AU2016204286A1 - Inhibitors of influenza viruses replication - Google Patents

Abstract

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

Description

INHIBITORS OF INFLUENZA VIRUSES REPLICATION ATTORNEY DOCKET NO. :VPI/09-103 WO

RELATED APPICATIONS

[00100] This application claims priority to U.S. Provisional Application No. 61/87,713, filed on June 17, 2009, and to U.S. Provisional Application No. 61/287,781, filed on December 18, 2009. The entire teachings of these applications are incorporated herein by reference.

BACKGROUND OF THE INVENTION

[00101] Influenza spreads around the world in seasonal epidemics, resulting in the deaths of hundreds of thousands annually - millions 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.

[00102] Influenza 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 persons. Transmission might also occur through direct contact or indirect contact with respiratory secretions, such as touching surfaces contaminated with influenza virus and then touching the eyes, nose or mouth. Adults might be able to spread influenza to others from 1 day before getting symptoms to approximately 5 days after symptoms start. Young children and persons with weakened immune systems might be infectious for 10 or more days after onset of symptoms.

[00103] Influenza viruses are RNA viruses of the family Orthomyxoviridae, which comprises five genera: Influenza virus A, Influenza virus B, Influenza virus C, lsavirus and Thogoto vims.

[00104] 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 human influenza pandemics. The type A viruses are the most virulent human pathogens among the three influenza types and cause the most severe disease. The influenza A virus can be subdivided into different serotypes based on the antibody response to these viruses. The serotypes that have been confirmed in humans, ordered by the number of known human pandemic deaths, are: H1N1 (which caused Spanish influenza in 1918), H2N2 (which caused Asian Influenza in 1957), H3N2 (which caused Hong Kong Flu in 1968), H5N1 (a pandemic threat in the 2007-08 influenza season), H7N7 (which has unusual zoonotic potential), H1N2 (endemic in humans and pigs), H9N2, H7N2 , H7N3 and H10N7.

[00105] The Influenza virus B genus has one species, influenza B virus. Influenza B almost exclusively infects humans and is less common than influenza A. The only other animal known to be susceptible to influenza B infection is the seal. This type of influenza 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. However, influenza B mutates enough that lasting immunity is not possible. This reduced rate of antigenic change, combined with its limited host range (inhibiting cross species antigenic shift), ensures that pandemics of influenza B do not occur.

[00106] 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.

[00107] Influenza A, B and C viruses are veiy similar in structure. The vims particle is 80-120 nanometers in diameter and usually roughly spherical, although filamentous forms can occur. Unusually for a virus, its genome is not a single piece of nucleic acid; instead, it contains seven or eight pieces of segmented negative-sense RNA. The Influenza A genome encodes II proteins: hemagglutinin (HA), neuraminidase (NA), nucleoprotein (NP), Ml, M2, NS1, NS2(NEP), PA, PB1, PB1-F2 and PB2.

[00108] HA and NA are large glycoproteins on the outside of the viral particles. HA is a lectin that mediates binding of the vims to target cells and entry of the viral genome into the target cell, while NA is involved in the release of progeny vims from infected cells, by cleaving sugars that bind the mature viral particles. Tlius, 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 antibody responses to HA and NA, forming the basis of the H and N distinctions (vide supra) in, for example, H5N1.

[00109] Influenza produces direct costs due to lost productivity and associated medical treatment, as well as indirect costs of preventative measures. In the United States, influenza is responsible for a total cost of over $10 billion per year, while it has been estimated that a future pandemic could cause hundreds of billions of dollars in direct and indirect costs.

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

[001X0] Current treatment options for influenza 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 elderly, or in people that have asthma, diabetes, or heart disease. However, it is possible to get vaccinated and still get influenza. The vaccine is reformulated 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 infected just before vaccination and get sick with the veiy strain that the vaccine is supposed to prevent, as the vaccine takes about two weeks to become effective.

[00111] Further, the effectiveness of these influenza vaccines is variable. Due to the high mutation rate of the virus, a particular influenza vaccine usually confers protection for no more than a few years. A vaccine formulated for one year may be ineffective in the following year, since the influenza virus changes rapidly over time, and different strains become dominant.

[00112] Also, because of the absence of RNA 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 influenza vRNA. Hence, nearly every newly-manufactured influenza virus is a mutant—antigenic drift. The separation of the genome into eight separate segments of vRNA allows mixing or reassortment of vRNAs if more than one viral line has infected a single cell. The resulting rapid change in viral genetics produces antigenic shifts and allows the virus to infect new host species and quickly overcome protective immunity.

[00113] Antiviral drugs can also be used to treat influenza, with neuraminidase inhibitors being particularly effective, but viiuses can develop resistance to the standard antiviral drugs.

[00114] Thus, there is still a need for drugs for treating influenza infections, such as for drugs with expanded treatment window, and/or reduced sensitivity to viral titer.

SUMMARY OF THE INVENTION

[00115] The present invention generally relates to methods of treating influenza, to methods of inhibiting the replication of influenza viruses, to methods of reducing the amount of influenza viruses, to compounds and compositions that can be employed for such methods.

[00116] In one aspect, the present invention is directed to a method of inhibiting the replication of influenza viruses in a biological sample or in a patient. In one embodiment, the method comprises administering to said biological sample or patient an effective amount of a compound represented by Structural Formula (IA):

(IA), or a pharmaceutically acceptable salt thereof, wherein: Z1 is -R*, -F, -Cl, ~CN, -OR*, -C02R*, -N02, or -CON(R*)2; Z2 is -R*, -OR*, -C02R*, -NR*2, or -CON(R*)2; Z3 is -H, -OH, halogen (e.g., -Cl or -Br), -NH2; -NH(Ci-C4 alkyl); -N(Ci-C4 alkyl)?,, -0(Ci-C4 alkyl), or Ci-Ce alkyl that is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, and -0(Ci-C4 alkyl); R1 is -H or Ci-Ce alkyl; R2 is -H; -F; -NH2; -NH(Ci-C4 alkyl); -N(C[-C4 alkyl)2; -C=N-OH; cyclopropyl that is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, -OCH3, and -CH3; or Ci-C4 alkyl that is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, and -0(Ci-C4 alkyl); and R3 is -H, -Cl, -F, -OH, -0(CrC4 alkyl), -NH2, -NH(CrC 4 alkyl), -N(C1-C4alkyl)2, -Br, -CN, or Ci-C4 aliphatic that is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(Ci-C4 alkyl), -N(Cj-C4 alkyl)2, -OCOfA-G, alkyl), -CO(C,-C4 alkyl), -C02H, -C02(Ci-C4 alkyl), and Ci-C4 alkoxy; R4 is: i)

wherein ring T is a C3-C10 non-aromatic carbocycle optionally substituted with one or more instances of JA, or a 3-10 membered non-aromatic heterocycle optionally substituted with one or more instances of JB, or ring T and R9 optionally form a non-aromatic C5-C10 membered carbocycle optionally substituted with one or more instances of JA or 5-10 membered non-aromatic heterocycle optionally substituted with one or more instances of JB; ii)

wherein ring J is a 3-10 membered non-aromatic heterocycle optionally substituted with one or more instances of JB; or iii)

wherein ring D is a 4-10 membered non-aromatic heterocycle optionally substituted with one or more instances of JD1; and each of JA and JB is independently selected from the group consisting of halogen, cyano, oxo, -NCO, and Q'-R5; or optionally two JA and two JB, respectively, together with the atom(s) to which they are attached, independently form a 4-8 membered ring (e.g., spiro ring or fused ring) that is optionally substituted with one or more instances of Jm; Q1 is independently a bond, -0-, -S-, -NR’-, -C(O)-, -C(=NR>, -C(=NR)NR-, -NRC(=NR)NR-, -CO2-, -OC(O)-, -C(0)NR’-, -C(0)NRC(0)0- -NRC(0)NRC(0)0--NRC(O)-, -NRC(0)NR’-, -NRC02- -0C(0)NR’- -S(O)-, -S02-, -S02NR’--NRSO,™ or -NRSO2NR’-, -P(0)(0R)0-, -0P(0)(0Ra)0-, -P(0)20-, -C02S02-, or -(CR^Vy1-; Y1 is independently a bond, -0-, -S-, -NR-, -C(0)~, -C(=NR)-, -C(=NR)NR-, -NRC(=NR)NR-„ -CO2-, -OC(O)-, -C(0)NR’-, -C(0)NRC(0)0-, -NRC(0)NRC(0)0--NRC(O)- -NRC(0)NR’-, -NRC02-, -0C(0)NR’-, -S(O)-, -S02- -S02NR’-, -NRS02- -NRS02NR’-, -P(0)(0R)0-, -0P(0)(0R°)0-, -P(0)20-, or -C02S02-; R5 is: i) -H; ii) a Ci-C6 aliphatic group optionally substituted with one or more instances of JC1; iii) a C3-C10 non-aromatic carbocycle, or a 6-10 membered carbocyclic atyd group, each optionally and independently substituted with one or more instances of JC1; or iv) a 4-10 membered non-aromatic heterocycle, or a 5-10 membered heteroaryl group, each optionally and independently substituted with one or more instances of JDI; or R5, together with Q1, optionally forms a 4-8 membered, non-aromatic ring optionally substituted with one or more instances of JE1; and R6 and R7 are each independently -H or C1-C6 alkyl optionally substituted with one or more substitutents selected from the group consisting of halogen, cyano, hydroxy, oxo, amino, carboxy, Ci-Cc alkoxy, Ci-Ce haloalkoxy, Ci-Ce aminoalkoxy, Ci-C6cyanoalkoxy, Ci-C6 hydroxyalkoxy and C2-C6 alkoxyalkoxy, or optionally R6 and R7, together with the carbon atom to which they are attached, form a cyclopropane ring optionally substituted with one or more instances of methyl; R9 is independently -H, halogen, cyano, hydroxy, amino, carboxy, Ci-Cg alkyl, Ci-Ce haloalkyl, Ci-C6 cyanoalkyl, C2-C6 alkoxyalkyl, Ci-Ce aminoalkyl, Ci-C6hydroxyalkyl, Ci-Cs carboxyalkyl, Ct-C6 alkoxy, Ci-C6 haloalkoxy, Ct-C6aminoalkoxy, Ci-C6cyanoalkoxy, Ci-Ce hydroxyalkoxy and C2-C6 alkoxy alkoxy; R13 and R14 are each independently -H, halogen, or Ct-C6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo, hydroxy, oxo, amino, carboxy, Ci-Ce alkoxy, Cj-Cg haloalkoxy, Ct-Ce aminoalkoxy, Ci-C6cyanoalkoxy, Ci-Ce hydroxyalkoxy, and C2-C6 alkoxyalkoxy; optionally, R13 and R14, together with the carbon atom to which they are attached, form a cyclopropane ring optionally substituted with one or more instances of methyl; R and R’ are each independently ~H or Cj-C6 alkyl optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, amino, carboxy, C|-C<-, alkoxy, Cj-Ce haloalkoxy, Ci-Ce aminoalkoxy, Ci-C6cyanoalkoxy, C1 -Cchydroxyalkoxy and C2-Ce alkoxyalkoxy; or optionally R\ together with R5 and the nitrogen atom to which they are attached, forms a 5-7 membered non-aromatic heterocycle optionally substituted with one or more instances of JD1; R* is independently: i)-H; ii) a Ci-Ce alkyl group optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, amino, carboxy, Ci-Cs non-aromatic carbocycle, 5-6 membered non-aromatic heterocycle, phenyl, 5-6 membered heteroaryl, -0(Ci-Ce alkyl), and -C(0)(CrCe-alkyl); wherein each of said alkyl groups in -CkCi-Cf, alkyl), and -C(O)CCi-Ce-alkyl) is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(Ci-C4 alkyl), -N(Ci-C4 alkyl)2, -OCO(Cs-C4 alkyl), -CO(Ci-C4 alkyl), -C02H, -C02(Ci-C4 alkyl), and C1-C4 alkoxy; and wherein each of said carbocycle, heterocycle, phenyl, and hcteroaryl is independently and optionally substituted with one or more instances of JE1; or iii) a Cj-Cs non-aromatic carbocycle, or a 4-8 membered non-aromatic heterocycle, each of which is independently and optionally substituted with one or more instances of JE1; and each of JC1 and JDI is independently selected from the group consisting of halogen, cyano, oxo, Ra, -ORb, -SRb, -S(0)Ra, -S02Ra, -NRbRc, -C(0)Rb, -C(=NR)Rc, -C(=NR)NRbRc, -NRC(=NR)NRbRc, -C(0)0Rb,.....0C(0)Rh, -NRC(0)Rb, -C(0)NRbRc, -NRC(0)NRbRc, -NRC(0)0Rb, -OCONRbRc, -C(0)NRC02Rb, -NRC(0)NRC(0)0Rb, -C(0)NR(0Rb), -S02NReRb, -NRS02Rb, -NRS02NRcRb, -P(0)(0Ra)2, -0P(0)(0Ra)2, -P(0)20Ra and -C02S02Rb, or optionally, two JC1 and two JD1, respectively, together with the atom(s) to which they are attached, independently form a 4-8-membered ring that is optionally substituted with one or more instances of JE1; each JE1 is independently selected from the group consisting of halogen, cyano, hydroxy, oxo, amino, carboxy, amido, Ci-Ce alkyl, -0(Ci-C6 alkyl), and -C(0)(Ci-C6-alkyl), wherein each of said alkyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(Ci-C4 alkyl), -N(C,-C4 alkyl)2, -OCO(CrC4 alkyl), -CO(Ci-C4 alkyl), -C02H, -C02(Ci-C4 alkyl), and Ci-C4 alkoxy; and

Ra is independently: i) a Ci-C6 aliphatic group optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, amino, carboxy, amido, -0(C,-C6 alkyl), -C(0)(Ci-C6-alkyl), C3-Cs non-aromatic carbocycle, 4-8 membered non-aromatic heterocycle, 5-10 membered heteroaryl group, and 6-10 membered carbocyclic aryl group; wherein each of said alkyl groups for the substituents of the Ci-Ce aliphatic group represented by Ra is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(Ci-C4 alkyl), -N(Ci-C4 alkyl)2, -OCO(Ci-C4 alkyl), -CO(Cr C4 alkyl), -C02H, -C02(Ct-C4 alkyl), and C1-C4 alkoxy; and wherein each of said carbocycle, heterocycle, heteroaryl and carbocyclic aryl groups for the substituents of the Ci-Ce aliphatic group represented by Ra is optionally and independently substituted with one or more instances of JE1; ii) a C2-Cs non-aromatic carbocycle, or a 4-8 membered non-aromatic heterocycle, each of which is optionally and independently substituted with one or more instances of JE1; or iii) a 5-10 membered heteroaryl, or 6-10 membered carbocyclic aryl group, each of which is optionally and independently substituted with one or more instances of JE1; and

Rb and Rc are each independently Ra or -H; or optionally, Rb and R°, together with the nitrogen atom(s) to which they are attached, each independently form a 5-7 membered nonaromatic heterocycle optionally substituted with one or more instances of JE1; p is independently 1,2,3 or 4; t is 0, 1 or 2; j is 1 or 2; and z is 1 or 2.

[00117] In another embodiment, the method comprises administering to said biological sample or patient an effective amount of a compound represented by Structural Formula (I):

:d, or a pharmaceutically acceptable salt thereof, wherein: R1 is -H; R2 is -H, -CHj, -NH2, -NH(Ci-C4 alkyl), or -N(CrC4 alkyl)2; R4 is; i) a C3-Cio non-aromatic carbocycle optionally substituted with one or more instances of JA; ii) a 4-10 membered non-aromatic heterocycle optionally substituted with one or more instances of JB; or iii) a Ci-C6 aliphatic group optionally substituted with one or more substituents independently selected from the group consisting of Jc; a C3-C8 non-aromatic carbocycle, or a 6-10 membered carbocyclic aryl group, each optionally and independently substituted with one or more instances of JA; and a 5-10 membered heteroaryl group, or a 410 membered non-aromatic heterocycle, each optionally and independently substituted with one or more instances of JB; each of JA and JB is independently selected from the group consisting of halogen, cyano, oxo, -NCO, andQ’-R5; or optionally two JA and two JB, respectively, together with the atom(s) to which they are attached, independently form a 5-7 membered ring that is optionally substituted with one or more instanced of JE1;

Jc is independently selected from the group consisting of halogen, cyano, oxo, -OR5, -SR5, -NR’R5, -C(0)R5, -C02R5, -OC(0)R5, -C(0)NR’R5, -C(0)NRC(0)0R5, -NRC(0)NRC(0)0R5, -NRC(0)R5, -NRC(0)NR’R5, -NRC02R5, -OC(0)NR’R5, -S(0)R5, -S02R5, -S02NR’R5, -NRS02R5, and -NRS02NR’R5; Q1 is independently a bond, -O- -S-, -NR’-, -0(0)-, -C(=NR)-, -C02-, -00(0)-, -C(0)NR’~, -C(0)NRC(0)0-, -NRC(0)NRC(0)0- -NRC(O)-, -NRC(0)NR’-, -NRC03-, -0C(0)NR’-, -S(0)-, -S02-, -S02NR’- -NRSCb- or -NRS02NR\ or -(CRfiR7)p-Y1-; Y'! is independently a bond, -0-, -S-, -NR’-, -0(0)-, -C(=NR)-, -C02-, -00(0)-, -C(0)NR’-, -C(0)NRC(0)0- -NRC(0)NRC(0)0- -NRC(O)--NRC(0)NR’-, -NRC02- -0C(0)NR-, -S(0)-, -S02-, -S02NR-, -NRS02-, or -NRS02NR’-; R5 is: i) -H; ii) a Ci-Ce aliphatic giOup optionally substituted with one or more instances of JCI; iii) a C3-C8 non-aromatic carbocycle, or a 6-10 membered carbocyclic aryl group, each optionally and independently substituted with one or more instances of JC1; or iv) a 4-8 membered non-aromatic heterocycle, or a 5-10 membered heteroaryl group, each optionally and independently substituted with one or more instances of JD1. Optionally, R5, together with Q1, optionally forms a 5-7 membered, non-aromatic ring optionally substituted with one or more instances of JE1; each of JC1 and JD1 is independently selected from the group consisting of halogen, cyano, oxo, Ra, -0Rb, -SRb, -S(0)Ra, -S02Ra, -NRbR°, -C(0)Rb, -C(0)0Rb, -0C(0)Rb, -NRC(0)Rb, -C(0)NRbRc, -NRC(0)NRbRc, -NRC(0)0Rb, -OCONRbRc, -C(0)NRC02Rb, -NRC(0)NRC(0)0Rb, -C(0)NR(0Rb), -S02NRcRb, -NRS02Rb, -NRS02NR°Rb, and -P(0)(0Rj)2-, or optionally, two JC1 and two JD!, respectively, together with the atoms to which they are attached, independently form a 5-7-membcrcd ring that is optionally substituted with one or more instances of JE1, and fused to the respective ring to which they are attached; and each of Z1, Z2, R3, R6, R7, R, R', R*, JE1, Ra, Rb, Rc and p is independently as described above for Structural Formula (IA).

[00118] hr another embodiment, the present invention is directed to a method of reducing the amount of influenza viruses in a biological sample or in a patient. The method comprises administering to said biological sample or patient an effective amount of a compound represented by Structural Formula (1) or Structural Formula (1A), each and independently as described above.

[00119] In yet another embodiment, the present invention is directed to a method of treating or preventing influenza in a patient, comprising administering to said patient an effective amount of a compound represented by Structural Formula (I) or Structural Formula (IA), each and independently as described above.

[00120] In yet another embodiment, the present invention is directed to a compound represented by Structural Formula (IA) or a pharmaceutically acceptable salt thereof: or a pharmaceutically acceptable salt thereof, wherein: R1 is -H, Ci-Co alkyl, -S(0)2-R”, or -C(0)0R”; or alternatively R1 is -H or Ci-C6 alkyl; R4 is:

ring A is a C3-C!0 non-aromatic carbocycle optionally further substituted with one or more instances of JA, or heterocyle optionally further substituted with one or more instances of JB; rings B and C are each independently a 4-10 membered, non-aromatic heterocycle optionally and independently further substituted with one or more instances of JG; ring D is a 4-10 membered, non-aromatic heterocycle optionally substituted with one or more instances of JD!; or ring A and R8 optionally form a non-aromatic, 5-10 membered, bridged carbocycle or heterocycle, or ring A and R9 optionally form a non-aromatic, 5-10 membered, bridged carbocycle or heterocycle, or ring A and R11 optionally form a non-aromatic, 5-10 membered, bridged carbocycle or heterocycle, wherein each carbocycle is optionally further substituted with one or more instances of JA, and wherein each heteroocycle is optionally further substituted with one or more instances of J8; and Q2is independently a bond, -Ο-, -S-, -NR-, -C(O)-, -C(=NR)-, -C(=NR)NR-, -NRC(=NR)NR-, -CO2-, -OC(0)-, -C(0)NR-, -C(0)NRC(0)0- -NRC(0)NRC(0)0-, -NRC(O)-, -NRC(0)NR-, -NRC02- -OC(0)NR-, -S(O)-, -S02-, -N(R)S02-, -S02N(R)-, -NRSO2NR-, -P(0)(0R)0-, -0P(0)(0Rn)0-, -P(0)20-, -C02S02-, or -(CR6R7)p-Y1-; Q3 is independently a bond, -C(O)-, -C(=NR)-, -C(=NR)NR-, -NRC(=NR)NR-, -C02-, -C(0)NR-, -S02-, -S02N(R)-, -C(0)NRC(0)0- or -(CRcR7),-Y1-; R” is independently: i) a Ci-Ce-alkyl optionally substituted with one or more substituents selected independently from the group consisting of halogen, cyano, hydroxyl, -NH2, -NH(Ci-C6 alkyl), -NfCi-Ce alkyl)2, Ci-Cealkoxy, Ci-Cg haloalkoxy, Ci-Ce aminoalkoxy, Ci-Ce cyanoalkoxy, Ci-Ce hydroxyalkoxy, and C2-C6 alkoxyalkoxy; or ii) aC3-Cf, carbocyclic group, a 5-6 membered heteroaryl group, or a phenyl group, each optionally and independently being substituted with one ore more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, nitro, -NH2, -NHfCi-CV, alkyl), -N(Ci-Ce alkyl)2, Ci-Cg alkyl, Ci-Ce haloalkyl, C]-Cc cyanoalkyl, Ci-Ce-hydroxyalkyl, C2-Ce-alkoxyalkyl, Ci-Ce-aminoalkyl, Ci-Cealkoxy, Ci-C6 haloalkoxy, Ci-C6aminoalkoxy, Cr C6 cyanoalkoxy, Ci-Cs-hy droxy alkoxy, and C2-C6 alkoxyalkoxy; each of Z1, Z2, Z3, Ql, Q2, Q3, Y1, R2, R3, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R, R', R*, JA, JB, JC1, JD1, JE1, Ra, Rb, Rc and p is independently as described above for Structural Formula (IA) for the method of inhibiting the replication of influenza viruses; n and m are each independently 0 or 1 when rings A and B are 3-6-membered; or n and m are each independently 0,1 or 2 when rings A and B are 7-10-membered; k is 0, 1 or 2; x and y are each independently 0, 1 or 2; z is 1 or 2; and provided that ifY1 is a bond, then R5 is neither-H nor a Ci-Cs aliphatic group; and provided that if each Q2 and Q3 independently is a bond, then R5 is neither -H nor a Cj-Cg aliphatic group.

[00121] In yet another embodiment, the present invention is directed to a compound represented by Structural Formula (I) or a pharmaceutically acceptable salt thereof, wherein: the values of the variables of Structural Formula (I) are as described below: R1 is -Η, C]-C6 alkyl, -S(0)2-R”, or-C(0)OR”; or alternatively R1 is -H or Cj-C6 alkyl. R4 is:

ring A is a C3-Cg non-aromatic carbocycle optionally further substituted with one or more instances of JA, or heterocycle optionally further substituedd with one or more instances of JB; rings B and C are each independently a 4-8 membered, non-aromatic heterocycle optionally and independently further substituted with one or more instances of JB; ring D is a 4-8 membered, non-aromatic heterocycle optionally substituted with one or more instances of Jm; R” is independently: i) a Ci-Ce-alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxyl, -NH2, -NH(Ci-Cs alkyl), -N(Ci-C6 alkyl)2, Ci-C6alkoxy, Ci-Cfi haloalkoxy, C,-C6 aminoalkoxy, Ci-Cs cyanoalkoxy, Ci-Ce hydroxyalkoxy and C2-CG alkoxyalkoxy; or ii) a C3-Ce carbocyclic group, 5-6 membered heteroaryl group, or phenyl group, each optionally and independently being substituted with one ore more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, nitro, -NH2, -NH(C|-Cc alkyl), -N(Ci-C6 alkyl)2, CrC6 alkyl, C,-C6 haloalkyl, C,-C6 cyanoalkyl, Ci-C6-hydroxyalkyl, C2-Cg-alkoxyalkyl, Ci-Ce-aminoalkyl, Ci-C6alkoxy, Ci-C6 haloalkoxy, Ci-CG aminoalkoxy, Ci-C6 cyanoalkoxy, Ci-Ce-hydroxyalkoxy, and C2-CG alkoxyalkoxy; each of Z1, Z2, Q1, Q2, Q3, Y1, R2, R3, R5, R6, R7, Rs, R9, R10, Ru, R12, R13, R14, R, R', R*, JC1, JD1, JE1, Ra, Rb, Rc and p is independently as described above for Structural Formula (I) for the method of inhibiting the replication of influenza viruses; n and m are each independently 0 or 1 when rings A and B are 4-6-membered; or n and m are each independently 0,1 or 2 when rings A and B are 7-8 membered; kisO, 1 or 2; x and y are each independently 0, 1 or 2; z is 1 or 2; provided that if Y1 is a bond, then R5 is neither -H nor an unsubstituted Ci-Ce aliphatic group; and provided that if each Q2 and Q3 independently is a bond, then R3 is neither -H nor a Ci-Ce aliphatic group.

[00122] In yet another embodiment, the present invention is directed to a pharmaceutical composition comprising a compound represented by Structural Formula (I) or Structural Formula (IA), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant or vehicle, wherein the values of the variable of Structural Formulae (I) and (IA) are each and independently as described above for the compounds of the invention.

[00123] The present invention also provides use of a compound described herein for inhibiting the replication of influenza viruses in a biological sample or patient, for reducing the amount of influenza viruses in a biological sample or patient, or for treating influenza in a patient.

[00124] Also provided herein is use of a compound described 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.

BRIEF DESCRIPTION OF THE DRAWINGS

[00125] FIG. 1 is a graph showing percentages of survial of Balb/c mice (4-5 weeks of age) over time for a prophylaxis study in which an initial dose of Compound 514 (100 mg/kg) or vehicle only (0.5% Methylcellulose/0.5% Tween 80) were administered 2 hours prior to infection by oral gavage (10 mL/kg) and continued twice daily for 5 days.

[00126] FIG. 2 is a graph showing percentages of survial of Balb/c mice (4-5 weeks of age) over time for a therapeutic treatment study in which Compound 588 (200 mg/kg) or vehicle only were administered by oral gavage 24 hours post infection and continued twice daily for 10 days.

[00127] FIGs.3-8 are tables showing some specific compounds of the invention. DETAILED DECRIPTION OF THE INVENTION

Uses of Disclosed Compounds [00128] One aspect of the present invention is generally related to the use of the compounds described herein or pharmaceutically acceptable salts, or pharmaceutically acceptable compositions comprising such a compound or a pharmaceutically acceptable salt thereof, for inhibiting the replication of influenza viruses in a biological sample or in a patient, for reducing the amount of influenza viruses (reducing viral titer) in a biological sample or in a patient, and for treating influenza in a patient.

[00129] In one embodiment, the present invention is generally related to the use of compounds represented by Structural Formula (I) or Structural Formula (IA), or pharmaceutically acceptable salts thereof for any of the uses specified above:

(I). A first set of variables of Structural Formulae (I) and (IA) is independently as follows: Z1 is -R*, -F, -Cl, -CN, -OR*, -C02R*, -N02, or -CON(R*)2. Specifically, Z1 is -H, Ci-Ce alkyl, -0(CrC6 alkyl), -F, -Cl, -CN, -C02H, -C02(CrC6 alkyl), -CONH2, -CONH(Ct-Cc alkyl), or -CONfCi-Ce alkyl)2, wherein each of said alkyl groups (e.g., represented by Ci-C6 alkyl, -0(Ci-C6 alkyl), -CO^CrCe alkyl), -CONH(C,-C6 alkyl), and -CON(Ci-C6 alkyl)2) is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(Ci-C4 alkyl), -N(C,-C4 alkyl)2, -OCO(C,-C4 alkyl), -CO(Ct-C4 alkyl), -C02H, -C02(C,-C4 alkyl), and C,-C4 alkoxy. Specifically, Zs is -H, -F, -Cl, Ci-C4 haloalkyl (e.g., -CF3), Ci-C4 alkyl, -CH2NH2, -C(0)NH2j -C(0)NH(CH3), -C(0)N(CH3)2, -0(Ci-C4 alkyl), or -CN. Specifically, Z1 is -H, -F, -Cl, -CF3, Ci-C4 alkyl, or -CN. Specifically, Z1 is -H, -F, -Cl, -CF3, -CH3, or -CN. Specifically, Z1 is -H, -F, or -CN. Specifically, Z1 is -H or -F. Z2 is -R* -OR*, -C02R*, -NR*2, or -CON(R*)2. Specifically, Z2 is -H, CrC6 alkyl, -0(Ci-C6 alkyl), -NH2, -NH(C|-C6 alkyl), or -N(C|-Crt alkyl)2, wherein each of said alkyl groups (e.g., represented by Ci-Ce alkyl, -0(Ci-Cc alkyl), -NH(Ci-Co alkyl), and -N(Ci-Ce alkyl)2) is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(Ci-C4 alkyl), -N(Ct-C4 alkyl)2, -OCO(Ci-C4 alkyl), -CO(Ci-C4 alkyl), -C02H, -C02(Ci-C4 alkyl), and Ci-C4 alkoxy. Specifically, Z2 is -H, Ci-Cc alkyl, or -0(Ci-C<; alkyl), wherein each of the alkyl groups is optionally and independently substituted. Specifically, Z2 is -H, or an optionally substituted Cj-Ce alkyl. Z3 in Structural Formula (IA) is -H, -OH, halogen, -NH2; -NH(Ci-C4 alkyl); -N(Ci-C4 alkyl)2, -0(Cs-C4 alkyl), or Ci-Ce alkyl that is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, and -0(Ci-C4 alkyl). Specifically, Z3 is -H, -0(Ci-C4 alkyl), or Ci-Cg alkyl that is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, and -(XC1-C4 alkyl). Specifically, Z3 is -H or Ci-C6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, and -0(Ci-C4 alkyl). Specifically, Z3 is -H. R1 is -H or Ci-e alkyl. Specifically, R1 is -H. R2 is -H; -F; -NH2; -NH(Ci-C4 alkyl); -N(C[-C4 alkyl)2; -C=N-OH; cyclopropyl that is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, -OCH3, and -CH3; or C[-C4 alkyl that is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, and -0(Ci-C4 alkyl). Specifically, R2 is -H, -CH3, -NH2, -NH(Ci-C4 alkyl), or -N(Ci-C4 alkyl)2. Specifically, R2 is -H, -F, -CH3, -CH2OH, or -NH2. Specifically, R2 is -H or -CH3. R3 is -H, -Cl, -F, -OH, -0(Ci-C4 alkyl), -NH2, -NH(CrC 4 alkyl), -N(Ci-C4 alkyl)2, -Br, -CN, or C1-C4 aliphatic that is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(C,-C4 alkyl), -N(C|-G, alkyl)2, -OCO(Ci-C4 alkyl), -CO(Ci-C4 alkyl), -C02H, ^C02(C]-C4 alkyl), and Ci-C4 alkoxy. Specifically, R3 is -H, -Cl, -F, -CF3, -OCH3, -NH2, -NH(C,-C 4alkyl), -N(Ci-C4 alkyl)2, -Br, -0(Ci-C4 alkyl), -CN, -CrC4 haloalkyl, -OH, or-Ci-C4 aliphatic. Specifically, R3 is -H, -Cl, -F, -CF3, -OCH3, -NH2, -NH(Ci-C 4alkyl), -N(C,-C4 alkyl)2, -Br, -0(C,-C4 alkyl), -CHCH(CH3), -CHCH2, -CN, -CH2CF3, -CH2F, -CHF2, -OH, or-Ci-C4 alkyl. Specifically, R3 is -H, -Cl, -F, -Br, -CN, -CF3, -0(C|-C4 alkyl), -OH, -NH2, -NH(Ci-C4 alkyl), or -N(Ci-C4 alkyl)2. Specifically, R3 is -H, -F, -Cl, -CF3, -NH2, -NH(CH3), or -N(CH3)2. Specifically, R3 is -H, -Cl, or -F. Specifically, R3 is -Cl. Specifically, R3 is -H, -Cl, -F, -Br, -CN, -CF3, -CH3, -C2H5, -0(C,-C4 alkyl), -OH, -NH2, -NH(Ci-C4 alkyl), or -N(C,-C4 alkyl)2. Specifically, R3 is -H, -F, -Cl, -CF3, -CH3, -C2H5, -NH2, -NH(CH3), or -N(CH3)2. Specifically, R3 is -F or-Cl. R4 is: i) a C3-C 10 non-aromatic carbocycle optionally substituted with one or more instances of JA; ii) a Ci-C6 aliphatic group (e.g., Ci-Ce alkyl or C2-C<; alkenyl group) optionally substituted with one or more substituents independently selected from the group consisting of Jc; a C3-Cs non-aromatic carbocycle, or a 6-10 membered carbocyclic aryl group, each optionally and independently substituted with one or more instances of JA; and a 5-10 membered heteroaryl group, or a 4-10 membered non-aromatic heterocycle, each optionally and independently substituted with one or more instances of JB; or iii) a 4-10 membered non-aromatic heterocycle optionally substituted with one or more instances of JB. Specifically, R4 is i) an optionally substituted C3-C10 carbocyclic ring; ii) a Ci-Ce aliphatic group (e.g., Ci-Cg alkyl or C2-Ce alkenyl group) that is substituted with one or more substituents independently selected from the group consisting of Jc, an optionally substituted C3-C8 non-aromatic carbocycle, and an optionally substituted 4-10 membered non-aromatic heterocycle; or iii) an optionally substituted, 4-10 membered non-aromatic heterocycle. Specifically, the C1-C6 aliphatic group represented by R4 is substituted with -OR5, -SR5, -NR’R5, -C(0)R5, -C02R5, -0C(0)R5, -C(0)NR’R5, -C(0)NRC(0)0R5, -NRC(0)NRC(0)0R5, -NRC(0)R5, -NRC(0)NR’R5, -NRC02R5, -0C(0)NR’R5, -SOR5, -S02R5, -S02NR’R5-, N(R)S02R5, -NRS02NR’R5, an optionally substituted C3-Cs nonaromatic carbocycle, and an optionally substituted 4-10 membered non-aromatic heterocycle. More specifically, R4 is: i)

wherein ring T (including rings A, B and C described below) is a C3-C10 non-aromatic carbocycle optionally substituted with one or more instances of JA, or a 3-10 membered non-aromatic heterocycle optionally substituted with one or more instances of JB, or ring T and R9 optionally form a non-aromatic C5-C10 membered carbocycle optionally substituted with one or more instances of JA or 5-10 membered nonaromatic heterocycle optionally substituted with one or more instances of JD ; ii)

wherein ring J is a 3-10 membered non-aromatic heterocycle optionally substituted with one or more instances of JB; or iii

wherein ring D is a 4-10 membered non-aromatic heterocycle optionally substituted with one or more instances of JD1. More specifically, R4 is:

(A) (B)

e R is: i) -H; ii) a Ci-Ce aliphatic group optionally substituted with one or more instances of J ; iii) a C3-C10 non-aromatic carbocycle, or a 6-10 merabered carbocyclic aryl group, each optionally and independently substituted with one or more instances of JC1; or iv) a 4-10 membered non-aromatic heterocycle, or a 5-10 membered heteroaryl group, each optionally and independently substituted with one or more instances of JD1. Specifically, R5 is: i) -H; ii) a Ci-Cg aliphatic group (e.g., Ci-C6 alkyl or C2-C6 alkenyl group) optionally substituted with one or more instances of JC1; iii) a C3-C8 non-aromatic carbocycle, or a 6-10 membered carbocyclic aryl group, each optionally and independently substituted with one or more instances of JC!; or iv) a 4-8 membered non-aromatic heterocycle, or a 5-10 membered heteroaryl group, each optionally and independently substituted with one or more instances of JD1. Optionally, Rs, together with each of Q1, Q2 and Q3, optionally and independently forms a 4-8 membered, non-aromatic ring optionally substituted with one or more instances of JE1.

It is understood that the non-aromatic ring formed with R5 and Q1 can employ a portion of Q1. in some embodiments, R5, together with Q2 and R8, optionally and independently forms a 5-7 membered, non-aromatic ring optionally substituted with one or more instances of JE1.

Specifically, R5 is independently i) -H; ii) a Ci-Co-alley 1 or Ca-Co-alkenyl group optionally substituted with one or more instances of JC1; iii) a C3-CS non-aromatic carbocycle optionally substituted with one or more instances of JCI; iv) a phenyl group optionally substituted with one or more instances of JC1; v) a 4-8 membered non-aromatic heterocycle optionally substituted with one or more instances of JD1; or vi) a 5-6 membered heteroaryl ring optionally substituted with one or more instances of JD1. Specifically, R5 is independently i) -H; ii) a Ci-C6-alkyl or C2-C6-alkenyl group optionally and independently substituted with one or more instances of JC1; or iii) a 4-8 membered non-aromatic heterocycle optionally substituted with one or more instances of JD1. Specifically, R5 is independently i) -H; or ii) a Ci-Ce-alkyl or C2-C6-alkenyl group optionally and independently substituted with one or more instances of JCI. R6 and R7 are each independently -H or Ci-Ce alkyl optionally substituted with one or more substitutents selected from the group consisting of halogen, cyano, hydroxy, oxo, amino, carboxy, Ci-Cgalkoxy, Ci-Ce haloalkoxy, Ci-Ceaminoalkoxy, Cs-C6cyanoalkoxy,

Ci -Ce hydroxyalkoxy, and C2-C6 alkoxyalkoxy, or optionally R6 and R7, together with the carbon atom to which they are attached, form a cyclopropane ring optionally substituted with one or more instances of methyl. Alternatively, R6 and R7 are each independently -H or C[-C4 alkyl optionally substituted with one or more substitutents selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(Ci-C6 alkyl), -N(Ci-Cg alkyl)2, -C(0)0H, -(C0)0(Ci-C6 alkyl), -0C(0)(Ci-C6 alkyl), CrCe alkoxy, Ci-C6 haloalkoxy, Ci-C6 aminoalkoxy, Ci-C6 cyanoalkoxy, Ci-C6 hydroxyalkoxy, and C2-C6 alkoxyalkoxy, or optionally R6 and R7, together with the carbon atom to which they are attached, form a cyclopropane ring optionally substituted with one or more instances of methyl.

Specifically, R6 and R7 are each independently -H or -CHj, or, together with the carbon atoms to which they are attached, they form a cyclopropane ring.

Each R8 is independently -H, halogen, cyano, hydroxy, amino, carboxy, CrC6 alkyl, Ci-Ce haloalkyl, Ci-Ce cyanoalkyl, C2-CG alkoxyalkyl, C]-CG aminoalkyl, Ci-C6 hydroxyalkyl, Ci-C6 alkoxy, Ci-CG haloalkoxy, Ci-CV, aminoalkoxy, Ci-CG cyanoalkoxy, Ci-CG hydroxyalkoxy, and C2-CG alkoxyalkoxy; or Rs, together with Q2 and R5, optionally and independently forms a 5-7 membered, non-aromatic ring optionally substituted with one or more instances of JE1.

Each R9 is independently -H, halogen, cyano, hydroxy, amino, carboxy, Ci-CG alkyl, Ci-CG haloalkyl, Ci-Cfi cyanoalkyl, C2-C6 alkoxyalkyl, Ci-CG aminoalkyl, Q.-CG hydroxyalkyl, Ci-CG carboxyalkyl, C)-CGalkoxy, Ci-CG haloalkoxy, Ci-CGaminoalkoxy, Cj-CGcyanoalkoxy, Ci-CG hydroxyalkoxy, and C2-CG alkoxyalkoxy; or R8, together with Q2 and R5, optionally and independently forms a 5-7 membered, non-aromatic ring optionally substituted with one or more instances of JE1. Specifically, each R9 is independently ~H, halogen, cyano, hydroxy, amino, carboxy, Ci-CG alkyl, C]-CG haloalkyl, Ci-CG cyanoalkyl, C2-CG alkoxyalkyl, Cj-CG aminoalkyl, Ci-C6 hydroxyalkyl, Ci-CG alkoxy, Ci-CG haloalkoxy, Ci-C6 aminoalkoxy, Ci-Ce cyanoalkoxy, Ci-CG hydroxyalkoxy, and C2-C6 alkoxyalkoxy; or R8, together with Q2 and R5, optionally and independently forms a 5-7 membered, nonaromatic ring optionally substituted with one or more instances of JE1.

Optionally, R9 and ring T form a non-aromatic C5-C10 membered carbocycle optionally substituted with one or more instances of JA or 5-10 membered non-aromatic heterocycle optionally substituted with one or more instances of JD .

Specifically, each Rs is independently-H, halogen, cyano, hydroxy, C1-C4 alkyl, Ci-C4 haloalkyl, C1-C4 hydroxyalkyl, C2-C4 alkoxyalkyl, -0(Ci-C4 alkyl), -NH2, -NH(Ci-C4 alkyl), or -N(Ci-C4 alkyl)2; and each R9 is independently -H or C1-C4 alkyl, more specifically, -H, -CH3, or-CH2CH3. R10 is independently -H; or a Ci-Ce alkyl group optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, amino, carboxy, Cs-Ce alkoxy, Ct-C6 haloalkoxy, Ci-C6 aminoalkoxy, Ci-C6 cyanoalkoxy, CrC6 hydroxyalkoxy, C2-Ce alkoxyalkoxy, C3-Cg non-aromatic carbocycle, phenyl, a 4-8 membered non-aromatic heterocycle, and a 5-6 membered heteroaryl group; wherein each of said carbocycle, phenyl, heterocycle, and heteroaiyl group for the substituents of the Ci-Ce alkyl group represented by R10 is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, amino, carboxy, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce cyanoalkyl, C2-CG alkoxyalkyl, Ci-C6 aminoalkyl, Ci-C6 hydroxyalkyl, Ci-C6 alkoxy, Ci-C6 haloalkoxy, Ci-C6 aminoalkoxy, Ci-Cg cyanoalkoxy, Ci-C6 hydroxyalkoxy, and C2-C6 alkoxyalkoxy. Specifically, R10 is independently -H, Ci-C6 alkyl, Ci-Ce haloalkyl, C2-Ce-alkoxyalkyl, C,-C6 hydroxyalkyl, Ci-C6 aminoalkyl, or Ct-C6 cyanoalkyl. Specifically, R10 is -H or Ci-Cfi-alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(Ci-C4 alkyl), -N(C[-C4 alkyl)2, -OCO(Ci-C4 alkyl), -C02H, -C02(Ci-C4 alkyl), and C1-C4 alkoxy. Specifically, R10 is -H or Ci-Ce-alkyl.

Ru, R12, R13 and R14 are each independently -H, halogen, or Ci-Ce alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo, hydroxy, amino, carboxy, C|-C6 alkoxy, CrC6 haloalkoxy, Ci-C6 aminoalkoxy, Ci-Ce cyanoalkoxy, Cj-Ce hydroxyalkoxy, and C2-Ce alkoxyalkoxy; or optionally, R13 and R14 together with the carbon atom to which they are attached form a cyclopropane ring, optionally substituted with one or more instances of methyl. Specifically, R11 and Ri2 are each independently -H or C1-C4 alkyl; and R13 and R14 are each independently -H or Ci-C4 alkyl, or together with the carbon atoms to which they are attached, they form a cyclopropane ring. Specifically, Ru and R12 are each independently -H or -CH3; and R13 and R14 are each independently -H, ~CH3, or -CH2CH3, or together with the carbon atoms to which they are attached, they form a cyclopropane ring.

Optionally R11 and ring A form a bridged ring optionally further substituted with one or more instances of JA.

Ring A is a C3-Cio non-aromatic carbocycle optionally further substituted with one or more instances of JA, or 3-10 membered non-aromatic heterocycle optionally further substituted with one or more instances of JB. Specifically, ring A is an optionally substituted C3-C8 non-aromatic carbocyclic or heterocyclic ring. Specifically, Ring A is a C3-C8 nonaromatic carbocycle optionally further substituted with one or more instances of JA. Specifically, Ring A is a non-aromatic, 4-7 or 5-7 membered, carbocyclic ring optionally further substituted with one or more instances of JA. A specific example of Ring A is an optionally substituted, cyclohexyl or cyclopentyl ring.

Optionally, ring A and R8 form a non-aromatic, 5-10 membered, bridged carbocycle or heterocycle, or ring A and R9 optionally form a non-aromatic, 5-10 membered, bridged carbocycle or heterocycle, ring A and Ru optionally form a non-aromatic, 5-10 membered, bridged carbocycle or heterocycle, wherein each carbocycle is optionally further substituted with one or more instances of JA, and wherein each heteroocycle is optionally further substituted with one or more instances of JB. In some embodiments, the bridged rings are each independently 6-10 membered. Exemplary bridged rings include:

wherein each of rings G1-G4 is independently a 5-10 membered non-aromatic bridged carbocycle optionally further substituted with one or more instances of JA, and ring G5 is a 5-10 membered non-aromatic bridged heterocycle optionally further substituted with one or more instances of JB; R21, R22, R23, R24, and R25are each independently -H, halogen, -OH, C]-CG alkoxy, or Cj-Ce alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo, hydroxy, oxo, amino, carboxy, Ci-CG alkoxy, Q-Cehaloalkoxy, Ci-CGaminoalkoxy, Ci-CGcyanoalkoxy, Ci-CG hydroxy alkoxy, and C2-CG alkoxyalkoxy; X is -Ο-, -S-, or-NR8-; Rs is -H or Ci-CG alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo, hydroxy, amino, carboxy, Ci-CG alkoxy, Cj-CGlialoalkoxy, Ci-CG aminoalkoxy, Ci-CGcyanoalkoxy, Ci-CG hydroxy alkoxy, and C2-C6 alkoxyalkoxy; q is 0, 1 or 2; x is 0} 1 or 2; r is 1 or 2. An additional example of the bridged rings includes an adamantyl ring.

Ring B is a 4-10 membered, non-aromatic, heterocyclic ring that is optionally further substituted with one or more instances of JB. Specifically, ring B is 4-8 membered. Specifically, ring B is 4-7 or 5-7 membered. Specific examples of Ring B include:

> wherein each of rings B1-B9 is optionally substituted.

Ring C is a 4-10 membered, non-aromatic, heterocyclic ring that is optionally further substituted with one or more instances of JB. Specifically, ring C is 4-8 membered. Specifically, ring C is 4-7 or 5-7 membered. Specific examples of Ring C include:

> wherein each of rings C1-C5 is optionally and independently substituted.

Ring D is a 4-10 membered, non-aromatic, heterocyclic ring that is optionally substituted with one or more substituents instances of JDl. Specifically, ring D is 4-8 membered. Specifically, ring D is 4-7 or 5-7 membered. Specific examples of ring D include:

wherein each of rings D1-D7 is optionally substituted.

Specifically, each of Rings A -D is independently and optionally substituted 4-8 or 47 membered ring.

Each Q1 is independently a bond, -0-, -S-, -NR’-, -0(0)-, -C(-NR)-, -C(=NR)NR-, -NRC (=NR)NR-, -C02-, -00(0)-, -C(0)NR’-, -C(0)NRC(0)0-, -NRC(0)NRC(0)0- -NRC(0)-, -NRC(0)NR!-, -NRC02-, -0C(0)NR'-, -S(0>, -S02--S02NR’-, -NRSO2-, or -NRSOjNR’-, -P(0)(0R)0-, -0P(0)(0Ra)0-, -P(0)20-, -C02S02-, or -(CR^ip-Y1-. Specifically, each Q1 is independently a bond, -0-, -S-, -NR5-, -0(0)-, -C(=NR)-, -CO2-, -00(0)-, -C(0)NR’-, -C(0)NRC(0)0-, -NRC(0)NRC(0)0-, -NRC(O)-, -NRC(0)NR’-, -NRC02- -0C(0)NR-, -S(0>, -S02-, -NRS02-, -S02NR’-, NRSOjNR’-, or -(CR6R7)P-Y1-. Specifically, each Q1 is independently a bond, -0-, -S-, -NR’-, -0(0)-, -C02-, -00(0)-, -C(0)NR’-, -C(0)NHC(0)0--C(0)N(CHj)C(0)0, -NHC(0)NHC(0)0-, -N(CH3)C(0)NHC(0)0- -NHC(O)-, -N(CH3)C(0)-, -NHC(0)NR’-, -N(CH3)C(0)NR’-, -NHC02-,-N(CH3)C02-, -0C(0)NR’-, -S(0)-, -S02-, -NHSO2-, -N(CH3)S02-, -S02NR’-, or-(CR'TiVY1-.

Each Q2 is independently a bond, -0-, -S-, -NR-, -0(0)-, -C(=NR)-, -C(=NR)NR-, -NRC(=NR)NR-, -C02-, -00(0)-, -C(0)NR-, -C(0)NRC(0)0-, -NRC(0)NRC(0)0-, -NRC(O)-, -NRC(0)NR- -NRC02-, -0C(0)NR-, -S(0)-, -S02-, -N(R)S02- -S02N(R)-, -NRS02NR-, -P(0)(0R)0-, -0P(0)(0Ra)0-, -P(0)20-, -C02S02-, or -(CRcR7)p-Y1. Specifically each Q2 is independently a bond, -0-, -S-, -NR’-, -0(0)-, -C(=NR)-, -C02-, -00(0)-, -C(0)NR’-, -C(0)NRC(0)0- -NRC(0)NRC(0)0--NRC(O)-, -NRC(0)NR’-, -NRC02-, -OC(0)NR’-, -S(0)-, -S02-, -NRS02--S02NR’-, NRSO2NR’-, or -(CR6R7)p-Y'-. Specifically, each Q2 is independently -0-, -NR’-, -0(0)-, -C02-, -C(0)NR’-, -NRC(O)-, -NRC(0)NR’-, -NRC02-, -0C(0)NR’-, -NRS02-, -S02NR’-, or -(CR^p-Y'-. Specifically, each Q2 is independently -C02-, -C(0)NR’-, -NRC(O)-, -NRC(0)NR’-, -NRC02-, -0C(0)NR’-, -NRS02-, or -(CR6R7)p-Y1-. Specifically, each Q2 is independently -NR’-, -C(0)NR’-, -NRC(O)-, -S02NR’-, -NRC(0)NR’-, -NRC02- -OCONR’-, or-(CR^ip-Y1-. Specifically, each Q2 is independently -C(0)NR’-, -NRC(O)-, -NRC(0)NR’-, -NRC02-, -OCONR’-, or -(CR^lp-Y1-. Specifically, each Q2 is independently -0-, -NR’-, -0(0)-, -C02-, -C(0)NR’-, -NHC(O)-, -N(CH3)C(0)- -NHC(0)NR’-, -N(CH3)C(0)NR’-, -NHCO2-, -N(CH3)C02- -0C(0)NR’-, -nhso2-, -N(CH3)S02-, -S02NR’-, or-(CR6R7)|-Y1-. Specifically, each Q2 is independently -C02-, -C(0)NR’-, -NHC(O)-, -N(CH3)C(0)-, -NHC(0)NR’-, -N(CH3)C(0)NR’-, -NHCO2-, -N(CH3)C02-, -0C(0)NR’-, -NHS02-, -N(CH3)S02-, -S02NH-, -S02N(CH3)-, or -(CR6R7)p-Y1-. Specifically, each Q2 is independently -NR’-, -C(0)NR’-, -NHC(O)-, -N(CH3)C(0)-, -NHC(0)NR’-, -N(CH3)C(0)NR’-, -NHC02- -N(CH3)C02--OCONR’-, or -(CR6R7)p-y1-· Specifically, each Q2 is independently -C(0)NR’--NHC(O)-, -N(CH3)C(0)-, -NHC(0)NR’-, -N(CH3)C(0)NR\ -NHC02- -N(CH3)C02-, -OCONR’-, or-iCR^VY1-.

Each Q3 is independently a bond, -C(O)-, -C(=NR)-, -C(=NR)NR-, -NRC(=NR)NR-, -C02-, -C(0)NR-, -S02--S02N(R)-, -C(0)NRC(0)0- or -(CR^^p-Y1-. Specifically, each Q3 is independently is a bond, -C(O)-, -C(=NR)-, ~C02~, -C(0)NR’-, -S02-, -S02NR’-, -C(0)NRC(0)0-, or -(CR6R7)P-Y1-. Specifically, each Q3 is independently -C(O)-, -C02-, -C(0)NR’-, -S02-, -S02NR’-, -C(0)NRC(0)0-, or -(CR6R7)p-Y!-. Specifically, each Q3 is independently -C(O)-, -C02-, -C(0)NH-, -C(0)N(CH3)-, -S02-,-S02NH-, -S02N(CH3)-, -C(0)NHC(0)0-, -C(0)N(CH3)C(0)0-, or -(CR^’ip-Y1-. Specifically, each Q3 is independently -C(O)-, -C02-, -C(0)NR’--C(0)NHC(0)0-, or -(CR6R7)P-Y1-. Specifically, each Q3 is independently -0(0)-, -C02-, -C(0)NR’-, or -(CR6R7)p-Y1-.

Optionally, Q2 and Q3, together with R5, each and independently can form a 5-7 membered, non-aromatic ring optionally substituted with one or more instances of JE1. It is understood that the non-aromatic ring formed with R5 and Q2 can employ a portion of Q2. It is also understood that the non-aromatic ring formed with R5 and Q3 can employ a portion of

Qs-

Each Y1 is independently a bond, -0-, -S-, -NR-, -C(0)-, -C(=NR)-, -C(=NR)NR-, -NRC(=NR)NR-, -CO2-, -0C(0)-, -C(0)NR- -C(0)NRC(0)0-, -NRC(0)NRC(0)0--NRC(O)-, -NRC(0)NR- -NRC02-, -0C(0)NR-, -S(0)-, -S02-, -N(R)S02-, -S02N(R)-, -NRS02NR-, -P(0)(OR)0-, -0P(0)(0Ra)0-, -P(0)20-, or -C02S02-. Specifically each Y1 is independently a bond, -0-, -S-, -NR’-, -C(0)-, -C(=NR)-, -C02-, -0C(0)-, -C(0)NR’-, -NRC(O)-, -NRC(0)NR’-, -NRC02- -0C(0)NR’-, -S(0)-, -S02-, -S02NR’-, -NRS02--NRSO2NR’-, -NRC(0)NRC(0)0-, or -C(0)NRC(0)0-. Specifically, each Y1 is independently a bond, -0-, -NR’-, -C(0)NR’-, -NRC(O)-, -NRC(0)NR’-, -NRC02-, -0C(0)NR’-, -NRC(0)NHC(0)0-, or -C(0)NHC(0)0-. Specifically, each Yl is independently a bond, -0-, -S-, -NR’-, -C(0)-, -C02- -0C(0)-, -C(0)NR’-, -NHC(O)-, -N(CH3)C(0)-, -NHC(0)NR’-, -N(CH3)C(0)NR’-, -nhco2-, -N(CH3)C02- -0C(0)NR’-, -S(0)-, -S02-, -NHS02-, -N(CH3)S02- -so2nh-, S02N(CH3)-, -NHS02NH-, -N(CH3)S02NH-, -N(CH3)S02N(CH3)-, -C(0)NHC(0)0-, -C(0)N(CH3)C(0)0-,.-NHC(0)NHC(0)0- or -N(CH3)C(0)NHC(0)0-. Specifically, each Y1 is independently a bond, -0-, -NR’-, -C(0)NR’-, -NHC(0)-, -N(CH3)C(0)-, -NHC(0)NR’-, -N(CH3)C(0)NR’-, -NHCO2-, -N(CH3)C02--0C(0)NR’-, -C(0)NHC(0)0- or -NHC(0)NHC(0)0-.

Each of JA and JB is independently selected from the group consisting of halogen, cyano, oxo, -NCO, andQ'-R5; or optionally two JA and two JB, respectively, together with the atom(s) to which they are attached, independently form a 4-8 membered ring (e.g., spiro ring or fused ring) that is optionally substituted with one or more instances of JEI.

Specifically each of JA and JB is independently selected from the group consisting of halogen, cyano, oxo, -NCO, andQ'-R5; or optionally two JA and two JB, respectively, together with the atom(s) to which they are attached, independently form a 5-7 membered ring that is optionally substituted with one or more instanced of JE1. The 5-7-membered ring formed with JA or JB can be aromatic or non-aromatic. The 5-7-membered ring formed with JA or JB can optionally be fused to the ring to which they are attached. In some embodiments, the 5- 7-membered ring can optionally be a spiro ring formed by two geminal JA and two geminal JB, respectively.

Jc is independently selected from the group consisting of halogen, cyano, oxo, -OR5, -SR5, -NR’R5, -C(0)R5, -CO2R5, -0C(0)R5, -C(0)NR’R3, -C(0)NRC(0)0R5, -NRC(0)NRC(0)0R5, -NRC(0)R5, -NRC(0)NR’R5, -NRC02R5, -0C(0)NR’R5, -S(0)R5, -S02R5, -S02NR’R5, -NRS02R5, -NRS02NR’R5, and -P(0)(0Ra)2-. Specifically, Jc is independently selected from the group consisting of-OR5, -SR5, -NR’R5, -C(0)R5, -C02R5, -0C(0)R5, -C(0)NR’R5, -C(0)NRC(0)0R5, -NRC(0)NRC(0)0R5, -NRC(0)R5, -NRC(0)NR’R5, -NRC02R5, -0C(0)NR’R5, -S(0)R5, -S02R5, -S02NR’R5, -NRS02R5, and -NRS02NR’R5. Specifically, Jc is selected from the group consisting of halogen, cyano, oxo, -OR5, -NR’R5, -C(0)R5, -C02R5, -0C(0)R5, -C(0)NR’R5, -C(0)NRC(0)0R5, -NRC(0)R5, -NRC(0)NR’R5, -NRC02R5, and -0C(0)NR’R5. Specifically, Jc is selected from the group consisting of halogen, cyano, oxo, -OR5, -NR’R5, -C(0)R5, -C02R5, -0C(0)R5, -C(0)NR’R5, and -NRC(0)R5. Specifically, Jc is selected from the group consisting of halogen, cyano, oxo, -OR5, -NR’R5, -C(0)NR’R5, and -NRC(0)R5. Specifically, Jc is selected from the group consisting of-OR5, -NR’R5, -C(0)NR’R5, and -NRC(0)R5.

Each of JC1 and JD1 is independently selected from the group consisting of halogen, cyano, oxo, Ra, -0Rb, -SRb, -S(0)Ra, -S02Ra, -NRbRc, -C(0)Rb, -C(=NR)RC, -C(=NR)NRbRc, -NRC(=NR)NRbRc, -C(0)0Rb, -0C(0)Rb, ~NRC(0)Rb, -C(0)NRbRc, -NRC(0)NRbRc, -NRC(0)0Rb, -OCONRbRc, -C(0)NRC02Rb, -NRC(0)NRC(0)0Rb, -C(0)NR(0Rb), -S02NRcRb, -NRS02Rb, -NRS02NRcRb, -P(0)(0Ra)2, -0P(0)(0Ra)2-, -P(0)2(0Ra), and -C02S02Rb, or optionally, two JCi and two JD1, respectively, together with the atom(s) to which they are attached, independently form a 4-8-membered ring that is optionally substituted with one or more instances of JEl. Specifically, each of JC1 and JD1 is independently selected from the group consisting of halogen, cyano, oxo, Ra, -ORb, -SRb, -S(0)Ra, -S02Ra, -NRbRc, -C(0)Rb, -C(0)0Rb, -0C(0)Rb, -NRC(0)Rb, ~C(0)NRbRc, -NRC(0)NRbRc, -NRC(0)0Rb, -OCONRbRc, -C(0)NRC02Rb, -NRC(0)NRC(0)0Rb, -C(0)NR(0Rb), -S02NRcRb, -NRS02Rb, and -NRS02NRcRb.

Optionally, two JC1 and two JDI, respectively, together with the atoms to which they are attached, independently form a 5-7-membered ring that is optionally substituted with one or more instances of JE1, and fused to the respective ring to which they are attached. It is understood that selections of values of each JC! and JD,are those that result in the formation of stable or chemically feasible compounds. For example, suitable values of each JC1 and JD1 on a carbon atom independently include halogen, cyano, oxo, Ra, -ORb, -SRb, -S(0)Ra, -S02Ra, -NRbRc, “C(0)Rb, -C(0)0Rb, -0C(0)Rb, -NRbC(0)Rb, -C(0)NRbRc, -NRC(0)NRbRc, -NRC(0)0Rb, -OCONRbRc, -C(0)NRC02Rb, -NRC(0)NRC(0)0Rb, -C(0)NR(0Rb), —S02NR‘Rb, -NRS02Rb, and -NRS02NRLRh; and suitable values of Jm on a nitrogen atom include Ra, -S02Ra, -S02N(R)Rb, -C(0)Rb, ~C(0)ORb, -C(0)NRbRc, -C(0)NRC02Rb, and -C(0)NR(0Rb). Specific examples of each JC1 and JDI on a carbon atom independently include halogen, cyano, oxo, Ra, -ORb, -SRb, -S(0)Ra, -S02Ra, -NHRC, -C(0)Rb, -C(0)0Rb, -0C(0)Rb, -NHC(0)Rb, -C(0)NHRc, -NHC(0)NHR°, -NHC(0)0Rb and -OCONHRc, -N(CH3)RC, -N(CH3)C(0)Rb, -C(0)N(CH3)R1:, -N(CH3)C(0)NHRc, -N(CH3)C(0)0Rb, -OCON(CH3)Rc, -C(0)NHC02Rb, -C(0)N(CH3)C02Rb, -NHC(0)NHC(0)0Rb, -N(CH3)C(0)NHC(0)0Rb, -C(0)NH(0Rb)-, C(0)N(CH3)(0Rb), -NHS02Rb, -S02NHRb, -S02N(CH3)Rb, and -N(CH3)S02Rb. Specific examples of each JD1 on a nitrogen atom independently include Ra, ~S02Ra, -C(0)Rb, -C(0)0Rb, -C(0)NHRc, -C(0)N(CH3)Rc, -C(0)NHC02Rb, -C(0)N(CH3)C02Rb, -C(0)NH(0Rb)-, and -C(0)N(CH3)(0Rb). More specific examples of each JC1 and JD1 on a carbon atom independently include halogen, cyano, hydroxy, oxo, C1-C4 alkyl, -(XC1-C4 alkyl), -NH2, -NH(Ci-C4 alkyl), -N(Ci-C4 alkyl)2, -C(0)(Ci-C4 alkyl), ~0C(0)(Ci-C4 alkyl), -C(0)0(Ci~C4 alkyl), C3-Ce cycloalkyl, and -C02H, wherein each of said alkyl groups (e.g., represented by C1-C4 alkyl, -0(Ci-C4 alkyl), -NH2, ™NH(C|-C4 alkyl), -N(Ci-C4 alkyl)2, -C(0)(Ci-C4 alkyl), -0C(0)(Ci-C4 alkyl), -C(0)0(Ct-C4 alkyl), and C3.....C6 cycloalkyl) is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(Ci-C4 alkyl), -N(Ci-C4 alkyl)2, -C(0)(C,-C4 alkyl), -OCO(Ci-C4 alkyl), -C02H, -C02(Ci-C4 alkyl), and C1-C4 alkoxy. More specific examples of each JD1 on a nitrogen atom independently include halogen, cyano, hydroxy, oxo, C1-C4 alkyl, -C(0)(Ci-C4 alkyl), -C(0)0(Ci-C4 alkyl), and C3-C6 cyclo(alkyl), wherein each of said alkyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(Ci-C4 alkyl), -N(Ci-C4 alkyl)2, -C(0)(Ci-C4 alkyl), -OCO(Ci-C4 alkyl), -C02H, -C02(Ci-C4 alkyl), and C1-C4 alkoxy.

Each JE1 is independently selected from the group consisting of halogen, cyano, hydroxy, oxo, amino, carboxy, amido, C[-C6 alkyl, -0(Ci-C6 alkyl), and -C(0)(Ci-C6-alkyl), wherein each of said alkyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(Ci-C4 alkyl), -N(Ci-C4 alkyl)2, -OCO(Ci'C4 alkyl), -CO(Ci-C4 alkyl), -C02H, -C02(Ci-C4 alkyl), and C1-C4 alkoxy. Specifically, each JE1 is independently selected from the group consisting of halogen, cyano, hydroxy, oxo, Cj-Cg alkyl, -0(Ci -Cr, alkyl), -C(0)(C,-C6-alkyl), -NH2, -NH(C,-C6 alkyl), -N(C,-C6 alkyl),, -C(0)NH2, -C(0)NH(CrC6 alkyl), -C(0)N(Cs-C6 alkyl)2, -C(0)(CrC6-alkyl), -C(0)0(Ci-C6 alkyl), -0C(0)(C|-C6 alkyl), -NHC(0)(C]-C6 alkyl), -M(C,-C6 alkyl)C(0)(C,-C6 alkyl), and -C02H, wherein each of said alkyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(Ct-C4 alkyl), -N(Ci-C* alkyl)2, -OCO(C,-C4 alkyl), -CO(Ci-C4 alkyl), -C02H, -C02(Ci-C4 alkyl), and C1-C4 alkoxy. It is understood that selections of suitable JEI are those that result in the formation of stable or chemically feasible compounds. For example, suitable substituents on a carbon atom independently include halogen, cyano, hydroxy, oxo, Ci-Cc alkyl, -0(Ci-Ce alkyl), -C(0)(C]-C6-alkyl), -NH2, -NH(Ci-Ce alkyl), -NfCrCe alkyl)* -C(0)NH2, -C(0)NH(C,-C6 alkyl), -C(0)N(Ci-C6 alkyl)2, -C(0)(Ct-C6-alkyl), -C(0)0(Ci-Cs alkyl), -0C(0)(Ci-C6 alkyl), -NHC(0)(Ci-Cfi alkyl), -N(CrC6 alkyl)C(0)(Ci-C6 alkyl), and -C02H, wherein each of said alkyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(C|-C4 alkyl), -N(CrC4 alkyl)2, -OCO(C|-C4 alkyl), -CO(CrC4 alkyl), -C02H, -C02(Ci-C4 alkyl), and C1-C4 alkoxy. For example, suitable substituents on a nitrogen atom independently include C[-Cr, alkyl, -C(0)NH(Ct-C6 alkyl), -C(0)N(Ci-C6 alkyl)2, -C(0)(Ci-CG-aIkyI), and -C(0)0(Ci-C<s alkyl), wherein each of said alkyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(Ci-C4 alkyl), -N(Ci-C4 alkyl)2, -OCO(Ci-C4 alkyl), -CO(Ci-C4 alkyl), -C02H, -C02(C,-C4 alkyl), and C,-C4 alkoxy.

Rand R’ are each independently -H or Ci-CGalkyl optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, amino, carboxy, Ci-CG alkoxy, Ci-C6 haloalkoxy, Ci-C6 aminoalkoxy, Ci-C6 cyanoalkoxy, C] -CG hydroxyalkoxy, and C2-C6 alkoxyalkoxy. Specifically, R and R’ are each independently -H or Ci-CG alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(CrC6 alkyl), -N(Ci-C6 alkyl)2, -C(0)0(Ct-C6 alkyl), -0C(0)(Cr Cfi alkyl), -C02H, Ci-CG haloalkoxy, Ci-CG aminoalkoxy, C1-C6cyanoalkoxy, Ci-CG hydroxyalkoxy, and Ci-C6 alkoxyalkoxy. Specifically, R and R’ are each independently -H or Ci-CG alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(Ci-C6 alkyl), -N(Ci-C(, alkyl)?, and -0(Ci-CG alkyl). Specifically, R and R’ are each independently -H or Ci-CG alkyl (e.g., -CH3 or -CH2CH3).

Optionally R’, together with R5 and the nitrogen atom to which they are attached, forms a 5-7 membered, non-aromatic, heterocyclic ring optionally substituted with one or more instances of IDI. Specifically, the non-aromatic heterocycle is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, Ci-C6 alkyl, Ci-Ce alkenyl, -NH2, -NH(Ci-Ce alkyl), -N(Ci-C6 alkyl)2, -0(Ci.C6 alkyl), -C(0)NH2, -CCO)NH(C!-C6 alkyl), -C(0)N(CrC6 alkyl)2, -0(0)((^-0 alkyl), -0C(0)(Ci-CG alkyl), -NHC(0)(Ci-C6 alkyl), -N(C,-C6 alkyl)C(0)(Ci-C6 alkyl), and -CO?Rb; wherein each of said alkyl and alkenyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(Ci-C4 alkyl), -N(Ci-C4 alkyl)2, -OCO(Ci-C4 alkyl), -C(0)(Ci-C4 alkyl), -C02H, -C02(C[-C4 alkyl), and Ci-C4 alkoxy. Specifically, the nonaromatic heterocycle is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, oxo, Ci-C4 alkyl, -0(Ci-C4 alkyl), -NH2, -NH(Ci-C4 alkyl), -N(Ci~C4 alkyl)2, -OCO(Ci-C4 alkyl), -C(0)(Ci-C4 alkyl), -C02H, and -C02(Ci-C4 alky!), wherein each of said alkyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(Ci-C4 alkyl), -N(Ci-C4 alkyl)2, -OCO(CrC4 alkyl), -C02H, -C02(Ci-C4 alkyl), and Cs-C4 alkoxy.

Each R* is independently: i) -H; ii) a CrC6 allcyl group optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, amino, carboxy, C2-Cs non-aromatic carbocycle, 5-6 membered non-aromatic heterocycle, phenyl, 5-6 membered heteroaryl, -0(Ci-Ce alkyl), and -C(0)(Ci-C6-alkyl); wherein each of said alkyl groups (e.g., represented by -0(Ci-Ce alkyl), and -C(0)(Ci-Cc-alkyl)) is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(C!-C4 alkyl), -N(Ci-C4 alkyl)3, -OCO(CrC4 alkyl), -CO(Ci-C4 alkyl), -C02H, -C02(Ci-C4 alkyl), and C1-C4 alkoxy; and wherein each of said C3-C8 non-aromatic carbocycle, 5-6 membered non-aromatic heterocycle, phenyl, and 5-6 membered heteroaryl is independently and optionally substituted with one or more instances of JE1; or iii) a C3-CS non-aromatic carbocycle, or a 4-8 membered non-aromatic heterocycle, each of which is independently and optionally substituted with one or more instances of JE!. Specifically, each R* independently is: i)-H; ii) Ci-C6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, amino, carboxy, C1-C4 alkoxy, C1-C4 haloalkoxy, Ci-C4aminoalkoxy, C1-C4 cyanoalkoxy, C1-C4 hydroxyalkoxy, and C2-C4 alkoxyalkoxy; or iii) a 3-7 membered carbocyclic ring optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, amino, carboxy, Ct-C4 alkyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C2-C4 alkoxyalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 aminoalkoxy, C1-C4 cyanoalkoxy, C1-C4 hydroxyalkoxy, and C2-C4 alkoxyalkoxy. Specifically, each R* is i) -H, ii) CpCe alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(Ci-C4 alkyl), -N(C]-C4 alkyl)2, -OCO(Ci-C4 alkyl), -CO(Ci-C4 alkyl), -C02H, -C02(Ci-C4 alkyl), and C1-C4 alkoxy; or iii) a 3-7 membered carbocyclic ring optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(Ci-C4 alkyl), -NCC1-C4 alkyl)2, -OCO(Ci-C4 alkyl), -CO(Ci-C4 alkyl), -C02H, -C02(Ci-C4 alkyl), C1-C4 alkoxy, and Ci-C6 alkyl, wherein each alkyl optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NHo, -NH(C|-C4 alkyl), -N(Ci-C4 alkyl)2, -OCO(Ci-C4 alkyl), -CO(CrC4 alkyl), -COjH, -C02(Ci-C4 alkyl), and Ci-C4 alkoxy.

Each Ra is independently: i) a CrCc aliphatic group optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, amino, carboxy, amido, -0(Ci-Cc alkyl), -C(0)(Ci-C6-alkyl), C3-Cs nonaromatic carbocycle, 4-8 membered non-aromatic heterocycle, 5-10 membered heteroaryl group, and 6-10 membered carbocyclic aryl group; wherein each of said alkyl groups for the substituents of the Ci-C6 aliphatic group represented by Ra is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(Ci-C4 alkyl), -N(Cj-C4 alkyl)2, -OCO(Ci-C4 alkyl), -CO(Ci-C4 alkyl), -CO2H, -C02(Ci-C4 alkyl), and Ct-C4 alkoxy; and wherein each of said carbocycle, heterocycle, heteroaryl and carbocyclic aiyl groups for the substituents of the Ci-Cg aliphatic group represented by Ra is optionally and independently substituted with one or more instances of JE1; ii) a C3-Cs non-aromatic carbocycle, or a 4-8 membered non-aromatic heterocycle, each of which is optionally and independently substituted with one or more instances of JEl; iii) a 5-10 membered heteroaryl, or 6-10 membered carbocyclic aryl group, each of which is optionally and independently substituted with one or more instances of JE1.

Alternatively, each Ra is independently: i) a CpCg aliphatic group optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(Ci-C6 alkyl), -N(Ci-C6 alkyl)2, -C(0)0(C,-Cfi-alkyl), -0C(0)(Ci-C6-alkyl), -C02H, -C(0)NH2, -C(0)NH(C,-C6 alkyl), -C(0)N(C1-Ce alkyl)2, -NHC(0)(Ci-C6 alkyl), -N(Ci-C6 alkyl)C(0)(C|-C6 alkyl), -0(CrC6 alkyl), -C(0)(Ci-C6-alkyl), C3-C8 non-aromatic carbocycle, 6-10 membered carbocyclic aryl, 4-8 membered non-aromatic heterocycle, and 5-10 membered heteroaryl; wherein each of said alkyl groups for the substituents of the Ci-Cg aliphatic group represented by Ra is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(C]-C4 alkyl), -N(Ci-C4 alkyl)2, -OCO(Ci-C4 alkyl), -CO(CrC4 alkyl), -C02H, -C02(CrC4 alkyl), and C(-C4 alkoxy; and wherein each of said carbocycle, phenyl, non-aromatic heterocycle, and heteroaryl groups for the substituents of the Ci-Cg aliphatic group represented by Ra is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, Ci-CG alkyl, -NH2, -NH(Ci-Cg alkyl), -N(Ci-C6 alkyl)2, -C(0)0(C|-C6-aIkyI), ~OC(O)(Ci-Ce-alkyl), -C02H, -C(0)NH2, -C(0)NH(Ci-C6 alkyl), -C(0)N(C,-C6 alkyl)2, -NHC(0)(Ct-C6 alkyl), -N(Ci-Ce alkyl)C(0)(CrC6 alkyl), -0(Ci-C6 alkyl), and -C(0)(Ci-C6-alkyl), each said alkyl groups being optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(Ci-C4 alkyl), -N(Ci-C4 alkyl)?,, -OCOfCrQ alkyl), -CO(Ci-C4 alkyl), -C02H, -C02(Ci-C4 alkyl), and Cr C4 alkoxy; ii) a C3-Cs non-aromatic carbocyclic group, or a 4-8 membered, non-aromatic heterocyclic group, each of which is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, C|-Ce alkyl, -NH2, --NH(Ci-Cc alkyl), -N(C|-Cs alkyl)2, -C(0)0(Ci-C6-alkyl), -OC(0)(Ci-Ce-alkyl), -C02H, -C(0)NH2, -C(0)NH(Ci-C6 alkyl), -C(0)N(CrC6 alkyl)2, -NHC(0)(Ci-C6 alkyl), -N(Ci-C6 alkyl)C(0)(Ci-C6 alkyl), -0(Ci-C6 alkyl), and -C(0)(Ci-C6-alkyl), wherein each of said alkyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(Ci-C4 alkyl), -N(Ci-C4 alkyl)2, -OCO(Ci-C4 alkyl), -CO(Ci-C4 alkyl), -C02H, -C02(Ci-C4 alkyl), and Ci-C4 alkoxy; or iii) a 5-10 membered heteroaryl group ora 6-10 membered carbocyclic aryl group, each of which is optionally and independently substituted with one or more instances of halogen, cyano, hydroxy, oxo, Ci-Ce alkyl, -NHa, -NH(C,-C6 alkyl), -N(Ci-C6 alkyl)2, -C(0)0(CrC6-alkyl), -0C(0)(Ci-C6-alkyl), -C02H, -C(0)NH2, -C(0)NH(C,-C6 alkyl), -C(0)N(Ci-C6 alkyl)2, -NHC(0)(Ci-C6 alkyl), -N(C,-C6 alkyl)C(0)(Ci-C6 alkyl), -0(Ci-C6 alkyl), and -C(0)(Ci-C6-alkyl), wherein each of said alkyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(Ci-C4 alkyl), -N(Ci-C4 alkyl)2, -OCO(Ci-C4 alkyl), -CO(C,-C4 alkyl), -C02H, -C02(C!-C4 alkyl), and Ci-C4 alkoxy.

Specifically, Ra is independently: i) a Ci-C6 aliphatic group optionally substituted with one or more substituents independently selected from the group consisting of halogen; cyano; hydroxy; oxo; -NH2; -NHlCrQ alkyl); -N(Ci-Ce alkyl)2; -C(0)0(Ci-C6-alkyl); -0C(0)(Ci-C6-alkyl); -C02H; -0(Cf-Ce alkyl); -C(0)(Ci-C6-alkyl); and a C3-C7 non-aromatic carbocyclic group, phenyl group, 4-7 membered non-aromatic heterocyclic group, or 5-6 membered heteroaryl group, each of which is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, Ci-Cc alkyl, -NH2, -NH(Ci-Cc alkyl), -N(CrCe alkyl)2, -C(0)0(Ci-C6-alkyl), -0C(0)(CrC6-alkyl), -C02H, -0(Ci-C6 alkyl), and-C(0)(Ci-Ce-alkyl); ii) a C3-C7 nonaromatic carbocyclic group optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, Ci-Ce alkyl, -NH2, -NH(CrC6 alkyl), -N(Ci-C6 alkyl)2, -C(0)0(Ci-C6-alkyl), -0C(0)(Ci-C6-alkyl), -C02H, -0(Ci-C6 alkyl), and -C(0)(Ci-C6-alkyl); ill) a 4-7 membered, non-aromatic heterocyclic group optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, Ci-Cg alkyl, -NH2, -NH(Ci-C6 alkyl), -N(C]-C6 alkyl)2, -C(0)0(Ci-C6-alkyI), -OC(0)(Ci-C6-alkyl), -C02H, -0(Ci-Cfi alkyl), and -C(0)(Ci-CG-alkyl); iv) a 5-6 membered heteroaryl group or a phenyl group, each of which is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, Ci-C6 alkyl, -NH2, -NH(Ci-Cg alkyl), -N(Ct-Ce alkyl)2, -C(0)0(Ci-C6-alkyl), -0C(0)(Ci-C6-alkyl), -C02H, -0(Ci-C6 alkyl), and -C(0)(Ci-C6-alkyl). Each of the alkyl groups referred to in the values of Ra, including substituents thereof, independently and optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(Ci-C4 alkyl), -N(Ci-C4 alkyl)2, -OCO(CrC4 alkyl), -CO(Ci-C4 alkyl), -C02H, -C02(Ci-C4 alkyl), and Ci-C4 alkoxy.

Specifically, the optionally substituted Ci-CG aliphatic group represented by Ra is an optionally substituted Ci-Ce alkyl group.

Rb and Rc are each independently Ra or -H; or optionally, Rb and Rc, together with the nitrogen atom(s) to which they are attached (e.g., represented by -NRbRc, -C(0)NRbRc, —NRC(0)NRbRc, or -OCONRbRc), each independently form a non-aromatic, 5-7 membered, heterocyclic ring that is optionally substituted with one or more instances of JE!. Suitable specific substituents for the heterocyclic ring formed with Rb and R° independently include halogen, cyano, hydroxy, oxo, amino, carboxy, amido, Ci-Ce alkyl, CrCc, haloalkyl, CrCo cyanoaikyl, C2-C6-alkoxyalkyl, Q-Ce aminoalkyl, C|-CG hydroxyalkyl, Ci-CG alkoxy, Cj-Ce haloalkoxy, Ci-Ceaminoalkoxy, Ci -CG cyanoalkoxy, Ci-Cg hydroxyalkoxy, C2-C6 alkoxy alkoxy, and -C(0)(Cj-C6-alkyl). Specific suitable substituents for the heterocyclic ring formed with Rb and Rc independently include halogen, cyano, hydroxy, oxo, -NH2, -NH(Ci-C4 alkyl), -N(Cs-C4 alkyl)2, Ci-C4 alkyl, Ci-C4 haloalkyl, Ci-C4 hydroxyalkyl, C2-C4 alkoxyalkyl, C[.C4 alkoxy, Ci-C4 haloalkoxy, Ci-C4 hydroxyalkoxy, C2-C4 alkoxyalkoxy, -C02(C,-C4 alkyl), -0C(0)(CrC4 alkyl), and -C02H.

It is understood that selections of suitable substituents for the heterocyclic ring formed with Rb and Rc are those that result in the formation of stable or chemically feasible compounds. For example, suitable substituents on a carbon atom independently include halogen, cyano, hydroxy, oxo, -NH2, -NH(Ci-Ce alkyl), -N(Ci-C<> alkyl)2, Ct-Ce alkyl, Ci-C6 haloalkyl, Ci-Ce hydroxyalkyl, C2-C6 alkoxyalkyl, Ci-CG aminoalkyl, Ci-Cg cyanoaikyl, Ci-

Ce alkoxy, Ci-C6 haloalkoxy, Ci-Cc-aminoalkoxy, Ci-C6-cyanoalkoxy, Ci-Ce-hydroxyalkoxy, C2-C6-alkoxyalkoxy, -C(0)(Ci-Ce-alkyl), -C(0 )0 (C l-Cc-alky 1), -00(0)(0r Οή-alkyl), -C02H, -C(0)NH2, -C(0)NH(C,-C6 alkyl), -0(0)Ν(0,-06 alkyl)2, -NHC(0)(Ci-C6 alkyl), and -Ν(0ι-06 alkyI)C(0)(Ci-C6 alkyl). In another example, suitable substituents on a carbon atom independently include halogen, cyano, hydroxy, oxo, -NH2, -NH(Ct-C4 alkyl), -N(C|-C4 alkyl)2, CrC4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, 02-04 alkoxyalkyl, C1-C4 alkoxy, C,-C4 haloalkoxy, C2-C4 hydroxyalkoxy, C2-C4 alkoxyaikoxy, -C0(Ci-C4 alkyl), -C02(Ci-C4 alkyl), and -C02H. For example, suitable substituents on a nitrogen atom independently include Ci-Cc alkyl, Ci-Cg haloalkyl, Ci-Cg hydroxyalkyl, C2-Cc alkoxyalkyl, Ci-Cg aminoalkyl, Ci-Cg cyanoalkyl, -C(0)(Ci-C6-alkyl), -C(0)0(Ci-C6-alkyl), -0C(0)(Ci-Ce-alkyl), -C02H, -C(0)NH2, -C(0)NH(Ci-C6 alkyl), and -C(0)N(Ci-C6 alkyl)2. In another example, suitable substituents on a nitrogen atom independently include C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C2-C4 alkoxyalkyl, C1-C4 alkoxy, Q-C4 haloalkoxy, 02-04 hydroxyalkoxy, -C0(Ci-C4 alkyl), -C02(Ci-C4 alkyl), and -C02H.

[00130] Each Rd is independently -H, Ci-Cc alkyl or -C(0)(Ci-C6 alkyl), wherein each of said alkyl moiety is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(Ci-C4 alkyl), -N(CrC4 alkyl)2, -OCO(Ci-C4 alkyl), -CO(Ci-C4 alkyl), -C02H, -C02(Cr C4 alkyl), and C1-C4 alkoxy. Specifically, each Rd is independently -H, or Ci-Cg alkyl optionally substituted with one or more groups selected from halogen, cyano, hydroxy, oxo, -NHa, -NH(C1-C4 alkyl), -N(Ci-C4 alkyl)2, -OCO(CrC4 alkyl), -CO(C!-C4 alkyl), -C02H, -C02(Ci-C4 alkyl), and C1-C4 alkoxy. p is independently I, 2, 3 or 4. Specifically, p is independently 1 or 2. k, n and m are each independently 0,1 or 2. Alternatively, when rings A and B are 3-6-membered, n and m are each independently 0 or 1; and k is independently 0, 1 or 2; and when rings A and B are 7-8-membered, n and m, are each independently 0, 1 or 2; and k is independently 0,1 or 2. x and y are each independently 0, 1 or 2. z is 1 or 2.

[00131] A second set of variables of Structural Formulae (I) and (IA) is as follows: R2 is -H or -CH3. R3 is -H, -Cl, -F, -Br, -CN, -CF3, -0(CrC4 alkyl), -OH, -NH2, -NH(CrC4 alkyl), or -N(Ci-C4 alky 1)2.

Values of the remaining variables of Structural Formulae (I) and (IA), including specific values, and provisos are each and independently as described above for the first set of variables of Structural Formulae (I) and (IA).

[00132] A third set of variables of Structural Formulae (I) and (I A) is as follows: R2 is -H or -CHj. R4 is i) an optionally substituted C3-C10 carbocyclic ring; ii) a Ci-Ce aliphatic group (e.g., CrC6 alkyl or C2-Cfi alkenyl group) that is substituted with one or more substituents independently selected from the group consisting of Jc, an optionally substituted, CrCs nonaromatic carbocycle, and an optionally substituted, 4-10 membered non-aromatic heterocycle; or iii) an optionally substituted, 4-10 membered non-aromatic heterocycle.

Values of the remaining variables of Structural Formulae (I) and (IA), including specific values, and provisos are each and independently as described above for the first set of variables of Structural Formulae (I) and (IA).

[00133] A fourth set of variables of Structural Formulae (I) and (IA) is as follows: R2 is -H or -CH3. R3 is -H, -Cl, -F, -Br, -CN, -CF3, -0(^-C4 alkyl), -OH, -NH2, -NH(C,-C4 alkyl), or -N(Ci-C4 alkyl)2. R4 is selected from formulae A-D depicted above.

The remaining variables of Structural Formulae (I) and (IA), including specific values, are each and independently as described above for the first set of variables of Structural Formulae (I) and (IA).

[00134] A fifth set of variables of Structural Formulae (I) and (IA) is as follows: R2 is -H or -CH3. R3 is -H, -F, -Cl, -CFj, -NH2, -NHMe or -NMe2. R4 is i) an optionally substituted C3-C10 carbocyclic ring; ii) a Ci-C<s aliphatic group (e.g., Ci-Cc alkyl or C2-Cr, alkenyl group) that is substituted with one or more substituents independently selected from the group consisting of Jc, an optionally substituted, C3-C8 nonaromatic carbocycle, and an optionally substituted, 4-10 membered non-aromatic heterocycle; or iii) an optionally substituted, 4-10 membered non-aromatic heterocycle.

Values of the remaining variables of Structural Formulae (I) and (IA), including specific values, and provisos are each and independently as described above for the first set of variables of Structural Formulae (I) and (IA).

[00135] A sixth set of variables of Structural Formulae (I) and (IA) is as follows: R2 is -H or -CH3. R3 is -H, -F, -Cl, -CF3, -NH2j -NH(CH3), or -N(CH3)2- R4 is selected from formulae A-D depicted above.

Values of the remaining variables of Structural Formulae (I) and (IA), including specific values, are each and independently as each and independently as described above for the first set of variables of Structural Formulae (I) and (IA).

[00136] A seventh set of variables of Structural Formulae (I) and (IA) is as follows: R2 is -H or -CH3. R3 is -H, -F, or -Cl. R4 is i) an optionally substituted C3-C10 carbocyclic ring; ii) a C1-C6 aliphatic group (e.g., C| -Cf, alkyl or C2-Ce alkenyl group) that is substituted with one or more substituents independently selected from the group consisting of Jc, an optionally substituted, C3-C8 nonaromatic carbocycle, and an optionally substituted, 4-10 membered non-aromatic heterocycle; or iii) an optionally substituted, 4-10 membered non-aromatic heterocycle.

Values of the remaining variables of Structural Formulae (I) and (IA), including specific values, and provisos are each and independently as each and independently as described above for the first set of variables of Structural Formulae (I) and (IA).

[00137] An eighth set of variables of Structural Formula I is as follows: R2 is -H or -CH3. R3 is -H, -F, or-Cl. R4 is selected from formulae A-D depicted above.

Values of the remaining variables of Structural Formulae (I) and (IA), including specific values, and provisos are each and independently as each and independently as described above for the first set of variables of Structural Formulae (I) and (IA), [00138] A ninth set of variables of Structural Formulae (I) and (IA) is as follows: R2 is -H. R3 is-H or-Cl. R4 is i) an optionally substituted C3-C10 carbocyclic ring; ii) a C\-C6 aliphatic group (e.g., Ci-Ce alkyl or C2-C6 alkenyl group) that is substituted with one or more substituents independently selected from the group consisting of Jc, an optionally substituted, Gj-Cg nonaromatic carbocycle, and an optionally substituted, 4-10 membered non-aromatic heterocycle; or iii) an optionally substituted, 4-10 membered non-aromatic heterocycle.

Values of the remaining variables of Structural Formulae (I) and (IA), including specific values, and provisos arc each and independently as each and independently as described above for the first set of variables of Structural Formulae (I) and (IA).

[00139] A tenth set of variables of Structural Formulae (I) and (IA) is as follows: R2 is -H. R3 is -H or -Cl. R4 is selected from formulae A-D depicted above.

Values of the remaining variables of Structural Formulae (I) and (IA), including specific values, and provisos are each and independently as each and independently as described above for the first set of variables of Structural Formulae (I) and (IA), [00140] An eleventh set of variables of Structural Formulae (I) and (IA) is as follows: Each of R2, R3 and R4 is independently as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, or tenth set of variables of Structural Formulae (I) and (IA). Z1 is -H, Ci-Ce alkyl, -0(C,-C6 alkyl), -F, -Cl, -CN, -C02H, -C02(Ci-C6 alkyl), -CONH2, -CONH(Ci-C6 alkyl), or -CON(Ci-C6 alkyl)2; and Z2 is -H, Ci-Ce alkyl, -0(Ci-C6 alkyl), -NH2, -NH(Ci-C<s alkyl), or -N(Ci-Cg alkyl)2; wherein each of said alkyl groups (e.g., represented by Ci-C6 alkyl, -0(Ci-C6 alkyl), -C02(CrC6 alkyl), -NH(C,-Cfi alkyl), and -N(C,-C6 alkyl)2) is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(Ci-C4 alkyl), -N(C,-C4 alkyl)* -OCO(C,-C4 alkyl), -CO(Ct-C4 alkyl), -C02H, -C02(Ci-C4 alkyl), and C1-C4 alkoxy.

Values of the remaining variables of Structural Formulae (I) and (IA), including specific values, and provisos are each and independently as described above for the first set of variables of Structural Formulae (I) and (IA).

[00141] A twelfth set of variables of Structural Formulae (I) and (IA) is as follows: Each of R2, R3 and R4 is independently as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, or tenth set of variables of Structural Formulae (I) and (IA).

Zl is -H, -F, -Cl, C1-C4 haloalkyl (e.g, -CF3), C1-C4 alkyl, -0(Ci-C4 alkyl), or -CN. Z2 is -H, Ci-Ce alkyl, -0(Ci-C6 alkyl), -NH2, -NH(Ci-Cfi alkyl), or -N(Ci-Ce alkyl)2; wherein each of said alkyl groups (e.g., represented by Ci-Ce alkyl, -0(Ci-CG alkyl), -NH(Cr CG alkyl), and -N(Ci-C6 alkyi)2) is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(C[-C4 alkyl), -N(Ci-C4 alkyl)2, -0C0(C,-C4 alkyl), -CO(Ci-C4 alkyl), -C02H, -C02(Ci-C4 alkyl), and C1-C4 alkoxy.

Values of the remaining variables of Structural Formulae (I) and (IA), including specific values, and provisos are each and independently as described above for the first set of variables of Structural Formulae (I) and (IA).

[00142] A thirteenth set of variables of Structural Formulae (I) and (IA) is as follows: Each of R2, R3 and R4 is independently as described in the first set, second set, third set, fourth set, fifth set, sixth set, seventh set, eighth set, ninth set, or tenth set, of variables of Structural Formulae (I) and (IA). Z1 is -H, -F, -Cl, C,-Oj haloalkyl (e.g, -CF3), C1-C4 alkyl, -0(Ci-C4 alkyl), or -CN. Z2 is -H or a CrCe alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(Ci-C4 alkyl), -N(Cx-C4 alkyl)2, -OCO(CrC4 alkyl), -CO(C,-C4 alkyl), -C02H, -C02(Cx-C4 alkyl), and Ci-C4 alkoxy.

Values of the remaining variables of Structural Formulae (I) and (IA), including specific values, and provisos are each and independently as described above for the first set of variables of Structural Formulae (I) and (IA), [00143] A fourteenth set of variables of Structural Formulae (I) and (IA) is as follows: Each of R2, R3 and R4 is independently as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, or tenth set of variables of Structural Formulae (I) and (IA). Z1 is -H, -F, -Cl, -CF3, -CHj, or-CN. Z2 is -H or a Ci-Cs alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(Ci-C4 alkyl), -N(Ci-C4 alkyl)2, -OCO(C(-C4 alkyl), -CO(Cx-C4 alkyl), -C02H, -C02(Cx-C4 alkyl), and Ci-C4 alkoxy.

Values of the remaining variables of Structural Formulae (I) and (IA), including specific values, and provisos are each and independently as described above for the first set of variables of Structural Formulae (I) and (IA).

[00144] In a fifteenth set of variables of Structural Formulae (I) and (IA), values of the the variables, except R*, R and R\ of Structural Formulae (I) and (IA), including specific values, and provisos are each and independently as described above in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, or fourteenth set of variables of Structural Formulae (I) and (IA); and, where applicable: each R* independently is: i) -H; ii) CrCe alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(C!-C4 alkyl), -N(Ci-C4 aUcyl)2, -OCO(Ci-C4 alkyl), -CO(C,-C4 alkyl), -CO2H, -COj(C]-C4 alkyl), and Ci-C4 alkoxy; or iii) a 3-7 raembered carbocyclic ring optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(C].-C4 alkyl), -N(Ci-C4 alkyl)2, -OCO(Ci-C4 alkyl), -CO(Ci-C4 alkyl), -C02H, -C02(Ci-C4 alkyl), Ci-C4 alkoxy, and C1-C6 alkyl, wherein each alkyl is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(Ci-C4 alkyl), -N(CrC4 alkyl)2, -OCO(Ct-C4 alkyl), -CO(CrC4 alkyl), -C02H, -C02(Ci-C4 alkyl), and Ci-C4 alkoxy; and R and R’ are each independently -H or Ci-Ce alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(C|-Ce alkyl), -N(Ci-Ce alkyl)2, and -0(Ct-C<5 alkyl); or optionally R’, together with R5 and the nitrogen atom to which they are attached, forms a 5-7 membered, non-aromatic, heterocyclic ring optionally substituted with one or more instances ofJD1.

[00145] A sixteenth set of variables of Structural Formulae (I) and (IA) is as follows:

Each of JA and JB is independently selected from the group consisting of halogen, cyano, oxo, andQ!-R5; or optionally two JA and two JB, respectively, together with the atom(s) to which they are attached, independently form a 5-7 membered ring that is optionally substituted with one or more instances of JE1, and fused to the ring to which they are attached, Q1 is independently a bond, -0-, -S-, -NR’-, -C(O)-, -C02-, -OC(O)-, -C(0)NR’-, -C(0)NRC(0)0- -NRC(0)NRC(0)0-, -NRC(O)-, -NRC(0)NR’-, -NRCO2-, -0C(0)NR’-, -S(O)-, -SO2-, -SO2NR’-, -NRSO2-, or -NRS02NR’-, or-(CRV)p-Y1-.

Each of JC1 and JD1 is independently selected from the group consisting of halogen, cyano, oxo, Ra, -ORb, -SRb, -S(0)Ra, -S02R°, -NRbRc, -C(0)Rb, -C(0)0Rb, -0C(0)Rb, -NRC(0)Rb, -C(0)NRbRc, -NRC(0)NRbRc, -NRC(0)0Rb, -OCONRbRc, -C(0)NRC02Rb, -NRC(0)NRC(0)0Rb, -C(0)NR(0Rb), -S02NRcRb, -NRS02Rb, and -NRS02NRcRb, or optionally, two JC1 and two JD1, respectively, together with the atoms to which they are attached, independently form a 5-7-membered ring that is optionally substituted with one or more instances of JEI, and fused to the respective ring to which they are attached.

Values of the remaining variables of Structural Formulae (I) and (IA), including specific values, and provisos are each and independently as described above for the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, or fourteenth set of variables of Structural Formulae (I) and (IA).

[00146] A seventeenth set of variables of Structural Formulae (I) and (IA) is as follows: R1 is -H. R2 is -H, -CH3, -CH2OH, or -NH2. Alternatively R2 is ~-H or -CH2OH. R3 is -H, -F, -Cl, Cm alkyl, or Cm halo alkyl. Alternatively, R3 is -H, -F, or -Cl. t is -H, -F, or -Cl. Z2 is -H or Ci-Ce alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, and -0(CrC4 alkyl). Z3 is -H or Ci -Ce alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, and -0(C£-C4 alkyl).

The remaining variables are as decribed above in any set of variables for Structural Formulae (IA) and (I) as applicable.

[00147] An eighteenth set of variables of Structural Formulae (I) and (IA) is as follows: R1 is -H. R2 is -H or -CH2OH. R3 is -H, -F, or -Cl. Alternatively R3 is -F or -Cl. Z1 is -H, -F, or-Cl. Z2 and Z3 are -H.

The remaining variables are each and independently as decribed above in any set of variables for Structural Formulae (IA) and (I).

[00148] A nineteenth set of variables of Structural Formulae (I) and (IA) is as follows: R5 is: i) -H; ii) an optionally substituted C£--C6 alkyl group; iii) an optionally substituted, C3-C7 non-aromatic carbocycle; iv) an optionally substituted, 4-7 membered nonaromatic hcterocycle; v) )an optionally substituted phenyl group; vi) an optionally substituted 5-6 membered heteroaryl ring; or optionally, together with R and the nitrogen atom to which it is attached, form a 5-7 membered, optionally substituted non-aromatic heterocycle; and said alkyl group represented by R5 is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(Ci-C4 alkyl), -N(C,-C4 alkyl)2, -OCO(C£-C4 alkyl), -CO(Ci-C4 alkyl), -C02H, -C02(CrC4 alkyl), C1-C4 alkoxy, -NRCO(Ci-C4 alkyl), -CONR(Ct-C4 alkyl), -NRC02(Ci-C4 alkyl), a C3-C7 non-aromatic carbocycle optionally substituted with one or more instances of JE1, a 4-7 membered non-aromatic heterocycle optionally substituted with one or more instances of JE!; and a phenyl optionally substituted with one or more instances of JE1; and wherein each of said carbocycle, heterocycle, phenyl and heteroary represented by R5 is independently and optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, C1-C4 alkyl, -0(Ci-C4 alkyl), -NH2, -NH(Ci-C4 alkyl), -N(Ci-C4 alkyl)2, -C(0)(Ci-C4 alkyl), -0C(0)(Ci-C4 alkyl), -C(0)0(Ci-C4 alkyl) and -C02H, wherein each of said alkyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(Ci-C4 alkyl), -N(Ci-C4 alkyl)2, -OCO(CrC4 alkyl), -CO(Ci-C4 alkyl), -C02H, -C02(C,-C4 alkyl), and CrC4 alkoxy. R\ R2, R3, Z1, Z2, and Z3 are each independently as described in the seventeenth or eighteenth set of variables above.

The remaining variables are each and independently as decribed above in any set of variables for Structural Formulae (IA) and (I). 100149] In some embodiments, the variables of Structural Formulae (IA) and (I) are each and independently as described above in any set of variables, provided that: R4 is:

* n and m are each independently 0 or 1 when rings A and B are 3-6-membered; or n and m are each independently 0,1 or 2 when rings A and B are 7-10-membered; and provided that ifY1 is a bond, then R5 is neither-H nor a Ci-C6 aliphatic group; and provided that if each Q2 and Q3 independently is a bond, then R5 is neither -H nor a Ci-Co aliphatic group.

[00150] In another embodiment, the present invention is directed to the use of compounds represented by any one of the Structural Formulae II, III, IY, and V, depicted below, or pharmaceutically acceptable salts thereof, for any of the uses described above:

[00151] The first set of variables of Structural Formulae II - V is as follows: Z1 is -H, -F, -Cl, C1-C4 haloalkyl (e.g, -CF3), C1-C4 alkyl, -0(Ci-C4 alkyl), or -CN. Z2 is -H, Ci-Ce alkyl, -0(C,-C6 alkyl), -NH2, -NH(CrC6 alkyl), or-N(C,-C6 alkyl)2l wherein each of said alkyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(Ci-C4 alkyl), -N(Ci-C4 alkyl)2, -OCO(Ct-C4 alkyl), -CO(C]-C4 alkyl), -C02H, -C02(Ci-C4 alkyl), and CrC4 alkoxy. R3 is -H, -Cl, -F, -Br, -CN, -CF3, -0(C,-C4 alkyl), -OH, -NH2, -NH(CrC4 alkyl), or -N(Ci-C4 alkyl)2. Specifically, R3 is -H, -F, -Cl, -CF3, -NH2, -NH(CHj), or -NiCHsfi. Specifically, R3 is -H, -Cl, or -F. Specifically, R3 is -Cl.

Each R and R’ are independently -H or C[-C 6alkyl.

Definitions of rings A-D of formulae II-V, including specific variables, are each and independently as described above for the first set of variables of Structural Formulae (I) and (IA), wherein each of rings A-D is independently an optionally substituted, 4-7 membered ring.

Values of the remaining variables of Structural Formulae II-V, including specific values, and provisos arc each and independently as described above for the first set of variables of Structural Formulae (I) and (IA).

[00152] A second set of variables of Structural Formulae II, III, IV and V is as follows: Z1 is -H, -F, -Cl, -CF3, -CH3, or-CN. Z is -H or Ci-Cs alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(C[-C,| alkyl), -N(CrC4 alkyl)* -OCO(C,-C, alkyl), -CO(CrC4 alkyl), -C02H, -C02(Ci-C4 alkyl), and C]-C4 alkoxy.

Values of the remaining variables of Structural Formulae II-V, including specific values, and provisos are each and independently as described above for the first set of variables of Structural Formulae II-V.

[00153] A third set of variables of Structural Formulae II, III, IV and V is as follows: Z1 is-H,-F or-CN. Z2 is -H or Ci-Cc alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(Ci-C4 alkyl), -N(Ci-C4 alkyl)2, -OCO(Ct-C4 alkyl), -CO(CrC4 alkyl), -C02H, -C02(Ci-C4 alkyl), and Ci-C4 alkoxy.

Values of the remaining variables of Structural Formulae II-V, including specific values, and provisos are each and independently as described above for the first set of variables of Structural Formulae II-V.

[00154] A fourth set of variables of Structural Formulae II, III, IV and V is as follows: 7} is -H, -F or -CN. Z is -H or Ci-Cfi alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(Ci-C4 alkyl), -N(Ci-C4 alkyl)2, -OCO(C,-C4 alkyl), -CO(Ct-C4 alkyl), -C02H, -C02(Ci-C4 alkyl), and Ci-C4 alkoxy. R3is-H, -Cl or -F.

Values of the remaining variables of Structural Formulae II-V, including specific values, and provisos are each and independently as described above for the first set of variables of Structural Formulae II-V.

[00155] A fifth set of variables of Structural Formulae II, III, IV and V is as follows: Zl is -H, -F or -CN. y Z" is -H or Cj-C4 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(CrC4 alkyl), -N(Ct-C4 alkyl)2, -OCO(CrC4 alkyl), -CO(CrC4 alkyl), -C02H, -C02(Cr C4 alkyl), and Ci-C4 alkoxy. R3 is -H, -Cl, -F, -CF3,-NH2, -NH(CH3), or-N(CH3)2. R6 and R7 are each independently -H or -CH3, or together with the carbon atoms to which they are attached they form a cyclopropane ring.

Each Rs is independently -H, halogen, cyano, hydroxy, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C2-C4 alkoxyalkyl, -0(Ci-C4 alkyl), -NH2, -NH(Ci-C4 alkyl), or “N(Ci-C4 alkyl)2.

Each R9 is independently -H or -CH3. R11 and R12 are each independently -H or -CH3. R13 and R14 are each independently -H or-CH3, or together with the carbon atoms to which they are attached they form a cyclopropane ring.

Values of the remaining variables of Structural Formulae II-V, including specific values, and provisos are each and independently as described above for the first set of variables of Structural Formulae II-V.

[00156] A sixth set of variables of Structural Formulae II, III, IV and V is as follows: Z1 is -H, -F or ™CN. Z2 is -H or an optionally substituted Ct-Ce alkyl. R3 is -H, -Cl or -F. R6 and R7 are each independently -H or -CH3, or together with the carbon atoms to which they are attached they form a cyclopropane ring.

Each R8 is independently -H, halogen, cyano, hydroxy, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C2-C4 alkoxyalkyl, -0(Ci-C4 alkyl), -NH2, -NH(Ci-C4 alkyl) or -N(C!-C4 alky 1)2.

Each R9 is independently -H or -CH3. R11 and R12 are each independently -H or-CH3. R13 and R14 are each independently -H or -CH3, or together with the carbon atoms to which they are attached they form a cyclopropane ring.

Values of the remaining variables of Structural Formulae II-V, including specific values, and provisos are each and independently as described above for the first set of variables of Structural Formulae II-V, [00157] In a seventh set of variables of Stiuctural Formulae II-V, values for variables, except R6, R7, R8, R9, R11, R12, R13, and R14, of Structural Formulae II-V, including specific values, are each and independently as described above for the first, second, third, or fourth set of variables of Structural Formulae II-V; and R6 and R7 arc each independently -H or -C1-C4 alkyl, or together with the carbon atoms to which they are attached they form a cyclopropane ring.

Each Rs is independently -H, halogen, cyano, hydroxy, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C2-C4 alkoxyalkyl, -0(<ν04 alkyl), -NH2, -NH(Ci-C4 alkyl) or -N(C,-C4 alky 1)2.

Each R9 is independently -H or-Ci-C4 alkyl.

Ru and R12 are each independently -H or-Ci-C4 alkyl. R13 and R14 are each independently -H or-Ci-C4 alkyl, or together with the carbon atoms to which they are attached they form a cyclopropane ring.

[00158] In an eighth set of variables of Structural Formulae II-V, values for variables of Structural Formulae II-V, including specific values, are each and independently as described above for the first set of variables of Structural Formulae II-V.

It is provided that when Q2-R5 is -OR5 or -NR’R5, ring A is further substituted with one or more instances of JA other than -H.

It is provided that if Q3 is -C(0)-, then R5 is a substituted Ci-Ce aliphatic group (e.g., Ci-Cg alkyl group or C2-C6 alkenyl group); an optionally substituted C3-C8 non-aromatic carbocyclc; an optionally substituted, 6-10-membered carbocyclic aryl group; an optionally substituted, 4-8 membered non-aromatic heterocycle; or an optionally substituted, 5-10 membered heteroaryl group. In one embodiment, the Ci-Ce aliphatic group is substituted with one or more instances of JC1, wherein JCI is independently selected from: an optionally substituted, C3-CS non-aromatic carbocycle; an optionally substituted, 6-10-membered carbocyclic aiyl group; an optionally substituted, 4-8 membered non-aromatic heterocycle; an optionally substituted, 5-10 membered heteroaryl group; -0Rb; -SRb; -S(0)Ra; -S02Ra; -NRbRc; -C(0)Rb; -C(0)0Rb; -0C(0)Rb; -NRC(0)Rb; -C(0)NRbRc; -NRC(0)NRbRc; -NRC(0)0Rb; -OCONRbR'; -C(0)NRC02Rb; -NRC(0)NRC02Rb; -C(0)NR(0Rb); -S02NRcRb; -NRS02Rb; and -NRS02NRcRb; or optionally two JC1 and two JD1, respectively, together with the atoms to which they are attached, independently form a 5-7-membered ring that is optionally substituted with one or more instances of JE!, and fused to the respective ring to which they are attached.

[00159] In a ninth set of variables of Structural Formulae II-V, values for variables of Structural Formulae II-V, including specific values, and provisos are each and independently as described above in the first set of variables of Structural Formulae (I) and (IA).

[00160] A tenth set of variables of Structural Formulae II-V is as follows:

Each of JA and JB is independently selected from the group consisting of halogen, cyano, oxo, and Q'-R3; or optionally two JA and two JB, respectively, together with the atom(s) to which they are attached, independently form a 5-7 membered ring that is optionally substituted with one or more instances of JEI, and fused to the ring to which they are attached. Q! is independently a bond, -0-, -S-, -NR- -C(0)~, -C02-, -0C(0)-, -CfOjNR- -C(0)NRC(0)0- -NRC(0)NRC(0)0-, -NRC(O)-, -NRC(0)NR-, -1nRC02-, -0C(0)NR- -S(0)-, -S02-, -N(R)S02- -S02N(R)-3 -NRS02NR-, or -(CR6R7)p-Y!- Q2 is independently a bond, -0-, -S-, -NR-, -C(0)-, -C02-, -0C(0)-, -C(0)NR- -C(0)NRC(0)0-, -NRC(0)NRC(0)0-, -NRC(O)-, -NRC(0)NR~, -NRC02- -0C(0)NR-, -S(0)-, -SO2-, -N(R)S02- -S02N(R)-; -NRS02NR-, or -(cr6rVy1-· Q3 is independently a bond, -C(0)-, -C02-, -C(0)NR-, -S02--S02N(R)-, -C(0)NRC(0)0- or -(CR6R7)P-Y1-. R5 is: i) -H; ii) a CrC6 aliphatic group optionally substituted with one or more instances of JC1; iii) a Cj-Cg non-aromatic carbocycle, or 6-10 membered carbocyclic aryl group, each optionally and independently substituted with one or more instances of JCI; or iv) a 4-8 membered non-aromatic heterocycle, or a 5-10 membered heteroaryl group, each optionally and independently substituted with one or more instances of JDi.

Each of JCI and JD1 is independently selected from the group consisting of halogen, cyano, oxo, Ra, -0Rb, -SRb, -S(0)Ra, -S02Ra, -NRhRc, -C(0)Rb, -C(0)0Rh, -0C(0)Rb, -NRC(0)Rb, -C(0)NRbRc, -NRC(0)NRbRc, -NRC(0)0Rb, -OCONRbRc, -C(0)NRC02Rb, -NRC(0)NRC(0)0Rb, -C(O)NR(0Rb), -S02NRcRb, -NRS02Rb, and -NRS02NRcRb, or optionally, two JC1 and two JD1, respectively, together with the atoms to which they are attached, independently form a 5-7-membered ring that is optionally substituted with one or more instances of JE1, and fused to the respective ring to which they are attached.

Ring A is a C3-C8 non-aromatic carbocycle optionally and independently further substituted with one or more instances of JA.

Values of the remaining variables of Structural Formulae II-V, including specific values, and provisos are each and independently as described above for the first, second, third, fourth, fifth, sixth, seventh, eighth, or ninth set of variables of Structural Formulae II-V.

[00161] In another embodiment, the present invention is directed to the use of compounds represented by the Structural Formula below XI(A) or XI(B), or a pharmaceutically acceptable salt thereof, for any of the uses described above.

XI(A) XI(B) A first set of variables of Structural formulae XI(A) and XI(B) is as follows:

Ring A is a 5-7 membered, non-aromatic carbocyclic ring optionally further substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, C1-C6 alkyl, C2-C6 alkenyl, -NH2, -NH(Ci-C6 alkyl), -NfCi-Ce alkyl)2, -0(Ci_C6 alkyl), -C(0)NH2) -C(0)NH(Ci-C6 alkyl), -C(0)N(C,-C6 alkyl)2, -C(0)(Ci-Cg-alky 1), -0C(0)(Ci-Ce alkyl), -NHC(0)(CrC6 alkyl), -N(C,-C6 alkyl)C(0)(Cl-C<5 alkyl), and -C02Rb; wherein each of said alkyl and alkenyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(Ci-C4 alkyl), -N(Ci-C4 alkyl)2, -OCO(Ci-C4 alkyl), -CO(Cj-C4 alkyl), -C02H, -C02(Ci-C4 alkyl), and Ci-CU alkoxy. Specifically, ring A is a 5-7 membered, non-aromatic carbocyclic ring optionally further substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, Ci-C4 alkyl, -0(Ci-C4 alkyl), -NH2, -NH(Ci~C4 alkyl), -N(Ci-C4 alkyl)2, -C(0)(CrC4 alkyl), -0C(0)(Ct-C4 alkyl), -C02H, and -C02(C,-C4 alkyl), wherein each of said alkyl groups is optionally and indepednently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(Ci-C4 alkyl), -N(Ci-C4 alkyl)2, -OCO(Ci-C4 alkyl), -CO(Cj-C4 alkyl), -C02H, -C02(Ci-C4 alkyl), and Ci-C4 alkoxy. Specifically, ring A is a 5-7 membered carbocyclic ring optionally further substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(Ci-C2 alkyl), -NH(Ci-C2 alkyl)2, Ci-C2 alkyl, CrC2 haloalkyl, Ci-C2 hydroxyalkyl, C2-C4 alkoxyalkyl, Ci-C2 alkoxy, C]-C2 hydroxyalkoxy, Cj-C2 haloalkoxy, C2-C4 alkoxy alkoxy, -C02H, and -C02(Ci-C4 alkyl). R6 and R7 are each independently -H or -CH3, or together with the carbon atoms to which they are attached they form a cyclopropane ring.

Each R8 is independently -H, halogen, cyano, hydroxy, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C2-C4 alkoxyalkyl, -0(Ci-C4 alkyl), -NH2, -NH(Ci-C4 alkyl), or -N(Ci-C4 alkyl)2.

Each R9 is independently -H or -CEE. R11 and R12 are each independently -H or -CEU. R13 and R14 are each independently -H or -CH3, or together with the carbon atoms to which they are attached they form a cyclopropane ring.

Each R and R’ are independently -H or C1-C6 alkyl.

Values of the remaining variables of Structural formulae XI(A) and X1(B), including specific values, and provisos are each and independently as described above in the first set of variables of Structural Formulae (I) and (IA).

[00162] A second set of variables for Structural formulae XI(A) and XI(B) is as follows:

Values of Ring A, R, R’, R6, R7, R8, R9, Rn, R12, R13 and R14, including specific values, are each and independently as described above in the first set of variables of Structural formulae XI(A) and XI(B).

Variable x is 0 or 1 and variable n is 0 or 1.

Values of the remaining other variables of Structural formulae XI(A) and XI(B), including specific values, and provisos are each and independently as described above in the first set of variables of Structural Formulae (I) and (IA).

[00163] A third set of variables for Structural formulae X1(A) and XI(B) is as follows: Values of Ring A, R, R% R6, R7, R8, R9, R11, R12, R13, R14, x and n, including specific values, are each and independently as described above in the second set of variables of Structural formulae XI(A) and XI(B). Q2 is -0-, -NR’-, -CO-, -CO2-, -C(0)NR’-, -NRC(O)-, -NRC(0)NR--NRCO2-, -OCONR’-, -NRS02- -S02NR'-, or -(CReR7)p-Y-. Specifically, Q2 is -Ο-, -NH-, -N(CH3)-, -C(0)-, -CO2-, -C(0)NH- -C(0)N(CH3)-, -NHC(O)-, -N(CH3)C(0)-, -NHC(0)NR’-, -N(CH3)C(0)NR’- -NHCO2-, -N(CH3)C02--0C(0)NR’-, -NHSO2-, -N(CH3)S02- -SO2NH-, -S02N(CH3)-, or -(CR^ip-Y1-.

Values of the remaining variables of Structural formulae XI(A) and XI(B), including specific values, and provisos are each and independently as described above in the first set of variables of Structural Formulae (1) and (IA).

[00164] A fourth set of variables for Structural formulae XI(A) and XI(B) is as follows:

Values of Ring A, Q2, R, R\ R6, R7, Rs, R9, Rn,R12, R13, R14, x and n, including specific values, are each and independently as described above in the third set of variables of Structural formulae XI(A) and XI(B). R5 is independently i) -H; ii) a Ci-Cs-aliphatic group (e.g., Ci-Ce-alkyl or Ci-Cg-alkenyl group) optionally substituted with one or more instances of /:1; iii) a C3-Cs nonaromatic carbocycle optionally substituted with one or more instances of JC1; iv) a phenyl group optionally substituted with one or more instances of JC1; v) a 4-8 membered nonaromatic heterocycle optionally substituted with one or more instances of Jm or vi) a 5-6 membered heteroaryl ring optionally substituted with one or more instances of JDi.

Each of JC1 and JD1 is independently selected from the group consisting of halogen, cyano, oxo, Ra, -ORb, -SRb, -S(0)Ra-, -S02Ra, -NHRC, -C(0)Rb, -C(0)0Rb, -0C(0)Rb, -NHC(0)Rb, -C(0)NHRc, -NHC(0)NHRc, -NHC(0)0Rb, -OCONHRf -NHC(0)NHC(0)0Rb, -N(CH3)Rc, -N(CH3)C(0)Rb, -C(0)N(CH3)R\ -N(CH3)C(0)NHRc, -N(CH3)C(0)0Rb, -OCON(CH3)Rc, -C(0)NHC02Rb, -C(0)N(CH3)C02Rb, -N(CH3)C(0)NHC(0)0Rb, -NHS02Rb, -S02NHRb, -S02N(CH3)Rb, and -N(CH3)S02Rb.

Values of the remaining variables of Structural formulae XI(A) and XI(B), including specific values, and provisos are each and independently as described above in the first set of variables of Structural Formulae (I) and (IA).

[00165] A fifth set of variables for structure Structural formulae XI(A) and XI(B) is as follows:

Values of Q2, R, R’, R5, R6, R7, R8, R9, R11, R12, R13, R14, x and n, including specific values, are each and independently as described above in the fourth set of variables of Structural formulae XI(A) and XI(B).

Ring A is optionally further substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, C1-C4 alkyl, -(XC1-C4 alkyl), -NH2, -NH(C,-C4 alkyl), -N(C!-C4 alkyl)2, -C(0)(Ci-C4 alkyl), -C02H, and -C02(Ci-C4 alkyl), wherein each of said alkyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, C1-C4 alkyl, -NH2, -NH(Ci-C4 alkyl), -N(Ci-C4 alkyl)2, -OCO(Ct-C4 alkyl), -CO(Cr-C4 alkyl), -C02H, -C02(Ci-C4 alkyl), and Cs-C4 alkoxy.

Values of the remaining variables of Structural formulae XI(A) and XI(B), including specific values, and provisos are each and independently as described above in the first set of variables of Structural Formulae (I) and (IA).

[00166] A sixth set of variables for Structural formulae XI(A) and XI(B) is as follows:

Values ofQ2, R, R’, R5, R6, R7, Rs, R9, R11, R12, R13, R14, x and n, including specific values, are each and independently as described above in the fifth set of variables of Structural formulae XI(A) and XI(B).

The group -[(C)o-iR13R14]-ringA-Q2-R5 is independently selected from one of the depicted below:

wherein each of rings A1-A27 is independently and optionally further substituted with one or more substituents. Suitable substituents are as described above for ring A in the first set of variables of Structural formulae XI(A) and XI(B).

Values of the remaining variables of Structural formulae XI(A) and XI(B), including specific values, and provisos are each and independently as described above in the first set of variables of Structural Formulae (1) and (IA).

[00167] A seventh set of variables of Structural formulae XI(A) and XI(B) is as follows:

Values of the group -[CR,3Rt4]x-ringA-Q2-R5, Q2, R, R’, R6, R7, R8, R9, Ru, R12, R13, R14, x and n, including specific values, are each and independently as described above in tlie sixth set of variables of Structural formulae XI(A) and XI(B).

Each R5 is independently: i).....H; ii) a Ci-C6-aliphatic group optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, C1-C4 alkyl, -0(Ct-C4 alkyl), -NH2j -NH(Ci-C4 alkyl), -N(Ci-C4 alky 1)2, -C(0)(Ct-C4 alkyl), -0C(0)(Ci-C4 alkyl), -0(0)0((^-04 alkyl), -C02H, 03-0« nonaromatic carbocycle, phenyl, 4-8 membered non-aromatic heterocycle, and 5-6 membered heteroaryl; or iii) a C3-C7 non-aromatic carbocycle, a 4-7 membered non-aromatic heterocycle, a phenyl group, or a 5-6 membered heteroaryl ring, each of which is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, Cj-C4 alkyl, -0(Ci-C4 alkyl), -NH2, -NH(Ci-C4 alkyl), -N(Ci-C4 alkyl)2, -C(0)(Ci-C4 alkyl), -0C(0)(C,-C4 alkyl), -C(0)0(Ci-C4 alkyl), and -C02H; wherein each of said alkyl groups for the substituents of the aliphatic group, carbocycle, heterocycle, phenyl and heteroaryl group represented by R5 is independently and optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(CrC4 alkyl), -N(Ci-C4 alkyl)2, -OCO(Ci-C4 alkyl), -CO(CrC4 alkyl), -C02H, -C02(Ci-C4 alkyl), and 0,-C4 alkoxy; and wherein each of said carbocycle, phenyl, heterocycle, and heteroaryl for the substituents of the Ct-Ce-aliphatic group represented by R5 is independently and optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, C]-C4 alkyl, -NH2, -NH(Ci-C4 alkyl), -N(Ci-C4 alkyl)2, -OCO(C,-C4 alkyl), -CO(C,-C4 alkyl), -C02H, -C02(C,-C4 alkyl), and C,-C4 alkoxy.

Values of the remaining variables of Structural formulae XI(A) and XI(B), including specific values, and provisos are each and independently as described above in the first set of variables of Structural Formulae (1) and (IA).

[00168] An eighth set of variables of Structural formulae XI(A) and XI(B) is as follows:

Values of Q2, R, R’, R5, R6, R7, Rs, R9, R11, R12, R13, R14, χ and n, including specific values, are each and independently as described above in the seventh set of variables of Structural formulae XI(A) and XI(B).

The group -[(C)o-iR13R14]-ringA-Q2-R5 is independently selected from one of the depicted below or

? wherein each of rings A6, A8, All, A14 and A15 is optionally and independently further substituted. R8 independently is halogen, cyano, hydroxy, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C2-C4 alkoxyalkyl, -0(Ci-C4 alkyl), -NH2, -NH(Ci-C4 alkyl), or -N(Ci~C4 alky 1)2.

Values of the remaining variables of Structural formulae XT(A) and XT(B), including specific values, and provisos are each and independently as described above in the first set of variables of Structural Formulae (I) and (IA).

[00169] A ninth set of variables of Structural formulae XI(A) and XI(B) is as follows:

Values of the group -[CR13R14]X“ringA-Q2-R5, Q2, R, R’, R6, R7, R8, R9, Rll,R12, R13, R14, x and n, including specific values, are each and independently as described above in the eighth set of variables of Structural formulae XI(A) and XI(B). R3 is: i) -H; ii) an optionally substituted Ci-Ce alkyl group; iii) an optionally substituted, C3-C7 non-aromatic carbocycle; or iv) an optionally substituted, 4-7 membered non-aromatic heterocycle. Each of said alkyl group represented by R3 is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(Ci-C4 alkyl), -N(Ci-C4 alkyl)2, -OCO(Ci-C4 alkyl), -CO(Ci-C4 alkyl), -C02H, -C02(Ci-C4 alkyl), C1-C4 alkoxy, optionally substituted, C3-C7 non-aromatic carbocycle, and optionally substituted, 4-7 membered non-aromatic heterocycle. Each of said carbocycles and heterocycles represented by R5, and referred to for the substituents of the Ci-Ce alkyl group represented by R3 is independently and optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, C1-C4 alkyl, -0(Ci-C4 alkyl), -NH2, -NH(Ci-C4 alkyl), -N(Ci-C4 alky 1)2, -C(0)(Ci-C4 alkyl), -0C(0)(Ci-C4 alkyl), -C(0)0(C,-C4 alkyl), and -C02H, wherein each of said alkyl groups (e.g., represented by C1-C4 alkyl, -0(Cr-C4 alkyl), -NH(Ci-~C4 alkyl), -N(Cl-C4 alkyl)2, -C(OXCi-C4 alkyl), -OC(0)(Ci-C4 alkyl), and -C(0)0(Ci-C4 alkyl)) is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(C1-C4 alkyl), -N(Ci-C4 alkyl)2, -0C0(CrC4 alkyl), -C0(Cj-C4 alkyl), -COjH, -C02(Ci-C4 alkyl), and Ci-C4 alkoxy.

Values of the remaining variables of Structural formulae XI(A) and XI(B), including specific values, and provisos are each and independently as described above in the first set of variables of Structural Formulae (I) and (IA).

[00170] A tenth set of variables of Structural formulae XI(A) and XI(B) is as follows: Values of Q2, R, R’, R5, R6, R7, Rs, R9, Ru, R12, R13, R14, x and n, including specific values, are each and independently as described above in the seventh set of variables of Structural formulae XI(A) and XI(B).

The group -[(C)o-iR13Rl4]-ringA~Q2-R5 is independently selected from one of the depicted below:

wherein each of rings A1-A4, A7-A20, A22, A23, A25 and A27 is independently and optionally further substituted. Suitable substituents are as described above for ring A in the first set of variables of Structural formulae XI(A) and XI(B).

Values of the remaining variables of Structural formulae XI(A) andXI(B), including specific values, and provisos are each and independently as described above in the first set of variables of Structural Formulae (I) and (IA).

[00171] An eleventh set of variables of Structural formulae XI(A) and XI(B) is as follows:

Values of Q2, R, R\ Rs, R6, R7, R8, R9, R11, R12, R13, R14, x and n, including specific values, are each and independently as described above in the seventh set of variables of Structural formulae XI(A) and XI(B).

The group -[(C)o-iR13R14]-ringA-Q2-R5 is independently selected from one of the depicted below:

wherein each of rings A5-A7, A21, A24 and A26 is independently and optionally further substituted. Suitable substituents are as described above for ring A in the first set of variables of Structure Formulae XT(A) and X1(B).

Values of the remaining variables of Structural formulae XI(A) and XI(B), including specific values, and provisos are each and independently as described above in the first set of variables of Structural Formulae (T) and (IA).

[00172] In a twelfth set of variables of Structural formulae XI(A) and XI(B), values of the variables for Structural formulae XI(A) and XI(B), including specific values, and provisos are each and independently as described above in the first set of variables of Structural Formulae (I) and (IA).

[00173] In a thirteenth set of variables of Structural Formulae XI (A) and XI(B), values of the variables for Structural Formulae XI(A) and XI(B), including specific values, are each and independently as described above in the sixteenth set of variables of Structural Formulae (I) and (IA), or in the tenth set of variables of Structural Formulae II-V.

[00174] In another embodiment, the present invention is directed to the use of compounds represented by Structural Formula below XII (A) or XII(B), or a pharmaceutically acceptable salt thereof, for any of the uses described above:

(ΧΙΙΑ) (XIIB), A first set of variables of Structural Formulae XII(A) and XII(B) is as follows:

Ring B is a 4-7 membered, non-aromatic, heterocyclic ring optionally further substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, Ci-C6 alkyl, C2-C6alkenyl, -NH2, -NH(Ci-C6 alkyl), -N(CrC6 alkyl)2, -0(Ci.C6 alkyl), -C(0)NH2, -C(0)NH(Ci-C6 alkyl), -C(0)N(C,-C6 alkyl)2, -C(0)(Ci-Ce-alky 1), -0C(0)(C,-Cc alkyl), -NHC(0)(CrC6 alkyl), -N(CrC6 alky 1)0(0)(0-Ce alkyl), and -C02Rb; wherein each of said alkyl and alkenyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(Ci-C4 alkyl), -N(Ci-C,i alkyl)2, -OCO(CrC4 alkyl), -CO(Ci-C4 alkyl), -C02H, -C02(Ci-C4 alkyl), and CrC4 alkoxy. Specifically, Ring B is optionally further substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, Ci-C4 alkyl, -0(Ci-C4 alkyl), -NH2, -NH(Ci-C4 alkyl), -N(Ci-C4 alkyl)2, -C(0)(CrC4 alkyl), -C02H, and -C02(C’i-C4 alkyl), wherein each of said alkyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(Ci-C4 alkyl), -N(Ci-C4 alkyl)2, -OCO(Ct-C4 alkyl), -CO(Ci-C4 alkyl), -C02H, -C02(Ci-C4 alkyl), and Ci-C4 alkoxy. Specifically, Ring B is optionally further substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(Ci-C2 alkyl), -NH(Ci-C2 alkyl)2, Ci-C2 alkyl, Ci-C2 haloalkyl, Ci-C2 hydroxyalkyl, C2-C4 alkoxyalkyl, C|-C2 alkoxy, Ci-C2 hydroxyalkoxy, Ci-C2 haloalkoxy, C2-C4 alkoxyalkoxy, -C02H, and -C02(Ci-C4 alkyl). R6 and R7 are each independently -H or -CH3, or together with the carbon atoms to which they are attached they form a cyclopropane ring. R9is-Hor~CH3.

Ru and R12 are each independently -H or -CH3. R13 and R14 are each independently -H or -CH3, or together with the carbon atoms to which they are attached they form a cyclopropane ring.

Each R and R5 are independently -FI or Ct-Ce alkyl.

Values of the remaining variables of Structural Formulae XII(A) and XII(B), including specific values, and provisos are each and independently as described above in the first set of variables of Structural Formulae (I) and (IA).

[00175] A second set of variables of Structural Formulae XII(A) and XII(S) is as follows:

Values of Ring B, R, R’, R6, R7, R9, Rn, R12, R13 and R14, including specific values, are each and independently as described above in the first set of variables of Structural Formulae XII(A) and XII(B).

Variable y = 0 or 1.

Values of the remaining variables of Structural Formulae XII(A) and XII(B), including specific values, and provisos are each and independently as described above in the first set of variables of Structural Formulae (I) and (IA).

[00176] A third set of variables of Structural Formulae XII(A) and XII(B) is as follows:

Values of Ring B, R, R’, R6, R7, R9, R11, R12, R13 and R14 and y, including specific values, are each and independently as described above in the second set of variables of Structural Formulae XII(A) and XII(B). Q3 is independently -C(O)-, -CO2- -C(0)NH-, -C(0)N(CH3)-, -C(0)NHC(0)0-, -C(0)N(CH3)C(0)0- -so?.-, -SO2NH-, -S02N(CH3)-, or-iCR^VY1-.

Values of the remaining variables of Structural Formulae XII(A) and XII(B), including specific values, and provisos are each and independently as described above in the first set of variables of Structural Formulae (I) and (JLA).

[00177] A fourth set of variables of Structural Formulae XII(A) and XII(B) is as follows:

Values of Ring B, Q3, R, R\ R6, R7, R9, RU, R12, R13 and R14 and y, including specific values, are each and independently as described above in the third set of variables of Structural Formulae XII(A) and X1I(B). R5 is independently i) -H; ii) Ci-Cs-aliphatic group (e.g., Ci-Cg-alkyl or C2-C<;-alkenyl group) optionally substituted with one or more instances of JC1; iii) a C3-Cs nonaromatic carbocycle optionally substituted with one or more instances of JC1; iv) a phenyl group optionally substituted with one or more instances of JC1; v) a 4-8 mcmbered nonaromatic heterocycle optionally substituted with one or more instances of JD1 or vi) a 5-6 membered heteroaryl ring optionally substituted with one or more instances of JDl.

Each of JC1 and JD1 is independently selected from the group consisting of halogen, cyano, oxo, Ra, -ORb, -SRb, -SORa, -S02Ra, -NHRC, ~C(0)Rb, -C(0)0Rb, -0C(0)Rb, -NHC(0)Rb, -C(0)NHR°, -NHC(0)NHRc, -NHC(0)0Rb, -OCONHRc, -NHC(0)NHC(0)0Rb, ~N(CHj)Rc, -N(CH3)C(0)Rb, -C(0)N(CF13)RC, -N(CH3)C(0)NHRc, -N(CH3)C(0)0Rb, -OCON(CH3)Rc, -C(0)NHC02Rb, -C(0)N(CH3)C02Rb, -N(CH3)C(O)NHC(O)0Rb, -NHS02Rb, -S02NHRb, -S02N(CH3jRb, and -N(CH3)S02Rb

Values of the remaining variables of Structural Formulae XII(A) and XII(B), including specific values, and provisos are each and independently as described above in the first set of variables of Structural Formulae (I) and (IA).

[00178] A fifth set of variables of Structural Formulae XII(A) and XII(B) is as follows:

Values of Ring B, Q3, R, R’, R5, R6, R7, R9, RU,R12, R13, R14, and y, including specific values, are each and independently as described above in the fourth set of variables of Structural Formulae XIT(A) and XII(B).

Ring B is optionally further substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, C1-C4 alkyl, -(XC1-C4 alkyl), -NH2, -NH(Ci-C4 alkyl), -N(Ci-C4 alkyl)2, -C(0)(Ci-C4 alkyl), -C02H, and -C02(Ci-C4 alkyl), wherein each of said alkyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, -NH2, -NH(Ci-C4 alkyl), -N(Ct-C4 alkyl)2, -OCO(Ci-C4 alkyl), -CO(Ci-C4 alkyl), -C02H, -C02(Ci-C4 alkyl), and C1-C4 alkoxy.

Values of the remaining variables of Structural Formulae XII(A) and XII(B), including specific values, and provisos are each and independently as described above in the first set of variables of Structural Formulae (I) and (IA), [00179] A sixth set of variables of Structural Formulae XII(A) and XII(B) is as follows:

Values of Q3, R, R’, R5, R6, R7, R9, Rn, R12, R13, R14, and y, including specific values, are each and independently as described above in the fifth set of variables of Structural Formulae XII(A) and XII(B).

Ring B is independently selected from one of the structures depicted below:

wherein each of rings B1-B9 is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, C1-C4 alkyl, -0(Ci-C4 alkyl), -NH2, -NH(Ct-C4 alkyl), -N(Ci-C4 alkyl)2, -C(0)(CrC4 alkyl), -C02H and -C02(Ci-C4 alkyl), wherein each of said alkyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(Ci-C4 alkyl), -N(Ci-C4 alkyl)2, -OCO(CrC4 alkyl), -CO(CrC4 alkyl), -C02H, -C02(CrC4 alkyl), and CrC4 alkoxy. Specifically, each of rings B1 to B9 is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(Ci-C2 alkyl), -NH(Ci-C2 alkyl)2, Ci-C? alkyl, Ci-C2 haloalkyl, Ci-C2 hydroxyalkyl, C2-C4 alkoxyalkyl, CrC2 alkoxy, Ci-C2 hydroxyalkoxy, Ci-C2haloalkoxy, C2-C4 alkoxyalkoxy, -C02H, and -C02(Ci-C4 alkyl).

Values of the remaining variables of Structural Formulae XII(A) and XII(B), including specific values, and provisos are each and independently as described above in the first set of variables of Structural Formulae (I) and (IA). 100180] A seventh set of variables of Structural Formulae XI1(A) and XII(B) is as follows:

Values of ring B, Q3, R, R’, R5, R6, R7, R9, R11, R12, R13, R14, and y, including specific values, are each and independently as described above in the sixth set of variables of Structural Formulae XII(A) and XII(B).

Each R5 is independently: i) -H; ii) a Cs-Ce-aliphatic group optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, Ci-C4 alkyl, -0(Cs™C4 alkyl), -NH2, ~NH(Ci-C4 alkyl), -N(Cr~C4 alkyl)2, -C(0)(Ci-C4 alkyl), -0C(0)(Ct-C4 alkyl), -C(0)0(Cr-C4 alkyl), -C02H, C3-Cs nonaromatic carbocycle, phenyl, 4-8 membered non-aromatic heterocycle, and 5-6 membered heteroaryl; or iii) a G3-C7 non-aromatic carbocycle, a 4-7 membered non-aromatic heterocycle, a phenyl group, or a 5-6 membered heteroaryl ring, each of which is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, C1-C4 alkyl, -0(Cf~C4 alkyl), -NH2, -NH(Ci-C4 alkyl), -N(Ci-C4 alkyl)2, -C(0)CCi-C4 alkyl), -0C(0)(Ci-C4 alkyl), -C(0)0(Cf-C4 alkyl), and -CO2H; wherein each of said alkyl groups for the substituents of the aliphatic group, carbocycle, heterocycle, phenyl and heteroaryl group represented by R5 is independently and optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(Ci-C4 alkyl), -N(CVC4 alkyl)2, -OCO(Ci-C4 alkyl), -CO(CrC4 alkyl), -C02H, -C02(C,-C4 alkyl), and Ci-C4 alkoxy; and wherein each of said carbocycle, phenyl, heterocycle, and heteroaryl for the substituents of the CrCValiphatic group represented by R5 is independently and optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, Ci-C4 alkyl, -NH2, -NH(Ci-C4 alley 1), ™N(Ci“C4 alkyl)2, -OCO(C,-C4 alkyl), -C0(C,-C4 alkyl), -C02H, -C02(Ci-C4 alkyl), and Ci-C4 alkoxy.

Values of the remaining variables of Structural Formulae XII(A) and XI1(B), including specific values, and provisos are each and independently as described above in the first set of variables of Structural Formulae (I) and (IA).

[00181] An eighth set of variables of Structural Formulae X1I(A) and XII(B) is as follows:

Values of Q3, R, R5, R5, R6, R7, R9, RU,R12, R13 and R14 and y, including specific values, are each and independently as described above in the seventh set of variables of Structural Formulae XII(A) and XII(B),

The group (ring B)-Q3-R5 is

wherein ring B2 is optionally and independently further substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(Cj-C2 alkyl), -NH(Ct-C2 alkyl)2, C,-C2 alkyl, C1-C2 haloalkyl, CrC2 hydroxyalkyl, C2-C4 alkoxyalkyl, Ci-C2 alkoxy, Ci-C2 hydroxyalkoxy, Ci-C2 haloalkoxy, C2-C4 alkoxyalkoxy, -C02H, and -C02(Ci-C4 alkyl).

Values of the remaining variables of Structural Formulae XIT(A) and XII(B), including specific values, and provisos are each and independently as described above in the first set of variables of Structural Formulae (I) and (IA).

[00182] A ninth set of variables of Structural Formulae XII(A) and XII(B) is as follows:

Values of the group (ring B)-Q3-R5, Q3, R, R\ R6, R7, R9, Rll,R12, R13, R14, and y, including specific values, are each and independently as described above in the eighth set of variables of Structural Formulae XII(A) and XII(B). R5 is: ί) -H; ii) an optionally substituted C1-C6 alkyl group; iii) an optionally substituted, C3-C7 non-aromatic carbocycle; or iv) an optionally substituted, 4-7 membered non-aromatic heterocycle, wherein said alkyl group represented by R5 is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(Ci-C4 alkyl), -N(Ci-C4 alkyl)2, -OCO(Ci-C4 alkyl), -CO(Ci-C4 alkyl), -C02H, -C02(Ci-C4 alkyl), C1-C4 alkoxy, optionally substituted, C3-C7 non-aromatic carbocycle, and optionally substituted, 4-7 membered non-aromatic heterocycle. Each of said carbocycles and hcterocycles represented by R5, and referred to for the substituents of the Ci-C6 alkyl group represented by R5 is independently and optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, C1-C4 alkyl, -0(Ci-C4 alkyl), -NH2, -NH(Ci-C4 alkyl), -N(Ci-C4 alkyl)2, -C(0)(Ci-C4 alkyl), -0C(0)(Ci-C4 alkyl), -C(0)0(Ci-C4 alkyl) and -C02H, wherein each of said alkyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(Ci-C4 alkyl), -N(Ci-C4 alkyl)2, -OCO(Ci-C4 alkyl), -C0(Ci-C4 alkyl), -C02H, -C02(Ci-C4 alkyl), and C1-C4 alkoxy.

Values of the remaining variables of Structural Formulae XII(A) and X1I(B), including specific values, and provisos are each and independently as described above in the first set of variables of Structural Formulae (I) and (LA).

[00183] In a tenth set of variables of Structural Formulae XII(A) and XII(B), values of the variables for Structural Formulae XII(A) and XII(B), including specific values, are each and independently as described above in the first set of variables of Structural Formulae (I) and (IA).

[00184] In an eleventh set of variables of Stractural Formulae XII(A) and XII(B), values of the variables for Structural Formulae XII(A) and XII(B), including specific values, are each and independently as described above in the sixteenth set of variables of Structural Formulae (I) and (IA), or in the tenth set of variables of Structural Formulae II-V.

[00185] In another embodiment, the present invention is generally directed to the use of compounds represented by Structural Formula below XIII, or a pharmaceutically acceptable salt thereof, for any of the uses described above.

(XIII). A first set of variables of Structural Formula XIII is as follows:

Ring C is a 5-7 membered, non-aromatic, heterocyclic ring optionally further substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, C1-C6 alkyl, CrCe alkenyl, -NH2, -NH(Ci-C6 alkyl), -N(C|-C6 alky 1)2, -OiCi.Ce alkyl), -C(0)NH2, -C(0)NH(Ci-C6 alkyl), -C(0)N(CrC6 alkyl)2, -C(0)(C,-Cfi-alkyl), -OC(0)(C,-C6 alkyl), -NHC(0)(Ct-C6 alkyl), -N(C,-Cfi alky 1)0(0)(0,-0, alkyl), and -C02Rb; wherein each of said alkyl and alkenyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, C1-C4 alkyl, -NH2, -NH(C,-C4 alkyl), -N(Ci-C4 alkyl)2, -OCO(Ci-C4 alkyl), -CO(Ci-C4 alkyl), -C02H, -C02(Ci-C4 alkyl), and 0,-C4 alkoxy. Specifically, ring C is optionally further substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, Ci-C4 alkyl, -0(Ci-C4 alkyl), -NH2, -NH(Ci-C4 alkyl), -N(C,-C4 alkyl)2, -C(0)(C,-C4 alkyl), -C02H, and -C02(Ci-C4 alkyl), wherein each of said alkyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, Ci-C4 alkyl, -NH2, -NH(Ci-C4 alkyl), -N(C,......C4 alkyl)2, -OCO(Ci-C4 alkyl), -CO(Cj-C4 alkyl), -C02H, -C02(CrC4 alkyl), and Ci-C4 alkoxy. Specifically, ring C is optionally further substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, “NH2, -NH(C]-C2 alkyl), -NH(Ci-C2 alkyl)2, Ci-C2 alkyl, Ct-C2 haloalkyl, C,-C2 hydroxyalkyl, C2-C4 alkoxyalkyl, C1-C2 alkoxy, Ci-C2 hydroxyalkoxy, Ci-C2 haloalkoxy, C2-C4 alkoxyalkoxy, -C02H, and -C02(C1-C4 alkyl). R6 and R7 are each independently -H or -CH3, or together with the carbon atoms to which they are attached they form a cyclopropane ring. R9 is -Η or -CH3.

Ru and R12 are each independently -H or -CH3.

Each R and R’ are independently -H or Ci-Ce alkyl.

Values of the remaining variables of Structural Formula XIII, including specific values, and provisos are each and independently as described above in the first set of variables of Structural Formulae (I) and (LA).

[00186] A second set of variables of Structural Formula XIII is as follows:

Values of Ring C, R, R\ R6, R7, R9, R11 andR12, including specific values, are each and independently as described above in the first set of variables of Structural Formula XIII, R10 is -H or Ci-Ce-alkyl.

Values of the remaining variables of Structural Formula XIII, including specific values, and provisos arc each and independently as described above in the first set of variables of Structural Formulae (I) and (IA).

[00187] A third set of variables of Structural Formula XIII is as follows:

Values of R, R’, R6, R7, R9, R10, R11 andR12, including specific values, are each and independently as described above in the first set of variables of Structure Formula XIII.

Ring C is a 5-7 membered, non-aromatic, heterocyclic group optionally further substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, C1-C4 alkyl, -0(Ci-C4 alkyl), -NH2, -NH(Ci“C4 alkyl), -N(Ci-C4 alkyl)2, -C(0)(Ci-C4 alkyl), -C02H and -C02(Ci-C4 alkyl), wherein each of said alkyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, Ci-C4 alkyl, -NH2, -NH(Ci~C4 alkyl), -N(Ci-C4 alkyl)2, -OCO(Ci-C4 alkyl), -CO(Ci-C4 alkyl), -C02H, -C02(Ci-C4 alkyl), and C1-C4 alkoxy.

Values of the remaining variables of Structural Formula ΧΠΙ, including specific values, and provisos are each and independently as described above in the first set of variables of Structural Formulae (I) and (IA).

[00188] A fourth set of variables of Structural Formula XIII is as follows:

Values of R, R\ R6, R7, R9, R10, Rn andR12, including specific values, are each and independently as described above in the second set of variables of Structure Formula XIII. Ring C is independently selected from:

wherein each of rings C1-C5 is optionally and independently substituted. Suitable substituents are as described above for ring C in the first set of variables of Structural Formula XIV.

Values of the remaining variables of Structural Formula XIII, including specific values, and provisos are each and independently as described above in the first set of variables of Structural Formulae (I) and (IA). 100189] In a fifth set of variables of Structural Formula XIII, values of the variables for Structural Formula XIII, including specific values, and provisos are each and independently as described above in the first set of variables of Structural Formulae (I) and (IA).

[00190] In another embodiment, the present invention is generally directed to the use of compounds represented by Structural Formula below XIV, or a pharmaceutically acceptable salt thereof for any of the uses described above.

(XIV). A first set of variables of Structural Formula XIV is as follows:

Ring D is 4-7 membered, non-aromatic, heterocyclic ring optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, Ci-Cs alkyl, Ca-Cg alkenyl, -NH2, -NH(Ci-C6 alkyl), -N(Ci-C6 alkyl)2, -0(Cj. C6 alkyl), -C(0)NH2, -C(0)NH(CrC6 alkyl), -C(0)N(C!-C6 alkyl)2, -C(0)(C,-C6-alkyl), -OC(0)(Ci-C6 alkyl), -NHC(0)(Ct-Ce alkyl), -N(Cj-C6 alkyl)C(0)(CrC6 alkyl), and -C02Rb; wherein each of said alkyl and alkenyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, C1-C4 alkyl, -NH2, -NH(C|-C4 alkyl), -N(Ci-C4 alkyl)2, -OCO(Ci-C4 alkyl), -CO(Ci-C4 alkyl), -C02H, -C02(Ci-C4 alkyl), and C1-C4 alkoxy. Specifically, ring D is optionally further substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, C1-C4 alkyl, -0(Ci-C4 alkyl), -NH2, -NH(Ci-C4 alkyl), -N(Ci-C4 alkyl)2, -C(0)(Ci-C4 alkyl), -CO2H and -C02(Ci-C4 alkyl), wherein each of said alkyl giOups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, C1-C4 alkyl, ~-NH2, -NH(Ci-C4 alkyl), “N(Cj-C4 alkyl)2, -OCO(Ci-C4 alkyl), -CO(Ci-C4 alkyl), -C02H, -C02(Ci-C4 alkyl), and Ci-C4 alkoxy. Specifically, ring D is optionally further substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(Ci-C2 alkyl), -NH(Ci-C2 alkyl)2, CrC2 alkyl, CrC2 haloalkyl, Ci-C2hydroxyalkyl, C2-C4 alkoxyalkyl, Ci-C2 alkoxy, Ci-C2 hydroxyalkoxy, Ci-C2 haloalkoxy, C2-C4 alkoxyalkoxy, -C02H, and-C02(Ci-C4 alkyl). R6 and R7 are each independently -H or -CH?, or together with the carbon atoms to which they are attached they form a cyclopropane ring. R13 and R14 are each independently -H or -CH3, or together with the carbon atoms to which they are attached they form a cyclopropane ring.

Each of R and R’ are independently -H or Ci-Ce alkyl.

Values of the remaining variables of Structural Formula XIV, including specific values, and provisos are each and independently as described above in the first set of variables of Structural Formulae (I) and (IA), [00191] A second set of variables of Structural Formula XIV is as follows:

Values for Ring D, R, R\ R6, R7, R13 and R14, including specific values, are each and independently as described above in the first set of variables of Structural Formula XIV. Value z is 1.

Values of the remaining variables of Structural Formula XIV, including specific values, and provisos are each and independently as described above for the first set of variables of Structural Formulae (I) and (IA).

[00192] A third set of variables of Structural Formula IV is as follows:

Values for z, R, R\ R6, R7, R13 and R14, including specific values, are each and independently as described above in the second set of variables of Structural Formula XIV. Ring D is independently selected from the group consisting of

* wherein each of rings D1-D7 is optionally and independently substituted. Suitable substituents are as described above for ring D in the first set of variables of Structural Formula XIV.

Each Rd is independently -H, C\-Ce alkyl or - C(0)(Ci-C6 alkyl), wherein each of said alkyl moiety is optionally and independently substituted with one or more groups selected from halogen, cyano, hydroxy, oxo, C1-C4 alkyl, -NH2, -NH(Ci-C4 alkyl), -N(C,-C4 alkyl)2, -OCO(C,-C4 alkyl), -CO(C,-C4 alkyl), -C02H, -C02(Ci-C4 alkyl), and C,-C4 alkoxy. Specifically, each Rd is independently -H or Ci-Ce alkyl optionally and independently substituted with one or more groups selected from halogen, cyano, hydroxy, oxo, Ci-C4 alkyl, -NH2, -NH(Ci-C4 alkyl), ~~N(Ci-C4 alkyl)2, -OCO(Ci-C* alkyl), -CO(Ci-C4 alkyl), -C02H, -C02(Ci-C4 alkyl), and Ci-C4 alkoxy.

Values of the remaining variables of Structural Formula XIV, including specific values, and provisos are each and independently as described above for the first set of variables of Structural Formulae (I) and (IA), [00193] In a fourth set of variables of Structural Formula XTV, values of the variables for Structural Formula XIV, including specific values, and provisos are each and independently as described above in the first set of variables of Structural Formulae (I) and (IA).

[00194] In another embodiment, the compounds of Structural Formulae I-IV and XI-XIV, and pharmaceutically acceptable salts thereof, are independently as described above; and provided that, where applicable, if Y1 is a bond, then R5 is neither -H, nor an unsubstituted Ci-C6 aliphatic group. Specifically, if Y1 is a bond, then R5 is a substituted Ci-Ce aliphatic group; an optionally substituted Ci-Cs non-aromatic carbocycle; an optionally substituted, 6-10-membered carbocyclic aryl group; an optionally substituted, 4-8 membered non-aromatic heterocycle; and an optionally substituted, 5-10 membered heteroary group. Specifically, the Ci-C6 aliphatic group represented by R5 is substituted with one or more instances of JC!, wherein JC1 is independently selected from: an optionally substituted, C3-CS non-aromatic carbocycle; an optionally substituted, 6-10-membered carbocyclic aryl group; an optionally substituted, 4-8 membered non-aromatic heterocycle; an optionally substituted, 5-10 membered heteroaryl group; -ORb; -SRb; -S(0)Ra; -S02Ra; -NRbR°; -C(0)Rb; -C(0)ORb; -OC(0)Rb; -NRC(0)Rb; -C(0)NRbR,;; -NRC(0)NRbRc; -NRC(0)ORb; -OCONRbR°; -C(0)NRC02Rb; -NRC(0)NRC02Rb; -C(0)NR(ORb); ~S02NRcRb; -NRS02Rb; and -NRS02NRcRb; or optionally two JC1 and two JD1, respectively, together with the atoms to which they are attached, independently form a 5-7-membered ring that is optionally substituted with one or more instances of JE1, and fused to the respective ring to which they are attached.

[00195] In yet another embodiment, the compounds of Structural Formulae IA-IV and XI-XIV, and pharmaceutically acceptable salts thereof, are independently as described above; and provided that, where applicable, if Q2 is a bond, then R5 is neither -H nor a Ci-Cg aliphatic group; and provided that if Q3 is a bond, then R5 is neither -H nor a Ci-Ce aliphatic group. Specifically, if Q2 and Q3 are each and independently a bond, then R5 is an optionally substituted C3-C8 non-aromatic carbocycle; an optionally substituted, 6-10-membered carbocyclic aryl group; an optionally substituted, 4-8 membered non-aromatic heterocycle; or an optionally substituted, 5-10 membered heteroary group. Specifically, if Q2 and Q3 are each and independently a bond, then R5 is an optionally substituted C3-C8 non-aromatic carbocycle; or an optionally substituted, 4-8 membered non-aromatic heterocycle.

[00196] In yet another embodiment, the compounds are represented by Structural Structural Formula (I), or pharmaceutically acceptable salts thereof, wheren each variables of the formulae are independently as described above; and wherein: R4 is:

Ring E is a Cj-Cg non-aromatic carbocycle optionally further substituted with one or more instances of JA.

Rings F is a 4-8 membered non-aromatic heterocycle optionally substituted with one or more instances of JEi.

Each of rings G1 and G2 is independently a 5-10 membered non-aromatic bridged carbocycle optionally substituted with one or more instances of JA. Q2 is independently bond, -Ο-, -S-, -NR-, -C(O)-, -C(=NR)-, -CO2--, -OC(O)-, -C(0)NR- -C(0)NRC(0)0-, -NRC(0)NRC(0)0-, -NRC(O)--, -NRC(0)NR--NRCO2-, -OC(0)NR- -S(O)-, -SO2-, -N(R)S02- -S02NR’-, -NRS02NR’-, or -(CR6R7)p-Y‘-. R5 is: i) -H; ii) an optionally substituted Cj-Ce alkyl group; iii) an optionally substituted, C3-C7 non-aromatic carbocycle; or iv) an optionally substituted, 4-7 membered non-aromatic heterocycle; or optionally, together with R and the nitrogen atom to which it is attached, form a 5-7 membered, optionally substituted non-aromatic heterocycle. The alkyl group represented by R5 is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(Ci-C4 alkyl), -N(Ci-C4 alkyl)2, -OCO(CrC4 alkyl), -CO(Ci-C4 alkyl), -C02H, -C02(Ci-C4 alkyl), CrC4 alkoxy, an optionally substituted, C3-C7 non-aromatic carbocycle, and an optionally substituted, 4-7 membered non-aromatic heterocycle; wherein each of said carbocycles and heterocycles represented by R5, and referred to for the substituents of the Ci-Ce alkyl group represented by R5 is independently and optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, Ct-C4 alkyl, -0(Ct~C4 alkyl), -NH2, -NH(Ci-C4 alkyl), -N(Ci-C4 alkyl)2, -C(0)(C,-C4 alkyl), -0C(0)(Ct-C4 alkyl), -C(0)0(Ci-C4 alkyl) and -CO2H, wherein each of said alkyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(Ci-C4 alkyl), -N(CrC4 alkyl)2, -OCO(Ci-C4 alkyl), -CO(C!-C4 alkyl), -C02H, -C02(CrC4 alkyl), and Ci-C4 alkoxy.

Each of R8 and R9 is independently -H, halogen, cyano, hydroxy, Ci-C4 alkyl, Ct-C4 haloalkyl, C]-C4 hydroxyalkyl, C2-C4 alkoxyalkyl, -0(Ci-C4 alkyl), ™NH2, -NH(Ci-C4 alkyl), or-N(C]-C4 alkyl)2. R , R , R and R are each independently -H, halogen, or Ci-Cc alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo, hydroxy, oxo, amino, carboxy, Ci-Cealkoxy, Ci-Cfi haloalkoxy, Ci-Cs aminoalkoxy, Ci-C6 cyanoalkoxy, Ci-Cr, hydroxy alkoxy, and C2-C6 alkoxyalkoxy; or optionally, R13 and R14, together with the carbon atom to which they are attached, form a cyclopropane ring, optionally substituted with one or more instances of methyl. R21, R22, R23 and R24 are each independently -H, halogen, -OH, or Cs-Ce alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo, hydroxy, oxo, amino, carboxy, Ci-C6 alkoxy, Ci-Cc haloalkoxy, Ci-C6 aminoalkoxy, Ci-Ce cyanoalkoxy, Ci-C6 hydroxyalkoxy, and C2-Ce alkoxyalkoxy. p and q are each independently 0, 1 or 2. x is 0, 1 or 2. r is 1 or 2.

Values of the remaining variables of Structural formula I, including specific values, and provisos are each and independently as described above in any one of the first through fifteenth sets of variables of Structural Formula I.

[00197] In yet another embodiment, the compounds represented by Structural Formula (I) or pharmaceutically acceptable salts thereof are independently as described above in the preceding paragraph; and ring F is selected from any one of rings F1-F6:

; each of rings F1-F6 optionally and independently substituted; and each Rf is independently -H or Ci-C6 alkyl optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, amino, carboxy, Ci-Ce alkoxy, Ci-Ce haloalkoxy, Ci-Ce aminoalkoxy, CpCecyanoalkoxy, CpCe hydroxyalkoxy and C2-C6 alkoxyalkoxy.

[00198] hi yet another embodiment, the compounds represented by Structural Formula (XIA) or (XIB), or pharmaceutically acceptable salts thereof are as described above; and the group -[C(Rl3R14)]x-ringA-Q2-R5 is independently:

; wherein: each of rings A14 and A28 is optionally and independently further substituted; and values of the remaining variables of Structural Formulae (XIA) and (XIB), including specific values, and provisos are each and independently as described above in any one of the first through eleventh sets of variables of Structural Formulae (XIA) and (XIB).

[00199] In yet another embodiment, the compounds represented by Structural Formula (XIA) or (XIB), or pharmaceutically acceptable salts thereof are independently as described above in the preceding paragraph; and R5 is an optionally substituted Ci-Cs alkyl group; an optionally substituted, C3-C? non-aromatic carbocycle; or an optionally substituted, 4-7 membered non-aromatic lieterocycle; or optionally, together with R and the nitrogen atom to which it is attached, form a 5-7 membered, optionally substituted non-aromatic heterocycle. Specifically, R5 is an optionally substituted, 4-7 membered non-aromatic heterocycle; or optionally, together with R and the nitrogen atom to which it is attached, form a 5-7 membered, optionally substituted non-aromatic heterocycle.

[00200] In yet another embodiment, the compounds are represented by Structural

Formula (IA) or (I), or pharmaceutically acceptable salts, wherein: R4 is:

Ring E is a C4-C10 non-aromatic carbocycle optionally further substituted with one or more instances of JA.

Rings F is a 4-8 membered non-aromatic heterocycle optionally substituted with one or more instances of JE1. Specific examples of ring F includes:

Additional example includes

.. Each of rings F1-F7 optionally and independently substituted. Exemplary substituents for ring F (including rings F1-F7) include halogen, cyano, hydroxy, C[-C4 alkoxy, and CrC4 alkyl optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, hydroxy, and -0(Ci-C,[ alkyl).

Rf is independently -H or Ci-C6 alkyl optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, amino, carboxy, Ci-Q, alkoxy, Ci-C6 haloalkoxy, Ci-Cgaminoalkoxy, Cj-Ce cyanoalkoxy, Ct-C6 hydroxy alkoxy and C2-C6 alkoxyalkoxy. R9 is independently -H, halogen, cyano, hydroxy, amino, carboxy, Ci-Ce alkyl, Cj-Ce haloalkyl, Ci-Ce cyanoalkyl, C2-C6 alkoxyalkyl, Ci-Ce aminoalkyl, Ci-Co hydroxyalkyl, Ci-Ce carboxyalkyl, Ci-Cealkoxy, Ci-C6haloalkoxy, Ci-Ceaminoalkoxy, Cj-Cecyanoalkoxy, C]-C6 hydroxyalkoxy, or C2-C6 alkoxyalkoxy.

Rn, R12, R13 and R14 are each independently -H, halogen, or CVC'e alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo, hydroxy, oxo, amino, carboxy, Ci-Cs alkoxy, Ci-Cg haloalkoxy, Ci-C6 aminoalkoxy, Ci-Cg cyanoalkoxy, Ci-C6 hydroxyalkoxy, and C2-C6 alkoxyalkoxy.

Optionally, R13 and R14, together with the carbon atom to which they are attached, form a cyclopropane ring, optionally substituted with one or more instances of methyl. s is 0, 1 or 2. x is 0, 1 or 2.

The remaining variables are each and independently as described above in any one of the sets of variables for Structural Formulae (IA) and (I).

[00201] In yet another embodiment, the compounds are represented by Structural Formula (I) or (IA), or pharmaceutically acceptable salts thereof, wherein:

Ring E is a C4-C8 non-aromatic carbocycle optionally further substituted with one or more instances of JA. R9 is independently -H, halogen, cyano, hydroxy, C1-C4 alkyl, C1-C4 haloalkyl, C4-C4 hydroxyalkyl, C2-C4 alkoxyalkyl, -(XC1-C4 alkyl), -NH2, -NH(Ci-C4 alkyl), or -N(Ci-C4 alkyl)2.

The other varibales are each and independently as described in the preceeding paragraph.

[00202] In yet another embodiment, the compounds are represented by Structural Formula (IA) or (I), or pharmaceutically acceptable salts, wherein: R4 is:

Each of rings G1-G4 is independently a 5-10 membered non-aromatic bridged ring optionally further substituted with one or more instances of JA.

Eing G5 is a 5-10 membered non-aromatic bridged ring optionally further substituted with one or more instances of JB. X is -0-, -S-, or -NR6-. R8 and R9 are each independently -H, halogen, cyano, hydroxy, amino, carboxy, Ci-Cg alkyl, Ci-Cg haloalkyl, Ci-C6 cyano alkyl, C2-Cg alkoxyalkyl, Ci-Cg aminoalkyl, Ci-Cg hydroxyalkyl, Ci-Cg carboxy alkyl, Ci-Cgalkoxy, Ci-Cg haloalkoxy, Ci-Cgaminoalkoxy, Ci-Cg cyanoalkoxy, Ci-Cg hydroxyalkoxy, or C2-Cg alkoxyalkoxy. R13 and R14 are each independently -H, halogen, or C1-C6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo, hydroxy, oxo, amino, carboxy, CrC6 alkoxy, Ci-Cg haloalkoxy, C1-C6 aminoalkoxy, Ci-Cecyanoalkoxy, Ci-Ce hydroxyalkoxy, and C2-Ce alkoxyalkoxy.

Optionally, R53 and R14, together with the carbon atom to which they are attached, form a cyclopropane ring, optionally substituted with one or more instances of methyl. R21, R22, R23, R24, and R25 are each independently -H, halogen, -OH, Ci-Cg alkoxy, or Ci-Cg alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo, hydroxy, oxo, amino, carboxy, Ci-Cg alkoxy, Ci-Cg haloalkoxy, C1-C6aminoalkoxy, Ci-Cecyanoalkoxy, Ci-Cg hydroxyalkoxy, and C2-Cg alkoxyalkoxy. Specifically, R21, R22, R23, R24, and R25 are each independently -H, halogen, -OH, Ci-Cgalkoxy, or Ci-Cg alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, Ci-C6 alkyl, -NH2, -NHfCrQ, alkyl), -N(Cl-C6 alkyl)2, -0(Cj.C6 alkyl), -C(0)NH2, -C(0)NH(C,-C6 alkyl), -C(0)N(Ci-C6 alkyl)2, -C(0)(Ci-C6-alkyl), -0C(0)(C!-C6 alkyl), -NHC(0)(Ci-C6 alkyl), -N(C,-C6 alkyl)C(0)(CrCc alkyl).

Rs is -H or Ci-Cg alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo, hydroxy, amino, carboxy, Ci-Cg alkoxy, Ci-Cr, haloalkoxy, Ci-Cg aminoalkoxy, C|-Cfi cyano alkoxy, Ci-Cf, hydroxyalkoxy, and C2-Cealkoxyalkoxy. q is 0, 1 or 2; x is 0, 1 or 2; and r is 1 or 2.

The remaining variables are each and independently as described above in any set of variables for Structural Formulae (IA) and (I).

[00203] In yet another embodiment, the compounds are represented by Structural Formula (IA) or (I), pharmaceutically acceptable salts thereof, wherein: R4 is:

wherein rings G1 and G2 are each and independently a 5-10 membered non-aromatic bridged ring optionally further substituted with one or more instances of J'\

Each of Rs and R9 is independently -H, halogen, cyano, hydroxy, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C2-C4 alkoxyalkyl, -0(C]-C4 alkyl), -NH2, -NH(C]-C4 alkyl), or -N(Ci-C4 alkyl)2. R21, R22, R23, and R24 are each independently -H, halogen, -OH, or Ci-Cg alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo, hydroxy, oxo, amino, carboxy, C1-C6 alkoxy, Ci-C6 haloalkoxy, Ci-Ce aminoalkoxy, Ci-Ce cyanoalkoxy, Ci-Ce hydroxyalkoxy, and C2-Ce alkoxy alkoxy. Q2is independently a bond, -0-, -S-, -NR-, -C(0)-, -C(=NR)-, -C02~, -00(0)-, -C(0)NR-, -C(0)NRC(0)0-, -NRC(0)NRC(0)0- -NRC(O)-, -NRC(0)NR- -NRC02--0C(0)NR-, -S(0)-, -SO2-, -N(R)S02-, -S02NR\ -NRS02NR’-, or -(CR6R7),-Y-. Alternatively Q2 is independently -0-, -C02-, -0C(0)-, -C(0)NR-, -NRC(O)-, -NRC(0)NR- -NRCO2-, -0C(0)NR-, -C02S02-, -P(0)20-, or -(CR6R7)P-Y-. Alternatively Q2 is independently -0- or -C02-.

[00204] In some embodiments, rings E and G (including G1-G5) are optionally and independently further substituted with one or more instances of JA (for carbocycle) or JB (for heterocycle), wherein each of JA and JB is independently selected from the group consisting of halogen, cyano, oxo, -NCO, andQ'-R5, and wherein: Q1 is independently a bond, -0-, -S-, -NR-, -C(O)-, -C(=NR)-, -CO2-, -OC(O)-, -C(0)NR-, -C(0)NRC(0)0-, -NRC(0)NRC(0)0-, -NRC(O)-, -NRC(0)NR-, -NRC02-, -0C(0)NR-, -S(O)-, -SO2-, -N(R)S02-, -S02NR\ -NRS02NR’-, or -(CR^p-Y1-; and Yl is independently a bond, -0-, "S-, -NR’-, -C(O)-, -C(=NR)-, -CO2-, -OC(O)--, -C(0)NR'-, -C(0)NRC(0)0-, -NRC(0)NRC(0)0-, -NRC(O)-, -NRC(0)NR’-, -NRC02~, -0C(0)NR’-, -S(O)-, -SO2-, -SO2NR-, -NRSO2-, or -NRS02NR’-.

Alternatively: Q1 is independently a bond, -0-, -S-, -NR-, -C(O)-, -C02-, -0C(0)-, -C(0)NR-, -C(0)NRC(0)0- -NRC(0)NRC(0)0-, -NRC(O)- -NRC(0)NR-, -NRC02-, -0C(0)NR- -S(0>, -S02~, ~N(R)S02-, -S02NR’-, -NRS02NR’-, or -(CR^ip-Y1-; and Y! is independently -0-, -CO2-, -00(0)-, -C(0)NR-, -NRC(O)-, —NRC(0)NR-, -NRC02-, or -0C(0)NR- [00205] In yet another embodiment, Q1 and Y1 are each independently as described above in the preceeding paragraph, and: R5 is independently i) -H; ii) a Ci-Of,-aliphatic group optionally substituted with one or more instances of JC1; iii) a C3-C8 non-aromatic carbocycle optionally substituted with one or more instances of J°; iv) a phenyl group optionally substituted with one or more instances of JC1; v) a 4-8 membered non-aromatic heterocycle optionally substituted with one or more instances of JD1 or vi) a 5-6 membered heteroaryl ring optionally substituted with one or more instances of JD1; and each of JC1 and JDl is independently selected from the group consisting of halogen, cyano, oxo, Ra, -ORb, -SRb, -S(0)Ra, -S02Ra, -NHRC, -C(0)Rb, -C(0)0Rb, -0C(0)Rb, -NHC(0)Rb, -C(0)NHRc, -NHC(0)NHRc, -NHC(0)0Rb, -OCONHRC, -NHC(0)NHC(0)0Rb, -N(CH3)RC, -N(CH3)C(0)Rb, -C(0)N(CH3)Rc, -N(CH3)C(0)NHRc; -N(CH3)C(0)0Rb, -OCON(CH3)Rc, -C(0)NHC02Rb, -C(0)N(CH3)C02Rb, -N(CH3)C(0)NHC(0)0Rb, -NHS02Rb, -S02NHRb, -S02N(CH3)Rb, and -N(CH3)S02Rb.

[00206] In some specific embodiments, the compounds are represented by Structural Formula (IA) or (I), wherein: R1 is -H. R2 is -H, -CH3, -CH2OH, or -NH2. Specifically, R2 is -H, or -CH2OH. R3 is -H, -F, -Cl, Cm alkyl, or Cm haloalkyl. Alternatively, R3 is -H, -F, or -Cl. Z1 is -H, -F, or -Cl. Z2 is -H or C[-Cfi alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, and -0(Ci-C4 alkyl). Z3 is -H or Ci-Cfi alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, and -0(Ci-C4 alkyl). R5 is: i) -H; ii) an optionally substituted Ci-Ce alkyl group; iii) an optionally substituted, Cj-Cb non-aromatic carbocycle; iv) an optionally substituted, 4-7 membered nonaromatic heterocycle; v) )an optionally substituted phenyl group; vi) an optionally substituted 5-6 membered heteroaryl ring; or optionally, together with R and the nitrogen atom to which it is attached, form a 5-7 membered, optionally substituted non-aromatic heterocycle; and said alkyl group represented by R5 is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(Ci-C4 alkyl), -N(Ci-C4 alkyl)2, -OCO(Ci-C4 alkyl), -CO(Ci-C4 alkyl), -C02H, -C02(CrC4 alkyl), Ci-C4 alkoxy, -NRCO(Ci-C4 alkyl), -CONR(C(-C4 alkyl), -NRC02(Ci-C4 alkyl), a C3-C? non-aromatic carbocycle optionally substituted with one or more instances of JEI, a 4-7 membered non-aromatic heterocycle optionally substituted with one or more instances of JE1; and a phenyl optionally substituted with one or more instances of JEf; and wherein each of said carbocycle, heterocycle, phenyl and heteroary represented by R5 is independently and optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, C1-C4 alkyl, -0(Ci™C4 alkyl), -NH2, -NH(C,-C4 alkyl), -N(Ci~C4 alkyl)2, -C(0)(C,-C4 alkyl), -0C(0)(Ci.....C4 alkyl), -C(0)0(Ci-C4 alkyl) and -C02H, wherein each of said alkyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(Ci-C4 alkyl), -N(Ci-C4 alkyl)2, -OCO(Ci-C4 alkyl), -CO(CrC4 alkyl), -C02H, -C02(Ci-C4 alkyl), and Cx-C4 alkoxy.

The remaining variables, including R4 that includes a spiro ring represented by rings E and F, or a bridged ring represented by rings G1-G5, are each and independently as described in any one of the preceeing four embodiments.

[00207] In yet another embodiment, the compounds are presented by Structural Formula (IA) or (I), wherein values of the variabels are each and independently as described in the preceeding embodiment, except: Z2 is -H; Z3 is -H; R5 is independently: i) -H or ii) a Ci-Ce-alkyl group optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, C]-C4 alkyl, -0(Ci-C4alkyl), -NH2, -NH(Ci-C4 alkyl), -N(Ci-C4 alkyl)2, -C(0)(Ci-C4 alkyl), -00(0)(0-0, alkyl), -C(0)0(Ci-C4 alkyl), -C02H, C3-Cs nonaromatic carbocycle, 4-8 membered non-aromatic heterocycle, phenyl, and 5-6 membered heteroaryl; wherein each of said alkyl groups referred to in the substituents of the Οι-Οΰ-alkyl group represented by R5 is independently and optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(C,-C4 alkyl), -N(Ci-C4 alkyl)2, -OCO(Ci-C4 alkyl), -CO(Ci-C4 alkyl), -C02H, -C02(Ci-C4 alkyl), and Ci-C4 alkoxy; and wherein each of said carbocycle, phenyl, heterocycle, and heteroaryl referred to in the substituents of the Ci-Ce-alkyl group represented by R5 is independently and optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, Ci-C4 alkyl, -NH2, -NH(Ci-C4 alkyl), -N(Ci-C4 alkyl)2, -OCO(Ci-C4 alkyl), -CO(Ci-C4 alkyl), -C02H, -C02(CrC4 alkyl), and C,-C4 alkoxy.

[00208] In yet another embodiment, each of rings E, G1-G5 is independently and optionally substituted with onr or more substituents selected from the group consisting of halogen, cyano, hydroxy, Ci-CG alkyl, -NH2, -NH(Ci-CG alkyl), -N(Ci-Cg alkyl)2, -0(Ci.CG alkyl), -C(0)NH2, -C(0)NH(Cl-Cg alkyl), -C(0)N(Ci-C6 alkyl)2, -C(0)(Ci-C6-alkyl), -0C(0)(Cl-C6 alkyl), -NHC(0)(Ci-C6 alkyl), -N(Ci-C6 alkyl)C(0)(Ci-C6 alkyl), and -C02Rb; wherein each of said alkyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(Ci-C4 alkyl), -N(C,-C4 alkyl)2, -OCO(CrC4 alkyl), -CO(Ci-C4 alkyl), -C02H, -C02(Ci-C4 alkyl), and C1-C4 alkoxy. Specifically, each of rings E, G1-G5 is independently and optionally substituted with onr or more substituents selected from the group consisting of halogen, cyano, hydroxy, -NH2, -NH(Ci-C4 alkyl), -N(Cl-C4 alkyl)2, -OCO(Ci-C4 alkyl), -CO(Ci-C4 alkyl), -C02H, -C02(Ci-C4 alkyl), C1-C4 alkoxy, and Ci-C4 alkyl optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, hydroxy, and -0(Ci-C4 alkyl).

[00209] In yet another embodiment, the compounds are represented by Structural Formula (IA) or (I), or pharmaceutically acceptable salts thereof, wherein: R4 is:

Ring A is a non-aromatic, 5-10 membered, bridged carbocylce or heterocycle, or ring A and Rs optionally form a non-aromatic, 5-10 membered, bridged carbocycle or heterocycle, or ring A and R9 optionally form a non-aromatic, 5-10 membered, bridged carbocycle or heterocycle, or ring A and Rn optionally form a non-aromatic, 5-10 membered, bridged carbocycle or heterocycle, wherein each of said carbocycle is independently and optionally substituted with one or more instances of JA and wherein each carbocycle is independently and optionally substituted with one or more instances of JB. R! is -H. R2 is -H, -CH:„ -CH2OH, or -NH2. Specifically, R2 is -H, or -CH2OH. R3 is -H, -F, -Cl, Ci^f. alkyl (e.g., -CH3 or -C2H5), or C1-4 haloalkyl (e.g., -CF3). Alternatively, R3 is -H, -F, or -Cl. Z1 is -H, -F, or -Cl. Z2 is -H or Cj-Ce alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, and -0(Cs-C4 alkyl). Z3 is -H or CrCe alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, and -0(Ci-C4 alkyl). Q2 is independently -0-, -CO2-, -0C(0)-, -C(0)NR’-, --C(0)NRC(0)0--NRC(O)-, -NRC(0)NR’-, -NRCO2-, -0C(0)NR’-, -P(0)(0R)0-, -0P(0)(0Ra)0-, -P(0)20-, -C02S02-, or -(CR6R7)p-Y1-. Y1 is -0-, -CO2-, -0C(0)-, -C(0)NR’~, -C(0)NRC(0)0-,-NRC(0)“ -NRC(0)NR’-, -NRCO2-, -0C(0)NR’“, -P(0)(0R)0-, -0P(0)(0Ra)0-, -P(0)20~, or -CO2SO2-. R5 is: i) -H; ii) an optionally substituted Ci-Ce alkyl group; iii) an optionally substituted, C3-C7 non-aromatic carbocycle; iv) an optionally substituted, 4-7 membered nonaromatic heterocycle; v) )an optionally substituted phenyl group; vi) an optionally substituted 5-6 membered heteroaryl ring; or optionally, together with R and the nitrogen atom to which it is attached, form a 5-7 membered, optionally substituted non-aromatic heterocycle; and said alkyl group represented by R5 is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(Ct-C4 alkyl), -N(Ct-C4 alkyl)2, -OCO(C,-C4 alkyl), -CO(CrC4 alkyl), -CO2H, -C02(CrC4 alkyl), CrC4 alkoxy, -NRCO(CrC4 alkyl), -CONR(C,-C4 alkyl), -NRCC>2(Ci-C4 alkyl), a C3-C7 non-aromatic carbocycle optionally substituted with one or more instances of JE!, a 4-7 membered non-aromatic heterocycle optionally substituted with one or more instances of JE1; and a phenyl optionally substituted with one or more instances of JE1; wherein each of said carbocycle, heterocycle, phenyl and heteroary represented by R5 is independently and optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, Ci-C4 alkyl, -0(Ci-C4 alkyl), -NH2) -NH(C,-C4 alkyl), -N(C,-C4 alkyl)2, -C(0)(C,-C4 alkyl), -0C(0)(Cs-C4 alkyl), -C(0)0(C|-C4 alkyl) and -C02H, wherein each of said alkyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(Ci-C4 alkyl), -N(Ci-C4 alkyl)2, -OCO(CrC4 alkyl), -CO(Ci-C4 alkyl), -C02H, -C02(Ci-C4 alkyl), and Ct-C4 alkoxy.

Each of R8 and R9 is independently -H, halogen, cyano, hydroxy, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C2-C4 alkoxyalkyl, -0(Ci-C4 alkyl), -NH2, -NH(Ci-C4 alkyl), or-N(Ci-C4 alkyl)2. II 1 λ I Ϊ «a R , R , R , and R are each independently -H, halogen, or Ci-Cc alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, and Q-Cg alkoxy.

Each of JA and JB is independently selected from the group consisting of halogen, cyano, hydroxy, Ci-C6 alkyl, -NH2, -NH(Ci-Ce alkyl), -N(Ci-C6 alkyl)2, -0(Ci.Ce alkyl), -C(0)NH2, -C(0)NH(Ci-C6 alkyl), -C(0)N(CrC6 alkyl)2, -C(0)(Ci-C6-aIkyl), -0C(0)(Ct-C6 alkyl), -NHC(0)(CrC6 alkyl), -N(Ci-C6 alkyl)C(0)(CrC6 alkyl), and -C02Rb; wherein each of said alkyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(Ci-C4 alkyl), -N(CrC4 alkyl)2, -OCO(Ci-C4 alkyl), -CO(Ci-C4 alkyl), -C02H, -C02(Ci-C4 alkyl), and C1-C4 alkoxy. n is 0 or 1. x is 0 or 1.

The remaining variables are each and independently as described above in any set of variables for Structural Formulae (IA) and (I).

[00210] In yet another embodiment, the compounds are represented by Structural Formula (IA) or (I), or pharmaceutically acceptable salts, wherein:

Each of rings G1-G4 is independently a 5-10 membered non-aromatic bridged carbocycle optionally further substituted with one or more instances of JA, and ring G5 is a 510 membered non-aromatic bridged heterocycle optionally further substituted with one or more instances of JB. X is -0-, -S-, or -NRg-. R21, R22, R23, R24, and R23are each independently -H, halogen, -OH, Ci-Cealkoxy, or Ci-Ce alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, Ci-Cs alkyl, -NH2, -NH(C]-C<; alkyl), -N(Ci-C6 alkyl)2, -0(Ci-C6 alkyl), -C(0)NH3, -C(0)NH(Ci-C6 alkyl), -C(0)N(C,-C6 alkyl)2, -C(0)(Ci-C6-alkyl), -0C(0)(Cj-Ce alkyl), -NHC(0)(C,-C6 alkyl), -N(CrC6 alkyl)C(0)(Ci-Cc alkyl).

Rs is -H or Ci-Ce alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo, hydroxy, amino, carboxy, Ci-Cealkoxy, C|-Cc haloalkoxy, Ci-Csaminoalkoxy, Ci-C6cyanoalkoxy, Ci-Ce hydroxyalkoxy, and C2-Ce alkoxyalkoxy. q is 0, 1 or 2. ris 1 or 2,

The remaining variables are each and independently as described above in the preceeding paragraph. 100211] In yet another embodiment, the compounds are represented by Structural Formula (IA) or (I), or pharmaceutically acceptable salts thereof, wherein the variables are each and independently as described above in the preceeding paragraph except those described below: R1 is -H. R2 is -H. R3 is -H, -F, -Cl, Ci-4 alkyl, or Cm haloalkyl. Alternatively, R3 is -H, -F, or -Cl. Z1 is ™H, -F, or-Cl. Z2 is -H. Z3 is -H. X is -0-, R5 is -H, an optionally substituted Ci-Q alkyl, or optionally substituted phenyl.

Each R8 is independently -H, halogen, hydroxy, Ci-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C2-C4 alkoxyalkyl, or -0(Ci-C4 alkyl).

Each of R9, R13, and R14is independently -H or C1-C4 alkyl. R21, R22, R23, R24, and R25 are each independently -H, halogen, -OH, Ci-C6alkoxy, or Ci-Ce alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, Ci-Ce alkyl, and -0(Ci-CY, alkyl). Specifically R21, R22, R23, R24, and R25 are each independently -H, Cm alkyl, or Cm haloalkyl.

Each rings G1-G5 are independently and optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, hydroxy, -Τ\Ή2, -NH(Ci-Ce alkyl), -N(Ci-Ce alkyl)2, -0(Ci.Cs alkyl), C1-C4 alkyl that is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, and C1-C4 alkoxy.

[00212] In yet another embodiment, the compounds are represented by any one of Structural Formulae I-V (hereinafter reference to Structural Formulae I-IV includes Structural Formulae I, ΙΑ, II, III, IV, V, and VI) and XI(A)-XIV (hereinafter reference to Structural Formulae XI(A)-XTV includes Structural Formulae ΧΙΑ, XIB, XIIA, XIIB, XIII, and XIV), wherein values of the variables therein are independently as described above in any embodiments except that R3 is C1-6 alkyl, such as methyl or ethyl.

[00213] In yet another embodiment, the compounds are represented by any one of Structural Formulae I-V and XI(A)-XIV, wherein values of the variables therein are independently as described above in any embodiments described above, except that x is 0, [00214] In yet another embodiment, the compounds are represented by any one of Structural Formulae I, ΙΑ, II, VI, XI(A), and XI(B), wherein values of the variables therein are independently as described above in any embodiments described above, except that ring A is bridged.

[00215] In yet another embodiment, the compounds are represented by any one of Structural Formulae I, ΙΑ, II, VI, XI(A), and XI(B), wherein values of the variables therein are independently as described above in any embodiments described above, except that Q2 is independently -C(=NR>, -C(=NR)NR-, -NRC(=NR)NR-, -C02-, -OC(O)-, -C(0)NR-, -C(0)NRC(0)0-, -NRC(0)NRC(0)0-, -NRC(O)-, -NRC(0)NR-, -NRC02-, -OC(0)NR-, -S(O)-, -SO2-, -N(R)SC>2- -SOiN(R)-, -NRSCbNR-, -P(0)(0R)0-, -0P(0)(0Ra)0-, -P(0)20-, -CO2SO2-, or -(CR6R7)P-Y-; or alternatively, Q2 is independently -C02- -OC(O)-, -C(0)NR-, -C(0)NRC(0)0-, -NRC(0)NRC(0)0--NRC(O)-, -NRC(0)NR-, -NRC02-, -0C(0)NR- -S(O)-, -S02-, -N(R)S02-, -S02N(R)-, -NRSO2NR-, -P(0)(0R)0-, -0P(0)(0Ra)0-, -P(0)20-, -C02S02-, or -(CR^Vy1-.

[00216] In yet another embodiment, the compounds are represented by any one of Structural Formulae I-V and XI(A)-XIV, wherein values of the variables therein are independently as described above in any embodiments described above, provided that when Q2 is -O- or -NR-, then ring A is further substituted with JA other than -H; and provided that if Q3 is —C(0)-, then R5 is a substituted Ci-Ce aliphatic group; an optionally substituted C3-Cs non-aromatic carbocycle; an optionally substituted, 6-10-membered carbocyclic aryl group; optionally substituted, 4-8 membered non-aromatic heterocycle; or an optionally substituted 5-10 membered heteroaryl group. In a specific embodiment, when Q2 is -0- or -NR-, then ring A is further substituted with JA other than -H at the geminal position to -Q2R5.

[00217] In yet another embodiment, the present invention is directed to the use of any compound selected from the compounds depicted in FIGs. 3,4, 5, 6, 7, and 8, or a pharmaceutically acceptable salt thereof, for any of the uses described above.

[00218] In some embodiments, the compounds are represented by any one of Structural Formulae I-V and XI(A)-XIV, and the variables are each independently as depicted in the compounds of FIGs. 1-8.

[00219] In yet another embodiment, the present invention is directed to the use of a compound described in any one of the embodiments, including various sets of variables, for Structural Formulae I-V and XI(A)-XIV described above, or a pharmaceutically acceptable salt thereof, for any of the uses described above, provided that when R3 is -Cl, Z1 is -F, and Z2 is -H, then R4 is not 2-NH2-cyclohexyl.

[00220] 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). |00221] The terms “influenza virus mediated condition”, “influenza infection”, or “Influenza”, as used herein, are used interchangeable to mean the disease caused by an infection with an influenza virus.

[00222] Influenza is an infectious disease that affects birds and mammals caused by influenza viruses. Influenza viruses are RNA viruses of the family Orthomyxoviridae, which comprises five genera: Influenzavirus A, Influenzavirus B, Influenzavirus C, Isavirus and Thogotovirus. Influenzavirus A genus has one species, influenza A vims which can be subdivided into different serotypes based on the antibody response to these viruses: H1N1, H2N2, H3N2, H5N1, H7N7, H1N2, H9N2, H7N2 , H7N3 and H10N7. Influenzavirus B genus has one species, influenza B vims. Influenza B almost exclusively infects humans and is less common than influenza A. Influenzavirus C genus has one species, Influenzavirus C vims, which infects 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.

[00223] In some embodiments 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 H1N1, H2N2, H3N2 or H5N1.

[00224] In humans, common symptoms of influenza are chills, fever, pharyngitis, muscle pains, severe headache, coughing, weakness, and general discomfort. In more serious cases, influenza causes pneumonia, which can be fatal, particularly in young children and the elderly. Although it is often confused with the common cold, influenza is a much more severe disease and is caused by a different type of virus. Influenza can produce nausea and vomiting, especially in children, but these symptoms are more characteristic of the unrelated gastroenteritis, which is sometimes called "stomach flu" or "24-hour flu".

[00225] Symptoms of influenza can start quite suddenly one to two days after infection. Usually the first symptoms arc chills or a chilly sensation, but fever is also common early in the infection, with body temperatures ranging from 38-39 °C (approximately 100-103 °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 pathogens (“influenza-like illness). Usually, laboratory data is needed in order to confirm the diagnosis.

[00226] The terms, “disease”, “disorder”, and “condition” may be used interchangeably here to refer to an influenza virus mediated medical or pathological condition.

[00227] 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), specifically a “mammal” including a non-primate (e.g., a cow, pig, horse, sheep, rabbit, guinea pig, rat, cat, dog, and mouse) and a primate (e.g., a monkey, chimpanzee and a human), and more specifically a human. In one embodiment, the subject 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 subject is a “human”, [00228] The term “biological sample”, as used herein, includes, without limitation, cell cultures or extracts thereof; biopsied material obtained from a mammal or extracts thereof; blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof.

[00229] As used herein, “multiplicity of infection” or “MOI” is the ratio of infectious agents (e.g. phage or virus) to infection targets (e.g. cell). For example, when referring to a group of cells inoculated with infectious virus particles, the multiplicity of infection or MOI is the ratio defined by the number of infectious virus particles deposited in a well divided by the number of target cells present in that well.

[00230] 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%.

[00231] Influenza virus replication can be measured by any suitable method known in the art. For example, influenza viral titre in a biological sample (e.g. an infected cell culture) or in humans (e.g. lung viral titre in a patient) can be measured. More 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, A/Puerto 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 exhaustion of the cell resources and eventual lysis of the cell. In the first type of cell assay, a low fraction of cells in the wells of a microtiter plate are infected (typically 1/10 to 1/1000), the virus is allowed to go through several rounds of 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 directly measured using the branched-chain DNA hybridization method (bDNA). In the second type of cell assay, a low number of cells are initially infected in wells of a microtiter plate, the virus is allowed to replicate in the infected cells and spread to additional rounds of cells, then the cells are lysed and viral RNA content is measured. This assay is stopped early, usually after 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.

[00232] 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 positive reading; 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 determine the titer, several dilutions will be prepared, such as 10"1, 1 O'2, 1 O'3,. ..,10-8. The lowest concentration of virus that still infects cells is the viral titer.

[00233] As used herein, the terms “treat”, “treatment” and “treating” refer to both therapeutic and prophylactic treatments. For example, therapeutic treatments includes the reduction or amelioration of the progression, severity and/or duration of influenza viruses mediated conditions, or the amelioration of one or more symptoms (specifically, one or more discernible symptoms) 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 invention). In specific embodiments, the therapeutic treatment includes the amelioration of at least one measurable physical parameter of an influenza virus mediated condition. In other embodiments the therapeutic treatment 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.

[00234] The term “chemotherapy” refers to the use of medications, e.g. small molecule drugs (rather than “vaccines”) for treating a disorder or disease.

[00235] The terms “prophylaxis” or “prophylactic use” and “prophylactic treatment” as used herein, refer to any medical or public health procedure whose purpose is to prevent, rather than treat or cure a disease. As used herein, the terms “prevent”, “prevention” and “preventing” refer to the reduction in the risk of acquiring or developing a given condition, or the reduction or inhibition 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 prevention of a disorder or disease.

[00236] As used herein, prophylactic use includes the use in situations in which an outbreak has been detected, to prevent contagion or spread of the infection in places where a lot of people that are at high risk of serious influenza complications live in close contact with each other (e.g. in a hospital ward, daycare center, prison, nursing home, etc). It also 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 treating a person who is not ill with the influenza or not considered at high risk for complications, in order to reduce the chances of getting infected with the influenza and passing it on to a high-risk person in close contact with him (for instance, healthcare workers, nursing home workers, etc).

[00237] According to the US CDC, an influenza “outbreak” is defined as a sudden increase of acute febrile respiratory illness (AFRI) occurring within a 48 to 72 hour period, in a group of people who arc 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 testing method is considered an outbreak.

[00238] A “cluster” is defined as a group of three or more cases of AFRI occurring within a 48 to 72 hour period, in a group of people who are in close proximity to each other (e.g. in the same area of an assisted living facility, in the same household, etc).

[00239] As used herein, the “index case”, “primary 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 determine how the disease spread and what reservoir holds the disease in between outbreaks. Note that the index case is the first patient that indicates the existence of an outbreak. Earlier cases may be found and are labeled primary, secondaty, tertiary, etc.

[00240] In one embodiment, the methods of the invention are a preventative or “preemptive” measure to a patient, specifically a human, having a predisposition to complications 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 an “index case” or an “outbreak” has been confirmed, in order to prevent the spread of infection in the rest of the community or population group.

[00241] In another embodiment, the methods of the invention are applied as a “preemptive” measure to members of a community or population group, specifically humans, in order to prevent the spread of infection.

[00242] As used herein, an “effective amount” refers to an amount sufficient to elicit the desired biological response. In the present invention the desired 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 infection, 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 another 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 tolerance to drugs. The skilled artisan will be able to determine appropriate dosages depending on these and other factors. When co-administered with other anti viral agents, e.g., when coadministered with an anti-influenza medication, an “effective 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 subject, the type of condition(s) being treated and the amount of a compound described herein being used. In cases where no amount is expressly noted, an effective amount should be assumed. For example, compounds described herein can be administered to a subject in a dosage range from between approximately 0.01 to 100 mg/kg body weight/day for therapeutic or prophylactic treatment.

[00243] Generally, dosage regimens can be selected in accordance with a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, 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 specific 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 described herein required to treat, to prevent, inhibit (fully or partially) or arrest the progress of the disease.

[00244] 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).

[00245] For therapeutic treatment, the compounds described herein can be administered to a patient within, for example, 48 hours (or within 40 hours, or less than 2 days, or less than 1.5 days, or within 24 hours) of onset of symptoms (e.g., nasal congestion, sore throat, cough, aches, fatigue, headaches, and chills/sweats). The therapeutic treatment can last for any suitable duration, for example, for 5 days, 7 days, 10 days, 14 days, etc. For prophylactic treatment during a community outbreak, the compounds described herein can be administered to a patient within, for example, 2 days of onset of symptoms in the index case, and can be continued for any suitable duration, for example, for 7 days, 10 days, 14 days, 20 days, 28 days, 35 days, 42 days, etc.

[00246] Various types of administration methods can be employed in the invention, and are described in detail below under the section entitled “Administration Methods.”

Combination Therapy [00247] An effective amount can be achieved in the method or pharmaceutical composition of the invention employing a compound of any one of Structural Formulae I-V (e.g., Structural Formulae I, ΙΑ, II, III, IV and V) and XI(A)-XIV (e.g., Structural Formulae XIA, XIB, XIIA, XIIB, XIII, and XIV) or a pharmaceutically acceptable salt or solvate (e.g., hydrate) thereof alone or in combination with an additional suitable therapeutic agent, for example, an antiviral agent or a vaccine. When “combination therapy” is employed, an effective amount can be achieved using a first amount of a compound of any one of Stmctural Formulae I-V and XI(A)-XIV, or a pharmaceutically acceptable salt or solvate (e.g., hydrate) thereof, and a second amount of an additional suitable therapeutic agent (e.g. an antiviral agent or vaccine).

[00248] In another embodiment of this invention, the compound of any one of Structural Formulae I-V and XI(A)-XIV, and the additional therapeutic agent, are each administered in an effective amount (i.e,, each in an amount which would be therapeutically effective if administered alone). In another embodiment, the compound of any one of Structural Formulae I-V and XI(A)-XIV, and the additional therapeutic agent, are each administered in an amount which alone does not provide a therapeutic effect (a subtherapeutic dose). In yet another embodiment, the compound of any one of Structural Formulae I-V and XI(A)-XIV can be administered in an effective amount, while the additional therapeutic agent is administered in a sub-therapeutic dose. In still another embodiment, the compound of any one of Structural Formulae I-V and XI(A)-XIV can be administered in a sub-therapeutic dose, while the additional therapeutic agent, for example, a suitable cancer-therapeutic agent is administered in an effective amount.

[00249] 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 agents). 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.

[00250] Coadministration encompasses administration of the first and second amounts of the compounds of the coadministration in an essentially simultaneous manner, such as in a single pharmaceutical composition, for example, capsule or tablet having a fixed ratio of first and second amounts, or in multiple, separate capsules or tablets for each. In addition, such coadministration also encompasses use of each compound in a sequential manner in either order.

[00251] 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 vims infections in patients using the compounds or pharmaceutical compositions of the invention of any one of Structural Formulae I-V and XI(A)-XIV. Accordingly, pharmaceutical compositions of the invention also include those comprising an inhibitor of Flu vims replication of this invention in combination with an antiviral compound exhibiting anti-influenza virus activity.

[00252] Methods of use of the compounds and compositions of the invention also include combination of chemotherapy with a compound or composition of any one of Structural Formulae I-V and XI(A)-XIV or with a combination of a compound or composition of this invention with another anti-viral agent and vaccination with a Flu vaccine.

[00253] When co-administration involves the separate administration of the first amount of a compound of any of Structural Formulae I-V and XI(A)-XIV 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 potency, solubility, bioavailability, plasma half-life and kinetic profile. For example, a compound of any one of Structural Formulae I-V and XI(A)-XIV 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.

[00254] 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 before), concomitantly with, or subsequent to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks after) the administration of a second therapy (e.g., a prophylactic or therapeutic agent such as an anti-cancer agent) to a subject.

[00255] It is understood that the method of co-administration of a first amount of a compound of any one of Structural Formulae I-V and XI(A)-XIV 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 additive effect that would result from separate administration of the first amount of the compound of any one of Structural Formulae I-V and XI(A)-XIV and the second amount of the additional therapeutic agent.

[00256] As used herein, the term “synergistic” refers to a combination of a compound of the invention and another therapy (e.g., a prophylactic or therapeutic agent), which is more effective than the additive effects of the therapies. 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 therapy to a subject without reducing the efficacy of said therapy in the prevention, management or treatment of a disorder. In addition, a synergistic effect can result in improved efficacy 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 prophylactic or therapeutic agents) may avoid or reduce adverse or unwanted side effects associated with the use of either therapy alone.

[00257] When the combination therapy using compounds of the present invention of any one of Structural Formulae T-V and XI(A)-XIV 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).

[00258] The presence of a synergistic effect can be determined using suitable methods for assessing 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 equation (Chou, T.C. and Talalay, P., Adv, Enzyme Regul, 22: 27-55 (1984)). Each equation referred to above can be applied with experimental data to generate a corresponding graph to aid in assessing the effects of the drug combination. The corresponding graphs associated with the equations referred to above are the concentration-effect curve, isobologram curve and combination index curve, respectively.

[00259] Specific examples that can be co-administered with a compound described herein include neuraminidase inhibitors, such as oseltamivir (Tamiflu®) and Zanamivir (Rlenza®), viral ion channel (M2 protein) blockers, such as amantadine (Symmetrel®) and rimantadine (Flumadine®), and antiviral drugs described in WO 2003/015798, including T-705 under development by Toyama Chemical of Japan. (See alsoRuruta et al., Antiviral Reasearch, 82: 95-102 (2009), “T-705 (flavipiravir) and related compounds: Novel broad-spectrum inhibitors of RNA viral infections.”) In some embodiments, the compounds described herein can be co-administerd with a traditional influenza vaccine.

Compounds of the Invention [00260] Another aspect of the present invention is generally related to compounds. In one embodiment, the present invention is generally related to compounds represented by Structural Formula (IA) or (I), or pharmaceutically acceptable salts thereof:

(ΙΑ) (I).

[00261] A first subset of variables of Structural Formulae (I) and (IA) for the compounds of the invention is as follows: R1 is -H, Ci-Cc alkyl, -S(0)2-R” or -C(0)OR”. Specifically, R1 is -H or S(0)2-R”. Specifically, R1 is -H or -S(0)2-(phenyl), wherein the phenyl is optionally substituted with one or more selected from the group consisting of C]-CG alkyl and C1-C6 haloalkyl. More specifically, the phenyl is optionally substituted with one or more selected from the group consisting of -CH3 and -CF3 (e.g., at its para position). Specifically, R1 is -H or Ci_6 alkyl. Specifically, R1 is -H. R4 is:

R” is independently: i) a Ci-Ce-alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxyl, -NH2, -NH(Ci-Ce alkyl), -N(Ci-C6 alkyl)2, Ci-C6 alkoxy, Ci-C6haloalkoxy, CrC6 aminoalkoxy, Ci-Ce cyanoalkoxy, Ci-Cq hydroxyalkoxy, and Cj-Cfi alkoxyalkoxy; or ii) a C3-Cc carbocyclic group, a 5-6 membered heteroaryl group, or a phenyl group, each optionally and independently being substituted with one ore more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, nitro, -NH2, -NHfCi-Ce alkyl), -N(C[-C6 alkyl)2, CrCe alkyl, Ci-Ce haloalkyl, CrC6 cyanoalkyl, Ci-Cg hydroxyalkyl, C2-C6 alkoxyalkyl, Ci-Ce aminoalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, Ci-Cg aminoalkoxy, Ct-Ce cyanoalkoxy, Ci-Ce hydroxyalkoxy, and C2-C6 alkoxyalkoxy. Specifically, R” is independently an optionally substituted, 5-6 membered heteroaryl group, or an optionally substituted phenyl group. Specifically, R” is independently a phenyl group optionally substituted with one or more substituents independently selected from the group consisting of Ci-Cs alkyl and Cj-Ce haloalkyl.

Values of Z1, Z2, Z3, Q1, Q2, Q3, Y\ rings A-D, R*, R, R’, R2, R3, R5, R6, R7, R8, R9, R10, Ru, R12, R13, R14 Ra, Rb, Rc, Rd, JA, JB, JC1, JD1 and JE1, including specific values and substituents therefor, are each and independently as described above in the first set of variables of Structural Formulae (IA) and (I) for the methods of the invention.

Value p is independently 1,2,3 or 4. Specifically, p is independently 1 or 2.

When rings A and B are 3-6-membered, n and m are each independently 0 or 1; and k is independently 0, 1 or 2. Alternatively, when rings A and B are 7-10-membered, n and m, are each independently 0, 1 or 2; and k is independently 0, 1 or 2.

Values x and y are each independently 0, 1 or 2.

Value z is 1 or 2.

It is provided that if Y1 is a bond, then R5 is neither -H, nor an unsubstituted Ci-Ce aliphatic group. Specifically, if Y1 is a bond, then R5 is a substituted Ci-Ce aliphatic group; an optionally substituted C3-Cs non-aromatic carbocycle; an optionally substituted 6-10-membered carbocyclic aryl group; an optionally substituted, 4-8 membered non-aromatic heterocycle; or an optionally substituted, 5-10 membered heteroary group. Specifically, the Ci-Cg aliphatic group represented by R5 is substituted with one or more instances of J°, wherein JC1 is independently selected from: an optionally substituted, Ci-Cg non-aromatic carbocycle; an optionally substituted, 6-10-membered carbocyclic aryl group; an optionally substituted, 4-8 membered non-aromatic heterocycle; an optionally substituted, 5-10 membered heteroaryl group; -ORb; -SRb; -S(0)Ra; -S02R‘; -NRbRc; -C(0)Rb; -C(0)ORb; -OC(0)Rb; -NRC(0)Rb; -C(0)NRbRc; -NRC(0)NRbRc; -NRC(0)ORb; -OCONRbRc; -C(0)NRC02Rb; -NRC(0)NRC02Rb; -C(0)NR(ORb); -S02N(R)Rb; -NRS02Rb; and -NRS02NRRb; or optionally two JCi and two JD1, respectively, together with the atoms to which they are attached, independently form a 5-7-membered ring that is optionally substituted with one or more instances of JE1, and fused to the respective ring to which they are attached.

It is provided that if Q2 and Q3 are each and independently a bond, then R5 is an optionally substituted Cg-Cg non-aromatic carbocycle; an optionally substituted 6-10-membered carbocyclic aiyl group; an optionally substituted, 4-8 membered non-aromatic heterocycle; or an optionally substituted, 5-10 membered heteroaiy group. Specifically, if Q2 and Q3 are each and independently a bond, then R5 is an optionally substituted Cg-Cg nonaromatic carbocycle; or an optionally substituted, 4-8 membered non-aromatic heterocycle.

Alternatively, it is provided that if rings A and B each and independently 5- or 6-membered, R1 and R2 are both -H, R3 is -Cl, Z2 is -H, and Z1 is -F, then Q2-R5 and Q3-R5, respectively, are not-H; and it is provided that the ring B-Q3-R5 moiety is not V-methyl-3- pyrrolidinyl

[00262] A second subset of variables of Structural Formulae (IA) and (I) for the compounds of the invention is as follows: R2 is -H or -CH3. R3 is -II, -Cl, -F, -Br, -CN, -CF3, -0(Ci-C4 alkyl), -OH, -NH2, -NH(Ci-C4 alkyl), or -N(Ci-C4 alkyl)2. R4 is selected from formulae A-D depicted above.

Values of the remaining variables of Structural Formulae (IA) and (I), including specific values, and provisos are each and independently as described above for the first subset of variables of Structural Formulae (IA) and (I).

[00263] A third subset of variables of Structural Formula I for the compounds of the invention is as follows: R2 is -H or -CH3. R3 is -H, -F, -Cl, -CFj, -NH2j -NH(CH3), or -N(CH3)2. R4 is selected from formulae A-D depicted above.

Values of the remaining variables of Structural Formulae (IA) and (I), including specific values, and provisos are each and independently as described above for the first subset of variables of Structural Formulae (IA) and (I).

[00264] A fourth subset of variables of Structural Formulae (IA) and (I)for the compounds of the invention is as follows: R2 is -H or -CH3. R3 is -H, -F, or-Cl. R4 is selected from formulae A-D depicted above.

Values of the remaining variables of Structural Formulae (IA) and (I), including specific values, are each and independently as described above for the first subset of variables of Structural Formulae (IA) and (I).

[00265] A fifth subset of variables of Structural Formulae (IA) and (I) for the compounds of the invention is as follows: R2 is -H. R3 is-H or-Cl. R4 is selected from formulae A-D depicted above.

Values of the remaining variables of Structural Formulae (IA) and (I), including specific values, and provisos are each and independently as described above for the first subset of variables of Structural Formulae (IA) and (I), [00266] A sixth subset of variables of Structural Formulae (IA) and (I)for the compounds of the invention is as follows:

Each of R2, R3 and R4 is independently as described in the first subset, second subset, third subset, fourth subset, or fifth subset, of variables of Structural Formulae (IA) and (I). Z1 is -H, Ci-Ce alkyl, -0(CrC6 alkyl), -F, -Cl, -CN, -C02H, -C02(Ci-C6 alkyl), -CONH2, -C0NH(Ci-C6 alkyl), or -CON(Ci-C6 alkyl)2; and Z2 is -H, Ci-Cg alkyl, -0(Ci-Ce alkyl), -NH2, -NH(Ci-C6 alkyl), or -N(Ci-Ce alkyl)2; wherein each of said alkyl groups (e.g., represented by CrCc alkyl, -0(Ci-C6 alkyl), -C02(CrC6 alkyl), -NH(C|-C6 alkyl), and -N(Ci-C6 alkyl)2) is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, C1-C4 alkyl, -NH2, -NH(Ci-C4 alkyl), -N(Ci-C4 alkyl)2, -OCO(C1-C4 alkyl), -CO(Ci-C4 alkyl), -C02H, -C02(Ci-C4 alkyl), and Ct-C4 alkoxy.

Values of the remaining variables of Structural Formulae (IA) and (I), including specific values, and provisos are each and independently as described above for the first subset of variables of Structural Formulae (IA) and (I), [00267] A seventh subset of variables of Structural Formulae (IA) and (I) for the compounds of the invention is as follows:

Each of R2, R3 and R4 is independently as described in the first subset, second subset, third subset, fourth subset, or fifth subset, of variables of Structural Formulae (IA) and (I). Z1 is -H, -F, -Cl, ~CF3, Ci-C4 alkyl, -0(Ci-C* alkyl), or-CN; and Z2 is -H, Ci-C6 alkyl, -0(Ci-Ce alkyl), -NH2, -NH(CrCe alkyl), or -N(Ci-Ce alkyl)2, wherein each of said alkyl groups (e.g., represented by C|-C6 alkyl, -0(Ci-C<; alkyl), -NBYCi-Ck alkyl), and -N(C|-Ce alkyl)2) is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, Ci-C4 alkyl, -NH2, -NH(C,-C4 alkyl), -N(C,-C4 alkyl)2, -OCO(C,-C4 alkyl), -CO(C,-C4 alkyl), -C02H, -C02(Ci-C4 alkyl), and Ct-C4 alkoxy.

Values of the remaining variables of Structural Formulae (IA) and (1), including specific values, and provisos are each and independently as described above for the first subset of variables.

[00268] An eighth subset of variables of Structural Formulae (IA) and (I) for the compounds of the invention is as follows:

Each of R2, R3 and R4 is independently as described in the first subset, second subset, third subset, fourth subset, or fifth subset, of variables of Structural Formulae (IA) and (I). Z1 is-H, -F, -Cl, Ci-C4haloalkyl (e.g, -CF3), Ci-C4 alkyl, -0(C]-C4 alkyl), or-CN. Z2 is -H or a Ci-C6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, Ci-C4 alkyl, -NH2, -NH(Ci~C4 alkyl), -N(Ci-C4 alkyl)2, -OCO(Ci-C4 alkyl), -CO(Ci-C4 alkyl), -C02H, -C02(Ci-C4 alkyl), and C1-C4 alkoxy.

Values of the remaining variables of Structural Formulae (IA) and (I), including specific values, and provios are each and independently as described above for the first subset of variables.

[00269] A ninth subset of variables of Structural Formulae (IA) and (I) for the compounds of the invention is as follows:

Each of R2, R3 and R4 is independently as described in the first subset, second subset, third subset, fourth subset, or fifth subset, of variables of Structural Formulae (IA) and (I). Z1 is -H, -F, -Cl, -CF3, -CH3j or ~CN. Z2 is -H or a Ci-C6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, C1-C4 alkyl, -NH2, -NH(Ci-C4 alkyl), -NfCi-G, alkyl)2, -OCO(Ci-C4 alkyl), -CO(Ci-C4 alkyl), -CO2H, -C02(Ci-C4 alkyl), and C1-C4 alkoxy.

Values of the remaining variables of Structural Formulae (IA) and (I), including specific values, and provisos are each and independently as described above for the first subset of variables of Structural Formulae (IA) and (I).

[00270] In a tenth subset of variables of Structural Formulae (IA) and (I) for the compounds of the invention, the variables of Structural Formulae (IA) and (I), including specific values, are each and independently as described above for the first, second, third, fourth, fifth, sixth, seventh, eighth, or ninth subset of variables of Structural Formulae (IA) and (I); and where applicable: each R* independently is: ί) -H; ii) Ci-Ce alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(Ci-C4 alkyl), -N(C]-C4 alkyl)2, -OCO(Cj-C4 alkyl), -CO(Ci-C4 alkyl), -CO?H, -C02(Ci-C4 alkyl), and Ci-C4 alkoxy; or iii) a 3-7 membered carbocyclic ring optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(Ci-C4 alkyl), -N(Cr-C4 alkyl)2, -OCO(Ci-C4 alkyl), -CO(Ci-C4 alkyl), -C02H, -C02(Ci-C4 alkyl), C1-C4 alkoxy, and Ci-Ce alkyl, wherein each alkyl is independently and optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(C|-C4 alkyl), ~N(Ct-C4 alkyl)2, -OCO(C,-C4 alkyl), -CO(C,-C4 alkyl), -C02H, -C02(Ci-C4 alkyl), and Ct-C4 alkoxy; and R and R’ are each independently -H or Ci-C6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(Ci-Ce alkyl), -N(Ci-Cg alkyl)2, and -0(Ci-Ce alkyl); or optionally R’, together with R5 and the nitrogen atom to which they are attached, forms a 5-7 membered, non-aromatic, heterocyclic ring optionally substituted with one or more instances of JD1; and R’ ’ is independently a phenyl group optionally substituted with one or more substituents independently selected from the group consisting of Ci-Ce alkyl and Ci-Ce haloalkyl.

[00271] In an eleventh subset of variables of Structural Formulae (I A) and (I) for the compounds of the invention, the variables of Structural Formulae (I A) and (I), including specific values, are each and independently as described above for the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, or tenth subset of variables of Structural Formulae (IA) and (I); and where applicable: provided that if Y1 is a bond, then Rs is a substituted Ci-Ce aliphatic group; an optionally substituted Cj-Cg non-aromatic carbocycle; an optionally substituted 6-10-membered carbocyclic aryl group; an optionally substituted, 4-8 membered non-aromatic heterocycle; or an optionally substituted, 5-10 membered heteroary group; and provided that if Q2 and Q3 are each and independently a bond, then R5 is an optionally substituted C3-C8 non-aromatic carbocycle; an optionally substituted 6-10-membered carbocyclic aryl group; an optionally substituted, 4-8 membered non-aromatic heterocycle; or an optionally substituted, 5-10 membered heteroary group.

[00272] In a twlefth subset of variables of Structural Formulae (IA) and (I) for the compounds of the invention , the variables of Structural Formulae (IA) and (I), including specific values, are each and independently as described above for the eleventh subset of variables of Structural Formulae (IA) and (I); and the Ci-Cg aliphatic group represented by R5, when Y1 is a bond, is substituted with one or more instances of JC1, wherein JC1 is independently selected from: an optionally substituted, C3-C8 non-aromatic carbocycle; an optionally substituted, 6-10-membered carbocyclic aryl group; an optionally substituted, 4-8 membered non-aromatic heterocycle; an optionally substituted, 5-10 membered heteroaryl group; -ORb; -SRb; -S(0)Ra; -S02Ra; -NRbRc; -C(0)Rb; -C(0)ORb; -0C(0)Rb; -NRC(0)Rb; -C(0)NRbRc; -NRC(0)NRbRc;......NRC(0)ORb; -OCONRbRc; -C(0)NRC02Rb; -NRC(0)NRC02Rb; -C(0)NR(0Rb); -S02NRcRb; -NRS02Rb; and -NRS02NRcRb; or optionally two JC1 and two JD1, respectively, together with the atoms to which they are attached, independently form a 5-7-membered ring that is optionally substituted with one or more instances of JEi, and fused to the respective ring to which they are attached.

[00273] A thirteenth subset of variables of Structural Formulae (IA) and (I) is as follows:

Each of JA and JB is independently selected from the group consisting of halogen, cyano, oxo, andC^-R5; or optionally two JA and two JB, respectively, together with the atom(s) to which they are attached, independently form a 5-7 membered ring that is optionally substituted with one or more instances of JE1, and fused to the ring to which they are attached. Q1 is independently a bond, -0-, -S-, -NR’-, -C(0)-, -COr-, -00(0)-, -C(0)NR’~, -C(0)NRC(0)0- -NRC(0)NRC(0)0- -NRC(O)-, -NRC(0)NR’--NRCO2-, -0C(0)NR’-, -S(0)-, -SO2-, -SO2NR’-, -NRSO2-, or-NRS02NR’-, or-(CR6R7)p-Y'-.

Each of JCI and JD1 is independently selected from the group consisting of halogen, cyano, oxo, Rn, -0Rb, -SRb, -S(0)Ra, -S02Ra, -NRbRc, -C(0)Rb, -C(0)0Rb, -0C(0)Rb, -NRC(0)Rb, -C(0)NRbRc, -NRC(0)NRbRc, -NRC(0)0Rb, -OCONRbRc, -C(0)NRC02Rb, -NRC(0)NRC(0)0Rb, -C(0)NR(0Rb), -S02NRcRb, -NRS02Rb, and -NRS02NR'°Rb, or optionally, two JC1 and two JD1, respectively, together with the atoms to which they are attached, independently form a 5-7-membered ring that is optionally substituted with one or more instances of JE1, and fused to the respective ring to which they are attached.

Values of the remaining variables of Structural Formulae (IA) and (I), including specific values, and provisos are each and independently as described above for the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, or twelfth subset of variables of Structural Formulae (IA) and (I).

[00274] In a fourteenth subset of variables of Structural Formulae (IA) and (I), values of the variables are independently as described above in the seventeenth set of variables of Structural Formulae (IA) and (I).

[00275] In a fifteenth subset of variables of Structural Formulae (IA) and (I), values of the variables are independently as described above in the eighteenth set of variables of Structural Formulae (IA) and (I).

[00276] In a sixteenth subset of variables of Structural Formulae (IA) and (I), values of the variables are independently as described above in the nineteenth set of variables of Structural Formulae (IA) and (I).

[00277] In some embodiments, the compounds are represented by Structural Formula (IA) or (I), or pharmaceutically acceptable salts thereof, wherein R1 is -H or Ci-e alkyl, and wherein values of the remaining variables are independently as described above in any one of the subsets of variables of Structural Formulae (IA) and (I).

[00278] In another embodiment, the present invention is generally related to compounds represented by Structural Formula VI, or pharmaceutically acceptable salts thereof.

;vi).

[00279] A first subset of variables of Structural Formula VI for the compounds of this invention is as follows: Z! is -H, Ci-Cfi alkyl, -0(C,-C6 alkyl), -F, -Cl, -CN, -C02H, -C02(C,-C6 alkyl), -CONH2, -CONH(Ci-Cg alkyl), or -CON(C[-Cc alkyl)2, wherein each of said alkyl groups (e.g., representd by Ci-Cs alkyl, -0(Cf-C6 alkyl), -C02(Ci-Ce alkyl), -CONH(Ci-Ce alkyl), and -CON(Ci-Cg alkyl)2) is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, C1-C4 alkyl, -NH2, -NH(Ci-C6 alkyl), -N(Ci-C6 alkyl)2, -OCO(CrC4 alkyl), -CO(Ci-C4 alkyl), -C02H, -C02(Ci-C4 alkyl), and C1-C4 alkoxy. Z2 is -H, Ci-Ce alkyl, -0(C,-C6 alkyl), -NH2, -NH(Ci-C6 alkyl), or -N(Ci-Cs alkyl)2, wherein each of said alkyl groups (e.g., represented by Ci-C6 alkyl, -0(Ci-Ce alkyl), -NH(Ci-Cfi alkyl), and -N(Ci-Ce alkyl)2) is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, Ct-C4 alkyl, -NH2, -NH(Ci-C6 alkyl), -N(Ci-C« alkyl)2, -OCO(Ci-C4 alkyl), -CO(CrC4 alkyl), -C02H, -C02(Ci-C4 alkyl), and C,-C4 alkoxy.

Values of the remaining variables of Structural Formula VI, including specific values, and provisos are each and independently as described above for the first subset of variables of Structural Formulae (IA) and (I).

[00280] A second subset of variables of Structural Formula VI for the compounds of this invention is as follows: Z1 is -H, Ci-Ce alkyl, -0(Ci-C6 alkyl), -F, -Cl, -CN, -C02H, -C02(Cj-C6 alkyl), -CONH2i -CONH(Ci-Cc alkyl), or -CON(Ci -CV, alkyl)2, wherein each of said alkyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, C1-C4 alkyl, -NH2, -NH(Ci-C6 alkyl), -N(Ci-C6 alkyl)2, -OCO(C,-C4 alkyl), -CO(C,-C, alkyl), -C02H, -C02(Ci-C4 alkyl), and C1-C4 alkoxy. Z2 is -H, Ci-Ce alkyl, -0(Ci-C6 alkyl), -NH2, -NH(Ci-C6 alkyl), or -N(Ci-C6 alkyl)2; wherein each of said alkyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, Ci-C4 alkyl, -NH2, -NH(Ci-Cfi alkyl), -N(Ci-Q, alkyl)2, -OCO(Ci-C4 alkyl), -CO(Ci-C4 alkyl), -C02H, -C02(Ci-C4 alkyl), and Ci-C4 alkoxy. R3 is -H, -Cl, -F, -Br, -CN, -CF3, -0(C!-C4 alkyl), -OH, -NH2, -NH(Ci-C4 alkyl), or -N(CrC4 alkyl)2.

Values of the remaining variables of Structural Formula VI, including specific values, and provisos are each and independently as described above for the first subset of variables of Structural Formulae (IA) and (I).

[00281] A third subset of variables of Structural Formula VI for the compounds of this invention is as follows: Z1 is -H, Ci-Ce alkyl, -0(Ci-C<; alkyl), -F, -Cl, -CN, -C02H, -C02(Ci-C6 alkyl), -CONH2, -CONH{Ci-C6 alkyl), or -CON(C|-Cfi alkyl)2, wherein each of said alkyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, Ci-C4 alkyl, -NH2, -NH(Ci-C6 alkyl), -N(Ci-C6 alkyl)2, -OCO(C,-C4 alkyl), -CO(C,-C4 alkyl), -C02H, -C02(Ci-C4 alkyl), and Ci-C4 alkoxy. Z2 is -H, Ci-Ce alkyl, -0(C,-C6 alkyl), -NH2, -NH(Ci-C6 alkyl), or -N(CrC6 alkyl)2; wherein each of said alkyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, Ci-C4 alkyl, -NH2, -NH(CrCa alkyl), -N(CrC<5 alkyl)2, -OCO(Ci-C4 alkyl), -CO(Ci-C4 alkyl), -C02H, -C02(Ci-C4 alkyl), and Ci-C4 alkoxy. R3 is -H, -F, -Cl, -CF3, -NH2j -NH(CH3), or -N(CH3)2. Specifically, R3 is -H, -Cl, or-F. Specifically, R3 is Cl.

Values of the remaining variables of Structural Formula VI, including specific values, and provisos are each and independently as described above for the first subset of variables of Structural Formulae (IA) and (I).

[00282] In a fourth subset of variables of Structural Formula VI for the compounds of this invention, values of the variables for Structural Formula VI, including specific values, and provisos are each and independently as described above in the first subset of variables of Structural Formulae (IA) and (I).

[00283] In a fifth subset of variables of Structural Formula VI for the compounds of this invention, values of the variables for Structural Formula VI, including specific values, and provisos are each and independently as described above in the first, second, third, or fourth subset of variables of Structural Formulae (IA) and (I); and where applicable: provided that if Q2-R3 is -OR5 or -NR’R5, then ring A is further substituted with one or more instances of JA other than -H; and provided that if Q3 is -C(O)-, then R5 is a substituted CrC6 aliphatic group; an optionally substituted C:,-Cg non-aromatic carbocycle; an optionally substituted, 6-10-membered carbocyclic aryl group; optionally substituted, 4-8 membered non-aromatic heterocycle; or an optionally substituted 5-10 membered heteroaryl group.

[00284] In a sixth subset of variables of Structural Formula VI for the compounds of this invention, values of the variables for Structural Formula VI, including specific values, and provisos are each and independently as described above in the fifth subset; and the Ci-Ce aliphatic group represented by R5, when Q3 is -C(O)-, is substituted with one or more instances of JC1, wherein JC1 is independently selected from: an optionally substituted, C;j-Cs non-aromatic carbocycle; an optionally substituted, 6-10-membered carbocyclic aryl group; an optionally substituted, 4-8 membered non-aromatic heterocycle; an optionally substituted, 5-10 membered heteroaryl group; -ORb; -SRb; -S(0)Ra; -SCbR*’1; -NRbRc; -C(0)Rb; -C(0)0Rb; -OC(0)Rb; -NRC(0)Rb; -C(0)NRbRc; -NRC(0)NRbRc; -NRC(0)ORb; -OCONRbRc; -C(0)NRC02Rb; -NRC(0)NRC02Rb; -C(0)NR(0Rb); -S02NRcRb; -NRS02Rb; and -NRS02NRcRb; or optionally two JC! and two JD1, respectively, together with the atoms to which they are attached, independently form a 5-7-membered ring that is optionally substituted with one or more instances of JE1, and fused to the respective ring to which they are attached.

[00285] In a seventh subset of variables of Structural Formula VI for the compounds of this invention, values of the variables for Structural Formula VI, including specific values, and provisos are each and independently as described above in the first, second, third, or fourth subset of variables of Structural Formulae (IA) and (I); and where applicable: provided that if Y1 is a bond, then R5 is a substituted C]-C6 aliphatic group; an optionally substituted C3-C8 non-aromatic carbocycle; an optionally substituted 6-10-membered carbocyclic aiyl group; an optionally substituted, 4-8 membered non-aromatic heterocycle; or an optionally substituted, 5-10 membered heteroary group; and provided that if Q2 and Q3 are each and independently a bond, then R5 is an optionally substituted Ci-Cs non-aromatic carbocycle; an optionally substituted 6-10-membered carbocyclic aryl group; an optionally substituted, 4-8 membered non-aromatic heterocycle; or an optionally substituted, 5-10 membered heteroary group.

[00286] In an eighth subset of variables of Structural Formula VI for the compounds of this invention, values of the variables for Structural Formula VI, including specific values, and provisos are each and independently as described above in the seventh subset of variables of Structural Formulae (IA) and (I); and the Ci-Ce aliphatic group represented by R5, when Y1 is a bond, is substituted with one or more instances of J0, wherein JC1 is independently selected from: an optionally substituted, C3-C8 non-aromatic carbocycle; an optionally substituted, 6-10-membered carbocyclic aryl group; an optionally substituted, 4-8 membered non-aromatic heterocycle; an optionally substituted, 5-10 membered heteroaryl group; -ORb; -SRb; -S(0)Ra; -S02R!>; -NRbRc; -C(0)Rb; -C(0)0Rb; -0C(0)Rb; -NRC(0)Rb;.....C(0)NRbRc; -NRC(0)NRbRc; -NRC(0)0Rb; -OCONRbRL; -C(0)NRC02Rb; -NRC(0)NRC02Rb; -C(0)NR(0Rb); -S02NRcRb; -NRS02Rb; and -MRS02NRcRb; or optionally two JCI and two JD1, respectively, together with the atoms to which they are attached, independently form a 5-7-membered ring that is optionally substituted with one or more instances of JEi, and fused to the respective ring to which they are attached.

[00287] In a ninth subset of variables of Structural Formula VI for the compounds of this invention, values of the variables for Structural Formula VI, including specific values, and provisos are each and independently as described above in the first, second, third, or fourth subset of variables of Structural Formulae (IA) and (I); and where applicable: provided that if Q2-R5 is -OR5 or -NR’R5, then ring A is further substituted with one or more instances of JA other than -H; provided that if Q3 is -C(O)-, then R5 is a substituted Ci-Ce aliphatic group; an optionally substituted C3-C8 non-aromatic carbocycle; an optionally substituted, 6-10-membered carbocyclic aryl group; optionally substituted, 4-8 membered non-aromatic heterocycle; or an optionally substituted 5-10 membered heteroaryl group; provided that if Y1 is a bond, then R5 is a substituted Ci-Ce aliphatic group; an optionally substituted C3-CS non-aromatic carbocycle; an optionally substituted 6-10-membered carbocyclic aryl group; an optionally substituted, 4-8 membered non-aromatic heterocycle; or an optionally substituted, 5-10 membered heteroary group; and provided that if Q2 and Q3 are each and independently a bond, then R5 is an optionally substituted C3-C8 non-aromatic carbocycle; an optionally substituted 6-10-membcred carbocyclic aiyl group; an optionally substituted, 4-8 membered non-aromatic heterocycle; or an optionally substituted, 5-10 membered heteroary group.

[00288] In a tenth subset of variables of Structural Formula VI for the compounds of this invention, values of the variables for Structural Formula VI, including specific values, and provisos are each and independently as described above in the ninth subset of variables of Structural Formulae (IA) and (I); and when Q3 is -C(O)-, or Y1 is a bond, the Ci-Ce aliphatic group represented by R5 is substituted with one or more instances of JC1, wherein JC1 is independently selected from: an optionally substituted, Ci-Cs non-aromatic carbocycle; an optionally substituted, 6-10-membered carbocyclic aryl group; an optionally substituted, 4-8 membered non-aromatic heterocycle; an optionally substituted, 5-10 membered heteroaryl group; -ORb; -SRb; -S(0)Ra; -S02Ra; -NRbRc; -C(0)Rb; -C(0)ORb; -OC(0)Rb; -NRC(0)Rb; -C(0)NRbRc; -NRC(0)NRbRc; -NRC(0)ORb; -OCONRbRe; -C(0)NRC02Rb; -NRC(0)NRC02Rb; -C(0)NR(ORb); -S02NRcRb; -NRS02Rb; and -NRS02NRcRb; or optionally two JC1 and two JDE, respectively, together with the atoms to which they are attached, independently form a 5-7-membcrcd ring that is optionally substituted with one or more instances of JE1, and fused to tire respective ring to which they are attached.

[00289] In an eleventh subset of variables of Structural Formula VI, values of the variables for Structural Formula VI, including specific values, are each and independently as described above in the thirteenth subset of variables of Structural Formulae (IA) and (I).

[00290] In another embodiment, the present invention is generally related to compounds represented by any one of Structural Formulae II, III, IV and V, or pharmaceutically acceptable salts thereof:

(II) (HI)

5 (IV) (V), [00291] A first subset of variables of Structural Formulae II, III, IV and V for the compounds of the invention is as follows:

Each Q2 is independently -0-, -S-, -NR’-, -C(O)-, -C02- “OC(O)-, -C(0)NR’-, -C(0)NRC(0)0- -NRC(O)NRC(0)0-, -NRC(O)-, -NRC(0)NR’- -NRC02--0C(0)NR’-, -S(0)-, -SO2-, -N(R)S02-, -S02NR’-, -NRS02NR\ or-fCR^jp-Y1-.

Each Q3 is independently -0(0)-, -CO2-, -C(0)NR’- ~S02- ,-S02NRS -C(0)NRC(0)0-, or -(CRVjp-Y1-. Z1 is -H, -F, -Cl, CrC4 haloalkyl (e.g., -CF3), CrQ alkyl, -0(C,-C4 alkyl), or -ON. Z2 is -H, C,-C6 alkyl, -0(Ci-C6 alkyl), -NH2, -NH(Ci-C6 alkyl), or-N(C,-C6 alkyl)2, wherein each of said alkyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, Ci-C4 alkyl, -NH2, -NHfCi-Ce alkyl), -NfCi-Ce alkyl)2, -OCO(Ct-C4 alkyl), -CO(CrC4 alkyl), -C02H, -C02(Ci-C4 alkyl), and Ci-C4 alkoxy. R3 is -H, -Cl, -F, -Br, -ON, -CF3, -0(Cs-C4 alkyl), -OH, -NH2, -NH(Ci-C4 alkyl) or -N(Ci-C4 alkyl)2. Specifically, R3 is -H, -F, -Cl, -CF3, -NH2, -NH(CH3), or -N(CH3)2. Specifically, R3 is -H, -Cl, or-F. Specifically, R3 is -Cl.

Each R and R’ is independently -H or Ci-C Galkyl.

Definitions of rings A-D of formulae II-V, including specific variables, are each and independently as described above for the first set of variables of Structural Formulae (IA) and (I), wherein each of rings A-D is independently an optionally substituted, 4-7 membered ring.

Values of the remaining variables of Structural Formulae II-V, including specific values, and provisos are each and independently as described above for the first subset of variables of Structural Formulae (IA) and (I).

[00292] A second subset of variables of Structural Formulae II, III, IV and V for the compounds of the invention is as follows: Z1 is -H, -F, -Cl, -CFj, -CH3, or-CN. Z2 is -H or Cj-Cf, alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, C1-C4 alkyl, -NH2, -NH(Ct-C6 alkyl), -N(C,-Crt alkyl)2, -0C0(CrC4 alkyl), -CO(CrC4 alkyl), -C02H, -C02(Ci-C4 alkyl), and Ci-C4 alkoxy.

Values of the remaining variables of Structural Formulae II-V, including specific values and provisos are each and independently as described above for the first subset of variables of Structural Formulae II-V.

[00293] A third subset of variables of Structural Formulae II, III, TV and V for the compounds of the invention is as follows: Z1 is -H, -F, or-CN. Z2 is -H or CrCfi alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, Ci-C4 alkyl, -NH2, -NH(Ci-C6 alkyl), -N(CrC6 alkyl)2, -OCO(Ci-C4 alkyl), -00(0^4 alkyl), -C02H, -C02(CrC4 alkyl), and Ct-C4 alkoxy.

Values of the remaining variables of Structural Formulae II-V, including specific values, and provisos are each and independently as described above for the first subset of variables of Structural Formulae II-V, [00294] A fourth subset of variables of Structural Formulae II, III, IV and V for the compounds of the invention is as follows: Z1 is-H, -F, or-CN. Z2 is -H or Ci-Ce alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, Ci-C4 alkyl, -NH2, -NH(Ci-Ce alkyl), -N(Ci-C6 alkyl)2, -OCO(CrC4 alkyl), -CO(Ci-C4 alkyl), -C02H, -C02(Ci-C4 alkyl), and Ci-C4 alkoxy. R3 is -H, -Cl or -F.

Values of the remaining variables of Structural Formulae II-V, including specific values, and provisos are each and independently as described above for the first subset of variables of Structural Formulae II-V.

[00295] A fifth subset of variables of Structural Formulae II, III, IV and V for the compounds of the invention is as follows: Z1 is-H,-F or-CN. Z2 is -H or Ci-Ce alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, Ci-C4 alkyl, -NH2, -NH(Ci-C6 alkyl), -N(Ci-C6 alkyl)2, -OCO(C(-C4 alkyl), -CO(CrC4 alkyl), -C02H, -C02(Ci-C4 alkyl), and C1-C4 alkoxy. R3 is -H, -Cl, -F, -CF:„-NH2, -NH(CH3), -N(CH3)2. R6 and R7 are each independently -H or -CH3, or together with the carbon atoms to which they are attached they form a cyclopropane ring.

Each R8 is independently -H, halogen, cyano, hydroxy, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C2-C4 alkoxyalkyl, -0(Ci-C4 alkyl), -NH2, -NH(Ci-"C4 alkyl) or -N(Ct-C4alkyl)2.

Each R9 is independently -H or-(¾.

Ru and R12 are each independently -H or -CH3. R13 and R14 are each independently -H or-CH3, or together with the carbon atoms to which they are attached they form a cyclopropane ring.

Values of the remaining variables of Structural Formulae II-V, including specific values, and provisos are each and independently as described above for the first subset of variables of Structural Formulae II-V.

[00296] A sixth subset of variables of Structural Formulae II, III, IV and V for the compounds of the invention is as follows: Z1 is ~H, -F or -CN. Z2 is -H or Ci-C6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, C1-C4 alkyl, -NH2, -NH(Ci-C6 alkyl), -N(Ci-C6 alkyl)2, -OCO(CrC4 alkyl), -CO(Ci-C4 alkyl), -C02H, -C02(Ci-C4 alkyl), and C1-C4 alkoxy. R3 is -H, -Cl or -F. R6 and R7 are each independently -H or -CH3, or together with the carbon atoms to which they are attached they form a cyclopropane ring.

Each R8 is independently -H, halogen, cyano, hydroxy, C[-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C2-C4 alkoxyalkyl, -0(Ci~C4 alkyl), -NH2, -NH(Ci-C4 alkyl), or “N(Ci-C4 alkyl)2.

Each R9 is independently -H or -CH3.

Ru and R12 are each independently -H or -CH3. R13 and R14 are each independently -H or-CH3, or together with the carbon atoms to which they are attached they form a cyclopropane ring.

Values of the remaining variables of Structural Formulae II-V, including specific values, and provisos are each and independently as described above for the first subset of variables of Structural Formulae II-V.

[00297] In a seventh subset of variables of Structural Formulae II-V for the compounds of the invention, values for variables, except for R6, R7, R8, R9, R11, R12, R!3 and R14, of Structural Formulae II-V, including specific values, and provisos are each and independently as described above in the first, second, third, or fourth subset of variables of Structural Formulae (IA) and (I). R6 and R7 are each independently -H or -C1-C4 alkyl, or together with the carbon atoms to which they are attached they form a cyclopropane ring.

Each R8 is independently -H, halogen, cyano, hydroxy, C1-C4 alkyl, C1-C4 haloalkyl, C4-C4 hydroxyalkyl, C2-C4 alkoxyalkyl, -0(Ci-C4 alkyl), ”-NH2, -NH(Ci-C4 alkyl) or ~N(Ci~C4 alky 1)2.

Each R9 is independently -H or -C1-C4 alkyl. R11 and R12 are each independently -H or-Ci-C4 alkyl. R13 and R14 are each independently -H or-Ci-C4 alkyl, or together with the carbon atoms to which they are attached they form a cyclopropane ring [00298] In an eighth subset of variables of Structural Formulae II-V for the compounds of the invention, values for variables of Structural Formulae II-V, including specific values, and provisos are each and independently as described above in the first subset of variables of Structural Formulae (IA) and (I).

[00299] In a ninth subset of variables of Structural Formulae II-V for the compounds of the invention, values for variables of Structural Formulae II-V, including specific values, are each and independently as described above for the first, second, third, fourth, fifth, sixth, seventh, or eighth subset of variables of Structural Formulae II-V; and where applicable: provided that if Q2-R5 is -OR5 or -NR’R5, then ring A is further substituted with one or more instances of JA other than -H; and provided that if Q3 is -C(O)-, then R5 is a substituted Ci-Cs aliphatic group; an optionally substituted CVCs non-aromatic carbocycle; an optionally substituted, 6-10-membered carbocyclic aiyl group; optionally substituted, 4-8 membered non-aromatic heterocycle; or an optionally substituted 5-10 membered hcteroaryl group.

[00300] In a tenth subset of variables of Structural Formulae II-V for the compounds of the invention, values for variables of Structural Formulae II-V, including specific values, are each and independently as described above for the ninth subset of variables of Structural Formulae II-V; and where applicable: when Q3 is -C(0)-, the Ct-C6 aliphatic group represented by Rs is substituted with one or more instances of JC1, wherein JC1 is independently selected from: an optionally substituted, C3-Cs non-aromatic carbocycle; an optionally substituted, 6-10-membered carbocyclic aryl group; an optionally substituted, 4-8 membered non-aromatic heterocycle; an optionally substituted, 5-10 membered heteroaryl group; -ORb; -SRb; -S(0)Ra; -S02Ra; -NRbRc; -C(0)Rb; -C(0)0Rb; -0C(0)Rb; -NRC(0)Rb; -C(0)NRbRc; ~NRC(0)NRbRc; -NRC(0)0Rb; -OCONRbRc; -C(0)NRC02Rb; -NRC(0)NRC02Rb; -C(0)NR(0Rb); -S02NR‘:Rb; -NRS02Rb; and -NRS02NRcRb; or optionally two JC1 and two JD1, respectively, together with the atoms to which they are attached, independently form a 5-7-membered ring that is optionally substituted with one or more instances of JE1, and fused to the respective ring to which they are attached.

[00301] In an eleventh subset of variables of Structural Formulae 1T-V for the compounds of the invention, values for variables of Structural Formulae II-V, including specific values, are each and independently as described above for the first, second, third, fourth, fifth, sixth, seventh, or eighth subset of variables of Structural Formulae II-V; and where applicable: provided that if Y1 is a bond, then R5 is a substituted Ci-Cg aliphatic group; an optionally substituted C3-Cg non-aromatic carbocycle; an optionally substituted, 6-10-membered carbocyclic aryl group; an optionally substituted, 4-8 membered non-aromatic heterocycle; or an optionally substituted, 5-10 membered heteroary group; and provided that if Q2 and Q3 are each and independently a bond, then R5 is an optionally substituted C3-C8 non-aromatic carbocycle; an optionally substituted, 6-10-membered carbocyclic aryl group; an optionally substituted, 4-8 membered non-aromatic heterocycle; or an optionally substituted, 5-10 membered heteroary group.

[00302] In a twlefth subset of variables of Structural Formulae II-V for the compounds of the invention, values for variables of Structural Formulae II-V, including specific values, are each and independently as described above for the eleventh subset of variables of Structural Formulae II-V; and where applicable: when Y1 is a bond, the Ci-Cs aliphatic group represented by R5 is substituted with one or more instances of JC1, wherein JCi is independently selected from: an optionally substituted, C3-Cs non-aromatic carbocycle; an optionally substituted, 6-10-membered carbocyclic aryl group; an optionally substituted, 4-8 membered non-aromatic heterocycle; an optionally substituted, 5-10 membered heteroaryl group; -ORb; -SRb; -S(0)Ra; -S02Ra; -NRbRc; -C(0)Rb;.....C(0)ORb; -OC(0)Rb; -NRC(0)Rb; -C(0)NRbRc; -NRC(0)NRbRc; -NRC(0)0Rb; -OCONRbRc; -C(0)NRC02Rb; -NRC(0)NRC02Rb; -C(0)NR(0Rb); -S02NRcRb; -NRS02Rb; and -NRS02NRcRb; or optionally two JC1 and two JDl, respectively, together with the atoms to which they are attached, independently form a 5-7-membered ring that is optionally substituted with one or more instances of JE1, and fused to the respective ring to which they are attached.

[00303] In a thirteenth subset of variables of Structural Formulae II-V for the compounds of the invention, values for variables of Structural Formulae II-V, including specific values, arc each and independently as described above for the first, second, third, fourth, fifth, sixth, seventh, or eighth subset of variables of Structural Formulae II-V; and where applicable: provided that if Q2-R5 is -OR5 or -NR’R5, then ring A is further substituted with one or more instances of JA other than -H; provided that if Q3 is -0(0)-, then R5 is a substituted Ci-Cg aliphatic group; an optionally substituted C2-Cs non-aromatic carbocycle; an optionally substituted, 6-10-membered carbocyclic aryl group; optionally substituted, 4-8 membcrcd non-aromatic heterocycle; or an optionally substituted 5-10 membered heteroaryl group. provided that if Y1 is a bond, then R5 is a substituted Ci-Ce aliphatic group; an optionally substituted Cs-Cs non-aromatic carbocycle; an optionally substituted, 6-10-membered carbocyclic aryl group; an optionally substituted, 4-8 membered non-aromatic heterocycle; or an optionally substituted, 5-10 membered heteroary group; and provided that if Q2 and Q3 are each and independently a bond, then R5 is an optionally substituted C3-CS non-aromatic carbocycle; an optionally substituted, 6-10-membered carbocyclic aryl group; an optionally substituted, 4-8 membered non-aromatic heterocycle; or an optionally substituted, 5-10 membered heteroary group.

[00304] In a fourteenth subset of variables of Structural Formulae II-V for the compounds of the invention, values for variables of Structural Formulae II-V, including specific values, are each and independently as described above for the thirteenth subset of variables of Structural Formulae II-V; and where applicable: when Q3 is -C(O)-, or Y! is a bond, the Cj-Cc aliphatic group represented by R5 is substituted with one or more instances of JC1, wherein JCI is independently selected from: an optionally substituted, Cj-Cs non-aromatic carbocycle; an optionally substituted, 6-10-membered carbocyclic aryl group; an optionally substituted, 4-8 membered non-aromatic heterocycle; an optionally substituted, 5-10 membered heteroary 1 group; -ORb; -SRb; -S(0)Ra; -S02Ra; -NRbRc; -C(0)Rb; -C(0)0Rb; -0C(0)Rb; -NRC(0)Rb; -C(0)NRbRc; -NRC(0)NRbRc; -NRC(0)0Rb; ~OCONRbRc; -C(0)NRC02Rb; -NRC(0)NRC02Rb; -C(0)NR(0Rb); -S02NRcRb; -NRS02Rb; and -NRS02NRcRb; or optionally two JC1 and two JD1, respectively, together with the atoms to which they are attached, independently form a 5-7-membered ring that is optionally substituted with one or more instances of JEl, and fused to the respective ring to which they are attached. (00305 ] A fifteenth subset of variables of Structural Formulae II-V is as follows:

Each of JA and JB is independently selected from the group consisting of halogen, cyano, oxo, and Q'-R5; or optionally two JA and two JB, respectively, together with the atom(s) to which they are attached, independently form a 5-7 membered ring that is optionally substituted with one or more instances of JE1, and fused to the ring to which they are attached. Q1 is independently a bond, -0-, -S-, -NR-, -C(O)-, -C02-, -OC(O)-, -C(0)NR- -C(0)NRC(0)0-, -NRC(0)NRC(0)0-, -NRC(O)-, -NRC(0)NR-, -NRC02-, -0C(0)NR- -S(O)-, -S02-, -N(R)S02-, -S02N(R)-, -NRS02NR-, or -(CR6R7)p-y'-. Q2 is independently a bond, -0-, -S-, -NR-, -C(O)-, -C02-, -OC(O)-, -C(0)NR-, -CC0)NRC(0)0-, -NRC(0)NRC(0)0- -NRC(O)-, -NRC(0)NR--NRCO2-, -0C(0)NR- -S(O)-, -S02-, ~N(R)S02-, -S02N(R)-, -NRSOaNR-, or -(CRfiR7)p-Y5-. Q3 is independently a bond, -C(O)-, -C02-, -C(0)NR-, -S02--S02N(R)-, -C(0)NRC(0)0~ or -(CR6R7)p-Y'-. R5 is: i) -H; ii) a Cj-Cs aliphatic group optionally substituted with one or more instances of JC1; iii) a Ch-Cg non-aromatic carbocycle, or 6-10 membered carbocyclic aryl group, each optionally and independently substituted with one or more instances of JC1; or iv) a 4-8 membered non-aromatic heterocycle, or a 5-10 membered heteroaryl group, each optionally and independently substituted with one or more instances of JD1.

Each of JC1 and JD1 is independently selected from the group consisting of halogen, cyano, oxo, Ra, -ORb, -SRb, -S(0)Ra, -S02Ra, -NRbRc, -C(0)Rb, -C(0)0Rb, ~0C(0)Rb, -NRC(0)Rb, -C(0)NRbRc, -NRC(0)NRbRc, -NRC(0)0Rb, -OCONRbRc, -C(0)NRC02Rb, -NRC(0)NRC(0)0Rb, -C(0)NR(0Rb), -S02NRcRb, -NRS02Rb, and -NRS02NRcRb, or optionally, two JC1 and two JD!, respectively, together with the atoms to which they are attached, independently form a 5-7-membered ring that is optionally substituted with one or more instances of JE1, and fused to the respective ring to which they are attached.

Ring A is a C3-C8 non-aromatic carbocycle optionally and independently further substituted with one or more instances of JA.

Values of the remaining variables of Structural Formulae II-V, including specific values, and provisos are each and independently as described above for the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, or fourteenth subset of variables of Structural Formulae II-V.

[00306] In another embodiment, the present invention is generally related to compounds of Structural Formula XI(A) or XI(B), or pharmaceutically acceptable salts thereof.

(ΧΙΑ) (XIB) [00307] A first subset of variables of Structural Formulae XI(A) and XI(B) for the compounds of the invention is as follows:

Each Q2 is independently -0-, -S-, -NR’-, -C(O)-, -CCb™, -00(0)-, -C(0)NR’--C(0)NRC(0)0- -NRC(0)NRC(0)0- -NRC(O)-, -NRC(0)NR’~, -NRC02--0C(0)NR’-, -S02- -N(R)S02- -S02NRS or-(CR6R7)i-Y1-.

Ring A is a 5-7 membered, non-aromatic carbocyclic ring optionally further substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, Ci-C6alkyl, C2-C<s alkenyl, -NH2, -NH(CrCe alkyl), -N(Ci-Ce alkyl)2, -0(Ci.C6 alkyl), -C(0)NH2, -C(0)NH(C,-C6 alkyl), -C(0)N(C,-C6 alkyl)2, -C(0)(C,-C6-alkyl), -00(0)(0,-C6 alkyl), -NHC(0)(C,-C6 alkyl), -N(C,-C6 alkyI)C(0)(C,-Ce alkyl), and -C02Rb; wherein each of said alkyl and alkenyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, C,-C4 alkyl, -NH2, -NH(C,-C6 alkyl), -N(C,-C6 alkyl)2, -OCO(C,-C4 alkyl), -CO(C]-C4 alkyl), -C02H, -C02(C,-C4 alkyl), and C,-C4 alkoxy. Specifically, ring A is a 5-7 membered, non-aromatic carbocyclic ring optionally further substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, C,-C4 alkyl, -0(Ci-C4 alkyl), -NH2, -NH(Ct-C4 alkyl), -N(Ci-C4 alkyl)2, -C(0)(Ci-C4 alkyl), -C02H, and -C02(Ci-C4 alkyl), wherein each of said alkyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, Ci-C4 alkyl, -NH2, -NH(Ci-Ce alkyl), --N(Ci-Cc alkyl)2, -OCO(Ci-C4 alkyl), -CO(Ci-C4 alkyl), -C02H, "C02(Ci-C4 alkyl), and C|-C4 alkoxy. Specifically, ring A is a 5-7 membered carbocyclic ring optionally further substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(CrC2 alkyl), -NH(CrC2 alkyl)2, C,-C2 alkyl, Ci-C2 haloalkyl, C,-C2 hydroxyalkyl, C2-C4 alkoxyalkyl, Ci-C2 alkoxy, Ci-C2 hydroxy alkoxy, Ci-C2 haloalkoxy, C2-C4 alkoxyalkoxy, -C02H, and -C02(CrC4 alkyl). R6 and R7 are each independently -H or -CH3, or together with the carbon atoms to which they are attached they form a cyclopropane ring.

Each Rs is independently -H, halogen, cyano, hydroxy, Ci-C4 alkyl, Cj-C4 haloalkyl, Ci-C4 hydroxyalkyl, C2-C4 alkoxyalkyl, -0(Ci-C4 alkyl), -NH2, -NH(Ci~C4 alkyl), or -N(Ci-C4 alkyl)2.

Each R9 is independently -H or-CEk R11 and R12 are each independently -H or -CH2, R13 and R14 are each independently -H or -CH?„ or together with the carbon atoms to which they are attached they form a cyclopropane ring.

Each R and R’ is independently -H or Ci-Ce alkyl.

Provided that if Q2-R5 is -OR5 or -NR’R5, then ring A is further substituted with one or more instances of JA other than -H.

Values of the remaining variables of Structural Formulae XI(A) and XI(B), including specific values, and provisos are each and independently as described above in the first subset of variables of Structural Formulae (I A) and (I).

[00308] A second subset of variables of Structural Formulae XI(A) and XI(B) for the compounds of the invention is as follows:

Values of Ring A, Q2, R, R’, R5, R6, R7, R8, R9, R11, R12, R13 and R14, including specific values, and provisos are each and independently as described above in the first subset of variables of Structural Formulae XI(A) and XI(B).

Variable x is 0 or 1 and variable n is 0 or 1,

Values of the remaining variables of Structural Formulae XI(A) or XI(B), including specific values, and provisos are each and independently as described above in the first subset of variables of Structural Formulae XI(A) and XI(B).

[00309] A third subset of variables of Structural Formulae XI(A) and XI(B) for the compounds of the invention is as follows:

Values of Ring A, R, R’, Re, R7, R8, R9, Rn, R12, R13, R14, x and n, including specific values, and provisos are each and independently as described above in the second subset of variables of Structural Formulae XI(A) and XI(B). Q2 is -0-, -NR’-, -CO-, -C02-, -C(0)NR’- -NRC(O)-, -NRC(0)NR--NRCO2- -OCONR-, -NRSO2- -SOaNRSor-CCR^RVY1-. Specifically, Q2 is -0-, -NH-, -N(CH3)-, -0(0)-, -CO2-, -C(0)NH- -C(OjN(CH?)- -NHC(O)-, -N(CH3)C(0)-, -NHC(0)NR’-, -N(CH3)C(0)NR’-, -NHCO2-, -N(CH3)C02-, -0C(0)NR’-, -NHSO2- -N(CH3)S02-, -SO2NH-, -S02N(CH3)-, or -(CR6R7)P-Y1-.

Values of the remaining variables of Structural Formulae XI(A) and XI(B), including specific values, and provisos are each and independently as described above in the first subset of variables of Structural Formulae (IA) and (I).

[00310] A fourth subset of variables of Structural Formulae XI(A) and XI(S) for the compounds of the invention is as follows:

Values of Ring A, Q2, R, R’, R6, R7, Rs, R9, RU,R12, R13, R14, x and n, including specific values, and provisos are each and independently as described above in the third subset of variables of Structural Formulae XI(A) and XI(B) R5 is independently i) -H; ii) a Ci-Ce aliphatic group (e.g., Ci-Ce-alkyl or C2-Cc alkenyl group) optionally substituted with one or more instances of JCi; iii) a C3-Cs nonaromatic carbocycle optionally substituted with one or more instances of JC1; iv) a phenyl group optionally substituted with one or more instances of JC1; v) a 4-8 membered nonaromatic heterocycle optionally substituted with one or more instances of JD1 or vi) a 5-6 membered heteroaryl ring optionally substituted with one or more instances of JD1.

Each JC1 and JD1 is independently selected from the group consisting of halogen, cyano, oxo, Ra, -ORb, -SRb, -S(0)Ra-, -S02Ra, -NHRC, -C(0)Rb, -C(0)0Rb, -0C(0)Rb, ~NHC(0)Rb, -C(0)NHRc, -NHC(0)NHRc, -NHC(0)0Rb, -OCONHRc, -NHC(0)NHC(0)0Rb, -N(CH3)RC, -N(CH3)C(0)Rb, -C(0)N(CH3)Rc, -N(CH3)C(0)NHRc, -N(CH3)C(0)0Rb, -OCON(CH3)Rc, -C(0)NHC02Rb, -C(0)N(CH3)C02Rb, -N(CH3)C(0)NHC(0)0Rb, -NHS02Rb, -S02NHRb, -S02N(CH3)Rb, and -N(CH3)S02Rb.

Values of the remaining variables of Structural Formulae XI(A) and XI(B), including specific values, and provisos are each and independently as described above in the first subset of variables of Structural Formulae (IA) and (I).

[00311] A fifth subset of variables of Structural Formulae XI(A) and XI(B) for the compounds of the invention is as follows:

Values of Q2, R, R’, R5, R6, R7, Rs, R9, R11, R12, R13, R!4, x and n, including specific values, and provisos are each and independently as described above in the fourth subset of variables of Structural Formulae XI(A) and XI(B).

Ring A is optionally further substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, C1-C4 alkyl, -0(Ci-C4 alkyl), -NH2, -NH(Ci-C4 alkyl), -N(Ci-CU alkyl)2, -C(0)(CrC4 alkyl), -C02H, and -C02(Ci-C4 alkyl), wherein each of said alkyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of h halogen, cyano, hydroxy, oxo, C1-C4 alkyl, -NH2, -NH(Ci-Ce alkyl), -N(CrCe alkyl)2, -OCO(C,-C4 alkyl), -CO(Ct-C4 alkyl), -C02H, -C02(Ct-C4 alkyl), and CrC4 alkoxy.

It is provided that if Q2-R5 is -OR5 or -NR’R5, then ring A is further substituted with one or more instances of JA other than —H.

Values of the remaining variables of Structural Formulae XI(A) and XI(B), including specific values, and provisos are each and independently as described above in the first subset of variables of Structural Formulae (IA) and (I).

[00312] A sixth subset of variables of Structural Formulae XI(A) and XI(B) for the compounds of the invention is as follows:

Values of Q2, R, R’, R5, R6, R7, R8, R9, R11, Ri2, R13, R14, x and n, including specific values, and provisos are each and independently as described above in the fifth subset of variables of Structural Formulae XI(A) and XI(B).

The group -[(C)o-iR13R14]-ringA-Q2-R5 is independently selected from one of the depicted below

wherein each of rings A1-A27 is independently and optionally further substituted with one or more substituents. Specifically, rings AS, A6, A21, A24, and A26 are each independently further substituted with one or more instances of substituents other than -H. Suitable substituents are as described above for ring A in the first subset of variables of Structural Formulae XI(A) and XI(B).

Values of the remaining variables of Structural Formulae XI(A) and X1(B), including specific values, and provisos are each and independently as described above in the first subset of variables of Structural Formulae (IA) and (I).

[00313] A seventh subset of variables of Structural Formulae XI(A) and XI(B) for the compounds of the invention is as follows:

Values of the group -[CRI3R14]x-ringA-Q2-R5, ring A, Q2, R, R’, R6, R7, Rs, R9, R11, R12, R13, R14, x and n, including specific values, and provisos are each and independently as described above in the sixth subset of variables of Structural Formulae XI(A) and XI(B).

Each R5 is independently: i) -H; ii) a Ci-Ce-aliphatic group optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, C1-C4 alkyl, -0(Ci-C4 alkyl), -NH2, -NH(Ci-C4 alkyl), -N(C)-C4 alkyl)2, -C(0)(C,-C4 alkyl), -0C(0)(Ci-C4 alkyl), -C(0)0(Ci-C4 alkyl), -C02H, C3-C3 nonaromatic carbocycle, phenyl, 4-8 membered non-aromatic heterocycle, and 5-6 membered heteroaryl; or ui) a C3-C7 non-aromatic carbocycle, a 4-7 membered non-aromatic heterocycle, a phenyl group, or a 5-6 membered heteroaryl ring, each of which is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, C1-C4 alkyl, -0(Ci-C4 alkyl), -NH2, -NH(Ci-C4 alkyl), -N(Ci-C4 alkyl)2, -C(0)(Ci-C4 alkyl), -0C(0)(C,-C4 alkyl), -C(0)0(Ci-C4 alkyl), and -CO2H; wherein each of said alkyl groups for the substituents of the aliphatic group, carbocycle, heterocycle, phenyl and heteroaryl group represented by R5 is independently and optionally substituted with one or more substituents independently . selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(Ci-C4 alkyl), -N(Ci-C4 alkyl)2, -OCO(Ci-C4 alkyl), -CO(C,-C4 alkyl), -C02H, -C02(Ct-C4 alkyl), and C1-C4 alkoxy; and wherein each of said carbocycle, phenyl, heterocycle, and heteroaryl for the substituents of the Ci-Ce-aliphatic group represented by R5 is independently and optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, Ci-C4 alkyl, -NH2, -NH(Ci-C4 alkyl), —N(Cl-C4 alkyl)2, -OCO(CrC4 alkyl), -CO(Ci-C4 alkyl), -C02H, -C02(CrC4 alkyl), and Cr C4 alkoxy.

Values of the remaining variables of Structural Formulae XI(A) and XI(B), including specific values, and provisos are each and independently as described above in the first subset of variables of Structural Formulae (IA) and (I). (00314] An eighth subset of variables of Structural Formulae XI(A) and XI(B) for the compounds of the invention is as follows:

Values of Q2, R, R\ R5, R6, R7, Rs, R9, R11, R12, R13, R14, x and n, including specific values, and provisos are each and independently as described above in the seventh subset of variables of Structural Formulae XI(A) and XI(B).

The group -[(C)o.iRl3RI4]-ringA~Q2-R5 is independently selected from one of the depicted below

or

, wherein each of rings A6, A8, All, A14 and A15 is optionally and independently further substituted. Suitable substituents are as described above for ring A in the first subset of variables of Structural Formulae XI(A) and XI(B).

Each R8 independently is halogen, cyano, hydroxy, O-C4 alkyl, C1-C4 haloalkyl, Ci-C4 hydroxy alkyl, C2-C4 alkoxyalkyl, -0(Ci-C4 alkyl), -NH2, -NH(Ci-C4 alkyl) or-N(Ci-C4 alkyl)2.

Values of the remaining variables of Structural Formulae XI(A) and XI(B), including specific values, and provisos are each and independently as described above in the first subset of variables of Structural Formulae (1A) and (I).

[00315] A ninth subset of variables of Structural Formulae XI(A) and XI(B) for the compounds of the invention is as follows:

Values of the group -[CRi3R14]>r~ringA-Q2-R5, ring A, Q2, R, R\ R6, R7, R8, R9, R11, R12, R13, R14, x and n, including specific values, and provisos are each and independently as described above in the eighth subset of variables of Structural Formulae XI(A) and XI(B).

Each R5 is independently: i) --H; ii) an optionally substituted Ci-Ce alkyl group; iii) an optionally substituted, C3-C7 non-aromatic carbocycle; or iv) an optionally substituted, 47 membered non-aromatic heterocycle, wherein said alkyl group represented by R5 is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, ™NH2, -NH(Ci-C4 alkyl), -N(Ci-C4 alkyl)?,, -OCO(Ci-C4 alkyl), -CO(Ci-C4 alkyl), -CO?H, -CC^C^ alkyl), C,-C4 alkoxy, optionally substituted, C3-C7 non-aromatic carbocycle, and optionally substituted, 4-7 membered nonaromatic heterocycle. Each of said carbocycles and heterocycles represented by R5, and referred to for the substituents of the Cj-Ce alkyl group represented by R5 is independently and optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, C1-C4 alkyl, -0(Ci-C4 alkyl), -NH2, -NH(Ci~C4 alkyl), -NfCr-C* alkyl)2, -C(0)(Ci-C4 alkyl), -0C(0)(C,-C4 alkyl), -C(0)0(C]-C4 alkyl) and -CO2H, wherein each of said alkyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NFL·, -NH(Ci-C4 alkyl). -N(Ci-C4 alkyl)2, -OCO(Ci-C4 alkyl), -CO(CrC4 alkyl), -C02H, -C02(Ci-C4 alkyl), and Ci-C4 alkoxy.

Values of the remaining variables of Structural Formulae XI(A) and XI(B), including specific values, and provisos are each and independently as described above in the first subset of variables of Structural Formulae (IA) and (I).

[00316] A tenth subset of variables of Structural Formulae XI(A) and XI(B) for the compounds of the invention is as follows:

Values of Q2, R, R\ R5, R6, R7, R8, R9, Rn, R12, Rl\ R14, x and n, including specific values, and provisos are each and independently as described above in the seventh subset of variables of Structural Formulae XI(A) and XI(B),

The group -[(C)o-iR13R14]-ringA-Q2“R5 is independently selected from one of the depicted below:

wherein each of rings A1-A4, A7-A20, A22, A23, A25 and A27 is independently and optionally further substituted. Suitable substituents are as described above for ring A in the first subset of variables of Structural Formulae XI(A) and XI(B).

Values of the remaining variables of Structural Formulae XI(A) and XI(B), including specific values, and provisos are each and independently as described above in the first subset of variables of Structural Formulae (IA) and (I).

[003X7] An eleventh subset of variables of Structural Formulae XI(A) and XI(B) for the compounds of the invention is as follows:

Values of Q2, R, R’, R5, R6, R7, R8, R9, Ru, R12, R13, R14, x, and n, including specific values, and provisos are each and independently as described above in the seventh subset of variables of Structural Formulae XI(A) and XI(B).

The group -[(C)o-iR13R14]~ringA-Q2-R5 is independently selected from one of the depicted below:

wherein each of rings A5-A7, A21, A24 and A26 is independently and optionally further substituted. Suitable substituents are as described above for ring A in the first subset of variables of Structural Formulae XI(A) and XI(B).

Each Rs independently is halogen, cyano, hydroxy, C1-C4 alkyl, C1-C4 haloalkyl, Ct-C4 hydroxyalkyl, C2-C4 alkoxyalkyl, -0(Ci-C4 alkyl), -NH2, -NH(Ct-C4 alkyl), or -N(Ci-C4 alkyl)2.

Values of the remaining variables of Structural Formulae XI(A) and XI(B), including specific values, and provisos are each and independently as described above in the first subset of variables of Structural Formulae (I A) and (I).

[00318] In a twelfth subset of variables of Structural Formulae XI(A) and XI(B) for the compounds of the invention, values of the variables for Structural Formulae XI(A) and XI(B), including specific values, and provisos are each and independently as described above in the first subset of variables of Structural Formulae (ΪΑ) and (I).

[00319] In a thirteenth subset of variables of Structural Formulae XI(A) and XI(B)for the compounds of the invention, values of the variables for Structural Formulae XI(A) and XI(B), including specific values, and provisos are each and independently as described above in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, or eleventh subset of variables of Structural Formulae XI(A) and XI(B); and where applicable: provided that if Y1 is a bond, then R5 is a substituted Q-Ce aliphatic group; an optionally substituted C3-C8 non-aromatic carbocycle; an optionally substituted, 6-10-membered carbocyclic aryl group; an optionally substituted, 4-8 membered non-aromatic heterocycle; or an optionally substituted, 5-10 membered heteroary group; and provided that if Q2 is a bond, then R5 is an optionally substituted Qi-Cg non-aromatic carbocycle; an optionally substituted, 6-10-membered carbocyclic aryl group; an optionally substituted, 4-8 membered non-aromatic heterocycle; or an optionally substituted, 5-10 membered heteroary group.

[00320] In a fourteenth subset of variables of Structural Formulae XI(A) and XI(B) for the compounds of the invention, values of the variables for Stiuctural Formulae XI(A) and XI(B), including specific values, and provisos are each and independently as described above in the thirteenth subset of variables of Structural Formulae XI(A) and XI(B); and where applicable: when Y1 is a bond, the Ci-C6 aliphatic group represented by R5 is substituted with one or more instances of JC1, wherein JCI is independently selected from: an optionally substituted, C3-CS non-aromatic carbocycle; an optionally substituted, 6-10-membered carbocyclic aryl group; an optionally substituted, 4-8 membered non-aromatic heterocycle; an optionally substituted, 5-10 membered heteroaryl group; -ORb; -SRb; -S(0)Ra; -S02Ra; -NRbRc; -C(0)Rb; -C(0)ORb; ~OC(0)Rb; -NRC(0)Rb; -C(0)NRbRc; --NRC(0)NRbRc; -NRC(0)ORb; -OCONRbRc; -C(0)NRC02Rb; -NRC(0)NRC02Rb; -C(0)NR(ORb); -S02NRcRb; -NRS02Rb; and -NRS02NRcRb; or optionally two JC1 and two JD1, respectively, together with the atoms to which they are attached, independently form a 5-7-membered ring that is optionally substituted with one or more instances of Jm, and fused to the respective ring to which they are attached.

[00321] In a fifteenth subset of variables of Structural Formulae XI(A) and XI(B), values of the variables for Structural Formulae XI(A) and XI(B), including specific values, are each and independently as described above in the thirteenth subset of variables of Stiuctural Formulae (IA) and (I), in the eleventh subset of variables of Structural Formula (VI), or in the fifteenth subset of variables of Structural Formulae (II)-(V).

In another embodiment, the present invention generally relates to compounds of Stiuctural Formula XII(A) or XII(B), or pharmaceutically acceptable salts thereof.

(ΧΙΙΑ) (XIIB).

[00322] A first subset of variables of Structural Formulae XII(A) and XII(B) for the compounds of the invention is as follows:

Each Q3 is independently -C(O)-, -C02-, -C(0)NR’-, -S02-, -SOjNR’-, -C(0)NRC(0)0- or -(CR6R7)P-Y-.

Ring B is a 4-7 membered, non-aromatic, heterocyclic ring optionally further substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, C,-Chalky], Ci-C6alkenyl, -NH2, -NH(C|-C6 alkyl), -N(Ci-C6 alkyl)2, -0(Ci.C6 alkyl), -C(0)NH2, -C(0)NH(Ci-C6 alkyl), -C(0)N(Ci-C6 alkyl)2, -C(0)(C1-C6-alkyl), -0C(0)(Ci-C6 alkyl), -NHC(0)(Ci-Q alkyl), -N(C,-C6 alkyl)C(0)(Ct-Ce alky!), and -C02Rb; wherein each of said alkyl and alkenyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, C]-C4 alkyl, -NH2, -NH(Ci-C6 alkyl), -N(Ci-C6 alkyl)2, -OCO(Ci-C4 alkyl), -CO(CrC4 alkyl), -C02H, -C02(C,-C4 alkyl), and C,-C4 alkoxy. Specifically, Ring B is optionally further substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, Ci-C4 alkyl, -0(Ci-C4 alkyl), -NH2, -NH(C,-C4 alkyl), -N(C,-C4 alkyl)2, -C(0)(Ci-C4 alkyl), -C02H, and -C02(Ci-C4 alkyl), wherein each of said alkyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, Ci-C4 alkyl, -NH2, -NH(Ci-C6 alkyl), -N(Ci-C6 alkyl)2, -OCO(CrC4 alkyl), -CO(Ci-C4 alkyl), -C02H, -C02(Ci-C4 alkyl), and C,-C4 alkoxy. Specifically, Ring B is optionally further substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(Ci-C2 alkyl), -NH(Ci-C2 alkyl)2, Ci-C2 alkyl, Cj-C2 haloalkyl, Ci-C2 hydroxyalkyl, C2-C4 alkoxyalkyl, Ci-C2 alkoxy, Ci-C2 hydroxyalkoxy, C[-C2 haloalkoxy, C2-C4 alkoxyalkoxy, -C02H, and ~C02(C,-C4 alkyl). R6 and R7 are each independently -H or -CH3, or together with the carbon atoms to which they are attached they form a cyclopropane ring. R9 is -H or -CH3. R11 and R12 are each independently -H or -CH3. R13 and R14 are each independently -H or -CH3, or together with the carbon atoms to which they are attached they form a cyclopropane ring.

Each R and R’ is independently -H or Ci-Ce alkyl.

Provided that if Q3 is --0(0)-, then R5 is a substituted Ci-Ce aliphatic group; an optionally substituted C3-Cs non-aromatic carbocycle; an optionally substituted, 6-10-membered carbocyclic aryl group; optionally substituted, 4-8 membered non-aromatic heterocycle; or an optionally substituted 5-10 membered heteroaryl group. Specifically, the Ci-Cc aliphatic group is substituted with one or more instances of JCI, wherein JC1 is independently selected from: an optionally substituted, C3-Cs non-aromatic carbocycle; an optionally substituted, 6-10-membered carbocyclic aryl group; an optionally substituted, 4-8 membered non-aromatic heterocycle; an optionally substituted, 5-10 membered heteroaryl group; -ORb; -SRb; -S(0)Ra; -S02Ra; -NRbRc; -C(0)Rb; -C(0)0Rb; -0C(0)Rb; -NRC(0)Rb; -C(0)NRbRc; -NRC(0)NRbRc; -NRC(0)0Rb; -OCONRbRc; -C(0)NRC02Rb; -NRC(0)NRC02Rb; -C(0)NR(0Rb); -S02NRcRb; -NRS02Rb; and -NRS02NRcRb; or optionally two JC1 and two JD1, respectively, together with the atoms to which they arc attached, independently form a 5-7-membered ring that is optionally substituted with one or more instances of JE1, and fused to the respective ring to which they are attached.

Values of the remaining variables of Structural Formulae XII(A) and XII(B), including specific values, and provisos are each and independently as described above in the first subset of variables of Structural Formulae (IA) and (I).

[00323] A second subset of variables of Structural Formulae XII(A) and XII(B) for the compounds of the invention is as follows:

Values of Ring B, Q3, R, R’, R6, R7, R9, R11, R12, R13, and R14, including specific values, and provisos are each and independently as described above in the first subset of variables of Structural Formulae XII(A) and XII(B).

Variable y = 0 or 1.

Values of the remaining variables of Structural Formulae XII(A) and XII(B), including specific values, and provisos are each and independently as described above in the first subset of variables of Structural Formulae (IA) and (I).

[00324] A third subset of variables of Structural Formulae XII(A) and XII(B) is as follows:

Values of Ring B, R, R’, R6, R7, R9, R11, R12, Rn, R14 and y, including specific values, and provisos are each and independently as described above in the second subset of variables of Structural Formulae XII(A) and XII(B). Q3 is independently -0(0)-, -C02- -C(0)NH- -C(0)N(CH3)-, -C(0)NHC(0)0--C(0)N(CH3)C(0)0-, -S02-, -SO2NH-, -S02N(CH3)-, or -(CRVjp-Y1-.

Values of the remaining variables of Structural Formulae XII(A) and XII(B), including specific values, and provisos are each and independently as described above in the first subset of variables of Structural Formulae (IA) and (I).

[00325] A fourth subset of variables of Structural Formulae XII(A) and XIIQB) for the compounds of the invention is as follows:

Values of Ring B, Q3, R, R’, R6, R7, R9, R11, R12, R13, R14, and y, including specific values, and provisos are each and independently as described above in the third subset of variables of Structural Formulae XII(A) and XII(B). R5 is independently i) -H; ii) a C1-C6 aliphatic group (e.g., Ci-CValkyl or C2-C6-alkenyl group) optionally substituted with one or more instances of JC1; iii) a C3-C8 nonaromatic carbocycle optionally substituted with one or more instances of JC1; iv) a phenyl group optionally substituted with one or more instances of JC1; v) a 4-8 membered nonaromatic heterocycle optionally substituted with one or more instances of JD1 or vi) a 5-6 membered heteroaryl ring optionally substituted with one or more instances of JD1.

Each of JC1 and JDi is independently selected from the group consisting of halogen, cyano, oxo, Ra, -ORb, -SRb, -S(0)Ra, -S02Ra, -NHR°, -C(0)Rb, -C(0)0Rb, -0C(0)Rb, -NHC(0)Rb, -C(0)NHRc, -NHC(0)NHRc, -NHC(0)0Rb, -OCONHRc, -NHC(0)NHC(0)0Rb, -N(CH3)Rc, -N(CH3)C(0)Rb, -C(0)N(CH3)Rc, -N(CH3)C(0)NHRc, -N(CH3)C(0)0Rb, -OCON(CH3)Rc, -C(0)NHC02Rb, -C(0)N(CH3)C02Rb, -N(CH3)C(0)NHC(0)0Rb, -NHS02Rb, -S02NHRb, -S02N(CH3)Rb, and -N(CH3)S02Rb.

Values of the remaining variables of Structural Formulae XII(A) and XII(B), including specific values, and provisos are each and independently as described above in the first subset of variables of Structural Formulae (IA) and (I).

[00326] A fifth subset of variables of Structural Formulae ΧΠ(Α) and XII(B)for the compounds of the invention is as follows:

Values of Q3, R, R’, R5, R6, R7, R9, Rn,R12, R13, R14, and y, including specific values, and provisos are each and independently as described above in the fourth subset of variables of Structural Formulae XII(A) and XII(B).

Ring B is optionally further substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, C1-C4 alkyl, -0(Ci-C4 alkyl), -NH2, -NH(Ci~C4 alkyl), -N(Ci~C4 alkyl)2, -C(0)(Ci-C4 alkyl), -C02H, and-C02(Ci-C4 alkyl), wherein each of said alkyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(Ci-Ce alkyl), -N(C[-Ce alkyl)2, -OCO(Cs-C4 alkyl), -CO(Ci-C4 alkyl), -C02H, -C02(Ci-C4 alkyl), and CrC4 alkoxy.

Values of the remaining variables of Structural Formulae XII(A) and XII(B), including specific values, and provisos are each and independently as described above in the first subset of variables of Structural Formulae (IA) and (I).

[00327] A sixth subset of variables of Structural Formulae XII(A) and XII(B) for the compounds of the invention is as follows:

Values of Q3, R, R’, R5, R6, R7, R9, Rn,R12, R13, R14, and y, including specific values, and provisos are each and independently as described above in the fifth subset of variables of Structural Formulae XTI(A) and XII(B).

Ring B is independently selected from one of the structures depicted below:

wherein each of rings Bl, B2 and B4-B9 is optionally and independently substituted.

Suitable substituents are independently as described above for ring B in the first subset of variables of Structural Formulae (IA) and (I),

Values of the remaining variables of Structural Formulae XII(A) and XII(B), including specific values, and provisos are each and independently as described above in the first subset of variables of Structural Formulae (IA) and (I).

[00328] A seventh subset of variables of Structural Formulae XII(A) and XII(B) for the compounds of the invention is as follows:

Values of the ring B, Q3, R, R\ Rc, R7, R9, R11, R12, R13, R14, and y, including specific values, and provisos are each and independently as described above in the sixth subset of variables of Structural Formulae XII(A) and XII(B).

Each R5 is independently: i) -H; ii) a Ci-Cs-aliphatic group optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, Ci-C4 alkyl, -0(Ci-C4 alkyl), -NH2, -NH(Ci~C4 alkyl), -N(Ci-C4 alkyl)2, -C(0)(Ci-C4 alkyl), -0C(0)(Ci-C4 alkyl), -C(0)0(Ci-C4 alkyl), -C02H, C3-Cs non-aromaiic carbocycle, phenyl, 4-8 membered non-aromatic heterocycle, and 5-6 membered heteroaryl; or iii) a C3-C7 non-aromatic carbocycle, a 4-7 membered non-aromatic heterocycle, a phenyl group, or a 5-6 membered heteroaryl ring, each of which is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, Ci-C4 alkyl, -0(C,-C4 alkyl), ~NH2, -NH(C,-C4 alkyl), -N(C,-C4 alkyl)2, -C(0)(Ci-C4 alkyl), -00(0)(0,-04 alkyl), -C(0)0(Ci-C4 alkyl), and -CO2H; wherein each of said alkyl groups for the substituents of the aliphatic group, carbocycle, heterocycle, phenyl and heteroaryl group represented by R5 is independently and optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(Ci-C4 alkyl), -N(Ci-C4 alkyl)2, -000(0,-C4 alkyl), -00(0,-04 alkyl), -C02H, -C02(C,-C4 alkyl), and Ci-C4 alkoxy; and wherein each of said carbocycle, phenyl, heterocycle, and heteroaryl for the substituents of the Ci-Cfi-aliphatic group represented by R5 is independently and optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, Ci-C4 alkyl, -NH2, -NH(C,-C4 alkyl), -N(Ci-C4 alkyl)2, -OCO(C,-C4 alkyl), -C0(C,-C4 alkyl), -C02H, -C02(Ci-C4 alkyl), and 0,-C4 alkoxy.

Values of the remaining variables of Structural Formulae XII(A) and XII(B), including specific values, and provisos arc each and independently as described above in the first subset of variables of Structural Formulae (IA) and (I).

[00329] An eighth subset of variables of Structural Formulae XII(A) and XII(B) for the compounds of the invention is as follows:

Values of Q3, R, R’, R5, R6, R7, R9, Ru, R12, R13, R14, and y, including specific values, and provisos are each and independently as described above in the seventh subset of variables of Structural Formulae XII(A) and XII(B).

The group -[C(R13Ri4)]x-ringB-Q2-R5:

wherein ring B2 is optionally and independently further substituted with one or more substituents independently selected from the group consisting of with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2) -NH(C|-C2 alkyl), -NH(Ci-C2 alkyl)2, Ci-C2 alkyl, CrC2 haloalky!, Ci-C2 hydroxyalkyl, C2-C4 alkoxyalkyl, Ci-C2 alkoxy, Ci-C2 hydroxyalkoxy, Ci-C2 haloalkoxy, C2-C4 alkoxyalkoxy, -C02H, and -C02(Ci-C4 alkyl).

Values of the remaining variables of Structural Formulae XII(A) and XII(B), including specific values, and provisos are each and independently as described above in the first subset of variables of Structural Formulae (IA) and (I).

[00330] A ninth subset of variables of Structural Formulae XII(A) and XII(B) for the compounds of the invention is as follows:

Values of ring B, Q3, R, R\ R6, R7, R9, RU,R12, R13, R14, andy, including specific values, and provisos are each and independently as described above in the eighth subset of variables of Structural Formulae XII(A) and XII(B).

Each R5 is independently: i) -H; ii) an optionally substituted Ci-Ce alkyl group; iii) an optionally substituted, C3-C7 non-aromatic carbocycle; or iv) an optionally substituted, 47 membered non-aromatic heterocycle, wherein said alkyl group represented by R5 is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(Ci-C4 alkyl), -N(Cj-C4 alkyl)2, -OCO(Ci-C4 alkyl), -CO(CrC4 alkyl), -C02H, -C02(Ci-C4 alkyl), Ci-C4 alkoxy, optionally substituted, C3-C7 non-aromatic carbocycle, and optionally substituted, 4-7 membered nonaromatic heterocycle. Each of said carbocycles and heterocycles represented by R5, and referred to for the substituents of the Ci-C6 alkyl group represented by R5 is independently and optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, C1-C4 alkyl, -0(Ci-C4 alkyl), -NH2, -NH(Ci-C4 alkyl), -N(C,-C4 alkyl)2, -C(0)(Ci-C4 alkyl), -0C(0)(C,-C4 alkyl), -C(0)0(Ci-C4 alkyl) and -C02H, wherein each of said alkyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(Ci-C4 alkyl), -N(Ci-C4 alkyl)2, -OCO(Ci-C4 alkyl), -CO(Ci-C4 alkyl), -C02H, -C02(Ci-C4 alkyl), and C1-C4 alkoxy.

Values of the remaining variables of Structural Formulae XII(A) and XII(B), including specific values, and provisos are each and independently as described above in the first subset of variables of Structural Formulae (IA) and (I).

[00331] In a tenth set of variables of Structural Formulae XII(A) and XII(B) for the compounds of the invention, values of the variables for Structural Formulae XII(A) and XH(B), including specific values, and provisos are each and independently as described above in the first subset of variables of Structural Formulae (IA) and (I).

[00332] In an eleventh subset of variables of Structural Formulae XII(A) and XII(B)for the compounds of the invention, values of the variables for Structural Formulae XII(A) and XII(B), including specific values, and provisos are each and independently as described above in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, or eleventh subset of variables of Structural Formulae XII(A) and XII(B); and where applicable: provided that ifY1 is a bond, then R5 is a substituted Ci-Ce aliphatic group; an optionally substituted C3-C8 non-aromatic carbocycle; an optionally substituted, 6-10-membered carbocyclic aiyl group; an optionally substituted, 4-8 membered non-aromatic heterocycle; or an optionally substituted, 5-10 membered heteroary group; and provided that if Q3 is a bond, then R5 is an optionally substituted C3-C8 non-aromatic carbocycle; an optionally substituted, 6-10-membered carbocyclic aryl group; an optionally substituted, 4-8 membered non-aromatic heterocycle; or an optionally substituted, 5-10 membered heteroary group.

[00333] In a twelfth subset of variables of Structural Formulae XII(A) and XII(B)for the compounds of the invention, values of the variables for Structural Formulae XII(A) and XII(B), including specific values, and provisos are each and independently as described above in the eleventh subset of variables of Structural Formulae XII(A) and XII(B); and where applicable: when Y1 is a bond, the Ci-Ce aliphatic group represented by R5 is substituted with one or more instances of JC1, wherein JC1 is independently selected from: an optionally substituted, C3-C8 non-aromatic carbocycle; an optionally substituted, 6-10-membered carbocyclic aiyl group; an optionally substituted, 4-8 membered non-aromatic heterocycle; an optionally substituted, 5-10 membered heteroaryl group; -ORb; - SRb; -S(0)Ra; -SOiR”; -NRbRc; -C(0)Rb; -C(0)ORb; -OC(0)Rb; -NRC(0)Rb; -C(0)NRbRc; -NRC(0)NRbRc; -NRC(0)0Rb; -OCONRbRc; -C(0)NRC02Rb; -NRC(0)NRC02Rb; -C(0)NR(ORb); -S02NRcRb; -NRS02Rb; and -NRSC>2NRcRb; or optionally two JCI and two JD1, respectively, together with the atoms to which they are attached, independently form a 5-7-membered ring that is optionally substituted with one or more instances of JE1, and fused to the respective ring to which they are attached.

[00334] hi a thirteenth subset of variables of Structural Formulae XII(A) and XII(B), values of the variables for Structural Formulae XII(A) and XII(B), including specific values, are each and independently as described above in the thirteenth subset of variables of Structural Formulae (IA) and (I), in the eleventh subset of variables of Structural Formula VI, or in the fifteenth subset of variables of Structural Formulae II-V.

[00335] In another embodiment, the present invention generally relates to compounds of Structural Formula XIII, or pharmaceutically acceptable salts thereof:

(XIII).

[00336] A first subset of variables of Structural Formula XIII for the compounds of the invention is as follows:

Ring C is a 5-7 membered, non-aromatic, heterocyclic ring optionally further substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, Ci-C6 alkyl, C2-Ce alkenyl, -NH2, -NH(Cj-C6 alkyl), -N(Ci-C6 alkyl)2, -0(CuCe alkyl), -C(0)NH2, -C(0)NH(Ct-C6 alkyl), -C(0)N(C,-Cfi alkyl)2, -C(0)(C,-C6-alkyl), -OC(OXCrC6 alkyl), -NHC(0)(Ci-C6 alkyl), -N(Ci-Ce alkyl)C(0)(Ci-C6 alkyl), and -C02Rb; wherein each of said alkyl and alkenyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(Ci-Ce alkyl), -N(Ci-C6 alkyl)2, -OCO(Ci-C4 alkyl), -CO(Ci-C4 alkyl), -C02H, -C02(C|-C4 alkyl), and C1-C4 alkoxy. Specifically, ring C is optionally further substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, Ci-C4 alkyl, -0(Ci-C4 alkyl), -NH2, -NH(Ci-C4 alkyl), -N(Ci-Ct alkyl)2, -C(0)(Ci-C4 alkyl), -C02H and -~C02(C|-C4 alkyl), wherein each of said alkyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(Ci-Ce alkyl), “N(Ci-Ce alkyl)2, -OCO(Ci-C4 alkyl), -CO(Ci-C4 alkyl), -C02H, -C02(Ci-C4 alkyl), and C1-C4 alkoxy. Specifically, ring C is optionally further substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, -NH2, -NH(Ci-C2 alkyl), -NH(Ci-C2 alltyl)2, Ci-C2 alkyl, C1-C2 haloalkyl, Ci-C2 hydroxyalkyl, C2-C4 alkoxyallcyl, Ct-C2 alkoxy, Ci-C2 hydroxy alkoxy, C]-C2 haloalkoxy, C2-C4 alkoxyalkoxy, -C02H, and -C02(Cj-C4 alkyl). R6 and R7 are each independently -H or -CH3, or together with the carbon atoms to which they are attached they form a cyclopropane ring. R9 is -H or -Cm R11 and R12 are each independently -H or -CH3.

Each R and R’ is independently -H or Ci-Cg alkyl.

Values of the remaining variables of Structural Formula XIII, including specific values, and provisos are each and independently as described above in the first subset of variables of Structural Formulae (IA) and (I). 100337] A second subset of variables of Structural Formula XIII for the compounds of the invention is as follows:

Values of Ring C, R, R\ R6, R7, R9, Ru, andR12, including specific values, are each and independently as described above in the first subset of variables of Structural Formula XIII. R10 is -H or Ci-Ce-alkyl.

Values of the remaining variables of Structural Formula XIII, including specific values, and provisos are each and independently as described above in the first subset of variables of Structural Formulae (IA) and (I).

[00338] A third subset of variables of Structural Formula XIII for the compounds of the invention is as follows:

Values of R, R\ R6, R7, R9, R10, R11, andR12, including specific values, are each and independently as described above in the second subset of variables of Structure Formula XIII.

Ring C is a 5-7 membered, non-aromatic, heterocyclic group optionally further substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, C1-C4 alkyl, -0(Ci-C4 alkyl), -NH2, -NH(Ci-C4 alkyl), -N(Ci-C4 alkyl)2, -C(0)CCi-C4 alkyl), -C02H, and -C02(Ci-C4 alkyl), wherein each of said alkyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NHfCj-Cg alkyl), -N(Ci-C6 alkyl)2, -OCO(Ci-C4 alkyl), -CO(Ci-C4 alkyl), -C02H, -C02(Ci-C4 alkyl), and Q-C4 alkoxy.

Values of the remaining variables of Structural Formula ΧΪΪΤ, including specific values, and provisos are each and independently as described above in the first subset of variables of Structural Formulae (IA) and (I).

[00339] A fourth subset of variables of Structural Formula XIII for the compounds of the invention is as follows:

Values of R, R’, R6, R7, R9, R10, R11, and R12, including specific values, are each and independently as described above in the third subset of variables of Structure Formula XIII.

Ring C is independently selected from:

wherein each of rings C1-C5 is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, C1-C4 alkyl, -0(Ci-C4 alkyl), -NH2, -NH(Ci-C4 alkyl), -N(Ct-C4 alkyl)2, -C(0)(Ci-C4 alkyl), -C02H, and -C02(Ci-C4 alkyl), wherein each of said alkyl groups is optionally and independently substituted with one or more independently substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(Ct-Co alkyl), -N(Ci-Cg alky 1)2, -OCO(Ci-C4 alkyl), -CO(C,-C4 alkyl), -C02H, -C02(C,-C4 alkyl), and Cj-C4 alkoxy.

Specifically, each of rings C1-C5 is optionally and independently further substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, -NH2, -NH(Ci-C2 alkyl), -NH(Ci-C2 alkyl)2, C1-C0 alkyl, C1-C2 haloalkyl, Ci-C2 hydroxyalkyl, C2-C4 alkoxyalkyl, C1-C2 alkoxy, C1-C2 hydroxyalkoxy, Ci-C2 haloalkoxy, C2-C4 alkoxyalkoxy, -C02H, and -C02(C]-C4 alley]).

Values of the remaining variables of Structural Formula XIII, including specific values, and provisos are each and independently as described above in the first subset of variables of Structural Formulae (IA) and (I).

[00340) In a fifth set of variables of Structural Formula XIII for the compounds of the invention, values of the variables for Structural Formula XIII, including specific values, are each and independently as described above in the first subset of variables of Structural Formulae (IA) and (I).

[00341] In another embodiment, the present invention generally relates to compounds represented by Structural Formula below XIV, or a pharmaceutically acceptable salt thereof:

(XIV).

[00342] A first subset of variables of Structural Formula XIV for the compounds of the invention is as follows:

Ring D is 4-7 membered, non-aromatic, heterocyclic ring optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, Ci-C6 alkyl, C2-C6 alkenyl, -NH2, -NH(CrCc alkyl), -N(Ci-C6 alkyl)2, -0(Ci-C6 alkyl), -C(0)NH2, -C(0)NH(Ci-C6 alkyl), ~C(0)N(Ci-C6 alkyl)2, -C(0)(CrC6-alkyl), -0C(0)(Ci-C6 alkyl), -NHC(0)(Ci-C6 alkyl), -N(Ci-C6 alkyl)C(0)(Ct-C6 alkyl), and -C02Rb; wherein each of said alkyl and alkenyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(Ci-C6 alkyl), -N(Ci-C6 alkyl)2, -OCO(Ci-C4 alkyl), -CO(C[-C4 alkyl), -C02H, -C02(C|-C4 alkyl), and C1-C4 alkoxy. Specifically, ring D is optionally further substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, C1-C4 alkyl, -0(Ci-C4 alkyl), -NH2, -~NH(Ci-C4 alkyl), -N(Ci-C4 alkyl)2, -0(0)(0^04 alkyl), -C02H and -C02(Ci-C4 alkyl), wherein each of said alkyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(Ci-C6 alkyl), -Ν(0]-06 alkyl)2, -OCO(Ci-C4 alkyl), -CO(Ci-C4 alkyl), -C02H, -C02(Ci-C4 alkyl), and C1-C4 alkoxy. Specifically, ringD is optionally further substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(C[-C2 alkyl), -NH(Ci-C2 alkyl)2, Ci-C2 alkyl, C[-C2 haloalkyl, Ci-C2 hydroxyalkyl, C2-C4 alkoxyalkyl, Ci-C2 alkoxy, Ci-C2 hydroxyalkoxy, C1-C2 haloalkoxy, C2-C4 alkoxyalkoxy, -C02H, and -C02(C|-C4 alkyl). R6 and R7 are each independently -H or -CH3, or together with the carbon atoms to which they are attached they form a cyclopropane ring. R13 and Ru are each independently -H or-CH3, or together with the carbon atoms to which they are attached they form a cyclopropane ring.

Each of R and R’ is independently -H or Ci-Ce alkyl.

Vlaues of the remaining variables of Structural Formula XIV, including specific values, and provisos are each and independently as described above in the first subset of variables of Structural Formulae (IA) and (I).

[00343] A second subset of variables of Structural Formula XIV for the compounds of the invention is as follows:

Values for Ring D, R, R\ R6, R7, R13, and Ru, including specific values, are each and independently as described above in the first subset of variables of Structural Formula XIV.

Variable z is 1.

All other variables of Structural Formula XIV, including specific values, and provisos are each and independently as described above for the first subset of variables of Structural Formulae (IA) and (I).

[00344] A third subset of variables of Structural Formula IV for the compounds of the invention is as follows:

Values for z, R, R\ R6, R7, Ri3, and R14, including specific values, are each and independently as described above in the second subset of variables of Structural Formula XIV.

Ring D is independently selected from the group consisting of

wherein each of rings D1-D7 is optionally and independently substituted one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, Ci-C4 alkyl, -0(CrC4 alkyl), -~NH2, -NH(C,-C4 alkyl), -N(Cj-C4 alkyl)2, -C(0)(C]-C4 alkyl), -C02H and -C02(Ci-C4 alkyl), wherein each of said alkyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NHfCrCe alkyl), -N(Ci-Ce alkyl)2, -OCO(Ct-C4 alkyl), -CO(C,-C4 alkyl), -C02H, -C02(Ci-C4 alkyl), and CrC4 alkoxy.

Specifically, each of rings D1-D7 is optionally and independently further substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(Ci-C2 alkyl), -NH(Ci-C2 alkyl)2, Ci-C2 alkyl, Ci-C2 haloalkyl, C1-C2 hydroxyalkyl, C2-C4 alkoxyalkyl, C1-C2 alkoxy, C1-C2 hydroxyalkoxy, Ci-C2 haloalkoxy, C2-C4 alkoxyalkoxy, -CO2H, and ™C02(Ci-C4 alkyl).

Each Rd is independently -H, Ci-Ce alkyl or - C(0)(Ci-Ce alkyl), wherein each of said alkyl moiety is optionally and independently substituted with one or more groups selected from halogen, cyano, hydroxy, oxo, -ΝΗ2, -NHfCi-Ce alkyl), -NfCi-Ce alkyl)2, -OCO(C!-C4 alkyl), -CO(C,-C4 alkyl), -C02H, -C02(C,-C4 alkyl), and C,-C4 alkoxy. Specifically, each Rd is independently -H or CpCe alkyl optionally and independently substituted with one or more groups selected from halogen, cyano, hydroxy, oxo, -NH2, -NH(Ci-Cfi alkyl), -N(Ci-Cc alkyl)2, -OCO(Ct-C4 alkyl), -CO(Ci-C4 alkyl), -C02H, -C02(Ci-C4 alkyl), and C1-C4 alkoxy.

Vlaues of the remaining variables of Structural Formula XIV, including specific values, and provisos are each and independently as described above for the first subset of variables of Structural Formulae (IA) and (I).

[00345] In a fourth subset of variables of Structural Formula XIV for the compounds of the invention, values of the variables for Structural Formula XIV, including specific values and provisos, are each and independently as described above in the first subset of variables of Structural Formulae (IA) and (I).

[00346] In yet another embodiment, the compounds are represented by Structural Structural Formula (I), or pharmaceutically acceptable salts thereof, wheren each variables of the formulae are independently as described above; and wherein: R4 is:

Ring E is a C4-Cg non-aromatic carbocycle optionally further substituted with one or more instances of JA.

Rings F is a 4-8 membered non-aromatic heterocyclc optionally substituted with one or more instances of JE1.

Each of rings G1 and G2 is independently a 5-10 membered non-aromatic bridged carbocycle optionally substituted with one or more instances of JA. Q2 is independently bond, -Ο-, -S-, -NR-, -C(0)-, -C(=NR)-, -C02- -OC(O)-, -C(0)NR-, -C(0)NRC(0)0-, -NRC(0)NRC(0)0-, -NRC(O)-, -NRC(0)NR™, -NRC02- -0C(0)NR- -S(0)-, -S02- -N(R)S02- -S02NR’-, -NRS02NR\ or -(CRfiR7)P-Y1-. R5 is: i) -H; ii) an optionally substituted Cy-Ce alkyl group; iii) an optionally substituted, C3--C7 non-aromatic carbocycle; or iv) an optionally substituted, 4-7 membered non-aromatic heterocycle; or optionally, together with R and the nitrogen atom to which it is attached, form a 5-7 membered, optionally substituted non-aromatic heterocycle. The alkyl group represented by R3 is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(Ci-C4 alkyl), -N(Cl-C4 alkyl>2, -OCO(CrC4 alkyl), -CO(Ci-C4 alkyl), -C02H, -C02(Ci-C4 alkyl), C,-C4 alkoxy, an optionally substituted, C3-C7 non-aromatic carbocycle, and an optionally substituted, 4-7 membered non-aromatic heterocycle; wherein each of said carbocycles and heterocycles represented by R5, and referred to for the substituents of the Ci-Cg alkyl group represented by R5 is independently and optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, Ci-C4 alkyl, -0(Ci-C4 alkyl), -NH2, -NH(Ci-C4 alkyl), -N(Cr~C4 alkyl)2, -C(0)(Ct-C4 alkyl), -0C(0)(Ci-Ci alkyl), -C(0)0(Ci-C4 alkyl) and -CO?H, wherein each of said alkyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(Cj-C4 alkyl), -N(Ci-C4 alkyl)2, -OCO(C,-C4 alkyl), -CO(C,-C4 alkyl), -C02H, -C02(C,-C4 alkyl), and Ct-C4 alkoxy.

Each of R8 and R9 is independently -H, halogen, cyano, hydroxy, Ci-C4 alkyl, Ci-C4 haloalkyl, Ct-C4 hydroxyalkyl, C2-C4 alkoxyalkyl, -0(Ct-C4 alley 1), -NH2, -NH(Ci-C4 alkyl), or -N(C,-C4 alkyl),.

Ru, R12, R13 and R14 arc each independently -H, halogen, or Ci-C6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo, hydroxy, oxo, amino, carboxy, Ci-Ce alkoxy, Ci-Cehaloalkoxy, Ci-Ce aminoalkoxy, Ci-Cecyanoalkoxy, Ci-Ce hydroxyalkoxy, and C2-Ce alkoxyalkoxy; or optionally, R13 and R14, together with the carbon atom to which they are attached, form a cyclopropane ring, optionally substituted with one or more instances of methyl. R21, R22, R23 and R24 are each independently -H, halogen, -OH, or Ci-C6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo, hydroxy, oxo, amino, carboxy, Ct-Ce alkoxy, Ci-Ce haloalkoxy, Ci-Cg aminoalkoxy, Ci-Cc cyanoalkoxy, Ci-Ce hydroxyalkoxy, and C2-C6 alkoxyalkoxy. p and q are each independently 0, 1 or 2. x is 0, 1 or 2. r is 1 or 2.

Values of the remaining variables of Structural formula I, including specific values, and provisos are each and independently as described above in any one of the first through fifteenth sets of variables of Structural Formula I.

[003471 In yet another embodiment, the compounds represented by Structural Formula (I) or pharmaceutically acceptable salts thereof are independently as described above in the preceding paragraph; and ring F is selected from any one of rings F1-F6:

; each of rings F1-F6 optionally and independently substituted; and each Rf is independently -H or Ci-Co alkyl optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, amino, carboxy, Ci-Co alkoxy, Ci-Cc haloalkoxy, Ci-Cc aminoalkoxy, Ct-Cecyanoalkoxy, Ci-Cghydroxyalkoxy and C2-C6 alkoxyalkoxy.

[00348] In yet another embodiment, the compounds represented by Structural Formula (XIA) or (XIB), or pharmaceutically acceptable salts thereof are as described above; and the group-[C(RBR14)]x-ringA-Q2-R5 is independently:

; wherein: each of rings A14 and A28 is optionally and independently further substituted; and values of the remaining variables of Structural Formulae (XIA) and (XIB), including specific values, and provisos are each and independently as described above in any one of the first through eleventh sets of variables of Structural Formulae (XIA) and (XIB), [00349] In yet another embodiment, the compounds represented by Structural Formula (XIA) or (XIB), or pharmaceutically acceptable salts thereof are independently as described above in the preceding paragraph; and R5 is an optionally substituted Cy-Ce alkyl group; an optionally substituted, C3-C7 non-aromatic carbocycle; or an optionally substituted, 4-7 membered non-aromatic heterocycle; or optionally, together with R and the nitrogen atom to which it is attached, form a 5-7 membered, optionally substituted non-aromatic heterocycle. Specifically, R5 is an optionally substituted, 4-7 membered non-aromatic heterocycle; or optionally, together with R and the nitrogen atom to which it is attached, form a 5-7 membered, optionally substituted non-aromatic heterocycle.

[00350] In yet another embodiment, the compounds are represented by Structural Formula (IA) or (I), or pharmaceutically acceptable salts, wherein: R4 is:

Ring E is a C4-C10 non-aromatic carbocycle optionally further substituted with one or more instances of JA.

Rings F is a 4-8 membered non-aromatic heterocycle optionally substituted with one or more instances of JE1. Specific examples of ring F includes:

Additional example includes

. Each of rings F1-F7 optionally and independently substituted. Exemplary substituents for ring F (including rings F1-F7) include halogen, cyano, hydroxy, Ci-C4 alkoxy, and C1-C4 alkyl optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, hydroxy, and -0(Ci-C4 alkyl).

Rf is independently -H or C|-C6 alkyl optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, amino, carboxy, Ci-Cg alkoxy, Ci-Ce haloalkoxy, Cj-Cg aminoalkoxy, Ci-Ce cyanoalkoxy, Ci-Cc hydroxy alkoxy and C2-C6 alkoxy alkoxy. R9 is independently-H, halogen, cyano, hydroxy, amino, carboxy, Ci-CV> alkyl, Ct-CG haloalkyl, Ci-Cs cyanoalkyl, C2-C6 alkoxyalkyl, Ci-Cc aminoalkyl, Ci-Cf, hydroxyalkyl, Ci-C6 carboxyalkyl, Ct-C6 alkoxy, Ci-C<> haloalkoxy, Ci-C6 aminoalkoxy, Ci-Cscyanoalkoxy, C,-C6 liydroxyalkoxy, or C2-Q, alkoxyalkoxy. R11, R12, R13 and R14 are each independently -H, halogen, or Ci-Ce alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo, hydroxy, oxo, amino, carboxy, Ci-Ce alkoxy, Ci-Ce haloalkoxy, Ci-Ce aminoalkoxy, Ci-Ce cyanoalkoxy, Ci-C6 liydroxyalkoxy, and C2-C6 alkoxyalkoxy.

Optionally, R13 and R14, together with the carbon atom to which they are attached, form a cyclopropane ring, optionally substituted with one or more instances of methyl, s is 0, 1 or 2. x is 0,1 or 2.

The remaining variables are each and independently as described above in any one of the sets of variables for Structural Formulae (IA) and (I).

[00351] In yet another embodiment, the compounds are represented by Structural Formula (I) or (IA), or pharmaceutically acceptable salts thereof, wherein:

Ring E is a C4-C8 non-aromatic carbocycle optionally further substituted with one or more instances of JA R9 is independently -H, halogen, cyano, hydroxy, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxy alkyl, C2-C4 alkoxyalkyl, -0(C,-C4 alkyl), -NH2, -NH(C,-C4 alkyl), or -N(C,-C4 alkyl)2.

The other varibales are each and independently as described in the preceeding paragraph.

[00352] In yet another embodiment, the compounds are represented by Structural Formula (IA) or (I), or pharmaceutically acceptable salts, wherein: R4 is:

Each of rings G1-G4 is independently a 5-10 membered non-aromatic bridged ring optionally further substituted with one or more instances of JA.

Eing G5 is a 5-10 membered non-aromatic bridged ring optionally further substituted with one or more instances of JB. X is -0-, -S-, or -NRS-.

Rs and R9 are each independently -H, halogen, cyano, hydroxy, amino, carboxy, Ci-Cg alkyl, Ci-Cg haloalkyl, Ci-Cg cyanoalkyl, C2-Cg alkoxyalkyl, Ci-Cg aminoalkyl, Ci-Cg hydroxyalkyl, Ci-Cg carboxyalkyl, Ci-Cgalkoxy, Ci-C6 haloalkoxy, Ci-Ceaminoalkoxy, Ci-Cg cyanoalkoxy, Ci-Cg hydroxy alkoxy, or C2-C6 alkoxyalkoxy. R13 and R14 are each independently -H, halogen, or Ci-Cg alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo, hydroxy, oxo, amino, carboxy, Ci-Cg alkoxy, Ci-Cg haloalkoxy, Ci-Cg aminoalkoxy, Ci-Cg cyanoalkoxy, Ci-Cg hydroxyalkoxy, and C2-Cg alkoxyalkoxy.

Optionally, R13 and R14, together with the carbon atom to which they are attached, form a cyclopropane ring, optionally substituted with one or more instances of methyl. R2', R22, R23, R24, and R25are each independently -H, halogen, -OH, Ci-Cg alkoxy, or Ci-Cg alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo, hydroxy, oxo, amino, carboxy, Ci-Cg alkoxy, Cr Cg haloalkoxy, Ci-Cg aminoalkoxy, Ci-Cg cyanoalkoxy, Ci-Cg hydroxyalkoxy, and C2-Cg alkoxyalkoxy. Specifically, R25, R22, R23, R24, and R25 are each independently -H, halogen, -OH, Ci-Cg alkoxy, or Ci-Cg alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, Ci-Cg alkyl, -NH2, -NH(Ci-C6 alkyl), -N(Ci-C6 alkyl)2, -OfCi-Ce alkyl), -C(0)NH2, -C(0)NH(Ci-C6 alkyl), -C(0)N(Ci-C6 alkyl)2, -C(0)(C,-C6-a1kyl), -OC(0)(C,-Ce alkyl), -NHC(0)(C,-Ce alkyl), -N(Ci-C6 alkyl)C(0)(Ci-C6 alkyl).

Rg is -H or Ci-Cg alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo, hydroxy, amino, carboxy, Ci-C6 alkoxy, Ci-C6 haloalkoxy, Ci-C6 aminoalkoxy, Ci-Cg cyanoalkoxy, Ci-Cg hydroxyalkoxy, and C2-Cg alkoxyalkoxy. q is 0, 1 or 2; x is 0, 1 or 2; and r is 1 or 2.

The remaining variables are each and independently as described above in any set of variables for Structural Formulae (IA) and (I).

[00353] In yet another embodiment, the compounds are represented by Structural Formula (IA) or (I), pharmaceutically acceptable salts thereof, wherein: R4 is:

wherein rings G1 and G2 are each and independently a 5-10 membered non-aromatic bridged ring optionally further substituted with one or more instances of JA.

Each of Rs and R9 is independently -H, halogen, cyano, hydroxy, C1-C4 alkyl, C1-C4 haloalkyl, Ct-C4 hydroxyalkyl, C2-C4 alkoxyalkyl, -0(Ci-C4 alkyl), -NH2, -NH(Ci-C4 alkyl), or -N(Ci-C4 alkyl)2. R21, R22, R23, and R24 are each independently -H, halogen, -OH, or Ci-Ce alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo, hydroxy, oxo, amino, carboxy, Ci-Qalltoxy, Ci-Cg haloalkoxy, Ci-Ceaminoalkoxy, Cj-Cc cyanoalkoxy, Ci-Ce hydroxyalkoxy, and C2-Cc alkoxyalkoxy. Q2 is independently a bond, -0-, -S-, -NR-, -C(0)-, -C(=NR)-, -C02-, -00(0)-, -C(0)NR-, -C(0)NRC(0)0-, -NRC(0)NRC(0)0-, -NRC(O)-, -NRC(0)NR-, -NRC02--0C(0)NR-, -S(0)-, -S02-, -N(R)S02-, -S02NR’-, -NRS02NR’-, or -(CRcR7),-Y1-. Alternatively Q2 is independently -0-, -C02-, -00(0)-, -C(0)NR-, -NRC(O)-, -NRC(0)NR- -NRC02-, -0C(0)NR- -CO2SO2-, -P(0)20-, or -(CR6^7)Ρ-γ1-· Alternatively Q2 is independently -0- or -C02-.

[00354] In some embodiments, rings E and G (including G1-G5) are optionally and independently further substituted with one or more instances of JA (for carbocycle) or JB (for heterocycle), wherein each of JA and JB is independently selected from the group consisting of halogen, cyano, oxo, -NCO, andQl-R5, and wherein: Q1 is independently a bond, -0-, -S~, -NR- -C(0)-, -C(=NR)-, -C02-, -00(0)-, -C(0)NR-, -C(0)NRC(0)0-, -NRC(0)NRC(0)0-, -NRC(O)-, -NRC(0)NR-, -NRC02--0C(0)NR-, -S(0)-, -S02- -N(R)S02- -S02NR’-, -NRS02NR’-, or -(CR6R7)P-Y[-; and Y! is independently a bond, -0-, -S-, -NR’-, -0(0)-, -C(=NR)-, -C02-, -00(0)-, -C(0)NR'-, -C(0)NRC(0)0-, -NRC(0)NRC(0)0-, -NRC(O)-, -NRC(0)NR’-, -NRCO2-, -0C(0)NR’-, -S(0)-, -S02-, -S02NR’-, -NRS02-, or -NRS02NR’-.

Alternatively: Q1 is independently a bond, -0-, -S-, -NR-, -0(0)-, -C02-, -00(0)-, -C(0)NR-, -C(0)NRC(0)0-, -NRC(0)NRC(0)0-, -NRC(O)-, -NRC(0)NR-, -NRC02-, -0C(0)NR- -S(0>, -SO2-, -N(R)S02-, -S02NR\ -NRS02NR\ or -(CR6R7)p-Y‘-; and Y1 is independently -Ο-, -C02-, -OC(O)-, -C(0)NR- -NRC(O)-, -NRC(0)NR-, -NRCO2- or -0C(0)NR-.

[00355] In yet another embodiment, Q1 and Y1 are each independently as described above in the preceeding paragraph, and: R5 is independently i) -H; ii) a Ci-C6-aliphatic group optionally substituted with one or more instances of JCI; iii) a C3-CS non-aromatic carbocycle optionally substituted with one or more instances of Jcl; iv) a phenyl group optionally substituted with one or more instances of JC1; v) a 4-8 membered non-aromatic heterocycle optionally substituted with one or more instances of JD1 or vi) a 5-6 membered heteroaryl ring optionally substituted with one or more instances of JDI; and each of JC1 and JD1 is independently selected from the group consisting of halogen, cyano, oxo, Ra, -ORb, -SRb, -S(0)Ra, -S02Ra, -NHRC, -C(0)Rb, -C(0)0Rb, -0C(0)Rb, -NHC(0)Rb, -C(0)NHRc, -NHC(0)NHRc, -NHC(0)0Rb, -OCONHRc, -NHC(0)NHC(0)0Rb, -N(CH3)RC, -N(CH3)C(0)Rb , -C(0)N(CH3)Rc, -N{CH3)C(0)NHRc, -N(CH3)C(0)0Rb, -OCON(CH3)Rc, -C(0)NHC02Rb, -C(0)N(CH3)C02Rb, -N(CH3)C(0)NHC(0)0Rb, -NHS02Rb, -S02NHRb, -S02N(CH3)Rb, and -N(CH3)S02Rb.

[00356] In some specific embodiments, the compounds are represented by Structural Formula (IA) or (I), wherein: R1 is -H. R2 is -H, -CH3, -CH2OH, or -NH2. Specifically, R2 is -H, or -CH2OH. R3 is -H, -F, -Cl, Cm alkyl, or Cm haloalkyl. Alternatively, R3 is -H, -F, or -Cl. Z! is -H, -F, or -Cl. Z2 is -H or Ci-C6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, and -CXC1-C4 alkyl). Z3 is -H or CrCfi alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, and -(XC1-C4 alkyl). R5 is: i) -H; ii) an optionally substituted Ci-C6 alkyl group; iii) an optionally substituted, C3-C7 non-aromatic carbocycle; iv) an optionally substituted, 4-7 membered nonaromatic heterocycle; v) )an optionally substituted phenyl group; vi) an optionally substituted 5-6 merabered heteroaryl ring; or optionally, together with R and the nitrogen atom to which it is attached, form a 5-7 membered, optionally substituted non-aromatic heterocycle; and said alkyl group represented by R5 is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(Ci-C4 alkyl), -N(Ci-C4 alkyl)2, -OCO(C,-C4 alkyl), -COfCj-Q alkyl), -C02H, -C02(Ct-C4 alkyl), C,-C4 alkoxy, -NRCO(C,-C4 alkyl), -CONR(C,-C4 alkyl), -NRC02(C|-C4 alkyl), a C3-C7 non-aromatic carbocycle optionally substituted with one or more instances of JE1, a 4-7 membered non-aromatic heterocycle optionally substituted with one or more instances of JE1; and a phenyl optionally substituted with one or more instances of JEI; and wherein each of said carbocycle, hetcrocyclc, phenyl and hctcroaiy represented by Rs is independently and optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, Ci-C4 alkyl, -0(Ci-C4 alkyl), -NH2, -NH(Ct-C4 alkyl), -N(Ci-C4 alkyl)2, -C(0)(Ci-C4 alkyl), -0C(0)(Ci-C4 alkyl), -C(0)0(C|-C4 alkyl) and -C02H, wherein each of said alkyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(Ci-C4 alkyl), -N(CrC4 alkyl)2, -OCOfCVa, alkyl), -CO(Ci-C4 alkyl), -C02H, -C02(C,-C4 alkyl), and Cs-C4 alkoxy.

The remaining variables, including R4 that includes a spiro ring represented by rings E and F, or a bridged ring represented by rings G1-G5, are each and Independently as described in any one of the preceeing four embodiments.

[00357] In yet another embodiment, the compounds are presented by Structural Formula (IA) or (I), wherein values of the variabels are each and independently as described in the preceeding embodiment, except: Z2 is -H; Z3 is -H; R5 is independently: i) -H or ii) a Ci-Ce-alkyl group optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, C1-C4 alkyl, -0(Ci-C4 alkyl), -NH2, -NH(Ci-C4 alkyl),......N(Cr-C4 alkyl)2, -C(0)(Ci-C4 alkyl), -0C(0)(Ct-C4 alkyl), -C(0)0(Ci-C4 alkyl), -C02H, C3-Cs nonaromatic carbocycle, 4-8 membered non-aromatic heterocycle, phenyl, and 5-6 membered heteroaryl; wherein each of said alkyl groups referred to in the substituents of the Ct-C<;-alkyl group represented by R5 is independently and optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(C,-C4 alkyl), -N(CrC4 alkyl)2, -OCO(CrC4 alkyl), -CO(Ci-C4 alkyl), -C02H, -C02(Ci-C4 alkyl), and Ci-C4 alkoxy; and wherein each of said carbocycle, phenyl, heterocycle, and heteroaryl referred to in the substituents of the Ci-Ce-alkyl group represented by R5 is independently and optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, Ci-C4 alkyl, -NH2, -NH(Ci-C4 alkyl), -N(Cl-C4 alkyl)2, -OCO(Ci-C4 alkyl), -CO(Ci-C4 alkyl), -C02H, -C02(CrC4 alkyl), and Ci-C4 alkoxy.

[00358] In yet another embodiment, each of rings E, G1-G5 is independently and optionally substituted with onr or more substituents selected from the group consisting of halogen, cyano, hydroxy, C1-C6 alkyl, -NH2, —NtfrCi-Ce alkyl), -N(Ct-C6 alkyl)2, -OfCi.Cs alkyl), -C(0)NH2, -C(0)NH(Ct-C6 alkyl), -C(0)N(C|-Gr alkyl)2, -C(0)(Ci-C6-alkyl), -0C(0)(C,-C6 alkyl), -NHC(0)(Ci-C6 alkyl), -N(CrC6 alkyl)C(0)(Ci-C6 alkyl), and -C02Rb; wherein each of said alkyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(C,-C4 alkyl), -N(Ci-C4 alkyl)2, -0C0(C,-C4 alkyl), -CO(Ci-C4 alkyl), -C02H, -C02(Ci-C4 alkyl), and Ci-C4 alkoxy. Specifically, each of rings E, G1-G5 is independently and optionally substituted with onr or more substituents selected from the group consisting of halogen, cyano, hydroxy, -NH2, -NH(Ci-C4 alkyl), -N(Ci-C4 alkyl)2, -OCO(Ci-C4 alkyl), -CO(C]-C4 alkyl), -C02H, -C02(Ci-C4 alkyl), Ci-C4 alkoxy, and Ci-C4 alkyl optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, hydroxy, and -0(Ci-C4 alkyl).

[00359] In yet another embodiment, the compounds are represented by Structural Formula (IA) or (I), or pharmaceutically acceptable salts thereof, wherein: R4 is:

Ring A is a non-aromatic, 5-10 membered, bridged carbocylce or heterocycle, or ring A and R8 optionally form a non-aromatic, 5-10 membered, bridged carbocycle or heterocycle, or ring A and R9 optionally form a non-aromatic, 5-10 membered, bridged carbocycle or heterocycle, or ring A and R11 optionally form a non-aromatic, 5-10 membered, bridged carbocycle or heterocycle, wherein each of said carbocycle is independently and optionally substituted with one or more instances of JA and wherein each carbocycle is independently and optionally substituted with one or more instances of JB. R1 is -H. R2 is -H, -CH3, -CH2OH, or -NH2. Specifically, R2 is -H, or -CH2OH. R3 is -H, -F, -Cl, Cm alkyl (e.g., -CH3 or-C2H5), or CM haloalkyl (e.g., -CF3). Alternatively, R3 is -H, -F, or -CI. Z1 is -H, -F, or -Cl. Z2 is -H or Ci-Ce alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, and -0(Ci-C4 alkyl). Z3 is -H or Ci-Ce alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, and -(XC1-C4 alkyl). Q2 is independently -0-, -C02-, -0C(0)-, -C(0)NR’-, -C(0)NRC(0)0--NRC(0)-, -NRC(0)NR’-, -NRCO2-, -0C(0)NR’-, -P(0)(0R)0-, -0P(0)(0Ra)0-, -P(0)20-, -C02S02-, or-fCRVip-Y1-.

Yl is -0-, -C02- -0C(0)-, -C(0)NR’-, -C(0)NRC(0)0--NRC(O)-, -NRC(0)NR’-, -NRC02-, -0C(0)NR’-, -P(0)(0R)0-, -0P(0)(0Ra)0-, -P(0)20-, or -C02S02-. R5 is: i) -H; ii) an optionally substituted Ci-Cg alkyl group; iii) an optionally substituted, C3-C7 non-aromatic carbocycle; iv) an optionally substituted, 4-7 membered nonaromatic heterocycle; v) )an optionally substituted phenyl group; vi) an optionally substituted 5-6 membered heteroaryl ring; or optionally, together with R and the nitrogen atom to which it is attached, form a 5-7 membered, optionally substituted non-aromatic heterocycle; and said alkyl group represented by R5 is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(C,-C4 alkyl), -N(Ci-C4 alkyl)* -OCO(C,-C4 alkyl), -CO(C,-C4 alkyl), -C02H, -C02(C,-C4 alkyl), C1-C4 alkoxy, -NRC0(C,-C4 alkyl), -CONR(C,-C4 alkyl), -NRC02(Ci-C4 alkyl), a C3-C7 non-aromatic carbocycle optionally substituted with one or more instances of JE1, a 4-7 membered non-aromatic heterocycle optionally substituted with one or more instances of JEI; and a phenyl optionally substituted with one or more instances of JE1; wherein each of said carbocycle, heterocycle, phenyl and heteroary represented by R5 is independently and optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, Ci-C4 alkyl, -0(Ci-C4 alkyl), ~NH2, -NH(C,-C4 alkyl), -N(Ci~C4 alkyl)2, -C(0)(C,-C4 alkyl), -0C(0)(Ci-C4 alkyl), -C(0)0(Ci-C4 alkyl) and -C02H, wherein each of said alkyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(Ci-C4 alkyl), -N(Ci-C4 alkyl)2, -OCO(Ci-C4 alkyl), -CO(Ci-C4 alkyl), -C02H, -C02(Ci-C4 alkyl), and CrC4 alkoxy.

Each of Rs and R9 is independently -H, halogen, cyano, hydroxy, Ci-C4 alkyl, C1-C4 haloalkyl, Ci-C4 hydroxyalkyl, C2-C4 alkoxyalkyl, -0(C|-C4 alkyl), --NH2, -NH(Ci-C4 alkyl), or -N(C,-C4 alkyl)2. R11, R12, R13, and R14 are each independently -H, halogen, or Ci-Ce alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, and CrCe alkoxy.

Each of JA and JB is independently selected from the group consisting of halogen, cyano, hydroxy, Ci-C0 alkyl, -NH2, -NHfCi-Ce alkyl), -N(Ci-Cg alkyl)2, -0(Ci.CG alkyl), -C(0)NH2, -C(0)NH(Ci-C6 alkyl), -C(0)N(Ci-C6 aikyl)2, -C(0)(CrC6-alkyl), -0C(0)(C,-C6 alkyl), -NHC(0)(C,-C6 alkyl), -N(Ci-C6 alkyl)C(0)(CrC6 alkyl), and -C02Rb; wherein each of said alkyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(C,-C4 alkyl), -N(CrC4 alkyl)* -OCO(CrC4 alkyl), -CO(CrC4 alkyl), -C02H, -C02(CrC4 alkyl), and Ci-C4 alkoxy. n is 0 or 1, x is 0 or 1.

The remaining variables are each and independently as described above in any set of variables for Structural Formulae (IA) and (I).

[00360] In yet another embodiment, the compounds are represented by Structural Formula (IA) or (I), or pharmaceutically acceptable salts, wherein:

Each of rings G1-G4 is independently a 5-10 membered non-aromatic bridged carbocycle optionally further substituted with one or more instances of JA, and ring G5 is a 510 membered non-aromatic bridged heterocycle optionally further substituted with one or more instances of JB. X is -0-, -S-, or -NR®-. R21, R22, R23, R24, and R25are each independently -H, halogen, -OH, Ci-Ce alkoxy, or Ci-C6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, Cj-Ce alkyl, -NH2, -NH(Ci-Ce alkyl), -N(Ci-C6 alkyl)2, -0(Ci-C6 alkyl), -C(0)NH2, -C(0)NH(Ci-C6 alkyl), -C(0)N(C,-C6 alkyl)2, -C(O)(Ci-Ce-alkyI), -0C(0)(C,-Crt alkyl), -NHC(0)(Ci-C6 alkyl), -N(Ci-C6 allcyl)C(0)(0,-C6 alkyl).

Rfi is -H or Ci-Ce alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo, hydroxy, amino, carboxy, Ci-Ce alkoxy, CrCo lialoalkoxy, Ci-Csaminoalkoxy, C|.-Cf,cyanoalkoxy, CrC6 hydroxyalkoxy, and Ci-C^ alkoxyalkoxy. q is 0, 1 or 2. r is 1 or 2.

The remaining variables are each and independently as described above in the preceeding paragraph.

[00361] In yet another embodiment, the compounds are represented by Structural Formula (IA) or (I), or pharmaceutically acceptable salts thereof, wherein the variables are each and independently as described above in the preceeding paragraph except those described below: R1 is -H. R2 is -H. R3 is -H, -F, -Cl, Cm alkyl, or Cm haloalkyl. Alternatively, R3 is -H, -F, or -Cl. 7} is -H, -F, or -Cl. Z2 is -H. Z3 is -H. X is -0-. R5 is -H, an optionally substituted Ci-Cc alkyl, or optionally substituted phenyl.

Each R8 is independently -H, halogen, hydroxy, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C2-C4 alkoxyalkyl, or -0(Ci-C4 alkyl).

Each of Ry, R13, and R14 is independently -H or C1-C4 alkyl R31, R22, R23, R24, and R2Sare each independently -H, halogen, -OH, Ci-Cgalkoxy, or CrC6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, Ci-Ce alkyl, and -0(Ci-Ce alkyl). Specifically R21, R23, R23, R24, and R25 are each independently -H, C1-6 alkyl, or Ci_6 haloalkyl.

Each rings G1-G5 are independently and optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, hydroxy, -NH2, -NH(Ci-C6 alkyl), -NfCi-Ce alkyl)2, -0(Ci_C6 alkyl), C1-C4 alkyl that is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, and C1-C4 alkoxy.

[00362] In yet another embodiment, the compounds are represented by any one of Structural Formulae I-VI (hereinafter reference to Structural Formulae I-VI includes Structural Formulae I, ΙΑ, II, III, IV, V, VI) and XI(A)-XIV (hereinafter reference to Structural Formulae XI(A)-XIV includes Structural Formulae ΧΙΑ, XIB, XIIA, XIIB, XIII, and XIV), wherein values of the variables therein are independently as described above in any embodiments for the compounds of the invention, except that R3 is Cj-e alkyl, such as methyl or ethyl.

[00363] In yet another embodiment, the compounds are represented by any one of Structural Formulae I-VI and XI(A)-XIV, wherein values of the variables therein are independently as described above in any embodiments for the compounds of the invention, except that x is 0.

[00364] In yet another embodiment, the compounds are represented by any one of Structural Formulae I, I A, II, VI, XI(A), and XI(B), wherein values of the variables therein are independently as described above in any embodiments for the compounds of the invention, except that ring A is bridged.

[00365] In yet another embodiment, the compounds are represented by any one of

Structural Formulae I, ΙΑ, II, VI, XI(A), and XI(B), wherein values of the variables therein are independently as described above in any embodiments for the compounds of the invention, except that Q2 is independently -C(=NR)-, -C(=NR)NR-, -NRC(=NR)NR-, -CO2-, -0C(0)~, -C(0)NR-, -C(0)NRC(0)0- -NRC(0)NRC(0)0......, -NRC(O)-, -NRC(0)NR- -NRCO2-, -0C(0)NR-, -S(0)-, -S02~, -N(R)S02-, -S02N(R)-, -NRS02NR-, -P(0)(0R)0-, -0P(0)(0Ra)0-, -P(0)20-, -C02S02-, or -(CR^Vy1-; or alternatively, Q2 is independently -C02-, -OC(O)- -C(0)NR-, -C(0)NRC(0)0--NRC(0)NRC(0)0- -NRC(0)-, -NRC(0)NR- -NRC02- -0C(0)NR~, -S(O)-, -S02-, -N(R)S02- -S02N(R)-, -NRSCbNR-, -P(0)(0R)0-, -0P(0)(0Ra)0-, -P(0)20-, -CO2SO2-, or -(CR6R7)p-Y1-.

[00366] In yet another embodiment, the compounds are represented by any one of Structural Formulae I-YI and XI(A)-XIV, wherein values of the variables therein are independently as described above in any embodiments for the compounds of the invention, provided that when Q2 is -0- or -NR-, then ring A is further substituted with JA other than -H; and provided that if Q3 is -C(O)-, then R5 is a substituted Ci-Ce aliphatic group; an optionally substituted C3-C8 non-aromatic carbocycle; an optionally substituted, 6-10-membered carbocyclic aryl group; optionally substituted, 4-8 membercd non-aromatic heterocycle; or an optionally substituted 5-10 membered heteroaryl group. In a specific embodiment, when Q2 is -0- or -NR-, then ring A is further substituted with JA other than -H at the geminal position to -Q2R3.

[00367] In yet another embodiment, the present invention is directed to any one of the compounds depicted in FIGs. 3-5, or pharmaceutically acceptable salts thereof.

[00368] In yet another embodiment, the present invention is directed to any one of the compounds depicted in FIG. 6, or pharmaceutically acceptable salts thereof. In yet another embodiment, the present invention is directed to any one of the compounds depicted in FIG. 7, or pharmaceutically acceptable salts thereof. In yet another embodiment, the present invention is directed to any one of the compounds depicted in FIG. 8, or pharmaceutically acceptable salts thereof.

[00369] In some embodiments, the variables of Structural Formulae I-VI and XI(A)-XIV are each and independently as depicted in the compounds of FIGs. 3-8.

[00370] Each and independently as described above for the methods of the invention, the aforementioned compounds of the invention can be useful as inhibitors of influenza virus replication in biological samples or in a patient. These compounds can also be useful in reducing the amount of influenza viruses (viral titer) in a biological sample or in a patient. They can also be useful for therapeutic and prophylactic treatment of infections caused by the influenza viruses in a biological sample or in a patient.

[00371] The present invention also provides methods of preparing a compound of the invention. In one embodiment, the methods are directed to prepare compounds represented by Structural Formula (IA) or pharmaceutically acceptable salts thereof. The methods comprise a step of reacting reacting compound A:

dth compound B :

to form a compound represented by Structural Formula (XX), as shown in

Scheme A below:

Scheme A

The variables of Structural Formulae (IA) and (XX), and compounds (A) and (B) are independently as defined in any one of the embodiments described above. Ts is tosyl. Any suitable reaction condition known in the art, for example, in WO 2005/095400 and WO 2007/084557 for the coupling of a dioxaboraolan with a chloro-pyrimidine can be employed for the reaction between compound (A) and (B). For example, the reaction between compound (A) and (B) can be performed in the presence of Pd(PPh3)4. Specific exemplary conditions are described in the Exemplification below (e.g., General Schemes 5A, 6A, 7,11, 14, 16, 31,32, 33,40, 44, 49, 51, 52, 58, 60, 61, 62, 63, 64, 66, 67, 68, 69, 70, 76).

[00372] In another embodiment, the methods comprise a step of reacting reacting compound Cl or C2 with NH2R4 to form a compound represented by Structural Formula (XX), as shown in Scheme B below:

Scheme B

The variables of Structural Formulae (IA) and (XX), compounds (Cl) and (C2), and R4 of NH2R4 are independently as defined in any one of the embodiments described above. Ts is tosyl. Any suitable reaction condition known in the art, for example, in WO 2005/095400 and WO 2007/084557 for the coupling of an amine with a sulfinyl group can be employed for the reaction of compounds (Cl) and (C2) with NH2R4. Specific exemplary conditions are described in the Exemplification below (e.g., General Schemes 13,15, 19,20, 23, 30, 39,41, 42,44, 45, 50, 53, 54, 65, 72, 73, 74, and 77).

[00373] The methods described above with reference to Schemes A and B optionally and independently further comprises deprotecting the Ts group of the compound of Structural Formula (XX) to form the compound of Structural Formula (IA). Any suitable condition for deprotecting a Ts group known in the art can be employed in the invention. Specific exemplary conditions are described in the Exemplification below. The de-tosylation can generate the compounds of Structural Formula (IA) where R1 is -H. If desired, the R1 position can be alkylated by any suitable method known in the art to from the compounds of Structural Formula (IA) where R1 is Ci-e alkyl.

[00374] Compounds (A), (B), (Cl), (C2), and NH2R4 can be prepared by any suitable method known in the art. Specific exemplary synthethic methods are described below in the Exemplification below. For example, compound (Cl) can be prepared as described in Scheme C: reaction between compounds (D) and (E), for example, in the presence of Pd(PPh3)4 can produce compound (F). Compound (F) can then be oxidated under suitable conditions, for example, by treatment with meta-chloroperbenzoic acid to form compound (C). (See, for example, detailed experimental details described in the Exemplification for

General Scheme 44.)

Definitions and General Terminology [00375] 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, M.B. and March, J., John Wiley &amp; Sons, New York: 2001, the entire contents of which are hereby incorporated by reference.

[00376] As described herein, compounds of the invention may optionally be substituted with one or more substituents, such as illustrated generally below, or as exemplified by particular classes, subclasses, and species of the invention. It will be appreciated that the phrase “optionally substituted” is used interchangeably with the phrase “substituted or unsubstituted.” In general, the term “substituted”, whether preceded by the term “optionally” or not, refers to the replacement 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 selected 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 structure is not identified or defined as “optionally substituted", the substituent radical or structure is unsubstituted. For example, ifX is optionally substituted C!.C3alkyl or phenyl; X may be either optionally substituted C1-C3 alkyl or optionally substituted phenyl. Likewise, if the term “optionally substituted” follows a list, said term also refers to all of the substitutable groups in the prior list unless otherwise indicated. For example: if X is Ci_ Cjalkyl or phenyl wherein X is optionally and independently substituted by Jx, then both Ci_ C3alkyl and phenyl may be optionally substituted by Jx. As is apparent to one having ordinary skill in the art, groups such as H, halogen, NCh, CN, NH2, OH, or OCFj would not be substitutable groups.

[00377] 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 specified 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.

[00378] Selection of substituents and combinations of substituents envisioned by this invention are those that result in the formation of stable or chemically feasible compounds. The term “stable”, as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, specifically, their recovery, purification, and use for one or more of the purposes disclosed herein. In some embodiments, a stable compound or chemically feasible compound is one that is not substantially altered when kept at a 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. |00379] The term “aliphatic” or “aliphatic group”, as used herein, means a straight-chain (l.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 1-10 aliphatic carbon atoms. I11 other embodiments, aliphatic groups contain 1-8 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain 1-6 aliphatic carbon atoms, and in yet other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms. Aliphatic groups may be linear or branched, substituted or unsubstituted alkyl, alkenyl, or alkynyl groups. Specific examples include, but are not limited to, methyl, ethyl, isopropyl, n-propyl, sec-butyl, vinyl, n-butenyl, ethynyl, and tert-butyl and acetylene.

[00380] The term “alkyl” as used herein means a saturated straight or branched chain hydrocarbon. The term “alkenyl” as used herein means a straight or branched chain hydrocarbon comprising one or more double bonds. The term “alkynyl” as used herein means a straight or branched chain hydrocarbon comprising one or more triple bonds. Each of the “alkyl”, “alkenyl” or “alkynyl” as used herein can be optionally substituted as set forth below. In some embodiments, the “alkyl” is Ci-C6 alkyl or C1-C4 alkyl. In some embodiments, the “alkenyl” is C2-C6 alkenyl or C2-C4 alkenyl. In some embodiments, the “alkynyl” is C2-C6 alkynyl or C2-C4 alkynyl.

[00381] The term “cycloaliphatic” (or “carbocycle” or “carbocyclyl” or “carbocyclic”) refers to a non-aromatic carbon only containing ring system which can be saturated or contains one or more units of unsaturation, having three to fourteen ring carbon atoms. In some embodiments, the number of carbon atoms is 3 to 10. In other embodiments, the number of carbon atoms is 4 to 7. In yet other embodiments, the number of carbon atoms is 5 or 6. The term includes monocyclic, bicyclic or polycyclic, fused, 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 attachment is on the carbocyclic ring. “Fused” bicyclic ring systems comprise two rings which share two adjoining ring atoms. Bridged bicyclic group comprise two rings which share three or four adjacent ring atoms. Spiro bicyclic ring systems share one ring atom. Examples of cycloaliphatic groups include, but are not limited to, cycloalky] and cycloalkenyl groups. Specific examples include, but are not limited to, cyclohexyl, cyclopropenyl, and cyclobutyl.

[00382] The term “heterocycle” (or “heterocyclyl”, or ‘heterocyclic” or “non-aromatic heterocycle”) as used herein refers to a non-aromatic ring system which can be saturated or 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 comprise up to three heteroatoms selected from N, S and O within the ring. In other embodiments, non-aromatic heterocyclic rings comprise up to two heteroatoms selected from N, S and O within the ring system. In yet other embodiments, non-aromatic heterocyclic rings comprise up to two hetero atoms selected from N and O within the ring system. The term includes monocyclic, bicyclic or polycyclic fused, spiro or bridged heterocyclic ring systems. The term also includes polycyclic ring systems in which the heterocyclic ring can be fused to one or more non-aromatic carbocyclic or heterocyclic rings or one or more aromatic rings or combination thereof, wherein the radical or point of attachment is on the heterocyclic ring. Examples of heterocycles include, but are not limited to, piperidinyl, piperizinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, azepanyl, diazepanyl, triazepanyl, azocanyl, diazocanyl, triazocanyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, oxazocanyl, oxazepanyl, thiazepanyl, thiazocanyl, benzimidazolonyl, tetraliydrofuranyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydrothiophenyl, morpholino, including, for example, 3-morpholino, 4-morpholino, 2-thiomorpholino, 3-thiomorpholino, 4-thiomorpholino, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 1-tetrahydropiperazinyl, 2-tetrahydropiperazinyl, 3-tetrahydropiperazinyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 1-pyrazolinyl, 3-pyrazolinyl, 4-pyrazolinyl, 5-pyrazolinyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 2-thiazolidinyl, 3-thiazolidinyl, 4-thiazolidinyl, 1-imidazolidinyl, 2-imidazolidinyl, 4-imidazolidinyl, 5-imidazolidinyl, indolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, benzothiolanyl, benzodithianyl, 3-(l-alkyl)-benzimidazol-2-onyl, and 1,3-dihydro-imidazoI-2-onyl.

[00383] The term “aryl” (or “aryl ring” or “aryl group”) used alone or as pail of a larger moiety as in “aralkyl”, “aralkoxy”, “aryloxyalkyl”, or “heteroaryl” refers to both carbocyclic or heterocyclic aromatic ring systems. The term “aryl” may be used interchangeably with the terms “aryl ring” or “aryl group”.

[00384] “Carbocyclic aromatic ring” groups have only carbon ring atoms (typically six to fourteen) and include monocyclic aromatic rings such as phenyl and fused polycyclic aromatic ring systems in which two or more carbocyclic aromatic rings are fused to one another. Examples include 1-naphthyl, 2-naphthyl, 1-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 nonaromatic 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.

[00385] The terms “heteroaiyl”, “heteroaromatic”, “heteroaryl ring”, “heteroaryl group”, “aromatic heterocycle” or “heteroaromatic 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 aromatic 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 “heteroaiyl”, 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), where the radical or point of attachment is on the aromatic ring, Bicyclic 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, pyrazolyl, triazolyl, tetrazolyi, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl or thiadiazolyl including, for example, 2-furanyl, 3-furanyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazoIyl, 5-isoxazolyl, 2-oxadiazolyl, 5-oxadiazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 3-pyrazolyl, 4-pyrazolyl, 1-pyrrolyl, 2-pyirolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-triazolyl, 5-triazolyl, tetrazolyi, 2-thienyl, 3-thienyl, carbazolyl, benzimidazolyl, benzothienyl, benzofuranyl, indolyl, benzotriazolyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, isoquinolinyl, indolyl, isoindolyl, acridinyl, benzisoxazolyl, isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, purinyl, pyrazinyl, 1,3,5-triazinyl, quinolinyl (e.g., 2-quinolinyl, 3-quinolinyl, 4-quinolinyl), and isoquinolinyl (e.g., 1-isoquinolinyl, 3-isoquinolinyl, or 4-isoquinolinyl).

[00386] As used herein, “cyclo”, “cyclic”, “cyclic group” or “cyclic moiety”, include mono-, bi-, and tri-cyclic ring systems including cycloaliphatic, heterocycloaliphatic, carbocyclic aryl, or heteroaryl, each of which has been previously defined.

[00387] As used herein, a “bicyclic ring system” includes 8-12 (e.g., 9, 10, or 11) membered structures that form two rings, wherein the two rings 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 bicyclic heteroaryls. ]00388] As used herein, a “bridged bicyclic ring system” refers to a bicyclic heterocycloalipahtic ring system or bicyclic cycloaliphatic ring system in which the rings are bridged. Examples of bridged bicyclic ring systems include, but are not limited to, adamantanyl, norbomanyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octyl, bicyclo[3.3.1]nonyl, bicyclo[3.2.3]nonyl, 2-oxa-bicyclo[2.2.2]octyl, l-aza-bicyclo[2.2.2]octyl, 3-aza-bicyclo[3.2.1]octyl, and 2,6-dioxa-tricyclo[3.3.1.03,7]nonyl. A bridged bicyclic ring system can be optionally substituted with one or more substituents such as alkyl (including carboxyalkyl, hydroxyalkyl, and haloalkyl such as trifluoromethyl), alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, carbocyclic aryl, hetcroaryl, alkoxy, cycloalkyloxy, heterocycloalkyloxy, (carbocyclic aryl)oxy, hcteroaiyloxy, aralkyloxy, heteroaralkyloxy, aroyl, heteroaroyl, nitro, carboxy, alkoxycarbonyl, alkylcarbonyloxy, aminocarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino, (cyc!oaIkylalkyl)carbony]amino, (carbocyclic aryl)carbonylamino, aralkylcarbonylamino, (Iieterocycloalkyl)carbonylamino, (heterocycloalkylalkyl)carbonylamino, heteroarylcarbonylamino, heteroaralkylcarbonylamino, cyano, halo, hydroxy, acyl, mercapto, aUkylsulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, or carbamoyl.

[00389] 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”.

[00390] As used herein, the term “spiro” refers to ring systems having one atom (usually a quaternary carbon) as the only common atom between two rings.

[00391] The term “ring atom” is an atom such as C, N, O or S that is in the ring of an aromatic group, cycloalkyl group or non-aromatic heterocyclic ring.

[00392] A “substitutable ring atom” in an aromatic group is a ring carbon or nitrogen atom bonded to a hydrogen atom. The hydrogen can be optionally replaced with a suitable substituent group. Thus, the term “substitutable ring atom” does not include ring nitrogen or carbon atoms which are shared when two rings are fused. In addition, “substitutable ring atom” does not include ring carbon or nitrogen atoms when the structure depicts that they are already attached to a moiety other than hydrogen.

[00393] The term “heteroatom” means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including, any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quatemized form of any basic nitrogen or; a substitutable nitrogen of a heterocyclic ring, for example N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR1 (as in N-substituted pyrrolidinyl)).

[00394] As used herein an optionally substituted aralkyl can be substituted on both the alkyl and the aiyl portion. Unless otherwise indicated as used herein optionally substituted aralkyl is optionally substituted on the aiyl portion.

[00395] 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 non-aromatic heterocyclic ring are selected from those listed above, for example, in the definitions of JA, JB, JC1, JD1, and JEI, 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(0)R*, =NNHC02(alkyI), =NNHS02(alkyl), or =NR’, wherein each R* is independently selected from hydrogen or an optionally substituted Cug aliphatic.

Optional substituents on the aliphatic group of R* are selected fromNH2, NH(Cm aliphatic), N(Ci-4 aliphatic)2, halogen, C1-4 aliphatic, OH, 0(Cm aliphatic), NO2, CN, C02H, C02(Cm aliphatic), 0(halo Cm aliphatic), or halo(Ci-4 aliphatic), wherein each of the foregoing Cu ^aliphatic groups of R” is unsubstituted.

[00396] In some embodiments, optional substituents on the nitrogen of a non-aromatic heterocyclic ring include those used above, for example, in the definitions of JB, JD1 and JE1. Other suitable substituents include -R+, -N(R+)2, -C(0)R+, -C02R+, -C(0)C(0)R+, -C(0)CH2C(0)R+, -SO?R', -S02N(R+)2, -C(=S)N(R+)2, -C(=NH)-N(R+)2, or -NR^OzR4"; wherein R+ is hydrogen, an optionally substituted Cm aliphatic, optionally substituted phenyl, optionally substituted -0(Ph), optionally substituted -CH2(Ph), optionally substituted -(CH2)i_2(Ph); optionally substituted -CH=CH(Ph); or an unsubstituted 5-6 membered heteroaryl or heterocyclic ring having one to four heteroatoms independently selected from oxygen, nitrogen, or sulfur, or, two independent occurrences of R+, on the same substituent or different substituents, taken together with the atom(s) to which each R+ group is bound, form a 5-8-membered heterocyclyl, carbocyclic aryl, or heteroaryl ring or a 3-8-membered cycloalkyl ring, wherein said heteroaryl or heterocyclyl ring has 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Optional substituents on the aliphatic group or the phenyl ring of R" are selected from NH2, NH(Ch aliphatic), N(CW aliphatic)2, halogen, Cm aliphatic, OH, 0(Cm aliphatic), N02, CN, C02H, C02(Cm aliphatic), O(halo Cm aliphatic), orhalo(CM aliphatic), wherein each of the foregoing CMaliphatic groups of R+ is unsubstituted.

[00397] In some embodiments, a carbocyclic aryl (including aralkyl, aralkoxy, aryloxyalkyl and the like) or heteroaryl (including heteroaralkyl and heteroarylalkoxy and the like) group may contain one or more substituents. Suitable substituents on the unsaturated carbon atom of a carbocyclic aryl or heteroaryl group are selected from those listed above, for example, in the definitions of JA, JB, JC1, JD1 and JE1. Other suitable substituents include: halogen; -R°; -OR0; -SR°; 1,2-methylenedioxy; 1,2-ethylenedioxy; phenyl (Ph) optionally substituted with R°; -O(Ph) optionally substituted with R°; -(CH2)i-2(Ph), optionally substituted with R°; -CH=CH(Ph), optionally substituted with R°; -N02; -CN; -N(R°)2; -NR°C(0)R°; -NR°C(S)R°; -NR°C(0)N(R°)2; -NR°C(S)N(R°)2; -NR°C02R°; -NR°NR°C(0)R°; -NR°NR°C(0)N(R°)2; -NR°NR°C02R0; -C(0)C(0)R°; -C(0)CH2C(0)R°; -C02R°; -C(0)R°; -C(S)R°; -C(0)N(R°)2; -C(S)N(R°)2; -0C(0)N(Ro)2; -0C(0)R°; -C(0)N(0R°) R°; -C(NOR°) R°; -S(0)2Ro; -S(0)3R°; -S02N(Ro)2; -S(0)Ro; -NR°S02N(R°)2; -NRoS02R°; -N(OR°)R°; -C(=NH)-N(R°)2; or -(CH2)o.2NHC(0)R°; wherein each independent occurrence of R° is selected from hydrogen, optionally substituted Cue aliphatic, an unsubstituted 5-6 membered heteroaryl or heterocyclic ring, phenyl, -O(Ph), or -CEbfPh), or, two independent occurrences of R°, on the same substituent or different substituents, taken together with the atom(s) to which each R° group is bound, form a 5-8-membered heterocyclyl, carbocyclic aryl, or heteroaryl ring or a 3-8-membered cycloalkyl ring, wherein said heteroaryl or heterocyclyl ring has 1 -3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Optional substituents on the aliphatic group of R° are selected from NH2, NH(Q^aliphatic), N(Ci^aliphatic)2, halogen, Ci ^aliphatic, OH, 0(Ci_ 4aliphatic), NO2, CN, CO2H, COziCt^aliphatic), 0(haloCi_4 aliphatic), or haloCi-4aliphatic, CHO, N(CO)(Ciji aliphatic), C(0)N(Ci_4 aliphatic), wherein each of the foregoing Ci. 4aliphatic groups of R° is unsubstituted.

[00398] 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 attached to the remainder of the molecule at the two, three or four position of the piperidinyl ring and substituted at the ring nitrogen with an alkyl group. Non-aromatic nitrogen containing heterocyclic rings such as pyrazinyl that are substituted on a ring nitrogen and attached to the remainder of the molecule at a second ring nitrogen atom are said to be Ν’ substituted-N-heterocycles. For example, an N5 acyl N-pyrazinyl 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.

[00399] The term "unsaturated", as used herein, means that a moiety has one or more units of unsaturation.

[00400] As detailed above, in some embodiments, two independent occurrences of R° (or R~, or any other variable similarly defined herein), may be taken together with the atom(s) to which each variable is bound to form a 5-8-membered heterocyclyl, carbocyclic aryl, or heteroaryl ring or a 3-8-membered cycloalkyl ring. Exemplary rings that are formed when two independent occurrences of R° (or R+, or any other variable similarly defined herein) are taken together with the atom(s) to which each variable is bound include, but are not limited to the following: a) two independent occurrences of R° (or R+, or any other variable similarly defined herein) that are bound to the same atom and are taken together with that atom to form a ring, for example, N(R°)2, where both occurrences of R° are taken together with the nitrogen atom to form a piperidin-l-yl, piperazin-l-yl, or morpholin-4-yl group; and b) two independent occurrences of R° (or R+, or any other variable similarly defined herein) that are bound to different atoms and are taken together with both of those atoms to form a ring, for example where a phenyl group is substituted with two occurrences of OR°

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

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

[00401] In some embodiments, an alkyl or aliphatic chain can be optionally interrupted with another atom or group. This means that a methylene unit of the alkyl or aliphatic chain is optionally replaced with said other atom or group. Examples of such atoms or groups would include, but are not limited to those listed in the definitions of Q , Y , Q and Q . Further examples include -NR- -Ο-, -S-, -C02-, -OC(O)-, -C(0)C0-, -C(O)-, -C(0)NR- -C(=N-CN)-, -NRCO-, -NRC(0)0- -S02NR- -NRS02-, -NRC(0)NR--0C(0)NR- -NRS02NR- -SO-, or -S02-, wherein R is as defined above.

[00402] As used herein, an “amino” group refers to -NRXRY wherein each of Rx and RY is independently -H, Ci-Ce aliphatic, a C3-7 non-aromatic carbocycle, a 5-6 membered carbocyclic aryl or heteroaryl, or a 4-7 membered non-aromatic heterocycle, each of which independently being defined herein and being optionally substituted. Suitable substituents for the carbocycle, carbocyclic aryl, heteroaryl, and heterocycl are each independently include halogen, cyano, hydroxy, oxo, -NH2, -NH(Ci-C6 alkyl), -N(Ci-C&amp; alkyl)2, C]-C6alkyl, -0(Ci-C6 alkyl), -C(0)OH, -C(0)0(Ci-C6 alkyl), -OC(0)(Ci-C6 alkyl), -NHC(0)(Ci-C6 alkyl), -NHC(0)0(CrC6 alkyl), -C(0)NH(Ci-C6 alkyl), and -C(0)N(Ci-Ce alkyl)2, wherein each of said alkyl groups is optionally and independently substituted with one or more substitutents selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(Ci-C4 alkyl), and -N(Ci-C4 alkyl)2, -OCO(Ci-C4 alkyl), -CO(Ci-C4 alkyl), -C02H, -C02(Cl-C4 alkyl), and C1-C4 alkoxy. Suitable substituents for the Ci-Ce aliphatic (including Ci-Ce alkyl) include halogen, cyano, hydroxy, oxo, -NH2, -NH(C|-Q alkyl), -N(Ci-C6 alkyl)2, -0(C)-CV, alkyl), -C(0)OH, -C(0)0(C,-C6 alkyl), -OC(0)(Ci-C6 alkyl), -NHC(0)(CrCe alkyl), -NHC(0)0(Ci-C<5 alkyl), -C(0)NH(C!-C6 alkyl), -C(0)N(Ci-C6 alkyl)2, phenyl, a 5-6 membered heteroaryl, a 5-6 membered non-aromatic heterocycle, and a C3-C7 carbocycle, wherein each of said alkyl groups is optionally and independently substituted with one or more substitutents selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(Ci-C4 alkyl), -N(Ci-C4 alkyl)2, -OCOCCi-Gt alkyl), -CO(Ci-C4 alkyl), -C02H, -C02(Ci-C4 alkyl), and C1-C4 alkoxy, and wherein each of said phenyl, heteroaryl, heterocycle and carbocycle is optionally and independently substituted with one or more substitutents described above for the carbocycle, carbocyclic aiyl, heteroaryl, and heterocycle represented by Rx and RY. In some embodiments, each of Rx and RY is independently -H, an optionally substituted Ci-β aliphatic group, or an optionally substituted C3.8 non-aromatic carbocycle. In some embodiments, each of Rx and RY is independently -H or an optionally substituted Ci_c aliphatic group, In some embodiments, each of Rx and RY is independently -H or Ci_e alkyl optionally substituted with one or more substitutents selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(Ci-C4 alkyl), -N(Ci-C4 alkyl)2, -OCO(Ci-C4 alkyl), -CO(Ci-C4 alkyl), -C02H, -C02(Ci-C4 alkyl), and C[-C4 alkoxy. Examples of amino groups include -NH2, aliphatic amino, alkylamino, dialkylamino, or ary lamino. As used herein, an “aliphatic amino” group refers to -NRXRY wherein Rx is a Ci-e aliphatic group optionally substituted as described above; and RY is -H or a Ci-6 aliphatic group optionally substituted as described above. As used herein, an “alkylamino” group refers to -NHRX wherein Rx is a Ci45 alkyl group optionally substituted as described above. As used herein, a “dialkylamino” group refers to -NRXRY wherein each of Rx and RYis independently a Ci-e alkyl group optionally substituted as described above. As used herein, an “arylamino” group refers to -NRXRY wherein Rx is 5-6 membered, carbocyclic aryl or heteroaryl, and RY is -H or 5-6 membered, carbocyclic aryl or heteroaryl, wherein each of said carbocyclic aryl and heteroaryl groups is independently and optionally substituted as described above. When the term “amino” is not the terminal group (e.g., alkylcarbonylamino), it is represented by -NRX-. R has the same meaning as defined above. In one embodiment, the amino group is -NH2 or an aliphatic amino. In another embodiment, the amino group is -NH2, alkylamino or dialkylamino. In yet another embodiment, the amino group is -NH2 or an arylamino. In yet another embodiment, the amino group is -NH2, -NH(Ci-Ce alkyl) or -N(C[-C6 alkyl)2, wherein each of the alkyl groups is optionally and independently substituted with one or more substitutents selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(Ci-C4 alkyl), -N(CrC4 alkyl),, -OCO(Ci-C4 alkyl), -C0(Cl-C4 alkyl), -C02H, -C02(C[-C4 alkyl), and C1-C4 alkoxy.

[00403] As used herein, an “amido” encompasses both “aminocarbonyl” and “carbonylamino”. These terms when used alone or in connection with another group refer to an amido group such as N(RxRY)-C(0)- or RYC(0)-N(Rx)- when used terminally and -C(O)- N(RX)- or -N(Rx)-C(0)- when used internally, wherein Rx and RY are defined above. Examples of amido groups include alkylamido (such as alkylcarbonylamino or alkylcarbonylamino or alkylaminocarbonyl), (heterocycloaliphatic)amido, (heteroaralky 1)amido, (heteroaryl)amido, (heterocycloalkyl)alkylamido, arylamido, aralkylamido, (cycloallcyl)alkylamido, or cycloalkylamido. In some embodiments, the amido group is -NHC(0)(Cj-C6 alkyl), -N(Ci-C6 alkyl)C(0)(C,-C6 alkyl), -C(0)NH2, -C(0)NH(Ci-C6 alkyl), or -C(0)NH(Ci-C6 alkyl)2, wherein each of said alkyl is optionally and independently substituted with one or more substitutents selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(Ci-Cg alkyl), -N(Ci-Ce alkyl)2, -OCO(Ci-C4 alkyl), -CO(Ci-C4 alkyl), -C02H, -C02(C|-C4 alkyl), and Ci-C4 alkoxy. In some embodiments, the amido group is -NHC(0)(Ci-C6 alkyl), -N(Ci-C6 alkyl)C(0)(C[-C6 alkyl), -C(0)NH2, -C(0)NH(Ci-Ce alkyl), or -C(0)NH(Ci-C6 alkyl)2, wherein each of the alkyl groups is optionally and independently substituted with one or more substitutents selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NI-TfCi-Ce alkyl), -N(Ci-C6 alkyl)2, -OCO(CrC4 alkyl), -CO(Ci-C4 alkyl), -C02H, -C02(Ci-C4 alkyl), and Cr C4 alkoxy.

[00404] As used herein, a “urea” group refers to the structure -NRx-CO-NRYRz and a “thiourea” group refers to the structure -NRX-CS-NRYRZ when used terminally and -NRX-CO-NRY- or -NRX-CS-NRY- when used internally, wherein Rx, RY, and Rz are each independently as defined above, [00405] As used herein, an “acyl” group refers to a formyl group or Rx-C(0)- (such as -alkyl-C(O)-, also referred to as “alkylcarbonyl”) where Rx and “alkyl” have been defined previously. Acetyl and pivaloyl are examples of acyl groups.

[00406] As used herein, a “carboxy” group refers to -CO OH, -COORx, -OC(0)H, -0C(0)Rx when used as a terminal group; or-OC(O)- or-C(0)0- when used as an internal group, wherein Rx is as defined above.

[00407] The term “hydroxyf’or “hydroxy” or “alcohol moiety” refers to -OH.

[00408] 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 (alky l-0)-C(0)-.

[00409] As used herein, a “carbonyl” refers to -C(O)-.

[00410] As used herein, an “oxo” refers to =0.

[00411] As used herein, the term “alkoxy”, or “alltylthio”, as used herein, refers to an alkyl group, as previously defined, attached to the molecule through an oxygen (“alkoxy” e.g., -Ο-alkyl) or sulfur (“alkylthio” e.g., -S-alkyl) atom.

[00412] As used herein, the terms “halogen”, “halo”, and “hal” mean F, Cl, Br, or I, |00413] As used herein, the term “cyano” or “nitrile” refer to --CM or -C=N.

[00414] 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.

[00415] The terms “haloalkyl”, “haloalkenyl”, “haloaliphatic”, and “haloalkoxy” mean alkyl, alkenyl, aliphatic or alkoxy, as the case may be, substituted with one or more halogen atoms. This term includes perfluorinated alkyl groups, such as -CF_i and -CF2CF3.

[00416] The terms “cyanoalkyl”, “cyanoalkenyl”, “cyanoaliphatic”, and “cyanoalkoxy” mean alkyl, alkenyl, aliphatic or alkoxy, as the case may be, substituted with one or more cyano groups. In some embodiments, the cyanoalkyl is (NC)-alkyl-.

[00417] The terms “aminoalkyr, “aminoalkenyl”, “aminoaliphatic”, and “aminoalkoxy” mean alkyl, alkenyl, aliphatic or alkoxy, as the case may be, substituted with one or more amino groups, wherein the amino group is as defined above. In some embodiments, the aminoaliphatic is a C1-C6 aliphatic group substituted with one or more -NH2 groups. In some embodiments, the aminoalkyl refers to the structure (RxRY)N-alkyl-, wherein each of Rx and RY independently is as defined above. In some specific embodiments, the aminoalkyl is C1-C6 alkyl substituted with one or more -NFb groups. In some specific embodiments, the aminoalkenyl is C1-C6 alkenyl substituted with one or more -NH2 groups. In some embodiments, the aminoalkoxy is -0(0-C6 alkyl) wherein the alkyl group is substituted with one or more -NH2 groups.

[00418] The terms “hydroxyalkyl”, “hydroxyaliphatic”, and “hydroxyalkoxy” mean alkyl, aliphatic or alkoxy, as the case may be, substituted with one or more -~OH groups.

[00419] 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.

[00420] The term “carboxyalkyl” means alkyl substituted with one or more carboxy groups, wherein alkyl and carboxy are as defined above.

[00421] In some embodiments, each of the amino groups referred to in the descriptions for the variables of Structural Formulae I-VI and XI(A)-XIV (e.g., R6, R7, JE1, R, R’, R”, R* Ra, Rb and R°) above is independently -NH2, -NH(Ci-Cfi alkyl), -NH(C3-C6 carbocylce), -N(Ci-C6 alkyl)2, or-N(Ci-Ce alkylffCj-Cc carbocycle), wherein said alkyl and carbocycle groups are each optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(Ci-C4 alkyl), -N(Ci-C4 alkyl)2, -OCO(Ci-C4 alkyl), -CO(Ci-C4 alkyl), -C02H, -C02(Ci-C4 alkyl), and Ci-C4 alkoxy; each of the carboxy groups referred to in the descriptions for the variables of Structural Formulae I-VI and X1(A)-XIV (e.g., R6, R7, JE1, R, R’, R”, R*, Ra, Rb and Rc) above is independently -C(0)0(CrCfi alkyl), -0C(0)(Ci-Cg alkyl), -C(0)0(C3-C6 carbocycle), -0C(0)(C3-C6 carbocycle), or -C02H, wherein said alkyl and carbocylce groups are each optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(Ci-C4 alkyl), -N(C(-C4 alkyl)2, -OCO(Ci-C4 alkyl), -CO(CrC4 alkyl), -C02H, -C02(Ci-C4 alkyl), and CrC4 alkoxy; each of the amido groups referred to in the descriptions for the variables of Structural Formulae I-VI and XI(A)-XIV (e.g., R6, R7, JE!, R, R\ R”, R*, Ra, Rb and Rc) above is independently -NHC(0)(Ci-Ce alkyl), -N(Ci-Ce alkyl)C(0)(Ci-C6 alkyl), -C(0)NH(Ci-C6 alkyl), -C(0)N(Ci-Ce alkyl)2, -NHC(0)(C3-C6 carbocycle), -N(Ci-C6 alkyl)C(0)(C3-Ce carbocycle), -C(0)NH(C3-Ce carbocycle), -C(0)N(Ci-Ce alkyl)(C3-C6 carbocycle), or -C(0)NH2, wherein said alkyl and carbocycle groups are each optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(Ci-C4 alkyl), -N(Ci-C4 alkyl)2, -OCO(Ci-C4 alkyl), -CO(Ci-C4 alkyl), -C02H, -C02(C,-C4 alkyl), and Ci-C4 alkoxy; each of the aminoalkyl groups referred to in the descriptions for the variables of Structural Formulae I-VI and XI(A)-XIV (e.g., Rs, R9, and R”) above is independently a C1-C6 alkyl group substituted with one or more aminogroups independently selected from the group consisting of-NH2, -NH(Ci-C4 alkyl), and -N(Ci-C4 alkyl)2; and each of the aminoalkoxy groups referred to in the descriptions for the variables of Structural Formulae I-VI and XI(A)-XIV (e.g., R6, R7, R8, R9, R10, Rn, R12, R!3, R14, R, R’, and R”) above is independently is a -0(C1-C6 alkyl) group wherein the alkyl group is substituted with one or more one or more aminogroups independently selected from the group consisting of-NH2, -NH(Ci-C4 alkyl), and -N(Ci-C4 alkyl)2.

[00422] In some embodiments, each of the amino groups referred to in the descriptions for the variables of Structural Formulae I-VI and XI(A)-XIV (e.g., R6, R7, JE1, R, R\ R”, R*, R“, Rb and Rc) above is independently -NH2, -NH(CrC6 alkyl), or -N(Ci-Ce alkyl)2, wherein said alkyl groups are each optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(Ci-C4 alkyl), -N(C,-C4 alkyl)2, -OCO(C,-C4 alkyl), -CO(C]-C4 alkyl), -C02H, -C02(Ci-C4 alkyl), and C1-C4 alkoxy; each of the carboxy groups referred to in the descriptions for the variables of Structural Formulae I-VI and XI(A)-XIV (e.g., R6, R7, JEI, R, R’, R”, R*, Ra, Rb and Rc) above is independently -C(0)0(Ci-Cs alkyl), -0C(0)(Ci-C6 alkyl), or -C02H, wherein said alkyl groups are each optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(Ci-C4 alkyl), -N(Cj-C4 alkyl)2, -OCO(Ci-C4 alkyl), -CO(Ci-C4 alkyl), -CO2H, -C02(Ci-C4 alkyl), and Ci-C4 alkoxy; each of the amido groups referred to in the descriptions for the variables of Structural Formulae I-VI and XI(A)-XIV (e.g., R6, R7, JE1, R, R’, R”, R*, Ra, Rb and Rc) above is independently -NHC(0)(CrCc alkyl), -N(Ci-Ce alkyl)C(0)(Ci-C6 alkyl), -C(0)NH(C,-C6 alkyl), -C(0)N(Ci-C6 alkyl)2, or -C(0)NH2, wherein said alkyl groups are each optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(C,-C4 alkyl), -N(Ci-C4 alkyl)2, -OCO(C,-C4 alkyl), -CO(Ci-C4 alkyl), -C02H, -C02(Ci-C4 alkyl), and C1-C4 alkoxy; each of the aminoalkyl groups referred to in the descriptions for the variables of Structural Formulae I-VI and XI(A)-XIV (e.g., R8, R9, and R”) above is independently a C1-C6 alkyl group substituted with one or more aminogroups independently selected from the group consisting of -NH2, -NH(Ci-C4 alkyl), and -N(Ci-C4 alkyl)2; and each of the aminoalkoxy groups referred to in the descriptions for the variables of Structural Formulae I-VI and X1(A)-XIV (e.g., R6, R7, Rs, R9, R10, R11, R12, R13, R14, R, R’, and R”) above is independently is a -0(C1-C6 alkyl) group wherein the alkyl group is substituted with one or more one or more aminogroups independently selected from the group consisting of-NH2, -NH(Ci-C4 alkyl), and -N(Ci-C4 alkyl)2.

[00423] The term “protecting group” and “protective group” as used herein, are interchangeable and refer to an agent used to temporarily block one or more desired functional groups 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 protected substrate that is b) stable to reactions occurring at one or more of the other reactive sites; and c) is selectively removable in good yield by reagents that do not attack the regenerated, deprotected functional group. As would be understood by one skilled in the art, in some cases, the reagents do not attack other reactive groups in the compound. In other cases, the reagents may also react with other reactive groups in the compound. Examples of protecting groups are detailed in Greene, T. W., Wuts, P. G in “Protective Groups in Organic Synthesis”, Third Edition, John Wiley &amp; 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 protecting groups are also detailed in Chapter 7 in Greene, T.W., Wuts, P. G in “Protective Groups in Organic Synthesis”, Third Edition, John Wiley &amp; Sons, New York: 1999, the entire contents of which are hereby incorporated by reference.

[00424] As used herein, the term “displaceable moiety” or “leaving group” refers to a group that is associated with an aliphatic or aromatic group as defined herein and is subject to being displaced by nucleophilic attack by a nucleophile.

[00425] 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 asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers are included in this invention, unless only one of the isomers is drawn specifically. As would be understood to one skilled in the art, a substituent can freely rotate around any rotatable

I bonds. For example, a substituent drawn as also represents [00426] 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.

[00427] Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention.

[00428] Additionally, unless otherwise indicated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopic ally enriched atoms. For example, compounds having the present structures except for the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a 13C- or l4C-enriched carbon are within the scope of this invention. For example, compounds of Structural Formulae I-VI (e.g., Structural Formulae I, ΙΑ, II, III, IV, V, and VI) and XI(A)-XIV (e.g., Structural Formulae ΧΙΑ, XIB, XIIA, XIIB, XIII, and XIV) that have -D at the position corresponding to R2 are also within the scope of this invention. Such compounds are useful, for example, as analytical tools or probes in biological assays. Such compounds, especially deuterium analogs, can also be therapeutically useful.

[00429] The terms “a bond” and “absent” are used interchangeably to indicate that a group is absent.

[00430] The compounds of the invention are defined herein by their chemical structures and/or chemical names. Where a compound is referred to by both a chemical structure and a chemical name, and the chemical structure and chemical name conflict, the chemical structure is determinative of the compound’s identity.

Pharmaceutically Acceptable Salts, Solvates, Chlatrates, Prodrugs and Other Derivatives [00431] 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.

[00432] As used herein, the term "pharmaceutically acceptable salt" refers to salts of a compound which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue side effects, such as, toxicity, imitation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.

[00433] Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et ah, describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds described herein include those derived from suitable inorganic and organic acids and bases. These salts can be prepared in situ during the final isolation and purification of the compounds. |00434] Where the compound described herein contains a basic group, or a sufficiently basic bioisostere, acid addition salts can be prepared by 1) reacting the purified compound in its free-base form with a suitable organic or inorganic acid and 2) isolating the 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.

[00435] 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, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, 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, nitrate, 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.

[00436] Where the compound described herein contains a carboxy group or a sufficiently acidic bioisostere, base addition salts can be prepared by 1) reacting the purified compound in its acid form with a suitable organic or inorganic base and 2) isolating the 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, lithium, and potassium), alkaline earth metal (e.g., magnesium and calcium), ammonium and N"(Ci-4alkyl)4 salts. This invention also envisions the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Water or oil-soluble or dispersible products may be obtained by such quaternization.

[00437] Basic addition salts include pharmaceutically acceptable metal and amine salts. Suitable metal salts include the sodium, potassium, calcium, barium, zinc, magnesium, and aluminium. The sodium and potassium salts are usually preferred. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate. Suitable inorganic base addition salts are prepared from metal bases which include sodium hydride, sodium hydroxide, potassium hydroxide, calcium hydroxide, aluminium hydroxide, lithium 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, ornithine, choline, N,N’-dibenzylethylenediamine, chloroprocaine, dietanolamine, procaine, N-benzylphenethylamine, drethylamrne, piperazine, tris(hydroxymethyl)-aminomethane, tetramethylammonium hydroxide, triethylamine, dibenzyl amine, ephcnaminc, dehydroabictylamine, N-ethylpiperidinc, benzylamine, tetramethylammonium, tetraethyl ammonium, methylamine, dimethylamine, trimethylamine, ethylamine, basic amino acids, dicyclohexylamine and the like.

[00438] Other acids and bases, while not in themselves pharmaceutically acceptable, may be employed in the preparation of salts useful as intermediates in obtaining the compounds described herein and their pharmaceutically acceptable acid or base addition salts.

[00439] 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.

[00440] In addition to the compounds described herein, pharmaceutically acceptable solvates (e.g., hydrates) and clathrates of these compounds may also be employed in compositions to treat or prevent the herein identified disorders.

[00441] As used herein, the term “pharmaceutically acceptable solvate," is a solvate formed from the association of one or more pharmaceutically acceptable solvent molecules to one of the compounds described herein. The term solvate includes hydrates (e.g., hemihydrate, monohydrate, dihydrate, trihydrate, tetrahydrate, and the like).

[00442] As used herein, the term “hydrate” means a compound described herein or a salt thereof that further includes a stoichiometric or non-stoichiometric amount of water bound by non-covalcnt intermolecular forces.

[00443] As used herein, he term “clathratc” 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.

[00444] In addition to the compounds described herein, pharmaceutically acceptable derivatives or prodrugs of these compounds may also be employed in compositions to treat or prevent the herein identified disorders.

[00445] A “pharmaceutically acceptable derivative or prodrug” includes any pharmaceutically acceptable ester, salt of an ester or other derivative 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 compounds when such compounds are administered to a patient (e.g., by allowing an orally administered compound to be more readily absorbed into the blood) or which enhance delivery of the parent compound to a biological compartment (e.g., the brain or lymphatic system) relative to the parent species.

[00446] As used herein and unless otherwise indicated, the term “prodrug” means a derivative of a compound that can hydrolyze, oxidize, 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 activity 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 biohydrolyzable 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, -NO2, -ONO, or -ONO2 moieties. Prodrugs can typically be prepared using well-known methods, such as those described by BURGER'S MEDICINAL CHEMISTRY AND DRUG DISCOVERY ¢1995) 172-178, 949-982 (Manfred E. Wolff cd„ 5th ed).

[00447] 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.

[00448] Pharmaceutically acceptable prodrugs of the compounds described herein include, without limitation, esters, amino acid esters, phosphate esters, metal salts and sulfonate esters.

Pharmaceutical Compositions [00449] The compounds described herein can be formulated into pharmaceutical compositions that further comprise a pharmaceutically acceptable carrier, diluent, adjuvant or vehicle. In one embodiment, the present invention relates to a pharmaceutical composition comprising a compound of the invention described above, and a pharmaceutically acceptable carrier, diluent, adjuvant or vehicle. In one embodiment, the present invention is a pharmaceutical composition comprising an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, diluent, adjuvant or vehicle. Pharmaceutically acceptable earners include, for example, pharmaceutical diluents, excipients or carriers suitably selected with respect to the intended form of administration, and consistent with conventional pharmaceutical practices.

[00450] An “effective amount” includes a “therapeutically effective amount” and a “prophylactically effective amount”. The term “therapeutically effective amount” refers to an amount effective in treating and/or ameliorating an influenza virus infection in a patient infected with influenza. The term “prophylactically effective amount” refers to an amount effective in preventing and/or substantially lessening the chances or the size of influenza virus infection outbreak. Specific examples of effective amounts are described above in the section entitled Uses of Disclosed Compounds.

[00451] A pharmaceutically acceptable earner may contain 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 undesired reactions or side-effects upon the administration to a subject. Standard pharmaceutical formulation techniques can be employed.

[00452] 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., Easton, Pa., 1980) discloses various carriers used in formulating pharmaceutically acceptable compositions and known techniques for the preparation thereof. Except insofar as any conventional carrier medium is incompatible with the compounds described herein, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component(s) of the pharmaceutically acceptable composition, its use is contemplated to be within the scope of this invention. As used herein, the phrase “side effects” encompasses unwanted and adverse effects of a therapy (e.g., a prophylactic or therapeutic agent). Side effects are always unwanted, but unwanted effects are not necessarily adverse. An adverse effect from a therapy (e.g., prophylactic or therapeutic agent) might be harmful or uncomfortable or risky. Side effects include, but are not limited to fever, chills, lethargy, gastrointestinal toxicities (including gastric and intestinal ulcerations and erosions), nausea, vomiting, neurotoxicities, nephrotoxicities, renal toxicities (including such conditions as papillary necrosis and chronic interstitial nephritis), hepatic toxicities (including elevated serum liver enzyme levels), myelotoxicities (including leukopenia, myelosuppression, thrombocytopenia and anemia), dry mouth, metallic taste, prolongation of gestation, weakness, somnolence, pain (including muscle pain, bone pain and headache), hair loss, asthenia, dizziness, extra-pyramidal symptoms, akathisia, cardiovascular disturbances and sexual dysfunction.

[00453] 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 saturated vegetable fatty acids, water, salts or electrolytes (such as protamine sulfate, disodium 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; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; safflower 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 compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator. A dministration Methods [00454] The compounds and pharmaceutically acceptable compositions described above can be administered to humans and other animals orally, rectally, parenterally, intracistemally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), bucally, as an oral or nasal spray, or the like, depending on the severity of the infection being treated.

[00455] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[00456] Injectable preparations, for example, sterile injectable 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 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, 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.

[00457] The injectable 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 sterile water or other sterile injectable medium prior to use.

[00458] In order to prolong the effect of a compound described herein, it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound then depends upon its rate of dissolution that, in turn, may depend upon ciystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form is accomplished by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the compound in biodegradable 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.

[00459] Compositions for rectal or vaginal administration are specifically suppositories which can be prepared by mixing the compounds described herein with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.

[00460] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.

[00461] Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric 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.

[00462] 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, tablets and pills, the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.

[00463] 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 acceptable carrier and any needed preservatives or buffers as may be required. Ophthalmic formulation, eardrops, and eye drops are also contemplated as being within the scope of this invention. Additionally, the present 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 enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.

[00464] The compositions described 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, intramuscular, intra-articular, intra-synovial, intrastemal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. Specifically, the compositions are administered orally, intraperitoneally or intravenously. 100465] Sterile injectable forms of the compositions described herein may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or di-glycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, 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 dispersing agents which are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions. Other commonly used surfactants, such as Tweens, Spans and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.

[00466] The pharmaceutical 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, carriers commonly used include, but are not limited to, lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration 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, [00467] 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.

[00468] The pharmaceutical compositions described herein may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.

[00469] Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically-trans dermal patches may also be used.

[00470] For topical applications, the pharmaceutical compositions may be formulated in a suitable ointment 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 petrolatum, white petrolatum, propylene glycol, polyoxyethylene, 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. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2 octyldodecanol, benzyl alcohol and water.

[00471] 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 pharmaceutical compositions may be formulated in an ointment such as petrolatum.

[00472] The pharmaceutical 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 prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents.

[004731 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 Preparation of Compounds

The compounds disclosed herein, including those of Structural Formulae I-VI (e.g., Structural Formulae I, ΙΑ, II, III, IV, V, and VI) and XI(A)-XIV (e.g., Structural Formulae ΧΙΑ, XIB, XILA, XIIB, XIII, and XIV) can be prepared by any suitble method known in the art, for example, WO 2005/095400 and WO 2007/084557. For example, the compounds depicted in FIGs. 3-8 can be prepared by any suitble method known in the art, for example, WO 2005/095400 and WO 2007/084557, and by the exemplary syntheses deserbied below.

In particular, the compounds depicted in FIG. 8 can be prepared as described in WO 2005/095400 and WO 2007/084557. Syntheses of certain exemplary compounds of Structural Formulae I-VI and XI(A)-XIV are described below. Generally, the compounds of Structural Formulae I-VI and XI(A)-XIV can be prepared as shown in those syntheses optionally with any desired appropriate modification.

General Analytical Methods.

[00474] As used herein the term RT (min) refers to the LCMS retention time, in minutes, associated with the compound. Unless otherwise indicated, the method employed to obtain the reported retention times is as follows:

Column: YMC-Pack Pro Cig, 50 mm x 4.6 mm id Gradient: 10-95 % methanol/FLO. Flow rate: 1.5 ml/min. UV-vis detection.

Methodology for Synthesis and Characterization of Compounds [00475] Syntheses of certain exemplary compounds of Structural Formulae I-VI (e.g., Structural Formulae I, ΙΑ, II, III, IV, V, and VI) and XI(A)-XIV (e.g., Structural Formulae ΧΙΑ, XIB, XIIA, XIIB, XIII, and XIV) are described below. NMR and Mass Spectroscopy data of certain specific compounds are summarized in Tables 1-5.

General Scheme 1

(a) (S)-1-Boc-3-aminopiperidine, 'P^NEt, DMF, 90 °C; (b) TFA, CH2CIZ (c) 2-(methoxymethyl)oxirane, EtOH, microwave, 140 °C (d) 1N LiOH, THF, microwave, 120 °C

[00476] Formation of (AJ-tot-butyl 3-(2-(5-chloro-l-tosyl-l//-pyrrolo[2,3-ir] py rid in-3-yl)-5-fluor opy rimidin-4-yla mino)pip eridine-1 -carboxylate (1 b).

To a solution of 5-chloro-3-(5-fluoro-4-methylsulfonyl-pyrimidin-2-yl)-l-(p-tolylsuIfonyl)pyrrolo[2,3-b]pyridine, la, (3.5 g, 7.5 mmol) and tert-butyl (35)-3-aminopiperidine-1-carboxylate (1.8 g, 9.0 mmol) in DMF (32 mL) was added diisopropylethylamine (2.6 mL, 15.1 mmol). The reaction mixture was heated at 90 °C for 75 minutes. The mixture was cooled to room temp and diluted into aqueous saturated NH4CI solution and extracted with EtOAc. The organic phase was washed with brine (3 times), dried (MgSCL), filtered and concentrated under vacuo. The resulting residue was purified via silica gel chromatography (0%-10% MeOH/CH2Cl2) to afford the desired product lb as a white solid. LCMS RT = 4.6 (M+l) 601.5, (M-l) 599.6.

[00477] Formation of (5)-2-(5-chloro-l-tosyl-l//-pyrrolo[2,3-/>]pyridin-3-yl)-5-fluoro-iV-(piperidin-3-yl)pyrimidin-4-amine (lc).

To a solution of tert-butyl (3S)-3-[[2-[5-chlon>l-(p-tolylsulfonyl)pyrrolo[5,4-b]pyridin-3-yl]-5-fluoro-pyrimidin-4-yI]amino]piperidine-l-carboxylate, lb, (2.1 g, 3.5 mmol) in CH2CI2 (30 mL) was added trifluoroacetic acid (20 mL). After stirring the reaction mixture at room temperature for 75 min, the mixture was concentrated under vacuo. The crude residue was diluted with EtOAc and neutralized with IN sodium hydroxide solution. The aqueous phase was separated and extracted again with EtOAc. The combined organic phases were dried (MgSO^, filtered and concentrated under vacuo to afford the desired product (lc) as a light yellow solid. *H NMR (300 MHz, /6-DMSO) δ 8.76 (d, / = 2.5, Hz, 1H), 8.50 (d, /= 2.5 Hz, 1H), 8.44 (s, 1H), 8.27 (d, / = 4.0 Hz, 1H), 8.06 (d,/ = 8.5 Hz, 2H), 7.66 (d, /= 6.9 Hz, 1H), 7.45 (d,/= 8.2 Hz, 2H), 4.17 (m, 1H), 3.17 (dd,/= 3.1, 11.8 Hz, 1H), 2.99-2.94 (m, 1H), 2.67 -2.60 (m, 1H), 2.38 - 2.34 (m, 1H), 2.06 - 2.02 (m, 1H), 1.77 - 1.73 (m, 1H) and 1.63 - 1.50 (m, 2H) ppm. LCMS RT = 2.1 (M+l) 501.5, (M-l) 499.5.

[00478] Formation of l-((iS')-3-(2-(5-ehIoro-l-tosyI-l//-pyrrolo[2,3-/>]pyridin-3-yl)-5-fluoropyrimidm-4-ylamino)piperidin-l-yl)-3-methoxypropan-2-ol (Id).

To a solution of 2-[5-chIoro-l-(p-tolylsulfonyl)pyrrolo[5,4-b]pyridin-3-yl]-5-fluoro-N-[(3Sr)-3-piperidyl]pyrimidin-4-amine, lc, (0.20 g, 0.40 mmol) in ethanol was added 2-(methoxymethyl)oxirane (0.04 mL, 0.40 mmol). The reaction mixture was heated in a microwave reactor at 140 "C for 5 minutes. The reaction was evaporated to dryness and the resulting residue was purified via silica gel chromatography (0-10 % MeOH: CH2CI2) to afford the desired product (I d). lK NMR (300 MHz, /6-DMSO) δ 8.78 (d, /= 2.5 Hz, 1H), 8.49 (d, /= 2.4 Hz, 1H), 8.43 (d, /= 1.2 Hz, 1H), 8.26 (d, /= 3.9 Hz, 1H), 8.07 (d, /= 8.4 Hz, 2H), 7.60 (d, /= 7.5 Hz, 1H), 7.45 (d, /= 8.2 Hz, 2H), 4.54 - 4.50 (m, 1H), 4.20 (m, 1H), 3.35 - 3.17 (m, 1H), 3.33 (s, 3H), 3.25 (m, 1H), 3.19 (d, 2H), 3.00 (m, 1H), 2.75 (d, J = 11.8 Hz, 1H), 2.44 - 2.26 (m, 4H), 1.93 (m, 1H), 1.73 (m, 2H), 1.63 (m, 1H) and 1.23 (m, 1H) ppm. LCMS RT = 2.4 (M+l) 589.6.

[00479] Formation of l-((5)~3-(2-(5-chloro-l//-pyrrolo[2,3-/»]pyridin-3-yl)-5-lluoropyrimidin-4-ylamino)piperidin-l-yl)-3-methoxypropan-2-ol (537).

To a solution of l-[(3iS)-3-[[2-[5-chIoro-l-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-5-fluoro-pyrimidin-4-yl]amino]-l-piperidyl]-3-methoxy-propan-2-ol, Id, (0.15 g, 0.24 mmol) in THF was added IN LiOH solution. The reaction mixture was heated in a microwave reactor at 120 °C for 5 minutes. The reaction mixture was diluted with water and the aqueous phase was extracted with EtOAc (twice). The combined organic phases were dried (MgS04), filtered and concentrated under vacuo. The resulting solid was purified by silica gel chromatography (5-20% MeOH: CH2CI2) to afford the desired product (537) as a white solid. NMR (300 MHz, /6-DMSO DMSO) 6 12.35 (s, 1H), 8.73 (d, /= 2.4 Hz, 1H), 8.29 (d, /= 2.4 Hz, 1H), 8.19 - 8.09 (m, 2H), 7.36 (d, /= 7.5 Hz, 1H), 4.53 (dd, /= 4.5, 8.0 Hz, 1H), 4.27 (s, 1H), 3.77 - 3.72 (m, 1H), 3.36 - 3.20 (m, 3H), 3.22 (s, 3H), 3.03 - 2.97 (m, 1H), 2.76 (d, /= 10.6 Hz, 1H), 2.44 - 2.14 (m, 2H), 2.08 (m, 2H), 1.99 - 1.94 (m, 1H), 1.71 -1.63 (m, 2H), 1.44 (m, lH)and 1.23 -1.15 (m, lH)ppm. LCMS RT = 1.6 (M+l) 435.5.

[00480] Other analogs that can be prepared in the same manner as 537 are described below:

Cl Cl H n^V-OH H v— 525 551 [00481] 3-((S)-3-(2-(5-chloro-l#-pyrro]o[2,3-£]pyridin“3-yl)-5-fluoropyrimidin-4-yIamino)piperidin-l-yl)propane-l,2-diol (525) Ή NMR (300 MHz, /6-DMSO) 8 12.31 (s, 1H), 8.72 (d, / = 2.4 Hz, 1H), 8.28 (d, / = 2.4 Hz, 1H), 8.20 (s, 1H), 8.17 (d, / = 4.0 Hz, 1H), 7.33 (d, / = 7.6 Hz, 1H), 4.51 (m, 1H), 4.37 (s, 1H), 4.25 (m, 1H), 3.64 (m, 1H), 3.35 (s, 2H), 3.08-2.95 (m, 1H), 2.80-2.70 (m, 1H), 2.47 - 2.25 (nt, 2H), 2.22 - 2.12 (m, 2H), 1.99 - 1.90 (m, 1H), 1.70 - 1.60 (m, 2H) and 1.45 (m, 1H) ppm. LCMS RT = 1.5 (M+l) 421.5.

[00482] l“((5)-3-(2-(5-chloro-l/ir-pyrrolo[2>3“6]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)piperidin-l-yl)-3-isopropoxypropan~2-ol (551). !H NMR (300 MHz, /6-DMSO) 8 12.32 (s, 1H), 8.72 (d, / = 2.4 Hz, 1H), 8.28 (d, /= 2.4 Hz, 1H), 8.19 - 8.16 (m, 2H), 7.32 (d,/ = 8.0 Hz, 1H), 4.42 - 4.37 (m, 2H), 3.70 (s, 1H), 3.52 - 3.42 (m, 1H), 3.35 - 3.25 (m, 1H), 2.99 (m, 1H), 2.73 (ra, 1H), 2.43 - 2.11 (m, 4H), 1.94 (m, 1H), 1.75 - 1.60 (m, 2H), 1.52 - 1.40 (Μ, 1H) and 1.10 - 0.99 (m, 6H). LCMS RT = 1.7 (M+l) 463.4, (M-l) 461.5.

Cl r\ t0vO'Fr~\ oh n n-O Ph H ^—V- H Wv 536 546 [00483] (5)-l-((,S)-3-(2-(5-chloro-l//-pyrrolo[2,3-b]pyridin-3-yi)-5-fluoropyrimidm-4-ylamino)piperidin-l-y])butan-2-ol (538). 'H NMR (300 MHz, /6-DMSO) 8 12.53 (s, 1H), 10.32 (s, 1H), 8.69 (dd, /= 2.5, 5.2 Hz, 1H), 8.56 (d, /= 2.4 Hz, 1H), 8.31 (m, 2H), 7.97 (s, 1H), 4.76 (m, 1H), 3.92 (m, 2H), 3.84 - 3.55 (m, 2H), 3.40 - 2.80 (m, 3H), 2.14 - 1.90 (m, 3H), 1.80 - 1.74 (m, 2H), 1.65 (m, 1H), 1.43 - 1.23 (m, 2H) and 0.96 - 0.85 (m, 3H) ppm. LCMS RT = 1.6 (M+l) 419.6.

[00484] (S)-l-(3-(2-(5-chlorO“l//-pyrrolo[2,3-6]pyridin~3-yl)-5-fluoropyrimidin-4-ylamino)pip eridin-1 -yl)-2-meihylpropa n-2-ol (546). ‘H NMR (300 MHz, CDCb) 8 9.60 (s, 1H), 8.87 (d, /= 2.3 Hz, 1H), 8.33 (d, /= 2.3 Hz, 1H), 8.17 (d, /= 2.7 Hz, 1H), 8.09 (d, /= 3.3 Hz, 1H), 5.34 (d, /= 11.5 Hz, 1H), 4.45 - 4.42 (m, 1H), 3.09 (d, /= 11.3 Hz, 1H), 2.75 - 2.59 (m, 4H), 2.40 (s, 2H), 1.94 - 1.70 (m, 4H) and 1.27 (s, 6H) ppm. LCMS RT = 1.6 (M+l) 419.5,

588 587 [00485] (R)-3-((5)-3-(2-(5-ch]oro-l//-pyirolo[2,3-6]pyridin-3-yl)-5-fluoropyrimidin-4-yla min o)piperidin-l-yl)p ropane-l,2-diol (588). lH NMR (300 MHz, DMSO) 5 12.31 (s, 1H), 8.72 (d, / = 2.4 Hz, 1H), 8.27 (d, / = 2.4 Hz, 1H), 8.19 (s, 1H), 8.16 (d, / = 4.0 Hz, 1H), 7.33 (d,/ = 7.8 Hz, 1H), 4.47 - 4.44 (m, 1H), 4.35 (d, / = 4.0 Hz, 1H), 4.28 - 4.17 (m, IH), 3.64 - 3.62 (m, 1H), 3.17 (d, / = 5.2 Hz, 1H), 3.02 - 2.98 (m, 1H), 2.78 - 2.73 (m, 1H), 2.37 (ddd, / = 12.8, 5.2, 5.2 Hz, 2H), 2.22 -2.10 (m, 2H), 1.99 - 1.89 (m, 1H), 1.73 - 1.63 (m, 2H) and 1.46 - 1.43 (m, 1H) ppm. LCMS RT= 1.5 (M+l) 421.4. LCMS RT = 1.6 (M+l) 419.3.

[00486] (S)-3-((iS)-3-(2-(5“Chloro-l/i-pyrrolo[2,3-/>]pyridin-3-yl)-5-fluoropyrimid in-4-yla mino)p iperidin-l-yl)prop ane- 1,2-diol (587). Ή NMR (300 MHz, DMSO) 6 12.31 (s, 1H), 8.72 (d, / = 2.4 Hz, 1H), 8.28 (d, / = 2.4 Hz, 1H), 8.20 (s, 1H), 8.16 (d, /= 4.0 Hz, 1H), 7.33 (d,/ = 7.5 Hz, 1H), 4.34 (s, 1H), 4.27 - 4.23 (m, 1H), 3.62 (s, 1H), 3.35 (d, /= 5.5 Hz, 1H), 3.06 - 3.03 (m, 1H), 2.78 - 2.74 (m, 1H), 2.44 (d, /= 5.0 Hz, IH), 2.27 (dd,/= 12.9, 6.9 Hz, 1H), 2.20 - 2.07 (m, 2H), 2.05 -1.90 (m, 1H), 1.75 - 1.59 (m,2H)and 1.49- 1.39 (m, lH)ppm.

[00487] 1-((35,45)-3-(2-(5-chloro-l//-pyr rolo [2,3-ft] pyridin-3-y 1)-5-fluoropyrimidin-4-ylamino)-4-methylpiperidm-l-yl)-3-methoxypropan-2-ol (550). 'HNMR (300 MHz, /6-DMSO) 5 12.33 (s, 1H), 8.72 (d, /= 2.5 Hz, 1H), 8.28 (d,/ = 2.4 Hz, 1H), 8.22 - 8.20 (m, 2H), 6.72 - 6.62 (m, IH), 4.61 (dd, / = 4.2, 10.0 Hz, 1H), 4.54 (m, IH), 3.75 - 3.71 (m, IH), 3.34 - 3.22 (m, IH), 3.22 (d, 3H), 2.88 - 2.42 (m, 4H), 2.41 - 2.25 (m, 4H), 1.93 (m, IH), 1.56 (m, 2H) and 0.90 (d, /= 6.7 Hz, 3H). LCMS RT = 1.6 (M+l) 449.5.

[00488] 3-((5)-3“(2-(5-chloro-l//-pyrroio[2,3-ft]pyridin-3-yI)-5-fhioropyrimidm-4-ylamino)piperidin-l-yl)-2-hydroxypropanamide (603). Ή NMR (300 MHz, DMSO) δ 12.31 (s, IH), 8.71 (d, /= 2.4 Hz, IH), 8.28 - 8.25 (m, IH), 8.19-8.16 (m,2H), 7.34-7.30 (m, IH), 7.19 (s, IH), 7.11 (s, lH),4.24(s, 1H),3.99 (dd, /= 3.5, 7.6 Hz, IH), 3.01 (d, /= 10.3 Hz, IH), 2.81 - 2.63 (m, 2H), 2.36 - 2.29 (m, 2H), 1.71 (s, 3H) and 1.51 -1.44 (m, 2H)ppm.

General Scheme 2

(a) ferf-butylbromoacetate, Na2C03, DMF (b) 1N LiOH, THF, microwave, 120 °C, 10 min (c) TFA, CH2CI2 [00489] Formation of (S)-te/*t-butyl 3-(2-(5-chloro-l-tosyl-l//-pyrrolo[2,3-b ]py ridin-3-yl)-5-flu oropy rim idin-4-yla mino)pip eridine-l-ca rboxy late (2a).

To a solution of 2-[5-chloro-n(p-tolylsulfonyl)pyrrolo[5,4-b]pyridin-3-yl]-5-fluoro-W-[(3iS)-3-piperidyl]pyrimidin-4-amine, lc, (0.25 g, 0.50 mmol) in DMF was added tert-butylbromoacetate (0.08 mL, 0,55 mmol) and Na2COj (0.11 g, 0.99 mmol). The reaction mixture was stirred at room temperature for 6 h. The resulting thick white precipitate was diluted with aqueous saturated NaCl solution and washed with water. The white solid was dissolved in CH2CI2 and the solution was dried (MgS04). filtered and concentrated in vacuo. The crude was purified via silica gel chromatography (0%-5% MeOH/ CH2CI2) to afford the desired product, 2a, as a white solid. ‘H NMR (300 MHz, /6-DMSO) δ 8.76 (d, / = 2.4 Hz, 1H), 8.48 (d, / = 3.6 Hz, 1H), 8.44 (s, 1H), 8.26 (d, / = 3.9 Hz, 2H), 8.07 (d, / = 8.4 Hz, 2H), 7.59 (d, / = 8.2 Hz, 1H), 7.44 (d, /= 8.1 Hz, 2H), 4.18 (m, 1H), 3.19 (s, 2H), 3.03 - 2.99 (m, 1H), 2.78 - 2.73 (m, 1H), 2.45 - 2.30 (m, 2H), 2.37 (s, 3H), 1.99 - 1.93 (m, 1H), 1.80 - 1.60 (m, 2H), 1.46 - 1.40 (m, 1H) and 1.36 (s, 9H) ppm. LCMS RT = 2.8 (Μ+Ϊ) 615.6, (M-l) 613.6.

[00490] Formation of (.S)-h?rt-butyl 2-(3-(2-(5-chloro-l//-pyrrolo[2,3-£]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)piperidin-l-yl)ethanoate (2b).

To a solution of te/7-butyl 2-[(35)-3-[[2-[5-chloro-l-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin- 3-yl]-5-fluorO'pyrimidin-4-yl]amino]-l-pipcridyl]acetate, 2a, (0.27 g, 0.44 mmol) in THF was added IN LiOH solution. The reaction mixture was heated in microwave at 120 degrees for 10 minutes. The reaction mixture diluted with brine, extracted with EtOAc, then with 20% isopropanol/CH2Cl2. The combined organic phases were dried (MgS04), filtered and concentrated in vacuo. The resulting product, 2b, was used without further purification. LCMS RT = 2.0 (M+l) 461.5.

[00491] Formation of (5)-2-(3-(2-(5-chloro-l/f-pyrrolo[2,3-Z»]pyridin-3~yl)-5-fluoropyrimidin-4-ylamino)piperidin-l-yl)ethanoic acid (577).

To a solution /erf-butyl 2-[(3S)-3-[[2-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-y 1]amino]-1-piperidyl]acetate, 2b, (0.12 g, 0.26 mmol) in CH2CI2 (4 mL) was added trifluoroacetic acid (4 mL). The reaction mixture was stirred at room temperature for 18 h and concentrated in vacuo. The crude residue was diluted with 5%McOH/ CH2CI2 and die resulting white precipitate was filtered and washed with CH2CI2 to afford the desired product, 577, as trifluoroacetic acid salt. Ή NMR (300 MHz, t/6-DMSO) 5 12.46 (s, 1H), 8.70 (d, / = 2.4 Hz, 1H), 8.36 (d,/ = 2.3 Hz, 1H), 8.31 (d, / = 2.4 Hz, 1H), 8.29 (d, / = 3.9 Hz, 1H), 7.79 (d, / = 7.0 Hz, 1H), 4.70 - 4.50 (m, 1H), 4.21 (s, 2H), 3.80 - 3.70 (m, 1H), 3.55 - 3.47 (m, 1H), 3.20 - 2.90 (m, 2H), 2.10 -1.95 (m, 3H) and 1.69 - 1.60 (m, 1H) ppm. LCMS RT = 1.9 (M+l) 405.4.

[00492] Other analogs that can be prepared in the same manner as 577:

5S7 583 [00493] (tS)-2-(3-(2-(5-chloro-lHr-pyrrolo[2,3-Z>]pyridin-3-yl)-5-fluoropyrimidin-4-yIamino)piperidin-l-yl)ethanamide (567). *HNMR (300 MHz, /6-DMSO) 8 12.29 (s, 1H), 8.72 (d,/= 2.4 Hz, 1H), 8.28 (d, /= 2.4 Hz, 1H), 8.21 (s, 1H), 8.17 (d, /= 4.0 Hz, 1H), 7.41 (d, /= 7.7 Hz, 1H), 7.29 (s, 1H), 7.10 (s, 1H), 4.35 - 4.29 (m, 1H), 2.98 - 2.75 (m, 1H), 2.92 (d, /= 6.8 Hz, 2H), 2.68 (d,/ = 10.8 Hz, 1H), 2.29 - 2.19 (m, 2H), 1.96 - 1.92 (m, 1H), 1.80 - 1.65 (m, 2H) and 1.53 - 1.42 (m, 1H) ppm. LCMS RT = 2.1 (M+l) 404,4, (M-l) 402.5.

[00494] 2-((5)-3-(2-(5-chloro-ljH-pyrrolo[2,3-Z»]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)piperidin-l-yl)propanamide (583). ^NMR(300 MHz, c/6-DMSO) 8 8.70 (d, / = 2.3 Hz, 1H), 8.52 (d,/= 8.7 Hz, 1H), 8.35 (dd, /= 5.0, 6.5 Hz, 2H), 4.10 (dd, /= 2.7, 7.0 Hz, 1H), 3.80-3.90 (m, 1H), 3.60 - 3.80 (m, 1H), 2.35-2.45 (m, 1H), 2.15-2.35 (m, 1H), 1.80 - 1.95 (m, 1H), and 1.60 - 1.65 (m, 3H) ppm. LCMS (M+l) 418.4.

654 620 [Ο0495] (S)-2-(3-(2-(5-chlor o-li/-py r rolo [2,3-/;] py ridin-3-yl)-5-cy anopy rimidin-4- y la mino)pip eridin-l-yl)ethanamide (654). LCMS RT = 2.9 (M+l) 411.4, (M-l) 409.4.

[00496] (S)-2-(3-(2-(5-chloro-l.ff-pyrrolo [2,3-6] pyridin-3-yl)-5-methylpyrimidiii-4-ylamino)piperidin-l-yl)ethanamide (620). LCMS RT = 1.9 (M+l) 400.4, (M-l) 398.3.

573 606 [00497] 2-((5)-3-(2-(5-chloro-l/f-pyrrolo[2,3-6]pyridin-3-yl)-5-fluoropyriinidm-4-ylamino)piperidin-l-yl)propanoic acid (573). ^NMR (300 MHz, /6-DMSO) δ 12.51 (s, 1H), 10.28 - 10.00 (m, 1H), 8.70 (s, 1H), 8.38 (s, 1H), 8.31 (d, /= 2.4 Hz, 1H), 8.30 (d, / = 4.2 Hz, 1H), 7.89 - 7.75 (m, 1H), 4.70 - 4.50 (m, 1H), 4.33 - 4.29 (m, 1H), 3.79 - 3.45 (m, 2H), 3.20 - 2.80 (m, 2H), 2.12 - 1.95 (m, 3H), 1.72 - 1.60 (m, 1H) and 1.52 (/, J = 5.5 Hz, 3H) ppm.

[00498] 2-((S)-3-(2-(5-chloro-li/-pyrrolo[2,3-6]pyridm-3-yl)-5-fliioropyriimdin-4-ylamino)piperidii»-l-yi)-Ar-methylpropananiide (606). ^HMR ¢300 MHz, /6-DMSO) δ 8.69 (d, /= 12.7 Hz, 1H), 8.54 - 8.49 (m, 1H), 8.32 (dd, /= 4.8, 7.2 Hz, 2H), 4.83 - 4.76 (m, 1H), 4.02 (m, 1H), 3.95 - 3.71 (m, 2H), 3.31 - 3.10 (m, 1H), 2.86 (s, 3H), 2.33 (d, /= 9.9 Hz, 1H), 2.40 - 2.14 (m, 3H), 1.94 (s, 1H), 1.66 - 1.58 (m, 3H) and 1.10 (d, /= 6.5 Hz, 3H) ppm. LCMS (M+l) 432.2.

590 598 [00499] (5)-2-(3-(2-(5-chloro-liT-pyrrolo[2,3-6]pyridin-3-yl)-5-fluoropyrimidin-4-yIamino)piperidin-I-yI)-2-methylpropanoic acid (590). ^NMR (300 MHz, MeOD) δ 8.81 (d, /= 2.3 Hz, 1H), 8.19 (t, /= 2.5 Hz, 2H), 7.98 (d, /= 4.2 Hz, 1H), 4.48 (s, 1H), 2.90 (d, /= 10.1 Hz, 1H), 2.74 - 2.66 (m, 2H), 2.60 (d,/= 5.7 Hz, 1H), 1.89 - 1.83 (m, 2H), 1.67 (s, 1H), 1.25 (d, /= 4.9 Hz, 6H) ppm. LCMS (M+l) 433.4.

[00500] (S)-2-(3-(2-(5-chIoro-l//-pyrroio[2,3-6]pyridin-3-yl)-5-fIuoropyriimdin-4-ylammo)piperidm-l-yl)-2-methy]propanamide (598). LCMS RT = 1.8 (M+l) 432.4.

599 600 [00501J (iS)-2-(3-(2-(5-chloro-l//-pyrro]o[2,3-A]pyridm-3-y])-5-fluoropyrimidm-4- ylamino)pip eridin- l-yl)wV,2-d imethylp ropana mid e (599). !HNMR (300 MHz, MeOD) 5 8.86 (d, /= 2.4 Hz, 1H), 8.23 (d, /= 2.3 Hz, 1H), 8.17 (s, 1H), 8.03 (d, /= 4.1 Hz, 1H), 4.46 (dd, /= 4.7, 8.8 Hz, 1H), 4.10 (q, /= 7.2 Hz, 1H), 3.05 (d, /= 12.8 Hz, 1H), 2.66 (s, 3H), 2.34 (dd, 7= 11.3, 20.6 Hz, 2H), 2.08 (d, /= 12.3 Hz, 1H), 1.89-1.71 (m, 2H), 1.66-1.54 (m, lH)and 1.19 (s, 6H)ppm. LCMS (M+l) 433.4.

[00502] (5r)-2-(3-(2-(5-chloro-li/-pyrrolo[2,3“/>]pyridin-3-yl)-5-lluoropyrimidm-4-ylammo)piperidin-l-yl)-AyV,2-trimethylpropanamide (600).

[HNMR (300 MHz, MeOD) δ 8.81 (d, /= 2.4 Hz, 1H), 8.22 (d, /= 2.4 Hz, 1H), 8.14 (s, 1H), 8.02 (d, /=4.0 Hz, 1H), 4.45 - 4.37 (m, 1H), 3.61 (s, 3H), 2.97 (d, /= 8.8 Hz, 1H), 2.80 (s, 3H), 2.72 (s, 1H), 2.39 (t,/= 10.0 Hz, 2H), 2.15 (dd,/= 3.6, 12.7 Hz, 1H), 1.91 - 1.79 (m, 2H), 1.53 - 1.47 (m, 1H) and 1.28 (s, 6H) ppm. LCMS (M+l) 460.5.

602 [00503] (5)-2-(3-(2-(5-chloro-l//-pyrrolo[2,3-£]pyridin-3-yl)-5-fIuoropyrimidin-4-ylamino)piperidm-l-yl)-A-(2-methoxyethyl)-2-methyipropanamide (601). ΧΗ NMR (300 MHz, MeOD) δ 8.88 (d, / = 2.3 Hz, 1H), 8.23 (d, / = 2.3 Hz, 1H), 8.17 (s, 1H), 8.02 (d, /= 4.1 Hz, 1H), 4.47-4.41 (m, 1H), 3.38 (dd, /= 1.6, 4.8 Hz, 4H), 3.12 - 3.07 (m, 1H), 2.73 (d,/= 10.8 Hz, 1H), 2.35 - 2.29 (m, 2H), 2.19 - 2.15 (m, 1H), 1.91-1.80 (m, 2H), 1.55 (s, 1H), 1.37 (s, 1H) and 1.20 (s, 6H) ppm..

[00504] (5)-2-(3-(2-(5-chloro-l/f-pyrrolo [2,3-6] pyridin-3-y l)-5-fluoropyrimid in-4-ylamino)piperidin-l-yl)-iV-cyclopropyl-2-methylpropanamide (602). !H NMR (300 MHz, MeOD) δ 8.82 (d, /= 2.3 Hz, 1H), 8.23 (d, /= 2.3 Hz, 1H), 8.15 (s, 1H), 8.01 (d, /=4.0 Hz, 1H), 4.41 (m, 1H), 3.02 (d, /= 10.0 Hz, 1H), 2.59 - 2.47 (m, 1H), 2.40 -2.30 (m, 2H), 2.09 - 2.01 (m, 1H), 1.89- 1.85 (m, 1H), 1.78- 1.66 (m, 1H), 1.61 - 1.55 (m, 1H), 1.26 - 1.16 (m, 1H), 1.10 (d, /= 6.6 Hz, 6H), 0.68-0.63 (m, 2H) and 0.44 -0.40 (m, 2H) ppm. LCMS (M+l) 472.4.

General Scheme 3

(a) CF3CH2S02CCI3, 'Pr2NEt, DMF (b) 1N LiOH, THF, microwave, 120 °C, 10 min [00505] Formation of (iS)-2-(5-chloro-l-tosyl-l//-pyrrolo[2,3-6|pyridin-3-yl)-5-fluoro-Ar-(l-(2,2,2-trifluoroethyl)piperidm-3~yl)pyrimidin-4-amine (3a).

To a solution of 2-[5-cbloro-l-(p-toly]sulfonyl)pynOlo[5,4-b]pyridin-3-yl]-5-fluoro-N-[(3S)-3-piperidyl]pyrimidin-4-amine, lc, (0.17 g, 0.34 mmol) in DMF (1.5 mL) was added 2,2,2-trifluoroethyl trichloromethanesulfonate (0.19 g, 0.68 mmol), followed by 'Pr2NEt (0.24 mL, 1,36 mmol). The reaction mixture was stirred at room temperature for 18 h. The mixture was poured into brine and extracted twice with EtOAc. The combined organic phases were washed twice with brine, dried (MgSCL), filtered, and concentrated in vacuo. The crude residue was purified by silica gel chromatography (0-10% MeOH/CH2Cl2) afforded the desired product, 3a, as a white solid. ’H NMR (300 MHz, /6-DMSO) 6 8.77 (d, /= 2.4 Hz, 1H), 8.48 (d, /= 2.4 Hz, 1H), 8.42 (s, 1H), 8.27 (d, /= 3.9 Hz, 1H), 8.05 (d, /= 8.4 Hz, 2H), 7.62 (d, /= 7.5 Hz, 1H), 7.44 (d, /= 8.2 Hz, 2H), 4.17 (m, 1H), 3.30 - 3.18 (m, 3H), 2.90 (m, 1H), 2.44 - 2.32 (m, 2H), 2.35 (s, 3H), 1.95 (m, 1H), 1.72 - 1.57 (m, 2H) and 1.51 - 1.40 (m, 1H) ppm. LCMS RT = 4.6 (M+l) 583.4, (M-l) 581.4.

[00506] Formation of (5)-2-(5-chloro-lf/-pyrrolo[2,3-6]pyridin-3-yl)-5-fluoro-Ar-(1-(2,2,2-trifluoroethyl)piperidin-3-yl)pyrimidm-4-amine (668).

To a solution of 2-[5-chloiO-l-(p-toIylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-5-fluoro-N-[(3S)-l-(2,2,2-trifluoroethyl)-3-piperidyl]pyrimidin-4-araine, 3a, (0.10 g, 0.18 mmol) in THF was added 1M LiOH (0.90 mL, 0.90 mmol) solution. The reaction mixture was heated in microwave at 120 °C for 10 minutes. The reaction mixture was diluted with brine, extracted with EtOAc, then with 20% isopropanol/CH2Cl2. The combined organic phases were dried (M.gS04), filtered and concentrated in vacuo. The resulting residue was purified via silica gel chromatography (0-10 % MeOH:CH2Cl2) to afford the desired product, 1339, as a white solid. !H NMR (300 MHz, /6-DMSO) δ 12.32 (s, 1H), 8.71 (d,/= 2.4 Hz, 1H), 8.28 (d, /= 2.4 Hz, 1H), 8.18 - 8.16 (m, 2H), 7.38 (d, /= 7.7 Hz, 1H), 4.22 - 4.17 (m, 1H), 3.31 - 3.16 (m, 3H), 2.90 (m, 1H), 2.40 (t,/= 10.2 Hz, 2H), 2.00 - 1.95 (m, 1H), 1.77 - 1.60 (m, 2H) and 1.50- 1.38 (m, 1H) ppm. LCMS RT = 3.5 (M+l) 429.4, (M-l) 427.4.

[00507] Other analogs that can be prepared in the same manner as 668:

1 595 [00508] Synthesis of (£)-2-(5-chloro-1J/-pyrrolo [2,3-/;]pyridm-3~yl)-/V-(l-(2,2-difluoroethyl)piperidin-3-yl)-5-fluoropyrimidin-4-amine (1). 'H NMR (300 MHz, /6-DMSO) δ 12.31 (s, 1H), 8.72 (d, / = 2.4 Hz, 1H), 8.28 (d, / = 2.4 Hz, 1H), 8.20 (s, 1H), 8.17 (d, / = 4.0 Hz, 1H), 7.33 (d, ./= 7.6 Hz, 1H), 4.51 (m, 1H), 4.37 (s, 1H), 4.25 (m, 1H), 3.64 (m, 1H), 3.35 (s, 2H), 3.08-2.95 (m, 1H), 2.80-2.70 (m, 1H), 2.47 - 2.25 (m, 2H), 2.22 - 2.12 (m, 2H), 1.99 - 1.90 (m, 1H), 1.70 - 1.60 (m, 2H) and 1.45 (m, lH)ppm. LCMS RT = 2.7 (M+l) 411.4, (M-l) 409.4.

[00509] (5)“2-(5-chlorO“l//-pyrrolo[2,3-6]pyridin-3-yl)-iV-(l-(2,2-difluoroethyl)piperidin-3-yl)-5-fluoropyrimidin-4-amine (595). 'HNMR (300 MHz, /6-DMSO) δ 12.32 (s, 1H), 8.71 (d, J = 2.4 Hz, 1H), 8.28 (d, J = 2.4 Hz, 1H), 8.18-8.15 (m, 2H), 7.32 (d, J = 7.1 Hz, 1H), 4.20 (d, J = 7.1 Hz, 1H), 3.46 (t, J = 5.8 Hz, 2H), 3.19 (s, 3H), 3.10 - 3.06 (m, 1H), 2.82 - 2.78 (m, 1H), 2.57 - 2.50 (m, 2H), 2.11-1.95 (m, 3H), 1.71-1.63 (m, 2H)and 1.48 - 1.35 (m, lH)ppm. LCMS RT = 1.7 (M+l) 405.4, (M-l) 403.4.

669 [00510] (S)-2-(3-(2-(5-chloro-l/7-pynOlo[2,3-£lpyridin-3-yl)~5-fluoropyriniidin-4-ylamino)piperidin-l -yl)ethanenitrile (669). !H NMR (300 MHz, ί/6-DMSO) δ 12.31 (s, 1H), 8.69 (d, /= 2.4 Hz, 1H), 8.28 (d,/ = 2.4 Hz, 1H), 8.19 - 8.17 (m, 2H), 7.47 (d, /= 7.7 Hz, 1H), 4.30 - 4.20 (m, 1H), 3.80 (s, 2H), 3.07 - 3.03 (m, 1H), 2.82 - 2.73 (m, 1H), 2.29 - 2.10 (m, 2H), 2.05 - 1.96 (m, 1H), 1.87 - 1.65 (m, 2H) and 1.49 - 1.40 (m, 1H) ppm.; LCMS RT = 2.3 (M+l) 386.1, (M-l) 384.2.

General Scheme 4

(a) 1H-imidazole-2-carbaldehyde, Na(OAc)3BH, HOAc, 1,2-dichloroethane, 60 °C (b) 1N UOH, THF, microwave, 120 DC, 10 min [00511] Formation of (S)-iV-(l-((li/-imidazol-2-yl)methyl)piperidiii-3-yl)-2-(5-chloro-l-tosyl-l/f-pyrrolo[2,3-/?]pyridin-3-yi)-5“fluoropyrimidin-4-amine (4a).

To a solution of 2-[5-chloro-l-(/?-tolylsulfonyl)pynOlo[5,4-b]pyridin-3-yl]-5-fluoiO-Ar-[(3S)-3-piperidyl]pyrimidin-4-amine, lc, (0.16 g, 0.32 mmol) in 1,2-dichloroethanc (2 mL) was added l/f-imidazole-2-carbaldehyde (0.03 g, 0.36 mmol) followed by 2 drops of acetic acid and Na(OAc)3BH (0.10 g, 0.49 mmol). The reaction mixture was heated at 60 "C for 18 h. The mixture was cooled to room temperature and diluted with aqueous saturated NaHC03 solution. The aqueous phase was extracted twice with EtOAc. The combined organic phases were dried (MgSCri), filtered and concentrated in vacuo. The crude residue was purified via silica gel chromatography (0-20% MeOH/CE^Ch) to afford the product, 4a. lH NMR (300 MHz, 76-DMSO) δ 11.83 (s, 1H), 8.75 (d, ,7= 2.4 Hz, 1H), 8.48 (d, ./= 2.4 Hz, 1H), 8.41 (s, 1H), 8.25 (d, 7 = 3.8 Hz, 1H), 8.07 (d, 7 = 8.3 Hz, 2H), 7.56 (d, 7 = 8.2 Hz, 1H), 7.44 (d, 7= 8.2 Hz, 2H), 7.00 - 6.80 (m, 2H), 4.22 (m, 1H), 3.58 (dd, 7= 18.9, 13.8 Hz, 2H), 2.95 (m, 1H), 2.75 - 2.72 (m, 1H), 2.36 (s, 3H), 2.16 - 2.04 (m, 2H), 1.99 - 1.93 (m, 1H), 1.78 - 1.55 (m, 2H) and 1.45 - 1.30 (m, 1H) ppm.

[00512] Formation of (S)-Ar-(l-((li/-imidazol-2-yl)methyl)piperidin-3-yl)-2-(5-chloro-17/-pyrrolo[2,3-A]pyridin-3-yl)-5-fluoropyrimidin-4-amine (589).

To a solution of 2-[5-chIoro-l-(p-tolylsuIfonyI)pyrrolo[2,3-b]pyridin-3-yl]-5-fIuoro-77-[(3S)-l-(177-imidazol-2-ylmethyl)-3-piperidyl]pyrimidin-4-amine, 4a, (0.08 g, 0.13 mmol) in THF (2.5 mL) was added 1M LiOH (0.67 mL, 0.65 mmol) solution. The reaction mixture was heated in microwave at 120 °C for 10 minutes. The mixture was cooled to room temperature and diluted with brine. The aqueous phase was extracted with CH2CI2, then twice with 20% isopropanol/ CH2CI2. The combined organic phases were dried (MgS04), filtered and concentrated in vacuo to afford the desired product, 589, as a white solid. *H NMR (300 MHz, dd-DMSO) δ 8.77 (d, 7 = 2.4 Hz, 1H), 8.48 (d, 7= 2.4 Hz, 1H), 8.42 (s, 1H), 8.27 (d, 7= 3.9 Hz, 1H), 8.05 (d, 7= 8.4 Hz, 2H), 7.62 (d, 7= 7.5 Hz, 1H), 7.44 (d, 7= 8.2 Hz, 2H), 4.17 (m, 1H), 3.30 - 3.18 (m, 3H), 2.90 (m, 1H), 2.44 - 2.32 (m, 2H), 2.35 (s, 3H), 1.95 (m, 1H), 1.72 - 1.57 (m, 2H) and 1.51 - 1.40 (m, 1H) ppm. LCMSRT= 1.6 (M+l) 427.4.

[00513] Other analogs which can be prepared in the same manner as 589:

[00514] A-(l-((Il/-imidazol-5-yl)methyl)piperiilin-3-y])-2-(5-chloro-l//-pyrrolo[2,3-b\pyridin-3-yl)-5-fluor opyrimidin-4-amine (594). lH NMR (300 MHz, ί/6-DMSO) 8 12.31 (s, 1H), 11.86 - 11.77 (m, 1H), 8.70 (d, J = 2.2 Hz, 1H), 8.28 (d, ./= 2.4 Hz, 1H), 8.15 (d, ./ = 3.9 Hz, 1H), 8.10 (d, J= 2.5 Hz, 1H), 7.54 (s, 1H), 7.31 (d, J= 7.6 Hz, 1H), 6.87 (s, 1H), 4.19 (m, 1H), 3.57 (d, J= 13.8 Hz, 1H), 3.48 (d, ,/ = 13.8 Hz, 1H), 3.04 (d, ,/= 8.3 Hz, 1H), 2.80 (d,7= 10.4 Hz, 1H), 2.10 - 1.90 (m, 3H), 1.72 - 1.62 (m, 2H) and 1.51 - 1.35 (m, 1H) ppm; LCMS RT = 1.6 (M+l) 427.4, (M-l) 425.4.

General Scheme 5A

(a) /erf-butyl (35)-3-aminopiperidine-1 -carboxylate, 'Pr2NEt base, 2-propanol, 80 °C (b) 5-chloro-l-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine, DME/H20, K2CO3, tetrakis triphenylphosphinepalladinm(0), 90 °C (c) NaOMe / MeOH (d) isopropanol/HCl (e) methanesulfonyl chloride, !Ργ2ΝΕϊ, CH2C12/DMF

[00515] Formation of tert-butyl (3S)-3-[(2-chloro-5-fluoro-pyrimidin-4-yl)amin 0] pip eridine- l-carb oxyl ate (5a).

To a solution of tert-butyl (35)-3-aminopiperidine-l-carboxylate (8.1 g, 40.4 mmol) and 2,4-dichloiO-5-fluoro-pyrimidine (6.6 g, 39.8 mmol) in isopropanol (80 mL) was added yVjV-diisopropyl-yV-ethylamine (9.0 mL, 51.7 mmol). The reaction mixture was warmed to 80 °C and stirred for 17 hours. All volatiles were removed at reduced pressure and the residue was dissolved in EtOAc. The organic layer was partitioned with water and the layers were separated. The organic phase was washed with brine, dried (MgSCL), filtered and concentrated in vacuo. The resulting residue was dissolved in CH2CI2 and purified by silica gel chromatography (0 - 50% EtOAc /Hexanes) to afford the desired product, 5a. LCMS RT = 3.3 (M+l) 331.1.

[00516] Formation of tert-butyl (3S)-3-[[2-[5-chloro-l-(p-tolylsuIfonyl)pyrrolo[5,4-b]pyridin“3-yl]-5-fluoro-pyriinidin-4-yl]amino]piperidine-l-carboxylate (lb).

To a solution of 5-chloro-l-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine (1.8 g, 4.2 mmol) and teri-butyl (3S)-3-[(2-chIoro-5-fluoro-pyrimidin-4-yl)amino]piperidine-1-carboxylate, 5a, (1.2 g, 3.7 mmol) in DME (15 mL) and H20 (5 mL) was added K2CO3 (1.7 g, 12.1 mmol). The mixture was purged with nitrogen for 15 min. To the mixture was added tetrakis triphenylphosphine palladium(O) (0.2 g, 0.2 mmol) and the reaction mixture was heated at 90 °C for 3 days. The reaction was cooled down to room temperature and then diluted with EtOAc / H2O. The layers were separated and the organic phase was washed with brine, dried (MgS04), filtered and evaporated to dryness. The resulting residue was dissolved in CH2CI2 and purified by silica gel chromatography (0 - 100 % EtOAc /Hexanes) to afford the desired product, lb. LCMS RT = 4.6 (M+l) 601.2.

[00517] Formation of teri-butyl (3^)-3-][2-(5-chloro-l//-pyrrolo[5,4-b]pyritlin-3-yl)-5-fluoro-pyrimidin-4-yl]amino]piperidine-l-carboxylate (2b).

To a solution of tert-butyl (35)-3-[[2-[5-chloro-l-(p-tolylsulfonyl)pyrrolo[5,4-b]pyridin-3-yI]-5-fluoro-pyrimidin-4-yl]amino]pipcridine-l-carboxylate, lb, (0.93 g, 1.55 mmol) in methanol (10 mL) was added sodium methoxide (10 mL of 1M solution). The reaction mixture was warmed to 45 °C. After stirring for 30 minutes the reaction was to cooled to room temperature and quenched by additon into water. The mixture was diluted with EtOAc and the layers were separated. The organic phase was washed with brine, dried (MgS04), filtered and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (0 -100% EtOAc/Hexanes) to afford the desired product, 2b. LCMS RT = 2.8 (M+l) 447.2.

[00518] Formation of (5>2-(5-chloro4i/-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-iV-(piperidin-3-yl)pyrirnidin-4-amine(5b).

To a suspension of ten-butyl (3S)-3-[[2-(5-chloro-l#-pyrrolo[5,4-b]pyridin-3-yI)-5-fluoro-pyrimidin-4-yl]amino]piperidine-l-carboxylate, 2b, (0.45 g, 1.01 mmol) in isopropanol (3 mL) was added propan-2-ol hydrochloride (1.5 mL of 5M solution, 7.500 mmol). The reaction mixture was warmed to 80 °C and stirred for 3 hours. The mixture was cooled to room temperature and all volatiles were removed at reduced pressure. The resulting crude product, 5b, was used without further purification. LCMS RT= 1.5 (M+l) 347.1.

[00519] Formation of (5r)-2-(5-chloro-l//-pyrrolo[2,3-b]pyridin-3-yl)-5-nuoro-A-(l-(methylsulfonyl)piperidin-3-yl)pyrimidin-4-amine (389).

To a solution of (6>2-(5-chloro-l/f-pynOlo[2,3-b]pyridin-3“yl)-5-fluoro-A-(piperidin-3-yl)pyrimidin-4-amine hydrochloride, 5b, (0.04 g, 0.11 mmol ) in CH2CI2 (1.4 mL) and DMF (0.30 mL) was added Ar,A-diisopropyl-A'-ethylamin.c (0.30 mL, 1.70 mmol) followed by methanesulfonyl chloride (0.02 g. 0.20 mmol). The reaction mixture was allowed to stir at room temperature for 17 hours. The mixture was concentrated in vacuo, dissolved in 1 mL of DMSO and purified by preparatory HPLC (0.1% ammonium formate-ΗίΟ/acetonitrile) to afford the desired product, 389. ” LCMS RT = 1.8 (M+l) 425.3.

[00520] Other analogs that can be prepared in the same manner as 389:

393 390 [00521] (S)-2-(5-chloro-17/-pyrrolo[2,3-/>]pyndin-3-yl)-A-(l-(ethylsuIfonyl)piperidin-3-yl)“5-fluoropyrimidm-4-amine (393). LCMS RT = 1.8 (M+l) 439.3.

[00522] (,S')-AT-(l-(butylsulfonyl)piperidin-3-yl)-2-(5-chloro-l//-pyrrolo[2,3-6]pyridm-3-yl)-5-fluoropyriniidin-4-arnine (390). LCMS RT = 2.1 (M+l) 467.3.

391 394 [00523] (5)-2-(5-cliloro-l//-pyrrolo[2,3-/>]pyridin-3-yl)-iV-(l-(cyclopropyIsulfonyl)piperidm-3-yI)-5-fluoropyrimidin-4-amine (391). LCMS RT = 1.9 (M+l) 451.3.

[00524] (5)-2-(5-chloro-lLr-pyrrolo[2,3-/;[pyridin-3-yl)-5-fluorowV-(l-(isopropylsulfonyl)-piperidin-3-yl)pyrimidin-4-amine (394). LCMS RT = 1.9 (M+l) 453.3.

392 [00525] (,S)-2-(5-chloro-1//-pyrrolo[2,3-/>]pyridin-3-yl)wV-(l-(cycIopentylmethyIsulfonyl)piperidin-3-yl)-5-fluoropyrimidin-4-amine (392). LCMS RT = 2.3 (M+l) 493.5.

General Scheme 5B

5c 316 |00526] Formation of (R)-2-(5-chIoro-l//-pyrroloI2,3-/r|pyridin-3-yl)-5-fluoro-/V-(l-(propylsulfoiiyl)piperidin-3-y l)pyrimidin-4-amine (316).

To a solution of 2-(5-chloro-li?-pyrrolo[2,3“i)]pyridm-3-yl)-5-fluoro-JV-(piperidin-3-yl)pyrimidin-4-amine, 5c, (0.40 g, 1.15 mmol) in 10:1 mixture of CH2CI2/DMF (8 mL) was added 'P^NEt (0.60 mL, 3.46 mmol) followed by 1-propanesulfonyl chloride (0.13 mL, 1.15 mmol). The reaction mixture was stirred at room temperature for 5 hours. The resulting residue was purified by preparatory HPLC (0. l%TFA-H20/acetonitrile) to afford the desired product, 316. LCMS RT = 2.5 (M+l) 453.3.

[00527] Other analogs that can be prepared in the same manner as 316:

321 322 306 [00528] (jR)-2-(5-chloro-l//-pyrrolo[2,3-6]pyridin-3-yl)-/V-(l -(ethyIsulfony])piperidin-3-yl)-5-fluo ropy rimidin-4-amine (321). LCMS RT = 2.7 (M+l) 439.1. 100529] (K)-2-(5-chloro-l//-pyrroIo[2,3-A]pyridin-3-yl)-5-fluoro-iV-(l-(isopropylsulfonyl)-piperidin-3-y])pyrimidin-4-amine (322). LCMS RT = 2.9 (M+l) 453.1.

[00530] (S)-2-(5-chloro-l//-pyrrolo[2,3-6]pyridin-3“yl)-5-fluoro-A'-(l-(pr opylsulfonyl)-piper idin-3-yl)py rimidin-4-amine (306). LCMS RT = 2.9 (M+l) 453.2.

General Scheme 5C

(a) cyclobutanecarbonyl chloride, ‘PrjNEt, CtLCfa/DMF

[00531] Formation of (5)-(3-(2-(5-chloro-lii-pyrrolo[2,3“b]pyridm-3-yl)-5-fluoropyrimidin-4-ylamino)piperidin-l-yI)(cyclobutyl)methanone (395).

To a solution of (,S)-2-(5-chIoro-l//-pyrrolo[2,3-b]pyridin-3-y])-5-fluorO-/vr-(piperidin-3-yl)pyrimidiii-4-amine hydrochloride, 5b, (0.04 g, 0.11 mmol ) in CH2CI2 (1.40 mL) and DMF (300 μ was added A^/V-diisopropyl-vV-ethylamine (0.30 mL, 1.70 mmol) followed fay cyclobutanecarbonyl chloride (0.01 g. 0.12 mmol). The reaction mixture was allowed to stir at room temperature for 17 hours. The mixture was concentrated in vacuo, dissolved in 1 mL of DMSO and purified by preparatory HPLC (0.1% ammonium formate-LLO/acetonitrile) to afford the desired product, 395. LCMS RT = 1.9 (M+l) 429.3.

[00532] Other analogs that can be prepared in the same manner as 395:

[00533] (,5)-1-(3-(2-(5-chloro-l//-pyrrolo[2,3-/>]pyridin-3-yI)-5-fluoropyrimidin~4-ylamino)piperidin-l-yl)propan-l-one (435). LCMS RT = 1.8 (M+l) 403.4.

[00534] (5)-l-(3-(2-(5-chloro-U7-pyrrolo[2,3-A]pyridin-3-yI)-5-fluoropyrimidin-4-yla mino)pip eridin-l-yl)-2-methylprop an-l-one (436) LCMS RT= 1.9 (M+l) 417.4.

[00535] (5)-l-(3“(2-(5-chloro-l H-py r rolo [2,3-Z>] py r idin-3-yl)-5-fluo r opy rimidin-4-ylamino)piperidin-l-yl)-2,2-dimethylpropan-l-one(437) LCMS RT = 2.0 (M+l) 431.4.

[00536] (5)-(3-(2-(5-chloro-lif-pyrrolo[2,3-i>]pyridin-3“yI)-5-fiuoropyrimidiii-4-ylamino)piperidin-X-yl)(cycIopropyl)methanone (451) LCMS RT = 1.8 (M+l) 415.4.

[00537] (5)-l-(3“(2-(5-chloro-lif-pyrrolo[2,3-A]pyridin-3-yl)-5-fluoropyrimidin-4-yla mino)p iperidin-1 -yl)-3-methoxyp ropan-l-one (396) LCMS RT= 1.7 (M+l) 433.3.

[00538] (S)-l-(3-(2-(5~chloro-li7-pyirolo[2,3-A]pyridin-3-y])-5-fIuoropyrimidin-4-ylamino)piperidin-l-yl)ethanone (434) LCMS RT = 1.6 (M+l) 389.4.

[00539] CR)-l-(3-(2-(5-chloro-12/-pyrrolo[2,3-/?]pyridin-3-yl)-5-fluoropyrimidiii-4-yla mino)p iperidin-l-yl)-3-methylbutan-l-one (318) LCMS RT = 2.9 (M+l) 431.1.

[00540] (l?)-(3-(2-(5-chloro-l//-pyrrolo[2,3-6jpyndin-3-yl)-5-fluoropyrimidin-4-ylamino)piperidin-l-yl)(cyclopropyl)methanone (317) LCMS RT = 2.7 (M+l) 415.1.

[00541] (JR)-l-(3-(2-(5-chloro-l//-pyrro]o[2,3-A]pyrid)n-3-yl)-5-fIuoropyriniitliii-4-yIammo)piperidin-l-yl)-3-methoxypropan-l-one (320) LCMS RT = 2.5 (M+l) 433.1.

[00542] (JffK3-(2-(5-chloro-l^pyrrolo[2,3-*]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)pip erid in-l-yl) (cy clob utyl)methanone (319) LCMS RT = 2.8 (M+l) 429.1.

[00543] C5)-l-(3-(2-(5-chloro-17/-pyrrolo[2,3-Z>Jpyridm-3-y])-5-fluoropyrimidin-4-ylamino)piperidin-l-yl)-3-niethylbiitan-l“One (332) LCMS RT = 2.0 (M+l) 431.2.

[00544] (i)-l-(3“(2“(5-chloro-l//-pyrrolo[2,3-A]pyridin-3-yl)pyrlmidin-4-ylamino)piperidin-l~yl)ethanone (485) LCMS RT = 1.9 (M+l) 371.5.

[00545] (5)-1 -(3-(2-(5-chloro-l//-pyr r olo [2,3-^] pyridin-3-yl)-5-fluoropy ri midin-4-ylamino)piperidin-l-yl)-2-methoxyethanone (486) LCMS RT = 1.9 (M+l) 401.5.

[00546] (5)-methyl 4-(3-(2-(5-chloro-l//-pyrroio[2,3-5]pyridm-3-yl)pyrimidin-4-ylamino)piperidin-l-yl)-4-oxobutanoate (487) LCMS RT = 2.0 (M+l) 443.9.

|00547] (5)-l-(3-(2-(5-chIoro-lf/-pyrroloI2,3-Z>lpyridin-3-yl)-5-fluoropyrimLtlin-4- ylamino)piperidin-l-yl)-3-methoxypropan-l-one (488) LCMSRT= 1.9 (M+l) 415.5.

[00548] (5)-l-(3-(2-(5-chk>ro-l//-pyrro]o[2,3-6]pyridin-3-yl)pyrimLdin-4-yIamino)piperidin-l-yl)-3-methylbutan-l-one (489) LCMS RT = 2.1 (M+l) 413.5.

General Scheme 5D

(a) l-methylcyclopropane-l -carboxylic acid, EDAC-HC1, HOBt, 'P^NEt, CH2CI2/DMF

[00549] Formation of (5)-(3-(2-(5-chloro-i/i-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-y]amino)piperidin-l-yl)(l-methylcyclopropyl)methanone (445)

To a solution of (5,)-2-(5-chloro-i/-/-pynOlo[2,3-b]pyridin-3-yl)-5-fluoro-.A/-(piperidin-3-yl)pyrimidin-4-amine hydrochloride, 5b, (0.04 g, 0.10 mmol) in CH2CI2 (1.4 mL) and DMF (0.3 mL) was added AW-diisopropyl-W-ethylamine (0.3 mL, 1.72 mmol), followed by 3-(ethyliminomethylcncaminoj-/f,;V-dimethyl-propan-l-amine hydrochloride (0.02 g, 0.12 mmol), 1-hydroxybenzotriazole hydrate (0.02 g, 0.12 mmol) and 1-methylcyclopropane-1-carboxylic acid (0.01 g, 0.12 mmol). The mixture was concentrated in vacuo, dissolved in 1 mL of DMSO and purified by preparatory HPLC (0.1% ammonium formate-ELO/acetonitrile) to afford the desired product, 445. LCMS RT = 2.1 (M+l) 429.5.

[00550] Analogs that can be prepared in the same manner as 445:

[00551] (5)-(3-(2-(5-chloro-lff-pyrrolo[2,3-Z>]pyridin-3-yi)-5-fluoropyrimidin-4- ylamino)piperidin-l-yl)(3-methyloxetan-3-yl)methanone (444) LCMS RT = 1.7 (M+l) 445.4.

General Scheme 5E

(a) isocyanatopropane, 'Pr.NEt, CEOCE/DME

[00552] Formation of (5>3-(2-(5-ch Ioro-1//-pyrrolo [2,3-b]pyridin-3-y 1)-5-fluoropyrimidin-4-ylamino)-N-isopropylpiperidine-l-carboxamide (439).

To a solution of (S)-2-(5-chloro-17/-pyiTolo[2,3-b]pyridin-3-yl)-5-fluoiO-Ar-(piperidin-3-yI)pyrimidin-4-amine hydrochloride, 5b, (0.042 g, 0.100 mmol) in CH2CI2 (1.4 mL) and DMF (0.3 mL) was added AryV-diisopropyl-/V-cthylamine (0.300 mL, 1.720 mmol) followed by isocyanatopropane (0.120 mmol). The reaction mixture was stirred at room temperature for 17 hours. The mixture was concentrated in vacuo, dissolved in 1 mL of DMSO and purified by preparatory HPLC (0.1% ammonium formate-FLO/acetonitrile) to afford the desired product, 439. LCMS RT = 1.8 (M+l) 432.4.

[00553] Other analogs that can be prepared in the same manner as 439:

[00554] (5)“3“(2“(5-chloro-lif-pyrrolo [2,3-6] pyridin-3-y l)-5-fluoropyrimidin-4-ylaraino)-lV-ethyIpiperidine-l-carboxamide (438). LCMS RT = 1.7 (M+l) 418.4.

[00555] Formation of 3-(2-(5-chloro-l/7-pyrrolo [2,3-6] pyridin-3-y 1)-5-iluoropyrimidin-4-ylamino)-lV-propylpiperidine-l-carboxaimde (196).

To a solution of 2-(5-chioro-17i-pyrrolo[2,3-Zj]pyridin-3-yl)-5-fluoro-Ar-(piperidin-3-yl)pyrimidin-4-amine, 5b, (0.020 g, 0.058 mmol) in 1:1 mixture of CThCL/pyridine (2 mL) was added propylisocyanate (0.005 mL, 0.058 mmol). The reaction mixture was stirred at room temperature for 12 hours. The resulting residue was purified by preparatory HPLC (0.1%TFA-H2O/acetonitrile) to afford the desired product, 196. LCMS RT = 2.6 (M+l) 432.1, (M-l) 430.1.

[00556] (5)”3-(2-(5-chloro-liy-pyrrolo[2,3-6]pyridin-3-yl)-5-fluoropyriinidiii-4” ylamino)-Ar-propylpiperidine-l-carboxamide (324). LCMS RT = 2.6 (M+l) 432.2.

[00557] (5)-iV-butyl-3-(2-(5-chloro-l£r-pyrrolo[2,3-A]pyridin-3-yl)-5“ fIuoropyrimidin-4-ylamino)piperidine-l-carboxamide (323). LCMS RT = 2.7 (M+l) 446.2.

[00558] (S)-3-(2-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyriimdin-4-ylamino)piperidine-l-carboxamide (507). LCMS (TFA buffer): Rt 1.69 min, ES+ 390.

General Scheme 5F

(a) methylchloro formate, TrjNEl, CHjClj/DMF

[00559] Formation of (S>methyl 3-(2-(5-ch]oro-l//-pyrrolo[2,3-/>]pyridin-3-yI)-5-fluo r opy rimid in-4-ylamino)piperidin e-l-carboxylate (440).

To a solution of (S)-2-(5-chloiO-l/7-pyn'olo[2,3-b]pyridin-3-yl)-5-fluoro-7v-(piperidin-3-yI)pyrimidin-4-aminc hydrochloride, 5b, (0.042 g, 0.100 mmol) in CH2CI2 (1.4 mL) and DMF (0.3 mL) was added A(A'-diisopropyl-/V-etliylamine (0.300 mL, 1.720 mmol) followed by methyl chloroformate (0.009 g, 0.120 mmol). The reaction mixture was stirred at room temperature for 17 hours. The mixture was concentrated in vacuo, dissolved in 1 mL of DMSO and purified by preparatory HPLC (0.1% ammonium formate-H20/aeetonitrile) to afford the desired product, 440. LCMS RT = 1.8 (M+l) 405.4.

[00560] Analogs that can be prepared in the same manner as 440:

[00561] (S)-ethyI 3-(2-(5-chIoro-l//-py rrolo [2,3-6] pyridin-3-y l)-5-fluoropyrimidin- 4-ylamino)piperidine-l-carboxyIate (441). LCMS RT = 1.9 (M+l) 419.4.

[00562] (5)-isopropyl 3-(2-(5-chloro-l//-pyrrolo [2,3-6] pyridin-3-y 1)-5-fluoropyrimidin-4-ylamino)piperidine-l-carboxylate (442). LCMS RT = 2.1 (M+l) 433.4.

General Scheme 5G

(a) (2,5-dioxopyrrolidin-l-yl) [(3S)-tetrahydrofuran-3-yl] carbonate, ’Pr2NEt, CUX’WDMF

[00563] Formation of (S)-((£)-tetrahydrofuran-3-yl) 3-(2-(5-0111(^0-1/6-pyrroIo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-yIamino)piperidine-l-carboxyIate (443).

To a solution of (S)-2-(5-chloro-l/7-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-jV-(piperidin-3-yl)pyrimidin-4-amine hydrochloride, 5b, (0.042 g, 0.100 mmol) in CH2C12 (1.4 mL) and DMF (0.3 mL) was added N,;V-diisopropyl-yV-ethy]amine (0.300 mL, 1.720 mmol) followed by (2,5-dioxopyrrolidin-l-yl) ](3S)-tetrahydrofuran-3-yl] carbonate (0.028 g, 0.120 mmol). The reaction mixture was stirred at room temperature for 17 hours. The mixture was concentrated in vacuo, dissolved in 1 mL of DMSO and purified by preparatory HPLC (0.1% ammonium formate-HLO/acetonitrile) to afford the desired product, 443. LCMS RT = 1.8 (M+l) 463.3.

General Scheme 6A

(a) 'Pr^NEt, THF (b) Pd(PPh3)4, 2M Na2C03 80 “C (c) 4N HCI/dioxane, MeOH, 80 "C (d) (S)-2,5-dioxopyrrolidin-1-yl t8trahydrofuran-3-yl carbonate, !Pr2NEt, THF (e) 25% NaOMe/MeOH or 1M LiOH, 150 °C, microwave, 10 min.

[00564] Formation of teri-butyl 3-(2-chloro-5-fluoropyrimidin-4-ylamino)-cyclobutylcarbamate (6a). A mixture of 2,4-dichloro-5-fluoro-pyrimidine (0.97 g, 5.81 mmol) and ‘P^NEt (2.53 mL, 14.50 mmol) in THF (50 mL) was treated with tm-butyl 3-aminoazetidine-l-carboxylate (1.00 g, 5.81 mmol) and stirred at room temperature until complete by LCMS. The mixture was concentrated to dryness then diluted with water and extracted with dichloromethane. The combined organic layers were dried over NajSCL and concentrated in vacuo to afford an oil that was purified by silica gel chromatography (0-100% petroleum ether/EtOAc gradient). Removal of the solvent under reduced pressure afforded 3.36g (89% yield) of a white solid after vacuum drying. LCMS: RT = 3.2 min, ES+ 303.

[00565] Formation of tert-butyl 3-(2-(5-chloro-l-tosyl-l#-pyrrolo[2,3-b]pyridin-3-yI)-5-fluoropyrimidin-4-yIamino)azetidine-l-carboxylate (6b). A solution of /er/-butyl 3-(2-chloro-5-fluoropyrimidin-4-ylamino)-cyclobutylcarbamate, 6a, (0.39 g, 1.28 mmol) and 5-chloro-3-(4,4,5,5-tetramethyl-l,3,2-dioxaboroIan-2-yI)-l-tosyl-l//-pyrrolo[2,3-Z?]pyridine (0.60 g, 1.39 mmol) in DME (10 mL) and 2M Na2C03 (5 mL) was degassed with argon (3x vacuum and back fill) then treated with catalytic Pd(PPh3)4 and the mixture heated at 80 °C under argon. After 3h the solvent was concentrated to a reduced volume then diluted with EtOAc and filtered through florisil (40 mL pad) and washed with EtOAc. The solvent was concentrated in vacuo and die resulting dark residue purified with silica-gel chromatography (0-100% petroleum ether/EtOAc gradient) to afford 230 mg (32% yield) of 6b, as white-pink solid. LCMS: RT = 4.7 min, ES+ 573.

[00566] Formation of 7V-(azetidin-3-yl)-2-(5-chloro-l-tosyl-li/-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-amine hydrochloride (6c). A suspension of iert-butyl 3 -(2-(5-chloro-1 -tosy 1- 1/7-pyrrolo[2,3 -b] pyridin-3 -y 1)-5-fluoiOpyrimidin-4-ylamino)azctidinc-I-carboxylatc, 6b, (0,23 g, 0.40 mmol) in methanol (10 mL) was treated with 4N HCl/dioxane (5 mL, 20 mmol) then heated at 80 °C for 30 minutes. The solvent was removed and the residue dried under vacuum to afford 240mg of a solid that was used without purification. LCMS RT = 2.4 min, ES+ 473.

[00567] Formation of (S)-tetrahydrofuran-3-yI 3-(2-(5-chIoro-l//-pyrrolo[2,3-b]pyridin-3-y l)-5-fluo ropy rimidin-4-y lamin o)azetidine-l -carboxylate (422). A suspension of N-(azetidin-3-yl)-2-(5-chloro-I-tosyl- l//-pyriOlo[2,3-b]pyridin-3-yl)- 5-fluoropyrimidin-4-amine hydrochloride, 6c, (0.06 g, 0.11 mmol) in THF (1 mL) was treated with ‘P^NEt (0.30 mL, 1.70 mmol) then solid (5)-2,5-dioxopyrrolidin-l-yl tetrahydrofuran-3-yl carbonate (0.03 g, 0.11 mmol) was added. The resulting mixture was stirred for 2 hours at room temperature and then quenched with 200 pL of morpholine and evaporated to dryness to afford (5)-tetrahydrofuran-3-yl 3-(2-(5-chloro-l-tosy 1-1//-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)azetidme-l-carboxylate, 6d, which was used without purification. LCMS RT = 3.8 min, ES+ 588. (5)-tetrahy drofuran-3 -yl 3 -(2-(5-chloro-1 -tosyl-1 //-pyrrolo [2,3 -b]pyridin-3 -y 1)-5 - fluoropyrimidin-4-ylamino)azetidine-l-carboxylate, 6d, was dissolved in methanol (2 mL) and then treated with of 25% sodium methoxide/methanol (0.5 mL) and heated at 60 C in sealed tube. LCMS showed complete reaction after 10 minutes. The resulting solution was quenched with aqueous saturated NH4CI solution (0.5mL) then evaporated to dryness and the residue dissolved in DMSO and purified by reverse phase HPLC (ammonium formate buffer) to afford 25.9mg (55% yield) of the desired product, 422, as a solid. LCMS RT = 1.8 min, ES+433.

General Scheme 6B

[00568] Formation of 2-(5-chloro-l-tosyl-l//-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-iV-(l-(p r opylsuIfonyl)azetidin-3-y l)pyrimidin-4-amine (423).

To a stirred suspension of iV-(azetidin-3-yI)-2-(5-chloro-l-tosyl-l//-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-amine hydrochloride, 6c, (0.055 g, 0.110 mmol) in THF (1 mL) was added ‘PrjNEt (0.300 mL, 1.720 mmol) followed by propane-1-sulfonyl chloride (0.012 mL, 0.108 mmol). The resulting homogenous light yellow solution mixture was heated at 50 C for one hour at which time LCMS showed complete reaction. Morpholine (0.20 mL) was added and the solution evaporated to dryness. The resulting residue was dissolved in methanol (2 mL) then treated with 25% sodium methoxide/methanol (0.5 mL) and heated at 60 C in sealed tube for 10 minutes. The resulting solution was quenched with aqueous saturated NH4CI solution (0.5mL) then evaporated to dryness. The resulting residue was dissolved in DMSO and purified by reverse phase HPLC (ammonium formate buffer) to afford 19.8 mg (43% yield) of the desired product, 423, as a solid. LCMS RT = 2.6 min, ES+ 425.

[00569] Other analogs that can be prepared in a manner similar to 423:

[00570] Formation of 2-(5-chloro-l//-pyrrolo[2,3-b]pyridin-3-yl)-A-(l-(cyclopentyl-methylsulfonyl)azetidin-3-yl)-5-fluoropyrimidin-4-amine (469).

To a stirred solution of iV-(azetidin-3-yl)-2-(5-chloro-l-tosyl-l//-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-amine hydrochloride, 6c, (0.03 g, 0.06 mmol) in dichloromethane (1 mL) was added 'P^NEt (0.33 pL, 1.90 mmol) followed by cyclopentylmethanesulfonyl chloride (0.01 g, 0.06 mmol). The resulting mixture was stirred 30 minutes at room temperature at which time LCMS showed complete reaction. Morpholine (0.20 mL) was added and the solution evaporated to dryness. The resulting residue was dissolved in methanol (2 mL) then treated with 25% sodium methoxide/methanol (0.5 mL) and heated at 60 C in sealed tube for 10 minutes. The solution was quenched with aqueous saturated NH4CI solution (0.5mL) then evaporated to dryness. The resulting residue was dissolved in DMSO and purified by reverse phase HPLC (ammonium formate buffer) to afford 27.4 mg (88% yield) of the desired product, 469, as a solid. LCMS RT = 3.1 min, ES' 465.

[00571] Formation of l-(3-(2-(5-chloro-lff-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropy rimid in-4-ylamino)azetid in-l-yl)-2-meth oxy ethano ne (468).

According to the procedure for compound 469 using methoxyacetyl chloride afforded 11.7 mg (51% yield) of 468, as a white solid. LCMS RT= 1.6 min, ES+ 390.

[00572] Formation of 3-(2-(5-chIoro-l//-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamin o)azetidine-l -ca rb oxamide (512).

According to the procedure for compound 469 using 61 mg (0.11 mmol) of 6c and isocyanatotrimethylsilane (15.14 pL, 0.11 mmol) afforded 87mg (79% yield) of 512, as a white solid: LCMS RT = 2.4 min, ES+ 362.

General Scheme 7

(a)2,4-dichloro-5-fluoropyrimidine, 'Pr2NEt, THF (b) 5-chloro-3-{4,4,5,5-tetramethyl-1,3,2-dioxaboroIan-2-yl)-1-tosyl-1W-pyrrolo[2,3-£>]pyridine, Pd(PPh3)4, 2M Na2C03 90°C (c) 4N HCI/dioxane, MeOH, 80 °C; (d) methanesulfonyl chloride, !Pr2NEt, THF, RT (e) 25% NaOMe/MeOH or 1M LiOH, 150 ”C, microwave, 10 min.

[00573] Formation of (S)-tert-butyl 3-(2-chIoro-5-fluoropyrimidin-4-yla mino)py rrolidine-1 -ca rb oxy late (7 a).

To a mixture of 2,4-dichloro-5-fluoro-pyrimidine (1.75 g, 10.48 mmol) and 'P^NEt (3.27 mL, 18.78 mmol) in THF (50 mL) was added iert-butyl (3S)-3-aminopyrrolidine-l-carboxylate (1.83 mL, 10.48 mmol) in THF (2 mL). The resulting solution was allowed to stir at room temperature for 2 hours. The mixture was concentrated to dryness, diluted with dichloromethane and washed with water. The organic layer was dried over Na2SC>4 and concentrated in vacuo to afford 3.41g of 7a, as a white foamy solid. LCMS RT = 3.0 min. ES+ 317.

[00574] Formation of (5)-ter t-butyl 3-{2-(5-chloro-l-tosyl-li7-pyrrolo[2,3-b]pyridin-3-yI)-5-fluoropyrimidin-4-ylamino)pyrrolidine-l-carboxylate (7b). A solution of 5-chloro-l-(p-tolylsulfonyI)-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan- 2- yI)pyrrolo[2,3-b]pyridine (2.41 g, 5.60 mmol) and iert-butyl (3S)-3-[(2-chloro-5-fluoro-pyrimidin-4-yl)amino]pyrrolidine-l-carboxylate, 7a, (1.69 g, 5.30 mmol) in DME (34 mL) and 2M Na2CC>3 (8.5 mL) was degassed with nitrogen (5 min) then treated with Pd(PPhj)4 (0.31 g, 0.27 mmol) then heated at 90 C overnight. The resulting dark solution was filtered through florisil, washed with EtOAc then concentrated in vacuo. The resulting residue was purified by silica-gel chromatography (0-100%) petroleum ether: EtOAc gradient. Removal of the solvent under reduced pressure afforded 1.33g (42% yield) of a white solid after vacuum drying. LCMS RT = 4.4 min. ES+ 588.

[00575] Formation of 2-[5-chloro-l-(p-toIylsulfonyI)pyrrolo[2,3-b]pyridin-3-yl]-5-fluoro-/V-[(3S)-pyrrolidin-3-yl]pyrimidin-4-amine (7c). A solution of fert-butyl (35)-3-[[2-[5-chloro-l-(/?-tolylsulfonyI)pyrrolo[5,4-b]pyridin- 3- yl]-5-fluoro-pyrimidin-4-yl]amino]pyrrolidine-l-carboxyIate, 7b, (1.33 g, 2.27 mmol) in THF (25 mL) was treated with hydrogen chloride (12 mL of 4M solution in dioxane, 48.00 mmol) at room temperature. The reaction was then heated at 90 =C until LCMS showed reaction was complete. The mixture was concentrated to dryness then dried under vacuum to afford 1.04g (88% yield) of 7c, as a tan solid. LCMS RT = 2.3 min. ES+ 487.

[00576] Formation of (S)-2-(5-chloro-li/-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-iV-(l-(nietiiylsuIf'onyl)pyrrolidin-3-yl)pyrimidin-4-amme (398).

To a stirred suspension of 2-[5-cbloro-L(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-5-fhioro-N-[(3S)-pymolidin-3-yl]pyrimidin-4-amine hydrochloride, 7c, (0.05 g, 0.10 mmol) in THF (1 mL) was added ‘PiTNLt (0.10 mL, 0.57 mmol) followed by methanesulfonyl chloride (0.04 mL, 0.57 mmol). The resulting homogenous light yellow mixture was heated at 50 °C for one hour at which time LCMS showed complete reaction. Morpholine (0.20 mL) was added and the solution evaporated to dryness. The resulting residue was dissolved in methanol (2 mL) then treated with 25% sodium methoxide/methanol (0.5 mL) and heated at 60 °C in sealed tube until LCMS showed reaction was complete. The resulting solution was quenched with aqueous saturated NH4CI (0.5mL) then evaporated to dryness. The residue was dissolved in DMSO and purified by reverse phase HPLC (ammonium formate buffer) to afford 15.8 mg (37% yield) of 398, as a solid. LCMS RT = 1.7 min. ES+411.

[00577] Other analogs that can be prepared in a manner similar to 398:

[00578] Formation of (5)-2-(5-chIoro-li7-pyrrolo[2,3-b]pyridin-3-yl)-iV-(l-(etliylsulfonyl)pyrrolidin-3-yl)-5-fluoropyrimidin-4-amine (399).

According to the procedure for compound 398 using 50 mg (O.lOmmol) of 7c and ethanesulfonyl chloride (54 pL, 0.57 mmol) afforded 21.7mg (49% yield) of 399, as a solid. LCMS RT - 1.8 min. ES+ 425.

[00579] Formation of (A)-2-(5-chloro-l//-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-/V-(l-(isop ropylsulfonyl)pyrrolidin-3-yl)pyrimidin-4-amine (400).

According to the procedure for compound 398 using 2-propanesulfonyl chloride (82 mg, 0.57 mmol) afforded 17.9 mg (39% yield) of 400, as a solid. LCMS RT == 1.9 min. ES+ 439.

[00580] Formation of (S>2-(5-chloro-l/7-pyrrolo[2,3-b]pyridin-3-yl)-iV-(l-(cydopropyIsulfonyl)pyrrolidin-3-yl)-5-fluoropyrimidin“4-amine (401).

According to the procedure for compound 398 using cyclopropanesulfonyl chloride (81 mg, 0.57 mmol) afforded 17.1 mg (37% yield) of 401, as a solid. LCMS RT = 1.9 min. ES+ 437.

[00581] Formation of (S)-7V-(l-(butylsulfonyl)pyrrolidin-3-yl)-2-(5-chloro-lf/-pyrroIo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-amine (402).

According to the procedure for compound 398 using 1-butanesulfonyl chloride (90mg, 0,57 mmol) afforded 21 mg (45% yield) of 402, as a solid. LCMS RT = 2.1 min. ES1 453.

[00582] Formation of (5)-2-(5-chloro-lJff-pyrrolo[2,3-b]pyridin-3-yl)-N-(l-(cyclopentylsu]fonyl)pyrro]idin-3-yI)-5-fluoropyrimidin-4-amine (403).

According to the procedure for compound 398 using cyclopentanesulfonyl chloride (97 mg, 0.57 mmol) afforded 9.7 mg (20% yield) of 403, as a solid. LCMS RT = 2.1 min. ES+ 465.

100583] Formation of (S)-2-(5-chloro-l//-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-N-(l-(propylsulfonyI)pyrrolidin-3-yI)pyrimidin-4-amine (410).

According to the procedure for compound 398 using propylsulfonyl chloride (20 mg, 0,14 mmol) afforded 15.5 mg (36% yield) of 410, as a solid. LCMS RT = 2.0 min. ES+ 439.

[00584] Formation of (S)-2-(5-chloro-l//-pyrrolo[2,3-b]pyridin-3-yl)-N-(l-(cyclopentylmethylsulfonyl)pyrrolidin-3-yl)-5-fluoropyrimidin-4-amine (479).

According to the procedure for compound 398 using cyclop entylmethyl sulfonyl chloride (30 mg, 0.16 mmol) afforded 26.7 mg (58% yield) of 479, as a solid. LCMS RT = 2.3 min. ES+ 479.

[00585] Formation of (S)-methyl 3-(2-(5-chloro-l//-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropy rimidin-4-yla mino)py r rolidine-l-carb oxylate (476).

According to the procedure for compound 398 using methylchloroformate (20 mg, 0.21 mmol) afforded 13.6 mg (52% yield) of 476, as a trifluoroacetic acid salt after preparatory HPLC purification. LCMS (ammonium formate buffer) RT = 2.6 min. ES+ 391.

[00586] Formation of (5)-isopropyl 3-(2-(5-chloro-l//-pyrrolo[2,3-b]pyridin-3-yl)-5-flu oropy rimidin-4-ylamino)pyr rolidine-1 -carboxylate (477).

According to the procedure for compound 476 using isopropyl chloroformate (20mg, 0.21 mmol) afforded 11.3mg (42% yield) of 477, as a trifluoroacetic acid salt after preparatory HPLC purification. LCMS (ammonium formate buffer) RT = 2.0 min. ES+ 419.

[00587] Formation of (35)-(tetrahydrofuran-3-yl)methyl 3-(2-(5-chloro-l/f-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)pyrrolidine-l-carboxylate (484).

According to the procedure for compound 398 using 2,5-dioxopyrrolidin-l-yI (tetrahydrofuran-3-yl)methyl carbonate (0.023 g, 0.096 mmol) afforded 5.7 mg (10% yield) of 484, as a trifluoroacetic acid salt after preparatory HPLC purification. LCMS (ammonium formate buffer) RT = 2.6 min. ES+ 461.

[00588] Formation of ((5)-3-(2-(5-chloro-Lff-pyrroIo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)pyrrolidin-l-yl)(tetrahydrofuran-3-yl)methanone (478).

According to the procedure for compound 398 using tetrahydrofuran-3-carboxylic acid (35 mg, 0.30 mmol) afforded 22.2mg (52% yield) of 478, as a solid. LCMS (TFA buffer) RT = 1.6 min. ES+ 431.

[00589] Formation of (5)-l-(3-(2-(5-chloro-li/-pyrrolo[2,3-b]py ridin-3-yl)-5-fluoropyrimidin-4-ylamino)pyrrolidin-l-yl)ethanone (480).

According to the procedure for compound 398 using acetyl chloride (45 uL, 0.64 mmol) afforded 4.2 mg (18% yield) of 480, as a solid. LCMS (TFA buffer) RT = 1.6 min, ES+ 375.

[00590] Formation of (5)-l-(3-(2-(5-chloro-ltf-pyrrolo [2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylammo)pyrrolidm-l-y!)-2-methoxyethanone (481).

According to the procedure for compound 398 using methoxyacetyl chloride (50 mg, 0.46 mmol) afforded 8.6 mg (33% yield) of 481, as a solid. LCMS (TFA buffer) RT = 1.6 min, ES+ 405.

[00591] Formation of (5)-(3-(2-(5-chloro-li/-pyrrolo[2,3-Z>]pyridin-3-yl)-5- fluoropyrimidin-4-ylaimno)pyrrolidm-l-yl)(3-methyloxetan-3-yl)methanone (482).

According to the procedure for compound 398 using 3-methyloxetane-3-carboxylic acid (15 mg, 0.13 mmol) afforded 17.7 mg (42% yield) of 482, as a solid. LCMS (TFA buffer) RT =1.6 min, ES+ 431.

|00592] Formation of ((S)-3-(2-(5-chioro-Ii/-pyrrolo[2,3-/>]pyridin-3-yl)-5- iluoropyrimidin-4-ylamino)pyrrolidin-l-yl)(morpholin-2-yl)methanone (483).

According to the procedure for compound 398 using morpholine 2-carboxylic acid (25mg, 0.11 mmol) afforded 3.6mg (8% yield) of 483 as a solid. LCMS (TFA buffer): Rt 1.4 min, ES+ 446.

[00593] Using a procedure equivalent to that for the preparation of 7c, the other enantiomer (8a) can be obtained.

[00594] Analogs that can be prepared from compound 8a.

General Scheme 8

(a) (5)-2,5-dioxopyrrolidin-l-yl tetrahydrofuran-3-yl carbonate, 'Pr2NEt, THF, RT (b) 25% NaOMe/MeOH or 1M LiOH, 150°C, microwave, 10 min.

[00595] Formation of (/f)-((5)-tetrahydrofuran-3-yl) 3-(2-(5-chloro-l/f-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)pyrrolidine-l-carboxylate (424).

According to the procedure for compound 398 using (7?)-tert-butyl 3-aminopyiTolidine-l-carboxylate and (S)-2,5-dioxopyriOlidin-l-yl tetrahydrofuran-3-yl carbonate afforded 19.8mg (47% yield) of424 as a solid. LCMS (TFA buffer) RT = 1.8 min, ES+ 447.

[00596] Formation of (2f)-(3-(2-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin~4-ylammo)pyrrolidin-l-yl)(3-methyloxetan-3-yl)methanone (473).

According to the procedure for compound 482 using (/?)-2-(5-chloro-! -tosyl-1 //-pyitoI o [2,3 -b ]pyridin-3-yl)-5 -flu oro-lV-(pyrrolidin-3 -yl)pyrimidin-4-amine hydrochloride, 8a, and 3-methyloxetane-3-carboxylic acid (50 mg, 0.46 mmol) afforded 18.6 mg (44% yield) of 473, as a solid. LCMS (TFA buffer) RT = 1.6 min, ES+ 431.

[00597] Formation of (S)-2-(5-chloro-l//-pyrrolo[2,3-b]pyridin-3-yl)-N-(l-(cyclop ropylm ethyl)pyrrolidin-3-yl)-5-fluo ropyrimidin-4-amine (415). A solution of (iS)-2-(5-chloiO-l-tosyl-l/7-pyiTolo[2,3-Z?]pyridin-3-yl)-5-fluoro-A-(pyrroIidin-3-yI)pyrimidin-4-amine hydrochloride, 7c, (0.05 g, 0.10 mmol) in methanol (3 mL) was treated with cyclopropane carboxaldehyde (0.30 mmol), sodium cyanoborohydride (0.30 mmol) and potassium acetate (0.04 g, 0.30 mmol) then stirred at 60 C until the reaction was complete. Aqueous workup afforded an oil that was dissolved in methanol (2 mL) then treated with of 25% sodium methoxide/methanol (0.5 mL) and heated at 60 C in sealed tube. LCMS showed complete reaction. The resulting solution was quenched with aqueous saturated NFUCl solution (0.5mL) then evaporated to diyness and the residue dissolved in DMSO and purified by reverse phase HPLC (ammonium formate buffer) to afford 6.2mg (17% yield) of 415 as a solid. LCMS RT = 1.5 min, ES+ 387.

[00598] Formation of .V-(2-(5-chloro-l//-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-yl)-l-(methylsulfonyl)azepan-4-amine (496).

According to the procedure for compound 398 using methanesulfonyl chloride afforded the desired product, 496, as a solid. LCMSRT= 1.8 min, ES+439.

[00599] Formation of l-(4-(2-(5-chloro-l//-pyrrolo[2,3-b]pyridin-3-yl)-5-fIuoropyrimidin-4-ylamino)azepan-l-yl)ethanone (497).

According to the procedure for compound 398 using acetyl chloride afforded the desired product, 497, as a solid. LCMS RT = 1.7 min, ES+ 403.

[00600] Formation of methyl 4-(2-(5-chloro-lilr-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-yiammo)azepane-l-carboxylate(498).

According to the procedure for compound 398 using methyl chloroformate afforded the desired product, 498, as a solid. LCMS RT = 1.9 min, ES+ 419.

[00601] Formation of 4-(2-(5-chlorO"l//-pyrrolo[2,3-b]pyridin-3-yl)-5-iluoropyrimidin-4-ylamino)-/V,/V-dimethylazepane-l“Carboxamide (499).

According to the procedure for compound 398 using dimethyl carbamoyl chloride afforded desired product, 499, as a solid. LCMS RT= 1.8 min, ES+432.

[00602] Formation of 4-(2-(5-chloro-lJ¥-pyrrolo[2,3-b]pyridin-3-yl)-5-fluor opyrimidin-4-yla min o)azepane-l -ca rb oxamide (509).

According to the procedure for compound 398 using trimethylsilylisocyanate afforded desired product, 509, as a solid. LCMS RT = 1.6 min, ES+ 404.

[00603] Formation of 4-{2-(5-chloro-l/f“pyrroIo[2,3-/;]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)-A-methylazepane-l-carboxamide (506).

According to the procedure for compound 398 using methyl isocyanate afforded the desired product, 506, as a hydrochloride salt after treating with HCl/dioxane. LCMS RT = 2.1 min, ES+ 418.

General Scheme 11

11c 327 (a)‘Pr2NEt, THF (b) 5-chloro-l-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan- 2- yl)pyiTolo[2,3-b]pyridine, Pd(Ph3P)4, Na2C03, DME, 130 °C (c) HCl/dioxane, CH2C12 (d)

3- methoxypropanoyl chloride, ‘Pr2NEt, CH2C12/DMF

[00604] Formation of (ff)-teri-butyl 3-((2-chloro-5-f!uoropyrimidin-4-yIamino)methyI)-piperidine-l -carboxylate (11a).

To a solution of 2,4-dichloro-5-fluoropyrimidine (0.43 g, 2.59 mmol) and (R)-tert-butyl 3-(aminomethyl)piperidine-l-carboxylate (0.56 g, 2.59 mmol) in THF (50 mL) was added ‘PiyNEt (0.45 mL, 2.59 mmol). The reaction mixture was heated at 80 °C at for 8h. The solvent was concentrated under reduced pressure and the resulting residue was purified by silica gel chromatography (5-30% EtOAc/hexanes) to afford the desired product, 11a. LCMS (M+l)345.1.

[00605] Formation of (JR)-te/ t-butyl 3-((2-(5-chloro-l//-pyrrolo[2,3-/>]pyridin-3-yl)_5-fluoropyrimidin-4-ylamino)methyl)piperidine-l-carboxylate (lib)

To a degassed solution of 5-chloro-l-(p-toIylsulfonyl)-3-(4,4,5,5-tetrametliyl-l ,3,2-dioxaborolan-2 -yl)py milo[2,3-b]pyridine (0.71 g, 1.65 mmol), (RWe/V-butyl 3-((2-chloro-5-fluoropyrimidin-4-ylamino)methyl)-piperidine-l-carboxyIate, 11a, (1.19 g, 3.60 mmol) and aqueous K2C03 (2.48 mL of 2 M solution, 4.97 mmol) in THF (30 mL) was added bis(tri-i£?r/-butylphosphine)palladium(0) (0.17 g, 0.33 mmol). The reaction mixture was degassed for an additional 15 min. The mixture was stirred at room temperature for 4 hours, concentrated in vacuo, and the resulting crude residue was purified by silica gel chromatography (10%-80% EtOAc/hexanes) to afford the desired product, lib. LCMS (M+l) 461.4, (M-l) 460.7.

[00606] Formation of 2-(5-chloro-l”tosyl-12/-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-A-(piperidin-3-ylmethyl)pyrimidin-4-amine (1 lc).

To a solution of (7?)-ie/-/-butyl 3-((2-(5-chloro-l//-pyrroio[2,3-/)]pyridin-3-yi)-5-fluoropyrimidin-4-ylamino)mcthyl)piperidine-l-carboxylatc, lib, (0.13 g, 2.8 mmol) in 5% MeOH/CH2Cl2 was added 0.7 ml 4N solution of HCl/dioxane. The reaction mixture was stirred at room temperature for 12 hours. The resulting precipitate was filtered and used without further purification, LCMS (M+l) 361.1.

[00607] Formation of (2?)-l-(3-((2-(5-chloro-lff-pyrroio[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)piperidin-l-yl)-3-methoxypropan-l-one(327).

To a solution of 2-(5-chloro-l-tosyl-l//-pynOlo[2,3-/2]pyridin-3-yl)-5-fluoro-iV-(piperidin-3-ylmethyl)pyrimidin-4-amine, 11c, (0.04 g, 0.11 mmol) in a 10:1 mixture of CH2C12/DMF (1 raL) was added iPr2NEt (0.058 mL, 0.33 mmol) and 3-mcthoxypropanoyl chloride (0.02 g, 0.17 mmol). After 12 hours, the solvent was concentrated in vacuo and the resulting crude was and the crude was purified by preparatory HPLC (0.1%TFA-H20/acetonitrile) to afford the desired product, 327. LCMS (M+l) 447.3.

[00608] Other analogs that can be prepared in the same manner as 327:

[00609] (fl)-(3-((2-(5-chloro-li/-pyrrolo[2,3-6]pyridin-3-yI)-5-fluoropyrimidin-4-ylamino)methyl)piperidin~l-yl)(2-methoxyphenyl)methanone (113). LCMS RT = 2.9 (M+l) 479.4, (M-l) 477.6.

[00610] (R)~ 1 -(3-((2-(5-chlor o-l//-py rrolo| 2,3-6] py r idin-3-y l)-5-fluor opy rimid in- 4-ylamino)methyl)piperidm-l-yl)-2-(thiophen-2-yl)ethanone (104). LCMS RT = 2.8 (M+l) 485.3, (M-l) 483.4.

[00611] (2?)-(3-((2-(5-chloro-lfi-py rr olo [2,3 -b) py ridin-3-y I)-5-fluor opyrimidin-4-ylaimno)methyI)piperidin-l-yl)(3,5-difluorophenyl)methanone (108). LCMS RT = 2.1 (M+l) 501.3.

[00612] (S)-1 -(3-((2-(5-chlor o-l/i-py rr olo [2,3-6]pyridin-3-yl)-5-flu oropy rimidin- 4- y la mino)m eth yl) pip eridin- l-yl)ethanone(lll). LCMS RT == 2.5 (M+l) 403.4.

[00613] (^)-benzo[6]thiophen-2-yl(3-((2-(5-chloro-l//-pyrro]o[2,3-6]pyridin-3-yl)- 5- fluoropyrimidin-4-ylamino)methyl)piperidin-l-yl)methanone (107). LCMS RT = 3.2 (M+l) 521.3.

[00614] (5,)-l-(3-((2-(5-chiorO“l//-pyrrolo[2,3-6]pyridin-3-yl)-5-fluoropyrimidin-4-yla mino)methyl)piperidin-l-yl)ethan one (37). LCMS RT = 2.5 (M+l) 403.3.

[00615] (Jff)-(3-((2-(5-chloro-l//-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyriniidin-4-ylamino)methyl)piperidiii“l-yl)(furan“2“yl)ineihanone (102). LCMS RT = 2.7 (M+l) 455.3, (M-l) 453.3.

[00616] (Ji)~2-(benzyIoxy)-l-(3-((2-(5-chloro-l//-pyrroIoI2,3-A]pyridiii-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)piperidin-l~yl)ethanone (106). LCMS RT = 3.0 (M+l) 509.3, (M-l) 507.5.

[00617] (R)-2-tluoroethyl3-((2-(5-chloro-l//-pyrrolo[2,3-Z>]pyridin-3-yl)-5-fluor opy r imidin-4-y lammo)methyl)p iperidine-l -ca rboxy late (126). LCMS RT = 2.1 (M+l) 451.4.

[00618] (R)-(3-((2-(5-chloro-lJff-pyrrolo[2,3-6]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)piperidin“l-yl)(thiophen-2-yl)methanone(97). LCMS RT = 2.9 (M+l) 471.2, (M-l) 469.6.

[00619] Cff)-l-(3-((2-(5-ch]oro-ltf-pyrrolo[2,3-£]pyridin-3-yI)-5-fluoropyrimidin- 4-yla mino)m ethyl)piper idin-l-yl)-2,2-dimethylp ropan- 1-one (105). LCMS RT = 3.0 (M+l) 445.3, (M-l) 443.4.

[00620] (R)-(3-((2-(5-chloro-ltf-pyrrolo[2,3-£]pyridin-3-yl)-5-fluoropyriinidin-4-ylamino)tnethyl)pxperidin-l-yl)(2,3-dimethylphenyl)methanone(157). LCMS RT = 2.0 (M+l) 493.1.

[00621] (if)“l -(3-((2-(5-chloro-l//-pyrroIo[2,3-/>] py ridin“3“yl)-5-fluoropy rimi din-4-ylamino)methyl)piperidin-l-yl)-2-phenoxyethanone (94). LCMS RT = 2.9 (M+l) 495.3, (M-l) 493.5.

[00622] (R)-2-(3-((2-(5-ch]oro-l//-pyrrolo[2,3-/>]pyridin-3-yl)-5-fluoropyrimidin-4-yIamino)methyl)piperidin-l-yl)-2-oxoethyl ethanoate (110). LCMS RT = 2.5 (M+l) 461.3, (M-l) 459.4.

[00623] (S)-ethyI 3-((2-(5-chloro-l//-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin“4“ylamino)methyl)piperidine-l-carboxylate (33). LCMS RT = 3.0 (M+l) 433.3, (M-l) 431.4.

[00624] (R)-prop-l-en-2-yl3~((2-(5-chloro-l/i'-pyiTolo[2,3-b]pyridm-3-yl)-5-fluoropyrimidin-4-ylainino)methyl)piperidine-l-carboxylate (74). LCMS RT - 3.1 (M+l) 445.2, (M-l) 443.4.

[00625] (7?)-3-(3-((2-(5-chloro-l//-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)piperidine-l-carbonyl)pyra/.ine-2-carboxyIic acid (82). LCMS RT = 1.6 (M+l) 511.3.

[00626] (lS,2.R)-2-((R)-3-((2-(5-chloro-ltf-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)piperidine-l-carbonyI)cyc!opropanecarboxylic acid (83). LCMS RT = 1.6 (M+l) 473.4.

[Ο0627] (5)-1 -(3-((2-(5-ch!or o-l//-py rr olo [2,3-b] py ridin-3-yl)-5-fluoropy rimidin-4- ylammo)methyl)piperidin-l“yl)-2-methoxyethanone (45). LCMS RT = 2.4 (M+l) 433.3, (M-l) 431.4.

[00628] (5)-allyl 3-((2-(5-chloro-l//-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)piperidine-l-carboxylate (17). LCMS RT = 3.1 (M+l) 445.3, (M-l) 443.4.

[00629] (jR)-prop-2-ynyl3-((2-(5-chloro-liT-pyrrolo [2,3-b] pyridin-3-yl)-5-fluoropyrimidin-4-ylarnino)nietIiyl)piperidine-l-carboxylate (122). LCMS RT = 2.9 (M+l) 443.3, (M-l) 441.5.

[00630] (5)-etliyl 5-(3-((2-(5-chloro-l//-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidm-4-ylamino)rnethyl)piperidm-l-yl)-5-oxopentanoate (19). LCMS RT = 2.8 (M+l) 503.4, (M-l) 501.5.

[00631] (jfif)-but-2-ynyl 3-((2-(5-chloro-l//-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidiii-4-ylan(iino)methyl)piperidine-l-carboxylate (127). LCMS RT = 3.1 (M+l) 457.3, (M-l) 455.6. |00632] (5)-methyl3-((2-(5-chloro-l//-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamiiio)methyl)piperidine-l-carboxylate (23). LCMS RT = 2.8 (M+l) 419.3, (M-l) 417.3.

[00633] (fl)-allyl 3-((2-(5-chloro-l//-pyrro]o[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-yiamiiio)methyl)piperidine-l-carboxylate (119). LCMS RT = 3.1 (M+l) 445.4, (M-l) 443.5.

[00634] (5>but-2-ynyl 3-((2-(5-chIoro-l//-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidiii-4-yIainmo)methyl)piperidiiie“l“CarboxyIate (30). LCMS RT = 3.1 (M+l) 457.3, (M-l) 455.6.

[00635] (R)-to-i-butyi 3-((2-(5-chloro-lV7-pyrrolo [2,3-6]pyridin-3-yl)-S-fIuoropyrimidin-4-ylamino)methyl)piperidine-l-carboxylate (15). LCMS RT = 2.7 (M+l) 461.3.

[00636] (S)-isobutyl 3-((2-(5-ch loro-1//-pyrrolo [2,3-6] py ridin-3-yl)-5-fluoropyrimidin-4-ylamin o)methyl)pip eridine-1 -ca r boxy late (28). LCMS RT = 3.3 (M+l) 461.4.

[00637] (5)-l-(3-((2-(5-cliloro-l//-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-yla mino)methy l)p ip eridin-l-yl)pr op an-1 -o ne (32). LCMS RT = 1.9 (M+l) 417.2.

[00638] (S)-l-(3-((2-(5-ch Ioro-l/7-pyrrolo [2,3-b Ipyrid in-3-yl)-5-fluor opy rimidm-4-ylamino)methyl)piperidin-l-yl)-2-methylpropan-l-one (34). LCMS RT - 3.2 (M+l) 447.4, (M-l) 445.5.

[00639] (Syisopropyl 3-((2-(5-chloro-li/-pyrroIol2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)pipericUne-l-carboxylate (35). LCMS RT = 3.0 (M+l) 447.3, (M-l) 445.4.

[00640] (ii)-(3-((2-(5-chloro-lH-pyrrolo[2,3-b]pyridm-3-yl)-5-fluoropyrimidin-4-ylamino)methyI)piperidin-l-yl)(cyclopeiityl)methanone (99). LCMS RT = 3.1 (M+l) 457.3, (M-l) 455.4Λ

[00641] (5)-l-(3-((2-(5-chloro-l/f-pyrrolo[2,3-b]pyridin-3-yl)-5-fiuoropyrimidm-4-yIamino)methyl)piperidin-l-yl)but-2-en-l-one (41) LCMS RT = 2.7 (M+l) 429.3, (M-l) 427.4.

[00642] (S)-l-(3-((2-(5-chloro-l//-pyrrolo[2,3-b]pyndin-3-yl)-5-fluoropyrimidm-4-ylamino)methyl)piperidxn-l-yl)-3,3-dimethylbutan-l-one(42) LCMS RT = 3.1 (M+l) 459.3, (M-l) 457.4.

[00643] (S)-l-(3-((2-(5-chioro-l!?-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)p iperidin-1 -yl)-3,3,3-trifluoroprop an-l-one (44) LCMS RT - 2.8 (M+l) 471.3, (M-l) 469.4.

[00644] (5)-2-(3-((2-(5-chloi-o-li/-pyrrolo[2,3-b)pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)piperidin-l-yl)-iV,Ar,Ar-trimethyl-2“Oxoethanammxum (43) LCMS RT = 2.4 (M+l) 460.3, (M-l) 458.5.

[00645] (5)-1 -(3-((2-(5-chIor o-l//-pyrrolo [2,3-b] pyridin-3-yl)-5-fluor opy r imidin~4-ylarnino)rnethyi)piperidin-l-yl)-2~(diroeihy]ainino)ethanone (46) LCMS RT = 2.2 (M+l) 446.4, (M-l) 444.5.

[00646] (5)-l-(3-((2-(5-chIoro-l//-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-y]amino)methyl)piperidin-l-yl)-2-(pyridin-3-yl)ethanone(47) LCMS RT = 2.4 (M+l) 480.3, (M-l) 478.6.

[00647] (5}-l-(3-((2-(5-chloro-l//-pyrrolo[2,3-b]pyridin-3-yI)-5-fluoropyrimidin-4-ylamino)methyl)piperidin-l-yl)but-3-en-l-one (49) LCMS RT = 2.7 (M+l) 429.3, (M-l) 427.4.

[00648] (5)-1-(3-((2-(5-chloro-l/7-pyrroIo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-yIammo)methyl)piperidin-l-yl)-2-(lH-tetrazol-l-yl)ethanone (48) LCMS RT = 2.4 (M+l) 471.3, (M-l) 469.4.

[00649] (2?)-5-((S)-3-((2-(5-chloro-l/af-pyrroIo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamiiio)methyl)piperidine-l-carbonyl)dihydrofuran-2(3H)-one (51) LCMS RT = 1.7 (M+l) 472.9.

[00650] (5)-l-(3-((2-(5-chIoro-l//-pyrroIo[2,3-/>]pyridin-3-yl)-5-fluoropyrimidiii-4 yla min o)m ethyl)pip er idin-l-yl)-2-( 177-i m idazol-1 -yl)eth an on e (50) LCMS RT = 2.3 (M+l) 469.3, (M-l) 467.4.

[00651] (5)-l-(3-((2-(5-chloro-ltf-pyrrolo[2,3-b]pyridin-3-yl)-5-iluoropyrimidin-4-yiannno)methyl)pipendin-l-yl)pent-4-yn-l-one (52) LCMS RT= 1.9 (M+l) 441.3.

[00652] (JR)-5-(3-((2-(5-chloro-l£T-py rrolo [2,3-b] py ridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)piperidin-l-yl)-5-oxopentanoic acid (53) LCMS RT = 1.8 (M+l) 475.3, (M-l) 473.4.

|00653] (R)-2-(2-(3-((2-(5-ch)oro-l//-pyrrolo]2,3“b]pyridin-3-yl)-5- fluoropyrimidin-4-ylamino)methyl)p iperidin-l-yl)-2-oxoethoxy) ethan oic acid (54) LCMS RT = 1.7 (M+l) 477.3, (M-l) 475.4.

[00654] (15,3R)-3-((jf?)-3-((2-(5-chloro-l//-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)piperidme-l-carbonyl)cyclopentanecarboxylic acid (55) LCMS RT = 2.5 (M+l) 501.3, (M-l) 499.6.

[00655] (R)-(3-((2-(5-chIoro-JJ/-py rrolo [2,3-b] pyridin-3-yl)-5-fluoropyrimidin-4-ylaimno)methyl)piperidin-l-yl)(2-fluorophenyl)methanoite (58) LCMS RT - 2.9 (M+l) 483.3, (M-l) 481.5.

[00656] (li)-5-(3-((2-(5-chloro-li7-pyrr©lo[2,3-b]pyridin-3-yI)-5-ftuoropyrimidin-4-ylamino)methyl)piperidin-l-yl)-3,3-dimethyl-5-oxopentanoic acid (80) LCMS RT = 1.9 (M+l) 503.3.

[00657] 2-chloro-i-((J?)~3"((2-(5-chIoro-l//-pyrrolo[2,3-b]pyridin~3-yl)-5-fluoropyrimidin-4-ylamino)methyl)piperidin-l-yl)propan-l-one (93) LCMS RT = 2.9 (M+l) 451.2, (M-l) 449.4.

[00658] (i?)-(3-((2-(5-chloro-1/7-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropynmidin-4-ylamino)methyl)piperidin-l-yI)(cyclohexyl)inethanone (95) LCMS RT = 3.2 (M+l) 471.3, (M-l) 449.4.

114 [00659] (JR)-to+-butyl 3-((2-(5-amino-l //-pyrrolo[2,3-/>]pyridin-3-yl)-5-fluoropyrimidin-4-ylamiao)methyl)piperidine-l-carboxylate (114) LCMS RT = 2.7 (M+l) 461.3.

[00660] (J?)-ethyl 3-((2-(5-chlorO“12/-pyrrolo[2,3-Z>]pyridin-3-yl)pyrimidin-4-ylamino)methyl)p ip erid ine-l-carboxylate (495) LCMS RT= 1.7 (M+l) 385.4.

[00661] (i?)-l-(3-((2-(5-chloro-l^-pyrr©lo[2,3-*]pyridin-3-yl)pyrimidin-4-ylamino)meihyl)piperidin-l-yl)-2-methoxyethanone (491) LCMSRT= 1.7 (M+l) 415.4.

[00662] (fi)-l-(3-((2-(5-chloro-l jfiF-py r rolo [2,3- £]py ridin-3-yl)py riimdin-4-ylamino)methyl)piperidin-l-yl)-3-methoxypropan-l-one(493) LCMS RT = 1.7 (M+l) 429.5.

[00663] (7?)-l-(3“((2-(5-chloro-]jy'-pyrroloI2,3-ji>]pyridin-3"yl)pyrLmidin-4-ylamino)methyl)piperidin-l-yI)-3-methylbutan-l-one (494) LCMS RT = 1.9 (M+l) 427.5.

[00664] (S)-2-methoxyethyl3-((2-(5-chloro-l//-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidm-4-ylamino)methyl)piperidine-l-carboxylate (24) LCMS RT = 2.8 (M+l) 463.2, (M-l) 461.3.

[00665] (/f)-l-(3-((2-(5-chloro~lflr-pyrrolo[2,3“b]pyridin-3-yl)-5-fluoropyriniidin-4-ylamino)methyl)piperidm-l-yl)-2-phenyiethanone (56) LCMS RT = 2.9 (M+l) 479.3, (M-l) 477.4.

[00666] (jR)-l-(3-((2-(5-chloro-l//-pyrrolo[2,3-b]pyridin-3-y])-5-fluoropyrimidiii-4-ylamino)m ethyl)piperidi n-1 -yl)-3~m ethy lbut-2-en-1 -ο n e (57) LCMS RT = 2.8 (M+l) 443.3, (M-l) 441.4.

[00667] (jR)-4-(methoxycarbonyi)phenyl 3-((2-( 5-chloro-l//-pyrrolo[2,3-b]pyridin- 3-yl)-5-fluoropyrimidin-4-y]ammo)methyl)piperidine-l-carboxylate (63) LCMS RT = 3.2 (M+l) 539.3, (M-l) 537.4.

[0066S] (Zf)-phenyl 3-((2“(5-chloro-l //-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)piperidine-l-carboxylate (68) LCMS RT = 3.2 (M+l) 481.4, (M-l) 479.4.

[00669] (7?)-2-chIorophenyl 3-((2-(5-chl or o-l 77-pyrrol o[2,3-b]pyridi n-3-y 1)-5-fluoropyrimidin-4-ylamino)methyl)piperidine-l-carboxylate (70) LCMS RT = 3.3 (M+l) 515.3, (M-l) 513.3.

[00670] (2?)-2-methoxyphenyl 3-((2-(5-chloro-l//-pyrrolo[2,3-6]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)pipeddine-l-carboxylate (69) LCMS RT = 3.2 (M+l) 511.3.

[00671] (jR)-p-tolyl 3-((2-(5-chloro-lJT-pyrrolo[2,3-b]pyridin“3-yl)-5-fluoropyrimidin-4-ylamino)methyI)piperidine-l“Carboxylate (71) LCMS RT = 3.4 (M+l) 495.3, (M-l) 493.4.

[00672] (/?)-3-(trifIuoromethyl)phenyl 3-((2-(5-chloro-17/-pvrroIo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)piperidine-l-carboxyIate (72) LCMS RT = 3.5 (M+l) 549.3, (M-l) 547.4.

[00673] (J?)-4-fluorophenyl 3-((2-(5-chloro-l//-pyrroIo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)piperidine“l-carboxylate (73) LCMS RT = 3.3 (M+l) 499.3, (M-l) 497.4.

[00674] (R)-2-(l-(2-(3-((2-(5-chloro-liY-pyrroIo[2,3-b]pyridm-3-yl)-5-fluoropyrimidin-4-yIamiiio)methyl)piperidm-l-yl)~2-oxoethyl)cyclopentyl)ethanoic add ¢81) LCMS RT = 2.0 (M+l) 529.3.

[00675] (i)-(3-((2-(5-chloro-ltf-pyrrolo[2,3-b]pyridm-3-yl)-5-fluoropyrimidin-4-y]amino)methyl)piperidin-l-yl)(2-chlorophenyl)methanone (84) LCMS RT = 2.0 (M+l) 499.4.

[00676] (Λ )-(3-((2-(5-chloro-l JY-py rr olo [2,3-b] py ridin-3-yl)-5-flu oropy rimidin-4-ylamino)methyl)piperidin~l-yl)(3,4-difluorophenyl)methanone (85) LCMS RT = 2.1 (M+l) 501.3.

[00677] (R)-2-ch lor o-l -(3-((2-(5-chloro-l/Y-pyrrolo[2,3-b]pynd in-3-y 1)-5-fluoropyrimidin-4-ylaimn©)methyl)piperidin-l-yl)ethanone (92) LCMS RT = 2.7 (M+l) 437.2, (M-l) 435.3.

[00678] (R)-(3-((2-(5-chloro-l//-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyriniidin-4-yla mino)methyl)p ip eridin-l-yl)(2,6-dichlo ropbenyl)methanone (96) LCMS RT = 2.9 (M+l) 535.2, (M-l) 533.2.

[00679] (7?)-l -(3-((2-(5-chlor o-l/f-py r rolo [2,3-b] pyridin-3-yl)-5-flu oropyrimidin- 4-ylamino)methyl)piperidin-l-yl)-2-(4-fluorophenyl)ethanone (98) LCMS RT = 2.9 (M+l) 497.3, (M-l) 495.4.

[00680] (if)-l-(3-((2-(5-chloro-l//-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)niethyl)piperidin-l-yl)-2-cyclopent>'lethanone (100) LCMS RT = 3.1 (M+l) 471.3, (M-l) 469.5.

[006811 (R )-(3-((2-(5-chlor ο-ΙΙΪ-py rr olo [2,3-b] py ridin-3-yI)-5-flu oropyrimidin-4- ylamino)methyl)piperidin-l-yI)(pyrazin-2-yl)methanone (111) LCMS RT = 2.5 (M+l) 467.2, (M-l) 465.4.

[00682] (R)-(3-((2-(5-chloro-l//-pyrrolo[2,3-bjpyridin-3-yI)-S-fluoropyrimidin-4-ylamino)methyl)piperidin-l-yl)(furan-2-yl)methanone (186) LCMS RT = 2.7 (M+l) 455.3, (M-l) 453.3.

[00683] (R)-benzo[d][l,3]dioxoI-5-yI(3-((2-(5-chloro-l/f-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylammo)methyl)piperidin-l-yl)methanone (103) LCMS RT = 2.8 (M+l) 509.3, (M-l) 507.5.

[00684] (flM3-((2-(5-chloro-l.ff-pyrrolo[2,3-b]pyridm-3-yI)-5-fluoropyrimidm-4-ylamino)methyl)piperidm-l-yl)(2,4-difluorophenyl)methanone (152) LCMS RT = 2.8 (M+l) 501.3, (M-l) 499.4.

[00685] (/?)-(3-((2-(5-chloro-li/-pyrrolo[2,3-b]pyridin-3-yI)-5-fluoropyrimidin-4-ylamino)methyl)piperidin-l-yl)(2-(methylamino)phenyl)methanone (112) LCMS RT = 3.0 (M+l) 494.3, (M-l) 492.5.

[00686] (/f)-(3-((2“(5-chlo r o-l Ιΐ-py rr o!o[2,3-b] pyridin-3-yl)-5-flu or opy rimidin-4-ylamino)methyl)pipcridin-l-yl)(3,4-dimethoxyphenyl)mcthanone (109) LCMS RT = 2.7 (M+l) 525.3, (M-l) 523.4.

[00687] (JR)-(3-((2~(5-chloro-l//-pyrrolo[2,3-A)pyridin-3-y])-5-fluoropyrimidm-4-ylamino) methyl)pip eridin-l-y 1)(3,5-dilluorophenyl) metha no ne (8 6) LCMS RT = 2.8 (M+l) 501, (M-l) 499.

[00688] (jR)-(3-((2-(5-chlor o-l/7-py rrolo [2,3-b ] py rid in-3-yl)~5-fluoropy rimidin-4-ylamino)methyI)piperidiii-l-yl)(6-fluoro-4H-benzo[d][l,3]dloxin-8-yl)methanone (142) LCMS RT = 2.8 (M+l) 541.5.

[00689] (i?)-(3-((2-(5-chloro-l JT-py rr olo [2,3-b ] py rid in-3-yl)-5-fluoropy rimidin-4-ylamino)methyl)piperidm-l-yl)(o-tolyl)methanone (143) LCMS RT = 2.9 (M+l) 479.4, (M-l) 477.6.

[00690] (if)-(3-((2-(5-ch]oro-l//-pyrrolo[2,3-b]pyridm-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)piperidin-l-yl)(2“(trifluoromethyl)phenyl)methanone (146) LCMS RT = 3.0 (M+l) 533.3, (M-l) 531.5.

[00691] (R)-(3-((2-(5-chlor o-l//-py rrolo [2,3-b] pyridin-3-y l)-5-flu oropy riniidin-4-ylammo)methyl)piperidin-l-yl)(2,3-dihydrobenzofuran-6-yl)methanone (145) LCMS RT = 2.9 (M+l) 507.3, (M-l) 505.5.

[00692] (R)-(3-((2-(5-chlor o-li/-py rrolo [2,3-b] py r idin-3-yl)-5-flu oropy rimid in-4-ylammo)methyl)piperidin-l-yl)(2,4-dichlorophenyI)methanone (147) LCMS RT = 3.2 (M+l) 533.3, (M-l) 531.4.

[00693] (R)-(3-((2-(5-chloro-li/-pyrrolo [2,3-b] pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)piperidm-l-yl)(2-ethoxyphenyl)methanone (158) LCMS RT = 3.0 (M+l) 509.4, (M-l) 507.5.

[00694] (/i)-(3-((2-(5-chloro-I/7-pyrrolo[2,3-b]pyridin-3-yI)-5-fluoropyriniidin-4-ylamino)methyl)piperidin~l~yl)(2-methoxy-3-methylphenyl)methanone (148) LCMS RT = 3.0 (M+l) 509.3, (M-l) 507.5.

[00695] (R)-(3-((2-(5-chloro-l.ff-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidm-4--ylamino)methyl)piperidin-l-yl)(2,5-difluorophenyl)methanone (151) LCMS RT = 2.9 (M+l) 501.2, (M-l) 499.5.

[00696] (fi)-(3-((2-(5-chloro-lJH-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-yla mino)methyl)piper id in-l-yl)(2-phenoxyphenyl)methano ne (150) LCMS RT = 3.2 (M+l) 557.3, (M-l) 555.6.

[00697] (R)-(3-((2-(5-chloro-lif-pyrrolo[2,3-b]pyridm-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)piperidin-l-yI)(2,4-dimethoxyphenyl)niethanone (154) LCMS RT = 2.3 (M+l) 525.3, (M-l) 523.2.

[00698] (jK)-(3-((2-(5-chloro-li/-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)piperidin-l-yI)(cyclopropyl)raetIianone (325) LCMS RT = 2.7 (M+l) 429.2.

[00699] (R)-(3-((5-fIuoro-2-(l//-pyrrolo[2,3-/;]pyridin-3-yl)pyrimidin-4-ylamino)methyl)piperidin-l“yl)(2-methoxyphenyl)methanoiie (272) LCMS RT = 2.5 (M+l) 461.3.

[00700] (R)-l-(3-((5-fluoro-2-(i//-pyrrolo[2,3-6]pyridin-3-yl)pyrimidiii-4-ylamino)methyl)piperidin-l“yl)ethanone (268) LCMS RT = 2.1 (M+l) 369.3.

[00701 ] (/i)-(3-((5-fluoro-2-(l//-pyrrolo [2,3 -b\pyridin-3-y l)pyrimidin-4- ylamino)methyl)piperidin-l-yl)(phenyl)methanone (271) LCMS RT = 2.5 (M+l) 431.4. 100702] (J?)-l-(3-((S-fluoro-2-(lJff-pyrrolo[2!3-A]pyridin-3-yl)pyrimidin-4-ylamino)methyl)piperidin-l-yl)butan-l-one (270) LCMS RT = 2.4 (M+l) 397.3.

[00703] (RM3-((5-fiuoro-2-(l//-pyrrolo[2,3-£]pyridin-3-yl)pyrimidin-4-yIamino)methyl)piperidin-l-yl)(phenyI)propan“l“One (269) LCMS RT = 2.3 (M+l) 383.3.

[00704] (S)-l-(3-((5-fluoro-2-(l//-pyrrolo[2,3“£]pyridin-3-yl)pyrimidin-4-ylamino)methyl)piperidin-l-yl)butan-l-one (225) LCMS RT = 2.4 (M+l) 397.4.

[00705] In a manner analogous to that of the preparation of compound 327, compounds with the opposite absolute stereochemistry, were prepared as follows:

General Scheme 12A.

(a) ferf-buty I isocyanate, pyridine, CH2CI2 [00706] Formation of (A)-A-tert-butyl-3-((2-(5-chloro-1//-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyI)piperidine-l-carboxamide (20).

To a solution of (R)-2-(5-chloro-l/f-pynOlo[2,3-6]pyridin-3-yI)-5-fluoiO-7V-(piperidin-3-ylmethyl)pyrimidin-4-amine, 12a, (0.013 g, 0.036 mmol) in mixture of pyridinc/CHaCL (1 mL of 1:1 mixture was added teri-butyl isocyanate (0.005 mL, 0.046 mmol). The reaction mixture was stirred at 40 °C for 12h. The solvent was concentrated under reduced pressure and the resulting residue was purified by preparatory HPLC (0.1%TFA-H2O/acetonitrile) to afford die desired product, 20. LCMS RT = 3.0 (M+l) 460.4, (M-l) 458.4.

[00707] Other analogs that can be prepared in the same manner as 20:

[00708] (/^-AMert-butyl-3K(2-(5-chloro-lj!T-pyrrolo[23-b]pyridm-3-yl)-5-fIuoropyrimidin-4-ylamino)methyl)piperidine-l -carboxamide (128) LCMS RT = 3.0 (M+l) 460.4, (M-I) 458.4.

[00709] (5)-3-((2-(5-chloro-li/-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-yiamino)methyl)-iV-(thLOphen-3-yl)piperidine-l“Carboxamide (22) LCMS RT = 2.9 (M+l) 486.3, (M-l) 484.6.

[00710] (S)-ethyl 2-(3-((2-(5-chloro-l//-pyrroIo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)piperidine-l-carboxamido)ethanoate (25) LCMS RT = 2.6 (M+l) 490.3, (M-l) 488.4.

[00711] (iS)-ethyl 3-((2-(5-chloro-lii-pyrroIo[2,3-b]pyridm-3-yI)-5-fluoropyrin*idin-4-ylamino)methyl)piperidine-l-carbonylcarbamate (26) LCMS RT = 2.5 (M+l) 476.3, (M-l) 474.5.

[00712] (1S)-3-((2-(5-chloro-li/-pyrrol©[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4“ yla mino)m ethyl)-7V-isopropyIpiperidin e-l-carboxa mide (27) LCMS RT = 2.7 (M+l) 446.4, (M-l) 444.5.

[00713] (S)-3-((2-(5-chloro-li/-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)-7V-methylpiperidine-l-carboxamide (29) LCMS RT = 2.4 (M+l) 418.3, (M-l) 416.1.

[00714] (1S,)wV-aUyl“3-((2-(5-chloro-l//-pyrrolo[2,3-b]pyridm-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)piperidine-l-carboxamide (39) LCMS RT = 2.6 (M+l) 444.4, (M-l) 442.4.

[00715] (iSJ-S-tiZ-fS-chloro-l/i-pyrrolo^^-bJpyridin-S-yli-S-fluoropyriiiiidin-d-ylamino)methy])-Ar-(pyridin-3-yl)piperidine-l-carboxaniide (40) LCMS RT = 2.5 (M+l) 481.3, (M-l) 479.4.

[00716] (R)-3-((2-(5-chloro-lJT-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)-Ar-(3-fluo roph enyl)piper idine-l-carboxa mid e (75) LCMS RT = 3.0 (M+l) 498.3, (M-l) 496.5.

[00717] (R)-3-((2-(5-chloro-l//-pyrro]o|2,3-b|pyriclm-3-yl)-5-fluoropyrmiidin-4-yla mino)m ethyl)-iV-(3-meth oxyphenyl)pip eridine-1 -ca rb oxamide (76) LCMS RT = 2.9 (M+l) 510.3, (M-l) 508.5.

[00718] (Λ)-3 -((2-(5-chIor o-l-fiT-py rrolo [2,3-b] pyridin-3-yl)-5-fluor opy rimidin-4-ylamino)methyl)-lV-(3-ethanoylphenyl)piperidine-l-carboxamide (77) LCMS RT = 2.8 (M+l) 522.3, (M-l) 520.4.

[00719] (R)-3-((2-(5-chloro-l//-pyrrolo[2,3-b]pyridin~3--yi)-5-f]uoropyrimidin-4-ylamino)methyl)-Ar-m-tolylpiperidine-l-carboxamide (78) LCMS RT = 3.0 (M+l) 494.3, (M-l) 492.4.

[00720] (fl)-3-((2-(5-chloro-lJY-pyrroIo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-y]amino)methyl)-Ar-(3“(trifluoromethyl)phenyl)piperidine-l"Carboxamide (79) LCMS RT = 3.3 (M+l) 548.3, (M-l) 546.4.

[00721] (jR)-ethyl 3-(3-((2-(5-chloro-l.flr-pyiTolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)nsethyl)piperidine-l-carboxamido)propanoate (118) LCMS RT = 2.6 (M+l) 504.2, (M-l) 502.5.

[00722] (R)-3-((2-(5-chloro-l//-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyriimdin-4-ylamino)methyl)-AH5-methyl-2-(trifluorornelhyl)furan-3-yl)piperidinc-l-carboxarnide (120) LCMS RT = 3.2 (M+l) 552.4, (M-l) 550.5.

[00723] (R)-methyl2-(3-((2-(5-chloro-12T-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-yla min o)m ethyl)p iperidine-l-carboxamido) ethanoate (12 5) LCMS RT = 2.6 (M+l) 490.4, (M-l) 488.6.

[00724] (ff)-iV-tert-butyl-3-((2-(5-chloro-l//-pyrrolo[2,3-b]pyridm-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)piperidine-l-carboxamide (117) LCMS RT = 2.8 (M+l) 486.3, (M-l) 484.5.

[00725] (Jfi)-3-((2-(5-ch]oro-li/-pyrrolo[2,3-b]pyridLH-3-yl)-5-iluoropyrimidin-4-yIamino)methyI)“iV-(thiopheii“2-yI)piperidine~l-carboxamide (129) LCMS RT = 2.8 (M+l) 486.3, (M-l) 484.5.

[00726] (fi)-methyl 3-((2-(5-chloro-177-py rrolo [2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-yIamino)methyl)piperidme-l-carbonylcarbamate (131) LCMS RT = 1.6 (M+l) 462.7.

[00727] (tf)-3-((2-(5-chloro-l#-pyrro]o[2,3-b]pyndm-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)-A-(4-methylthiophen-2-yI)piperidine- 1-carboxamide (130) LCMS RT = 2.0 (M+l) 500.6.

[00728] (5)-3-((5-fluoro-2-(ljff:pyrrolo[2,3-A,]pyridin-3-yl)pyrimidin-4-ylamino)methyl)-7\iA!-dimethylpiperidine“l-carboxamide (228) LCMS RT = 2.3 (M+l) 398.3.

[00729] (.fi)-3-((5-fluoro-2-(lii-pyrrolo[2,3“Z>]pyridin-3-yI)pyrimidin-4-yIamino)methyl)-7V-methylpiperidine-l-carboxamide (274) LCMS RT = 2.1 (M+l) 384.3.

[00730] ethyl-3-((5-fluo r 0-2-( 1 //-pyrrolo [2,3-Λ] py ridin-3-yl)pyrimidin-4~ ylamino)methyl)piperidine-l-carboxamide (275) LCMS RT = 2.2 (M+l) 398.4. IΟ0731 ] (i7)-3-((5-fluoro-2-(l JT-pyrroIo [2,3-/»] pyridi n-3-yl)py rimidin-4- yla mino)m ethyl)-A-propylp iperidine-l-carboxa mide (276) LCMSRT = 2.3 (M+l) 412.4.

General Scheme 12B

(b) propylisocyanate, lPr2NEt, pyridine, CH2CI2 [00732] (iS)-2-(5-chloro-l//-pyrrolo[2,3-b)pyridin-3-yl)-5-fluorO“jV-((l-(methylsulfonyl)-piperidin-3-yl)methyl)pyrimidin-4-amine(36).

To a solution of (R)-2-(5-chloro-l//-pyiTolo[2,3-Z?]pyridin-3-yl)-5-fluoiO-iV-(piperidin-3-ylmcthyl)pyrimidin-4-amine, 12a, (0.018 g, 0.050 mmol) and pyridine (0.7 mL) in CH2CI2 (0.7 mL) was added methanesulfonyl chloride (0.004 mL, 0.050 mmol). The reaction mixture was stirred at room temperature for 24 hours. The solvent was concentrated under reduced pressure and the resulting residue was purified by preparatory HPLC (0.1%TFA-H2O/acetonitrile) to afford the desired product, 36. LCMS RT = 2.7 (M+l) 439.3, (M-l) 437.3.

[00733] Other analogs that can be prepared in the same manner as 36:

[00734] (if)-2-(5-chloro-llT-pyrrolo[2,3-b]pyridin-3-yl)-Ar-((l-(cyclopropylsulfonyl)piperidin-3-yl)methyI)-5-fluoropyrimidin“4-amme (61) LCMS RT = 2.8 (M+l) 465.3, (M-l) 463.3.

[00735] (£,£)-2-(5-chloro-l//-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-yV-((l-(styry!sulfony])piperidm-3-yl)methyl)pyrimidin-4-amine (60) LCMS RT = 3.2 (M+l) 525.3.

[00736] (i?)-2-(5-chloro-17/“pyrroIo[2,3-b]pyridin-3-yl)-5-fluoro-iY-((l-(3-methoxyphenylsulfonyl)piperidin-3-yI)methyl)pyrimidin-4-aniine (62) LCMS RT = 3.1 (M+l) 531.3, (M-l) 529.4.

[00737] (i?)“2-(5-chlorO“ljff-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-lV-((l-(4-fluorophenylsulfonyl)piperidin-3-yl)methyl)pyrimidin-4-amine (64) LCMS RT = 3.1 (M+l) 519.3, (M-l) 517.4

[007381 (/f)-2-(5-chlo ro-l//-pyrrolo [2,3-b ]py ridin-3-yl)-5-flu oro-iV-((l-(3- fluorophenyIsulfonyI)piperidin-3-yl)methyl)pyrimidin“4-amine (65) LCMS RT = 3.1 (M+l) 519.2, (M-l) 517.4.

[00739] (7Z)-2-(5-chloro-li7-pyrrolo[2,3-b]pyridin-3-yl)“5-fluorO“jV-((l-(m-tolyIsulfonyl)piperidin-3-yl)methyl)pyrimidin-4-affline (66) LCMS RT - 3.2 (M+l) 515.3, (M-l) 513.4

[00740] (jR)-lV-((l-(3-bromopheiiylsulfonyl)piperidm-3-yl)inethyl)-2-(5-chlor(>-lii-pyrrolo[2,3-6]pyridin-3-yI)-5-fluoropyriimdin-4-amine (67) LCMS RT = 3.3 (M+l) 579.2, (M-l) 577.2.

[00741] (i?)-2-(5-chloro-l/7-pyrrolo[2,3-i]pyridiii-3-yl)-5-fluoro-^V-((l-(phenylsulfonyl)piperidm-3-yl)methyl)pyrimidin-4-anime (87) LCMS RT = 2.1 (M+l) 501.3.

[00742] (j¥)-Ar-((1-(3-bromophenylsulfonyl)pipcridin-3-yl)metliyl)-2-(5-chloro-l//-pyrrolo[2,3-Z>]pyridm-3-yl)-5-fluoropyrimidin-4-amine (88) LCMS RT = 2.0 (M+l) 561.3.

[00743] (y?)-2-(5-chloro-l/7-pyrrolo[2,3-Zi]pyridin-3-yl)-5"fluoro-/V-((l-(phenylsuIfonyl)piperidin-3-yI)methyl)pyrimklm-4-amine (89) LCMS RT = 2.1 (M+l) 507.2.

[00744] (R)-2-(5-chloro-lZ/“pyrrolo[2,3-A]pyridin-3-yl)-5-fluoro-jY-((l-(2-fluorophenylsulfonyl)piperidin~3-yl)methyl)pyrimidin-4-amme (90) LCMS RT = 2.1 (M+l) 519.2.

[00745] (S)-2-(5“diloro-l//-pyrrolo[2,3-A]pyridm-3-yl)-5-fluoro-JV-((l-(l-methyI-l//-iniidazol-4-ylsulfonyl)piperidiii-3-yl)methyl)pyrimidin-4-amine (91) LCMS RT = 1.8 (M+l) 505.3.

General Scheme 12C

(a) (/?)-3 -bromo-2-methy Ipropan-1 -ol, ‘PrjNEt, THF

[00746] Formation of (5)-3-((5)-3-((2-(5-chioro-l//-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methy])piperidm-l-yl)-2-methylpropan-l-ol (135).

To a solution of (R)-3-bromo-2-methylpropan-l-ol (0.006 mL, 0.055 mmol) and (R)-2“(5-chloro-l//-pyrTolo[2,3-i]pyridin-3-yl)-5-fluoro-Ar-(piperidin-3-ylmethyl)-pyrimidin-4-amine, 12a, (0.020 g, 0.055 mmol) in CH3CN (2 mL) was added K2CO3 (0.023 g, 0.165 mmol). The reaction mixture was heated at 80 °C at for 24h. The solvent was concentrated under reduced pressure and the resulting residue was purified by preparatory HPLC (0.1%TFA-H2O/acetonitrile) to afford the desired product, 135. LCMS RT = 2.5 (M+l) 433.4, (M-l) 431.6.

[00747] Other analogs that can be prepared in the same manner as 135:

[00748] (5)-1-(3-((2-(5-chloro-l//-pyrrolo[2,3-b]pyridin-3-yl)-5-lluoropyrimidin-4-y]amino)methyl)piperidin-l-yl)-3,3-dimethylbutan-2-one (140) LCMS RT = 2.9 (M+l) 459.3, (M-l) 457.5.

[00749] (ft)-3-((5r)-3-((2-(5-chloro-l//-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)piperidin-l-yl)-2-methylpropan-l-ol (141) LCMS RT - 1.4 (M+l) 433.5.

[00750] (5)-2-(5-chIoro-l//-pyrrolo[2,3-b]pyridm-3-yl)-5-fluoro-iV-((l-(2-methy lb enzyl)p iperidin-3-yl)m ethyl)py rimidin-4-amine (139) LCMS RT = 3.2 (M+l) 465.3, (M-l) 463.4.

[00751] (5)-2-(5-chloro-yT-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-A/-((l-(3-methylbenzyl)piperidin-3-yI)methyl)pyrimidin-4-amine (137) LCMS RT = 3.1 (M+l) 465.4, (M-l) 463.6.

[00752] (SJ-Z^S-chloro-ltf-pyrrolop^-blpyridin-S-yli-AHil-(cyclohexylmethyl)piperidin-3-yl)methyl)-5-fluoropyrimidin-4-amme (134) LCMS RT = 3.1 (M+l) 457.3, (M-l) 455.5.

[00753] (5)-2-(3-((2-(5-chloro-lir-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)piperidiii-l-yl)ethano] (133) LCMS RT == 2.3 (M+l) 405.3, (M-l) 403.6.

[00754] (5>2-(5-chloro-ltf-pyrrolo[2}3-b]pyridm-3-yl)-AH(l-(2,2-dimethoxyethyl)piperidin-3-yl)methyl)-5-fluoropyrimidin-4-amine (132) LCMS RT - 2.2 (M+l) 449.7.

[00755] (5,£)-methyI 4-(3-((2-(5-chloro-l//-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)piperldin-l-yl)but-2-enoate (138) LCMS RT = 2.8 (M+l) 459.3, (M-l) 457.7.

666 [00756] (5)-4-(3-((2-(5-chloro~l//-pyrrolo[2,3-b]pyridin~3-yl)-5-fluoropyrimidm-4-ylamino)methyl)piperidin-l-yl)butanenitrile (666) LCMS RT = 2.6 (M+l) 428.3, (M-l) 426.5.

[00757] (5)-3-(3-((2-(S-chloro-lJy-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyriniidin-4-ylamino)methyl)piperidin-l-yl)propanenitrile (667) LCMS RT = 1.4 (M+l) 414.5.

[00758] (JR)-2-(5-chloro-l//-pyrrolo[2,3-A]pyridin-3-y])-5-fluoro-A-((l-(pyrimidin- 2-yl)piperidin-3-yl)methyl)pyrimidin-4-amme (124) LCMS RT = 3.1 (M+l) 439.3 (M-H) 437.4.

General Scheme 13

(a) Benzyl chloroformate, triethylamine, CH2C12; (b) dimethyl sulfoxide, oxalyl chloride, iriethylamine, CH2C12; (c) DAST, THF; (d) 10% Pd/C, MeOH, H2, di-tert-butyl dicarbonate (e) LiOH, THF/MeOH/Water; (f) Pyridine, di-terf-butyl dicarbonate, NH4HCO3, 1,4-Dioxane; (g) triethylamine, TFAA, CH2C12; (h) Raney Ni, MeOH, H2; (i) 5-chloro-3-(5-fluoro-4-(tnethylsulfmy!)pyrimidin-2-yl)-l-tosyl-l//-pyrrolo[2,3-b]pyridine, "Pr2NEt, THF, microwave, 130 °C 15 min.; (j) NaOMe, MeOH (k) isoproponal/HCI, 45 °C; (1) 3-metboxy propanoyl chloride, 'Pr2NEt, CH2C12, DMF.

[00759] Formation of 1-benzyl 2-methyl 4-hydroxypiperidine-l,2-dicarboxylate (13b).

To a cold (5 °C) solution of methyl 4-hydroxypiperidine-2-carboxylate, 13a, (5.17 g, 32.48 mmol) and triethylamine (6.00 mL, 43.05 mmol) in CH2CI2 (135 mL) was added dropwise benzyl chloroformate (6.20 mL, 43.43 mmol) over 10 min. The resulting solution was stirred at 5 °C for 1 hour and then allowed to warm to room temperature. The reaction mixture was diluted with water and the layers were separated. The aqueous was re-extracted with CH2CI2 and the combined organics were dried over MgS04s filtered and evaporated to dryness. The crude was passed through a plug of silica gel, eluting with 30 - 80% EtOAc/Hexanes to afford the desired product, 13b, *H NMR (300 MHz, CDCI3) δ 7.36 - 7.33 (m, 5H), 5.17 (s, 2H), 4.89 - 4.78 (m, 1H), 4.18 - 4.09 (m, 1H), 3.96 (s, 1H), 3.76 - 3.70 (m, 3H), 3.53 - 3.41 (m, 2H), 2.44 (s, 1H), 1.96 -1.91 (m, 1H) and 1.71 (s, 2H) ppm.

[00760] Formation of 1-benzyl 2-methyl 4-oxopiperidine-l,2-dicarboxylate (13c).

To a 500 ml flask, flamed dry under N2 was added CH2CI2 (65 mL) followed by oxalyl chloride (5.2 mL, 59.6 mmol). After cooling the reaction mixture to -78 °C, dimethyl sulfoxide (8.4 mL, 118.4 mmol) was added, followed by 1-benzyl 2-methyl 4-hydroxypiperidine-l,2-dicarboxylate, 13b, (8.6 g, 29.2 mmol) in CH2CI2 (65 mL). The reaction was allowed to stir at -78 °C for 45 min. To the mixture was added triethylamine (24.4 mL, 175.1 mmol) and the mixture was allowed to warm to room temperature. The reaction mixture was diluted with CH2CI2 and IN HC1. The layers were separated and the aqueous phase was re-extracted with CH2CI2. The combined organic phases were washed with water, dried over MgS04, filtered and evaporated to dryness. The crude was purified by silica gel chromatography (30 -50% EtOAc/hexanes) to give the desired product, 13c. 'HNMR (300 MHz, CDCI3) δ 7.37 (s, 5H), 5.24 - 5.18 (m, 3H), 5.02 (s, 1H), 4.12 (q, /= 7.1 Hz, 1H), 3.74 - 3.65 (m, 3H), 2.79 (d, /= 7.0 Hz, 2H) and 2.53 (s, 2H) ppm.

[00761] Formation of 1-benzyl 2-methyl 4,4-difluoropiperidine-l,2-dicarboxyIate (13d).

To a cold (0 °C) solution of 1-benzyl 2-methyl 4-oxopiperidine-l,2-dicarboxylate, 13c, (7.4 g, 25.4 mmol) in THF (75 mL) was added (diethy!amino)sulfur trifluoride (25.0 mL, 189.2 mmol). After 2 hours at 0 °C, the reaction was quenched by the careful addition of water. The mixture was diluted with EtOAc and water. Solid NaHC03 was added to adjust the pH to neutral. The layers were separated and the organic was washed with water, brine, dried over MgS04, filtered and evaporated to dryness. The crude was passed through a plug of silica gel eluting with 15-20% EtOAc/hexanes to afford the desired product, 13d. ’H NMR (300 MHz, CDC13) δ 7.37 - 7.31 (m, 5H), 5.30 - 5.06 (m, 3H), 4.45 - 4.22 (m, 1H), 3.76 - 3.52 (m, 3H), 3.45 (d, /= 9.0 Hz, 1H), 2.76 (s, 1H) and 2.23 - 1.93 (m, 3H) ppm.

[00762] Formation of l-terf-butyl 2-methyl 4,4-diflu or opiperidine-1,2-dicarboxylate (13e).

To a PaiT flask (1L) was charged 10% palladium on carbon (0.57 g) and di-iert-butyl dicarbonate (4.47 g, 20.49 mmol). A solution of I-benzyl 2-metliyl-4,4-difluoropiperidine-1,2-dicarboxylate, 13d, ¢4.28 g, 13.66 mmol) in methanol (150 mL) was added and hydrogen was introduced via parr shaker (46 PSI). The reaction mixture was shaken over weekend at room temperature. The mixture was filtered through Celite and washed throughly with CH2CI2. The filtrate was concentrated to dryness and redissolved in 10% EtOAc/hexanes. The crude was purified by silica gel chromatography (10-20% EtOAc/hexanes) to afford 5.1 g of a mixture of desired product, 13e, plus approximately 840 mg of contaminated product. The resulting crude mixture was used directly in next step without further purification. *H NMR (300 MHz, CDCI3) δ 5.08 (s, 1H), 4.89 (s, 1H), 4.12 (q, 7 = 7.2 Hz, 1H), 3.76 (s, H), 3.74 (s, 3H), 3.34 (s, 1H), 3.29 (t, 7 = 7.2 Hz, 1H), 2.77 (s, 1H), 2.04 (m, 1H) and 1.53 (s, 9H) ppm.

[00763] Formation of l-(tei-t-butoxycarbonyl)-4,4-difluoropiperidine-2-carboxylic acid (13f)

To a solution of 1-terf-butyl 2-methyl 4,4-diiluoropiperidine-l,2-dicarboxylate, 13e, (4.6 g, 16.5 mmol) in THF (18 mL), methanol (18 mL) and H2O (9 mL) was added lithium hydroxide (3.45 g, 82.22 mmol). The reaction mixture was stirred at room temperature for 1 hour. All volatiles were removed under reduced pressure. The residue was diluted with a slight amount of water and ether. The layers were separated and the organic phase was discarded. The aqueous phase was acidified to pH 3 with the addition of aqueous saturated KHSO4 solution. The product was extracted with EtOAc. The organic phase was washed with water, dried over MgSO^, Filtered and evaporated to dryness. The resulting product was used without further purification. lR NMR (300 MHz, CDCI3) 5 5.14 (s, 1H), 4.93 (s, 1H), 4.12 (q, 7= 7.1 Hz, 1H), 3.28 (d, 7= 6.3 Hz, 1H), 2.75 (d, 7- 8.7 Hz, 1H), 2.06 (d, 7- 8.5 Hz, 1H), 1.99 - 1.81 (m, 1H) and 1.47 (s, 9H) ppm.

[00764] Formation of fert-butyl 2-carbamoyl-4,4-difluoropiperidine-l-carboxylate (13g)

To a solution of l-/m-butoxycarbonyl-4,4-difluoro-piperidine-2-carboxylic acid, 13f, (1.67 g, 6.30 mmol) in 1,4-dioxane (12 mL) was added pyridine (0.35 mL, 4.33 mmol), followed by di-teri-butyl dicarbonate (1.78 g, 8.17 mmol) and ammonium bicarbonate (0.63 g, 7.86 mmol). The reaction mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure and the residue was taken up in EtOAc. The organic phase was washed with water, aqueous saturated KHSO4 solution, brine, dried over Na2S04, filtered and evaporated to dryness. The crude residue was used without further purification.

[00765] Formation of tert-butyl 2-cyano-4,4-difluoropiperidine-l-carboxylate (13h)

To a solution of ter/-butyl 2-carbamoy 1-4,4-difluoro-piperidine-l-carboxylate, 13g, (1.72 g, 6.51 mmol) in CH2CI2 (50 mL) was added was N,A-triethylaminc (2.03 mL, 14.61 mmol) followed by the dropwise addition of (2,2,2-trifluoroacetyl)-2,2,2-trifIuoroacetate (1.02 mL, 7.32 mmol). After 15 minutes, the mixture was diluted with aqueous saturated NaHCOs solution and the layers were separated. The organic phase was washed with water, dried over Na2S04, filtered and evaporated to dryness. The crude residue was passed through a plug of silica gel and eluted with 10 - 30%EtOAc/hexanes to afford the desired product, 13h. *H NMR (300 MHz, CDCI3) 5 5.43 (s, 1H), 4.19 (s, 1H), 3.25 (s, 1H), 2.36 (m, IH), 2.23 - 2.12 (m, 1H), 1.83 (s, 1H), 1.70 (s, 1H) and 1.53 - 1.46 (m, 9H) ppm.

[00766] Formation of tert-butyl 2-(aminomethyI)-4,4-difluoropiperidine-l-carboxylate (13i)

Raney nickel (0.36 mL, 5.40 mmol) was washed with MeOH (2X) and charged into a parr shaker. A solution of fert-butyl 2-cyano-4,4-difluoro-piperidine-l-carboxylate, 13h, (1.33 g, 5.40 mmol) in methanol (50 mL). The reaction mixture was subject to hydrogenation conditions overnight on the parr shaker (46PSI). The mixture was filtered through celite and washed throughly with CH2CI2. All volatiles were removed at reduced pressure and the crude material was used without further purification. 100767] Formation of tert-butyl 2-((2-(5-chloro-l-tosyl-li7-pyrrolo[2,3-b]pyridin- 3-yl)-5-fluoropyrimidin-4-ylamino)methyI)-4,4-difluoropiperidine-l-carboxylate (13j)

To a solution of ferf-butyl 2-(aminomethy 1)-4,4-difluoro-piperidine-l-carboxy late, 13i, (0.10 g, 0.41 mmol) and 5-chloro-3-(5-fluoro-4-methylsulfinyl-pyrimidin-2-yl)-l-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridine (0.18 g, 0.38 mmol) in THF (2 mL) was added 'Pr2NEt (0.20 mL, 1.15 mmol). The reaction mixture was heated in microwave at 130 °C for 15 minutes. The reaction was cooled to room temperature and the volatiles were removed under reduced pressure. The crude residue was purified via silica gel chromatography (0-100% EtOAc/hexanes) to afford the desired product, 13j. LCMS (M-l) 649.52. 100768] Formation of ierf-butyl 2-((2-(5-chloro-l//-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylammo)methyl)-4,4-difluoropiperidine-l-carboxylate (13k).

To a solution of ieri-butyl 2-[[[2-[5-chloro-l-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-5-fluoro-pyrimidin-4-yl]amino]methyl]-4,4-difluoro-piperidine-l-carboxylate, 13j, (0.23 g, 0.35 mmol) in methanol (4 mL) was added sodium methanolate (4 mL of 25 %w/v, 18.51 mmol). The reaction mixture was allowed to stir at room temperature for 15 minutes. All volatiles were removed at reduced pressure and the residue was quenched with water. EtOAc was added and the layers were separated. The organic phase was washed with brine, dried (MgSCL), filtered and evaporated to dryness. The crude residue was pure enough to be used without further purification. LCMS (M+l) 497.44, (M-l) 495.52.

[00769] Formation of 2-(5-chloro-lf7-pyrrolo[2,3-b]pyridin-3-yl)-Ar-((4,4-difluoropiperidin-2-yl)methyl)-5-fIuoropyrimidin-4-amine (13m)

To a solution of tert-butyl 2-((2-(5-chloro-l/i-pyrrolo[2,3-b]pyridin-3-yl)-5-fhioropyrimidin-4-ylamino)methyl)-4,4-difluQiOpiperidine-l-carboxylate, 13k, (0.09 g, 0.18 mmol) in 2-propanol (2 mL) was added propan-2-ol hydrochloride (2 mL of 6 M, 12.00 mmol). After stirring the reaction mixture at room temperature for 17 hours, an additional 1 mL of IPA/HC1 was added and the reaction mixture was heated at 45 °C for 1 hour. All volatiles were removed at reduced pressure and the residue was used directly in the next step without further purification. LCMS (M+l) 397.40, (M-l) 395.44.

[00770] Formation of l-(2-((2-(5-chloro~li/-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)-4,4-difluoropiperidin-l-yl)“3-methoxypropan-l-one (584)

To a solution of 2-(5-chloiO-li/-pyrrolo[2,3-b]pyridin-3-yl)-A'-[(4,4-difluoiO-2-piperidyl)methyl]-5-fluoro-pyrimidin-4-amine, 13k, (0.086 g, 0.198 mmol) in CH2CI2 (1 mL), DMF (0.5 mL) and ‘Pr2NEt (0.10 mL, 0.57 mmol) was added 3-methoxypropanoyl chloride (2.43 g, 0.20 mmol). The reaction mixture was stirred at room temperature for 17 hours. All volatiles were removed at reduced pressure and the residue was purified via silica gel chromatography to give a mixture enriched in desired product, 13, which was repurified via preparatory HPLC. ’H NMR (300 MHz, tfb-DMSO) δ 12.45 (m, 1H), 8.71 (d, J= 8.5 Hz, 1H), 8.31 (m, 2H), 8.01 (m, 1H), 5.33 (s, 1H), 4.62 - 4.43 (m, 2H), 4.39 - 3.72 (m, 5H), 3.68 (s, 2H), 3.43 -3.40 (m, 1H), 3.15 (s, 1H), 3.07 (s, 1H), 2.33 (s, 2H) and 2.08 (s, 2H) ppm: LCMS (M+l) 483.44, (M-l) 481.52.

[00771] Other analogs that may be prepared in the same manner as 584 are described below:

[00772] Ar-((4-benzy]morj)holin-2-y])metliyl)-2-(5-ch]oro-I//-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-amine (388). *HNMR ¢300 MHz, CDC13) δ 9.14 - 9.09 (m, 1H), 8.81 - 8.71 (m, 1H), 8.29 (d, /= 2.3 Hz, 1H), 8.07 (d, /= 2.5 Hz, 1H), 7.34 (s, 5H), 5.58 - 5.41 (m, 1H), 3.92 - 3.43 (m, 4H), 2.83 - 2.72 (m, 2H), 2.38 - 2.28 (m, 2H) and 1.62 (m, 2H) ppm. LCMS RT = 1.8 (M+l) 453.4.

[00773] 2-((2-(5~chlorO“ljff-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyriimdin-4-ylamino)methyl)-7V-isopropylmorpholine-4-carboxamide (446). LCMS RT = 1.7 (M+l) 448.4

[00774] Isopropyl 2-((2-(5-chloro-li/-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)morpholine-4-carboxyIate (447). LCMS RT = 2.0 (M+l) 449.3

[00775] 2-(5-chloro-l//-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-iV-((4“ (is opropylsulfonyl)morpholin-2-yl)m ethyl)py rimidin-4-amin e (448). LCMS RT= 1.9 (M+l) 469.3

[00776] l-(2-((2-(5-chloro-lir-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-yla mino)methyl)mo rpholino)p ropan-l-one (449). LCMS RT = 1.7 (M+l) 419.4

[00777] (2“((2-(5-chloro-l/f-py r r olo [2,3-b] py ridin-3-yl)-5-fluo ropy ri midin-4-ylamino)methyl)morpholino)(cyclopropyl)methanone (450). LCMS RT = 1.7 (M+l) 431.4

[00778] teri“Butyl3-((2-(5-chloro-l//-pyrroio [2,3-b] pyridin-3-y 1)-5-fluoropyrimidin-4-ylaniino)methyl)morpholine-4-carboxylate (515). 'H NMR (300 MHz, CDC13) 5 10.38 (s, 1H), 8.81 (d, /= 2.0 Hz, 1H), 8.49 (d, /= 2.3 Hz, 1H), 8.38 (s, 1H), 8.08 (d, /= 3.4 Hz, 1H), 6.11 (d, /= 5.0 Hz, 1H), 4.44 (d, /= 9.4 Hz, 1H), 4.02 - 3.62 (m, 6H), 3.55 (dd, /= 2.4, 12.1 Hz, 1H), 3.35 - 3.27 (m, 1H) and 1.40 - 1.22 (m, 9H) ppm. LCMS RT = 2.5 (M+l) 463.5.

[00779] I-(3-((2-(5-ch]oro-l//-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropynmidin-4-ylamino)methyl)morphoIino)propan-l-one (516). LCMS RT= 1.9 (M+l) 419.4

[00780] 3-((2-(5-chIoro-li/-py r rolo [2,3-b j py ridin-3-yl)-5-fluor opy rimidin-4-ylamino)methyl)-./V-p ropylmorpholine-4-ca rb oxamide (517). 'H NMR ¢300 MHz, /6-DMSO) δ 12.54 (s, 1H), 8.76 (d, / = 2.0 Hz, 1H), 8.46 (s, 1H), 8.32 (d, / = 2.1 Hz, 1H), 8.26 (d, /= 3.9 Hz, 1H), 8.08 (d, /= 7.5 Hz, 1H), 6.30 (s, 1H), 4.28 (s, 1H), 3.93 - 3.74 (m, 3H), 3.51 - 3.47 (m, 2H), 3.39 - 3.20 (m, 2H), 2.95 (dd, / = 6.2, 13.1 Hz, 3H), 1.35 - 1.25 (ra, 2H) and 0.76 (t, /= 7.3 Hz, 3H) ppm. LCMS RT = 2.3 (M+l) 448.54.

[00781] Methyl 3-((2-(5-chloro-lii-pyrrolo [2,3-b]pyridin-3-yl)-5-fluoropyrimidin- 4-yIamino)methyl)morphoime-4-carboxylate (526). LCMS RT = 2.4 (M+l) 421.0.

[00782] Ethyl3-((2-(5-chIoro-lir-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylaimno)methyl)morpholme-4-carboxy]ate (527). LCMS RT = 2.5 (M+l) 435.1.

[00783] Allyl 3-((2-(5-chloro-17/-pyrrolo[2,3-b]pyridin-3-y])“5-fluoropyrinndin-4-yla mino)methyl)morpholin e-4-carboxylate (528). LCMS RT = 2.6 (M+l) 447.1.

[00784] 1-(3-((2-(5-chloro-l//-pyrrolo[2,3-bjpyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)morpholino)-2-methylpropan-l-one (529). LCMS RT= 2.5 (M+l) 433.1.

[00785] l-(3-((2-(5-chloro-li/-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyriinidin-4-ylamino)mcthyl)morpholino)-2,2-dinietiiylpropan-l-one (530). LCMS RT= 1.9 (M+l) 447.1.

[00786] (3-((2-(5-chloro-li/-pyrrolo[2,3-b]pyridin-3-y])-5-fluoropyrimidin-4-ylamino)methyl)morpholino)(cyclobutyl)methanone (531). LCMS RT = 2.6 (M+l) 445.1.

[00787] 2-(5-chloro-li/“pyrrolo[2,3-b]pyridm-3-yl)-5-fluoro-iV-((4-(methyIsulfonyl)morpholin-3-yl)methyl)pyrimidin-4-amine (532). LCMS RT = 2.4 (M+l) 441.0.

[00788] 2-(5-chloro-i//-pyrrolo[2,3-b]pyridin-3-y])-Ar-((4- (cyclopropylsuIfonyl)morpholin-3-yl)methyl)-5-fluoropyrimidin-4-amine (533). LCMS RT = 2.4 (M+l) 467.0.

100789 ] 3-((2-(5-chloro- l//-pyr r ol© 12,3 -b] pyridin-3-y l)-5-fluoropy rimidin-4- ylamino)methyl)morpholine-4-carboxamide (534). LCMS RT = 2.0 (M+l) 406.0.

[00790] 3-((2-(5-chloro-127-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyI)-iV-ethylmorpholine-4-carboxaniide (535). LCMS RT = 2.2 (M+l) 434.1.

[00791] 3-((2-(5-chloro-l//-pyr rolo [2,3-b] py ridin-3-y l)-5-fluor opy rimidin-4-ylamino)methyl)-Ar-isopropylmoi*pholine-4-carboxamide (536). LCMS RT = 2.3 (M+l) 448.1.

[00792] (jR)-2-fluoroethyl 2-((2-(5-chloro-l//-pyrrolo [2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-yIamxno)methyl)pxperidine-l-carboxylate (180). LCMS RT = 2.1 (M+l) 451.4.

[00793] (S)-2-m ethoxy ethyl 2~((2-(5-chloro-l//-pyrrolo[2,3-b]pyridin-3-yl)-5-flxxoropyrimidin-4-ylammo)methyl)piperidiiie-l-carboxylate (161). LCMS RT = 2.8 (M+l) 463.4.

[00794] (£)-2-chloroethyl2-((2-(5-chloro-lJ7-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimxdin-4-ylamino)inethyl)piperidxne-l-carboxylate ¢163). LCMS RT = 3.1 (M+l) 467.4.

[00795] (£)-prop-2-ynyl 2-((2-(5-chloro-li/-pyrrolo[2,3-b]pyridin-3-yl)-5-fluor opyr imidin-4-yla mino)m ethyl)pip eridixxe-1 -carboxy late (164). LCMS RT - 3.0 (M+l) 443.5.

[00796] (iS)-(2-((2-(5-chloro-l//-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)piperidin-l-yI)(thxazol-2-yl)methanone (165). LCMS RT = 2.8 (M+l) 472.5.

[00797] (S)-(2-((2^5-chloro-lff-pyrroIo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyI)piperidin-l-yl)(3“methoxyphenyl)methanone (174). LCMS RT = 2.8 (M+l) 495.6.

[00798] (^-methyl 2-((2-(5-chloro-l/i-pyrTolo[2,3-£]pyridin-3-yI)-5-fluor opy r imidin-4-yla mino)methyI)p iperidine-l-ca rboxylate (166). LCMS RT = 2.9 (M+l) 419.5.

[00799] (R)-l-(2-((2-(5-chloro-l//-pyrrolo[2,3-6]pyridin-3-yl)-5-fluoropyriniidin-4-ylamino)methyl)piperidm-l-yI)ethanone (179). LCMS RT = 2.5 (M+l) 403.4.

[00800] (5)-ethyl 2-((2-(5-chloro-lfl-py rrolo [2,3-6] py rid in-3-yl)-5-fluoropyrimidin-4-ylammo)methyl)piperidine-l-carboxylate (171). LCMS RT = 3.0 (M+l) 433.3.

[00801] (jR)-(2-((2-(5”Chloro-l/f-pyrrolo[2,3-0]pyridin“3“yl)-5-fluoropyrimidin-4-ylamino)methyl)piperidin-l-yl)(3-methoxyphenyl)methanone (184). LCMS RT = 2.7 (M+l) 495.5.

[00802] (J?)-l-(2-((2-(5-cliloro-177-pyrroIo [2,3 -b\ py r idin-3-yl)-5-fluoropy rimidin-4-ylammo)methyl)pip eridin-l-yl)propan-l-one (208). LCMS RT = 1.9 (M+l) 417.2.

[00803] (fi)-(2-((2-(5-chloro-l//-pyrrolo[2,3-6]pyridm-3-yl)-5-fiuoropyrimidin-4-yIamino)methyl)pxperidin-l-yl)(2-methoxyphenyI)methanone (190). LCMS RT = 2.9 (M+l) 495.4.

[00804] (i?)-(2-((2-(5-chloro-li/-pyrrolo[2,3-Z>]pyridin-3-yl)-5-fluor©pyrimidin-4-ylaraino)methyl)piperidm-l-yl)(4-fluorophenyl)niethanoiie (209). LCMS RT = 2.0 (M+l) 483.1.

[00805] (jR)-(2-((2-(5-chloro-lii-pyrrolo[2,3-6]pyridin-3-yl)~5-fluoropyrimidm-4-ylami n o)m ethyl)pip eridin-l-yl)(3-(trifluoro m ethyl)ph enyl)methanon e (210). LCMS RT = 2.2 (M+l) 533.1.

[00806] (R)-4-chloro-l-(2-((2-(5-chloro-l//-pyrrolo[2,3-/i]pyridin-3-yI)-5-fluoropyriinidin-4-ylamino)methyl)piperidin-i-yl)butan-l-one (278). LCMS RT = 2.4 (M+l) 465.1.

[00807] (R)“l-(2-((2-(5-chloro-l//-pyrrolo[2,3-A]pyridin-3-yl)-5-fluoropyrimidin-4-yIamino)methyl)piperidin-l-yI)pent-4-en-l-one (279). LCMS RT = 2.1 (M+l) 443.2.

[00808] (jR)-l-(2-((2-(5-chl oro-l//-py rrolo [ 2,3-*] py rid in-3-y l)-5-fIuoropy ri mi din-4-ylamino)methyl)piperidin-l-yl)-3,3s3-trifluoropropan-l-one (280). LCMS RT == 2.1 (M+l) 471.2.

[00809] (/?)-l-(2-((2-(5-chloro-17/-pyrrolo[2,3-6]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)piperidin-l-yl)hex-5-yn-l-one (281). LCMS (M+l) 454.2.

[00810] (Λ)-1 -(2-((2-(5-chloro-l.H-py rr olo [2,3 -b\ py ridin-3-yl)-5-fluor opy rimidin-4-ylamino)methyl)piperidin-l-yl)-3-phenylpropan-l-one (293). LCMS RT = 3.1 (M+l) 493.2.

[00811] (ff)-l -(2-((2-(5-chlor o-ltf-py rrolo [2,3 -b] py ridin-3-y l)-5-fluoropy rimidin-4-ylamino)methyl)piperidin-l-yl)-2-cyclohexylethanone (294). LCMS RT = 3.3 (M+l) 485.2.

[00812] (ff )-1 -(2-((2-(5-chloro-l/i-py rrolo [2,3-6] py ridin-3-y l)-5-fluor opy rimidin-4-yiamino)methyl)piperidin-l-yI)butan-l-one (295). LCMS RT = 2.9 (M+l) 431.2.

[00813] (J?)-l-(2-((2-(5-chloro-l//-pyrroIo[2,3-A]pyridin-3-yI)-5-fluoropyrimidin-4-yIamino)methyl)piperidin-l-yI)pentaii-l-one (326). LCMS RT = 3.0 (M+l) 445.2.

100814] (S)-l-(2-((5-fluoro-2-(ltf-pyrroIo[2,3-6]pyridm-3-yl)pyrimidin-4-ylamino)methyl)piperid in-1 -yl) ethan one (256). LCMS RT = 2.2 (M+l) 369.3.

[00815] (S)-l-(2-((5-fluoro-2-(l#-pyrrolo[2,3-6]pyridin-3-yl)pyrimidin-4-y la min o)methy l)piperidin-l-y l)pr opan-1 -one (257). LCMS RT - 2.3(M+l) 383.3.

[00816] (5)-l-(2-((5-fluoro“2“(ljfif-pyrrolo[2,3-6]pyridin-3-yi)pyrimidin-4-ylamino)methyl)piperidm-l-yl)butan-l-one (258). LCMS RT - 2.5(M+1) 397.3.

[00817] (5r)-(2-((5-fluoro-2-(l/7-pyrrolo[2,3-A]pyridin-3-yl)pyrimidin-4-ylamino)methyl)piperidin-l-yl)(phenyl)methanone(259). LCMS RT = 2.4 (M+l) 431.3.

[00818] (5)-(2-((5-fluoro-2-(1//-pyrrolo[2,3-/j]pyridin-3-yl)pyrimidin-4-ylamino)methyl)piperidin-l-yl)(2-methoxyphenyl)methanone (260). LCMS RT = 2.4 (M+l) 461.3.

[00819] (l?)-2-(5-chloro-l/7-pyrroio[2,3-b]pyridin-3-yl)-5-fluorowV-((l-(methylsulfonyl)-piperidin-2-yl)methyl)pyrimidin-4-amine(381). LCMS RT = 2.7 min, (M+H) 439.3 [00820] (jR)-2“(5“Chloro-l//-pyrrolo[2,3-b]pyridin-3-yl)-5-tluorowV-((l-(ethylsulfonyl)-piperidin-2-yl)methyl)pyrimidin-4“amine(382). LCMS RT = 2.9 min, (M+H) 453.3.

[00821] (iZ)“2“(5“Chloro-llf-pyrrolo[2,3-/i]pyridin-3-yl)“5-fluoro-iV-((l-(propylsuIfonyl)piperidin-2-yI)methyl)pyrimidin-4-amine (328). LCMS RT = 2.2 min, (M+H) 467.1.

[00822] (R)-2-(5-chloro-l//-pyrroIo[2,3-b]pyridin-3-yl)-5-fluoro-/V-((l-(2,2,2-trifluoro-ethylsulfonyi)-piperidin-2-yl)methyl)pyrimidin-4-amiiie (383). LCMS RT - 3.0 min, (M+H) 507.3.

[00823] (5)-2-(5-chIoro-l//-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-Ar-((l-(methylsulfonyl)-piperidin-2-yl)methyl)pyrimidin-4-amine (384). LCMS RT = 2.7 min, (M+H) 439.3.

[00824] CR)-iV-((l-(butylsulfonyl)piperidin-2-yI)methyl)-2-(5-chloro-l//-pyrrolo[2,3-£]pyridm-3-yl)-5-fiuoropyrimidin-4-amine (329). LCMS RT = 2.3 min, (M+H) 481.2.

[00825] (S)-2-(5-chloro-l//-pyrrolo[2,3-b]pyridm-3-yl)-5-fiuoro-iV-((l“ (cyclopropylsulfonyl)-piperidin-2-yl)methyl)pyrimidin-4-amine (386). LCMS RT = 2.9 min, (M+H) 465.3.

[00826] (ii)-2“(5-chIorO“lii“pyrroIo[2,3-6]pyridin-3-yl)-7V-((l-(3~ chloropropylsulfonyl)piperidin-2-yl)methyl)-5-fluoropyrimidin-4-amine (330). LCMS RT = 2.2 min, (M+H) 501.1.

[00827] (i?)-2-((5-fluoro-2-(li/-pyrroIo[2,3-b]pyridm-3-yl)pyrimidin-4-ylamino)methyl)-iV-isopropylpiperidine-l-carboxamide (371). LCMS RT = 1.8 min, (M+H) 412.2.

[00828] CR)-iV-cyclopropyl-2-((5-fluoro-2-(l//-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)-methyl)piperidine-l-carboxamide (372). LCMS RT = 1.9 min, (M+H) 424.2.

[00829] (R)-A'-ethyl-2-((5-fluoro-2-(l//-pyrrolo[2,3-blpyridin-3-yl)pyrimidin“4“ ylamino)-methyl)piperidine-l-carboxamide (373). LCMS RT = 1.7 min, (M+H) 398.2.

[00830] (tf)-2-((5-fluor o-2-(l.ff-py r r olo [2,3-b]py r idin-3-y l)py rimid in-4-ylammo)methyl)-N-methylpiperidine-l-carboxamide (374). LCMS RT = 1.6 min, (M+H) 384.2.

[00831] (/?)-2-((5-fluoro-2-(l//-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)methyl)-N-propylpiperidine-l-carboxamide (375). LCMS RT = 1.8 min, (M+H) 412.2.

General Scheme 14

(a) 'Pr2NEt, isopropanol, 80 °C (b) 5-chloro-3-(4,4,5,5-tetramethy!-1,3,2-dioxaborolan-2-yl)-1-tosyI-1H-pyrrolo[2,3-b]pyridine, Pd(Ph3P)4. Na2C03, DME, 130 °C (c) HCi/dioxane, Ch^Cfe (d) propyiisocyanate, pyridine, CH2Ci2 [00832] Formation of l-((2-chloro-5-fluoropyrimidin-4- ylamino)methyl)cyclohexanol (14a).

To a solution of 2-(aminomethyl)cyclohexanol hydrochloride (0.09 g, 0.54 mmol) and 2,4-dichloro-5-fluoro-pyrimidine (0.10 g, 0.60 mmol) in isopropanol (2 mL) was added 'P^NEt (0.21 mL, 1.20 mmol). The reaction mixture was heated at 80 DC for 12 hours. The reaction mixture was was concentrated under reduced pressure and the resulting residue was purified by silica gel chromatography (25%-75% EtOAc/hexanes) to afford desired product, 14a. LCMS (M+l) 260.1, (M-l) 258.3.

[00833] Formation of 2-((2-(5~chioro-l-tosyl-Li/-pyrrolo[2,3“bjpyridin“3-yl)-5-fluoropyrimidin-4-ylamino)methyl)cyclohexanol (14b)

To a degassed solution of 5-chloro-1 -(p-tolylsulfonyl)-3 -(4,4,5,5-tctramethyl-1,3,2-dioxaborolari“2-yl)pyrrolo[2,3-b]pyridine (0.15 g, 0.35 mmol), l-((2-chloro-5-fluoropyrimidin-4-ylamino)methyl)cyclohexanol, 14a, (0.09 g, 0.35 mmol) and aqueous KOAc solution (1.04 mL of 1M solution, 1,04 mmol) in dimethylacetamide was added palladium triphenylphosphine (0.04 g, 0.03 mmol). The reaction mixture was heated at 140 °C in microwave for 15 min and then cooled to room temperature. The reaction mixture was filtered through celite, concentrated in vacuo, and the resulting crude residue was purified by by preparatory HPLC (0. l%TFA-I-LO/aceionitrile) to afford the desired product, 14b: LCMS RT = 2.6 (M+l) 530.3.

[00834] Formation of (2R)-2-((2-(5-chioro-l//-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-y!amino)methyl)cyclohexanol (12)

To a solution of 2-((2-(5-chloro-l-tosyl-l//-pyrrolo[2,3-&amp;]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)cyclohexanol, 14b, (0.10 g, 0.19 mmol) inTHF (3 mL) was added aqueous lithium hydroxide (1 mL of IN solution). The reaction mixture was stirred at room temperature for 12 hours. The resulting residue was purified by preparatory HPLC (0.1%TFA-H2O/acetonitrile) to afford the desired product, 12. LCMS FIA RT = 1.9 (M+l) 376.2.

[00835] 2-(2-(5-chloro-l/f-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)cyclohexanol (13) LCMS FIA RT = 1.8 (M+l) 362.2.

[00836] 2-(2-(5-chloro-li/-pyrrolo[2,3-£]pyridin-3-yl)-5-fluoropyrimidm-4-ylamino)cyclopentanol (14) LCMS FIA RT = 1.0 (M+l) 348.3.

657 [00837] (IJi, IS, 3R, 5//)-3-(2-(5-chloro-l//-pyrro]o[2,3-Z>]pyndin-3-yi)-5-fluoropyrimidin-4-yIamino)-5-(hydroxymethyl)cyclopentane-l,2-diol(657) 'H NMR (300 MHz, DMSO) 5 12.41 (s, 1H), 8.80 (d, J= 2.3 Hz, 1H), 8.28 (d,/= 2.4 Hz, 1H), 8.25 (s, 1H), 8.17 (d, J= 4.0 Hz, 1H), 7.64 (s, 1H), 4.80 - 4.50 (m, 3H), 4.47 (dd, ./= 7.5, 14.8 Hz, 1H), 3.89 (dd, ,/= 5.3, 6.3 Hz, 1H), 3.77 (dd, ./= 5.1, 5.0 Hz, 1H), 3.50 - 3.37 (m, 2H), 2.36-2.24 (m, 1H), 2.04 (dd,/= 8.3, 13.5 Hz, 1H), 1.99 (s, 1H), 1.27 (td, ./ = 8.4, 4.4 Hz, 1H) and 1.21 (s, 1H) ppm. LCMS RT = 3.0 (M+l) 399.4.

General Scheme 14B

(a) Raney-Νί, H2 (50 PSI), EtOH (b) 15a, THF, 70 °C (c) TFA, CHZCI2 (d) 1N LiOH, THF, 120°C

[00838] Formation of te/7-butyl t#wis-2-(aminomethyl)cycIohexyIcarbamate (14d) A solution of teri-butyl /ra«.y-2-cyanocyclohexylcarbamate and Raney-Ni in absolute EtOH was stirred under H2 atmosphere (50 PSI) for 24 hours. Filtration and evaporation of the solvent followed by flash chromatography (S1O2,0-20% MeOH-CH2CL, gradient elution) provided the target compound, 14d, as a racemic mixture of trans isomers (286 mg, 66% yield): FIA (M+H) 229.33.

[00839] Formation of tot-butyl tom.v-2-((2-(5-ch loro-1-tosyl-l/7-pyr rolo [2,3-A]pyndm-3-yl)-5-fluoro-pyrimidm-4-yl-amino)methyl)cydohexylcarhamate (14e) A mixture of 5-cbloro-3-(5-fluoro-4-(mcthyisulfmyl)pyrirnidin-2-yl)-l-tosyl-l//-pyrrolo[2,3-i]pyridine, 15a, (0.42 g, 0.90 mmol) and tot-butyl p-««s-2-(aminomethyl) cyclohexylcarbamate (0.24 g, 1.06 mmol) were heated in THF (10 mL) to 70 °C. After 1.3 hours, the mixture was concentrated in vacuo. Flash chromatography (SiCb, 0-60% EA/Hex, gradient elution) provided the desired intermediate, ten-butyl tr««s-2-((2-(5-chloro-l-tosyl-l//-pyrrolo[2,3-/)]pyridin-3-y])-5-fluoropyrimidin-4-ylamino)m.cthyl)cyclohexylcarbamate, 14e, as a racemic mixture of trans isomers, which was taken into the next reaction without further purification (0.52g, 92% yield).

[00840] Formatio n of tV-((tra/rv-2-aminocyclo hexyI)methyl)-2-(5-chloro-l -tosyl-lZL/-pyrroIo[2,3-/>]pyridin-3-yl)-5-fluoropyrimidin-4-amine (14f) A solution of the to'i-butyl //r»j.w2-((2-(5-chloro-l-tosyl-l//-pyrrolo[2,3-i>]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)cyclohexylcarbamate, 14e, (0.52g) in CH2CI2 (5mL) was treated with TFA (2.5 mL) for 30 min. the solution was concentrated in vacuo and the resulting crude material was taken up in CH3CN and concentrated in vacuo several times to remove excess TFA and to provide the desired amine, 14f, as racemic mixture of trans isomers, as the TFA salt, which was sufficiently pure for use in the next reaction. LCMS RT = 1.93 min, (M+H) 529.0

[00841] Formation of Ar-((trajix-2-aminocyclohexyl)methyl)-2-(5-chloro-l/f-pyrrolo[2,3-b\pyridin-3-yl)-5-fluoropyrimidin-4-amine (555) A solution of A-((toins-2-aminocyclohexy l)methyl)-2-(5-chloro-l-tosy 1-1//-pyrrolo[2,3-h]pyridin-3-yl)-5-fluoropyrimidin-4-amine, 14f, (0.050g, 0.077 mmol) in THF was treated with LiOH (0.5 mL, 1.0M) at 60 °C. After 5 min, at 120 °C, the solution was diluted with EtOAc, and washed with brine, filtered and concentrated in vacuo. Preparative HPLC provided the desired compound, 555, as a racemic mixture of trans isomers (12 mg, 33% yield). lB NMR (300 MHz, MeOD) δ 8.75 (d, J= 2.4 Hz, 1H), 8.31 (d, /= 2.4 Hz, 1H), 8.29 (s, 1H), 8.24 (d, 4.4 Hz, 1H), 3.96 (dd, J= 5.8, 14.4 Hz, 1H), 3.73 (dd, J= 4.3, 14.3 Hz, 1H), 3.08 - 3.00 (m, 1H), 2.05 - 1.87 (m, 3H), 1.80 (m, 3H) and 1.48 - 1.39 (m, 4H) ppm; LCMS RT = 1.9 min, (M+H) 375.0.

General Scheme 14C

(a) i: RCOCI, DIEA, CH2CI2 ii: 1N LiOH, THF, 120°C, [00842] Formation of AHftwJS-2-((2-(5-chloro-l/J-pyrrolo[2,3-6]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)methyl)cyciohexyl)-2-methoxyethanamide (556)

To a cooled mixture of ΛL((l/^m.s-2-an^inocyclohexyl)methyl)-2-(5-chloIΌ-i-tosyl-l//-pyrrolo[2,3-fφyridin-3-yl)-5-fluoropyrimidin-4-amine (0.060 g, 0.093 mmol) and ‘Pr2NEt (0.057 mL, 0.330 mmol) in CH2C12 (2mL) at 0 °C, was added 2-methoxyacetyl chloride (0.010 g, 0.098 mmol). After 5 min, the solution was allowed to warm to room temperature. After 3 hours, the mixture was concentrated in vacuo, taken up in THF (1 mL) and treated with LiOH (0.326 mL, 1.0 M solution) at 120 °C for 10 min. The resulting mixture was cooled to room temperature and partitioned and the aqueous layer extracted with EtOAc and the combined organics were concentrated in vacuo. Preparative HPLC provided the desired product, 556, as a racemic mixture of TFA salts (8.6 mg, 17% yield). lK NMR (300 MHz, MeOD) 5 8.74 (d, /= 2.3 Hz, 1H), 8.42 (s, 1H), 8.38 (d, / = 2.3 Hz, 1H), 8.27 (d, / = 5.4 Hz, 1H), 3.85 - 3.81 (m, 2H), 3.75 (d, /= 8.5 Hz, 2H), 3.26 (s, 3H), 1.97 - 1.77 (m, 5H) and 1.43 - 1.35 (m, 4H) ppm; LCMS RT = 2.8 min, (M+H) 446.8.

[00843] The following analogs can be prepared in same manner as 556.

[00844] Formation of jV-(n an,s-2-((2-(5-chloro-l//-pyrrolo[2,3-/)]pyridin-3-yl)-5-fluoropyrimidin-4-yla min o)methyl)cyclohexyl)metha nesulfonam ide (557)

Sulfonamide 557 was prepared according to the procedure for compound 36 (Scheme 12B) using A-((ira«.y-2-aminocyc]ohexyT)mefhyl)-2-(5-chloro-1 -tosyl-1 //-pyrrolo[2,3-Z?]pyridin-3-yl)-5-fluoropyrimidin-4-amme, 14f, and methane sulfonyl chloride, afforded desired product, 557, as a racemic mixture of trans isomers. *H NMR (300.0 MHz, MeOD) 5 8.78 (d, 7= 2.4 Hz, 1H), 8.45 (d, / = 4.2 Hz, 1H), 8.37 (d, ./= 2.3 Hz, 1H), 8.26 (d,/= 5.4 Hz, 1H), 4.12 (dd,/= 4.5, 13.7 Hz, 1H), 3.89 (dd, / = 7.1, 13.8 Hz, 1H), 3.26 - 3.16 (m, 1H), 3.00 (s, 3H), 2.18 - 1.90 (m, 2H), 1.79 - 1.74 (m, 2H) and 1.50 - 1.25 (m, 4H) ppm; LCMS RT = 2.8 min, (M+H) 452.6.

[00845] Formation of 3-(irans-2-((2-(5-chIoro-l,ff-pyrroIo[2,3-A]pyridin-3-yl)-5-fluoropyrimidin-4-yla min o)methyl) cyclohexy 1)-1,1 -dimethylu rea (564)

Urea 564 was prepared according to the procedure for compound 20 (Scheme 12A) using A-((fra«.9-2-aminocyclohexyl)methyl)-2-(5-chIoro-l-tosyl-l//-pyrrolo[2,3-/j]pyridin-3- yl)-5-fluoiOpyrimidm-4-amine, 14f, and dimethylcarbomoyl chloride, afforded desired product, 564, as a racemic mixture of trans isomers. 'H NMR (300.0 MHz, MeOD) 5 8.78 (d, / = 2.4 Hz, 1H), 8.45 (d, / = 4.2 Hz, 1H), 8.37 (d, / = 2.3 Hz, 1H), 8.26 (d, /= 5.4 Hz, 1H), 4.12 (dd, /=4.5, 13.7 Hz, 1H), 3.89 (dd, / = 7.1, 13.8 Hz, 1H), 3.26 - 3.16 (m, 1H), 3.00 (s, 3H), 2.18 - 1.90 (m, 2H), 1.79 - 1.74 (m, 2H) and 1.50 - 1.25 (m, 4H) ppm; LCMS RT - 1.9 min, (M+H) 445.7.

General Scheme 15

(a) (1 S,2S)-cyclohexane-1,2-diamine, THF, 140 °C (b) AcCI, 'P^NEt, CH2CS2 (c) 1M LiOH, DCE, 150 °C, microwave 20 min.

[00846] Formation of (15, 25)-AT-(2-(5-chloro-l-tosyH//-pyrrolo[2,3-b]pyridm“3-yl)-5-fluoropyrimidin-4-yl)cyclohexane-l,2-diamine (15b) 5-Cliloro-3-(5-f:luoro-4-mcthylsulfmyl-pynmidin-2-yl)-l-(Jy-tolylsu]ibnyl)pyrroIo[2,3-bjpyridine, 15a, (0.25 g, 0.53 mmol) and (15,25)-cyclohexane-l,2-diamine (0.12 g, 1.08 mmol) were dissolved in THF (3.0 mL), and heated to 140 °C for 20 minutes in a sealed vial. The solvent was evaporated in vacuo and the residue was purified by silica gel chromatography (0%-15% MeOH/CH2Cl2) to provide product, 15b, as a white foamy solid (220 mg, 79% yield). Ή NMR (300 MHz, CDCI3) δ 8.85 (d, / =2.4 Hz, 1H), 8.52 (s, 1H), 8.40 (d, / =2.4 Hz, 1H), 8.13 - 8.09 (m, 3H), 7.31 - 7.28 (m, 2H), 5.14 (d, /=6.6 Hz, 1H), 3.96 - 3.85 (m, 1H), 2.69 (td, /=10.2, 4.7 Hz, 1H), 2.40 (s, 3H), 2.33 (d, /=5.6 Hz, 1H), 2.12 - 2.06 (m, 1H), 1.88 - 1.84 (m, 2H) and 1.60 - 1.21 (m, 4H) ppm; LCMS RT - 2.33 (M+l) 515.2.

[00847] Formation of iV-[(lS, 2S)-2-[[2-(5-chloro-17/-pyrrolo[2,3-b]pyridin-3-yl)-5“fluoro-pyrimidin-4~yl]amino]cyclohexyl]acetamide (433). (15,25)-Ab[2-[5-chloro-l-(p-tolylsulfonyl)pyrrolo[5,4-b]pyridin-3-yl]-5-fluoro-pyrimidin-4-yl]cyclohexane-l,2-diamine, 15b, (0.100 g, 0.194 mmol) was dissolved in dichloromethane (2 mL) and treated with lPr2NEt (0.075 g, 0.301 mL, 0.583 mmol). Acetyl chloride (0.021 mL, 0.291 mmol) was added and the reaction was allowed to stir at room temperature for 30 minutes. The volatiles were evaporated under reduced pressure, and the residue was dissolved in dichloroethane (2 mL) and treated with LiOH (0.097 mL of 1 M solution, 0.971 mmol). The reaction mixture was heated in the microwave at 150 °C for 10 minutes. The reaction was diluted with EtOAc (5 mL) and water (5 mL) and the layers were separated. The aqueous layer was extracted with EtOAc (2x5 mL), and the combined organic extracts were dried over Na2S04 and concentrated in vacuo to provide the crude product, which was purified by silica gel chromatography (0%-15% MeOH/CH2Cl2) to provide N-[(15, 25)-2-[[2-(5-chloro-lH-pyiTolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4- yl]amino]cyclohexyl]acetamide, 433, (34 mg, 44% yield). 'HNMR (300 MHz, /6-DMSO) δ 13.03 (s, 1H), 9.10 (s, 1H), 9.05 (s, 1H), 8.67 (d, / =2.1 Hz, 1H), 8.48 (d,/=5.4Hz, 1H), 8.43 (d,/ =2.3 Hz, 1H), 7.97 (d, / =7.7 Hz, IH), 4.15 - 4.07 (m, 1H), 3.93 - 3.87 (m, 1H), 2.20 - 2.15 (m, 1H), 1.99 - 1.92 (m, 1H), 1.85 - 1.79 (m, 2H), 1.74 (s, 3H) and 1.52 - 1.36 (m, 4H) ppm; LCMS RT = 2.41 (M+l) 403.4.

General Scheme 16

(a) cyclohexane-cis-1,2-diamine, isopropanol, 'Pr2NEt(b) 3-(4,4,5,S-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-i>]pyridine, Pd(PPh3)4, Na2C03, DME: DCE, 150 °C, microwave; (c) 1M LiOH 150 °C, microwave; (d) MeS02CI, 'Pr2NEt, DMF:DCM.

[00848] Formation of M-(2-chloro-5-fluoropyrimidin-4-yl)cyclohexane-ds-l,2-diamine (16a) 2,4-Dichloro-5-fluoropyrimidine (0.50 g, 2.99 mmol) was dissolved in isopropanol (7 mL) and treated with 'Pr2NEt (1.50 mL, 8.98 mmol). Cyclohcxane-m-1,2-diamine (0.46 g, 4.03 mmol) was added and the reaction was allowed to stir at room temperature overnight. The solvent was evaporated and the reaction mixture was diluted in EtOAc (15 mL) and washed with aqueous saturated NaHCC>3 solution. The aqueous layer was extracted with EtOAc (15 mL) and the combined organic layers were dried over Na2S04 and concentrated in vacuo to provide the crude product. The resulting crude was purified by silica gel chromatography (5%-30% MeOH/CH2Cl2) to provide 16a (370 mg, 50% yield) as a white solid. ‘HKMR (300 MHz, CDCla) δ 7.83 (d, /=2.8 Hz, 1H), 6.16 (s, 1H), 4.08 (s, 1H), 3.13 (d, /=3.9 Hz, 1H) and 1.84 - 1.44 (m, 8H) ppm; LCMS RT = 0.8 (M+l) 245.1.

[00849] Formation of M-(5-fiuoro-2-(lH-pyrrolo[2,3-b]pyridin~3-yl)pyrimidin-4-yl)cyclohexa ne-1,2-dia mine (16b) 3-(4,4,5,5-Tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyriOlo[2,3-b]pyridine (0.26 g, 0.65 mmol) was dissolved in DME (8 mL) and treated with Al-(2-chloro-5-fluoropyrimidin-4-yl)cyclohexane-cis- 1,2-diamine, 16a, (0.16 g, 0.65 mmol). Pd(PPli3)4 (0.10 mg, 0.08 mmol) and 2M aqueous Na2C02 (3.25 mL) were added and the suspension was heated in the microwave to 150 °C for 20 minutes. 1M aqueous LiOH (5 mL) was added, and the reaction was heated in the microwave to 150 °C for an additional 15 minutes. The organic solvent was evaporated under reduced pressure and the aqueous phase was extracted with CH2C12 (2x20 mL). The combined organic phases were dried over Na2SC>4 and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (0%-100% CH2Cb/EtOAc) to provide product 16b (140 mg, 66% yield) as a brown foam. "'HNMR (300 MHz, /6-DMSO) 6 12.14 (s, 1H), 8.66 (d, /=8.0 Hz, 1H), 8.29 - 8.22 (m, 3H), 7.81 (s, 2H), 7.28 - 7.19 (m, 2H), 4.55 (s, 1H), 3.74 (s, 1H) and 1.92 - 1.49 (m, 8H) ppm; LCMS RT = 1.8 (M+l) 327.2.

[00850] Formation of Ar-[cis-2-[[5-fluoro-2-(lj?/-pyrrolo[2,3-b]pyridm“3-y l)py rim idin-4-yl J amino] cycloh exyl] methanesu!fonamide(337) M-(5-fluoro-2-(l//-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)cyclohexane-l,2-diamine, 16b, (0.009 g, 0.027 mmol) was dissolved in an 8:2 mixture of CH2C12/DMF (1 mL) and treated with 'Pr2NEt (0.019 mL, 0.110 mmol) and methanesulfonyl chloride (0.006 mL, 0.083 mmol). The reaction was stirred at room temperature overnight, concentrated in vacuo and the residue was purified by HPLC with 10%-90% acetonitrile/water with 0.03% TFA to provide compound 337. ^NMR (300 MHz, d6-DMSO) 5 12.47 (s, 1H), 8.64 (d, / =7.8 Hz, 1H), 8.45 - 8.34 (m, 3H), 7.29 (dd, /=4.8, 7.8 Hz, 1H), 7.06 (d, / =7.5 Hz, 1H), 4.47 - 4.25 (m, 1H), 4.05 -3.89 (m, 1H), 2.80 (s, 3H), 1.95 - 1.62 (m, 6H) and 1.49 - 1.24 (m, 2H) ppm.; LCMS RT = 2.3 (M+l) 405.3.

[00851] The following compounds can be prepared in a manner similar to the one described in either Scheme 15 or Scheme 16:

[00852] A'-[m-2-[[5-fluorO“2-(l//“pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl] amino] -cycIohexyl]propanamide (341) lH NMR (300 MHz, /6-DMSO) δ 12.47 (s, 1H), 8.65 (d,/=8.1 Hz, 1H), 8.49 - 8.23 (m, 3H), 7.61 (d, /=7.8 Hz, 1H), 7.29 (dd, / =4.7, 8.0 Hz, 1H), 4.39 (d, / = 19.5 Hz, 2H), 2.10 (q,/=7.6 Hz, 2H), 1.79- 1.64 (m, 6H), 1.48 (d,/=6.4 Hz, 2H) and 0.91 0,/=7.6 Hz, 3H) ppm; LCMS RT = 2.3 (M+l) 383.4.

[00853] -'V-[c/s-2-|[5-fluoro-2-(lJ//-pyrrolo|2,3-b|pyridin-3-yl)pyrimidin-4-yE]amino]cyclohexyl]butanamide (342) LCMS RT = 2.5 (M+l) 397.4.

[00854] /V-[m-2-[[5-fluoro-2-(l//-pyrrolo[2,3“b]pyridin-3-yI)pyrimidin-4-yl] amin o] cyclohexyl] cyclopenta necarboxamid e (343) LCMS RT = 2.7 (M+l) 423.4.

[00855] iV-[cis-2-[[5-fluoro-2-(lff“pyrrolo[2,3-b]pyridin-3-yl)pyrimidm-4-yl] amino] cyclohexyl] b enza mide (344) LCMS RT = 2.7 (M+l) 431.4.

[00856] Ar-[cis-2~[[5-fluoro-2-(lJ?-pyrrolo[2,3-b]pyridin-3-yl)pyrimidiii-4-yl]amino]cyclohexyl]propane-l-sulfonamide (346) lHNMR (300 MHz, /6-DMSO) 8 12.41 (s, 1H), 8.65 (d, / =7.8 Hz, 1H), 8.38 - 8.33 (m, 3H), 7.28 (dd,/=4.7, 7.9 Hz, 1H), 7.06 (d, /=8.1 Hz, 1H), 4.36 (s, 1H), 3.88 (s, 1H), 2.83 (t, / =7.7 Hz, 2H), 1.85 - 1.70 (m, 6H), 1.59 (q, / =7.8 Hz, 2H), 1.47 - 1.24 (m, 2H) and 0.82 (t, / =7.4 Hz, 3H) ppm; LCMS RT = 2.6 (M+l) 433.3.

[00857] l-Im-2-j[5-fluoro-2-(ljW-pyrrolo|2,3-b]pyridin-3-yl)pyrimidin-4-yl] amino] cyclohexyl]-3-p ropyl-urea (347) SH NMR (300 MHz, /6-DMSO) 8 12.47 (s, 1H), 8.64 (d, / = 7.8 Hz, 1H), 8.45 - 8.34 (m, 3H), 7.29 (dd, / = 4.8, 7.8 Hz, 1H), 7.06 (d, / = 7.5 Hz, 1H), 4.47 - 4.25 (m, 1H), 4.05 -3.89 (m, 1H), 2.80 (s, 3H), 1.95 - 1.62 (m, 6H) and 1.49 - 1.24 (m, 2H) ppm; LCMS RT = 2.4 (M+l) 412.4. 100858] ^-[(ΙΛ, 2R)-2-[[5-fluoro-2-(l//-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4- yl] amino] cyclohexyl] acetamide (348) LH NMR (300 MHz, /6-DMSO) 8 12.53 (s, 1H), 8.66 (d, /=7.6 Hz, 1H), 8.43 (s, 1H), 8.39 - 8.36 (m, 2H), 7.91 (d, /=7.9 Hz, 1H), 7.32 (dd, /=4.7, 7.9 Hz, 1H), 4.08 - 3.94 (m, 1H), 3.86 (d,/=8.4 Hz, 1H), 2.13 (d, / =24.3 Hz, 1H), 1.95 (d, / = 10.2 Hz, 1H), 1.81 1.73 (m, 2H), 1.73 (s, 3H) and 1.43 - 1.14 (m, 4H) ppm; LCMS RT = 2.2 (M+l) 369.4.

[00859] N-\trans-2-[ [2-(5-chloro-liT-pyrrolo [2,3-b]pyridin-3-y l)-5-fluoro-pyrimidin-4-yl]amino]cyclohexyl]propanamide (349) LCMS RT = 2.7 (M+l) 417.3.

[00860] A4(li?, 2R)-2-[[2-(5-chloro-l/7-pyrrolo[2,3-bJpyridin-3-yl)-5-fluoro-pyrimidin-4-yl]amino]cyclohexyl]cyclopentanecarboxamide (351) LCMS RT = 3.1 (M+l) 457.3.

[00861] iV-Kljff, 2_R)-2-[[2-(5-chloro-l//-pyrroloI2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-yl] amino]cyclohexyl]benzamide (352) LCMS RT = 3.0 (M+l) 465.3.

[00862] lV-[(li?, 2ff)-2-[[2-(5-chloro-li7-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-yl] amino] cyclo hexyl] methanesulfonamide (353) LCMS RT = 2.7 (M+l) 439.4.

[00863] ΐν-[(1Λ, 2R)-2-[[2-(5-chloro-l/7-pyrrolo[2,3-bjpyridin-3“yl)-5“fluoro-pyrimidin-4-yl]amino]cyclohexyl]propane-l-sulfonamide (354) LCMS RT = 3.0 (M+l) 467.3.

[00864] 1-[(1ϋ, 2i?)-2-[[2-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-yI)-5-fluoro-pyrimidin-4-yl]amino]cyclohexyl]-3-propyl-urea (355) LCMS RT = 2.8 (M+l) 446.3.

[008651 N-[(1R, 2/i)-2-[[5-fluoro-2“(l//-pyrroIo[2,3-b]pyridin-3-yl)pyrimidin-4“ yl] amino] cyclohexyl] butanamide (358) LCMS RT = 2.5 (M+l) 397.4.

[00866] lV-[(l.fi, 2/f)-2“[[5-fluorO“2“(l//-pyrrolo[2,3“b]pyridin“3"yl)pyrimidin-4-yl]amino]cyclohexyl]cyc!opentanecarboxamide (359) LCMS RT = 2.7 (M+l) 423.4.

100867| 2fi)-2-[[5-fluoro-2-(l//-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4- yl] amino] cyclohexyl] b enza mid e (360) LCMS RT = 2.63 (M+l) 431.4.

[00868] N-[(\R, 2/f)-2-[[5-fluorO”2-(lff-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl] amino] cyclohexyl] methanesulfonamide (361) NMR (300 MHz, d6-DMSO) δ 12.54 (s, 1H), 8.66 (d, J =8.0 Hz, 1H), 8.43 - 8.36 (m, 3H), 7.32 (dd,7=4.7, 7.9 Hz, 1H), 7.21 (d,/=8.3 Hz, lH),4.16(d,/=9.3 Hz, 1H), 3.35 (d, J =9.8 Hz, 1H), 2.91 (d, J =8.9 Hz, 3H), 2.12 - 2.02 (m, 2H), 1.79 - 1.73 (m, 2H) and 1.64 - 1.15 (m, 4H) ppm; LCMS RT = 2.4 (M+l) 405.3.

[00869] Ar-[(12f,2/?)-2-[[5-fluoro-2“(12/-pyrrolo[2,3-b]pyridin“3-yl)pyrimidin-4-yl]amino|cyclohexyl]propane-l-sulfonamide (362) 'H NMR (300 MHz, d6-DMSO) δ 12.43 (s, 1H), 8.68 (d, J =7.9 Hz, 1H), 8.38 - 8.33 (m, 3H), 7.29 (dd, J =4.7, 7.8 Hz, 1H), 7.17 (d, J =8.6 Hz, 1H), 4.14 (d,/ =6.9 Hz, 1H), 3.33 - 3.26 (m, 1H), 3.07 - 2.89 (m, 2H), 2.07 (d, 7 = 12.6 Hz, 2H), 1.76 (d, /=7.9 Hz, 2H), 1.61 - 1.33 (m, 6H) and 0.90 (1,/=7.4 Hz, 3H) ppm; LCMS RT = 2.6 (M+l) 433.3.

[00870] AL[/ra/ix-2-[[2-(5-chloro-li6-pyrrolo[2,3-b]pyridiii-3-yl)-5"fluoro-pyrimidin-4-yI] amin o] cyclo hexyl] butanamide (363) LCMS RT = 2.9 (M+l) 431.3.

[00871] /V-[(iranx-2-[[2-(5-chloro-lJ7-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-yl]amino]cyclohexyl]cyclopentanecarboxamide (364) LCMS RT = 3.1 (M+l) 457.3.

[00872] Ar~[i‘rans'-2-[[2-(5-chloro-lJ?-pyrroIo[2J3-b]pyridin-3-yl)-5-fluoro-py rimidin-4-yl] amino] cyclohexyl] benzamid e (365) LCMS RT = 3.0 (M+l) 465.3.

[00873] Ar-[ft,a«s-2-[[2-(5-chloro-Lflr-pyrrolo[2,3“b]pyridin-3-yl)-5-fluoro-pyrimidin-4-yl]amino]cyclohexyl]propane-l-sulfonaniide (367) LCMS RT - 3.0 (M+l) 467.3.

[00874] 1- [tra ns-2- [ [2-(5-ch loro-1 //-pyrrolo [2,3-b ]pyridin-3-y l)-5-flu oro-pyrimidin-4-yl]amino]cyclohexyl]-3-propyl-urea (368) LCMS RT = 2.8 (M+l) 446.3.

[00875] Methyl N-[(1S, 2,S')-2-[[2-(5-chloiO-m-pyrrolo[2,3-b]pyridin-3-yI)-5- fIuoro-pyrimidm-4-yi]amino]cyclohexyl]carbamate (425) Ή NMR (300 MHz, d6-DMSO) δ 13.02 (s, 1H), 9.10 (s, 2H), 8.67 (s, 1H), 8.44 -8.40 (m, 2H), 7.26 (d, J =6.5 Hz, 1H), 4.19 (s, 1H), 3.66 (d, J =9.8 Hz, 1H), 3.48 (s, 3H), 2.13 (s, 1H), 2.02 (d, J =9.2 Hz, 1H), 1.78 (d, J =9.6 Hz, 2H) and 1.47 - 1.34 (m, 4H) ppm; LCMS RT = 2.1 (M+l) 419.2.

[00876] 1-[(15, 25)-2-[[2-(5“Chloro-lf/-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro- py rimidin-4-yl] amino] cycloh exy l]-3-methyl-urea (426) *H NMR (300 MHz, /6-DMSO) 6 12.56 (s, 1H), 8.70 (d, J =2.2 Hz, 1H), 8.35 (dd, / =2.4, 6.8 Hz, 2H), 8.28 (d, / =4.2 Hz, 1H), 5.99 (d, /=7.0 Hz, 1H), 5.80 - 5.63 (m, 1H), 3.91 - 3.87 (m, 1H), 3.66 - 3.45 (m, 1H), 2.54 (s, 3H), 2.30 (d, /=13.0 Hz, 1H), 2.04 (d, / =46.9 Hz, 1H), 1.78 (d, /=8.5 Hz, 2H) and 1.56 - 1.23 (m, 4H) ppm; LCMS RT = 2.5 (M+l) 419.5.

[00877] 3-[(15, 2S)-2-[[2-(5-chloro-lJt/-pyrrolo[2,3-b]pyndin-3-yl)-5-fluoro- pyrimidin-4-yl] amino]cyclohexyl]-l,l“dimethyl-urea (427) *H NMR (300 MHz, /6-DMSO) δ 12.59 (s, 1H), 8.72 (d, / =2.3 Hz, 1H), 8.41 (d, / =2.7 Hz, 1H), 8.35 (d, / =2.3 Hz, 1H), 8.29 (d, / =4.4 Hz, 1H), 8.23 (s, 1H), 6.19 (d, / =7.8 Hz, 1H), 4.04 - 3.97 (m, 1H), 3.78 - 3.69 (m, 1H), 2.68 (s, 6H), 2.31 (d, / =11.6 Hz, 1H), 1.95 (d, / =9.8 Hz, 1H), 1.79 (d, / =10.4 Hz, 2H) and 1.60 - 1.32 (m, 4H) ppm; LCMS RT = 2.7 (M+l) 432.4.

[00878] N-[{IS, 2jS)-2-[[2-(5-chloro-l//-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro- pyrxmidin-4-y 1] amino] cyclohexyl] methanesulfonamide (428) NMR (300 MHz, t/6-DMSO) 5 12.54 (s, 1H), 8.72 (d, J =2.3 Hz, 1H), 8.38 - 8.29 (m, 3H), 7.82 (s, 1H), 7.21 (d, J =8.3 Hz, 1H), 4.52 (bis, 1H), 4.12 - 4.05 (m, 1H), 2.92 (s, 3H), 2.09 (d, /=12.8 Hz, 2H), 1.78 (brs, 2H) and 1.49 - 1.39 (m, 4H) ppm; LCMS RT = 2.7 (M+l) 439.4.

[00879] l-[c/s-2-[[2-(5-chloro-liT-pyrrolo[2J3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-yl]amino] cycloh exyl] -3-methyl-urea (430) ‘H NMR (300 MHz, /6-DMSO) 6 12.61 (s, 1H), 8.68 (d, J =2.2 Hz, 1H), 8.39 - 8.31 (m, 4H), 6.12 (d, J =6.7 Hz, 1H), 5.91 - 5.83 (m, 1H), 4.29 - 4.13 (m, 1H), 4.02 - 3.91 (m, 1H), 2.55 (s, 3H), 1.93 (d, J =12.8 Hz, 1H) and 1.74 - 1.53 (m, 7H) ppm; LCMS RT = 2.6 (M+l) 418.5.

[00880] 3-[ax-2-[[2-(5-chloro-liT-pyrrolo[2,3-blpyridin~3-yl)-5-fluoro-pyrimidm-4-yl] amino] cyclohexyl]-1,1-dimethyl-urea (431) lH NMR (300 MHz, x/6-DMSO) 5 12.54 (s, 1H), 8.68 (d, J =2.3 Hz, 1H), 8.33 - 8.29 (m, 3H), 7.96 (s, 1H), 5.72 (d, J =6.9 Hz, 1H), 4.36 (s, 1H), 4.10 (s, 1H), 2.76 (s, 6H), 1.96 - 1.87 (m, 2H), 1.74 - 1.63 (m, 4H) and 1.55 - 1.45 (m, 2H) ppm; LCMS RT = 2.8 (M+l) 432.4.

[00881] Methyl Ar-[m-2-[[2-(5-chloro-ljfiT-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-yl]ammo] cycloh exyl] carbamate (432) λΚ NMR (300 MHz, /6-DMSO) 6 12.54 (s, 1H), 8.67 (d, J =2.2 Hz, 1H), 8.35 - 8.29 (m, 3H), 7.62 (s, 1H), 7.05 (d, J =7.2 Hz, 1H), 4.50 - 4.40 (m, 1H), 4.20 - 4.10 (m, 1H), 3.46 (s, 3H), 1.87 (d, J =10.9 Hz, 2H), 1.71 - 1.65 (m, 4H) and 1.43 (d, J =7.4 Hz, 2H) ppm; LCMS RT = 2.9 (M+l) 419.4.

[00882] yV-[5-fluoro-2-(l//-pyrrolo[5,4-b]pyridin-3-yl)pyrimidin-4-yl]cyclohexane-cisA ,2-diamine (206) LCMS RT= 1.9 (M+l) 327.2.

[00883] f/'«HS“2“[[5“fluoro-2-(l//-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl] amino ]cyclohexanoI (207) LCMS RT = 2.2 (M+l) 328.2.

[00884] m-2-[[5-fluoro-2-(li/-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl] amino] cy do hexanol (277) LCMS RT = 1.6 (M+l) 328.2.

[00885] Ar~[cis-2-[[2-(5-chloro-l//-pyrrolo[2,3-b]pyridin-3-yl)-5“fluoro-pyrimidin-4-yl] amino] cyclohexyl] propanamide (333) LCMS RT = 2.7 (M+l) 417.4.

[00886] Ar-[m-2-[[2-(5-chlorO“lif-pyrrolo[2,3-b]pyridin-3-yl)~5-fluoro-pyrimidin-4-yl] amino] cyclohexyljbutanamide (334) LCMS RT = 2.9 (M+l) 431.4.

[00887] /V-i(.7i-2-[[2-(5-chlorO“li/“p\Trolo[2)3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-yl] amino] cyclohexyl] cyclopentanecarboxamide (335) LCMS RT = 3.1 (M+l) 457.3. 100888] ^-[«5-2- [ |2-(5-chlor o-l//-py rrolo [ 2,3-b ] py ridin-3-yl)-5-fluoro-pyrimidin~ 4-yl] amino] cyclohexyljbenzamide (336) LCMS RT = 3.0 (M+l) 465.4.

[00889] A-[m'-2-[[2-(5-chloro-li7-pyrrolo[2,3-b]pyridin-3-yI)-5-fluoro-pyrimidin-4-yl]amino]cyclohexyl]propane-l-sulfonamide (338) LCMS RT = 2.9 (M+l) 467.3.

[00890] l-[c/s-2-|[2-(5-chloro-l//-pyrrolo|2,3-bipyridin-3-y])-5-fluorO“pyrimidin- 4-yl]amino]cyclohexyl]-3-propyl-urea (339) LCMS RT = 2.9 (M+l) 446.3.

[00891] 1- [*υη/χ-2-[ [2-(5-chlor o-l if-py r r olo [2,3-b] py ridin-3-yl)-5-fluoro-pyrimidin-4-yI]amino]cyclohexyl]-3-propyl-urea (350) LCMS RT = 2.6 (M+l) 403.3.

[00892] JV~[(1jR, 2/£)-2-[[5-fluoro-2-(l/7-pyrrolo[2,3-bJpyridm-3-y])pyrimidin-4-yl] amin o] cyclohexyl]propanamide (356) LCMS RT = 2.3 (M+l) 383.4.

[00893] (1R, 2R)-7Vl-(2-(5-chloro-lJT-pyrrolft[2,3-A]pyridin-3-yl)-5- (trifluoromethyl)pyrimidin-4-yl)cyclohexane-l, 2-diamine (31) LCMS RT = 2.2 (M+l) 411.2.

[00894] M-(5-fluoro-2-(li7-pyrrolo[2,3-6]pyridin-3-yl)pyrimidin-4-yl)cyclohexane-l,2-diamine (4) LCMS RT = 2.2 (M+l) 327.2.

[00895] (1R, 2R)-/Vl-(5-chloro-2-(5-chIoro-177-pyrro]o[2,3-/;]pyridm-3- yl)py rimidin-4-yl)cyclo hexane-1,2-d iamine(115) LCMS RT= 1.3 (M+l) 377.2.

[00896] M-(2-(5-chloro-l/7-pyrrolo[2,3-A]pyridin-3-yl)-5-methylpyrimidin-4-yl)cyclohexane-l,2-diamine (116) LCMS RT = 3.3 (M+l) 357.2.

[00897] iV-[(lii, 2R)-2-\ [2-(5-chIoro-ltf-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-yl] amino] cyclohexyl] butanamide (369) LCMS RT = 2.9 (M+l) 431.3.

[00898] 2R)-2-[[5-fluoro-2-(l//-pyrrolo[2,3“b]pyridin-3-yl)pyrimidin“4“ yl]amino]cyclohexyl]-3-propyl-urea (370) LCMS RT = 2.4 (M+l) 412.4.

[00899] 2-(5-chloro-lf/-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-/V-(2-methoxycycIohexyl)-pyrimidin-4~amine (412) LCMS RT = 3.5 (M+l) 376.4. 100900] General Scheme 18

i. DPPA, EtjN, toluene, 110 °C; ii BnOH, 85 °C (b) LiOH, THF: H20 (c) Boc20, pyridine, NH4HCO3, dioxane (d) BTIB, CH3CN:H20.

[00901] Formation of (IS, 3/?)-3-(ethoxycarbonyl)cycIohexanecarboxylic acid (18a)

(IS, 3i?)-3-(ethoxycarbonyl)cyclohexanecarboxylic acid can be prepared following the literature procedures described in : Barnett, C. J., Gu, R. L.} Kobierski, Μ. E., WO-2002024705, Stereoselective process for preparing cyclohexyl amine derivatives.

[00902] Formation of ethyl (1Λ, 35)-3- benzyloxycarbonylaminocyclohexanecarboxylate (18b) (IS, 372)-3-(Ethoxycarbonyl)cyclohexanecarboxylic acid, 18a, (10.0 g, 49.9 mmol) was dissolved in toluene (100 mL) and treated with triethylamine (7.6 mL, 54.9 mmol) and DPPA (12.2 mL, 54.9 mmol). The resulting solution was heated to 110 °C and stirred for 1 hour. After cooling to 70 °C, benzyl alcohol (7.7 mL, 74.9 mmol) was added, and the mixture was heated to 85 °C overnight. The resulting solution was cooled to room temperature, poured into EtOAc (150 mL) and water (150 mL) and the layers were separated. The aqueous layer was extracted with EtOAc (2x75 mL) and the combined organic extracts were washed with water (lOOmL) and brine (100 mL), dried over Na2S04 and concentrated in vacuo. The crude material was purified by silica gel chromatography (0%-50% EtOAc/hexanes) to provide 18b (15.3 g, containing -25% benzyl alcohol), which was used for the next step without further purification.

[00903] Formation of (LR, 3£)-3-benzyloxycarbonylaminocyclohexanecarboxylic acid (18c)

Ethyl (17?, 3-S)-3-benzyloxycarbonylaminocyclohexanecarboxylate, 18b, (36 g, 117.9 mmol) was dissolved in THF (144.0 mL) and treated with a solution of LiOH (5.647 g, 235.8 mmol) in water (216.0 mL). After stirring overnight, the reaction mixture was diluted with water (100 mL), washed with methyl fe/t-butyl ether (150 mL) and brought to pH 3 by addition of 3N HC1. The acidic solution was extracted with EtOAc (3x100 mL), and the combined organic layers were washed with water and brine, dried on Na2S04 and concentrated in vacuo.

The crude product was triturated with methyl Zert-butyl ether (30 mL) and filtered to provide a first crop of crystals. The filtrate was treated with heptane (20 mL), concentrated to 30 mL and allowed to stand at room temperature for 3 hours to provide a second crop of crystals that were collected by filtration for a total of 14.4 g (44%yield) 18c. *H NMR (300 MHz, CDCI3) 5 7.38 - 7.33 (m, 5H), 5.11 (s, 2H), 4.68 (s, 1H), 3.55 (s, 1H), 2.44 (d, ,/=11.0 Hz, 1H), 2.32 (d, J =11.7 Hz, 1H), 2.03 - 1.86 (m, 3H) and 1.48 - 0.88 (m, 4H) ppm.

[00904] Formation of benzyl A-[(1S, 3jR)-3-carbamoylcyclohexyl]carbamate (18d)

To a solution of (17?, 3S)-3-Benzyloxycarbonylaminocyclohexanecarboxylic acid, 18c, (10.0 g, 36.1 mmol) in 1,4-dioxane (300 mL) was added pyridine (2.9 mL, 36.1 mmol), followed by di-fe?t-butyl dicarbonate (10.7 mL, 46.9 mmol) and ammonium bicarbonate (10.1 g, 126.2 mmol). After 3 hours, another portion of di-teri-butyl dicarbonate (1.5 g, 6.8 mmol) and ammonium bicarbonate (1.5 g, 6.8 mmol) was added and stirring was continued overnight. The reaction was quenched by addition of 2N HC1 (400 mL) and stirred for 1 hour. The resulting suspension was filtered under reduced pressure, washed with 2N HC1 (50mL), water (8x50mL) and hexanes (3x50mL) and vacuum dried to provide benzyl A/-[(1 S', 37?)-3-carbamoylcyclohexyl]carbamate, 18d, (9.1 g, 91%) as a white solid. NMR (300 MHz, CDCI3) δ 7.40 - 7.24 (m, 5H), 5.08 (s, 2H), 3.58 - 3.44 (m, 1H), 2.38-2.21 (m, 1H), 2.17 (d, 7 = 12.7, 1H), 2.05- 1.78 (m, 8H), 1.54 - 0.97 (m, 5H).

[00905] Formation of benzyl 7V-[(1S, 37?)-3-aminocyclohexyl] carbamate (18e)

Benzyl 37?)-3-carbamoylcyclohexyl]carbamate, 18d, (9.1 g, 32.9 mmol) was suspended in a mixture of acetonitrile (100 mL) and water (100 mL) and treated with . bis(trifluoroacetoxy)iodobenzene (15.5 g, 36.1 mmol). The suspension was allowed to stir at room temperature overnight and was then quenched with IN HC1 (lOOmL). After evaporation of the acetonitrile, the acidic aqueous solution was washed with EtOAc (2xl50mL). The pH was adjusted to basic by addition of solid KOH and the resulting emulsion was extracted with EtOAc (3x200 mL). The combined organic layers were dried over Na?S04 and concentrated in vacuo to provide product 18e (6.2 g, 75% yield). fH NMR (300 MHz, CDC13) δ 7.31 - 7.45 (m, 5H), 5.11 (s, 2H), 4.90 (br. s., 1H), 3.58 (br. s., 1H), 2.72 - 2.97 (m, 1H), 2.14 (d, J =11.90 Hz, 1H), 1.87 - 2.02 (m, 1H), 1.73 - 1.87 (m, 2H), 1.21 - 1.46 (m, 1H), 0.89 - 1.18 (m, 3H).

(a) MeOCOCI, Et3N, THF (b) H2, Pd/C, EtOH (c) 5-chloro-3-(5-fluoro~4-methylsulfinyl-pyrimidin-2-yl)-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridine, THF, 130 °C, microwave (d) LiOH, 130 °C, microwave.

[00907] Formation of methyl iV-[(12i, 3£)-3-benzyloxycarbonyI-aminocyclohexyl] carbamate (19a)

Benzyl ^-((15, 3i?)-3-aminocyclohexyl]carbamate, 18e, (0,99 g, 3.99 mmol) was dissolved in THF (20 mL) and treated with methyl chloroformate (0.62 mL, 7.97 mmol), followed by triethylamine (1.67 mL, 11.96 mmol). After stirring for 1 hour at room temperature, the solvent was evaporated under reduced pressure and the residue was diluted into 1:3 mixture of CH2Cl2:EtOAc (130 mL) and washed with IN HC1 (50 mL) and 2N Na2CC>3 (50 mL). The organic layer was dried over Na2SCU and concentrated under reduced pressure to afford the desired product, 19a, as a white solid (1.09g, 89% yield). ‘H NMR (300 MHz, CDClj) δ 7.21 - 7.37 (m, 5H), 5.02 (s, 2H), 4.26 - 4.62 (m, 1H), 3.58 (s, 3H), 3.34 - 3.54 (m, 2H), 2.24 (d, J =11.71 Hz, 1H), 1.82 - 2.03 (m, 2H), 1.72 (dt, J =3.14, 13.93 Hz, 1H), 1.23 - 1.44 (m, 1H), 0.79 - 1.02 (m, 3H).

[00908] Formation of methyl N-[(1ϋ, 35)-3-aminocyclohexyl]carbamate (19b)

Methyl 1V-[(1R, 3iS)-3-benzyloxycarbonylaminocyclohexyl]carbamate, 19a, (1.09 g, 3.56 mmol) was dissolved in ethanol (100 mL) and treated with 10% Pd/C (0.38 g, 0.36 mmol). The flask was capped, degassed and fitted with a hydrogen balloon and allowed to stir overnight. The reaction mixture was filtered under nitrogen and concentrated in vacuo to provide the product, 19b, as a white solid. *H NMR (300 MHz, CDCfe) 5 3.31 - 3.56 (m, 1H), 3.03 (s, 4H), 2.81 (t, J =10.67 Hz, 1H), 2.03 - 2.20 (m, 1H), 1.71 - 2.01 (m, 3H), 1.27 - 1.49 (m, 1H), 0.92 - 1.14 (m, 3H).

[00909] Formation of methyl iV-[(l.S, 35)-3-( [2-(5-chloro-lf/-pyrroIo [2,3- b]pyridin-3-yl)-5-fluoro-pyrimidin-4-yl]amino]cyclohexyl]carbamate (570) 5-chloro-3-(5-fhioro-4-methylsuIfmyl-pyrimidin-2-yl)-l-(p-tolylsulfony])-pyrrolo[2,3-b]pyridine, 19b, (2.04 g, 4.39 mmol) and methyl N-[(\R, 3S)-3-amino-cyclohexyl]carbamate (0.60 g, 3.14 mmol) were suspended in THF (16 mL) and heated in the microwave to 130 °C for 20 minutes. Lithium hydroxide (15.67 mL of 1M solution, 15.67 mmol) was added, and the resulting mixture was heated in the microwave for 20 min at 130 °C. The resulting solution was diluted with water (150 mL) and ethyl acetate (200 mL) and tire layers were separated. The aqueous layer was extracted with EtOAc (100 mL) and t organic layers were combined, dried over Na2SC>4 and concentrated in vacuo. The crude product was purified by silica gel chromatography (40-100% EtOAc/hexanes) followed by treatment of the pure fractions with 4N HC1 in dioxane to provide the hydrochloride of compound, 570, as an off white solid. *H NMR (300 MHz, MeOD) 5 8.81 (d, J =2.1 Hz, 1H), 8.20 (d, J =2.3 Hz, 1H), 8.15 (s, 1H), 7.97 (d, J =4.1 Hz, 1H), 4.26 - 4.18 (m, 1H), 3.71 - 3.52 (m, 1H), 3.59 (s, 3H), 2.36 (d, /=10.5 Hz, 1H), 2.18 (d, J =10.7 Hz, 1H), 2.04 - 1.86 (m, 2H), 1.57 (s, 1H) and 1.43 - 1.15 (m, 3H) ppm; LCMS RT = 2.0 (M+l) 419.4 (M-l) 417.3. 1009101 General Scheme 20.

(a) 5-chloro-3-{5-fluoro-4-methylsulfinyl“Pyrimidin-2-yl)-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridine, THF (b) CH2CI2, trifluoroacetic acid (c) acetyl chloride, E^N, THF (d) LiOH, 130 °C, microwave.

[00911] Formation of tert-butyl ΛΓ-[(1/ί, 3S)-3-[[2-[5-chloro-l-(p- tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-5-fluoro-pyrimidin-4- y 1] amin o] cyclo hexyl] carba mate (20b) te/T-Butyl N-[(1R, 35)-3-aminocyclohexyl]carbamate, 20a, (0.15 g, 0.70 mmol) and 5-chloro-3-(5-fluoro-4-methylsulfinyl-pyrimidin-2-yl)-l-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridine, la, (0.49 g, 1.05 mmol) were dissolved in THF (30 mL) and allowed to stir at room temperature overnight. The solvent was evaporated under reduced pressure and the residue was purified by two rounds of silica gel chromatography - first with (0%-10% MeOH/CH2Cl·)) second with (10%-50% EtOAc/hexanes) to provide tert-butyl *"-[(17?, 35)-3- [[2-[5-chloro-l-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-5-fluoro-pyrimidin-4- yl]amino]cyclohexyl]carbamate (20b) (330 mg, 38%). SH NMR (300 MHz, CDCh) 5 8.74 (d, ./ = 2.4 Hz, 1H), 8.58 (s, 1H), 8.38 (d, J= 2.4 Hz, 1H), 8.13 (s, 1H), 8.09 (t, J =3.3 Hz, 2H), 7.29 (d, J* 8.1 Hz, 2H), 5.02 (d, /= 7.1 Hz, 1H), 4.47 (d, ./ = 7.7 Hz, 1H), 4.25 - 4.16 (m, 1H), 3.68 (d, ./= 2.0 Hz, 1H), 2.48 (d, ./= 11.7 Hz, 1H), 2.38 (s, 3H), 2.26 (d, J= 12.8 Hz, 1H), 2.11 (d, J= 11.9 Hz, 1H), 1.95 - 1.89 (m, 1H), 1.69 - 1.56 (m, 1H), 1.44 (s, 9H) and 1.28 - 1.11 (m, 3H) ppm.

[00912] Formation of (17?, 35)-7Vl-[2-[5-chloro-l-(/>-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yi]-5-fluoro-pyrimidin-4-yl] cyclohexane-1,3-diamine (20c) ie/T-Butyl *-[(15, 37?)-3-[[2-[5-cldoro-l-(p-tolylsulfonyl)pynOlo[2,3-b]pyridin-3-yI]-5-fluoro-pyrimidin-4-yl]amino]cyclohexyl]carbamate, 20b, (0.33 g, 0.53 mmol) was dissolved in CH2CI2 (10 mL) and treated with trifluoroacetic acid (2 mL). After stirring for 2 hours, the solvent was evaporated under reduced pressure and the resulting residue was passed through a polymer supported carbonate column to provide the free base of (17?, 35)-M - [2- [5 -chloro-1 -(/?-toly lsulfonyl)py rrolo[2,3 -b]pyridin-3 -yl] -5 -fluoro-pyrimidin-4-yl]cyclohexane- 1,3-diamine , 20c, (0.25 g, 0.43 mmol, 81%). !H NMR (300 MHz, CDC13) δ 8.76 (dd, J = 2.4, 6.3 Hz, 1H), 8.52 - 8.49 (m, 1H), 8.39 (d, S = 2.4 Hz, 1H), 8.14 - 8.04 (m, 3H), 7.29 (d, J = 7.5 Hz, 2H), 5.61 (s, 1H), 4.28 - 4.16 (m, 1H), 3.19 - 3.10 (m, 1H), 2.39 (s, 3H), 2.39 - 2.31 (m, 1H), 2.08 - 1.90 (m, 3H), 1.63 - 1.50 (m, 1H) and 1.40- 1.17 (m, 3H)ppm .

[00913] Formation of N-[(XR, 35)-3-[[2-(5-chloro-li/-pyrrolo[2,3-b]pyridin-3-yl)- 5-fIuoro-pyrimidin-4-yl] amino] cyclohexyl] acetamide (547) (17?, 35)-M-[2-[5-chloro-l-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridm-3-yl]-5-fluoro-pyrimidin-4-yl]cyclohexanc- 1,3-diamine, 20c, (0.050 g, 0.097 mmol) was dissolved in THF (1.0 mL) and treated with triethylamine (0.041 mL, 0.290 mmol) and acetyl chloride (0.013 mL, 0.190 mmol). After stirring overnight, the solvent was evaporated and the residue was taken into THF (1.0 mL) and treated with 1M LiOH (1.0 mL, 1.0 mmol) . The reaction mixture was heated in the microwave to 130 °C for 10 minutes. The solvent was evaporated under reduced pressure, and the residue was purified by HPLC, using 5%-70% HoO/acetonitrile with 0.1%TFA. The purified fractions were concentrated to dryness to provide the TFA salt of the product, which was dissolved in MeOH and passed through a polymer bound carbonate cartridge to provide the free base of product 547. lH NMR (300 MHz, MeOD) δ 8.81 (s, 1H), 8.20 (s, 1H), 8.15 (s, 1H), 7.99 (d, / =4.1, 1H), 4.23 (t, / =11.4, 1H), 3.90 (t, / =11.4, 1H), 2.35 (d, / =11.6, 1H), 2.20 (d, / = 12.5, 1H), 2.00 (d, / =15.9, 2H), 1.92 (s, 3H), 1.67 (dd, / = 26.3, 13.2, 1H), 1.53 -1.06 (m, 3H) ppm LCMS RT = 2.1 (M+l) 403.2. 100914] The following compounds can be prepared by methods similar to those described in Scheme 19 and Scheme 20:

[00915] (\R, 35)-ΛΊ-[2-(5-chloro-l//-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-yl]cyclohexane-l ,3-diamine (542) LCMS RT = 1.4 (M+l) 361.4.

[00916] jV-[(l.fl, 3A)-3-[[2-(5-chIoro-l//-pyrroIo [2,3-b ]pyridin-3-yl)-5-fluo ropy r imidin-4-yl] amino] cyclohexyl] a cetamide (576) ‘HNMR (300 MHz, MeOD) δ 8.81 (s, 1H), 8.20 (s, 3H), 8.15 (s, 1H), 7.99 (d,/=4.1, 1H), 4.23 (t, / =11.4, 1H), 3.90 (t, / = 11.4, 1H), 2.35 (d, / = 11.6, 1H), 2.20 (d, /= 12.5, 1H), 2.00 (d, / = 15.9, 2H), 1.92 (s, 3H), 1.67 (dd, / = 26.3, 13.2, 1H), 1.53 -1.06 (m, 3H) ppm; LCMS RT = 1.8 (M+l) 403 (M-l) 401.4.

[00917] Methyl At[(iJ, 3R)-3-[[2-(5-chloro-ll/-pyrrolo[2,3-b]pyridin-3-yl)-5-f]uoro-pyrimldin-4-yl]amino]cydohexyl]carbamate (548). LCMS RT = 2.8 (M+l) 419.5.

[00918] 3- [(15,3-K)-3- [ [2-(5-chIoro-l/f-pyr rolo [2,3-b ]py ridin-3-y l)-5-fluor o-pyrimidin-4-yl]amino]cyclohexyl]-l,l-dimethyI-urea (549). LCMS RT = 2.6 (M+l) 432.5.

[00919] IV-[(IR, 3S)-3-[[2-(5-chloro-l/f-pyrrolo[2,3-b]pyndin-3-yl)-5-fluoro-pyrimidin-4-yl]ammo]cyclohexyl]-2-methoxy-acetamide (591) lH NMR (300 MHz, MeOD) 6 8.82 (d, J = 2.4 Hz, 1H), 8.21 (d, J = 2.3 Hz, 1H), 8.16 (s, 1H), 7.99 (d, /= 4.1 Hz, 1H), 4.29-4.21 (m, 1H), 4.04 - 3.96 (m, 1H), 3.87 (s, 2H), 3.40 (s, 3H), 2.34 (d, J= 11.6 Hz, 1H), 2.21 (d, J= 12.5 Hz, 1H), 2.02 - 1.93 (m, 2H), 1.74 -1.62 (m, 1H) and 1.54 - 1.28 (m, 3H) ppm. LCMS RT = 2.6 (M+l) 433.4.

[00920] 2-methoxyethyl iV-[(LR, 3.^)-3-([2-(5-chloro-l/7-pyrrolo[2,3-b]pyridm-3-yl)-5-fluoro-pyrimidin-4-yl]amino]cyclohexyl]carbamate (592) lH NMR (300 MHz, MeOD) δ 8.84 (s, 1H), 8.21 (s, 1H), 8.16 (s, 1H), 7.99 (d, J =3.97 Hz, 1H), 4.18 - 4.34 (m, 1H), 4.14 (br. s., 2H), 3.49 - 3.74 (m, 3H), 3.3 (s, 3H) 2.38 (d, J =9.06 Hz, 1H), 2.19 (d, J =13.41 Hz, 1H), 1.84-2.11 (m, 2H), 1.51 - 1.78 (m, 1H), 1.12 1.47 (m, 3H) ppm. LCMS RT = 2.5 (M+l) 463.4.

General Scheme 21:

(a) tetrahydrofuran-2-carboxylic acid, EDC, HOBt, DIPEA, CH2CI2, rt (b) LiOH, 130°C, microwave [00921] Formation of jV-[(LR, 3S)-3-[[2-(5-chloro-lH-pyrrolo[2,3-b|pyridin-3-yl)-5-fIuoro-pyrimidin-4-yl]ammo]cyclohexyl]tetrahydrofuran-2-carboxamide hydrochloride (638).

To a solution of (IS, 3S)-Al-[2-[5-chloro-l-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-5-fluoro-pyrimidin-4-yl]cyclohexane-1,3-diamine, 20c, (60 mg, 0.12 mmol) in CH2CI2 (3mL) was added tetrahydrofuran-2-carboxylic acid (20.3 mg, 0.17 mmol), EDC (26.8 mg, 0.14 mmol), HOBt (17.8mg, 0.12 mmol) and DIPEA (60.2mg, 0.47 mmol), and the reaction mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, and the residue was dissolved in THF (4mL) and treated with 1M aqueous lithium hydroxide (3.0 mL, 3.0 mmol). The reaction mixture was heated in the microwave to 130°C for 20 min. The solvent was evaporated under reduced pressure, and the residue was purified by HPLC, using 5-70% MCOH//H2O with 6mM HC1 over 15 minutes. The purified fractions were concentrated to provide the hydrochloride of N-[(IR, 3S)-3-[[2-(5-chloro-lH-py rrolo[2,3-b]py ridin-3-y 1)-5 -flu oro-pyrimidin-4-y 1] amino ]cyclohexy 1] tetrahy drofuran-2 -carboxamide, 638. ‘H NMR (300 MHz, MeOD) δ 8.55 (d, / = 1.0 Hz, 1H), 8.46 - 8.45 (m, 1H), 8.29 - 8.27 (m, 2H), 4.28 (d, / = 6.1 Hz, 2H), 4.00 - 3.87 (m, 3H), 2.36 - 2.16 (m, 3H), 2.00 -1.91 (m, 5H) and 1.75 -1.41 (m, 4H) ppm. LCMS RT = 3.77 (M+l) 459.37, (M-l) 457.35.

[00922] The following compounds can be prepared by methods similar to those described in Scheme 19, Scheme 20 and Scheme 21:

[00923] (lR, 35)-Arl-[2-(5-chIoro-l/f-pyrrolo[2,3“b]pyridin-3-yl)-S-fluoro-pyrimidin-4-yl]cyclohexane-l,3-diamine (542) LCMS RT = 1.4 (M+l) 361.4.

[00924] iV-[(ljff, 3S)-3-[[2-(5~chloro-l//-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-yI]amino]cyclohexyl]acetamide (576) ‘H NMR (300 MHz, MeOD)68.81 (s, 1H), 8.20 (s, 1H),8.15 (s, 1H), 7.99 (d,/=4.1, 1H), 4.23(t,J=11.4, 1H), 3.90 (t,/ = 11.4, 1H), 2.35 (d, / = 11.6, 1H), 2.20 (d,/ = 12.5, 1H), 2.00 (d, / = 15.9, 2H), 1.92 (s, 3H), 1.67 (dd, / = 26.3, 13.2, 1H), 1.53 -1.06 (m, 3H) ppm; LCMS RT = 1.8 (M+l) 403 (M-l) 401.4.

[00925] Methyl A-[(IS1,3R)-3-[[2-(5-chIoro-l//-pyrroIo[2,3-b]pyridin-3-yI)-5-fluoro-pyrimidin-4-yl]amino]cyclohexyl] carbamate (548). LCMS RT = 2.8 (M+l) 419.5.

[00926] 3-[(lS, 3/f)-3-[[2-(5-chloro-lflr-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-yI] amino] cyclohexyl]-l, 1-dimethyl-urea (549). LCMS RT = 2.6 (M+l) 432.5.

[00927] A^-[(lR,3S)-3-[[2-(5-chloro-lJff-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4~yl] amino] cyclohexyl]-2-methoxy-acetamide (591) ‘η NMR (300 MHz, MeOD) 5 8.82 (d, J = 2.4 Hz, 1H), 8.21 (d, / = 2.3 Hz, 1H), 8.16 (s, 1H), 7.99 (d, / = 4.1 Hz, 1H), 4.29 - 4.21 (m, 1H), 4.04 - 3.96 (m, 1H), 3.87 (s, 2H), 3.40 (s, 3H), 2.34 (d, / = 11.6 Hz, 1H), 2.21 (d, J = 12.5 Hz, 1H), 2.02 - 1.93 (m, 2H), 1.74 -1.62 (m, 1H) and 1.54 - 1.28 (m, 3H) ppm. LCMS RT = 2.6 (M+l) 433.4. 100928] 2-methoxyethyl N-\(1R, 35)-3-|[2-(5-chloro-ltf-pyrrolo[2,3-b]pyridin-3- yl)-5-fluoro-pyriniidin-4-yll amino] cyclohexyl] carbamate (592) Ή NMR (300 MHz, MeOD) δ 8.84 (s, 1H), 8.21 (s, 1H), 8.16 (s, 1H), 7.99 (d, / =3.97 Hz, 1H), 4.18 - 4.34 (m, 1H), 4.14 (br. s., 2H), 3.49 - 3.74 (m, 3H), 3.3 (s, 3H) 2.38 (d, /=9.06 Hz, 1H), 2.19 (d,/=13.41 Hz, 1H), 1.84-2.11 (m, 2H), 1.51 - 1.78 (m, 1H), 1.12 1.47 (m, 3H) ppm. LCMS RT = 2.5 (M+l) 463.4.

[00929] Λ4(1/ϊ, 35)-3-( [2-(5-chloro-lfl-pyrrolo [2,3-b] pyridin-3-yl)-5-fluoro-pyrimidin-4-yl]amino]cycIohexyl]-3-hydroxy-2,2-dimethyl-propanamide hydrochloride (650) ‘H NMR (300 MHz, MeOD) δ 8.56 - 8.54 (m, 2H), 8.34 (s, 1H), 8.30 (t, /= 5.4 Hz, 1H), 4.29 (t,/ = 11.4 Hz, 1H), 3.93 (t,/= 11.6 Hz, 1H), 3.54 (s, 2H), 2.34 (d,/ = 10.8 Hz, 1H), 2.18 (d, / = 11.4 Hz, 1H), 2.01 (d, /= 11.3 Hz, 2H), 1.73 - 1.37 (m, 4H) and 1.15 (s, 6H) ppm. LCMS RT = 3.79 (M+l) 461.38, (M-l) 459.4.

[00930] iV-[(lJi, 35)-3-( [2-(5-chloro-ljfif-pyrrolo [2,3-b] pyridin-3-yl)-5-fluoro-pyrimidin-4-yl]amino]cyclohexyl]tetrahydropyran-3-carboxamide hydrochloride (633) 'H NMR (300 MHz, MeOD) δ 8.64 (d, / = 2.2 Hz, 1H), 8.51 (s, 1H), 8.36 (d, /= 2.2 Hz, 1H), 8.29 (d, /= 5.5 Hz, 1H), 4.39 (t, /= 11.9 Hz, 1H), 3.93 - 3.82 (m, 3H), 3.54 - 3.30 (m, 2H), 2.52 - 2.43 (m, 1H), 2.37 - 2.33 (m, 1H), 2.20 (d,/= 11.6 Hz, 1H), 2.01 (d,/= 11.3 Hz, 2H), 1.90 - 1.88 (m, 1H), 1.83 - 1.63 (m, 4H) and 1.59 - 1.26 (m, 3H) ppm. LCMS RT = 3.25 (M+l) 473.42, (M-l) 471.1.

[00931] Ar-[(15,35)-3-[[2-(5-chloro-lii-pyrroIo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-yl]amino]cyclohexyl]-3-hydroxy-propanamide hydrochloride (634) *H NMR (300 MHz, MeOD) δ 8.61 (d, /= 2.1 Hz, 1H), 8.53 (s, 1H), 8.35 (d, /= 2.0 Hz, 1H), 8.29 (d, /= 5.5 Hz, 1H), 4.37 (t, /= 11.2 Hz, 1H), 3.95 (s, 1H), 3.80 (s, 2H), 2.42 (t, / = 5.5 Hz, 3H), 2.20 (d, J = 11.5 Hz, 1H), 2.03 (d, / = 11.0 Hz, 2H) and 1.76 - 1.29 (m, 4H) ppm. LCMS RT = 3.47 (M+l) 433.21, (M-l) 431.3.

[00932] N-\(IR, 35)-3-( [2-(5-chloro-l/7-pyrrolo [2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-yl]amino]cyclohexyl]-3-methyl-oxetane-3-carboxamide hydrochloride (635) 'H NMR (300 MHz, MeOD) δ 8.48 - 8.45 (m, 2H), 8.29 - 8.23 (m, 2H), 4.84 (d, / = 6.0 Hz, 1H), 4.38 (d, / = 6.0 Hz, 1H), 4.26 - 4.23 (m, 1H), 3.96 (s, 1H), 3.77 - 3.62 (m, 2H), 2.36 (s, 1H), 2.18 (d,/ = 11.5 Hz, 1H), 2.02 (d, / = 12.3 Hz, 2H), 1.70 - 1.25 (m, 4H) and 1.59 (s,3H) ppm. LCMS RT = 3.12 (M+l) 459.38, (M-l) 457.4.

[00933] lV-[(li?, 35)-3-[[2-(5-chlor o-17/-pyrrolo [2,3-b]pyr idin-3-y l)-5-fluoro~ pyrimidin-4-yl]amino]cyclohexyl]tetrahydropyran-4-carboxamide hydrochloride (636) 'H NMR (300 MHz, MeOD) δ 8.64 (d, 7= 2.3 Hz, 1H), 8.51 (s, 1H), 8.36 (d, / = 2.3 Hz, 1H), 8.29 (d, / = 5.6 Hz, 1H), 4.44 - 4.36 (m, 1H), 3.96 - 3.87 (m, 3H), 3.47 - 3.37 (m, 2H), 2.49 - 2.35 (m, 2H), 2.21 (d, / = 12.4 Hz, 1H), 2.02 (d, / = 11.9 Hz, 2H) and 1.83 - 1.23 (m, 8H) ppm. LCMS RT = 3.12 (M+1) 473.4, (Μ-1) 471.4.

[00934] N-[(1^35)-3-[[2-(5-chIoro-lfl-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-py rimidin-4-yl] amino] cycle hexyl] -3-liydroxy-butanamide hydrochloride (640) *H NMR (300 MHz, MeOD) δ 8.69 (d, /= 2.3 Hz, 1H), 8.51 (s, 1H), 8.37 (d,/ = 2.2 Hz, 1H), 8.29 (d,/= 5.6 Hz, 1H), 4.43 (1,/= 11.9 Hz, 1H), 4.14 (q,/= 6.1 Hz, 1H), 3.94 (t, /= 11.9 Hz, 1H), 2.40 - 2.19 (m, 4H), 2.03 (d, / = 8.2 Hz, 2H), 1.78 - 1.69 (m, 1H), 1.59 -1.44 (m, 3H) and 1.18 (d, /= 6.1 Hz, 3H) ppm. LCMS RT = 3.37 (M+l) 447.41, (M-l) 445.1.

[00935] /V-[(1J?, 35)-3-( [2-(5-chloro-l/7-pyrroIo [2,3-b]pyridin-3-yI)-5-fluoro-pyrimidin-4-yl]amino]cyclohexyI]-2-hydroxy-propanamide hydrochloride (642) Ή NMR (300 MHz, MeOD) δ 8.68 (s, 1H), 8.56 (s, 1H), 8.39 (d, / = 1.5 Hz, 1H), 8.31 (d, /= 5.3 Hz, 1H), 4.47 - 4.40 (m, 1H), 4.15 (s, 1H), 3.98 (m, 1H), 2.41 (s, 1H), 2.23 (d, /= 10.6 Hz, 1H), 2.04 (d, /= 11.0 Hz, 2H) and 1.77 - 1.36 (m, 7H) ppm. LCMS RT = 3.52 (M+I) 433.58, (M-l) 431.3.

[00936] iV- [(ϋϊ, 35)-3 - [ [2-(5-chlor o-l J/-py r rolo [2,3-b ] py ridin-3-yl)-5-iluoro- pyrimidin-4-yl] amino] cyclohexyl]tetrahydropyran-2-carboxamide hydrochloride (651) ’H NMR (300 MHz, MeOD) 5 8.56 - 8.51 (m, 2H), 8.33 - 8.29 (m, 2H), 4.30 (d, / = 3.0 Hz, 1H), 3.98 (dd, / = 11.5, 23.4 Hz, 2H), 3.83 - 3.79 (m, IK), 3.55 (t,J= 8.9 Hz, 1H), 2.35 (d, / = 11.1 Hz, 1H), 2.19 (d, / = 11.2 Hz, 1H), 2.03 - 1.90 (m, 4H) and 1.73 - 1.37 (m, 8H) ppm. LCMS RT = 4.1 (M+l) 473.41, (M-l) 471.4.

[00937] ΛΓ-[(1Λ, 35)-3-1 [2-(5-chloro-l //-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-yl]amino]cyclohexyl]tetrahydrofuran-3-carboxamide hydrochloride (652) ’H NMR (300 MHz, MeOD) 5 8.72 (d, /= 2.3 Hz, 1H), 8.56 (s, 1H), 8.42 (d, /= 2.2 Hz, 1H), 8.34 (d, /= 5.6 Hz, 1H), 4.51 - 4.43 (m, 1H), 4.02 - 3.88 (m, 3H), 3.86 - 3.78 (m, 2H), 3.07 - 3.02 (m, 1H), 2.42 (d, /= 7.5 Hz, 1H), 2.25 (d, /= 12.0 Hz, 1H), 2.19 - 2.06 (m, 4H) and 1.79- 1.35 (m, 4H) ppm. LCMS RT = 3.9 (M+l) 459.41, (M-l) 457.4.

[00938] (5)-tetrahydrofuran-3-yl (1Λ, 3<S)-3-(2-(5-chloro-lJ/-pyrrolo[2,3-A]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)cyclohexyIcarbamate (649) LCMS RT = 3.3 (M+l) 475.37, (M-l) 473.35.

[00939] iV-((ljR, 3iS)-3-(2-(5-chloro-119r-pyrrolo[2,3-*]pyridin-3-yl)-5-fluoropyrimidin-4-ylaminio)cyclohexyl)-3-methoxypropanamide (611) LCMS RT = 2.0 (M+l) 447.4, (M-l) 445.4.

[00940] /V-[2-(5-chloro-177-pyrro]o[5,4-b]pyridm-3-yl)-5-fluoro-pyrimidin-4-yi]cycIohexane-cis-l,3-diamine (540) LCMS RT= 1.4 (M+l) 361.5.

[00941] iV-[m-3-[[2-(5-chloro-l//-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-yl] amino] cyclohexyl] acetamide (452) (prepared from cis/trans l,3diamino cyclohexane; separated by HPLC from trans diastereomer) LCMSRT= 1.3 (M+l) 403.1 (M-l) 401.1.

[00942] iV-[rtYms-3-[[2-(5-chloro-l/7-pyrrolo[2,3~b]pyridin-3-y])-5-fluoro-pyrimidin-4-yl]amino]cyclohexyl]acetamide acetamide (457) (separated by HPLC from cis diastereomer) LCMS RT= 1.6 (M+l) 403.2 (M-l) 401.1.

[00943] l-[c/s-3-[[2-(5-chloro-17/-pyrrolo[2,3-b]pyridin-3-yI)-5-fluoro-pyrimidin-4-yl] amino] cyclohexyl]-3-methyl-urea (455) (prepared from cis/trans l,3diamino cyclohexane; separated by HPLC from trans diastereomer) LCMS RT = 1.7 (M+l) 416.2.

[00944] \-[trans-5-[ [2-(5-chlor o- l/f-pyrrolo [2,3-b] py ridin-3-y l)-5-fluo ro-pyrimidin-4-yl] amino] cyclohexyl]-3-methyl-urea (458) (prepared from cis/trans 1,3-diamino cyclohexane; separated by HPLC from cis diastereomer) LCMS RT = 0.8 (M+l) 418.2 (M-l) 416.1.

[00945] 3-[m-3-[ [2-(5-chloro-l£f-pyr rolo [2,3-b] py ridin-3-yl)-5-fluoro-py rimidin-4-yI] amino] cyclohexyl] -1,1 -dimethyl-u rea (456) (prepared from cis/trans 1,3 diamino cyclohexane; separated by HPLC from trans diastereomer) LCMS RT = 1.5 (M+l) 432.2 (M-l) 430.2.

[00946] 3-[ii*«HA’-3-[[2-(5-chIoro-l.ff-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidm-4-yl]aminolcyclohexyl]-l,1-dimethyl-urea (459) (prepared from cis/trans l,3diamino cyclohexane; separated by HPLC from cis diastereomer) LCMS RT = 1.5 (M+l) 432.2 (M-l) 430.2.

[00947] Methy]-c/s-3-[[2-(5-chloro-l//"pyrrolo[2,3-b]pyridin-3-yi)-5-fluoro-pyrimidin-4-yl]amino]cyclohexylcarbamate (514) - (racemic cis mixture - prepared from cis-1,3-dtaminocyclohexane) LCMS RT - 1.3 (M+l) 418.8.

[00948] iV-(( IR, 35)-3-(2-(5-chlor o-l//-py rrolo [2,3-6] py ridin-3-yl)-5- fluoropyrimidin-4-ylamino)cyclohexyl)morpholine-4-carboxamide(647) LCMS RT = 3.6 (M+l) 474.4 (M-l) 472.5.

[00949] jV-[3-[[2-(5“ChIoro-l/i-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-yl] amino] cyclohexyl] methanesulfonamide (454) LCMS RT= 1.6 (M+l) 439.1 (M-l) 437.1.

[00950] (tetrahydrofuran-3-yl)methyl (17?,35)-3-(2-(5-chloro-li7-pyrrolo[2,3-b\py ridin-3-yl)-5-fluoropy ri midin-4-ylamin o)cy clohexylcarbam ate (648) LCMS RT = 3.7 (M+l) 489.38, (M-l) 487.49.

General Scheme 22:

(a) 4-lerl-butoxycarbonyImorpholine-2-carboxylic acid, EDC, HOBl, 'Pr^NEl, CtECh, rt (b) CIECE, TFA (c) LiOH, 13 0°C, microwave [00951] Formation iV-[(l,ff, 35)-3-] [2-(5-chloro-li/-pyrrolo [2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-yl]amino]cyclohexyl]morpholine-2-carboxamide bishydrochloride (637)

To a solution of (15, 3/?)-/Vl-[2-[5-ch]oiO-l-(p-tolylsulfony])pynOlo[2,3-b]pyridin-3-yl]-5-fluoro-pyrimidin-4-yl]cyclohexane-l,3-diamine (0.06 g, 0.12 mmol) in CH2CI2 (3 mL) was added 4-ie/'t-butoxycarbonylmorpholine-2-carboxylic acid (40.4 mg, 0.17 mmol), EDC (0.03 g, 0.14 mmol), HOBt (0.02 g, 0.12 mmol) and 'PriNEt (0.06 g, 0.47 mmol), and the reaction mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, and the residue was dissolved in CH2CI2 (2 mL) and TFA (2 mL) and allowed to stir at room temperature for 2 hours. The resulting solution was concentrated in vacuo, dissolved in THE (4mL) and treated with IN aqueous lithium hydroxide (3,0 mL, 3.0 mmol). The reaction mixture was heated in the microwave to 130 °C for 20 min. The solvent was evaporated under reduced pressure, and the residue was purified by HPLC, using 5-70% MeOH/H-iO with 6mM HCI over 15 minutes. The purified fractions were concentrated to provide the bis-hydrochloride of 35)-3-[[2-(5-chloro-l//-pyrrolo[2,3-b]pyridin-3-yl)- 5-fluoro-pyrimidin-4-yl]amino]cyclohexyl]morpholine-2-carboxamide. 'H NMR (300 MHz, MeOD) δ 8.68 (s, 1H), 8.62 (s, 1H), 8.40 (s, 1H), 8.33 (d, /= 4.7 Hz, 1H), 4.44 - 4.35 (m, 2H), 4.21 (d, /= 12.2 Hz, 1H), 4.04 - 3.92 (m, 2H), 3.58 (d, ./ = 12.3 Hz, 1H), 3.23 - 3.08 (m, 2H), 2.37 (d, / = 8.1 Hz, 1H), 2.23 (d,/= 11.1 Hz, 1H), 2.05 (d, / = 9.7 Hz, 2H), 1.72 (m, 2H) and 1.59 - 1.44 (m, 2H) ppm; LCMS RT = 2.4 (M+l) 474.43, (ΜΙ) 472.4.

[00952] Other analogs that can be prepared in the same manner as 637 are described below:

[00953] ΛΓ-[(1Α, 35)-3-] [2-(5-chloro-li/-pyrrolo [2,3-bjpyridin-3-yl)-5-fluoro-pyrimidin-4-yl] amino] cyclohexyl]piperidine-4-carboxamide bishydrochloride (639) XH NMR (300 MHz, MeOD) δ 8.66 (s, 1H), 8.60 (s, 1H), 8.38 (s, 1H), 8.31 (d, /= 4.7 Hz, 1H), 4.43 - 4.36 (m, 1H), 3.98 - 3.91 (m, 1H), 3.43 (d, / = 10.3 Hz, 2H), 3.03 (t, / = 10.6

Hz, 2H), 2.60 (s, 1H), 2.38 (d, J= 10.2 Hz, 1H), 2.21 (d, J= 10.6 Hz, 1H), 2.07 - 1.92 (m, 6H) and 1.74 - 1.30 (m, 4H) ppm. LCMS RT = 2.4 (M+l) 472.46, (M-l) 470.4.

General Scheme 23

(a) (15, 25)-cyclohexane-l,2-diamine, THF, 120 °C microwave (b) methyl-chloro formate, 'Pr^NEt, CI-ECL (c) L1AIH4, THF.

[00954] Formation of (15, 25)-M-(2-(5-chloro-l-tosyl-li/-pyrrolo[2,3-6]pyridin-3-yI)-5-fluoropyrimidin“4-yl)cyclohexane-l,2-diamine (23b) A solution of 5-chloro-3-(5-fluoro-4-methylsulfinyl-pyrimidin-2-yl)-l-(/?-tolylsulfonyl)pyrrolo[2,3-b]pyridines 23a, (0.50 g, 1.08 mmol) in THF (4 mL) was treated with (15,2^-cyclohexane- 1,2-diamine (0.27 g, 2.37 mmol) and 'PrjNEt (2.15 mmol) at 120 °C for 10 minutes. The mixture was concentrated in vacuo. The resulting residue was purified by silica gel chromatography (0-20% MeOH-CHaCk) to provide the desired intermediate as a white solid (410 mg). LCMS RT = 2.2 (M+l) 515.5.

[00955] Formation of methyl (15, 25)-2-(2-(5-chloro-l-tosyHif-pyrrolo[2,3- i]pyridin-3-yl)-5-fluoro-pyrimidin-4-ylamino)cyclohexylcarbamate (23c)

To a mixture of (15, 25)-M-(2-(5-chloro-l-tosyl-l//-pyrrolo[2}3-Z>]pyridin-3-yl)-5-fluoropyrimidin-4-yl)cyclohexane-l,2-diamine, 23b, (0.18 g, 0.35 mmol) in dichloromethane (4 mL) at room temperature was added ‘P^NEt (0.12 mL, 0.70 mmol) followed by methyl chloroformate (0.03 mL, 0.37 mmol). After 35 minutes, the mixture was diluted with EtOAc, washed successively with aqueous saturated NH4CI and aqueous saturated NaHCC>3 and brine, dried over Na2S04 filtered and concentrated in vacuo to provide the crude product sufficiently pure for use in the next reaction. LCMS RT = 4.1 (M+l) 573.4.

[00956] Formation of (15, 25)-M-(2-(5-chloro-l//-pyrrolo [2,3-6] pyridin-3-yl)-5-fluoropyrimidin-4-yl)-7V2-methylcycl©hexane-l, 2-diamine (522)

To a stirred solution of methyl (15,25)-2-(2-(5-chloro-l-tosyl-l/7-pyiTolo[2,3-/)]pyridin-3-yI)-5-fluoropyrimidin-4-ylamino)cyclohexylcarbamate, 23c, (0.09 g, 0.16 mmol) in THF (3 mL) at room temperature was added LiAIHf (0.06 g, 1.66 mmol) and the mixture was stirred at room temperature for additional 2 hours. The reaction was quenched with 0.06 mL KOH (5% aq) followed by water (3 x 0.06 mL). Then, additional Et20 (6 mL) was added and stirring was continued for 20 minutes. The milky white suspension was filtered and rinsed with EtOAc and the cake was rinsed with additional EtOAc. The combined organic phases were concentrated in vacuo and purified by preparative HPLC followed by preparative TLC to provide the desired product as the free base that was then converted to the HC1 salt by treatment with HCI (4N in dioxane). LCMS RT = 1.7 (M+l) 375.5.

General Scheme 24:

(a) NaCNBH3, (CH20)„, HOAc, CH3CN

[00957] Formation of (15, 25)-A'l-(2-(5-chloro-I//-pyrrolo[2,3-/>]pyridin-3-yl)-5-fluoropyrimidin-4-yl)-jV2, Ar2-dimethyIcyclohcxanc-l ,2-diamine (523)

To a mixture of (15, 2S)-M-(2^5 “Chloro-l//-pyrrolo[2,3-b]pyridin-3-yl)-5- fluoropyrimidin-4-yl)cycIohexane- 1,2-diamine, 23b, (0.08 g, 0.22 mmol) in acetonitrile (1.6 mL) at room temperature was added formaldehyde (0,09 mL of 37 %w/v, 1.11 mmol) followed by NaCNBT-L (0.04 g, 0.56 mmol). A gelatinous mix formed and after 4 min the mixture became fluid again. After 4 hours, the reaction was quenched with 5 mL of 2N NaOH and the mixture was stirred overnight. The mixture was diluted with EtOAc and stirred until all solid dissolved. The layer was extracted with EtOAc several times, dried over Na2S04, filtered and concentrated in vacuo. Silica gel chromatography (0-15% MeOH-CHoCL) followed by preparatory HPLC provided the desired product, which was converted to the corresponding HCI salt with HCI (4N in dioxane). lK NMR (300 MHz, MeOD) δ 8.65 (d, /= 2.3 Hz, 1H), 8.54 (s, 1H), 8.43 (d,/ = 5.1 Hz, 1H), 8.40 (d, /= 2.3 Hz, 1H), 4.82 - 4.72 (m, 1H), 3.66 - 3.53 (m, 1H), 2.96 (s, 3H), 2.77 (s, 3H), 2.33 (d, / = 12.3 Hz, 2H), 2.10 - 1.97 (m, 2H) and 1.75 - 1.48 (m, 4H) ppm; LCMS RT= 1.7 (M+l) 389.5.

General Scheme 25:

(a) 2-(methoxymethyl)oxirane, methanol, 130°C, microwave (b) LiOH, 130°C, microwave [00958] Formation of l-[[(1 R, 35)-3-[[2-(5-chloro-lfT-pyrrolo[2,3-b]pyridin-3-yl)-5-flu or o-py rimidin-4-y 1] amino] cyclohexyl] a mino] -3-methoxy-pr op an-2-ol (610)

To a solution of (15, 3R)-M-[2-[5-chloro-l-(p-tolylsulfonyl)pyriOlo[2,3-b]pyridin-3-yl]“5-fluoro-pyrimidin-4“yl]cyclohexane-l,3-diamine, 20c, (50 mg, 0.09 mmol) in methanol (2 mL) was added 2-(methoxymethyl)oxirane (9.4 mg, 0.11 mmol) and the reaction mixture was heated in the microwave to 140°C for 10 min. 1M aqueous LiOH (1.0 mL, 1.0 mmol) was added, and the reaction mixture was heated in the microwave to 130°C for 10 min.

The solvent was evaporated under reduced pressure, and the residue was purified by HPLC, using 5-70% CH3CN//H20 with 0.1% TFA over 15 minutes. The purified fractions were concentrated, redisolved in MeOH and passed through a carbonate-PS column to provide the free base of the desired product l-[[(lR,3S)-3-[[2-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-yl]amino]cyclohexyl]amino]-3-methoxy-propan-2-ol, 610. !H NMR (300 MHz, MeOD) δ 8.85 (d, /= 2.3 Hz, 1H), 8.22 (d, /= 2.2 Hz, 1H), 8.15 (s, 1H), 7.98 (d, / = 4.1 Hz, 1H), 4.20 (m, 1H), 3.82 (dd, /= 3.9, 8.2 Hz, 1H), 3.55 - 3.45 (m, 1H), 3.30 (s, 3H), 3.23 - 3.07 (m, 1H), 2.86 - 2.77 (m, 2H), 2.68 - 2.59 (m, 1H), 2.44 (d, / = 10.9 Hz, 1H), 2,15 (d, / = 9.8 Hz, 1H), 2.07 - 1.94 (m, 2H), 1.65 - 1.56 (m, 1H) and 1.42 - 1.17 (m, 3H) ppm; LCMS RT = 1.52 (M+l) 449.42.

General Scheme 26:

(a) 2-bromoacetamide, Na2C03, DMF, rt (b) LiOH, 130°C, microwave.

[00959] Formation of 2-[[LR, 35)-3-[2-(5-chloro-1//-pyrrolo[2,3-b]pyridin-3-yl)-5- fluor opyrimidin-4-yI] amino] cyclohexylamino] -acetamid e (593)

To a solution of (15, 3R)-M-[2-[5-chloro-l-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-5-fluoro-pyrimidin-4-yl]cyclohexane-1,3-diamine, 20c, (0.050 g, 0.100 mmol) in DMF (2 mL) was added 2-bromoacetamide (0.015 g, 0.100 mmol) and Na2C02 (0.021 g, 0.190 mmol) . The reaction mixture was stirred at room temperature overnight 1M aqueous lithium hydroxide (2.0 mL, 2.0 mmol) was added, and the reaction mixture was heated in the microwave to 130°C for 10 min. The solvent was evaporated under reduced pressure, and the residue was purified by HPLC, using 5-70% CH3CN//H2O with 0.1% TFA over 15 minutes. The purified fractions were concentrated, redisolved in MeOH and passed through a carbonate-PS column to provide the free base of the desired product 2-[[lR,3S)-3-[2-(5-chloiO-lH-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-yl]amino]cyclohexylamino]-acetamide, 593. *H NMR (300 MHz, MeOD) 5 8.85 (d, J= 2.3 Hz, 1H), 8.22 (d, /= 2.2 Hz, 1H), 8.15 (s, 1H), 7.99 (d, /= 4.1 Hz, 1H), 4.28 - 4.20 (m, 1H), 2.82 - 2.73 (m, 1H), 2.65 (s, 2H), 2.40 (d, / = 10.2 Hz, 1H), 2.15 (d,/ = 8.5 Hz, 1H), 2.05 - 1.92 (m, 2H), 1.64 - 1.55 (m, 1H) and 1.44 - 1.12 (m, 3H) ppm; LCMS RT = 1.47 (M+l) 418.21.

General Scheme 27:

a) 3-Aminocyclohexanol, 'Pr2NEt, THF, MW 130 °C; b) Ag?0, CaS04, CH3I, r.t.; c) sodium methoxide, THF.

[00960] Formation of (5r)-3-(2-(5-chloro-l-tosyl-l//-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)cyclohexanol (27a).

To a solution of 5-chloro-3-(5-fluon>4-(methylsulfonyl)pyrimidin-2-y])-l-tosyl-l//-pyrrolo[2,3-6]pyridine, la, (1.09g, 2.34 mmol) and 3-aminocyclohexanol (0.32 g, 2.82 mmol) in THF was added DIEA (0.60 g, 4.69 mmol). The reaction mixture was heated at 130 °C in microwave for 10 min. The solvent was removed under reduced pressure and the resulting residue was purified by silica gel chromatography to afford 550 mg of the desired product, 27a. Ή NMR (300 MHz, CDCb) δ 8.88 (s, 1H), 8.56 (s, 1H), 8.40 (d, J = 2.4 Hz, 1H), 8.12 - 8.07 (m, 3H), 7.32 - 7.28 (m, 2H), 5.70 (m, 1H), 4.35 (m, 1H), 4.10 (m, 1H), 2.40 (s, 3H), 2.32 (d, J= 12.3 Hz, 1H), 2.0 - 1.95 (m, 2H), 1.70-1.45 (m 4H).

[00961] Formation of 2-(5-chloro-l-tosyl-l//-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-Ar-((lS)-3-methoxycyclohexyl)pyrimidin-4-amme (27b).

To a suspension of methyl iodide (0.20 g, 0.41 mmol) and 3-[[2-[5-chloro-l-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-5-fluoro-pyrimidin-4-yl]amino]-cyclohexanoI, 27a, (0.47 g, 2.04 mmol) was added silver oxide (0.578 g, 4.07 mmol and calcium sulfate (0.28 g, 2.04(mmol). The reaction mixture was stirred at room temperature for 18h. The mixture was filtered through celite and the resulting filtrate was concentrated in vacuo. The resulting crude mixture was purified by silica gel chromatography to afford 120 mg of the desired product, 27b. *H NMR (300 MHz, CDCI3) 6 8.88 (s, 1H), 8.56 (s, 1H), 8.4 (d, J= 2.4 Hz, 1H), 8.13 - 8.06 (m, 3H), 7.30 (d, J= 8.7 Hz, 2H), 6.00 (s, 1H), 4.42-4.32 (m, 1H), 3.60-3.50 (m, 1H), 3.4 (s, 3H), 2.4 (s, 3H), 2.25 (dd, ./= 3.4, 9.7 Hz, 1H), 2.00-1.84 (m 3H), 1.75-1.60 (m, 3H), 1.60-1.50 (m, 1H).

[00962] Formation of 2-(5-chIoro-l/7-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-N-((lS)-3-methoxycyclohexyl)pyrimidin“4-amine (552).

To a solution of 2-[5-chloro-l-(p-tolylsulfonyl)pynOlo[2,3-b]pyridin-3-yl]-5-fiuoro-7V'-(3-mcthoxycyclohexyl)pyrimidin-4-aminc, 27b, (0.08 g, 0.15 mmol) in THF were added a few drops of NaOMe. The reaction mixture was stirred at room temperature for 20 min. To the reaction mixture was added ethyl acetate and brine. The organic phase was separated, dried (MgSOi), filtered and concentrated in vacuo. The residue was dissolved in CH3CN/H2O and the mixture was purified by preparatory HPLC to afford 23 mg of the desired product, 552. ‘HNMR ¢300 MHz, CD3OD) 5 8.70 (d, / = 2.3 Hz, 1H), 8.45 (s, 1H), 8.35(d, / = 2.3 Hz, 1H), 8.25(d, /= 5.4 Hz, 1H), 4.35 (m, 1H), 3.52 (m, 1H), 3.4 (s, 3H), 2.53 (d, /= 12.1 Hz, 1H), 2.18 (d, /= 11.4 Hz, 2H), 2.05-1.95 (m, 1H), 1.65-1.4 (m, 3H), 1.38-1.25 (m, 1H); LCMS RT = 2.22 min (M+l) 376.23

[00963] (3«y)-3-(2-(5-chlor o-IH-py rr ol 0 [2,3 -b] py r idin -3-yl)-5-fluo ropy rimidin-4-ylamino)cyclohexanol (524). LCMS RT = 2.0 (M+l) 362.48.

[00964] 3-(2-(5-chloro-U7-pyrrolo[2,3-Z>]pyridin-3-yl)-5-fluoropyrimidin-4-y!amino)cyclohexyl ethylcarbamate (608). LCMS RT = 2.9 (M+l) 433.4.

General Scheme 28:

571, 572 a) Dess-Martin periodinane, CH2CI2; b) CH3MgBr, THF; c) sodium methoxide, THF.

[00965] Formation of 3-(2-(5-chloro-l-(phenylsulfonyl)-li9r“pyrrolo[2,3-b]pyridin-3-yl)“5-fluoropyrimidin-4-ylamino)cyclohexanone(28a).

To a solution of3-[[2-[5-chloro-l-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-5-fluoro-pyrimidin-4-yl]amino]cyclohexanol, 27a, (0.54 g, 1.05 mmol) in 20 ml CH2CI2 was added Dess-Martin periodinane (0.62 g, 1.47 mmol). The suspension was stirred at room temperature for 6h. The reaction mixture was filtered through celite and the filtrate was concentrated in vcicuo. The resulting residue was purified by silica gel chromatography (45% ethyl acetate/hexanes gradient) to afford 430mg of the desired product. lK NMR (300MHz, CDC13) 8 8.66 (d, J - 2.4 Hz, 1H), 8.42(slH), 8.31 (d, J = 2.3 Hz, 1H), 8.05-8.02 (m, 3H), 7.24-7.19 (m, 2H), 2.99 (d, /= 5.2 Hz, 1H), 4.56 (s, 1H), 2.85 (dd, /= 4.7, 13.9 Hz, 1H), 2.50-2.40 (m, 3H), 2.40 (s, 3H), 1.95-1.80 (m, 2H), 1.70-1.50 (m, 2H).

[00966] Formation of 3-(2“(5-chloro-l-(phenylsulfonyl)-lH-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)-l-methylcycIohexanol (28b).

To a cold (0 °C) solution of 3-[[2-[5-chloro-l-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-5-fIuoro-pyrimidin-4-yl]amino]cyclohexanone, 28a, (0.47 g, 0.92 mmol) in THF (5 mL) was added methylmagnesium bromide (3.30 ml of 1.4M solution, 4.58 mmol). The reaction mixture was stirred at 0 °C for 1 h. The reaction mixture was diluted with ethyl acetate and aqueous saturated NH4CI solution. The organic phase was separated, dried (MgSO.i), filtered and concentrated in vacuo. The products were purified by silica chromatography with DCM and methanol, two products were eluded with 95% DCM and 5% methanol no separation. The two diastereomeis were taken on as a mixture without further purification. LCMS (10-90% 3/5min(grad/run) w/FA) indicated 2 peaks for the desired products. Peak 1: retention time = 4.04 min (M + 1: 530.42); peak 2: retention time = 4.18min (M + 1: 530.45).

[00967] Formatio n of (35)-3-(2-(5-chloro-lFlr-pyrrolo [2,3-b] pyridin-3-y 1)-5-fluoropyrimidin-4-ylamino)-l-methylcyclohexanol (571 and 572).

To a solution of 3-(2-(5-chloro-l-(phenylsulfonyl)-lH-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)-l-methylcyclohexanol, 28b, in THF was added a few drops of 25% sodium methoxide at room temperature. The reaction mixture was stirred at room temperature for 5 min. The reaction mixture was diluted with ethyl acetate and brine. The organic phase was separated, dried (MgSCU), filtered and concentrated in vacuo. The product was purified by preparatory HPLC to afford two diastereomers.

Diastereomer 1 - 571. 'HNMR (300MHz, CD3OD) δ 8.78 (d, /= 2.2 Hz, 1H), 8.60 (s, 1H), 8.36 (s, 1H), 8.30 (dd, / = 5.6, 9.9 Hz, 1H), 4.85 (m, 1H) 2.25-1.95 (m, 3H), 1.86-1.6(m 4H), 1.40-1.3(m 2H), 1.3(s, 3H); LCMS RT 2.39 (M+l) 376.42.

Diastereomer 2 - 572. *H NMR (300 MHz, CD3OD) 8.66 (d, / = 2.1 Hz, 1H), 8.55 (d, /= 2.7 Hz, 1H), 8.38 (s, 1H), 8.258 (dd, /= 5.6, 9.5 Hz, 1H), 4.6(s, 1H), 2.00-1.50 (m, 9H), 1.30 (s, 3H); LCMS RT 1.97 (M+l) 376.41.

[00968] 3-(2-(5-chloro-l/7-pyrrolo[2,3-6]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)-l-ethynylcyclohexanol (617 and 618).

Diastereomer 1 - 617; LCMS RT = 3.6 (M+l) 386.4.

Diastereomer 2 - 618; LCMS RT = 3.2 (M+l) 386.3.

[00969] 3-(2-(5-chloro-i//-pyrrolo[2,3-A]pyridin-3-y])-5-f]uoropyrimidin-4-ylamino)-l-vinylcyclohexanol (627 and 628).

Diastereomer 1 - 627: LCMS RT = 4.0 (M+l) 388.4.

Diastereomer 2 - 628: LCMS RT = 3.7 (M+l) 388.4.

[00970] 3-(2-(5-chloro-l//-pyrro!o]2,3-6]pyridin-3-yl)-5-fIuoropyrimidin-4-ylamino)-! -(hydroxymethyl)cy clohexan ol (646). LCMS RT = 3.4 (M+l) 392.4.

[00971] 3-(2-(5-chloro-lff-pyrrolo[2,3-6]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)-l-ethylcyclohexanol (626). LCMS RT = 4.1 (M+l) 390.4.

General Scheme 29

[00972] Formation of (35)-3-(2-chloro-5-fluoropyrimidin-4-ylamino) cyclohexanol (29a).

The starting racemic alcohol, (3<S)-3-aminocyclohexanol, was prepared following the procedure described by Bemardelli, P., Bladon, M., Lorthiois, E., Manage, A., Vergne, F. and Wrigglesworth, R., Tetrahedron Asymmetry 2004,15, 1451-1455. (35)-3-(2-chloro-5-fluoropyrimidin^4-ylamino) cyclohexanol was prepared according to the procedure for compound 16a using (3S)-3-aminocyclohexanol, afforded desired product, 29a, as a solid.

[00973] Formation of (5)-3-(2-chloro-5-fluoropyrimidin-4-ylamino) cyclohexanone (29b).

To 700 ml DCM solution of 7.9g (32.16 mmol) (3S)-3-[(2-chloro-5-fluoro-pyrimidin-4-yl)amino]cyclohexanol, 29a, (7.90 g, 32.16 mmol) in CH2CI2 (700 mL) was added Dess-Martin reagent (17.73 g, 41,81 mmol). The reaction mixture was stiired at room temperature for 20 hours until TLC chromatography indicated reaction was complete. The reaction mixture was filtered through a pad of celite, and the resulting filtrate was washed with 200 mL of aqueous saturated NaHCCb solution and 200 mL brine. The organic phase was dried with MgSCL, filtered and the solvent was removed under reduced pressure. The product was purified by silica gel chromatography (50% EtOAc/hexanes) to afford 7.3g of the desired product, 29b (93% yield). ‘H NMR (300MHz, CD3OD) δ H NMR (300 MHz, CDC13) 8 7.96 - 7.93 (m, 1H), 7.28 (s, 1H), 5.12(s, 1H), 4.57-4.48 (m, 1H), 2.87 (dd,/=4.8, 14.0 Hz, 1H), 2.51 -2.23 (m, 4H), 2.12 - 2.02 (m, 1H); LCMS RT = 2.97 (M+l) 244.26.

[00974] Formation of (3S)-3-(2“Chloro-5-iluoropyrimidin-4-yIamino)-l-methylcyclohexanol (29c, 29d).

To a solution of (3S)-3-[(2-chloro-5-fluoiO-pyrimidin-4-yl)amino]cyclohexanone (1.83 g, 7.49 mmol) in THF (100 mL) was added methylmagnesium bromide (21.4 ml of 1.4M solution, 29.96 mmol) at room temperature. The reaction mixture was stirred at room temperature for 5 minutes. To the reaction mixture was added aqueous saturated NH4CI solution and EtOAc. The organic phase was washed with brine and dried with MgSC>4, filtered and concentrated in vacuo. The two spots were separated by silica gel chromatography (120g silica gel column).

Fraction-1 (29c): ‘H NMR (300MHz, CD3OD) δ 8 7.81 (d, /= 2.8 Hz, 1H), 7.28 (d, /= 0.5 Hz, H), 4.47 (q, /= 3.8 Hz, 1H), 1.92 - 1.87 (m, 2H), 1.82 - 1.77 (m, 1H), 1.69 (dd, / = 4.2, 14.0 Hz, 2H) and 1.56 - 1.48 (m, 4H) ppm; LCMS RT = 3.43 (M+l) 260.3.

Fraction-2 (29d): *H NMR (300MHz, CD3OD) 8 7.87 (d, J = 2.8 Hz, H), 7.28 (s, H), 4.95 (d, J = 5.0 Hz, 1H), 4,45 - 4.33 (m, 1H), 2.17 (s, H), 2.12 - 2.06 (m, 1H), 1.93 - 1.78 (m, 1H), 1.71 (dd, J = 3.1, 5.6 Hz, 2H), 1.39 - 1.25 (m, 4H) and 1.19 - 1.05 (m, 1H) ppm; LCMS RT = 3.10 (M+l) 260.29.

[00975] Formation of (35)-3-(2-(5-chloro-l-tosyl-l//-pyrrolo[2,3-6]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)-l-methylcyclohexanoI (29e, 29f)·

Degassed a solution of 5-chIoro-l-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl-l,3,2-dioxaboroIan-2-yl)pyrrolo[2,3-b]pyridine (1.46g, 3.37 mmol), (35)-3-[(2-chloro-5-fluoro-pyrimidin-4-yl)amino]-l-methyl-cyclohexanoI, 29c, (0.72g, 2.81 mmol) and Na2C03 (4.21 mL of 2M solution, 8.433 mmol) in dimethoxyethane (15 mL) for 30 min with nitrogen. To the reaction mixture was added palladium tetrakis-triphenylphosphane (0.16 g, 0.14 mmol). The reaction mixture was heated at 130 °C in Q-tube apparatus for 45 minutes. The reaction mixture was filtered through a pad of 1 cm of silica gel and 2 cm celite. The product was purified by silica gel chromatography (hexanes/EtOAc) to afford the desired product, 29e (63% yield). 'H NMR (300MHz, CD3OD) 8 8.81 (d, / = 2.4 Hz, 1H), 8.50 (s, 1H), 8.38 (d, /= 2.4 Hz, 1H), 8.10 (d, /= 8.3 Hz, 2H), 8.04 (d, /= 3.3 Hz, 1H), 7.29 (d, /= 8.1 Hz, 2H), 6.85 (d, /= 5.7 Hz, H), 4.58 (t, /= 3.7 Hz, 1H), 2.39 (s, H), 1.98 - 1.93 (m, 2H), 1.86 (d, /= 4.0 Hz, 2H), 1.72- 1.56 (m, 5H), 1.36 (d, J = 3.8 Hz, 3H) and 1.30- 1.26 (m, 1H) ppm. LCMS RT = 4.62 (M+l) 530.4.

The diastereomer, 29f, was made according to the same procedure as 29e, substituting 29d as the starting material for the Suzuki coupling procedure. ‘HNMR (300MHz, CD3OD) 8 8.89 (d, /= 2.4 Hz, 1H), 8.55 (s, 1H), 8.39 (d, /= 2.4 Hz, 1H), 8.09 (t, /= 8.4 Hz, 2H), 8.08 (s, 1H), 7.29 (d, /= 8.2 Hz, 2H), 4.89 (d, /= 6.6 Hz, 1H), 4.55 (m, 1H), 2.39 (s, 3H), 2.24 (t, /= 1.8 Hz, 2H), 2.02 - 1.93 (m, 1H), 1.77 (t,/= 3.3 Hz, 2H), 1.46 - 1.33 (m, 5H) and 1.29 - 1.15 (m, lH)ppm. LCMS RT = 4.36 (M+l) 530.3.

[00976] Formation of (35)-3-(2-(5-chloro~l-tosyI-l//-pyrrolo[2,3-6]pyridin-3-yl)- 5-fluoropyrimidin-4-ylamino)-l-methylcycIohexanol (655, 656).

To a solution of (3S)-3-[[2-[5-chloro-l-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-5-fluoro-pyrimidin-4-yl]amino]-l-methyl-cyclohexanol, 29f, (2,85 g, 5.38 mmol) in THF (200 mL) was added 1.5 ml 25%W/W sodium methoxide solution at room temperature. The reaction mixture was immediately injected into LC/MS. LC/MS indicated the reaction was complete. The reaction mixture was diluted with 200 ml EtOAc and the organic phase was washed twice with aqueous saturated NaHCOs and then twice with brine. The organic phase was dried with MgSCU, filtered and concentrated in vacuo. The product was purified by silica gel chromatography (80g silica, 5% MeOH/CH2Cl2) to afford 1.7 g of the desired product. The resulting product was dissolved in 70 ml THF, to it was added 1.8 ml 5M HC1/IPA. The resulting suspension was stirred for 1 hour at room temperature. The solvent was removed under reduced pressure to afford 1.7g of the desired product, 655 as an HC1 salt. ‘H NMR (300MHz, CD3OD) 5 9.54 (s, 1H), 8.86 (d, /= 2.3 Hz, 1H), 8.31 (d, /= 2.4 Hz, 1H), 8.15 (d, / = 2.7 Hz, 1H), 8.04 (d, /= 3.5 Hz, 1H), 7.28 (s, H), 6.66 (s, 1H), 4.62 - 4.59 (ra, 1H), 1.96 - 1.88 (m, 4H), 1.81 (dd, / = 4.5, 14.9 Hz, 1H) and 1.68 - 1.57 (m, 6H) ppm; LCMS RT = 4.01 (M+l) 376.4.

[00977] The corresponding diastereomer, 656, can be prepared in the same fashion. General Scheme 30

562, 563 (a) mCPBA, CH2CI2 (b) NH40H, water, 50 °C, 72 h (c) 5-chtoro-3-(3-fluoro-4-(methylsulfinyl)pyrimidin-2-yl)-l-tosy]-l/7-pytTolo[2,3-b]pyridine,1Pr2NEi>DMF1 90 °C, 17 h (d) 1N LiOH, THF, microwave, 120 °C, 10 min.

[00978] Formation of l-methyl-7-oxabicyclo(4.1.0[heptane (30a)

To a cold (0 °C) solution of 1-methylcyclohexene (3.0 g, 31.2 mmol) in CH2CI2 (150 mL) was added mCPBA (8.4 g, 48.7 mmol). The reaction mixture was stirred at 0 °C for 1 h. The reaction mixture was diluted into aqueous saturated NaHCOj solution and extracted with ether. The organic phase was washed again with aqueous saturated NaHC03 solution, dried (MgSC>4), filtered and concentrated in vacuo to afford the desired product as anoil that was used without further purification, [00979] Formation of 2-amino-l-methylcyclohexanol (30b)

To a solution of l-methyl-7“Oxabicyclo[4.1,0]heptane, 30a, (1.0 g, 7.1 mmol) in water was added ammonium hydroxide (6.0 mL, 154.1 mmol). The mixture was heated to 50 °C for 48 hours. The mixture was diluted with water, extracted with EtOAc and then twice with 20%MeOH/CHCI3. The organic phases were dried (MgS04), filtered and concentrated in vacuo to provide the desired product, 30b, as an amorphous white solid. lH NMR (300.0 MHz, DMSO) 6 2.44 (dd, / = 3.4, 10.8 Hz, 1H), 1.64 - 1.45 (m, 4H), 1.28 - 1.01 (m, 4H) and 0.97 (s, 3H) ppm.

[00980] Formation of 2-(2-(5-chIoro-l-tosyl-lH-pyrroIo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)-l-methylcyclohexanol (30c)

To a solution of 5-chloro-3-(5-fluoro-4-methylsulfinyl-pyrimidin-2-yl)-l-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridine, la, (0.97 g, 2.09 mmol) and 2-amino-l-methylcyclohexanol, 30b, (0.40 g, 3.13 mmol) in DMF (10 mL) was added ‘Pr2NEt (0.73 mL, 4.17 mmol). The reaction mixture was heated at 90 C for 17 hours. The reaction mixture was cooled to room temperature and diluted into aqueous saturated NaCl solution. The aqueous phase was extracted twice with EtOAc. The organic phases were washed with twice with aqueous saturated NaCl solution, dried (MgSCU), filtered and concentrated in vacuo. The crude residue was purified via silica gel chromatography (0-50% EtOAc/hexanes-loaded with CH2CI2) to afford the desired product, 30c, as a white solid. !H NMR (300.0 MHz, DMSO) δ 9.00 (d, / = 2.4 Hz, 1H), 8.49 (dd, /= 2.4, 10.3 Hz, 1H), 8.42 (s, 1H), 8.23 (d, /= 4.1 Hz, 1H), 8.10-8.01 (m, 2H), 7.52 - 7.43 (m, 2H), 7.21 (d, /= 9.1 Hz, 1H), 4.52 (s, 1H), 4.28 (s, 1H), 2.35 (s, 3H), 1.78 - 1.50 (m, 6H), 1.34 (m, 2H) and 1.15 (s, 3H). LCMS RT = 4.1 (M+l) 530.6.

[00981] Formation of 2-(2-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-y!)-5-fluoropyrimidm-4-ylamino)-l-methylcyclohexanol (562 and 563)

To a solution of 2-[[2-[5-chloro-l-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-5-fluoro-pyrimidin-4-yl]amino]-l-methyl-cyclohexanoI, 30c, (0.41 g, 0.77 mmol) in THF was added 1M LiOH solution. The reaction mixture was heated in microwave at 120 °C for 5 minutes. The reaction mixture diluted with water, twice extracted with EtOAc and then twice with 10% MeOH/CH2Cl2. The combined organic phases were dried (MgSO-O, filtered and concentrated in vacuo. The crude residue was purified via silica gel chromatography (5-20% MeOH: CH2CI2) to afford a white solid as a mixture of trans-enantiomers. The two transenantiomers were separated by chiral preparatory HPLC to afford 562 and 563.

Enantiomer 1 - 563: !H NMR (300.0 MHz, DMSO) 812.32 (s, 1H), 8.86 (d, ./= 2.4 Hz, 1H), 8.28 (d, /= 2.4 Hz, 1H), 8.20 (d, 1H), 8.15 (d, 1H), 6.92 (d, /= 8.2 Hz, 1H), 4.56 (s, 1H), 4,31 (dd, / = 5.9, 8.6 Hz, 1H), 1.89 - 1.35 (m, 8H) and 1.17 (s, 3H); LCMS RT = 2.5 (M+l) 376.4.

General Scheme 31:

(a) 214-dichloro-5-fluoropyrimidine, acetonitrile/isopropanol, reflux 1.5hrs. (b) 5-chloro-3-(4,4,5,5-teUarnethyl-i,3,2-dioxaborolan-2-yl)-l-tosyI-l//-pyrrolo[2,3-i>]pyridine, Pd(PPh3)4,2M Na2C03 , acetonitrile, 120 °C microwave 15 min., (c) TBAF, THF.

[00982] Formation of (1R, 25, 35)-3-(2-chloro-5-fluoropyrimidin-4-ylamino) cyclohexane-1,2-diol (31b).

The starting racemic diol, 31a, (17?, 25, 35)-3-aminocyclohexane-l,2-diol, was prepared following the procedure described in: Org. Bio. Chem. (2008) 6, 3751 and 3762, Davies, et. al To a solution of racemic diol 31a (0.66 g, 5.00 mmol) in acetonitrile (5 mL) and isopropanol (5 mL) was added 2,4-dichloro-5-fluoro-pyrimidine (0.84 g, 5.03 mmol) and *Pr2NEt (3.25 g, 4.38 mL, 25.20 mmol). The reaction mixture was sealed and heated to 100 °C for 90 minutes and then concentrated to dryness. The crude was purified via silica gel chromatography (40%-l 00% EtOAc/Hex) to afford a racemate, which was further purified via chiral HPLC separation to give compound 31b (0.26 g) as a white solid. ‘H NMR (300 MHz, MeOH-i74) δ 7.80 (s, 1H), 4.60 (s, 6H), 4.10 (m, 1H), 3.80 (s, 1H), 3.60 (m, 1H), 3.20 (s, 1H), 3.15 (s, 2H), 1.50 - 1.70 (m, 5H), 1.20 (m, 1H) ppm. LCMS RT = 2.8 (M+l) 262.0, (M-l) 260.1.

[00983] Formation of (1/f, 25,35)-3-(2-(5-ch loro-l -tosyl-l//-pyrrolo [2,3-b\ py ridin-3-yl)-5-fluo ropy rimidin-4-ylamin o)cyclo hexane-1,2-diol (31c).

To a deoxygenated solution of 5-chloro-l-(/>-tolylsulfonyl)-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pynOlo[2,3-b]pyridine (0.22 g, 0.51 mmol) and (1R, 25, 35)-3-(2-chloro-5-fluoropyrimidin-4-ylamino)cycIohexane-l,2-diol, 31b, (0.08 g, 0.24 mmol) in acetonitrile (6 ml) was added 2M sodium carbonate (0.45 mL of 2 M solution, 0.894 mmol) and Pd(PPh3)4 (34.5 mg, 0.030 mmol). The reaction was sealed and heated to 120°C for 15 minutes in the microwave. The rxn was diluted with EtOAc and filtered thru florisil. The solution was concentrated to crude and purified via silica gel chromatography (DCM to 20% MeOH/DCM) to give compound 31c (0.11 g) as a pink solid. LCMS RT = 3.8 (M+l) 532.2, (M-l) 530.2.

[00984] Formation of (1Λ, 25,35)-3-(2-(5-chloro-l//-pyrrolo[2,3-/>]pyridin-3-yl)-5-lluoropyrimidin-4-ylamino)cyciohexane-l,2-diol (632).

To a solution of (17?, 25, 35)-3-(2-(5-chloro-l-tosyl-l//-pyrrolo[2,3-/;]pyridin-3-y 1)-5-fluoropyrimidin-4-ylamino)cyclohexane-l,2-diol, 31c, (0.11 g, 0.21 mmol) in THF was added TBAF (0.23 g, 0.84 mmol). The reaction was aged at room temperature 1 hour, quenched with IN HC1 (1 ml), and purified via reverse phase chromatography (5-70% MeCN/H20 with 0.1% TFA). The product was desalted on an SPE bicarbonate cartridge, concentrated to dryness, and then triturated from MeOH to provide 18 mg of compound 632. ‘H NMR (300 MHz, MeOH-J4) δ 8.42 (s, 1H), 7.90 (s, 1H), 7.82 (s, 1H), 7.70 (s, 1H), 4.15 (m, 1H), 3.95 (m, 1H), 3.70 (m, 1H), 1.75 (ra, 5H), 1.50 (m, 1H) ppm. LCMS RT = 3.0 (M+l) 378.2, (M-l) 376.0.

General Scheme 32:

(a) 2,4-dich[oro-5-fluoropyrimidine, acetonitrile, isopropanol, reflux 1.5 hours, (b) 5-cliloro-3-(4,4,5,5-tetramethyi-l,3,2-dioxaboroIaii-2-yI)-l-tosy]-i//-pyrroto[2,3-6]pyridine, Pd(PPh3)4 , 2M Na2C03 , acetonitrile, 120 °C microwave, 15 min., (c) TBAF, THF

[00985] Formation of (15, 25, 35)-3-(2-chIoro-5-fluoropyrimidin-4-y]amino) cyclohexane-1,2-diol (32b).

The starting racemic diol, 32a, (15, 25, 35)-3-aminocyclohexane-l,2-diol, was prepared following the procedure described in: Org. Bio. Chem. (2008) 6, 3751 and 3762, Davies, et. al.

According to the method for compound 632, except use the racemate of diol 32a (0.07 g, 0.53 mmol), to give compound 32b (0.03 g, 0.11 mmol) as a white solid. 'H NMR (300 MHz, MeOH-c/4) 5 7.90 (s, 1H), 4.45 (m, 1H), 3.80 (s, 1H), 3.62 (s, 1H), 1.40 - 1.80 (m, 6H), 0.85 (m, 1H) ppm. LCMS RT = 2.7 (M+l) 262.0.

[00986] Formation of (15, 25, 35)-3-(2-(5-chloro-I-tosyl-17/-pyrrolo [2,3-b] pyridin-3-yl)-5-fluoropyrimidin-4-ylamin o)cyclo hexane-1,2-d iol (32 c).

According to the method for compound 31c, except use compound 32b (0.03 g, 0.11 mmol), to give compound 32c (0.06 g, 0.11 mmol). LCMS RT = 3.9 (M+l) 532.2, (M-l) 530.3.

[00987] Formation of (15, 25, 35)-3-(2-(5-chloro-Lff-pyrrolo [2,3-A]pyridin-3-yl)-5-fiu or opy rimidin-4-ylamino)cy cloh exane-l,2-diol(615).

According to the method for compound 624, except use compound 32c (0.06 g, 0.11 mmol) to give compound 615 (0.015 g, 0.035 mmol) as a white solid. ‘H NMR (300 MHz, MeOH-t/4) δ 8.83 (s, 1H), 8.51 (s, 1H), 8.40 (s, 1H), 8.30 (s, 1H), 4.00 (bs, 2H), 0.60 - 0.90 (m, 4H), 0.50 (m, 2H) ppm. LCMS RT = 3.7 (M+l) 378.3, (M-l) 376.3.

General Scheme 33

(a) 2,4-dichloro-5-fluoropyrimidine, acetonitrile, isopropanol, reflux 1.5 hours, (b) 5-chloro-3-(4,4,5,5- tetram€ihyl-l,3.2-dioxaboiOian-2-yl)-l-Losyl-l//-pyrrolo[2,3-/j]pyridine1 PdfPPha),),2M Na2C03 , acetonitrile, 120 °C microwave, 15 min., (c) TBAF, THF.

[00988] Formation of (1R, 2R, 3S)-3-(2-chIoro-5-fluoropyrimidin-4-ylamino) cyciohexane-1,2-diol (33b).

The starting racemic diol, 33a, (1R, 2R, 35)-3-aminocyclohexane-l,2-diol, was prepared following the procedure described in: Org. Lett. (2009) 6, 1333, Davies, et. al. According to the method for compound 632, except use the racemate of diol 33a (0.13 g, 1.01 mmol) to give compound 33b (0.14 g, 0.53 mmol) as a white solid. NMR (300 MHz, MeOH-d4) δ 7.90 (s, 1H), 4.05 (m, 2H), 3.70 - 3.80 (m, 0.6H), 1.95 (bs, 2.5H), 1.70 (m, 1.6H), 1.30 - 1.60 (m, 5.4H) ppm; ,3C-APT NMR (300 MHz, MeOH-d4) 5 148,6, 145.2, 140.0, 139.8, 78.9, 75.2, 55.4, 49.15 (m, MeOH-d4), 33.9, 31.9, 22.4 ppm. LCMS RT = 2.4 (M+l) 262.0, (M-l) 260.1.

[00989] Formation of (1Λ, 2 R, 3S)-3-(2-(5-chIoro-l-tosyl-l#-pyrrolo [2,3- 6]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)cyclohexane-l,2-diol (33c).

According to the method for compound 31c, except use compound 33b (0.07 g, 0.26 mmol) to give compound 33c (0.008 g, 0.015 mmol). DME was used as solvent, not acetonitrile. LCMS RT = 4.2 (M+l) 532.3, (M-l) 530.3.

[00990] Formation of (1Λ, 2R, 35)-3-(2-(5-chIoro-l//-pyrrolo [2,3-6]pyridin-3-yl)- 5-fluoropyrimidin-4-yIamino)cycIohexane-l,2-diol (625).

According to the method for compound 624, except use compound 33c (0.008 g, 0.015 mmol to give compound 625 (0.005 g, 0.012 mmol). >H NMR (300 MHz, MeOH-d4) δ 8.80 (s, 1H), 8.48 (s, 1H), 8.40 (s, 1H), 8.20 (s, 1H), 4.5 (m, 1H), 3.55 (m, 2H), 2.12 (m, 2H), 1.95(m, 1H), 1.61 (m, 2H), 1.58 (m, lH)ppm. LCMS RT = 2.4 (M+l) 378.2, (M-l) 376.2.

[00991] The following compounds, 631, 616 and 624, are enantiomers of 632, 615 and 625 and can be prepared by isolation from chiral preparatory HPLC chromatography from their respective enantiomeric mixtures.

General scheme 35

(a) (1S, 2S)-2-aminocyclohexanecarboxylic acid, 'Pr2NEt, Na2C03, THF- CH3CN (3:1), 135 °C microwave; (b) 1N LiOH, THF, microwave, 120 °C (c) 4N HCi-dioxane, EtOH, 70 °C.

[00992] Formation of (15, 2S)-2-(2-(5-chloro-1 //-pyrrolo [2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)cyclohexanecarboxylic acid (553). A mixture of 5-chloro-3-(5-fluoro-4-methylsulfonyl-pyrimid in-2-yl)-l-()?-tolylsulfonyl)pyn'olo[2,3-b]pyridine, la, (0.49 g, 1.05 mmol), (15,25)-2-amino-cyclohexanecarboxylic acid (0.30 g, 2.10 mmol), freshly ground Na2C03 (0.22 g, 2.10 mmol), and 'Pr2NEt (0.37 mL, 2.10 mmol) in THF (10 mL) and CH3CN (2 mL) were heated in a sealed vessel to 130 °C for 30 minutes under microwave irradiation. The mixture was cooled to room temperature. A solution of IN ΠΟΗ (3.1 mL, 3.1 mmol) was added and the mixture was stirred at 120 °C for 10 minutes under microwave irradiation. The mixture was acidified with IN HC1 until pH 2 under vigorous stirring. The newly formed solid was collected by vacuum filtration. The solid was washed with small amounts of water and EtOAc. The solid was dried in vacuo to provide the desired product. ‘H NMR (300 MHz, MeOD) 5 8.89 (d, /= 2,4 Hz, 1H), 8.44 (s, 1H), 8.38 (d, /= 2.3 Hz, 1H), 8.29 (d, /= 5.6 Hz, 1H), 4.75 (m, 1H), 2.75 - 2.66 (m, 1H), 2.25 - 2.16 (m, 2H), 1.99 - 1.89 (m, 2H), 1.71 - 1.29 (m, 4H) ppm; LCMS RT = 2.0 min, (M+H) 390.4.

[00993] Other analogs that can be prepared in the same manner as 553 are described below:

[00994] iraHs-2-(2-(5-chloro-l JT-pyrroIo [2,3-b] pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)cyclohexanecarboxylic acid (541) LCMS RT = 2.4 min, (M+H) 390.5.

[00995] (1R, 27?)-2-(2-(5-ch loro-1 /7-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)cyclohexanecarboxylic acid (554) NMR (300 MHz, MeOD) δ 8.89 (d, / = 2.4 Hz, 1H), 8.44 (s, 1H), 8.38 (d, / = 2.4 Hz, 1H), 8.29 (d,/ = 5.6 Hz, 1H), 4.77 (m, 1H), 2.75 - 2.66 (m, 1H), 2.24 - 2.17 (m, 2H), 1.94 - 1.89 (m, 2H) and 1.74 - 1.36 (m, 4H) ppm. LCMS RT = 2.3 min, (M+H) 390.4.

[00996] C/i-2-(2-(5-chloro-l//-pyrrolo[2,3“b]pyridin-3-yl)-5-nuoropyrimidin-4~ ylamino)cyclohexanecarboxy!ic add (559) !H NMR (300 MHz, MeOD) δ 8.75 (d, / = 2.4 Hz, 1H), 8.38 - 8.35 (m, 2H), 8.24 (d, / = 5.1 Hz, 1H), 4.70 - 4.62 (m, 1H), 3.25 - 3.17 (m, 1H), 2.32 (m, 1H), 2.14 - 1.80 (m, 4H) and 1.68 - 1.54 (m, 3H) ppm. LCMS RT = 2.3 min, (M+H) 389.8.

[00997] (IS, 2R)-2-(2-(5-chloro-l//-pyrrolo[2,3-b]pyridm-3-yI)-5-fluoropyrimidin-4-ylamino)cyclohexanecarboxylic acid (579) 'HNMR (300 MHz, ί/6-DMSO) δ 12.52 (s, 1H), 8.68 (d, /= 2.3 Hz, 1H), 8.33 (d,/ = 2.5 Hz, 2H), 8.30 (d, / = 4.4 Hz, 1H), 7.57 (s, 1H), 4.53 (m, 1H), 3.05 (m, 1H), 2.15 - 2.07 (m, 1H), 1.96 (m, 1H), 1.81 - 1.76 (m, 3H) and 1.51 (m, 3H) ppm. LCMS RT = 2.9 min, (M+H) 390.4.

[00998] (1R, 2S)-2-(2-(5-chloro-l//-pyrrolo[2,3-b]pyridin-3-yl)~5-fluoropyrimidin-4-ylamino)cycIohexanecarboxylic acid (578) 1H NMR (300 MHz, /6-DMSO) δ 12.51 (s, 1H), 8.68 (d, / = 2.3 Hz, 1H), 8.33 (d, / = 2.3 Hz, 2H), 8.29 (d, / = 4.3 Hz, 1H), 7.55 (s, 1H), 4.53 (s, 1H), 3.05 (m, 1H), 2.13 (m, 1H), 1.96 (m, 1H), 1.79 (m, 3H) and 1.51 (m, 3H) ppm. LCMS RT = 2.8 min, (M+H) 390.4.

558 (+/-) 566 [00999] Ci.s-2-(2-(5-chloro-l//-pyrrolo[2,3-b]pyridin-3-yI)-5-fluoropyrimidin-4-ylamino)cyclopentanecarboxylic acid (558) !H NMR (300 MHz, MeOD) 5 8.78 (d, /= 2.4 Hz, 1H), 8.38 (s, 1H), 8.33 (d, /= 2.2 Hz, 1H), 8.25 (d, /= 5.2 Hz, 1H), 4.98 (dd, /= 7.2 Hz, 1H), 2.27 - 2.03 (m, 5H) and 1.86 - 1.76 (m, 1H) ppm. LCMS RT = 2.5 min, (M+H) 376.2.

[001000] (1R, 35)-3-(2-(5-chloro-li/-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropynmidin-4-ylamino)cyclopentanecarboxylic acid (566) 'H NMR (300 MHz, /6-DMSO) 5 12.42 (s, 1H), 8.72 (d, /= 2.2 Hz, 1H), 8.29 (m, 2H), 8.22 (d, / = 4.1 Hz, 1H), 7.87 (s, 1H), 4.56 - 4.49 (m, 1H), 2.87 (dd, /= 8.4, 25.0 Hz, 1H), 2.87 (s, 1H), 2.42 - 2.33 (m, 1H), 2.15 - 2.04 (m, 1H), 2.00 - 1.85 (m, 3H) and 1.81 - 1.70 (m, 1H) ppm. LCMS RT = 2.3 min, (M+H) 376.4.

[001001] (1S, 3R)-3-(2-(5-chloro-l/7-pyrrolo [2,3-b ] pyridin-3-yI)-5-fiuoropyrimidin-4-ylamino)cycIopentanecarboxylic acid (565) lH NMR (300 MHz, c/6-DMSO) δ 12.48 (s, 1H), 8.71 (d, / = 2.3 Hz, 1H), 8.35 - 8.31 (m, 2H), 8.26 (d, /= 4.3 Hz, 2H), 8.02 (s, 1H), 4.57 - 4.44 (m, 1H), 2.87 (qn, /= 8.3 Hz, 1H), 2.39 - 2.32 (m, 1H), 2.15 - 2.05 (m, 1H), 2.00 - 1.86 (m, 3H) and 1.82 - 1.70 (m, 1H) ppm. LCMS RT = 2.4 min, (M+H) 376.4.

[001002] (1R, 35)-3-(2-(5-chloro-l//-pyrrolo [2,3-/j]pyridin-3-yl)-5-fluoropyrimidin-4-yIa min o)cyclohexanecar boxy lie acid (630)

Compound 630 was prepared in same fashion from intermediate 18c, by removal of Cbz-protecting group and reaction with intermediate la, followed by removal of tosyl protecting group. LCMS RT = 3.2 min, (M+H) 390.4, (M-H) 388.1.

582 585,586 {+/-) (+/.) [001003] 7>«H5'-2-(2-(5“Chloro-ll¥-pyrrolo[2,3-b]pyridin-3-yl)“5-fluoropyrimidiii~4-ylamino)-l-methylcyclohexanecarboxylic acid (582) *H NMR (300.0 MHz, /6-DMSO) δ 12.46 (s, 1H), 8.72 (d, / = 2.4 Hz, 1H), 8.32 - 8.28 (m, 3H), 7.10 (d, /= 7.1 Hz, 1H), 4.27 - 4.20 (m, 1H), 2.26 (d, / = 10.1 Hz, IH), 1.93 (m, 1H), 1.83 (m, 1H), 1.68 - 1.59 (m, 3H), 1.36 (m, 2H) and 1.24 (s, 3H) ppm. LCMS RT = 3.2 min, (M+H) 404.4.

[001004] Racemic ir«HS-2-(2-(5-chioro-li?-py r r olo [2,3-b ]py ridin-3-y 1)-5-fluoropyrimidm-4-y]amino)-l-ethylcyclohexanecarboxylic acid (586) ‘H NMR (300 MHz, MeOD) δ 8.93 (s, 1H), 8.85 (m, 2H), 8.93 - 8.87 (m, 1H), 8.31 (dd, /= 4.5, 1.2 Hz, 2H), 8.31 (dd, /= 4.5, 1.2 Hz, 2H), 8.30 (d, /= 2.3 Hz, 1H), 8.19 (d, /= 5.0 Hz, 1H), 5.26 - 5.20 (m, 1H), 3.37 (dd, /= 3.3 Hz, 1.6, 2H), 3.33 (ddt, / = 6.6, 3.3, 1.6 Hz, 118H), 2.11 (dd, /= 8.0, 5.8 Hz, 2H), 1.80 (tdd, /= 21.2, 18.9, 11.6 Hz, 8H), 1.63 - 1.54 (m, 3H), 0.86 (q, /= 7.4 Hz, 4H) ppm. LCMS RT = 2.9 min, (M+H) 418.4.

[001005] Racemic c«-2-(2-(5-chloro-l//-pyrrolo [2,3-b] pyridin-3-yI)-5-fluoropyrimidin-4-ylamin o)-l-ethylcyclohexanecarboxylic acid (585) lR NMR (300 MHz, MeOD) δ 8.80 - 8.76 (m, 1H), 8.37 (s, 1H), 8.35 (d, /= 2.3 Hz, 1H), 8.27 - 8.23 (m, 1H), 4.49 - 4.42 (m, 1H), 2.43 - 2.34 (m, 1H), 2.09 (d,/ = 6.2 Hz, 1H), 1.98- 1.36 (m, 12H),0.94 (dd,/= 11.3, 3.8 Hz, 3H) ppm. LCMS RT = 3.2 min, (M+H) 418.4.

670 671 I001006] (3S, 4R, 5R)-ethyl 3-(2-(5-chloro-l//-pyrrolo[2,3-6]pyridin-3-yl)-5- fluoropyrimidin-4-ylamino)-4-ethanamido-5-(pentan-3-yloxy)cyclohex-l-enecarboxylate (670) HNMR (300.0 MHz, MeOD) d 8.64 (d, J = 2.3 Hz, 1H), 8.40 (s, IH), 8.32 (d, J = 2.3 Hz, IH), 8.29 (d, J = 5.0 Hz, 1H), 6.96 (m, 1H), 4.84 - 4.80 (m, 1H), 4.34 (m, 1H), 4.29 - 4.19 (m, 3H), 3.54 - 3.47 (m, IH), 3.15 - 3.07 (m, IH), 2.68 - 2.58 (m, IH), 1.92 (s, 3H), 1.59 - 1.51 (m, 4H), 1.26 (t, J = 7.1 Hz, 3H), 0.95 (t, J = 7.4 Hz, 3H) and 0.89 (t, J = 7.4 Hz, 3H) ppm LCMS RT = 3.6 (M+l) 559.4.

[001007] (35,47?, 57?)-3-(2-(5-chloro-17/-pyrrolo[2,3-Ajpyridin-3-yl)-5-fluoropyrimidin-4-ylaniino)-4-ethanamidO“5“(pentan-3-yloxy)cyclohex-l-enecarboxylic acid (671) H NMR (300.0 MHz, McOD) d 8.66 (d, J = 2.3 Hz, 1H), 8.39 (s, 1H), 8.32 (d, J = 2.3 Hz, 1H), 8.29 (d, J = 5.0 Hz, 1H), 6.97 (m, 1H), 4.82 - 4.79 (m, 1H), 4.34 (m, 1H), 4.25 (dd, J = 7.6, 10.1 Hz, 1H), 3.54-3.47 (m, 2H), 3.11 - 3.04 (m, 1H), 2.65-2.57 (m, 1H), 1.91 (s, 3H), 1.59 (m, 4H), 0.95 (t, J = 7.4 Hz, 3H) and 0.89 (t, J = 7.4 Hz, 3H) ppm LCMS RT = 3.1 (M+l) 531.4.

General Scheme 36

553 561 [001008] (IS, 25)-ethyl 2-(2-(5-chloro-177-pyrrolo[2,3-b)pyridin-3-yl)-5-flu or opy r i midi n-4-y lami n o)cyclo hexanecarb oxylate (561)

To a mixed slurry of (IS, 2S)-2-[[2-(5-chloro-lH-pyrrolo[5,4-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-yl]amino]cyclohexane-l-carboxylic acid, 553, (0.090 g, 0.231 mmol), in ethanol (1.5 mL) at room temperature was added HC1 (0.577 mL of 4 M solution, 2.309 mmol). The solution was wanned to 50 °C. After 6 hours, the mixture was basified with IN NaOH, brine was added and the aqueous layer was and extracted repeatedly with EtOAc. The organic layer was dried over MgSCL, and filtered through a short plug of silica gel and concentrated in vacuo to provide the desired product. ‘H NMR (300 MHz, MeOD) δ 8.95 (s, 1H), 8.19 (m, 2H), 7.99 (s, 1H), 4.61 (m, 1H), 3.93 (m, 2H), 2.61 (m, 1H), 2.17 - 2.05 (m, 2H), 1.89 - 1.32 (m, 7H) and 1.00 (m, 3H) ppm. LCMS RT = 2.7 min, (M+H) 418.4.

[001009] The following compounds can also be prepared in a manner similar to the one described in Scheme 36.

560 575 [001010] (17?, 27?)-ethyl 2-(2-(5-chloro-177-pyrroIo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)cyclohexanecarboxylate (560) ‘H NMR (300 MHz, MeOD) δ 8.95 (s, 1H), 8.23 - 8.14 (m, 2H), 8.00 (m, 1H), 4.61 (m, 1H), 3.96 - 3.92 (m, 2H), 2.61 (m, 1H), 2.14 - 2.04 (m, 2H), 1.89 - 1.35 (m, 7H) and 1.04 - 0.99 (m, 3H) ppm. LCMS RT = 3.2 min, (M+H) 418.5.

[001011] (15, 25)-methyl 2-(2-(5-chloro-l//-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)cycIohexanecarboxylate (575) 'H NMR (300 MHz, /6-DMSO) 5 8.76 (d, /= 2.5 Hz, 1H), 8.26 (d, /= 2.4 Hz, 1H), 8.19 (s, 1H), 8.13 (d, / = 4.0 Hz, 1H), 7.53 (d, /= 8.5 Hz, 1H), 4.47 - 4.37 (m, 1H), 3.40 (s, 3H), 2.68 - 2.59 (m, 1H), 2.05 - 1.97 (m, 2H), 1.84 - 1.75 (m, 2H), 1.63 - 1.40 (m, 3H) and 1.31 - 1.23 (m, 1H) ppm. LCMS RT = 3.1 min, (M+H) 404.4.

574 568 [001012] (15,25>2-methoxyethyl 2-(2-(5-chIoro-l//-pyrroIo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)cyclohexanecarboxylate (574) lH NMR (300 MHz, /6-DMSO) d 8.74 (d, J = 2.4 Hz, 1H), 8.24 (d, J = 2.4 Hz, 1H), 8.19 (s, 1H), 8.12 (d, J = 4.0 Hz, 1H), 7.55 (d, J = 8.6 Hz, 1H), 4.42 (m, 1H), 4.02 - 3.86 (m, 2H), 3.35 - 3.23 (m, 2H), 3.08 (s, 3H), 2.69 - 2.60 (m, 1H), 1.99 (m, 2H), 1.77 (m, 2H), 1.62 - 1.40 (m, 3H) and 1.27 (m, 1H) ppm. LCMS RT = 3.0 min, (M+H) 448.4.

[001013] (1R, 2fl)-isopropyl 2-(2-(5-chloro-1//-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-yla mino) cyclohexaneca rb oxylate (568) *H NMR (300 MHz, J6-DMSO) 5 8.80 (d, /= 2.5 Hz, 1H), 8.27 (d, /= 2.4 Hz, 1H), 8.19 (s, 1H), 8.13 (d, /= 4.0 Hz, 1H), 7.60 (d, /= 8.6 Hz, 1H), 4.72 (qn, / = 6.2 Hz, 1H), 4.55 - 4.48 (m, 1H), 2.61 - 2.54 (m, 1H), 1.96 (m, 2H), 1.77 (m, 2H), 1.63 - 1.41 (m, 3H), 1.30 - 1.23 (m, 1H) and 0.93 (d, /= 6.2 Hz, 6H) ppm. LCMS RT = 3.08 min, (M+H) 432.46.

569 [001014] (15, 25)-isopropyl 2-(2-(5-chloro-l//-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)cyclohexanecarboxylate (569) *H NMR (300 MHz, /6-DMSO) δ 12.57 (s, 1H), 8.80 (d, /= 2.4 Hz, 1H), 8.36 - 8.28 (m,4H), 4.75 (td,/= 12.5, 6.2 Hz, 1H),4.52 (m, 1H), 2.65 - 2.56 (m, lH),2.00(m, 2H), 1.83 - 1.76 (m, 2H), 1.57 - 1.42 (m, 3H), 1.32 - 1.24 (m, 1H) and 0.94 (d, J = 6.2 Hz, 6H) ppm. LCMS RT = 2.7 min, (M+H) 432.5.

General Scheme 37:

Preparation of m-2-amino-l-methylcycIohexanecarboxylic acid (37c)

{+/-) (a) NaH, iodomethane DMF (b) NH2OH- HCI, pyridine, EtOH (c) Ai (Hg), THF-H20 (4:1).

[001015] Formation of ethyl l-methyl-2-oxocyclohexanecarboxyIate (37a):

The title compound was prepared following the procedure described in: Tetrahedron Letters (2005) 46, 681-685 and JCS, Perkin Trans 1(2000) 3277-3289.

Sodium hydride (1.48 g, 37.14 mmol, 60% in oil) was rinsed twice with hexanes to remove oil and suspended in DMF (57 mL) at 0 °C. Then, ethyl 2-oxocyclohexanecarboxylate (5.40 mL, 33.76 mmol) was added over 5 minutes. The mixture was stirred for 20 minutes and Mel (2.21 mL, 35.45 mmol) was added over 10 minutes. The mixture was warmed to room temperature and after 30 minutes, diluted with EtOAc (150 mL) and quenched with saturated NH4CI. The layers were separated and the aqueous layer was extracted twice more with EtOAc (2 x lOOmL). The organic layer was washed with brine (2 x) dried over MgS04, filtered through silica gel and concentrated to provide the desired product (37a).

[001016] Formation of 3a-methyl-4, 5, 6, 7-tetrahydrobenzo[c]isoxazol-3(3a/7)-one (37b):

To a mixture of ethyl l-methyl-2-oxo-cyclohexanecarboxylate, 37a, (2.05 g, 11.10 mmol) in EtOH (20 mL) was added hydroxylamine hydrochloride (0.97 g, 13.96 mmol) and pyridine (0.99 mL, 12.20 mmol). The mixture was heated to 65 °C overnight. Tire solution was concentrated in vacuo and the crude material was partitioned between water and EtOAc. The aqueous layer was extracted with EtOAc twice more. The combined organic phases were washed with brine, dried over MgS04, filtered and concentrated in vacuo. The resulting residue was purified via silica gel chromatography (0-35% EtOAc/hexanes) to afford the desired product, 37b. lH NMR (300 MHz, CDCI3) δ 2.72 - 2.65 (m, 1H), 2.29 (td, ./= 13.3, 6.3 Hz, 1H), 2.18 - 2.09 (m, 1H), 2.07 - 2.03 (m, 1H), 1.84 - 1.79 (m, 1H), 1.76 - 1.56 (m, 2H), 1.54 - 1.42 (m, 1H) and 1.40 (s, 3H) ppm.

[001017] Formation of rrans-2-amino-l-methylcyclohexanecarboxylic acid (37c):

To a solution of 3a-methyl-4,5,6,7-tetrahydro-2,l-benzoxazol-3-one, 37b, (0.075 g, 0.490 mmol) in THF-H2O (2.5 mL of 4:1 mixture) at room temperature was added fresh Al(Hg) amalgam. Aluminum was amalgamated by dipping small strips of Aluminum foil in 2% HgCh solution, rinsing with water and EtOH. After 1 hour, an additional 65 mg AI(Hg) was added and the mixture was allowed to stir overnight. The thick gray emulsion that formed was filtered through celite and rinsed with water and THF. The clear solution was concentrated in vacuo, stripped with methanol and THF to remove residual water and concentrated in vacuo to provide the desired product as a glassy solid as mixture of trans and cis isomers (~9:1) with the trans isomer as the predominant isomer. The product was sufficiently pure for use in the next reaction. ‘H NMR (300 MHz, MeOD) 6 2.91 (dd, J = 3.9, 11.9 Hz, 1H), 2.25 (dd, / = 1.9, 13.4 Hz, 1H), 1.89 - 1.85 (m, 1H), 1.78 - 1.53 (m, 3H), 1.47 - 1.32 (m, 2H), 1.21 (s, 3H) and 1.09 -0.99 (m, 1H) ppm. FIA (M+H) 158.1, (M-H) 156.2.

[001018] Formation of 2-amino-l-ethylcyclohexanecarboxylic acid:

This compound was prepared by the methods described above as an inseparable mixture of cis and tram isomers (70:30) and was used without further purification.

General Scheme 38

Preparation of cis-2-amino-l-alkyl-cyclohexanecarboxylic acids:

(a) LDA, iodoethane, THF (b) Ha Pd-C, MeOH

An alternative scheme for the preparation ci'A-2-amino-l-alkyl-cyclohexanecarboxyIic acid is exemplified above. The method is described in: (a) Nemoto, T.; Fukuyama, T.; Yamamoto, E.; Tamura, S.; Fukuda, T.; Matsumoto, T.; Akimoto, Y.; Hamada, Y. Org. Lett. 2007, 9 (5), 927-930. (b) Seebach, D,; Estermann, H, Tetrahedron Lett. 1987, 28 (27), 31033106.

[001019] (Iff, 2*S)-methyl 2-(benzyloxycarbonylamino)-l- ethylcyclohexanecarboxylate (38b)

To a cold (-78 °C) solution of iV-isopropylpropan-2-amine (0.77 mL, 5.49 mmol) in THF (7 mL) was added, dropwise, n-butyllithium (3.43 mL of 1.6 M solution, 5.49 mmol). The mixture was stirred at -78 °C for 10 minutes. Then a solution of methyl (15, 25)-2-benzyloxycarbonylaminocyclohexanecarboxylate, 38a, (0.40 g, 1.37 mmol) in THF (2,5 mL) was added over a period of 3 minutes. After 15 minutes, the mixture was warmed slightly (40 °C) for 15 minutes and recooled to -78 °C for a further 10 minutes. Then, iodoethane (0.86 g, 0.44 mL, 5.49 mmol) was added, dropwise over 3-5 minutes. The reaction mixture was maintained at -78 °C for 2 hours and allowed to warm to room temperature overnight. The reaction was quenched with 5 mL aqueous saturated NH4CI solution, extracted with EtOAc (3 x), washed successively with IN HC1 and brine. The combined organic layers were dried over Na2SO.i, filtered and concentrated in vacuo. Flash chromatography (Si02, 0-20% EA/Hex slow gradient elution) provided 275 mg (63% yield) of the desired product (38b). NMR indicated a diastereomeric ratio greater than 10 to 1 (cis vs trans). ’H NMR (300.0 MHz, MeOD) 5 7.35 - 7.28 (m, 5H), 6.62 (d, J= 9.2 Hz, 1H), 5.07 (dd, /= 12.5, 16.6 Hz, 2H), 3.67 (s, 3H), 3.59 (td, /= 10.0, 4.6 Hz, 1H), 2.14 (m, 1H), 1.76 - 1.29 (m, 9H) and 0.83 (t, /= 7.6 Hz, 3H) ppm.

[001020] (Iff, 25)-methyl 2-amino-l-ethylcyclohexanecarboxylate (38c) A solution of methyl (Iff, 25)-2-benzyloxycarbonylamino-l-ethyl-cyclohexanecarboxylate, 38b, (0.27 g, 0.85 mmol) in MeOH (7.5 mL) was purged with nitrogen and a catalytic amount of Pd (5% Pd on carbon) was added. The solution was placed under H2 atmosphere and stirred at room temperature. After 1 hour, the MeOH solution suspension was filtered through celite, and concentrated in vacuo to provide the desired product (138 mg, 88% yield). The material was diluted in acetonitrile and concentrated to remove residual methanol. *H NMR (300.0 MHz, MeOD) δ 3.69 (s, 3H), 2.71 (m, 1H), 2.07 - 2.01 (m, 1H), 1.82 (m, 2H), 1.71 - 1.27 (m, H), 1.64 (m, 2H), 1.56 - 1.27 (m, 5H) and 0.85 (t, /= 7.5 Hz, 3H) ppm.

General Scheme 39 preparation of tra«A-2-amino-l-alkyl-cyclohexanecarboxylic acids:

(a) Benzyl alcohol, toluene, 4 angstrom sieves, reflux (b) NaH, Mel, DMF (c) benzylamine, TiCU, CH2Cl2, then NaCNBH3, MeOH, 0 oC (d) H2, Pd-C, MeOH (e) 5-chloro-3-(5-fluoro-4-methyls ulfinyl-pyrimidin-2-yl)-1-(p-tolylsulfonyl)pyrrolo[2,3-b3pyridine, Na2C03, THF/CH3CN, microwave irradiation 135 °C (f) HCI, CH3CN, dioxane, 80 °C, [001021] A general method for the synthesis of tram-2-amino- 1-alkyl-cyclohexanecarboxylic acids is shown in the scheme above.

[001022] Benzyl 2-oxocyclohexanecarboxylate (39b)

This compound was prepared following literature procedures described in: Matsuo, J. etal. Tetmhedon: A symmetry 2007,18, 1906-1910.

[001023] Benzyl l-methyl-2-oxocyclohexanecarboxylate (39c)

This compound was prepared following the literature procedures described in: (a) Hayashi, Y.; Shoji, M.; Kishida, S. Tetrahedron Lett 2005, 46, 681-685. (Winfield, C. J.; Al-Mahrizy, Z.; Gravestock, M.; Bugg, T. D. H. J. Chem. Soc., Perltin Trans. 1, 2000, 3277.

[001024] 7V«Hs-Benzyl 2-(benzylamino)-l-methylcyclohexanecarboxylate (39d)- (racemic trans)

To a solution of benzyl l-methyl-2-oxo-cyclohexanecarboxylate, 39c, (0.50 g, 2.03 mmol) and benzylamine (0.61 g, 0.63 mL, 5.75 mmol) in dichloromethane (10.0 mL), was added TiCl4 (1.93 mL of 1 M solution, 1.93 mmol) dropwise, at room temperature. The mixture was stirred for 2 hours. The mixture was cooled to 0 °C and a solution of NaBH^CN (0.21 g, 3.34 mmol) in MeOH was added dropwise over a period of 3 minutes. After 15 min, the solution was warmed to RT and stirred for an additional 45 min. Then, the mixture was diluted with EtOAc, quenched with 10 mL 1M NaOH. The mixture was partitioned with Et20 and the aqueous layer was extracted several times with Et20 (2 x) and EtOAc (1 x). The combined organic phases were dried over MgS04, filtered and concentrated in vacuo. Flash chromatography (Si02, 0-50% EtOAc-Hexanes gradient elution) and isolation of the major component provided the desired product (320 mg) as a single racemic trans isomer. ΉNMR (300.0 MHz, MeOD) 5 7.34 - 7.16 (m, 10H), 5.07 (dd,J= 12.4, 31.2 Hz, 2H), 3.78 (d, J= 13.0 Hz, 1H), 3.57 (d, J= 13.0 Hz, 1H), 2.96 (m, 1H), 1.86 (m, 1H), 1.74 -1.57 (m, 3H), 1.52 - 1.25 (m, 4H) and 1.20 (s, 3H) ppm.

[001025] 7>wis-2-Amino-l-methylcyclohexanecarboxyIic acid (39e)

To a solution of racemic trans-benzyl (15, 25)-2-(benzylamino)-l-ethyl-cyclohexanecarboxylate, 39d, (0.32 g, 0.91 mmol) in MeOH (12.8 mL), was added Pd (5%

Pd on carbon, 0.07 g). The solution was degassed and placed under 50 PSIH2 (Parr shaker) overnight. The mixture was filtered through celite and the filtrate was rinsed with MeOH. Concentration of the mother liquor followed by acetonitrile azeotrope (2 x) to remove residual MeOH provided the desired product (162 mg). 'HNMR (300.0 MHz, MeOD) δ 3.22 (m, 1H), 1.93 (m, 1H), 1.77 (m, 2H), 1.57 -1.23 (m, 5H) and 1.17 (s, 3H) ppm.

[001026] ir«Hs-2-[[2-[5-chloro“l“(p-tolylsulfonyl)pyrrolo[2,3-b]pyridm-3-yl]-5-fluoro-pyrimidin-4-yl]amino]-l-methyl-cyclohexanecarboxylic add (39f)

To a vessel charged with 5-chloro-3-(5-fhroro-4-methylsulfmyl-pyrimidin-2-yl)-l-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridine, 15a, (0.27 g, 0.58 mmol) and irawi'-2-amino-1 -methyl-cyclohexanecarboxylic acid, 39e, (0.08 g, 0.47 mmol) and freshly ground Na2C03 (0.19 g, 1.75 mmol) was added anhydrous THF (4.5 mL) and CH3CN (0.9 mL). The vessel was sealed and heated to 135 °C for 35 min (microwave irradiation). LC-MS indicated complete consumption of starting material. Next, the reaction mixture was slowly poured into a vigorously stirred solution of IN HC1 (13.5 mL). The pH of the final solution was 1-2. The mixture was extracted with EtOAc (3 x), dried over Na2S04 and filtered through Celite and concentrated in vacuo. Flash chromatography (Si02, 0-10% MeOH-dichloromethane, gradient elution) provided a sticky yellow foam, which was suspended in acetonitrile. Sonication followed by evaporation of the solvent provided white amorphous solid (240mg, 74% yield) as a racemic mixture of trans stereoisomers. lE NMR (300.0 MHz, MeOD) δ 9.02 (d, / = 2.4 Hz, 1H), 8.52 (s, 1H), 8.33 (d, / = 2.4 Hz, 1H), 8.09 - 8.05 (m, 3H), 7.38 (d, /= 8.1 Hz, 2H), 5.04 (dd, /= 3.6, 9.5 Hz, 1H), 2.38 (s, 3H), 2.09 (m, 1H), 1.83 - 1.59 (m, 7H), 1.29 (s, 3H) and 1.23 (m, 1H) ppm. LCMS RT = 4.00 min, (M+H) 558.34.

[00X027] T/Ym.v-2-I|2-(5-chloro-l//-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrirnidin-4-yl]amino]“l-methyl-cyciohexanecarboxyIic acid (643)

To a slurry of racemic tra«x-2-[[2-[5-chloro-l-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-5-fhioro-pyrimidin-4-yl]amino]-l-rnethyl-cyclohexanecarboxylic acid, 39f, (0.047 g, 0.084 mmol) in CH3CN (2.35 mL) was added HC1 (1.26 mL of 4 M solution, 5.05 mmol) in dioxane. The suspension became a clear solution. The vial was sealed and heated to 80 °C for 2 hours during which time a thick slurry formed. The slurry was allowed to cool to room temperature overnight. Additional CHjCN was added and the mixture was centrifuged. The organic layer was discarded and the solid was triturated with CH3CN three times more to provide an amorphous white solid as racemic mixture of trans stereoisomers. *H NMR (300.0 MHz, MeOD) 5 8.98 (d, J= 2.3 Hz, 1H), 8.45 (s, 1H), 8.38 (d, J = 2.3 Hz, 1H), 8.30 (d, J= 5.7 Hz, 1H), 5.26 - 5.22 (m, 1H), 2.17 - 2.10 (m, 1H), 1.87 - 1.82 (m, 4H), 1.68 - 1.59 (m, 3H) and 1.36 (s, 3H) ppm. LCMS RT = 3.30 min, (M+H) 404.36.

General scheme 40

€29 a) ferz-butylmagnesium chloride; I2, Et3N, THF, DME (b) 5-chloro-L-(p-tolylsulfonyl)-3-(4,4,5,5-teiraniethyl-l,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine, DME/H-.0, NaoCOj, tetrakis triphenylphosphinepalladium(O), 130 °C, microwave (c) rnCPBA, CPECE (d) (IS, 2iS)-2-aminocyclohexanecarboxylic acid, Na2C03, THF-CH3CN (3:1), 150 °C microwave.

[001028] Formation of 4-terf-butyI-2-chloro-5-fluoro-6“(methyIthio)pyrimidine (40a)

To a cold (0 °C) solution of teri-butylmagnesium chloride (7.5 mL, 1M solution in THF, 7.5 mmol) in THF (15 mL) was added slowly a solution of 2-chloro-5-fluoro-4-(methylthio)pyrimidine (0.9 g, 5.0 mmol) in 1,2-dimethoxyethane (5 mL). The reaction mixture was stirred at 15 °C for 1 hour, then cooled to 0 °C and triethylamine (0.7 mL, 5.0 mmol) was added, followed by the addition of a solution of iodine (1.3 g, 5,0 mmol) in tetrahydrofuran (3 mL). Water (10 mL) was added to quench the reaction and pH was adjusted to 1 using 6N hydrochloric acid. The aqueous phase was extracted twice with ethyl acetate (2 x 15 mL). The combined organic phases were washed with aqueous sodium thiosulfate and then brine, dried over MgSC>4, filtered and concentrated in vctcuo to give a brown solid which was used without further purification. *H NMR (300.0 MHz, CDC13) δ 2.52 (s, 3H), 1.30 (s, 9H) ppm. LCMS (M+l) 233.0.

[001029] Formation of 3-(ferf-butyl-5-fluoro-6-(methylthio)pyrimidin-2-yl)-5-chloro-l//-pyrrolo[2,3-/>]pyridine (40b)

To a degassed solution of 5-chloro-l-(/>tolylsulfonyl)-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine (0.22 g, 0.50 mmol), 4-feri-butyl-2-chloro-5-fluoro- 6-thiomethoxypyrimidine, 40a, (0.12 g, 0.50 mmol) in 1,2-dimethoxyethane (3 mL) and aqueous Na2C03 (0.75 mL of 2 M solution, 1.5 mmol) was added tetrakis(triphenylphosphine)palladium(0) (0.03 g, 0.03 mmol). The reaction mixture was degassed for an additional 15 minutes. The mixture was heated in a microwave at 150 °C for 20 minutes. Ethyl acetate (15 mL) was added. The organic layer was separated and washed with brine, dried over MgSC>4, filtered and concentrated in vacuo. The resulting crude residue was purified by silica gel chromatography (0%-100% EtOAc/hexanes) to afford the desired product, 40b (47 mg). 'H NMR (300 MHz, CDC13) δ 10.82 (br, 1H), 8.81 (d, /= 2.2 Hz, 1H), 8.27 (d, / = 2.3 Hz, 1H), 8.20 (dd, /= 7.2, 2.2 Hz, 1H), 7.18 (s, 1H), 2.63 (s, 3H), 1.41 (s, 9H) ppm. LCMS (M+l) 352.3.

[001030] Formation of 3-(terf-butyl-5-fluoro-6-(methylsulfinyl)pyrimidin-2-yl)-5-ch loro-1 //-pyrrolo [2,3-ό[ pyridine (40 c)

To the solution of 3-(ter/-butyl-5-fluoro-6-(methylthio)pyrimidin-2-yl)-5-chloro-l//-pyrrolo[2,3-6]pyridine, 40b, (0.05 g, 0.11 mmol) in CH2CI2 (3.4 mL) was added mCPBA (0.02 g, 0.11 mmol). The reaction mixture was stirred for 1 h. The reaction mixture was diluted with CH2CI2 (10 mL) and saturated NaHC03 solution (5 mL). The aqueous layer was extracted with CH2CI2 (10 mL). The combined organic phases were washed again with aqueous saturated NaHCCh solution, dried over NaaSCL, filtered and concentrated in vacuo to afford the desired product that was used without further purification. *H NMR (300 MHz, CDCh) δ 10.93 (br, 1H), 8.79 (d, / = 2.2 Hz, 1H), 8.34 (s, 1H), 8.25 (d,/= 2.2 Hz, 1H), 7.19 (s, 1H), 2.98 (s, 3H), 1.47 (s, 9H) ppm. LCMS (M+l) 368.3.

[001031] Formation of (IS, 25)-2-(6- fcrt-butyl-2-(5-chloro-l/7-pyrrolo[2,3- 6]pyridin-3-yl)-5-fluoropyrimidin-4-yIamino)cyclohexanecarboxylic acid (629). A mixture of 3-(ieri-butyl-5-fluoro-6-(methylsulfinyl)pyrimidin-2-yl)-5-chloro-l/A pyrrolo[2,3-/)]pyridine, 40c, (0.05 g, 0.14 mmol), (15, 25)-2-amino-cyclohexanecarboxylic acid (0.04 g, 0.27 mmol), freshly ground Na2CC>3 (0.04 g, 0.41 mmol), and ‘Pr2NEt (0.37 mL, 0.27 mmol) in THF (1 mL) and CH3CN (0.5 mL) was heated in a sealed vessel to 140 °C for 30 minutes under microwave irradiation. The mixture was cooled to room temperature. A solution of IN HC1 (0.5 mL, 0.5 mmol) was added and the mixture was concentrated to give a yellow solid, which was purified by reverse phase HPLC (0%-50% methanol in water) to afford the desired product, 629, as off-white solid. *H NMR (300 MHz, DMSO) 6 12.26 (s, 1H), 8.79 (d, / = 2.4 Hz, 1H), 8.28 (d,/ = 2.4 Hz, 1H), 8.13 (d, J = 2.7 Hz, 1H), 7.25 (d, J = 8.3 Hz, 1H), 4.34 (m, 1H), 2.62 (m, 1H), 2.05 (m, 2H), 1.75 (m, 2H), 1.57 (m, 2H), 1.39 (s, 9H) and 1.26 - 1.17 (m, 2H) ppm. LCMS (M+l) 446.23.

General Scheme 41

(b) 3“amino-1-methylpynOlidin-2-one, DMA, 140 °C microwave; (b) i: LiOH, THF. microwave, 120 °C, or ii: NaOMe, MeOH.

[001032] Formation of 3-(2-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-yl)-5“ fluoropyrimidin-4-ylamino)-l-methylpyrrolidin-2-one (379) A solution of 5-chloro-3-(5-fluoro-4-methylsulfmyl-pyrimidin-2-yl)-l“(p-tolyIsulfonyl)pyrrolo[2,3-b]pyridine, 15a, (0.060 g, 0.129 mmol) in DMA (0.5 mL) was treated with 3-amino-l-methylpyrrolidin-2-one (0.030 g, 0.258 mmol) and the reaction was heated at 140 °C for 20 minutes. The reaction mixture was cooled to room temperature and then treated with 0.5 mL of 25% NaOMe in MeOH and heated at 50 °C for 15 min. The mixture was then partitioned between aqueous saturated Na2C03 solution and EtOAc. The aqueous layer was extracted with EtOAc twice more and the combined organic phases were concentrated in vacuo. The crude material was purified by preparative HPLC. The isolated product was filtered through basic resin to remove residual TEA and provide the desired product. lH NMR (300 MHz, MeOD) 6 8.72 (d, /= 2.3 Hz, 1H), 8.21 (d, /= 2.4 Hz, 1H), 8.11 - 8.07 (m, 2H), 4.94 (t, /= 9.3 Hz, 1H), 3.64 - 3.51 (m, 2H), 2.97 (s, 3H), 2.68 - 2.54 (m, 1H) and 2.37-2.23 (m, lH)ppm. LCMS RT = 2.3 min, (M+H) 361.3.

[001033] The following compounds can also be prepared in a manner similar to the one described in Scheme 41.

380 397 [001034] 3-(2-(5-chlor©-lH-pyrrolo[2,3-b]pyridm-3-yl)-5-fluoropyrimidm-4-ylamino)pyrrolidin-2-one (380) 'HNMR (300 MHz, MeOD) 5 8.79 (d, / = 2.4 Hz, 1H), 8.20 (d, / = 2.4 Hz, 1H), 8.13 (s, 1H), 8.07 (d, /= 3.9 Hz, 1H), 4.91 (dd, /= 8.7, 10.6 Hz, 1H), 3.61 - 3.46 (m, 2H), 2.68 -2.58 (m, 2H) and 2.48 - 2.31 (m, 1H) ppm. LCMS RT = 2.3 min, (M+H) 347.3.

[001035] (5r)-3-(2-(5-chloro-l//“pyrrolo[2,3-A]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)-l-methylpiperidin-2-one (397) lH NMR (300.0 MHz, DMSO) δ 8.65 (d, /= 2.5 Hz, 1H), 8.27 (d, / = 2.4 Hz, 1H), 8.20 - 8.19 (m, 2H), 7.63 (d, /= 7.8 Hz, 1H), 4.78 - 4.74 (m, 1H), 3.41 (t, / = 5.4 Hz, 2H), 3.17 (MeOH), 2.89 (s, 3H), 2,50 (DMSO), 2.18 - 2.15 (m, 1H) and 1.99 (d, /= 7.4 Hz, 2H) ppm. LCMS RT = 2.2 min, (M+H) 375.4.

416 417 [001036] (S)-3-(2-(5-chIor o-l //-pyrrolo [ 2,3-b ]py ridin-3-yl)-5-flu or opy rimidin-4-ylamino)piperidin-2-one (416) LCMS RT = 1.6 min, (M+H) 361.3.

[001037] (5)-3-(2-(5-chloro-lff“pyrrolo [2,3-b] pyridin-3-yl)-5-fluor opy rimidin-4-yiamino)azepan-2-one (417) *H NMR (300 MHz, DMSO) δ 12.33 (s, 1H), 8.74 (d, / = 2.3 Hz, 1H), 8.28 (d, J = 2.4 Hz, 1H), 8.21 (t, / = 3.7 Hz, 2H), 8.02 - 7.98 (m, 1H), 7.21 (d, /= 5.8 Hz, 1H), 4.86 (dd, / = 6.3, 10.5 Hz, 1H), 3.51 - 3.41 (m, 1H), 3.25 - 3.16 (m, 1H), 2.13 - 1.85 (m, 4H), 1.66 - 1.52 (m, 1H) and 1.40 - 1.20 (m, 1H) ppm. LCMS RT = 1.7 min, (M+H) 375.4.

[001038] (.y)-3-(2-(5-chloro-ljtf-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-yla mino)-l -ethylpip eridin-2-one (460) LCMS RT = 2.0 min, (M+H) 389.1.

[001039] (<S)-3-(2-(5-chloro-lJy“pyrrolo [2,3-b] pyridm-3-yl)-5-fluoropyrimidin-4-yla mino)-l -m ethylazepan-2-on e (461) LCMS RT = 2.0 min, (M+H) 389.1.

[001040] (5>3-(2“(5-chloro-U/-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-yla mino)- l-ethylazepan-2-o ne (462) ‘HNMR (300 MHz, /6-DMSO) δ 12.35 (s, 1H), 8.68 (d, /= 1.7 Hz, 1H), 8.27 (d,/ = 2.0 Hz, 1H), 8.21 (m, 2H), 7.28 (d,/ = 6.0 Hz, 1H), 4.98 (dd, /= 6.9, 10.7 Hz, 1H), 3.88 - 3.79 (m, 1H), 3.84 (dd,/= 11.4, 15.5 Hz, 1H), 3.49 - 3.17 (m, 5H), 2.08 (d,/= 13.1 Hz, 1H), 1.95 - 1.88 (m, 3H), 1.65 - 1.58 (m, 1H), 1.42 (m, 1H) and 1.04 (t, /= 7.0 Hz, 3H) ppm. LCMS RT = 3.3 min, (M+H) 403.4. 1001041 ] (A)-5-((2-(5-chlo ro-l//-pyrrolo [2,3-b]pyridin-3-yl)-5-iluoropyrimidm-4- y la mino)methyl)py rr olid in-2-one (503) LCMS RT = 2.2 min, (M+H) 361.2.

[001042] (<S)-3-(5-fluoro-2-(5-(trifluoromethyl)-l//-pyrrolo[2,3-b] pyridin-3-yl)pyrimidin-4-ylamino)azepan-2-one (502). LCMS RT = 2.3 min, (M+H) 409.

[001043] (S)-6-(2-(5-chloro-l/f-py r rolo [2,3-b] py r idin-3-yl)-5-flu or opyrimidin-4-ylamino)-4-(4-methoxybenzyl)-l,4-oxazepan-5-one (505) LCMS RT = 3.1 min, (M+H) 497.7.

The starting amine for this compound was prepared following established procedures as described in: Blizzard, Timothy A.; Chen, Helen Y.; Wu, Jane Yang; Kim, Seongkon; Ha, Sookhee; Mortko, Christopher J.; Variankaval, Narayan; Chiu, Anna. 7-Oxo-2,6-Diazabicyclo[3.2.0]heptane-6-sulfonic acid derivatives as b -lactamase inhibitors and their preparation, pharmaceutical compositions and use in the treatment of bacterial infections. PCT Int. Appl. (2008), 101pp. W02008039420. '

[001044] (£)-3-(2-(5-chloro-l //-pyrrol o [2,3-b] pyridin-3-y l)py rimid in-4-ylamino)azepan-2-one (500). LCMS RT = 1.6 min, (M+H) 357.6.

[001045] (5)-3-(2-(5-fluor o-l AF-pyr rolo [2,3-b\ pyridin-3-yl)py rim idin-4-yIamino)azepan-2-one (501) LCMS RT = 1.6 min, (M+H) 341.4.

[001046] 3-(2-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidm-4-ylamino)-7,7-dimethylazepan-2-one (504) LCMS RT = 3.2 min, (M+H) 403.6.

The amine for this compound was prepared following procedures as described in: J. A. Robl, E, Sieber-McMaster, R. Sulsky Synthetic routes for the generation of 7,7-dialky 1-2-azepinones. Tetrahedron Letters ¢1996), 37(50), 8985-8988

General Scheme 42

(a) 3-amino-l-methylpyLTolidin-2-one, DMA, 140 °C microwave; (b) LiOH, TIIF, microwave, 120 °C (c) EDCI, IiOAt, iPr2NEt, DCM-DMF (2:1).

[001047] 6-(2-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-yiamino)-l,4-oxazepan-5-one (513) A mixture of 5-chloro-3-(5-fluoro-4-methylsulfinyl-pyrimidin-2-yl)-l-(p-toIylsulfonyl)pynOlo[2,3-b]pyridine, 15a, (0.17 g, 0.36 mmol) and (6iS)-6-amino-l,4-oxazepan-5-one (0.06 g, 0.43 mmol) in DMF (2 mL) with 'PrjNEt (0.10 mL, 0.57 mmol) was heated to 90 °C. After 1 hour, the temperature was raised to 100 °C. After 24 hours, the mixture was heated to 140 °C for 15 min (microwave). The mixture was partitioned between water and EtOAc and the aqueous layer was extracted with EtOAc twice more. The combined organic phases were dried organic over Na2SC>4, filtered and concentrated in vacuo.

The resulting crude material (0.16 g) was treated with LiOH (IN solution, lmL) in THF (3mL) overnight. LC-MS indicates hydrolysis of amide along with detosylation. The mixture was concentrated in vacuo and purified by preparative HPLC to provide semi pure product (23mg). This material was subjected to cyclization conditions without further purification.

To a flask was charged with the crude material (0.020 g, 0.051 mmol), EDCI (0.010 g, 0.056 mmol) and HO At (0.002 g, 0.015 mmol) and DCM (1 mL) was added 'P^NEt (0.018 mL, 0.100 mmol) and DMF (0.5 mL). After 1 hour, additional EDCI was added (0.7 eq). After 3.5 hour, the reaction was complete and the mixture was concentrated in vacuo. Purification by preparative HPLC followed by removal of TFA salt by filtration through basic resin provided the desired product: LCMS RT = 1.9 min, (M+H) 377.5.

The starting amine for this compound was prepared following the established procedures as described in: J, A. Robl, E. Sieber-McMaster, R. Sulsky Synthetic routes for the generation of 7,7-dialkyl-2-azepinones. Tetrahedron Letters (1996), 37(50), 8985-8988.

General Scheme 43 [001048] The following are general procedures for conversion of the cyclohexane carboxylic acids, 553 or 35a, to carboxamides of type 43a:

(a) Amine, HATU, DMF (b) B0C20, NH4CO3H, pyridine, DMF; (c) i: Amine, HATU, DMF; then ii: 1N LiOH.

[001049] Formation of (15, 25)-2-(2-(5-chloro-l//-pyrrolo|2,3-0]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)-A-ethylcyclohexanecarboxamide (521)

To a mixture of (IS, 2S)-2-[[2-(5-chloro-l/f-pyrrolo[5,4-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-yl]amino]cyclohexane-l-carboxylic acid, 553, (0.049 g, 0.126 mmol) and HATU (0.056 g, 0.147 mmol) in DMF (1.0 mL) at room temperature was added ethylamine (0.189 mL of 2 M solution, 0.377 mmol). The mixture was stirred at room temperature until all starting material had been converted as judged by HPLC. After 45 minutes, the mixture was partitioned between aqueous K2CO3 and EtOAc and the organic layer was separated and dried over Na2S04 and concentrated in vacuo. Preparative HPLC provide the desired product as the TFA salt, which was converted to the parent compound by elution through a basic PSA cartridge with MeOH followed by concentration in vacuo. (14 mg, 30% yield). 'H NMR (300 MHz, MeOD) δ 8.93 (d, /= 2.4 Hz, 1H), 8.22 (d, J= 2.3 Hz, 1H), 8.18 (s, 1H), 7.99 (d,/-4.0 Hz, 1H), 4.53 (ddd,/= 7.1, 11.1 Hz, 1H), 3.15-3.02 (m, 2H), 2.43 - 2.34 (m, 1H), 2.30 - 2.26 (m, 1H), 1.97 - 1.82 (m, 3H), 1.77 - 1.65 (m, 2H), 1.47 - 1.35 (m, 2H) and 0.97 (t, J= 7.3 Hz, 3H) ppm. LCMS RT = 2.0 min, (M+H) 417.5.

[001050] (IS, 2S)-2-(2-(5-chloro“lJ?“pyrrolo [2,3-A]pyridm-3-yl>5-fhioropyrimidin-4-yJamino)-iV,7V-diethylcyclohexanecarboxamide LCMS RT - 2.26 min, (M+H) 445.58.

1001051] Formation of C7.v-2-(2-(5-chloro-17/-pyrrolo[2,3-/>]pyridin-3-yI)-5-fluoropyrimidin-4-ylamino)cyclohexanecarboxamide (544) and C/x-2-(2-(5-chloro-l//-pyrrolo[2,3-A]pyridin-3-yl)-5“fluoropyrimidin-4-ylamino)-lV,Ar-dimethylcyclo hexanecarb oxamide (543)

To a mixture of cis-2-[[2-(5-chloro-l 77-pyrrol o [2,3·-b]pyri din-3·-y 1)-5 -fluoro-pyrimidin-4-yl]ammo]cyclohexanecarboxylic acid, 554, (0.30 g, 0.77 mmol) in DMF (5 mL) at room temperature was added pyridine (0.61 g, 0.62 mL, 7.70 mmol) followed by di-tert-butyl dicarbonate (0.50 g, 2.31 mmol), and NH4CO3H (0.33 g, 4.22 mmol). The mixture was stirred overnight at room temperature, LC-MS indicated the presence of the desired primary amide as well as the MA-dimcthylamidc product. A 1 mL aliquot of the reaction solution was acidified with HOAc and diluted with DMSO. Preparative HPLC chromatography provided small amounts both products.

Primary amide, 544, racemic mixture - (8.6mg): LCMS RT = 1.94 min, (M+H) 389.42.

Dimethylamide, 543, racemic mixture - (3.7 mg): LCMS RT = 2.52 min, (M+H) 417.44.

[001052] Formation of (1Λ, 25')-2-(2-(5-chloro-l//-pyrrolo[2,3-7>]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)-AyV-diethylcyclobexanecarboxamide(518)

To a mixture of (LR, 2,Sr)-2-[[2-[5“Chloro-l-(p-toIyIsulfonyl)pyrrolo[5,4-b]pyridin-3-yl]-5-fluoro-pyrimidin-4-yl]amino]cyclohexane-l-carboxyIic acid (0,050 g, 0.092 mmol), and HATU (0.045 g, 0.120 mmol) in DMF (1 mL) at room temperature was added N,N-diethylamine (0.138 mL of 2 M solution, 0.280 mmol). When the reaction appeared complete as judged by HPLC, LiOH (0.4 mL of 1 M solution, 0.4 mmol) in water was added. After 6 hours, LiOH (0.4 mL of 1 M, 0.4 mmol) was added again and the mixture was stirred overnight. The mixture was quenched with aqueous saturated NH4CI solution. Aqueous K2CO3 was added and the mixture was extracted with EtOAc (3 x), The combined organic phases were washed with aqueous saturated NH4C1 solution, filtered and concentrated in vacuo. Preparative HPLC provided the desired product as the TFA salt which was converted to the HC1 salt by treatment with HC1 in MeOH followed by evaporation of the solvents (12,9 mg, 28% yield). *H NMR (300 MHz, MeOD) δ 8.67 (d, ./ = 2.3 Hz, 1H), 8.53 (s, 1H), 8.41 (d, J= 2.3 Hz, 1H), 8.35 (d, ./ = 5.5 Hz, 1H), 4.75 - 4.73 (m, 1H), 3.74 - 3.58 (m, 1H), 3.42 (m, 2H), 3.29 - 3.22 (m, 2H), 2.57 (m, 1H), 2.09 - 2.03 (m, 1H), 1.96 - 1.76 (m, 4H), 1.06 (t, J= 7.1 Hz, 3H) and 0.94 (t, J= 7.1 Hz, 3H) ppm. LCMS RT = 3.3 min, (M+H) 445.6.

[001053] (1R, 25)-2-(2-(5-chIoro-l//-pyrrolo|2,3-6]pyridin-3-yl)-5-fluoropyrimidm-4-ylamino)-/V-ethylcyclohexaneca rboxamide (519) LCMS RT = 2.95 min, (M+H) 417.5.

[001054] Cfe-2-(2-(5-chIoro-Lff-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-y la minoHV-methylcycloh exa neca rboxamide (539) - racemic mixture LCMS RT = 2.13 min, (M+H) 403.44.

General Scheme 44

(a) Pd(PPh3)4, sodium carbonate, DME/water, reflux (b) meta-chloroperbenzoic acid, dichloromethane, rt. (c) 20a, tetrahydrofuran, 50°C (d) trifluoroacetic acid, dichloromethane, rt. (e) morpholine-4-carbonyl chloride, dimethylformamide, rt (f) sodium methoxide, methanol, rt.

[001055] Formation of 5-fluoro-3-[5-fluoro-4-(methylthio)pyrimidin-2-yl]-! -tosyl-lH-pyrrolo[2,3-b]pyridine (44b) 2-Chloro-5-fluoro-4-methylsulfanyl-pynmidine (34.1 g, 191.0 mmol) , 5-fluoro-l-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yI)pyrrolo[2,3-b]pyridine, 44a} (53.0 g, 127.3 mmol) andNa2C03 (40.5 g, 381.9 mmol) were dissolved in a mixture of DME (795 mL) and water (159 mL). The mixture was purged with nitrogen for 20 minutes and treated with Pd(PPh3)4(7.4 g, 6.6 mmol). After purging with nitrogen for another 20 minutes, the reaction was heated to reflux overnight, cooled to room temperature and diluted with water (600mL). The resulting suspension was stirred at room temperature for 30 minutes and the precipitate was then collected by filtration, washed with water and acetonitrile and dried at 50 °C to afford 48.2 g of 5-fluoro-3-[5-fluoro-4-(methylthio)pyrimidin-2-yl]-l-tosyl-lH-pyrrolo[2,3-b]pyridine as a white solid. ΧΗ NMR (300 MHz, DMSO-d6) 6 8.70 - 8.58 (m, 2H), 8.54 - 8.41 (m, 2H), 8.09 (d, / = 8.4 Hz, 2H), 7.45 (d, / = 8.2 Hz, 2H), 2.76 (s, 3H), 2.36 (s, 3H).

[001056] Formation of 5-fluoro-3-[5-fluoro-4-(methylsulfmyI)pyrimidin-2-yl]-l-tosyI-lH-pyrrolo[2,3-b]pyridine (44c) 5-fluoro-3-[5-fluoro-4-(methylthio)pyrimidin-2-yl]-l-tosyl-lH-pyrrolo[2,3-b]pyridine, 44b, (48.2 g, 111.5 mmol) was dissolved in dichloromethane (2.3 L) and treated portionwise with m-CPBA (27.5 g, 122.6 mmol) while keeping the temperature below 20 °C. After addition was complete, the reaction was stirred at room temperature for 2 hours, then treated with another portion of m-CPBA (1.9 g) and stirred for another hour. The reaction mixture was washed with 12% aqueuous K2C03 (2 x 1.0 L) and the organic layer was dried on Na2S04 and concentrated in vacuo to provide 50 g of 5-fluoro-3-[5-fluoro-4-(methylsulfmyl)pyrimidin-2-yl]-l-tosyl-lH-pyriOlo[2,3-b3pyridine as a yellow solid. *H NMR (300 MHz, DMSO-A5) δ 9.11 (d, /= 1.5 Hz, 1H), 8.69 (s, 1H), 8.65 (dd, / = 9.0, 2.9 Hz, 1H), 8.52 (dd, / = 2.8, 1.2 Hz, 1H), 8.11 (d, /= 8.4 Hz, 2H), 7.46 (d, /= 8.3 Hz, 2H), 3.05 (s, 3H), 2.36 (s, 3H).

[001057] Formation of tert-butyl Ar-[(1R, 35)-3-[[5-fluoro-2-[5-fluoro-l-(p-tolyIsulfonyI)pyrrolo[2,3“b]pyridin-3-yl]pyrimidin-4-yl]amino]cydohexyl]carbamate (44d) 5-fluorO“3-(5-fluoro-4-methylsulfmyi-pyrimidin-2-yl)-l-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridine, 44c, (5.9 g, 10.5 mmol) and tert-butyl N-[(IR, 35>3-aminocyclohexyl]carbamate (3 g, 12.60 mmol) were dissolved in THF (100 mL). The reaction mixture was heated to 50 °C for 6 hours, then cooled to room temperature. Celite was added and the solvent was removed under reduced pressure. The Celite-supported residue was purified by silica gel chromatography (20-80% EtOAc/hexanes gradient to provide 3.7 g of ierf-butyl jV-[(1R, 35)-3“[[5-f]uoro-2-[5-fluoro-l-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]pyrimidin-4-yl]amino]cyclohexyl]carbamate. ]H NMR (300 MHz, CDCIj) δ 8.51 (s, 1H), 8.46 - 8.41 (m, 1H), 8.29 (d, /= 1.6 Hz, 1H), 8.11 (s, 1H), 8.08 (s, 1H), 8.06 (d,/= 3.2 Hz, 1H), 7.27 (d,/= 8.4 Hz, 2H), 4.91 (d,/ = 8.0 Hz, 1H), 4.41 (s, 1H), 4.29 - 4.01 (m, 1H), 3.64 (s, 1H), 2.47 (d, /= 11.5 Hz, 1H), 2.36 (s, 3H), 2.24 (d, /= 13.1 Hz, 1H), 2.08 (d, / = 10.9 Hz, 1H), 1.91 (d, /= 13.8 Hz, 1H), 1.43 (s, 9H), 1.30- 1.03 (m, 4H).

[001058] Formation of (15, 3if)-M-[5-fluoro-2-[5-fluoro-l-(p-tolylsu]fonyl)pyrrolo[2,3-b]pyridin-3-yl]pyrimidin-4-yl] cyclohexane-1,3-diamine (44e) iert-Butyl N-[(IR, 3S)-3-[[5-fluoro-2-[5-fluoro-1 -(p-tolylsulfonyl)pyrrolo[2,3- b]pyridin-3-yl]pyrimidin-4-yl]aniino]cyclohexyl]carbamate, 44d, (3.7 g, 6.2 mmol) was dissolved in dichloromethane (105 mL) and treated with trifluoroacetic acid (31 mL). After 5 minutes, the volatiles were evaporated under reduced pressure, and the resulting residue was treated with IN NaOH (75 mL). The resulting precipitate was collected by filtration, washed with water (3 x 30 mL) and vacuum dried to provide 2.7 g of (15, 37?)-JVl-[5-fluoro-2-[5-fluoro-l-(p-tolylsuIfonyl)pyrroIo[2,3-b]pyridin-3-yl]pyrimidin-4-yl]cyclohexane-l, 3-diamine as a white solid. Ή NMR (300 MHz, MeOD) d 8.56 (dd, J= 8.0, 3.9 Hz, 2H), 8.35 - 8.26 (m, 1H), 8.12 (dd, J= 10.3, 6.1 Hz, 3H), 7.43 (d, J= 8.4 Hz, 2H), 4.36 - 4.21 (m, 1H), 3.28 - 3.13 (m, 1H), 2.48 (d, J= 12.3 Hz, 1H), 2.46 (s, 3H), 2.25 - 1.97 (m, 17.3, 10.6, 4.1 Hz, 4H), 1.76 - 1.28 (m, 3H).

[001059] Formation of 1V-K1/?, 35)-3-[[5-fluoro-2-[5-fluoro-l-(p-tolylsulfonyljpyrrolo [2,3 -b] pyridin-3-yl] pyrimidin-4-yl] amino] cyclohexyl] morpholine-4-carboxamide (44f) (15, 37?)-M -[5-fluoro-2- [5-fluoro-1 -(p-tolylsulfony l)pyrrolo [2,3 -b]pyridin-3 - yl]pyrimidin-4-yl]cyclohexane-l,3-diamine, 44e, (2.3 g, 4.6 mmol) was dissolved in DMF (50mL) and treated with morpholine-4-carbonyl chloride (2.1 g, 13.8 mmol) and DIPEA (4.2 g, 5.6 mL, 32.3 mmol). After one hour, the resulting solution was diluted with water (400 mL) and stirred for an additional two hours. The resulting precipitate was collected by filtration, washed with water (3 x 50 mL) and dried to provide the crude product. This material was purified by flash chromatography on a 40g column using EtOAc/DCM 20100%, to provide 2.0 g of M-[(17?, 35)-3-[[5-fluoro-2-[5-fluoro-l-(p- toIylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]pyrimidin-4-yl]amino]cyclohexyl]morpholine-4-carboxamide as a white solid. lH NMR (300 MHz, DMSO-t/<5) 5 8.53 - 8.43 (m, J = 11.9, 2.7 Hz, 3H), 8.22 (d, J = 3.9 Hz, 1H), 8.07 (d, J= 8.4 Hz, 2H), 7.44 (d, J= 8.3 Hz, 2H), 6.32 (d, J= 7.5 Hz, 1H), 4.05 (s, J= 19.4 Hz, 1H), 3.62 (s, 1H), 3.58 - 3.45 (m, 4H), 3.27 - 3.18 (m, 4H), 2.36 (s, 3H), 2.12 (d,./= 11.7 Hz, 1H), 1.99 (d,./ = 9.5 Hz, 1H), 1.83 (d, ,/= 10.3 Hz, 2H), 1.53 - 1.11 (m,./ = 32.3,22.8, 10.9 Hz, 4H).

[001060] Formation of 7V-[(1jR, 3jS)-3-[[5-fluoro-2-(5-fluoro-lH-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl]amino]cycIohexyl]morpholine-4-carboxamide(706) 1V-[(17?, 35)-3-[[5-fluoro-2-[5-fluoro-l-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]pyrimidin-4-yl]amino]cyclohexyI]morpholine-4-carboxamide, 44f, (2.0 g, 3.2 mmol) was suspended in methanol (50 mL) and treated with 25% sodium methoxide in methanol (19.9 mL, 92.3 mmol) . After stirring for 1 hour, the solvent was evaporated under reduced pressure, and the residue was partitioned between water (100 mL) and ethyl acetate (100 mL). The organic layer was collected, dried on Na2SC>4 and concentrated to provide the crude product as a yellow solid. This material was purified by silica gel chromatography on a 40g column, using DCM/MeOH 1-6%. The purified fractions were treated with 2N HC1 in ether and concentrated to provide 1.5 g of N-[(IR, 35)-3-[[5-fluoro-2-(5-fluoro-lH-pyrro lo [2,3 -b]pyridin-3 -yl)pyrimid in-4-y 1] amino]cyclohexyl]-morpholine-4-carboxami de as a white solid.

44e [001061] Formation of (15, 3.ft)-./Vl-(2-fluoro-5-(5-fluoro-l.ff-pyrrolo[2,3-6]pyridin-3-yl)phenyl)cyclohexane-l,3-diamine (44e)

To a solution of reri-butyl (1/Ϊ, 35)-3-(2-fluoro-5-(5-fluoro-l-tosyl-l/f-pyrro]o-[2,3-£>]pyridin-3-yl)phenylamino)cyclohexylcarbamate, 44d, (0.65 g, 1.09 mmol) in methylene chloride (22 mL) was added hydrogen chloride (2.71 mL of 4M solution in 1,4-dioxane, 10.86 mmol). The reaction was heated to 50 °C and stirred for 6 hours. The mixture was cooled to room temperature and concentrated in vacuo, producing a yellow solid. The crude residue was purified via silica gel chromatography (25-50% Ethyl Acetate/hexanes gradient). Desired fractions were combined and concentrated in vacuo to produce 350 mg of 44e as a yellow powder.

[001062] Synthesis of 1-cyano-A-((U?, 35)-3-(2-fluoro-5-(5-fluoro-li/-pyrrolo [2,3-6]pyridin-3-yl)phcnylamino)cyclohexyl)cyclopropanecarboxamide (871)

To a solution of 1-cyano-l-cyclopropane-carboxylic acid (0.058 g, 0.527 mmol) in THF at room temperature was added HATU (0.200 g, 0.527 mmol) followed by N,N-diisopropylethylamine (0.334 mL, 1.91 mmol). The solution was stirred for 10 minutes. (IS, 3i?)-M-(2-fluoro-5-(5-fluoro-lii-pyrrolo[2,3-Z>]pyridin-3-yI)phenyl)cyclohexane-l,3-diamine, 44e, (0.200 g, 0.584 mmol) was then added and solution stirred at room temperature for 4 hours. The mixture was concentrated in vacuo and purified via silica gel chromatography (30-60% Ethyl Acetate/hexanes) to give 80 mg of 871 as off-white solid. lK NMR (300 MHz, DMSO) δ 12.80 (s, 1H), 8.95 (s, 1H), 8.78 (s, 1H), 8.43 (d,/ = 5.2 Hz, 1H), 8.37 (d, J= 1.6 Hz, 1H), 8.07 (d, J= 7.9 Hz, 1H), 4.22 (s, 2H), 3.80 (s, 1H), 2.17 - 1.94 (m, 2H), 1.90 - 1.71 (m, 2H), 1.71 - 1.06 (m, 8H).

General Scheme 45

(a) 4-chlorobutanoyi chloride, Et3N, CH2CI2; (b) KOtBu, THF; (c) Hz> Pd-C, MeOH; (d) 45c, Na2C03, THF-CH3CN, 135 °C; (e)4M HCI, dioxane-CH3CN.

[001063] Formation of benzyl (15, 3//)-3-(4-chlorob utana mid o) cy ciohexylcarbamate (45a)

To a stirred slurry of benzyl jV-[(15, 3//)-3-aminocyclohexyljcarbamate, 18e, (0.97 g, 3,41 mmol) in CH2CI2 (34 mL), was added Et3N (1.00 mL, 7.15 mmol) , followed by 4-chlorobutanoyl chloride (0.40 mL, 3,58 mmol). After stirring at room temperature, the mixture was diluted with CH2Cl2, washed with IN HCI (2 x), IN NaOH (2x), and brine. The organic layer was dried over Na2SC>4, filtered and concentrated in vacuo to give 1.07 g of the desired product. *HNMR (300 MHz, MeOD) 6 7.33 - 7.26 (m, 5H), 5.04 (s, 2H), 3.73 - 3.65 (m, 1H), 3.56 (t, J= 6.5 Hz, 2H), 3.44 (dq, J= 3.9, 15.6 Hz, 1H), 2.33 - 2.28 (m, 2H), 2.11 - 1.97 (m, 3H), 1.90 - 1.75 (m, 3H), 1.45 - 1.28 (m, 1H) and 1.18 - 1.02 (m, 3H) ppm.

[001064] Formation of benzyl (15, 3//)-3-(2-oxopyrroIidin-l-yI)cyc!ohexylcarbamate (45b)

To a slurry of benzyl (15, 3/?)-3-(4-chlorobutanamido)cyclohexyIcarbamate, 45a, (0.21 g, 0.58 mmol) in THF (8.2 mL) was added potassium tert-butoxide (0.08 g, 0.69 mmol) at room temperature. After stirring at room temperature for 25 h, the mixture was quenched with aqueous saturated NH4CI and extracted with Et20 (3x). The combined organic layers were washed with brine, dried over Na2SC>4, filtered and concentrated in vacuo. Flash chromatography (S1O2, 0-100% EtOAc-hexanes, gradient) provided a single fraction consisting of desired product and a small amount of starting material (168 mg). This material was immediately subjected to deprotection conditions. 'HNMR (300 MHz, MeOD) δ 7.33 - 7.27 (m, 5H), 5.04 (s, 2H), 3.95 - 3.88 (m, 1H), 3.58 - 3.38 (m, 3H), 2.38 - 2.28 (m, 2H), 2.11 - 1.76 (m, 6H), 1.63 (d, J= 2.7 Hz, 1H), 1.46 - 1.34 (m, 3H) and 1.21 - 1.06 (m, 2H) ppm.

[001065] Formation of 1-((1//, 35)-3-aminocyclohexyl)pyrrolidin-2-one (45c) A degassed solution of benzyl (15, 3//)-3-(2-oxopyrroIidin-l-yl)cyclohexylcarbamate, 45b, (0.165 g, 0.522 mmol) and Pd on C (10% wet, Degussa, 0.050 g, 0.024 mmol) in MeOH (15 mL) was placed under H2 atm (balloon). After 105 min, TLC (10% MeOH-DCM) indicated complete consumption of starting material. H2 was removed and the solution filtered and concentrated in vacuo. The crude product was azeotroped with CH3CN (2 x) to remove any residual MeOH and provided the desired product (96 mg): FLA (M + H+) 183.27 [001066] Formation of 1-((1//, 35)-3-(2-(5-chloro-l-tosyl-l//-pyrrolo[2,3-b]pyridin-3-yl)-5-fiuoropyrimidin-4-ylamino)cyclohexyl)pyrrolidin-2-one (45d) A mixture of 5-chloro-3-(5-fluoro-4-methylsulfinyI-pyrimidin-2-yl)-l-(p-tolylsulfonyl)-pyrrolo[2,3-b]pyridine, la, (0.14 g, 0.29 mmol) and 1-((1//, 35)-3-aminocyclohexyI)pyrrolidin-2-one, 45c, (0.10 g, 0.53 mmol) and Na2CC>3 (0.09 g, 0.88 mmol) freshly ground, in THF (2.25 mL) and CH3CN (0.45 mL) and heat to 135 °C for 30 min. The mixture was slowly poured into 15 mL 1M HCI and extracted with EtOAc (5 x). The combined organic layers were washed with brine, dried over NajSCL and filtered and concentrated in vacuo. Flash chromatography (Si02, 0-20% MeOH-CH2Cl2 gradient) provided the final product as a sticky residue. Trituration with CH3CN provided an off white powder (105 mg) which was impure, but which was taken directly to the final deprotection step. LC/MS R, = 3.90 min, (M+H) 589.49.

[001067] Formation of 1-((1//, 35)-3-(2-(5-ch!oro-l/7-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyriimdin-4-ylamino)cyclohexyl)pyrrolidin-2-one (956) A mixture of partially purified 1-((1R, 35)-3-(2-(5-chloro-I-tosyl-l//-pyrroIo[2,3-b]pyridin-3~yl)-5-fluoropyrimidin-4-ylamino)cyclohexyl)pyrrolidin-2-oneJ 45d, (0.105 g, 0.180 mmol) in CH3CN (5mL) was treated with HC1 (2 mL of 4 M, 8.00 mmol) in dioxane at 70 °C. After 2H, the mixture was cooled to room temperature. Then CH3CN was added and the solid that precipitated was triturated with more CH3CN (3 x). Preparative HPLC provided the desired product as the HC1 salt (35 mg). 'HNMR (300 MHz, MeOD) δ 8.72 (d, 2.2 Hz, 1H), 8.49 (s, 1H), 8.39 (d, J= 2.1

Hz, 1H), 8.29 (d, J= 5.5 Hz, 1H), 4.54 - 4.47 (m, 1H), 4.13 (t, ./= 11.8 Hz, 1H), 3.57 - 3.45 (m, 2H), 2.42 - 2.36 (m, 2H), 2.25 (m, 1H), 2.15 - 2.00 (m, 4H), 1.90 - 1.59 (m, 4H) and 1.53 -1.43 (m, 1H) ppm; LC/MS RT = 3.15 min, (M+H) 429.53.

General Scheme 46

(a) 30% ammonium hydroxide, water, 50°C (b) Acetyl chloride, diisopropylethylamine, dichioromethane, it (c) 5-chloro-3-(4,4,5,5-tetramethyi-1,3,2-dioxaborolan-2-yI)-1 -tosyl-1 H- pyrrolo[2,3-b]pyridine, Pd(PPh3)4,2M sodium carbonate, acetonitrile, 130 ®C, microwave [001068] Formation of (15, 3S)-l-(aminomethyl)-3-(2-chloro-5-fluoropyrimidin-4-ylamino)cyclohexanol (46b) 2-Chloro-5 -fluoro-JV-[(3 S, 55)-1 -oxaspiro [2.5] octan-5 -y l]py rimidin-4-amin e, 46a, (0.19 g, 0.73 mmol) was dissolved in water (75 mL) and treated with 30% ammonium hydroxide (10 mL, 86.0 mmol) . The suspension was heated to 50 °C for 5 hrs then allowed to stir at room temperature overnight. The volatiles were evaporated under reduced pressure, and the residue, (IS, 3S)-l-(aminomethyl)-3-(2-chloro-5-fluoro-pyrimidin-4-ylamino)cyclohexanol, was taken into the next step without further purification.

[001069] Formation of A-{[(15, 3S)-3-(2-chloro-5-fluoropyrimidm-4-ylamino)-l-hydroxycyclohexyl]methyl} acetamide (46c) (IS, 3S)-l-(ammomethyl)-3-(2-chloro-5-fluoropyrimidin-4-ylamino)cyclohexanol, 46b, (0.19 g, 0.69 mmol) was dissolved in dichioromethane (15 mL) and treated with DIPEA (1.20 mL, 6.91 mmol) and acetyl chloride (0.10 mL, 1.38 mmol). After 5 minutes, the reaction mixture was diluted into IN HC1 (30 mL), and the aqueous layer was brought to a basic pH by addition of IN NaOH. The resulting suspension was extracted with dichioromethane (50 mL). The organic layer was dried on Na2S04 and concentrated in vacuo to provide the crude product, which was purified by silica gel chromatography (20-100% EtOAc/hexanes gradient) to afford 195 mg of A-{[(IS, 36)-3-(2-chloro-5-fluoropyrimidin-4-ylamino)-l-hydroxycyclo-hexyl]methyl}acetamide as a white foamy solid. LCMS RT = 2.82 (M+l) 317.33.

[0010701 Formation of ^-{[(15, 3S)-3-(2-(5-chloro-li/-pyrrolo[2,3-blpyridin-3-yl)-5-fluoropyrimidin-4-yiamino)-l-hydroxycyclohexyl]methyl} acetamide (857) A-{[(IS, 3 5)-3 -(2-chloro-5 -fluoropyrimidin-4-y lamino)-1 -hy droxycyclohexy 13- methyl}-acetamide, 46c, (0.2 g, 0.6 mmol) was dissolved in acetonitrile (6 mL) and treated with 5-chloro-l-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pynOlo[2,3-b]pyridine (0.5 g, 1.2 mmol) followed by Pd(PPh3)4 (0.07 g, 0.06 mmol). Aqueous 2M sodium carbonate (3.0 mL, 6.1 mmol) was added, and the vial was sealed and heated in the microwave to 130 °C for 30 min. The organic layer was collected and concentrated in vacuo to provide the crude product, which was dissolved in DMSO and purified by HPLC using 570% McOH/PLO with 6mM HCI over 15 minutes to provide after concentration 75 mg of N-{[(15, 35)-3-(2-(5-chloro-l//-pyrrolo[2,3-b]pyridin-3-yI)-5-fluoropyrimidm-4-ylammo)-l-hydroxycyclohexy 1] methyl} aceta midc hydrochloride as an off-white crystalline solid. ’H NMR (300 MHz, DMSO-/6) δ 13.02 (s, 1H), 9.22 (s, 1H), 9.03 (d, /= 2.4 Hz, 1H), 8.71 (d, /= 2.1 Hz, 1H), 8.46 (d, / = 5.5 Hz, 1H), 8.41 (d, / = 2.1 Hz, 1H), 7.81 (t, / = 5.8 Hz, 1H), 4.64 (d, /= 8.0 Hz, 1H), 3.16 - 2.99 (m, 2H), 2.09 - 1.73 (m, 3H), 1.85 (s, 3H), 1.73 - 1.42 (m, 3H), 1.28 (dd, /= 27.5, 10.6 Hz, 2H).; LCMS RT = 3.47 (M+l) 433.37

General Scheme 47

(a) ierf-butyl W-methyl-N-(2-oxoethyl)carbamate, diisopropylethylamine, THF/EtOH, 70 °C (b) HCI/dioxane, THF/MeOH (c) bis(4-nitrophenyl) carbonate, diisopropylethylamine, DMF.

[001071] Formation of tart-butyl 2-((1Λ, 35)-3-(2-(5-chloro-l//-pyrroIo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)cyclohexyl-amino)ethyI(methyl)carbamate (47b)

In a flask containing (15, 3i?)-M-(2-(5-chloro-li7-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-yl)cyclohexane-1,3-diamine, 47a, (0.14 g, 0.39 mmol) in THF/EtOH was added fert-butyl ,V-methyl-yV-(2-oxo ethyl {carbamate (0.10 g, 0.58 mmol) and diisopropylethylamine (0.13 mL, 0.77 mmol). The solution was heated at 70 °C for 30 min. Sodium triacetoxyborohydride (0.08 g, 0.39 mmol) was added. The solution was stirred at room temperature for 12 hrs. The solution was filtered and the solvent evaporated under reduced pressure. The resulting residue was purified by HPLC using 5-70% MeOH/H20 with 6mM HCI to provide the desired product, [001072] Formation of (15, 3fl)-M-(2-(5-chloro-l//-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-yl)-jV3-(2-(methylamino)ethyl)cyclohexane-1,3-diamine (47c)

In a flask containing tert-butyl 2-((1 J?, 35)-3-(2-(5-chloro-l/7-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)cyclohexylamino)ethyl(methyl)carbamate, 47b, (0.02 g, 0.04 mmol) in dichloromethane/MeOH mixture was added HCI in Dioxane (3.86 mL of 4 M solution, 15.44 mmol). The solution was stirred at room temperature for 12 hrs. The solvent was evaporated under reduced pressure and used without further purification.

[001073] Formation of l-((li?, 35)-3-(2-(5-chIoro-l/f-pyrrolo[2,3-b]pyridin-3-yI)-5-fluoropyrimidin-4-ylamino)cyclohexyl)-3-methylimidazolidin-2-one (958)

In a flask containing (15, 3R)-M-(2-(5-chloro-l//-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-yl)-Ar3-(2-(mcthylamino)ethyl)cyclohexane-3,3-diamine, 47c, (0.020 g, 0.048 mmol) in DMF was added diisopropylethylamine (0.025 mL, 0.144 mmol) and bis(4-nitrophenyl) carbonate (0.016 g. 0.053 mmol). The reaction mixture was stirred at room temperature for 3 hrs. The resulting residue was purified by HPLC using 5-70% MeOH/HjO with 6mM HC1 to provide the desired product.

General Scheme 48

(a) 2-Methoxyethanamine, HATU, D1EA, CH3CN, DMF

[001074] Formation of (lif, 35)-3-(2-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)-Ar-(2-methoxyethyl)cyclohexanecarboxamide (789) (1Λ, 3S)-3-[[2-(5-chloro-17/-pyiTolo[2,3-b]pyndin-3-yl)-5-fluoro-pyrimidin-4- yl]amino]cyclohexanecarboxylie acid (HC1 salt)(0.05 g, 0.12 mmol), HATH (0.09 g, 0.24 mmol), diisopropylethylamine (0.06 g, 0.47mmol) and 2-methoxyethanamine (0.04 g, 0.47 mmol) were stirred together in 1 ml each of DMF and CHUCN at room temperature overnight. All volatiles were removed with a stream of nitrogen and heat. The residue was dissolved in methanol and purification with phase preparatory HPLC with 10 - 90% MeOH/water (HC1 modifier) gave the desired product as the HC1 salt.

General Scheme 49

PCT/US2010/038988 WO 2010/148197 2016204286 23 Jun2016 (a) methyI(tripheriyl)phosphonium bromide, (bis(tnmethylsilyl)amino)lithium, THF (b) 3-chloroperoxybenzoic acid, MeOH, H20. (c) methylsulfanylsodium, THF (d) 5-chloro-l-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine, Na2CC>3, tetrakis triphenylphosphinepalladium(0), CH3CN (e) 3-chloroperoxybenzoic acid, CH2C12 (f) NaOMe, MeOH.

[001075] Formation of (5}-2-chloro-5-fluoro-/V-(3-methylenecyclohexyl)pyrimidin-4-amine (49a)

To a suspension of methy](triphenyl)phosphoniurn bromide (0.86 g, 2.40 mmol) in THF (100 mL) in a flamed dry flask was added (bis(trimethylsilyl)amino)lithium (2.40 mL of 1 M solution, 2.40 mmol) at room temperature. The reaction mixture was allowed to stir at room temperature for 1 hr. A solution of (S)-3-(2-chloro-5“fluoropyrimidin-4-ylamino)cyclohexanone, 29b, (0.48 g, 2.00 mmol) in 20 mL of THF was added. The reaction was allowed to stir at room temperature for 2 hrs. The mixture was quenched by pouring into brine and the aqueous phase was extracted with EtOAc. The layers were separated and the organic was dried over MgSCL, filtered and evaporated to dryness. The crude residue was purified via silica gel chromatography (0-100%EtOAc/hexanes gradient) to afford 270 mg of the desired product: LCMS RT: 3.83 min, (M+l): 242.2.

[001076] Formation of 2-chloro-5-fluoro-iV-((3J?, 55)-l-oxaspiro[2.5]octan-5-yl)pyrimidin-4-amine (49b, 49c) 3-chloroperoxybenzoic acid (0.40 g, 1.79 mmol) was added to a solution of (S)-2-chloro-5-fluoro-Af-(3-methylenecyclohexyl)pyrimidin-4-amine, 49a, (0.27 g, 1.12 mmol) in water (0.6 mL) and MeOH (1.5 mL) at room temperature, The reaction mixture was allowed to stir at room temperature for 1 hr. The mixture was diluted with EtOAc and washed with aqueous saturated NaHCOj solution. The organic phase was dried (MgS04), filtered and evaporated to dryness. The crude residue was purified via silica gel chromatography (0-100% EtOAc/hexanes gradient) which yielded both diastereomers, 49b and 49c. The isolated upper (less polar) spot, 49b, was carried forward: LCMS RT = 3.21 (M+l) 258.2.

[001077] Formation of (17?, 3jS)-3-(2-chloro-5-fluor©pyrimldin-4-ylamino)-l-(methyl-thiomethyl)cyclohexanol (49d) 2-chloi'0-5-fluoro-/V-((3/?, 5S)-l-oxaspiro[2.5]octan-5-yl)pyrimidin-4-amine, 49b, (0.10 g, 0.38 mmol) was dissolved in THE (2 mL). Methylsulfanylsodium (0.08 g, 1.15 mmol) was added to the reaction and the mixture was allowed to stir at room temperature for 3 hrs. An additional 36 mg portion of methylsulfanylsodium in THF (2 mL) was added and the reaction mixture was stirred overnight at room temperature. After LCMS showed starting material was still present, the reaction was warmed to 50 °C and stirred for 1 hr. The reaction was quenched with water and diluted with EtOAc. The layers were separated and the organic phase was washed with brine, dried (MgS04), filtered and evaporated to dryness. The crude residue was purified via silica gel chromatography (0-100%Etoac/hexanes gradient). The product (contaminated with small amount of staring material) was carried on to the next step without further purification, LCMS RT = 3.56 (M+l) 306.2.

[001078] Formation of (11?, 35)-3-(2-(5-chIoro-l-tosyl-UT-pyrrolo[2,3“b]pyndin-3-y])-5-fluoropyrimidin-4-ylamino)-l-(methylthiomethyl)cyclohexanoI (49e)

To a solution of (1/?, 3S)-3-(2-chloro-5-fluoropyrimidin-4-ylamino)-l-(methylthiomethyl)cyclohexanol, 49d, (0.09 g, 0.28 mmol) in CH3CN (4 mL) was added 5-chloro-l-(p-tolylsulfonyI)-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrrolo[2,3- -315-

In a 1000 mL flamed-dried round bottom flask, a mixture of (5)-BINAP (6.2 g, 10.0 mmol) and Rh2(cod)2Cl2 (2.1 g, 4.2 mmol) in anhydrous THF (350 mL), was stirred under nitrogen for 30 minutes at room temperature. The homogeneous red reaction mixture was then cooled to 0 °C and cyclohex-2-en-l-one (16.0 g, 166.4 mmol) was added followed by dropwise addition of neat trimethylaluminium (12.4 g, 16.5 mL, 166.4 mmol). The mixture was allowed to warm to room temperature for 30 min and then stirred for 1 hour. The reaction was monitored by NMR and a worked up aliquot indicated complete conversion to tertiary alcohol.

When the reaction was complete, its temperature was lowered to 0°C and quenched carefully with aqueous saturated NH4CI solution (500 mL). The layers were separated and the aqueous phase was further washed with ether (5 X 100 mL) and the combined organics were dried (MgS04) filtered over a celite pad and concentrated in vacuo to a yellow-brownish crude oil. Vacuum distillation (38 °C at 0.5-1 mm Hg), provided 13.9 g (72%) of light amber color oil.

[001082] Formation of CR)-feri-butyldimethyl(l“tnethylcyclohex-2-enyloxy)silane (50b)

To a solution of (R')~ 1 -mefhylcyclohcx-2-en.ol, 50a, (1.00 g, 8.91 mmol) in 20 dry DMF at room temperature was added 4/7-imidazole (1.82 g, 26.74 mmol), tert-butyldimethylchlorosilane (2.02 g, 13.33 mmol) and a catalytic amount of 4-dimethylaminopyridine (0.11 g, 0.89 mmol). The resulting mixture was stirred at room temperature overnight. It was then diluted with ether, washed consecutively with water, citric acid and water. The organic phase was dried with MgS04, filtered and concentrated in vacuo. The colorless crude oil 1.98 g was used directly in the next step without further purification.

[001083] Formation of ta*i-butyldimethyl((li?, 2 R, 6/f)-2-methyl-7- oxabicyclo[4.1.0]heptan-2-yloxy)silane (50c) 3-clilorobenzenecarboperoxoic acid (2.47 g, 11.00 mmol) was added in one portion to a stirred solution of (7?)-ie/Y-butyldimethyl(l-methyIcyclohex-2-enyloxy)silane, 50b, (1.98 g, 8.87 mmol) and sodium hydrogen carbonate in 30 mL of dry dichloromethane at room temperature under nitrogen. The resulting mixture was stirred for 20 hours. Then, 25% sodium sulfite solution (30 mL) was added and the resulting biphasic mixture was stirred for 15 minutes. The 2 layers were separated and the aqueous layer was extracted with dichloromethane (2X20 mL). The combined organic phases were washed with aqueous saturated NaHCC>3, dried (Na2S04) and concentrated in vacuo. The crude residue was purified by silica gel chromatography (0-10% EtOAc-hexanes gradient) to provide 647 mg of compound 50 c.

[001084] Formation of (1/ϊ, 21Ϊ, 3A)-3-azido-l-(to/-butyldimethylsilyloxy)-l-methylcyclo-hexan-2-ol (50d)

To a stirred solution of terf-butyl-dimethyl-[[(lJ?, 5 R, 67?)-5-mefhyI-7-oxabicyclo[4.1.0]heptan-5-yl]oxy] silane, 50c, (0.05 g, 2.15 mmol) in methanol (5 mL) and H2O(0.6 mL) was added NH4C1 (0.23 g, 0.15 mL, 4.30 mmol), followed by portion wise addition of sodium azide (0.42 g, 1.26 mL, 6.45 mmol). The resulting reaction mixture was warmed to 60 °C, stirred for 12 h, at which point TLC-analysis revealed traces of the starting material. The reaction mixture was cooled to ambient temperature, quenched with FLO (2 mL), concentrated under reduced pressure to remove methanol, extracted with ethyl acetate (3 x 15 mL), washed with brine (10 mL), dried over MgS04, filter and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (2.5-10 % ethyl ether in hexanes gradient) to afford 254 mg of (I/?, 2S, 67?)-2-azido-6-[tert-butyl(dimethyl)silyl]oxy-cyclohexanol, 50d, as a clear oil.

[001085] Formation of (1/?, 27?, 35)-3-amiiio-l-(rm-butyIdimethylsilyloxy)-l-methylcyclohexan-2-ol (50e) A solution of azide, 50d, (0.25 g; 0.89 mmol) in 20 mL of ethyl acetate was hydrogenated with Degussa palladium (20 mole%) under 1 atmosphere of hydrogen overnight. The reaction mixture was filtered over celite and the celite was eluted with 2X10 mL of EtOAc. The filtrate was concentrated in vacuo to afford 230 mg of an oil that was used directly for the next step without further purification.

[001086] Formation of (17?, 2R, 6S)-2-(teiT-butyldimethylsiIyloxy)-6-(2-(5-chioro-l-tosyl-Lff-pyrrolo[2,3-6]pyridin-3-yl)-5-fluoropyriinidm-4-yIamino)-2-methylcyclohexanol (50f)

To a stilted suspension of (17?, 27?, 6£)-6-amino-2-[ieri-butyl(dimethyl)silyl]oxy-2-methyl-cyclohexanol, 50e, (0.16 g, 0.62 mmol) in THF (8 mL) in a microwave sealed tube vessel was added 5-chloro-3-(5-fluoro-4-(methylsulfinyl)pyrimidin-2-yl)-l-tosyl-lH-pyrrolo[2,3-b]pyridine, la, (0.29 g, 0.63 mmol) followed by A-ethyl-A-isopropyI-propan-2-amine (0.13 mL, 0.74 mmol). The resulting reaction mixture was capped and warmed to 70 °C, stirred for 14 h. The reaction mixture was cooled to ambient temperature, added water (2 mL), concentrated under reduced pressure to remove THF. The crude product was diluted with ethyl acetate (25 mL), insoluble material (sulfone la) was removed by filtration. The organic layer was separated, washed with brine (2x5 mL), dried over Na2SC>4, filter and concentrated under reduced pressure. The crude product was purified by silica-gel plug using 10-30 % ethyl acetate in hexanes as eluant to afford 350 mg of (17?, 27?, 6S)-2-[tert-butyl(dimethyl)silyl]oxy-6-[[2-methyl[5-chloro-l-(p-tolylsulfonyl)-pyrrolo[2,3-b]pyridin-3-yl]-5-fluoro-pyridin-4-yl]amino]cyclohexanol (50f).

[001087] Formation of (17?, 27?, 3S>3-{2-(5-chloro-17T-pyrrolo[2,3-7>]pyri(lin-3-yl)-5-fluoro-pyrimidin-4-ylamino)-l-methylcyclohexane-l,2-diol (860)

To a stirred solution of (17?, 27?, 6S)-2-[ierr-butyl(dimethyl)silyl]oxy-6-[[2-methyl[5- chloro-l-(p-toIylsulfonyl)-pyrrolo[2,3-b]pyridin-3-yl]-5-fluoro-pyridin-4- y 1]amino]cyclohexanol, 50f, (0.11 g; 0.16 mmol) in THF (2 mL) at room temperature, was added tetrabutylammonium fluoride (1.5 equiv) and the reaction mixture stirred for 1.5 h, at which point HPLC-analysis revealed no starting material but the de-tosylated product was observed with minor desilylation. An additional equivalent of TBAF was added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was suspended in ethyl acetate (10 mL), washed with H2O (2x4 mL), aqueous saturated NH4CI solution (2 mL) and brine (2 mL). The organic phase was dried (Na2S04) and concentrated in vacuo to provide 139 mg of crude. The crude residue was purified by reverse phase HPLC (5-95% MeOH/water w/ HCI buffer over 15 minutes), to afford 15 mg of desired product, 860. LCMS M+l = 392.34

(a) NaH, BnBr, THF, 60 °C (b) 3-chloroperoxybenzoic acid, CH2CI2, 0 DC (c) H2SO4, MeOH (d) TBSCI, imidazole, DMAP, DMF (e) H2, Pd-C (10%), EtOAc (f) triphenylphosphine, diisopropylazadicarboxylate, diphenylphosphoryl azide, THF (g) H2, Pd-C (10%), EtOAc (h) 2,4-dichloro-5-fluoropyrimidine, K2C03, CH3CN/IPA (i) TsOH, MeOH (j) 5-chloro-3-(4,4,5,5-te£ramethyM,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine, aq Na2C03, CH3CN, microwave, 120 °C (k) LiOH, H20/THF, microwave, 120 °C. I001088] Formation of ((cyclohex-2-enyloxy)methyl)benzene (51a) A solution of cyclohex-2-en-l-ol (10,0 g, 101.9 mmol) in anhydrous THF (100 mL) was added to a stirred suspension containing sodium hydride (8.0 g, 199.7 mmol) (60% dispersion in oil) and benzyl bromide in anhydrous THF (250 mL) maintained at 50 °C. The resulting solution was stirred at 55-60 °C for 18 h. After cooling to ambient temperature, water was added to quench the reaction and the mixture was diluted with ether (500 mL). The organic phase was separated, dried (Na2SC>4), filtered and concentrated in vacuo to an oil that was subjected to a short silica plug filtration to provide 16. lg of desired product 51a that was used directly in the next step without further purification.

[001089] Formation of racemic cis and rtvms-l-benzyloxy)-7- oxabicyclo|4.1.0]heptane (51b and 51c) A solution of benzyl ether 51a (16.10 g, 0.89 mol) in 500 mL of CH2C12 at 0 °C was treated with 77% m-CPBA (21,08 g; 0.09 mol) portionwise. The reaction mixture was stirred at 0 °C for 2h then at room temperature for 12h. When the reaction is complete, it was quenched with sodium thiosulfate (100 mL) and the organic phase was further washed with another 100 mL of sodium thiosulfate, followed by aqueous NaHC03 solution, 5% NaOH (200 mL) and finally water. The organic phase was dried (Na2SC>4) and concentrated in vacuo to afford an oil that was purified by silica gel chromatography (5% to 20% Et20/ hexanes) to afford 11.44 g of trans-epoxide 51b and 3.95 g of c/s-epoxide 51c were isolated (66:34 ratio).

[001090] Formation of racemic l-benzyIoxy-3-methoxycyclohexan-2-ol (51d) A solution of e?'s-l-benzyloxy)-7-oxabicyclo[4.1.0]heptanes 51c, (2.0 g; 9.8 mmol) in 0.2N sulfuric acid (9.8 mmol) in 30 mL of anhydrous methanol was stirred at room temperature for 30 minutes. The reaction was diluted with water and extracted with ether. The organic phase was dried (Na2S04) and concentrated in vacuo to afford 2.31 g of an oil that was used directly in the next step without further purification.

[001091] Formation of racemic [l-benzyloxy-3-methoxy-2-cyclohexanoxy]/i?i-i-butyl-dimethylsilane (51 e)

To a solution of 1 -benzyloxy-3-methoxy-cyclohexan-2-ol, 51ds (2.31 g, 9.78 mmol), te/7-butyl-chlorodimethyl-silane (2.21 g, 2.73 mL, 14.66 mmol) in 20 diy DMF at room temperature was added 4H-imidazole (1.997 g, 29.33 mmol) and a catalytic amount of 4-dimethylaminopyridine (0.12 g, 0.98 mmol). The resulting mixture was stirred at room temperature overnight, It was then diluted with ether, washed with water, aqueous saturated citric acid solution and water again. The organic phase was dried with MgS04, filtered and concentrated in vacuo. The colorless crude oil was used directly in the next step without further purification.

[001092] Formation of racemic [l-Hydroxy-3-methoxy-2-cyclohexanoxy]fert-butyl-dimethylsilane (51f) A solution of racemic [l-benzyloxy-3-methoxy-2-cyclohexanoxy]tm-butyl- dimethylsilane, 51 e, (3.4 g, 9.7 mmol) was dissolved in ethyl acetate (50 mL) and hydrogenated under 45 PSI of hydrogen with Pd-C 10% for lh. The reaction mixture was filtered over a nylon/fiberglass filter to provide, after concentration in vacuo 2.72 g of desired product 51 f. This material was used directly in the next step without further purification.

[001093] Formation of racemic [l-Azido-3-methoxy-2-cyclohexanoxy]teri-butyl-dimethylsilane (51 g)

To a solution of racemic [l-Hydroxy-3-methoxy-2-cyclohexanoxy]ie/'f-butyl- dimethylsilane, 51f, (2.5 g; 9.6 mmol) in 60 mL of dry THF at room temperature was added, triphenylphosphine (5.0 g; 19.2 mmol), DIAD (3.9 g; 19.2 mmol) and diphenylphosphoryl azide (5.3 g; 19.2 mmol) and the reaction mixture was stirred at room temperature for 60h. The solvent was concentrated in vacuo and the resultant oil was purified by silica gel chromatography (10% FLO-Hcxane to ether gradient) to afford 2,57 g of the desired product 51 g.

[001094] Formation of racemic [l-Amino-3-methoxy-2-cyclohexanoxy]fcrf-butyl-dimethylsilane (51h) A solution of racemic [l-Azido-3-methoxy-2-cyclohcxanoxy]zm-buiyl- dimethylsilane, 51g, (2.57 g; 6.3 mmol) in 20 mL of ethyl acetate was hydrogenated with Pd-C 10% (5 mole %; Degussa) at 45 PSI in a Parr hydrogenation apparatus for 1 h. The reaction mixture was filtered over a nylon and glass fiber filter and concentrated in vacuo to provide 2.32 g of the desired product 51h as a white solid.

[001095] Formation of racemic A-((l-2-(tert-butyldimethylsilyloxy)-3-methoxycyciohexyl)-2-chioro-5“fluoropyrimidin-4-amine (51i)

In a flask was placed racemic [1-Amino-3-methoxy-2-cyclohexanoxy]/ert-butyl-dimethylsilane, 51h, (2.32 g; 6.26 mmol). To this was added MeCN and IPA (1.5:1 v/v) to a total volume of 125 mL. To the solution was added dipotassium carbonate (4,32 g, 31.30 mmol) and the mixt urc was allowed to stir 30 minutes at room temperature (to remove any water that might be present). To this mixture was added 2, 4-dichloro-5-fluoro-pyrimidine (3.14 g, 18.78 mmol) and the mixture was stirred at room temperature for 60h. The reaction was filtered thru celite and concentrated in vacuo. The crude residue was purified by silica gel chromatography (20-100% Ether/hexanes gradient) to afford 2.27g pure racemate compound 51 i.

[001096] Formation of (1Λ, 2S, 6/t)-2-(2-ch!oro-5-fluoropyrimidin-4-ylamino)-6-methoxy-cyclohexanol (51j)

To a solution of compound racemic A-((l-2-(ie;t-butyldimethylsilyloxy)-3-metboxycyclohexyl)-2-chloro-5-fluoropyrimidin-4-amine, 51i, (1.96 g, 5.03 mmol) in 30 mL of MeOH was added p-TsOH (1.73 g; 10.06 mmol). The reaction mixture was stirred at room temperature for 3h and then was concentrated to dryness. The residue was dissolved in EtOAc (125 mL) and washed with aqueous potassium carbonate 1M (2 X 50 mL), then brine. The organic phase was dried (Na2S04), filtered and concentrated in vacuo to give, after SFC enantiomers separation (50% EtOH-50% C02; 10 mL/min; 100 bar) 635 mg of chiral alcohol 51j as a white solid.

[001097] Formation of (11?, 25, 6j?)-2-(2-(5-chloro-l“tosyl“lf/-pyrrolo[2,3- 6Ipyridin-3-yl)-5-fluoropyrimidin-4-ylamino)-6-methoxycycIohexanol (51k)

In a microwave tube was placed 5-chloro-l -(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine (0.10 g, 0.23 mmol). To this was added acetonitrile (0.61 mL) and the solution was deoxygenated with nitrogen. To the reaction was added (1/?, 25, 6I?)“2-(2-ch]oiO-5-fluoropyrimidin-4-ylamino)-6-mcthoxy-cyclohcxanol, 51j, (0.04 g, 0.14 mmol) and palladium catalyst (24 mg), and then aqueous sodium carbonate (0.21 mL of 2 M solution, 0.41 mmol). The reaction was sealed and heated to 120 °C in the microwave reactor for 15 min. The reaction was diluted with ethyl acetate (40 mL), filtered thru florisil, and concentrated in vacuo to give crude as a green solid. This was purified by silica gel chromatography (20-75% EtOAc/hexanes gradient). Used resulting product directly in the next step. LCMS (M+l) = 546.35.

[001098] Formation of (12Ϊ, 25, 6/f)-2-(2-(5-chloro-lif-pyrrolo[2,3-6]pyridin-3-yl)-5-flu oropy rimidin-4-ylamino)-6-methoxy cyclohexanol (831)

In a microwave vial was placed azaindole 51k (0.050 g; 0.092 mmol). To this was added 3 mL of THF and 0.9 mL of 0.8 M LiOH. The vial was sealed and heated to 120 °C for 15 minutes in the microwave. When the reaction is complete, it was neutralized with 9 equivalents of 114 HC1 (0.704 mL), then aqueous saturated NaHCCh solution was added and the organic phase was separated and loaded onto silica gel for purification and eluted w/ 2% MeOH to 12% gradient over 10 minutes (4 g column) to provide 34.5 mg (91%) desired product 831,

(a) LDA, iodornethane, THF, -78 °C (b) SOCl2, DMF, CH2Ci2, reflux, then NFUOH (c) TMSOTf, iodine, Et3N, pentane, CH2CI2 <d) Boc20, DMAP, CH2C12 (e) 1,8-Diazabicyclo[5.4.0]undec-7-ene, toluene, reflux (f) Cs2C03, MeOH (g) H2, Pd-C (5%), MeOFI, 2 days (h) HCI, MeOH; 2,4-dichloro-5-fluoropyrimidine, 'Pr2NEt, DMF; SFC chiral separation (i) 5-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1 -tosy 1-1 H-pyrrolo[2,3-b]pyridine, Pd(Ph3P)4, Na2C03, THF/H20, reflux (j) NaH, MeOH (k) LIOH, H20/MeOH (l) benzotriazol-l-yl-[bis(dimcthylamino)methylene]oxonium hexafluorophosphate, 'Pr2Net, THF, NH4Ci.

[001099] Formation of l-methylcyclohex-3-ene-l-carboxylic acid (52a) Λ-isopropyfpropan-2-amine (50.1 g, 69.5 mL, 495.5 mmol) was dissolved in 50 mL of THF. To the solution was added n-butyllithium (174.4 mL of 2.5 M solution in hexanes, 436.0 mmol) at -78 °C. The resulting solution was stirred for 30 minutes at -78 °C. To the reaction was then added cyclohex-3-ene-1-carboxylic acid (25.0 g, 198.2 mmol) and the reaction was allowed to warm to 60 °C for 2 hrs. The reaction was cooled to room temp and iodornethane (29.5 g, 13.0 mL, 208.1 mmol) was added and the reaction was allowed to stir overnight and then quenched with 1 N HCI until the pH < 4. The crude product was extracted into CH2CI2 and water. The organic phase was concentrated in vacuo to a yellow oil (27 g) and used without further purification. MS/RT: 141.09 (M+H)/1.65 1001100] Formation of l-methylcyclohex-3-ene-l-carboxamide (52b)

To a solution of l-methylcyclohex-3-ene-1 -carboxylic acid, 52a, (54.0 g, 385.2 mmol) dissolved in CH2CI2 (200 mL) was added thionyl chloride (56.2 mL, 770.4 mmol) and 1 mL of DMF. The reaction was warmed to reflux for 3 hrs, then cooled and concentrated in vacuo. The residue was redissolved in 200 mL of CH2C12. To the reaction was added ammonium hydroxide (148.2 mL of 13 M solution, 1.9 mol) slowly. The reaction was stirred overnight. The reaction was extracted into CH2Q2 and water. The organic phase was concentrated in vacuo and purified via flash silica gel chromatography (EtOAc), yielding 25 g of l-methylcyclohex-3-ene-i-carboxamide. MS/RT: 139.96 (M+H)/2.66 [001101] Formation of 4-iodo-l-methyI-6-azabicyclo[3.2.1]octan-7-one (52c) A solution of l-methylcyclohex-3-ene-1-carboxamide, 52b, (5.0 g, 35.9 mmol) dissolved in 100 mL of pentane and CH2CI2 was cooled to 0 °C and treated with triethylamine (11.0 mL, 79.0 mmol) and trimethylsilyl-triflate (14.3 mL, 79.0 mmol) sequentially. The resulting mixture was stirred for 1 hour at room temperature. The lower layer was removed via pipette. The upper pentane layer was concentrated in vacuo and the resulting residue was dissolved in THF (100 mL). To the stirred reaction was added iodine (20.1 g, 79.02 mmol) and the reaction was allowed to stir overnight at room temperature. After quenching with Na2S03 and NaHC03, the reaction was partitioned between CH2CI2 and water. The organic layers were combined, dried over Na2S04, concentrated in vacuo to a dark yellow oil (9.5 g) that was used without further purification. MS/RT: 266.06(M+H)/2,39 [001102] Formation of tert butyl 4-iodo-l-methyl-7-oxo-6-azabicyclo[3.2.1]octane- 6-carboxylate (52d)

To a solution of 4-iodo-l-methyl-6-azabicyclo[3.2.1]octan-7-one, 52c, (9.5 g, 35.8 mmol) in CH2CI2 (100 mL) was added DMAP ¢0.2 g, 1.8 mmol), triethylamine (15.0 mL, 107.5 mmol) and fert-butoxycarbonyi tert-butyl carbonate (7.8 g, 35.8 mmol). The reaction was stirred overnight at room temperature. The product was extracted into CH2C12 and water. The organic layer was concentrated in vacuo and the residue was purified via silica gel chromatography (4:1 Hexanes:EtOAc), yielding 7.6 g. MS/RT: 366.06 (M+H)/3.95 [001103] Formation of tert butyl 4-iodo-l-methyI-7-oxo-6-azabicyclo[3.2.1]oct-3-ene-6-carboxyIate (52e).

To a solution of iert-butyl 4-iodo-l-methyl-7-oxo-6-azabicycIo[3.2.1]octane-6-carboxylate, 52d, (7.6 g, 20.8 mmol) in 100 mL of toluene was added 1,8-diazabicycIo[5.4.0]undec-7-ene (6.2 mL, 41.6 mmol). The reaction was warmed to reflux and stirred overnight. The reaction was concentrated in vacuo and the resulting residue was purified by silica gel chromatography (4:1 Hexanes:EtOAc), yielding 4.9 g of the desired product, 52e. MS/RT: 238.14 (M+H)/3.33 [001104] Formation of methyl 5-(ie/t-butoxycarbonylamino)-l-methylcyclohex-3-enecarboxylate (521)

To a solution of iert-butyl l-methyl-7-oxo-6-azabicyclo[3.2.1]oct-3-ene-6-carboxylate, 52e, (4.93 g, 20.78 mmol) in MeOH (100 mL) was added cesium carbonate (13.54 g, 41.56 mmol). The reaction was stilted overnight and then concentrated in vacuo. The cesium salts were precipitated with Et20 and filtered. The ether filtrate was evaporated to give 5.5 g of a yellow oil that was used without further purification. MS/RT: 270.17 (M+H)/3.64 [001105] Formation of methyl 5-(ferf-butoxycarbonylamino)-l- methylcyclohexanecarboxylate (52g)

Methyl 5-(/er/-butoxycarbonylamino)-l-methylcyclohex-3-enecarboxylate, 52f, (5.59 g, 20.75 mmol) was dissolved in 100 mL of MeOH. To the stirred solution was added 5% palladium on carbon (1.11 g, 10.38 mmol) and the reaction was stirred under a hydrogen balloon for 2 days. The reaction was filtered through celitc, and the filtrate was concentrated in vacuo and used without further purification. MS/RT: 272.24(M+H)/3.62 [001106] Isolation of (Iff, 3S)-methyl 3-(2-chloro-5-fluoropyrimidin-4-ylamino)-l-methyl-cyclohexanecarboxylate (52h). A stirred solution of methyl 5-(ie/'i-butoxycarbonylamino)-l-methylcyclohexanecarboxylate, 52g, (5.63 g, 20.75 mmol) in MeOH (20 mL) was treated with HC1 gas for 10 minutes. The resulting solution was stirred at room temperature for 1 hour, then concentrated to dryness and redissolved in THF (50 mL). To the reaction mixture was added T^NEt (10.84 mL, 62.25 mmol) and 2, 4-dichloro-5-fluoro-pyrimidine (5.20 g, 31.12 mmol) sequentially. The reaction was stirred at reflux overnight, concentrated in vacuo and resulting residue was purified by silica gel chromatography (1:1 Hexane:EtOAc), yielding 2.2 g of the racemic product as a yellow oil. 300 mg of the racemic methyl 3-(2-chloro-5-fluoropyrimidin-4-ylamino)-l-methylcyclohexanecarboxylate was submitted for SFC chiral separation, yielding 100 mg of the desired product, 52h, as a yellow oil. MS/RT: 302.16 (M+H)/3.68 [001107] Formation of (Iff, 3S)-methyl 3-(2-(5-chloro-l~tosyl-l//-pyrrolo[2,3-A]pyridin-3-y])-5-fiuoropyriinidin-4-ylamino)-l-methylcyclohexanecarboxylate (52i).

In a 25 mL round-bottomed flask were combined (Iff, 3)S)-methyl 3-(2-chloro-5-fluoiOpyrimidin-4-y]amino)-l-methylcyclohexanecarboxylate, 52h, (0.061 g, 0.202 mmol) , 5-chloro- l-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl) pyrrolo[2,3-b]pyridine (0.096 g, 0.222 mmol) , disodium carbonate (0.064 g, 0.607 mmol) in 5 mL of THF and 1 ml of water. The reaction mixture was degassed via a stream of nitrogen. To the reaction was added tetrakis triphenyl phosphine palladium (0) (0.021 g, 0.202 mmol) and the reaction was stirred at reflux overnight. The reaction was concentrated in vacuo and purified by silica gel chromatography (4:1 Hexanes:EtOAc), yielding 85 mg of desired product, 52i. MS/RT: 572.33 (M+H)/6.27 [001108] Formation of (Iff, 3S)-methyl 3-(2-(5-chloro-l//-pyrrolo[2,3-6]pyridin-3-yl)-5-fluoropyriimdin-4-ylamino)-l-methylcyclohexanecarboxylate (52j)

To a stirred solution of (Iff, 3S)-methyl 3-(2-(5-chloro-l-tosyl-I//-pyrrolo[2,3-Z>]pyridm-3-yl)-5-fluoropyrimidin-4-ylamino)-1 -meihylcyclohexanecarboxylate, 52i, (0.085 g, 0.149 mmol) in 10 mL of MeOH was added NaH (0.004 g, 0.178 mmol) at room temperature. The resulting suspension was stirred for 2 hrs, quenched with solid NH4CI. The mixture was concentrated in vacuo and purified via silica gel chromatography (3:1 Hexane:EtOAc), yielding 55 mg of the desired product, 52j. MS/RT: 418.32 (M+H)/3.30 [001109] (Iff, 3£)-3-(2-(5-chloro-l//-pyrrolo[2,3-Z>]pyridin-3-y])-5-fluoropyrimidin-4-ylamino)-l-methylcyclohexanecarboxylic acid (826)

To a solution of (Iff, 35)-methyl 3-(2-(5-chloro-177-pynolo[2,3-b)pyridin-3-y 1)-5 -fluoropyrimidin-4-ylamino)-l-methylcyclohexanecarboxylate, 52j, (0.035 g, 0.083 mmol) dissolved in MeOH (5 mL) and water (1 mL) was added LiOH (0.004 g, 0.168 mmol). The reaction was allowed to stir for 2 days at room temperature and then concentrated to dryness. The residue was washed with ethanol. The combined ethanol washings were concentrated in vacuo, yielding 30 mg of desired product as an off white solid. *Η NMR: (300 MHz, DMSO) 5 12.34 (s, H), 8.74 (d, 2.3 Hz, H), 8.33 (d, J= 2.3

Hz, H), 8.28 (d, ./= 1.6 Hz, H), 8.17-8.12 (m, H), 4.34 (s, H), 4.29 (s, H), 3.89 (s, H), 3.55

PCT/US2010/038988 WO 2Θ10/148197 2016204286 23 Jun2016

This compound was prepared as a mixture of trans isomers (endo : exo = 84 : 16) following literature procedures described in: Chang, Linda L.; Truong, Quang; Doss, George A.; MacCoss, Malcolm; Lyons, Kathryn; McCauley, Ermengilda; Mumford, Richard;

Forrest, Gail; Vincent, Stella; Schmidt, John A.; Hagmann, William K. Bioorg. Med. Chem. Lett. 2007,17(3), 597-601.

[001114] Formation of (+/-)-2,3-Tn/ns-methyl 3-aminobicyclo[2.2.1]heptane-2-carboxylate (53b) A mixture of (+/-)-2, 3-trans-methyl 3-nitrobicyclo[2.2.1]hept-5-ene-2-carboxylate, 53a, (0.32 g, 1.62 mmol) and Pd-C (10%) in MeOH was purged and placed under H2 atm (50 PSI) and shaken overnight. The mixture was filtered through celite, concentrated in vacuo and azeotroped twice with CH3CN to remove traces of MeOH. 'Η NMR of the crude mixture indicated the presence of both the endo and exo products (84 :16 = endo : exo) which were taken directly into the next reaction without further purification.

[001115] Formation of (+/-)-2,3-7#wis-methyl 3-(2-(5-chloro-l-tosyl-l//- pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)bicyclo[2.2.1]heptane-2-carboxylate (53c) A mixture of 5-chIoro-3-(5-fluoro-4-(methylsulfinyl)pyrimidin-2-yl)-l-tosyl-lH-pyrrolo[2,3-b]pyridine, la, (0.46 g, 1.00 mmol) and (+/-)-ira«s-methyl 3-aminobicyclo[2.2.1]heptane-2-carboxylate, 53b, (0.27 g, 1.60 mmol) (84 : 16 = endo : exo) and freshly ground Na2COj (0.32 g, 2.99 mmol in THF (3.7 mL) and CH3CN (1,2 mL) was heated to 120 °C for 20 min in microwave. The reaction mixture was filtered and the solid was rinsed with £t20 and THF, The organic layer was concentrated in vacuo to provide crude product which was purified by silica gel chromatography (0^40% EtOAc/hexanes, gradient) to provide the desired product (352 mg) as an inseparable mixture of trans-endo and trans-exo isomers (endo : exo = 85 : 15) as indicated by NMR. LC/MS R/ = 6.13 min, (M+H) 570.34.

[001116] (+/-)-2,3-trans-endo-methyi 3-(2-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-yI)-5-fluoropyrimidin-4-ylamino)bicyclo[2.2.1]heptane-2-carboxylate(53d) &amp; (+l-)-2(3-tram-exo-m ethyl 3-(2-(5-chloro-lH-pyrroIo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin^4-ylamino)bicyclo[2.2.1]heptane-2-carboxylate (53d)

To a solution of trans-endo- and trans-exo-mdihy\ 3-(2-(5-chloro-l-tosyl-lH-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)bicyclo[2.2.1]heptane-2-carboxylate, 53c, (0.18 g, 0.31 mmol) in MeOH (3mL) and CH2C12 (lmL) was added NaOMe (3 mL of 25 %w/v, 13.88 mmol). After 90 sec, NH4CI solution (5 mL) was added to quench the reaction. The mixture was partitioned between aqueous NH4CI (half saturated) and EtOAc. The aqueous layer was extracted again and the combined organic layers were washed with brine, dried over Na2S04, filtered and concentrated in vacuo. Flash chromatography (Si02, 0-15% MeOH-DCM, gradient) gave the desired products as a mixture, (white solid): 112 mg 'H NMR indicated desired product existed as a mixture of endo and exo isomers (endo : exo = 84 : 16) which was taken forward into the hydrolysis step. (+/-)-2,3-Trans-exo-methyl 3-(2-(5-chIoro-lH-pyrrolo[2,3-b]pyridin-3“yl)-5-fluoropyrimidin-4-ylamino)bicyclo[2.2,l]heptane-2-carboxylate (53d): minor isomer (exo)\ LC/MS (method: ml 17) R, = 3.17 min, (M+H) 416.27. -327-

Ν Η 1070

Compound 1070 was made in a similar fashion as described above for compounds 946 and 947.

General Scheme 54 -JL_ _L_ O'"®" 1Sd 54a S'L'If 54b

Ts rts. /V^ rw o^r ΌΤ ^ Cry g4c n" n BS5 (a) Cyanogen Chloride, DMF, 0 °C , (b) Pd(OH)2/Carbon, H2; 5-ch]oro-3-(5-fluoro-4-(methylsulfmyl)pyrimidin-2-yl)-l-tosyl-li/r-pyrrolo[2J3-b]pyridine, 'Pr2NEt/THF 45 °C, (c) Na/MeOH, (d) (n-Bu)2SnO, TMSN3, toluene, 110 °C. (001120] Formation of benzyl (IS, 3Λ)-3 -cya n ocyclohexylcarb am a te (54a) A suspension of benzyl iV-[(lS, 37?)-3-carbamoylcyclohexyl]carbamate, 18d, (0.69 g, 2.50 mmol) in DMF (10 mL) at 0 °C was treated with 2,4, 6-trichloro-l, 3, 5-triazine (0.61 g, 3.29 mmol) and allowed to stir while slowly warming to room temperature. After 20 minutes, the solution became gold in color. After 1 hour a precipitate had formed. Stirred for an additional 3 hours then quenched with ice water (100 mL) and extracted with CH2C12 (2 x 125 mL) then washed with IN HC1 (100 mL), The organic layer was concentrated in vacuo to afford an 730 mg of a residue drat was purified using a pad of silica gel (45 mL) using 30% EtOAc/hexanes as eluent to afford 621 mg of a white solid after vacuum drying. ’HNMR (300 MHz, CDC13) 5 7.45 - 7.30 (m, 5H), 5.09 (s, 2H), 4.67 (s, 1H), 3.49 (s, 1H), 2.66 - 2.32 (m, 2H), 2.16 - 1.79 (m, 3H), 1.52 - 1.03 (m, 4H).

[001121] Preparation of (1/f, 3S)-3-(2-(5-chloro-l-tosyl-l//-pyrrolo[2,3-b]pyridin-3-yl)“5“fluoropyrimidin-4-ylamino)cyclohexanecarbonitrile (54b)

Benzyl N-[(1S, 3/f)-3-cyanocyclohexyl]carbamate (0.26 g, 1.02 mmol) was dissolved in THF (15 mL) and treated with 0.13 g of 20% Pearlman's catalyst (50% wet by weight). The suspension was degassed with hydrogen for 2 min then placed under static hydrogen atmosphere. After 135 min, TLC showed no remaining starting material. The suspension was filtered through celite, washed with THF and degassed with nitrogen followed by the addition oflPr2NEt (0.21 mL, 1.23 mmol) and 5-chloro-3-(5-fluoro-4-(methylsulfmyr)pyrimidin-2-yl)- l-tosyl-l/f-pyrroIo[2,3“b]pyridine, la, (0.48 g, 1.02 mmol). The mixture was allowed to stir overnight at 45 °C then concentrated to dryness, absorbed on silica-gel and purified by silica gel chromatography using 0-60% EtOAc/hexanes gradient to afford 293 mg of a white solid. 'HNMR (300 MHz, CDC13) δ 8.74 (d, /= 2.4 Hz, 1H), 8.49 (s, 1H), 8.39 (d, / = 2.4 Hz, 1H), 8.15 - 8.05 (m, 3H), 7.37 - 7.23 (m, 2H), 5.01 (d, / = 6.2 Hz, 1H), 4.13 (s, 1H), 2.75 (d, /= 23.0 Hz, 1H), 2.58 (s, 1H), 2.38 (s, 3H), 2.20 (d, /= 9.1 Hz, 2H), 2.03 (d, /= 7.8 Hz, 1H), 1.78 - 1.43 (m, 4H), 1.26 (s, 1H).

[001122] Preparation of (IK, 35)-3-(2-(5-chloro-ll/-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)cyclohexanecarbonitrile (54c) (IK, 36>3-[[2-[5-chloro-l-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-5-fluoiO- pyrimidin-4-yl)amino]cyclohexanecarbonitrile, 54b, (0.29 g, 0.55 mmol) was suspended in MeOH (15 ml .) and sodium metal added and the mixture heated at 45 °C. The sodium dissolved in advance of the compound. The mixture was allowed to stir until complete by TLC and LCMS. Concentrated to reduced volume then quenched with 1:1 aqueous saturated NH4CI:water mixture (1 ml) then concentrated to diyness. The residue was diluted with EtOAc and washed with water and brine. The organic layer was concentrated in vacuo to give 0.3 g of a yellow solid that was adsorbed on silica-gel and purified using 40g isco column with the following gradient using 20% MeOH:DCM as the eluent: 0-25%/6 min hold 4 min; 25-50%/4 min hold 9 min to give 146 mg of a white solid. LCMS (10-90% MeOH:water with formic acid).LCMS RT 4.01 ES+ 371, ES- 369.

[001123] Preparation of (IK, 35)-3-(2-(5-chloro-lif-pyrrolo[2,3-b]pyridin-3-yl)-5- fluoropyrimidin-4-ylamino)cyclohexanecarboxamide (847) A sample of (IK, 3S)-3-(2-(5-chloro-17f-pyrrolo[2,3-b]pyridin-3-yl)-5-

fluoropyrimidin-4-ylamino)cyclohexanecarbonitrile was treated with 4N HCl/dioxane and heated at 78 °C overnight. Concentrated to diyness then quenched with aqueous saturated sodium bicarbonate and CH2C12 were added to give a sluriy. Filtered and extracted with CH2CI2. The organic phase was dried over NajSCL and concentrated in vacuo to give 189 mg of an orange residue that was purified by silica gel chromatography (0-10% MeOH:CH2Cl2 gradient) to afford 9.9 mg of a solid: LCMS (10-90% MeOH:water with formic acid): RT 3.79 minES+ 389.

[001124] Preparation of A-((15, 3K)-3-(lH-tetrazol-5-yl)cyclohexyl)-2-(5-chloro- l/f-pyrrolo[2,3-b]pyridin-3-yI)-5-fluoropyrimidin-4-amine (855) A suspension of dibutyl(oxo)tin (0.016 g, 0.064 mmol) and (IK, 3S)-3-[[2-(5-chloro- l//-pyiTolo[2,3-b]pyridin-3-yl)-5-fiuoro-pyrimidin-4-yl]amino]cyclohexane-carbonitrile (54c) (0.043 g, 0.107 mmol) in toluene (3 mL) was treated with azido(trimethyl)silane (0.200 mL, 1.507 mmol). The mixture was heated in a sealed tube at 120 °C overnight. The mixture was absorbed onto silica-gel and purified by silica gel chromatography (25-50% gradient of 20%MeOH:DCM containing 0.5% AcOH modifier). The combined fractions were concentrated to dryness to give a residue that was triturated with ether then dried under vacuum at 45 °C to afford 44mg of a yellow solid. *H NMR (300 MHz, DMSO) δ 12.33 (s, 1H), 8.74 (d,/ = 2.4 Hz, 1H), 8.41 - 8.04 (m,3H), 7.62 (d,/= 7.4 Hz, 1H),4.30 (s, 1H), 3.54-3.06 (m, 3H), 2.67 -2.31 (m, 1H),2.23 -1.33 (m,6H).

General Scheme 55

(a) hydroxylamine-HCl, EtOH; (b) 5-ethyl-2-methyl-pyridinium borane, HC1, MeOH; (c) N-(oxomethylene)carbamoyl chloride, THF; (d) NaOMe, MeOH.

[001125] Formation of (iS,)-3-(2-(5-chloro-l-tosyl-l//-pyrrolo[2,3-b]pyridin-3-yl)-5-fIuoro-pyrimidin-4-ylamino)cyclohexanone oxime (55a)

To solution of (35)-3-[[2-[5-chloro-l-(p-tolylsulfonyl)pyriOlo[2,3-b]pyridin-3-yl]-5-fhioro-pyrimidin-4-yl]amino]cyclohexanone (0.41 g, 0.81 mmol) in EtOH (8.2 mL) was added hydroxylamine hydrochloride (0.11 g, 1.61 mmol). The reaction mixture was stirred at room temperature overnight. Then the mixture was warmed to 70 °C for 15 min. The reaction mixture was concentrated in vacuo, suspended in EtOAc-DCM, washed with half saturated brine (2 x) and filtered through a S1O2 plug. The resulting residue was azeotroped with CH3CN (2x) to provide an off white powder which was used without further purification. lH NMR (300 MHz, MeOD) δ 8.78 (d, ,/ = 2.4 Hz, 1H), 8.51 (d, ./ = 10,8 Hz, 1H), 8.32 (d, / = 2.3 Hz, 1H), 8.10 - 8.04 (m, 3H), 7.38 (d, J = 8.2 Hz, 2H), 4.29 - 4.15 (m, 1H), 3.79 - 3.74 (m, 0.6H), 2.41 (m, 1H), 2.38 (s, 3H), 2.30 - 2.16 (m, 2H), 2.06 - 1.84 (m, 4H) and 1.66 - 1.59 (m, 2H) ppm; LC/MS (method: m!20) R/ = 3.90 min, (M+H) 529.44.

[001126] 2-(5-chloro-l-tosyl-lH-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-N-((lS,3R)-3-(hydroxyamino)cyclohexyl)pyrimidin-4-amine (S5c) &amp; 2-(5-chloro-l-tosyl-lH-pyrrolo[2,3-bjpyridin-3-y])-5-fluoro-N-((lS,3S)-3-(hydroxyamino)cyclohexyl)pyrimidin-4-amine (55b) :

To a stirred solution of (S>3-(2-(5-chloro4-tosyl-ltf-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylaminQ)cycIohexanone oxime (0.20 g, 0.38 mmol) and HC1 (0.19 mL of 6 M, 1.134 mmol) in MeOH (10 mL) was added (5-ethyl-2-methyl-pyndinium borane (0.12 mL, 0.76 mmol) at room temperature. After 30 min, the reaction was quenched with NaHC03. The mixture was extracted successively with Et20, EtOAc, CH2C12 and EtOAc. Each organic portion was washed with brine and the combined organic layers were dried over Na2S04, filtered and concentrated in vacuo. Flash chromatography (Si02, 20-100% EtOAc-hexanes) provided the cis-4 (74 mg) and trans-3 (64 mg) isomers.

[001127] 2-(5-chloro-l-tosyl-ltf-pyrrolo[2,3-b]pyridm-3-yl)-5-iluorO”lV-((l1S, 35)-3-(hydroxyamino)cycIohexyl)pyrimidin-4-amiiie (stereoisomer - 3) NMR (300 MHz, MeOD) δ 8.83 (d, J= 2.4 Hz, 1H), 8.50 (s, 1H), 8.33 (d, J= 2.4 Hz, 1H), 8.07 - 8.04 (m, 1H), 7.37 (d,/ = 8.4 Hz, 1H), 4.24 - 4.17 (m, 1H), 3.07 - 3.00 (m, 1H), 2.34 (m, 1H), 2.14 - 2.08 (m, 1H), 1.93 (t, ./= 3.5 Hz, 2H), 1.66 - 1.53 (m, 1H) and 1.44 - 1.12 (m, 3H) ppm; LC/MS RT = 3.64 min, (M+H) 531.47.

[001128] 2-(5-chloro-l-tosyI"lif-pyrroio[2,3-b]pyridin-3-yl)“5“fluoro-Ai-((15,3if)-3“ (hydroxyamino)cycIohexyl)pyrimidin-4-amine (stereoisomer - 4) XH NMR (300 MHz, MeOD) 5 8.84 (d, J= 2.4 Hz, 1H), 8.53 (s, 1H), 8.32 (d, J= 2.4 Hz, 1H), 8.07 - 8.04 (m, 1H), 7.37 (d, J = 8.2 Hz, 1H), 4.58 - 4.54 (m, 1H), 3.26 - 3.23 (m, 1H), 2.38 (s, 3H), 1.98 - 1.83 (m, 4H) and 1.69 - 1.60 (m, 4H) ppm; LC/MS RT = 3.67 min, (M+H) 531.47.

[001129] 2-((1 R, 3A>3-(2-(5-chloro-l//-pyrrolo[2,3-b]pyridin-3-yl)-5- fluoropyrintidin-4-yl-amino)cyclohexyl)-l,2,4-oxadiazolidine-3,5-dione (796)

To a solution of 2-(5-chloro-l-tosyl-lZ/-pyrrolo[2,3-b]pyridm-3-yl)-5-fluoro-Ar-((l>S', 3R)-3-(hydroxyamino)cyclohexyl)pyrimidin-4-amine, 55b, (0.072 g, 0.136 mmol) in THF (2 mL) at 0 °C was added N-(oxomethylene)carbamoyI chloride (0.014 mL, 0.176 mmol). A white solid formed immediately. The slurry was shaken and sonicated to make an even suspension/slurry. Then, CH2C12 (1 mL)) was added to help solvate the slurry. After 135 min, the mixture was treated with NaOMe (2 mL, 25% w/v). After 2 min, the mixture was quenched with saturated NH4C1 and acidified with 1M HCI. The mixture was extracted with EtOAc (3x) and the combined organic layers were dried over Na2S04, filtered and concentrated in vacuo. Preparative HPLC provided the desired product (25mg). Ή NMR (300 MHz, MeOD) δ 8.73 (s, 1H), 8.52 (s, 1H), 8.38 (s, 1H), 8.31 (br s, 1H), 4.34 (m, 1H), 2.60 - 2.56 (m, 1H), 2.27 (m, 1H), 2.08 (m, 3H) and 1.89 - 1.78 (m, 3H) ppm; LC/MS RT - 3.12 min, (M+H) 446.45.

[001130] 2-((15, 35)-3-(2-(5-chloro-l//-pyrrolo[2,3-b]pyridin-3-yl)-5- fluoropyrimidin-4-y]amino)cycIohexyI)-l,2,4-oxadiazolidme-3,5-dione (798) lB NMR (300 MHz, MeOD) δ 8.67 (s, 1H), 8.56 (s, 1H), 8.38 (s, 1H), 8.31 (br s, 1H), 4.47 (m, 1H), 4.21 (m, 1H), 2.41 (m, 1H), 2.22 (m, 1H), 2.10 - 1.90 (m, 3H), 1.72 (m, 2H) and 1.50 (m, 1H) ppm; LC/MS RT = 3.37 min, (M+H) 446.34.

General Scheme 56

(a) paraformaldehyde, mefhoxyphosphonoyloxymethane, 4A sieves, toluene, 90 °C , (b) NaOMe, MeOH.

[001131J Formation of (5)-dimethyI (3-(2-(5-chloro-l-tosyl-lH-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)piperidin-l-yl)methylphosphonate (56a)

To a solution of 2-[5-chloro-l-(p-toIylsulfonyI)pyrrolo[5,4-b]pyridin-3-yl]-5-fluoro-A-[(3S)-3-piperidyl]pyrimidin-4-amine, lc, (2.00 g, 3.99 mmol) in dry toluene was added 4 angstrom molecular sieves and methoxyphosphonoyloxymethane (0.97 g, 0.81 mL, 8.78 mmol). While stirring under nitrogen, paraformaldehyde (0.90 g, 9.98 mmol) was added portionwise. The mixture was heated at 90 °C for 90 minutes. The reaction was cooled to room temperature, diluted with aqueous saturated NaHCCb solution, extracted twice with EtOAc. The combined organic phases were dried (MgSCU), filtered and concentrated in vacuo. The resulting residue was purified by silica gel chromatography using 0-10% McOH/CH2C12 gradient to afford 2.0 g of desired product. LCMS RT = 4.47 (M+H) 623.3, [001132] Formation of (S)-dimethyl (3-(2-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)piperidin-l-yl)methylphosphonate (690)

To a solution of 2-[5-chloro-l-(p-tolylsulfonyl)pyrroIo[2,3-b]pyridin-3-yI]-Ar-[(35)-l-(dimethoxyphosphoryhnethyl)-3-piperidyl]-5“fluoro-pyrimidin-4-amine, 56a, (1.00 g, 1.61 mmol) in MeOH (40 mL) was added sodium methanolate (20 mL of 25 %w/v, 92.55 mmol) and the reaction mixture was stirred at room temperature for 30 minutes. All volatiles were removed at reduced pressure and the resulting residue was diluted with aqueous saturated NH4CI solution and extracted twice with CH2CI2. The combined organic phases were dried (MgSCL), filtered and concentrated in vacuo. The resulting residue was purified via silica gel chromatography using 0-10% MeOH:CH2Cl2 gradient to provide 270 mg of a white solid. ‘H NMR (300.0 MHz, DMSO) 6 12.33 (s, 1H), 8.70 (d, / = 2.4 Hz, 1H), 8.28 (d, /= 2.4 Hz, 1H), 8.20 (d,/ = 2.6 Hz, 1H), 8.17 (d,/= 4.0 Hz, IH), 7.35 (d,/= 7.8 Hz, 1H),4.27 - 4.17 (m, 1H), 3.67 (s, 3H), 3.64 (s, 3H), 3.21 - 3.16 (m, 1H), 2.96 - 2.90 (m, 3H), 2.33 - 2.20 (m, 2H), 1.99 - 1.94 (ra, 1H), 1.80 - 1.60 (m, 2H) and 1.47 - 1.35 (m, 1H) ppm; LCMS RT = 3.84 (M+l) 469.47.

(a) pyrazole-l-carboxamidine hydrochloride, ‘Pr2NEt, 4A sieves, toluene, 90 °C (b) NaOMe, MeOH.

[001133] Formation of ((S)-3-(2-(5-chloro-l-tosyl-l./7-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-ylamino)piperidine-l-carboximidamide (57a)

To a solution of pyrazole-l-carboxamidine hydrochloride (0.12 g, 0.80 mmol) and 2-[5-chloro-1 -(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3 -y l]-5-iluoro-W-[(3 S)-3 -piperidyl]pyrimidin-4-amine, lc, (0.40 g, 0.80 mmol) in DMF (0.9 mL) was added *Pr2NEt (0.14 mL, 0.80 mmol). The reaction mixture was stirred at room temperature for 4 hours. The mixture was diluted into water, filtered, washed with additional water, then ether. The filtrate was concentrated in vacuo. The resulting residue was purified by silica gel chromatography using 5-20% MeOH/CH2CI2 gradient (product elutes with 20% MeOH) to afford 190 mg of the desired product. NMR (300 MHz, DMSO) 6 8.73 (d, / = 2.2 Hz, 1H), 8.50 - 8.45 (m, 2H), 8.33 (d, J = 3.7 Hz, 1H), 8.07 (d, /= 8.2 Hz, 2H), 7.90 (d, /= 7.0 Hz, 1H), 7.53 - 7.42 (m, J= 9.0 Hz, 6H), 3.87 (d, / = 13.6 Hz, 1H), 3.17 (d, / = 5.2 Hz, 1H), 3.03 (q,/= 10.9 Hz, 2H), 2.36 (s, 3H), 2.11 (d, / = 9.9 Hz, 1H), 1.90 (d, / = 12.6 Hz, 1H), 1.68 (dd, /= 24.5, 13.9 Hz, 2H); LCMS RT = 3.07 (M+l) 543.34.

[001134] Formation of (S)-3-(2-(5-chloro-lH-pyrrolo[2>3-b]pyridin-3-yl)-5-fluor opyrimidin-4-yia min o)piperidine-l -carboximid amide(881)

To a solution of (3S)-3-[[2-[5-chloro-l-(p-tolylsuIfonyl)pyrrolo[2,3-b]pyridin-3-yl]-5-fluoro-pyrimidin-4-yl]amino]piperidrae-l-carboxarnidine, 57b, (0.18 g, 0.32 mmol) in MeOH (5 mL) was added sodium methanolate (3 mL of 25 %w/v, 13.88 mmol) and the reaction was stirred at room temperature. After 5 min, the mixture was concentrated in vacuo to light yellow solid. The crude residue was purified via preparatory HPLC (MeOH/1% aqueous HC1) to afford the desired product. *H NMR (300 MHz, DMSO) δ 12.79 (s, 1H), 8.77 (s, 1H), 8.60 (d, /= 2.3 Hz, 1H), 8.43 (d, /= 4.8 Hz, 1H), 8.37 (d, / = 2.3 Hz, 1H), 7.52 (s, 3H), 4.29 (s, 1H), 4.08 (d, / = 12.6 Hz, 1H), 3.90 (d, /= 13.7 Hz, 1H), 3.16 - 2.95 (m, 2H), 2.17 (d, /= 9.7 Hz, 1H), 1.92 (d, / = 8.5 Hz, 1H), 1.81 - 1.57 (m, 2H); LCMS RT = 2.03 (M+l) 389.27.

General Scheme 58

(a) 3-bromoprop-l-ene, Zn dust, DMF (b) 5-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-y!)-1-tosyl-1H-pyrrolo[2,3-b]pyridine, Pd(Ph3P)i, ^CCb, acetonitrile, water, 120 °C, microwave, (c) 0s04, pyridine, 4-mcthylmorpholme-/Vr-oxide, tert-butanol, water, THF, 120 °C (d) NaOMe, MeOH.

[001135] Formation of (3£)-l-allyI-3-(2-chloro-5-fluoropyrimidin-4- ylamino)cyclohexanol (58a)

To a solution of (3S)-3-[(2-chloiO-5-fluoro-pyrimidin-4-yl)amino]cyclohexanone, 29b, (0.60 g, 2.46 mmol) and 3-bromoprop-l-ene (0.43 mL, 4.92 mmol) in DMF was added Zn dust (0.32 g, 4.92 mmol). The reaction was stirred at room temperature for 3 days. The mixture was diluted into aqueous saturated NH4C1 solution, extracted twice with EtOAc. The combined organic phases were washed twice with brine, dried (MgS04), filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography using 050% EtOAc/hexanes gradient to afford 553 mg of desired product, 58a, as an oil. LC/MS -two peaks corresponding to two diastereomeric products: 286.4 (M+H), RT = 3.41 and 3.78.

[001136] Formation of (1Λ, 35)-l-allyl-3-(2-(5-chloro-l-tosyl-liyr-pyrrolo[2,3- b|pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)cyclohexanol and (1/i, 3S)-l-allyl-3-(2-(5-ch lo ro-1 -tosyl- IH-py rrolo [2,3-b] pyridin-3-y l)-5-fluor opy rimidin-4-ylamino)cyclohexanol (58b and 58c)

In a microwave tube was placed 5-chloro-l-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine (0.57 g, 1.32 mmol) and (3S)-l-allyl-3-[(2-chloro-5-fluoro-pyrimidin-4-yl)amino]cyclohexanol, 58a, (0.32 g, 1.10 mmol) in acetonitrile (12 mL) and Na2C03 (1.65 mL of 2 M aqueous solution, 3.31 mmol). The mixture was deoxygenated with nitrogen for 15 min. To the mixture was added tetrakis triphenyl phosphine palladium (0) (0.03 g, 0.02 mmol). The reaction was sealed and heated to 120 °C for 20 min. The mixture was diluted with brine, extracted twice with CH2CI2. The combined organic phases were dried (MgS04), filtered and concentrated in vacuo. The resulting residue was purified via silica gel chromatography using a 10-60% EtOAc/hexanes gradient to afford two diastereomers:

Diastereomer 1 (more polar spot - 58c): LCMS RT = 4.45 min, (M+H) = 556.48 Diastcreomer 2 (less polar spot - 58b): LCMS RT = 4,48 min (M+H) = 556.48 [001137] Formation of 3-((1 R, 3jS)-3-(2-(5-chloro-l-tosyl-l//-pyrrolo [2,3-b] pyridin- 3-yl)-5-fluoropyrimidin-4-yIamino)-l-hydroxycyclohexyl)propane-lj2-diol (58d)

To a solution of (35)-l-aIlyl-3-[[2-[5-chloro-l-(p-tolylsuIfonyl)pyrrolo[2,3-b]pyridin-3-yl]-5-fIuoro-pyrimidin-4-yl]amino]cyclohexanol, 58c, (0.30 g, 0.54 mmol) in 2-methyl-2-propanol (9.23 mL), THF (3.69 mL) and water (1.85 mL) was added pyridine (0.09 mL, 1.08 mmol) and osmium tetroxide (0.27 mL of 2.5 %w/v, 0.03 mmol) and 4-methylmorpholine N-oxide (0.07 mL, 0.65 mmol). The reaction mixture was heated to 80 °C for 20 hours. After cooling to room temperature, the mixture was diluted into aqueous saturated sodium bisulfite solution and extracted twice with 20% isopropanol/CH2Cl2. The combined organic phases were washed with more aqueous saturated sodium bisulfite solution, dried (MgS04), filtered and concentrated in vacuo. The crude residue was purified via silica gel chromatography using 5-10% MeOH/CH2Cl2 gradient to afford 175 mg of the desired product as a racemic mixture, 58d. ’H NMR (d6-DMSO) δ 8.77 (t, / = 2.6 Hz, 1H), 8.48 (d, / = 2.4 Hz, 1H), 8.42 (d, / = 6.0 Hz, 1H), 8.25 - 8.23 (m, 1H), 8.07 (d, /= 7.4 Hz, 2H), 7.74 (dd, j = 7.6, 13.5 Hz, 1H), 7.44 (d, J = 8.3 Hz, 2H), 4.97 (d, J = 12.8 Hz, 1H), 4.76 - 4.72 (m, 1H), 4.54 - 4.51 (m, 1H), 4.31 (m, 1H), 3.83 (m, 1H), 2.36 (s, 3H), 1.99 - 1.91 (m, 2H), 1.77 - 1.63 (m, 4H) and 1.57 -1.46 (m, 4H) ppm; LCMS RT = 4.31 (M+H) 590.5.

[001138] Formation of 3-((lJ?, 35)-3-(2-(5-cliloro-l//-pyrrolo[2,3-b]pyridin-3-yI)-5-fluoropyrimidin-4-ylamino)-l-hydroxycyclohexyl)propane-l,2-diol (718)

To a solution of 3-((LR, 35)-3-(2-(5-chloro-l-tosyl-lif-pyrrolo[2,3-b]pyridm-3»yl)-5-fluoropyrimidin-4-ylamino)-l-hydroxycyclohexyl)propane-l,2-diol, 58d, (0.11 g, 0.18 mmol) in MeOH (5 mL) was added sodium methanolate (2 mL of 25 %w/v solution, 9.26 mmol) and the reaction mixture was stirred at room temperature. After 20 min, the reaction mixture was diluted with aqueous saturated NH4CI solution and extracted twice with 20% IPA/CH2C12. The combined organic phases were dried (MgS04), filtered and concentrated in vacuo. Purification via silica gel chromatography using 5-20% MeOH: CH2CI2 gradient to afford 56 mg of a white solid. ‘HNMR (300 MHz, d6-DMSO) δ 12.29 (s, 1H), 8.71 (t, J = 2.3 Hz, 1H), 8.27 (d, J = 2.4 Hz, 1H), 8.19 (dd, J = 2.8, 4.5 Hz, 1H), 8.15 (t, J = 3.7 Hz, 1H), 7.52 (t, J = 7.7 Hz, 1H), 4.97 (d, J = 16.0 Hz, 1H), 4.77 (dd, J = 3.8, 10,5 Hz, 1H), 4.54 (t, J = 5.6 Hz, 1H), 4.32 (m, 1H), 3.86 (m, 1H), 2.00 - 1.97 (m, 2H), 1.82 - 1.63 (m, 4H) and 1.59 - 1.45 (m, 4H) ppm; LCMS RT - 3.71 (M+l) 436.48.

General Scheme 59

(a) benzyloxyphosphonoyloxymethylbenzene, triethylamine, 95 °C, microwave, (b) NaOMe, MeOH.

[001139] Formation of dibenzyl (15, 35)-3-(2-(5-chIoro-l-tosyM//-pyrroIo[2,3- b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)-l-hydroxycyclohexylphosphonate and dibenzyl (1Λ, 35)-3-(2-(5-chloro-l-tosyM/?-pyrrolo[2,3-b]pyridin-3-yl)-5- fluoropyrimidin-4-ylamino)-l-hydroxycyclohexylphosphonate (59a and 59b)

To a solution of (3S)-3-[[2-[5-chloro-l-(p-tolylsulfonyI)pyriOlo[2,3-b]pyridin-3-yl]-5-fluoro-pyrimidin-4-yl]amino]cyclohexanone, 28a, (0.40 g, 0.78 mmol) in benzyloxyphosphonoyloxymethylbenzene (2.58 mL, 11.67 mmol) was added triethylamine (0.22 mL, 1.56 mmol). The reaction mixture was heated to 95 °C for 15 hours. The mixture was diluted with aqueous saturated NaHCOs solution, extracted with EtOAc, washed again with aqueous saturated NaHCOj solution. The organic phase was dried (MgSCL), filtered and concentrated in vacuo to white solid. The crude product was purified via silica gel chromatography using 0-10% MeOH/CH2Cl2 gradient to afford 518 mg of a mixture of diastereomers, which contains somebenzyloxyphosphonoylmethylbenzene. The mixture was used without further purification in the next step. LCMS RT = 4.6 (M+H) 776.32.

[001140] Formation of dimethyl (15, 35)-3-(2-(5-chloro-lJ?-pyrrolo[2,3-b]pyridin-3_yi)_5-flUoropyrimidin-4-y]amino)-l-hydroxycyclohexylphosphonate and dimethyl (ΙΛ, 35)-3-(2-(5-chloro-l//-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylaniino)-l-hydroxycyclohexylphosphonate (741, 742)

To a solution of (17?, 35)-3-[[2-[5-chloro-l-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-5-fluoro-pyrimidin-4-yl]amino]-l-dibenzyloxyphosphoryI-cyclohexano] and (15, 35)-3-[ [2- [5 -chloro-1 -(p-toly lsulfony l)pyrrolo [2,3 -b]pyridin-3-y l]-5 -fluoro-py rimidin-4-y 1] amino] -l-dibenzyloxy in MeOH was added sodium methanolate and the reaction was stirred at room temperature. After 15 min, the reaction mixture was diluted with aqueous saturated NEUCl solution and extracted twice with 20% IPA/CH2CI2. The combined organic phases were dried (MgSCU), filtered and concentrated in vacuo. The resulting residue was purified via silica gel chromatography using 0-5% MeOH:CH2Cl2 to elute impurity, 5%-10% to elute bottom two spots.

Diastereomer 1 [741]: lH NMR (300 MHz, DMSO) 8 12.32 (s, 1H), 8.70 (d, /= 2.4 Hz, 1H), 8.27 (d, / = 2.4 Hz, 1H), 8.26 (d, / = 2.8 Hz, 1H), 8.18 (d, J = 3.9 Hz, 1H), 7.34 (d, /= 7.1 Hz, 1H), 5.77 (d, /= 2.9 Hz, 1H), 4.60 (s, 1H), 3.73 (dd, / = 10.1, 6.3 Hz, 6H), 2.30 - 2.15 (m, 1H), 2.04 - 1.86 (m, 1H), 1.85 - 1.50 (m, 6H); LCMS RT = 3.82 (M+l) 470.5.

Diastereomer 2 [742]: lE NMR (300 MHz, DMSO) 8 12.30 (s, 1H), 8.75 (d, /= 2.4 Hz, 1H), 8.27 (d, / = 2.4 Hz, 1H), 8.18 (d, /=2.8 Hz, 1H), 8.14 (d,/= 4.0 Hz, 1H), 7.44 (d, / = 7.7 Hz, 1H), 5.38 (s, 1H), 4.55 - 4.36 (m, 1H), 3.71 (d, /= 3.1 Hz, 3H), 3.68 (d, /= 3.2 Hz, 3H), 2.16 - 2.01 (m, 2H), 2.00 - 1.72 (m, 3H), 1.71 - 1.41 (m, 2H), 1.39 - 1.18 (m, 1H); LCMS RT = 3.70 (M+l) 470.5.

General Scheme 60

[001141] Formation of Ethyl 2-((1/2, 35>3-(2-chIoro-5-fluoropyrimUlin-4-ylamino)- l-hydroxy-cyclohexyI)ethanoate (60a)

Zinc dust (1.61 g, 24.62 mmol) was heated with a heat gun under N2. THF (8.0 mL) was added, then a solution of chloro(trimethyl)silane (0.63 mL, 4.93 mmol) in THF (8.0 mL) was added and stirred for 15 min at room temperature then heated to reflux. After cooling to room temperature, a solution of ethyl 2-bromoacetate (2.73 mL, 24.62 mmol) in THF (6.0 mL) was added slowly to the zinc mixture. Then, a solution of (35)-3-[(2-chloro-5-fluoro-pyrimidin-4-yl)amino]cyclohexanone, 29b, (2.00 g, 8.21 mmol) in THF (6.0 mL) was added. The mixture was refluxed for 2 hours then concentrated in vacuo. EtOAc and aqueous saturated NaHCCL solution were added and the product was extracted with additional EtOAc (3x), dried (Na2SC>4) and concentrated in vacuo. Purification by silica gel chromatography (Hexanes :EtOAc) separated 2 products. The first peak was 60a (2,05 g, 6.18 mmol, 75%). LCMS+: 332.20 at 3.57 min (10-90% MeOH, 3/5 grad/run, Formic Acid).

[001142] Formation of Ethyl 2-((1 R, 35)-3-(2-(5-chloro-l-tosyl-l tf-pyrroIo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)-l-hydroxycyclohexyl)ethanoate (60c)

To a solution of 5-chloro-1-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine (0.31 g, 0.72 mmol) in acetonitrile ¢6.0 mL) was added ethyl 2-((1/2, 35)-3-(2-chloro-5-fluoropyrimidin-4-yIamino)-l-hydroxy- cyclohexyI)ethanoate, 60a, (0.20 g, 0.60 mmol) and degassed under N2. Na2COj ¢0.90 mL of 2 M, 1.81 mmol) was added followed by Pd(PPh2)4 (0,10 g, 0.09 mmol). The reaction was sealed and microwaved at 120 °C for 30 min. The material was concentrated under reduced pressure then diluted in EtOAc and aqueous saturated NaHCCL, then extracted with additional EtOAc (3x), dried (Na2SC>4) and concentrated in vacuo. The material was diluted in DCM and silica gel chromatography (Hexanes:EtOAc) gave 217 mg of product 60c. LC MS+: 602.49 at 4.62 min (10-90% MeOH, 3/5 grad/run, Formic Acid).

[001143] Formation of 2-((1/2, 36>3-(2-(5-chloro-l//-pyrrolo[2,3-b]pyrkUn-3-yl)-5-fluoro-pyrimidin-4-ylamino)-l-hydroxycyclohexyl)ethanoic acid (60d)

To a solution of ethyl 2-((1/2, 35)-3-(2-(5-chloro-l-tosyl-l/7-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)-l-hydroxycyclohexyl)ethanoate, 60c, (0.14 g, 0.22 mmol) in THF (5.0 mL) was added LiOH (1.12 mL of 1 M aqueous solution, 1.12 mmol). The reaction was microwaved at 130 ° C for 30 min, neutralized with HC1 (0.56 mL of 2 M, 1.12 mmol) and concentrated under reduced pressure, diluted in toluene and concentrated (2x) to give 60d which was used without further purification. LC MS+: 420.30 at 3.05 min (10-90% MeOH, 3/5 grad/run, Formic Acid).

[001144] Formation of 2-((1/2, 36)-3-(2-(5-chloro-l//-pyrrolo[2,3-b]pyridm-3-yl)-5-fluoro-pyrimidin-4-ylamino)-l-hydroxycyclohexyl)-N-methylethanamide (751)

To a solution of 2-((1 R, 35)-3-(2-(5-chloro-l/7-pyriOlo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)-l-hydroxycyclohexyl)ethanoic acid, 60d, (0.032 g, 0.076 mmol) in MeCN (1.6 mL) and DMF (1.6 mL) was added HATU (0.058 g, 0.152 mmol), Methanamine (0.154 mL of 2 M solution, 0.305 mmol) and 'Pr2NEt (0.053 mL, 0.305 mmol). The reaction was heated to 60 °C overnight then concentrated in vacuo. The resulting residue was purified by reverse phase HPLC (Water/HCl:MeOH). Pure fractions were combined and concentrated in vacuo to give 29 mg of 751 as the HC1 salt.

[001145] Formation of Ethyl 2-((15,35)-3-(2-chloro-5-fluoropyriniidin-4-ylamino)- l-hydroxycyclohexyl)propanoate (61b). (Step A):

Zinc dust (1.21 g, 18.47 mmol, 3 eq.) was heated with a heat gun under N2. THF (6.0 mL) was added then a solution of chloro(trimethyl)silane (0.47 mL, 3.69 mmol) in THF (6.0 mL) was added and stirred for 15 min at room temperature then heated to reflux and cooled. A solution of ethyl 2-bromopropanoate (3.34 g, 18.47 mmol) and (35)-3-[(2-chloro-5-fluoro-pyrimidin-4-yl)amino]cyclohexanone (61a) (1.50 g, 6.16 mmol) in THF (6.0 mL) was added to the zinc mixture slowly. This mixture was refluxed for 2 hours then concentrated in vacuo. EtOAc and aqueous saturated NaHCCL were added and the product was extracted with EtOAc (3x), dried (Na2S04) and concentrated in vacuo. Purification by silica gel chromatography (Hexanes:EtOAc) separated 2 products. The first product eluted at 20-35% ethyl acetate and second product eluted at 35-40%. The fractions of the 2nd product were concentrated in vacuo to give 760 mg of 61b. LCMS+: 346.23 at 3.35 min (10-90% MeOH, 3/5 grad/run, Formic Acid), [001146] Formation of Ethyl 2-((15, 35)-3-(5-fluoro-2-(5-fluoro-l-tosy 1-1/7-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)-l-hydroxycyclohexyl)propanoate (61c).

To a solution of 5-fluoro-l-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yI)pyriOlo[2,3-b]pyridine (0.21 g, 0.38 mmol) in acetonitrile (3.6 mL) was added ethyl 2-((15, 35)-3-(2-chloro-5-fluoropyrimidin-4-ylamino)-l-hydroxy- cyclohexyl)propanoate (61b) (0.12 g, 0.35 mmol) and degassed under N2. Na2C03 (0.52 mL of 2 M aqueous solution, 1.041 mmol) was added followed by Pd(PPh3)4 (0.06 g, 0.052 mmol). The reaction was sealed and heated in a microwave at 120 °C for 30 min. The material was concentrated under reduced pressure and then diluted in EtOAc and aqueous saturated NaHC03, then extracted with additional EtOAc (3x). The combined organic phases were dried (Na2S04) and concentrated in vacuo. The material was diluted in CH2CI2 and silica gel chromatography (Hexanes :EtOAc) gave product 200 mg of 61c. LCMS+: 600.35 at 4.22 min (10-90% MeOH, 3/5 grad/run, Formic Acid).

[001147] Formation of 2-((15, 35)-3-(5-fluoro-2-(5-fluoro-17/-pyrrolo[2,3-b]pyridin-3-yI)pyrimidin-4-ylamino)-l-hydroxycyclohexyl)propanoic acid (61d).

To a solution of ethyl 2-((15, 35)-3-(5-fluoro-2-(5-fluoro-l-tosyl-l//-pyrrolo[2.3-b]pyridin-3-yl)pyrimidin-4-ylamino)-l-hydroxycyclohexyl)propanoate (61c) (0.20 g, 0.33 mmol) in THF (3 mL) was added LiOH (3 mL of 1 M aqueous solution, 3.0 mmol). The reaction was allowed to stir over 2 days at room temperature then neutralized with HC1 (1.5 mL of 2M, 3.0 mmol) and concentrated to dryness, diluted in toluene and concentrated again (2x) to give hid which was used without further purification. LCMS+: 418.32 at 2.62 min (10-90% MeOH, 3/5 grad/run, Formic Acid).

[001148] Formation of (4R, 55, 75)-7-(5-fluoro-2-(5-fluoro-l//-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)-4-methyl-l-oxa-3-azaspiro[4.5]decan-2-one (967).

To a solution of 2-[(lS, 35)-3-[[5-fluoro-2-(5-fluoro-l.tf-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl]amino]-l-hydroxy-cyclohexyl]propanoic acid (61d) (0.095 g, 0.228 mmol) in toluene (5 mL) and triethylamine (0.048 mL, 0.341 mmol) was added (azido(phenoxy)phosphoryl)oxybenzene (0.059 mL, 0.273 mmol). The reaction was heated to 120 °C in a sealed tube overnight. The reaction was concentrated in vacuo and purified by reverse phase HPLC (Water/HChMeOH) to separate the diastereomers. To remove a trace amount of leftover starting material, the first peak was diluted in MeOH (1 mL) and passed through a PL-HC03 MP SPE cartridge to obtain the free base. This material was then salted (HC1 in water) and concentrated in vacuo to give 16 mg of 967 as the HC1 salt.

General Scheme 62

[001149] Formation of (5)-ethyl 2-(3-(2-chloro-5-fluoropyrimidin-4-ylamino)cyclohexylidene)ethanoate (62a).

To a solution of (35)-3-[(2-chloro-5-fluoro-pyrimidin-4-yl)amino]cyclohexanone (29b) (2,00 g, 8.21 mmol) in toluene (40 mL) was added ethyl 2- triphenylphosphoranylideneacetate (4.29 g, 12.31 mmol). The reaction was refluxed overnight then concentrated in vacuo and purified by silica gel chromatography (Hexanes:EtOAc). The desired product eluted at 15% ethyl acetate. Clean fractions were combined and concentrated to give 2.57 g of 62a. LCMS+: 314.18 at 3.75 min (10-90% MeOH, 3/5 grad/run, Formic Acid).

[001150] Formation of Ethyl 2-((35)-3-(2-chloro-5-fluoropyrimidin-4-ylamino)-l-(nitromethyl)cyclohexyl)ethanoate (62b)

To a solution of (5)-ethyl 2-(3-(2-chloro-5-fluoropyrimidin-4-ylamino)cyclohexylidene)ethanoate, 62a, (2.58 g, 8.22 mmol) in nitromethane (44.53 mL, 822.3 mmol) was added 1,1,3,3-tetramethylguanidine (1.55 mL, 12,33 mmol). The reaction was refluxed overnight then concentrated in vacuo and purified by silica gel chromatography (Hexanes:EtOAc) then a second chromatography (CH2CI2 :20% MeOH in CH2CI2). Fractions containing pure product were combined and concentrated to give 1.8 g of 62b LCMS+: 375.32 at 3.64 min (10-90% MeOH, 3/5 grad/run, Formic Acid).

[001151] Formation of (7S)-7-(2-chloro-5-fluoropyrimidin-4-yIamino)-2- azaspiro[4.5]decan-3-one (62c)

To a solution of ethyl 2-((3 S)-3-(2-chloro-5-fluoropyrimidin-4-ylamino)-l-(nitiOmethyl)cyclohexyl)cthanoate, 62b, (1.60 g, 4.27 mmol) in MeOH (20 mL) was added Raney Nickel (0.03 g, 0.43 mmol). The reaction was shaken on a Parr apparatus at 40 psi of H2 overnight. The reaction was filtered, concentrated in vacuo and purified by silica gel chromatography (CH2Cl2:20% MeOH in CH2C12) to give 155 mg of 62c, LCMS-I-; 299.13 at 2.87 min (10-90% MeOH, 3/5 grad/run, Formic Acid).

[001152] Formation of (75)-7-(2-(5-chloro-l-tosyl-lZ/-pyrrolo[2,3-b]pyridin-3-yl)-5- fluoropyrimidin-4-ylamino)-2-azaspiro[4.5]decan-3-one (62d).

To a solution of 5-chloro-l-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine (0.083 g, 0.195 mmol) in acetonitrile (1.6 mL) was added (7S)-7-(2-chloro-5-fluoiOpyrimidin-4-ylamino)-2-azaspiro[4.5]dccan-3-onc (62c) (0.053 g, 0.177 mmol) and degassed under N2. Aqueous Na2C03 (0.266 mL of 2 M solution, 0.5320 mmol) was added followed by Pd(PPh3)4 (0.031 g, 0.027 mmol). The reaction was sealed and heated in a microwave at 120 °C for 30 min then concentrated in vacuo. The material was diluted in CH2C12 and silica gel chromatography using a gradient of Hexane$:EtOAc then 20% MeOH in CH2C12. Pure fractions were combined and concentrated to give 91 mg of 62d. LCMS+: 569.26 at 4.20 min (10-90% MeOH, 3/5 grad/run, Formic Acid).

[001153] Formation of (7S)-7-(2-(5-chloro-l/7-pyrrolo[2,3-b]pyridin-3-yl)-5- fhioropyrimidin-4-ylamino)-2-azaspiro[4.5]decan-3-one (969).

To a solution of (75)-7-(2-chloro-5-fIuoropyrimidin-4-ylamino)-2-azaspiro[4.5]decan-3-one, 62d, (0.091 g, 0.159 mmol) in MeOH (2 mL) was added NaOMe (2 mL of 25 %w/v, 9.255 mmol). The reaction was stirred for 0.5 hours then concentrated in vacuo. The material was purified by reverse phase HPLC (Water/HCkMeOH) to give a mixture of diastereomers. The fractions containing pure product were combined and concentrated to give 50 mg of the HC1 salt of 969.

General Scheme 63 N /)—NH _/==A · * J \ nu

M /)—NH Kv // NH cL" V« >"

Cl u 29b 63a 63b

\ />-NH CIN_ *'V~N

/-N Cl,^ y-N ci 4. x> 63c 63d N Jj 971

Ts [001154] Formation of ethyl 2-((15,35)-3-(2-chloro-5-fluoropyrimidin-4-ylamino)-1 -hydroxycyclohexyl)ethanoate (63a)

Zinc dust (1.61 g, 24.62 mmol) was heated with a heat gun under N2. THF (8.0 mL) was added, then a solution of chloro(trimethyI)silane (0.63 mL, 4.93 mmol) in THF (8.0 mL) was added and stirred for 15 min at room temperature then heated to reflux and cooled. A solution of ethyl 2-bromoacetate (2.73 mL, 24.62 mmol) in THF (6.0 mL) was added slowly to the zinc mixture, then a solution of (35)-3-[(2-chloro-5-fluoro-pyrimidin-4-yl)amino]cyclohexanone, 29b, (2.00 g, 8.21 mmol) in THF (6.0 mL) was added. The mixture was refluxed for 2 hours then concentrated in vacuo. EtOAc and aqueous saturated NaiTCOj solution were added and the product was extracted with additional EtOAc (3x), dried (Na2S04) and concentrated in vacuo. Purification by silica gel chromatography (Hexanes:EtOAc) separated 2 products. Fractions containing the second (minor) peak were combined and concentrated to give 470 mg of 63a. LCMS+: 332.13 at 3.2 min (10-90% MeOH, 3/5 grad/run, Formic Acid). |001155| Formation of (55, 75)-7-(2-chloro-5-fluoropyrimidin-4-ylamino)-l-oxa-3- azaspiro[4.5]decan-2-one (63b).

To a solution of ethyl 2-((15, 35)-3-(2-chloro-5-fluoropyrimidin-4-ylamino)-l-hydroxycyclohexyl)ethanoate, 63a, (0.40 g, 1.20 mmol) in dry MeOH (6 mL) was added hydrazine (0.75 mL, 23.4 mmol). The reaction was stirred overnight at room temperature then concentrated under a stream of No. The reaction was diluted with HCI (20 mL of a 1M solution, 20 mmol) until acidic and cooled to 0° - 5° C. Then NaN02 (1.44 mL of a 1M solution, 1.44 mmol) was added slowly. 1:1 Benzene:CHCL (20 mL) was added and the mixture was stirred. The organic layer was separated and added slowly to refluxing benzene. This was refluxed for 0.5h then concentrated. Silica gel chromatography (CH2C12:20% MeOH in CH2C12) gave 92 mg of pure product 63b. LCMS+: 301.15 at 2.76 min (10-90% MeOH, 3/5 grad/run, Formic Acid).

[001156] Formation of (55, 75)-7~(2-chIoro-5-fluoropyrimidin-4-ylamino)-3-methyl-l-oxa-3-azaspiro[4.5]decan-2-one (63c) A solution of (55, 95)-9-[(2-chloro-5-fluoro-pyrimidin-4-yl)amino]-l-oxa-3-azaspiro[4.5]decan-2-one, 63b, (0.049 g, 0.163 mmol) in DMF (8.2 mL) was cooled to 0 °C. NaH (0.010 mg, 0.244 mmol) was added followed by Mel (0.011 mL, 0.179 mmol). The reaction was allowed to warm to room temperature overnight. The reaction was quenched with water and concentrated in vacuo. Aqueous saturated NaHCCh solution was added and the product was extracted with EtOAc (3x), washed with brine, dried (Na2S04) and concentrated in vacuo. The material was purified using silica gel chromatography (CH2C12:20% MeOH in CH2C12) to give 63b. LCMS+: 315.19 at 2.83 min (10-90% MeOH, 3/5 grad/run, Formic Acid).

[001157] Formation of (5S,7S)-7-(2-(5-chloro-l-tosyl-lH-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)-3-methyl-l-oxa-3-azaspiro[4.5]decan-2-one (63d)

To a solution of 5-chloiO-l-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine (0.031 g, 0.0724 mmol) in acetonitrile (0.570 mL) was added (55, 7S)-7-(2-chloro-5-fluoropyrimidin-4-ylamino)-3-methyl-l-oxa-3- azaspiro[4.5]decan-2-one, 63c, (0.019 g, 0.060 mmol) and degassed under N2. Na2C03 (0.091 mL of 2 M, 0.1810 mmol) was added followed by Pd(PPh3)4 (0.010 g, 0.009 mmol). The reaction was sealed and heated in a microwave at 120 °C for 30 min. The mixture was then concentrated in vacuo. The material was diluted in CH2C12 and silica gel chromatography (Hexanes :EtOAc then 20% MeOH in CH2C12) gave product 63d. LCMS+: 585.25 at 4.17 min (10-90% MeOH, 3/5 grad/run, Formic Acid).

[001158J (5S,7S)-7-(2-(5-chloro-lH-pyrroIo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin- 4-ylamino)-3“methyl-l-oxa-3-azaspiro[4.5]decan-2-one (971)

To a solution of (SS) 7iS)-7-(2-(5-chloro-l-tosyl-lf7-pyrrolo[2,3-b]pyridm-3-yI)-5-fluoiOpyrimidin-4-ylamino)-3-methyI-] -oxa-3-azaspiro[4.5]dccan-2-one, 63d, (0.035 g, 0.060 mmol) in MeOH (2 mL) was added NaOMe (2 mL of 25 %w/v, 9.255 mmol). The mixture was stirred for 30 min then concentrated in vacuo and purified by reverse phase HPLC (Water/HChMeOH). Pure fractions were combined and concentrated in vacuo to afford product 971 as the HC1 salt.

Opnpral Srhimp 64

[001159] Formation of (35)-3-[[2-[5-chloro-l-(p-tolylsuIfonyl)pyrrolo[2,3-b]pyridin-3“yl]-5-fluoro-pyrimidin-4-yl]amino] cyclohexanone (64a) A microwave tube was placed 5-chloro-l-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl-lJ3J2-dioxaborolan-2-yl)pynOlo[2,3-b]pyridine (2.13 g, 4.93 mmol) and (3S)-3-[(2-chloro-5-fluoro-pyrimidin-4-yl)amino]cyclohexanone in DME (22.2 mL) and aqueous Na2C03 (5.13 mL of 2 M solution, 10.26 mmol) solution. The mixture was deoxygenated with nitrogen for 20 min. To the reaction mixture was added tetrakis triphenylphosphane palladium (0.47 g, 0.41 mmol). The reaction was sealed and heated to 120 °C for 30 min. The reaction was diluted with ethyl acetate (40 mL), filtered through Celite. The filtrate was washed with brine, dried (MgSCL), filtered and concentrated in vacuo. Purification via silica gel chromatography using 10-80% EtOAc/ hexanes gradient afforded (3iS)-3-[[2-[5-chloro-l-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-5-fluoro-pyrimidin-4-yl]amino]cyclohexanone, 64a.

[001160] Formation of (3S)-3-[[2-[5-chloro-l-(/;-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-5-fiuoro-pyrimidin-4-yl]ammo]-l-trimethylsilyloxy-cyclohexanecarbonitrile (64b)

To a solution of (3S)-3-[[2-[5-chloro-l-(p-tolylsuIfonyl)pyrrolo[2,3-b]pyridin-3-yl]-5-fluoro-pyrimidin-4-yl]amino]cycIohexanone, 64a, (0.58 g, 1.13 mmol) in CH2C12 (20 mL) was added diiodozinc (0.36 g, 1.13 mmol) and trimethylsilylformonitrile (0.30 mL, 2.26 mmol) at room temperature. The reaction was refluxed overnight. The mixture was purified by silica gel chromatography to afford 600 mg of (3iS)-3-[[2-[5-chloro-l-(p-toly lsulfony l)py rrolo [2,3 -b]py ridin-3 -y l]-5 -fluoro-py rimi din-4-y 1] amino]-1 -tri methy 1-silyloxy-cyclohexanecarbonitrile, 64b.

[001161] Formation of (151, 3^r)-3-[[2-(5-chloro-l/f-pyrrolo[2,3-bJpyridin-3-yl)-5-fluo ro-pyrimidin-4-y 1] amino]-l-hydroxy-cyclohexaneca rb oxylic a cid (64c) (3 S)-3 - [[2- [ 5-chl oro-1 -(p-tolylsulfony l)py rrolo[2,3 -b]py ridin-3-y l]-5 -fluoro-pyrimidin-4-yl]amino]-l-trimethylsilyloxy-cyclohexanecarbonitrile, 64b, (0.57 g, 0.93 mmol) was heated in HC1 (20 mL of 12 M solution, 240.0 mmol) at 80 °C in a sealed tube overnight. The solvent was evaporated and the crude product was purified by preparatory HPLC to provide 200 mg of (15, 3S)-3-[[2-(5-chloro-l//-pyrroIo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-yl]amino]- 1-hydroxy-cyclohexanecarboxylic acid, 64c. Ή NMR (300 MHz, MeOD) δ 8.70 (d, /= 2.2 Hz, 1H), 8.47 (s, 1H), 8.37 (d, /= 2.2 Hz, 1H), 8.28 (d, /= 5.5 Hz, 1H), 5.37 - 4.57 (m, 49H), 3.38 - 3.26 (m, 26H), 2.42 (dd,/ = 13.3, 4.2 Hz, 2H), 2.15 (d, /= 10.4 Hz, 1H), 2.07 - 1.87 (m, 3H), 1.77 (dd, /= 18.1, 8.6 Hz, 3H); LCMS: 406.35 (M+l).

[001162] Formation of (IS, 35)-3-( [2-(5-chloro-l//-pyrroIo[2,3-b]pyridm-3-yl)-5-fluoro-pyrimidin-4-y]]amino]"N-ethyl-l-hydroxy-cyclohexanecarboxamide (779) (IS, 3S)-3-[[2-(5-chloro-l//-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4- yl]amino]-l-hydroxy-cyciohexanecarboxylic acid, 64c, (0.040 g, 0.090 mmol) was dissolved in DMF (3 mL), then 'Pr2NEt (0.047 mL, 0.271 mmol) and ethanamine (0.135 mL of 2 M solution, 0.271 mmol) was added, followed by HATU (0.080 g, 0.210 mmol). The reaction was stirred at room temperature for another 2 hours. The solution was evaporated and the product was purified by Preparatory HPLC to afford 10 mg of (IS, 3S)-3-[[2-(5-chloro-17f-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-yl]amino]-lV-ethyl-l-hydroxy-cyclohexanecarboxamide, 779. 'H NMR (300 MHz, MeOD) d 8.72 (d, J = 2.2 Hz, 2H), 8.48 (s, 2H), 8.34 (dd,/ = 23.7, 3.9 Hz, 3H), 4.99 (d, /= 5.4 Hz, 3H), 4.88 (s, 1H), 4.85 - 4.67 (m, 32H), 3.44 - 2.95 (m, 4H), 2.29 (dd, J = 13.5, 4.1 Hz, 3H), 2.11 (d, /= 9.5 Hz, 2H), 2.04 - 1.80 (m, 7H), 1.76 (s, 3H), 1.13 (t, /= 7.2 Hz, 4H); LCMS: 433.42 (M+l).

General Scheme 65

[001163] Formation of 3-amino-2-hydroxy-cyclohexanecarboxylic acid (65a) 2-Hydroxy-3-nitro-benzoic acid (5.0 g, 27.3 mmol) was mixed with HC1 (125 mL of 0.5 M, 62.5 mmol) and dioxoplatinum (1.0 g, 4.4 mmol) in a hydrogenation bottle. The mixture was placed on a Parr shaker (50 psi H2) for 24 hours. The catalyst was filtered and washed with hot H20. The filtrate was evaporated to provide 3-amino-2-hydroxy-cyclohexanecarboxylic acid as a mixture of stereoisomers which was utilized to the next step without further purification.

[001164] Formation of 3-[[2-[5-chIoro-l-(p-tolylsulfonyI)pyrrolo[2,3-b]pyridin-3-yI]-5-fluoro-pyrimidm-4-yl]amino]-2-hydroxy-cycIohexanecarboxyIic acid (65b) 5-chloro-3-(5-fh.ioro-4-metliylsulfinyl-pyrimidin-2-yl)-l-(p-tolylsulfonyl)-pyrrolo[2,3-b]pyridine, 65a, (0.30 g, 0.64 mmol), 3-amino-2-hydroxy-cyclohexanecarboxylic acid (0.19 g, 0.97 mmol), lPr2NEt (0.45 mL, 2.58 mmol) in DMF (23.2 mL) solution was heated in microwave at 130 °C for 10 min. The solvent of the reaction mixture was removed under reduced pressure and the residue was purified by preparatory HPLC to give 240 mg of 3-[[2-[5-chloiO-l-(p~tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-5-fluoro-pyrimidin-4-yl] amino]-2-hydroxy-cyclohexanecarboxy lie acid, 65b, as a mixture of stereoisomers.

[001165] Formation of 3-[[2-[5~chloro-l-(p-toly]sulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-5“fluoro-pyrimidin-4-yl]amino]-A-cthyl-2-hydroxy-cyclohexanecarboxamide (65c) 3-[[2-[5-chloro-l-(p-toly]sulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-5-fluoro-pyrimidin-4-yl]amino]-2-hydroxy-cyclohexanecarboxylic acid, 65b, (0.100 g, 0.179 mmol) was dissolved in DMF (2 mL) and ‘Pr2NEt (0.124 mL, 0.714 mmol) and ethanamine hydrochloride (0.029 g, 0.357 mmol) was added at room temperature. Then HATU (0.081 g, 0.214 mmol) was added to die solution at room temperature. After 30 min, EtOAc was added and the mixture was washed with 1 N HC1, aqueous saturated NH4CI solution, and brine. The organic phase was dried over Na2S04, filtered and concentrated in vacuo. The crude product was used in the next step without further purification.

[001166] Formation of 3-[[2-(5-chloro-lH-pyrrolb[2,3-b]pyridm“3-yI)“5-fluoro-pyriimdin-4-yI]amino]-!V-ethyl-2-hydroxy-cydohexanecarboxamide (815) 3-[[2-[5-chloro-l-(p-tolylsulfonyl)pyiTolo[2,3-b]pyridin-3-yl]-5-fluoiO-pyrirnidin-4-yl]amino]-Ar-ethyl-2-hydroxy-cyclohexanecarboxamide, 65c, was treated with NaOMe in MeOH. The product was purified by preparatory HPLC to provide 3-[[2-(5-chloro-177-pyrrolo[2,3-b]pyridin-3-y])-5-fluoro-pyrimidin-4-yl]amino]-N-etliyl-2-hydroxy-cyclohexanecarboxamide as a mixture of stereoisomers. LCMS: 433.35 (M+l).

General Scheme 66

[001167] Formation of Methyi-l-methylcyclohex-2-ene-l-carboxylate (66a)

To a cold (0 °C) solution of freshly distilled jV-isopropylpropan-2-aminc (4.20 mL, 29.96 mmol) in THF (150 mL) under argon was added dropwise nBuLi (12.65 mL of 2.2 M solution, 27.82 mmol). After 15 min the solution was cooled to -78 °C and dry HMPA (4.84 mL, 27.82 mmol) was added. The mixture was stirred for 30 min at -78 °C and methyl cyclohexene-1-carboxylate (3.00 g, 21,40 mmol) was then added. After stirring an additional 10 min, methyl iodide (2.00 mL, 32.10 mmol) was added. The solution was then allowed to warm to -5 °C over 2 h. An aqueous saturated solution of NH4CI was poured into the orange mixture. After dilution with hexanes and washing with brine, the organic layer was dried over Na2SC»4 and carefully evaporated to 3.3 g of generate methyl l-methylcyclohex-2-ene-l-carboxylate, 66a, which was used without further purification. *H NMR (300 MHz, CDC13) δ 5.77 (dt, / = 10.1, 3.5 Hz, 1H), 5.66 (s, 1H), 3.71 -3.58 (m, 3H), 2.16 (ddd, /= 12.9, 7.0, 3.4 Hz, 1H), 2.03 - 1.88 (m, 2H), 1.72 - 1.53 (m, 2H), 1.49 - 1.37 (m, 1H), 1.32 - 1.14 (m, 3H).

[001168] Formation of racemic cis-methyl 5-methyl-7-oxabicyclo[4.1.0]heptane-5-carboxylate (66b)

Methyl l-methylcydohcx-2-ene-l-carboxylate, 66a, (3.30 g, 21.40 mmol) was treated with 3-chloroperoxybenzoic acid (7.39 g, 42.80 mmol) in CH2CI2 (75 mL) at room temperature for 2 hours. The solution was clear but white precipitate was observed after 1 hour. The resulting white solid was filtered and washed with hexanes, and the filtration was diluted with EtOAc and washed with aqueous saturated NaHC03 solution followed by brine. The organic phase was then dried over Na2S04, concentrated in vacuo and the crude residue was purified by silica gel chromatography (Hexanes/Ethyl acetate 100/0 to 10/1 gradient) to provide two products. The less polar spot is a colorless oil, which is assigned by 1H NMR to be cfr-methyl 5-methyl-7-oxabicyclo[4.1.0]heptane-5-carboxylate (1.2 g) and the second fraction is a white solid, which is iranx-methyl -5-methyl-7-oxabicycIo[4.1.0]heptane-5-carboxylate (2.2 g).

Racemic cis-isomer (66b): *H NMR (300 MHz, CDC13) δ 3.67 (d, / = 4.3 Hz, 3H), 3.23 - 3.12 (m, 1H), 3.08 (d, /= 3.8 Hz, 1H), 2.02 - 1.78 (m, 2H), 1.68 (dtd, /= 9.7, 6.8, 3.2 Hz, 1H), 1.49 - 1.27 (m, 2H), 1.25- 1.15 (m, 3H), 1.06 (ddd,/= 9.1, 7.4, 3.2 Hz, 1H).

[001169] Formation of racemic methyl-3-azido-2-hydroxy-l-methyl-cyclohexanecarboxylate (66c)

Racemic cfr-methyl-5-methyl-7-oxabicyclo[4.1.0]heptane-5-carboxylate, 66b, (2.2 g, 12.93 mmol) was added to a flask containing MeOH (90 mL) and H20 (10 mL) under nitrogen atmosphere. NH4CI (1.38 g, 0.90 mL, 25.86 mmol) and NaN3 (2.52 g, 38.79 mmol) were then added to the reaction mixture. The mixture was heated to reflux for 16 hours. The solvent was evaporated under reduced pressure and the oil was taken up in H20 and extracted with EtOAc. The combined organic phases were washed with brine and dried over Na2S04. The crude product was purified by silica gel chromatography to afford 900 mg of racemic methyl-3 -azido-2-hy droxy-1 -methy 1-cyclohexanecarb oxy late. lK NMR (300 MHz, CDC13) 5 3.74 (d, /=3.1 Hz, 3H), 3.64 - 3.43 (m, 2H), 3.25 - 3.05 (m, 1H), 2.25 - 2.09 (m, 1H), 2.00 (ddd, / = 9.7, 4.8, 2.9 Hz, 1H), 1.73 - 1.50 (m, 1H), 1.40 (d, J = 6.3 Hz, 3H), 1.32 - 1.03 (m, 3H).

[001170] Formation of racemic methyl-3-amino-2-hydroxy-l-methyI-cyclohexanecarboxylate (66d) A solution of racemic methyl-3-azido-2-hydroxy-l-methyl-cyclohexane-carboxylate, 66c, (0.90 g, 4.22 mmol) in a mixture of MeOH (50 mL) and AcOH (10 mL) was stirred under a hydrogen atmosphere (balloon) with the presence of palladium (0.50 g, 0.47 mmol) overnight at room temperature. The mixture was filtered through a celite bed and washed with MeOH. The combined filtrates were evaporated to provide methyl-3-amino-2-hydroxy-1-methyl-cyclohexanecarboxylate as a oil. Et20 was added and the resulted acetic acid salt was stirred for 0.5 hour and was then filtered to give 1.0 g of racemic methyl-3-amino-2-hydroxy-1-methy 1-cyclohexanecarboxylate acetic acid salt as a white solid.

[001171] Formation of racemic Methyl-3-[(2-chloro-5-fluoro-pyrimidin-4-yl)amino] -2-hydroxy- 1-methyl-cyclohexanecarboxylate (66e)

To a solution of 2,4-dichloro-5-fluoro-pyrimidine (0.43 g, 2.58 mmol) and racemic methyl-3-amino-2-hydroxy-l-methy 1-cyclohexanecarboxy late acetic acid salt, 66d, (0.58 g, 2.35 mmol) in THF (10 mL) and MeOH (8 mL) at room temperature was added ’Pr2NEt (1.23 mL, 7.04 mmol). After stirring the reaction overnight at room temperature, the solvent was evaporated under reduced pressure and the crude residue was purified by silica gel chromatography (Hexanes/EtOAc 100/0 to 0/100, Rf=0.7 in Hexanes/EtOAc 2/1) to provide 650 mg of racemic methyl-3-[(2-chloro-5-fluoro-pyrimidin-4-yl)amino]-2-hydroxy-l-methyl-cyclohexanecarboxylate, 66e, as a white solid. LCMS: 318.16 (M+l).

[001172] Formation of racemic MethyI-3-[[2-|5-chloro-l-(p-tolylsulfonyI)pyrrolo[2,3-b]pyridin-3-yl]-5-fluoro-pyrimidin-4-yl]amino]-2-hydroxy-l-methyl-cyclohexanecarboxylate (66f)

To a solution of racemic methyl-3-[(2-chloro-5-fluoro-pyrimidin-4-yl)amino]-2-hydroxy-1-methyl-cyclohexanecarboxylate, 6fie, (0.65 g, 2.05 mmol) and 5-chloro-l-(p-toIylsulfonyl)-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine (1.32 g, 3.05 mmol) in THF (20 mL) was added aqueous Na2C03 (3.52 mL of 2 M solution, 7.04 mmol). The solution was degassed with N2 for 20 minutes. Tetrakis triphenylphosphane palladium (0) (0.14 g, 0.12 mmol) was added and the mixture was refluxed overnight. LCMS showed good conversion, but some starting materials remained. More degassed 2 N Na2C03 was added followed by another portion of Tetrakis triphenylphosphane palladium (0.14 g, 0.12 mmol). The reaction was refluxed for another 4 hours. The mixture was cooled to room temperature, extracted with EtOAc. The organic phase was washed by brine and dried over Na2S04. After evaporation of solvent the crude mixture was purified by silica gel chromatography (Hexanes/EtOAc 100/0 to 0/100) to provide 1.0 g of racemic methyl-3-[[2-[5-chloro-l-(p-tolylsulfonyI)pyrrolo[2,3-b]pyridin-3-yl]-5-fluoro-pyrimidin-4-yl]amino]-2-hydroxy-1-methyl-cyclohexanecarboxylate, 66f. LCMS: 588.26 (M+l).

[001173] Formation of (15,25, 35)-3-] I2-(5-chloro-l//-pyrrolo [2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-yl] amino]-2-hydroxy-l-methyl-cyclohexanecarboxylic acid (928)

Racemic methyl-3-[[2-[5-chIoro-l-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridm-3-y]]-5-fluoro-pyrimidin-4-yl]amino]-2-hydroxy-l-methyl-cyclohexanecarboxylate, 66f, (0.100 g, 0.170 mmol) was dissolved in MeOH (1 mL) and THF (1 mL) and treated with aqueous LiOH (0.24 mL of 1 M solution, 0.24 mmol) and the reaction was heated to reflux overnight. The reaction was cooled to room temperature and the resulting material directly purified by preparatory HPLC to afford 20 mg of racemic 3-[[2-(5-chloro-lHr-pyriOlo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-yl]amino]-2-hydroxy-l-methyl-cyclohexanecarboxylic acid. The enantiomers of the racemic material were separated by chiral SFC purification to afford 6 mg of (1R, 2 R, 3R)-3-[[2-(5-chIoro-17i-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4- yl]amino]-2-hydroxy-l-methyl-cyclohexanecarboxylic acid and 6 mg of (15, 25, 35)-3-[[2-(5-chloro-l/7-pyrrolo[2,3-b]pyridin-3-yl)-5-fIuoro-pyrimidin-4-yl]amino]-2-hydroxy-l-methyl-cyclohexanecarboxylic acid. LCMS: 420.36 (M+l).

(a) Pd/C (wet, Degussa), hydrogen, EtOH (b) 2,4-dichloro-5-fluoropyrimidine, 'Pr2NEt, THF, reflux (c) LiOI-I, TUF/water, 50°C (d) DPPA, Et3N, THF, 85 °C (e) 5-fluoro-3-(4,4,5,5-tetramet!iyl-!,3,2-dioxaborolan-2-yl)4-tosyl-l//-pyrrolo[2,3-/>]pyridine, XPhos, Pd2(dba)3, K3P04,2-niethylTHF, water, 125 nC (f)

Formation (1J?, 3£)-ethyl 3-aminocyclohexanecarboxylate (67b)

To a solution of (IR, 3S)-ethyl 3-(benzyloxycarbonylamino)cycIoliexane-carboxylate, X8b, (14.0 g, 45.9 mmol) in ethanol (3 mL) was added Pd/C (wet, Degussa (2.4 g, 2.3 mmol). The mixture was evacuated and then stirred under atmosphere of nitrogen at room temperature overnight. The reaction mixture was filtered through a pad of celite and the resulting filtrate concentrated in vacuo to provide an oil that was used without further purification.

Formation (1.R, 3iS)-ethyl 3-(2-chloro-5“fluoropyrimidin-4-ylamino)cyclohexane-carboxylate (67c)

To a solution of (1/i, 3S>ethyl 3-aminocyclohexanecarboxylate, 67b, (5.1 g, 24.1 mmol) and 2,4-dichloro-5,-fluoiOpyrimidine (6.0 g, 36.0 mmol) in THF (60 mL) was added diisopropylcthylaminc (9.6 mL, 55.4 mmol). The mixture was heated to reflux overnight. The reaction was cooled to room temperature and concentrated in vacuo. The residue was diluted with water and extracted twice with ethyl acetate. The combined organic phases were dried (MgS04), filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (0-40% EtOAc/hexanes gradient) to provide 6.7 g of (\ R, 35>ethyl 3-(2-chloro-5-fluoropyrimidin-4-ylamino)cyclohexane-carboxylate as a white solid: LCMS R.T = 3.1 (M+H) 302.2.

Formation (1 if, 3S)-3-(2-chloro-5-fluoropyrimidin-4-ylamino)cyclohexanecarboxylic acid (67d)

To a solution of (LR, 35>ethyl 3-(2-chloro-5-fluoropyrimidin-4- ylamino)cyclohexane-carboxylate, 67c, (20.0 g, 66.3 mmol) in THF (150 mL) was added added a solution of LiOH hydrate (8.3 g, 198.8 mmol) in 100ml water. The reaction mixture was stirred at 50 °C overnight, To the reaction mixture was added HC1 (16.6 mL of 12 M solution, 198.8 mmol) and EtOAc. The organic phase was washed with brine and dried over MgSC>4 and the solvent was removed under reduced pressure to afford 17.5 g of product that was used without further purification: lH NMR (300 MHz, CDC13) δ 7.91 (d, J= 2.7 Hz, 2H), 5.24 (d, / = 7.3 Hz, 2H), 4.19 - 4.03 (m, 3H), 3.84 - 3.68 (m, 3H), 2.59 (ddd, / = 11.5, 8.2, 3.6 Hz, 2H), 2.38 (d, / = 12.4 Hz, 2H), 2.08 (d, / = 9.6 Hz, 6H), 1.99 - 1.76 (m, 5H), 1.63 - 1.34 (m, 6H), 1.32-1.15 (m, 4H). F or mation iV-((L/?, 35)-3-(2-chIo ro-5-fluoropy rim idin-4-ylamino)cyclohexy 1)- pyrrolidine-l-carboxamide (67e) A solution of (17Ϊ, 35)-3-(2-chIoro-5-fluoropyrimidin-4-ylamino)cycIohexane-carboxylic acid, 67d, (8.2 g, 30.0 mmol), (azido(phenoxy)phosphoryl)oxybenzene (9.7 mL, 45.0 mmol) and triethylamine (5.8 mL, 42.0 mmol) in THF (200 mL) was degassed under nitrogen for 15 minutes. The reaction mixture was heated at 85 °C for 30 minutes until LC/MS indicated complete consumption of carboxylic acid, 67d. To the reaction mixture was added pyrrolidine (7.5 mL, 90.0 mmol) and the reaction was heated at 85 °C for an additional 15 min. The mixture was diluted into brine and extracted with EtOAc, The organic phase was separated, dried over MgSCL. The product was isolated (6.25 g) by filtration after partial removal of solvent in vacuo: EH NMR (300 MHz, CDC13) δ 7.87 (d, / = 2.8 Hz, 2H), 5.04 (d, / = 8.1 Hz, 2H), 4.09 (ddd, / = 26.9, 13.4, 5.6 Hz, 4H), 3.91 - 3.71 (m, 2H), 3.32 (t, 7-6.5 Hz, 7H), 2.45 (d, / = 11.5 Hz, 2H), 2.08 (dd, /= 22.1, 12.0 Hz, 4H), I. 96- 1.82 (m, 9H), 1.54 (dd, /= 18.6, 8.5 Hz, 2H), 1.22 - 1.01 (m, 6H).

Formation N-((IR, 3 5)-3-(5-f)uoro-2-(5-iluoro-l-tosyl-l//“pyrrolo[2,3-b]pyridin-3- yl)pyrimidin-4-ylamino)cyclohexyl)pyrrolidine-l-carboxamide (671) A solution of N-((1R, 35)-3-(2-chloro-5-fluoropyrimidin-4-ylamino)cyclohexyl)-pyrrolidine-l-carboxamide, 67e, ¢6.8 g, 20.0 mmol), 5-fluoro-l-(p-tolylsulfonyI)-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pynOlo[2,3-b]pyridine, 44a, (12.5 g, 30.0 mmol) and K3PO4 (17.0 g, 80.0 mmol) in 2-methyl THF (180 mL) and water (20 mL) was degassed under nitrogen for 30 min. To the mixture was added dicyclohexyl-[2-(2,4,6-triisopropylphenyI)phenyl]phosphane (XPhos) (1.1 g, 2.4 mmol) and Pd2(dba)3 (0.5 g, 0.5 mmol). The reaction mixture was heated in a pressure bottle at 125 °C for 2.5 hr. The reaction mixture was filtered through celitc, the solvent was removed under reduced pressure. The resulting residue was purified by silica gel chromatography (8%MeOH/CH2Cl2) to afford II. 5 g of the desired product: JH NMR ¢300 MHz, CDC13) 5 8.54 (s, 1H), 8.49 (dd, / = 9.0, 2.8 Hz, 1H), 8.32 (d,/=2.1 Hz, 1H), 8.13 (d,/= 8.3 Hz, 2H), 8.07 (d,/= 3.2 Hz, 1H), 7.30 (d, / = 8.5 Hz, 2H), 4.98 (d, /= 6.3 Hz, 1H), 4.37 - 4.16 (m, 1H), 4.08 (d, / = 7.3 Hz, 1H), 3.99-3.80 (m, 1H), 3.33 (t,/= 6.5 Hz, 4H), 2.52 (d, /= 11.6 Hz, 1H), 2.39 (s, 3H), 2.29 (d, /=11.3 Hz, 1H), 2.12 (d,/= 11.1 Hz, 1H), 1.99-1.81 (m, 5H), 1.70- 1.55 (m, 1H), 1.22 1.08 (m, 2H).

Formation iV-((l R, 35)-3-(5-fluoro-2-(5-fluoro-lii-pyrrolo[2,3-b]pyridin-3-yl)- pyrimidin-4-yIamino)cyclohexyl)pyrrolidine-l-carboxamide (895) A solution of N-((IR, 35)-3-(5-fluoro-2-(5-fluoro-l-tosyl-iZf-pyrrolo[2,3-b]pyridin-3-yI)pyrimidin-4-ylamino)cyclohexyl)pyrrolidine-l-carboxamide, 67f, (11.5 g, 19.3 mmol) in THF (150 mL) was added sodium methoxide (4.173 g, 19.31 mmol). After stirring the reaction mixture for 2 minutes, the mixture was poured into an aqueous saturated solution of NaHCOi. The organic phase was washed with brine, dried over MgSC>4 and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel chromatography (lO/fiMeOH/CTLCb) to afford 6.5g of the desired product. The product was converted to an HC1 salt by dissolving in MeOH (100 mL) and adding 2.4 mL of 12M HC1 solution at room temperature. The solution was stirred at for Ihour and the HC1 salt precipitated out and filtered to provide 7.05g of the HC1 salt: 1H NMR (300 MHz, DMSO) δ 9.36 (s, 2H), 9.05 (d, /= 3.0 Hz, 2H), 8.49 (d, /= 5.6 Hz, 2H), 8.41 (dd, /= 2.6, 1.4 Hz, 2H), 8.31 (d, J= 9.5 Hz, 2H), 5.92 (s, 3H), 4.24 (s, 3H), 3.64 (s, 2H), 3.18 (t, J= 6.6 Hz, 7H), 2.07 (dt, J = 22.7, 11.5 Hz, 4H), 1.87 (t,i= 12.6 Hz, 4H), 1.77 (dd, J = 8.0, 5.3 Hz, 7H), 1.65 - 1.13 (m,8H).

General Scheme 68

(a) TsCl, NaH, DMF, 45 °C (h) methyl iodide, K2C03, DMF (c) bromine, CHC13,0 °C to rt (d) bis(pinacol)dibor»ne, palladium (II) diehloro bis(lricyclohexylphosphane), KOAc, 2-methylTHF, 125 °C (e) (R)-N-((IR, 3iS)-3-((2-chloro-5-fluoropyrimidin-4-yl)amino)cyclohexyI)-3-fluoropyrrolidine-l-carboxamide, XPhoa, Pd2(dba)3l K3PO4, 2-methylTHF, water, 125 °C

Formation of 5-fluoro-l-tosyH//“pyrrolo[2,3-ijpyridin-4-ol (68a)

To a solution of 5-fluoro-l//-pyrrolo[2,3-b]pyridin-4-oI (1.2 g, 7.9 mmol) in 80 mL DMF at 0 °C was added toluenesulfonyl chloride (1.8 g, 9.5 mmol) followed by NaH (0.8 g, 19.7 mmol, 60% w/w). The reaction was slowly warmed to 45 °C after 3 hours and stirred for an additional 3 hours. The mixture was then concentrated in vacuo. The crude oil was dissolved in 100 mL EtOAc and washed with water (2x50 mL) and brine. The organic phase was dried over sodium sulfate and concentrated in vacuo. The resulting residue was purified via silica gel chromatography (10% EtOAc/Hexanes) to afford 1.5 g of the desired product.

Formation of 5-fluoro-4-methoxy-l-tosyl-l//-pyrrolo|2,3-6|pyridine (68b)

To a solution of 5-fluoro-l-tosyl-l/i-pyrrolo[2,3“i>]pyridin-4-ol, 68a, (0.70 g, 2.29 mmol) in DMF (25 mL) was added methyl iodide (0.14 mL, 2.29 mmol) and K2CO3 (0.32 g, 2.29 mmol). The reaction mixture was stirred for 3 hours at ambient temperature, The reaction was diluted with deionized water and EtOAc. The organic phase was washed with brine, dried over sodium sulfate and concentrated in vacuo to afford 720 mg of the desired product that was used in next step without further purification.

Formation of 5-fluoro-4-methoxy-3-bromo-1-tosyl-lif-pyrrolo[2,3-/j]pyridine (68c)

To a cold (0 °C) solution of 5-fluoro-4-mctlioxy-l-tosyl-l/7-pyriOlo[2,3-6]pyridine, 68b, (0.79 g, 2.45 mmol) in chloroform (50 mL) was added bromine (0.13 mL, 2.45 mmol). The reaction mixture was stirred at 0 °C for 3 hours and then slowly warmed to ambient temperature. The mixture was diluted with deionized water and quenched with aqueous sodium bicarbonate. The aqueous phase was extracted with methylene chloride and dried over sodium sulfate. The resulting solid was purified via silica gel chromatography (15-30% EtOAc/Hexanes) to give 170 mg of the desired product.

Formation of 5-fluoro-4-methoxy-3-(4,4,5:i5-tetramethyH,3,2-dioxaboroian-2-yl)-l-tosyl-l//-pyrroloI2,3-6jpyridine (68d)

To a solution of 5-fluoro-4-methoxy-3-bromo-l-tosyl-l£r-pyiTolo[2,3-Z>]pyridine, 68c, (0.17 g, 0.43 mmol) in 2-Me-THF (9 mL) in a microwave vial was added bis(pinacol)diborane (0.16 g, 0.64 mmol), followed by potassium acetate (0,23 g, 1.06 mmol) and palladium (II) dichloro bis(tricyclohexylphosphane) (0.02 g, 0.02 mmol). Reaction vial was sealed and irradiated with microwaves at 125 °C for 90 minutes. The mixture was filtered and purified via silica gel chromatography (10-30% EtOAc/Hexanes) to afford 100 mg of the desired product.

Formation of (R)-3-fluorowV-((1 R, 3,S)-3-((5-fluoro-2-(5“fluoro-4-methoxy-l//- pyrroIo[2,3-/>]pyridin-3-yl)pynmidin-4-y])amino)cyclohexyI)pyrrolidine-l-carboxaniide (1104):

To a solution of 5-fluoro-4-methoxy-3-(4,4,5,5-tctramcthyl-l,3,2-dioxaborolan-2-yl)-l-tosyl-l#-pyrrolo[2,3-6]pyridine, 68d, (0.100 g, 0.220 mmol) in 2-Me-THF (2 mL) was added (R)-N-((\R. 3<S)-3-((2-chloro-5-fluoropyrimidin-4-yl)amino)cyclohexyl)-3-fluoropyrrolidine-1-carboxamide (0.060 g, 0.170 mmol). Potassium phosphate (0.130 g, 0.600 mmol) and deionized water (0.5 mL) were then added and solution was degassed under a flow of nitrogen for 10 minutes. 2-Dicyclohexylphosphino-2’,4’,6’-triisopropylbiphenyI (XPhos) (0.006 g, 0.012 mmol) and tris(dibenzylideneacetone)-dipalladium (0) (0.023 mg, 0.026 mmol) were then added and solution was again degassed under flow of nitrogen for 5 minutes. Vial was sealed and heated to 80 °C for 3 hours. Solution cooled to ambient temperature and was filtered and concentrated in vacuo. The crude oil was redissolved in anhydrous THF (5 mL) and a solution of 2N LiOH (2 mL) was added. The reaction mixture was heated to 80 °C for 2 hours. Solution was cooled to ambient temperature and concentrated in vacuo. Purification by preparative HPLC afforded 6 mg of the desired product.

General Scheme 69

(a) NaCN, LiCKh, CILCN (b) 5-fluoro-l-(p-tolylsulfonyI)-3-(4,4,5)5-tetramethyl-l,3,2-dioxaborolan-2-yI)pyrrolo[2,3-b]pyridine, Na2C03, Pd(PPh3)4, dimethoxyethane,! 20 °C (c) sodium methoxide, MeOH

Formation of 2-((15, 35)-3-(2-chloro-5-fluoropyrimidin-4-ylammo)-l-hydroxy-cyc!ohexyl)-ethanenitrile (69a) A suspension of 2-chloro-5-fluoro-N-[(35)-l-oxaspiro[2.5]octan-7-yl]pyrimidin-4-amine, 49c, (0.50 g, 1.94 mmol), NaCN (0.11 g, 2.33 mmol) and lithium perchlorate (0.25 g, 2.33 mmol) in CH3CN was heated at 100 °C in a pressure tube for 3h. The mixture was diluted into EtOAc and the organic phase was washed with aqueous saturated Nal-ICCb solution, dried with MgSC>4, filtered and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel chromatography (EtOAc/hexanes) afforded the desired product: ltt NMR (300.0 MHz, CDC13) 6 7.78 (d, /= 2.7 Hz, 1H), 4.85 (d, / = 6.6 Hz, 1H), 4.28 (qn, / = 4.0 Hz, 1H), 2.45 (s, 2H), 2.16 (d, /= 13.0 Hz, 1H), 2.05 (d, / = 11.7 Hz, 1H), 1.80 - 1.71 (ra, 3H), 1.46 - 1.28 (m, 2H) and 1.17 - 1.06 (m, 1H) ppm; LCMS RT = 2.15 (M+H) 285.34.

Formation of 2-((15, 35)-3-(5-fluoro-2-(S-fluora-l-tosyl-l//-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)-l-hydroxycyclohexyl)ethanenitrile (69b) A solution of 5-fluoro-l-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl-l,3,2-dioxaboroIan-2-yl)pyrrolo[2,3-b]pyridine, 44a, (0.23 g, 0.55 mmol), 2-((15, 35)-3-(2-chloro-5-fluoropyrimidin-4-ylamino)-l-hydroxycycIohexyl)-ethanenitrile, 69a, (0.14 g, 0.50 mmol) and Na2C03 (0.75 mL of 2M solution, 1.50 mmol) in dimethoxyethane (15 mL) was degassed with nitrogen for 30 min. To the reaction mixture was added palladium; triphenylphosphane (0.03 g, 0.03 mmol) and continued to degas the solution for 15 min. The reaction mixture was heated at 120 °C in a pressure tube for 45 min. The reaction mixture was filtered through celite and the filtrate was removed under reduced pressure. The resulting residue was purified by silica gel chromatography (40%EtOAc/Hexanes) to afford 150 mg of desired product: LCMS RT = 3.55 (M+H) 539.42. 2- ((15, 35)-3-(5-fluoro-2“(5-fluoro-l//-pyrrolo[2,3-b]pyridm-3-yl)pyrimidin-4-ylamino)- l-hydroxycyclohexyl)ethanenitrile (979)

To a solution of 2-((15, 35)-3-(5-fluoro-2-(5-fluoro-l-tosyl-l//-pyrrolo[2,3-b]pyridin- 3- yl)pyrimidin-4-ylamino)-l-hydroxycyclohexyl)ethanenitrile, 69b,(0.14 g, 0.26 mmol) in methanol (10 mL) was added sodium methoxide (0.06 g, 0.26 mmol). After stirring at room temperature for 2 minutes, the reaction mixture was diluted into EtOAc and brine. The separated organic phase was dried over MgSO,», filtered, and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (10%MeOH/CH2Cl2) to afford 46 mg of desired product: lH NMR (300.0 MHz, MeOD) δ 8.65 (dd, /= 2.8, 9.6 Hz, 1H), 8.19 (s, 1H), 8.14 (dd, / = 2.0,2.5 Hz, 1H), 7.98 (d, /=4.1 Hz, 1H), 4.66 (dd, /= 8.0, 15.8 Hz, 1H), 2.64 (s, 2H), 2.20 (d, /= 12.6 Hz, 2H), 2.01 (dd, /= 3.4, 9.8 Hz, 2H), 1.84 - 1.75 (m, 1H), 1.63 - 1.47 (m, 2H), 1.33 (dd, J = 3.6,12.4 Hz, 1H) ppm; LCMS RT = 2.31 (M+H) 385.45.

(a) ten-butyl W-(iV-tert-butoxycarbonyl-C-pyrazol-l-yl-carbonimidoyl)carbamate, CH1CI2 (b) 5-fluoro-i-(p-toly]sulfbnyl)-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrroIo[2,3-b]pyridine, Na2C03, Pd(PPh3)4, dimethoxyethane, 120 °C (c) sodium methoxide, THF, MeOH

Formation of teri-butyl (tei'i-butoxycarbony!amino)((lJ?, 35)-3-(2-chIoro-5- fluoropyrimidin-4-y]amino)cyclohexylamino)methylenecarbamate (70b)

To a solution of (IS1, 37?)-7/l-(2-chloro-5-fluoro-pyrimidin-4-yl)cyclohexane-l,3-diamine, 70a, (0.122 g, 0.500 mmol) in CH2CI2 (10 mL) was added ie/t-butyl N-(N-tert-butoxycarbonyl-C-pyrazol-l-yl-carbonimidoyl)carbamate (0.155 g, 0.500 mmol). The reaction mixture was stirred at room temperature for 2 days. The reaction mixture was concentrated in vacuo and used without further purification: 'l-l NMR (300 MHz, CDC13) 5 11.51 (s, 3H), 8.29 (d, / = 8.3 Hz, 3H), 7.88 (d, / = 2.8 Hz, 3H), 5.01 (d, / = 7.4 Hz, 3H), 4.28 - 4.18 (m, 4H), 2.48 (d,/ = 11.7 Hz, 3H), 2.12 (d,/= 9.4 Hz, 3H), 1.87 (dd,/= 10.3, 3.5 Hz, 3H), 1.52 (s, 24H), 1.50 (s, 25H), 1,24 - 1.10 (m, 8H); LCMS RT = 3.97 (M+H) 487.12.

Formation of 7ej/-butyl /V-bV-[(17?, 3S)-3-[[5-fluoro-2-[5-fluoro-l-(p-tolylsulfonyl)-py r rolo [2,3-b ] py ridin-3-yl] pyrimidin-4-yl] amino] cyclohexyl] carb amimidoylj-carbam ate (70c)

Degassed a solution of (Z)-tm-butyl (/erz-butoxycarbonylamino) ((17?, 35)-3-(2-chloiO-5-fluoiOpyrimidin-4-ylamino)cycIohexylamino) methylenecarbamate, 70b, (0.200 g, 0.411 mmol), 5-fluoro-l-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine, 44a, (0.205 g, 0.493 mmol) and Na2COj (0.616 mL of 2M solution, 1.232 mmol) in dimethoxyethane (15 mL) for 30 min. To the mixture was added palladium triphenylphosphane (0.023 g, 0.021 mmol) and the reaction mixture was heated in a pressure tube at 120 °C for 45 rain. The reaction mixture was filtered through a pad of celite and the filtrate concentrated in vacuo. Attempted purification of the resulting residue by silica gel chromatography (10% MeOH/CHaClj) yielded a mixture containing mostly desired product that was used without further purification: LCMS RT = 2.30 (M+H) 641.02.

Formation of 1-((1J?, 35)-3-(5-fluoro-2-(5-fluoro-l//-pyrrolo [2,3-b] pyridin-3- yI)pyrimidin-4-ylamino)cyclohexyl)guanidine (1143)

To a solution of /c/Y-butyl 7/-(7/-((172, 35)-3-((5-fluoro-2-(5-fluoro-1-()7- tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]pyrimidin-4-yl]amino]cyclohexyl] carbamimidoyl]carbamate, 70c, (0,100 g, 0.156 mmol) in THF (20 mL) was added sodium methoxide (0.033 g, 0.156 mmol) at room temperature. After 1 minute, the reaction mixture was diluted into EtOAc and aqueous saturated NaHCOi solution. The organic phase was dried over MgS04, filtered and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel chromatography to afford 95mg of the desired product. To 10 ml MeOH solution of the product was added hydrochloride/IPA (0.031 mL of 5 M solution, 0.156 mmol). The reaction mixture was stirred at room temperature for 1 hour after which the solvent was removed under reduced pressure to afford the product, as hydrochloride salt: !H NMR (300 MHz, MeOD) δ 8.63 (s, 1H), 8.40 (dd, /= 9.1, 2.7 Hz, 1H), 8.36 (s, 1H), 8.32 (d, .7= 5.5 Hz, 1H), 4.46 (d, /= 11.7 Hz, 1H), 3.78 - 3.53 (m, 1H), 2.41 (d, 1=11.7 Hz, 1H), 2.28 (d,/= 12.0 Hz, 1H), 2.18-1.98 (m, 2H), 1.69 (dd,/= 23.6, 11.8 Hz, 2H), 1.56 - 1.28 (m, 2H); LCMS RT = 1.45 (M+H) 387.06.

General Scheme 71

(a) DBU, methyl 2-chlorooxazole-4-carboxylate, DMF, 75 °C (b) LiOH, THF

Formation of methyl 2-((lR, 3S)-3-(5-fluoro-2-(5-fluoro-l-tosyI-l/T-pyrrolo[2,3“ b]pyridin-3~yl)pyrimidin-4-ylamino)cyclohexylamino)oxazoIe-4-carboxylate (71a)

To a solution of (IS, 3Λ)-ΛΠ-[5-fluoro-2-[5-fluoro-1 -(/>tolylsulfonyl)pyriOlo[2,3-b]pyridin-3-yl]pyrimidin-4-yl]cyclohexane- 1,3-diamine, 44e, (0.089 g, 0.178 mmol) in DMF (1.5 mL) was added methyl 2-chlorooxazole-4-carboxylate (0.031 g, 0.195 mmol), followed by DBU (0.029 mL, 0.195 mmol). The reaction mixture was allowed to stir at room temperature overnight. The reaction was warmed to 75 °C and allowed to stir for 3 hours. Added an additional 16 mg of the chlorooxazole ester and the reaction was heated at 75 °C overnight. The mixture was diluted into water and EtOAc. The layers were separated and the organic phase was washed with brine, dried over MgSO.i, filtered and evaporated to dryness. The crude residue was purified by silica gel chromatography (0-20%MeOH/CH2Cl2) to afford 28 mg of desired product: LCMS RT = 3.73 (M+l) 624.12.

Formation of 2-((XR, 3S)-3-(5-fluoro-2-(5-fluoro-l//-pyrrolo[2,3-b]pyridin-3-y!)pynmidin-4-ylamino)cyclohexylamino)oxazole-4-carboxylic acid (1144)

To a solution of methyl 2-[[(lR, 35>3-[[5-fluoro-2-[5-fluoro-l-(p-tolylsulfonyI)-pyrrolo[2,3-b]pyridin-3-yl]pyrimidin-4-yl]amino]cyclohexyl]-amino]oxazole-4-carboxyIate, 71a, (0.028 g, 0.045 mmol) in THF (1 mL) was added LiOH (1 mL of 1 M solution, 1.000 mmol) and the reaction mixture was warmed to 130 °C via microwave irradiation. After heating and stirring for 20 minutes, the mixture was cooled to room temperature. All volatiles were removed under a stream of nitrogen and heat. The ciude residue was suspended in MeOH and a few drops of trifluoroacetic acid were added to protonate molecule (solution occurs). The mixture was filtered and purified by reverse phase HPLC (5-95% CH3CN/H2O) to afford 5 mg of the desired product as a TFA salt: 'H NMR (300 MHz,

MeOD) δ 8.83 (s, 1H), 8.67 - 8.09 (m, 4H), 2.67 (s, 3H), 2.18 (m, 5H), 1.34 (d, J= 29.6 Hz, 3H); LCMS RT = 1.78 (M+l) 456.07.

General Scheme 72

(a) NaHCOj, Br2, H20 (b) NaOH (c) TMSC1, MeOH (d) sodium methoxide, MeOH, 150 °C (e) sodium borohydride, MeOH (f) ethyl 2-(/ert-butoxycarbonylamino)-2-oxo-acetate, DEAD, PPh3, 85 °C (g) NaOH, MeOH (h) trifluoroacetic acid, CH2C12, IN HCl/ether (i) 5-fluoro-3-(5-fluoro-4-(methy]suIfinyl)pyrimidiii-2-yl)-l-tosyl-lI-I-pyiToio[2,3-b]pyridine, 'Pr-NEt, THF (j) lithium hydroxide, THF (k) DPPA, Et3N, pyrrolidine

Formation of 6-bromohexahydro-2H-3,5“methanocyclopenta[b]furan-2-one (72a)

To a solution of bicyclo[2.2,l]hept-5-ene-3-carboxylic acid (25.0 mL, 204.3 mmol) in NaHC03 (51.5 g, 612.9 mmol) in water was added bromine (32.7 g, 204.3 mmol) dropwise at 0 °C, The solution was stirred for 1 hour and extracted with ether, and the organic phase was washed successively with 1 N Na2S2S03 solution and brine, and the organic phase was then dried (Na2SC>4), filtered and concentrated in vacuo to afford 30 g of crude product that was used without further purification.

Formation of 6-oxonorbornane-2-carboxylic acid (72b) 6-bromohexahydro-2/f-3,5-methanocycIopenta[b]furan-2“One, 72a, (28.0 g, 129.0 mmol) was treated with NaOH (258.0 mL of 2 M solution, 516.0 mmol) in H20 (350 mL) for 2 hour at room temperature. The reaction mixture was acidified with cone. HC1, extracted with Et20. The organic phase was dried (Na2S04), filtered and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (0-20% MeOH/CH2Cl2 gradient) to provide 16 g of 6-oxonorbomane-2-carboxylic acid.

Formation of Endo methyl 6-oxonorbornane-2-carboxylate (72c) A solution of 6-oxonorbomane-2-carboxylic acid, 72b, (16.0 g, 103.8 mmol) in methanol (350.0 mL) was treated with TMSC1 (42.04 g, 49.11 mL, 387.0 mmol). The reaction mixture was stirred at room temperature overnight. Solvent was evaporated under reduced pressure and the crude product was purified by silica gel chromatography (10% EtOAc/hexanes) to provide 12 g of Endo methyl 6-oxonorbornane-2-carboxylate,

Formation of Exo methyl 6-oxonorbornane-2-carboxylate (72d)

Endo methyl 6-oxonorbornane-2-carboxylate, 72c, (3.5 g, 20,8 mmol) was heated in a sealed tube in sodium methoxide (2.1 mL of 2 M solution in methanol, 4.2 mmol) at 150 °C for 17 hours. The solvent was evaporated and the crude product was purified by silica gel chromatography (0-16% EtOAc/hexanes gradient) to afford 3.3 g of starting endo methyl 6-oxonorbomane-2-carboxylate as the first fraction (PMA staining) and 4.0 g of the desired exo product as the second spot. The recovered starting material was treated with the same conditions again to generate another 1.0 g desired exo-product.

Formation of methyl 6-hydroxynorbornane-2-carboxylate (72e)

To a solution of exo methyl 6-oxonorbornane-2-carboxylate, 72d, (4.7 g, 27.9 mmol) in MeOH (50 mL) was added sodium borohydride (1.6 g, 41.9 mmol) in five portions at 0 °C. TLC showed completed conversion after 2 hours. Aqueous saturated NH4CI solution was added to quench the reaction. The MeOH was evaporated under reduced pressure and then the aqueous phase was extracted with EtOAc. The combined organic phases were washed with brine, dried over Na2S04, filtered and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (0-100% EtOAc/hexanes, Rf = 0.5 in 50% EtOAc/hexanes) to afford 3.96 g of the desired product: 'H NMR (300 MHz, CDCI3) δ 4.23 - 4.06 (m, 1H), 3.56 (s, 3H), 3.37 (s, 1H), 3.03 (dd, /= 8.9, 5.5 Hz, 1H), 2.41 (d, /= 3.9 Hz, 1H), 2.13 (s, 1H), 1.93 - 1.69 (m, 2H), 1.63 - 1.42 (m, 1H), 1.34 (ddt, / = 10.3, 3.2, 1.6 Hz, IH), 1.20 (dd, J = 10.4, 0.7 Hz, 1H), 0.77 (dt, /= 12.6, 3.4 Hz, 1H).

Formation of methyl 6-(-A-(/ert-butoxycarbonyl)-2-ethoxy-2-oxoacetamido)bicycle [2.2.1] heptane-2-carboxylate (72f)

To a cold (0 °C) solution of methyl 6-hydroxynorbornane-2-carboxylate, 72e, (3.2 g, 18.8 mmol) in THF (150 mL) was added ethyl 2-(te/-f-butoxycarbonylamino)-2-oxo-acetate (4.9 g, 22.6 mmol) and triphenylphosphine (5.9 g, 22.6 mmol) followed by dropwise addition of diisopropyl azodicarboxylate (4.5 g, 22.6 mmol). The reaction was then heated to 85 °C and maintained at that temperature for 2 days. The solvent was evaporated under reduced pressure and the crude product was purified by silica gel chromatography (0-100% EtOAc/hexanes gradient) to provide 6 g of methyl 6-(Ar-(tert-butoxycarbonyl)-2-ethoxy-2-oxoacetamido)bicyclo[2,2.1]heptane-2-carboxylate: LCMS 392.34 (M+Na+); 1H NMR. (300 MHz, CDC13) δ 4.26 (q, / = 7.2 Hz, 2H), 4.08 (dt, /= 14.3, 7.2 Hz, 1H), 3.62 (d, /= 2.1 Hz, 3H), 2.72 (s, 1H), 2.42-2.26 (m, 2H), 2.08 - 1.80 (m, 2H), 1.80-1.51 (m, 3H), 1.45 (s, 9H), 1.38- 1.25 (m, 3H).

Formation of 6-(/crt-butoxycarbonylamino)norbornane-2-carboxylic acid (72g)

To a solution of methyl 6-[tert-butoxycarbonyl-(2-cthoxy-2-oxo-acetyI)amino]norbomane-2-carboxylate, 72f, (0.80 g, 2.17 mmol) in methanol (20 mL) was added NaOH (4.33 mL of 2N solution, 8.66 mmol) at room temperature. The reaction mixture was stirred overnight. The mixture was diluted into 0.5 N HC1 in ice, and extracted twice with EtOAc. The combined organic phases were dried (Na2S04), filtered and concentrated in vacuo to afford 600 mg of desired product that was used without further purification

Formation of 6-aminobicyclo[2.2.1]heptane-2-carboxylic acid (72h) A solution of 6-(tert-butoxycarbonylamino)norbomane-2-carboxylic acid, 72g , in dichloromethane (5 mL) was treated with trifluoroacetic acid (5 mL) for 1 hour at room temperature. The solvent was evaporated under reduced pressure and the resulting product was dissolved in 2 mL TFA and added to a stirring IN HC1 in Et20 solution. After stirring the mixture for 0.5 hour, the resulting precipitate was filtered and washed with dry Et20 to give 6-aminobicyclo[2.2.1]heptane-2-carboxylic acid.

Formation of 6-(5-fiuoro-2-(5-fluoro-l//-pyrrolo[2,3-b]pyridin-3-yl)pynmidm-4-ylamino)bicyclo[2.2.1]heptane-2-carboxyIic acid (72j)

To a solution of 5-fluoro-3-(5-fluoro-4-methylsulfinyl-pyrimidin-2-yl)-l-(p-tolylsulfonyl)pyrrolo [2,3-b]pyridine (0.187 g, 0.417 mmol) and 6-aminobicyclo-[2.2.1]heptane-2-carboxylie acid, 72h, (0.080 g, 0.417 mmol) in THE (3 mL) was added diisopropylethylamine (0.291 mL, 1.670 mmol). The reaction mixture was heated at 80 °C overnight. Aqueous LiOH (3 mL of 2M solution, 6.000 mmol) was added and the mixture was heated for another 7 hours. The mixture was diluted with MeOH, neutralized with trifluoroacctic acid, filtered and the resulting filrate was purified by preparatory HPLC chromatography to afford 50 mg of desired product.

Formation of /V-[6-[[5-fluoro-2-(5-fluoro-l//-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl] amino] norbornan-2-yl] pyrrolidine-l-carboxamide (1045)

To a solution of 6-[[5-fluoro-2-(5-fluoro-l/Lpyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl]amino]norbornane-2-carboxylic acid, 72j, (0.030 g, 0.078 mmol) in THF (0.375 mL) was added triethylamine (0.032 mL, 0.234 mmol) and (azido(phenoxy)phosphoryl)oxybenzene (0.018 mL, 0.085 mmol). The reaction mixture was heated to 95 °C for 2.5 hours, cooled down to 5 °C, and treated with pyrrolidine (0.010 mL, 0.117 mmol). The reaction was stirred for 3 days at room temperature. The reaction mixture was injected directly into a preparatory HPLC system for purification to provide the product as a racemic mixture. The single enantiomers were obtained by separation using SFC chiral purification to afford 5.7 mg of the desired product as well as 1.4 mg of the enantiomer.

General Scheme 73 .

(a) 'PrjNEt, THF, reflux (b) IN LiOH, THF/H,0, 130 °C, microwave

Formation of (1Λ, 2R, 3A)-3-((5-fluoro-2-(5-fluoro-l-tosyl-l//-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)cycloheptane-l,2-diol (73b)

Aminodiol, 73a, was synthesized by following the literature procedure (JOC 2009, 74, 6735). Aminodiol (0.040 mg), diisopropylethylamine (0.054 mL, 0.310 mmol) and 5-iluoro-3-(5-fluoro-4-methylsulfinyl-pyrimidin-2-yl)-l-(p-toIylsulfonyl)pyrroIo[2,3-b]pyridine (0.139 g, 0.310 mmol) in THF was refluxed overnight. The solution was concentrated in vacuo and purified by silica gel chromatography (0-100% EtOAc/CT^CL) to give 43 mg of desired product as a white solid: lH NMR (300 MHz, CDC13) δ 8.40 (q, / = 2.8 Hz, 2H), 8.22 (d, / = 1.8 Hz, 1H), 8.08 - 7.94 (m, 3H), 7.20 (d, /= 10.1 Hz, 3H), 5.26 (d, / = 4.9 Hz, 1H), 4.21 - 3.99 (m, 1H), 3.84 (s, 1H), 3.75 - 3.57 (m, 1H), 3.43 (t, /= 8.7 Hz, 1H), 2.73 (s, 1H), 2.30 (s, 3H), 2.11 - 1.85 (m, 2H), 1.84 - 1.36 (m, 8H), 1.18 (s, 2H), 0.79 (dd, / = 15.0, 6.8 Hz, 2H). LCMS (+ Η): M/Z = 530.29

Formation of (lii, 2R, 36)-3“((5-fluoro-2-(5-fluoro-l//-pyrrolo]2,3-b]pyridin-3- yl)pyrimidin-4-yI)amino)cycloheptane-l,2-diol (984)

LiOH (0.5 mL of IN solution, 0.5 mmoL) was added to (15, 2R, 35)-3-((5-fluoro-2-(5-fluoro-l-tosyl-l/7-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)cycloheptane-l,2-diol, 73a, in THF (3 mL). The reaction mixture was heated in microwave at 130 °C for 40 minutes. HC1 (0.5 mL of 1.25 N solution in MeOH) and MeOH was added to the mixture. The solution was purified by preparative HPLC (MeCN/FhO 10-70%) to give desired product as TFA salt. Neutralization and re-acidification with hydrogen chloride (IN in MeOH) afforded the desired product (28 mg) as a white solid (HC1 salt): *H NMR (300 MHz, MeOD) 5 8.52 (s, 1H), 8.48 (d, J= 2.8 Hz, 1H), 8.34 (s, 1H), 8.28 (d, J= 5.6 Hz, 1H), 4.62 - 4.35 (m, 1H), 3.65 (m, 2H), 2.11 - 1.43 (m, 8H); 19F NMR (282 MHz, MeOD) δ -137.38 - -137.51 (m, 1H), -156.06 (d, J= 5.6 Hz, 1H); LCMS (+ Η): M/Z = 376.28.

General Scheme 74

(a) Cul, 2-(2- metliySpropanoy])cyclohexanone, DMF (b) H2, Pd/C, MeOH (c) S-fluoro-S-iS-fluoro-^meUiylsulfinyl-pyriimdm-2-y])-l-(p-to]yIsuSibnyl)pyiTCilo[2,3-b]pyridinc (d) IN LiOH, THF/H2G. 130 “C microwave

Formation of benzyl ((15, 3f?)-3-(pyrazin-2-ylamino)cyclohexyl)carbamate (74a) A suspension of Cul (0.006 g, 0.030 mmol), benzyl //-[(15, 35)-3-aminocycIo-hexyljcarbamate, 18e, (0.075 g, 0.302 mmol) and cesium carbonate (0.197 g, 0.604 mmol) in DMF was evacuated and refilled with nitrogen multiple times. 2-iodopyrazine (0.036 mL, 0.362 mmol) and 2-(2- methylpropanoyl)cyclohexanone (0.020 mL g, 0,121 mmol) were then added and the reaction was stirred at room temperature overnight. The reaction was diluted into ethyl acetate and aqueous saturated sodium bicarbonate. The organic phase was separated, dried (MgSOj), filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (0-10% MeOH/CH2Cl2) to afford 40 mg of the desired product as yellow solid.

Formation of (11?, 35)-Al-(pyrazin-2-yl)cyciohexane-l,3-diamine (74b)

To a solution of benzyl //-[(15, 35)-3-(pyrazin-2-ylamino)cyclohexyl]carbamate, 74a, (0.040 g, 0.123 mmol) in methanol (10 mL) was added 10% Pd/C (0.043 g, 0.040 mmol) and the resulting suspension was stirred under an atmosphere of hydrogen for three hours until LCMS indicated completion of the reaction. The solution was filtered through a bed of celite and concentrated in vacuo to give a yellow solid, which was used without further purification.

Formation of (15, 31i)-M-(5-fluoro-2-(5-fluoro-l-tosyI-l//-pyrrolo[2,3-b]pyridin-3- yl)py ri midin-4-yl)-/V3-(pyrazin-2-yl) cyclohexane-1,3-diamine (74 c) A solution of (1/2, 3 5)-//1-pyrazin-2-y]cyclohcxanc-l,3-diaminc 74b, diisopropylethylamine (0.30 mmol) and 5-chloro-3-(5-fluoro-4-methyIsulfinyl-pyrimidin-2-yl)-l-(/j-tolylsulfonyl)-pyiTolo[2,3-b]pyridine (0.06 g, 0.13 mmol) in THF (3 mL) was refluxed overnight. The mixture was then concentrated in vacuo and the resulting residue was purified by silica gel chromatography (0-20% MeOH/CH2Cl2 gradient) to afford 39 mg of desired product: Ή NMR (300 MHz, CDC13) δ 8.91 - 8.72 (m, 1H), 8.50 (d, J = 11.8 Hz, 1H), 8.38 (t, / = 7.5 Hz, 1H), 8.06 (dd, / = 14.8, 5.9 Hz, 3H), 7.88 (d, /= 1.4 Hz, 1H), 7.82 (s, 1H), 7.62 (t, / = 6.8 Hz, 1H), 7.33 (dd, / = 16.6, 7.1 Hz, 3H), 5.91 (s, 1H), 4.27 (s, 1H), 3.98 (t, / = 11.3 Hz, 1H), 2.59 (d, /= 12.0 Hz, 1H), 2.39 (s, 3H), 2.34 - 2.09 (m, 2H), 1.99 (d, /= 14.0 Hz, 1H), 1.72 (dd, /= 26.6, 13.1 Hz, 1H), 1.48 - 1.08 (m, 4H). LCMS (+H): M/Z = 593.25

Formation of (15, 3/f)-M-(5-fluoro-2-(5-fluoro-l/7-pyrrolo[2,3-b]pyridm-3- yl)pyrimidin-4-yl)-A3-(pyrazin-2-yl)cyclohexane-l,3-diamine (985)

LiOH (0.3 mL of IN solution, 0.3 mmoL) was added to a solution of (15, 3/2)-//1-(5-fhioro-2-(5-fluoro-l-tosyI-l/?-pyrrolo[2,3-b]pyridin-3-yl)pyrimidm-4-yl)-7/3-(pyrazin-2-yl)cyclohexane-l,3-diamine, 74c, (35 mg) in THF (3 mL) and the reaction was heated in the microwave at 130 °C for 40 minutes. A solution of HC1 (0.5 mL of a 1.25N in MeOH) was added and the resulting solution was purified by Gilson HPLC (MeCN/THhO 10-70% in 8 mins) to give pure TFA salt product. Neutralization and re-acidification with hydrogen chloride (1.25N in MeOH) afforded 23 mg of the HC1 salt of the desired product as a light yellow solid: *H NMR (300 MHz, MeOD) δ 8.76 (d, / = 2.4 Hz, 1H), 8.63 (s, 1H), 8.41 (d, / = 2.3 Hz, 1H), 8.36 (d, /= 5.7 Hz, 1H), 8.16 (s, 1H), 7.96 (s, 1H), 7.76 (s, 1H), 4.51 (m, / = 11.8 Hz, 1H), 4.16 - 3.92 (m, 1H), 2.35 - 2.14 (m, 2H), 2.09 (m, /= 13.8 Hz, 1H), 1.63 (d, / = 11.8 Hz, 4H); !9F NMR (282 MHz, MeOD) δ -155.25 (s, 1H); LCMS (+ Η): M/Z = 439.24.

(a) NaBH), MeOI-I (b) 5-fluoro-3-(4,4,5,5-letramethy]-l,3,2-dioxaboro!an-2-yl)-l-tosyl-lH-pyrrolo[2,3-b]pyridino, 2-Mc-THF, water, K3POj, Pd(PPh3)4, XPhos, Tris(dibonzylidencacctone)dipalladium,reflux (c) bis(2,5-dioxopyiTolidin-l-yl) carbonate, 'Pr2NEt, CH3CN (d) (37f)-3-fl.uoropyrrolidine,, 'Pr2NEt, CHjCN (e) 2N LiOH, TI-1F

Formation of (1Λ, 35)-3-((2-chloro-5-fluoropyrimidin-4-y])amino)cyclohexanQ] (75a)

Mixed (35)-3-[(2-chloiO-5-fluoro-pyrimidin-4-yl)amino]cyclohexanone, 18e, (1.05 g, 4.31 mmol) in MeOH (20 mL) and dichloromethane (10 mL) and cooled to -78 °C using an external dry-ice/acetone bath and monitored with an internal thermometer. After 30 minutes, NaBH4 (0.16 g, 4.31 mmol) was added in one portion and continued to stir, (slight exotherm) and then cooled back down to -78°C. The reaction was monitored by HPLC for consumption of starting material as it was allowed to warm to room temperature overnight. The reaction was diluted with brine and EtOAc. The organic phase was dried (MgSCL), filtered and concentrated in vacuo. The resulting residue was purified by silica gel chromatography to afford l.Og of a colorless foamy solid: LCMS method m201:10-90 CH3CN/H2O, formic acid modifier, 5 minutes, (Cl8); RT = 2.08min, MH+ = 246.21.

Formation of (1Λ, 35)-3-((5-fluoro-2-(5-fluoro-l-tosyl-lJT-pyrrolo[2,3-b]pyridin-3-yl)pyrim idin-4-yl)am in o)cyclo hexanol (75b) K3PO4 (2,59 g, 12.21 mmol) in water (6 mL) and 2-Me-THF (20 mL) was purged with a flow of nitrogen for 30 min. Added (17?,35)-3-[(2-chloro-5-fluoro-pyrimidin-4-yl)amino)cyclohexanol, 75a, (1.00 g, 4.07 mmol) and 5-fluoro-3-(4,4,5,5-tetrametliyl-l,3,2-dioxaborolan-2-yl)-l-tosyl-lH-pyrroIo[2,3-b]pyridme, 44a, (2.03 g, 4.88 mmol) and then purged with nitrogen for another 15 min. The reaction was then heated to 70 °C and then charged with Tris(dibenzylideneacetone)dipalladium (0.07 g, 0.08 mmol) and X-Phos (0.14 g, 0.28 mmol) under nitrogen. (Note Color changed from purple to hunter green). The reaction was heated to reflux for 1 h and 20 min. The reaction was cooled slowly to room temperature overnight. The mixture was treated with 100 mL of brine and 100 mL of ethyl acetate and separated the two layers. The aqueuous phase was extracted again with EtOAc (50 mL). Combined organic layers and passed through a plug of fluoracil, dried over Na2S04, decanted and removed the solvent by rotoevaporation to give crude product which was then purified by silica gel chromatography (25-50% EtOAc/Hexanes) to afford the desired product. 2,5-dioxopyrrolidin-l-vl ((15, 37?)-3-((5-fluoro-2-(5-fluoro-l-tosyl-l/f-pyrrolo [2,3- />]pyridin-3-yl)pyrimidin-4-yl)amino)cyclohexyl) carbonate (75c)

To a solution of (1Λ, 35)-3-((5-fluoro-2-(5-fhioro-l-tosyl-l.tf-pynOlo[2,3-i>]pyridin-3-yI)-pyrimidin-4-yl)arnino)cyclohcxano], 75b, (0.50 g, 1.00 mmol) and N,N- diisopropylethylamine (1.40 mL, 10.01 mmol) was added bis(2,5-dioxopyrrolidin-l-yl) carbonate (1.28 g, 5.01 mmol) in CH3CN (4 mL) and stirred at room temperature overnight. Used reaction mixture as is in next reaction. Using LCMS method m201:10-90 CH3CN/H20, formic acid modifier, 5 minutes, (C18); RT = 3.73min, MH+ = 641.43 (strong).

Formation of (R)-(15, 3/f)“3“((5-fluoro-2-(5-fluoro-l-tosyl-l/7-pyrrolo[2,3-/>]pyridin-3-yl)pyrimidin~4-yl)amino)cyclohexyl3-fluoropyrroIidine-l-carboxylate (75d)

To (2,5-dioxopyrrolidin-l-yI) [(1/i, 3S)-3-[[5-fluoro-2-[5-fluoro-l-(p- tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]pyrimidin-4-yl]amino]cyclohexyl] carbonate, 75c, (0.125 g, 0.195 mmol) already in acetonitrile was added (3/?)-3-fluoropyrrolidine (0.445 g, 4.991 mmol) and the reaction mixture was stirred at room temperature for 20 hours; The reaction was monitored by HPLC until no more starting material was remaining. The reaction mixture was concentrated in vacuo and was carried on into the next reaction without further purification.

Formation of (5)-(15, 3-ft)-3-((5-fluoro-2-(5-fiuoro-l//-pyrrolo[2,3-/j]pyridin-3-yl)-pyrimidin-4-yl)amino)cyclohexyl3-fluoropyrrolidine-l-carboxylate (1151)

To a solution of ciude (fl)-(lS, 3R)-3-((5-fluoro-2-(5-fluoro-l-tosyl-lif-pyrrolo[2,3-b] pyr idin-3 -y l)pyrimidin-4-y l)amino)cyclohexy 1 3-fluoropy rrolidine-1 -carboxy late, 75d, (0.119 g, 0.019mmol) in THF (2mL) was added 5mL 2N LiOH (10 mmol). The reaction mixture was heated at 50 °C for 2 hours. The mixture was diluted into aqueous saturated ammonium chloride (2mL), and extracted with EtOAc (2 x lOmL), dried over sodium sulfate, filtered and concentrated in vacuo. The resulting residue was purified on the semi-prep HPLC, 10-70% CH3CN/H20; Three runs; homogeneous fractions were combined and the solvent removed under a stream of nitrogen and then removed residual solvent on roto-evaporator to afford 74 mg of the desired product: LCMS RT = 2.15 min (M+H) 461.51.

(a) Rh/Al203, H20,100 ’C, 105 atm H2, 19 hrs (b) 2,4-dich!oro-5-fluoropyrimidine, IPA, MeCN, room temperature (c) CDI, !Pr2NEt, (S)-3-fluoropyrro!idine, THF, RT, 2 days(d) 5-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaboro[an-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine, MeTHF, K3P04, X-Phos, Pd2dba3, H20, microwave, 120 °C, 20 minutes (e) 25% NaOMe in MeOH, RT, 30 min. (f) SFC separation

Formation of 5-methylcyclohexane-l,3-diamine (76a)

The 3-methyl-5-nitroaniline (10.0 g, 65.7 mmol) was added to water (146 ml) and treated with 6N HC1 (22,5 ml, 135.0 mmol) and 5% Rhodium on Alumina (1.9 g, 0.9 mmol). The mixture was charged to 105 atm of Hydrogen and heated to 100 °C for 19 hours. The reaction was cooled and filtered through celite and concentrated to dryness to give 5-methylcyclohexane-1,3-diamine dihydrochloride (12.9 g, 64.5 mmol) as a racemic mixture. The salt (6.5 g, 32.5 mmol) was dissolved in isopropyl alcohol (100 ml) and acetonitrile (100 ml) and treated with potassium carbonate (25.2 g, 182.0 mmol). The mixture was stirred at room temperature overnight, filtered thru celite, and concentrated in vacuo to afford 2.2 g of 5-methylcyclohexane-l,3-diamine as a racemic brown oil: LCMS RT = 0.41 (M+l) 128.9.

Formation of lV1-(2-chloro-5-fluoropyrimidin-4-yl)-5-methylcyclohexane-l,3-diamine (76b)

To a solution of 5-methylcyclohexane-l,3-diamine, 76a, (2.2 g, 17.2 mmol) in isopropyl alcohol (40 ml) and acetonitrile (40 ml) was added 2,4-dichloro-5-fluoropyrimidine (1,4 g, 8.6 mmol). The mixture was stirred at room temperature overnight, concentrated to dryness, and purified on silica gel eluted with 1-20% methanol/dichloromethane, to give 0.6 g of racemic V-(2-chloro-5-fhioropyrimidin-4-yl)-5-methylcyclohexane-l,3-diamine: H NMR (300 MHz, MeOD) 5 7.85 (d, J= 3.5 Hz, 1H), 4.07 (ddd, J = 11.9, 7.9, 4.1 Hz, 1H), 3.54 (qd, J = 11.3, 4.2 Hz, 1H), 2.82 (tt, J = 11.4, 3.7 Hz, 1H), 2.16 (dd, J= 15.0, 13.0 Hz, 1H), 1.89 (t, J= 13.4 Hz, 2H), 1.50 (dd, J= 76.0, 21.9 Hz, 2H), 1.10 (dt, / = 17.9, 9.0 Hz, 1H), 0.99 (dd, /= 8.5, 5.0 Hz, 3H), 0.81 (ddd, /= 23.8, 12.0, 8.2 Hz, 1H); LCMS RT = 1.24 (M+l) 259.1.

Formation of (SSHAHS-^-chloro-S-fluoropyriimdin-d-ylJaminoi-S-methylcycIahexyl)-3-fluoropyrrolidine-l-carboxamide (76c)

To a solution of Af1-(2-chloro-5-fluoropyrimidin-4-yI)-5-methylcyclohexane-l,3-diamine, 76b, (0.14 g. 0.54 mmol) in THF (2.5 ml) was added carbonyldiimidazole (0.10 g, 0.60 mmol) and 'Pr2NEt (0.28 mL, 1.62 mmol). The reaction was aged 2 hours at room temp, and treated with (S)-3-fluoropyrrolidine hydrochloride (0.07 g, 0.54 mmol). The reaction was stirred at room temperature for 2 days and then concentrated to dryness to afford 202 mg of (31S)-Ar-(3-((2-chloro-5-fluoropyrimidin-4-yl)amino)-5-methylcyclohexyl)-3-fluoropyrrolidine-1 -carboxamide which was used without purification: LCMS RT = 2.46 (M+l) 374.2, (M-l)372.

Formation of (SiSJ-S-fluoro-iV-iS-ifS-fluoro-Z-fS-fluoro-l-tosyl-l/f-pyrroIopjS-ilpyridin-3-y1)pyrimidin-4-yl)amino)-5-inethylcyc]ohexyl)pyrroIidine-l-carboxamide (76d)

To a solution of (35)-A-(3-((2-chloro-5-fluoropyrimidin-4-yl)amino)-5-methyl-cyclohexyI)-3-fluoropyrrolidine-l-carboxamide, XXc, (0.101 g, 0.270 mmol) in 2-methyltetrahydrofuran (4 ml) was added potassium phophate (0.090 g, 0.950 mmol) in water (1.2 ml), x-phos (0.027 g, 0.057 mmol), and Pd2dba3 (0.015 g, 0.016 mmol). The reaction was heated in a microwave at 120 °C, for 20 minutes, and the organic phase was filtered thru a pad of florisil and the filtrate concentrated in vacuo. The crude was purified on silica gel eluted with EtOAc to afford 127 mg of racemic (3S)-3-fluoro-A,-(3-((5-fluoro-2-(5-fluoro-l-tosyl-l//-pyrrolo[2,3-h]pyridin-3-yl)pyrimidin-4-yl)amino)-5-methylcyclohexyl)pyrrolidine-1-carboxamide: LCMS RT = 3.58 (M+l) 628.3, (M-l) 626.

Formation of (5)-3-fluoro-iV-((lJ?, 3S, 5J?)-3-((5-fluoro-2-(5-fluoro-lff-pyrrolo[2,3- f>]pyridin-3-yl)pyrimidin-4-yI)amino)-5-methylcyclohexyl)pyrrolidine-l-carboxamide (76e)

To a solution of (35)-3-fluoro-A-(3-((5-f[uoro-2-(5-fluoro-l-tosyl-l//-pyirolo[2,3-h]pyridin-3-yl)pyrimidin-4-yl)amino)-5-methylcyclohexyl)pyrrolidine-l-carboxamide, 76d, (0.090 g, 0.143 mmol) in MeOH (2.5 ml) was added 25% sodium methoxide in methanol (2 ml). The reaction was stirred at room temperature for 30 minutes and quenched with aqueous saturated NH4CI. The methanol was removed in-vacuo and the residue was extracted with EtOAc and water. The organics were dried over sodium sulfate and concentrated to dryness. The resulting crude racemate was purified by SFC separation on a chiral column. The second peak was concentrated in vacuo to afford 32 mg of enantiomerically pure (5)-3-fluoro-A-((1Λ, 35', 5R)-3-((5-fluoro-2-(5-fluoiO-liT-pyrrolo[2,3-h]pyridin-3-yl)pyrimidin-4-yI)amino)-5-methylcyclohexyl)pyrrolidine-l-carboxamide as a white solid: LCMS RT = 1.89 (M+l) 474.2, (M-l) 472.4; SFC RT = 3.2 min., 15% MeOH @ 5mL/min on an ODH (4,6*100), 100 bar, 35C, 220nm; !H NMR (300 MHz, DM80) 5 12.26 (s, 1H), 8.41 (dd, / = 9.9, 2.8 Hz, 1H), 8.32 - 8.18 (m, 2H), 8.14 (d, / = 4.0 Hz, 1H), 7.53 (d, ,/= 7.6 Hz, 1H), 6.02 (d, / = 7.9 Hz, 1H), 5.28 (d, /= 53.6 Hz, 1H), 4.35 - 4.00 (m, 1H), 3.81 - 3.09 (m, 12H), 2.24 - 1.77 (m,/= 41.2, 26.1, 10.6 Hz, 4H), 1.74- 1.51 (m, 1H), 1.51 - 1.22 (m, 1H), 1.14-0.70 (m, 4H).

General Scheme 77

(a) (7?)-nopinone, 0-methylhydroxylamine hydrochloride, pyridine, EtOH (b) nBuLi, THF, -78 °C, ethyl formate (c) NaBIi*, MeOH (d) TBDPSCI, imidazole, DMF (e) BH3-THF, THF, 75 °C (f) 5-chloro-3-(5-fluoroA-(methylsulfinyl)pyrimidin-2-yI)-l-tosyl-lH-pyrrolo[2,3-b]pyridine, 'PAN Ft, 75 °C (g) HC1, dioxane

Formation of (15, 55)-6,6-dimethylbicyclo[3.1.1]heptan-2-one O-methyl oxime (77a)

To a solution of (15, 55)-6,6-dimethy)norpinan-2-one (3.09 g, 22.35 mmol) in ethanol (70 mL) was added 0-raethylhydroxylamine hydrochloride (2.05 g, 24.59 mmol) and pyridine (1.29 mL, 15.92 mmol). Heated reaction mixture to 80 °C for 4 hours. Removed solvent under reduced pressure. Diluted residue with IN HC1 and extracted twice with ether. The combined organic phases were washed with aqueous saturated NaHCOj, dried (MgS04), filtered, concentrated in vacuo to afford 3.36 g of a colorless oil (mixture of oxime isomers) that was used without further purification.

Formation of (15, 35, 55)-2-(methoxyimino)-6,6-dimethylbicyclo[3.1.1]heptane-3-carbaldehyde (77b)

To a cold (-78 °C) solution of (15, 5S)-6,6-dimethylbicyclo[3.1.1]heptan-2-one O-methyl oxime, 77a, (1.27 g, 7.59 mmol) in THF (33 mL) was added dropwise a solution of n-butyllithium (3.34 mL of 2.5 M solution in hexanes, 8.35 mmol). After stirring the mixture 20 min at -78 °C ethyl formate (0.61 mL, 7.59 mmol) was added dropwise. The reaction mixture was stirred at -78 °C for 3 hours and then quenched by pouring into aqueous saturated NaHCCL solution. The mixture was extracted with EtOAc. The organic phase was dried (MgS04), filtered and concentrated in vacuo. The resulting residue was purified via silica gel chromatography (0-20% EtOAc/Hexanes gradient) to afford 810 mg yellow oil: LCMS RT = 3.54 (M+H) 196.28.

Formation of (15, 35, 55)-3-(hydroxymethyl)-6,6-dimethylbicyclo[3.1.1]heptan-2-one O-methyl oxime (77c)

To a solution of (15, 35, 55)-2-(metlioxyimino)-6,6-dimethylbicyclo [3.1.1]heptane-3-carbaldehyde, 77b, (0.70 g, 3.58 mmol) in methanol (15 mL) was added sodium borohydride (0.16 g, 4.30 mmol). After stirring at room temperature for 30 minutes, the reaction was diluted into aqueous saturated NaHCCh solution and extracted with EtOAc. The organic phase was dried (MgS04), filtered and concentrated in vacuo. The resulting residue was purified via silica gel chromatography (0-50% EtOAc/Hexanes gradient) to afford 330 mg of the desired alcohol as mixture of oxime isomers.

Formation of (15, 35, 55)-3-(((fci7-butyldiphenylsiIyl)oxy)methyl)-6,6-dimethyl-bicyclo[3.1.1]heptan-2-one O-methyl oxime (77d)

To a solution of (15, 35, 55)-3-(hydroxymethy 1)-6,6-dimethylbicyclo[3.1.1]-heptan- 2-one O-methyl oxime, 77c, (0.32 g, 1.60 mmol) in DMF (6 mL) was added tert-butylchlorodiphenylsilane (0.55 g, 2.00 mmol) and imidazole (0.22 g, 3.20 mmol). The reaction mixture was stirred at room temperature for 18 hours. The reaction was diluted into aqueous saturated NH4CI solution and extracted twice with EtOAc. The combined organic phases were washed twice with brine, dried (MgS04), filtered and concentrated in vacuo. The resulting residue was purified via silica gel chromatography (0-15% EtOAc/Hexanes gradient) to afford 200 mg of one oxime isomer and 197 mg of second oxime isomer.

Formation of (15, 35, 55)-3-(((fcrf-butyldiphenylsiIyl)oxy)methyl)-6,6-dimethyl-bicyclo[3.1 ,l]heptan-2-amine (77e)

To a solution of (15, 35, 55)-3-(((iert-butyldiphenylsilyl)oxy)methyl)-6,6-dimethyl-bicyclo[3.1.1]heptan-2-one O-methyl oxime, 77d, (0,20 g, 0.46 mmol) in THE (3 mL) was added borane-THF (1.38 mL of 1 M solution, 1.38 mmol). The reaction was heated to 75 °C for 18 hours. The mixture was diluted into IN NaOH (50 mL) and extracted twice with EtOAc. The combined organic phases were dried (MgS04), filtered and concentrated in vacuo to afford 178 mg of a colorless oil that was used without further purification: LCMS RT = 2.53 (M+H) 408.54.

Formation of N-((IR, 2 5, 3 5, 5/i)-3-(((mrt-butyIdiphenylsilyl)oxy)methyl)-6,6- dimethylbicyclo[3.1.1]heptan-2-yl)-2-(5-chloro-l-tosyI-li/-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-amine (77f)

To a solution of (1R, 35, 5R)-3-(((tert-butyldiphenylsilyl)oxy)mcthyl)-6,6-dimethyl-bicyclo[3.1.1]heptan-2-amine, 77e, (0.20 g, 0.46 mmol) and 5-chloro-3-(5-fluoro-4-(methylsuIfmyl)pyTimidin-2-yl)-l-losyl-lH-pyrrolo[2,3-b]pyridine (0.14 g, 0.30 mmol) in DMF (1.5 mL) was added diisopropylethylamine (0.11 mL, 0.61 mmol). The reaction was heated to 75 °C for 18 hours. The mixture was diluted into aqueous saturated NH4C1 solution and extracted twice with EtOAc. The combined organic phases were washed twice with brine, dried (MgSC*4), filtered and concentrated in vacuo. The crude residue was purified via silica gel chromatography (0-5% MeOH/CH2Cl2 gradient) to afford 78 mg of the desired product.

Formation of ((1Λ, 25, 35, 5/i)-2-((2-(5-chloro-l//-pyrrolo[2,3-b]pyridin-3-yI)-5-fluoropyrimidin-4-yl)amino)-6,6-dimethylbicyclo[3.1.1]heptan-3-yl)methanol (1229)

To a solution of jV-((lR, 25, 35, 5i?)-3-(((terf-butyldiphenylsilyl)oxy)methyl)-6,6-dimethylbicyclo[3.1.1]heptan-2-yl)-2-(5-chloro-l-tosyl-l//-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-amine, 77f, (0.037 g, 0.046 mmol) in acetonitrile (1.1 mL) was added HC1 (0.221 mL of a 4 M solution in dioxane, 0.883 mmol). The mixture was heated to 70 °C for 18 h, during which a precipitate formed. The reaction was concentrated in vacuo and triturated three times with CH3CN to afford 4 mg of the desired product as a white solid: *H NMR ¢300.0 MHz, MeOD) δ 8.72 - 8.64 (m, 1H), 8.39 (s, 1H), 8.32 (d, ./= 2.3 Hz, 1H), 8.21 (d, /= 5.2 Hz, 1H), 4.71 (d, / = 6.3 Hz, 1H), 3.67 - 3.57 (m, 2H), 2.33 - 2.26 (m, 1H), 2.10 (m, 1H), 1.78 - 1.70 (m, 1H), 1.28 - 1.25 (m, 7H) and 1.19 (s, 3H) ppm; LCMS RT = 3.13 (M+H) 416.42.

Influenza Antiviral Assay [001174] Antiviral assays were performed using two cell-based methods: A 3 84-well microtiter plate modification of the standard cytopathic effect (CPE) assay method was developed, similar to that of Noah, et al. (Antiviral Res. 73:50-60, 2006).

Briefly, MDCK cells were incubated with test compounds and influenza A virus (A/PR/8/34), at a low multiplicity of infection (approximate MOI=0.005), for 72 hours at 37°C, and cell viability was measured using ATP detection (CellTiter Glo, Promega Inc.). Control wells containing cells and viius show cell death while wells containing cells, virus, and active antiviral compounds show cell survival (cell protection). Different concentrations of test compounds were evaluated, in quadruplicate, for example, over a range from approximately 20 μΜ to 1 nM. Dose-response curves were prepared using standard 4-parameter curve fitting methods, and the concentration of test compound resulting in 50% cell protection, or cell survival equivalent to 50% of the uninfected wells, was reported as the IC50. A second cell-based antiviral assay was developed that depends on the multiplication ofvirus-specific RNA molecules in the infected cells, with RNA levels being directly measured using the branched-chain DNA (bDNA), hybridization method (Wagaman et al, L Virol Meth, 105:105-114,2002). In this assay, cells are initially infected in wells of a 96-well microtiter plate, the virus is allowed to replicate in the infected cells and spread to additional rounds of cells, then the cells are lysed and viral RNA content is measured. This assay is stopped earlier that the CPE assay, usually after 18-36 hours, while all the target cells are still viable. Viral RNA is quantitated by hybridization of well lysates 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, according 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. Control wells containing cells and virus were used to define the 100% viral replication level, and dose-response 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 EC so

Vims and Cell culture methods: Madin-Darby Canine Kidney cells (CCL-34 American Type Culture Collection) were maintained in Dulbecco’s Modfied Eagle Medium (DMEM) supplemented with 2mM L-glutamine, l,000U/ml penicillin, 1,000 ug/ml streptomycin, 10 mM HEPES, and 10% fetal bovine medium. For the CPE assay, the day before the assay, cells were suspended by trypsinization and 10,000cells per well were distributed to wells of a 384 well plate in 50 μΐ. On the day of the assay, adherent cells were washed with three changes of DMEM containing 1 ug/ml TPCK-treated trypsin, without fetal bovine serum. Assays were initiated with the addition of 30 TCED50 of vims and test compound, in medium containing 1 pg/'ml TPCK-treated trypsin, in a final volume of 50 μΐ. Plates were incubated for 72 hours at 37°C in a humidified, 5% CO2 atmosphere. Alternatively, cells were grown in DMEM + fetal bovine semm 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, without the need for washing.

Influenza vims, strain A/PR/8/34 (tissue culture adapted) was obtained from ATCC (VR-1469). Low-passage vims 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 results using the Karber method.

Mean ICSo values (mean all) for certain specific compounds are summarized in Tables 1-5: A: ICsoCmean all) < 5 μΜ; B 5μΜ < ICso (mean all) < 20 μΜ; C IC50(mean all) > 10 μΜ; D IC50 (mean all) > 20 μΜ; E ICsotmean all) >3.3 μΜ.

Mean EC50 values (mean all) for certain compounds are also summarized in Tables 1-5: A: EC50 (mean all) < 5 μΜ; B 5μΜ < ECsoimean all) <10 μΜ; C ECso(mean all) > 3.3 μΜ; D ECso(naean all) > 10 μΜ.

As can be seen in Tables 1-5, a lot of compounds of the invention showed positive effect on the survial of the A/PR/8/34 infected cells, and inhibitory effect on the replication of A/PR/8/34 influenza virus. Exemplary IC50 and EC50 values are as follows: Compound 428 had 0.03 μΜ of IC50; Compound 895 had 0.0008 μΜ of IC50 and 0.001 μΜ of EC50; Compound 833 had 5.6 μΜ of ICsoand 3.5 μΜ of EC50.

Table 1: IC50, EC50, NMR and LCMS Data of Compounds of FIG. 3:

In Vivo Assay [001175] For efficacy studies, Balb/c mice (4-5 weeks of age) were challenged with 5x103TCID5O in a total volume of 50 μΐ by intranasal by intranasal instillation (25 μΙ/nostril) under general anesthesia (Ketamine/Xylazine). Uninfected controls were challenged with tissue culture media (DMEM, 50 μΐ total volume). For the prophylaxis study (FIG. 1), the initial dose of Compound 514 (100 mg/kg) or vehicle only (0.5% Methylcellulose/0.5% Tween 80) were administered 2 hours prior to infection by oral gavage (10 mL/kg) and continued twice daily for 5 days. For the treatment study (FIG. 2), Compound 588 (200 mg/kg) or vehicle only (0.5% Methylcellulose/0.5% Tween 80) were administered by oral gavage 24 hours post infection and continued twice daily for 10 days. Animals were monitored for survival for 21 days and Kaplan Meier plots. As shown in FIGs. 1 and 2, Compound 514 and Compound 588 provided complete survival that was statistically significant from vehicle treated controls (P<0.0001).

Table 6. Influneza Therapeutic Mouse Model (Dosing @ 48 hours post infection with 30 mg/kg BID X 10 days)

[001176] 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 literature. See, e.g., Janet S. Dodd, ed., The ACS Style Guide: A Manual for Authors and Editors, 2nd Ed., Washington, D.C.: American Chemical Society, 1997. 1001177] It is to be understood that while the invention has been described in conjunction with the detailed description thereof, the foregoing description is intended to illustrate and not limit the scope of the invention, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims.

Claims (156)

1. CLAIMS What is claimed is:

   1. 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 represented by the following structural formula (I):

   or a pharmaceutically acceptable salt thereof, wherein: Z! is -R*, -F, -Cl, -CN, -OR*, -C02R*, -N02, or -CON(R*)2; Z2 is -R* -OR*, -C02R*, -NR*2, or -CON(R*)2; Z3 is -H, -OH, halogen, -NH2; -NH(C]-C4 alkyl); -N(CrC4 alkyl)2, -0(Ci-C4 alkyl), or CfCfi alkyl that is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, and -0(Ci-C4 alkyl); R1 is -H or Ci-Ce alkyl; R2 is -H; -F; -NH2; -NH(Ci-C4 alkyl); -N(Cl-C4 alkyl)2; -C=N-OH; cyclopropyl that is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, -OCH3, and -CH3; or C1-C4 alkyl that is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, and -0(Cj-C4 alkyl); and R3 is -H, -Cl, -F, -OH, -0(C,-C4 alkyl), -NH2, -NH(C,-C 4 alkyl), -N(Ci-C4alkyl)2, -Br, -CN, or C1-C4 aliphatic that is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(C,-C4 alkyl), -N(Ci-C4 alkyl)2, -OCO(Ct-C4 alkyl), -CO(Ci-C4 alkyl), -C02H, -C02(Ci-C4 alkyl), and C1-C4 alkoxy; R4 is:

   I i) wherein ring T is a C3-C10 non-aromatic carbocycle optionally substituted with one or more instances of JA, or a 3-10 membered non-aromatic heterocycle optionally substituted with one or more instances of JB, or ring T and R9 optionally form a non-aromatic C5-C10 membered carbocycle optionally substituted with one or more instances of JA or 5-10 membered non-aromatic heterocycle optionally substituted with one or more instances of JB ; ii)

   wherein ring J is a 3-10 membered non-aromatic heterocycle optionally substituted with one or more instances of JB; or

   • iii) wherein ring D is a 4-10 membered non-aromatic heterocycle optionally substituted with one or more instances of JD1; and each of JA and JB is independently selected from the group consisting of halogen, cyano, oxo, -NCO, and Q!-R5; or optionally two JA and two JB, respectively, together with the atom(s) to which they are attached, independently form a 4-8 membered ring that is optionally substituted with one or more instances of JE1; Q1 is independently a bond, -0-, -S-, -NR’-, -C(O)-, -C(=NR)-, -C(=NR)NR-, -NRC(=NR)NR-, -CO2- -OC(O)-, -C(0)NR’-, -C(0)NRC(0)0- -NRC(0)NRC(0)0-, -NRC(O)-, -NRC(0)NR’-, -NRC02- -0C(0)NR’-, -S(O)-, -S02- -S02NR’-, -NRSO2-, or -NRS02NR\ -P(0)(0R)0-, -0P(0)f0Ra)0-, -P(0)20-, -C02S02-, or -(crcrVy1-; Y1 is independently a bond, -0-, -S-, -NR’-, -C(O)-, -C(=NR)-, -C(=NR)NR-, -NRC(-NR)NR-„ -CO2-, -OC(O)-, -C(0)NR’-, -C(0)NRC(0)0-, -NRC(0)NRC(0)0-, -NRC(O)-, -NRC(0)NR’-, -NRC02-, -0C(0)NR’-, -S(O)-, -S02- -S02NR’-, -NRSO2-, -NRSO2NR’-, -P(0)(0R)0-, -0P(0)(0Ra)0-, -P(0)20-, or -C02S02-; R5 is: i) -H; ii) a C|-C6 aliphatic group optionally substituted with one or more instances of JC1; in) a C3-C10 non-aromatic carbocycle, or a 6-10 membered carbocyclic aryl group, each optionally and independently substituted with one or more instances of Jcs; or iv) a 4-10 membered non-aromatic heterocycle, or a 5-10 membered heteroatyl group, each optionally and independently substituted with one or more instances of JD1; or R5, together with Q1, optionally forms a 4-8 membered, non-aromatic ring optionally substituted with one or more instances of JE1; and R6 and R7 are each independently -H or Cj-Cg alkyl optionally substituted with one or more substitutents selected from the group consisting of halogen, cyano, hydroxy, oxo, amino, carboxy, Ci-Cgalkoxy, Ci-Cghaloalkoxy, Ci-Cg aminoalkoxy, Ci-Cgcyanoalkoxy, Ci-Cghydroxyalkoxy and C2-Ce alkoxyalkoxy, or optionally R6 and R7, together with the carbon atom to which they are attached, form a cyclopropane ring optionally substituted with one or more instances of methyl; R9 is independently -H, halogen, cyano, hydroxy, amino, carboxy, C|-Cc alkyl, Ci-Ce haloalkyl, Ci-Cs cyanoalkyl, C2-C6 alkoxyalkyl, C1-C6 aminoalkyl, Ci-Ce hydroxyalkyl, Ci-C6 carboxyalkyl, Ci-Cealkoxy, Ci-Cc haloalkoxy, Ci-C6 aminoalkoxy, Ci-Cscyanoalkoxy, C1-Ce hydroxyalkoxy and C2-C6 alkoxyalkoxy; R13 and R14 are each independently -H, halogen, or Ci-CV, alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo, hydroxy, oxo, amino, carboxy, Ci-Ce alkoxy, Ci-Ce haloalkoxy, Ci-Ce aminoalkoxy, Ci-Cecyanoalkoxy, Ci-Ce hydroxy alkoxy, and C2-Ce alkoxyalkoxy; optionally, R13 and R14, together with the carbon atom to which they are attached, form a cyclopropane ring optionally substituted with one or more instances of methyl; R and R’ are each independently -H or Ci-C6 alkyl optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, amino, carboxy, Ci-Ce alkoxy, Ci-C6 haloalkoxy, C1-C6 aminoalkoxy, Ci-Ce cyanoalkoxy, Ci-Ce hydroxy alkoxy and C2-Ce alkoxyalkoxy; or optionally R’, together with R5 and the nitrogen atom to which they arc attached, forms a 5-7 membered non-aromatic heterocycle optionally substituted with one or more instances of JD1; R* is independently: i)-H; ii) a Ci-C6 alkyl group optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, amino, carboxy, C3-CS non-aromatic carbocycle, 5-6 membered non-aromatic heterocycle, phenyl, 5-6 membered heteroaiyl, -0(Ci-Ce alkyl), and -C(0)(Ci-C6-alkyl); wherein each of said alkyl groups in -0(Ci-C6 alkyl), and -C(0)(Ci-C6-alkyl) is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(Ci-C4 alkyl), -N(Ci-C4 alkyl)2, -OCO(Ci-C4 alkyl), -CO(Ci-C4 alkyl), -C02H, -C02(Ci-C4 alkyl), and C4-C4 alkoxy; and wherein each of said carbocycle, heterocycle, phenyl, and heteroaiyl is independently and optionally substituted with one or more instances of JE1; or iii) a C3-C8 non-aromatic carbocycle, or a 4-8 membered non-aromatic heterocycle, each of which is independently and optionally substituted with one or more instances of JE1; and each of JC1 and JDi is independently selected from the group consisting of halogen, cyano, oxo, Ra, -ORb, -SRb, -S(0)Ra, -S02Ra, -NRbR°, -C(0)Rb, -C(=NR)RC, -C(=NR)NRbRc, -NRC(=NR)NRbRc, -C(0)0Rb, -0C(0)Rb, -NRC(0)Rb, -C(0)NRbRc, -NRC(0)NRbRc, -NRC(0)0Rb, -OCONRbRc, -C(0)NRC02Rb, -NRC(0)NRC(0)0Rb, -C(0)NR(0Rb), -S02NRcRb, -NRS02Rb, -NRS02NRcRb, -P(0)(0Ra)2, -0P(0)(0Ra)2, -P(0)20Ra and -C02S02Rb, or optionally, two JC1 and two JDl, respectively, together with the atom(s) to which they are attached, independently form a 4-8-membered ring that is optionally substituted with one or more instances of JE1; each JE1 is independently selected from the group consisting of halogen, cyano, hydroxy, oxo, amino, carboxy, amido, Ci-C6 alkyl, -0(Ct-C6 alkyl), and -C(0)(Ci-C6-alkyl), wherein each of said alkyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(Ci-C4 alkyl), -N(CrC4 alkyl)* -OCO(Ci-C4 alkyl), -CO(C,-C4 alkyl), -C02H, -C02(Ci-C4 alkyl), and Ci-C4 alkoxy; and Ra is independently: i) a Ci-Ce aliphatic group optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, amino, carboxy, amido, -0(Ci-Cs alkyl), -C(0)(Cj-Q;-alkyl), Cg-Cg non-aromatic carbocycle, 4-8 membered non-aromatic heterocycle, 5-10 membered heteroaryl group, and 6-10 membered carbocyclic aryl group; wherein each of said alkyl groups for the substituents of the Ci-Cfi aliphatic group represented by Ra is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(Ci-C4 alkyl), -N(C,-C4 alkyl)2, -OCO(Ci-C4 alkyl), -CO(Ci-C4 alkyl), -C02H, -C02(Ci-C4 alkyl), and Ci-C4 alkoxy; and wherein each of said carbocycle, hctcrocycle, heteroaryl and carbocyclic aryl groups for the substituents of the Ci-Ce aliphatic group represented by Ra is optionally and independently substituted with one or more instances of JE1; ϋ) a C3-C8 non-aromatic carbocycle, or a 4-8 membered non-aromatic heterocycle, each of which is optionally and independently substituted with one or more instances of JEI; or iii) a 5-10 membered heteroaryl, or 6-10 membered carbocyclic aiyl group, each of which is optionally and independently substituted with one or more instances of JEI; and Rb and Rc are each independently Ra or -H; or optionally, Rb and Rc, together with the nitrogen atom(s) to which they are attached, each independently form a 5-7 membered nonaromatic heterocycle optionally substituted with one or more instances of JE1; p is independently 1, 2, 3 or 4; t is 0, 1 or 2; j is 1 or 2; and z is 1 or 2.
2. 2. The method of claim 1, represented by Structural Formula (I):

   or a pharmaceutically acceptable salt thereof.
3. 3. The method of claim 1 or 2, wherein R1 is -H.
4. 4. The method of any one of claims 1-3, wherein R2 is --H, -F, -CH3, -CT-HOH, or -NH2.
5. 5. The method of claim 4, wherein R2 is -H or -CHj.
6. 6. The method of any one of claims 1-5, wherein R3 is -H, -Cl, -F, -Br, -CN, -CF3, -0(CrC4 alkyl), -OH, -NH2, -NH(Ci-C4 alkyl) or-N(Ci-C4 alkyl)2.
7. 7. The method of any one of claims 1-6, wherein R4 is:

   ; and wherein: ring A is a C3-C10 non-aromatic carbocyclc optionally further substituted with one or more instances of JA or a 3-10 membered non-aromatic heterocycle optionally further substituted with one or more instances of JB; rings B and C are each independently a 4-10 membered non-aromatic heterocycle optionally and independently further substituted with one or more instances of JB; ring D is a 4-10 membered non-aromatic heterocycle optionally substituted with one or more instances of JDI; or ring A and R optionally form a non-aromatic, 5-10 membered, bridged carbocycle or heterocycle, or ring A and R9 optionally form a non-aromatic, 5-10 membered, bridged carbocycle or heterocycle, or ring A and Ru optionally form a non-aromatic, 5-10 membered, bridged carbocycle or heterocycle, wherein each carbocycle is optionally further substituted with one or more instances of JA, and wherein each heteroocycle is optionally further substituted with one or more instances of JB, Q2 is independently a bond, -0-, -S-, -NR’-, -C(O)-, -C(=NR)-, -C(=NR)NR-, -NRC(™NR)NR-, -C02-, -OC(O)-, -C(0)NR’-, -C(0)NRC(0)0- -NRC(0)NRC(0)0--NRC(O)-, ~NRC(0)NR’—, -NRC02- -0C(0)NR’-, -S(O)-, -S02-, -S02NR’-, -NRSO2-, or -NRSO2NR’-, -P(0)(0R)0-, -0P(0)(0Ra)0-, -P(0)20-, -C02S02-, or -(CR6R7)P-Y1-; Q3 is independently a bond, -C(O)-, -C(=NR)-, -C(=NR)NR-, -C02-, -C(0)NR’-, -SO2-, -S02NR’- -C(0)NRC(0)0-, or-fCR^lp-Y1-; optionally, each Q2 and Q'\ together with R5, independently form a 5-7 membered ring optionally substituted with one or more instances of JE1; Rs and R9 are each independently -H, halogen, cyano, hydroxy, amino, carboxy, Ci-C6 alkyl, Ci-C6 haloalkyl, Ci-Cg cyanoalkyl, C2-Ce alkoxyalkyl, Ci-Ce aminoalkyl, Ci-C6 hydroxyalkyl, Ci-C6 carboxyalkyl, C|-Cc alkoxy, Ci-C<; haloalkoxy, CpCe aminoalkoxy, Ci-Cs cyanoalkoxy, Ci-Cs hydroxyalkoxy , or C2-Ce alkoxyalkoxy; or Rs, together with Q2 and R5, optionally and independently forms a 5-7 membered, non-aromatic ring optionally substituted with one or more instances of JEt; R10 is independently -H or a Ci-Cs alkyl group optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, amino, carboxy, Ci-Cralkoxy, Ci-Ce haloalkoxy, Ci-C6aminoalkoxy, Ci-Cs cyanoalkoxy, Ci-C6 hydroxyalkoxy, C2-C6 alkoxyalkoxy, C3-C8 non-aromatic carbocycle, phenyl, a 4-8 membered non-aromatic heterocycle, and a 5-6 membered heteroaiyl group, wherein each of said carbocycle, phenyl, heterocycle and heteroaryl group is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, amino, carboxy, Ci-Cs alkyl, Ci-Ce haloalkyl, C[-C<5 cyanoalkyl, C2-C6 alkoxyalkyl, Ci-Cs aminoalkyl, Ci-Ce hydroxyalkyl, Cr Q alkoxy, Cj-Ce haloalkoxy, Ci-C6 aminoalkoxy, Ci-Ce cyanoalkoxy, Ci-Ce hydroxyalkoxy, and C2-Ce alkoxyalkoxy; Rn, R12, R13 and R14 are each independently -H, halogen, or Ci-Ce alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo, hydroxy, amino, carboxy, Q-Cealkoxy, Ci-C6 haloalkoxy, Ci-Cg aminoalkoxy, Cj-Cr, cyanoallcoxy, Ci-Ce hydroxyalkoxy, and C2-Cg alkoxyalkoxy; optionally, R13 and R14, together with the carbon atom to which they are attached, form a cyclopropane ring, optionally substituted with one or more instances of methyl; n, m and k are each independently 0, 1 or 2; x and y are each independently 0, 1 or 2; and z is 1 or 2.
8. 8. The method of claim 7, wherein: n and m are each independently 0 or 1 when rings A and B are 3-6 membered; or n and m are each independently 0, 1 or 2 when rings A and B are 7-10 membered; provided that if Yl is a bond, then R5 is neither H nor a Ci-s aliphatic group; and provided that if each Q2 and Q3 independently is a bond, then R5 is neither -H nor a Ci-6 aliphatic group.
9. 9. The method of claim 7 or 8, wherein: ring A is a Cj-Cs non-aromatic carbocycle or heterocycle, the carbocycle and heterocylce ptionally further substituted with one or more instances of JA and JB, respectively; rings B and C are each independently a 4-8 membered non-aromatic heterocycle optionally and independently further substituted with one or more instances of JB; ring D is a 4-8 membered non-aromatic heterocycle optionally substituted with one or more instances of JDl; Q1 is independently a bond, -0-, -S-, -NR’-, -C(O)-, -C(=NR)-, -C02--OC(O)-, -C(0)NR’-, -C(0)NRC(0)0- -NRC(0)NRC(0)0-, -NRC(O)-, -NRC(0)NR’-, -NRCOa- -0C(0)NR’-, -S(0>, -S02- -S02NR’-, -NRS02- or -NRS02NR’-, or -(CR6R7)p-Y1-; Q2 is independently a bond, -Ο-, -S-, -NR’-, -C(O)-, -C(=NR)-, -C02-, -OC(O)-, -C(0)NR’“, -C(0)NRC(0)0™, -NRC(0)NRC(0)0-, -NRC(O)-—NRC(0)NR’-, -NRCO2-, -0C(0)NR’-, -S(O)-, ~S02- -S02NR’-, -NRS02- or -NRS02NR’-, or-(CR6R7)p-Y'-; Q3 is independently a bond, -C(O)-, -C(=NR)-, -C02-, -C(0)NR’-, -S02- -S02NR’-, -C(0)NRC(0)0-, or -(CRfiR7)p.......Y1-; optionally, each of Q2 and Q3, togetlrer with R5, independently forms a 5-7 membered ring optionally substituted with one or more instances of J'; Y1 is independently a bond, -0-, -S-, -NR’--, -0(0)-, -C(=NR)-, -CO2-, -0C(0)-, -C(0)NR-, -C(0)NRC(0)0-, -NRC(0)NRC(0)0- -NRC(O)-, -NRC(0)NR’-, -NRCO2-, -0C(0)NR’-, -S(0)-, -S02-, -S02NR’-, -NRS02-, or -NRS02NR’-; R is: i) -H; ii) a Ci-Cg aliphatic group optionally substituted with one or more instances of JCI; iii) a C3-C8 non-aromatic carbocycle, or a 6-10 membered carbocyclic aryl group, each optionally and independently substituted with one or more instances of JC1; or iv) a 4-8 membered non-aromatic heterocycle, or a 5-10 membered heteroaiyl group, each optionally and independently substituted with one or more instances of JDS; or R5, together with Q1, optionally forms a 5-7 membered, non-aromatic ring optionally substituted with one or more instances of JE1; and R8 and R9 are each independently -H, halogen, cyano, hydroxy, amino, carboxy, Ci-Cc alkyl, Ci-Cg haloalkyl, Ci-Cg cyanoalkyl, C2-Ce alkoxyalkyl, Ci-C6 aminoalkyl, Ci-Cg hydroxyalkyl, C|-Cg alkoxy, Ci-Cg haloalkoxy, Ci-Cg aminoalkoxy, C1 -Cgcy an oalkoxy, Ci-Ce hydroxyalkoxy, or C2-C<; alkoxyalkoxy; Ru, R12, R13 and R14 are each independently -H, halogen, or Ct-Cg alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo, hydroxy, amino, carboxy, Ci-Cg alkoxy, Ci-Cg haloalkoxy, C|-Ce aminoalkoxy, Ci-Cgcyanoalkoxy, Ci-Cg hydroxyalkoxy, and C2-C6 alkoxyalkoxy; each of JA and JB is independently selected from the group consisting of halogen, cyano, oxo, -NCO, andQ'-R5; or optionally two JA and two JB, respectively, together with the atom(s) to which they are attached, independently form a 5-7 membered ring that is optionally substituted with one or more instances of Jm; and each of JC1 and JD! is independently selected from the group consisting of halogen, cyano, oxo, Ra, -ORb, -SRb, -S(0)Ra, -S02Ra, -NRbRc, -C(0)Rb, -C(0)0Rb, -0C(0)Rb, -NRC(0)Rb, -C(0)NRbRc, -NRC(0)NRbRc, -NRC(0)0Rb, -OCONRbRc, -C(0)NRC02Rb, -NRC(0)NRC(0)0Rb, -C(0)NR(0Rb), -S02NRcRb, -NRS02Rb, -NRS02NRcRb, and -P(0)(0Ra)2, or optionally, two JCi and two JD1, respectively, together with the atoms to which they are attached, independently form a 5-7-membered ring that is optionally substituted with one or more instances of JE!, and fused to the respective ring to which they are attached.
10. 10. The method of claim 9, wherein: ring A is a CrCs non-aromatic carbocycle optionally and independently is further substituted with one or more instances of JA; rings B and C are each independently a 4-8 membered non-aromatic heterocycle optionally and independently further substituted with one or more instances of JB; ring D is a 4-8 membered non-aromatic heterocycle optionally substituted with one or more instances of JD1; Q1 is independently a bond, -0-, -S-, -NR’-, -C(0)-, -C02-, -0C(0)-, -C(0)NR’-, -C(0)NRC(0)0- -NRC(0)NRC(0)0- -NRC(O)-, -NRC(0)NR’-, -NRCOo- -0C(0)NR’-, -S(0)-, -S02- -S02NR’-, -NRS02-, or-NRS02NR’-, or -(CR6R7)P-Y1-; Q2is independently bond, -0-, -S-, -NR-, -C(0)-, -C02-, -0C(0)-, -C(0)NR-, -C(0)NRC(0)0- -NRC(0)NRC(0)0- -NRC(0)-, -NRC(0)NR-, ~NRC02--0C(0)NR- -S(0)-, -S02- -N(R)S02-, -S02NR’-, -NRS02NR’-, or -(CR6R7)p-Y-; Q3 is independently a bond, -C(0)-, ~C02-, -C(0)NR’-, -S02- -S02NR’--C(0)NRC(0)0-, or -(CRfiR7)P-Y1-; optionally, each of Q2 and Q3, together with R5, independently forms a 5-7 membered Hi ring optionally substituted with one or more instances of J ; Y1 is independently a bond, -0-, -S-, -NR’-, -C(0)-, -C02-, -0C(0)-, -C(0)NR’-, -C(0)NRC(0)0~, -NRC(0)NRC(0)0-, -NRC(O)-, -NRC(0)NR’-, -NRC02-, -0C(0)NR’-, -S(0)-, -S02~, -S02NR’-, -NRSO2-, or -NRS02NR’-; each of JA and JB is independently selected from the group consisting of halogen, cyano, oxo, andQ'-R5; or optionally two JA and two JB, respectively, together with the atom(s) to which they are attached, independently form a 5-7 membered ring that is optionally substituted with one or more instances of JE£ and fused to the ring to which they are attached; and each of JC1 and JD1 is independently selected from the group consisting of halogen, cyano, oxo, Ra, -0Rb, -SRb, -S(0)Ra, -S02Ra, -NRbRc, -C(0)Rb, -C(0)0Rb, -0C(0)Rb, -NRC(0)Rb, -C(0)NRbRc, -NRC(0)NRbRc, -NRC(0)0Rb, -OCONRbRc, -C(0)NRC02Rb, -NRC(0)NRC(0)0Rb, -C(0)NR(0Rb), -S02NRcRb, -NRS02Rb, and -NRS02NRcRb, or optionally, two JC1 and two JDI, respectively, together with the atoms to which they are attached, independently form a 5-7-membered ring that is optionally substituted with one or more instances of JEl, and fused to the respective ring to which they are attached.
11. 11. The method of any one of claims 1-10, wherein: Z1 is -H, Ci-Cs alkyl, -0(Ci-Cfi alkyl), -F, -Cl, -CN, -C02H, -C02(Ci-CG alkyl), -CONH2, -CONH(Ci-C6 alkyl), or -CON(Ci-Ce alkyl)2, wherein each of said alkyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(Ci-C4 alkyl), -N(C,-C4 alkyl)2, -OCO(Ci-C4 alkyl), -CO(Ci-C4 alkyl), -C02H, -C02(C,-C4 alkyl), and Ci-C4 alkoxy; and Z2 is -H, CrC6 alkyl, -0(Ci-C6 alkyl), -NH2, -NH(Ci-C6 alkyl), or -N(Ci-C6 alkyl)2, wherein each of said alkyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(Ci-C4 alkyl), -N(CrC4 alkyl)2, -OCO(Ct-C4 alkyl), -CO(C,-C4 alkyl), -C02H, -C02(Ci-C4 alkyl), and Ci-C4 alkoxy.
12. 12. The method of any one of claims 1-11, wherein: Z1 is -H, -F, -Cl, -CF3, -CH3, or-CN; and Z2 is ™H or an optionally substituted Ci-Cs alkyl.
13. 13. The method of any one of claims 1-12, wherein: R2 is -H; and R3 is -H, -F, -Cl, -CF3, -CH3, -C2Hs, -NH2j -NH(CH3), or-N(CH3)2.
14. 14. The method of any one of claims 1-13, wherein: Z1 is -H, -F, -Cl, -CF3, -CH3, or-CN; Z is -H or Ci-Ce alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, and -0(Ct-C4 alkyl); Z is -H or C|-Ce alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, and -0(Ct-C4 alkyl); R1 is -H; R2 is -H; R3 is independently -H, -Cl or -F; Re and R7 are each independently -H or -CH3, or together with the carbon atoms to which they arc attached they form a cyclopropane ring; each R8 is independently -H, halogen, cyano, hydroxy, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C2-C4 alkoxyalkyl, -(XC1-C4 alkyl), -ΝΗ2, -NH(Ci-C4 alkyl), or -N(C,-C4 alky 1)2; each R9 is independently -H or -CH3; R11 and R12 are each independently ~H or -CH3; and R13 and R14 are each independently -H or -CH3, or together with the carbon atoms to which they are attached they form a cyclopropane ring.
15. 15. The method of any one of claims 9-Π, wherein the compound is represented by any one of the structural formulae below (II), (III), (IV) and (V):

    (IV) (V) or a pharmaceutically acceptable salt thereof, wherein: R3 is -H, -F, -Cl, -CFj, -NH2, -NH(CH3), or-N(CH3)2; Z1 is -H, -F, -Cl, -CF3, C1-C4 alkyl,-CH2NH2, -C(0)NH2j -C(0)NH(CH3), -C(0)N(CH3)2, -0(Ci-C4 alkyl), or -CN; each R and R’ are independently -H or Ci-Ce alkyl; ring A is an optionally substituted, C4-C7 non-aromatic carbocycle; rings B and C are each independently an optionally substituted, 4-7 membered nonaromatic heterocycle; ring D is an optionally substituted, 4-7 membered non-aromatic heterocyclc;
16. 16. The method of claim 15, wherein: Zl is -H, -F, -Cl, -CF3, -CH3, or-CN; and Z2 is -H or an optionally substituted Ci-Ce alkyl.
17. 17. The method of claim 13, wherein R3 is independently -H, -Cl or -F.
18. 18. The method of claim 17, wherein: R6 and R7 are each independently -H or -CH>„ or together with the carbon atoms to which they are attached they form a cyclopropane ring; each R8 is independently -H, halogen, cyano, hydroxy, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C2-C4 alkoxyalkyl, -0{Ci-C4 alkyl), -NH2, -NHCC1-C4 alkyl), or -N(Cj-C4 alkyl)2. each R9 is independently -H or -CH3; R11 and R12 are each independently-H or -CH3; and R1'· and R14 are each independently -H or -CH3, or together with the carbon atoms to which they are attached they form a cyclopropane ring.
19. 19. The method of any one of claims 15-18, wherein the compound is represented by the following structural formula (XIA) or (XIB):

    (ΧΙΑ), (XIB), or a pharmaceutically acceptable salt thereof, wherein: ring A is a 5-7 membered ring optionally further substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, Ci-Ce alkyl, C2-C6 alkenyl, -NH2, -NH(Ci-C6 alkyl), -N(C]-C6 alkyl)2, -0(Ci-C6 alkyl), -C(0)NH2, -C(0)NH(C,-C6 alkyl), -C(0)N(Ci-C6 alkyl)2, -C(0)(Ci-C6-alkyl), -0C(0)(Ci-C6 alkyl), -NHC(0)(CrC6 alkyl), -N(Cl-C6 alkyl)C(0)(CrC6 alkyl), and -C02Rb; wherein each of said alkyl and alkenyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(Ci-C4 alkyl), -N(Ci-C4 alkyl)?., -OCO(Ci-C4 alkyl), -CO(Ci-C4 alkyl), -C02H, -C02(Ci-C4 alkyl), and C1-C4 alkoxy.
20. 20. The method of claim 19, wherein x is 0 or 1; and n is 0 or 1.
21. 21. The method of claim 20, wherein Q2 is -Ο-, -NH-, -N(CH3>, -C(O)-, -C02-, -C(0)NH-, -C(0)N(CH3)-, -NHC(O)-, -N(CH3)C(0)-, -NHC(0)NR’--N(CH3)C(0)NR’- -NHC02- -N(CH3)C02- -0C(0)NR’-, -NHSO2-, -N(CH3)S02-, -SO2NR-, or-(CR6R7)p-Y'-.
22. 22. The method of claim 21, wherein: R5 is independently i) -H; ii) a CpCs-aliphatic group optionally substituted with one or more instances of JC1; iii) a C3-Cs non-aromatic carbocycle optionally substituted with one or more instances of JC1; iv) a phenyl group optionally substituted with one or more instances of JC1; v) a 4-8 membered non-aromatic heterocycle optionally substituted with one or more instances of JD1 or vi) a 5-6 membered heteroaiyl ring optionally substituted with one or more instances of JD1; and each of JC1 and JDI is independently selected from the group consisting of halogen, cyano, oxo, Ra, -ORb, -SRb, -S(0)Ra, -S02Ra, -NHRC, -C(0)Rb, -C(0)0Rb, -0C(0)Rb, -NHC(0)Rb,.....C(0)NHRc, -NHC(0)NHRc, -NHC(0)0Rb, -OCONHRc, -NHC(0)NHC(0)0Rb, -N(CH3)RC, -N(CH3)C(0)Rb , -C(0)N(CH3)Rc, -N(CH3)C(0)NHRc, -N(CH3)C(0)0Rb, -OCON(CH3)R£, -C(0)NHC02Rb, -C(0)N(CH3)C02Rb, -N(CH3)C(0)NHC(0)0Rb, -NHS02Rb, -S02NHRb, -S02N(CH3)Rb, and -N(CH3)S02Rb.
23. 23. The method of claim 22, wherein: ring A is optionally further substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, C1-C4 alkyl, -OCC1-C4 alkyl), -NH2, -NH(Cj-C4 alkyl), -N(Ci-G, alkyl)2, -C(0)(Ci-C4 alkyl), -OCO(Ci-C4 alkyl), -C02H, and -C02(C|-C4 alkyl), wherein each of said alkyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(Ci-C4 alkyl), -N(Ci-C4 alkyl)2, -OCO(Ci-C4 alkyl), -CO(Ci-C4 alkyl), -C02H, -C02(Ci-C4 alkyl), and C1-C4 alkoxy.
24. 24. The method of any one of claims 19-23, wherein the group ~-[C(R13R14)]x-ringA-Q2-R5 is independently selected from:

    wherein each of rings A1-A27 is independently and optionally further substituted.
25. 25. The method of claim 24, wherein each of rings A1-A27 is optionally and independently further substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, ™NH2, -NH(Ci-C2 alkyl), -NH(Ci-C2 alkyl)2} C1-C2 alkyl, C1-C2 haloalkyl, C1-C2 hydroxyalkyl, C2-C4 alkoxyalkyl, Ci-C2 alkoxy, Ci-C2 hydroxyalkoxy, C[-C2 haloalkoxy, C2-C4 alkoxyalkoxy, -CO2H, and -C02(C!-C4 alkyl).
26. 26. The method of 25, wherein R5 is independently: i) -Η; ϋ) a Ci-Ce-aliphatic group optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, C1-C4 alkyl, -0(C]-C4 alley 1), -NH2, -NH(Ci-C4 alkyl), -N(Ci-G, alkyl)2, -C(0)(Ci-C4 alkyl), -0C(0)(C,-C4 alkyl), -C(0)0(Ci-C4 alkyl), -C02H, C:,-Cg non-aromatic carbocycle, 4-8 membered non-aromatic heterocycle, phenyl, and 5-6 membered heteroaryl; iii) a C3-C7 non-aromatic carbocycle, a 4-7 membered nonaromatic heterocycle, a phenyl group, or a 5-6 membered heteroaryl ring, each of which is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, C1-C4 alkyl, -0(Ci-Gi alkyl), -NH2, -NH(C,-C4 alkyl), -N(Ci-C4 alkyl)2, -C(0)(Ci-C4 alkyl), -0C(0)(C|-C4 alkyl), -C(0)0(Ci-C4 alkyl), and -C02H; wherein each of said alkyl groups for the substituents of R5 is independently and optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(Ci-C4 alkyl), -N(Ci-C4 alkyl)2, -OCO(Ci-C4 alkyl), -CO(Ci-C4 alkyl), -C02H, -C02(Ci-C4 alkyl), and C1-C4 alkoxy; and wherein each of said carbocycle, phenyl, heterocycle, and heteroaryl for the substituents of the CrC6-aliphatic group represented by R5 is ndependcntly and optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, C1-C4 alkyl, -NH2, -NH(Ci-C4 alkyl), -N(Ci-C4 alkyl)2, -0C0(Ci-C4 alkyl), -CO(Ct-C4 alkyl), -C02H, -C02(Ci-C4 alkyl), and CrC4 alkoxy.
27. 27. The method of claim 26, wherein the group -[C(R13R14)]x-ringA-Q2-R5 is selected from one of the structures depicted below:

    each of rings A6, A8, All, A14 and A15 is optionally and independently further substituted; and each R8 independently is halogen, cyano, hydroxy, Ci-C4 alkyl, C!-C4haloallcyl, Ci-C4 hydroxyalkyl, C2-C4 alkoxyalkyl, -0(Ci-C4 alkyl), -NH2, -NH(Ci-C4 alkyl), or -N(Ci-C* alkyl)2.
28. 28. The method of claim 27, wherein R5 is: i) -H; ii) an optionally substituted Ci-Ce alkyl group; iii) an optionally substituted, C3-C7 non-aromatic carbocycle; or iv) an optionally substituted, 4-7 membered non-aromatic heterocycle; wherein said alkyl group represented by R5 is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(Ci-C4 alkyl), -N(C, -C4 alkyl)2, -OCO(Ci-C4 alkyl), -CO(Ci-C4 alkyl), -C02H, -C02(Ci-C4 alkyl), Ci-C4 alkoxy, an optionally substituted, C3-C7 non-aromatic carbocycle, and an optionally substituted, 4-7 membered non-aromatic heterocycle; and wherein each of said carbocycles and heterocycles represented by Rs, and referred to for the substituents of the Ci-Q alkyl group represented by R5 is independently and optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, Ci-C4 alkyl, -0(Ci-C4 alkyl), -NH2, -NH(Ci-C4 alkyl), ~N(C^C4 alkyl)2, -C(0)(Ci-C4 alkyl), -0C(0)(Ci-C4 alkyl), -C(0)0(Ci-C4 alkyl) and -C02H, each of said alkyl groups being optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(Ci-C4 alkyl), -N(Ci-C4 alkyl)2, -OCO(Ci-C4 alkyl), -CO(Ci-C4 alkyl), -C02H, -C02(Ci-C4 alkyl), and Ci-C4 alkoxy.
29. 29. The method of any one of claims 15-18, wherein the compound is represented by the following structural formula (ΧΠΑ) or (XIIB):

    or

    (XIIA) (XIIB), or a pharmaceutically acceptable salt thereof; wherein: ring B is optionally further substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, Ci-Cs alkyl, C2-Cr, alkenyl, -NH2, -NH(Ci-C6 alkyl), -N(C,-C6 alkyl)2, -0(Ci.Cc alkyl), -C(0)NH2, -C(0)NH(Ct-C6 alkyl), -C(0)N(C,-C6 alkyl)2, -0(0)((^-C6-alkyl), -0C(0)(Ci-C6 alkyl), -NHC(0)(Ci-C6 alkyl), -N(Ci-Cg alkyl)C(0)(Ci-C6 alkyl), and -C02Rb; wherein each of said alkyl and alkenyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(C!-C4 alkyl), -N(Ci-C4 alkyl)2, -OCO(Ci-C4 alkyl), -CO(Ci-C4 alkyl), -C02H, -C02(Ci-C4 alkyl), and Ci-C4 alkoxy.
30. 30. The method of claim 29, wherein y is 0 or 1.
31. 31. The method of claim 30, wherein Q3 is independently -C(O)-, -C02-, -C(0)NH-, -C(0)N(C%)-, -C(0)NHC(0)0- -C(0)N(CH3)C(0)0-, -S02-, -S02NH--S02N(CH3)-,or -fCRVjp-Y1-.
32. 32. The method of claim 31, wherein: R5 is independently i) -H; ii) a Ci-Cg-alipahtic group optionally substituted with one or more instances of JCi; iii) a C3~CS non-aromatic carbocycle optionally substituted with one or more instances of JC1; iv) a phenyl group optionally substituted with one or more instances of JC1; v) a 4-8 membered non-aromatic heterocycle optionally substituted with one or more instances of JD1 or vi) a 5-6 membered heteroaiyl ring optionally substituted with one or more instances of JD1; and each of JC1 and JD1 is independently selected from the group consisting of halogen, cyano, oxo, Ra, -ORb, -SRb, -S(0)Ra,.....S02Ra, -NHRC, -C(0)Rb, -C(0)0Rb, ~0C(0)Rb, ~-NHC(0)Rb, -C(0)NHRc, -NHC(0)NHRc, -NHC(0)0Rb, -OCONHRc, -NHC(0)NHC(0)0Rb, -N(CH3)Rc, -N(CH3)C(0)Rb, -C(0)N(CHj)Rc, -N(CH3)C(0)NHRc, “N(CH3)C(0)0Rb, -OCON(CH3)Rc, -C(0)NHC02Rb, -C(0)N(CH3)C02Rb, -N(CH3)C(0)NHC(0)0Rb, -NHS02Rb, -S02NHRb, -S02N(CH3)Rb, and -N(CH3)S02Rb.
33. 33. The method of claim 32, wherein ring B is optionally further substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, C1-C4 alkyl, -0(Ci-C4 alkyl), ~NH2, -NH(Ci-C4 alkyl), -N(Ci-C4 alkyl)2, -0C(0)(Ci-C4 alkyl), -C(0)(Ci-C4 alkyl), -C02H, and -C02(C]-C4 alkyl), wherein each of said alkyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(C,-C4 alkyl), -N(Ci-CU alkyl)2, -OCO(C,-C4 alkyl), -CO(C,-C4 alkyl), -C02H, -COz(Ct-C4 alkyl), and C1-C4 alkoxy.
34. 34. The method of any one of claims 29-33, wherein ring B is independently selected from one of the structures depicted below:

    wherein each of rings B1-B9 is optionally and independently substituted.
35. 35. The method of claim 34, wherein each of rings B1 to B9 is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(Ci-C2 alkyl), -NH(Ci-C2 alkyl)2, Ci-C2 alkyl, Ci-C2 haloalkyl, Q-C? hydroxyalkyl, C2-C4 alkoxyallcyl, Ci-C2 alkoxy, Ci-C2 hydroxy alkoxy, Ci-C2 haloalkoxy, C2-C4 alkoxy alkoxy, -C02H, and -C02(Ci-C4 alkyl).
36. 36. The method of claim 35, wherein R5 is independently: i) -H; ii) a CrCe-aliphatic group optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, C[-C4 alkyl, -0(Ci-C4 alkyl), -NH2, -NH(Ci-C4 alkyl), -N(Ci-C4 alkyl)2, -C(0)CCi-C4 alkyl), -0C(0)(Ci-C4 alkyl), -C(0)O(Ci-C4 alkyl), -C02H, C3-C8 noil-aromatic carbocycle, 4-8 membered non-aromatic heterocycle, phenyl, and 5-6 membered heteroaryl; iii) a C3-C7 non-aromatic carbocycle, a 4-7 membered non-aromatic heterocycle, a phenyl group, or a 5-6 membered heteroaryl ring, each of which is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, C1-C4 alkyl, -0(Ci-C4 alkyl), -NH2, -NH(Ci-C4 alkyl), -N(Ci.....C4 alkyl)2, -C(0)(Ci-C4 alkyl), -0C(0)(C1-C4 alkyl), -C(0)0(Ci-C4 alkyl), and -C02H; wherein each of said alkyl groups for the substituents of R5 is independently and optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(Ci-C4 alkyl), -N(Ci-C4 alkyl)2, -OCO(Ct-C4 alkyl), -CO(Cs-C4 alkyl), -C02H, -CCriCC^ alkyl), and C1-C4 alkoxy; and wherein each of said carbocycle, phenyl, heterocycle, and heteroaryl for the substituents of the Ci-Ce-aliphatic group represented by R5 is independently and optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, Cj-C4 alkyl, -NH2, -NH(Ci-C4 alkyl), -N(Ci-C4 alkyl)2, -OCO(Ci-C4 alkyl), -C0(Ci-C4 alkyl), -COjH, -C02(Ci-C4 alkyl), and C,-C4 alkoxy.
37. 37. The method of claim 36, wherein the group (ring B)-Q3-R5 is

    wherein: ring B2 is optionally and independently further substituted; and R5 is: i) -H; ii) an optionally substituted Ci-Cc alkyl group; iii) an optionally substituted, C3-C7 non-aromatic carbocycle; or iv) an optionally substituted, 4-7 membered non-aromatic heterocycle; wherein said alkyl group represented by R5 is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NHfCrCj alkyl), -N(Ci-C4 alkyl)2, -OCO(Ci-C4 alkyl), -CO(Ci-C4 alkyl), -C02H, -C02(Ci-C4 alkyl), Ci-C4 alkoxy, an optionally substituted, C3-C7 non-aromatic carbocycle, and an optionally substituted, 4-7 membered non-aromatic heterocycle; and wherein each of said carbocycles and heterocycles represented by R5, and referred to for the substituents of the Cj-Ce alkyl group represented by R5 is independently and optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, Ci-C4 alkyl, -0(Ci-C4 alkyl), -NH2, -NH(Ci-C4 alkyl), -N(C,-C4 alkyl)2, -C(0)(C,-C4 alkyl), -0C(0)(Ci~C4 alkyl), -C(0)0(Ci-C4 alkyl) and -C02H, wherein each of said alkyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(Ci-C4 alkyl), -N(Ct-C4 alkyl)2, -OCO(Ci-C4 alkyl), -CO(Ci-C4 alkyl), -C02H, -C02(Ct-C4 alkyl), and C1-C4 alkoxy.
38. 38. The method of any one of claims 15-18, wherein the compound is represented by the following structural formula (XIII):

    (XIII), or a pharmaceutically acceptable salt thereof, wherein: ring C is 5-6 membered and optionally further substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, C[-Ce alley 1, C2-C6 alkenyl, -NH2, -NH(Ci-C6 alkyl), -N(Ci-C6 alkyl)2, -0(Ci.C6 alkyl), -C(0)NH2, -C(0)NH(CrC6 alkyl), -C(0)N(C!-C6 alkyl)2, -C(0)(CrC6-alkyl), -0C(0)(CrC6 alkyl), -NHC(0)(Ci-C6 alkyl), -N(Ci-C6 alkyl)C(0)(Ci-C6 alkyl), and -C02Rb; wherein each of said alkyl and alkenyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(C,-Q alkyl), -N(Ci-C4 alkyl)2, -OCO(CrO, alkyl), -COCC1-C4 alkyl), -C02H, -C02(Ci-C4 alkyl), and C1-C4 alkoxy.
39. 39. The method of claim 38, wherein R10 is -H or Ci-C6-alkyl.
40. 40. The method of claim 39, wherein ring C is optionally further substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, C1-C4 alkyl, -0(C,-C4 alkyl), -NH2, -NH(Ci-C4 alkyl), -N(Ci-C4 alkyl)2, -C(0)(Ci-C4 alkyl), -0C(O)(Ci-C4 alkyl), -C02H, and -C02(Ci-C4 alkyl), wherein each of said alkyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(Ci-C4 alkyl), -N(Ci-C4 alkyl)2, -OCO(C!-C4 alkyl), -CO(Ci-C4 alkyl), -C02H, -C02(Ci-C4 alkyl), and C1-C4 alkoxy.
41. 41. The method of any one of claims 38-40, wherein ring C is independently selected from

    wherein each of rings C1-C5 is optionally and independently substituted.
42. 42. The method of claim 41, wherein each of rings C1-C5 is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(Ci-C2 alkyl), ™NH(Ci-C2 alkyl)2, Ci-C2 alkyl, Ci-C2 haloalkyl, CrC2 hydroxyalkyl, C2-C4 alkoxyalkyl, CrC2 alkoxy, C1-C2 hydroxyalkoxy, C1-C2 haloalkoxy, C2-C4 alkoxyalkoxy, -C02H, and -C02(C|-C4 alkyl).
43. 43. The method of any one of claims 15-18, wherein the compound is represented by the following structural formula (XIV):

    (XIV), or a pharmaceutically acceptable salt thereof, wherein: ring D is optionally further substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, Ci-Cs alkyl, C2-Ce alkenyl, -NH2, -NH(Ci-C6 alkyl), -N(Ci-C0 alkyl)2, -0(Ci.C6 alkyl), -C(0)NH2, -C(0)NH(Ci-C6 alkyl), -C(0)N(C,-C6 alkyl)2, -C(0)(Ci-C6-alkyl), -0C(0)(Ci-C6 alkyl), -NHC(0)(Ci-C6 alkyl), -N(C,-C6 alkyl)C(0)(CrCe alkyl), and -C02Rb; wherein each of said alkyl and alkenyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(CrC4 alkyl), -N(C,-C4 alkyl)2, -OCO(C]-C4 alkyl), -CO(Ci-C4 alkyl), -C02H, -C02(Ci-C4 alkyl), and Ci-C4 alkoxy.
44. 44. The method of claim 43, wherein z is 1.
45. 45. The method of claim 44, wherein ring D is independently selected from the group consisting of

    wherein: each of rings D1-D7 is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, C1-C4 alkyl, -0(Ci-C4 alkyl), -NH2, -NH(Ci-C4 alkyl), -N(C,-C4 alkyl)2, -C(0)(Ci-C4 alkyl), -C02H, and -C02(Ci-C4 alkyl), wherein each of said alkyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(Ci-C4 alkyl), -N(Ci-C4 alkyl)2, -OCO(Ci-C4 alkyl), -CO(Ci-C4 alkyl), -C02H, -C02(Ci-C4 alkyl), and C5-C4 alkoxy; and each Rd is independently -H, Ch-Ce alkyl or - C(0)(Ci-C6 alkyl), wherein each of said alkyl moiety is optionally and independently substituted with one or more groups selected from halogen, cyano, hydroxy, oxo, -NH2, -NH(Ci-C4 alkyl), -N(Ci-C4 alkyl)2, -OCO(Ci-C4 alkyl), -CO(C,-C4 alkyl), -C02H, -C02(C,-C4 alkyl), and C,-C4 alkoxy.
46. 46. The method of any one of claims 1-8, wherein R4 is:

    wherein: ring E is a C4-Ci0 non-aromatic carbocycle optionally further substituted with one or more instances of JA; rings F is a 4-8 membered non-aromatic heterocycle optionally substituted with one or more instances of JE1; R9 is independently-H, halogen, cyano, hydroxy, amino, carboxy, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce cyanoalkyl, C2-Ce alkoxyalkyl, CrC6 aminoalkyl, Ci-C6 hydroxyalkyl, Cj-Cc carboxyalkyl, Ci-Ce alkoxy, Cj-Cehaloalkoxy, Ci-Ce aminoalkoxy, Ci-Q cyano alkoxy, Ci-Ce hydroxyalkoxy, or C?-Ce alkoxyalkoxy; R11, R12, R13 and R14 are each independently -H, halogen, or C1-C6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo, hydroxy, oxo, amino, carboxy, Ci-C6 alkoxy, CrCc haloalkoxy, Ci-Ce aminoalkoxy, Ci-Ce cyanoalkoxy, Ci-Ce hydroxyalkoxy, and C2-Ce alkoxyalkoxy; optionally, R13 and R14, together with the carbon atom to which they are attached, form a cyclopropane ring, optionally substituted with one or more instances of methyl; s is 0,1 or 2; and x is 0, 1 or 2.
47. 47. The method of claim 46, wherein ring F is selected from any one of rings F1-F6:

    > each of rings F1-F6 optionally and independently substituted; and each Rf is independently -H or Ci-Ce alkyl optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, amino, carboxy, C\-C(, alkoxy, Cj-CV, haloalkoxy, Ci-C6aminoalkoxy, Ci-Cecyanoalkoxy, Ci-Ce hydroxyalkoxy and C2-C6 alkoxyalkoxy.
48. 48. The method of claim 47, wherein each rings F1-F6 are independnetly and optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, hydroxy, C1-C4 alkoxy, and C1-C4 alkyl optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, hydroxy, and -CXC1-C4 alkyl).
49. 49. The method of any one of claims 46-48, wherein: R9 is independently -H, halogen, cyano, hydroxy, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C2-C4 alkoxyalkyl, -CXC1-C4 alkyl), -NH2, -NH(Ci-C4 alkyl), or -N(Ci~C4 alkyl)?.; and ring E is a C4-C8 non-aromatic carbocycle optionally further substituted with one or more instances of JA.
50. 50. The method of claim 49, wherein ring F is selected from any one of rings F1-F5:

    wherein each of rings F1-F5 optionally and independently substituted.
51. 51. The method of any one of claims 1-13, wherein R4 is:

    each of rings G1-G4 is independently a 5-10 membered non-aromatic bridged carbocycle optionally further substituted with one or more instances of JA, and ring GS is a 510 membered non-aromatic bridged heterocycle optionally further substituted with one or more instances of JB; X is -0-, -S-, or -NRg-; Rs and R9 are each independently -H, halogen, cyano, hydroxy, amino, carboxy, Ci-Ce alkyl, Ci-Cs haloalkyl, C|-C6 cyanoalkyl, C2-C6 alkoxyalkyl, C1-C6 aminoalkyl, Ci-Ce hydroxyalkyl, Ci-Ce carboxyalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, Ci-Ce aminoalkoxy, Ci-Cecyanoalkoxy, Ci-Ce hydroxyalkoxy, or C2-C5 alkoxyalkoxy; R13 and R14 are each independently -H, halogen, or C|-Ce alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo, hydroxy, oxo, amino, carboxy, Ci-Ce alkoxy, Ci-Ce haloalkoxy, Ci-C6 aminoalkoxy, Ci-Ce cyanoalkoxy, C1 -Co hydroxy alkoxy, and C2-C6 alkoxyalkoxy; optionally, RB and R14, together with the carbon atom to which they are attached, form a cyclopropane ring, optionally substituted with one or more instances of methyl; R21, R22, R23, R24, and R25are each independently -H, halogen, -OH, Ci-Ce alkoxy, or Ct-C6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo, hydroxy, oxo, amino, carboxy, Ci-Cg alkoxy, Ci-Ce haloalkoxy, C1-C6 aminoalkoxy, Ct-Ce cyanoalkoxy, Ci-Ce hydroxyalkoxy, and Cj-Ce alkoxyalkoxy; Rg is -H or C1-C6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo, hydroxy, amino, carboxy, Ci-Cealkoxy, Q-C6 haloalkoxy, Ci-Ce aminoalkoxy, Ci-Cecyanoalkoxy, Ci-Cfi hydroxyalkoxy, and C2-C6 alkoxyalkoxy; q is 0, 1 or 2; x is 0,1 or 2; and r is 1 or 2.
52. 52. The method of claim 51, wherein R4 is:
53. 53. The method of claim 52, wherein each of R8 and R9 is independently -H, halogen, cyano, hydroxy, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C2-C4 alkoxyalkyl, -0(Ci-C4 alley]), -NH2, -NH(Ci-C4 alkyl), or -N(Ci-C4 alkyl)2; and r21, an(j ^24 are eacj1 indepencjently -H, halogen, -OH, or Cj-Ce alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo, hydroxy, oxo, amino, carboxy, Cj-Ce alkoxy, Ci-Ce haloalkoxy, CrC6aminoalkoxy, Ci-Cecyanoalkoxy, Ci-Ce hydroxyalkoxy, and C2-Cc alkoxyalkoxy.
54. 54. The method of any one of claims 51-53, wherein: Q2 is independently a bond, -0-, -S-, -NR-, -C(O)-, -C(=NR)-, -C02~, -OC(O)-, -C(0)NR- -C(0)NRC(0)0-, -NRC(0)NRC(0)0- -NRC(O)-, -NRC(0)NR-, -NRC02-, -0C(0)NR-, -S(O)-, -SO2-, -N(R)S02- -S02NR\ -NRS02NR’-, or -(CR6R7)P-Y-.
55. 55. The method of any one of claims 51-53, wherein: Q2is independently -0-, -C02-, -OC(O)-, -C(0)NR-, -NRC(O)-, -NRC(0)NR--NRCO2-, -OC(0)NR....., -CO2SO2-, -P(0)20-, or -(CR6R7)p-Y'-.
56. 56. The method of claim 55, wherein Q2 is independently -O- or -C02-
57. 57. The method of any one of claims 46-56, wherein: Q1 is independently a bond, -0-, -S-, -NR~, -C(0>-, -C(=NR)-, -C02- -0C(0)-, -C(0)NR- -C(0)NRC(0)0-, -NRC(0)NRC(0)0~, -NRC(O)-, -NRC(0)NR-, -NRC02--0C(0)NR-, -S(0)-, -S02- -N(R)S02-, -SCRNR’-, -NRS02NR’-, or -(CR^p-Y1-; and Y1 is independently a bond, -0-, -S-, -NR’-, -0(0)-, -C(=NR)-, -C02--0C(0)-, -C(0)NR’-, -C(0)NRC(0)0- -NRC(0)NRC(0)0- -NRC(O)--NRC(0)NR’—, -NRC02- -0C(0)NR’-, -S(0)-, -S02-, -S02NR’-, -NRS02-, or -NRS02NR’-.
58. 58. The method of claim 57, wherein: Q1 is independently a bond, -0-, -S-, -NR-, -C(0)-, -C02-, -0C(0)-, -C(0)NR- -C(0)NRC(0)0- -NRC(0)NRC (0)0--, -NRC(O)-, -NRC(0)NR-, -NRC02™, ~OC(0)NR“, -S(0)-, -S02- -N(R)S02-, -S02NR\ -NRS02NR’-, or -(CR^^p-Y1-; and Y1 is independently -0-, -C02-, -0C(0)-, -C(0)NR-, -NRC(O)- -NRC(0)NR--NRCO,-, or -0C(0)NR-.
59. 59. The method of any one of claims 46-58, wherein: R5 is independently i) -H; ii) a Ci-Ce-aliphatic group optionally substituted with one or more instances of JC1; iii) a C3-C8 non-aromatic carbocycle optionally substituted with one or more instances of JC1; iv) a phenyl group optionally substituted with one or more instances of JCI; v) a 4-8 membered non-aromatic heterocycle optionally substituted with one or more instances of JD1 or vi) a 5-6 membered heteroaiyl ring optionally substituted with one or more instances of JD1; and each of JC1 and JDI is independently selected from the group consisting of halogen, cyano, oxo, Ra, -0Rb, -SRb, -S(0)Ra, -S02R;', -NHRC, -C(0)Rb, -C(0)0Rb, -0C(0)Rb, -NHC(0)Rb, --C(0)NHRc, -NHC(0)NHRc, -NHC(0)0Rb, -OCONHRc, -NHC(0)NHC(0)0Rb, -N(CH3)Rc, -N(CH2)C(0)Rb , -C(0)N(CH3)Rc, -N(CH3)C(0)NHRc, -N(CH3)C(0)0Rb, -OCON(CH3)Rc, -C(0)NHC02Rb, -C(0)N(CH3)C02Rb, -N(CH3)C(0)NHC(0)0Rb, -NHS02Rb, -S02NHRb, -S02N(CH3)Rb, and -N(CH3)S02Rb.
60. 60. The method of claim 59, wherein: R! is -H; R2 is -H, -CH3, -CH2OH, or -NH2; R3 is -H, -F, -Cl, Cs-4 alkyl, or C1.4 haloalkyl; Z1 is -H, -F, or -Cl; Z2 is -H or Ci-Ce alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, and -0(Ci-C4 alkyl); Z? is -H or C1-C6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, and -0(Ci-C4 alkyl); R5 is: i) -H; ii) an optionally substituted C1-C6 alkyl group; iii) an optionally substituted, C3-C7 non-aromatic carbocycle; iv) an optionally substituted, 4-7 membered nonaromatic heterocyclc; v) )an optionally substituted phenyl group; vi) an optionally substituted 5-6 membered heteroaryl ring; or optionally, together with R and the nitrogen atom to which it is attached, form a 5-7 membered, optionally substituted non-aromatic heterocycle; and said alkyl group represented by R5 is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(C,-C4 alkyl), -N(Ci-C4 alkyl)2, -OCO(C,-C4 alkyl), -CO(Ci-C4 alkyl), -CO2H, -C02(CrC4 alkyl), Ci-C4 alkoxy, -NRCO(Ci-C4 alkyl), -CONR(Ci-C4 alkyl), -NRC02(Ci-C4 alkyl), a C3-C7 non-aromatic carbocycle optionally substituted with one or more instances of JE1, a 4-7 membered non-aromatic heterocycle optionally substituted with one or more instances of JE1; and a phenyl optionally substituted with one or more instances of JE!; and wherein each of said carbocycle, heterocycle, phenyl and heteroary represented by R is independently and optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, Ci-C4 alkyl, -0(Ct-C4 alkyl), -NH2, -NH(Ci-C4 alkyl), -N(C,-C4 alkyl)2, -C(0)(Ci-C4 alkyl), -0C(0)(Ci-C4 alkyl), -C(0)0(Ci-C4 alkyl) and -C02H, wherein each of said alkyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(Ci-C4 alkyl), -N(Ci-C4 alkyl)2, -OCO(C,-C4 alkyl), -CO(Ci-C4 alkyl), -C02H, -C02(Ci-C4 alkyl), and Ci-C4 alkoxy.
61. 61. The method of any one of claims 46-60, wherein: R5 is: i) -H; ii) an optionally substituted Ci-Cg alkyl group; iii) an optionally substituted, C3-C7 non-aromatic carbocycle; or iv) an optionally substituted, 4-7 membered non-aromatic heterocycle; or optionally, together with R and the nitrogen atom to which it is attached, form a 5-7 membered, optionally substituted non-aromatic heterocycle; and said alkyl group represented by R5 is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(C[-C,i alkyl), -N(Ci-C4 alkyl)2, -OCO(C,-C4 alkyl), -CO(Ci-C4 alkyl), -C02H, -C02(Ci-C4 alkyl), Ci-C4 alkoxy, an optionally substituted C3--C7 non-aromatic carbocycle, and an optionally substituted 4-7 membered non-aromatic heterocycle; and wherein each of said carbocycles and heterocycles represented by R5, and referred to for the substituents of the Ci-Cg alkyl group represented by R5 is independently and optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, Ct-C4 alkyl, -0(C]-C4 alkyl), -NH2, -NH(Ci-C4 alkyl), -N(Ci-C4 alkyl)2, -C(0)(Ci~C4 alkyl), -0C(0)(Ci-C4 alkyl), -C(0)0(Ci-C4 alkyl) and -C02H, wherein each of said alkyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(Ci-C4 alkyl), -N(CrC4 alkyl)2, -OCO(Ci-C4 alkyl), -CO(Ci-C4 alkyl), -C02H, -C02(CrC4 alkyl), and Ci-C4 alkoxy.
62. 62. The method of any one of claims 46-60, wherein: R1 is -H; R2 is -H or -CH2OH; R3 is -H, -F, or -Cl; Z1 is -H, -F, or -Cl; Z2 is -H; Z3 is -H; Rs is independently: i) -H or ii) a Ci-C<;-alkyl group optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, CrC4 alkyl, -0(Ci-C4 alkyl), -NH2, -NHfQ-Q alkyl), -N(Ci-C4 alkyl)2, -C(0)(Ci-C4 alkyl), -0C(0)(Ct-C4 alkyl), -C(0)0(Ci-C4 alkyl), -C03H, C3-C8 nonaromatic carbocycle, 4-8 membered non-aromatic heterocycle, phenyl, and 5-6 membered heteroaryl; wherein each of said alkyl groups referred to in the substituents of the Cj-Ce-alkyl group represented by R5 is independently and optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(Ci-C4 alkyl), -N(Ci-C4 alkyl)2, -OCO(C,-C4 alkyl), -CO(Ci-C4 alkyl), -C02H, -C02(Ci-C4 alkyl), and CrC4 alkoxy; and wherein each of said carbocycle, phenyl, heterocycle, and heteroaryl referred to in the substituents of the Ci-Ce-alkyl group represented by R5 is independently and optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, Ci-C4 alkyl, -NH2, -NH(Ci-C4 alkyl), -N(Ci-C4 alkyl)2, -OCO(Ci-C4 alkyl), -CO(Ci-C4 alkyl), -C02H, -C02(Ci-C4 alkyl), and C,-C4 alkoxy.
63. 63. The method of any one of claims 46-62, wherein each of JA and JB is selected from the group consisting of halogen, cyano, hydroxy, CrC6 alkyl, -NH2, -NH(CrC6 alkyl), -N(Ct-C6 alkyl)2, -0(C,.C6 alkyl), -C(0)NH2, -C(0)NH(Ci-C6 alkyl), -C(0)N(Ci-C6 alkyl)2, -C(0)(Ci-C6-alkyl), -OC(0)(CrCo alkyl), -NHC(0)(Ci-C6 alkyl), -N(Ci-C6 alkyl)C(0)(Ci-C6 alkyl), and -C02Rb; wherein each of said alkyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(CfC4 alkyl), -N(Ci-C4 alkyl)2, -0C0(Ci-C4 alkyl), -CO(Ci-C4 alkyl), -C02H, -C02(Ct-C4 alkyl), and Ct-C4 alkoxy.
64. 64. The method of claim 63, wherein each of JA and JB is selected from the group consisting of halogen, cyano, hydroxy, -NH2, -NH(Ci-C4 alkyl), -N(Ci-C4 alkyl)2, -OCO(Ci-C4 alkyl), -CO(CrC4 alkyl), -C02H, -C02(CrC4 alkyl), CrC,t alkoxy, and CrC4 alkyl optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, hydroxy, and -0(Ci-C4 alkyl).
65. 65. The method of claims 1 -6, wherein: R4 is:

    ring A is a non-aromatic, 5-10 membered, bridged carbocylce or heterocycle, or ring A and R8 optionally form a non-aromatic, 5-10 membered, bridged carbocycle or heterocycle, or ring A and R9 optionally form a non-aromatic, 5-10 membered, bridged carbocycle or heterocycle, or ring A and Rn optionally form a non-aromatic, 5-10 membered, bridged carbocycle or heterocycle, wherein each of said carbocycle is independently and optionally substituted with one or more instances of JA and wherein each carbocycle is independently and optionally substituted with one or more instances of JB; R1 is -H; R2 is -H, -CHj, -CH2OH, or -NH2; R3 is -H, -F, -Cl, C]_4 alkyl, or Cm haloalkyl; Z1 is -H, -F, or -Cl; Z2 is -H or Ci-Ce alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, and -CXC1-C4 alkyl); Z3 is -H or Ci-C6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, and -0(Ci-C4 alkyl); Q2 is independently -O- -C02-, -0C(0)-, -C(0)NR-, -C(0)NRC(0)0-,-NRC(0)- -NRC(0)NR’-, -NRC02-, -0C(0)NR’-, -P(0)(0R)0-, -0P(0)(0Ra)0-, -P(0)20-, -C02S02-, or -(CReR7)p-Y1-; Y1 is -0-, -CO2-, -0C(0)-, -C(0)NR’-, -C(0)NRC(0)0-,-NRC(0)-, —NRC(0)NR’-, -NRCO2-, -0C(0)NR’-, -P(0)(0R)0-, -0P(0)(0Ra)0-, -P(0)20-, or -C02S02-; R5 is: i) -H; ii) an optionally substituted Ci-Ce alkyl group; iii) an optionally substituted, C3-C7 non-aromatic carbocycle; iv) an optionally substituted, 4-7 membered nonaromatic heterocycle; v) )an optionally substituted phenyl group; vi) an optionally substituted 5-6 membered heteroaryl ring; or optionally, together with R and the nitrogen atom to which it is attached, form a 5-7 membered, optionally substituted non-aromatic heterocycle; and said alkyl group represented by R5 is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(Ci-C4 alkyl), -N(Ci-C4 alkyl)2, -OCO(Ci-C4 alkyl), -CO(C,-C4 alkyl), -C02H, -C02(Ci-C4 alkyl), C,-C4 alkoxy, -NRCO(Ci-C4 alkyl), -CONR(Ci-C4 alkyl), -NRC02(Ci-C4 alkyl), a C3-C7 non-aromatic carbocycle optionally substituted with one or more instances of JE1, a 4-7 membered non-aromatic heterocycle optionally substituted with one or more instances of JE!; and a phenyl optionally substituted with one or more instances of JE1; wherein each of said carbocycle, heterocycle, phenyl and heteroary represented by R5 is independently and optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, C1-C4 alkyl, -0(Ci-C4 alkyl), -NH2) -NH(Cj-C4 alkyl), -N(Ci-C4 alkyl)2, -C(0)(Ci-C4 alkyl), -0C(0)(Ci~C4 alkyl), -C(0)0(Ci-C4 alkyl) and -CO?H, wherein each of said alkyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(Ci-C4 alkyl), -N(Ci-C4 alkyl)2, -OCO(Ci-C4 alkyl), -CO(Ci-C4 alkyl), -C02H, -C02(Ci-C4 alkyl), and Ci-C4 alkoxy; each of Rs and R9 is independently -H, halogen, cyano, hydroxy, Ci-C4 alkyl, Ci-C4 haloalkyl, Ci-C4 hydroxyalkyl, C2-C4 alkoxyalkyl, -0(Ci-C4 alkyl), -~NH2, -NH(Ci-C4 alkyl), or -N(C|-C4 alkyl)2; R11, R12, R13, and R14 are each independently -H, halogen, or Ci-Ce alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, and Ci-Ce alkoxy; and each of JA and JB is independently selected from the group consisting of halogen, cyano, hydroxy, C,-C6 alkyl, -NH2, -NH(Ci-C6 alkyl), -N(Ci-Ce alkyl)2, -0(C,.C6 alkyl), -C(0)NH2, -C(0)NH(C,-C6 alkyl), -C(0)N(Ci-C6 alkyl)2, -C(0)(Ci-C6-alkyl), -0C(0)(Cr C6 alkyl), -NHC(0)(CrC6 alkyl), -N(Ci-C6 alkyl)C(0)(CrC6 alkyl), and -C02Rb; wherein each of said alkyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(Ci-C4 alkyl), -N(CrC4 alkyl)2, -OCO(C,-C4 alkyl), -CO(CrC4 alkyl), -C02H, -C02(Ci-C4 alkyl), and Ci-C4 alkoxy; and n is 0 or 1; x is 0 or 1.
66. 66, The method of claim 65, wherein:

    each of rings G1-G4 is independently a 5-10 membered non-aromatic bridged carbocycle optionally further substituted with one or more instances of JA, and ring G5 is a 5- 10 membered non-aromatic bridged heterocycle optionally further substituted with one or more instances of JB; X is -0-, -S-, or -NR8-; R21, R22, R23, R24, and R25 are each independently -H, halogen, -OH, Ci-Cg alkoxy, or C1-C6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, C1-C6 alkyl, -NH2, -NH(C| -CV, alkyl), -N(Ct-C6 alkyl)2, -0(Ci_Ce alkyl), -C(0)NH2, -C(0)NH(Ci-Ce alkyl), -C(0)N(CrCe alkyl)2, -C(0)(Ci-C6-alkyl), -0C(0)(CrC6 alkyl), -NHC(0)(Ct-C6 alkyl), -N(Ci-C6 alkyl)C(0)(Cr C6 alkyl); Rg is Ή or Ci-Ce alkyl ptionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo, hydroxy, oxo, amino, carboxy, Q-Ce alkoxy, Cs-C6 haloalkoxy, C1-C6 aminoalkoxy, Ci-Cecyanoalkoxy, Ci-Ce hydroxyalkoxy, and Ci-Ce alkoxy alkoxy; and q is 0, 1 or 2; and r is 1 or 2,
67. 67. The method of claim 66, wherein: R1 is -H; R2 is -H; R3 is -H, -F, or -Cl; Z1 is -H, -F, or -Cl; Z2 is -H; Z3 is -H; X is -0-; R5 is -H, an optionally substituted Ci -Cg alkyl, or optionally substituted phenyl; each R® is independently -H, halogen, hydroxy, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C2-C4 alkoxyalkyl, or -0(Ci~C4 alkyl); each of R9, R13, and R14is independently -H or C1-C4 alkyl; R21, R22, R23, R24, and R25 are each independently -H, halogen, -OH, Ci-Cg alkoxy, or Ci-Ce alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, Ci-C6 alkyl, and -0(Ci.Ce alkyl); and each rings G1-G5 are independently and optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, hydroxy, -NH2, -NH(Ci-Ce alkyl), -N(Ci-Ce alkyl)2, -0(Ci.Ce alkyl), C1-C4 alkyl that is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, and C1-C4 alkoxy.
68. 68. The method of claim 26, wherein the group -[C(R13R14)]x-ringA-Q2-R5 is independently:

    ; wherein: each of rings A14 and A28 is optionally and independently further substituted; and R5 is an optionally substituted C1-C6 alkyl group; an optionally substituted, C3-C7 non-aromatic carbocycle; or an optionally substituted, 4-7 membered non-aromatic heterocycle; or optionally, together with R and the nitrogen atom to which it is attached, form a 5-7 membered, optionally substituted non-aromatic heterocycle.
69. 69. The method of any one of claims 1-68, further comprising co-administering and additional therapeutic agent.
70. 70. The method of claim 69, wherein the additional therapeutic agent is selected from an antiviral agent or an Influenza vaccine, or both.
71. 71. A compound represented by structural formula (IA):

    ;ia), or a pharmaceutically acceptable salt thereof, wherein: Z1 is -R*, -F, -Cl, -CN, -OR*, -C02R*, -N02s or -CON(R*)2; Z2 is -R*, -OR*, -CO2R*, -NR*2, or -CON(R*)2; Z3 is -H, -OH, halogen, -NH2; -NH(CrC4 alkyl); -N(Ci-C4 alkyl)2, -0(C,-C4 alkyl), or CpCe alkyl that is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, and -0(Ci-C4 alkyl); R1 is -H, Ci-Ce alkyl, -S(0)a-R”, or-C(0)OR”; R2 is -H; -F; -NH2; -NH(C,-C4 alkyl); -N(Ct-C4 alkyl)2; -C-N-OH; cyclopropyl that is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, -OCH3, and -CH3; or C1-C4 alkyl that is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, and -0(Ci-C4 alkyl); and R3 is -H, -Cl, -F, -Br, -OH, -0(Ci-C4 alkyl), -NH2, -NH(C,-C4 alkyl), -N(Ci-C4 alky 1)2, -CN, or C|-C4 aliphatic that is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(Ci-C4 alkyl), -N(C,.-C4 alkyl)2, -OCO(CrC4 alkyl), -CO(CrC4 alkyl), -C02H, -C02(Ci-C4 alkyl), and Ci-C4 alkoxy; R4 is:

    ring A is a C3-Cio non-aromatic carbocycle optionally further substituted with one or more instances of JA or a 3-10 membered non-aromatic heterocycle optionally further substituted with one or more instances of JB; rings B and C are each independently a 4-10 membered, non-aromatic heterocycle optionally and independently further substituted with one or more instances of JB; ring D is a 4-10 membered, non-aromatic heterocycle optionally substituted with one or more instances of JDI; ring A and R8 optionally form a non-aromatic, 5-10 membered, bridged carbocycle or heterocycle, or ring A and R9 optionally form a non-aromatic, 5-10 membered, bridged carbocycle or heterocycle, or ring A and R11 optionally form a non-aromatic, 5-10 membered, bridged carbocycle or heterocycle, wherein each carbocycle is optionally further substituted with one or more instances of JA, and wherein each heteroocycle is optionally further substituted with one or more instances of JB; each of JA and JB is independently selected from the group consisting of halogen, cyano, oxo, -NCO, and Q'-R5; or optionally two JA and two JB, respectively, together with the atom(s) to which they are attached, independently form a 4-8 membered ring that is optionally substituted with one or more instances of JE1; Q1 is independently a bond, -0-, -S-, -NR’-, -C(0)-, -C(=NR)-, -C(=NR)NR-, -NRC(-NR)NR-, -CO2-, -0C(0)-, -C(0)NR’-, -C(0)NRC(0)0- -NRC(0)NRC(0)0--NRC(O)-, -NRC(0)NR’-, -NRC02-, -0C(0)NR-, -S(0)-, -S02-, -S02NR’--NRSO2-, or -NRS02NR’-, -P(0)(0R)0-, -0P(0)(0Ra)0-; -P(0)20-, -C02S02-, or -(cr6rVy1~; Q2is independently a bond, -0-, -S--, -NR- -C(0)-, -C(=NR)-, -C(=NR)NR-, -NRC(=NR)NR-, -CO2-, -0C(0)-, -C(0)NR- -C(0)NRC(0)0-, -NRC(0)NRC(0)0- -NRC(O)- -NRC(0)NR-, -NRCOa- -0C(0)NR......, -S(0)-, -S02- -N(R)S02- -S02N(R)-, -NRSO2NR-, -P(0)(OR)0-, -0P(0)(0Ra)0-, -P(0)20-, -C02S02-, or -(CR6R7)P-Y-; and Q3 is independently a bond, -C(0)~, -C(=NR>, -C(=NR)NR-, -NRC(=NR)NR-, -CO2-, -C(0)NR-, -S02- -S02N(R)-, -C(0)NRC(0)0- or -(CR^ip-Y1-; each Y1 is independently a bond, -0-, -S-, -NR-, -C(0)-, -C(=NR)-, -C(=NR)NR-, -NRC(=NR)NR-, -C02-, -0C(0)-, -C(0)NR-, -C(0)NRC(O)0-, -NRC(0)NRC(0)0-, -NRC(O)-, -NRC(0)NR-, -NRCOz-, -0C(0)NR- -S(0)-, -S02-, -N(R)S02-, -S02N(R)-, -NRS02NR-, -P(0)(0R)0-, -0P(O)(0Ra)0-, -P(0)20-, or -C02S02-; R5 is: i) -H; ii) a Ci-CG aliphatic group optionally substituted with one or more instances of JC1; iii) a C3-C10 non-aromatic carbocycle, or a 6-10 membered carbocyclic aiyl group, each optionally and independently substituted with one or more instances of JC1; or iv) a 4-10 membered non-aromatic heterocycle, or a 5-10 membered heteroaryl group, each optionally and independently substituted with one or more instances of JD1; or R5, together with each of Q1, Q2 and Q3, optionally and independently forms a 4-8 membered, non-aromatic ring optionally substituted with one or more instances of JE1; and R6 and R7 are each independently -H or Ci-C6 alkyl optionally substituted with one or more substitutents selected from the group consisting of halogen, cyano, hydroxy, oxo, amino, carboxy, Ci-Ccalkoxy, Ci-Cehaloalkoxy, Ci-Ceaminoalkoxy, Ci-Cecyanoalkoxy, Cj-Ce hydroxyalkoxy, and C2-Ce alkoxyalkoxy, or optionally Re and R7, together with the carbon atom to which they are attached, form a cyclopropane ring optionally substituted with one or more instances of methyl; Rs and R9 are each independently -H, halogen, cyano, hydroxy, amino, carboxy, Ci-C6 alkyl, Ci-C6 haloalkyl, Ci-Ce cyanoalkyl, C2-CG alkoxyalkyl, CpCg aminoalkyl, Ci-C6 hydroxyalkyl, Ci-Ca carboxyalkyl. Ci-C6 alkoxy, Ci-Ca haloalkoxy, Ci-Ce aminoalkoxy, Cr Cfi cyanoalkoxy, Ci-Ca hydroxyalkoxy, or C2-CG alkoxyalkoxy; or R8, together with Q2 and R5, optionally and independently forms a 5-7 membered, non-aromatic ring optionally substituted with one or more instances of JE1; or R10 is independently -H or a Ct-CG alkyl group optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, amino, carboxy, Ct-CG alkoxy, CrCe haloalkoxy, Cl-Ca aminoalkoxy, C|-C6 cyanoalkoxy, Ci-CG hydroxyalkoxy, C2-CG alkoxyalkoxy, C3-C8 non-aromatic carbocycle, phenyl, 4-8 membered non-aromatic heterocycle, and 5-6 membered hetcroaryl group, wherein each of said carbocycle, phenyl, heterocycle and heteroaryl group is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, amino, carboxy, C]-CG alkyl, Ci-Ce haloalkyl, Ci-CG cyanoalkyl, C2-C6 alkoxyalkyl, Ci-CG aminoalkyl, Ci-CG hydroxyalkyl, Ci-Cc alkoxy, Ci-Ca haloalkoxy, C|-CG aminoalkoxy, Ct-CG cyanoalkoxy, Ci-Cs hydroxyalkoxy, and C2-CG alkoxyalkoxy; R1', Ri2, R13 and R14 are each independently -H, halogen, or Ci-CG alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo, hydroxy, amino, carboxy, Ci-Ca alkoxy, C]-CG haloalkoxy, Ci-CG aminoalkoxy, Ci-CG cyanoalkoxy, Ci-CG hydroxyalkoxy, and C2-C6 alkoxyalkoxy; optionally, R13 and R14 together with the carbon atom to which they are attached form a cyclopropane ring, optionally substituted with one or more instances of methyl; R and R’ are each independently -H or Ci-C6 alkyl optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, amino, carboxy, Ci-CG alkoxy, Ci-Cahaloalkoxy, C|-C6 aminoalkoxy, Ci-Cg cyanoalkoxy, CpCe hydroxyalkoxy, and C2-C6 alkoxyalkoxy; or optionally R’, together with R5 and the nitrogen atom to which they are attached, forms a 5-7 membered non-aromatic heterocycle optionally substituted with one or more instances of JD1; R” is independently: i) a Ci-Ce-alkyl optionally substituted with one or more substituents selected independently from the group consisting of halogen, cyano, hydroxyl, ™NH2, -NH(Ci-Cs alkyl), -N(Ci-Ca alkyl)2, Ci-Caalkoxy, Ci-Ca haloalkoxy, Ci-Ca aminoalkoxy, Ci-C6 cyanoalkoxy, Ci-Ce hydroxyalkoxy, and C2-Ca alkoxyalkoxy; or ii) a C3-Ce carbocyclic group, a 5-6 membered heteroaryl group, or a phenyl group, each optionally and independently being substituted with one ore more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, nitro, -NH2, -NH(Ci-Cg alkyl), ~N(CrC6 alkyl)2, Ci-C6 alkyl, CrC6 haloalkyl, Ci-C6 cyanoalkyl, C,-C6-hydroxy alkyl, C2-Ce-alkoxyalkyl, Ci-Q-aminoalkyl, Ci-C6 alkoxy, Q-Cg haloalkoxy, Ci-C6aminoalkoxy, Ci-Ce cyano alkoxy, Ci-C6-hydiOxy alkoxy, and C2-C6 alkoxyalkoxy; R" is independently: i)-H; ii) a Ci-C6 alkyl group optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, amino, carboxy, C3-C8 non-aromatic carbocycle, 5-6 membered non-aromatic heterocycle, phenyl, 5-6 membered heteroaryl, -0(Ci-C6 alkyl), and -C(0)(Ci-C<;-alkyl); wherein each of said alkyl groups in -0(Ci-Ce alkyl), and -C(0)(C 1 -Ce-alkyl) is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(Cj-C4 alkyl), -N(Ci-C4 alkyl)2, -OCO(Ci-C4 alkyl), -CO(Ci-C4 alkyl), -C02H, -C02(Ci-C4 alkyl), and C1-C4 alkoxy; and wherein each of said carbocycle, heterocycle, phenyl, and heteroaryl is independently and optionally substituted with one or more instances of JE!; or iii) a C3-C8 non-aromatic carbocycle, or a 4-8 membered non-aromatic heterocycle, each of which is independently and optionally substituted with one or more instances of JE1; and each of JC1 and JD1 is independently selected from the group consisting of halogen, cyano, oxo, Ra, -ORb, -SRb, -S(0)Ra, -S02Ra, -NRbRc, -C(0)Rb, -C(=NR)RC, -C(=NR)NRbRc, -NRC(=NR)NRbRc, ~C(0)0Rb, -0C(0)Rb, -NRC(0)Rb, -C(0)NRbR°, -NRC(0)NRbRc, -NRC(0)0Rb, -OCONRbRc, -C(0)NRC02Rb, -NRC(0)NRC(0)0Rb, -C(0)NR(ORb), -S02NRcRb, -NRS02Rb, -NRS02NRcRb, -P(0)(0Ra)2, -0P(0)(0Ra)2, -P(0)2(0Ra), and -C02SO2Rb, or optionally, two JC1 and two JD1, respectively, together with the atom(s) to which they are attached, independently form a 4-8-membered ring that is optionally substituted with one or more instances of JE1; each JE1 is independently selected from the group consisting of halogen, cyano, hydroxy, oxo, amino, carboxy, amido, Ci-Ce alkyl, -0(Ci-C6 alkyl), and -C(0)(Ci-C6-alkyl), wherein each of said alkyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(C,-C4 alkyl), -N(C,-C4 alkyl)2, -OCOfCj-C,, alkyl), -CO(Ci-C4 alkyl), -C02H, -C02(Ci-C4 alkyl), and C1-C4 alkoxy; and each Ra is independently: Γ) a Ci-Ce aliphatic group optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, amino, carboxy, amido, -0(Ci-C6 alkyl), -C(0)(Ci-C6-alkyl), C3-Cs nonaromatic carbocycle, 4-8 membered non-aromatic heterocycle, 5-10 membered heteroaryl group, and 6-10 membered carbocyclic aryl group; wherein each of said alkyl groups for the substituents of the Q-Ce aliphatic group represented by Ra is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -Nth, -NH(Ci-C4 alkyl), -N(Ci-C4 alkyl)2, -OCO(Ci-C4 alkyl), -CO(Ci-C4 alkyl), -CO2H, -C02(Ci-C4 alkyl), and CrC4 alkoxy; and wherein each of said carbocycle, heterocycle, heteroaryl, and carbocyclic aryl groups for the substituents of the Ci-Cfi aliphatic group represented by Ra is optionally and independently substituted with one or more instances of JE1; ii) a C3-Cs non-aromatic carbocycle, or a 4-8 membered non-aromatic heterocycle, each of which is optionally and independently substituted with one or more instances of JE1; iii) a 5-10 membered heteroaryl, or 6-10 membered carbocyclic aryl group, each of which is optionally and independently substituted with one or more instances of JEi; and Rb and Rc are each independently Ra or -H; or optionally, Rb and R°, together with the nitrogen atom(s) to which they are attached, each independently form a 5-7 membered nonaromatic heterocycle optionally substituted with one or more instances of JE1; p is independently 1, 2, 3 or 4; n and m are each independently 0 or 1 when rings A and B are 3-6-membered; or n and m are each independently 0, 1 or 2 when rings A and B are 7-10-membered; and k is 0, 1 or 2; x and y are each independently 0, 1 or 2; z is 1 or 2; and provided that if Y1 is a bond, then R5 is neither -H nor a Ci-C6 aliphatic group; and provided that if each Q2 and Q3 independently is a bond, then R5 is neither -H nor a Cs-Ce aliphatic group.
72. 72. The compound of claim 71, represented by structural formula (T):

    or a pharmaceutically acceptable salt thereof, wherein: R2 is -H; -CH3, -NH2, -NH(CrC4 alkyl), -N(CrC4 alkyl)2; ring A is a C3-C8 non-aromatic carbocycle or heterocycle, the carbocycle and heterocylce ptionally further substituted with one or more instances of JA and JB, respectively; rings B and C are each independently a 4-8 membered, non-aromatic heterocycle optionally and independently further substituted with one or more instances of JB; ring D is a 4-8 membered, non-aromatic heterocycle optionally substituted with one or more instances of JD1; Q1 is independently a bond, -0-, -S-, -NR’-, -0(0)-, -C(=NR)-, -CO2-, -0C(0)-, -C(0)NR’-, -C(0)NRC(0)0-, -NRC(0)NRC(0)0-, -NRC(O)....., -NRC(0)NR’-, -NRCOa-, -0C(0)NR’-, -S(0)-, -S02- -S02NR’-, -NRS02-, or -NRS02NR\ or -(CR6R7)p-Y1-; Q2 is independently a bond, -0-, -S-, -NR-, -C(0)-, -C(=NR)-, -C02-, -0C(0)-, -C(0)NR-, -C(0)NRC(0)0~, -NRC(0)NRC(0)0- -NRC(O)-, -NRC(0)NR--NRCO2-, -0C(0)NR- -S(0>, -SO2- -N(R)S02-, -S02N(R>, -NRSO2NR-, or -(CR6R7)p-Y1-; and Q3 is independently a bond, -C(0)-, -C(=NR)-, -C02~, -C(0)NR-, -S02--S02N(R)-, -C(0)NRC(0)0- or -(CR6R7)P-Y1-; each of Q2 and Q3, together with R5, optionally and independently forms a 5-7 membered, non-aromatic ring optionally substituted with one or more instances of JI;1; each Y1 is independently a bond, -0-, -S-, -NR-, -C(0)-, -C02- -0C(0)-, -C(0)NR-, -C(0)NRC(0)0-, -NRC(0)NRC(0)0-, -NRC(O)-, -NRC(0)NR-, -NRC02--0C(0)NR- -S(0)-, -SO2-, -N(R)S02-, -S02N(R)-, or -NRS02NR-; R5 is: i) -H; ii) a C[-Cn aliphatic group optionally substituted with one or more instances of JC1; iii) a C3-C8 non-aromatic carbocycle, or a 6-10 membered carbocyclic aryl group, each optionally and independently substituted with one or more instances of JC!; or iv) a 4-8 membered non-aromatic heterocycle, or a 5-10 membered heteroaiyl group, each optionally and independently substituted with one or more instances of JD1; or R3, together with Q2 and R8, optionally and independently forms a 5-7 membered, non-aromatic ring optionally substituted with one or more instances of JE1; R8 and R9 are each independently -H, halogen, cyano, hydroxy, amino, carboxy, Ci-Ce allcyl, Ci-C6 haloalkyl, Ci-Q, cyanoalkyl, C2-C6 alkoxyalkyl, Ci-C6 aminoalkyl, C1-C6 hydroxyalkyl, Ci-C6alkoxy, Ci-Ce haloalkoxy, Ci-C6 aminoalkoxy, Ci-C6 cyanoalkoxy, Cr C6 hydroxyalkoxy, or C2-Ccalkoxyalkoxy; or Rs, together with Q2 and R5, optionally and independently forms a 5-7 membered, non-aromatic ring optionally substituted with one or more instances of JEi; and Ru, R12, R13 and R14 are each independently -H, halogen, or Ci-C6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo, hydroxy, amino, carboxy, Ci-Cealkoxy, C]-C<-, haloalkoxy, Ci-C6 aminoalkoxy, Ci-Cecyanoalkoxy, Ci-Ce hydroxyalkoxy, and Ci-Cc, alkoxyalkoxy; optionally, R° and Ri4 together with the carbon atom to which they are attached form a cyclopropane ring, optionally substituted with one or more instances of methyl; each of JC1 and JD1 is independently selected from the group consisting of halogen, cyano, oxo, Ra, -ORb, -SRb, -S(0)Ra, ~S02Ra, -NRbRc, -C(0)Rb, -C(0)0Rb, -0C(0)Rb, -NRC(0)Rb, -C(0)NRbRc, -NRC(0)NRbRc, ~NRC(0)0Rb, -OCONRbRc, -C(0)NRC0?Rb, -NRC(0)NRC(0)0Rb, -C(0)NR(0Rb), -S02NRcRb, -NRS02Rb, -NRS02NRcRb, and -P(0)2(0R“), or optionally, two JC1 and two JD1, respectively, together with the atom(s) to which they are attached, independently form a 5-7-membered ring that is optionally substituted with one or more instances of Jbl and fused to the respective ring to which they are attached; and n and m are each independently 0 or 1 when rings A and B are 3-6-mcmbered; or n and m are each independently 0, 1 or 2 when rings A and B are 7-8-membercd.
73. 73. The compound of claim 72, wherein: ring A is a Cg-Cg non-aromatic carbocycle optionally and independently further substituted with one or more instances of JA; rings B and C are each independently a 4-8 membered, non-aromatic heterocycle optionally and independently further substituted with one or more instances of JB; ring D is a 4-8 membered, non-aromatic heterocycle optionally substituted with one or more instances of JD1; each of JA and JB is independently selected from the group consisting of halogen, cyano, oxo, andQ’-R5; or optionally two JA and two JB, respectively, together with the atom(s) to which they are attached, independently form a 5-7 membered ring that is optionally substituted with one or more instances of JE1 and fused to the ring to which they are attached; and each of JC1 and JD1 is independently selected from the group consisting of halogen, cyano, oxo, Ra, -ORb, -SRb, -S(0)Ra, -S02Ra, -NRbRc, -C(0)Rb, -C(0)0Rb, -0C(0)Rb, -NRC(0)Rb, -C(0)NRbRc, -NRC(0)NRbRc, -NRC(0)0Rb, -OCONRbRc, -C(0)NRC02Rb, -NRC(0)NRC(0)0Rb, -C(0)NR(0Rb), -S02NRcRb, -NRS02Rb, and -NRS02NRcRb, or optionally, two JC1 and two JDI, respectively, together with the atoms to which they are attached, independently form a 5-7-membered ring that is optionally substituted with one or more instances of JE1, and fused to the respective ring to which they are attached; Q1 is independently a bond, -0-, -S-, —NR-, -C(0)-, -C02-, -0C(0)-, -C(0)NR~, -C(0)NRC(0)0- -NRC(0)NRC(0)0- -NRC(O)-, -NRC(0)NR--NRCO2- -0C(0)NR-, -S(0>, -S02- -N(R)S02-, -S02N(R>, -NRS02NR-, or -(CR^RVY1-; Q2 is independently a bond, -0-, -S-, -NR-, -C(0)-, -C02-, -0C(0)-, -C(0)NR- -C(0)NRC(0)0- -NRC(0)NRC(0)0- -NRC(O)-, -NRC(0)NR--NRC02- -0C(0)NR-, -S(0>, -S02-, -N(R)S02- -S02N(R)-, -NRS02NR-, or -(CR6R7)p......Y1-; and Q3 is independently a bond, -0(0)-, -C02- -C(0)NR-, -S02-, -S02N(R)-, -C(0)NRC(0)0- or -(CReR7)p-Y'-; or each of Q2 and Q3, together with R5, optionally and independently forms a 5-7 membered, non-aromatic ring optionally substituted with one or more instances of JE1; each Yl is independently a bond, -0-, -S-, -NR-, -C(0)-, -C02-, -0C(0)-, -C(0)NR- -C(0)NRC(0)0-, -NRC(0)NRC(0)0-, -NRC(O)-, -NRC(0)NR- -NRC02--0C(0)NR- -S(0)-, -S02-, -N(R)S02- -S02N(R)-, or -NRS02NR-; R5 is: i) -H; ii) a Ci-Ce aliphatic group optionally substituted with one or more instances of JC!; iii) a Cs-Cs non-aromatic carbocycle, or 6-10 membered carbocyclic aiyl group, each optionally and independently substituted with one or more instances of J ; or iv) a 4-8 membered non-aromatic heterocycle, or a 5-10 membered heteroaryl group, each optionally and independently substituted with one or more instances of JDI; and R8 and R9 are each independently -H, halogen, cyano, hydroxy, amino, carboxy, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce cyanoalkyl, C2-Ce alkoxyalkyl, Ci-Ce aminoalkyl, Ci-C6 hydroxyalkyl, Ci-Cealkoxy, Ci-Ce haloalkoxy, C[-C6aminoalkoxy, Ci-Cecyanoalkoxy, Ci-Cfi hydroxyalkoxy, or C2-Cfi alkoxyalkoxy,
74. 74. The compound of any one of claims 71-73, wherein R1 is -H or Cj-Ce alkyl.
75. 75. The compound of claim 74, wherein R1 is -H.
76. 76. The compound of any one of claims 71-75, wherein R2 is -H, -F, -CH3, -CH2OH, or -NH2.
77. 77. The compound of claim 76, wherein R2 is -H or -CH3.
78. 78. The compound of any one of claims 71-77, wherein R3 is -H, -Cl, ™F, -Br, -CN, -CF3, -0(Ci-C4 alkyl), -OH, -NH2, -NH(C1-C4 alkyl), or -N(Ci-C4 alkyl)2.
79. 79. The compound of any one of claims 71-78, wherein the compound is represented by the following structural formula (VI):

    (VI), or a pharmaceutically acceptable salt thereof.
80. 80. The compound of claim 79, wherein: Z1 is -H, Ci-C6 alkyl, -0(CrC6 alkyl), -F, -Cl, -CN, -C02H, -C02(C,-C6 alkyl), -CONH2i -CONH(C]-Ce alkyl), or -CON(Ci-Cs alkyl)2, wherein each of said alkyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(Ci-C4 alkyl), -N(Ci-C4 alkyl)2, -OCO(C,-C4 alkyl), -CO(C,-C4 alkyl), -C02H, -C02(C,-C4 alkyl), and C,-C4 alkoxy; and Z2 is -H, Ci-Ce alkyl, -0(Ci-C6 alkyl), -NH2, -NH(Ci-C6 alkyl), or -N(Ci-C6 alkyl)2, wherein each of said alkyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(Ci-C4 alkyl), -N(Ci-C4 alkyl)2, -OCO(CrC4 alkyl), -CO(Ci-C4 alkyl), -C02H, -C02(Ci-C4 alkyl), and C[-C4 alkoxy.
81. 81. The compound of any one of claims 71-80, wherein: 7) is -H, -F, -Cl, -CF3, -CH3, or -CN; and Z2 is -H or an optionally substituted Ci-Ce alkyl.
82. 82. The compound of any one of claims 71-81, wherein: R2 is -H; and R3 is -H, -F, -Cl, -CF3, -CH3j -C2H5, -NH2j -NH(CH3), or-N(CH3)2.
83. 83. The compound of claim 79, wherein: Z1 is -H, -F, -Cl, -CF3, -CH3j or-CN; Z2 is -H or Ci-C6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, and -0(Ci-C4 alkyl); Z3 is -H or Ci-Co alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, and -CXC1-C4 alkyl); R! is -H; R2 is -H; R3 is independently -H, -Cl or -F; R6 and R7 are each independently -H or -CH3, or together with the carbon atoms to which they are attached they form a cyclopropane ring; each R8 is independently -H, halogen, cyano, hydroxy, Ci-C4 alkyl, C1-C4 haloalkyl, Cs-Co hydroxy alkyl, C2-C4 alkoxyalkyl, -0(Ci-C4 alkyl), -NH2, -NH(Ci-C4 alkyl), or -N(Ci-C4 alky 1)2. each R9 is independently -H or -CH3; R11 and R12 are each independently -H or -CIi3; and R13 and R14 are each independently -H or -CH3, or together with the carbon atoms to which they are attached they form a cyclopropane ring.
84. 84. The compound of any one of claims 71-83, wherein the compound is represented by any one of structural formulae (II), (HI), (IV) and (V):

    (ii) cm)

    (IV) (V), or a pharmaceutically acceptable salt thereof, wherein: R3 is -H, -F, -Cl, -CF3, -NH2, -NH(CH3), or-N(CH3)2; Z1 is -H, -F, -Cl, -CF3, C1-C4 alkyl,-CH2NH2, -C(0)NH2, -C(0)NH(CH3), -C(0)N(CH3)2, -0(Ci-C4 alkyl), or -CN; each R and R’ are independently -H or Ci-C6 alkyl; ring A is an optionally substituted, C4-C7 non-aromatic carbocycle; rings B and C are each independently an optionally substituted 4-7 membered nonaromatic heterocycle; ring D is an optionally substituted 4-7 membered non-aromatic heterocycle; each of JA and JB is independently selected from the group consisting of halogen, cyano, oxo, and Q'-R5; or optionally two JA and two JB, respectively, together with the atom(s) to which they are attached, independently form a 5-7 membered ring that is optionally substituted with one or more instances of JE1 and fused to the ring to which they are attached; each of JC1 and JD1 is independently selected from the group consisting of halogen, cyano, oxo, Ra, -ORb, -SRb, -S(0)Ra, -S02Rn, -NRbR:;, -C(0)Rb, -C(0)0Rb, -0C(0)Rb, -NRC(0)Rb, -C(0)NRbRc, -NRC(0)NRbRc, -NRC(0)0Rb, -OCONRbRc, -C(0)NRC02Rb, -NRC(0)NRC(0)0Rb, -C(0)NR(0Rb), -S02NRcRb, -NRS02Rb, and -NRS02NRcRb, or optionally, two JC1 and two JD1, respectively, together with the atoms to which they are attached, independently form a 5-7-membered ring that is optionally substituted with one or more instances of Jhl, and fused to the respective ring to which they are attached; Q1 is independently a bond, -0-, -S-, -NR’-, ~C(0)-, -C02- -OC(O)-, -C(0)NR’-, -C(0)NRC(0)0-, -NRC(0)NRC(0)0-, -NRC(O)-, -NRC(0)NR’-, -NRC02-, -0C(0)NR’-, -S(0)-, -S02- -S02NR’-, -NRS02-, or -NRS02NR’-, or -(cr^-Vy1-; Q2 is independently bond, -0-, -S-, -NR-, -0(0)-, -CO2-, -00(0)-, -C(0)NR-, -C(0)NRC(0)0-, -NRC(0)NRC(0)0-, -NRC(0)-, -NRC(0)NR- -NRC02--0C(0)NR-, -S(0)-, -SO2-, -N(R)S02- -S02NR\ -NRS02NR\ or -(CR^Vy1-; and Q3 is independently a bond, -0(0)-, -C02-, -C(0)NR’-, -S02--S02NR’-, -C(0)NRC(0)0-, or -(CR6R\-Y1-·, provided that if Q2-R5 is -OR5 or -NR’R5, then ring A is further substituted with one or more instances of JA other than -H; and provided that if Q3 is --0(0)-, then R5 is a substituted Ci-Ce aliphatic group; an optionally substituted CrCs non-aromatic carbocycle; an optionally substituted, 6-10-membered carbocyclic aryl group; an optionally substituted, 4-8 membered non-aromatic heterocycle; or an optionally substituted 5-10 membered heteroaryl group.
85. 85. The compound of claim 84, wherein: Z1 is -H, -F, -Cl, -CF3, -CH3, or -ON; and Z2 is -H or an optionally substituted Ci-C6 alkyl.
86. 86. The compound of claim 85, wherein R3 is -H, -01 or -F.
87. 87. The compound of claim 86, wherein: R6 and R7 are each independently -H or -0¾, or together with the carbon atoms to which they are attached they form a cyclopropane ring; each Rs is independently -H, halogen, cyano, hydroxy, C1-C4 alkyl, Ci-C4haloalkyl, C1-C4 hydroxyalkyl, C2-C4 alkoxyalkyl, -0(01-C4 alkyl), -NH2, -NH(Ci-C4 alkyl), or -Ν(0ι-04 alkyl)2. each R9 is independently -H or -CH3; Ru and R12 are each independently -H or-CH3; and R13 and R14 are each independently -H or-CH3, or optionally R13 and R14, together with the carbon atom to which they are attached, form a cyclopropane ring.
88. 88. The compound of any one of claims 84-87, wherein the compound is represented by structural formula (XIA) or (XIB):

    (ΧΙΑ) (ΧΙΒ) or a pharmaceutically acceptable salt thereof, wherein: ring A is a 5-7 membered non-aromatic carbocycle optionally further substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, C,-C<s alkyl, C2-Ce alkenyl, -NH2, -NH(C,-C6 alkyl), -N(C,-C6 alkyl)2, -0(C,. C6 alkyl), -C(0)NH2, -C(0)NH(C,-C6 alkyl), -C(0)N(C,-C6 alkyl)2, -C(0)(C,-C6-alkyl), -00(0)(0,-C6 alkyl), -NHC(0)(C,-C6 alkyl), -N(C,-C6 alky 1)0(0)(0,-C6 alkyl), and -C02Rb; wherein each of said alkyl and alkenyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(C,-C4 alkyl), -N(C|-C4 alkyl)2, -000(0,-04 alkyl), -CO(CrC4 alkyl), -C02H, -002(0,-04 alkyl), and C,-C4 alkoxy.
89. 89. The compound of claim 88, wherein x is 0 or 1; and n is 0 or 1.
90. 90. The compound of claim 89, wherein Q2 is -Ο-, -NH-, -N(CH3)-, -0(0)-, -C02-, -C(0)NH- -C(0)N(CHj)-, -NHC(O)-, -N(CH3)C(0)- -NHC(0)NR’-, -N(CH3)C(0)NR’-, -NHC02-, -N(CH3)C02-, -0C(0)NR’-, -NHS02-, -N(CH3)S02-, -S02NR'-, or-(CR6R7)[,-Y1-.
91. 91. The compound of claim 90, wherein: R5 is independently i) -H; ii) a C,-Ce-aliphatic group optionally substituted with one or more instances of JC1; iii) a C3-Cg non-aromatic carbocycle optionally substituted with one or more instances of JC1; iv) a phenyl group optionally substituted with one or more instances of JC1; v) a 4-8 membered non-aromatic heterocycle optionally substituted with one or more instances of JD! or vi) a 5-6 membered heteroaryl ring optionally substituted with one or more instances of JDI; and each of JCi and JD1 is independently selected from the group consisting of hhalogen, cyano, oxo, R:t, -0Rb, -SRb, -S(0)Ra, -S02R“, -NHRC, -C(0)Rb, -C(0)0Rb, -0C(0)Rh, -NHC(0)Rb, -C(0)NHRc, -NHC(0)NHRc, -NHC(0)0Rb, -OCONHRc, -NEC (0)NHC(0)0Rb, -N(CH3)RC, -N(CH3)C(0)Rb, -C(0)N(CH3)Rc, -N(CH3)C(0)NHRc, -N(CH3)C(0)0Rb, -OCON(CH3)Rc, -C(0)NHC02Rb, -C(0)N(CH3)C02Rb, -N(CH3)C(0)NHC(0)0Rb, -NHS02Rb! -S02NHRb, -S02N(CH3)Rb, and -N(CH3)S02Rb.
92. 92, The compound of claim 91, wherein ring A is optionally further substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, C1-C4 alkyl, -0(Ci-C4 alkyl), -NH2, -NH(Ci-C4 alkyl), -N(Ci-C4 alkyl)2, -C(0)(Ci-p4 aUcyl), -0C(0)(Ci-C4 alkyl), -C02H, and -C02(Ci-C4 alkyl), wherein each of said alkyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(C,-C4 alkyl), -N(Ci-C4 alkyl)2, -OCO(Ci-C4 alkyl), -CO(Ct-C4 alkyl), -C02H, -C02(C,-C4 alkyl), and C1-C4 alkoxy.
93. 93. The compound any one of claims 88-92, wherein the group -[C(Ri3R14)]x-ringA-Q2-R5 is independently selected from one of the depicted below:

    wherein each of rings A1-A27 is independently and optionally further substituted.
94. 94. The compound of Claim 93, wherein the group -[C(R13Rl4)]x-ringA-Q2-R5 is independently selected from one of the depicted below:

    wherein each of rings A1-A4, A7-A20, A22, A23, A25 and A27 is independently and optionally further substituted.
95. 95. The compound of Claim 93, wherein the group -[C(Ri3R14)]x-ringA-Q2-R5 is independently selected from one of the depicted below:

    wherein: each of rings A5-A7, A21, A24 and A26 is independently and optionally further substituted; and each Rs independently is halogen, cyano, hydroxy, C1-C4 alkyl, C1-C4 haloalkyl, Ci-C4 hydroxyalkyl, C2-C4 alkoxyalkyl, -0(Cj-C4 alkyl), -NH2, -NH(Ci-C4 alkyl) or -N(Ci-C4 alkyl)?.
96. 96. The compound of any one of claims 93-95, wherein each of rings A1-A27 is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -ΝΗ(€ι-02 alkyl), -NH(Ci-C2 alkyl)2, Ci-C2 alkyl, C|-C2 haloalkyl, Ci-C2 hydroxyalkyl, C2-C4 alkoxyalkyl, Ci-C2 alkoxy, Ci-C2 hydroxyalkoxy, Ci-C2 haloalkoxy, C2-C4 alkoxyalkoxy, -C02H, and-C02(CrC4 alkyl).
97. 97. The compound of claim 96, wherein R5 is independently: i) -H; xi) a Ci-Cg-aliphatic group optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, C1-C4 alkyl, -O^-C* alkyl), -NH2, -NH(Cr-C., alkyl), -NfCi-C* a!kyl)2, -C(0)(C,-C4 alkyl), -0C(0)(Ci-C4 alkyl), -C(0)0(Ci-C4 alkyl), -C02H, C3-C8 non-aromatic carbocycle, phenyl, 4-8 membered non-aromatic heterocycle, and 5-6 membered heteroaryl; iii) a C3-C7 non-aromatic carbocycle, a 4-7 membered non-aromatic heterocycle, a phenyl group, or a 5-6 membered heteroaryl ring, each of which is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, CrC4 alkyl, -0(Ci-C4 alkyl), -NH2, -NH(Cl-C4 alkyl), -N(C!-C4 alkyl)2, -C(0)(C[-C4 alkyl), -0C(0)(Ci-C4 alkyl), -C(0)0(C,-C4 alkyl), and -C02H; wherein each of said alkyl groups for the substituents of R5 is independently and optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(Ci-C4 alkyl), -N(Ci-C4 alkyl)2, -OCO(Ci-C4 alkyl), -CO(Ci-C4 alkyl), -C02H, -C02(Ci-C4 alkyl), and Ci-C4 alkoxy; and wherein each of said carbocycle, phenyl, heterocycle, and heteroaryl for the substituents of the C[-C6-aliphatic group represented by R5 is independently and optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, C1-C4 alkyl, -NH2, -NH(Ci-C4 alkyl), -N(Ci-C4 alkyl)2, -OCO(Ci-C4 alkyl), -CO(Ci-C4 alkyl), -C02H, -C02(Ci-C4 alkyl), and CrC4 alkoxy.
98. 98. The compound of claim 97, wherein the group -[C(R13R14)]x-ringA-Q2-Rs is

    each of rings A6, A8, All, A14 and A15 is optionally and independently further substituted; and each R8 independently is halogen, cyano, hydroxy, C1-C4 alkyl, C1-C4 haloalkyl, Ci-C4 hydroxyalkyl, C2-C4 alkoxyalkyl, -0(Ci-C4 alkyl), -NH2, -NH(Ci~C4 alkyl), or -N(Ci-C4 alky 1)2.
99. 99. The compound of claim 98, wherein: R5 is: i) -H; ii) an optionally substituted Q-CV, alkyl group; iii) an optionally substituted, C3-C7 non-aromatic carbocycle; or iv) an optionally substituted, 4-7 membered non-aromatic heterocycle; wherein said alkyl group represented by R5 is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(Ci-C4 alkyl), -N(Ci-C4 alkyl)2, -OCO(Ci-C4 alkyl), -CO(Ci-C4 alkyl), -C02H, -C02(Ci-C4 alkyl), and C1-C4 alkoxy, an optionally substituted, C3-C7 non-aromatic carbocycle, and an optionally substituted, 4-7 membered non-aromatic heterocycle; and wherein each of said carbocycles and heterocycles represented by R5 and referred to for the substituents of the Ci-C6 alkyl group represented by R5 is independently and optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, C1-C4 alkyl, -0(Ci-C4 alkyl), -NH2, -NH(Ci-C4 alkyl), -N(C,-C4 alkyl)2, -C(0)(C,-C4 alkyl), -0C(0)(C,-C4 alkyl), -C(0)0(Ci-C4 alkyl), and -C02H, wherein each of said alkyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(Ci-C4 alkyl), -N(Ci-C4 alkyl^, -OCO(Ci-C4 alkyl), -CO(Ci-C4 alkyl), -C02H, -C02(Ci-C4 alkyl), and CrC4 alkoxy.
100. 100. The compound of any one of claims 84-87, wherein the compound is represented by structural formula (XIIA) or (XIIB):

     (ΧΙΙΑ) (ΧΪΙΒ), or a pharmaceutically acceptable salt thereof; wherein: ring B is optionally further substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, Ci-Ce alkyl, C2-C6 alkenyl, -NH2, -NHfCrCe alkyl), -N(Ci-C6 alkyl)2, -0(Ci.C6 alkyl), -C(0)NH2, -C(0)NH(Ci-C6 alkyl), ~C(0)N(CrC6 alkyl)2, -C(0)(C,-C6-alkyl), -0C(0)(C,-Cfi alkyl), -NHC(0)(C,-C6 alkyl), -N(Ci -C6 alkyl) CCOXCrQ alkyl), and -C02Rb; wherein each of said alkyl and alkenyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(Ci-C4 alkyl), -N(Ci-C4 alkyl)2, -OCO(Ci-C4 alkyl), -CO(Ci-C4 alkyl), -C02H, -C02(C,-C4 alkyl), and CrC4 alkoxy.
101. 101. The compound of claim 100, wherein y is 0 or 1.
102. 102. The compound of claim 101, wherein Q3 is independently -C(O)-, -C02-, -C(0)NH~, -C(0)N(CH3)-, -C(0)NHC(0)0-, -C(0)N(CH3)C(0)0-, -S02-, -S02NH-, -S02(CH3>, or -(CR6R7)P-Y1-.
103. 103. Tire compound of claim 102, wherein: R5 is independently i) -H; ii) a Ci-Ce-alkyl optionally substituted with one or more instances of JC1; iii) a C3-Cs non-aromatic carbocycle optionally substituted with one or more instances of JC1; iv) a phenyl group optionally substituted with one or more instances of JC1; v) a 4-8 membered non-aromatic heterocycle optionally substituted with one or more instances of JDt or vi) a 5-6 membered heteroaryl ring optionally substituted with one or more instances of JD1; and each of JC1 and JD1 is independently selected from the group consisting ofhhalogen, cyano, oxo, Ru, -ORb, -SRb, -S(0)Ra, -S02R‘, -NHRr, -C(0)Rb, -C(0)0Rb, -0C(0)Rb, -NHC(0)Rb, -C(0)NHRc, -NHC(0)NHRc, -NHC(0)0Rb, -OCONHRc, -NHC(0)NHC(0)0Rb, -N(CH3)RC, -N(CH3)C(0)Rb, -C(0)N(CH3)Rc, -N(CH3)C(0)NHRc, -N(CH3)C(0)0Rb, -OCON(CH3)Rc, -C(0)NHC02Rb, -C(0)N(CH3)C02Rb, -N(CH3)C(0)NHC(0)0Rb, -NHS02Rb, -S02NHRb, -S02N(CH3)Rb, and -N(CH3)S02Rb.
104. 104. The compound of claim 103, wherein ring B is optionally further substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, C1-C4 alkyl, -0(Ci-C4 alkyl), -NH2, -NH(Cj-C4 alkyl), —N(Ci—C4 alkyl)2, -C(0)(Ci-C4 alkyl), -0C(0)(Ci-C4 alkyl), -C02H, and -C02(C|-C4 alkyl), wherein each of said alkyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(Ci-C4 alkyl), -N(Ci-C4 alkyl)2, -OCO(Ci-C4 alkyl), -CO(C,-C4 alkyl), -C02H, -C02(Ci-C4 alkyl), and CrC4 alkoxy.
105. 105. The compound of any one of claims 100-104, wherein ring B is independently selected from:

     wherein each of rings Bl, B2 and B4-B9 is optionally and independently substituted.
106. 106. The compound of claim 105, wherein each of rings Bl, B2 and B4-B9 is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(Ci-C2 alkyl), -N(Ci-C2 alkyl)2, Ci-C2 alkyl, C]-C2 haloalkyl, C1-C2 hydroxyalkyl, C2-C4 alkoxyalkyl, Ci-C2 alkoxy, Ci-C2 hydroxy alkoxy, Ci-C2 haloalkoxy, -C02H, and -C02(Ci-C4 alkyl).
107. 107. The compound of claim 106, wherein Rs is independently: i) -H; ii) a Ci-Ce-alipliatic group optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, Ci-C4 alkyl, -0(Ci-C4 alkyl), -NHa, -NH(Ci-C4 alkyl), -N(C,-C4 alkyl)2, -C(0)(C,-C4 alkyl), -0C(0)(Ci-C4 alkyl), -C(0)0(Ci-C4 alkyl), -C02H, C3-Cg non-aromatic carbocycle, phenyl, 4-8 merabered non-aromatic heterocycle, and 5-6 membered heteroaryl; iii) a C3-C7 non-aromatic carbocycle, a 4-7 membered non-aromatic heterocycle, a phenyl group, or a 5-6 membered heteroaryl ring, each of which is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, C1-C4 alkyl, -0(Ci-C4 alkyl), -NH2, -NH(Ci-C* alkyl), -N(Ci-C4 alkyl)2, -C(OXC,-C4 alkyl), -0C(0)(C,-C4 alkyl), -C(0)0(Ci-C4 alkyl), and -C02H; wherein each of said alkyl groups for the substituents of R5 is independently and optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(Ci-C4 alkyl), -N(Ci-C4 alkyl)2, -OCO(Ci-C4 alkyl), -CO(Ci-C4 alkyl), -C02H, -C02(Ci-C4 alkyl), and C1-C4 alkoxy; and wherein each of said carbocycle, phenyl, heterocycle, and heteroaryl for the substituents of the Ci-Ce-aliphatic group represented by R5 is independently and optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, C1-C4 alkyl, -NH2, -NH(Ci-C4 alkyl), -N(C|-C4 alkyl)2, -OCO(Ci-C4 alkyl), -CO(Ci-C4 alkyl), -C02H, -C02(Ci-C4 alkyl), and Ci-C4 alkoxy.
108. 108. The compound of claim 107, wherein the group (ring B)-Q3-R5 is wherein:

     ring B2 is optionally and independently further substituted; and R5 is: Ϊ) -Η; ii) an optionally substituted Ci-Cs alkyl group; iii) an optionally substituted, C3-C7 non-aromatic carbocycle; or iv) an optionally substituted, 4-7 membered non-aromatic heterocycle; wherein said alkyl group represented by R5 is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(Cl-C4 alkyl), -N(Ct-C4 alkyl)2, -OCO(Ci-C4 alkyl), -CO(Ci-C4 alkyl), -C02H, -C02(Ci-C4 alkyl), Cj-C4 alkoxy, an optionally substituted, C3-C7 non-aromatic carbocycle, and an optionally substituted, 4-7 membered non-aromatic heterocycle; and wherein each of said carbocycles and heterocycles represented by R5, and referred to for the substituents of the C|-C6 alkyl group represented by Rs is independently and optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, C1-C4 alkyl, -CXC1-C4 alkyl), -NH2, -NH(Ci-C4 alkyl), -N(Ci-C4 alkyl)2, -C(0)(Ci-C4 alkyl), -0C(0)(Ci-C4 alkyl), -C(0)0(Ci-C4 alkyl), and -CO2H, wherein each of said alkyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(C]-Ci alkyl), -N(Ci-C4 alkyl)2, -OCO(Ci-C4 alkyl), -CO(Ci-C4 alkyl), -CCbH, -C02(Ci-C4 alkyl), and C1-C4 alkoxy.
109. 109. The compound of any one of claims 84-87, wherein the compound is represented by structural formula (ΧΠΙ):

     (Xlil), or a pharmaceutically acceptable salt thereof, wherein: ring C is a 5-6 membered non-aromatic heterocycle optionally further substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, C]-Ce alley I, C2-C6 alkenyl, -NH2, -NH(Ci-Ce alkyl), —N(Ci-Cc alkyl)2, -0(C|-Ce alkyl), -C(0)NH2, -C(0)NH(Ci-C6 alkyl), -C(0)N(Ci-C6 alkyl)2, -C(0)(Ci-C6-alkyl), -0C(0)(CrC6 alkyl), -NHC(0)(Ci-C6 alkyl), -N(C,-Crt alkyl)C(0)(Ci-C6 alkyl), and -C02Rb; wherein each of said alkyl and alkenyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(Ci-C4 alkyl), -N(Ci-C4 alkyl)2, -OCO(C[-C4 alkyl), -CO(Ci-C4 alkyl), -C02H, -C02(Ci-C4 alkyl), and C1-C4 alkoxy.
110. 110. The compound of claim 109, wherein R10 is -H or Ci-Cs-alkyl.
111. 111. The compound of claim 110, wherein ring C is optionally further substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, CrC4 alkyl, -0(C,-C4 alkyl), -NH2, ~NH(C,-C4 alkyl), -N(Ci-G, alkyl)2, -C(0)(Ci-C4 alkyl), -C02H, and -C02(C[-C4 alkyl), wherein each of said alkyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NI-I(Ci-C,i alkyl), -N(Ci-C4 alkyl)2, -OCO(Ci-C4 alkyl), -CO(Ci-C4 alkyl), -C02H, -C02(Ci-C4 alkyl), and Ci-C4 alkoxy.
112. 112. The compound of any one of claims 109-111, wherein ring C is independently selected from:

     wherein each of rings C1-C5 is optionally and independently substituted.
113. 113. The compound of claim 112, wherein each of rings C1-C5 is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, -NH2, -NH(Ci-C2 alkyl), -NH(Ci-C2 alkyl)2, Ci-C2 alkyl, C|-C2 haloalkyl, Ci-C2 hydroxyalkyl, C2-C4 alkoxyalkyl, Ci-C2 alkoxy, Ci-C2 hydroxyalkoxy, Ci-C2 haloalkoxy, C2-C4 alkoxyalkoxy, -C02H, and -C02(Ci-C4 alkyl).
114. 114. The compound of any one of claims 84-87, wherein the compound is represented by the following structural formula (XIV):

     (XIV), or a pharmaceutically acceptable salt thereof, wherein: ring D is optionally further substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, C[-C6 alkyl, C2-Ce alkenyl, -NH2, -NH(Ct-C6 alkyl), -N(Ci-C6 alkyl)2, -0(Cf.C6 alkyl), -C(0)NH2, -C(0)NH(Cl-C6 alkyl), -C(0)N(C,-C6 alkyl)2, -0(0)((^-Ce-alkyl), -OCXOXCrCe alkyl), -NHC(0)(Ci-Ce alkyl), -N(Ci-Ce a1kyl)C(0)(Ci-C6 alkyl), and -C02Rb; wherein each of said alky] and alkenyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NHa, -NH(Ci-C4 alkyl), -N(C,-C4 alkyl)2, -OCO(Ci-C4 alkyl), -CO(Ci-C4 alkyl), -C02H, -C02(Ci-C4 alkyl), and Ci-C4 alkoxy.
115. 115. The compound of claim 114, wherein z is 1.
116. 116. The compound of claim 114 or 115, wherein ring D is independently selected from the group consisting of

     7 wherein: each of rings D1-D7 is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, Ci-C4 alkyl, -0(C,-C4 alkyl), -NH2, -NH(C,-C4 alkyl), -N(Cr-C4 alkyl)2, -C(0)(Ci-G, allcyl), -C02H and -C02(Cj-C4 alkyl), wherein each of said alkyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, ~NH(CrC4 alkyl), -N(C|-C4 alkyl)2, -OCO(CrC4 alkyl), -CO(Ci-C4 alkyl), -C02H, -C02(Ci-C4 alkyl), and C,-C4 alkoxy; and each Rd is independently -H, CrCo alkyl or-C(0)(C|-Cc alkyl), wherein each of said alkyl moiety is optionally and independently substituted with one or more groups selected from halogen, cyano, hydroxy, oxo, -NH2, -NH(Ci-C4 alkyl), -N(CpC4 alkyl)2, -OCO(C]-C4 alkyl), -CO(C,-C4 alkyl), -C02H, -C02(Ci-C4 alkyl), and CrC4 alkoxy.
117. 117. The compound of any one of claims 71-83, wherein R4 is:

     , wherein: ring E is a C4-Cio non-aromatic carbocycle optionally further substituted with one or more instances of JA; rings F is a 4-8 membered non-aromatic heterocycle optionally substituted with one or more instances of JE!; R9 is independently -H, halogen, cyano, hydroxy, amino, carboxy, Q-Ce alkyl, Ci-C6 haloalkyl, CrC6 cyanoalkyl, C2-C6 alkoxyalkyl, Ci-Ce aminoalkyl, Q-Ce hydroxyalkyl, Ci-Cg carboxyalkyl, Ci-Cs alkoxy, Ci-Ce haloalkoxy, Ci-C6aminoalkoxy, Ci-Cg cyanoalkoxy, Ci -C(i hydroxyalkoxy, or C2-Ce alkoxyalkoxy; R11, R12, R13 and R14 are each independently -H, halogen, or Ci-C6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo, hydroxy, oxo, amino, carboxy, Ci-Cc alkoxy, C1-C6 haloalkoxy, Ci-C<> aminoalkoxy, C1-C6 cyanoalkoxy, CpCe hydroxyalkoxy, and C2-C6 alkoxyalkoxy; optionally, R13 and R14, together with the carbon atom to which they are attached, form a cyclopropane ring, optionally substituted with one or more instances of methyl; s is 0, 1 or 2; and x is 0, 1 or 2.
118. 118. The compound of claim 117, wherein ring F is selected from any one of rings F1-F6:

     j each of rings F1-F6 optionally and independently substituted; and each Rris independently -H or C1-C6 alkyl optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, amino, carboxy, Ci-Ce alkoxy, CpCe haloalkoxy, C1-C6 aminoalkoxy, Ci-Cecyanoalkoxy, Ct-Cs hydroxyalkoxy and C2-C6 alkoxyalkoxy.
119. 119. The compound of claim 118, wherein each rings F1-F6 are independnetly and optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, hydroxy, C1-C4 alkoxy, and C1-C4 alkyl optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, hydroxy, and -0(Ci-C4 alkyl).
120. 120. Hie compound of any one of claims 117-119, wherein: R9 is independently -H, halogen, cyano, hydroxy, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C2-C4 alkoxyalkyl, -0(Ci-C4 alkyl), -NH2, -NH(Ci-C4 alkyl), or -NfCi-Ca alky 1)2; and ring E is a C4-C8 non-aromatic carbocycle optionally further substituted with one or more instances of JA
121. 121. The compound of claim 120, wherein ring F is selected from any one of rings F1-F5:

     wherein each of rings Fl-FS optionally and independently substituted.
122. 122. The compound of any one of claims 71-83, wherein R4 is:

     each of rings G1-G4 is independently a 5-10 rnembered non-aromatic bridged carbocycle optionally further substituted with one or more instances of JA, and ring G5 is a 510 rnembered non-aromatic bridged heterocycle optionally further substituted with one or more instances of JB; X is -0-, -S-, or -NRE-; R8 and R9 are each independently -H, halogen, cyano, hydroxy, amino, carboxy, Ci-C6 alkyl, Ci-Ce haloalkyl, Ci-Ce cyanoalkyl, C2-C6 alkoxyalkyl, Ci-Ce aminoalkyl, Ci-C6 hydroxyalkyl, Ci-C6 carboxyalkyl, Ci-C6alkoxy, Ci-C6 lialoalkoxy, C[-C6aminoalkoxy, Cr Cecyanoalkoxy, C]-C6 hydroxyalkoxy, or C2-C6 alkoxyalkoxy; R13 and R14 are each independently -H, halogen, or Ci-Gs alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo, hydroxy, oxo, amino, carboxy, Ci-Cg alkoxy, Ci-C6 haloalkoxy, Ci-C6 aminoalkoxy, Ci-Cccyanoalkoxy, Ci-Cg hydroxyalkoxy, and C2-Ce alkoxyalkoxy; optionally, R13 and R14, together with the carbon atom to which they are attached, form a cyclopropane ring, optionally substituted with one or more instances of methyl; R21, R22, R23, R24, and R25 are each independently -H, halogen, -OH, Ci-Cg alkoxy, or Ci-Ce alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo, hydroxy, oxo, amino, carboxy, Ci-Ce alkoxy, Ci-Cs haloalkoxy, Ci-Ce aminoalkoxy, Ci-C6cyanoalkoxy, Ci-Ce hydroxyalkoxy, and C2-Cg alkoxyalkoxy; Rg is -H or Ci-Cf, alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo, hydroxy, amino, carboxy, CpCe alkoxy, Ci-C6 haloalkoxy, Ci-Ce aminoalkoxy, Ct-Cecyanoalkoxy, Cj-Q hydroxyalkoxy, and Ca-Ce alkoxyalkoxy; q is 0, 1 or 2; x is 0, 1 or 2; and ris 1 or 2.
123. 123. The compound of claim 122, wherein R4 is:
124. 124. The compound of claim 123, wherein: each of Rs and R9 is independently -H, halogen, cyano, hydroxy, C1-C4 alkyl, C1-C4 halo alkyl, C1-C4 hydroxy alkyl, C2-C4 alkoxy alky I, -0(Ci-C4 alkyl), -NH2, -NH(Ci-C4 alkyl), or~N(Ci~C4 alkyl)2; and R21, R22, R23, and R24 are each independently -H, halogen, -OH, or Ci-C6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo, hydroxy, oxo, amino, carboxy, Cj-Cg alkoxy, Ci-Ce haloalkoxy, Ci-Ce aminoalkoxy, Ci-Gs cyanoalkoxy, Ci-Ce hydroxyalkoxy, and C2-C6 alkoxyalkoxy.
125. 125. The compound of any one of claims 122-124, wherein: Q2is independently a bond, -0-, -S-, -NR-, -0(0)-, -C(=NR)-, -CO2-, -00(0)-, -C(0)NR- -C(0)NRC(0)0-, -NRC(0)NRC(0)0- -NRC(O)-, -NRC(0)NR- -NRC03--0C(0)NR- -5(0)-, -SO2- -N(R)S02-, -S02NR\ -NRS02NR\ or -(CR6R7)P-Y1-.
126. 126. The compound of any one of claims 122-124, wherein: Q2 is independently -0-, -C02-, -00(0)-, -C(0)NR- -NRC(O)-, -NRC(0)NR--NRCO2-, -OC(0)NR-, -CO2SO2-, -P(0)20-, or -(CR6R7)p-Y‘-.
127. 127. The compound of claim 126, wherein Q2 is independently -0- or -CO?-.
128. 128. The compound of any one of claims 117-127, wherein: Q1 is independently a bond, -0-, -S-, -NR-, -0(0)-, -C(=NR)-, -C02-, -00(0)-, -0(O)NR- -C(0)NRC(0)0-, -NRC(0)NRC(0)0-, -NRC(O)-, -NRC(0)NR-, -NRC02--0C(0)NR- -S(0)-, -SO2-, -N(R)S02-, -S02NR\ -NRS02NR’-, or -(CR6R7)p-Y‘-; and Y* is independently a bond, -0- -S-, -NR’-, -0(0)-, -C(=NR)-, -CO2-, -00(0)-, -C(0)NR’-, -C(O)NRC(O)0-, -NRC(0)NRC(0)0- -NRC(O)- -NRC(0)NR’-,.......NRCO2-, -0C(0)NR’-, -S(0)-, -SO2-, -SO2NR-, -NRS02-, or -NRS02NR’-.
129. 129. The compound of claim 128, wherein: Q1 is independently a bond, -0-, -S-, -NR-, -0(0)-, -C02-, -00(0)-, -C(0)NR-, -C(0)NRC(0)0-, -NRC(0)NRC(0)0-, -NRC(O)-, -NRC(0)NR-, -NRC02-, -0C(0)NR-, -S(0)-, -SO2-, -N(R)S02- -S02NR’-, -NRS02NR5-, or -(CR6R7)p-Y’-; and Y1 is independently -0-, -C02- -00(0)-, -C(0)NR-, -NRC(O)-, -NRC(0)NR--NRC02- or -0C(0)NR-.
130. 130. The compound of any one of claims 117-129, wherein: R5 is independently i) -H; ii) a Ci-Cg-aliphatic group optionally substituted with one or more instances of JC1; iii) a C3-Cg non-aromatic carbocycle optionally substituted with one or more instances of JC1; iv) a phenyl group optionally substituted with one or more instances of JC1; v) a 4-8 membered non-aromatic heterocycle optionally substituted with one or more instances of JD1 or vi) a 5-6 membered heteroaryl ring optionally substituted with one or more instances of JD1; and each of JC1 and JD1 is independently selected from the group consisting of halogen, cyano, oxo, Ra, -ORb, -SRb, -S(0)Ra, -S02Ra, -NHRC, -C(0)Rb, -C(0)0Rb, -0C(0)Rb, -NHC(0)Rb, -C(0)NHRc, ~NHC(0)NHRc, -NHC(0)0Rb, -OCONHRc: -NHC(0)NHC(0)0Rb, -N(CH3)RC, -N(CHi)C(0)Rb, -C(0)N(CH3)Rc, -N(CH3)C(0)NHRc, -N(CH3)C(0)0Rb, -OCON(CH3)Rc, -C(0)NHC02Rb, -C(0)N(CH3)C02Rb, -N(CH3)C(0)NHC(0)0Rb, -NHS02Rb, -S02NHRb, -S02N(CH3)Rb, and -N(CH3)S02Rb.
131. 131. The compound of any one of claims 117-129, wherein: R1 is -H; R2 is -H, -CH3, -CH2OH, or -NH2; R3 is -H, -F, -Cl, Cm alkyl, or Cm haloalkyl; Z1 is -H, -F, or -Cl; Z“ is -H or Ci-Ce alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, and -0(Ct-C4 alkyl); Z3 is —H or C|-Cr> alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, and -0(Ci-C4 alkyl); R5 is: i) -H; ii) an optionally substituted C[-Cg alkyl group; iii) an optionally substituted, C3-C7 non-aromatic carbocycle; or iv) an optionally substituted, 4-7 membered non-aromatic heterocycle; or optionally, together with R and the nitrogen atom to which it is attached, form a 5-7 membered, optionally substituted non-aromatic heterocycle; and said alkyl group represented by R5 is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(Cl-C4 alkyl), -N(Cl-C4 alkyl)2, -OCO(C!-C4 alkyl), -CO(C,-C4 alkyl), -C02H, -C02(Ci-C4 alkyl), Ci-C4 alkoxy, a C3-C7 non-aromatic carbocycle optionally substituted with one or more instances of JE!, a 4-7 membered non-aromatic heterocycle optionally substituted with one or more instances of JE1; and a phenyl optionally substituted with one or more instances of JEI; and wherein each of said carbocycles and heterocycles represented by R5, and referred to for the substituents of the Ci-Ce alkyl group represented by R5 is independently and optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, Ci-C4 alkyl, -0(Ci-C4 alkyl), -NH2, -NH(Ci-C4 alkyl), -N(Ci~C4 alkyl)2) -C(0)(Ci-C4 alkyl), -0C(0)(C,-C4 alkyl), -C(0)0(Ci-C4 alkyl) and -CO2H, wherein each of said alkyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(Ci-C4 alkyl), -N(Ci-C4 alkyl)2, -OCO(Ci-C4 alkyl), -CO(Ci-C4 alkyl), -C02H, -C02(CrC4 alkyl), and Ci-C4 alkoxy.
132. 132. The compound of any one of claims 117-129, wherein: R5 is: i) -H; ii) an optionally substituted Cj-Ce alkyl group; iii) an optionally substituted, C3-C7 non-aromatic carbocycle; or iv) an optionally substituted, 4-7 membered non-aromatic heterocycle; or optionally, together with R and the nitrogen atom to which it is attached, form a 5-7 membered, optionally substituted non-aromatic heterocycle; and said alkyl group represented by R5 is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(Ci-C4 alkyl), -N(Ci-C4 alkyl)2, -OCO(Ci-C4 alkyl), -CO(Ci-C4 alkyl), -C02H, -C02(Ci-C4 alkyl), Ci-C4 alkoxy, an optionally substituted C3-C7 non-aromatic carbocycle, and an optionally substituted 4-7 membered non-aromatic heterocycle; and wherein each of said carbocycles and heterocycles represented by R5, and referred to for the substituents of the Ci-C6 alkyl group represented by R5 is independently and optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, Ci-C4 alkyl, -0(Ci-C4 alkyl), -NH2, -NH(Ci-C4 alkyl), -N(Ci-C4 alkyl)2, -C(0)(C,-C4 alkyl), -0C(0)(C,-C4 alkyl), -C(0)0(C,-C, alkyl) and -C02H, wherein each of said alkyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(Ci-C4 alkyl), -N(Ci-C4 alkyl)2, -OCO(Ci-C4 alkyl), -CO(Ci-C4 alkyl), -C02H, -C02(Ci-C4 alkyl), and Ci-C4 alkoxy.
133. 133. The compound of any one of claims 117-129, wherein: R1 is -H; R2 is -H or -CH2OH; R3 is -H, -F, or -Cl; Z1 is -H, -F, or -Cl; Z2 is -H; Z3 is -H; R5 is independently: i) -H or ii) a Ci-Ce-alkyl group optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, C1-C4 alkyl, -0(Ci-C4 alkyl), -NH2, -NH(Ci-C4 alkyl), -N(Cr-C4 alkyl)2, -C(0)(Ci-C4 alkyl), -0C(0)(Ci-C4 alkyl), -C(0)0(Ci-C4 alkyl), -C02H, C3-Cs nonaromatic carbocycle, 4-8 membered non-aromatic heterocycle, phenyl, and 5-6 membered heteroaryl; wherein each of said alkyl groups referred to in the substituents of the Ci-Ce-alkyl group represented by R5 is independently and optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(Ci-C4 alkyl), -N(Ci-C4 alkyl)2, -OCO(Ci-C4 alkyl), -CO(Ci-C4 alkyl), -CO2H, -C02(CrC4 alkyl), and Ci-C4 alkoxy; and wherein each of said carbocycle, phenyl, heterocycle, and hetcroaryl referred to in the substituents of the C|-CValkyl group represented by R5 is independently and optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, Ci-C4 alkyl, -NH2, -NH(Ci-C4 alkyl), -N(Ci-C4 alkyl)2, -OCO(CrC4 alkyl), -CO(Ci-C4 alkyl), -C02H, -C02(Ct-C4 alkyl), and Ct-C4 alkoxy.
134. 134. The compound of any one of claims 117-133, wherein each of JA and JB is selected from the group consisting of halogen, cyano, hydroxy, C\-C6 alkyl, -NH2, -NH(Ci-C6 alkyl), -N(Ci-C6 alkyl)2, -0(CuC6 alkyl), -C(0)NH2, -C(0)NH(Ci-C6 alkyl), -C(0)N(C,-C6 alkyl),, -C(O)(Ci-Ce-alky 1), -0C(0)(C,-Cfi alkyl), ^NHC(0)(C,-Cfi alkyl), -N(C,-C6 alkyl)C(0)(C,-Ce alkyl), and -C02Rb; wherein each of said alkyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(Ci-C4 alkyl), -N(C|-C4 alkyl)2, -OCO(Ci-C4 alkyl), -CO(Ci-C4 alkyl), -C02H, -C02(Ci-C4 alkyl), and CrC4 alkoxy.
135. 135. The compound of claim 134, wherein each of JA and JB is selected from the group consisting of halogen, cyano, hydroxy, -NH2, -NH(Ci-C4 alkyl), -N(Ci-C4 alkyl)2, -OCO(Ci-C4 alkyl), -CO(CrC4 alkyl), -C02H, -C02(Ci-C4 alkyl), Ci-C4 alkoxy, and CrC4 alkyl optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, hydroxy, and -0(Cj-C4 alkyl).
136. 136. The compound of any one of claims 71-83, wherein: R4 is:

     ring A is a non-aromatic, 5-10 membered, bridged carbocylce or heterocycle, or ring A and R8 optionally form a non-aromatic, 5-10 membered, bridged carbocycle or heterocycle, or ring A and R9 optionally form a non-aromatic, 5-10 membered, bridged carbocycle or heterocycle, or ring A and R11 optionally form a non-aromatic, 5-10 membered, bridged carbocycle or heterocycle, wherein each of said carbocycle is independently and optionally substituted with one or more instances of JA and wherein each carbocycle is independently and optionally substituted with one or more instances of JB; R1 is -H; R2 is -H, -CH3, -CH2OH, or -NH2; R3 is -H, -F, -Cl, C1-4 alkyl, or Ci_4 haloalkyl; Z1 is -H, -F, or-Cl; Z2 is -H or Ci-C6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, and -0(Ct-C4 alkyl); Z3 is -H or Ci-Cf, alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, and -0(Ci-C4 alkyl); Q2 is independently -0-, -COi....., -OC(O)-, -C(0)NR’-, -C(0)NRC(0)0- ,-NRC(0)-, -NRC(0)NR-, -NRCO2-, -0C(0)NR’-, -P(0)(0R)0-, -0P(0)(0Ra)0-, -P(O)30-, -C02S02-, or-(CR6R7)p-Y-; Y1 is -0-, -C02-, -OC(O)-, -C(0)NR’-, -C(0)NRC(0)0-,-NRC(0)--NRC(0)NR’-, -NRCO2-, -0C(0)NR’-, -P(0)(0R)0-, -0P(0)(0Ra)0-, -P(0)20-, or -C02S02-; R5 is: i) -H; ii) an optionally substituted Ci~Cr, alkyl group; iii) an optionally substituted, C3-C7 non-aromatic carbocycle; iv) an optionally substituted, 4-7 membered nonaromatic heterocycle; v) )an optionally substituted phenyl group; vi) an optionally substituted 5-6 membered heteroaiyl ring; or optionally, together with R and the nitrogen atom to which it is attached, form a 5-7 membered, optionally substituted non-aromatic heterocycle; and said alkyl group represented by R5 is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(Ci-C4 alkyl), -N(Ci-C4 alkyl)2, -0C0(Ci-C4 alkyl), -C0(CrC4 alkyl), -C02H, -C02(Ci-C4 alkyl), C]-C4 alkoxy, -NRCO(Ci-C4 alkyl), -CONR(CrC4 alkyl), -NRC02(Ci-C4 alkyl), a C3-C7 non-aromatic carbocycle optionally substituted with one or more instances of JE1, a 4-7 membered non-aromatic heterocycle optionally substituted with one or more instances of JE1; and a phenyl optionally substituted with one or more instances of JE1; wherein each of said carbocycle, heterocycle, phenyl and heteroary represented by R5 is independently and optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, C1-C4 alkyl, -0(Ct-C4 alkyl), -NH2, -NH(Ci-C4 alkyl), -N(Ci-C4 alkyl)2, -0(0)(0,-04 alkyl), -0C(0)(Cl-C4 alkyl), -C(0)0(Ci-C4 alkyl) and -C02H, wherein each of said alkyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(Ci-C4 alkyl), -N(Ci-C4 alkyl)2, -OCO(Ci-C4 alkyl), -CO(CrC4 alkyl), -C02H, -C02(Ci-C4 alkyl), and Ci-C4 alkoxy; each of R8 and R9 is independently -H, halogen, cyano, hydroxy, Ci-C4 alkyl, C[-C4 haloalkyl, CrC4 hydroxyalkyl, C2-C4 alkoxyalkyl, -0(C|-C4 alkyl), -NH2, -NH(Ci-C4 alkyl), or-N(Ci-C4 alley 1)2; Ru, R13, R13, and R14 are each independently -H, halogen, or Ci-Ce alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, and C|-Ce alkoxy; and each of JA and JB is independently selected from the group consisting of halogen, cyano, hydroxy, Ci-Cfi alkyl, -NH2, -NH(Ci-C6 alkyl), -N(Ci-C6 alkyl)2, -0(Ci.C6 alkyl), -C(0)NH2, -C(0)NH(CrC6 alkyl), -C(0)N(Ci-C6 alkyl)2, -C(0)(Ci-C6-alkyl), -0C(0)(Cr C6 alkyl), -NHC(0)(C,-C6 alkyl), -N(Ci-Ce aikyl)C(0)(Ci-C6 alkyl), and -C02Rb; wherein each of said alkyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(Ci-C4 alkyl), -N(Ci-C4 alkyl)2, -OCO(Ci-C4 alkyl), -CO(Ci-C4 alkyl), -C02H, -C02(Ci-C4 alkyl), and Ci-C4 alkoxy; and n is 0 or 1; x is 0 or 1.
137. 137. Thecompound of claim 136, wherein:

     each of rings G1-G4 is independently a 5-10 membered non-aromatic bridged carbocycle optionally further substituted with one or more instances of JA, and ring G5 is a 510 membered non-aromatic bridged heterocycle optionally further substituted with one or more instances of JB; X is -0-, -S-, or -NRS-; R21, R32, R23, R24, and R25 are each independently -H, halogen, -OH, CrCe alkoxy, or CrC6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, Ci-C6 alkyl, -NH2, -NH(Ci-Ce alkyl), -N(Ci-C6 alkyl)2, -0(Ci-C6 alkyl), -C(0)NH2, -C(0)NH(CrC6 alkyl), -C(0)N(Ct-C6 alkyl)2, -C(0)(Ci-Ce-a]kyI), -0C(0)(C,-C6 alkyl), -NHC(0)(C,-Cfi alkyl), -N(C,-Cfi alkyl)C(0)(C,-C6 alkyl); R® is -H or Ci-Ce alkyl ptionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, oxo, hydroxy, oxo, amino, carboxy, Ci-C6 alkoxy, Ci-Q, haloalkoxy, Ci-Ce aminoalkoxy, Ci-Cecyanoalkoxy, C i -Cg hydroxyalkoxy, and C2-C6 alkoxyalkoxy; and q is 0, 1 or 2; and r is 1 or 2.
138. 138. The compound of claim 137, wherein: R1 is -H; R2 is -H; , R3 is -H, -F, or-Cl; Z1 is -H, -F, or -Cl; Z2 is -H; Z3 is -H; X is -0-; R5 is ~~H, an optionally substituted Ci-Ce alkyl, or optionally substituted phenyl; each R8 is independently -H, halogen, hydroxy, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C2-C4 alkoxyalkyl, or -0(C|-C4 alkyl); each of R9, R13, and R14is independently -H or C1-C4 alkyl; R21, R22, R23, R24, and R25 are each independently -H, halogen, -OH, Ci-C6 alkoxy, or C]-Cc alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, Cj-C6 alkyl, and -0(Ci_Cc alkyl); and each rings G1-G5 are independently and optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, hydroxy, -NH2, -NH(Cr Cfi alkyl), -N(Ci-C6 alkyl)2, -0(Ci-Ce alkyl), C1-C4 alkyl that is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, and C1-C4 alkoxy.
139. 139. The compound of claim 88, wherein the group -[C(R13R14)]x-ringA-Q2-R3 is independently:

     ; wherein: each of rings A14 and A28 is optionally and independently further substituted; and R5 is an optionally substituted Q-Cg alkyl group; an optionally substituted, C3-C7 non-aromatic carbocycle; or an optionally substituted, 4-7 membered non-aromatic heterocycle; or optionally, together with R and the nitrogen atom to which it is attached, form a 5-7 membered, optionally substituted non-aromatic heterocycle.
140. 140. The compound of any one of claims 71-87, wherein x is 0 or 1; and y is 0 or 1.
141. 141. The compound of any one of claims 117-135, wherein x is 0 or 1,
142. 142. The compound of any one of claims 71-82, wherein R3 is methyl or ethyl.
143. 143. The compound of claim 71, wherein the compound is selected from any of the structures depicted in FIG. 3, FIG. 4, FIG. 5, and FIG. 6, or a pharmaceutically acceptable salt thereof.
144. 144. A compound selected from any of the structures depicted in FIG. 7 or a pharmaceutically acceptable salt thereof.
145. 145. A pharmaceutical composition, comprising an effective amount of a compound according to any one of claims 71 to 144, or a pharmaceutically acceptable salt of the same, and a pharmaceutically acceptable carrier, adjuvant or vehicle.
146. 146. The pharmaceutical composition of claim 145, additionally comprising a therapeutic agent selected from an antiviral agent or a vaccine.
147. 147. The method of any one of claims 1 -6, wherein t is 0 or 1; and j is 0 or 1.
148. 148. The method of any one of claims 7-28, wherein x is 0 or 1; and y is 0 or 1.
149. 149. The method of any one of claims 46-64, wherein x is 0 or 1.
150. 150. The method of any one of claims 1-13, wherein R3 is methyl or ethyl
151. 151. The method of claim 1, wherein the compound is selected from the compounds depicted in FIG. 3, FIG. 4, FIG. 5, FIG. 6, FIG. 7, and FIG. 8, or a pharmaceutically acceptable salt thereof.
152. 152. A method of reducing the amount of influenza viruses in a biological sample or- in a patient, comprising administering to said biological sample or patient an effective amount of a compound as described in any one of claims 1-70 and 147-151, or a combination of said compounds thereof.
153. 153. A method of treating influenza in a patient, comprising administering to said patient an effective amount of a compound as described in any one of claims 1-70 and 147-151, or a combination of said compounds thereof.
154. 154. A method preparing a compound represented by Structural Formula (IA):

     or a pharmaceutically acceptable salt thereof, comprising the step of: i) reacting compound A:

     vith compound B :

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

     ; and ΪΪ) optionally deprotecting the Ts group of the compound of Structural Formula (XX) to form the compound of Structural Formula (IA),wherein: the variables of Structural Formulae (IA) and (XX), and compounds (A) and (B) are independently as defined in any one of claims 71-143; and Ts is tosyl.
155. 155. A method preparing a compound represented by Structural Formula (IA):

     or a pharmaceutically acceptable salt thereof, comprising the step of: i) reacting compound Cl or C2:

     vith NH2R4 to form a compound represented by Structural Formula (XX):

     ; and ii) optionally deprotecting the Ts group of the compound of Structural Formula (XX) to form the compound of Structural Formula (IA),wherein: the variables of Structural Formulae (IA) and (XX), and compounds (Cl) and (C2) are independently as defined in any one of claims 71-143; and Ts is tosyl.
156. 156. The method of claim 154 or 155, further comprising the deprotection stco, and wherein R1 of Structural Formula (IA) is -H.