EP2858984A1 - Inhibitors of influenza viruses replication - Google Patents

Inhibitors of influenza viruses replication

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Publication number
EP2858984A1
EP2858984A1 EP13729577.0A EP13729577A EP2858984A1 EP 2858984 A1 EP2858984 A1 EP 2858984A1 EP 13729577 A EP13729577 A EP 13729577A EP 2858984 A1 EP2858984 A1 EP 2858984A1
Authority
EP
European Patent Office
Prior art keywords
alkyl
optionally substituted
independently
compound
group
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP13729577.0A
Other languages
German (de)
French (fr)
Inventor
Paul S. Charifson
Mark W. Ledeboer
Michael P. Clark
Michael J. BOYD
Huai Gao
Brian Ledford
Francois Maltais
Emanuele Perola
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Vertex Pharmaceuticals Inc
Original Assignee
Vertex Pharmaceuticals Inc
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Filing date
Publication date
Application filed by Vertex Pharmaceuticals Inc filed Critical Vertex Pharmaceuticals Inc
Publication of EP2858984A1 publication Critical patent/EP2858984A1/en
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/06—Peri-condensed systems

Definitions

  • 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.
  • 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.
  • Influenza viruses are RNA viruses of the family Orthomyxoviridae, which comprises five genera: Influenza virus A, Influenza virus B, Influenza virus C, Isavirus and Thogoto virus.
  • influenza A virus 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.
  • Hl l 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 are: Hl l (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.
  • influenza B virus 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.
  • influenza C The Influenza virus C genus has one species, influenza C virus, which infects humans and pigs and can cause severe illness and local epidemics. However, influenza C is less common than the other types and usually seems to cause mild disease in children.
  • Influenza A, B and C viruses are very similar in structure.
  • the virus particle is 80-120 nanometers in diameter and 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 1 1 proteins: hemagglutinin (HA), neuraminidase (NA), nucleoprotein (NP), Ml, M2, NS1, NS2( EP), PA, PB1, PB1-F2 and PB2.
  • HA and NA are large glycoproteins on the outside of the viral particles.
  • HA is a lectin that mediates binding of the virus to target cells and entry of the viral genome into the target cell, while NA is involved in the release of progeny virus from infected cells, by cleaving sugars that bind the mature viral particles.
  • these proteins have been targets for antiviral drugs.
  • they are antigens to which antibodies can be raised.
  • Influenza A viruses are classified into subtypes based on antibody responses to HA and NA, forming the basis of the H and N distinctions (vide supra) in, for example, H5N1.
  • Influenza produces direct costs due to lost productivity and associated medical treatment, as well as indirect costs of preventative measures. In the United States, influenza is responsible for a total cost of over $ 10 billion per year, while it has been estimated that a future pandemic could cause hundreds of billions of dollars in direct and indirect costs.
  • influenza vaccine 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.
  • 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 very strain that the vaccine is supposed to prevent, as the vaccine takes about two weeks to become effective.
  • influenza vaccines are 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.
  • 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.
  • 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.
  • Antiviral drugs can also be used to treat influenza, with neuraminidase inhibitors being particularly effective, but viruses can develop resistance to the standard antiviral drugs.
  • 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, and to compounds and compositions that can be employed for such methods.
  • the present invention is directed to a compound represented by Structural Formula (I) or a pharmaceutically acceptable salt thereof:
  • X 1 is -CI, -CN, -CF 3 , or -CH 3 ;
  • X 2 is -H, -F, or -CI
  • Ring T is a C3-C1 0 carbocyclic group optionally further substituted with one or more
  • Z 1 and Z 2 are each independently CH or N;
  • Q 1 is -C(O)-, -C(0)0-, -OC(O)-, -0-, -C(0)NR'-, NRC(O)-, -NRC(0)NR'-, -OC(0)NR'-,-S(0)-, -S(0) 2 -, -S0 2 NR'-, -NRS0 2 - -NRS0 2 NR'-, -P(0)(OR)0-,
  • optionally -Q x -R 2 forms, together with the carbon atom of Ring T to which -Q x -R 2 is attached, forms a 4-10 membered (or 5-7 membered), non-aromatic, spiro ring optionally substituted with one or more instances of J R ;
  • Q 2 is -CH 2 -[C(R 7 R 8 )] n -;
  • R 2 is -H, a C1-C6 aliphatic group optionally substituted with one or more J A , a C3-C8 carbocyclic group optionally substituted with one or more J B , or a 4-10 membered heterocyclic group optionally substituted with one or more J c , or optionally R 2 , together with R' and the nitrogen atom of Q 1 to which they are attached (that is NR'R 2 of Q l R 2 when Q 1 is -C(0)NR'-, NRC(O)-, -NRC(0)NR'-, -OC(0)NR'-, -SO2NR'-, -NRSO2-, or-NRS0 2 NR'-), forms a 4-8 membered heterocyclic group optionally substituted with one or more instances of J R ; or
  • R 2 is a C1-C6 aliphatic group substituted with one or more M, a 5-7 membered heterocyclic group optionally substituted with one or more J 2 , or a 5-6 membered heteroaryl group optionally substituted with one or more J 3 ;
  • R 3 is -C(0)OR, -S(0)R 9 , -S(0) 2 R 9 , -S(0) 2 NRR 10 , -OR, P(0)(OR) 2 , or CH 2 OR;
  • R 4 , R 5 , and R 6 are each and independently -CH 3 , -CH 2 F, -CF 3 , -C 2 H 5 , -CH 2 CH 2 F, or -CH 2 CF 3 ; or optionally R 5 and R 6 , or R 4 , R 5 and R 6 , together with the carbon atom to which they are attached, form a C3-C1 0 carbocyclic ring;
  • R 7 and R 8 are each and independently -H, -OH, -CH 3 , or -CF 3 ; or optionally, R 7 and R 8 together with the carbon atoms to which they are attached form a cyclopropane ring; each R 9 is independently -OR or C1-C6 alkyl optionally substituted with one or more instances of J 1 ;
  • R 10 is -H or C1-C6 alkyl optionally substituted with one or more instances of J 1 ;
  • R and R' are each independently -H or C1-C6 alkyl optionally substituted with one or more instances of J 1 , or optionally R and R', together with the nitrogen to which they are attached, form a 4-8 membered heterocyclic group optionally substituted with one or more instances of J R ;
  • J T is selected from the group consisting of halogen, cyano, oxo, hydroxy, -NH 2 , -NH(Ci-C 4 alkyl), -N(Ci-C 4 alkyl) 2 , -OCO(Ci-C 4 alkyl), -CO(Ci-C 4 alkyl), -C0 2 H, -C0 2 (Ci- C 4 alkyl), Ci-C 4 alkyl, Ci-C 4 haloalkyl, C 3 -C 6 cycloalkyl, and -0(Ci-C 4 alkyl);
  • J A is halogen, cyano, oxo, R d , or M;
  • J B and J c are each and independently selected from the group consisting of halogen, cyano, oxo, M, -R a , and -R a -M; or
  • R a is independently:
  • Ci-Ce aliphatic group optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH 2 , -NH(Ci-C 4 alkyl), -N(C 1 -C 4 alkyl) 2 , -OCO(Ci-C 4 alkyl), -CO(Ci-C 4 alkyl), -C0 2 H, -C0 2 (Ci-C 4 alkyl), -0(Ci-C 4 alkyl), C3-C8 carbocyclic group optionally substituted with one or more instances of J 2 , 4-8 membered heterocyclic group optionally substituted with one or more instances of J 2 , 5-6 membered heteroaryl group optionally substituted with one or more instances of J 3 , and phenyl optionally substituted with one or more instances of J 3 ;
  • R b and R c are each independently R a or -H; or optionally, R b and R c , together with the nitrogen atom(s) to which they are attached, each independently form a 4-8 membered heterocyclic group optionally substituted with one or more instances of J R ;
  • R d is C3-C8 carbocyclic group optionally substituted with one or more instances of J 2 , 4-8 membered heterocyclic group optionally substituted with one or more instances of J 2 , 5-6 membered heteroaryl group optionally substituted with one or more instances of J 3 , or phenyl optionally substituted with one or more instances of J 3 ;
  • each J 1 is independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH 2 , -NH(Ci-C 4 alkyl), -N(Ci-C 4 alkyl) 2 , -OCO(Ci-C 4 alkyl), -CO(Ci-C 4 alkyl), -C0 2 H, -C0 2 (Ci-C 4 alkyl), -0(Ci-C 4 alkyl), and phenyl;
  • each J 2 is independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH 2 , -NH(Ci-C 4 alkyl), -N(Ci-C 4 alkyl) 2 , -OCO(Ci-C 4 alkyl), -CO(Ci-C 4 alkyl), -C0 2 H, -C0 2 (Ci-C 4 alkyl), Ci-C 4 alkyl, Ci-C 4 haloalkyl, and -0(Ci-C 4 alkyl);
  • each of J 3 and J R is independently selected from the group consisting of halogen, cyano, hydroxy, -NH 2 , -NH(Ci-C 4 alkyl), -N(Ci-C 4 alkyl) 2 , -OCO(Ci-C 4 alkyl), -CO(Ci-C 4 alkyl), -C0 2 H, -C0 2 (Ci-C 4 alkyl), Ci-C 4 alkyl, Ci-C 4 haloalkyl, and -0(Ci-C 4 alkyl); and n is independently 0 or 1.
  • the present invention is directed to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound disclosed herein (e.g., a compound represented by any one of Structural Formulae (I) - (V), or a pharmaceutically acceptable salt thereof) and a pharmaceutically acceptable carrier, adjuvant or vehicle.
  • the present invention is directed to a method of inhibiting the replication of influenza viruses in a biological sample or patient, comprising the step of administering to said biological sample or patient an effective amount of a compound disclosed herein (e.g., a compound represented by any one of Structural Formulae (I) - (V), or a pharmaceutically acceptable salt thereof).
  • a compound disclosed herein e.g., a compound represented by any one of Structural Formulae (I) - (V), or a pharmaceutically acceptable salt thereof.
  • the present invention is directed to a method of reducing the amount of influenza viruses in a biological sample or in a patient, comprising administering to said biological sample or patient an effective amount of a compound disclosed herein (e.g., a compound represented by any one of Structural Formulae (I) - (V), or a pharmaceutically acceptable salt thereof).
  • a compound disclosed herein e.g., a compound represented by any one of Structural Formulae (I) - (V), or a pharmaceutically acceptable salt thereof.
  • the present invention is directed to a method of method of treating influenza in a patient, comprising administering to said patient an effective amount of a compound disclosed herein (e.g., a compound represented by any one of Structural Formulae (I) - (V), or a pharmaceutically acceptable salt thereof).
  • a compound disclosed herein e.g., a compound represented by any one of Structural Formulae (I) - (V), or a pharmaceutically acceptable salt thereof.
  • the present invention also provides use of the compounds 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.
  • Also provided herein is use of the compounds 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.
  • the compounds of Structural Formula (XX) can be used for synthesizing the compounds of Formula (I).
  • the variables of Structural Formula (XX) are each and independently as defined herein; and G is trityl (-C(Ph) 3 ).
  • the invention also provides methods of preparing a compound represented by
  • Structural Formula (I) or a pharmaceutically acceptable salt thereof employ the steps of:
  • L 2 is a halogen
  • G is trityl
  • the compounds of the invention are as described in the claims.
  • the compounds of the invention are represented by any one of Structural Formulae (I) - (V), or pharmaceutically acceptable salts thereof, wherein the variables are each and independently as described in any one of the claims.
  • the compounds of the invention are represented by any chemical formulae depicted in Table 1, or pharmaceutically acceptable salts thereof.
  • the compounds of the invention are presented by Structural Formulae (I) - (V), or a pharmaceutically acceptable salt thereof, wherein the variables are each and independently as depicted in the chemical formulae in Table 1.
  • the compounds of the invention are represented by Structural Formula (I) or pharmaceutically acceptable salts thereof:
  • X 1 is -CI, -CN, -CF 3 , or -CH 3 . In one aspect, X 1 is -CI, or -CF 3 . In another aspect, X 1 is -CI.
  • X 2 is -H, -F, or -CI. In one aspect, X is -F or -CI. In another aspect, X is -F.
  • Ring T is a C3-C 10 carbocyclic group optionally further substituted with one or more J T .
  • Ring T can be a mono-cyclic, bi-cyclic, polycyclic, bridged, non-bridged, or fused ring system.
  • Ring T is an optionally substituted C5-C 10 carbocyclic ring.
  • Ring T is an optionally substituted C5-C6 mono-cyclic group.
  • Ring T is an optionally substituted C7-C 10 bridged carbocyclic ring.
  • a typical example of (Ring T)-Q -R Ring A is a C5-C7 monocyclic group or C7-C 10 bridged carbocyclic group, each of which independently and optionally further substituted with one or more instances of J T ; or optionally Ring A and R 13 , Ring A and R 14 , or Ring A and R 15 , form a C7-C 10 bridged carbocyclic ring optionally further substituted with one or more instances of J T .
  • Certain more typical examples of (Ring T)-Q 1 - R 2 include:
  • rings A1-A4 is independently a C7-C1 0 bridged, carbocyclic ring optionally further substituted with one or more substituents selected from the group consisting of halogen, cyano, hydroxy, C1-C4 alkyl, C 1 -C 4 haloalkyl, and -0(Ci-C 4 alkyl); and each of rings A5-A6 is independently and optionally further substituted with one or more substituents selected from the group consisting of halogen, cyano, hydroxy, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C3-C5 cycloalkyl, and -0(Ci-C 4 alkyl).
  • Z 1 and Z 2 are each independently CH or N. In one aspect, Z 1 and Z 2 are each independently CH.
  • Each Q 1 is independently -C(O)-, -C(0)0-, -OC(O)-, -0-, -C(0)NR'-, NRC(O)-, -NRC(0)NR'-, -OC(0)NR'-,-S(0)-, -S(0) 2 -, -S0 2 NR'-, -NRS0 2 - -NRS0 2 NR'-,
  • Q 1 is -C(0)0-, -NRC(O)-, -C(0)NR'-, or -NRC(0)NR'-.
  • each Q 1 is independently -C(0)0-, -NHC(O)-, or -NHC(0)NR'-.
  • each Q 1 is independently -C(0)0-.
  • each Q 1 is independently -NHC(O)- or -NHC(0)NR'-.
  • -Q x -R 2 forms, together with the carbon atom of Ring T to which -Q x -R 2 is attached, forms a 4-10 membered, non-aromatic, spiro ring optionally substituted with one or more instances of J R .
  • the spiro ring formed with -Q x -R 2 is an optionally substituted, 5-7 membered ring.
  • Q 2 is -CH 2 -[C(R 7 R 8 )]n-. In one aspect, -CH 2 -[CH 2 ] n -. In another aspect, Q 2 is -CH 2 .
  • R 2 is -H, a C1-C6 aliphatic group optionally substituted with one or more J A , a C3-C8 carbocyclic group optionally substituted with one or more J B , or a 4-10 membered heterocyclic group optionally substituted with one or more J c , or optionally, R 2 , together with R' and the nitrogen atom of Q 1 to which they are attached (that is NR'R 2 of Q X R 2 when Q 1 is -C(0)NR'-, NRC(O)-, -NRC(0)NR'-, -OC(0)NR'-, -S0 2 NR'-, -NRSO 2 -, or-NRS0 2 NR'-), form a 4-8 membered heterocyclic group optionally substituted with one or more instances of J R .
  • R 2 is a C 1 -C6 aliphatic group substituted with one or more M, a 5-7 membered heterocyclic group optionally substituted with one or more J 2 , or a 5-6 membered heteroaryl group optionally substituted with one or more J 3 .
  • Q 1 is other than a bond; and R 2 is independently -H, an optionally substituted C 1 -C6 alkyl, an optionally substituted 5-7 membered heterocyclic group, an optionally substituted phenyl group, or an optionally substituted 5-6 membered heteroaryl group; or optionally R 2 and R', together with the nitrogen atom to which they are attached, form an optionally substituted, 5-7 membered heterocyclic group; wherein said C 1 -C6 alkyl is optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, hydroxy, and -0(Ci-C 4 alkyl); and each of said heterocyclic, phenyl and heteroaryl groups is independently and optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, Ci-C 4 alkyl, Ci-C 4 haloalkyl, and -0(Ci-C 4 alkyl
  • Q 1 is other than a bond; and R 2 is - H, optionally substituted Ci_6 alkyl, optionally substituted 5-6 membered heterocyclic, or optionally substituted 5-6 membered heteroaryl.
  • Q 1 is other than a bond; and R 2 is -H, optionally substituted Ci_6 alkyl, or optionally substituted 5-6 membered heterocyclic.
  • Q 1 is other than a bond; and R 2 is -H or optionally substituted Ci_6 alkyl.
  • R 2 when Q 1 is a bond, R 2 is a C 1 -C6 alkyl group substituted with one or more M; an optionally substituted, 5-7 membered, heterocyclic group; or an optionally substituted, 5-6 membered heteroaryl group. In yet another aspect, when Q 1 is a bond, R 2 is a C1-C6 alkyl group substituted with one or more M.
  • R 3 is -C(0)OR, -S(0)R 9 , -S(0) 2 R 9 , -S(0) 2 NRR 10 , -OR, P(0)(OR) 2 , or CH 2 OR.
  • R 3 is -C(0)OR, -OH, -CH 2 OH, -S(0) 2 R 9 , or -S(0) 2 -NRR 10 .
  • R 3 is -C(0)OR, -S(0) 2 R 9 , or -S(0) 2 -NRR 10 .
  • R 3 is -C(0)OR.
  • R 4 , R 5 , and R 6 are each and independently -CH 3 , -CH 2 F, -CF 3 , -C 2 H 5 , -CH 2 CH 2 F, or -CH 2 CF 3 ; or optionally R 5 and R 6 , or R 4 , R 5 and R 6 , together with the carbon atom to which they are attached, form a 3-10 membered carbocyclic ring.
  • R 4 , R 5 , and R 6 are each and independently -CH 3 , -CH 2 F, -CF 3 , or -C 2 H 5 ; or R 4 is -CH 3 , -CH 2 F, -CF 3 , or -C 2 H 5 ; and R 5 and R 6 together with the carbon atom to which they are attached form a C 3 -C6 carbocyclic ring.
  • R 4 , R 5 , and R 6 are each and independently -CH 3 or - C2H5.
  • R 4 is -CH 3 or -C2H5; and R 5 and R 6 together with the carbon atom to which they are attached form a C3-C6 carbocyclic ring.
  • R 7 and R 8 are each and independently -H, -OH, -CH 3 , or -CF 3 ; or optionally, R 7 and R 8 together with the carbon atoms to which they are attached form a cyclopropane ring.
  • R 7 and R 8 are each and independently -H, -OH, -CH 3 , or -CF 3 .
  • R 7 and R 8 are each and independently -H or -CH 3 .
  • R 7 and R 8 are each and independently -H.
  • Each R 9 is independently -OR or C -Ce alkyl optionally substituted with one or more instances of J 1 . In one aspect, each R 9 is -OH.
  • R 10 is -H or Ci-Ce alkyl optionally substituted with one or more instances of J 1 .
  • R 10 is C 1-4 alkyl optionally substituted with one or more substituents selected from the group consisting of halogen, -OR and -C(0)OR.
  • R and R' are each independently -H or Ci-Ce alkyl optionally substituted with one or more instances of J 1 , or optionally R and R', together with the nitrogen to which they are attached, form a 4-8 membered heterocyclic group optionally substituted with one or more instances of J R .
  • J T is selected from the group consisting of halogen, cyano, oxo, hydroxy, -NH 2 , -NH(Ci-C 4 alkyl), -N(Ci-C 4 alkyl) 2 , -OCO(Ci-C 4 alkyl), -CO(Ci-C 4 alkyl), -C0 2 H, -C0 2 (Ci- C 4 alkyl), Ci-C 4 alkyl, Ci-C 4 haloalkyl, C 3 -C 6 cycloalkyl, and -0(Ci-C 4 alkyl).
  • J A is halogen, cyano, oxo, R d , or M.
  • J B and J c are each and independently selected from the group consisting of halogen, cyano, oxo, M, -R a , and -R a -M.
  • two J T , two J A , two J B , and two J c 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 J R .
  • each M is independently selected from the group consisting of -OR b , -SR b , -S(0)R a , -S0 2 R a , -NR b R c , -C(0)R a , -C(0)OR b , -OC(0)R b , -NRC(0)R b , -C(0)NR b R c ,
  • each M is independently selected from the group consisting of -OR b , -NR b R c , -C(0)R a , -C(0)OR b , -OC(0)R b , -NRC(0)R b , -C(0)NR b R c , -NRC(0)NR b R c , -NRC(0)OR b , -OCONR b R c , -S0 2 NR c R b , -NRS0 2 R b , and -NRS0 2 NR b R c .
  • each M is independently selected from the group consisting of -OR b , -NHR C , -C(0)R a , -C(0)OR b , -OC(0)R b , -NHC(0)R b , -C(0)NHR c , -C(0)NR b R c , -NHC(0)NHR c , -NHC(0)OR b , -OCONHR c , -S0 2 NHR b , -NHS0 2 R b , and -NHS0 2 NHR c , wheren R b and R c of -C(0)NR b R c , form a 5-6 membered heterocyclic group.
  • each M is independently selected from the group consisting of -OH, -0(Ci-C 6 alkyl), -NH(Ci-C 6 alkyl), -C(0)(Ci-C 6 alkyl), -C(0)OH, -C(0)0(Ci-C 6 alkyl), -OC(0)(Ci-C 6 alkyl), -NHC(0)(Ci-C 6 alkyl), -NHC(0)(5- 6 membered heteroaryl), -NHC(0)(5-6 membered heterocyclic group), -C(0)NH(Ci-C6 alkyl), -NHC(0)NH(Ci-C 6 alkyl), -NHC(0)0(Ci-C 6 alkyl), -OCONH(Ci-C 6 alkyl), -S0 2 NH(Ci-C 6 alkyl), -NHS0 2 (Ci-C 6 alkyl), and -NHS0 2 NH(Ci-C 6 alkyl)
  • each M is independently selected from the group consisting of -OH, -0(Ci-C6 alkyl), -NH(Ci-C 6 alkyl), -C(0)OH, -C(0)0(Ci-C 6 alkyl), -OC(0)(Ci-C 6 alkyl), -NHC(0)(Ci-C 6 alkyl), -NHC(0)(5-6 membered heterocyclic group), -C(0)NH(Ci-C 6 alkyl), -S0 2 NH(Ci- C 6 alkyl), and -NHS0 2 (Ci-C 6 alkyl).
  • Each R a is independently: i) a C 1 -C6 aliphatic group optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH 2 , -NH(Ci-C 4 alkyl), -N(Ci-C 4 alkyl) 2 , -OCO(Ci-C 4 alkyl), -CO(Ci-C 4 alkyl), -C0 2 H, -C0 2 (Ci- C 4 alkyl), -0(Ci-C 4 alkyl), C3-C8 carbocyclic group optionally substituted with one or more instances of J 2 , 4-8 membered heterocyclic group optionally substituted with one or more instances of J 2 , 5-6 membered heteroaryl group optionally substituted with one or more instances of J 3 , and phenyl optionally substituted with one or more instances of J 3 ; ii) a C3-C8
  • each R a is independently an optionally substituted C 1 -C6 alkyl group, an optionally substituted C3-C7 carbocyclic group, an optionally substituted 5-7 membered heterocyclic group, an optionally substituted 5-6 membered heteroaryl group, or an optionally substituted phenyl group.
  • R b and R c are each independently R a or -H; or optionally, R b and R c , together with the nitrogen atom(s) to which they are attached, each independently form a 4-8 membered heterocyclic group optionally substituted with one or more instances of J R .
  • R b and R c are each independently R a or -H; or optionally, R b and R c , together with the nitrogen atom(s) to which they are attached, each independently form an optionally substituted 5-7 membered heterocyclic group.
  • R d is C3-C8 carbocyclic group optionally substituted with one or more instances of J 2 , 4-8 membered heterocyclic group optionally substituted with one or more instances of J 2 , 5-6 membered heteroaryl group optionally substituted with one or more instances of J 3 , or phenyl optionally substituted with one or more instances of J 3 .
  • R d is independently an optionally substituted C3-C6 carbocyclic group, an optionally substituted 5-7 membered heterocyclic group.
  • J A is halogen, cyano, oxo, an optionally substituted C3-C6 carbocyclic group, an optionally substituted 5-7 membered heterocyclic group, or M. In another aspect, J A is halogen, cyano, oxo, or M.
  • J A is halogen, cyano, oxo, -OH, - 0(Ci-C 6 alkyl), -NH(Ci-C 6 alkyl), -C(0)OH, -C(0)0(Ci-C 6 alkyl), -OC(0)(Ci-C 6 alkyl), -NHC(0)(Ci-C 6 alkyl), -NHC(0)(5-6 membered heterocyclic group), -C(0)NH(Ci-C 6 alkyl), -S0 2 NH(Ci-C 6 alkyl), or -NHS0 2 (Ci-C 6 alkyl).
  • J B and J c are each and independently is halogen, cyano, oxo, M, an optionally substituted C1-C6 alkyl group, an optionally substituted C3-C6 carbocyclic group, an optionally substituted 5-7 membered heterocyclic group, an optionally substituted 5-7 membered heteroaryl group, or an optionally substituted phenyl group.
  • J B and J c are each and independently is halogen; cyano; oxo; -OH; -0(Ci-C6 alkyl); - H(Ci-C6 alkyl); -C(0)OH; -C(0)0(Ci-C 6 alkyl); -OC(0)(Ci-C 6 alkyl); -NHC(0)(Ci-C 6 alkyl); -NHC(0)(5-6 membered heterocyclic group); -C(0)NH(Ci-C 6 alkyl); -S0 2 NH(Ci-C 6 alkyl),; - HS0 2 (Ci-C6 alkyl); or a C1-C6 alkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH 2 , -NH(Ci-C 4 alkyl), -N(Ci-C 4 alkyl) 2 ,
  • Each J 1 is independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH 2 , -NH(Ci-C 4 alkyl), -N(Ci-C 4 alkyl) 2 , -OCO(Ci-C 4 alkyl), -CO(Ci-C 4 alkyl), -C0 2 H, -C0 2 (Ci-C 4 alkyl), -0(Ci-C 4 alkyl), and phenyl.
  • Each J 2 is independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH 2 , -NH(Ci-C 4 alkyl), -N(Ci-C 4 alkyl) 2 , -OCO(Ci-C 4 alkyl), -CO(Ci-C 4 alkyl), -C0 2 H, -C0 2 (Ci-C 4 alkyl), Ci-C 4 alkyl, Ci-C 4 haloalkyl, and -0(Ci-C 4 alkyl).
  • Each of J 3 and J R is independently selected from the group consisting of halogen, cyano, hydroxy, -NH 2 , -NH(Ci-C 4 alkyl), -N(Ci-C 4 alkyl) 2 , -OCO(Ci-C 4 alkyl), -CO(Ci-C 4 alkyl), -C0 2 H, -C0 2 (Ci-C 4 alkyl), Ci-C 4 alkyl, d-C 4 haloalkyl, and -0(Ci-C 4 alkyl).
  • n is independently 0 or 1.
  • x is 0, 1 or 2. In one aspect, x is 0 or 1.
  • Each p is independently 1, 2, or 3. In one aspect, each p is independently 2 or 3.
  • Each q is independently 0, 1 or 2. In one aspect, each q is independently 0 or 1.
  • Each r is independently 1 or 2.
  • X 1 is -CI, or -CF 3 .
  • X 2 is -F or -CI.
  • X 1 and X 2 are each independently as described above in the first or second set of set of values of the variables of Structural Formula (I).
  • M is independently selected from the group consisting of -OR b , -SR b , -S(0)R a ,
  • X 1 and X 2 are each independently as described above in the first or second set of set of values of the variables of Structural Formula (I).
  • M is each independently as described above in the first or third set of set of values of the variables of Structural Formula (I).
  • J T is selected from the group consisting of halogen, cyano, hydroxy, -NH 2 , -NH(Ci-C 4 alkyl), -N(Ci-C 4 alkyl) 2 , -OCO(Ci-C 4 alkyl), -CO(Ci-C 4 alkyl), -C0 2 H, -C0 2 (Ci-C 4 alkyl), Ci-C 4 alkyl, d-C 4 haloalkyl, C 3 -C 6 cycloalkyl, and -0(Ci-C 4 alkyl).
  • J A is halogen, cyano, oxo, R d , -OR b , -NHR C , -C(0)R b , -C(0)OR b , -OC(0)R b , -NHC(0)R b , -C(0)NHR c , -NHC(0)NHR c , -NHC(0)OR b , -OCONHR c , -N(CH 3 )R C , -N(CH 3 )C(0)R b , -C(0)N(CH 3 )R c , -N(CH 3 )C(0)NHR c , -N(CH 3 )C(0)OR b , -NHS0 2 R b , -S0 2 NHR b , -S0 2 N(CH 3 )R b , and -N(CH 3 )S0 2 R b .
  • J and J are each and independently selected from the group consisting of halogen, cyano, oxo, R a , -OR b , -NHR C , -C(0)R b , -C(0)OR b , -OC(0)R b , -NHC(0)R b , -C(0)NHR c , -NHC(0)NHR c , -NHC(0)OR b , -OCONHR c , -N(CH 3 )R C , -N(CH 3 )C(0)R b ,
  • X 1 and X 2 are each independently as described above in the first or second set of set of values of the variables of Structural Formula (I).
  • M is each independently as described above in the first or third set of set of values of the variables of Structural Formula (I).
  • J T , J A , J B , and J c is independently as described above in the first or fourth set of set of values of the variables of Structural Formula (I).
  • R a is independently an optionally substituted C1-C6 alkyl group, an optionally substituted C3-C7 carbocyclic group, an optionally substituted 5-7 membered heterocyclic group, an optionally substituted 5-6 membered heteroaryl group, or an optionally substituted phenyl group;
  • R b and R c are each independently R a or -H; or optionally, R b and R c , together with the nitrogen atom(s) to which they are attached, each independently form an optionally substituted 5-7 membered heterocyclic group.
  • R d is independently an optionally substituted C 3 -C6 carbocyclic group or an optionally substituted 5-7 membered heterocyclic group.
  • the compounds of the invention are represented by any one of Structural Formula (II) or pharmaceutically acceptable salts thereof:
  • values of the variables of Structural Formula (II) are each and independently as described above in any one of the first through fifth sets of values of the variables of Structural Formula (I).
  • Q 1 is -C(0)0-, -NRC(O)-, -C(0)NR'-, or -NRC(0)NR'-.
  • Values of the other variables are each and independently as described above in any one of the first through fifth sets of values of the variables of Structural Formula (I).
  • Ring T is an optionally substituted C5-C1 0 carbocyclic ring. In one aspect, Ring T is an optionally substituted C5-C6 mono-cyclic group. In another aspect, Ring T is an optionally substituted C7-C1 0 bridged carbocyclic ring.
  • Values of the other variables are each and independently as described above in any one of the first through fifth sets of values of the variables of Structural Formula (I).
  • Q 1 is as described above in any one of the first through fifth sets of values of the variables of Structural Formula (I) or in the sixth set of values of the variables of Structural Formula (II).
  • Ring T-Q ⁇ R 2 is:
  • Ring A is a C5-C7 monocyclic group or C7-C1 0 bridged carbocyclic group, each of which independently and optionally further substituted with one or more instances of J T ; or optionally Ring A and R 13 , Ring A and R 14 , or Ring A and R 15 , independently form a C7-C1 0 bridged carbocyclic ring optionally further substituted with one or more instances of J T ;
  • R 12 , R 13 , and R 14 are each independently -H, -F, hydroxy, -NH 2 , -NH(Ci-C 4 alkyl), -N(Ci-C 4 alkyl) 2 , -OCO(Ci-C 4 alkyl), -CO(Ci-C 4 alkyl), -C0 2 H, -C0 2 (Ci-C 4 alkyl), Ci-C 4 alkyl, Ci-C 4 haloalkyl, or -0(Ci-C 4 alkyl);
  • R 15 is -H, -F, hydroxy, Ci-C 4 alkyl, or Ci-C 4 haloalkyl
  • x 0, 1 or 2.
  • Values of the other variables are each and independently as described above in any one of the first through fifth sets of values of the variables of Structural Formula (I).
  • Ring A and x are each independently as described above in the eighth set of values of the variables of Structural Formula (II).
  • R 12 is -H, hydroxy, d-C 4 alkyl, Ci-C 4 haloalkyl, or -0(Ci-C 4 alkyl).
  • R 13 is -H, hydroxy, Ci-C 4 alkyl, Ci-C 4 haloalkyl, or -0(Ci-C 4 alkyl), or optionally, together with Ring A, forms an optionally substituted C7-C1 0 bridged, carbocyclic ring.
  • R 14 is -H, Ci-C 4 alkyl, or Ci-C 4 haloalkyl; or optionally, together with Ring A, forms an optionally substituted C7-C1 0 bridged, carbocyclic ring.
  • R 15 is -H, C 1 -C 4 alkyl, or Ci-C 4 haloalkyl; or optionally, together with Ring A, forms an optionally substituted, C7-C1 0 bridged, carbocyclic ring.
  • Values of the other variables are each and independently as described above in any one of the first through fifth sets of values of the variables of Structural Formula (I).
  • Q 1 is as described above in any one of the first through fifth sets of values of the variables of Structural Formula (I) or in the sixth set of values of the variables of Structural Formula (II).
  • Ring A and x are each independently as described above in the eighth set of values of the variables of Structural Formula (II).
  • R is -H.
  • R is -H or optionally, together with Ring A, forms an optionally substituted C7-C1 0 bridged, carbocyclic ring.
  • R is -H or optionally, together with Ring A, forms an optionally substituted, C7-C1 0 bridged, carbocyclic ring.
  • R 15 is -H or C1-C4 alkyl, or optionally, together with Ring A, forms an optionally substituted C7-C1 0 bridged, carbocyclic ring.
  • Values of the other variables are each and independently as described above in any one of the first through fifth sets of values of the variables of Structural Formula (I).
  • Q 1 is as described above in any one of the first through fifth sets of values of the variables of Structural Formula (I) or in the sixth set of values of the variables of Structural Formula (II).
  • Ring A is a C7-C1 0 bridged, carbocyclic group; and R 12 , R 13 , and R 14 are each independently -H, and R 15 is -H or Ci alkyl; or ii) Ring A and R 15 , Ring A and R 14 , or Ring A and R 13 independently form an optionally substituted, C7-C1 0 bridged, carbocyclic group; and R is -H.
  • R 12 , R 13 , R 14 , R 15 , and x are each independently as described above in any one of the first through tenth sets of values of the variables of Structural Formula (II).
  • Values of the other variables are each and independently as described above in any one of the first through fifth sets of values of the variables of Structural Formula (I).
  • Q 1 is as described above in any one of the first through fifth sets of values of the variables of Structural Formula (I) or in the sixth set of values of the variables of Structural Formula (II).
  • Ring T-Q ⁇ R 2 is:
  • Each of rings A1-A4 is independently a C7-C1 0 bridged, carbocyclic ring optionally further substituted with one or more substituents selected from the group consisting of halogen, cyano, hydroxy, C1-C4 alkyl, C 1 -C 4 haloalkyl, and -0(Ci-C 4 alkyl).
  • Each of rings A5-A6 is independently and optionally further substituted with one or more substituents selected from the group consisting of halogen, cyano, hydroxy, C1-C4 alkyl, C1-C4 haloalkyl, C3-C5 cycloalkyl, and -0(Ci-C 4 alkyl).
  • Each R 14 is independently -H, C1-C4 alkyl, or C1-C4 haloalkyl.
  • R 12 and R 15 are each and independently -H, hydroxy, C1-C4 alkyl, or C1-C4 haloalkyl.
  • R 21 , R 22 , R 23 , R 24 , and R 25 are each independently -H, -F, hydroxy, -0(Ci-C 4 alkyl), C1-C4 alkyl, or C1-C4 haloalkyl.
  • Each p is independently 1, 2, or 3. In one aspect, each of p is independently 2.
  • Each q is independently 0, 1 or 2. In one aspect, each of q is independently 1.
  • Each r is independently 1 or 2.
  • Values of the other variables are each and independently as described above in any one of the first through fifth sets of values of the variables of Structural Formula (I).
  • Q 1 is as described above in any one of the first through fifth sets of values of the variables of Structural Formula (I) or in the sixth set of values of the variables of Structural Formula (II).
  • Ring T-Q x -R 2 is as described above in the twelfth set of values of the variables of Structural Formula (II).
  • R 12 , R 14 and R 15 are each independently -H or C1-C4 alkyl.
  • R , R , R , and R are each independently -H or C1-C4 alkyl.
  • Values of the other variables are each and independently as described above in any one of the first through fifth sets of values of the variables of Structural Formula (I).
  • Q 1 is independently -C(0)0-, -NHC(O)-, or -NHC(0)NR'-.
  • Ring T-Q ⁇ R 2 , R 12 , R 14 , R 15 , R 21 , R 22 , R 23 , R 24 , and R 25 are each independently as described above in any one of the first through the thirteenth set of values of the variables of Structural Formula (II).
  • Values of the other variables are each and independently as described above in any one of the first through fifth sets of values of the variables of Structural Formula (I).
  • R 2 is independently -H, an optionally substituted C1-C6 alkyl, an optionally substituted 5-7 membered heterocyclic group, an optionally substituted phenyl group, or an optionally substituted 5-6 membered heteroaryl group; or optionally R 2 and R', together with the nitrogen atom to which they are attached, form an optionally substituted, 5-7 membered heterocyclic group; wherein said C1-C6 alkyl is optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, hydroxy, and -0(Ci-C 4 alkyl); and each of said heterocyclic, phenyl and heteroaryl groups is independently and optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, C1-C4 alkyl, C1-C4 haloalkyl, and -0(Ci-C 4 alkyl).
  • R 2 is H, optionally substituted Ci_6 alkyl, optionally substituted 5-6 membered heterocyclic, or optionally substituted 5-6 membered hereroaryl. In another aspect, R 2 is H or optionally substituted Ci_6 alkyl. In yet another aspect, R 2 is H, optionally substituted 5-6 membered heterocyclic, or optionally substituted 5-6 membered heteroaryl.
  • Values of the other variables are each and independently as described above in any one of the first through fifth sets of values of the variables of Structural Formula (I).
  • R 2 is H or optionally substituted Ci_6 alkyl; and R 12 , R 14 , R 15 , R 21 , R 22 , R 23 , R 24 , and R 25 are each independently -H.
  • Values of the other variables are each and independently as described above in any one of the first through fifth sets of values of the variables of Structural Formula (I).
  • Z 1 is CH.
  • X 1 is -CI.
  • X 2 is -F.
  • Values of the other variables are each and independently as described above in any one of the first through fifth sets of values of the variables of Structural Formula (I).
  • the compounds of the invention are represented by any one of Structural Formulae (III) - (V), or pharmaceutically acceptable salts thereof:
  • ring P is a C3-C6 carbocyclic ring, and values of the other variables of Structural
  • Formulae (III) - (V) are each and independently as described above in any one of the first through fifth sets of values of the variables of Structural Formula (I).
  • Z 2 is CH.
  • R 3 is -C(0)OR, -OH, -CH 2 OH, -S(0) 2 R 9 , or -S(0) 2 -NRR 10 .
  • Values of the other variables are each and independently as described above in any one of the first through fifth sets of values of the variables of Structural Formula (I).
  • Z 2 and R 3 are each independently as described above in any one of the first set through the sixth set of values of the variables of Structural Formulae (III) - (V).
  • R 4 , R 5 , and R 6 are each and independently -CH 3 , -CH2F, -CF 3 , or -C2H5; or
  • R 4 is -CH 3 , -CH2F, -CF 3 , or -C2H5; and R 5 and R 6 together with the carbon atom to which they are attached form a C 3 -C6 carbocyclic ring.
  • Values of the other variables are each and independently as described above in any one of the first through fifth sets of values of the variables of Structural Formula (I).
  • Z 2 , R 3 , R 4 , R 5 , and R 6 are each and independently as described above in any one of the first set through the seventh set of values of the variables of Structural Formulae (III) - (V).
  • Values of the other variables are each and independently as described above in any one of the first through fifth sets of values of the variables of Structural Formula (I).
  • Q 2 , Z 2 , R 3 , R 4 , R 5 , and R 6 are each and independently as described above in any one of the first set through the eighth set of values of the variables of Structural Formulae (III) - (V).
  • R is -H or Ci-4 alkyl.
  • R 9 is -OH.
  • R 10 is Ci-4 alkyl optionally substituted with one or more substituents selected from the group consisting of halogen, -OR and -C(0)OR.
  • Values of the other variables are each and independently as described above in any one of the first through fifth sets of values of the variables of Structural Formula (I).
  • Q 2 , Z 2 , R, R 4 R 5 , R 6 , R 9 , and R 10 are each and independently as described above in any one of the first set through the ninth set of values of the variables of Structural Formulae (III) - (V).
  • R 3 is -C(0)OR, -S(0) 2 R 9 , or -S(0) 2 -NRR 10 .
  • Values of the other variables are each and independently as described above in any one of the first through fifth sets of values of the variables of Structural Formula (I).
  • Q 2 , Z 2 , R, R 4 , R 3 , R 5 , R 6 , R 9 , and R 10 are each and independently as described above in any one of the first set through the tenth set of values of the variables of Structural Formulae (III) - (V).
  • Z 1 is CH.
  • X 1 is -CI.
  • X 2 is -F.
  • Values of the other variables are each and independently as described above in any one of the first through fifth sets of values of the variables of Structural Formula (I).
  • the compounds of the invention are represented by any one of Structural Formulae (I) - (V) or a pharmaceutically acceptable salt thereof, wherein values of the variables are each and independently as shown in the compounds of Table 1.
  • the compounds of the invention are represented by any one of the structural formulae depicted in Table 1, or a pharmaceutically acceptable salt thereof.
  • the compounds of the invention described herein can be prepared by any suitable method known in the art. For example, they can be prepared in accordance with procedures described in WO 2005/095400, WO 2007/084557, WO 2010/01 1768, WO 2010/01 1756, WO 2010/011772, WO 2009/073300, and PCT/US2010/038988 filed on June 17, 2010.
  • the compounds shown in Table 1 can be prepared by any suitable method known in the art, for example, WO 2005/095400, WO 2007/084557, WO 2010/011768, WO
  • the present invention provides methods of preparing a compound represented by any one of Structural Formulae (I) - (V).
  • the compounds of the invention can be prepared as depicted in General Scheme 1. Any suitable condition known in the art can be employed in the invention for each step depicted in the scheme.
  • the methods comprise reacting Compound (A) with Compound (B) under suitable conditions to form a compound of Structural Formula (XX), wherein each of L 1 and L 2 independently is a halogen (F, CI, Br, or I), G is trityl and the remaining variables of Compounds (A), (B) and Structural Formula (XX) are each and independently as described above for Structural Formulae (I) - (V).
  • XX Structural Formula
  • Typical examples for L 1 and L 2 are each and independently CI or Br.
  • the methods further comprise deprotecting the G group under suitable conditions to form the compounds of Structural Formula (I).
  • Any suitable condition known in the art can be employed in the invention for each step depicted in the scheme.
  • any suitable condition described in WO 2005/095400 and WO 2007/084557 for the coupling of a dioxaboraolan with, for example, a chloro-pyrimidine can be employed for the reaction between Compounds (A) and (B).
  • the reaction between compounds (A) and (B) can be performed in the presence of Pd(PPh 3 ) 4 or Pd2(dba) 3 (dba is dibenzylidene acetone).
  • the de- tritylation step can be performed under an acidic condition (e.g., trifluoroacetic acid (TFA)) in the presence of, for example, EtsSiH (Et is ethyl).
  • an acidic condition e.g., trifluoroacetic acid (TFA)
  • EtsSiH Et is ethyl
  • the method further comprises the step of preparing Compound (A) by reacting Compound (E) with Compound (D).
  • Any suitable conditions know in the art can be employed in this step, and Compounds (E) and (D) can be prepared by any suitable method known in the art. Specific exemplary conditions are described in the Exemplification below. Compounds (E) and (D) can be prepared by any suitable method known in the art. Specific exemplary synthetic methods of these compounds are described below in the
  • the present invention is directed to a compound represented by Structural Formula (XX), wherein the variables of Structural Formula (XX) are each and independently as defined in any one of the claims, and G is trityl.
  • XX Structural Formula
  • Specific examples of the compounds represented by Structural formula (XX) are shown below in the Exemplification. Some specific examples include: Compounds 11a, 19a, and 42a, which are shown in the Exemplification below.
  • 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.
  • substituents such as illustrated generally below, or as exemplified by particular classes, subclasses, and species of the invention.
  • the phrase “optionally substituted” is used interchangeably with the phrase “substituted or unsubstituted.”
  • substituted refers to the replacement of one or more hydrogen radicals in a given structure with the radical of a specified substituent.
  • an optionally substituted group may have a substituent at each substitutable position of the group.
  • substituent 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, if X is optionally substituted Ci.Csalkyl or phenyl; X may be either optionally substituted C1-C3 alkyl or optionally substituted phenyl.
  • up to refers to zero or any integer number that is equal or less than the number following the phrase.
  • up to 3 means any one of 0, 1, 2, and 3.
  • 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.
  • 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
  • aliphatic or "aliphatic group”, as used herein, means a straight- chain (i.e., unbranched), or branched, hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation but is non-aromatic. Unless otherwise specified, aliphatic groups contain 1-20 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-10 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-8 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain 1-6 aliphatic carbon atoms, and in yet other embodiments, aliphatic groups contain 1 -4 aliphatic carbon atoms.
  • Aliphatic groups may be linear or branched, substituted or unsubstituted alkyl, alkenyl, or alkynyl groups. Specific examples include, but are not limited to, methyl, ethyl, isopropyl, n-propyl, sec -butyl, vinyl, n-butenyl, ethynyl, and tert-butyl and acetylene.
  • alkyl as used herein means a saturated straight or branched chain hydrocarbon.
  • alkenyl as used herein means a straight or branched chain hydrocarbon comprising one or more double bonds.
  • 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.
  • the "alkyl” is Ci-Ce alkyl or C1-C4 alkyl.
  • the "alkenyl” is C2-C6 alkenyl or C2-C4 alkenyl.
  • the "alkynyl” is C2-C6 alkynyl or C2-C4 alkynyl.
  • cycloaliphatic 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, cycloalkyl and
  • cycloalkenyl groups include, but are not limited to, cyclohexyl, cyclopropenyl, and cyclobutyl.
  • heterocycle 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.
  • non-aromatic heterocyclic rings comprise up to three heteroatoms selected from N, S and O within the ring.
  • non-aromatic heterocyclic rings comprise up to two heteroatoms selected from N, S and O within the ring system.
  • non-aromatic heterocyclic rings comprise up to two heteroatoms selected from N and O within the ring system.
  • the term includes monocyclic, bicyclic or polycyclic fused, spiro or bridged heterocyclic ring systems.
  • the term also includes polycyclic ring systems in which the heterocyclic ring can be fused to one or more non-aromatic carbocyclic or heterocyclic rings or one or more aromatic rings or combination thereof, wherein the radical or point of attachment is on the heterocyclic ring.
  • 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, tetrahydrofuranyl,
  • aryl (or "aryl ring” or “aryl group”) used alone or as part of a larger moiety as in “aralkyl”, “aralkoxy”, or “aryloxyalkyl” refers to carbocyclic aromatic ring systems.
  • aryl may be used interchangeably with the terms “aryl ring” or “aryl group”.
  • Carbocyclic aromatic ring groups have only carbon ring atoms (typically six to fourteen) and include monocyclic aromatic rings such as phenyl and fused polycyclic 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.
  • Carbocyclic aromatic ring or “carbocyclic aromatic”, as it is used herein, is a group in which an aromatic ring is “fused” to one or more non- aromatic rings (carbocyclic or heterocyclic), such as in an indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl, where the radical or point of attachment is on the aromatic ring.
  • heteroaryl refers 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.
  • heteroaryl 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.
  • heteroaryl groups include pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl or thiadiazolyl including, for example, 2-furanyl, 3-furanyl, N-imidazolyl, 2-imidazolyl, 4- imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxadiazolyl, 5- oxadiazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 3 -pyrazolyl, 4-pyrazolyl, 1 -pyrrolyl, 2- pyrrolyl, 3 -pyrrolyl, 2-pyri
  • cyclo include mono-, bi-, polycyclic, fused, spiro, or bridged ring systems including cycloaliphatic, heterocycloaliphatic, carbocyclic aryl, or heteroaryl, each of which has been previously defined.
  • 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.
  • bridged bicyclic ring system refers to a bicyclic heterocycloalipahtic ring system or bicyclic cycloaliphatic ring system in which the rings are bridged.
  • bridged bicyclic ring systems include, but are not limited to, adamantanyl, norbornanyl, 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, heteroaryl, alkoxy, cycloalkyloxy, heterocycloalkyloxy, (carbocyclic aryl)oxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, aroyl, heteroaroyl, nitro, carboxy, alkoxycarbonyl,
  • substituents such as alkyl (including carboxyalkyl, hydroxyalkyl, and haloalkyl such as trifluoromethyl), alkenyl, alkynyl, cycloalkyl, (cycloalky
  • alkylcarbonyloxy aminocarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino
  • heteroarylcarbonylamino heteroaralkylcarbonylamino, cyano, halo, hydroxy, acyl, mercapto, alkylsulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, or carbamoyl.
  • 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”.
  • spiro refers to ring systems having one atom (usually a quaternary carbon) as the only common atom between two rings.
  • ring atom is an atom such as C, N, O or S that is in the ring of an aromatic group, cycloalkyl group or non-aromatic heterocyclic ring.
  • a "substitutable ring atom" in an aromatic group is a ring carbon or nitrogen atom bonded to a hydrogen atom.
  • the hydrogen can be optionally replaced with a suitable substituent group.
  • substituted ring atom does not include ring nitrogen or carbon atoms which are shared when two rings are fused.
  • substituted 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.
  • heteroatom means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including, any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized 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 NR + (as in N-substituted pyrrolidinyl)).
  • an optionally substituted aralkyl can be substituted on both the alkyl and the aryl portion. Unless otherwise indicated as used herein optionally substituted aralkyl is optionally substituted on the aryl portion.
  • each R * is independently selected from hydrogen or an optionally substituted Ci_6 aliphatic.
  • Optional substituents on the aliphatic group of R are selected from NH 2 , NH(Ci_ 4 aliphatic), N(Ci_ 4 aliphatic) 2 , halogen, Ci_ 4 aliphatic, OH, 0(Ci_ 4 aliphatic), O 2 , CN, CO 2 H, C0 2 (Ci_ 4 aliphatic), 0(halo Ci_ 4 aliphatic), or halo(Ci_ 4 aliphatic), wherein each of the foregoing Ci_ 4 aliphatic groups of R is unsubstituted.
  • optional substituents on the nitrogen of a heterocyclic ring include those used above.
  • Optional substituents on the aliphatic group or the phenyl ring of R + are selected from NH 2 , NH(Ci_ 4 aliphatic), N(Ci_ 4 aliphatic) 2 , halogen, Ci_ 4 aliphatic, OH, 0(Ci_ 4 aliphatic), N0 2 , CN, C0 2 H, C0 2 (Ci_ 4 aliphatic), 0(halo Ci_ 4 aliphatic), or halo(Ci_ 4 aliphatic), wherein each of the foregoing Ci_ 4 aliphatic groups of R + is unsubstituted.
  • an aryl (including aralkyl, aralkoxy, aryloxyalkyl and the like) or heteroaryl (including heteroaralkyl and heteroarylalkoxy and the like) group may contain one or more substituents. Suitable substituents on the unsaturated carbon atom of a carbocyclic aryl or heteroaryl group are selected from those listed above. Other suitable substituents include: halogen; -R°; -OR°; -SR°; 1,2-methylenedioxy; 1,2-ethylenedioxy; phenyl (Ph) optionally substituted with R°; -O(Ph) optionally substituted with R°;
  • Optional substituents on the aliphatic group of R° are selected from NH 2 , NH(Ci-4aliphatic), N(Ci-4aliphatic) 2 , halogen, Ci-4aliphatic, OH, 0(Ci- 4 aliphatic), N0 2 , CN, C0 2 H, C0 2 (Ci_ 4 aliphatic), 0(haloCi_ 4 aliphatic), or haloCi_ 4 aliphatic, CHO, N(CO)(Ci_4 aliphatic), C(0)N(Ci_ 4 aliphatic), wherein each of the foregoing Ci_ 4 aliphatic groups of R° is unsubstituted.
  • Non-aromatic nitrogen containing heterocyclic rings that are substituted on a ring nitrogen and attached to the remainder of the molecule at a ring carbon atom are said to be N substituted.
  • 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 N' substituted-N-heterocycles.
  • an N' 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.
  • two independent occurrences of R° 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- 1 -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
  • hydroxyl'Or hydroxy or “alcohol moiety” refers to -OH.
  • an "alkoxycarbonyl,” which is encompassed by the term carboxy, used alone or in connection with another group refers to a group such as
  • a "carbonyl” refers to -C(O)-.
  • alkoxy refers to an alkyl group, as previously defined, attached to the molecule through an oxygen (“alkoxy” e.g., -O-alkyl) or sulfur (“alkylthio” e.g., -S-alkyl) atom.
  • halogen means F, CI, Br, or I.
  • cyano or "nitrile” refer to -CN or -C ⁇ N.
  • alkoxyalkyl alkoxyalkenyl
  • alkoxyaliphatic alkoxyaliphatic
  • alkoxyalkoxy mean alkyl, alkenyl, aliphatic or alkoxy, as the case may be, substituted with one or more alkoxy groups.
  • haloalkyl 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 3 and -CF 2 CF 3 .
  • 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 ( C)-alkyl-.
  • aminoalkyl aminoalkenyl
  • aminoaliphatic aminoalkyl
  • 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.
  • aminoaliphatic is a C1-C6 aliphatic group substituted with one or more - H2 groups.
  • aminoalkyl refers to the structure (R x R Y )N-alkyl-, wherein each of R x and R Y independently is as defined above.
  • the aminoalkyl is C1-C6 alkyl substituted with one or more -NH2 groups.
  • the aminoalkenyl is C1-C6 alkenyl substituted with one or more - H2 groups.
  • the aminoalkoxy is -0(C1-C6 alkyl) wherein the alkyl group is substituted with one or more -NH 2 groups.
  • hydroxyalkyl means alkyl, aliphatic or alkoxy, as the case may be, substituted with one or more -OH groups.
  • alkoxyalkyl means alkyl, aliphatic or alkoxy, as the case may be, substituted with one or more alkoxy groups.
  • alkoxyalkyl refers to an alkyl group such as (alkyl-O)-alkyl-, wherein alkyl is as defined above.
  • carboxyalkyl means alkyl substituted with one or more carboxy groups, wherein alkyl and carboxy are as defined above.
  • a 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.
  • 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.
  • the reagents may also react with other reactive groups in the compound.
  • protecting groups are detailed in Greene, T. W., Wuts, P. G in "Protective Groups in Organic Synthesis", Third Edition, John Wiley & Sons, New York: 1999 (and other 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 & Sons, New York: 1999, the entire contents of which are hereby incorporated by reference.
  • 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.
  • structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, cis-trans, conformational, and rotational) forms of the structure.
  • isomeric e.g., enantiomeric, diastereomeric, cis-trans, conformational, and rotational
  • 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.
  • a substituent can freely rotate around any rotatable
  • structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms.
  • compounds having the present structures except for the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a 13 C- or 14 C-enriched carbon are 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.
  • 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.
  • 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.
  • 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, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • 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.
  • acid addition salts might be a more convenient form for use and use of the salt amounts to use of the free basic form.
  • Examples of pharmaceutically acceptable, non-toxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, 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.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid
  • 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.
  • 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, ox
  • 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.
  • 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 + (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.
  • 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.
  • the compounds described herein can also exist as pharmaceutically acceptable solvates (e.g., hydrates) and clathrates.
  • 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.
  • solvate includes hydrates (e.g., hemihydrate, monohydrate, dihydrate, trihydrate, tetrahydrate, and the like).
  • hydrate means a compound described herein or a salt thereof that further includes a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces.
  • clathrate means a compound described herein or a salt thereof in the form of a crystal lattice that contains spaces (e.g., channels) that have a guest molecule (e.g., a solvent or water) trapped within.
  • compositions to treat or prevent the herein identified disorders.
  • 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.
  • 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.
  • 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.
  • 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, -N0 2 , -ONO, or -ONO 2 moieties.
  • Prodrugs can typically be prepared using well-known methods, such as those described by BURGER'S MEDICINAL CHEMISTRY AND DRUG DISCOVERY (1995) 172-178, 949-982 (Manfred E. Wolff ed., 5th ed).
  • a "pharmaceutically acceptable derivative” is an adduct or derivative which, upon administration to a patient in need, is capable of providing, directly or indirectly, a compound as otherwise described herein, or a metabolite or residue thereof.
  • pharmaceutically acceptable derivatives include, but are not limited to, esters and salts of such esters.
  • Pharmaceutically acceptable prodrugs of the compounds described herein include, without limitation, esters, amino acid esters, phosphate esters, metal salts and sulfonate esters.
  • 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.
  • the present invention is generally related to the use of compounds represented by any one of Structural Formulae (I) - (V), or pharmaceutically acceptable salts thereof for any of the uses specified above:
  • the present invention is directed to the use of any compound selected from the compounds depicted in Table 1 or a pharmaceutically acceptable salt thereof, for any of the uses described above.
  • the compounds are represented by any one of
  • 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).
  • Influenza as used herein, are used interchangeable to mean the disease caused by an infection with an influenza virus.
  • Influenza is an infectious disease that affects birds and mammals caused by influenza 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 virus which can be subdivided into different serotypes based on the antibody response to these viruses: H1 1, H2N2, H3N2, H5N1, H7N7, H1N2, H9N2, H7N2 , H7N3 and H10N7.
  • Influenzavirus B genus has one species, influenza B virus. Influenza B almost exclusively infects humans and is less common than influenza A.
  • Influenzavirus C genus has one species, Influenzavirus C virus, which infects humans and pigs and can cause severe illness and local epidemics.
  • Influenzavirus C is less common than the other types and usually seems to cause mild disease in children.
  • 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 H1 1, H2N2, H3N2 or H5 1.
  • influenza 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”.
  • Symptoms of influenza can start quite suddenly one to two days after infection. Usually the first symptoms are chills or a chilly sensation, but fever is also common early in the infection, with body temperatures ranging from 38-39 °C
  • 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).
  • influenza virus mediated medical or pathological condition
  • 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.
  • a non-primate e.g., a cow, pig, horse, sheep, rabbit, guinea pig, rat, cat, dog, and mouse
  • a primate e.g., a monkey, chimpanzee and a human
  • 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).
  • a farm animal e.g., a horse, cow, pig or sheep
  • a pet e.g., a dog, cat, guinea pig or rabbit
  • the subject is a "human”.
  • biological sample 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.
  • multiplicity of infection is the ratio of infectious agents (e.g. phage or virus) to infection targets (e.g. cell).
  • infectious agents e.g. phage or virus
  • infection targets e.g. cell
  • 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.
  • the term "inhibition of the replication of influenza viruses” includes both the reduction in the amount of virus replication (e.g. the reduction by at least 10 %) and the complete arrest of virus replication (i.e., 100% reduction in the amount of virus replication). In some embodiments, the replication of influenza viruses are inhibited by at least 50%, at least 65%, at least 75%, at least 85%, at least 90%, or at least 95%.
  • Influenza virus replication can be measured by any suitable method known in the art.
  • influenza viral titre in a biological sample e.g. an infected cell culture
  • humans e.g. lung viral titre in a patient
  • 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.
  • test agent e.g. an infected cell culture
  • virus-dependent endpoint e.g. the Madin-Darby canine kidney cells (MDCK) and the standard tissue culture adapted influenza strain, A/Puerto Rico/8/34 can be used.
  • MDCK Madin-Darby canine kidney cells
  • 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.
  • CPE cytopathic effect
  • 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
  • RNA levels being directly measured using the branched-chain DNA hybridization method (bDNA).
  • bDNA branched-chain DNA hybridization method
  • 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.
  • 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 , 10 "2 , 10 "3 ,..., 10 "8 . The lowest concentration of virus that still infects cells is the viral titer.
  • the terms “treat”, “treatment” and “treating” refer to both therapeutic and prophylactic treatments.
  • 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).
  • the therapeutic treatment includes the amelioration of at least one measurable physical parameter of an influenza virus mediated condition.
  • 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.
  • 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.
  • chemotherapy refers to the use of medications, e.g. small molecule drugs (rather than “vaccines”) for treating a disorder or disease.
  • medications e.g. small molecule drugs (rather than “vaccines”
  • vaccines small molecule drugs
  • 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.
  • 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.
  • chemoprophylaxis refers to the use of medications, e.g. small molecule drugs (rather than "vaccines”) for the prevention of a disorder or disease.
  • 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).
  • an influenza "outbreak” is defined as a sudden increase of acute febrile respiratory illness (AFRI) occurring within a 48 to 72 hour period, in a group of people who are in close proximity to each other (e.g. in the same area of an assisted living facility, in the same household, etc) over the normal background rate or when any subject in the population being analyzed tests positive for influenza.
  • AFRI acute febrile respiratory illness
  • 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).
  • index case is the initial patient in the population sample of an epidemiological investigation.
  • primary case or “patient zero” is the initial patient in the population sample of an epidemiological investigation.
  • the term is not capitalized.
  • 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, secondary, tertiary, etc.
  • 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.
  • 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.
  • 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.
  • an "effective amount” refers to an amount sufficient to elicit the desired biological response.
  • 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.
  • 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.
  • 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.
  • 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.
  • Dosages of the compounds described herein can range from between about
  • 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).
  • 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.
  • 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.
  • An effective amount can be achieved in the method or pharmaceutical composition of the invention employing a compound of the invention (including a pharmaceutically acceptable salt or solvate (e.g., hydrate)) alone or in combination with an additional suitable therapeutic agent, for example, an antiviral agent or a vaccine.
  • an additional suitable therapeutic agent for example, an antiviral agent or a vaccine.
  • an effective amount can be achieved using a first amount of a compound of the invention and a second amount of an additional suitable therapeutic agent (e.g. an antiviral agent or vaccine).
  • a compound of the invention and the additional therapeutic agent are each administered in an effective amount (i.e., each in an amount which would be therapeutically effective if administered alone).
  • a compound of the invention and the additional therapeutic agent are each administered in an amount which alone does not provide a therapeutic effect (a subtherapeutic dose).
  • a compound of the invention can be administered in an effective amount, while the additional therapeutic agent is administered in a sub-therapeutic dose.
  • a compound of the invention 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.
  • 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).
  • 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.
  • 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.
  • coadministration also encompasses use of each compound in a sequential manner in either order.
  • the present invention is directed to methods of combination therapy for inhibiting Flu viruses replication in biological samples or patients, or for treating or preventing Influenza virus infections in patients using the compounds or pharmaceutical compositions of the invention.
  • pharmaceutical compositions of the invention also include those comprising an inhibitor of Flu virus replication of this invention in combination with an anti-viral compound exhibiting anti-Influenza virus activity.
  • Methods of use of the compounds and compositions of the invention also include combination of chemotherapy with a compound or composition of the invention, or with a combination of a compound or composition of this invention with another anti-viral agent and vaccination with a Flu vaccine.
  • the compounds are administered sufficiently close in time to have the desired therapeutic effect.
  • 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.
  • a compound of the invention and the second therapeutic agent can be administered in any order within about 24 hours of each other, within about 16 hours of each other, within about 8 hours of each other, within about 4 hours of each other, within about 1 hour of each other or within about 30 minutes of each other.
  • a first therapy e.g., a prophylactic or therapeutic agent such as a compound of the invention
  • a first therapy 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.
  • a second therapy e.g., a prophylactic or therapeutic agent such as an anti-cancer agent
  • the method of co-administration of a first amount of a compound of the invention and a second amount of an additional therapeutic agent can result in an enhanced or synergistic therapeutic effect, wherein the combined effect is greater than the additive effect that would result from separate administration of the first amount of a compound of the invention and the second amount of an additional therapeutic agent.
  • 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 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.
  • a synergistic effect can result in improved efficacy of agents in the prevention, management or treatment of a disorder.
  • a synergistic effect of a combination of therapies e.g., a combination of prophylactic or therapeutic agents
  • both therapeutic agents can be administered so that the period of time between each administration can be longer (e.g. days, weeks or months).
  • 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, FL, Arch. Exp. Pathol Pharmacol. 1 14: 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.
  • neuraminidase inhibitors such as oseltamivir (Tamiflu®) and Zanamivir (Rlenza®)
  • viral ion channel (M2 protein) blockers such as amantadine (Symmetrel®) and rimantadine (Flumadine®)
  • antiviral drugs described in WO 2003/015798, including T- 705 under development by Toyama Chemical of Japan.
  • the compounds described herein can be co-administered with a traditional influenza vaccine.
  • the compounds described herein can be formulated into pharmaceutical compositions that further comprise a pharmaceutically acceptable carrier, diluent, adjuvant or vehicle.
  • 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.
  • 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 carriers include, for example, pharmaceutical diluents, excipients or carriers suitably selected with respect to the intended form of administration, and consistent with conventional pharmaceutical practices.
  • an “effective amount” includes a “therapeutically effective amount” and a “prophylactically effective amount”.
  • therapeutically effective amount refers to an amount effective in treating and/or ameliorating an influenza virus infection in a patient infected with influenza.
  • prolactically 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.
  • a pharmaceutically acceptable carrier 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.
  • the pharmaceutically acceptable carrier, adjuvant, or vehicle 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 are contemplated to be within the scope of this invention.
  • 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.
  • 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
  • compositions described above can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), bucally, as an oral or nasal spray, or the like, depending on the severity of the infection being treated.
  • Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • 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.
  • the oral compositions can also include
  • 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.
  • the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S. P. and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil can be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid are used in the preparation of injectables.
  • 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.
  • the rate of compound release can be controlled.
  • biodegradable polymers include poly(orthoesters) and poly(anhydrides).
  • Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.
  • compositions for rectal or vaginal administration are specifically suppositories which can be prepared by mixing the compounds described herein with suitable non-irritating excipients or carriers such as cocoa 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.
  • 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.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • 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
  • 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.
  • 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.
  • 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.
  • 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.
  • buffering agents include polymeric substances and waxes.
  • Dosage forms for topical or transdermal administration of a compound described herein include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches.
  • the active component is admixed under sterile conditions with a pharmaceutically 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.
  • 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.
  • compositions described herein may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir.
  • parenteral as used herein includes, but is not limited to, subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques.
  • the compositions are administered orally, intraperitoneally or intravenously.
  • 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.
  • the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • 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.
  • 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.
  • compositions described herein may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions.
  • carriers commonly used include, but are not limited to, lactose and corn starch.
  • Lubricating agents such as magnesium stearate, are also typically added.
  • useful diluents include lactose and dried cornstarch.
  • 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.
  • compositions described herein may be administered in the form of suppositories for rectal administration.
  • suppositories for rectal administration.
  • 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.
  • suitable non-irritating excipient include, but are not limited to, cocoa butter, beeswax and polyethylene glycols.
  • compositions described herein may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.
  • Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically- transdermal patches may also be used.
  • 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.
  • 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.
  • 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
  • compositions may be formulated in an ointment such as petrolatum.
  • 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.
  • the compounds for use in the methods of the invention can be formulated in unit dosage form.
  • 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.
  • the compounds disclosed herein can be prepared by any suitble method known in the art, for example, WO 2005/095400, WO 2007/084557, WO 2010/011768, WO 2010/011756, WP 2010/01 1772, WO 2009/073300, and PCT/US2010/038988 filed on June 17, 2010.
  • the compounds shown in Table 1 can be prepared by any suitble method known in the art, for example, WO 2005/095400, WO 2007/084557, WO
  • reaction mixture was diluted with Et 2 0, poured into aqueous saturated NaHCC ⁇ solution and partitioned. The aqueous phase was extracted with additional Et 2 0 and the combined organic phases were washed with water and brine. The organic layer was dried and filtered through celite and concentrated in vacuo.
  • (+/-)-ir «s-methyl 3-(((benzyloxy)carbonyl)amino)bicyclo[2.2.2]oct-5-ene- 2-carboxylate (16a)
  • (+/-)-ir «s-methyl 3-((2-bromo-5-fluoropyridin-4-yl)amino)bicyclo- [2.2.2] octane-2-carboxylate (18a)
  • Racemic- trans-methyl 3-aminobicyclo[2.2.2]octane-2-carboxylate (2.34 g, 12.75 mmol) in 1,4-dioxane (46 mL) was degassed under a stream of nitrogen for 15 minutes and this solution was added to the mixture of solids which was then evacuated and flushed with nitrogen three times again.
  • the reaction mixture was heated to 115 °C for 15 minutes.
  • the mixture was cooled to room temperature and flushed through a pad of celite.
  • the filtrate was concentrated in vacuo and the crude residue was purified by silica gel chromatography (EtOAc/Hexanes gradient) to afford the desired product.
  • (+/-)-ir «s-methyl 3-((2-(2-chloro-5-trityl-5H-pyrrolo[2,3-b]pyrazin-7-yl)- 5-fluoropyridin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate (19a)
  • (+/-)-ir «s-methyl 3-((2-(2-chloro-5H-pyrrolo[2,3-b]pyrazin-7-yl)-5- fluoropyridin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate (Comp. 1)
  • (+/-)-ir «s-3-((2-(2-chloro-5H-pyrrolo[2,3-b]pyrazin-7-yl)-5-fluoropyridin-
  • Lithium aluminum hydride (2.1 g, 59.4 mmol) was suspended in ether (150 mL) and cooled to 0 °C.
  • the mixture was stirred 2 hours in an ice bath then quenched slowly with IN HC1. The layers were separated and the aqueous layer was washed with ether.
  • N-benzylhydroxylamine (hydrochloric acid) (0.28 g, 1.80 mmol) and triethylamine (0.28 mL, 2.00 mmol) were added to a solution of methyl 3-(l-methylcyclobutyl)acrylate, 25a, (0.26 g, 1.50 mmol) in dichloromethane (9.5 mL).
  • the reaction mixture was stirred at 50 °C overnight.
  • the reaction mixture was cooled to room temperature and the mixture was diluted with dichloromethane and water. The layers were separated with a phase separator and the aqueous layer was washed with dichloromethane. The organic layers were combined and the volatiles removed under reduced pressure.
  • Racemic 3-amino-3-(l-methylcyclobutyl)propanoic acid, 27a, (2.3 g, 14.4 mmol) was dissolved in methanol (104 mL). The solution was cooled in an ice bath and acetyl chloride (5.6 g, 71.9 mmol) was added dropwise (Temp kept ⁇ 10 °C). The reaction mixture was heated to 65 °C and stirred at that temperature for 3 hours. The reaction mixture was cooled to room temperature and then flushed with toluene to remove volatiles. Crude racemic 3- methoxy-l-(l-methylcyclobutyl)-3-oxopropan-l-aminium chloride, 28a, was used without further purification.
  • (IS, 3R)-3-(ethoxycarbonyl)cyclohexanecarboxylic acid starting material can be prepared following the literature procedures described in : Barnett, C. J., Gu, R. L., Kobierski, M. E., WO-2002024705, Stereoselective process for preparing cyclohexyl amine derivatives.
  • 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 Na 2 S0 4 and concentrated in vacuo.
  • the crude material was purified by silica gel chromatography (0%-50% EtOAc/hexanes) to provide the product (15.3 g, containing -25% benzyl alcohol), which was used for the next step without further purification.
  • thiophene-3-carbonyl chloride (0.009 g, 0.062 mmol) was added. Monitoring of the reaction by LC-MS showed both mono and bis-acylation products. The mixture was quenched with 2 ⁇ NaOH and stirred for 5 min to cleave any of the indole- thiophene amide side-product. The mixture was diluted with EtOAc and neutralized with 2N HC1, separated and extracted three times with EtOAc. The combined organic phases were dried (Na 2 S0 4 ), filtered and concentrated in vacuo.
  • CPE cytopathic effect
  • a second cell-based antiviral assay was developed that depends on the multiplication of virus-specific RNA molecules in the infected cells, with RNA levels being directly measured using the branched-chain DNA (bDNA), hybridization method (Wagaman et al, J. Virol Meth, 105: 105-114, 2002).
  • bDNA branched-chain DNA
  • 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 EC5 0 .
  • DMEM Dulbecco's Modified Eagle Medium
  • 2mM L-glutamine 2mM L-glutamine
  • l,000U/ml penicillin
  • 1,000 ug/ml streptomycin 10 mM HEPES
  • 10% fetal bovine medium 10% fetal bovine medium.
  • 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 ⁇ . On the day of the assay, adherent cells were washed with three changes of DMEM containing lug/ml TPCK-treated trypsin, without fetal bovine serum.
  • Assays were initiated with the addition of 30 TCID 50 of virus and test compound, in medium containing 1 ⁇ g/ml TPCK-treated trypsin, in a final volume of 50 ⁇ . Plates were incubated for 72 hours at 37°C in a humidified, 5% CO 2 atmosphere.
  • cells were grown in DMEM + fetal bovine serum as above, but on the day of the assay they were trypsinized, washed 2 times and suspended in serum-free EX-Cell MDCK cell medium (SAFC Biosciences, Lenexa, KS) and plated into wells at 20,000 cells per well. These wells were then used for assay after 5 hours of incubation, without the need for washing.
  • serum-free EX-Cell MDCK cell medium SAFC Biosciences, Lenexa, KS
  • Influenza virus strain A/PR/8/34 (tissue culture adapted) was obtained from ATCC
  • ICso and EC5 0 values of Compound 6 were 0.01 ⁇ and 0.009 ⁇ .
  • Table 1 IC50, EC50, NMR and LCMS Data of Compounds of Invention.

Abstract

Compound according to Formula (I): or a pharmaceutically acceptable salt thereof, wherein the values of Structural Formula (I) are as described herein. A pharmaceutical composition comprises an effective amount of such a compound or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant or vehicle. Uses 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.

Description

INHIBITORS OF INFLUENZA VIRUSES REPLICATION
INVENTORS: Paul S. Charifson, Mark W. Ledeboer, Michael P. Clark, Michael J. Boyd, Huai Gao, Brian Ledford, Francois Maltais, and Emanuele Perola
RELATED APPLICATION
[00100] This application claims the priority to the United States Patent Application No.
61/657,236, filed on June 08, 2012. The entire teachings of the priority application 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, Isavirus and Thogoto virus.
[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: Hl l (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 very similar in structure. The virus particle is 80-120 nanometers in diameter and usually roughly spherical, although filamentous forms can occur. Unusually for a virus, its genome is not a single piece of nucleic acid; instead, it contains seven or eight pieces of segmented negative-sense RNA. The Influenza A genome encodes 1 1 proteins: hemagglutinin (HA), neuraminidase (NA), nucleoprotein (NP), Ml, M2, NS1, NS2( EP), 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 virus to target cells and entry of the viral genome into the target cell, while NA is involved in the release of progeny virus from infected cells, by cleaving sugars that bind the mature viral particles. Thus, these proteins have been targets for antiviral drugs. Furthermore, they are antigens to which antibodies can be raised. Influenza A viruses are classified into subtypes based on 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 H5 1 avian influenza pandemic, with costs associated with purchasing drugs and vaccines as well as developing disaster drills and strategies for improved border controls.
[00110] 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 very 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 viruses 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, and to compounds and compositions that can be employed for such methods.
[00116] In one embodiment, the present invention is directed to a compound represented by Structural Formula (I) or a pharmaceutically acceptable salt thereof:
wherein:
X1 is -CI, -CN, -CF3, or -CH3;
X2 is -H, -F, or -CI;
Ring T is a C3-C10 carbocyclic group optionally further substituted with one or more
JT-
Z1 and Z2 are each independently CH or N;
Q1 is -C(O)-, -C(0)0-, -OC(O)-, -0-, -C(0)NR'-, NRC(O)-, -NRC(0)NR'-, -OC(0)NR'-,-S(0)-, -S(0)2-, -S02NR'-, -NRS02- -NRS02NR'-, -P(0)(OR)0-,
-OP(0)(ORa)0-, or a bond;
optionally -Qx-R2 forms, together with the carbon atom of Ring T to which -Qx-R2 is attached, forms a 4-10 membered (or 5-7 membered), non-aromatic, spiro ring optionally substituted with one or more instances of JR; and
Q2 is -CH2-[C(R7R8)]n-;
i) when Q1 is other than a bond, R2 is -H, a C1-C6 aliphatic group optionally substituted with one or more JA, a C3-C8 carbocyclic group optionally substituted with one or more JB, or a 4-10 membered heterocyclic group optionally substituted with one or more Jc, or optionally R2, together with R' and the nitrogen atom of Q1 to which they are attached (that is NR'R2 of QlR2 when Q1 is -C(0)NR'-, NRC(O)-, -NRC(0)NR'-, -OC(0)NR'-, -SO2NR'-, -NRSO2-, or-NRS02NR'-), forms a 4-8 membered heterocyclic group optionally substituted with one or more instances of JR; or
ii) when Q1 is a bond, R2 is a C1-C6 aliphatic group substituted with one or more M, a 5-7 membered heterocyclic group optionally substituted with one or more J2, or a 5-6 membered heteroaryl group optionally substituted with one or more J3; and
R3 is -C(0)OR, -S(0)R9, -S(0)2R9, -S(0)2NRR10, -OR, P(0)(OR)2, or CH2OR;
R4, R5, and R6 are each and independently -CH3, -CH2F, -CF3, -C2H5, -CH2CH2F, or -CH2CF3; or optionally R5 and R6, or R4, R5 and R6, together with the carbon atom to which they are attached, form a C3-C10 carbocyclic ring;
R7 and R8 are each and independently -H, -OH, -CH3, or -CF3; or optionally, R7 and R8 together with the carbon atoms to which they are attached form a cyclopropane ring; each R9 is independently -OR or C1-C6 alkyl optionally substituted with one or more instances of J1;
R10 is -H or C1-C6 alkyl optionally substituted with one or more instances of J1;
R and R' are each independently -H or C1-C6 alkyl optionally substituted with one or more instances of J1, or optionally R and R', together with the nitrogen to which they are attached, form a 4-8 membered heterocyclic group optionally substituted with one or more instances of JR;
JT is selected from the group consisting of halogen, cyano, oxo, hydroxy, -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 alkyl, Ci-C4 haloalkyl, C3-C6 cycloalkyl, and -0(Ci-C4 alkyl);
JA is halogen, cyano, oxo, Rd, or M; and
JB and Jc are each and independently selected from the group consisting of halogen, cyano, oxo, M, -Ra, and -Ra-M; or
optionally, two JT, two JA, two JB, and two Jc, 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 JR; and
M is independently selected from the group consisting of -ORb, -SRb, -S(0)Ra, -S02Ra, -NRbRc, -C(0)Ra, -C(=NR)RC, -C(=NR)NRbRc, -NRC(=NR)NRbRc, -C(0)ORb, -OC(0)Rb, -NRC(0)Rb, -C(0)NRbRc, -NRC(0)NRbRc, -NRC(0)ORb, -OCONRbRc, -C(0)NRC02Rb, -NRC(0)NRC(0)ORb, -C(0)NR(ORb), -OS02NRbRc, -S02NRcRb, -NRS02Rb,
-NRS02NRbRc,
-P(0)(ORb)2, -OP(0)(ORb)2, -P(0)2ORb and -C02S02Rb;
Ra is independently:
i) a Ci-Ce aliphatic group optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH(Ci-C4 alkyl), -N(C1-C4 alkyl)2, -OCO(Ci-C4 alkyl), -CO(Ci-C4 alkyl), -C02H, -C02(Ci-C4 alkyl), -0(Ci-C4 alkyl), C3-C8 carbocyclic group optionally substituted with one or more instances of J2, 4-8 membered heterocyclic group optionally substituted with one or more instances of J2, 5-6 membered heteroaryl group optionally substituted with one or more instances of J3, and phenyl optionally substituted with one or more instances of J3;
ii) a C3-C8 carbocyclic group or 4-8 membered heterocyclic group, each of which is optionally and independently substituted with one or more instances of J2; or
iii) a 5-6 membered heteroaryl group or phenyl, each of which is optionally and
independently substituted with one or more instances of J3; 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 4-8 membered heterocyclic group optionally substituted with one or more instances of JR;
Rd is C3-C8 carbocyclic group optionally substituted with one or more instances of J2, 4-8 membered heterocyclic group optionally substituted with one or more instances of J2, 5-6 membered heteroaryl group optionally substituted with one or more instances of J3, or phenyl optionally substituted with one or more instances of J3;
each J1 is 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), -0(Ci-C4 alkyl), and phenyl;
each J2 is 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 alkyl, Ci-C4 haloalkyl, and -0(Ci-C4 alkyl);
each of J3 and JR is independently selected from the group consisting of halogen, cyano, hydroxy, -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 alkyl, Ci-C4 haloalkyl, and -0(Ci-C4 alkyl); and n is independently 0 or 1.
[00117] In another embodiment, the present invention is directed to a pharmaceutical composition comprising a compound disclosed herein (e.g., a compound represented by any one of Structural Formulae (I) - (V), or a pharmaceutically acceptable salt thereof) and a pharmaceutically acceptable carrier, adjuvant or vehicle.
[00118] In yet another embodiment, the present invention is directed to a method of inhibiting the replication of influenza viruses in a biological sample or patient, comprising the step of administering to said biological sample or patient an effective amount of a compound disclosed herein (e.g., a compound represented by any one of Structural Formulae (I) - (V), or a pharmaceutically acceptable salt thereof).
[00119] In yet 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, comprising administering to said biological sample or patient an effective amount of a compound disclosed herein (e.g., a compound represented by any one of Structural Formulae (I) - (V), or a pharmaceutically acceptable salt thereof).
[00120] In yet another embodiment, the present invention is directed to a method of method of treating influenza in a patient, comprising administering to said patient an effective amount of a compound disclosed herein (e.g., a compound represented by any one of Structural Formulae (I) - (V), or a pharmaceutically acceptable salt thereof).
[00121] The present invention also provides use of the compounds 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.
[00122] Also provided herein is use of the compounds 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.
[00123] Also provided herein are the compounds represented by Structural Formula (XX):
or a pharmaceutically acceptable salt thereof. Without being bound to a particular theory, the compounds of Structural Formula (XX) can be used for synthesizing the compounds of Formula (I). The variables of Structural Formula (XX) are each and independently as defined herein; and G is trityl (-C(Ph)3).
[00124] The invention also provides methods of preparing a compound represented by
Structural Formula (I) or a pharmaceutically acceptable salt thereof. In one embodiment, the methods employ the steps of:
reacting compound A: (A) with compound B
a compound represented by Structural Formula (XX):
ii) deprotecting the G group of the compound of Structural Formula (XX) under suitable conditions to form the compound of Structural Formula (I),wherein:
the variables of Structural Formulae (I) and (XX), and compounds (A) and (B) are independently as defined herein; and
L2 is a halogen; and
G is trityl.
DETAILED DECRIPTION OF THE INVENTION
Compounds and Syntheses
[00125] The compounds of the invention are as described in the claims. In some embodiments, the compounds of the invention are represented by any one of Structural Formulae (I) - (V), or pharmaceutically acceptable salts thereof, wherein the variables are each and independently as described in any one of the claims. In some embodiments, the compounds of the invention are represented by any chemical formulae depicted in Table 1, or pharmaceutically acceptable salts thereof. In some embodiments, the compounds of the invention are presented by Structural Formulae (I) - (V), or a pharmaceutically acceptable salt thereof, wherein the variables are each and independently as depicted in the chemical formulae in Table 1.
[00126] In one embodiment, the compounds of the invention are represented by Structural Formula (I) or pharmaceutically acceptable salts thereof:
(I)
wherein the values of the variables of Structural Formula (I) are as described below.
[00125] The first set of values of the variables of Structural Formula (I) is as follows:
X1 is -CI, -CN, -CF3, or -CH3. In one aspect, X1 is -CI, or -CF3. In another aspect, X1 is -CI.
X2 is -H, -F, or -CI. In one aspect, X is -F or -CI. In another aspect, X is -F.
Ring T is a C3-C10 carbocyclic group optionally further substituted with one or more JT. Ring T can be a mono-cyclic, bi-cyclic, polycyclic, bridged, non-bridged, or fused ring system. In one aspect, Ring T is an optionally substituted C5-C10 carbocyclic ring. In another aspect, Ring T is an optionally substituted C5-C6 mono-cyclic group. In another aspect, Ring T is an optionally substituted C7-C10 bridged carbocyclic ring.
1 2
A typical example of (Ring T)-Q -R Ring A is a C5-C7 monocyclic group or C7-C10 bridged carbocyclic group, each of which independently and optionally further substituted with one or more instances of JT; or optionally Ring A and R13, Ring A and R14, or Ring A and R15, form a C7-C10 bridged carbocyclic ring optionally further substituted with one or more instances of JT. Certain more typical examples of (Ring T)-Q1- R2 include:
rings A1-A4 is independently a C7-C10 bridged, carbocyclic ring optionally further substituted with one or more substituents selected from the group consisting of halogen, cyano, hydroxy, C1-C4 alkyl, C1-C4 haloalkyl, and -0(Ci-C4 alkyl); and each of rings A5-A6 is independently and optionally further substituted with one or more substituents selected from the group consisting of halogen, cyano, hydroxy, C1-C4 alkyl, C1-C4 haloalkyl, C3-C5 cycloalkyl, and -0(Ci-C4 alkyl).
Z1 and Z2 are each independently CH or N. In one aspect, Z1 and Z2 are each independently CH.
Each Q1 is independently -C(O)-, -C(0)0-, -OC(O)-, -0-, -C(0)NR'-, NRC(O)-, -NRC(0)NR'-, -OC(0)NR'-,-S(0)-, -S(0)2-, -S02NR'-, -NRS02- -NRS02NR'-,
-P(0)(OR)0-, -OP(0)(ORa)0-, or a bond. In one aspect, Q1 is -C(0)0-, -NRC(O)-, -C(0)NR'-, or -NRC(0)NR'-. In another aspect, each Q1 is independently -C(0)0-, -NHC(O)-, or -NHC(0)NR'-. In yet another aspect, each Q1 is independently -C(0)0-. In yet another aspect, each Q1 is independently -NHC(O)- or -NHC(0)NR'-.
Optionally -Qx-R2 forms, together with the carbon atom of Ring T to which -Qx-R2 is attached, forms a 4-10 membered, non-aromatic, spiro ring optionally substituted with one or more instances of JR. In one aspect, the spiro ring formed with -Qx-R2 is an optionally substituted, 5-7 membered ring.
Q2 is -CH2-[C(R7R8)]n-. In one aspect, -CH2-[CH2]n-. In another aspect, Q2 is -CH2.
When Q1 is other than a bond, R2 is -H, a C1-C6 aliphatic group optionally substituted with one or more JA, a C3-C8 carbocyclic group optionally substituted with one or more JB, or a 4-10 membered heterocyclic group optionally substituted with one or more Jc, or optionally, R2, together with R' and the nitrogen atom of Q1 to which they are attached (that is NR'R2 of QXR2 when Q1 is -C(0)NR'-, NRC(O)-, -NRC(0)NR'-, -OC(0)NR'-, -S02NR'-, -NRSO2-, or-NRS02NR'-), form a 4-8 membered heterocyclic group optionally substituted with one or more instances of JR. Alternatively, when Q1 is a bond, R2 is a C1-C6 aliphatic group substituted with one or more M, a 5-7 membered heterocyclic group optionally substituted with one or more J2, or a 5-6 membered heteroaryl group optionally substituted with one or more J3.
In one aspect, Q1 is other than a bond; and R2 is independently -H, an optionally substituted C1-C6 alkyl, an optionally substituted 5-7 membered heterocyclic group, an optionally substituted phenyl group, or an optionally substituted 5-6 membered heteroaryl group; or optionally R2 and R', together with the nitrogen atom to which they are attached, form an optionally substituted, 5-7 membered heterocyclic group; wherein said C1-C6 alkyl is optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, hydroxy, and -0(Ci-C4 alkyl); and each of said heterocyclic, phenyl and heteroaryl groups is independently and optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, Ci-C4 alkyl, Ci-C4 haloalkyl, and -0(Ci-C4 alkyl). In another aspect, Q1 is other than a bond; and R2 is - H, optionally substituted Ci_6 alkyl, optionally substituted 5-6 membered heterocyclic, or optionally substituted 5-6 membered heteroaryl. In yet another aspect, Q1 is other than a bond; and R2 is -H, optionally substituted Ci_6 alkyl, or optionally substituted 5-6 membered heterocyclic. In yet another aspect, Q1 is other than a bond; and R2 is -H or optionally substituted Ci_6 alkyl.
In another aspect, when Q1 is a bond, R2 is a C1-C6 alkyl group substituted with one or more M; an optionally substituted, 5-7 membered, heterocyclic group; or an optionally substituted, 5-6 membered heteroaryl group. In yet another aspect, when Q1 is a bond, R2 is a C1-C6 alkyl group substituted with one or more M.
R3 is -C(0)OR, -S(0)R9, -S(0)2R9, -S(0)2NRR10, -OR, P(0)(OR)2, or CH2OR. In one asepct, R3 is -C(0)OR, -OH, -CH2OH, -S(0)2R9, or -S(0)2-NRR10. In another aspect, R3 is -C(0)OR, -S(0)2R9, or -S(0)2-NRR10. In yet another aspect, R3 is -C(0)OR.
R4, R5, and R6 are each and independently -CH3, -CH2F, -CF3, -C2H5, -CH2CH2F, or -CH2CF3; or optionally R5 and R6, or R4, R5 and R6, together with the carbon atom to which they are attached, form a 3-10 membered carbocyclic ring. In one aspect, R4, R5, and R6 are each and independently -CH3, -CH2F, -CF3, or -C2H5; or R4 is -CH3, -CH2F, -CF3, or -C2H5; and R5 and R6 together with the carbon atom to which they are attached form a C3-C6 carbocyclic ring. In another aspect, R4, R5, and R6 are each and independently -CH3 or - C2H5. In yet another aspect, R4 is -CH3 or -C2H5; and R5 and R6 together with the carbon atom to which they are attached form a C3-C6 carbocyclic ring.
R7 and R8 are each and independently -H, -OH, -CH3, or -CF3; or optionally, R7 and R8 together with the carbon atoms to which they are attached form a cyclopropane ring. In one aspect, R7 and R8 are each and independently -H, -OH, -CH3, or -CF3. In another aspect, R7 and R8 are each and independently -H or -CH3. In yet another aspect, R7 and R8 are each and independently -H.
Each R9 is independently -OR or C -Ce alkyl optionally substituted with one or more instances of J1. In one aspect, each R9 is -OH.
R10 is -H or Ci-Ce alkyl optionally substituted with one or more instances of J1. In one aspect, R10 is C1-4 alkyl optionally substituted with one or more substituents selected from the group consisting of halogen, -OR and -C(0)OR.
R and R' are each independently -H or Ci-Ce alkyl optionally substituted with one or more instances of J1, or optionally R and R', together with the nitrogen to which they are attached, form a 4-8 membered heterocyclic group optionally substituted with one or more instances of JR.
JT is selected from the group consisting of halogen, cyano, oxo, hydroxy, -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 alkyl, Ci-C4 haloalkyl, C3-C6 cycloalkyl, and -0(Ci-C4 alkyl).
JA is halogen, cyano, oxo, Rd, or M.
JB and Jc are each and independently selected from the group consisting of halogen, cyano, oxo, M, -Ra, and -Ra-M.
Optionally, two JT, two JA, two JB, and two Jc, 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 JR.
Each M is independently selected from the group consisting of -ORb, -SRb, -S(0)Ra, -S02Ra, -NRbRc, -C(0)Ra, -C(=NR)RC, -C(=NR)NRbRc, -NRC(=NR)NRbRc, -C(0)ORb, -OC(0)Rb, -NRC(0)Rb, -C(0)NRbRc, -NRC(0)NRbRc, -NRC(0)ORb, -OCONRbRc, -C(0)NRC02Rb, -NRC(0)NRC(0)ORb, -C(0)NR(ORb), -OS02NRbRc, -S02NRcRb, -NRS02Rb, -NRS02NRbRc, -P(0)(ORb)2, -OP(0)(ORb)2, -P(0)2ORb and -C02S02Rb. In one aspect, each M is independently selected from the group consisting of -ORb, -SRb, -S(0)Ra, -S02Ra, -NRbRc, -C(0)Ra, -C(0)ORb, -OC(0)Rb, -NRC(0)Rb, -C(0)NRbRc,
-NRC(0)NRbRc, -NRC(0)ORb, -OCONRbRc, -C(0)NRC02Rb, -NRC(0)NRC(0)ORb, -OS02NRbRc, -S02NRcRb, -NRS02Rb, and -NRS02NRbRc. In another aspect, each M is independently selected from the group consisting of -ORb, -NRbRc, -C(0)Ra, -C(0)ORb, -OC(0)Rb, -NRC(0)Rb, -C(0)NRbRc, -NRC(0)NRbRc, -NRC(0)ORb, -OCONRbRc, -S02NRcRb, -NRS02Rb, and -NRS02NRbRc. In yet another aspect, each M is independently selected from the group consisting of -ORb, -NHRC, -C(0)Ra, -C(0)ORb, -OC(0)Rb, -NHC(0)Rb, -C(0)NHRc, -C(0)NRbRc, -NHC(0)NHRc, -NHC(0)ORb, -OCONHRc, -S02NHRb, -NHS02Rb, and -NHS02NHRc, wheren Rb and Rc of -C(0)NRbRc, form a 5-6 membered heterocyclic group. In yet another aspect, each M is independently selected from the group consisting of -OH, -0(Ci-C6 alkyl), -NH(Ci-C6 alkyl), -C(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)(5- 6 membered heteroaryl), -NHC(0)(5-6 membered heterocyclic group), -C(0)NH(Ci-C6 alkyl), -NHC(0)NH(Ci-C6 alkyl), -NHC(0)0(Ci-C6 alkyl), -OCONH(Ci-C6 alkyl), -S02NH(Ci-C6 alkyl), -NHS02(Ci-C6 alkyl), and -NHS02NH(Ci-C6 alkyl). In yet another aspect, each M is independently selected from the group consisting of -OH, -0(Ci-C6 alkyl), -NH(Ci-C6 alkyl), -C(0)OH, -C(0)0(Ci-C6 alkyl), -OC(0)(Ci-C6 alkyl), -NHC(0)(Ci-C6 alkyl), -NHC(0)(5-6 membered heterocyclic group), -C(0)NH(Ci-C6 alkyl), -S02NH(Ci- C6 alkyl), and -NHS02(Ci-C6 alkyl).
Each Ra is independently: i) a C1-C6 aliphatic group optionally substituted with one or more substituents 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), -0(Ci-C4 alkyl), C3-C8 carbocyclic group optionally substituted with one or more instances of J2, 4-8 membered heterocyclic group optionally substituted with one or more instances of J2, 5-6 membered heteroaryl group optionally substituted with one or more instances of J3, and phenyl optionally substituted with one or more instances of J3; ii) a C3-C8 carbocyclic group or 4-8 membered heterocyclic group, each of which is optionally and independently substituted with one or more instances of J2; or iii) a 5-6 membered heteroaryl group or phenyl, each of which is optionally and independently substituted with one or more instances of J3. In one aspect, each Ra is independently an optionally substituted C1-C6 alkyl group, an optionally substituted C3-C7 carbocyclic group, an optionally substituted 5-7 membered heterocyclic group, an optionally substituted 5-6 membered heteroaryl group, or an optionally substituted phenyl 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, each independently form a 4-8 membered heterocyclic group optionally substituted with one or more instances of JR. In one aspect, 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 an optionally substituted 5-7 membered heterocyclic group.
Rd is C3-C8 carbocyclic group optionally substituted with one or more instances of J2, 4-8 membered heterocyclic group optionally substituted with one or more instances of J2, 5-6 membered heteroaryl group optionally substituted with one or more instances of J3, or phenyl optionally substituted with one or more instances of J3. In one asepct, Rd is independently an optionally substituted C3-C6 carbocyclic group, an optionally substituted 5-7 membered heterocyclic group.
In one aspect, JA is halogen, cyano, oxo, an optionally substituted C3-C6 carbocyclic group, an optionally substituted 5-7 membered heterocyclic group, or M. In another aspect, JA is halogen, cyano, oxo, or M. In yet another aspect, JA is halogen, cyano, oxo, -OH, - 0(Ci-C6 alkyl), -NH(Ci-C6 alkyl), -C(0)OH, -C(0)0(Ci-C6 alkyl), -OC(0)(Ci-C6 alkyl), -NHC(0)(Ci-C6 alkyl), -NHC(0)(5-6 membered heterocyclic group), -C(0)NH(Ci-C6 alkyl), -S02NH(Ci-C6 alkyl), or -NHS02(Ci-C6 alkyl).
In one aspect, JB and Jc are each and independently is halogen, cyano, oxo, M, an optionally substituted C1-C6 alkyl group, an optionally substituted C3-C6 carbocyclic group, an optionally substituted 5-7 membered heterocyclic group, an optionally substituted 5-7 membered heteroaryl group, or an optionally substituted phenyl group. In another aspect, JB and Jc are each and independently is halogen; cyano; oxo; -OH; -0(Ci-C6 alkyl); - H(Ci-C6 alkyl); -C(0)OH; -C(0)0(Ci-C6 alkyl); -OC(0)(Ci-C6 alkyl); -NHC(0)(Ci-C6 alkyl); -NHC(0)(5-6 membered heterocyclic group); -C(0)NH(Ci-C6 alkyl); -S02NH(Ci-C6 alkyl),; - HS02(Ci-C6 alkyl); or a C1-C6 alkyl group optionally substituted with one or more substituents 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 -0(Ci-C4 alkyl).
Each J1 is 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), -0(Ci-C4 alkyl), and phenyl.
Each J2 is 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 alkyl, Ci-C4 haloalkyl, and -0(Ci-C4 alkyl). Each of J3 and JR is independently selected from the group consisting of halogen, cyano, hydroxy, -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 alkyl, d-C4 haloalkyl, and -0(Ci-C4 alkyl).
n is independently 0 or 1.
x is 0, 1 or 2. In one aspect, x is 0 or 1.
Each p is independently 1, 2, or 3. In one aspect, each p is independently 2 or 3.
Each q is independently 0, 1 or 2. In one aspect, each q is independently 0 or 1.
Each r is independently 1 or 2.
[00126] The second set of values of the variables of Structural Formula (I) is as follows:
X1 is -CI, or -CF3.
X2 is -F or -CI.
Values of the other variables are each and independently as described above in the first set of values of the variables of Structural Formula (I).
[00127] The third set of values of the variables of Structural Formula (I) is as follows:
X1 and X2 are each independently as described above in the first or second set of set of values of the variables of Structural Formula (I).
M is independently selected from the group consisting of -ORb, -SRb, -S(0)Ra,
-S02Ra, -NRbRc, -C(0)Ra, -C(0)ORb, -OC(0)Rb, -NRC(0)Rb, -C(0)NRbRc,
-NRC(0)NRbRc, -NRC(0)ORb, -OCONRbRc, -C(0)NRC02Rb, -NRC(0)NRC(0)ORb,
-OS02NRbRc, -S02NRcRb, -NRS02Rb, and -NRS02NRbRc.
Values of the other variables are each and independently as described above in the first set of values of the variables of Structural Formula (I).
[00128] The fourth set of values of the variables of Structural Formula (I) is as follows:
X1 and X2 are each independently as described above in the first or second set of set of values of the variables of Structural Formula (I).
M is each independently as described above in the first or third set of set of values of the variables of Structural Formula (I).
JT 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(Ci-C4 alkyl), -C02H, -C02(Ci-C4 alkyl), Ci-C4 alkyl, d-C4 haloalkyl, C3-C6 cycloalkyl, and -0(Ci-C4 alkyl).
JA is halogen, cyano, oxo, Rd, -ORb, -NHRC, -C(0)Rb, -C(0)ORb, -OC(0)Rb, -NHC(0)Rb, -C(0)NHRc, -NHC(0)NHRc, -NHC(0)ORb, -OCONHRc, -N(CH3)RC, -N(CH3)C(0)Rb , -C(0)N(CH3)Rc, -N(CH3)C(0)NHRc, -N(CH3)C(0)ORb, -NHS02Rb, -S02NHRb, -S02N(CH3)Rb, and -N(CH3)S02Rb.
J and J are each and independently selected from the group consisting of halogen, cyano, oxo, Ra, -ORb, -NHRC, -C(0)Rb, -C(0)ORb, -OC(0)Rb, -NHC(0)Rb, -C(0)NHRc, -NHC(0)NHRc, -NHC(0)ORb, -OCONHRc, -N(CH3)RC, -N(CH3)C(0)Rb ,
-C(0)N(CH3)Rc, -N(CH3)C(0)NHRc, -N(CH3)C(0)ORb, -NHS02Rb, -S02NHRb,
-S02N(CH3)Rb, and -N(CH3)S02Rb.
Values of the other variables are each and independently as described above in the first set of values of the variables of Structural Formula (I).
[00129] The fifth set of values of the variables of Structural Formula (I) is as follows:
X1 and X2 are each independently as described above in the first or second set of set of values of the variables of Structural Formula (I).
M is each independently as described above in the first or third set of set of values of the variables of Structural Formula (I).
Each of JT, JA, JB, and Jc is independently as described above in the first or fourth set of set of values of the variables of Structural Formula (I).
Ra is independently an optionally substituted C1-C6 alkyl group, an optionally substituted C3-C7 carbocyclic group, an optionally substituted 5-7 membered heterocyclic group, an optionally substituted 5-6 membered heteroaryl group, or an optionally substituted phenyl 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, each independently form an optionally substituted 5-7 membered heterocyclic group.
Rd is independently an optionally substituted C3-C6 carbocyclic group or an optionally substituted 5-7 membered heterocyclic group.
Values of the other variables are each and independently as described above in the first set of values of the variables of Structural Formula (I).
[00127] In another embodiment, the compounds of the invention are represented by any one of Structural Formula (II) or pharmaceutically acceptable salts thereof:
wherein values of the variables of Structural Formula (II) are each and independently as described above in any one of the first through fifth sets of values of the variables of Structural Formula (I).
[00128] The sixth set of values of the variables of Structural Formula (II) is as follows:
Q1 is -C(0)0-, -NRC(O)-, -C(0)NR'-, or -NRC(0)NR'-.
Values of the other variables are each and independently as described above in any one of the first through fifth sets of values of the variables of Structural Formula (I).
[00129] The seventh set of values of the variables of Structural Formula (II) is as follows:
Q1 is as described above in any one of the first through fifth sets of values of the variables of Structural Formula (I) or in the sixth set of values of the variables of Structural Formula (II). Ring T is an optionally substituted C5-C10 carbocyclic ring. In one aspect, Ring T is an optionally substituted C5-C6 mono-cyclic group. In another aspect, Ring T is an optionally substituted C7-C10 bridged carbocyclic ring.
Values of the other variables are each and independently as described above in any one of the first through fifth sets of values of the variables of Structural Formula (I).
[00130] The eighth set of values of the variables of Structural Formula (II) is as follows:
Q1 is as described above in any one of the first through fifth sets of values of the variables of Structural Formula (I) or in the sixth set of values of the variables of Structural Formula (II).
Ring T-Q^R2 is:
and wherein:
Ring A is a C5-C7 monocyclic group or C7-C10 bridged carbocyclic group, each of which independently and optionally further substituted with one or more instances of JT; or optionally Ring A and R13, Ring A and R14, or Ring A and R15, independently form a C7-C10 bridged carbocyclic ring optionally further substituted with one or more instances of JT;
R12, R13, and R14 are each independently -H, -F, hydroxy, -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 alkyl, Ci-C4 haloalkyl, or -0(Ci-C4 alkyl);
R15 is -H, -F, hydroxy, Ci-C4 alkyl, or Ci-C4 haloalkyl; and
x is 0, 1 or 2. Values of the other variables are each and independently as described above in any one of the first through fifth sets of values of the variables of Structural Formula (I).
[00131] The ninth set of values of the variables of Structural Formula (II) is as follows:
Q is as described above in any one of the first through fifth sets of values of the variables of Structural Formula (I) or in the sixth set of values of the variables of Structural Formula (II).
wherein Ring A and x are each independently as described above in the eighth set of values of the variables of Structural Formula (II).
R12 is -H, hydroxy, d-C4 alkyl, Ci-C4 haloalkyl, or -0(Ci-C4 alkyl).
R13 is -H, hydroxy, Ci-C4 alkyl, Ci-C4 haloalkyl, or -0(Ci-C4 alkyl), or optionally, together with Ring A, forms an optionally substituted C7-C10 bridged, carbocyclic ring.
R14 is -H, Ci-C4 alkyl, or Ci-C4 haloalkyl; or optionally, together with Ring A, forms an optionally substituted C7-C10 bridged, carbocyclic ring.
R15 is -H, C1-C4 alkyl, or Ci-C4 haloalkyl; or optionally, together with Ring A, forms an optionally substituted, C7-C10 bridged, carbocyclic ring.
Values of the other variables are each and independently as described above in any one of the first through fifth sets of values of the variables of Structural Formula (I).
[00132] The tenth set of values of the variables of Structural Formula (II) is as follows:
Q1 is as described above in any one of the first through fifth sets of values of the variables of Structural Formula (I) or in the sixth set of values of the variables of Structural Formula (II).
wherein Ring A and x are each independently as described above in the eighth set of values of the variables of Structural Formula (II).
R is -H.
R is -H or optionally, together with Ring A, forms an optionally substituted C7-C10 bridged, carbocyclic ring. R is -H or optionally, together with Ring A, forms an optionally substituted, C7-C10 bridged, carbocyclic ring.
R15 is -H or C1-C4 alkyl, or optionally, together with Ring A, forms an optionally substituted C7-C10 bridged, carbocyclic ring.
Values of the other variables are each and independently as described above in any one of the first through fifth sets of values of the variables of Structural Formula (I).
[00133] The eleventh set of values of the variables of Structural Formula (II) is as follows:
Q1 is as described above in any one of the first through fifth sets of values of the variables of Structural Formula (I) or in the sixth set of values of the variables of Structural Formula (II).
wherein i) Ring A is a C7-C10 bridged, carbocyclic group; and R12, R13, and R14 are each independently -H, and R15 is -H or Ci alkyl; or ii) Ring A and R15, Ring A and R14, or Ring A and R13 independently form an optionally substituted, C7-C10 bridged, carbocyclic group; and R is -H.
R12, R13, R14, R15, and x are each independently as described above in any one of the first through tenth sets of values of the variables of Structural Formula (II).
Values of the other variables are each and independently as described above in any one of the first through fifth sets of values of the variables of Structural Formula (I).
[00134] The twelfth set of values of the variables of Structural Formula (II) is as follows:
Q1 is as described above in any one of the first through fifth sets of values of the variables of Structural Formula (I) or in the sixth set of values of the variables of Structural Formula (II).
Ring T-Q^R2 is:
Each of rings A1-A4 is independently a C7-C10 bridged, carbocyclic ring optionally further substituted with one or more substituents selected from the group consisting of halogen, cyano, hydroxy, C1-C4 alkyl, C1-C4 haloalkyl, and -0(Ci-C4 alkyl).
Each of rings A5-A6 is independently and optionally further substituted with one or more substituents selected from the group consisting of halogen, cyano, hydroxy, C1-C4 alkyl, C1-C4 haloalkyl, C3-C5 cycloalkyl, and -0(Ci-C4 alkyl).
Each R14 is independently -H, C1-C4 alkyl, or C1-C4 haloalkyl.
R12 and R15 are each and independently -H, hydroxy, C1-C4 alkyl, or C1-C4 haloalkyl.
R21, R22, R23, R24, and R25 are each independently -H, -F, hydroxy, -0(Ci-C4 alkyl), C1-C4 alkyl, or C1-C4 haloalkyl.
Each p is independently 1, 2, or 3. In one aspect, each of p is independently 2.
Each q is independently 0, 1 or 2. In one aspect, each of q is independently 1.
Each r is independently 1 or 2.
Values of the other variables are each and independently as described above in any one of the first through fifth sets of values of the variables of Structural Formula (I).
[00135] The thirteenth set of values of the variables of Structural Formula (II) is as follows:
Q1 is as described above in any one of the first through fifth sets of values of the variables of Structural Formula (I) or in the sixth set of values of the variables of Structural Formula (II).
Ring T-Qx-R2 is as described above in the twelfth set of values of the variables of Structural Formula (II).
R12, R14 and R15 are each independently -H or C1-C4 alkyl. R , R , R , R , and R are each independently -H or C1-C4 alkyl.
Values of the other variables are each and independently as described above in any one of the first through fifth sets of values of the variables of Structural Formula (I).
[00136] The fourteenth set of values of the variables of Structural Formula (II) is as follows:
Q1 is independently -C(0)0-, -NHC(O)-, or -NHC(0)NR'-.
Ring T-Q^R2, R12, R14, R15, R21, R22, R23, R24, and R25 are each independently as described above in any one of the first through the thirteenth set of values of the variables of Structural Formula (II).
Values of the other variables are each and independently as described above in any one of the first through fifth sets of values of the variables of Structural Formula (I).
[00137] The fifteenth set of values of the variables of Structural Formula (II) is as follows:
Q1, Ring T-Q^R2, R12, R14, R15, R21, R22, R23, R24, and R25 are each independently as described above in any one of the first through the fourteenth set of values of the variables of Structural Formula (II).
R2 is independently -H, an optionally substituted C1-C6 alkyl, an optionally substituted 5-7 membered heterocyclic group, an optionally substituted phenyl group, or an optionally substituted 5-6 membered heteroaryl group; or optionally R2 and R', together with the nitrogen atom to which they are attached, form an optionally substituted, 5-7 membered heterocyclic group; wherein said C1-C6 alkyl is optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, hydroxy, and -0(Ci-C4 alkyl); and each of said heterocyclic, phenyl and heteroaryl groups is independently and optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, C1-C4 alkyl, C1-C4 haloalkyl, and -0(Ci-C4 alkyl). In one aspect, R2 is H, optionally substituted Ci_6 alkyl, optionally substituted 5-6 membered heterocyclic, or optionally substituted 5-6 membered hereroaryl. In another aspect, R2 is H or optionally substituted Ci_6 alkyl. In yet another aspect, R2 is H, optionally substituted 5-6 membered heterocyclic, or optionally substituted 5-6 membered heteroaryl.
Values of the other variables are each and independently as described above in any one of the first through fifth sets of values of the variables of Structural Formula (I).
[00138] The fifteenth set of values of the variables of Structural Formula (II) is as follows:
Q1 and Ring T-Qx-R2 are each independently as described above in any one of the first through the fourteenth set of values of the variables of Structural Formula (II).
R2 is H or optionally substituted Ci_6 alkyl; and R12, R14, R15, R21, R22, R23, R24, and R25 are each independently -H.
Values of the other variables are each and independently as described above in any one of the first through fifth sets of values of the variables of Structural Formula (I).
[00139] The sixteenth set of values of the variables of Structural Formula (II) is as follows:
Q1, Ring T-Q^-R2, R12, R14, R15, R21, R22, R23, R24, and R25 are each independently as described above in any one of the first through the fourteenth set of values of the variables of Structural Formula (II).
Z1 is CH.
X1 is -CI.
X2 is -F.
Values of the other variables are each and independently as described above in any one of the first through fifth sets of values of the variables of Structural Formula (I).
[00140] In another embodiment, the compounds of the invention are represented by any one of Structural Formulae (III) - (V), or pharmaceutically acceptable salts thereof:
wherein ring P is a C3-C6 carbocyclic ring, and values of the other variables of Structural
Formulae (III) - (V) are each and independently as described above in any one of the first through fifth sets of values of the variables of Structural Formula (I).
[00141] The sixth set of values of the variables of Structural Formulae (III) - (V) is as follows:
Z2 is CH.
R3 is -C(0)OR, -OH, -CH2OH, -S(0)2R9, or -S(0)2-NRR10. Values of the other variables are each and independently as described above in any one of the first through fifth sets of values of the variables of Structural Formula (I).
[00142] The seventh set of values of the variables of Structural Formulae (III) - (V) is as follows:
Z2 and R3 are each independently as described above in any one of the first set through the sixth set of values of the variables of Structural Formulae (III) - (V).
R4, R5, and R6 are each and independently -CH3, -CH2F, -CF3, or -C2H5; or
R4 is -CH3, -CH2F, -CF3, or -C2H5; and R5 and R6 together with the carbon atom to which they are attached form a C3-C6 carbocyclic ring.
Values of the other variables are each and independently as described above in any one of the first through fifth sets of values of the variables of Structural Formula (I).
[00143] The eighth set of values of the variables of Structural Formulae (III) - (V) is as follows:
Z2, R3, R4, R5, and R6 are each and independently as described above in any one of the first set through the seventh set of values of the variables of Structural Formulae (III) - (V).
Values of the other variables are each and independently as described above in any one of the first through fifth sets of values of the variables of Structural Formula (I).
[00144] The ninth set of values of the variables of Structural Formulae (III) - (V) is as follows:
Q2, Z2, R3, R4, R5, and R6 are each and independently as described above in any one of the first set through the eighth set of values of the variables of Structural Formulae (III) - (V).
R is -H or Ci-4 alkyl.
R9 is -OH.
R10 is Ci-4 alkyl optionally substituted with one or more substituents selected from the group consisting of halogen, -OR and -C(0)OR.
Values of the other variables are each and independently as described above in any one of the first through fifth sets of values of the variables of Structural Formula (I).
[00145] The tenth set of values of the variables of Structural Formulae (III) - (V) is as follows:
Q2, Z2, R, R4 R5, R6, R9, and R10 are each and independently as described above in any one of the first set through the ninth set of values of the variables of Structural Formulae (III) - (V). R3 is -C(0)OR, -S(0)2R9, or -S(0)2-NRR10.
Values of the other variables are each and independently as described above in any one of the first through fifth sets of values of the variables of Structural Formula (I).
[00146] The eleventh set of values of the variables of Structural Formulae (III) - (V) is as follows:
Q2, Z2, R, R4, R3, R5, R6, R9, and R10 are each and independently as described above in any one of the first set through the tenth set of values of the variables of Structural Formulae (III) - (V).
Z1 is CH.
X1 is -CI.
X2 is -F.
Values of the other variables are each and independently as described above in any one of the first through fifth sets of values of the variables of Structural Formula (I).
[00147] In yet another embodiment, the compounds of the invention are represented by any one of Structural Formulae (I) - (V) or a pharmaceutically acceptable salt thereof, wherein values of the variables are each and independently as shown in the compounds of Table 1.
[00148] In yet another embodiment, the compounds of the invention are represented by any one of the structural formulae depicted in Table 1, or a pharmaceutically acceptable salt thereof.
[00149] As used herein, a reference to compound(s) of the invention (for example, the compound(s) of Structural Formula (I), or compound(s) of claim 1) will include
pharmaceutically acceptable salts thereof.
[00150] The compounds of the invention described herein can be prepared by any suitable method known in the art. For example, they can be prepared in accordance with procedures described in WO 2005/095400, WO 2007/084557, WO 2010/01 1768, WO 2010/01 1756, WO 2010/011772, WO 2009/073300, and PCT/US2010/038988 filed on June 17, 2010. For example, the compounds shown in Table 1 can be prepared by any suitable method known in the art, for example, WO 2005/095400, WO 2007/084557, WO 2010/011768, WO
2010/01 1756, WP 2010/011772, WO 2009/073300, or PCT/US2010/038988, and by the exemplary syntheses described below under Exemplification.
[00151] The present invention provides methods of preparing a compound represented by any one of Structural Formulae (I) - (V). In one embodiment, the compounds of the invention can be prepared as depicted in General Scheme 1. Any suitable condition known in the art can be employed in the invention for each step depicted in the scheme.
[00152] In a specific embodiment, as shown in General Scheme 1, the methods comprise reacting Compound (A) with Compound (B) under suitable conditions to form a compound of Structural Formula (XX), wherein each of L1 and L2 independently is a halogen (F, CI, Br, or I), G is trityl and the remaining variables of Compounds (A), (B) and Structural Formula (XX) are each and independently as described above for Structural Formulae (I) - (V).
Typical examples for L1 and L2 are each and independently CI or Br. The methods further comprise deprotecting the G group under suitable conditions to form the compounds of Structural Formula (I). Any suitable condition known in the art can be employed in the invention for each step depicted in the scheme. For example, any suitable condition described in WO 2005/095400 and WO 2007/084557 for the coupling of a dioxaboraolan with, for example, a chloro-pyrimidine can be employed for the reaction between Compounds (A) and (B). Specifically, the reaction between compounds (A) and (B) can be performed in the presence of Pd(PPh3)4 or Pd2(dba)3 (dba is dibenzylidene acetone). For example, the de- tritylation step can be performed under an acidic condition (e.g., trifluoroacetic acid (TFA)) in the presence of, for example, EtsSiH (Et is ethyl). Specific exemplary conditions are described in the Exemplification below
[00153] Optionally, the method further comprises the step of preparing Compound (A) by reacting Compound (E) with Compound (D). Any suitable conditions know in the art can be employed in this step, and Compounds (E) and (D) can be prepared by any suitable method known in the art. Specific exemplary conditions are described in the Exemplification below. Compounds (E) and (D) can be prepared by any suitable method known in the art. Specific exemplary synthetic methods of these compounds are described below in the
Exemplification.
General Scheme 1
[00130] In some embodiments, the present invention is directed to a compound represented by Structural Formula (XX), wherein the variables of Structural Formula (XX) are each and independently as defined in any one of the claims, and G is trityl. Specific examples of the compounds represented by Structural formula (XX) are shown below in the Exemplification. Some specific examples include: Compounds 11a, 19a, and 42a, which are shown in the Exemplification below.
Definitions and General Terminology
[00131] 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 & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference.
[00132] 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, if X is optionally substituted Ci.Csalkyl 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_ C3alkyl or phenyl wherein X is optionally and independently substituted by Jx, then both Ci_ C3alkyl and phenyl may be optionally substituted by Jx.
[00133] 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.
[00134] 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.
[00135] The term "aliphatic" or "aliphatic group", as used herein, means a straight- chain (i.e., unbranched), or branched, hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation but is non-aromatic. Unless otherwise specified, aliphatic groups contain 1-20 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-10 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-8 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain 1-6 aliphatic carbon atoms, and in yet other embodiments, aliphatic groups contain 1 -4 aliphatic carbon atoms. Aliphatic groups may be linear or branched, substituted or unsubstituted alkyl, alkenyl, or alkynyl groups. Specific examples include, but are not limited to, methyl, ethyl, isopropyl, n-propyl, sec -butyl, vinyl, n-butenyl, ethynyl, and tert-butyl and acetylene.
[00136] 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-Ce 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.
[00137] 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, cycloalkyl and
cycloalkenyl groups. Specific examples include, but are not limited to, cyclohexyl, cyclopropenyl, and cyclobutyl.
[00138] 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 heteroatoms selected from N and O within the ring system. The term includes monocyclic, bicyclic or polycyclic fused, spiro or bridged heterocyclic ring systems. The term also includes polycyclic ring systems in which the heterocyclic ring can be fused to one or more non-aromatic carbocyclic or heterocyclic rings or one or more aromatic rings or combination thereof, wherein the radical or point of attachment is on the heterocyclic ring. Examples of heterocycles include, but are not limited to, piperidinyl, piperizinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, azepanyl, diazepanyl, triazepanyl, azocanyl, diazocanyl, triazocanyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, oxazocanyl, oxazepanyl, thiazepanyl, thiazocanyl, benzimidazolonyl, tetrahydrofuranyl,
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 l,3-dihydro-imidazol-2-onyl.
[00139] The term "aryl" (or "aryl ring" or "aryl group") used alone or as part of a larger moiety as in "aralkyl", "aralkoxy", or "aryloxyalkyl" refers to carbocyclic aromatic ring systems. The term "aryl" may be used interchangeably with the terms "aryl ring" or "aryl group".
[00140] "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 non- aromatic rings (carbocyclic or heterocyclic), such as in an indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl, where the radical or point of attachment is on the aromatic ring.
[00141] The terms "heteroaryl", "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 "heteroaryl", 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, tetrazolyl, 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-isoxazolyl, 5-isoxazolyl, 2-oxadiazolyl, 5- oxadiazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 3 -pyrazolyl, 4-pyrazolyl, 1 -pyrrolyl, 2- pyrrolyl, 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, tetrazolyl, 2-thienyl, 3-thienyl, carbazolyl, benzimidazolyl, benzothienyl, benzofuranyl, indolyl, benzotriazolyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, isoquinolinyl, indolyl, isoindolyl, acridinyl, benzisoxazolyl, isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3 -triazolyl, 1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, purinyl, pyrazinyl, 1,3,5-triazinyl, quinolinyl (e.g., 2-quinolinyl, 3-quinolinyl, 4-quinolinyl), and isoquinolinyl (e.g., 1 -isoquinolinyl, 3 -isoquinolinyl, or 4-isoquinolinyl).
[00142] As used herein, "cyclo", "cyclic", "cyclic group" or "cyclic moiety", include mono-, bi-, polycyclic, fused, spiro, or bridged ring systems including cycloaliphatic, heterocycloaliphatic, carbocyclic aryl, or heteroaryl, each of which has been previously defined.
[00143] 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.
[00144] 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, norbornanyl, 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, heteroaryl, alkoxy, cycloalkyloxy, heterocycloalkyloxy, (carbocyclic aryl)oxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, aroyl, heteroaroyl, nitro, carboxy, alkoxycarbonyl,
alkylcarbonyloxy, aminocarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino,
(cycloalkylalkyl)carbonylamino, (carbocyclic aryl)carbonylamino, aralkylcarbonylamino, (heterocycloalkyl)carbonylamino, (heterocycloalkylalkyl)carbonylamino,
heteroarylcarbonylamino, heteroaralkylcarbonylamino, cyano, halo, hydroxy, acyl, mercapto, alkylsulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, or carbamoyl.
[00145] 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".
[00146] 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.
[00147] 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.
[00148] 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.
[00149] 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 quaternized 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 NR+ (as in N-substituted pyrrolidinyl)).
[00150] As used herein an optionally substituted aralkyl can be substituted on both the alkyl and the aryl portion. Unless otherwise indicated as used herein optionally substituted aralkyl is optionally substituted on the aryl portion.
[00151] In some embodiments, an aliphatic or heteroaliphatic group, or a non-aromatic heterocyclic ring may contain one or more substituents. Suitable substituents on the saturated carbon of an aliphatic or heteroaliphatic group, or of a heterocyclic ring are selected from those listed above. Other suitable substitutents include those listed as suitable for the unsaturated carbon of a carbocyclic aryl or heteroaryl group and additionally include the following: =0, =S, alkyl),
alkyl), or =NR*, wherein each R* is independently selected from hydrogen or an optionally substituted Ci_6 aliphatic. Optional substituents on the aliphatic group of R are selected from NH2, NH(Ci_4 aliphatic), N(Ci_4 aliphatic)2, halogen, Ci_4 aliphatic, OH, 0(Ci_4 aliphatic), O2, CN, CO2H, C02(Ci_4 aliphatic), 0(halo Ci_4 aliphatic), or halo(Ci_4 aliphatic), wherein each of the foregoing Ci_4aliphatic groups of R is unsubstituted.
[00152] In some embodiments, optional substituents on the nitrogen of a heterocyclic ring include those used above. Other suitable substituents include -R+, -N(R+)2, -C(0)R+, -C02R+, -C(0)C(0)R+, -C(0)CH2C(0)R+, -S02R+, -S02N(R+)2, -C(=S)N(R+)2, -C(=NH)- N(R+)2, or - R+S02R+; wherein R+ is hydrogen, an optionally substituted Ci_6 aliphatic, optionally substituted phenyl, optionally substituted -O(Ph), optionally substituted -CH2(Ph), optionally substituted -(CH2)i-2(Ph); optionally substituted -CH=CH(Ph); or an unsubstituted 5-6 membered heteroaryl or heterocyclic ring having one to four heteroatoms independently selected from oxygen, nitrogen, or sulfur, or, two independent occurrences of R+, on the same substituent or different substituents, taken together with the atom(s) to which each R+ group is bound, form a 5-8-membered heterocyclyl, carbocyclic aryl, or heteroaryl ring or a 3-8- membered cycloalkyl ring, wherein said heteroaryl or heterocyclyl ring has 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Optional substituents on the aliphatic group or the phenyl ring of R+ are selected from NH2, NH(Ci_4 aliphatic), N(Ci_4 aliphatic)2, halogen, Ci_4 aliphatic, OH, 0(Ci_4 aliphatic), N02, CN, C02H, C02(Ci_4 aliphatic), 0(halo Ci_4 aliphatic), or halo(Ci_4 aliphatic), wherein each of the foregoing Ci_4aliphatic groups of R+ is unsubstituted.
[00153] In some embodiments, an aryl (including aralkyl, aralkoxy, aryloxyalkyl and the like) or heteroaryl (including heteroaralkyl and heteroarylalkoxy and the like) group may contain one or more substituents. Suitable substituents on the unsaturated carbon atom of a carbocyclic aryl or heteroaryl group are selected from those listed above. Other suitable substituents include: halogen; -R°; -OR°; -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°NR0C(0)N(R°)2; -NR°NR0C02R°; -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; -OC(0)N(R°)2; -OC(0)R°; -C(0)N(OR°) R°; -C(NOR°) R°; -S(0)2R°; -S(0)3R°; -S02N(R°)2; -S(0)R°; - NR°S02N(R°)2; -NR°S02R°; -N(OR°)R°; -C(=NH)-N(R°)2; or -(CH2)0-2NHC(O)R°; wherein each independent occurrence of R° is selected from hydrogen, optionally substituted Ci_6 aliphatic, an unsubstituted 5-6 membered heteroaryl or heterocyclic ring, phenyl, -O(Ph), or -CH2(Ph), or, two independent occurrences of R°, on the same 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(Ci-4aliphatic), N(Ci-4aliphatic)2, halogen, Ci-4aliphatic, OH, 0(Ci- 4aliphatic), N02, CN, C02H, C02(Ci_4aliphatic), 0(haloCi_4 aliphatic), or haloCi_4aliphatic, CHO, N(CO)(Ci_4 aliphatic), C(0)N(Ci_4 aliphatic), wherein each of the foregoing Ci_ 4aliphatic groups of R° is unsubstituted.
[00154] 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 N' substituted-N-heterocycles. For example, an N' 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.
[00155] The term "unsaturated", as used herein, means that a moiety has one or more units of unsaturation.
[00156] 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- 1 -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° x°R0 , 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.
[00157] The term "hydroxyl'Or "hydroxy" or "alcohol moiety" refers to -OH.
[00158] As used herein, an "alkoxycarbonyl," which is encompassed by the term carboxy, used alone or in connection with another group refers to a group such as
(alkyl-O)-C(O)-.
[00159] As used herein, a "carbonyl" refers to -C(O)-.
[00160] As used herein, an "oxo" refers to =0.
[00161] As used herein, the term "alkoxy", or "alkylthio", as used herein, refers to an alkyl group, as previously defined, attached to the molecule through an oxygen ("alkoxy" e.g., -O-alkyl) or sulfur ("alkylthio" e.g., -S-alkyl) atom.
[00162] As used herein, the terms "halogen", "halo", and "hal" mean F, CI, Br, or I.
[00163] As used herein, the term "cyano" or "nitrile" refer to -CN or -C≡N.
[00164] 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.
[00165] 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 -CF3 and -CF2CF3.
[00166] 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 ( C)-alkyl-.
[00167] The terms "aminoalkyl", "aminoalkenyl", "aminoaliphatic", and
"aminoalkoxy" mean alkyl, alkenyl, aliphatic or alkoxy, as the case may be, substituted with one or more amino groups, wherein the amino group is as defined above. In some embodiments, the aminoaliphatic is a C1-C6 aliphatic group substituted with one or more - H2 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 -NH2 groups. In some specific embodiments, the aminoalkenyl is C1-C6 alkenyl substituted with one or more - H2 groups. In some embodiments, the aminoalkoxy is -0(C1-C6 alkyl) wherein the alkyl group is substituted with one or more -NH2 groups.
[00168] The terms "hydroxyalkyl", "hydroxyaliphatic", and "hydroxyalkoxy" mean alkyl, aliphatic or alkoxy, as the case may be, substituted with one or more -OH groups.
[00169] 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.
[00170] The term "carboxyalkyl" means alkyl substituted with one or more carboxy groups, wherein alkyl and carboxy are as defined above.
[00171] 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 & 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 & Sons, New York: 1999, the entire contents of which are hereby incorporated by reference.
[00172] 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.
[00173] 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
bonds. For example, a substituent drawn as also represents .
[00174] 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.
[00175] Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention.
[00176] Additionally, unless otherwise indicated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a 13C- or 14C-enriched carbon are 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.
[00177] The terms "a bond" and "absent" are used interchangeably to indicate that a group is absent.
[00178] 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
[00179] 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.
[00180] 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, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
[00181] Pharmaceutically acceptable salts are well known in the art. For example, S.
M. Berge et al, describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 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.
[00182] 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.
[00183] 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.
[00184] 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 +(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.
[00185] 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, diethylamine, piperazine, tris(hydroxymethyl)-aminomethane, tetramethylammonium hydroxide, triethylamine, dibenzylamine, ephenamine, dehydroabietylamine, N-ethylpiperidine, benzylamine, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, ethylamine, basic amino acids, dicyclohexylamine and the like. [00186] 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.
[00187] 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.
[00188] The compounds described herein can also exist as pharmaceutically acceptable solvates (e.g., hydrates) and clathrates. As used herein, the term "pharmaceutically acceptable solvate," is a solvate formed from the 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).
[00189] 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-covalent intermolecular forces.
[00190] As used herein, the term "clathrate" means a compound described herein or a salt thereof in the form of a crystal lattice that contains spaces (e.g., channels) that have a guest molecule (e.g., a solvent or water) trapped within.
[00191] 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.
[00192] 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.
[00193] 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, -N02, -ONO, or -ONO2 moieties. Prodrugs can typically be prepared using well-known methods, such as those described by BURGER'S MEDICINAL CHEMISTRY AND DRUG DISCOVERY (1995) 172-178, 949-982 (Manfred E. Wolff ed., 5th ed).
[00194] A "pharmaceutically acceptable derivative" is an adduct or derivative which, upon administration to a patient in need, is capable of providing, directly or indirectly, a compound as otherwise described herein, or a metabolite or residue thereof. Examples of pharmaceutically acceptable derivatives include, but are not limited to, esters and salts of such esters. Pharmaceutically acceptable prodrugs of the compounds described herein include, without limitation, esters, amino acid esters, phosphate esters, metal salts and sulfonate esters.
Uses of the Compounds
[00195] 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.
[00196] In one embodiment, the present invention is generally related to the use of compounds represented by any one of Structural Formulae (I) - (V), or pharmaceutically acceptable salts thereof for any of the uses specified above:
[00197] In yet another embodiment, the present invention is directed to the use of any compound selected from the compounds depicted in Table 1 or a pharmaceutically acceptable salt thereof, for any of the uses described above.
[00198] In some embodiments, the compounds are represented by any one of
Structural Formulae (I) - (V), and the variables are each independently as depicted in the compounds of Table 1.
[00199] 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).
[00200] 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.
[00201] 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 virus which can be subdivided into different serotypes based on the antibody response to these viruses: H1 1, H2N2, H3N2, H5N1, H7N7, H1N2, H9N2, H7N2 , H7N3 and H10N7. Influenzavirus B genus has one species, influenza B virus. Influenza B almost exclusively infects humans and is less common than influenza A. Influenzavirus C genus has one species, Influenzavirus C virus, 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.
[00202] 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 H1 1, H2N2, H3N2 or H5 1.
[00203] 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".
[00204] Symptoms of influenza can start quite suddenly one to two days after infection. Usually the first symptoms are chills or a chilly sensation, but fever is also common early in the infection, with body temperatures ranging from 38-39 °C
(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.
[00205] The terms, "disease", "disorder", and "condition" may be used
interchangeably here to refer to an influenza virus mediated medical or pathological condition.
[00206] 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".
[00207] 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.
[00208] 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.
[00209] 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%.
[00210] 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.
[00211] 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, 10"2, 10"3,..., 10"8. The lowest concentration of virus that still infects cells is the viral titer.
[00212] 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.
[00213] The term "chemotherapy" refers to the use of medications, e.g. small molecule drugs (rather than "vaccines") for treating a disorder or disease.
[00214] 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.
[00215] 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).
[00216] According to the US CDC, an influenza "outbreak" is defined as a sudden increase of acute febrile respiratory illness (AFRI) occurring within a 48 to 72 hour period, in a group of people who are in close proximity to each other (e.g. in the same area of an assisted living facility, in the same household, etc) over the normal background rate or when any subject in the population being analyzed tests positive for influenza. One case of confirmed influenza by any testing method is considered an outbreak.
[00217] 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).
[00218] 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, secondary, tertiary, etc.
[00219] 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.
[00220] 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.
[00221] 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.
[00222] 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.
[00223] 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).
[00224] 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.
[00225] 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
[00226] An effective amount can be achieved in the method or pharmaceutical composition of the invention employing a compound of the invention (including a pharmaceutically acceptable salt or solvate (e.g., hydrate)) alone or in combination with an additional suitable therapeutic agent, for example, an antiviral agent or a vaccine. When "combination therapy" is employed, an effective amount can be achieved using a first amount of a compound of the invention and a second amount of an additional suitable therapeutic agent (e.g. an antiviral agent or vaccine).
[00227] In another embodiment of this invention, a compound of the invention and the additional therapeutic agent, are each administered in an effective amount (i.e., each in an amount which would be therapeutically effective if administered alone). In another embodiment, a compound of the invention and the additional therapeutic agent, are each administered in an amount which alone does not provide a therapeutic effect (a subtherapeutic dose). In yet another embodiment, a compound of the invention can be administered in an effective amount, while the additional therapeutic agent is administered in a sub-therapeutic dose. In still another embodiment, a compound of the invention can be administered in a sub-therapeutic dose, while the additional therapeutic agent, for example, a suitable cancer-therapeutic agent is administered in an effective amount.
[00228] 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.
[00229] 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.
[00230] In one embodiment, the present invention is directed to methods of combination therapy for inhibiting Flu viruses replication in biological samples or patients, or for treating or preventing Influenza virus infections in patients using the compounds or pharmaceutical compositions of the invention. Accordingly, pharmaceutical compositions of the invention also include those comprising an inhibitor of Flu virus replication of this invention in combination with an anti-viral compound exhibiting anti-Influenza virus activity.
[00231] Methods of use of the compounds and compositions of the invention also include combination of chemotherapy with a compound or composition of the invention, or with a combination of a compound or composition of this invention with another anti-viral agent and vaccination with a Flu vaccine.
[00232] When co-administration involves the separate administration of the first amount of a compound of the invention and a second amount of an additional therapeutic agent, the compounds are administered sufficiently close in time to have the desired therapeutic effect. For example, the period of time between each administration which can result in the desired therapeutic effect, can range from minutes to hours and can be determined taking into account the properties of each compound such as potency, solubility, bioavailability, plasma half-life and kinetic profile. For example, a compound of the invention and the second therapeutic agent can be administered in any order within about 24 hours of each other, within about 16 hours of each other, within about 8 hours of each other, within about 4 hours of each other, within about 1 hour of each other or within about 30 minutes of each other.
[00233] 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.
[00234] It is understood that the method of co-administration of a first amount of a compound of the invention and a second amount of an additional therapeutic agent can result in an enhanced or synergistic therapeutic effect, wherein the combined effect is greater than the additive effect that would result from separate administration of the first amount of a compound of the invention and the second amount of an additional therapeutic agent.
[00235] 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.
[00236] When the combination therapy using the compounds of the present invention is in combination with a Flu vaccine, both therapeutic agents can be administered so that the period of time between each administration can be longer (e.g. days, weeks or months).
[00237] 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, FL, Arch. Exp. Pathol Pharmacol. 1 14: 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.
[00238] 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-administered with a traditional influenza vaccine.
Pharmaceutical Compositions
[00239] 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 carriers include, for example, pharmaceutical diluents, excipients or carriers suitably selected with respect to the intended form of administration, and consistent with conventional pharmaceutical practices.
[00240] 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.
[00241] A pharmaceutically acceptable carrier 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.
[00242] 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.
[00243] 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.
Administration Methods
[00244] The compounds and pharmaceutically acceptable compositions described above can be administered to humans and other animals orally, rectally, parenterally, intracisternally, 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.
[00245] 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.
[00246] 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.
[00247] 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.
[00248] 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 crystal 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.
[00249] 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.
[00250] 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.
[00251] 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.
[00252] 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.
[00253] 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.
[00254] 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, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. Specifically, the compositions are administered orally, intraperitoneally or intravenously.
[00255] 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.
[00256] 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.
[00257] 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.
[00258] 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.
[00259] Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically- transdermal patches may also be used.
[00260] 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.
[00261] 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.
[00262] 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.
[00263] 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
Example 1: Synthesis of Compounds of the Invention
[00264] The compounds disclosed herein can be prepared by any suitble method known in the art, for example, WO 2005/095400, WO 2007/084557, WO 2010/011768, WO 2010/011756, WP 2010/01 1772, WO 2009/073300, and PCT/US2010/038988 filed on June 17, 2010. For example, the compounds shown in Table 1 can be prepared by any suitble method known in the art, for example, WO 2005/095400, WO 2007/084557, WO
2010/01 1768, WO 2010/011756, WP 2010/011772, WO 2009/073300, and
PCT/US2010/038988, and by the exemplary syntheses described below. Generally, the compounds of the invention can be prepared as shown in those syntheses optionally with any desired appropriate modification.
Methodology for Synthesis and Characterization of Compounds
[00265] Syntheses of certain exemplary compounds of the invention are described below. NMR and Mass Spectroscopy data of certain specific compounds are summarized in Table 1. As used herein the term RT (min) refers to the LCMS retention time, in minutes, associated with the compound.
Preparation of Compound 8a
Synthetic Scheme 1
(a) Cul, Et3N, PdCl2(PPh)3, THF, ethynyl-TMS, 55 °C; (b) KOlBu, THF, 120 °C; (c) S, 2- MeTHF; (d) NBS, DMF; (e) Ph3CCl, Na2C03, DMF, 45 °C; (f) 'PrMgCl, THF
Formation of 5-chloro-3-((trimethylsilyl)ethynyl)pyrazin-2-amine (2a)
To a degassed solution of 3-bromo-5-chloro-pyrazin-2-amine, la, (20.80 g, 99.79 mmol), Et3N (41.74 mL, 299.4 mmol), iodocopper (0.6 g, 2.99 mmol) and dichloropalladium; triphenylphosphine (1.40 g, 2.00 mmol) in THF (388 mL) was added ethynyl-trimethyl-silane (14.10 mL, 99.79 mmol) over 5 minutes. The reaction mixture was warmed to 55 °C for 1 hour. The reaction mixture was cooled to room temperature and filtered through a pad of celite. The filtrate was concentrated in vacuo and the resulting solid was washed with ether and filtered to provide 14 g of the desired product (62% yield) in sufficient purity for use in the subsequent reaction: XH NMR (400 MHz, CDC13) δ 7.94 (s, 1H), 5.00 (d, J = 44.2 Hz, 2H), 0.26 (s, 9H) ppm; LCMS Gradient 10-90%, 0.1% formic acid, 5 min, C18/ACN, RT = 3.42 min (M+H) 226.39.
Formation of 2-chloro-5H-pyrrolo[2,3-b]pyrazine (3a)
To a stirred solution of 5-chloro-3-(2-trimethylsilylethynyl)pyrazin-2-amine, 2a, (2.28 g, 10.10 mmol) in THF (100 mL) at room temperature was added KO'Bu (1.13 g, 10.10 mmol). The reaction mixture was heated to 120 °C in a sealed tube. Upon completion of the reaction, the mixture was cooled, filtered through a pad of celite and concentrated in vacuo to provide the desired product in sufficient purity for use in the subsequent reaction: XH NMR (400 MHz, CDC13) δ 8.18 (d, J = 2.3 Hz, 1H), 7.64 (d, J = 3.3 Hz, 1H), 6.70 - 6.53 (m, 1H) ppm; LCMS Gradient 10-90%, 0.1% formic acid, 5 min, C18/ACN, RT = 2.07 min (M+H) 154.05.
Formation of 2-chloro-7-iodo-5H-pyrrolo[2,3-b]pyrazine (4a)
To stirred solution of 2-chloro-5H-pyrrolo[2,3-b]pyrazine, 3a, (0.50 g, 3.26 mmol) in 2-MeTHF (28 mL) was added N-iodosuccinimide (0.73 g, 3.26 mmol). The solution was stirred at room temperature overnight. The mixture was partitioned between water and 2- MeTHF. The combined organic layer was dried ( a2S04), filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (0-100% EtOAc/Hexanes gradient) followed by trituration with CH2CI2 to afford the desired product: XH NMR (400 MHz, ί/6-DMSO) δ 12.81 (s, 1H), 8.36 (s, 1H), 8.21 (s, 1H) ppm; LCMS Gradient 10-90%, 0.1% formic acid, 5 min, C18/ACN, RT = 2.72 min (M+H) 279.96.
Formation of 7-bromo-2-chloro-5H-pyrrolo[2,3-b]pyrazine (5a)
To a stirred solution of 2-chloro-5H-pyrrolo[2,3-b]pyrazine, 3a, (1.54 g, 0.01 mol) in DMF (38 mL) was N-bromsuccinimide (1.78 g, 10.00 mmol). The mixture was stirred at room temperature for 1.5h until the reaction was complete. The mixture was poured into EtOAc and the organic layer was washed with several portions of brine. The organic layer was dried (MgS04), filtered and concentrated in vacuo. The resulting solid was triturated with Et20 to afford 1.88 g of the desired product (80% yield): XH NMR (400 MHz, d6- DMSO) δ 12.82 (s, 1H), 8.44 (d, J = 21.1 Hz, 1H), 8.25 (d, J = 2.5 Hz, 1H) ppm; LCMS Gradient 10-90%, 0.1% formic acid, 5 min, C18/ACN, RT = 2.59 min (M+H) 231.97.
Formation of 2-chloro-7-iodo-5-trityl-5H-pyrrolo[2,3-b]pyrazine (6a)
To a mixture of 2-chloro-7-iodo-5H-pyrrolo[2,3-b]pyrazine, 4a, (2.71 g, 9.02 mmol), a2C03 (1.91g, 18.00 mmol) and (chloro-diphenyl-methyl)benzene (2.59 g, 9.29 mmol) was added DMF (27 mL). The resulting mixture was heated at 45 °C for lhour. The mixture was diluted with 2-MeTHF (200 mL) and washed with water and then 4 times with brine. The organic layer was dried over Na2S04, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (0-100% EtOAc/ Hexanes gradient) afforded 4.18 g of the desired product (89% yield) as a white solid: XH NMR (400 MHz, CDC13) δ 7.91 (s, 1H), 7.62 (s, 1H), 7.38 - 7.27 (m, 9H), 7.19 - 7.02 (m, 6H) ppm; LCMS Gradient 10-90%, 0.1% formic acid, 5 min, C18/ACN, RT = 2.97 min (M+H) 522.12.
Formation of 7-bromo-2-chloro-5-trityl-5H-pyrrolo[2,3-b]pyrazine (7a)
This compound was prepared in by the method described for 2-chloro-7-iodo-5-trityl- 5H-pyrrolo[2,3-b]pyrazine, 6a: XH NMR (400 MHz, CDC13) δ 7.96 (s, 1H), 7.60 (s, 1H), 7.31 (d, J = 2.6 Hz, 9H), 7.17 (d, J = 3.8 Hz, 6H); LCMS Gradient 10-90%, 0.1% formic acid, 5 min, C18/ACN, RT = 2.89 min (M+H) 474.31.
Formation of 2-chloro-7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-5-trityl-5H- pyrrolo[2,3-b]pyrazine (8a)
To a stirred mixture of freshly distilled 2-isopropoxy-4,4,5,5-tetramethyl-l,3,2- dioxaborolane (5.85 mL, 28.65 mmol) and 2-chloro-7-iodo-5-trityl-5H-pyrrolo[2,3- b]pyrazine, 6a, (11.50 g, 22.04 mmol) in THF (230 mL) at -20 °C was added dropwise a solution of isopropyl magnesium chloride (14.32 mL of 2M, 28.65 mmol) over a period of 10 minutes. The mixture was stirred and the temperature was kept below -20 °C for a further 1.5h. The reaction mixture was diluted with Et20, poured into aqueous saturated NaHCC^ solution and partitioned. The aqueous phase was extracted with additional Et20 and the combined organic phases were washed with water and brine. The organic layer was dried and filtered through celite and concentrated in vacuo. The resulting residue was triturated with a mixture of CH2CI2 and heptane, filtered with heptane and concentrated in vacuo to afford 7.6 g of the desired product (67% yield) in > 85% purity, sufficient for use in the subsequent reactions: XH NMR (400 MHz, CDC13) δ 8.02 (s, 1H), 7.88 (s, 1H), 7.35 - 7.25 (m, 9H), 7.21 - 7.08 (m, 6H), 1.37 (s, 12H) ppm; LCMS Gradient 10-90%, 0.1% formic acid, 5 min, C18/ACN, RT = 3.25 min (M+H) 522.28.
(a) S0C12, MeOH, 0 °C to 60 °C; (b) 2-bromo-5-fluoro-4-iodopyridine, Cs2C03, Xantphos, Pd(OAc)2, 1,4-dioxane, 115 °C; (c) 2-chloro-7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)- 5-trityl-5H-pyrrolo[2,3-b]pyrazine (8a), K3PO4, THF, H20, Pd(PPh3)4, 120 °C; (d) Et3SiH, TFA, CH2C12; (e) LiOH, H20, THF.
Formation of (+/-)-methyl 3-amino-4,4-dimethylpentanoate hydrochloride (9a)
A 500 niL 3 -neck RB flask with magnetic stirrer, temperature probe and additional funnel was charged with racemic 3-amino-4,4-dimethyl-pentanoic acid (135.0 g, 929.8 mmol) in methanol (1.35 L), cooled to 0 °C, and then thionyl chloride (74.6 mL, 1.0 mol) was added dropwise over 45 minutes. The reaction mixture was slowly allowed to warm to ambient temperature over 1 h. The resulting reaction mixture was warmed to 60 °C, stirred at this temperature for 2 h, at which point XH NMR of the aliquot revealed consumption of the starting material. The reaction mixture was cooled to ambient temperature and concentrated under reduced pressure. The residue was azeotroped with toluene (3 x 150 mL) and dried under vacuum for 14 h to afford 180 g of the desired product as the hydrochloride salt (99 % yield) as an off-white solid.
Formation of (+/-)-methyl 3-((2-bromo-5-fluoropyridin-4-yl)amino)-4,4-dimethyl- pentanoate (10a)
To a vial charged with 2-bromo-5-fluoro-4-iodo-pyridine (0.25 g, 0.83 mmol), racemic methyl 3-amino-4,4-dimethylpentanoate hydrochloride HC1, 9a, (0.23 g, 1.16 mmol) and Cs2C03 (0.95 g, 2.92 mmol), Xantphos (0.03 g, 0.06 mmol) and Pd(OAc)2 (0.01 g, 0.05 mmol) was added 1,4-dioxane (5 mL). The mixture was purged with nitrogen. The vial sealed and heated to 115 °C for 16 h. The mixture was cooled, poured into a half saturated brine solution and the aqueous phase was extracted three times with EtOAc. The combined organic phases were dried over Na2S04, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (0-100% EtOAc/Hexanes gradient) afforded 65 mg of the desired product: XH NMR (400 MHz, CDC13) δ 7.88 (d, J = 2.9 Hz, 1H), 6.90 (d, J = 6.4 Hz, 1H), 4.47 (d, J = 7.9 Hz, 1H), 3.82 - 3.70 (m, 1H), 3.63 (s, 3H), 2.74 (dd, J = 15.4, 3.8 Hz, 1H), 2.39 (dd, J = 15.3, 9.7 Hz, 1H), 0.99 (s, 9H) ppm; LCMS Gradient 10-90%, 0.1% formic acid, 5 min, C18/ACN, RT = 3.22 min (M+H) 577.49. Formation of (+/-)-methyl 3-((2-(2-chloro-5-trityl-5H-pyrrolo[2,3-b]pyrazin-7-yl)-5- fluoropyridin-4-yl)amino)-4,4-dimethylpentanoate (11a)
A solution of 2-chloro-7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-5-trityl-5H- pyrrolo[2,3-b]pyrazine, 8a, (0.115 g, 0.220 mmol), racemic methyl 3-((2-bromo-5- fluoropyridin-4-yl)amino)-4,4-dimethylpentanoate, 10a, (0.061 g, 0.180 mmol) and K3PO4 (0.1 17 g, 0.549 mmol) in THF (3.3 mL) and water (660 μί) was purged with a stream of nitrogen for 15 minutes. Pd(PPh3)4 (0.011 g, 0.009 mmol) was added to the mixture and the vial was capped and heated to 120 °C for 30 minutes. The mixture was cooled and twice extracted with MTBE. The combined organics were dried over a2S04, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (0-100% EtOAc/Hexanes gradient) afforded 65 mg of the desired product (24 % yield) in sufficient purity for use in the next reaction: LCMS Gradient 10-90%, 0.1% formic acid, 5 min, C18/ACN, RT = 3.36 min (M+H) 648.34.
Formation of (+/-)-methyl 3-((2-(2-chloro-5H-pyrrolo[2,3-b]pyrazin-7-yl)-5- fluoropyridin-4-yl)amino)-4,4-dimethylpentanoate (Comp. 12)
To a stirred solution of methyl 3-[[2-(2-chloro-5-trityl-5H-pyrrolo[2,3-b]pyrazin-7- yl)-5-fluoro-4-pyridyl]amino]-4,4-dimethyl-pentanoate, 11a, (0.107 g, 0.165 mmol) in CH2CI2 (3.1 mL) at room temperature was added triethylsilane (0.805 mL, 5.040 mmol) followed by trifluoroacetic acid (1.2 mL, 15.0 mmol). The clear solution was stirred at room temperature for 90 minutes. After the reaction was complete, the mixture was poured into aqueous saturated aHC03 solution and extracted with CH2CI2. The organic phase was separated and concentrated in vacuo. The crude residue was purified by silica gel chromatography (S1O2, 0-10% MeOH/CH2Ci2 gradient) afforded 65 mg of the desired product (24 % yield) in sufficient purity for use in the next reaction: LCMS Gradient 10- 90%, 0.1% formic acid, 5 min, C18/ACN, RT = 1.95 min (M+H) 406.22.
Formation of (+/-)-3-((2-(2-chloro-5H-pyrrolo [2,3-b] pyrazin-7-yl)-5-fluoropyridin-4- yl)amino)-4,4-dimethylpentanoic acid (Comp. 3)
To a solution of methyl 3-[[2-(2-chloro-5H-pyrrolo[2,3-b]pyrazin-7-yl)-5-fluoro-4- pyridyl] amino] -4,4-dimethyl-pentanoate, 12, (0.022 g, 0.054 mmol) in THF (0.5 mL) was added LiOH (0.163 mL of 1.0 M, 0.163 mmol). After 45 minutes, the solution was cooled, and aqueous HC1 (2M) was added to neutralize the mixture. The reaction was concentrated in vacuo. Reverse phase preparative HPLC (10-90% acetonitrile-water, gradient elution, TFA modifier) afforded 8.8 mg of the desired product (30% yield) as the TFA salt: XH NMR (400 MHz, MeOD) 8.68 (s, 1H), 8.47 (s, 1H), 8.30 (d, J = 6.2 Hz, 1H), 8.23 (d, J = 7.5 Hz, 1H), 4.20 (t, J = 48.6 Hz, 1H), 2.80 (dt, J = 17.1, 12.8 Hz, 2H), 1.10 (s, 9H) ppm; LCMS Gradient 10-90%, 0.1% formic acid, 5 min, C18/ACN, RT = 2.24 min (M+H) 392.22.
Preparation of Compound 17a
Synthetic Scheme 3
(a) CHC13; (b) NaOMe, MeOH; (c) DPPA, Et3N, BnOH; (d) H2, Pd/C, THF, MeOH
Formation of meso-e«< 0-tetrahydro-4,7-ethanoisobenzofuran-l,3-dione (14a)
To a cold (0 °C) solution of maleic anhydride (210.0 g, 2142.0 mmol) in CHC13 (2.3 L) was added cyclohexa-l,3-diene (224.5 mL, 2356.0 mmol) slowly over 50 minutes. The reaction was warmed to room temperature and stirred overnight in the dark. After removing the solvent under reduced pressure, 2.1 L of MeOH was added to the mixture and the mixture was heated to 50 °C for 10 minutes and then cooled down to 0 °C. The resulting precipitate was filtered and dried in an oven at 45 °C overnight to afford 283 g of a white solid. The resulting endo (meso) Diels-Alder cycloaddition product was used without further purification.
Formation of (+/-)-ir««s-3-(methoxycarbonyl)bicyclo[2.2.2]oct-5-ene-2-carboxylic acid (15a)
A solution of meso-endo-tetrahydro-4,7-ethanoisobenzofuran-l,3-dione, 14a, (74.5 g, 418.1 mmol) was stirred in NaOMe (764.9 mL of 25 %w/w solution in MeOH, 3345.0 mmol). The reaction mixture was stirred at room temperature for 4 days yielding a white suspension. The reaction mixture was concentrated in vacuo to remove approximately 300 mL of MeOH. In another flask, HCl (315.9 mL of 36.5 %w/w, 3763.0 mmol) in 300 mL of water was cooled to 0 °C. Added reaction mixture into this HCl solution slowly, white solid precipitated. The remaining methanol was removed under reduced pressure. The mixture was cooled to 0 °C and stirred for 30 minutes. The precipitate was filtered, washed with water 3 times, giving an off-white solid. The remaining water was removed under reduced pressure to afford 82 g of a white solid.
Formation of (+/-)-ir««s-methyl 3-(((benzyloxy)carbonyl)amino)bicyclo[2.2.2]oct-5-ene- 2-carboxylate (16a)
Dissolved racemic ?ra«s-3-methoxycarbonylbicyclo[2.2.2]oct-5-ene-2-carboxylic acid, 15a, (100.0 g, 475.7 mmol) in toluene (1.0 L). Added diphenylphosphoryl azide (1 12.8 mL, 523.3 mmol) and triethylamine (72.9 mL, 523.3 mmol). Heated reaction mixture to 90 °C for 2 hours. Added benzyl alcohol (49.2 mL, 475.7 mmol) and heated to 90 °C over 3 days. The mixture was cooled to room temperature and diluted with EtOAc (500 mL) and aqueous saturated aHC03 solution. The organic phase was washed with brine, dried (MgS04), filtered and concentrated in vacuo. The resulting crude material was purified by silica gel chromatography with dichloromethane to afford 1 15 g oil. XH NMR show it contains BnOH (about 0.05 equiv). Product was used without further purification: XH NMR (300 MHz, CDCI3) δ 7.40 - 7.24 (m, 5H), 6.41 (t, J= 7.4 Hz, 1H), 6.21 - 6.04 (m, 1H), 5.15 - 4.94 (m, 2H), 4.63 - 4.45 (m, 1H), 4.30 - 4.18 (m, 1H), 3.70 (s, 2H), 3.49 (s, 1H), 2.81 (br s, 1H), 2.68 (br s, 1H), 2.08 (s, 1H), 1.76 - 1.56 (m, 1H), 1.52 - 1.35 (m, 1H), 1.33 - 1.14 (m, 1H), 1.12 - 0.87 (m, lH) ppm.
Formation of (+/-)-ir««s-methyl 3-aminobicyclo[2.2.2]octane-2-carboxylate (17a)
A solution of racemic trans-methyl 3-(((benzyloxy)carbonyl)amino)- bicyclo[2.2.2]oct-5-ene-2-carboxylate, 16a, (115.0 g, 364.7 mmol) in THF (253 mL) and MeOH (253 mL) was placed under 40 psi of hydrogen overnight. Some exotherm was observed. Filtered reaction mixture through celite, and washed with MeOH. Concentrated filtrate in vacuo to afford 69 g of the desired product as an oil: ¾ NMR (400 MHz, CDC13) δ 3.63 (d, J = 5.6 Hz, 3H), 3.30 (d, J = 6.7 Hz, 1H), 2.1 1 (d, J = 6.6 Hz, 1H), 1.91 (t, J = 7.3 Hz, 1H), 1.80 - 1.64 (m, 1H), 1.63 - 1.38 (m, 6H), 1.36 - 1.23 (m, 2H) ppm.
Preparation of Compounds 1, 2, 4 and 5
Synthetic Scheme 4
(a) 2-bromo-5-fluoro-4-iodopyridine, CS2CO3, Xantphos, Pd(OAc)2, 1,4-dioxane, 115 °C; (b) 2-chloro-7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-5-trityl-5H-pyrrolo[2,3-b]pyrazine (8a), K3PO4, THF, H20, Pd(PPh3)4, 120 °C; (c) Et3SiH, TFA, CH2C12; (d) LiOH, H20, THF.
Formation of (+/-)-ir««s-methyl 3-((2-bromo-5-fluoropyridin-4-yl)amino)bicyclo- [2.2.2] octane-2-carboxylate (18a)
To a solution of racemic-iraws-methyl 3-aminobicyclo[2.2.2]octane-2-carboxylate hydrochloride, 17a, (2.34 g, 12.75 mmol) in dichloromethane was added aqueous saturated aHC03 solution. The mixture was stirred at room temperature for 15 minutes. The organic phase was separated and washed with water and concentrated in vacuo.
Pd(OAc)2 (0.13 g, 0.58 mmol), Xantphos (0.40 g, 0.70 mmol), 2-bromo-5-fluoro-4- iodo-pyridine (3.50 g, 1 1.59 mmol), Cs2C03 (7.55 g, 23.18 mmol) were weighed into a schlenk tube. The flask was evacuated and flushed with nitrogen three times. Racemic- trans-methyl 3-aminobicyclo[2.2.2]octane-2-carboxylate (2.34 g, 12.75 mmol) in 1,4-dioxane (46 mL) was degassed under a stream of nitrogen for 15 minutes and this solution was added to the mixture of solids which was then evacuated and flushed with nitrogen three times again. The reaction mixture was heated to 115 °C for 15 minutes. The mixture was cooled to room temperature and flushed through a pad of celite. The filtrate was concentrated in vacuo and the crude residue was purified by silica gel chromatography (EtOAc/Hexanes gradient) to afford the desired product.
Formation of (+/-)-ir««s-methyl 3-((2-(2-chloro-5-trityl-5H-pyrrolo[2,3-b]pyrazin-7-yl)- 5-fluoropyridin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate (19a)
To a thoroughly degassed mixture of 2-chloro-7-(4,4,5,5-tetramethyl- 1,3,2- dioxaborolan-2-yl)-5-trityl-5H-pyrrolo[2,3-b]pyrazine, 8a, (0.150 g, 0.173 mmol) and racemic trans-methyl 3-((2-bromo-5-fluoropyridin-4-yl)amino)bicyclo[2.2.2]octane-2- carboxylate, 18a, (0.092 g, 0.259 mmol) and K3P04 (0.252 g, 1.189 mmol) in THF (8.5 mL) and water (1.7 mL) was added X-Phos (0.021 g, 0.043 mmol) followed by Pd2(dba)3 (0.010 g, 0.011 mmol). The mixture was degassed under a stream of nitrogen for a further 15 minutes. Then the vial was capped and the mixture was heated to 90 °C. After 2.5 hours, the mixture was cooled to room temperature. The layers were separated and the organic layer was concentrated in vacuo. The crude residue was purified by silica gel chromatography (0- 75 % EtOAc/Hexanes gradient) to afford 69 mg of the desired product: LCMS Gradient 10- 90%, 0.1% formic acid, 5 min, C18/ACN, RT = 3.55 min (M+H) 671.95.
Formation of (+/-)-ir««s-methyl 3-((2-(2-chloro-5H-pyrrolo[2,3-b]pyrazin-7-yl)-5- fluoropyridin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate (Comp. 1)
A stirred solution of racemic -trans-methyl 3-((2-(2-chloro-5-trityl-5H-pyrrolo[2,3- b]pyrazin-7-yl)-5-fluoropyridin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate, 19a, (0.069 g, 0.103 mmol) in (¾(¾ (2 mL) at room temperature was treated with triethylsilane (0.500 mL, 3.130 mmol) followed by trifluoroacetic acid (0.250 mL, 3.245 mmol). The mixture was stirred at room temperature overnight. The mixture was diluted with (¾(¾ and washed with aqueous saturated aHC03 solution. The aqueous layer was extracted with EtOAc and the combined organic phases were dried (Na2S04), filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (0-20% methanol/CH2Cl2 gradient) afforded the desired product: ¾ NMR (300 MHz, MeOD) δ 8.64 (s, 1H), 8.47 (s, 1H), 8.31 (d, J= 6.1 Hz, 1H), 8.13 (d, J= 7.8 Hz, 1H), 4.42 (d, J= 7.0 Hz, 1H), 3.71 (s, 2H), 2.98 (d, J = 7.0 Hz, 1H), 2.24 - 1.98 (m, 3H), 1.96 - 1.43 (m, 6H) ppm; LCMS Gradient 10-90%, 0.1% formic acid, 5 min, C18/ACN, RT = 2.57 min (M+H) 430.25.
Formation of (+/-)-ir««s-3-((2-(2-chloro-5H-pyrrolo[2,3-b]pyrazin-7-yl)-5-fluoropyridin-
4- yl)amino)bicyclo[2.2.2]octane-2-carboxylic acid (Comp. 2)
A solution of racemic trans-methyl -3-[[2-(2-chloro-5H-pyrrolo[2,3-b]pyrazin-7-yl)-
5- fluoro-4-pyridyl]amino]bicyclo[2.2.2]octane-2-carboxylate, 1, (0.035 g, 0.079 mmol) in THF (0.600 mL) and water was treated with NaOH (0.225 mL of 2M solution, 0.450 mmol). After stirring for 4h at room temperature, the mixture was concentrated in vacuo. The mixture was poured into aqueous HC1 and the resulting desired product was collected by filtration to afford 16 mg of desired product (48% yield): XH NMR (400 MHz, ί/6-DMSO) δ 13.98 (s, 1H), 13.36 (s, 1H), 12.39 (s, 1H), 9.04 (s, 1H), 8.64 - 8.54 (m, 2H), 8.54 - 8.40 (m, 1H), 8.09 (d, J = 7.9 Hz, 1H), 4.31 - 4.12 (m, lH), 3.04 (d, J = 5.8 Hz, 1H), 2.07 (br s, 1H), 2.05 - 1.95 (m, 1H), 1.93 (br s, 1H), 1.83 - 1.59 (m, 3H), 1.59 - 1.33 (m, 4H) ppm; LCMS Gradient 10-90%, 0.1% formic acid, 5 min, C18/ACN, RT = 2.36 min (M+H) 416.04.
A chiral separation of Compound 1 (racemic mixture) provided the corresponding enantiopure esters which were then individually hydrolyzed according to the procedure for Compound 2 to afford Compounds 4 and 5.
Preparation of Compound 28a Synthetic Scheme 5
(a) LDA, Mel, THF; (b) LiAlH4, ether; (c) PCC, CH2C12; (d) 2-(triphenylphosphoran- ylidene)acetate, CH2C12; (e) N-benzylhydroxylamine-HCl, CH2C12; (f) H2, Pd/C, MeOH; (g) AcCl, MeOH, reflux; (h) 2-bromo-5-fluoro-4-iodopyridine, Cs2C03, Xantphos, Pd(OAc)2, 1,4-dioxane, 1 15 °C
Formation of ethyl 1-methylcyclobutanecarboxylate (22a)
A solution of ethyl cyclobutanecarboxylate (20.0 g, 156.0 mmol) in THF (160 mL) was added dropwise to a cold (-78 °C) solution of LDA (164 mmol of 2M solution) in THF (40 mL). The solution was warmed to 0 °C and then cooled again to -40 °C before the addition of iodomethane (10.2 mL, 163.8 mmol). The solution was slowly warmed to room temperature and stirred overnight. The reaction was quenched with an aqueous saturated solution of ammonium chloride and ether was added. The layers were separated and the aqueous layer was washed with ether. The combined organic layers were washed with IN HC1 then dried over MgS04. The product was purified by distillation: XH NMR (400 MHz, MeOD) δ 4.20 - 4.05 (m, 2H), 2.57 - 2.33 (m, 2H), 2.08 - 1.94 (m, 1H), 1.94 - 1.77 (m, 3H), 1.40 (s, 3H), 1.27 (tt, J= 7.1, 1.5 Hz, 3H) ppm.
Formation of (l-methylcyclobutyl)methanol (23a)
Lithium aluminum hydride (2.1 g, 59.4 mmol) was suspended in ether (150 mL) and cooled to 0 °C. A solution of ethyl 1-methylcyclobutanecarboxylate, 22a, (13.0 g, 91.4 mmol) in ether (60 mL) was added dropwise to the LiAlH4 suspension. The mixture was stirred 2 hours in an ice bath then quenched slowly with IN HC1. The layers were separated and the aqueous layer was washed with ether. The combined organic layers were washed with brine and the volatiles were removed with a gentle stream of nitrogen to afford the desired product that was used without further purification: XH NMR (400 MHz, CDCI3) δ 3.54 - 3.39 (m, 4H), 1.99 - 1.74 (m, 8H), 1.74 - 1.62 (m, 4H), 1.46 - 1.18 (m, 3H), 1.13 (d, J = 1.7 Hz, 6H) ppm.
Formation of 1-methylcyclobutanecarbaldehyde (24a) and methyl 3-(l- methylcyclobutyl)acrylate (25a)
A solution of (l-methylcyclobutyl)methanol, 23a, (1.00 g, 9.98 mmol) in dichloromethane (25 mL) was added to a suspension of PCC (2.69 g, 12.50 mmol) and Celite (2.70 g) in dichloromethane (25 mL). The reaction mixture was stirred 2 hours and filtered through a pad of silica gel (eluting with dichloromethane). The solvents were removed with a stream of nitrogen until volume was approximately 20 mL. 2-(triphenyl- phosphoranylidene)acetate (0.98 g, 10.00 mmol) was added in one portion and the mixture was stirred for 7 hours. The volatiles were removed under reduced pressure and a solution of 10% Hexanes/ether was added. The resulting solid was filtered off and discarded. The resulting solution was poured directly on silica gel and eluted with EtOAc/Hexanes to afford the desired product: XH NMR (400 MHz, CDC13) δ 7.05 (d, J = 15.8 Hz, 1H), 5.66 (dd, J = 15.8, 1.3 Hz, 1H), 4.21 - 4.00 (m, 2H), 2.12 - 1.73 (m, 7H), 1.29 - 1.17 (m, 6H) ppm.
Formation (+/-)-2-benzyl-3-(l-methylcyclobutyl)isoxazolidin-5-one (26a)
N-benzylhydroxylamine (hydrochloric acid) (0.28 g, 1.80 mmol) and triethylamine (0.28 mL, 2.00 mmol) were added to a solution of methyl 3-(l-methylcyclobutyl)acrylate, 25a, (0.26 g, 1.50 mmol) in dichloromethane (9.5 mL). The reaction mixture was stirred at 50 °C overnight. The reaction mixture was cooled to room temperature and the mixture was diluted with dichloromethane and water. The layers were separated with a phase separator and the aqueous layer was washed with dichloromethane. The organic layers were combined and the volatiles removed under reduced pressure. The residue was purified on silica gel (EtOAc/Hexanes) to afford the desired product as a racemic mixture: LCMS Gradient 10- 90%, 0.1% formic acid, 5 minutes, C18/ACN, RT = 1.47 minutes (M+H) 246.10.
Formation of (+/-)-3-amino-3-(l-methylcyclobutyl)propanoic acid (27a)
A solution of racemic 2-benzyl-3-(l-methylcyclobutyl)isoxazolidin-5-one, 26a, (0.18 g, 1.28 mmol) in MeOH (2.9 mL) was shaken overnight under 50 psi hydrogen in the presence of 50 mg palladium hydroxide catalyst. The mixture was filtered through Celite and the volatiles were removed under reduced pressure to afford the desired product that was used without further purification: XH NMR (400 MHz, MeOD) δ 3.42 (dd, J = 11.0, 1.9 Hz, 1H), 2.26 (ddd, J = 27.8, 16.7, 6.5 Hz, 2H), 1.86 (dddd, J = 36.9, 26.3, 11.2, 7.6 Hz, 6H), 1.18 (s, 3H) ppm.
Formation of (+/-)-methyl 3-((2-chloro-5-fluoropyrimidin-4-yl)amino)-3-(l- methylcyclobutyl)propanoate (28a)
Racemic 3-amino-3-(l-methylcyclobutyl)propanoic acid, 27a, (2.3 g, 14.4 mmol) was dissolved in methanol (104 mL). The solution was cooled in an ice bath and acetyl chloride (5.6 g, 71.9 mmol) was added dropwise (Temp kept <10 °C). The reaction mixture was heated to 65 °C and stirred at that temperature for 3 hours. The reaction mixture was cooled to room temperature and then flushed with toluene to remove volatiles. Crude racemic 3- methoxy-l-(l-methylcyclobutyl)-3-oxopropan-l-aminium chloride, 28a, was used without further purification.
Preparation of Compounds 8 and 9
Compound 8 and 9 were prepared in a similar fashion as that for Compound 3 described above.
(+/-)-3-((2-(2-chloro-5H-pyrrolo[2,3-b]pyrazin-7-yl)-5-fluoropyridin-4-yl)amino)-3-(l- methylcyclobutyl)propanoic acid (Comp. 9)
'H NMR (400 MHz, MeOD) δ 8.46 (s, 1H), 8.29 (s, 1H), 8.27 (d, J = 7.8 Hz, 1H), 8.01 (d, 1H), 4.37 (dd, J = 9.1, 4.1 Hz, 1H), 2.62 - 2.47 (m, 2H), 2.28 (dd, J = 19.7, 9.1 Hz, 1H), 2.12 (dd, J = 18.7, 9.0 Hz, 1H), 2.07 - 1.93 (m, 2H), 1.82 - 1.70 (m, 1H), 1.70 - 1.55 (m, 1H), 1.31 (s, 3H) ppm; LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, RT = 2.31 minutes (M+H) 404.23
Preparation of Compound 35a
Synthetic Scheme 6
32a 33 35a
a
(a) DPPA, Et3N, toluene, 110 °C; ii BnOH, 85 °C (b) LiOH, THF: H20; (c) Boc20, pyridine, NH4HCO3, dioxane; (d) BTIB, CH3CN:H20; (e) Boc20, K2C03, THF; (f) H2, 10% Pd/C, MeOH.
Formation of (IS, 3 ?)-3-(ethoxycarbonyl)cyclohexanecarboxylic acid
(IS, 3R)-3-(ethoxycarbonyl)cyclohexanecarboxylic acid starting material can be prepared following the literature procedures described in : Barnett, C. J., Gu, R. L., Kobierski, M. E., WO-2002024705, Stereoselective process for preparing cyclohexyl amine derivatives.
Formation of ethyl (1R, 3S)-3-benzyloxycarbonylaminocyclohexanecarboxylate (30a)
(IS, 3R)-3-(Ethoxycarbonyl)cyclohexanecarboxylic acid (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 the product (15.3 g, containing -25% benzyl alcohol), which was used for the next step without further purification.
Formation of (l ?,3S)-3-(((benzyloxy)carbonyl)amino)cyclohexanecarboxylic acid (31a)
Ethyl (1R, 35)-3-benzyloxycarbonylaminocyclohexanecarboxylate, 30a, (36.0 g, 1 17.9 mmol) was dissolved in THF (144.0 mL) and treated with a solution of LiOH (5.7 g, 235.8 mmol) in water (216.0 mL). After stirring overnight, the reaction mixture was diluted with water (100 mL), washed with methyl tert-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 tert-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 of desired product: 1H NMR (300 MHz, CDC13) δ 7.38 - 7.33 (m, 5H), 5.1 1 (s, 2H), 4.68 (s, 1H), 3.55 (s, 1H), 2.44 (d, J = 11.0 Hz, 1H), 2.32 (d, J = 1 1.7 Hz, 1H), 2.03 - 1.86 (m, 3H) and 1.48 - 0.88 (m, 4H) ppm.
Formation of benzyl TV- [(IS, 3 ?)-3-carbamoylcyclohexyl]carbamate (32a)
To a solution of (1R, 35)-3-Benzyloxycarbonylaminocyclohexanecarboxylic acid, 31a, (10.0 g, 36.1 mmol) in 1,4-dioxane (300 mL) was added pyridine (2.9 mL, 36.1 mmol), followed by di-tert-butyl dicarbonate (10.7 mL, 46.9 mmol) and ammonium bicarbonate (10.1 g, 126.2 mmol). After 3 hours, another portion of di-tert-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 N-[(1«S, 3R)-3-carbamoylcyclohexyl]carbamate (9.1 g, 91%) as a white solid: XH 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, J =12.7, 1H), 2.05 - 1.78 (m, 8H), 1.54 - 0.97 (m, 5H) ppm.
Formation of benzyl TV- [(IS, 3/?)-3-aminocyclohexyl] carbamate (33a)
Benzyl N-[(1«S, 3R)-3-carbamoylcyclohexyl]carbamate, 32a, (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 Na2S04 and concentrated in vacuo to provide 6.2 g of the desired product: XH NMR (300 MHz, CDCI3) 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) ppm.
Formation of benzyl teri-butyl (1R, 3S)-cyclohexane-l,3-diyldicarbamate (34a)
To a solution of benzyl N-[(1«S, 3R)-3-aminocyclohexyl]carbamate, 33a, (2.04 g, 8.22 mmol) in THF (20 mL) was added potassium carbonate (3.41 g, 24.64 mmol) followed by di- tert-butyldicarbonate (1.97 g, 9.04 mmol). The reaction mixture was stirred overnight at room temperature. The solids were filtered and the filtrate was concentrated in vacuo. The crude residue was purified by silica gel chromatography (10%-25% EtOAc/hexanes) to afford the desired Boc-protected intermediate.
Formation of tert-butyl ((1R, 3S)-3-aminocyclohexyl)carbamate (35a)
To a solution benzyl tert-butyl (1R, 3,S)-cyclohexane-l,3-diyldicarbamate, 34a,
(168.0 g, 0.5 mol) in MeOH (2 L) was added 10% Pd/C (24 g). After flushing with nitrogen, the mixture was stirred under 1 bar hydrogen pressure. Conversion had reached 80% overnight according to NMR. After an additional 48 h the conversion was complete. The mixture was filtered through Celite and the filter cake was washed with MeOH. Concentration of the filtrate gave the final product (103 g) that was used without further purification.
Preparation of Compound 7
Synthetic Scheme 7
(a) 2-bromo-5-fluoro-4-iodopyridine, CS2CO3, Xantphos, Pd(OAc)2, 1,4-dioxane, 115 °C; (b) 2-chloro-7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-5-trityl-5H-pyrrolo[2,3-b]pyrazine (8a), K3PO4, THF, H20, Pd(PPh3)4, 120 °C; (c) Et3SiH, TFA, CH2C12; (d) thiophene-3- carbonyl chloride, DMAP, N,N-diisopropylethylamine, THF, DMF.
Formation of tert-butyl ((l ?,35)-3-((2-bromo-5-fluoropyridin-4- yl)amino)cyclohexyl)carbamate (36a)
Pd(OAc)2 (0.019 g, 0.083 mmol), Xantphos (0.057 g, 0.099 mmol), 2-bromo-5- fluoro-4-iodo-pyridine (0.500 g, 1.656 mmol), Cs2C03 (1.079 g, 3.312 mmol) were weighed into a schlenk tube. The flask was evacuated and flushed with nitrogen three times, tert- Butyl ((1R, 35)-3-aminocyclohexyl)carbamate, 35a, (0.390 g, 1.822 mmol) in 1,4-dioxane (6.6 mL) was degassed under a stream of nitrogen for 15 minutes and this solution was added to the mixture of solids which was then evacuated and flushed with nitrogen three times again. The reaction mixture was heated to 115 °C for 60 minutes. The mixture was cooled to room temperature and flushed through a pad of celite. The filtrate was concentrated in vacuo and the crude residue was purified by silica gel chromatography (EtOAc/Hexanes gradient) to afford the desired product: LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, RT = 3.15 minutes (M+H) 388.20.
Formation of tert-butyl ((l ?,3S)-3-((2-(2-chloro-5-trityl-5H-pyrrolo[2,3-b]pyrazin-7-yl)- 5-fluoropyridin-4-yl)amino)cyclohexyl)carbamate (37a) A mixture of 2-chloro-7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-5-trityl- pyrrolo[2,3-b]pyrazine, 8a, (0.526 g, 1.008 mmol), tert-butyl ((lR^^-S-^-bromo-S- fluoropyridin-4-yl)amino)cyclohexyl)carbamate, 36a, (0.300 g, 0.840 mmol) and K3PO4 (0.535 g, 2.519 mmol) dissolved in THF/water (8.17 mL of 5: 1 mixture THF/water) was degassed under a stream of nitrogen for 15 minutes. To the mixture was added Pd(PPh3)4 (0.049 g, 0.042 mmol). The reaction mixture was sealed and heated in a microwave reactor at 120 °C for 30 minutes. The reaction was deemed incomplete by LCMS analysis. The mixture was again degassed under nitrogen and an additional 200 mg of boranate ester, 8a, was added along with another 5% Pd-catalyst. The reaction was heated in a microwave reactor at 120 °C for 45 minutes. After cooling to room temperature, the mixture was diluted with 2 volumes of dichloromethane and 1 volume of water. The aqueous phase was extracted with additional dichloromethane. The combined organic phases were concentrated in vacuo. The crude residue was purified by silica gel chromatography (EtOAc/hexanes) to afford the desired product which still contained slight impurities, but deemed pure enough to carry on to the next reaction.
Formation of (lS,3 ?)-7Vl-(2-(2-chloro-5H-pyrrolo[2,3-b]pyrazin-7-yl)-5-fluoropyridin-4- yl)cyclohexane-l,3-diamine (38a)
To a stirred solution of tert-butyl ((lR,35)-3-((2-(2-chloro-5-trityl-5H-pyrrolo[2,3- b]pyrazin-7-yl)-5-fluoropyridin-4-yl)amino)cyclohexyl)carbamate, 37a, (0.39 g, 0.55 mmol) in dichloromethane (5 mL) at room temperature was added triethylsilane (0.22 mL, 1.38 mmol) followed by trifluoroacetic acid (5.00 mL). The clear solution was stirred at room temperature for 6h. The volaties were removed. The residue was flushed with acetonitrile and then with THF. The desired product was precipitated from Et20 (triturate with Et20 repeatedly): LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, RT = 1.25 minutes (M+H) 361.22.
Formation of TV-CCl^SS -CC -C -chloro-SH- rroloI ^-bl razin^- l^S- fluoropyridin-4-yl)amino)cyclohexyl)thiophene-3-carboxamide (Comp. 7)
To a stirred solution of (lS,3R)-Nl-(2-(2-chloro-5H-pyrrolo[2,3-b]pyrazin-7-yl)-5- fluoropyridin-4-yl)cyclohexane-l,3-diamine TFA salt, 38a, (0.030 g, 0.051 mmol) in THF (0.8 mL) at room temperature was added N,N-diisopropylethylamine (0.050 mL, 0.287 mmol) followed by DMF (0.2 mL) and DMAP (0.006g, 0.005 mmol). Once the solid was fully in solution, thiophene-3-carbonyl chloride (0.009 g, 0.062 mmol) was added. Monitoring of the reaction by LC-MS showed both mono and bis-acylation products. The mixture was quenched with 2Ν NaOH and stirred for 5 min to cleave any of the indole- thiophene amide side-product. The mixture was diluted with EtOAc and neutralized with 2N HC1, separated and extracted three times with EtOAc. The combined organic phases were dried (Na2S04), filtered and concentrated in vacuo. Reverse phase preparative HPLC (10- 90% acetonitrile-water, gradient elution, TFA modifier) afforded 31 mg of the desired product: ¾ NMR (400 MHz, MeOD) δ 8.77 (s, 1H), 8.47 (s, 1H), 8.31 (d, J = 5.9 Hz, 1H), 8.30 - 8.24 (m, 1H), 8.05 (d, J = 1.7 Hz, 1H), 7.95 (d, J = 7.8 Hz, 1H), 7.50 (d, J = 5.1 Hz, 1H), 7.48 - 7.42 (m, 1H), 4.19 - 4.02 (m, 1H), 4.00 - 3.84 (m, 1H), 2.47 - 2.36 (m, 1H), 2.22 - 2.12 (m, 1H), 2.11 - 1.96 (m, 2H), 1.76 - 1.37 (m, 4H) ppm; LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, RT = 2.22 minutes (M+H) 471.18.
Preparation of Compound 6
Synthetic Scheme 8
(a) pyrrolidine- 1-carbonyl chloride, pyridine, DMF.
Formation of 3-((Lff ,3S)-3-((2-(2-chloro-5H-pyrrolo [2,3-b] pyrazin-7-yl)-5-fluoropyridin- 4-yl)amino)cyclohexyl)-pyrrolidine urea (Comp. 6)
To a stirred solution of (lS,3R)-Nl-(2-(2-chloro-5H-pyrrolo[2,3-b]pyrazin-7-yl)-5- fluoropyridin-4-yl)cyclohexane-l,3-diamine TFA salt, 38a, (0.039 g, 0.066 mmol) in DMF (0.5 mL) was added pyridine (0.027 mL, 0.331 mmol) followed by pyrrolidine- 1-carbonyl chloride (0.008 mL, 0.073 mmol). Monitoring of the reaction by LC-MS showed the reaction was incomplete after 2 hours. The mixture was heated at 60 °C overnight. Added additional pyridine and pyrrolidine- 1-carbonyl chloride (0.8 equiv) and raised the temperature to 80 °C and maintained at this temperature overnight. Reverse phase preparative HPLC (10-90% acetonitrile-water, gradient elution, TFA modifier) afforded 38 mg of the desired product: XH NMR (400 MHz, MeOD) δ 9.30 (s, 1H), 8.73 (s, 2H), 8.49 (s, 2H), 8.33 (d, J = 6.1 Hz, 2H), 7.98 (d, J = 7.6 Hz, 2H), 4.09 - 3.97 (m, 2H), 3.97 - 3.84 (m, 2H), 2.36 (d, J = 1 1.7 Hz, 2H), 2.18 (d, J = 12.8 Hz, 2H), 2.08 - 1.94 (m, 3H), 1.76 - 1.55 (m, 3H), 1.55 - 1.33 (m, 3H) ppm; LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, RT = 2.25 minutes (M+H) 457.19.
(a) 2,4-dichloro-5-fluoropyrimidine, N,N-diisopropylethylamine, DMF; (b) 2-chloro-7- (4,4,5,5 -tetramethy 1- 1 , 3 ,2 -dioxaborolan-2 -y l)-5 -trity l-5H-pyrrolo [2 , 3 -b]pyrazine (8a), K3PO4, THF, H20, Pd(PPh3)4, 120 °C; (c) Et3SiH, TFA, CH2C12; (d) thiophene-3-carbonyl chloride, DMAP, 'P^ Et, THF, DMF.
Formation of (2S,3S)-methyl 3-((2-chloro-5-fluoropyrimidin-4-yl)amino)bicyclo- [2.2.2]octane-2-carboxylate (41a) To a solution of (25,,35')-methyl 3-aminobicyclo[2.2.2]octane-2-carboxylate, 17a, (1.30 g, 7.09 mmol) and 2,4-dichloro-5-fluoro-pyrimidine (1.77 g, 10.64 mmol) in DMF (20 mL) was added N,N-diisopropylethylamine (4.94 mL, 28.38 mmol). The reaction mixture was stirred at room temperature for 100 minutes. The mixture was diluted into aqueous saturated NH4C1 solution and extracted twice with EtOAc. The combined organic phases were washed three times with brine, dried (MgS04), filtered and concentrated in vacuo. The crude residue was purified via silica gel chromatography (0-10% MeOH/CH2Cl2 gradient) to afford 1.41 g of the desired product: LC/MS Gradient 10-90%, 0.1% formic 5 minutes, C18/AC RT = 1.14 min (M+H) 314.1 1.
Formation of (2S,3S)-methyl 3-((2-(2-chloro-5-trityl-5H-pyrrolo[2,3-b]pyrazin-7-yl)-5- fluoropyrimidin-4-yl)amino)bicyclo [2.2.2] octane-2-carboxylate (42a)
A mixture of 2-chloro-7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-5-trityl-5H- pyrrolo[2,3-b]pyrazine, 8a, (0.101 g, 0.1 16 mmol) and methyl (25,,35)-3-[(2-chloro-5-fluoro- pyrimidin-4-yl)amino]bicyclo[2.2.2]octane-2-carboxylate, 41a, (0.044 g, 0.139 mmol) with K3PO4 (0.099 g, 0.464 mmol) in tetrahydrofuran (3 mL) and water (0.5 mL) was degassed under a stream of nitrogen for 15 minutes. X-Phos (0.005 g, 0.012 mmol) and Pd2(dba)3 (0.003 g, 0.003 mmol) was added and the mixture was degassed under nitrogen again. The vial was capped and heated to 100 °C for 25 minutes. The layers were separated and the aqueous phase was extracted with 2-MeTHF. The combined organic phases were dried (Na2S04), filtered and concentrated in vacuo. The crude residue was taken onto the next step without further purification.
Formation of (2S,3S)-methyl 3-((2-(2-chloro-5H-pyrrolo[2,3-b]pyrazin-7-yl)-5- fluoropyrimidin-4-yl)amino)bicyclo [2.2.2] octane-2-carboxylate (Comp. 10)
To a solution of crude (25,,35')-methyl 3-((2-(2-chloro-5-trityl-5H-pyrrolo[2,3- b]pyrazin-7-yl)-5-fluoropyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate, 42a, (100 mg) in dichloromethane was added triethylsilane (0.5 mL, 3.1 mmol) followed by
trifluoroacetic acid (0.5 mL, 6.5 mmol). The mixture was stirred at room temperature. After 4.5h, the mixture was concentrated in vacuo. The residue was diluted with DMSO (lmL) and rinsed with 3 x 2mL hexanes to remove Et3SiH. Reverse phase preparative HPLC (10- 90% acetonitrile-water, gradient elution, TFA modifier) afforded 16 mg of the desired product which was sufficiently pure to take onto the next step: LC/MS Gradient 10-90%, 0.1% formic 5 minutes, C18/ACN RT = 2.37 min (M+H) 431.05.
Formation of (2S,35)-3-((2-(2-chloro-5H-pyrrolo[2,3-b]pyrazin-7-yl)-5-fluoro- pyrimidin-4-yl)amino)bicyclo [2.2.2] octane-2-carboxylic acid (Comp. 11)
To a solution of (25,,35')-methyl 3-((2-(2-chloro-5H-pyrrolo[2,3-b]pyrazin-7-yl)-5- fluoropyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate trifluoroacetic acid, 10, (0.016 g, 0.029 mmol) in THF (0.3 mL) a n d MeOH (0.1 mL) was added NaOH (0.058 mL of 2 M solution, 0.117 mmol). The solution was stirred at room temperature. After 1 hour, the temperature was increased to 55 °C. After 4 hours, the mixture was diluted with THF and concentrated in vacuo. The mixture was again diluted with THF, neutralized with HC1 (2N) and concentrated in vacuo. Reverse phase preparative HPLC (10-90% acetonitrile-water, gradient elution, TFA modifier) afforded 16 mg of the desired product which was sufficiently pure to take onto the next step: XH NMR (400 MHz, MeOD) δ 8.85 (s, 1H), 8.52 (s, 1H), 8.35 (d, J = 5.6 Hz, 1H), 4.95 - 4.93 (m, 1H), 2.82 (d, J = 6.1 Hz, 1H), 2.19 - 2.09 (m, 1H), 2.04 - 1.97 (m, 1H), 1.97 - 1.79 (m, 3H), 1.79 - 1.65 (m, 3H), 1.64 - 1.49 (m, 2H) ppm; LC/MS Gradient 10-90%, 0.1% formic 5 minutes, C18/ACN RT = 2.19 min (M+H) 417.0. Example 2: Influenza Antiviral Assay
[00266] Antiviral assays were performed using two cell-based methods:
A 384-well microtiter plate modification of the standard cytopathic effect (CPE) assay method was developed, similar to that of Noah, et al. (Antiviral Res. 73:50-60, 2006).
Briefly, MDCK cells were incubated with test compounds and influenza A virus (A/PR/8/34), at a low multiplicity of infection (approximate MOI=0.005), for 72 hours at 37°C, and cell viability was measured using ATP detection (CellTiter Glo, Promega Inc.). Control wells containing cells and virus show cell death while wells containing cells, virus, and active antiviral compounds show cell survival (cell protection). Different 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 of virus-specific RNA molecules in the infected cells, with RNA levels being directly measured using the branched-chain DNA (bDNA), hybridization method (Wagaman et al, J. Virol Meth, 105: 105-114, 2002). In this assay, cells are initially infected in wells of a 96- well microtiter plate, the virus is allowed to replicate in the infected cells and spread to additional rounds of cells, then the cells are lysed and viral RNA 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 EC50.
Virus and Cell culture methods: Madin-Darby Canine Kidney cells (CCL-34
American Type Culture Collection) were maintained in Dulbecco's Modified 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 lug/ml TPCK-treated trypsin, without fetal bovine serum. Assays were initiated with the addition of 30 TCID50 of virus and test compound, in medium containing 1 μg/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 serum as above, but on the day of the assay they were trypsinized, washed 2 times and suspended in serum-free EX-Cell MDCK cell medium (SAFC Biosciences, Lenexa, KS) and plated into wells at 20,000 cells per well. These wells were then used for assay after 5 hours of incubation, without the need for washing.
Influenza virus, strain A/PR/8/34 (tissue culture adapted) was obtained from ATCC
(VR-1469). Low-passage virus stocks were prepared in MDCK cells using standard 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 IC50 values (mean all) for certain specific compounds are summarized in Table 1. A: IC50 (mean all) < 0.3 μΜ;
B 0.3 μΜ < IC50 (mean all) < 3.3 μΜ;
C IC50 (mean all) > 3.3 μΜ.
Mean EC50 values (mean all) for certain compounds are also summarized in Table 1 :
A: EC50 (mean all) < 0.3 μΜ;
B 0.3 μΜ < EC50 (mean all) < 3.3μΜ;
C EC50 (mean all) > 3.3 μΜ.
For example, ICso and EC50 values of Compound 6 were 0.01 μΜ and 0.009 μΜ.
[00267] Table 1 : IC50, EC50, NMR and LCMS Data of Compounds of Invention.
1H NMR(300 MHz,
MeOD) δ 8.64 (s, 1H), 8.47 (s, 1H), 8.31 (d, J = 6.1 Hz, 1H), 8.13 (d, J =
A 2.57 430.25 7.8 Hz, 1H), 4.42 (d, J =
7.0 Hz, 1H), 3.71 (s, 2H), 2.98 (d, J = 7.0 Hz, 1H), ij j 2.24- 1.98 (m, 3H), 1.96- 1.43 (m, 6H). H"""I,:"'
1H NMR(400 MHz, c/6- DMSO)513.98 (s, 1H), 13.36 (s, 1H), 12.39 (s, 1H), 9.04 (s, 1H), 8.64- 8.54 (m, 2H), 8.54-8.40 (m, 1H), 8.09 (d, J = 7.9
A 2.36 416.04
Hz, 1H), 4.31 -4.12(m, 1H), 3.04 (d, J = 5.8 Hz, ..Ct ■--, - Ci 1H), 2.07 (brs, 1H), 2.05- 1.95 (m, 1H), 1.93 (brs, 1H), 1.83- 1.59 (m, 3H), 1.59- 1.33 (m, 4H).
\ *
A 2.24 392.2
\ -H .a
O' ':r
[00268] 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.
[00269] 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

What is claimed is:
1. A compound represented by Structural Formula (I) or a pharmaceutically acceptable salt thereof:
wherein:
X1 is -CI, -CN, -CF3, or -CH3;
X2 is -H, -F, or -CI;
Ring T is a C3-C10 carbocyclic group optionally further substituted with one or more
JT-
Z1 and Z2 are each independently CH or N; and
Q1 is -C(O)-, -C(0)0-, -OC(O)-, -0-, -C(0)NR'-, NRC(O)-, -NRC(0)NR'-, -OC(0)NR'-,-S(0)-, -S(0)2-, -S02NR'-, -NRS02- -NRS02NR'-, -P(0)(OR)0-,
-OP(0)(ORa)0-, or a bond; or
optionally -Q^R2, together with the carbon atom of Ring T to which -Qx-R2 is attached, forms a 4-10 membered, non-aromatic, spiro ring optionally substituted with one or more instances of JR; and
Q2 is -CH2-[C(R7R8)]n-;
i) when Q1 is other than a bond, R2 is -H, a C1-C6 aliphatic group optionally substituted with one or more JA, a C3-C8 carbocyclic group optionally substituted with one or more JB, or a 4-10 membered heterocyclic group optionally substituted with one or more Jc, or optionally R2, together with R' and the nitrogen atom of Q1 to which they are attached, forms a 4-8 membered heterocyclic group optionally substituted with one or more instances of JR; or
ii) when Q1 is a bond, R2 is a C1-C6 aliphatic group substituted with one or more M, a 5-7 membered heterocyclic group optionally substituted with one or more J2, or a 5-6 membered heteroaryl group optionally substituted with one or more J3; and R3 is -C(0)OR, -S(0)R9, -S(0)2R9, -S(0)2NRR10, -OR, -P(0)(OR)2, or -CH2OR;
R4, R5, and R6 are each and independently -CH3, -CH2F, -CF3, -C2H5, -CH2CH2F, or -CH2CF3; or optionally R5 and R6, or R4, R5 and R6, together with the carbon atom to which they are attached, form a C3-C10 carbocyclic ring;
R7 and R8 are each and independently -H, -OH, -CH3, or -CF3; or optionally, R7 and R8 together with the carbon atoms to which they are attached form a cyclopropane ring; each R9 is independently -OR or C1-C6 alkyl optionally substituted with one or more instances of J1;
R10 is -H or C1-C6 alkyl optionally substituted with one or more instances of J1;
R and R' are each independently -H or C1-C6 alkyl optionally substituted with one or more instances of J1, or optionally R and R', together with the nitrogen to which they are attached, form a 4-8 membered heterocyclic group optionally substituted with one or more instances of JR;
JT is selected from the group consisting of halogen, cyano, oxo, hydroxy, -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 alkyl, Ci-C4 haloalkyl, C3-C6 cycloalkyl, and -0(Ci-C4 alkyl);
JA is selected from the group consisting of halogen, cyano, oxo, Rd, or M;
JB and Jc are each and independently selected from the group consisting of halogen, cyano, oxo, M, -Ra, and -Ra-M; or
optionally, two JT, two JA, two JB, and two Jc, 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 JR; and
each M is independently selected from the group consisting of -ORb, -SRb, -S(0)Ra, -S02Ra, -NRbRc, -C(0)Ra, -C(=NR)RC, -C(=NR)NRbRc, -NRC(=NR)NRbRc, -C(0)ORb, -OC(0)Rb, -NRC(0)Rb, -C(0)NRbRc, -NRC(0)NRbRc, -NRC(0)ORb, -OCONRbRc, -C(0)NRC02Rb, -NRC(0)NRC(0)ORb, -C(0)NR(ORb), -OS02NRbRc, -S02NRcRb, -NRS02Rb, -NRS02NRbRc, -P(0)(ORb)2, -OP(0)(ORb)2, -P(0)2ORb and -C02S02Rb;
each Ra is independently:
i) a C1-C6 aliphatic group optionally substituted with one or more substituents 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), -0(Ci-C4 alkyl), C3-Cs carbocyclic group optionally substituted with one or more instances of J2, 4-8 membered heterocyclic group optionally substituted with one or more instances of J2, 5-6 membered heteroaryl group optionally substituted with one or more instances of J3, and phenyl optionally substituted with one or more instances of J3;
ii) a C3-C8 carbocyclic group or 4-8 membered heterocyclic group, each of which is optionally and independently substituted with one or more instances of J2; or
iii) a 5-6 membered heteroaryl group or phenyl, each of which is optionally and
independently substituted with one or more instances of J3; 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 4-8 membered heterocyclic group optionally substituted with one or more instances of JR;
Rd is C3-C8 carbocyclic group optionally substituted with one or more instances of J2, 4-8 membered heterocyclic group optionally substituted with one or more instances of J2, 5-6 membered heteroaryl group optionally substituted with one or more instances of J3, or phenyl optionally substituted with one or more instances of J3;
each J1 is 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), -0(Ci-C4 alkyl), and phenyl;
each J2 is 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 alkyl, Ci-C4 haloalkyl, and -0(Ci-C4 alkyl);
each of J3 and JR is independently selected from the group consisting of halogen, cyano, hydroxy, -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 alkyl, Ci-C4 haloalkyl, and -0(Ci-C4 alkyl); and n is independently 0 or 1.
2. The compound of claim 1, wherein X1 is -CI or -CF3.
3. The compound of claim 1 or 2, wherein X2 is-F or -CI.
4. The compound of any one of claims 1-3, wherein M is independently selected from the group consisting of -ORb, -SRb, -S(0)Ra, -S02Ra, -NRbRc, -C(0)Ra, -C(0)ORb, -OC(0)Rb, -NRC(0)Rb, -C(0)NRbRc, -NRC(0)NRbRc, -NRC(0)ORb, -OCONRbRc, -C(0)NRC02Rb,
-NRC(0)NRC(0)ORb, -OS02NRbRc, -S02NRcRb, -NRS02Rb, and -NRS02NRbRc.
5. The compound of any one of claims 1 -4, wherein:
JT is selected from the group consisting of halogen, cyano, hydroxy, -NH2, -NH(C1-C4 alkyl), -N(d-C4 alkyl)2, -OCO(Ci-C4 alkyl), -CO(Ci-C4 alkyl), -C02H, -C02(Ci-C4 alkyl), Ci-C4 alkyl, Ci-C4 haloalkyl, C3-C6 cycloalkyl, and -0(Ci-C4 alkyl);
JA is halogen, cyano, oxo, Rd, -ORb, -NHRC, -C(0)Rb, -C(0)ORb, -OC(0)Rb, -NHC(0)Rb, -C(0)NHRc, -NHC(0)NHRc, -NHC(0)ORb, -OCONHRc, -N(CH3)RC, -N(CH3)C(0)Rb , -C(0)N(CH3)Rc, -N(CH3)C(0)NHRc, -N(CH3)C(0)ORb, -NHS02Rb, -S02NHRb, -S02N(CH3)Rb, and -N(CH3)S02Rb; and
JB and Jc are each and independently selected from the group consisting of halogen, cyano, oxo, Ra, -ORb, -NHRC, -C(0)Rb, -C(0)ORb, -OC(0)Rb, -NHC(0)Rb, -C(0)NHRc, -NHC(0)NHRc, -NHC(0)ORb, -OCONHRc, -N(CH3)RC, -N(CH3)C(0)Rb ,
-C(0)N(CH3)Rc, -N(CH3)C(0)NHRc, -N(CH3)C(0)ORb, -NHS02Rb, -S02NHRb,
-S02N(CH3)Rb, and -N(CH3)S02Rb.
6. The compound of any one of claims 1 -5, wherein:
Ra is independently an optionally substituted C1-C6 alkyl group, an optionally substituted C3-C7 carbocyclic group, an optionally substituted 5-7 membered heterocyclic group, an optionally substituted 5-6 membered heteroaryl group, or an optionally substituted phenyl 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, each independently form an optionally substituted 5-7 membered heterocyclic group; and
Rd is independently an optionally substituted C3-C6 carbocyclic group or an optionally substituted 5-7 membered heterocyclic group.
7. The compound of any one of claims 1 -6, wherein:
JA is halogen, cyano, oxo, -OH, -0(Ci-C6 alkyl), -NH(Ci-C6 alkyl), -C(0)OH, -C(0)0(Ci-C6 alkyl), -OC(0)(Ci-C6 alkyl), -NHC(0)(Ci-C6 alkyl), -NHC(0)(5-6 membered heterocyclic group), -C(0)NH(Ci-C6 alkyl), -S02NH(Ci-C6 alkyl), or
-NHS02(Ci-C6 alkyl); and
JB and Jc are each and independently is halogen; cyano; oxo; -OH; -0(Ci-C6 alkyl); -NH(Ci-C6 alkyl); -C(0)OH; -C(0)0(Ci-C6 alkyl); -OC(0)(Ci-C6 alkyl); -NHC(0)(Ci-C6 alkyl); -NHC(0)(5-6 membered heterocyclic group); -C(0)NH(Ci-C6 alkyl); -S02NH(Ci- Ce alkyl),; -NHS02(Ci-C6 alkyl); or a C1-C6 alkyl group optionally substituted with one or more substituents 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 -0(Ci-C4 alkyl).
8. The compound of any one of claims 1-7, represented by Structural Formula (II) or a pharmaceutically acceptable salt thereof:
9. The compound of any one of claims 1-8, wherein Q is -C(0)0-, -NRC(O)-,
-C(0)NR'-, or -NRC(0)NR'-.
10. The compound of any one of claims 1-9, wherein Ring T is an optionally substituted C5-C10 carbocyclic ring.
11. The compound of claim 10, wherein Ring T is an optionally substituted C5-C6 monocyclic group.
12. The compound of claim 10, wherein Ring T is an optionally substituted, C7-C10 bridged carbocyclic ring.
13. The compound of clai T-Qx-R2 is:
and wherein:
Ring A is a C5-C7 monocyclic or C7-C10 bridged carbocyclic group, each of which independently and optionally further substituted with one or more instances of JT; or optionally Ring A and R13, Ring A and R14, or Ring A and R15 independenty form a C7-C10 bridged carbocyclic ring optionally further substituted with one or more instances of JT; R , R , and R are each independently -H, -F, hydroxy, -NH2, -NH(Ci-C4 alkyl), -N(Ci-C4 alkyl)2, -OCO(Ci-C4 alkyl), -CO(Ci-C4 alkyl), -C02H, -C02(Ci-C4 alkyl), d-C4 alkyl, Ci-C4 haloalkyl, or -0(Ci-C4 alkyl);
R15 is -H, -F, hydroxy, C1-C4 alkyl, or C1-C4 haloalkyl; and
x is 0, 1 or 2.
14. The compound of claim 13, wherein:
R12 is -H, hydroxy, C1-C4 alkyl, C1-C4 haloalkyl, or -0(Ci-C4 alkyl);
R13 is -H, hydroxy, C1-C4 alkyl, C1-C4 haloalkyl, or -0(Ci-C4 alkyl), or optionally, together with Ring A, forms an optionally substituted C7-C10 bridged, carbocyclic ring;
R14 is -H, C1-C4 alkyl, or C1-C4 haloalkyl; or optionally, together with Ring A, forms an optionally substituted C7-C10 bridged, carbocyclic ring; and
R15 is -H, C1-C4 alkyl, or C1-C4 haloalkyl; or optionally, together with Ring A, forms an optionally substituted, C7-C10 bridged, carbocyclic ring.
15. The compound of claim 13 or 14, wherein:
R12 is -H;
R13 is -H or optionally, together with Ring A, forms an optionally substituted C7-C10 bridged, carbocyclic ring;
R14 is -H or optionally, together with Ring A, forms an optionally substituted, C7-C10 bridged, carbocyclic ring; and
R15 is -H or C1-C4 alkyl, or optionally, together with Ring A, forms an optionally substituted C7-C10 bridged, carbocyclic ring.
16. The compound of any one of claims 13-15, wherein:
i) Ring A is a C7-C10 bridged, carbocyclic group; and R12, R13, and R14 are -H, and R15 is -H or Ci-C4 alkyl; or
ii) Ring A and R15, Ring A and R14, or Ring A and R13 independently form an optionally substituted, C7-C10 bridged, carbocyclic group; and R12 is -H.
17. The compound of any one of claims 1-16, wherein Ring T-Qx-R2 is:
wherein:
each of rings A1-A4 is independently a C7-C10 bridged, carbocyclic ring optionally further substituted with one or more substituents selected from the group consisting of halogen, cyano, hydroxy, C1-C4 alkyl, C1-C4 haloalkyl, and -0(Ci-C4 alkyl);
each of rings A5-A6 is independently and optionally further substituted with one or more substituents selected from the group consisting of halogen, cyano, hydroxy, C1-C4 alkyl, C1-C4 haloalkyl, C3-C5 cycloalkyl, and -0(Ci-C4 alkyl);
each R14 is independently -H, C1-C4 alkyl, or C1-C4 haloalkyl;
R12 and R15 are each and independently -H, hydroxy, C1-C4 alkyl, or C1-C4 haloalkyl; R21, R22, R23, R24, and R25 are each independently -H, -F, hydroxy, -0(Ci-C4 alkyl), C1-C4 alkyl, or C1-C4 haloalkyl;
each p is independently 1, 2, or 3;
each q is independently 0, 1 or 2; and
each r is independently 1 or 2.
18. The compound of claim 17, wherein:
R12, R14 and each R15 are each independently -H or C1-C4 alkyl; and
R21, R22, R23, R24, and R25 are each independently -H or Ci-C4 alkyl.
19. The compound of claim 17 or 18, wherein Q1 is independently -C(0)0-, -NHC(O)-, or -NHC(0)NR'-.
20. The compound of any one of claims 17-19, wherein: R2 is independently -H, an optionally substituted Ci-Ce alkyl, an optionally substituted 5-7 membered heterocyclic group, an optionally substituted phenyl group, or an optionally substituted 5-6 membered heteroaryl group; or optionally R2 and R', together with the nitrogen atom to which they are attached, form an optionally substituted, 5-7 membered heterocyclic group;
wherein said Ci-Ce alkyl is optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, hydroxy, and -0(Ci-C4 alkyl); and each of said heterocyclic, phenyl and heteroaryl groups is independently and optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, Ci-C4 alkyl, Ci-C4 haloalkyl, and -0(Ci-C4 alkyl).
21. The compound of any one of claims 17-20, wherein:
R2 is H, optionally substituted Ci_6 alkyl, optionally substituted 5-6 membered heterocyclic, or optionally substituted 5-6 membered heteroaryl; and
R12, R14, R15, R21, R22, R23, R24, and R25 are each independently -H.
22. The compound of any one of claims 17-21, wherein each p is independently 2 and each q is independently 1.
23. The compound of any one of claims 1 -22, wherein Z1 is CH.
24. The compound of any one of claims 1 -23, wherein X1 is -CI.
25. The compound of any one of claims 1 -24, wherein X2 is -F.
26. The compound of any one of claims 1 -6, represented by the following structural formula or a pharmaceutically acceptable salt thereof:
27. The compound of claim 26, wherein Z2 is CH.
28. The compound of claim 26 or 27, wherein R3 is -C(0)OR, -OH, -CH2OH, -S(0)2R9, or -S(0)2-NRR10.
29. The compound of any one of claims 26-28, wherein:
R4, R5, and R6 are each and independently -C¾, -CH2F, -CF3, or or
R4 is -CH3, -CH2F, -CF3, or -02¾; and R5 and R6 together with the carbon atom to which they are attached form a C3-C6 carbocyclic ring.
30. The compound of any one of claims 26-29, wherein Q2 is -CH2-.
31. The compound of any one of claims 26-30, wherein:
R is -H or Ci-4 alkyl;
R9 is -OH; and
R10 is Ci-4 alkyl optionally substituted with one or more substituents selected from the group consisting of halogen, -OR and -C(0)OR.
32. The compound of any one of claims 26-31, wherein each R3 is -C(0)OR, -S(0)2R9, or -S(0)2-NRR10.
33. The compound of any one of claims 26-32, wherein X1 is -CI.
34. The compound of any one of claims 26-33, wherein X2 is -F.
The compound of any one of claims 26-34, wherein R is -H or -CH3
36. The compound of any one of claims 26-35, wherein the compound is represented by the following structural formula or a pharmaceutically acceptable salt thereof:
or a pharmaceutically acceptable salt thereof, wherein: R4, R5, and R6 are each and independently -C¾ or -C2H5; and
ring P is a C3-C6 carbocyclic ring.
37. The compound of any one of claims 26-36, wherein each R3 is -C(0)OR.
38. The compound of claim 1, selected from any one of the compounds depicted below or a pharmaceutically acceptable salt thereof:
39. A pharmaceutical composition, comprising a compound according to any one of claims 1-38, and a pharmaceutically acceptable carrier, adjuvant or vehicle.
40. 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 as described in any one of claims 1-38.
41. The method of claim 40, further comprising co-administering an additional therapeutic agent.
42. The method of claim 41, wherein the additional therapeutic agent is selected from an antiviral agent or an Influenza vaccine.
43. 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 1-38.
44. 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 1-38.
A method preparing a compound represented by Structural Formula (I)
or a pharmaceutically acceptable salt thereof, comprising:
reacting compound A: (A) with compound B
a compound represented by Structural Formula (XX):
(XX); and
ii) deprotecting the G group of the compound of Structural Formula (XX) under suitable conditions to form the compound of Structural Formula (I),wherein:
the variables of Structural Formulae (I) and (XX), and compounds (A) and (B) are independently as defined in any one of claims 1-38; and
L2 is a halogen; and
G is trityl.
46. The method of claim 45, wherein L is Br or CI.
47. A compound represented by Structural Formula (XX) or a pharmaceutically acceptable salt thereof:
wherein the variables of Structural Formula (XX) are each and independently as defined in any one of claims 1-38; and
G is trityl.
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