OA17028A

OA17028A - Inhibitors of influenza viruses replication.

Info

Publication number: OA17028A
Application number: OA1201400042
Authority: OA
Inventors: Paul Charifson; Michael P. Clark; Upul Bandarage; Randy S. Bethiel; Michael J. BOYD; Ioana Davies; Hongbo Deng; John P. Duffy; Luc J. Farmer; Huai Gao; Wenxin Gu; Joseph M. Kennedy; Brian Ledford; Mark W. Ledeboer; Francois Maltais; Emanuele Perola; Tiansheng Wang
Original assignee: Vertex Pharmaceuticals, Incorporated
Priority date: 2011-08-01
Filing date: 2012-08-01
Publication date: 2016-03-04

Abstract

Methods of inhibiting the replication of influenza viruses in a biological sample or patient, of reducing the amount of influenza viruses in a biological sample or patient, and of treating influenza in a patient, comprises administering to said biological sample or patient an effective amount of a compound represented by Structural Formula (I) : <img file="OA17028A_A0001.tif"/> or a pharmaceutically acceptable salt thereof, wherein the values of Structural Formula (I) are as described herein. A compound is represented by Structural Formula (I) or a pharmaceutically acceptable salt thereof, wherein the values of Structural Formula (I) are as described herein. A pharmaceutical composition comprises an effective amount of such a compound or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant or vehicle.

Description

Influenza spreads around the world in seasonal épidémies, resulting in the deaths of hundreds of thousands annually - millions in pandémie years. For example, three influenza pandémies occurîed in the 20th century and killed tens of millions of people, with each of these pandémies being caused by the appearance of a new strain of the virus in humans. Often, these new strains resuit from the spread of an existing influenza virus to humans from other animal species.

Influenza is primarily transmitted from person to person via large virus-laden drop Jets that are generated when infected persons cough or sneeze; these large droplets can then settle on the mucosa! surfaces of the upper respiratory tracts of susceptible individuals who are near (e.g. within about 6 feet) infected persons. Transmission mîght also occur through direct contact or indirect contact with respiratory sécrétions, such as touching surfaces contaminated with influenza virus and then touching the eyes, nose or mouth. Adults might be able to spread influenza to others from 1 day before getting symptoms to approximately 5 days after symptoms start. Young children and persons with weakened immune Systems might be infectious for 10 or more days after onset of symptoms.

Influenza viruses are RNA viruses of the family Orthomyxoviridae, which comprises five généra: Influenza virus A, Influenza virus B, Influenza virus C, Isavirus and Thogoto virus. The Influenza virus A genus has one species, influenza A virus. Wild aquatic birds are the naturel hosts for a large variety of influenza A. Occasionally, viruses are transmitted to other species and may then cause devastating outbreaks in domestic poultry or give rise to human influenza pandémies. The type A viruses are the most virulent human pathogens among the three influenza types and cause the most severe disease. The influenza A virus can be subdivided into different serotypes based on the antibody response to these viruses. The serotypes that hâve been confirmed in humans, ordered by the number of known human pandémie deaths, are: H1N1 (which caused Spanish influenza in 1918), H2N2 (which caused Asian Influenza in 1957), H3N2 (which caused Hong Kong Flu in 1968), H5N1 (a pandémie threat in the 2007-08 influenza season), H7N7 (which has unusual zoonotic potential), H1N2 (endemic in humans and pigs), H9N2, H7N2, H7N3 and H10N7. The Influenza virus B genus has one species, influenza B virus. Influenza B almost exclusively infects humans and is less common than influenza A. The only other animal known to be susceptible to influenza B infection is the seal. This type of influenza mutâtes at a rate 2-3 times slower than type A and consequently is less genetically diverse, with only one influenza B serotype. As a resuit of this lack of antigenic diversity, a degree of immunity to influenza B is usually acquired at an early âge. However, influenza B mutâtes enough that lasting immunity is not possible. This reduced rate of antigenic change, combined with its limited host range (inhibiting cross species antigenic shift), ensures that pandémies of influenza B do not occur.

The Influenza virus C genus has one species, influenza C virus, which infects humans and ptgs and can cause severe illness and local épidémies. However, influenza C is less common than the other types and usually seems to cause mild disease in children.

Influenza A, B and C viruses are very similar in structure. The virus particle is 80-120 nanometers in diameter and usually roughly spherical, although filamentous forms can occur. Unusually for a virus, its genome is not a single piece of nucleic acid; instead, it contains seven or eight pièces of segmented negative-sense RNA. The Influenza A genome encodes 11 proteins: hemagglutinin (HA), neuraminidase (NA), nucleoprotein (NP), Ml, M2, NSI, NS2(NEP), PA, PBI, PB1-F2 and PB2.

HA and NA are large glycoproteins on the outside of the viral particles. HA is a lectin that médiates binding of the virus to target cells and entry of the viral genome into the target cell, while NA is involved in the release of progeny virus from infected cells, by cleaving sugars that bind the mature viral particles. Thus, these proteins hâve been targets for antiviral drugs. Furthermore, they are antigens to which antibodies can be raised. Influenza A viruses are classified into subtypes based on antibody responses to HA and NA, forming the basis of the H and N distinctions (vide supra) in, for example, H5N1.

Influenza produces direct costs due to lost productivity and associated medical treatment, as well as indirect costs of preventative measures. In the United States, influenza is responsible for a total cost of over $ 10 billion per year, while it has been estimated that a future pandémie could cause hundreds of billions of dollars in direct and indirect costs.

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Preventative costs are also high. Govemments worldwide hâve spent billions of U.S. dollars preparing and planning for a potentia! H5N1 avian influenza pandémie, with costs associated with purchasing drugs and vaccines as well as developing disaster drills and strategies for improved border controls.

Current treatment options for influenza include vaccination, and chemotherapy or chemoprophylaxis with anti-viral médications. Vaccination against influenza with an influenza vaccine is oflen recommended for high-risk groups, such as children and the elderly, or in people that hâve asthma, diabètes, or heart disease. However, it is possible to get vaccinated and still get influenza. The vaccine is reformulated each season for a few spécifie influenza strains but cannot possibly include ail the strains actively infect in g people 15 in the world for that season. It takes about six months for the manufacturera to formulate and produce the millions of doses required to deal with the seasonal épidémies; occasionally, a new or overlooked strain becomes prominent during that time and infects people although they hâve been vaccinated (as by the H3N2 Fujian flu in the 2003-2004 influenza season). It îs also possible to get infected just before vaccination and get sick with the very strain that 20 the vaccine is supposed to prevent, as the vaccine takes about two weeks to become effective.

Further, the effectiveness of these influenza vaccines is variable. Due to the high mutation rate of the virus, a particular influenza vaccine usually confers protection for no more than a few years. A vaccine formulated for one year may be ineffective in the following year, since the influenza virus changes rapidly over time, and different strains become dominant.

Also, because of the absence of RNA proofreading enzymes, the RNA-dependent RNA polymerase of influenza vRNA makes a single nucléotide insertion error roughly every 10 thousand nucléotides, which is the approximate length ofthe influenza vRNA. Hence, nearly every newly-manufactured influenza virus is a mutant—antigenic drift. The séparation of the genome into eight separate segments of vRNA allows mîxing or reassortment of vRNAs if more than one viral line has infected a single cell. The resulting rapid change in viral genetics produces antigenic shifts and allows the virus to infect new host species and quickly overcome protective immunity.

Antiviral drugs can also be used to treat influenza, with neuraminidase inhibitors being particularly effective, but viruses can develop résistance to the standard antiviral drugs.

Thus, there is still a need for drugs for treating influenza infections, such as for drugs with expanded treatment window, and/or reduced sensitivity to viral titer.

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SUMMARY OF THE INVENTION

The présent invention generally relates to methods of treating influenza, to methods of inhibiting the réplication of influenza viruses, to methods of reducing the amount of influenza viruses, and to compounds and compositions that can be employed for such methods.

In one embodiment, the présent invention is directed to a compound represented by Structural Formula (I):

or a pharmaceutically acceptable sait thereof, wherein:

X¹ is -F, -Cl, -CF₃, -CN, or CHj;

X²is-H,-F, or-Cl;

Z¹ isNorCH;

Z²isNorCR°;

Z³ is CH or N;

Y is -C(R⁴R⁵)-[C(R⁶R⁷)]_n-Q or-C(R⁴)=C(R⁶)-Q;

R°is-H, -F.orCN;

R¹, R², and R³ are each and independently-CH₃, -CHîF, -CF₃, -C2H5, -CH2CH2F, -CH2CF₃; or optionally R² and R³, or R¹, R² and R³, together with the carbon atom to which they are attached, form a 3-10 membered carbocyclic ring;

R⁴ and R³ are each and independently -H;

R⁶ and R⁷ are each and independently-H, -OH, -CH₃, or-CF₃; or optionally, R^s and R⁷ together with the carbon atoms to which they are attached form a cyclopropane ring; and

-417028 each Q is independently -C(O)OR, -OH, -CH₂OH, -S(O)R’, -P(0)(0H)2, -S(O)jR·,

-S(O)₂-NR”R’”, or a 5-membered heterocycle selected from the group consisting of:,

J^is-H, -OH or-CH₂OH; Ris-H or Cm alkyl;

R’ is-OH, Cm alkyl, or -CH₂C(O)OH;

R”is-H or-CHj;

R*” is -H, a 3-6 membered carbocyclic ring, or Cm alkyl optionally substituted with one or more substituents selected from the group consisting of halogen, -OR* and C(O)OR·;

R‘ is -H or Cm alkyl; and n isOor 1.

In another embodiment, the présent invention is directed to a pharmaceutical composition comprising a compound disclosed herein (e.g., a compound represented by any one of Structural Formulae (I) - (X), or a pharmaceutically acceptable sait thereof) and a pharmaceutically acceptable carrier, adjuvant or vehicle.

In yet another embodiment, the présent invention is directed to a method of inhîbiting the réplication of influenza viruses in a biological sample or patient, comprising the step of administering to said biological sample or patient an effective amount of a compound disclosed herein (e.g., a compound represented by any one of Structural Formulae (I) - (X), 25 or a pharmaceutically acceptable sait thereof).

In yet another embodiment, the présent invention is directed to a method of reducing the amount of influenza viruses in a biological sample or in a patient, comprising administering to said biological sample or patient an effective amount of a compound disclosed herein (e.g., a compound represented by any one of Structural Formulae (I) - (X), or a pharmaceutically 30 acceptable sait thereof).

In yet another embodiment, the présent invention is directed to a method of method of treating influenza in a patient, comprising administering to said patient an effective amount of a compound disclosed herein (e.g., a compound represented by any one of Structural Formulae (I) - (X), or a pharmaceutically acceptable sait thereof).

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The présent invention also provides use of the compounds described herein for inhibiting the réplication of influenza viroses in a biologicai sample or patient, for reducing the amount of influenza viroses in a biologicai sample or patient, or for treating influenza in a patient. Also provided herein is use of the compounds described herein for the manufacture of a médicament for treating influenza in a patient, for reducing the amount of influenza viruses in a biologicai sample or in a patient, or for inhibiting the réplication of influenza viruses in a biologicai sample or patient.

Also provided herein are the compounds represented by Structural Formula (XX):

or a pharmaceutically acceptable sait thereof. Without being bound to a particular theory, the compounds of Structural Formula (XX) can be used for synthesizing the compounds of Formula (I). The variables of Structural Formula (XX) are each and independently as defîned herein; and when Z* is N, G is trityl (i.e., C(Ph)i where Ph is phenyl), and when Z¹ is CH, G is tosyl (Ts: CHiCîH^SOî) or trityl.

The invention also provides methods of preparing a compound represented by Structural Formula (I) or a pharmaceutically acceptable sait thereof. In one embodiment, the methods empïoy the steps of:

reacting compound A:

(A) with compound B :

’ [Dl

G ¹ 'to form a compound represented by Structural Formula (XX):

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deprotecting the G group of the compound of Structural Formula (XX) under suitable conditions to form the compound of Structural Formula (I),wherein:

the variables of Structural Formulae (I) and (XX), and compounds (A) and (B) are 10 independently as defined herein; and

I? is a halogen; and when Z’ is N, G is trityl; when Z¹ is CH, G is tosyl or trityl.

In yet another embodiment, the methods employ the steps of:

compound represented by Structural Formula (XX):

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deprotecting the G group of the compound of Structural Formula (XX) under suïtable conditions to form the compound of Structura! Formula (I),wherein:

the variables of Structura! Formulae (I) and (XX), and compounds (L), (K), and (D) are each and independently as defined herein; and when Z¹ is N, G is trityl; when Z¹ is CH, G is tosy! or trityl.

In yet another embodiment, the methods employ the steps of:

reacting Compound (G) with Compound (D):

under suitable conditions to form a compound represented by Structural Formula (XX):

deprotecting the G group ofthe compound of Structura! Formula (XX) under suitable conditions to form the compound of Structural Formula (I),wherein:

-817028 the variables of Structural Formulae (I) and (XX), and Compounds (G) and (D) are each and independently as defined herein;

L¹ is a halogen; and when Z* is N, G is trityl; when Z¹ is CH, G is tosyl or trityl.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 shows certain compounds of the invention.

DETAILED DECRIPTION OF THE INVENTION

The compounds of the invention are as described in the claims. In some embodiments, the compounds of the invention are represented by any one of Structural Formulae (I) - (X), or pharmaceutically acceptable salts thereof, wherein the variables are each and independently as described in any one ofthe daims. In some embodiments, the compounds ofthe invention are represented by any chemical formulae depicted in Table 1 and FIG. 1, or pharmaceutically acceptable salts thereof. In some embodiments, the compounds ofthe invention are presented by Structural Formulae (I) - (X), or a pharmaceutically acceptable sait thereof, wherein the variables are each and independently as depicted in the chemical formulae in Table 1 and FIG. 1.

In one embodiment, the compounds of the invention are represented by Structural Formula (I) or pharmaceutically acceptable salts thereof:

wherein the values ofthe variables of Structural Formula (I) are as described below.

The first set of values of the variables of Structura! Formula (I) is as follows:

X¹ is -F, -Cl, -CFj, -CN, or CH3. In one aspect, X* is -F, -Cl, or -CF3. In another aspect, X¹ is -F or-CI.

X² is -H, -F, -CI, or -CF3. In one aspect, X² is -F, -CI, or -CF3, ln another aspect, X²is-For-Cl.

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Z¹ is N or CH. In one aspect, Z* is CH. In another aspect, Z* is N.

Z² is N or CR°. In one aspect, Z² is N, C-F, or C-CN. In another aspect, Z² is N.

Z³ is CH or N. In one aspect, Z² is CH.

Y is “C(R⁴R^s)-[C(R⁶R⁷)]_n-Q or-C(R*)=C(R⁶)-Q.

R° is-H,-F, or CN.

R¹, R², and R³ are each and independently -CHj, -CH2F, -CFj, “C2H5, -CH2CH2F, -CH2CFj; or optionally R² and R³, or R¹, R² and R³, together with the carbon atom to which they are attached, form a 3-10 membered carbocyclic ring (including bridged carbocyclic ring, such as adamantly ring). In one aspect, R¹, R², and R³ are each and independently-CHj, or-C2H5, or optionally R² and R³, or R¹, R² and R³, together with the carbon atom to which they are attached, form a 3-10 membered carbocyclic ring. In another aspect, each of R , R , and R is independently-CH3, -CH2F, -CFj, or -C2H5, or R* is -CH3, and R² and R³ together with the carbon atom to which they are attached form a 3-6 membered carbocyclic ring. In another aspect, R¹, R², and R³are each and independently -CH3, -CH2F, -CFj, or -C2H5. In yet another aspect, R¹, R², and R³ are each and independently -CH3, or optionally R² and R³, or R¹, R² and R³, together with the carbon atom to which they are attached, form a 3-6 membered carbocyclic ring. Spécifie examples of carbocyclic ring include cyclopropyl, cyclobutyl, cyclopentyl, cylcohexyl, and bridged rings, such as adamantly group. In yet another aspect, R¹, R², and R³ are each and independently -CH3.

R* and R⁵ are each and independently-H.

R⁶ and R⁷ are each and independently-H, -OH, -CH3, or-CFs; or optionally, R^s and R⁷ together with the carbon atoms to which they are attached form a cyclopropane ring. In one aspect, R⁶ and R⁷ are each and independently-H, -OH, -CH3, or-CF3. In another aspect, R⁶ and R⁷ are each and independently -H.

Each Q is independently-C(O)OR, -OH, -CH₂OH, -S(O)R’, -P(O)(OH)₂, -S(O)₂R’, -S(O)2-NR*’R’*’, or a 5-membered heterocycle selected from the group consisting of:,

/³ is -H, -OH or -CH₂OH. Spécifie examples of the 5-membered heterocycles

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S(O)2R\ -S(O)2-NR*’R”\ or a 5-membered heterocycle selected from the group

CH2OH, -S(O)2R’, -S(O)2-NR”R”*, or a 5-membered heterocycle selected from the

S(O)2R’, or -S(O)2-NR”R*”. In yet another aspect, each Q is independently

C(O)OH, -OH, -S(O)₂R’, or -S(O)2-NR”R’”.

R is -H or Cm alkyl. In one aspect, R is -H.

R’ is -ΌΗ, Cm alkyl, or -CH2C(O)OH. In one aspect, R* is -ΌΗ or -CH2C(O)OH.

R” is -H or -CHj. In one aspect, R” is -H.

R’’’ is-H, a 3-6 membered carbocyclic ring, or Cmalkyl optionally substituted with one or more substituents selected from the group consisting of halogen, -OR* and C(O)OR*. In one aspect, R”’ is -H, a 3-6 membered carbocyclic ring, or optionally substituted Cmalkyl. In another aspect, R’” is -H or optionally substituted Cmalkyl. R* is -H or Cm alkyl. In one aspect, R is -H.

nisOor I.

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The second set of values of the variables of Structura! Formula (I) is as follows:

X¹ is-For-Cl.

X² is-For-Cl.

Values of the other variables are each and independently as described above in the first set of values of the variables of Structural Formula (I).

The third set of values of the variables of Structural Formula (I) is as follows:

X¹ is-For-Cl.

Z¹ isCH.

The fourth set of values of the variables of Structural Formula (I) is as follows:

X² is-For-Cl.

Z* is CH.

The fifth set of values of the variables of Structural Formula (I) is as follows:

X¹ Îs-For-Cl.

Z¹ isN

The sixth set of values of the variables of Structural Formula (I) is as follows:

X² is-For-Cl.

Z* isN

The seventh set of values of the variables of Structural Formula (I) is as follows:

X¹ is-For-Cl.

X² is-For-Cl.

Z* isCH.

The eighth set of values of the variables of Structural Formula (I) is as follows:

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X* is-For-Cl.

X² is-For-Cl.

Z¹ isN.

The ninth set of values of the variables of Structural Formula (I) is as follows:

X¹ is-For-Cl.

Z²is N, C-F, orC-CN.

The tenth set of values of the variables of Structural Formula (I) is as follows:

X² is-For-Cl

Z² isN, C-F, orC-CN.

The eleventh set of values of the variables of Structural Formula (I) is as follows:

Z* isCH.

Z²isN, C-F, orC-CN.

Z’ isN.

Z²isN, C-F, orC-CN.

The twelfih set of values of the variables of Structural Formula (I) is as follows:

X¹ is-For-Cl.

X² is-For-Cl.

Z¹ isN.

Z²isN, C-F, orC-CN.

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The thirteenth set of values of the variables of Structural Formula (I) is as follows:

X¹, X², Z¹, and Z² are each and independently as described above in any one of the first through twelfth sets of values of the variables of Structural Formula (I).

Each of R¹, R², and R³ is independently -CHî, -CH₂F, -CFj, or -C₂Hs_; or R* is -CHj, A 1 and R and R together with the carbon atom to which they are attached form a 3-6 membered carbocyclic ring.

The fourteenth set of values of the variables of Structural Formula (I) is as follows:

X , X , Z , Z, R, R , and R are each and independently as described above in any one of the first through thirteenth sets of values of the variables of Structural Formula (I)·

R⁶ and R⁷ are each and independently-H, -OH, -CHj, or -CFj.

The fifteenth set of values of the variables of Structural Formula (I) is as follows:

X¹, X², Z¹, Z², R¹, R², R³, R⁶, and R⁷ are each and independently as described above in any one of the first through fourteenth sets of values of the variables of Structural Formula (I).

Each Q is independently -C(O)OR, -OH, -CH₂OH, -S(O)₂R\ -S(O)₂-NR”R‘”, or a

5-membered heterocycle selected from the group consisting of:

The sixteenth set of values of the variables of Structural Formula (I) is as follows:

Each Q independently is -C(O)OR, -OH, -S(O)₂R’, or -S(O)₂-NR’’R’”.

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The seventeenth set of values of the variables of Structural Formula (I) is as follows:

Each Q independently is -C(O)OH, -OH, -S(O)₂R’, or -S(Oh-NR”R”*.

The eighteenth set of values of the variables of Structural Formula (I) is as follows:

Each Q independently is -C(O)OH, -S(O)₂R’, or -S(O)₂-NR”R’’’.

The nineteenth set of values of the variables of Structural Formula (I) is as follows: X¹, X², Z¹, Z², R¹, R², R³, R⁶, R⁷, and Q are each and independently as described above in any one of the first through sixteenth sets of values of the variables of Structural Formula (I).

R’ is-OH or-CH₂C(O)OH.

R”is-H.

R’” is-H, a 3-6 membered carbocyclic ring, or optionallysubstituted Cmalkyl. Values of the other variables are each and independently as described above in the first set of values of the variables of Structural Formula (I).

The twentieth set of values of the variables of Structural Formula (I) is as follows:

X¹, X², Z¹, Z², R¹, R², R³, R^e, and R⁷ are each and independently as described above in any one of the first through sixteenth sets of values of the variables of Structural Formula (I).

Each Q independently is-C(O)OH, -S(O)₂OH, -S(O)₂CH₂C(O)OH, -S(0)₂-NH(Cm alkyl).

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In another embodiment, the compounds of the invention are represented by any one of Structural Formulae (II) - (V), or pharmaceutically acceptable salts thereof:

wherein values of the variables of Structural Formulae (II) - (V) are each and independently as described above in any one of the first through twentieth sets of values of the variables of Structural Formula (I).

In another embodiment, the compounds of the invention are represented by any one of the Structural Formulae (VI) - (X), or pharmaceutically acceptable salts thereof:

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or a pharmaceutical ly acceptable sait thereof, wherein: R¹, R², and R³ are each and independently-CHj, -CH2F, -CFj, -C2H5, -CH2CH2F, -CH2CF3; and ring P is 3-6 membered carbocyclic ring; and wherein values of the other variables of Structural Formulae (VI) and (X) are each and independently as described above in any one of the first through twentieth sets of values of the variables of Structural Formula (I).

The twenty first set of values of the variables of Structural Formulae (II) - (X) is as follows: Ris H;

R’ is-OH or -CH₂C(O)OH.

R” is-H.

R*’’ is -H, a 3-6 membered carbocyclic ring, or optionally substituted Cm alkyl. Values of the other variables are each and independently as described above.

It is noted that, for example, Structural Formulae (VI), (VIII), and (IX) can also be shown as follows,

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In yct another embodiment, the compounds of the invention are represented by any one of Structural Formulae (I) - (X) or a pharmaceutically acceptable sait thereof, wherein values of the variables are each and independently as shown in the compounds of Table 1 or FIG. 1.

In yet another embodiment, the compounds of the invention are represented by any one of the structural formulae depicted in Table 1 and FIG. 1, or a pharmaceutically acceptable sait thereof.

As used herein, a reference to compound(s) of the invention (for example, the compound(s) of Structural Formula (I), or compound(s) of claim 1) will include pharmaceutically acceptable salts thereof.

The compounds of the invention described herein can be prepared by any suitable method known in the art. For example, they can be prepared in accordance with procedures described in WO 2005/095400, WO 2007/084557, WO 2010/011768, WO 2010/011756, WO 2010/011772, WO 2009/073300, and PCT/US2010/038988 filedon June 17,2010. For example, the compounds shown in Table I and FIG. 1 and the spécifie compounds depicted above can be prepared by any suitable method known in the art, for example, WO 2005/095400, WO 2007/084557, WO 2010/011768, WO 2010/011756, WP 2010/011772, WO 2009/073300, and PCT/US2010/038988, and by the exemplary synthèses described below under Exemplification.

The présent invention provides methods of preparing a compound represented by any one of Structural Formulae (I) - (X). In one embodiment, the compounds of the invention can be

-1817028 prepared as depicted in General Schemes 1-4. Any suitable condition(s) known in the art can be employed in the invention for each step depicted in the schemes.

In a spécifie embodiment, as shown in General Scheme 1, the methods comprise the step of reacting Compound (A) with Compound (B) under suitable conditions to form a compound of Structural Formula (XX), wherein each of L and L independently is a halogen (F, Cl, Br, or I), G is trityl and the remaining variables of Compounds (A), (B) and Structural Formula (XX) are each and independently as described above for Structural Formulae (I) - (X). Typical examples for L¹ and L² are each and independently Cl or Br. The methods further comprise the step of deprotecting the G group under suitable conditions to form the compounds of Structural Formula (I). Any suitable condition(s) known in the art can be employed in the invention for each step depicted in the schemes. For example, any suitable condition described in WO 2005/095400 and WO 2007/084557 for the coupling of a dioxaboraolan with a chloro-pyrimidine can be employed for the reaction between Compounds (A) and (B). Specifically, the reaction between compounds (A) and (B) can be performed in the presence ofPd(PPhj)< or Pdî(dba)3 (dba is dibenzylidene acetone). For example, the de-tritylation step can be performed under an acidic condition (e.g., trifluoroacetic acid (TFA)) in the presence of, for example, EtjSiH (Et is ethyl). Spécifie exemplary conditions are described in the Exemplification below Optionally, the method further comprises the step of preparing Compound (A) by reacting Compound (E) with Compound (D). Any suitable conditions know in the art can be employed in this step, and Compounds (E) and (D) can be prepared by any suitable method known in the art. Spécifie exemplary conditions are described in the Exemplification below.

General Scheme 1

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In another spécifie embodiment, as shown in General Scheme 2, the methods comprise the step of reacting Compound (G) with Compound (D) under suitable conditions to form a compound of Structural Formula (XX), wherein each of L¹ and L² independently is a halogen (F, Cl, Br, or I)> G is trityl, and the remaining variables of Compounds (G), (D) and

Structural Formula (XX) are each and independently as described above for Structural Formulae (I) - (X). Typical examples for L¹ and L² are each and independently Cl or Br. The methods further comprise the step of deprotecting the G group under suitable conditions to form the compounds of Structural Formula (I). Any suitable condition(s) known in the art

-2017028 can be employed in the invention for each step depicted in the schemes. For ex amp le, any suitable amination condition known in the art can be employed in the invention for the reaction of Compounds (G) and (D), and any suitable condition for deprotecting a Tr group can be employed in the invention for the deprotection step. For example, the amination step can be performed in the presence of a base, such as NEtj or NfPr^Et. For example, the detritylation step can be performed under an acidic condition (e.g., trifluoroacetîc acid (TFA)) in the presence of, for example, EtjSiH (Et is ethyi). Additional spécifie exempt a ry conditions are described in the Exemplification below Optionally, the method further comprises the step of preparing Compound (G) by reacting Compound (E) with Compound (B). Any suitable conditions know in the art can be employed in this step. For example, any suitable condition described in WO 2005/095400 and WO 2007/084557 for the coupling of a dioxaboralan with a chloro-pyrimîdine can be employed for the reaction between Compounds (E) and (B). Specifically, the reaction between compounds (E) and (B) can be performed in the presence of Pd(PPhj)4 or Pd2(dba)j (dba îs dibenzylidene acetone). Spécifie exemplary conditions are described in the Exemplification below.

General Scheme 2

-2117028

(G)

In yet another spécifie embodiment, as shown in General Scheme 3, the methods comprise the step of reacting Compound (K) with Compound (D) under suitable conditions to form a compound of Structura! Formula (XX), wherein G is trityl and the remaining variables of Compounds (K), (D) and Structura! Formula (XX) are each and independently as described above for Structural Formulae (I) - (X). The methods further comprise the step of deprotecting the G group under suitable conditions to form the compounds of Structural Formula (I). Any suitable condition(s) known in the art can be employed in the invention for each step depicted in the schemes. For example, any suitable reaction condition known in

-2217028 the art, for example, in WO 2005/095400 and WO 2007/084557 for the coupling of an amine with a sulfinyl group can be employed for the reaction of Compounds (K) with Compound (D). For example, Compounds (D) and (K) can be reacted in the presence of a base, such as NEtj or N(*Pr)2(Et). For example, the de-tritylation step can be performed under an acidic condition (e.g., trifluoroacetic acid (TFA)) in the presence of, for example, EtjSiH (Et is ethyl). Additional spécifie exemplary conditions are described in the Exemplification below Optionally, the method further comprises the step of preparing Compound (K) by oxidizing Compound (J), for example, by treatment with meta-chloroperbenzoîc acid.

Optionally, the method further comprises the step of preparing Compound (J) by reacting Compound (H) with Compound (B). Any suitable conditions know in the art can be employed in this step. For example, any suitable condition described in WO 2005/095400 and WO 2007/084557 for the coupling of a dioxaboraolan with a chloro-pyrimidine can be employed for the reaction between Compounds (H) and (B). Specifically, the reaction between compounds (H) and (B) can be performed in the presence of Pd(PPhj)4 or Pd2(dba)j (dba is dibenzylîdene acetone). Spécifie exemplary conditions are described in the

Exemplification below.

General Scheme 3

-2317028

(B)

G

In yet another spécifie embodiment, as shown in General Scheme 4, the methods comprise the step of reacting Compound (L) with Compound (D) under suitable conditions to form a compound of Structural Formula (XX), wherein G îs trityl and the remaining variables of 10 Compounds (L), (D) and Structural Formula (XX) are each and independently as described above for Structural Formulae (I) - (X). The methods further comprise the step of deprotecting the G group under suitable conditions to form the compounds of Structural Formula (I). Any suitable condition(s) known în the art can be employed in the invention for each step depicted in the schemes. For example, any suitable reaction condition known in

-2417028 the art, for example, in WO 2005/095400 and WO 2007/084557 for the coupling of an amine with a sulfonyl group can be employed for the reaction of Compounds (L) with Compound (D). For example, Compounds (D) and (L) can be reacted in the presence of a base, such as NEtj or N('Pr)2(Et). For example, the de-tritylation step can be performed under an acidic condition (e.g., trifluoroacetic acid (TFA)) in the presence of, for exemple, EtjSiH (Et is ethyl). Additional spécifie exemplary conditions are described in the Exemplification below Optionally, the method further comprises the step of preparing Compound (L) by oxidizing Compound (J), for example, by treatment with meta-chloroperbenzoic acid. Optionally, the method further comprises the step of preparing Compound (J) by reacting Compound (H) with Compound (B). Reaction conditions are as described above for General

Scheme 3.

General Scheme 4

-2517028

(B)

G

(D

Compounds (A)-(K) can be prepared by any suitable method known in the art. Spécifie exemplary synthetic methods of these compounds are described below in the Exemplification. In one embodiment, Compounds (A), (G), (J), (K) and (L) can be prepared 10 as described in General Schemes 1-4.

In some embodiments, the présent invention is directed to a compound represented by Structural Formula (XX), wherein the variables of Structural Formula (XX) are each and independently as defined in any one of the daims and G is trityl. Spécifie examples of the compounds represented by Structural formula (XX) are shown below in the Exemplification.

-2617028

Some spécifie examples include: Compounds 3a, 8a, 28a, 34a, 39a, 42a, 51a, 57a, 80a, 84a, 90a, 101a, 119a, 144a, 148a, 154a, 159a, 170a, 176a, 182a, 184a, 191a, 197a, 207a, and 218a, which are shown in the Exemplification below.

Définitions and General Termlnolozv

For purposes of this invention, the chemical éléments are identified in accordance with the Periodic Table of the Eléments, CAS version, Handbook of Chemistry and Physics, 75th Ed. Additionally, general principles of organic chemistry are described in “Organic Chemistry”, Thomas Sorrell, University Science Books, Sausolito: 1999, and “March’s Advanced Organic Chemistry”, 5th Ed., Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference.

As described herein, compounds of the invention may optionally be substituted with one or more substituents, such as illustrated generally below, or as exemplified by particular classes, subclasses, and species of the invention. It will be appreciated that the phrase “optionally substituted” is used interchangeably with the phrase “substituted or unsubstituted.” In general, the term “substituted”, whether preceded by the terni “optionally” or not, refers to the replacement of one or more hydrogen radicale in a given structure with the radical of a specified substituent. Unless otherwise indicated, an optionally substituted group may hâve a substituent at each substitutable position of the group. When more than one position in a given structure can be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at each position. When the term “optionally substituted” précédés a list, said term refers to ail of the subséquent substitutable groups in that list. If a substituent radical or structure is not identified or defined as “optionally substituted”, the substituent radical or structure is unsubstituted. For example, if X is optionally substituted Ci.Cjalkyl or phenyl; X may be either optionally substituted C1-C3 alkyl or optionally substituted phenyl. Likewise, if the term “optionally substituted” follows a list, said term also refers to ail of the substitutable groups in the prior list unless otherwise indicated. For example: if X is Cj.C₃alkyl or phenyl wherein X is optionally and independently substituted by J^x, then both Cj.C₃alkyl and phenyl may be optionally substituted by J^x.

The phrase up to, as used herein, refers to zéro or any integer number that is equal or less than the number following the phrase. For example, up to 3 means any one of 0,1,2, and -2717028

3. As described herein, a specified number range ofatoms inciudes any integer therein. For example, a group having from 1-4 atoms could hâve 1,2,3, or 4 atoms.

Sélection of substituents and combinations of substituents envisioned by this invention are those that resuit in the formation of stable or chemically feasible compounds. The term “stable”, as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, détection, and, specifically, their recovery, purification, and use for one or more of the purposes disclosed herein. In some embodiments, a stable compound or chemically feasible compound is one that is not substantially altered when kept at a température of 40°C or less, in the absence of moisture or other chemically reactive conditions, for at least a week Only those choices and combinations of substituents that resuit in a stable structure are contemplated. Such choices and combinations will be apparent to those of ordinary ski 11 in the art and may be determined without undue expérimentation.

The term “aliphatic” or “aliphatic group”, as used herein, means a straight-chain (i.e., unbranched), or branched, hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation but is non-aromatic, U ni es s otherwise specified, aliphatic groups contain 1-20 aliphatic carbon atoms. In some embodiments, aliphatic groups contain

1-10 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-8 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain 1-6 aliphatic carbon atoms, and in yet other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms. Aliphatic groups may be linear or branched, substituted or unsubstituted alkyl, alkenyl, or alkynyl groups. Spécifie examples include, but are not limited to, methyl, ethyl, isopropyl, npropyl, sec-butyl, vinyl, n-butenyl, ethynyl, and tert-butyl and acetylene.

The term “alkyl” as used herein means a saturated straight or branched chain hydrocarbon. The term “alkenyl” as used herein means a straight or branched chain hydrocarbon comprising one or more double bonds. The term “alkynyl” as used herein means a straight or branched chain hydrocarbon comprising one or more triple bonds. Each of the “alkyl”, “alkenyl” or “alkynyl as used herein can be optionally substituted as set forth below. In some embodiments, the “alkyl” is Ci-C^ alkyl or C1-C4 alkyl. In some embodiments, the “alkenyl” is C₂-Cs alkenyl or C₂-C< alkenyl. In some embodiments, the “alkynyl” is C₂-Ce alkynyl or C₂-C< alkynyl.

The term “cycloaliphatic” (or “carbocycle” or “carbocyclyl” or “carbocyclic”) refers to a

-2817028 non-aromatic carbon only containing ring System which can be saturated or contains one or more units of unsaturation, having three to fourteen ring carbon atoms. In some embodiments, the number of carbon atoms is 3 to 10. In other embodiments, the number of carbon atoms is 4 to 7. In yet other embodiments, the number of carbon atoms îs 5 or 6. The term includes monocyclic, bicyclic or polycyclic, fused, spire or bridged carbocyclic ring Systems. The term also includes polycyclic ring Systems in which the carbocyclic ring can be “fused” to one or more non-aromatic carbocyclic or heterocyclic rings or one or more aromatic rings or combination thereof, wherein the radical or point of attachment is on the carbocyclic ring. “Fused” bicyclic ring Systems comprise two rings which share two adjoining ring atoms. Bridged bicyclic group comprise two rings which share three or four adjacent ring atoms. Spiro bicyclic ring Systems share one ring atom. Examples of cycloaliphatic groups include, but are not limited to, cycloalkyl and cycloalkenyl groups. Spécifie examples include, but are not limited to, cyclohexyl, cyclopropenyl, and cyclobutyl. The term “heterocycle” (or “heterocyclyl”, or “heterocyclic” or “non-aromatic heterocycle”) as used herein refers to a non-aromatic ring System which can be saturated or contaîn one or more units of unsaturation, having three to fourteen ring atoms in which one or more ring carbons is replaced by a heteroatom such as, N, S, or O and each ring in the System contains 3 to 7 members. In some embodiments, non-aromatic heterocyclic rings comprise up to three heteroatoms selected from N, S and O within the ring. In other embodiments, non-aromatic heterocyclic rings comprise up to two heteroatoms selected from N, S and O within the ring System. In yet other embodiments, non-aromatic heterocyclic rings comprise up to two heteroatoms selected from N and O within the ring System. The term includes monocyclic, bicyclic or polycyclic fused, spiro or bridged heterocyclic ring Systems. The term also includes polycyclic ring Systems in which the heterocyclic ring can be fused to one or more non-aromatic carbocyclic or heterocyclic rings or one or more aromatic rings or combination thereof, wherein the radical or point of attachment is on the heterocyclic ring. Examples of heterocycles include, but are not limited to, piperidinyl, piperizinyl, pyrrolidinyl, pyrazolîdinyl, imidazolidinyl, azepanyl, diazepanyl, triazepanyl, azocanyl, diazocanyl, triazocanyl, oxazolîdinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, oxazocanyl, oxazepanyi, thiazepanyl, thiazocanyl, benzimidazolonyl, tetrahydrofuranyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydrothiophenyl, morpholino, inciuding, for example, 3-morpholino, 4-morphoIino, 2-thiomorpholino, 3-thiomorpholino, 4-2917028 thiomorpholino, 1-pyrrolidinyl, 2-pyrroIidinyl, 3-pyrrolidinyI, I-tetrahydropiperazinyl, 2tetrahydropiperazinyl, 3-tetrahydropiperazinyl, I-piperidinyl, 2-piperidinyI, 3-piperidinyl, 1pyrazolinyl, 3-pyrazolinyl, 4-pyrazoIinyl, 5-pyrazolinyl, 1-piperidinyl, 2-piperidinyl, 3piperidinyl, 4-piperidinyl, 2-thiazolidinyl, 3-thiazolidinyl, 4-thiazolidinyl, 1-imidazolidinyI,

2-imîdazolidinyl, 4-imidazolidinyl, 5-imidazolidinyI, indolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, benzothiolanyl, benzodîthianyl, 3-(l-alkyI)-benzimidazoI-2-onyI, and l,3-dihydro-imidazol-2-onyl.

The term “aryl” (or “aryl ring” or “aryl group”) used alone or as part of a larger moiety as in “aralkyl, “aralkoxy”, or “aryloxyalkyl” refers to carbocyclîc aromatic ring Systems. The term '‘aryl may be used interchangeably with the terms ‘‘aryl ring” or “aryl group”. “Carbocyclîc aromatic ring” groups hâve only carbon ring atoms (typically six to fourteen) and include monocyclic aromatic rings such as phenyl and fused polycyclic aromatic ring Systems in which two or more carbocyclîc aromatic rings are fused to one another. Examples include l-naphthyl, 2-naphthyI, l-anthracyl and 2-anthracyl. Also included within the scope of the term “carbocyclîc aromatic ring” or “carbocyclîc aromatic”, as it is used herein, is a group in which an aromatic ring is “fused” to one or more non-aromatic rings (carbocyclîc or heterocyclic), such as ïn an indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl, where the radical or point of attachment is on the aromatic ring.

The terms “heteroaryl”, “heteroaromatîc”, “heteroaryl ring”, “heteroaryl group”, “aromatic heterocycle” or “heteroaromatîc group”, used alone or as part of a larger moiety as in “heteroaralkyl” or “heteroarylalkoxy”, refer to heteroaromatîc ring groups having fîve to fourteen members, including monocyclic heteroaromatîc rings and polycyclic aromatic rings in which a monocyclic aromatic ring is fused to one or more other aromatic ring. Heteroaryl groups hâve one or more ring heteroatoms. Also included within the scope of the term “heteroaryl”, as it is used herein, is a group in which an aromatic ring is “fused” to one or more non-aromatic rings (carbocyclîc or heterocyclic), where the radical or point of attachment is on the aromatic ring. Bicyclic 6,5 heteroaromatîc ring, as used herein, for example, is a six membered heteroaromatîc ring fused to a second fîve membered ring, wherein the radical or point of attachment is on the six membered ring. Examples of heteroaryl groups include pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl or thiadiazolyl including, for example, 2-furanyl, 3-furanyl, N-imidazolyl, 2-imidazolyl, 4

-3017028 imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxadiazolyl, 5oxadiazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 3-pyrazolyl, 4-pyrazolyl, 1-pyrrolyl, 2pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5pyrimidinyl, 3-pyridazinyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-triazolyl, 5-triazolyl, tetrazolyl, 2-thienyl, 3-thienyl, carbazolyl, benzimidazolyl, benzothienyl, benzofuranyl, indolyl, benzotriazolyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, isoquinolinyl, indolyl, isoindolyl, acridinyl, benzisoxazolyl, isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, purinyl, pyrazinyl, 1,3,5-triazinyl, quinolinyl (e.g., 2-quinolinyl, 3-quinolinyl, 4-quinolinyl), and isoquinolinyl (e.g., 1-isoquinolinyl, 3-isoquinolinyl, or 4-isoquinolinyl).

As used herein, “cyclo”, “cyclic”, “cyclic group” or “cyclic moiety”, include mono-, bi-, and tri-cyclic ring Systems including cycloaliphatic, heterocycloaliphatic, carbocyclic aryl, or heteroaryl, each of which has been previously defined.

As used herein, a “bicyclic ring System includes 8-12 (e.g., 9, 10, or 11) membered structures that form two rings, wherein the two rings hâve at least one atom in common (e.g., 2 atoms in common). Bicyclic ring Systems include bicycloaliphatics (e.g., bicycloalkyl or bicycloalkenyl), bicycloheteroaliphatics, bicyclic carbocyclic aryls, and bicyclic heteroaryls. As used herein, a “bridged bicyclic ring system” refers to a bicyclic heterocycloalipahtic ring System or bicyclic cycloaliphatic ring system in which the rings are bridged. Examples of bridged bicyclic ring Systems include, but are not limited to, adamantanyl, norbomanyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octyl, bicyclo[3.3.1]nonyl, bicyclo[3.2.3]nonyl, 2-oxabicyclo[2.2.2]octyl, l-aza-bicyclo[2.2.2]octyl, 3-aza-bicyclo[3.2.1]octyl, and 2,6-dioxatricyclo[3.3.1.03,7]nonyl. A bridged bicyclic ring system can be optionally substituted with one or more substituents such as alkyl (including carboxyalkyl, hydroxyalkyl, and haloalkyl such as trifluoromethyl), alkenyl, alkynyl, cycloalkyi, (cycloalkyl)alkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, carbocyclic aryl, heteroaryl, alkoxy, cycloalkyloxy, heterocycloalkyloxy, (carbocyclic aryl)oxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, aroyl, heteroaroyl, nitro, carboxy, alkoxycarbonyl, alkylcarbonyloxy, aminocarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino, (cycloalkylalkyl)carbonylamino, (carbocyclic aryl)carbonylamino, aralkylcarbonylamino, (heterocycloalkyl)carbonylamino, (heterocycloalkylalkyl)carbonylamino, heteroarylcarbonylamino, heteroaralkylcarbonylamino, cyano, halo, hydroxy, acyl, mercapto, alkylsulfanyl, sulfoxy,

-3117028 urea, thiourea, sulfamoyl, sulfamide, oxo, or carbamoyl.

As used herein, “bridge” refers to a bond or an atom or an unbranched chain of atoms connecting two different parts of a molécule. The two atoms that are connected through the bridge (usualiy but not always, two tertiary carbon atoms) are denotated as “bridgeheads”. As used herein, the term “spiro” refera to ring Systems having one atom (usualiy a quatemary carbon) as the on] y common atom between two rings.

The term “ring atom” is an atom such as C, N, O or S that is in the ring of an aromatic group, cycloalkyl group or non-aromatic heterocyclic ring.

A “substitutable ring atom in an aromatic group is a ring carbon or nitrogen atom bonded to a hydrogen atom. The hydrogen can be optionally replaced with a suitable substituent group. Thus, the term “substitutable ring atom” does not include ring nitrogen or carbon atoms which are shared when two rings are fused. In addition, “substitutable ring atom does not include ring carbon or nitrogen atoms when the structure depîcts that they are already attached to a moiety other than hydrogen.

The term “heteroatom” means one or more of oxygen, sulfur, nitrogen, phosphores, or sîlicon (includîng, any oxidized form of nitrogen, sulfur, phosphores, or silicon; the quatemized form of any basic nitrogen or; a substitutable nitrogen of a heterocyclic ring, for example N (as în 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) orNR⁺ (as in N-substituted pyrrolidinyl)).

As used herein an optionally substituted aralkyl can be substituted on both the alkyl and the aryl portion. Unless otherwise indicated as used herein optionally substituted aralkyl is optionally substituted on the aryl portion.

In some embodiments, an aliphatic or heteroaliphatic group, or a non-aromatic heterocyclic ring may contain one or more substituents. Suitable substituents on the saturated carbon of an aliphatic or heteroaliphatic group, or of a heterocyclic ring are selected from those listed above. Other suitable substitutents include those listed as suitable for the unsaturated carbon of a carbocyclic aryl or heteroaryl group and additionally include the following: =0, =S, -NNHR*, =NN(R*)₂, =NNHC(O)R*. =NNHCO₂(C_M alkyl), =NNHSO₂(C_M alkyl), or =NR*, wherein each R* is independently selected from hydrogen or an optionally substituted Ct^ aliphatic. Optional substituents on the aliphatic group of R* are selected from NH₂, NH(Cm aliphatic), N(Cm aliphatic)₂, halogen, C_u aliphatic, OH, 0(Cm aliphatic), NO₂, CN, CO₂H, C0₂(Cm aliphatic), O(halo Cm aliphatic), or halo (Cm aliphatic), wherein each ofthe

-3217028 foregoing Cualiphatic groups of R* is unsubstituted.

In some embodiments, optional substituents on the nitrogen of a heterocyclic ring include those used above. Other suitable substituents include -R⁺, -N(R*)2, -C(O)R⁺, -CO2R⁺, -C(O)C(O)R⁺, -C(O)CH2C(O)R⁺, -SO2R⁺, -SO2N(R*)2, -C(=S)N(R⁺)2, -C(=NH)-N(R⁺)2, or NR⁺SO2R⁺; wherein R⁺ is hydrogen, an optional ly substituted Ci^ aliphatic, optionally substituted phenyl, optionally substituted -O(Ph), optionally substituted -CH₂(Ph), optionally substituted -(CH₂)i.₂(Ph); optionally substituted -CH=CH(Ph); or an unsubstituted 5-6 membered heteroaryl or heterocyclic ring having one to four heteroatoms independently selected from oxygen, nitrogen, or sulfur, or, two independent occurrences of R⁺, on the same substituent or different substituents, taken together with the atom(s) to which each R⁺group is bound, form a 5-8-membered heterocyclyl, carbocyclic aryl, or heteroaryl ring or a

3-8-membered cycloalkyl ring, wherein said heteroaryl or heterocyclyl ring has 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Optional substituents on the aliphatic group or the phenyl ring of R⁺ arc selected from NH₂, NH(Cm aliphatic), N(C_m aliphatic)₂, halogen, Ομ aliphatic, OH, 0(Cm aliphatic), NO₂, CN, CO₂H, C0₂(Cm aliphatic), O(halo aliphatic), or halo(Ci_4 aliphatic), wherein each of the foregoing Ci^aliphatic groups of R⁺ is unsubstituted.

In some embodiments, an aryl (including aralkyl, aralkoxy, aryloxyalkyl and the like) or heteroaryl (including heteroaralkyl and heteroarylalkoxy and the like) group may contain one or more substituents. Suitable substituents on the unsaturated carbon atom of a carbocyclic aryl or heteroaryl group are selected from those listed above. Other suitable substituents include: halogen; -R°; -OR⁰; -SR°; 1,2-methylenedioxy; 1,2-ethylenedioxy; phenyl (Ph) optionally substituted with R°; -O(Ph) optionally substituted with R°; -(CH2)i.2(Ph), optionally substituted with R°; -CH=CH(Ph), optionally substituted with R°; -NO2; -CN; -N(R°)2; -NR°C(O)R°; -NR°C(S)R°; -NR°C(O)N(R°)2; -NR°C(S)N(R°)2; -NR°CO2R°; -NR°NR°C(O)R°; -NR°NR°C(O)N(R°)2; -NR°NR°CO2R°; -C(O)C(O)R°; -C(O)CH2C(O)R°; -CO2R°; -C(O)R°; -C(S)R°; -C(O)N(R°)2; -C(S)N(R°)2; -OC(O)N(R°)2; -OC(O)R°; -C(O)N(OR°) R°; -C(NOR°) R°; -S(O)2R°; -S(O)3R°; -SO2N(R°)2; -S(O)R°; NR°SO2N(R°)2; -NR°SO2R^o; -N(OR°)R°; -C(=NH)-N(R°)2; or -(CH₂)₀.₂NHC(O)R°; wherein each independent occurrence of R° is selected from hydrogen, optionally substituted C|^ aliphatic, an unsubstituted 5-6 membered heteroaryl or heterocyclic ring, phenyl, -O(Ph), or -CH₂(Ph), or, two independent occurrences of R°, on the same substituent or different

-3317028 substituents, taken together with the atom(s) to which each R° group is bound, form a 5-8membered heterocyclyl, carbocyclic aryl, or heteroaryl ring or a 3-8-membered cycloalkyl ring, wherein said heteroaryl or heterocyclyl ring has 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Optional substituents on the aliphatic group of R° are selected from NH2, NH(Cmaliphatic), N(CMaliphatic)2, halogen, Cmaliphatic, OH, 0(C>.

4aliphatic), NO2, CN, CO2H, CC^Cmaliphatic), O(haloCm aliphatic), or haloCi^aliphatic, CHO, N(C0)(Cm aliphatic), C(0)N(Cm aliphatic), wherein each of the foregoing C|. 4aliphatic groups of R° is unsubstituted.

Non-aromatic nitrogen containing heterocyclic rings that are substituted on a ring nitrogen and attached to the remainder of the molécule at a ring carbon atom are said to be N 15 substituted. For example, an N alkyl piperidinyl group is attached to the remainder of the molécule at the two, three or four position of the piperidinyl ring and substituted at the ring nitrogen with an alkyl group. Non-aromatic nitrogen containing heterocyclic rings such as pyrazinyl that are substituted on a ring nitrogen and attached to the remainder of the molécule at a second ring nitrogen atom are said to be N* substîtuted-N-heterocycles. For 20 example, an N’ acyl N-pyrazinyl group is attached to the remainder of the molécule at one ring nitrogen atom and substituted at the second ring nitrogen atom with an acyl group. The term unsaturated, as used herein, means that a moiety has one or more units of unsaturation.

As detailed above, in some embodiments, two independent occurrences of R° (or R⁺, or any 25 other variable sîmilarly defined herein), may be taken together with the atom(s) to which each variable is bound to form a 5-8-membered heterocyclyl, carbocyclic aryl, or heteroaryl ring or a 3-8-membered cycloalkyl ring. Exemplary rings that are formed when two independent occurrences of R° (or R⁺, or any other variable sîmilarly defined herein) are taken together with the atom(s) to which each variable is bound inciude, but are not limited 30 to the following: a) two independent occurrences of R° (or R⁺, or any other variable sîmilarly defined herein) that are bound to the same atom and are taken together with that atom to form a ring, for example, N(R°)2. where both occurrences of R° are taken together with the nitrogen atom to form a piperidin-l-yl, piperazin-l-yl, or morpholin-4-yl group; and b) two independent occurrences of R° (or R⁺, or any other variable sîmilarly defined herein) 35 that are bound to different atoms and are taken together with both of those atoms to form a ring, for example where a phenyl group is substituted with two occurrences of OR⁰

-3417028

, these two occurrences of R° are taken together with the oxygen atoms to which they are bound to form a fiised 6-membered oxygen containing ring:

It will be appreciated that a variety of other rings can be formed when two independent occurrences of R° (or R⁺, or any other variable similarly defined herein) are taken together with the atom(s) to which each variable is bound and that the examples detailed above are not intended to be limiting.

The term “hydroxyl”or “hydroxy” or “alcohol moiety” refers to -OH.

As used herein, an “alkoxycarbonyl,” which is encompassed by the term carboxy, used alone or in connection with another group refers to a group such as (alkyl-O)-C(O)-.

As used herein, a “carbonyl” refers to -C(O)-.

As used herein, an “oxo” refers to =0.

As used herein, the term alkoxy”, or “alkylthîo”, as used herein, refers to an alkyl group, as previously defined, attached to the molécule through an oxygen (“alkoxy” e.g., -O-alkyl) or sulfur (“alkylthio” e.g., -S-alkyl) atom.

As used herein, the terms “halogen”, halo”, and hal” mean F, Cl, Br, or I.

As used herein, the term “cyano” or “nitrile” refer to -CN or -C^N.

The terms “alkoxyalkyl”, “alkoxyalkenyl”, “alkoxyaliphatic”, and “alkoxyalkoxy” mean alkyl, alkenyl, aliphatic or alkoxy, as the case may be, substituted with one or more alkoxy groups.

The terms “haloalkyl”, “haloalkenyl”, “haloaliphatic”, and “haloalkoxy” mean alkyl, alkenyl, aliphatic or alkoxy, as the case may be, substituted with one or more halogen atoms. This term includes perfluorinated alkyl groups, such as -CFj and -CF2CF3.

The terms “cyanoalkyl”, “cyanoalkenyl”, “cyanoaliphatic”, and “cyanoalkoxy” mean alkyl, alkenyl, aliphatic or alkoxy, as the case may be, substituted with one or more cyano groups. In some embodiments, the cyanoalkyl is (NC)-alkyl-.

The terms “aminoalkyl, “aminoalkenyl”, “aminoaliphatic”, and “aminoalkoxy*’ mean alkyl, alkenyl, aliphatic or alkoxy, as the case may be, substituted with one or more amino groups, wherein the amino group is as defined above. In some embodiments, the aminoaliphatic is a C1-C6 aliphatic group substituted with one or more -NH2 groups. In some embodiments, the

-3517028 aminoalkyl refers to the structure (R^xR^Y)N-alkyl-, wherein each of R^xand R^Y independently is as defîned above. In some spécifie embodiments, the aminoalkyl îs C1-C6 alkyl substituted with one or more -NH₂ groups. In some spécifie embodiments, the aminoalkenyl is C1-C6 alkenyl substituted with one or more -NH₂ groups. In some embodiments, the aminoalkoxy is -O(C1-C6 alkyl) wherein the alkyl group is substituted with one or more •NH₂ groups.

The terms “hydroxyalkyl”, “hydroxyaliphatic, and “hydroxyalkoxy” mean alkyl, aliphatic or alkoxy, as the case may be, substituted with one or more -OH groups.

The terms “alkoxyalkyl”, “alkoxyaliphatîc”, and alkoxyalkoxy” mean alkyl, aliphatic or alkoxy, as the case may be, substituted with one or more alkoxy groups. For example, an “alkoxyalkyl’’ refers to an alkyl group such as (alkyl-O)-alkyl-, wherein alkyl is as defined above.

The term “carboxyalkyl means alkyl substituted with one or more carboxy groups, wherein alkyl and carboxy are as defined above.

The term “protecting group” and “protective group as used herein, are interchangeable and refer to an agent used to temporarily block one or more desired functional groups în a compound with multiple reactive sites. In certain embodiments, a protecting group has one or more, or specifically ail, of the following characteristics: a) is added selectively to a functional group in good yield to give a protected substrate that is b) stable to reactions occurring at one or more of the other reactive sites; and c) is selectively removable in good yield by reagents that do not attack the regenerated, deprotected functional group. As would be understood by one skilled in the art, in some cases, the reagents do not attack other reactive groups in the compound. In other cases, the reagents may also react with other reactive groups in the compound. Examples of protecting groups are detailed in Greene, T.

W., Wuts, P. G in “Protective Groups in Organic Synthesis”, Third Edition, John Wiley & Sons, New York: 1999 (and other éditions of the book), the entîre contents of which are hereby incorporated by reference. The term “nitrogen protecting group”, as used herein, refers to an agent used to temporarily block one or more desired nitrogen reactive sites in a multifunctional compound. Preferred nitrogen protecting groups also possess the characteristics exemplified for a protecting group above, and certain exemplary nitrogen protecting groups are also detailed in Chapter 7 in Greene, T.W., Wuts, P. G in “Protective Groups in Organic Synthesis”, Third Edition, John Wiley & Sons, New York: 1999, the

-3617028 entire contents of which are hereby incoiporated by référencé.

As used herein, the term “displaceable moiety” or “leaving group” refers to a group that is associated with an aliphatic or aromatic group as defined herein and is subject to being displaced by nucleophilic attack by a nucleophile.

Unless otherwise indicated, structures depicted herein are also meant to include ail isomeric (e.g., enantiomeric, diastereomeric, cis-trans, conformational, and rotational) forms of the structure. For example, the R and S configurations for each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers are included in this invention, unless only one of the isomers is drawn specifically. As would be understood to one skilled in the art, a substituent can free!y rotate around any rotatable bonds. For exemple, a

ON N y k also represents

Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, cis/trans, conformational, and rotational mixtures of the présent compounds are within the scope of the invention.

Unless otherwise indicated, ail tautomeric forms of the compounds of the invention are within the scope of the invention.

Additionally, unless otherwise indicated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the présent structures except for the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a ^1JC- or ¹⁴C-enriched carbon are within the scope of this invention. Such compounds are useful, for example, as analytical tools or probes in biologica! assays. Such compounds, especially deuterium analogs, can also be therapeutically useful.

The terms “a bond” and “absent” are used interchangeably to indicate that a group is absent. The compounds of the invention are defined herein by their chemical structures and/or chemical names. Where a compound is referred to by both a chemical structure and a chemical name, and the chemical structure and chemical name conflict, the chemical structure is determinative of the compound’s identity.

Pharmaceuticallv Acceptable Salts, Solvatés, Chia (rates, Prodrugs and Other Dérivatives

The compounds described herein can exist in free form, or, where appropriate, as salts.

-3717028

Those salts that are pharmaceutically acceptable are of particular interest since they are usefu! in administering the compounds described below for medical purposes. Salts that are not pharmaceutically acceptable are useful in manufacturing processes, for isolation and purification purposes, and in some instances, for use in separating stereoisomeric forms of the compounds of the invention or intermediates thereof.

As used herein, the terni pharmaceutically acceptable sait refers to salts of a compound which are, within the scope of Sound medical judgment, suitable for use in contact with the tissues of humans and lower animais without undue side effects, such as, toxicity, irritation, allergie response and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et a!., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977,66,

1-19, incorporated herein by référencé. Pharmaceutically acceptable salts of the compounds described herein include those derived from suitable inorganic and organic acids and bases. These salts can be prepared in situ during the final isolation and purification of the compounds.

Where the compound described herein contains a basic group, or a sufficiently basic bioisostere, acid addition salts can be prepared by 1) reacting the purified compound in its free-base form with a suitable organic or inorganic acid and 2) isolating the sait thus formed. In practice, acid addition salts might be a more convenient form for use and use of the sait amounts to use of the free basic form.

Examples of pharmaceutically acceptable, non-toxîc acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycérophosphate, glycolate, gluconate, glycolate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2hydrox y-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesu!fonate, nicotinate, nitrate, oleate, oxalate, palmitate, palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate,

-3817028 propionate, salicylate, stéarate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like.

Where the compound described herein contains a carboxy group or a sufïiciently acidic bioisostere, base addition salts can be prepared by 1) reacting the purified compound in its acid form with a suitable organic or inorganic base and 2) isolating the sait thus formed. In practice, use of the base addition sait might be more convenient and use of the sait form inherently amounts to use of the free acid form. Salts derived from appropriate bases include alkali métal (e.g., sodium, lithium, and potassium), alkaline earth métal (e.g., magnésium and calcium), ammonium and N⁺(Ci_4alkyl)4 salts. This invention also envisions the quatemization of any basic nitrogen-containing groups of the compounds disclosed herein. Water or oil-soluble or dispersible produc ts may be obtained by such quatemization.

Basic addition salts include pharmaceutically acceptable métal and amine salts. Suitable métal salts include the sodium, potassium, calcium, barium, zinc, magnésium, and aluminium. The sodium and potassium salts are usually preferred. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quatemary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate. Suitable inorganic base addition salts are prepared from métal bases which include sodium hydride, sodium hydroxide, potassium hydroxide, calcium hydroxide, aluminium hydroxide, lithium hydroxide, magnésium hydroxide, zinc hydroxide and the like. Suitable amine base addition salts are prepared from amines which are frequently used in médicinal chemistry because of their Iow toxicity and acceptability for medical use. Ammonia, ethylenediamine, N-methyl-glucamine, lysine, arginine, omithine, choline, N, N’-dibenzylethylenediamine, chloroprocaine, dietanolamine, procaine, N-benzylphenethylamine, diethylamine, piperazine, tris(hydroxymethyl)-aminomethane, tétraméthylammonium hydroxide, triethylamine, dibenzyl amine, ephenamine, dehydroabietylamine, N-ethylpiperidine, benzylamine, tétraméthylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, ethylamine, basic amino acids, dicyclohexylamine and the like.

Other acids and bases, while not in themselves pharmaceutically acceptable, may be employed in the préparation of salts useful as intermediates in obtaining the compounds described herein and their pharmaceutically acceptable acid or base addition salts. It should be understood that this invention includes mixtures/combinations of different

-3917028 pharmaceutically acceptable salts and also mixtures/combinations of compounds in free form and pharmaceutically acceptable salts.

The compounds described herein can also exist as pharmaceutically acceptable solvatés (e.g., hydrates) and clathrates. As used herein, the term “pharmaceutically acceptable solvaté, is a solvaté formed from the association of one or more pharmaceutically acceptable solvent molécules to one of the compounds described herein. The term solvaté includes hydrates (e.g., hemihydrate, monohydrate, dihydrate, trihydrate, tetrahydrate, and the like).

As used herein, the term “hydrate means a compound described herein or a sait thereof that further includes a stoichiometric or non-stoichiometric amount of water bound by noncovalent întermolecular forces.

As used herein, the term “clathrate” means a compound described herein or a sait thereof in the form of a crystal lattice that contains spaces (e.g., channels) that hâve a guest molécule (e.g., a solvent or water) trapped within.

In addition to the compounds described herein, pharmaceutically acceptable dérivatives or prodrugs of these compounds may also be employed in compositions to treat or prevent the herein identified disorders.

A “pharmaceutically acceptable dérivative or prodrug” includes any pharmaceutically acceptable ester, sait of an ester or other dérivative or sait thereof of a compound described herein which, upon administration to a récipient, is capable of providing, either directly or indirectly, a compound described herein or an inhibitorily active métabolite or residue thereof. Particularly favoured dérivatives or prodrugs are those that increase the bioavailability of the compounds when such compounds are administered to a patient (e.g., by allowing an orally administered compound to be more readily absorbed into the blood) or which enhance delivery of the parent compound to a biologicai compartment (e.g., the brain or lymphatic System) relative to the parent species.

As used herein and unless otherwise indicated, the term “prodrug” means a dérivative of a compound that can hydrolyze, oxidize, or otherwise react under biologicai conditions (in vitro or in vivo) to provide a compound described herein. Prodrugs may become active upon such reaction under biologicai conditions, or they may hâve activity in their unreacted forms. Examples of prodrugs contemplated in this invention include, but are not limited to, analogs or dérivatives of compounds of the invention that comprise biohydrolyzable moieties such as biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates,

-4017028 biohydrolyzable carbonates, biohydrolyzable ureides, and biohydrolyzable phosphate analogues. Other exemples of prodrugs include dérivatives of compounds described herein that comprise -NO, -NO₂, -ONO, or -ONO₂ moieties. Prodrugs can typically be prepared using well-known methods, such as those described by BURGER'S MEDICINAL CHEMISTRY AND DRUG DISCOVERY (1995) 172-178, 949-982 (Manfred E. Wolff ed., 5th ed).

A “pharmaceutically acceptable dérivative is an adduct or dérivative which, upon administration to a patient in need, is capable of providing, directly or indirectly, a compound as otherwise described herein, or a métabolite or residue thereof. Examples of pharmaceutically acceptable dérivatives include, but are not limited to, esters and salts of such esters. Pharmaceutically acceptable prodrugs of the compounds described herein include, without limitation, esters, amino acid esters, phosphate esters, métal salts and sulfonate esters.

Uses of Disclosed Compounds

One aspect of the présent invention is generally related to the use of the compounds described herein or pharmaceutically acceptable salts, or pharmaceutically acceptable compositions comprising such a compound or a pharmaceutically acceptable sait thereof, for inhibiting the réplication of influenza viruses in a biological sample or in a patient, for reducing the amount of influenza viruses (reducing viral titcr) in a biological sample or in a patient, and for treating influenza in a patient.

In one embodiment, the présent invention is generally related to the use of compounds represented by any one of Structural Formulae (I) - (X), or pharmaceutically acceptable salts thereof for any of the uses specified above:

In yet another embodiment, the présent invention is directed to the use of any compound selected from the compounds depicted in Table I or a pharmaceutically acceptable sait thereof, for any of the uses described above.

In some embodiments, the compounds arc represented by any one of Structural Formulae (I) - (X), and the variables are each independently as depicted in the compounds of Table I.

In yet another embodiment, the compounds described herein or pharmaceutically acceptable salts thereof can be used to reduce viral titre in a biological sample (e.g. an infected cell culture) or in humans (e.g. lung viral titre in a patient).

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The tenus “influenza viras mediated condition”, “influenza infection”, or “Influenza”, as used herein, are used interchangeable to mean the disease caused by an infection with an influenza virus.

Influenza is an infectious disease that affects birds and mammals caused by influenza virases. Influenza virases are RNA virases of the family Orthomyxoviridae, which comprises five généra: Influenzavirus A, Influenzavirus B, Influenzavirus C, Isavirus and Thogotoviras. Influenzavirus A genus has one species, influenza A virus which can be subdivided into different serotypes based on the antibody response to these virases: H INI, H2N2, H3N2, H5N1, H7N7, H1N2, H9N2, H7N2, H7N3 and H10N7. Influenzavirus B genus has one species, influenza B virus. Influenza B almost exclusively infects humans and is less common than influenza A. Influenzavirus C genus has one species, Influenzavirus C viras, which infects humans and pigs and can cause severe îllness and local épidémies. However, Influenzavirus C is less common than the other types and usually seems to cause mild disease in children.

In some embodiments of the invention, influenza or influenza virases are associated with Influenzavirus A or B. In some embodiments of the invention, influenza or influenza virases are associated with Influenzavirus A. In some spécifie embodiments of the invention, Influenzavirus A is H1N1, H2N2, H3N2 or H5N1.

In humans, common symptoms of influenza are chills, fever, pharyngitis, muscle pains, severe headache, coughing, weakness, and general discomfort. In more serious cases, influenza causes pneumonia, which can be fatal, particularly in young children and the elderly. Although it is often confused with the common cold, influenza is a much more severe disease and is caused by a different type of virus. Influenza can produce nausea and vomiting, especially in children, but these symptoms are more characteristîc of the unrelated gastroenteritis, which is sometimes called stomach flu or 24-hour flu.

Symptoms of influenza can start quite suddenly one to two days after infection. Usually the first symptoms are chills or a chilly sensation, but fever is also common early in the infection, with body températures ranging from 38-39 °C (approximately 100-103 °F). Many people are so ill that they are confined to bed for severai days, with aches and pains throughout their bodies, which are worse in their backs and legs. Symptoms of influenza may include: body aches, especiallyjoints and throat, extreme coldness and fever, fatigue, Headache, irritated watering eyes, reddened eyes, skin (especially face), mouth, throat and

-4217028 nose, abdominal pain (in children with influenza B). Symptoms of influenza are non-specific, overlapping with many pathogens (“influenza-like illness). Usually, laboratory data is needed in order to confirm the diagnosis.

The terms, “disease, “disorder, and “condition” may be used interchangeably here to refer to an influenza virus mediated medical or pathological condition.

As used herein, the terms “subject” and “patient” are used interchangeably. The terms “subject” and “patient” refer to an animal (e.g., a bird such as a chicken, quail or turkey, or a mammal), specifïcally a “mammal” including a non-primate (e.g., a cow, pig, horse, sheep, rabbit, guinea pig, rat, cat, dog, and mouse) and a primate (e.g., a monkey, chimpanzee and a human), and more specificafly a human. In one embodiment, the subject is a non-human animal such as a farm anima) (e.g., a horse, cow, pig or sheep), or a pet (e.g., a dog, cat, guinea pig or rabbit). In a preferred embodiment, the subject is a “human”.

The term “biological sample”, as used herein, includes, without limitation, cell cultures or extracts thereof; biopsied material obtained from a mammal or extracts thereof; blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof.

As used herein, “multiplicity of infection or “MOI” is the ratio of infectious agents (e.g. phage or virus) to infection targets (e.g. cell). For example, when referring to a group of cells inoculated with infectious virus particles, the multiplicity of infection or MOI is the ratio defined by the number of infectious virus particles deposited in a well divided by the number of target cells présent in that well.

As used herein the term “inhibition of the réplication of influenza viruses includes both the réduction in the amount of virus réplication (e.g. the réduction by at least 10 %) and the complété arrest of virus réplication (i.e., 100% réduction in the amount of virus réplication). In some embodiments, the réplication of influenza viruses are inhibitedby at least 50%, at least 65%, at least 75%, at least 85%, at least 90%, or at least 95%.

Influenza virus réplication can be measured by any suitable method known in the art. For example, influenza viral titre in a biological sample (e.g. an infected cell culture) or in humans (e.g. lung viral titre in a patient) can be measured. More specifïcally, for cell based assays, in each case cells are cultured in vitro, virus is added to the culture in the presence or absence of a test agent, and after a suitable length of time a virus-dependent endpoint is evaluated. For typical assays, the Madîn-Darby canine kidney cells (MDCK) and the standard tissue culture adapted influenza strain, A/Puerto Rico/8/34 can be used. A first type

-4317028 of cell assay that can be used in the invention dépends on death of the infected target cells, a process called cytopathic effect (CPE), where virus infection causes exhaustion of the cell resources and eventual lysis of the cell. In the first type of cell assay, a low fraction of cells in the wells of a microtiter plate are infected (typically 1/10 to 1/1000), the virus is allowed to go through several rounds of réplication over 48-72 hours, then the amount of cell death is 10 measured using a decrease in cellular ATP content compared to uninfected controls. A second type of cell assay that can be employed in the invention dépends on the multiplication of virus-specific RNA molécules in the infected cells, with RNA levels being directly measured using the branched-chain DNA hybridization method (bDNA). In the second type of cell assay, a low number of cells are initially infected in wells of a microtiter plate, the virus is allowed to replicate in the infected cells and spread to additional rounds of cells, then the cells are lysed and viral RNA content is measured. This assay is stopped early, usually after J 8-36 hours, while ail the target cells are still viable. Viral RNA is quantitated by hybridization to spécifie oligonucleotide probes fixed to wells of an assay plate, then amplification of the signal by hybridization with additional probes linked to a reporter enzyme.

As used herein a “viral titer (or titre)” is a measure of virus concentration. Titer testing can employ serial dilution to obtain approximate quantitative information from an analytical procedure that inherently only évaluâtes as positive or négative. The titer corresponds to the highest dilution factor that still yields a positive reading; for example, positive readings in the 25 first 8 serial twofold dilutions translate into a titer of 1:256. A spécifie example is viral titer.

To détermine the titer, several dilutions will be prepared, such as 10'*, 10‘²,10^,...,10^-8. The lowest concentration of virus that still infects cells is the viral titer.

As used herein, the terms “treat, “treatment” and “treating” refer to both therapeutic and prophylactic treatments. For example, therapeutic treatments includes the réduction or amelioration of the progression, severity and/or duration of influenza viruses mediated conditions, or the amelioration of one or more symptoms (specifically, one or more discemible symptoms) of influenza viruses mediated conditions, resulting from the administration of one or more thérapies (e.g., one or more therapeutic agents such as a compound or composition of the invention). In spécifie embodiments, the therapeutic treatment includes the amelioration of at least one measurable physical para me ter of an influenza virus mediated condition. In other embodiments the therapeutic treatment includes

-4417028 the inhibition of the progression of an influenza virus mediated condition, either physically by, e.g., stabilization of a discemible symptom, physiologically by, e.g., stabilization of a physical parameter, or both. In other embodiments the therapeutic treatment indudes the réduction or stabilization of influenza viruses mediated infections. Antiviral drugs can be used in the community setting to treat people who already hâve influenza to reduce the severity of symptoms and reduce the number of days that they are sick.

The term “chemotherapy” refers to the use of médications, e.g. small molécule drugs (rather than “vaccines”) for treating a disorder or disease.

The terms “prophylaxie” or “prophylactic use” and “prophylactic treatment” as used herein, refer to any medical or public health procedure whose purpose is to prevent, rather than treat or cure a disease. As used herein, the terms “prevent”, “prévention” and “preventing” refer to the réduction in the risk of acquiring or developing a given condition, or the réduction or inhibition of the récurrence or said condition in a subject who is not ill, but who has been or may be near a person with the disease. The term “chemoprophylaxis” refers to the use of médications, e.g. small molécule drugs (rather than “vaccines) for the prévention of a disorder or disease.

As used herein, prophylactic use indudes the use in situations in which an outbreak has been detected, to prevent contagion or spread of the infection in places where a lot of people that are at high risk of serious influenza complications live in close contact with each other (e.g. in a hospital ward, daycare center, prison, nursing home, etc). It also indudes the use among populations who require protection from the influenza but who either do not get protection after vaccination (e.g. due to weak immunse System), or when the vaccine is unavailable to them, or when they cannot get the vaccine because of side effects. It also indudes use during the two weeks following vaccination, since during that time the vaccine is still ineffective. Prophylactic use may also include treating a person who is not ill with the influenza or not considered at high risk for complications, in order to reduce the chances of getting infected with the influenza and passing it on to a high-risk person in close contact with him (for instance, healthcare workers, nursing home workers, etc).

According to the US CDC, an influenza “outbreak” is defined as a sudden increase of acute febrile respiratory illness (AFRI) occurring within a 48 to 72 hour period, in a group of people who are in close proximity to each other (e.g. in the same area of an assisted living facility, in the same household, etc) over the normal background rate or when any subject in

-4517028 the population being analyzed tests positive for influenza. One case of confirmed influenza by any testing method is considered an outbreaL

A “cluster” is defined as a group of three or more cases of AFRI occurring within a 48 to 72 hour period, in a group of people who are in close proximity to each other (e.g. in the same area of an assisted living facility, in the same household, etc).

As used herein, the “index case”, “primary case” or “patient zéro” is the initial patient in the population sample of an epidemiological investigation. When used in general to refer to such patients in epidemiological investigations, the term is not capital ized. When the term is used to refer to a spécifie person in place of that person’s name within a report on a spécifie investigation, the term is capitalized as Patient Zéro. Often scientists search for the index case to détermine how the disease spread and what réservoir holds the disease in between outbreaks. Note that the index case is the first patient that indicates the existence of an outbreaL Earlier cases may be found and are labeled primary, secondary, tertiary, etc. In one embodiment, the methods of the invention are a preventative or “pre-emptive” measure to a patient, specifically a human, having a prédisposition to complications resulting 20 from infection by an influenza virus. The term “pre-emptive” as used herein as for example in pre-emptive use, “pre-emptively”, etc, is the prophylactic use in situations in which an “index case” or an “outbreak” has been confirmed, in order to prevent the spread of infection in the rest of the community or population group.

In another embodiment, the methods of the invention are applied as a “pre-emptive” measure 25 to members of a community or population group, specifically humans, in order to prevent the spread of infection.

As used herein, an “effective amount” refers to an amount sufficient to elîcit the desired biological response. In the présent invention the desired biological response is to inhibit the réplication of influenza virus, to reduce the amount of influenza viruses or to reduce or amelîorate the severity, duration, progression, or onset of a influenza virus infection, prevent the advancement of an influenza viruses infection, prevent the récurrence, development, onset or progression of a symptom associated with an influenza virus infection, or enhance or improve the prophylactic or therapeutic effect(s) of another therapy used against influenza infections. The précisé amount of compound administered to a subject will dépend on the mode of administration, the type and severity of the infection and on the characteristics of the subject, such as general health, âge, sex, body weight and tolérance to drugs. The skilled

-4617028 artisan will be able to détermine appropriate dosages depending on these and other factors. When co-administered with other anti viral agents, e.g., when co-administered with an antiinfluenza médication, an “effective amount of the second agent will dépend on the type of drag used. Suitable dosages are known for approved agents and can be adjusted by the skilled artisan according to the condition of the subject, the type of condition(s) being treated and the amount of a compound described herein being used. In cases where no amount is expressly noted, an effective amount should be assumed. For example, compounds described herein can be administered to a subject in a dosage range from between approximately 0.01 to 100 mg/kg body weight/day for therapeutic or prophylactic treatment.

Generally, dosage régi mens can be selected in accordance with a variety of factors including the disorder being treated and the severity of the disorder, the activity of the spécifie compound employed; the spécifie composition employed; the âge, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excrétion of the spécifie compound employed; the rénal and hepatic function of the subject; and the particular compound or sait thereof employed, the duration of the treatment; drugs used in combination or coincidental with the spécifie compound employed, and like factors well known in the medical arts. The skilled artisan can readily détermine and prescribe the effective amount of the compounds described herein required to treat, to prevent, inhibit (fully or partially) or arrest the progress of the disease.

Dosages of the compounds described herein can range from between about 0.01 to about 100 mg/kg body weight/day, about 0.01 to about 50 mg/kg body weight/day, about 0.1 to about 50 mg/kg body weight/day, or about 1 to about 25 mg/kg body weight/day. It is understood that the total amount per day can be administered in a single dose or can be administered in multiple dosing, such as twice a day (e.g., every 12 hours), tree times a day (e.g., every 8 hours), or four times a day (e.g., every 6 hours).

For therapeutic treatment, the compounds described herein can be administered to a patient within, for example, 48 hours (or within 40 hours, or less than 2 days, or less than 1.5 days, or within 24 hours) of onset of symptoms (e.g., nasal congestion, sore throat, cough, aches, fatigue, headaches, and chills/sweats). The therapeutic treatment can last for any suitable duration, for example, for 5 days, 7 days, 10 days, 14 days, etc. For prophylactic treatment during a community outbreak, the compounds described herein can be administered to a patient within, for example, 2 days of onset of symptoms in the index case, and can be

-4717028 continued for any suitable duration, for example, for 7 days, 10 days, 14 days, 20 days, 28 days, 35 days, 42 days, etc.

Various types of administration methods can be employed in the invention, and are described in detail below under the section entitled “Administration Methods.”

Combination Therapy

An effective amount can be achieved in the method or pharmaceutical composition of the invention employing a compound of the invention (inciuding a pharmaceutically acceptable sait or solvaté (e.g., hydrate)) alone or in combination with an additional suitable therapeutic agent, for example, an antiviral agent or a vaccine. When “combination therapy” is employed, an effective amount can be achieved using a first amount of a compound of the invention and a second amount of an additional suitable therapeutic agent (e.g. an antiviral agent or vaccine).

In another embodiment of this invention, a compound of the invention and the additional therapeutic agent, are each administered in an effective amount (i.e., each in an amount which would be therapeutically effective if administered alone). In another embodiment, a compound of the invention and the additional therapeutic agent, are each administered in an amount which alone does not provide a therapeutic effect (a sub-therapeutic dose). In yet another embodiment, a compound of the invention can be administered in an effective amount, while the additional therapeutic agent is administered in a sub-therapeutic dose. In still another embodiment, a compound of the invention can be administered in a subtherapeutic dose, while the additional therapeutic agent, for example, a suitable cancertherapeutic agent is administered in an effective amount.

As used herein, the terms “in combination” or “co-administration” can be used înterchangeably to refer to the use of more than one therapy (e.g., one or more prophylactic and/or therapeutic agents). The use of the terms does not restrict the order in which thérapies (e.g., prophylactic and/or therapeutic agents) are administered to a subject.

Coadministration encompasses administration ofthe first and second amounts ofthe compounds of the coadministration in an essentially simultaneous manner, such as in a single pharmaceutical composition, for example, capsule or tablet having a fixed ratio of first and second amounts, or in multiple, separate capsules or tablets for each. In addition, such coadministration also encompasses use of each compound in a sequential manner in either

-4817028 order.

In one embodiment, the présent invention is directed to methods of combination therapy for inhibiting Flu viruses réplication in biological samples or patients, or for treating or preventing Influenza virus infections in patients using the compounds or pharmaceutical compositions of the invention. Accordingly, pharmaceutical compositions of the invention also include those comprising an inhibitor of Flu virus réplication of this invention in combination with an anti-viral compound exhibiting anti-Influenza virus activity. Methods of use of the compounds and compositions of the invention also include combination of chemotherapy with a compound or composition of the invention, or with a combination of a compound or composition of this invention with another anti-viral agent and vaccination with a Flu vaccine.

When co-administration involves the separate administration of the first amount of a compound of the invention and a second amount of an additional therapeutic agent, the compounds are administered sufficiently close in time to hâve the desired therapeutic effect. For example, the period of time between each administration which can resuit in the desired therapeutic effect, can range from minutes to hours and can be determined taking into account the properties of each compound such as potency, solubility, bioavailability, plasma half-life and kinetic profile. For exemple, a compound of the invention and the second therapeutic agent can be administered in any order within about 24 hours of each other, within about 16 hours of each other, within about 8 hours of each other, within about 4 hours of each other, within about I hour of each other or within about 30 minutes of each other. More, specifically, a first therapy (e.g., a prophylactic or therapeutic agent such as a compound ofthe invention) can be administered prior to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before), concomitantly with, or subséquent to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks after) the administration of a second therapy (e.g., a prophylactic or therapeutic agent such as an anticancer agent) to a subject.

It is understood that the method of co-administration of a first amount of a compound of the invention and a second amount of an additional therapeutic agent can resuit in an enhanced

-4917028 or synergistic therapeutic effect, wherein the combined effect is greater than the additive effect that would resuit from separate administration of the first amount of a compound of the invention and the second amount of an additional therapeutic agent.

As used herein, the term “synergistic” refers to a combination of a compound of the invention and another therapy (e.g., a prophylactic or therapeutic agent), which is more effective than the additive effects of the thérapies. A synergistic effect of a combination of thérapies (e.g., a combination of prophylactic or therapeutic agents) can permit the use of lower dosages of one or more of the thérapies and/or less frequent administration of said thérapies to a subject. The ability to utilize lower dosages of a therapy (e.g., a prophylactic or therapeutic agent) and/or to administer said therapy less frequently can reduce the toxicity associated with the administration of said therapy to a subject without reducing the efficacy of said therapy in the prévention, management or treatment of a disorder. In addition, a synergistic effect can resuit in improved efficacy of agents in the prévention, management or treatment of a disorder. Finally, a synergistic effect of a combination of thérapies (e.g., a combination of prophylactic or therapeutic agents) may avoid or reduce adverse or unwanted side effects associated with the use of either therapy alone.

When the combination therapy using the compounds of the présent invention is in combination with a Flu vaccine, both therapeutic agents can be administered so that the period of time between each administration can be longer (e.g. days, weeks or months). The presence of a synergistic effect can be determined using suitable methods for assessing dru g interaction. Suitable methods include, for example, the Sigmoid-Emax équation (Holford, N.H.G. and Scheiner, L.B., Clin. Pharmacokinet. 6:429-453 (1981)), the équation of Loewe additivity (Loewe, S. and Muischnek, H., Arch. Exp. Pathol Pharmacol. 114:313326 (1926)) and the median-effect équation (Chou, T.C. and Talalay, P., Adv. Enzyme Regul. 22:27-55 (1984)). Each équation referred to above can be applied with experimental data to generate a corresponding graph to aid in assessing the effects of the drug combination. The corresponding graphs associated with the équations referred to above are the concentration-effect curve, isobologram curve and combination index curve, respectively. Spécifie examples that can be co-administered with a compound described herein include neuraminidase inhibitors, such as oseltamîvir (Tamiflu®) and Zanamivir (Rlenza®), viral ion channel (M2 protein) blockers, such as amantadine (Symmetrel®) and rimantadine (Flumadine®), and antiviral drugs described in WO 2003/015798, including T-705 under

-5017028 development byToyama Chemical of Japan. (See also Ruruta et al., Antiviral Reasearch, 82: 95-102 (2009), “T-705 (flavipiravir) and related compounds: Novel broad-spectrum inhibitors of RNA viral infections.”) In some embodiments, the compounds described herein can be co-administered with a traditional influenza vaccine. In some embodiments, the compounds described herein can be co-administered with Zanamivir. In some embodiments, the compounds described herein can be co-administered with oseltamivir. In some embodiments, the compounds described herein can be co-administered with T-705. Pharmaceutical Compositions

The compounds described herein can be formulated into pharmaceutical compositions that further comprise a pharmaceutically acceptable carrier, diluent, adjuvant or vehicle. In one embodiment, the présent invention relates to a pharmaceutical composition comprising a compound of the invention described above, and a pharmaceutically acceptable carrier, diluent, adjuvant or vehicle. In one embodiment, the présent invention is a pharmaceutical composition comprising an effective amount of a compound of the présent invention or a pharmaceutically acceptable sait thereof and a pharmaceutically acceptable carrier, diluent, adjuvant or vehicle. Pharmaceutically acceptable carriers include, for example, pharmaceutical diluents, excipients or carriers suitably selected with respect to the intended form of administration, and consistent with conventional pharmaceutical practices.

An effective amount” includes a therapeutically effective amount” and a “prophylactically effective amount”. The term “therapeutically effective amount” refers to an amount effective in treating and/or ameliorating an influenza virus infection in a patient infected with influenza. The term “prophylactically effective amount” refers to an amount effective in preventing and/or substantially lessening the chances or the size of influenza virus infection outbreak Spécifie examples of effective amounts are described above in the section entitled Uses of Disclosed Compounds.

A pharmaceutically acceptable carrier may contain inert ingrédients which do not unduly inhibit the biologicai activity of the compounds. The pharmaceutically acceptable carriers should be biocompatible, e.g., non-toxic, non-inflammatory, non-immunogenic or devoid of other undesired reactions or side-effects upon the administration to a subject. Standard pharmaceutical formulation techniques can be employed.

The pharmaceutically acceptable carrier, adjuvant, or vehicle, as used herein, includes any and ail solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active

-5117028 agents, isotonie agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired. Remington's Pharmaceutical Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various carriers used in formulating pharmaceutically acceptable compositions and known techniques for the préparation thereof. Except insofar as any conventional carrier medium is incompatible with the compounds described herein, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component(s) of the pharmaceutically acceptable composition, its use is contemplated to be within the scope of this invention. As used herein, the phrase “side effects encompasses unwanted and adverse effects of a therapy (e.g., a prophylactic or therapeutic agent). Side effects are always unwanted, but unwanted effects are not necessarily adverse. An adverse effect from a therapy (e.g., prophylactic or therapeutic agent) might be harmful or uncomfortable or risky. Side effects include, but are not limited to fever, chills, lethargy, gastrointestinal toxicities (including gastric and intestinal ulcérations and érosions), nausea, vomiting, neurotoxicities, nephrotoxicities, rénal toxicities (including such conditions as papillary necrosis and chronic interstitial nephritis), hepatic toxicities (including elevated sérum liver enzyme levels), myelotoxicities (including leukopenia, myelosuppression, thrombocytopénie and anémia), dry mouth, metallic taste, prolongation of gestation, weakness, somnolence, pain (including muscle pain, bone pain and headache), hair loss, asthenia, dizziness, extra-pyramidal symptoms, akathisia, cardiovascular disturbances and sexual dysfunction.

Some examples of matériels which can serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stéarate, lecithin, sérum proteins (such as human sérum albumin), buffer substances (such as twin 80, phosphates, glycine, sorbic acid, or potassium sorbate), partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes (such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, or zinc salts), colloïdal silica, magnésium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropyleneblock polymers, methylcellulose, hydroxypropyl methylcellulose, wool fat, sugars such as lactose, glucose and sucrose; starches such as com starch and potato s tare h; cellulose and its dérivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository

-5217028 waxes; oils such as peanut oil, cottonseed oil; safilower oil; sesame oil; olive oil; com oil and soybean oil; glycols; such a propylcne glycol or polyethylcne glycol; esters such as ethyl oleate and ethyl laurate; agar; bufTering agents such as magnésium hydroxide and aluminum hydroxi de; alginic acid; pyrogen-free water, isotonie saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible fabricants such as sodium lauryl sulfate and magnésium stéarate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfaming agents, preservatives and antioxidants can also be présent in the composition, according to the judgment of the formulator.

Administration Methods

The compounds and pharmaceutically acceptable compositions described above can be administered to humans and other animais orally, rectally, parenterally, intracistemally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), bucally, as an oral or nasal spray, or the like, depending on the severity of the infection being treated. Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable émulsions, microemulsions, solutions, suspensions, syrups and élixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylcne glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, com, germ, olive, castor, and sesame oils), glycerol, tetrahydrofarfaryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfaming agents.

Injectable préparations, for example, stérile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The stérile injectable préparation may also be a stérile injectable solution, suspension or émulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonie sodium chloride solution. In addition, stérile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or

-5317028 diglycerides. In addition, fatty acids such as oleic acid are used in the préparation of injectables.

The injectable formulations can be sterilized, for example, by filtration through a bacterialretaining fïlter, or by incorporating sterilizing agents in the form of stérile solid compositions which can be dissolved or dispersed in stérile water or other stérile injectable medium prior to use.

In order to prolong the effect of a compound described herein, it is oflen désirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate ofabsorption of the compound then dépends upon its rate of dissolution that, in turn, may dépend upon crystal size and crystalline form. Altematively, delayed absorption of a parenterally administered compound form is accomplished by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the compound in biodégradable polymers such as polylactide-polyglycolide. Depending upon the ratio ofcompound to polymer and the nature of the particular polymer employed, the rate of compound release can be control led. Examples of other biodégradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.

Compositions for rectal or vaginal administration are specifically suppositories which can be prepared by mixing the compounds described herein with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient température but liquid at body température and therefore melt in the rectum or vaginal cavity and release the active compound.

Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar—agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as parafïin, f) absorption

-5417028 accelerators such as quatemary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stéarate, magnésium stéarate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatîngs and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polethylene glycols and the like.

The active compounds can also be in microencapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnésium stéarate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.

Dosage forms for topical or transdermal administration of a compound described herein include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active component is admixed under stérile conditions with a pharmaceutically

-5517028 acceptable carrier and any needed preservatives or bufïers as may be required. Ophthalmic formulation, eardrops, and eye drops are also contemplated as being within the scope of this invention. Additionally, the présent invention contemplâtes the use of transdermal patches, which hâve the added advantage of providing controlled delivery of a compound to the body. Such dosage forms can be made by dissol ving or dispensing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.

The compositions described herein may be administered oratty, parenterally, by inhalation spray, topically, rectally, nasatly, buccatly, vaginally or via an implanted réservoir. The term parentéral as used herein includes, but is not limited to, subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrastemal, intrathécal, intrahepatic, intralesional and intracrania! injection or infusion techniques. Specifically, the compositions are administered orally, intraperitoneally or intravenously.

Stérile injectable forms of the compositions described herein may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The stérile injectable préparation may also be a stérile injectable solution or suspension in a non-toxic parenterallyacceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be emptoyed are water, Ringer's solution and isotonie sodium chloride solution. In addition, stérile, fixed oils are conventionally emptoyed as a solvent or suspending medium. For this purpose, any bland fixed oil may be emptoyed including synthetic mono- or di-glycerides. Fatty acids, such as oleic acid and its glyceride dérivatives are useful in the préparation of injectables, as are naturel pharmaceutically-acceptable oils, such as olive oil or castor oit, especiatly in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chaîn atcohot diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents which are commonly used in the formulation of pharmaceuticalty acceptable dosage forms including émulsions and suspensions. Other commonly used surfactants, such as Tweens, Spans and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.

-5617028

The pharmaceutical compositions described herein may be orally administered in any orally acceptable dosage form including, but not limîted to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, carriers commonly used include, but are not limited to, lactose and corn starch. Lubricating agents, such as magnésium stéarate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried comstarch. When aqueous suspensions are required for oral use, the active ingrédient is combined with emulsifying and suspending agents. Ifdesired, certain sweetening, flavoring or coloring agents may also be added.

Altematively, the pharmaceutical compositions described herein may be administered in the form of suppositories for rectal administration. These can be prepared by mixing the agent with a suitable non-irritating excipient which is solid at room température but liquid at rectal température and therefore wili melt în the rectum to release the drug. Such materiels include, but are not limited to, cocoa butter, beeswax and polyethylene glycols.

The pharmaceutical compositions described herein may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.

Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically-transdermal patches may also be used.

For topical applications, the pharmaceutical compositions may be formulated in a suitable ointment containing the active component suspended or dissolved în one or more carriers. Carriers for topical administration of the compounds of this invention include, but are not limited to, minerai oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Altematively, the pharmaceutical compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, minerai oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2 octyldodecanol, benzyl alcohol and water.

For ophthalmic use, the pharmaceutical compositions may be formulated as micronized suspensions in isotonie, pH adjusted stérile saline, or, specifically, as solutions in isotonie,

-5717028 pH adjusted stérile saline, either with or without a preservative such as benzylalkonium chloride. Altematively, for ophthalmîc uses, the pharmaceutical compositions may be formulated in an oîntment such as petrolatum.

The pharmaceutical compositions may also be administered by nasal aérosol or inhalation. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersîng agents.

The compounds for use in the methods of the invention can be formulated in unit dosage form. The term “unit dosage form” refers to physical ly discrète units suitable as unitary dosage for subjects undergoing treatment, with each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, optionally in association with a suitable pharmaceutical carrier. The unit dosage form can be for a single daily dose or one of multiple daily doses (e.g., about 1 to 4 or more times per day). When multiple daily doses are used, the unit dosage form can be the same or different for each dose.

EXEMPLIFICATION

Example k Synthesis of Compounds of the Invention

The compounds disclosed herein can be prepared by any suitble method known in the art, for example, WO 2005/095400, WO 2007/084557, WO 2010/011768, WO 2010/011756, WP 2010/011772, WO 2009/073300, and PCT/US2010/038988 filed on June 17, 2010. For example, the compounds shown in Table 1 and FIG. 1 can be prepared by any suitble method known in the art, for example, WO 2005/095400, WO 2007/084557, WO 2010/011768, WO 2010/011756, WP 2010/011772, WO 2009/073300, and PCT/US2010/038988, and by the exemplary synthèses described below. Generally, the compounds of the invention can be prepared as shown in those synthèses optionally with any desired appropriate modification.

MethodoloEV for Synthesis and Characterization of Compounds

Synthèses of certain exemplary compounds of the invention are described below. NMR and Mass Spectroscopy data of certain spécifie compounds are summarized in Table l. As used herein the term RT (min) refers to the LCMS rétention time, in minutes, associated with the compound.

-5817028

Préparation of Compound 1

Synthetic Scheme 1 iO

Na₂COj, THF, CHjCN, microwave, 135 °C; (b) NaOMe, MeOH, 0°C;

Formation of (Æ)-3-(2-(5-chloro-l-tosyI-lZf-pyrroloI2,3-ô]pyridin-3-yI)-5-fluoropyrimidin-4-ylamino)-4,4-dimethyipentanoic acid (3a)

To a solution of 5-chloro-3-(5-fluoro-4-methyIsuIfînyl-pyrimidin-2-yl)-l-(ptolylsulfonyl)pyrrolo[2,3-b]pyridine, la, (0.100 g, 0.215 mmol: prepared in a similar manner as described below for Compound 25a in scheme 4) and (R)-3-amino-4,4dimethylpentanoic acid, 2a, (0.031 g, 0.215 mmol) in tetrahydrofuran (1.66 mL) was added freshly ground Na₂COj (0.068 g, 0.645 mmol) followed by acetonitrile (0.331 mL). The reaction mixture was heated to 135 °C for 30 minutes in a microwave reactor. The reaction mixture was slowiy poured into 75 mL of 1N HCl. The pH of final solution was adjusted to 1. The aqueous was extracted with EtOAc (3X5 mL), washed with brine, dried over Na₂SO< and fïltered to obtain a crude solid residue. The crude residue was purified via silica gel chromatography (0-10% MeOH-CH₂Cl₂gradient) afforded 78 mg of the desired product 3a: LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, RT= 3.9 minutes (M+H) 546.22.

(Æ)-3-(2-(5-Chloro-l/f-pyrrolo|2,3-ô|pyrldin-3-yl)-5-fluoropyrimidin-4-ylamino)-4,4dimethyipentanoic acid (1) .

To a cold (0 °C) solution of (A)-3-(2-(5-chloro-l-tosyl-177-pyrrolo[2,3-6]pyridin-3yl)-5-fluoro-pyrimidin-4-ylamino)-4,4-dimethylpentanoic acid, 3a, (0.08 g, 0.14 35 mmol) in MeOH (2.6 mL) was added sodium methanolate (2.91 mL of 25 %w/v,

13.46 mmol). The reaction was stirred at room température for 30 min and then quenched by dilution into aqueous saturated ammonium chloride solution. The

-5917028

MeOH was evaporated in vacuo and the resulting aqueous phase diluted with EtOAc, then extracted with EtOAc (3X). The organics were dried (Na₂SO₄), filtered and concentrated in vacuo. Recrystalization from MeOH provided 52 mg of the desired product 1 as a white powder: ^lH NMR (J6-DMSO) 5 12.25 (s, 1H): 12.0 (bs, 1H):

8.8 (s, 1H): 8.3 (s, 1H): 8.25 (s, 1H); 8.1 (s, 1H): 7.45 (d, 1H); 4.75 (t, 1H); 2.5 (m, 2H), 1.0 (s, 9H); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, RT = 2.06 minutes (M+H) 392.21.

Préparation of Compounds 2, 43, 89 and 90

Synthetic Scheme 2

Hjl^ OH y2«

8a

AcCl, MeOH, reflux; (b) 2,4-dichloro-5fluoropyrimidine, EtjN, EtOH, THF, 55 °C; (c) 5fluoro-1 -(p-toiylsulfonyi)-3-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine, 7a, Pd₂(dba)₃, XPhos, K₃PO₄,2-MeTHF, H₂O,115 °C; (d) HCl, dioxane, acetonitrile, 65°C; (e) LiOH, THF, H₂O,50 °C.

Formation of (R)-l-methoxy-4,4-dlmethyl-l-oxopentan-3-amInium chloride (Sa) (R)-3-amino-4,4-dimethylpentanoic acid, 2a, was dissolved in methanol (1.4 L). The solution was cooled in an ice bath and acetyl chloride (67.0 mL, 947.0 mmol) was added dropwise (maintaining the température below 10 °C). The reaction mixture was heated to 65 °C and stirred at that température for 3 h. The reaction mixture was cooled to room température and then flushed with toluene to remove volatiles. The crude material was used without further purification: 'H NMR (400 MHz, MeOH-J₄) δ 3.75 (s, 3H), 3.41 (t, 1H), 2.88 (dd, 1H), 2.64 - 2.46 (m, 1H), 1.04 (s, 9H).

Formation of (R)-methyl 3-((2-chloro-5-fluoropyrimidln-4-yl)amlno)-4,4dimethylpentanoate (6a)

-6017028 (Æ)-l-methoxy-4,4-dimethyl-l-oxopentan-3-aminium chloride, 5a, (37 g, 189 mmol) was dissolved in a mixture of tetrahydrofuran (667 mL) and EtOH (74 mL). The solution was cooled in an ice bath. 2,4-dichloro-5-fluoro-pyrimidine (35 g, 208 mmol) was added, followed by the dropwise addition of triethylamine (85 mL, 606 mmol). The reaction mixture was heated at 55 °C for 17 h. The reaction mixture was then cooled to room température after which water (625 mL) and dichloromethane (625 mL) were added. The phases were separated and the aqueous layer was washed with dichloromethane (625 mL). The organic layers were combined and washed with brine. The solvents were removed and the residue was purified on silica gel (EtOAc/Hexanes): LCMS Gradient 10-90%, 0.1% formic acid, 5min, C18/ACN, RT = 3.10 minutes (M+H) 291.02.

Formation of (Zî)-methyl 3-((5-fluoro-2-(5-fluoro-l-tosyl-l£f-pyrroIo[2,3-bJpyrldln-3yI)pyrlmldin-4-yI)amino)-4,4-dimethyIpentanoate (8a)

A 2-MeTHF (253 mL)/water (56 mL) solution of 5-fluoro-l-(p-tolylsulfonyl)-3(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine, 7a, (24.3 g, 58.3 mmol), methyl (Æ)-methyl 3-((2-chloro-5-fluoropyrimidin-4-yl)amino)-4,4dimethylpentanoate, 6a, (14.1 g, 48.6 mmol) and KjPO< (30.9 g, 146 mmol) was purged with nitrogen for 0.75 h. XPhos (2.8 g, 5.8 mmol) and Pd₂(dba)₃ (1.1 g, 1.2 mmol) were added and the reaction mixture was stirred at 115 °C in a sealed tube for 2 h. The reaction mixture was cooled and the aqueous phase was removed. The organic phase was filtered through a pad of Cetite and the mixture was concentrated to dryness. The residue was purified on silica gel (EA/Hex) to provide the desired product, 8a, (23.2g): LCMS Gradient 10-90%, 0.1% formic acid, 5min, C18/ACN, RT = 2.18 minutes (M+H) 245.28.

Formation of (Æ)-methyl 3-((5-fluoro-2-(5-fluoro-lH-pyrroIo[2,3-b|pyridin-3yI)pyrimidin-4-yI)amino)-4,4-dimethyIpentanoate (9a)

To a solution of ( 7?)-m ethyl 3-((5-fluoro-2-(5-fluoro-l-tosyl-l/7-pyrrolo[2,3b]pyridin-3-yl)pyrimidin-4-yl)amino)-4,4-dimethyIpentanoate, 8a, (21 g, 39 mmol) in acetonitrile (157 mL) was added 4M HCl in dioxane (174 mL). The reaction mixture was heated to 65 °C for 4 h. The solution was cooled to room température and the solvents were removed under reduced pressure. The mixture was flushed with acetonitrile after which dichloromethane (lOOmL), sat. aqueous NaHCOj (355 mL) and ethyl acetate (400 mL) were added. The phases were separated and the aqueous layer washed with ethyl acetate (500 mL). The organic layers were combined, dried (NaîSOi), filtered and concentrated in vacuo. The resulting residue was purified on silica gel (EtOAc/Hexanes) to provide the desired product, 9a, (12.1g): LCMS Gradient 10-90%, 0.1% formic acid, 5min, C18/ACN, RT = 2.26 minutes (M+H) 391.05.

Formation (Æ)-3-((5-nuoro-2-(5-nuoro-lW-pyrroIo[2,3-bIpyridin-3-yl)pyrimidln-4yl)amino)-4,4-dimetbyIpentanoic acid (2) (Æ)-Methyl 3-((5-fluoro-2-(5-fluoro-l//-pyrrolo[2,3-b]pyridin-3-yl)pyrimÎdin-4yl)amino)-4,4-dimethylpentanoate, 9a, (18.4 g, 47.1 mmol) was dissolved in tetrahydrofuran (275 mL) and aqueous IM LiOH (141 mL) was added. The mixture was heated to 50 °C for 3.5 h. The reaction mixture was cooled to room température

-6117028 and 180 mL of water was added. The tetrahydrofuran was removed under reduced pressure and the residue was then flushed twice with hexanes. Diethylether (60 mL) was added and the layers separated. The pH of the aqueous layer was adjusted to 6 with IN HCl. Ethy! acetate (540 mL) was added, the layers were separated and the aqueous layer was extracted with ethyl acetate (720 mL), then again with ethyl acetate (300 mL). The organic layers were combined, washed with brine (100 mL) and dried (Na2SO<). The solvents were removed while flushing with heptanes to provide the desired product, 2, (17.5g): *H NMR (400 MHz, DMSO-<4) δ 12.23 (s, 1H), 12.03 (s, 1H), 8.68 - 8.52 (m, 1H), 8.27 (s, 1H), 8.19 (d, J= 2.5 Hz, 1H), 8.13 (d, 4.0 Hz, 1H), 7.39 (d, 9.2 Hz, 1H), 4.83 (t, J= 9.3 Hz, 1H), 2.71 - 2.51 (m,

2H), 0.97 (s, 9H); LCMS Gradient 10-90%, 0.1% formic acid, 5min, C18/ACN, RT = 1.96 minutes (M+H) 377.02.

The following analog was prepared in a similar fashion as the procedure described above for Compound 2:

(R)-3-((5-fluoro-2-(5-(trinuoromethyl)-l£Apyrrolo[23-b]pyridin-3-yl)pyrimidln-4yl)amlno)-4,4-d!methylpentano!c acid (43) ’H NMR (300 MHz, CDC1₃) δ 11.16 (s, 1H), 8.70 (s, 1H), 8.04 (d, J = 3.2 Hz, !H), 7.96 (s, 1H), 7.87 (s, 1H), 5.02 (d, J= 8.1 Hz, 1H), 4.80 (t, 9.6 Hz, 1H), 2.81 (d, 9.9 Hz, 1H),

2.34 (t, 11.3 Hz, 1H), 1.14 (s, 9H); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, Rétention Time = 2.49 minutes (M+H) 426.47.

OH (R)-3-((5-nuoro-2-(5-methyl-l£f-pyrroio|23-blpyrldin-3-y!)pyrlmldln-4-y))amino)-4,4dimcthylpcntanolc acid (90) ’H NMR (300 MHz, CDCI3) δ 8.68 (s, 1H), 8.43 (d, J = 14.1 Hz, 2H), 8.23 (s, 1H), 4.96 (s, 2H), 2.88 - 2.55 (m, 4H), 2.45 (s, 3H), 1.00 (s, 9H); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, Rétention Time = 1.8 minutes (M+H) 372.5.

NC

-6217028 (Λ)-3-((2 - (5-cy a no-1 W-pyr rolo [ 2,3-b] pyrl dln-3-yl)-5-fl uo ropy rimldi n-4-yl)ami no)-4,4dlmethylpentanolc acid (89)

LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, Rétention Time = 2.1 minutes (M+H) 383.38.

(5)-3-((5-fluoro-2-(5-fluoro-l//-pyrrolo[2,3-blpyridin-3-yl)pyrimldin-4-yl)amino)-4,4dimethylpentanolc acid (4)

LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, CI8/ACN, Rétention Time = 1.93 minutes (M+H) 376.21.

F

(S)-3-((2-(5-chloro-lZf-pyrroloI23-b]pyrldln-3-yl)-5-nuoropyrimldln-4-yl)amlno)-4,4dimethylpcntanoic acid (3)

LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, Rétention Time = 2.06 minutes (M+H) 392.21.

Préparation of Compound 69

Synthctic Scheme 3

-6317028

2,4-dichloro-5-fluoropyrimidine, EtjN, DMF; (b) oxalyl chloride, DMF, DMSO, EtjN, CH₂C1₂; (c) [(‘PrOhPOhCH:, NaH, THF; (d) 5-fluoro-l-(ptolylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine, 7a, Pd₂(dba)j, XPhos, KjPO₄,2-MeTHF, H₂O,100 °C;

(e) NaOMe, MeOH; (t) H₂, Pd/C, MeOH, 40 psi; (g) trimethylsilyliodide, CH₂C1₂.

Formation of (S)-2-((2-chloro-5-fluoropyrimldln-4-yl)amlno)-33-dlmethylbutan-l-ol (14a)

To a mixture of (2S)-2-amino-3,3-dimethyl-butan-l-ol (5.0 g, 42.7 mmol) and 2,4dichloro-5-fluoro-pyrimidine (5.7 g, 42.7 mmol) in DMF (50 mL) was added triethylamine (7.1 mL, 51.2 mmol). After 90 minutes, the reaction was diluted into aqueous saturated NH^Cl solution and extracted twice with EtOAc. The combined organic phases were washed twice with brine, dried (MgSO<), filtered and concentrated in vacuo. The crude residue was purified via silica gel chromatography (0-10% MeOH/CH₂Cl₂ gradient) to afford 6.7 g of the desired product, 1, as a sticky solid: LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, RT = 2.48 minutes (M+H) 248.32.

Formation of (.S)-2-((2-chloro-5-fluoropyrimidin-4-yl)amino)-3,3-dimethylbutanal (15a)

To a cold (-78 °C) solution of oxalyl chloride (1.06 mL, 12.11 mmol) in dichloromethane (10 mL) was added dimethyl sulfoxide (1.43 mL, 20.18 mmol) dropwise. After stirring the mixture for 10 minutes at -78 °C, a suspension of (2S)-2[(2-chloro-5-fluoro-pyrimidin-4-yi)amino]-3,3-dimethyl-butan-l-ol, 14a, (1.0 g, 4.04 mmol) in dichloromethane (10 mL) was added. The reaction mixture was stirred for 30 minutes at -78 °C and triethylamine (3.38 mL, 24.22 mmol) was added. The mixture was slowly warmed to 0 °C over 2hours. The mixture was diluted into aqueous saturated NaHCOj solution and extracted twice with EtOAc. The combined

-6417028 organic phases were dried (MgSO^), filtered and concentrated in vacuo. The crude residue was purified via silica gel chromatography (0-15% EtOAc/CH₂Cl₂ gradient) to afford 680 mg of the desired product as a white solid.

Formation of (/?,E)-diisopropyl (3-((2-chloro-5-fluoropyrimidin-4-yl)amino)-4,4dimethylpent-l-en-l-yl)phosphonate (16a)

To a cold (0 °C) suspension of sodium hydride (0.163 g, 7.083 mmol) i n THF (8.0 mL) was added 2-(diisopropoxyphosphorylmethyl(isopropoxy)phosphoryl)oxypropane (1.220 g, 3.542 mmol). After 15 minutes, a solution of (S)-2-((2-chloro5-fluoropyrimidin-4-yl)amino)-3,3-dimethylbutanal, 15a, (0.580 g, 2.361 mmol) in THF (4 mL) was added dropwise. The reaction mixture was slowly warmed to room température over 1 hour. The mixture was diluted into aqueous saturaied NH4CI solution and extracted with EtOAc. The organic phase was dried (MgSO«), filtered and concentrated in vacuo. The resulting crude residue was purified via silica gel chromatography (10-50% EtOAc/CH₂Cl₂ gradient) to afford 810 mg of the desired product: LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, RT « 3.28 minutes (M+H) 408.36.

Formation of (R,E)-diisopropyl (3-((5-fluoro-2-(5-fluoro-l-tosyl-lZZ-pyrrolo[2,3h] py ridi n-3-y l)pyri mi di n-4-yl)a mi no)-4,4-di methylp en t-1-en-1-y l)phosphona te (17a)

To a solution of (Æ,£)-diisopropyl (3-((2-chloro-5-fluoropyrimidïn-4-yl)amino)-4,4dimethylpent-l-en-l-yl)phosphonate, 16a, (0.81 g, 1.99 mmol) and 5-fluoro-l-(ptol ylsul fonyl)-3 -(4,4,5,5 -tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3 -bjpyridine, 7a, (1.24 g, 3.00 mmol) in 2-Me-THF (16 mL) was added K3PO4 (1.27 g, 3.00 mmol) and water (4 mL). The biphasic mixture was degassed under a stream of nitrogen for 15 minutes. Then, X-Phos (0.11 g, 0.24 mmol) and Pd₂(dba)3 (0.06 g, 0.06 mmol) was added to the mixture. After degassing with nitrogen for an additional 5 minutes, the vessel was sealed and heated at 100 °C for 2 hours. The mixture was cooled to room température and diluted with EtOAc, filtered through celite. The filtrate was washed with brine, dried (MgSO<), filtered and concentrated in vacuo. The crude residue was purified via silica gel chromatography (0-50% EtOAc/CH₂Ci₂ gradient) to afford 1.123 g of the desired product: 'H NMR (400 MHz, J6-DMSO) δ 8.55 -

8.42 (m, 3H), 8.31 (d, J » 3.7 Hz, I H), 8.06 (d, J = 8.3 Hz, 2H), 7.73 (d, J = 8.9 Hz, IH), 7.44 (d, J = 8.4 Hz, 2H), 6.80 (ddd, J - 22.2, 17.1, 6.9 Hz, 1H), 5.99 (dd, J = 20.3, 17.1 Hz, 1H), 4.95 (t, 7.6 Hz, 1H), 4.51 - 4.32 (m, 2H), 2.35 (s, 3H), 1.19 -

1.14 (m, 6H), 1.11 (dd, J= 6.0, 4.4 Hz, 6H), 1.02 (s, 9H).); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, RT= 4.06 minutes (M+H) 662.35.

Formation of (Æ,E)-diisopropyl (3-((5-fluoro-2-(5-fluoro-l£f-pyrrolo[23h]pyridin-3-yl)pyrimidin-4-yl)amino)-4,4-dimethylpent-l-en-l-yl)phosphonate (18a)

To a solution of (Æ,E)-diisopropyl (3-((5-fluoro-2-(5-fluoro-l-tosyl-lH-pyrrolo[2,3b]pyridin-3-yl)pyrimidin-4-yl)amino)-4,4-dimethylpent-1 -en-1 -yl)phosphonate, 17a, (1.0 g, 1.51 mmol) in methanol (30 mL) was added sodium methoxide (8.2 mL of 25% wt solution in MeOH). After 3 minutes, the mixture was diluted into aqueous saturated NH4CI solution and extracted twice with EtOAc. The combined organic

-6517028 phases were dried (MgSO<), filtered and concentrated in vacuo. The crude residue was purified via silica gel chromatography (0-15% MeOH/CHîClî gradient) to afford 724 mg of the desired product: LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, RT = 2.76 minutes (M+H) 508.13.

Formation of (/?)-diisopropyi-(3-((5-fluoro-2-(5-fluoro-17Z-pyrrolo[2,3-b]pyridin-3yl)pyrlmidin-4-yi)amino)-4,4-dimethylpentyi)phosphonate (19a)

To a solution of (Æ,£)-diisopropyl (3-((5-fluoro-2-(5-fluoro-lZ/-pyrrolo[2,3b]pyridin-3-yl)pyrimidin-4-yl)amino)-4,4-dimethylpent-l-en-I-yl)phosphonate, 18a, (0.36 g, 0.71 mmol) in McOH (7 mL) was added Pd on Carbon (10%, wet, Degussa, 0.07 g, 0.07 mmol). The reaction mixture was stirred in a Parr hydrogénation flask under 50 psi of hydrogen ovemight. The mixture was diluted with EtOAc and filtered through celite. The filtrate was concentrated in vacuo to give the desired product as dark gray solid: *H NMR (400 MHz, </6-DMSO) δ 12.28 (s, 1H), 8.46 (dd, 9.9, 2.7 Hz, 1H), 8.30-8.21 (m, 2H), 8.15 (d, J=3.9 Hz, 1H), 7.29 (d,J =

9.5 Hz, 1H), 4.51 (dt, 12.3, 6.2 Hz, 2H), 4.37 (t, 9.8 Hz, 1H), 1.95 - 1.60 (m,

3H), 1.59 - 1.35 (m, 1H), 1.24 - 1.09 (m, 12H), 0.99 (s, 9H); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, RT = 2.46 minutes (M+H) 510.56.

Formation of (/î)-(3-((5-fluoro-2-(5-fluoro-lH-pyrrolo[2,3-b]pyridin-3-yl)pyrimldin-4yl)amino)-4,4-dimethyipentyl)phosphonic acid (69)

To a solution of (/?)-diisopropyl-(3-((5-fluoro-2-(5-fIuoro-17/-pyrro!o[2,3-b]pyridin3-yl)pyrimidin-4-yl)amino)-4,4-dimethylpentyl)phosphonate, 19a, (0.16 g, 0.32 mmol) in dichloromethane (8 mL) was added iodotrimethylsilane (0.45 mL, 3.18 mmol). The reaction mixture was stirTed at room température. After 1 hour, LCMS showed the réaction to be incomplète. An additional 0.90 mL of iodotrimethylsilane (0.64 mmol) was added to the reaction mixture. After 5 hours, the mixture was concentrated in vacuo and the resulting residue was purified via preparatory HPLC (CHîCN/1% aqueous TFA) to afford 8 mg of phosphonic acid, 69, and 34 mg of phosphonate, 21a.

Spectral data for phosphonic acid, 69: *H NMR (300 MHz, MeOD) δ 8.59 - 8.39 (m, 2H), 8.32 (t, J = 5.3 Hz, 2H), 4.59 (d, 9.5 Hz, 2H), 2.21 (s, 1H), 1.79 (dddd, J =

28.6, 23.0, 13.2, 6.9 Hz, 3H), 1.11 (d, J= 9.5 Hz, 9H); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, RT ® 1.81 minutes (M+H) 426.09.

Spectral data for phosphonate 21a: ’H NMR (300 MHz, MeOD) δ 8.57 - 8.41 (m, 2H), 8.32 (d, J = 5.6 Hz, 2H), 4.73 - 4.41 (m, 2H), 2.25 (d, J - 25.7 Hz, 1H), 2.06 -

1.43 (m, 3H), 1.32 - 1.20 (m, 6H), 1.11 (d, 11.2 Hz, 9H); LCMS Gradient 10-

90%, 0.1% formic acid, 5 minutes, C18/ACN, RT = 2.06 minutes (M+H) 468.13.

Préparation of Compounds 16 and 17

Synthetlc Scheme 4

-6617028

NaH, TsCl, DMF; (b) KOAc, PdCl₂(dppf), dioxane, water, reflux; (c) Pd(PPhj)4, Na₂COj, DME, water; (d) morpholine-4-carbonyl chloride, 'Pr₂NEt, CH₂C1₂;

Formation of 3-bromo-5-fluoro-l-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridlne (22a)

3-bromo-5-fluoro-lW-pyrrolo[2,3-b]pyridine (5.0 g, 23.3 mmol) was dissolved in DMF (37.5 mL) and cooled to 0 °C. Sodium hydride (1.5 g, 37.2 mmol) was added and the reaction mixture was stirred for 10 minutes and then treated with tosyl chloride (6.6 g, 34.9 mmol). The mixture was stirred for 30 minutes at 0 °C and then at room température for another 90 minutes. The reaction mixture was poured into water (100 mL) and the resulting solid was collected, washed with water and hexanes three times and dried in vacuo to afford 8.26 g of 3-bromo-5-fluoro-l-(ptolylsulfonyl)pyrrolo[2,3-b]pyridine, 22a: ’H NMR (300 MHz, DMSO-Je) δ 8.48 (s, 1H), 8.31 (s, IH), 8.01 (d, J= 8.3 Hz, 2H), 7.92 (dd, J- 8.4,2.7 Hz, IH), 7.44 (d,

8.5 Hz, 2H), 2.35 (s, 3H).

Formation of 5-fluoro-l-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl-l,3.2-dloxaborolan-2yl)pyrrolo[23-b]pyridine (7a)

3-bromo-5-fluoro-l-(p-tolylsulfonyi)pyrroIo[2,3-b]pyridine, 22a, (4.0 g, 10.8 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2dioxaborolane (8.3 g, 32.5 mmol) and potassium acetate (3.2 g, 32.5 mmol) were taken in dioxane (40 mL) containing a few drops of water. After purging with nitrogen for 30 minutes, PdCl₂(dppf) (0.8 g, 1.1 mmol) was added. Nitrogen purging was continued for an additional 40 minutes, then the reaction mixture was heated to reflux ovemight. After cooling down, the mixture was filtered through Florisil (60g), washed with dichloromethane (220 mL) and concentrated in vacuo to provide a brown oil. The crude product was taken into hexane (40 mL) and TBME (14 mL) and heated to reflux. After cooling to room température, the resulting suspension was filtered to provide 2.6 g of the desired product as a white solid: 'H NMR (300 MHz, DMSO-4j) δ 8.42 (dd, J = 2.7, 1.4 Hz, IH), 8.14 (s, IH), 8.06 (d, J= 8.4 Hz, 2H), 7.85 (dd, 8.6,2.8 Hz, IH), 7.44 (d,J= 8.3 Hz, 2H), 2.36 (s, 3H), 1.32 (s, 12H).

-6717028

Formation of 5-fluoro-3~(5-fluor(>-4-methylsulfanyi-pyrimldin-2-yi)-l*(ptolylsulfonyl)pyrrolo[23'b]pyrldlne (24a)

2-chloro-5-fluoro-4-methylsulfanyl-pyrimidine (1.6 g, 9.0 mmol), 5-fluoro-l-(ptolylsulfonyi)-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine, 7a, (2.5 g, 6.0 mmol) and NaîCOj (1.9 g, 18.0 mmol) were dissolved in DME (37.5 10 mL) and water (7.5 mL). The mixture was purged with nitrogen for 20 minutes, treated with Pd(PPhj)4, purged with nitrogen for another 20 minutes and heated to reflux ovemight. After cooling to room température, water (35 mL) was added and the resulting suspension was stirred for 30 minutes. The precipitate was collected by filtration, washed with water and acetonitrile and dried ovemight at 50 °C, affording 15 2.3 g (88.5%) of the desired product as a white solid: ^lH NMR (300 MHz, DMSOd₆) δ 8.70 - 8.57 (m, 2H), 8.55 - 8.42 (m, 2H), 8.09 (d, 8.4 Hz, 2H), 7.45 (d, J~

8.4 Hz, 2H), 2.76 (s, 3H), 2.36 (s, 3H).

Formation of 5-fluoro-3-(5-fluoro-4-methylsulfinyl-pyrlmldln-2-yI)-l-(ptolylsul fo nyl)py r roi o [2^3-b ] py ri din e (25 a)

5-fluoro-3-(5-fluoro-4-methylsul fanyl-pyrimidin-2-yl)- l-(p-tolylsulfonyl)pyrrolo[2,3bjpyridine, 24a, (2.30 g, 5.32 mmol) was dissolved in dichloromethane (107 mL) and treated portionwise with 3-chloropeibenzoic acid (1.19 g, 5.30 mmol), keeping the température below 20°C. After stîrring for 2 hours, another portion of 3chloroperbenzoic acid (0.18 g, 0.80 mmol) was added, and stinïng was continued for 25 another hour. A third portion of 3-chloroperbenzoic acid (0.07 g, 0.05 mmol) was added and stîrring was continued for 30 minutes. The reaction mixture was treated with an aqueous 15% K2CO3 solution (30 mL) and the layers were separated. The organic layer was washed with 15% KiCOj and brine, dried (NajSO^), filtered and concentrated in vacuo to afford 2.3 g (96%) of the desired product as a yellow solid, 30 which was used without further purification: *H NMR (300 MHz, DMSO-rfe) δ 9.12 (d, J = 1.5 Hz, 1H), 8.70 (s, 1H), 8.67 (dd, 9.1, 2.8 Hz, 1H), 8.53 (d, J- 1.5 Hz, 1H), 8.11 (d, 8.4 Hz, 2H), 7.46 (d, J= 8.2 Hz, 2H), 3.05 (s, 3H), 2.36 (s, 3H).

The following analog was prepared in a similar fashion as the procedure described above for sulfoxide, 25a:

Tr

5-chloro-3-(5-fluoro-4-(methylsuirinyl)pyrimidin-2-yl)-l-tosyl-l/7-pyrroloI2^bjpyridinc (la) 'H NMR (300 MHz, J6-DMSO) δ 9.12 (d, 1.3 Hz, 1H), 8.90 (d, 2.4 Hz, 1H), 8.68 (s,

IH), 8.53 (d, J = 2.4 Hz, 1H), S. 12 (¢/, J = 8.4 Hz, 2H), 7.46 (d, J= 8.4 Hz, 2H), 2.54 - 2.48 40 (m, 3H), 2.36 (s, 3H).

-6817028

Synthetic Scheme 5

Et2Û; b) malonic acid, ammonium acetate, éthanol, 80 °C; c) 5-fluoro-3-(5-fluoro-4(methylsulfinyl)pyrimidin-2-yl)-l-tosyl-l/Zpyrrolo[2,3-b]pyridme, 25a, T^NEt, THF, 80 °C; (d) LiOH, THF- H₂O (3:1), 130 °C microwave; e) SFC chiral séparation

Formation of 2,2-dimethyibutanal (26a)

To a solution of 1,1-dimethyipropyl magnésium chloride (20.0 mL of 1 M, 20.0 mmol) in ether (25 mL) was added N-methyl-jV-phenyl formamide (5.26 mL, 20.0 mmol) in one portion (exothermic). The yellow solution was gently refluxed for two hours and stirred at room température for three hours. At the end of this period the Grignard complex was quenched by pouring onto 500 g of crushed ice and 20 ml. of concentrated sulfuric acid. The ether layer was separated and the aqueous phase extracted three times with 50 mL portions of ether. The combined ether extracts were dried (MgSO<) and concentrated in vactio. The crude residue was purified by short-path distillation to afïord 1.0 g of pure 2,2dimethylbutanal as a colorless oil: ‘H NMR (400 MHz, CDCIj) δ 4.17 (q, J = 7.1 Hz, 2H), 3.03 (dd, 10.9, 2.3 Hz, 1H), 2.53 (dd, 15.3, 2.3 Hz, 1H), 2.15 (dd, J= 15.3, 10.9 Hz, 1H), 1.50- 1.33 (m, 3H), 1.28 (dd, 9.0,5.3 Hz, 3H), 1.26-1.17 (m, 1H), 0.85 (d, 5.8

Hz, 6H).

Formation of ethyl 3-amlno-4,4-dlmethylhexanoate (27a)

-6917028

A mixture of 2,2-dimethylbutanal, 26a, (3.00 g, 26.75 mmol), malonic acid (2.08 g, 1.29 mL, 20.00 mmol), ammonium acetate (3.08 g, 40.00 mmol) in éthanol (5 mL) was refluxed for three hours. The precipîtate was removed by filtration and washed with éthanol. The solution was used without further purification.

Sulfuric acid (1.962 g, 1.066 mL, 20.00 mmol) was added to above éthanol solution and the resultîng mixture was heated to reflux for two hours. The solvent was removed under reduced pressure. Water (20 mL) and ether (10 mL) were added to the crude residue. The aqueous layer was separated and washed with ether (10 mL). The organic layers were discarded. The aqueous solution was neutralized with sodium hydroxîde solution (6N) and saturated sodium bicarbonate solution to basic, and extracted with ethyl acetate (3x10 mL). The combîned organic layers were washed with water (10 mL), brine (lOmL), filtered, dried (MgSO^), filtered and concentrated in vacuo to give 0.5 g of the desired product as a light yellow sticky oil, which tumed into solid upon standing. The crude product was used without further purification: *H NMR (400 MHz, CDCIj) 6 4.17 (q, 7.1 Hz, 2H), 3.03 (dd, J= 10.9, 2.3 Hz, 1H), 2.53 (dd, J = 15.3, 2.3 Hz, 1H), 2.15 (dd, J= 15.3, 10.9 Hz, 1H),

1.50 - 1.33 (m, 3H), 1.28 (dd, J = 9.0, 5.3 Hz, 3H), 1.26-1.17 (m, 1H), 0.85 (d, J- 5.8 Hz, 6H).

Formation of ethyl 3-((5-fluoro-2-(5-fluoro-l-tosyI-l/f-pyrrolo|23-blpyrIdln-3yI)pyrimidln-4-yl)amino)-4,4-dimethyIhexanoate (28a)

To a suspension of ethyl 3-amîno-4,4-dimethyIhexanoate, 27a, (0.19 g. 1.00 mmol) and 5fluoro-3 -(5 -fluoro-4-methylsulfinyi-pyri mîdin-2-yt)-1 -(p-tolylsulfonyl)pyrrolo[2,3bjpyridine, 25a, (0.54 g, 1.20 mmol) in THF (14.4 mL) was added N,Ndiisopropylethylamine (0.26 mL, 1.50 mmol). The mixture was refluxed at 80 °C ovemight. After removing the solvents under reduced pressure, the crude product was purified by silica gel chromatography (0-50% EtOAc/Hexane gradient) to afford 155 mg of the desired product as a light yellow solid: ^lH NMR (300 MHz, CDCIj) 6 8.61 (dd, J= 9.0,2.9 Hz, 1H), 8.56 (s, 1H), 8.33 (dd, J = 2.7, 1.0 Hz, 1H), 8.11 (d, 8.4 Hz, 2H), 7.30 (d, J= 8.2 Hz, 2H), 5.19 (dd, J = 10.1, 2.2 Hz, 1H), 4.94 (td,J= 10.0, 3.7 Hz, IH), 3.99 (dt, J = 13.7, 6.8 Hz, 2H), 2.40 (s, 3H), 1.42 (dt, J= 14.1,6.9 Hz, 2H), 1.05 (t,J= 7.1 Hz, 3H), 1.01 -0.94(m, 8H); ¹⁹F NMR (282 MHz, CDCIj) δ -130.39 -133.75 (dd, J= 9.0,1.1 Hz, 1F), -158.56 (s, 1F); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, CÎ8/ACN, RT = 4.18 minutes (M+H) 572.07.

Formation of 3-((5-fluoro-2-(5-fluoro-17/-pyrroIo|2,3-h|pyridin-3-yI)pyriinidin-4yl)amino)-4,4-dimethylhexanoic acid (16,17)

To a solution of ethyl 3-((5-fluoro-2-(5-fluoro-l-tosyl-l/7-pyrrolo[2,3-è]pyridin-3yl)pyrimidin-4-yl)amino)-4,4-dimethylhexanoate, 28a, (0.16 g, 0.27 mmol) in THF (6 mL) was added LiOH (1.50 mL of I M solution, 1.50mmot). The reaction mixture was heated in a microwave reactor at 130 °C for thirty minutes. The reaction was quenched by the addition of aqueous saturated NHjCl solution. The resulting white precipîtate was collected and washed with water, acetonitrile and ether. The combined organic phases were then concentrated in vacuo to give pure desired carboxylic acid as a solid. The solid was dituted with hydrochloric acid (2 mL of IN solution) and iyophitized to give 110 mg of the desired product as a hydrochloride sait (light yellow powder): *H NMR (300 MHz, MeOD) δ 8.73 (d, J =9.5 Hz, 1H), 8.16 (s, 1H), 8.15-8.10 (m, 1H), 7.93 (d, J = 4.0 Hz, 1H), 5.02 (d,J =

6.4 Hz, 1H), 3.75 (ddd, J= 6.7, 4.2, 2.5 Hz, 3H), 2.66 (d, J= 11.2 Hz, IH), 2.45 (dd, J = 14.0, 9.9 Hz, IH), 1.93 - 1.83 (m, 3H), 1.46 (d, J= 7.5 Hz, 2H), 1.05 - 0.93 (m, 9H); ^,9F

-7017028

NMR (282 MHz, MeOD) δ -139.17 (s, 1F), -160.86 (s, 1F); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, RT « 2.04 minutes (M+H) 390.23.

The racemic mixture was submitted to SFC chiral séparation to give the individual enantiomers, 16, and 17.

Préparation of Compounds 14 and 15

Synthetic Scheme 6

LiHMDS, Mel, THF -78 °C; b) DIBAL,

CHîCiî, -78 °C; c) malonic acid, ammonium acetate, éthanol, 80 °C; d)’PnNEt, THF, 80 °C;

e) LiOH, THF- H₂O (3:1), 130 °C, microwave;

f) SFC chiral séparation

Formation of 1-methylcyclopentanecarbonitrile (31a)

To a cold (-78 °C) solution of LiHMDS (48.0 mL of 1 M solution in tetrahydrofuran, 48.0 mmol) in tetrahydrofuran was added dropwise a solution of cyclopentanecarbonitrile (3.81 g, 25 40.0 mmol) in tetrahydrofuran (10 mL) over a 5 minute period. After stirring at -78 °C for thirty minutes, methyl iodide (3.74 mL, 60.00 mmol) was added in one portion. The reaction was allowed to warm to room température ovemight. The solution was cooled to 0 °C, ethyl acetate (50 mL) and aqueous saturated ammonium chloride solution (20 mL) was added. Additional water (10 mL) was added to dissolve the solid. The organic layer was separated 30 and washed with aqueous saturated ammonium chloride (20 mL). The aqueous layer was

-7117028 extracted with ethyl acetate (2 X 20 mL). The combined organic phases were washed with brine, dried (MgSO^), filtcred and concentrated in vacuo to give a 4.7g of a yellow oil that was used without further purification: *H NMR (400 MHz, CDClj) δ 2.04 - 1.93 (m, 2H), 1.77- 1.65 (m, 2H), 1.66 - 1.55 (m, 2H), 1.54 (m, 2H), 1.25 (s, 3H).

Formation of l-methylcyclopentanecarbaldehyde (32a)

To a cold (-78 °C) solution of diisobutylaluminum hydride (100.0 mL of 1 M solution, 100.0 mmol) in dichloromethane was added dropwise a solution of 1methylcyclopentanecarbonitrile, 31a, (4.3 g, 40.0 mmol) in dichloromethane (5 mL). The réaction was kept at -78 °C for thîrty minutes. The dry-ice bath was removed and methanol (I mL) was added to quench the reaction. Potassium sodium tartrate solution (30 mL, 10% solution) was added and the mixture stîrred vigorously. The organic layer was separated and the aqueous layer was extracted with dichloromethane (3 X 20 mL). The combined organic phases were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to give 3 g of a light yellow oil that was used without further purification: *H NMR (400 MHz, CDCh) 5 2.04 - 1.93 (m, 2H), 1.77- 1.65 (m, 2H), 1.66 - 1.55 (m, 2H), 1.54 (m, 2H), 1.25 (s, 3 H).

Formation of ethyl 3-amino-3-(l-methyicyclopentyI)propanoate (33a)

A mixture of 1-methylcyclopentanecarbaldehyde, 32a, (3.00 g, 26.75 mmol), malonic acid (1.29 mL, 20.00 mmol) and ammonium acétate (3.08 g, 40.00 mmol) in éthanol (5 mL) was refluxed for 12 hours. The precipitate was removed by filtration and washed with éthanol. The filtrate was used without further purification.

Sulfuric acid (1.07 mL, 20.00 mmol) was added to the above éthanol solution and heated to reflux for 2h. The solvent was removed under reduced pressure. The residue was diluted with water (20 mL) and ether (10 mL). The aqueous layer was separated and washed with ether (10 mL). The organic layers were discarded. The aqueous solution was neutralized with sodium hydroxide solution (6N) to basic, and extracted with ethyl acetate (3x10 mL). The combined organic layers were washed with water (10 mL), brine (10 mL), filtered, dried (MgSO<), filtered and concentrated in vacuo to give 1.5 g of a light yellow sticky oil that tumed into solid upon standing. The crude product was used without further purification: ^lH NMR (400 MHz, CDC13) δ 4.25 - 4.14 (q, 2H), 3.40 (bs, 2H), 3.20 - 3.09 (m, 1H), 2.48 (ddd, 26.2,16.0,6.6 Hz, 2H), 1.77- 1.58 (m, 4H), 1.52 (m, 2H), 1.47 - 1.32 (m, 2H), 1.25 (m, 3H), 0.94 (s, 3H).

Formation of ethyl 3-((5-fluoro-2-(5-fluoro-l-tosyl-lH-pyrrolo[2,3-b]pyridln-3yl)pyrimidln-4-yl)amlno)-3-(l-methylcyclopentyl)propanoate (34a)

A suspension of ethyl 3-amîno-3-(l-methylcyclopentyl)propanoate, 33a, (0.20 g, 1.00 mmol ), 5 -fluoro-3-(5 · fluoro-4-methylsulfinyl-pyri midin-2-yl)-1 -(p-tolylsul fonyl)pyrrolo[2,3-b]pyridine, 25a (0.54 g, 1.20 mmol), and ΛΓ,ΛΓ-diisopropylethylamine (0.26 mL,

1.50 mmol) in THF (14.4 mL) was refluxed at 80 °C ovemight. After removîng the solvent in vacuo, the crude product was purified by silica gel chromatography (0-50% EtOAc/Hexanes gradient) to afford 300 mg of the desired product as a light yellow solid: *H NMR (400 MHz, CDCh) δ 8.49 (dd, J- 9.0, 2.8 Hz, 1H), 8.46 (s, 1H), 8.23 (d, 1.5 Hz,

1H), 8.02 (d, J= 8.3 Hz, 2H), 7.99 (d, J- 3.1 Hz, 1H), 7.20 (d, 7.8 Hz, 2H), 5.23 (d, J =

8.9 Hz, 1H), 4.80 (td, 9.7,3.6 Hz, 1H), 4.04 (q, 7.1 Hz, IH), 3.91 (q, 7.1 Hz, 2H),

2.73 - 2.58 (m, 1H), 2.44 (dd, 14.7, 9.6 Hz, 1H), 2.33 - 2.21 (m, 3H), 1.72 - 1.46 (m,

-7217028

7H), 1.42-1.31 (m, 1H), 1.28 (ζ J =6.1 Hz, 1H), 1.17 (dd, J - 13.4,6.2 Hz, 2H), 0.98 (t, J=

7.1 Hz, 6H); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, RT = 4.25 minutes (M+H) 584.29.

Formation of ethyl 3-((5-fluoro-2-(5-fluoro-l-tosyl-lW-pyrrolo|2,3-b]pyridin-3yi)pyrlmidin-4-yI)amino)-3-(l-methyicyclopentyi)propanoate (14,15)

To a solution of ethyl 3-((5-fluoro-2-(5-fluoro-l-tosyi-17Z-pyrrolo[2,3-à]pyridin-3yi)pyrimidin-4-y!)amino)-3-(I-methy!cyclopentyl)propanoate, 34a, (0.16 g, 0.27 mmol) in THF (6 mL) was added LiOH (1.50 mL of I M solution, 1.50 mmol). The reaction mixture was irradiated in a microwave reactor for 30 minutes at 130 °C. Aqueous saturated NH4CI solution was added to acidify the mixture. The resulting white precipitate was collected and washed with water, acetonitrile and ether. The solid was then dried in vacuo to give pure desired acid. To the solid was added hydrochloric acid (2 mL of IN solution) and the mixture was lyophilized to give 120 mg of the desired product as a hydrochloride sait (light yellowpowder): *H NMR (400 MHz, MeOD) δ 8.64 (d, 9.3 Hz, 1H), 8.14 (d, J= 8.3 Hz,

2H), 7.97 (d, J = 3.6 Hz, 1H), 4.99 (d, J= 6.3 Hz, 1H), 3.37 (s, 1H), 2.75 (dd, J= 14.9, 3.6 Hz, 1H), 2.55 (dd, 14.8, 9.7 Hz, 1H), 1.83 - 1.57 (m, 6H), 1.54- 1.42 (m, 1H), 1.37 (dd, J= 11.9,5.6 Hz, 1H), 1.11 (d, 19.2 Hz, 3 H); LCMS Gradient 10-90%, 0.1% formic acid, minutes, CI8/ACN, RT » 2.10 minutes (M+H) 401.94.

The racemic mixture of carboxylic acids was submitted to SFC chiral séparation to give the individua! enantiomers, 14 and 15.

Préparation of Compounds 20 and 23

Synthetic Scheme 7

Ti

ethyl-2-triphenylphosphoranylideneacetate, CH₂C1₂;

(b) 5-fluoro-3-(4,4,5,5-tetramethyl-l,3,2- dioxaboro!an-2-yl)- 1-tosyl- lH-pyrrolo[2,3b]pyridine, 7a, aq. KjPO<, 2-Me-THF, H₂O, X-Phos, Pd₂(dba)₃; (c) H₂,10% Pd/C, MeOH; (d) CHjCN, 4N HCl/Dioxane

Formation of (Æ,£)-ethyl 4-((2-chIoro-5-fluoropyrim!din-4-yl)amino)-5,5dimethyihex-2-enoate (37a)

To a solution of (S)-2-((2-chloro-5-fluoropyrimidin-4-yl)amino)-3,3-dimethylbutanal, 15a, (0.45 g, 1.84 mmol) in dichloromethane (9.0 mL) was added ethyl 2-7317028 triphenylphosphoranylideneacetate (0.96 g, 2.75 mmol). After allowing the reaction mixture to stir at room température ovemight, approximately half of the solvent was removed under reduced pressure. The remaining crude mixture was purified by directly loading onto a silica gel column (0-100% EtOAc/hexanes) to afiord 535 mg of the desired product: LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, 10 Cl8/ACN, RT = 3.41 minutes(M+H) 316.32.

Formation of (Z?,£)-ethyl 4-((5-fluoro-2-(5-fluoro-l-tosyl-lZ/-pyrroloI23-b]pyrldln-3yl)pyrlmidin-4-yl)amino)-5,5-dimethylhex-2-enoate (38a)

K3PO4 (1.078 g, 5.079 mmol) was dissolved in water (3.2 mL) and added to a 15 solution of (R,£)-ethyl 4-((2-chloro-5-fluoropyrimidin-4-yl)amino)-5,5-dîmethylhex-

2-enoate, 37a, (0.534 g, 1.693 mmol) in 2-methyl-THF (10.7 mL) and the mixture was purged with nitrogen for 30 minutes. 5-fluoro-l-(p-tolylsulfonyl)-3-(4,4,5,5tetramethyl-l,3,2-dioxaborolan-2-yl)pyiTolo[2,3-b]pyridine, 7a, (0.775 g, 1.862 mmol) was added and the nitrogen purging was continued for an additional 15 min.

X-Phos (0.048 g, 0.102 mmol) and Pd2(dba)j (0.031 g, 0.034 mmol) were added and the mixture was heated at 80 °C ovemight. After cooling to room température, the reaction mixture was diluted with water and extracted with EtOAc. The layers were separated and the organic phase was washed with brine, dried over MgSC>4, filtered and evaporated to dryness. The crude residue was dissolved in a minimum volume of dichloromethane and purified by si!ica gel chromatography (0-100%EtOAc/hexanes gradient) to afford 650 mg of desired product: *H NMR (400 MHz, CDClj) 6 8.57 8.38 (m, 2H), 8.30 (s, 1H), 8.11 (dd, J- 10.5, 5.5 Hz, 3H), 7.08 (dt, J= 36.7, 18.3 Hz, 1H), 6.01 (d, J = 15.7 Hz, 1H), 5.11 (d, J= 8.7 Hz, 1H), 4.97 - 4.77 (m, 1H),

4.19 (q, 7.1 Hz, 2H), 2.39 (d, 10.7 Hz, 3H), 1.27 (q, 7.4 Hz, 4H), 1.10 (s,

9H); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, Cl8/ACN, RT = 3.99 minutes (M+H) 570.01.

Formation of (Æ)-ethyl 4-((5-fiuoro-2-(5-fluoro-l-tosyl-lZApyrrolo[23-b]pyridin-3yl)pyrlmldln-4-yl)amlno)-5,5-dimethylhexanoate (39a)

To a nitrogen purged flask charged with 10% Pd/C (0.033 g, 0.310 mmol) was added enough methanol to cover the catalyst. To this mixture was added a solution of (R,£>ethyl 4-((5-fluoro-2-(5-fluoro-l-tosyÎ-lW-pyrrolo[2,3-b]pyridin-3-yi)pyrimidin-

4-yl)amîno)-5,5-dimethylhex-2-enoate, 38a, (0.330 g, 0.579 mmol) in MeOH. Note, a small amount of EtOAc was added to fully solubilize the starting material. The 40 reaction mixture was then stîrred under 1 atmosphère of hydrogen for 3 hours.

LCMS shows presence of significant amounts of starting material. The contents of the reaction mixture were transferred to a pressure vessel containing a fresh source of palladium (0.033 g, 0.310 mmol). The reaction mixture was stirred in a Parr hydrogénation flask under 46 psi of hydrogen ovemight. The mixture was diluted 45 with methanol and filtered through celite. The fîltrate was concentrated in vacuo to afford 331 mg of the desired product that was used without further purification: LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, RT = 3.75 minutes (M+H) 572.35.

-7417028

Formation of (Zï)-4-((5-fluoro-2-(5-fluoro-l£Apyrrolo[23-b]pyridin-3-yl)pyrimidin-4y!)amino)-5,5-dimethylhexanoic acid (20)

To a solution of (Jî)-ethyl 4-((5-fluoro-2-(5-fluoro-l-tosyI-iH-pyrrolo[2,3-b]pyridin-

3-yI)pyrimidin-4-yl)amino)-5,5-dimethylhexanoate, 39a, (0.30 g, 0.53 mmol) was in acetonitrile (5 mL) was added HCI (0.70 mL of 4 M solution in dioxane, 2.80 mmol).

The reaction mixture was heated at 60 °C for 3 hours and then heated to 80 °C for 6 hours to drive the reaction to completion. After cooling to room température, the mixture was then stirred ovemight. LC MS showed remaining starting material. Fresh HCl (0.7 mL of 4 M solution in dioxane, 2.80 mmol) was added and the mixture was heated to 80 °C ovemight. Ail volatiles were removed under reduced pressure and the residue was diluted with EtOAc and aqueous saturated NaHCOj solution. The layers were separated and the organic phase was washed with brine, dried over MgSO^, filtered and evaporated to dryness. The crude residue was purified by silica gel chromatography (0-100% EtOAc/hexanes gradient) to afiord 144 mg of (R)-ethyl 4-((5-fluoro-2-(5-fluoro-lH-pyrroIo[2,3-b]pyridin-320 yl)pyrimidin-4-yI)amino)-5,5-dîmethylhexanoate, 23, and 29 mg of (R)-4-((5-fluoro-

2-(5-fluoro-IH-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-5,5dimethylhexanoic acid, 20. Spectral data for 20: *H NMR (400 MHz, DMSO) δ

12.23 (s, 1 H), 11.93 (s, 1H), 8.48 (d, 9.9 Hz, 1H), 8.33 - 8.07 (m, 3H), 7.i8 (d, J=

9.3 Hz, 1H), 4.39 (t, 10.2 Hz, iH), 2.38 - 2.07 (m, 2H), 1.99 - 1.92 (m, 1H), 1.80 25 1.64 (m, iH), 1.00 (d, 20.2 Hz, 9H); LCMS Gradient 10-90%, 0.1% formic acid, minutes, CI8/ACN, RT - 2.14 minutes (M+H) 390.06.

Préparation of Compound 59

Formation of (Æ,£)-4-((5-fluoro-2-(5-fluoro-17Z-pyrrofo|2,3-b]pyridin-3-yl)pyrlmldin-435 yl)amino)-5,5-dimethylhex-2-enoic acid (59)

Starting ethyl ester, 42a, was prepared in the same fashion as the enantiomeric ethyl ester, 38a, shown in Synthetic Scheme 7.

To a solution of (££)-ethyl 4-((5-fluoro-2-(5-fluoro-l-tosjd-lW-pyrroIo[2,3b]pyridin-3-yl)pyrimidin-4-yl)amino)-5,5-dimethylhex-2-enoate, 42a, (0.064 g, O.i i2 40 mmol) in dioxane (2 mL) was added LiOH (2 mL of 2N solution). After heating at

100 °C for 2 hours, the mixture was acidified to pH 6 with 2N HCl. The aqueous phase was extracted with ethyl acetate (3x), dried (MgSO4), filtered and concentrated in vacuo. The resulting residue was purified via preparatory HPLC (CHjCN/lLO

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TFA modifier) to afïord 35 mg of the desired product as a TFA-sa!t: *H NMR (300 MHz, MeOD) δ 8.54 (s, 1H), 8.50 - 8.18 (m, 3H), 7.18 (dd, J = 15.7, 7.1 Hz, 1H), 6.08 (dd, J - 15.7, 1.3 Hz, 1H), 5.21 (t, J = 22.5 Hz, 1 H), 1.12 (s, 9H); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, (M+H) 388.23.

Préparation of Compound 44

Synthetic scheme 9

Pyridinium chlorochromate, CH2CI2; (b) ethyl-2-triphenyl-phosphoranylideneacetate, CH2CI2; (c) N-benzylhydroxylamine, EtjN, CH2CI2 (d) H2, palladium hydroxide, EtOH (e) diazomethyl-trimethylsilane, MeOH, benzene (f) 2,4-dichloro-5-fluoro-pyrimidine, EtjN, THF, EtOH (g) 5-fluoro-3-(4,4,5,5-tetramethyI-i,3,2-dioxaboro!an-2-yl)-l-tosy!-lZZpyrrolo[2,3-b]pyridine, 7a, Aq. KjPO^, 2-Me-THF, H2O, X-Phos, Pd2(dba)j, 80 °C; (h) MeOH, NaOMe (i) aq. NaOH, THF, MeOH

Formation of cydohutanecarbaldehyde (45a)

To a stirred suspension of pyridinium chlorochromate (14.9 g, 69.1 mmol) in dichloromethane (150 mL) was added a solution of cyclobut ylmethano! (4.0 g, 46.4 mmol) î n dichloromethane (60 mL). The reaction mixture tumed black within a few minutes and was allowed to stir at room température for 1 hour. The mixture was diluted with diethyl ether (500 mL) and fiitered through a bed of florisil (100-200 mesh). The crude material was used without further purification. Note: the product is volatile, the solvent was carried with the product onto the next step.

-7617028

Formation of (£)-ethyl 3-cyclobutylacrylate (46a)

Ethyl 2-triphenylphosphoranylideneacetate (9.32 g, 26.74 mmol) was added to a solution of cyclobutanecarbaldehyde, 45a, (1.50 g, 17.83 mmol) in dichloromethane (30 mL). The reaction mixture was briefly purged with nitrogcn and capped allowed to stir at room température ovemîght. All volatiles were removed at reduced pressure and the residue was dissolved in EtîO (100 mL) and hexanes (25 mL). The resulting pink precipitate was fdtered off and discarded. The solvent was removed from the filtrate at reduced pressure. The crude product was purified via silica gel chromatography (0-20% EtOAc/Hexanes gradient) to afford 646 mg (23%) of the desired product: *H NMR (400 MHz, CDClj) δ 7.05 (dd, J= 15.6, 6.8 Hz, 1H), 5.73 (dd, J= 15.6,1.4 Hz, 1H), 4.29 - 4.09 (m, 2H), 3.20 - 2.98 (m, 1H), 2.28 - 2.09 (m, 2H), 2.04- 1.78 (m, 4H), 1.36 - 1.18 (m, 3H).

Formation of 2-benzyl-3-cydobutylisoxazolidln-5-one (47a) jV-benzylhydroxylamine hydrochloride (0.77 g, 4.82 mmol) and triethylamine (0.76 mL, 5.45 mmol) were successively added to a solution of (E)-ethyl 3cyclobutylacrylate, 46a, (0.65 g, 4.19 mmol) in dry dichloromethane (23.5 mL). The reaction mixture was allowed to stir at room température under an atmosphère of nitrogcn for 3 days. The mixture was diluted with 75 mL of water and the layers were separated. The aqueous phase was reextracted twice more with dichloromethane (50 mL). The combined organic phases were dried over MgSO< , filtered and evaporated to dryness. The residue was purified via silica gel chromatography (ΟΙ 00% EtOAc/Hexanes gradient) to afford 834 mg (86%) of the desired product: Ή NMR (400 MHz, CDClj) δ 7.38 - 7.26 (m, 5H), 4.64 (s, 1H), 3.82 (q, J = 13.5 Hz, 2H), 3.37 - 3.18 (m, 1H), 2.80 - 2.52 (m, 2H), 2.33 (dd, J= 14.5, 5.1 Hz, 1H), 2.22 2.09 (m, 1H), 2.01 - 1.68 (m, 5H).

Formation of (+/-)-3-amino-3-cydobutylpropanoic acid (48a)

Dihydroxypalladium (0.252 g, 1.794 mmol) was charged into a flask and flushed with nitrogcn. Ethanol (30 mL) was added followed by a solution of 2-benzyl-3cyclobutyl-isoxazolidin-5-one, 47a, (0.834 g, 3.605 mmol) in approximately 90 mL of éthanol. The reaction mixture was subjected to 50 psi of hydrogen for 4 hours. The pressure was vcnted and the catalyst was filtered off. All volatiles were removed at reduced pressure. ^lH NMR shows the presence of starting material, 47a. The mixture was dissolved in approximately 100 mL of MeOH and added to 83 mg of 10%Pd/C that had been wet with 20 mL of MeOH. The mixture was subjected to 50 psi of H2 ovemîght. The pressure was vented and the catalyst was filtered off. All volatiles were removed at reduced pressure to afford 340 mg of product. The resulting crude residue was used without fiirther purification: *H NMR (400 MHz, J6-DMSO) δ 3.06 - 2.83 (m, 1H), 2.28 (ddd, J = 23.7, 11.8, 7.7 Hz, 1H), 2.19 - 1.99 (m, 2H), 1.99 1.56 (m, 6H).

Formation of (+/-)· methyl 3-amino-3-cydobutylpropanoate (49a)

To a solution of racemic 3-amino-3-cyclobutyl-propanoic acid, 48a, (0.34 g, 2.38 mmoi) in MeOH (10.2 mL) and benzene (10.2 mL) was added diazomethyltrimethylsilane (3.56 mL of 2 M solution, 7.13 mmol) and the reaction mixture was allowed to

-7717028 stir at room température under a nitrogen atmosphère ovemight. The mixture was diluted with EtOAc and brine. The layers were séparaied and the organic phase was dried (MgSO<), filtered and concentrated in vacuo to afïord 354 mg (95%) of crude product that was used without further purification: ‘H NMR (400 MHz, CDClj) δ 3.71 -3.66 (m, 3H), 3.18-2.98 (m, 1H), 2.46-2.32 (m, 2H), 2.27- 1.63 (m, 10H).

Formation of methyl (+/-)-3-((2-chloro-5-fluoropyrimldfn-4-yl)amlno)-3cyclobutylpropanoate (50a)

To a racemic solution of methyl 3-amino-3-cyclobutylpropanoate, 49a, (0.354 g, 2.252 mmol) and 2,4-dichloro-5-fluoro-pyrimidine (0.414 g, 2.477 mmol) in THF (10 mL) and éthanol (1 mL) was added triethylamine (0.628 mL, 4.504 mmol). The reaction mixture was heated and stîrred at 70 °C for 5 hours. The mixture was filtered and the filtrate was concentrated in vacuo to approximately 5 mL final volume. The crude residue was purified via silica gel chromatography (0 -100% EtOAC/hexanes gradient) to afiord 289 mg (45%) of the desired product: *H NMR (300 MHz, CDC1³) δ 7.87 (s, 1H), 5.80 (s, 1H), 4.71 - 4.38 (m, 1H), 3.68 (s, 3H), 2.84 - 2.37 (m, 3H), 2.23 - 1.67 (m, 6H); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, RT = 3.08 minutes (M+H) 287.98.

Formation of (+/-)-3-cyclobutyl-3-((5-fluoro-2-(5-fluoro-l-tosyl-l/Apyrrolo[23Z>]pyridin-3-yl)pyrimidin-4-yl)amino)propanoate (51a)

A solution of tripotassium phosphate (0.640 g, 3.021 mmol) in water (1.735 mL) was added to a solution of racemic methyl 3-[(2-chloro-5-fluoro-pyrimidin-4-yl)amino]-3cyclobutyl-propanoate, 50a, (0.289 g, 1.005 mmol) in 2-methyltetrahydrofuran (5.782 mL). The mixture was then purged with nitrogen for 20 minutes. 5-f!uoro-l-(ptolylsul fon yl)-3 -(4,4,5,5 -tetramethyl-1,3,2-dioxaborolan-2-yl)pyrro lo[2,3-b]pyri dine, 7a, (0.460 g, 1.106 mmol) was added and the mixture was purged with nitrogen for an additional 10 minutes. Dicyclohexyl-[2-(2,4,6triisopropylphenyl)phenyl]phosphane (X-Phos: 0.029 g, 0.060 mmol) and PdîtdbaJj (0.018 g, 0.020 mmol) were added and the reaction mixture was warmed to 80 °C and stîrred at this température for 5 hours. The mixture was allowed to cool to room température. The réaction mixture was diluted with water and extracted with EtOAc. The layers were separated and the organic phase was washed with brine, dried over MgSO<, filtered and evaporated to dryness. The crude was dissolved in a minimum volume of dichloromethane and purified via silica gel chromatography (0100%EtOAc/Hexanes).to afiord 385 mg (71%) of the desired product: LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, RT= 3.68 minutes (M+H) 542.27.

Formation of (+/-)-methyl 3-cyciobutyl-3-((5-fluoro-2-(5-fluoro-l JApyrrolo|2,3b]pyridin-3-yi)pyrimidin-4-yi)amino)propanoate (52a)

To a racemic solution of methyl 3-cyclobutyJ-3-((5-fluoro-2-(5-fluoro-l-tosyJ-lWpyrrolo[2,3-à]pyridin-3-yl)pyrimidin-4-yl)amino)propanoate, Sla, (0.151 g, 0.280 mmol) in methanol (1.5 mL) was added NaOMe (1.5 mL of 25 %w/v solution, 6.941 mmol). After stirring the reaction mixture at room température for 5 minutes, the mixture was quenched with aqueous saturated NH«C1 solution and diluted with EtOAc and water. The layers were separated and the organic phase was washed with

-7817028 brine, dried (MgSCh), filtered and evaporated to dryness. The resulting crude residue was dissolved in a minimum volume of dichloromethane and purified via silica gel chromatography (0-100%EtOAc/Hexanes gradient) to afford 108 mg of the desired product: LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, RT -

2.29 minutes (M+H) 388.07.

Formation of (+/-)-3-cyclobutyl-3-((5-fluoro-2-(5-fluoro-l/Z-pyrro)o[2,3-6]pyridin-3yl)pyrimidln-4-yl)amlno)propanoic acid (44)

To a racemic solution of methyl 3-cyclobutyl-3-((5-fluoro-2-(5-fluoro-l/fpyrrolo[2,3-6]pyridin-3-yl)pyrimidin-4-yi)amino)propanoate (0.042 g, 0.109 mmol) in THF (1.5 mL) and MeOH (0.5 mL) was added NaOH (0.300 mL of 2 M solution, 0.600 mmol) and the reaction mixture was warmed to 50 ’C. After stirring the reaction mixture for 1 hour, the mixture was diluted with aqueous saturated NH4CI solution and EtOAc. The organic layer was dried (MgSOj), filtered and evaporated to dryness to afford 36 mg of the desired product that was used without further purification: *H NMR (400 MHz, 4/6-DMSO) δ 12.26 (s, 2H), 8.55 (d, J = 9.7 Hz, 1H), 8.19 (dd,J= 45.1,15.8 Hz, 3H), 7.48 (d,J-=8.1 Hz, lH),4.79(s, 1H), 2.58 (dd, J= 20.6, 12.2 Hz, 2H), 1.85 (ddd, J= 29.4, 26.5, 21.1 Hz, 7H); LCMS Gradient 1090%, 0.1% formic acid, 5 minutes, C18/ACN, RT = 2.10 minutes (M+H) 374.02.

Préparation of Compounds 10,11,19, 21, 22, 32,33,34.35, 38,39, 40, 49, 57, and 58

Synthetic Scheme 10

T·

5-fluoro-1-(p-tolylsul fonyl)-3-(4,4,5,5-tetramethyl- l,3,2-dioxaboro!an-2-yl)pyrrolo-[2,3-b]pyridine, 7a, K3PO4, X-Phos, Pd₂(dba)₃, 2-MeTHF, water, 120 °C;

(b) MsCl. CH₂C1₂; (c) KOAc, DMF, 80 °C; (d) 30% H₂O₂, HCOOH, RT, 2 hr; (e) oxalyl chloride, DMF,

-7917028

CH₂C1₂; (t) (i) methylamine, THF (ii) 4M HCl, CHjCN, 65 °C.

(S)-2-(5-fluoro-2-(5-fluoro-l-tosyl-lH-pyrroloI2,3-b] pyrldin-3-yl)pyridin-4-ylamlno)-

3.3- dlmethylbutan-l-ol (54a).

A mixture of 5-fluoro-l-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan2-yl)pyrrolo[2,3-b]pyridine, 7a, (11.09 g, 26.64 mmol), (5)-2-((2-chloro-5fluoropyrimidin-4-yl)amino)-3,3-dimethylbutan-l-ol, 14a,(6.00 g, 24.22 mmol ) and K₃PO₄ (15.42 g, 72.66 mmol) in 2-methyl THF (90 mL) and water (12.00 mL) was purged with nitrogen for 30 minutes. X-Phos (0.92 g, 1.94 mmol) and Pd₂(dba)₃ (0.44 g, 0.48 mmol) were added and the reaction mixture was heated at 120 °C in a pressure via! for 2 hr. The reaction mixture was cooled to room température, filtered and concentrated in vacuo. The residue was dissolved in EtOAc (100 mL) and washed with water. The organic layer was dried (MgSO₄), filtered and concentrated in vacuo. The crude product was purified by s il ica gel chromatography (0-40% EtOAc/Hexanes gradient) to afford 10 g of the desired product as a foamy solid: *H NMR (400 MHz, CDClj) δ 8.54 -8.40 (m, 2H), 8.22 (s, 1H), 8.09 - 8.00 (m, 3H), 7.29- 7.16 (m, 2H),

5.15 (m, 1H), 4.32-4.14 (m, 1H),3.98 (m, 1H), 3.70 (m, 1H), 2.30 (s, 3H), 1.01 (m, 9H); LC/MS (60-90% ACN/water 5 min with 0.9% FA, C4) m/z 502.43 (M+H) RT = 1.52 min.

(S)-2-(5-fluoro-2-(5-fluoro-l-tosyl-lZr-pyrrolo]23-b] pyridin-3-yl)pyridln-4-yiamino)-

3.3- dimethyIbutyl methanesulfonate (55a).

Methanesulfony! chloride (1.83 mL, 23.67 mmol) was added to a cold (0 °C) solution of fS)-2-(5-fluoro-2-( 5- fluoro-1 -tosyl-1 H-pyrrolo[2,3 -b] pyridin-3 -yl)pyrid in-4ylamino)-3,3-dimethylbutan-l-ol, 54a, (9.50 g, 18.94 mmol) and triethylamine (3.30 mL, 23.67 mmol) in dîchloromethane (118 mL). The reaction mixture was stirred at room température for 1 hour. The solvent was removed under reduced pressure and the residue was diluted with water (100 mL) and EtOAc (200 mL). The organic layer was separated, dried (MgSO₄), filtered and concentrated under reduced pressure to afford 10.5 g of the desired product as a pale yellow foam: LC/MS (60-90% ACN/water 5 min with 0.9% FA, C4) m/z 580.41 (M+H) RT = 2.00 minutes.

(S)-2-(5-fluoro-2-(5-fluoro-l-tosyl-lZf-pyrrolo|2,3-b]pyridin-3-yl)pyridin-4-ylamlno)-

3.3- dimethyibutyl ethanethioate (56a).

To a solution of fS)-2-(5-fluoro-2-(5-fluoro-l-tosyl-l//-pyrrolo[2,3-b] pyridin-3yl)pyridin-4-ylamino)-3,3-dimethylbutyl methanesulfonate, 55a, (10.5 g, 18.11 mmol) in dry DMF (200 mL) was added potassium thioacetate (3.1 g, 27.1 mmol). The brown solution was heated with stirring at 80 °C for 1 hour. The thick brown suspension was poured into water and extracted with EtOAc (3x 100 mL). The combined organic phases were dried (MgSO₄), filtered and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (030% EtOAc/Hexanes gradient) to afford 6.8 g of the desired product, 56a, as a pale brown solid: 'H NMR (400 MHz, CDClj) δ 8.41 (m, 2H), 8.23 (s, 1H), 8.01 (m, 3H),

7.23 -7.16 (m, 2H), 4.99 (d, J = 10.1 Hz, 1H), 4.37 (m, 1H), 3.21 (dd, J = 13.8, 2.3 Hz, 1H), 3.09-2.95 (m, 1H), 2.31 (s, 3H), 2.16 (s, 3H), 1.02 (s,9H); LC/MS (10-90% ACN/water 5 min with 0.9% FA) m/z 560.99 (M+H) RT = 4.14 minutes.

-8017028 (5)-2-(S-fluoro-2-(5-fluoro-l-to5yl-l/7-pyrrolo|2,3-b]pyridin-3yl)pyridin-4-yiamino)-3,3dimethylbutane-l-sulfonic acid (57a).

To a cold (0 °C) solution of formic acid ( i 03.4 mL, 2.7 mol) was added H2O2 (34.2 mL of 30% solution, 0.3 mol). The solution was stirred at 0 °C for I hour. A solution of (3)-2-(5-fluoro-2-(5-fluoro-l-tosyl-iH-pyrTolo[2,3-b]pyridin-3-yi)pyridin-4ylamino)-3,3-dimethylbutyl ethanethioate, 56a, (6.7 g, 12.0 mmol) in formic acid (20.0 mL) was added dropwise. The resuiting mixture was stirred at room température for 2 hours to give a yellow solution. The solvent was removed under reduced pressure to afford the desired product as a foamy pale yeliow solid that was used without further purification: *H NMR (400 MHz, MeOD) δ 8.72 (m, 2H), 8.31 (s, 1H), 8.21 (d, J = 4.8 Hz, 1H), 8.06 (d, 8.1 Hz, 2H), 7.39 (d, J= 8.0 Hz, 2H),

5,08 (d, J = 10.0 Ηζ,ΙΗ), 3.19 (m, 2H), 2.36 (s, 3H), 1.04(m, 9H); LC/MS (10-90% ACN/water 5 min with 0.9% TFA, C18) m/z 566.0 (M+H) RT = 2.66 minutes.

(5)-2-(5-fluoro-2-(5-fluoro-l-tosyl-lH-pyrrolo[23-b] pyridin-3-yl)pyridin-4-ylamino)-

3,3-dimethylbutane-l-suifonyl chloride (58a).

Oxalyl chloride (3.5 mL, 38.7 mmol) was added to a solution of (S)-2-(5-fluoro-2-(5fluoro-l-tosyl-l/Z-pyrrolo[2,3-b]pyridin-3yl)pyridin-4-ylamino)-3,3-dimethylbutane|-sulfonic acid, 57a, (7.3 g, 12.9 mmol) in dichloromethane (130 mL), foliowed by the slow, dropwise addition of DMF (2 mL). The yellow colored solution was stirred at room température for 1 hour. The solvent was removed under reduced pressure to afford 8.4 g of the desired product as a foamy yellow solid: LC/MS (60-90% ACN/water 5 min with 0.9% FA) m/z 585.72 (M+H) RT = 2.30 minutes.

fST-Z-tS-fluoro-Z-tS-fluoro-lZf-pyrrolotZ^-blpyridin-S-yOpyrimidinMylamlnoJ-A^S^* trimethylbutane-l-suifonamide (19)

Methylamine (0.75 mL of 2M solution, 1.53 mmol) was added to a solution of (S)-2(5-fluoro-2-(5-fluoro-1 -tosyl-17/-pyrrolo[2,3-b] pyridin-3-yl)pyridin-4-ylamino)-3,3dimethylbutane-l-sulfonyl chloride, 58a, (0.15 g, 0.26 mmol) in THF (1 mL). TTie solution was stirred for 1 hour at room température and the solvent was then removed under reduced pressure. The crude sulfonamide was dissolved in acetonitrile (3 mL) and HCl (2 mL of a 4M solution in dîoxane) was added. The mixture was heated at 65 °C for 3 hours and then cooled to room température. The solvent was removed under reduced pressure and the resuiting crude residue was purified by préparative HPLC chromatography (10-80% CHjCN/water, 0.5% TFA, 15 min) to give 26 mg of the desired product as a white solid: *H NMR (400 MHz, CDClj) δ 9.75 (s, IH), 8.12 (d, J= 9.3 Hz, IH), 7.94 (s, 1H), 7.73 (s, 2H), 7.67 (brs, 1H), 4.93 - 4.78 (m, 2H), 3.08 (m, IH), 2.76 (s, 3H), 0.99 (m,9H); LC/MS (10-90% ACN/water 5 min with 0.9% FA) m/z 425.3 (M+H), RT - 2.0 minutes.

The foliowing compounds can be prepared in a similar fashion as the procedure described above for Compound 19:

-8117028

F

(5)-/V-Cyclopropyl-2-(5-fluoro-2-(5-fluoro-17/-pyrrolo[23-b]pyridin-3-yI)pyrimldIn-4yIamino)-3,3-dimethyIbutane-l-sulfonamide (21) 'H NMR (400 MHz, CDC1₃) δ 8.68 (dd, J = 9.6, 2.5 Hz, 1H), 8.24 - 8.11 (m, 2H), 8.03 (d, J 10 =3.8 Hz, IH), 5.12 (d, J = 8.5 Hz, IH), 3.48 (d, J = 9.2 Hz, 2H), 2.60 - 2.47 (m, IH),

I.13(s,9H), 0.68 - 0.48 (m, 4H): LC/MS (10-90% ACN/water 5 min with 0.9% FA) m/z

451.14 (M+H) RT = 2.2 minutes.

(5)-2-(5-FluorD-2-(5-fluoro-lJ7-pyrrolo[2,3-b]pyrIdin-3-yI)pyrimIdin-4-ylamIno)-/V-(2methoxyethyl)-3,3-dimetbylbutane-l-sulfonamide (35)

LC/MS (10-90% ACN/water 5 min with 0.9% FA) m/z 469.28 (M+H) RT = 2.11 minutes.

(5)-2-(5-Fluoro-2-(5-fluoro-17/-pyrrolo[23-b]pyridin-3-yI)pyrimIdIn-4-yIamino)-33 dImethyl-/V-propylbutane-l-sulfonamIde (34) *H NMR (400 MHz, CDCIj) δ 9.84 (s, IH), 8.10 (d, J= 9.5 Hz, IH), 7.92 (d, J= i.2 Hz, 25 IH), 7.72 (d, J= 14.2 Hz, 2H), 4.92 (m, IH), 4.81 (m, IH), 3.41 (d, J= 15.0 Hz, IH), 3.19 2.84 (m, 3H), 1.59 - 1.38 (m, 3H), 0.98 (s, 9H), 0.84 (t, J = 7.4 Hz, 3H): LC/MS (10-90%

ACN/water 5 min with 0.9% FA) m/z 453.44 (M+H) RT = 2.42 minutes.

-8217028 (S)-2-(5-Fluoro-2-(5-fluoro-lH-pyrroloI2,3-b]pyridin-3-yI)pyrimidin-4-yIamino)-./VisopropyI-3,3-dimethyI-A'-propy!butane-l-sulfonamide (39) ^lH NMR (400 MHz, CDCIj) δ 9.89 (s, 1H), 8.07 (d, 8.9 Hz, 1H), 7.90 (s, 1H), 7.68 (s,

2H), 4.96 (t, J = 9.8 Hz, 1H), 4.76 (d, 9.8 Hz, 1H), 3.60 (dd, 13.0, 6.6 Hz, 1H), 3.42 (m, 1H), 3.09 - 2.86 (m, 1H), 1.20 (d, J - 4.9 Hz, 6H), 0.97 (s, 9H); LC/MS (10-90% ACN/water 5 min with 0.9% FA) m/z 453.19 (M+H) RT = 2.22 minutes.

F

(S)-2-(5-Fluoro-2-(5-fluoro-lH-pyrrolo[23*b]pyridin-3-yl)pyrimidln-4-ylamino)- N-tertbutyl-33*dimethyl-5^r-propyibutane-l-5ulfonamide (40)

LC/MS (10-90% ACN/water 5 min with 0.9% FA) m/z 467.20 (M+H) RT = 2.36 minutes.

(S)-./V-Ethy!-2-(5-fluoro-2-(5-fluoro-17/-pyrroIo[2,3-b]pyridin-3-yi)pyrimidin-4ylamino)-33-dimethyIbutane-l-suifonamIde (33) ^lH NMR (400 MHz, CDCIj) δ 9.89 (brs, 1H), 8.07 (d, J= 9.3 Hz, 1H), 7.89 (s, 1H), 7.66 (m, 2H), 4.95 (t, 10.2 Hz, 1 H), 4.80 (d, J « 9.6 Hz, 1H), 3.38 (m, 1 H), 3.18 - 2.96 (m, 3H),

1.35 - 1.12 (m, 3H), 0.90 (m, 9H); LC/MS (10-90% ACN/water 5 min with 0.9% FA) m/z 439.30 (M+H) RT = 2.25 minutes.

F

(S)-A^r-(2^-difluoroethyl)-2-(5-nuoro-2-(5-nuoro-lH-pyrroio[23-&]pyridin-3yl)pyrimidin-4-ylamino)-33*dimethylbutane-l-su!fonamide (57) ^lH NMR (400 MHz, CDCIj) δ 8.05 (d, 7.9 Hz, 1H), 7.81 (d, J= 2.1 Hz, 1H), 7.63 (s,

1H), 7.55 (s, 1H), 5.87 (t, 54.9 Hz, 1H), 5.03 (t, 10.4 Hz, 1H), 4.86 (m, 1H), 3.68 (brs,

1H), 3.43 (m, 2H), 3.19 (m, 1 H), 0.94 (s, 9H); LC/MS (10-90% ACN/water 5 min with 0.9% FA) m/z 475.23 (M+H) RT = 2.26 minutes.

-831

NH F

M* (S)-2-(5-fluoro-2-(5-nuoro-lff-pyrroIo[23*A]pyridin-3-yI)pyriniidin-4-yIaniino)-33' dimethyI-JV-(2,2,2-trifluoroethyI)butane-l-suIfonamlde (58) 'H NMR (400 MHz, CDCIj) δ 8.03 (dd, J = 9.3,2.4 Hz, 1H), 7.82 (t, 11.2 Hz, 1H), 7.59 (s, IH), 7.46 (s, 1H), 5.07 (t, 10.6 Hz, 1H), 4.77 (m, 1H), 3.45 (m, 1H), 3.16 - 2.99 (m,

IH), 0.97 - 0.86 (m, 9H); LC/MS (10-90% ACN/water 5 min with 0.9% FA) m/z 493.31 (M+H) RT = 2.37 minutes.

F

O À' ^s'NH₂ (S)-2-(5-nuoro-2-(5-fluoro-17/-pyrroIo[2,3-6]pyridin-3-yI)pyrimidin-4-yIamino)-3,3dimethylbutane-l-sulfonamide (22)

Concentrated NH4OH (1.0 mL, 25.7 mmol) was added dropwise to a solution of (S)· 2-(5-fluoro-2-(5-fluoro-l-tosyl-l//-pyrrolo[2,3-b] pyridin-3-y!)pyridin-4-ylamino)-

3,3-dimethylbutane-l-sulfonyl chloride, 58a, (0.3 g, 0.5 mmol) in THF (3 mL). The reaction mixture was stirred for 15 minutes at room température, resulting in a I-to-1 mixture of the desired sulfonamide and sulfonic acid. The solvent was removed under reduced pressure. The crude product was purified by silica gel chromatography (0-70% EtOAc/Hexanes gradient) to afford 93 mg of the tosylated sulfonamide intermediate as a foamy solid.

The tosylated sulfonamide (93 mg) was dissoived in THF (10 mL) and a solution of NaOMe (0.15 mL of 25% solution in MeOH, 0.66 mmol) was added. The resulting yellow solution was stirred at room température for 15 minutes and then diluted into aqueous saturated NH4CI solution (5 mL). The solvent was removed under reduced pressure and the residue was dissoived in water (10 mL). The aqueous layer was extracted with EtOAc (3x10 mL) and dried (MgSO<), fiitered, and concentrated in vacuo. The crude residue was purified by HPLC préparative chromatography (1080% CHîCN/water, 0.5% TFA, 15 min) to afford 40 mg of the desired product, 22, as a white solid: *H NMR (400 MHz, MeOD) δ 8.65 (d, 9.3,1H), 8.47 (s, IH), 8.34 (m, 2H), 5.28 (d, J = 10.4 Hz, IH), 3.55 (m, 2H), 1.10 (m, 9H); LC/MS (10-90% ACN/water 5 min with 0.9% FA) m/z 411.0,1.96 (M+H) RT 1.96 minutes.

-8417028

F

(Æ)-2-((5-fluoro-2-(5-nuoro-lH-pyrrolo|23-b]pyridln-3-yl)pyrimldin-4yl)amino)-A^r33*t>'imethyIbutane-l-su!ronamlde(38) 'H NMR (300 MHz, J6-DMSO) δ 12.2! (s, 1H), 8.55 (dd, 10.0,2.8 Hz, !H), 8.29 - 8.23 (m, !H), 8.19 (d, 2.7 Hz, !H), 8.15 (d, 4.0 Hz, !H), 7.47 (d, 8.4 Hz, !H), 6.77-6.69(m, 1H), 4.88(t,J=9.1 Hz, ! H), 3.49 - 3.36 (m, ! H), 3.36 - 3.28 (m, J = 10.5 Hz, !H), 2.55 (t, 5.6 Hz, 3H), 0.98 (s, 9H); LCMS Gradient 10-90%,

0. !% formic acid, 5 minutes, C ! 8/ACN, RT « 2.1 ! minutes (M+H) 425.03.

F

(5)-2-(5- fluoro-2-(5-fluoro-lW-pyrrolo|23’6]pyridIn-3-yl)pyrlmIdin-4-ylamino)-33 dimethylbutane-l-ol (32)

Alcohol, 32, was synthesized in a manner similar to compound 70a utilizing the same deprotection procedure, starting with compound 54a: *H NMR (400 MHz, CDCI3) δ

10.77 (brs, 1H), 8.25 (d, J- 8.4 Hz, 1H), 8.07 (s,lH), 8.03 (s, !H), 7.88 (s, 1H), 5.59 (brs, ! H), 4.36 (t, J - 8.3 Hz, 2H), 4. ! ! (m, 1H), 3.72 (m, 2H), 1.06 (s, 9H); LC/MS (10-90% ACN/water 5 min with 0.9% FA) m/z 348.13 (M+H) RT = 1.83 minutes.

(S)-2-((2-(5-ch!oro-lH-pyrrolo|23-b|pyridIn-3-yl)-5-nuoropyrlm!dln-4-yl)am!no)-33· dimethy!butan-l-ol (49)

Alcohol, 49, was synthesized in a manner similar to compound 32: *H NMR (400 MHz, CDCIj) δ 10.77 (brs, 1H), 8.25 (d, J = 8.4 Hz, 1H), 8.07 (s,!H), 8.03 (s, 1H), 7.88 (s, 1H), 5.59 (brs, !H), 4.36 (t, 8.3 Hz, 2H), 4.!1 (m, !H), 3.72 (m, 2H),

1.06 (s, 9H); LC/MS (10-90% ACN/water 5 min with 0.9% FA) m/z 348.13 (M+H)

RT = 1.83 minutes.

-8517028

(S)-2-(5-fiuoro-2-(5-fiuoro-17/-pyrroIo[23-/’|pyridin-S-yI)pyrimidin-4-yia m in 0)-3,3dimethylbutane-l-sulfonic acid (H)

Sulfonic acid, 11, was synthesized in a manner similar to Compound 25 described below, using compound, 57a, as the starting material: ’H NMR (400 MHz, MeOD) δ

8.44 (s, 1 H), 8.34 (dd, 9.2,2.6 Hz, !H), 8.22 (d, 5.7 Hz, IH), 8.13 (s, IH),

5.16 (d, J-4.1 Hz, IH), 3.46-3.33 (m,2H), 1.10 (d, 9H); LC/MS (10-90% ACN/water 5 min with 0.9% TFA, C18) m/z 412.19 (M+H) rétention time = 1.91 minutes.

(S)-2-((2-(5-ch!oro-177-pyrro!o[23*b]pyridin-3-y!)-5-fluoropyrimidin-4-yi)amino)-33' dimethylbutane-l-sulfonic acid (10)

Sulfonic acid, 10, was synthesized in a manner similar to Compound 11, using 5chloro-3-(4,4,5,5-tetramethy!-l ,3,2-dioxaborolan-2-y!)- 1-tosyl- !/7-pyrro!o[2,3bjpyridine instead ofboronate ester, 7a, as the starting material: *H NMR (400 MHz, MeOD) δ 8.44 (s, IH), 8.34 (dd, J= 9.2,2.6 Hz, 1Η), 8.22 (d, 5.7 Hz, IH), 8.13 (s, IH), 5.16 (d, J= 4.1 Hz, IH), 3.46 - 3.33 (m, 2H), 1.10 (d, 9H); LC/MS (10-90% ACN/water 5 min with 0.9% TFA, Cl 8) m/z 412.19 (M+H) rétention time = 1.91 minutes.

Préparation of Compounds 46

Synthetlc Scheme 11

-8617028

14a

76a

MsCl. CH₂CI₂; (b) KOAc, DMF; (c) NaOMe, MeOH; (d) Mel, K₂CO₃, acetone, 70 °C; (e) Oxone, water, MeOH, 3 hr, RT; (f) 5-fIuoro-l-(p-tolylsulfony[)-3(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2y[)pynolo[2,3-b]pyridine, 7a, KjPO^ X-Phos, Pd₂(dba)j, 2-MeTHF, water, 120 °C, 3 hr then 80 °C, 1 hr; (g) NaOMe, MeOH.

(S)-2-(2-chloro-5-fluoropyriniidin-4-ylamino)-3,3“diniethylbutyl methanesulfonate (75a).

To a cold (0 °C) solution of (S)-2-((2-chIoro-5-fluoropyrimidin-4-yl)amino)-3,3dimethylbutan-l-ol, 14a, (1.95 g, 7.87 mmol) and triethylamine (1.37 mL, 9.84 mmol) in dichloromethane (25 mL) was added methanesulfonyl chloride (0.76 mL, 20 9.84 mmol). The solution was stirred at room température for I hour. The solvent was removed under reduced pressure and water (100 mL) and EtOAc (50 mL) were added. The organic phase was separated, dried (MgSO<) and concentrated under reduced pressure to afford 2.55 g of the desired product as a pale yellow foamy solid: LC/MS (10-90% ACN/water 5 min with 0.9% FA, C4) m/z 326.99 (M+H) RT = 2.96 25 mintues.

(S)-5-2-(2-chIoro-5-iluoropyrimidin-4-yIamino)-33'dimethyIbutyl ethanethioate (76a).

Potassium thioacetate (1.30 g, 11.51 mmol) was added to a stirring solution of (S)-2(2-chloro-5- fluoropyrimidin-4-ylamino)-3,3 -di methylbutyl methanesu I fonate, 75a, (2.50 g, 7.67 mmol) in dry DMF (50 mL). The resulting brown solution was heated 30 with stirring at 78 °C for 1 hour. The brown suspension was poured into water and

-8717028 extracted with EtOAc (3x 100 mL). The combined organic phases were dried (MgSO₄), filtered and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (0-30% EtOAc/Hexanes gradient) to afford 2.1 g of compound 76a as a pale brown solid: *H NMR (400 MHz, CDCI3) δ 7.81 (s, 1H), 5.12 (m, 1H), 4.21 (t, J = 9.1 Hz, 1H), 3.15-2.90 (m, 2H), 2.23 (s, 3H), 0.95 (m, 9H); LC/MS (10-90% ACN/water 5 min with 0.9% FA) m/z 306.02 (M+H) RT =

3.32 min.

(S)-2-(2-chloro-5-fluoropyrimidin-4-ylamlno)-3,3-dlmethylbutane-l-thlol (77a)

To a nitrogen-purged solution of (S)-S-2-(2-chloro-5-fluoropyrimidin-4-ylamino)-3,3dimethylbutyl ethanethioate, 76a, (1.00 g, 3.27 mmol) in methanol (20 mL) was added NaOMe (1.457 mL of 25% solution in MeOH, 6.540 mmol) and the solution was stirred at room température for 1 hour. The reaction mixture was concentrated in vacuo and the residue was dissolved in water (25 mL) and slowly acidified with 2N HCI to give a white precipitate that was extracted twice with EtOAc. The combined organic phases were dried (MgSO₄), filtered and concentrated under reduced pressure to afford 0.85 g of the desired product as a paie beige color solid: LC/MS (10-90% ACN/water 5 min with 0.9% FA) m/z 264.92 (M+H) RT = 3.32 min.

(S)-2-ehloro-/V-(3,3-dimethyl-l-(methylthio)butan-2-yl)- 5-fluoropyrlmldln-4-amine (78a)

To a suspension of (S)-2-(2-chloro-5-fluoropyrimidin-4-ylamino)-3,3dimethylbutane-l-thiol, 77a, (0.85 g, 3.60 mmol) and K2CO3 (2.26 g, 16.35 mmol) in acetone was added iodomethane (0.82 mL, 13.08 mmol). The suspension was heated at 70 °C for 1.30 hours and then cooled to room température. The solid was filtered and the solution was concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (0-10% EtOAc/Hexanes gradient) to afford 310 mg of the desired product as a white solid: *H NMR (400 MHz, CDCI3) δ 7.81 (s, 1H), 5.12 (m, IH), 4.21 (t, J= 9.1 Hz, 1H), 3.15-2.90 (m, 2H), 2.23 (s, 3H), 0.95 (m, 9H); LC/MS (60-90% ACN/water 5 min with 0.9% FA) m/z 278.29 (M+H) RT =

1.35 minutes.

6$')-2-chloro-7V-(3,3-dimethyl-l-(methylsulfonyl)butan-2-yl)-5-nuoropyrimidin-4-ainine (79a)

To a cold (0 °C) solution of (S)-2-chlon>-N-(3,3-dimethyl-l-(methylthio)butan-2-yl)5-fluoropyrimidin-4-amine, 78a, (0.15 g, 0.54 mmol) in methanol (10 mL) was added Oxone (0.50 g, 0.81 mmol). The solution was stirred at room température for 3 hours. The solution was concentrated in vacuo to give a white residue which was dissolved in water (10 mL). The aqueous layer was extracted with EtOAc (3x10 mL). The combined organic phases were dried (MgSO₄), filtered and concentrated in vacuo to afford 150 mg of the desired product as a white solid: LC/MS (60-90% ACN/water 5 min with 0.9% FA) m/z 310.31(M+H) RT = 2.60 minutes.

(5)-7V-(3^-dlmethyl-l-(methylsulfonyl)butan-2-yl)-5-fluoro-2-(5-fluoro-l-tosyl-17/pyrrolo[23*b]pyrldin-3-yl)pyrimidin-4-amine. (80a)

A solution of (S)-2-chloro-N-(3,3-dimethyl-I-(methylsulfonyl)butan-2-yl)-5fluoropyrimidin-4-amine, 79a, (0.15 g, 0.48 mmol), 5-nuoro-l-(p-toIylsulfonyl)-3(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine (0.24 g, 0.58 mmol), and K3PO₄ (0.25 g, 1.16 mmol) in 2-methyl THF (5 mL) and water (1 mL)

-8817028 was purged with nitrogen for 30 minutes. X-Phos (0.015 g, 0.031 mmol) and Pd?(dba)j (0.007 g, 0.008 mmol) were added and the reaction mixture was heated at 120 ^eC in a pressure vial for 2 hours. The reaction mixture was cooled to room température, filtered and concentrated in vacuo. The residue was dissolved in EtOAc (50 mL) and washed with water. The organic layer was dried (MgSO<), filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (0-40% EtOAc/Hexanes gradient) to afiord 210 mg of the desired product as a white foamy solid: *H NMR (400 MHz, CDClj) δ 8.54 - 8.43 (m, 2H), 8.24 (d, J= 1.3 Hz, 1H), 8.09 (s, 1H), 8.03 (d, 8.2 Hz, 2H), 7.23 (s, 1H), 4.99 (dt, J= 20.3, 10.1 Hz,

2H), 3.37 (d, 14.4 Hz, 1H), 3.07 (dt, J= 31.3, 15.7 Hz, 1H), 2.83 (s, 3H), 2.33 (d,

J = 19.0 Hz, 3H), 0.98 (d, J- 20.7 Hz, 9H); LC/MS (10-90% ACN/water 5 min with 0.9% FA, C4) m/z 564.20 (M+H) RT = 3.70 minutes.

(S)-/V-(3,3-dImethyl-l-(methylsulfonyl)butan-2-yl)-5-nuoro-2-(5-fluoro-l/f-pyrrolo[23b]pyrldIn-3-yl)pyrlmldtn-4-amlne (46)

To a solution of (S)-N-(3,3-dimethyi-l-(methylsuIfonyI)butan-2-yI)-5-fluoro-2-(5fluoro-l-tosyl-lH-pynOlo[2,3-b]pyridin-3-yl)pyrimidin-4-amine, 80a, (0.21 g, 0.37 mmol) in THF (10 mL) was added NaOMe (0.33 mL of 25% solution in MeOH, 1.45 mmol). The solution was stirred at room température for 10 minutes, then diluted into aqueous saturated NH4CI solution. The solvent was removed under reduced pressure and the residue was dissolved in water (10 mL). The aqueous layer was extracted with EtOAc (3x10 mL), dried (MgSO<), filtered and concentrated in vacuo. The product was purified by silica gel chromatography (0-10% MeOH/CHîCh gradient) to afford 109 mg of the desired product as a white solid: *H NMR (400 MHz, CDClj) δ 9.38 (s, 1H), 8.53 (d, J = 6.9 Hz, 1H), 8.16 (m, 2H), 8.06 (s, 1H), 5.09 - 4.89 (m, 1H), 3.42 - 3.31 (m, 1H), 3.1 l(m, 1H), 2.84 (s, 3H), 1.00 (s, 9H); LC/MS (10-90% ACN/water 5 min with 0.9% FA) m/z 410.19 (M+H) RT = 2.03 minutes.

Préparation of Compound 62

Synthetic Scheme 12

-8917028

LiBH4, THF, IN HCl; (b) 2-iodoxybenzoic acid, THF, reflux; (c) Toluene; (d) Br₂, HBr, AcOH, 65°C; (e) NaOH, hydroxyurea, MeOH.

Formation of (+/-)-3-((5-fluoro-2-(5-fluoro-l-tosyl-lZ7-pyrrolo[2,3-b]pyridin-3yl)pyrimIdin-4-yl)amIno)-4,4-dimethylpentan-l-ol (82a)

To a coid (0 °C) solution of racemic methyl 3-((5-fluoro-2-(5-fluoro-l-tosyl-lWpyrrolo[2,3 -b] pyridin-3-yl)pyrimi din-4-yl)amino) -4,4-dimethylpentanoate (4.00 g,

7.36 mmol) in THF (160 mL) and MeOH (10 mL) was added lithium borohydride (29.44 mL of 2 M solution, 58.87 mmol) dropwise over 30 minutes. The reaction mixture was slowly warmed to room température and then re-cooled to 0 °C. A IN HCl solution (294 mL, 294 mmol) was added dropwise. The mixture was stirred for 15 minutes and then diluted with dichloromethane. The phases were separated and the aqueous phase was extracted again with dichloromethane. The combined organic phases were washed with aqueous saturated NaHCOj solution and brine, dried (Na₂SO4), filtered and concentrated in vacuo. The resulting residue was purified via silica gel chromatography (EtOAc/Hexanes) to afford 3.79 g of the desired product.

Formation of (+/-)-3-((5-fluoro-2-(5-fluoro-l-tosyl-l/f-pyrrolo[2,3-b]pyridln-3yl)pyrimldin-4-yl)amino)-4,4-dImethylpentanal (83a)

To a solution of racemic 3-((5-fluoro-2-(5-fluoro-l-tosyl-lW-pyrrolo[2,3-b]pyridin-3yl)pyrimidin-4-yl)amino)-4,4-dimethylpentan-l-ol, 82a, (1.60 g, 3.10 mmol) in THF (64 mL) was added 2-iodoxybenzoic acid (Ibx) (3.86 g, 6.21 mmol). The reaction mixture was heated to reflux under at atmosphère of nitrogen for 30 minutes. After cooling the mixture to room température, the solids were filtered. An aqueous saturated NaHCOj solution was added to the filtrate and the biphasic mixture was stirred for 30 minutes. The mixture was further diluted with dichloromethane and the phases separated. The aqueous layer was extracted again with dichloromethane. The

-9017028 combined organic phases were dried (NaîSCh), filtered and concentrated in vacuo. The resulting residue was purified via silica gel chromatography (EtOAc/Hexanes) to afford 1.59 g of the desired product

Formation of (+/-)-methyl 5-((5-fluoro-2-(5-fluoro-l-tosyi-l/7-pyrrolo|23*b]pyridln-3yi)pyrimldin-4-yi)amino)-6,6-dimethylhept-2-enoate (84a)

To a solution of 3-((5-fluoro-2-(5-fluoro-l-tosyl-177-pynOlo[2,3-b]pyridin-3yl)pyrimidin-4-yl)amino)-4,4-dimethylpentanal, 83a, (0.295 g, 0.574 mmoi) in toluene (5.9 mL) was added methyi 2-(triphenyiphosphoranylidene)acetate (0.300 g, 0.862 mmol). The mixture was stirred ovemîght at room température and then purified directly on siiica gel (EtOAc/Hexanes) to afford 278 mg of the desired product: LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, RT =

2.54 minutes (M+H) 584.12.

Formation (+/-)-metbyl 2,3-dlbromo-5-((5-fluoro-2-(5-fluoro-lJ7-pyrrolol2,3-b]pyridln-

3- yl)pyrlmldin-4-yl)amino)-6,6-dimethylheptanoate (85a)

To a solution of racemic methyi 5-((5-fluoro-2-(5-fluoro-l-tosyl-l/7-pyrrolo[2,3b]pyridin-3-yl)pyrimidin-4-yl)amino)-6,6-dimethylhept-2-enoate, 84a, (0.278 g, 0.476 mmol) acetic acid (2.5 mL) was added bromine (0.099 g, 0.620 mmol) followed by HBr (0.085 mL of 5.6 M solution in AcOH). The reaction mixture was heated at 65 °C ovemîght. The mixture was diiuted into dichloromethane and aqueous saturated sodium bicarbonate solution. The phases were separated and the aqueous layer was washed with dichloromethane. The organic layers were combined and the solvents were removed under reduced pressure. The residue was purified via silica gel chromatography (EtOAc/Hexanes) to give the desired product: LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, RT = 3.00 minutes (M+H)

590.94.

Formation of (+/-)-5-(2-((5-fluoro-2-(5-fluoro-l/7-pyrrolol2,3-b]pyridin-3-yl)pyrimldin-

4- yl)amino)-33-dimethy)butyl)isoxazoi-3-ol (62)

To a solution of NaOH (0.015 g) dissolved in water (0.4 iO mL) was added hydroxyurea (0.008 g, 0.100 mmol). The resulting mixture was stirred for 30 minutes before the dropwise addition of methyi 2,3-dibromo-5-((5-fluoro-2-(5-fluoro-l/Zpyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-6,6-dimethylheptanoate, 85a, (0.064 g, 0.110 mmol) in MeOH (0.150 mL). The solution was stirred for 6 hours before the addition of AcOH (0.03 i mL). The residue was purified by reverse phase préparative HPLC to afford the desired product: ^JH NMR (300 MHz, MeOD) δ 8.57 (dd, J= 9.7, 2.8 Hz, 1H), 8.16 (d, J= 5.5 Hz, 2H), 8.00 (d, J= 4.1 Hz, 1H), 5.68 (s, IH), 3.03 (ddd, J = 27.4, 15.4, 12.3 Hz, 2H), 1.10 (d, 3.3 Hz, 11H); LCMS

Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, RT ^e 2.15 minutes (M+H) 416.04.

Préparation of Compound 45

Synthetic Scheme 13

-9i17028

LiOH, dioxane, H₂0,100 C.

Formation of (+/-)-3-((5-fluoro-2-(5-fluoro-lZf-pyrroloI23-blpyridin-3-yl)pyrimidin-4yl)amino)-4,4-dimcthylpentan-l-oi (45) i 0 To a solution of racemic 3-((5-fluoro-2-(5-fluoro-l-tosyl-1 H-pyrroio[2,3-b]pyridin-3yl)pyrimidin-4-yl)amino)-4,4-dimethylpentan-l-ol, 82a, (0.187 g, 0.363 mmol) in dioxane (4 mL) was added LiOH (0.91 mL of 2 M solution, 1.8 i mmoi). The reaction mixture was heated at 100 °C for 2 hours. The mixture was diluted with water (30 mL) and extracted twice with EtOAc. The combïned organic phases were 15 washed with brine, dried (MgSO4), filtered and concentrâted in vacuo. The crude residue was washed with Hexanes to afford 76 mg of the desired product: *H NMR (300 MHz, CDClj) δ 10.42 (s, 1H), 8.47 (dd, J- 9.3, 2.7 Hz, 1H), 8.13 (d, J= 11.2 Hz, 1H), 8.10 (s, 1H), 8.04 (d, 3.2 Hz, 1H), 4.89 (d, 9.0 Hz, 1H), 4.26 (t, J =

9.9 Hz, 1H), 3.65 (d. J-= 9.2 Hz, IH), 3.54 (td, J= 1 i.4, 2.9 Hz, 1H), 2.i7 -1.99 (m, 20 IH), i.40 (dd, J= 14.0, i i.9 Hz, iH), 0.96 (d, 18.4 Hz, 9H), 0.90 - 0.73 (m, 1H);

LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, (M+H) 362.

Préparation of Compounds 50, 51, and 52

Synthctic Schemc 14

2-nitrophenylselenocyanate, BujP, THF; (b) mCPBA, CHC1₃; (c) Rh₂(OAc)₄, N₂CH₂CO₂Et, CH₂C1₂; (d) LiOH, dioxane, H₂O.

Formation of (+/-)-A^r-(4,4-dimcthyi-l-((2-nitrophenyl)selanyl)pentan-3-yl)-5-fluoro-2-(5fluoro-l-tosyi-l/Z-pyrroloI2,3-b|pyridln-3-yl)pyrimidin-4-aminc (88a)

-9217028

To a solution of racemic 3-[[5-fluoro-2-[5-fluoro-l-(p-tolylsulfonyl)pyrrolo[2,3bîpyridin-3-yHpyrimidin-4-yl]amino]-4,4-dimethyl-pentan-l-ol, 82a, (1.093 g, 2.120 mmol) and (2-nitrophenyl) selenocyanate (0.722 g, 3.180 mmol) in THF (8 mL) was added tributylphosphane (0.792 mL, 3.180 mmol). The reaction mixture was stirred ovemight and then concentrated under reduced pressure. The crude residue was purified by silica gel (0 to 100% EtOAc/Hexanes gradient) to afford 1.20 g of the desired product.

Formation of (+/-)-/V-(4,4-dImethyIpent-l-en-3-yl)-5-nuoro-2-(5-fluoro-l-tosyl-lZfpyrrolo|23-b]pyridin-3-yl)pyrim!dIn-4-amIne (89a)

To a cold (0 °C) solution of racemic jV-(4,4-dimethy!-1-((2nitrophenyl)selanyl)pentan-3-yl)-5-fluoro-2-(5-fluoro-l-tosyl-l//-pyrrolo[2,3b]pyridin-3-yl)pyrimidin-4-amine, 88a, (1.01 g, 1.45 mmol) in chloroform (15 mL) was added mCPBA (0.40 g of 77%, 1.79 mmol). After stirring for 1 hour at room température, the mixture was diluted with dichloromethane (100 mL) and the resulting solution was washed with aqueous sodium bicarbonate solution. The organic phase was dried (MgSO<), filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (0 to 100% EtOAc/Hexanes) to afford 623 mg of the desired product: LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, Cl 8/ACN, (M+H) 496.76.

Formation of 2-(l-((5-fluoro-2-(5-fluoro-l//-pyrroloI2,3-b]pyridin-3-yl)pyrimldtn-4yl)amino)-2,2-dimethylpropyl)cyclopropanecarboxylic acid (50,51, and 52)

To racemic A/'-(4,4-dimethylpent-l -en-3-yl)-5-fluoro-2-(5-fluoro-I-tosy!-i//pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-amine, 89a, (0.105 g, 0.211 mmol) and rhodium(II) acetate (0.019 g, 0.042 mmol) in dichloromethane (6.2 mL) was added dropwise a solution of ethyl 2-diazoacetate (0.181 g, 0.166 mL, 1.582 mmol) in 2 mL dichloromethane over 30 minutes. Pd(OAc)2 (0.019 g, 0.042 mmol) in dichloromethane (2 mL) was added followed by ethyl 2-diazoacetate (0.181 g, 0.166 mL, 1.582 mmol) in dichloromethane (2 mL) dropwise. The réaction was stirred ovemight and the solvent was concentrated in vacuo. The resulting crude residue was purified by silica gel chromatography (0 to 100% EtOAc/Hexanes gradient) to afford a racemic mixture of diasteromeric esters, 90a. The mixture of esters was dissolved in dioxane (2 mL) and 2N LiOH (1 mL). After heating at 100 °C for 2 h and cooling to room température, the mixture was acidified pH 6.5 with 2N HCl. The aqueous phase was extracted twice with EtOAc and once with dichloromethane. The combined organic phases were dried (MgSO<), filtered and concentrated under reduced pressure. The crude residue was subjected to silica gel chromatography (020% MeOH/EtOAc gradient) to isolate the mixture of diastereomeric acids, which were further purified by preparatory HPLC (CH3CN/H2O - TFA modifier) to afford 3 diastereomers. Two of the diastereomers, 51 and 52, were isolated as a single diastereomer each. The third diastereomer, 50, was isolated as a mixture of diastereomers. Ail three diastereomers showed same LCMS: LCMS Gradient 1090%, 0.1% formic acid, 5 minutes, Cl8/ACN, (M+H) 402.45.

1“ fraction - a mixture of diastereomers with 4 peaks at 1.8,1.9,2.06 and 2.16 minutescontai ns 50;

-9317028

2^nd fraction - single peak at 2.06 minutes* (51)

3^rt fraction - single peak at 2.16 minutes- (52)

Préparation of Compound 4Î

Synthetic Scheme 15

F

Cl b

B-0

'pr₂NEt, EtOH, 75 °C; (b) Pd₂(dba)₃, XPhos, K₃PO₄, THF, H₂0,135 °C, microwave.

Formation of (+/-)-2-chloro-5-nuoro-6-(l-hydroxy-4,4-dimethylpentan-3ylamlno)pyridine-3-carbonltrlle (95a)

To a solution of 3-amino-4,4-dimethylpentan-l-ol (2.00 g, 8.64 mmol) in éthanol (20 mL) was added racemic 2,6-dichloro-5-fluoro-pyridine-3-carbonitrile (1.65 g, 8.64 mmol) and 5 mL of y/V.-diisopropylethyiamine. The solution was stirred at 75 °C for 12 hours and concentrated in vacuo. The residue was purified by silica gel chromatography (methylene chloride), yielding 2.2 g of 2-chloro-5-fluoro-6-(lhydroxy-4,4-dimethylpentan-3-ylamino)pyridine-3-carbonitrile, 95a: LCMS

Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, RT = 3.02 minutes (M+H) 286.16

Formation of (+/-)-5-fluoro-2-(5-fluoro-l/Apyrrolo[23-bIpyridin-3-yl)-6-(l-hydroxy-4,4 -dimethylpentan-3-ylamino)pyridine-3-carbonitrile (41)

To a racemic solution of 2-chloro-5-fluoro-6-(l-hydroxy-4,4-dimethyipentan-3ylamino)pyridine-3-carbonitrile, 95a, (0.20 g, 0.70 mmol) and 5-fluoro-3-(4,4,5,5tetramethyl-l,3,2-dioxaborolan-2-yl)-l-tosyl-lW-pyrrolo[2,3-Z>]pyridine, 7a, (0.44 g, 1,05 mmol) in THF (15 mL) was added a solution of potassium phosphate (0.45 g) in 3 mL of water. The resulting mixture was degassed under a stream of nitrogen for 15 minutes. To the mixture was then added X-Phos (0.03 g, 0.07 mmol) and Pd₂(dba)₃(0.02 g, 0.04 mmol). The reaction was warmed to 135 °C via microwave irradiation for 15 minutes and then extracted into EtOAc (3x15 mL) vs. water. The organic layers were combined and concentrated in vacuo to a dark oil which was redissolved in 20 mL of THF. To the solution was added 5 mL of 2 N LiOH and the reaction was

-9417028 warmed to 65 °C for 12 hrs and then concentrated in vacuo. The resulting residue was purified via silica gel chromatography (EtOAc) to afford 108 mg of the desired product, 41, as a yellow solid: 'H NMR (300 MHz, J6-DMSO) δ 12.40 (s, H), 8.63 (dd, 2.8,10.1 Hz, H), 8.37 - 8.32 (m, H), 7.83 (d, J= 11.4 Hz, H), 7.31 (d, J= 9.7 Hz, H), 4.56 - 4.50 (m, H), 4.41 (dd, 4.1,5.2 Hz, H), 3.69 (s, H), 3.57 (s, H), 3.49 (t, 6.6 Hz, H), 3.48 (s. H), 3.36 - 3.28 (m, H), 2.50 (qn, J= 1.8 Hz, H), 1.86 -1.67 (m, 2 H), 1.21 (dd, J= 7.0, 16.1 Hz, H) and 0.94 (s, 9 H) ppm; LCMS Gradient 1090%, 0.1% formic acid, 5 minutes, C18/ACN, RT = 3.09 minutes (M+H) 386.39.

Préparation of Compounds 11, 24, 25 26, 27, 28, 29,30, and 31

Synthetlc Scheme 16

2-chIoro-5,6-di fluoropyridine-3-carbonitri le, 'Pr₂NEt,THF, MeOH, 95 °C; (b) 5-fluoro-l-(ptolylsulfonyl )-3-(4,4,5,5-tetramethyl-l,3,2dioxaborolan-2-yl)pyrroIo[2,3-b]pyrîdine, 7a, K3PO4, X-Phos, Pd₂(dba)3,2-Me THF, water, 120 °C; (c) MsCl. CH₂C1₂; (d) KOAc, DMF, 80 °C; (e) 30% H₂O₂, HCOOH; (0 (COCi)₂, DMF, CH₂C1₂. (g) i. Amine, THF; ii. 4M HCl, CH3CN, 65 °C.

(S)-2-chloro-5-fluoro-6-((l*hydroxy-33-dimethylbutan-2-yi)amino)nicotinonitriIe (97a).

A mixture of 2-chIoro-5,6-difluoropyridine-3-carbonitrile (6.52 g, 34.13 mmol), (25)2-amino-3,3-dîmethyl-butan-l-ol (4.00 g, 34.13 mmol) and triethylamine (9.51 mL, 68.26 mmol) in CHjCN (50 mL) and THF (50 mL) was heated at 80 °C for 4 hours. The mixture was cooled to room température and the solvent was evaporated under reduced pressure. The crude product was purified via silica gel chromatography (0

-9517028

60% EtOAc/Hexanes gradient) to afford 6.7 g of the desired product as an off white solid: ^lH NMR (400 MHz, CDC1₃) δ 7.25 (d, J = 9.7 Hz, 1H), 5.32 (m, 1H), 4.194.08 (m, 1H), 3.95-3.83 (m, 1H), 3.74 -3.51 (m, 1H), 0.92 (s, 9H); LC/MS (60-90% ACN/water 5 min with 0.9% FA) m/z 272.02 (M+H), rétention time 1.02 minutes.

(3)-5-Π uo ro-2-(5-fluo r o-l -tosyl-1 H-py rrolo [ 2,3-b[ pyridln-3-yl)-6-(( 1 -hydroxy-3,3dimethylbutan-2-yl)amino)nicotinonitrile (98a).

A solution of 5-fluoro-l-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethy]-l,3,2-dioxaborolan-

2- yl)pyrrolo[2,3-b]pyridine, 7a, (1.84 g, 4.42 mmol), (5)-2-chloro-5-fluoro-6-((l- hydroxy-3,3-dimethylbutan-2-yl)amino)nicotinonitrile, 97a, (1.00 g, 3.68 mmol) and K3PO4 (2.40 g, 11.22 mmol) in 2-methyl-THF (12 mL) and water (2 mL) was purged with nitrogen for 30 minutes. X-Phos (0.14 g, 0.294 mmol) and Pd2(dba)î(0.07 g, 0.07 mmol) were added and the reaction mixture was heated at 120 °C in a pressure vial for 2 hours. The reaction mixture was cooled to room température, filtered and concentrated in vacuo. The residue was dissolved in EtOAc (50 mL) and washed with water. The organic layer was dried (MgSO<), filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography (0-40% EtOAc/Hexanes gradient) to afford 1.88 g as a foamy solid: *H NMR (300 MHz, CDCIj) δ 8.64 (s, 1H), 8.36 (d, J= 2.0 Hz, 1H), 8.26 (m, 1H), 8.14 (d, 8.4 Hz, 2H), 7.46 (d, J- 12

Hz, 2H), 7.33 (d, J- 7.5 Hz, 1H), 5.34 (m, 1H), 4.42-4.31 (m, 1H), 4.02 (m, 1H), 3.75 (m, 1H), 2.40 (s, 3H), 1.26(s, 9H); LC/MS (60-90% ACN/water 5 min with 0.9% FA, C4) m/z 526.49 (M+H), rétention time = 1.83 minutes.

(S)-2-((5-cyano-3-nuoro-6-(5-nuoro-l-tosyl-l£f-pyrroloI23-b]pyridin-3-yi)pyridin-2yl)amino)-3,3-dimethylbutyl methanesulfonate (99a).

To a cold (0 °C) solution of (S)-5-fluoro-2-(5-fluoro-l-tosyl-H7-pyiTolo[2,3b]pyridin-3 -yl )-6-(( 1 -hydroxy-3,3 -dimethylbutan-2-yl)amino)nicotinon i tri 1 e, 98 a, (3.77 g, 7.17 mmol) and triethylamine (1.25 mL, 8.96 mmol) in dichloromethane (75 mL) was added methanesulfonyl chioride (0.69 mL, 8.96 mmol). The solution was stirred at room température for 1 hour. The solvent was removed under reduced pressure and water (100 mL) and EtOAc (200 mL) were added. The organic phase was separated, dried (MgSO<), filtered and concentrated under reduced pressure to afford 4.22 g of the desired product as a yeliow foamy solid that was used without further purification: LC/MS (60-90% ACN/water 5 min with 0.9% FA, C4) m/z 604.45 (M+H) rétention time = 2.03 minutes.

(S)-2-(5-Cyano-3-fluoro-6-(5-fluoro-l-tosyl-l£f-pyrroloI23-b]pyridin-2ylamlno)-33dimethylbutyl ethanethiolate (100a).

Potassium thioacetate (1.2 g, 10.5 mmol) was added to a solution of (S)-2-((5-cyano-

3- fIuoro-6-(5-fluoro-l-tosyl-lH-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2-yl)amino)-3,3- dimethylbutyl methanesulfonate, 99a, (4.22 g, 6.99 mmol) in dry DMF (90 mL). The brown solution was heated with stirring at 80 °C for 1 hour. The thick brown suspension was poured into water and extracted with EtOAc (3x 100 mL). The organic layers were dried (MgSOJ, filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (0-30% EtOAc/Hexanes gradient) to afford 6.8 g of the desired product as a pale brown solid: *H NMR (400 MHz, CDCb) δ 8.57 (s, 1H), 8.28 (d, J- 1.3 Hz, 1H), 8.11 (dd, J= 8.5, 2.3 Hz, 1H), 8.05 (d, J= 8.3 Hz, 2H), 7.33 (d, 10.2 Hz, 1H), 7.24 (d, J = 8.3 Hz, 2H), 5.11 (m,

1H), 4.31 (m, 1H), 3.19 (dd, J = 14.0, 3.0 Hz, 1H), 3.03 (dt,J= 13.6, 6.9 Hz, 1H),

-9617028

2.31 (s, 3H), 2.10 (m, 3H), 10.97(s, 9H); LC/MS (60-90% ACN/water 5 min with 0.9% FA) m/z 584.0 (M+H) rétention time = 2.66 minutes.

f5)-2-(5-Cyano-3-fluoro-6-(5-fluoro-l-tosyl-lW-pyrrolo[2,3-Ô]pyrldln-2ylamino)-33dimethylbutane-l-sulfonic acid (101a).

To a cold (0 °C) solution of formic acid (22.2 mL, 588.5 mmol) was added H2O2 (7.35 mL of 30% solution, 71.96 mmol). The mixture was stirred at 0 °C for 1 hour. A solution of f3)-S-2-(5-cyano-3-fluoro-6-(5-fluoro-l-tosyl-lW-pyrrolo[2,3b]pyridin-2yIamino)-3,3-dimethylbutyl ethanethiolate, 99a, (1.5 g, 2.57 mmol) in formic acid (5 mL) was added dropwise to the reaction mixture. The resulting solution was stirred for 2 hours at room température. The solvent was removed under reduced pressure 1.72 g of the desired sulfonic acid as a pale yellow foamy solid: LC/MS (10-90% ACN/water 5 min with 0.9% FA) m/z 586 (M+H) rétention time = 3.95 minutes.

(5)-2-(5-Cyano-3-fluoro-6-(5-fluoro-l-tosyl-l//-pyrroIoI23-/>lpyridin-2ylamino)-33dimethylbutane-l-sulfonyl chloride (102a).

To a solution of (3)-2-(5 -cyano-3-fluoro-6- (5-fluoro-l-tosyl-l/Z-pyrrolo[2,3b]pyridin-2ylamino)-3,3-dimethylbutane-i-sulfonic acid, 101a, (1.5 g, 2.54 mmol) and DMF (0.5 mL) in dichloromethane (30 mL) was added oxalyl dichloride (0.68 mL, 7.63 mmol) dropwise. The solution was stirred at room température for 1 hour. The solvent was removed under reduced pressure to afford 1.6 g of the desired product as a yellow solid: LC/MS (60-90% ACN/water 5 min with 0.9% FA) m/z 608 (M+H) rétention time = 2.40 minutes.

fS)-2-(5-Cyano-3-fluoro-6-(5-fluoro-l/f-pyrroIo|23-/’|pyridln-3-yl)pyridin-2yiamlno)JV33*ti*lmethyIbutane-l-suIfonamlde (26)

Methyl amine (0.41 mL of 2M solution, 0.82 mmol) was added to a solution of (3)-2(5-cyano-3-fluoro-6-(5-fluoro-l-tosyl-l//-pyrrolo[2,3-&]pyridin-2ylamino)-3,3dimethylbutane-l-sulfonyl chloride, 102a, (0.10 g, 0.16 mmol) in THF (1 mL). The solution was stirred for 1 hour at room température and the solvent was removed under reduced pressure. The crude sulfonamide was dissolved in CHjCN (3 mL) and HCl (2 mL of 4M solution in dioxane) was added. The réaction mixture was heated at 65 °C for 3 hours and then cooled to room température. The solvent was removed under reduced pressure and the resulting residue was purified by préparative HPLC chromatography (10-80% CHjCN/water, 0.5% TFA, 15 min) to afford 26 mg of the desired product as a white solid: *H NMR (400 MHz, CDCI3) δ 9.68 (s, 1H), 8.45 -

8.33 (m, 1H), 8.17 (d, J= 2.8 Hz, 1H), 7.88 (s, 1H), 7.36 (d, J = 10.3 Hz, 1H), 6.47 (d, J= 4.9 Hz, 1H), 5.11 (d, J= 7.8 Hz, 1H), 4.90 (d, J= 10.4 Hz, 1H), 3.52 (s, 1H), 3.04 (dd, J= 15.0, 10.5 Hz, 1H), 2.67 (d, J= 5.0 Hz, 3H), 1.02 (s, 9H); LC/MS (1090% ACN/water 5 min with 0.9% FA) m/z 449.22 (M+H) rétention time = 2.97 minutes.

The following compounds can be prepared in a similar fashion as the procedure described above for Compound 26:

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(S)-2-(5-Cyano-3-fluoro-6-(5-fluoro-l/f-pyrroIoI2,3-éJpyridin-3-yI)pyridÎn-2yIamIno)JV,/V,3,3-tetramethylbutane-l-sulfonamide (27) 'H NMR (400 MHz, CDCIj) δ 8.59 (dd, J = 9.7,2.6 Hz, 1H), 8.38 (s, 1H), 8.21 (s, IH), 7.31 (m, IH), 5.12 (brs, 1H), 4.97 (brs, 1H), 3.33 (m, 1H), 2.70 (s, 6H), 0.95 (m, 9H); LC/MS (1090% ACN/water 5 min with 0.9% FA) m/z 463.49 (M+H) rétention time = 3.12 minutes.

(S)-2-(5-Cyano-3-fluoro-6-(5-fluoro-l//-pyrroIo]2,3-ôlpyrIdin-3-yI)pyridin-2yIamino)/V-ryr/opropyZ-S^-dimethylbutane-l-suIfonamide (28)

LC/MS (10-90% ACN/water 5 min with 0.9% FA) m/z 475.0 (M+H) rétention time = 3.12 minutes.

F

(S)-2-((5-cyano-3-fluoro-6-(5-fluoro-lZf-pyrroIo[23-b]pyridin-3-yI)pyridin-2-yl)amIno)A^r-(2-methoxyethyl)-3,3-dimethyIbutane-l-sulfonamide (29) ‘H NMR (400 MHz, MeOD) δ 8.71 (dd, J= 9.7,2.6 Hz, IH), 8.37 (s, IH), 8.20 (s, IH), 7.57 (d, J= 10.9 Hz, IH), 5.08 (d, J= 8.8 Hz, IH), 3.54 - 3.40 (m, 2H), 3.32 (m, 5H), 3.15 (t, J =

5.4 Hz, 2H), 1.03 (s,9H); LC/MS (10-90% ACN/water 5 min with 0.9% FA) m/z 493.50 (M+H) rétention time = 3.05 minutes.

-9817028 (S)-2-((5-cyano-3-fluoro-6-(5-fluoro-l/7-pyrrolo[23-b]pyridin-3-yl)pyridin-2-yl)amino)-

3,3-dimethyl-N-propylbuta ne-1 -sulfonamlde (31)

LC/MS (10-90% ACN/water 5 min with 0.9% FA) m/z 477.65 (M+H) rétention time = 3.27 minutes.

F

(S)-2-((5-cyano-3-fl uo ro-6-(5-fluoro-1 H-py rrolo [ 2,3-b] pyridi n-3-y 1) pyridin-2-y ljamlno)33-dlmethylbutane-l-sulfonamlde (30)

LC/MS (10-90% ACN/water 5 min with 0.9% FA) m/z 435.46 (M+H) rétention time = 2.80 minutes.

F

(S)-5-fluoro-2-(5-fluoro-l£Z-pyrrolo[23-b]pyrldin-3-yl)-6-((l-hydroxy-33· dimethylbutan-2-yl)amlno)nlcotinonitrile (24)

Alcohol, 24, was synthesized in a manner similar to compound 32 utilizing the same deprotection procedure, starting with compound 98a: *H NMR (400 MHz, CDCIj) δ 10.27 (brs, IH), 8.25 (d, 9.4 Hz, IH), 8.17 (s, IH), 8.11 (s, IH), 7.23 (d, J = 10.3

Hz, IH), 5.20 (d, 9.6 Hz, IH), 4.41 (t, 7.4 Hz, IH), 4.09 (d, J= 11.3 Hz, IH),

3.82 - 3.58 (m, IH), 0.99 (d, 19.5 Hz, 9H).

F

(S)-2-(5-cyano-3-fluoro-6-(5-fluoro-lJApyrrolo[2,3-d]pyridin-3-yl)pyridln-2-ylamlno)-

3,3-dimethylbutane-l-sulfonlc acid (25)

To a solution of (S)-2-((5-cyano-3-fluoro-6-(5-fluoro-l-tosyl-lH-pyrrolo[2,3b]pyridin-3-yl)pyridin-2-yl)amino)-3,3-dimethylbutane-l-sulfonic acid, 101a, (0.12 g, 0.21 mmol)in CHjCN (5 mL) was added HCl (2 mLof 4M solution in dioxane). The reaction mixture was heated at 100 °C for 18 hours in a pressure vial and then cooled to room température. The solvent was removed under reduced pressure and the product was purified by préparative HPLC chromatography (10-80%

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CHjCN/water, 0.5% TFA, 15 min) to give 42 mg of the desired product as an offwhite solid: 'H NMR (400 MHz, MeOD) δ 8.44 (s, 1 H), 8.34 (dd, J= 9.2,2.6 Hz, IH), 8.22 (d, 5.7 Hz, IH), 8.13 (s, IH), 5.16 (m, 1Η), 3.46 - 3.33 (m, 3Η), 1.10 (s,

9H); LC/MS (10-90% ACN/water 5 min with 0.9% TFA, C18) m/z 449.22 (M+H).

(S)-2-((5-nuoro-2-(5-fIuoro-lW-pyrro!o|23-b]pyridin-3-yl)pyrimidin-4-yl)amino)-33’ dimethylbutane-l-sulfonic acid (11)

Sulfonic acid, 11, was synthesized in a manner similar to compound 30, using compound 57a: 'H NMR (400 MHz, MeOD) δ 8.44 (s, IH), 8.34 (dd, 9.2, 2.6 Hz, IH), 8.22 (d, 5.7 Hz, IH), 8.13 (s, IH), 5.16 (d, 4.1 Hz, IH), 3.46 - 3.33 (m, 2H), 1.10 (d, 9H); LC/MS (10-90% ACN/water 5 min with 0.9% TFA, C18) m/z

412.19 (M+H) rétention time = 1.91 minutes.

Préparation of Compounds 62, 87, and 88

Syntbetic Scbeme 17

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LDA, Mel, THF; (b) LiAlH₄, ether; (c) PCC, CH₂C1₂;

(d) 2-(triphenylphosphoran-ylidene)acetate, CH₂C1₂;

(e) Y-benzylhydroxylamine-HCl, CH₂C1₂; (f) H₂,

Pd/C, MeOH; (g) AcCl, MeOH, reflux; (h) 2,4dichloro-5-fluoropyrimidine, EtjN, EtOH, THF, 55 °C; (i) 5-fluoro-l-(p-tolylsulfonyl)-3-(4,4,5,5tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo-[2,3 · bjpyridine, 7a, Pd₂(dba)₃, XPhos, K₃PO₄, 2-MeTHF, H₂O, 115 °C; (j) HCl, dioxane, acetonitrile, 65°C; (k) LiOH,THF,H₂0,50°C.

Formation of ethyl 1-methylcyclobutanecarboxylate (111a)

A solution of ethyl cyclobutanecarboxylate (20.0 g, 156.0 mmol) in THF (160 mL) was added dropwise to a cold (-78 °C) solution of LDA (164 mmol of 2M solution) in THF (40 mL). The solution was warmed to 0 °C and then cooled again to -40 °C before the addition of iodomethane (10.2 mL, 163.8 mmol). The solution was slowly warmed to room température and stîrred ovemight. The reaction was quenched with an aqueous saturai ed solution of ammonium chloride and ether was added. The layers were separated and the aqueous layer was washed with ether. The combined organic layers were washed with IN HCl then dried over MgSO₄. The product was purified by distillation: *H NMR (400 MHz, MeOD) δ 4.20 - 4.05 (m, 2H), 2.57 -10117028

2.33 (m, 2H), 2.08 - 1.94 (m, 1H), 1.94 - 1.77 (m, 3H), 1.40 (s, 3H), 1.27 (tt, J= 7.1,

1.5 Hz, 3H).

Formation of (l-methylcyclobutyl)methanol (112a)

Lithium aluminum hydride (2.1 g, 59.4 mmol) was suspended in ether (150 mL) and cooled to 0 °C. A solution of ethyl 1-methylcyclobutanecarboxylate, 111a, (13.0 g,

91.4 mmol) in ether (60 mL) was added dropwise to the L1AIH4 suspension. The mixture was stirred 2 hours in an ice bath then quenched slowly with IN HCl. The layers were separated and the aqueous layer was washed with ether. The combined organic layers were washed with brine and the volatiles were removed with a gentle stream of nitrogen to afford the desired product that was used without further purification: ^lH NMR (400 MHz, CDCIj) δ 3.54 - 3.39 (m, 4H), 1.99 -1.74 (m, 8H), 1.74-1.62 (m, 4H), 1.46-1.18 (m, 3H), 1.13 (d, 1.7 Hz, 6H).

Formation of 1-methylcydobutanecarbaldehyde (113a) and methyl 3-(lmethylcyclobutyl)acrylate (114a)

A solution of (l-methylcyclobutyl)methanol, 112a, (1.00 g, 9.98 mmol) in dichloromethane (25 mL) was added to a suspension of PCC (2.69 g, 12.50 mmol) and Celite (2.70 g) in dichloromethane (25 mL). The reaction mixture was stirred 2 hours and filtered through a pad of silica gel (eluting with dichloromethane). The solvents were removed with a stream of nitrogen until volume was approximately 20 mL. 2-(triphenyl-phosphoranylidene)acetate (0.98 g, 10.00 mmol) was added in one portion and the mixture was stirred for 7 hours. The volatiles were removed under reduced pressure and a solution of 10% Hexanes/ether was added. The resulting solid was filtered off and discarded. The resulting solution was poured directly on silica gel and eluted with EtOAc/Hexanes to afford the desired product: *H NMR (400 MHz, CDCIj) δ 7.05 (d, J= 15.8 Hz, 1H), 5.66 (dd, 15.8, 1.3 Hz, 1H), 4.21 -4.00 (m, 2H), 2.12-1.73 (m, 7H), 1.29- 1.17 (m, 6H).

Formation (+/-)-2-benzyl-3-(l-methylcyclobutyl)isoxazolidin-5-one (115a) jV-benzylhydroxylamine (hydrochloric acid) (0.28 g, 1.80 mmol) and triethylamine (0.28 mL, 2.00 mmol) were added to a solution of methyl 3-(lmethylcyclobutyl)acrylate, 114a, (0.26 g, 1.50 mmol) in dichloromethane (9.5 mL). The reaction mixture was stirred at 50 °C ovemight. The réaction mixture was cooled to room température and the mixture was diluted with dichloromethane and water. The layers were separated with a phase separator and the aqueous layer was washed with dichloromethane. The organic layers were combined and the volatiles removed under reduced pressure. The resîdue was purified on silica gel (EtOAc/Hexanes) to afford the desired product as a racemic mixture: LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, RT = 1.47 minutes (M+H) 246.10.

Formation of (+/-)-3-amino-3-(l*methylcyclobutyl)propanoic acid (116a)

-10217028

A solution of racemic 2-benzyI-3-(l-methylcyclobutyl)isoxazolîdin-5-one, 115a, (0.18 g, 1.28 mmol) in MeOH (2.9 mL) was shaken overnight under 50 psi hydrogen in the presence of 50 mg palladium hydroxîde catalyst. The mixture was fiitered through Celite and the volatiles were removed under reduced pressure to afford the desired product that was used without further purification: *H NMR (400 MHz, MeOD) δ 3.42 (dd, J= 11.0,1.9 Hz, IH), 2.26 (ddd, 27.8,16.7,6.5 Hz, 2H), 1.86 (dddd, J= 36.9,26.3,11.2, 7.6 Hz, 6H), 1.18 (s, 3H).

Formation of (+/-)-methyl 3-((2-chloro-5-fluoropyrlmldln-4-yl)amino)-3-(lmethylcyclobutyl)propanoate (118a)

Racemic 3-amino-3-(l-methylcyclobutyI)propanoic acid, 116a, (2.3 g, 14.4 mmol) was dissoived in methanol (104 mL). The solution was cooled in an ice bath and acetyl chloride (5.6 g, 71.9 mmol) was added dropwise (Temp kept <10 °C). The reaction mixture was heated to 65 °C and stirred at that température for 3 hours. The réaction mixture was cooled to room température and then fiushed with toluene to remove volatiles. Crude racemic 3-methoxy-l-(l-methylcyclobutyl)-3-oxopropan-laminium chloride, 117a, was used without further purification.

Racemic 3-methoxy-l-(l-methylcyclobutyl)-3-oxopropan-l-aminium chloride, 117a, (3.3 g, 15.9 mmol) was dissoived in a mixture of 59 mL THF and 6.6 mL EtOH and the solution was cooled in an ice bath. 2,4-Dichloro-5-fluoro-pyrimidine (2.9 g, 18.0 mmol) was added followed by dropwise addition of triethylamine (5.1 g, 51.0 mmol). The reaction mixture was stirred at 55 °C for 17 hours. The reaction mixture was cooled to room température after which water and dichloromethane were added. The phases were separated and the aqueous layer was washed with dichloromethane. The organic layers were combined and washed with brine. The solvents were removed and the residue was purified via sitîca gel chromatography (EtOAc/Hexanes) to afford the desired product: LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, RT = 3.23 minutes (M+H) 302.35.

Formation of (+/-)-methyl 3-((5-fluoro-2-(5-fluoro-l-tosyl-lH-pyrrolo[2,3-b]pyridln-3yl)pyrimldin-4-yl)amino)-3-(l-methylcyclobutyl)propanoate (119a)

A solution of 5-fluoro-l-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan2-yl)pyrrolo[2,3-b]pyridine, 7a, (3.31 g, 7.95 mmol), racemic methyl 3-((2-chloro-5fluoropyrimidin-4-yI)amino)-3-(l-methylcyclobutyl)propanoate, 118a, (2.00 g, 6.63 mmol) and K3PO4 (4.22 g, 20.00 mmol) in 2-MeTHF (253 mL) and water (56 mL) was purged with nitrogen for 0.75 h. XPhos (0.38 g, 0.80 mmol) and Pdj(dba)j (0.15 g, 0.17 mmol) were added and the reaction mixture was stirred at 115 °C in a sealed tube for 2 hours. The reaction mixture was cooled and the aqueous phase was removed. The organic phase was fiitered through a pad of Celite and the mixture was concentrated to dryness. The residue was purified via silica gel chromatography (EtOAc/Hexanes) to afford the desired product: LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, RT = 2.32 minutes (M+H) 556.44.

Formation of (+/-)-methyI 3-((5-fluoro-2-(5-fluoro-l//-pyrrolo[23-b]pyr!din-3yl)pyrimidln-4-yl)amlno)-3-(l-methylcyclobutyl)propanoate (120a)

-10317028

To a racemic solution of methyl 3-((5-fluoro-2-(5-fluoro-l-tosyl-lH-pyrrolo[2,3b]pyridin-3-yl)pyrimidin-4-yl)amino)-3-(l-methylcyclobutyl)propanoate, 119a, (3.3 g, 5.9 mmol) in acetonitrile (25 mL) was added HCl (26 mL of 4N solution in dioxane). The reaction mixture was heated to 65 °C for 4 hours. The solution was cooled to room température and the solvents were removed under reduced pressure. The mixture was flushed with acetonitrile after which aqueous sodium bicarbonate and ethyl acetate were added. The phases were separated and the aqueous layer washed with ethyl acetate. The combined organic phases were dried with NajSCh, filtered and concentrated in vacuo. The resuiting residue was purified via silica gel chromatography (EtOAc/Hexanes) to afford the desired product: LCMS Gradient 1090%, 0.1% formic acid, 5 minutes, C18/ACN, RT - 2.34 minutes (M+H) 403.11.

For mati on of 3-((5-fl uoro-2- (5-fl uoro-1 H-py r rolo|2,3-b] py ri d i n -3-y l)py ri mldln-4yl)amlno)-3-(l-methylcyclobutyl)propanolc acid (87 and 88)

To a solution of methyl 3-((5-fluoro-2-(5-fluoro-l/f-pyrroio[2,3-b]pyridin-3yi)pyrimidin-4-yl)amino)-3-(l-methylcyclobutyl)propanoate (11) (1.75 g, 4.36 mmol) in THF (25 mL) was added aqueous IN LiOH (13.1 mL). The mixture was heated to 50 °C for 3.5 hours. The reaction mixture was cooled to room température and diluted with water. The THF was removed under reduced pressure and the residue was then flushed twice with hexanes. Ether was added and the layers separated (the ether layer was discarded). The pH was adjusted to 5.5 with IN HCl and the resuiting solid was filtered and washed with water. The solid was flushed with heptanes and dried over PjOj to give the desired product: *H NMR (400 MHz, DMSO) δ 12.17 (d, J = 60.2 Hz, 2H), 8.59 (d, J= 8.4 Hz, IH), 8.39 - 8.05 (m, 3H), 7.52 (s, IH), 5.00 (s, IH), 2.23 (d, J= 7.7 Hz, IH), 2.00 (s, IH), 1.81 (d, J - 48.3 Hz, 2H), 1.62 (s, IH),

1.46 (s, IH), 1.21 (s, 3H); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, Cl 8/ACN, RT - 2.08 minutes (M+H) 388.46. The racemic mixture was submitted to SFC chiral séparation to obtain the individual enantiomers, 87 and 88.

Préparation of Compound 65

Synthetlc Scheme 18

-10417028

125a

AlMej, NH4CI, toluene; (b) hydroxylamine, DMSO, 140 °C; (c) CDI, Îr₂NEt, THF.

Formation of (+/-)-3-((5-iluoro-2-(5-fluoro-l-tosyl-l//-pyrrolo[2,3-b[pyridin-3yl)pyrlmidin-4-yl)amino)-4,4-dlmethylpentanenitrile (124a)

Ammonium chloride (0.12 g, 2.30 mmol) was suspended in toluene (4.5 mL). The mixture was cooled in an ice bath and AlMej (1.15 mL of a 2 M solution in toluene,

2.30 mmol) was added dropwise. The mixture was stirred 30 minutes and another 30 min at room température. A solution of racemic methyl 3-[[5-fluoro-2-[5-fluoro-i(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]pyrimidin-4-yl]amino]-4,4-dimethylpentanoate (0.25 g, 0.46 mmol) in 4.5 mL toluene was added and the resuiting mixture was stirred 60 °C ovemight. The reaction mixture was cooled in an ice bath and quenched with IN HCI. The mixture was extracted with dîchloromethane and filtered through a phase separator. The residue was purified on silica gel (EA/Hex): LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, RT ^e 2.04 minutes (M+H) 511.42.

Formation of (+/-)-3-((5-fluoro-2-(5-fluoro-l/f-pyrrolo[2,3-b]pyrfdîn-3-yl)pyrimidin-4yi)amino)-JV’-hydroxy-4,4-dlmethylpentanimidamide (125a)

To a solution of racemic 3-[[5-fluoro-2-[5-fluoro-l-(p-toiyIsuIfonyl)pyrrolo[2,3b]pyridin-3-yl]pyrimidin-4-yi]amino]-4,4-dimethyl-pentanenitriie, 124a, (0.059 g, 0.116 mmol) in DMSO (0.500 mL) was added hydroxylamine (0.031 g, 0.470 mmol). The mixture was heated in a microwave at 140 °C for 30 minutes. The residue was purified on a Cl8 column (acetonitrile/0.1% formic acid) to afford the desired product: LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, CI8/ACN, RT 1.58 minutes (M+H) 390.06.

Formation of (+/-)-3-(2-((5-fluoro-2-(5-fluoro-l//-pyrrolo[2,3-b]pyrldin-3-yl)pyrimidln4-yl)amino)-3,3-dImcthylbutyl)-l,2,4-oxadiazoi-5(2Z7)-one (65)

-10517028

To a solution of racemic 3-[[5-fluoro-2-(5-fluoro-l//-pyrrolo[2,3-b]pyridin-3yl)pyrimidin-4-yl]amino]-N'-hydroxy-4,4-dimethyl-pentanamidine, 125a, (0.034 g, 0.087 mmol) and carbonyl diimidazole (0.014 g, 0.087 mmol) in THF (1 mL) was added jV.jV-diisopropylethylamine (0.045 mL, 0.260 mmol). The reaction mixture was stirred at room température for 48 hours. Aqueous ammonium chloride and dichloromethane were added and the layers were separated with a phase separator. The residue was purified on a Cl8 column (acetonitrile/0.1% formic acid) to aflord the final product: ’H NMR (400 MHz, Acetone) δ 11.23 (s, 1H), 8.54 (dd, J = 9.8,

2.8 Hz, 1H), 8.36 (s, 1H), 8.20 (s, 1H), 8.13 (d, 3.7 Hz, 1H), 6.81 (s, 1H), 5.00 (d,

11.2 Hz, 1H), 3.15 (d, J- 14.8 Hz, 3 H), 2.94 (dd, J - 14.4,11.9 Hz,2H), 1.16 (s, 8H); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, RT = 1.58 minutes (M+H) 390.06.

Préparation of Compound 47

Synthetic Scheme 19

Na₂CO₃, CH₃CN-THF, 125-150 °C; (b) 4M HCI, 1,4dioxane-CH₃CN, 60 °C (Æ)-3-((2-(5-fluoro-l-tosyl-lH-pyrrolo[2,3-b]pyridin-3-yi)pyrimldin-4-yl)amino)-4,4dimethyipentanoic acid (128a).

Sulfoxide, 127a, was prepared in same fashion as sulfoxide, 25a, (see Synthetic Scheme 4) using 2,4-dichloropyrimidine instead of 2-chloro-5-fluoro-4methylsul fanyl-pyrimidi ne.

A mixture of 5-fluoro-3-(4-(methylsulfinyl)pyrimidin-2-yl)-l-tosyl-l/7-pyrrolo[2,3bjpyridine, 127a, (0.052 g, 0.121 mmol) and (3Æ)-3-amino-4,4-dimethyl-pentanoic acid, 2a, (0.035 g, 0.242 mmol) along with Na₂CO₃ (0.051 g, 0.483 mmol) in a mixture of THF (0.780 mL) and acetonitrile (0.260 mL) was heated to 125 °C for 30 minutes under microwave irradiation. Then, the température was raised to 150 °C for a further 2.5 hours. The mixture was neutralized with aqueous 2N HCi and extracted with several portions of EtOAc. The organic solvents were evaporated in vacuo. Purification by flash chromatography (SiO₂, 0-100 % hexanes-EtOAc (with 10% MeOH)) provided i9 mg of the desired material (31% yield), which was used in the next step without further purification: LCMS Gradient 10-90%, 0.1% trifluoroacetic acid, 5 minutes, C18/ACN, RT = 2.70 minutes (M+H) 512.00.

-10617028 (/ï)-3-((2-(5-fluoro-lFr-pyrrolo|23-b|pyridin-3-yl)pyrimldin-4-yl)amlno)-4,4dimethylpentanolc add (47).

To a solution of (/î)-3-((2-(5-fluoro-l-tosyl-lF/-pynOlo[2,3-b]pyridin-3-y!)pyrimidin4-yl)amino)-4,4-dimethyipentanoic acid, 128a (0.019 g, 0.037 mmol) in acetonitriie (0.6 mL) was added HCl (0.15 mL of 4 M in dioxane, 0.60 mmol). The solution was 10 heated to 60 °C for 18 hours. Then, additional HCl (0.36 mL of 4 M in dioxane) was added and heating was continued for 4 hours. The mixture was cooied and concentrated in vacuo. Trituration with Et₂O followed by purification by preparatory HPLC provided 17.5 mg of the desired product as a TFA sait:. The NMR indicated a 4 to I ratio of atropisomers: *H NMR (400 MHz, MeOD, major atropsomer) δ 8.70 15 (dd, J - 8.9, 2.3 Hz, IH), 8.50 (s, IH), 8.35 (s, IH), 7.99 (d, J = 7.3 Hz, IH), 6.60 (d,

J = 7.2 Hz, IH), 5.05 (d, J = 10.7 Hz, IH), 2.93 (dd, J = 15.9, 1.8 Hz, IH), 2.53 (dd, J = 15.9, 11.2 Hz, IH), 1.08 (d, J - 0.8 Hz, 9H); LCMS Gradient 10-90%, 0.1% trifluoroacetic acid, 5 minutes, CI8/ACN, RT = 2.17 minutes (M+H) 358.02.

Préparation of Compound 48

Synthetic Scheme 20

(CO)₂C1₂, DMF/CH₂C1₂, NH<OH; (b) Et₃N, TFAA, CH₂CI₂ (c) Ν₂Η<Ή₂Ο, nBuOH, reflux; (d) tBuNO₂, BrjCH, 60-90 °C; (e) PhjCCI, K₂CO₃, DMF; (f) KOAc, 4,4,5,5-tetramethyI-225 (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-I,3,2-dioxaboro!ane, Pd(dppf)₂Cl₂, DMF, 100 °C; (g) 2-chloro-4-methylsu!fanyl-pyrimidine, Pd₂(dba)₃, XPhos, K3PO4, 2-MeTHF, H₂O, 115 °C; (h) mCPBA, CH₂C1₂, 0 °C; (t) Na₂CO3, CHjCN-THF, 125-150 °C; (c) EtjSiH, TFA, CH₂CI₂.

Formation of 2-chloro-5-fluoropyridine-3-carboxamlde (130a)

-10717028

To the suspension of 2-chloro-5-fluoropyridine-3-carboxylic acid (37.0 g, 210.8 mmol) in dichloromethane (555 mL) was added oxalyl chloride (56.2 g, 442.7 mmol) under nitrogen. DMF (1.54 g, 21.08 mmol) was added slowly to the reaction mixture. The mixture was stirred at room température for 2 h and dichloromethane was removed under reduced pressure. The residue was dissolved in THF (300 mL) and cooled down to 0 °C by ice bath. Ammonium hydroxide (28-30%, 113.0 mL, 1.8 mmol) was added in one portion. The mixture was stined for another 15 min. The mixture was diluted into ethyl acetate (300 mL) and water (300 mL) and the phases were separated. The organic layer was washed with brine and dried over Na₂SO4, filtered, and concentrated in vacuo to afford 29.8 g desired product as white solid: *H NMR (300 MHz. DMSO-î/6) δ 8.53 (d, J » 3.0 Hz, IH), 8.11 (s, IH), 8.00 (dd, J = 8.0, 3.0 Hz, IH), 7.89 (s, IH); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, RT= 1.11 minutes, (M+H) 175.02.

Formation of 2-chloro-5-fluoropyridlne-3-carbonitriie (131a)

To a suspension of 2-chloro-5-fluoropyridine-3-carboxamide, 130a, (29.8 g, 170.4 mmol) in dichloromethane (327 mL) was added triethylamine (52.3 mL, 374.9 mmol). This mixture was cooled down to 0 °C. Trifluoroacetic anhydride (26.1 mL, 187.4 mmol) was added slowly over period of 15 min. The mixture was stirred at 0 °C for 90 min. The mixture was diluted into dichloromethane (300 mL) and the resulting organic phase was washed with aqueous saturated NaHCOj solution (300 mL) and brine (300 mL). The organic layer was dried over Na₂SO«, filtered, concentrated in vacuo. The product was purified by silica gel chromatography (40% to 60% ethyl acetate/hexanes gradient) giving 24.7 g of product as a white solid: *H NMR (300 MHz, CDCIj) δ 8.50 (d, J = 3.0 Hz, IH), 7.77 (dd, J= 6.8, 3.0 Hz, IH); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, Rétention Time « 2.50 minutes, (M+H) 157.06.

Formation of 5-fluoro-lW-pyrazolo(3,4-à|pyridin-3-amlne (132a)

To the mixture of 2-chIoro-5-fluoropyridine-3-carbonitrile, 131a, (29.6 g, 157.1 mmol) in n-butanol (492 mL) was added hydrazine hydrate (76.4 mL, 1.6 mol). This mixture was heated to reflux for 4.5 h and cooled down. n-Butanol was removed under reduced pressure and water (300 mL) was added resulting in a yellow precipitate. The suspension was filtered and washed with water twice, followed by a MTBE wash. The yellow solid was dried in a vacuum oven to give 18 g of the desired product: ’H NMR (300 MHz, DMSO-</6) δ 12.08 (s, IH), 8.38 (dd, J = 2.7,

1.9 Hz, IH), 7.97 (dd, y = 8.8, 2.7 Hz, IH), 5.56 (s, 2H). LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, Rétention Time = 1.25 minutes (M+H)

152.95.

Formation of 3-bromo-5-fluoro-lFApyrazolo|3,4-ÔIpyridine (133a)

To a mixture of 5-fluoro-l/Z-pyrazolo[3,4-&]pyridin-3-amine, 132a, (0.88 g, 5.79 mmol) in bromoform (8.8 mL) was added ferï-butyl nitrite (1.38 mL, 11.57 mmol). This mixture was heated to 61 °C for 1 h and then heated to 90 °C for an additional hour. The mixture was cooled to room température and bromoform was removed

-10817028 under reduced pressure. The resulting crude residue was purified by silica gel chromatography (5-50% ethyl acetate/hexanes) to afïbrd 970 mg of the desired product as a white solid: ^lH NMR (300 MHz, DMSO-J6) δ 14.22 (s, 1H), 8.67 (dd, J = 2.7, 1.9 Hz, 1H), 8.07 (dd, J= 8.2, 2.7 Hz, 1H); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, Cl 8/ACN, RétentionTime = 2.42 minutes (M+H) 216.11.

Formation of 3-bromo-5-fluoro-l-trityl-lJf-pyrazoIoI3,4-5Ipyrldine (134a)

A mixture of 3-bromo-5-fluoro-17/-pyrazolo[3,4-5]pyridine, 133a, (0.97 g, 4.49 mmol) and K2CO3 (1.86 g, 13.47 mmol) in DMF (9.7 mL) was cooled to 0 °C. Chlorodiphenylmethylbenzene (1.38 g, 4.94 mmol) was added. The mixture was stirred at room température ovemight. The mixture was diluted into ethyl acetate (40 mL) and water (30 mL) and the layers were separated. The organic layer was washed with brine, dried over NaiSOi, filtered and concentrated in vacuo. The product was purified by silica gel chromatography (40% ethyl acetate/hexanes) to afford 1.68 g of the desired product as a white solid: H NMR (300 MHz, DMSO-J6) δ 8.45 — 8.38 (m, 1H), 8.04 (dd, J= 8.0, 2.7 Hz, 1H), 7.35 - 7.16 (m, 15H); LCMS Gradient 1090%, 0.1% formic acid, 5 minutes, Cl 8/ACN, Rétention Time = 3.03 minutes (M+H) 459.46.

Formation of 5-fluoro-3-(4,4,5,5-tetramethyl-13,2-dioxaboroIan-2-yI)-l-trityl-l//pyrazoiol3,4-bjpyrldlne (135a)

A solution of 3-bromo-5-fluoro-l-trityl-pyrazolo[3,4-b]pyridine, 134a (3.43 g, 7.48 mmol), KOAc (2.20 g, 22.45 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,S-tétraméthylia,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (2.85 g, 11.23 mmol) in DMF (50 ml) was degassed under a stream of nitrogen for 40 min. To the mixture was added Pd(dppf)iC12 (0.610 g, 0.748 mmol) The reaction mixture was heated at 100 °C for 90 minutes. The reaction mixture was filtered through a pad of Celite. To the resulting filtrate was added ether and brine. The organic phase was dried over MgSO<, filtered and concentrated in vacuo to afford 4.0 g crude product that was used in the next step without further purification (note, the product décomposés if purification is attempted via silica gel chromatography).

Formation of 5-nuoro-3-(4-(methyIthio)pyrlmidin-2-yI)-l-trityI-l£f-pyrazoIo[3,4bjpyridine (136a)

A solution of 2-chloro-4-methylsulfanyl-pyrimidine (0.25 g, 1.56 mmol), K3PO4 (0.99 g, 4.67 mmol) and 5-fluoro-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-ltrityl-lH-pyrazolo[3,4-b]pyridine, 135a, (0.87 g, 1.71 mmol) in water (1 mL) and 2methyltetrahydrofuran (9 mL) was degassed under a stream of nitrogen for 15 minutes. Then, Pd2(dba)î (0.04 g, 0.05 mmol) was added and the mixture was degassed for an additional 2-3 minutes. The vessel was sealed and heated to 95 °C ovemight. After separating the layers, the organic phase was washed with water. The resulting solid was filtered and washed with ether and MeTHF. Filtered through PSA cartridge with MeOH/dichloromethane mixture to give the desired product as a white solid: LCMS Gradient 60-98%, 0.1% formic acid, 7min, C4/ACN, Rétention Time = 2.68 min (M+Na) 526.1.

Formation of 5-fluoro-3-(4-(methyIsuIfinyI)pyrimidin-2-yi)-l-trltyI-17/-pyrazoIoI3,4z*

-10917028 bjpyridlne (137a)

To a cold (0 °C) mixture of 5-fluoro-3-(4-(methylthio)pyrimidin-2-yl)-l-trityI-177pyrazolo[3,4-b]pyridine, 135a, (0.70 g, 1.38 mmol) in dichloromethane (10.4 mL) was added mCPBA (0.43 g, 1.93 mmol). After 30 minutes, the mixture was diluted with dichloromethane and washed with 2N NaOH and brine. The organic phase was brine dried over Na₂SO4, filtered and stripped down twice with CHjCN to afford 660 mg of desired product that was used without further purification: LCMS Gradient 6098%, 0.1% formic acid, 7min, C4/ACN, Rétention Time = 2.68 minutes (M+H) 520.

(Æ)-3-((2-(5-fluoro-l-trityl-177-pyrazoloI3,4-b]pyrid!n-3-yl)pyr!m!dîn-4-yl)amlno)-4,4dimethylpentanoic acid (138a).

A stirred suspension of 5-fluoro-3-(4-(methylsulfinyl)pyrimidin-2-yl)-l-trityl-l/7indazole, 137a, (0.09 g, 0.18 mmol), (3/î)-3-amino-4,4-dimethyl-pentanoic acid (0.05 g, 0.36 mmol) and Na₂COj (0.76 g, 0.72 mmol) in acetonitrile (0.62 mL) and 2MeTHF (0.31 mL) was heated to 125 °C in microwave reactor for 1 hour. After cooling to room température, the mixture was diluted with EtOAc, neutralized with HCl (0.72 mL of 2 M solution, 1.42 mmol) and the product was extracted with several portions of EtOAc and CH₂CI₂. Evaporation of the combined organic phases provided 109 mg of the desired crude product which was used in the next reaction without further purification: LCMS Gradient 10-90%, 0.1% trifluoroacetic acid, 5 minutes, C18/ACN, Rétention Time = 3.08 minutes (M+H) 601.05.

(R)-3-((2-(5-fluoro-17Z-pyrazoioI3,4-b[pyridÎn-3-yl)pyrimidin-4-yl)amino)-4,4dlmethylpentanolc acid (48)

To a solution of crude (Æ)-3-((2-(5-fluoro-l-trityl-177-pyrazolo[3,4-b]pyridin-3yl)pyrimidin-4-yl)amino)-4,4-dimethylpentanoic acid, 138a, (0.11 g, 0.21 mmol) in CH₂CI₂ was added triethylsilane (0.15 mL, 0.94 mmol) followed by trifluoroacetic acid (0.15 mL, 1.95 mmol). After stirring the resulting solution at room température for 1 hour, the reaction mixture was kept below 5 °C ovemight (refrigerator). The mixture was then allowed to warm to room température and kept at that température for an additional 5 hours. The solution was diluted with toluène and concentrated in vacuo. Trituration with Et₂O followed by préparative HPLC purification provided 15 mg of the desired product as the TFA sait. Ή NMR indicated a 3 to 1 mixture of atropisomers: ’H NMR (400 MHz, MeOD, major isomer) δ 8.63 - 8.45 (m, 2H), 7,96 (d, J = 7.3 Hz, 2H), 6.66 (d, J = 7.3 Hz, 2H), 4.95 (d, J = 10.6 Hz, 2H), 2.84 (dd, J15.4, 2.4 Hz, 2H), 2.44 (dd, J= 15.9, 10.7 Hz, 2H), 0.98 (s, 9H); LCMS Gradient 1090%, 0.1% trifluoroacetic acid, 5 minutes, C18/ACN, Rétention Time = 2.12 minutes (M+H) 359.02.

Préparation of Compound 42

Synthetic Scheme 21

-11017028

F

c	/=( %-OEt	/=( °V-OH NC-C ^Nlt>
	W “O	T)
	^N H 145a	^N n 42

2-chloro-5,6-difluoropyridine-3-carbonitrile, Et₃N, THF, EtOH; (b) 5-fluoro-l-(p-tolylsulfonyl)-3(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)pyrrolo[2,3-b]pyridine, 7a, X-phos, Pd₂(dba)₃, K₃PO₄, 2-methyl THF, H₂O, 130 °C; c) NaOMe, THF; d) LiOH, THF, H₂O.

Formation of (R)-ethyl 3-(6-chloro-5-cyano-3-fluoropyridln-2-ylamlno)-3-(lmethylcyclopentyl)propanoate (143a)

To a solution of racemic ethyl 3-amino-3-(l-methylcyclopentyl)propanoate, 33a, (0.40 g, 2.01 mmol) and 2,6-dichloro-5-fluoro-pyridine-3-carbonitrile (0.46 g, 2.41 mmol) in THF (20 mL) was added triethylamine (0.67 mL, 4.82 mmol). The reaction mixture was stirred at 90 °C in a pressure tube for 18 hours. The reaction mixture was filtered and the resulting filtrate was concentrated in vacuo. The product was purified by silica gel chromatography f25%EtOAc/Hexanes) to afford 380 mg of the desired product as a racemic mixture: H NMR (400 MHz, CDC1₃) δ 7.31 (d, J- 9.7 Hz, IH), 5.56 (d, 8.9 Hz, IH), 4.68 (td, 9.6, 3.6 Hz, IH), 4.07 (q, J= 7.1 Hz,

2H), 2.68 (dd, J= 14.8,3.7 Hz, IH), 2.46 (dd, J= 14.8, 9.3 Hz, IH), 1.77 - 1.62 (m, 4H), 1.61 - 1.49 (m, 2H), 1.47 - 1.37 (m, IH), 1.35 - 1.26 (m, IH), 1.19 (t, J = 7.1 Hz, 3H), 1.01 (s, 3H); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, Rétention Time = 3.81 minutes (M+H) 354.98. The racemic mixture was submitted to SFC chiral séparation to give the individual enantiomers, 143a and 143b. The (R)-enantiomer, 143a, was taken forward into the next synthetic step.

Formation of (Æ)-ethyl 3-(5-cyano-3-fluoro-6-(5-nuoro-l-tosyI-117-pyrroIo[2,3b]pyridIn-3-yI)pyridIn-2-ylamIno)-3-(l-methyIcycIopentyI)propanoate (144a)

A solution of 5-fluoro-l-(p-toIylsulfonyl)-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2yl)pyrrolo[2,3-b]pyridine, 7a, (0.155 g, 0.373 mmol), racemic ethyl 3-[(6-chloro-5-cyano-3fluoro-2-pyridyl)amino]-3-(l-methylcyclopentyl)propanoate, 143a, (0.120 g, 0.339 mmol) and K₃rô₄ (0.288 g, 1.357 mmol) in 2-methyl THF (10.0 mL) and H₂O (0.24 mL) was degassed under a stream of nitrogen for 30 minutes. To the mixture was added X-phos (0.020 g, 0.041 mmol) and Pd₂(dba)₃ (0.008 g, 0.008 mmol). The réaction mixture was stirred at 130 °C in a pressure tube for 45 minutes. The organic phase was filtered through a

-11117028 pad of celite and concentrated in vacuo. The resulting crude material was purified by silica gel chromatography (30% EtOAc/Hexanes) to afford 150 mg of the desired product: ‘H NMR (400 MHz, CDClj) δ 8.67 (s, 1H), 8.44 (dt, 15.3, 7.7 Hz, 1H), 8.37 (d, J = 1.5 Hz, 1H), 8.13 (t, J “7.6 Hz, 2H), 7.41 (d,J“ 10.3 Hz, IH), 7.32 (d, J“ 7.5 Hz, 2H), 5.38 (t, J=

9.7 Hz, 1H), 4.89 (td, 10.1, 3.3 Hz, 1H), 4.02-3.91 (m, 2H), 2.74 (dd, J= 15.1, 3.5 Hz, 1H), 2.52 (dd, J= 15.1, 10.2 Hz, 1H), 2.40 (s, 3H), 1.61 (ddt, J= 32.0, 20.7, 7.7 Hz, 7H),

1.49 - 1.30 (m, 3H), 1.27 (t, J= 7.1 Hz, 3H), 1.08 - 0.97 (m, 3H). LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, Rétention Time « 4.22 min (M+H) 608.29.

Formation of (ZQ-methyl 3-(5-cyano-3-fluoro-6-(5-fluoro-l//-pyrroio[23-b]pyridin-3yl)pyridin-2-yIamino)-3-(l-methylcyciopentyI)propanoate (145a)

To a solution of racemic ethyl 3-(5-cyano-3-fluoro-6-(5-fluoro-l-tosyi-lHpyrrolo[2,3-b]pyridin-3-yl)pyridin-2-ylamino)-3-(l-methylcyclopentyl)propanoate, 144a, (0.150 g, 0.247 mmol) in THF (20 mL) was added sodium methoxide (0.053 mL of 25% wt solution in MeOH, 0.247 mmol). The réaction mixture was stirred at room température for 5 minutes. The reaction mixture was diluted with aqueous saturated NaHCOj solution and EtOAc. The organic phase was dried over MgSO<, filtered and concentrated in vacuo. The product was purified by silica gel chromatography (40% EtOAc/Hexanes) to afford 90 mg of the desired product as a mixture of ethyl and methyi esters. The mixture was taken onto the next step without further purification: *H NMR (400 MHz, CDClj) δ 10.18 (s, 1H), 8.65 (dd, J = 9.6,

2.5 Hz, 1H), 8.48 (d, J= 2.8 Hz, 1H), 8.32 (s, 1H), 7.37 (t, J“ 14.1 Hz, iH), 5.38 (d, J= 7.9 Hz, 1H), 5.02 (td, J= 9.8,3.5 Hz, 1H), 3.54 (s, 3H), 2.80 (dt, J= 15.8,7.9 Hz, 1H), 2.57 (dd, J- 14.9, 9.8 Hz, 1H), 1.80 - 1.57 (m, 7H), 1.43 (ddd, J = 24.5, 14.1, 6.0 Hz, 3H), 1.08 (s, 3H); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, Rétention Time “ 3.60 minutes (M+H) 440.26.

Formation of (R)-3-(5-cyano-3-fluoro-6-(5-fluoro-l//-pyrroIo[23-b]pyridin-3y])pyridin-2-yIamino)-3-(l-methyIcyclopentyl)propanoic acid (42)

To a solution of racemic methyi 3-(5-cyano-3-fluoro-6-(5-fluoro-lW-pyrrolo[2,3-b]pyridin-3yl)pyridin-2-ylamino)-3-(l-methylcyclopentyl)propanoate, 145a, (0.090 g, 0.204 mmol) in THF (30 mL) was added a solution of lithium hydroxide (0.035 g, 0.819 mmol) in H2O (10 mL). The reaction mixture was stirred at 70 °C ovemight. The organic phase was removed under reduced pressure and the resulting residue was purified by preparatory HPLC. The appropriate HPLC fractions were extracted with EtOAc, and the solvent was removed under reduced pressure: ^lHNMR(400 MHz, MeOD) δ 8.64 (dd, J= 8.4,2.4 Hz, 1H), 8.57 (s, IH),

8.24 (d, J“ 4.4 Hz, IH), 5.19 (d, J= 8.7 Hz, IH), 2.78 (qd, J= 15.9, 6.6 Hz,2H), 1.85 - 1.57 (m, 6H), 1.48 (dd, J- 11.8, 6.0 Hz, IH), 1.36 (dt, 12.0, 6.0 Hz, IH), 1.11 (s, 3H); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, CI8/ACN, Rétention Time = 3.21 minutes (M+H) 426.25.

Préparation of Compounds 5, 6 and 12

Synthetic Scheme 22

-11217028

EtjN, THF, EtOH; (b) 5-fluoro-3-(4,4,5,5tetramethyl-1,3,2-di oxaborolan-2-yl)-1 -trityl-1 H· pyrazolo[3,4-b]pyridine, 135a, X-phos, Pd₂(dba)₃, K₃PO₄,2-methyl THF, H₂0,135 °C; (c) Et₃SiH, TFA, CH₂C1₂; (d) LiOH, THF, H₂O.

Formation of (+/-)-ethyl 3-(2-chloro-5-fluoropyrlmldln-4-ylamlno)-3-(lmethylcyclopentyl)propanoate (147a)

To a solution of 2,4-dichloro-5-fluoro-pyrimidine (0.184 g, 1.100 mmol) and racemic ethyl 3-amino-3-(l-methylcyclopentyi)propanoate, 33a, (0.199 g, 1.000 mmol) in THF (10 mL) and éthanol (1 mL) was added triethylamine (0.307 mL, 2.200 mmol). The reaction mixture was stirred at 70 °C for 5 hours. The mixture was fîltered and the filtrate was concentrated in vacuo. The resulting residue was purified via silica gel chromatography (25%EtOAc/Hexanes) to afford 180 mg of the desired product: Ή NMR (400 MHz, CDCIj) δ 7.88 (d, J = 2.7 Hz, 1H), 5.54 (d, J = 9.2 Hz, 1H),4.74 - 4.54 (m, 1H), 4.08 (q, J= 7.2 Hz, 2H), 2.68 (dd, J= 14.8,3.7 Hz, 1H), 2.46 (dd, 14.8, 9.3 Hz, 1H), 1.69 (dd, J= 12.8, 8.8 Hz, 4H), 1.63 - 1.50 (m, 2H), 1.46 - 1.38 (m, 1H), 1.37 - 1.23 (m, 1H), 1.23-1.14 (m, 3H), 1.00 (s, 3H). LCMS Gradient 1090%, 0.1% formic acid, 5 minutes, C18/ACN, Rétention Time = 3.54 minutes (M+H) 330.17.

Formation of (+/-)-ethyI 3-(5-fluoro-2-(5-fluoro-l-trltyl-l£f-pyrazoIo[3,4-b]pyrldin-3yl)pyrimldln-4-yIamino)-3-(l-methylcyclopentyI)propanoate(148a)

A solution of K₃PO₄ (0.464 g, 2.183 mmol), racemic ethyl 3-[(2-chloro-5-fluoro-pyrimidin4-yl)amino]-3-(l-methylcyclopentyl)propanoatc, 147a, (0.180 g, 0.546 mmol) and 5-fluoro3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l-trityl-pyrazolo[3,4-b]pyridine, 135a, (303.4 mg, 0.6004 mmol) in 2-Methyl THF (3.240 mL) and H₂O (0.360 mL) was degassed under a stream of nitrogen for 30 minutes. To this mixture was added X-phos (0.031 g, 0.066 mmol) and Pd₂(dba)₃ (0.013 g, 0.014 mmol). The reaction mixture was stirred at 135 °C in a pressure tube for 1 hour. The organic phase was filtcred through a pad of celite and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (30% EtOAc/Hexanes) to afford 240 mg of the desired product: ^lH NMR (400 MHz, CDC1₃) δ

8.55 (dd, J= 8.5,2.7 Hz, 1H), 8.15 (d, J = 2.4 Hz, 2H), 7.27 (dd, J= 11.0, 5.0 Hz, 15H), 5.38

-11317028 (d, J = 9.7 Hz, 1H), 4.89 (dd, J = 9.7, 6.0 Hz, 1H), 3.99 (q, J = 7.1 Hz, 2H), 2.73 (dd, J = 14.7, 3.8 Hz, 1H), 2.52 (dd, J= 14.8, 9.4 Hz, IH), 1.68 (dd, 12.0, 6.6 Hz, 2H), 1.64 1.52 (m, 4H), 1.47 - 1.36 (m, 1H), 1.30 (dt, J= 14.3, 7.2 Hz, 2H), l.ll - 0.99 (m, 4H). LCMS Gradient 60-98%, formic acid, 7 minutes, C18/can, Rétention Time = 3.24 minutes (M+H) 672.85.

Formation of (+/-)-ethyl 3-(5-fluoro-2-(5-fluoro-l//-pyrazolo[3,4-b]pyrldln-3yl)pyrimidin-4-ylamino)-3-(l-methylcyclopentyl)propanoate (149a)

To a solution of racemic ethyl 3-[[5-fluoro-2-(5-fluoro-l-trityl-pyrazolo[3,4b]pyridin-3-yl)pyrimidin-4-yl]amino]-3-(l-methyIcycIopentyi)propanoate, 148a, (0.240 g, 0.357 mmol) in dichloromethane (20 mL) was added triethylsilane (0.285 mL, 1.784 mmol) followed by trifluoroacetic acid (0.275 mL, 3.567 mmol). The reaction mixture was stîrred at room température ovemight. The reaction mixture was concentrated in vacuo and the resulting crude residue was purified by silica gel chromatography (5% MeOH/CH₂Ci₂) to afiord the desired product: *H NMR (400 MHz, CDCij) δ 11.80 (s, 2H), 8.59 (d, J = 12.3 Hz, 2H), 8.48 (d, J= 7.9 Hz, IH), 6.60 (d, J= 8.3 Hz, IH), 5.07 (s, 1H), 4.09 (q, J= 7.0 Hz, 2H), 2.97 - 2.59 (m, 2H), 1.70 (dd, J ~ 27.7, 13.9 Hz, 6H), 1.57- 1.33 (m, 2H), 1.16 (dd, 18.1, 11.1 Hz, 6H); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, Rétention Time = 2.97 minutes (M+H) 431.24.

Formation of (+/-)-3-(5-fluoro-2-(5-fluoro-lZ/-pyrazolo[3,4-b]pyridln-3-yl)pyrlmldin-4ylamlno)-3-(l-methylcyclopentyl)propanoic acid (12)

To a solution of racemic ethyl 3-[[5-fluoro-2-(5-fluoro-l//-pyrazolo[3,4-b]pyridin-3yl)pyrimidin-4-yI]amino]-3-(l-methyicycIopentyl)propanoate, 149a, (0.110 g, 0.256 mmol) in THF (30 mL) was added a solution of lithium hydroxide hydrate (0.043g, 1.022 mmol) in H₂O (20 mL). The reaction mixture was stîrred at 70 °C ovemight. The organic solvent was removed under reduced pressure and the remaining aqueous phase was used directiy in the purification via preparatory HPLC. The resulting HPLC fractions were extracted with EtOAc. The organic phase was dried over MgSO₄, filtered and the solvent was removed under reduced pressure to afford the desired product: *H NMR (400 MHz, MeOD) δ 8.64 (dd, J = 8.4, 2.4 Hz, IH), 8.57 (s, IH), 8.24 (d, J = 4.4 Hz, IH), 5.19 (d, J = 8.7 Hz, IH), 2.78 (qd, 15.9, 6.6 Hz,

2H), 1.85 - 1.57 (m, 6H), 1.48 (dd, J= 11.8, 6.0 Hz, IH), 1.36 (dt, 12.0, 6.0 Hz,

IH), 1.11 (s, 3H). LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, Rétention Time = 2.37 min, (M+H) 403.22.

The following compounds can be prepared in a similar fashion as the procedure described above for Compound 12:

N

-11417028 (R)-3-((5-fluoro-2-(5-fluoro-lW-pyrazolo[3,4-b]pyridin-3-yl)pyrim!din-4-y!)amino)-4,4dimethylpentanolc acid (5)

Compound 5 was synthesized in a manner similar to compound 12, starting with compound 6a: *H NMR (400 MHz, c/6-DMSO) δ 12.65 (s, IH), 9.43 (s, IH), 9.15 (s, IH), 8.44 (d, J - 4.7 Hz, IH), 8.41 - 8.29 (m, 2H), 3.93 (s, IH), 3.54 (s, IH), 1.19 (d, 20.0 Hz, 9H); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, CI8/ACN, Rétention Time = 2.70 min, (M+H) 393.32.

(R)-3-((3,5-difluoro-6-(5-fluoro-l//-pyrazo!oI3,4-b]pyridin-3-yI)pyridin-2-yl)amino)-4,4dimethylpentanolc acid (6)

Compound 6 was synthesized in a manner similar to compound 12, utilizing (R)-ethyl 3-((6-bromo-3,5-difluoropyridin-2-yl)amino)-4,4-dimethylpentanoate as the intermediate for the Suzuki coupling. (R)-ethyl 3-((6-bromo-3,5-difluoropyridin-2yl)amino)-4,4-dimethyl-pentanoate was prepared in the same fashion as intermediate, 143a, utilizing 2-bromo-3,5,6-trifluoropyridine as the starting material instead of 2chloro-5,6-difluoropyridine-3-caibonitrile: *H NMR (400 MHz, CDClj) δ 8.31 (d, J=

6.4 Hz, IH), 8.06 (s, IH), 7.06 (t, 9.7 Hz, IH), 4.58 (s, 2H), 2.80 (d, 13.2 Hz,

IH), 2.29 (dd, J = 13.3, 8.7 Hz, IH), 0.98 (s, 9H).; LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, Rétention Time = 2.92 min, (M+H) 394.19.

(Æ)-3-((2-(5-ch!oro-l£f-pyrazolo]3,4-b]pyridln-3-yl)-5-fluoropyrimidin-4-yl)amino)-4,4dimethylpentanolc acid (97) and methylester (96)

Compounds 96 and 97 were synthesized in a manner similar to compound 12, starting with compound 6a; ^lH NMR (300 MHz, MeOD) for Compound 97: δ 8.95 (d, J = 2.3 Hz, IH), 8.66 (d, J«= 2.3 Hz, IH), 8.35 (d, J= 5.2 Hz, IH), 5.12 (dd, J= 10.7,2.9 Hz, !H), 2.93 (dd, J= 16.5, 2.9 Hz, IH), 2.73 (dd, 16.4, 10.7 Hz, IH), 1.10 (s, 9H); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, Rétention Time = 2.79 min, (M+H) 407.37.

Préparation of Compounds 54, 56 and 53

Synthetic Scheme 23

-11517028

tert-butylhydrazine-HCl, EtjN, THF, EtOH; (b) 2bromoethyl acetate, KjCOj, CHjCN; (c) 3-(4,4,5,5tetramethyl-1,3,2-dioxaboroIan-2-yI)-1 -tosyl-5(trifluoromethyl)-l//-pyrrolo[2,3-b]pyridine, 153a, Xphos, Pd₂(dba)j, KjPO₄, THF, H₂O; (d) TBAF/THF; (e) LiOH, H₂O, THF.

Formation of 4-(2-tert-butylhydrazlnyl)-2-chloro-5-nuoropyrlmIdine (151a)

To a solution of 2,4-dichloro-5-fluoro-pyrimidine (1.84 g, II.00 mmol) and tertbutylhydrazine hydrochloride (1.25 g, 10.00 mmol) in THF (50 mL) and EtOH (5 mL) was added triethylamine (4.18 mL, 30.00 mmol). The reaction mixture was stirred at room température ovemight. The reaction mixture was filtered to remove triethylamine HCl sait and the filtrate concentrated in vacuo. The resulting residue was purified by silica gel chromatography (EtOAc/Hexanes) to afford I.7g of the desired product: *H NMR (400 MHz, CDClj) δ 7.82 (d, J= 2.8 Hz, IH), 6.47 (s, 1H), 4.60 (d, J= 5.8 Hz, IH), 1.09 (s, 9H). LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, Cl8/ACN, Rétention Time = 2.19 minutes (M+H) 218.81.

Formation of ethyl 2-(l-fert-butyl-2-(2-chIoro-5-fluoropyrimIdin-4yl)hydrazinyl)ethanoate (152a)

To a suspension of 4-(2-fôrt-butylhydrazinyI)-2-ch!oro-5-fluoropyrimidine, 151a, (1.50 g,

6.86 mmol) in acetonitrile (68 mL) was added 2-bromoethyl acetate (0.84 mL, 7.55 mmol) and K₂COj (2.28 g, 16.46 mmol). The reaction mixture was stirred at room température ovemight. The mixture was diluted into EtOAc and brine. The organic phase was dried over

MgSO<, filtered and concentrated in vacuo. The residue was purified by silica gel

-11617028 chromatography (30%EtOAc/Hexanes) to afford 1 g of the desired product: *H NMR (400 MHz, CDCIj) δ 7.96 (d, J= 3.1 Hz, IH), 4.16 (dt, 7 = 7.1, 5.9 Hz, 2H), 3.74 (s, 2H), 1.30 1,23 (m, 3H), 1.20 (s, 9H). LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, Rétention Time = 2.69 minutes (M+H) 305.09.

Formation of ethyl 2-(l-teri-butyl-2-(5-fluoro-2-(l-tosyl-5-(trifluoromethyl)-lHpyrrolo[23-b]pyridin-3-yl)pyrimidin-4-yl)hydrazinyi)ethanoate (154a)

Boronate ester, 153a, was prepared in same fashion as boronate ester, 7a, (see Synthetic Scheme 4) using 3-bromo-5-(trifluoromethyl)-177-pyrrolo[2,3-b]pyridine instead of 3-bromo-5-fluoro- 17/-pyrrolo[2,3-b]pyridine.

A solution of l-(p-tolylsuifonyl)-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-5(trifluoromethyl)pyrro!o[2,3-b]pyridine, 153a, (0.551 g, 1.181 mmol), ethyl 2-(l-terAbutyl-2(2-chloro-5-fluoropyrimidin-4-yl)hydrazinyl)ethanoate, 152a, (0.300 g, 0.984 mmol) and K3PO4 (0.627 g, 2.953 mmol) in 2-MethylTHF (26 mL) and H2O (5 mL) was degassed under a stream of nitrogen for 45 minutes. To the reaction mixture was added X-phos (0.056 g, 0.118 mmol) and Pd₂(dba)₃ (0.022 g, 0.025 mmol). The reaction mixture was heated at 120 °C for 75 minutes. The aqueous phase was removed and the organic phase was filtered through a pad of celite, concentrated in vacuo and purified by silica gel chromatography (30% EtOAc/Hexanes) to afford 540 mg ofthe desired product: *H NMR (400 MHz, CDCI3) δ 9.49 (s, IH), 8.71 (t,7=7.0 Hz, 1 H), 8.63 (d,7= 11.1 Hz, iH), 8.16-8.11 (m, 3H), 7.31 (d, 7= 8.2 Hz, 2H), 7.11 (d, 7= 21.4 Hz, IH), 4.10 (dd, 7= 13.4, 6.3 Hz, 2H), 3.79 (s, 2H), 2.39 (s, 3H), 1.24 (s, 9H), 1.17 (t, 7= 7.1 Hz, 3H); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, Rétention Time = 4.18 minutes (M+H) 609.37.

Formation of ethyl 2-(l-(teri-butyl)-2-(5-fluoro-2-(5-(trifluoroinethyl)-l/f-pyrrolo[2,3b] py rI di n-3-yl) py ri ml din-4-yl) hy d razi ny l)acetate ( 155a)

To a solution of. ethyl 2-(l-rer/-butyl-2-(5-fluoro-2-(l-tosyl-5-(trifluoromethyl)-17/· pyrrolo[2,3-b]pyridin-3-y!)pyrimidin-4-yl)hydrazinyl)ethanoate, 154a, (0.54 g, 0.89 mmol) in THF (20 mL) was added tetrabutylammonium fluoride (i .78 mL of 1 M, 1.78 mmol). The reaction mixture was stirred at room température for 30 minutes. The reaction mixture was diluted into EtOAc and brine. The organic phase was dried over MgSO«, filtered and concentrated in vacuo. The resulting residue was purified via silica gel chromatography (70%EtOAc/Hexanes) to afford 300 mg of the desired product *H NMR (400 MHz, CDCIj) δ 10.59 (s, IH), 9.55 (s, IH), 8.66 (s, IH), 8.29 (d,7= 2.2 Hz, IH), 8.13 (dd,7= 3.8,1.5 Hz, IH), 7.14 (s, IH), 4.20 - 4.04 (m, 2H), 3.85 (s, 2H), 1.28 (d, J = 9.1 Hz, 9H), 1.19 (dt, 7 =

7.1, 3.6 Hz, 3H). LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, CI8/ACN, Rétention Time = 2.93 min, (M+H) 455.43.

Formation of2-(l-(/erf-butyl)-2-(5-fluoro-2-(5-(trifluoroinethyl)-lZi»pyrrolo[2,3b]pyridin-3-yl)pyrimidin-4-yl)hydrazinyl)acetlc acid (54)

To a solution of ethyl 2-[terAbutyl-[[5-fluoro-2-[5-(trifluoromethyl)-l//-pyiTo!o[2,3b]pyridin-3-yl]pyrimidin-4-y!]amino]amino]acetate, 155a, (0.200 g, 0.440 mmol) in THF (40 mL) was added a solution of lithium hydroxide hydrate (0.074 g, i.760 mmol) in H₂O (4 mL). The reaction mixture was stirred at room température ovemight. The reaction mixture concentrated in vacuo to remove the THF. The remaining aqueous phase was diluted to 8 mL and the solution was used directly in a preparatory HPLC. The product precipicated when the fraction was concentrated on rotavaporator. The solid was filtered and dried in

-11717028 desiccator with P2O5 to afford 120mg of the desired product: ’H NMR (400 MHz, d6DMSO) δ 12.65 (s, 1H), 12.41 (s, IH), 9.28 (s, 1H), 8.86 (s, 1H), 8.65 (s, 1H), 8.30 (d, J =

3.5 Hz, 2H), 3.97-3.70 (m, 1H), 3.51 (s, 1H), 1.18 (s, 9H); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, Rétention Time = 2.92 min, (M+H) 427.40

The following compounds can be prepared in a similar fashion as the procedure described above for Compound 54:

Formation of 2-(l-(tert-butyl)-2-(2-(5-chloro-lH-pyrroIoI2,3-ô]pyridln-3-yI)-5fluoropyrimidîn-4-yl)hydrazinyl)acetic acid-TFA (trifluoro acetic acid) sait (56) ’H NMR (400 MHz, J6-DMSO) δ 12.65 (s, 1H), 9.43 (s, 1H), 9.15 (s, 1H), 8.44 (d, J » 4.7 Hz, 1H), 8.41 - 8.29 (m, 2H), 3.93 (s, 1H), 3.54 (s, 1H), 1.19 (d, 20.0 Hz,

9H); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, Rétention Time = 2.70 min, (M+H) 393.32.

F

Formation of 2-(l-(tert-butyI)-2-(5-fluoro-2-(5-fluoro-lH-pyrroIo[2,3-b]pyridin-3yl)pyrimidin-4-yl)hydrazlnyI)acetic acid- TFA sait (53) 'H NMR (400 MHz, </6-DMSO) δ 12.57 (s, 1H), 9.40 (s, 1H), 8.88 (s, IH), 8.40 (d, J = 18.7 Hz, 2H), 8.34 (s, IH), 3.93 (s, IH), 3.52 (s, IH), 1.20 (s, 9H); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, Rétention Time = 2.50 min, (M+H) 377.42.

Préparation of Compounds 7, 8, and 18

Synthetic Scheme 24

-i 1817028

F

27a

159a 18

2,6-dichloro-5-fluoro-pyridine-3-carbonitrile, EtjN, acetonitrile; (b) 5-fluoro-l-(p-tolylsulfonyl)-3(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yt)pyrroto[2,3-b]pyridine, 7a, Pd₂(dba)3, X-Phos, K3PO4,2-MeTHF, H₂O, 125 °C; (c) LiOH, THF, H₂O

Formation of ethyi 3-[(6-chloro-5-cyano-3-fluoro-2-pyrldyi)amino]-4,4-dimethyihexanoate(158a)

A solution of ethyi 3-amino-4,4-dimethyl-hexanoate, 27a, (0.24 g, 1.28 mmol), 2,6dichloro-5-fluoro-pyridine-3-carbonitrile (0.29 g, 1.53 mmol) and EtjN (0.43 mL, 3.07 mmol) in acetonitrile (4.8 mL) was stirred at 70 °C ovemight. The reaction mixture was concentrated in vacuo and purified by silica gel chromatography (1040% EtOAc/Hexanes gradient) to provide 205 mg of ethyi 3-[(6-chtoro-5-cyano-3fluoro-2-pyridyl)amino]-4,4-dimethyl-hexanoate; LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, Rétention Time « 3.75 minutes (M+H) 342.04.

Formation of ethyi 3-[[5-cyano-3-fluoro-6-15-fluoro-l-(p-tolylsulfonyl)pyrrolo[23’ b]pyrldin-3-yl|-2-pyridyl]amino]-4,4-dîmethyl-hexanoate(159a)

A solution of ethyi 3-[(6-chloro-5-cyano-3-fluoro-2-pyridyl)amino]-4,4-dimethylhexanoate, 158a, (0.21 g, 0.600 mmol) , 5-fluoro-l-(p-tolylsulfonyl)-3-(4,4,5,5tetramethyl- 1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine, 7a, (0.30 g, 0.72 mmol) and K3PO4 (0.51 g, 2.40 mmol) in 2-methyl THF (20.5 mL) and H₂O (2.7 mL) was degassed for 45 minutes and treated with X-phos (0.03 g, 0.07 mmol) and Pd₂(dba)₂(0.01 g, 0.02 mmol). The reaction vessel was sealed and heated to 125 °C for 90 minutes. After cooting to room température, the aqueous phase was removed and the organic phase was filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (0-40% EtOAc/Hexanes gradient) to provide 270 mg of the desired product: ^lH NMR (400 MHz, CDCIj) δ 8.69 (s, IH), 8.51 (dd, J= 9.1,2.7 Hz, iH), 8.37 (d, J- 1.8 Hz, 1H), 8.15 (d, 8.4 Hz, 2H), 7.41 (d, 10.3 Hz, 1H),

7.33 (d, J= 8.1 Hz, 2H), 5.28 - 5.22 (m, IH), 4.92 (td, 10.4, 3.2 Hz, IH), 4.03 3.91 (m, 2H), 2.75 (dd, J= 14.9,3.5 Hz, IH), 2.45 (dd, J= 12.6, 8.2 Hz, IH), 2.40 (s,

4.7 Hz, 3H), 1.36 (q, J= 7.4 Hz, 2H), 1.01 (t, 7.1 Hz, 3H), 0.92 (d, J= 8.8 Hz,

-11917028

6H), 0.88 (t,J = 7.5 Hz, 3H). LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, Cl 8/ACN, Rétention Time = 2.86 minutes (M+H) 596.02.

Forma tion of 3-1 (5-cya n o-3-fl uoro-6- (5-fluoro-1 W-py rrolo 123-bJ py ri dl n-3-y l)-2pyridyl|aminoI-4,4-dimethyl-hexanoic acid (18)

Ethyl 3-[[5-cyano-3-fluoro-6-[5-fluoro-l-(p-tolyisulfonyl)pyrrolo[2,3-b]pyridin-3-yl]2-pyridyl]amino]-4,4-dimethyl-hexanoate, 159a, (0.27 g, 0.45 mmol) was dissolved in THF (7 mL) and treated with LiOH (4.50 mL of 1 M, 4.50 mmol). The reaction mixture was heated to 70 °C for 10 hours. After cooling to room température, water (20 mL) and ethyl acetate (20 mL) were added and the layers were separated. The aqueous layer was brought to a neutral pH by addition of IN HCl, and the resulting precipitate was collected by filtration, washed with water and concentrated in vacuo to provide 77 mg of the desired product: *H NMR (400 MHz, DMSO-rfd) δ 12.37 (s, 1H), 12.12 (s, 1H), 8.75 (d, J = 9.9 Hz, 1H), 8.32 (s, 2H), 7.83 (d, J= 11.4 Hz, 1H), 7.48 (d, J= 9.5 Hz, 1H), 5.00 (t, 9.1 Hz, 1H), 2.71 - 2.54 (m, 2H), 1.30 (d, J= 7.4

Hz, 2H), 0.80 (t, J = 18.7 Hz, 9H); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, Rétention Time =3.14 minutes (M+H) 414.31.

The following compounds can be prepared in a similar fashion as the procedure described above for Compound 18:

F

Formation of (/y-3-(5-cyano-3-fluoro-6-(5-fluoro-lf7-pyrroiol23-b]pyridin-3yl)pyridin ’H NMR (400 MHz, MeOD) Ô 8.81 (dd, J= 9.8, 2.7 Hz, 1H), 8.36 (s, 1H), 8.20 (s, 1H), 7.53 (d,J= 11.0 Hz, 1 H), 5.04 (d, J = 8.7 Hz, 1H), 2.80 (dd, J= 15.2,2.5 Hz, 1H), 2.59 (dd, J= 15.0, 11.0 Hz, 1H), 0.99 (s, 9H); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, Cl 8/ACN, Rétention Time = 3.0 minutes (M+H) 400.39.

π 8

Formation of (Æ)-3-(5-cyano-3-nuoro-6-(5-fluoro-lf7-pyrrolo|2,3-b]pyridin-3yl)pyridin-2-ylamlno)-3-(l-methylcyclopentyl)propanoic acid (8) ’H NMR (300 MHz, CDClj) δ 10.70 (s, 1H), 8.42 (dd, J= 9.6, 2.6 Hz, 1H), 8.05 (s, 1H), 7.73 (s, 1H), 7.40 (t, 8.4 Hz, 1H), 5.32 (d, J= 6.6 Hz, 1H), 4.83 (t, J= 9.4 Hz, 1H), 2.89 (d, J= 5.3 Hz, 1H), 2.34 (dd, J= 12.8,9.6 Hz, 1H), 1.92-1.37 (m, 8H), 1.32 - 1.24 (m, 1H), 1.20 - 1.06 (m, 3H); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, Ci8/ACN,

-120-

Rétention Time = 3.27 minutes (M+H) 426.31.

Préparation of Compound 55

Synthetîc Scheme 25

(i) NHj, HBTU, THF, (iî) 2N LiOH, MeOH; (b) TF AA, pyridine; (c) BujSnNj, dioxane, 130 °C;

Formation of (+/-)-3-(5-fluoro-2-(5-fluoro-l/7-pyrroIo[2,3-6]pyridin-3-yî)pyrimidin-4yIamino)-4,4-dîmethy!pentanamîde (164a)

To a solution of racemic 3-(5-fluoro-2-(5-fluoro-l-tosyl-i/7-pyrrolo[2,3-Z>]pyridin-3yl)pyrimidin-4-ylamino)-4,4-dimethylpentanoic acid, 163a, (0.50 g, 0.94 mmol) in 15 mL of THF was added HBTU (0.36 g, 0.95 mmol). The reaction was stirred for 15 minutes and then ammonia gas was bubbled through for 5 minutes. The reaction was allowed to stir for 12 hours and then concentrated to dryness. The residue was 25 redissolved in 20 mL of MeOH and treated with 3 mL of 2N LiOH. The reaction was warmed to 60 °C for 3 hours and then concentrated to dryness. The residue was purifîed by silica gel chromatography (EtOAc) to afford 250 mg of desired product: LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, Rétention Time = 1.78 minutes (M+H) 375.45.

Formation of (+/-)-3-(5-iluoro-2-(5-fluoro-lZf-pyrroio[23-6|pyrWin*3-y!)pyrimidln-4yiam!no)-4,4-dimethyipentanenitriie (165a)

A solution of racemic 3-(5-fluoro-2-(5-fluoro-U7-pyrrolo[2,3-i>]pyridin-335 yl)pyrimidin-4-ylamino)-4,4-dimethylpentanamide, 164a, (0.250 g, 0.668 mmol) in pyridine was cooled to 0 °C and treated with trifluoroacetic acid anhydride (0.278 mL, 2.003 mmol). After 2 hours at 0 °C, the reaction was concentrated to dryness and the residue was purifîed by silica gel chromatography (EtOAc) to afford 150 mg of desired product: LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, 40 C18/ACN, Rétention Time = 2.41 minutes (M+H) 357.47.

-12117028

Fo rma ti on of (+-/-)-7V- (3,3-dl methyl-l- (2 W-tetrazol-5-yI) b u tan-2-yI)-5-fluoro-2-(5-fl uo rol//-pyrroIo[23-6]pyridin-3-yl)pyrimIdin-4-amine (55)

To a solution of racemic 3-(5-fluoro-2-(5-fluoro-l//-pyrrolo[2,3-i>]pyridin-3yl)pyrimidin-4-ylamino)-4,4-dimethylpentanenitrile, 165a, (0.150 g, 0.420 mmol) in 10 mL of dioxane was added azido-tributylstannane (0.221 g, 0.668 mmol). The reaction vessel was sealed and warmed to 130 °C for 12 hours. Upon cooling, the reaction was concentrated to dryness and the resuiting residue was purified by silica gel chromatography to afford 48 mg of desired product: *H NMR (300.0 MHz, </6DMSO) δ 12.23 (s, H), 8.49 (d, J = 9.6 Hz, H), 8.26 - 8.05 (m, H), 4.03 (d, J « 7.1 Hz, H), 3.48 - 3.35 (m, H), 3.17 (s, H), 2.50 (s, H), 1.99 (s, H), 1.13 (dt, J= 25.1, 8.0 Hz, H), 1.01 (s, H), 0.96 (s, H) and 0.87 (d, 6.6 Hz, H) ppm; LCMS Gradient 1090%, 0.1% formic acid, 5 minutes, CI8/ACN, Rétention Time = 1.94 minutes (M+H) 400.46.

Préparation of Compounds 60 and 61

Synthetic Scheme 26

tert-butylbromoacetate, K₂COj, acetone; (b) Oxone, water, MeOH; (c) 5-fluoro-l-(p-tolylsulfonyl)-3(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2yl)pyrrolo[2,3-b]pyridine, 7, K3PO4 X-Phos, Pd₂(dba)₃,2-MeTHF, water, 120 °C; (d) 25% NaOMe, MeOH; (e) TFA, CH₂C1₂, 50 °C.

Formation of (S)-tert-Butyl 2-(2-(2-chloro-5-fluoropyrimidin-4-ylamlno)-3,3-dimethylbutylthio)ethanoate (168a)

To a stirring suspension of (S)-2-((2-chloro-5-fluoropyrimÎdin-4-yl)amino)-3,3dimethylbutane-l-thiol, 77a, (1.50 g, 5.69 mmol) and K₂CO₃ (2.36 g, 17.06 mmol) in acetone (15 mL) was added /ert-butyl bromoacetate (1.26 mL, 8.53 mmol). The suspension was stirred at room température for 18 hours. The resuiting solid was filtered, washed with acetone and the filtrate was concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (0-30% EtOAc/Hexanes gradient) to afford 1.6 g of the desired product as an off-white solid: LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, Rétention Time = 3.81 minutes (M+H) 378.06.

-12217028

Formation of (S)-iert-Butyl 2-(2-(2-chloro-5-fluoropyrimidin-4-ylamino)-33dimethylbutyl-sulfonyl)ethanoate (169a)

Oxone (5,37 g, 8.73 mmol) was added to a solution of (S)-tert-Butyi 2-(2-(2-ch!oro-5fluoropyrimidin-4-ylamino)-3,3-dimethyl-butylthio)ethanoate, 168a, (1.10 g, 2.91 mmol) in methanol (50 mL) and water (20 mL) and the solution was stirred 3 hours at room température. The solution was concentrated in vacuo to give a white residue that was dissolved in water (100 mL). The aqueous layer was extracted with EtOAc (3x 50 mL) and the combined organic phases was dried (MgSO₄), filtered and concentrated in vacuo to afford 750 mg of the desired product as a white solid: LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, CI8/ACN, Rétention Time =

1.29 minutes (M+H) 410.19.

Formation of (SJ-tert-Butyl 2-(2-(5-fluoro-2-(5-fluoro-l-tosyl-lÆ-pyrrolo[2,3-à)pyridin-

3-yl)pyrlmldin-4-ylamino)-3,3-dimethylbutylsulfonyI)ethanoatc (170a)

A solution of 5-fluoro-i-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan2-yl)pyrrolo[2,3-b]pyridine, 7a, (0.76 g, 1.83 mmol), (S)-tert-Butyl 2-(2-(2-chloro-5fluoropyrimidin-4-y!amino)-3,3-dimethylbutyl-sulfonyl)ethanoate, 169a, (0.75 g,

1.83 mmol) and K3PO4 (0.93 g, 4.39 mmol) in 2-methyl THF (10 mL) and water (2 mL) was degassed under a stream of nitrogen for 30 minutes. X-Phos (0.06 g, 0.12 mmol) and Pd₂(dba)j (0.03 g, 0.03 mmol) were added and the reaction mixture was heated at 115 °C in a pressure vial for 2.5 hours. The réaction mixture was cooled to room température, filtered and concentrated in vacuo. The residue was dissolved in EtOAc (50 mL) and washed with water. The organic layer was dried (MgSO₄), filtered and concentrated in vacuo. The crude product was purified via silica gel chromatography (0-60% EtOAc/Hexanes gradient) to afford 1.0 g of the desired product as a foamy solid: LCMS Gradient 60-98% ACN/water, 0.9% formic acid, 7 minutes, C4, Rétention Time = 2.39 minutes (M+H) 564.34.

Formation of 6$7-2-(2-(5-nuoro-2-(5-fluoro-lJ7-pyrroio|2,3-àlpyridin-3-yl)pyriniidin-4ylamino)-33-dlniethyIbutylsulfonyl)ethanolc acid (60)

To a solution of (SJ-terZ-butyl 2-(2-(5-fluoro-2-(5-fluoro-l-tosyl-lH-pyrro!o[2,36]pyridin-3-y!)pyrimi din-4-yl amino)-3,3 -dimethylbutylsul fon yi )ethanoate, 170a, (1.00 g, 1.50 mmol) in THF (50 mL) was added NaOMe (1.30 mL of 25% solution in MeOH, 1.45 mmol). The yellow colored solution was stirred at room température for 30 minutes and then the mixture was diluted with aqueous saturated NH4CI solution. The solvent was removed under reduced pressure and the residue was dissolved in water (50 mL). The aqueous layer was extracted with EtOAc (3x50 mL) and dried (MgSO₄), filtered and concentrated in vacuo. The product was purified by silica gel chromatography (0-10% MeOH/CH₂Cl₂ gradient) to afford 0.50 g of the detosylated ester intermediate as a white solid.

The ester (0.50 g) was dissolved in CH₂C1₂ (4 mL) and trifluoroacetic acid (2 mL) was added. The solution was heated at 50 °C for 2 hours. The solvent was evaporated under reduced pressure. The residue was diluted with water (10 mL) and the solution was neutralized with aqueous saturated NaHCOj solution. The aqueous phase was extracted with EtOAc (3x 10 mL), dried (MgSO<), filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography (0-15% MeOH/CH₂Cl₂ gradient) to afford 204 mg of the desired product, 60, as a

-12317028 white solid: LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, Rétention Time = 2.01 minutes (M+H) 454.21.

The following compounds can be prepared in the same fashion using the procedure described above:

F

(S)-2-(2-(2-(5-c hloro- lZ/-pyr rolo [2,3 -h] pyrl di n-3-yl)-5-fl uoropyrlmi din-4-yI a mino)-3,3dimcthylbutylsulfonyl)ethanoic acid (61) *H NMR (300 MHz, MeOD) δ 8.95 (s, 1H), 8.29 - 8.14 (m, 2H), 8.08 (d, 4.0 Hz,

1H), 5.26 (m, 1H), 4.21 (d, J = 15.3 Hz, 1H), 3.92 (dd, 30.0, 14.5 Hz, 2H), 3.77 3.57 (m, 1H), 1.10 (s, 9H); LCMS Gradient 60-98% ACN/water, 0.9% formic acid, 7 minutes, C4, Rétention Time = 2.23 minutes (M+H) 470.14.

Préparation of Compound 64

Synthetlc Scheme 28

168a ^175a

Oxone, MeOH; (b) 5-fluoro-l-(p-tolylsulfonyl)-3(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)pyrrolo[2,3-b]pyridine, 7a, K3PO4 X-Phos, Pd₂(dba)₃,2-Me THF, water, 120 °C; (c) NaOMe, MeOH, THF.

Formation of rert-butyl-((5)-2(2-chIoro-5-fIuoropyrlmldin-4-yIamino)-33dimethylbutylsulfinyl)ethanoatc (175a)

Oxone (1,04 g, 1.69 mmol) was added to a stirring solution of (S)-ZerZ-Butyl 2-(2-(2chloro-5-fluoropyrimidin-4-ylamino)-3,3-dimethyl-butylthio)ethanoate, 168a, (0.53 g, 1.41 mmol) in methanol (20 mL). The solution was stirred for 15 minutes at room

-12417028 température. The solution was concentrated to give white residue which was dissolved in water (50 mL). The aqueous layer was extracted with EtOAc (3x 25 mL) and the organic layer was dried (MgSO^), filtered and concentrated in vacuo to give 540 mg of the desired product as a white solid: LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, Rétention Time = 3.05 minutes (M+H) 394.28.

tert-Butyl 2-((S)-2-(5-fluoro-2-(5-fluoro-l-tosyl-lH-pyrrolo[23-ô]pyridln-3yl)pyrimidin-4-ylamino)-33-dimethylbutylsulfinyl)ethanoate (176a)

A solution of 5-fluoro-l-(p-to!ylsulfonyl)-3-(4,4,5,5-tetramethyI-l,3,2-dioxaborolan2-y!)pyrrolo[2,3-b]pyridine, 7a, (0.66 g, 1.58 mmol), tert-butyl((S)-2(2-chloro-5fluoropyrimidin-4-y!amino)-3,3-dimethyibutyIsulfîny!)ethanoate, 175a, (0.50 g, 1.27 mmol) and K3PO4 (0.65 g, 3.05 mmol) in 2-methyl THF (10 mL) and water (2 mL) was degassed under a stream of nitrogen for 30 minutes. X-Phos (0.04 g, 0.08 mmol) and Pd₂(dba)j(0.02 g, 0.02 mmol) were added and the reaction mixture was heated at 115 °C in a pressure vial for 4 hours. The reaction mixture was cooled to room température, filtered and concentrated in vacuo. The residue was dissolved in EtOAc (50 mL) and washed with water. The organic layer was dried (MgSO4), filtered and concentrated in vacuo. The crude residue was purifîed by sîlica gel chromatography (0-60% EtOAc/Hexanes gradient) to afford 450 mg of the desired product as a white foamy solid: LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, Rétention Time ·= 3.91 minutes (M+H) 648.40.

2-((S)-2-(5-fluoro-2-(5-fluoro-lJZ-pyrrolo[2,3-ô]pyridin-3-y])pyrimidin-4-y]amino)-3,3dimethylbutylsulfinyl)ethanoic acid (64)

To a solution of tert-butyl 2-((S)-2-(5-fluoro-2-(5-fluoro-l-tosyl-lH-pyrrolo[2,3i>]pyridin-3-y!)pyrimidin-4-y!amino)-3,3-dimethyIbutylsulfinyl)ethanoate, 176a, (0.42 g, 0.64 mmol) in THF(10 mL) was added NaOMe (0.21 mL of 25% solution in MeOH, 0.96 mmol). The solution was stirred at room température for 30 minutes. Aqueous saturated NH4CI solution was added and the solvent was removed under reduced pressure. The residue was dissolved in water (20 mL) and the aqueous layer was extracted with EtOAc (3 x 20 mL). The combined organic phases were dried (MgSO4), filtered and concentrated in vacuo. The residue was purifîed by siüca gel chromatography (0-15% MeOH/CH₂Cl₂ gradient) to afford 36 mg of the desired product as a white solid: *H NMR (400 MHz, MeOD) δ 8.60 - 8.52 (m, IH), 8.46 (s, IH), 8.32 (d, 5.3 Hz, 2H), 5.16 (m, 2H), 4.00 (d, 14.7 Hz, IH), 3.80 (d, J =

14.7 Hz, IH), 3.59(d, J= 13.9, IH), 1.12 (s, 9H); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, Rétention Time = 1.93 minutes (M+H) 438.25.

Préparation of Compounds 66, 67, 72, and 73

Synthetic Scheme 29

-12517028

b

181· ------7a

i.TMS-CF₃, CsF, THF, ii. TFA, CH₂Cl₂; (b) 5-fluoro-l-(p-tolylsulfonyl)-3-(4,4,5,5tetramethyl-l,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine, 7a, X-phos, Pd₂(dba)₃, KjPO<, 120 °C; (c) NaOMe, THF; (d) TB AF, THF.

Formation of (4Æ)-4-((2-chloro-5-nuoropyrimidin-4-yl)amino)-l,l,l-trinuoro-5,5dimethylhexan-2-oi (180a) and (181a)

To a solution of (3Æ)*3-[(2-chloro-5-nuoro-pyrimidin-4-yi)amino]-4,4-dimethyi-pentanal (0.212 g, 0.817 mmoi) and (trifluoromethyl)trimethyisilane (1.96 mL, 0.980 mmol) in THF (20 mL) was added césium fluoride (0.001 g, 0.008 mmol). The reaction mixture was stirred at room température for 1 hour. The reaction mixture was diluted into brine and EtOAc. The organic phase was dried over MgSO<, filtered and concentrated in vacuo, The crude residue was purified via silica gel chromatography (EtOAc/Hexanes) to afford 190 mg of the silylated alcohol. This intermediate was diluted with dichloromethane (10 mL) and trifluoroacetic acid (1 mL) was added to the mixture. The reaction mixture was stirred at room température for 30 minutes. The reaction mixture was concentrated in vacuo and the resulting residue was purified via silica gel chromatography (60%EtOAc/Hexanes) to afford 60 mg of diastereomer 180a and 100 mg of diastereomer 181a. Each diastereomer was taken on separately through the remaining synthetic sequence.

Diastereomer, 180a: *H NMR (400 MHz, CDClj) δ 7.93 (dd, J= 43.4,2.6 Hz, IH), 5.i0 (d, J =8.9 Hz, IH), 4.13 (dd,J = 15.8, 5.8 Hz, IH), 3.94-3.71 (m, 1 H), 2.05 (ddd, J = 13.7,

9.2, 2.1 Hz, IH), 1.64 (t, 12.9 Hz, IH), 1.05 (s, 9H); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, Rétention Time =3.18 minutes (M+H) 330.42.

Diastereomer, 181a: 'H NMR (400 MHz, CDCl₃) δ 7.79 (d, 2.7 Hz, IH), 5.30 (d, J =

11.6 Hz, IH), 4.22 - 4.07 (m, 2H), 2.19 (ddd, 28.7, 15.3, 13.4 Hz, IH), 1.74 - 1.59 (m, IH), 1.04 (s, 9H). LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, Rétention Time = 3.26 minutes (M+H) 330.42.

-12617028

Formation of ^ZO-l^l-trlfluoro-l-ftS-fluoro^-fS-fluoro-l-tosyl-lH-pyrroiop^blpyridin-S-yijpyrimidin^-yOaminoj^S-dimethylhexan^-oi (182a)

A solution of 5-fluoro-l-(p-to!ylsulfonyl)-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2y!)pyrro!o[2,3-b]pyridine (0.091 g, 0.218 mmol), 7a, (4R)-4-[(2-ch!oro-5-fluoro-pyrimidin-4y!)amino]-l,l,i-trifluoro-5,5-dimethyl-hexan-2-ol, 180a, (0.060 g, 0.182 mmol) and K3PO4 (0.116 g, 0.546 mmo!) in 2-methyl THF (5 mL) and H₂O (1.5 mL) was degassed under a stream of nitrogen for 45 minutes. To the reaction mixture was added X-phos (0.010 g, 0.022 mmol) and Pd₂(dba)3 (0.004 g, 0.005 mmol). The reaction mixture was stirred at 120 °C in a pressure tube for 2 hours. The aqueous phase was removed. The organic phase was filtered through a pad of celite and concentrated in vacuo. The resulting residue was purified via silica gel chromatography (40%EtOAc/Hexanes) to afford 60 mg of the desired product: 'H NMR (400 MHz, CDCI3) δ 8.41 (s, 1H), 8.37 (dd, J= 8.9, 2.8 Hz, 1H), 8.24 (t, J = 8.7 Hz, 1H), 8.16 (d, 2.9 Hz, 1H), 8.00 (d, 8.4 Hz, 2H), 7.24 (d, J= 8.1 Hz, 2H), 4.92 (t, J

- 7.8 Hz, 2H), 4.44 (t, J= 10.3 Hz, 1H), 4.06 (s, 1H), 2.34 (s, 3H), 2.13 (dt, J= 13.6,4.9 Hz, 1H), 1.66 (dd, 23.0,9.3 Hz, 1H), 1.07 (d,J= 8.4 Hz, 9H). LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, Rétention Time = 4.02 min (M+H) 584.41.

The second diastereomeric alcohol, 181a, was also reacted in the same fashion to produce the diastereomeric Suzuki product. 184a: ’H NMR (400 MHz, CDCI3) δ 8.53 (s, 1H), 8.47 (dt, J= 11.5, 5.7 Hz, 1H), 8.30 (d, J= 1.9 Hz, 1H), 8.11 - 8.06 (m, 1H), 7.29 - 7.24 (m, 1H),

5.30 - 5.21 (m, 1H), 4.61 (d, J= 4.1 Hz, 1H), 4.29 - 4.16 (m, 2H), 2.43 - 2.33 (m, 4H), 1.75

- 1.66 (m, 1H), 1.09 (d, 10.8 Hz, 9H). LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C 18/ACN, Rétention Time = 4.02 minutes (M+H) 584.44.

Formation of (47?)-l,l,l-trifluoro-4-((5-fluoro-2-(5-fluoro-lH-pyrrolo[2,3-b]pyridin-3yi)pyrimidin-4-yi)amino)-5,5-dimethylhexan-2-ol (66 and 67)

To a solution of (4R)-i,l,i-trifluoro-4-((5-fluoro-2-(5-fluoro-l-tosyl-lH-pyrrolo[2,3b]pyridin-3-yi)pyrimidin-4-yl)amino)-5,5-dimethy!hexan-2-ol, 182a, (0.053 g, 0.091 mmol) was added NaOMe (0.019 g of 25% solution in MeOH, 0.091 mmol). The reaction mixture was stirred at room température for 5 minutes. The reaction mixture was diluted into EtOAc and aqueous saturated NaHCOs solution. The organic phase was dried over MgSO«, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (EtOAc/Hexanes) to afford 26 mg of the desired product, 66: ’H NMR (400 MHz, CDCI3) δ 9.40 (s, 1H), 8.47 (dd, J= 9.3,2.7 Hz, 1H), 8.15 (s, 1H), 8.10 (d, 2.7 Hz, 1H), 7.99 (d, J = 2.8 Hz, 1H), 5.54 (s, 1H), 4.84 (d, J= 7.5 Hz, 1H), 4.23 (t, 9.9 Hz, 1H), 3.91 (s, 1H),

2.07 - 1.97 (m, 1H), 1.62 (t, 13.0 Hz, 1H), 1.01 (s, 9H); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C 18/ACN, Rétention Time = 2.42 minutes (M+H) 430.44.

The second diastereomeric product, 67, was made by removal of the tosyl-protecting group on intermediate, 184a, using the foliowing procedure:

To a solution of (4R)-l,l,i-trifluoro-4-[[5-fluoro-2-[5-fluoro-l-(p-tolylsulfonyl)pyno!o[2,3b]pyridin-3-yl]pyrimidin-4-yl]amino]-5,5-dimethyl-hexan-2-ol, 184a, (0.060 g, 0.103 mmol) in THF (5 mL) was added tetrabutylammonium fluoride (0.411 mL of 1 M solution, 0.412 mmol) at room température. The reaction mixture was stirred at room température for 30 minutes. The reaction mixture was diluted into EtOAc and aqueous saturated NaHCO3 solution. The organic phase was dried over MgSO«, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (50% EtOAc/Hexanes) to afford 30mg of

-12717028 desired product. ‘H NMR (400 MHz, CDClj) δ 10.15 (s, IH), 8.49 (dd, J= 9.3,2.6 Hz, IH),

8.16 (s, IH), 8.10 (d, J= 2.6 Hz, IH), 8.06 (d, 3.0 Hz, IH), 5.30 (d, J= 15.0 Hz, IH),

5.19 - 5.10 (m, IH), 4.32 - 4.24 (m, IH), 4.23 - 4.17 (m, IH), 2.37 (dt, J= 14.9, 3.4 Hz, IH), 1.85 - 1.71 (m, 2H), 1.09 (s, 9H); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, Cl8/ACN, RétentionTime = 2.37 minutes (M+H) 430.47.

The following two diastereomers can be prepared in a similar fashion as the procedure described above:

(4R)-4-((5-FIuoro-2-(5-fluoro-lZr-pyrrolo[23-b]pyridin-3-yl)pyrimidin-4-yl)amino)-5,5dimethylhexan-2-ol (72 and 73)

Diastereomer 72; *H NMR (400 MHz, CDClj) δ 9.99 (s, IH), 8.60 (dd, J = 9.4, 2.7 Hz, IH), 8.26 (s, IH), 8.20 (d, 2.6 Hz, IH), 8.10 (d, 3.2 Hz, IH), 5.06 (t, 12.3 Hz,

IH), 4.28 (dd, J = 9.6, 7.2 Hz, IH), 3.96 (d, 5.7 Hz, iH), 2.71 (s, IH), 1.97 (ddd, J =

14.2, 5.8, 2.9 Hz, IH), 1.66-1.58 (m, IH), 1.28 (dd, J= 6.5, 5.5 Hz, 4H), 1.04 (d, J= 10.1 Hz, 9H); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, Rétention Time = 1.93 minutes (M+H) 376.46.

Diastereomer 73: ^JH NMR (400 MHz, CDClj) δ 10.81 (s, IH), 8.47 (dd, J = 9.3, 2.7 Hz, IH), 8.14 (s, IH), 8.05 (dd, 8.4,2.9 Hz, 2H), 4.95 (s, IH), 4.81 (d, 8.3 Hz, IH), 4.31-

4.14 (m, IH), 3.72 (dd, J= 8.9,6.0 Hz, IH), 1.83-1.70 (m, IH), 1.48-1.32 (m, IH), 1.24-1.11 (m, 4H), 0.98 (s, 9H); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, Rétention Time = 2.01 minutes (M+H) 376.46.

Préparation of Compounds 70 and 71

Synthetic Scheme 30

F F — 0K ^α > ^α Ά

econd dl»»t«r»omer

-12817028

PhjP-Br, LiHMDS, THF; (b) OsO₄,4methyl morpholine 4-oxide, THF, Η₂Ο; (c) X-phos, Pd₂(dba)₃, K₃PO₄,2-methyl THF, H₂O; (d) MeONa, THF; (e) 5-fluoro-l-(p-tolylsulfonyl)-3-(4,4,5,5tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3b]pyridine, 7a, X-phos, Pd₂(dba)j, KjPO₄,2-methyl THF, H₂0,120 °C; (f) MeONa, THF

Formation of (R)-2-chloro-JV-(2,2-dimethyihex-5-en-3-yl)-5-fluoropyrimidln-4-amine (188a):

To a solution of methyl(triphenyl)phosphonium bromide (0.983 g, 2.753 mmol) in THF (40 mL) was added LiHMDS (2.753 mL of 1 M solution, 2.753 mmol). The reaction mixture was stirred at room température for 1 hour. A solution of (3Λ)-3[(2-chloro-5-fluoro-pyrimidin-4-yl)amino]-4,4-dimethyl-pentanal (0.550 g, 2.118 mmol) in THF (20 mL) was added to the reaction mixture resulting in significant precipitate formation. The reaction mixture was stirred at room température for 45 minutes. The reaction mixture was diluted into EtOAc and aqueous saturated NH₄C1 solution. The organic phase was separated, dried over MgSO₄, filtered and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (EtOAc/Hexanes) to afford 180 mg of desired product: *H NMR (400 MHz, CDCIj) 6 7.80 (d, J= 2.8 Hz, IH), 5.76 - 5.60 (m, IH), 5.05 - 4.91 (m, 2H), 4.82 (t, J =22.1 Hz, IH), 4.26-4.11 (m, IH), 2.58 - 2.48 (m, IH), 2.07-1.92 (m, IH), 0.94 (s, 9H); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, Rétention Time = 3.60minutes (M+H) 258.38.

Formation of (4R)-4-((2-chloro-5-fluoropyrimldin-4-yl)amlno)-5^-dimethylhexane-l,2diol (189a) and (190a):

To a solution of (Æ)-2-chloro-N-(2,2-dimethylhex-5-en-3-yl)-5-fluoropyrimidin-4amine, 188a, (0.140 g, 0.543 mmol) in THF (10 mL) and H₂O (10 mL) was added osmium tetraoxide (0.138 g, 0.014 mmol) and 4-methylmorpholine-4-oxide (0.085 mL, 0.815 mmol). The reaction mixture was stirred at room température for 2.5 hours. The mixture was diluted with aqueous saturated Na₂S₂Oj. The resulting mixture was stirred for 20 minutes and extracted with EtOAc. The organic phase was dried over MgSO₄, filtered and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (MeOH/CH₂Cl₂) to afford 90 mg of the first diastereomer, 189a, and 65 mg of the second diastereomer, 190a.

Diastereomer 189a: *H NMR (400 MHz, CDCI3) δ 7.86 (d, J= 2.6 Hz, IH), 5.00 (d, J= 9.2 Hz, IH), 4.17 (s, IH), 4.08 - 3.96 (m, IH), 3.49 (dd, J= 19.2, 8.4 Hz, 3H),

2.15 (s, IH), 1.74 (ddd, J= 13.2, 10.8, 2.2 Hz, IH), 1.27 (dd, J= 19.3, 7.0 Hz, IH), 0.92 (d, J= 10.5 Hz, 9H); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, Rétention Time = 2.24 minutes (M+H) 292.36.

Diastereomer 190a: ^lHNMR (400 MHz, CDCIj) δ 7.88 (d, J= 2.7 Hz, IH), 5.29 (d, J= 8.9 Hz, IH), 4.12 - 4.02 (m, IH), 3.74 (d, J= 9.0 Hz, 2H), 3.50 (s, IH), 3.22 (s, IH), 2.12 (s, IH), 1.95 (dt, J= 14.7, 4.2 Hz, IH), 1.56 (ddd, J= 14.8, 9.2, 7.4 Hz, IH), 0.99 (s, 9H); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, CI8/ACN, Rétention Time = 2.24 minutes (M+H) 292.39.

-12917028

Formation of (4R)-4-((5-fiuoro-2-(5-fluoro-l-tosyI-l//-pyrroIol2,3-b]pyridin-3yI)pyrimidIn-4-yI)amino)-5,5-diniethyIhcxane-l,2-dioI (191a)

To a solution of (4Æ)-4-[(2-chloro-5-fluoro-pyrimidin-4-yl)amino]-5,5-dimethylhexane-1,2-diol, 189a, (0.090 g, 0.309 mmol), 5-fluoro-l-(p-tolylsulfonyl)-3-(4,4,5,5tetramethyl-l,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine (0.167 g, 0.401 mmol) and K3PO4 (0.196 g, 0.926 mmol) in 2-Methyl THF (15 mL) and H2O (2 mL) was degassed under a stream of nitrogen for 45 minutes. To the reaction mixture was added X-phos (0.018 g, 0.037 mmol) and Pd₂(dba)j (0.007 g, 0.008 mmol). The reaction mixture was stirred at 120 °C in a pressure tube for 2 hours. The aqueous phase was removed and the organic phase was fiitered through a pad of celite and concentrated in vacuo. The resulting crude material was purified by silica gel chromatography (60%EtOAc/Hexanes) to afford 140 mg of the desired product, 191a: 'H NMR (400 MHz, CDCIj) δ 8.51 (dt,J= 7.6,3.8 Hz, IH), 8.48 (s, IH), 8.32 (d, J= 1.7 Hz, IH), 8.12 (dd, J= 7.2, 5.7 Hz, 3H), 7.30 (d, J= 8.1 Hz, 2H), 4.99 (d, J = 10.1 Hz, IH), 4.42 - 4.28 (m, 2H), 3.72 - 3.47 (m, 3H), 2.40 (s, 3H), 2.19 - 2.09 (m, IH), 1.97- 1.83 (m, IH), 1.49- 1.34 (m, IH), 1.06 (s, 9H); LCMS Gradient 1090%, 0.1% formic acid, 5 minutes, C 18/ACN, Rétention Time = 3.53 minutes (M+H) 546.49.

The second diastereomeric 1,2-diol, 190a, was also reacted in the same fashion to produce the diastereomeric Suzuki product. 193a: *H NMR (400 MHz, CDCIj) δ

8.56 - 8.49 (m, 2H), 8.32 (dd, J= 2.8, 1.1 Hz, IH), 8.15 - 8.02 (m, 3H), 7.30 (d, J =

9.2 Hz, 2H), 5.21-5.12 (m, IH), 4.27 (td, J= 9.7, 3.0 Hz, 1H), 3.93 - 3.74 (m, 2H), 3.55 (d, J=7.7Hz, 1 H), 3.11 (s, IH), 2.39 (s, 3H), 2.01 (m, IH), 1.65-1.50 (m, IH), 1,05 (s, 9H). LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, CI8/ACN, Rétention Time = 3.54 minutes (M+H) 546.49.

Formation of(4R)-4-((5-fluoro-2-(5-fiuoro-lH-pyrroIoI23-blpyridin-3-yI)pyrlmidin-4yl)amlno)-5,5-dimethyIhexane-l,2-dIol (70,71)

To a solution of (4Æ)-4-[[5-fluoro-2-[5-fluoro-l-(p-tolylsuIfonyl)pyrrolo[2,3b]pyridin-3-yl]pyrimidin-4-yl]amino]-5,5-dimethyl-hexane- 1,2-diol, 191a, (0.140 g, 0.257 mmol) in THF (10 mL) was added sodium methoxide (0.055 g of 25% w/w solution, 0.257 mmol). The reaction mixture was stirred at room température for 5 minutes. The reaction mixture was diiuted into EtOAc and aqueous saturated NaHCOj solution. The organic phase was dried over MgSOi, fiitered and concentrated in vacuo. The crude residue was purified via silica gel chromatography (MeOH/CH2C12) followed by préparative HPLC to afford 10 mg pure desired product: *H NMR (400 MHz, J6-DMSO) δ 8.61 (dd, J= 9.9, 2.6 Hz, IH), 8.26 (s, IH), 8.18 (s, IH), 8.11 (d, J = 4.1 Hz, IH), 4.66 (d, J = 10.4 Hz, IH), 4.43 (s, IH),

4.29 (d, J= 4.1 Hz, IH), 4.04 (s, IH), 3.35 (s, IH), 3.26 (d, J= 6.1 Hz, 2H), 1.69 (t, J = 12.3 Hz, IH), 1.59- 1.45 (m, IH), 0.96 (s, 9H). LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, Rétention Time = 1.76 minutes (M+H) 392.46.

The second diastereomeric 1,2-diol, 193a, was also reacted în the same fashion to produce the diastereomeric final product: *H NMR (400 MHz, CDCI3) δ 8.61 (dd, J = 9.6, 2.7 Hz, IH), 8.17 (s, 2H), 8.01 (d, J= 4.1 Hz, IH), 4.53 (d, J= 10.0 Hz, IH), 3.75 - 3.56 (m, 2H), 3.48 (dd, 11.0, 6.3 Hz, IH), 2.08 - 1.97 (m, IH), 1.75 (dt, J = 28.7, 9.4 Hz, IH), 1.04 (s, 9H). LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C 18/ACN, Rétention Time = 1.79 minutes (M+H) 392.46.

-13017028

Préparation of Compounds 75, 76, 79, 85, 93, and 95

Synthetic Scheme 31

i. carbonyl dtimidazoie, CH₂Ci2; ii. potassium ethyl malonate, MgCl₂, DMAP, EtjN, THF, CHjCN; (b) i. ammonium acetate, EtOH, reflux; it. sodium cyanoborohydride, AcOH, EtOAc; iii. 2,4-dichloro-5fluoropyrimidine, ’Pr₂NEt, EtOH; (c) 5-fluoro-i-(ptolylsul fonyi)-3-(4,4,5,5-tetramethyl-1,3,2dioxaboroIan-2-yl)pyrrolo[2,3-b]pyridine, 7a, Xphos, Pd₂(dba)₃, K₃PO₄, 2-methyi THF, H₂O, 135 °C, microwave; (d) LiOH, MeOH, 65 °C.

Formation of ethyl 3-oxo-3-(l-(trifluoromethyl)cyclopentyl)propanoate (195a).

To a solution of l-(trifluoromethyl)cyclopentanecarboxylic acid (1.30 g, 7.14 mmol) in dichloromethane (14 mL) was added carbonyl diîmtdazole (5.46 g, 33.68 mmol). After stîrring 5 hours at room température, the réaction was concentrated in vacuo to a residue.

in another flask, 3-ethoxy-3-oxo-propanoate (Potassium ion) (2.03 g, 11.90 mmol) was mixed with dichloromagnestum (1.13 g, 11.90 mmol) and DMAP (72.65 mg, 0.59 mmol) în THF (23.13 mL) and acetonitrile (11.57 mL). After 3 hours, the above crude solution in THF ( 10 mL) was added, followed by triethylamine ( 1.66 mL, 1 i .90 mmol). The reaction was ailowed to stir at 25 °C for 8 hours. The crude product was isolated by extracting into ethyl acetate (2 x 100 mL) vs IN HCl (100 mL), dried over sodium sulfate and concentrated in vacuo to afford 1.0 g of the desired product as a yellow oil: ^lH NMR (300 MHz, CDClj) δ 12.58 (s, H), 5.32 (s, H), 4.27 - 4.18 (m, 2 H), 2.33 - 2.14 (m, 2 H), 2.05 - 1.85 (m, 4 H), 1.77 - 1.69 (m, 2 H) and 1.30 (td, J = 7.1, 3.2 Hz, 3 H) ppm.

-13117028

Formation of (+/-)-ethyl 3-(2-chloro-5-fluoropyrimidin-4-ylamlno)-3-(l(trlfluoro methyl)-cyclopentyl)propanoate (196a)

A solution of ethyl 3-oxo-3-(l-(trifluoromethyl)cyclopentyl)propanoate, 195a, (0.500 g, 1.982 mmol) and ammonium acetate (0.458 g, 5.946 mmol) in EtOH (20 mL) was warmed to reflux for 3 hours. The crude reaction was concentrated in vacuo to a residue and redissolved in EtOAc (20 mL). The new mixture was cooled to 0 °C, and acetic acid (0.338 mL, 5.946 mmol) and sodium cyanoborohydride (0.498 g, 7.928 mmol, 4 equiv) were added to the mixture. The reaction was allowed to warm to room température and stirred ovemight. The reaction was quenched with aqueous saturated sodium bicarbonate solution (10 mL) and extracted with ethyl acetate (2 x 20 mL). The organic phase was concentrated in vacuo and redissolved in EtOH (20 mL). To the solution was added 2,4-dichloro-5-fluoro-pyrimidine (0.496 g, 2.973 mmol) and ΛζΛΓ-diisopropylethylamine base (2.0 mL). The reaction was refluxed for 12 hours and then concentrated in vacuo. The residue was purifîed by silica gel chromatography (EtOAc) yielding 84 mg of the desired product as a yellow oil: LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, Rétention Time = 3.54 minutes (M+H) 384.40.

Formation of (+/-)-ethyl 3-(5-fluoro-2-(5-fluoro-l-tosyl-l//-pyrrolo[23-6|pyrldin-3yl)pyrimidin-4-ylamIno)-3-(l-(trIfluoromethyl)cyclopentyl)propanoate (197a)

To a solution of racemic ethyl 3-(2-chloro-5-fluoropyrimidin-4-ylamino)-3-(l(trifluoromethyl)cyclopentyl)propanoate, 196a, (0.084 g, 0.219 mmol) in THF (10 mL) and water (1 mL) was added 5-fluoro-l-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridîne, 7a, (0.137 g, 0.328 mmol) and potassium phosphate (0.140 g, 0.657 mmol). The resulting mixture was degassed under a stream of nitrogen for 10 minutes. To the reaction was then added X-Phos (0.010 g, 0.021 mmol) and Pd₂(dba)₃ (0.010 g, 0.011 mmol). The reaction was irradiated for 15 minutes at 135 °C in a microwave. The resulting mixture was concentrated in vacuo to a brown oil which was purifîed by silica gel chromatography (EtOAc/CH₂Cl₂) to afford 80 mg of the desired product as a pale yellow solid: LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, Rétention Time = 4.22 minutes (M+H) 638.42.

Formation of (+/-)-3-(5-fluoro-2-(5-fluoro-lH-pyrrolo[2,3-i]pyrldin-3-yl)pyrimIdln-4ylamino)-3-(l-(trinuoromethyl)cyclopentyl)propanolc acid (75)

To a solution of racemic ethyl 3-(5-fluoro-2-(5-fluoro-l-tosyl-l//-pyrrolo[2,3b]pyridin-3-yl)pyrimidin-4-ylamino)-3-(l-(trifluoromethyl)cyclopentyl)propanoate, 197a, (0.080 g, 0.120 mmol) in THF (10 mL) was added lithium hydroxide (2 mL of 2N solution). The reaction was refluxed for 3 hours and cooled to room température. The non aqueous solvent was removed under reduced pressure and the aqueous layer was adjusted to pH 4. The aqueous layer was extracted with ethyl acetate (2 x 20 mL). The combined organic phases concentrated in vacuo to afford 16 mg of the desired product as a pale yellow solid: *H NMR (300 MHz, c/6-DMSO) δ 8.51 (s, H), 8.25 - 7.97 (m, 2 H), 7.58 - 7.42 (m, 2 H), 7.12 (d, 7.5 Hz, H), 4.35 (m, H), 2.85 (m, 2 H) and 1.27 - 0.70 (m, 8 H) ppm; LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, Rétention Time = 2.55 minutes (M+H) 456,45.

-13217028

The following analogs can be prepared in a similar fashïon as the procedure described above Compound 75:

(+/-)-5,5,5-Trifluoro-3-(5-fluoro-2-(5-fluoro-l//-pyrrolo[2,3-ô]pyridin-3-yl)pyrimidin-4ylamIno)-4,4-dimethyipentanoic acid (79) 'H NMR (300 MHz, MeOD) δ 8.66 (d, 8.9 Hz, H), 8.29 (s, H), 8.22 - 8.18 (m, 2

H), 4.16 - 4.06 (m, H), 2.97 (s, H), 2.92 (s, H), and 1.27 -1.21 (m, 6 H) ppm; LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, Rétention Time = 2.22 minutes (M+H) 430.41.

(+/-)-5-Fluoro-3-((5-fluoro-2-(5-fluoro-l/ApyrroioJ23-blpyridIn-3-yl)pyrimldin-4yl)amino)-4,4-dimethylpentanoic acid (76) ’H NMR (300 MHz, MeOD) δ 8.70 (dd, 9.7, 2.8 Hz, 1H), 8.15 (dd, J = 6.1, 4.0 Hz, 2H), 8.02 (d, J = 4.1 Hz, 1H), 5.23 (dd, J= 10.7, 3.1 Hz, 1H), 4.30 (d, 47.9

Hz, 2H), 3.63 (d, J = 18.2 Hz, 1 H), 3.31 (dt,J=3.3, 1.6 Hz, 3H), 2.83 (dd,J=15.3,

3.3 Hz, 1H), 2.63 (dd, J= 15.3, 10.8 Hz, 1H), 1.07 (s, 6H); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, (M+H) 394.

F

(R)-3-((5-fluoro-2-(5-fluoro-17/-pyrrolo[23-b]pyridin-3-yl)pyrimidin-4-yl)amino)-3-(lmethyicyclopropyl)propanoic acid (91)

LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, (M+H) 374.

-13317028

(+/-)-3-((5-Fiuoro-2-(5-fluoro-lZf-pyrroIo[23*bIpyridin-3-yI)pyrimIdln-4-yI)amIno)-3(l*(trifluoromethyl)cyclopropyl)propanolc acid (93)

LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, CI8/ACN, Rétention Time =

2.37 minutes (M+H) 428.49.

(+/-)-3-(BIcycIo[2.2.1]heptan-l-yI)-3-(5-fluoro-2-(5-fluoro-lH-pyrroIo[2,3-0]pyrIdin-3yI)pyrimidin-4-yIamIno)propanoIc acid (95) ’H NMR (400 MHz, CDjOD) δ 8.62 (dd, J = 9.3, 2.6 Hz, IH), 8.48 (t, J = 5.4 Hz, IH), 8.32 (s, IH), 8.29 (d, J= 5.5 Hz, IH), 5.42 (dd, J = 10.0, 3.4 Hz, IH), 2.84 (m, 15 2H), 2.18 (s, IH), 1.65 (m, 4H), 1.39 (m, 6H); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, Rétention Time = 2.12 minutes (M+H) 414.28.

F

(+/-)-5-Fluoro-3-((5-fluoro-2-(5-fluoro-lH-pyrroIo[2,3-bJpyridin-3-yI)pyrimidin-4yl)amlno)-4-(fluoromethyI)-4-methylpentanoic acid (84) ’H NMR (300 MHz, MeOD) δ 8.67 (dd, J= 9.6, 2.8 Hz, IH), 8.16 (m, 2H), 8.04 (d, J = 4.0 Hz, IH), 5.38 (dd, J= 10.8,3.2 Hz, IH), 4.72-4.23 (m, 4H), 2.86 (dd, J= 15.5,

3.3 Hz, IH), 2.70 (dd, J= 15.5, 10.9 Hz, IH), 1.15(s, 3H); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, (M+H) 412.

-13417028

(+/-)-3-((5-chloro-2-(5-fluoro-li7-pyrrolo[2,3-bJpyridin-3-yl)pyriniidin-4-yi)amino)-4,4dimethylpentanolc acid (85)

Carboxylic acid, 203, was prepared in same fashion as carboxylic acid, 4, (see Synthetic Scheme 1) using 5-ch!oro-3-(5-chloro-4-(methvlsulfinyl)pyrimidin-2-yl)-ltosyl-lH-pyrrolo[2,3-b]pyridine instead of sulfoxide, 1: Ή NMR (400 MHz, MeOD) δ 8.68 (dd, J= 9.3,2.7 Hz, IH), 8.47 (s, IH), 8.38 (s, IH), 8.32 (s, IH), 5.17 (dd, J = 9.8, 3.5 Hz, IH), 2.87 (m, 2H), 1.06 (s, 9H); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, Rétention Time *= 2.1 minutes (M+H) 383.38.

Préparation of Compounds 77, 78, 83, 86, and 94

NH4OAC, malonic acid, EtOH, reflux; (b) 2,4dichloro-5-fluoropyrimidine, ‘PrîNEt, THF, MeOH, 95 °C; (c) 5-fluoro-l-(p-tolylsulfonyl)-3-(4,4,5,5tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3b]pyridine, K₃PO₄ X-Phos, Pd₂(dba)₃, 2-MeTHF, water, 120 °C; (d) 4N HCl, CH₃CN, 65 °C; (e) LiOH, water, THF.

Formation of (+/-)-ethyl-3-amino-3-(l-methylcyclohexyl)propanoate (205a)

A solution of 1-methylcyclohexanecarbaldehyde (2.75 g, 21.79 mmol), malonic acid (2.27 g, 21.79 mmol) and ammonium acetate (3.36 g, 43.58 mmol) in absolute éthanol (5 mL) was heated at reflux for 4 hours. The solid was filtered and washed with éthanol (10 mL). The filtrate was concentrated in vacuo to give a thick oil that

-13517028 was diluted with CH2CI2 (50 mL). The precipitated solid was filtered and the filtrate was concentrated in vacuo to afford 4.3 grams of a yellow oil. Concentrâted sulfurie acid (1.16 mL, 21.79 mmol) was added to a solution of the crude material in absolute éthanol (25 mL) and the mixture was refluxed for 12 hours. The solution was cooled to room température and concentrated in vacuo to give a thick oil. Water (10 mL) was added and the solution was neutralized with 2N NaOH. The aqueous layer was extracted with EtOAc (3x 25 mL), dried (MgSO₄), filtered and concentrated in vacuo to afford 2.4 grams of desired product: LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, Rétention Time = 1.54 minutes (M+H) 214.14.

Formation of (+/-)-ethyl 3-(2-chloro-5-fluorropyrlmidin-4-ylamino)-3-(lmethylcyclohexyl)propanoate (206a)

A mixture of 2,4-dichloro-5-fluoro-pyrimidine (1.83 g, 85.33 mmol), racemic ethyl-3amino-3-(l-methylcyclohexyi)propanoate, 205a, (2.34 g, 11.0 mmol) and N,Ndiisopropylethylamine (4.79 g, 27.50 mmol) in THF (40 mL) and methanol (10 mL) was heated at 95 °C for 3 hours. The solution was cooled to room température and the solvent was evaporated under reduced pressure. The crude residue was purified by silica gel chromatography (0-60% EtOAc/Hexanes gradient) to afford 620 mg of the desired product as a white foamy solid: ’H NMR (400 MHz, CDClj) δ 7.80 (d, J = 2.6 Hz, IH), 5.37 (m, 1 H), 4.59 (m, iH), 4.00 (q, 7.2 Hz, 2H), 2.62 (dd, J~ 14.7,

3.8 Hz, IH), 1.67(m,lH),l.i7 (m, 10H), 1.10 (t,J= 7.1 Hz, 3H), 0.85 (s, 3H); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, Rétention Time = 3.69 minutes (M+H) 344.39.

Formation of (+/-)-ethyl 3-(5-fluoro-2-(5-fluoro-l-tosyl-lJZ-pyrrolo]2,3-61pyr[din-3yl)pyrlmldln-4ylamlno)-3-(l- methylcyclohexyl)propanoate (207a)

A solution of 5-fluoro-l-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl-i,3,2-dioxaborolan2-yl)pyrrolo[2,3-b]pyridine, 7a, (0.51 g, 1.22 mmol), racemic ethyl 3-(2-chloro-5fluorropyrimidin-4-ylamino)-3-(l-methylcyciohexyl)propanoate, 206a, (0.35 g, 1.02 mmol) and K3PO4 (0.52 g, 2.44 mmol) in 2-methyl THF (8 mL) and water (2 mL) was degassed under a stream of nitrogen for 30 minutes. X-Phos (0.03 g, 0.07 mmol) and Pd₂(dba)3 (0.02 g, 0.02 mmol) were added and the resulting mixture was heated at 115 °C in a pressure viai for 4 hours. The reaction mixture was cooled to room température, filtered and concentrated in vacuo. The residue was dissolved in EtOAc (50 mL) and washed with water. The organic layer was dried (MgSO<), filtered and concentrated in vacuo. The crude residue was purified via silica gel chromatography (0-35% EtOAc/Hexanes gradient) to afford 486 mg of the desired product as a white solid: *H NMR (400 MHz, CDClj) δ 8.50 (m, IH), 8.48 (s, IH), 8.24 (d, J= 1.7 Hz, IH), 8.01 (m, 3H), 7.20(m, 2H), 5.12 (m, IH), 4.88 (m, IH), 3.89(q, J= 7.4 Hz, 2H), 2.71 (dd, J= 14.5,3.8 Hz, IH), 2.39 ? 2.32 (m, IH), 2.31 (s, 3H), 1.60-1.32 (m 10H), 0.95 (t, J =7.4 3H). 0.87 (s, 3H); LCMS Gradient 60-98%, 0.1% formic acid, 7 minutes, C18/ACN, Rétention Time * 2.81 minutes (M+H) 599.19.

Formation of (+/-)-ethyl 3-(5-fluoro-2-(5-fluoro-lH-pyrrolo]2,3-6]pyridin-3yl)pyrimidln-4-ylamino)-3-(l-methylcyclohexyl)propanoate (77)

To a solution of ethyl 3-(5-fluoro-2-(5-fluoro-l-tosyl-17/-pyrrolo[2,3-è]pyridin-3yl)pyrimidin-4ylamino)-3-(l- methylcyclohexyl)propanoate, 207a, (0.49 mg, 0.81

-13617028 mmol) in CHjCN (3 mL) was added HCl (2.0 mL of 4M solution in dioxane, 8.1 mmol). The solution was heated at 70 °C for 3 hours and then cooled to room température. The solvent was removed under reduced pressure and the product was neutralized with aqueous saturated NaHCOj solution. The precipitate was extracted with EtOAc (3x10 mL). The solvent was dried (MgSO₄), filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (070%EtOAc/Hexanes gradient) to afiord 230 mg of the desired product as an ofT-white solid: ‘H NMR (400 MHz, CDClj) δ 9.55 (s, IH), 8.58 (dd, J = 9.3, 2.5 Hz, IH), 8.18 (s, 2H), 8.00 (d, J= 2.7 Hz, IH), 5.13 (brs, IH), 4.95 (t, J= 8.2 Hz, IH), 3.84 (m, 2H), 2.72 (m, IH), 2.38 (m, IH), 1.67 - 1.15 (m, 10H), 0.94 (m, 3H); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, Rétention Time = 2.77 minutes (M+H) 444.36.

3-(5-fluoro-2-(5-fluoro-lZ/-pyrrolo[2,3-é]pyridln-3-yi)pyrimidin-4-ylamino)-3-(lmethylcyclohexyOpropanoic acid (78)

LiOH (0.118 mg, 4.927 mmol) was added to a solution of ethyl 3-(5-fluoro-2-(5fluoro-1 Z/-pyrroio[2,3 -ô]pyridin-3 - yl)p yri midin-4-ylamino)-3 -( I -méthyle yclohexy! )propanoate, 77, (0.23 g, 0.49 mmol) in water (5 mL) and THF (5 mL). The solution was stîrred at 95 °C for 18 hours and then cooled to room température. The solvent was removed under reduced pressure. The residue was diluted with water (10 mL) and neutralized with 2N HCl. The resulting precipitate was extracted with EtOAc (3x10 mL). The organic phase was dried (MgSO₄), filtered and concentrated in vacuo to afiord 210 mg of the desired product as an off-white solid: *H NMR (400 MHz, CDjOD) δ 8.78 (dd, 9.7, 2.7 Hz, IH), 8.16 (s, 2H), 7.99 (d, 4.1 Hz, IH),

5.20 (d, J= 9.9 Hz, IH), 2.86 - 2.69 (m, IH), 2.53 (dd, J = 14.7, 11.0 Hz, IH), 1.76 -

1.56 (m, 2H), 1.53 (m, 4H), 1.29 (m, 4H), 1.02 (s, 3H); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, Rétention Time = 2.20 minutes (M+H) 416.27.

(+/-)-3-(2-(5-Chloro-lZ/-pyrrolo[2,3-ô]pyridin-3-yl)-5-fiuoropyrimldln-4-ylamino)-3-(lmethylcyclohexyOpropanoic acid (83)

Compound 83 was synthesized in a manner similar to 3-(5-fluoro-2-(5-fluoro-l/7pyrrolo[2,3-i>]pyridin-3 -yljpyrimidi n-4-y!amino)-3 -( 1 -methylcyclohexyOpropanoic acid, 78, using 5-ch!oro-l-(p-toly!sulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2dioxaboro!an-2-yl)pyrrolo[2,3-b]pyridine instead of boronate ester, 7a: *H NMR (400 MHz, MeOD) δ 9.05 (d, 2.1 Hz, IH), 8.39 - 8.24 (m, 2H), 8.16 (d, J- 4.9

Hz, IH), 5.23 (d, J= 10.4 Hz, IH), 2.86 (d, J= 15.6 Hz, IH), 2.65 (m, IH), 1.58 (m, 7H), 1.37 (m, 3H), 1.05 (s, 3H); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, Rétention Time = 2.37 minutes (M+H) 442.36.

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(+/-)-3-(l-Adamanty!)-3-[[5-fluoro-2-(5-fluoro-lZ/-pyrro!o[2,3-b]pyridin-3y!)pyrimidin-4-yl]amino]propionic acid (86)

Compound 86 was synthesized in a manner similar to 3-(5-fluoro-2-(5-fluoro-l//pyrrolo[2,3-i»]pyridin-3 -yi)pyrimidi n-4-yiamino)-3 -( 1 -methylcyc!ohexyl)propanoic acid, 78, using adamantine-l-carba!dehyde as the starting material: *H NMR (400 MHz, CDjOD) δ 8.75 (dd, J-9.7,2.7 Hz, 1H), 8.18 (s, 2H), 8.00 (d, J- 4.2 Hz, 1H), 2.81(dd,J= 15.2,3.1 Hz, 1H), 2.55 (dd,J=15.2, 10.8 Hz, 1H),2.OO (m, 3H), 1.82-

1.49 (m, 12H); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, Rétention Time = 2.40 minutes (M+H) 454.34.

(+/-)-3-(l-Adamantyl)-3-J[2-(5-ch!oro-17/-pyrro!o|23-b]pyridin-3-yl)-5-fluoropyrimidin-4-y!]amino]propanoic acid (94)

Compound 94 was synthesized in a manner similar to 3-(l-Adamanty!)-3-[[5-fluoro2-(5-fluoro-lH-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yi]amino]propionic acid, 86, using 5-chloro-l-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethy!-l,3,2-dioxaborolan-2yl)pyrrolo[2,3-b]pyridine instead of boronate ester, 7a: *H NMR (400 MHz, CDjOD) δ 9.02 (d, J= 2.3 Hz, 1H), 8.40 - 8.24 (m, 2H), 8.18 (d, J = 5.0 Hz, 1H), 4.91 (d, J =

11.6 Hz, !H), 2.88 (dd, J- 16.0,2.8 Hz, 1H), 2.65 (dd, J = 15.9, 11.0 Hz, 1 H), 2.01 (s, 3H), 1.77 (dd, J= 27.9, 11.9 Hz, 12H); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, Rétention Time = 2.60 minutes (M+H) 470.27.

Préparation of Compound 68

Synthetic Schemc 33

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NaNj, DMF, 70 “C; (b) propargyl alcohol, THF, toluene, 120 °C; (c) 5-fluoro-l-(p-tolylsulfony])-3(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)pyrrolo[2,3-b]pyridine, K3PO4, X-Phos, Pd₂(dba)j, 2-MeTHF, water, 120 °C; (d) 4N HCl, CHjCN, 65 °C.

Formation of (5>jV-(l-azido-33-dimethylbutan-2-yl)-2-chloro-5-fluoropyrimidin-4amine (216a)

A mixture of (5)-2-((2-chloro-5-fluoropyrimidin-4-yl)amino)-3,3-dimethylbutyl methanesulfonate, 75a, (2.37 g, 7.26 mmol) and sodium azide (1.89 g, 29.07 mmol) în DMF (50 mL) was heated at 70 °C for 6 hours. The reaction mixture was cooled to room température and poured into water. The aqueous phase was extracted with EtOAc (2x 25 mL), dried (MgSO<), filtered and concentrated in vacuo. The crude product was purified via silica gel chromatography (0-20% EtOAc/Hexanes gradient) to afford 1.2 g of the desired product as a white crystalline solid: *H NMR (400 MHz, CDCI3) δ 7.86 (dd, J= 2.6, 1.1 Hz, IH), 5.07 (m, IH), 4.32-4.09 (m, IH), 3.60 (dd, J= 12.8, 3.9 Hz, IH), 3.34 (dd, J= 12.8, 7.6 Hz, IH), 0.96 (m, 9H); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, Rétention Time = 3.28 minutes (M+H) 273.14.

Formation of (S)-(l-(2-((2-ch)oro-5-fluoropyrimldin-4-yl)amino)-3,3-dimethylbutyl)IH-1,2,3*trlazol-4-yl)methanol (217a)

A mixture of prop-2-yn-l-ol (0.22 g, 3.85 mmol) and (S)-7V-(l-azido-3,3dimethylbutan-2-yl)-2-chloro-5-fluoropyrimidin-4-amine, 216a, (0.21 g, 0.77 mmol) in THF (4 mL) and toluene (4 mL) was heated in a pressure vial at 120 °C for 8 hours. The reaction mixture was cooled to room température and concentrated under reduced pressure. The crude product which contained two regioisomers was purified by silica gel chromatography (0-5% MeOH/CH₂Cl₂ gradient) to afford 100 mg of desired regioisomer, 217a, as well as 70 mg of the minor regioisomer (5hydroxymethyl triazole).

4-Hydroxymethyl triazole regioisomer 217a: *H NMR (400 MHz, CDClj) δ 7.71 (d, J= 2.6 Hz, IH), 7.19 (s, IH), 5.31 -5.16 (m, IH), 4.86 (m, IH), 4.79-4.60 (m, 2H),

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4.44 (m, IH), 1.07 (s, 9H); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, Rétention Time = 2.26 minutes (M+H) 329.31.

Formation of (S)-(l-(2-((5-f]uoro-2-(5-fluoro-l-tosyl-lf/-pyrroIo[23-ô]pyridin-3yI)pyrlmidin-4-yl)amino)-33-dimethyIbutyl)-lH-l,23-triazoI-4-yI)methanoI (218a)

A solution of 5-fluoro-l-(p-tolylsulfonyI)-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan2-yl)pyrrolo[2,3-b]pyridine, 7a, (0.158 g, 0.380 mmol), (<S)-(l-(2-((2-chloro-5fluoropyrimid in-4-yl)ami no)-3,3 -d imethylbutyl)-1//-1,2,3 -triazol -4-yl)methanol, 217a, (0.100 g, 0.304 mmol) and K3PO4 (0.520 g, 2.440 mmol) in 2-methyl THF (8 mL) and water (2 mL) was degassed under a stream of nitrogen for 30 minutes. XPhos (0.008 g, 0.018 mmol) and Pd₂(dba)j (0.006 g, 0.006 mmol) were added and the reaction mixture was heated at 115 °C in a pressure via! for 4 hours. The reaction mixture was cooled to room température and filtered. The filtrate was concentrated in vacuo. The residue was dissolved in EtOAc (50 mL) and washed with water. The organic layer was dried (MgSO4), filtered concentrated in vacuo. The crude residue was purified via silica gel chromatography (0-70% EtOAc/Hexanes gradient) to afford 120 mg of the desired product as a white foamy solid: ’H NMR (400 MHz, CDCIj) δ 8.37 (s,lH), 8.33 (s, 1H), 8.21 (s, IH), 8.03 (d, J= 8.4 Hz, 2H), 7.90 (d,J= 3.0 Hz, IH), 5.37(m, IH), 4.92 ? 4.83 (m, IH), 4.78 -4.69 (m, 2H), 4.44 (dd, J= 13.9,

11.3 Hz, IH), 2.32 (s, 3H), 1.11 (s, 9H); LCMS Gradient 60-98%, 0.1% formic acid, 7 minutes, C18/ACN, Rétention Time « 1.29 minutes (M+H) 583.33

Formation of (5)-(l-(2-((5-fluoro-2-(5-fluoro-lZ/-pyrrolo[23-/’]pyridin-3-yl)pyrlmldin-

4-yl)amlno)-33-dimethylbutyl)-l//-l,23-trlazol-4-yl)methanol (68)

To a solution of (5)-(1-(2-((5-fluoro-2-(5-fluoro-l-tosyl-l//-pyrrolo[2,3-6]pyridin-3yI)pyrimidin-4-yI)amino)-3,3 -dimethylbutyl)-1 Η· 1,2,3 -tri azol -4-yl)methanol, 218a, (0.11 g, 0.19 mmol) in THF (5 mL) was added NaOMe (0.17 mL of 25% solution in MeOH, 0.75 mmol). After stirring the reaction mixture at room température for 30 minutes, the mixture was diluted into aqueous saturated NH4CI solution(5 mL) and EtOAc (10 mL). The organic layer was separated, dried (MgSO4), filtered concentrated in vacuo. The crude product was purified by silica gel chromatography (0-10% MeOH/CH₂Cl₂) to afford 41 mg of the desired product as an off-white solid: H NMR (400 MHz, CDjOD) δ 8.51 (d, J= 8.0 Hz, IH), 8.16 (s, IH), 8.09 (s, IH),

7.93 (d, J= 3.5 Hz, IH), 7.38 (s, IH), 5.08 (m, IH), 5.00-4.90 (m, IH), 4.74 (s, 2H), 4.60 (m, IH), 1.2 (s, 9H); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, Rétention Time 1.90 minutes (M+H) 429.26.

Example 2: Influenza Antiviral Assay

Antiviral assays were performed using two cell-based methods*.

A 384-well microtiter plate modification of the standard cytopathic effect (CPE) assay method was developed, similar to that of Noah, et al. (Antiviral Res. 73:50-60, 2006). Briefly, MDCK cells were incubated with test compounds and influenza A virus (A/PR/8/34), at a low multiplicity of infection (approximate MOI=0.005), for hours at 37°C, and cell viability was measured using ATP détection (CellTiter Glo,

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Promega Inc.). Control wells containing cells and virus show cell death while wells containing cells, virus, and active antiviral compounds show cell survival (cell protection). Different concentrations of test compounds were evaluated, in quadruplicate, for example, over a range from approximately 20 μΜ to 1 nM. Doseresponse curves were prepared using standard 4-parameter curve fitting methods, and the concentration of test compound resulting in 50% cell protection, or cell survival équivalent to 50% of the uninfected wells, was reported as the ICso.

A second cell-based antiviral assay was developed that dépends on the multiplication of virus-specific RNA molécules in the infected cells, with RNA levels being directly measured using the branched-chain DNA (bDNA), hybridization method (Wagaman et aï, J. Virol Meth, 105:105-114,2002). In this assay, cells are initially infected in wells of a 96-well microtiter plate, the virus is allowed to replicate in the infected cells and spread to additional rounds of cells, then the cells are lysed and viral RNA content is measured. This assay is stopped earlîer that the CPE assay, usually after 18-36 hours, while ail the target cells are still viable. Viral RNA is quantitated by hybridization of well lysâtes to spécifie oligonucleotide probes fixed to wells of an assay plate, then amplification of the signal by hybridization with additional probes linked to a reporter enzyme, according to the kit manufacturées instructions (Quantigene 1.0, Panomics, Inc.). Minus-strand viral RNA is measured using probes designed for the consensus type A hémagglutination gene. Control wells containing cells and virus were used to define the 100% viral réplication level, and doseresponse curves for antiviral test compounds were analyzed using 4-parameter curve fitting methods. The concentration of test compound resulting in viral RNA levels equal to that of 50% of the control wells were reported as EC50.

Virus and Cell culture methods: Madin-Darby Canine Kidney cells (CCL-34 American Type Culture Collection) were maintained in Dulbecco’s Modfied Eagle Medium (DMEM) supplemented with 2mM L-glutamine, l,000U/ml penicillin, 1,000 ug/ml streptomycin, 10 mM HEPES, and 10% fêtai bovine medium. For the CPE assay, the day before the assay, cells were suspended by trypsinization and 10,000cells per well were distributed to wells of a 384 well plate in 50 μΙ. On the day of the assay, adhèrent cells were washed with three changes of DMEM containing 1 ug/ml TPCK-treated trypsin, without fêtai bovine sérum. Assays were initiated with

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5	the addition of 30 TCID50 of virus and test compound, in medium containing 1 pg/ml TPCK-treated trypsin, in a final volume of 50 μΐ. Plates were incubated for 72 hours at 37°C in a humidified, 5% CO₂ atmosphère. Altematively, cells were grown in DMEM + fêtai bovine sérum as above, but on the day of the assay they were trypsinized, washed 2 times and suspended in serum-free EX-Cell MDCK cell
10	medium (SAFC Biosciences, Lenexa, KS) and plated into wells at 20,000 cells per well. These wells were then used for assay after 5 hours of incubation, without the need for washing. Influenza virus, strain A/PR/8/34 (tissue culture adapted) was obtained from ATCC (VR-1469). Low-passage virus stocks were prepared in MDCK cells using standard
15	methods (WHO Manual on Animal Influenza Diagnosis and Surveillance, 2002), and TCID50 measurements were performed by testing serial dilutions on MDCK cells in the 384-well CPE assay format, above, and calculating results using the Karber method.
20	Mean IC50 values (mean ail) for certain spécifie compounds are summarized in Table 1: A: IC50 (mean ail) < 0.3 μΜ; B 0.3 μΜ < ICso (mean ail) <3.3 μΜ; C IC50 (mean ail) >3.3 μΜ.
25	Mean EC30 values (mean ail) for certain compounds are also summarized in Table 1: A: ECso (mean ail) < 0.3 μΜ; B 0.3 μΜ < ECso (mean ail) <3.3μΜ; C EC50 (mean ail) > 3.3 μΜ.
30	Mean EC99 values (mean ail) for certain compounds are also summarized in Table 1: A: EC99 (mean ail) < 0.3 μΜ; B 0.3 μΜ < ECçq (mean ail) < 3.3μΜ; C EC99 (mean ail) > 3.3 μΜ.
35	Some exemplary data are as follows: Compound 1: ICso=O.OO6 μΜ, ECso=O.OO9 μΜ, EC_w=0.0094 μΜ; Compound 2: IC_ÎO=0.004 μΜ, ECso=0.009 μΜ, EC99=0.0063 μΜ; Compound 6: ICso=O.OO4 μΜ, EC_So=0.015 μΜ, ECw=0.082 μΜ; Compound 69: ICso-2.31 μΜ, EC$o=O.8 μΜ, EC99=8.4 μΜ; Compound 76: ICso=O.423 μΜ, EC₅o=O,25 μΜ, EC_W=1.4 μΜ.

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For comparison purposes, some compounds disclosed in W02005/095400 were also tested against influenza virus using the bDNA and MDCK. cell protection assays described above, and their mean IC50, EC$o, and EC99 values are summarized in Table

2.

Table 1: IC50, EC_So, NMR and LCMS Data of Compounds of Invention.

Compound nos.	MDCK IC50 (uM)	bDNA ECSO (uM)	bDNA EC99 (uM)	NMR	M+1	LCMS RT
1	A	A	A	12.25 (s, 1H): 12.0 (bs, 1 H): 8.8 (s, 1H): 8.3 (s, 1H): 8.25 (s, 1H); 8.1 (s, 1H): 7.45 (d, 1H); 4.75 (t, 1H); 2.5 (m, 2H), 1.0 (s, 9H).	392.21	2.07
2	A	A	A	12.25 (s. 1H): 12.0 (bs, 1H): 8.6 (d, 1H):8.3 (s, 1H): 8.2 (s, 1H); 8.15 (s, 1H): 7.45 (d, 1H); 4.8 (t, 1H); 2.5 (m. 2H). 1.0 (s, 9H).	376.21	1.92
3	B	B	C		392.21	2.06
4	C	C	C		376.21	1.93
5	A	A	A	1HNMR (300 MHz. MeOD) d 8.60 (d, J = 7.7 Hz, 2H). 8.33 (S, 1 H), 5.08 (t, J = 17.2 Hz, 1H), 2.93 (dd, J = 16.3, 2.8 Hz, 1H). 2.73 (dd, J = 16.3. 10.6	377.24	2.17

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				Hz, 1H). 1.08 (s. 9H).
6	A	A	A	1H NMR (400 MHz. CDCI3) d 8.31 (d. J = 6.4 Hz. 1H). 8.06 (s, 1H). 7.06 (t, J = S.7 Hz. 1H), 4.58 (s, 2H). 2.80 (d. J = 13.2 Hz. 1H). 2.29 (dd, J = 13.3. 8.7 Hz, 1H), 0.98 (s, 9H).	394.19	2.92
7	A	A	A	1HNMR (300 MHz, MeOD) ? 8.86 (dd. J = 9.8, 2.8 Hz, 1H). 8.37 (s. 1H), 8.26 8.14 (m, 1H), 7.53 (d. J = 11.0 Hz, 1H), 5.04 (dd, J = 11.0, 2.9 Hz. 1H), 2.81 (dd, J = 15.4, 3.0 Hz, 1H). 2.60 (dd, J = 15.4, 11.0 HZ, 1H), 0.99 (s. 9H).	400.27	2.99
8 (diastereomer of Compound 15)	A	A	A		401.94	2.1
9	A	A	A		390.23	2.04
10	A	A	A	1HNMR (400 MHz, MeOD) ? 8.60 (s, 1H). 8.44 (s, 1H), 8.23 (d, J = 5.3 Hz, 1H). 8.16 (s, 1H). 5.15 (m. 1H), 3.39 (d, J= 8 Hz, 2H). 1.08(s 9H).	428	2.02

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11	A	A	A	1HNMR (400 MHz, MeOD) ? 8.44 (s, 1H), 8.34 (dd, J = 9.2, 2.6 Hz. 1H), 8.22 (d, J = 5.7 Hz. 1H), 8.13 (s. 1H), 5.16 (d, J = 4.1 Hz, 1 H), 3.46- 3.33 (m, 3H), 1.10 (d, J = 19.9 Hz, 10H).	412.13	1.91
12	A	A	A	1H NMR (400 MHz. MeOD) ? 8.64 (dd, J = 8.4,2.4 Hz. 1H). 8.57 (s, 1H). 8.24 (d. J = 4.4 Hz, 1H), 5.19 (d, J = 8.7 Hz, 1H), 2.78 (qd. J = 15.9. 6.6 Hz, 2H). 1.85-1.57 (m. 6H), 1.48 (dd, J = 11.8, 6.0 Hz, 1H), 1.36 (dt, J 12.0, 6.0 Hz. 1H), 1.11 (S, 3H).	403.22	2.37
13	A	A	A	1H NMR (400 MHz, MeOD) ? 8.64 (dd. J = 8.4, 2.4 Hz. 1H), 8.57 (s, 1H), 8.24 (d. J = 4.4 Hz, 1H), 5.19 (d, J = 8.7 Hz. 1H), 2.78 (qd. J = 15.9, 6.6 Hz, 2H), 1.85-1.57 (m, 6H), 1.48 (dd. J = 11.8, 6.0 Hz, 1H), 1.36 (dt, J 12.0, 6.0 Hz. 1H). 1.11 (s, 3H).	426.25	3.21
14	A	A	A		402.32	2.13
15 (diastereomer of Compound 8)	B	B	C		402.38	2.12

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16	A	A	A		390.35	2.03
17	B	B	C		389.97	2.03
18	A	A	A	1HNMR (400 MHz. DMSO) ? 12.37 (s, 1H). 12.12 (s, 1H), 8.75 (d, J = 9.9 Hz, 1H), 8.32 (s, 2H). 7.83 (d, J = 11.4 Hz. 1H). 7.48 (d, J »9.5Hz. 1H), 5.00 (t. J = 9.1 Hz, 1H), 2.71 - 2.54 (m. 2H), 1.30 (d, J = 7.4 Hz. 2H). 0.80 (t, J = 18.7 Hz. 9H).	414.31	3.14
19	A	A	A	1HNMR (400 MHz. CDCI3) ? 9.75 (s. 1H), 8.12 (d. J = 9.3 Hz. 1H). 7.94 (s,1H). 7.73 (s. 2H), 7.67 (brs. 1H). 4.934.78 (m, 2H). 3.08 (m, 1H). 2.76 (s. 3H). 0.99 (m. 9H).	425.3	1.98
20	A	A	A	1HNMR (400 MHz, DMSO) ? 12.23 (s. 1H). 11.93 (s, 1H). 8.48 (d, J = 9.9 Hz, 1H). 8.33- 8.07 (m. 3H). 7.18 (d. J = 9.3 Hz. 1 H). 4.39 (t, J = 10.2 Hz, 1H). 2.382.07 (m, 2H). 1.99-1.92 (m. 1H). 1.80 - 1.64 (m, 1H). 1.00 (d, J = 20.2 Hz, 9H).	390.06	2.14

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21	A	A	A	1HNMR (400 MHz, MeOD) ? 8.68 (dd, J = 9.6, 2.5 Hz, 1H). 8.24- 8.11 (m, 2H), 8.03 (d. J = 3.8 Hz, 1H), 5.12 (d, J = 8.5 Hz. 1H), 3.48 (d, J = 9.2 Hz, 2H). 2.60-2.47 (m, 1H), 0.68- 0.48 (m, 4H).	451.14	2.2
22	A	A	B	1H NMR (400 MHz, MeOD) ? 8.65 (d, J = 9.3,1 H). 8.47 (s. 1H), 8.34 (m,, 2H), 5.28 (d, J = 10.4 Hz, 1H). 3.55 (dt, J = 14.5, 13.0 Hz, 2H), 1.201.03 (m. 9H).	411	1.96
23	B	B	C	1HNMR (400 MHz, DMSO) 7 12.23 (s, 1H), 8.44 (d. J = 7.6 Hz, 1H), 8.32- 8.06 (m. 3H). 7.18 (d, J «9.6 Hz, 1 H). 4.36 (t, J « 10.4 Hz, 1H). 4.00- 3.67 (m, 2H). 2.41 -2.13 (m, 2H), 2.08 - 1.93 (m, 1H). 1.87-1.65 (m, 1H), 1.06- 0.84 (m, 12H).	419.08	2.41
24	A	A	A	1HNMR (400 MHz, CDCI3) 7 10.27 (brs, 1H), 8.25 (d, J «9.4 Hz, 1H), 8.17 (S, 1H). 8.11 (s, 1H). 7.23 (d. J = 10.3 Hz, 1H), 5.20 (d. J « 9.6 Hz, 1 H), 4.41 (t, J = 7.4 Hz. 1H), 4.09 (d, J «11.3 Hz, 1H). 3.82 - 3.58 (m,	373.03	3.08

-14717028

				1H). 0.99 (d. J = 19.5 Hz, 9H).
25	A	A	A	1HNMR (400 MHz, MeOD) ? 9.26 (dd, J 9.0, 2.2 Hz, 1H). 8.43 (S, 1H), 8.22 (s, 1H). 7.667.35 (m, 1H), 5.00 (m, 1H), 3.45 - 3.17 (m, 2H), 1.03(m, 9H).	436	2.54
26		A	A	1H NMR (400 MHz, CDCI3) ? 9.68 (s, 1 H), 8.45 - 8.33 (m. 1H), 8.17 (d, J = 2.8 Hz, 1 H). 7.88 (S. 1H), 7.36 (d, J = 10.3 Hz, 1H), 6.47 (d, J = 4.9 Hz, 1H), 5.11 (d, J » 7.8 Hz. 1H), 4.90 (d. J = 10.4 Hz, 1 H), 3.52 (s,1H), 3.04 (dd, J = 15.0, 10.5 Hz, 1H), 2.67 (d, J = 5.0 Hz. 3H). 1.02 (s, 9H).	449.22	2.97
27		A	B	1H NMR (400 MHz, CDCI3) ? 8.59 (dd, J = 9.7, 2.6 Hz, 1H), 8.38 (s, 1H). 8.21 (s. 1H), 7.31 (m, 1H), 5.12 (brs, 1H). 4.97 (brs, 1H), 3.33 (m. 1H). 2.70 (s, 6H), 0.95 (m, 9H).	463.49	3.12

-14817028

28		A	A		475	3.12
29		A	B	1H NMR (400 MHz, MeOD) ? 8.71 (dd, J = 9.7, 2.6 Hz, 1H), 8.37 (s, 1H). 8.20 (S, 1H), 7.57 (d, J = 10.9 Hz. 1H), 5.08 (d, J = 8.8 Hz. 1 H), 3.54- 3.40 (m, 2H), 3.32 (m, 5H), 3.15 (t. J = 5.4 Hz, 2H). 1.03 (s,9H)	493.5	3.05
30		A	A		435.46	2.8
31		A	A		477.65	3.27
32	A	A	A	1HNMR (400 MHz, CDCI3) ? 10.77 (brs, 1H).8.25(d, J = 8.4 Hz, 1H). 8.07 (s,1H), 8.03 (S,1H). 7.88 (s, 1H), 5.59 (brs, 1H), 4.36 (t, J = 8.3 Hz, 2 H), 4.11 (m, 1H), 3.72 (m. 2H), 1.06 (s, 9H).	348.13	1.83
33	A	A	A	1HNMR (400 MHz, CDCI3) ? 9.89 (brs, 1H). 8.07 (d, J = 9.3 Hz, 1H), 7.89 (s, 1H), 7.66 (m. 2H), 4.95 (t, J = 10.2 Hz, 1H), 4.80 (d, J = 9.6 Hz. 1H). 3.38 (m,, 1H),	439.3	2.25

-14917028

				3.18-2.96 (m, 3H). 1 1.351.12 (m, 3H). 1.08-0.90 (m, 9H).
34	A	A	B	.1HNMR (400 MHz. CDCI3) ? 9.84 (s, 1H). 8.10 (d, J = 9.5 Hz. 1H). 7.92 (d. J= 1.2 Hz. 1H). 7.72 (d, J = 14.2 Hz. 2H). 4.92 (m. 1H). 4.81 (m. 1H). 3.41 (d, J = 15.0 Hz. 1H). 3.19-2.84 (m, 3H). 1.59- 1.38 (m, 3H), 0.98 (s. 9H), 0.84 (t. J = 7.4 Hz. 3H).	453.44	2.42
35	A	A	B		469.18	2.11
36	B	C	C		390.29	1.98
37	C	C	C	1HNMR (300 MHz, d6DMSO) ? 12.21 (s. 1H). 8.52 (dd. J = 9.9, 2.9 Hz. 1H), 8.30- 8.23 (m, J = 2.8,1.5 Hz, 1H), 8.20 (d. J = 2.6 Hz. 1H), 8.12 (d, J = 4.1 Hz, 1H), 7.07 (d. J = 8.9 Hz. 1H). 4.53 (t. J = 5.4 Hz. 1H). 4.44 - 4.27 (m, J = 9.1, 5.8 Hz. 1H). 3.77 (ddd, J = 11.0, 5.1, 3.5 Hz. 1H). 3.59 (ddd. J = 11.1, 8.9, 5.8 Hz, 1H). 0.99 (S, 9H).

-15017028

38	C	C	C	1HNMR (300 MHz, d6DMSO) ? 12.21 (s, 1H). 8.55 (dd. J = 10.0, 2.8 Hz. 1H). 8.29- 8.23 (m, 1H). 8.19 (d, J = 2.7 Hz. 1H), 8.15 (d. J = 4.0 Hz, 1H), 7.47 (d, J = 8.4 Hz, 1H). 6.77-6.69 (m, 1H). 4.88 (t, J = 9.1 Hz. 1H). 3.49 - 3.36 (m, 1 H). 3.36- 3.28 (m, J = 10.5 Hz, 1H), 2.55 (t. J = 5.6 Hz, 3H), 0.98 (s. 9H).	425.03	2.11
39	A	A	B	1H NMR (400 MHz, CDCI3) ? 9.89 (s, 1H), 8.07 (d, J = 8.9 Hz, 1 H), 7.90 (S, 1 H), 7.68 (s, 2H), 4.96 (t, J = 9.8 Hz, 1H). 4.76 (d, J = 9.8 Hz. 1H). 3.60 (dd, J = 13.0, 6.6 Hz, 1H). 3.42 (m, 1H). 3.09 - 2.86 (m, 1H), 1.20 (d. J = 4.9 Hz, 6H). 0.97 (s, 9H).	453.19	2.22
40	A	A	B		467.2	2.36
41	A	A	B		386.39	3.09
42	A	A	A	1 H NMR (300 MHz. CDCI3) ? 10.70 (S, 1 H), 8.42 (dd, J = 9.6, 2.6 Hz. 1H), 8.05 (s. 1H), 7.73 (s.	426.31	3.27

-15117028

				1 H), 7.40 (t. J = 8.4 Hz. 1H). 5.32 (d. J = 6.6 Hz, 1H), 4.83 (t. J = 9.4 Hz. 1H). 2.89 (d. J = 5.3 Hz. 1 H), 2.34 (dd, J = 12.8,9.6 Hz, 1H). 1.921.37 (m, 8H), 1.32-1.24 (m. 1H). 1.201.06 (m, 3H).
43	A	A	A	1HNMR (300 MHz, CDCI3) ? 11.16 (s, 1H). 8.70 (s, 1H), 8.04 (d, J = 3.2 Hz. 1H), 7.96 (s, 1H), 7.87 (s, 1 H). 5.02 (d. J = 8.1 Hz, 1H), 4.80 (t. J = 9.6 Hz, 1H), 2.81 (d. J = 9.9 Hz. 1H), 2.34 (t J = 11.3 Hz. 1H). 1.14 (s, 9H).	426.47	2.49
44	A	B	B	1H NMR (400 MHz, DMSO) ? 12.26 (S, 2H), 8.55 (d, J = 9.7 Hz, 1H), 8.19 (dd, J =45.1. 15.8 Hz. 3H), 7.48 (d, J - 8.1 Hz. 1H). 4.79 (s, 1H), 2.58 (dd, J = 20.6, 12.2 Hz, 2H). 1.85 (ddd. J = 29.4, 26.5, 21.1 Hz, 7H).	374.02	2.1
45	B	A	C	1HNMR (300 MHz, CDCI3) 7 10.42 (s, 1H), 8.47 (dd, J = 9.3, 2.7 Hz, 1H), 8.13 (d. J = 11.2 Hz, 1H), 8.10 (s. 1H), 8.04 (d. J = 3.2 Hz, 1H). 4.89 (d, J = 9.0 Hz, 1H), 4.26 (t, J = 9.9 Hz, 1H),	362.39	1.89

-15217028

				3,65 (d, J = 9,2 Hz, 1H), 3.54 (td, J = 11.4, 2.9 Hz, 1H). 2.17-1.99 (m, 1H). 1.40 (dd. J = 14.0, 11.9 Hz, 1H). 0.96 (d, J = 18.4 Hz, 9H). 0.90 - 0.73 (m, 1H).
46	A	B	C	1H NMR (400 MHz. CDCI3) ? 9.38 (s, 1H), 8.53 (d. J = 6.9 Hz. 1H), 8.16 (m, 2H), 8.06 (s, 1 H), 5.09- 4.89 (m, 1H). 3.42 - 3.31 (m. 1H), 3.11 (m, 1H). 2.84 (s, 3H). 1.00 (s, 9H).	410.19	2.03
47	A	A	B	1HNMR (400 MHz. MeOD) ? 8.70 (dd. J = 8.9, 2.3 Hz. 1H). 8.50 (S, 1H), 8.35 (s, 1H). 7.99 (d, J = 7.3 Hz. 1H), 6.60 (d. J = 7.2 Hz, 1H). 5.05 (d, J = 10.7 Hz. 1H), 2.93 (dd, J = 15.9,1.8 Hz, 1H), 2.53 (dd, J = 15.9,11.2 Hz. 1H), 1.08 (d, J = 0.8 Hz, 9H)	358.02	2.17
48	A	B	B	1H NMR (400 MHz, MeOD) ? 8.63 - 8.45 (m. 2H), 7.98 (d, J = 7.3 Hz, 2H), 6.66 (d. J = 7.3 Hz, 2H). 4.95 (d, J = 10.6 Hz, 2H). 2.84 (dd, J = 15.4, 2.4 Hz, 2H), 2.44 (dd. J = 15.9,10.7 Hz, 2H). 0.98 (s. 9H).	359.02	2.12

-15317028

49	A	A	B	1H NMR (300 MHz, MeOD) ? 8.73 (t, J = 5.0 Hz, 1H), 8.44 (s, 1 H), 8.378.22 (m, 2H), 4.69 (dd, J = 9.9, 2.9 Hz, 1H), 4.11 (dd, J = 11.5,3.1 Hz. 1H), 3.83 (dd, J = 11.4,10.0 Hz, 1H), 3.32 (dt,J = 3.3, 1.6 Hz, 1H), 1.12 (s. 9H).	364.44	2.1
50 (diastereomer of Compounds 51 and 52)	A	A	B		402.45	1.98
51 (diastereomer of Compounds 50 and 52)	A	A	C		402.45	2.06
52 (diastereomer of Compounds 50 and 51)	A	A	B		402.25	2.16
53	A	A	B	1HNMR (400 MHz, DMSO) ? 12.57 (s, 1H), 9.40 (s,1H), 8.88 (s. 1H). 8.40 (d, J = 18.7 Hz. 2H). 8.34 (s, 1H), 3.93 (s, 1H). 3.52 (s, 1H), 1.20 (s, 9H).	377.42	2.5
54	A	A	B	1H NMR (400 MHz, DMSO) ? 12.65 (s, 1H), 12.41 (s, 1H). 9.28 (s, 1H), 8.86 (s. 1H). 8.65 (s, 1H). 8.30 (d, J = 3.5 Hz. 2H), 3.97 - 3.70 (m, 1H). 3.51 (s, 1H). 1.18 (s. 9H)	427.4	2.92

-154·

55	A	A	B		400.46	1.94
56	A	A	A	1 H NMR (400 MHz, DMSO) 7 12.65 (s, 1H). 9.43 (S, 1H), 9.15 (s, 1 H). 8.44 (d, J = 4.7 Hz, IH), 8.41 - 8.29 (m, 2H), 3.93 (s, 1H), 3.54(s. IH), 1.19 (d, J = 20.0 Hz. 9H).	393.32	2.7
57	A	A	A	1HNMR (400 MHz. CDCI3) 7 8.05 (d, J ~ 7.9 Hz, 1H). 7.81 (d, J = 2.1 Hz, 1H), 7.63 (s, 1H), 7.55 (s, 1 H), 5.87 (t, J = 54.9 Hz, 1H), 5.03 (t, J = 10.4 Hz, 1H), 4.86 (m, 1H), 3.68 (brs, 1H), 3.43 (m, 2H), 3.19 (m, 1 H), 0.94 (s, 9H).	475.23	2.26
58	A	A	A	1H NMR (400 MHz, CDCI3) ? 8.03 (dd, J = 9.3. 2.4 Hz, 1H). 7.82 (t, J = 11.2 Hz, 1H), 7.59 (s. 1H), 7.46 (s, 1 H). 5.07 (t, J « 10.6 Hz. 1H), 4.77 (m. 1H), 3.45 (m. 1H), 3.16-2.99 (m. IH), 0.970.86 (m, 9H).	493.31	2.37
59	A	A	B	1H NMR (300 MHz, MeOD) 7 8.54 (s, 1H), 8.50-8.18 (m, 3H). 7.18 (dd. J = 15.7, 7.1 Hz, 1H). 6.08 (dd. J = 15.7,1.3 Hz, 1H), 5.21 (t,J = 22.5 Hz, 1H).	388.23	2.21

-15517028

				1.12 (s, 9H).
60	A	B	C		454.21	2.01
61	A	A	B	1HNMR (300 MHz, MeOD) ? 8.95 (s. 1H), 8.29-8.14 (m, 2H), 8.08 (d, J = 4.0 Hz, 1H), 5.26 (m, 1H), 4.21 (d, J = 15.3 Hz, 1H), 3.92 (dd, J = 30.0, 14.5 Hz, 2H), 3.77 3.57 (m, 1H), 1.10 (s, 9H).	470.14	2.23
62	A	B	B		416.04	2.15
63	A	A	A		389.06	2.08
64		A	C	1H NMR (400 MHz. MeOD) 7 8.60 - 8.52 (m, 1H), 8.46 (S, 1H), 8.32 (d, J = 5.3 Hz, 2H), 5.16 (m, 2H), 4.00 (d, J = 14.7 Hz, 1H), 3.80 (d, J = 14.7 Hz. 1H), 3.59(d, J = 13.9, 1H), 1.12 (s. 9H).	438.25	1.93

-15617028

65	A	A	B		416.07	2.11
66 (diastereomer of Compound 67)	A	A	B	1H NMR (400 MHz, CDCI3) ? 10.15 (s, 1H), 8.49 (dd, J = 9.3, 2.6 Hz. 1H). 8.16 (s, 1H), 8.10 (d, J = 2.6 Hz, 1H), 8.06 (d, J = 3.0 Hz, 1H), 5.30 (d, J = 15.0 Hz. 1H), 5.19- 5.10 (m, 1H). 4.32 - 4.24 (m, 1H), 4.234.17 (m, 1H), 2.37 (dt. J = 14.9, 3.4 Hz, 1H). 1.85- 1.71 (m, 2H), 1.09 (s, 9H).	430.47	2.37
67 (diastereomer of Compound 66)	A	A	B	1HNMR (400 MHz. CDCI3) ? 9.40 (S, 1H). 8.47 (dd, J = 9.3, 2.7 Hz. 1H), 8.15 (s, 1H). 8.10 (d. J = 2.7 Hz. 1H). 7.99 (d. J = 2.8 Hz. 1H), 5.54 (s, 1H), 4.84 (d, J = 7.5 Hz. 1H), 4.23 (t. J = 9.9 Hz, 1H), 3.91 (S, 1H), 2.07-1.97 (m, 1 H). 1.62 (t. J = 13.0 Hz, 1H), 1.01 (S, 9H).	430.44	2.42
68	B	A	B	1HNMR (400 MHZ, MeOD) ? 8.51 (d. J = 8.0 Hz, 1H). 8.16 (s, 1H), 8.09 (s, 1H). 7.93 (d, J = 3.5 Hz, 1H). 7.38 (s, 1H), 5.08 (m, 1H), 5.00-4.90 (m. 1H), 4.74 (s, 2H), 4.60 (m,	429.26	1.9

-15717028

				1H). 1.2 (s. 9H).
69	B	B	C	1HNMR (300 MHz, MeOD) ? 8.59 - 8.39 (m, 2H), 8.32 (t, J = 5.3 Hz, 2H), 4.59 (d, J = 9.5 Hz, 2H). 2.21 (S, 1H), 1.79 (dddd, J = 28.6, 23.0, 13.2, 6.9 Hz, 3H), 1.11 (d, J “9.5 Hz, 9H).	426.09	1.81
70 (diastereomer of Compound 71)	A	A	B	1H NMR (400 MHz, DMSO) ? 8.61 (dd, J = 9.9, 2.6 Hz, 1H), 8.26 (s, 1H). 8.18 (s, 1H), 8.11 (d, J = 4.1 Hz, 1H), 4.66 (d, J = 10.4 Hz, 1H), 4.43 (s, 1 H), 4.29 (d, J = 4.1 Hz, 1H), 4.04 (s. 1H), 3.35 (S, 1H), 3.26 (d, J = 6.1 Hz, 2H), 1.69 (t, J = 12.3 Hz, 1H), 1.59-1.45 (m, 1H), 0.96 (s, 9H).	392.46	1.76
71 (diastereomer of Compound 70)	A	A	A	1HNMR (400 MHz, MeOD) ? 8.61 (dd, J = 9.6, 2.7 Hz, 1H), 8.17 (s, 2H), 8.01 (d, J = 4.1 Hz, 1H), 4.53 (d, J = 10.0 Hz, 1H), 3.75 - 3.56 (m, 2H), 3.48 (dd, J = 11.0,6.3 Hz, 1H), 2.08- 1.97 (m, 1H), 1.75 (dt. J =	392.46	1.79

158·

				28.7,9.4 Hz, 1H), 1.04 (s. 9H).
72 (diastereomer of Compound 73)			C	1HNMR (400 MHz, CDCI3) ? 9.99 (s, 1H), 8.60 (dd, J = 9.4, 2.7 Hz. 1H), 8.26 (s. 1 H), 8.20 (d, J = 2.6 Hz, 1 H). 8.10 (d, J = 3.2 Hz, 1H), 5.06 (t. J = 12.3 Hz, 1H), 4.28 (dd, J = 9.6, 7.2 Hz. 1H). 3.96 (d, J = 5.7 Hz, 1 H), 2.71 (s, 1H), 1.97 (ddd. J = 14.2, 5.6, 2.9 Hz, 1 H), 1.66 7 1.58 (m, 1H), 1.28 (dd, J = 6.5, 5.5 Hz, 4H), 1.04 (d. J = 10.1 Hz, 9H).	376.46	1.93
73 (diastereomer of Compound 72)	C	B	C	1HNMR (400 MHz, CDCI3) ? 10.81 (s, 1H), 8.47 (dd, J = 9.3, 2.7 Hz. 1H), 8.14 (s, 1H). 8.05 (dd, J = 8.4, 2.9 Hz, 2H), 4.95 (s, 1H), 4.81 (d, J = 8.3 Hz, 1H), 4.31 7 4.14 (m, 1H), 3.72 (dd, J = 8.9,6.0 Hz. 1H). 1.83? 1.70 (m. 1H), 1.48 71.32 (m, 1H), 1.24? 1.11 (m, 4H). 0.98 (s, 9H).	376.46	2.01

-15917028

74	B	B	B	1HNMR (300 MHz, MeOD) ? 8.59 (dd. J = 9.6, 2.9 Hz. 1H), 8.15 (d, J = 2.7 Hz, 2H). 8.01 (d, J = 4.1 Hz, 1H), 4.60 (dd, J = 8.3, 6.0 Hz. 1H). 2.90 - 2.68 (m, 2H). 1.17 (s, 3H). 0.85 (dt, J = 9.7,6.7 Hz, 1H), 0.64 (dt, J » 9.4. 4.9 Hz. 1H), 0.470.33 (m, 1H), 0.27 (ddd, J = 21.3, 12.8, 10.1 Hz, 1H).	374.42	1.94
75	C	B	C		456.45	2.55
76	B	A	B	1HNMR (300 MHz, MeOD) ? 8.70 (dd. J = 9.7, 2.8 Hz. 1H). 8.15 (dd. J = 6.1, 4.0 Hz. 2H), 8.02 (d. J = 4.1 Hz. 1H), 5.23 (dd. J = 10.7, 3.1 Hz. 1H), 4.30 (d. J = 47.9 Hz, 2H), 3.63 (d. J = 18.2 Hz, 1H), 3.31 (dt, J = 3.3, 1.6 Hz, 3H). 2.83 (dd. J = 15.3, 3.3 Hz, 1H). 2.63 (dd. J = 15.3, 10.8 Hz, 1H), 1.07 (s, 6H).	394.45	1.87
77	C	B	C	1HNMR (400 MHz, CDCI3) ? 9.55 (s. 1H), 8.58 (dd, J = 9.3, 2.5 Hz. 1H). 8.18 (s, 2H). 8.00 (d, J = 2.7 Hz. 1 H), 5.13 (brs, 1 H).	444.36	2.77

-16017028

				4.95 (t. J = 8.2 Hz, 1H). 3.84 (m,2H). 2.72 (m, 1H), 2.38 (m, 1 H), 1.67- 1.15 (m. 10H), 0.94 (m, 3H).
78	A	A	B	1HNMR (400 MHz, MeOD) ? 8.78 (dd, J = 9.7, 2.7 Hz. 1H), 8.16 (s, 2H), 7.99 (d, J = 4.1 Hz, 1H), 5.20 (d, J = 9.9 Hz, 1H), 2.86- 2.69 (m, 1H). 2.53 (dd, J = 14.7,11.0 Hz. 1H). 1.76- 1.56 (m, 2H), 1.53 (m, 4H), 1.29 (m, 4H), 1.02 (s, 3H).	416.27	2.2
79	B	A	B	H NMR (300.0 MHz, MeOD) d 8.66 (d, J = 8.9 Hz, H), 8.29 (s, H), 8.22-8.18 (m, H), 5.49 (s, H), 4.16 - 4.06 (m, H). 2.97 (s, H), 2.92 (s. H). 2.86 - 2.78 (m, H). 2.45 (s. H), 2.06 (s. H), 1.93 (s. H). 1.80 (s, H) and 1.27-1.21 (m, 6 H) ppm	430.41	2.22
80	C	B	C	1H NMR (400 MHz. CDCI3) ? 8.66 (dd, J = 9.2, 2.6 Hz, 1H). 8.53 (d. J = 9.6 Hz, 2H), 8.43 (s, 1H), 8.36 (S, 1H), 5.27-5.13 (m, 1H). 3.60 (s. 3H), 3.02 2.87 (m, 2H). 1.94 (s, 1H), 1,06 (S, 9H).	406.09	2.41

• 16117028

81	C	C	C	1H NMR (300 MHz, CDCI3) ? 9.83 (s, 1H), 8.58 (dd, J = 9.3,2.7 Hz. 1H). 8.37 (s, 1H). 8.25 (s. 1H), 8.13 (d, J = 3.3 Hz, 1 H). 5.66 (s, 1H), 5.32-5.16 (m, 1H). 4.714.32 (m, 4H), 4.04 (q, J = 7.1 Hz, 2H), 2.94 2.77 (m, 1H). 2.70 (dd, J = 15.1,9.1 Hz. 1H), 1.26 (s, 3H), 1.081.04 (t, J = 7.1 Hz,3 H).	440.45	2.35
82	C	C	C	1HNMR (400 MHz, CDCI3) ? 9.93(s. 1H). 8.89 (d, J = 2.1 Hz, 1H), 8.24 (d, J= 2.4 Hz, 1H), 8.18 (S. 1H), 8.00 (d, J = 3.4 Hz. 1H). 5.19 (m. 1H). 4.98 (m. 1H). 3.98 - 3.65 (m, 2H), 2.73 (dd, J = 14.3, 3.6 Hz. 1 H), 2.38 (m. 1H), 1.69 1.23 (m. 10H), 0.93 (t, J = 6.8, 3H).	460.29	3.08
83	B	A	B	1HNMR (400 MHz, MeOD) ? 9.05 (d. J = 2.1 Hz, 1H). 8.39- 8.24 (m. 2H), 8.16 (d, J = 4.9 Hz. 1H), 5.23 (d, J = 10.4 Hz, 1H). 2.86 (d, J = 15.6 Hz. 1H). 2.65 (m, 1H). 1.58 (m.. 7H), 1.37 (m,3H). 1.05 (s, 3H).	432.36	2.37

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84	B	B	C	1H NMR (300 MHz. MeOD) 7 8.67 (dd, J = 9.6,2.8 Hz, 1H), 8.16 (m. 2H), 8.04 (d, J = 4.0 Hz. 1H), 5.38 (dd, J = 10.8, 3.2 Hz, 1H), 4.724.23 (m, 4H). 2.86 (dd, J = 15.5, 3.3 Hz, 1H). 2.70 (dd, J = 15.5, 10.9 Hz, 1H), 1.15(s, 3H).	412.43	1.9
85	B	A	C	1H NMR (400 MHz, MeOD) 7 8.68 (dd, J = 9.3, 2.7 Hz, 1H). 8.47 (s. 1H), 8.38 (s, 1H), 8.32 (s, 1H), 5.17 (dd, J = 9.8, 3.5 Hz. 1H), 2.87 (m, 2H). 1.06 (s. 9H).	392.1	2.23
86	A	A	B	1HNMR (400 MHz, MeOD) ? 8.75 (dd, J = 9.7, 2.7 Hz, 1H). 8.18 (s, 2H), 8.00 (d, J = 4.2 Hz, 1H), 2.81 (dd, J = 15.2, 3.1 Hz, 1H), 2.55 (dd, J = 15.2,10.8 Hz, 1H), 2.00 (m, 3H), 1.821.49 (m, 12H).	454.34	2.4
87	A	A	A		389.13	2.02
88	A	A	B		388.36	2.01

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89	A	A	B		383.38	2.1
90	A	A	B	1HNMR (300 MHz, DMSO) ? 8.68 (s, 1H). 8.43 (d, J = 14.1 Hz, 2H). 8.23 (s, 1H). 4.96 (s. 2H). 2.68 - 2.55 (m, 4 H). 2.45 (s. 3H), 1.00 (s, 9H).	372.5	1.8
91	A	A	B		374.42	1.96
92	B	B	C		374.42	1.94
93	B	B	C		428.49	2.37
94	A	A	A	1HNMR (400 MHz, MeOD) ? 9.02 (d, J = 2.3 Hz, 1H). 8.40- 8.24 (m, 2H), 8.18 (d. J = 5.0 Hz, 1 H), 4.91 (d, J= 11.6 Hz, 1 H). 2.88 (dd, J = 16.0, 2.8 Hz, 1H), 2.65 (dd, J = 15.9,11.0 Hz, 1H). 2.01 (s, 3H). 1.77 (dd, J = 27.9, 11.9 Hz, 12H).	470.27	2.6

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85	A	A	B	1H NMR (400 MHz. MeOD) ? 8.62 (dd. J = 9.3, 2.6 Hz, 1H), 8.48 (t, J = 5.4 Hz, 1H). 8.32 (s. 1H), 8.29 (d, J = 5.5 Hz, 1H), 5.42 (dd. J = 10.0, 3.4 Hz, 1H), 2.84 (m. 2H), 2.18 (S, 1H). 1.65 (m. 4H), 1.39 (m. 6H).	414.28	2.12
86	A	A	B		407.37	2.79
87	A	A	A	Ή NMR (300 MHz, MeOD) δ 8.95 (d, J = 2.3 Hz. 1 H). 8.66 (d. J =2.3 Hz, 1H), 8.35 (d. J = 5.2 Hz, 1H), 5.12 (dd. J = 10.7, 2.9 Hz, 1H). 2.93 (dd, J = 16.5, 2.9 Hz. 1H). 2.73 (dd. J = 16.4, 10.7 Hz, 1H). 1.10 (s, 9H); LCMS Gradient 1090%, 0.1% formic acid, 5 minutes, C18/ACN, Rétention Time = 2.79 min. (M+H) 407.37	393.43	2.5

Table 2: IC_S0, EC_S0, NMR and LCMS Data of Compounds of W02005/095400

Compound s

Molecuie

MDCK cell IC50 (uM)

bDNA EC50 (uM)

bDN A EC99 (uM)

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C1	H	>20 (C)
C2	H	>20 (C)
C3		>20 (C)	3.38 (C)	9.37 (C)
C4		2.33 (B)	6.4 (C)	>16.7 (C)

Example 3: In Vivo Assay

For efficacy studies, Balb/c mice (4-5 weeks of âge) were challenged with 5x10³ TCIDjo in a total volume of 50 μΙ by intranasal by intranasal instillation (25 μΐ/nostril) under general anesthésia (Ketamine/Xylazine). Uninfected controls were challenged with tissue culture 10 media (DMEM, 50 μΙ total volume). 48 hours post infection mice began treatment with

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Compounds 1 and 2 at 30 mg/kg bîd for 10 days. Body weights and survival is scored daily for 21 days. In addition, Whole Body Plethysmography is conducted approximately every third day following challenge and is reported as enhanced pause (Penh). Total Survival, Percent Body Weight Loss on post challenge day 8 and Penh on study day 6/7 are reported.

Table 3. Influneza Therapeutic Mouse Mode! (Dosing @ 48 hours post infection with 30 mg/kg BID X 10 days)

Compounds	Percent Survival	Percent Weight Loss (Day 8)‘	WBP (Penh; Day 6)¹
1	100	26.6	1.88
2	100	14	2.03

¹ Average weight loss for untreated controls on day 8 is 30-32%.

² Average Penh scores for untreated controls on study day 6 or 7 is 2.2-2.5, and for uninfected mice is ~O.35-O.45.

Example 4: Synergystic/Antagonism Analyses

For synergy/antagonism analysis, test compounds were evaluated in a three day MDCK cell

CPE-bascd assay, infected with A/Puerto Rico/8/34 at an MOI of 0.01, in combination experiments with either the neuraminidase inhibitors oseltamivir carboxylate or zanamivir, or the polymerase inhibitorT-705 (see, e.g., Ruruta et al., Antiviral Reasearch, 82: 95-102 (2009), “T-705 (flavipiravir) and related compounds: Novel broad-spectrum inhibitors of RNA viral infections”), using the Blîss independence method (Macsynergy, Pritchard and Shipman, 1990). See, e.g., Prichard, M.N. and C. Shipman, Jr.,/1 three-dimensional model to analyze drug-drug interactions. Antiviral Res, 1990.14(4-5): p. 181-205. This standard method involves testing different concentration combinations of inhibitors in a checkerboard fashion and a synergy volume is calculated by comparing the observed response surface with the expected resuit calculated from simple additivity of the single agents alone. Synergy volumes greater than 100 are considered strong synergy and volumes between 50 and 100 are considered moderate synergy. Synergy volumes of zéro represent additivity and négative synergy volumes represent antagonism between the agents.

Table 4. Synergy/Antagonism Data

Combination experiments using the Bliss Independence (Macsynergy) Method
Biiss Independence	Synergy Volume, 95% Confidence	Resuit
Compound 1 + oseltamivir	360	strong synergy
Compound 1 + faviplravir	1221	strong synergy
Compound 1 +zanamivir	231	strong synergy
Compound 2 + oseltamivir	250	strong synergy
Compound 2 + favipiravir	100	synergy

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Compound 2 + zanamivir	220	strong synergy
Compound 14 + oseltamivir	545	strong synergy
Compound 14 + favipiravir	349	strong synergy
Compound 14 +zanamivir	255	strong synergy
Compound 57 + oseltamivir	268	strong synergy
Compound 57 + favipiravir	430	strong synergy
Compound 57 + zanamivir	171	strong synergy
Compound 57 + oseltamivir	348	strong synergy
Compound 87 + favipiravir	412	strong synergy
Compound 87 + zanamivir	2.7	insignificant

AU référencés provided herein are incorporated herein in its entirety by référencé. As used herein, ail abbreviations, symbols and conventions are consistent with those used in the contemporary scientific literature. See, e.g., Janet S. Dodd, ed., The ACSStyle Guide: A ManualforAuthors and Editors, 2nd Ed., Washington, D.C.: American Chemical Society, 10 1997.

It is to be understood that while the invention has been described in conjunction with the detailed description thereof, the foregoing description is intended to illustrate and not limit the scope of the invention, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims.

Claims

5 CLAIMS

What is claimed is:

1. A compound represented by Structural Formula (I):

or a pharmaceutically acceptable sait thereof, wherein:

ΙΟ X¹ is -F, -Cl, -CFj, -CN, or CH₃;

X² is-H,-F, or-Cl;

Z* isNorCH;

Z²isNorCR°;

Z³ is CH or N;

15 Y is -C(R⁴R^î)-[C(R⁶R⁷)]_n-Q or -C(R⁴)=C(R⁵)-Q;

R°is-H, -F, orCN;

R¹, R², and R² are each and independently-CH₃, -CH₂F, -CF₃, -C₂Hj, -CH₂CH₂F, -CH₂CF₃; or optionally R² and R³, or R¹, R² and R³, together with the carbon atom to which they are attached, form a 3-10 membered carbocyclic ring;

20 R⁴ and R⁵ are each and independently -H;

R⁶ and R⁷ are each and independently-H, -OH, -CHj, or-CF₃; or optionally, R^s and R⁷ together with the carbon atoms to which they are attached form a cyclopropane ring; and each Q is independently-C(O)OR, -OH, -CH₂OH, -S(O)R’, -P(O)(OH)₂, -SfO^R’,

25 -S(O)₂-NR”R”’, or a 5-membered heterocycle selected from the group consisting of:

y’is-H, -OH or-CH₂OH;

R is-H or Cm alkyl;

R’ is -OH, C_M alkyl, or -CH₂C(O)OH;

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R” is -H or-CHj;

R’” is -H, a 3-6 membered carbocyclic ring, or alkyl optionally substituted with one or more substîtuents selected from the group consisting of halogen, -OR* and -C(O)OR’;

R* is -H or Cm alkyl; and nisOor 1.
2. The compound of claim 1, wherein X¹ is -F or -Cl.
3. The compound of claim 1 or 2, wherein X is -F or -Cl.
4. The compound of any one of daims 1-3, wherein Z¹ is CH.
5. The compound of any one of daims 1-3, wherein Z¹ is N.
6. The compound of any one of daims 1 -5, wherein Z² is N, C-F, or C-CN.
7. The compound of any one of daims 1-6, wherein R¹, R², and R³ are each and independently -CHj or-C₂H_s; or optionally R² and R³, or R¹, R² and R³, together with the carbon atom to which they are attached, form a 3-10 membered carbocyclic ring.
8. The compound of any one of daims 1-6, wherein R , R , and R are each and independently -CHj, -CH₂F, -CFj, or -C₂H_S; or R¹ is -CH3, and R² and R³ together with the carbon atom to which they are attached form a 3-6 membered carbocyclic ring.
9. The compound of claim 8, wherein each of R¹, R², and R³ is independently -CHj or -C₂Hs; or R¹ is -CH3, and R² and R³ together with the carbon atom to which they are attached form a 3-6 membered carbocyclic ring.
10. The compound of any one of daims 1-9, wherein:

R⁶ and R⁷ are each and independently -H, -OH, -CHj, or -CFj.

-17017028
11. The compound of any one of daims 1-10, wherein each Q is independently -C(O)OR,

-OH, -CH₂OH, -SfO^R’, -S(O)₂-NR”R’”, or a 5-membered heterocycle selected from the group consisting of:
12. The compound of claim 11, wherein Q is -C(O)OR, -OH, -SfO^R’, or -S(O)₂-NR”R*’’.
13. The compound of any one of daims 1-12, wherein:

R* Îs-OH or-CH₂C(O)OH;

R” is-H; and

R”’ Îs-H, a 3-6 membered carbocyclîc ring, or optionally substituted Cmalkyl.
14. The compound of any one of daims 1-13, wherein R is -H.
15. The compound of any one of daims 1-14, wherein the compound is represented by

Structural Formula II:

or a pharmaceutically acceptable sait thereof.
16. The compound o f daim l, wherein the compound is represented by Structural Formula

-17117028 or a pharmaceutically acceptable sait thereof.
17. The compound of claim 16, wherein X* is -F or -Cl.
18. The compound of claim 16 or 17, wherein X² is -F or -Cl.
19. The compound of any one of daims 16-18, wherein Z¹ is CH.
20. The compound of any one of daims 16-18, wherein Z¹ is N.
21. The compound of any one of daims 16-20, wherein Z² is N, C-F, or C-CN.

M *
22. The compound o f any one o f daims 16-21, wherein R , R, and R are each and independently -CH3 or -C2H5; or optionally R² and R³, or R¹, R² and R³, together with the carbon atom to which they are attached, form a 3-10 membered carbocyclic ring.
23. The compound of any one of daims 16-21, wherein R¹, R², and R³ are each and independently-CH3, -CH₂F, -CF3, or-C2Hj; or R¹ is -CH3, and R² and R³ together with the carbon atom to which they are attached form a 3-6 membered carbocyclic ring.
24. The compound of daim 23, wherein each of R¹, R², and R³ is independently -CH3 or -C2HJ. or R¹ is -CHj, and R² and R³ together with the carbon atom to which they are attached form a 3-6 membered carbocyclic ring.
25. The compound of any one of daims 16-24, wherein Q is -C(O)OR, -OH, -S(O)₂R’, or -S(O)₂-NR”R”*.
26. The compound of any one of daims 16-25, wherein:

R’ is-OH or-CH₂C(O)OH;

R”is-H; and

R”* is -H, a 3-6 membered carbocyclic ring, or optionally substituted Ομ alkyl.

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5
27. The compound of any one of daims 16-26, wherein R is -H.
28. The compound of any one of claims 16-27, wherein the compound is represented by

Structural Formula (IV) or (V):

10 or a pharmaceutical ly acceptable sait thereof.
29. The compound of claim 1, wherein the compound is represented by any one of Structural Formulae (VI)-(X):

»

-17317028 or a pharmaceutically acceptable sait thereof, wherein:

R¹, R², and R³ are each and independently-CH₃, -CH₂F, -CF₃, -C₂H₃, -CH₂CH₂F, -CH₂CF₃; and ring P is a 3-6 membered carbocyclic ring.
30. The compound of claim 29, wherein X¹ is -F or -Cl.
31. The compound of claim 29 or 30, wherein X² is -F or -Cl.
32. The compound of any one of daims 29-31, wherein Z¹ is CH.
33. The compound of any one of daims 29-31, wherein Z¹ is N.
34. The compound of any one of daims 29-33, wherein Z² is N, C-F, or C-CN.
35. The compound of any one of daims 29-34, wherein R¹, R², and R³ are each and independently -CH₃ or -C₂H₃.
36. The compound of any one of daims 29-35, wherein:

R’ is-OH or-CH₂C(O)OH;

R” is-H;and

R”’ is-H, a 3-6 membered carbocyclic ring, or optionally substituted Cm alkyl.
37. The compound of any one of daims 29-36, wherein R is -H.
38. The compound of daim 1, selected from any one of the compounds depicted in FIG. 1 or a pharmaceutically acceptable sait thereof.
39. A pharmaceutical composition, comprising a compound according to any one of daims

1-38, and a pharmaceutically acceptable carrier, adjuvant or vehicle.

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5
40. A compound as described in any one of ctaims 1-38 for use in a method of inhibiting the réplication of influenza viruses in a biological sample or patient, the method comprising the step of administering to said biological sample or patient an effective amount of the compound.
41. The compound of claim 40, further comprising co-administering an additional therapeutic 10 agent.
42. The compound of claim 41, wherein the additional therapeutic agent is selected from an antiviral agent or an Influenza vaccine.

15
43. A compound as described in any one of daims 1-38 for use in a method of reducing the amount of influenza viruses in a biological sample or in a patient, the method comprising administering to said biological sample or patient an effective amount of the compound.
44. A compound as described in any one of daims 1-38 for use in a method of treating

20 influenza in a patient, the method comprising administering to said patient an effective amount ofthe compound.
45. A method preparing a compound represented by Structural Formula (I):

or a pharmaceutically acceptable sait thereof, comprising the steps of:

form a compound represented by Structural Formula (XX):

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G (XX); and ii) deprotecting the G group of the compound of Structural Formula (XX) under suitable conditions to form the compound of Structura! Formula (I),wherein:

the variables of Structural Formulae (I) and (XX), and compounds (A) and (B) are independently as defined in any one of claîms 1-38; and

L is a halogen; and when Z* is N, G is trityl; when Z¹ is CH, G is tosyl or trityl.
46. The method of claim 45, wherein L² is Br or Cl.
47.

A method preparing a compound represented by Structural Formula (I):

or a pharmaceutically acceptable sait thereof, comprising the steps of:

compound D: NH₂-Z^Î((CR^,R²R^Î)-Y to form a compound represented by Structural Formula (XX):

-17617028 ii) deprotecting the G group of the compound of Structural Formula (XX) under suitable conditions to form the compound of Structural Formula (I),wherein:

the variables of Structural Formulae (I) and (XX), and compounds (L), (K), and (D) are each and independently as defined in any one of daims 1-38; and

10 when Z¹ is N, G is trityl; when Z* is CH, G is tosyl or trityl.
48. A method preparing a compound represented by Structural Formula (I):

or a pharmaceutically acceptable sait thereof, comprising the steps of:

15 i) reacting Compound (G) with Compound (D):

under suitable conditions to form a compound represented by Structural Formula (XX):

-17717028 ii) deprotecting the G group of the compound of Structural Formula (XX) under suitable conditions to form the compound of Structural Formula (I),wherein:

the variables of Structural Formulae (I) and (XX), and Compounds (G) and (D) are each and independently as defîned in any one of daims 1-38;

L¹ is a halogen; and when Z¹ is N, G is trityl; when Z¹ is CH, G is tosyl or trityl.
49. The method of claim 48, wherein L¹ is Br or CI.
50. A compound represented by Structural Formula (XX) or a pharmaceutically acceptable sait thereof:

wherein the variables of Structural Formula (XX) are each and independently as defîned in any one of daims 1-38; and when Z¹ is N, G is trityl; when Z¹ is CH, G is tosyl or trityl.