NZ716783B2

NZ716783B2 - Inhibitors of influenza viruses replication

Info

Publication number: NZ716783B2
Application number: NZ716783A
Authority: NZ
Inventors: Upul K Bandarage; Randy S Bethiel; Michael J Boyd; Paul S Charifson; Michael P Clark; Ioana Davies; Hongbo Deng; John P Duffy; Luc J Farmer; Huai Gao
Original assignee: Vertex Pharmaceuticals Incorporated
Priority date: 2011-08-01
Filing date: 2012-08-01
Publication date: 2017-11-28

Abstract

Disclosed are 3-((2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-4,4-dimethylpentanoic acid and 3-((6-(1H-pyrazolo[3,4-b]pyridin-3-yl)pyridin-2-yl)amino)-4,4-dimethylpentanoic acid derivatives and analogues as represented by Formula (IV): or a pharmaceutically acceptable salt thereof, wherein: X1 is fluoro, chloro, trifluoromethyl, cyano, or methyl; X2 is hydrogen, fluoro, or chloro; Z1 is N or CH; Z2 is N or CH, CF, or CCN; R1, R2, and R3 are each independently methyl, fluoromethyl, trifluoromethyl, ethyl, 2-fluoroethyl, or 2,2,2,-trifluoroethyl; R4 and R5 are hydrogen; Q is –C(O)OR; and R is hydrogen or alkyl; provided that the compound of Formula (IV) is not (R)-3-((5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-4,4-dimethylpentanoic acid. Also disclosed is a pharmaceutical composition which comprises a compound of Formula (IV) or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier, adjuvant or vehicle; for treating or preventing influenza virus infection in a patient. n: X1 is fluoro, chloro, trifluoromethyl, cyano, or methyl; X2 is hydrogen, fluoro, or chloro; Z1 is N or CH; Z2 is N or CH, CF, or CCN; R1, R2, and R3 are each independently methyl, fluoromethyl, trifluoromethyl, ethyl, 2-fluoroethyl, or 2,2,2,-trifluoroethyl; R4 and R5 are hydrogen; Q is –C(O)OR; and R is hydrogen or alkyl; provided that the compound of Formula (IV) is not (R)-3-((5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-4,4-dimethylpentanoic acid. Also disclosed is a pharmaceutical composition which comprises a compound of Formula (IV) or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier, adjuvant or vehicle; for treating or preventing influenza virus infection in a patient.

Description

PATENTS FORM NO. 5 Our ref: SGR 237146NZPR DIVISIONAL APPLICATION FILED OUT OF NZ 620086 NEW ZEALAND PATENTS ACT 1953 COMPLETE SPECIFICATION Inhibitors of influenza s replication We, Vertex Pharmaceuticals Incorporated of 50 Northern Avenue, Boston, 02210, Massachusetts, United States of America hereby declare the invention, for which we pray that a patent may be granted to us and the method by which it is to be med, to be particularly described in and by the following statement: (Followed by page 1a) 103786555_1.docx:SGR:ewa INHIBITORS OF INFLUENZA VIRUSES REPLICATION RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No. 61/513,793, filed August 01, 2011, the entire teachings of which are incorporated herein by reference.

BACKGROUND OF THE INVENTION Influenza spreads around the world in seasonal epidemics, resulting in the deaths of hundreds of thousands annually - ns in pandemic years. For example, three influenza pandemics occurred in the 20th century and killed tens of millions of people, with each of these pandemics being caused by the appearance of a new strain of the virus in humans. Often, these new strains result from the spread of an existing influenza virus to humans from other animal species. nza is primarily transmitted from person to person via large virus-laden droplets that are generated when infected persons cough or sneeze; these large droplets can then settle on the mucosal surfaces of the upper respiratory tracts of susceptible individuals who are near (e.g. within about 6 feet) infected s. Transmission might also occur through direct contact or indirect contact with respiratory ions, such as touching surfaces contaminated with influenza virus and then ng the eyes, nose or mouth. Adults might be able to spread influenza to others from 1 day before g symptoms to approximately 5 days after ms start. Young children and s with weakened immune s might be infectious for 10 or more days after onset of ms.

Influenza viruses are RNA viruses of the family Orthomyxoviridae, which comprises five genera: Influenza virus A, Influenza virus B, nza virus C, Isavirus and Thogoto virus.

The Influenza virus A genus has one species, influenza A virus. Wild aquatic birds are the natural 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 - 1a - (Followed by page 2) human inﬂuenza pandemics. The type A s 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 have been conﬁrmed in humans, ordered by the number ofknown human pandemic , 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 pandemic threat in the 2007—08 inﬂuenza season), H7N7 (which has l 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 ion is the seal. This type of inﬂuenza mutates at a rate 2—3 times slower than type A and consequently is less genetically diverse, with only one inﬂuenza B serotype. As a result of this lack of antigenic diversity, a degree of immunity to inﬂuenza B is usually acquired at an early age. r, inﬂuenza B s enough that lasting immunity is not le. This reduced rate of antigenic change, combined with its d host range (inhibiting cross species antigenic shift), s that pandemics of inﬂuenza B do not occur.

The Inﬂuenza virus C genus has one species, inﬂuenza C virus, which infects humans and pigs and can cause severe illness and local epidemics. 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 y roughly spherical, although ntous forms can occur. Unusually for a virus, its genome is not a single piece of nucleic acid; instead, it contains seven or eight pieces of segmented negative-sense RNA. The Inﬂuenza A genome encodes 11 proteins: hemagglutinin (HA), neuraminidase (NA), nucleoprotein (NP), M1, M2, NSl, NSZ(NEP), PA, PB 1, PB 1 -F2 and PB2.

HA and NA are large glycoproteins on the outside of the viral particles. HA is a lectin that mediates 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 have been targets for antiviral drugs. Furthermore, they are antigens to which antibodies can be raised. Inﬂuenza A viruses are classiﬁed into subtypes based on dy responses to HA and NA, forming the basis of the H and N ctions (vide supra) in, for example, H5Nl.

Inﬂuenza produces direct costs due to lost productivity and ated medical treatment, as well as indirect costs of preventative measures. In the United , inﬂuenza is responsible for a total cost of over $10 billion per year, while it has been estimated that a future pandemic could cause hundreds of billions of dollars in direct and indirect costs. tative costs are also high. Governments worldwide have spent billions ofUS. dollars preparing and planning for a potential H5Nl avian inﬂuenza pandemic, with costs ated with sing drugs and vaccines as well as developing disaster drills and strategies for improved border controls.

Current treatment options for za include vaccination, and chemotherapy or chemoprophylaxis with anti-viral medications. Vaccination against inﬂuenza with an inﬂuenza vaccine is often recommended for high-risk groups, such as children and the y, or in people that have asthma, diabetes, or heart disease. However, it is possible to get vaccinated and still get inﬂuenza. The vaccine is ulated each season for a few speciﬁc inﬂuenza strains but cannot possibly include all the strains actively infecting people in the world for that season. It takes about six months for the manufacturers to formulate and produce the millions of doses required to deal with the seasonal epidemics; occasionally, a new or overlooked strain becomes prominent during that time and infects people although they have been vaccinated (as by the H3N2 Fujian ﬂu in the 2003—2004 inﬂuenza season). It is also possible to get ed just before vaccination and get sick with the very strain that the vaccine is ed to t, 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 e 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 ofRNA proofreading enzymes, the RNA-dependent RNA polymerase of inﬂuenza vRNA makes a single nucleotide insertion error roughly every 10 thousand nucleotides, which is the approximate length of the za vRNA. Hence, nearly every newly-manufactured inﬂuenza virus is a mutant—antigenic drift. The separation of the genome into eight separate segments ofvRNA allows mixing or reassortment ofvRNAs if more than one viral line has ed a single cell. The resulting rapid change in viral genetics produces antigenic shifts and allows the virus to infect new host species and y overcome WO 19828 protective immunity. ral drugs can also be used to treat inﬂuenza, with neuraminidase inhibitors being particularly effective, but viruses can develop resistance to the standard antiviral drugs.

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

SUMMARY OF THE INVENTION The present invention lly relates to methods of treating inﬂuenza, to methods of inhibiting the replication 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 present invention is directed to a compound represented by Structural Formula (1): R1fRs | \ / ,21 N N or a pharmaceutically acceptable salt f, n: X1 is —F, —c1, -CF3, —CN, or CH3; X2 is —H, —F, or —Cl; Z1 is N or CH; Z2 is N or CR0; Z3 is CH or N; Y is —C(R4R5)-[C(R6R7)]n-Q or —C(R4)=C(R6)-Q; R0 is —H, -F, or CN; R1, R2, and R3 are each and independently —CH3, -CH2F, -CF3, —C2H5, -CH2CH2F, -CH2CF3; or optionally R2 and R3, or R1, R2 and R3, er with the carbon atom to which they are attached, form a 3-10 membered carbocyclic ring; R4 and R5 are each and independently —H; R6 and R7 are each and independently —H, -OH, -CH3, or —CF3; or optionally, R5 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, -CH20H, -S(O)R’, -P(O)(OH)2, -S(O)2R’, -S(O)2-NR’ ’R”’, or a 5-membered heterocycle selected from the group ting of:, 2“ij 1 Hi] E V7” JQ is —H, —OH or —CH20H; R is —H or C1_4 alkyl; R’ is —OH, C1_4 alkyl, or -CH2C(O)OH; R’ ’ is —H or -CH3; R’’ ’ is —H, a 3-6 membered yclic ring, or C1_4 alkyl optionally substituted with one or more substituents selected from the group consisting of halogen, -ORa and —C(O)ORa; R81 is —H or C1_4 alkyl; and n is 0 or 1.

In another embodiment, the present 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 salt thereof) and a pharmaceutically acceptable carrier, adjuvant or vehicle.

In yet another embodiment, the present invention is directed to a method of inhibiting the replication 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 sed herein (e.g., a compound represented by any one of ural Formulae (I) — (X), or a pharmaceutically acceptable salt thereof).

In yet another embodiment, the present ion is directed to a method of ng the amount of inﬂuenza viruses in a biological sample or in a patient, sing stering 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 acceptable salt thereof).

] In yet r ment, the present 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 sed herein (e.g., a compound represented by any one of Structural Formulae (I) — (X), or a pharmaceutically acceptable salt thereof).

The present invention also provides use of the compounds described herein for inhibiting the replication of za viruses in a biological sample or patient, for reducing the amount of inﬂuenza viruses in a biological sample or patient, or for ng inﬂuenza in a Also provided herein is use of the compounds bed herein for the manufacture of a medicament for treating inﬂuenza in a patient, for reducing the amount of inﬂuenza viruses in a biological sample or in a patient, or for inhibiting the replication of inﬂuenza viruses in a biological sample or patient.

Also provided herein are the nds represented by Structural Formula (XX): ZWNH\ 3/Y R 1iRs | \21 N/ / or a pharmaceutically acceptable salt thereof. Without being bound to a particular , 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 deﬁned herein; and when Z1 is N, G is trityl (i.e., C(Ph)3 where Ph is phenyl), and when Z1 is CH, G is tosyl (Ts: CH3C6H4S02) or trityl.

] The invention also provides methods of preparing a compound represented by Structural Formula (I) or a pharmaceutically acceptable salt thereof. In one embodiment, the methods employ the steps of: / N R1):R3 / \ I 21 L2 R N N B i) reacting compound A: (A) ( with compound B : G )to form a compound represented by Structural Formula (XX): | \ / ,z1 N 'l G (XX); and ii) deprotecting the G group of the compound of Structural Formula (XX) under suitable conditions to form the nd of Structural Formula (I),wherein: the variables of ural Formulae (I) and (XX), and nds (A) and (B) are independently as deﬁned herein; and L2 is a halogen; and when Z1 is N, G is trityl; when Z1 is CH, G is tosyl or trityl.

In yet another embodiment, the methods employ the steps of: i) reacting compound K or L: i: (K) i: (L) with compound D: NHz-Z3(C(R1R2R3))-Y to form a compound represented by Structural Formula (XX): H\ \ 3/Y /N R I \21 / / N “1‘ G (XX); and 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 ndently as deﬁned herein; and when Z1 is N, G is trityl; when Z1 is CH, G is tosyl or trityl.

In yet another embodiment, the methods employ the steps of: i) ng nd (G) with Compound (D): G (G), NHz-Z3(C(R1R2R3))-Y (D), under suitable conditions to form a compound represented by Structural Formula (XX): ZWNH\ 3/Y R1iv N “1‘ G (XX); and ii) deprotecting the G group of the nd of ural 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 deﬁned herein; L1 is a halogen; and when Z1 is N, G is trityl; when Z1 is CH, G is tosyl or trityl.

BRIEF DESCRIPTION OF DRAWINGS shows certain compounds of the ion.

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 of the claims. In some embodiments, the compounds of the invention are represented by any chemical formulae depicted in Table l and or pharmaceutically able salts thereof. In some embodiments, the compounds of the invention are presented by Structural Formulae (I) - (X), or a pharmaceutically able salt f, wherein the variables are each and independently as depicted in the chemical formulae in Table l and In one embodiment, the compounds of the invention are represented by Structural Formula (I) or pharmaceutically acceptable salts thereof: /N R1 ’l‘Rs2 X1 R N N wherein the values of the variables of ural Formula (I) are as described below.

The first set of values of the variables of Structural Formula (I) is as follows: X1 is —F, —Cl, -CF3, —CN, or CH3. In one aspect, X1 is —F, —Cl, or -CF3. In r aspect, X1 is —F or —Cl.

X2 is —H, —F, —Cl, or -CF3. In one aspect, X2 is —F, —Cl, or -CF3. In another aspect, X2 is— F or —Cl.

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

Z2 is N or CR0. 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, Z3 is CH.

Y is —C(R4R5)-[C(R6R7)]n-Q or —C(R4)=C(R6)-Q.

R0 is —H, -F, or CN.

R1, R2, and R3 are each and ndently —CH3, -CH2F, -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 (including bridged carbocyclic ring, such as adamantly ring). In one aspect, R1, R2, and R3 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. In another aspect, each of R1, R2, and R3 is independently —CH3, -CH2F, -CF3, or —C2H5; 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. In another 2012/049097 aspect, R1, R2, and R3 are each and independently —CH3, -CH2F, -CF3, 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 with the carbon atom to which they are attached, form a 3-6 membered carbocyclic , together ring. Speciﬁc examples of carbocyclic ring include cyclopropyl, utyl, cyclopentyl, cylcohexyl, and bridged rings, such as adamantly group. In yet r aspect, R1, R2, and R3 are each and independently —CH3.

R4 and R5 are each and independently —H.

R6 and R7 are each and ndently —H, -OH, -CH3, or —CF3; or optionally, R5 and R7 together with the carbon atoms to which they are attached form a ropane 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, -CH20H, -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:, z/NQJQE \EL “til E W JQ, wherein IQ is —H, -OH or -CH20H. Speciﬁc examples of the 5-membered heterocycles include: MN?” “:0 ”15%WE \Efﬁ/EE/”E\~ ‘1? \ l OH. In one aspect, each Q is ndently —C(O)OR, -OH, -CH20H, -S(O)2R’, -S(O)2-NR”R’ ’ ’, or a ered N\ H / \N \o /N E B / \ heterocycle selected from the group ting of: N CH70H, o, O‘\\N E < E//N‘\\l EM N/N . .

H and OH. In another aspect, each Q is independently —C(O)OH, -OH, -CH20H, -S(O)2R’, -S(O)2-NR’ ’R’”, or a 5-membered heterocycle selected from the group N N o /§N N\O /\ \N EVE/”\A/K/ EVE/hie”/N EV] consisting of: N CH70H, o, H ,and OH. In another aspect, each Q is independently —C(O)OR, -OH, -S(O)2R’, or -S(O)2-NR’ ’R’ ”. In yet another aspect, each Q is ndently —C(O)OH, -OH, -S(O)2R’, or -NR’ ’R”’.

R is —H or C1_4 alkyl. In one aspect, R is —H.

R’ is —OH, C1_4 alkyl, or -CH2C(O)OH. In one aspect, R’ is —OH or -CH2C(O)OH.

R” is —H or -CH3. In one aspect, R” is —H.

R’’ ’ is —H, a 3-6 membered carbocyclic ring, or C1_4 alkyl optionally tuted with one or more substituents selected from the group consisting of halogen, -ORa and —C(O)ORa. In one aspect, R’ ” is —H, a 3-6 ed carbocyclic ring, or optionally substituted C1_4 alkyl. In another , R’ ’ ’ is —H or optionally substituted C1_4 alkyl.

R81 is —H or C1_4 alkyl. In one aspect, R81 is —H. n is 0 or 1.

The second set of values of the variables of Structural Formula (I) is as follows: X1 is —F or —Cl.

X2 is —F or —Cl.

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

The third set of values of the variables of ural Formula (I) is as follows: X1 is —F or —Cl. 21 is CH.

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 fourth set of values of the variables of Structural Formula (I) is as follows: X2 is —F or —Cl. 21 is CH.

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

The ﬁfth set of values of the variables of Structural Formula (I) is as follows: X1 is —F or —Cl.

Z1 is N 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 sixth set of values of the variables of Structural Formula (I) is as follows: -1]- X2 is —F or —Cl.

The seventh set of values of the variables of Structural Formula (I) is as follows: X1 is —F or —Cl.

X2 is —F or —Cl. 21 is CH.

The eighth set of values of the variables of ural a (I) is as follows: X1 is —F or —Cl.

X2 is —F or —Cl.

Z1 is N.

] The ninth set of values of the variables of Structural Formula (I) is as s: X1 is —F or —Cl. 22 is N, C-F, or C—CN.

The tenth set of values of the variables of Structural Formula (I) is as follows: X2 is —F or —Cl 22 is N, C-F, or C—CN.

The eleventh set of values of the variables of Structural Formula (I) is as follows: 21 is CH. 22 is N, C-F, or C—CN.

The eleventh set of values of the variables of Structural a (I) is as follows: Z1 is N. 22 is N, C-F, or C—CN.

] The twelfth set of values of the variables of Structural a (I) is as follows: X1 is —F or —Cl.

X2 is —F or —Cl.

Z1 is N. 22 is N, C-F, or C—CN.

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

] The thirteenth set of values of the variables of Structural Formula (I) is as follows: X1, X2, Z, 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 (1).

Each of R1, R2, and R3 is independently —CH3, -CH2F, -CF3, or —C2H5; 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.

The fourteenth set of values of the variables of Structural Formula (I) is as follows: X1, X2, Zl, Zz, R1, R2, and R3 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, -CH3, or —CF3.

The ﬁfteenth set of values of the variables of Structural a (I) is as s: X1, X2, Zl, Zz, 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, -CH20H, -S(O)2R’, -S(O)2-NR”R”’, or a 5- a} A membered heterocycle selected from the group consisting of: CH70H, “\O O\ \BN/K i \D l o, and OH.

The sixteenth set of values of the variables of Structural a (I) is as s: X1, X2, Zl, Zz, R1, R2, R3, R6, and R7 are each and independently as bed above in any one of the ﬁrst through fourteenth sets of values of the variables of Structural Formula (1).

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

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

The seventeenth set of values of the variables of Structural Formula (I) is as follows: X1, X2, Zl, Zz, R1, R2, R3, R6, and R7 are each and independently as bed above in any one of the ﬁrst through fourteenth sets of values of the variables of Structural Formula (1).

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

The eighteenth set of values of the variables of Structural Formula (I) is as follows: X1, X2, Zl, Zz, 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 les of Structural Formula (1).

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

The nineteenth set of values of the variables of ural Formula (I) is as follows: WO 19828 X1, X2, Zl, Zz, 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 O)OH.

R” is —H.

R’’ ’ is —H, a 3-6 membered carbocyclic ring, or optionally substituted C1_4 alkyl.

The twentieth set of values of the variables of Structural a (I) is as follows: X1, X2, Zl, Zz, R1, R2, R3, R6, 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 (1).

Each Q independently is —C(O)OH, -S(O)20H, -S(O)2CH2C(O)OH, -S(O)2-NH(C1_4 alkyl).

In another embodiment, the nds of the invention are represented by any one of Structural Formulae (II) - (V), or pharmaceutically acceptable salts thereof: X2 R5 R4 Q X2 R5 R4 Q WW3: SLR?n NH z KKK\ ”R7 Z R6 5 2 R6 / N Rl+ N R1 3 X1 X1 \ R2 \ R2 | \ \ Z1 l /Z1 / N/ / N N N H (11), H (111), X2 R5 X2 R5 R4 R4 g \ NH 0 g \ NH ﬂoj—Q Z Z /N /N R1 R1 1 R3 1 R3 \ R2 X \ R2 | \ \ Z1 l 21 / N/ / N N/ H (IV), and N H (V). wherein values of the variables of Structural Formulae (II) - (V) are each and independently as described above in any one of the ﬁrst h twentieth sets of values of the variables of ural a (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: x2 R5 4 X2 R5 ZWNH R\kl—COZR WNHR4kl—CozR Z /N R19\ 1 3 N R R X1 R2 x1 N/ / / N N (VI), H (VII), x2 R5 WNHR4\l_ OH \ S(O)2R‘ /N N R1 R1 R3 9\R3 X1 x1 R2 R2 \ \ l \ \ Z1 l 21 / / ’ / N N N N H (VIII), H (IX), X2 R5 WNHR4‘kl—S(O)2NR"R'" z N R19\R3 X1 R2 | \21 / / N N H (X), or a pharmaceutically acceptable salt thereof, wherein: R1, R2, and R3 are each and independently —CH3, -CH2F, -CF3, —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: R is H; R’ is —OH or -CH2C(O)OH.

R” is —H.

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, respectively: In yet another embodiment, the nds of the invention are represented by any one of Structural Formulae (I) — (X) or a pharmaceutically acceptable salt thereof, wherein values of the variables are each and independently as shown in the compounds of Table l or FIG.

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

] As used herein, a reference to compound(s) of the invention (for example, the compound(s) of ural Formula (I), or compound(s) of claim 1) will include pharmaceutically acceptable salts thereof The nds of the ion described herein can be prepared by any le method known in the art. For example, they can be prepared in accordance with procedures described in WO 95400, , , , W0 2010/011772, , and ﬁled on June 17, 2010. For example, the compounds shown in Table 1 and and the c compounds depicted above can be prepared by any suitable method known in the art, for example, WO 95400, , , , WP 2010/011772, , and 8988, and by the exemplary syntheses described below under Exempliﬁcation.

The t invention provides s of preparing a compound represented by any one of Structural Formulae (I) — (X). In one embodiment, the compounds of the invention can be prepared as depicted in General Schemes 1-4. Any suitable condition(s) known in the art can be employed in the ion for each step depicted in the schemes.

] In a speciﬁc 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 nd 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 (A), (B) and Structural Formula (XX) are each and independently as described above for Structural ae (I) — (X).

Typical examples for L1 and L2 are each and independently C1 or Br. The methods further comprise the step of deprotecting the G group under suitable conditions to form the compounds of Structural Formula (1). Any suitable condition(s) known in the art can be employed in the invention for each step ed in the schemes. For example, any suitable condition described in and 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 of 3)4 or Pd2(dba)3 (dba is dibenzylidene acetone). For e, the de-tritylation step can be performed under an acidic condition (e.g., triﬂuoroacetic acid (TFA)) in the presence of, for example, EthiH (Et is ethyl). Speciﬁc 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. c exemplary ions are described in the Exempliﬁcation below.

General Scheme 1 CR1RR2 3 )-Y —> ZWNH\Zs/Y N (D) R1+R3 L2 R2 \ \21 N/ N, /N R3 | \ / ,z1 N I}! (XX) ZWNW/Y R1+R3 | \ / / ] In another speciﬁc embodiment, as shown in General Scheme 2, the methods comprise the step of reacting Compound (G) with nd (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 ing variables of Compounds (G), (D) and Structural a (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 (1). 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 amination condition known in the art can be ed in the invention for the reaction of nds (G) and (D), and any suitable condition for deprotecting a Tr group can be employed in the invention for the ection step. For example, the amination step can be performed in the presence of a base, such as NEt3 or N(iPr)2Et. For example, the de-tritylation step can be performed under an acidic ion (e.g., roacetic acid (TFA)) in the presence of, for example, EthiH (Et is ethyl). Additional speciﬁc exemplary conditions are described in the Exempliﬁcation below Optionally, the method further comprises the step of preparing Compound (G) by ng 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 and for the coupling of a dioxaboralan with a chloro-pyrimidine can be ed for the on between Compounds (E) and (B). Speciﬁcally, the reaction between compounds (E) and (B) can be performed in the presence of Pd(PPh3)4 or Pd2(dba)3 (dba is dibenzylidene acetone). Specif1c exemplary conditions are described in the Exemplification below.

General Scheme 2 22 / L1 + \ —> _N \ 1 / I \ L 2 Z1 (E) hcl; / N’ (B) G NH2_Z3((CR1R2R3)- zWNW/Y /N R1+R3 | \ / ,21 N '1“ (XX) WNH\3/Y z /N R1LR3 | \ / / N N In yet another speciﬁc 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 ural Formula (XX), wherein G is trityl and the remaining variables of Compounds (K), (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 ural Formula (1). Any le ion(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 the art, for example, in WO 2005/095400 and for the coupling of an amine with a sulﬁnyl group can be employed for the reaction of nds (K) with Compound (D). For example, nds (D) and (K) can be reacted in the presence of a base, such as NEt3 or N(iPr)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, EthiH (Et is ethyl). Additional speciﬁc 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-chloroperbenzoic acid. ally, the method r ses the step of preparing Compound (J) by reacting nd (H) with Compound (B). Any suitable conditions know in the art can be employed in this step. For example, any suitable condition described in and 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(PPh3)4 or Pd2(dba)3 (dba is dibenzylidene e). Speciﬁc ary conditions are described in the Exempliﬁcation below.

General Scheme 3 X H O\B/O zis/\\_N/ 22— S/ X1 X1 —> \ \ / + \ \ N | z1 / / / L2 N N N N (J G ) (H) G R2 \ X1 \ \ (CRRR)-Y3 1 2 3 1 \ I / ,2 / ,21 (D) N N.

N '1‘ (XX) G () ZWNH‘ﬁ/Y3 | \21 / / N N In yet another speciﬁc embodiment, as shown in l 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 is trityl and the remaining variables of Compounds (L), (D) and ural Formula (XX) are each and ndently 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 (1). Any le 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 the art, for example, in W0 2005/095400 and 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 d in the presence of a base, such as NEt3 or N(iPr)2(Et). For e, the de-tritylation step can be performed under an acidic condition (e.g., triﬂuoroacetic acid (TFA)) in the presence of, for example, EtgsiH (Et is ethyl). onal c 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 hloroperbenzoic 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 R2 \ \ NH2_Z3((CR1R2R3)-Y I /z1 I \ 1 / / /Z (D) N N.

N I]! (XX) G ZWNH\Z3/Y R1+R3 | \ N N/ ] Compounds (A)—(K) can be prepared by any suitable method known in the art.

Speciﬁc exemplary synthetic s of these compounds are described below in the Exempliﬁcation. In one embodiment, Compounds (A), (G), (J), (K) and (L) can be prepared as described in General Schemes 1-4.

In some ments, the present 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 claims and G is trityl. Speciﬁc examples of the compounds ented by Structural formula (XX) are shown below in the Exempliﬁcation.

Some speciﬁc examples include: Compounds 33, 83, 28a, 34a, 39a, 42a, 513, 57a, 80a, 84a, 9021, 101a, 119a, 144a, 148a, 154a, 159a, 170a, 176a, 182a, 184a, 191a, 197a, 207a, and 21821, which are shown in the Exempliﬁcation below.

Definitions and General Terminology For purposes of this invention, the chemical elements are identiﬁed in accordance with the Periodic Table of the Elements, 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, MB. 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 rated 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 l, the term “substituted”, whether preceded by the term “optionally” or not, refers to the ement of one or more hydrogen radicals in a given structure with the radical of a speciﬁed substituent. Unless otherwise indicated, an optionally substituted group may have 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 ed from a speciﬁed group, the substituent may be either the same or different at each position. When the term “optionally substituted” precedes a list, said term refers to all of the subsequent substitutable groups in that list. If a substituent radical or ure is not identiﬁed or deﬁned as “optionally substituted”, the substituent radical or structure is unsubstituted. For example, ifX is optionally tuted C1_ C3alkyl or ; X may be either optionally substituted C1-C3 alkyl or optionally tuted . Likewise, if the term “optionally substituted” follows a list, said term also refers to all of the substitutable groups in the prior list unless ise indicated. For example: ifX is C1- C3alkyl or phenyl wherein X is optionally and independently substituted by JX, then both C1- C3alkyl and phenyl may be ally substituted by JX.

The phrase "up to", as used herein, refers to zero 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 3. As described herein, a ed number range of atoms includes any integer therein.

For example, a group having from 1-4 atoms could have 1, 2, 3, or 4 atoms.

Selection of substituents and combinations of substituents oned by this ion are those that result in the formation of stable or chemically le compounds. The term “stable”, as used herein, refers to compounds that are not substantially altered when ted to conditions to allow for their production, detection, and, speciﬁcally, their recovery, puriﬁcation, and use for one or more of the purposes sed herein. In some embodiments, a stable nd or chemically feasible compound is one that is not substantially d when kept at a temperature 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 result in a stable structure are contemplated. Such choices and combinations will be apparent to those of ordinary skill in the art and may be determined without undue experimentation.

The term “aliphatic” or atic 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. Unless otherwise speciﬁed, aliphatic groups contain 1-20 aliphatic carbon atoms. In some embodiments, aliphatic groups contain l- 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 n 1-4 aliphatic carbon atoms. Aliphatic groups may be linear or branched, substituted or unsubstituted alkyl, alkenyl, or alkynyl groups.

Specific examples include, but are not limited to, methyl, ethyl, isopropyl, n-propyl, tyl, 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 arbon 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 C1-C6 alkyl or C1-C4 alkyl. In some embodiments, the yl” is C2-C6 alkenyl or C2-C4 l. In some embodiments, the “alkynyl” is C2-C6 alkynyl or C2-C4 alkynyl.

The term “cycloaliphatic” (or “carbocycle” or “carbocyclyl” or cyclic”) refers to a omatic 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 cmmnWmmm4mTInwuﬂmemmmmmmdwmmbmdkmmnmeESm6fme term includes monocyclic, bicyclic or polycyclic, ﬁlSGd, spiro 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 ment is on the carbocyclic ring. “Fused” bicyclic ring systems se two rings which share two ing ring atoms.

Bridged ic group comprise two rings which share three or four adjacent ring atoms. Spiro bicyclic ring systems share one ring atom. Examples of liphatic groups include, but are not limited to, cycloalkyl and cycloalkenyl groups. Speciﬁc examples include, but are not limited to, cyclohexyl, cyclopropenyl, and cyclobutyl.

The term ocycle” (or “heterocyclyl”, or “heterocyclic” or “non-aromatic heterocycle”) as used herein refers to a non-aromatic ring system which can be saturated or contain 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 se up to three heteroatoms selected from N, S and 0 within the ring. In other ments, non-aromatic heterocyclic rings comprise up to two heteroatoms ed from N, S and 0 within the ring system. In yet other embodiments, non-aromatic cyclic rings comprise up to two heteroatoms selected from N and 0 within the ring system. The term includes monocyclic, bicyclic or polycyclic ﬁlSGd, 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, pyrazolidinyl, imidazolidinyl, azepanyl, diazepanyl, triazepanyl, azocanyl, diazocanyl, triazocanyl, oxazolidinyl, olidinyl, thiazolidinyl, isothiazolidinyl, oxazocanyl, oxazepanyl, thiazepanyl, thiazocanyl, benzimidazolonyl, ydroﬁlranyl, ydroﬁlranyl, tetrahydrothiophenyl, tetrahydrothiophenyl, morpholino, including, for example, 3-morpholino, 4-morpholino, 2- thiomorpholino, 3-thiomorpholino, 4-thiomorpholino, l-pyrrolidinyl, 2-pyrrolidinyl, 3- pyrrolidinyl, l-tetrahydropiperazinyl, 2-tetrahydropiperazinyl, 3-tetrahydropiperazinyl, l- piperidinyl, 2-piperidinyl, 3-piperidinyl, l-pyrazolinyl, 3-pyrazolinyl, 4-pyrazolinyl, 5- pyrazolinyl, l-piperidinyl, 2-piperidinyl, 3-piperidinyl, ridinyl, 2-thiazolidinyl, 3- thiazolidinyl, 4-thiazolidinyl, l-imidazolidinyl, 2-imidazolidinyl, 4-imidazolidinyl, 5- imidazolidinyl, indolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, benzothiolanyl, benzodithianyl, 3-(1-alkyl)-benzimidazolonyl, and l,3-dihydro-imidazolonyl.

The term “aryl” (or “aryl ring” or “aryl group”) used alone or as part of a larger moiety as in “aralkyl”, oxy”, or “aryloxyalkyl” refers to carbocyclic aromatic ring systems.

The term “aryl” may be used interchangeably with the terms “aryl ring” or “aryl group”.

“Carbocyclic aromatic ring” groups have only carbon ring atoms (typically six to fourteen) and include monocyclic aromatic rings such as phenyl and fused polycyclic ic ring systems in which two or more carbocyclic aromatic rings are fused to one another. es include l-naphthyl, 2-naphthyl, l-anthracyl and 2-anthracyl. Also included within the scope of the term “carbocyclic aromatic ring” or “carbocyclic aromatic”, as it is used herein, is a group in which an aromatic ring is “fused” to one or more non-aromatic rings (carbocyclic or heterocyclic), such as in an indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl, where the radical or point of attachment is on the aromatic ring.

The terms “heteroaryl”, “heteroaromatic”, “heteroaryl ring”, “heteroaryl group”, “aromatic heterocycle” or oaromatic group”, used alone or as part of a larger moiety as in “heteroaralkyl” or “heteroarylalkoxy”, refer to heteroaromatic ring groups haVing ﬁve to fourteen members, including monocyclic heteroaromatic rings and polycyclic ic rings in which a monocyclic aromatic ring is fused to one or more other aromatic ring. Heteroaryl groups have one or more ring heteroatoms. Also included within the scope of the term oaryl”, as it is used herein, is a group in which an ic ring is “ﬁased” to one or more omatic rings (carbocyclic or heterocyclic), where the radical or point of attachment is on the ic ring. ic 6,5 heteroaromatic ring, as used herein, for example, is a six membered heteroaromatic ring fused to a second ﬁve 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, lyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl or thiadiazolyl including, for example, 2-ﬁ1ranyl, nyl, N—imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4- isoxazolyl, 5-isoxazolyl, 2-oxadiazolyl, 5-oxadiazolyl, olyl, 4-oxazolyl, olyl, 3- pyrazolyl, 4-pyrazolyl, l-pyrrolyl, 2-pyrrolyl, olyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2- pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2- lyl, 5-triazolyl, olyl, 2-thienyl, 3-thienyl, carbazolyl, benzimidazolyl, benzothienyl, benzofuranyl, indolyl, riazolyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, isoquinolinyl, l, isoindolyl, acridinyl, benzisoxazolyl, isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, l,2,4-oxadiazolyl, l,2,3-triazolyl, l,2,3-thiadiazolyl, l,3,4-thiadiazolyl, 1,2,5- thiadiazolyl, purinyl, nyl, l,3,5-triazinyl, quinolinyl (e.g., 2-quinolinyl, 3-quinolinyl, 4- inyl), and isoquinolinyl (e.g., l-isoquinolinyl, 3-isoquinolinyl, or 4-isoquinolinyl).

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

As used herein, a “bicyclic ring ” includes 8-12 (e.g., 9, 10, or 11) membered structures that form two rings, wherein the two rings have 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 ic heteroaryls.

As used , a “bridged bicyclic ring ” 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 d to, adamantanyl, norbomanyl, bicyclo[3.2.l]octyl, bicyclo[2.2.2]octyl, bicyclo[3.3.l]nonyl, bicyclo[3.2.3]nonyl, bicyclo[2.2.2]octyl, l-aza-bicyclo[2.2.2]octyl, 3-aza-bicyclo[3.2.l]octyl, and 2,6-dioxatricyclo [3.3.l.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, cycloalkyl, (cycloalkyl)all<yl, heterocycloalkyl, (heterocycloalkyl)alkyl, carbocyclic aryl, heteroaryl, alkoxy, cycloalkyloxy, heterocycloalkyloxy, (carbocyclic xy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, aroyl, heteroaroyl, nitro, carboxy, alkoxycarbonyl, alkylcarbonyloxy, aminocarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino, (cycloalkylalkyl)carbonylamino, (carbocyclic aryl)carbonylamino, aralkylcarbonylamino, ocycloalkyl)carbonylamino, (heterocycloalkylalkyl)carbonylamino, arylcarbonylamino, heteroaralkylcarbonylamino, cyano, halo, hydroxy, acyl, mercapto, alkylsulfanyl, sulfoxy, 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 molecule. The two atoms that are connected through the bridge (usually but not always, two tertiary carbon atoms) are denotated as “bridgeheads”.

As used , the term “spiro” refers to ring systems having one atom (usually a quaternary carbon) as the only 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 cyclic ring.

A “substitutable ring atom” in an ic group is a ring carbon or en atom bonded to a hydrogen atom. The hydrogen can be optionally ed 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 e ring carbon or nitrogen atoms when the structure depicts that they are already attached to a moiety other than hydrogen.

The term “heteroatom” means one or more of oxygen, , nitrogen, phosphorus, or n (including, any oxidized form of nitrogen, sulfur, phosphorus, or n; the quatemized form of any basic en or; a substitutable nitrogen of a cyclic ring, for example N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR+ (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 ed 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*, =NNHCOZ(C1_4 alkyl), =NNHSOZ(C1_4 alkyl), or =NR*, wherein each R* is independently selected from hydrogen or an optionally substituted C1_6 aliphatic. Optional substituents on the aliphatic group of R* are selected from NHZ, NH(C1_4 aliphatic), N(C1_4 aliphatic)2, halogen, C1_4 tic, OH, O(C1_4 aliphatic), N02, CN, COZH, COZ(C1_4 aliphatic), O(halo C1_4 aliphatic), or halo(C1_4 aliphatic), wherein each of the foregoing C1_4aliphatic 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, +, -COZR+, -C(O)C(O)R+, -C(O)CH2C(O)R+, —sozR+, R+)2, -C(=S)N(R+)2, -C(=NH)—N(R+)2, or — NR+SOZR+g wherein R+ is hydrogen, an optionally substituted C1_6 aliphatic, ally substituted phenyl, optionally substituted -O(Ph), optionally substituted h), optionally substituted -(CH2)1_2(Ph); optionally substituted (Ph); or an unsubstituted 5-6 membered heteroaryl or heterocyclic ring haVing one to four atoms 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 3membered cycloalkyl ring, wherein said heteroaryl or heterocyclyl ring has 1-3 heteroatoms ndently selected from nitrogen, oxygen, or sulfur. Optional substituents on the aliphatic group or the phenyl ring of R+ are selected from NHZ, NH(C1_4 aliphatic), N(C1_4 aliphatic)2, halogen, C1_4 aliphatic, OH, O(C1_4 aliphatic), N02, CN, COZH, COZ(C1_4 tic), O(halo C1_4 aliphatic), or halo(C1_4 aliphatic), wherein each of the foregoing C1_4aliphatic groups of R+ is unsubstituted.

In some ments, an aryl ding aralkyl, aralkoxy, aryloxyalkyl and the like) or heteroaryl (including heteroaralkyl and arylalkoxy 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°; -OR°; -SR°; l,2-methylenedioxy; l,2-ethylenedioxy; phenyl (Ph) optionally substituted with R0; -O(Ph) optionally substituted with R0; -(CH2)1_2(Ph), optionally substituted with R0; -CH=CH(Ph), optionally substituted with R0; -NOZ; -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°COZR°; -NR°NR°C(O)R°; -NR°NR°C(O)N(R°)2; °COZR°; -C(O)C(O)R°; -C(O)CH2C(O)R°; -COZR°; -C(O)R°; -C(S)R°; -C(O)N(R°)2; -C(S)N(R°)2; N(R°)2; -OC(O)R°; -C(O)N(OR°) RO; -C(NOR°) RO; -S(O)2R°; -S(O)3R°; R°)2; -S(O)R°; -NR°SOZN(R°)2; -NR°SOZR°; )R°; )—N(R°)2; or -(CH2)0_2NHC(O)R°; wherein each independent occurrence of R° is selected from hydrogen, optionally substituted C1_6 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 tuent or different substituents, taken together with the atom(s) to which each R° group is bound, form a 5membered heterocyclyl, yclic aryl, or aryl ring or a 3 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 ed from NHZ, NH(C1_4aliphatic), N(C1_4aliphatic)2, halogen, C1_4aliphatic, OH, O(C1_4aliphatic), N02, CN, COZH, C02(C1_4aliphatic), O(haloC1_4 aliphatic), or haloC1_ 4aliphatic, CHO, N(CO)(C1_4 aliphatic), C(O)N(C1_4 aliphatic), wherein each of the foregoing C1- 4aliphatic groups of RO is unsubstituted.

Non-aromatic nitrogen containing heterocyclic rings that are substituted on a ring nitrogen and attached to the remainder of the molecule at a ring carbon atom are said to be N substituted. For example, an N alkyl piperidinyl group is ed to the remainder of the molecule at the two, three or four position of the piperidinyl ring and tuted 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 molecule at a second ring nitrogen atom are said to be N’ substituted-N—heterocycles. For example, an N’ acyl zinyl group is attached to the remainder of the molecule 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 ences of R0 (or R+, or any other variable similarly deﬁned ), may be taken together with the atom(s) to which each variable is bound to form a 5membered heterocyclyl, carbocyclic aryl, or heteroaryl ring or a 3membered cycloalkyl ring. Exemplary rings that are formed when two ndent occurrences of R0 (or Rl, or any other variable similarly deﬁned ) are taken together with the atom(s) to which each variable is bound include, but are not limited to the following: a) two independent ences of R0 (or R+, or any other variable similarly deﬁned ) that are bound to the same atom and are taken together with that atom to form a ring, for example, , where both occurrences of R0 are taken together with the nitrogen atom to form a piperidin- l -yl, piperazin-l-yl, or morpholinyl group; and b) two independent occurrences of R0 (or R+, or any other variable similarly deﬁned herein) that are bound to different atoms and are taken together with both of those atoms to form a ring, for e where a phenyl group is Ila/(ZOROORO substituted with two occurrences of OR0 these two occurrences of R0 are taken together with the oxygen atoms to which they are bound to form a fused 6-membered oxygen containing ring: £133 . It will be appreciated that a variety of other rings can be formed when two independent occurrences of R0 (or RI, 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 ed 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 “alkylthio”, as used herein, refers to an alkyl group, as previously defined, attached to the molecule through an oxygen (“alkoxy” e.g., —O—alkyl) or sulfur (“alkylthio” e.g., yl) 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 —CEN.

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, tuted with one or more halogen atoms. This term includes perﬂuorinated alkyl groups, such as —CF3 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 lkyl is (NC)-alkyl—.

The terms “aminoalkyl”, “aminoalkenyl”, “aminoaliphatic”, and “aminoalkoxy” mean alkyl, l, 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 liphatic is a Cl-C6 tic group substituted with one or more -NH2 groups. In some embodiments, the aminoalkyl refers to the structure (RXRY)N-alkyl-, n each of RX and RY independently is as defined above. In some specific ments, the aminoalkyl is Cl-C6 alkyl substituted with one or more —NH2 groups. In some ic embodiments, the aminoalkenyl is Cl-C6 alkenyl substituted with one or more -NH2 groups. In some embodiments, the aminoalkoxy is -O(Cl-C6 alkyl) wherein the alkyl group is substituted with one or more -NH2 groups.

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

The terms “alkoxyalkyl”, “alkoxyaliphatic”, 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 ctive group” as used herein, are hangeable and refer to an agent used to temporarily block one or more desired functional groups in a compound with multiple reactive sites. In certain embodiments, a protecting group has one or more, or speciﬁcally all, of the following characteristics: a) is added selectively to a functional group in good yield to give a ted 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 rated, 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 c Synthesis”, Third Edition, John Wiley & Sons, New York: 1999 (and other editions of the book), the entire 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 ting groups are also detailed in r 7 in Greene, T.W., Wuts, P. G in “Protective Groups in Organic Synthesis”, Third n, John Wiley & Sons, New York: 1999, the entire contents of which are hereby incorporated by reference.

As used herein, the term “displaceable moiety” or “leaving group” refers to a group that is associated with an aliphatic or ic group as deﬁned herein and is t to being ced by philic attack by a nucleophile.

Unless otherwise indicated, structures depicted herein are also meant to include all isomeric (e. g., enantiomeric, diastereomeric, cis-trans, conformational, and rotational) forms of the structure. For example, the R and S conﬁgurations for each tric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers are ed 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 freely rotate around any rotatable bonds. For example, a substituent / N N / | I drawn as \ also represents \ ] Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, cis/trans, conformational, and rotational mixtures of the present compounds are within the scope of the invention.

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

] Additionally, unless otherwise indicated, structures ed 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 t structures except for the replacement of en by deuterium or tritium, or the replacement of a carbon by a 13C- or 14C-enriched carbon are within the scope of this ion. Such compounds are useful, for example, as analytical tools or probes in biological assays. Such compounds, especially deuterium analogs, can also be therapeutically useful.

The terms “a bond” and “absent” are used hangeably 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 al structure and a chemical name, and the chemical structure and chemical name conﬂict, the chemical structure is determinative of the compound’s identity. ceutically Accegtable Salts, es, Chlatrates, Prodrugs and Other Derivatives ] The compounds described herein can exist in free form, or, where appropriate, as salts. Those salts that are pharmaceutically acceptable are of particular interest since they are useful 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 term "pharmaceutically acceptable salt" refers to salts of a compound which are, within the scope of sound l judgment, suitable for use in contact with the tissues of humans and lower animals t undue side effects, such as, toxicity, irritation, allergic response and the like, and are commensurate with a reasonable t/risk ratio.

] Pharmaceutically acceptable salts are well known in the art. For example, S. M.

Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, l-l9, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds described herein e those derived from suitable inorganic and organic acids and bases. These salts can be ed in situ during the final isolation and cation of the compounds.

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

Examples of pharmaceutically acceptable, non-toxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, ic 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 able salts include e, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, rate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, eptonate, glycerophosphate, glycolate, gluconate, glycolate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2- hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2—naphthalenesulfonate, nicotinate, e, oleate, oxalate, palmitate, palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, salicylate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like.

Where the compound described herein contains a carboxy group or a ently acidic bioisostere, base addition salts can be prepared by l) reacting the puriﬁed compound in its acid form with a suitable c or inorganic base and 2) ing the salt thus formed. In practice, use of the base addition salt might be more convenient and use of the salt form inherently amounts to use of the free acid form. Salts derived from appropriate bases include alkali metal (e. g., sodium, m, and potassium), alkaline earth metal (e. g., magnesium and calcium), ammonium and N+(C1_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 products may be obtained by such quatemization.

] Basic on salts include pharmaceutically acceptable metal and amine salts.

Suitable metal salts include the sodium, potassium, calcium, barium, zinc, magnesium, and ium. The sodium and ium salts are usually preferred. Further ceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as , hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate. Suitable inorganic base addition salts are prepared from metal bases which include sodium hydride, sodium hydroxide, potassium hydroxide, calcium hydroxide, aluminium ide, m hydroxide, magnesium hydroxide, zinc hydroxide and the like. Suitable amine base addition salts are prepared from amines which are frequently used in medicinal chemistry because of their low 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, ethylammonium hydroxide, triethylamine, dibenzylamine, mine, dehydroabietylamine, N—ethylpiperidine, benzylamine, tetramethylammonium, tetraethylammonium, amine, dimethylamine, trimethylamine, ethylamine, basic amino acids, dicyclohexylamine and the like.

Other acids and bases, while not in themselves pharmaceutically acceptable, may be ed in the preparation 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 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 solvates (e.g., hydrates) and clathrates. As used herein, the term “pharmaceutically acceptable solvate,” is a solvate formed from the ation of one or more pharmaceutically acceptable solvent les to one of the compounds described herein. The term solvate es hydrates (e.g., hemihydrate, monohydrate, dihydrate, trihydrate, tetrahydrate, and the like).

As used herein, the term te” means a nd described herein or a salt thereof that ﬁarther es a iometric or non-stoichiometric amount of water bound by non-covalent intermolecular .

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

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

A “pharmaceutically acceptable derivative or prodrug” es any pharmaceutically acceptable ester, salt of an ester or other tive or salt thereof of a compound described herein which, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound described herein or an inhibitorily active metabolite or residue thereof Particularly favoured derivatives or prodrugs are those that increase the bioavailability of the nds 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 biological 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 derivative of a compound that can yze, e, or otherwise react under biological conditions (in vitro or in vivo) to provide a compound described herein. Prodrugs may become active upon such reaction under biological conditions, or they may have ty in their unreacted forms. Examples of prodrugs contemplated in this invention include, but are not limited to, analogs or derivatives of compounds of the invention that comprise rolyzable moieties such as biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable carbonates, biohydrolyzable ureides, and biohydrolyzable phosphate analogues.

Other examples of prodrugs include derivatives of compounds described herein that comprise - NO, -N02, -ONO, or -ON02 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 derivative” is an adduct or derivative Which, upon administration to a patient in need, is capable of providing, directly or indirectly, a compound as otherwise described herein, or a metabolite or residue thereof. Examples of pharmaceutically acceptable derivatives 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, metal salts and sulfonate esters.

Uses of Disclosed Comgounds One aspect of the present invention is generally related to the use of the nds described herein or pharmaceutically acceptable salts, or pharmaceutically acceptable compositions comprising such a compound or a ceutically acceptable salt thereof, for inhibiting the replication of inﬂuenza viruses in a biological sample or in a patient, for ng the amount of inﬂuenza viruses ing viral titer) in a biological sample or in a patient, and for treating inﬂuenza in a patient.

] In one embodiment, the present 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 present invention is directed to the use of any compound selected from the compounds depicted in Table l or a ceutically able salt thereof, for any of the uses described above.

] In some embodiments, the nds are ented by any one of Structural Formulae (I) — (X), and the variables are each ndently as depicted in the compounds of Table 1.

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).

The terms “inﬂuenza virus mediated condition”, “inﬂuenza ion”, or nza”, as used herein, are used hangeable 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 s. Inﬂuenza viruses are RNA viruses of the family Orthomyxoviridae, which comprises ﬁve genera: Inﬂuenzavirus A, zavirus B, Inﬂuenzavirus C, Isavirus and Thogotovirus. Inﬂuenzavirus A genus has one species, inﬂuenza A virus which can be ided into different serotypes based on the antibody response to these viruses: HlNl, H2N2, H3N2, HSNl, 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 s, Inﬂuenzavirus C virus, which s humans and pigs and can cause severe illness and local epidemics. However, Inﬂuenzavirus C is less common than the other types and usually seems to cause mild disease in children.

In some ments of the invention, inﬂuenza or inﬂuenza viruses are associated with Inﬂuenzavirus A or B. In some embodiments of the invention, inﬂuenza or inﬂuenza viruses are associated with Inﬂuenzavirus A. In some speciﬁc embodiments of the invention, Inﬂuenzavirus A is HlNl, H2N2, H3N2 or H5Nl.

In humans, common ms of inﬂuenza are chills, fever, gitis, muscle pains, severe headache, coughing, weakness, and l discomfort. In more serious cases, inﬂuenza causes pneumonia, which can be fatal, particularly in young children and the elderly. gh 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 e nausea and vomiting, especially in children, but these symptoms are more characteristic of the unrelated gastroenteritis, which is sometimes called "stomach ﬂu" or ur 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 temperatures ranging from 38-39 c’C (approximately 100-103 c’F). Many people are so ill that they are conﬁned to bed for several days, with aches and pains throughout their bodies, which are worse in their backs and legs. Symptoms of inﬂuenza may include: body aches, especially joints and throat, extreme coldness and fever, fatigue, Headache, irritated watering eyes, reddened eyes, skin (especially face), mouth, throat and nose, abdominal pain (in children with inﬂuenza B). Symptoms of inﬂuenza are non-speciﬁc, overlapping with many ens (“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), cally a “mammal” including a non-primate (e. g., a cow, pig, horse, sheep, rabbit, guinea pig, rat, cat, dog, and mouse) and a e (e. g., a , chimpanzee and a human), and more speciﬁcally a human. In one embodiment, the t is a non-human animal such as a farm animal (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 t 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 ts thereof ] As used herein, “multiplicity of infection” or “MOI” is the ratio of infectious agents (e. g. phage or virus) to ion 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 present in that well.

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

Inﬂuenza virus ation can be measured by any suitable method known in the art. For example, inﬂuenza viral titre in a ical sample (e.g. an infected cell culture) or in humans (e.g. lung viral titre in a patient) can be measured. More speciﬁcally, 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 Madin-Darby canine kidney cells (MDCK) and the standard tissue culture adapted inﬂuenza strain, to Rico/8/34 can be used. A ﬁrst type of cell assay that can be used in the invention depends on death of the infected target cells, a process called cytopathic effect (CPE), where virus infection causes tion of the cell ces and eventual lysis of the cell. In the ﬁrst type of cell assay, a low ﬁaction of cells in the wells of a microtiter plate are infected (typically 1/10 to l/ 1000), the virus is allowed to go through several rounds of replication over 48-72 hours, then the amount of cell death is 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 depends on the multiplication of virus-speciﬁc RNA molecules in the infected cells, with RNA levels being ly 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 18-36 hours, while all the target cells are still viable. Viral RNA is quantitated by hybridization to speciﬁc 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 evaluates as positive or negative. The titer corresponds to the highest dilution factor that still yields a ve g; for example, positive readings in the ﬁrst 8 serial twofold dilutions translate into a titer of 1:256. A specific example is viral titer.

To ine the titer, l dilutions will be prepared, such as 101, 102, 10'3,...,10'8. The lowest concentration of virus that still infects cells is the viral titer.

As used , the terms “treat”, “treatment” and “treating” refer to both therapeutic and lactic treatments. For example, eutic treatments includes the reduction or amelioration of the progression, ty and/or duration of inﬂuenza viruses mediated conditions, or the amelioration of one or more symptoms (specifically, one or more nible ms) of inﬂuenza viruses mediated conditions, resulting from the administration of one or more therapies (e.g., one or more therapeutic agents such as a compound or composition of the ion). In specific ments, the therapeutic treatment includes the amelioration of at least one measurable physical parameter of an inﬂuenza virus mediated condition. In other ments the therapeutic ent includes the inhibition of the progression of an inﬂuenza virus mediated condition, either physically by, e.g., stabilization of a discernible symptom, physiologically by, e. g., stabilization of a physical parameter, or both. In other embodiments the therapeutic treatment includes the reduction or stabilization of inﬂuenza viruses mediated infections. Antiviral drugs can be used in the community setting to treat people who already have 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 tions, e. g. small molecule drugs (rather than “vaccines”) for ng a er or disease.

The terms “prophylaxis” or ylactic 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”, “prevention” and nting” refer to the reduction in the risk of acquiring or developing a given condition, or the reduction or tion of the recurrence 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 medications, e.g. small molecule drugs (rather than “vaccines”) for the tion of a disorder or disease.

As used herein, prophylactic use includes the use in situations in which an ak 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 includes 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 includes use during the two weeks following vaccination, since during that time the vaccine is still ineffective. Prophylactic use may also include ng 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 isk person in close t with him (for instance, healthcare workers, nursing home workers, etc).

According to the US CDC, an inﬂuenza “outbrea ” 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 the population being analyzed tests positive for inﬂuenza. One case of confirmed inﬂuenza by any g method is considered an ak.

A “cluster” is defined as a group of three or more cases ofAFRI 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”, ry case” or “patient zero” 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 capitalized. When the term is used to refer to a specific person in place of that person's name within a report on a speciﬁc investigation, the term is capitalized as Patient Zero. Often scientists search for the index case to ine how the disease spread and what reservoir holds the disease in between outbreaks. Note that the index case is the ﬁrst t that indicates the existence of an outbreak.

Earlier cases may be found and are labeled primary, secondary, tertiary, etc.

In one embodiment, the s of the invention are a preventative or “pre- emptive” measure to a patient, specifically a human, having a predisposition to cations resulting 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 ” has been confirmed, in order to prevent the spread of infection an “index case” or an “outbrea in the rest of the community or population group.

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

As used herein, an tive amount” refers to an amount sufﬁcient to elicit the desired biological response. In the present ion the d biological response is to inhibit the replication of inﬂuenza virus, to reduce the amount of inﬂuenza viruses or to reduce or ameliorate the severity, duration, progression, or onset of a inﬂuenza virus ion, prevent the advancement of an inﬂuenza viruses infection, prevent the recurrence, development, onset or progression of a symptom associated with an inﬂuenza virus infection, or enhance or improve the prophylactic or therapeutic effect(s) of r therapy used against inﬂuenza infections.

The precise amount of compound administered to a subject will depend on the mode of administration, the type and severity of the infection and on the characteristics of the subject, such as general health, age, sex, body weight and nce to drugs. The skilled artisan will be able to determine appropriate dosages depending on these and other s. When co- administered with other anti viral agents, e.g., when co-administered with an anti-inﬂuenza medication, an tive amount” of the second agent will depend on the type of drug used.

Suitable dosages are known for approved agents and can be adjusted by the skilled artisan according to the condition of the t, 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 /day for therapeutic or prophylactic treatment.

Generally, dosage regimens can be selected in accordance with a y of factors ing the disorder being treated and the severity of the disorder; the activity of the speciﬁc compound employed; the speciﬁc composition employed; the age, body weight, general , sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the speciﬁc compound employed; the renal and hepatic function of the subject; and the particular compound or salt thereof employed, the duration of the treatment; drugs used in combination or coincidental with the c compound employed, and like factors well known in the medical arts. The skilled artisan can readily determine and prescribe the effective amount of the compounds bed herein required to treat, to prevent, inhibit (ﬁJlly or lly) 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 stered 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 ms (e.g., nasal congestion, sore , cough, aches, fatigue, headaches, and chills/sweats). The therapeutic treatment can last for any suitable duration, for e, for 5 days, 7 days, 10 days, 14 days, etc. For prophylactic treatment during a community outbreak, the nds described herein can be administered to a patient within, for example, 2 days of onset of symptoms in the index case, and can be 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 Theragy An effective amount can be achieved in the method or pharmaceutical composition of the invention employing a compound of the invention (including a ceutically acceptable salt or solvate (e.g., hydrate)) alone or in combination with an additional suitable therapeutic agent, for example, an antiviral agent or a e. 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 ion 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 . In r embodiment, a compound of the ion 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 ment, a compound of the invention can be administered in an ive amount, while the additional therapeutic agent is administered in a sub-therapeutic dose. In still another embodiment, a compound of the invention can be stered in a sub-therapeutic dose, while the additional therapeutic agent, for example, a suitable cancer-therapeutic agent is administered in an ive amount.

As used herein, the terms “in combination” or “co-administration” can be used interchangeably to refer to the use of more than one therapy (e.g., one or more prophylactic and/or therapeutic ). The use of the terms does not restrict the order in which therapies (e.g., prophylactic and/or therapeutic agents) are administered to a subject. nistration encompasses administration of the first and second amounts of the compounds of the coadministration in an ially 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 order.

In one embodiment, the present invention is directed to methods of combination therapy for inhibiting Flu viruses replication 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, ceutical compositions of the invention also include those comprising an inhibitor of Flu Virus replication of this invention in combination with an iral 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 r 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 have the desired therapeutic effect. For example, the period of time between each administration which can result 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 y, solubility, bioavailability, plasma half-life and kinetic proﬁle. For example, 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 1 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 of the 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 ), concomitantly with, or subsequent to (e. g., 5 minutes, 15 minutes, 30 minutes, 45 s, 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 anti-cancer agent) to a ] 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 result in an enhanced or synergistic therapeutic effect, wherein the combined effect is greater than the ve effect that would result from separate stration of the ﬁrst amount of a compound of the invention and the second amount of an additional therapeutic agent.

As used , the term “synergistic” refers to a combination of a compound of the invention and another y (e.g., a prophylactic or therapeutic agent), which is more effective than the additive effects of the ies. A synergistic effect of a combination of therapies (e.g., a combination of prophylactic or therapeutic agents) can permit the use of lower dosages of one or more of the therapies and/or less frequent administration of said therapies 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 y to a subject without reducing the efficacy of said y in the prevention, management or ent of a disorder. In addition, a synergistic effect can result in improved cy of agents in the prevention, management or treatment of a disorder. Finally, a synergistic effect of a combination of therapies (e.g., a combination of lactic or eutic agents) may avoid or reduce adverse or unwanted side effects associated with the use of either therapy alone.

When the combination y using the compounds of the present 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 s for ing drug interaction. Suitable methods include, for example, the Sigmoid-Emax equation (Holford, N.H.G. and Scheiner, L.B., Clin. Pharmacokinet. 6: 429-453 (1981)), the equation of Loewe additiVity (Loewe, S. and Muischnek, H., Arch. Exp. Pathol Pharmacol. 114: 313-326 (1926)) and the median-effect on (Chou, TC. and Talalay, P., Adv. Enzyme Regul. 22: 27- 55 (1984)). Each equation ed to above can be applied with experimental data to generate a corresponding graph to aid in assessing the s of the drug combination. The corresponding graphs associated with the equations referred to above are the concentration-effect curve, isobologram curve and combination index curve, respectively.

Specific examples that can be co-administered with a compound described herein include neuraminidase inhibitors, such as oseltamiVir (Tamiﬂu®) and Vir (Rlenza®), Viral ion l (M2 protein) blockers, such as dine (Symmetrel®) and rimantadine (Flumadine®), and antiviral drugs described in WC 2003/015798, including T-705 under development by Toyama Chemical of Japan. (See also Ruruta et al., Antiviral Reasearch, 82: 95- 102 (2009), “T-705 iravir) 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 2012/049097 described herein can be co-administered with oseltamivir. In some embodiments, the compounds described herein can be co-administered with T-705.

Pharmaceutical Comgositions The nds described herein can be formulated into pharmaceutical compositions that ﬁarther comprise a pharmaceutically acceptable carrier, diluent, adjuvant or vehicle. In one embodiment, the t invention relates to a pharmaceutical composition comprising a nd of the invention described above, and a pharmaceutically able carrier, diluent, adjuvant or vehicle. In one embodiment, the present invention is a pharmaceutical ition comprising an effective amount of a compound of the present ion or a pharmaceutically acceptable salt thereof and a pharmaceutically able carrier, diluent, adjuvant or e. Pharmaceutically acceptable rs include, for e, 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 ” 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. Specific examples of effective amounts are bed above in the n ed Uses of Disclosed Compounds.

A pharmaceutically acceptable carrier may n inert ingredients which do not unduly inhibit the biological activity of the compounds. The pharmaceutically acceptable carriers should be biocompatible, e.g., non-toxic, non-inﬂammatory, non-immunogenic or devoid of other red 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 all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic 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., , Pa., 1980) discloses various carriers used in formulating pharmaceutically acceptable compositions and known techniques for the preparation thereof. Except insofar as any conventional carrier 2012/049097 medium is incompatible with the compounds described herein, such as by producing any undesirable biological effect or otherwise cting 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 e effect from a therapy (e.g., lactic or therapeutic agent) might be harmful or uncomfortable or risky. Side effects include, but are not limited to fever, chills, lethargy, intestinal toxicities (including gastric and intestinal ulcerations and erosions), nausea, vomiting, neurotoxicities, nephrotoxicities, renal toxicities (including such conditions as papillary necrosis and chronic interstitial tis), hepatic toxicities (including elevated serum liver enzyme levels), myelotoxicities (including leukopenia, myelosuppression, thrombocytopenia and anemia), dry mouth, metallic taste, gation 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 materials which can serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffer substances (such as twin 80, phosphates, glycine, sorbic acid, or potassium sorbate), partial glyceride mixtures of ted vegetable fatty acids, water, salts or electrolytes (such as protamine sulfate, um hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, or zinc salts), colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, methylcellulose, hydroxypropyl methylcellulose, wool fat, sugars such as lactose, glucose and sucrose; es such as corn starch and potato starch; cellulose and its tives such as sodium ymethyl cellulose, ethyl cellulose and cellulose e; powdered tragacanth; malt; gelatin; talc; ents such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; er oil; sesame oil; olive oil; corn oil and soybean oil; glycols; such a propylene glycol or polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic ible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, ing agents, coating agents, sweetening, ng and perﬁlming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator.

Administration Methods The nds and pharmaceutically acceptable compositions described above can be administered to humans and other animals orally, ly, erally, istemally, 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, ceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents ly 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, l,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurﬁlryl 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 , ning, ﬂavoring, and perﬁlming agents.

Inj ectable preparations, for example, sterile inj ectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in l,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's on, U.S.P. and isotonic sodium chloride solution. In addition, e, 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 diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

] The inj ectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in e water or other sterile inj ectable medium prior to use.

In order to prolong the effect of a compound bed herein, it is often desirable WO 19828 to slow the tion 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 of absorption of the compound then depends upon its rate of dissolution that, in turn, may depend upon crystal size and lline form. Alternatively, delayed absorption of a parenterally administered compound form is accomplished by dissolving or suspending the compound in an oil vehicle. Inj ectable depot forms are made by forming microencapsule matrices of the compound in radable polymers such as polylactide- polyglycolide. Depending upon the ratio of compound to polymer and the nature of the particular polymer employed, the rate of compound release can be controlled. Examples of other biodegradable 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 , polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or l 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 ate 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, e, and acacia, c) humectants such as glycerol, d) egrating agents such as agar--agar, calcium carbonate, potato or tapioca starch, c acid, certain silicates, and sodium carbonate, e) solution retarding agents such as parafﬁn, f) absorption rators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl l and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene s, sodium lauryl sulfate, and mixtures f. In the case of capsules, s 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, es, pills, and granules can be prepared with gs and shells such as enteric coatings 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 magnesium stearate and microcrystalline cellulose. In the case of capsules, s and pills, the dosage forms may also comprise buffering . They may ally contain opacifying agents and can also be of a composition that they release the active ient(s) only, or entially, in a certain part of the inal tract, optionally, in a delayed manner. es 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 sterile conditions with a pharmaceutically able carrier and any needed preservatives or buffers as may be ed. Ophthalmic ation, eardrops, and eye drops are also contemplated as being within the scope of this invention. Additionally, the t invention contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body.

Such dosage forms can be made by dissolving or dispensing the compound in the proper medium. Absorption ers can also be used to increase the ﬂux of the compound across the skin. The rate can be controlled by either providing a rate lling membrane or by dispersing the compound in a polymer matrix or gel.

The compositions bed herein may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir.

The term "parenteral" as used herein includes, but is not limited to, subcutaneous, intravenous, uscular, intra-articular, intra-synovial, intrastemal, intrathecal, intrahepatic, intralesional and intracranial injection or inﬁlsion ques. Speciﬁcally, the itions are administered , intraperitoneally or intravenously.

Sterile injectable forms of the itions 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 sterile injectable preparation may also be a sterile inj ectable on or suspension in a non-toxic parenterally- acceptable diluent or solvent, for example as a solution in l,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In on, sterile, ﬁxed oils are conventionally employed as a solvent or suspending medium. For this e, any bland ﬁxed oil may be ed including synthetic mono- or di-glycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of inj ectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar sing agents which are commonly used in the formulation of pharmaceutically able dosage forms including emulsions and suspensions. Other commonly used surfactants, such as Tweens, Spans and other emulsifying agents or bioavailability enhancers which are ly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.

The ceutical compositions described herein may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, rs commonly used e, but are not limited to, lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral stration in a capsule form, useful diluents include lactose and dried cornstarch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, ﬂavoring or coloring agents may also be added.

Alternatively, 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 temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug. Such materials include, but are not limited to, cocoa butter, beeswax and polyethylene glycols.

] The pharmaceutical compositions described herein may also be stered lly, 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 y prepared for each of these areas or organs.

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

] For l applications, the pharmaceutical compositions may be formulated in a suitable nt containing the active component suspended or dissolved in one or more carriers. Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid atum, white petrolatum, propylene glycol, yethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, 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. le carriers include, but are not limited to, mineral 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 isotonic, pH adjusted sterile saline, or, speciﬁcally, as solutions in isotonic, pH adjusted sterile saline, either with or without a preservative such as benzylalkonium chloride. Alternatively, for ophthalmic uses, the ceutical compositions may be formulated in an nt such as petrolatum.

The ceutical compositions may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be ed as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, ﬂuorocarbons, and/or other conventional solubilizing or sing 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 physically discrete 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 e 1: Synthesis of ds of the Invention The compounds disclosed herein can be prepared by any suitble method known in the art, for example, , , , , WP 2010/011772, , and filed on June 17, 2010. For example, the compounds shown in Table 1 and can be ed by any suitble method known in the art, for example, , WO 84557, , WO 2010/011756, WP 11772, , and , and by the exemplary syntheses described below. Generally, the compounds of the invention can be prepared as shown in those syntheses optionally with any desired appropriate modification. ology for Synthesis and Characterization of Coonands Syntheses of certain exemplary compounds of the invention are described below.

NMR and Mass oscopy data of certain specific compounds are summarized in Table 1. As used herein the term RT (min) refers to the LCMS retention time, in minutes, associated with the compound.

Pre n 0 Com oandl Synthetic Scheme 1 \ NWNH N NH2 \ / CI \\\\ WOH- I \ >\ :L /I \ 1‘ O N N \ 1a 2a 0 OH N N 3a H 1 (a) Na2C03, THF, CH3CN, microwave, 135 0C; (b) NaOMe, MeOH, 0 0C; Formation of (R)(2-(5-chlor0t0syl-1H-pyrrolo[2,3-b]pyridinyl)—5-ﬂuoro-pyrimidin- 4-ylamin0)—4,4-dimethylpentan0ic acid (3a) To a on of 5-chloro(5-ﬁuoromethylsulﬁnyl-pyrimidinyl)(p- tolylsulfonyl)pyrrolo[2,3-b]pyridine, 1a, (0.100 g, 0.215 mmol: prepared in a similar manner as described below for Compound 25a in scheme 4) and amino-4,4-dimethylpentanoic acid, 2a, (0.031 g, 0.215 mmol) in tetrahydrofuran (1.66 mL) was added freshly ground N32C03 (0.068 g, 0.645 mmol) followed by acetonitrile (0.331 mL). The reaction mixture was heated to 135 0C for 30 minutes in a microwave reactor. The reaction mixture was slowly poured into 75 mL of 1N HCl. The pH of ﬁnal solution was adjusted to 1. The aqueous was extracted with EtOAc (3 X 5 mL), washed with brine, dried over Na2S04 and ﬁltered to obtain a crude solid residue. The crude residue was puriﬁed via silica gel chromatography (0-10% MeOH-CHzClz gradient) ed 78 mg of the desired product 3a: LCMS Gradient 10-90%, 0.1% formic acid, s, C18/ACN, RT = 3.9 minutes (M+H) 546.22.

(R)(2-(5-Chloro-lH—pyrrolo [2,3-b]pyridinyl)—5-ﬂu0r0pyrimidinylamin0)—4,4- dimethylpentanoic acid (1) To a cold (0 oC) solution of (R)(2-(5-chlorotosyl-1H—pyrrolo[2,3-b]pyridinyl) ﬁuoro-pyrimidinylamino)-4,4-dimethylpentanoic acid, 3a, (0.08 g, 0.14 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 temperature for 30 min and then quenched by dilution into aqueous saturated ammonium de solution. The MeOH was ated in vacuo and the resulting aqueous phase diluted with EtOAc, then extracted with EtOAc (3X). The organics were dried (Na2S04), ﬁltered and concentrated in vacuo. Recrystalization from MeOH ed 52 mg of the desired product 1 as a white powder: 1H NMR (d6-DMSO) 8 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 s (M+H) 392.21.

WO 19828 Pre arationo Com 0unds2 43 89 and 90 Synthetic Scheme 2 2a 5a 6a \N'N 7a FgiNH O 0/ d iNH O 0/ e iNH O H OH —» M —» M F F F / 7\ / 7\ / 7\ I \ I \ I \ \ \ \ N N N N N N ‘ H H 8a 9a 2 (a) AcCl, MeOH, reﬂux; (b) 2,4-dichlor0ﬂu0r0pyrimidine, Eth, EtOH, THF, 55 0C; (c) -ﬂuor0(p-tolylsulf0nyl)-3 -(4,4,5 ,5 -tetramethyl- 1 ,3 ,2-dioxaborolanyl)pyrrolo [2,3 - b]pyridine, 7a, Pd2(dba)3, XPhos, K3P04, 2-MeTHF, H20, 115 0C; (d) HCl, e, acetonitrile, 65°C; (e) LiOH, THF, H20, 50 0C.

Formation of (R)methoxy-4,4-dimethyloxopentanaminium chloride (5a) (R)amino-4,4-dimethylpentanoic acid, 2a, was dissolved in ol (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 temperature below 10 CC). The reaction mixture was heated to 65 °C and stirred at that temperature for 3 h. The on mixture was cooled to room temperature and then ﬂushed with e to remove volatiles. The crude material was used without r puriﬁcation: 1H NMR (400 MHz, MeOH-d4) 5 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-chloroﬂuoropyrimidinyl)amino)—4,4- dimethylpentanoate (6a) (R)methoxy-4,4-dimethyl0x0pentanaminium 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-dichloroﬂuoro-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 CC for 17 h. The reaction mixture was then cooled to room temperature 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 d 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 (R)—methyl 3-((5-fluoro(5-fluorotosyl-1H-pyrrolo[2,3-b]pyridin yl)pyrimidinyl)amino)-4,4-dimethylpentanoate (8a) A 2-MeTHF (253 mL)/water (56 mL) on of 5-ﬁuoro(p-tolylsulfonyl)(4,4,5,5- tetramethyl-l,3,2-dioxaborolanyl)pyrrolo[2,3-b]pyridine, 7a, (24.3 g, 58.3 mmol), methyl (R)- methyl chloroﬁuoropyrimidinyl)amino)-4,4-dimethylpentanoate, 6a, (14.1 g, 48.6 mmol) and K3P04 (30.9 g, 146 mmol) was purged with nitrogen for 0.75 h. XPhos (2.8 g, 5.8 mmol) and a)3 (1.1 g, 1.2 mmol) were added and the reaction e was d at 115 0C 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 Celite 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 , 0.1% formic acid, 5min, C18/ACN, RT = 2.18 minutes (M+H) 245.28.

Formation of (R)—methyl 3-((5-ﬂuoro(5—fluoro-lH-pyrrolo[2,3-b]pyridinyl)pyrimidin- 4-yl)amino)-4,4-dimethylpentanoate (9a) To a solution of (R)—methyl 3-((5-ﬁuoro(5-ﬁuorotosyl-1H—pyrrolo[2,3-b]pyridin yl)pyrimidinyl)amino)-4,4-dimethylpentanoate, 8a, (21 g, 39 mmol) in acetonitrile (157 mL) was added 4M HCl in dioxane (174 mL). The reaction mixture was heated to 65 CC for 4 h. The solution was cooled to room temperature and the solvents were removed under d pressure.

The mixture was ﬂushed with acetonitrile after which dichloromethane (100mL), sat. aqueous NaHC03 (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 (Na2S04), ﬁltered and concentrated in vacuo. The resulting residue was puriﬁed on silica gel (EtOAc/Hexanes) to provide the desired t, 9a, (12.1 g): LCMS Gradient 10-90%, 0.1% formic acid, 5min, C18/ACN, RT = 2.26 minutes (M+H) 391.05.

Formation (R)—3-((5-fluoro(5-fluoro-lH-pyrrolo[2,3-b]pyridinyl)pyrimidin yl)amino)—4,4-dimethylpentanoic acid (2) (R)-Methyl 3-((5-ﬂuoro(5-ﬂuoro-1H—pyrrolo[2,3-b]pyridinyl)pyrimidin yl)amino)-4,4-dimethylpentanoate, 9a, (18.4 g, 47.1 mmol) was ved in tetrahydrofuran (275 mL) and aqueous 1M LiOH (141 mL) was added. The mixture was heated to 50 0C for 3.5 h. The reaction mixture was cooled to room temperature 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 ed to 6 with 1N HCl. Ethyl acetate (540 mL) was added, the layers were ted 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 (Na2S04). The solvents were removed while ﬂushing with heptanes to e the desired product, 2, (17.5g): 1H NMR (400 MHz, DMSO-dg) 5 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, J: 4.0 Hz, 1H), 7.39 (d, J: 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 s (M+H) 377.02.

The following analog was prepared in a similar fashion as the procedure described above for Compound 2: N , \ NL>—OH fr?4\ N S“ N N (R)—3-((5-ﬂu0r0(5-(triﬂu0r0methyl)—lH-pyrrolo [2,3-b]pyridinyl)pyrimidin yl)amin0)-4,4-dimethylpentan0ic acid (43) 1H NMR (300 MHz, CDC13) 5 11.16 (s, 1H), 8.70 (s, 1H), 8.04 (d, J: 3.2 Hz, 1H), 7.96 (s, 1H), 7.87 (s, 1H), 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); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, Retention Time = 2.49 minutes (M+H) 426.47.

N/N|\-I_>—OHFyo \Nse / I\7\ (R)—3-((5-ﬂu0r0(5-methyl-lH-pyrrolo [2,3-b] pyridinyl)pyrimidinyl)amin0)-4,4- dimethylpentanoic acid (90) 1H NMR (300 MHz, CDC13) 8 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, minutes, C18/ACN, Retention Time = 1.8 minutes (M+H) 372.5.

N NH / OH /I \ 7\ N N (R)—3-((2-(5-cyan0-lH-pyrrolo [2,3-b] nyl)ﬂu0r0pyrimidinyl)amin0)-4,4- dimethylpentanoic acid (89) LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, N, Retention Time = 2.1 minutes (M+H) 383.38.

F870NH OH F/ [RN/ﬂ \ I\ (S)((5-ﬂu0r0(5-ﬂu0r0-lH-pyrrolo [2,3-b] pyridinyl)pyrimidinyl)amin0)-4,4- dimethylpentanoic acid (4) LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, N, Retention Time = 1.93 minutes (M+H) 376.21. a, O N\ N/ NH OH I \ N N (S)((2-(5-chlor0-lH-pyrrolo ] pyridinyl)-S-ﬂuor0pyrimidinyl)amino)—4,4- dimethylpentanoic acid (3) LCMS nt 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, Retention Time = 2.06 minutes (M+H) 392.21.

Pre aration 0 Com ound 69 Synthetic Scheme 3 H2N OH a N/ngH 0 ~— b §_/ _, OH —, NH —— N o —> no 7\ >\’N¢}_/ >Lh/lF/< F."o NﬂNUﬁko, ”0L g Ffjji/N 5 OH I]???\N c o N o / , 7‘\ F/ Ff, 7\ 7’ \IN\ 19a 69 21a (a) 2,4-dichloroﬂuoropyrimidine, Eth, DMF; (b) oxalyl chloride, DMF, DMSO, Eth, CHZCIZ; (c) [(lPrO)2PO]2CH2, NaH, THF; (d) 5-ﬂuoro(p-tolylsulfonyl)—3-(4,4,5,5- tetramethyl-l,3,2-dioxaborolanyl)pyrrolo[2,3-b]pyridine, 7a, Pd2(dba)3, XPhos, K3PO4, 2- MeTHF, H20, 100 0C; (e) NaOMe, MeOH; (f) H2, Pd/C, MeOH, 40 psi; (g) trimethylsilyliodide, CHzClz.

Formation of (S)((2-chloro-S-ﬂu0r0pyrimidinyl)amino)—3,3-dimethylbutan01 (14a) To a mixture of -amino-3,3-dimethyl-butanol (5.0 g, 42.7 mmol) and 2,4- dichloroﬂuoro-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 NH4C1 solution and extracted twice with EtOAc. The combined organic phases were washed twice with brine, dried (MgSO4), ﬁltered and concentrated in vacuo. The crude residue was puriﬁed Via silica gel chromatography (0-10% MeOH/CH2C12 gradient) to afford 6.7 g of the desired t, 1, as a sticky solid: LCMS Gradient , 0.1% formic acid, 5 minutes, N, RT = 2.48 minutes (M+H) 248.32.

Formation of (S)((2-chlor0ﬂu0r0pyrimidinyl)amin0)—3,3-dimethylbutanal (153) To a cold (-78 oC) solution of oxalyl chloride (1.06 mL, 12.11 mmol) in dichloromethane (10 mL) was added yl sulfoxide (1.43 mL, 20.18 mmol) se. After stirring the mixture for 10 minutes at -78 0C, a suspension of (2S)[(2-chloroﬁuoro-pyrimidin yl)amino]-3,3-dimethyl-butanol, 143, (1.0 g, 4.04 mmol) in dichloromethane (10 mL) was added. The reaction mixture was stirred for 30 minutes at -78 CC and triethylamine (3.38 mL, 24.22 mmol) was added. The mixture was slowly warmed to 0 0C over 2hours. The mixture was diluted into aqueous saturated NaHC03 solution and extracted twice with EtOAc. The ed organic phases were dried (MgSO4), ﬁltered and concentrated in vacuo. The crude residue was puriﬁed Via silica gel chromatography (0-15% EtOAc/CHzClz gradient) to afford 680 mg of the desired product as a white solid.

Formation of (R,E)—diis0pr0pyl (3-((2—chlor0ﬂu0r0pyrimidinyl)amino)—4,4— dimethylpent—1-enyl)ph0sph0nate (163) To a cold (0 oC) 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-chloroﬂuoropyrimidinyl)amino)- 3,3-dimethylbutanal, 1521, (0.580 g, 2.361 mmol) in THF (4 mL) was added dropwise. The on mixture was slowly warmed to room temperature over 1 hour. The mixture was diluted into aqueous saturated NH4Cl solution and extracted with EtOAc. The organic phase was dried (MgSO4), ﬁltered and concentrated in vacuo. The resulting crude residue was puriﬁed Via silica gel chromatography (10-50% EtOAc/CH2C12 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)—diis0pr0pyl (3-((5-ﬂu0r0(5—ﬂu0r0t0syl-1H-pyrr010[2,3- b]pyridinyl)pyrimidinyl)amin0)-4,4-dimethylpent-l-enyl)ph0sph0nate (173) To a solution of (R,E)-diisopropyl (3-((2-chloroﬂuoropyrimidinyl)amino)-4,4- dimethylpent-l-enyl)phosphonate, 163, (0.81 g, 1.99 mmol) and 5-ﬂuoro(p-tolylsulfonyl)- 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)pyrrolo[2,3-b]pyridine, 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 ed 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 onal 5 minutes, the vessel was sealed and heated at 100 °C for 2 hours. The mixture was cooled to room temperature and diluted with EtOAc, ﬁltered through celite. The ﬁltrate was washed with brine, dried (MgSO4), d and concentrated in vacuo. The crude residue was puriﬁed Via silica gel chromatography (0-50% CHgClz gradient) to afford 1.123 g ofthe desired t: 1H NMR (400 MHz, d6-DMSO) 8 8.55 - 8.42 (m, 3H), 8.31 (d, J = 3.7 Hz, 1H), 8.06 (d, J: 8.3 Hz, 2H), 7.73 (d, J: 8.9 Hz, 1H), 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, J: 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 nt 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, RT = 4.06 minutes (M+H) 662.35. ion of (R,E)—diisopropyl (3-((5-ﬂuoro(5-ﬂuoro-lH-pyrrolo[2,3-b]pyridin- 3-yl)pyrimidinyl)amino)-4,4-dimethylpentenyl)phosphonate (18a) To a solution of (R,E)-diis0pr0pyl (3-((5-ﬁuor0(5-ﬂu0r0t0syl-1H-pyrrolo[2,3- b]pyridinyl)pyrimidinyl)amin0)-4,4-dimethylpentenyl)phosph0nate, 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 NH4Cl solution and extracted twice with EtOAc. The combined organic phases were dried (MgSO4), ﬁltered and trated in vacuo. The crude residue was puriﬁed Via silica gel chromatography (0-15% MeOH/CHzClz gradient) to afford 724 mg of the desired t: LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, RT = 2.76 minutes (M+H) 508.13.

Formation of isopropyl-(3-((5-fluoro(5-fluoro-lH-pyrrolo [2,3-b]pyridin yl)pyrimidinyl)amino)-4,4-dimethylpentyl)phosphonate (19a) To a on of (R,E)—diis0pr0pyl (3-((5-ﬁu0r0(5-ﬁu0r0-1H—pyrrolo[2,3-b]pyridin yl)pyrimidinyl)amin0)—4,4-dimethylpentenyl)ph0sph0nate, 18a, (0.36 g, 0.71 mmol) in MeOH (7 mL) was added Pd on Carbon (10%, wet, Degussa, 0.07 g, 0.07 mmol). The reaction mixture was stirred in a Parr hydrogenation ﬂask under 50 psi of hydrogen ght. The mixture was diluted with EtOAc and ﬁltered through celite. The ﬁltrate was concentrated in vacuo to give the desired t as dark gray solid: 1H NMR (400 MHz, d6-DMSO) 5 12.28 (s, 1H), 8.46 (dd, J: 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, J: 12.3, 6.2 Hz, 2H), 4.37 (t, J: 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 (R)—(3-((5-fluoro(5-fluoro-lH-pyrrolo[2,3-b]pyridinyl)pyrimidin yl)amino)—4,4-dimethylpentyl)phosphonic acid (69) To a solution of (R)-diis0pr0pyl-(3-((5-ﬁuoro(5-ﬁuor0-1H—pyrrolo[2,3-b]pyridin yl)pyrimidinyl)amin0)—4,4-dimethylpentyl)ph0sph0nate, 19a, (0.16 g, 0.32 mmol) in dichloromethane (8 mL) was added iodotrimethylsilane (0.45 mL, 3.18 mmol). The reaction mixture was stirred at room temperature. After 1 hour, LCMS showed the reaction to be incomplete. An additional 0.90 mL of iodotrimethylsilane (0.64 mmol) was added to the reaction mixture. After 5 hours, the e was concentrated in vacuo and the resulting residue was puriﬁed Via preparatory HPLC (CH3CN/1% aqueous TFA) to afford 8 mg of phosphonic acid, 69, and 34 mg of phosphonate, 21a.

Spectral data for phosphonic acid, 69: 1H NMR (300 MHZ, MeOD) 5 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); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, RT = 1.81 minutes (M+H) 426.09.

Spectral data for onate 21a: 1H NMR (300 MHz, MeOD) 5 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, J: 11.2 Hz, 9H); LCMS Gradient 10-90%, 0.1% formic acid, 5 s, Cl8/ACN, RT = 2.06 minutes (M+H) 468.13.

Pregaration of Comgounds I6 and I 7 Synthetic Scheme 4 \ \I —»F N N N O H -z _ U? .03.% |\ _| / (I) O. 22a Nm 2 'l'l 'l'l NWR L, N \ CIANN/jl: F s \ / | \/, \ \ l N N 24a 25a (a) NaH, TsCl, DMF; (b) KOAc, PdC12(dppf), dioxane, water, reﬂux; (c) Pd(PPh3)4, N32C03, DME, water; (d) morpholinecarbonyl chloride, lPI'zNEt, CH2ClZ; Formation of 3-br0m0ﬂu0r0(p-tolylsulf0nyl)pyrrolo[2,3-b]pyridine (22a) 3-bromoﬂuoro-1H—pyrrolo[2,3-b]pyridine (5.0 g, 23.3 mmol) was dissolved in DMF (37.5 mL) and cooled to 0 oC. Sodium hydride (1.5 g, 37.2 mmol) was added and the on 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 CC and then at room temperature for another 90 minutes.

The reaction e 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 ﬂuoro(p-tolylsulfonyl)pyrrolo[2,3-b]pyridine, 22a: 1H NMR (300 MHZ, DMSO-dg) 5 8.48 (s, 1H), 8.31 (s, 1H), 8.01 (d, J: 8.3 Hz, 2H), 7.92 (dd, J: 8.4, 2.7 Hz, 1H), 7.44 (d, J: 8.5 Hz, 2H), 2.35 (s, 3H).

Formation of S-ﬂuoro(p-tolylsulf0nyl)—3-(4,4,5,5-tetramethyl-1,3,2-di0xab0rolan yl)pyrrolo[2,3-b]pyridine (7a) oﬂuoro(p-tolylsulfonyl)pyrrolo[2,3-b]pyridine, 22a, (4.0 g, 10.8 mmol), 4,4,5,5-tetramethyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1,3,2-dioxaborolane (8.3 g, 32.5 mmol) and ium 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 s, PdC12(dppf) (0.8 g, 1.1 mmol) was added. Nitrogen purging was continued for an onal 40 minutes, then the reaction mixture was heated to reﬂux overnight. 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 temperature, the resulting suspension was d to provide 2.6 g of the desired product as a white solid: 1H NMR (300 MHz, DMSO-dg) 8 8.42 (dd, J = 2.7, 1.4 Hz, 1H), 8.14 (s, 1H), 8.06 (d, J: 8.4 Hz, 2H), 7.85 (dd, J: 8.6, 2.8 Hz, 1H), 7.44 (d, J: 8.3 Hz, 2H), 2.36 (s, 3H), 1.32 (s, 12H).

Formation of o(5-fluoromethylsulfanyl-pyrimidin-Z-yl)—1-(p- ulfonyl)pyrrolo[2,3-b]pyridine (24a) 2-chlor0ﬂuoromethylsulfanyl-pyrimidine (1.6 g, 9.0 mmol), 5-ﬂuor0(p- tolylsulfonyl)(4,4,5,5-tetramethyl-1,3,2-di0xaborolanyl)pyrrolo[2,3-b]pyridine, 7a, (2.5 g, 6.0 mmol) and N32CO3 (1.9 g, 18.0 mmol) were dissolved in DME (37.5 mL) and water (7.5 mL). The mixture was purged with nitrogen for 20 minutes, treated with Pd(PPh3)4, purged with nitrogen for another 20 minutes and heated to reﬂux overnight. After cooling to room temperature, water (35 mL) was added and the resulting suspension was stirred for 30 minutes.

The precipitate was ted by ﬁltration, washed with water and acetonitrile and dried overnight at 50 oC, affording 2.3 g (88.5%) of the desired product as a white solid: 1H NMR (300 MHz, DMSO-d6) 8 8.70 — 8.57 (m, 2H), 8.55 — 8.42 (m, 2H), 8.09 (d, J: 8.4 Hz, 2H), 7.45 (d, J: 8.4 Hz, 2H), 2.76 (s, 3H), 2.36 (s, 3H).

Formation of 5-fluoro(5-ﬂuoromethylsulﬁnyl-pyrimidin-Z-yl)—1-(p- tolylsulfonyl)pyrrolo[2,3-b]pyridine (25a) -ﬁu0r0-3 -(5 -ﬂu0r0methylsulfanyl-pyrimidinyl)(p-tolylsulf0nyl)pyrrolo [2,3 - b]pyridine, 24a, (2.30 g, 5.32 mmol) was dissolved in dichloromethane (107 mL) and treated portionwise with 3-chloroperbenzoic acid (1.19 g, 5.30 mmol), keeping the temperature below °C. After ng for 2 hours, another portion of 3-chloroperbenzoic acid (0.18 g, 0.80 mmol) was added, and stirring was continued for r hour. A third portion of 3-chlor0perbenz0ic acid (0.07 g, 0.05 mmol) was added and stirring was continued for 30 minutes. The on mixture was treated with an aqueous 15% K2C03 solution (30 mL) and the layers were separated. The organic layer was washed with 15% K2C03 and brine, dried (Na2S04), ﬁltered and concentrated in vacuo to afford 2.3 g (96%) of the desired product as a yellow solid, which was used without ﬁthher puriﬁcation: 1H NMR (300 MHz, DMSO-d6) 5 9.12 (d, J = 1.5 Hz, 1H), 8.70 (s, 1H), 8.67 (dd, J: 9.1, 2.8 Hz, 1H), 8.53 (d, J: 1.5 Hz, 1H), 8.11 (d, J: 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: Na,9S/ \ \ I \ N N 1a -chloro(5-ﬂuoro(methylsulﬁnyl)pyrimidinyl)—1-tosyl—1H-pyrrolo [2,3-b]pyridine (la) 1H NMR (300 MHz, d6-DMSO) 8 9.12 (d, .1: 1.3 Hz, 1H), 8.90 (d, .1: 2.4 Hz, 1H), 8.68 (s, 1H), 8.53 (d, J: 2.4 Hz, 1H), 8.12 (d, J = 8.4 Hz, 2H), 7.46 (d, .1: 8.4 Hz, 2H), 2.54 _ 2.48 (m, 3H), 2.36 (s, 3H). tic Scheme 5 H O NH2 0 Cm; _. 96H _.QMOBN H a b MgBr 26a 27a H 16 H 17 a) EtzO; b) malonic acid, ammonium acetate, ethanol, 80 0C; c) o(5-ﬂuoro (methylsulﬁnyl)pyrimidinyl)tosyl-1H—pyrrolo[2,3-b]pyridine, 25a, 1PerEt, THF, 80 0C; (d) LiOH, THF- H20 (3:1), 130 °C microwave; e) SFC chiral tion Formation of 2,2-dimethylbutanal (263) To a solution of 1,1-dimethylpropyl magnesium chloride (20.0 mL of 1 M, 20.0 mmol) in ether (25 mL) was added N—methyl-N—phenyl ide (5.26 mL, 20.0 mmol) in one portion (exothermic). The yellow solution was gently reﬂuxed for two hours and stirred at room temperature 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 sulﬁaric acid. The ether layer was separated and the aqueous phase ted three times with 50 mL portions of ether. The combined ether extracts were dried (MgSO4) and concentrated in vacuo. The crude residue was puriﬁed by short-path distillation to afford 1.0 g of pure 2,2-dimethylbutanal as a colorless oil: 1H NMR (400 MHz,CDC13)8 4.17 (q, J: 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, .3 Hz, 3H), 1.26 — 1.17 (m, 1H), 0.85 (d, J: 5.8 Hz, 6H).

Formation of ethyl 3-amin0-4,4-dimethylhexanoate (273) 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 ethanol (5 mL) was reﬂuxed for three hours. The precipitate was removed by ﬁltration and washed with ethanol. The solution was used without ﬁarther puriﬁcation. ic acid (1.962 g, 1.066 mL, 20.00 mmol) was added to above ethanol solution and the resulting e 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 hydroxide solution (6N) and ted sodium bicarbonate solution to basic, and extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed with water (10 mL), brine (10mL), ﬁltered, dried ), ﬁltered and concentrated in vacuo to give 0.5 g of the d product as a light yellow sticky oil, which turned into solid upon standing. The crude product was used without r puriﬁcation: 1H NMR (400 MHz, CDC13)5 4.17 (q, J: 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-ﬂu0r0(5-ﬂu0r0t0syl-1H-pyrrolo[2,3-b]pyridin yl)pyrimidinyl)amino)—4,4-dimethylhexanoate (28a) To a suspension of ethyl 3-amino-4,4-dimethylhexanoate, 27a, (0.19 g. 1.00 mmol) and 5- ﬁuoro-3 -(5-ﬁuoromethylsulﬁnyl-pyrimidinyl)(p-tolylsulfonyl)pyrrolo [2,3 -b]pyridine, 25a, (0.54 g, 1.20 mmol) in THF (14.4 mL) was added N,N—diisopropylethylamine (0.26 mL, 1.50 mmol). The mixture was reﬂuxed at 80 CC overnight. 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: 1H NMR (300 MHz, CDCl3) 5 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, J: 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, 1H), 3.99 (dt, .1: 13.7, 6.8 Hz, 2H), 2.40 (s, 3H), 1.42 (dt, J: 14.1, 6.9 Hz, 2H), 1.05 (t, .1 = 7.1 Hz, 3H), 1.01 — 0.94 (m, 8H); ”P NMR (282 MHz, CDClg) 5 9 — 133.75 (dd, J: 9.0, 1.1 Hz, 1F), -158.56 (s, 1F); LCMS Gradient , 0.1% formic acid, 5 minutes, N, RT = 4.18 minutes (M+H) 572.07.

Formation of 3-((5-ﬂu0r0(5-ﬂu0r0-lH-pyrrolo[2,3-b]pyridinyl)pyrimidin yl)amino)—4,4-dimethylhexanoic acid (16, 17) To a solution of ethyl 3-((5-ﬁuoro(5-ﬁuoro-l-tosyl-1H—pyrrolo[2,3-b]pyridin yl)pyrimidinyl)amino)-4,4-dimethylhexanoate, 28a, (0.16 g, 0.27 mmol) in THF (6 mL) was added LiOH (1.50 mL of 1 M solution, 1.50mmol). The reaction mixture was heated in a microwave reactor at 130 CC for thirty minutes. The reaction was quenched by the addition of aqueous saturated NH4Cl solution. The resulting white precipitate 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 diluted with hydrochloric acid (2 mL of 1N solution) and lyophilized to give 110 mg of the d t as a hydrochloride salt (light yellow powder): 1H NMR (300 MHZ, MeOD) 5 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, 1H), 2.45 (dd, J: 14.0, 9.9 Hz, 1H), 1.93 — 1.83 (m, 3H), 1.46 (d, J = 7.5 Hz, 2H), 1.05 — 0.93 (m, 9H); ”P NMR (282 MHz, MeOD) 5 — 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) .

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

Pre aration 0 Com ounds I4 and 15 Synthetic Scheme 6 ON ON H NH2 0 (5 —> (5 ma b c —* We 31a 32a 33a F F all a, O N\ , s\ NH d N\ / OEt ef \ \ N N 25a N N TS TS a, F N\ N NH\_>_OH ’ OH F N / F I \ / \ I \ N N H N N 14 H 15 a) LiHMDS, MeI,_THF -78 0C; b) DIBAL, CH2C12, -78 0C; c) malonic acid, ammonium acetate, ethanol, 80 0C; d) , THF, 80 0C; e) LiOH, THF- H20 (3:1), 130 °C, microwave; f) SFC chiral separation Formation of 1-methylcyclopentanecarbonitrile (313) To a cold (-78 oC) 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, 40.0 mmol) in tetrahydrofuran (10 mL) over a 5 minute period. After stirring at -78 CC for thirty minutes, methyl iodide (3.74 mL, 60.00 mmol) was added in one portion. The reaction was allowed to warm to room temperature overnight. The on was cooled to 0 oC, 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 c layer was separated and washed with s saturated ammonium chloride (20 mL). The aqueous layer was extracted with ethyl acetate (2 X 20 mL). The combined organic phases were washed with brine, dried (MgSO4), ﬁltered and concentrated in vacuo to give a 4.7g of a yellow oil that was used without ﬁarther puriﬁcation: 1H NMR (400 MHz, CDClg) 8 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 1-methylcyclopentanecarbaldehyde (323) To a cold (-78 oC) solution of diisobutylaluminum hydride (100.0 mL of 1 M solution, 100.0 mmol) in dichloromethane was added dropwise a solution of 1- methylcyclopentanecarbonitrile, 3121, (4.3 g, 40.0 mmol) in dichloromethane (5 mL). The reaction was kept at -78 CC for thirty minutes. The e bath was d and methanol (1 2012/049097 mL) was added to quench the reaction. Potassium sodium tartrate solution (30 mL, 10% solution) was added and the mixture d usly. The organic layer was separated and the s 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: 1H NMR (400 MHz, CDClg) 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, 3H).

Formation of ethyl 3-amin0(1-methylcyclopentyl)pr0pan0ate (33a) A mixture of 1-methylcyclopentanecarbaldehyde, 32a, (3.00 g, 26.75 mmol), c acid (1.29 mL, 20.00 mmol) and ammonium acetate (3.08 g, 40.00 mmol) in ethanol (5 mL) was reﬂuxed for 12 hours. The itate was removed by ﬁltration and washed with ethanol. The ﬁltrate was used without further puriﬁcation.

Sulﬁaric acid (1.07 mL, 20.00 mmol) was added to the above ethanol 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 (3 x 10 mL). The combined organic layers were washed with water (10 mL), brine (10 mL), ﬁltered, dried ), ﬁltered and concentrated in vacuo to give 1.5 g of a light yellow sticky oil that turned into solid upon standing. The crude product was used without r puriﬁcation: 1H NMR (400 MHz, CDCl3) 8 4.25 — 4.14 (q, 2H), 3.40 (bs, 2H), 3.20 — 3.09 (m, 1H), 2.48 (ddd, J: 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). ion of ethyl 3-((5-ﬂu0r0(5-ﬂu0r0t0syl-1H-pyrrolo[2,3-b]pyridin yl)pyrimidinyl)amin0)(1-methylcyclopentyl)pr0pan0ate (34a) A suspension of ethyl 3-amino(1-methylcyclopentyl)propanoate, 33a, (0.20 g, 1.00 mmol), 5-ﬁuoro-3 -(5 -ﬁuoromethylsulﬁnyl-pyrimidinyl)(p-tolylsulfonyl)-pyrrolo [2,3 - b]pyridine, 25a (0.54 g, 1.20 mmol), and N,N—diisopropylethylamine (0.26 mL, 1.50 mmol) in THF (14.4 mL) was reﬂuxed at 80 OC overnight. After removing 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: 1H NMR (400 MHz, CDClg) 8 8.49 (dd, J = 9.0, 2.8 Hz, 1H), 8.46 (s, 1H), 8.23 (d, J: 1.5 Hz, 1H), 8.02 (d, J: 8.3 Hz, 2H), 7.99 (d, J: 3.1 Hz, 1H), 7.20 (d, J: 7.8 Hz, 2H), 5.23 (d, J: 8.9 Hz, 1H), 4.80 (td, J: 9.7, 3.6 Hz, 1H), 4.04 (q, J: 7.1 Hz, 1H), 3.91 (q, J: 7.1 Hz, 2H), 2.73 — 2.58 (m, 1H), 2.44 (dd, J: 14.7, 9.6 Hz, 1H), 2.33 — 2.21 (m, 3H), 1.72 — 1.46 (m, 7H), 1.42 — 1.31 (m, 1H), 1.28 (t, 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, Cl8/ACN, RT = 4.25 minutes (M+H) 584.29.

Formation of ethyl 3-((5-ﬂu0r0(5-ﬂu0r0t0syl-1H-pyrrolo[2,3-b]pyridin yl)pyrimidinyl)amin0)(1-methylcyclopentyl)pr0pan0ate (14, 15) To a solution of ethyl 3-((5-ﬁuoro(5-ﬁuorotosyl-1H—pyrrolo[2,3-b]pyridin yl)pyrimidinyl)amino)(1-methylcyclopentyl)propanoate, 34a, (0.16 g, 0.27 mmol) in THF (6 mL) was added LiOH (1.50 mL of 1 M solution, 1.50 mmol). The reaction mixture was irradiated in a microwave reactor for 30 minutes at 130 oC. Aqueous ted NH4Cl solution was added to acidify the e. 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 1N solution) and the mixture was lyophilized to give 120 mg of the desired product as a hydrochloride salt (light yellow powder): 1H NMR (400 MHz, MeOD) 8 8.64 (d, J: 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, J: 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, J: 19.2 Hz, 3H); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, N, RT = 2.10 minutes (M+H) 401.94.

The c mixture of carboxylic acids was submitted to SFC chiral separation to give the individual enantiomers, 14 and 15.

Pre aration 0 Com ounds 20 and 23 Synthetic Scheme 7 _ o — O b N/NH —>a \N~ ﬁg N’NwF; N\/NH/O —F \N‘/O 0' 7\ H N7\ —\ CI F Q>§< \// \ 7\ 15a 37a / \ \B‘O N '1 38a N’ 7a Ts & o a o a o c N\ d F [ﬂy—H01 N\ N‘ F N/ NW0 F N/ NMOH \ / \ 7\ \ / \ 7\ 8 \ / \ 7\ TS 39a 23 20 (a) ethyltriphenylphosphoranylideneacetate, CH2C12; (b) 5-ﬂuoro(4,4,5,5-tetramethyl- 1,3,2-dioxaborolanyl)tosyl-1H—pyrrolo[2,3-b]pyridine, 7a, aq. K3PO4, 2-Me-THF, H20, X- Phos, Pd2(dba)3; (c) H2, 10% Pd/C, MeOH; (d) CH3CN, 4N HCl/Dioxane Formation of (R,E)—ethyl 4-((2-chlor0ﬂu0r0pyrimidinyl)amin0)—5,5- dimethylhex-Z-enoate (373) To a solution of ((2-chloroﬂuoropyrimidinyl)amino)-3,3-dimethylbutanal, 153, (0.45 g, 1.84 mmol) in dichloromethane (9.0 mL) was added ethyl 2- triphenylphosphoranylideneacetate (0.96 g, 2.75 mmol). After allowing the reaction mixture to stir at room temperature overnight, imately half of the solvent was removed under reduced pressure. The remaining crude mixture was puriﬁed by ly g onto a silica gel column (0-100% EtOAc/hexanes) to afford 535 mg of the desired product: LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, RT = 3.41 minutes (M+H) 316.32.

Formation of (R,E)—ethyl 4-((5-ﬂu0r0(5—ﬂu0r0t0syl-1H—pyrrolo[2,3-b]pyridin yl)pyrimidinyl)amino)—5,5-dimethylhexen0ate (383) K3P04 (1.078 g, 5.079 mmol) was dissolved in water (3.2 mL) and added to a solution of (R,E)-ethyl 4-((2-chloroﬂuoropyrimidinyl)amino)-5,5-dimethylhexenoate, 373, (0.534 g, 1.693 mmol) in yl-THF (10.7 mL) and the mixture was purged with nitrogen for 30 minutes. 5 -ﬂuoro(p-tolylsulfonyl)-3 -(4,4,5 ,5 -tetramethyl- 1 ,3 ,2-dioxaborolan yl)pyrrolo[2,3-b]pyridine, 73, (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)3 (0.031 g, 0.034 mmol) were added and the mixture was heated at 80 0C ght. After cooling to room WO 19828 2012/049097 temperature, the reaction mixture was diluted with water and extracted with EtOAc. The layers were separated and the c phase was washed with brine, dried over MgSO4, d and ated to dryness. The crude residue was dissolved in a m volume of dichloromethane and puriﬁed by silica gel chromatography (0-100%EtOAc/hexanes gradient) to afford 650 mg of desired product: 1H NMR (400 MHz, CDClg) 8 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), .11 (d, J: 8.7 Hz, 1H), 4.97 — 4.77 (m, 1H), 4.19 (q, J: 7.1 Hz, 2H), 2.39 (d, J: 10.7 Hz, 3H), 1.27 (q, J = 7.4 Hz, 4H), 1.10 (s, 9H); LCMS Gradient 10-90%, 0.1% formic acid, 5 s, C18/ACN, RT = 3.99 minutes (M+H) 570.01.

Formation of (R)-ethyl 4-((5-ﬂu0r0(5-ﬂu0r0t0syl-1H—pyrrolo[2,3-b]pyridin yl)pyrimidinyl)amin0)-5,5-dimethylhexan0ate (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,E)-ethyl 4- ((5 (5 -ﬁuorotosyl-1H—pyrrolo[2,3 -b]pyridin-3 -yl)pyrimidinyl)amino)-5 ,5 - dimethylhexenoate, 38a, (0.330 g, 0.579 mmol) in MeOH. Note, a small amount of EtOAc was added to ﬁllly solubilize the ng material. The reaction e was then stirred under 1 atmosphere of hydrogen for 3 hours. LCMS shows presence of signiﬁcant amounts of starting material. The contents of the reaction e 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 enation ﬂask under 46 psi of hydrogen overnight. The mixture was diluted with methanol and ﬁltered through celite. The e was concentrated in vacuo to afford 331 mg of the desired product that was used without ﬁarther puriﬁcation: LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, RT = 3.75 minutes (M+H) 572.35.

Formation of ((5—ﬂu0r0(5-ﬂu0r0-lH-pyrrolo[2,3-b]pyridinyl)pyrimidin yl)amino)—5,5-dimethylhexanoic acid (20) To a solution of (R)-ethyl 4-((5-ﬁuoro(5-ﬁuorotosyl-1H—pyrrolo[2,3-b]pyridin yl)pyrimidinyl)amino)-5,5-dimethylhexanoate, 39a, (0.30 g, 0.53 mmol) was in acetonitrile (5 mL) was added HCl (0.70 mL of 4 M solution in dioxane, 2.80 mmol). The reaction mixture was heated at 60 0C for 3 hours and then heated to 80 0C for 6 hours to drive the reaction to completion. After cooling to room temperature, the mixture was then stirred overnight. LCMS 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 oC overnight. All volatiles were removed under reduced pressure and the residue was diluted with EtOAc and aqueous saturated NaHC03 solution. The layers were separated and the organic phase was washed with brine, dried over MgSO4, ﬁltered and evaporated to dryness. The crude residue was puriﬁed by silica gel chromatography (0-100% EtOAc/hexanes gradient) to afford 144 mg of (R)-ethyl 4-((5-ﬂuoro (5-ﬁuoro-1H-pyrrolo[2,3-b]pyridinyl)pyrimidinyl)amino)-5,5-dimethylhexanoate, 23, and 29 mg of (R)((5-ﬁuoro(5-ﬁuoro-1H—pyrrolo[2,3-b]pyridinyl)pyrimidinyl)amino)-5,5- dimethylhexanoic acid, 20. Spectral data for 20: 1H NMR (400 MHz, DMSO) 5 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, 1H), 4.39 (t, J: .2 Hz, 1H), 2.38 - 2.07 (m, 2H), 1.99 - 1.92 (m, 1H), 1.80 - 1.64 (m, 1H), 1.00 (d, J: 20.2 Hz, 9H); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, RT = 2.14 minutes (M+H) 390.06.

Pre aration 0 Com ound 59 Synthetic Scheme 8 / F N : H \ ’ \ J‘ N // \ 7\ I\\I 42a \N Ts H 59 Formation of (R,E)—4-((5-ﬂuoro(5-ﬂuoro-lH-pyrrolo[2,3-b]pyridinyl)pyrimidin yl)amino)-5,5-dimethylhexenoic acid (59) Starting ethyl ester, 42a, was prepared in the same fashion as the enantiomeric ethyl ester, 38a, shown in tic Scheme 7.

To a solution of (S,E)-ethyl 4-((5-ﬂuor0(5-ﬂuorot0syl-1H—pyrrolo[2,3-b]pyridin yl)pyrimidinyl)amin0)-5,5-dimethylheXen0ate, 42a, (0.064 g, 0.112 mmol) in dioxane (2 mL) was added LiOH (2 mL of 2N solution). After heating at 100 0C for 2 hours, the mixture was ed 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 (CH3CN/H20 — TFA r) to afford 35 mg of the desired product as a TFA-salt: 1H NMR (300 MHz, MeOD) 5 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), 1.12 (s, 9H); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, (M+H) .

Pre aration 0 Com ound 44 Synthetic scheme 9 NH2 0 NH2 0 ” f 0' e NH OH 0 N\ / OMe —> —> —> N 483 49a CI ,. o N / NH OMe \ -——-" O N h 9 F N / NH OMe —> / —’ \ 73 F \ I N N 513 I \ 52a 1'. \ S N N h _, o N / NH OH _, \ I \ 44 N N (a) Pyridinium chlorochromate, CHZCIZ; (b) ethyltriphenyl-phosphoranylideneacetate, ; (c) N—benzylhydroxylamine, Et3N, CHzClz (d) H2, palladium hydroxide, EtOH (e) diazomethyl-trimethylsilane, MeOH, benzene (f) 2,4-dichloroﬂuoro-pyrimidine, Et3N, THF, EtOH (g) o(4,4,5 ,5-tetramethyl-1,3 ,2-dioxaborolanyl)tosyl-1H—pyrrolo[2,3- b]pyridine, 7a, Aq. K3P04, 2-Me-THF, H20, X-Phos, Pd2(dba)3, 80 0C; (h) MeOH, NaOMe (i) aq. NaOH, THF, MeOH Formation of cyclobutanecarbaldehyde (453) To a stirred suspension of pyridinium chlorochromate (14.9 g, 69.1 mmol) in dichloromethane (150 mL) was added a solution of cyclobutylmethanol (4.0 g, 46.4 mmol) i n dichloromethane (60 mL). The reaction mixture turned black within a few s and was allowed to stir at room temperature for 1 hour. The mixture was diluted with diethyl ether (500 mL) and ﬁltered through a bed of ﬁorisil (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.

Formation of (E)-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 romethane (30 mL). The reaction mixture was brieﬂy purged with nitrogen and capped allowed to stir at room temperature overnight. All volatiles were removed at reduced re and the residue was ved in EtzO (100 mL) and hexanes (25mL). The resulting pink precipitate was ﬁltered off and discarded. The solvent was removed from the ﬁltrate at reduced pressure. The crude t was puriﬁed via silica gel chromatography (0-20% EtOAc/Hexanes gradient) to afford 646 mg (23%) ofthe desired product: 1H NMR (400 MHz, CDClg) 8 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-benzylcyclobutylisoxazolidin0ne (47a) N—benzylhydroxylamine hydrochloride (0.77 g, 4.82 mmol) and triethylamine (0.76 mL, .45 mmol) were successively added to a solution of (E)-ethyl 3-cyclobutylacrylate, 46a, (0.65 g, 4.19 mmol) in dry dichloromethane (23.5 mL). The reaction mixture was allowed to stir at room temperature under an atmosphere of nitrogen for 3 days. The mixture was diluted with 75 mL of water and the layers were ted. The aqueous phase was reextracted twice more with dichloromethane (50 mL). The combined organic phases were dried over MgSO4 ﬁltered and evaporated to dryness. The residue was puriﬁed via silica gel chromatography (0-100% EtOAc/Hexanes nt) to afford 834 mg (86%) of the desired product: 1H NMR (400 MHZ, CDC13)5 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 (+/-)amin0cyclobutylpr0panoic acid (48a) oxypalladium (0.252 g, 1.794 mmol) was charged into a ﬂask and ﬂushed with nitrogen. Ethanol (30 mL) was added followed by a solution of 2-benzyl-3 -cyclobutyl- isoxazolidin—5-one, 47a, (0.834 g, 3.605 mmol) in approximately 90 mL of ethanol. The reaction mixture was subjected to 50 psi of hydrogen for 4 hours. The pressure was vented and the catalyst was ﬁltered off. All volatiles were removed at reduced pressure. 1H NMR shows the presence of starting material, 47a. The mixture was dissolved in approximately 100 mL of MeOH and added to 83 mg of C that had been wet with 20 mL of MeOH. The mixture was subjected to 50 psi of H2 overnight. The pressure was vented and the st was ﬁltered off. All volatiles were removed at reduced pressure to afford 340 mg of product. The resulting crude residue was used without ﬁthher puriﬁcation: 1H NMR (400 MHz, d6-DMSO) 8 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 0cyclobutylpropanoate (49a) To a solution of racemic 3-aminocyclobutyl-propanoic acid, 48a, (0.34 g, 2.38 mmol) in MeOH (10.2 mL) and benzene (10.2 mL) was added diazomethyltrimethyl-silane (3.56 mL of 2 M solution, 7.13 mmol) and the on e was allowed to stir at room ature under a nitrogen atmosphere overnight. The mixture was diluted with EtOAc and brine. The layers were separated and the organic phase was dried (MgSO4), ﬁltered and concentrated in vacuo to afford 354 mg (95%) of crude product that was used t r puriﬁcation: 1H NMR (400 C13)5 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 (+/-)((2-chloro-S-ﬂuor0pyrimidinyl)amin0)—3- cyclobutylpropanoate (50a) To a racemic solution of methyl 3-aminocyclobutylpropanoate, 49a, (0.354 g, 2.252 mmol) and 2,4-dichloroﬂuoro-pyrimidine (0.414 g, 2.477 mmol) in THF (10 mL) and ethanol (1 mL) was added triethylamine (0.628 mL, 4.504 mmol). The reaction mixture was heated and d at 70 0C 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 afford 289 mg (45%) of the desired product: 1H NMR (300 MHz, CDC13) 5 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 (+/-)cyclobutyl((5-ﬂu0r0(5-ﬂu0r0t0syl-1H-pyrrolo[2,3-b]pyridin yl)pyrimidinyl)amin0)pr0panoate (Sla) A solution of tripotassium phosphate (0.640 g, 3.021 mmol) in water (1.735 mL) was added to a on of racemic methyl chloroﬂuoro-pyrimidinyl)amino]cyclobutyl- propanoate, 503, (0.289 g, 1.005 mmol) in 2-methyltetrahydrofuran (5.782 mL). The mixture was then purged with nitrogen for 20 minutes. 5-ﬂuoro(p-tolylsulfonyl)(4,4,5,5- tetramethyl-l,3,2-dioxaborolanyl)pyrrolo[2,3-b]pyridine, 73, (0.460 g, 1.106 mmol) was added and the mixture was purged with nitrogen for an additional 10 s. Dicyclohexyl-[2- (2,4,6-triisopropylphenyl)phenyl]phosphane (X-Phos: 0.029 g, 0.060 mmol) and a}3 (0.018 g, 0.020 mmol) were added and the reaction mixture was warmed to 80 OC and stirred at this temperature for 5 hours. The e was allowed to cool to room temperature. 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 MgSO4 ﬁltered and evaporated to s. The crude was dissolved in a minimum volume of dichloromethane and puriﬁed via silica gel tography (0-100%EtOAc/Hexanes).to afford 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-cyclobutyl—3-((5-ﬂu0r0(5-ﬂu0r0-lH-pyrrolo[2,3-b]pyridin- 3-yl)pyrimidinyl)amin0)pr0pan0ate (523) To a racemic on of methyl 3-cyclobutyl((5-ﬂuoro(5-ﬂuorotosyl-1H— pyrrolo[2,3-b]pyridinyl)pyrimidinyl)amino)propanoate, 5121, (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 e at room temperature for 5 minutes, the mixture was quenched with aqueous saturated NH4Cl solution and d with EtOAc and water. The layers were separated and the organic phase was washed with brine, dried (MgSO4), 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 t: LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, RT = 2.29 minutes (M+H) 388.07.

Formation of 3-cyclobutyl((5-ﬂu0r0(5-ﬂu0r0-lH-pyrrolo[2,3-b]pyridin yl)pyrimidinyl)amin0)pr0pan0ic acid (44) To a racemic solution of methyl 3-cyclobutyl((5-ﬂuoro(5-ﬂuoro-1H—pyrrolo[2,3- b]pyridinyl)pyrimidinyl)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 CC. After stirring the reaction mixture for 1 hour, the mixture was diluted with aqueous ted NH4C1 solution and EtOAc. The organic layer was dried (MgSO4), ﬁltered and evaporated to dryness to afford 36 mg of the desired product that was used without r puriﬁcation: 1H NMR (400 MHZ, d6-DMSO) 5 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: .6, 12.2 Hz, 2H), 1.85 (ddd, J = 29.4, 26.5, 21.1 Hz, 7H); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, RT = 2.10 minutes (M+H) 374.02.

Pre arationo Com 0unds10 II 19 21 22 32 33 34 35 38 39 40 49 57 and 58 Synthetic Scheme 10 F F '1in’ OMS a N/—§*NH OH N/—§’NH b \ Nu F/ u_,F C' 7\ \ F Q>€< \N/ \ J‘ \N/ 14a / \ B70 N 54a \ 55a , \ Ts TS N 7a F F C / \ J< \ OH F N F ‘ i / 3 \ / \ 7\ \ / \ N N \ \ Ts TS 56a 57a NWNL/H _ — o NWN o H 0%” f \‘2 / e, ‘9' \ \—/ F N N —> N / \ / \ ;\ \ l N N \ H Ts 58a 19 (a) 5 -ﬂuoro(p-tolylsulfonyl)—3 -(4,4,5 ,5 -tetramethyl- 1 ,3 ,2-dioxaborolanyl)pyrrolo-[2,3 - b]pyridine, 7a, K3P04, X-Phos, Pd2(dba)3, 2-MeTHF, water, 120 0C; (b) MsCl. CH2C12; (c) KOAc, DMF, 80 0C; (d) 30% H202, HCOOH, RT, 2 hr; (e) oxalyl chloride, DMF, CHzClz; (f) (i) methylamine, THF (ii) 4M HC1, CH3CN, 65 0C.

(S)—2-(5-ﬂu0r0(5-ﬂu0r0tosyl-1H-pyrrolo[2,3-b] pyridinyl)pyridinylamin0)-3,3- dimethylbutan-l-ol (543).

A mixture of 5-ﬁuoro(p-tolylsulfonyl)(4,4,5,5-tetramethyl-1,3,2-dioxaborolan yl)pyrrolo[2,3-b]pyridine, 73, (11.09 g, 26.64 mmol), (S)((2-chloroﬁuoropyrimidin yl)amino)-3,3-dimethylbutanol, 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 s. X- Phos (0.92 g, 1.94 mmol) and a)3 (0.44 g, 0.48 mmol) were added and the on e was heated at 120 0C in a pressure Vial for 2 hr. The on mixture was cooled to room temperature, 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 silica gel chromatography (0-40% EtOAc/Hexanes gradient) to afford 10 g of the desired product as a foamy solid: 1H NMR (400 MHz, CDC13) 5 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-ﬂu0r0(5-ﬂu0r0t0syl—1H—pyrrolo[2,3-b] pyridinyl)pyridinylamin0)-3,3- dimethylbutyl methanesulfonate (553).

Methanesulfonyl de (1.83 mL, 23.67 mmol) was added to a cold (0 0C) solution of (S)—2-(5 -fluoro(5 -ﬂuorotosyl-1H-pyrrolo [2,3 -b] pyridin-3 -yl)pyridinylamino)-3 ,3 - dimethylbutan-l-ol, 5421, (9.50 g, 18.94 mmol) and triethylamine (3.30 mL, 23.67 mmol) in dichloromethane (118 mL). The reaction mixture was stirred at room temperature for 1 hour.

The solvent was removed under reduced re 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 d 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. (5-ﬂuoro-Z-(S-ﬂuorot0syl-1H—pyrrolo [2,3-b]pyridinyl)pyridinylamin0)-3,3- dimethylbutyl ethanethioate (56a).

To a solution of (S)(5-ﬂuoro(5-ﬂuorotosyl-1H—pyrrolo[2,3-b] pyridin yl)pyridinylamino)-3,3-dimethylbutyl methanesulfonate, 5521, (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 0C 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), ed and concentrated under reduced pressure. The crude residue was puriﬁed by silica gel chromatography (0-30% EtOAc/Hexanes gradient) to afford 6.8 g of the desired product, 563, as a pale brown solid: 1H NMR (400 MHz, CDClg) 5 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 ; LC/MS (10-90% ACN/water 5 min with 0.9% FA) m/Z 560.99 (M+H) RT = 4.14 minutes.

(S)(5-ﬂuoro-Z-(S-ﬂuorot0syl-1H—pyrrolo ]pyridin-3yl)pyridinylamin0)-3,3- dimethylbutane—1-sulf0nic acid (573).

To a cold (0 0C) solution of formic acid (103.4 mL, 2.7 mol) was added H202 (34.2 mL of % solution, 0.3 mol). The solution was d at 0 0C for 1 hour. A solution of (5- fluoro(5-ﬂuorotosyl- 1H-pyrrolo [2,3 -b]pyridin-3 -yl)pyridinylamino)-3 ,3 -dimethylbutyl ethanethioate, 563, (6.7 g, 12.0 mmol) in formic acid (20.0 mL) was added dropwise. The resulting mixture was stirred at room temperature for 2 hours to give a yellow solution. The solvent was d under reduced pressure to afford the desired product as a foamy pale yellow solid that was used without further purification: 1H NMR (400 MHz, MeOD) 5 8.72 (m, 2H), 8.31 (s, 1H), 8.21 (d, J: 4.8 Hz, 1H), 8.06 (d, J: 8.1 Hz, 2H), 7.39 (d, J: 8.0 Hz, 2H), .08 (d, J: 10.0 Hz,1H), 3.19 (m, 2H), 2.36 (s, 3H), 1.04(m, 9H); LC/MS (10-90% ACN/water min with 0.9% TFA, C18) m/z 566.0 (M+H) RT = 2.66 minutes.

(S)—2-(5-ﬂu0r0(5-ﬂu0r0t0syl—1H—pyrrolo[2,3-b] pyridinyl)pyridinylamin0)-3,3- dimethylbutane—l-sulfonyl chloride (58a).

Oxalyl chloride (3.5 mL, 38.7 mmol) was added to a solution of (S)—2-(5-ﬂuoro(5- ﬂuorotosyl- 1H-pyrrolo [2,3 -b]pyridin-3yl)pyridinylamino)-3 ,3 hylbutanesulfonic acid, 573, (7.3 g, 12.9 mmol) in dichloromethane (130 mL), ed by the slow, dropwise addition of DMF (2 mL). The yellow colored solution was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure to afford 8.4 g of the d 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.

(S)—2-(5-ﬂu0r0(5-ﬂu0r0-lH-pyrrolo ] pyridinyl)pyrimidin-4ylamin0)-N,3,3- trimethylbutane—l-sulfonamide (19) Methylamine (0.75 mL of 2M solution, 1.53 mmol) was added to a solution of (S)—2-(5- fluoro(5-ﬂuoro- l -tosyl- l H—pyrrolo [2,3 -b] pyridin-3 -yl)pyridinylamino)-3 ,3 - dimethylbutane-l-sulfonyl chloride, 5821, (0.15 g, 0.26 mmol) in THF (1 mL). The solution was stirred for 1 hour at room temperature 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 e) was added. The mixture was heated at 65 0C for 3 hours and then cooled to room temperature. The t was removed under reduced pressure and the resulting crude residue was puriﬁed by preparative HPLC tography (10-80% CH3CN/water, 0.5% TFA, 15 min) to give 26 mg of the desired product as a white solid: 1H NMR (400 MHz, CDClg) 8 9.75 (s, 1H), 8.12 (d, J: 9.3 Hz, 1H), 7.94 (s, 1H), 7.73 (s, 2H), 7.67 (brs, 1H), 4.93 - 4.78 (m, 2H), 3.08 (m, 1H), 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 following compounds can be prepared in a similar fashion as the procedure described above for Compound 19: H\\S\_ OH0» F \N \—/H / t \/\ 7\ N N (S)—N—Cyclopropyl-Z-(S-ﬂuor0(5-ﬂu0r0—lH-pyrrolo [2,3-b] pyridinyl)pyrimidin ylamino)—3,3-dimethylbutane—l-sulfonamide (21) 1H NMR (400 MHz, CDClg) 8 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), 1.13(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.

N/—§7NH OQS/l\N/\/— O O\ F N \—/ / t \ / \ 7\ N N (S)—2-(5-Flu0r0(5-ﬂuoro-lH-pyrrolo [2,3-b]pyridinyl)pyrimidinylamin0)-N-(2- yethyl)—3,3-dimethylbutane—1-sulf0namide (35) LC/MS % ACN/water 5 min with 0.9% FA) m/Z 469.28 (M+H) RT = 2.11 minutes.

NWNH Oeél\N/\/_ o F N \—/ / t \ / \ 7 \ N N (S)(5-Flu0r0(5-ﬂuoro-lH-pyrrolo [2,3-b] pyridinyl)pyrimidinylamin0)-3,3- dimethyl-N—propylbutane-l-sulfonamide (34) 1H NMR (400 MHz, CDC13) 5 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): LC/MS (10-90% ACN/water 5 min with 0.9% FA) m/Z 453.44 (M+H) RT = 2.42 minutes.

N/—§*NH— O 0 II \\S\ F N §__// NH \ / \ ;\ N N (S)—2-(5-Flu0r0(5-ﬂuoro-lH-pyrrolo[2,3-b]pyridinyl)pyrimidinylamin0)-N- isopropyl-3,3-dimethyl-N—propylbutane-l-sulfonamide (39) 1H NMR (400 MHz, CDC13) 8 9.89 (s, 1H), 8.07 (d, J: 8.9 Hz, 1H), 7.90 (s, 1H), 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); LC/MS (10-90% ter 5 min with 0.9% FA) m/Z 453.19 (M+H) RT = 2.22 minutes.

(S)(5-Flu0r0(5-ﬂuoro-lH-pyrrolo [2,3-b]pyridinyl)pyrimidinylamin0)-N-tert- butyl-3,3-dimethyl-N—propylbutane-l-sulfonamide (40) LC/MS (10-90% ACN/water 5 min with 0.9% FA) m/z 467.20 (M+H) RT = 2.36 minutes.

NiNH_ o Ox‘s” \ ‘NH F N \—/.

/ § \\ \ / \ ;\ N N (S)-N-Ethyl(5-ﬂu0r0(5-ﬂu0r0-lH-pyrrolo [2,3-b]pyridinyl)pyrimidinylamin0)- 3,3-dimethylbutane—l-sulfonamide (33) 1H NMR (400 MHz, CDC13) 8 9.89 (brs, 1H), 8.07 (d, J: 9.3 Hz, 1H), 7.89 (s, 1H), 7.66 (n1, 2H), 4.95 (t, J: 10.2 Hz, 1H), 4.80 (d, J = 9.6 Hz, 1H), 3.38 (n1, 1H), 3.18 - 2.96 (n1, 3H), 1.35 - 1.12 (m, 3H), 0.90 (n1, 9H); LC/MS (10-90% ACN/water 5 min with 0.9% FA) m/z 439.30 (M+H) RT = 2.25 minutes. _ o OQI/ / \’< \ / \ 7\ N N (S)-N-(2,2-diﬂu0r0ethyl)(5-ﬂu0r0(5-ﬂu0r0-lH-pyrrolo [2,3-b] nyl)pyrimidin- 4-ylamino)—3,3-dimethylbutane—l-sulfonamide (57) 1H NMR (400 MHz, CDC13) 8 8.05 (d, J: 7.9 Hz, 1H), 7.81 (d, J: 2.1 Hz, 1H), 7.63 (s, 1H), 7.55 (s, 1H), 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 (n1, 2H), 3.19 (n1, 1H), 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.

N/—§*NH— O \‘S ‘ F \N }_/ NH F / C < F \ /\ ;\ N N (S)(5-ﬂu0r0(5-ﬂuoro-lH-pyrrolo [2,3-b]pyridinyl)pyrimidinylamin0)-3,3- dimethyl-N—(Z,2,2-triﬂu0r0ethyl)butane—l-sulfonamide (58) 1H NMR (400 MHz, CDC13) 8 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, 1H), 5.07 (t, J: 10.6 Hz, 1H), 4.77 (m, 1H), 3.45 (m, 1H), 3.16 - 2.99 (m, 1H), 0.97 = - 0.86 (n1, 9H); LC/MS (10-90% ter 5 min with 0.9% FA) m/z 493.31 (M+H) RT 2.37 minutes.

NﬁgiNH_ o O\II \N/ \/3 F 1 NH2 / S \ / \ 7\ N N (S)(5-ﬂu0r0(5-ﬂuoro-lH-pyrrolo [2,3-b]pyridinyl)pyrimidinylamin0)-3,3- dimethylbutane—l-sulfonamide (22) trated NH4OH (1.0 mL, 25.7 mmol) was added dropwise to a solution of (S)—2-(5- WO 19828 fluoro(5-ﬂuorotosyl- 1H-pyrrolo [2,3 -b] pyridin-3 -yl)pyridinylamino)-3 ,3 - dimethylbutanesulfonyl de, 5821, (0.3 g, 0.5 mmol) in THF (3 mL). The reaction mixture was stirred for 15 minutes at room temperature, resulting in a 1-to-1 mixture of the d sulfonamide and sulfonic acid. The solvent was removed under reduced re. The crude product was puriﬁed by silica gel chromatography (0-70% EtOAc/Hexanes gradient) to afford 93 mg of the ted sulfonamide intermediate as a foamy solid.

The tosylated sulfonamide (93 mg) was dissolved 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 on was stirred at room temperature for 15 minutes and then diluted into aqueous saturated NH4C1 solution (5 mL). 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) and dried (MgSO4), ﬁltered, and concentrated in vacuo. The crude residue was puriﬁed by HPLC preparative chromatography (10-80% CHgCN/water, 0.5% TFA, 15 min) to afford 40 mg of the desired product, 22, as a white solid: 1H NMR (400 MHz, MeOD) 8 8.65 (d, J = 9.3,1H), 8.47 (s, 1H), 8.34 (m, 2H), 5.28 (d, J: 10.4 Hz, 1H), 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.

(R)—2-((5-ﬂu0r0(5-ﬂu0r0-lH-pyrrolo [2,3-b] pyridinyl)pyrimidinyl)amin0)— N,3,3-trimethylbutane—l-sulfonamide (38) 1H NMR (300 MHz, d6-DMSO) 5 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, 1H), 3.36 - 3.28 (m,.]= 10.5 Hz, 1H), 2.55 (t, J = 5.6 Hz, 3H), 0.98 (s, 9H); LCMS nt 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, RT = 2.11 minutes (M+H) .

NWNH OH F \N \—/ / t \ / \ ;\ N N (S)(5-ﬂu0r0(5-ﬂuoro-lH-pyrrolo [2,3-b]pyridinyl)pyrimidinylamin0)-3,3- ylbutane—l-ol (32) Alcohol, 32, was synthesized in a manner similar to compound 703 utilizing the same deprotection procedure, starting with compound 543: 1H NMR (400 MHz, CDClg) 8 10.77 (hrs, 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, 2H), 4.11 (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.

NWNH OH CI N }—/ / S \ / \ 7\ N N (S)((2-(5-chlor0-lH-pyrrolo [2,3-b] pyridinyl)-S-ﬂuor0pyrimidinyl)amin0)—3,3- dimethylbutan-l-ol (49) l, 49, was synthesized in a manner similar to compound 32: 1H NMR (400 MHz, CDC13) 8 10.77 (hrs, 1H), 8.25 (d, J: 8.4 Hz, 1H), 8.07 (s,lH), 8.03 (s, 1H), 7.88 (s, 1H), 5.59 (brs, 1H), 4.36 (t, J: 8.3 Hz, 2H), 4.11 (m, 1H), 3.72 (m, 2H), 1.06 (s, 9H); LC/MS (10-90% ter 5 min with 0.9% FA) m/z 348.13 (M+H) RT = 1.83 minutes.

N/—§~NH— O 0 II ‘\S\ / S \ / \ 7\ N N (S)(5-ﬂu0r0(5-ﬂu0r0-lH-pyrrolo[2,3-b]pyridinyl)pyrimidinylamin0)-3,3- dimethylbutane—l-sulfonic acid (11) Sulfonic acid, 11, was synthesized in a manner similar to Compound 25 described below, using compound, 5721, as the starting material: 1H NMR (400 MHz, MeOD) 5 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, 1H), 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) retention time = 1.91 s.

NWNH— o O\II \ ‘3‘ }_/ OH CI N / ¢ \ / \ 7\ N N 10 (S)((2-(5-chlor0-lH-pyrrolo [2,3-b] pyridinyl)-S-ﬂuor0pyrimidinyl)amin0)—3,3- dimethylbutane—l-sulfonic acid (10) Sulfonic acid, 10, was synthesized in a manner similar to Compound 11, using 5-chloro(4,4,5 ,5 -tetramethyl-1,3 ,2-dioxaborolanyl)— 1 -tosyl- 1H-pyrrolo [2,3 -b]pyridine instead of boronate ester, 73, as the ng material: 1H NMR (400 MHz, MeOD) 5 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, 1H), 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) retention time = 1.91 minutes.

Pre aration 0 Com ounds 46 Synthetic Scheme 11 fé’ F F 'T i— b — o OH c N / NH a >\,N \_/ N _, I: NN 0, Ms _, s f\ N\i/ NH = s—/( _» C | S H U:: C' 7\ CI 7 14a 75a 76a F F F NfgiNH— — d — e O\|| SH NﬁgiNH s— ‘s— >—N\ \—/ _’ >LN \ / N/—§*NH —> \ \ / N 0' 7\ 0' 7‘\ 0' 7‘\ 77a 78a 79a F F Nfg‘NH o NiNH 0*"— _ O f 0%” s\ g \ \ \ / —» F N :‘—/ _. F hf / \ >€< \ / \ 7 \ \ / \ ; \ F Q N N N N / \ BTO \ H \ Ts 80a 46 / 7a (a) MsCl. CHzClz; (b) KOAc, DMF; (c) NaOMe, MeOH; (d) Mel, K2C03, acetone, 70 0C; (e) Oxone, water, MeOH, 3 hr, RT; (f) 5-ﬂuoro(p-tolylsulfonyl)—3-(4,4,5,5-tetramethyl-l,3,2- dioxaborolanyl)pyrrolo[2,3-b]pyridine, 7a, K3P04 X-Phos, Pd2(dba)3, 2-MeTHF, water, 120 OC, 3 hr then 80 0C, 1 hr; (g) NaOMe, MeOH.

(S)—2-(2-chlor0ﬂuor0pyrimidinylamin0)—3,3-dimethylbutyl methanesulfonate (75a).

To a cold (0 0C) solution of ((2-chloroﬂuoropyrimidinyl)amino)-3,3- dimethylbutan-l-ol, 143, (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, 9.84 mmol). The solution was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure and water (100 mL) and EtOAc (50 mL) were added. The organic phase was separated, dried (MgSO4) and concentrated under reduced pressure to afford 2.55 g of the desired t 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 mintues.

(S)-S(2-chlor0ﬂu0r0pyrimidinylamin0)—3,3-dimethylbutyl ethanethioate (76a). ium thioacetate (1.30 g, 11.51 mmol) was added to a stirring solution of (S)(2- chloroﬂuoropyrimidinylamino)—3,3-dimethylbutyl esulfonate, 753, (2.50 g, 7.67 mmol) in dry DMF (50 mL). The ing brown solution was heated with stirring at 78 0C for 1 hour. The brown sion 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 (0-30% EtOAc/Hexanes gradient) to afford 2.1 g of compound 763 as a pale brown solid: 1H NMR (400 MHZ, CDClg) 5 7.81 (s, 1H), 5.12 (m, 1H), 4.21 (t, .1: 9.1 Hz, 1H), .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-chlor0ﬂu0r0pyrimidiny13min0)-3,3-dimethylbut3nethiol (773) To a nitrogen-purged solution of (S)—S—2-(2-chloro-5 -ﬂuoropyrimidinylamino)-3,3- dimethylbutyl ethanethioate, 763, (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 temperature for 1 hour. The reaction e was concentrated in vacuo and the residue was dissolved in water (25 mL) and slowly acidiﬁed with 2N HCl to give a white precipitate that was extracted twice with EtOAc. The ed organic phases were dried (MgSO4), d and concentrated under reduced re to afford 0.85 g of the desired product as a pale 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-chlor0-N—(3,3-dimethyl—1-(methylthi0)but3nyl)- 5-ﬂu0r0pyrimidin3mine (783) To a suspension of (S)(2-chloroﬂuoropyrimidinylamino)-3,3-dimethylbutane thiol, 773, (0.85 g, 3.60 mmol) and K2C03 (2.26 g, 16.35 mmol) in e was added iodomethane (0.82 mL, 13.08 mmol). The suspension was heated at 70 0C for 1.30 hours and then cooled to room temperature. 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: 1H NMR (400 MHz, CDC13) 8 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 (60-90% ACN/water 5 min with 0.9% FA) m/z 278.29 (M+H) RT = 1.35 minutes.

(S)—2-chlor0-N—(3,3-dimethyl—1-(methylsulf0nyl)but3nyl)—5-ﬂuoropyrimidin3mine (793) To a cold (0 0C) solution of (S)chloro-N-(3,3-dimethyl(methylthio)butanyl)- 5- ﬂuoropyrimidinamine, 783, (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 temperature 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 d product as a white solid: LC/MS (60-90% ACN/water 5 min with 0.9% FA) m/z (M+H) RT = 2.60 minutes.

(S)—N—(3,3-dimethyl(methylsulf0nyl)but3nyl)ﬂu0r0(5-ﬂu0r0-l-tosyl-lH- pyrrolo[2,3-b]pyridinyl)pyrimidin3mine. (803) A solution of (S)—2-chloro-N—(3 ,3 -dimethyl(methylsulfonyl)butanyl)-5 - ﬂuoropyrimidinamine, 793, (0.15 g, 0.48 mmol), 5-ﬁuoro(p-tolylsulfonyl)(4,4,5,5- tetramethyl-l,3,2-dioxaborolanyl)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) was purged with nitrogen for 30 minutes. X-Phos (0.015 g, 0.031 mmol) and a)3 (0.007 g, 0.008 mmol) were added and the reaction mixture was heated at 120 0C in a pressure vial for 2 hours. The reaction mixture was cooled to room temperature, ﬁltered and trated in vacuo. The residue was dissolved in EtOAc (50 mL) and washed with water. The organic layer was dried (MgSO4), d and concentrated in vacuo. The crude residue was puriﬁed by silica gel chromatography (0-40% EtOAc/Hexanes gradient) to afford 210 mg of the desired product as a white foamy solid: 1H NMR (400 MHz, CDClg) 8 8.54 — 8.43 (m, 2H), 8.24 (d, J: 1.3 Hz, 1H), 8.09 (s, 1H), 8.03 (d, J = 8.2 Hz, 2H), 7.23 (s, 1H), 4.99 (dt, J: 20.3, 10.1 Hz, 2H), 3.37 (d, J: 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. (3,3-dimethyl(methylsulf0nyl)butanyl)—5-ﬂu0r0(5-ﬂu0r0-lH-pyrrolo [2,3- b]pyridinyl)pyrimidinamine (46) To a solution of (3,3-dimethyl(methylsulfonyl)butanyl)ﬂuoro(5-ﬂuoro- 1-tosyl-1H—pyrrolo[2,3-b]pyridinyl)pyrimidinamine, 8021, (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 temperature for 10 minutes, then diluted into aqueous ted NH4Cl solution.

The solvent was removed under d pressure and the residue was dissolved in water (10 mL). The aqueous layer was extracted with EtOAc (3X10 mL), dried (MgSO4), ﬁltered and concentrated in vacuo. The product was puriﬁed by silica gel chromatography (0-10% MeOH/CHzClz gradient) to afford 109 mg of the desired product as a white solid: 1H NMR (400 MHz,CDC13)8 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), 3.11(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.

Pre aration 0 Com ound 62 Synthetic Scheme 12 \ 84a N Ts H 85a H 62 (a) LiBH4, THF, 1N HCl; (b) 2-iodoxybenzoic acid, THF, reﬂux; (c) Toluene; (d) Brg, HBr, AcOH, 65°C; (e) NaOH, hydroxyurea, MeOH.

Formation of (+/-)((5-ﬂu0r0(5-ﬂu0r0t0syl-lH-pyrrolo[2,3-b]pyridin yl)pyrimidinyl)amin0)—4,4-dimethylpentan01 (823) To a cold (0 0C) on of racemic methyl 3-((5-ﬂuoro(5-ﬂuorotosyl-1H- pyrrolo[2,3-b]pyridinyl)pyrimidinyl)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 e was slowly warmed to room temperature and then re-cooled to 0 0C. A 1N HCl solution (294 mL, 294 mmol) was added dropwise. The mixture was stirred for 15 minutes and then d with dichloromethane. The phases were separated and the aqueous phase was extracted again with dichloromethane. The combined organic phases were washed with s saturated NaHC03 solution and brine, dried (Na2S04), ﬁltered and concentrated in vacuo. The resulting residue was puriﬁed via silica gel chromatography (EtOAc/Hexanes) to afford 3.79 g of the d product.

Formation of (+/-)((5-ﬂu0r0(5-ﬂu0r0t0syl-lH-pyrrolo[2,3-b]pyridin yl)pyrimidinyl)amin0)-4,4-dimethylpentanal (83a) To a solution of racemic 3-((5-ﬂuoro(5-ﬁuoro-l-tosyl-1H—pyrrolo[2,3-b]pyridin yl)pyrimidinyl)amino)-4,4-dimethylpentanol, 82a, (1.60 g, 3.10 mmol) in THF (64 mL) was added 2-iodoxybenzoic acid (be) (3.86 g, 6.21 mmol). The on mixture was heated to reﬂux under at atmosphere of nitrogen for 30 minutes. After g the mixture to room temperature, the solids were ﬁltered. An aqueous saturated NaHC03 solution was added to the ﬁltrate and the ic 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 combined organic phases were dried (Na2S04), 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 ion of (+/-)-methyl 5-((5-ﬂu0r0(5-ﬂu0r0t0syl—lH-pyrrolo[2,3-b]pyridin yl)pyrimidinyl)amin0)-6,6-dimethylhepten0ate (84a) To a on of 3-((5-ﬂuoro(5-ﬁuoro-l-tosyl-lH—pyrrolo[2,3-b]pyridin yl)pyrimidinyl)amino)-4,4-dimethylpentanal, 83a, (0.295 g, 0.574 mmol) in toluene (5.9 mL) was added methyl 2-(triphenylphosphoranylidene)acetate (0.300 g, 0.862 mmol). The mixture was stirred overnight at room temperature and then puriﬁed directly on silica gel (EtOAc/Hexanes) to afford 278 mg of the desired product: LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, N, RT = 2.54 minutes (M+H) . ion (+/-)-methyl 2,3-dibrom0((5-ﬂu0r0(5-ﬂu0r0-lH-pyrrolo[2,3-b]pyridin yl)pyrimidinyl)amin0)-6,6-dimethylheptan0ate (85a) To a solution of racemic methyl 5-((5-ﬂuoro(5-ﬂuorotosyl-1H—pyrrolo[2,3- b]pyridinyl)pyrimidinyl)amino)-6,6-dimethylheptenoate, 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 .6 M solution in AcOH). The reaction mixture was heated at 65 0C overnight. The mixture was diluted 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 d under reduced pressure. The e was puriﬁed via silica gel chromatography (EtOAc/Hexanes) to give the desired product: LCMS Gradient -90%, 0.1% formic acid, 5 minutes, Cl8/ACN, RT = 3.00 minutes (M+H) 590.94.

Formation of (+/-)-5—(2-((5-ﬂu0r0(5-ﬂu0r0-lH-pyrrolo[2,3-b]pyridinyl)pyrimidin yl)amin0)—3,3-dimethylbutyl)is0xazolol (62) To a solution of NaOH (0.015 g) dissolved in water (0.410 mL) was added hydroxyurea (0.008 g, 0.100 mmol). The resulting e was stirred for 30 minutes before the dropwise addition of methyl 2,3-dibromo-5 -((5-ﬂuoro(5-ﬂuoro- 1H-pyrrolo [2,3 -b]pyridin-3 - yl)pyrimidinyl)amino)-6,6-dimethylheptanoate, 8521, (0.064 g, 0.110 mmol) in MeOH (0.150 mL). The solution was stirred for 6 hours before the addition of AcOH (0.031 mL). The residue was puriﬁed by reverse phase preparative HPLC to afford the desired product: 1H NMR (300 MHz, MeOD) 5 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), .68 (s, 1H), 3.03 (ddd, J: 27.4, 15.4, 12.3 Hz, 2H), 1.10 (d, J: 3.3 Hz, 11H); LCMS Gradient -90%, 0.1% formic acid, 5 minutes, C18/ACN, RT = 2.15 minutes (M+H) 416.04.

Pre aration 0 Com ound 45 Synthetic Scheme 13 Nf; / NH OH \ a NWNH OH N \ F N N "l 82a N N Ts H (a) LiOH, dioxane, H20, 100 0C.

Formation of (+/-)((5-ﬂu0r0(5-ﬂu0r0-lH-pyrrolo[2,3-b]pyridinyl)pyrimidin yl)amin0)—4,4-dimethylpentan-l-ol (45) To a solution of racemic 3-((5-ﬂuoro(5-ﬂuorotosyl-1H—pyrrolo[2,3-b]pyridin imidinyl)amino)-4,4-dimethylpentanol, 8221, (0.187 g, 0.363 mmol) in dioxane (4 mL) was added LiOH (0.91 mL of 2 M solution, 1.81 mmol). The reaction mixture was heated at 100 CC for 2 hours. The mixture was diluted with water (30 mL) and extracted twice with EtOAc. The ed organic phases were washed with brine, dried (MgSO4), ed and concentrated in vacuo. The crude residue was washed with Hexanes to afford 76 mg of the desired product: 1H NMR (300 MHz, CDClg) 8 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), 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); LCMS Gradient -90%, 0.1% formic acid, 5 minutes, C18/ACN, (M+H) 362.

Pre aration 0 Com ounds 50 51 and 52 Synthetic Scheme 14 NdiNHI OH F8, “02 N\ / NH Se F8, / NH N b N\ a / N N F —» —.

” F F I \ // \ \ \ I \ I N N. 823 N N 88a N N 89a TS TS TS N/:J/>—NH a, H O N\ O c F » / —» / \ \ I \ l \ N N N N \ H TS 90a 50, 51, and 52 (a) 2-nitrophenylselenocyanate, BU3P, THF; (b) mCPBA, CHC13; (c) c)4, NZCHZCOzEt, CHZCIZ; (d) LiOH, dioxane, H20.

Formation of (+/-)-N-(4,4-dimethyl—1-((2-nitrophenyl)selanyl)pentanyl)—5-ﬂuoro(5- ﬂuoro-l-tosyl—lH-pyrrolo[2,3-b]pyridinyl)pyrimidinamine (88a) To a solution of racemic 3-[[5-ﬂuor0[5-ﬂu0ro(p-tolylsulf0nyl)pyrrolo[2,3- b]pyridinyl]pyrimidinyl]amino]-4,4-dimethyl-pentanol, 82a, (1.093 g, 2.120 mmol) and (2-nitr0phenyl) 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 overnight 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 (+/-)-N-(4,4-dimethylpent—1-enyl)ﬂuoro(5-ﬂuorotosyl—1H- pyrrolo[2,3-b]pyridinyl)pyrimidinamine (89a) To a cold (0 0C) solution of racemic N—(4,4-dimethyl((2-nitr0phenyl)selanyl)pentan yl)ﬁu0r0(5-ﬁu0rot0syl-1H—pyrrolo[2,3-b]pyridinyl)pyrimidinamine, 88a, (1.01 g, 1.45 mmol) in chloroform (15 mL) was added mCPBA (0.40 g of 77%, 1.79 mmol). After ng for 1 hour at room temperature, the mixture was diluted with romethane (100 mL) and the resulting solution was washed with aqueous sodium bicarbonate solution. The organic phase was dried (MgSO4), d and trated 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 , 0.1% formic acid, 5 minutes, C18/ACN, (M+H) 496.76.

Formation of 2-(1-((5-ﬂuoro(5-ﬂuoro-lH-pyrrolo[2,3-b]pyridinyl)pyrimidin yl)amino)-2,2-dimethylpropyl)cyclopropanecarboxylic acid (50, 51, and 52) To racemic N—(4,4-dimethylpenten-3 -yl)ﬂuor0(5-ﬁu0rot0syl- 1H-pyrrolo [2,3 - b]pyridinyl)pyrimidinamine, 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-diaz0acetate (0.181 g, 0.166 mL, 1.582 mmol) in 2 mL romethane over 30 minutes. )2 (0.019 g, 0.042 mmol) in dichloromethane (2 mL) was added followed by ethyl 2-diaz0acetate (0.181 g, 0.166 mL, 1.582 mmol) in dichloromethane (2 mL) dropwise. The reaction was stirred overnight 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 0C for 2 h and g to room temperature, the mixture was acidiﬁed pH 6.5 with 2N HCl. The s phase was extracted twice with EtOAc and once with romethane. The combined organic phases were dried (MgSO4), ﬁltered and concentrated under reduced pressure. The crude residue was subjected to silica gel chromatography (0-20% MeOH/EtOAc gradient) to isolate the mixture of diastereomeric acids, which were further puriﬁed by preparatory HPLC (CH3CN/H20 — 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. All three diastereomers showed same LCMS: LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, (M+H) 402.45. 1St ﬁaction - a mixture of diastereomers with 4 peaks at 1.8, 1.9, 2.06 and 2.16 minutes —contains 211d fraction - single peak at 2.06 s- (51) 3rd fraction — single peak at 2.16 minutes- (52) Pre aration 0 Com ound 41 Synthetic Scheme 15 NH NH —— 2 NC \ / C' NCQ OH ———————> N Cl 0' OH b F 9W ’— NC \ / N OH B’0 F Fm / 7a \ I N N N N Ts H 41 (a) iPerEt, EtOH, 75 0C; (b) Pd2(dba)3, XPhos, K3PO4, THF, H20, 135 0C, microwave. ion of 2-chlor0ﬂu0r0(1-hydroxy-4,4-dimethylpentanylamin0)pyridine- 3-carb0nitrile (953) To a solution of 3-amino-4,4-dimethylpentanol (2.00 g, 8.64 mmol) in ethanol (20 mL) was added racemic 2,6-dichloroﬁuoro-pyridinecarbonitrile (1.65 g, 8.64 mmol) and 5 mL of N,N,-diisopropylethylamine. The solution was stirred at 75 CC for 12 hours and concentrated in vacuo. The residue was puriﬁed by silica gel chromatography (methylene chloride), yielding 2.2 g of roﬂuoro(1-hydroxy-4,4-dimethylpentan ylamino)pyridinecarbonitrile, 953: LCMS nt 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, RT = 3.02 minutes (M+H) 286.16 Formation of 5-fluoro-Z-(S-fluoro-lH-pyrrolo[2,3-b]pyridinyl)—6-(1-hydroxy-4,4 - dimethylpentanylamino)pyridinecarbonitrile (41) To a racemic solution of 2-chloroﬂuoro(1-hydroxy-4,4-dimethylpentan ylamino)pyridinecarb0nitrile, 95a, (0.20 g, 0.70 mmol) and 5-ﬂuor0(4,4,5,5-tetramethyl- 1,3,2-dioxab0rolanyl)t0syl-1H—pyrrolo[2,3-b]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 CC Via microwave irradiation for 15 minutes and then extracted into EtOAc (3 x 15 mL) vs. water. The organic layers were combined and trated 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 warmed to 65 0C for 12 hrs and then concentrated in vacuo. The resulting residue was puriﬁed Via silica gel tography (EtOAc) to afford 108 mg of the desired product, 41, as a yellow solid: 1H NMR (300 MHz, d6-DMSO) 8 12.40 (s, H), 8.63 (dd, J = 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, J: 4.1, 5.2 Hz, H), 3.69 (s, H), 3.57 (s, H), 3.49 (t, J: 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 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, RT = 3.09 minutes (M+H) 386.39.

Pre aration 0 Com ounds II 24 25 26 27 28 29 30 and 31 tic Scheme 16 F F H2N OH _ 3 b _. NH OH NC NH NC pH \ N \ F [\1 7\ 5‘ / 3~ 0| 7\ F O>§< \ / \ 7 97a /’\ 8‘0 \ N 98a N 73 N T8 F F — 0 d No \N 9 F \N NH\_/OMs N\H F /S_< NC \ / NH 0*é’a OH —’ / s / 3‘ —> F N §—’ \ / \ Z \ \ l \ 7 \ 7‘\ N N \// \ N N \T 99a \ 100a N N 8 T3 \ 101a O — o — O I] \ NC NH e / f NC \ / NH mél‘m 9 \ / S‘N F N ~‘ \ —» H —> N / 5 / ;\ \ \ / \ 7\ \ / N N "1‘ H Ts 102a 26 (a) 2-chlor0-5,6-diﬂu0r0pyridinecarb0nitrile, lPerEt,THF, MeOH, 95 0C; (b) 5-fluor0-l-(ptolylsulfonyl )—3-(4,4,5,5-tetramethyl-1,3,2-di0xaborolanyl)pyrrolo[2,3-b]pyridine, 7a, K3P04, X-Phos, Pd2(dba)3, 2-Me THF, water, 120 0C; (c) MsCl. CH2C12; (d) KOAc, DMF, 80 0C; (e) % H202, HCOOH; (f) 2, DMF, CHzClz. (g) i. Amine, THF; ii. 4M HCl, CH3CN, 65 0C.

(S-Z-chloro-S-ﬂuoro((1-hydr0xy-3,3-dimethylbutan-Z-yl)amin0)nic0tin0nitrile (973).

A mixture of ro-5,6-diﬁuoropyridinecarbonitrile (6.52 g, 34.13 mmol), (2S) amino-3,3-dimethyl-butanol (4.00 g, 34.13 mmol) and triethylamine (9.51 mL, 68.26 mmol) in CH3CN (50 mL) and THF (50 mL) was heated at 80 0C for 4 hours. The mixture was cooled to room temperature and the solvent was ated under reduced pressure. The crude t was puriﬁed via silica gel chromatography (0-60% EtOAc/Hexanes gradient) to afford 6.7 g of the desired product as an off white solid: 1H NMR (400 MHz, CDClg) 8 7.25 (d, J = 9.7 Hz, 1H), 5.32 (m, 1H), 4.19-4.08 (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), retention time 1.02 minutes.

(S)—5-ﬂu0r0(5-ﬂu0r0t0syl-1H-pyrrolo[2,3-b]pyridinyl)—6-((1-hydr0xy-3,3- dimethylbutan-Z-yl)amin0)nic0tin0nitrile (98a).

A solution of 5-ﬁuoro(p-tolylsulfonyl)(4,4,5,5-tetramethyl-1,3,2-dioxaborolan yl)pyrrolo[2,3-b]pyridine, 7a, (1.84 g, 4.42 mmol), (S)chloroﬁuoro((1-hydroxy-3,3- dimethylbutanyl)amino)nicotinonitrile, 9721, (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)3(0.07 g, 0.07 mmol) were added and the reaction mixture was heated at 120 0C in a pressure vial for 2 hours. The reaction mixture was cooled to room ature, 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 by silica gel chromatography (0-40% EtOAc/Hexanes nt) to afford 1.88 g as a foamy solid: 1H NMR (300 MHZ, CDClg) 5 8.64 (s, 1H), 8.36 (d, J: 2.0 Hz, 1H), 8.26 (m, 1H), 8.14 (d, J: 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), l.26(s, 9H); LC/MS (60-90% ACN/water 5 min with 0.9% FA, C4) m/Z 526.49 (M+H), retention time = 1.83 minutes.

(S)((5-cyan0ﬂu0r0(5—ﬂu0r0tosyl—lH-pyrrolo [2,3-b]pyridinyl)pyridin n0)—3,3-dimethylbutyl methanesulfonate (993).

To a cold (0 0C) solution of (S)—5-ﬁuoro(5-ﬁuorotosyl-1H—pyrrolo[2,3-b]pyridin yl)((1-hydroxy-3,3-dimethylbutanyl)amino)nicotinonitrile, 9821, (3.77 g, 7.17 mmol) and triethylamine (1.25 mL, 8.96 mmol) in dichloromethane (75 mL) was added methanesulfonyl chloride (0.69 mL, 8.96 mmol). The solution was stirred at room temperature for 1 hour. The t was removed under reduced pressure and water (100 mL) and EtOAc (200 mL) were added. The organic phase was separated, dried (MgSO4), ﬁltered and concentrated under d re to afford 4.22 g of the desired product as a yellow 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) retention time = 2.03 minutes.

(S)(5-Cyan0ﬂu0r0(5-ﬂu0r0tosyl—1H-pyrrolo [2,3-b] pyridin-Zylamino)—3,3- dimethylbutyl thiolate (1003).

Potassium thioacetate (1.2 g, 10.5 mmol) was added to a on of (S)((5-cyano ﬁuoro(5-ﬁuorotosyl- 1H-pyrrolo [2,3 -b]pyridin-3 -yl)pyridinyl)amino)-3 ,3 -dimethylbutyl methanesulfonate, 993, (4.22 g, 6.99 mmol) in dry DMF (90 mL). The brown solution was heated with stirring at 80 0C for 1 hour. The thick brown suspension was poured into water and extracted with EtOAc (3x 100 mL). The organic layers were dried (MgSO4), 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: 1H NMR (400 MHz, CDC13)5 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, J: 10.2 Hz, 1H), 7.24 (d, J = 8.3 Hz, 2H), .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), 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) retention time = 2.66 minutes.

(S)(5-Cyan0ﬂu0r0(5-ﬂu0r0tosyl—1H-pyrrolo[2,3-b]pyridin-Zylamino)—3,3- dimethylbutane—l-sulfonic acid (101a).

To a cold (0 0C) solution of formic acid (22.2 mL, 588.5 mmol) was added H202 (7.35 mL of 30% solution, 71.96 mmol). The mixture was stirred at 0 0C for 1 hour. A solution of (S)- S—2-(5-cyanoﬂuoro(5-ﬂuorotosyl-1H—pyrrolo[2,3-b]pyridin-2ylamino)-3 ,3 - dimethylbutyl ethanethiolate, 993, (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 temperature. The solvent was removed under reduced pressure 1.72 g of the desired sulfonic acid as a pale yellow foamy solid: LC/MS % ACN/water 5 min with 0.9% FA) m/z 586 (M+H) retention time = 3.95 s.

(S)(5-Cyan0ﬂu0r0(5-ﬂu0r0tosyl—1H-pyrrolo[2,3-b]pyridin-Zylamino)—3,3- ylbutane—l-sulfonyl chloride (1023).

To a solution of (5-cyanoﬂuoro(5-ﬂuorotosyl-1H—pyrrolo[2,3-b]pyridin- 2ylamino)-3,3-dimethylbutanesulfonic acid, 10121, (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 temperature for 1 hour. The solvent was removed under reduced re to afford 1.6 g of the desired t as a yellow solid: LC/MS (60-90% ACN/water 5 min with 0.9% FA) m/z 608 (M+H) retention time = 2.40 s.

(S)—2-(5-Cyan0ﬂu0r0(5-ﬂu0r0-lH-pyrrolo [2,3-b] pyridinyl)pyridin-2ylamin0)— N,3,3-trimethylbutane—l-sulfonamide (26) Methyl amine (0.41 mL of 2M solution, 0.82 mmol) was added to a solution of (S)—2-(5- cyanoﬂuoro(5-ﬂuorotosyl-1H—pyrrolo[2,3-b]pyridin-2ylamino)-3 ethylbutane sulfonyl chloride, 1023, (0.10 g, 0.16 mmol) in THF (1 mL). The solution was stirred for 1 hour at room ature and the solvent was removed under reduced pressure. The crude sulfonamide was dissolved in CH3CN (3 mL) and HCl (2 mL of 4M solution in dioxane) was added. The reaction mixture was heated at 65 0C for 3 hours and then cooled to room temperature. The solvent was removed under reduced pressure and the resulting residue was purified by preparative HPLC tography (10-80% CH3CN/water, 0.5% TFA, 15 min) to afford 26 mg of the desired product as a white solid: 1H NMR (400 MHz, CDClg) 5 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, .5 Hz, 1H), 2.67 (d, J: 5.0 Hz, 3H), 1.02 (s, 9H); LC/MS (10-90% ACN/water 5 min with 0.9% FA) m/Z 449.22 (M+H) retention time = 2.97 minutes.

The following compounds can be prepared in a similar fashion as the procedure bed above for Compound 26: 2012/049097 (S)—2-(5-Cyan0ﬂu0r0(5-ﬂu0r0-lH-pyrrolo [2,3-b]pyridinyl)pyridin-2ylamin0)- N,N,3,3-tetramethylbutane—l-sulfonamide (27) 1H NMR (400 MHz, CDC13) 5 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); LC/MS (10-90% ACN/Water 5 min with 0.9% FA) m/z 463.49 (M+H) retention time = 3.12 minutes. _ 0 » O\II NC \ / NH ‘S\ F N §—/ H / S \ / \ ;\ N N (S)—2-(5-Cyan0ﬂu0r0(5-ﬂu0r0-lH-pyrrolo ] pyridinyl)pyridin-2ylamin0)—N- cyclopropyl—3,3-dimethylbutane—l-sulfonamide (28) LC/MS (10-90% ACN/Water 5 min With 0.9% FA) m/z 475.0 (M+H) retention time = 3.12 minutes.

— O 0\ NC \ , NH 0*3'LNN F N }—/ H / S \ / \ 2 \ N N (S)((5-cyan0ﬂu0r0(5—ﬂu0ro-lH-pyrrolo [2,3-b]pyridinyl)pyridinyl)amino)—N— (2-meth0xyethyl)—3,3-dimethylbutane—l-sulfonamide (29) 1H NMR (400 MHz, MeOD) 8 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, 1H), 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) retention time = 3.05 minutes.

(S)((5-cyan0ﬂu0r0(5—ﬂu0ro-lH-pyrrolo [2,3-b]pyridinyl)pyridinyl)amino)—3,3- dimethyl-N-propylbutane—1-sulf0namide (31) LC/MS (10-90% ACN/water 5 min with 0.9% FA) m/z 477.65 (M+H) retention time = 3.27 minutes. _ o O\II NC \ NH \ F N/ /3 \\ NH2 / § \ / \ 7\ N N (S)((5-cyan0ﬂu0r0(5—ﬂu0ro-lH-pyrrolo [2,3-b]pyridinyl)pyridinyl)amino)—3,3- dimethylbutane—1-sulf0namide (30) LC/MS (10-90% ACN/water 5 min with 0.9% FA) m/z 435.46 (M+H) retention time = 2.80 minutes.

NC \ / NH OH F N 9—’ / S \ / \ 7\ N N (S)ﬂu0r0(5-ﬂu0r0—1H-pyrrolo[2,3-b]pyridinyl)—6-((1-hydr0xy-3,3-dimethylbutan yl)amin0)nic0tin0nitrile (24) Alcohol, 24, was synthesized in a manner similar to compound 32 utilizing the same deprotection ure, starting with compound 983: 1H NMR (400 MHz, CDClg) 8 10.27 (hrs, 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, 1H), 4.41 (t, J: 7.4 Hz, 1H), 4.09 (d, J: 11.3 Hz, 1H), 3.82 - 3.58 (m, 1H), 0.99 (d, J: 19.5 Hz, 9H).

— O 0 ll NC / NH \\S\ / S \ / \ ;\ N N (5-cyan0ﬂu0r0(5-ﬂu0ro-lH-pyrrolo [2,3-b] pyridinyl)pyridinylamino)—3,3- dimethylbutane—1-sulf0nic acid (25) To a solution of (S)((5-cyanoﬂuoro(5-ﬂuorotosyl-1H—pyrrolo[2,3-b]pyridin yl)pyridinyl)amino)-3,3-dimethylbutanesulfonic acid, 1013, (0.12 g, 0.21 mmol)in CH3CN (5 mL) was added HCl (2 mL of4M solution in dioxane). The reaction mixture was heated at 100 0C for 18 hours in a pressure vial and then cooled to room temperature. The solvent was d under reduced pressure and the product was puriﬁed by preparative HPLC chromatography (10-80% water, 0.5% TFA, 15 min) to give 42 mg of the desired 2012/049097 t as an off-White solid: 1H NMR (400 MHZ, MeOD) 5 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 (m, 1H), 3.46 - 3.33 (m, 3H), 1.10 (s, 9H); LC/MS (10-90% ACN/Water 5 min with 0.9% TFA, C18) m/z 449.22 (M+H).

NiNH— O O\II // S \ / \ 7\ N N (S)((5-ﬂu0r0(5-ﬂu0r0-lH-pyrrolo[2,3-b]pyridinyl)pyrimidinyl)amino)—3,3- dimethylbutane-l-sulfonic acid (11) Sulfonic acid, 11, was synthesized in a manner similar to compound 30, using compound 57a: 1H NMR (400 MHz, MeOD) 8 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, 1H), 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) retention time = 1.91 minutes.

Pre aration 0 Com ounds 62 87 and 88 Synthetic Scheme 17 o x— o /— O b C 0 d O a —> \ O /Ph3P 111a M 112a 113a /0 114a Cle N/ F / / Bn HO (3 0 CIA/ 0 N O —> —> —> —, 116a 115a 117a 118a / O / i f=i;_ f=i;_ N/gjoﬁj Kl N/NH0_, 119a 120a W0 2013/019828 (a) LDA, Mel, THF; (b) LiAlH4, ether; (c) PCC, ; (d) 2-(triphenylph0sph0ranylidene te, CHzClz; (e) N—benzylhydroxylamine-HCl, ; (f) H2, Pd/C, MeOH; (g) AcCl, MeOH, reﬂux; (h) 2,4-dichlor0ﬂu0r0pyrimidine, Eth, EtOH, THF, 55 0C; (i) 5-ﬂu0r0- 1-(p-tolylsulfonyl)-3 -(4,4,5 ,5 -tetramethyl-1,3 ,2-di0xaborolanyl)pyrrolo- [2,3 -b]pyridine, 7a, Pd2(dba)3, XPhos, K3P04, F, H20, 115 0C; (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 rnL) was added dropwise to a cold (-78 0C) solution of LDA (164 mmol of 2M solution) in THF (40 rnL).

The on was warmed to 0 0C and then cooled again to -40 0C before the addition of iodornethane (10.2 rnL, 163.8 mmol). The solution was slowly warmed to room temperature and stirred overnight. The reaction was quenched with an aqueous saturated 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 1N HCl then dried over MgSO4. The product was puriﬁed by distillation: 1H NMR (400 MHz, MeOD) 5 4.20 — 4.05 (m, 2H), 2.57 — 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 (1-methylcyclobutyl)methanol (112a) m aluminum hydride (2.1 g, 59.4 mmol) was suspended in ether (150 rnL) and cooled to 0 0C. A solution of ethyl 1-methylcyclobutanecarboxylate, 111a, (13.0 g, 91.4 mmol) in ether (60 rnL) was added dropwise to the LiAlH4 suspension. The mixture was stirred 2 hours in an ice bath then quenched slowly with 1N HCl. The layers were separated and the aqueous layer was washed with ether. The combined c layers were washed with brine and the volatiles were removed with a gentle stream of en to afford the desired t that was used without ﬁlrther puriﬁcation: 1H NMR (400 MHZ, CDClg) 5 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, J: 1.7 Hz, 6H).

Formation of 1-methylcyclobutanecarbaldehyde (113a) and methyl 3-(1- methylcyclobutyl)acrylate (1 14a) A on of (1-methylcyclobutyl)methanol, 112a, (1.00 g, 9.98 mmol) in dichloromethane (25 rnL) was added to a suspension of FCC (2.69 g, 12.50 mmol) and Celite (2.70 g) in romethane (25 rnL). 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-(triphenylphosphoranylidene )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: 1H NMR (400 MHz, CDClg) 8 7.05 (d, J: 15.8 Hz, 1H), 5.66 (dd, J: 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 (+/-)benzyl(1-methylcyclobutyl)isoxazolidinone (115a) N—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-(1-methylcyclobutyl)acrylate, 114a, (0.26 g, 1.50 mmol) in dichloromethane (9.5 mL). The on mixture was stirred at 50 0C ght. The reaction mixture was cooled to room temperature 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 les d under d pressure. The residue 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 (+/-)amin0(1-methylcyclobutyl)pr0pan0ic acid (116a) A solution of racemic 2-benzyl(1-methylcyclobutyl)isoxazolidinone, 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 hydroxide catalyst. The mixture was filtered through Celite and the volatiles were removed under reduced pressure to afford the desired product that was used without further purification: 1H NMR (400 MHZ, MeOD) 5 3.42 (dd, J = 11.0, 1.9 Hz, 1H), 2.26 (ddd, J = 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-chlor0ﬂuor0pyrimidinyl)amin0)(1- methylcyclobutyl)pr0panoate (1 18a) Racemic 3-amino(1-methylcyclobutyl)propanoic acid, 116a, (2.3 g, 14.4 mmol) was dissolved in methanol (104 mL). The on was cooled in an ice bath and acetyl de (5.6 g, 71.9 mmol) was added dropwise (Temp kept <10 0C). The reaction mixture was heated to 65 OC and stirred at that temperature for 3 hours. The reaction mixture was cooled to room temperature and then ﬂushed with e to remove volatiles. Crude racemic oxy(1- methylcyclobutyl)oxopropanaminium chloride, 117a, was used without further puriﬁcation.

Racemic 3-methoxy(1-methylcyclobutyl)oxopropanaminium chloride, 117a, (3.3 g, 15.9 mmol) was dissolved in a mixture of 59 mL THF and 6.6 mL EtOH and the solution was cooled in an ice bath. 2,4-Dichloroﬂuoro-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 0C for 17 hours. The reaction mixture was cooled to room temperature 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 silica gel chromatography /Hexanes) to afford the desired t: LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, RT = 3.23 minutes (M+H) .

Formation of (+/-)-methyl 3-((5-ﬂu0r0(5-ﬂu0r0t0syl-lH-pyrrolo[2,3-b]pyridin yl)pyrimidinyl)amin0)(1-methylcyclobutyl)propanoate (1 19a) A solution of 5-ﬂuoro(p-tolylsulfonyl)(4,4,5,5-tetramethyl-1,3,2-dioxaborolan yl)pyrrolo[2,3-b]pyridine, 7a, (3.31 g, 7.95 mmol), c methyl chloro ﬂuoropyrimidinyl)amino)(1-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 Pd2(dba)3 (0.15 g, 0.17 mmol) were added and the reaction mixture was stirred at 115 0C in a sealed tube for 2 hours. The reaction mixture was cooled and the aqueous phase was removed. The organic phase was ﬁltered through a pad of Ce1ite 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 (+/-)-methyl 3-((5-ﬂu0r0(5-ﬂu0r0-lH-pyrrolo[2,3-b]pyridin yl)pyrimidinyl)amin0)(1-methylcyclobutyl)propanoate (120a) To a racemic solution of methyl ﬂuoro(5-ﬁuorotosyl-1H-pyrrolo[2,3- b]pyridinyl)pyrimidinyl)amino)(1-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 e was heated to 65 0C for 4 hours. The solution was cooled to room ature and the solvents were removed under reduced re. The mixture was ﬂushed with acetonitrile after which aqueous sodium onate and ethyl e were added. The phases were separated and the aqueous layer washed with ethyl acetate. The combined organic phases were dried with Na2S04, ﬁltered and concentrated in vacuo. The resulting residue was puriﬁed via silica gel tography (EtOAc/Hexanes) to afford the desired product: LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, N, RT = 2.34 minutes (M+H) 403.11.

Formation of 3-((5-ﬂu0r0(5-ﬂu0r0-lH-pyrrolo[2,3-b]pyridinyl)pyrimidin yl)amino)—3-(1-methylcyclobutyl)pr0pan0ic acid (87 and 88) To a solution of methyl 3-((5-ﬁuoro(5-ﬁuoro-1H—pyrrolo[2,3-b]pyridin yl)pyrimidinyl)amino)(1-methylcyclobutyl)propanoate (11) (1.75 g, 4.36 mmol) in THF (25 mL) was added aqueous 1N LiOH (13.1 mL). The mixture was heated to 50 0C for 3.5 hours. The reaction mixture was cooled to room temperature and diluted with water. The THF was removed under reduced pressure and the residue was then ﬂushed twice with s. Ether was added and the layers separated (the ether layer was ded). The pH was adjusted to 5.5 with 1N HCl and the resulting solid was ﬁltered and washed with water. The solid was ﬂushed with heptanes and dried over P205 to give the desired product: 1H NMR (400 MHz, DMSO) 8 12.17 (d, J: 60.2 Hz, 2H), 8.59 (d, J: 8.4 Hz, 1H), 8.39 — 8.05 (m, 3H), 7.52 (s, 1H), 5.00 (s, 1H), 2.23 (d, J: 7.7 Hz, 1H), 2.00 (s, 1H), 1.81 (d, J: 48.3 Hz, 2H), 1.62 (s, 1H), 1.46 (s, 1H), 1.21 (s, 3H); LCMS nt 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, RT = 2.08 minutes (M+H) 388.46. The racemic mixture was submitted to SFC chiral separation to obtain the individual enantiomers, 87 and 88.

Pre aration 0 Com ound 65 Synthetic Scheme 18 WO 19828 @3fowﬂ;A’Za/ 124a F87 F Jk H2N ,OH N _ N//$*NH_, ‘0 / NH N\ N \ C \ F N / —, F \ / \ I \ \ I N N H N N H 65 125a (a) AlMCg, NH4Cl, toluene; (b) hydroxylamine, DMSO, 140 0C; (c) CD1, 1PerEt, THF.

Formation of (+/-)((5-ﬂu0r0(5-ﬂu0r0t0syl-lH-pyrrolo[2,3-b]pyridin yl)pyrimidinyl)amin0)-4,4-dimethylpentanenitrile (124a) Ammonium chloride (0.12 g, 2.30 mmol) was ded in e (4.5 mL). The mixture was cooled in an ice bath and AlMe3 (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 temperature. A solution of racemic methyl 3 -[[5 -ﬂuoro [5 -ﬁuoro(p- tolylsulfonyl)pyrrolo[2,3-b]pyridinyl]pyrimidinyl]amino]-4,4-dimethyl-pentanoate (0.25 g, 0.46 mmol) in 4.5 mL toluene was added and the resulting mixture was stirred 60 0C overnight.

The reaction mixture was cooled in an ice bath and quenched with 1N HCl. The mixture was ted with dichloromethane and ﬁltered through a phase tor. The residue was puriﬁed on silica gel (EA/Hex): LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, RT = 2.04 minutes (M+H) 511.42.

Formation of (+/-)((5-ﬂu0r0(5-ﬂu0r0-lH-pyrrolo[2,3-b]pyridinyl)pyrimidin yl)amin0)-N'-hydr0xy-4,4-dimethylpentanimidamide (125a) To a solution of racemic 3-[[5-ﬂuoro[5-ﬂuoro(p-tolylsulfonyl)pyrrolo[2,3- b]pyridinyl]pyrimidinyl]amino]-4,4-dimethyl-pentanenitrile, 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 0C for 30 minutes. The residue was puriﬁed on a C18 column (acetonitrile/0.1% formic acid) to afford the desired product: LCMS nt 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, RT = 1.58 minutes (M+H) 390.06.

Formation of 3-(2-((5-ﬂu0r0(5-ﬂu0r0-lH-pyrrolo[2,3-b]pyridinyl)pyrimidin yl)amin0)—3,3-dimethylbutyl)—1,2,4-0xadiazol-5(2H)-0ne (65) To a solution of racemic 3-[[5-ﬂuoro(5-ﬂuoro-1H—pyrrolo[2,3-b]pyridin yl)pyrimidinyl]amino]-N'-hydroxy-4,4-dimethyl-pentanamidine, 125a, (0.034 g, 0.087 mmol) WO 19828 and carbonyl diimidazole (0.014 g, 0.087 mmol) in THF (1 mL) was added N,N— diisopropylethylamine (0.045 mL, 0.260 mmol). The reaction mixture was stirred at room temperature for 48 hours. Aqueous ammonium chloride and dichloromethane were added and the layers were separated with a phase tor. The residue was puriﬁed on a C18 column (acetonitrile/0.1% formic acid) to afford the final product: 1H NMR (400 MHz, Acetone) 5 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, J: 3.7 Hz, 1H), 6.81 (s, 1H), 5.00 (d, J: 11.2 Hz, 1H), 3.15 (d, J: 14.8 Hz, 3H), 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.

Preparation ofCompound 47 Synthetic Scheme 19 OH OH O O \‘ H H s\ N N W N (\< - :— = F O OH F F / \ I HZNJ / \ / \ / I I I ,N / / N ‘l— 2a /N N n N TS 127a Ts 128a 47 (a) Nazcog, CH3CN—THF, 125-150 0C; (b) 4M HC1, 1,4-dioxane—CH3CN, 60 °C (R)((2-(5-ﬂu0r0—1-tosyl-1H-pyrrolo [2,3-b]pyridinyl)pyrimidinyl)amin0)-4,4- dimethylpentanoic acid (128a).

Sulfoxide, 1273, was prepared in same n as sulfoxide, 25a, (see Synthetic Scheme 4) using 2,4-dichloropyrimidine instead of 2-chloroﬂuoromethylsulfanyl-pyrimidine.

A mixture of 5-ﬂuoro(4-(methylsulf1nyl)pyrimidinyl)tosyl-1H—pyrrolo[2,3- b]pyridine, 12721, (0.052 g, 0.121 mmol) and (3R)amino-4,4-dimethyl-pentanoic acid, 23, (0.035 g, 0.242 mmol) along with N32CO3 (0.051 g, 0.483 mmol) in a mixture of THF (0.780 mL) and acetonitrile (0.260 mL) was heated to 125 0C for 30 minutes under ave irradiation. Then, the temperature was raised to 150 CC for a ﬁarther 2.5 hours. The mixture was neutralized with aqueous 2N HCl and ted with several portions of EtOAc. The organic ts were evaporated in vacuo. Puriﬁcation by ﬂash chromatography (SiOz, 0-100 % hexanes-EtOAc (with 10% MeOH)) provided 19 mg of the desired material (31% yield), which was used in the next step without r purification: LCMS Gradient 10-90%, 0.1% triﬂuoroacetic acid, 5 minutes, C18/ACN, RT = 2.70 minutes (M+H) 512.00.

(R)((2-(5-ﬂu0r0-lH-pyrrolo [2,3-b]pyridinyl)pyrimidinyl)amin0)-4,4- dimethylpentanoic acid (47).

To a solution of (R)((2-(5-ﬂuorotosyl-1H—pyrrolo[2,3-b]pyridinyl)pyrimidin no)-4,4-dimethylpentanoic acid, 12821 (0.019 g, 0.037 mmol) in acetonitrile (0.6 mL) was added HCl (0.15 mL of 4 M in dioxane, 0.60 mmol). The solution was heated to 60 0C 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 cooled and trated in vacuo. Trituration with EtzO followed by puriﬁcation by preparatory HPLC provided 17.5 mg of the desired product as a TFA salt: .

The NMR ted a 4 to 1 ratio of atropisomers: 1H NMR (400 MHz, MeOD, major atropsomer) 8 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 = .9, 11.2 Hz, 1H), 1.08 (d, J = 0.8 Hz, 9H); LCMS Gradient 10-90%, 0.1% triﬂuoroacetic acid, minutes, C18/ACN, RT = 2.17 minutes (M+H) 358.02.

Pre aration 0 Com ound 48 Synthetic Scheme 20 O O FIf ﬂ If —> b F CN F a F c d \ OH \ NH2 \ / I/ —> \I \ N CI N CI N CI N N 130a 131a 1323 N NW3/ Br B r F F Bro ’N / f F / e F \ I \ / g / —> - \ \ I N \ ,N N —> \ I I \N N N N N , \ N N , H )rPh N N 133 Ph )1 Ph a )Vph 134a Ph P“ 135a Ph ph 136a Ph N N 0 F F 3 H2N , \ / \ OH N. I N\ I ph 3 , Ph >\ N N/ M N 137a 2a phPh7<Ph 138" 48 (a) (CO)2Clz, 2C12, NH4OH; (b) Eth, TFAA, CH2C12 (C) N2H4'H20, nBuOH, reﬂux; (d) tBuNOz, BT3CH, 60-90 0C; (e) PthCl, K2C03, DMF; (f) KOAc, 4,4,5,5-tetramethyl- 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1,3,2-dioxaborolane, Pd(dppf)2Clz, DMF, 100 0C; (g) 2-chloromethylsulfanyl-pyrimidine, Pd2(dba)3, XPhos, K3P04, 2-MeTHF, H20, 115 0C; (h) mCPBA, CHzClz, 0 0C; (i) N32C03, CH3CN—THF, 125-150 CC; (C) Et3SiH, TFA, CHzClz.

Formation of 2-chlor0ﬂu0r0pyridinecarboxamide (130a) To the suspension of 2-chloroﬂuoropyridinecarboxylic 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 on mixture. The mixture was stirred at room ature for 2 h and dichloromethane was removed under reduced pressure. The residue was dissolved in THF (300 mL) and cooled down to 0 0C by ice bath. Ammonium hydroxide (28-30%, 113.0 mL, 1.8 mmol) was added in one portion. The mixture was stirred for another 15 min. The mixture was diluted into ethyl acetate (300 mL) and water (300 mL) and the phases were ted. The organic layer was washed with brine and dried over Na2S04, ﬁltered, and concentrated in vacuo to afford 29.8 g desired product as white solid: 1H NMR (300 MHz, DMSO-d6) 5 8.53 (d, J: 3.0 Hz, 1H), 8.11 (s, 1H), 8.00 (dd, J: 8.0, 3.0 Hz, 1H), 7.89 (s, 1H); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, RT = 1.11 minutes, (M+H) 175.02.

Formation of 2-chlor0ﬂuoropyridine—3-carb0nitrile (131a) To a suspension of 2-chloroﬂuoropyridinecarboxamide, 1303, (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 0C. Triﬂuoroacetic anhydride (26.1 mL, 187.4 mmol) was added slowly over period of 15 min. The mixture was stirred at 0 0C for 90 min. The mixture was diluted into dichloromethane (300 mL) and the resulting organic phase was washed with aqueous saturated NaHC03 solution (300 mL) and brine (300 mL). The organic layer was dried over Na2S04, ﬁltered, concentrated in vacuo. The product was purified by silica gel tography (40% to 60% ethyl e/hexanes gradient) giving 24.7 g of product as a white solid: 1H NMR (300 MHz, CDClg) 5 8.50 (d, J = 3.0 Hz, 1H), 7.77 (dd, J: 6.8, 3.0 Hz, 1H); LCMS Gradient 10- 90%, 0.1% formic acid, 5 minutes, C18/ACN, ion Time = 2.50 minutes, (M+H) 157.06. ion of S-ﬂuoro-lH-pyrazolo[3,4-b]pyridinamine (132a) To the mixture of 2-chloroﬂuoropyridinecarbonitrile, 13121, (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 d 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: 1H NMR (300 MHz, DMSO-d6) 8 12.08 (s, 1H), 8.38 (dd, J: 2.7, 1.9 Hz, 1H), 7.97 (dd, J: 8.8, 2.7 Hz, 1H), 5.56 (s, 2H). LCMS nt , 0.1% formic acid, 5 minutes, C18/ACN, Retention Time = 1.25 s (M+H) 152.95.

Formation of 3-br0m0ﬂu0r0-lH-pyrazolo[3,4-b]pyridine (133a) To a mixture of 5-ﬂuoro-1H—pyrazolo[3,4-b]pyridinamine, 13221, (0.88 g, 5.79 mmol) in bromoform (8.8 mL) was added tert—butyl nitrite (1.38 mL, 11.57 mmol). This mixture was heated to 61 0C for 1 h and then heated to 90 0C for an additional hour. The mixture was cooled to room temperature and bromoform was removed under reduced pressure. The resulting crude residue was purified by silica gel chromatography (5-50% ethyl acetate/hexanes) to afford 970 mg of the desired t as a white solid: 1H NMR (300 MHz, DMSO-d6) 5 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, C18/ACN, Retention Time = 2.42 minutes (M+H) 216.11.

Formation of 0ﬂu0r0trityl-lH-pyrazolo[3,4-b]pyridine (134a) A mixture of 3-bromoﬂuoro-1H—pyrazolo[3,4-b]pyridine, 13321, (0.97 g, 4.49 mmol) and K2C03 (1.86 g, 13.47 mmol) in DMF (9.7 mL) was cooled to 0 0C.

Chlorodiphenylmethylbenzene (1.38 g, 4.94 mmol) was added. The mixture was d at room temperature overnight. 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 Na2S04, 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: 1H NMR (300 MHz, DMSO-d6) 5 8.45 — 8.38 (m, 1H), 8.04 (dd, J: 8.0, 2.7 Hz, 1H), 7.35 — 7.16 (m, 15H); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, Retention Time = 3.03 minutes (M+H) 459.46.

Formation of 5-ﬂu0r0(4,4,5,5-tetramethyl-1,3,2-di0xab0rolanyl)trityl—1H- pyrazolo[3,4-b]pyridine (135a) A solution of 3-bromoﬁuorotrityl-pyrazolo[3,4-b]pyridine, 134a (3.43 g, 7.48 mmol), KOAc (2.20 g, 22.45 mmol) and 5-tetramethyl(4,4,5,5-tetramethyl-1,3,2- dioxaborolanyl)-1,3,2-dioxaborolane (2.85 g, 11.23 mmol) in DMF (50 ml) was ed under a stream of nitrogen for 40 min. To the mixture was added f)2Clz (0.610 g, 0.748 mmol) The reaction mixture was heated at 100 0C for 90 minutes. The reaction mixture was ﬁltered through a pad of Celite. To the resulting ﬁltrate was added ether and brine. The c phase was dried over MgSO4, ﬁltered and concentrated in vacuo to afford 4.0 g crude product that was used in the next step without ﬁarther puriﬁcation (note, the product decomposes if puriﬁcation is attempted via silica gel chromatography).

Formation of 5-ﬂu0r0(4-(methylthi0)pyrimidinyl)trityl-1H-pyrazolo[3,4-b]pyridine (136a) A solution of 2-chloromethylsulfanyl-pyrimidine (0.25 g, 1.56 mmol), K3PO4 (0.99 g, 4.67 mmol) and 5-ﬁuoro-3 -(4,4,5 ,5 -tetramethyl-1,3 ,2-dioxaborolanyl)trityl- 1H- pyrazolo[3,4-b]pyridine, 135a, (0.87 g, 1.71 mmol) in water (1 mL) and 2-methyltetrahydroﬁ1ran (9 mL) was ed under a stream of nitrogen for 15 minutes. Then, Pd2(dba)3 (0.04 g, 0.05 mmol) was added and the mixture was degassed for an onal 2-3 minutes. The vessel was sealed and heated to 95 0C overnight. After ting 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, Retention Time = 2.68 min (M+Na) 526.1.

Formation of S-ﬂuor0(4-(methylsulﬁnyl)pyrimidinyl)—1-trityl-1H-pyrazolo [3,4- b]pyridine (137a) To a cold (0 0C) e of 5-ﬂuoro(4-(methylthio)pyrimidinyl)trityl-1H- pyrazolo[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 Na2S04, ﬁltered and stripped down twice with CH3CN to afford 660 mg of desired t that was used without further puriﬁcation: LCMS Gradient 60-98%, 0.1% formic acid, 7min, C4/ACN, Retention Time = 2.68 minutes (M+H) 520.

(R)—3-((2-(5-ﬂu0r0trityl-1H-pyrazolo [3,4-b] pyridinyl)pyrimidinyl)amino)—4,4- ylpentanoic acid (138a).

A d suspension of 5-ﬁuoro(4-(methylsulﬁnyl)pyrimidinyl)trityl-1H- indazole, 137a, (0.09 g, 0.18 mmol), (3R)—3-amino-4,4-dimethyl-pentanoic acid (0.05 g, 0.36 mmol) and Na2C03 (0.76 g, 0.72 mmol) in acetonitrile (0.62 mL) and F (0.31 mL) was heated to 125 CC in microwave reactor for 1 hour. After cooling to room temperature, the —104— 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 CH2C12. 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, Retention Time = 3.08 minutes (M+H) .

(R)((2-(5-ﬂu0r0-lH-pyrazolo [3,4-b] nyl)pyrimidinyl)amino)—4,4- dimethylpentanoic acid (48) To a solution of crude (R)((2-(5-ﬂuorotrityl-1H—pyrazolo[3,4-b]pyridin yl)pyrimidinyl)amino)-4,4-dimethylpentanoic acid, 1383, (0.11 g, 0.21 mmol) in CHzClz was added triethylsilane (0.15 mL, 0.94 mmol) followed by triﬂuoroacetic acid (0.15 mL, 1.95 mmol). After ng the resulting solution at room temperature for 1 hour, the reaction mixture was kept below 5 0C overnight (refrigerator). The mixture was then allowed to warm to room temperature and kept at that temperature for an additional 5 hours. The on was d with toluene and trated in vacuo. Trituration with EtZO followed by preparative HPLC puriﬁcation provided 15 mg of the desired product as the TFA salt. 1H NMR indicated a 3 to 1 e of atropisomers: 1H NMR (400 MHz, MeOD, major isomer) 8 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, J: 15.4, 2.4 Hz, 2H), 2.44 (dd, J = 15.9, 10.7 Hz, 2H), 0.98 (s, 9H); LCMS Gradient 10-90%, 0.1% triﬂuoroacetic acid, 5 minutes, C18/ACN, Retention Time = 2.12 minutes (M+H) 359.02.

Pre aration 0 Com ound 42 Synthetic Scheme 21 F O 0 o .. OEt H2N OEt ’- jOEt NH a NH b NC / NC , \ \ N _= N —> F : 2 / CI U 02% \ \ I U 8’0 N N 33a 143a Fm ‘Ts 144a N, "l F F ,. ﬁoa ..

NH NH NC NC C \ [(1 d \ \Oj’OH _= [G E F = F = —’ _’ / / I \ I \ U \ \ N N N N H H 145a 42 (a) 2-chloro-5,6-diﬂuoropyridinecarbonitrile, Eth, THF, EtOH; (b) 5-ﬂuoro(ptolylsulfonyl )(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)pyrrolo[2,3-b]pyridine, 721, X- phos, Pd2(dba)3, K3P04, 2-methyl THF, H20, 130 0C; c) NaOMe, THF; d) LiOH, THF, H20.

Formation of (R)-ethyl 3-(6-chlor0cyan0ﬂu0r0pyridinylamin0)—3-(1- methylcyclopentyl)pr0pan0ate (143a) To a solution of c ethyl 3-amino(1-methylcyclopentyl)propanoate, 3321, (0.40 g, 2.01 mmol) and 2,6-dichloroﬂuoro-pyridinecarbonitrile (0.46 g, 2.41 mmol) in THF (20 mL) was added triethylamine (0.67 mL, 4.82 mmol). The reaction e was stirred at 90 0C in a pressure tube for 18 hours. The reaction mixture was ﬁltered and the resulting ﬁltrate was trated in vacuo. The product was puriﬁed by silica gel chromatography (25%EtOAc/Hexanes) to afford 380 mg of the desired product as a racemic mixture: 1H NMR (400 MHz, CDC13) 8 7.31 (d, J: 9.7 Hz, 1H), 5.56 (d, J: 8.9 Hz, 1H), 4.68 (td, J: 9.6, 3.6 Hz, 1H), 4.07 (q, .1: 7.1 Hz, 2H), 2.68 (dd, J: 14.8, 3.7 Hz, 1H), 2.46 (dd, J: 14.8, 9.3 Hz, 1H), 1.77 — 1.62 (m, 4H), 1.61 — 1.49 (m, 2H), 1.47 — 1.37 (m, 1H), 1.35 — 1.26 (m, 1H), 1.19 (t, J: 7.1 Hz, 3H), 1.01 (s, 3H); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, Retention Time = 3.81 minutes (M+H) 354.98. The racemic mixture was ted to SFC chiral separation to give the indiVidual enantiomers, 143a and 143b. The (R)-enantiomer, 143a, was taken forward into the next synthetic step.

Formation of (R)—ethyl 3-(5-cyan0ﬂu0r0(5-ﬂu0r0t0syl—lH-pyrrolo[2,3-b]pyridin yl)pyridinylamin0)(1-methylcyclopentyl)pr0panoate (144a) A solution of o(p-tolylsulfonyl)(4,4,5,5-tetramethyl-1,3,2-dioxaborolan rolo[2,3-b]pyridine, 7a, (0.155 g, 0.373 mmol), racemic ethyl 3-[(6-chlorocyano ﬂuoropyridyl)amino](1-methylcyclopentyl)propanoate, 143a, (0.120 g, 0.339 mmol) and K3P04 (0.288 g, 1.357 mmol) in 2-methyl THF (10.0 mL) and H20 (0.24 mL) was ed 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 reaction mixture was stirred at 130 0C in a pressure tube for 45 minutes. The organic phase was ﬁltered through a pad of celite and concentrated in vacuo. The resulting crude al was d by silica gel chromatography (30% EtOAc/Hexanes) to afford 150 mg of the desired product: 1H NMR (400 MHz, CDClg) 5 8.67 (s, 1H), 8.44 (dt, .1: 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, 1H), 7.32 (d, J: 7.5 Hz, 2H), 5.38 (t, J: 9.7 Hz, 1H), 4.89 (td, J: 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, Retention Time = 4.22 min (M+H) 608.29.

Formation of thyl 3-(5-cyan0ﬂu0r0(5-ﬂu0r0-lH-pyrrolo[2,3-b]pyridin yl)pyridinylamin0)(1-methylcyclopentyl)pr0panoate (145a) To a solution of c ethyl 3-(5-cyanoﬂuoro(5-ﬂuorotosyl-1H—pyrrolo[2,3- b]pyridinyl)pyridinylamino)(1-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 reaction e was stirred at room temperature for 5 minutes. The reaction mixture was diluted with aqueous saturated NaHC03 solution and EtOAc. The organic phase was dried over MgSO4, ﬁltered and concentrated in vacuo. The product was puriﬁed by silica gel chromatography (40% EtOAc/Hexanes) to afford 90 mg of the d product as a mixture of ethyl and methyl esters. The mixture was taken onto the next step without further puriﬁcation: 1H NMR (400 MHz, CDClg) 5 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, 1H), 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, .1: 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, Retention Time = 3.60 minutes (M+H) 440.26.

Formation of (R)—3-(5-cyan0ﬂu0r0(5-ﬂu0r0-lH-pyrrolo[2,3-b]pyridinyl)pyridin ylamino)—3-(1-methylcyclopentyl)pr0pan0ic acid (42) To a solution of racemic methyl yanoﬂuoro(5-ﬂuoro-lH—pyrrolo[2,3-b]pyridin- 3-yl)pyridinylamino)(1-methylcyclopentyl)propanoate, 14521, (0.090 g, 0.204 mmol) in THF (30 mL) was added a solution of lithium hydroxide (0.035 g, 0.819 mmol) in H20 (10 mL).

The reaction mixture was stirred at 70 OC overnight. The organic phase was removed under reduced pressure and the resulting residue was d by preparatory HPLC. The appropriate HPLC ons were extracted with EtOAc, and the solvent was removed under reduced pressure: 1H NMR (400 MHz, MeOD) 8 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); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, ion Time = 3.21 minutes (M+H) 426.25.

Pre aration 0 Com ounds 5 6 and 12 Synthetic Scheme 22 F o O 0 OEt ’— CE HZN OEt NH a NH b / N\Féi/ N \ N CI I \ ,N B’0 N N 33a 147a F \ 148a | \ ‘Tr / 135a N N Fé’ O o OEt /¢§7 OH N / N N / N c \ d \ N N F —> F / / \ \ \ I ,N \ I IN N N N N H H 149a 12 (a) Eth, THF, EtOH; (b) 5-ﬂuoro(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)trityl-1H- pyrazolo[3,4-b]pyridine, 135a, X-phos, Pd2(dba)3, K3P04, 2-methyl THF, H20, 135 0C; (c) Et3SiH, TFA, CH2C12; (d) LiOH, THF, H20.

Formation of (+/-)-ethyl 3-(2-chlor0ﬂu0r0pyrimidinylamin0)(1- methylcyclopentyl)pr0pan0ate (147a) To a solution of 2,4-dichloroﬂuoro-pyrimidine (0.184 g, 1.100 mmol) and c ethyl 3-amino(1-methylcyclopentyl)propanoate, 3321, (0.199 g, 1.000 mmol) in THF (10 mL) and ethanol (1 mL) was added triethylamine (0.307 mL, 2.200 mmol). The reaction e was stirred at 70 0C for 5 hours. The mixture was ﬁltered and the ﬁltrate was concentrated in vacuo.

The resulting residue was puriﬁed via silica gel chromatography (25%EtOAc/Hexanes) to afford 180 mg ofthe desired product: 1H NMR (400 MHz, CDClg) 8 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, J: 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 , 0.1% formic acid, 5 minutes, C18/ACN, Retention Time = 3.54 minutes (M+H) 330.17.

Formation of (+/-)-ethyl 3-(5-ﬂu0r0(5-ﬂu0r0trityl-1H—pyrazolo[3,4-b]pyridin yl)pyrimidinylamin0)(1-methylcyclopentyl)pr0pan0ate (1483) A solution of K3P04 (0.464 g, 2.183 mmol), racemic ethyl 3-[(2-chloroﬂuoropyrimidinyl )amino](1-methylcyclopentyl)propanoate, 147a, (0.180 g, 0.546 mmol) and 5- ﬂuoro-3 -(4,4,5 ,5 -tetramethyl- 1 ,3 ,2-dioxaborolanyl)trityl-pyrazolo [3 ,4-b]pyridine, 135a, (303.4 mg, 0.6004 mmol) in 2-Methyl THF (3.240 mL) and H20 (0.360 mL) was degassed under a stream of nitrogen for 30 s. 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 0C in a pressure tube for 1 hour. The organic phase was ﬁltered 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: 1H NMR (400 MHZ, CDClg) 5 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 (d, J: 9.7 Hz, 1H), 4.89 (dd, J: 9.7, 6.0 Hz, 1H), 3.99 (q, .1: 7.1 Hz, 2H), 2.73 (dd, J: 14.7, 3.8 Hz, 1H), 2.52 (dd, J: 14.8, 9.4 Hz, 1H), 1.68 (dd, J: 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), 1.11 — 0.99 (m, 4H). LCMS Gradient 60-98%, formic acid, 7 minutes, C18/can, Retention Time = 3.24 minutes (M+H) 672.85.

Formation of (+/-)-ethyl 3-(5-ﬂu0r0(5-ﬂu0r0-lH-pyrazolo[3,4-b]pyridinyl)pyrimidin- 4-ylamin0)(1-methylcyclopentyl)pr0pan0ate (149a) To a solution of racemic ethyl 3-[[5-ﬁuoro(5-ﬁuorotrityl-pyrazolo[3,4-b]pyridin yl)pyrimidinyl]amino](1-methylcyclopentyl)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 on mixture was stirred at room temperature ght. The on e was concentrated in vacuo and the resulting crude e was puriﬁed by silica gel chromatography (5% MeOH/CHzClz) to afford the desired product: 1H NMR (400 MHz, CDClg) 5 11.80 (s, 2H), 8.59 (d, J: 12.3 Hz, 2H), 8.48 (d, J: 7.9 Hz, 1H), 6.60 (d, J: 8.3 Hz, 1H), 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, J: 18.1, 11.1 Hz, 6H); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, ion Time = 2.97 minutes (M+H) 431.24.

Formation of (+/-)(5-ﬂu0r0(5-ﬂu0r0—lH-pyrazolo[3,4-b]pyridinyl)pyrimidin ylamin0)(1-methylcyclopentyl)pr0pan0ic acid (12) To a solution of racemic ethyl 3-[[5-ﬁuoro(5-ﬁuoro-1H—pyrazolo[3,4-b]pyridin yl)pyrimidinyl]amino](1-methylcyclopentyl)propanoate, 149a, (0.110 g, 0.256 mmol) in THF (30 mL) was added a solution of lithium hydroxide e (0.043g, 1.022 mmol) in H20 (20 mL). The reaction mixture was stirred at 70 0C overnight. The organic solvent was removed under reduced pressure and the remaining aqueous phase was used directly in the ation 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 d product: 1H NMR (400 MHz, MeOD) 8 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).

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

The ing compounds can be prepared in a similar fashion as the procedure described above for Compound 12: PS’ O /I\ 7 \ ,N N N (R)((5-ﬂu0r0(5-ﬂu0r0-lH-pyrazolo ]pyridinyl)pyrimidinyl)amin0)-4,4- dimethylpentanoic acid (5) Compound 5 was synthesized in a manner similar to compound 12, starting with nd 6a: 1H NMR (400 MHz, d6-DMSO) 8 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, J: 20.0 Hz, 9H); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, Retention Time = 2.70 min, (M+H) 393.32.

(R)((3,5-diﬂu0r0(5-ﬂu0r0-lH-pyrazolo [3,4-b]pyridinyl)pyridinyl)amin0)-4,4- dimethylpentanoic acid (6) nd 6 was synthesized in a manner similar to compound 12, utilizing (R)-ethyl 3- ((6-bromo-3,5-diﬂuoropyridinyl)amino)-4,4-dimethylpentanoate as the intermediate for the Suzuki ng. (R)-ethyl 3-((6-bromo-3,5-diﬂuoropyridinyl)amino)-4,4-dimethyl- pentanoate was prepared in the same fashion as ediate, 143a, utilizing 2-bromo-3,5,6- triﬂuoropyridine as the starting material instead of 2-chloro-5,6-diﬂuoropyridinecarbonitrile: 1H NMR (400 MHz, CDClg) 5 8.31 (d, J: 6.4 Hz, 1H), 8.06 (s, 1H), 7.06 (t, J: 9.7 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).; LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, Retention Time = 2.92 min, (M+H) 394.19. 96 / ' I2 97 (R)((2-(5-chlor0-lH-pyrazolo[3,4-b]pyridinyl)ﬂu0r0pyrimidinyl)amino)—4,4- dimethylpentanoic acid (97) and methylester (96) Compounds 96 and 97 were synthesized in a manner similar to compound 12, starting with compound 6a: 1H NMR (300 MHz, MeOD) for Compound 97: 8 8.95 (d, J = 2.3 Hz, 1H), WO 19828 2012/049097 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 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, Retention Time = 2.79 min, (M+H) 407.37.

Pre aration 0 Com ounds 54 56 and 53 tic Scheme 23 F F F ﬂ a O z b c N / CI —> N / NH —> NF87/ \ \ N\H4>*OE1 —.

N N NH >\’N N 34% CI CI 78 CI 7’\ ‘B—O 151a 152a \/ I 153a N N.

F F N\ N NH}OE1‘N d N‘ N NH}OE1‘N 9 / 7K F30 I \ I \ 7K \ \ N N N N 154a H 155a .2 o N / \ N\H4>*OH F C3 \ N7<N N N (a) tert—butylhydrazine-HCl, Eth, THF, EtOH; (b) 2-bromoethyl acetate, K2C03, CH3CN; (c) 3- (4,4,5 ,5 -tetramethyl-1 ,3 ,2-dioxaborolanyl)tosyl-5 -(triﬁuoromethyl)— 1H-pyrrolo [2,3 - b]pyridine, 153a, X-phos, Pd2(dba)3, K3P04, THF, H20; (d) TBAF/THF; (e) LiOH, H20, THF.

Formation of 4-(2-tert-butylhydrazinyl)chlor0-S-ﬂuoropyrimidine (1513) To a solution of 2,4-dichloroﬁuoro-pyrimidine (1.84 g, 11.00 mmol) and tert- butylhydrazine 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 temperature overnight. The reaction e was ﬁltered to remove triethylamine HCl salt and the ﬁltrate concentrated in vacuo. The resulting residue was puriﬁed by silica gel tography (EtOAc/Hexanes) to afford 1.7g of the desired product: 1H NMR (400 MHZ, CDClg) 8 7.82 (d, J: 2.8 Hz, 1H), 6.47 (s, 1H), 4.60 (d, J: 5.8 Hz, 1H), 1.09 (s, 9H). LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, Retention Time = 2.19 minutes (M+H) 218.81.

Formation of ethyl 2-(1-tert-butyl(2-chlor0ﬂu0r0pyrimidinyl)hydrazinyl)ethanoate (1523) To a suspension of 4-(2-tert—butylhydrazinyl)chloroﬁuoropyrimidine, 15121, (1.50 g, 6.86 mmol) in itrile (68 mL) was added 2-bromoethyl acetate (0.84 mL, 7.55 mmol) and K2C03 (2.28 g, 16.46 mmol). The reaction mixture was stirred at room temperature overnight.

The mixture was diluted into EtOAc and brine. The organic phase was dried over MgSO4, ﬁltered and concentrated in vacuo. The residue was puriﬁed by silica gel chromatography (30%EtOAc/Hexanes) to afford 1 g of the d product: 1H NMR (400 MHz, CDClg) 8 7.96 (d, J: 3.1 Hz, 1H), 4.16 (dt, J: 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, N, Retention Time = 2.69 minutes (M+H) 305.09.

Formation of ethyl 2-(1-tert-butyl—2—(5-ﬂu0r0-2—(1-t0syl(triﬂu0r0methyl)—lH-pyrrolo[2,3- b]pyridinyl)pyrimidinyl)hydrazinyl)ethan0ate (154a) Boronate ester, 153a, was ed in same fashion as boronate ester, 7a, (see Synthetic Scheme 4) using 3-bromo(triﬁuoromethyl)-1H—pyrrolo[2,3-b]pyridine instead of 3-bromo ﬁuoro- 1H—pyrrolo [2,3 -b]pyridine.

A solution of 1-(p-tolylsulfonyl)(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl) (triﬁuoromethyl)pyrrolo[2,3-b]pyridine, 153a, (0.551 g, 1.181 mmol), ethyl 2-(1-tert—butyl(2- ﬁuoropyrimidinyl)hydrazinyl)ethanoate, 152a, (0.300 g, 0.984 mmol) and K3P04 (0.627 g, 2.953 mmol) in 2-MethleHF (26 mL) and H20 (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 a)3 (0.022 g, 0.025 mmol). The reaction mixture was heated at 120 0C 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 of the desired product: 1H NMR (400 MHz, CDClg) 8 9.49 (s, 1H), 8.71 (t, J: 7.0 Hz, 1H), 8.63 (d, J: 11.1 Hz, 1H), 8.16 — 8.11 (m, 3H), 7.31 (d, J: 8.2 Hz, 2H), 7.11 (d, J: 21.4 Hz, 1H), 4.10 (dd, J: 13.4, 6.3 Hz, 2H), 3.79 (s, 2H), 2.39 (s, 3H), 1.24 (s, 9H), 1.17 (t, J: 7.1 Hz, 3H); LCMS Gradient , 0.1% formic acid, 5 minutes, C18/ACN, Retention Time = 4.18 minutes (M+H) 609.37.

Formation of ethyl tert-butyl)—2-(5-ﬂu0r0(5-(triﬂu0r0methyl)-lH-pyrrolo[2,3- b]pyridinyl)pyrimidinyl)hydrazinyl)acetate (155a) To a solution of ethyl 2-(1-tert—butyl(5-ﬁuoro(1-tosyl(triﬁuoromethyl)-1H- pyrrolo[2,3-b]pyridinyl)pyrimidinyl)hydrazinyl)ethanoate, 154a, (0.54 g, 0.89 mmol) in THF (20 mL) was added tetrabutylammonium ﬂuoride (1.78 mL of 1 M, 1.78 mmol). The reaction mixture was stirred at room temperature for 30 s. The reaction mixture was diluted into EtOAc and brine. The organic phase was dried over MgSO4, 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. 1H NMR (400 MHz, CDClg) 5 .59 (s, 1H), 9.55 (s, 1H), 8.66 (s, 1H), 8.29 (d, J: 2.2 Hz, 1H), 8.13 (dd, J: 3.8, 1.5 Hz, 1H), 7.14 (s, 1H), 4.20 — 4.04 (m, 2H), 3.85 (s, 2H), 1.28 (d, J = 9.1 Hz, 9H), 1.19 (dt, J: 7.1, 3.6 Hz, 3H). LCMS Gradient , 0.1% formic acid, 5 minutes, C18/ACN, Retention Time = 2.93 min, (M+H) 455.43.

Formation of 2-(1-(tert-butyl)(5-ﬂu0r0(5-(triﬂu0r0methyl)—lH-pyrrolo[2,3-b]pyridin- 3-yl)pyrimidinyl)hydrazinyl)acetic acid (54) To a solution of ethyl 2-[tert—butyl-[[5-ﬁuoro[5-(triﬁuoromethyl)-1H—pyrrolo[2,3- b]pyridinyl]pyrimidinyl]amino]amino]acetate, 155a, (0.200 g, 0.440 mmol) in THF (40 mL) was added a solution of m hydroxide hydrate (0.074 g, 1.760 mmol) in H20 (4 mL).

The on mixture was stirred at room temperature overnight. 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 desiccator with P205 to afford 120mg of the desired t: 1H NMR (400 MHZ, d6-DMSO) 5 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); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, Retention Time = 2.92 min, (M+H) 427.40 The ing compounds can be prepared in a similar fashion as the procedure described above for Compound 54: NWN‘HfOH,. o N N N N Formation of 2-(1-(tert-butyl)(2-(5-chlor0-lH-pyrrolo[2,3-b]pyridinyl)—5- ﬂuor0pyrimidinyl)hydrazinyl)acetic acid-TFA (triﬂuoro acetic acid) salt (56) 1H NMR (400 MHz, d6-DMSO) 8 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, J: 20.0 Hz, 9H); LCMS nt 10-90%, 0.1% formic acid, 5 s, C18/ACN, ion Time = 2.70 min, (M+H) 393.32.

Formation of 2-(1-(tert-butyl)(5-ﬂu0r0(5—ﬂu0r0—1H-pyrrolo[2,3-b]pyridin yl)pyrimidinyl)hydrazinyl)acetic acid— TFA salt (53) 1H NMR (400 MHz, d6-DMSO) 8 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); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, Retention Time = 2.50 min, (M+H) 377.42.

Pre aration 0 Com ounds 7 8 and 18 Synthetic Scheme 24 159a 1 8 (a) 2,6-dich10r0ﬁu0r0-pyridinecarb0nitri1e, Eth, acetonitrile; (b) 5-ﬁu0r0(pt01y1su1f0ny1 )-3 -(4,4,5 ,5 -tetramethy1— 1 ,3 ,2-dioxab0r01any1)pyrr010 [2,3 -b]pyridine, 7a, Pd2(dba)3, X-Phos, K3P04, 2-MeTHF, H20, 125 0C; (c) LiOH, THF, H20 Formation of ethyl 3-[(6-chlorocyanoﬂuoropyridyl)amino]-4,4—dimethyl-hexanoate (158a) A on of ethyl 3-amin0-4,4-dimethy1—hexanoate, 27a, (0.24 g, 1.28 mmol), 2,6- dich10roﬁuoro-pyridinecarbonitri1e (0.29 g, 1.53 mmol) and Eth (0.43 mL, 3.07 mmol) in acetonitrile (4.8 mL) was stirred at 70 0C overnight. The reaction e was concentrated in vacuo and puriﬁed by silica gel chromatography (10-40% EtOAc/Hexanes gradient) to provide 205 mg of ethyl 3-[(6-ch10rocyanoﬁu0r0pyridy1)amin0]-4,4-dimethy1—hexan0ate; LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, N, Retention Time = 3.75 minutes (M+H) 342.04.

Formation of ethyl 3-[[5-cyanoﬂuoro[S-ﬂuoro(p-tolylsulfonyl)pyrrolo[2,3- b]pyridinyl]pyridyl]amino]-4,4-dimethyl-hexanoate (159a) A solution of ethyl 3-[(6-ch10rocyanoﬁu0r0pyridy1)amin0]-4,4-dimethy1— hexanoate, 158a, (0.21 g, 0.600 mmol) , o(p-t01y1su1f0ny1)(4,4,5,5-tetramethy1— 1,3,2-di0xaborolany1)pyrr010[2,3-b]pyridine, 7a, (0.30 g, 0.72 mmol) and K3PO4 (0.51 g, 2.40 mmol) in 2-methy1 THF (20.5 mL) a n d H20 (2.7 mL) was degassed for 45 minutes and d with X-phos (0.03 g, 0.07 mmol) and Pd2(dba)3 (0.01 g, 0.02 mmol). The reaction vessel was sealed and heated to 125 0C for 90 minutes. After cooling to room temperature, 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 nt) to provide 270 mg of the desired product: 1H NMR (400 MHz, CDC13) 8 8.69 (s, 1H), 8.51 (dd, J: 9.1, 2.7 Hz, 1H), 8.37 (d, J: 1.8 Hz, 1H), 8.15 (d, J: 8.4 Hz, 2H), 7.41 (d, J: 10.3 Hz, 1H), 7.33 (d, J: 8.1 Hz, 2H), 5.28 - 5.22 (m, 1H), 4.92 (td, J: 10.4, 3.2 Hz, 1H), 4.03 - 3.91 (m, 2H), 2.75 (dd, J = 14.9, 3.5 Hz, 1H), 2.45 (dd, J: 12.6, 8.2 Hz, 1H), 2.40 (s, .1: 4.7 Hz, 3H), 1.36 (q, .1: 7.4 Hz, 2H), 1.01 (t, J: 7.1 Hz, 3H), 0.92 (d, J: 8.8 Hz, 6H), 0.88 (t, J: 7.5 Hz, 3H). LCMS Gradient -90%, 0.1% formic acid, 5 minutes, N, Retention Time = 2.86 minutes (M+H) 596.02.

Formation of 3-[[5-cyanoﬂuoro(5-ﬂuoro-lH-pyrrolo[2,3-b]pyridinyl)—2- pyridyl]amino]-4,4-dimethyl-hexanoic acid (18) Ethyl 3 -[[5 -cyano-3 -ﬂuoro[5 -ﬂuoro(p-tolylsulfonyl)pyrrolo [2,3 -b]pyridin-3 -yl] 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 e was heated to 70 °C for 10 hours. After cooling to room temperature, 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 1N HCl, and the resulting precipitate was collected by ion, washed with water and concentrated in vacuo to provide 77 mg of the desired product: 1H NMR (400 MHz, DMSO-d6) 8 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, 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); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, Retention 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: NC\/NH OH F N5 [\ 7‘ Formation of (R)(5-cyan0ﬂu0r0(5-ﬂu0r0-lH-pyrrolo[2,3-b]pyridinyl)pyridin ylamino)—4,4-dimethylpentanoic acid (7) 1H NMR (400 MHz, MeOD) 8 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, 1H), 5.04 (d, J: 8.7 Hz, 1H), 2.80 (dd, J: 15.2, 2.5 Hz, 1H), 2.59 (dd, J: .0, 11.0 Hz, 1H), 0.99 (s, 9H); LCMS nt 10-90%, 0.1% formic acid, 5 minutes, N, Retention Time = 3.0 minutes (M+H) .

NC\/NH OH F/ s \ [\U Formation of (R)—3-(5-cyan0ﬂu0r0(5-ﬂu0r0-lH-pyrrolo[2,3-b]pyridinyl)pyridin ylamino)—3-(1-methylcyclopentyl)pr0pan0ic acid (8) 1H NMR (300 MHz, CDClg) 8 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, 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, 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, C18/ACN, Retention Time = 3.27 minutes (M+H) 426.31.

Pre aration 0 Com ound 55 Synthetic Scheme 25 —114— WO 19828 (a) (i) NH3, HBTU, THF, (ii) 2N LiOH, MeOH; (b) TFAA, pyridine; (c) Bu3SnN3, dioxane, 130 0C; Formation of (+/-)(5-ﬂuoro(5-ﬂuoro-lH-pyrrolo[2,3-b]pyridinyl)pyrimidin ylamino)-4,4-dimethylpentanamide (164a) To a on of racemic 3-(5-ﬂuor0(5-ﬂu0r0t0syl-1H—pyrrolo[2,3-b]pyridin yl)pyrimidinylamin0)—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 redissolved in 20 mL of MeOH and treated with 3 mL of 2N LiOH. The on was warmed to 60 0C for 3 hours and then concentrated to dryness. The residue was puriﬁed by silica gel chromatography (EtOAc) to afford 250 mg of desired product: LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, N, Retention Time = 1.78 minutes (M+H) 375.45.

Formation of (+/-)(5-ﬂuoro(5-ﬂuoro-lH-pyrrolo[2,3-b]pyridinyl)pyrimidin ylamino)—4,4-dimethylpentanenitrile (165a) A solution of racemic 3-(5-ﬂuoro(5-ﬂuoro-1H—pyrrolo[2,3-b]pyridinyl)pyrimidin- ino)-4,4-dimethylpentanamide, 164a, (0.250 g, 0.668 mmol) in pyridine was cooled to 0 CC and treated with triﬂuoroacetic acid anhydride (0.278 mL, 2.003 mmol). After 2 hours at 0 0C, the reaction was concentrated to s and the residue was puriﬁed by silica gel chromatography ) to afford 150 mg of desired product: LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, Retention Time = 2.41 minutes (M+H) 357.47.

Formation of (+/-)-N-(3,3-dimethyl(2H-tetrazolyl)butanyl)ﬂuoro(5-ﬂuoro-1H- pyrrolo[2,3-b]pyridinyl)pyrimidinamine (55) To a solution of racemic 3-(5-ﬂu0r0(5-ﬂuoro-1H—pyrrolo[2,3-b]pyridin yl)pyrimidinylamin0)—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 0C for 12 hours. Upon g, the reaction was concentrated to dryness and the resulting residue was puriﬁed by silica gel chromatography to afford 48 mg of desired product: 1H NMR (300.0 MHz, d6-DMSO) 8 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, J = 6.6 Hz, H) ppm; LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, Retention Time = 1.94 minutes (M+H) .

Pre aration 0 Com ounds 60 and 61 Synthetic Scheme 26 170a Ts 60 (a) utylbromoacetate, K2C03, acetone; (b) Oxone, water, MeOH; (c) 5-ﬂuoro(p- tolylsulfonyl)(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)pyrrolo[2,3-b]pyridine, 7, K3PO4 X-Phos, Pd2(dba)3, 2-Me THF, water, 120 0C; (d) 25% NaOMe, MeOH; (e) TFA, CHzClz, 50 0C. ion of (S)-tert-Butyl 2-(2-(2-chlor0ﬂuor0pyrimidinylamin0)—3,3-dimethyl- butylthi0)ethan0ate (168a) To a ng suspension of (S)((2-chloroﬂuoropyrimidinyl)amino)-3,3- dimethylbutane-l-thiol, 773, (1.50 g, 5.69 mmol) and K2C03 (2.36 g, 17.06 mmol) in acetone (15 mL) was added tert—butyl cetate (1.26 mL, 8.53 mmol). The suspension was stirred at room ature for 18 hours. The resulting 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 nt 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, ion Time = 3.81 minutes (M+H) 378.06.

Formation of (S)-tert-Butyl 2-(2-(2-chlor0ﬂu0r0pyrimidinylamin0)—3,3-dimethylbutyl- sulfonyl)ethanoate (169a) Oxone (5.37 g, 8.73 mmol) was added to a solution of (S)—tert—Butyl 2-(2-(2-chloro ﬂuoropyrimidinylamino)-3,3-dimethyl-butylthio)ethanoate, 1683, (1.10 g, 2.91 mmol) in methanol (50 mL) and water (20 mL) and the solution was stirred 3 hours at room temperature.

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 d product as a white solid: LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, Retention Time = 1.29 minutes (M+H) 410.19.

Formation of (S)-tert—Butyl 2-(2-(5-fluoro(5-fluorotosyl-1H-pyrrolo[2,3-b]pyridin yl)pyrimidinylamino)-3,3-dimethylbutylsulfonyl)ethanoate (170a) A solution of 5-ﬂu0r0(p-tolylsulfonyl)(4,4,5,5-tetramethyl-1,3,2-di0xab0rolan yl)pyrrolo[2,3-b]pyridine, 7a, (0.76 g, 1.83 mmol), (S)—tert—Butyl 2-(2-(2-chloro ﬂuoropyrimidinylamino)-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)3 (0.03 g, 0.03 mmol) were added and the reaction mixture was heated at 115 0C in a pressure vial for 2.5 hours.

The reaction mixture was cooled to room temperature, ﬁltered and concentrated in vacuo. The residue was dissolved in EtOAc (50 mL) and washed with water. The organic layer was dried ), 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 d t as a foamy solid: LCMS Gradient 60-98% ACN/water, 0.9% formic acid, 7 minutes, C4, Retention Time = 2.39 s (M+H) 564.34.

Formation of (S)-2—(2—(5-fluoro(5-fluoro—lH-pyrrolo[2,3-b]pyridinyl)pyrimidin ylamino)—3,3-dimethylbutylsulfonyl)ethanoic acid (60) To a solution of (S)-tert—butyl 2-(2-(5-ﬁuoro(5-ﬁuorotosyl-1H—pyrrolo[2,3- b]pyridinyl)pyrimidinylamin0)—3,3-dimethylbutylsulf0nyl)ethanoate, 170a, (1.00 g, 1.50 mmol) in THF (50 mL) was added NaOMe (1.30 mL of 25% on in MeOH, 1.45 mmol).

The yellow colored solution was stirred at room temperature for 30 minutes and then the mixture was diluted with aqueous saturated NH4C1 solution. The solvent was removed under d 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/CHgClz gradient) to afford 0.50 g of the detosylated ester intermediate as a white solid.

The ester (0.50 g) was dissolved in CHzClz (4 mL) and roacetic acid (2 mL) was added. The solution was heated at 50 0C 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 ted NaHC03 solution. The aqueous phase was extracted with EtOAc (3x 10 mL), dried (MgSO4), ﬁltered and trated in vacuo. The crude product was puriﬁed by silica gel chromatography (0-15% MeOH/CHzClz gradient) to afford 204 mg of the desired product, 60, as a white solid: LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, Retention Time = 2.01 minutes (M+H) 454.21.

The following compounds can be prepared in the same fashion using the procedure described above: \ \—/ —>/~—OH CI 71 o N N (2-(2-(5-chloro-lH-pyrrolo ] pyridinyl)—5-fluoropyrimidinylamino)—3,3- dimethylbutylsulfonyl)ethanoic acid (61) 1H NMR (300 MHz, MeOD) 8 8.95 (s, 1H), 8.29 - 8.14 (m, 2H), 8.08 (d, J: 4.0 Hz, 1H), .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); LCMS Gradient 60-98% ACN/water, 0.9% formic acid, 7 minutes, C4, Retention Time = 2.23 minutes (M+H) 470.14.

Pre aration 0 Com ound 64 Synthetic Scheme 28 Nﬁ’NH ,— O .— O O O a “‘th j/ b N \./\S N 5 ‘ S 7\ n 7a CI 7\ Cl 0 168a 175a F F Nﬁ—N.— H O j’o ,— O \:/\ c \ NW“ N \ \e/\ F j "S —> N F ,,s N N ‘ N 176a Ts H 64 (a) Oxone, MeOH; (b) 5-ﬁuoro(p-tolylsulfonyl)(4,4,5,5-tetramethyl-1,3,2-dioxaborolan yl)pyrrolo[2,3-b]pyridine, 7a, K3PO4 X-Phos, Pd2(dba)3, 2-Me THF, water, 120 0C; (c) NaOMe, MeOH, THF.

Formation of tert-butyl-((S)—2(2-chlor0ﬂu0r0pyrimidinylamin0)—3,3- dimethylbutylsulﬁnyl)ethan0ate (1753) Oxone (1.04 g, 1.69 mmol) was added to a stirring solution of (S)—tert—Butyl 2-(2-(2- chloroﬁuoropyrimidinylamino)-3,3-dimethyl-butylthio)ethanoate, 1683, (0.53 g, 1.41 mmol) in ol (20 mL). The solution was d for 15 minutes at room ature. 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 (MgSO4), d 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, Retention Time = 3.05 minutes (M+H) 394.28. tert-Butyl 2—((S)(5-ﬂu0r0(5-ﬂu0r0t0syl—1H-pyrrolo[2,3-b]pyridinyl)pyrimidin ylamino)—3,3-dimethylbutylsulﬁnyl)ethanoate (176a) A on of 5-ﬁuoro(p-tolylsulfonyl)(4,4,5,5-tetramethyl-1,3,2-dioxaborolan rolo[2,3-b]pyridine, 7a, (0.66 g, 1.58 mmol), tert—butyl((S)—2(2-chloroﬁuoropyrimidin- 4-ylamino)-3,3-dimethylbutylsulﬁnyl)ethanoate, 17521, (0.50 g, 1.27 mmol) and K3PO4 (0.65 g, 3.05 mmol) in yl 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)3(0.02 g, 0.02 mmol) were added and the reaction mixture was heated at 115 0C in a pressure vial for 4 hours. The reaction mixture was cooled to room temperature, 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 puriﬁed by silica gel chromatography (0-60% EtOAc/Hexanes nt) 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, Retention Time = 3.91 minutes (M+H) 648.40. 2-((S)(5-ﬂu0r0(5-ﬂu0ro-lH-pyrrolo [2,3-b] nyl)pyrimidinylamin0)—3,3- dimethylbutylsulﬁnyl)ethan0ic acid (64) To a solution of tert—butyl (5-ﬂuoro(5-ﬂuorotosyl-1H-pyrrolo[2,3- b]pyridinyl)pyrimidinylamino)-3,3-dimethylbutylsulﬁnyl)ethanoate, 17621, (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 on was stirred at room temperature for 30 minutes. Aqueous saturated NH4C1 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 ed organic phases were dried (MgSO4), ﬁltered and concentrated in vacuo. The residue was puriﬁed by silica gel chromatography (0-15% MeOH/CHgClz gradient) to afford 36 mg of the desired product as a white solid: 1H NMR (400 MHz, MeOD) 8 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); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, Retention Time = 1.93 minutes (M+H) .

Pre aration 0 Com ounds 66 67 72 and 73 Synthetic Scheme 29 F F F _, 0 HO a ng HO N\ / NL>—H , N\FS’/ NUCF3+ N‘N NUCF3 H of m5 CI 7\ CI”a“ 180a 181a //§’NH~' HO "‘ HO F 5 C N s 18°a—’ /: \ 7\ F / 7\ 7a \N N \ I \ 182a N m 66 first diastereomer ' HO ,_ HO F s d N s “"a—’ / F I \ 7\ / 7\ 7a \N I \ N \ \ 184a N N Ts H second diastereomer (a) i.TMS-CF3, CsF, THF, ii. TFA, CHzClz; (b) 5-ﬂuoro(p-tolylsulfonyl)(4,4,5,5- tetramethyl-l,3,2-dioxaborolanyl)pyrrolo[2,3-b]pyridine, 7a, X-phos, Pd2(dba)3, K3P04, 120 0C; (c) NaOMe, THF; (d) TBAF, THF.

Formation of (4R)—4-((2-chlorofluoropyrimidinyl)amino)—1,1,1-trifluoro-5,5- dimethylhexan-Z-ol (180a) and (181a) To a solution of (3R)[(2-chloroﬁuoro-pyrimidinyl)amin0]-4,4-dimethyl-pentanal (0.212 g, 0.817 mmol) and oromethyl)trimethylsilane (1.96 mL, 0.980 mmol) in THF (20 mL) was added cesium ﬂuoride (0.001 g, 0.008 mmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted into brine and EtOAc. The organic phase was dried over MgSO4, ﬁltered and concentrated in vacuo. The crude residue was puriﬁed Via silica gel chromatography (EtOAc/Hexanes) to afford 190 mg of the silylated l. 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 temperature for 30 minutes. The reaction mixture was trated in vacuo and the resulting residue was puriﬁed Via silica gel tography (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: 1H NMR (400 MHZ, CDClg) 5 7.93 (dd, J: 43.4, 2.6 HZ, 1H), 5.10 (d, J: 8.9 HZ, 1H), 4.13 (dd, J: 15.8, 5.8 HZ, 1H), 3.94 — 3.71 (m, 1H), 2.05 (ddd, J: 13.7, 9.2, 2.1 HZ, 1H), 1.64 (t, J: 12.9 HZ, 1H), 1.05 (s, 9H); LCMS Gradient 10-90%, 0.1% formic acid, minutes, C18/ACN, Retention Time = 3.18 minutes (M+H) 330.42.

Diastereomer, 181a: 1H NMR (400 MHZ, CDClg) 5 7.79 (d, J: 2.7 HZ, 1H), 5.30 (d, J: 11.6 HZ, 1H), 4.22 — 4.07 (m, 2H), 2.19 (ddd, J: 28.7, 15.3, 13.4 HZ, 1H), 1.74 — 1.59 (m, 1H), 1.04 (s, 9H). LCMS nt 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, Retention Time = 3.26 s (M+H) 330.42.

Formation of (4R)-1,1,1-trifluoro((5—fluoro(5-fluorotosyl-1H-pyrrolo[2,3-b]pyridin- 3-yl)pyrimidinyl)amino)-5,5-dimethylhexanol (182a) A on of 5-ﬁu0r0(p-tolylsulf0nyl)(4,4,5,5-tetramethyl-1,3,2-di0xab0rolan yl)pyrrolo[2,3-b]pyridine (0.091 g, 0.218 mmol), 7a, (4R)[(2-chlor0ﬁuor0-pyrimidin yl)amin0]—1,1,1-triﬁu0ro-5,5-dimethyl-hexanol, 180a, (0.060 g, 0.182 mmol) and K3P04 (0.116 g, 0.546 mmol) in 2-methyl THF (5 mL) and H20 (1.5 mL) was degassed under a stream of nitrogen for 45 minutes. To the reaction e was added X-phos (0.010 g, 0.022 mmol) and Pd2(dba)3 (0.004 g, 0.005 mmol). The on mixture was stirred at 120 0C 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 OAc/Hexanes) to afford 60 mg of the desired product: 1H NMR (400 MHZ, CDCl3) 5 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, J: 2.9 HZ, 1H), 8.00 (d, J: 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, J: 23.0, 9.3 HZ, 1H), 1.07 (d, J = 8.4 HZ, 9H). LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, Cl8/ACN, Retention Time = 4.02 min (M+H) 584.41.

The second reomeric alcohol, 181a, was also reacted in the same fashion to produce the diastereomeric Suzuki product. 184a: 1H NMR (400 MHZ, CDClg) 5 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 — .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, J = 10.8 HZ, 9H). LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, ion Time = 4.02 minutes (M+H) 584.44.

Formation of ,1,1-trifluoro((5—fluoro(5-fluoro-lH-pyrrolo[2,3-b]pyridin yl)pyrimidinyl)amino)—5,5-dimethylhexanol (66 and 67) To a solution of (4R)-1,1,1-triﬂu0r0((5-ﬂu0r0(5-ﬂu0rot0syl-1H—pyrrolo[2,3- dinyl)pyrimidinyl)amin0)-5,5-dimethylhexanol, 182a, (0.053 g, 0.091 mmol) was added NaOMe (0.019 g of 25% on in MeOH, 0.091 mmol). The reaction mixture was stirred at room ature for 5 minutes. The reaction mixture was diluted into EtOAc and aqueous saturated NaHC03 solution. The organic phase was dried over MgSO4, 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: 1H NMR (400 MHz, CDClg) 8 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, 1H), 1.62 (t, J: 13.0 Hz, 1H), 1.01 (s, 9H); LCMS nt 10-90%, 0.1% formic acid, s, C18/ACN, Retention Time = 2.42 minutes (M+H) 430.44.

The second reomeric product, 67, was made by removal of the tosyl-protecting group on intermediate, 1843, using the following procedure: To a solution of (4R)—1,1,1-triﬂuor0[[5-ﬂu0r0[5-ﬂu0ro(p- ulfonyl)pyrrolo[2,3-b]pyridinyl]pyrimidinyl]amin0]-5,5-dimethyl-hexanol, 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 temperature. The reaction mixture was stirred at room temperature for 30 minutes. The reaction e was diluted into EtOAc and aqueous saturated NaHC03 solution. The organic phase was dried over MgSO4, ﬁltered and concentrated in vacuo.

The residue was puriﬁed by silica gel chromatography (50% EtOAc/Hexanes) to afford 30mg of desired product. 1H NMR (400 MHz, CDClg) 8 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 — .10 (m, 1H), 4.32 — 4.24 (m, 1H), 4.23 — 4.17 (m, 1H), 2.37 (dt, J: 14.9, 3.4 Hz, 1H), 1.85 — 1.71 (m, 2H), 1.09 (s, 9H); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, Retention Time = 2.37 minutes (M+H) 430.47.

The following two diastereomers can be prepared in a similar fashion as the procedure described above: F F iHO HO N\ NH ,j J N\i,ﬁ Mil—7* F F / / \ l ‘ I \ l ‘ \ I \ N H N 72 H 73 (4R)—4-((5-Fluoro(5-fluoro-lH-pyrrolo [2,3-b]pyridinyl)pyrimidinyl)amino)-5,5- dimethylhexan-Z-ol (72 and 73) Diastereomer 72: 1H NMR (400 MHz, CDC13) 8 9.99 (s, 1H), 8.60 (dd, J: 9.4, 2.7 Hz, 1H), 8.26 (s, 1H), 8.20 (d, J: 2.6 Hz, 1H), 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, 1H), 2.71 (s, 1H), 1.97 (ddd, J: 14.2, 5.8, 2.9 Hz, 1H), 1.66-1.58 (m, 1H), 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, Retention Time = 1.93 minutes (M+H) 376.46.

W0 2013/019828 reomer 73: 1H NMR (400 MHz, CDClg) 8 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), 4.31-4.14 (m, 1H), 3.72 (dd, J: 8.9, 6.0 Hz, 1H), 1.83-1.70 (m, 1H), 1.48-1.32 (m, 1H), 1.24-1.11 (m, 4H), 0.98 (s, 9H); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, Retention Time = 2.01 minutes (M+H) 376.46.

Pre aration 0 Com ounds 70 and 71 Synthetic Scheme 30 F F F F o ,, HO OH _, HO OH N/N'\'l_>_H_, a,N/NH——>N/Nl\'l_)_/b _, \ N/N\H_)—/ \—/— \ ‘ >\’N >\/N N CI 7\ CI CI 7\‘ CI 7? 188a 189a 190a first diastereomer second diastereomer F F FS’ HO OH HO OH N / NW \ N\ N|\-I_)—/ c N ,1 [\1 F .

S d 189a —> / 7\ —> 1 \ 73 \N \ N fr? 7 \T 191a IZ/ 70, 71 (a) Pth-Br, LiHMDS, THF; (b) OsO4, 4-methylmorpholine e, THF, H20; (c) X-phos, Pd2(dba)3, K3P04, 2-methyl THF, H20; (d) MeONa, THF; (e) 5-ﬁuoro(p-tolylsulfonyl) (4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)pyrrolo[2,3-b]pyridine, 7a, X-phos, Pd2(dba)3, K3P04, 2-methyl THF, H20, 120 0C; (i) MeONa, THF Formation of (R)chlor0-N—(2,2-dimethylhex-S-enyl)ﬂu0r0pyrimidinamine (18821): 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 on, 2.753 mmol). The reaction mixture was stirred at room temperature for 1 hour. A solution of (3R)[(2-chloroﬁuoro-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 temperature 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: 1H NMR (400 MHz, CDClg) 8 7.80 (d, J = 2.8 Hz, 1H), 5.76 — 5.60 (m, 1H), 5.05 — 4.91 (m, 2H), 4.82 (t, J: 22.1 Hz, 1H), 4.26 — 4.11 (m, 1H), 2.58 — 2.48 (m, 1H), 2.07 — 1.92 (m, 1H), 0.94 (s, 9H); LCMS Gradient , 0.1% formic acid, 5 minutes, N, Retention Time = 3.60minutes (M+H) 258.38.

Formation of (4R)((2-chlor0ﬂuor0pyrimidinyl)amin0)-5,5-dimethylhexane-1,2-diol (189a) and (19021): To a on of (R)chloro-N-(2,2-dimethylhexenyl)ﬁuoropyrimidinamine, 18821, (0.140 g, 0.543 mmol) in THF (10 mL) and H20 (10 mL) was added osmium tetraoxide (0.138 g, 0.014 mmol) and 4-methylmorpholineoxide (0.085 mL, 0.815 mmol). The reaction mixture was stirred at room ature for 2.5 hours. The mixture was d with aqueous saturated g. 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/CH2C12) to afford 90 mg of the ﬁrst diastereomer, 1893, and 65 mg of the second diastereomer, 1903.

Di3stere0mer 1893: 1H NMR (400 MHz, CDClg) 8 7.86 (d, J: 2.6 Hz, 1H), 5.00 (d, J = 9.2 Hz, 1H), 4.17 (s, 1H), 4.08 — 3.96 (m, 1H), 3.49 (dd, J: 19.2, 8.4 Hz, 3H), 2.15 (s, 1H), 1.74 (ddd, J: 13.2, 10.8, 2.2 Hz, 1H), 1.27 (dd, J: 19.3, 7.0 Hz, 1H), 0.92 (d, J: 10.5 Hz, 9H); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, Retention Time = 2.24 minutes (M+H) 292.36.

Di3stere0mer 1903: 1H NMR (400 MHz, CDClg) 8 7.88 (d, J: 2.7 Hz, 1H), 5.29 (d, J: 8.9 Hz, 1H), 4.12 — 4.02 (m, 1H), 3.74 (d, J: 9.0 Hz, 2H), 3.50 (s, 1H), 3.22 (s, 1H), 2.12 (s, 1H), 1.95 (dt, .1: 14.7, 4.2 Hz, 1H), 1.56 (ddd, J: 14.8, 9.2, 7.4 Hz, 1H), 0.99 (s, 9H); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, Retention Time = 2.24 minutes (M+H) 292.39.

Formation of (4R)—4-((5-ﬂu0r0(5-ﬂu0r0t0syl-1H—pyrrolo[2,3-b]pyridin yl)pyrimidinyl)3min0)—5,5-dimethylhex3ne—1,2-diol (1913) To a solution of (4R)[(2-chloroﬁuoro-pyrimidinyl)amino]-5,5-dimethyl-hexane- 1,2-diol, 1893, (0.090 g, 0.309 mmol), 5-ﬁuoro(p-tolylsulfonyl)(4,4,5,5-tetramethyl-1,3,2- dioxaborolanyl)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 H20 (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)3 (0.007 g, 0.008 mmol). The reaction mixture was stirred at 120 0C in a pressure tube for 2 hours.

The aqueous phase was removed and the c phase was d through a pad of celite and concentrated in vacuo. The ing crude material was puriﬁed by silica gel tography (60%EtOAc/Hexanes) to afford 140 mg of the desired product, 1913: 1H NMR (400 MHz, CDCl3) 5 8.51 (dt, J: 7.6, 3.8 Hz, 1H), 8.48 (s, 1H), 8.32 (d, J: 1.7 Hz, 1H), 8.12 (dd, J: 7.2, .7 Hz, 3H), 7.30 (d, J: 8.1 Hz, 2H), 4.99 (d, J: 10.1 Hz, 1H), 4.42 — 4.28 (m, 2H), 3.72 — 3.47 (m, 3H), 2.40 (s, 3H), 2.19 — 2.09 (m, 1H), 1.97 — 1.83 (m, 1H), 1.49 — 1.34 (m, 1H), 1.06 (s, 9H); LCMS nt 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, Retention Time = 3.53 minutes (M+H) 546.49.

The second diastereomeric 1,2-diol, 1903, was also reacted in the same fashion to produce the diastereomeric Suzuki product. 1933: 1H NMR (400 MHz, CDClg) 8 8.56 — 8.49 (m, 2H), 8.32 (dd, J: 2.8, 1.1Hz, 1H), 8.15 — 8.02 (m, 3H), 7.30 (d, J: 9.2 Hz, 2H), 5.21 — 5.12 (m, 1H), 4.27 (td, J: 9.7, 3.0 Hz, 1H), 3.93 — 3.74 (m, 2H), 3.55 (d, J: 7.7 Hz, 1H), 3.11 (s, 1H), 2.39 (s, 3H), 2.01 (m, 1H), 1.65 — 1.50 (m, 1H), 1.05 (s, 9H). LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, Retention Time = 3.54 minutes (M+H) 546.49.

Form3ti0n of (4R)—4-((5-ﬂu0r0(5-ﬂu0r0—lH-pyrrolo[2,3-b]pyridinyl)pyrimidin yl)3min0)—5,5-dimethylhex3ne—1,2-diol (70, 71) To a on of (4R)—4-[[5-ﬂuoro[5-ﬂuoro(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin yl]pyrimidinyl]amino]-5,5-dimethyl-hexane-1,2-diol, 1913, (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 e was stirred at room temperature for 5 minutes. The reaction e was d into EtOAc and aqueous saturated NaHC03 solution. The organic phase was dried over MgSO4, ﬁltered and concentrated in vacuo. The crude residue was puriﬁed Via silica gel chromatography (MeOH/CHZClz) followed by ative HPLC to afford 10 mg pure desired product: 1H NMR (400 MHz, d6-DMSO) 5 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, 1H), 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). LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, Retention Time = 1.76 minutes (M+H) 392.46.

The second diastereomeric 1,2-diol, 1933, was also reacted in the same fashion to produce the diastereomeric ﬁnal product: 1H NMR (400 MHz, CDC13) 8 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: 28.7, 9.4 Hz, 1H), 1.04 (s, 9H).

LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, Retention Time = 1.79 minutes (M+H) .

Pre arationo Com ounds 75 76 79 85 93 and 95 Synthetic Scheme 31 o o o o c FC3 FC3 b OH _a> DB _> iN\,\1 NH OEt of ._ CF3 ‘2‘0 ‘N/ \ 195a 196a 7“ INF 197a [Q (a) i. carbonyl diimidazole, CH2C12; ii. ium ethyl malonate, MgClz, DMAP, Eth, THF, CH3CN; (b) i. ammonium acetate, EtOH, reﬂux; ii. sodium cyanoborohydride, AcOH, EtOAc; iii. chloroﬂuoropyrimidine, 1PerEt, EtOH; (c) 5-ﬂuoro(p-tolylsulfonyl)—3-(4,4,5,5- tetramethyl-l,3,2-dioxaborolanyl)pyrrolo[2,3-b]pyridine, 7a, X-phos, Pd2(dba)3, K3P04, 2- methyl THF, H20, 135 OC, microwave; (d) LiOH, MeOH, 65 0C.

Formation of ethyl 3-0x0(1-(triﬂu0r0methyl)cyclopentyl)pr0pan0ate (195a).

To a on of 1-(triﬂuoromethyl)cyclopentanecarboxylic acid (1.30 g, 7.14 mmol) in dichloromethane (14 mL) was added carbonyl azole (5.46 g, 33.68 mmol). After stirring 5 hours at room temperature, the reaction was concentrated in vacuo to a residue.

In another ﬂask, 3-ethoxyoxo-propanoate (Potassium Ion) (2.03 g, 11.90 mmol) was mixed with dichloromagnesium (1.13 g, 11.90 mmol) and DMAP (72.65 mg, 0.59 mmol) in THF (23.13 mL) and acetonitrile (11.57 mL). After 3 hours, the above crude on in THF (10 mL) was added, followed by triethylamine (1.66 mL, 11.90 mmol). The reaction was allowed to stir at 25 0C for 8 hours. The crude product was isolated by extracting into ethyl acetate (2 x 100 mL) vs 1N HCl (100 mL), dried over sodium sulfate and concentrated in vacuo to afford 1.0 g of —124— the desired product as a yellow oil: 1H NMR (300 MHz, CDClg) 8 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.

Formation of (+/-)-ethyl hlor0ﬂu0r0pyrimidinylamin0)(1-(triﬂu0r0methyl)— cyclopentyl)propanoate (196a) A solution of ethyl 3-oxo(1-(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 0C, and acetic acid (0.338 mL, 5.946 mmol) and sodium cyanoborohydride (0.498 g, 7.928 mmol, 4 equiv) were added to the e. The reaction was allowed to warm to room temperature and stirred overnight. The reaction was quenched with aqueous ted 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-dichloroﬂuoro-pyrimidine (0.496 g, 2.973 mmol) and N,N—diisopropylethylamine base (2.0 mL). The reaction was reﬂuxed for 12 hours and then concentrated in vacuo. The residue was puriﬁed by silica gel chromatography ) yielding 84 mg of the desired product as a yellow oil: LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, Retention Time = 3.54 minutes (M+H) 384.40.

Formation of ethyl 3-(5-ﬂu0r0(5-ﬂu0r0t0syl—1H-pyrrolo[2,3-b]pyridin yl)pyrimidinylamin0)(1-(triﬂu0r0methyl)cyclopentyl)pr0pan0ate (197a) To a solution of c ethyl 3-(2-chloroﬂuoropyrimidinylamino)—3-(1- (triﬂuoromethyl)cyclopentyl)propanoate, 196a, (0.084 g, 0.219 mmol) in THF (10 mL) and water (1 mL) was added 5-ﬂuoro(p-tolylsulfonyl)(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)pyrrolo[2,3-b]pyridine, 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 ated for 15 minutes at 135 CC in a microwave. The resulting mixture was concentrated in vacuo to a brown oil which was d by silica gel chromatography (EtOAc/CHzClz) to afford 80 mg of the desired product as a pale yellow solid: LCMS Gradient -90%, 0.1% formic acid, 5 minutes, C18/ACN, Retention Time = 4.22 minutes (M+H) 638.42.

Formation of (+/-)(5-ﬂuoro-Z-(S-ﬂuoro-lH-pyrrolo[2,3-b]pyridinyl)pyrimidin o)—3-(1-(triﬂuoromethyl)cyclopentyl)pr0pan0ic acid (75) To a solution of racemic ethyl 3-(5-ﬂuoro(5-ﬂuorotosyl-1H—pyrrolo[2,3-b]pyridin- yrimidinylamino)(1-(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 temperature. 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 ed organic phases concentrated in vacuo to afford 16 mg of the desired product as a pale yellow solid: 1H NMR (300 MHz, d6-DMSO) 8 8.51 (s, H), 8.25 - 7.97 (m, 2 H), 7.58 - 7.42 (m, 2 H), 7.12 (d, J: 7.5 Hz, H), 4.35 (m, H), 2.85 (m, 2 H) and 1.27 - 0.70 (m, 8 H) ppm; LCMS Gradient , 0.1% formic acid, 5 minutes, C18/ACN, Retention Time = 2.55 minutes (M+H) 456.45.

The following analogs can be prepared in a r fashion as the procedure described above Compound 75: H 79 (+/-)-5,5,5-Triﬂu0r0(5-ﬂu0r0(5-ﬂu0r0-1H-pyrrolo[2,3-b]pyridinyl)pyrimidin ylamino)—4,4-dimethylpentanoic acid (79) 1H NMR (300 MHz, MeOD) 8 8.66 (d, J: 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, Retention Time = 2.22 minutes (M+H) 430.41.

H 76 (+/-)Fluor0((5-ﬂu0r0(S-ﬂuoro-lH-pyrrolo [2,3-b] pyridinyl)pyrimidin n0)—4,4-dimethylpentan0ic acid (76) 1H NMR (300 MHz, MeOD) 8 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: .3, 10.8 Hz, 1H), 1.07 (s, 6H); LCMS nt 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, (M+H) 394.

N , \ N\H_>—OH \ D N ﬁ 91 (R)((5-ﬂu0r0(5-ﬂu0r0-lH-pyrrolo [2,3-b]pyridinyl)pyrimidinyl)amino)—3-(1- methylcyclopr0pyl)pr0pan0ic acid (91) LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, (M+H) 374.

WO 19828 H 93 (+/-)((5-Flu0r0(5—ﬂu0r0—lH-pyrrolo [2,3-b] pyridinyl)pyrimidinyl)amino)—3-(1- (triﬂuor0methyl)cyclopropyl)pr0panoic acid (93) LCMS nt 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, Retention Time = 2.37 minutes (M+H) 428.49.

N/\/$*NH/ O FYr?\ N H 95 (+/-)(Bicyclo[2.2.1]heptanyl)(5-ﬂu0r0(5-ﬂu0r0-lH-pyrrolo[2,3-b]pyridin yl)pyrimidinylamin0)propanoic acid (95) 1H NMR (400 MHz, CDgOD) 5 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); LCMS Gradient 10-90%, 0.1% formic acid, 5 s, C18/ACN, Retention Time = 2.12 minutes (M+H) 414.28.

H 84 (+/-)Fluor0((5-ﬂu0r0(5-ﬂu0ro-1H-pyrrolo [2,3-b] pyridinyl)pyrimidin yl)amin0)(ﬂu0r0methyl)methylpentan0ic acid (84) 1H NMR (300 MHz, MeOD) 8 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), 4.72 - 4.23 (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); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, (M+H) 412. (+/-)((5-chlor0(5-ﬂu0r0-lH-pyrrolo ] nyl)pyrimidinyl)amin0)-4,4- dimethylpentanoic acid (85) Carboxylic acid, 203, was prepared in same fashion as carboxylic acid, 4, (see Synthetic Scheme 1) using 5-chloro(5-chloro(methylsulﬁnyl)pyrimidinyl)tosyl-1H-pyrrolo[2,3- b]pyridine instead of sulfoxide, 1: 1H NMR (400 MHZ, MeOD) 5 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); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, Retention Time = 2.1 minutes (M+H) 383.38.

Pre arationo Com ounds 77 78 83 86 and 94 tic Scheme 32 o H2N o H _a, 0E1 _. F‘S—NH QTQ\N_/N\‘Bo 205a 206a 7a 9”ng 951915780;\ \ NTS N N H H 207a 880” (a) NH4OAc, malonic acid, EtOH, reﬂux; (b) 2,4-dichloroﬂuoropyrimidine, iPerEt, THF, MeOH, 95 0C; (c) 5-ﬂuoro(p-tolylsulfonyl)(4,4,5,5-tetramethyl-1,3,2-dioxaborolan yl)pyrrolo[2,3-b]pyridine, K3PO4 X-Phos, Pd2(dba)3, 2-MeTHF, water, 120 0C; (d) 4N HCl, CH3CN, 65 0C; (e) LiOH, water, THF.

Formation of (+/-)-ethylamin0(1-methylcyclohexyl)pr0pan0ate (205a) A on 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 ethanol (5 mL) was heated at reﬂux for 4 hours. The solid was ﬁltered and washed with ethanol (10 mL). The ﬁltrate was concentrated in vacuo to give a thick oil that was diluted with CHZClz (50 mL). The precipitated solid was ﬁltered and the ﬁltrate was concentrated in vacuo to afford 4.3 grams of a yellow oil. Concentrated sulfuric acid (1.16 mL, 21.79 mmol) was added to a solution of the crude material in absolute l (25 mL) and the mixture was reﬂuxed for 12 hours. The solution was cooled to room temperature 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, Retention Time = 1.54 minutes (M+H) 214.14.

Formation of (+/-)-ethyl 3-(2-chlor0ﬂu0rropyrimidinylamin0)(1- methylcyclohexyl)pr0pan0ate (206a) A mixture of 2,4-dichloroﬂuoro-pyrimidine (1.83 g, 85.33 mmol), racemic 3- amino(1-methylcyclohexyl)propanoate, 205a, (2.34 g, 11.0 mmol) and MN- diisopropylethylamine (4.79 g, 27.50 mmol) in THF (40 mL) and methanol (10 mL) was heated at 95 0C for 3 hours. The solution was cooled to room temperature and the t was evaporated under reduced pressure. The crude residue was purified by silica gel tography (0-60% EtOAc/Hexanes gradient) to afford 620 mg of the desired product as a white foamy solid: 1H NMR (400 MHz, CDC13)5 7.80 (d, J: 2.6 Hz, 1H), 5.37 (m, 1H), 4.59 (m, 1H), 4.00 (q, 7.2 Hz, 2H), 2.62 (dd, J: 14.7, 3.8 Hz, 1H), 1.67(m,1H),1.17 (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, Retention Time = 3.69 minutes (M+H) 344.39.

Formation of ethyl 3-(5-ﬂu0r0(5-ﬂu0r0t0syl—1H—pyrrolo[2,3-b]pyridin yl)pyrimidin-4ylamin0)—3-(1- cyclohexyl)pr0pan0ate (207a) A solution of 5-ﬂuoro(p-tolylsulfonyl)(4,4,5,5-tetramethyl-1,3,2-dioxaborolan yl)pyrrolo[2,3-b]pyridine, 7a, (0.51 g, 1.22 mmol), racemic ethyl 3-(2-chloro ﬂuorropyrimidinylamino)(1-methylcyclohexyl)propanoate, 206a, (0.35 g, 1.02 mmol) and K3P04 (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 0C in a re vial for 4 hours.

The reaction mixture was cooled to room temperature, filtered and concentrated in vacuo. The residue was dissolved in EtOAc (50 mL) and washed with water. The c layer was dried (MgSO4), 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: 1H NMR (400 MHz, CDClg) 5 8.50 (m, 1H), 8.48 (s, 1H), 8.24 (d, J: 1.7 Hz, 1H), 8.01 (m, 3H), 7.20(m, 2H), 5.12 (m, 1H), 4.88 (m, 1H), 3.89(q, J: 7.4 Hz, 2H), 2.71 (dd, J: 14.5, 3.8 Hz, 1H), 2.39 ? 2.32 (m, 1H), 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, ion Time = 2.81 minutes (M+H) 599.19.

Formation of (+/-)-ethyl 3-(5-ﬂu0r0(5—ﬂu0r0-lH-pyrrolo[2,3-b]pyridinyl)pyrimidin ylamino)—3-(1-methylcyclohexyl)pr0pan0ate (77) To a solution of ethyl 3-(5-ﬂuoro(5-ﬂuorotosyl-1H—pyrrolo[2,3-b]pyridin yl)pyrimidin-4ylamino)(1- methylcyclohexyl)propanoate, 207a, (0.49 mg, 0.81 mmol) in CH3CN (3 mL) was added HCl (2.0 mL of 4M solution in dioxane, 8.1 mmol). The solution was heated at 70 0C for 3 hours and then cooled to room temperature. The solvent was removed under reduced pressure and the product was lized with s saturated NaHC03 solution. The precipitate was ted with EtOAc (3x10 mL). The solvent was dried (MgSO4), ﬁltered and concentrated in vacuo. The crude residue was ed by silica gel chromatography (0-70%EtOAc/Hexanes nt) to afford 230 mg of the desired product as an off-white solid: 1H NMR (400 MHz,CDC13)8 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, 1H), 5.13 (brs, 1H), 4.95 (t, J: 8.2 Hz, 1H), 3.84 (m, 2H), 2.72 (m, 1H), 2.38 (m, 1H), 1.67 - 1.15 (m, 10H), 0.94 (m, 3H); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, ion Time = 2.77 s (M+H) 444.36. 3-(5-ﬂu0r0(5-ﬂu0r0-lH-pyrrolo [2,3-b] pyridinyl)pyrimidinylamin0)(1- methylcyclohexyl)propan0ic acid (78) LiOH (0.118 mg, 4.927 mmol) was added to a solution of ethyl 3-(5-ﬂuoro(5-ﬂuoro- 1H—pyrrolo [2,3 -b]pyridin-3 -yl)pyrimidinylamino)-3 -(1 -methylcyclohexyl)-propanoate, 77, (0.23 g, 0.49 mmol) in water (5 mL) and THF (5 mL). The solution was stirred at 95 0C for 18 hours and then cooled to room temperature. The t was removed under reduced pressure.

The residue was diluted with water (10 mL) and neutralized with 2N HCl. The ing precipitate was extracted with EtOAc (3x10 mL). The organic phase was dried (MgSO4), ﬁltered and concentrated in vacuo to afford 210 mg of the desired product as an off-white solid: 1H NMR (400 MHz, CDgOD) 5 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); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, Retention Time = 2.20 s (M+H) 416.27. i o N/NH OH \ [\ NM 83 (+/-)(2-(5-Chlor0-lH-pyrrolo [2,3-b]pyridinyl)—5-ﬂu0r0pyrimidinylamin0)—3-(1- cyclohexyl)propan0ic acid (83) Compound 83 was synthesized in a manner similar to 3-(5-ﬂuoro(5-ﬂuoro-1H- pyrrolo[2,3-b]pyridinyl)pyrimidinylamino)(1-methylcyclohexyl)propanoic acid, 78, using 5 -chloro(p-tolylsulfonyl)-3 -(4,4,5 ,5 -tetramethyl- 1 ,3 ,2-dioxaborolanyl)pyrrolo [2,3 - b]pyridine instead of boronate ester, 7a: 1H NMR (400 MHz, MeOD) 5 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); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, Retention Time = 2.37 minutes (M+H) 442.36. .. o N/NH OH \ ]\ NHN 86 3-(1-Adamantyl)—3-[[5-ﬂu0r0(5-ﬂu0r0-1H-pyrr010[2,3-b]pyridinyl)pyrimidin yl]amin0]pr0pi0nic acid (86) nd 86 was synthesized in a manner similar to 3-(5-ﬂuoro(5-ﬂuoro-1H- pyrrolo[2,3-b]pyridinyl)pyrimidinylamino)(1-methylcyclohexyl)propanoic acid, 78, using adamantinecarbaldehyde as the ng material: 1H NMR (400 MHz, CDgOD) 5 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), 1.82 -1.49 (m, 12H); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, Retention Time = 2.40 minutes (M+H) 454.34.

..— O N /NH OH \ [\ NHN 94 (+/-)(1-Adamantyl)—3-[[2-(5-chlor0-1H-pyrr010[2,3-b]pyridinyl)—5-ﬂu0r0-pyrimidin yl]amin0]pr0pan0ic acid (94) Compound 94 was synthesized in a manner similar to 3-(1-Adamantyl)[[5-ﬂuoro(5- ﬂuoro-1H—pyrrolo[2,3-b]pyridinyl)pyrimidinyl]amino]propionic acid, 86, using 5-chloro (p-tolylsulfonyl)-3 -(4,4,5 ,5 -tetramethyl- 1 ,3 ,2-dioxaborolanyl)pyrrolo [2,3 -b]pyridine d of boronate ester, 73: 1H NMR (400 MHz, CDgOD) 8 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, 1H), 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); LCMS Gradient 10- 90%, 0.1% formic acid, 5 minutes, C18/ACN, Retention Time = 2.60 minutes (M+H) 470.27.

Pre aration 0 Com ound 68 tic Scheme 33 F F F ,N b — r Ni a / NH OMS N / NH N3 _, N / NH N H y \H H ‘H y 0' 7“\ C' 7\ 7°\ 75;,l 216a 217a or? —’FC ijHd NfgiNHNNJAOHN F /\ \OB\O \/N/\7\N 218a H N’ m\z/ 68 (a) NaNg, DMF, 70 0C; (b) propargyl alcohol, THF, toluene, 120 0C; (c) 5-ﬂuoro(p- tolylsulfonyl)(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)pyrrolo[2,3-b]pyridine, K3P04, X- Phos, Pd2(dba)3, 2-MeTHF, water, 120 0C; (d) 4N HCl, CH3CN, 65 0C.

Formation of (S)-N-(1-azido-3,3-dimethylbutanyl)—2-chloroﬂuoropyrimidinamine (216a) A mixture of (S)((2-chlor0ﬁuoropyrimidinyl)amino)-3,3-dimethylbutyl methanesulfonate, 75a, (2.37 g, 7.26 mmol) and sodium aZide (1.89 g, 29.07 mmol) in DMF (50 mL) was heated at 70 0C for 6 hours. The reaction mixture was cooled to room temperature and poured into water. The aqueous phase was extracted with EtOAc (2x 25 mL), dried (MgSO4), 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: 1H NMR (400 MHZ, CDClg) 8 7.86 (dd, J: 2.6, 1.1 HZ, 1H), 5.07 (m, 1H), 4.32-4.09 (m, 1H), 3.60 (dd, J: 12.8, 3.9 HZ, 1H), 3.34 (dd, J: 12.8, 7.6 HZ, 1H), 0.96 (m, 9H); LCMS Gradient 10-90%, 0.1% formic acid, 5 s, C18/ACN, Retention Time = 3.28 s (M+H) 273.14.

Formation of -(2-((2-chlorofluoropyrimidinyl)amino)-3,3-dimethylbutyl)—1H- 1,2,3-triazolyl)methanol (217a) A mixture of propynol (0.22 g, 3.85 mmol) and (S)-N-(1-aZid0-3,3-dimethylbutan- 2-chloroﬁu0ropyrimidinamine, 216a, (0.21 g, 0.77 mmol) in THF (4 mL) and toluene (4 mL) was heated in a pressure Vial at 120 0C for 8 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude product which contained two regioisomers was puriﬁed by silica gel chromatography (0-5% MeOH/CHzClz gradient) to afford 100 mg of desired regioisomer, 217a, as well as 70 mg of the minor regioisomer (5- hydroxymethyl triazole). 4-Hydr0xymethyl triazole somer 217a: 1H NMR (400 MHZ, CDClg) 5 7.71 (d, J = 2.6 HZ, 1H), 7.19 (s, 1H), 5.31 -5.16 (m, 1H), 4.86 (m, 1H), 4.79-4.60 (m, 2H), 4.44 (m, 1H), 1.07 (s, 9H); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, Retention Time = 2.26 minutes (M+H) 329.31.

Formation of (S)-(1-(2-((5-ﬂuoro(5-fluorotosyl-1H-pyrrolo [2,3-b]pyridin yl)pyrimidinyl)amino)-3,3-dimethylbutyl)—1H-1,2,3-triazolyl)methanol (218a) A solution of 5-ﬁu0r0(p-tolylsulfonyl)(4,4,5,5-tetramethyl-1,3,2-di0xab0rolan yl)pyrrolo[2,3-b]pyridine, 7a, (0.158 g, 0.380 mmol), (S)-(1-(2-((2-chloroﬁuoropyrimidin yl)amin0)-3,3-dimethylbutyl)—1H—1,2,3-triaZ01yl)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 ed under a stream of nitrogen for 30 minutes. X-Phos (0.008 g, 0.018 mmol) and Pd2(dba)3 (0.006 g, 0.006 mmol) were added and the on mixture was heated at 115 0C in a pressure Vial for 4 hours.

The reaction mixture was cooled to room temperature and ﬁltered. The e 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: 1H NMR (400 MHZ, CDClg) 5 8.37 , 8.33 (s, 1H), 8.21 (s, 1H), 8.03 (d, J: 8.4 HZ, 2H), 7.90 (d, J: 3.0 HZ, 1H), 5.37(m, 1H), 4.92 ? 4.83 (m, 1H), 4.78 - 4.69 (m, 2H), 4.44 (dd, J: 13.9, 11.3 HZ, 1H), 2.32 (s, 3H), 1.11 (s, 9H); LCMS Gradient 60- 98%, 0.1% formic acid, 7 minutes, N, Retention Time = 1.29 minutes (M+H) 583.33 Formation of -(2-((5-ﬂuoro(5-ﬂuoro-lH-pyrrolo[2,3-b]pyridinyl)pyrimidin yl)amino)—3,3-dimethylbutyl)—1H-1,2,3-triazolyl)methanol (68) To a solution of (S)-(1-(2-((5-ﬂuoro(5-ﬂuorotosyl-1H—pyrrolo[2,3-b]pyridin yl)pyrimidinyl)amino)-3,3-dimethylbutyl)-1H-1,2,3-triazolyl)methanol, 2183, (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 ng the reaction mixture at room temperature for 30 minutes, the mixture was diluted into aqueous saturated NH4C1 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% MGOH/CH2C12) to afford 41 mg of the desired product as an off-white solid: 1H NMR (400 MHz, CDgOD) 5 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, 1H), 1.2 (s, 9H); LCMS Gradient 10-90%, 0.1% formic acid, 5 s, C18/ACN, Retention Time = 1.90 minutes (M+H) 429.26.

Examgle 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/P1V8/3 4), at a low multiplicity of infection (approximate MOI=0.005), for 72 hours at 37°C, and cell viability was measured using ATP detection (CellTiter Glo, 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 trations of test compounds were evaluated, in quadruplicate, for e, over a range from approximately 20 uM to 1 nM. Dose-response curves were prepared using standard 4-parameter curve ﬁtting methods, and the concentration of test compound resulting in 50% cell tion, or cell survival equivalent to 50% of the uninfected wells, was reported as the ICso.

A second cell-based antiviral assay was developed that depends on the lication of virus-speciﬁc RNA molecules in the infected cells, with RNA levels being directly measured using the branched-chain DNA (bDNA), hybridization method (Wagaman et al, 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 t is ed. This assay is stopped earlier that the CPE assay, usually after 18-36 hours, while all the target cells are still . Viral RNA is quantitated by ization of well lysates to speciﬁc ucleotide probes ﬁxed to wells of an assay plate, then ampliﬁcation of the signal by ization with additional probes linked to a er enzyme, ing to the kit manufacturer’s instructions (Quantigene 1.0, Panomics, Inc.). Minus-strand viral RNA is measured using probes designed for the consensus type A hemagglutination gene. l wells containing cells and virus were used to deﬁne the 100% viral replication level, and esponse 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) mented with 2mM L-glutamine, l,000U/ml penicillin, l,000 ug/ml streptomycin, 10 mM HEPES, and 10% fetal bovine . 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 ul. On the day of the assay, adherent cells were washed with three changes ofDMEM containing lug/ml TPCK-treated trypsin, without fetal bovine serum. Assays were ted with the addition of 30 TCID50 of virus and test compound, in medium containing 1 ug/ml TPCK- d trypsin, in a ﬁnal volume of 50 ul. Plates were incubated for 72 hours at 37°C in a humidiﬁed, 5% C02 atmosphere. Alternatively, cells were grown in DMEM + fetal bovine serum as above, but on the day of the assay they were trypsinized, washed 2 times and suspended in serum-free EX-Cell MDCK cell 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, t the need for washing.

Inﬂuenza virus, strain A/PIVS/34 (tissue culture adapted) was obtained from ATCC (VR— 1469). Low-passage virus stocks were prepared in MDCK cells using standard 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 s using the Karber method.

Mean IC50 values (mean all) for certain speciﬁc compounds are summarized in Table l: A: IC50 (mean all) < 0.3 uM; B 0.3 uM S IC50 (mean all) 5 3.3 uM; C ICso (mean all) > 3.3 uM.

Mean EC50 values (mean all) for certain compounds are also summarized in Table l: A: EC50 (mean all) < 0.3 uM; B 0.3 uM S EC50 (mean all) 5 3.3uM; C EC50 (mean all) > 3.3 uM.

Mean EC99 values (mean all) for certain compounds are also summarized in Table l: —134— A: EC99 (mean all) < 0.3 uM; B 0.3 uM S EC99 (mean all) 5 3.3uM; C EC99 (mean all) > 3.3 uM.

Some exemplary data are as follows: Compound 1: IC50=0.006 uM, EC50=0.009 uM, EC99=0.0094 uM; Compound 2: IC50=0.004 uM, EC50=0.009 uM, .0063 uM; Compound 6: IC50=0.004 uM, EC50=0.015 uM, EC99=0.082 uM; Compound 69: IC50=2.31 uM, EC50=0.8 uM, EC99=8.4 uM; Compound 76: IC50=0.423 uM, EC50=0.25 uM, EC99=l.4 uM.

For comparison purposes, some nds disclosed in W02005/095400 were also tested against inﬂuenza Virus using the bDNA and MDCK cell protection assays described above, and their mean ICso, ECso, and EC99 values are ized in Table 2.

Table l: ICso, ECso, NMR and LCMS Data of Compounds of Invention. bDNA bDNA Compound LCMS nos. RT 12.25 (s, 1H): 12.0 (bs, 1H): 8.8 (s, 1H): 8.3 (s, 1H): 8.25 (s, 1H); 8.1 (s, 2 07 1H): 7.45 (d, 1H); 4.75 (t, 1H); 2.5 (m, ' 2H), 1.0 (s, 9H). 12.25(s,1H): 12.0 (bs, 1H): 8.6 (d, 1H): 8.3 (s, 1H): 8.2 (s, 1H); 8.15 (s, 1 92 1H): 7.45 (d, 1H); 4.8 (t, 1H); 2.5 (m, ' 2H), 1.0 (s, 9H). 2.06 1.93 1H NMR (300 MHz, MeOD) d 8.60 (d, J = 7.7 Hz, 2H), 8.33 (s, 1H), 5.08 (t, J = 17.2 Hz, 1H), 2.93 (dd, J = 16.3, 2.8 2.17 Hz, 1H), 2.73 (dd, J =16.3, 10.6 Hz, 1H), 1.08 (s, 9H). -l35- 1H NMR (400 MHz, CDCI3) d 8.31 (d, J = 6.4 Hz, 1H), 8.06 (s, 1H), 7.06 (t, J 6 A = 9.7 Hz, 1H), 4.58 (s, 2H), 2.80 (d, J 394.19 2.92 = 13.2 Hz, 1H), 2.29 (dd, J = 13.3, 8.7 Hz,1H),098(s,9H) 1H NMR (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 7 A Hz, 1H), 5.04 (dd, J = 11.0, 2.9 Hz, 2.99 1H), 2.81 (dd, J = 15.4, 3.0 Hz,1H), 2.60 (dd, J =15.4,11.0 Hz, 1H), 0.99 (diastereomer A ZJ ofCompound 9 A 2.04 1H NMR (400 MHz, MeOD) ? 8.60 (s, 1H), 8.44 (s, 1H), 8.23 (d, J = 5.3 Hz, 1° A 2'02 1H), 8.16 (s, 1H), 5.15 (m, 1H), 3.39 (d, J: 8 Hz, 2H), 1.08(s 9H). 1H NMR (400 MHz, MeOD) ? 8.44 (s, 1H), 8.34 (dd, J = 9.2, 2.6 Hz, 1H), 11 A 8.22 (d,J=5.7 Hz, 1H), 8.13(s, 1H), 1.91 .16 (d, J = 4.1 Hz, 1H), 3.46 - 3.33 m, 3H 1.10 , d, J = 19.9 Hz, 10H. 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 = 12 A 8.7 Hz, 1H), 2.78 (qd, J = 15.9, 6.6 2.37 Hz, 2H), 1.85 - 1.57 (m, 6H), 1.48 (dd, J = 11.8, 6.0 Hz, 1H), 1.36 (dt, J = )Hz,1H),111(s,3H) 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 = 13 A 8.7 Hz, 1H), 2.78 (qd, J =15.9,6.6 3.21 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. (diastereomer B 402.38 2.12 ofCompound 16 A 390.35 2.03 WO 19828 17 B B C 389.97 2.03 1H NMR (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=9.5 Hz, 1H), 3.14 .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). 1H NMR (400 MHz, CDCI3) ? 9.75 (s, 1H), 8.12 (d, J = 9.3 Hz, 1H), 7.94 (s,1H), 7.73 (s, 2H), 7.87 (brs, 1H), 1.98 4.93 - 4.78 (m, 2H), 3.08 (m, 1H), 2.78 (s, 3H), 0.99 (m, 9H). 1H NMR (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, 1H), 4.39 (t, J = 10.2 Hz, 2.14 1H), 2.38 - 2.07 (m, 2H), 1.99 - 1.92 (m, 1H), 1.80- 1.84 (m, 1H), 1.00 (d, J = 20.2 Hz, 9H). 1H NMR (400 MHz, MeOD) ? 8.68 (dd, J = 9.8, 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), 2.80 - 2.47 (m, 1H), 0.88 - 1H NMR (400 MHz, MeOD) ? 8.85 (d, J = 9.3,1H), 8.47 (s, 1H), 8.34 (m, 2H), 5.28 (d, J = 10.4 Hz, 1H), 3.55 1.98 (dt, J = 14.5, 13.0 Hz, 2H), 1.20 - 1.03 (m, 9H). 1H NMR (400 MHz, DMSO) ? 12.23 (s, 1H), 8.44 (d, J = 7.8 Hz, 1H), 8.32 - 8.08 (m, 3H), 7.18 (d, J = 9.8 Hz, 1H), 4.38 (t, J =10.4 Hz, 1H), 4.00 - 2.41 3.87 (m, 2H), 2.41 - 2.13 (m, 2H), 2.08- 1.93 (m, 1H), 1.87 - 1.85 (m, 1H 1.08 -0.84 , m, 12H. 1H NMR (400 MHz, CDCI3) ? 10.27 (brs, 1H), 8.25 (d, J = 9.4 Hz, 1H), 8.17 (s, 1H), 8.11 (s, 1H), 7.23 (d, J = .3 Hz, 1H), 5.20 (d, J = 9.8 Hz, 1H), 3.08 4.41 (t, J = 7.4 Hz, 1H), 4.09 (d, J = 11.3 Hz, 1H), 3.82 - 3.58 (m, 1H), 0.99 (d, J = 19.5 Hz, 9H). 1H NMR (400 MHz, MeOD) ? 9.26 (dd, J = 9.0, 2.2 Hz, 1H), 8.43 (s, 1H), A A A 8.22 (s, 1H), 7.66 - 7.35 (m, 1H), 5.00 436 2.54 (m, 1H), 3.45 - 3.17 (m, 2H), 1.03(m, 9H). 1H NMR (400 MHz, CDCI3) ? 9.68 (s, 1H), 6.45 - 8.33 (m, 1H), 6.17 (d, J = 2.8 Hz, 1H), 7.66 (s, 1H), 7.36 (d, J = .3 Hz, 1H), 6.47 (d, J = 4.9 Hz, 1H), 2.97 .11 (d, J = 7.6 Hz, 1H), 4.90 (d, J = .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. 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, 3.12 1H), 4.97 (brs, 1H), 3.33 (m, 1H), 2.70 (s, 6H), 0.95 (m, 9H). 3.12 1H NMR (400 MHz, MeOD) ? 6.71 (dd, J = 9.7, 2.6 Hz, 1H), 8.37 (s, 1H), 8.20 (s, 1H), 7.57 (d, J = 10.9 Hz, 3 05 1H), 5.08 (d, J = 6.6 Hz, 1H), 3.54 - ' 3.40 (m, 2H), 3.32 (m, 5H), 3.15 (t, J = 5.4 Hz, 2H).1.03 (s,9H) 3.27 1H NMR (400 MHz, CDCI3) ? 10.77 (brs, 1H), 8.25 (d, J = 6.4 Hz, 1H), 8.07 , 8.03 (s,1H), 7.88 (s, 1H), 1 83 .59 (brs, 1H), 4.36 (t, J = 8.3 Hz, 2H), 4.11 (m, 1H), 3.72 (m, 2H), 1.06 (s, 9H).

WO 19828 1H NMR (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 = 33 A A A 10.2 Hz, 1H), 4.80 (d, J = 9.6 Hz, 1H), 439.3 2.25 3.38 (m, 3.18- 2.96 (m, 3H),1 , 1H), 1.35- 1.12 (m, 3H), 1.08- 0.90 (m, 9H . .1H NMR (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 34 A Hz, 2H), 4.92 (m, 1H), 4.81 (m, 1H), 453.44 2.42 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).

A 469.18 2.11 36 B 390.29 1.98 1H NMR (300 MHz, d6-DMSO) ? 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 37 c 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 . 1H NMR (300 MHz, d6-DMSO) ? 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, 38 C C 1H), 7.47 (d, J = 8.4 Hz, 1H), 6.77 - 425.03 2.11 6.69 (m, 1H), 4.88 (t, J = 9.1 Hz, 1H), 3.49 - 3.36 (m, 1H), 3.36 - 3.28 (m, J = 10.5 Hz, 1H), 2.55 (t, J = 5.6 Hz, 1H NMR (400 MHz, CDCI3) ? 9.89 (s, 1H), 8.07 (d, J = 8.9 Hz, 1H), 7.90 (s, 1H), 7.68 (s, 2H), 4.96 (t, J = 9.8 Hz, 39 A A B 1H), 4.76 (d, J = 9.8 Hz, 1H), 3.60 453.19 2.22 (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). 40 A A B 467.2 2.36 41 386.39 3.09 1 H NMR (300 MHz, CDCI3) ? 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, J = 8.4 Hz, 1H), 5.32 (d, J = 6.6 Hz, 1H), 42 426.31 3.27 4.63 (t, J = 9.4 Hz, 1H), 2.69 (d, J = .3 Hz, 1H), 2.34 (dd, J = 12.6, 9.6 Hz, 1H), 1.92 - 1.37 (m, 6H), 1.32 - 1.24 m,1H,1.20-1.06 m,3H. 1H NMR (300 MHz, CDCI3) ? 11.16 (s, 1H), 6.70 (s, 1H), 6.04 (d, J = 3.2 Hz, 1H), 7.96 (s, 1H), 7.67 (s, 1H), 43 426.47 2.49 .02 (d, J = 6.1 Hz, 1H), 4.60 (t, J = 9.6 Hz, 1H), 2.61 (d, J = 9.9 Hz, 1H), 2.34 (t, J = 11.3 Hz, 1H), 1.14 (s, 9H). 1H NMR (400 MHz, DMSO) ? 12.26 (s, 2H), 8.55 (d, J = 9.7 Hz, 1H), 6.19 (dd, J = 8 Hz, 3H), 7.48 (d, J 44 374.02 2.1 = 6.1 Hz, 1H), 4.79 (s, 1H), 2.58 (dd, J = 206,122 Hz, 2H), 1.65 (ddd, J = 29.4, 26.5, 21.1 Hz, 7H). 1H NMR (300 MHz, CDCI3) ? 10.42 (s, 1H), 8.47 (dd, J = 9.3, 2.7 Hz, 1H), 6.13 (d, J = 11.2 Hz, 1H), 6.10 (s, 1H), 6.04 (d, J = 3.2 Hz, 1H), 4.69 (d, J = 9.0 Hz, 1H), 4.26 (t, J = 9.9 Hz, 45 362.39 1.89 1H), 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 1H NMR (400 MHz, CDCI3) ? 9.38 (s, 1H), 8.53 (d, J = 6.9 Hz, 1H), 8.16 (m, 46 2H), 8.06 (s, 1H), 5.09 - 4.89 (m, 1H), 410.19 2.03 3.42 - 3.31 (m, 1H), 3.11 (m, 1H), 2.84 (s, 3H), 1.00 (s, 9H). 1H NMR (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), 47 6.60 (d, J = 7.2 Hz, 1H), 5.05 (d, J = 358.02 2.17 .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) —140— 1H NMR (400 MHz, MeOD) ? 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 = 48 35902 2'12 .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). 1H NMR (300 MHz, MeOD) ? 8.73 (t, J = 5.0 Hz, 1H), 8.44 (s, 1H), 8.37 - 8.22 (m, 2H), 4.69 (dd, J = 9.9, 2.9 49 Hz, 1H), 4.11 (dd, J = 11.5, 3.1 Hz, 364.44 2.1 1H), 3.83 (dd, J =11.4, 10.0 Hz,1H), 3.32 (dt, J = 3316 Hz, 1H), 1.12 (s, 9H). (diastereomer of 402.45 1.98 Compounds 51 and 52) ereomer of 2.06 Compounds 50 and 52) (diastereomer of 2.16 Compounds 50 and 51) 1H NMR (400 MHz, DMSO) ? 12.57 (s, 1H), 9.40 (s, 1H), 8.88 (s, 1H), 53 8.40 (d, J = 18.7 Hz, 2H), 8.34 (s, 2.5 1H), 3.93 (s, 1H), 3.52 (s, 1H), 1.20 (s, 9H). 1H NMR (400 MHz, DMSO) ? 12.65 (s, 1H), 12.41 (s, 1H), 9.28 (s, 1H), 54 8.86 (s, 1H), 8.65 (s, 1H), 8.30 (d, J = 2.92 3.5 Hz, 2H), 3.97 - 3.70 (m, 1H), 3.51 (s, 1H), 1.18 (s, 9H) 55 400.46 1.94 —141— WO 19828 1 H NMR (400 MHz, DMSO) ? 12.65 (s, 1H), 9.43 (s, 1H), 9.15 (s, 1H), 56 8.44 (d, J = 4.7 Hz, 1H), 8.41 - 8.29 393.32 2.7 (m, 2H), 3.93 (s, 1H), 3.54 (s, 1H), 1.19 (d, J = 20.0 Hz, 9H). 1H NMR (400 MHz, CDCI3) ? 8.05 (d, J = 7.9 Hz, 1H), 7.81 (d, J = 2.1 Hz, 1H), 7.63 (s, 1H), 7.55 (s, 1H), 5.87 (t, 57 J = 54.9 Hz, 1H), 5.03 (t, J = 10.4 Hz, 475.23 2.26 1H), 4.86 (m, 1H), 3.68 (brs, 1H), 3.43 (m, 2H), 3.19 (m, 1H), 0.94 (s, 9H). 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, 58 493.31 2.37 1H), 5.07 (t, J = 10.6 Hz, 1H), 4.77 (m, 1H), 3.45 (m, 1H), 3.16 -2.99 (m, 1H), 0.97 - 0.86 (m, 9H). 1H NMR (300 MHz, MeOD) ? 8.54 (s, 1H), 8.50 - 8.18 (m, 3H), 7.18 (dd, J = 59 15.7, 7.1 Hz, 1H), 6.08 (dd, J = 15.7, 2.21 1.3 Hz, 1H), 5.21 (t, J = 22.5 Hz, 1H), 1.12 (s, 9H). 60 2.01 1H NMR (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 = 61 2.23 .3 Hz, 1H), 3.92 (dd, J = 300,145 Hz, 2H), 3.77 - 3.57 (m, 1H), 1.10 (s, 9H). 62 416.04 2.15 63 389.06 2.08 —142— 1H NMR (400 MHz, MeOD) ? 8.60 - 8.52 (m, 1H), 8.46 (s, 1H), 8.32 (d, J = .3 Hz, 2H), 5.16 (m, 2H), 4.00 (d, J = 64 438.25 1.93 14.7 Hz, 1H), 3.80 (d, J =14.7 Hz, 1H), 3.59(d, J = 13.9, 1H), 1.12 (s, 9H). 65 416.07 2.11 1H NMR (400 MHz, CDCI3) ? 10.15 (s, 1H), 8.49 (dd, J = 9.3, 2.6 Hz, 1H), 66 8.16 (s, 1H), 8.10 (d, J = 2.6 Hz, 1H), (diastereomer 8.06 (d, J = 3.0 Hz, 1H), 5.30 (d, J = A 430.47 2.37 of Compound 15.0 Hz, 1H), 5.19 -5.10 (m, 1H), 67) 4.32 - 4.24 (m, 1H), 4.23 - 4.17 (m, 1H), 2.37 (dt, J = 14.9, 3.4 Hz, 1H), 1.85-1.71 m,2H,1.09 s,9H. 1H NMR (400 MHz, CDCI3) ? 9.40 (s, 1H), 8.47 (dd, J = 9.3, 2.7 Hz, 1H), 67 8.15 (s, 1H), 8.10 (d, J = 2.7 Hz, 1H), (diastereomer 7.99 (d, J = 2.8 Hz, 1H), 5.54 (s, 1H), A 430.44 2.42 of Compou nd 4.84 (d, J = 7.5 Hz, 1H), 4.23 (t, J = 66) 9.9 Hz, 1H), 3.91 (s, 1H), 2.07 - 1.97 (m, 1H), 1.62 (t, J = 13.0 Hz, 1H), 1.01 (s, 9H). 1H NMR (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, 68 429.26 1.9 1H), 5.08 (m, 1H), 5.00 - 4.90 (m, 1H), 4.74 (s, 2H), 4.60 (m, 1H), 1.2 (s, 9H). 1H NMR (300 MHz, MeOD) ? 8.59 - 8.39 (m, 2H), 8.32 (t, J = 5.3 Hz, 2H), 69 4.59 (d, J = 9.5 Hz, 2H), 2.21 (s,1H), 426.09 1.81 1.79 (dddd, J = 28.6, 23.0, 13.2, 6.9 Hz, 3H), 1.11 (d, J = 9.5 Hz, 9H). 1H NMR (400 MHz, DMSO) ? 8.61 (dd, J = 9.9, 2.6 Hz, 1H), 8.26 (s, 1H), 70 8.18 (s, 1H), 8.11 (d, J = 4.1 Hz, 1H), ereomer 4.66 (d, J = 10.4 Hz, 1H), 4.43 (s, A 392.46 1.76 of Compound 1H), 4.29 (d, J = 4.1 Hz, 1H), 4.04 (s, 71) 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). —143— 1H NMR (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 = (diastereomer .0 Hz, 1H), 3.75 - 3.56 (m, 2H), 392.46 1.79 of Compound 3.48 (dd, J = 11.0, 6.3 Hz, 1H), 2.08 - 1.97 (m, 1H), 1.75 (dt, J = 26.7, 9.4 Hz, 1H), 1.04 (s, 9H). 1H NMR (400 MHz, CDCI3) ? 9.99 (s, 1H), 8.60 (dd, J = 9.4, 2.7 Hz, 1H), 6.26 (s, 1H), 6.20 (d, J = 2.6 Hz, 1H), 72 6.10 (d, J = 3.2 Hz, 1H), 5.06 (t, J = (diastereomer 12.3 Hz, 1H), 4.28 (dd, J = 9.6, 7.2 1.93 of nd Hz, 1H), 3.96 (d, J = 5.7 Hz, 1H), 2.71 73) (s, 1H), 1.97 (ddd, J = 14.2, 5.8, 2.9 Hz, 1H), 1.66 ? 1.58 (m, 1H), 1.28 (dd, J = 6.5, 5.5 Hz, 4H), 1.04 (d, J = .1 Hz, 9H . 1H NMR (400 MHz, CDCI3) ? 10.81 (s, 1H), 8.47 (dd, J = 9.3, 2.7 Hz, 1H), 73 6.14 (s, 1H), 8.05 (dd, J = 6.4, 2.9 Hz, (diastereomer 2H), 4.95 (s, 1H), 4.61 (d, J = 8.3 Hz, 2.01 of Compound 1H), 4.31 ? 4.14 (m, 1H), 3.72 (dd, J = 72) 8.9, 6.0 Hz, 1H), 1.63 ? 1.70 (m, 1H), 1.46 ? 1.32 (m, 1H), 1.24 ?1.11 (m, 4H), 0.98 (s, 9H). 1H NMR (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 = 6.3, 6.0 Hz, 1H), 2.90 - 74 1.94 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), 0.47 - 0.33 (m, 1H), 0.27 (ddd, J = 21.3,12.8,10.1Hz,1H). 75 2.55 1H NMR (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), 76 4.30 (d, J = 47.9 Hz, 2H), 3.63 (d, J = 1.87 18.2 Hz, 1H), 3.31 (dt, J = 33,16 Hz, 3H), 2.83 (dd, J = 15.3, 3.3 Hz,1H), 2.63 (dd, J =15.3, 10.8 Hz,1H), 1.07 —144— 2012/049097 1H NMR (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, 1H), 77 5.13 (brs, 1H), 4.95 (t, J = 8.2 Hz, 444.36 2.77 1H), 3.84 (m, 2H), 2.72 (m, 1H), 2.38 (m, 1H), 1.87 - 1.15 (m, 10H), 0.94 (m, 3H). 1H NMR (400 MHz, MeOD) ? 8.78 (dd, J = 9.7, 2.7 Hz, 1H), 8.18 (s, 2H), 7.99 (d, J = 4.1 Hz, 1H), 5.20 (d, J = 78 A 9.9 Hz, 1H), 2.88 - 2.89 (m, 1H), 2.53 416.27 2.2 (dd, J =14.7, 11.0 Hz, 1H), 1.78 - 1.58 (m, 2H), 1.53 (m, 4H), 1.29 (m, 4H), 1.02 (s, 3H).

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 79 (m, H), 2.97 (s, H), 2.92 (s, H), 2.86 - 430.41 2.22 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 1H NMR (400 MHz, CDCI3) ? 8.88 (dd, J = 9.2, 2.8 Hz, 1H), 8.53 (d, J = 9.6 Hz, 2H), 8.43 (s, 1H), 8.38 (s, 1H), 80 406.09 2.41 .27 - 5.13 (m, 1H), 3.80 (s, 3H), 3.02 - 2.87 (m, 2H), 1.94 (s, 1H), 1.08 (s, 9H). 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, 1H), 5.88 (s, 1H), 5.32 - 5.18 81 440.45 2.35 (m, 1H), 4.71 - 4.32 (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), 1.28 ,1.08- 1.04 t, J = 7.1Hz,3 H. 1H NMR (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 82 460.29 3.08 (m, 1H), 3.98 - 3.85 (m, 2H), 2.73 (dd, J = 14.3, 3.8 Hz, 1H), 2.38 (m, 1H), 1.89 - 1.23 (m, 10H), 0.93 (t, J = 1H NMR (400 MHz, MeOD) ? 9.05 (d, J = 2.1 Hz, 1H), 8.39 - 8.24 (m, 2H), 8.18 (d, J = 4.9 Hz, 1H), 5.23 (d, J = 83 432.36 2.37 .4 Hz, 1H), 2.88 (d, J = 15.8 Hz, 1H), 2.85 (m, 1H), 1.58 (m, , 7H), 1.37 (m, 3H), 1.05 (s, 3H). —145— WO 19828 1H NMR (300 MHz, MeOD) ? 8.67 (dd, J = 9.6, 2.8 Hz, 1H), 8.16 (m, 2H), 6.04 (d, J = 4.0 Hz, 1H), 5.36 84 (dd, J = 10.6, 3.2 Hz, 1H), 4.72 - 4.23 412.43 1.9 (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 . 1H NMR (400 MHz, MeOD) ? 8.68 (dd, J = 9.3, 2.7 Hz, 1H), 8.47 (s, 1H), 85 8.38 (s, 1H), 8.32 (s, 1H), 5.17 (dd, J 392.1 2.23 = 9.6, 3.5 Hz, 1H), 2.87 (m, 2H), 1.06 (s, 9H). 1H NMR (400 MHz, MeOD) ? 6.75 (dd, J = 9.7, 2.7 Hz, 1H), 6.16 (s, 2H), 8.00 (d, J = 4.2 Hz, 1H), 2.81 (dd, J = 86 45434 2'4 .2, 3.1 Hz, 1H), 2.55 (dd, J = 15.2, .8 Hz, 1H), 2.00 (m, 3H), 1.62 - 1.49 (m, 12H). 87 389.13 2.02 88 388.36 2.01 89 383.38 2.1 1H NMR (300 MHz, DMSO) ? 8.68 (s, 1H), 8.43 (d, J = 14.1 Hz, 2H), 8.23 9° 3725 1'8 (3, 1H), 4.96 (s, 2H), 2.88 - 2.55 (m, 4H), 2.45 (s, 3H), 1.00 (s, 9H). 91 374.42 1.96 92 B B C 374.42 1.94 2.37 1H NMR (400 MHz, MeOD) ? 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 = 11.8 Hz, 1H), 2.88 (dd, J = 18.0, 2.8 2.8 Hz, 1H), 2.85 (dd, J =15.9, 11.0 Hz, 1H), 2.01 (s, 3H), 1.77 (dd, J = 27.9, 11.9 Hz, 12H . 1H NMR (400 MHz, MeOD) ? 8.82 (dd, J = 9.3, 2.8 Hz, 1H), 8.48 (t, J = .4 Hz, 1H), 8.32 (s, 1H), 8.29 (d, J = 2'12 .5 Hz, 1H), 5.42 (dd, J = 10.0, 3.4 Hz, 1H), 2.84 (m, 2H), 2.18 (s, 1H), 1.85 (m, 4H), 1.39 (m, 8H). 2.79 1H NMR (300 MHz, MeOD) 6 8.95 (d, J = 2.3 Hz, 1H), 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: 2.5 164,107 Hz, 1H), 1.10 (s, 9H); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, Retention Time = 2.79 min, M+H 407.37 Table 2: ICso, ECso, NMR and LCMS Data of nds of W02005/095400 MDCKceII bDNA bDNA Compounds IC50(uM) EC50(uM) EC99(uM) —147— C1 CkTﬁ‘K\ N H' >20 ((3) l | C3 _} >20 (C) 3.38 (C) 9.37 (C) C4 2.33 (B) 6.4 (C) >137 (C) Example 3: In Vivo Assay For efﬁcacy studies, Balb/c mice (4-5 weeks of age) were challenged with 5x103 TCID50 in a total volume of 50 ul by intranasal by intranasal instillation (25 ul/nostril) under general anesthesia (Ketamine/Xylazine). Uninfected controls were nged with tissue e media (DMEM, 50 ul total volume). 48 hours post infection mice began treatment with Compounds 1 and 2 at 30 mg/kg bid 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 ed.

Table 3. Inﬂuneza Therapeutic Mouse Model (Dosing @ 48 hours post infection with 30 mg/kg BID X 10 days) Compounds t Survival Percent Weight Loss WBP (Penh; Day 6)2 (Day 8)1 1 100 26.6 1.88 Average weight loss for untreated controls on day 8 is 30-32%.

Average Penh scores for untreated controls on study day 6 or 7 is 2.2-2.5, and for uninfected mice is ~0.35-0.45. e 4: Synergystic/Antagonism Analyses For synergy/antagonism analysis, test compounds were evaluated in a three day MDCK cell CPE-based assay, infected with to Rico/8/34 at an MOI of 0.01, in combination ments with either the neuraminidase tors oseltamivir carboxylate or zanamivir, or the polymerase inhibitor T-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 Bliss independence method (Macsynergy, Pritchard and Shipman, 1990). See, e.g., Prichard, MN. and C. Shipman, Jr., A three-dimensional model to e drag-drag interactions. Antiviral Res, 1990. 14(4-5): p. 181-205. This rd method involves testing different concentration combinations of tors in a checkerboard fashion and a synergy volume is calculated by comparing the observed response surface with the expected result 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 te synergy. Synergy volumes of zero represent vity and negative synergy volumes represent antagonism n the agents.

Table 4. S ner /Anta onism Data Combination experiments using the Bliss Independence (Macsynergy) Method Bliss Independence Synergy Volume, Result 95% Confidence Compound 1 + oseltamivir 360 strong synergy Compound 1 + favipiravir 1221 strong synergy Compound 1 +zanamivir 231 strong synergy Compound 2 + oseltamivir 250 strong synergy —149— Compound 2 + favipiravir 100 synergy Compound 2 + zanamivir 220 strong synergy Compound 14 + oseltamivir 545 strong synergy nd 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 87 + oseltamivir 348 strong synergy Compound 87 + favipiravir 412 strong synergy Compound 87 + zanamivir 2.7 insignificant All references provided herein are incorporated herein in its entirety by reference.

As used herein, all abbreviations, symbols and conventions are consistent with those used in the contemporary scientiﬁc ture. See, e. g., Janet S. Dodd, ed., The ACS Style Guide: A Manual for Authors and Editors, 2nd Ed., Washington, DC: American al Society, 1997.

It is to be understood that while the invention has been described in conjunction with the ed ption thereof, the foregoing description is intended to illustrate and not limit the scope of the invention, which is deﬁned by the scope of the ed claims. Other aspects, advantages, and ations are within the scope of the following claims.

Claims

1. A compound of Formula (IV): X2 R4 H R5 Z2 N R1 R3 X1 Z1 NH (IV) or a pharmaceutically acceptable salt thereof, wherein: X1 is –F, –Cl, –CF3, –CN, or –CH3; X2 is –H, –F, or –Cl; Z1 is N or CH; Z2 is N or CR0; R0 is –H, –F, or –CN; R1, R2, and R3 are each independently –CH3, –CH2F, –CF3, –C2H5, –CH2CH2F, or –CH2CF3; R4 and R5 are each independently –H; Q is R; and R is –H or C1-4 alkyl; provided that the compound of Formula (IV) is not compound (2) or a pharmaceutically acceptable salt f.

2. A compound of Formula (V): or a pharmaceutically acceptable salt thereof, wherein: X1 is –F, –Cl, –CF3, –CN, or –CH3; X2 is –H, –F, or –Cl; Z1 is N or CH; Z2 is N or CR0; R0 is –H, –F, or –CN; R1, R2, and R3 are each independently –CH3, –CH2F, –CF3, –C2H5, –CH2CH2F, or –CH2CF3; R4 and R5 are each independently –H; Q is –C(O)OR; and R is –H or C1-4 alkyl; provided that the compound of Formula (V) is not nd (2) or a pharmaceutically acceptable salt f.

3. The compound of any one of claims 1 or 2, wherein X1 is –F or –Cl.

4. The compound of any one of claims 1 or 2, wherein X2 is –F or –Cl.

5. The compound of any one of claims 1 or 2, wherein Z1 is CH.

6. The compound of any one of claims 1 or 2, wherein Z1 is N.

7. The compound of any one of claims 1 or 2, wherein Z2 is N, C-F, or C-CN.

8. The compound of any one of claims 1 or 2, wherein R1, R2, and R3 are each independently –CH3 or –C2H5.

9. The compound of any one of claims 1 or 2, wherein R is –H.

10. The compound of claim 1, wherein the compound of a (IV) is selected from 1 3 4 5 6 7 9 16 17 18 43 47 48 76 79 80 81 84 85 89 90 96 97 or a pharmaceutically acceptable salt thereof.

11. A pharmaceutical composition comprising a nd of Formula (IV) X2 R4 H R5 Z2 N R1 R3 X1 Z1 NH (IV) or a pharmaceutically acceptable salt thereof, wherein: X1 is –F, –Cl, –CF3, –CN, or –CH3; X2 is –H, –F, or –Cl; Z1 is N or CH; Z2 is N or CR0; R0 is –H, –F, or –CN; R1, R2, and R3 are each ndently –CH3, –CH2F, –CF3, –C2H5, 2F, or –CH2CF3; R4 and R5 are each independently –H; Q is –C(O)OR; and R is –H or C1-4 alkyl; provided that the compound of Formula (IV) is not compound (2) or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier, adjuvant or vehicle.

12. A pharmaceutical composition comprising a compound of Formula (V): or a pharmaceutically acceptable salt thereof, n: X1 is –F, –Cl, –CF3, –CN, or –CH3; X2 is –H, –F, or –Cl; Z1 is N or CH; Z2 is N or CR0; R0 is –H, –F, or –CN; R1, R2, and R3 are each independently –CH3, –CH2F, –CF3, –C2H5, –CH2CH2F, or –CH2CF3; R4 and R5 are each independently –H; Q is –C(O)OR; and R is –H or C1-4 alkyl; provided that the nd of Formula (V) is not compound (2) or a pharmaceutically acceptable salt thereof; and a pharmaceutically able carrier, vehicle, or adjuvant.

13. The pharmaceutical composition of any one of claims 11 or 12, wherein X1 is –F or –Cl.

14. The pharmaceutical composition of any one of claims 11 or 12, wherein X2 is –F or –Cl.

15. The pharmaceutical composition of any one of claims 11 or 12, wherein Z1 is CH.

16. The pharmaceutical composition of any one of claims 11 or 12, wherein Z1 is N.

17. The pharmaceutical composition of any one of claims 11 or 12, wherein Z2 is N, C-F, or C-CN.

18. The pharmaceutical composition of any one of claims 11 or 12, wherein R1, R2, and R3 are each independently –CH3 or –C2H5.

19. The pharmaceutical ition of any one of claims 11 or 12, wherein R is –H.

20. The pharmaceutical composition of claim 11, wherein the compound of Formula (IV) is selected from 1 3 4 5 6 7 9 16 17 18 43 47 48 76 79 80 81 84 85 89 90 96 97 or a pharmaceutically acceptable salt f.

21. A method of inhibiting the replication or reducing the number of influenza viruses in an in vitro biological sample, comprising the step of stering to said in vitro biological sample an effective amount of a compound of Formula (IV) X2 R4 H R5 Z2 N R1 R3 X1 Z1 NH (IV) or a pharmaceutically acceptable salt thereof, wherein: X1 is –F, –Cl, –CF3, –CN, or –CH3; X2 is –H, –F, or –Cl; Z1 is N or CH; Z2 is N or CR0; R0 is –H, –F, or –CN; R1, R2, and R3 are each independently –CH3, –CH2F, –CF3, –C2H5, –CH2CH2F, or –CH2CF3; R4 and R5 are each independently –H; Q is –C(O)OR; and R is –H or C1-4 alkyl; provided that the compound of Formula (IV) is not compound (2) or a pharmaceutically acceptable salt thereof.

22. A method of inhibiting the replication or reducing the number of influenza viruses in an in vitro biological sample, sing the step of administering to said in vitro biological sample an effective amount of a compound of Formula (V) or a pharmaceutically acceptable salt thereof, wherein X1 is –F, –Cl, –CF3, –CN, or –CH3; X2 is –H, –F, or –Cl; Z1 is N or CH; Z2 is N or CR0; R0 is –H, –F, or –CN; R1, R2, and R3 are each independently –CH3, –CH2F, –CF3, –C2H5, –CH2CH2F, or –CH2CF3; R4 and R5 are each independently –H; Q is –C(O)OR; and R is –H or C1-4 alkyl; provided that the compound of a (V) is not compound (2) or a pharmaceutically able salt thereof.

23. The method of any one of claims 21 or 22, wherein X1 is –F or –Cl.

24. The method of any one of claims 21 or 22, wherein X2 is –F or –Cl.

25. The method of any one of claims 21 or 22, wherein Z1 is CH.

26. The method of any one of claims 21 or 22, wherein Z1 is N.

27. The method of any one of claims 21 or 22, wherein Z2 is N, C-F, or C-CN.

28. The method of any one of claims 21 or 22, wherein R1, R2, and R3 are each independently –CH3 or –C2H5.

29. The method of any one of claims 21 or 22, wherein R is –H.

30. The method of claim 21, wherein the compound of Formula (IV) is selected from 1 3 4 5 6 7 9 16 17 18 43 47 48 76 79 80 81 84 85 89 90 96 97 or a pharmaceutically acceptable salt f.

31. Use of a compound of Formula (IV) X2 R4 H R5 Z2 N R1 R3 X1 Z1 NH (IV) or a pharmaceutically acceptable salt f, wherein X1 is –F, –Cl, –CF3, –CN, or –CH3; X2 is –H, –F, or –Cl; Z1 is N or CH; Z2 is N or CR0; R0 is –H, –F, or –CN; R1, R2, and R3 are each independently –CH3, –CH2F, –CF3, –C2H5, –CH2CH2F, or R4 and R5 are each independently –H; Q is –C(O)OR; and R is –H or C1-4 alkyl; provided that the compound of Formula (IV) is not compound (2) or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for treating or preventing influenza virus infection in a patient.

32. Use of a compound of Formula (V) or a pharmaceutically acceptable salt thereof, wherein X1 is –F, –Cl, –CF3, –CN, or –CH3; X2 is –H, –F, or –Cl; Z1 is N or CH; Z2 is N or CR0; R0 is –H, –F, or –CN; R1, R2, and R3 are each independently –CH3, –CH2F, –CF3, –C2H5, –CH2CH2F, or R4 and R5 are each independently –H; Q is –C(O)OR; and R is –H or C1-4 alkyl; provided that the compound of a (V) is not compound (2) or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating or preventing influenza virus infection in a patient.

33. The use of any one of claims 31 or 32, wherein X 1 is –F or –Cl.

34. The use of any one of claims 31 or 32, wherein X 2 is –F or –Cl.

35. The use of any one of claims 31 or 32, wherein Z 1 is CH.

36. The use of any one of claims 31 or 32, wherein Z 1 is N.

37. The use of any one of claims 31 or 32, wherein Z 2 is N, C-F, or C-CN.

38. The use of any one of claims 31 or 32, wherein R 1, R2, and R3 are each independently – CH3 or –C2H5.

39. The use of any one of claims 31 or 32, wherein R is –H.

40. The use of claim 30, n the compound of Formula (IV) is selected from 1 3 4 5 6 7 9 16 17 18 43 47 48 76 79 80 81 84 85 89 90 96 97 or a pharmaceutically acceptable salt thereof.

41. A method of preparing a compound of Formula (IV) X2 R4 H R5 Z2 N R1 R3 X1 Z1 NH (IV) or a pharmaceutically able salt thereof, wherein X1 is –F, –Cl, –CF3, –CN, or –CH3; X2 is –H, –F, or –Cl; Z1 is N or CH; Z2 is N or CR0; R0 is –H, –F, or –CN; R1, R2, and R3 are each independently –CH3, –CH2F, –CF3, –C2H5, –CH2CH2F, or –CH2CF3; R4 and R5 are each independently –H; Q is –C(O)OR; and R is –H or C1-4 alkyl; provided that the compound of Formula (IV) is not compound (2) or a pharmaceutically acceptable salt thereof, comprising the steps of: (i) reacting a compound having the formula wherein L2 is a halogen, with compound B , wherein G is trityl, to form a compound ; and (ii) deprotecting the G group of the compound synthesized in step (i) under suitable conditions to form a nd of Formula (IV) or a pharmaceutically able salt thereof.

42. A compound according to claim 1 or claim 2, substantially as herein described with reference to any one of the examples and/or figures.

43. A pharmaceutical composition according to claim 11 or claim 12, substantially as herein bed with reference to any one of the examples and/or figures.

44. A method of inhibition according to claim 21 or claim 22, substantially as herein described with reference to any one of the examples and/or figures.

45. A use ing to claim 31 or claim 32, substantially as herein bed with reference to any one of the examples and/or figures.

46. A method of preparation according to claim 41, substantially as herein described with reference to any one of the examples and/or figures.