (CDCb. 400MHz); ó 9,31 (s, IH), 8.28- 8.1? |

Ún, IH), 8.05 (d, IH), 7.79 | {t, IH), 7.45 (s, IH), 7,28- | | 7,24 Os, 2H), 7,0? (d. IH), |

7.00 (d, IH), 5.08- 4.96 (tn, |

IH), 4.93- 4.77 ¡&gt;, IH), ) ΐ 4.75- 4,56 (rn, lií), 4.63- ! 0 002 í 4,54 (rn, ¡ H), 4.31- 4.21 (rn, i ¡ 2H), 3,86- 3.75 (m, 2H), ¡ ¡ 3.33- 3.21 (m, 2H), 2,95- | | 2.83 u», 3H), 2.8 í (4, 3H)_S |

2.18- 1.96 (tn, 2H): LCMS: | m/z- 83.62%, 576.45 (M~); | HPLC: 98.59%, rl: 3.58 i min, ::

149

<img file="CU20160020A7_D0063.tif" />

O 'n Λ : ^:Α^Κ Α ' Ρ'-ϋ;'· 'W u j ^{Λ χ}*'’ ^si&lt;

i ο « ο, ... ,eA-L ··

I * ν γ γ ν-3 ί % ..ν % Α, ,·ΐ, ,-L %

I I ί .3 .3

Γ 'ϊ

U...H _ν..·Ο

Ν” $ν 'Sto·' χ,Χ ·Ϊ4

Οϊ

- .·ί· .„, ’HNMR (CDCL, 300Mfe): |

9,26 (s&lt; I Η), 8,64 ¡d, 2Η), ¹

8.35- 8.25 (m, ΓΗ), 8.10 (d,

ÍH), 7,.59- 7,46 int. 2H),

7.5i (dd, ÍH), 7.15 (l, IH),

5.i5- 4.95 im, 2H). 4.30 (d,

2H)&gt; 4.02- 5.84 {&gt;, 2H),

3.10 (t, 2H), 2.82 (s, 3H),

2.54- 2.12 (m. 4H); LCMS:

94.8?%, m/z® 614.5 (M+I);

HPLC: 96.4656. rt: 3.64 min, '’íiNMR{CDCb“lO®»F 6 9 3; A ÍH), 8.56 &lt;d, IH) ,8.34- 8.Í4 (ra, 2H), 7.64- j 7,45 ím, 2Η'χ 7.32 (dd, 1H),

7.01- 6,98 (in, IH), 5,454,77 int, 2H), 4.4 í - 4. i 0 (m,

2H), 3.85 (d, IH), 3.473,29 (d. ÍH), 3.04- 3.87 im,

2H). .2,84 ís, 3H), 2,54- .2.00 ira, 4H); LCMS: 97.87%, tn/z= 565.45 (Mil); HPLC;

94,75% ,rt: 3.74 rain, ^ríiÑMR~......(DMSÓ-“.....&lt;£'

400MHz); δ 9.20 (s, IH),

8.54- S. !9 (ra, ÍH), S.Í48,03 (ra, 2H). 7,82- 7,66 ira, í

Π4), 7.59- 7.54 (ra. IH), | Q.Otíi?

7.36- 7.28 íraJH), LOO (d, |

ÍH). 6.98 (dd, IH), 5.48-|

5,24 (ra, Hi), 4.65- 4.55 (ra, ¡

2H). 4,16- 4,03 ira, 2H), ¡

0.191

0,0)

550

Μα

4$ _s. &amp;3 \ . :/ &gt;

;......... %\M su.. ·ί_:Ν-^..,&lt;

Vjs5%b&lt;fe&lt; :%%%,&lt;% ρ·' /Sí-- :_: u -%Ά ^:Ά ^&amp;.....

O¹).......luá®us;OY9rtA-l··· i : 5% i οι . ;M&lt; ¿O&lt; CG-t- '/ &gt; 9. x ' \

.........^.............. ....... ...../.Α,^::&gt;;Λ_χ^:&lt;.ν ..........

...... ; -«ν 'U&lt; -mu .........

3,97- 3.86 (m. 2H). 2.952,80 (m, 2H), 2.77 ís_; 3H), 2.28- 2 O i ira, 2H); LCMS: 98.13 %, nvz~ 564,2O (M-H); HP1C: 97.09%, rt.: 3,97 min.

^πΗΝ^''7ΰΜ8Ο-~''^“4ίΊ0 MHz): δ 9.18 (s, IH), 8,62 (s, IH), S.32 (s, IH), 8,05 (tí, IH), 7.78- 67 (m, IH), 7.63- 7.55 (m, IH}, 7,4 i7,53 (ra, ÍH), 5.50- 4.92 (tu, IH). 4.66- 4.54 (ro, 2H). 4.16- 4,02 (ra. 2H). 3,963.87 (ra, 2H)_t 2.96- 2.82 (m,

IH), 2,78 (s, 3HK 2,47 (s, 3H). 2.49- 2.05 Oh, 3H), LCMS: i00%. 578.9 (M): .HPLC: 97.87%, rt: 4.27 rain.

' HÑmF(CÍX?% 40Q.M.Bz): tí 9,31 (tí, ÍH), 8,68- 8,60 (ra. 2Ή), 8.34 (tí, 0.5H), i 8,12- 8.01 &lt;tn. ί 5H), 7.59 (tí, 0.5H). 7.54» 7.43 (m, j,5H), 7.37- 7.30 (m, IH), 7.18- 7,11 (m, IH), S.695,16 (m, 2H). 4,99- 4.61 ftn, J 3H&gt;, 4,37- 4.25 (ra, O.SH), ¡ 4.01- 3.88 (m, 0.5H), 3.50 | (tí, IH), 3.03- 2.90 (m, 2H), ¡

2.88 {s, 1.5H1, 2.81 fs

0,011 bb.....;.........

¡ 0232

...........

1.5H), 2.50- 2,33 (m. 1H)_; Ϊ

L™.

151

<td>fo.............SS: ^/ ........1L1 7.......;fo77fo^:</td><td></td><td>2.22 (s&gt; L5H), 2.07 (s, Í.5.H); LCMS: 90,24%. rafe- 608.45 (M+l); HPLC: 90 76%. ¡r 4.52. rain.</td><td> ;.....</td><td></td>

<td>7 ΐ : fes .........</td><td>ií/ /“W/·- &lt;///_:........ .........7;s· f-S'¡e ;ss s&lt; ....................fo &gt; Wfo- /fofeofofo J 7SSS V- fofe-fo</td><td>’IÍNMR «CDCl·., 300MÜz): S 9.29 (d, IH), 8.65- 8.56 (m, 2H}„ 8,31-8. í 8 (ra, 3H). 8.12- 8,02 (m. IH), 7.60- 7.41 (rn. 211). 7.35- 7,28 (ra, IH), 7.20- 7.17 (ra, IH), 5.00- 5.20 (ra, L5H). 4,75- 4,5? (_m&gt; Q.SH), 4,47- 4.33 (ra, IH), 4.13-4.00 (ra, IH). 3.09- 2,95 (ra, 2H), 2.96 (fe 1,5H), 2.89 (s, L5H), 2.7? (s, 1.5.H), 2.71 (s, 1..5.H), 2,65- 2.50 (ra. IH), 2.43- 2,15 (fe, IH); LCMS; 97.71%, rafe- 585.1 (Mfe HPLC: 98.58%, rt: 3,83 rafe.</td><td> 0,01.2.</td><td>fe//i'/7/ 7</td>

<td>fe w -fo ' 7 7 7 .............. 7 i SI</td><td>.....Lfo^sl/ó·....... ..........7/.............................(;Ofo7J7..............fo......_rVw«^v'W fe* WA» s?\ .A A ^//// //fo r '.C _N-</td><td>’HÑMR (CDQj, 300MHz): 5 9.32 (fe 113), 8.85 (d, IHfe 8.08 (fe 2H). 7.95- 7.87 (m, ÍH), 7,52 is, IH), 7,46 (fe H¡}_; 7.32 (dd, ÍH), 5 60- 5.20 (ra, 2H), 4.05- 4,68 ira, IH), 4.20- 4.05 (ra, IH), : / : . 7'77 7&lt;7 7 7 7 77 7 : . 7 /7 777 3.84- 3.20 (ra, ÍH), 3 40- 3.16 (fe, 2H), 2.98- 2.82 (ra, 2H), 2,79 (s, 3H.1, 2.43-2.13 (ni, 2.H): LCMS: 94.03%, rafe- 633, i (Mil); HPLC:</td><td> 0,001</td><td>/fe/|7 //fo ...... ....... .)</td>

15.2

97, ί 6%, rt; 4.17 mm.

<td></td><td>Wr (bKí$(\ «C : 300MHz): 3 9.21 (d, ÍH), i 8.80- 8.56 fin. 2H), 8. L5- ; 7,95 (ro, 2H), 7,78- 7.48 (m, § 2H). 7,44- '7.24 (ro, 2H),</td><td>P 77 7 Jfi )..........P&lt; 7..... ......PllPPPPPPPrP?: &lt;; P ...................i|p| !^M....................1 1 1í^:......1</td>

<td>o ? h~\ ., f : ?' ’' '</td><td>i 5.7í- 5.0? (ro, 2H), 4.95- ΐ 4.78 fin. iH). 4,55- 4.45 fin, i , </td><td rowspan="2">............................ ......... :Í;00#-&lt;_:.....p“Pl_:: /553/)/1</td>

<td>τ ?·%. &gt;¿- -/7 7 &amp; 7^:</td><td>i ÍH). 4.38- 4.i0 fin. ÍH).</td>

<td>^ΧΥ' ^-Ύ 7? 7 1 ¡ : ,?&lt; ,-ζ^··. ,.$/: r -:- '¡ψ</td><td>i 3.95- 3.73 (ro, 2H), 3.0&lt;l ¡_s. i í 3W). 2.89- 2.68 fin, 4H), [ 2.39- 2,!5 (m, 2H): LCMS: ! 93.15%, ro/z- 579.2 &lt;Mró¡);^: HPLC: 99.63%, rt: 3.99 ¡ min.</td><td>[ p i )/// ΐ ////i) 7 P))) 77/7: P:7 ^: //////7 ) / 55555/ :&lt; 5/ 55 / .....................................i </td>

<td>7 7&lt;\ HO; *</td><td>pMNMR iCÓCIí, 300MHz); ξ δ 9,32 (s. 5 H). 8.30 fis, ÍH), ¡ 8.06 id, ÍH), 7.95- 7.86 (ro, ÍH), 7.58- 7,35 (ro, 2H), I 7.30- 7.26 (ro, ÍH), 5.71! 5.08 (ro, 2H), 4.96- 4.70 (ro.</td><td>^tZ^ipp!^;ip)| p·' PPPPP.........PG i ......IJ 77· Izp^ZlF/»^ ¡&gt; IG.........i 1 fl</td>

<td>^κ''---\:^:, ^:..... &lt;</td><td>i 111), 4.32- 4,05 fin, 2H),</td><td></td>

<td>wBiiP:: ..&lt;G, .-y. .-^</td><td>i 3.85- 3,68 (ro, ÍH), 3 64- ( _ , .. &lt; ....</td><td>:1;OO02PPP)Í7 P- S)P</td>

<td> V '&lt;γ.</td><td>i 3.52 (ro, Hi), 3,35- 3.)3 fin.</td><td></td>

<td></td><td>| ÍH), 3.00- 2,87 (ro, 2H), ¡ 2.79 (s, 3H), 2.56 (d. 3H), ¡ 2.28- 2.10 (ro, ÍH): LCMS: ¡ 98,34%, m/z- 597,1 (M-H); P HPLC; 98.81%, rt; 3.95 ¡min.</td><td>)................... .................. i P)..... }pp' PP /; (') / 5; / G |Gp $ :/)5:/5: ..... ΖΖ.ΖΖ,.,.,,,,,,.ΖΖΡΐρ.ρρ 'ZpphZpZ^:'pp</td>

153

<td>W'Y 1</td><td>3|ss.^: %..........s ΥΥΎ....... -s ^: ' Y - .................-X..........Y ; Y Y · X - K V Xtó⁵* F' N :SS ;SSSS _:&gt;SS_:J;S^:</td><td>HNMR iCDCL, aÓOMite): δ 9,27 (s, iH), 8.33 (d, IH), 8,24 id. 1H&gt;, 8.05 í'd. ;H,¡, 7,58- 7.50 im. iH). 7.48 (d. IH), 7.27 Cdd, IH). 7.97 (s, IH), .5.35- 5.24 im, 0,5H), 4,97 (d, IH), 4.88- 4,75 (rn, 0,5H). 4.35-4.14 (rn, ¡ 5H). 3.82 id, iH). 3. i 5- 3.04 im, 0.5H), 3.3.3- 3.21 Cm, Hi), 2.%- 2.83 Cm, 2.H), 2.81 (s, 3M), 2.4]·· 2.25 im, 2H). 2,06- i .98 (m, 2H), 1.28- 1.10 (ro, 5H); LCMS: 93.42%, m/Y 587.2 &lt;M^!); HPLC: 97.30%, rt: 3.89 min.</td><td> 0.0015</td><td> ........ .</td>

<td> '55</td><td>Yá .......... .....Y......'gYtg·.......^.. ....... : ':' _: Yy : : ó </td><td>^:HNMR (DMSO- d_s4θΟΜΒζ&gt;: δ 9.19 (d, IH), 8.71 id, 2H). 8.09- 8.02 (ro, IH), 7.76- 7.64 (m, ÍH), 7.58 id. ÍH), 7.43 id, ÍH), 7.38- 7.32 im, 2H), 5.65- 5,51 (ro, Í..C3H), 5.19- 5.05 ¡X 0.7H), 3.82- 3.54 (m, 2H), '3.30- 3.21 iY ?.H)_;3.Í0- 2,97 (m, 211}, 2.8- 2,74 (m, 4H)_t 2.45- 2.28 Cm. IH); LCMS: mY93,88Y. 538.40 (MY); HPLC: 95,13%, rt; 3.55 min.</td><td> 0.047</td><td>........jijl</td>

154

5b f»..................

xx x , ^:*x ..·, ,x, . ·&lt; x - , X, -5 ^si..............ic.....liSté........

H'S'MR (DMSO- &lt;4,

300MHz.}: ü 9.23 id. IH), 8.73 &lt;d. 2H), 8.62- 8.34 (m_;IH), 8.15- 8.05 ím, 3 H). 7.83- 7.73 (m, IH). 7.707,66 (in, IH), 7,41 (dd, ÍH), 7.55 (i, ÍH), 5.89- 5.42 &lt;ro, ; 3H), 5.35- 5,28 (m. 0.5H). 5.18- 5.32 (tn, 0.5H), 4.254.04 Or, 2Hj, 3.87- 3.42 ím, 2.H), 3.31- 2.99 (m, 2H), 2.80 (s, 2.7ΕΪ, 2.76 ís, 0.3H); LCMS; 53.05% -* 29.00%, jn/z=^: 508.1 (M*); HPLC; 72.37%, rt; 3,97 min, 27.62%. rt: 3.87 min.

0.28 ., ,í% ...ó;.,

7'¿7 ...............

i. rt fx - x.„.·· x£:'

S 'LTNMR(CDCM00\ffiz);

δ 9.32 (s, 1Π). 8.69- 8.67 {d, •Si), 8.40- 8.39 (d, 3H), 8.08- 8.05 (d, IH), 7.527.45 (m. 2H), 7.28- 7.25 ím, 1.H), 7.03- 75.30 (d ,ÍH), ; 5.76- 5.63 (m, 1E), 4.734.65 (ro. IH). 3.54- 3.55 (m, 3H), 3.01- 2.93 (m, 2H), 2,81- 2.6? ím, 5Η), 2.56 (s, 3Hi, 2.24- 2.17 ím, ÍH), LCMS: 99.48%. mOt- 559.7 (MH); HR!,C: 99,10%, λα. 79 min.; Columna: ZORBAX XDB C3 8, 5 micro (4.6x150jnm): Chira! 3-ÍP1..C: 99.64%. rt- 23.05

0.019

155

<td>&lt; 7 ............... τΒβΒ Β</td><td></td><td>min.; Columna: AG/CHTRALPAK AD- H/03.</td><td>B.....^......................</td><td></td>

<td>Jl 77&lt;777|7 / κ 77s|7 ( 3 : / / / 7</td><td>n i ζ. · ·\ j .................................................................................vil M,&gt;3 W</td><td>⁷H NMR (CDf.k, 400MHz): S 9.32 (s, i H), 8.69- 8.67 (A ÍH), 8.40- S.39 (d, LH), 8.08- 8.05 (d, IH), 7.52- 7.30 (d, iH), 7.45- 7J4 (A 1 Hí, 7.28-7.25 (ra, IH), 7.05- 7.00 (A IB). 5.85- 5.55 (ni, IH), 4.71- 4.63 (ra, IH). 3.50- 3.36 (m, 3H)_S3.0- 2.95 (ra, 2H), 2.77 (s. 3H), 2.74- 2.68 (ra, 2K), 2.67 (s, 3H). 2.24- 2.18 (ra, ÍH): LCMS: 98.75%, m/z- 559.8 (MM): HPI..C: 99.47%. rt- 4.512 rain.; Columna: ZORBAX XDB CIA 5 micro (4.6xi50mm); Chira! HPLC; 99.31%, ΜΙ 8.13 nii«,; Columna: AG/CHIRALPAK AD- H/03.</td><td> ......7^::: 777777: g; 0.003</td><td> 7 / 71</td>

<td>7SO77......7</td><td>X %-- N,, , _s .... U , .7 7:V7'^:Í';7-a&gt;^J7'A '''? 7- ........... ; Ύ ÍO!</td><td>⁵H NMR (C.Í.3CA 400MHz): δ 9.29 (s, IH), 8.92 (bs, 5H), 8,06 (A ÍH), 7.61 (A 1H)_S 7.4? ($, IH), 7.26- 7.22 (dA SH), 7.05 (s, !H), 5.20 (m, IH), 3.50 (s, 2H), 3.5 5 (A 2H), 2.80 (bs, 4H), 2 62 (ra., 6H), 2 05 (bs, 2H); LCMS: 94.69% . m/z-</td><td> 0.018.....</td><td>itl/i</td>

156

<td></td><td>. ....... .............. Izli;.................;.....</td><td>566.7 (M-ti); HPLC: 95,08%, rt: 4.70 min.</td><td></td><td></td>

<td>/—rI i¹......7 i.......1 ¡¡ ; 1 / 7 _............. '</td><td> / ///::////// ://^: tK®·:'-··,//(// //........../ /^:/7_s/· &lt;ν'Ά......: _:....... :...... /j/C/' /.?/ ^::;/&lt;;/^:............/ /_:;/9ψ·Α^'- A?9C-9?' ^:Ά-^'-................. 7Α</td><td>22 NMR (CÍ'iCij, 400MHzj; Ó 9.27 ís, Π-1), 8,9 (bs, IH), 8,04 (d. 2H), 7,53 (d. IH), 7,37 (s, IH),, 728 Lid, IH). // / ' /&lt; / _: y.· /&lt; / / / &lt; &lt; &lt; // 5.86 {.$, IH), 3.53 («. ~5H). 3,06-3.95 {nt. 3H), 2.80 (bs, 4H), 2.66- 2.60 ({, 3H), 1.28 (d, 5H): LCMS; 93.39%, m/z» 558.3O (M-H): HPLC: 9 i .5%, rt: 3.63 min.</td><td>/ //// / 02 i 5</td><td>/ / ΐ??/·);......i) </td>

<td>/2? 41? 1 ' ?O/:1 111? ........//// / ; 7 7 ^:</td><td>iii?·-^: Z?......... ........ΐ-:!???; W?............ ......A;14L/;2/i.....^.... 7/............ _f--'-íí ',.····</td><td>Ti NMR (CDCL, 400MHz): 6 9.30 «s. IH). 8.64- 8.60 (ro, 3H), 8.03- 8,00 (d, IH), 7.41- 7,39 id, IH), 725- 723 ¡m, ÍH), 7.0L- 6 94 tro, 2H), 5.79- 5.65 (m, i H), 4.70- 4.62 {m, IH), 3,83 fs, 3H), 3.57- 3.47 (ro, 3H), 3.03- 2.95 (ro. 211), 2.78 (s, 3H), 2.72- 2.70 ¡m&lt; 2H). 2.25- 2.22 &lt;m. ÍH); LCMS: 96.23%, m/z» 542.5 (MM); HPLC: 98.3 i %, rt- 6.63mro.; Columna: ZORBAX XDB Ci.C 4microM 6xL50mm , Ch¡ra· HPLC: 9735%, rt»! 8.522 rom.; CMumna: LHX 5n AMYLOSE- 2{i50X4 60M.M), 5Micron,</td><td> 0,212</td><td>W1|l</td>

157

<td>k ...................................i............................................................. .............. ...........: γΥγ ...................._..........:::......_....................._.................:..... ...............................</td><td> 'KNMRíCDCb: 400MHz}: : 6 9.2? (s, IH), 8.62- 8 57 : Om 3H), 8.00- 7,97 (d. IH), . 7.38- 7.36 (d, IH), 7.1 ΣΙ 7JO ira, IH). 6.93- 6.9; fd. 2H), 5.77- 5.62 (tn, IH).^: 4.68- 4.60 (m, IH), 3.81 (s, i 3H.k 3.44- 3.33 -Im. 3H),_v . 3.02- 2.97 (m, 2H), 2.78 (s._tη π. .-χ / W 2.72- 2.65 (m, 2H), íi Ύ 'I Y ' 9 λ C,·* :2.22- 2.17 (m, IB); LCMS: s- ·' ^s-^;··'« 95,36%. m/z® 542.5 (ΜΗ}; HPLC: 96.54%, rt® 6.63min.', Columna:_; ZÜRBAX XDB CIS, Smicro (4.6x1 Stírmn); Chlral HPLC: 96.18%, rt® ; 20,44 irdíi,; Columna. LUX 5u AMYLOSE- 2( 150X4,60MM), 5Micnm.</td><td> 0.0037</td><td>YLs Γ</td>

<td> ·&lt;©.</td><td>MC:_X ρ : Ji NMR (CÜCL, 400MHz): o ? '/ 4 9 3f, (_3; iH). 8 21- 8.20 (d, X^'CíXM ί» ^s* « ™&lt; .A,Á,3 7.30 (a. Sf-1), 7,28- 7.26^: (m, 2H), 7.17- 7.16 (d, IH),^: 7.04- 7.0: (dd. ΪΗ), 6.26- 6.22 (i.. IH). 5.35- 5.30 (m, : IH), 4.90- 5,00 (m, 2Hí, í 4.25- 4.28 (m, IH), 3.89- 3,78 {m, IH), 3.66 (κ, 5H), ' 3.39- 3.20 (tn, IH), 3.02- 2.90 (tn, IH), 2.80 (s, 314), 2,41 - 2.25 (m, 4H); LCMS:</td><td> 0,0085</td><td> 1</td>

158

<td>y ) - ) /'</td><td>y........................................ _:Ñ</td><td>94.13%, m/z- 576.3 (MH); HPl'.C: 93.22%. rt: 3.28 min.</td><td></td><td></td>

<td> 64</td><td>: Ω :^Κ/6/.'·£/ί£( &lt;( y........... V- ............M &lt;y-”7 )/,£/M-/é ·]................ y ....... 1/}}:.....</td><td>^;B NMR (DMSO- 4. 400MHz): δ 9,35 is, JH), 8.73 (d, 3H), 8.55 (ti. IH), 8.12 (d, IH), 7-68 ¡d. IH), 7,64 (d. IH)&gt; 7.41 ídd, lí-n ,7.39 (k IH), 5.9 í (s, 2H)_S3.65- 3.56 (m, 2Π), 3.44- 3.32. (m, 2H), 2.52- 2.50 (m, 21Í), 2.25- 2.15 (m, 2H), 1,94 ú, 3H): LCMS: 98,76%, m/z- 532.05 (MM); HPLC: 99.18%.. rt: 3.90 mm.</td><td> 0.0053</td><td>uc</td>

<td>£......................................................................................................................J</td><td> &amp; ·^: ,y&gt;/y£.y 66&gt;_:yA_fM^^_aMy££_B)/.....:y.......y : ):%/6 ^: :/£y &lt;^{K :}y i '(:)£BM£y(iy........</td><td>^!H ÑMR. (DMSO- &lt;/,. 400MHz): δ 9,35 (s, IH}, 8.72 (s, IH). 8.53 (d, 2H), 8.15 (ti ?H), 7.66 (d, IH), 7.59 id, IH). 7.38 (dd, IH), 7.23 (d, ÍH), 5.88 (s, 2H), 3.65- 3.56 (m, 2H), .3,44- 3.32 Cm, 21Π, 2.62-2.50 fm. 2H), 2.50 (re 511),2..25-2,55 (m, 210, 1.94 (s, 3H): LCMS: 190%, m/z- 545,90 (MU); HPLC: 98.8236, rt: 4.10 min.</td><td> 0 0024 // _sssssssss</td><td>/% ly</td>

<td> 66</td><td>y^: i)yy))()66tef)yy ·; .................</td><td>’HNMJÍ (CDCh, 400MHz}:</td><td> 0.01</td><td></td>

<td>i cy^s iy</td><td>....................................... ....... 'N^y. ............. ..... ^::(y-.....-(iypiysy...../ ...... V W£ ........... .........:«8i£o</td><td>6 9.4.2 (s, 110, 8.44-8.42 (&lt;1, ÍH). 8.32 (s. IH), 8.11-8.08 id, IH), 7.528- 7.523</td><td> .................... : : : .............................</td><td>sT.y^: y)i : :.............//..:/</td>

159

<td>γ^: Y'YY / V :/ Y'YY γ ^:;</td><td>í ) 11111111111111 ||^:7| 1 llllllllllii él Y) 1111111111111 1.........&lt;</td><td>(d, IH), 7.47- 7.45 id, IB), 7.33- 7.31 (dd. lB),6.40(s. IH), 4.3- 4.1 &gt;m. 2H), 3.97 &lt;s, 3B), 5.7 (s, IB), 3.56- 3,3 ím, 4H.1, 2,90- 2,7? (bs, 2H). 2.44 (s, 3H), 2.30- 2.1,5 . '.· . : · : : : fhs, 2H), 2.09 (s, 3B); LCMS: 95.21%, πΥζ- 59Ϊ.5 (M-H); HPLC: 98.58%, re 4.62 min.</td><td></td><td></td>

<td> 67</td><td>/ áY</td><td>“VÑMR (CDCh, 4Ü0MBz):</td><td> 0.0.53</td><td></td>

<td>1...../Y/ / : : / /</td><td>.......... ....... /Y’YY s¿...........SS ^: : léilYiéXllil¹.......i. 11- v!.....ιγ/γ11Αί|1 ^slli...........</td><td>S 9,3¡ ís. IH), 8.43 (d, IB), 8.32 id, IB), 8,13 id, IB), 7.49 ís, 2H). 7.33 (d, IK), 7.00 ft, IH), 5,41- 5.18 (m, SH), 5,02- 4.82 (m, IH), 4.35- 4.15 Ου, 3Bi, 3.55- 3.01 (m, 5B), 2.85- 2.65 (m. 5H}, 2.56 (s. 310,2.40- 2,1 S (m, 2H); LCMS: 96.42%, m/z- 575.4 (MM); HPLC: 95.10%, rt: 3,67 mtn.</td><td></td><td> 11.......</td>

<td> 68</td><td>........ .....(YY........( /-</td><td>0-1 NMR (ClOCl··, 400MIL'):</td><td> 0.0047</td><td></td>

<td></td><td>Y«r.</td><td>6 9 32 (s, SH), 8 44 &lt;&lt;i. BI),</td><td></td><td></td>

<td></td><td>..........- éé</td><td>8,06 id, IB). 7.94 (s, HB,</td><td></td><td></td>

<td>y yv/ Y</td><td>...... .........ll,J'YllOé¿.....i........</td><td>7.60- 7.36 (m, 2B). 7,29 ís, IB), 6.99 (d, fH), 5.65- 5.21 (ni, 2B). 4.95- 4.70 (ni, Bi). 4.36- 4.11 (tn, 3H), 3.92- 3.73 (m, 2H}, 3.40- 3.15 (¡n, IH), 3.05-2.75 (m, 5B), 2.57 ís. 3H), 2.29- 2.10 íin, SH); LCMS: 99.65%,</td><td></td><td>s^:lY Y^{s :}Y YY) γ_:</td>

ISO

<td>Γ......^/1 %</td><td></td><td>m/z- 579.25 ÍM%; HPLC: ......-ιι.....; ι χ |/-| 72| 'X Χ;Χ 97.96%, 4: 5.62 ¡rara</td><td>BB:::::: · &lt; : s s s s s s s t :: &lt;s :^:_: ......77777/, B) s|................</td>

<td>69 II I III 7 /| 77777 (7 7 : 7:/7 72 2 2 2::7// II IIII</td><td>... C 77 2 7 7 7 7 7 7: ,:^(77/í/XsX^ &lt;χΝ'··Βι.......... ÍSB'-BB^í'Sbi........7....... •* ,· ^f¡ ^ψϋ- X.-Xj. %,/ ............... IlxliPxi..... ...... :F ^ν· \! ·</td><td>^rH NMR (CDCSj, 400MHz}: 6 9.42(5, SH), 8.40 id, SH}, 8,32 (s. IH), 8.1 i- 8.09 (m. 2H), 7.48 (0, IH), 7.38 (d, iH), 7.20- 7.18 (m, SH), 5.97 ís. SH?, 4.25- 4 18 (ro. SH), 4,17 ís, 2.H), 4.05 (d, IH), 3 54 (s. 3H), 3,42- 3.38 ím, 3H), 2.86- 2.78 (m, 2H), 2,23 (t, 2H). 2,09 (s, 3SI); LCMS; 85.5%. m-'z-* 576.90 (M+-); HPLC; 93.5%. ru 3,28 rara.</td><td> 9.059 : ^&lt;:í^: 7/ 7777 7 77777 · i 77 &lt;&lt;</td>

<td>ϊΟΐΙΙΙΙ·^;;ΙΙ^;Ι ' / 7χχ: ΧΙΧ 1|I</td><td> ....... ..... ^: 0·. ........ ..... /11......)Ιί^:ΝΙΙιΒΐ1|1ίΙι I..... xXw^r^W 7........ .......7d:&lt;1¿sj/X&lt;y/7.......lis......... ;:· ν.:- -_κ· I ιιιιιιιιιιιΐιιιιιιιΐ: ιι sj^:</td><td>^fH ÑMR (CDCi₃. 400MHz): S 9.23 (s, SH), 8.37 ls, 2H), 8.01 (d, ÍH), 7.60- 7.47 (m, SH), 7.22- 7.12 (ro. 2H). 6,96 (d, 1H), 4.92- 4.68 (ra, 3H), 4.2.9., 4.25 fin, 2H), 3.SO- 2.96 (ra, 2H), 2,77 (s, 3S-1), 2,53 (s,3H). 2.10- 1.89 un, 4H); LCMS. 99 78%, miz- 530.35 í%l· S); HPLC: 95. S1%. rt: 3.18 min.</td><td>0.0043 tlLlI?)!'·</td>

<td>ι......1 i .....€ II II 71 II ................</td><td>*%...&lt; ;s ;ΐιι:χ ............ι/%/ΐ...... |ΒιΒΒΒ^77“ιΒ|7|7! 7117/ X 'χΟΒ*</td><td colspan="2">Π NMR (ΠΜ9Ο- ₍/_d, o0.X 400MHz): 8 9.18 (s, IH), ' 8,53 (d. SH), 8.31 ($, SH), _:8.05 (d. IH). 7.90- 7 65 (ro, _; i₅SH), 7.38- 7.30 (ra, 1H)J 7.22 (dd, 2H), 5.SO- 4.957 '71', , 7 7 i (ro. IH). 4.75-4.55 (ro. )H}x</td>

161

<td>/ ÍN i 0 47747 7 7</td><td></td><td>4.20- 3.90 (m, 3H), 3.40- 3.22 (ro, 2H&gt;, 2.98- 2.80 (m, 2H), 2.7S is. 3H). 2.50 (s, 3Hj, 2.30- 2.00 ¡m, 211): LCMS: 90.93%, m/?~ 545,2 (Mri), HPLC: 93.33%, rt: 3.29 min.</td><td></td><td></td>

<td> 72</td><td>::........................ .......... ................... ............... .....7&gt;p9 M. m &gt;: : 0 . &gt;&lt; , .;&gt;, ,:v ¿Ct . /' A y n 77s......¢:7 -7: 2.(, 27 - :::............</td><td>'H NMR (CDCh, 400MHz); 5 4.28 ($, 1H&gt;, 8.21 id. ! Hj, 8.09- 8.04 (í, 2H). 7.39 (d, il·!}, 7.26 (s. Uí), 7.20- 7.18 ím, IH), 5.97 (hs. IH). 5 22 (ro, 1H), 4 98 id, 2H). 4.22 (d, 2H). 3.82 id. 2H), 3.53 (s. 311). 3.25 íí, 211), 2.89 (s, 3B), 2.50- 2.23 (m, 2H): LCMS: 99.3%, m/z- 577.2 ÍM-M); HPLC: 97.37%, rt:3 27 min</td><td> 0.045</td><td> 1%7 7/</td>

<td>yB|gssg7: 2 .........</td><td>......... ..... * ........... ........ ........... .....i ::K27^Í_R222(i(......_.......-A......... .....)7:7-7: ) Ww^C! M . F'-. &gt;,-·'</td><td>’W NMR (CDjGD, 400MHz): δ 9.12 (s, IH), 8.45- 8.43 (d, 1H), 7,93- 7.90 id, IH), 7.62- 7.60 íd,lH), 7.49- 7.40 íro,2H), 7. i 5 (s, Hí), 7.03- 7.0 i (d, 1H), 6.45- 6.41 « ¡H). 5.03- 4.95 (m, Π-Ϊ), 431- 4.20 (ro, 2H), 3.64 &lt;s, 3H), 3.H- 2.99 (m, 2Hi. 2.81 ís, 311), 2.72,- 2.61 (ro, 2H‘_S2.05- 1.95 (m, 2H); LCMS: 99 72%, roft- 560.95 (ΜΗ·): HPLC: 95.59%, rt: 3.10</td><td>0.O036</td><td> 1 /41 ^: 7 /7 4 4 7 /:</td>

162

<td> 7747'™·.....</td><td>...../W^WSAllls.............14 :&gt;9 -A 7™]|b</td><td>Ή NMR (CDC!,, 400MHz): b 9.29 A ÍH), 8.44 A *Hk 8.06 A 2H)₍ 7.53 A IH), 7,35 (s, IH), 7.22 A Π-0, 5.97 (bs, IH), 4.88- 4.55 (m, 3H), 4755- 4. i'5 ím, 2H), 3.53 (s, 3H). 3.05 (bs, 2H), 2.80 A 3H). 2.78- 2.65 (tn, 2H), 2.10- i.05 A, 2H); LCMS; 90.8%, m/F» 562.2 {M-H): HPLC; 97.04%, rt: 2.42 min.</td><td> 0,01 4 : 4: 4:4 : '7 : 7 7 7 7 . ^:'447:44?77777777_: :</td><td> ;:5?7^|r' % 7777: 7</td>

<td>?S 7 *.............7:</td><td>Γ e *'&gt;4 ’ V’ N^-·' 77:444 7pA/A....... ......</td><td>^!H NMR (CDCb, 400MHz): δ 9.39 A ÍH), 8.69 A IH). 8.36 A IH), 8.Ο5 (d. IH), 7.38- 7,28 (re, 3H). 7 15-⁷.1O (m. 1H1 7,05- 6.9? {ni, ÍH). 0,28 it, ÍH), 4,89 (bs, 2H), 4.02- 3.93 (m, 2H), 3.68 A 3H), 3.18- 2,96 (m, 4H), 2.07 A 3H), 1.96- 1.8? (re, 2H); LCMS; 100%, πν'ζ^:- 56!, 5 {M * i); S ÍPLC: 98 J 6%. rt: 6.36 roin.</td><td> 0.0038 &gt; 4 4</td><td>7 '4774444777 &gt; ........ :: ..... 7 W&lt; ^:'</td>

<td> *</td><td>4 4*&gt;......... ......ép........................^&lt;:4444e 444: 0¾.^. 44:444: 4:4 ............................._.....R17PWP.................._;í................ %.-« '^:A..-^:·· .,,··&gt;.,.···&gt;&lt;,.’'· 4444.pAAAA'4774:::4444</td><td>’H NMR (ClX'b, 400MHz): δ 9.27 A ÍH), 035 A ÍH), 8.26 (bs, IH). 8.02 (d, ÍH), 7.36 (s, IH), 7,26 is. 2Hk</td><td>W</td><td></td>

6.93 id, iH&gt;. 5,25- 5.05 (A 1H)_: 4.78 (ha, 2.Η), 4.354.11) (m, ¿H), .155- 3.38 (a, 2H), 3.03 (í. 2M). 2.79 A

1S3

<td> ; </td><td> ( 1 ......11</td><td>3H), 3.55 (\ 3H), 3.25 (s, 3H), 3.01- 1.89 áte 2H); LCMS; 100%, tnáte 526.4 (\%i): HPLC; 98.8%. rt: 3.71 min.</td><td>i.....il.................n</td><td></td>

<td></td><td>^rtA....( Λ Vte Ά% A 1111111........i.......................ni.................ri : : - : ....... - : ..... : </td><td>Al NMR (CliCU 400MHz): δ 9.27 ís, IH). 8,H id, IH), 8.11 (hs, IH), 8.03 id, IH). 7.31 (s, ΠΠ. 7.35- 7.18 (m, 2H), 6.95 (d, IH), 5.40- 5.20 (m, IH). 5.02- 4.90 (na, IH), 425- 4 ÍO (m, IH)_:8.90- 3,78 áte 2H). 3.30- 3.15 áte 211\ 2.95-2,70 áte 5H), 2.56 i\ 3H), 2.29 &lt;s, OH), 2.01- 1.89 {m, 2H): LCMS: 98.8 A , m/z- 541.35 íM~A HPLC: ;.....5--_: ........ ......... ................... 96.43%, rt: 3.82 mín</td><td> 0.08</td><td>i);:........ (^N</td>

<td> (7855:-5:55 :5 ............ 5 : || : .... </td><td>AÍ%/......................... -s-s........-......... 5; .............. .....0 5..7:- 5^S5 5 5^105.-^73(5(^-37:^:........ ............ .: ..................... : 3:35 _.........333 5:53- |3.....5 (I: _gs3</td><td>ΑΪ Ñ\ÍR (DMS(% .A, 300MHz): δ 9.16 (s, IH), 8.50 (td, ¡H), 8.45 td, IH), 8,04 (d, 1 H), 7.76- 7.66 im, 2H). 7.57 (d, 2H), 7.19 id, Hi), 5,05- 4.90 On, IH), 4.70 01, IH). 4.55- 4.45 (m. IH), 4 20- 4.10 ám 2H), 4.00 (d, IH), 3 28- 5.16 im, 2H). 5.00- 2.85 (m, HO, 2.79 (s, 3H). 2.59 is, 3H), 2,30- 2.05 im, 3H): LCMS: 93,23%, m/z- 527.20 (M+l); HPÍ.C' 96.31%, m</td><td> 0.179</td><td>1ÍÍ.............</td>

164

<td></td><td></td><td>3.76 min.</td><td></td><td></td>

<td>................ ............ 1 ::.......... η 1:............. : ............:............ &lt;::</td><td>:O 1..............:::................... . /1 1 .................. ........... : ,. ............. :: :Τ *1 t-r \ ....... ............. i - ......_.¹ / ¹ i; ::: .....: : -, .\. .0, ,:'x * fe U UUT&gt; :....... ..............^:: :fe: .fe: A:^:: ........... ......i::: ::_{: :S};...... : :::::1 ....... :</td><td>li NMR (DMSO· A, 300MHz): δ 917 (s, IH), 8.75 is. IH?, 8,65 id, IH), 8,53 (d, !H), 8,14 (d, IH), 7.69 (5, IH), 7.41 (dd, ÍH), 7.25 (dd, 2H), 5.93 is. 2H), 3.70- 3.55 im, 2Hb 5,58- 3.20 (m. 2H), 2.69- 2 58 im, 2Hi, 2.47 (s, 3H), 2.22- 2.07 (m, 2H), 1.97 &lt;_s, 3Hj; LCMS: 100%, m/z» 550.7 •M-l), HPLC: 98.60%, re 3.99 min.</td><td> 0.0092</td><td> 111:1</td>

<td>80 ί 2 /11 ::&lt;:.....:: : / 1 :/ : ::</td><td> : _K. . . .: :^γ y yfeyyXg:: ._w; 111 ......... ^s 'i 111 : 11 ........1:</td><td>Ü NMR (DMSÓ- ¿A 300MHz): δ 9.35 (s, IH), 8.75 (d. 3H&gt;, 8.62 id, IH). 8.14 (d. ÍH), 7,71 (í, ÍH). 7.43 (dd, IH), 7.56 o, ¡Hs. 7 28 (dd, Uí). 5.95 &lt;fe 2fi), 3.70- 3.55 (ra, 2H). 2,65- 2.50 (m, 4H). 2.2.5- 2.08 (ra, 2H), 1.9? (s, 311): LCMS: 93 81%, rafe- 516.2 t'M-Nl; HPLC: 99.27)¾. rt: 3.44 min.</td><td> 0,013</td><td>11:::1 Tli 11:</td>

<td>Μ G RI A</td><td>.....ιιΙμ,αιιιβι-ιιι φ ·. L'^: WPM * X ^:/:l ll: ...... ιχΟ^ΐχΒίΐί................ * ' * - '. * 'fe ‘ 'fe.' :&gt;feAfe</td><td>ii NMR (CDCb, 300MHz): 8 9.25 Is, IH), 8,25- 8,17 im, IH), 8.01 (d, IH), 7.44- 7.31 (m, 2Ht, 7.15 (s, IH), 7.05 id, IH), 6.24 (b 1H)_:5.38- 5.20 int. IH). 5.04- 4.75 (ra, 2H), 4.69- 4.39 tra,</td><td>0,007 1 .......... j</td><td>IN ::::: ; .....fe #.........._: 1 : ....... :: : &lt;</td>

165

<td> ........^............ /: /:/ ?..... : ...... ........</td><td></td><td>2H), 4,5 2- 3.93 (ra, )H). 3.80- 3.78 (ra, IH), 3.65 (s, 3H), 3-45- 3 17 ím, IH), 2.95- 2.75 (ra, 4H), 2.45- 2,16 im, 2Π), 2.10-2.00¡m, IH). L45- ¡.30 (rn, 2R); LCMS; 100%. m/z- 590.5 ÍM-)&gt;; HPLC; 98.96%. rt: 6.43 m;n.</td><td> / /7 /_: ?////..............</td><td></td>

<td>/82li////// ///A //: /7 i //// ;/ :/ / // /://&lt; //. ,?&lt;/:/</td><td>•^*· n-\ /Í///F/. A/;/'/////A/A 7/ : WaLO^;/:&lt;·;:/^/··· ..... ///_s-a«//(BBO-W/_:........ :/ _: :/: , yóy /: F V··:.· ::_γ y y _:</td><td>Έ NMR (DMSO- % 400MHz): S 9.19 (s, ÍH), 8.36 (m. Π0, 8.05 (d, SU). 7,66 (m, i H), 7.55 (ra, IH), 7.47 (d, ΪΗ), 7.37 id, IH), 6 78 % IH), 6.05·· 5.70 (m,2H), 5.15- 5.20 (ra, 2H), 4.19 (d. 2Π). 3.52 (s, 3H), 2,92- 2.89 (ra, 2H), 2,7? (s. 3.H), 2.33 (ra, IH), 2.11- 2,19 (ra. 211}: LCMS: ,//: /:// 77 //7': /: ,, / /: / :&lt;; -.. .// // / 7 96,41%, ra/z- 5624 (M-M); HPLC: 97.48%, rt: .3.46 rain.</td><td> 0.0045</td><td>//L:/ ?.....</td>

<td>783//////1 |ir?7/ 7 1 m i /// 7 ^: // // /</td><td>/ / ;//:&lt;&lt;//:////Í%a|7: / // i' .........'¡i pp|'s,,r.......i¹......i/ /ifBffflB·/ .....·/ to-/',.-···%-A, A // /// ................_......../ /% %//%/ ^: ............. : : s- ---/ V</td><td>Ή NMR (DMSO- A, 300MHz); 6 9.35 is, iíl), 8.73 (₅, IH), 8,52 (1, 2R), 8.13 (d, IH), 7.75 it. 111). 7.40 id. Hí), 7.24 (ί, 2H). 4,48 ii, IH), 4.10 (d, ÍH), 3.69 (d, IH), 3.60- 3.35 (ra. 414), 2.73- 2,58 (ra. 2H), 2,47 (s, ,3H), 2.3.5- 2.20 ím. 2H), 1.97 (s, 3H) : LCMS:</td><td>0.047 / ...... i// .:-:-:-7....... Ñ /.....' : ' /.//////////////////// 7 /7</td><td> / :/7// :7 1 7 :/ ::/ _: : ./ :: ...... : /1// //? : / : : : : / / ^: : / / 7 , /</td>

166

IV ;» \ : ¢, : :

,¡Ng »Á¿: YA,:γΥ ί-ΆΥΎ :/ν. ,α ,.·

Λ’. SV ν ^7Υνε&lt;;_κ^:·'Υ

Ai ^Ζ ^‘γΐ*·’’ ‘V’ Α

/. .Λ. .&lt;· ? ^ν Ν’

68.16%. m/z- 544.85 i'M-’b: HF’LC; 98.855¼ rt: 3.74 min.

ΪΗ.....NMR (DMSO- cC,

400MHz).- 8 9.21 (s, SH), 8.73 &lt;d, 2H), 8.06 (d, IH). 7 75 (s, Uh» 7.64 (d, SH), 7.43 (dd, 2H), 7.37 ({, IH), 4,90 O, IB), 3.70 (s, 2H), 3.02 (d_: 3H), 2.77 (s, 3H), 2.30-2.40 (to, 2H). 2. i i (s, 3H), LCMS: m/z - 96.73%, 528.1 (MM); HPLC 96,48%. it: 4.04 mim

ΗΪ'.........NMR (CDCL?

400MHz): δ 9,33 (s, IH), 8.70 id, IH), 8.63 «i 2H'i, 8.08 (d, IH), 7.53 (dd, IH), 7.46 (d, IH), 7.29 (d, Hí), 7.16 (t, ÍH), 5/70 (d, IH), 4.68 (&lt;j, IH). »3.58 -3.30 (m, 3H), 3.02 (s. 2H), 2 78 (s, 3Fí), 2.78- 2.65 (m, 2H), 2.21 (di, iW); LCM.S: m/z 91.66%. 546.] (M+I);

HPLC: 98.87%, rt : 4.65 min: 0.01% TEA m water, ACN:Me()H (LLí,

Columna: AO/C i8/ i 5- 016,

167

χ. ,Χ &gt;·*’·«·,··&lt;· · t·.· &lt;:.’·

<td></td><td>¡ ’HNMR</td><td>•DMSO- A.</td>

<td>&amp;T7137</td><td>&gt; 300MHz) Í : </td><td>: t) 9.22 (d, 111),</td>

<td>Χ:'&lt;·κ &gt; ..... 1W&lt;:......</td><td>I 8,7.3 t(L</td><td>i. 7H)₄ 8,61 (d.</td>

<td>^v%^z</td><td> ¡ 0.31-1), 8.</td><td>12- 7,91 (tn, 2H),</td>

<td></td><td>i 7.80- ?,í</td><td>&gt;4 (ro, 2Π), 7.43</td>

<td></td><td>_; (dd, IH).</td><td>7.37 ít, IH), 5.72-</td>

<td></td><td>: 5.50 tro,</td><td>1 H\ 5,41- 5.15 (tn.</td>

Α_χ ηο_χ 9 η

Ν.

!

Ν\

7^:: ίδνό^? \ (£(/ -'Λ

Ν; 211), 4.61- 4.45 (m, 3Π,ί, | 3.82- 3,65 (ro, ÍH). 3,13] 2.95 (m, 2 Η), 2.85- 2.80 (ro, I 211),2.7015. 311), 2.37-2.21 ¡(m, 2H); LCMS; 100%, ¡nvz« 59LO (M+); HPLC' ¡ 98.8.5%, rt; 4.41 roin. IVÍÑMR^DChTIOOMÍÍz): ¡ ó 9.32 (s, JH), 8.30 (s, 1 Ht, | 8.06 (d. 1 íl), 7.95- 786 (m. 1 JH), 7.58- 7.35 (ro, 211), I 7.30- 7.26 (ro, iH). 5.7.1¡ 5.08 (ro, 2H), 4.96- 4.70 (m, ¡ IH), 432, 4.05 (m, 2H), ^: 3,85- 3 68 tro, i H). 3,641 3,52 (ro, IB), 3.35- 3,13 (tn. j 111), 3..00- 2.8? (ro, 2H), i 2.79 ts, 3B), 2.56 (d. 3.B), ¡ 2.28- 2.10 (ro, IB); LCMS: i 98.34%, rn/z~ 597.1 (M + l); ¡ HPLC: 98.8154, rt; 3.95 i m'ro.

4..'

0.01 í [o.oot

168

HQ o /W\/

Vvvn .-v._v

1HNMR (CDCÍ3,

4Ü0MHz); &lt;5 9.3! &lt;s, SH). 8.65 (d, 2H), 8 03 (d, 20), 7.44- 7.35 ítn, HO, 7.Í2 0, HO, 7.02- 6,96 (m, 2H), 5.83- 5.58 ón, 00. 5,204.67 (m, 20), 4.32- 4,01 tm, 20), 3.85 (s, 30), 3,78- 3.Ó? (m, IH), 3.35-3,11 ím, IH), 3.08- 2 82 (m, 20), 2.80 (s. 3H), 2,50- 2.22 (m, IH). 2,2 J- 008 &lt;m, 10); i.CMS: 99.03%, nvz« 561.2 (M-H); HPLC; 98.83%, «: 3.20 min.

0,0057

......................................... ...........^:: / Til/ _Ki &lt; &lt; /......kWL / O ^&lt;: //%.%4.....

'⁷HÑMr· β 9,39 (s, U-í), 8.23 (d, HO,

8.69 (d, HO, 8.01- 7,82 (_fn,

Oí), 7.52 (s. Oí). 7,5!- 7.36 ( (m. IH), 7.31 (d, ÍH), 7.12 | (d, HO, 5.65- 5.20 (m, 2H),'

4.90- 4,71 (m, 2H), 4.69 (d. i

2H). 4.31- 4, ¡8 (m, 1H)J -4//.7) .................. ////////

4,17- 4,09 fnv, ÍH), 3.85-j

3.75 (m, HO, 3.35- 3,18 (m, ¡

10), 2.98- 2.8! ím, 2¡O. ) ' 1

2.86 ($, 30), 2 45- 2.25 (m, ¡ 00, 2.24- 2,12 (m₅ 10);' LCMS: 98.125% «vz^ 50.5.1 (Mil); HPLC: 95.343% r(: 3.37 min.

0,0026

<td> 90</td><td>^r 3 i Λ ¡ ................ ...............................................................................11 ibiwiiili 1| -Cy f I V : Uu) ; uá &lt;7 uuubub) ^: 5 sus)%u&gt;. (uu) uúuuV; &lt;&lt; &lt;-j</td><td>’.HNMR íCDCh, 300MHz); δ 9.32 (s, Π1% 8.04 id, 2H), 8.0? (d, )H), 7.86 {&lt;!, ¡H), 7,25- 7.16 fm, 3H). ?.tl tt. IH), 5.62- 5.2i (ra, 2H&gt;, 4.96- 4.68 (-o, ÍH). 4,31- 4.65 (ra, Hl), 4.61- 3.66 tm. 2.H), 3.48- 3.12 (ra, IH), 3.65- 2.86 (ra, IH). 2.86 t.s, 3H). 2.3-5 ts, 3H). 2.32- 2.10 (ra. 2H); ¡..CMS; 99,2.0%. nvr 5-15.2 (MM); HPLC: 98,15%, rt; 3.80 min.</td><td>b5b 5::5 : ub % 0.0026</td><td>. ;uu_::: uu U :U : : i ' i'i_::iii i......ilí j 11155 55 53 uuu u ::</td>

<td>91 'A ub :</td><td>A-M... ° Qbb ^N, ...Cu, .-Cl ^-Ά U ν_γΎζΧ^: r'-_fD b ib SU u</td><td>^rHNMR tpMSO- &lt;L„ 600MHz): S 9.28 (d. IH), 8.86- 8,72 (m, S.SH), 8.65 (d, O.SH), 8.12- 7.98 (ra, 1.5H), 7.92- 7.86 (m, 0.5H), 7.23 &lt;d, O.SH), 7,67 (d, O.SH) ⁷ 57- 7 49 (ra. 0 5Hi. 7.46- 7.42 Ora 0.5H), 7.39- 7.31 (m, ÍHI. 7.28- 7.23 (m. O.SH), 7.20- 7.12 (ra, O.SH), 5.68- 5.56 (m, Hí.\ S 54- 5.46 (m, O.SH). 5.27- 5.13 (m, SH). 4.89- 4.77 (ra, 0.5Í-Í), 4.6-1- 4.56 un. O.SH). 4.50- 4.40 (ra, 2Hi, 4.37- 4.22 (ra, 0.5H), 4.i7- 4.03 (ra, IH). 3.10- 2.93 (ra, IH), 2.82 vi, ?H). 7.76 (x, ÍH), 2.35- 2.15 (ra, 2.H); LCMS; 100%, m/z= 645.3 ÍM+);</td><td> 0.018</td><td>............íi 5 1 5:55 bbb ' (3.......i.....1</td>

170

ΗΟ re— fo. X\fo.

Ν-'ί,ί'ΐ!

F zA F &gt;.j íj fe Ϊ fe ,-K fe-~\ ,F \&lt;' z (L-feíZ’ . j 'n

A^.fo·'·

ÉA %·'’ fofofefefoy'· Ct „ A.

<img file="CU20160020A7_D0064.tif" />

HPLC: 93.05*%, rt: 3.56 rafe, ’HÑMR ''(CÍXK‘3OÓMH2):·

9.32 (b, 15-1), 8.66 (4 2H),

8.09 (dd_; 21T), 7.5? (i, IH), | 7.21- 7.13 Lfo 3H), 5.7 i J 5,15 (ra. 2H), 5.10- 4.65 (ra, j IH), 4.42- 4.05 (m, 2H), 4.01- 3 63 (ra, IB). 3,553.10 ira. 1H), 3.08- 2.90 ira, IH), 2.81 is, 3H). 2.50- 1.97 j (ra, 2H); LCMS: 92.79%, ί m'z-= 549.2 (MM); HPLC: j 96.64%. rt: 4.13 mín. | ’H.......NMR......(DMSO-......ίξ”|

400MHz): δ 9.23 fe ÍH), | 8.71 (fe 2H), 8.30 (s, IH), |

8.10- 7.95 (ra. 2H), 7.730- ¡

7,50 (ra, 2Hi, 7.45- 7.25 | ím. 2H), 5.60- 5.40 (ra, i * e' ;^: &lt; ^:f ;&lt;·&lt;; 4 -_:4;

IH), 5.22- 5.07 (ra, 1.H), j

4,60 - 4.38 (ra, IH), 2.81 | (s, 3H), 2,74 (fe JH ), 2.35- )

2.05 ira. 2H), 1.89- 1.68 (ra, j

2H)i LCMS: 97.7;%, _m,'z= ¡

549.3 (MM); HPl.C: i ; ; ...../7; L

96.77%, rt: 4,14 mira ΊΪ ‘ÑM^fCD&lt;M¡&lt;m 8 9.33 (s, 1H), 8.60 (d. 2H),

8.10- 8.02 (ra. 2H), 7,52 (d, ¡ IB), 7.42 O. ÍH), 7.35-i 7.28 (m, ÍH), 7.14 (í, IH), ¡ 5.70- 5.40 un, ÍH). 5.90 (fe i

0.032

0.025

0.0027

<img file="CU20160020A7_D0065.tif" />

Ί γ*.

| 2HÍ, 4.82- 4.45 (m, 2H), Í4H0- 3.95 (m. IH), 3,95[ 2.85 (ro. 31 i ¡. 2.79 (s, 31-1)» | 2.22- 2.08 (m, IH): LCMS: 3 97.71%, n¡-2^::- 550.2 (M-H);

HPí.C: 99.09%. rt: 3.49 m ni.

<td></td><td></td><td>} Ή NMR. (DMSO- d, UoOMHs): δ 9,29 is. Ηΐ),</td><td></td>

<td>i ..-0-,., Lfi f</td><td>....... í&lt;?;í XXX X ... · χ ΥΊ N'·^’</td><td>| 8,70 (d, 2Η). 8,01 id. 2Η),</td><td></td>

<td>y íh i_:%' L x</td><td>Ά rtx A &gt; r r y ητ Ct ,·%. b</td><td>| 7.70- 7,46 (ro, 2Η)« 7.42¹ 7.25 ím, 2Π). 5,65- 5.02 } (m, 2Η5, 4.83- 70 (ro, 1 Η), i 4.62- 4,25 ím, 2H), 3,28s 5.05 (m, ?H¡, 2.78 ís. 3Hj, . i 2,67- 2,64 (m, 131), 2.54| 2,50 (rn, 3H), 2.45- 2.40 (ro, 1.H), 2.37- 2.23 (ro, 2H), i 2.05- 1.92 (m. IH); LCMS: 98.84%, m/z- 578.75 (M-t-V, : ; 1-iPLC: 98.71%, rí: 4,15 min θ _ÍJÍ1?,</td><td>i Cxx</td>

<td></td><td>0 Μ PC f y 7 Ί% /</td><td>ϊ ‘H NMR (CDCÍi, 400 · ¡ Mlk): 6 9.27 (s, H-í), 8.63</td><td></td>

<td>í N.</td><td>Χ_:χφ Αχ χ&lt; X &lt;·χ»χ%&gt;ν_:·</td><td>i (d, 211), 8.27 (d, IH), 8.06</td><td>Ycccci ' ' L</td>

<td></td><td>&lt; ϋ Λ ί ν Ν. -&lt;Ά .-· Χ&lt;&gt;' ι_: -.......^χΒαΙ........... £ &gt;Χ.&lt; ·\ί</td><td>(d, IH), 7.57- 7,47 ím, 2H), 7,33 (dt!, 1H)« 7,33 (i, IH), i 5,38- 5,2 i (tn, 3 Hj, 5.30- i 3 4,88 (ro, 3H), 4.22- 4,30 (ro, | SH), 3.37- 3.23 (ro, Hí), j 2.92.- 2.83 (ro, 2H), 2.81 ís, AH), 2,48- 2,23 (ro, 3H); 1 LCMS: 99,01%, ro. z- 549, i</td><td> :,^?U 7</td>

<td></td><td></td><td>1 (MM); HPLC: 95.02%, rt:</td><td></td>

172

9?

<td></td><td>3.95 -ib in.</td>

<td> 0</td><td>41 NMR ÍCDCk 300MHz):</td>

<td></td><td></td>

<td>N -\ ,· .....7 M'-w ' /x</td><td>δ 9.31 (s, ÍH), 8.62 (d, 2H),</td>

<td>,·ί·χ. )l Ν-'ν,ί*</td><td>8.32 td. SH). 8.11- 7.90</td>

<td>’x. .·**·, V ^s'v·- '^•Z</td><td>2H). 7.54- 7.86 int, IH),</td>

<td>¿i &lt;-^:. £ ' *sj </td><td>7,35- 7,2? (m, 1H ¡, 7.12 (t,</td>

<td></td><td>ÍH), 5.60- 5.32 (m, IH),</td>

<td></td><td>5.30- 5.0? (rn&lt; SH), 4,99-</td>

<td></td><td>4.65 (m, 2H), 4,63- 4.3? (m.</td>

<td></td><td>íK); 4»jíí* 4Ate· (π\ 1Ι'Ϊ)&gt;</td>

<td></td><td>3.45- 3,14 &lt;m, IH), 3.05-</td>

Η0~\ //

Ό τ

GS ·Μ\

....._............wfe •'S. •y’S,· ’.W

Ύ&lt;χ x.f S.y* íf'b

Ν'

2.85 (rm ÍH), 2.79 (s, 3Π), 2.44- 2.32 (m, IH), 2.262,13 (m, IH): LCMS;

96.27%, m-z® 507.0 (M-H ); HPLC: 98.21%, rí: 6.96 min.

^rBNMR (CÜCb, 400MHz): &lt;&gt; 9.29 (d, 1Π), 8.63 (¿, 2H). 8 30 (¡L 0.5H), 8.03 {d. SH). 8.00 (d, 0.5H), 7.99 (d, IH), 7.56 (d, 0.5H). 7.47 (d, I 1.5H), 7,29 (d, ÍH), 7.13 (í, IH), 5,61- 5.15 (ín, 2H), 5.13- 4.85 (m, SH), 4.814.59 (m, IH), 4.52- 4.31 (m, SH}, 4,19- 4,01 (m, IH). 3.93 íbrs, IH), 3,79- 3.4) &lt;)n, IH), 3.39- 3.16 On, IH), 3.00- 2.87 (m, 2H), 2.83 ís, 3H), 2.68- 2.48 (ni, 21 i); LCMS: 97.88%, m/z®

580.05 (M+H: HPLC:

i 0 011

0.04

1?3

<td></td><td colspan="2">98,68%, rt; 3,58 min.</td><td></td><td></td>

<td> 99</td><td>.-vY</td><td>TfNMR (CDC¡₃, 40&lt;&gt;MHz):</td><td></td><td></td>

<td>hiiij</td><td>V- :7Y-lfííA_:^K: - N·Ye ....... .......................................:</td><td>ó 9.32 (s, 1H), 8.73 {$, 1H),</td><td></td><td></td>

<td colspan="2">.........A............ ............................_..</td><td>8,79 id, Π1), 7.9? (bts, iH),</td><td></td><td></td>

<td colspan="2">Ύ</td><td>7.55- 7,46 im, 2M5, 7.3i</td><td></td><td></td>

<td colspan="2">] Y</td><td>(dd, ÍH), 5.81- 5.23 im,</td><td></td><td></td>

<td colspan="2">.....mi i......... . ......lis</td><td>2H), .5,1.0- 4.72 (m, IH),</td><td></td><td></td>

<td colspan="2">i</td><td>4.28- 4.10 (rn. ÍH), 4 09 G,</td><td></td><td></td>

<td colspan="2">7)7 Ίϊ 1 1)</td><td>3ΪΒ, 3.90- 3.75 (rn. 11 í).</td><td></td><td>S.f s</td>

<td colspan="2">Lz ιΐι^ί^¹</td><td>5.45 (brs, IH), 3.39- 3.15'</td><td></td><td></td>

<td colspan="2">^:: sss tí : SS</td><td>(ni. ÍH), 3.10- 2,91 Cm, ÍH),</td><td></td><td></td>

<td colspan="2"> : ^::</td><td>2,82 (s, 3H&gt;, 2.50- 2,15 im,</td><td></td><td></td>

<td colspan="2">iiril</td><td>2H); LCMS: 100%, n: /</td><td></td><td></td>

<td colspan="2"> 7? 711111^: 7^7</td><td>596.2 ÍMH'I; HPLC:</td><td></td><td></td>

<td colspan="2"> 1 ...................................... ...... -.........</td><td>97.88%, rt: 3.83 min.</td><td> 0.0085</td><td></td>

Ensayos (01)272i Los compuestos de fa invención se evaluaron para medir s or ability to inhibit MLK activity. The unique properties of the compounds of the invention described herein can be evidenced by the tests of any of the following tests, [00273] A BRAF-MEK-ERK cascade test. [MEKI m i mM 1C5Ó uM [is used to evaluate the effects of these compounds as inhibitors of MAP kinase sia. An enzymatic cascade assay is fused using an activated reombtnant human BRAE kinase (V599E) (CaL No. 14-557), full-length human MEK1 quinase (CaL No, 14- 706} and an active human MAR kinase 2 / ERK2 of full length tCat N 14 536) enzymes obtained from Upstate. TRFRET detection technology (resonance of energy transfer time resuscitation) is used for reading. The assay buffer solution contains 50 mM Tris pH 7.5. 10 roM MgCb, 1 m.M 'OTE, 0.01% Tween 20, 0.1 nM BRAE. 2 nM of MEKI inactive, 10 nM ERK2 inactive, ΛΤΡ I mM and 500 n M of long-chain Molina activated peptide substrate 174:

ÍL.CI3- FFKNÍYTPRTPPP} in a format of 384 wells. The kinase reaction was stopped after 90 minutes with EDTA ÍO roM and the Lance detection mixture (phospboscan &amp; 'lre-onin antibody labeled with Eu 2 "M (Caí. No.ADO! 76- Perktn Elmer) , 20 oM SA- A PC is added (Cat.No CRÍ 30-100- Perkín Elmer). The signal from 'TR-FRKT (excitation at 840 nm, emission at 6 and 5 nm and 665 nia) is given with a delay time of 50 m&gt; in a Viciara V flow, the data is calculated using the reading ratio at 665 nm to 615 nm. The final concentration of DMSÜ is 2.5% in the assay. The compounds are screened in a concentration of 50 µM with a pre-incubation of the enzymes in the presence of the test compound for 45 minutes.

(00274) Each individual IC is determined using a 10-point dose response curve generated by Version 4 GraphPad Prism software (San Diego, Ca lifornia, USA,), using a linear non-regression curve adjustment for the sigmoidal dose response (variable slope). The CI values ​​obtained for the compounds of the invention are listed in Lab 1.2 above.

(00275) An in vitro MAP kinase assay is configured through qumttsa

MAR activated 2 / ERK2 (Caí. N 54- 550), obtained from Upstate. TR-FREI 'detection technology is used for reading.

) 00276) The test buffer solution contains Ttis 50 rn, M p 7.5. MgCU 10 n) M&gt;

ELE! I mM, 0.058o of Tween 2.0, LRh.2 activates InM. 100 ®M ATP and 500 nM peptide substrate; long chain biotiua activated (LCB-íTKNi VTPRTPPP) in a 384 well format. The kinase reaction was stopped after 90 minutes with 10 mM EDTA and the phosphoric serine / threonine &amp; Lance Antibody detection mixture labeled with 2 nM Eu (art. AD0176-Perkin Elmer). 20 nM SA-APC is added (art. CR130 - 100- Perkin El mer). The TR-FRET signal (excitation at 340 nm, emission at 65 5 nm and 665 nm) is read with 50 ms as the delay time on a Vieorl V rain. The data is calculated using the ratio of readings cn 665 nm at or i 5 nm. The final concentration of DMSO is 2.5% in the assay. The compounds are screened in a concentration of 50 mM with a pre-incubation of the enzymes in the presence of the test compound for 45 minutes. 5. The compounds of the invention were inactive in this test, for example, the example. 14 (16% inhibition at 10 uM), e? example. 1A (55% inhibition at 10 uM),

175 [00277 (The radioactive filter binding assay has been standardized using human activated BKAF kinase (V599E) tecombinatne (Cat. No. 14-55?) And dead MEKi quinase (R97R) (Cat. No, 14-737) acquired The incorporation of P 'into MFK i (K9? R) by BKAF (V599E) is measured with finel test conditions of 59 mM Tris pH 7.5, 10 mM Muf-b, B IT i¡NM. 100 ntM sucrose, 100 tnM orthovanaditium of «sodium, ATP 5 tnM and 2. Cí ['32P γ' (ATP and 500 mg of kina substrate »MEK1 dead. The enzyme reaction stopped after 120 minutes with HCi hydrochloric acid) 8N and A'í'P i tnM. The solution was seen in Papal Litro PX i and washed 4 times with 0.75% orthophosphoric acid and finally with acetone. The dried P81 filter papers are read in a micro-beta frmlux cemclieo counter. The final Je DMSO concentration is 1% in the assay. The Cutiipttesios are screened at a concentration of 1 0 ntM with a pre-incubation of the enzymes in the presence of the test compound for 45 minutes. Sos compounds of the invention were found to be inactive in this assay, for example, 33 (13% inhibition at 10 µM), and, for example, 1 ejemplo (0% inhibition at tOuM),

IO02? #! These tests described above are fully detailed in estuary. Shulin, et, a!, Fíoorganic &amp; Medicinal Chemistry Letíers (¿005) 35, 5467-5473, and in Yeh, et. al .. Cito Cancer Res. (2007) 13 (5). and 576-1583.

[00279 (Cl cell viability assay in A.375 cells (0 50 IC Λ375 in ia

Table 2) is configured in a form of 96-plate, wells-using-XTX XTT is a yellow salt that degrades to orange dye from tormazano by the mitochondria of the metabolically active cells. The procedure allows rapsda to be determined in a pktca of ruveblvrak ur, ob'emcn lo resn t, uf t teroodikíhlcs \ sensible [60280 (A375 cells were grown in DMLM medium containing 10% FBS and sodium pyruvate mM , The cells are treated with trypsin and seeded at 7,000 well cells 7. After allowing the cells to adhere for u-, nu, that compound is added to Sos wells at the following lucial concentrations: 10, 3, I, 0.3 , 0.1, 0.03, 0.01. 0.00). and 0.0001 wM, the test is performed in triplicate for each concentration n. DMSO concentrations are maintained at 0.5% 7 well, just days after the compound is added, the ΧΤΪ test is performed. The wells were washed once with BBS. 100 pL of DMEM medium without a phenol or l-'Bb mixture are added to each well. 0.85 mg mi wek; by poop 5 ipí 50 μί ue! a solueron de traMt'o Je X¹'¹, add to each well ΐ to abrro'bíÍnna de ^!or pitea l% é a 4¡ \ 5 ¡hoop using a Speetramav YO iMohmuidr Pinire-a equipment) Absorbing it from ios wells · with culture media and only X i 1, but without udiutas it is considered a census of the Macau \ Maneo \ -c&gt; ta of the Icetuias of all the wells of the feasibility test eetulat deviated tonalmente ep Seudiero, et al. Canesú · Research Od'W a8, from 4837 rusta 4831- C isolates », et añ, to Nati Institute of⁵ C-UK'f, i Y89} 81, S ??. sg_{f} i}&gt; Bochín, et uL J IromunuLM cthods [ 19911 '.42 257- 2u? I os aalores de Clv obtenidos pasa ios compuestos de ¡a tuvensíon se enumesan en la. tabla 2 a continuación

<td rowspan="2">00281J Ejemplo</td><td colspan="2">Γ,ιΜη 2 Todos ’os \ afores dr Ci-, están en la 1 ‘M.</td><td rowspan="2">A3”S XI'!' ICSOa.M</td>

<td>MERÍAÍT 1 mM 050</td><td>A3”5 if \\ 1C50</td>

<td>i A</td><td>0 00’s</td><td> 0.0(,39</td><td>0U0?</td>

<td>IB</td><td> 0.158</td><td></td><td></td>

<td>*ϊ</td><td>0,72o</td><td> 3 27</td><td> 2 41</td>

<td> 3</td><td> 0.101</td><td>O t'52</td><td> 0 468</td>

<td> 4</td><td> 0.30°</td><td></td><td></td>

<td>A</td><td> 0.04</td><td> 0 28</td><td> 0 521</td>

<td> 6</td><td>o.o&lt;-&gt;?.</td><td> 0 267</td><td>u.232</td>

<td> '7</td><td> 0.468</td><td></td><td></td>

<td> 8</td><td> 0.015</td><td> 0.34</td><td>O .3 i 9</td>

<td> 0</td><td> 0 103</td><td> 0 244</td><td> 0 7^</td>

<td> 1!)</td><td> ' 0.213</td><td> 2 62</td><td> 2 09</td>

<td> 11</td><td> 2.55</td><td> &gt; 10</td><td> 6,55</td>

<td>i ·*&gt; •l ώ</td><td> 0.212</td><td> 0 712</td><td>Pal 14</td>

<td> 13</td><td> 0 515</td><td> 1 88</td><td> 5.11</td>

<td> 14</td><td>i' 007 ¡</td><td> 0 055</td><td> 0.076</td>

<td> 15</td><td> 0 016</td><td>0 i 18</td><td> 0 088</td>

<td>i 6</td><td>ü,0&gt;4</td><td>0 6p7</td><td> 0 587</td>

<td> 17</td><td> 0 093</td><td> ’’’ 0 224</td><td> 0.132</td>

<td> 18</td><td> 0.01?</td><td> 0.247</td><td>0 Y</td>

<td>id</td><td> 0 353</td><td>t g í „ /</td><td>O 64 5</td>

<td> 20</td><td> 0 157</td><td> 0.669</td><td>0 68 ΐ</td>

<td> 21</td><td> 0 028</td><td> ‘0,071</td><td> 0.086</td>

<td>si</td><td> 54ft</td><td> 10</td><td> &gt; 10</td>

<td> 23</td><td> 0 322</td><td></td><td></td>

<td> 24</td><td> 0 021</td><td> 0 22</td><td>0 16 í</td>

<td> 25</td><td>o 655</td><td> 4 05</td><td>1 *π· . . . . í r ;· ¿i·.:</td>

<td>zh</td><td> 0.0043</td><td> 0 004</td><td>0 di S</td>

177

<td> £.} </td><td></td><td> 0.073</td><td> 0.365</td><td> 0.362</td>

<td> 28</td><td></td><td> 0.00.3?</td><td> 0.0047</td><td> 0 0048</td>

<td> 29</td><td></td><td> 0 0’9</td><td> 0.08!</td><td> 0,091</td>

<td> 30</td><td></td><td> 0.011</td><td> 0.017</td><td> 0.014</td>

<td> 31</td><td></td><td> 0.003</td><td> 0.006</td><td> 0.0047</td>

<td> 32</td><td></td><td> 0.032</td><td> 0,1</td><td> 0.094</td>

<td>• X&gt; Χ .0 3</td><td></td><td> 0.028</td><td> 0 06</td><td> 0,054</td>

<td> 34</td><td></td><td> 0.088</td><td> 0,151</td><td> 0.212</td>

<td> 35</td><td></td><td> 0 019</td><td> 0.018</td><td> 0.026</td>

<td> 36</td><td></td><td> 0.026</td><td>U Ο '· ^</td><td> 0 001</td>

<td>“Í?</td><td></td><td> 0.002?</td><td> 0-009</td><td> 0.008</td>

<td> 38</td><td></td><td> 0.0046</td><td> 0,063</td><td> 0.1 1«</td>

<td> 39</td><td></td><td> 0.455</td><td></td><td></td>

<td> 40</td><td></td><td> 0.186</td><td></td><td></td>

<td> 4?</td><td></td><td> 0.022</td><td> 0.62</td><td> 2.8</td>

<td> 42</td><td></td><td> 0.085</td><td> 0,239</td><td> 0.208</td>

<td></td><td></td><td> 0,06</td><td> 0,848</td><td> 0.677</td>

<td></td><td></td><td> 0 51?</td><td> 3,8</td><td> 2.38</td>

<td> 44</td><td></td><td> 0.002</td><td> 0.026</td><td> 0,0! 1</td>

<td> 45</td><td></td><td> 0:.101 &gt; 10</td><td></td><td> 4.2?</td>

<td> 46</td><td></td><td> 0.01</td><td> 1 0.206</td><td> 2.63</td>

<td> 47</td><td></td><td> 0,0017</td><td> 0,016</td><td> 0.011</td>

<td> 48</td><td></td><td> 0.011</td><td> 0.044</td><td> 0,025</td>

<td> 49</td><td></td><td> 0.232</td><td> 0.019</td><td> 0,034</td>

<td> 50</td><td></td><td> 0.012</td><td> 0.072</td><td> 0,067</td>

<td> 5!</td><td></td><td> ......0:.001.....</td><td> 0:.0211 .</td><td> 0.004</td>

<td> 52</td><td></td><td> 0.009</td><td> 0,109</td><td> 0.159</td>

<td> '53</td><td></td><td> 0.0062</td><td> 01029</td><td> 0.012</td>

<td> 54</td><td></td><td> 0.0015</td><td> 0.042</td><td> 0.025</td>

<td> 55</td><td></td><td> 0.04?</td><td> 0.231</td><td> 0.319</td>

<td> 56</td><td></td><td> 0.28</td><td></td><td></td>

<td>57 j</td><td></td><td> 0.019</td><td> 0.089</td><td> 0041</td>

<td> 58</td><td></td><td> &lt;003</td><td> 0.014</td><td> 0.008</td>

<td> 59</td><td></td><td> 0.018</td><td> 0.609</td><td> 1.6</td>

<td> 60</td><td></td><td> &lt;113</td><td> 0.499</td><td>!? ί</td>

<td> 61</td><td></td><td> :::::7: -//-^/::0^^2/-</td><td> ................:^: 0,168.............</td><td> 0.193</td>

<td> 62</td><td></td><td> 0.0037</td><td> 0.049</td><td>Ο.Ο55</td>

<td> 63</td><td></td><td> 0.0085</td><td> 0,245</td><td> 0.714</td>

<td> 64</td><td></td><td> 0/0053</td><td> 0,007</td><td> 0,016</td>

<td> 65</td><td></td><td> 0.0024</td><td> 0,005</td><td> 0,007</td>

<td> 66</td><td></td><td>:: // 1 //////: /; / &lt;01ί; 1 /// 1_:&lt;&lt;.//////</td><td></td><td></td>

<td> 67</td><td></td><td> 0.053</td><td> 0.539</td><td> 0.281</td>

<td> 68</td><td></td><td> 0.004?</td><td> 0.007</td><td> 0.0025</td>

<td> 69</td><td></td><td> 0,059</td><td> 0.272</td><td> 0,708</td>

0.0043 0.033 0.06

..................................................&lt;039......................................................0.076.............................................0.144

................................................ 0.045. ........................................OR. i97 &lt;625

178

<td> 73</td><td> 0.0056</td><td> 0.175</td><td> 0,254</td>

<td> 74</td><td> 0.01</td><td> 1,55</td><td> .3,69</td>

<td>lliJsééY</td><td> 0.0058</td><td> 0.250</td><td>s7: S-Í9 |_::</td>

<td> 70</td><td> 0 04</td><td> 0.022</td><td> 0.013</td>

<td>177- i) .....</td><td> 0.08</td><td> 0.005</td><td> 0.09</td>

<td> 1387777;:;</td><td>YYYY-^:YllYY2; éif7922 ..... 7ί; ι?; 9 | 7ΐ;: 77ΐ- ;;</td><td></td><td></td>

<td> 39-7-77</td><td> 0.0092</td><td> 0.007</td><td> 0.0056</td>

<td> 80</td><td> 0.013</td><td> 0,06</td><td> 0.08</td>

<td> 81</td><td>0Ό07</td><td> 0381</td><td> 1.148</td>

<td> 82</td><td> 0,0045</td><td> ......::27.8,</td><td> 71</td>

<td> 83</td><td> ....... 0.047</td><td> 0 088</td><td> 0 30?</td>

<td> 84</td><td> 0.022</td><td> 0.058</td><td> 0.225</td>

<td> 85</td><td>7 7? : / 27: 72 íí ;;;; íOT; í; íi; í; ííí ;; í lililí</td><td> 0.016</td><td>_;; :0,:02:1</td>

<td> &gt;861</td><td> :::: 7.9 &lt;0i.): 1: 12 :: 7Ϊ '</td><td> 0.! 76</td><td> 0,175</td>

<td> 87</td><td> 0.0062</td><td> 0.020</td><td> 0.012</td>

<td> 88</td><td> 0,0057</td><td> 0.053</td><td> 0708</td>

<td> 89</td><td> 0.0026</td><td> 0.04</td><td> 0.045</td>

<td> 00</td><td> 0 0026</td><td> .0,019</td><td> 0,02</td>

<td> 01</td><td> 0 018 10</td><td> &gt; 10</td><td></td>

<td> 02</td><td> 0:.032</td><td> 0 145</td><td> 0.135</td>

<td> 03</td><td> 0,025:</td><td> 0 004</td><td> 0.061</td>

<td> 94</td><td>2: ;; 77l7; -? 2? 2: s; ÓÍO272^;; ÍH; 7 ^ l ^</td><td> 0:006</td><td> 0 00?</td>

<td> 105-11¾..........</td><td> • 0,0073: ...,·</td><td> '77: ::7077::77:::73(-)7:7::7:</td><td> 0,031</td>

<td>0fi</td><td> 0.04</td><td> 0.359</td><td> 0.394</td>

<td> 07</td><td>0.01 i</td><td>0 and 12</td><td> 0.09</td>

<td> 48</td><td>7777 ···:;? - ®, 047 / Y;</td><td> 0 547</td><td> 0.55?</td>

<td> 99</td><td>0 í¡ (¡85</td><td> ::::::7 3703:5::,1:7-,:............</td><td> 0.531</td>

1002821 } 00283] The viability percentage is calculated taking into account the value subtracted as target of Sos wells treated with DMSO as 00% viable. Clso values ​​are calculated using GrapbPad Prista, using regression curve adjustment nonlinear for the sigrooldal dose response (variable slope). The cranposes of the invention were evaluated in this cell viability assay. Bear values ​​obtained for the compounds of the invention are listed in Table 2 2 above.

A3? 5 P- Erk fin- Cell-western) (Clynde A375 ICW in Table 2i:

00284] Human melanoma A375 cells were seeded at 50,000 cells per well vn 1O0 μΐ of growth medium in 96-well Costar ciaras pe black bottom plates and cohxed at 37 ^toC i 5% of &lt;. '&lt;&gt;&gt; overnight. The compounds of! Assay was diluted in DMSO to generate a concentration curve. A stock solution of 5 irsM was used for concentration beyond 500 times; to obtain a final concentration of 179 μλί with dilutions of 3 times descending I started O.OOÍHpM. t μΐ of diluted compound was added to 500 μΐ of the cell culture medium and mixed well. The middle of the cells and 200 ul of the medium containing the compound was added. The cells were treated for 3 years with the compound at 37^l'C, 5% CLL [0128S] After incubation of the compound, the cells were washed once with

PñS (Mg \ Ca '') and were fixed in 4% paralbnnaldehyde / PBS for 1 hour at room temperature. After fixation, the cells were washed three times with PBS.'I riten X-100 ai 0.1% (PBSY), and then 5% skimmed milk / EBST toa were blocked, for 2 hours 50 were added μΐ per well of a primary antibody (rabbit uniform antibody-ERKI / 2) at 1: 30 in skim milk · PRST% and incubated overnight at 4 ° C. The cells were washed four times with i 00 p! DELE! wash ismpon A and were added. 50 ul per well of the secondary antibody (anti-rabbit antibody labeled with DELYÍA-UE-Ni} ai: 306 () in DLLEÍA test lamp and incubated for 2 hours at a temperature Tura atmosphere in the dark (covered). The cells are washed 4 times with 100 μΐ of RELEIA wash lamp. 56 nor per well VVallacDELF1A motor solution was added. The plates were stirred at room temperature for 20 min and then read in the Perkin Linter Yietorív reader with the configuration of .Europium (emission / excitation of 615/340 nm), | 0O286j The Clm values ​​were calculated using the DMSO dilution values ​​as 0% inhibitor: and the highest concentration counts tested for the 100% inhibition reference inhibitor. Iodine concentrations: analyzed with DMSO were performed in triplicate. The values ​​obtained from C'bs for the compounds of the present invention are indicated in Table 2.

| 00287j It is understood that the examples and embodiments described herein are for illustrative purposes only and that the various modifications or changes in the light thereof will be suggested to experts. The technical nature and scope of the spirit and scope of the present application and the scope of the appended claims must be included.

t00288] Brief Description of Your Drawings

180

Figure 1 shows the XRPD pattern for Form A of the free form of 1- ((38,45) - 4 (8- (2- doro- 4- (pyrimidin- 2- íio \ í) foni.!) - 7- fluoro- 2- methyl- IB · imidazo ^ ,? · cjquínohn · 1 il) ~ 3- fluoropiperidin- J-yl) - 2- hydroxyetonone.