WO2010038081A2 - Heterocyclic derivatives and methods of use thereof - Google Patents

Heterocyclic derivatives and methods of use thereof Download PDF

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WO2010038081A2
WO2010038081A2 PCT/GB2009/051299 GB2009051299W WO2010038081A2 WO 2010038081 A2 WO2010038081 A2 WO 2010038081A2 GB 2009051299 W GB2009051299 W GB 2009051299W WO 2010038081 A2 WO2010038081 A2 WO 2010038081A2
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optionally substituted
alkyl
mmol
nitrogen
infection
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PCT/GB2009/051299
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French (fr)
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WO2010038081A3 (en
Inventor
Ann Boriack-Sjodin
Daniel Robert Carcanague
Daemian David Dussault
Holia Hatoum-Mokdad
Kenneth Gregory Hull
Georgine Ioannidis
John Irvin Manchester
Helen Maureen Mcguire
David Charles Mckinney
Suzanne Stokes
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Astrazeneca Ab
Astrazeneca Uk Limited
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Publication of WO2010038081A3 publication Critical patent/WO2010038081A3/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/48—Two nitrogen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • 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
    • 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
    • C07D401/12—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 linked by a chain containing hetero atoms as chain links
    • 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
    • C07D401/14—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 three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • 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
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to pyrimidine and pyridine derivatives which demonstrate antibacterial activity, processes for their preparation, pharmaceutical compositions containing them as the active ingredient, to their use as medicaments and to their use in the manufacture of medicaments for use in the treatment of bacterial infections in warm-blooded animals such as humans.
  • this invention relates to compounds useful for the treatment of bacterial infections in warm-blooded animals such as humans, more particularly to the use of these compounds in the manufacture of medicaments for use in the treatment of bacterial infections in warm-blooded animals such as humans.
  • bacterial pathogens may be classified as either Gram-positive or Gram-negative pathogens.
  • Antibiotic compounds with effective activity against both Gram-positive and Gram-negative pathogens are generally regarded as having a broad spectrum of activity.
  • the compounds of the present invention are regarded as effective against both Gram-positive and certain Gram-negative pathogens.
  • Gram-positive pathogens for example Staphylococci, Enterococci, Streptococci and mycobacteria
  • Staphylococci Enterococci
  • Streptococci mycobacteria
  • MRSA methicillin resistant staphylococcus aureus
  • MRCNS methicillin resistant coagulase negative staphylococci
  • penicillin resistant Streptococcus pneumoniae and multiple resistant Enterococcus faecium.
  • Vancomycin is a glycopeptide and is associated with various toxicities, including nephrotoxicity. Furthermore, and most importantly, antibacterial resistance to vancomycin and other glycopeptides is also appearing. This resistance is increasing at a steady rate rendering these agents less and less effective in the treatment of Gram-positive pathogens. There is also now increasing resistance appearing towards agents such as ⁇ -lactams, quinolones and macro lides used for the treatment of upper respiratory tract infections, also caused by certain Gram negative strains including H. influenzae and M.catarrhalis.
  • DNA gyrase is a member of the type II family of topoisomerases that control the topological state of DNA in cells (Champoux, J. J.; 2001. Ann. Rev. Biochem. 70: 369-413). Type II topoisomerases use the free energy from adenosine triphosphate (ATP) hydrolysis to alter the topology of DNA by introducing transient double-stranded breaks in the DNA, catalyzing strand passage through the break and resealing the DNA.
  • ATP adenosine triphosphate
  • DNA gyrase is an essential and conserved enzyme in bacteria and is unique among topoisomerases in its ability to introduce negative supercoils into DNA.
  • the enzyme consists of two subunits, encoded by gyrA and gyrB, forming an A 2 B 2 tetrameric complex.
  • the A subunit of gyrase (GyrA) is involved in DNA breakage and resealing and contains a conserved tyrosine residue that forms the transient covalent link to DNA during strand passage.
  • the B subunit (GyrB) catalyzes the hydrolysis of ATP and interacts with the A subunit to translate the free energy from hydrolysis to the conformational change in the enzyme that enables strand-passage and DNA resealing.
  • topoisomerase IV Another conserved and essential type II topoisomerase in bacteria, called topoisomerase IV, is primarily responsible for separating the linked closed circular bacterial chromosomes produced in replication. This enzyme is closely related to DNA gyrase and has a similar tetrameric structure formed from subunits homologous to Gyr A and to Gyr B. The overall sequence identity between gyrase and topoisomerase IV in different bacterial species is high. Therefore, compounds that target bacterial type II topoisomerases have the potential to inhibit two targets in cells, DNA gyrase and topoisomerase IV; as is the case for existing quinolone antibacterials (Maxwell, A. 1997, Trends Microbiol. 5: 102-109).
  • DNA gyrase is a well- validated target of antibacterials, including the quinolones and the coumarins.
  • the quinolones e.g. ciprofloxacin
  • the quinolones are broad-spectrum antibacterials that inhibit the DNA breakage and reunion activity of the enzyme and trap the GyrA subunit covalently complexed with DNA (Drlica, K., and X. Zhao, 1997, Microbiol. Molec. Biol.
  • cyclothialidine is a poor antibacterial agent showing activity only against some eubacterial species (Nakada, N, 1993, Antimicrob. Agents Chemother. 37: 2656-2661).
  • Synthetic inhibitors that target the B subunit of DNA gyrase and topoisomeraseIV are known in the art.
  • coumarin-containing compounds are described in patent application number WO 99/35155
  • 5,6-bicyclic heteroaromatic compounds are described in patent application WO 02/060879
  • pyrazole compounds are described in patent application WO 01/52845 (US patent US6,608,087).
  • AstraZeneca has also published certain applications describing anti-bacterial compounds: WO2005/026149, WO2006/087544, WO2006/087548, WO2006/087543, WO2006/092599, WO2006/092608, and WO2007/071965.
  • X is CH or N
  • R 4 for each occurrence, is independently selected from the group consisting of halo, cyano, nitro, hydroxy, Ci_ 6 alkyl, d_ 6 alkoxy, Ci_ 6 alkanoyl, carbamoyl, N-Ci_ 6 alkylcarbamoyl, N-Ci_6alkoxycarbamoyl, N,N-(Ci_6alkyl) 2 carbamoyl, N-(S ⁇ 2R')carbamoyl, N-Ci_6alkyl, Ci_ 6 alkyl-S(O) a -, R 17 R 18 N-S(O) a -, C 3 -i 4 carbocyclyl, and heterocyclyl; or two R 4 taken together with the carbon atoms to which they are attached form a C3_i4carbocyclyl or a heterocyclyl, wherein each R 4 may be optionally substituted on carbon by one or more R 16 , wherein if either of
  • R 7 , R 9 , R 15 and R 23 are each independently selected from the group consisting of Ci_6alkyl, Ci_6alkoxycarbonyl, Ci_6alkanoyl, carbamoyl, N-C 1-
  • R 25 for each occurrence, is independently selected from hydrogen or Ci_ 6 alkyl and s is 0, 1 or 2;
  • R 10 and R 12 are independently selected from the group consisting of Ci- ⁇ alkyl, phenyl, halo, cyano, nitro, oxo, carboxy, hydroxy, Ci_6alkoxy, Ci_ ⁇ alkoxycarbonyl, amino, N-Ci_6alkylamino, N,N-(Ci_6alkyl) 2 amino, Ci_6alkanoylamino, Ci_ 6alkylSO 2 NH-, carbamoyl, N-Ci_6alkylcarbamoyl, N,N-(Ci_6alkyl) 2 carbamoyl, N-C 1-
  • R 11 , R 13 , R 13 , and R 26 are each independently selected from the group consisting of C ⁇ alkyl, Ci_ 6 alkoxycarbonyl, C ⁇ alkanoyl, C 3 _ 6 cycloalkanoyl, carbamoyl, Ci_6alkanoyloxy, Ci_6alkylS(0) a , arylS(O) a wherein a is 0 to 2, carboxy, sulphamoyl and urea wherein said R 11 , R 13 , R 13 , and R 26 are independently optionally substituted on carbon by one or more amino, C ⁇ aUcyl, Ci_6alkoxy or heterocyclyl;
  • R 16 for each occurrence, is independently, a halo, hydroxy, a d_ 6 alkyl, or a C 1- 6 alkoxy;
  • R 17 and R 18 are independently hydrogen or a Ci_ 6 alkyl; or R 17 and R 18 , together with the nitrogen to which they are attached form a heterocyclyl; R 22 , for each occurrence, is independently selected from the group consisting of halo,
  • X is CH or N
  • R 4 for each occurrence, is independently selected from the group consisting of halo, cyano, nitro, hydroxy, Ci_ 6 alkyl, Ci_ 6 alkoxy, Ci_ 6 alkyl-S(O) a , R 17 R 18 N-S(O) a , C 3 .
  • each R 4 may be optionally substituted on carbon by one or more R 16 ; provided that ring B together with -(R 4 ) n is not 3,4,5-trimethoxyphenyl; n is an integer from 1 to 5; a is 0, 1, or 2;
  • L for each occurrence, is independent selected from a direct bond, -O-, -N(R 25 )-, -C(O)-, -N(R 25 )C(O)-, -C(O)N(R 25 )-, -S(O) 8 -, -SO 2 N(R 25 )- or -N(R 25 )SO 2 -; wherein R 25 , for each occurrence, is independently selected from hydrogen or Ci_ 6 alkyl and s is 0, 1 or 2;
  • R 10 and R 12 are independently selected from the group consisting of Ci_6alkyl, phenyl, halo, cyano, nitro, carboxy, hydroxy, Ci_6alkoxy, Ci_6alkoxycarbonyl, amino, N-Ci_6alkylamino, N,N-(Ci_6alkyl)2amino, carbamoyl, N-Ci_6alkylcarbamoyl, N 5 N- (Ci_6alkyl)2carbamoyl and N-Ci_6alkyloxycarbamoyl; and
  • R 11 and R 13 are each independently a Ci_ 6 alkyl
  • R 16 for each occurrence, is independently, a halo, hydroxy, a d_ 6 alkyl, or a C 1- ⁇ alkoxy;
  • R 17 and R 18 are independently hydrogen or a Ci_ 6 alkyl; or R 17 and R 18 , together with the nitrogen to which they are attached form a heterocyclyl; provided that -NR 1 R 2 is not -NHCH 3 , -N(CH 3 ) 2 .
  • the invention provides pharmaceutical compositions comprising a compound represented by formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier.
  • the invention provides a method of inhibiting bacterial DNA gyrase and/or bacterial topoisomerase IV in a warm-blooded animal in need of such treatment, comprising administering to the animal an effective amount of a compound represented by formula (I), or a pharmaceutically acceptable salt thereof.
  • the warm-blooded animal is a human.
  • the invention provides a method of producing an antibacterial effect in a warm-blooded animal in need of such treatment, comprising administering to the animal an effective amount of a compound represented by formula (I), or a pharmaceutically acceptable salt thereof.
  • the warm-blooded animal is a human.
  • the invention provides a method of treating a bacterial infection in a warm-blooded animal in need thereof, comprising administering to the animal an effective amount of a compound represented by formula (I), or a pharmaceutically acceptable salt thereof.
  • the warm-blooded animal is a human.
  • the bacterial infection is selected from the group consisting of community- acquired pneumoniae, hospital-acquired pneumoniae, skin and skin structure infections, acute exacerbation of chronic bronchitis, acute sinusitis, acute otitis media, catheter-related sepsis, febrile neutropenia, osteomyelitis, endocarditis, urinary tract infections and infections caused by drug resistant bacteria such as Penicillin-resistant Streptococcus pneumoniae, methicillin- resistant Staphylococcus aureus, methicillin-resistant Staphylococcus epidermidis and Vancomycin-Resistant Enterococci.
  • the warm-blooded animal is a human.
  • the invention provides compounds of formula (I) or a pharmaceutically acceptable salt thereof, for use as a medicament.
  • the invention provides the use of a compound represented by formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for use in the production of an antibacterial effect in a warm-blooded animal.
  • the warm-blooded animal is a human.
  • the invention provides the use of a compound represented by formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for use in inhibition of bacterial DNA gyrase and/or topoisomerase IV in a warm-blooded animal.
  • the warm-blooded animal is a human.
  • the invention provides the use of a compound represented by formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for use the treatment of a bacterial infection in a warm-blooded animal.
  • the bacterial infection is selected from the group consisting of community-acquired pneumoniae, hospital-acquired pneumoniae, skin and skin structure infections, acute exacerbation of chronic bronchitis, acute sinusitis, acute otitis media, catheter-related sepsis, febrile neutropenia, osteomyelitis, endocarditis, urinary tract infections, Penicillin-resistant Streptococcus pneumoniae, methicillin-resistant Staphylococcus aureus, methicillin-resistant Staphylococcus epidermidis and Vancomycin-Resistant Enterococci.
  • the warm-blooded animal is a human.
  • the invention provides a compound represented by formula (I), or a pharmaceutically acceptable salt thereof, for use in production of an anti-bacterial effect in a warm-blooded animal.
  • the invention provides a compound represented by formula (I), or a pharmaceutically acceptable salt thereof, for use in inhibition of bacterial DNA gyrase and/or topoisomerase IV in a warm-blooded animal.
  • the invention provides a compound represented by formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of a bacterial infection in a warm-blooded animal.
  • the invention provides a compound represented by formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of community-acquired pneumoniae, hospital-acquired pneumoniae, skin and skin structure infections, acute exacerbation of chronic bronchitis, acute sinusitis, acute otitis media, catheter-related sepsis, febrile neutropenia, osteomyelitis, endocarditis, urinary tract infections, Penicillin-resistant Streptococcus pneumoniae, methicillin-resistant Staphylococcus aureus, methicillin-resistant Staphylococcus epidermidis or Vancomycin-Resistant Enterococci.
  • alkyl includes both straight chained and branched saturated hydrocarbon groups.
  • “Ci_ 6 alkyl” refers to an alkyl that has from 1 to 6 carbon atom and includes, for example, methyl, ethyl, propyl, isopropyl and t-butyl.
  • references to individual alkyl groups such as propyl are specific for the straight chain version only unless otherwise indicated (e.g., isopropyl).
  • An analogous convention applies to other generic terms.
  • alkyl groups when two or more alkyl groups are indicated by, for example, the term (Ci_ 6 alkyl) 2 (such as in the term ⁇ /, ⁇ /-(Ci_ 6 alkyl) 2 amino), the alkyl groups can be the same or different.
  • C 2 - 6 alkenyl refers to a straight chain or branched hydrocarbon having at least one double bond.
  • C 2 _ 6 alkynyl refers to a straight chain or branched hydrocarbon having at least one triple bond.
  • halo refers to fluoro, chloro, bromo, and iodo.
  • a “heterocyclyl” is a saturated, partially saturated or unsaturated, mono or bicyclic ring containing 4-14 atoms of which at least one atom is chosen from nitrogen, sulphur or oxygen, which may, unless otherwise specified, be carbon or nitrogen linked, wherein a -CH 2 - group can optionally be replaced by a -C(O)- and a ring nitrogen may be optionally substituted with one oxo to form an N-oxide and a ring sulfur may be optionally substituted with one or two oxo groups to form S-oxide(s).
  • a “heterocyclyl” is a saturated, partially saturated or unsaturated, monocyclic ring containing 5 or 6 atoms of which at least one atom is chosen from nitrogen, sulphur or oxygen, it may, unless otherwise specified, be carbon or nitrogen linked.
  • a “heterocyclyl” is an unsaturated, carbon-linked, monocyclic ring containing 5 or 6 atoms of which at least one atom is chosen from nitrogen, sulphur or oxygen.
  • heterocyclyl examples and suitable values of the term "heterocyclyl” are azepanyl, azetidinyl, morpholinyl, piperidinyl, piperazinyl, pyridinyl, pyranyl, pyrrolyl, pyrazolyl, isothiazolyl, indolinyl, quinolinyl, thienyl, 1,3-benzodioxolyl, benzothiazolyl, thiadiazolyl, oxadiazolyl, piperazinyl, thiazolidinyl, pyrrolidinyl, thiomorpholino, pyrrolinyl, homopiperazinyl, 3,5-dioxapiperidinyl, tetrahydropyranyl, imidazolyl, 4,5-dihydro-oxazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, isoxazolyl,
  • a nitrogen linked heterocyclyl are morpholino, piperazin-1-yl, piperidin-1-yl and imidazol-1-yl.
  • a “heterocyclyl” is a heteroaryl.
  • the term “heteroaryl” refers to an unsaturated and aromatic heterocyclyl which has 5-14 ring atoms wherein at least one atom is chosen from nitrogen, sulphur or oxygen.
  • heteroaryl groups examples include pyridinyl, IH- pyrrolyl, lH-pyrazolyl, isothiazolyl, quinolinyl, thienyl, benzofuranyl, benzothiophenyl, benzothiazolyl, benzimidazolyl, thiadiazolyl, oxadiazolyl, lH-imidazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, isoxazolyl, thiazolyl, thiophenyl, lH-pyrazolyl, lH-tetrazolyl, IH- triazolyl, JV-methylpyrrolyl, 4-oxo-l,4-dihydroquinolinyl, pyridin-2(lH)-one, imidazo[l,2- ajpyridinyl, lH-indazol-1-yl, 1-isoquinolone,
  • the heteroaryl is a 5- or 6-membered heteroaryl, for example, pyridinyl, lH-pyrrolyl, lH-pyrazolyl, isothiazolyl, thienyl, thiadiazolyl, oxadiazolyl, lH-imidazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, isoxazolyl, thiazolyl, lH-tetrazolyl, lH-triazolyl, JV-methylpyrrolyl, and pyridine- ⁇ /-oxide.
  • heteroaryl also includes pyridinyl-2(lH)-one and indolyl.
  • a "carbocyclyl” is a saturated, partially saturated or unsaturated, mono-, bi- or tricyclic carbon ring that contains 3-14 atoms; wherein a -CH 2 - group can optionally be replaced by a -C(O)-.
  • "carbocyclyl” is a monocyclic ring containing 5 or 6 atoms or a bicyclic ring containing 9 or 10 atoms.
  • carbocyclyls examples include cyclopropyl, cyclobutyl, 1-oxocyclopentyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, phenyl, naphthyl, tetralinyl, indanyl or 1-oxoindanyl.
  • carbocyclyl encompasses both cycloalkyl and aryl groups.
  • cycloalkyl refers to a C 3 . i4carbocyclyl which is completely saturated, for example cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • aryl refers to a carbocyclyl which is completely unsaturated and is aromatic.
  • a C ⁇ -waryl is an aromatic, mono-, bi- or tricyclic carbon ring that contains 6-14 atoms, for example phenyl or naphthenyl.
  • Ci_6alkanoyloxy is acetoxy.
  • Examples of “Ci_6alkoxycarbonyl” are methoxycarbonyl, ethoxycarbonyl, n- and t-butoxycarbonyl.
  • Examples of “Ci_ 6 alkoxycarbonylamino” are methoxycarbonylamino, ethoxycarbonylamino, n- and t-butoxycarbonylamino.
  • Examples of “Ci_6alkoxy” are methoxy, ethoxy, isopropoxy, and tert- butoxy.
  • Examples of “Ci_6alkanoylamino” are formamido, acetamido and propionylamino.
  • Examples of “Ci_6alkylS(O) a wherein a is 0, 1, or 2" are methylthio, ethylthio, methylsulphinyl, ethylsulphinyl, methylsulfonyl and ethylsulphonyl.
  • Examples of “Ci_6alkanoyl” are propionyl and acetyl.
  • Examples of "N-(Ci_6alkyl)amino” are methylamino and ethylamino.
  • N 1 N-(C i_6alkyl)2amino are N,N-dimethylamino, N,N-diethylamino and N-ethyl-N-methylamino.
  • C2-6alkenyl are vinyl, allyl and 1-propenyl.
  • Examples of "C 2 - 6 alkynyl” are ethynyl, 1-propynyl and 2-propynyl.
  • N-(Ci_6alkyl)sulphamoyl are N-(methyl)sulphamoyl and N-(ethyl)sulphamoyl.
  • N,N-(Ci_6alkyl)2Sulphamoyl are N,N-(dimethyl)sulphamoyl and
  • N-(methyl)-N-(ethyl)sulphamoyl N-(methyl)-N-(ethyl)sulphamoyl.
  • An example of "N,N-(Ci_6alkyl)2Sulphamoylamino” are N,N-dimethylsulphamoylamino.
  • Examples of "N-(Ci_ 6 alkyl)carbamoyl” are methylaminocarbonyl and ethylaminocarbonyl.
  • Examples of "N 1 N-(C i_ 6 alkyl) 2 carbamoyl” are dimethylaminocarbonyl and methylethylaminocarbonyl.
  • N-(Ci_ 6 alkoxy)carbamoyl are methoxyaminocarbonyl and isopropoxyaminocarbonyl.
  • N-(Ci_6alkyl)-N-(Ci_6alkoxy)carbamoyl are examples of “N-(Ci_6alkyl)-N-(Ci_6alkoxy)carbamoyl.
  • N-methyl-N-methoxyaminocarbonyl and N-methyl-N-ethoxyaminocarbonyl are N-methyl-N-methoxyaminocarbonyl and N-methyl-N-ethoxyaminocarbonyl.
  • Examples of “C3-6cycloalkyl” are cyclopropyl, cyclobutyl, cyclopropyl and cyclohexyl.
  • Examples of “Ci_6alkylsulphonylamino” are methylsulphonylamino, isopropylsulphonylamino and t-butylsulphonylamino.
  • Examples of “Ci_6alkylsulphonylaminocarbonyl” are methylsulphonylaminocarbonyl, isopropylsulphonylaminocarbonyl and t-butylsulphonylaminocarbonyl.
  • Examples of “Ci_ 6 alkylsulphonyl” are methylsulphonyl, isopropylsulphonyl and t-butylsulphonyl.
  • Ci_3alkylsulphonylcarbamoyl are methylsulphonylcarbamoyl, i.e. CH 3 SO 2 NHC(O)-, and ethylsulphonylcarbamoyl, i.e. CH 3 CH 2 SO 2 NHC(O)-.
  • a carbon atom is substituted by "oxo" a -C(O)- is formed.
  • a pyridyl group is substituted on carbon by oxo
  • a pyridinyl-one is formed, e.g. if the carbon in the two position of pyridine is substituted by oxo, pyridinyl-2(lH)-one is formed.
  • a compound of formula (I) may form stable acid or basic salts, and in such cases administration of a compound as a salt may be appropriate, and pharmaceutically acceptable salts may be made by conventional methods such as those described below.
  • Suitable pharmaceutically-acceptable salts include acid addition salts such as methanesulfonate, tosylate, ⁇ -glycerophosphate, fumarate, hydrochloride, citrate, maleate, tartrate and (less preferably) hydrobromide. Also suitable are salts formed with phosphoric and sulfuric acid.
  • suitable salts are base salts such as an alkali metal salt for example sodium, an alkaline earth metal salt for example calcium or magnesium, an organic amine salt for example triethylamine, morpholine, ⁇ /-methylpiperidine, TV-ethylpiperidine, procaine, dibenzylamine, JV, ⁇ /-dibenzylethylamine, tris-(2-hydroxyethyl)amine, JV-methyl d-glucamine and amino acids such as lysine.
  • base salts such as an alkali metal salt for example sodium, an alkaline earth metal salt for example calcium or magnesium, an organic amine salt for example triethylamine, morpholine, ⁇ /-methylpiperidine, TV-ethylpiperidine, procaine, dibenzylamine, JV, ⁇ /-dibenzylethylamine, tris-(2-hydroxyethyl)amine, JV-methyl d-glucamine and amino acids such as lys
  • a compound of the formula (I), or a salt thereof may exhibit the phenomenon of tautomerism and that the formulae drawings within this specification can represent only one of the possible tautomeric forms. It is to be understood that the invention encompasses any tautomeric form which inhibits DNA gyrase and / or topoisomerase IV and is not to be limited merely to any one tautomeric form utilized within the formulae drawings.
  • the formulae drawings within this specification can represent only one of the possible tautomeric forms and it is to be understood that the specification encompasses all possible tautomeric forms of the compounds drawn not just those forms which it has been possible to show graphically herein. The same applies to compound names.
  • H represents any isotopic form of hydrogen including 1 H, 2 H (D), and 3 H (T);
  • C represents any isotopic form of carbon including 12 C, 13 C, and 14 C;
  • O represents any isotopic form of oxygen including 16 O, 17 O and 18 O;
  • N represents any isotopic form of nitrogen including 13 N, 14 N and 15 N;
  • P represents any isotopic form of phosphorous including 31 P and 32 P;
  • S represents any isotopic form of sulfur including 32 S and 35 S;
  • F represents any isotopic form of fluorine including 19 F and 18 F;
  • Cl represents any isotopic form of chlorine including 35 Cl, 37 Cl and 36 Cl; and the like.
  • compounds represented by formula (I) comprises isomers of the atoms therein in about their naturally occurring abundance. However, in certain instances, it is desirable to enrich one or more atom in a particular isotope which would normally be present in less abundance. For example, 1 H would normally be present in greater than 99.98% abundance; however, a compound of the invention can be enriched in 2 H or 3 H at one or more positions where H is present.
  • the symbol "D" is used to represent the enrichment in deuterium.
  • a compound of the invention when enriched in a radioactive isotope, for example 3 H and 14 C, they may be useful in drug and/or substrate tissue distribution assays. It is to be understood that the invention encompasses all such isotopic forms which inhibit DNA gyrase and / or topoisomerase IV.
  • R 2 is hydrogen or a Ci_ 6 alkyl
  • R 4 for each occurrence, is independently selected from the group consisting of halo, cyano, nitro, hydroxy, Ci_ 6 alkyl, Ci_ 6 alkoxy, Ci_ 6 alkyl-S(O) a -, R 17 R 18 N-S(O) a -, C 3 - i 4 carbocyclyl, and heterocyclyl; or two R 4 taken together with the carbon atoms to which they are attached form a C3_i4carbocyclyl or a heterocyclyl, wherein each R 4 may be optionally substituted on carbon by one or more R 16 ; provided that ring B together with -(R 4 ) n is not 3,4,5-trimethoxyphenyl; n is an integer from 1 to 5; a is 0, l, or 2; R 6 , R 8 , and R 14 , for each occurrence, are each independently selected from the group consisting of hydroxy, halo, cyano, nitro, Ci_ 6 alkyl, C
  • L for each occurrence, is independent selected from a direct bond, -O-, -N(R 25 )-, -C(O)-, -N(R 25 )C(O)-, -C(O)N(R 25 )-, -S(O) 8 -, -SO 2 N(R 25 )- or -N(R 25 )SO 2 -; wherein R 25 , for each occurrence, is independently selected from hydrogen or d_ 6 alkyl and s is 0, 1 or 2; R 10 and R 12 , for each occurrence, are independently selected from the group consisting of Ci_6alkyl, phenyl, halo, cyano, nitro, carboxy, hydroxy, Ci_6alkoxy, Ci_6alkoxycarbonyl, amino, N-Ci_6alkylamino, N,N-(Ci_6alkyl) 2 amino, carbamoyl, N-Ci_6alkylcarbamoyl, N
  • R 17 and R 18 are independently hydrogen or a d_ 6 alkyl; or R 17 and R 18 , together with the nitrogen to which they are attached form a heterocyclyl; provided that -NR 1 R 2 is not -NHCH 3 , -N(CH 3 ) 2 .
  • the invention provides compounds represented by formula (I), or a pharmaceutically acceptable salt thereof, wherein X is N. In another embodiment the invention provides compounds represented by formula (I), or a pharmaceutically acceptable salt thereof, wherein X is CH.
  • the invention provides compounds represented by formula (I), or a pharmaceutically acceptable salt thereof, wherein R 1 is a C ⁇ alkyl that is optionally substituted on carbon by one or more R 6 ; and R 2 is hydrogen.
  • R 1 is n-propyl, 3-(N 5 N- dimethylamino)-propyl, 3-(2-oxo-pyrrolidino)-propyl, l-acetyl-piperidine-4-yl, 2- morpho lino-ethyl, 2-acetamido-ethyl, 3-acetamido-propyl, pyridin-2-ylmethyl, pyridin-3- ylmethyl, pyridin-4-ylmethyl, 2-[(tert-butoxycarbonyl)amino]-ethyl, 2-carbamoyl-ethyl, 2- (pyridin-2-yl)-
  • the invention provides compounds represented by formula (I), or a pharmaceutically acceptable salt thereof, wherein R 1 is a Ci_ 6 alkyl which is optionally substituted with amino, carboxy, N,N-dimethylamino, 2-oxo-pyrrolidino, acetamido, pyridin- 2-yl, pyridin-3-yl, pyridin-4-yl, (tert-butoxycarbonyl)amino, carbamoyl, methylsulfonylamino, morpholino, 1,1-dioxo-thiomorpholino, methoxy, tetrahydrofuran-2-yl, isopropoxy, furan-2-yl, ethoxycarbonyl, phenoxy, methoxycarbonyl, 6-methyl-pyrazin-3-yl, benzoimidazol-2-yl, [(6-methyl-pyrazin-3-yl)carbonyl]amino, lH-imidazol-2
  • the invention provides compounds represented by formula (I), or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 , together with the nitrogen to which they are attached, form a lH-pyrazol-1-yl, wherein said lH-pyrazol-1-yl may be optionally substituted on carbon by one or more R 8 .
  • the invention provides compounds represented by formula (I), or a pharmaceutically acceptable salt thereof, wherein R 8 is independently a Ci_ 6 alkyl or a C 3 . ⁇ cycloalkyl wherein said R 8 is optionally substituted on carbon by one or more halo.
  • the invention provides compounds represented by formula (I), or a pharmaceutically acceptable salt thereof, wherein R 8 is independently a Ci_ 3 alkyl or a C 3 . ⁇ cycloalkyl wherein said R 8 is optionally substituted on carbon by one or more fluoro.
  • the invention provides compounds represented by formula (I), or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 , together with the nitrogen to which they are attached, form a lH-pyrazol-1-yl, wherein lH-pyrazol-1-yl may be optionally substituted on carbon by one or more methyl, cyclopropyl or trifluoromethyl.
  • the invention provides compounds represented by formula (I), or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 , together with the nitrogen to which they are attached, form piperidino, 4-hydroxy-piperidino, 3-hydroxymethyl-piperidino, 4-morpholino-piperidino, 4-( ⁇ /-methyl-carbamoyl)-piperidino, 4-fluoro-piperidino, A- methoxy-piperidino, 4-acetamido-piperidino, pyrrolidino, 3-hydroxy-pyrrolidino, 2-methyl- pyrrolidino, 2,5-dimethyl-pyrrolidino, azetidine-1-yl, 4-acetamidopiperidino, 3- trifluoromethyl-lH-pyrazol-1-yl, 3-trifluoromethyl-5-methyl-lH-pyrazol-l-yl, lH-imidazol- 1-yl, 4,5-dichloro-lH-imidazol-
  • R 8 for each occurrence, is independently selected from hydroxy, hydroxymethyl, morpholino, N-methylcarbamoyl, fluoro, methoxy, methyl, acetamido, trifluoromethyl, chloro, and pyridin-4-yl.
  • R 9 for each occurrence, is independently selected from a Ci_ 6 alkyl, 2-methoxyethyl, acetyl, N,N- dimethylcarbamoyl, cyclopropylcarbonyl, methylsulfonyl and tert-butoxycarbonyl.
  • R 1 is a C 3 _i 4 carbocyclyl; wherein R 1 may be optionally substituted on carbon by one or more R 6 ; provided that R 1 is not a substituted or unsubstituted phenyl.
  • R 1 is cyclohexyl.
  • R 6 is hydroxy.
  • R 1 is piperidinyl or tetrahydrofuranyl which may be optionally substituted on carbon by one or more R 6 ; and wherein the -NH- moiety of piperidinyl may be optionally t substituted by a group selected from R 7 .
  • the invention provides compounds represented by formula (I), or a pharmaceutically acceptable salt thereof, wherein R 3 is a C 6-14 aryl; wherein R 3 may be optionally substituted on carbon by one or more R 14 ; provided that R 3 is not an unsubstituted phenyl.
  • the invention provides compounds represented by formula (I), or a pharmaceutically acceptable salt thereof, wherein R 3 is phenyl substituted on carbon by two R 14 which taken together with the carbon atoms to which they are attached form a C 3 .
  • the invention provides compounds represented by formula (I), or a pharmaceutically acceptable salt thereof, wherein R 14 , for each occurrence, is independently selected from methoxycarbonyl, (methylsulfonyl)amino, ethoxycarbonyl, acetyl, amino, 5-oxo-4,5-dihydro-l,2,4-oxadiazolyl, trifluoromethyl, methoxy, (dimethylsulfamoyl)amino, cyano, fluoro, nitro, (E)-2-carboxyethenyl, 2-carboxy-ethyl, carboxy, (E)-2-ethoxycarbonylethenyl, (E)-2-carbamoyl-ethenyl, (E)-2-(N-methylcarbamoyl)- ethenyl, (E)-2-(N-methoxycarbamoyl)-ethenyl, N-methoxycarbamoyl,
  • the invention provides compounds represented by formula (I), or a pharmaceutically acceptable salt thereof, wherein R 3 is phenyl; wherein R 3 is substituted on carbon by one or more R 14 .
  • R 14 for each occurrence, is independently selected from methoxycarbonyl, (methylsulfonyl)amino, ethoxycarbonyl, trifluoromethyl, methoxy, (dimethylsulfamoyl)amino, cyano, fluoro, nitro, (E)-2-carboxyethenyl, 2-carboxy- ethyl, carboxy, (E)-2-ethoxycarbonylethenyl, (E)-2-carbamoyl-ethenyl, (E)-2-(N- methylcarbamoyl)-ethenyl, (E)-2-(N-methoxycarbamoyl)-ethenyl, N-methoxycarbamoyl, N-methoxycarbam
  • R 14 for each occurrence, is independently selected from methoxycarbonyl, ethoxycarbonyl, acetyl, amino, 5-oxo-4,5-dihydro-l,2,4-oxadiazolyl, methoxy, carboxy, N-ethyl-carbamoyl, N-benzyl-carbamoyl, N,N-dimethylcarbamoyl, piperidinocarbonyl, 3,3-difluoro-piperidinocarbonyl, or N'-hydroxycarbamimidoyl.
  • R 15 for each occurrence, is independently selected from tert-butyl- dimethyl-silyl, 2-methoxyethyl, or tert-butoxycarbonyl.
  • the invention provides compounds represented by formula (I), or a pharmaceutically acceptable salt thereof, wherein R 3 is 2-methoxyphenyl, 3- methoxyphenyl, 4-methoxyphenyl, 3-(methoxycarbonyl)-phenyl, 4-(ethoxycarbonyl)-phenyl, 3 -[(methylsulfony)amino] -phenyl, 4-methoxy-3 -trifluoromethyl, 3,4,5-trimethoxy-phenyl, 3- [(dimethylsulfamoyl)amino]-phenyl, 3-cyano-4-fluoro-phenyl, 3-nitrophenyl, 4- carboxyphenyl, 3-carboxyphenyl, 4-(2-carboxyethyl)-phenyl, 4-[(E)-2-carboxyethenyl]- phenyl, 3-[(E)-2-carboxyethenyl]-phenyl, 3 -[(E)-2-ethoxycarbon
  • the invention provides compounds represented by formula (I), or a pharmaceutically acceptable salt thereof, wherein R 3 is 2-methoxypyrimidin-5-yl, indolin-6-yl, 5-ethoxycarbonyl-pyridin-3-yl, 2,6-dimethoxypyridin-4-yl, benzofuran-2-yl, 5- acetyl-thiophen-2-yl, 5-cyano-pyridin-3-yl, l-(tert-butoxy-dimethyl-silyl)-lH-indolin-3-yl, 5- carboxy-thiophen-2-yl, 6-methoxy-pyridin-3-yl, 2-amino-pyrimidin-5-yl, lH-pyrazol-4-yl, 6- amino-pyridin-3 -yl, 2-methoxycarbonyl-benzothiophen-5 -yl, 2-carboxy-benzothiophen-5 -yl, pyridin-3-yl, pyrimidin-5
  • the invention provides compounds represented by formula (I), or a pharmaceutically acceptable salt thereof, wherein R 3 is 1 -ethyl -(2-methoxyethyl)-4-oxo- l,4-dihydroquinolin-6-yl-carboxylate or lH-indol-6-yl.
  • the invention provides compounds represented by formula (I), or a pharmaceutically acceptable salt thereof, wherein R 3 is a pyridin-3-yl or 2-oxo-pyridin-5- yl group wherein said pyridin-3-yl or 2-oxo-pyridin-5-yl group may be optionally substituted on carbon by one or more R 14 and wherein the N of said 2-oxo-pyridin-5-yl is substituted by a group selected from R 15 .
  • R 3 is a pyridin-3-yl or 2-oxo-pyridin-5- yl group wherein said pyridin-3-yl or 2-oxo-pyridin-5-yl group may be optionally substituted on carbon by one or more R 14 and wherein the N of said 2-oxo-pyridin-5-yl is substituted by a group selected from R 15 .
  • the invention provides compounds represented by formula (I), or a pharmaceutically acceptable salt thereof, wherein R 14 , for each occurrence, is independently a carboxy, Ci_ 6 alkoxy, Ci_ 6 alkylsulphonylcarbamoyl, Ci_ 6 alkoxycarbamoyl, or Ci_6alkylS(O) a wherein a is 0, 1 or 2.
  • the invention provides compounds represented by formula (I), or a pharmaceutically acceptable salt thereof, wherein R 15 , for each occurrence, is independently a C ⁇ alkyl wherein said C ⁇ alkyl is optionally substituted by C ⁇ alkoxy or saturated heterocyclyl.
  • the invention provides compounds represented by formula (I), or a pharmaceutically acceptable salt thereof, wherein R 14 , for each occurrence, is independently a carboxy, Ci_3alkoxy, Ci_3alkylsulphonylcarbamoyl, Ci_3alkoxycarbamoyl, or Ci_3alkylS(O) a wherein a is 0, 1 or 2.
  • the invention provides compounds represented by formula (I), or a pharmaceutically acceptable salt thereof, wherein R 15 , for each occurrence, is independently a Ci_ 3 alkyl wherein said Ci_ 3 alkyl is optionally substituted by Ci_ 3 alkoxy or saturated heterocyclyl.
  • the invention provides compounds represented by formula (I), or a pharmaceutically acceptable salt thereof, wherein R 15 , for each occurrence, is independently a Ci_ 3 alkyl wherein said Ci_ 3 alkyl is optionally substituted by Ci_ 3 alkoxy or morpholino.
  • the invention provides compounds represented by formula (I), or a pharmaceutically acceptable salt thereof, wherein R 3 is a 6-membered heteroaryl containing at least one nitrogen atom wherein one of the carbon atoms of said 6-membered heteroaryl ring may be optionally substituted with O to form a -(CO)-, and further wherein said 6-membered heteroaryl may be optionally substituted on carbon by one or more R 14 and when one of the carbon atoms of said 6-membered heteroaryl ring is substituted with O to form a -(CO)-, the nitrogen of that 6-membered heteroaryl is substituted by a group selected from R 15 .
  • the invention provides compounds represented by formula (I), or a pharmaceutically acceptable salt thereof, wherein R 3 is 2 -oxo-3 -carboxy- 1-ethyl-pyridin- 5-yl, 2-0X0-3 -carboxy- 1 -(2 -methoxyethyl)-pyridin-5-yl, 3-carboxy-6-(2- dimethylaminoethoxy)-pyridin-5 -yl, 3 -(N-2-hydroxyethylcarbamoyl)-pyridin-5 -yl, 3 -N-(I- methylsulfonylethyl)carbamoyl-pyridin-5 -yl, 2-methoxy-3 -carboxy-pyridin-5 -yl, 3 -N- methylcarbamoyl-pyridin-5-yl, 2-oxo-3 -carboxy- 1 -methyl-pyridin-5-yl, 2-oxo-3-N-N-
  • the invention provides compounds represented by formula (I), or a pharmaceutically acceptable salt thereof, wherein n is 2. In another embodiment the invention provides compounds represented by formula (I), or a pharmaceutically acceptable salt thereof, wherein n is 3.
  • the invention provides compounds represented by formula (I), or a pharmaceutically acceptable salt thereof, wherein n is 4. In another embodiment the invention provides compounds represented by formula (I), or a pharmaceutically acceptable salt thereof, wherein n is 4.
  • the invention provides compounds represented by formula (I), or a pharmaceutically acceptable salt thereof, wherein R 4 , for each occurrence, is independently a halo, Ci_ 6 alkyl or Ci_ 6 alkoxy.
  • the invention provides compounds represented by formula (I), or a pharmaceutically acceptable salt thereof, wherein n is 2 and R 4 , for each occurrence, is independently a halo, Ci_ 6 alkyl or d_ 6 alkoxy.
  • the invention provides compounds represented by formula (I), or a pharmaceutically acceptable salt thereof, wherein n is 2 and R 4 , for each occurrence, is independently a F, Cl, methyl or methoxy.
  • the invention provides compounds represented by formula (I), or a pharmaceutically acceptable salt thereof, wherein R 4 , for each occurrence, is independently selected from methyl, hydroxymethyl, fluoro, chloro, bromo, lH-tetrazole-1-yl, methoxy, cyano, 5-methyl-lH-tetrazole-l-yl, 2-methoxyethoxy, nitro, morpholinosulfonyl, or trifluoromethyl.
  • R 4 for each occurrence, is independently selected from methyl, hydroxymethyl, fluoro, chloro, bromo, lH-tetrazole-1-yl, methoxy, cyano, 5-methyl-lH-tetrazole-l-yl, 2-methoxyethoxy, nitro, morpholinosulfonyl, or trifluoromethyl.
  • the invention provides compounds represented by formula (I), or a pharmaceutically acceptable salt thereof, wherein n is 2 and one R 4 is fluoro and the other is chloro.
  • the invention provides compounds represented by formula (I), or a pharmaceutically acceptable salt thereof, wherein two adjacent R 4 together with ring B form lH-indolinyl.
  • X is N;
  • R 1 is a Ci_ 6 alkyl which is optionally substituted with on carbon with one or more R 6 ;
  • R 2 is hydrogen;
  • R 3 is 5-carboxy-pyridin-3-yl, S-ethoxycarbonyl-pyridin-S-yl, 3-[(E)-2- carboxyethenyl] -phenyl, 3 - [(E)-2-ethoxycarbonylethenyl] -phenyl, 3 -[(E)-2-(N- methylcarbamoyl)ethenyl]-phenyl, or 3-[(E)-2-carbamoylethenyl]-phenyl;
  • n is 2; and
  • R 4 for each occurrence is independently selected from a halo.
  • X is N;
  • R 1 is n-propyl, 3-( ⁇ f, ⁇ /-dimethylamino)-propyl, 2-(pyridin-2-yl)-ethyl, 2-(pyridin-3- yl)-ethyl, or 2-(pyridin-4-yl)ethyl;
  • R 2 is hydrogen;
  • R 3 is 5-carboxy-pyridin-3-yl, 5-ethoxycarbonyl-pyridin-3-yl, 3-[(E)-2- carboxyethenyl] -phenyl, 3-[(E)-2-ethoxycarbonylethenyl]-phenyl, 3-[(E)-2-(7V- methylcarbamoyl)ethenyl]-phenyl, or 3-[(E)-2-carbamoylethenyl]-phenyl; n is 2; and one of R 4 is fluoro and the other is chloro.
  • X is N
  • R 1 and R 2 together with the nitrogen to which they are attached, form pyrazol-1-yl wherein said pyrazol-1-yl may be optionally substituted on carbon by one or more R 8 ;
  • R 3 is a 6-membered heteroaryl containing at least one nitrogen atom wherein one of the carbon atoms of said 6-membered heteroaryl ring may be optionally substituted with O to form a -(CO)-, and further wherein said 6-membered heteroaryl may be optionally substituted on carbon by one or more R 14 and when one of the carbon atoms of said 6-membered heteroaryl ring is substituted with O to form a -(CO)-, the nitrogen of that 6-membered heteroaryl is substituted by a group selected from R 15 ; n is 2;
  • R 4 for each occurrence, is independently a halo, Ci_6alkyl or Ci_6alkoxy;
  • R 8 for each occurrence, is independently a d_ 6 alkyl or a C 3 _ 6 cycloalkyl wherein said R 8 is optionally substituted on carbon by one or more fluoro;
  • R 14 for each occurrence, is independently a carboxy, Ci_6alkoxy, Ci_
  • the invention provides compounds represented by formula (I), or a pharmaceutically acceptable salt thereof, wherein: X is N;
  • R 1 and R 2 together with the nitrogen to which they are attached, form pyrazol-1-yl wherein said pyrazol-1-yl may be optionally substituted on carbon by one or more R 8 ;
  • R 3 is a 6-membered heteroaryl containing at least one nitrogen atom wherein one of the carbon atoms of said 6-membered heteroaryl ring may be optionally substituted with O to form a -(CO)-, and further wherein said 6-membered heteroaryl may be optionally substituted on carbon by one or more R 14 and when one of the carbon atoms of said 6-membered heteroaryl ring is substituted with O to form a -(CO)-, the nitrogen of that 6-membered heteroaryl is substituted by a group selected from R 15 ; n is 2; R 4 , for each occurrence, is independently a halo, Ci_6alkyl or Ci_6alkoxy;
  • R 8 for each occurrence, is independently a methyl, trifluoromethyl or a cyclopropyl
  • R 14 for each occurrence, is independently a carboxy, Ci_6alkoxy, Ci_
  • Ci_6alkylS(O) a wherein a is 0, 1 or 2 wherein said R 14 may be optionally substituted on carbon by one or more hydroxy, (Ci_ 3 alkyl) 2 N, or C ⁇ alkylsulfonyl;
  • R 15 for each occurrence, is independently a Ci_ 6 alkyl wherein said Ci_ 6 alkyl is optionally substituted by Ci_6alkoxy or saturated heterocyclyl.
  • the invention provides compounds represented by formula (I), or a pharmaceutically acceptable salt thereof, wherein: X is N;
  • R 1 and R 2 together with the nitrogen to which they are attached, form pyrazol-1-yl wherein said pyrazol-1-yl may be optionally substituted on carbon by one or more R 8 ;
  • R 3 is a pyridin-3-yl or 2-oxo-pyridin-5-yl group wherein said pyridin-3-yl or 2-oxo- pyridin-5-yl group may be optionally substituted on carbon by one or more R 14 and wherein the N of said 2-oxo-pyridin-5-yl is substituted by a group selected from R 15 ;
  • n is 2;
  • R 4 for each occurrence, is independently a halo, Ci_3alkyl or Ci_3alkoxy;
  • R 8 for each occurrence, is independently a Ci_ 3 alkyl optionally substituted on carbon by one or more fluoro;
  • R 14 for each occurrence, is independently a carboxy, Ci_ 3 alkoxy, Ci_
  • Ci_3alkylsulphonylcarbamoyl N-Ci_3alkylcarbamoyl, N-Ci_3alkoxycarbamoyl, or Ci_3alkylS(O) a wherein a is 0, 1 or 2, wherein said R 14 may be optionally substituted on carbon by one or more hydroxy, (C 1-3 alky I) 2 N-, or Ci_ 3 alkylsulfonyl;
  • R 15 for each occurrence, is independently a C ⁇ alkyl wherein said Ci_ 3 alkyl is optionally substituted by Ci_ 3 alkoxy or saturated heterocyclyl.
  • the invention provides compounds represented by formula (I), or a pharmaceutically acceptable salt thereof, wherein: X is N;
  • R 4 for each occurrence is independently a halo
  • R 8 for each occurrence, is independently hydroxy, hydroxymethyl, morpholino, N- methylcarbamoyl, fluoro, methoxy, methyl, acetamido, trifluoromethyl, chloro, or pyridin-4- yi
  • R 9 for each occurrence, is independently a Ci ⁇ alkyl, 2-methoxyethyl, acetyl, NJV- dimethylcarbamoyl, cyclopropylcarbonyl, methylsulfonyl or tert-butoxycarbonyl.
  • Particular compounds of the invention are the compounds of the Examples, and pharmaceutically acceptable salts thereof, each of which provides a further independent aspect of the invention.
  • a further independent aspect of the invention is those specific salts as well as other pharmaceutically acceptable salts thereof and the free bases therof.
  • the present invention also comprises any two or more compounds of the Examples.
  • the invention provides compounds of Examples 319, 675, 677, 679, 681, 683, 684, 761, 815, 854, 861, 863, 909, 918, 919, 1019, 1026, 1075, 1076, 1086, 1087, 1088, 1143, 1145, 1152, 1159 and 1160, and or a pharmaceutically acceptable salt thereof.
  • the invention provides compounds of Examples 319, 638, 675, 677, 679, 681, 683, 684, 761, 815, 854, 861, 863, 909, 918, 919, 1019, 1026, 1075, 1076, 1086, 1087, 1088, 1143, 1145, 1152, 1159 and 1160, and or a pharmaceutically acceptable salt thereof.
  • the invention provides pharmaceutical compositions comprising a pharmaceutically acceptable excipient or carrier and a compound represented by formula (I), or a pharmaceutically acceptable salt thereof.
  • the present invention provides a process for preparing a compound of formula (I), or a pharmaceutically-acceptable salt thereof, wherein variable groups in the schemes below are as defined in formula (I) unless otherwise specified.
  • the compounds of the invention can be prepared by adding Ring B, -NR 1 R 2 and R 3 to a pyrimidine or pyridine core in any order.
  • formula (I) can be prepared by the following methods:
  • R 19 and R 20 are each independently hydrogen or a Ci_ ⁇ alkyl; or R 19 and R 20 together form a C 2 - 4 alkylene bridge which may be optionally substituted with one or more independently selected Ci_ 4 alkyl groups.
  • Process B Reacting a compound of formula (iii):
  • R 21 is a Ci_ 6 alkyl or a C 6-14 aryl; with a compound represented by formula (iv):
  • L 1 and L 2 are each, independently, displaceable groups, such as a halo.
  • a compound represented by formula (v) can be prepared from a pyrimidine or pyridine derivative by reacting a compound represented by formula (vii):
  • Compounds represented by formula (xi) can be prepared by treating a compound represented by formula (xii): with a peroxide, such as 3-chloroperoxybenzoic acid.
  • Compounds represented by formula (xii) can be prepared by reacting a compound represented by formula (x) with an aniline derivative represented by formula (vi) in the presence of an acid, such as HCl and heat.
  • Introduction of substituents into a ring may convert one compound of the formula (I) into another compound of the formula (I).
  • Such reactions and modifications include, for example, introduction of a substituent by means of an aromatic substitution reaction, reduction of substituents, alkylation of substituents, oxidation of substituents, esterification of substituents, amidation of substituents, formation of heteroaryl rings.
  • aromatic substitution reactions include the introduction of alkoxides, diazotization reactions followed by introduction of thiol group, alcohol group, halogen group.
  • modifications include; oxidation of alkylthio to alkylsulphinyl or alkylsulphonyl. (See
  • an ester substituent on a compound of formula (I) may be converted to a carboxylic acid by treating the ester with a base, such as sodium hydroxide, barium hydroxide, or trimethyltin hydroxide.
  • a base such as sodium hydroxide, barium hydroxide, or trimethyltin hydroxide.
  • a carboxylic acid substituent on a compound of formula (I) may be converted to an amide by reacting the carboxylic acid group with a primary or secondary amine in the presence of a peptide coupling reagent, such as O-(7-azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), dicyclohexylcarbodiimide (DCC), or l-ethyl-3-(3- dimethyllaminopropyl)carbodiimide (EDC).
  • HATU O-(7-azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate
  • DCC dicyclohexylcarbodiimide
  • EDC l-ethyl-3-(3- dimethyllaminopropyl)carbodiimide
  • the skilled organic chemist will be able to use and adapt the information contained and referenced within the above references, and accompanying Examples therein and also the Examples herein, to obtain necessary starting materials, and products.
  • the necessary starting materials for the procedures such as those described above may be made by procedures which are selected from standard organic chemical techniques, techniques which are analogous to the synthesis of known, structurally similar compounds, or techniques which are analogous to the above described procedure or the procedures described in the examples. It is noted that many of the starting materials for synthetic methods as described above are commercially available and/or widely reported in the scientific literature, or could be made from commercially available compounds using adaptations of processes reported in the scientific literature.
  • a suitable protecting group for a hydroxy group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an aroyl group, for example benzoyl, a silyl group such as trimethylsilyl or an arylmethyl group, for example benzyl.
  • the deprotection conditions for the above protecting groups will necessarily vary with the choice of protecting group.
  • an acyl group such as an alkanoyl or an aroyl group may be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
  • silyl group such as trimethylsilyl may be removed, for example, by fluoride or by aqueous acid; or an arylmethyl group such as a benzyl group may be removed, for example, by hydrogenation in the presence of a catalyst such as palladium-on-carbon.
  • a suitable protecting group for an amino group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an alkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl or t-butoxycarbonyl group, an arylmethoxycarbonyl group, for example benzyloxycarbonyl, or an aroyl group, for example benzoyl.
  • the deprotection conditions for the above protecting groups necessarily vary with the choice of protecting group.
  • an acyl group such as an alkanoyl or alkoxycarbonyl group or an aroyl group may be removed for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
  • a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
  • an acyl group such as a t-butoxycarbonyl group may be removed, for example, by treatment with a suitable acid as hydrochloric, sulphuric or phosphoric acid or trifluoroacetic acid and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon, or by treatment with a Lewis acid for example boron tris(trifluoroacetate).
  • a suitable acid as hydrochloric, sulphuric or phosphoric acid or trifluoroacetic acid
  • an arylmethoxycarbonyl group such as a benzyloxycarbonyl group
  • a suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group which may be removed by treatment with an alkylamine, for example dimethylaminopropylamine or 2-hydroxyethylamine, or with hydrazine.
  • a suitable protecting group for a carboxy group is, for example, an esterifying group, for example a methyl or an ethyl group which may be removed, for example, by hydrolysis with a base such as sodium hydroxide, or for example a t-butyl group which may be removed, for example, by treatment with an acid, for example an organic acid such as trifluoroacetic acid, or for example a benzyl group which may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon, or for example, an allyl group which may be removed, for example, by use of a palladium catalyst such as palladium acetate.
  • an esterifying group for example a methyl or an ethyl group which may be removed, for example, by hydrolysis with a base such as sodium hydroxide, or for example a t-butyl group which may be removed, for example, by treatment with an acid, for example an organic acid such as trifluoroacetic acid, or for
  • the protecting groups may be removed at any convenient stage in the synthesis using conventional techniques well known in the chemical art, or they may be removed during a later reaction step or work-up.
  • an optically active form of a compound of the invention When an optically active form of a compound of the invention is required, it may be obtained by carrying out one of the above procedures using an optically active starting material (formed, for example, by asymmetric induction of a suitable reaction step), or by resolution of a racemic form of the compound or intermediate using a standard procedure, or by chromatographic separation of diastereoisomers (when produced). Enzymatic techniques may also be useful for the preparation of optically active compounds and/or intermediates.
  • a pure regioisomer of a compound of the invention when required, it may be obtained by carrying out one of the above procedures using a pure regioisomer as a starting material, or by resolution of a mixture of the regioisomers or intermediates using a standard procedure.
  • E.coli GyrB ATPase Inhibition Activity Compounds may be tested for inhibition of E. coli GyrB ATPase activity using an ammonium molybdate/malachite green-based phosphate detection assay (Lanzetta, P. A., L. J. Alvarez, P. S. Reinach, and O. A. Candia, 1979, 100: 95-97).
  • Assays are performed in multiwell plates in 30 ⁇ l reactions containing: 50 mM Hepes buffer pH 7.5, 75 mM ammonium acetate, 8.0 mM magnesium chloride, 0.5 mM ethylenediaminetetraacetic acid, 5% glycerol, 1 mM 1 ,4-Dithio-DL-threitol, 200 nM bovine serum albumin, 1.6 ⁇ g/ml sheared salmon sperm DNA, 400 pM E. coli GyrA, 400 pM E. coli GyrB, 250 ⁇ M ATP, and the test compound in dimethylsulfoxide.
  • Reactions are quenched with 30 ⁇ l of ammonium molybdate/malachite green detection reagent containing 1.2 mM malachite green hydrochloride, 8.5 mM ammonium molybdate tetrahydrate, and 1 M hydrochloric acid. Plates can be read in an absorbance plate reader at 650 nm and percent inhibition values are calculated using dimethylsulfoxide (2%)-containing reactions as 0% inhibition and EDTA-containing (2.4 ⁇ M) reactions as 100% inhibition controls. An IC50 measurement of compound potency for each compound can be determined from reactions performed in the presence of 10 different compound concentrations.
  • E. coli Topoisomerase IV ATPase Inhibition Activity Compounds may be tested for inhibition of E. coli topoisomerase IV ATPase activity as described above for E. coli GyrB except the 30 ⁇ l reactions contained the following: 20 mM TRIS buffer pH 8, 50 mM ammonium acetate, 8 mM magnesium chloride, 5% glycerol, 5 mM 1 ,4-Dithio-DL-threitol, 0.005% Brij-35, 5 ⁇ g/ml sheared salmon sperm DNA, 500 pM E. coli ParC, 500 pM E. coli ParE, 160 ⁇ M ATP, and test compound in dimethylsulfoxide.
  • S. aureus GyrB ATPase Inhibition Activity Compounds may be tested for inhibition of S. aureus GyrB ATPase activity using an ammonium molybdate/malachite green-based phosphate detection assay (Lanzetta, P. A., L. J. Alvarez, P. S. Reinach, and O. A. Candia, 1979, 100: 95-97).
  • Assays are performed in multiwell plates in 30 ⁇ l reactions containing: 50 mM Hepes buffer pH 7.5, 75 mM ammonium acetate, 8.0 mM magnesium chloride, 0.5 mM ethylenediaminetetraacetic acid, 5% glycerol, 1.0 mM 1 ,4-Dithio-DL-threitol, 200 nM bovine serum albumin, 1.0 ⁇ g/ml sheared salmon sperm DNA, 250 pM E. coli GyrA, 250 pM S. aureus GyrB, 250 ⁇ M ATP, and test compound in dimethylsulfoxide.
  • Reactions are quenched with 30 ⁇ l of ammonium molybdate/malachite green detection reagent containing 1.2 mM malachite green hydrochloride, 8.5 mM ammonium molybdate tetrahydrate, and 1 M hydrochloric acid. Plates are read in an absorbance plate reader at 650 nm and percent inhibition values can be calculated using dimethylsulfoxide (2%)-containing reactions as 0% inhibition and EDTA-containing (2.4 ⁇ M) reactions as 100% inhibition controls. An IC50 measurement of compound potency for each compound can be determined from reactions performed in the presence of 10 different compound concentrations.
  • S. pneumoniae Topoisomerase IV ATPase Inhibition Activity Compounds may be tested for inhibition of S. pneumoniae ParE ATPase activity using an ammonium molybdate/malachite green-based phosphate detection assay (Lanzetta, P. A., L. J. Alvarez, P. S. Reinach, and O. A. Candia, 1979, 100: 95-97).
  • Assays are performed in multiwell plates in 30 ⁇ l reactions containing: 20 mM Tris buffer pH 8.0, 50 mM ammonium acetate, 8.0 mM magnesium chloride, 0.5 mM ethylenediaminetetraacetic acid, 5% glycerol, 5 mM 1 ,4-Dithio-DL-threitol, 0.005 % Brij-35, 5 ⁇ g/ml sheared salmon sperm DNA, 1.25 nM S. pneumoniae ParE, 160 ⁇ M ATP, and test compound in dimethylsulfoxide.
  • Reactions are quenched with 30 ⁇ l of ammonium molybdate/malachite green detection reagent containing 1.2 mM malachite green hydrochloride, 8.5 mM ammonium molybdate tetrahydrate, and 1 M hydrochloric acid. Plates are read in an absorbance plate reader at 650 nm and percent inhibition values are calculated using dimethylsulfoxide (2%)-containing reactions as 0% inhibition and EDTA-containing (20 ⁇ M) reactions as 100% inhibition controls. An IC50 measurement of compound potency for each compound can be determined from reactions performed in the presence of 10 different compound concentrations.
  • the compounds of the examples (Ex) were tested in an assay substantially similar to the assay described above for measuring the inhibition of S. pneumoniae Topoisomerase IV ATPase and were found to have a percent inhibition (% Inh) of S. pneumoniae Topoisomerase IV ATPase as shown in the table below.
  • Compounds may be tested for antimicrobial activity by susceptibility testing in liquid media.
  • Compounds may be dissolved in dimethylsulfoxide and tested in 10 doubling dilutions in the susceptibility assays.
  • the organisms used in the assay may be grown overnight on suitable agar media and then suspended in a liquid medium appropriate for the growth of the organism.
  • the suspension can be a 0.5 McFarland and a further 1 in 10 dilution can be made into the same liquid medium to prepare the final organism suspension in 100 ⁇ L. Plates can be incubated under appropriate conditions at 37 0 C for 24 hrs prior to reading.
  • the Minimum Inhibitory Concentration (MIC) may be determined as the lowest drug concentration able to reduce growth by 80% or more.
  • a compound of the formula (I), or a pharmaceutically-acceptable salt thereof for use in a method of treatment of the human or animal body by therapy.
  • the invention provides a method of treating a bacterial infection in an animal, such as a human, comprising administering to the animal or human an effective amount of a compound of any one of formulas (I), or a pharmaceutically acceptable salt thereof.
  • compounds of the present invention inhibit bacterial DNA gyrase and / or topoisomerase IV and are therefore of interest for their antibacterial effects.
  • the compounds of the invention inhibit bacterial DNA gyrase and are therefore of interest for their antibacterial effects.
  • the compounds of the invention inhibit topoisomerase IV and are therefore of interest for their antibacterial effects.
  • the compounds of the invention inhibit both DNA gyrase and topoisomerase IV and are therefore of interest for their antibacterial effects.
  • the compounds of the invention are useful in treating or preventing bacterial infections.
  • an “infection” or “bacterial infection” refers to an infection caused by Acinetobacter baumanii. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Acinetobacter haemolyticus . In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Acinetobacter junii. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Acinetobacter johnsonii. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Acinetobacter Iwoffi.
  • an “infection” or “bacterial infection” refers to an infection caused by Bacteroides bivius. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Bacteroides fragilis . In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Burkholderia cepacia. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Campylobacter jejuni. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Chlamydia pneumoniae.
  • an “infection” or “bacterial infection” refers to an infection caused by Chlamydia urealyticus . In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Chlamydophila pneumoniae. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Clostridium difficile. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Enterobacter aerogenes. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Enterobacter cloacae. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Enterococcus faecalis . In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by an infection caused by
  • an "infection” or “bacterial infection” refers to an infection caused by Escherichia coli. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Gardnerella vaginalis. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Haemophilus par ⁇ influenzae. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Haemophilus influenzae. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Helicobacter pylori.
  • an “infection” or “bacterial infection” refers to an infection caused by Klebsiella pneumoniae. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Legionella pneumophila. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Methicillin-resistant Staphylococcus aureus. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Methicillin-susceptible Staphylococcus aureus. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Moraxella catarrhalis.
  • an “infection” or “bacterial infection” refers to an infection caused by Morganella morganii. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Mycoplasma pneumoniae. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Neisseria gonorrhoeae. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Penicillin- resistant Streptococcus pneumoniae. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Penicillin-susceptible Streptococcus pneumoniae.
  • an “infection” or “bacterial infection” refers to an infection caused by Peptostreptococcus magnus. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Peptostreptococcus micros. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Peptostreptococcus anaerobius. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Peptostreptococcus asaccharolyticus . In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Peptostreptococcus prevotii.
  • an “infection” or “bacterial infection” refers to an infection caused by Peptostreptococcus tetradius. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Peptostreptococcus vaginalis. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Proteus mirabilis. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Pseudomonas aeruginosa. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Quino lone-Resistant Staphylococcus aureus.
  • an “infection” or “bacterial infection” refers to an infection caused by Quinolone-Resistant Staphylococcus epidermis. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Salmonella typhi. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Salmonella paratyphi. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Salmonella enteritidis. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Salmonella typhimurium.
  • an “infection” or “bacterial infection” refers to an infection caused by Serratia marcescens. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Staphylococcus aureus. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Staphylococcus epidermidis. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Staphylococcus saprophyticus . In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Streptoccocus agalactiae.
  • an “infection” or “bacterial infection” refers to an infection caused by Streptococcus pneumoniae. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Streptococcus pyogenes. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Stenotrophomonas maltophilia. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Ureaplasma urealyticum. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Vancomycin-Resistant Enterococcus faecium.
  • an “infection” or “bacterial infection” refers to an infection caused by Vancomycin-Resistant Enterococcus faecalis. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Vancomycin-Resistant Staphylococcus aureus. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Vancomycin-Resistant Staphylococcus epidermis. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Mycobacterium tuberculosis.
  • an “infection” or “bacterial infection” refers to an infection caused by Clostridium perfringens. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Klebsiella oxytoca. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Neisseria miningitidis. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Fusobacterium spp. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Peptococcus spp.
  • an “infection” or “bacterial infection” refers to an infection caused by Proteus vulgaris. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Coagulase-negative Staphylococcus (including Staphylococcus lugdunensis, Staphylococcus capitis, Staphylococcus hominis, and Staphylococcus saprophytic ).
  • an “infection” or “bacterial infection” refers to an infection caused by Acinetobacter spp. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Bacteroides spp. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Burkholderia spp. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Campylobacter spp. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Chlamydia spp. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Chlamydophila spp.
  • an “infection” or “bacterial infection” refers to an infection caused by Clostridium spp. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Enterobacter spp. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Enterococcus spp. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Escherichia spp. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Gardnerella spp. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Haemophilus spp.
  • an “infection” or “bacterial infection” refers to an infection caused by Helicobacter spp. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Klebsiella spp. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Legionella spp. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Moraxella spp. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Morganella spp. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Mycoplasma spp.
  • an “infection” or “bacterial infection” refers to an infection caused by Neisseria spp. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Peptostreptococcus spp. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Proteus spp. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Pseudomonas spp. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Salmonella spp. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Serratia spp.
  • an “infection” or “bacterial infection” refers to an infection caused by Staphylococcus spp. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Streptoccocus spp. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Stenotrophomonas spp. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Ureaplasma spp. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by aerobes. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by obligate anaerobes.
  • an “infection” or “bacterial infection” refers to an infection caused by facultative anaerobes. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by gram-positive bacteria. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by gram-negative bacteria. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by gram- variable bacteria. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by atypical respiratory pathogens. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Enterics.
  • an “infection” or “bacterial infection” refers to an infection caused by Shigella spp. In one aspect of the invention an “infection” or “bacterial infection” refers to an infection caused by Citrobacter. In one aspect of the invention “infection” or “bacterial infection” refers to a gynecological infection. In one aspect of the invention “infection” or “bacterial infection” refers to a respiratory tract infection (RTI). In one aspect of the invention “infection” or “bacterial infection” refers to a sexually transmitted disease. In one aspect of the invention “infection” or “bacterial infection” refers to a urinary tract infection.
  • infection refers to acute exacerbation of chronic bronchitis (ACEB).
  • infection or “bacterial infection” refers to acute otitis media.
  • infection or “bacterial infection” refers to acute sinusitis.
  • infection or “bacterial infection” refers to an infection caused by drug resistant bacteria.
  • infection or “bacterial infection” refers to catheter-related sepsis.
  • infection or “bacterial infection” refers to chancroid.
  • infection or “bacterial infection” refers to chlamydia.
  • infection refers to community-acquired pneumonia (CAP).
  • infection or “bacterial infection” refers to complicated skin and skin structure infection.
  • infection or “bacterial infection” refers to uncomplicated skin and skin structure infection.
  • infection or “bacterial infection” refers to endocarditis.
  • infection or “bacterial infection” refers to febrile neutropenia.
  • infection or “bacterial infection” refers to gonococcal cervicitis.
  • infection or “bacterial infection” refers to gonococcal urethritis.
  • infection refers to hospital-acquired pneumonia (HAP). In one aspect of the invention “infection” or “bacterial infection” refers to osteomyelitis. In one aspect of the invention “infection” or “bacterial infection” refers to sepsis. In one aspect of the invention “infection” or “bacterial infection” refers to syphilis. In one aspect of the invention “infection” or “bacterial infection” refers to ventilator-associated pneumonia. In one aspect of the invention “infection” or “bacterial infection” refers to intraabdominal infections. In one aspect of the invention “infection” or “bacterial infection” refers to gonorrhoeae.
  • infection refers to meningitis. In one aspect of the invention “infection” or “bacterial infection” refers to tetanus. In one aspect of the invention “infection” or “bacterial infection” refers to tuberculosis.
  • the compounds of the present invention will be useful in treating bacterial infections including, but not limited to community-acquired pneumoniae, hospital-acquired pneumoniae, skin & skin structure infections, acute exacerbation of chronic bronchitis, acute sinusitis, acute otitis media, catheter-related sepsis, febrile neutropenia, osteomyelitis, endocarditis, urinary tract infections and infections caused by drug resistant bacteria such as Penicillin-resistant Streptococcus pneumoniae, methicillin- resistant Staphylococcus aureus, methicillin-resistant Staphylococcus epidermidis and Vancomycin-Resistant Enterococci.
  • bacterial infections including, but not limited to community-acquired pneumoniae, hospital-acquired pneumoniae, skin & skin structure infections, acute exacerbation of chronic bronchitis, acute sinusitis, acute otitis media, catheter-related sepsis, febrile neutropenia, osteomyelitis, endocarditis
  • a method for producing an antibacterial effect in a warm blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of the present invention, or a pharmaceutically-acceptable salt thereof.
  • a method for inhibition of bacterial DNA gyrase and / or topoisomerase IV in a warm-blooded animal, such as a human being in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof as defined hereinbefore.
  • a method of treating a bacterial infection in a warm-blooded animal which comprises administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof as defined hereinbefore.
  • a method of treating a bacterial infection selected from community-acquired pneumoniae, hospital-acquired pneumoniae, skin & skin structure infections, acute exacerbation of chronic bronchitis, acute sinusitis, acute otitis media, catheter-related sepsis, febrile neutropenia, osteomyelitis, endocarditis, urinary tract infections and infections caused by drug resistant bacteria such as Penicillin-resistant Streptococcus pneumoniae, methicillin-resistant Staphylococcus aureus, methicillin-resistant Staphylococcus epidermidis and Vancomycin-Resistant Enterococciin a warm-blooded animal, such as a human being, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof as defined hereinbefore.
  • a further feature of the present invention is a compound of formula (I), and pharmaceutically acceptable salts thereof for use as a medicament.
  • the medicament is an antibacterial agent.
  • a compound of formula (I), or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in the production of an anti-bacterial effect in a warm-blooded animal such as a human being.
  • a compound of formula (I), or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in inhibition of bacterial DNA gyrase and / or topoisomerase IV in a warm-blooded animal such as a human being.
  • a compound of formula (I), or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in the treatment of a bacterial infection selected from community- acquired pneumoniae, hospital-acquired pneumoniae, skin & skin structure infections, acute exacerbation of chronic bronchitis, acute sinusitis, acute otitis media, catheter-related sepsis, febrile neutropenia, osteomyelitis, endocarditis, urinary tract infections and infections caused by drug resistant bacteria such as Penicillin-resistant Streptococcus pneumoniae, methicillin- resistant Staphylococcus aureus, methicillin-resistant Staphylococcus epidermidis and Vancomycin-Resistant Enterococci in a warm-blooded animal such as a human being.
  • a bacterial infection selected from community- acquired pneumoniae, hospital-acquired pneumoniae, skin & skin structure infections, acute exacerbation of chronic bronchitis, acute sinusitis, acute otitis media, catheter-
  • a compound of formula (I), or a pharmaceutically acceptable salt thereof for use in the production of an anti- bacterial effect in a warm-blooded animal such as a human being.
  • a compound of formula (I), or a pharmaceutically acceptable salt thereof for use in inhibition of bacterial DNA gyrase and / or topoisomerase IV in a warm-blooded animal such as a human being.
  • a compound of formula (I), or a pharmaceutically acceptable salt thereof for use in the treatment of a bacterial infection in a warm-blooded animal such as a human being.
  • a compound of formula (I), or a pharmaceutically acceptable salt thereof for use in the treatment of a bacterial infection selected from community-acquired pneumoniae, hospital-acquired pneumoniae, skin & skin structure infections, acute exacerbation of chronic bronchitis, acute sinusitis, acute otitis media, catheter-related sepsis, febrile neutropenia, osteomyelitis, endocarditis, urinary tract infections and infections caused by drug resistant bacteria such as Penicillin-resistant Streptococcus pneumoniae, methicillin-resistant Staphylococcus aureus, methicillin-resistant Staphylococcus epidermidis and Vancomycin-Resistant Enterococci in a warm-blooded animal such as a human being.
  • a bacterial infection selected from community-acquired pneumoniae, hospital-acquired pneumoniae, skin & skin structure infections, acute exacerbation of chronic bronchitis, acute sinusitis, acute otitis media, catheter-related
  • a compound of the formula (I), or a pharmaceutically-acceptable salt thereof, (hereinafter in this section relating to pharmaceutical composition "a compound of this invention") for the therapeutic (including prophylactic) treatment of mammals including humans, in particular in treating infection, it is normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition.
  • the present invention provides a pharmaceutical composition which comprises a compound of the formula (I), or a pharmaceutically-acceptable salt thereof, and a pharmaceutically-acceptable diluent or carrier.
  • a pharmaceutical composition which comprises a compound of formula (I), as defined hereinbefore or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable excipient or carrier for use in producing an anti-bacterial effect in an warm-blooded animal, such as a human being.
  • a pharmaceutical composition which comprises a compound of formula (I), as defined hereinbefore or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable excipient or carrier for use in inhibition of bacterial DNA gyrase and / or topoisomerase IV in an warm-blooded animal, such as a human being.
  • a pharmaceutical composition which comprises a compound of formula (I), as defined hereinbefore or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable excipient or carrier for use in the treatment of a bacterial infection in an warm-blooded animal, such as a human being.
  • a pharmaceutical composition which comprises a compound of formula (I), as defined hereinbefore or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable excipient or carrier for use in the treatment of a bacterial infection selected from community- acquired pneumoniae, hospital-acquired pneumoniae, skin & skin structure infections, acute exacerbation of chronic bronchitis, acute sinusitis, acute otitis media, catheter-related sepsis, febrile neutropenia, osteomyelitis, endocarditis, urinary tract infections and infections caused by drug resistant bacteria such as Penicillin-resistant Streptococcus pneumoniae, methicillin- resistant Staphylococcus aureus, methicillin-resistant Staphylococcus epidermidis and Vancomycin-Resistant Enterococci in an warm-blooded animal, such as a human being.
  • a bacterial infection selected from community- acquired pneumoniae, hospital-acquired pneumoniae, skin & skin structure infections, acute exacerbation of chronic bron
  • compositions of the invention may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular or intramuscular dosing or as a suppository for rectal dosing).
  • oral use for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixir
  • compositions of the invention may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art.
  • compositions intended for oral use may contain, for example, one or more coloring, sweetening, flavoring and/or preservative agents.
  • Suitable pharmaceutically acceptable excipients for a tablet formulation include, for example, inert diluents such as lactose, sodium carbonate, calcium phosphate or calcium carbonate, granulating and disintegrating agents such as corn starch or algenic acid; binding agents such as starch; lubricating agents such as magnesium stearate, stearic acid or talc; preservative agents such as ethyl or propyl p-hydroxybenzoate, and anti-oxidants, such as ascorbic acid.
  • Tablet formulations may be uncoated or coated either to modify their disintegration and the subsequent absorption of the active ingredient within the gastrointestinal tract, or to improve their stability and/or appearance, in either case, using conventional coating agents and procedures well known in the art.
  • Compositions for oral use may be in the form of hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or an oil such as peanut oil, liquid paraffin, or olive oil.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
  • water or an oil such as peanut oil, liquid paraffin, or olive oil.
  • Aqueous suspensions generally contain the active ingredient in finely powdered form together with one or more suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents such as lecithin or condensation products of an alkylene oxide with fatty acids (for example polyoxethylene stearate), or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol
  • the aqueous suspensions may also contain one or more preservatives (such as ethyl or propyl p-hydroxybenzoate, anti-oxidants (such as ascorbic acid), colouring agents, flavouring agents, and/or sweetening agents (such as sucrose, saccharine or aspartame).
  • OiIy suspensions may be formulated by suspending the active ingredient in a vegetable oil (such as arachis oil, olive oil, sesame oil or coconut oil) or in a mineral oil (such as liquid paraffin).
  • the oily suspensions may also contain a thickening agent such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set out above, and flavouring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water generally contain the active ingredient together with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients such as sweetening, flavoring and coloring agents, may also be present.
  • the pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions.
  • the oily phase may be a vegetable oil, such as olive oil or arachis oil, or a mineral oil, such as for example liquid paraffin or a mixture of any of these.
  • Suitable emulsifying agents may be, for example, naturally-occurring gums such as gum acacia or gum tragacanth, naturally-occurring phosphatides such as soya bean, lecithin, an esters or partial esters derived from fatty acids and hexitol anhydrides (for example sorbitan monooleate) and condensation products of the said partial esters with ethylene oxide such as polyoxy ethylene sorbitan monooleate.
  • the emulsions may also contain sweetening, flavoring and preservative agents.
  • Syrups and elixirs may be formulated with sweetening agents such as glycerol, propylene glycol, sorbitol, aspartame or sucrose, and may also contain a demulcent, preservative, flavoring and/or coloring agent.
  • sweetening agents such as glycerol, propylene glycol, sorbitol, aspartame or sucrose, and may also contain a demulcent, preservative, flavoring and/or coloring agent.
  • compositions may also be in the form of a sterile injectable aqueous or oily suspension, which may be formulated according to known procedures using one or more of the appropriate dispersing or wetting agents and suspending agents, which have been mentioned above.
  • a sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example a solution in 1,3-butanediol.
  • Compositions for administration by inhalation may be in the form of a conventional pressurized aerosol arranged to dispense the active ingredient either as an aerosol containing finely divided solid or liquid droplets.
  • Conventional aerosol propellants such as volatile fluorinated hydrocarbons or hydrocarbons may be used and the aerosol device is conveniently arranged to dispense a metered quantity of active ingredient.
  • the amount of active ingredient that is combined with one or more excipients to produce a single dosage form will necessarily vary depending upon the host treated and the particular route of administration.
  • a formulation intended for oral administration to humans will generally contain, for example, from 0.5 mg to 2 g of active agent compounded with an appropriate and convenient amount of excipients which may vary from about 5 to about 98 percent by weight of the total composition.
  • Dosage unit forms will generally contain about 1 mg to about 500 mg of an active ingredient.
  • Suitable classes and substances may be selected from one or more of the following: i) other antibacterial agents for example macrolides e.g. erythromycin, azithromycin or clarithromycin; quinolones e.g. ciprofloxacin or levofloxacin; ⁇ -lactams e.g. penicillins e.g.
  • amoxicillin or piperacillin cephalosporins e.g. ceftriaxone or ceftazidime
  • carbapenems e.g. meropenem or imipenem etc
  • aminoglycosides e.g. gentamicin or tobramycin; or oxazolidinones
  • anti-infective agents for example, an antifungal triazole e.g. or amphotericin
  • biological protein therapeutics for example antibodies, cytokines, bactericidal/permeability-increasing protein (BPI) products; and/or iv) efflux pump inhibitors.
  • a compound of the formula (I), or a pharmaceutically acceptable salt thereof and a chemotherapeutic agent selected from: i) one or more additional antibacterial agents; and/or ii) one or more anti-infective agents; and/or iii) biological protein therapeutics for example antibodies, cytokines, bactericidal/permeability-increasing protein (BPI) products; and/or iv) one or more efflux pump inhibitors.
  • a chemotherapeutic agent selected from: i) one or more additional antibacterial agents; and/or ii) one or more anti-infective agents; and/or iii) biological protein therapeutics for example antibodies, cytokines, bactericidal/permeability-increasing protein (BPI) products; and/or iv) one or more efflux pump inhibitors.
  • the invention in another embodiment, relates to a method of treating a bacterial infection in an animal, such as a human, comprising administering to the animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a chemotherapeutic agent selected from: i) one or more additional antibacterial agents; and/or ii) one or more anti-infective agents; and/or iii) biological protein therapeutics for example antibodies, cytokines, bactericidal/permeability-increasing protein (BPI) products; and/or iv) one or more efflux pump inhibitors.
  • a chemotherapeutic agent selected from: i) one or more additional antibacterial agents; and/or ii) one or more anti-infective agents; and/or iii) biological protein therapeutics for example antibodies, cytokines, bactericidal/permeability-increasing protein (BPI) products; and/or iv) one or more efflux pump inhibitors.
  • the size of the dose required for the therapeutic or prophylactic treatment of a particular disease state will necessarily be varied depending on the host treated, the route of administration, the severity of the illness being treated, and whether or not an additional chemotherapeutic agent is administered in combination with a compound of the invention.
  • a daily dose in the range of 1-50 mg/kg is employed.
  • the daily dose will necessarily be varied depending upon the host treated, the particular route of administration, the severity of the illness being treated, and whether or not an additional chemotherapeutic agent is administered in combination with a compound of the invention. Accordingly the optimum dosage may be determined by the practitioner who is treating any particular patient.
  • one embodiment of the present invention is directed to treating or preventing diseases caused by bacterial infections, wherein the bacteria comprise a GyrB ATPase or topoisomerase IV ATP ase enzyme.
  • Treating a subject with a disease caused by a bacterial infection includes achieving, partially or substantially, one or more of the following: the reducing or amelioration of the progression, severity and/or duration of the infection, arresting the spread of an infection, ameliorating or improving a clinical symptom or indicator associated with a the infection (such as tissue or serum components), and preventing the reoccurrence of the infection.
  • preventing a bacterial infection refers to the reduction in the risk of acquiring the infection, or the reduction or inhibition of the recurrence of the infection.
  • a compound of the invention is administered as a preventative measure to a patient, preferably a human, before a surgical procedure is preformed on the patient to prevent infection.
  • the term "effective amount" refers to an amount of a compound of this invention for treating or preventing a bacterial infection is an amount which is sufficient to prevent the onset of an infection, reduce or ameliorate the severity, duration, or progression, of an infection, prevent the advancement of an infection, cause the regression of an infection, prevent the recurrence, development, onset or progression of a symptom associated with an infection, or enhance or improve the prophylactic or therapeutic effect(s) of another therapy.
  • compounds of formula (I), and their pharmaceutically acceptable salts are also useful as pharmacological tools in the development and standardization of in-vitro and in-vivo test systems for the evaluation of the effects of inhibitors of DNA gyrase and / or topoisomerase IV in laboratory animals such as cats, dogs, rabbits, monkeys, rats and mice, as part of the search for new therapeutic agents.
  • each intermediate was purified to the standard required for the subsequent stage and was characterised in sufficient detail to confirm that the assigned structure was correct; purity was assessed by high pressure liquid chromatography, thin layer chromatography, or NMR and identity was determined by infra-red spectroscopy (IR), mass spectroscopy or NMR spectroscopy as appropriate;
  • CDCI3 is deuterated chloroform
  • DBU is l,8-diazabicyclo[5.4.0]undec-7-ene
  • DCM is dichloromethane
  • DIEA is diisopropyl ethylamine
  • DMF is ⁇ /, ⁇ /-dimethylformamide
  • DMSO dimethylsulfoxide
  • EDC is l-ethyl-3-(3-dimethylaminopropyl)carbodiimide
  • EtOAc is ethyl acetate
  • HATU is N-[(dimethylamino)-lH,2,3-triazolo[4,5-b-]pyridin-l- ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide;
  • HOBT 1-hydroxybenzotriazole
  • MeOH is methanol
  • MS is mass spectroscopy
  • NMP is N-Methylpyrrolidone
  • RT or rt is room temperature
  • SM is starting material
  • T 3 P is n-propyl phosphonic acid cyclic anhydride
  • TBTU is O-(Benzotriazol-l-yl)- ⁇ /, ⁇ /, ⁇ /"-tetramethyluronium tetrafluoroborate;
  • TFA is trifluoroacetic acid
  • TFAA is trifluoroacetic anhydride
  • THF is tetrahydrofuran
  • (ix) temperatures are quoted as 0 C;
  • (x) vol designates 1 mL of solvent or reagent per g of material used as the limiting agent.
  • the resulting mixture was stirred for 3 hours and then poured into a 100 mL separatory funnel containing ethyl acetate (50 mL) and ice-cold IN HCl (5 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (50 mL x 2). The organic layers were combined and washed with saturated aqueous sodium bicarbonate solution (2 x 50 mL) and brine (50 mL).
  • the mixture was warmed over a 90 0 C heating block Ihl5m.
  • the mixture was allowed to cool, diluted to ⁇ 40 ml with CH 2 Cl 2 , filtered and evaporated then applied to a 4Og silica cartridge and eluted with 0 to 10% ethyl acetate / hexanes.
  • Trimethylsulfoxonium iodide (1.084 g, 4.93 mmol) was combined with dimethylsulfoxide (5 ml) and 60% sodium hydride dispersion in oil (0.183 g, 4.58 mmol) and stirred at room temperature for 50 minutes to give a clear solution, then (E)-tert-butyl 3-(5-bromopyridin-3- yl)acrylate Intermediate 177 (1 g, 3.52 mmol) was added together with dimethylsulfoxide (1 ml) to give a yellow-orange suspension which was stirred at room temperature for 45 minutes.
  • reaction mixture was cooled to room temperature, filtered through celite bed, washed with ethyl acetate twice and concentrated in vacuo. Then the residue was diluted with ethyl acetate (10 mL), washed with water (5 mL), brine solution (5 mL), dried over Na 2 SO 4 and concentrated in vacuo.
  • the reaction mixture was concentrated in vacuo and the residue taken in ethyl acetate (50 mL) was washed with water and brine. The organic layer was dried over sodium sulfate, filtered and concentrated. The crude compound was purified by silica gel column chromatography using 50 % ethyl acetate/hexanes as an eluent to yield the title compound (300 mg).
  • the reaction mixture was diluted with ethyl acetate (50 mL) and the organic layer was separated, dried over sodium sulfate, filtered and concentrated.
  • the crude compound was purified by silica gel column chromatography using EtOAc/hexanes as an eluent to yield the title compound (1.02 g).
  • the reaction mixture was concentrated in vacuo and the residue taken in ethyl acetate (50 mL) was washed with water and brine. The organic layer was dried over sodium sulfate, filtered and concentrated. The crude compound was purified by silica gel column chromatography using 50 % ethyl acetate/hexanes as an eluent to yield the title compound (400 mg).
  • the reaction mixture was diluted with ethyl acetate (50 mL) and the organic layer was separated, dried over sodium sulfate, filtered and concentrated.
  • the crude compound was purified by silica gel column chromatography using EtOAc/hexanes as an eluent to yield the title compound (1.05 g).
  • the reaction mixture was then quenched with ice cold water at 0-5 0 C, and the p ⁇ adjusted to 2 with 1.5 N HCl solution. It was then was extracted with ethyl acetate, and the organic layer was washed with water, dried over Na 2 SO 4 and concentrated in vacuo. The crude mass was purified by column chromatography using 10-15 % ethyl acetate/hexanes to yield 900 mg of the title compound.
  • the reaction mixture was concentrated in vacuo.
  • the residue obtained was taken in ethyl acetate, washed with water and brine, dried over sodium sulfate and concentrated.
  • the crude mass was purified by silica gel column chromatography (60-120 mesh) using 35 % ethyl acetate/hexanes as an eluent.
  • the compounds in the below table were prepared using this method and the specified starting material.
  • the reaction mixture was concentrated in vacuo.
  • the residue obtained was taken in ethyl acetate, washed with water and brine, dried over sodium sulfate and concentrated.
  • the crude mass was purified by silica gel column chromatography (60-120 mesh) using 30 % ethyl acetate/hexanes as an eluent to give the product.
  • the compounds in the below table were prepared using this method and the specified starting material.
  • reaction mixture was cooled to room temperature, diluted with ethyl acetate, filtered through a celite bed and concentrated in vacuo to obtain 0.7 g of the crude mass which was taken to the next step without further purification LCMS analysis indicated the presence of a mixture of boronic acid (42 %) and boronate (17 %).
  • the reaction mixture was quenched with cold water (200 mL) and extracted with ethyl acetate (200 mL x 3). The combined organic layer was washed with water (200 mL), brine solution (200 mL), dried over anhydrous Na 2 SO 4 and evaporated under reduced pressure to get crude compound.
  • the crude compound was purified by column chromatography (Silica gel, 100-200 mesh) using 6% ethyl acetate in pet ether as mobile phase to get 6.5 g of the title compound.
  • the compounds in the below table were prepared using this method and the indicated starting material.
  • Methyl 5-bromo-l-methyl-2-oxo-l,2-dihydropyridine-3-carboxylate (Intermediate 322, 2 mmol, 0.5 g), bis(pinacolato)diboron (2.42 mmol, 0.619 g), [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.3 mmol, 0.244 g) and potassium acetate (6 mmol, 0.59 g) were suspended in dry dioxane (10 mL) and degassed with nitrogen for 10 min. The reaction was then heated to 100 0 C for 1 h.
  • the reaction mixture was concentrated in vacuo.
  • the residue obtained was taken in ethyl acetate, washed with water and brine, dried over sodium sulfate and concentrated.
  • the crude mass was purified by silica gel column chromatography (60-120 mesh) using 15% ethyl acetate/hexanes to yield 300 mg of the title compound.

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Abstract

Compounds of formula (I) and their pharmaceutically acceptable salts are described. Processes for their preparation, pharmaceutical compositions containing them, their use as medicaments and their use in the treatment of bacterial infections are also described.

Description

HETEROCYCLIC DERIVATIVES AND METHODS OF USE THEREOF
Field of the Invention
The present invention relates to pyrimidine and pyridine derivatives which demonstrate antibacterial activity, processes for their preparation, pharmaceutical compositions containing them as the active ingredient, to their use as medicaments and to their use in the manufacture of medicaments for use in the treatment of bacterial infections in warm-blooded animals such as humans. In particular, this invention relates to compounds useful for the treatment of bacterial infections in warm-blooded animals such as humans, more particularly to the use of these compounds in the manufacture of medicaments for use in the treatment of bacterial infections in warm-blooded animals such as humans.
Background of the Invention
The international microbiological community continues to express serious concern that the evolution of antibiotic resistance could result in strains against which currently available antibacterial agents will be ineffective. In general, bacterial pathogens may be classified as either Gram-positive or Gram-negative pathogens. Antibiotic compounds with effective activity against both Gram-positive and Gram-negative pathogens are generally regarded as having a broad spectrum of activity. The compounds of the present invention are regarded as effective against both Gram-positive and certain Gram-negative pathogens.
Gram-positive pathogens, for example Staphylococci, Enterococci, Streptococci and mycobacteria, are particularly important because of the development of resistant strains which are both difficult to treat and difficult to eradicate from the hospital environment once established. Examples of such strains are methicillin resistant staphylococcus aureus (MRSA), methicillin resistant coagulase negative staphylococci (MRCNS), penicillin resistant Streptococcus pneumoniae and multiple resistant Enterococcus faecium.
The preferred clinically effective antibiotic for treatment of last resort of such resistant Gram-positive pathogens is vancomycin. Vancomycin is a glycopeptide and is associated with various toxicities, including nephrotoxicity. Furthermore, and most importantly, antibacterial resistance to vancomycin and other glycopeptides is also appearing. This resistance is increasing at a steady rate rendering these agents less and less effective in the treatment of Gram-positive pathogens. There is also now increasing resistance appearing towards agents such as β-lactams, quinolones and macro lides used for the treatment of upper respiratory tract infections, also caused by certain Gram negative strains including H. influenzae and M.catarrhalis.
Consequently, in order to overcome the threat of widespread multi-drug resistant organisms, there is an on-going need to develop new antibiotics, particularly those with either a novel mechanism of action and/or containing new pharmacophoric groups.
Deoxyribonucleic acid (DNA) gyrase is a member of the type II family of topoisomerases that control the topological state of DNA in cells (Champoux, J. J.; 2001. Ann. Rev. Biochem. 70: 369-413). Type II topoisomerases use the free energy from adenosine triphosphate (ATP) hydrolysis to alter the topology of DNA by introducing transient double-stranded breaks in the DNA, catalyzing strand passage through the break and resealing the DNA. DNA gyrase is an essential and conserved enzyme in bacteria and is unique among topoisomerases in its ability to introduce negative supercoils into DNA. The enzyme consists of two subunits, encoded by gyrA and gyrB, forming an A2B2 tetrameric complex. The A subunit of gyrase (GyrA) is involved in DNA breakage and resealing and contains a conserved tyrosine residue that forms the transient covalent link to DNA during strand passage. The B subunit (GyrB) catalyzes the hydrolysis of ATP and interacts with the A subunit to translate the free energy from hydrolysis to the conformational change in the enzyme that enables strand-passage and DNA resealing.
Another conserved and essential type II topoisomerase in bacteria, called topoisomerase IV, is primarily responsible for separating the linked closed circular bacterial chromosomes produced in replication. This enzyme is closely related to DNA gyrase and has a similar tetrameric structure formed from subunits homologous to Gyr A and to Gyr B. The overall sequence identity between gyrase and topoisomerase IV in different bacterial species is high. Therefore, compounds that target bacterial type II topoisomerases have the potential to inhibit two targets in cells, DNA gyrase and topoisomerase IV; as is the case for existing quinolone antibacterials (Maxwell, A. 1997, Trends Microbiol. 5: 102-109).
DNA gyrase is a well- validated target of antibacterials, including the quinolones and the coumarins. The quinolones (e.g. ciprofloxacin) are broad-spectrum antibacterials that inhibit the DNA breakage and reunion activity of the enzyme and trap the GyrA subunit covalently complexed with DNA (Drlica, K., and X. Zhao, 1997, Microbiol. Molec. Biol.
Rev. 61 : 377-392). Members of this class of antibacterials also inhibit topoisomerase IV and as a result, the primary target of these compounds varies among species. Although the quinolones are successful antibacterials, resistance generated primarily by mutations in the target (DNA gyrase and topoisomerase IV) is becoming an increasing problem in several organisms, including S. aureus and Streptococcus pneumoniae (Hooper, D. C, 2002, The Lancet Infectious Diseases 2: 530-538). In addition, quinolones, as a chemical class, suffer from toxic side effects, including arthropathy that prevents their use in children (Lipsky, B. A. and Baker, C. A., 1999, Clin. Infect. Dis. 28: 352-364). Furthermore, the potential for cardiotoxicity, as predicted by prolongation of the QTC interval, has been cited as a toxicity concern for quinolones.
There are several known natural product inhibitors of DNA gyrase that compete with ATP for binding the GyrB subunit (Maxwell, A. and Lawson, D. M. 2003, Curr. Topics in Med. Chem. 3: 283-303). The coumarins are natural products isolated from Streptomyces spp., examples of which are novobiocin, chlorobiocin and coumermycin Al . Although these compounds are potent inhibitors of DNA gyrase, their therapeutic utility is limited due to toxicity in eukaryotes and poor penetration in Gram-negative bacteria (Maxwell, A. 1997, Trends Microbiol. 5: 102-109). Another natural product class of compounds that targets the GyrB subunit is the cyclothialidines, which are isolated from Streptomyces filipensis
(Watanabe, J. et al 1994, J. Antibiot. 47: 32-36). Despite potent activity against DNA gyrase, cyclothialidine is a poor antibacterial agent showing activity only against some eubacterial species (Nakada, N, 1993, Antimicrob. Agents Chemother. 37: 2656-2661).
Synthetic inhibitors that target the B subunit of DNA gyrase and topoisomeraseIV are known in the art. For example, coumarin-containing compounds are described in patent application number WO 99/35155, 5,6-bicyclic heteroaromatic compounds are described in patent application WO 02/060879, and pyrazole compounds are described in patent application WO 01/52845 (US patent US6,608,087). AstraZeneca has also published certain applications describing anti-bacterial compounds: WO2005/026149, WO2006/087544, WO2006/087548, WO2006/087543, WO2006/092599, WO2006/092608, and WO2007/071965.
Summary of the Invention
We have discovered a new class of compounds which are useful for inhibiting DNA gyrase and / or topoisomerase IV. In one embodiment, according to the present invention there is provided a compound of formula (I):
Figure imgf000005_0001
or a pharmaceutically acceptable salt thereof, wherein:
X is CH or N;
R1 is hydrogen, a Ci_6alkyl, C2-6alkenyl, C2_6alkynyl, C3_i4carbocyclyl, or a heterocyclyl, wherein R1 may be optionally substituted on carbon by one or more R6; and wherein if said hetercyclyl contains an =N- or a -S- moiety that nitrogen may be optionally substituted by one oxo group and that sulfur may be optionally substituted by one or two oxo groups; and wherein if said heterocyclyl contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from R7; provided that R1 is not a substituted or unsubstituted phenyl;
R2 is hydrogen or a Ci_6alkyl; or R1 and R2, together with the nitrogen to which they are attached, form a heterocyclyl, wherein said heterocyclyl may be optionally substituted on carbon by one or more R8; wherein if said hetercyclyl contains an =N- or a -S- moiety that nitrogen may be optionally substituted by one oxo group and that sulfur may be optionally substituted by one or two oxo groups; and wherein if said heterocyclyl contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from R9;
R3 is a Cβ-uaryl or a heteroaryl; wherein R3 may be optionally substituted on carbon by one or more R14; and wherein if said heteraryl contains an =N- or a -S- moiety that nitrogen may be optionally substituted by one oxo group and that sulfur may be optionally substituted by one or two oxo groups; and wherein if said heteroaryl contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from R15; provided that R3 is not an unsubstituted phenyl or an unsubstituted thiophenyl;
R4, for each occurrence, is independently selected from the group consisting of halo, cyano, nitro, hydroxy, Ci_6alkyl, d_6alkoxy, Ci_6alkanoyl, carbamoyl, N-Ci_6alkylcarbamoyl, N-Ci_6alkoxycarbamoyl, N,N-(Ci_6alkyl)2carbamoyl, N-(Sθ2R')carbamoyl, N-Ci_6alkyl, Ci_ 6alkyl-S(O)a-, R17R18N-S(O)a-, C3-i4carbocyclyl, and heterocyclyl; or two R4 taken together with the carbon atoms to which they are attached form a C3_i4carbocyclyl or a heterocyclyl, wherein each R4 may be optionally substituted on carbon by one or more R16, wherein if either of said heterocyclyl contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from R26; provided that ring B together with -(R4)n is not 3,4,5-trimethoxyphenyl; n is an integer from 1 to 5; a is 0, 1, or 2;
R6, R8, and R14, for each occurrence, are each independently selected from the group consisting of hydroxy, halo, cyano, nitro, Ci_6alkyl, C2-6alkenyl, C2-6alkynyl, mercapto, Ci_6alkoxy, Ci_6alkylS(O)a wherein a is 0 to 2, -C(=N-OH)NH2, -C(O)NHNH2, phenoxy, carboxy, oxo, amino, N-Ci_6alkylamino, N,N-(Ci_6alkyl)2amino, Ci_6alkoxycarbonyl, Ci_6alkanoyl, Ci_6alkanoyloxy, Ci_6alkanoylamino, Ci_6alkoxycarbonylamino, carbamoyl, N- Ci_6alkylcarbamoyl, N-C i_6alkoxy carbamoyl, N,N-(Ci_6alkyl)2carbamoyl, N-Ci_6alkyl-N- alkoxycarbamoyl, N-(SO2R' )carbamoyl, N-Ci_6alkyl-N-(SO2R')carbamoyl,
Ci_6alkylsulphonylamino, sulphamoyl, iV-(Ci_6alkyl)sulphamoyl, TV, TV-(C i_6alkyl)2sulphamoyl, sulphamoylamino, Λ/-(Ci_6alkyl)sulphamoylamino, Λ/,Λ/-(Ci_6alkyl)2sulphamoylamino, C3. πcarbocyclyl-L- and heterocyclyl-L-; or two R14 taken together with the carbon atoms to which they are attached form a C3_i4carbocyclyl or a heterocyclyl; wherein R6, R8, and R14 may be each independently optionally substituted on carbon by one or more R10; and wherein if said hetercyclyl contains an =N- or a -S- moiety that nitrogen may be optionally substituted by one oxo group and that sulfur may be optionally substituted by one or two oxo groups; and wherein if either of said heterocyclyl contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from R11; R' and R", for each occurrence, are independently selected from the group consisting of Ci_6alkyl, Cβ-uaryl and heterocyclyl, wherein R' and R"may be optionally substituted on carbon by one or more R22 and wherein if said heterocyclyl contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from R23;
R7, R9, R15 and R23, for each occurrence, are each independently selected from the group consisting of Ci_6alkyl, Ci_6alkoxycarbonyl, Ci_6alkanoyl, carbamoyl, N-C1-
6alkylcarbamoyl, N,N-(Ci_6alkyl)2carbamoyl, C3_i4carbocyclyl-C(O)-, heterocyclyl-C(O)-, (Ci_6alkyl)3silyl, Ci_6alkylS(O)a wherein a is 0 to 2, wherein R7, R9, and R15 may be each independently optionally substituted on carbon by one or more R12; and wherein if said hetercyclyl contains an =N- or a -S- moiety that nitrogen may be optionally substituted by one oxo group and that sulfur may be optionally substituted by one or two oxo groups; and wherein if said heterocyclyl contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from R13; L, for each occurrence, is independent selected from a direct bond, -O-, -N(R25)-,
-C(O)-, -N(R25)C(O)-, -C(O)N(R25)-, -S(O)8-, -SO2N(R25)- or -N(R25)SO2-; wherein R25, for each occurrence, is independently selected from hydrogen or Ci_6alkyl and s is 0, 1 or 2;
R10 and R12, for each occurrence, are independently selected from the group consisting of Ci-βalkyl, phenyl, halo, cyano, nitro, oxo, carboxy, hydroxy, Ci_6alkoxy, Ci_ βalkoxycarbonyl, amino, N-Ci_6alkylamino, N,N-(Ci_6alkyl)2amino, Ci_6alkanoylamino, Ci_ 6alkylSO2NH-, carbamoyl, N-Ci_6alkylcarbamoyl, N,N-(Ci_6alkyl)2carbamoyl, N-C1-
6 6aSlkyloxycarbamoyl, Ci_6alkylS(0)a wherein a is O to 2, and heterocyclyl, wherein said R 10 and R12 are independently optionally substituted on carbon by one or more C^alkyl and wherein if said heterocyclyl contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from R13 ;
R11, R13, R13 , and R26, for each occurrence, are each independently selected from the group consisting of C^alkyl, Ci_6alkoxycarbonyl, C^alkanoyl, C3_6cycloalkanoyl, carbamoyl, Ci_6alkanoyloxy, Ci_6alkylS(0)a, arylS(O)a wherein a is 0 to 2, carboxy, sulphamoyl and urea wherein said R11, R13, R13 , and R26 are independently optionally substituted on carbon by one or more amino, C^aUcyl, Ci_6alkoxy or heterocyclyl;
R16, for each occurrence, is independently, a halo, hydroxy, a d_6alkyl, or a C1- 6alkoxy;
R17 and R18, for each occurrence, are independently hydrogen or a Ci_6alkyl; or R17 and R18, together with the nitrogen to which they are attached form a heterocyclyl; R22, for each occurrence, is independently selected from the group consisting of halo,
Ci_6alkyl, S(O)aR" wherein a is 0 to 2, Ci_6alkanoyl, Ci_6alkanoylamino and heterocyclyl wherein R22 may be optionally substituted on carbon by one or more R24; R24 is selected from halo, Ci_6alkanoylamino, and heterocyclyl; provided that -NR1R2 is not -NHCH3 or -N(CH3)2. In another embodiment, according to the present invention there is provided a compound of formula (I):
Figure imgf000008_0001
or a pharmaceutically acceptable salt thereof, wherein:
X is CH or N;
R1 is hydrogen, a Ci_6alkyl, C2-6alkenyl, C2_6alkynyl, C3_i4carbocyclyl, or a heterocyclyl, wherein R1 may be optionally substituted on carbon by one or more R6; and wherein if said hetercyclyl contains an =N- or a -S- moiety that nitrogen may be optionally substituted by one oxo group and that sulfur may be optionally substituted by one or two oxo groups; and wherein if said heterocyclyl contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from R7; provided that R1 is not a substituted or unsubstituted phenyl;
R2 is hydrogen or a Ci_6alkyl; R1 and R2, together with the nitrogen to which they are attached, form a heterocyclyl, wherein said heterocyclyl may be optionally substituted on carbon by one or more R8; wherein if said hetercyclyl contains an =N- or a -S- moiety that nitrogen may be optionally substituted by one oxo group and that sulfur may be optionally substituted by one or two oxo groups; and wherein if said heterocyclyl contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from R9;
R3 is a Cβ-uaryl or a heteroaryl; wherein R3 may be optionally substituted on carbon by one or more R14; and wherein if said heteraryl contains an =N- or a -S- moiety that nitrogen may be optionally substituted by one oxo group and that sulfur may be optionally substituted by one or two oxo groups; and wherein if said heteroaryl contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from R15; provided that R3 is not an unsubstituted phenyl or an unsubstituted thiophenyl;
R4, for each occurrence, is independently selected from the group consisting of halo, cyano, nitro, hydroxy, Ci_6alkyl, Ci_6alkoxy, Ci_6alkyl-S(O)a, R17R18N-S(O)a, C3. i4carbocyclyl, and heterocyclyl; or two R4 taken together with the carbon atoms to which they are attached form a C3_i4carbocyclyl or a heterocyclyl, wherein each R4 may be optionally substituted on carbon by one or more R16; provided that ring B together with -(R4)n is not 3,4,5-trimethoxyphenyl; n is an integer from 1 to 5; a is 0, 1, or 2;
R6, R8, and R14, for each occurrence, are each independently selected from the group consisting of hydroxy, halo, cyano, nitro, Ci_6alkyl, C2-6alkenyl, C2-6alkynyl, mercapto, Ci_6alkoxy, Ci_6alkylS(O)a wherein a is 0 to 2, -C(=N-OH)NH2, phenoxy, carboxy, amino, N- Ci_6alkylamino, N,N-(Ci_6alkyl)2amino, a heterocyclyl, Ci_6alkoxycarbonyl, Ci_6alkanoyl, Ci_6alkanoyloxy, Ci_6alkanoylamino, Ci_6alkoxycarbonylamino, carbamoyl, N-C1- 6alkylcarbamoyl, N,N-(C1-6alkyl)2carbamoyl, Ci_6alkylsulphonylamino, sulphamoyl, Λ/-(Ci_6alkyl)sulphamoyl, Λ/,N-(Ci_6alkyl)2sulphamoyl, sulphamoylamino, Λ/-(Ci_6alkyl)sulphamoylamino, Λ/,Λ/-(Ci_6alkyl)2sulphamoylamino, C3_i4carbocyclyl-L- and heterocyclyl-L-; wherein R6, R8, and R14 may be each independently optionally substituted on carbon by one or more R10; and wherein if said hetercyclyl contains an =N- or a -S- moiety that nitrogen may be optionally substituted by one oxo group and that sulfur may be optionally substituted by one or two oxo groups; and wherein if said heterocyclyl contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from R11;
R7, R9, and R15, for each occurrence, are each independently selected from the group consisting of Ci-βalkyl, Ci_6alkoxycarbonyl, Ci_6alkanoyl, carbamoyl, N-Ci_6alkylcarbamoyl, N,N-(Ci_6alkyl)2carbamoyl, C3_i4carbocyclyl-C(O)-, heterocyclyl-C(O)-, (Ci_6alkyl)3silyl, Ci_6alkylS(O)a wherein a is 0 to 2, wherein R7, R9, and R15 may be each independently optionally substituted on carbon by one or more R12; and wherein if said hetercyclyl contains an =N- or a -S- moiety that nitrogen may be optionally substituted by one oxo group and that sulfur may be optionally substituted by one or two oxo groups; and wherein if said heterocyclyl contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from R13;
L, for each occurrence, is independent selected from a direct bond, -O-, -N(R25)-, -C(O)-, -N(R25)C(O)-, -C(O)N(R25)-, -S(O)8-, -SO2N(R25)- or -N(R25)SO2-; wherein R25, for each occurrence, is independently selected from hydrogen or Ci_6alkyl and s is 0, 1 or 2;
R10 and R12, for each occurrence, are independently selected from the group consisting of Ci_6alkyl, phenyl, halo, cyano, nitro, carboxy, hydroxy, Ci_6alkoxy, Ci_6alkoxycarbonyl, amino, N-Ci_6alkylamino, N,N-(Ci_6alkyl)2amino, carbamoyl, N-Ci_6alkylcarbamoyl, N5N- (Ci_6alkyl)2carbamoyl and N-Ci_6alkyloxycarbamoyl; and
R11 and R13, for each occurrence, are each independently a Ci_6alkyl;
R16, for each occurrence, is independently, a halo, hydroxy, a d_6alkyl, or a C1- βalkoxy;
R17 and R18, for each occurrence, are independently hydrogen or a Ci_6alkyl; or R17 and R18, together with the nitrogen to which they are attached form a heterocyclyl; provided that -NR1R2 is not -NHCH3, -N(CH3)2.
In another embodiment, the invention provides pharmaceutical compositions comprising a compound represented by formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier.
In another embodiment, the invention provides a method of inhibiting bacterial DNA gyrase and/or bacterial topoisomerase IV in a warm-blooded animal in need of such treatment, comprising administering to the animal an effective amount of a compound represented by formula (I), or a pharmaceutically acceptable salt thereof. In a particular embodiment, the warm-blooded animal is a human.
In another embodiment, the invention provides a method of producing an antibacterial effect in a warm-blooded animal in need of such treatment, comprising administering to the animal an effective amount of a compound represented by formula (I), or a pharmaceutically acceptable salt thereof. In a particular embodiment, the warm-blooded animal is a human.
In another embodiment, the invention provides a method of treating a bacterial infection in a warm-blooded animal in need thereof, comprising administering to the animal an effective amount of a compound represented by formula (I), or a pharmaceutically acceptable salt thereof. In a particular embodiment, the warm-blooded animal is a human. In one embodiment, the bacterial infection is selected from the group consisting of community- acquired pneumoniae, hospital-acquired pneumoniae, skin and skin structure infections, acute exacerbation of chronic bronchitis, acute sinusitis, acute otitis media, catheter-related sepsis, febrile neutropenia, osteomyelitis, endocarditis, urinary tract infections and infections caused by drug resistant bacteria such as Penicillin-resistant Streptococcus pneumoniae, methicillin- resistant Staphylococcus aureus, methicillin-resistant Staphylococcus epidermidis and Vancomycin-Resistant Enterococci. In a particular embodiment, the warm-blooded animal is a human. In another embodiment, the invention provides compounds of formula (I) or a pharmaceutically acceptable salt thereof, for use as a medicament.
In another embodiment, the invention provides the use of a compound represented by formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for use in the production of an antibacterial effect in a warm-blooded animal. In a particular embodiment, the warm-blooded animal is a human.
In another embodiment, the invention provides the use of a compound represented by formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for use in inhibition of bacterial DNA gyrase and/or topoisomerase IV in a warm-blooded animal. In a particular embodiment, the warm-blooded animal is a human.
In another embodiment, the invention provides the use of a compound represented by formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for use the treatment of a bacterial infection in a warm-blooded animal. In one embodiment, the bacterial infection is selected from the group consisting of community-acquired pneumoniae, hospital-acquired pneumoniae, skin and skin structure infections, acute exacerbation of chronic bronchitis, acute sinusitis, acute otitis media, catheter-related sepsis, febrile neutropenia, osteomyelitis, endocarditis, urinary tract infections, Penicillin-resistant Streptococcus pneumoniae, methicillin-resistant Staphylococcus aureus, methicillin-resistant Staphylococcus epidermidis and Vancomycin-Resistant Enterococci. In a particular embodiment, the warm-blooded animal is a human.
In another embodiment, the invention provides a compound represented by formula (I), or a pharmaceutically acceptable salt thereof, for use in production of an anti-bacterial effect in a warm-blooded animal.
In another embodiment, the invention provides a compound represented by formula (I), or a pharmaceutically acceptable salt thereof, for use in inhibition of bacterial DNA gyrase and/or topoisomerase IV in a warm-blooded animal.
In another embodiment, the invention provides a compound represented by formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of a bacterial infection in a warm-blooded animal. In another embodiment, the invention provides a compound represented by formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of community-acquired pneumoniae, hospital-acquired pneumoniae, skin and skin structure infections, acute exacerbation of chronic bronchitis, acute sinusitis, acute otitis media, catheter-related sepsis, febrile neutropenia, osteomyelitis, endocarditis, urinary tract infections, Penicillin-resistant Streptococcus pneumoniae, methicillin-resistant Staphylococcus aureus, methicillin-resistant Staphylococcus epidermidis or Vancomycin-Resistant Enterococci.
Detailed Description of the Invention
In this specification the term alkyl includes both straight chained and branched saturated hydrocarbon groups. For example, "Ci_6alkyl" refers to an alkyl that has from 1 to 6 carbon atom and includes, for example, methyl, ethyl, propyl, isopropyl and t-butyl. However references to individual alkyl groups such as propyl are specific for the straight chain version only unless otherwise indicated (e.g., isopropyl). An analogous convention applies to other generic terms. Unless otherwise specified, when two or more alkyl groups are indicated by, for example, the term (Ci_6alkyl)2 (such as in the term Λ/,Λ/-(Ci_6alkyl)2amino), the alkyl groups can be the same or different.
The term "C2-6alkenyl," as used herein refers to a straight chain or branched hydrocarbon having at least one double bond.
The term "C2_6alkynyl," as used herein refers to a straight chain or branched hydrocarbon having at least one triple bond.
As used herein, the term "halo" refers to fluoro, chloro, bromo, and iodo.
A "heterocyclyl" is a saturated, partially saturated or unsaturated, mono or bicyclic ring containing 4-14 atoms of which at least one atom is chosen from nitrogen, sulphur or oxygen, which may, unless otherwise specified, be carbon or nitrogen linked, wherein a -CH2- group can optionally be replaced by a -C(O)- and a ring nitrogen may be optionally substituted with one oxo to form an N-oxide and a ring sulfur may be optionally substituted with one or two oxo groups to form S-oxide(s). In one embodiment of the invention a "heterocyclyl" is a saturated, partially saturated or unsaturated, monocyclic ring containing 5 or 6 atoms of which at least one atom is chosen from nitrogen, sulphur or oxygen, it may, unless otherwise specified, be carbon or nitrogen linked. In a further aspect of the invention a "heterocyclyl" is an unsaturated, carbon-linked, monocyclic ring containing 5 or 6 atoms of which at least one atom is chosen from nitrogen, sulphur or oxygen. Examples and suitable values of the term "heterocyclyl" are azepanyl, azetidinyl, morpholinyl, piperidinyl, piperazinyl, pyridinyl, pyranyl, pyrrolyl, pyrazolyl, isothiazolyl, indolinyl, quinolinyl, thienyl, 1,3-benzodioxolyl, benzothiazolyl, thiadiazolyl, oxadiazolyl, piperazinyl, thiazolidinyl, pyrrolidinyl, thiomorpholino, pyrrolinyl, homopiperazinyl, 3,5-dioxapiperidinyl, tetrahydropyranyl, imidazolyl, 4,5-dihydro-oxazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, isoxazolyl, thiazolyl, lH-tetrazolyl, lH-triazolyl, JV-methylpyrrolyl, 4-pyridone, quinolin- 4(lH)-one, pyridin-2(lH)-one, imidazo[l,2-a]pyridinyl, 1-isoquinolone, 2-pyrrolidone, 4-thiazolidone, quinoxalinyl, 5,6-dihydro[l,3]thiazolo[4,5-<i]pyridazinyl, pyridine-Λ/-oxide and quinoline-iV-oxide. Suitable examples of "a nitrogen linked heterocyclyl" are morpholino, piperazin-1-yl, piperidin-1-yl and imidazol-1-yl. In a further aspect of the invention a "heterocyclyl" is a heteroaryl. The term "heteroaryl" refers to an unsaturated and aromatic heterocyclyl which has 5-14 ring atoms wherein at least one atom is chosen from nitrogen, sulphur or oxygen. Examples and suitable values for heteroaryl groups include pyridinyl, IH- pyrrolyl, lH-pyrazolyl, isothiazolyl, quinolinyl, thienyl, benzofuranyl, benzothiophenyl, benzothiazolyl, benzimidazolyl, thiadiazolyl, oxadiazolyl, lH-imidazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, isoxazolyl, thiazolyl, thiophenyl, lH-pyrazolyl, lH-tetrazolyl, IH- triazolyl, JV-methylpyrrolyl, 4-oxo-l,4-dihydroquinolinyl, pyridin-2(lH)-one, imidazo[l,2- ajpyridinyl, lH-indazol-1-yl, 1-isoquinolone, quinoxalinyl, pyridine -iV-oxide and quinoline-Λ/-oxide. In a particular embodiment, the heteroaryl is a 5- or 6-membered heteroaryl, for example, pyridinyl, lH-pyrrolyl, lH-pyrazolyl, isothiazolyl, thienyl, thiadiazolyl, oxadiazolyl, lH-imidazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, isoxazolyl, thiazolyl, lH-tetrazolyl, lH-triazolyl, JV-methylpyrrolyl, and pyridine-Λ/-oxide. In another embodiment heteroaryl also includes pyridinyl-2(lH)-one and indolyl. A "carbocyclyl" is a saturated, partially saturated or unsaturated, mono-, bi- or tricyclic carbon ring that contains 3-14 atoms; wherein a -CH2- group can optionally be replaced by a -C(O)-. In one embodiment, "carbocyclyl" is a monocyclic ring containing 5 or 6 atoms or a bicyclic ring containing 9 or 10 atoms. Examples of carbocyclyls include cyclopropyl, cyclobutyl, 1-oxocyclopentyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, phenyl, naphthyl, tetralinyl, indanyl or 1-oxoindanyl. The term carbocyclyl encompasses both cycloalkyl and aryl groups. The term cycloalkyl refers to a C3. i4carbocyclyl which is completely saturated, for example cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. The term "aryl" refers to a carbocyclyl which is completely unsaturated and is aromatic. A Cβ-waryl is an aromatic, mono-, bi- or tricyclic carbon ring that contains 6-14 atoms, for example phenyl or naphthenyl.
An example of "Ci_6alkanoyloxy" is acetoxy. Examples of "Ci_6alkoxycarbonyl" are methoxycarbonyl, ethoxycarbonyl, n- and t-butoxycarbonyl. Examples of "Ci_6alkoxycarbonylamino" are methoxycarbonylamino, ethoxycarbonylamino, n- and t-butoxycarbonylamino. Examples of "Ci_6alkoxy" are methoxy, ethoxy, isopropoxy, and tert- butoxy. Examples of "Ci_6alkanoylamino" are formamido, acetamido and propionylamino. Examples of "Ci_6alkylS(O)a wherein a is 0, 1, or 2" are methylthio, ethylthio, methylsulphinyl, ethylsulphinyl, methylsulfonyl and ethylsulphonyl. Examples of "Ci_6alkanoyl" are propionyl and acetyl. Examples of "N-(Ci_6alkyl)amino" are methylamino and ethylamino. Examples of "N1N-(C i_6alkyl)2amino" are N,N-dimethylamino, N,N-diethylamino and N-ethyl-N-methylamino. Examples of "C2-6alkenyl" are vinyl, allyl and 1-propenyl. Examples of "C2-6alkynyl" are ethynyl, 1-propynyl and 2-propynyl. Examples of "N-(Ci_6alkyl)sulphamoyl" are N-(methyl)sulphamoyl and N-(ethyl)sulphamoyl. Examples of "N,N-(Ci_6alkyl)2Sulphamoyl" are N,N-(dimethyl)sulphamoyl and
N-(methyl)-N-(ethyl)sulphamoyl. An example of "N,N-(Ci_6alkyl)2Sulphamoylamino" are N,N-dimethylsulphamoylamino. Examples of "N-(Ci_6alkyl)carbamoyl" are methylaminocarbonyl and ethylaminocarbonyl. Examples of "N1N-(C i_6alkyl)2carbamoyl" are dimethylaminocarbonyl and methylethylaminocarbonyl. Examples of "N-(Ci_6alkoxy)carbamoyl" are methoxyaminocarbonyl and isopropoxyaminocarbonyl. Examples of "N-(Ci_6alkyl)-N-(Ci_6alkoxy)carbamoyl" are
N-methyl-N-methoxyaminocarbonyl and N-methyl-N-ethoxyaminocarbonyl. Examples of "C3-6cycloalkyl" are cyclopropyl, cyclobutyl, cyclopropyl and cyclohexyl. Examples of "Ci_6alkylsulphonylamino" are methylsulphonylamino, isopropylsulphonylamino and t-butylsulphonylamino. Examples of "Ci_6alkylsulphonylaminocarbonyl" are methylsulphonylaminocarbonyl, isopropylsulphonylaminocarbonyl and t-butylsulphonylaminocarbonyl. Examples of "Ci_6alkylsulphonyl" are methylsulphonyl, isopropylsulphonyl and t-butylsulphonyl.
Examples of "Ci_3alkylsulphonylcarbamoyl" are methylsulphonylcarbamoyl, i.e. CH3SO2NHC(O)-, and ethylsulphonylcarbamoyl, i.e. CH3CH2SO2NHC(O)-.
When a carbon atom is substituted by "oxo" a -C(O)- is formed. Thus, for example, if a pyridyl group is substituted on carbon by oxo, a pyridinyl-one is formed, e.g. if the carbon in the two position of pyridine is substituted by oxo, pyridinyl-2(lH)-one is formed.
The term "formula (I)", unless otherwise specified, refers to all embodiments of formula (I).
A compound of formula (I) may form stable acid or basic salts, and in such cases administration of a compound as a salt may be appropriate, and pharmaceutically acceptable salts may be made by conventional methods such as those described below. Suitable pharmaceutically-acceptable salts include acid addition salts such as methanesulfonate, tosylate, α-glycerophosphate, fumarate, hydrochloride, citrate, maleate, tartrate and (less preferably) hydrobromide. Also suitable are salts formed with phosphoric and sulfuric acid. In another aspect suitable salts are base salts such as an alkali metal salt for example sodium, an alkaline earth metal salt for example calcium or magnesium, an organic amine salt for example triethylamine, morpholine, Λ/-methylpiperidine, TV-ethylpiperidine, procaine, dibenzylamine, JV,Λ/-dibenzylethylamine, tris-(2-hydroxyethyl)amine, JV-methyl d-glucamine and amino acids such as lysine. There may be more than one cation or anion depending on the number of charged functions and the valency of the cations or anions.. However, to facilitate isolation of the salt during preparation, salts which are less soluble in the chosen solvent may be preferred whether pharmaceutically-acceptable or not.
Within the present invention it is to be understood that a compound of the formula (I), or a salt thereof may exhibit the phenomenon of tautomerism and that the formulae drawings within this specification can represent only one of the possible tautomeric forms. It is to be understood that the invention encompasses any tautomeric form which inhibits DNA gyrase and / or topoisomerase IV and is not to be limited merely to any one tautomeric form utilized within the formulae drawings. The formulae drawings within this specification can represent only one of the possible tautomeric forms and it is to be understood that the specification encompasses all possible tautomeric forms of the compounds drawn not just those forms which it has been possible to show graphically herein. The same applies to compound names. It will be appreciated by those skilled in the art that certain compounds of formula (I) contain an asymmetrically substituted carbon and/or sulfur atom, and accordingly may exist in, and be isolated in, optically-active and racemic forms. Some compounds may exhibit polymorphism. It is to be understood that the present invention encompasses any racemic, optically-active, polymorphic or stereoisomeric form, or mixtures thereof, which form possesses properties useful in the inhibition of DNA gyrase and / or topoisomerase IV, it being well known in the art how to prepare optically-active forms (for example, by resolution of the racemic form by recrystallization techniques, by synthesis from optically-active starting materials, by chiral synthesis, by enzymatic resolution, by biotransformation, or by chromatographic separation using a chiral stationary phase) and how to determine efficacy for the inhibition of DNA gyrase and / or topoisomerase IV by the standard tests described hereinafter. By way of clarity, compounds of the invention included all isotopes of the atoms present in formula (I) and any of the examples or embodiments disclosed herein. For example, H (or hydrogen) represents any isotopic form of hydrogen including 1H, 2H (D), and 3H (T); C represents any isotopic form of carbon including 12C, 13C, and 14C; O represents any isotopic form of oxygen including 16O, 17O and 18O; N represents any isotopic form of nitrogen including 13N, 14N and 15N; P represents any isotopic form of phosphorous including 31P and 32P; S represents any isotopic form of sulfur including 32S and 35S; F represents any isotopic form of fluorine including 19F and 18F; Cl represents any isotopic form of chlorine including 35Cl, 37Cl and 36Cl; and the like. In a preferred embodiment, compounds represented by formula (I) comprises isomers of the atoms therein in about their naturally occurring abundance. However, in certain instances, it is desirable to enrich one or more atom in a particular isotope which would normally be present in less abundance. For example, 1H would normally be present in greater than 99.98% abundance; however, a compound of the invention can be enriched in 2H or 3H at one or more positions where H is present. In particular embodiments of the compounds of formula (I), when, for example, hydrogen is enriched in the deuterium isotope, the symbol "D" is used to represent the enrichment in deuterium. In one embodiment, when a compound of the invention is enriched in a radioactive isotope, for example 3H and 14C, they may be useful in drug and/or substrate tissue distribution assays. It is to be understood that the invention encompasses all such isotopic forms which inhibit DNA gyrase and / or topoisomerase IV.
It is also to be understood that certain compounds of the formula (I), and salts thereof can exist in solvated as well as unsolvated forms such as, for example, hydrated forms. It is to be understood that the invention encompasses all such solvated forms which inhibit DNA gyrase and / or topoisomerase IV. There follow particular and suitable values for certain substituents and groups referred to in this specification. These values may be used where appropriate with any of the definitions and embodiments disclosed hereinbefore, or hereinafter. For the avoidance of doubt each stated species represents a particular and independent aspect of this invention. In one embodiment the invention provides compounds represented by formula (I):
Figure imgf000017_0001
or a pharmaceutically acceptable salt thereof, wherein: X is CH or N;
R1 is hydrogen, a Ci_6alkyl, C2-6alkenyl, C2-6alkynyl, C3_i4carbocyclyl, or a heterocyclyl, wherein R1 may be optionally substituted on carbon by one or more R6; and wherein if said hetercyclyl contains an =N- or a -S- moiety that nitrogen may be optionally substituted by one oxo group and that sulfur may be optionally substituted by one or two oxo groups; and wherein if said heterocyclyl contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from R7; provided that R1 is not a substituted or unsubstituted phenyl;
R2 is hydrogen or a Ci_6alkyl;
R1 and R2, together with the nitrogen to which they are attached, form a heterocyclyl, wherein said heterocyclyl may be optionally substituted on carbon by one or more R8; wherein if said hetercyclyl contains an =N- or a -S- moiety that nitrogen may be optionally substituted by one oxo group and that sulfur may be optionally substituted by one or two oxo groups; and wherein if said heterocyclyl contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from R9; R3 is a C6_i4aryl or a heteroaryl; wherein R3 may be optionally substituted on carbon by one or more R14; and wherein if said heteraryl contains an =N- or a -S- moiety that nitrogen may be optionally substituted by one oxo group and that sulfur may be optionally substituted by one or two oxo groups; and wherein if said heteroaryl contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from R15; provided that R3 is not an unsubstituted phenyl or an unsubstituted thiophenyl;
R4, for each occurrence, is independently selected from the group consisting of halo, cyano, nitro, hydroxy, Ci_6alkyl, Ci_6alkoxy, Ci_6alkyl-S(O)a-, R17R18N-S(O)a-, C3- i4carbocyclyl, and heterocyclyl; or two R4 taken together with the carbon atoms to which they are attached form a C3_i4carbocyclyl or a heterocyclyl, wherein each R4 may be optionally substituted on carbon by one or more R16; provided that ring B together with -(R4)n is not 3,4,5-trimethoxyphenyl; n is an integer from 1 to 5; a is 0, l, or 2; R6, R8, and R14, for each occurrence, are each independently selected from the group consisting of hydroxy, halo, cyano, nitro, Ci_6alkyl, C2-6alkenyl, C2-6alkynyl, mercapto, Ci_6alkoxy, Ci_6alkylS(O)a wherein a is 0 to 2, -Q=N-OH)NH2, phenoxy, carboxy, amino, N- Ci_6alkylamino, N,N-(Ci_6alkyl)2amino, a heterocyclyl, Ci_6alkoxycarbonyl, Ci_6alkanoyl, Ci_6alkanoyloxy, Ci_6alkanoylamino, Ci_6alkoxycarbonylamino, carbamoyl, N-C1- 6alkylcarbamoyl, N,N-(C1-6alkyl)2carbamoyl, Ci_6alkylsulphonylamino, sulphamoyl, Λ/-(Ci_6alkyl)sulphamoyl, Λ/,N-(Ci_6alkyl)2sulphamoyl, sulphamoylamino, Λ/-(Ci_6alkyl)sulphamoylamino, Λ/,Λ/-(Ci_6alkyl)2sulphamoylamino, C3_i4carbocyclyl-L- and heterocyclyl-L-; wherein R6, R8, and R14 may be each independently optionally substituted on carbon by one or more R10; and wherein if said hetercyclyl contains an =N- or a -S- moiety that nitrogen may be optionally substituted by one oxo group and that sulfur may be optionally substituted by one or two oxo groups; and wherein if said heterocyclyl contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from R11;
R7, R9, and R15, for each occurrence, are each independently selected from the group consisting of Ci-βalkyl, Ci_6alkoxycarbonyl, Ci_6alkanoyl, carbamoyl, N-Ci_6alkylcarbamoyl, N,N-(Ci_6alkyl)2carbamoyl, C3-i4carbocyclyl-C(O)-, heterocyclyl-C(O)-, (Ci_6alkyl)3silyl, Ci_6alkylS(O)a wherein a is 0 to 2, wherein R7, R9, and R15 may be each independently optionally substituted on carbon by one or more R12; and wherein if said hetercyclyl contains an =N- or a -S- moiety that nitrogen may be optionally substituted by one oxo group and that sulfur may be optionally substituted by one or two oxo groups; and wherein if said heterocyclyl contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from R13;
L, for each occurrence, is independent selected from a direct bond, -O-, -N(R25)-, -C(O)-, -N(R25)C(O)-, -C(O)N(R25)-, -S(O)8-, -SO2N(R25)- or -N(R25)SO2-; wherein R25, for each occurrence, is independently selected from hydrogen or d_6alkyl and s is 0, 1 or 2; R10 and R12, for each occurrence, are independently selected from the group consisting of Ci_6alkyl, phenyl, halo, cyano, nitro, carboxy, hydroxy, Ci_6alkoxy, Ci_6alkoxycarbonyl, amino, N-Ci_6alkylamino, N,N-(Ci_6alkyl)2amino, carbamoyl, N-Ci_6alkylcarbamoyl, N5N- (Ci_6alkyl)2carbamoyl and N-Ci_6alkyloxycarbamoyl; and R11 and R13, for each occurrence, are each independently a Ci_6alkyl; R16, for each occurrence, is independently, a halo, hydroxy, a Ci-βalkyl, or a Ci_ 6alkoxy;
R17 and R18, for each occurrence, are independently hydrogen or a d_6alkyl; or R17 and R18, together with the nitrogen to which they are attached form a heterocyclyl; provided that -NR1R2 is not -NHCH3, -N(CH3)2.
In one embodiment the invention provides compounds represented by formula (I), or a pharmaceutically acceptable salt thereof, wherein X is N. In another embodiment the invention provides compounds represented by formula (I), or a pharmaceutically acceptable salt thereof, wherein X is CH.
In another embodiment the invention provides compounds represented by formula (I), or a pharmaceutically acceptable salt thereof, wherein R1 is a C^alkyl that is optionally substituted on carbon by one or more R6; and R2 is hydrogen. In another embodiment the invention provides compounds represented by formula (I), or a pharmaceutically acceptable salt thereof, wherein R1 is n-propyl, 3-(N5N- dimethylamino)-propyl, 3-(2-oxo-pyrrolidino)-propyl, l-acetyl-piperidine-4-yl, 2- morpho lino-ethyl, 2-acetamido-ethyl, 3-acetamido-propyl, pyridin-2-ylmethyl, pyridin-3- ylmethyl, pyridin-4-ylmethyl, 2-[(tert-butoxycarbonyl)amino]-ethyl, 2-carbamoyl-ethyl, 2- (pyridin-2-yl)-ethyl, 2-(pyridin-3-yl)-ethyl, 2-(pyridin-4-yl)ethyl, 2-(l , 1-dioxo- thiomorpholino)-ethyl, 3-(l,l-dioxo-thiomorpholino)-propyl, 3-morpholino-propyl, 2- methoxyethyl, tetrahydrofuran-2-ylmethyl, 2-(isopropoxy)ethyl, furan-2-ylmethyl, ethoxycarbonylmethyl, phenoxy ethyl, l-(methoxycarbonyl)ethyl, 6-methyl-pyrazin-3- ylmethyl, isopropyl, 3 -[(fert-butoxycarbonyl)amino] -propyl, 3-methoxypropyl, 2-(7V5TV- dimethylamino)-ethyl, 3-(lH-benzimidazol-2-yl)-propyl, 3-[(6-methyl-pyrazin-3- ylcarbonyl)amino] -propyl, 1 -methyl- 1 H-imidazol-5 -ylmethyl, 1 -methyl- 1 H-imidazol-4- ylmethyl, tetrahydrofuran-3-yl, 1 -methyl- lH-pyrazol-4-ylmethyl, 2-methoxy-l- methoxymethyl-ethyl, 3 -amino-propyl, carboxymethyl, 1-carboxy-ethyl, lH-benzimidazol-2- ylmethyl, 2-(lH-imidazol-4-yl)-ethyl, 2-(lH-benzimidazol-2-yl)-ethyl, 2-(lH-imidazol-l-yl)- ethyl, 2-(lH-pyrazol-l-yl)-ethyl, 2-(lH-pyrazol-4-yl)-ethyl, 2-(4-methyl-thiazole-5-yl)-ethyl, 2-(4-methyl-piperazino)-ethyl, 3-(lH-benzimidazol-2-yl)-propyl, 2-(5-methyl- lH-pyrazol-4- yl)-ethyl, 3 -[(methylsulfonyl)amino] -propyl, or [l-(ter£-butoxycarbonyl)-lH-benzimidazol-2- yljmethyl. In another embodiment the invention provides compounds represented by formula (I), or a pharmaceutically acceptable salt thereof, wherein R1 is a Ci_6alkyl which is optionally substituted with amino, carboxy, N,N-dimethylamino, 2-oxo-pyrrolidino, acetamido, pyridin- 2-yl, pyridin-3-yl, pyridin-4-yl, (tert-butoxycarbonyl)amino, carbamoyl, methylsulfonylamino, morpholino, 1,1-dioxo-thiomorpholino, methoxy, tetrahydrofuran-2-yl, isopropoxy, furan-2-yl, ethoxycarbonyl, phenoxy, methoxycarbonyl, 6-methyl-pyrazin-3-yl, benzoimidazol-2-yl, [(6-methyl-pyrazin-3-yl)carbonyl]amino, lH-imidazol-2-yl, IH- imidazol-1-yl, 1 -methyl- lH-imidazol-2-yl, 1 -methyl- lH-pyrazol-4-yl, 5-methyl-lH-pyrazol- 4-yl, lH-pyrazol-1-yl, lH-pyrazol-4-yl, 4-methyl-thiazole-5-yl, or 4-methyl-piperazino.
In another embodiment the invention provides compounds represented by formula (I), or a pharmaceutically acceptable salt thereof, wherein R1 and R2, together with the nitrogen to which they are attached, form a heterocyclyl, wherein said heterocyclyl may be optionally substituted on carbon by one or more R8; wherein if said hetercyclyl contains an =N- or a -S- moiety that nitrogen may be optionally substituted by one oxo group and that sulfur may be optionally substituted by one or two oxo groups; and wherein if said heterocyclyl contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from R9.
In another embodiment the invention provides compounds represented by formula (I), or a pharmaceutically acceptable salt thereof, wherein R1 and R2, together with the nitrogen to which they are attached, form a lH-pyrazol-1-yl, wherein said lH-pyrazol-1-yl may be optionally substituted on carbon by one or more R8.
In another embodiment the invention provides compounds represented by formula (I), or a pharmaceutically acceptable salt thereof, wherein R8 is independently a Ci_6alkyl or a C3. βcycloalkyl wherein said R8 is optionally substituted on carbon by one or more halo. In another embodiment the invention provides compounds represented by formula (I), or a pharmaceutically acceptable salt thereof, wherein R8 is independently a Ci_3alkyl or a C3. βcycloalkyl wherein said R8 is optionally substituted on carbon by one or more fluoro.
In another embodiment the invention provides compounds represented by formula (I), or a pharmaceutically acceptable salt thereof, wherein R1 and R2, together with the nitrogen to which they are attached, form a lH-pyrazol-1-yl, wherein lH-pyrazol-1-yl may be optionally substituted on carbon by one or more methyl, cyclopropyl or trifluoromethyl.
In another embodiment the invention provides compounds represented by formula (I), or a pharmaceutically acceptable salt thereof, wherein R1 and R2, together with the nitrogen to which they are attached, form piperidino, 4-hydroxy-piperidino, 3-hydroxymethyl-piperidino, 4-morpholino-piperidino, 4-(Λ/-methyl-carbamoyl)-piperidino, 4-fluoro-piperidino, A- methoxy-piperidino, 4-acetamido-piperidino, pyrrolidino, 3-hydroxy-pyrrolidino, 2-methyl- pyrrolidino, 2,5-dimethyl-pyrrolidino, azetidine-1-yl, 4-acetamidopiperidino, 3- trifluoromethyl-lH-pyrazol-1-yl, 3-trifluoromethyl-5-methyl-lH-pyrazol-l-yl, lH-imidazol- 1-yl, 4,5-dichloro-lH-imidazol-l-yl, 2-methyl-lH-imidazol-l-yl, lH-pyrrol-1-yl, morpholino, 2,6-dimethylmorpholino, 3,5-dimethyl-pyrazol-l-yl, 4-(pyridin-4-yl)-lH-pyrazol-l-yl, A- chloro- lH-pyrazol- 1 -yl, 4-trifluoromethyl- lH-imidazol- 1 -yl, 2 -methyl- lH-imidazol- 1 -yl, l,2,3-2H-triazol-2-yl, 1,2,3-lH-triazol-l-yl, 1,2,3-lH-benzotriazol-l-yl, 1,2,3-2H- benzotriazol-2-yl, IH-[1, 2,3]triazolo[4,5-b]pyridin-l-yl, 2H-[l,2,3]triazolo[4,5-b]pyridin-2- yl, azepan-1-yl, 4-aceto-piperazino, 4-(2-methoxy-ethyl)-piperazino, 4-methyl-piperazino, A- [(N,Λ/-dimethylamino)carbonyl]-piperazino, 4-(methylsulfonyl)-piperazino, or A- cyclopropylcarbonyl-piperazino .
In another embodiment the invention provides compounds represented by formula (I), or a pharmaceutically acceptable salt thereof, wherein R1 and R2, together with the nitrogen to which they are attached, form a heterocyclyl selected fromlH-pyrazol-1-yl, lH-benzotriazol- 1-yl, 2H-benzotriazol-2-yl, and lH-l,2,3-triazol-l-yl, wherein said heterocyclyl may be optionally substituted on carbon by one or more R8; wherein if said hetercyclyl contains an =N- or a -S- moiety that nitrogen may be optionally substituted by one oxo group and that sulfur may be optionally substituted by one or two oxo groups; and wherein if said heterocyclyl contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from R9. In one embodiment, R8, for each occurrence, is independently selected from hydroxy, hydroxymethyl, morpholino, N-methylcarbamoyl, fluoro, methoxy, methyl, acetamido, trifluoromethyl, chloro, and pyridin-4-yl. In another embodiment, R9, for each occurrence, is independently selected from a Ci_6alkyl, 2-methoxyethyl, acetyl, N,N- dimethylcarbamoyl, cyclopropylcarbonyl, methylsulfonyl and tert-butoxycarbonyl.
In another embodiment, R1 is a C3_i4carbocyclyl; wherein R1 may be optionally substituted on carbon by one or more R6; provided that R1 is not a substituted or unsubstituted phenyl. In one embodiment, R1 is cyclohexyl. In another embodiment, R6 is hydroxy. In another embodiment, R1 is a heterocycyl; wherein R1 may be optionally substituted on carbon by one or more R6; and wherein if said hetercyclyl contains an =N- or a -S- moiety that nitrogen may be optionally substituted by one oxo group and that sulfur may be optionally substituted by one or two oxo groups; and wherein if said heterocyclyl contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from R7; provided that R1 is not a substituted or unsubstituted phenyl. In one embodiment, R1 is piperidinyl or tetrahydrofuranyl which may be optionally substituted on carbon by one or more R6; and wherein the -NH- moiety of piperidinyl may be optionally t substituted by a group selected from R7.
In another embodiment the invention provides compounds represented by formula (I), or a pharmaceutically acceptable salt thereof, wherein R3 is a C6-14aryl; wherein R3 may be optionally substituted on carbon by one or more R14; provided that R3 is not an unsubstituted phenyl. In another embodiment the invention provides compounds represented by formula (I), or a pharmaceutically acceptable salt thereof, wherein R3 is phenyl substituted on carbon by two R14 which taken together with the carbon atoms to which they are attached form a C3. i4carbocyclyl or a heterocyclyl; wherein R14 may be independently optionally substituted on carbon by one or more R10; and wherein if said hetercyclyl contains an =N- or a -S- moiety that nitrogen may be optionally substituted by one oxo group and that sulfur may be optionally substituted by one or two oxo groups; and wherein if said heterocyclyl contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from R11.
In another embodiment the invention provides compounds represented by formula (I), or a pharmaceutically acceptable salt thereof, wherein R3 is a heteroaryl; wherein R3 may be optionally substituted on carbon by one or more R14; and wherein if said heteraryl contains an =N- or a -S- moiety that nitrogen may be optionally substituted by one oxo group and that sulfur may be optionally substituted by one or two oxo groups; and wherein if said heteroaryl contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from R15; provided that R3 is not an unsubstituted thiophenyl. In another embodiment the invention provides compounds represented by formula (I), or a pharmaceutically acceptable salt thereof, wherein R14, for each occurrence, is independently selected from methoxycarbonyl, (methylsulfonyl)amino, ethoxycarbonyl, acetyl, amino, 5-oxo-4,5-dihydro-l,2,4-oxadiazolyl, trifluoromethyl, methoxy, (dimethylsulfamoyl)amino, cyano, fluoro, nitro, (E)-2-carboxyethenyl, 2-carboxy-ethyl, carboxy, (E)-2-ethoxycarbonylethenyl, (E)-2-carbamoyl-ethenyl, (E)-2-(N-methylcarbamoyl)- ethenyl, (E)-2-(N-methoxycarbamoyl)-ethenyl, N-methoxycarbamoyl, N-ethyl-carbamoyl, N- benzyl-carbamoyl, N,N-dimethylcarbamoyl, piperidinocarbonyl, 3,3-difluoro- piperidinocarbonyl, or N'-hydroxycarbamimidoyl. In another embodiment the invention provides compounds represented by formula (I), or a pharmaceutically acceptable salt thereof, wherein R3 is phenyl; wherein R3 is substituted on carbon by one or more R14. For example, R14, for each occurrence, is independently selected from methoxycarbonyl, (methylsulfonyl)amino, ethoxycarbonyl, trifluoromethyl, methoxy, (dimethylsulfamoyl)amino, cyano, fluoro, nitro, (E)-2-carboxyethenyl, 2-carboxy- ethyl, carboxy, (E)-2-ethoxycarbonylethenyl, (E)-2-carbamoyl-ethenyl, (E)-2-(N- methylcarbamoyl)-ethenyl, (E)-2-(N-methoxycarbamoyl)-ethenyl, N-methoxycarbamoyl, N- ethyl-carbamoyl, N-benzyl-carbamoyl, or N,N-dimethylcarbamoyl.
In another embodiment the invention provides compounds represented by formula (I), or a pharmaceutically acceptable salt thereof, wherein R3 is pyrimidinyl, indolinyl, pyridinyl, benzofuranyl, benzothiophenyl, thiophenyl, lH-pyrazolyl, 4-oxo-l,4-dihydroquinolinyl, thiazolyl, quinolinyl, and benzimidazolyl; wherein R3 may be optionally substituted on carbon by one or more R14; and wherein if R3 contains an =N- or a -S- moiety that nitrogen may be optionally substituted by one oxo group and that sulfur may be optionally substituted by one or two oxo groups; and wherein if R3 contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from R15; provided that R3 is not an unsubstituted thiophenyl. In one embodiment, R14, for each occurrence, is independently selected from methoxycarbonyl, ethoxycarbonyl, acetyl, amino, 5-oxo-4,5-dihydro-l,2,4-oxadiazolyl, methoxy, carboxy, N-ethyl-carbamoyl, N-benzyl-carbamoyl, N,N-dimethylcarbamoyl, piperidinocarbonyl, 3,3-difluoro-piperidinocarbonyl, or N'-hydroxycarbamimidoyl. In another embodiment, R15, for each occurrence, is independently selected from tert-butyl- dimethyl-silyl, 2-methoxyethyl, or tert-butoxycarbonyl.
In another embodiment the invention provides compounds represented by formula (I), or a pharmaceutically acceptable salt thereof, wherein R3 is 2-methoxyphenyl, 3- methoxyphenyl, 4-methoxyphenyl, 3-(methoxycarbonyl)-phenyl, 4-(ethoxycarbonyl)-phenyl, 3 -[(methylsulfony)amino] -phenyl, 4-methoxy-3 -trifluoromethyl, 3,4,5-trimethoxy-phenyl, 3- [(dimethylsulfamoyl)amino]-phenyl, 3-cyano-4-fluoro-phenyl, 3-nitrophenyl, 4- carboxyphenyl, 3-carboxyphenyl, 4-(2-carboxyethyl)-phenyl, 4-[(E)-2-carboxyethenyl]- phenyl, 3-[(E)-2-carboxyethenyl]-phenyl, 3 -[(E)-2-ethoxycarbonylethenyl] -phenyl, 3-[(E)-2- (JV-methylcarbamoyl)ethenyl]-phenyl, 3 -[(E)-2-carbamoylethenyl] -phenyl, 3-[(E)-2-(N- methyloxycarbamoyl)ethenyl]-phenyl, 3-(7V-ethylcarbamoyl)-phenyl, 3-(7V-benzylcarbamoyl)- phenyl, 4-(7V-ethylcarbamoyl)-phenyl, 4-(Λf,Λ/-dimethylcarbamoyl)-phenyl, or 4-(N- benzylcarbamoyl)-phenyl. In another embodiment the invention provides compounds represented by formula (I), or a pharmaceutically acceptable salt thereof, wherein R3 is 2-methoxypyrimidin-5-yl, indolin-6-yl, 5-ethoxycarbonyl-pyridin-3-yl, 2,6-dimethoxypyridin-4-yl, benzofuran-2-yl, 5- acetyl-thiophen-2-yl, 5-cyano-pyridin-3-yl, l-(tert-butoxy-dimethyl-silyl)-lH-indolin-3-yl, 5- carboxy-thiophen-2-yl, 6-methoxy-pyridin-3-yl, 2-amino-pyrimidin-5-yl, lH-pyrazol-4-yl, 6- amino-pyridin-3 -yl, 2-methoxycarbonyl-benzothiophen-5 -yl, 2-carboxy-benzothiophen-5 -yl, pyridin-3-yl, pyrimidin-5-yl, 5-carboxy-pyridin-3-yl, 5-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3- yl)-pyridin-3-yl, 4-oxo-3-ethoxycarbonyl-l-(2-methoxyethyl)-l,4-dihydroquinolin-6-yl, 4- oxo-3-carboxy- 1 -(2-methoxyethyl)- 1 ,4-dihydroquinolin-6-yl, 4-methoxy-thiazol-2-yl, 3- carboxy-quinolin-6-yl, 5-(N,N-dimethylcarbamoyl)-thiophen-2-yl, 5-(N-methylcarbamoyl)- thiophen-2-yl, 5-(N-benzylcarbamoyl)-thiophen-2-yl, 5-(piperdinocarbonyl)-thiophen-2-yl, 5- (3 ,3 -difluoropiperdinocarbonyl)-thiophen-2-yl, 5 -(N-benzylcarbamoyl)-pyridin-3 -yl, 5 -(N'- hydroxycarbamimidoyl)-pyridin-3-yl, or 5-(5-oxo-4,5-dihydro-l ,2,4-oxadiazol-3-yl)-pyridin- 3-yl. In another embodiment the invention provides compounds represented by formula (I), or a pharmaceutically acceptable salt thereof, wherein R3 is 1 -ethyl -(2-methoxyethyl)-4-oxo- l,4-dihydroquinolin-6-yl-carboxylate or lH-indol-6-yl.
In another embodiment the invention provides compounds represented by formula (I), or a pharmaceutically acceptable salt thereof, wherein R3 is a pyridin-3-yl or 2-oxo-pyridin-5- yl group wherein said pyridin-3-yl or 2-oxo-pyridin-5-yl group may be optionally substituted on carbon by one or more R14 and wherein the N of said 2-oxo-pyridin-5-yl is substituted by a group selected from R15.
In another embodiment the invention provides compounds represented by formula (I), or a pharmaceutically acceptable salt thereof, wherein R14, for each occurrence, is independently a carboxy, Ci_6alkoxy, Ci_6alkylsulphonylcarbamoyl, Ci_6alkoxycarbamoyl, or Ci_6alkylS(O)a wherein a is 0, 1 or 2.
In another embodiment the invention provides compounds represented by formula (I), or a pharmaceutically acceptable salt thereof, wherein R15, for each occurrence, is independently a C^alkyl wherein said C^alkyl is optionally substituted by C^alkoxy or saturated heterocyclyl.
In another embodiment the invention provides compounds represented by formula (I), or a pharmaceutically acceptable salt thereof, wherein R14, for each occurrence, is independently a carboxy, Ci_3alkoxy, Ci_3alkylsulphonylcarbamoyl, Ci_3alkoxycarbamoyl, or Ci_3alkylS(O)a wherein a is 0, 1 or 2.
In another embodiment the invention provides compounds represented by formula (I), or a pharmaceutically acceptable salt thereof, wherein R15, for each occurrence, is independently a Ci_3alkyl wherein said Ci_3alkyl is optionally substituted by Ci_3alkoxy or saturated heterocyclyl.
In another embodiment the invention provides compounds represented by formula (I), or a pharmaceutically acceptable salt thereof, wherein R15, for each occurrence, is independently a Ci_3alkyl wherein said Ci_3alkyl is optionally substituted by Ci_3alkoxy or morpholino.
In another embodiment the invention provides compounds represented by formula (I), or a pharmaceutically acceptable salt thereof, wherein R3 is a 6-membered heteroaryl containing at least one nitrogen atom wherein one of the carbon atoms of said 6-membered heteroaryl ring may be optionally substituted with O to form a -(CO)-, and further wherein said 6-membered heteroaryl may be optionally substituted on carbon by one or more R14 and when one of the carbon atoms of said 6-membered heteroaryl ring is substituted with O to form a -(CO)-, the nitrogen of that 6-membered heteroaryl is substituted by a group selected from R15.
In another embodiment the invention provides compounds represented by formula (I), or a pharmaceutically acceptable salt thereof, wherein R3 is 2 -oxo-3 -carboxy- 1-ethyl-pyridin- 5-yl, 2-0X0-3 -carboxy- 1 -(2 -methoxyethyl)-pyridin-5-yl, 3-carboxy-6-(2- dimethylaminoethoxy)-pyridin-5 -yl, 3 -(N-2-hydroxyethylcarbamoyl)-pyridin-5 -yl, 3 -N-(I- methylsulfonylethyl)carbamoyl-pyridin-5 -yl, 2-methoxy-3 -carboxy-pyridin-5 -yl, 3 -N- methylcarbamoyl-pyridin-5-yl, 2-oxo-3 -carboxy- 1 -methyl-pyridin-5-yl, 2-oxo-3-N- (methylsulfonyl)-carbamoyl- 1 -methyl-pyridin-5-yl, 3 -N-methoxycarbamoyl-pyridin-5 -yl, 3 - carboxy-pyridin-5 -yl, 2-oxo-3 -carboxy- 1 -(2-morpholinoethyl)-pyridin-5-yl, 3-carboxy-2- methylsulphanyl-pyridin-5 -yl, 3 -carboxy-pyridin-5 -yl, 2-methoxy-3 -(N- methylsulfonylcarbamoyl)-pyridin-5 -yl, and 2-methoxy-3 -(N-ethylsulfonylcarbamoyl)- pyridin-5-yl. In another embodiment the invention provides compounds represented by formula (I), or a pharmaceutically acceptable salt thereof, wherein n is 1.
In another embodiment the invention provides compounds represented by formula (I), or a pharmaceutically acceptable salt thereof, wherein n is 2. In another embodiment the invention provides compounds represented by formula (I), or a pharmaceutically acceptable salt thereof, wherein n is 3.
In another embodiment the invention provides compounds represented by formula (I), or a pharmaceutically acceptable salt thereof, wherein n is 4. In another embodiment the invention provides compounds represented by formula (I), or a pharmaceutically acceptable salt thereof, wherein n is 4.
In another embodiment the invention provides compounds represented by formula (I), or a pharmaceutically acceptable salt thereof, wherein R4, for each occurrence, is independently a halo, Ci_6alkyl or Ci_6alkoxy. In another embodiment the invention provides compounds represented by formula (I), or a pharmaceutically acceptable salt thereof, wherein n is 2 and R4, for each occurrence, is independently a halo, Ci_6alkyl or d_6alkoxy.
In another embodiment the invention provides compounds represented by formula (I), or a pharmaceutically acceptable salt thereof, wherein n is 2 and R4, for each occurrence, is independently a F, Cl, methyl or methoxy.
In another embodiment the invention provides compounds represented by formula (I), or a pharmaceutically acceptable salt thereof, wherein R4, for each occurrence, is independently selected from methyl, hydroxymethyl, fluoro, chloro, bromo, lH-tetrazole-1-yl, methoxy, cyano, 5-methyl-lH-tetrazole-l-yl, 2-methoxyethoxy, nitro, morpholinosulfonyl, or trifluoromethyl.
In another embodiment the invention provides compounds represented by formula (I), or a pharmaceutically acceptable salt thereof, wherein n is 2 and one R4 is fluoro and the other is chloro.
In another embodiment the invention provides compounds represented by formula (I), or a pharmaceutically acceptable salt thereof, wherein two adjacent R4 together with ring B form lH-indolinyl.
In another embodiment the invention provides compounds represented by formula (I), or a pharmaceutically acceptable salt thereof, wherein:
X is N; R1 is a Ci_6alkyl which is optionally substituted with on carbon with one or more R6;
R2 is hydrogen; R3 is 5-carboxy-pyridin-3-yl, S-ethoxycarbonyl-pyridin-S-yl, 3-[(E)-2- carboxyethenyl] -phenyl, 3 - [(E)-2-ethoxycarbonylethenyl] -phenyl, 3 -[(E)-2-(N- methylcarbamoyl)ethenyl]-phenyl, or 3-[(E)-2-carbamoylethenyl]-phenyl; n is 2; and R4, for each occurrence is independently selected from a halo.
In another embodiment the invention provides compounds represented by formula (I), or a pharmaceutically acceptable salt thereof, wherein:
X is N; R1 is n-propyl, 3-(Λf,Λ/-dimethylamino)-propyl, 2-(pyridin-2-yl)-ethyl, 2-(pyridin-3- yl)-ethyl, or 2-(pyridin-4-yl)ethyl; R2 is hydrogen;
R3 is 5-carboxy-pyridin-3-yl, 5-ethoxycarbonyl-pyridin-3-yl, 3-[(E)-2- carboxyethenyl] -phenyl, 3-[(E)-2-ethoxycarbonylethenyl]-phenyl, 3-[(E)-2-(7V- methylcarbamoyl)ethenyl]-phenyl, or 3-[(E)-2-carbamoylethenyl]-phenyl; n is 2; and one of R4 is fluoro and the other is chloro.
In another embodiment the invention provides compounds represented by formula (I), or a pharmaceutically acceptable salt thereof, wherein:
X is N;
R1 and R2, together with the nitrogen to which they are attached, form pyrazol-1-yl wherein said pyrazol-1-yl may be optionally substituted on carbon by one or more R8;
R3 is a 6-membered heteroaryl containing at least one nitrogen atom wherein one of the carbon atoms of said 6-membered heteroaryl ring may be optionally substituted with O to form a -(CO)-, and further wherein said 6-membered heteroaryl may be optionally substituted on carbon by one or more R14 and when one of the carbon atoms of said 6-membered heteroaryl ring is substituted with O to form a -(CO)-, the nitrogen of that 6-membered heteroaryl is substituted by a group selected from R15; n is 2;
R4, for each occurrence, is independently a halo, Ci_6alkyl or Ci_6alkoxy;
R8, for each occurrence, is independently a d_6alkyl or a C3_6cycloalkyl wherein said R8 is optionally substituted on carbon by one or more fluoro; R14, for each occurrence, is independently a carboxy, Ci_6alkoxy, Ci_
3alkylsulphonylcarbamoyl, N-Ci_3alkylcarbamoyl, N-Ci_3alkoxycarbamoyl, or Ci_6alkylS(O)a wherein a is 0, 1 or 2 wherein said R14 may be optionally substituted on carbon by one or more hydroxy, (Ci_3alkyl)2N, or Ci_3alkylsulfonyl; and R15, for each occurrence, is independently a Ci_6alkyl wherein said Ci_6alkyl is optionally substituted by Ci_6alkoxy or saturated heterocyclyl.
In another embodiment the invention provides compounds represented by formula (I), or a pharmaceutically acceptable salt thereof, wherein: X is N;
R1 and R2, together with the nitrogen to which they are attached, form pyrazol-1-yl wherein said pyrazol-1-yl may be optionally substituted on carbon by one or more R8;
R3 is a 6-membered heteroaryl containing at least one nitrogen atom wherein one of the carbon atoms of said 6-membered heteroaryl ring may be optionally substituted with O to form a -(CO)-, and further wherein said 6-membered heteroaryl may be optionally substituted on carbon by one or more R14 and when one of the carbon atoms of said 6-membered heteroaryl ring is substituted with O to form a -(CO)-, the nitrogen of that 6-membered heteroaryl is substituted by a group selected from R15; n is 2; R4, for each occurrence, is independently a halo, Ci_6alkyl or Ci_6alkoxy;
R8, for each occurrence, is independently a methyl, trifluoromethyl or a cyclopropyl;
R14, for each occurrence, is independently a carboxy, Ci_6alkoxy, Ci_
3alkylsulphonylcarbamoyl, N-Ci_3alkylcarbamoyl, N-Ci_3alkoxycarbamoyl, or Ci_6alkylS(O)a wherein a is 0, 1 or 2 wherein said R14 may be optionally substituted on carbon by one or more hydroxy, (Ci_3alkyl)2N, or C^alkylsulfonyl; and
R15, for each occurrence, is independently a Ci_6alkyl wherein said Ci_6alkyl is optionally substituted by Ci_6alkoxy or saturated heterocyclyl.
In another embodiment the invention provides compounds represented by formula (I), or a pharmaceutically acceptable salt thereof, wherein: X is N;
R1 and R2, together with the nitrogen to which they are attached, form pyrazol-1-yl wherein said pyrazol-1-yl may be optionally substituted on carbon by one or more R8; R3 is a pyridin-3-yl or 2-oxo-pyridin-5-yl group wherein said pyridin-3-yl or 2-oxo- pyridin-5-yl group may be optionally substituted on carbon by one or more R14 and wherein the N of said 2-oxo-pyridin-5-yl is substituted by a group selected from R15; n is 2; R4, for each occurrence, is independently a halo, Ci_3alkyl or Ci_3alkoxy;
R8, for each occurrence, is independently a Ci_3alkyl optionally substituted on carbon by one or more fluoro;
R14, for each occurrence, is independently a carboxy, Ci_3alkoxy, Ci_
3alkylsulphonylcarbamoyl, N-Ci_3alkylcarbamoyl, N-Ci_3alkoxycarbamoyl, or Ci_3alkylS(O)a wherein a is 0, 1 or 2, wherein said R14 may be optionally substituted on carbon by one or more hydroxy, (C 1-3 alky I)2N-, or Ci_3alkylsulfonyl;
R15, for each occurrence, is independently a C^alkyl wherein said Ci_3alkyl is optionally substituted by Ci_3alkoxy or saturated heterocyclyl.
In another embodiment the invention provides compounds represented by formula (I), or a pharmaceutically acceptable salt thereof, wherein: X is N;
R1 and R2, together with the nitrogen to which they are attached, form a heterocyclyl selected fromlH-pyrazol-1-yl, lH-benzotriazol-1-yl, 2H-benzotriazol-2-yl, and 1H-1,2,3- triazol-1-yl, wherein said heterocyclyl may be optionally substituted on carbon by one or more R8; wherein if said hetercyclyl contains an =N- or a -S- moiety that nitrogen may be optionally substituted by one oxo group and that sulfur may be optionally substituted by one or two oxo groups; and wherein if said heterocyclyl contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from R9; R3 is 5-carboxy-pyridin-3-yl, 5-ethoxycarbonyl-pyridin-3-yl, 3-[(E)-2- carboxyethenyl] -phenyl, 3-[(E)-2-ethoxycarbonylethenyl]-phenyl, 3-[(E)-2-(7V- methylcarbamoyl)ethenyl]-phenyl, or 3-[(E)-2-carbamoylethenyl]-phenyl; n is 2;
R4, for each occurrence is independently a halo; R8, for each occurrence, is independently hydroxy, hydroxymethyl, morpholino, N- methylcarbamoyl, fluoro, methoxy, methyl, acetamido, trifluoromethyl, chloro, or pyridin-4- yi; R9, for each occurrence, is independently a Ci^alkyl, 2-methoxyethyl, acetyl, NJV- dimethylcarbamoyl, cyclopropylcarbonyl, methylsulfonyl or tert-butoxycarbonyl.
Particular compounds of the invention are the compounds of the Examples, and pharmaceutically acceptable salts thereof, each of which provides a further independent aspect of the invention. For those examples which are themselves in the form of a salt, a further independent aspect of the invention is those specific salts as well as other pharmaceutically acceptable salts thereof and the free bases therof. In further aspects, the present invention also comprises any two or more compounds of the Examples.
In another embodiment the invention provides compounds of Examples 319, 675, 677, 679, 681, 683, 684, 761, 815, 854, 861, 863, 909, 918, 919, 1019, 1026, 1075, 1076, 1086, 1087, 1088, 1143, 1145, 1152, 1159 and 1160, and or a pharmaceutically acceptable salt thereof.
In another embodiment the invention provides compounds of Examples 319, 638, 675, 677, 679, 681, 683, 684, 761, 815, 854, 861, 863, 909, 918, 919, 1019, 1026, 1075, 1076, 1086, 1087, 1088, 1143, 1145, 1152, 1159 and 1160, and or a pharmaceutically acceptable salt thereof.
In another embodiment, the invention provides pharmaceutical compositions comprising a pharmaceutically acceptable excipient or carrier and a compound represented by formula (I), or a pharmaceutically acceptable salt thereof. In a further aspect the present invention provides a process for preparing a compound of formula (I), or a pharmaceutically-acceptable salt thereof, wherein variable groups in the schemes below are as defined in formula (I) unless otherwise specified. In general, the compounds of the invention can be prepared by adding Ring B, -NR1R2 and R3 to a pyrimidine or pyridine core in any order. For example, formula (I) can be prepared by the following methods:
Process a: Reacting a compound of formula (i):
Figure imgf000030_0001
with a compound of formula (ii):
Figure imgf000031_0003
in the presence of a palladium(O) catalyst and a base, such as sodium carbonate, wherein L1 is a displaceable group such as a halo; and R19 and R20 are each independently hydrogen or a Ci_ βalkyl; or R19 and R20 together form a C2-4alkylene bridge which may be optionally substituted with one or more independently selected Ci_4alkyl groups.
Process B: Reacting a compound of formula (iii):
Figure imgf000031_0001
wherein R21 is a Ci_6alkyl or a C6-14aryl; with a compound represented by formula (iv):
Figure imgf000031_0002
in the presence of a base, such as NaH, diisopropylethylamine, or NaOH. In some instances, it may be necessary to heat the reaction. Compounds represented by formula (i) can be prepared by reacting a compound represented by formula (v):
Figure imgf000032_0001
with a compound represented by formula (vi):
Figure imgf000032_0002
in the presence of an acid, such as HCl and heat, wherein L1 and L2 are each, independently, displaceable groups, such as a halo.
A compound represented by formula (v) can be prepared from a pyrimidine or pyridine derivative by reacting a compound represented by formula (vii):
Figure imgf000032_0003
with a compound represented by formula (iv) in the presence of a base and optionally heat, wherein L1, L2 and L3 are each, independently, displaceable groups, such as a halo.
Compounds represented by formula (iii) can be prepared by treating a compound represented by formula (viii):
Figure imgf000032_0004
with a peroxide, such as 3-chloroperoxybenzoic acid. Compounds represented by formula (viii) can be prepared by reacting a compound represented by formula (ix):
Figure imgf000033_0001
with a compound represented by formula (vi) in the presence of an acid, such as HCl and heat.
Compounds represented by formula (ix) can be prepared by reacting a compound represented by formula (x):
Figure imgf000033_0002
with a compound represented by formula (ii) in the presence of a palladium(O) catalyst and a base, such as sodium carbonate.
Alternatively, compounds represented by formula (iii) can be prepared by reacting a compound represented by formula (xi):
Figure imgf000033_0003
with a compound of formula (ii) in the presence of a palladium(O) catalyst and a base, such as sodium carbonate.
Compounds represented by formula (xi) can be prepared by treating a compound represented by formula (xii):
Figure imgf000034_0001
with a peroxide, such as 3-chloroperoxybenzoic acid.
Compounds represented by formula (xii) can be prepared by reacting a compound represented by formula (x) with an aniline derivative represented by formula (vi) in the presence of an acid, such as HCl and heat.
Compounds represented by formulas (ii), (iv), (vi), (vii) and (x) can be purchased or prepared by standard methods known in the art. The formation of a pharmaceutically-acceptable salt is within the skill of an ordinary organic chemist using standard techniques.
It will be appreciated that certain of the various ring substituents in the compounds of the present invention may be introduced by standard aromatic substitution reactions or generated by conventional functional group modifications either prior to or immediately following the processes mentioned above, and as such are included in the process aspect of the invention. The reagents used to introduce such ring substituents are either commercially available or are made by processes known in the art.
Introduction of substituents into a ring may convert one compound of the formula (I) into another compound of the formula (I). Such reactions and modifications include, for example, introduction of a substituent by means of an aromatic substitution reaction, reduction of substituents, alkylation of substituents, oxidation of substituents, esterification of substituents, amidation of substituents, formation of heteroaryl rings. Particular examples of aromatic substitution reactions include the introduction of alkoxides, diazotization reactions followed by introduction of thiol group, alcohol group, halogen group. Examples of modifications include; oxidation of alkylthio to alkylsulphinyl or alkylsulphonyl. (See
Advanced Organic Chemistry, 4th Edition, by Jerry March, published by John Wiley & Sons 1992). In one embodiment, an ester substituent on a compound of formula (I) may be converted to a carboxylic acid by treating the ester with a base, such as sodium hydroxide, barium hydroxide, or trimethyltin hydroxide. In another embodiment, a carboxylic acid substituent on a compound of formula (I) may be converted to an amide by reacting the carboxylic acid group with a primary or secondary amine in the presence of a peptide coupling reagent, such as O-(7-azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), dicyclohexylcarbodiimide (DCC), or l-ethyl-3-(3- dimethyllaminopropyl)carbodiimide (EDC). The reagents and reaction conditions for such procedures are well known in the chemical art.
The skilled organic chemist will be able to use and adapt the information contained and referenced within the above references, and accompanying Examples therein and also the Examples herein, to obtain necessary starting materials, and products. If not commercially available, the necessary starting materials for the procedures such as those described above may be made by procedures which are selected from standard organic chemical techniques, techniques which are analogous to the synthesis of known, structurally similar compounds, or techniques which are analogous to the above described procedure or the procedures described in the examples. It is noted that many of the starting materials for synthetic methods as described above are commercially available and/or widely reported in the scientific literature, or could be made from commercially available compounds using adaptations of processes reported in the scientific literature. The reader is further referred to Advanced Organic Chemistry, 4th Edition, by Jerry March, published by John Wiley & Sons 1992, for general guidance on reaction conditions and reagents. It will also be appreciated that in some of the reactions mentioned herein it may be necessary/desirable to protect any sensitive groups in compounds. The instances where protection is necessary or desirable are known to those skilled in the art, as are suitable methods for such protection. Conventional protecting groups may be used in accordance with standard practice (for illustration see T. W. Greene, Protective Groups in Organic Synthesis, John Wiley and Sons, 1991).
Examples of a suitable protecting group for a hydroxy group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an aroyl group, for example benzoyl, a silyl group such as trimethylsilyl or an arylmethyl group, for example benzyl. The deprotection conditions for the above protecting groups will necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or an aroyl group may be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively a silyl group such as trimethylsilyl may be removed, for example, by fluoride or by aqueous acid; or an arylmethyl group such as a benzyl group may be removed, for example, by hydrogenation in the presence of a catalyst such as palladium-on-carbon.
A suitable protecting group for an amino group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an alkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl or t-butoxycarbonyl group, an arylmethoxycarbonyl group, for example benzyloxycarbonyl, or an aroyl group, for example benzoyl. The deprotection conditions for the above protecting groups necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or alkoxycarbonyl group or an aroyl group may be removed for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively an acyl group such as a t-butoxycarbonyl group may be removed, for example, by treatment with a suitable acid as hydrochloric, sulphuric or phosphoric acid or trifluoroacetic acid and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon, or by treatment with a Lewis acid for example boron tris(trifluoroacetate). A suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group which may be removed by treatment with an alkylamine, for example dimethylaminopropylamine or 2-hydroxyethylamine, or with hydrazine.
A suitable protecting group for a carboxy group is, for example, an esterifying group, for example a methyl or an ethyl group which may be removed, for example, by hydrolysis with a base such as sodium hydroxide, or for example a t-butyl group which may be removed, for example, by treatment with an acid, for example an organic acid such as trifluoroacetic acid, or for example a benzyl group which may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon, or for example, an allyl group which may be removed, for example, by use of a palladium catalyst such as palladium acetate.
The protecting groups may be removed at any convenient stage in the synthesis using conventional techniques well known in the chemical art, or they may be removed during a later reaction step or work-up.
When an optically active form of a compound of the invention is required, it may be obtained by carrying out one of the above procedures using an optically active starting material (formed, for example, by asymmetric induction of a suitable reaction step), or by resolution of a racemic form of the compound or intermediate using a standard procedure, or by chromatographic separation of diastereoisomers (when produced). Enzymatic techniques may also be useful for the preparation of optically active compounds and/or intermediates.
Similarly, when a pure regioisomer of a compound of the invention is required, it may be obtained by carrying out one of the above procedures using a pure regioisomer as a starting material, or by resolution of a mixture of the regioisomers or intermediates using a standard procedure.
Enzyme Potency Testing Methods
E.coli GyrB ATPase Inhibition Activity: Compounds may be tested for inhibition of E. coli GyrB ATPase activity using an ammonium molybdate/malachite green-based phosphate detection assay (Lanzetta, P. A., L. J. Alvarez, P. S. Reinach, and O. A. Candia, 1979, 100: 95-97). Assays are performed in multiwell plates in 30μl reactions containing: 50 mM Hepes buffer pH 7.5, 75 mM ammonium acetate, 8.0 mM magnesium chloride, 0.5 mM ethylenediaminetetraacetic acid, 5% glycerol, 1 mM 1 ,4-Dithio-DL-threitol, 200 nM bovine serum albumin, 1.6 μg/ml sheared salmon sperm DNA, 400 pM E. coli GyrA, 400 pM E. coli GyrB, 250 μM ATP, and the test compound in dimethylsulfoxide. Reactions are quenched with 30 μl of ammonium molybdate/malachite green detection reagent containing 1.2 mM malachite green hydrochloride, 8.5 mM ammonium molybdate tetrahydrate, and 1 M hydrochloric acid. Plates can be read in an absorbance plate reader at 650 nm and percent inhibition values are calculated using dimethylsulfoxide (2%)-containing reactions as 0% inhibition and EDTA-containing (2.4 μM) reactions as 100% inhibition controls. An IC50 measurement of compound potency for each compound can be determined from reactions performed in the presence of 10 different compound concentrations.
E. coli Topoisomerase IV ATPase Inhibition Activity: Compounds may be tested for inhibition of E. coli topoisomerase IV ATPase activity as described above for E. coli GyrB except the 30μl reactions contained the following: 20 mM TRIS buffer pH 8, 50 mM ammonium acetate, 8 mM magnesium chloride, 5% glycerol, 5 mM 1 ,4-Dithio-DL-threitol, 0.005% Brij-35, 5 μg/ml sheared salmon sperm DNA, 500 pM E. coli ParC, 500 pM E. coli ParE, 160 μM ATP, and test compound in dimethylsulfoxide. An IC50 measurement of compound potency for each compound can be determined from reactions performed in the presence of 10 different compound concentrations. S. aureus GyrB ATPase Inhibition Activity: Compounds may be tested for inhibition of S. aureus GyrB ATPase activity using an ammonium molybdate/malachite green-based phosphate detection assay (Lanzetta, P. A., L. J. Alvarez, P. S. Reinach, and O. A. Candia, 1979, 100: 95-97). Assays are performed in multiwell plates in 30μl reactions containing: 50 mM Hepes buffer pH 7.5, 75 mM ammonium acetate, 8.0 mM magnesium chloride, 0.5 mM ethylenediaminetetraacetic acid, 5% glycerol, 1.0 mM 1 ,4-Dithio-DL-threitol, 200 nM bovine serum albumin, 1.0 μg/ml sheared salmon sperm DNA, 250 pM E. coli GyrA, 250 pM S. aureus GyrB, 250 μM ATP, and test compound in dimethylsulfoxide. Reactions are quenched with 30 μl of ammonium molybdate/malachite green detection reagent containing 1.2 mM malachite green hydrochloride, 8.5 mM ammonium molybdate tetrahydrate, and 1 M hydrochloric acid. Plates are read in an absorbance plate reader at 650 nm and percent inhibition values can be calculated using dimethylsulfoxide (2%)-containing reactions as 0% inhibition and EDTA-containing (2.4 μM) reactions as 100% inhibition controls. An IC50 measurement of compound potency for each compound can be determined from reactions performed in the presence of 10 different compound concentrations.
S. pneumoniae Topoisomerase IV ATPase Inhibition Activity: Compounds may be tested for inhibition of S. pneumoniae ParE ATPase activity using an ammonium molybdate/malachite green-based phosphate detection assay (Lanzetta, P. A., L. J. Alvarez, P. S. Reinach, and O. A. Candia, 1979, 100: 95-97). Assays are performed in multiwell plates in 30μl reactions containing: 20 mM Tris buffer pH 8.0, 50 mM ammonium acetate, 8.0 mM magnesium chloride, 0.5 mM ethylenediaminetetraacetic acid, 5% glycerol, 5 mM 1 ,4-Dithio-DL-threitol, 0.005 % Brij-35, 5 μg/ml sheared salmon sperm DNA, 1.25 nM S. pneumoniae ParE, 160 μM ATP, and test compound in dimethylsulfoxide. Reactions are quenched with 30 μl of ammonium molybdate/malachite green detection reagent containing 1.2 mM malachite green hydrochloride, 8.5 mM ammonium molybdate tetrahydrate, and 1 M hydrochloric acid. Plates are read in an absorbance plate reader at 650 nm and percent inhibition values are calculated using dimethylsulfoxide (2%)-containing reactions as 0% inhibition and EDTA-containing (20 μM) reactions as 100% inhibition controls. An IC50 measurement of compound potency for each compound can be determined from reactions performed in the presence of 10 different compound concentrations.
Many of the compounds of the invention were tested in an assay substantially similar to the assays described above for measuring the inhibition of E. coli GyrB ATPase, E. coli Topoisomerase IV ATPase, S. aureus GyrB ATPase, and S. pneumoniae Topoisomerase IV ATPase, and had IC50 values of <200μM in one or more assays.
The compounds of the examples (Ex) were tested in an assay substantially similar to the assay described above for measuring the inhibition of S. pneumoniae Topoisomerase IV ATPase and were found to have a percent inhibition (% Inh) of S. pneumoniae Topoisomerase IV ATPase as shown in the table below.
Figure imgf000039_0001
Figure imgf000040_0001
Figure imgf000041_0001
Figure imgf000042_0001
Figure imgf000043_0001
Figure imgf000044_0001
Figure imgf000045_0001
Figure imgf000046_0001
Figure imgf000047_0001
Figure imgf000048_0001
Figure imgf000049_0001
Figure imgf000050_0001
Figure imgf000051_0001
Note: Examples which are marked with "*" are an average of two or more data points. Bacterial Susceptibility Testing Methods
Compounds may be tested for antimicrobial activity by susceptibility testing in liquid media. Compounds may be dissolved in dimethylsulfoxide and tested in 10 doubling dilutions in the susceptibility assays. The organisms used in the assay may be grown overnight on suitable agar media and then suspended in a liquid medium appropriate for the growth of the organism. The suspension can be a 0.5 McFarland and a further 1 in 10 dilution can be made into the same liquid medium to prepare the final organism suspension in 100 μL. Plates can be incubated under appropriate conditions at 37 0C for 24 hrs prior to reading. The Minimum Inhibitory Concentration (MIC) may be determined as the lowest drug concentration able to reduce growth by 80% or more.
In an assay comparable to the above, compounds of the invention had MICs as shown in the table below:
Figure imgf000052_0001
According to a further feature of the invention there is provided a compound of the formula (I), or a pharmaceutically-acceptable salt thereof, for use in a method of treatment of the human or animal body by therapy.
In one embodiment, the invention provides a method of treating a bacterial infection in an animal, such as a human, comprising administering to the animal or human an effective amount of a compound of any one of formulas (I), or a pharmaceutically acceptable salt thereof.
We have found that compounds of the present invention inhibit bacterial DNA gyrase and / or topoisomerase IV and are therefore of interest for their antibacterial effects. In one aspect of the invention the compounds of the invention inhibit bacterial DNA gyrase and are therefore of interest for their antibacterial effects. In one aspect of the invention, the compounds of the invention inhibit topoisomerase IV and are therefore of interest for their antibacterial effects. In one aspect of the invention, the compounds of the invention inhibit both DNA gyrase and topoisomerase IV and are therefore of interest for their antibacterial effects. Thus, the compounds of the invention are useful in treating or preventing bacterial infections.
In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Acinetobacter baumanii. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Acinetobacter haemolyticus . In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Acinetobacter junii. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Acinetobacter johnsonii. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Acinetobacter Iwoffi. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Bacteroides bivius. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Bacteroides fragilis . In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Burkholderia cepacia. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Campylobacter jejuni. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Chlamydia pneumoniae. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Chlamydia urealyticus . In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Chlamydophila pneumoniae. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Clostridium difficile. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Enterobacter aerogenes. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Enterobacter cloacae. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Enterococcus faecalis . In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by
Enterococcus faecium. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Escherichia coli. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Gardnerella vaginalis. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Haemophilus par ^influenzae. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Haemophilus influenzae. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Helicobacter pylori. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Klebsiella pneumoniae. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Legionella pneumophila. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Methicillin-resistant Staphylococcus aureus. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Methicillin-susceptible Staphylococcus aureus. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Moraxella catarrhalis. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Morganella morganii. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Mycoplasma pneumoniae. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Neisseria gonorrhoeae. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Penicillin- resistant Streptococcus pneumoniae. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Penicillin-susceptible Streptococcus pneumoniae. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Peptostreptococcus magnus. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Peptostreptococcus micros. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Peptostreptococcus anaerobius. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Peptostreptococcus asaccharolyticus . In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Peptostreptococcus prevotii. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Peptostreptococcus tetradius. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Peptostreptococcus vaginalis. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Proteus mirabilis. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Pseudomonas aeruginosa. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Quino lone-Resistant Staphylococcus aureus. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Quinolone-Resistant Staphylococcus epidermis. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Salmonella typhi. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Salmonella paratyphi. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Salmonella enteritidis. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Salmonella typhimurium. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Serratia marcescens. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Staphylococcus aureus. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Staphylococcus epidermidis. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Staphylococcus saprophyticus . In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Streptoccocus agalactiae. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Streptococcus pneumoniae. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Streptococcus pyogenes. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Stenotrophomonas maltophilia. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Ureaplasma urealyticum. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Vancomycin-Resistant Enterococcus faecium. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Vancomycin-Resistant Enterococcus faecalis. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Vancomycin-Resistant Staphylococcus aureus. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Vancomycin-Resistant Staphylococcus epidermis. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Mycobacterium tuberculosis. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Clostridium perfringens. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Klebsiella oxytoca. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Neisseria miningitidis. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Fusobacterium spp. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Peptococcus spp. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Proteus vulgaris. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Coagulase-negative Staphylococcus (including Staphylococcus lugdunensis, Staphylococcus capitis, Staphylococcus hominis, and Staphylococcus saprophytic ).
In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Acinetobacter spp. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Bacteroides spp. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Burkholderia spp. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Campylobacter spp. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Chlamydia spp. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Chlamydophila spp. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Clostridium spp. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Enterobacter spp. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Enterococcus spp. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Escherichia spp. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Gardnerella spp. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Haemophilus spp. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Helicobacter spp. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Klebsiella spp. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Legionella spp. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Moraxella spp. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Morganella spp. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Mycoplasma spp. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Neisseria spp. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Peptostreptococcus spp. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Proteus spp. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Pseudomonas spp. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Salmonella spp. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Serratia spp. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Staphylococcus spp. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Streptoccocus spp. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Stenotrophomonas spp. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Ureaplasma spp. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by aerobes. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by obligate anaerobes. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by facultative anaerobes. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by gram-positive bacteria. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by gram-negative bacteria. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by gram- variable bacteria. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by atypical respiratory pathogens. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Enterics. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Shigella spp. In one aspect of the invention an "infection" or "bacterial infection" refers to an infection caused by Citrobacter. In one aspect of the invention "infection" or "bacterial infection" refers to a gynecological infection. In one aspect of the invention "infection" or "bacterial infection" refers to a respiratory tract infection (RTI). In one aspect of the invention "infection" or "bacterial infection" refers to a sexually transmitted disease. In one aspect of the invention "infection" or "bacterial infection" refers to a urinary tract infection. In one aspect of the invention "infection" or "bacterial infection" refers to acute exacerbation of chronic bronchitis (ACEB). In one aspect of the invention "infection" or "bacterial infection" refers to acute otitis media. In one aspect of the invention "infection" or "bacterial infection" refers to acute sinusitis. In one aspect of the invention "infection" or "bacterial infection" refers to an infection caused by drug resistant bacteria. In one aspect of the invention "infection" or "bacterial infection" refers to catheter-related sepsis. In one aspect of the invention "infection" or "bacterial infection" refers to chancroid. In one aspect of the invention "infection" or "bacterial infection" refers to chlamydia. In one aspect of the invention "infection" or "bacterial infection" refers to community-acquired pneumonia (CAP). In one aspect of the invention "infection" or "bacterial infection" refers to complicated skin and skin structure infection. In one aspect of the invention "infection" or "bacterial infection" refers to uncomplicated skin and skin structure infection. In one aspect of the invention "infection" or "bacterial infection" refers to endocarditis. In one aspect of the invention "infection" or "bacterial infection" refers to febrile neutropenia. In one aspect of the invention "infection" or "bacterial infection" refers to gonococcal cervicitis. In one aspect of the invention "infection" or "bacterial infection" refers to gonococcal urethritis. In one aspect of the invention "infection" or "bacterial infection" refers to hospital-acquired pneumonia (HAP). In one aspect of the invention "infection" or "bacterial infection" refers to osteomyelitis. In one aspect of the invention "infection" or "bacterial infection" refers to sepsis. In one aspect of the invention "infection" or "bacterial infection" refers to syphilis. In one aspect of the invention "infection" or "bacterial infection" refers to ventilator-associated pneumonia. In one aspect of the invention "infection" or "bacterial infection" refers to intraabdominal infections. In one aspect of the invention "infection" or "bacterial infection" refers to gonorrhoeae. In one aspect of the invention "infection" or "bacterial infection" refers to meningitis. In one aspect of the invention "infection" or "bacterial infection" refers to tetanus. In one aspect of the invention "infection" or "bacterial infection" refers to tuberculosis.
In one embodiment, it is expected that the compounds of the present invention will be useful in treating bacterial infections including, but not limited to community-acquired pneumoniae, hospital-acquired pneumoniae, skin & skin structure infections, acute exacerbation of chronic bronchitis, acute sinusitis, acute otitis media, catheter-related sepsis, febrile neutropenia, osteomyelitis, endocarditis, urinary tract infections and infections caused by drug resistant bacteria such as Penicillin-resistant Streptococcus pneumoniae, methicillin- resistant Staphylococcus aureus, methicillin-resistant Staphylococcus epidermidis and Vancomycin-Resistant Enterococci.
According to a further feature of the present invention there is provided a method for producing an antibacterial effect in a warm blooded animal, such as man, in need of such treatment, which comprises administering to said animal an effective amount of a compound of the present invention, or a pharmaceutically-acceptable salt thereof. According to a further feature of the invention there is provided a method for inhibition of bacterial DNA gyrase and / or topoisomerase IV in a warm-blooded animal, such as a human being, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof as defined hereinbefore.
According to a further feature of the invention there is provided a method of treating a bacterial infection in a warm-blooded animal, such as a human being, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof as defined hereinbefore.
According to a further feature of the invention there is provided a method of treating a bacterial infection selected from community-acquired pneumoniae, hospital-acquired pneumoniae, skin & skin structure infections, acute exacerbation of chronic bronchitis, acute sinusitis, acute otitis media, catheter-related sepsis, febrile neutropenia, osteomyelitis, endocarditis, urinary tract infections and infections caused by drug resistant bacteria such as Penicillin-resistant Streptococcus pneumoniae, methicillin-resistant Staphylococcus aureus, methicillin-resistant Staphylococcus epidermidis and Vancomycin-Resistant Enterococciin a warm-blooded animal, such as a human being, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof as defined hereinbefore.
A further feature of the present invention is a compound of formula (I), and pharmaceutically acceptable salts thereof for use as a medicament. Suitably the medicament is an antibacterial agent. According to a further aspect of the invention there is provided the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in the production of an anti-bacterial effect in a warm-blooded animal such as a human being.
According to a further aspect of the invention there is provided the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in inhibition of bacterial DNA gyrase and / or topoisomerase IV in a warm-blooded animal such as a human being.
Thus according to a further aspect of the invention there is provided the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of a bacterial infection in a warm-blooded animal such as a human being.
Thus according to a further aspect of the invention there is provided the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of a bacterial infection selected from community- acquired pneumoniae, hospital-acquired pneumoniae, skin & skin structure infections, acute exacerbation of chronic bronchitis, acute sinusitis, acute otitis media, catheter-related sepsis, febrile neutropenia, osteomyelitis, endocarditis, urinary tract infections and infections caused by drug resistant bacteria such as Penicillin-resistant Streptococcus pneumoniae, methicillin- resistant Staphylococcus aureus, methicillin-resistant Staphylococcus epidermidis and Vancomycin-Resistant Enterococci in a warm-blooded animal such as a human being.
According to a further aspect of the invention there is provided a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in the production of an anti- bacterial effect in a warm-blooded animal such as a human being.
According to a further aspect of the invention there is provided a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in inhibition of bacterial DNA gyrase and / or topoisomerase IV in a warm-blooded animal such as a human being.
Thus according to a further aspect of the invention there is provided a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of a bacterial infection in a warm-blooded animal such as a human being.
Thus according to a further aspect of the invention there is provided a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of a bacterial infection selected from community-acquired pneumoniae, hospital-acquired pneumoniae, skin & skin structure infections, acute exacerbation of chronic bronchitis, acute sinusitis, acute otitis media, catheter-related sepsis, febrile neutropenia, osteomyelitis, endocarditis, urinary tract infections and infections caused by drug resistant bacteria such as Penicillin-resistant Streptococcus pneumoniae, methicillin-resistant Staphylococcus aureus, methicillin-resistant Staphylococcus epidermidis and Vancomycin-Resistant Enterococci in a warm-blooded animal such as a human being.
In order to use a compound of the formula (I), or a pharmaceutically-acceptable salt thereof, (hereinafter in this section relating to pharmaceutical composition "a compound of this invention") for the therapeutic (including prophylactic) treatment of mammals including humans, in particular in treating infection, it is normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition.
Therefore in another aspect the present invention provides a pharmaceutical composition which comprises a compound of the formula (I), or a pharmaceutically-acceptable salt thereof, and a pharmaceutically-acceptable diluent or carrier. According to a further aspect of the invention there is provided a pharmaceutical composition which comprises a compound of formula (I), as defined hereinbefore or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable excipient or carrier for use in producing an anti-bacterial effect in an warm-blooded animal, such as a human being.
According to a further aspect of the invention there is provided a pharmaceutical composition which comprises a compound of formula (I), as defined hereinbefore or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable excipient or carrier for use in inhibition of bacterial DNA gyrase and / or topoisomerase IV in an warm-blooded animal, such as a human being.
According to a further aspect of the invention there is provided a pharmaceutical composition which comprises a compound of formula (I), as defined hereinbefore or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable excipient or carrier for use in the treatment of a bacterial infection in an warm-blooded animal, such as a human being.
According to a further aspect of the invention there is provided a pharmaceutical composition which comprises a compound of formula (I), as defined hereinbefore or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable excipient or carrier for use in the treatment of a bacterial infection selected from community- acquired pneumoniae, hospital-acquired pneumoniae, skin & skin structure infections, acute exacerbation of chronic bronchitis, acute sinusitis, acute otitis media, catheter-related sepsis, febrile neutropenia, osteomyelitis, endocarditis, urinary tract infections and infections caused by drug resistant bacteria such as Penicillin-resistant Streptococcus pneumoniae, methicillin- resistant Staphylococcus aureus, methicillin-resistant Staphylococcus epidermidis and Vancomycin-Resistant Enterococci in an warm-blooded animal, such as a human being.
The compositions of the invention may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular or intramuscular dosing or as a suppository for rectal dosing). The compositions of the invention may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art. Thus, compositions intended for oral use may contain, for example, one or more coloring, sweetening, flavoring and/or preservative agents. Suitable pharmaceutically acceptable excipients for a tablet formulation include, for example, inert diluents such as lactose, sodium carbonate, calcium phosphate or calcium carbonate, granulating and disintegrating agents such as corn starch or algenic acid; binding agents such as starch; lubricating agents such as magnesium stearate, stearic acid or talc; preservative agents such as ethyl or propyl p-hydroxybenzoate, and anti-oxidants, such as ascorbic acid. Tablet formulations may be uncoated or coated either to modify their disintegration and the subsequent absorption of the active ingredient within the gastrointestinal tract, or to improve their stability and/or appearance, in either case, using conventional coating agents and procedures well known in the art.
Compositions for oral use may be in the form of hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or an oil such as peanut oil, liquid paraffin, or olive oil.
Aqueous suspensions generally contain the active ingredient in finely powdered form together with one or more suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents such as lecithin or condensation products of an alkylene oxide with fatty acids (for example polyoxethylene stearate), or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives (such as ethyl or propyl p-hydroxybenzoate, anti-oxidants (such as ascorbic acid), colouring agents, flavouring agents, and/or sweetening agents (such as sucrose, saccharine or aspartame). OiIy suspensions may be formulated by suspending the active ingredient in a vegetable oil (such as arachis oil, olive oil, sesame oil or coconut oil) or in a mineral oil (such as liquid paraffin). The oily suspensions may also contain a thickening agent such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set out above, and flavouring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water generally contain the active ingredient together with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients such as sweetening, flavoring and coloring agents, may also be present.
The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, such as olive oil or arachis oil, or a mineral oil, such as for example liquid paraffin or a mixture of any of these. Suitable emulsifying agents may be, for example, naturally-occurring gums such as gum acacia or gum tragacanth, naturally-occurring phosphatides such as soya bean, lecithin, an esters or partial esters derived from fatty acids and hexitol anhydrides (for example sorbitan monooleate) and condensation products of the said partial esters with ethylene oxide such as polyoxy ethylene sorbitan monooleate. The emulsions may also contain sweetening, flavoring and preservative agents.
Syrups and elixirs may be formulated with sweetening agents such as glycerol, propylene glycol, sorbitol, aspartame or sucrose, and may also contain a demulcent, preservative, flavoring and/or coloring agent.
The pharmaceutical compositions may also be in the form of a sterile injectable aqueous or oily suspension, which may be formulated according to known procedures using one or more of the appropriate dispersing or wetting agents and suspending agents, which have been mentioned above. A sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example a solution in 1,3-butanediol. Compositions for administration by inhalation may be in the form of a conventional pressurized aerosol arranged to dispense the active ingredient either as an aerosol containing finely divided solid or liquid droplets. Conventional aerosol propellants such as volatile fluorinated hydrocarbons or hydrocarbons may be used and the aerosol device is conveniently arranged to dispense a metered quantity of active ingredient.
For further information on formulation the reader is referred to Chapter 25.2 in Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press 1990.
The amount of active ingredient that is combined with one or more excipients to produce a single dosage form will necessarily vary depending upon the host treated and the particular route of administration. For example, a formulation intended for oral administration to humans will generally contain, for example, from 0.5 mg to 2 g of active agent compounded with an appropriate and convenient amount of excipients which may vary from about 5 to about 98 percent by weight of the total composition. Dosage unit forms will generally contain about 1 mg to about 500 mg of an active ingredient. For further information on Routes of Administration and Dosage Regimes the reader is referred to Chapter 25.3 in Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press 1990.
The compounds of the invention described herein may be applied as a sole therapy or may involve, in addition to a compound of the invention, one or more other substances and/or treatments. Such conjoint treatment may be achieved by way of the simultaneous, sequential or separate administration of the individual components of the treatment. Where the administration is sequential or separate, the delay in administering the second component should not be such as to lose the beneficial effect of the combination. Suitable classes and substances may be selected from one or more of the following: i) other antibacterial agents for example macrolides e.g. erythromycin, azithromycin or clarithromycin; quinolones e.g. ciprofloxacin or levofloxacin; β-lactams e.g. penicillins e.g. amoxicillin or piperacillin; cephalosporins e.g. ceftriaxone or ceftazidime; carbapenems, e.g. meropenem or imipenem etc; aminoglycosides e.g. gentamicin or tobramycin; or oxazolidinones; and/or ii) anti-infective agents for example, an antifungal triazole e.g. or amphotericin; and/or iii) biological protein therapeutics for example antibodies, cytokines, bactericidal/permeability-increasing protein (BPI) products; and/or iv) efflux pump inhibitors. Therefore, in a further aspect of the invention there is provided a compound of the formula (I), or a pharmaceutically acceptable salt thereof, and a chemotherapeutic agent selected from: i) one or more additional antibacterial agents; and/or ii) one or more anti-infective agents; and/or iii) biological protein therapeutics for example antibodies, cytokines, bactericidal/permeability-increasing protein (BPI) products; and/or iv) one or more efflux pump inhibitors.
In another embodiment, the invention relates to a method of treating a bacterial infection in an animal, such as a human, comprising administering to the animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a chemotherapeutic agent selected from: i) one or more additional antibacterial agents; and/or ii) one or more anti-infective agents; and/or iii) biological protein therapeutics for example antibodies, cytokines, bactericidal/permeability-increasing protein (BPI) products; and/or iv) one or more efflux pump inhibitors.
As stated above the size of the dose required for the therapeutic or prophylactic treatment of a particular disease state will necessarily be varied depending on the host treated, the route of administration, the severity of the illness being treated, and whether or not an additional chemotherapeutic agent is administered in combination with a compound of the invention. Preferably a daily dose in the range of 1-50 mg/kg is employed. However the daily dose will necessarily be varied depending upon the host treated, the particular route of administration, the severity of the illness being treated, and whether or not an additional chemotherapeutic agent is administered in combination with a compound of the invention. Accordingly the optimum dosage may be determined by the practitioner who is treating any particular patient.
As noted above, one embodiment of the present invention is directed to treating or preventing diseases caused by bacterial infections, wherein the bacteria comprise a GyrB ATPase or topoisomerase IV ATP ase enzyme. "Treating a subject with a disease caused by a bacterial infection" includes achieving, partially or substantially, one or more of the following: the reducing or amelioration of the progression, severity and/or duration of the infection, arresting the spread of an infection, ameliorating or improving a clinical symptom or indicator associated with a the infection (such as tissue or serum components), and preventing the reoccurrence of the infection.
As used herein, the terms "preventing a bacterial infection" refer to the reduction in the risk of acquiring the infection, or the reduction or inhibition of the recurrence of the infection. In a preferred embodiment, a compound of the invention is administered as a preventative measure to a patient, preferably a human, before a surgical procedure is preformed on the patient to prevent infection.
As used herein, the term "effective amount" refers to an amount of a compound of this invention for treating or preventing a bacterial infection is an amount which is sufficient to prevent the onset of an infection, reduce or ameliorate the severity, duration, or progression, of an infection, prevent the advancement of an infection, cause the regression of an infection, prevent the recurrence, development, onset or progression of a symptom associated with an infection, or enhance or improve the prophylactic or therapeutic effect(s) of another therapy.
In addition to its use in therapeutic medicine, compounds of formula (I), and their pharmaceutically acceptable salts, are also useful as pharmacological tools in the development and standardization of in-vitro and in-vivo test systems for the evaluation of the effects of inhibitors of DNA gyrase and / or topoisomerase IV in laboratory animals such as cats, dogs, rabbits, monkeys, rats and mice, as part of the search for new therapeutic agents.
In the above pharmaceutical composition, process, method, use and medicament manufacture features, the alternative and particular embodiments of the compounds of the invention described herein also apply.
Experimental
The invention is now illustrated but not limited by the following Examples in which unless otherwise stated :- (i) evaporations were carried out by rotary evaporation in- vacuo and work-up procedures were carried out after removal of residual solids by filtration;
(ii) operations were generally carried out at ambient temperature, that is typically in the range 18-26 0C and without exclusion of air unless otherwise stated, or unless the skilled person would otherwise work under an inert atmosphere; (iii) column chromatography (by the flash procedure) was used to purify compounds and was performed on Merck Kieselgel silica (Art. 9385) unless otherwise stated; (iv) yields are given for illustration only and are not necessarily the maximum attainable; the structure of the end-products of the invention were generally confirmed by NMR and mass spectral techniques; proton magnetic resonance spectra is quoted and was generally determined in DMSO-dβ unless otherwise stated using a Bruker DRX-300 spectrometer operating at a field strength of 300 MHz or a Bruker Avance-II spectrometer operating at a field strength of 400 MHz. Chemical shifts are reported in parts per million downfϊeld from tetramethysilane as an internal standard (δ scale) and peak multiplicities are shown thus: s, singlet; d, doublet; AB or dd, doublet of doublets; dt, doublet of triplets; dm, doublet of multiplets; t, triplet, m, multiplet; br, broad; fast-atom bombardment (FAB) mass spectral data were generally obtained using a Platform spectrometer (supplied by Micromass) run in electrospray and, where appropriate, either positive ion data or negative ion data were collected or using Agilent 1 lOOseries LC/MSD equipped with Sedex 75ELSD, run in atmospheric pressure chemical ionisation mode and, where appropriate, either positive ion data or negative ion data were collected; mass spectra were run with an electron energy of 70 electron volts in the chemical ionization (CI) mode using a direct exposure probe; where indicated ionization was effected by electron impact (EI), fast atom bombardment (FAB) or electrospray (ESP); values for m/z are given; generally, only ions which indicate the parent mass are reported;
(vi) each intermediate was purified to the standard required for the subsequent stage and was characterised in sufficient detail to confirm that the assigned structure was correct; purity was assessed by high pressure liquid chromatography, thin layer chromatography, or NMR and identity was determined by infra-red spectroscopy (IR), mass spectroscopy or NMR spectroscopy as appropriate;
(vii) Where unspecified, the total amount of solvent(s) used in a given transformation was such that the concentration of the limiting substrate in the reaction mixture was between 0.1 to 0.5 Molar, (viii) the following abbreviations may be used: ACN is acetonitrile;
CDCI3 is deuterated chloroform;
DBU is l,8-diazabicyclo[5.4.0]undec-7-ene;
DCM is dichloromethane; DIEA is diisopropyl ethylamine;
DMF is Λ/,Λ/-dimethylformamide;
DMSO is dimethylsulfoxide;
EDC is l-ethyl-3-(3-dimethylaminopropyl)carbodiimide; EtOAc is ethyl acetate;
EtOH is ethanol;
HATU is N-[(dimethylamino)-lH,2,3-triazolo[4,5-b-]pyridin-l- ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide;
HOBT is 1-hydroxybenzotriazole; MeOH is methanol;
MS is mass spectroscopy;
NMP is N-Methylpyrrolidone;
RT or rt is room temperature;
SM is starting material; T3P is n-propyl phosphonic acid cyclic anhydride
TBTU is O-(Benzotriazol-l-yl)-Λ/,Λ/,Λ^Λ/"-tetramethyluronium tetrafluoroborate;
TFA is trifluoroacetic acid;
TFAA is trifluoroacetic anhydride;
THF is tetrahydrofuran; (ix) temperatures are quoted as 0C; and
(x) vol designates 1 mL of solvent or reagent per g of material used as the limiting agent.
Intermediates
Intermediate 1 : N'-( 5-Bromo-2-chloro-pyrimidin-4-yl)-N,N-dimethyl-pr()pane-l.l3- diamine
Figure imgf000068_0001
To a stirred solution of N,N-dimethyl-propane- 1,3 -diamine (40 mmol, 5 mL) in dioxane (40 mL) at room temperature under nitrogen atmosphere was added 5-bromo-2,4- dichloro-pyrimidine (6.6 g, 30 mmol) as a solid. Further dilution (ethyl acetate 30 mL) became necessary as the reaction progressed. The mixture was stirred overnight; the un- reacted hydrochloride salt of N,N-dimethyl-propane-l,3-diamine was removed by filtration. The filtrate was concentrated to give the title compound as a yellow solid in 86% yield (7.6 g)-
MS(ES): 293.1(M) and 295.1(M+2) for C9Hi4BrClN4.
1H-NMR (400 MHz, CDCl3): δ 1.77-1.80 (m, 2H), 2.32 (s, 6H), 2.56 (t, J= 5.76 Hz, 2H), 3.60 (dt, J= 9.36, 4.68 Hz, 2H), 8.05 (s, IH), 8.7 ( br s, IH).
The following intermediates were prepared using the general method described above for Intermediate 1 using 5-bromo-2,4-dichloro-pyrimidine and the starting material (SM) indicated.
Figure imgf000069_0001
Figure imgf000070_0001
Figure imgf000071_0001
Figure imgf000072_0001
Figure imgf000073_0001
Figure imgf000074_0001
Figure imgf000075_0001
The following intermediates were prepared using the general method described above for Intermediate 1 using the starting materials (SM) indicated.
Figure imgf000076_0002
Intermediate 26 : 5-Br omo-N2-( 3-chlor o-4-fluoro-phenvD-7V*-( 3-dimethylamino-propyD- pyrimidine-2,4-diamine
Figure imgf000076_0001
A solution of N'-(5-Bromo-2-chloro-pyrimidin-4-yl)-N,N-dimethyl-propane-l,3-diamine
(Intermediate 1, 10 g, 34 mmol), 3-chloro-4-fluoroaniline (34 mmol, 4.95 g) and 2.6 M HCl in 1,4-dioxane (40 mL) was warmed to 100 0C with constant stirring. The reaction was monitored by TLC. Upon completion of reaction, the mixture was cooled to room temperature. The white solid was filtered off, washed with n-butanol and ether to afford the product as a fluffy white solid in 73 % yield (24 mmol; 10 g). MS(ES): 402 (M) and 404 (M+2) for Ci5Hi8BrClFN5
1H-NMR (400 MHz, DMSO-d6): 1.95-1.98 (m, 2H), 2.72 (s, 3H), 2.73 (s, 3H), 3.03-3.07 (m, 2H), 3.43-3.48 (m, 2H), 7.37 (t, J = 9.20 Hz, IH), 7.54 (m, IH), 8.02 (dd, J = 6.80, 2.40 Hz, IH), 8.13 (s, IH), 9.80 (s, IH), 10 (s, IH). The following intermediates were prepared using the general method described above for Intermediate 26 using N'-(5-Bromo-2-chloro-pyrimidin-4-yl)-N,N-dimethyl-propane-l,3- diamine Intermediate 1 and the starting material (SM) indicated.
Figure imgf000077_0001
Figure imgf000078_0001
Figure imgf000079_0001
The following intermediates were prepared using the general method described above for Intermediate 26 using 3-chloro-4-fluoroaniline and the starting material (SM) indicated.
Figure imgf000079_0002
Figure imgf000080_0001
Figure imgf000081_0001
Figure imgf000082_0001
Figure imgf000083_0001
Figure imgf000084_0001
Figure imgf000085_0001
Figure imgf000086_0001
The following intermediates were prepared using the general method described above for Intermediate 26 using the starting materials (SM) indicated
Figure imgf000086_0002
Figure imgf000087_0002
Intermediate 60: 5-Bromo-2-chloro-4-methoxypyrimidine
Figure imgf000087_0001
To a stirred solution of 5-bromo-2,4-dichloropyrimidine (65 mmol, 15 g) in methanol (150 mL) at room temperature under nitrogen atmosphere, sodium methoxide (72 mmol, 3.91 g) was added portionwise. The mixture was stirred at RT for 4h and the solvent was removed in vacuo. The resulting solid was dissolved in chloroform (2 x 250 mL), washed with water and brine. The organic layer was dried over sodium sulfate and concentrated under vacuum to yield 5-bromo-2-chloro-4-methoxypyrimidine as a white solid in 92 % yield (60.4 mmol, 13.5 g). The compound was taken to the next step without further purification. MS(ES): 223.0(M) and 224.8(M+2) for C5H4BrClN2O. 1H-NMR (300 MHz, CDCl3): δ 4.11 (s, 3H), 8.44 (s, IH)
Intermediate 61 : ( 5-bromo-4-methoxy-pyrimidin-2-ylH3-chloro-4-fluoro-phenyl)-amine
Figure imgf000088_0001
To a stirred solution of 5-bromo-2-chloro-4-methoxypyrimidine (Intermediate 60, 60 mmol, 13.5 g) and 3-chloro-4-fluoroaniline (60.3 mmol, 9.23 g) in acetonitrile (140 mL), 4 M HCl in 1,4-dioxane (14 mL) was added dropwise. The resulting solution was refluxed at 100 C with constant stirring. The solvent was removed in vacuo and the residue was basified with 10% NaHCO3 solution, then extracted with ethyl acetate (2 x 250 mL). The combined organic layers were washed with water and brine, dried over sodium sulfate and concentrated under vacuum. The residue was purified by column chromatography (silicagel, 60-120 mesh) using 5% EtOAc in hexane to yield (5-bromo-4-methoxy-pyrimidin-2-yl)-(3-chloro-4-fluoro- phenyl)-amine as a white solid in 70 % yield (42 mmol, 14 g). MS(ES): 332 (M) for CnH8BrClFN3O.
1H-NMR (400 MHz, DMSO-d6): δ 4.0 (s, 3H), 7.37 (t, J= 9.20 Hz, IH), 7.62 (ddd, J = 9.02, 4.12, 2.84 Hz, IH), 8.04 (dd, J= 6.80, 2.60 Hz, IH), 8.41 (s, IH), 9.94 (s, IH).
Intermediate 62 : 5-Br omo-2-( 3-chloro-4-fluoroanilino)-pyrimidin-4-one
Figure imgf000088_0002
(5-Bromo-4-methoxy-pyrimidin-2-yl)-(3-chloro-4-fluoro-phenyl)-amine (Intermediate 61, 12 mmol, 4 g) was dissolved in 30-33% HBr in acetic acid (AcOH, 60 mmol, 13.5 g; 40 mL) and cooled to 0-5 0C. 47% aqueous HBr (20 mL) was added and refluxed for 4 h. The reaction mass was cooled to RT and poured over crushed ice. After all of the ice melted, the product was collected by filtration and dried under vacuum to provide 5- bromo-2-(3-chloro-4-fluoroanilino)-pyrimidin-4-one (11.67 mmol, 3.7 g, 97% yield). MS(ES): 318 (M) and 320 (M+2) for Ci0H6BrClFN3O.
1H-NMR (400 MHz, DMSO-d6): δ 7.34-7.43 (m, IH), 7.44-7.45 (m, IH), 7.91 (dd, J= 6.74, 2.56 Hz, IH), 8.08 (s, IH), 9.11 (br s, IH).
Intermediate 63 : 5-Bromo-2-( 3-chloro-4-fluoroanilino)-4-chloro-pyrimidine
Figure imgf000089_0001
A solution of 5-bromo-2-(3-chloro-4-fluoroanilino)-pyrimidin-4-one (Intermediate 62, 18.3 mmol, 6.5 g) in phosphorus oxychloride (21 mL) was heated to reflux for 2 hours, cooled to RT, poured carefully onto a mixture of ice (200 mL) and saturated NaHCO3 (20 mL) with stirring. The product was extracted with EtOAc (2 x 250 mL). The combined organic layers were washed with water, brine, dried over sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography (silicagel, 60-120 mesh) using 3% EtOAc in hexane to yield 5-bromo-2-(3-chloro-4-fluoroanilino)-4- chloro-pyrimidine (15 mmol, 5.1 g). MS(ES): 318 (M) and 320 (M+2) for Ci0H5BrCl2FN3
1H NMR (400 MHz, DMSO-d6): δ 7.37 (t, J= 9.12 Hz, 1 H), 7.57 (ddd, J= 8.90, 4.19, 2.54 Hz, 1 H), 7.93 (dd, J= 6.69, 2.54 Hz, 1 H), 8.71 (s, 1 H), 10.38 (s, 1 H).
19 F NMR (376 MHz, DMSO-d6): δ -124.12 (s, 1 F). Intermediate 64: 5-bromo-7V2-(3-chloro-4-fluorophenyl)-7V4-r2-(lH-imidazol-l- vDethyll pyrimidine-2,4-diamine
Figure imgf000090_0001
To 500 mg of 5-bromo-4-chloro-Λ/-(3-chloro-4-fluorophenyl)pyrimidin-2-amine
(Intermediate 63, 1.48 mmol) in NMP (5 niL), was added N, JV-diisopropylethylamine (3.04 niL, 1.78 mmol) and 2-imidazol-l-yl-ethylamine (1.63 mmol, 181 mg) under inert atmosphere. The reaction mixture was heated to 90 0C for 30 min. After completion of the reaction, the reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous Na2SO4. The crude mixture was purified by column chromatography using 2 % MeOH in CHCI3 to obtain 5-bromo-Λ/2- (3-chloro-4-fluorophenyl)-Λ/4-[2-(lH-imidazol-l-yl)ethyl]pyrimidine-2,4-diamine in 26 % yield (0.39 mmol, 160 mg). MS(ES): 411 (M) and 413 (M+2) for Ci5Hi3BrClFN6. 1H-NMR (400 MHz, DMSO-d6): δ 3.71 (q, J = 6.00 Hz, 2H), 4.22 (t, J = 6.20 Hz, 2H), 6.86 (s, IH), 7.11 (s, IH), 7.17 (t, J = 5.64 Hz, IH), 7.29 (t, J = 9.12 Hz, IH), 7.53-7.56 (m, IH), 7.56 (s, IH), 8.02 (dd, J= 2.64, 6.84 Hz, IH), 8.07 (s, IH), 9.45 (s, IH).
Intermediate 65 : ( 5-Bromo-4-methylsulfanyl-pyrimidin-2-ylH 3-chlor o-4-fluoro-phenvD- amine
Figure imgf000090_0002
5-Bromo-2-chloro-4-(methylthio)pyrimidine (125 mmol, 30 g) was suspended in n-BuOH (300 mL) with 3-chloro-4-fluoroaniline (125 mmol, 18.22 g). The reaction was then treated with 4 N HCl (100 mmol, 25 niL) in dioxane and refluxed at 100 0C for 1.5 h under nitrogen. The reaction was cooled to room temperature, diluted with diethyl ether and the solid was filtered and dried to afford 29 g of (5-bromo-4-methylsulfanyl-pyrimidin-2-yl)-(3-chloro-4- fluoro-phenyl)-amine as a pale yellow solid (83 mmol, 67 %). MS(ES): 348(M) and 350(M+2) for CnH8BrClFN3S.
1H-NMR 300MHz DMSO-d6 : δ 2.55 (s, 3H), 7.34 (t, J= 9.0 Hz, IH), 7.56-7.59 (m, IH), 8.08 (t, J= 4.5 Hz, IH), 8.33 (s, IH), 9.98 (s, IH).
The following intermediates were prepared using the general method described above for Intermediate 65 using 5-bromo-2-chloro-4-(methylthio)pyrimidine and the starting material (SM) indicated.
Figure imgf000091_0001
Figure imgf000092_0002
Intermediate 69 : ( 5-Bromo-4-methanesulfonyl-pyrimidin-2-yl)-( 3-chlor o-4-fluoro- phenvD-amine
Figure imgf000092_0001
5-Bromo-2-[N-(3-chloro-4-fluorophenyl)]-4-(methylthio)pyrimidin-2-amine (Intermediate 65, 86 mmol, 30 g) was suspended in DCM (450 mL), cooled to 0 0C and 3- chloroperoxybenzoic acid (m-CPBA, 344 mmol, 59 g) was added. The suspension became a solution after stirring at 0 0C for 30 min. The reaction mixture was then allowed to warm up slowly to room temperature. IN aqueous sodium hydroxide solution (344 mL) was added and the solution was stirred for 10 minutes. The solid which precipitated was filtered off and washed with water, dichloromethane, diethyl ether and dried. The first crop of the title compound, thus obtained, weighed 1O g. The mother liquor was dried over sodium sulfate and concentrated to yield a residue. Diethyl ether was added to the residue and the mixture was stirred for 15 minutes. The ether layer was filtered off. The residual solid was dissolved in
CHCl3-MeOH, then hexane was added to this mixture. The solid that precipitated was filtered off and dried. The second crop of the title compound, thus obtained, weighed 3.5 g. The total yield of (5-bromo-4-methanesulfonyl-pyrimidin-2-yl)-(3-chloro-4-fluoro-phenyl)-amine was 41 % (35.3 mmol, 13.5 g). MS(ES): 380 (M) for CnH8BrClFN3O2S. 1H-NMR 400MHz DMSO-d6 : δ 3.45 (s, 3H), 7.40 (t, J = 9.08 Hz, IH), 7.55-7.58 (m, IH), 7.96 (dd, J = 6.74, 2.60 Hz, IH), 8.93 (s, IH), 10.51 (s, IH). The following intermediates were prepared using the general method described above for Intermediate 69 using m-CPBA and the starting material (SM) indicated.
Figure imgf000093_0002
Intermediate 72: l-{4-[5-Bromo-2-f3-chloro-4-fluoro-phenylamino)-pyrimidin-4- ylaminol-piperidin-1-vU-ethanone
Figure imgf000093_0001
5 - Bromo-2- [N-(3 -chloro-4-fluorophenyl)] -4-(methy 1 sulfonyl)pyrimidin-2 -amine (Intermediate 69, Ig, 2.63 mmol) was suspended in NMP (5 mL), treated with N5N- diisopropylethylamine (0.5 mL, 3.02 mmol), and l-(4-amino-piperidin-l-yl)-ethanone (1 eq 2.63 mmol) in a sealed tube. The reaction was heated in the microwave reactor at 100 0C for 30 min. The reaction mixture was added to water and stirred for 15 min. The precipitated solid was filtered and dried to provide the l-{4-[5-bromo-2-(3-chloro-4-fluoro-phenylamino)-pyrimidin- 4-ylamino]-piperidin- 1 -yl} -ethanone (800 mg). MS(ES): 442.7 (M) and 444 (M+2) for Ci7Hi8BrClFN5O.
400 MHz, DMSO-de : δ 1.4-1.75 (m, 2H), 1.83-1.88 (m, 2H), 2.02 (s, 3H), 2.6-2.63 (m, IH), 3.11 (t, J = 12.00 Hz, IH), 3.87-3.9 (m, IH), 4.15-4.19 (m, IH), 4.42-4.45 (m, IH), 6.71 (d, J = 8.00 Hz, IH), 7.32 (t, J = 9.04 Hz, IH), 7.49-7.53 (m, IH), 8.06 (s, IH), 8.11 (dd, J = 6.86, 2.60 Hz, IH), 9.50 (s, IH).
The following intermediates were prepared using the general method described above for Intermediate 72 using 5- bromo-2-[N-(3-chloro-4-fluorophenyl)]-4-(methyl sulfonyl)pyrimidin-2-amine (Intermediate 69) and the starting material (SM) indicated.
Figure imgf000094_0001
Figure imgf000095_0001
Figure imgf000096_0001
Figure imgf000097_0001
Figure imgf000098_0001
Figure imgf000099_0001
Figure imgf000100_0001
Figure imgf000101_0001
Figure imgf000102_0001
Figure imgf000103_0001
Figure imgf000104_0001
Figure imgf000105_0002
Intermediate 111: 5-Bromo-N-(3-chloro-4-fluorophenyl)-4-morpholin-4-ylpyrimidin-2- amine
Figure imgf000105_0001
5-Bromo-2-[N-(3-chloro-4-fluorophenyl)]-4-(methylsulfonyl)pyrimidin-2-amine
(Intermediate 69, 15.7 mmol, 6 g) was suspended in NMP (30 rnL) and treated with N ,N- diisopropylethylamine (23.6 mmol, 4 mL) and morpholine (18.9 mmol, 1.64 g) in a 100 mL round-bottomed flask. The reaction was heated to 90 0C for 45 min. The reaction mixture was added to water and stirred for 15 min. The precipitated solid was filtered and washed successively with water, diethyl ether and hexanes and dried to afford 4.96 g of the title compound (12.56 mmol, 80 %).
MS(ES): 387 (M) and 389 (M+2) for Ci4Hi3BrClFN4O.
1H NMR 400 MHz DMSO-d6: δ 3.57-3.59 (m, 4H), 3.71-3.73 (m, 4H), 7.32 (t, J = 9.08 Hz,
IH), 7.55 (ddd, J = 9.00, 4.18, 2.68 Hz, IH), 8.04 (dd, J = 6.86, 2.64 Hz, IH), 8.26 (d, J = 1.20
Hz, IH), 9.71 (s, IH). Intermediate 112: 5-Bromo-7V-(3-chloro-4-fluorophenyl)-4-(3.,5-dimethyl-lH-pyraz()l-l- yl)pyrimidin-2-amine
Figure imgf000106_0001
A solution of 3,5-dimethyl-lH-pyrazole (554 mg, 5.78 mmol) in DMF (1 ml) was added slowly to a suspension of sodium hydride (60%, 208 mg, 5.52 mmol) in DMF (1 ml) at 0 0C and the resultant mixture was stirred for 25 min. A solution of 5-bromo-N-(3-chloro-4-fluorophenyl)-4- (methylsulfonyl)pyrimidin-2-amine (Intermediate 69, 1.0 g, 2.63 mmol) in DMF (2 mL) was added slowly to the reaction mixture, and the mixture was stirred for 1 h. Water was added to the reaction mixture (~6 mL) and the solid that formed was filtered and dried to yield 5-bromo- Λ/-(3-chloro-4-fluorophenyl)-4-(3,5-dimethyl-lH-pyrazol-l-yl)pyrimidin-2-amine (800 mg). MS(ES): 396 (M) and 398 (M+2) for Ci5Hi2BrClFN5
400 MHz, DMSO-d6: δ 2.19 (s, 3H), 2.34 (s, 3H), 6.14 (s, IH), 7.38 (t, J = 9.08 Hz, IH), 7.54- 7.58 (m, IH), 7.96 (dd, J = 2.48, 6.68 Hz, IH), 8.83 (s, IH), 10.24 (s, IH).
The following intermediates were prepared using the general method described above for Intermediate 112 using 5- bromo-2-[N-(3-chloro-4-fluorophenyl)]-4-(methyl sulfonyl)pyrimidin-2-amine (Intermediate 69), sodium hydride and the starting material (SM) indicated.
Figure imgf000107_0001
Figure imgf000108_0001
The following intermediates were prepared using the general method described above for Intermediate 112 using sodium hydride and the starting materials (SM) indicated.
Figure imgf000109_0001
Figure imgf000110_0002
Intermediate 123 : N-( 3-chloro-4-fluorophenyl)-4-methylsulfonyl-5-pyrimidin-5- ylpyrimidin-2-amine
Figure imgf000110_0001
A suspension of Intermediate 69 (1.05mmol, 400 mg), pyrimidine-5-boronic acid
(1.68mmol, 208 mg), tris(dibenzyledeneacetone)dipalladium(0) (10 mol %, 0.1 mmol, 96 mg), 2-dicyclohexyl phosphino-2',4',6'-triiso-propyl-l,r-biphenyl (30 mol %, 0.3 mmol, 148 mg) and sodium carbonate (1.05 mmol, 112 mg) in acetonitrile/water (4:1) was heated to 90° C for 30 min in an oil bath. The reaction mixture was diluted with ethyl acetate (10 mL) and the organic layer was separated, dried over sodium sulfate, filtered and concentrated. The crude compound was purified by silica gel column chromatography using chloroform:methanol (9:1) as an eluent in 20% yield. MS(ES): 380 (M+l) for Ci5HnClFN5O2S. 300 MHz DMSO-J6 : δ 3.4 (s, 3H), 7.44 (t, J= 9.2 Hz, IH), 7.63 (brs, IH), 8.0 (br s, IH), 8.86 (s, IH), 8.89 (s, 2H), 9.21(s, IH), 10.63 (s, IH). Intermediate 124: Ethyl 5-{2-[f3-chloro-4-fluorophenyl)aminol-4- (methylsulfonyl)pyrimidin-5-yl}pyridine-3-carboxylate
-
Figure imgf000111_0001
A suspension of Intermediate 69 (1.31 mmol, 0.5 g), ethyl 5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)pyridine-3-carboxylate (1.38 mmol, 382 mg), [1,1'- bis(diphenylphosphino)ferrocene] dichloropalladium (II) complex with CH2Cl2 (10 mol %, 0.13 mmol, 107 mg), 2-dicyclohexyl phosphino-2',4',6'-triisopropyl-l,l '-biphenyl (30 mol0 %, 0.394 mmol, 188 mg) and sodium carbonate (2.62 mmol, 279 mg) in acetonitrile/water (20 mL : 5 mL) was heated to 90 0C for 5 min in an oil bath under inert atmosphere. After completion of the reaction, as monitored by TLC, the reaction mixture was diluted with EtOAc (30 mL). The organic layer was separated, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography using hexane:5 ethyl acetate (3:2) as an eluent. The title compound was obtained in 51 % combined yield (0.3O g, 1.33 mmol).
MS (ES) : 451 (M+l) for Ci9Hi6ClFN4O4S.
1H NMR (300 MHz, DMSO-d6) : δ 1.34 (t, J= 7.08 Hz, 3H), 3.38 (s, 3H), 4.37 (q, J= 7.0 Hz, 2H), 7.44 (t, J= 8.97 Hz, IH), 7.64 (m, IH), 8.0-8.01 (m, IH), 8.39 (s, IH), 8.83 (s, IH),0 8.87 (d, J= 2.01 Hz, IH), 9.11 (d, J= 1.83 Hz, IH), 10.59 (s, IH). - Ill -
Intermediate 125: Ethyl (2ip-3-(3-{2-r(3-chloro-4-fluorophenvDaminol-4- (methylsulfonvDpyrimidin-5-yl}phenvDprop-2-enoate
Figure imgf000112_0001
A suspension of Intermediate 69 (2.11 mmol, 800 mg), {3-[(liT)-3-ethoxy-3-oxoprop-l-en- l-yl]phenyl}boronic acid (2.32 mmol, 510 mg), tris(dibenzylideneacetone)dipalladium(0) (IO mol %, 0.21 mmol, 192 mg), 2-dicyclohexylphosphino-2',4',6'-triisopropyl-l,r-biphenyl (30 mol %, 0.63 mmol, 300 mg) and sodium carbonate (3.15 mmol, 330 mg) in acetonitrile/water (40 mL; 4:1 mixture) was heated to 90 0C for 15-20 min in an oil bath. Acetonitrile was evaporated from the reaction mixture and water was added. The mixture was extracted with ethyl acetate (10 mL), and the organic layer was separated, dried over sodium sulfate, filtered and concentrated. The crude compound was purified by silica gel column chromatography using hexane-ethyl acetate (13:7) as an eluent to yield the title compound as a pale yellow solid in 52 % yield (0.52 g, 1.08 mmol). MS(ES): 476 (M+ 1) for C22Hi9ClFN3O4S
1H-NMR (400 MHz, DMSO-d6): δ 1.26 (t, J= 7.04 Hz, 3H), 3.36 (s, 3H), 4.20 (q, J= 7.08 Hz, 2H), 6.68 (d, J= 16.04 Hz, IH), 7.43 (t, J= 9.08 Hz, IH), 7.50 (t, J= 7.64 Hz, IH), 7.56 (d, J = 7.76 Hz, IH), 7.64 (ddd, J= 2.72, 4.12, 9.05 Hz, IH), 7.69 (d, J= 16.04 Hz, IH), 7.77 (d, J = 7.68 Hz, IH), 7.84 (s, IH), 8.02 (dd, J= 2.48, 6.72 Hz, IH), 8.80 (s, IH), 10.51 (s, IH).
Intermediate 126: Tert-buty\ 2-[[[5-bromo-2-[f3-chloro-4-fluorophenyl)aminolpyrimidin- 4-yll aminol methyll benzimidazole- 1-carboxylate
Figure imgf000113_0001
To a stirred solution of Intermediate 55 (Ig, 2.23 mmol) and triethylamine (1.24 rnL, 8.93 mmol) in dichloromethane (20 rnL) under nitrogen atmosphere was added di-t- butyldicarbonate(1.46g, 6.7 mmol) at 5-100C. The reaction mixture was stirred overnight at room temperature, then diluted with water (20 mL) and extracted with dichloromethane (2 x 20 mL). The combined extracts were washed with water (2 x 20 mL), brine solution, dried over sodium sulfate, filtered and concentrated to give the title compound as a white solid in 83 % yield (1.2g, 1.85 mmol). MS(ES): 547 (M) and 549 (M+2) for C23H2IBrClFN6O2. 1H NMR (300 MHz) DMSO-d6 : δ 1.67 (s, 9H), 5.01 (d, J= 5.46 Hz, 2H), 7.05 (t, J= 9.12 Hz, IH), 7.27-7.36 (m, 3H), 7.57 (t, J= 4.5 Hz, IH), 7.66 (d, J= 7.44 Hz, IH), 7.78 (t, J= 2.4 Hz, IH), 7.92 (d, J= 7.59 Hz, IH), 8.14 ( s, IH), 9.44 (s, IH).
Intermediate 127: 2-(3-Chloro-4-fluorophenylamino)-4-(3- methoxypropylamino)pyrimidine-5-carbonitrile
Figure imgf000114_0001
A stirred suspension of Intermediate 119 (4.01 g, 10.3 mmol), zinc powder (168 mg, 2.57 mmol), zinc cyanide (784 mg, 6.67 mmol), tris(dibenzylideneacetone)dipalladium (0) (188 mg, 0.210 mmol), 1 , r-bis(diphenylphosphino)ferrocene (230 mg, 0.410 mmol), and zinc acetate (75 mg, 0.41 mmol) in degassed N,N-dimethylformamide (25 mL) was prepared. The vessel was purged with nitrogen gas for one minute. The mixture was placed under an atmosphere of nitrogen atmosphere and heated to 100 degrees C. A check of progress by LCMS after about an hour indicated complete conversion to desired product. Stirring continued while the mixture was allowed to cool to room temperature; the mixture was then diluted with small volumes of water. The dark solution became cloudy with addition of water. Larger volumes were added until a maximum of precipitation was reached. Stirring continued for ten minutes. The solid was collected and washed with water. Normal-phase chromatography (0-3% methanol in methylene chloride) was used to isolate the pure product (3.3 g, 95%). MS: ES+ 336 for Ci5Hi5ClFN5O. IH NMR (300 MHz, DMSO-J6) δ ppm 1.74 - 1.90 (m, J=6.76, 6.76, 6.64, 6.40 Hz, 2 H) 3.22 (s, 3 H) 3.39 (t, J=6.22 Hz, 2 H) 3.46 (q, J=6.53 Hz, 2 H) 7.33 (t, J=9.04 Hz, 1 H) 7.60 (ddd, J=9.04, 4.24, 2.73 Hz, 1 H) 7.86 (br. s., 1 H) 8.11 (dd, J=6.78, 2.45 Hz, 1 H) 8.36 (s, 1 H) 9.99 (br. s., 1 H) Intermediate 128: 2-(3-Chloro-4-fluorophenylamino)-4-(3-methoxy propylamino)pyrimidine-5-carbothioamide
Figure imgf000115_0001
A stirred solution of Intermediate 127 (750 mg, 2.2 mmol) in methanol (4 rnL) and N ,N- dimethylformamide (4 mL) was prepared under ambient conditions. The reaction vessel was purged with nitrogen, and the contents were placed under an atmosphere of nitrogen. The mixture was heated to 90 degrees C. At that time 1 mL of a 22 wt% aqueous solution of ammonium sulfide (about 3 mmol ammonium sulfide) was added slowly by syringe. Volumes of a similar size were added every thirty minutes until conversion to desired product was complete as monitored by LCMS. The mixture was allowed to cool to room temperature with stirring. Water (5 mL) was then added very slowly with stirring, precipitating a grey solid. This was collected, washed with water and dried to yield the title compound (768 mg, 93%). MS: ES+ 369 for CI5HI7CIFN5OS.
IH NMR (300 MHz, DMSO-J6) δ ppm 1.84 (qd, J=6.22, 6.03 Hz, 2 H) 3.24 (s, 3 H) 3.44 (t, J=6.03 Hz, 2 H) 3.52 (q, J=5.90 Hz, 2 H) 7.32 (t, J=9.04 Hz, 1 H) 7.52 - 7.70 (m, 1 H) 8.22 (d, J=4.90 Hz, 1 H) 8.36 (s, 1 H) 9.27 (br. s., 1 H) 9.39 (br. s., 1 H) 9.64 (br. s., 1 H) 9.80 (br. s., 1 H). Intermediate 129: 5-bromo-N-(3-chloro-4-fluorophenyl)-4-(piperazin-l-yDpyrimidin-2- amine hydrochloride
Figure imgf000116_0001
To a stirred solution of Intermediate 110 (500mg, 1.30 mmol) in 1,4- dioxane (10 rnL) under nitrogen atmosphere was added 4N hydrochloric acid in 1,4-dioxane (3 rnL) dropwise. The reaction mixture was stirred at room temperature for 24 h. The reaction mixture was concentrated to give the hydrochloride salt title compound as a white solid (320 mg). MS(ES): 386 (M) 388 (M+2) for Ci4Hi4BrClFN5
IH NMR (300 MHz, DMSO- d6) δ ppm 3.22 (s, 4 H) 3.67 - 3.91 (m, 4 H) 7.33 (t, J=9.04 Hz, 1 H) 7.41 - 7.63 (m, 1 H) 8.00 (d, J=6.03 Hz, 1 H) 8.33 (s, 1 H) 9.34 (d, J=20.91 Hz, 1 H) 9.83 (s, 1 H).
Intermediate 130: 5-Bromo-N-(3-chloro-4-fluorophenyl)-4-(4-(methylsulfonyl)piperazin- l-yl)pyrimidin-2-amine
Figure imgf000116_0002
A solution of methanesulfonyl chloride (30mg, 0.26 mmol) was added to Intermediate 129
(100 mg, 0.26 mmol), triethylamine (0.054ml, 0.39 mmol) and methylene chloride (1.5 ml) under nitrogen. The resultant mixture was stirred for Ih and concentrated under vacuum.
The residue was chromatographed using 40-70% ethyl acetate/ hexane to yield the title compound (88 mg).
MS(ES): 386 (M) 388 (M+2) for Ci5Hi6BrClFN5O2S
IH NMR (300 MHz, DMSO- dβ) δ ppm 2.92 (s, 3 H) 3.12 - 3.30 (m, 4 H) 3.55 - 3.84 (m, 4
H) 7.33 (t, J=9.14 Hz, 1 H) 7.47 - 7.71 (m, 1 H) 7.93 - 8.11 (m, 1 H) 8.30 (s, 1 H) 9.74 (s, 1
H).
Intermediate 131: Methyl 6-bromoquinoline-3-carboxylate
Figure imgf000117_0001
ό-Bromoquinoline-S-carboxylic acid (2.5 g, 9.92 mmol) was suspended in methyl alcohol
(40.2 ml, 991.81 mmol) and treated with sulfuric acid (2.64 ml, 49.59 mmol). The reaction was refluxed overnight. TLC analysis of a small aliquot showed complete reaction. The reaction was cooled to room temperature and concentrated at reduced pressure. The residue was diluted with EtOAc and carefully neutralized with a solution of sodium carbonate. The biphasic suspension was diluted with EtOAc/DCM until all solid dissolved. The layers were then separated, and the organic was washed with brine and dried over sodium sulfate. The solvent was removed at reduced to afford the desired product with good purity. It was used without further purification.
MS(ES): 266 (M), 268 (M+2) for CnH8BrNO2
IH NMR (300 MHz, DMSO-D6) δ ppm 3.95 (s, 3 H) 8.03 (d, J=I.13 Hz, 2 H) 8.52 (s, 1 H)
8.99 (d, J=2.07 Hz, 1 H) 9.31 (d, J=2.07 Hz, 1 H).
Intermediate 132: (Z)-ethyl 3-(dimethylamino)-2-(2-fluoro-5-iodobenzovDacrylate
Figure imgf000117_0002
2-Fluoro-5-iodobenzoic acid (3.76 mmol, 1 g) was treated with thionyl chloride (3 rnL) and DMF (2 drops). The reaction mixture was heated at 700C for 1.5 h to form the acid chloride, then cooled and concentrated under reduced pressure. Toluene was added, and the mixture was concentrated again. The crude acid chloride was dissolved in toluene and treated with triethylamine (3.76 mmol, 0.524 mL) and ethyl 3-(dimethylamino)acrylate (4.89 mmol, 0.700 g). The reaction mixture was heated to 90 0C for 1.5 h. The reaction mixture was filtered and the resulting solution was purified using flash column chromatography (silica, 2.5:1 hexanes/ethyl acetate) to give the desired product in 47 % yield. (1.79 mmol, 0.7 g) MS(ES): 391.9 (M+l) for Ci4Hi5FINO3.
1H NMR (300 MHz) DMSO-d6 δ : 0.95 (t, J= 7.14 Hz, 3H), 2.89 (br s, 3H), 3.33 (br s, 3H), 4.0(q, J= 7.08 Hz, 2H), 6.80 (t, J= 1.17 Hz, IH), 7.64-7.69(m, IH), 7.79 (m, IH), 7.87 (br s, IH).
Intermediate 133: Ethyl 6-iodo-l-f2-methoxyethyl)-4-oxo-l,4-dihydroαuinoline-3- carboxylate
Figure imgf000118_0001
A suspension of (Z)-ethyl 3-(dimethylamino)-2-(2-fluoro-5-iodobenzoyl)acrylate Intermediate 132 (1.79 mmol, 0.7 g) in ethanol (3 mL) at room temperature was treated with 2-methoxyethylamine (2.26 mmol, 0.17 mL). The reaction mixture was stirred until a yellow solution resulted and concentrated under reduced pressure after 1 h. Potassium carbonate (2.69 mmol, 0.372 g) and DMF (2 mL) were added. The reaction mixture was heated to 70 0C for 3 h, then cooled to room temperature and allowed to stand overnight. The reaction mixture was poured into water. The solid that formed was collected by filtration, washed with water and dried under vacuum for 4 h to give desired product in 80 % yield (1.44mmol, 0.580 g). MS(ES): 402 (M+l) for Ci5Hi6INO4. 1H NMR (400MHz) DMSO-d6 δ : 1.27 (t, J= 7.08 Hz, 3H), 3.32 (s, 3H), 3.64 (t, J= 4.84 Hz, 2H), 4.22 (q, J= 7.08 Hz, 2H), 4.54 (t, J= 4.92 Hz, 2H), 7.68 (d, J= 9.00 Hz, IH), 8.05 (dd, J = 8.94, 2.16 Hz, IH), 8.49 (d, J= 2.16 Hz, IH), 8.59 (s, IH).
Intermediate 134: Ethyl l-(2-methoxyethyl)-4-oxo-6-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-l,4-dihvdroquinoline-3-carboxylate
Figure imgf000119_0001
Ethyl 6-iodo-l-(2-methoxyethyl)-4-oxo-l,4-dihydroquinoline-3-carboxylate (Intermediate 133, 400 mg, 1.00 mmol) was suspended in dioxane (4 mL) and degassed with nitrogen for 10 minutes at which time bis(pinacolato)diboron (506 mg, 1.99 mmol), 1,1'- bis(diphenylphosphino)ferrocene-palladium dichloride (41.0 mg, 0.05 mmol), and potassium acetate (294 mg, 2.99 mmol) were added. After the reaction was heated at 90 0C overnight, LC/MS showed completion of the reaction. The reaction was then cooled to room temperature, diluted with DCM and filtered through a pad of diatomaceous earth. The filtrate was concentrated at reduced pressure and quickly purified by silica gel chromatography with 8% MeOH in DCM to yield the title compound. MS(ES): 402 (M+l) for C2iH28BNO6
IH NMR (300 MHz, DMSO-D6) δ ppm 1.20 - 1.45 (m, 15 H) 3.17 - 3.27 (s, 3 H) 3.67 (t, J=4.71 Hz, 2 H) 4.24 (q, J=6.97 Hz, 2 H) 4.57 (t, J=4.71 Hz, 2 H) 7.75 - 7.91 (m, 1 H) 7.90 - 8.04 (m, 1 H) 8.49 - 8.74 (m, 2 H).
The following intermediate was prepared using the general method described above for Intermediate 134 using bis(pinacolato)diboron, l,l'-bis(diphenylphosphino)ferrocene- palladium dichloride, potassium acetate and the starting material (SM) indicated.
Figure imgf000120_0003
Intermediate 136: 4-(5-Bromo-2-chloro-pyrimidin-4-vD-morpholine
Figure imgf000120_0001
To a stirred solution of 2, 4-dichloro-5-bromopyrimidine (22 mmol, 5 g) in dioxane (100 niL), at room temperature under nitrogen atmosphere, was added morpholine (29.2 mmol, 2.54 g). The reaction mixture was stirred overnight at room temperature, diluted with ethyl acetate (50 mL) and the resulting white solid formed was removed by filtration. The filtrate was concentrated and the resulting residue was purified by column chromatography (using 60-120 mesh silica gel and 4% of ethyl acetate in petroleum ether) to yield the title compound. (4.7 g).
MS(ES): 278 (M) and 280 (M+2) for C8H9BrClN3O. 1H-NMR (300 MHz, CDCl3): δ 3.79 (s, 8H), 8.27 (s, IH).
Intermediate 137: 5-f2-Chloro-4-morpholin-4-yl-pyrimidin-5-yl)-nicotinic acid ethyl ester
Figure imgf000120_0002
A suspension of Intermediate 136 (3.5 mmol, 1 g), 5-(4,4,5,5-Tetramethyl- [l,3,2]dioxaborolan-2-yl)-nicotinic acid ethyl ester (3.6 mmol, 1.01 g), [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with CH2Cl2 (10 mol %, 0.35 mmol, 285 mg) and sodium carbonate (3.5 mmol, 370 mg) in acetonitrile/water (20 mL:5 niL) was degassed and heated to 90 0C for 20 min under an inert atmosphere. The solvent was removed in vacuo and the crude mixture was taken in CHCI3 (30 mL). It was then washed with water and brine. The organic layer was separated, dried over sodium sulfate, filtered and concentrated. The crude material was purified by silica gel column chromatography, using Hexane: Ethyl Acetate (3:1) as eluent to get Intermediate 137 (0.69 g). MS (ES) : 349 (M+l) for Ci6Hi7ClN4O3.
1H-NMR (300 MHz, DMSO-d6): δ 0.81 (t, J= 6.54 Hz, 3H), 3.24-3.25 (m, 4H), 3.49-3.50 (m, 4H), 4.37 (q, J= 7.05 Hz, 2H), 8.20 (s, IH), 8.37 (s, IH), 8.91 (d, J= 1.98 Hz, IH), 9.07 (d, J = 1.80 Hz, IH).
Intermediate 138: f5-Bromo-4-methylsulfanyl-pyrimidin-2-yl)-f3.,5-(iifluoro-phenyl)- amine
Figure imgf000121_0001
5-Bromo-2-chloro-4-(methylthio)pyrimidine (8.3 mmol, 2 g) was suspended in n- BuOH (20 mL) and treated with 3,5-difluoroaniline (9.1 mmol, 1.18 g), HCl in dioxane (4 mL) was added under nitrogen atmosphere and the mixture was refluxed at 100 0C for 3 h. The reaction was cooled to room temperature, diluted with diethyl ether and the solid was filtered and dried to afford Intermediate 138. MS(ES): 333.8 (M+2) for CnH8BrF2N3S.
1H-NMR (400 MHz, DMSO-d6): δ 2.58 (s, 3H), 6.78 (tt, J= 2.32, 9.27 Hz, IH), 7.50 (dd, J = 2.20, 10.36 Hz, 2H), 8.40 (s, IH), 10.19 (s, IH).
Intermediate 139: f5-Bromo-4-methanesulfonyl-pyrimidin-2-yl)-f3.,5-difluoro-phenyl)- amine
Figure imgf000121_0002
Intermediate 138 (3 mmol, 1 g) was suspended in acetone (10 mL), cooled to 0 0C and 3-chloroperoxybenzoic acid (15 mmol, 2.59 g) was added portion wise. The suspension became a clear solution after stirring at 0 0C for 30 min. The reaction mixture was then allowed to warm up slowly to room temperature and stirred for 5 h. The reaction mixture pH was raised to 8 with the addition of aq. NaHCO3 solution (50 mL), extracted with ethyl acetate (3x10 mL), combined extracts were washed with brine, dried over Na2SO4, filtered and concentrated to get crude Intermediate 139 (1 g). MS(ES): 363.9 (M) and 365 (M+ 1) for CnH8BrF2N3O2S.
1H-NMR (300 MHz, DMSO-d6): δ 3.54 (s, 3H), 6.86 (t, J = 9.24 Hz, IH), 7.44 (d, J = 8.82 Hz, 2H), 8.99 (s, IH), 10.72 (s, IH).
Intermediate 140: f5-Bromo-4-morpholin-4-yl-pyrimidin-2-yl)-f3.,5-(iifluoro-phenyl)- amine
Figure imgf000122_0001
Intermediate 139 (2.7 mmol, 1 g) was suspended in NMP (10 mL), treated with N5N- diisopropylethylamine (3.4 mmol, 0.56 mL), morpholine (30 mmol, 263 mg) in a sealed tube.
The reaction was heated at 90 0C for 30 min then cooled to room temperature, added to water and stirred for 15 min. The precipitate was filtered and dried to afford Intermediate 140.
MS(ES): 371 (M) and 373 (M+2) for Ci4Hi3BrF2N4O.
1H-NMR (300 MHz, DMSO-d6): δ 3.59 (d, J = 3.93 Hz, 4H), 3.72 (s, 4H), 6.72 (t, J = 9.36 Hz, IH), 7.45 (d, J= 10.32 Hz, 2H), 8.30 (s, IH), 9.91 (s, IH).
Intermediate 141 : ( 5-Bromo-4-methoxy-pyrimidin-2-yl)-(3,5-dimethyl-phenyl)-amine
Figure imgf000122_0002
To a stirred solution of 5-bromo-2-chloro-4-methoxypyrimidine (17.9 mmol, 4 g) and 3,5-dimethylaniline (18.8 mmol, 2.2 g) in acetonitrile (50 mL), 4 M HCl in 1,4-dioxane (5 mL) was added drop wise. The resulting solution was refluxed at 100 0C with constant stirring. The solvent was removed in vacuo and basified with 10% NaHCO3 solution, extracted with EtOAc (2x150 niL). The combined organic layer was washed with water and brine, dried over sodium sulfate and concentrated under vacuo to yield Intermediate 141 as a white solid (9.7 mmol, 3 g, 54%).
MS(ES): 310 (M+2) for Ci3Hi4BrN3O.
1H-NMR (400 MHz, DMSO-d6): δ 2.23 (s, 6H), 3.99 (d, J= 1.84 Hz, 3H), 6.62 (s, IH), 7.34
(s, 2H), 8.35 (d, J= 2.0 Hz, IH), 9.63 (s, IH).
Intermediate 142: 5-Bromo-2-(3,5-dimethyl-phenylamino)-pyrimidin-4-ol
Figure imgf000123_0001
A mixture of Intermediate 141 (9.7 mmol, 3 g) and aq. sodium thiomethoxide (38.9 mmol, 18 niL, 21% w/v,) and DMF (75 mL) was heated at 60 0C for 2 h; cooled to room temperature, poured into water (150 mL) and acidified with 1.5 N HCl solution. The precipitated solid was filtered to yield Intermediate 142 as off-white solid (2.5 g). MS(ES): 294 (M) and 296 (M+2) for Ci2Hi2BrN3O. 1H-NMR (400 MHz, DMSO-d6): δ 2.23 (s, 6H), 6.69 (s, IH), 7.14 (s, 2H), 8.04 (s, IH), 8.79 (br s, IH), 11.33 (br s, IH).
Intermediate 143 : ( 5-Bromo-4-chloro-pyrimidin-2-yl)-( 3,5-dimethyl-phenvD-amine
Figure imgf000123_0002
A solution of Intermediate 142 (8.4 mmol, 2.5 g) in phosphorus oxychloride (13 mL) was heated to reflux for 45 min, cooled to RT, poured carefully onto a mixture of ice (100 mL) and saturated aq. NaHCO3 solution (20 mL) with constant stirring. It was further extracted with ethyl acetate (2x150 mL). The combined organic layer was washed with water and brine, dried over sodium sulfate and concentrated under vacuo to yield Intermediate 143 (1.7 g).
MS(ES): 312 (M) and 314 (M+2) for Ci2HnBrClN3.
1H-NMR (400 MHz, DMSO-d6): δ 2.23 (s, 6H), 6.67 (s, IH), 7.27 (s, 2H), 8.66 (s, IH), 10.05
(s, IH). Intermediate 144: (5-Bromo-4-morpholin-4-yl-pyrimidin-2-yl)-(3.,5-dimethyl-phenyl)- amine
Figure imgf000124_0001
A mixture of Intermediate 143 (5.4 mmol, 1.7 g) and morpholine (10.8 mmol, 0.94 g) in dioxane (40 rnL) was stirred at room temperature for 18 h. Then the reaction mixture was concentrated under vacuo to yield white solid. The solid was dissolved in ethyl acetate (150 mL) and washed with water, brine and dried over sodium sulfate. The solvent was concentrated under vacuo to yield Intermediate 144 as a white solid (1.5 g). MS(ES): 365 (M+2) for Ci6Hi9BrN4O.
1H-NMR (400 MHz, DMSO-d6): δ 2.21 (s, 6H), 3.57-3.59 (m, 4H), 3.72-3.73 (m, 4H), 6.57 (s, IH), 7.32 (s, 2H), 8.21 (d, J= 1.2 Hz, IH), 9.35 (s, IH).
Intermediate 145: 3-r3-(2-Chloro-4-morpholin-4-yl-pyrimidin-5-yl)-phenyll-acrylic acid ethyl ester
Figure imgf000124_0002
A suspension of 4-(5-Bromo-2-chloro-pyrimidin-4-yl)-morpholine Intermediate 136
(3.5 mmol, 1 g), ethyl boronocinnamate (3.95 mmol, 0.87 g), [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with CH2Cl2 (0.35 mmol, 285 mg) and sodium carbonate (3.5 mmol, 370 mg) in acetonitrile/water (20 mL : 5 mL) was degassed and heated to 90 0C for 15-20 min under inert atmosphere. The solvent was removed in vacuo and the crude mixture was taken in CHC I3 (30 mL). It was then washed with water and brine. The organic layer was separated, dried over sodium sulfate, filtered and concentrated. The crude material was purified by 60-120 mesh silica gel column chromatography using Hexane:Ethylacetate (91 :9) to get 3-[3-(2-Chloro-4-morpholin-4-yl- pyrimidin-5-yl)-phenyl] -acrylic acid ethyl ester Intermediate 145 ( 0.63 g). MS (ES) : 374 (M+ 1) for Ci9H20ClN3O3. 1H-NMR (300 MHz, DMSO-d6): δ 1.25 (t, J= 7.05 Hz, 3H), 3.25-3.32 (m, 4H), 3.49-3.50 (m, 4H), 4.19 (q, J = 7.05 Hz, 2H), 6.74 (d, J = 16.05 Hz, IH), 7.50-7.59 (m, 2H), 7.69 (d, J = 16.14 Hz, IH), 7.73 (br s, IH), 7.83 (s, IH), 8.11 (s, IH) .
Intermediate 146: 5-bromo-N-(3-chloro-4-fluorophenyl)-4-morpholinopyrimidin-2-amine
Figure imgf000125_0001
5-Bromo-2-[N-(3-chloro-4-fluorophenyl)]-4-(methylsulfonyl)pyrimidin-2-amine Intermediate 69 (15.7 mmol, 6 g) was suspended in NMP (30 niL) and treated with N5N- diisopropylethylamine (23.6 mmol, 4 mL) and morpholine (18.9 mmol, 1.64 g) in a 100 mL round-bottomed flask. The reaction was refluxed at 90 0C for 45 min. The reaction mixture was added to water and stirred for 15 min. The precipitated solid was filtered and washed successively with water, diethyl ether and hexanes and dried to afford 4.96 g of Intermediate 146 (12.56 mmol, 80 %). MS(ES): 387 (M) and 389 (M+2) for Ci4Hi3BrClFN4O. 1H NMR 400 MHz DMSO-d6: δ 3.57-3.59 (m, 4H), 3.71-3.73 (m, 4H), 7.32 (t, J = 9.08 Hz, IH), 7.55 (ddd, J = 9.00, 4.18, 2.68 Hz, IH), 8.04 (dd, J = 6.86, 2.64 Hz, IH), 8.26 (d, J = 1.20 Hz, IH), 9.71 (s, IH).
Intermediate 147: 5-bromo-7V-f4-fluoro-3-nitrophenyl)-4-methoxypyrimidin-2-amine
Figure imgf000125_0002
To a stirred solution of 5-bromo-2-chloro-4-methoxypyrimidine (8.96 mmol, 2 g) and (4- fluoro-3-nitrophenyl)amine (9.41 mmol, 1.47 g) in butanol (40 mL), 4 M HCl in 1,4-dioxane (2.5 mL) was added dropwise. The resulting solution was refluxed at 100 C with constant stirring. The solvent was removed in vacuo and basified with 10% NaHCO3 solution. It was further extracted with EtOAc (2 x 100 mL). The combined organic layer was washed with water and brine, dried over sodium sulfate and concentrated under vacuum to yield 5-bromo- Λ/-(4-fluoro-3-nitrophenyl)-4-methoxypyrimidin-2-amine Intermediate 147 as a white solid
(2 g).
MS(ES): 343 (M)and 345 (M+2) for CnH8BrFN4O3.
1H-NMR (400 MHz, DMSO-d6 : δ 4.04 (s, 3H), 7.53 (dd, J= 9.28, 11.02 Hz, IH), 7.92-7.96 (m, IH), 8.45 (s, IH), 8.79 (dd, J= 2.56, 6.76 Hz, IH), 10.24 (br s, IH).
Intermediate 148: 5-bromo-2-[(4-fluoro-3-nitrophenyl)aminolpyrimidin-4-ol
Figure imgf000126_0001
A mixture of 5 -bromo-jV-(4-fluoro-3 -nitrophenyl)-4-methoxypyrimidin-2-amine
Intermediate 147 (5.82 mmol, 2 g) and HBr in AcOH (12 mL) and aq. HBr (6 mL) was heated at 100 0C for 3 h; The reaction mixture was cooled to RT, extracted with ethyl acetate (2 x 10OmL), washed with brine, dried over Na2SO4 and concentrated to yield 1.3 g of 5- bromo-2-[(4-fluoro-3-nitrophenyl)amino]pyrimidin-4-ol Intermediate 148 as an off-white solid.
MS(ES): 329 (M) and 331 (M+2) for Ci0H6BrFN4O3.
1H-NMR (400 MHz, DMSO-d6): δ 7.55 (dd, J= 9.16, 11.04 Hz, IH), 7.87-7.89 (m, IH), 8.12
(s, IH), 8.47 (dd, J= 2.80, 6.74 Hz, IH), 9.39 (br s, IH), 11.8 (br s, IH).
Intermediate 149: 5-bromo-4-chloro-N-(4-fluoro-3-nitrophenyl)pyrimidin-2-amine
Figure imgf000126_0002
A solution of 5-bromo-2-[(4-fluoro-3-nitrophenyl)amino]pyrimidin-4-ol Intermediate 148 (3.95 mmol, 1.3 g) in phosphorus oxychloride (6 mL) was heated to reflux for 45 minutes, cooled to RT, poured carefully onto a mixture of ice (100 mL) and sat. NaHCO3 (20 mL) with constant stirring. It was further extracted with EtOAc (2 x 150 mL). The combined organic layers were washed with water and brine, dried over sodium sulfate and concentrated under vacuum to yield 5-bromo-4-chloro-Λ/-(4-fluoro-3-nitrophenyl)pyrimidin-2-amine Intermediate 149 (1 g). MS(ES): 347 (M) and 349 (M+2) for Ci0H5BrClFN4O2. 1H-NMR (300 MHz, DMSO-d6): δ 7.57 (dd, J= 9.24, 11.05 Hz, IH), 7.93-7.98 (m, IH), 8.57 (dd, J= 2.73, 6.73 Hz, IH), 8.77 (s, IH), 10.63 (br s, IH).
Intermediate 150: 5-bromo-N-( 4-fluoro-3-nitrophenyl)-4-morpholin-4-ylpyrimidin-2- amine
Figure imgf000127_0001
A mixture of 5-bromo-4-chloro-Λ/-(4-fluoro-3-nitrophenyl)pyrimidin-2-amine Intermediate 149 (2.88 mmol, 1 g) and morpholine (3.45 mmol, 0.3 g) was stirred at room temperature for 18 h. Then the reaction mixture was concentrated under vacuum to yield white solid. The solid was dissolved in EtOAc (100 mL) and washed with water, brine and dried over sodium sulfate. The solvent was concentrated under vacuum to yield 5-bromo-iV-(4-fluoro-3- nitrophenyl)-4-morpholin-4-ylpyrimidin-2-amine Intermediate 150 as a white solid (1 g). MS(ES): 398 (M) and 400 (M+2) for Ci4Hi3BrFN5O3. 400 MHz, DMSO-d6: δ 3.62-3.63 (m, 4H), 3.71-3.72 (m, 4H), 7.50 (t, J= 10.24 Hz, IH), 7.83-7.86 (m, IH), 8.30 (s, IH), 8.81 (d, J= 6.24 Hz, IH), 10.04 (s, IH).
Intermediate 151 : 4-( 5-Bromo-2-chloro-pyrimidin-4-yl)-morpholine
Figure imgf000127_0002
To a stirred solution of 2,4-dichloro-5-bromopyrimidine (22 mmol, 5 g) in dioxane (50 mL), at room temperature under nitrogen atmosphere was added morpholine (29.2 mmol, 2.54 g). Further dilution with dioxane (50 mL) became necessary as the reaction progressed. The reaction mixture was stirred overnight at room temperature, then diluted with ethyl acetate (50 mL) and white solid formed was removed by filtration. The filtrate was concentrated and the resulting residue was purified by column chromatography (using 60-120 mesh silica gel and 4 % of ethylacetate in petroleum ether) to give 4-(5-Bromo-2-chloro-pyrimidin-4-yl)- morpholine Intermediate 151 (4.7 g). MS (ES): 278 (M) and 280 (M+2) for C8H9BrClN3O. 1H-NMR (300 MHz, CDCl3): δ 3.79 (s, 8H), 8.27 (s, IH).
Intermediate 152: 5-f2-Chloro-4-morpholin-4-yl-pyrimidin-5-yl)-nicotinic acid ethyl ester
Figure imgf000128_0001
A suspension of 4-(5-Bromo-2-chloro-pyrimidin-4-yl)-morpholine Intermediate 151 (3.5 mmol, 1 g), 5-(4,4,5,5-Tetramethyl-[l,3,2]dioxaborolan-2-yl)-nicotinic acid ethyl ester (3.6 mmol, 1.01 g), [l,r-bis(diphenylphosphino)ferrocene]dichloropalladium(II)complex with CH2Cl2 (10 mol %, 0.35 mmol, 0.285 g) and sodium carbonate (3.5 mmol, 0.370 g) were taken in acetonitrile/water (20 mL : 5 mL), degassed and heated to 90 0C for 15-20 min under inert atmosphere. The solvent was removed in vacuo and the crude mixture was taken in CHCl3 (30 mL). It was then washed with water and brine. The organic layer was separated, dried over sodium sulfate, filtered and concentrated. The crude material was purified by silica gel column chromatography. The product eluted with Hexane: Ethyl Acetate (3 : 1) eluent mixture. The title compound Intermediate 152 was obtained (0.69 g). MS (ES) : 349 (M+l) for Ci6Hi7ClN4O3.
1H-NMR (300 MHz, DMSO-d6): δ 0.81 (t, J= 6.54 Hz, 3H), 3.24-3.25 (m, 4H), 3.49-3.50 (m, 4H), 4.37 (q, J= 7.05 Hz, 2H), 8.20 (s, IH), 8.37 (s, IH), 8.91 (d, J= 1.98 Hz, IH), 9.07 (d, J = 1.80 Hz, IH).
Intermediate 153: 3- [3-f2-Chloro-4-morpholin-4-yl-pyrimidin-5-yl)-phenyll -acrylic acid ethyl ester
Figure imgf000128_0002
A suspension of 4-(5-Bromo-2-chloro-pyrimidin-4-yl)-morpholine Intermediate 151_(3.5 mmol, 1 g), ethyl boronocinnamate (3.95 mmol, 0.87 g), [l,l'-bis(diphenyl- phosphino)ferrocene]dichloropalladium(II)complex with CH2Cl2 (10 mol %, 0.35 mmol, 0.285 g) and sodium carbonate (3.5 mmol, 0.370 g) in acetonitrile/water (20 rnL : 5 rnL) was degassed and heated to 90 0C for 15-20 min under inert atmosphere. Completion of the reaction was monitored by TLC. The solvent was removed in vacuo and the crude mixture was taken in CHCI3 (30 mL). It was then washed with water and brine. The organic layer was separated, dried over sodium sulfate, filtered and concentrated. The crude material was purified by silica gel column chromatography. The product eluted with Hexane : Ethyl Acetate (91 : 9) eluent mixture. The title compound Intermediate 153 was obtained (0.63 g). MS (ES) : 374 (M+l) for Ci9H20ClN3O3.
1H-NMR (300 MHz, DMSO-d6): δ 1.25 (t, J= 7.05 Hz, 3H), 3.25-3.32 (m, 4H), 3.49-3.50 (m, 4H), 4.19 (q, J = 7.05 Hz, 2H), 6.74 (d, J = 16.05 Hz, IH), 7.50-7.59 (m, 2H), 7.69 (d, J = 16.14 Hz, IH), 7.73 (br s, IH), 7.83 (s, IH), 8.11 (s, IH) .
Intermediate 154: methyl 6-bromo-4-oxo-4H-chromene-3-carboxylate
Figure imgf000129_0001
To a solution of 6-bromo-4-oxo-4H-chromene-3-carboxylic acid (3.7 mmol, 1 g) in methanol (15 mL) was added thionyl chloride (5 mL) slowly at 0 0C. The reaction mixture was then refluxed at 70 0C for 2 h and then cooled to room temperature. Methanol was removed in vacuo and the residue was poured on to ice water (25 mL), extracted with ethyl acetate (2 xlO mL). The combined organic extracts were washed with 10 % sodium bicarbonate solution (2 xlO mL), brine, dried over anhydrous sodium sulphate, filtered and concentrated to get methyl 6-bromo-4-oxo-4H-chromene-3-carboxylate Intermediate 154 as yellow solid (900 mg). MS(ES): 283 (M) and 285.2 (M+2) for CnH7BrO4.
1H-NMR(400 MHz, DMSO-d6): δ 3.80 (s, 3H), 7.74 (d, J= 8.80 Hz, IH), 8.03 (dd, J= 2.80, 9.00 Hz, IH), 8.16 (d, J= 2.40 Hz, IH), 9.01 (s, IH). Intermediate 155: methyl 4-oxo-6-(4,4,5,5-tetramethyl-l,3i2-dioxabor()lan-2-yl)-4H- chromene-3-carboxylate and [3-fmethoxycarbonyl)-4-oxo-4H-chromen-6-yllboronic acid
Figure imgf000130_0001
A mixture of methyl 6-bromo-4-oxo-4H-chromene-3-carboxylate Intermediate 154 (1.41 mmol, 400 mg), bis(pinacolato)diboron (3.94 mmol, 1 g), 2-Dicyclohexylphosphino-2',4',6'- triisopropylbiphenyl (20 mol%, 0.28 mmol, 135 mg), palladium acetate (4 mol%, 0.06 mmol, 16 mg) and triethylamine (5.6 mmol, 570 mg) in dioxane (20 mL) was degassed and then refluxed at 100 0C for 20 min under nitrogen atmosphere. The solvent was removed in vacuo, residue diluted with dichloromethane (20 mL), washed with water (2x 20 mL), brine. The organic layer was dried over anhydrous sodium sulphate, filtered and concentrated and the resulting residue was then recrystallized with dichloromethane-hexane to get 300 mg of a mixture of methyl 4-oxo-6-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)-4H-chromene-3- carboxylate and [3-(methoxycarbonyl)-4-oxo-4H-chromen-6-yl]boronic acid, Intermediate 155.
MS(ES): 249.2 (M+l) for CnH9BO6. LC = 58.64 % of boronic acid and 331.2 (M+ 1) for Ci7Hi9BO6 LC = 36.05 % for pinacol boronate.
Intermediate 156: 3-Chloro-4-fluoro-phenylH 4-methanesulfonyl-2 '-methoxy-
[5,5' 'lbipvrimidinyl-2-vD-amine
Figure imgf000130_0002
A suspension of sulfone Intermediate 69 (7.8 mmol, 3 g), methoxypyrimidineboronic acid (8.6 mmol, 1.38 g), dichlorobis(triphenyl-phosphine)palladium(II) (0.6 mmol, 437 mg) and sodium carbonate (7.8 mmol, 826 mg) in dioxane (20 mL)-water (5 mL) was degassed and refluxed at 100 0C for 15-20 minutes. Dioxane was removed under vacuum and the residue taken in chloroform (50 mL), washed with water (50 mL) and brine. The layers were separated and the organic layer was dried over sodium sulphate, filtered and concentrated. The resulting residue was then purified by column chromatography using 230-400 mesh silica gel and 2% of methanol in chloroform as eluent. The solid thus obtained was stirred with acetonitrile for 15 minutes. The solid was filtered and dried under vacuum to yield the title compound as solid (1.4 g). MS(ES): 410.2 (M+ 1) for Ci6Hi3ClFN5O3S.
1H-NMR(SOO MHz, DMSO-d6): δ 3.39 (s, 3H), 3.96 (s, 3H), 7.43 (t, J= 9.09 Hz, IH), 7.60- 7.65 (m, IH), 8.00 (dd, J= 2.40, 6.61 Hz, IH), 8.67 (s, 2H), 8.81 (s, IH), 10.57 (s, IH).
Intermediate 157: methyl 4-{2-[f3-chloro-4-fluorophenyl)aminol-4- (methylsulfonyl)pyrimidin-5-yl}pyridine-2-carboxylate
Figure imgf000131_0001
A mixture of methyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine-2-carboxylate (1.1 eq, 0.289 mmol, 0.076 g) and 2,8,9-Triisobutyl-2,5,8,9-tetraaza-l- phosphabicyclo[3.3.3]undecane (0.1 eq, 0.024 mmol, 8.1 mg) was stirred for 20 min under N2 in acetonitrile (3 mL). [Flask I]
In a separate flask, 5-bromo-N-(3-chloro-4-fluorophenyl)-4-(methylsulfonyl)pyrimidin-2- amine, (Intermediate 69) (1 eq, 0.263 mmol, 100 mg) was mixed with [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II)complex with CH2Cl2 (10 mol%, 21.5 mg) and stirred for 10 min under N2 in acetonitrile (3 mL). [Flask II]
The contents of [Flask I] were quickly transferred to [Flask II]. Water (1.5 mL) was added and the mixture was heated at 90 0C for 20-25 minutes then concentrated in vacuo. The resulting slurry was taken in EtOAc and washed with water and brine. The organic layer was separated, dried over sodium sulfate, filtered and concentrated. The reaction was repeated on the same scale using the above procedure. The crude materials from both batches were combined and purified by silica gel column chromatography (60-120 mesh) using ethyl acetate/hexanes (2:3 to 3: 2) as an eluent. The title compound was thus obtained (0.09 g). MS(ES): 437 (M+l) for Ci8Hi4ClFN4O4S. 400 MHz, DMSO-de: δ 3.38 (s, 3H), 3.90 (s, 3H), 7.44 (t, J = 9.08 Hz, IH), 7.64 (ddd, J = 2.72, 4.10, 9.03 Hz, IH), 7.75 (dd, J = 1.76, 4.94 Hz, IH), 8.00 (dd, J = 2.40, 6.66 Hz, IH), 8.19 (d, J = 1.12 Hz, IH), 8.78 (d, J = 4.96 Hz, IH), 8.82 (s, IH), 10.63 (s, IH).
Intermediate 158: 2-(3-chloro-4-fluorophenylamino)-4-(3- methoxypropylamino)pyrimidine-5-carbonitrile
Figure imgf000132_0001
To a stirred suspension of 5-bromo-Λ/2-(3-chloro-4-fluorophenyl)-Λ/4-(3- methoxypropyl)pyrimidine-2,4-diamine, Intermediate 119 (7.7 mmol, 3 g, 1 eq), zinc acetate (0.306 mmol, 0.056 g, 0.04 eq), zinc (1.9 mmol, 0.124 g, 2.5 eq), tris(dibenzylideneacetone)- dipalladium (0) (0. 15 mmol, 0. 135 g, 0.02 eq) and 1 , r-bis(diphenylphosphino)ferrocene (0.3 mmol, 0. 168 g, 0.04 eq) in degassed DMF (30 mL) was added zinc cyanide (0. 580 g, 4.9 mmol). The vessel was evacuated and backfilled with argon; this process was repeated once. The mixture was placed under an atmosphere of nitrogen, stirred, and heated to 100 0C for 3 hours. The stirring was continued while the mixture was allowed to cool to room temperature; the mixture was then diluted with small volumes of water. The dark solution became cloudy with addition of water. Larger volumes were added until a maximum of precipitation was reached. The stirring was continued for ten minutes. The solid was collected and washed with water to give the title compound (2.1 g). MS(ES): 336 (M+l) for Ci5Hi5ClFN5O.
300 MHz, DMSO-J6: δ 1.76-1.85 (m, 2H), 3.21 (s, 3H), 3.38 (t, J= 6.15 Hz, 2H), 3.41-3.47 (m, 2H), 7.33 (t, J= 9.09 Hz, IH), 7.57-7.62 (m, IH), 7.87 (br s, IH), 8.09-8.12 (m, IH), 8.36 (s, IH), 9.99 (br s, IH). Intermediate 159: 2-[f3-chloro-4-fluorophenyl)aminol-4-[f3- methoxypropyl)aminolpyrimidine-5-carbothioamide
Figure imgf000133_0001
To 2-(3 -chloro-4-fluorophenylamino)-4-(3 -methoxypropylamino)pyrimidine-5 -carbonitrile, Intermediate 158 (6.8 mmol, 2.3 g) in 5 niL DMF, ammonium sulfide, (20 % aq solution, 14 mL, 41 mmol) was added and heated at 70 0C in a sealed tube for 4 h. The reaction mixture was quenched with water and the solid was filtered to give the title compound (2 g). MS(ES): 368 (M-I) for CI5HI7CIFN5OS.
400 MHz, DMSO-J6: δ 1.80-1.87 (m, 2H), 3.32 (s, 3H), 3.43 (t, J= 6.12 Hz, 2H), 3.52 (q, J = 6.56 Hz, 2H), 7.32 (t, J= 9.08 Hz, IH), 7.59-7.63 (m, IH), 8.21 (dd, J= 2.48, 6.84 Hz, IH), 8.35 (s, IH), 9.26 (br s, IH), 9.37 (br s, IH), 9.63 (br s, IH), 9.79 (br s, IH).
Intermediate 160: 2- \( 3-chloro-4-fluorophenyl)aminol -4-( morpholin-4-yl)pyrimidine-5- carboxylic acid
Figure imgf000133_0002
To 5-bromo-Λ/-(3-chloro-4-fluorophenyl)-4-(morpholin-4-yl)pyrimidin-2-amine Intermediate 146, 0.51 mmol, 0.2 g) in dry THF at-78° C under nitrogen atmosphere, n-BuLi (1.6 M in Hexanes, 1.02 mmol, 0.64 mL) was added dropwise and stirred for 20 min. Carbon dioxide gas was passed into the reaction mixture for 10 min with constant stirring. The solvent was evaporated and the residue was dissolved in water followed by washing with ethyl acetate. The aqueous layer was acidified with 1 N HCl and the precipitate formed was filtered and dried to yield 45 mg of 2-[(3-chloro-4-fluorophenyl)amino]-4-(morpholin-4- yl)pyrimidine-5 -carboxylic acid.
Figure imgf000134_0002
Intermediate 161: N-( 2-aminophenyl)-2- \( 3-chloro-4-fluorophenyl)aminol -4-( morpholin- 4-yl)pyrimidine-5-carboxamide
Figure imgf000134_0001
To a mixture of 2-[(3-chloro-4-fluorophenyl)amino]-4-(morpholin-4-yl)pyrimidine-5- carboxylic acid (Intermediate 160, 0.85 mmol, 0.3 g) and (Benzotriazol-1- yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (1 mmol, 442 mg) in DMF at 0° C, Et3N (2.14 mmol, 216 mg, 0.3 mL) was added and stirred for 5 min. 1 ,2-phenylenediamine (1 mmol, 110 mg) in DMF was added drop wise to the reaction mixture and stirred at RT for 4-5 h. Water was added to the mixture and stirred overnight. The solid thus obtained was filtered and purified by column chromatography using methanol: chloroform (3: 97) to yield the title compound (70 mg).
Figure imgf000135_0003
Intermediate 162: 7V-methoxy-7V,5-dimethylisoxazole-4-carboxamide
Figure imgf000135_0001
To a mixture of 5-methylisoxazole-4-carboxylic acid (3.5 mmol, 500 mg), triethylamine (11.8 mmol, 1.19 g, 1.6 mL) and Λ/,0-Dimethylhydroxylamine hydrochloride (5.1 mmol, 498 mg) in DCM, was added T3P (50 % in EtOAc, 3.3 mL, 6 mmol) slowly at 0 0C. The reaction mixture was slowly raised to room temperature and stirred for 12 h. Reaction mixture was then diluted with dichloromethane (12 mL) and the dichloromethane layer was successively with water (2x50 mL), 10% aq sodium bicarbonate solution (50 mL) and brine. The organic layer was dried over sodium sulphate, filtered and concentrated. The residue was further purified using column chromatography (60-120 mesh; product eluted at 15% ethyl acetate/hexanes) to yield 480 mg of the title compound.
Figure imgf000135_0002
Intermediate 163: l-(5-methylisoxazol-4-yl)ethanone
Figure imgf000136_0001
To 480 mg of Λ/-methoxy-Λ/,5-dimethylisoxazole-4-carboxamide (Intermediate 162, 2.8 mmol) taken in dry ether at 0 0C, was added drop wise a solution of methyl magnesium bromide (3 M in ether) (2.8 mL, 8.4 mmol, 3 eq). The contents of the flask were then slowly brought to room temperature and stirred for 3 h. The reaction was quenched with saturated ammonium chloride (2 x20 mL) and extracted with Et2O. The organic layer was dried over sodium sulphate, filtered and concentrated to yield 200 mg of the title compound.
Figure imgf000136_0003
Intermediate 164: 2-bromo-l-(5-methylisoxazol-4-yl)ethanone
Figure imgf000136_0002
To 340 mg of l-(5-methylisoxazol-4-yl)ethanone (Intermediate 163, 2.7 mmol) taken in dry THF at room temperature, was added phenyltrimethylammonium tribromide (3 mmol, 1.12 g) and refluxed for 2 h. The reaction was quenched with water (2 x20 mL) and extracted with ethyl acetate. The organic layer was dried over sodium sulphate, filtered and concentrated. The resulting residue was purified by silica gel column chromatography (60-120 mesh; product eluted at 15% ethyl acetate/hexanes) to afford 100 mg of the title compound.
Figure imgf000137_0003
Intermediate 165: 7V-methoxy-7V,l-dimethyl-lH-imidazole-5-carboxamide
Figure imgf000137_0001
To a mixture of l-methyl-lH-imidazole-S-carboxylic acid (7.93 mmol, 1 g), triethylamine (19.83 mmol, 2.77 mL) and Λ/,0-Dimethylhydroxylamine hydrochloride (9.52 mmol, 928 mg) in DCM, was added T3P (50 % in EtOAc, 11.89 mol, 7.57 mL) slowly at 0 0C. The reaction mixture was slowly raised to room temperature and stirred overnight. Reaction mixture was then diluted with dichloromethane (12 mL), washed the dichloromethane solution successively with water (2x50 mL), 10% aq sodium bicarbonate solution (50 mL) and brine. The organic layer was dried over sodium sulphate, filtered and concentrated. The residue was further purified using column chromatography (hexane-ethyl acetate as the eluent) to yield the title compound (1.13 g).
Figure imgf000137_0004
Intermediate 166: l-(l-methyl-l//-imidazol-5-vDethanone
Figure imgf000137_0002
To 1.3 g of JV-methoxy-iV, 1 -dimethyl- lH-imidazole-5-carboxamide (Intermediate 165, 7.68 mmol) taken in dry ether at O 0C, was added drop wise a solution of methyl magnesium bromide (3 M in ether) (7.69 mL, 23 mmol). The contents of the flask were then slowly brought to room temperature and stirred for 3 h. The reaction was quenched with 1.5 N HCl (2 x20 mL) and extracted with Et2O. The organic layer was dried over sodium sulphate, filtered and concentrated to yield 800 mg of the title compound.
Figure imgf000138_0002
Intermediate 167: 2-bromo-l-(l-methyl-lH-imidazol-5-yl)ethanone and 2,2-dibromo-l- (l-methyl-lH-imidazol-5-yl)ethanone
Figure imgf000138_0001
1 -(I -methyl- lH-imidazol-5-yl)ethanone (2.89 mmol, 0.36 g) was dissolved in 5 mL of 48 % hydrogen bromide. To the stirred solution at 25 0C was added over a 5 min period bromine (3.19 mmol, 0.163 mL, 0.51 g) dissolved in 5 mL of 48 % hydrogen bromide. The reaction mixture was heated at 70 0C for 2.5 h and then concentrated in vacuo to a dark oil. A mixture of isopropyl alcohol/diethyl ether was added, and trituration of the oil gave a solid. This was collected by filtration and washed with diethyl ether to give 0.28 g of a mixture of 2-bromo-l- (1 -methyl- lH-imidazol-5-yl)ethanone and 2,2-dibromo-l-(l-methyl-lH-imidazol-5- yl)ethanone.
Figure imgf000139_0003
Intermediate 168: [ 1-ethoxy- 1 ,3-dioxo-3-f pyridin-2-yl)propan-2-ylidenel diazenium
Figure imgf000139_0001
To a mixture of ethyl 3-oxo-3-(pyridin-2-yl)propanoate (0.52 mmol, 100 mg),p- Acetamidobenzene sulfonyl azide (0.52 mmol, 114 mg) in dry acetonitrile (5 mL) was added triethyl amine (1.56 mmol, 157 mg) slowly at 0 0C. The reaction mixture was slowly raised to room temperature and stirred for 2-3 h. The solvent was removed in vacuo and the resulting residue was stirred with petroleum ether: diethyl ether (1 :1) mixture for 0.5 h and filtered. The filtrate was concentrated to yield 100 mg of the title compound as brownish liquid, which was used in the next step without further purification. MS(ES): 220 (M+l) for Ci0H9N3O3.
Intermediate 169: l-methyl-lH-pyrazole-3-carbonyl chloride
Figure imgf000139_0002
To a suspension of l-methyl-lH-pyrazole-3-carboxylic acid (0.3 g, 2.38 mmol) in dichloromethane (10 mL) was added oxalyl chloride (0.3 mL, 3.6 mmol) dropwise at 0 °C. The resulting mixture was stirred at room temperature for 1 h and then heated to 70 0C for 2 h. After cooling to room temperature, the excess oxalyl chloride and solvent was removed by rotary evaporator (with water bath temperature below 40 0C) to afford the title compound as a gum, which was used in the next step without further purification.
Intermediate 170: ethyl 3-( l-methyl-lH-pyrazol-3-yl)-3-oxopropanoate
Figure imgf000140_0001
0.53 g of ethyl hydrogen malonate (4.05 mmol) was taken in anhydrous tetrahydrofuran (10 mL) in a 2-necked 100 mL round bottom flask equipped with a nitrogen inlet. After cooling to -78 0C, n-butyl lithium (2.7 mL, 8.1 mmol, 3 M solution in hexanes) was added through a syringe while the temperature was allowed to rise to approximately -10 0C. The heterogeneous solution was recooled to -75 0C and acid chloride, Intermediate 169, prepared above in anhydrous TΗF (5 mL) was added over 10-15 minutes. The resulting mixture was stirred for 3 hours and then poured into a 100 mL separatory funnel containing ethyl acetate (50 mL) and ice-cold IN HCl (5 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (50 mL x 2). The organic layers were combined and washed with saturated aqueous sodium bicarbonate solution (2 x 50 mL) and brine (50 mL). The solvent was removed under vacuum to afford a purple solid, which was purified by RP-ΗPLC (Symmetry Cl 8 column(19 x 300 mm, 7μm); using a binary solvent mixture of 10 mM NH4OAc (A)/CH3CN (B) (0-20 min: 0-40% B, 20-30 min: 40% B and 30-40 min: 40-100% B; flow rate of 15 mL/min; Separation was monitored at 254 nm) to get the title compound as a semi-solid (100 mg).
Figure imgf000141_0002
Intermediate 171: ethyl 2-chloro-3-(l-methyl-lH-pyrazol-3-vD-3-oxopropanoate
Figure imgf000141_0001
To a solution of ethyl 3-(l-methyl-lH-pyrazol-3-yl)-3-oxopropanoate (Intermediate 170, 100 mg, 0.510 mmol) in ethyl acetate (5 mL) was added N-chlorosuccinimide (75 mg, 0.56 mmol, 1.1 equiv) and Amberlyst-15 resin (100 mg). The resulting mixture was stirred for 4 hours at room temperature. The solid was removed by filtration and the solvent was removed in vacuo to afford the title compound (100 mg) which was used for the next step without further purification.
Figure imgf000141_0003
Intermediate 173: (l.,3-?ra«s)-tert-butyl 3-(3-bromophenyl)-2.,2- dimethylcyclopropanecarboxylate
Figure imgf000142_0001
Isopropyltriphenylphosphonium iodide (1.621 g, 3.75 mmol) was suspended in THF (8 ml) and cooled to -78 0C. 2.4 M butyllithium in hexanes (1.563 niL, 3.75 mmol) was added dropwise over 2 minutes. The mixture was then stirred over an ice-water bath 30 min to give a clear dark red solution. The mixture was cooled to -78 0C and a solution of (E)-tert-butyl 3- (3-bromophenyl)acrylate (590 mg, 2.08 mmol) in THF (3 ml) was added. The mixture was cooled over an ice-water bath and allowed to slowly warm to room temperature overnight. Methyl iodide (0.6 mL, 9.60 mmol) was added to the mixture followed by stirring at room temperature 1 hour. The mixture was poured into 0.5M HCl, extracted with EtOAc, dried over MgSO4 and evaporated. The residue was dissolved in dichloromethane and filtered over silica gel, rinsed with 200 ml 5% ethyl acetate in hexane. The filtrate was evaporated to give the crude product as a yellow oil: (550 mg).
1H NMR (400 MHz, CHLOROFORM-D) δ ppm 0.90 (s, 3 H), 1.34 (s, 3 H), 1.48 (s, 9 H), 1.86 (d, 1 H), 2.56 (d, 1 H), 7.06 - 7.17 (m, 2 H), 7.29 - 7.35 (m, 2 H).
Intermediate 174: (l,3-fmns)-tert-butyl 2,2-dimethyl-3-(3-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)phenyl)cyclopropanecarboxylate
Figure imgf000142_0002
(1 ,3-trans)-tevt-butyl 3-(3-bromophenyl)-2,2-dimethylcyclopropanecarboxylate ) Intermediate 173 (1.3 g, 4.00 mmol), 4,4,4>,4>,5,5,5>,5>-octamethyl-2,2'-bi(l,3,2- dioxaborolane (2.030 g, 7.99 mmol), potassium acetate (1.177 g, 11.99 mmol), PdC12(dppf> CH2Cl2 Adduct (0.326 g, 0.40 mmol) and dioxane (10 mL) were combined and degassed by bubbling an argon stream through the mixture for 10 minutes. The mixture was warmed over a 90 0C heating block Ihl5m. The mixture was allowed to cool, diluted to ~40 ml with CH2Cl2, filtered and evaporated then applied to a 4Og silica cartridge and eluted with 0 to 10% ethyl acetate / hexanes. The title compound was obtained as a thick clear oil (1.124 g) IH NMR (400 MHz, CHLOROFORM-D) δ ppm 0.89 (s, 3 H), 1.25 (s, 3 H), 1.34 (s, 12 H), 1.48 (s, 9 H), 1.93 (d, 1 H), 2.61 (d, IH), 7.25 (d, 1 H), 7.28 (t, 1 H), 7.59 (s, 1 H), 7.64 (d, 1 H)
The intermediates in the table below were prepared using the procedure described above and the specified starting material.
Figure imgf000143_0001
Intermediate 176: (l.,3-trans)-tert-butyl 3-(3-(2-(3-chloro-4-fluorophenylamino)-4-(3- ftrifluoromethyl)-lH-pyrazol-l-yl)pyrimidin-5-yl)phenyl)-2,2- dimethylcyclopropanecarboxylate
Figure imgf000144_0001
(1 S,3S)-tert-butyl 2,2-dimethyl-3-(3-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2- yl)phenyl)cyclopropanecarboxylate Intermediate 174 (300 mg, 0.81 mmol), 5-bromo-N-(3- chloro-4-fluorophenyl)-4-(3 -(trifluoromethyl)- 1 H-pyrazol- 1 -yl)pyrimidin-2-amine [Intermediate 115] (200 mg, 0.46 mmol), Tris(dibenzylideneacetone)dipalladium(0) (41.9 mg, 0.05 mmol), 2-Dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (65.5 mg, 0.14 mmol), Na2CO3 (72.8 mg, 0.69 mmol), acetonitrile (3 mL) and water (0.750 mL) were combined and degassed with an argon stream for 10 min. The mixture was warmed at 80 0C Ihl5m, allowed to cool, diluted with acetonitrile, filtered and adsorbed on 15 ml silica gel. Flash chromatography (40 g cartridge) 20 to 100% dichloromethane/hexane gave the pure title compound (35 mg). MS: ES+ 602 for C30H28ClF4N5O2.
IH NMR (400 MHz, CHLOROFORM-D) δ ppm 0.86 (s, 3 H), 1.32 (s, 3 H), 1.46 (s, 9 H), 1.79 (d, 1 H), 2.57 (d, 1 H), 6.56 (s, 1 H), 6.92 (s, 1 H), 7.00 (d, 1 H), 7.09 - 7.21 (m, 2 H), 7.25 - 7.32 (m, 2 H), 7.35 - 7.41 (m, 1 H), 7.85 - 7.95 (m, 2 H), 8.52 (s, 1 H).
Intermediate 177: (E)-tert-butyl 3-(5-bromopyridin-3-yl)acrylate
Figure imgf000144_0002
tert-Butyl 2-(diethoxyphosphoryl)acetate (2.291 mL, 9.75 mmol) and tetrahydrofuran (5 mL) were combined and cooled over a dry-ice ethanol bath at -70 C then Sodium bis(trimethylsilyl)amide, 2M solution in THF (4.82 mL, 9.63 mmol) was added dropwise over 5 minutes to give a clear yellow solution. The mixture was stirred over the cold bath 30 minutes, then a solution of 5-bromonicotinaldehyde (1.629 g, 8.76 mmol) in 5 ml THF was added. The cold bath was removed and the mixture was stirred 20 minutes. The mixture was poured into 0.5M HCl and extracted ethyl acetate, washed with saturated sodium chloride, dried over MgSO4 and evaporated to give the title compound as a light yellow solid (2.78 g). IH NMR (400 MHz, CHLOROFORM-D) δ ppm 1.52 (s, 9 H), 6.44 (d, 1 H), 7.48 (d, 1 H), 7.98 (d, 1 H), 8.55 - 8.73 (m, 2 H)
Intermediate 178: ( l,2-?m«s)-tert-butyl l-fS-bromopyridin-S-yDcyclopropanecarboxylate
Figure imgf000145_0001
Trimethylsulfoxonium iodide (1.084 g, 4.93 mmol) was combined with dimethylsulfoxide (5 ml) and 60% sodium hydride dispersion in oil (0.183 g, 4.58 mmol) and stirred at room temperature for 50 minutes to give a clear solution, then (E)-tert-butyl 3-(5-bromopyridin-3- yl)acrylate Intermediate 177 (1 g, 3.52 mmol) was added together with dimethylsulfoxide (1 ml) to give a yellow-orange suspension which was stirred at room temperature for 45 minutes. The mixture was poured into 50 ml water, extracted twice with ethyl acetate and the organic layer was dried over magnesium sulfate and evaporated to give a clear oil. Purification by flash chromatography, 0 to 15% ethyl acetate in hexane gave the title compound as a white solid (455 mg). IH NMR (400 MHz, CHLOROFORM-D) δ ppm 1.20 - 1.28 (m, 1 H), 1.47 (s, 9 H), 1.56 - 1.63 (m, 1 H), 1.82 - 1.90 (m, 1 H), 2.38 - 2.45 (m, 1 H),7.51 (s, 1 H), 8.35 (d, 1 H), 8.50 (d, 1 H). Intermediate 179: (l,2-fmns)-tert-butyl 2-(5-(4,4.,5,5-tetramethyl-l.l3,2-dioxaborolan-2- yl)pyridin-3-yl)cvclopropanecarboxylate
Figure imgf000146_0001
(l,2-trans)-tert-butyl 2-(5-bromopyridin-3-yl)cyclopropanecarboxylate Intermediate 178 (0.435 g, 1.46 mmol), 4,4,4>,4>,5,5,5>,5>-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (0.741 g, 2.92 mmol), potassium acetate (0.430 g, 4.38 mmol), PdC12(dppf)-dichloromethane adduct (0.119 g, 0.15 mmol) and dioxane (5 mL) were combined and degassed by bubbling and argon stream through the mixture for 10 minutes. The mixture was warmed at 90 °for 1.5 hours, allowed to cool and filtered. The solids were rinsed with dichloromethane and the filtrate was evaporated. The residue was filtered over 25 ml silica gel, eluting with dichloromethane (200 ml), then 25% ethyl acetate in dichloromethane (200 ml). The filtrate was discarded before the silica gel was further eluted with 200 ml 5% methanol in dichloromethane. Evaporation gave the title compound as a crude brown solid (270 mg). 1H NMR (400 MHz,
CHLOROFORM-D) δ ppm 0.79 - 0.99 (m, 1 H), 1.34 (s, 12 H), 1.46 (s, 9 H), 1.51 - 1.59 (m, 1 H), 1.83 - 1.90 (m, 1 H), 2.38 - 2.47 (m, 1 H), 7.68 (s, 1 H), 8.49 (m, 1 H), 8.76 (m, 1 H). Intermediate 180: fl,2-trans)-tert-butyl 2-f5-f2-f3-chloro-4-fluorophenylamino)-4-f3- ftrifluoromethyD-lH-pyrazol-l-vDpyrimidin-S-vDpyridin-S-vDcvclopropanecarboxylate
Figure imgf000146_0002
(lR,2R)-tert-butyl 2-(5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-3- yl)cyclopropanecarboxylate, Intermediate 179 (270 mg, 0.55 mmol), 5-bromo-N-(3-chloro- 4-fluorophenyl)-4-(3 -(trifluoromethyl)- 1 H-pyrazol- 1 -yl)pyrimidin-2-amine [Intermediate 115] (159 mg, 0.36 mmol), Tris(dibenzylideneacetone) dipalladium(O) (33.4 mg, 0.04 mmol), 2-Dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (52.2 mg, 0.11 mmol), sodium carbonate (58.0 mg, 0.55 mmol), acetonitrile (2 niL) and water (0.500 rnL) were combined and degassed with an argon stream for 10 min. The mixture was warmed at 80 0C for 1 hour 15 minutes, allowed to cool, diluted with acetonitrile, filtered and adsorbed on silica gel. Purification by flash chromatography (25 g cartridge) 0.5 to 5% methanol in dichloromethane gave the solid title compound (110 mg). MS: ES+ 575 for C27H23ClF4N6O2. IH NMR (400 MHz, DMSO-D6) δ ppm 1.21 - 1.30 (m, 2 H), 1.41 (s, 9 H), 1.78 - 1.86 (m, 1 H), 2.33 - 2.42 (m, 1 H), 7.02 (d, 1 H), 7.23 (s,l H), 7.41 (t, 1 H), 7.65 - 7.75 (m, 1 H), 8.08 (dd, 1 H), 8.21 (d, 1 H), 8.45 (d, 2 H), 8.81 (s, 1 H), 10.42 (s, 1 H). Intermediate 181: (1,2-trans)- tert-butyl 2-(3-bromophenvDcvclopropanecarboxylate
Figure imgf000147_0001
The title compound was prepared using the general method described above for Intermediate 178 using (E)-tert-butyl 3-(3-bromophenyl)acrylate as a starting material. 1H NMR (300 MHz, CHLOROFORM-D) δ ppm 0.76 - 0.94 (m, 1 H), 1.16 - 1.23 (m, 1 H), 1.46 (s, 9 H), 1.77 - 1.86 (m, 1 H), 2.33 - 2.43 (m, 1 H), 7.01 (d, 4 H), 7.12 (t, 1 H), 7.21 (s, 1 H), 7.31 (d, 1 H).
Intermediate 182: fl,2-trans)-tert-butyl 2-(3-(4,4.,5,5-tetramethyl-l.l3,2-dioxaborolan-2- vDphenvDcvclopropanecarboxylate
Figure imgf000147_0002
The title compound was prepared using the general method described above for Intermediate 178 using Intermediate 181 as a starting material. 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 0.80 - 0.93 (m, 1 H), 1.45 (s, 12 H), 1.45 (s, 9 H), 1.47 - 1.53 (m, 1 H), 1.79 - 1.89 (m, 1 H), 2.40 - 2.50 (m, 1 H), 7.17 (d, 1 H), 7.28 (d, 1 H), 7.52 (s, 1 H), 7.63 (d, 1 H). Intermediate 183: (l.,2-trans)-tert-butyl 2-(3-(2-(3-chloro-4-fluorophenylamino)-4-(3- ftrifluoromethyD-lH-pyrazol-l-vDpyrimidin-S-vDphenvDcvclopropanecarboxylate
Figure imgf000148_0001
The title compound was prepared using the general method described above for Intermediate 178 using Intermediate 182 and Intermediate 115 as starting materials. MS: ES+ 574 for C27H23ClF4N6O2.
1H NMR (400 MHz, DMSO-D6) δ ppm 1.17 - 1.22 (m, 1 H), 1.30 - 1.37 (m, 1 H), 1.40 (s, 9 H), 1.68 - 1.76 (m, 1 H), 2.23 - 2.33 (m, 1 H), 6.79 (s,l H), 6.96 (d, 1 H), 7.00 (d, 1 H), 7.13 - 7.18 (m, 1 H), 7.24 (t, 1 H), 7.39 (t, 1 H), 7.65 - 7.73 (m, 1 H), 8.12 (dd, 1 H), 8.25 (s, 1 H), 8.79 (s, l H),10.38 (s, I H).
Intermediate 184: methyl 5-bromo-2-(methylamino)nicotinate
Figure imgf000148_0002
Methyl 5-bromo-2-chloronicotinate (1 g, 3.99 mmol) and methylamine, 2M solution in THF (4 ml, 8.00 mmol) were combined and warmed in a microwave reactor at 125 0C for 1 hour. The mixture was combined with 50 ml ethyl acetate, washed with 0.2M HCl, dried over magnesium sulfate and evaporated to give the title compound as an off-white solid (0.956 g). 1H NMR (300 MHz, DMSO-d6) δ ppm 2.93 (d, 3 H), 3.82 (s, 3 H), 7.87 (br. s., 1 H), 8.12 (d, 1 H), 8.39 (d, 1 H) Intermediate 185: methyl 5-bromo-2-(dimethylamino)nicotinate
Figure imgf000149_0001
The title compound was prepared using the general method described above for Intermediate 184 using dimethylamine, 2M solution in THF as a reagent. 1H NMR (300 MHz, DMSO-d6) d ppm 2.92 (s, 6 H), 3.82 (s, 3 H), 7.97 (d, 1 H), 8.30 (d, 1 H)
Intermediate 186: methyl 5-bromo-2-flH-l,2,4-triazol-l-yl)nicotinate
Figure imgf000149_0002
4H-l,2,4-triazole (0.4 g, 5.79 mmol) was dissolved in NMP (5 mL) then sodium hydride (60% dispesion in oil) (200 mg, 5.00 mmol) was added. The mixture was stirred at room temperature for 30 minutes, then methyl 5-bromo-2-chloronicotinate (1 g, 3.99 mmol) was added. The mixture was stirred for 2 hours, diluted with water, extracted with ethyl acetate, washed with saturated sodium chloride, dried over magnesium sulfate and evaporated.
Purification of the residue by flash chromatography (25 g cartridge, 20 to 60% ethyl acetae / hexanes) gave the title compound as an off-white solid (0.42 g).
MS: ES+ 284 for C9H7BrN4O2.
1H NMR (400 MHz, DMSO-d6) δ ppm 3.76 (s, 3 H), 8.29 (s, 1 H), 8.56 (d, 1 H), 8.89 (d, 1 H), 9.29 (s, 1 H).
Intermediate 187 methyl 5-bromo-2-(lH-pyrazol-l-yl)nicotinate
Figure imgf000149_0003
The title compound was prepared using the general method described above for Intermediate 186 using lH-pyrazole as a reagent. MS: ES+ 283 for Ci0H8BrN3O2.
1H NMR (400 MHz, DMSO-d6) δ ppm 3.75 (s, 3 H), 6.53 - 6.64 (m, 1 H), 7.81 (d, 1 H), 8.41
(d, 1 H), 8.51 (d, 1 H), 8.76 (d, 1 H).
Intermediate 188 methyl 5-bromo-2-(2-(methylsulf()nyl)ethylamino)nicotinate
Figure imgf000150_0001
Methyl 5-bromo-2-chloronicotinate (800 mg, 3.19 mmol), 2-(methylsulfonyl)ethanamine hydrochloride (586 mg, 3.67 mmol), NMP (4 mL) and N,N-diisopropylethylamine (0.893 mL, 5.11 mmol) were combined and warmed over at 80 °for 18h, , diluted with water (50 ml) to give a solid precipitate which was collected and rinsed with water, then 1 : 1 ether/hexanes to give the title compound as a beige solid (0.687 g). MS: ES+ 338 for Ci0Hi3BrN2O4S.
1H NMR (400 MHz, DMSO-d6) δ ppm 3.02 (s, 3 H), 3.40 (t, 2 H), 3.83 (s, 3 H), 3.90 (q, 2 H), 8.18 (d, 1 H), 8.16 (t, 1 H), 8.42 (d, 1 H)
Intermediate 189 methyl 5-bromo-2-(lH-imidazol-l-yl)nicotinate
Figure imgf000150_0002
Methyl 5-bromo-2-chloronicotinate (1 g, 4 mmol) and imidazole (820 mg, 12 mmol) combined with NMP (5 mL) and warmed at 70 0C for 17 hours, then at 100 0C for 5 hours. The mixture was diluted with water, extracted with ethyl acetate, washed with saturated sodium chloride, dried over magnesium sulfate and evaporated. The residue was purified by flash chromatography (25 g cartridge, 10 to 40% acetonitrile in dichloromethane) to give the title compounds as an off-white solid: 236 mg . MS: ES+ 283 for Ci0H8BrN3O2.
1H NMR (400 MHz, DMSO-d6) δ ppm 3.78 (s, 3 H), 7.07 (s, 1 H), 7.50 (s, 1 H), 8.03 (s, 1 H), 8.58 (d, 1 H), 8.90 (d, 1 H) Intermediate 190: methyl 5-bromo-l-methyl-6-oxo-l,6-dihvdr()pyridine-3-carboxylate
Figure imgf000151_0001
Methyl 5-bromo-6-oxo-l,6-dihydropyridine-3-carboxylate (2 g, 8.62 mmol) was combined with DMF (20 mL) and triethylamine (3.60 mL, 25.86 mmol) to give a clear solution which was cooled over an ice-water bath. Dimethylsulfate (2.452 mL, 25.86 mmol) was added to the cold solution dropwise over several minutes. The clear solution was removed from the cold bath and stirred at room temperature for 1.5 hours to give a suspension. The mixture was diluted with 0.2M NaOH to 200 ml and the solids were filtered and rinsed with water to give the title compound as a white solid (0.84 g). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.68 (s, 3 H), 3.88 (s, 3 H), 8.19 (d, 1 H), 8.27 (d, 1 H).
General procedure for reaction of amino acids with 1,3-dibromobenzene:
Figure imgf000151_0002
A suspension of 1,3-dibromobenzene (1 eq), amino acid (2-2.5 eq), CuI (20 mol%) and potassium carbonate (3 eq) in DMF (5 mL) was taken in sealed tube, degassed and heated to 90 0C overnight under inert atmosphere. The reaction mixture was then cooled to RT and filtered through a celite bed. The filtrate was acidified with 1.5 N HCl. The solvent was removed under vacuum and the crude mixture taken in CHCI3 (50 mL), washed with water and brine, dried over Na2SO4, filtered and concentrated. The crude material was purified by silica gel column chromatography using chloroform: methanol (9:1) as an eluent to give the product. The compounds in the table below were prepared using this general procedure and the starting material specified.
Figure imgf000152_0001
eneral procedure for esterification of TV-aryl amino acids
Figure imgf000153_0001
To a suspension of amino acid derivative (1.5 eq) taken in excess of MeOH at 0 0C, was added thionyl chloride (1 vol) slowly and the reaction mixture re fluxed for 2 h. The solvent was removed under vacuum and the crude mixture was taken in EtOAc (30 mL), washed with aq. NaHCO3 solution, water and brine, dried over Na2SO4, filtered and concentrated. The crude material was taken to the next step as such without further purification.
The compounds in the table belowwere prepared using this general procedure and the starting material specified.
Figure imgf000153_0002
Figure imgf000154_0002
General procedures for the preparation of boronate esters from aryl bromides
Figure imgf000154_0001
Method I:
A suspension of aryl bromide (1 eq), bis(pinacolato)diboron (2 eq), [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with CH2Cl2 (20 mol%) and potassium acetate (3 eq) was taken in dioxane and it was degassed for 10 min. Then the reaction mixture was heated overnight at 90 0C. The reaction mixture was cooled to room temperature, filtered through a celite bed, washed with ethyl acetate twice and concentrated in vacuo. The residue was diluted with ethyl acetate (2x), washed with water (Ix) and brine (Ix), dried over Na2SO4 and concentrated in vacuo. The crude mass was purified by 60-120 silica gel column chromatography using ethyl acetate/hexanes and as eluent to give the product. Method II:
A suspension of aryl bromide (1 eq), bis(pinacolato)diboron (3 eq), palladium(II) acetate (20-40 mol%), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (20 mol%) and triethylamine (3 eq) was taken in dioxane and it was degassed for 10 min. Then the reaction mixture was heated overnight at 90-100 0C. The reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate (2x). The organic layer was washed with water (Ix) and brine (Ix), dried over Na2SO4 and concentrated in vacuo. Then the crude mass was purified by 60-120 silica gel column chromatography using ethyl acetate/hexanes and as eluent to give the product.
The compounds in the below table were prepared using this general procedure and the starting material specified.
Figure imgf000155_0001
Figure imgf000156_0002
a) Method I; b) Method II
Intermediate 206: 7V-(3-bromophenyl)glvcine
Figure imgf000156_0001
To a suspension of 3-bromoaniline (5.8 mmol, 1 g), and bromoacetic acid (8.7 mmol, 1.2 g) in ethanol (50 mL), was added triethylamine (17.3 mmol, 1.75 g) and 4- (Dimethylamino)pyridine (1.7 mmol, 0.2 g). The mixture was refluxed for 2 days. The reaction mixture was concentrated in vacuo, acidified with 1.5 N HCl and extracted with ethyl acetate (50 mL).The organic layer was washed with brine solution (25 mL), dried over Na2SO4 and concentrated in vacuo. The crude mass was purified by 60-120 silica gel column chromatography using chloroform and methanol (2 %) as eluent to give the title compound (0.5 g). Taken for next step on basis of LCMS.
Figure imgf000157_0002
Intermediate 207: methyl l-(3-bromophenyl)pyrrolidine-3-carboxylate
Figure imgf000157_0001
A suspension of JV-(3-bromophenyl)glycine Intermediate 206 (3.04 mmol, 0.7 g), 30% aq. formaldehyde solution (4.56 mmol, 0.14 g) and methyl acrylate (4.65 mmol, 0.4 g) in toluene (5 mL) was refluxed for 2 days. The reaction mixture was concentrated in vacuo and diluted with ethyl acetate (10 mL). The ethyl acetate layer was washed with water (5 mL), brine solution (5 mL), dried over Na2SO4 and concentrated in vacuo. The crude mass was purified by 60-120 silica gel column chromatography using 8 % ethyl acetate/hexanes as eluent to give the title compound (0.15 g). Taken for next step on basis of LCMS.
Figure imgf000157_0003
Intermediate 208: methyl l-[3-(4,4,5.,5-tetramethyl-l,3i2-(iioxaborolan-2- yl)phenyllpyrrolidine-3-carboxylate and {3-r3-(methoxycarbonyl)pyrrolidin-l- yllphenyllboronic acid
Figure imgf000158_0001
A suspension of methyl l-(3-bromophenyl)pyrrolidine-3-carboxylate (Intermediate 207, 0.42 mmol, 120 mg), bis(pinacolato)diboron (0.84 mmol, 215 mg), [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.084 mmol, 61 mg) and potassium acetate (1.26 mmol, 125 mg) was taken in dioxane (10 mL) and it was degassed for 10 min. Then the reaction mixture was heated overnight at 90 0C. The reaction mixture was cooled to room temperature, filtered through celite bed, washed with ethyl acetate twice and concentrated in vacuo. Then the residue was diluted with ethyl acetate (10 mL), washed with water (5 mL), brine solution (5 mL), dried over Na2SO4 and concentrated in vacuo. The crude mass was purified by 60-120 silica gel column chromatography using 10 % ethyl acetate/hexanes and as eluent to give 0.1 g of a 72:19 mixture of methyl l-[3-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]pyrrolidine-3-carboxylate and {3-[3-
(methoxycarbonyl)pyrrolidin-l-yl]phenyl}boronic acid which was taken for next step on basis ofLCMS.
Figure imgf000158_0002
Intermediate 209: 5-bromo-7V-(3,5-dimethoxyphenyl)-4-methoxypyrimidin-2-amine
To a stirred solution of 5-bromo-2-chloro-4-methoxypyrimidine (53.81 mmol, 12 g,) and dimethoxyaniline (54.9 mmol, 8.4 g) in n-BuOH (150 mL) was added dioxane-HCl (12 mL) slowly. The reaction mixture was heated to 110 0C for 3 h. It was then cooled to room temperature, diethyl ether (150 mL) was added and the resulting solid was filtered to yield the title compound (15 g).
Figure imgf000159_0001
Intermediate 210: 5-bromo-7V-( 3-fluorophenyl)-4-methoxypyrimidin-2-amine
To a stirred solution of 5-bromo-2-chloro-4-methoxypyrimidine (11.21 mmol, 2.5 g) and 3- fluoroaniline (12.28 mmol, 1.37 g, 1.18 mL) in 2,2,2-trifluoroethanol (15 mL), trifluoroacetic acid (22.34 mmol, 2.55 g, 1.66 mL) was added and the solution was refluxed at 75 0C with constant stirring. After completion of the reaction, as monitored by TLC, water was added to the reaction mixture and extracted with EtOAc (2x50 mL). The organic layer was washed with water, 10% NaHCO3 solution and brine, dried over sodium sulfate and concentrated in vacuo to yield the title compound (2.8 g).
Figure imgf000159_0002
Intermediate 211: 5-bromo-2- \( 3,5-dimethoxyphenvDaminol pyrimidin-4-ol
A solution of 5-bromo-Λ/-(3,5-dimethoxyphenyl)-4-methoxypyrimidin-2-amine (Intermediate 209, 14.7 mmol, 5 g) in n-BuOH (50 niL) and dioxane-HCl (15 niL) were heated to 110 0C in a sealed tube and stirred for 9 h. The reaction mixture was cooled to room temperature and BuOH was concentrated under vacuum. To the residue obtained, was added water (50 mL) and neutralized using 10% NaHCO3 solution. The resulting solid was filtered to yield 3.5 g of 5-bromo-2-[(3,5-dimethoxyphenyl)amino]pyrimidin-4-ol as a white solid.
Figure imgf000160_0002
Intermediate 212: 5-bromo-2-[f3-fluorophenyl)aminolpyrimidin-4-ol
Figure imgf000160_0001
A solution of 5-bromo-N-(3-fluorophenyl)-4-methoxypyrimidin-2-amine (Intermediate 210, 5.03 mmol, 1.5 g) in n-BuOH (15 mL) and dioxane-HCl (4.5 mL) was heated to 110 0C in a sealed tube and stirred for 36 h. The reaction mixture was cooled to room temperature and BuOH was concentrated under vacuum. To the residue obtained, was added water (50 mL) and neutralized using 10% NaHCO3 solution. The resulting solid was filtered to yield 0.6 g of 5-bromo-2-[(3-fluorophenyl)amino]pyrimidin-4-ol.
Figure imgf000160_0003
General procedure for the synthesis of 5-bromo-4-chloro-7V-(aryl)pyrimidin-2-amine
Figure imgf000161_0001
A solution of 5-bromo-2-[arylamino]pyrimidin-4-ol (Intermediate 211 or Intermediate 212, 1 eq) in POCI3 (15 eq) was heated to reflux for 1 h. The mixture was cooled to RT and POCI3 was removed in vacuo. To the residue obtained, was added crushed ice with stirring, and the pH was adjusted to 7-8 using 10% sodium bicarbonate solution. The solid obtained was filtered and washed with chilled water to yield the title compound. The compounds in the below table were prepared using this method and the specified starting material.
Figure imgf000161_0002
General procedure for 5-bromo-7V-(arvD-4-r3-(trifluoromethvD-lH-pyrazol-l- yllpyrimidin-2-amine and 5-bromo-7V-faryl)-4-[5-methyl-3-ftrifluoromethyl)-lH- pyrazol-l-yllpyrimidin-2-amine
Figure imgf000162_0001
NaH (1.2 eq) was dissolved in 1 mL of NMP and stirred for about 5 min at 0 0C. Then either 3-(trifluoromethyl)-lH-pyrazole or 5-methyl-3-(trifluoromethyl)-lH-pyrazole (1.1 eq) in NMP was added dropwise at 0 0C for about 10 min and stirring continued for about 20 min under N2. Then the 5-bromo-4-chloro-Λ/-(aryl)pyrimidin-2-amine starting material in NMP was added dropwise and the reaction was stirred at room temperature overnight. After completion of the reaction, water was added and the solid obtained was filtered, dried and purified by silica gel column chromatography using ethyl acetate/hexanes as eluent to yield the desired product. The compounds in the below table were prepared using this method and the specified starting material.
Figure imgf000162_0002
Figure imgf000163_0001
Figure imgf000164_0002
Intermediate 221: 5-bromo-4-(methylsulfanyl)-7V-r3-(methylsulfonyl)phenyllpyrimidin- 2-amine
Figure imgf000164_0001
To 6 g of 5-bromo-2-chloro-4-(methylsulfanyl)pyrimidine (25.1 mmol) suspended in n-BuOH (20 mL), was added 3-(methylsulfonyl)aniline hydrochloride (25.1 mmol, 5.2 g) followed by HCl in dioxane (25 mL) and refluxed at 100 0C for 3 h. The reaction was cooled to room temperature, diluted with diethyl ether and the solid was filtered and dried to give the title compound (3.1 g).
Figure imgf000164_0003
Intermediate 222: 5-bromo-4-(methylsulfonyl)-Λ^3-(methylsulfonyl)phenyllpyrimidin- 2-amine
Figure imgf000165_0001
A suspension of 5-bromo-4-(methylsulfanyl)-iV-[3-(methylsulfonyl) phenyljpyrimidin- 2-amine (Intermediate 221, 8.02 mmol, 3 g) in dichloromethane (125 niL) was cooled to 0 0C and 3-chloroperoxybenzoic acid (77 %, 27.72 mmol, 6.22 g) was added portion wise. The suspension became a clear solution after stirring at 0 0C for 30 min. The reaction mixture was then allowed to warm up slowly to room temperature and stirred for 5 h. The pH of the reaction mixture was raised to 8 with the addition of 10 % aq. NaHCO3 solution (50 mL), extracted with dichloromethane (3x10 mL) and the combined organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated to give the title compound (1.78 g).
Figure imgf000165_0002
Intermediate 223: ethyl (2Jg)-3-(3-{2-r(3,5-difluorophenyl)aminol-4- (methylsulfonyl)pyrimidin-5-yl}phenyl)prop-2-enoate
A suspension of 5-bromo-Λ/-(3,5-difluorophenyl)-4-(methylsulfonyl)pyrimidin-2-amine Intermediate 139 (0.85 mmol, 0.3 g), {3-[(liT)-3-ethoxy-3-oxoprop-l-en-l- yl]phenyl}boronic acid (0.93 mmol, 0.206 g), bis(diphenylphosphino)ferrocene] dichloropalladium(II) complex with CH2Cl2 (0.14 mmol, 0.112 g) and sodium carbonate (1.27 mmol, 0.14 g) in acetonitrile/water (5 mL:2 mL) was heated to 90 0C for 30 minutes. The reaction mixture was concentrated in vacuo and the residue taken in ethyl acetate (50 mL) was washed with water and brine. The organic layer was dried over sodium sulfate, filtered and concentrated. The crude compound was purified by silica gel column chromatography using 50 % ethyl acetate/hexanes as an eluent to yield the title compound (300 mg).
Figure imgf000166_0002
Intermediate 224: ethyl (2Jg)-3-{3-[4-(methylsulfonyl)-2-{r3- (methylsulfonyl)phenyllamino}pyrimidin-5-vHphenyl}prop-2-enoate
Figure imgf000166_0001
A suspension of 5-bromo-4-(methylsulfonyl)-Λ/-[3-(methylsulfonyl)phenyl]pyrimidin-2- amine Intermediate 222 (3.69 mmol, 1.5 g), {3-[(liT)-3-ethoxy-3-oxoprop-l-en-l- yl]phenyl}boronic acid (4.06 mmol, 0.89 g), bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with CH2Cl2 (0.41 mmol, 0.34 g), 2-dicyclohexylphosphino-2',4',6'-triisopropyl-l,r-biphenyl (1.11 mmol, 0.53 g) and sodium carbonate (4.43 mmol, 0.47 g) in acetonitrile/water (5:1) was heated to 90 0C for 30 minutes. The reaction mixture was diluted with ethyl acetate (50 mL) and the organic layer was separated, dried over sodium sulfate, filtered and concentrated. The crude compound was purified by silica gel column chromatography using EtOAc/hexanes as an eluent to yield the title compound (1.02 g).
Figure imgf000167_0002
Intermediate 225: ethyl 5-{2-r(3,5-difluorophenyl)aminol-4-(methylsulfonyl)pyrimidin-5- yl| pyridine-3 -carboxylate
Figure imgf000167_0001
A suspension of 5-bromo-Λ/-(3,5-difluorophenyl)-4-(methylsulfonyl)pyrimidin-2-amine Intermediate 139 (1.38 mmol, 0.5 g), ethyl 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)pyridine-3-carboxylate (1.65 mmol, 0.46 g), bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with CH2Cl2 (0.14 mmol, 0.112 g) and sodium carbonate (1.37 mmol, 0.146 g) in acetonitrile/water (10 mL:3 mL) was heated to 90 0C for 30 minutes. The reaction mixture was concentrated in vacuo and the residue taken in ethyl acetate (50 mL) was washed with water and brine. The organic layer was dried over sodium sulfate, filtered and concentrated. The crude compound was purified by silica gel column chromatography using 50 % ethyl acetate/hexanes as an eluent to yield the title compound (400 mg).
Figure imgf000168_0002
Intermediate 226: ethyl 5-r4-(methylsulfonv0-2-(r3- (methylsulfonyl)phenyll amino I pyrimidin-5 -yllpyridine-3 -carboxylate
Figure imgf000168_0001
A suspension of 5-bromo-4-(methylsulfonyl)-Λ/-[3-(methylsulfonyl)phenyl]pyrimidin-2- amine Intermediate 224 (3.94 mmol, 1.6 g), ethyl 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan- 2-yl)pyridine-3 -carboxylate (4.33 mmol, 1.2 g), bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with CH2Cl2 (0.44 mmol, 0.36 g), 2-dicyclohexylphosphino-2',4',6'-triisopropyl-l,r-biphenyl (1.12 mmol, 0.56 g) and sodium carbonate (4.72 mmol, 0.5 g) in acetonitrile/water (5:1) was heated to 90 0C for 30 minutes. The reaction mixture was diluted with ethyl acetate (50 mL) and the organic layer was separated, dried over sodium sulfate, filtered and concentrated. The crude compound was purified by silica gel column chromatography using EtOAc/hexanes as an eluent to yield the title compound (1.05 g).
Figure imgf000169_0002
Intermediate 227: 5-bromo-2-chloro-4-[3-ftrifluoromethyl)-lH-pyrazol-l-yllpyrimidine
Figure imgf000169_0001
To a suspension Of K2COs (8.8 mmol, 1.2 g) in acetonitrile (25 rnL), was added 5-bromo-2,4- dichloropyrimidine (8.8 mmol, 2 g) and the reaction mixture was cooled to -5 to -10 0C. 3- (trifluoromethyl)-lH-pyrazole (8.8 mmol, 1.2 g) was dissolved in 25 mL of acetonitrile and added drop wise. After the addition, the reaction mixture was slowly warmed to RT and stirred for 5 h. The reaction mixture was filtered through a celite bed and acetonitrile was removed in vacuo. The crude mass was purified by silica gel column chromatography (60- 120 mesh; product eluted with 2% EtOAc/hexanes) to yield 1.4 g of the product.
Figure imgf000169_0003
Intermediate 228: 5-bromo-7V-(3,5-dimethylphenyl)-4-r3-(trifluoromethyr)-lH-pyrazol- l-yllpyrimidin-2-amine
Figure imgf000170_0001
To a suspension Of Cs2COs (2.4 mmol, 780 mg) in DMF (4 niL), were added 5-bromo-2- chloro-4-[3-(trifluoromethyl)-lH-pyrazol-l-yl]pyrimidine (Intermediate 227, 1.2 mmol, 400 mg) and 3,5-dimethylaniline (1.4 mmol, 177 mg) and heated to 100 0C in a sealed tube for 3 h. The reaction mixture was then diluted with EtOAc and passed through a celite bed. The organic layer was washed with brine and dried over sodium suphate. It was further concentrated and the crude mass was purified by silica gel column chromatography (60-120 mesh; product eluted with 5% EtOAc/hexanes) to yield 330 mg of 5-bromo-JV-(3,5- dimethylphenyl)-4-[3-(trifluoromethyl)- lH-pyrazol- 1 -yl]pyrimidin-2-amine.
Figure imgf000170_0003
General procedures for the synthesis of 5-bromo-7V-(aryl)-4-methoxypyrimidin-2-amine
Figure imgf000170_0002
Method A To a stirred solution of 5-bromo-2-chloro-4-methoxypyrimidine (1 eq) and arylamine (1.02 eq) in n-BuOH (12 v/w) was added dioxane-HCl (1 v/w) slowly. The reaction mixture was heated to 110 0C for 3 h. It was then cooled to room temperature, diethyl ether (150 mL) was added and the resulting solid was filtered to yield the product. Method B
To a stirred solution of 5-bromo-2-chloro-4-methoxypyrimidine (1.3-1.5 eq) and arylamine (1 eq) in 2,2,2-trifluoroethanol (10 v/w), trifluoroacetic acid (2-4 eq) was added and the solution was refluxed at 75 0C for 2-12 h with constant stirring. Water was added to the reaction mixture and extracted with EtOAc (2x50 mL). The organic layer was washed with water, 10% NaHCO3 solution and brine, dried over sodium sulfate and concentrated in vacuo to yield the product. The compounds in the below table were prepared using the above methods as indicated and the starting material specified.
Figure imgf000171_0001
Figure imgf000172_0002
General procedures for the Synthesis of 5-bromo-2-[arylaminolpyrimidin-4-ol
Figure imgf000172_0001
Method C
A mixture of the 4-methoxypyrimidine derivative (1 eq) and aq. sodium thiomethoxide (21% w/v, 4 eq) and DMF (8 ml/g SM) was heated to 60 0C for 2 h; cooled to room temperature, poured into water (150 mL) and acidified with 1.5 N HCl solution. The precipitated solid was filtered to yield the product. Method D
A solution of the 4-methoxypyrimidine derivative (1 g) in n-BuOH (7 ml/g SM) and 4M HCl in dioxane (4 ml/g SM) were heated to 110 0C in a sealed tube and stirred for 18-36 h. The reaction mixture was cooled to room temperature and BuOH was concentrated under vacuum. To the residue obtained, was added water (50 mL) and neutralized using 10% NaHCO3 solution. The resulting solid was filtered and further purified by column chromatography using ethyl acetate/hexanes as eluent to yield the product.
The compounds in the below table were prepared using the above methods as indicated and the starting material specified.
Figure imgf000173_0001
General procedure for the synthesis of 5-bromo-4-chloro-7V-(aryl)pyrimidin-2-amine
Figure imgf000174_0001
A solution of 5-bromo-2-[arylamino]pyrimidin-4-ol derivative in POCI3 (3- 10 ml/g SM) was heated to reflux for 1 h. It was cooled to RT and POCI3 was removed in vacuo. To the residue obtained, was added crushed ice with stirring, and the pH was adjusted 7-8 using 10% sodium bicarbonate solution. The solid obtained was filtered and washed with chilled water to yield the title compound. The compounds in the below table were prepared using the above method and the starting material specified.
Figure imgf000174_0002
Figure imgf000175_0002
General procedure for the synthesis of 5-bromo-7V-faryl)-4-[3-ftrifluoromethyl)-lH- pyrazol-1-yll pyrimidin-2-amine and 5-bromo-7V-( aryl)-4- [5-methyl-3-f trifluoromethyl)- lH-pyrazol-l-yllpyrimidin-2-amine
Figure imgf000175_0001
NaH (1.2 eq)was dissolved in 1 mL of NMP and stirred for about 5 min at 0 0C. Then either 3-(trifluoromethyl)-lH-pyrazole or 5-methyl-3-(trifluoromethyl)-lH-pyrazole (1.1 eq) in NMP was added dropwise at 0 0C for 10 min and stirring continued for 20 min under N2. Then the 5-bromo-4-chloro-Λ/-(aryl)pyrimidin-2-amine derivative (1 eq) in NMP was added dropwise and the reaction was stirred at room temperature overnight. After completion of the reaction, water was added and the solid obtained was filtered, dried and purified by silica gel column chromatography using ethyl acetate/hexanes as eluent to yield the desired product. The compounds in the below table were prepared using the above method and the starting material specified.
Figure imgf000176_0001
Figure imgf000177_0001
Intermediate 247: 5-bromo-7V-[3-methoxy-5-fmethylsulfonyl)phenyll-4- (methylsulfanyl)pyrimidin-2-amine.
Figure imgf000178_0001
To 6 g of 5-bromo-2-chloro-4-(methylsulfanyl)pyrimidine (1.5 eq) suspended in n- BuOH (30 v/w), was added 3-methoxy-5-(methylsulfonyl)aniline (1 eq followed by. HCl in dioxane (25 mL) and refluxed at 100 0C for 3 h. The reaction was cooled to room temperature, diluted with diethyl ether and the solid was filtered and dried to get.
Figure imgf000178_0003
Intermediate 248: 5-bromo-7V-[3-methoxy-5-fmethylsulfonyl)phenyll-4- (methylsulfonyl)pyrimidin-2-amine (PE-048-017-II)
Figure imgf000178_0002
A suspension of 5-bromo-Λ/-[3-methoxy-5-(methylsulfonyl)phenyl]-4- (methylsulfanyl)pyrimidin-2-amine (Intermediate 247, 1 eq) in acetone was cooled to 0 0C and 3-chloroperoxybenzoic acid (77 %, 2 eq) was added portion wise. After the completion of the reaction, acetone was removed in vacuo and the residue taken in EtOAc was washed with 10 % aq. NaHCO3 solution (50 mL) and water, dried over Na2SO4, filtered and concentrated to give the title compound.
Figure imgf000179_0002
Intermediate 249: ethyl (2Jπ-3-{3-r2-{r3-methoxy-5-(methylsulfbnyl)phenyllamino}-4- fmethylsulfonyl)pyrimidin-5-yllphenyl}prop-2-enoate
Figure imgf000179_0001
A suspension of 5-bromo-Λ/-[3-methoxy-5-(methylsulfonyl)phenyl]-4- (methylsulfonyl)pyrimidin-2-amine Intermediate 248 (1 eq), {3-[(lii)-3-ethoxy-3-oxoprop- l-en-l-yl]phenyl}boronic acid (1.5 eq), bis
(diphenylphosphino)ferrocene]dichloropalladium(II) complex with CH2Cl2 (10 mol %) and sodium carbonate (1.5 eq) in acetonitrile/water (10 mL:5 mL) was heated to 90 0C for 30 minutes. The reaction mixture was concentrated in vacuo and the residue taken in ethyl acetate (50 mL) was washed with water and brine. The organic layer was dried over sodium sulfate, filtered and concentrated. The crude compound was purified by silica gel column chromatography using 50 % ethyl acetate/hexanes as an eluent to yield Intermediate 249. MS(ES): 532 (M+l) for C24H25N3O7S2. Intermediate 250: 5-bromo-7V-[3-methoxy-5-fmethylsulfonyl)phenyll-4-[3-
(trifluoromethvD-lH-pyrazol-l-vHpyrimidin-2-amine
Intermediate 251: 5-bromo-7V-[3-methoxy-5-fmethylsulfonyl)phenyll-4-[5-methyl-3-
(trifluoromethvD-lH-pyrazol-l-vUpyrimidin-2-amine
Figure imgf000180_0001
NaH (60 % dispersion in mineral oil, 2 eq) was dissolved in 1 rnL of DMF and stirred for about 5 min at 0 0C. Then 3-(trifluoromethyl)-lH-pyrazole or 5-methyl-3-(trifluoromethyl)- lH-pyrazole (2 eq) in NMP (2 rnL) was added dropwise at 0 0C for about 10 min and stirring continued for about 20 min under N2. Then 5-bromo-iV-[3-methoxy-5-
(methylsulfonyl)phenyl]-4-(methylsulfonyl)pyrimidin-2-amine (Intermediate 248, 1 eq) in DMF was added dropwise and the reaction was stirred overnight at room temperature. Water was added and the solid obtained was filtered off, dried and purified by silica gel column chromatography using ethyl acetate/hexanes as eluent to yield the product. The compounds in the below table were prepared following this procedure and using the specified starting material.
Figure imgf000180_0002
Figure imgf000181_0002
Intermediate 252: 5-bromo-7V-f3.,5-dimethoxyphenyl)-4-[5-methyl-3-ftrifluoromethyl)- lH-pyrazol-l-yllpyrimidin-2-amine
Figure imgf000181_0001
A solution of 3-methyl-5-trifluoromethyl pyrazole (2.87 mmol, 431 mg) in NMP (4 rnL) was added slowly to a suspension of sodium hydride (3.13 mmol, 75 mg) in NMP (1 mL) at 0 0C. The reaction mixture was stirred for 10 min at 0 0C. A solution of 5-bromo-4- chloro-N-(3,5-dimethoxyphenyl)pyridine-2-amine (Intermediate 213, 2.61 mmol, 900 mg) in NMP (4 mL) was added slowly to the reaction mixture at 0 0C and stirred overnight at RT. The reaction mixture was then quenched with ice cold water at 0-5 0C, and the pΗ adjusted to 2 with 1.5 N HCl solution. It was then was extracted with ethyl acetate, and the organic layer was washed with water, dried over Na2SO4 and concentrated in vacuo. The crude mass was purified by column chromatography using 10-15 % ethyl acetate/hexanes to yield 900 mg of the title compound.
Figure imgf000182_0002
Intermediate 253 : 1- {3- \( 5-bromo-4-hvdroxypyrimidin-2-yl)aminol phenyl} ethanone Intermediate 254 : 5-bromo-2- \( 3-methylphenyl)aminol pyrimidin-4-ol
Figure imgf000182_0001
To a stirred solution of 5-bromo-2-chloro-4-methoxypyrimidine (1 eq) and arylamine (1.02 eq) in n-BuOH (12 v/w based on the former), was added dioxane-4M HCl (4 v/w based on the former) and heated to 110 0C in a sealed tube for 18-36 h. The reaction mixture was cooled to room temperature and BuOH was concentrated under vacuum. To the residue obtained, was added water (50 mL) and 10% NaHCO3 solution. The resulting solid was filtered and further purified by column chromatography to yield the product. The compounds in the below table were prepared using this method and the specified starting material.
Figure imgf000182_0003
Figure imgf000183_0002
Intermediate 255 : 1- {3- IY 5-bromo-4-chlor opyrimidin-2-yl)aminol phenyl} ethanone Intermediate 256 : 5-bromo-4-chloro-7V-( 3-methylphenyl)pyrimidin-2-amine
Figure imgf000183_0001
A solution of 5-bromo-2-[arylamino]pyrimidin-4-ol (1 eq) in POCl3 (3- 10 v/w) was heated to reflux for 1 h. It was cooled to RT and POCI3 was removed in vacuo. To the residue obtained, was added crushed ice with stirring, and the pH was adjusted to 7-8 using 10% sodium bicarbonate solution. The solid obtained was filtered and washed with chilled water to yield the title compound. The compounds in the below table were prepared using this method and the specified starting material.
Figure imgf000183_0003
General method for the synthesis of 5-bromo-7V-(aryD-4-r3-(trifluoromethyD-lH- pyrazol-1-yll pyrimidin-2-amine and 5-bromo-7V-( aryl)-4- [5-methyl-3-( trifluoromethyl)- lH-pyrazol-l-yllpyrimidin-2-amine
Figure imgf000184_0001
NaH (1.2 eq) was dissolved in 1 mL of NMP and stirred for about 5 min at 0 0C. Then 3- (trifluoromethyl)-lH-pyrazole/5-methyl-3-(trifluoromethyl)-lH-pyrazole (1.1 eq) in NMP was added dropwise at 0 0C for about 10 min and stirring continued for about 20 min under N2. Then 5-bromo-4-chloro-Λ/-(aryl)pyrimidin-2-amine (1 eq) in NMP was added dropwise and the reaction was stirred overnight at room temperature. Water was added and the solid obtained was filtered, dried and purified by silica gel column chromatography using ethyl acetate/hexanes as eluent to yield the desired product. The compounds in the below table were prepared using this method and the specified starting material.
Figure imgf000184_0002
Figure imgf000185_0002
Intermediate 261: 5-bromo-2-chloro-4-[5-methyl-3-ftrifluoromethyl)-lH-pyrazol-l- yllpyrimidine
Figure imgf000185_0001
To a suspension of 5-bromo-2,4-dichloropyrimidine (44 mmol, 10 g) in acetonitrile (100 mL), was added K2CO3 (44 mmol, 6.1 g) and the reaction mixture was cooled to -5 to -10 0C. 5- methyl-3-(trifluoromethyl)-l/-f-pyrazole (44 mmol, 6.6 g) was dissolved in 100 mL of acetonitrile and added drop wise. After the addition, the reaction mixture was slowly warmed to RT and stirred overnight. The reaction mixture was filtered through a celite bed and acetonitrile was removed in vacuo. The crude mass was purified by silica gel column chromatography (60-120 mesh; product eluted with 1% EtOAc/hexanes) to yield 5 g of the product.
Figure imgf000186_0002
General method for the synthesis of 5-bromo-7V-(aryl)-4-r3-(trifluoromethyl)-lH- pyrazol-1-yll pyrimidin-2-amine and 5-bromo-7V-f aryl)-4- [5-methyl-3-f trifluoromethyl)- lH-pyrazol-l-yllpyrimidin-2-amine
Figure imgf000186_0001
To a suspension of cesium carbonate (2 eq) in dry DMF (4 mL), were added 3- aminobenzamide (1.15 eq) and 5-bromo-2-chloro-4-[3-(trifluoromethyl)-lH-pyrazol-l- yl]pyrimidine (Intermediate 227, 1 eq) or 5-bromo-2-chloro-4-[5-methyl-3- (trifluoromethyl)-lH-pyrazol-l-yl]pyrimidine (Intermediate 261, 1 eq). The reaction vessel was sealed and heated to 100 0C for 5 h. The reaction mixture was diluted with EtOAc and filtered through a celite bed. The filtrate was washed with water and brine, dried over sodium sulfate and concentrated. The crude mass was purified by silica gel column chromatography (60-120 mesh). The column was eluted with 3% Methanol/Chloroform to yield the desired product. The compounds in the below table were prepared using this method and the specified starting material.
Figure imgf000187_0002
Intermediate 264: 3-{[5-bromo-4-fmethylsulfanyl)pyrimidin-2-yllamino}benzonitrile
Figure imgf000187_0001
To 6 g of 5-bromo-2-chloro-4-(methylsulfanyl)pyrimidine (1.7 eq) suspended in n- BuOH (20 v/w), was added 3-aminobenzonitrile (1 eq) followed by 4M HCl in dioxane (0.25 eq) and refluxed overnight at 100 0C. The reaction was cooled to room temperature, diluted with diethyl ether and the solid was filtered and dried to give Intermediate 264.
Figure imgf000187_0003
Intermediate 265: 3-{[5-bromo-4-fmethylsulfonyl)pyrimidin-2-yllamino}benzonitrile
Figure imgf000188_0001
A suspension of 3-{[5-bromo-4-(methylsulfanyl)pyrimidin-2-yl]amino}benzonitrile (Intermediate 264, 1 eq) in dichloromethane (50 v/w) was cooled to 0 0C and 3- chloroperoxybenzoic acid (77 %, 4.5 eq) was added portion wise and stirred for 4 h. It was further diluted with dichloromethane and washed with 10 % aq. NaHCO3 solution and water, dried over Na2SO4, filtered and concentrated to give Intermediate 265.
Figure imgf000188_0003
Intermediate 266: 3-f{5-bromo-4-[3-ftrifluoromethyl)-lH-pyrazol-l-yllpyrimidin-2- yl| am ino)benzon iti'ile
Intermediate 267: 3-({5-bromo-4-r5-methyl-3-(trifluoromethvD-lH-pyrazol-l- yll pyrimidin-2-yl} amino)benzonitrile
Figure imgf000188_0002
NaH (60 % dispersion in mineral oil, 2 eq) was dissolved in 1 mL of DMF and stirred for about 5 min at 0 0C. Then 3-(trifluoromethyl)-lH-pyrazole/5-methyl-3-(trifluoromethyl)-lH- pyrazole (2 eq) in DMF (2 mL) was added dropwise at 0 0C for about 10 min and stirring continued for about 20 min under N2. Then 3-{[5-bromo-4-(methylsulfonyl)pyrimidin-2- yl] amino }benzonitrile (Intermediate 265, 1 eq) in DMF was added dropwise and the reaction was stirred for 2.5 h at room temperature. After completion of the reaction, water was added and the solid obtained was filtered off, dried and purified by silica gel column chromatography using ethyl acetate/hexanes as eluent to yield the title compound. The compounds in the below table were prepared using this method and the specified starting material.
Figure imgf000189_0001
Intermediate 268: (2Jg)-3-(3-{2-chloro-4-r3-(trifluoromethyl)-lH-pyrazol-l- yll pyrimidin-5-yl}phenyl)prop-2-enoic acid
Intermediate 269: α^-3-(3-{2-chloro-4-r5-methyl-3-(trifluoromethyl)-lH-Pyrazol-l- yll pyrimidin-5-yl}phenyl)prop-2-enoic acid
Figure imgf000190_0001
A suspension of 5 -bromo-2-chloro-4- [3 -(trifluoromethyl)- lH-pyrazol- 1 -yljpyrimidine (Intermediate 227, 1 eq) or 5-bromo-2-chloro-4-[5-methyl-3-(trifluoromethyl)-lH-pyrazol-l- yl]pyrimidine (Intermediate 261, 1 eq), 3-(£ra/?s-2-carboxyvinyl)phenylboronic acid (1.1 - 1.2 eq), [ 1 , 1 '-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (10 mol%) and sodium carbonate (2 eq) in acetonitrile/water (4 : 1) was degassed and heated to 90 0C for 15-30 min under inert atmosphere. The solvent was removed in vacuo and the crude mixture taken in CΗCI3 was washed with water, brine, dried over Na2SO4, filtered and concentrated. The crude material was purified by silica gel column chromatography using 3-5% MeOH/CHCl3 as an eluent to give the product. The compounds in the below table were prepared using this method and the specified starting material.
Figure imgf000190_0002
Figure imgf000191_0002
Intermediate 270: ethyl 5-{2-chloro-4-[3-ftrifluoromethyl)-lH-pyrazol-l-yllpyrimidin-5- yllpyridine-3-carboxylate Intermediate 271: ethyl 5-{2-chloro-4-[5-methyl-3-ftrifluoromethyl)-lH-pyrazol-l- yllPyrimidin-5-yl}pyridine-3-carboxylate
Figure imgf000191_0001
A solution of 5-bromo-2-chloro-4-[3-(trifluoromethyl)-lH-pyrazol-l-yl]pyrimidine (Intermediate 227, 1 eq) or 5-bromo-2-chloro-4-[5-methyl-3-(trifluoromethyl)-lH-pyrazol-l- yl]pyrimidine (Intermediate 261, 1 eq), ethyl 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)pyridine-3-carboxylate (1 eq), [l,r-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (20 mol%) and sodium carbonate (1 eq) in acetonitrile (10 mL)/water (10 mL) was degassed and heated to 90 0C for 20' under nitrogen. The reaction mixture was concentrated in vacuo. The residue obtained was taken in ethyl acetate, washed with water and brine, dried over sodium sulfate and concentrated. The crude mass was purified by silica gel column chromatography (60-120 mesh) using 35 % ethyl acetate/hexanes as an eluent. The compounds in the below table were prepared using this method and the specified starting material.
Figure imgf000192_0002
Intermediate 272: methyl 5-{2-chloro-4-[3-ftrifluoromethyl)-lH-pyrazol-l-yllpyrimidin-
5-yl}-2-methoxypyridine-3-carboxylate
Intermediate 273: methyl 5-{2-chloro-4-[5-methyl-3-ftrifluoromethyl)-lH-pyrazol-l- yllpyrimidin-5-yl}-2-methoxypyridine-3-carboxylate
Figure imgf000192_0001
A solution of 5-bromo-2-chloro-4-[3-(trifluoromethyl)-lH-pyrazol-l-yl]pyrimidine (Intermediate 227, 1 eq) or 5-bromo-2-chloro-4-[5-methyl-3-(trifluoromethyl)-lH-pyrazol- l-yl]pyrimidine (Intermediate 261, 1 eq), methyl 2-methoxy-5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)pyridine-3-carboxylate (1 eq), [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (20 mol%) and sodium carbonate (1 eq) in acetonitrile (10 mL)/water (10 niL) was degassed and heated to 90 °C for 20 hours under nitrogen. The reaction mixture was concentrated in vacuo. The residue obtained was taken in ethyl acetate, washed with water and brine, dried over sodium sulfate and concentrated. The crude mass was purified by silica gel column chromatography (60-120 mesh) using 30 % ethyl acetate/hexanes as an eluent to give the product. The compounds in the below table were prepared using this method and the specified starting material.
Figure imgf000193_0002
Intermediate 274 : 5-bromo-2- \( 3-chlorophenyl)aminol pyrimidin-4-ol
Figure imgf000193_0001
To a stirred solution of 5-bromo-2-chloro-4-methoxypyrimidine (53.8 mmol, 12 g) in n- BuOH (60 mL) was added 3-chloroaniline (59.1 mmol, 7.47 g, 6.2 mL) and 4 N HCl in dioxane (36 mL). The reaction mixture was heated at 80 0C for 20 h. It was then cooled to room temperature, acetonitrile (120 mL) was added and the resulting solid was filtered to yield 6 g of 5-bromo-2-[(3-chlorophenyl)amino]pyrimidin-4-ol as white solid.
Figure imgf000194_0002
Intermediate 275 : 5-bromo-4-chloro-7V-( 3-chlorophenyl)pyrimidin-2-amine
Figure imgf000194_0001
To 6 g of 5-bromo-2-[(3-chlorophenyl)amino]pyrimidin-4-ol (Intermediate 274, 20 mmol), was added 30 mL OfPOCl3 (323 mmol, 49.5 g) and the mixture heated to reflux for 1 h. It was cooled to room temperature and POCl3 was removed in vacuo. It was then diluted with water then extracted with ethyl acetate, organic layer washed successively with 10% sodium bicarbonate solution and water, dried over Na2SO4, filtered and concentrated to yield 3.O g of 5-bromo-4-chloro-Λ/-(3-chlorophenyl)pyrimidin-2-amine.
Figure imgf000194_0003
Intermediate 276: 5-bromo-7V-(3-chlorophenyl)-4-r3-(trifluoromethyl)-lH-pyrazol-l- yll pyrimidin-2-amine
Intermediate 277: 5-bromo-7V-f3-chlorophenyl)-4-[5-methyl-3-ftrifluoromethyl)-lH- pyrazol-l-yllpyrimidin-2-amine
Figure imgf000195_0001
A solution of 3-(trifluoromethyl)-lH-pyrazole or 5-methyl-3-(trifluoromethyl)-lH- pyrazole (1.2 eq) in DMF (4.0 rnL) was added slowly to a suspension of sodium hydride (1.2 eq) in DMF (4.0 rnL) at 0 0C. The reaction mixture was stirred for 1 h at room temperature. A solution of 5-bromo-4-chloro-Λ/-(3-chlorophenyl)pyrimidin-2-amine (Intermediate 275, 1 eq) in DMF (4.0 mL) was added slowly to the reaction mixture at 0 0C and allowed to warm to ambient temperature over 2-3 h. The mixture was quenched with ice cold water at 0-5 0C, pΗ adjusted to 2 with 1.5 N HCl and then extracted with ethyl acetate. The organic layer was washed with water, dried over Na2SO4, filtered and concentrated. The crude mass was purified by silica gel column chromatography (product eluted with 10-15 % ethyl acetate/hexanes) to yield the desired product. The compounds in the below table were prepared using this method and the specified starting materials.
Figure imgf000195_0002
Figure imgf000196_0002
Intermediate 278 : 5-bromo-7V-( 3-fluoro-5-methylphenyl)-4-methoxypyrimidin-2-amine
Figure imgf000196_0001
To a stirred solution of 5-bromo-2-chloro-4-methoxypyrimidine (1 eq) and 3-fluoro-5- methylaniline (1.01 eq) in n-BuOΗ (5 v/w based on the former) was added dioxane-ΗCl (3 v/w based on the former) and heated to 80 0C in a sealed tube for 3 h. The reaction mixture was cooled to room temperature and BuOH was concentrated under vacuum. To the residue obtained, was added MeCN and stirred at 10-15 0C for 30 minutes. The resulting solid was filtered and washed with MeCN to yield Intermediate 278.
Figure imgf000196_0003
Intermediate 279 : 5-bromo-2- \( 3-fluor o-5-methylphenyl)aminol pyrimidin-4-ol
Figure imgf000197_0001
A mixture of 5-bromo-N-(3-fluoro-5-methylphenyl)-4-methoxypyrimidin-2-amine Intermediate 278 (1 eq) and aq. sodium thiomethoxide (21% aq. soln (w/v), 5 v/w based on Intermediate 278) and DMF (10 v/w) was heated to 80 0C for 2 h. The reaction mass was cooled to room temperature and quenched with ice-cold water and the pH adjusted to 2 with 1.5 N HCl solution. The precipitated solid was filtered and washed with water to yield Intermediate 279.
Figure imgf000197_0003
General procedure for the synthesis of 5-bromo-2-[faryl)aminolpyrimidin-4-ol
Figure imgf000197_0002
To a stirred solution of 5-bromo-2-chloro-4-methoxypyrimidine (1 eq) and arylamine (1.02 eq) in n-BuOH (12 v/w based on the former) was added 4M HCl in dioxane (4 v/w based on the former) and heated to 110 0C in a sealed tube for 18-36 h. The reaction mixture was cooled to room temperature and BuOH was concentrated under vacuum. To the residue obtained, was added water (50 mL) and 10% NaHCO3 solution. The resulting solid was filtered and further purified by column chromatography to yield the product. The compounds in the below table were prepared using this procedure and the specified starting material.
Figure imgf000198_0002
General procedure for the synthesis of 5-bromo-4-chloro-7V-(aryl)pyrimidin-2-amine
Figure imgf000198_0001
A solution of 5-bromo-2-[arylamino]pyrimidin-4-ol (1 eq) in POCl3 (5 eq) was heated to reflux for 1 h. It was cooled to RT and POCl3 was removed in vacuo. To the residue obtained, was added crushed ice with stirring, and the pH was adjusted to 7-8 using 10% NaHCO3 solution. The solid obtained was filtered and washed with chilled water to yield the title compound. The compounds in the below table were prepared using this procedure and the specified starting material.
Figure imgf000199_0001
General procedure for the synthesis of 5-bromo-7V-(aryD-4-r3-(trifluoromethyD-lH- pyrazol-1-yll pyrimidin-2-amine and 5-bromo-7V-( aryl)-4- [5-methyl-3-( trifluoromethyl)- lH-pyrazol-l-yllpyrimidin-2-amine
Figure imgf000200_0001
NaH (1.2 eq) was dissolved in 1 niL of DMF and stirred for about 5 min at 0 0C. Then 3- (trifluoromethyl)-lH-pyrazole or 5-methyl-3-(trifluoromethyl)-lH-pyrazole (1.1 eq) in NMP was added drop-wise at O0C over about 10 min and stirring continued for about 20 min under N2. Then 5-bromo-4-chloro-Λ/-(aryl)pyrimidin-2-amine (1 eq) in DMF was added dropwise and the reaction was stirred overnight at RT. Water was added and the solid obtained was filtered, dried and purified by silica gel column chromatography using ethyl acetate/hexanes (2:8) as eluent to yield the product. The compounds in the below table were prepared using this procedure and the specified starting material.
Figure imgf000200_0002
Figure imgf000201_0001
Figure imgf000202_0001
Figure imgf000203_0002
Intermediate 295: S-bromo^-rd-methylpyrrolidin-S-yDoxylpyridine-S-carboxylic acid
Figure imgf000203_0001
To 5-bromo-2-chloropyridine-3-carboxylic acid (4.21 mmol, 1 g) and 1- methylpyrrolidin-3-ol (17.5 mmol, 1.88 mL, 1.77 g) taken in tert-butanol (25 mL), was added sodium te/t-butoxide (16.9 mmol, 1.64 g) and heated to 85 0C for 2 h. The solvent was removed in vacuo and the reaction mixture was diluted with water. The aqueous layer was washed with EtOAc, then carefully acidified with 1 N HCl (pH=5). Water was distilled off and the residue taken in a mixture of MeOH and EtOAc (1 :1) was passed through was a celite bed and the resultant crude product (2 g) was used without further purification in the next step.
Figure imgf000204_0003
Intermediate 296: methyl 5-bromo-2-r(l-methylpyrrolidin-3-yl)oxylpyridine-3-carboxylate
Figure imgf000204_0001
To a suspension of 5-bromo-2-[(l-methylpyrrolidin-3-yl)oxy]pyridine-3-carboxylic acid (Intermediate 295, 4.52 mmol, 1.36 g) in MeOH (13 ml) at 0 0C, was slowly added thionyl chloride (8.4 mmol, 0.999 g). After the addition was complete, the reaction mixture was refluxed for 2 h. The solvent was concentrated in vacuo and the crude mixture was taken in EtOAc (30 mL), washed with aq. NaHCO3 solution, water and brine, dried over Na2SO4, filtered and concentrated to obtain 1.2 g of the title compound.
Figure imgf000204_0002
Intermediate 297 : (5 -(methoxycarbonvD-6- IY 1 -methylpyrrolidin-3 -yl)oxylpyridin-3 - vUboronic acid
Figure imgf000205_0001
A suspension of methyl 5-bromo-2-[(l-methylpyrrolidin-3-yl)oxy]pyridine-3- carboxylate (Intermediate 296, 1.5 mmol, 0.5 g), bis(pinacolato)diboron (3.1 mmol, 0.804 g), [l,r-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.3 mmol, 0.219 g) and potassium acetate (4.6 mmol, 0.444 g) was taken in dioxane (5 mL) and it was degassed for 10 min. Then the reaction mixture was heated to 100 0C for 1 h. The reaction mixture was diluted with EtOAc, filtered through a celite bed, washed with water (5 mL) and brine (5 mL), dried over Na2SO4 and concentrated in vacuo to obtain the title compound as a crude mass (0.7 g) which was taken to the next step without further purification. HPLC-MS analysis indicates the presence of both the boronic acid and boronate pinacol ester.
Figure imgf000205_0003
Intermediate 298: 5-bromo-2-[l-fpyridin-4-yl)ethoxylpyridine-3-carboxylic acid
Figure imgf000205_0002
To 5-bromo-2-chloropyridine-3-carboxylic acid (4.2 mmol, 1 g) and l-(pyridin-4- yl)ethanol (16.9 mmol, 2.08 g) taken in tert-butanol (20 mL), was added sodium te/t-butoxide (16.9 mmol, 1.63 g) and the mixture heated to 85 0C for 1 h. The solvent was removed in vacuo and the reaction mixture was diluted with water. The aqueous layer was washed with EtOAc, then carefully acidified with 1 N HCl (pH=5). Water was distilled off and the residue taken in a mixture of MeOH and EtOAc (1 :1) was passed through was a celite bed. The filtrate was concentrated in vacuo and the resultant crude product (2.2 g) was used in the next step without further purification.
Figure imgf000206_0002
Intermediate 299: methyl 5-bromo-2-ri-(pyridin-4-yl)ethoxylpyridine-3-carboxylate
Figure imgf000206_0001
A solution of 5-bromo-2-[l-(pyridin-4-yl)ethoxy]pyridine-3-carboxylic acid
(Intermediate 298, 6.81 mmol, 2.2 g) taken in MeOH (20 mL) was cooled to 0 0C. Thionyl chloride (0.99 mL, 13.62 mmol, 2 eq) was added slowly to the reaction mixture. After the addition was complete, the reaction mixture was refluxed for 2 h. The solvent was removed in vacuo and the crude mixture was taken in EtOAc (30 mL), washed with aq. NaHCO3 solution, water, brine, dried over Na2SO4, filtered and concentrated. The crude material was purified by silica gel column chromatography using 20 % ethyl acetate/ hexane as the eluent to yield 1 g of the title compound.
Figure imgf000207_0002
Intermediate 300: methyl 241-(pyridin-4^)ethoxyl-5-(4A5.5-tetramethyl-1.3.2- dioxaborolan-2-yl)pyridine-3-carboxylate
Figure imgf000207_0001
A suspension of methyl 5-bromo-2-[l-(pyridin-4-yl)ethoxy]pyridine-3-carboxylate (Intermediate 299, 1.3 mmol, 0.440 g), bis(pinacolato)diboron (2.61 mmol, 0.663 g), [1,1'- bis(diphenylphosphino)ferrocene] dichloropalladium(II) complex with CH2Cl2 (0.261 mmol, 0.213 g) and potassium acetate (3.91 mmol, 0.384 g) was taken in dioxane (10 mL) and it was degassed for 10 min. Then the reaction mixture was heated to 100 0C for 90 min. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, filtered through a celite bed and concentrated in vacuo to yield the product as a crude mass (0.5 g) which was taken to the next step without further purification LCMS analysis indicated the presence of a mixture of Boronic acid (50 %) and boronate (30 %).
Figure imgf000208_0002
Intermediate 301: S-bromo-l-n-dH-imidazol-l-yDethoxylpyridine-S-carboxylic acid
Figure imgf000208_0001
To 5-bromo-2-chloropyridine-3-carboxylic acid (4.2 mmol, 1 g) and 2-(lH-imidazol- l-yl)ethanol (12.6 mmol, 1.42 g) taken in te/t-butanol (25 mL) was added sodium tert- butoxide (12.7 mmol, 1.231 g) and the reaction mixture heated to 90 0C for 2 h. The solvent was removed in vacuo and the reaction mixture was diluted with water. The aqueous layer was washed with EtOAc, then carefully acidified with 1 N HCl (pH=5). Water was distilled off and the residue taken in a mixture of MeOH and EtOAc (1 :1) was passed through was a celite bed. The filtrate was concentrated in vacuo and the resultant crude product was taken to the next step without further purification (1.3 g).
Figure imgf000209_0002
Intermediate 302: methyl 5-bromo-2-[2-flH-imidazol-l-yl)ethoxylpyridine-3- carboxylate
Figure imgf000209_0001
To a suspension of 5-bromo-2-[2-(lH-imidazol-l-yl)ethoxy]pyridine-3-carboxylic acid (Intermediate 301, 4.16 mmol, 1.3 g) in MeOH (50 niL) at 0 0C, was slowly added thionylchloride (6.4 mmol, 0.74 g). After the addition was complete, the reaction mixture was refluxed at 85 0C for 2 h. The solvent was removed in vacuo and the crude mixture taken in EtOAc (30 mL), was washed with aq. NaHCO3 solution, water and brine, dried over Na2SO4, filtered and concentrated to obtain 1.3 g of the title compound which was taken as such to the next step.
Figure imgf000209_0003
Intermediate 303: {6-r2-(lH-imidazol-l-vDethoxyl-5-(methoxycarbonvDpyridin-3- yllboronic acid
Figure imgf000210_0001
A suspension of Intermediate 302 (1.53 mmol, 0.5 g), bis(pinacolato)diboron (3.06 mmol, 0.778 g), [l,r-bis(diphenylphosphino)ferrocene] dichloropalladium(II) (0.31 mmol, 0.224 g) and potassium acetate (4.6 mmol, 0.452 g) was taken in dioxane (50 mL) and it was degassed for 10 min. Then the reaction mixture was heated to 100 0C for 1 h. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, filtered through a celite bed and concentrated in vacuo to obtain 0.7 g of the crude mass which was taken to the next step without further purification LCMS analysis indicated the presence of a mixture of boronic acid (42 %) and boronate (17 %).
Figure imgf000210_0003
Intermediate 304: ethyl 5-bromo-2-fl,3-dimethoxypropan-2-yloxy)nicotinate
Figure imgf000210_0002
To a suspension of t-BuONa (4.36 g, 45 mmol) in THF (100 mL) was added a solution of 1,3- dimethoxypropan-2-ol (4.55 g, 37.8 mmol in 50 mL THF) at 0 0C over a period of 30 min. The reaction mixture was stirred at 10 0C for 1 h and then cooled to 0 0C. To this reaction mixture was added a solution of ethyl 5-bromo-2-chloronicotinate (10.0 g, 37.8 mmol in 100 mL THF) over a period of 45 min. The reaction mixture was allowed to come to room temperature and stirred for 2 h. The reaction mixture was quenched with cold water (200 mL) and extracted with ethyl acetate (200 mL x 3). The combined organic layer was washed with water (200 mL), brine solution (200 mL), dried over anhydrous Na2SO4 and evaporated under reduced pressure to get crude compound. The crude compound was purified by column chromatography (Silica gel, 100-200 mesh) using 6% ethyl acetate in pet ether as mobile phase to get 6.5 g of the title compound. The compounds in the below table were prepared using this method and the indicated starting material.
Figure imgf000211_0001
Figure imgf000212_0001
Intermediate 310: 2-(2-acetamidoethoxy)-5-bromonicotinic acid
5-Bromo-2-chloronicotinic acid (1.25 g, 5.27 mmol) was suspended in tert-butanol (35.4 ml) and JV-(2-hydroxyethyl)acetamide (1.95 ml, 21.08 mmol) was added. Potassium tert-butoxide (2.37 g, 21.08 mmol) was added and the reaction mixture was heated at 90 0C for 1 hour. Tert-butanol was removed in vacuo and the resulting material was diluted in ethyl acetate and neutralized with IN HCl (2 mL). The organic layers were washed with 5 mL of IN HCl, water, then brine. Combined organic layers were dried over magnesium sulfate, filtered, and concentrated to dryness, then dried under high vacuum to obtain the title compound as an off- white solid (1.44 g).
MS(ES): 304.9 (M+H) for Ci0HnBrN2O4
IH NMR (300 MHz, DMSO-d6) δ ppm 1.80 (s, 3 H) 3.40 (q, J=5.97 Hz, 2 H) 4.34 (t, J=5.93 Hz, 2 H) 8.22 (d, J=2.64 Hz, 1 H) 8.46 (d, J=2.64 Hz, 1 H) 13.24 (br. s., 1 H)
The compound in the below table was prepared using the general method described above for Intermediate 310 and the starting material (SM) indicated.
Figure imgf000213_0001
Intermediate 312: ethyl 2-(2-acetamidoethoxy)-5-bromonicotinate
2-(2-acetamidoethoxy)-5-bromonicotinic acid, Intermediate 310 (1.44 g, 4.74 mmol) was suspended in ethanol (15.5 ml), and concentrated sulfuric acid (0.38 ml, 7.12 mmol) was added. The reaction mixture was heated at 60 0C for 3 h then stirred at rt overnight. The reaction mixture was concentrated, diluted with ethyl acetate, washed with water, brine, and dried over MgSOφ The crude material was purified by flash chromatography (4g, silica column, 0-8% methanol in dichlormethane over 25 min). Fractions were combined to give the title compound as a white solid (1.47 g).
MS(ES): 333.0 (M+H) for Ci2Hi5BrN2O4
IH NMR (300 MHz, DMSO-J6) δ ppm 1.25 - 1.33 (m, 3 H) 1.80 (s, 3 H) 3.39 (q, 2 H) 4.24
4.31 (m, 2 H) 4.33 (t, J=5.37 Hz, 2 H) 7.96 (br. s., 1 H) 8.25 (d, J=2.64 Hz, 1 H) 8.49 (d, J=2.45 Hz, 1 H)
The compound in the below table was prepared using the general method described above for Intermediate 312 and the starting material (SM) indicated.
Figure imgf000213_0002
Intermediate 314 ethyl 5-bromo-2-(3-(methylsulfbnyl)propoxy)nicotinate
Ethyl 5-bromo-2-(3-(methylthio)propoxy)nicotinate (Intermediate 313, 0.4504 g, 1.35 mmol) and mCPBA (0.997 g, 4.04 mmol) were suspended in dichloromethane (5.37 ml) and stirred at rt for 3h. Then added 3 mL of dichloromethane and 0.17 g of mCPBA were added and the reaction mixture was stirred overnight. Additional 0.46 g of mCPBA were added and the mixture was stirred at rt 5 hours. The reaction mixture was concentrated in vacuo, dissolved in DCM, and filtered. The filtrate was purified by flash chromatography (12 g silica column, 0-10% methanol in dichloromethane over 30 min). Fractions were combined and dried in vacuo to obtain the title compound as a white solid (0.45 g). MS(ES): 368.0 (M+H) for Ci2Hi6BrNO5S
1H-NMR (300 MHz, DMSO-d6): δ ppm 1.30 (t, J=7.16 Hz, 3 H) 2.08 - 2.22 (m, 2 H) 3.00 (s, 3 H) 3.23 - 3.30 (m, 2 H) 4.29 (q, J=I .16 Hz, 2 H) 4.42 (t, J=6.22 Hz, 2 H) 8.27 (d, J=2.45 Hz, 1 H) 8.50 (d, J=2.45 Hz, 1 H).
The compound in the table below was prepared using the general sequence described above for the preparation of Intermediates 313 and 314 and the starting material (SM) indicated.
Figure imgf000214_0002
Intermediate 315: ethyl 2-fl,3-dimethoxypropan-2-yloxy)-5-f4,4,5.,5-tetramethyl-l,3i2- dioxaborolan-2-yl)nicotinate
Figure imgf000214_0001
To an argon purged solution of ethyl 5-bromo-2-(l,3-dimethoxypropan-2-yloxy)nicotinate (Intermediate 308, 4.5 g, 12.9 mmol) in dioxane (135 mL, 30 vol.) was added bis(pinacolato)diboron (3.93 g, 15.5 mmol) at room temperature. The reaction mixture was degassed for 15 min. (argon) and was added Pd(dppf)Cl2 (1.89 g, 2.5 mmol) followed by potassium acetate (3.8 g, 38 mmol). The reaction mixture was heated at 90 0C for 2 h. The solvent was evaporated under reduced pressure and the residue was diluted with 30% ethyl acetate in pet-ether (200 mL) and passed through neutral alumina bed. The filtrate was evaporated under reduced pressure to get the crude title compound.
The compounds in the table below were prepared using this method and the indicated starting material.
Figure imgf000216_0001
Figure imgf000217_0001
Figure imgf000218_0002
Intermediate 322 : Methyl S-bromo-l-methyl-l-oxo-l^-dihydropyridine-S-carboxylate
Figure imgf000218_0001
To a suspension of cesium carbonate (18.2 mmol, 5.9 g) in dry methanol (20 mL), 5-bromo-2- hydroxypyridine-3-carboxylic acid (9.2 mmol, 2 g) and iodomethane (27.3 mmol, 3.87 g) were added and heated to 80 0C for 3 h in a sealed tube. The mixture was diluted with methanol and filtered through a celite bed. The filtrate was concentrated and purified by silica gel (60-120 mesh) (product eluted with 2% Methanol in Chloroform) to yield 1.6 g of the title compound.
Figure imgf000218_0003
Intermediate 323: methyl l-methyl-2-oxo-5-f4,4,5.,5-tetramethyl-l,3i2-(iioxaborolan-2- yl)-l.,2-dihvdropyridine-3-carboxylate
Figure imgf000219_0001
Methyl 5-bromo-l-methyl-2-oxo-l,2-dihydropyridine-3-carboxylate (Intermediate 322, 2 mmol, 0.5 g), bis(pinacolato)diboron (2.42 mmol, 0.619 g), [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.3 mmol, 0.244 g) and potassium acetate (6 mmol, 0.59 g) were suspended in dry dioxane (10 mL) and degassed with nitrogen for 10 min. The reaction was then heated to 100 0C for 1 h. The reaction mixture was diluted with DCM and filtered through a diatomaceous earth bed and concentrated. Then the crude mass was taken to the next step without purification. HPLC-MS analysis indicated the presence of a mixture of Boronic acid (23 %) and boronate (42 %).
Figure imgf000219_0002
The compound in the below table was prepared using the general method described above for Intermediate 323 and the starting material (SM) indicated.
Figure imgf000220_0002
Intermediate 325: methyl 5-{2-chloro-4-[3-ftrifluoromethyl)-lH-pyrazol-l-yllpyrimidin- 5-yl}-2-methoxypyridine-3-carboxylate
Figure imgf000220_0001
A solution of 5-bromo-2-chloro-4-[3-(trifluoromethyl)-l/-f-pyrazol-l-yl]pyrimidine (Intermediate 227, 2.3 mmol, 750 mg), methyl 2-methoxy-5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)pyridine-3-carboxylate (2.3 mmol, 680 mg), [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.46 mmol, 340 mg) and sodium carbonate (2.3 mmol, 250 mg) in acetonitrile (10 mL)/water (10 mL) was degassed and heated to 90 0C for 20 min under nitrogen. The reaction mixture was concentrated in vacuo. The residue obtained was taken in ethyl acetate, washed with water and brine, dried over sodium sulfate and concentrated. The crude mass was purified by silica gel column chromatography (60-120 mesh) using 15% ethyl acetate/hexanes to yield 300 mg of the title compound.
Figure imgf000221_0002
Intermediate 326 : 5-bromo-2-chloro-4- [5-methyl-3-( trifluoromethyl)- lH-pyr azol- 1- yllpyrimidine
Figure imgf000221_0001
To a suspension of 5-bromo-2,4-dichloropyrimidine (44 mmol, 10 g) in acetonitrile (100 mL), was added K2CO3 (44 mmol, 6.1 g) and the reaction mixture was cooled to -5 to -10 0C. 5- methyl-3-(trifluoromethyl)-lH-pyrazole (44 mmol, 6.6 g) was dissolved in 100 mL of acetonitrile and added drop wise. After the addition, the reaction mixture was slowly warmed to RT and stirred overnight. The reaction mixture was filtered through a celite bed and acetonitrile was removed in vacuo. The crude mass was purified by silica gel column chromatography (60-120 mesh; product eluted with 1% EtOAc/hexanes) to yield 5 g of the product.
Figure imgf000222_0002
Intermediate 327: methyl 5-{2-chloro-4-[5-methyl-3-ftrifluoromethyl)-lH-pyrazol-l- yllPyrimidin-5-yl}-2-methoxypyridine-3-carboxylate
Figure imgf000222_0001
A solution of 5-bromo-2-chloro-4-[5-methyl-3-(trifluoromethyl)-lH-pyrazol-l-yl]pyrimidine
(Intermediate 326, 2.05 mmol, 700 mg), methyl 2-methoxy-5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)pyridine-3-carboxylate (2.46 mmol, 725 mg), [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.4 mmol, 300 mg) and sodium carbonate (2.05 mmol, 210 mg) in acetonitrile (25 mL)/water (5 mL) was degassed and heated to 90 0C for 20 min under nitrogen. The reaction mixture was concentrated in vacuo. The residue obtained was taken in ethyl acetate, washed with water and brine, dried over sodium sulfate and concentrated. The crude mass was purified by silica gel column chromatography (60-120 mesh) using 15-20% ethyl acetate/hexanes to yield 280 mg of the title compound.
Figure imgf000223_0003
Intermediate 328: Ethanesulfonamide
Figure imgf000223_0002
Ammonia gas was passed into a cooled THF solution (25 mL) of ethanesulfonyl chloride (19.4 mmol, 2.5 g) for 1 h. The reaction mixture was sealed and stirred at RT for 2-3 h. After completion of reaction, the reaction mixture was diluted with chloroform (20 mL) and filtered through a bed of diatomaceous earth. The filtrate was concentrated under reduced pressure and dried to get quantitative yield of the title compound as a white solid.
Figure imgf000223_0004
Intermediate 329: propane-1-sulfonamide
Figure imgf000223_0001
Ammonia gas was passed into a cooled THF solution (25 niL) of propane- 1-sulfonyl chloride (17.5 mmol, 2.5 g) for 1 h. The reaction mixture was sealed and stirred at RT for 2-3 h. After completion of reaction, the reaction mixture was diluted with chloroform (20 mL) and filtered through a bed of diatomaceous earth. The filtrate was concentrated under reduced pressure and dried to yield the sulfonamide as a white solid.
Figure imgf000224_0003
Intermediate 330: propane-2-sulfonamide
Figure imgf000224_0001
Ammonia gas was passed into a cooled THF solution (25 mL) of propane-2-sulfonyl chloride (17.5 mmol, 2.5 g) for 1 h. Then the reaction mixture was sealed and stirred at RT for 2-3 h. After completion of reaction was monitored by TLC, the reaction mixture was diluted with chloroform (20 mL), filtered through a celite bed, concentrated under reduced pressure & dried to get quantitative yield of the sulfonamide as a pale yellow thick mass.
Figure imgf000224_0004
Intermediate 331: 3-chloropropane-l-sulfonamide
Figure imgf000224_0002
Ammonia gas was passed into a cooled THF solution (25 mL) of 3 -chloropropane- 1-sulfonyl chloride (14.2 mmol, 2.5 g) for 1 h. Then the reaction mixture was sealed and stirred at RT for 2-3 h. After completion of reaction, the reaction mixture was diluted with chloroform (20 mL) and filtered through celite bed, concentrated under reduced pressure and dried to get quantitative yield of the desired sulfonamide as a white solid.
Figure imgf000225_0003
Intermediate 332: 3-(morpholin-4-yl)propane-l-sulfonamide
Figure imgf000225_0001
The solution of 3 -chloropropane- 1 -sulfonamide Intermediate 331 (1.58 mmol, 0.250 g), Morpholine (1.58 mmol, 0.138 g), Na2CO3 (3.16 mmol, 0.335 g) and NaI (0.158 mmol, 24 mg) in dry Dioxane (5 mL) was heated to 75 0C, overnight, in a sealed tube. After completion of reaction, the reaction mixture was diluted with chloroform (20 mL) and filtered through celite bed and the filtrate was concentrated under reduced pressure and dried to get the desired compound as a colorless mass (0.21 g).
Figure imgf000225_0004
Intermediate 333: 4-bromo-2-methylbenzenesulfonamide
Ammonia gas was passed into a cooled THF solution (25 mL) of 4-bromo-2- methylbenzenesulfonyl chloride (9.27 mmol, 2.5 g) for 1 h. Then the reaction mixture was sealed and stirred overnight at rt. After completion of reaction, as monitored by TLC, the reaction mixture was diluted with chloroform (20 mL) and filtered through celite bed and the filtrate was concentrated under reduced pressure and dried to get quantitative yield of the desired sulfonamide as a white solid.
Figure imgf000226_0002
Intermediate 334: 5-bromo-l,2-benzothiazol-3f2H)-one 1,1-dioxide
Figure imgf000226_0001
A suspension of 4-bromo-2-methylbenzenesulfonamide (Intermediate 333, 9.6 mmol, 2.4 g), periodic acid (76.8 mmol, 17.5 g), Chromium oxide (4.8 mmol, 0.047 g) in dry acetonitrile (25 mL) was heated to reflux for 3 h. Isopropyl alcohol (5 mL) was added slowly and the reaction mixture was heated to reflux for another 10 min. Then the reaction mixture was cooled to rt and it was filtered and washed with acetone (10 mL x 3). The filtrate was concentrated and triturated with 10 mL of 2 N H2SO4 and filtered to get 1.5 g of the title compound as an off-white solid.
Figure imgf000226_0003
Intermediate 335: (lJ-dioxido-3-oxo-2,3-dihvdro-l,2-benzothiazol-5-yl)boronic acid
Figure imgf000227_0001
5-bromo-l,2-benzothiazol-3(2H)-one 1,1 -dioxide (Intermediate 334, 0.954 mmol, 0.25 g), bis(pinacolato)diboron (2.862 mmol, 0.726 g), [l,r-bis(diphenylphosphino) ferrocene] dichloropalladium(II) (0.0954 mmol, 0.077 g) and potassium acetate (2.862 mmol, 0.28 g) were suspended in dry DMSO (5 mL) and degassed with nitrogen for 10 min. The reaction was then subjected to microwave condition at 100 0C for 30 min. The reaction mixture was concentrated under vacuum. The residue obtained was washed with hexane (5 mL), decanted and dried to give the product. Taken to the next step without purification.
Figure imgf000227_0003
Intermediate 336: 7V-f4-methyl-5-sulfamoyl-l,3-thiazol-2-yl)acetamide
Figure imgf000227_0002
Ammonia gas was passed into a cooled THF solution (2 mL) of 2-(acetylamino)-4-methyl- l,3-thiazole-5-sulfonyl chloride (0.39 mmol, 0.1 g) for 1 h. Then the reaction mixture was sealed and stirred at RT for 2-3 h. After completion of reaction, the reaction mixture was diluted with chloroform (20 mL) and filtered through a celite bed. The filtrate was concentrated under reduced pressure and dried to get quantitative yield of an off- white solid.
Figure imgf000228_0003
Intermediate 337: 2,2,2-trifluoroethanesulfonamide
Figure imgf000228_0001
Ammonia gas was passed into a cooled THF solution (2 mL) of 2,2,2-trifluoroethanesulfonyl chloride (5.48 mmol, 1 g) for 1 h. Then the reaction mixture was sealed and stirred at RT for 2 h. Completion of reaction was monitored by TLC. The reaction mixture was diluted with dichloromethane (50 mL) and filtered through celite bed and the filtrate was concentrated under reduced pressure and dried to get 800 mg of the title compound as a white solid.
Figure imgf000228_0004
Intermediate 338: 3,5-dimethyl-l,2-oxazole-4-sulfonamide
Figure imgf000228_0002
Ammonia gas was passed into a cooled THF solution (2 mL) of 3, 5 -dimethyl- l,2-oxazole-4- sulfonyl chloride (0.76 mmol, 150 mg) for 1 h. Then the reaction mixture was sealed and stirred at RT for 2-3 h. The reaction mixture was diluted with chloroform (20 mL) and filtered through celite bed and the filtrate was concentrated under reduced pressure and dried to get 120 mg of the title compound as a white solid.
Figure imgf000229_0002
Intermediate 339: 2,4-dimethyl-l,3-thiazole-5-sulfonamide
Figure imgf000229_0001
Ammonia gas was passed into a cooled THF solution (25 mL) of 2,4-dimethyl-l,3-thiazole-5- sulfonyl chloride (0.47 mmol, 100 mg) for 1 h. Then the reaction mixture was sealed and stirred at RT for 2 h. The reaction mixture was diluted with chloroform (20 mL) and filtered through celite bed and the filtrate was concentrated under reduced pressure and dried to get 90 mg of the desired sulfonamide as a white solid.
Figure imgf000229_0003
Intermediate 340: l-dnethylsulfonvDmethanesulfonamide
Ammonia gas was passed into a cooled THF solution (2 mL) of
(methylsulfonyl)methanesulfonyl chloride (1.1 mmol, 200 mg) for 1 h. Then the reaction mixture was sealed and stirred at RT for 2 h. After completion of reaction, as monitored by TLC, the reaction mixture was diluted with chloroform (20 mL) and filtered through celite bed and the filtrate was concentrated under reduced pressure and dried to get 65 mg of white solid.
Figure imgf000230_0003
Intermediate 341: 7V-(4-methoxybenzvD-l-methyl-lH-imidazole-4-sulfbnamide
Figure imgf000230_0002
To a solution of 1 -methyl- lH-imidazole-4-sulfonyl chloride (4.4 mmol, 0.8 g) in dry CH2Cl2 (10 mL), was added 4-methoxybenzylamine (3.5 mmol, 0.49 g) and Et3N (1.33 mmol, 1.34 g) and left to stir overnight at RT. The reaction mixture was diluted with dichloromethane (20 mL) and water. The organic layer was separated, dried over Na2SO4 and concentrated. The solid that was obtained was further recrystallised from CHCl3 and petroleum ether to get 500 mg of the desired protected sulfonamide.
Figure imgf000231_0003
Intermediate 342: l-methyl-l//-imidazole-4-sulfonamide
Figure imgf000231_0001
To a cooled solution of Λ/-(4-methoxybenzyl)-l -methyl- lH-imidazole-4-sulfonamide (Intermediate 341, 1.06 mmol, 0.3 g), was added TFA (15 mL) and the reaction mixture was stirred at 0 0C for 1 hour. The mixture was concentrated and methanol was added to the residue and further concentrated to get 150 mg of the desired sulfonamide.
Figure imgf000231_0004
Intermediate 343: 2,5-dihydrothiophene-3-sulfonamide 1,1-dioxide
Figure imgf000231_0002
Ammonia gas was passed into a cooled THF solution (25 niL) of 2,5-dihydrothiophene-3- sulfonyl chloride 1,1 -dioxide (0.93 mmol, 200 mg) for around 20 min. Then the reaction mixture was sealed and stirred at RT for 2-3 h. The reaction mixture was diluted with ethyl acetate (20 mL) and filtered. The filtrate was concentrated under reduced pressure and dried to get quantitative yield of the desired sulfonamide as a white solid.
Figure imgf000232_0002
Intermediate 344: 7V-f4-methoxybenzyl)-6-methyl-2,4-dioxo-l.,2,3i4- tetrahydropyrimidine-5-sulfonamide
Figure imgf000232_0001
To a solution of 6-methyl-2,4-dioxo-l,2,3,4-tetrahydropyrimidine-5-sulfonyl chloride (2.23 mmol, 500 mg) in dry CH2Cl2 (10 mL), was added 4-methoxybenzylamine (1.78 mmol, 244 mg) and Et3N (11.6 mmol, 1.13 g) and left to stir overnight at RT. The reaction mixture was diluted with dichloromethane (20 mL) and water. The organic layer was separated and the precipitate formed in aqueous layer was filtered and dried to get 350 mg of the product.
Figure imgf000233_0003
Intermediate 345: 6-methyl-2,4-dioxo-l.,2,3i4-tetrahvdropyrimidine-5-sulfonamide
Figure imgf000233_0001
To a cooled solution of Λ/-(4-methoxybenzyl)-6-methyl-2,4-dioxo-l,2,3,4- tetrahydropyrimidine-5-sulfonamide (Intermediate 344, 1.07 mmol, 350 mg), was added TFA (10 mL) and the reaction mixture was stirred at rt for 6 h. The mixture was concentrated and methanol was added to the residue and further concentrated to get 200 mg of the desired sulfonamide.
Figure imgf000233_0002
Intermediate 346: l,3i5-trimethyl-lH-pyrazole-4-sulfonamide
Figure imgf000234_0001
Ammonia gas was passed into a cooled THF solution (25 mL) of 1,3,5-trimethyl-lH pyrazole-4-sulfonyl chloride (0.96 mmol, 0.2 g) for around 1 h. Then the reaction mixture was sealed and stirred at RT for 2-3 h. After completion of reaction, the reaction mixture was diluted with chloroform (15 mL) and filtered through celite bed. The filtrate was concentrated under reduced pressure and dried to get the title compound as a white solid (149 mg).
Figure imgf000234_0003
Intermediate 347: 3-methyl-2-oxo-2,3-dihvdro-l,3-benzoxazole-6-sulfonamide
Figure imgf000234_0002
Ammonia gas was passed into a cooled THF solution (25 mL) of 3-methyl-2-oxo-2,3- dihydro-l,3-benzoxazole-6-sulfonyl chloride (0.5 mmol, 0.125 g) for 1 h and sealed. Then the reaction mixture was stirred at RT for 2-3 h. The reaction mixture was diluted with chloroform (20 mL) and filtered through celite bed. The filtrate was concentrated under reduced pressure and dried to get quantitative yield of the title compound as an off- white solid.
Figure imgf000235_0003
Intermediate 348: 3-acetylbenzenesulfonamide
Figure imgf000235_0001
Ammonia gas was passed into a cooled solution (25 mL) of 3-acetylbenzenesulfonyl chloride (2.2 mmol, 500 mg) in dry l,4-dioxane(15 mL) for 20 min and sealed. Then the reaction mixture was stirred at RT for 2 h. It was then diluted with ethyl acetate (20 mL) and filtered. The filtrate was concentrated under reduced pressure and dried to get the desired sulfonamide as a white solid in quantitative yield.
Figure imgf000235_0004
Intermediate 349: l-methyl-3-(trifluoromethyl)-lH-pyrazole-4-sulfonamide
Figure imgf000235_0002
Ammonia gas was passed into a cooled THF solution (25 mL) of l-methyl-3- (trifluoromethyl)-lH-pyrazole-4-sulfonyl chloride (0.5 mmol, 0.125 g) for 1 h. Then the reaction mixture was sealed and stirred at RT for 2-3 h. After completion of reaction, the reaction mixture was diluted with chloroform (20 mL) and filtered through celite bed. The filtrate was concentrated under reduced pressure and dried to get quantitative yield of the title compound as a white solid.
Figure imgf000236_0002
Intermediate 350: 7V-{4-[f4-methoxybenzyl)sulfamoyll benzyl} acetamide
Figure imgf000236_0001
To a cooled solution of 4-methoxybenzylamine (4.24 mmol, 0.581 g) and Et3N (0.99 mL, 7.07 mmol) in dry dichloromethane, was added 4-[(acetylamino)methyl]benzenesulfonyl chloride (2.83 mmol, 0.7 g) and the reaction mixture was stirred overnight at RT. The reaction mixture was diluted with chloroform (20 mL) and the organic layer was washed with 10 % citric acid solution (50 mL), 10 % sodium bicarbonate solution (50 mL) and brine (25 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure and dried to get 0.2 g of the protected sulfonamide as an off-white solid.
Figure imgf000237_0004
Intermediate 351: 7V-(4-sulfamoylbenzyl)acetamide
Figure imgf000237_0001
To a cooled solution of Λ/-{4-[(4-methoxybenzyl)sulfamoyl]benzyl}acetamide (PE-66-14-I, 0.56 mmol, 195 mg), was added TFA (10 mL) and the reaction mixture was stirred overnight at rt. The mixture was concentrated and methanol was added to the residue and further concentrated to get 200 mg of the desired sulfonamide as a pale brown solid which was taken to the next step without further purification.
Figure imgf000237_0003
Intermediate 352: l,3-dimethyl-2,4-dioxo-l,2,3,4-tetrahvdropyrimidine-5-sulfonamide
Figure imgf000237_0002
Ammonia gas was passed into a cooled THF solution (25 niL) of l,3-dimethyl-2,4-dioxo- l,2,3,4-tetrahydropyrimidine-5-sulfonyl chloride (0.53 mmol, 0.125 g) for 1 h and sealed. Then the reaction mixture was stirred at RT for 2-3 h. After completion of reaction, the reaction mixture was diluted with chloroform (20 mL) and filtered through celite bed. The filtrate was concentrated under reduced pressure and dried to get quantitative yield of the title compound as a white solid.
Figure imgf000238_0002
Intermediate 353: 2-(2,5-dioxopyrrolidin-l-yl)ethanesulfonamide
Figure imgf000238_0001
Ammonia gas was passed into a cooled solution (25 mL) of 2-(2,5-dioxopyrrolidin-l- yl)ethanesulfonyl chloride (1.77 mmol, 400 mg) in dry 1,4-dioxane (10 mL) for 20 min and sealed. Then the reaction mixture was stirred at RT for 2 h. It was then diluted with ethyl acetate (20 mL) and filtered. The filtrate was concentrated under reduced pressure and dried to get 150 mg of the desired sulfonamide as a white solid.
Figure imgf000238_0003
Intermediate 354: lH-pyrazole-4-sulfonamide
Figure imgf000239_0001
Ammonia gas was passed into a cooled THF solution (25 mL) of lH-pyrazole-4-sulfonyl chloride (0.75 mmol, 0.125 g) for 1 h and sealed. Then the reaction mixture was stirred at RT for 2-3 h. After completion of reaction, the reaction mixture was diluted with chloroform (20 mL) and filtered through celite bed. The filtrate was concentrated under reduced pressure and dried to get quantitative yield of the title compound as a white solid.
Figure imgf000239_0003
Intermediate 355: 5-Bromo-2-hvdroxypyridine-3-carboxylic acid
Figure imgf000239_0002
To a solution of 2-hydroxypyridine-3-carboxylic acid (35.94 mmol, 5 g) in dry DMF cooled with an ice-water bath, a solution of bromine (57.51 mmol, 3 mL, 9.19 g in cooled DMF) was added dropwise at 0 0C over 1 h. The reaction mixture was stirred at rt for 3 h and then quenched with ice-water. The resulting yellow solid was filtered, washed with water and dried under vacuum to get 6 g of the title compound.
Figure imgf000240_0003
Intermediate 356: S-bromo-l-chloropyridine-S-carboxylic acid
Figure imgf000240_0001
A solution of 5-bromo-2-hydroxypyridine-3-carboxylic acid (Intermediate 355, 26.83 mmol, 5.85 g) in POCl3 (14.63 rnL, 2.5 v/w) was heated to reflux for 12 h. It was cooled to RT and POCl3 was removed in vacuo. Then ice water was added to the reaction mixture and extracted with EtOAc. The EtOAc layer was concentrated to get a yellow solid. The solid obtained was washed with chilled CHCl3 to yield the title compound (2.86 g).
Figure imgf000240_0004
Intermediate 357: 5-bromo-2-fmethylsulfanyl)pyridine-3-carboxylic acid
Figure imgf000240_0002
To a solution of 5 -bromo-2-chloropyridine-3 -carboxylic acid (Intermediate 356, 10.57 mmol, 2.5 g) in dioxane was added 21% aqueous solution of NaSMe (8.8 mL, 26.43 mmol, 1.85 g) and the mixture was heated in a sealed tube at 110 0C for 2 h. After completion of the reaction, the crude mass was dissolved in water and acidified with 10% citric acid solution and the solid obtained was filtered and dried to yield the product (2 g).
Figure imgf000241_0002
Intermediate 358: Methyl 5-bromo-2-(methylsulfanyl)pyridine-3-carboxylate
To a suspension of 5-bromo-2-(methylsulfanyl)pyridine-3-carboxylic acid (Intermediate 357, 7.66 mmol, 1.9 g) in MeOH (20 ml) at 0 0C, was slowly added thionyl chloride (15.32 mmol, 1.82 g). After the addition was complete, the reaction mixture was refluxed for 3 h. The solvent was concentrated in vacuo and the crude mixture was taken in EtOAc (30 mL), washed with aq. NaHCO3 solution, water and brine, dried over Na2SO4, filtered and concentrated to obtain 1.6 g of the title compound.
Figure imgf000241_0003
Intermediate 359: methyl 2-(methylsulfanyl)-5-(4A5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)pyridine-3 -carboxylate
Figure imgf000242_0001
A suspension of methyl 5-bromo-2-(methylsulfanyl)pyridine-3-carboxylate (Intermediate 358, 5.7 mmol, 1.5 g), bis(pinacolato)diboron (6.2 mmol, 1.59 g), [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (0.57 mmol, 0.467 g) and potassium acetate (17.17 mmol, 1.685 g) was taken in dioxane (5 mL) and degassed for 10 min. Then the reaction mixture was heated to 100 0C for 1 h. The reaction mixture was passed through a column and the product was eluted at 5% EtOAc in hexanes. The residue obtained upon evaporation of the product containing fractions was then triturated with petroleum ether to get 1.3 g of the title compound. LCMS analysis indicated the presence of a mixture of boronic acid (86%) and boronate (12%).
Figure imgf000242_0003
Intermediate 360: ethyl 5-bromo-l-ethyl-2-oxo-l,2-dihvdropyridine-3-carboxylate
Figure imgf000242_0002
To a suspension of cesium carbonate (12.3 mmol, 4 g) in dry ethanol (20 mL), 5-bromo-2- hydroxypyridine-3-carboxylic acid (9.2 mmol, 2 g) and iodoethane (24.3 mmol, 3.8 g) were added and heated to 80 0C for 3 h in a sealed tube. The mixture was diluted with methanol and filtered through a celite bed. The filtrate was concentrated to yield 2.2 g of the title compound.
Figure imgf000243_0002
Intermediate 361: ethyl l-ethyl-2-oxo-5-f4,4,5.,5-tetramethyl-l,3i2-dioxaborolan-2-yl)- l,2-dihvdropyridine-3-carboxylate
Figure imgf000243_0001
Ethyl 5 -bromo-l-ethyl-2-oxo-l,2-dihy dropyridine-3 -carboxylate (Intermediate 360, 1.82 mmol, 0.5 g), bis(pinacolato)diboron (2.1 mmol, 0.56 g), [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II)complex with CH2Cl2 (0.27 mmol, 0.22 g) and potassium acetate (5.4 mmol, 0.53 g) were suspended in dry dioxane (10 mL) and degassed with nitrogen for 10 min. The reaction was then heated to 100 0C for 1 h. The reaction mixture was diluted with DCM and filtered through a celite bed and concentrated to give the crude title compound which was used in the next step without further purification. HPLC-MS analysis indicated the presence of a mixture of boronic acid (39 %) and boronate (35 %).
Figure imgf000244_0002
Intermediate
Figure imgf000244_0001
362: 2-methoxy-5-f4,4,5.,5-tetramethyl-l,3i2-dioxaborolan-2-yl)nicotinonitrile
5-Bromo-2-methoxynicotinonitrile (0.5 g, 2.35 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'- bi(l,3,2-dioxaborolane) (0.834 g, 3.29 mmol), 1 , l'-bis(diphenylphosphino)ferrocene- palladium dichloride-dichloromethane adduct (0.575 g, 0.70 mmol), and potassium acetate (0.691 g, 7.04 mmol) were suspended in 1,4-dioxane (20 ml) and degassed with nitrogen for 10 min. The reaction was then heated at 90 0C for 2 h, diluted with dichloromethane and purified by flash chromatography (25g silica column, 0-8% methanol in dichloromethane). Fractions were combined to obtain reddish-brown solid corresponding to title compound. MS(ES): 260.99 (M+H) for Ci3Hi7BN2O3 1H-NMR (400 MHz, DMSO-d6): δ ppm 1.30 (s, 12H) 4.03 (s, 3 H) 8.30 (d, J=I.70 Hz, 1 H) 8.62 (d, J=I.70 Hz, 1 H).
Intermediate 363 : 5-bromo-7V-( 3-,5-dimethoxy)phenyll -4-( methylthio)pyrimidin-2-amine The title compound was prepared using the general method described above for Intermediate 65 using 5-bromo-2-chloro-4-(methylthio)pyrimidine and 3,5-dimethoxy-aniline.
Figure imgf000245_0002
Intermediate 364 : 2-(3 -chloro-4-fluorophenylamino)- 4-(3 -(trifluoromethyl)- 1 H-pyrazol- 1 - yl)pyrimidin-5-ylboronic acid
Figure imgf000245_0001
5 -bromo-N-(3 -chloro-4-fluorophenyl)-4-(3 -(trifluoromethyl)- 1 H-pyrazol- 1 -yl)pyrimidin-2- amine Intermediate 115 (300 mg, 0.69 mmol) and triisopropyl borate (0.319 mL, 1.37 mmol) were combined in anhydrous THF (3.00 mL) and anhydrous toluene (12 mL) to give a colorless solution under argon. The mixture was cooled to -78 0C, then 2.5M BuLi in Hexanes (0.550 mL, 1.37 mmol) was added dropwise over 1 hour. After 30 minutes, 1 M HCl (20 ml) was added at -78 0C, then the the ice bath was removed and the mixture was allowed to warm to RT. The mixture was concentrated followed by addition of water and ethyl acetate. The water layer was extracted with ethyl acetate. The combined organic layers were washed with brine (1 x 50 mL) then dried over MgSO4. The residue after filtration and evaporation was purified by silica gel chromatography using 0-10% MeOH in methylene chloride. The title compound was isolated as a white solid. (80mg). MS (Electrosprav): 402 (MH+) Ci4H9BClF4N5O2 Intermediate 365: 5-Bromo-2-methoxy-N-fmethylsulfonyl)nicotinamide
Figure imgf000246_0001
To a stirred suspension of 5-bromo-2-methoxynicotinic acid (1.15 g, 4.96 mmol) and oxalyl chloride (0.649 ml, 7.43 mmol) in methylene chloride (10 mL), under an atmosphere of nitrogen at ambient temperature, were added two drops of DMF. This mixture was allowed to stir for 2 hours. The solution was concentrated under vacuum; the residue was redissolved in methylene chloride (5 mL) and added dropwise to a stirred suspension of methanesulfonamide (0.471 g, 4.96 mmol) and pyridine (0.802 ml, 9.91 mmol) in methylene chloride (5 mL), under an atmosphere of nitrogen at ambient temperature. This mixture was stirred overnight, concentrated and purified by flash chromatography (silica gel, 0-6% methanol in methylene chloride) to yield the title compound (1.1 g). MS: ES+ 310 for C8H9BrN2O4S.
IH NMR (300 MHz, CHLOROFORM-J) δ ppm 3.41 (s, 3 H) 4.16 (s, 3 H) 8.43 (d, J=2.64 Hz, 1 H) 8.58 (d, J=2.64 Hz, 1 H) 10.05 (br. s., 1 H)
Intermediate 366: Methyl 5-bromo-l-methyl-2-oxo-l.,2-dihvdropyridine-3-carboxylate
Figure imgf000246_0002
Methyl 5-bromo-2-hydroxynicotinate (0.9 g, 3.88 mmol), dimethyl sulfate (1.186 mL, 12.41 mmol), and triethylamine (1.730 mL, 12.41 mmol) were dissolved in MeOH (10.5 mL) and heated in a microwave reactor at 100 0C for 30 min. The reaction was diluted with DCM, washed with water, and the organic layer was evaporated and purified by flash chromatography (silica gel, 0-12% MeOH in DCM) to afford the desired product (847 mg). MS: ES+ 247 for C8H8BrNO3 IH NMR (300 MHz, DMSO-J6) d ppm 3.45 (s, 3 H) 3.75 (s, 3 H) 8.04 (d, J=3.01 Hz, 1 H) 8.36 (d, J=2.83 Hz, 1 H) The compound in the table below was prepared using the procedure described above for Intermediate 366 using iodoethane as the alkylating agent, potassium carbonate as the base and ethanol as solvent.
Figure imgf000247_0001
The intermediates in the table below were prepared using the procedure for Intermediate 134 and the specified starting material.
Figure imgf000247_0002
Figure imgf000248_0002
The compounds in the table below were prepared using the procedure for Intermediate 65 and the specified starting materials.
Figure imgf000248_0001
The compounds in the table below were prepared using the procedure for Intermediate 69 and the specified starting material.
Figure imgf000249_0001
The compounds in the table below were prepared using the procedure for Intermediate 112 and the specified starting materials.
Figure imgf000249_0002
Figure imgf000250_0001
Intermediate 379: 5-(2-(3-chloro-4-fluorophenylamino)-4-(3- fdimethylamino)propylamino)pyrimidin-5-yl)nicotinohydrazide
Figure imgf000251_0001
A solution of Example 5 (100 mg, 0.21 mmol) and hydrazine hydrate (0.015 mL, 0.32 mmol) in 1,4-dioxane (1 mL) was stirred and heated to 115 degrees for 60 minutes. Solvent was removed under reduced pressure, affording the title compound (83 mg).
MS: ES+ 459 for C2IH24ClFN8O.
IH NMR (300 MHz, DMSO-J6) d ppm 1.70 (quin, J=6.59 Hz, 2 H) 2.02 (s, 6 H) 2.33 (t, J=6.50 Hz, 2 H) 3.38 - 3.50 (m, 2 H) 7.30 (t, J=9.14 Hz, 1 H) 7.41 (t, J=4.99 Hz, 1 H) 7.63 (ddd, J=9.14, 4.24, 2.64 Hz, 1 H) 7.86 (s, 1 H) 8.13 (t, J=2.07 Hz, 1 H) 8.26 (dd, J=6.97, 2.64 Hz, 1 H) 8.68 (d, J=2.07 Hz, 1 H) 8.93 (d, J=I.88 Hz, 1 H) 9.48 (s, 1 H) 9.99 (br. s., 1 H)
Intermediate 380: 2-(3-chloro-4-fluorophenylamino)-4-(3- methoxypropylamino)pyrimidine-5-carboxamide
Figure imgf000251_0002
Intermediate 127 (120 mg, 0.35 mmol) was suspended in methanol (0.5 mL) and water (0.5 mL) and stirred under ambient conditions. To this mixture was added aqueous sodium hydroxide (50 wt %, 84 mg, 1.05 mmol). Upon warming to 50 degrees a small amount of dioxane was added to aid in solubility. After 90 minutes the mixture was removed from heating then water was added to precipitate a solid; this was collected and washed with water to give the title compound (87 mg). MS: ES+ 354 for Ci5Hi7ClFN5O2. IH NMR (300 MHz, DMSO-J6) δ ppm 1.81 (quin, J=6.50 Hz, 2 H) 3.22 (s, 3 H) 7.18 (br. s., 1 H) 7.30 (t, J=9.14 Hz, 1 H) 7.54 - 7.66 (m, 1 H) 7.80 (br. s., 1 H) 8.20 (dd, J=6.78, 2.45 Hz, 1 H) 8.52 (s, 1 H) 9.20 (t, J=5.37 Hz, 1 H) 9.69 (s, 1 H).
The following intermediates were prepared using the general method described above for Intermediate 72 using 5- bromo-2-[N-(3-chloro-4-fluorophenyl)]-4-(methyl sulfonyl)pyrimidin-2-amine (Intermediate 69) and the starting material (SM) indicated.
Figure imgf000252_0001
Intermediate 383 : ( 4-( 5-bromo-2-f3-chloro-4-fluorophenylamino)pyrimidin-4- vDmorpholin-2-vDmethanol
Figure imgf000253_0001
To 600 mg of 5-bromo-4-chloro-N-(3-chloro-4-fluorophenyl)pyrimidin-2-amine (Intermediate
63, 1.78 mmol) in 1,4-Dioxane (8 mL), was added triethylamine (0.27 mL, 1.96 mmol) and 2- hydroxymethylmorpholine (1.78 mmol, 209 mg) under inert atmosphere. The reaction mixture was stirred at room temperature for 2 days. The reaction mixture was diluted with ethyl acetate and MeOH and adsorbed on silica gel. The mixture was purified by column chromatography using 0-10 % MeOH in DCM to obtain (4-(5-bromo-2-(3-chloro-4- fluorophenylamino)pyrimidin-4-yl)morpholin-2-yl)methanol (473 mg). MS(ES): 417 (M) and
419 (M+2) for Ci5Hi5BrClFN4O2.
1H NMR (300 MHz, DMSO-D6) δ ppm 2.71 - 2.94 (m, 1 H) 2.94 - 3.14 (m, 1 H) 3.33 - 3.76 (m, 4 H) 3.92 (d, J=I 1.1 I Hz, 1 H) 4.09 (d, J=12.81 Hz, 1 H) 4.22 (d, J=13.00 Hz, 1 H) 4.82
(t, J=5.27 Hz, 1 H) 7.30 (t, J=9.14 Hz, 1 H) 7.43 - 7.70 (m, 1 H) 7.89 - 8.14 (m, 1 H) 8.26 (s,
1 H) 9.70 (s, 1 H).
The following compound was prepared using the general method described for Intermediate 383 and the starting materials (SM) indicated.
Figure imgf000253_0002
The following compound was prepared using the general method described for Intermediate 131 and the starting material (SM) indicated.
Figure imgf000254_0002
Intermediate 386: 1-tert-butyl 2-methyl 6-bromo-lH-indole-l.,2-dicarboxylate
Figure imgf000254_0001
To 1 g of methyl 6-bromo-lH-indole-2-carboxylate (Intermediate 385, 3.94 mmol) in THF (20 mL) was added di-t-Butyl dicarbonate (1.074 g, 4.92 mmol) and treated with 4- dimethylaminopyridine (48 mg, 0.39 mmol). The mixture was stirred at room temperature under nitrogen for 4 days. The mixture was concentrated at reduced pressure and the residue was adsorbed on silica gel and purified by column chromatography with 0-25% EtOAc in hexanes to afford 1-tert-butyl 2-methyl 6-bromo-lH-indole-l,2-dicarboxylate (1.33 g). 1H NMR (300 MHz, DMSO-D6) δ ppm 1.55 (s, 9 H) 3.86 (s, 3 H) 7.29 (s, 1 H) 7.49 (dd, J=8.48, 1.70 Hz, 1 H) 7.69 (d, J=8.48 Hz, 1 H) 8.13 (s, 1 H).
The following compound was prepared using the general method described above for Intermediate 386 using the starting material (SM) indicated.
Figure imgf000254_0003
The following compounds were prepared using the general method described above for Intermediate 133 using Intermediate 132 and the starting material (SM) indicated.
Figure imgf000255_0002
Intermediate 390: 3-bromo-5-fmethylsulfonyl)pyridine
Figure imgf000255_0001
A solution of 3-bromo-5-(methylthio)pyridine (2.17 g, 10.63 mmol) in DCM (40 rnL) was cooled to 0 0C. The reaction was then treated with m-Chloroperbenzoic acid (4.89 g, 21.27 mmol) and allowed to stir at 0 0C for 30 min (reaction became a suspension after mcpba addition) before it was allowed to warm up to room temperature for 1 hr. The reaction mixture was diluted with EtOAc, basified with sodium carbonate, and the layers were separated. The organic layer was washed with brine and dried over MgSOφ The solvent was removed at reduced pressure and the residue was adsorbed on silica and purified by column chromatography with 50-100% EtOAc in hexanes to afford 3-bromo-5- (methylsulfonyl)pyridine (1.97 g). MS(ES): 236 (M) and 238 (M+2) for C6H6BrNO2S. 1U NMR (300 MHz, DMSO-D6) δ ppm 3.39 (s, 3 H) 8.57 (t, J=2.07 Hz, 1 H) 9.04 (d, J=I.88 Hz, 1 H) 9.07 (d, J=2.07 Hz, 1 H).
Intermediate 391: tert-butyl 2-(3-bromophenylthio)acetate
Figure imgf000256_0001
A solution of 3-bromobenzenethiol (0.788 niL, 6.66 mmol) in DMF (12 niL) was treated with tert-butyl 2-bromoacetate (1.034 mL, 7.00 mmol) and potassium carbonate (1.842 g, 13.33 mmol). The reaction was stirred at room temperature under nitrogen overnight. The reaction was diluted with EtOAc/^O and the layers were separated. The organic phase was washed with brine and dried over sodium sulfate. The solvent was removed at reduced pressure and the residue was adsorbed on silica and purified by column chromatography with 0-20% EtOAc in hexanes to afford tert-butyl 2-(3-bromophenylthio)acetate (1.6 g). 1H NMR (300 MHz, DMSO-J6) δ ppm 1.35 (s, 9 H) 3.82 (s, 2 H) 7.15 - 7.47 (m, 3 H) 7.54 (t, J=I.79 Hz, I H).
The following compound was prepared using the general method described above for Intermediate 390 using mcpba and the starting material (SM) indicated.
Figure imgf000256_0003
Intermediate 393: Ethyl 2-(3-bromophenylamino)-2-oxoacetate
Figure imgf000256_0002
3-Bromoaniline (0.759 mL, 6.98 mmol) was dissolved in THF (20 mL), treated with triethylamine (0.972 mL, 6.98 mmol), and cooled to 0 0C. The solution was then treated with ethyl 2-chloro-2-oxoacetate (0.779 mL, 6.98 mmol) and allowed to slowly warm up to room temperature and stir overnight under nitrogen. The reaction was diluted with EtOAc/^O and the layers were separated. The organic phase was washed with brine and dried over sodium sulfate. The solvent was removed at reduced pressure, the residue was adsorbed on silica, and purified by column chromatography with 0-60% EtOAc in hexanes to afford Ethyl 2-(3- bromophenylamino)-2-oxoacetate (1.78 g).
MS(ES): 272 (M) and 274 (M+2) for Ci0Hi0BrNO3.
1H NMR (300 MHz, DMSO-J6) δ ppm 1.32 (t, J=7.06 Hz, 3 H) 4.31 (q, J=7.16 Hz, 2 H) 7.19
- 7.44 (m, 2 H) 7.74 (dt, J=6.45, 2.33 Hz, 1 H) 7.90 - 8.17 (m, 1 H) 10.92 (s, 1 H)
Intermediate 394: 3-Bromo-N-(ethylcarbamovDbenzenesulfonamide
Figure imgf000257_0001
A solution of 3-bromobenzenesulfonamide (400 mg, 1.69 mmol) in acetone (4.20 mL) was treated with a solution of potassium hydroxide (95 mg, 1.69 mmol) in water (0.6 mL). The reaction was stirred at room temperature for 15 min at which time the solvent was removed at reduced pressure. The residue was re-dissolved in DMF (4.20 mL), treated with ethyl isocyanate (0.266 mL, 3.39 mmol), and stirred overnight. The solvent was removed at reduced pressure and the residue was basifϊed with 2 mL of 1 N NaOH, diluted with water, and then acidified with concentrated HCl. The solid formed was then filtered and dried to afford the desired product (350 mg).
1H NMR (300 MHz, DMSO-J6) δ ppm 0.95 (t, 3 H) 2.81 - 3.13 (m, 2 H) 6.61 (t, J=5.37 Hz, 1 H) 7.58 (t, J=7.91 Hz, 1 H) 7.90 (dt, J=8.15, 1.77 Hz, 2 H) 8.03 (t, J=I.79 Hz, 1 H) 10.73 (s, I H)
Intermediate 395: 5-bromo-N-ethylpyridine-3-sulfonamide
Figure imgf000257_0002
5-bromopyridine-3-sulfonyl chloride hydrochloride (1 g, 3.41 mmol) and ethanamine hydrochloride (0.306 g, 3.75 mmol) were treated with pyridine (2.76 ml, 34.13 mmol) and stirred at room temperature under nitrogen for 2 hrs. The reaction mixture was then diluted with EtOAc, washed with water, and dried over sodium sulfate. The solvent was removed at reduced pressure, the residue was adsorbed on silica, and purified on column chromatography with 10-80% EtOAc in hexanes to afford 5 -bromo-N-ethylpyridine-3 -sulfonamide (466 mg). MS(ES): 265 (M) and 267 (M+2) for C7H9BrN2O2S.
1H NMR (300 MHz, DMSO-J6) δ ppm 0.99 (t, J=7.16 Hz, 3 H) 2.78 - 2.96 (m, 2 H) 7.93 (br. s., 1 H) 8.37 (t, J=2.07 Hz, 1 H) 8.92 (d, J=I.88 Hz, 1 H) 9.00 (d, J=2.07 Hz, 1 H).
Intermediate 396: 3-Bromo-N-fmethylsulfonyl)benzamide
Figure imgf000258_0001
3-Bromobenzoic acid (1 g, 4.97 mmol), methanesulfonamide (0.521 g, 5.47 mmol), l-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.144 g, 5.97 mmol), and 4- dimethylaminopyridine (0.304 g, 2.49 mmol) were dissolved in THF (10 mL) and stirred at room temperature overnight. The residue was diluted with EtOAc, washed with water and brine, and dried over sodium sulfate. The solvent was removed at reduced pressure, the residue was adsorbed on silica, and purified by column chromatography with 20-100% EtOAc in hexanes to afford 3-bromo-N-(methylsulfonyl)benzamide (350 mg). 1H NMR (300 MHz, CHLOROFORM-^) δ ppm 3.46 (s, 3 H) 7.40 (t, J=7.91 Hz, 1 H) 7.68 ■ 7.86 (m, 2 H) 8.03 (t, J=I.70 Hz, 1 H) 8.67 (br. s., 1 H).
Intermediate 397: 5-bromo-l-f2-morpholinoethyl)-2-oxo-l,2-dihvdropyridine-3- carboxylic acid
Figure imgf000258_0002
A suspension of methyl 5-bromo-2-hydroxynicotinate (1 g, 4.31 mmol), 4-(2- chloroethyl)morpholine hydrochloride (0.802 g, 4.31 mmol), and potassium carbonate (1.787 g, 12.93 mmol) in MeOH (20 mL) was refluxed overnight. The solvent was removed at reduced pressure and the residue was dissolved in H2O and neutralized with IN HCl. The solid formed was filtered (unreacted starting hydroxynicotinate) and the desired product remained in the aqueous layer, which was then concentrated. The residue was re-dissolved in DCM/MeOH, adsorbed on silica, and purified by column chromatography with 0-20% MeOH in DCM to afford bromo-l-(2-morpholinoethyl)-2-oxo-l,2-dihydropyridine-3-carboxylic acid (750 mg)
1U NMR (300 MHz, DMSO-J6) δ ppm 2.31 - 2.47 (m, 4 H) 2.64 (t, J=6.12 Hz, 2 H) 3.43 - 3.69 (m, 4 H) 4.18 (t, J=6.03 Hz, 2 H) 8.36 (d, J=2.83 Hz, 1 H) 8.50 (d, J=2.83 Hz, 1 H) 14.30 (br. s., 1 H)
Intermediate 398: methyl 5-bromo-l-(2-morpholinoethyl)-2-oxo-l.,2-dihydropyridine-3- carboxylate
Figure imgf000259_0001
A suspension of 5-bromo-l-(2-morpholinoethyl)-2-oxo-l,2-dihydropyridine-3-carboxylic acid (Intermediate 397, 750 mg, 2.26 mmol) in methanol (9162 μl, 226.47 mmol) was treated with sulfuric acid (483 μl, 9.06 mmol). The reaction was refluxed for 4 hrs at which time the solvent was removed at reduced pressure. The residue was diluted with EtOAc and carefully neutralized with a solution of sodium carbonate. The layers were then separated and the organic was washed with brine and dried over sodium sulfate. The solvent was removed at reduced pressure and the residue was adsorbed on silica and purified by column chromatography with 0-15% MeOH in DCM toyield methyl 5-bromo-l-(2-morpholinoethyl)- 2-oxo-l,2-dihydropyridine-3-carboxylate (664 mg). 1U NMR (300 MHz, DMSO-J6) δ ppm 2.33 - 2.46 (m, 4 H) 2.54 (t, J=6.22 Hz, 2 H) 3.39 - 3.60 (m, 4 H) 3.74 (s, 3 H) 4.02 (t, J=6.22 Hz, 2 H) 8.05 (d, J=3.01 Hz, 1 H) 8.26 (d, J=3.01 Hz, 1 H) Intermediate 399: Methyl 5-bromo-2-(2-morpholinoethylamino)nicotinate
Figure imgf000260_0001
A suspension of methyl S-bromo^-chloronicotinate (0.5 g, 2.00 mmol) and 2- morpholinoethanamine (0.390 niL, 2.99 mmol) in EtOH (3 mL) was heated in a microwave reactor at 140 0C for 45 min. The mixture was concentrated at reduced pressure. The residue was then diluted with water, treated with sodium bicarbonate, and extracted with EtOAc. The organic layer was washed with brine and dried over sodium sulfate. The solvent was removed at reduced pressure and the residue was adsorbed on silica and purified by column chromatography with 0-16% MeOH in DCM to afford methyl 5-bromo-2-(2- morpholinoethylamino)nicotinate (582 mg).
1U NMR (300 MHz, DMSO-J6) δ ppm 2.29 - 2.46 (m, 4 H) 2.51 - 2.60 (m, 2 H) 3.43 - 3.67 (m, 6 H) 3.84 (s, 3 H) 8.05 - 8.26 (m, 2 H) 8.37 (d, J=2.45 Hz, 1 H)
The following compound was prepared using the general method described above for Intermediate 399 using methyl 5-bromo-2-chloronicotinate and the starting material (SM) indicated.
Figure imgf000260_0002
The following compounds were prepared using the general method described above for Intermediate 367 using methyl 5-bromo-2-hydroxynicotinate and the starting material (SM) indicated.
Figure imgf000261_0001
The following compound was prepared using the general method described above for Intermediate 366 using methyl 5-bromo-2-hydroxynicotinate and the starting material (SM) indicated.
Figure imgf000262_0002
Intermediate 405: S-bromo-l-methyl-l-oxo-l^-dihydropyridine-S-carboxylic acid
Figure imgf000262_0001
Methyl 5 -bromo-l-methyl-2-oxo-l,2-dihy dropyridine-3 -carboxylate (Intermediate 366, 2.00 g, 8.13 mmol) was dissolved in MeOH (40 rnL) and treated with sodium hydroxide (16.26 mL, 16.26 mmol). The reaction was stirred at room temperature for 2 hrs. The reaction was neutralized with 1 N HCl and the solvent was removed at reduced pressure. The residue was suspended in water and filtered to afford 5 -bromo-l-methyl-2-oxo-l,2-dihy dropyridine-3 - carboxylic acid (1.77 g).
MS (ES): (M) 232 and 234 (M+2) for C7H6BrNO3.
1H NMR (300 MHz, DMSO-J6) δ ppm 3.62 (s, 3 H) 8.35 (d, J=2.83 Hz, 1 H) 8.61 (d, J=2.83
Hz, 1 H) 14.38 (s, 1 H)
The following compounds were prepared using the general method described for Intermediate 365 using the starting materials (SM) indicated.
Figure imgf000263_0001
The following compounds were prepared using the general method described above for Intermediate 134 using bis(pinacolato)diboron, l,l'-bis(diphenylphosphino)ferrocene- palladium dichloride, potassium acetate and the starting material (SM) indicated.
Figure imgf000264_0001
Figure imgf000265_0001
Figure imgf000266_0001
Figure imgf000267_0001
Figure imgf000268_0001
Figure imgf000269_0001
Figure imgf000270_0002
Intermediate 435: S-bromo-N-butan-l-yl-l-chloropyrimidin^-amine
Figure imgf000270_0001
Prepared using the general method described above for Intermediate 1 using 5-bromo-2,4- dichloro-pyrimidine and butan-2-amine. MS(ES): 265.8 (M+2) for C8HnBrClN3. IH NMR (300 MHz, CHLOROFORM-D) δ ppm 0.93 - 1.03 (m, 3 H), 1.26 (d, J=6.59 Hz, 3 H), 1.55 - 1.70 (m, 2 H), 4.06 - 4.36 (m, 1 H), 5.30 (s, 1 H), 8.12 (s, 1 H).
Intermediate 436: 5-bromo-N'-butan-2-yl-N-(3-chloro-4-fluorophenyl)pyrimidine-2.,4- diamine
Figure imgf000271_0001
Prepared using the general method described above for Intermediate 26 using Intermediate
435 and 3-chloro-4-fluoroaniline.
MS(ES): 375 (M+2) for Ci4Hi5BrClFN4.
IH NMR (300 MHz, CHLOROFORM-D) δ ppm 0.98 - 1.03 (m, 3 H), 1.29 (d, J=6.59 Hz, 3
H), 1.55 - 1.70 (m, 2 H), 4.06 - 4.30 (m, 1 H), 5.17 (m, 1 H), 7.07 (m, 1 H), 7.23 (m, 2 H),
7.97-8.00 (m, 2 H).
The following intermediates were prepared using the general method described above for Intermediate 112 using Intermediate 69 and the starting material (SM) indicated.
Figure imgf000271_0002
Figure imgf000272_0001
The following intermediates were prepared using the general method described above for Intermediate 65 using 5-bromo-2-chloro-4-(methylthio)pyrimidine and the starting material (SM) indicated.
Figure imgf000272_0002
The following intermediates were prepared using the general method described above for Intermediate 69 using m-CPBA and the starting material (SM) indicated.
Figure imgf000273_0001
The following intermediates were prepared using the general method described above for Intermediate 112 using the starting materials (SM) indicated.
Figure imgf000274_0001
Intermediate 448: 5-bromo-N-(3,5-dimethoxyphenyl)-4-hvdrazinylpyrimidin-2-amine
Figure imgf000275_0001
5-bromo-N-(3,5-dimethoxyphenyl)-4-(methylthio)pyrimidin-2-amine Intermediate 363 (1 g, 2.81 mmol), hydrazine anhydrous (12 ml, 382.34 mmol) and dioxane (4 rnL) were combined to give a white suspension. The reaction mixture was heat at 100 0C for 2 hours. The reaction mixture was cooled over an ice bath and 60 ml of water was slowly added. The precipitated solid was filtered and washed with water to give the crude title compound (462 mg), used without further purification in the next step.
MS (Electrosprav): 341.18 (MH+) for Ci2Hi4BrN5O2
Intermediate 449: 5-bromo-4-(3-(^ifluoromethyl)-5-methyl-lH-pyrazol-l-yl)-N-(3.,5- dimethoxyphenyl)pyrimidin-2-amine Intermediated 450: 5-bromo-4-f5-fdifluoromethyl)-3-methyl-lH-pyrazol-l-yl)-N-f3.,5 dimethoxyphenyl)pyrimidin-2-amine
Figure imgf000275_0002
5-bromo-N-(3-chloro-4-fluorophenyl)-4-hydrazinylpyrimidin-2-amine (487 mg, 1.43 mmol), l,l-difluoropentane-2,4-dione (214 mg, 1.57 mmol), acetic acid (0.082 mL, 1.43 mmol) and butan-1-ol (4 mL) were combined to give a yellow suspension. The mixture was heated at 150 0C for one hour. The resulting mixture of two product isomers was separated using flash chromatography, silica gel, 5-45% ethyl acetate in hexanes. Intermediate 449 was isolated as a solid (210 mg). Intermediate 450 was isolated as a solid (102 mg). MS:ES+ 440 for Ci7Hi6BrF2N5O2
These materials gave the same mass spectral results and were taken onto the next step without further characterization. The assigned regioisomeric identities of these intermediates were based on NMR analysis of the products obtained in the next reactions.
Intermediate 451: tert-butyl N-[f2-methylpropan-2-yl)oxycarbonyll-N-f4-morpholin-4- ylpyridin-2-yl)carbamate
Figure imgf000276_0001
4-morpholinopyridin-2-amine (prepared according to literature procedure : Bioorganic & Medicinal Chemistry Letters, 16(4), 839-844, 2006) (1.082 g, 6.04 mmol), di-t-butyl- dicarbonate (1.542 mL, 6.64 mmol), and TEA (1.010 mL, 7.24 mmol) were combined in Dioxane (20 mL) to give a colorless solution. DMAP (0.738 g, 6.04 mmol) was added and the mixture allowed to stir at RT for 2 hours, then heated to 70 0C for 1 hour. An additional amount of di-t-butyl-dicarbonate (2 g, 9.17 mmol) was added and the mixture was heated at 70 0C overnight. The reaction mixture was concentrated and diluted with methylene chloride and water. The layers were separated and the organic layer was washed with water, dried over Na2SO4 then concentrated. The resulting residue was triturated with diethyl ether, filtered and further washed with diethyl ether to give the pure title compound. (1.654 g).
MS (Electrosprav): 380.45 (MH+) for Ci9H29N3O5 Intermediate 452: tert-butyl N-(5-bromo-4-morpholin-4-ylpyridin-2-vD-N-r(2- methylpropan-2-yl)oxycarbonyllcarbamate
Figure imgf000277_0001
tert-butyl N-[(2-methylpropan-2-yl)oxycarbonyl]-N-(4-morpholin-4-ylpyridin-2-yl)carbamate Intermediate 451 (51 mg, 0.29 mmol) was dissolved in DMF (20 mL). N-bromosuccinimide (51.6 mg, 0.29 mmol) was added and the mixture was heated to 85 0C for 1 hour. The mixture was concentrated and purified by flash chromatography (silica gel column, 40 g, eluted with 0-40% ethyl acetate in hexanes) to give the title compound. (95 mg). MS (Electrosprav): 459.35 (MH+) for Ci9H28BrN3O5
Intermediate 453: 5-bromo-4-morpholinopyridin-2-amine
Figure imgf000277_0002
tert-butyl N-(5 -bromo-4-morpholin-4-ylpyridin-2-yl)-N- [(2-methylpropan-2- yl)oxycarbonyl]carbamate Intermediate 452 (1.632 g, 3.56 mmol) was dissolved in anhydrous MeOH (10 ml) and HCl 4M in Dioxane (2.67 ml, 10.68 mmol) was added. The mixture was allowed to stir at rt ovenight, then heat at 50 0C for 7 hours. The reaction mixture was concentrated to give the crude title compound (926 mg) which was used in the next step without further purification. MS (Electrospray): 259.12 (MH+) for C9Hi2BrN3O
Intermediate 454: 5-bromo-N-(3-chloro-4-fluorophenyl)-4-morpholinopyridin-2-amine
Figure imgf000278_0001
5-bromo-4-morpholinopyridin-2-amine Intermediate 453 (320 mg, 0.97 mmol), 3-chloro-4- fluorophenylboronic acid (337 mg, 1.93 mmol), and 5-bromo-4-morpholinopyridin-2-amine (320 mg, 0.97 mmol) were combined with methylene chloride (5 ml) to give a yellow solution. Copper (II) acetate (176 mg, 0.97 mmol) was added followed by anhydrous powdered 3 angstrom molecular sieves (200 mg). The mixture was allowed to stir at rt overnight. Filtration, evaporation and purification by flash chromatography (0-100% ethyl acetate in hexanes) afforded the title compound (82 mg). MS (Electrosprav): 387.65 (MH+) for Ci5Hi4BrClFN3O
Intermediate 455: 5-bromo-2-(2-methoxyethoxy)nicotinic acid
Figure imgf000278_0002
methyl 5-bromo-2-chloronicotinate (500 mg, 2.00 mmol) and 2-methoxyethanol (456 mg, 5.99 mmol) were combined in tert-butanol (20 mL) to give a yellow solution. Sodium 2- methylpropan-2-olate (576 mg, 5.99 mmol) was added. The mixture was heated at 90 0C for 1 hour then concentrated. 1 N HCl was added to the residue followed by extraction with ethyl acetate. The organic layer was washed with water then brine, dried with MgSO4 and concentrated to give the title compound (454 mg). MS (Electrospray): 277.08 (MH+) for
C9Hi0BrNO4
The compounds in the table below were prepared using this procedure and the specified starting materials.
Figure imgf000279_0001
Intermediate 460: methyl 5-bromo-2-(2-methoxyethoxy)nicotinate
Figure imgf000280_0001
5-bromo-2-(2-methoxyethoxy)nicotinic acid Intermediate 455 (454 mg, 1.64 mmol) was dissolved in anhydrous methanol (20 rnL) and H2SO4 (0.088 rnL, 1.64 mmol) was added to give a brown solution. The mixture was stirred overnight at room temperature. An additional amount Of H2SO4 (0.088 mL, 1.64 mmol) was added and the mixture was heated at 60 0C for 5 hours. The reaction mixture was concentrated down to dryness, ethyl acetate followed by water was added and the layers were separated. The organic layer was washed with water, then brine and dried over MgSO4. Evaporation gave the title compound (440 mg). MS (Electrosprav): 291.11 (MH+) for Ci0Hi2BrNO4
The compounds in the table below were prepared using this procedure and the specified starting materials.
Figure imgf000280_0002
Figure imgf000281_0002
Intermediate 465: methyl 2-f2-methoxyethoxy)-5-f4,4,5.,5-tetramethyl-l,3i2- dioxaborolan-2-yl)nicotinate and 5-(methoxycarbonyl)-6-(2-methoxyethoxy)pyridin-3- ylboronic acid
Figure imgf000281_0001
methyl 5-bromo-2-(2-methoxyethoxy)nicotinate Intermediate 460 (440 mg, 1.52 mmol), bis(pinacolato)diboron (539 mg, 2.12 mmol), and potassium acetate (447 mg, 4.55 mmol) were combined in 1,4-dioxane (20 mL). PdC12(dppf)-CH2Cl2 Adduct (1239 mg, 1.52 mmol) was added and the reaction was degassed with argon then heated to 90 0C for 3 hours. Purification by flash chromatography (10-100% ethyl acetate in hexanes) afforded the title compound as a mixture of boronic acid and pinacol ester (365 mg, ester: acid 1 : 1 mixture). MS (Electrosprav): 338.18 (MH+) for Ci6H24BNO6 MS (Electrosprav): 256.03 (MH+) for CI0HI4BNO6 The compounds in the below table were prepared using this procedure and the specified starting materials.
Figure imgf000282_0001
Figure imgf000283_0002
Intermediate 471: 5-bromo-4-f3-cvclopropyl-lH-pyrazol-l-yl)-N-f3.,5- dimethoxyphenyl)pyrimidin-2-amine
Figure imgf000283_0001
NaH (0.07 g, 1.75 mmol) was suspended in anhydrous NMP (5 mL) and cooled to 0 0C, 3- cyclopropyl-lH-pyrazole (0.235 g, 2.18 mmol) was then added slowly and the mixture was stirred for 15 minutes. 5-Bromo-4-chloro-N-(3,5-dimethoxyphenyl)pyrimidin-2-amine Intermediate 213 (0.5 g, 1.45 mmol) in a solution of 10 ml of NMP under argon was added and the reaction mixture was allowed to warm to room temperature overnight. Water (60 ml) was added to give a precipitate, which was filtered, washed with water and dried under vacuum to give the title compound as an off- white solid (503 mg). MS (Electrosprav): 417.27 (MH+) for Ci8Hi8BrN5O2
The compound below was prepared according the above procedure for Intermediate 471 using the specified starting materials.
Figure imgf000284_0002
Intermediate 473: methyl 5-bromo-6-fluoronicotinate
Figure imgf000284_0001
Methyl S-bromo-β-chloronicotinate (2.885 g, 11.52 mmol), potassium fluoride (2.68 g, 46.07 mmol), and tetraphenylphosphonium bromide (2.90 g, 6.91 mmol) combined in acetonitrile (75 mL) to give a yellow suspension. The reaction mixture was warmed at reflux or overnight. Additional potassium fluoride(l g, 17 mmol) was added and the mixture was refluxed for 5 days more. Evaporation and purification by flash chromatography (0-25% ethyl acetate in hexanes) afforded the title compound (1.53 g). MS (Electrosprav): 235.02 (MH+) for C7H5BrFNO2 Intermediate 474: Methyl 5-bromo-6-(2-(dimethylamino)ethoxy)nicotinate
Figure imgf000285_0001
2-(dimethylamino)ethanol (503 mg, 5.64 mmol) was dissolved in THF (6 mL) and cooled to 0 0C. IM Lithium bis(trimethylsilyl)amide in THF (6.41 mL, 6.41 mmol) was added slowly and the mixture was allowed stir for 15 minutes. A solution of methyl 5-bromo-6- fluoronicotinate Intermediate 473 (600 mg, 2.56 mmol) in THF (4ml) was then added to the reaction mixture. The reaction was allowed to reach room temperature over 4 hours, IM NH4Cl and dichloromethane were added and the layers were separated. The water layer was extracted with 5% methanol in methylene chloride. The pooled organic layers were dried over MgSO4 and purified by flash chromatography (3-10% methanol in methylene chloride) to afford the title compound (312 mg). MS (Electrosprav): 304.15 (MH+) for CnHi5BrN2O3
Intermediate 475: methyl 5-bromo-l-(2-methoxyethyD-2-oxo-l.,2-dihydropyridine-3- carboxylate
Figure imgf000285_0002
Sodium hydride (0.207 g, 5.17 mmol) was suspended in DMF (12 mL) in an oven dried flask under nitrogen and treated with methyl 5-bromo-2-hydroxynicotinate (1.2 g, 5.17 mmol). The mixture was stirred at room temperature for 30 minutes then 2-Bromoethyl methylether (1.458 mL, 15.52 mmol) was added dropwise. The mixture was then heated at 60 0C overnight. The mixture was diluted with water and extracted with EtOAc. The extracts were washed with brine, dried over sodium sulfate, and the solvent removed at reduced pressure. The residue was purified by flash chromatography, silica gel, 20-100 % EtOAc in DCM to afford the desired product.
Figure imgf000286_0001
The following compounds were prepared using the general method described above for Intermediate 134 using bis(pinacolato)diboron, l,l'-bis(diphenylphosphino)ferrocene- palladium dichloride, potassium acetate and the starting material (SM) indicated.
Figure imgf000286_0002
Figure imgf000287_0002
Intermediate 477: 2-methoxy-5-{2-[f3-methoxy-5-methylphenyl)aminol-4-[3- ftrifluoromethyl)-lH-pyrazol-l-yllpyrimidin-5-yl}pyridine-3-carbohvdrazide
Figure imgf000287_0001
To a solution of 2-methoxy-5-{2-[(3-methoxy-5-methylphenyl)amino]-4-[3-(trifluoromethyl)- lH-pyrazol-l-yl]pyrimidin-5-yl}pyridine-3-carboxylic acid (Example 760, 0.15 mmol, 75 mg) in CH2Cl2 (10 mL), were added Hydrazine monohydrate (0.38 mmol, 19 mg), triethylamine (0.6 mmol, 0.08 mL), 2-chloro-l-methylpyridinium iodide (0.19 mmol, 48 mg) and 4-(Dimethylamino)pyridine (0.03 mmol, 4 mg) and stirred overnight at RT. Six batches of the same size were run and all the reaction mixtures were combined, diluted with dichloromethane (10 mL) and further washed with 25% citric acid solution (2 x 10 mL), water (15 mL) and brine (15 mL). The organic layer was dried over Na2SO4 and concentrated. The crude mass was purified by flash chromatography (product eluted with 2 -3% MeOH in CHCl3) to afford 300 mg of the title compound.
Figure imgf000288_0002
Intermediate 478 : 2-methoxy-5- {2- \( 3-methoxy-5-methylphenyl)aminol -4- [5-methyl-3- ftrifluoromethyl)-l//-pyrazol-l-yllpyrimidin-5-yl}pyridine-3-carbohvdrazide
Figure imgf000288_0001
To a solution of 2-methoxy-5-{2-[(3-methoxy-5-methylphenyl)amino]-4-[5-methyl-3- (trifluoromethy^-lH-pyrazol-l-y^pyrimidin-S-yllpyridine-S-carboxylic acid (Example 761, 0.19 mmol, 100 mg) in DMSO (2 rnL) was added triethylamine (0.97 mmol, 98 mg) and stirred for 10 min. To this, 2-chloro-l-methyl-pyridinium iodide (0.23 mmol, 60 mg), 4- (dimethylamino)pyridine (0.038 mmol, 5 mg) and hydrazine hydrate (0.48 mmol, 24 mg,
0.023 mL) were added and stirred for 4 h at RT. The reaction mixture was diluted with DCM (25 mL) and further washed with 25% citric acid solution (2 x 15 mL), water (25 mL) and brine (25 mL). The organic layer was dried over Na2SO4 and concentrated. The crude mass was purified by flash chromatography (product eluted with 1-2% MeOH in CHCl3) to afford the title compound as 85 mg of white solid.
Figure imgf000289_0001
Examples
Example 1: 7V2-f3-chloro-4-fluorophenyl)-7V4-f3-fdimethylamino)propyl)-2'-methoxy-5.l5' bipyrimidine-2,4-diamine
Figure imgf000290_0001
A suspension of 5-bromo-N2-(3-chloro-4-fluoro-phenyl)-//-(3-dimethylamino-propyl)- pyrimidine-2,4-diamine (Intermediate 26, 160 mg, 0.40 mmol), 2-methoxy-5-pyrimidineboronic acid (92 mg, 0.60 mmol), tris(dibenzylideneacetone)dipalladium(0) (36.3 mg, 0.04 mmol), 2- dicyclohexylphosphino-2',4',6'-triiso-propyl-l,r-biphenyl (56.7 mg, 0.12 mmol) and sodium carbonate (42.0 mg, 0.40 mmol) in acetonitrile/water (4ml: ImI) was degassed with bubbling nitrogen for 10 min. and then heated to 90 0C. After 1 h LC-MS indicated complete reaction, and the reaction mixture was diluted with ethyl acetate (50 mL). The organic layer was separated, dried over sodium sulfate, filtered and concentrated. Flash chromatography (12g column, 0-6% MeOH/CH2Cl2 with 0.75% triethylamine) provided 125 mg of the desired product. MS: ES+ 432 for C20H23ClFN7O.
IH NMR (300 MHz, DMSO-D6) δ ppm 1.58 - 1.75 (m, 2 H) 2.02 (s, 6 H) 2.27 (t, J=6.59 Hz, 2 H) 3.34 - 3.44 (m, 2 H) 3.95 (s, 3 H) 7.23 - 7.37 (m, 2 H) 7.55 - 7.67 (m, 1 H) 7.74 - 7.80 (m, 1 H) 8.25 (dd, J=6.78, 2.64 Hz, 1 H) 8.56 (s, 2 H) 9.42 (s, 1 H).
The following examples were prepared using the general method described above for Example 1 using 5 -bromo-iV2-(3 -chloro-4-fluoro-phenyl)-N4-(3 -dimethylamino-propyl)-pyrimidine-2 ,4- diamine (Intermediate 26) and the starting material (SM) indicated.
Figure imgf000291_0001
Figure imgf000292_0001
Figure imgf000293_0001
Figure imgf000294_0001
Figure imgf000295_0001
Figure imgf000296_0001
Figure imgf000297_0001
Figure imgf000298_0001
Figure imgf000299_0001
Figure imgf000300_0001
Figure imgf000301_0001
Figure imgf000302_0001
Figure imgf000303_0001
The following examples were prepared using the general method described above for Example 1 using pyrimidin-5-ylboronic acid and the starting material (SM) indicated.
Figure imgf000303_0002
Figure imgf000304_0001
Figure imgf000306_0001
Figure imgf000307_0001
Figure imgf000308_0001
Figure imgf000309_0001
Figure imgf000310_0001
Figure imgf000311_0001
Figure imgf000312_0001
Figure imgf000313_0001
Figure imgf000314_0001
Figure imgf000315_0001
Figure imgf000316_0001
Figure imgf000317_0001
The following examples were prepared using the general method described above for Example 1 using (2-methoxypyrimidin-5-yl)boronic acid, tris(dibenzyledeneacetone)-dipalladium(0), 2- dicyclohexyl phosphino-2',4',6'-triiso-propyl-l,r-biphenyl, sodium carbonate and the starting material (SM) indicated.
Figure imgf000318_0002
Example 79: (Z)-5-(2-(3-chloro-4-fluorophenylamino)-4-(3- fdimethylamino)propylamino)pyrimidin-5-yl)-N'-hvdroxynicotinimidamide
Figure imgf000318_0001
A stirred mixture of 5-{2-(3-chloro-4-fluorophenylamino)-4-[3-(dimethylamino) propylamino]pyrimidin-5-yl}nicotinonitrile (Example 15, 350 mg, 0.82 mmol) and aqueous hydroxylamine 50 weight % (0.097 mL, 1.64 mmol) in dioxane (3 mL) was prepared under nitrogen and heated to 80 0C. After three hours, dioxane was removed under vacuum, and the residue was suspended in methanol. The mixture was cooled to near-zero while being stirred. The title compound was collected as a white solid (200 mg, 53 %). MS: ES+ 459 for C2iH24ClFN8O.
Example 80: 3-(5-(2-(3-chloro-4-fluorophenylamino)-4-(3- fdimethylamino)propylamino)pyrimidin-5-yl)pyridin-3-yl)-l.,2,4-oxa(iiazol-5f4H)-one
Figure imgf000319_0001
A stirred suspension of (Z)-5-(2-(3-chloro-4-fluorophenylamino)-4-(3-
(dimethylamino)propylamino)pyrimidin-5-yl)-N'-hydroxynicotinimidamide (Example 79, 100 mg, 0.22 mmol), triethylamine (0.045 mL, 0.33 mmol), and 1 , l'-carbonyldiimidazole (35 mg, 0.22 mmol) in dioxane (2 mL) were combined under nitrogen and heated to 80 degrees C. The suspension became a solution, and after 2 hours, the solvent was removed under vacuum. Reverse-phase chromatography (acetonitrile and water with ammonium acetate additive) was used to isolate the title compound (25 mg, 98%). MS: ES+ 485 for C22H22ClFN8O2.
1H NMR (300 MHz, DMSO-J6) δ ppm 1.86 - 1.99 (m, 2 H) 2.72 (s, 6 H) 2.98 - 3.09 (m, 2 H) 3.39 - 3.51 (m, 2 H) 7.06 (t, J=5.46 Hz, 1 H) 7.33 (t, J=9.14 Hz, 1 H) 7.56 - 7.70 (m, 1 H) 7.90 (s, 1 H) 8.13 (s, 1 H) 8.21 (dd, J=6.88, 2.54 Hz, 1 H) 8.60 (s, 1 H) 8.92 (s, 1 H) 9.50 (s, 1 H). Example 81: Sodium 3-(5-(2-(3-chloro-4-fluorophenylamino)-4-(3- (^imethylamino)propylamino)pyrimidin-5-yl)pyridin-3-yl)-5-oxo-l,2,4-oxadiazol-4-ide
Figure imgf000320_0001
3 -(5 -(2-(3 -Chloro-4-fluorophenylamino)-4-(3 -(dimethylamino)propylamino)pyrimidin-5 - yl)pyridin-3-yl)-l,2,4-oxadiazol-5(4H)-one (Example 80, 21 mg, 0.04 mmol) was dissolved in dioxane with stirring. 0.1 N NaOH (0.4 rnL, 0.04 mmol) was added to the stirred solution. After another 20 minutes of stirring the solvent was removed under vacuum. The residue was placed under high vacuum overnight and characterized (21 mg, 91%). MS: ES+ 485 for C22H22ClFN8O2 (free acid detected by LCMS).
1H NMR (300 MHz, DMSO-J6) δ ppm 0.70 - 0.86 (m, 2 H) 1.12 - 1.26 (m, 2 H) 1.59 - 1.74 (m, 2 H) 2.06 (br. s., 6 H) 7.17 - 7.34 (m, 2 H) 7.53 - 7.64 (m, 1 H) 7.77 (s, 1 H) 7.98 (t, J=I.88 Hz, 1 H) 8.18 (dd, 1 H) 8.47 (d, J=2.07 Hz, 1 H) 8.84 (d, J=I.70 Hz, 1 H) 9.39 (s, 1 H).
Example 82: 7V-(3-chloro-4-fluorophenyl)-4-(3,5-dimethyl-lH-pyrazol-l-yl)-5,5'- bipyrimidin-2-amine
Figure imgf000321_0001
A solution of 3,5-dimethyl-lH-pyrazole (555 mg, 5.78 mmol, 2.2 eq) in DMF (2 mL) was added slowly to a suspension of sodium hydride (60%, 220 mg, 5.52 mmol, 2.1 eq) in DMF (1 mL) at 0 0C. The reaction mixture was stirred for 25 min at room temperature. A solution of N-(3-chloro- 4-fluorophenyl)-4-methylsulfonyl-5-pyrimidin-5-ylpyrimidin-2-amine (Intermediate 123, 1.0 g, 2.63 mmol, 1 eq) in DMF (1 mL) was added slowly to the reaction mixture, and the mixture was stirred for 1 h. Water was added to the reaction mixture (~6 mL) and the solid formed was filtered and dried to provide the title compound (750 mg). MS(ES): 396 (M+l) for Ci9Hi5ClFN7.
1H NMR 400 MHz, CDCl3 : δ 2.04 (s, 3H), 2.43 (s, 3H), 5.98 (s, IH), 7.13 (t, J= 8.72 Hz, IH), 7.34-7.37 (m, IH), 7.53 (br s, IH), 7.86 (dd, J= 2.52, 6.40 Hz, IH), 8.45 (br s, 2H), 8.53 (s, IH), 9.14 (br s, IH). The following examples were prepared using the general method described above for Example 82 using Intermediate 123, sodium hydride and the starting material (SM) indicated.
Figure imgf000322_0001
Figure imgf000323_0001
Figure imgf000324_0001
The following examples were prepared using the general method described above for Example 1 using 3-(ethoxycarbonyl)pyridine-5-boronic acid pinacol ester, tris(dibenzyledeneacetone)- dipalladium(O), 2-dicyclohexyl phosphino-2',4',6'-triiso-propyl-l,l '-biphenyl, sodium carbonate and the starting material (SM) indicated.
Figure imgf000324_0002
Figure imgf000325_0001
Figure imgf000326_0001
Figure imgf000327_0001
Figure imgf000328_0001
Figure imgf000329_0001
Figure imgf000330_0001
Figure imgf000331_0001
Figure imgf000332_0001
Figure imgf000333_0001
Figure imgf000334_0001
Figure imgf000335_0001
Figure imgf000336_0001
Figure imgf000337_0001
Figure imgf000338_0001
Figure imgf000339_0001
Figure imgf000340_0001
Figure imgf000341_0001
Figure imgf000342_0001
Figure imgf000343_0001
Figure imgf000344_0001
Figure imgf000345_0001
Figure imgf000346_0001
Figure imgf000347_0001
Figure imgf000348_0001
Example 154: Ethyl 5-(2-r(3-chloro-4-fluorophenyl)aminol-4-{r2-αH-imidazol-4- yl)ethyllamino}pyrimidin-5-yl)pyridine-3-carboxylate
Figure imgf000349_0001
Ethyl 5 - {2- [(3 -chloro-4-fluorophenyl)amino] -4-(methylsulfonyl)pyrimidin-5 -yl} pyridine-3 - carboxylate (Intermediate 124, 200 mg, 0.44 mmol) was suspended in NMP (1 mL), treated with N,N-diisopropylethylamine (1 eq) and the 2-(lH-imidazol-4-yl)ethanamine (49 mg, 0.44 mmol). The mixture was heated at 90 0C for 30 min in a sealed tube. The reaction mixture was added to water and stirred for 15 min. The precipitated solid was filtered, washed with water and dried to afford the crude product. It was further purified by flash chromatography (chlorofornrmethanol (9:1)) to provide the title compound (100 mg). MS (ES) 482 (M+l) for C23H2IClFN7O2.
1H NMR 300 MHz, DMSO-d6: δ 1.34 (t, J= 6.96 Hz, 3H), 3.16 (br s, 2H), 3.58 (br s, 2H), 4.36 (q, J= 7.68 Hz, 2H), 6.82 (s, IH), 7.09 (br s, IH), 7.29 (t, J= 7.95 Hz, IH), 7.51 (s, IH), 7.7 (br s, IH), 7.86 (s, IH), 8.16 (br s, IH), 8.21 (s, IH), 8.76 (s, IH), 9.04 (s, IH), 9.47 (s, IH), 11.8 (br s, IH).
The following examples were prepared using the general method described above for Example 154 using ethyl 5-{2-[(3-chloro-4-fluorophenyl)amino]-4-(methylsulfonyl)pyrimidin-5- yl}pyridine-3-carboxylate Intermediate 124, N,N-diisopropylethylamine and the starting material (SM) indicated.
Figure imgf000350_0001
Figure imgf000351_0002
Example 158: ethyl q^-3-(3-{2-r(3-chloro-4-fluorophenyl)aminol-4-(3,5-dimethyl-lH- Pyrazol-l-yl)pyrimidin-5-yl}phenyl)prop-2-enoate
Figure imgf000351_0001
A suspension of 5-bromo-Λ/-(3-chloro-4-fluorophenyl)-4-(3,5-dimethyl-l/-f-pyrazol-l- yl)pyrimidin-2-amine (Intermediate 112, 1 eq, 3.5 mmol), {3-[(liT)-3-ethoxy-3-oxoprop-l-en-l- yl]phenyl}boronic acid (1.1 eq, 3.95 mmol), [1,1 '-bis (diphenylphosphino) ferrocene] dichloropalladium(II) complex with CH2Cl2 (10 mol %) and sodium carbonate (1 eq, 3.5 mmol) in acetonitrile/water (20 mL : 5 mL) was degassed and heated to 90 0C for 15-20 min in an oil bath under inert atmosphere. Completion of the reaction was monitored by TLC. The solvent was removed under vacuum and the crude mixture was taken up in CHCI3 (30 mL). It was then washed with water, brine, dried over sodium sulfate, filtered and concentrated. The crude material was purified by silica gel column chromatography using chloroform-methanol as an eluent to provide the title compound (620 mg, 63%). MS(ES): 492 (M+l) for C26H23ClFN5O2.
1H NMR 400 MHz, DMSO-d6 : δ 1.25 (dt, J= 1.28, 7.06 Hz, 3H), 2.02 (s, 3H), 2.13 (s, 3H), 4.18 (dq, J= 1.12, 7.14 Hz, 2H), 6.03 (s, IH), 6.54 (dd, J= 1.24, 16.02 Hz, IH), 7.01 (d, J= 7.24 Hz, IH), 7.34 (t, J= 7.76 Hz, IH), 7.37-7.42 (m, 2H), 7.56-7.60 (m, 2H), 7.63-7.67 (m, IH), 8.10 (d, J= 6.76 Hz, IH), 8.87 (d, J= 1.36 Hz, IH), 10.30 (s, IH).
The following examples were prepared following the general procedure described above for Example 158 using {3-[(lE)-3-ethoxy-3-oxoprop-l-en-l-yl]phenyl}boronic acid, [1,1 '-bis (diphenylphosphino) ferrocene] dichloropalladium(II), sodium carbonate and the starting material (SM) listed.
Figure imgf000352_0001
Figure imgf000353_0001
Figure imgf000354_0001
Figure imgf000355_0001
Figure imgf000356_0001
Figure imgf000357_0001
Figure imgf000358_0001
The following examples were prepared using the general method described above for Example 1 using tris(dibenzyledeneacetone)-dipalladium(0), 2-dicyclohexyl phosphino-2',4',6'-triiso- propyl-1,1 '-biphenyl, sodium carbonate and the starting materials (SM) indicated.
Figure imgf000358_0002
Figure imgf000359_0001
Figure imgf000360_0001
Figure imgf000361_0001
Figure imgf000362_0002
Example 183: Ethyl (2Jg)-3-r3-(2-r(3-chloro-4-fluorophenyl)aminol-4-{r2-αH-imidazol-4- vDethyll amino}pyrimidin-5-yl)phenyll prop-2-enoate
Figure imgf000362_0001
A solution of 2-(lH-imidazol-4-yl)ethanamine (46 mg, 0.4 mmol) in THF (1 mL) was added slowly by syringe to a stirred suspension of sodium hydride (60%, 16 mg, 0.4 mmol) in THF (1 ml) at 0 0C. After 30 min, ethyl (2£)-3-(3-{2-[(3-chloro-4-fluorophenyl)amino]-4- (methylsulfonyl)pyrimidin-5-yl}phenyl)prop-2-enoate (Intermediate 125, 200 mg, 0.4 mmol) in THF (2 mL) was added slowly by syringe to the stirred mixture while maintaining the temperature at 0 0C. The mixture was stirred under nitrogen for 2 h and poured into ice-water, extracted with ethyl acetate (3 x 50 rnL). The ethyl acetate layer was then washed with brine, dried over Na2SO4, filtered and concentrated. The crude product was purified by column chromatography using 1% MeOH in CHCI3 to yield the title compound (150 mg). MS(ES): 506 (M+l) for C26H24ClFN6O2.
1H NMR 400 MHz, DMSO-d6: δ 1.26 (t, J= 7.08 Hz, 3H), 2.81-2.85 (m, 2H), 3.62-3.94 (m, 2H), 4.20 (q, J= 7.12 Hz, 2H), 6.68 (d, J= 16.08 Hz, IH), 6.84 (br s, IH), 6.93 (s, IH), 7.26 (t, J = 9.12 Hz, IH), 7.38 (d, J= 7.92 Hz, IH), 7.48 (t, J= 7.64 Hz, IH), 7.66-7.76 (m, 4H), 7.84 (s, IH), 8.17 (dd, J= 2.64, 6.82 Hz, IH), 9.41 (s, IH), 12.50 (br s, IH).
The following examples were prepared using the general method described above for Example 183 using ethyl (2E)-3-(3-{2-[(3-chloro-4-fluorophenyl)amino]-4-(methylsulfonyl)pyrimidin-5- yl}phenyl)prop-2-enoate Intermediate 125, sodium hydride and the starting material (SM) indicated.
Figure imgf000363_0001
Figure imgf000364_0001
Figure imgf000365_0001
Figure imgf000366_0001
Figure imgf000367_0001
Figure imgf000368_0001
The following examples were prepared using the general method described above for Example 1 using {3-[(lE)-3-ethoxy-3-oxoprop-l-en-l-yl]phenyl}boronic acid, tris(dibenzylideneacetone)dipalladium(0), 2-dicyclohexylphosphino-2',4',6'-triisopropyl- 1,1'- biphenyl, sodium carbonate and the starting material (SM) indicated.
Figure imgf000368_0002
Figure imgf000369_0001
Figure imgf000370_0001
Figure imgf000371_0002
Example 203: Ethyl 5-{2-[f3-chloro-4-fluorophenyl)aminol-4-[4-fpyridin-4-yl)-lH-pyrazol- l-yllPyrimidin-5-yl}pyridine-3-carboxylate
Figure imgf000371_0001
A solution of 4-(lH-pyrazol-4-yl)-pyridine (838 mg, 5.78 mmol) in DMF (2 rnL) was added slowly to a suspension of sodium hydride (60%, 220 mg, 5.52 mmol) in DMF (2 mL). The reaction mixture was stirred for 25 min at room temperature. A solution of ethyl 5-{2-[(3-chloro- 4-fluorophenyl)amino]-4-(methylsulfonyl)pyrimidin-5-yl}pyridine-3-carboxylate (Intermediate 124, 1.18 g, 2.63 mmol) in DMF (1 mL) was added slowly to the reaction mixture and the mixture was stirred for 1 h. Water was added (~6 mL), and the solid formed was filtered, dried to yield the title compound (900 mg). MS(ES): 516 (M+l) for C26Hi9ClFN7O2. 1H NMR (400 MHz, DMSO-d6): δ 1.30 (t, J= 7.20 Hz, 3H), 4.34 (q, J= 7.20 Hz, 2H), 7.46 (t, J = 8.80 Hz, IH), 7.70-7.76 (m, 3H), 8.14-8.16 (m, 2H), 8.27 (s, IH), 8.59 (s, 2H), 8.71 (s, IH), 8.76 (s, IH), 9.03 (s, IH), 9.09 (s, IH), 10.41 (s, IH).
The following examples were prepared using the general method described above for Example 203 using ethyl 5-{2-[(3-chloro-4-fluorophenyl)amino]-4-(methylsulfonyl)pyrimidin-5- yl}pyridine-3-carboxylate (Intermediate 124), sodium hydride and the starting material (SM) indicated.
Figure imgf000372_0001
Figure imgf000373_0001
Figure imgf000374_0001
Example 210: ethyl 5-[4-flH-benzimidazol-2-ylmethylamino)-2-[f3-chloro-4- fluor ophenvDaminol pyrimidin-5-yll pyridine-3-carboxylate hydrochloride
Figure imgf000375_0001
To a stirred solution of tert-butyl 2-[[[2-[(3-chloro-4-fluorophenyl)amino]-5-(5- ethoxycarbonylpyridin-3 -yl)pyrimidin-4-yl] amino]methyl]benzimidazole- 1 -carboxylate
(Example 114, 500mg, 0.81mmol) in 1,4- dioxane (10 mL) under nitrogen atmosphere was added 4N hydrochloric acid in 1,4-dioxane (1OmL) dropwise. The reaction mixture was stirred at room temperature for 24 h, then concentrated to give ethyl 5-[4-(lH-benzimidazol-2- ylmethylamino)-2- [(3 -chloro-4-fluorophenyl)amino]pyrimidin-5 -yl]pyridine-3 -carboxylate hydrochloride as a white solid in 37 % yield (150 mg, 0.29 mmol). MS(ES):518.2 (M+l) for C26H2IClFN7O2.
1H NMR (400 MHz) DMSO-d6: δ 1.35 (t, J= 7.08 Hz, 3H), 4.40 (q, J= 2.88 Hz, 2H), 4.98 (d, J = 5.16 Hz, 2H), 7.12 (t, J= 0.00 Hz, IH), 7.45 (br IH), 7.52 (dd, J= 6.12, 3.20 Hz, IH), 7.60 (s 7.77 (dd, J= 6.16, 3.12 Hz, 2H), 8.09 (s, IH), 8.49 (t, J= 2.08 Hz, IH), 9.03 (d, J= 2.20 Hz, IH), 9.13 (d, J= 2.00 Hz, IH), 10.00 (br s, IH).
The following examples were prepared by the general method described above for Example 210 using 4N hydrochloric acid in dioxane and the starting material (SM) indicated.
Figure imgf000376_0002
Example 212: Methyl 2-(2-(3-chloro-4-fluorophenylamino)-4-(3- methoxypropylamino)pyrimidin-5-yl)thiazole-4-carboxylate
Figure imgf000376_0001
A stirred suspension of 2-(3-chloro-4-fluorophenylamino)-4-(3-methoxy propylamino)pyrimidine-5-carbothioamide (Intermediate 128, 171 mg, 0.46 mmol) and methyl 3-bromo-2-oxopropanoate (84 mg, 0.46 mmol) in ethanol (2 mL) was purged with a stream of nitrogen and then placed under an atmosphere of nitrogen. This was heated to 80 degrees C for several days, with ethanol replaced as necessary. The reaction mixture was allowed to cool to room temperature. The mixture was diluted with dimethylsulfoxide (5 mL). The title compound was isolated (80 mg, 38%) via reverse-phase chromatography (acetonitrile/water/ammonium acetate). MS: ES+ 452 for Ci9Hi9ClFN5O3S. 1H NMR (300 MHz, DMSO-J6) δ ppm 1.89 (quin, J=6.45 Hz, 2 H) 3.27 (s, 3 H) 3.51 (t, J=6.12 Hz, 2 H) 3.63 (q, J=6.40 Hz, 2 H) 3.87 (s, 3 H) 7.33 (t, J=9.04 Hz, 1 H) 7.57 - 7.71 (m, 1 H) 8.24 (dd, J=6.88, 2.35 Hz, 1 H) 8.45 (s, 1 H) 8.60 (s, 1 H) 9.37 (t, J=5.09 Hz, 1 H) 9.88 (s, 1 H).
Example 213: 4-fazepan-l-yl)-N-(3-chloro-4-fluorophenyl)-5-pyrimidin-5-ylpyrimidin-2- amine
Figure imgf000377_0001
N-(3 -Chloro-4-fluorophenyl)-4-methylsulfonyl-5 -pyrimidin-5 -ylpyrimidin-2-amine (Intermediate 123, 0.21 mmol, 80 mg) was suspended in NMP (1 niL), then treated with N ,N- diisopropylethylamine (0.25 mmol , 32 mg) and hexamethyleneimine (2.63 mmol). The mixture was heated at 90 0C for 30 min in a sealed tube. The reaction mixture was added to water and stirred for 15 min. The precipitated solid was filtered, washed with water and dried to afford the crude product which was further purified by flash chromatography to yield 18 mg of the title compound (0.045 mmol, 21%). MS(ES):399 (M+ 1) for C20H20ClFN6.
1H NMR 400 MHz DMSO-J6 : δ 1.41 (br s, 4H), 1.62 (br s, 4H), 3.31 (br s, 4H), 7.32 (t, J= 9.12 Hz, IH), 7.56 (ddd, J= 9.00, 4.06, 2.76 Hz, IH), 7.93 (s, IH), 8.26 (dd, J= 6.90, 2.52 Hz, IH), 8.80 (s, 2H), 9.10 (s, IH), 9.57 (s, IH). Example 214: 5-(2-(3-chloro-4-fluorophenylamino)-4-(3- fdimethylamino)propylamino)pyrimidin-5-yl)nicotinic acid
Figure imgf000378_0001
A solution of ethyl 5 -(2-(3 -chloro-4-fluorophenylamino)-4-(3 -(dimethylamino) propylamino)pyrimidin-5-yl) nicotinate (Example 5, 50 mg, 0.09 mmol) in methanol (0.3 ml) was stirred under ambient conditions; if solubility was less than complete to the naked eye then small volumes of THF were added as necessary. Sodium hydroxide (aqueous, 1 N, 0.341 ml) was added to the solution, which was stirred under ambient conditions until high or complete conversion was indicated by LCMS or TLC. Careful acidification with 1 N HCl (aq) was followed by an aqueous workup, using methylene chloride and methanol (9:1) as the organic phase to extract the water layer (4 x 25 ml). The organic extracts were combined, dried over sodium sulfate, and concentrated, affording product of high purity (15 mg) which was characterized by LCMS and 1H NMR. MS: ES+ 445 for C2iH22ClFN6O2
1U NMR (300 MHz, DMSO-D6) δ ppm 1.85 - 2.01 (m, 2 H) 2.60 (s, 6 H) 2.93 (t, J=7.06 Hz, 2 H) 3.36 - 3.52 (m, 2 H) 7.14 (t, J=5.18 Hz, 1 H) 7.32 (t, J=9.14 Hz, 1 H) 7.58 - 7.67 (m, 1 H) 7.85 (s, 1 H) 8.17 (t, J=2.07 Hz, 1 H) 8.21 (dd, J=6.97, 2.64 Hz, 1 H) 8.69 (d, J=2.07 Hz, 1 H) 8.88 (d, J=I.51 Hz, 1 H) 9.50 (s, 1 H)
The following examples were prepared using the general method described above for Example 214 using IN sodium hydroxide and the starting material (SM) indicated.
Figure imgf000379_0001
Figure imgf000380_0001
Figure imgf000381_0001
Figure imgf000382_0001
Figure imgf000383_0001
Figure imgf000384_0001
Figure imgf000385_0001
Figure imgf000386_0001
Figure imgf000387_0001
Figure imgf000388_0001
Figure imgf000389_0001
Figure imgf000390_0001
Figure imgf000391_0001
Figure imgf000392_0001
Figure imgf000393_0001
Figure imgf000394_0001
Figure imgf000395_0001
Figure imgf000396_0001
Figure imgf000397_0001
Figure imgf000398_0001
Figure imgf000399_0001
Figure imgf000400_0001
Figure imgf000401_0001
Figure imgf000402_0001
Figure imgf000403_0001
Figure imgf000404_0001
Figure imgf000405_0001
Figure imgf000406_0001
Figure imgf000407_0001
Figure imgf000408_0001
Figure imgf000409_0001
Figure imgf000410_0001
Figure imgf000411_0001
Figure imgf000412_0001
The following examples were prepared using the general method described above for Example 214 using IN sodium hydroxide (1-2 equivalents), dioxane or THF as solvent and the starting material (SM) indicated.
Figure imgf000413_0001
Figure imgf000414_0001
Figure imgf000415_0002
Example 316: 5-{2-r(3-chloro-4-fluorophenyl)aminol-4-(3,5-dimethyl-lH-pyrazol-l- yl)pyrimidin-5-yl}pyridine-3-carboxylic acid
Figure imgf000415_0001
Ethyl 5-{2-[(3-chloro-4-fluorophenyl)amino]-4-(3,5-dimethyl-l/-f-pyrazol-l-yl)pyrimidin-5- yl}pyridine-3-carboxylate (Example 133, 100 mg, 0.22 mmol) was dissolved in tetrahydrofuran (1 ml) and treated with a suspension of aqueous barium hydroxide (35 mg, 0.88 mmol) in water (1 ml). The mixture was allowed to stir at room temperature for 4 h. After completion of the reaction, the mixture was then carefully acidified with 1 N HCl and the precipitate that formed was filtered, washed with water, and dried to yield the title compound (65 mg).
MS(ES): 439 (M+l) for C2IHi6ClFN6O2.
1H NMR (400 MHz, DMSO-d6) δ 1.92 (s, 3H), 2.36 (s, 3H), 6.07 (s, IH), 7.41 (t, J= 9.08 Hz,
IH), 7.62-7.67 (m, IH), 7.88 (t, J= 2.12 Hz, IH), 8.09 (dd, J= 2.48, 6.74 Hz, IH), 8.37 (d, J =
1.80 Hz, IH), 8.83 (s, IH), 8.91 (d, J= 1.88 Hz, IH), 10.28 (s, IH).
The following examples were prepared using the general method described above for Example 316 using barium hydroxide (2-4 equivalents), dioxane or THF and the starting material (SM) indicated.
Figure imgf000416_0001
Figure imgf000417_0001
Figure imgf000418_0001
Figure imgf000419_0001
Example 327: S-^-r^-chloro^-fluorophenvDaminoM-^S-dichloro-lH-imidazol-l- yl)pyrimidin-5-yl}pyridine-3-carboxylic acid
Figure imgf000420_0001
To a solution of ethyl 5-{2-[(3-chloro-4-fluorophenyl)amino]-4-(4,5-dichloro-lH-imidazol-l- yl)pyrimidin-5-yl}pyridine-3-carboxylate Example 133 (289 mg, 0.57 mmol) in 1,2- dichloroethane, was added trimethyltin hydroxide (10 eq, 5.7 mmol) and the mixture was heated to 80-85 0C until TLC analysis indicated a complete reaction. After completion of the reaction, the mixture was concentrated in vacuum and the residue was taken up in ethyl acetate (~15 mL).
The organic layer was washed with 5 % HCl, brine and dried over anhydrous Na2SO4. Removal of the solvent afforded the crude carboxylic acid. The crude compound was purified by RP- ΗPLC (Kromosil Cl 8 column) to provide (150 mg) of pure 5-{2-[(3-chloro-4- fluorophenyl)amino] -4-(4 ,5 -dichloro- lH-imidazol- 1 -yl)pyrimidin-5 -yl} pyridine-3 -carboxylic acid.
MS(ES): 479 (M+l) for Ci9HiOCl3FN6O2.
1H NMR (400 MHz, DMSO-d6): δ 7.42 (t, J= 9.12 Hz, IH), 7.69 (ddd, J= 2.76, 4.04, 9.05 Hz, IH), 7.97 (br s, IH), 8.05 (ddd, J= 1.92, 6.48 Hz, IH), 8.12 (br s, IH), 8.60 (br s, IH), 9.01 (br s,
IH), 9.04 (s, IH), 10.62 (s, IH), 13.59 (br s, IH).
The following examples were prepared using the general method described above for (Example 327) using trimethyltin hydroxide and the starting material (SM) indicated.
Figure imgf000421_0001
Figure imgf000422_0001
Figure imgf000423_0001
The following examples were prepared using the general method described for Example 1 using the starting materials (SM) indicated.
Figure imgf000424_0001
Figure imgf000425_0001
Figure imgf000426_0001
Figure imgf000427_0001
Figure imgf000428_0001
Figure imgf000429_0001
Figure imgf000430_0001
Figure imgf000431_0001
Figure imgf000432_0001
Figure imgf000433_0001
Figure imgf000434_0001
Example 360: 3-(2-(3-chloro-4-fluorophenylamino)-4-(3- fdimethylamino)propylamino)pyrimidin-5-yl)-N-methoxybenzamide
Figure imgf000435_0001
To a stirred solution of 3-(2-[(3-chloro-4-fluorophenyl)amino]-4-{[3- (dimethylamino)propyl]amino}pyrimidin-5-yl)benzoic acid (Example 31, 52 mg, 0.12 mmol) and triethylamine (0.057 ml, 0.4 mmol) in DMF (1.5 ml) under ambient conditions was added O- (7-azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU; 44 mg, 0.12 mmol) as a solid. The mixture was stirred for 10 minutes; to it was then added methoxylamine hydrochloride (8 mg, 0.12 mmol) as a solid. The mixture was stirred until complete conversion was seen by LCMS. The reaction mixture was diluted with 1-3 mL water while stirring continued; a light pink precipitate formed. Stirring continued for several minutes, and the vessel was then transferred to an ice bath for 10 minutes. 3-(2-(3-Chloro-4- fluorophenylamino)-4-(3-(dimethylamino)propylamino)pyrimidin-5-yl)-N-methoxybenzamide was collected (22 mg) and characterized by LCMS and H NMR. MS : ES+ 473 for C23H26ClFN6O2
1H NMR (300 MHz, DMSO-D6) δ ppm 1.84 - 2.01 (m, 2 H) 2.76 (d, J=4.71 Hz, 6 H) 2.97 - 3.12 (m, 2 H) 3.35 - 3.49 (m, 2 H) 3.72 (s, 3 H) 7.42 (t, J=9.04 Hz, 1 H) 7.50 - 7.64 (m, 4 H) 7.76 - 7.84 (m, 2 H) 7.89 (s, 1 H) 8.07 (dd, J=6.78, 2.64 Hz, 1 H) 9.50 (s, 1 H) 10.22 (s, 1 H) 11.84 (s, 1
H)
The following examples were prepared using the general HATU coupling method described above for Example 360 using the starting materials (SM) indicated.
Figure imgf000436_0001
Figure imgf000437_0001
Figure imgf000438_0001
Figure imgf000439_0001
Figure imgf000440_0001
Figure imgf000441_0001
Figure imgf000442_0002
Example 377: N-(3-d-(3-chloro-4-fluorophenylamino)-5,5'-bipyrimidin-4- ylamino)propyl)acetamide
Figure imgf000442_0001
A solution of acetic anhydride (0.012 ml, 0.13 mmol) was added to N'-(3-aminopropyl)-N-(3- chloro-4-fluorophenyl)-5-pyrimidin-5-ylpyrimidine-2,4-diamine hydrochloride (Example 211, 53 mg, 0.13 mmol), triethylamine (0.054ml, 0.39 mmol) and methylene chloride (1.5 ml) under nitrogen. The resultant mixture was stirred for Ih, then concentrated under vacuum. The residue was chromatographed using 1-10% methanol/methylene chloride to yield the title compound (38 mg).
MS(ES): 416 (M+l) for Ci9Hi9ClFN7O
1H NMR (300 MHz, DMSO- dβ) δ ppm 1.53 - 1.73 (m, 2 H) 1.75 (s, 3 H) 3.05 (q, J=6.03 Hz, 2 H)
3.21 - 3.49 (m, 2 H) 7.41 (t, J=9.04 Hz, 1 H) 7.49 - 7.66 (m, 1 H) 7.68 - 7.98 (m, 3 H) 8.06 (dd,
J=6.78, 2.64 Hz, 1 H) 8.83 (s, 2 H) 9.23 (s, 1 H) 10.05 (s, 1 H).
The following examples were prepared by the general method described above for Example 377 using the starting materials (SM) indicated.
Figure imgf000443_0001
General procedure for the coupling of anilines to Intermediate 137
Figure imgf000444_0001
Intermediate 137 (1 eq) was suspended in a suitable solvent (e.g. acetonitrile, dioxane, or ethanol) (20 vol) and treated with the corresponding aniline (1 eq). The reaction was then treated with 4 N HCl (5 vol) in dioxane and refluxed under nitrogen. The reaction was monitored by TLC and then cooled to room temperature, diluted with diethyl ether and the solid was filtered and dried to afford the product. The compounds in the below table were prepared using this method with the specified starting material and solvent.
Figure imgf000444_0002
Figure imgf000445_0001
Example 385: 5-[2-(3,5-Difluoro-phenylamino)-4-morpholin-4-yl-pyrimidin-5-yl1-nicotinic acid ethyl ester
Figure imgf000446_0001
A suspension of Intermediate 140 (1.3 mmol, 0.5 g), 3-(ethoxycarbonyl)pyridine-5- boronic acid pinacolester (1.4 mmol, 0.4 g), tris(dibenzyledeneacetone)dipalladium(0) (0.4 mmol, 0.19 g), 2-dicyclohexylphosphino-2',4',6'-triisopropyl-l,l'-biphenyl (0.13 mmol, 0.12 g) and sodium carbonate (1.3mmol, 0.146 g) in acetonitrile/water (10 mL:3 mL) was heated to 90 0C for 30 minutes. The reaction mixture was diluted with ethyl acetate (50 mL) and the organic layer was separated, dried over sodium sulfate, filtered and concentrated. The crude compound was purified by silica gel column chromatography using chloroform: methanol (9:1) as an eluent to yield Example 385 (0.2 g). MS(ES): 442.2 (M+l) for C22H2IF2N5O3. 1H-NMR (400 MHz, DMSOd6): δ 1.35 (q, / = 7.08 Hz, 3H), 3.23 (d, / = 3.76 Hz, 4H), 3.57 (d, / = 3.64 Hz, 4H), 4.37 (q, J = IAl Hz, 2H), 6.74 (t, / = 2.24 Hz, IH), 7.54 (d, / = 10.12 Hz, 2H), 8.22 (d, / = 2.84 Hz, IH), 8.40 (t, J = 1.96 Hz, IH), 8.94 (d, / = 2.04 Hz, IH), 9.01 (d, / = 1.80 Hz, IH), 9.95 (s, IH).
Example 386: 5-[2-(3,5-Dimethyl-phenylamino)-4-morpholin-4-yl-pyrimidin-5-yl1-nicotinic acid ethyl ester
Figure imgf000446_0002
A suspension of Intermediate 144 (1.3 mmol, 0.5 g), 3-(ethoxycarbonyl)pyridine-5- boronic acid ester (1.4 mmol, 0.4 g), tris(dibenzyledeneacetone)dipalladium(0) (0.4 mmol, 0.19 g), 2-dicyclohexylphosphino-2',4',6'-triisopropyl-l,l'-biphenyl (0.13 mmol, 0.12 g) and sodium carbonate (1.3mmol, 0.146 g) in acetonitrile/water (20 mL:5 mL) was heated to 9O0C for 30 minutes. The reaction mixture was diluted with ethyl acetate (50 mL) and the organic layer was separated, dried over sodium sulfate, filtered and concentrated. The crude compound was purified by silica gel column chromatography using chloroform: methanol (9:1) as an eluent to yield
Example 386 (0.46 mmol, 0.2 g, 33%).
MS(ES): 433 (M) for C24H27N5O3.
1H-NMR (400 MHz, DMSO-d6): δ 1.34 (t, /= 7.08 Hz, 3H), 2.22 (s, 6H), 3.21 (t, /= 4.48 Hz,
4H), 3.56 (t, / = 4.16 Hz, 4H), 4.37 (q, / = 7.08 Hz, 2H), 6.58 (s, IH), 7.40 (s, 2H), 8.15 (s, IH),
8.38 (t, /= 2.12 Hz, IH), 8.93 (d, /= 2.2 Hz, IH), 8.98 (d, /= 1.96 Hz, IH), 9.39 (s, IH).
General procedure for the synthesis of 5-(4-Morpholin-4-yl-2-arylamino-pyrimidin-5-yl)- nicotinic acids from the corresponding esters.
Figure imgf000447_0001
To a solution of carboxylic acid ester derivative (0.46 mmol) in tetrahydrofuran (5 mL) and water (5 mL), 1 N aq. sodium hydroxide (1.84 mmol, 1.84 ml) was added. The reaction was allowed to stir at room temperature for 2 h. After completion of reaction, the reaction mixture was carefully acidified with 1 N HCl and the solid that precipitated was filtered, washed with water and dried under vacuo to yield the desired 5-(4-Morpholin-4-yl-2-arylamino-pyrimidin-5- yl)-nicotinic acid. The compounds in the below table were prepared using this procedure and the specified starting material.
Figure imgf000447_0002
Figure imgf000448_0001
Figure imgf000449_0002
General procedure for the coupling of anilines to Intermediate 145: {(E)-3-[3-(4-Morpholin- 4-yl-2-arylamino-pyrimidin-5-yl)-phenyl1-acrylic acid ethyl ester}
Figure imgf000449_0001
Intermediate 145 (1 eq) was suspended in acetonitrile/ethanol and treated with corresponding aniline (1 eq). The reaction was then treated with 4 N HCl (3 vol) in dioxane and refluxed under nitrogen for 5 hours. The mixture was cooled to room temperature, diluted with diethyl ether and the solid was filtered and dried to afford the product. The compounds in the below table were prepared using this procedure and the specified starting material and solvent.
Figure imgf000450_0001
Figure imgf000451_0001
Example 401 (E)-3-{3-[2-(3,5-Difluoro-phenylamino)-4-morpholin-4-yl-pyrimidin-5-yl1- phenyll-acrylic acid ethyl ester
Example 402 (E)-3-{3-[2-(3,5-Dimethyl-phenylamino)-4-morpholin-4-yl-pyrimidin-5-yl1- phenyll-acrylic acid ethyl ester
Figure imgf000452_0001
A suspension of the 5-bromopyrimidine derivative (1 eq), ethyl-3-borono cinnamate (1.1 eq), tris(dibenzyledeneacetone)dipalladium(0) (30 mol%), 2-dicyclohexylphosphino-2',4',6'- triisopropyl-l,l'-biphenyl (10 mol%) and sodium carbonate (1 eq) in acetonitrile/water (20:5 vol) was heated to 9O0C for 30 minutes. The reaction mixture was diluted with ethyl acetate (30 vol) and the organic layer was separated, dried over sodium sulfate, filtered and concentrated. The crude compound was purified by silica gel column chromatography using petroleum ether: EtOAc (7:3) as an eluent to yield the product. The compounds in the below table were prepared using this method and the specified starting material.
Figure imgf000452_0002
General procedure for the synthesis of (E)-3-[3-(4-Morpholin-4-yl-2-arylamino-pyrimidin- 5-yl)-phenyl1-acrylic acid
Figure imgf000453_0001
Ester compound (0.43 mmol, 0.2 g) was dissolved in tetrahydrofuran (5 rnL), treated with 1 N aq. sodium hydroxide or Barium hydroxide (1.72 mmol) and was heated at 60 0C for 24 h. The reaction mixture was then carefully acidified with 1 N HCl and the solid that precipitated was filtered, washed with water and dried under vacuo to yield the product. The compounds in the below table were prepared using this procedure and the starting material and base specified.
Figure imgf000453_0002
Figure imgf000454_0001
Figure imgf000455_0002
Example 411: 5-[2-(4-Fluoro-3-nitro-phenylamino)-4-morpholin-4-yl-pyrimidin-5-yl1- nicotinic acid ethyl ester
Figure imgf000455_0001
A suspension of 5-bromo-N-(4-fluoro-3-nitrophenyl)-4-morpholin-4-ylpyrimidin-2-amine
Intermediate 150 (0.87 mmol, 0.35 g), (4,4,5,5-Tetramethyl-[l,3,2]dioxaborolan-2-yl)-nicotinic acid ethyl ester (0.92 mmol, 0.25 g), tris(dibenzylideneacetone)dipalladium(0) (10 mol %, 0.087 mmol, 80 mg), XPHOS (30 mol %, 0.26 mmol, 125 mg) and sodium carbonate (0.87 mmol, 92 mg) in acetonitrile/water (20 mL : 5 mL) was degassed and heated to 90 0C for 30 min under inert atmosphere. The solvent was removed in vacuo and the crude mixture was taken in EtOAc (30 mL). It was then washed with water and brine. The organic layer was separated, dried over sodium sulfate, filtered and concentrated. The crude material was purified by silica gel column chromatography. The product eluted with CHCl3 : MeOH (98 : 2) eluent mixture. The title compound was obtained (0.2 g). MS (ES) : 469 (M+l) for C22H2IFN6O5.
1H-NMR (400 MHz, DMS0-d6): δ 1.35 (t, /= 7.04 Hz, 3H), 3.24-3.26 (m, 4H), 3.55-3.58 (m, 4H), 4.37 (q, / = 7.08 Hz, 2H), 7.52 (dd, / = 9.16, 11.14 Hz, IH), 7.90 (dt, / = 3.20, 6.10 Hz, IH), 8.21 (s, IH), 8.39 (t, / = 2.08 Hz, IH), 8.94 (d, / = 2.24 Hz, IH), 8.95-8.96 (m, IH), 9.01 (d, / = 1.92 Hz, IH), 10.04 (br s, IH).
Example 412: 3-{3-[2-(4-Fluoro-3-nitro-phenylamino)-4-morpholin-4-yl-pyrimidin-5-yl1- phenyll-acrylic acid ethyl ester
Figure imgf000456_0001
A suspension of 5-bromo-N-(4-fluoro-3-nitrophenyl)-4-morpholin-4-ylpyrimidin-2-amine Intermediate 150 (0.87 mmol, 0.35 g), ethyl boronocinnamate (0.92 mmol, 0.203 g), tris(dibenzylideneacetone)dipalladium(0) (10 mol %, 0.087 mmol, 80 mg), XPHOS (30 mol %, 0.26 mmol, 125 mg) and sodium carbonate (0.87 mmol, 92 mg) in acetonitrile/water (20 mL : 5 mL) was degassed and heated to 90 0C for 30 min under inert atmosphere. The solvent was removed in vacuo and the crude mixture was taken in EtOAc (30 mL). It was then washed with water and brine. The organic layer was separated, dried over sodium sulfate, filtered and concentrated. The crude material was purified by silica gel column chromatography. The product eluted with Hexane : Ethyl Acetate (90 : 10) eluent mixture. The title compound was obtained (0.2 g).
MS (ES) : 494 (M+l) for C25H24FN5O5.
1H-NMR (400 MHz, DMSO-d6): δ 1.25 (t, /= 7.08 Hz, 3H), 3.27-3.28 (m, 4H), 3.55-3.57 (m, 4H), 4.19 (q, / = 7.08 Hz, 2H), 6.73 (d, / = 16.04 Hz, IH), 7.46-7.55 (m, 3H), 7.67 (d, / = 7.36 Hz, IH), 7.69 (d, / = 16.08 Hz, IH), 7.83 (s, IH), 7.88-7.91 (m, IH), 8.11 (s, IH), 8.96 (dd, / = 2.80, 6.86 Hz, IH), 9.94 (s, IH).
General procedure for the reaction of anilines with 5-(2-Chloro-4-morpholin-4-yl- pyrimidin-5-yl)-nicotinic acid ethyl ester (Intermediate 152)
Figure imgf000457_0001
To a suspension of 5-(2-Chloro-4-morpholin-4-yl-pyrimidin-5-yl)-nicotinic acid ethyl ester
Intermediate 152 (0.6 mmol, 1 eq.) taken in n-BuOH / acetonitrile / dioxane (10 rnL) was added the corresponding aniline. The reaction mixture was then treated with 4 N HCl in dioxane (2 rnL) and refluxed at 100 0C for 1.5 h. The reaction mixture was cooled to room temperature, diluted with diethyl ether, the solid filtered and dried to yield the corresponding nicotinic acid ethyl ester. The compounds in the table below were prepared using this general procedure and the starting material and solvent specified.
Figure imgf000457_0002
Figure imgf000458_0001
Figure imgf000459_0002
General procedure for the reaction of anilines with 3-[3-(2-Chloro-4-morpholin-4-yl- pyrimidin-5-yl)-phenyl1-acrylic acid ethyl ester (Intermediate 153)
Figure imgf000459_0001
To a suspension of 3-[3-(2-Chloro-4-morpholin-4-yl-pyrimidin-5-yl)-phenyl]-acrylic acid ethyl ester Intermediate 153 (1 eq.) taken in n-BuOH / acetonitrile / dioxane was added the corresponding aniline. The reaction mixture was then treated with 4 N HCl in dioxane and refluxed at 100 0C for 1.5 h. The reaction mixture was cooled to room temperature, diluted with diethyl ether and the solid was filtered and dried to afford the corresponding cinnamic acid ethyl ester.
The compounds in the below table were prepared using this general procedure with the starting material and solvent specified.
Figure imgf000460_0001
Figure imgf000461_0001
Figure imgf000462_0001
Figure imgf000463_0002
Solvents used in the reaction (a) n-butanol (b) acetonitrile (c) dioxane
General procedure for the hydrolysis of pyridyl ester derivatives
Figure imgf000463_0001
Ester compound (1 eq, 0.22 mmol) was dissolved in a mixture of tetrahydrofuran (1 mL) and water (1 mL) and treated with sodium hydroxide (35 mg, IN, 0.88 mmol). The reaction was allowed to stir at room temperature for 1 hr. After completion of reaction, the reaction mixture was carefully acidified with 1 N HCl. The solid that precipitated was filtered off, washed with water and dried under vacuum.
The compounds in the below table were prepared using this general procedure and the specified starting material.
Figure imgf000463_0003
Figure imgf000464_0001
Figure imgf000465_0001
Figure imgf000466_0002
General procedure for the hydrolysis of cinnamyl ester derivatives
Figure imgf000466_0001
Ester compound (1 eq, 0.22 mmol) was dissolved in a mixture of tetrahydrofuran (1 mL) and water (1 mL) and treated with sodium hydroxide (35 mg, IN, 0.88 mmol). The reaction was allowed to stir at room temperature for 1 hr. After completion of reaction, the reaction mixture was carefully acidified with 1 N HCl. The solid that precipitated was filtered off, washed with water and dried under vacuum.
The compounds in the below table were prepared using this general procedure and the specified starting material.
Figure imgf000467_0001
Figure imgf000468_0001
Figure imgf000469_0001
Example 458: (E)-3-(3-(2-(3-cvano-4-fluorophenylamino)-4-morpholinopyrimidin-5- vDphenvDacrylic acid
Figure imgf000470_0001
To 3- { 3- [2-(3-Cyano-4-fluoro-phenylamino)-4-morpholin-4-yl-pyrimidin-5-yl] -phenyl} -acrylic acid ethyl ester (Example 428) (0.12 g, 0.25 mmol) in THF (1 rnL) and water (0.2 rnL), sodium hydroxide (0.5 mmol, 20 mg) was added and the mixture was heated at 60 0C overnight. The reaction mixture was then acidified using 1.5 N HCl and the solid obtained was filtered, washed with water and dried. LCMS analysis indicated that the solid was a 17 :3 mixture of the title compound and the corresponding carboxamide resulting from nitrile hydrolysis. A pure sample of the title compound was produced by converting the carboxamide to the nitrile using the procedure below.
The mixture obtained as above (0.07 g) was taken in POCl3 (1 mL) and heated at 100 0C for 3 h. The reaction mixture was cooled and concentrated under vacuo. Crushed ice was then added to the slurry to obtain an off-white solid, which was filtered, further washed with water and dried to give the pure title compound (0.06 g). MS(ES): 446 (M+l) for C24H20FN5O3.
400 MHz, DMSOd6: δ 3.34 (br s, 4H), 3.55 (br s, 4H), 6.63 (d, / = 16.04 Hz, IH), 7.49-7.56 (m, 3H), 7.64 (d, / = 16.04 Hz, IH), 7.69 (d, /= 6.72 Hz, IH), 7.78 (s, IH), 7.95 (br s, IH), 8.06 (s, IH), 8.21 (m, IH), 10.36 (br s, IH).
Example 459: 6-(2-(3-chloro-4-fluorophenylamino)-4-morpholinopyrimidin-5-yl)-4-oxo-4H- chromene-3-carboxylic acid
Figure imgf000471_0001
A suspension of 5-bromo-N-(3-chloro-4-fluorophenyl)-4-morpholin-4-ylpyrimidin-2- amine [Intermediate 146] (0.56 mmol, 220 mg), 2:1 mixture of boronic acid and pinacol boronate, Intermediate 155 (52 mg), tris(dibenzylideneacetone)dipalladium(0) (IO mol%, 0.054 mmol, 52 mg), 2-Dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (30 mol%, 0.17 mmol, 81 mg) and sodium carbonate (0.56 mmol, 60 mg) in 4:1 acetonitrile-water (10 mL) was degassed and then heated to 90 0C for 30 minutes. Solvent was removed in vacuo, resulting residue was redissolved in ethyl acetate (20 mL), filtered through a bed of celite and washed with water (2x10 mL). The filtrate was then acidified with 1.5N HCl, and the precipitate formed was filtered, washed with water and dried to yield the title compound as a brown solid (0.16 mmol, 80 mg, 29 %).
MS(ES): 497 (M+l) for C24Hi8ClFN4O5. 400 MHz, DMSOd6 : δ 3.23 (br s, 4H), 3.55 (br s, 4H), 7.25-7.30 (m, IH), 7.40 (t, / = 8.96 Hz, IH), 7.54-7.58 (m, IH), 7.62 (d, / = 8.24 Hz, IH), 7.91-7.93 (m, IH), 7.97-8.00 (m, 2H), 9.92 (s, IH), 9.98 (br s, IH).
Example 460: N2-(3-chloro-4-fluorophenyl)-2'-methoxy-N4-r2-(pyridin-3-yl)ethyl1-5,5'- bipyrimidine-2,4-diamine
Example 461: ^-O-chloro^-fluorophenvD^'-methoxy-A^-^-Cpyridin^-vDethyli-S^'- bipyrimidine-2,4-diamine
Figure imgf000471_0002
A suspension of 5-bromo-N-(3-chloro-4-fluorophenyl)-4-[alkylamino]pyrimidin-2-amine (1 eq), (2-methoxypyrimidin-5-yl)boronic acid (1.05 eq), tris(dibenzylideneacetone)dipalladium(0) (10 mol%), 2-dicyclohexylphosphino-2',4',6'- triisopropyl-l,l'-biphenyl (30 mol%) and sodium carbonate (1.1 eq) in acetonitrile/water (4:1) was heated to 90 0C for 30 minutes. The reaction mixture was diluted with ethyl acetate (25 mL); organic layer was separated, dried over sodium sulfate, filtered and concentrated. The resulting residue was purified by silica gel column chromatography using chloroform:methanol (9:1) as an eluent to afford the product.
The compounds in the below table were prepared using this method and the specified starting material.
Figure imgf000472_0001
Example 462: N2-(3-chloro-4-fluorophenyl)-N4-r2-(lH-imidazol-4-yl)ethyl1-2'-methoxy-5,5'- bipyrimidine-2,4-diamine
Figure imgf000473_0001
To a suspension of NaH (2.2 mmol, 60% dispersion in oil) in NMP, 2-(lH-Imidazol-4-yl)- ethylamine (1 eq) was added and stirred for 30 min. N-(3-chloro-4-fluorophenyl)-2'-methoxy-4- (methylsulfonyl)-5,5'-bipyrimidin-2-amine Intermediate 156 (leq) in NMP was added to the reaction mixture drop wise and stirred at RT for overnight. Water was added to the reaction mixture; the solid thus obtained was filtered and purified by column chromatography using chloroform-methanol to yield the title compound.
The compounds in the below table were prepared using this method and the specified starting material.
Figure imgf000473_0002
Figure imgf000474_0001
Figure imgf000475_0001
Figure imgf000476_0002
Example 471: N2-(3-chloro-4-fluorophenyl)-N4-r2-(lH-imidazol-4-yl)ethyl1-5,5'- bipyrimidine-2,4-diamine
Figure imgf000476_0001
To a suspension of NaH (2.2 mmol, 60% dispersion in oil) in DMF, 2-(lH-Imidazol-4- yl)-ethylamine (1 eq) was added and stirred for 30 minutes. N-(3-chloro-4-fluorophenyl)-4- methylsulfonyl-5-pyrimidin-5-ylpyrimidin-2-amine Intermediate 123 (1 eq) in DMF was added to the reaction mixture drop wise and stirred at room temperature 16 hours. The reaction mixture was added to water and stirred for 15 min. The precipitated solid was filtered, washed with water and dried to afford the crude product. It was further purified by flash chromatography using chloroform:methanol (9:1) to get the pure product.
Figure imgf000476_0003
General procedure for conversion of pyridine carboxylic esters to carboxamide derivatives
Figure imgf000477_0001
To a solution of ester (1 eq) in THF (2 rnL) was added aqueous ammonia solution (20 mL) and the mixture was heated to 60 0C in a sealed tube for 16 -24 h. The reaction mixture was cooled to room temperature, the solid thus obtained was filtered, washed with water and dried to give product.
Compounds in the below table were prepared using this general procedure and the specified starting material.
Figure imgf000477_0002
Figure imgf000478_0002
Synthesis of N-methoxy carboxamides from carboxylic acids
Figure imgf000478_0001
Method A:
To a mixture of (Example 257) (leq), triethylamine (3 eq) and methoxylamine hydrochloride (1.2 eq) in DMF was added HOBt (5 mol %), EDCI (1.2 eq) slowly at 0 0C. The reaction mixture was slowly raised to room temperature and stirred for overnight. Water was added and the precipitate thus formed was filtered and dried to yield Example 475. Method B:
To a mixture of (Example 229) (leq), triethylamine (4 eq) and methoxylamine hydrochloride (1.2 eq) in EtOAc:DCM (1:1) was added T3P (50%, 1.5 eq) slowly at 0 0C. The reaction mixture was slowly raised to room temperature and stirred for overnight. Reaction mixture was then diluted with dichloromethane (12 mL), washed the dichloromethane solution successively with water (2x50 mL), 10% aq sodium bicarbonate solution (50 mL) and brine. The organic layer was dried over sodium sulphate, filtered, concentrated and dried to yield Example 476. Method C:
To a mixture of (Example 230) (leq), triethylamine (3.5 eq) and methoxylamine hydrochloride (1.0 eq) in DMF was added BOP (1.2 eq) slowly at 0 0C. The reaction mixture was slowly raised to room temperature and stirred for 3-4 h. Water was added followed by extraction with EtOAc. The organic layer was dried over sodium sulphate, filtered and concentrated. The resulting residue was purified by silica gel column chromatography using chloroform:methanol (9:1) as an eluent to afford Example 477.
The compounds in the below table were prepared following the methods described above as indicated with the starting material listed.
Figure imgf000479_0001
Figure imgf000480_0002
General procedure for Aryl-aryl coupling reaction using Intermediate 146
Figure imgf000480_0001
A suspension of Intermediate 146 (1 eq), boronic acid (1.05 eq), tris(dibenzylideneacetone)dipalladium(0) (10 mol%), 2-dicyclohexylphosphino-2',4',6'- triisopropyl-l,l'-biphenyl (30 mol%) and sodium carbonate (2 eq) in acetonitrile/water (4:1) was heated to 90 0C for 30 minutes. The reaction mixture was diluted with ethyl acetate; organic layer was separated, dried over sodium sulfate, filtered and concentrated. The resulting residue was purified by silica gel column chromatography using chloroform:methanol (9:1) as an eluent to afford the product.
The compounds in the below table were prepared using this general method and the specified starting material.
Figure imgf000480_0003
Figure imgf000481_0001
Figure imgf000482_0001
General procedure for hydrolysis of carboxylic acid ester derivatives
Figure imgf000483_0001
Starting ester (leq, 0.22 mmol) was dissolved in a mixture of tetrahydrofuran (1 rnL) and water (1 rnL) and treated with 1 N sodium hydroxide (4 eq, 0.88 mmol) and allowed to stir at room temperature for 16 hours. Reaction mixture was then carefully acidified with 1 N HCl and the precipitate formed was filtered, washed with water and dried to yield the product. The compounds in the below table were prepared using this general method and the specified starting material.
Figure imgf000483_0002
Figure imgf000484_0002
Example 491: 3-amino-5-{2-[(3-chloro-4-fluorophenyl)amino1-4-(morpholin-4-yl)pyrimidin- 5-vUbenzoic acid
Figure imgf000484_0001
To 3-(tert-butoxycarbonylamino)-5-(2-(3-chloro-4-fluorophenylamino)-4-morpholinopyrimidin- 5-yl)benzoic acid, Example 484 (0.25 mmol, 110 mg), HCl in dioxane (4 rnL) was added and the mixture was stirred at room temperature for 16 hours. The solvent was evaporated and the residue was triturated with diethyl ether. The solid thus obtained was dried to yield the title compound. MS (ES): 444 (M+l) for C2IHi9ClFN5O3. 400 MHz, DMSO-d6: δ 3.38 (br s, 4H), 3.58 (br s, 4H), 7.09 (s, IH), 7.40-7.45 (m, 3H), 7.52- 7.56 (m, IH), 7.95 (dd, J = 2.32, 6.66 Hz, IH), 7.99 (s, IH), 10.50 (br s, IH).
Example 492: methyl 4-{2-[(3-chloro-4-fluorophenyl)amino1-4-(morpholin-4-yl)pyrimidin- 5-yl}pyridine-2-carboxylate
Figure imgf000485_0001
To a mixture of methyl 4-{2-[(3-chloro-4-fluorophenyl)amino]-4-(methylsulfonyl)pyrimidin-5- yl}pyridine-2-carboxylate (Intermediate 157), 0.23 mmol, 0.1 g) and morpholine (0.28 mmol,
24 mg) in NMP (2.5 mL), was added DIPEA (0.28 mmol, 36 mg) and heated to 90 0C for 1 h.
Water (3 mL) was added to the reaction mixture and the solid thus formed was filtered and dried to yield the title compound.
MS(ES): 444 (M+l) for C2IHi9ClFN5O3 400 MHz, DMSOd6: δ 3.24 (t, J = 4.16 Hz, 4H), 3.59 (t, J = 4.20 Hz, 4H), 3.90 (s, 3H), 7.34 (t, J
= 9.08 Hz, IH), 7.61-7.62 (m, IH), 7.77 (d, J = 3.60 Hz, IH), 8.13 (dd, J = 2.52, 6.68 Hz, IH),
8.17 (br s, IH), 8.24 (s, IH), 8.72 (d, J = 5.00 Hz, IH), 9.81 (br s, IH).
Example 493: 4-{2-[(3-chloro-4-fluorophenyl)amino1-4-(morpholin-4-yl)pyrimidin-5- vUpyridine-2-carboxylic acid
Figure imgf000485_0002
Methyl 4-{2-[(3-chloro-4-fluorophenyl)amino]-4-(morpholin-4-yl)pyrimidin-5-yl}pyridine-2- carboxylate Example 492, 0.23 mmol, 0.1 g) was dissolved in tetrahydrofuran (1 mL) and treated with aq.l N sodium hydroxide (0.11 mmol, 4 mg) and allowed to stir at room temperature for 1 h. After completion of the reaction, the mixture was then carefully acidified with 1 N HCl and the precipitate formed was filtered, washed with water and dried to yield the title compound. MS(ES): 428 (M-I) for C20H17ClFN5O3. 400 MHz, DMSOd6: δ 3.25 (br s, 4H), 3.60 (br s, 4H), 7.35 (t, J = 9.20 Hz, IH), 7.63-7.65 (m, IH), 7.75 (d, J = 3.60 Hz, IH), 8.14 (dd, J = 2.00, 6.40 Hz, IH), 8.18 (s, IH), 8.24 (s, IH), 8.71 (s, IH), 9.81 (br s, IH).
Example 494: methyl 4-{2-[(3-chloro-4-fluorophenyl)amino1-4-[3-(trifluoromethyl)-lH- Pyrazol-l-yl1pyrimidin-5-yl}pyridine-2-carboxvlate
Figure imgf000486_0001
A suspension of sodium hydride (2 eq, 0.23 mmol, 5.5 mg) in NMP was cooled to 0 0C and a solution of 3-(trifluoromethyl)-lH-pyrazole (2.2 eq, 0.13 mmol, 17 mg) in NMP (1 mL) was added slowly and the reaction mixture was gradually allowed to attain room temperature. The mixture was then stirred for 30 min at room temperature. It was recooled to 0 0C and a solution of methyl 4-{2-[(3-chloro-4-fluorophenyl)amino]-4-(methylsulfonyl)pyrimidin-5-yl}pyridine-2- carboxylate (Intermediate 157, 0.114 mmol, 50 mg) in DMSO (1 mL) was added slowly to the reaction mixture and stirred for 4 h. The reaction mixture was poured into ice-water (6 mL), and filtered and dried to yield the title compound. MS(ES):493 (M+l) for C2IHi3ClF4N6O2.
400 MHz, DMSO-d6: δ 3.85 (s, 3H), 7.08 (d, J = 2.40 Hz, IH), 7.44 (t, J = 9.20 Hz, IH), 7.52 (br s, IH), 7.71-7.75 (m, IH), 7.76 (s, IH), 8.07 (dd, J = 2.40, 6.80 Hz, IH), 8.55 (s, IH), 8.68 (d, J = 5.20 Hz, IH), 8.85 (s, IH), 10.54 (br s, IH).
Example 495: 4-{2-[(3-chloro-4-fluorophenyl)amino1-4-[3-(trifluoromethyl)-lH-pyrazol-l- yllpyrimidin-S-ylIpyridine^-carboxylic acid
Figure imgf000486_0002
To methyl 4- { 2-[(3-chloro-4-fluorophenyl)amino] -4- [3-(trifluoromethyl)- lH-pyrazol- 1 - yl]pyrimidin-5-yl}pyridine-2-carboxylate Example 494 (0.32 mmol, 0.16 g) taken in tetrahydrofuran (1 niL) and water (1 rnL), was added Lithium hydroxide monohydrate (0.64 mmol, 28 mg) at 0 0C and was gradually allowed to attain room temperature over a period of 1 h. After completion of the reaction, the mixture was then carefully acidified with 1 N HCl and the precipitate formed was filtered, washed with water and dried to yield the title compound. MS(ES): 479 (M+l) for C2OHnClF4N6O2 (Taken to the next step on the basis of LCMS).
Example 496: 4-{2-[(3-chloro-4-fluorophenyl)amino1-4-[3-(trifluoromethyl)-lH-pyrazol-l- yl1pyrimidin-5-yl}pyridine-2-carboxamide
Figure imgf000487_0001
To a solution of 4-{2-[(3-chloro-4-fluorophenyl)amino]-4-[3-(trifluoromethyl)-lH-pyrazol-l- yl]pyrimidin-5-yl}pyridine-2-carboxylic acid, Example 495 (0.38 mmol, 180 mg, 1 eq), pyridine (0.38 mmol, 30 mg, 1 eq) and di-te/t-butyl dicarbonate (0.48 mmol, 107 mg, 1.3 eq) in DMSO (5 mL), was added ammonium hydrogencarbonate (0.48 mmol, 39 mg 1.26 eq) and the mixture stirred for 24 h at ambient temperature. After completion of the reaction, the reaction mixture was poured into crushed ice. The solid that was formed was filtered off and further purified by column chromatography. MS(ES): 478 (M+l) for C20Hi2ClF4N7O.
Example 497: 5-(lH-benzimidazol-2-yl)-N-(3-chloro-4-fluorophenyl)-4-(morpholin-4- yl)pyrimidin-2-amine
Figure imgf000487_0002
N-(2-aminophenyl)-2-[(3-chloro-4-fluorophenyl)amino]-4-(morpholin-4-yl)pyrimidine-5- carboxamide Intermediate 161 (0.16 mmol, 70 mg) was dissolved in acetic acid (3 mL) and the reaction mixture was heated at 90 0C for 8 h. The solid that had precipitated out was filtered. The filtrate was basified with NaOH and extracted with EtOAc. The organic layer was washed with water, brine, dried over Na2SO4 and further purified by column chromatography using methanol: chloroform (2: 98) to yield 10 mg of the title compound as a white solid.
Figure imgf000488_0002
Example 498: 4-(2-{2-r(3-chloro-4-fluorophenyl)amino1-4-r(3- methoxypropyl)aminolpyrimidin-5-yl}-l,3-thiazol-4-yl)benzonitrile
Figure imgf000488_0001
To a suspension of 2-[(3-chloro-4-fluorophenyl)amino]-4-[(3-methoxypropyl)amino]pyrimidine- 5-carbothioamide (Intermediate 159, 0.14 mmol, 50 mg) and magnesium sulphate (0.14 mmol, 16 mg) in dry acetone (2 mL) under nitrogen atmosphere, was added 4-cyanophenacyl bromide (0.14 mmol, 33 mg). The resulting mixture was stirred at reflux temperature for 3 h, concentrated and purified by silica gel column chromatography (60- 120 mesh) using ethyl acetate/hexanes as eluent to afford the title compound (23 mg).
Figure imgf000488_0003
Figure imgf000489_0002
Example 499: ^-O-chloro^-fluorophenvD-A^-O-methoxypropyD-S-N-Cpyridin-S-vD-l^- thiazol-2-yllpyrimidine-2,4-diamine
Figure imgf000489_0001
To a solution of 2-[(3-chloro-4-fluorophenyl)amino]-4-[(3-methoxypropyl)amino]pyrimidine-5- carbothioamide (Intermediate 159), 0.54 mmol, 200 mg) in ethanol (2 niL) was added 3- bromoacetylpyridine hydrobromide (0.59 mmol, 0.167 g) and triethylamine (0.5 mmol, 50 mg). The resulting mixture was subjected to microwave irradiation at 150 0C for 2 h. The precipitated solid was filtered, washed with water and dried to afford the crude product. It was further purified by silica gel column chromatography (60-120 mesh) to afford the title compound (40 mg).
Figure imgf000489_0003
Example 500: ^-O-chloro^-fluorophenvD-A^-O-methoxypropyD-S-N-Cpyridin^-vD-l^- thiazol-2-yl1pyrimidine-2,4-diamine
Figure imgf000490_0001
To a suspension of 2-[(3-chloro-4-fluorophenyl)amino]-4-[(3-methoxypropyl)amino]pyrimidine- 5-carbothioamide (Intermediate 159), 0.22 mmol, 80 mg) in DMF (2 niL), was added A- bromoacetylpyridine hydrobromide (0.23 mmol, 65 mg) and wanned to 80 0C for 3 h. After completion of the reaction, as monitored by TLC, the reaction mixture was quenched with water. The solid that precipitated out was filtered. It was further stirred with acetonitrile, filtered and dried to afford the title compound (60 mg).
Figure imgf000490_0003
Example 501: ethyl 5-(2-{2-r(3-chloro-4-fluorophenyl)amino1-4-r(3- methoxypropyl)amino1pyrimidin-5-yl}-l,3-thiazol-4-yl)isoxazole-3-carboxylate
Figure imgf000490_0002
To a suspension of 2-[(3-chloro-4-fluorophenyl)amino]-4-[(3-methoxypropyl)amino]pyrimidine- 5-carbothioamide (Intermediate 159, 0.54 mmol, 200 mg) and magnesium sulfate heptahydrate (0.65 mmol, 160 mg) in dry acetone (2 rnL) under nitrogen atmosphere, was added ethyl 5- (bromoacetyl)-l,2-oxazole-3-carboxylate (0.59 mmol, 155 mg). The resulting mixture was stirred at reflux temperature for 3 hours, concentrated and purified by silica gel column chromatography (60- 120 mesh; product eluted at 1% MeOH/CHCl3) as eluent to afford the title compound (64 mg).
Figure imgf000491_0002
Example 502: 5-(2,4'-bi-l,3-thiazol-2'-yl)-N2-(3-chloro-4-fluorophenyl)-N4-(3- methoxypropyl)pyrimidine-2,4-diamine
Figure imgf000491_0001
To a suspension of 2-[(3-chloro-4-fluorophenyl)amino]-4-[(3-methoxypropyl)amino]pyrimidine- 5-carbothioamide (Intermediate 159), 0.14 mmol, 50 mg) in DMF (2 mL), was added 2-bromo- l-(l,3-thiazol-2-yl)ethanone (0.13 mmol, 27 mg) and warmed to 100 0C for 3 h. The reaction mixture was quenched with water. The solid that precipitated out was filtered, washed with acetonitrile and dried to afford the title compound (35 mg).
Figure imgf000492_0002
Example 503: N2-(3-chloro-4-fluorophenyl)-N4-(3-methoxypropyl)-5-[4-(5-methylisoxazol-4- yl)-l,3-thiazol-2-yllpyrimidine-2,4-diamine
Figure imgf000492_0001
To a suspension of 2-[(3-chloro-4-fluorophenyl)amino]-4-[(3-methoxypropyl)amino]pyrimidine- 5-carbothioamide (Intermediate 159, 0.27 mmol, 100 mg) in DMF (2 rnL), was added 2-bromo- l-(5-methylisoxazol-4-yl)ethanone (Intermediate 164, 0.2 mmol, 60 mg) and warmed to 80 0C for 3 h. The reaction mixture was quenched with water and the solid that precipitated out was filtered, washed with acetonitrile and dried to afford the title compound (35 mg).
Figure imgf000492_0003
Figure imgf000493_0003
Example 504: N2-(3-chloro-4-fluorophenyl)-N4-(3-methoxypropyl)-5-r4-(l-methyl-lH- imidazol-5-yl)-l,3-thiazol-2-yl1pyrimidine-2,4-diamine
Figure imgf000493_0001
To a suspension of 2-[(3-chloro-4-fluorophenyl)amino]-4-[(3-methoxypropyl)amino]pyrimidine- 5-carbothioamide (Intermediate 159, 0.56 mmol, 206 mg,) in ethanol (5 niL), was added the mixture of 2-bromo-l -(I -methyl- IH- imidazol-5-yl)ethanone and 2,2-dibromo-l -(I -methyl- IH- imidazol-5-yl)ethanone (Intermediate 165, 1.12 mmol based on the former, 226 mg,) and warmed to 80 0C for 3 h. The reaction mixture was concentrated and subjected to purification by RP-ΗPLC (C 18 column(19 x 250 mm, 7μm); using a binary solvent mixture of 20 mM NH4OAc (A)/CH3CN (B) (0-20 min: 10-60% B, 20-35 min: 60% B and 35-45 min: 60-100% B; flow rate of 15 niL/min; Separation was monitored at 210 and 254 nm) to give the title compound (98 mg).
Figure imgf000493_0002
Example 505: methyl 2-{2-[(3-chloro-4-fluorophenyl)amino1-4-[(3- methoxypropyl)aminolpyrimidin-5-yl}-4-methyl-l,3-thiazole-5-carboxvlate
Figure imgf000494_0001
To a solution of 2-[(3-chloro-4-fluorophenyl)amino]-4-[(3-methoxypropyl)amino]pyrimidine-5- carbothioamide (Intermediate 159, 200 mg, 0.5 mmol) in ethanol (1 niL) was added methyl-2- chloroacetoacetate (0.072 niL, 0.089 g, 0.6 mmol). The resulting mixture was subjected to microwave irradiation at 150 0C for 2 h. The precipitated solid was filtered, washed with water and dried to afford the crude product. It was further purified by silica gel column chromatography (60-120 mesh; product eluted at 20 % ethyl acetate/hexanes) as eluent to afford the title compound (40 mg).
Figure imgf000494_0002
Example 506: ethyl 2-{2-r(3-chloro-4-fluorophenyl)amino1-4-r(3- methoxypropyl)amino1pyrimidin-5-yl}-4-phenyl-l,3-thiazole-5-carboxylate
Figure imgf000495_0001
To a solution of 2-[(3-chloro-4-fluorophenyl)amino]-4-[(3-methoxypropyl)amino]pyrimidine-5- carbothioamide (Intermediate 159, 100 mg, 0.27 mmol) in ethanol (10 niL) was added ethyl 2- bromo-3-oxo-3-phenylpropanoate (80 mg, 0.29 mmol). The resulting mixture was stirred overnight at RT. The solvent was removed in vacuo and the slurry taken in ethyl acetate was washed with water and brine. It was dried over sodium sulfate and further purified by silica gel column chromatography (60 - 120 mesh) using 1% MeOH/ CHCl3 as eluent to afford the title compound (32 mg).
Figure imgf000495_0002
Example 507: ethyl 2-{2-r(3-chloro-4-fluorophenyl)amino1-4-r(3- methoxypropyDaminoipyrimidin-S-vU^-Cpyridin^-vD-l^-thiazole-S-carboxylate
Figure imgf000496_0001
To 2-[(3-chloro-4-fluorophenyl)amino]-4-[(3-methoxypropyl)amino]pyrimidine-5- carbothioamide (Intermediate 159, 1 mmol, 0.37 g) and [l-ethoxy-l,3-dioxo-3-(pyridin-2- yl)propan-2-ylidene]diazenium (Intermediate 168, 0.91 mmol, 200 mg) taken in dry toluene (5 mL), Copper(I) bromide dimethyl sulfide complex (0.76 mmol, 157 mg) was added and heated at 110 0C for 0.5 h. The reaction mixture was cooled to room temperature, quenched with water and extracted with ethyl acetate. The organic layer was washed with brine (50 mL x 2) and dried over sodium sulphate. The solvent was removed under vacuum to afford a solid, which was purified by silica gel column chromatography using chloroform: methanol (9:1) as eluent. It was further purified by RP-HPLC (Kromasil Cl 8 column (50 x 250 mm, lOμm); using a binary solvent mixture of 20 mM NH4OAc (A)/CH3CN (B) (0-20 min: 10-80% B, 20-30 min: 80% B, flow rate of 40 niL/min; Separation was monitored at 210 nm and 254 nm) to give the title compound (42 mg).
Figure imgf000496_0002
Example 508: ethyl 2-{2-r(3-chloro-4-fluorophenyl)amino1-4-r(3- methoxypropyl)amino1pyrimidin-5-yl}-4-(l-methyl-lH-pyrazol-3-yl)-l,3-thiazole-5- carboxylate
Figure imgf000497_0001
To a solution of 2-[(3-chloro-4-fluorophenyl)amino]-4-[(3-methoxypropyl)amino]pyrimidine-5- carbothioamide (Intermediate 159, 95 mg, 0.25 mmol) in ethanol (10 niL) was added ethyl 2- chloro-3-(l -methyl- lH-pyrazol-3-yl)-3-oxopropanoate (Intermediate 171, 130 mg, 0.56 mmol). The resulting mixture was refluxed at 90 0C for 3 d. The solvent was removed in vacuo and the slurry was taken in ethyl acetate and washed with water and brine. The organic solution was dried over sodium sulfate and further purified by silica gel column chromatography (60 - 120 mesh) using 1% MeOH/ CHCl3 as eluent to afford the title compound (24 mg).
Figure imgf000497_0002
Example 509: 2-{2-[(3-chloro-4-fluorophenyl)amino1-4-[(3-methoxypropyl)amino1pyrimidin- 5-yl}-4-methyl-l,3-thiazole-5-carboxylic acid
Figure imgf000498_0001
Example 505 (0.16 mmol 75 mg,) was dissolved in tetrahydrofuran (2 niL) and treated with 1 N aq. NaOH (0.6 rnL). The reaction mixture was warmed to 60 0C for 24 h. The reaction mixture was concentrated and the aqueous layer carefully acidified with 1.5 N HCl. The solid that precipitated was filtered out, washed with water and dried under vacuum to yield the title compound (15 mg).
Figure imgf000498_0002
Example 510: 2-{2-[(3-chloro-4-fluorophenyl)amino1-4-[(3-methoxypropyl)amino1pyrimidin- S-ylM-phenyl-l^-thiazole-S-carboxylic acid
Figure imgf000499_0001
To a suspension of 150 mg of Example 506 (0.28 mmol, 150 mg) taken in tetrahydrofuran (2.5 niL) and water (2.5 rnL), Lithium hydroxide monohydrate (1.11 mmol, 46 mg) was added and the reaction was warmed overnight at 60 0C. After completion of reaction, the reaction mixture was concentrated and the aqueous layer was carefully acidified with 1.5 N HCl. The solid that precipitated was filtered out, washed with water and dried under vacuum to yield the title compound (110 mg).
Figure imgf000499_0003
Example 511: 2-{2-[(3-chloro-4-fluorophenyl)amino1-4-[(3- methoxypropyl)amino1pyrimidin-5-yl}-4-(pyridin-2-yl)-l,3-thiazole-5-carboxylic acid
Figure imgf000499_0002
To 40 mg of ethyl 2-{2-[(3-chloro-4-fluorophenyl)amino]-4-[(3- methoxypropyl)amino]pyrimidin-5-yl}-4-(pyridin-2-yl)-l,3-thiazole-5-carboxylate (Example 507, 0.07 mmol) taken in THF (1 niL) and water (1 rnL), was added Lithium hydroxide monohydrate (0.29 mmol, 12 mg) and the reaction was warmed overnight at 65 0C. The reaction mixture was concentrated then the aqueous layer was carefully acidified with 1.5 N HCl. The solid that precipitated was filtered out, washed with water and dried under vacuum to yield 18 mg of the title compound as a yellow powder.
Figure imgf000500_0002
Example 512: 2-{2-[(3-chloro-4-fluorophenyl)amino1-4-[(3- methoxypropyl)amino1pyrimidin-5-yl}-4-(l-methyl-lH-pyrazol-3-yl)-l,3-thiazole-5- carboxylic acid
Figure imgf000500_0001
To 80 mg of ethyl 2-{2-[(3-chloro-4-fluorophenyl)amino]-4-[(3- methoxypropyl)amino]pyrimidin-5-yl}-4-(l-methyl-lH-pyrazol-3-yl)-l,3-thiazole-5-carboxylate (Example 508, 0.16 mmol) taken in THF (5 niL) was added Barium hydroxide monohydrate (0.44 mmol, 0.083 g) and water (5 mL). The reaction mixture was allowed to stir at RT overnight. After completion of the reaction, the mixture was then carefully acidified with 1.5 N HCl to pH=2 and the precipitate formed was filtered, washed with water and dried to yield the title compound (24 mg).
Figure imgf000501_0002
Example 513: ethyl (2£)-3-{3-[2-{r4-fluoro-3-(hvdroxymethyl)phenyl1amino}-4-(morpholin- 4-yl)pyrimidin-5-yl1phenyl}prop-2-enoate
Figure imgf000501_0001
A suspension of (2£')-3-{3-[2-chloro-4-(morpholin-4-yl)pyrimidin-5-yl]phenyl}prop-2- enoate (Intermediate 145) (0.8 mmol, 0.30 g, 1 eq), (5-amino-2-fluorophenyl)methanol (0.88 mmol, 0.12 g, 1.1 eq), tris(dibenzyledeneacetone) dipalladium(O) (0.24 mmol, 0.22 g, 30 mol%), 2-dicyclohexylphosphino-2',4',6'-triisopropyl-l,l'-biphenyl (0.24 mmol, 0.11 g, 30 mol%) and sodium carbonate (0.8 mmol, 0.08 g, 1 eq) in acetonitrile/water (6 mL:2 mL) was heated to 90 0C for 30 minutes. The reaction mixture was concentrated and the residue was taken in ethyl acetate (50 niL), washed with water (2x) and brine (Ix). The organic layer was separated, dried over sodium sulfate, filtered and concentrated. The crude compound was purified by silica gel column (60-120 mesh) chromatography using hexane: ethyl acetate (3:1) as an eluent to yield the title compound (0.190 g).
Figure imgf000502_0002
Example 514: ethyl (2£)-3-{3-[2-(lH-indol-7-ylamino)-4-(morpholin-4-yl)pyrimidin-5- vHphenyl}prop-2-enoate
Figure imgf000502_0001
A suspension of (2£')-3-{3-[2-chloro-4-(morpholin-4-yl)pyrimidin-5-yl]phenyl}prop-2- enoate (Intermediate 145) (0.67 mmol, 0.25 g, 1 eq), lH-indol-7-amine (0.8 mmol, 0.10 g, 1.2 eq), tris(dibenzyledeneacetone)dipalladium(0) (0.2 mmol, 0.184 g, 30 mol%), 2- dicyclohexylphosphino-2',4',6'-triisopropyl-l,l'-biphenyl (0.20 mmol, 0.1 g, 30 mol%) and sodium carbonate (0.7 mmol, 0.07 g, 1 eq) in acetonitrile/water (10 mL:2.5 mL) was heated to 90 0C for 30 minutes. The reaction mixture was concentrated and the residue was taken in ethyl acetate (50 mL), washed with water (2x) and brine (Ix). The organic layer was separated, dried over sodium sulfate, filtered and concentrated. The crude compound was purified by silica gel column (230-400 mesh) chromatography using chloroform: methanol (98:2) as an eluent to yield the title compound (0.17 g).
Figure imgf000503_0002
General procedure for hydrolysis of carboxylic acid ester to acid
Figure imgf000503_0001
To ester derivative (1 eq) suspended in tetrahydrofuran (1 mL) was added 1 N aq. NaOH (4 eq) and stirred overnight at room temperature. After completion of reaction, the reaction mixture was carefully acidified with 1 N HCl and the solid that precipitated was filtered, washed with water and dried in vacuo to yield the desired carboxylic acid product. The compounds in the below table were prepared using this method and the indicated starting material.
Figure imgf000504_0001
General methods for the synthesis of ethyl 5-{2-[(3-chloro-4-fluorophenyl)amino1-4-(azol-l- yl)pyrimidin-5-yl}pyridine-3-carboxylate
Figure imgf000505_0001
Method A:
A solution of azole (2.2 eq) in DMF (1 niL) was added slowly to a suspension of sodium hydride (2.1 eq) in DMF (1 niL). The reaction mixture was stirred for 30 min at room temperature. A solution of ethyl 5-(2-(3-chloro-4-fluorophenylamino)-4-(methylsulfonyl)pyrimidin-5- yl)nicotinate Intermediate 124 (1 eq) in DMF (1 mL) was added slowly to the reaction mixture at 0 0C with stirring and allowed to warm to ambient temperature over 2.5 h. Water was added (~6 mL) and the solid formed was filtered and dried to yield the product. Method B:
A solution of azole (2.2 eq) in DMSO (1 mL) was added slowly to a suspension of sodium hydride (2.1 eq) in DMSO (1 mL). The reaction mixture was stirred for 30 min at room temperature. A solution of Intermediate 124 (1 eq) in DMSO (1 mL) was added slowly to the reaction mixture at 0 0C with stirring and allowed to warm to ambient temperature over 2.5 h. Water was added (~6 mL) and the solid formed was filtered and dried to yield the product.
The compounds in the below table were prepared using the methods described above as indicated and the starting material specified.
Figure imgf000506_0001
Figure imgf000507_0001
Figure imgf000508_0001
Figure imgf000509_0002
General method for the synthesis of 5-{2-[(3-chloro-4-fluorophenyl)amino1-4-(azol-l- vDpyrimidin-S-vUpyridine-S-carboxylic acid
Figure imgf000509_0001
Method C:
A solution of ethyl 5-{2-[(3-chloro-4-fluorophenyl)amino]-4-(azol-l-yl)pyrimidin-5-yl}pyridine- 3-carboxylate derivative (1 eq) in a mixture of tetrahydrofuran (1 rnL) and water (1 rnL) was treated with 1 N aq. sodium hydroxide (4 eq) and allowed to stir at room temperature for 3-8 h. After completion of the reaction, the mixture was carefully acidified with 1 N HCl and the precipitate formed was filtered, washed with water and dried to yieldthe product. Method D:
A solution of ethyl 5-{2-[(3-chloro-4-fluorophenyl)amino]-4-(azol-l-yl)pyrimidin-5-yl}pyridine- 3-carboxylate derivative (1 eq) in a mixture of dioxane (1 mL) and water (1 mL) was treated with 1 N aq. Barium hydroxide (2 eq) and allowed to stir at room temperature for 2-8 h. After completion of the reaction, the mixture was carefully acidified with 1 N HCl and the precipitate formed was filtered, washed with water, dried to yield the product.
The compounds in the below table were prepared using the methods described above as indicated and the starting material specified.
Figure imgf000510_0001
Figure imgf000511_0001
Figure imgf000512_0001
Figure imgf000513_0001
General method for the synthesis of 5-{2-[(3-chloro-4-fluorophenyl)amino1-4-[azol-l- yllpyrimidin-5-yl}pyridine-3-carboxamide
Figure imgf000514_0001
Method E:
To a stirred solution of the carboxylic acid derivative (1 eq), pyridine (0.5 ml) and di-tert-buty\ dicarbonate (1.3 eq) in dioxane (10-15 rnL), ammonium hydrogencarbonate (1.26 eq) was added and the mixture was stirred for 4-16 h. The reaction mixture was then diluted with water (30-40 ml), stirred until precipitation was complete and the residue was then collected by filtration, washed with water, dried and further purified by column chromatography to give the product. Method F:
A solution of carboxylic acid derivative (1.02 mmol) taken in thionyl chloride (2 mL) was heated to 85 0C for 2 h. Thionyl chloride was then removed in vacuo and the solid obtained was quenched with a saturated solution of NH3 in 1,4 dioxane (25 mL) and stirred for 20 min. The solid obtained was filtered and dried. The crude material was further purified by RP-HPLC to give the product.
The compounds in the below table were prepared using the methods described above as indicated and the starting material specified.
Figure imgf000515_0001
Figure imgf000516_0001
Figure imgf000517_0001
General method for the synthesis of 5-{2-[(3-chloro-4-fluorophenyl)amino1-4-[azol-l- yl1pyrimidin-5-yl}-N-methoxypyridine-3-carboxamide
Figure imgf000518_0001
Method G:
To a mixture of carboxylic acid derivative (1 eq), triethylamine (3 eq) and methoxylamine hydrochloride (2 eq) in DCM was added T3P (50% in EtOAc, 1.5 eq) slowly at 0 0C. The reaction mixture was slowly raised to room temperature and stirred overnight. The reaction mixture was then diluted with dichloromethane (12 mL) and washed successively with water, 10% aq sodium bicarbonate solution and brine. The organic layer was dried over sodium sulphate, filtered, concentrated and further purified by silica gel column chromatography to yield the product. Method H:
To a mixture of carboxylic acid derivative (1 eq) and HATU (1.5 eq) in NMP, was added triethylamine (3 eq) and methoxylamine hydrochloride (1.2 eq) and the reaction mixture was stirred overnight. The reaction mixture was then diluted with water and the aqueous layer was extracted with EtOAc. The organic layer successively washed with 10% aq sodium bicarbonate solution and brine. The organic layer was dried over sodium sulphate, filtered, concentrated and further purified by silica gel column chromatography to yield the product. The compounds in the below table were prepared using the methods described above as indicated and the starting material specified.
Figure imgf000519_0001
Figure imgf000520_0001
Figure imgf000521_0001
Figure imgf000522_0002
General method for the synthesis of ethyl (2£)-3-(3-{2-[(3-chloro-4-fluorophenyl)amino1-4-( azol-l-yl)pyrimidin-5-yl}phenyl)prop-2-enoate
Figure imgf000522_0001
Method I:
A solution of azole (2.2 eq) in DMF (1 rnL) was added slowly to a suspension of sodium hydride (2.1 eq) in DMF (1 mL). The reaction mixture was stirred for 30 min at room temperature. A solution of (E)-ethyl 3-(3-(2-(3-chloro-4-fluorophenylamino)-4-(methylsulfonyl)pyrimidin-5- yl)phenyl)acrylate Intermediate 125 (1 eq) in DMF (1 mL) was added slowly to the reaction mixture at 0 0C with stirring and allowed to warm to ambient temperature over 2.5 h. Water was added (~6 mL) and the solid formed was filtered, dried to yield the product.
Method J:
A solution of azole (2.2 eq) in DMSO (1 mL) was added slowly to a suspension of sodium hydride (2.1 eq) in DMSO (1 mL). The reaction mixture was stirred for 30 min at room temperature. A solution of (E)-ethyl 3-(3-(2-(3-chloro-4-fluorophenylamino)-4- (methylsulfonyl)pyrimidin-5-yl)phenyl)acrylate Intermediate 125 (1 eq) in DMSO (1 mL) was added slowly to the reaction mixture at 0 0C with stirring and allowed to warm to ambient temperature over 2.5 h. Water was added (~6 mL) and the solid formed was filtered, dried to yield the product.
Method K:
A suspension of azole (1.2 eq), potassium te/t-butoxide (1.5 eq) and (E)-ethyl 3-(3-(2-(3- chloro-4-fluorophenylamino)-4-(methylsulfonyl)pyrimidin-5-yl)phenyl)acrylate Intermediate 125 (1 eq) in DMSO (3 mL) was subjected to microwave irradiation at 130 0C for 1 h. After the reaction cooled to RT, the mixture was diluted with EtOAc, washed successively with water and brine. The organic layer was dried over sodium sulphate, filtered, concentrated and further purified by silica gel column chromatography to yield the product. The compounds in the below table were prepared using the methods described above as indicated and the starting material specified.
Figure imgf000524_0001
Figure imgf000525_0001
Figure imgf000526_0001
Figure imgf000527_0002
General method for the synthesis of (2£)-3-(3-{2-[(3-chloro-4-fluorophenyl)amino1-4-[azol- l-yllpyrimidin-5-yl}phenyl)prop-2-enoic acid
Figure imgf000527_0001
Method L:
A solution of carboxylic ester derivative (1 eq) in a mixture of tetrahydrofuran (1 rnL) and water (1 rnL) was treated with 1 N aq. sodium hydroxide (4 eq) and allowed to stir at room temperature for 1 h. After completion of the reaction, the mixture was carefully acidified with 1 N HCl and the precipitate formed was filtered, washed with water and dried to the product. Method M:
A solution of carboxylic ester derivative (1 eq) in a mixture of dioxane (1 mL) and water (1 mL) was treated with 1 N aq. Barium hydroxide (2 eq) and warmed to 60 0C for 3-10 h. After completion of the reaction, the mixture was carefully acidified with 1 N HCl and the precipitate formed was filtered, washed with water, dried to yield the product.
Figure imgf000528_0001
Figure imgf000529_0001
Figure imgf000530_0001
Figure imgf000531_0002
Example 569: methyl 3-(2-(3-chloro-4-fluorophenylamino)-4-(3-(trifluoromethyl)-lΗ- pyrazol-l-yl)pyrimidin-5-yl)benzoate
Figure imgf000531_0001
The title compound was prepared using the general method described above for Example 1 using 3-(methoxycarbonyl)phenylboronic acid and intermediate 115 as starting materials. MS: ES+ 492 for C22Hi4ClF4N5O2.
IH NMR (300 MHz, DMSO-D6) δ ppm 3.82 (s, 3 H), 6.99 (d, 1 H), 7.35 - 7.55 (m, 3 H), 7.64 - 7.76 (m, 2 H), 7.91 (d, 1 H), 8.09 (dd, 1 H), 8.40 (s, 1 H), 8.80 (s, 1 H), 10.43 (s, 1 H). Example 570: 3-(2-(3-chloro-4-fluorophenylamino)-4-(3-(trifluoromethyl)-lH-pyrazol-l- yl)pyrimidin-5-yl)benzoic acid
Figure imgf000532_0001
The title compound was prepared using the general method described above for Example 214 using IN sodium hydroxide (2 equivalents), dioxane : THF (1:1) as solvent and (Example 569 as a starting material.
MS: ES+ 478 for C2IHi2ClF4N5O2.
IH NMR (400 MHz, DMSO-D6) δ ppm 6.98 (d, 1 H), 7.37-7.51 (m, 3 H), 7.66 (s, 1 H), 7.69 -
7.76 (m, 1 H), 7.88 (d, 1 H), 8.10 (dd, 1 H), 8.39 (s, 1 H), 8.79 (s, 1 H), 10.40 (s, 1 H), 12.93 (s, 1
H).
Example 571: (l,3-trα«^)-3-(3-(2-(4-fluorophenylamino)-4-(3-(trifluoromethyl)-lH-pyrazol-l- yl)pyrimidin-5-yl)phenyl)-2,2-dimethylcvclopropanecarboxylic acid
Figure imgf000532_0002
(l,3-tran5ι)-tert-butyl 2,2-dimethyl-3-(3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl)cyclopropanecarboxylate Intermediate 174 ( 342 mg, 0.92 mmol), 5-bromo-N-(3- chloro-4-fluorophenyl)-4-(3-(trifluoromethyl)-lH-pyrazol-l-yl)pyrimidin-2-amine (200 mg, 0.46 mmol) (Intermediate 115), Tris(dibenzylideneacetone)dipalladium(0) (41.9 mg, 0.05 mmol), 2- Dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (65.5 mg, 0.14 mmol), Na2CO3 (200 mg, 1.89 mmol), acetonitrile (3 mL) and water (0.750 mL) were combined and degassed with an argon stream for 10 min. The mixture was warmed at 8O0C for 2.5 hrs, allowed to cool, diluted with acetonitrile, filtered and adsorbed on 15 ml silica gel. Purified by flash chromatography (80 g cartridge, 0-10% ethyl acetate in hexane). A crude sample of the tert-butyl ester of the title compound was thus obtained as a yellow-orange solid: (100 mg). This sample was converted to the title compound as follows: Sample was first combined with dichloromethane (1 mL) and trifluoroacetic acid (1 mL, 12.98 mmol). The clear solution was stirred at room temperature for 45 min then evaporated. The mixture was dissolved in dichloromethane and applied to 5 ml silica gel column. Eluted with 20% ethyl acetate in hexane, then with 50% ethyl acetate in hexane. Pure fractions evaporated and dissolved in 0.25 ml ethyl acetate then precipitated with 5 ml hexanes. Filtered to give a white solid (9 mg).
MS: ES+ 512 for C26H2IF4N5O2.
IH NMR (400 MHz, DMSO-D6) δ ppm 0.91 (s, 3 H), 1.32 (s, 3 H), 2.05 (d, 1 H), 2.56 (d, 1 H), 7.14 (d, 1 H), 7.24 - 7.28 (m, 1 H), 7.31 (d, 2 H), 7.37 (s, 1 H), 7.40 - 7.44 (m, 2 H), 7.80 - 7.87 (m, 2 H), 8.64 (d, 1 H), 8.72 (d, 1 H), 10.06 (s, 1 H), 12.20 (s, 1 H).
Example 572: (l,3-trans)-3-(3-(2-(3-chloro-4-fluorophenylamino)-4-(3-(trifluoromethyl)-lH- Pyrazol-l-yl)pyrimidin-5-yl)phenyl)-2,2-dimethylcvclopropanecarboxylic acid
Figure imgf000533_0001
(lS,3S)-tert-butyl 3-(3-(2-(3-chloro-4-fluorophenylamino)-4-(3-(trifluoromethyl)-lH-pyrazol-l- yl)pyrimidin-5-yl)phenyl)-2,2-dimethylcyclopropanecarboxylate Intermediate 176 (35 mg, 0.06 mmol) was dissolved in dichloromethane (1 mL) then trifluoroacetic acid (1 ml, 12.98 mmol) was added to give a clear yellow solution. The mixture was stirred at room temperature for 30 minutes. The solution was concentrated and the residue was triturated with 3 ml hexane to give the title compound as a light yellow solid (30 mg). MS: ES+ 546 for C26H20ClF4N5O2.
IH NMR (400 MHz, DMSO-D6) δ ppm 0.77 (s, 3 H), 1.26 (s, 3 H), 1.87 (d, 1 H), 2.40 (d, 1 H), 6.90 (s, 1 H), 6.93 (d, 1 H), 7.06 (d, 1 H), 7.17 (d,l H), 7.29 (t, 1 H), 7.39 (t, 1 H), 7.66 - 7.73 (m, 1 H), 8.12 (dd, 1 H), 8.24 (s, 1 H), 8.77 (s, 1 H), 10.38 (s, 1 H).
Example 573: (l,2-trans)-2-(5-(2-(3-chloro-4-fluorophenylamino)-4-(3-(trifluoromethyl)-lH- pyrazol-l-yl)pyrimidin-5-yl)pyridin-3-yl)cvclopropanecarboxylic acid
Figure imgf000534_0001
The title compound was prepared using the general method described above for Example 572 using Intermediate 180 as a starting material. MS: ES+ 519 for C23H15C1F4N6O2.
IH NMR (300 MHz, DMSO-D6) δ ppm 0.78 - 0.90 (m, 1 H), 1.28 - 1.38 (m, 1 H), 1.40 - 1.51 (m, 1 H), 1.81 - 1.93 (m, 1 H), 7.05 (d, 1 H), 7.42 (t,l H), 7.48 (m, 1 H), 7.67 - 7.76 (m, 1 H), 8.08 (dd, 1 H), 8.31 (s, 1 H), 8.49 (s, 1 H), 8.54 (s, 1 H), 8.82 (s, 1 H), 10.47 (s, 1 H). Example 574: (l,2-trans)-2-(3-(2-(3-chloro-4-fluorophenylamino)-4-(3-(trifluoromethyl)-lH- Pyrazol-l-yl)pyrimidin-5-yl)phenyl)cvclopropanecarboxylic acid
Figure imgf000535_0001
The title compound was prepared using the general method described above for Example 572 using Intermediate 183 as a starting material.
MS: ES+ 518 for C24H16C1F4N5O2.
IH NMR (400 MHz, DMSO-D6) δ ppm 1.17 - 1.27 (m, 1 H), 1.33 - 1.41 (m, 1 H), 1.68 - 1.76
(m, 1 H), 2.28 - 2.37 (m, 1 H), 6.86 (s, 1 H), 6.94 -7.00 (m, 2 H), 7.16 (d, 1 H), 7.24 (t, 1 H), 7.39 (t, 1 H), 7.66 - 7.73 (m, 1 H), 8.12 (dd, 1 H), 8.24 (s, 1 H), 8.79 (s, 1 H), 10.38 (s, 1 H), 12.25 (s,
IH).
Examples 575 and 576: (lR,2R)-2-(3-(2-(3-chloro-4-fluorophenylamino)-4-(3- (trifluoromethyl)-lH-pyrazol-l-yl)pyrimidin-5-yl)phenyl)cvclopropanecarboxylic acid and (lS,2R)-2-(3-(2-(3-chloro-4-fluorophenylamino)-4-(3-(trifluoromethyl)-lH-pyrazol-l- yl)pyrimidin-5-yl)phenyl)cvclopropanecarboxylic acid
Figure imgf000535_0002
Racemic (1 ,2-trans)-tert-butyl 2-(3-(2-(3-chloro-4-fluorophenylamino)-4-(3-(trifluoromethyl)- lH-pyrazol-l-y^pyrimidin-S-y^pheny^cyclopropanecarboxylate Intermediate 183 (170 mg) was subjected to preparative chiral supercritical fluid chromatography using an instrument manufactured by Berger. Column: Chiralpak AD-H, dimensions: 250 x 21mm, 5μ; modifier: 25% isopropanol with 0.4% dimethylethylamine; flow rate: 60 ml/min; oven temperature: 40 0C, outlet pressure: 100 bar. Samples of the separate ester enantiomers were thus obtained in >98% e.e. (60 mg each). These samples were separately deprotected under the conditions described for the racemate Example 574 to give the enantiopure title compounds. The absolute stereochemistry of the samples was unassigned, Example 575 displays a (+) rotation and Example 576 displays a (-) rotation. Mass spectral and IH NMR data for both enantiomers are identical to that of the racemic sample.
Example 577: methyl 5-(2-(3,5-dimethoxyphenylamino)-4-(3-(trifluoromethyl)-lH-pyrazol-l- yl)pyrimidin-5-yl)-2-(2-(methylsulfonyl)ethylamino)nicotinate
Figure imgf000536_0001
Methyl 5-bromo-2-(2-(methylsulfonyl)ethylamino)nicotinate Intermediate 188 (200 mg, 0.59 mmol), PdC12(dppf)-CH2Cl2 adduct (72.7 mg, 0.09 mmol), bis(pinacolato)diboron (181 mg, 0.71 mmol) and potassium acetate (175 mg, 1.78 mmol) were combined in dioxane (4 mL). Argon was bubbled through the mixture for 10 minutes and then it was warmed at 90 0C for 18 hours. The dark suspension was filtered through a celite pad and the solids were rinsed thoroughly with dichloromethane. The filtrate was concentrated to give the crude boronate ester intermediate: methyl 2-(2-(methylsulfonyl)ethylamino)-5-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2- yl)nicotinate (420 mg). This material was combined with 5-bromo-N-(3,5-dimethoxyphenyl)-4- (3-(trifluoromethyl)-lH-pyrazol-l-yl)pyrimidin-2-amine Intermediate 215 (133 mg, 0.30 mmol), Tris(dibenzylideneacetone)dipalladium(0) (27.4 mg, 0.03 mmol) , Sodium carbonate (95 mg, 0.90 mmol) and 2-Dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (42.8 mg, 0.09 mmol) then suspended in acetonitrile (3 mL) and water (0.75 mL). The mixture was degassed with argon stream for 10 min then heated at 80 0C for 1 hour. The mixture was diluted with acetonitrile and adsorbed on 10 ml silica gel. Flash chromatography (0 to 50% acetonitrile in dichloromethane, 25g cartridge) gave the title compound as a yellow solid (133 mg).
MS: ES+ 662 for C26H26F3N7O6S.
IH NMR (400 MHz, DMSO-d6) δ ppm 3.02 (s, 3 H), 3.41 (t, 2 H), 3.74 (s, 6 H), 3.77 (s, 3 H),
3.89 - 3.99 (m, 2 H), 6.20 (t, 1 H), 7.02 (d, 1 H),7.10 (d, 2 H), 7.80 (d, 1 H), 8.19 (t, 1 H), 8.22 (d,
1 H), 8.43 (d, 1 H), 8.77 (s, 1 H), 10.12 (s, 1 H)
The compounds in the table below were prepared using the general procedure described above for Example 577 and the starting materials listed.
Figure imgf000537_0001
Figure imgf000538_0001
Figure imgf000539_0001
The compounds in the below table were prepared using the general method described above for Example 214 using IN sodium hydroxide (2 equivalents), dioxane : THF (1:1) as solvent and the starting material indicated.
Figure imgf000540_0001
Figure imgf000541_0001
Figure imgf000542_0002
General method for biaryl synthesis
Figure imgf000542_0001
A suspension of 5-bromo-N-(3-chloro-4-fluorophenyl)-4-[3-(trifluoromethyl)-lH- pyrazol-l-yl]pyrimidin-2-amine (Intermediate 115, 1 eq), boronate derivative (1.1 eq), [1,1 '-bis (diphenylphosphino)ferrocene]dichloropalladium(II) (20 mol%) and sodium carbonate (1 eq) in acetonitrile/water (4 : 1) was degassed and heated to 90 0C for 15-20 min under inert atmosphere.
The solvent was removed in vacuo and the crude mixture taken in CHCl3 was washed with water, brine, dried over Na2SO4, filtered and concentrated. The crude material was purified by silica gel column chromatography using chloroform: methanol (9:1) as eluent to give the product. The compounds in the below table were prepared using this general procedure and the starting material specified.
Figure imgf000543_0001
Figure imgf000544_0001
General method for the hydrolysis of amino ester derivatives
Figure imgf000545_0001
Method I:
To the amino ester derivative (1 eq) taken in a mixture of tetrahydrofuran and water (3:1), was added Barium hydroxide monohydrate (2 eq) and allowed to stir at room temperature for 12 h. After completion of the reaction, the mixture was then carefully acidified with 1 N HCl and the precipitate formed was filtered, washed with water and dried to yield the product. Method II:
To the amino ester derivative (1 eq) taken in a mixture of tetrahydrofuran and water (3:1), was added Sodium hydroxide (2 eq) and allowed to stir at room temperature for 3 h. After completion of the reaction, the mixture was then carefully acidified with 1 N HCl and the precipitate formed was filtered, washed with water and dried to yield the product. Method III:
To the amino ester derivative (1 eq) taken in a mixture of acetonitrile and water (3:1), was added 1 N aq. Sodium hydroxide (2.5 eq) and the mixture was heated at 85 0C for 1 h. After completion of the reaction, the mixture was then carefully acidified with 1.5 N HCl and the precipitate formed was filtered, washed with water and dried. It was further dissolved in minimum amount of ethyl acetate, then hexane was added dropwise with constant stirring. The precipitate formed was filtered, washed with water and dried to yield to yield the product. Method IV:
To the amino ester derivative (1 eq) taken in a mixture of dioxane and water (3:1), was added Sodium hydroxide (2 eq) and the reaction mixture allowed to stir at room temperature for 3 h. After completion of the reaction, the mixture was then carefully acidified with 1 N HCl, extracted with ethyl acetate. The organic layer was concentrated and the solid obtained was dissolved in minimum amount of CH2Cl2. Hexane was added dropwise with constant stirring and the precipitate formed was filtered, washed with water and dried to yield the product. The compounds in the below table were prepared using this general procedure and the starting material specified.
Figure imgf000546_0001
Figure imgf000547_0001
Figure imgf000548_0002
c) Method I; d) Method II; e) Method III; f) Method IV
Example 603: methyl l-(3-{2-[(3-chloro-4-fluorophenyl)amino1-4-[3-(trifluoromethyl)-l//- Pyrazol-l-yl1pyrimidin-5-yl}phenyl)pyrrolidine-3-carboxylate
Figure imgf000548_0001
A suspension of 5-bromo-N-(3-chloro-4-fluorophenyl)-4-[3-(trifluoromethyl)-lΗ- pyrazol-l-yl]pyrimidin-2-amine(Intermediate 115, 0.34 mmol, 0.15 g), the mixture of methyl 1- [3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]pyrrolidine-3-carboxylate and {3-[3- (methoxycarbonyl)pyrrolidin-l-yl]phenyl}boronic acid (Intermediate 208, 0.34 mmol based on the boronic ester, 113 mg), [1,1 '-bis (diphenylphosphino)ferrocene]dichloropalladium(II) (0.068 mmol, 50 mg) and sodium carbonate (0.44 mmol, 47 mg) in acetonitrile/water (20 mL : 5 mL) was degassed and heated to 90 0C for 15-20 min under inert atmosphere. The solvent was removed under vacuum and the crude mixture was taken in CHCl3 (50 mL), washed with water, brine, dried over Na2SO4, filtered and concentrated. The crude material was purified by silica gel column chromatography using 12 % ethyl acetate/hexanes as eluent to yield 65 mg of the title compound.
Figure imgf000549_0001
Example 604: l-(3-{2-[(3-chloro-4-fluorophenyl)amino1-4-[3-(trifluoromethyl)-lH-pyrazol- l-ylipyrimidin-S-vUphenvDpyrrolidine-S-carboxylic acid
To a suspension of Example 603 (0.15 mmol, 85 mg) taken in acetonitrile (6 mL) and water (3 mL), was added NaOH (0.42 mmol, 18 mg) and the mixture heated to 85 0C for 1 h. The reaction mixture was concentrated in vacuo, acidified with 1.5 N HCl and extracted with ethyl acetate (20 mL). The organic layer was washed with brine (10 mL), dried over Na2SO4 and concentrated in vacuo. The crude mass was purified by silica gel column chromatography (60-120 mesh) using chloroform and methanol (1%) as eluent to give the title compound (31 mg).
Figure imgf000550_0002
General procedure for ethyl (2£)-3-(3-{2-[arylamino1-4-[3-(trifluoromethyl)-lH-pyrazol-l- yl1pyrimidin-5-yl}phenyl)prop-2-enoate and ethyl (2£)-3-(3-{2-[arylamino1-4-[5-methyl-3- (trifluoromethyl)-lH-pyrazol-l-yl1pyrimidin-5-yl}phenyl)prop-2-enoate
Figure imgf000550_0001
suspension of 5-bromo-N-(aryl)-4-[3-(trifluoromethyl)-lH-pyrazol-l-yl]pyrimidin-2-amine or 5- bromo-N-(aryl)-4-[5-methyl-3-(trifluoromethyl)-lH-pyrazol-l-yl]pyrimidin-2-amine (1 eq), {3- [(l£)-3-ethoxy-3-oxoprop-l-en-l-yl]phenyl}boronic acid (1.1 - 1.2 eq), [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (20 mol%) and sodium carbonate (1 eq) in acetonitrile/water (4 : 1) was degassed and heated to 90 0C for 15-30 min under inert atmosphere. The solvent was removed in vacuo and the crude mixture taken in CHCl3 was washed with water, brine, dried over Na2SO4, filtered and concentrated. The crude material was purified by silica gel column chromatography using chloroform: methanol (9:1) as eluent to give the product.
Figure imgf000551_0001
Figure imgf000552_0001
Example 611: ethyl (2£)-3-(3-{2-r(3,5-difluorophenyl)amino1-4-r3-(trifluoromethyl)-lH-
Pyrazol-l-yl1pyrimidin-5-yl}phenyl)prop-2-enoate
Example 612: ethyl (2£)-3-(3-{2-r(3,5-difluorophenyl)amino1-4-r5-methyl-3-
(trifluoromethyl)-lH-pyrazol-l-yl1pyrimidin-5-yl}phenyl)prop-2-enoate
Figure imgf000553_0001
A suspension of either 3-(trifluoromethyl)-lH-pyrazole or 5-methyl-3-(trifluoromethyl)-lH- pyrazole (1.2-1.5 eq), potassium te/t-butoxide (1.5 eq) and ethyl (2£>3-(3-{2-[(3,5- difluorophenyl)amino]-4-(methylsulfonyl)pyrimidin-5-yl}phenyl)prop-2-enoate (Intermediate 223, 1 eq) in DMSO (3 rnL) was subjected to microwave irradiation at 130 0C for 1 h. After the reaction was cooled to RT, the mixture was diluted with EtOAc, washed successively with water and brine. The organic layer was dried over sodium sulphate, filtered, concentrated and further purified by silica gel column chromatography using ethyl acetate/hexanes to yield the product. The compounds in the below table were prepared using this procedure and the specified starting material.
Figure imgf000554_0001
Example 613: ethyl (2£)-3-r3-(2-{r3-(methylsulfonyl)phenyl1amino}-4-r3-(trifluoromethyl)- lH-Pyrazol-l-yl1pyrimidin-5-yl)phenyl1prop-2-enoate
Example 614: ethyl (2£)-3-r3-(2-{r3-(methylsulfonyl)phenyl1amino}-4-r5-methyl-3-
(trifluoromethyl)-lH-pyrazol-l-yl1pyrimidin-5-yl)phenyl1prop-2-enoate NaH (60 % dispersion in mineral oil, 2 eq) was suspended in 1 rnL of DMF and stirred for about 5 min at 0 0C. Then either 3-(trifluoromethyl)-lH-pyrazole or 5-methyl-3-(trifluoromethyl)-lH- pyrazole (2 eq) in DMF (2 rnL) was added dropwise at 0 0C for about 10 min and stirring continued for about 20 min under N2. Then ethyl (2£)-3-{3-[4-(methylsulfonyl)-2-{ [3- (methylsulfonyl)phenyl] amino }pyrimidin-5-yl]phenyl}prop-2-enoate (Intermediate 224, 1 eq) in DMF was added dropwise and the reaction was stirred overnight at room temperature. After completion of the reaction, water was added and the solid obtained was filtered off, dried and purified by silica gel column chromatography using ethyl acetate/hexanes as eluent to yield the product. The compounds in the below table were prepared using this procedure and the specified starting material.
Figure imgf000555_0001
Figure imgf000556_0002
Hydrolysis of carboxylic esters to acids
Figure imgf000556_0001
Example 615: (2£)-3-(3-{2-r(3,5-dimethoxyphenyl)amino1-4-r3-(trifluoromethyl)-lH- Pyrazol-l-yl1pyrimidin-5-yl}phenyl)prop-2-enoic acid
To a suspension of Example 605 (1 eq) taken in dioxane and water (1:1), was added Barium hydroxide monohydrate (2 eq) and the mixture was stirred at RT for 2 days. The reaction mixture was concentrated in vacuo, acidified with 1 N HCl and the precipitate formed was filtered off. The solid was taken in acetonitrile and stirred for 1 h. The solid was then filtered off, washed with dichloromethane and dried to give the title compound.
Example 616: (2£)-3-(3-{2-[(3,5-dimethoxyphenyl)amino1-4-[5-methyl-3-(trifluoromethyl)- l//-Pyrazol-l-yl1pyrimidin-5-yl}phenyl)prop-2-enoic acid
To a suspension of Example 606 (1 eq) taken in dioxane and water (1:1), was added Barium hydroxide monohydrate (2 eq) and the mixture was warmed to 60 0C for 2 h. The reaction mixture was concentrated in vacuo, acidified with 1 N HCl and the precipitate formed was filtered and dried to give the title compound.
Example 617: (2£)-3-(3-{2-r(3,5-dimethylphenyl)amino1-4-r3-(trifluoromethyl)-lH-pyrazol- l-yl1pyrimidin-5-yl}phenyl)prop-2-enoic acid To a suspension of Example 607 (1 eq) taken in THF and water (2:1), was added Barium hydroxide monohydrate (3 eq) and the mixture was allowed to stir at RT for 2 days and refluxed at 60 0C for 2 days. The reaction mixture was concentrated in vacuo, acidified with 1 N HCl and the precipitate formed was filtered, washed with water and dried to give the title compound.
Example 618: (2£)-3-(3-{2-r(3,5-dimethylphenyl)amino1-4-r5-methyl-3-(trifluoromethyl)- lH-Pyrazol-l-yl1pyrimidin-5-yl}phenyl)prop-2-enoic acid
To a suspension of Example 608 (1 eq) taken in THF and water (2:1), was added sodium hydroxide (2 eq) and the mixture was heated to 50 0C for 5 days. The reaction mixture was concentrated in vacuo, acidified with 1 N HCl and the precipitate formed was filtered, washed with water and dried to give the title compound.
Example 619: (2£)-3-(3-{2-r(3,5-difluorophenyl)amino1-4-r3-(trifluoromethyl)-lH-pyrazol- l-yl1pyrimidin-5-yl}phenyl)prop-2-enoic acid
To a suspension of Example 611 (1 eq) taken in THF and water (2:1), was added Barium hydroxide monohydrate (4 eq) and the mixture was allowed to stir overnight at RT. The reaction mixture was concentrated in vacuo, acidified with 1 N HCl and the precipitate formed was filtered off. The solid was taken in 10 mL of dichloromethane and stirred for 1 h. The solid was then filtered off, washed with dichloromethane and dried to give the title compound.
Example 620: (2£)-3-(3-{2-r(3,5-difluorophenyl)amino1-4-r5-methyl-3-(trifluoromethyl)-lH- Pyrazol-l-yl1pyrimidin-5-yl}phenyl)prop-2-enoic acid
To a suspension of Example 612 (1 eq) taken in dioxane and water (1:1), was added Barium hydroxide monohydrate (4 eq) and the mixture was heated overnight at 70 0C. The reaction mixture was concentrated in vacuo, acidified with 1 N HCl and the precipitate formed was filtered off. The solid was taken in dichloromethane and stirred for 1 h. The solid was then filtered off, washed with dichloromethane and dried to give the title compound.
Example 621: (2£)-3-(3-{2-r(3-fluorophenyl)amino1-4-r3-(trifluoromethyl)-lH-pyrazol-l- yl1pyrimidin-5-yl}phenyl)prop-2-enoic acid To a suspension of Example 609 (1 eq) taken in THF and water (1:1), was added lithium hydroxide monohydrate (4 eq) and the mixture was stirred overnight at RT. The reaction mixture was concentrated in vacuo, acidified with 1 N HCl and the precipitate formed was filtered off.
The solid was taken in acetonitrile and stirred overnight. The solid was then filtered off, washed with acetonitrile and dried to give the title compound.
Example 622: (2£)-3-(3-{2-r(3-fluorophenyl)amino1-4-r5-methyl-3-(trifluoromethyl)-lH-
Pyrazol-l-yl1pyrimidin-5-yl}phenyl)prop-2-enoic acid
To a suspension of Example 610 (1 eq) taken in THF and water (1:1), was added lithium hydroxide monohydrate (4 eq) and the mixture was stirred at RT for 2 days. The reaction mixture was concentrated in vacuo, acidified with 1 N HCl and the precipitate formed was filtered off. The solid was taken in acetonitrile and stirred for 1 h. The solid was then filtered off, washed with acetonitrile and dried to give the title compound.
Example 623: (2£)-3-r3-(2-{r3-(methylsulfonyl)phenyl1amino}-4-r3-(trifluoromethyl)-lH- pyrazol-l-ylipyrimidin-S-vDphenyliprop^-enoic acid
To a suspension of Example 613 (1 eq) taken in dioxane and water (2:1), was added sodium hydroxide (2 eq) and the mixture was allowed to stir overnight at RT. The reaction mixture was concentrated in vacuo, acidified with 1 N HCl and the precipitate formed was filtered, washed with water and dried to give the title compound.
Example 624: (2£)-3-r3-(2-{r3-(methylsulfonyl)phenyl1amino}-4-r5-methyl-3-
(trifluoromethvD-lH-pyrazol-l-ylipyrimidin-S-vDphenyliprop^-enoic acid
To a suspension of Example 614 (1 eq) taken in dioxane and water (2:1), was added sodium hydroxide (2 eq) and the mixture was allowed to stir overnight at RT. The reaction mixture was concentrated in vacuo, acidified with 1 N HCl and the precipitate formed was filtered, washed with water and dried to give the title compound.
Figure imgf000559_0001
Figure imgf000560_0001
Figure imgf000561_0001
Figure imgf000562_0002
General procedure for the synthesis of ethyl 5-{2-[arylamino1-4-[lΗ-azol-l-yl1pyrimidin-5- vUpyridine-3-carboxylate
Figure imgf000562_0001
A suspension of either 5-bromo-N-(aryl)-4-[3-(trifluoromethyl)-lH-pyrazol-l-yl]pyrimidin-2- amine or 5-bromo-N-(aryl)-4-[5-methyl-3-(trifluoromethyl)-lH-pyrazol-l-yl]pyrimidin-2-amine (1 eq), ethyl 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine-3-carboxylate (1.1-1.2 eq), [l,r-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (10-20 mol%) and sodium carbonate (1-2 eq) in acetonitrile/water (4:1) was degassed and heated to 90 0C for 15-30 min under inert atmosphere. The solvent was removed in vacuo and the crude mixture taken in CHCl3 was washed with water, brine, dried over Na2SO4, filtered and concentrated. The crude material was purified by silica gel column chromatography using 30 % ethyl acetate / hexanes as eluent to give the product. The compounds in the below table were prepared using this method and the specified starting material.
Figure imgf000563_0001
Figure imgf000564_0001
Example 631: ethyl 5-{2-[(3,5-difluorophenyl)amino1-4-[3-(trifluoromethyl)-lH-pyrazol-l- yl1pyrimidin-5-yl}pyridine-3-carboxylate
Example 632: ethyl 5-{2-[(3,5-difluorophenyl)amino1-4-[5-methyl-3-(trifluoromethyl)-lH-
Pyrazol-l-yl1pyrimidin-5-yl}pyridine-3-carboxylate A suspension of either 3-(trifluoromethyl)-lH-pyrazole or 5-methyl-3-(trifluoromethyl)-lH- pyrazole (1.2-1.5 eq), potassium te/t-butoxide (1 eq) and ethyl 5-{2-[(3,5-difluorophenyl)amino]- 4-(methylsulfonyl)pyrimidin-5-yl}pyridine-3-carboxylate Intermediate 225 (1 eq) in DMSO was subjected to microwave irradiation at 130 0C for 1 h. After the reaction was cooled to RT, the mixture was diluted with EtOAc, washed successively with water and brine. The organic layer was dried over sodium sulphate, filtered, concentrated and further purified by silica gel column chromatography using ethyl acetate/hexanes to yield the product. The compounds in the below table were prepared using this method and the specified starting material.
Figure imgf000565_0001
Figure imgf000566_0001
Example 633: ethyl 5-(2-{r3-(methylsulfonyl)phenyl1amino}-4-[3-(trifluoromethyl)-l//-
Pyrazol-l-yl1pyrimidin-5-yl)pyridine-3-carboxylate
Example 634: ethyl 5-(2-{[3-(methylsulfonyl)phenyl1amino}-4-[5-methyl-3-
(trifluoromethyl)-l//-pyrazol-l-yl1pyrimidin-5-yl)pyridine-3-carboxylate
NaH (60 % dispersion in mineral oil, 2 eq) was dissolved in 1 rnL of DMF and stirred for about 5 min at 0 0C. Then either 3-(trifruoromethyl)-lH-pyrazole or 5-methyl-3-(trifruoromethyl)-lH- pyrazole (2 eq) in DMF (2 rnL) was added dropwise at 0 0C for about 10 min and stirring continued for about 20 min under N2. Then ethyl 5-[4-(methylsulfonyl)-2-{ [3-
(methylsulfonyl)phenyl] amino }pyrimidin-5-yl]pyridine-3-carboxylate (Intermediate 226, 1 eq) in DMF was added dropwise and the reaction was stirred overnight at room temperature. Water was added and the solid obtained was filtered off, dried and purified by silica gel column chromatography using ethyl acetate/hexanes as eluent to yield the product. The compounds in the below table were prepared using this method and the specified starting material.
Figure imgf000567_0001
Example 635: 5-{2-[(3,5-Dimethoxyphenyl)amino1-4-[3-(trifluoromethyl)-lH-pyrazol-l- ylipyrimidin-S-vUpyridine-S-carboxylic acid
To a suspension of Example 625 (1 eq) taken in dioxane and water (1:1) was added barium hydroxide monohydrate (2 eq) and the mixture was stirred at RT for 2 days. The reaction mixture was concentrated in vacuo, acidified with 1 N HCl and the precipitate formed was filtered, washed with water and dried to give the title compound. Example 636: 5-{2-[(3,5-Dimethoxyphenyl)amino1-4-[5-methyl-3-(trifluoromethyl)-lH- pyrazol-l-yllpyrimidin-S-ylIpyridine-S-carboxylic acid
To a suspension of Example 626 (1 eq) taken in dioxane and water (1:1), was added Barium hydroxide monohydrate (2 eq) and the mixture was stirred at RT for 24 h. The reaction mixture was concentrated in vacuo, acidified with 1 N HCl and the precipitate formed was filtered and dried to give the title compound.
Example 637: 5-{2-[(3,5-dimethylphenyl)amino1-4-[3-(trifluoromethyl)-lH-pyrazol-l- yllpyrimidin-S-ylIpyridine-S-carboxylic acid
To a suspension of Example 627 (1 eq) taken in THF and water (1:1), was added sodium hydroxide (2 eq) and the mixture was stirred at RT for 2 days. The reaction mixture was concentrated in vacuo, acidified with 1 N HCl and the precipitate formed was filtered, washed with water and dried to give the title compound.
Example 638: 5-{2-[(3,5-dimethylphenyl)amino1-4-[5-methyl-3-(trifluoromethyl)-lH- pyrazol-l-ylipyrimidin-S-vUpyridine-S-carboxylic acid
To a suspension of Example 628 (1 eq) taken in THF and water (1:1), was added sodium hydroxide (2 eq) and the mixture was heated to 50 0C for 5 days. The reaction mixture was concentrated in vacuo, acidified with 1 N HCl and the precipitate formed was filtered, washed with water and dried to give the title compound.
Example 639: 5-{2-[(3,5-difluorophenyl)amino1-4-[3-(trifluoromethyl)-lH-pyrazol-l- yllpyrimidin-S-ylIpyridine-S-carboxylic acid
To a suspension of Example 631 (1 eq) taken in THF and water (3:1), was added Barium hydroxide monohydrate (2 eq) and the mixture was stirred at RT for 1 h. The reaction mixture was concentrated in vacuo, acidified with 1 N HCl and the precipitate formed was filtered, washed with water and dried to give the title compound. Example 640: 5-{2-[(3,5-difluorophenyl)amino1-4-[5-methyl-3-(trifluoromethyl)-lH- pyrazol-l-yllpyrimidin-S-ylIpyridine-S-carboxylic acid
To a suspension of Example 632 (1 eq) taken in THF and water (2:1), was added sodium hydroxide (2 eq) and the mixture was allowed to stir at RT for 2 h. The reaction mixture was concentrated in vacuo, acidified with 1 N HCl and the precipitate formed was filtered, washed with water and dried to give the title compound.
Example 641: 5-{2-[(3-fluorophenyl)amino1-4-[3-(trifluoromethyl)-lH-pyrazol-l- yllpyrimidin-S-ylIpyridine-S-carboxylic acid To a suspension of Example 629 (1 eq) taken in THF and water (1:1), was added lithium hydroxide monohydrate (4 eq) and the mixture was stirred for 30' at RT. The reaction mixture was concentrated in vacuo, acidified with 1 N HCl and the precipitate formed was stirred with acetonitrile. It was then filtered, washed with acetonitrile and dried to give the title compound.
Example 642: 5-{2-[(3-fluorophenyl)amino1-4-[5-methyl-3-(trifluoromethyl)-lH-pyrazol-l- yllpyrimidin-S-ylIpyridine-S-carboxylic acid
To a suspension of Example 630 (1 eq) taken in acetonitrile and water (1:1), was added sodium hydroxide (4 eq) and the mixture was stirred at RT for 1 h. The reaction mixture was concentrated in vacuo, acidified with 1 N HCl and the precipitate formed was filtered, washed and dried to give the title compound.
Example 643: 5-(2-{r3-(methylsulfonyl)phenyl1amino}-4-[3-(trifluoromethyl)-lH-pyrazol-l- ylipyrimidin-S-vDpyridine-S-carboxylic acid
To a suspension of Example 633 (1 eq) taken in dioxane and water (2:1), was added Barium hydroxide monohydrate (2 eq) and the mixture was allowed to stir overnight at RT. The reaction mixture was concentrated in vacuo, acidified with 1 N HCl and the precipitate formed was filtered, washed with water and dried to give the title compound. Example 644: 5-(2-{r3-(methylsulfonyl)phenyl1amino}-4-[5-methyl-3-(trifluoromethyl)-lH- pyrazol-l-yllpyrimidin-S-vDpyridine-S-carboxylic acid
To a suspension of Example 634 (1 eq) taken in dioxane and water (2:1), was added Barium hydroxide monohydrate (2 eq) and the mixture was allowed to stir overnight at RT. The reaction mixture was concentrated in vacuo, acidified with 1 N HCl and the precipitate formed was filtered, washed with water and dried to give the title compound.
Figure imgf000570_0001
Figure imgf000571_0001
Figure imgf000572_0001
Figure imgf000573_0002
Example 645: methyl 5-{2-[(3,5-dimethylphenyl)amino1-4-[5-methyl-3-(trifluoromethyl)- l//-Pyrazol-l-yl1pyrimidin-5-yl}-2-methoxypyridine-3-carboxylate
Figure imgf000573_0001
A suspension of 5-bromo-N-(3,5-dimethylphenyl)-4-[5-methyl-3-(trifluoromethyl)-lH-pyrazol-l- yl]pyrimidin-2-amine (Intermediate 218, 0.59 mmol, 250 mg), methyl 2-methoxy-5-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine-3-carboxylate(0.58 mmol, 171 mg), [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (0.099 mmol, 81 mg) and sodium carbonate(0.58 mmol, 61 mg) were taken in a mixture of acetonitrile and water (20 mL : 5 mL) and heated to 90 0C for 10-20'. Acetonitrile was concentrated in vacuo. The residue was taken in ethyl acetate, washed with water and brine, dried over sodium sulphate, filtered and concentrated. The crude mass was purified by silica gel column chromatography (230-400 mesh) using 20 % ethyl acetate/hexanes to yield 150 mg of the product.
Figure imgf000574_0002
Example 646: 5-{2-[(3,5-dimethylphenyl)amino1-4-[5-methyl-3-(trifluoromethyl)-l//- pyrazol-l-yllpyrimidin-S-vU^-methoxypyridine-S-carboxylic acid
Figure imgf000574_0001
To a suspension of methyl 5-{2-[(3,5-dimethylphenyl)amino]-4-[5-methyl-3-(trifluoromethyl)- lH-pyrazol-l-yl]pyrimidin-5-yl}-2-methoxypyridine-3-carboxylate (Example 645, 0.29 mmol, 0.15 g) in TΗF and water (1:1), NaOH (0.58 mmol, 23 mg) was added and the mixture was stirred for 4 hours at rt. The TΗF was removed in vacuo and the reaction mixture diluted with water, acidified to pΗ = 2 using 1.5 N HCl and the solid that precipitated was filtered and dried to get 0.065 g of the title compound.
Figure imgf000575_0002
Example 647: methyl 5-{2-[(3,5-dimethylphenyl)amino1-4-[3-(trifluoromethyl)-lH-pyrazol- l-yl1pyrimidin-5-yl}-2-methoxypyridine-3-carboxylate
Figure imgf000575_0001
A solution of 5-bromo-N-(3,5-dimethylphenyl)-4-[3-(trifluoromethyl)-lH-pyrazol-l- yl]pyrimidin-2-amine (Intermediate 217, 0.8 mmol, 330 mg), methyl 2-methoxy-5-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine-3-carboxylate (0.8 mmol, 234 mg), [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II)complex with CH2Cl2 (0.16 mmol, 130 mg) and sodium carbonate (0.8 mmol, 85 mg) in acetonitrile (16 mL)/water (4 mL) was degassed and heated to 90 0C for 20' under nitrogen. The reaction mixture was concentrated in vacuo. The residue obtained was taken in ethyl acetate, washed with water and brine, dried over sodium sulfate and concentrated. The crude mass was purified by silica gel column chromatography (60- 120 mesh) using 15% ethyl acetate/hexanes to yield 150 mg of methyl 5-{2-[(3,5- dimethylphenyl)amino] -4-[3-(trifluoromethyl)- lH-pyrazol- 1 -yl]pyrimidin-5-yl } -2- methoxypyridine-3-carboxylate.
Figure imgf000576_0002
Example 648: 5-{2-[(3,5-dimethylphenyl)amino1-4-[3-(trifluoromethyl)-lH-pyrazol-l- yl1pyrimidin-5-yl}-2-methoxypyridine-3-carboxylic acid
Figure imgf000576_0001
A solution of methyl 5-{2-[(3,5-dimethylphenyl)amino]-4-[3-(trifluoromethyl)-lH-pyrazol-l- yl]pyrimidin-5-yl}-2-methoxypyridine-3-carboxylate (Example 647, 0.3 mmol, 150 mg) and sodium hydroxide (0.6 mmol, 24 mg) in TΗF (3 mL) and water (3 mL) was stirred at room temperature for 3 h. TΗF was removed in vacuo and the reaction mixture was neutralized using 1.5 N HCl. The solid that precipitated out was filtered, washed with water and dried to give the title compound (65 mg).
Figure imgf000577_0002
General method for the synthesis of ethyl (2£)-3-(3-{2-[arylamino1-4-[3-(trifluoromethyl)- lH-Pyrazol-l-yl1pyrimidin-5-yl}phenyl)prop-2-enoate, ethyl (2£)-3-(3-{2-[arylamino1-4-[5- methyl-3-(trifluoromethyl)-lH-pyrazol-l-yl1pyrimidin-5-yl}phenyl)prop-2-enoate and (2£)- 3-[3-(2-{[3-methoxy-5-(methylsulfonyl)phenyl1amino}-4-[5-methyl-3-(trifluoromethyl)-lH- pyrazol-l-ylipyrimidin-S-vDphenyliprop^-enoic acid
Figure imgf000577_0001
A suspension of 5-bromo-N-(aryl)-4-[3-(trifluoromethyl)-lH-pyrazol-l-yl]pyrimidin-2-amine derivative or 5-bromo-N-(aryl)-4-[5-methyl-3-(trifluoromethyl)-lH-pyrazol-l-yl]pyrimidin-2- amine derivative (1 eq), {3-[(l£')-3-ethoxy-3-oxoprop-l-en-l-yl]phenyl}boronic acid or 3-(trans- 2-carboxyvinyl)phenylboronic acid (1.1 - 1.2 eq), [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (20 mol%) and sodium carbonate (1 eq) in acetonitrile/water (4 : 1) was degassed and heated to 90 0C for 15-30 min under inert atmosphere. The solvent was removed in vacuo and the crude mixture taken in CHCl3 was washed with water, brine, dried over Na2SO4, filtered and concentrated. The crude material was purified by silica gel column chromatography using chloroform: methanol (9:1) as eluent to give the product. The compounds in the below table were prepared using the above method and the starting material specified.
Figure imgf000578_0001
Figure imgf000579_0001
Figure imgf000580_0002
Example 654: ethyl (2£)-3-{3-[2-{[3-methoxy-5-(methylsulfonyl)phenyl1amino}-4- (methylsulfonyl)pyrimidin-5-yl1phenyl}prop-2-enoate
Figure imgf000580_0001
suspension of 3-(trifluoromethyl)-lH-pyrazole (1.2-1.5 eq), potassium te/t-butoxide (1.5 eq) and ethyl (2£')-3-{3-[2-{ [3-methoxy-5-(methylsulfonyl)phenyl]amino}-4-(methylsulfonyl)pyrimidin- 5-yl]phenyl}prop-2-enoate (Intermediate 249, 1 eq) in DMSO (3 rnL) was subjected to microwave irradiation at 130 0C for 1 h. After the reaction was cooled to RT, the mixture was diluted with EtOAc, washed successively with water and brine. The organic layer was dried over sodium sulphate, filtered, concentrated and further purified by silica gel column chromatography using ethyl acetate/hexanes to yield the title compound.
Figure imgf000581_0002
General procedure for the synthesis of (2£)-3-(3-{2-(arylamino)-4-[-lH-pyrazol-l- yl1pyrimidin-5-yl}phenyl)prop-2-enoic acid
Figure imgf000581_0001
To 1 eq of the ethyl (2£)-3-(3-{2-[arylamino]-4-[lH-azol-l-yl]pyrimidin-5-yl}phenyl)prop-2- enoate derivative taken in dioxane (5 rnL), was added Barium hydroxide (2- 6 eqs) and was warmed to 60 0C for 1 to 2 h. The reaction mixture was carefully acidified with 1 N HCl and the solid that precipitated was filtered, washed with water and dried in vacuo to yield the desired carboxylic acid. The compounds in the below table were prepared using the above method and the starting material specified.
Figure imgf000582_0001
Figure imgf000583_0001
Figure imgf000584_0002
General procedure for the synthesis of ethyl 5-(2-{arylamino}-4-[l//-azol-l-yl1pyrimidin-5- yl)pyridine-3-carboxylate
Figure imgf000584_0001
A suspension of 5-bromo-N-(aryl)-4-[3-(trifluoromethyl)-lH-pyrazol-l-yl]pyrimidin-2-amine or 5-bromo-N-(aryl)-4-[5-methyl-3-(trifluoromethyl)-lH-pyrazol-l-yl]pyrimidin-2-amine (1 eq), ethyl 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine-3-carboxylate (1.1-1.2 eq), [1,1'- bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (10-20 mol%) and sodium carbonate (1- 2 eq) in acetonitrile/water (4:1) was degassed and heated to 90 0C for 15-30 min under inert atmosphere. The solvent was removed in vacuo and the crude mixture taken in CHCl3 was washed with water, brine, dried over Na2SO4, filtered and concentrated. The crude material was purified by silica gel column chromatography using 30 % ethyl acetate / hexanes as eluent to give the product. The compounds in the below table were prepared using this method and the specified starting material.
Figure imgf000585_0001
Figure imgf000586_0002
Example 665: ethyl 5-(2-{r3-methoxy-5-(methylsulfonyl)phenyl1amino}-4-[3- (trifluoromethyl)-l//-pyrazol-l-yl1pyrimidin-5-yl)pyridine-3-carboxylate Example 666: ethyl 5-(2-{r3-methoxy-5-(methylsulfonyl)phenyl1amino}-4-[5-methyl-3- (trifluoromethyl)-l//-pyrazol-l-yl1pyrimidin-5-yl)pyridine-3-carboxylate
Figure imgf000586_0001
A suspension of 5-bromo-N-[3-methoxy-5-(methylsulfonyl)phenyl]-4-[3-(trifluoromethyl)-lH- pyrazol-l-yl]pyrimidin-2-amine (Intermediate 250) or 5-bromo-iV-[3-methoxy-5- (methylsulfonyl)phenyl] -4- [5-methyl-3-(trifluoromethyl)- lH-pyrazol- 1 -yl]pyrimidin-2-amine (Intermediate 251) ( 1 eq), ethyl 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine-3- carboxylate (1.1-1.2 eq), [l,r-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (10-20 mol%) and sodium carbonate (1-2 eq) in acetonitrile/water (4:1) was degassed and heated to 90 0C for 15-30 min under inert atmosphere. The solvent was removed in vacuo and the crude mixture taken in CHCl3 was washed with water, brine, dried over Na2SO4, filtered and concentrated. The crude material was purified by silica gel column chromatography using 50 % ethyl acetate / hexanes as eluent to give the product. The compounds in the below table were prepared following this procedure and using the specified starting material.
Figure imgf000587_0001
Figure imgf000588_0002
General procedure for the synthesis of 5-{2-(arylamino)-4-[lH-pyrazol-l-yl1pyrimidin-5- vUpyridine-3-carboxylic acid
Figure imgf000588_0001
To 1 eq of the ethyl 5-(2-{arylamino}-4-[lH-azol-l-yl]pyrimidin-5-yl)pyridine-3- carboxylate derivative taken in dioxane (5 rnL), was added 1 N aq. sodium hydroxide/Barium hydroxide (2- 6 eqs) and was heated to 60 0C for 1 h. The reaction mixture was carefully acidified with 1 N HCl and the solid that precipitated was filtered, washed with water and dried in vacuo to yield the desired carboxylic acid. The compounds in the below table were prepared following this procedure and using the specified starting material.
Figure imgf000589_0001
Figure imgf000590_0001
Figure imgf000591_0002
Example 674: methyl 5-{2-[(3,5-dimethoxyphenyl)amino1-4-[3-(trifluoromethyl)-l//- pyrazol-l-yllpyrimidin-S-vU^-methoxypyridine-S-carboxylate
Figure imgf000591_0001
A suspension of 5-bromo-N-(3,5-dimethoxyphenyl)-4-[3-(trifluoromethyl)-lH-pyrazol-l- yl]pyrimidin-2-amine (Intermediate 215, 0.36 mmol, 160 mg), methyl 2-methoxy-5-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine-3-carboxylate (0.36 mmol, 106 mg), [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with CH2Cl2 (0.073 mmol, 60 mg) and sodium carbonate (0.36 mmol, 40 mg) in acetonitrile/water (5 : 1) was degassed and heated to 100 0C for 45 min under an inert atmosphere. The reaction mass was passed through a celite bed. The solvent was concentrated in vacuo and the resultant crude mass was taken in EtOAc (50 mL), washed with water, brine, dried over Na2SO4, filtered and concentrated. The crude material was purified by silica gel column chromatography to give the title compound (120 mg).
Figure imgf000592_0002
Example 675: 5-{2-[(3,5-dimethoxyphenyl)amino1-4-[3-(trifluoromethyl)-l//-pyrazol-l- yl1pyrimidin-5-yl}-2-methoxypyridine-3-carboxylic acid
Figure imgf000592_0001
To 120 mg of methyl 5-{2-[(3,5-dimethoxyphenyl)amino]-4-[3-(trifluoromethyl)-lH- pyrazol-l-yl]pyrimidin-5-yl}-2-methoxypyridine-3-carboxylate (Example 674, 0.22 mmol) dissolved in a mixture of dioxane (1 mL) and water (0.33 mL), was added Barium hydroxide monohydrate (0.6 mmol, 114 mg) and allowed to stir overnight at room temperature. After completion of the reaction, the mixture was then carefully acidified with 1 N HCl and then diluted with ethyl acetate (50 mL), washed with water, brine, dried over Na2SO4 and concentrated to yield 70 mg of the title compound.
Figure imgf000593_0002
Example 676: methyl 5-{2-[(3,5-dimethoxyphenyl)amino1-4-[5-methyl-3-(trifluoromethyl)- l//-Pyrazol-l-yl1pyrimidin-5-yl}-2-methoxypyridine-3-carboxylate
Figure imgf000593_0001
A suspension of 5-bromo-N-(3,5-dimethoxyphenyl)-4-[5-methyl-3-(trifluoromethyl)-lH-pyrazol- l-yl]pyrimidin-2-amine (Intermediate 216, 0.44 mmol, 200 mg) methyl 2-methoxy-5-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine-3-carboxylate (0.48 mmol, 141 mg), [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.087 mmol, 64 mg) and sodium carbonate (0.44 mmol, 46 mg) in acetonitrile/water (8:2) was degassed and heated to 90 0C for 15 min under an inert atmosphere. After completion of the reaction, the reaction mass was diluted with ethyl acetate (30 mL). The organic layer was separated, washed with water and brine, dried over Na2SO4, filtered and concentrated. The crude material was purified by silica gel column chromatography using ethyl acetate/hexanes (45:55) to obtain 150 mg of Example 676.
Figure imgf000594_0002
Example 677: 5-{2-[(3,5-dimethoxyphenyl)amino1-4-[5-methyl-3-(trifluoromethyl)-l//- Pyrazol-l-yl1pyrimidin-5-yl}-2-methoxypyridine-3-carboxylic acid
Figure imgf000594_0001
To 150 mg of methyl 5-{2-[(3,5-dimethoxyphenyl)amino]-4-[5-methyl-3- (trifluoromethyl)- lH-pyrazol- 1 -yl]pyrimidin-5-yl } -2-methoxypyridine-3-carboxylate (Example 676, 0.27 mmol) taken in a mixture of tetrahydrofuran (1.5 mL), was added 1 N aq. sodium hydroxide (1.07 mmol) and stirred in a room temperature for 4 h. After completion of reaction, reaction mixture was then carefully acidified with 1 N HCl and the solid that precipitated was filtered, washed with water and dried in vacuo to yield 120 mg Example 677.
Figure imgf000595_0002
Example 678: 5-{2-[(3,5-dimethoxyphenyl)amino1-4-[3-(trifluoromethyl)-l//-pyrazol-l- yl1pyrimidin-5-yl}-N-methylpyridine-3-carboxamide
Figure imgf000595_0001
To a mixture of 5-{2-[(3,5-dimethoxyphenyl)amino]-4-[3-(trifluoromethyl)-lH-pyrazol- l-yl]pyrimidin-5-yl}pyridine-3-carboxylic acid (Example 635, 0.56 mmol, 270 mg), triethylamine (1.67 mmol, 0.23 mL, 0.17 g) and methylamine hydrochloride (1.11 mmol, 75 mg) in dichloromethane was added T3P in 50 % EtOAc (l.llmmol, 0.7 mL, 353 mg) at 0 0C. The reaction mixture was slowly raised to room temperature and stirred overnight. After completion of the reaction, the mixture was then diluted with dichloromethane (15 mL), and the organic layer was successively washed with water (2x20 mL), 10 % aq sodium bicarbonate solution (15 mL) and brine. The organic layer was dried over sodium sulphate and concentrated. The crude material was purified by silica gel column chromatography (230-400 mesh) using 8 % methanol/chloroform to yield 80 mg of the title compound.
Figure imgf000596_0002
Example 679: 5-{2-[(3,5-dimethoxyphenyl)amino1-4-[5-methyl-3-(trifluoromethyl)-l//- pyrazol-l-yllpyrimidin-5-yl}-./V-methylpyridine-3-carboxamide
Figure imgf000596_0001
To a mixture of 5-{2-[(3,5-dimethoxyphenyl)amino]-4-[5-methyl-3-(trifluoromethyl)-lH- pyrazol-l-yl]pyrimidin-5-yl}pyridine-3-carboxylic acid (Example 636, 0.35 mmol, 175 mg), triethylamine (1.05 mmol, 0.14 mL, 106 mg) and methylamine hydrochloride (0.70 mmol, 47 mg) in dichloromethane (10 mL) was added T3P (50 % EtOAc) (0.70 mmol,0.45 mL, 223 mg) slowly at 0 0C. The reaction mixture was slowly raised to room temperature and stirred for 3 h. The reaction mixture was then diluted with dichloromethane (15 mL) and the dichloromethane layer was washed successively with water (2x20 mL), 10 % aq sodium bicarbonate solution (15 mL) and brine. The organic layer was dried over sodium sulphate, filtered, concentrated and dried to yield 120 mg of the title compound.
Figure imgf000597_0002
Example 680: 5-{2-[(3,5-dimethoxyphenyl)amino1-4-[3-(trifluoromethyl)-l//-pyrazol-l- yl1pyrimidin-5-yl}-N-methoxypyridine-3-carboxamide
Figure imgf000597_0001
To a mixture of 5-{2-[(3,5-dimethoxyphenyl)amino]-4-[3-(trifluoromethyl)-lH-pyrazol- l-yl]pyrimidin-5-yl}pyridine-3-carboxylic acid (Example 635, 0.41 mmol, 200 mg), triethylamine (0.82 mmol, 0.12 mL, 80 mg) and methoxylamine hydrochloride (0.5 mmol, 42 mg) in dichloromethane, was added. TBTU (0.49 mmol, 158 mg) slowly at 0 0C. The reaction mixture was slowly raised to room temperature and stirred overnight. The reaction mixture was then diluted with dichloromethane (15 mL) and the dichloromethane solution was washed successively with water (2x20 mL), 10 % aq sodium bicarbonate solution (20 mL) and brine. The organic layer was dried over sodium sulphate, and concentrated. The crude material was purified by silica gel column chromatography using 8 % methanol/chloroform to yield 90 mg of the title compound.
Figure imgf000598_0002
Example 681: 5-{2-[(3,5-dimethoxyphenyl)amino1-4-[5-methyl-3-(trifluoromethyl)-l//- Pyrazol-l-yl1pyrimidin-5-yl}-N-methoxypyridine-3-carboxamide
Figure imgf000598_0001
To a mixture of 5-{2-[(3,5-dimethoxyphenyl)amino]-4-[5-methyl-3-(trifluoromethyl)-lH- pyrazol-l-yl]pyrimidin-5-yl}pyridine-3-carboxylic acid (Example 636, 0.34 mmol, 170 mg), triethylamine (0.68 mmol, 0.1 mL) and methoxylamine hydrochloride (0.51 mmol, 43 mg) in dichloromethane, was added TBTU (131 mg, 0.41 mmol, 1.2 eq) at 0 0C. The reaction mixture was slowly raised to room temperature and stirred overnight. The reaction mixture was then diluted with dichloromethane (15 mL) and the dichloromethane solution was washed successively with water (2x20 mL), 10 % aq. sodium bicarbonate solution (20 mL) and brine. The organic layer was dried over sodium sulphate, filtered, concentrated and dried to yield 120 mg of the title compound.
Figure imgf000599_0002
Example 682: 5-{2-[(3,5-dimethoxyphenyl)amino1-4-[3-(trifluoromethyl)-l//-pyrazol-l- yl1pyrimidin-5-yl}-N-(2-hvdroxyethyl)pyridine-3-carboxamide
Figure imgf000599_0001
To a mixture of T3P (4.11 mmol, 1.3 g) and Et3N (5.14 mmol, 520 mg) taken in dry dichloromethane (20 rnL), was added ethanolamine (2.03 mmol, 128 mg). Then 5-{2-[(3,5- dimethoxyphenyl)amino] -4- [3-(trifruoromethyl)- lH-pyrazol- 1 -yl]pyrimidin-5-yl }pyridine-3- carboxylic acid (Example 635, 1.03 mmol, 500 mg) in dry TΗF (20 mL) was added slowly for 15 min. The reaction mixture was stirred overnight at room temperature. The solvent was removed in vacuo, water was added and extracted with EtOAc. The organic layer was further washed with brine, dried over Na2SO4 and concentrated. The crude mass was purified by column chromatography (230-400 mesh) using 10 % MeOΗ/dichloromethane as an eluent to yield 120 mg product. The compound was further purified by RP-ΗPLC (Atlantis Cl 8 column(19x250mm;10μm); using a binary solvent mixture of 0.1 % TFA in water (A)/ MeOH (B) (0-20 min: 10-65 % B, 20-30 min: 65-75 % B and 30-40 min: 75-100 % B; flow rate of 15 mL/min; Separation was monitored at 210 and 290 nm) to get 0.057 g of the pure title compound
Figure imgf000600_0002
Example 683: 5-{2-[(3,5-dimethoxyphenyl)amino1-4-[5-methyl-3-(trifluoromethyl)-l//- Pyrazol-l-yl1pyrimidin-5-yl}-N-(2-hvdroxyethyl)pyridine-3-carboxamide
Figure imgf000600_0001
To 100 mg of 5-{2-[(3,5-dimethoxyphenyl)amino]-4-[5-methyl-3-(trifluoromethyl)-lH- pyrazol-l-yl]pyrimidin-5-yl}pyridine-3-carboxylic acid (Example 636, 0.19 mmol) in dry dichloromethane (1 mL), was added Et3N (1.19 mmol, 0.121 g) with constant stirring. To this solution, TBTU (0.51 mmol, 0.167 g) and ΗOBt (0.51 mmol, 0.070 g) were added and the reaction mixture was stirred for 15 min. Then ethanolamine (0.47 mmol, 0.029 g) was added and allowed to stir for 12 h. The reaction mixture was diluted with dichloromethane and the organic layer was further washed with brine and 10 % NaHCO3 solution, dried over Na2SO4 and concentrated. The crude mass was purified by column chromatography (230-400 mesh) using 2 % MeOH/CHCl3 as an eluent to yield a solid. The solid obtained was dissolved in minimum amount of dry dichloromethane and n-hexane was added to it and stirred for 1 h. The precipitate was filtered and dried under vacuum to give the title compound as a brown solid (20 mg).
Figure imgf000601_0002
Example 684: 5-{2-[(3,5-dimethoxyphenyl)amino1-4-[3-(trifluoromethyl)-l//-pyrazol-l- yl1pyrimidin-5-yl}-N-[2-(methylsulfonyl)ethyl1pyridine-3-carboxamide
Figure imgf000601_0001
To 100 mg of 5-{2-[(3,5-dimethoxyphenyl)amino]-4-[3-(trifluoromethyl)-lH-pyrazol-l- yl]pyrimidin-5-yl}pyridine-3-carboxylic acid (Example 635, 0.21 mmol) taken in dry dichloromethane (1 mL), was added Et3N (1.23 mmol, 0.125 g) with constant stirring. To this solution, TBTU (0.53 mmol, 0.171 g) followed by ΗOBt (0.53 mmol, 0.072 g) were added and the reaction mixture was left for stirring for 15 min. Then 2-aminoethylmethylsulfone hydrochloride (0.38 mmol, 61 mg) was added and allowed to stir for 12 h. The reaction mixture was diluted with dichloromethane and the organic layer was further washed with brine and 10 % NaHCO3 solution, dried over Na2SO4 and concentrated. The crude mass was purified by column chromatography (230-400 mesh) using 1.5 % MeOH/CHCl3 as an eluent to yield a solid. The solid obtained was dissolved in minimum amount of dry dichloromethane and n-hexane was added to it and stirred for 1 h. The precipitate was filtered and dried under vacuum to yield the title compound as a fine white solid (30 mg).
Figure imgf000602_0002
Example 685: 5-{2-[(3,5-dimethoxyphenyl)amino1-4-[5-methyl-3-(trifluoromethyl)-l//- Pyrazol-l-yl1pyrimidin-5-yl}-N-r2-(methylsulfonyl)ethyl1pyridine-3-carboxamide
Figure imgf000602_0001
To 100 mg of 5-{2-[(3,5-dimethoxyphenyl)amino]-4-[5-methyl-3-(trifluoromethyl)-lH-pyrazol- l-yl]pyrimidin-5-yl}pyridine-3-carboxylic acid (Example 636, 0.19 mmol) taken in dry dichloromethane (ImL), was added Et3N (0.49 mmol, 0.051 g,) with constant stirring. To this ΗATU (0.25 mmol, 0.099 g) followed by HO At (0.25 mmol, 0.035 g) were added and stirred for 15 min. Then 2-aminoethylmethylsulfone hydrochloride (0.19 mmol, 0.03 g) was added and the reaction mixture allowed to stir for 12 h. The reaction mixture was diluted with dichloromethane and the organic layer was further washed with brine and 10 % NaHCO3 solution, dried over Na2SO4 and concentrated. The crude mass was purified by column chromatography (230-400 mesh) using 3 % MeOH/CHCl3 as an eluent to yield a solid. The solid obtained was dissolved in minimum amount of dry dichloromethane and n-hexane was added to it and stirred for 1 h. The precipitate was filtered and dried under vacuum to get the title compound as an off-white solid (60 mg).
Figure imgf000603_0002
Example 686: 5-{2-[(3,5-dimethoxvphenvl)aminol-4-[3-(trifluoromethvl)-lH-Pvrazol-l- vllPvrimidin-5-vl}-N-(methvlsulfonvl)pvridine-3-carboxamide
Figure imgf000603_0001
A suspension of 5-{2-[(3,5-dimethoxyphenyl)amino]-4-[3-(trifluoromethyl)-lH-pyrazol- l-yl]pyrimidin-5-yl}pyridine-3-carboxylic acid (Example 635, 0.41 mmol, 0.2 g), methane sulfonamide (1.02 mmol, 0.097 g), ΗATU (0.533 mmol, 0.2 g) HO At (0.533 mmol, 0.072 g) and triethylamine (1.23 mmol, 0.124 g) in dichloromethane (2 mL) was stirred at room temperature for 4 h. The reaction mixture was diluted with dichloromethane (5 mL), washed with 10 % sodium bicarbonate solution (5x2 mL), water (5 mL) and brine (5 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. Then the crude mass was purified by RP- HPLC (Sunfire C18 column(19x250mm;10μm); using a binary solvent mixture of 10 mM aq. NH4OAc (A)/ MeCN (B) (0-20 min: 10-60 % B, 20-30 min: 60 % B; 30-40 min: 60-70 % B and 40-50 min: 70-100 % B; flow rate of 15 niL/min; Separation was monitored at 210 and 300 nm) to get 0.04 g of Example 686.
Figure imgf000604_0002
Example 687: 5-{2-[(3,5-dimethoxyphenyl)amino1-4-[5-methyl-3-(trifluoromethyl)-l//- Pyrazol-l-yllpyrimidin-5-yl}-A^methylsulfonyl)pyridine-3-carboxamide
Figure imgf000604_0001
A suspension of 5-{2-[(3,5-dimethoxyphenyl)amino]-4-[5-methyl-3-(trifluoromethyl)- lH-pyrazol-l-yl]pyrimidin-5-yl}pyridine-3-carboxylic acid (Example 636, 0.1 g, 0.2 mmol), methane sulfonamide (0.5 mmol, 0.047 g), ΗATU (0.26 mmol, 0.099 g), ΗOAt (0.26 mmol, 0.035 g) and triethylamine (0.6 mmol, 0.061 g) in dichloromethane (1 mL) was stirred at room temperature for 4 h. After completion of reaction, the reaction mixture was diluted with dichloromethane (2 mL) and washed with 10 % sodium bicarbonate solution (2x2 mL), water (2 niL) and brine (2 rnL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. Then the crude mass was purified by column chromatography (230-400 mesh) using 3 % MeOH/CHCl3 as an eluent to yield to get 0.04 g of Example 687.
Figure imgf000605_0002
General method for the synthesis of (2£)-3-(3-{2-[arylamino1-4-[l//-azol-l-yl1pyrimidin-5- yl}phenyl)prop-2-enoic acid derivatives
Figure imgf000605_0001
A suspension of 5-bromo-N-(aryl)-4-[3-(trifluoromethyl)-lH-pyrazol-l-yl]pyrimidin-2-amine or 5-bromo-N-(aryl)-4-[5-methyl-3-(trifluoromethyl)-lH-pyrazol-l-yl]pyrimidin-2-amine (1 eq), 3- (trans-2-caή)θΥ,y vinyl )phenylboronic acid (1.1 - 1.5 eq), [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (20 mol%) and sodium carbonate (1.5-2 eq) in acetonitrile/water (4 : 1) was degassed and heated to 90 0C for 15-30 min under inert atmosphere. The solvent was removed in vacuo and the crude mixture taken in CHCl3 was washed with water, brine, dried over Na2SO4, filtered and concentrated. The crude material was purified by silica gel column chromatography using chloroform: methanol (9:1) as eluent to give the product. The compounds in the below table were prepared using this procedure and the starting material indicated.
Figure imgf000606_0001
Figure imgf000607_0001
Figure imgf000608_0002
General method for the synthesis of ethyl 5-(2-{arylamino}-4-[l//-azol-l-yl1pyrimidin-5- yl)pyridine-3-carboxylate
Figure imgf000608_0001
A suspension of 5-bromo-N-(aryl)-4-[3-(trifluoromethyl)-lH-pyrazol-l-yl]pyrimidin-2-amine or 5-bromo-N-(aryl)-4-[5-methyl-3-(trifluoromethyl)-lH-pyrazol-l-yl]pyrimidin-2-amine (1 eq), ethyl 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine-3-carboxylate (1.1-1.2 eq), [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (10-20 mol%) and sodium carbonate (1-2 eq) in acetonitrile/water (4:1) was degassed and heated to 90 0C for 15-30 min under inert atmosphere. The solvent was removed in vacuo and the crude mixture taken in CHCl3 was washed with water, brine, dried over Na2SO4, filtered and concentrated. The crude material was purified by silica gel column chromatography using 30 % ethyl acetate / hexanes as eluent to give the product. The compounds in the below table were prepared using this method and the specified starting material.
Figure imgf000610_0001
Figure imgf000611_0001
General method for the synthesis of 5-{2-(arylamino)-4-[lH-pyrazol-l-yl1pyrimidin-5- vUpyridine-3-carboxylic acid
Figure imgf000612_0001
To 1 eq of ethyl 5-(2-{arylamino}-4-[lH-azol-l-yl]pyrimidin-5-yl)pyridine-3-carboxylate taken in dioxane and water, was added sodium hydroxide (2- 2.5 eq) and stirred at RT for 4 h. The reaction mixture was carefully acidified with 1 N HCl and the solid that precipitated was filtered, washed with water and dried in vacuo to yield the desired carboxylic acid.
Figure imgf000612_0002
Figure imgf000613_0001
Figure imgf000614_0001
General method for the synthesis of methyl 5-(2-{arylamino}-4-[lH-azol-l-yl1pyrimidin-5- yl)-2-methoxypyridine-3-carboxylate
Figure imgf000615_0001
A suspension of 5-bromopyrimidine derivative (1 eq), methyl 2-methoxy-5-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)pyridine-3-carboxylate (1.1-1.2 eq), [1,1'- bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (10-20 mol%) and sodium carbonate (1- 2 eq) in acetonitrile/water (4:1) was degassed and heated to 90 0C for 15-30 min under inert atmosphere. The solvent was removed in vacuo and the crude mixture taken in CHCl3 was washed with water, brine, dried over Na2SO4, filtered and concentrated. The crude material was purified by silica gel column chromatography using 50 % ethyl acetate / hexanes as eluent to give the product. The compounds in the below table were prepared using this method and the specified starting material.
Figure imgf000615_0002
Figure imgf000616_0001
Figure imgf000617_0001
Figure imgf000618_0002
General procedure for the synthesis of 5-{2-(arylamino)-4-[lH-pyrazol-l-yl1pyrimidin-5- yll^-methoxypyridine-S-carboxylic acid
Figure imgf000618_0001
To 1 eq of methyl 5-(2-{arylamino}-4-[lH-azol-l-yl]pyrimidin-5-yl)-2-methoxypyridine- 3-carboxylate taken in dioxane (5 mL), was added 1 N aq. sodium hydroxide or Barium hydroxide (2- 6 eqs) and was heated to 60 0C for 1 h. The reaction mixture was carefully acidified with 1 N HCl and the solid that precipitated was filtered, washed with water and dried in vacuo to yield the desired carboxylic acid. The compounds in the below table were prepared using this method and the specified starting material.
Figure imgf000619_0001
Figure imgf000620_0001
Figure imgf000621_0001
Example 728: (2£)-3-(3-{2-r(3-cvano-5-methoxyphenyl)amino1-4-r3-(trifluoromethyl)-lH-
Pyrazol-l-yl1pyrimidin-5-yl}phenyl)prop-2-enoic acid
Example 729: (2£)-3-(3-{2-r(3-cvano-5-methoxyphenyl)amino1-4-r5-methyl-3-
(trifluoromethyl)-l//-pyrazol-l-yl1pyrimidin-5-yl}phenyl)prop-2-enoic acid
Figure imgf000622_0001
A suspension of (2£')-3-(3-{2-chloro-4-[3-(trifluoromethyl)-lH-pyrazol-l-yl]pyrimidin-5- yl}phenyl)prop-2-enoic acid (Intermediate 268, 1 eq) or (2£')-3-(3-{2-chloro-4-[5-methyl-3- (trifluoromethyl)-lH-pyrazol-l-yl]pyrimidin-5-yl}phenyl)prop-2-enoic acid (Intermediate 269, 1 eq), 3-amino-5-methoxybenzonitrile (1 eq), tris(dibenzylideneacetone)dipalladium(0) (IO mol%), 2-dicyclohexylphosphino-2',4',6'-triisopropyl-l,l'-biphenyl (20 mol%) and sodium carbonate (2 eq) in acetonitrile/water (5:1) was heated to 90 0C for 30 min. The reaction mixture was concentrated, the residue was taken in ethyl acetate and washed with water and brine. The organic layer was separated, dried over sodium sulfate, filtered and concentrated. The crude mass was purified by silica gel column chromatography (60-120 mesh) using MeOΗ/CΗCl3 as an eluent to give the product. The compounds in the below table were prepared using this method and the specified starting material.
Figure imgf000622_0002
Figure imgf000623_0002
Example 730: ethyl 5-{2-[(3-cvano-5-methoxyphenyl)amino1-4-[3-(trifluoromethyl)-lH-
Pyrazol-l-yl1pyrimidin-5-yl}pyridine-3-carboxylate
Example 731: ethyl 5-{2-[(3-cvano-5-methoxyphenyl)amino1-4-[5-methyl-3-
(trifluoromethyl)-lH-pyrazol-l-yl1pyrimidin-5-yl}pyridine-3-carboxylate
Figure imgf000623_0001
A suspension of ethyl 5-{2-chloro-4-[3-(trifluoromethyl)-lH-pyrazol-l-yl]pyrimidin-5- yl}pyridine-3-carboxylate (Intermediate 270, 1 eq) or ethyl 5-{2-chloro-4-[5-methyl-3- (trifluoromethyl)-lH-pyrazol-l-yl]pyrimidin-5-yl}pyridine-3-carboxylate (Intermediate 271, 1 eq), 3-amino-5-methoxybenzonitrile (1.2 eq), tris(dibenzylideneacetone)dipalladium(0) (10 mol%), 2-dicyclohexylphosphino-2',4',6'-triisopropyl-l,l'-biphenyl (20 mol%) and sodium carbonate (1 eq) in acetonitrile/water (5:1) was heated to 90 0C for 30 minutes. The reaction mixture was concentrated. The residue taken in ethyl acetate was washed with water and brine. The organic layer was separated, dried over sodium sulfate, filtered and concentrated. The crude mass was purified by silica gel column chromatography (60-120 mesh) using ethyl acetate/hexanes as an eluent to give the product. The compounds in the below table were prepared using this method and the specified starting material.
Figure imgf000624_0001
Example 732: 5-{2-[(3-cvano-5-methoxyphenyl)amino1-4-[3-(trifluoromethyl)-l//-pyrazol- l-yllpyrimidin-S-vUpyridine-S-carboxylic acid
Example 733: 5-{2-[(3-cvano-5-methoxyphenyl)amino1-4-[5-methyl-3-(trifluoromethyl)-l//- pyrazol-l-ylipyrimidin-S-vUpyridine-S-carboxylic acid
Figure imgf000625_0001
To ethyl 5-{2-[(3-cyano-5-methoxyphenyl)amino]-4-[3-(trifluoromethyl)-lH-pyrazol-l- yl]pyrimidin-5-yl}pyridine-3-carboxylate (Example 730, 1 eq) or ethyl 5-{2-[(3-cyano-5- methoxyphenyl)amino] -4- [5-methyl-3-(trifluoromethyl)- lH-pyrazol- 1 -yl]pyrimidin-5- yl}pyridine-3-carboxylate (Example 731, 1 eq) taken in a mixture of dioxane (5 rnL) and water (5 rnL), was added sodium hydroxide (2.5 eq) and stirred at room temperature for 3-5 h. The reaction mixture was carefully acidified with 1 N HCl and further extracted with ethyl acetate (50 mL). The organic layer was washed with water and brine, dried over Na2SO4 and concentrated to give the product. The compounds in the below table were prepared using this method and the specified starting material.
Figure imgf000625_0002
Figure imgf000626_0002
Example 734: methyl 5-{2-[(3-cvano-5-methoxyphenyl)amino1-4-[3-(trifluoromethyl)-lH- pyrazol-l-ylipyrimidin-S-vU^-methoxypyridine-S-carboxylate
Example 735: methyl 5-{2-[(3-cvano-5-methoxyphenyl)amino1-4-[5-methyl-3-
(trifluoromethyl)-lH-pyrazol-l-yl1pyrimidin-5-yl}-2-methoxypyridine-3-carboxylate
Figure imgf000626_0001
A suspension of methyl 5-{2-chloro-4-[3-(trifluoromethyl)-lH-pyrazol-l-yl]pyrimidin-5-yl}-2- methoxypyridine-3-carboxylate (Intermediate 325, 1 eq) or methyl 5-{2-chloro-4-[5-methyl-3- (trifluoromethyl)- lH-pyrazol- 1 -yl]pyrimidin-5-yl } -2-methoxypyridine-3-carboxylate (Intermediate 273, 1 eq), 3-amino-5-methoxybenzonitrile (1.0 eq), tris(dibenzylideneacetone)dipalladium(0) (10 mol%), 2-dicyclohexylphosphino-2',4',6'- triisopropyl-l,l'-biphenyl (20 mol%) and sodium carbonate (1 eq) in acetonitrile/water (5:1) was heated to 90 0C for 30 min. The reaction mixture was concentrated. The residue was taken in ethyl acetate, washed with water and brine. The organic layer was separated, dried over sodium sulfate, filtered and concentrated. The crude mass was purified by silica gel column chromatography (60-120 mesh) using ethyl acetate/hexanes as an eluent to give the product. The compounds in the below table were prepared using this method and the specified starting material.
Figure imgf000627_0001
Example 736: 5-{2-[(3-cvano-5-methoxyphenyl)amino1-4-[3-(trifluoromethyl)-l//-pyrazol- l-yl1pyrimidin-5-yl}-2-methoxypyridine-3-carboxylic acid
Example 737: 5-{2-[(3-cvano-5-methoxyphenyl)amino1-4-[5-methyl-3-(trifluoromethyl)-l//- Pyrazol-l-yl1pyrimidin-5-yl}-2-methoxypyridine-3-carboxylic acid
Figure imgf000628_0001
To methyl 5-{2-[(3-cyano-5-methoxyphenyl)amino]-4-[3-(trifluoromethyl)-lH-pyrazol-l- yl]pyrimidin-5-yl}-2-methoxypyridine-3-carboxylate (Example 734, 1 eq) or methyl 5-{2-[(3- cyano-5-methoxyphenyl)amino]-4-[5-methyl-3-(trifluoromethyl)-lH-pyrazol-l-yl]pyrimidin-5- yl}-2-methoxypyridine-3-carboxylate (Example 735, 1 eq) dissolved in a mixture of dioxane (5 mL) and water (5 mL), was added sodium hydroxide (2.5 eq) and stirred at room temperature for 3-5 h. The reaction mixture was carefully acidified with 1 N HCl and further extracted with ethyl acetate (50 mL). The organic layer was washed with water and brine, dried over Na2SO4 and concentrated. The compounds in the below table were prepared using this method and the specified starting material.
Figure imgf000628_0002
Figure imgf000629_0002
Example 738: methyl 5-{2-[(3-chlorophenyl)amino1-4-[3-(trifluoromethyl)-lH-pyrazol-l- yl1pyrimidin-5-yl}-2-methoxypyridine-3-carboxylate
Example 739: methyl 5-{2-[(3-chlorophenyl)amino1-4-[5-methyl-3-(trifluoromethyl)-lH- pyrazol-l-yllpyrimidin-S-vU^-methoxypyridine-S-carboxylate
Figure imgf000629_0001
A suspension of 5-bromo-N-(3-chlorophenyl)-4-[3-(trifluoromethyl)-lH-pyrazol-l- yl]pyrimidin-2-amine Intermediate 276 or 5-bromo-N-(3-chlorophenyl)-4-[5-methyl-3- (trifluoromethyl)-lH-pyrazol-l-yl]pyrimidin-2-amine Intermediate 277 (1 eq), methyl 2- methoxy-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine-3-carboxylate (1.1 eq), [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with CH2Cl2 (10 mol%) and sodium carbonate (l.leq) in acetonitrile/water (4:1) was degassed and heated to 100 0C for 45 minutes under an inert atmosphere. The reaction mass was passed through a celite bed. The solvent was concentrated in vacuo and the resultant crude mass was taken in CHCl3 (50 mL), washed with water, brine, dried over Na2SO4, filtered and concentrated. The crude material was purified by silica gel column chromatography using 1 : 1 ethyl acetate/hexanes as an eluent to give the product. The compounds in the below table were prepared using this method and the specified starting material.
Figure imgf000630_0001
Example 740: ethyl 5-{2-[(3-chlorophenyl)amino1-4-[3-(trifluoromethyl)-l//-pyrazol-l- yl1pyrimidin-5-yl}pyridine-3-carboxylate
Example 741: ethyl 5-{2-[(3-chlorophenyl)amino1-4-[5-methyl-3-(trifluoromethyl)-l//- Pyrazol-l-yl1pyrimidin-5-yl}pyridine-3-carboxylate
Figure imgf000631_0001
A suspension of 5-bromo-N-(3-chlorophenyl)-4-[3-(trifluoromethyl)-lH-pyrazol-l- yl]pyrimidin-2-amine or 5-bromo-N-(3-chlorophenyl)-4-[5-methyl-3-(trifluoromethyl)-lH- pyrazol-l-yl]pyrimidin-2-amine (1 eq), (1 eq), ethyl 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)pyridine-3-carboxylate (1.1 eq), [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II)complex with CH2Cl2 (10 mol%) and sodium carbonate (1.1 eq) in acetonitrile/water (4:1) was degassed and heated to 100 0C for 45 min. The reaction mass was passed through a celite bed. The solvent was concentrated in vacuo and the resultant crude mass was taken in CHCl3 (50 mL), washed with water, brine, dried over Na2SO4, filtered and concentrated. The crude material was purified by silica gel column chromatography using 1 : 1 ethyl acetate/hexanes as an eluent to give the product. The compounds in the below table were prepared using this method and the specified starting material.
Figure imgf000631_0002
Figure imgf000632_0002
General methods for carboxylic ester hydrolysis
Figure imgf000632_0001
To a suspension of ester derivative (100 mg, 1 eq) taken in a mixture of dioxane (1 rnL) and water (0.33 rnL), was added Barium hydroxide (2 eq) and the mixture was allowed to stir at 45°C for 2 h. The mixture was carefully acidified with 1 N HCl and the precipitate formed was filtered, washed with water and dried to yield the product. The compounds in the below table were prepared using this method and the specified starting material.
Figure imgf000633_0001
Figure imgf000634_0001
Ester derivative (100 mg, leq) was dissolved in tetrahydrofuran (3 rnL) and treated with potassium trimethyl silanolate (10 eq) and allowed to stir at room temperature for 1 h. The solvent was concentrated in vacuo and the resultant crude mass was carefully acidified with 1 N HCl, then diluted with ethyl acetate (50 mL), washed with water, brine, dried over Na2SO4, filtered and concentrated. The crude material was purified by silica gel column chromatography using chloroform: methanol (9:1) as an eluent to yield the product. The compound in the below table was prepared using this method and the specified starting material.
Figure imgf000635_0002
General method for the synthesis of methyl 5-(2-{arylamino}-4-[lH-azol-l-yl1pyrimidin-5- yl)-2-methoxypyridine-3-carboxylate
Figure imgf000635_0001
A suspension of 5-bromopyrimidine derivative (1 eq), methyl 2-methoxy-5-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)pyridine-3-carboxylate (1.1-1.2 eq), [1,1'- bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (10-20 mol%) and sodium carbonate (1- 2 eq) in acetonitrile/water (4:1) was degassed and heated to 90 0C for 15-30 minutes under inert atmosphere. The solvent was removed in vacuo and the crude mixture taken in CHCl3 was washed with water, brine, dried over Na2SO4, filtered and concentrated. The crude material was purified by silica gel column chromatography using 50 % ethyl acetate / hexanes as eluent. The compounds in the below table were prepared using this procedure and the specified starting material.
Figure imgf000636_0001
Figure imgf000637_0001
Figure imgf000638_0001
General procedure for the synthesis of 5-{2-(arylamino)-4-[lH-pyrazol-l-yl1pyrimidin-5- yll^-methoxypyridine-S-carboxylic acid
Figure imgf000639_0001
To 1 eq of methyl 5-(2-{arylamino}-4-[lH-azol-l-yl]pyrimidin-5-yl)-2-methoxypyridine-3- carboxylate taken in dioxane (5 niL), was added 1 N aq. Barium hydroxide (2 eq) and stirred for the amount of time indicated in the below table. The reaction mixture was carefully acidified with 1 N HCl and the solid that precipitated was filtered, washed with water and dried in vacuo to yield the carboxylic acid product. The compounds in the below table were prepared using this procedure and the specified starting material.
Figure imgf000639_0002
Figure imgf000640_0001
Figure imgf000641_0001
Figure imgf000642_0002
General procedure for the synthesis of ethyl 5-(2-{arylamino}-4-[lH-azol-l-yl1pyrimidin-5- yl)pyridine-3-carboxylate
Figure imgf000642_0001
A suspension of 5-bromo-N-(aryl)-4-[3-(trifluoromethyl)-lH-pyrazol-l-yl]pyrimidin-2-amine or 5-bromo-N-(aryl)-4-[5-methyl-3-(trifluoromethyl)-lH-pyrazol-l-yl]pyrimidin-2-amine (1 eq), ethyl 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine-3-carboxylate (1.1-1.2 eq), [1,1'- bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (10-20 mol%) and sodium carbonate (1- 2 eq) in acetonitrile/water (4:1) was degassed and heated to 90 0C for 15-30 min under inert atmosphere. The solvent was removed in vacuo and the crude mixture taken in CHCl3 was washed with water, brine, dried over Na2SO4, filtered and concentrated. The crude material was purified by silica gel column chromatography using 30 % ethyl acetate / hexanes as eluent to give the product. The compounds in the below table were prepared using this procedure and the specified starting material.
Figure imgf000643_0001
Figure imgf000644_0001
Figure imgf000645_0002
General procedure for the synthesis of 5-{2-(arylamino)-4-[lH-pyrazol-l-yl1pyrimidin-5- vU^-methoxypyridine-S-carboxylic acid
Figure imgf000645_0001
To 1 eq of ethyl 5-(2-{arylamino}-4-[lH-azol-l-yl]pyrimidin-5-yl)pyridine-3-carboxylate taken in dioxane (5 mL), was added 1 N aq. Barium hydroxide (2 eq) and stirred for the time indicated in the below table. The reaction mixture was carefully acidified with 1 N HCl and the solid that precipitated was filtered, washed with water and dried in vacuo to yield the carboxylic acid product. The compounds in the below table were prepared using this procedure and the specified starting material.
Figure imgf000646_0001
Figure imgf000647_0001
Figure imgf000648_0001
Example 778: methyl 5-{2-[(3-cvano-5-methylphenyl)amino1-4-[3-(trifluoromethyl)-lH- Pyrazol-l-yl1pyrimidin-5-yl}-2-methoxypyridine-3-carboxylate Example 779: methyl 5-{2-[(3-cvano-5-methylphenyl)amino1-4-[5-methyl-3- (trifluoromethyl)-lH-pyrazol-l-yl1pyrimidin-5-yl}-2-methoxypyridine-3-carboxvlate
Figure imgf000649_0001
A suspension of methyl 5-{2-chloro-4-[3-(trifluoromethyl)-lH-pyrazol-l-yl]pyrimidin-5-yl}-2- methoxypyridine-3-carboxylate (Intermediate 325, 1 eq) or methyl 5-{2-chloro-4-[5-methyl-3- (trifluoromethyl)- lH-pyrazol- 1 -yl]pyrimidin-5-yl } -l-methoxypyridine-S-carboxylate (Intermediate 273, 1 eq), 3-amino-5-methylbenzonitrile (1.0 eq), tris(dibenzylideneacetone)dipalladium(0) (10 mol%), 2-dicyclohexylphosphino-2',4',6'- triisopropyl-l,l'-biphenyl (20 mol%) and sodium carbonate (1 eq) in acetonitrile/water (5:1) was heated to 90 0C for 30 min. The reaction mixture was concentrated. The residue was taken in ethyl acetate, washed with water and brine. The organic layer was separated, dried over sodium sulfate, filtered and concentrated. The crude mass was purified by silica gel column chromatography (60-120 mesh) using ethyl acetate/hexanes as an eluent to give the product. The compounds in the below table were prepared using this procedure and the specified starting material.
Figure imgf000650_0002
Example 780: 5-{2-[(3-cvano-5-methylphenyl)amino1-4-[3-(trifluoromethyl)-lH-pyrazol- 1- yl1pyrimidin-5-yl}-2-methoxypyridine-3-carboxylic acid
Example 781: 5-{2-[(3-cvano-5-methylphenyl)amino1-4-[5-methyl-3-(trifluoromethyl)-lH- Pyrazol-l-yl1pyrimidin-5-yl}-2-methoxypyridine-3-carboxylic acid
Figure imgf000650_0001
To 1 eq of methyl 5-{2-[(3-cyano-5-methylphenyl)amino]-4-[lH-azol-l-yl]pyrimidin-5-yl}-2- methoxypyridine-3-carboxylate taken in dioxane (5 niL), was added 1 N aq. sodium hydroxide (1 - 3 eqs) and stirred at RT for 1 h. The reaction mixture was carefully acidified with 1 N HCl and the solid that precipitated was filtered, washed with water and dried in vacuo to yield the carboxylic acid product. The compounds in the below table were prepared using this procedure and the specified starting material.
Figure imgf000651_0001
Example 782: ethyl 5-{2-[(3-cvano-5-methylphenyl)amino1-4-[3-(trifluoromethyl)-lH-
Pyrazol-l-yl1pyrimidin-5-yl}pyridine-3-carboxylate
Example 783: ethyl 5-{2-[(3-cvano-5-methylphenyl)amino1-4-[5-methyl-3-(trifluoromethyl)- lH-Pyrazol-l-yl1pyrimidin-5-yl}pyridine-3-carboxylate
Figure imgf000652_0001
A suspension of ethyl 5-{2-chloro-4-[3-(trifluoromethyl)-lH-pyrazol-l-yl]pyrimidin-5- yl}pyridine-3-carboxylate (Intermediate 270, 1 eq) or ethyl 5-{2-chloro-4-[5-methyl-3- (trifluoromethyl)-lH-pyrazol-l-yl]pyrimidin-5-yl}pyridine-3-carboxylate (Intermediate 271, 1 eq), 3-amino-5-methylbenzonitrile (1.2 eq), tris(dibenzylideneacetone)dipalladium(0) (10 mol%), 2-dicyclohexylphosphino-2',4',6'-triisopropyl-l,l'-biphenyl (20 mol%) and sodium carbonate (1 eq) in acetonitrile/water (5:1) was heated to 90 0C for 30 min. The reaction mixture was concentrated. The residue taken in ethyl acetate was washed with water and brine. The organic layer was separated, dried over sodium sulfate, filtered and concentrated. The crude mass was purified by silica gel column chromatography (60-120 mesh) using ethyl acetate/hexanes as an eluent to give the product. The compounds in the below table were prepared using this procedure and the specified starting material.
Figure imgf000652_0002
Figure imgf000653_0002
Example 784: 5-{2-[(3-cvano-5-methylphenyl)amino1-4-[3-(trifluoromethyl)-lH-pyrazol-l- ylipyrimidin-S-vUpyridine-S-carboxylic acid
Example 785: 5-{2-[(3-cvano-5-methylphenyl)amino1-4-[5-methyl-3-(trifluoromethyl)-lH- pyrazol-l-ylipyrimidin-S-vUpyridine-S-carboxylic acid
Figure imgf000653_0001
To 1 eq of ethyl 5-{2-[(3-cyano-5-methylphenyl)amino]-4-[lH-azol-l-yl]pyrimidin-5- yl}pyridine-3-carboxylate taken in dioxane (5 rnL), was added 1 N aq. sodium hydroxide (1 - 3 eq) and stirred at RT for 1 h. After completion of reaction, reaction mixture was carefully acidified with 1 N HCl and the solid that precipitated was filtered, washed with water and dried in vacuo to yield the carboxylic acid product. The compounds in the below table were prepared using this procedure and the specified starting material.
Figure imgf000654_0002
Example 786: methyl 5-{2-[(3-chloro-4-fluorophenyl)amino1-4-[5-methyl-3- (trifluoromethyl)-lH-pyrazol-l-yl1pyrimidin-5-yl}-2-[(l-methylpyrrolidin-3- yl)oxy1pyridine-3-carboxylate
Figure imgf000654_0001
A suspension of 5-bromo-N-(3-chloro-4-fluorophenyl)-4-[5-methyl-3-(trifluoromethyl)-lH- pyrazol-l-yl]pyrimidin-2-amine (Intermediate 113, 0.75 mmol, 0.340 g), a mixture of {5- (methoxycarbonyl)-6-[(l-methylpyrrolidin-3-yl)oxy]pyridin-3-yl}boronic acid and methyl 2-[(l- methylpyrrolidin-3-yl)oxy]-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine-3- carboxylate (Intermediate 297, 1.5 mmol based on the boronic acid, 0.423 g), [1,1'- bis(diphenylphosphino)ferrocene] dichloropalladium(II) (0.15 mmol, 0.109 g) and sodium carbonate (0.75 mmol, 0.074 g) in acetonitrile/water (5 : 1) was degassed and heated to 90 0C for 15 min under an inert atmosphere. The reaction mass was passed through a celite bed and solvent was concentrated in vacuo. The resultant residue taken in EtOAc (50 mL) was washed with water, brine, dried over Na2SO4, filtered and concentrated. The crude mass was further purified by silica gel column chromatography (eluted with 3 % Et3N in EtOAc) to yield 0.210 g of the product.
Example 787: 5-{2-[(3-chloro-4-fluorophenyl)amino1-4-[5-methyl-3-(trifluoromethyl)-lH- pyrazol-l-ylipyrimidin-S-vU^-rd-methylpyrrolidin-S-vDoxyipyridine-S-carboxylic acid
Figure imgf000656_0001
To 130 mg of methyl 5-{2-[(3-chloro-4-fluorophenyl)amino]-4-[5-methyl-3- (trifluoromethyl)- lH-pyrazol- 1 -yl]pyrimidin-5-yl } -2-[( 1 -methylpyrrolidin-3-yl)oxy]pyridine-3- carboxylate (Example 786, 0.2 mmol) taken in a mixture of TΗF (5 mL) and water (5 mL), was added Barium hydroxide monohydrate (0.162 g, 0.8 mmol) and stirred at room temperature for 7 h. The mixture was carefully acidified with 1 N HCl. It was extracted with ethyl acetate (50 mL) and the organic layer was washed with water and brine, dried over Na2SO4 and concentrated to yield 85 mg of Example 787.
Figure imgf000656_0002
Example 788: methyl 5-{2-[(3-chloro-4-fluorophenyl)amino1-4-[3-(trifluoromethyl)-lH- Pyrazol-l-yl1pyrimidin-5-yl}-2-[(l-methylpyrrolidin-3-yl)oxy1pyridine-3-carboxylate
Figure imgf000657_0001
A suspension of 5-bromo-N-(3-chloro-4-fluorophenyl)-4-[3-(trifluoromethyl)-lH- pyrazol-l-yl]pyrimidin-2-amine (Intermediate 115, 1.1 mmol, 0.5 g), a mixture of {5- (methoxycarbonyl)-6-[(l-methylpyrrolidin-3-yl)oxy]pyridin-3-yl}boronic acid and methyl 2-[(l- methylpyrrolidin-3-yl)oxy]-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine-3- carboxylate (Intermediate 297, 2.3 mmol based on the boronic acid, 0.644 g), [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.22 mmol, 0.160 g) and sodium carbonate (1.1 mmol, 0.116 g) in acetonitrile/water (20 : 5, v/v) was degassed and heated to 90 0C for 15 min under an inert atmosphere. The reaction mass was passed through a celite bed. The solvent was concentrated in vacuo and the resultant crude mass was taken in EtOAc (50 mL), washed with water, brine, dried over Na2SO4, filtered and concentrated. The crude mass was further purified by silica gel column chromatography (eluted with 4 % Et3N in EtOAc) to yield 0.240 g of the product.
Figure imgf000658_0002
Example 789: 5-{2-[(3-chloro-4-fluorophenyl)amino1-4-[3-(trifluoromethyl)-lH-pyrazol-l- ylipyrimidin-S-vU^-rd-methylpyrrolidin-S-vDoxyipyridine-S-carboxylic acid
Figure imgf000658_0001
To 180 mg of methyl 5-{2-[(3-chloro-4-fluorophenyl)amino]-4-[3-(trifluoromethyl)-lH- pyrazol-l-yl]pyrimidin-5-yl}-2-[(l-methylpyrrolidin-3-yl)oxy]pyridine-3-carboxylate (Example 788, 0.3 mmol, 1 eq) taken in a mixture of TΗF (5 mL) and water (5 mL), was added Barium hydroxide monohydrate (0.231 g, 1.2 mmol, 4 eq) and stirred at room temperature for 7 h. The mixture was carefully acidified with 1 N HCl. It was extracted with ethyl acetate (50 mL) and the organic layer was washed with water and brine, dried over Na2SO4 and concentrated to yield 120 mg of the product.
Figure imgf000659_0002
Example 790: methyl 5-{2-[(3-chloro-4-fluorophenyl)amino1-4-[5-methyl-3-
(trifluoromethvD-lH-pyrazol-l-ylipyrimidin-S-vU^-ri-Cpyridin^-vDethoxyipyridine-S- carboxylate
Figure imgf000659_0001
suspension of 5-bromo-N-(3-chloro-4-fluorophenyl)-4-[5-methyl-3-(trifluoromethyl)-lH-pyrazol- l-yl]pyrimidin-2-amine (Intermediate 113, 0.97 mmol, 0.440 g), a mixture of methyl 2-[l- (pyridin-4-yl)ethoxy] -5-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)pyridine-3-carboxylate and {5-(methoxycarbonyl)-6-[l-(pyridin-4-yl)ethoxy]pyridin-3-yl}boronic acid (Intermediate 300, 1.46 mmol based on the boronic acid, 0.442 g), [l,r-bis(diphenylphosphino)ferrocene] dichloropalladium(II) complex with CH2Cl2 (0.2 mmol, 0.159 g) and sodium carbonate (0.97 mmol, 0.103 g) in acetonitrile/water (4 : 1) was degassed and heated to 90 0C for 30 min under an inert atmosphere. The reaction mixture was diluted with EtOAc (50 mL), washed with water and brine, dried over Na2SO4, filtered and concentrated. The crude material was purified by silica gel column chromatography (product eluted with 45 % ethyl acetate/hexanes) to yield 0.440 g of product.
Figure imgf000660_0002
Example 791: 5-{2-[(3-chloro-4-fluorophenyl)amino1-4-[5-methyl-3-(trifluoromethyl)-l//- Pyrazol-l-yl1pyrimidin-5-yl}-2-[l-(pyridin-4-yl)ethoxy1pyridine-3-carboxylic acid
Figure imgf000660_0001
To 162 mg of methyl 5-{2-[(3-chloro-4-fluorophenyl)amino]-4-[5-methyl-3- (trifluoromethyl)- lH-pyrazol- 1 -yl]pyrimidin-5-yl } -2- [ 1 -(pyridin-4-yl)ethoxy]pyridine-3- carboxylate (Example 790, 0.25 mmol, 0.162 g) taken in a mixture of dioxane (4 mL) and water (4 mL) was added Barium hydroxide monohydrate (0.51 mmol, 0.098 g) and stirred at 50 0C for 1 h. After completion of the reaction, the mixture was then carefully acidified with 1 N HCl. It was then extracted with ethyl acetate (50 rnL), and the organic layer was washed with water and brine, dried over Na2SO4 and concentrated to yield 120 mg of the title compound.
Figure imgf000661_0002
Example 792: methyl 5-{2-[(3-chloro-4-fluorophenyl)amino1-4-[3-(trifluoromethyl)-l//- pyrazol-l-ylipyrimidin-S-vU^-ri-Cpyridin^-vDethoxyipyridine-S-carboxylate
Figure imgf000661_0001
A suspension of 5-bromo-N-(3-chloro-4-fluorophenyl)-4-[3-(trifluoromethyl)-lH-pyrazol-l- yl]pyrimidin-2-amine (Intermediate 115, 0.95 mmol, 0.415 g), a mixture of methyl 2-[l- (pyridin-4-yl)ethoxy] -5-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)pyridine-3-carboxylate and {5-(methoxycarbonyl)-6-[l-(pyridin-4-yl)ethoxy]pyridin-3-yl}boronic acid (Intermediate 300, 1.42 mmol based on the boronic acid, 0.431 g), [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with CH2Cl2 (0.19 mmol, 0.155 g) and sodium carbonate (0.95 mmol, 0.101 g) in acetonitrile/water (5 : 1) was degassed and heated to 90 0C for 30 min under an inert atmosphere. The solvent was concentrated in vacuo and the resultant crude mass was taken in EtOAc (50 mL), washed with water, brine, dried over Na2SO4, filtered and concentrated. The crude mass was purified by silica gel column chromatography (product eluted with 45 % ethyl acetate/hexanes) to yield 0.415 g of the product.
Figure imgf000662_0002
Example 793: 5-{2-[(3-chloro-4-fluorophenyl)amino1-4-[3-(trifluoromethyl)-lH-pyrazol-l- yl1pyrimidin-5-yl}-2-[l-(pyridin-4-yl)ethoxy1pyridine-3-carboxylic acid
Figure imgf000662_0001
To 100 mg of methyl 5-{2-[(3-chloro-4-fluorophenyl)amino]-4-[3-(trifluoromethyl)-lH- pyrazol-l-yl]pyrimidin-5-yl}-2-[l-(pyridin-4-yl)ethoxy]pyridine-3-carboxylate (Example 792, 0.16 mmol) taken in a mixture of dioxane (4 mL) and water (4 mL), was added Barium hydroxide monohydrate (0.32 mmol, 0.062 g) and allowed to stir overnight at room temperature. The mixture was then carefully acidified with 1 N HCl and then diluted with ethyl acetate (50 mL), washed with water and brine, dried over Na2SO4 and concentrated. It was further purified by column chromatography using 1 % MeOH in CHCl3 to yield 0.080 g of the product.
Figure imgf000663_0002
Example 794: methyl 5-{2-[(3-chloro-4-fluorophenyl)amino1-4-[5-methyl-3-
(trifluoromethyl)-lH-pyrazol-l-yl1pyrimidin-5-yl}-2-[2-(lH-imidazol-l-yl)ethoxy1pyridine-
3-carboxylate
Figure imgf000663_0001
A suspension of 5-bromo-N-(3-chloro-4-fluorophenyl)-4-[5-methyl-3-(trifluoromethyl)-lH- pyrazol-l-yl]pyrimidin-2-amine (Intermediate 113, 1.11 mmol, 0.5 g), a mixture of {6-[2-(lH- imidazol-l-yl)ethoxy]-5-(methoxycarbonyl)pyridin-3-yl}boronic acid and methyl 2-[2-(1H- imidazol-l-yl)ethoxy]-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine-3-carboxylate (Intermediate 303, 1.66 mmol based on the boronic acid, 0.486 g), [1,1'- bis(diphenylphosphino)ferrocene] dichloropalladium(II) (0.22 mmol, 0.162 g) and sodium carbonate (1.1 mmol, 0.117 g) in acetonitrile/water (5 : 1) was degassed and heated to 90 0C for 1 h under an inert atmosphere. The solvent was concentrated in vacuo and the resultant crude mass taken in EtOAc (50 mL), was washed with water, brine, dried over Na2SO4, filtered and concentrated. The crude material was further purified by silica gel column chromatography (product eluted with 0.5 % Et3N in EtOAc) to yield 0.31 g of the product.
Figure imgf000664_0002
Example 795: 5-{2-[(3-chloro-4-fluorophenyl)amino1-4-[5-methyl-3-(trifluoromethyl)-l//- Pyrazol-l-yl1pyrimidin-5-yl}-2-[2-(l//-imidazol-l-yl)ethoxy1pyridine-3-carboxylic acid
Figure imgf000664_0001
To 170 mg of methyl 5-{2-[(3-chloro-4-fluorophenyl)amino]-4-[5-methyl-3- (trifluoromethyl)-lH-pyrazol-l-yl]pyrimidin-5-yl}-2-[2-(lH-imidazol-l-yl)ethoxy]pyridine-3- carboxylate (Example 794, 0.27 mmol) taken in a mixture of dioxane (20 mL) and water (20 mL), was added Barium hydroxide monohydrate (0.27 mmol, 0.052 g) and the reaction mixture warmed to 50 0C for 24 h. Another equivalent of Barium hydroxide monohydrate (0.27 mmol, 0.052 g) was added and the reaction continued at 50 0C for 3 h more. The mixture was then carefully acidified with 1 N HCl. It was extracted with ethyl acetate (50 mL) and the organic layer was washed with water and brine, dried over Na2SO4 and concentrated to yield 0.112 g of Example 795.
Example 796: methyl 5-{2-[(3-chloro-4-fluorophenyl)amino1-4-[3-(trifluoromethyl)-l//- Pyrazol-l-yl1pyrimidin-5-yl}-2-[2-(l//-imidazol-l-yl)ethoxy1pyridine-3-carboxylate
Figure imgf000665_0001
A suspension of 5-bromo-N-(3-chloro-4-fluorophenyl)-4-[3-(trifluoromethyl)-lH- pyrazol-l-yl]pyrimidin-2-amine (Intermediate 115, 1.14 mmol, 0.5 g), a mixture of {6-[2-(lH- imidazol-l-yl)ethoxy]-5-(methoxycarbonyl)pyridin-3-yl}boronic acid and methyl 2-[2-(1H- imidazol-l-yl)ethoxy]-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine-3-carboxylate (Intermediate 303, 1.72 mmol based on the boronic acid, 0.502 g), [1,1'- bis(diphenylphosphino)ferrocene] dichloropalladium (II) (0.22 mmol, 0.167 g) and sodium carbonate (1.14 mmol, 0.121 g) in acetonitrile/water (3 : 1) was degassed and heated to 90 0C for 1 h under an inert atmosphere. The solvent was concentrated in vacuo and the resultant crude mass was taken in EtOAc (50 mL), washed with water, brine, dried over Na2SO4, filtered and concentrated. The crude material was further purified by silica gel column chromatography (product eluted with 0.5 % Et3N in EtOAc) to yield 0.24 g of the product.
Figure imgf000666_0002
Example 797: 5-{2-[(3-chloro-4-fluorophenvl)aminol-4-[3-(trifluoromethvD-lH-Pvrazol-l- vllPvrimidin-S-vU^-^-dH-imidazol-l-vDethoxvlPvridine-S-carboxvlic acid
Figure imgf000666_0001
To 75 mg of methyl 5-{2-[(3-chloro-4-fluorophenyl)amino]-4-[3-(trifluoromethyl)-lH- pyrazol-l-yl]pyrimidin-5-yl}-2-[2-(lH-imidazol-l-yl)ethoxy]pyridine-3-carboxylate (Example 796, 0.12 mmol) taken in a mixture of dioxane (20 mL) and water (20 mL), was added Barium hydroxide monohydrate (0.48 mmol, 0.094 g) and warmed to 50 0C for 3 h. The mixture was then carefully acidified with 1 N HCl. It was extracted with ethyl acetate (50 mL) and the organic layer was washed with water and brine, dried over Na2SO4 and concentrated to yield 0.05 g of the title compound.
Figure imgf000667_0002
Example 798: methyl 5-{2-[(3-chloro-5-methylphenyl)amino1-4-[3-(trifluoromethyl)-l//- pyrazol-l-ylipyrimidin-S-vU^-methoxypyridine-S-carboxylate
Figure imgf000667_0001
A suspension of methyl 5-{2-chloro-4-[3-(trifluoromethyl)-lH-pyrazol-l-yl]pyrimidin-5-yl}-2- methoxypyridine-3-carboxylate (Intermediate 325, 0.73 mmol, 0.30 g), 3-chloro-5- methylaniline (0.87 mmol, 0.12 g), tris(dibenzylideneacetone)dipalladium(0) (0.073 mmol, 0.07 g), 2-dicyclohexylphosphino-2',4',6'-triisopropyl-l,l'-biphenyl (0.15 mmol, 0.07 g) and sodium carbonate (0.73 mmol, 0.08 g) in acetonitrile/water (25 mL:6 mL) was heated to 90 0C for 30 min. The reaction mixture was concentrated. The residue was taken in ethyl acetate, washed with water and brine. The organic layer was separated, dried over sodium sulfate, filtered and concentrated. The crude mass was purified by silica gel column chromatography (60-120 mesh) using 25% ethyl acetate/hexanes as an eluent to yield 0.200 g of Example 798.
Figure imgf000668_0002
Example 799: 5-{2-[(3-chloro-5-methylphenyl)amino1-4-[3-(trifluoromethyl)-l//-pyrazol-l- ylipyrimidin-S-vU^-methoxypyridine-S-carboxylic acid
Figure imgf000668_0001
To 185 mg of methyl 5-{2-[(3-chloro-5-methylphenyl)amino]-4-[3-(trifluoromethyl)-lH-pyrazol- l-yl]pyrimidin-5-yl}-2-methoxypyridine-3-carboxylate (Example 798, 0.36 mmol) taken in a mixture of dioxane (5 mL) and water (5 mL), was added sodium hydroxide (0.9 mmol, 36 mg) and stirred at room temperature for 3 h. The reaction mixture was carefully acidified with 1 N HCl and further extracted with ethyl acetate (50 mL). The organic layer was washed with water and brine, dried over Na2SO4 and concentrated. The residue was dissolved in a minimum amount of CH2Cl2, then hexanes was added and the solid that precipitated was filtered, washed and dried in vacuo to yield 85 mg of the title compound.
Figure imgf000669_0002
Example 800: 5-{2-[(3-chloro-5-methylphenyl)amino1-4-[3-(trifluoromethyl)-lH-pyrazol-l- yl1pyrimidin-5-yl}-2-methoxy-N-(methylsulfonyl)pyridine-3-carboxamide
Figure imgf000669_0001
To a solution of 5-{2-[(3-chloro-5-methylphenyl)amino]-4-[3-(trifluoromethyl)-lH-pyrazol-l- yl]pyrimidin-5-yl}-2-methoxypyridine-3-carboxylic acid (Example 799, 0.089 mmol, 45 mg) in CH2Cl2 (5mL), were added methanesulfonamide (0.22 mmol, 21 mg), 2-chloro-l- methylpyridinium iodide (0.11 mmol, 28 mg), 4-(Dimethylamino)pyridine (0.018 mmol, 2.1 mg) and triethylamine (0.27 mmol, 30 mg), and the solution stirred for 90 min at RT. The reaction mixture was diluted with dichloromethane and further washed with 25% citric acid solution, water and brine. The organic layer was dried over Na2SO4 and concentrated. The crude mass was purified by 60-120 mesh silica (product eluted with 1% MeOH in CHCl3) to afford 30 mg of Example 800 as an off-white solid.
Figure imgf000670_0002
Example 801: methyl 5-{2-[(3-chloro-5-methylphenyl)amino1-4-[5-methyl-3- (trifluoromethyl)-lH-pyrazol-l-yl1pyrimidin-5-yl}-2-methoxypyridine-3-carboxylate
Figure imgf000670_0001
A suspension of methyl 5-{2-chloro-4-[5-methyl-3-(trifluoromethyl)-lH-pyrazol-l- yl]pyrimidin-5-yl}-2-methoxypyridine-3-carboxylate (Intermediate 327, 0.82 mmol, 0.35 g), 3- chloro-5-methylaniline (0.98 mmol, 0.14 g), tris(dibenzylideneacetone)dipalladium(0) (0.08 mmol, 0.075 g), 2-dicyclohexylphosphino-2',4',6'-triisopropyl-l,l'-biphenyl (0.16 mmol, 0.08 g) and sodium carbonate (0.8 mmol, 0.09 g) in acetonitrile/water (25 mL:6 mL) was heated to 90 0C for 30 min. The reaction mixture was concentrated. The residue was taken in ethyl acetate, washed with water and brine. The organic layer was separated, dried over sodium sulfate, filtered and concentrated. The crude mass was purified by silica gel column chromatography (60-120 mesh) using 20-25% ethyl acetate/hexanes as an eluent to yield 0.230 g of Example 801.
Figure imgf000671_0002
Example 802: 5-{2-[(3-chloro-5-methylphenyl)amino1-4-[5-methyl-3-(trifluoromethyl)-lH- pyrazol-l-yllpyrimidin-S-vU^-methoxypyridine-S-carboxylic acid
Figure imgf000671_0001
To 230 mg of methyl 5-{2-[(3-chloro-5-methylphenyl)amino]-4-[5-methyl-3- ( trifluoromethyl)- lH-pyrazol- 1 -yl]pyrimidin-5-yl } -2-methoxypyridine-3-carboxylate (Example 801, 0.43 mmol) taken in a mixture of dioxane (10 mL) and water (5 mL), was added 1 N aq. sodium hydroxide (1.08 mmol) and stirred overnight at room temperature. The reaction mixture was carefully acidified with 1 N HCl and further extracted with ethyl acetate (50 mL). The organic layer was washed with water and brine, dried over Na2SO4 and concentrated. The oily compound that was obtained was further stirred with hexanes and the solid that precipitated was filtered, and dried in vacuo to yield 150 mg of the title compound.
Figure imgf000672_0002
Example 803: 5-{2-[(3-chloro-5-methylphenyl)amino1-4-[5-methyl-3-(trifluoromethyl)-lH- Pyrazol-l-yllpyrimidin-5-yl}-2-methoxy-A^methylsulfonyl)pyridine-3-carboxamide
Figure imgf000672_0001
To a solution of 5-{2-[(3-chloro-5-methylphenyl)amino]-4-[5-methyl-3-(trifluoromethyl)-lH- pyrazol-l-yl]pyrimidin-5-yl}-2-methoxypyridine-3-carboxylic acid (Example 802, 0.22 mmol, 0.115 g) in CH2Cl2 (10 mL), were added methanesulfonamide (0.55 mmol, 52 mg), 2-chloro-l- methylpyridinium iodide (0.27 mmol, 70 mg), 4-(Dimethylamino)pyridine (0.044 mmol, 5.4 mg) and triethylamine (0.06 mmol, 0.1 mL), and the solution stirred for 90 min at RT. The reaction mixture was diluted with dichloromethane and further washed with 25% citric acid solution, water and brine. The organic layer was dried over Na2SO4 and concentrated. The crude mass was purified by 60-120 mesh silica (product eluted with 1% MeOH in CHCl3) to afford 90 mg of Example 803.
Figure imgf000673_0002
Example 804: 5-{2-[(3,5-dimethoxyphenyl)amino1-4-[5-methyl-3-(trifluoromethyl)-lH- Pyrazol-l-yl1pyrimidin-5-yl}-2-methoxypyridine-3-carbohvdrazide
Figure imgf000673_0001
To a solution of 5-{2-[(3,5-dimethoxyphenyl)amino]-4-[5-methyl-3-(trifluoromethyl)-lH- pyrazol-l-yl]pyrimidin-5-yl}-2-methoxypyridine-3-carboxylic acid (Example 677, 0.37 mmol, 200 mg) and 4-(Dimethylamino)pyridine (0.075 mmol, 9 mg) in CH2Cl2 (25 mL) were added Hydrazine monohydrochloride (0.94 mmol, 64 mg), triethylamine (1.89 mmol, 0.255 mL), 2- chloro-1-methylpyridinium iodide (0.47 mmol, 120 mg) and stirred for 2 h at RT. The reaction mixture was diluted with dichloromethane (50 mL) and further washed with water (100 mL) and brine (75 mL). The organic layer was dried over Na2SO4 and concentrated. The crude mass was purified by 230-400 mesh silica (product eluted with 3-4% methanol/ dichloromethane) to afford 100 mg of the title compound.
Figure imgf000674_0002
Example 805: 5-(5-{2-[(3,5-dimethoxyphenyl)amino1-4-[5-methyl-3-(trifluoromethyl)-l//- Pyrazol-l-yl1pyrimidin-5-yl}-2-methoxypyridin-3-yl)-l,3,4-oxadiazol-2(3/f)-one
Figure imgf000674_0001
5-{2-[(3,5-dimethoxyphenyl)amino]-4-[5-methyl-3-(trifluoromethyl)-lH-pyrazol-l-yl]pyrimidin- 5-yl}-2-methoxypyridine-3-carbohydrazide (Example 804, 0.18 mmol,100 mg), 1,1'- carbonyldiimidazole (0.28 mmol, 44 mg), and iV,iV-diisopropylethylamine (0.28 mmol, 36 mg) in DMF (2 mL) were combined to give a white suspension. The reaction mixture was stirred at room temperature over 1 h, and then stirred at 50 0C for 1 h. The reaction mixture was poured onto ice- water, then extracted with ethyl acetate(50 mL x 2) and further washed with water (75 mL) and brine (50 mL). The organic layer was dried over Na2SO4 and concentrated. The crude mass was purified by 230-400 mesh silica (product eluted with 1% methanol/ dichloromethane) to afford Example 805 as off-white solid (46 mg).
Figure imgf000675_0002
Example 806: 5-{2-[(3,5-dimethoxyphenyl)amino1-4-[3-(trifluoromethyl)-l//-pyrazol-l- yl1pyrimidin-5-yl}-2-methoxypyridine-3-carbohvdrazide
Figure imgf000675_0001
To a solution of 5-{2-[(3,5-dimethoxyphenyl)amino]-4-[3-(trifluoromethyl)-lH-pyrazol-l- yl]pyrimidin-5-yl}-2-methoxypyridine-3-carboxylic acid (Example 675, 0.38 mmol, 200 mg) and 4-(Dimethylamino)pyridine (0.077 mmol, 9 mg) in CH2Cl2 (25 mL) were added Hydrazine monohydrochloride (0.97 mmol, 66 mg), triethylamine (1.94 mmol, 2.62 mL), 2-chloro-l- methylpyridinium iodide (0.48 mmol, 124 mg) and stirred 8 h at RT. The reaction mixture was diluted with dichloromethane (50 mL) and further washed with water (100 mL) and brine (75 mL). The organic layer was dried over Na2SO4 and concentrated. The crude mass was purified by 230-400 mesh silica (product eluted with 3-4% methanol/ dichloromethane) to afford 120 mg of Example 806.
Figure imgf000676_0002
Example 807: 5-(5-{2-[(3,5-dimethoxyphenyl)amino1-4-[3-(trifluoromethyl)-l//-pyrazol-l- yl1pyrimidin-5-yl}-2-methoxypyridin-3-yl)-l,3,4-oxadiazol-2(3/f)-one
Figure imgf000676_0001
5-{2-[(3,5-dimethoxyphenyl)amino]-4-[3-(trifluoromethyl)-lH-pyrazol-l-yl]pyrimidin-5-yl}-2- methoxypyridine-3-carbohydrazide (Example 806, 0.36 mmol, 190 mg), 1,1'- carbonyldiimidazole (0.54 mmol, 87 mg), and N,N-diisopropylethylamine (0.54 mmol, 70 mg) in DMF (2 mL) were combined to give a white suspension. The reaction mixture was stirred at room temperature over 1 h, and then stirred at 50 0C for 1 h. The reaction mixture was poured on to ice- water, then extracted with ethyl acetate(50 mL x 2) and further washed with water (75 mL) and brine (50 mL). The organic layer was dried over Na2SO4 and concentrated. The crude mass was purified by 230-400 mesh silica (product eluted with 1% methanol/ dichloromethane) to afford Example 807 as light brown solid (33 mg).
Figure imgf000677_0002
Example 808: 5-{2-[(3,5-dimethoxyphenyl)amino1-4-[5-methyl-3-(trifluoromethyl)-l//- pyrazol-l-ylipyrimidin-S-vU^-methoxy-N-methylpyridine-S-carboxamide
Figure imgf000677_0001
To a mixture of 5-{2-[(3,5-dimethoxyphenyl)amino]-4-[5-methyl-3-(trifluoromethyl)-lH- pyrazol-l-yl]pyrimidin-5-yl}-2-methoxypyridine-3-carboxylic acid (Example 677, 0.47 mmol, 250 mg), triethylamine (1.41 mmol, 0.2 mL, 0.143 mg) and methylamine hydrochloride (0.94 mmol, 64 mg) in dichloromethane was added T3P (50 % w/w solution in EtOAc; 0.94 mmol, 0.6 mL, 300 mg) at 0 0C. The reaction mixture was slowly raised to room temperature and stirred 2 h. The mixture was then diluted with dichloromethane (15 mL), and the organic layer was successively washed with water (2x20 mL), 10 % aq sodium bicarbonate solution (15 mL) and brine. The organic layer was dried over sodium sulphate and concentrated to yield 180 mg of Example 808.
Figure imgf000678_0002
Example 809: 5-{2-[(3,5-dimethoxyphenyl)amino1-4-[3-(trifluoromethyl)-l//-pyrazol-l- yl1pyrimidin-5-yl}-2-methoxy-N-methylpyridine-3-carboxamide
Figure imgf000678_0001
To a mixture of 5-{2-[(3,5-dimethoxyphenyl)amino]-4-[3-(trifluoromethyl)-lH-pyrazol- l-yl]pyrimidin-5-yl}-2-methoxypyridine-3-carboxylic acid (Example 675, 0.48 mmol, 250 mg), triethylamine (1.46 mmol, 0.20 mL, 145 mg) and methylamine hydrochloride (0.97 mmol, 66 mg) in dichloromethane (10 mL) was added T3P (50 % w/w solution in EtOAc, 0.97 mmol, 0.62 mL, 310 mg) slowly at 0 0C. The reaction mixture was slowly raised to room temperature and stirred for 2 h. The reaction mixture was then diluted with dichloromethane (15 mL) and the dichloromethane layer was washed successively with water (2x20 mL), 10 % aq sodium bicarbonate solution (15 mL) and brine. The organic layer was dried over sodium sulphate and concentrated. The crude material was purified by silica gel column chromatography (230-400 mesh) using 2 % methanol/chloroform to yield 230 mg of Example 809.
Figure imgf000679_0002
Example 810: 5-{2-[(3,5-dimethoxyphenyl)amino1-4-[5-methyl-3-(trifluoromethyl)-l//- Pyrazol-l-yl1pyrimidin-5-yl}-N,2-dimethoxypyridine-3-carboxamide
Figure imgf000679_0001
To a mixture of 5-{2-[(3,5-dimethoxyphenyl)amino]-4-[5-methyl-3-(trifluoromethyl)-lH- pyrazol-l-yl]pyrimidin-5-yl}-2-methoxypyridine-3-carboxylic acid (Example 677, 0.47 mmol, 250 mg), triethylamine (0.94 mmol, 0.13 mL, 94 mg) and methoxylamine hydrochloride (0.7 mmol, 59 mg) in dichloromethane, was added TBTU (0.56 mmol, 182 mg) slowly at 0 0C. The reaction mixture was slowly raised to room temperature and stirred for 2 h. The reaction mixture was then diluted with dichloromethane (15 mL) and the dichloromethane solution was washed successively with water (2x20 mL), 10 % aq sodium bicarbonate solution (20 mL) and brine. The organic layer was dried over sodium sulphate, and concentrated to yield 170 mg of Example 810.
Figure imgf000680_0002
Example 811: 5-{2-[(3,5-dimethoxyphenyl)amino1-4-[3-(trifluoromethyl)-l//-pyrazol-l- yl1pyrimidin-5-yl}-N,2-dimethoxypyridine-3-carboxamide
Figure imgf000680_0001
To a mixture of 5-{2-[(3,5-dimethoxyphenyl)amino]-4-[3-(trifluoromethyl)-lH-pyrazol- l-yl]pyrimidin-5-yl}-2-methoxypyridine-3-carboxylic acid (Example 675, 0.48 mmol, 250 mg), triethylamine (0.97 mmol, 0.14 mL, 98 mg) and methoxylamine hydrochloride (0.73 mmol, 61 mg) in dichloromethane, was added TBTU (0.58 mmol, 187 mg) slowly at 0 0C. The reaction mixture was slowly raised to room temperature and stirred for 2 h. The reaction mixture was then diluted with dichloromethane (15 mL) and the dichloromethane solution was washed successively with water (2x20 mL), 10 % aq sodium bicarbonate solution (20 mL) and brine. The organic layer was dried over sodium sulphate, and concentrated. The crude material was purified by silica gel column chromatography using 2 % methanol/chloroform to yield 220 mg of Example 811.
Figure imgf000681_0002
Example 812: 5-{2-[(3,5-dimethoxyphenyl)amino1-4-[5-methyl-3-(trifluoromethyl)-l//- pyrazol-l-ylipyrimidin-S-vU^-methoxy-N-^-CmethylsulfonvDethylipyridine-S- carboxamide
Figure imgf000681_0001
To a solution of 5-{2-[(3,5-dimethoxyphenyl)amino]-4-[5-methyl-3-(trifluoromethyl)-lH- pyrazol-l-yl]pyrimidin-5-yl}-2-methoxypyridine-3-carboxylic acid (Example 677, 0.28 mmol, 150 mg) and [2-(methylsulfonyl)ethyl] amine (0.71 mmol, 87 mg) in CH2Cl2 (5 mL), were added 2-chloro-l-methylpyridinium iodide (0.35 mmol, 90 mg), 4-(Dimethylamino)pyridine (0.056 mmol, 7 mg) and triethylamine (0.85 mmol, 85 mg), and the solution stirred for 90 min at RT. The reaction mixture was diluted with dichloromethane and further washed with 25% citric acid solution, water and brine. The organic layer was dried over Na2SO4 and concentrated. The crude mass was purified by 60-120 mesh silica (product eluted with 1% MeOH in CHCl3) to afford 80 mg of Example 812 as an off-white solid.
Figure imgf000682_0002
Example 813: 5-{2-[(3,5-dimethoxyphenyl)amino1-4-[3-(trifluoromethyl)-l//-pyrazol-l- yl1pyrimidin-5-yl}-2-methoxy-N-[2-(methylsulfonyl)ethyl1pyridine-3-carboxamide
Figure imgf000682_0001
To a solution of 5-{2-[(3,5-dimethoxyphenyl)amino]-4-[3-(trifluoromethyl)-lH-pyrazol-l- yl]pyrimidin-5-yl}-2-methoxypyridine-3-carboxylic acid (Example 675, 0.29 mmol, 150 mg) and [2-(methylsulfonyl)ethyl] amine (0.72 mmol, 89 mg)in CH2Cl2 (5mL), were added 2-chloro- 1-methylpyridinium iodide (0.36 mmol, 92 mg), 4-(Dimethylamino)pyridine (0.058 mmol, 7 mg) and triethylamine (0.87 mmol, 88 mg), and the solution stirred for 90 min at RT. The reaction mixture was diluted with dichloromethane and further washed with 25% citric acid solution, water and brine. The organic layer was dried over Na2SO4 and concentrated. The crude mass was purified by 60-120 mesh silica (product eluted with 1% MeOH in CHCl3) to afford 95 mg of Example 813 as an off-white solid.
Figure imgf000683_0002
Example 814: 5-{2-[(3,5-dimethoxyphenyl)amino1-4-[3-(trifluoromethyl)-l//-pyrazol-l- yllpyrimidin-5-yl}-A^ethylsulfonyl)-2-methoxypyridine-3-carboxamide
Figure imgf000683_0001
To a solution of 5-{2-[(3,5-dimethoxylphenyl)amino]-4-[3-(trifluoromethyl)-lH-pyrazol-l- yl]pyrimidin-5-yl}-2-methoxypyridine-3-carboxylic acid Example 675 (0.48 mmol, 0.250 g) in CH2Cl2 (25 rnL), were added ethanesulfonamide (Intermediate 328, 1.16 mmol, 0.126 g), triethylamine (1.45 mmol, 0.204 mL), 2-chloro-l-methylpyridinium iodide (0.58 mmol, 0.148 g) and 4-(Dimethylamino)pyridine (0.097 mmol, 0.012 g) and stirred overnight at RT. The reaction mixture was diluted with dichloromethane (50 mL) and further washed with 25% citric acid solution (2 x 50 mL), water (100 mL) and brine (75 mL). The organic layer was dried over Na2SO4 and concentrated. The crude mass was purified by 60-120 mesh silica (product eluted with 1-2% MeOH in CHCl3) to afford 120 mg of white solid of Example 814.
Figure imgf000684_0002
Example 815: 5-{2-[(3,5-dimethoxyphenyl)amino1-4-[5-methyl-3-(trifluoromethyl)-l//- Pyrazol-l-yl1pyrimidin-5-yl}-N-(ethylsulfonyl)-2-methoxypyridine-3-carboxamide
Figure imgf000684_0001
To a solution of 5-{2-[(3,5-dimethoxyphenyl)amino]-4-[5-methyl-3-(trifluoromethyl)-lH- pyrazol-l-yl]pyrimidin-5-yl}-2-methoxypyridine-3-carboxylic acid (Example 677, 0.19 mmol, 100 mg) in CH2Cl2 (10 mL), were added ethanesulfonamide (Intermediate 328, 0.47 mmol, 52 mg), triethylamine (0.56 mmol, 57 mg), 2-chloro-l-methylpyridinium iodide (0.23 mmol, 60 mg) and 4-(Dimethylamino)pyridine (0.037 mmol, 4.5 mg) and stirred at RT for 3-4 h. The reaction mixture was diluted with dichloromethane and further washed with water and brine. The organic layer was dried over Na2SO4 and concentrated. The crude mass was purified by 60-120 mesh silica (product eluted with 1% MeOH in CHCl3) to afford 40 mg of the title compound.
Figure imgf000685_0002
Example 816: 5-{2-[(3,5-dimethoxyphenyl)amino1-4-[3-(trifluoromethyl)-l//-pyrazol-l- yllpyrimidin-5-yl}-2-methoxy-A^propylsulfonyl)pyridine-3-carboxamide
Figure imgf000685_0001
To a solution of 5-{2-[(3,5-dimethoxylphenyl)amino]-4-[3-(trifluoromethyl)-lH-pyrazol-l- yl]pyrimidin-5-yl}-2-methoxypyridine-3-carboxylic acid (0.48 mmol, 0.250 g) in CH2Cl2 (25 mL), were added propane- 1- sulfonamide (Intermediate 329, 1.16 mmol, 0.143 g), triethylamine (1.45 mmol, 0.204 mL), 2-chloro-l-methylpyridinium iodide (0.58 mmol, 0.148 g) and 4- (Dimethylamino)pyridine (0.097 mmol, 0.012 g) and stirred overnight at RT. The reaction mixture was diluted with dichloromethane (50 rnL) and further washed with 25% citric acid solution (2 x 50 rnL), water (100 mL) and brine (75 rnL). The organic layer was dried over Na2SO4 and concentrated. The crude mass was purified by 60-120 mesh silica (product eluted with 1.5-2.5% MeOH in CHCl3) to afford 170 mg of Example 816 as a white solid.
Figure imgf000686_0002
Example 817: 5-{2-[(3,5-dimethoxyphenyl)amino1-4-[5-methyl-3-(trifluoromethyl)-l//- Pyrazol-l-yllpyrimidin-5-yl}-2-methoxy-A^propylsulfonyl)pyridine-3-carboxamide
Figure imgf000686_0001
To a solution of 5-{2-[(3,5-dimethoxyphenyl)amino]-4-[5-methyl-3-(trifluoromethyl)-lH- pyrazol-l-yl]pyrimidin-5-yl}-2-methoxypyridine-3-carboxylic acid (Example 677, 0.19 mmol, 100 mg) in CH2Cl2 (10 niL), were added propane- 1 -sulfonamide (Intermediate 329, 0.47 mmol, 60 mg), triethylamine (0.56 mmol, 57 mg), 2-chloro-l-methylpyridinium iodide (0.23 mmol, 60 mg) and 4-(Dimethylamino)pyridine (0.037 mmol, 4.5 mg) and stirred at RT for 1 h. The reaction mixture was diluted with dichloromethane and further washed with water and brine. The organic layer was dried over Na2SO4 and concentrated. The crude mass was purified by 60-120 mesh silica (product eluted with 1% MeOH in CHCl3) to afford 40 mg of the title compound.
Figure imgf000687_0001
Example 818: 5-{2-[(3,5-dimethoxyphenyl)amino1-4-[3-(trifluoromethyl)-lH-pyrazol-l- yllpyrimidin-5-yl}-2-methoxy-A^propan-2-ylsulfonyl)pyridine-3-carboxamide
Figure imgf000688_0001
To a solution of 5-{2-[(3,5-dimethoxylphenyl)amino]-4-[3-(trifluoromethyl)-lH-pyrazol-l- yl]pyrimidin-5-yl}-2-methoxypyridine-3-carboxylic acid (Example 675, 0.38 mmol, 0.2 g) in CH2Cl2 (10 niL), were added propane-2-sulfonamide (Intermediate 330, 0.58 mmol, 0.07 g), triethylamine (0.86 mmol, 0.12 mL, 86 mg), 2-chloro-l-methylpyridinium iodide (0.45 mmol, 0.116 g) and 4-(Dimethylamino)pyridine (0.06 mmol, 7 mg) and stirred at RT for 3-4 h. The reaction mixture was diluted with dichloromethane and further washed with 25% citric acid solution, water and brine. The organic layer was dried over Na2SO4 and concentrated. The crude mass was purified by 60-120 mesh silica (product eluted with 1% MeOH in CHCl3) to afford 100 mg of the title compound.
Figure imgf000689_0002
Example 819: 5-{2-[(3,5-dimethoxyphenyl)amino1-4-[5-methyl-3-(trifluoromethyl)-l//- Pyrazol-l-yllpyrimidin-5-yl}-2-methoxy-A^propan-2-ylsulfonyl)pyridine-3-carboxamide
Figure imgf000689_0001
To a solution of 5-{2-[(3,5-dimethoxyphenyl)amino]-4-[5-methyl-3-(trifluoromethyl)-lH- pyrazol-l-yl]pyrimidin-5-yl}-2-methoxypyridine-3-carboxylic acid (Example 677, 0.37 mmol, 0.2 g) in CH2Cl2 (10 rnL), were added propane-2-sulfonamide (Intermediate 330, 0.56 mmol, 0.07 g), triethylamine (1.1 mmol, 0.15 mL), 2-chloro-l-methylpyridinium iodide (0.45 mmol, 0.116 g) and 4-(Dimethylamino)pyridine (0.06 mmol, 7 mg) and stirred at RT for 3-4 h. The reaction mixture was diluted with dichloromethane and further washed with 25% citric acid solution, water and brine. The organic layer was dried over Na2SO4 and concentrated. The crude mass was purified by 60-120 mesh silica (product eluted with 1% MeOH in CHCl3) to afford 130 mg of the title compound.
Figure imgf000690_0002
Example 820: 5-{2-[(3,5-dimethoxyphenyl)amino1-4-[3-(trifluoromethyl)-l//-pyrazol-l- yl1pyrimidin-5-yl}-2-methoxy-N-{[3-(morpholin-4-yl)propyl1sulfonyl}pyridine-3- carboxamide
Figure imgf000690_0001
To a solution of 5-{2-[(3,5-dimethoxylphenyl)amino]-4-[3-(trifluoromethyl)-lH-pyrazol-l- yl]pyrimidin-5-yl}-2-methoxypyridine-3-carboxylic acid (Example 675, 0.38 mmol, 0.2 g) and 4-(Dimethylamino)pyridine (0.06 mmol, 7 mg) in CH2Cl2 (10 mL), were added 3-(morpholin-4- yl)propane-l- sulfonamide (Intermediate 332, 0.58 mmol, 0.12 g), triethylamine (0.86 mmol, 0.12 mL, 86 mg), 2-chloro-l-methylpyridinium iodide (0.45 mmol, 0.116 g) and stirred at RT for 3-4 h. The reaction mixture was diluted with dichloromethane and further washed with 25% citric acid solution, water and brine. The organic layer was dried over Na2SO4 and concentrated. The crude mass was purified by 60-120 mesh silica (product eluted with 1% MeOH in CHCl3) to afford 70 mg of the title compound.
Figure imgf000691_0001
Example 821: 5-{2-[(3,5-dimethoxyphenyl)amino1-4-[5-methyl-3-(trifluoromethyl)-lH- Pyrazol-l-yl1pyrimidin-5-yl}-2-methoxy-N-{r3-(morpholin-4-yl)propyl1sulfonyl}pyridine-3- carboxamide
Figure imgf000692_0001
To a solution of 5-{2-[(3,5-dimethoxyphenyl)amino]-4-[5-methyl-3-(trifluoromethyl)-lH- pyrazol-l-yl]pyrimidin-5-yl}-2-methoxypyridine-3-carboxylic acid (Example 677, 0.37 mmol, 0.2 g) and 4-(Dimethylamino)pyridine (0.06 mmol, 7 mg) in CH2Cl2 (10 mL) were added 3- (morpholin-4-yl)propane-l -sulfonamide (Intermediate 332, 0.58 mmol, 0.12 g), triethylamine (1.1 mmol, 0.15 mL), 2-chloro-l-methylpyridinium iodide (0.45 mmol, 0.116 g) and stirred at RT for 3-4 h. The reaction mixture was diluted with dichloromethane and further washed with 25% citric acid solution, water and brine. The organic layer was dried over Na2SO4 and concentrated. The crude mass was purified by 60-120 mesh silica (product eluted with 3% MeOH in CHCl3) to afford 130 mg of the title compound.
Figure imgf000693_0002
Example 822: 5-{2-r(3,5-dimethvlϋhenvl)aminol-4-r3-(trifluoromethvl)-lH-ϋvrazol-l- vllPvrimidin-5-vl}-N-(ethvlsulfonvl)-2-methoxvPvridine-3-carboxamide
Figure imgf000693_0001
To a solution of 5-{2-[(3,5-dimethylphenyl)amino]-4-[3-(trifluoromethyl)-lH-pyrazol-l- yl]pyrimidin-5-yl}-2-methoxypyridine-3-carboxylic acid (Example 648, 0.52 mmol, 0.250 g) and 4-(Dimethylamino)pyridine (0.104 mmol, 0.013 g) in CH2Cl2 (25 mL) were added ethanesulfonamide (Intermediate 328, 1.3 mmol, 0.14 g), triethylamine (1.61 mmol, 0.225 mL), 2-chloro-l-methylpyridinium iodide (0.63 mmol, 0.16 g) and stirred overnight at RT. The reaction mixture was diluted with dichloromethane (50 rnL) and further washed with 25% citric acid solution (2 x 50 rnL), water (100 mL) and brine (75 rnL). The organic layer was dried over Na2SO4 and concentrated. The crude mass was purified by 60-120 mesh silica (product eluted with 1-1.5% methanol/chloroform) to afford 208 mg of white solid with 94 % purity by LCMS. This was further purified using RP-HPLC (Atlantis Cl 8 column(19 x 250 mm, 10 μm); using a binary solvent mixture of 20 mM NH4OAc (A)MeOH (B) (0-20 min: 10-65% B, 20-30 min: 65% B and 30-45 min: 65-100% B; 45-50 min: 100% B flow rate of 15 niL/min; Separation was monitored at 210, 254 and 300 nm) to give 1 lOmg of the title compound.
Figure imgf000694_0001
Example 823: 5-{2-r(3,5-dimethylphenyl)amino1-4-r5-methyl-3-(trifluoromethyl)-lH- Pyrazol-l-yllpyrimidin-5-yl}-A^ethylsulfonyl)-2-methoxypyridine-3-carboxamide
Figure imgf000695_0001
To a solution of 5-{2-[(3,5-dimethylphenyl)amino]-4-[5-methyl-3-(trifluoromethyl)-lH-pyrazol- l-ylJpyrimidin-S-ylj-l-methoxypyridine-S-carboxylic acid (Example 646, 0.3 mmol, 0.150 g) and 4-(Dimethylamino)pyridine (0.06 mmol, 7 mg) in CH2Cl2 were added ethanesulfonamide (Intermediate 328, 0.75 mmol, 0.082 g), triethylamine (0.9 mmol, 0.125 mL), 2-chloro-l- methylpyridinium iodide (0.36 mmol, 0.095 g) and stirred at RT for 3-4 h. The reaction mixture was diluted with dichloromethane and further washed with 25% citric acid solution, water and brine. The organic layer was dried over Na2SO4 and concentrated. The crude mass was purified by 60-120 mesh silica (product eluted with 1% MeOH/CHCl3) to afford 130 mg of the title compound.
Figure imgf000696_0002
Example 824: 5-{2-[(3,5-dimethylphenyl)amino1-4-[3-(trifluoromethyl)-lH-pyrazol-l- ylipyrimidin-S-vU^-methoxy-N-CpropylsulfonvDpyridine-S-carboxamide
Figure imgf000696_0001
To a solution of 5-{2-[(3,5-dimethylphenyl)amino]-4-[3-(trifluoromethyl)-lH-pyrazol-l- yl]pyrimidin-5-yl}-2-methoxypyridine-3-carboxylic acid (Example 648, 0.52 mmol, 0.250 g) and 4-(Dimethylamino)pyridine (0.61 mmol, 0.075 g) in CH2Cl2 (25 mL) were added propane-1- sulfonamide (Intermediate 328, 1.3 mmol, 0.16 g), triethylamine (1.61 mmol, 0.225 mL), 2- chloro-1-methylpyridinium iodide (0.63 mmol, 0.16 g) and stirred overnight at RT. The reaction mixture was diluted with dichloromethane (50 mL) and further washed with 25% citric acid solution (2 x 50 niL), water (100 rnL) and brine (75 rnL). The organic layer was dried over Na2SO4 and concentrated. The crude mass was purified by 230-400 mesh silica (product eluted with 40-45% ethyl acetate/hexanes) to afford 200 mg of white solid with 81 % purity by LCMS. This was further purified using RP-HPLC (Atlantis Cl 8 column(19 x 250 mm, 10 μm); using a binary solvent mixture of 20 mM NH4OAc (A)MeOH (B) (0-20 min: 10-65% B, 20-30 min: 65% B and 30-45 min: 65-100% B; 45-50 min: 100% B flow rate of 15 niL/min; Separation was monitored at 210, 254 and 300 nm) to give 125 mg of Example 824.
Figure imgf000697_0002
Example 825 : 5-{2- r(3,5-dimethylphenyl)amino1 -4- r5-methyl-3-(trifluoromethyl)- IH- Pyrazol-l-yllpyrimidin-5-yl}-2-methoxy-A^propylsulfonyl)pyridine-3-carboxamide
Figure imgf000697_0001
To a solution of 5-{2-[(3,5-dimethylphenyl)amino]-4-[5-methyl-3-(trifluoromethyl)-lH-pyrazol- l-yl]pyrimidin-5-yl}-2-methoxypyridine-3-carboxylic acid (Example 646, 0.3 mmol, 0.150 g) and 4-(Dimethylamino)pyridine (0.06 mmol, 7 mg) in CH2Cl2 were added propane- 1- sulfonamide (Intermediate 329, 0.75 mmol, 0.092 g), triethylamine (0.9 mmol, 0.125 mL, 92 mg), 2-chloro-l-methylpyridinium iodide (0.37 mmol, 0.095 g) and stirred at RT for 3-4 h. The reaction mixture was diluted with dichloromethane and further washed with 25% citric acid solution, water and brine. The organic layer was dried over Na2SO4 and concentrated. The crude mass was purified by 60-120 mesh silica (product eluted with 1% MeOHZCHCl3) to afford 90 mg of the title compound.
Figure imgf000698_0002
Example 826: 5-{2-[(3,5-dimethylphenyl)amino1-4-[3-(trifluoromethyl)-lH-pyrazol-l- yllpyrimidin-5-yl}-2-methoxy-A^propan-2-ylsulfonyl)pyridine-3-carboxamide
Figure imgf000698_0001
To a solution of 5-{2-[(3,5-dimethylphenyl)amino]-4-[3-(trifluoromethyl)-lH-pyrazol-l- yl]pyrimidin-5-yl}-2-methoxypyridine-3-carboxylic acid (Example 648, 0.412 mmol, 0.200 g) and 4-(Dimethylamino)pyridine (0.082 mmol, 0.010 g) in CH2Cl2 (25 mL) were added propane- 2-sulfonamide (Intermediate 330, 0.99 mmol, 0.122 g), triethylamine (1.236 mmol, 0.173 mL), 2-chloro-l-methylpyridinium iodide (0.49 mmol, 0.126 g) and stirred overnight at RT. The reaction mixture was diluted with dichloromethane (50 mL) and further washed with 25% citric acid solution (2 x 50 mL), water (100 mL) and brine (75 mL). The organic layer was dried over Na2SO4 and concentrated. The crude mass was purified by 60-120 mesh silica (product eluted with 1.5-2.5% MeOH in CHCl3) to afford 110 mg of white solid with 86 % purity by LCMS. This was further purified using RP-HPLC (kromasil Cl 8 column(50 x 250 mm, 10 μm); using a binary solvent mixture of 0.1% TFA in water (A)MeOH (B) (0-20 min: 10-70% B, 20-30 min: 70-80% B and 30-40 min: 80-90% B; 40-50 min: 90% B,50-55 min: 90-100%B flow rate of 40 niL/min; Separation was monitored at 210 and 290 nm) to give 40 mg of Example 826.
Figure imgf000699_0002
Example 827: 5-{2-r(3,5-dimethylphenyl)amino1-4-r5-methyl-3-(trifluoromethyl)-lH- Pyrazol-l-yllpyrimidin-5-yl}-2-methoxy-A^propan-2-ylsulfonyl)pyridine-3-carboxamide
Figure imgf000699_0001
To a solution of 5-{2-[(3,5-dimethylphenyl)amino]-4-[5-methyl-3-(trifluoromethyl)-lH-pyrazol- l-yl]pyrimidin-5-yl}-2-methoxypyridine-3-carboxylic acid (Example 646, 0.3 mmol, 0.150 g) in CH2Cl2 (10 mL), were added propane-2-sulfonamide (Intermediate 330, 0.45 mmol, 0.055 g), triethylamine (0.9 mmol, 0.125 mL, 92 mg), 2-chloro-l-methylpyridinium iodide (0.37 mmol, 0.095 g) and 4-(Dimethylamino)pyridine (0.06 mmol, 7 mg), and refluxed at 45 0C for 30'. The reaction mixture was cooled, diluted with dichloromethane and further washed with 25% citric acid solution, water and brine. The organic layer was dried over Na2SO4 and concentrated. The crude mass was purified by 60-120 mesh silica (product eluted with 1% MeOHZCHCl3) to afford 95 mg of the title compound.
Figure imgf000700_0002
Example 828: 5-{2-r(3,5-dimethylphenyl)amino1-4-r3-(trifluoromethyl)-lH-pyrazol-l- yl1pyrimidin-5-yl}-2-methoxy-N-{[3-(morpholin-4-yl)propyl1sulfonyl}pyridine-3- carboxamide
Figure imgf000700_0001
To a solution of 5-{2-[(3,5-dimethylphenyl)amino]-4-[3-(trifluoromethyl)-lH-pyrazol-l- yl]pyrimidin-5-yl}-2-methoxypyridine-3-carboxylic acid (Example 648, 0.52 mmol, 0.250 g) and 4-(Dimethylamino)pyridine (0.104 mmol, 0.013 g) in CH2Cl2 (25 mL) were added 3- (morpholin-4-yl)propane-l -sulfonamide (Intermediate 332, 1.25 mmol, 0.26 g), triethylamine (1.61 mmol, 0.225 mL), 2-chloro-l-methylpyridinium iodide (0.63 mmol, 0.16 g) and stirred overnight at RT. The reaction mixture was diluted with dichloromethane (50 mL) and further washed with 25% citric acid solution (2 x 50 mL), water (100 mL) and brine (75 mL). The organic layer was dried over Na2SO4 and concentrated. The crude mass was purified by 60-120 mesh silica (product eluted with 5-7% methanol/chloroform) to afford 170 mg of Example 828.
Figure imgf000701_0002
Example 829: 5-{2-r(3,5-dimethylphenyl)amino1-4-r5-methyl-3-(trifluoromethyl)-lH- pyrazol-l-ylipyrimidin-S-vU^-methoxy-N-irS-Cmorpholin^-vDpropylisulfonvUpyridine-S- carboxamide
Figure imgf000701_0001
To a solution of 5-{2-[(3,5-dimethylphenyl)amino]-4-[5-methyl-3-(trifluoromethyl)-lH-pyrazol- l-ylJpyrimidin-S-ylj-l-methoxypyridine-S-carboxylic acid (Example 646, 0.4 mmol, 0.2 g) and 4-(Dimethylamino)pyridine (0.08 mmol, 9 mg) in CH2Cl2 were added 3-(morpholin-4- yl)propane-l- sulfonamide (Intermediate 332, 0.8 mmol, 0.17 g), triethylamine (1.2 mmol, 0.16 mL, 121 mg), 2-chloro-l-methylpyridinium iodide (0.48 mmol, 0.122 g) and stirred at RT for 3-4 h. The reaction mixture was diluted with dichloromethane and further washed with 25% citric acid solution, water and brine. The organic layer was dried over Na2SO4 and concentrated. The crude mass was purified by 60-120 mesh silica (product eluted with 4% MeOHZCHCl3) to afford 120 mg of the title compound.
Figure imgf000702_0002
Example 830: 5-{2-[(3,5-dimethoxyphenyl)amino1-4-[5-methyl-3-(trifluoromethyl)-l//- Pyrazol-l-yllpyrimidin-5-yl}-l,2-benzothiazol-3(2//)-one 1,1-dioxide
Figure imgf000702_0001
A solution of 5-bromo-N-(3,5-dimethoxyphenyl)-4-[5-methyl-3-(trifluoromethyl)-lH-pyrazol-l- yl]pyrimidin-2-amine (Intermediate 216, 0.96 mmol, 440 mg), (l,l-dioxido-3-oxo-2,3-dihydro- l,2-benzothiazol-5-yl)boronic acid (Intermediate 335, 1.32 mmol, 300 mg), [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with CH2Cl2 (0.19 mmol, 158 mg) and sodium carbonate (0.96 mmol, 103 mg) in acetonitrile (5 mL)/water (1 mL) was degassed and heated to 90 0C for 20 min under nitrogen. Solvent was removed in vacuo and the residue obtained was taken in ethyl acetate, washed with water and brine, dried over sodium sulfate and concentrated. The crude mass was purified by silica gel column chromatography (60- 120 mesh) using 10% methanol/chloroform to yield 157 mg of the title compound.
Figure imgf000703_0002
Example 831: 5-{2-[(3,5-dimethoxyphenyl)amino1-4-[3-(trifluoromethyl)-l//-pyrazol-l- yl1pyrimidin-5-yl}-l,2-benzothiazol-3(2/f)-one 1,1-dioxide
Figure imgf000703_0001
A solution of 5-bromo-N-(3,5-dimethoxyphenyl)-4-[3-(trifluoromethyl)-lH-pyrazol-l- yl]pyrimidin-2-amine (Intermediate 215, 0.97 mmol, 430 mg), (l,l-dioxido-3-oxo-2,3-dihydro- l,2-benzothiazol-5-yl)boronic acid (Intermediate 335, 1.32 mmol, 300 mg), [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with CH2Cl2 (0.19 mmol, 160 mg) and sodium carbonate (0.97 mmol, 103 mg) in acetonitrile (5 mL)/water (1 mL) was degassed and heated to 90 0C for 20 min under nitrogen. Solvent was removed in vacuo and the residue obtained was taken in ethyl acetate, washed with water and brine, dried over sodium sulfate and concentrated. The crude mass was purified by silica gel column chromatography (60- 120 mesh) using 9% methanol/chloroform to yield 190 mg of the title compound.
Figure imgf000704_0002
Example 832: 5-{2-r(3,5-dimethylphenyl)amino1-4-r5-methyl-3-(trifluoromethyl)-lH- Pyrazol-l-yllpyrimidin-5-yl}-l,2-benzothiazol-3(2//)-one 1,1-dioxide
Figure imgf000704_0001
A solution of 5-bromo-N-(3,5-dimethylphenyl)-4-[5-methyl-3-(trifluoromethyl)-lH-pyrazol-l- yl]pyrimidin-2-amine (Intermediate 218, 0.97 mmol, 413 mg), (l,l-dioxido-3-oxo-2,3-dihydro- l,2-benzothiazol-5-yl)boronic acid (Intermediate 335, 1.32 mmol, 300 mg), [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with CH2Cl2 (0.19 mmol, 158 mg) and sodium carbonate (0.97 mmol, 103 mg) in acetonitrile (5 mL)/water (1 mL) was degassed and heated to 90 0C for 20 min under nitrogen. Solvent was removed in vacuo and the residue was taken in ethyl acetate, washed with water and brine, dried over sodium sulfate and concentrated. The crude mass was purified by silica gel column chromatography (60-120 mesh) using 10% methanol/chloroform to yield 195 mg of the title compound.
Figure imgf000705_0002
Example 833 : 5-{2- [(3,5-dimethylphenyl)amino1 -4- [3-(trifluoromethyl)- lH-pyrazol- 1- yllpyrimidin-5-yl}-l,2-benzothiazol-3(2//)-one 1,1-dioxide
Figure imgf000705_0001
A solution of 5-bromo-N-(3,5-dimethylphenyl)-4-[3-(trifluoromethyl)-lH-pyrazol-l- yl]pyrimidin-2-amine (Intermediate 217, 0.97 mmol, 399 mg), (l,l-dioxido-3-oxo-2,3-dihydro- l,2-benzothiazol-5-yl)boronic acid (Intermediate 335, 1.32 mmol, 300 mg), [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with CH2Cl2 (0.19 mmol, 158 mg) and sodium carbonate (0.97 mmol, 103 mg) in acetonitrile (5 mL)/water (1 mL) was degassed and heated to 90 0C for 20 min under nitrogen. Solvent was removed in vacuo and the residue obtained was taken in ethyl acetate, washed with water and brine, dried over sodium sulfate and concentrated. The crude mass was purified by silica gel column chromatography (60- 120 mesh) using 9 % methanol/chloroform to yield 200 mg of the title compound.
Figure imgf000706_0002
Example 834: N-{r2-(acetylamino)-4-methyl-l,3-thiazol-5-yl1sulfonyl}-5-{2-r(3,5- dimethoxyphenyl)amino1-4-[5-methyl-3-(trifluoromethyl)-lH-pyrazol-l-yl1pyrimidin-5-yl}-
2-methoxypyridine-3-carboxamide
Figure imgf000706_0001
To a solution of 5-{2-[(3,5-dimethoxyphenyl)amino]-4-[5-methyl-3-(trifluoromethyl)-lH- pyrazol-l-yl]pyrimidin-5-yl}-2-methoxypyridine-3-carboxylic acid (Example 675, 0.19 mmol, 0.100 g) and iV-(4-methyl-5-sulfamoyl-l,3-thiazol-2-yl)acetamide (Intermediate 336, 0.38 mmol, 0.089 g) in CH2Cl2 (25 mL), were added triethylamine (0.57 mmol, 0.08 mL), 2-chloro-l- methylpyridinium iodide (0.23 mmol, 58 mg) and 4-(Dimethylamino)pyridine (0.038 mmol, 5 mg) and stirred for 4-5 h at RT. The reaction mixture was diluted with dichloromethane (50 mL) and further washed with 25% citric acid solution (2 x 5OmL), water (100 mL) and brine (75 mL). The organic layer was dried over Na2SO4 and concentrated. The crude mass was purified by 60- 120 mesh silica (product eluted with 4-5% methanol/chloroform) to afford 110 mg of white solid with 89 % purity by LCMS. This was further purified using RP-HPLC (Kromasil Cl 8 column(50 x 250 mm, 10 μm); using a binary solvent mixture of 0.1% TFA in water(A)/MeOH (B) (0-20 min: 10-70% B, 20-30 min: 70-80% B and 30-40 min: 80% B; 40-45 min: 80-100% B, 45-50 min: 100% B, 50-52 min: 100- 10 B, flow rate of 40 niL/min; Separation was monitored at 210 and 300 nm) to give 55 mg of the title compound.
Figure imgf000707_0002
Example 835: 5-{2-[(3,5-dimethoxyphenyl)amino1-4-[5-methyl-3-(trifluoromethyl)-l//-
Pyrazol-l-yl1pyrimidin-5-yl}-2-methoxy-N-[(2,2,2-trifluoroethyl)sulfonyl1pyridine-3- carboxamide
Figure imgf000707_0001
To a solution of 5-{2-[(3,5-dimethoxyphenyl)amino]-4-[5-methyl-3-(trifluoromethyl)-lH- pyrazol-l-yl]pyrimidin-5-yl}-2-methoxypyridine-3-carboxylic acid (Example 675, 0.19 mmol, 0.100 g) and 2,2,2-trifluoroethanesulfonamide (Intermediate 337, 0.43 mmol, 0.07 g) in CH2Cl2 (25 niL), were added triethylamine (0.94 mmol, 0.14 rnL), 2-chloro-l-methylpyridinium iodide (0.23 mmol, 60 mg) and 4-(Dimethylamino)pyridine (0.08 mmol, 10 mg) and stirred for 1 h at RT. The reaction mixture was diluted with dichloromethane (50 mL) and further washed with 25% citric acid solution (2 x 50 mL), water (100 mL) and brine (75 mL). The organic layer was dried over Na2SO4 and concentrated. The crude mass was purified by 60-120 mesh silica (product eluted with 2% methanol/chloroform) to afford 45 mg of the title compound as a white solid.
Figure imgf000708_0002
Example 836: 5-{2-[(3,5-dimethoxyphenyl)amino1-4-[5-methyl-3-(trifluoromethyl)-l//- pyrazol-l-ylipyrimidin-S-vU-N-rCS^-dimethyl-l^-oxazol^-vDsulfonyli^-methoxypyridine- 3-carboxamide
Figure imgf000708_0001
To a solution of 5-{2-[(3,5-dimethoxyphenyl)amino]-4-[5-methyl-3-(trifluoromethyl)-lH- pyrazol-l-yl]pyrimidin-5-yl}-2-methoxypyridine-3-carboxylic acid (Example 675, 0.28 mmol, 0.15 g) and 3,5-dimethyl-l,2-oxazole-4-sulfonamide (Intermediate 338, 0.42 mmol, 74 mg) in CH2Cl2 (10 mL), were added triethylamine (0.84 mmol, 0.12 mL), 2-chloro-l-methylpyridinium iodide (0.3 mmol, 78 mg) and 4-(Dimethylamino)pyridine (0.05 mmol, 6 mg) and stirred for 2 h at RT. The reaction mixture was diluted with dichloromethane (50 mL) and further washed with 25% citric acid solution, water and brine. The organic layer was dried over Na2SO4 and concentrated. The crude mass was purified by 60-120 mesh silica (product eluted with 2% methanol/chloroform) to afford 85 mg of the title compound.
Figure imgf000709_0001
Example 837: 5-{2-[(3,5-dimethoxyphenyl)amino1-4-[5-methyl-3-(trifluoromethyl)-l//-
Pyrazol-l-yl1pyrimidin-5-yl}-N-[(2,4-dimethyl-l,3-thiazol-5-yl)sulfonyl1-2-methoxypyridine-
3-carboxamide
Figure imgf000710_0001
To a solution of 5-{2-[(3,5-dimethoxyphenyl)amino]-4-[5-methyl-3-(trifluoromethyl)-lH- pyrazol-l-yl]pyrimidin-5-yl}-2-methoxypyridine-3-carboxylic acid (Example 675, 0.37 mmol, 0.200 g) in CH2Cl2 (10 mL), were added 2,4-dimethyl-l,3-thiazole-5-sulfonamide (Intermediate 339, 0.56 mmol, 0.11 g), triethylamine (0.84 mmol, 0.12 mL), 2-chloro-l-methylpyridinium iodide (0.44 mmol, 0.11 g) and 4-(Dimethylamino)pyridine (0.05 mmol, 6 mg) and stirred at RT for 2 h. The reaction mixture was diluted with dichloromethane and further washed with 10% citric acid solution, water and brine. The organic layer was dried over Na2SO4 and concentrated. This was further purified using RP-HPLC (Kromasil Cl 8 column(250 x 50 mm, 10 μm); using a binary solvent mixture of 10 mM NH4OAc (A)MeOH (B) (0-20 min: 20-70% B, 20-30 min:70- 80% B and 30-35 min: 80-100% B; 35-40 min: 100% B flow rate of 40 niL/min; Separation was monitored at 210, 254 and 300 nm) to afford 100 mg of the title compound.
Figure imgf000710_0002
Example 838: 5-{2-[(3,5-dimethoxyphenyl)amino1-4-[5-methyl-3-(trifluoromethyl)-lH- Pyrazol-l-yl1pyrimidin-5-yl}-2-methoxy-N-{r(methylsulfonyl)methyl1sulfonyl}pyridine-3- carboxamide
Figure imgf000711_0001
To a solution of 5-{2-[(3,5-dimethoxyphenyl)amino]-4-[5-methyl-3-(trifluoromethyl)-lH- pyrazol-l-yl]pyrimidin-5-yl}-2-methoxypyridine-3-carboxylic acid (Example 675, 0.23 mmol, 0.125 g) and l-(methylsulfonyl)methanesulfonamide (Intermediate 340, 0.34 mmol, 0.06 g) in CH2Cl2 (10 mL), were added triethylamine (0.6 mmol, 0.1 mL), 2-chloro-l-methylpyridinium iodide (0.27 mmol, 0.07 g) and 4-(Dimethylamino)pyridine (0.04 mmol, 5 mg) and stirred at RT for 2 h. The reaction mixture was diluted with dichloromethane and further washed with 10% citric acid solution, water and brine. The organic layer was dried over Na2SO4 and concentrated. The crude mass was purified by 60-120 mesh silica (product eluted with 2% MeOH in CHCI3) to afford 70 mg of the title compound.
Figure imgf000711_0002
Example 839: 5-{2-[(3,5-dimethoxyphenyl)amino1-4-[5-methyl-3-(trifluoromethyl)-lH-
Pyrazol-l-yl1pyrimidin-5-yl}-2-methoxy-N-[(l-methyl-lH-imidazol-4-yl)sulfonyl1pyridine-3- carboxamide
Figure imgf000712_0001
To a solution of 5-{2-[(3,5-dimethoxyphenyl)amino]-4-[5-methyl-3-(trifluoromethyl)-lH- pyrazol-l-yl]pyrimidin-5-yl}-2-methoxypyridine-3-carboxylic acid (Example 675, 0.28 mmol, 0.15 g) and l-methyl-lH-imidazole-4-sulfonamide (Intermediate 341, 0.84 mmol, 0.14 g) in CH2Cl2 (10 mL), were added triethylamine (1.69 mmol, 0.23 mL), 2-chloro-l-methylpyridinium iodide (0.35 mmol, 0.09 g) and 4-(Dimethylamino)pyridine (0.056 mmol, 7 mg) and stirred at RT for 2 h. The reaction mixture was diluted with dichloromethane and further washed with 5 % citric acid solution, water and brine. The organic layer was dried over Na2SO4 and concentrated. The crude mass was purified by 60-120 mesh silica (product eluted with 2% MeOH in CHCI3) to afford 150 mg of the title compound.
Figure imgf000712_0002
Example 840: 5-{2-[(3,5-dimethoxyphenyl)amino1-4-[5-methyl-3-(trifluoromethyl)-lH-
Pyrazol-l-yl1pyrimidin-5-yl}-N-[(l,l-dioxido-2,5-dihvdrothiophen-3-yl)sulfonyl1-2- methoxypyridine-3-carboxamide
Figure imgf000713_0001
To a solution of 5-{2-[(3,5-dimethoxyphenyl)amino]-4-[5-methyl-3-(trifluoromethyl)-lH- pyrazol-l-yl]pyrimidin-5-yl}-2-methoxypyridine-3-carboxylic acid (Example 675, 0.56 mmol, 0.3 g) and 2,5-dihydrothiophene-3-sulfonamide 1,1-dioxide (Intermediate 343, 0.85 mmol, 0.17 g) in DMSO (10 mL), were added triethylamine (1.68 mmol, 0.23 mL), 2-chloro-l- methylpyridinium iodide (0.7 mmol, 0.18 g) and 4-(Dimethylamino)pyridine (0.11 mmol, 14 mg) and stirred at RT for 1 h. The reaction mixture was diluted with water and extracted into ethyl acetate. The organic layer was further washed with 10% citric acid solution, water and brine, dried over Na2SO4 and concentrated. The crude mass was purified by 60-120 mesh silica (product eluted with 2% MeOH in CHCl3) to afford 200 mg of the title compound as a 7:3 mixture of two isomers.
Figure imgf000714_0002
Example 841: 5-{2-[(3,5-dimethoxyphenyl)amino1-4-[5-methyl-3-(trifluoromethyl)-l//-
Pyrazol-l-yl1pyrimidin-5-yl}-2-methoxy-N-[(6-methyl-2,4-dioxo-l,2,3,4- tetrahvdropyrimidin-5-yl)sulfonyl1pyridine-3-carboxamide
Figure imgf000714_0001
To a solution of 5-{2-[(3,5-dimethoxyphenyl)amino]-4-[5-methyl-3-(trifluoromethyl)-lH- pyrazol-l-yl]pyrimidin-5-yl}-2-methoxypyridine-3-carboxylic acid (Example 675, 0.28 mmol, 0.15 g) and 6-methyl-2,4-dioxo-l,2,3,4-tetrahydropyrimidine-5-sulfonamide (Intermediate 345, 0.42 mmol, 0.09 g) in DMSO (6 mL), were added triethylamine (1.4 mmol, 0.2 mL), 2-chloro-l- methylpyridinium iodide (0.42 mmol, 0.11 g) and 4-(Dimethylamino)pyridine (0.08 mmol, 10 mg) and stirred at RT for 1 h. The reaction mixture was diluted with water and extracted into ethyl acetate. The organic layer was further washed with 10% citric acid solution, water and brine, dried over Na2SO4 and concentrated in vacuo. The crude mass was purified by 60-120 mesh silica (product eluted with 2% MeOH in CHCl3) to afford 70 mg of the title compound.
Figure imgf000715_0002
Example 842: 5-{2-[(3,5-dimethoxyphenyl)amino1-4-[5-methyl-3-(trifluoromethyl)-l//-
Pyrazol-l-yl1pyrimidin-5-yl}-2-methoxy-N-[(l,3,5-trimethyl-l//-pyrazol-4- yl)sulfonyl1pyridine-3-carboxamide
Figure imgf000715_0001
To a solution of 5-{2-[(3,5-dimethoxyphenyl)amino]-4-[5-methyl-3-(trifluoromethyl)-lH- pyrazol-l-yl]pyrimidin-5-yl}-2-methoxypyridine-3-carboxylic acid (Example 675, 0.31 mmol, 0.165 g) and l,3,5-trimethyl-lH-pyrazole-4-sulfonamide (Intermediate 346, 0.78 mmol, 0.147 g) in CH2Cl2 (15 niL), were added triethylamine (0.933 mmol, 0.1302 mL), 2-chloro-l- methylpyridinium iodide (0.38 mmol, 99 mg) and 4-(Dimethylamino)pyridine (0.062 mmol, 8 mg) and stirred at RT for 90 min. The reaction mixture was diluted with dichloromethane (30 mL) and further washed with 25% citric acid solution (2 x 25 mL), water (50 mL) and brine (25 mL). The organic layer was dried over Na2SO4 and concentrated. The crude mass was purified by 60-120 mesh silica (product eluted with 1-2% MeOH in CHCl3) to afford 60 mg of the title compound as a white solid.
Figure imgf000716_0001
Example 843: 5-{2-[(3,5-dimethoxyphenyl)amino1-4-[5-methyl-3-(trifluoromethyl)-l//- pyrazol-l-ylipyrimidin-S-yll^-methoxy-N-rCS-methyl^-oxo^^-dihydro-l^-benzoxazol-ό- yl)sulfonyl1pyridine-3-carboxamide
Figure imgf000717_0001
To a solution of 5-{2-[(3,5-dimethoxyphenyl)amino]-4-[5-methyl-3-(trifluoromethyl)-lH- pyrazol-l-yl]pyrimidin-5-yl}-2-methoxypyridine-3-carboxylic acid (Example 675, 0.38 mmol, 0.2 g) and 3-methyl-2-oxo-2,3-dihydro-l,3-benzoxazole-6-sulfonamide (Intermediate 347, 0.46 mmol, 0.1 g) in CH2Cl2 (25 mL) were added triethylamine (1.14 mmol, 0.16 mL), 2-chloro-l- methylpyridinium iodide (0.46 mmol, 0.116 g) and 4-(Dimethylamino)pyridine (0.076 mmol, 10 mg) and stirred for 90 min at RT. The reaction mixture was diluted with dichloromethane (50 mL) and further washed with 25 % citric acid solution (2 x 5OmL), water (100 mL) and brine (75 mL). The organic layer was dried over Na2SO4 and concentrated. The crude mass was purified by 60-120 mesh silica (product eluted with 1-1.5% methanol/chloroform) to afford 200 mg of white solid Example 843.
Figure imgf000717_0002
Example 844: N-[(3-acetylphenyl)sulfonyl1-5-{2-[(3,5-dimethoxyphenyl)amino1-4-[5- methyl-S-CtrifluoromethvD-lH-pyrazol-l-ylipyrimidin-S-vU^-methoxypyridine-S- carboxamide
Figure imgf000718_0001
To a solution of 5-{2-[(3,5-dimethoxyphenyl)amino]-4-[5-methyl-3-(trifluoromethyl)-lH- pyrazol-l-yl]pyrimidin-5-yl}-2-methoxypyridine-3-carboxylic acid (Example 675, 0.19 mmol, 0.100 g) and 3-acetylbenzenesulfonamide (Intermediate 348, 0.37 mmol, 75 mg) in CH2Cl2 (10 mL), were added triethylamine (0.57 mmol, 0.08 mL), 2-chloro-l-methylpyridinium iodide (0.23 mmol, 60 mg) and 4-(Dimethylamino)pyridine (0.03 mmol, 5 mg) and stirred for 1 h at RT. The reaction mixture was diluted with dichloromethane (50 mL) and further washed with water (100 mL) and brine (75 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo. The crude mass was purified by 60-120 mesh silica (product eluted with 1.5% methanol/chloroform) to afford 60 mg of the title compound as a white solid.
Figure imgf000718_0002
Example 845: 5-{2-[(3,5-dimethoxyphenyl)amino1-4-[5-methyl-3-(trifluoromethyl)-lH- Pyrazol-l-yl1pyrimidin-5-yl}-2-methoxy-N-{ri-methyl-3-(trifluoromethyl)-lH-pyrazol-4- yllsulfonvUpyridine-3-carboxamide
Figure imgf000719_0001
To a solution of 5-{2-[(3,5-dimethoxyphenyl)amino]-4-[5-methyl-3-(trifluoromethyl)-lH- pyrazol-l-yl]pyrimidin-5-yl}-2-methoxypyridine-3-carboxylic acid (Example 675, 0.19 mmol, 0.100 g) and l-methyl-3-(trifluoromethyl)-lH-pyrazole-4-sulfonamide (Intermediate 349, 0.38 mmol, 0.087 g) in CH2Cl2 (25 mL), were added 2-chloro-l-methylpyridinium iodide (0.23 mmol, 58 mg), triethylamine (0.57 mmol, 0.08 mL) and 4-(Dimethylamino)pyridine (0.038 mmol, 5 mg) and stirred for 4-5 h at RT. The reaction mixture was diluted with dichloromethane (50 mL) and further washed with 25% citric acid solution (2 x 5OmL), water (100 mL) and brine (75 mL). The organic layer was dried over Na2SO4 and concentrated. The crude mass was purified by 60- 120 mesh silica (product eluted with 4-5% methanol/chloroform) to afford 110 mg of white solid in 78 % purity by LCMS. This was further purified using RP-HPLC (Kromasil Cl 8 column(50 x 250 mm, 10 μm); using a binary solvent mixture of 0.1% TFA in water(A)/MeOH (B) (0-20 min: 10-70% B, 20-30 min: 70-80% B and 30-40 min: 80% B; 40-45 min: 80-100% B, 45-50 min: 100% B, 50-52 min: 100- 10 B, flow rate of 40 niL/min; Separation was monitored at 210 and 300 nm) to give 63 mg of Example 845.
Figure imgf000720_0002
Example 846: N-({4-[(acetylamino)methyl1phenyl}sulfonyl)-5-{2-[(3,5- dimethoxyphenyl)amino1-4-[5-methyl-3-(trifluoromethyl)-l//-pyrazol-l-yl1pyrimidin-5-yl}-
2-methoxypyridine-3-carboxamide
To a solution of 5-{2-[(3,5-dimethoxyphenyl)amino]-4-[5-methyl-3-(trifluoromethyl)-lH- pyrazol-l-yl]pyrimidin-5-yl}-2-methoxypyridine-3-carboxylic acid (Example 675, 0.19 mmol, 0.100 g) and ΛΗ4-sulfamoylbenzyl)acetamide (Intermediate 351 0.23 mmol, 52 mg) in CH2Cl2 (25 mL) were added triethylamine (0.57 mmol, 0.08 mL), 2-chloro-l-methylpyridinium iodide (0.23 mmol, 58 mg) and 4-(Dimethylamino)pyridine (0.038 mmol, 5 mg) and stirred for 4-5 h at RT. The reaction mixture was diluted with dichloromethane (50 mL) and further washed with 25% citric acid solution (2 x 5OmL), water (100 rnL) and brine (75 rnL). The organic layer was dried over Na2SO4 and concentrated. The crude mass was purified by RP-HPLC (Kromasil Cl 8 column(50 x 250 mm, 10 μm); using a binary solvent mixture of 0.1% HCOOH in water(A)/MeOH (B) (0-20 min: 20-70% B, 20-30 min: 70-80% B and 30-45 min: 80-100% B; 45-55 min: 100% B, 55-57 min: 100-20% B, flow rate of 40 niL/min; Separation was monitored at 210,280 and 320 nm) to give 62 mg of Example 846.
Figure imgf000721_0002
Example 847: 5-{2-[(3,5-dimethoxyphenyl)amino1-4-[5-methyl-3-(trifluoromethyl)-l//- Pyrazol-l-yl1pyrimidin-5-yl}-N-[(l,3-dimethyl-2,4-dioxo-l,2,3,4-tetrahvdropyrimidin-5- yl)sulfonyl1-2-methoxypyridine-3-carboxamide
Figure imgf000721_0001
To a solution of 5-{2-[(3,5-dimethoxyphenyl)amino]-4-[5-methyl-3-(trifluoromethyl)-lH- pyrazol-l-yl]pyrimidin-5-yl}-2-methoxypyridine-3-carboxylic acid (Example 675, 0.19 mmol, 0.100 g) and l,3-dimethyl-2,4-dioxo-l,2,3,4-tetrahydropyrimidine-5-sulfonamide (Intermediate 352 0.23 mmol, 48 mg) in CH2Cl2 (25 mL) were added triethylamine (0.57 mmol, 0.08 mL), 2- chloro-1-methylpyridinium iodide (0.23 mmol, 58 mg) and 4-(Dimethylamino)pyridine (0.038 mmol, 5 mg) and stirred 4-5 h at RT. The reaction mixture was diluted with dichloromethane (50 mL) and further washed with 25% citric acid solution (2 x 50 mL), water (100 mL) and brine (75 mL). The organic layer was dried over Na2SO4 and concentrated. The crude mass was purified by RP-HPLC (Kromasil Cl 8 column(50 x 250 mm, 10 μm); using a binary solvent mixture of 0.1% HCOOH in water( A)MeOH (B) (0-20 min: 20-70% B, 20-30 min: 70-80% B and 30-45 min: 80-100% B; 45-55 min: 100% B, 55-57 min: 100-20% B, flow rate of 40 niL/min; Separation was monitored at 210, 280 and 320 nm) to give 55 mg of Example 847.
Figure imgf000722_0001
Example 848: 5-{2-[(3,5-dimethoxyphenyl)amino1-4-[5-methyl-3-(trifluoromethyl)-l//- Pyrazol-l-yl1pyrimidin-5-yl}-N-{[2-(2,5-dioxopyrrolidin-l-yl)ethyl1sulfonyl}-2- methoxypyridine-3-carboxamide
Figure imgf000723_0001
To a solution of 5-{2-[(3,5-dimethoxyphenyl)amino]-4-[5-methyl-3-(trifluoromethyl)-lH- pyrazol-l-yl]pyrimidin-5-yl}-2-methoxypyridine-3-carboxylic acid (Example 675, 0.36 mmol, 0.19 g) and 2-(2,5-dioxopyrrolidin-l-yl)ethanesulfonamide (Intermediate 353, 0.9 mmol, 0.19 g) in DMSO (10 mL), were added triethylamine (1.07 mmol, 0.15 mL), 2-chloro-l- methylpyridinium iodide (0.45 mmol, 0.12 g) and 4-(Dimethylamino)pyridine (0.07 mmol, 10 mg) and stirred at RT for 1 h. The reaction mixture was diluted with water and extracted into ethyl acetate. The organic layer was further washed with 10% citric acid solution, water and brine, dried over Na2SO4 and concentrated. The crude mass was purified by 60-120 mesh silica (product eluted with 2% MeOH in CHCl3) followed by washing with water and 1.5 N HCl to afford 58 mg of the title compound (0.08 mmol, 22 %).
Figure imgf000723_0002
Example 849: 5-{2-[(3,5-dimethoxyphenyl)amino1-4-[5-methyl-3-(trifluoromethyl)-lH- Pyrazol-l-yl1pyrimidin-5-yl}-2-methoxy-N-(lH-pyrazol-4-ylsulfonyl)pyridine-3- carboxamide
Figure imgf000724_0001
To a solution of 5-{2-[(3,5-dimethoxyphenyl)amino]-4-[5-methyl-3-(trifluoromethyl)-lH- pyrazol-l-yl]pyrimidin-5-yl}-2-methoxypyridine-3-carboxylic acid (Example 675, 0.38 mmol, 0.2 g) and lH-pyrazole-4-sulfonamide (Intermediate 354, 0.45 mmol, 0.07 g) in CH2Cl2 (25 mL) were added triethylamine (1.14 mmol, 0.16 mL), 2-chloro-l-methylpyridinium iodide (0.46 mmol, 0.116 g) and 4-(Dimethylamino)pyridine (0.076 mmol, 10 mg) and stirred for 4-5 h at RT. The reaction mixture was diluted with dichloromethane (50 mL) and further washed with 25 % citric acid solution (2 x 5OmL), water (100 mL) and brine (75 mL). The organic layer was dried over Na2SO4 and concentrated. The crude mass was purified by 60-120 mesh silica (product eluted with 5-6% methanol/chloroform) to afford 36 mg of white solid Example 849.
Figure imgf000725_0002
Example 850: methyl 5-{2-[(3,5-dimethoxyphenyl)amino1-4-[3-(trifluoromethyl)-l//- Pyrazol-l-yllpyrimidin-5-yl}-2-(methylsulfanyl)pyridine-3-carboxylate
Figure imgf000725_0001
A suspension of 5-bromo-N-(3,5-dimethoxyphenyl)-4-[3-(trifluoromethyl)-lH-pyrazol-l- yl]pyrimidin-2-amine (Intermediate 215, 0.45 mmol, 0.2 g), a mixture of methyl 2- (methylsulfanyl)-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine-3-carboxylate and [5- (methoxycarbonyl)-6-(methylsulfanyl)pyridin-3-yl]boronic acid (Intermediate 359, 0.58 mmol based on the boronic ester, 0.180 g), [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (0.04 mmol, 0.0367 g) and sodium carbonate (0.45 mmol, 0.0477 g) in acetonitrile/water (5 : 1) was degassed and heated to 90 0C for 30 min under an inert atmosphere. The reaction mass was passed through a celite bed and solvent was concentrated in vacuo. The resultant residue taken in EtOAc (50 rnL) was washed with water, brine, dried over Na2SO4, filtered and concentrated. The crude mass was further purified by silica gel column chromatography (product eluted with 3 % Et3N EtOAc) to yield 0.22 g of the product.
Figure imgf000726_0002
Example 851: 5-{2-[(3,5-dimethoxyphenyl)amino1-4-[3-(trifluoromethyl)-l//-pyrazol-l- yl1pyrimidin-5-yl}-2-(methylsulfanyl)pyridine-3-carboxylic acid
Figure imgf000726_0001
To 160 mg of methyl 5-{2-[(3,5-dimethoxyphenyl)amino]-4-[3-(trifluoromethyl)-lH-pyrazol-l- yl]pyrimidin-5-yl}-2-(methylsulfanyl)pyridine-3-carboxylate (Example 850, 0.29 mmol) taken in a mixture of TΗF (5 mL) and water (5 mL), was added Sodium hydroxide (0.73 mmol, 0.029 g) and stirred at room temperature for 3 h. The mixture was carefully acidified with 1 N HCl and the solid obtained was filtered, dried to yield the desired product (0.13 g).
Figure imgf000727_0002
Example 852: 5-{2-[(3,5-dimethoxyphenyl)amino1-4-[3-(trifluoromethyl)-l//-pyrazol-l- yl1pyrimidin-5-yl}-2-(methylsulfanyl)-N-(methylsulfonyl)pyridine-3-carboxamide
Figure imgf000727_0001
To a solution of 5-{2-[(3,5-dimethoxyphenyl)amino]-4-[3-(trifluoromethyl)-lH-pyrazol-l- yl]pyrimidin-5-yl}-2-(methylsulfanyl)pyridine-3-carboxylic acid (Example 851, 0.187 mmol, 0.1 g) in DCM was added TEA (0.56 mmol, 0.057 g), 2-chloro-l-methylpyridinium iodide (0.225 mmol, 0.0575 g), DMAP (0.037 mmol, 5 mg) and methanesulfonamide (0.28 mmol, 0.0268 g) stirred at RT for 2 h. The reaction mixture was diluted with DCM (20 mL), washed with water, 10% citric acid and brine, dried over Na2SO4, filtered and concentrated. The crude material was stirred with MeOH and hexane to give the pure title compound (0.1 g).
Figure imgf000728_0002
Example 853: Methyl 5-{2-[(3,5-dimethoxyphenyl)amino1-4-[5-methyl-3-(trifluoromethyl)- l//-Pyrazol-l-yl1pyrimidin-5-yl}-2-(methylsulfanyl)pyridine-3-carboxylate
Figure imgf000728_0001
A suspension of 5-bromo-N-(3,5-dimethoxyphenyl)-4-[5-methyl-3-(trifluoromethyl)-lH-pyrazol- l-yl]pyrimidin-2-amine (Intermediate 216, 0.43 mmol, 0.2 g), a mixture of methyl 2- (methylsulfanyl)-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine-3-carboxylate and [5- (methoxycarbonyl)-6-(methylsulfanyl)pyridin-3-yl]boronic acid (Intermediate 359, 0.56 mmol, 0.175 g), [l,r-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (0.04 mmol, 0.036 g) and sodium carbonate (0.43 mmol, 0.0462 g) in acetonitrile/water (5 : 1) was degassed and heated to 90 0C for 30 min under an inert atmosphere. The reaction mass was passed through a diatomaceous earth bed and the solvent was concentrated in vacuo. The resultant residue taken in EtOAc (50 rnL) was washed with water, brine, dried over Na2SO4, filtered and concentrated. The crude mass was further purified by silica gel column chromatography with (25% EtOAc/hexanes) to yield 0.18O g of the product.
Figure imgf000729_0002
Example 854: 5-{2-[(3,5-dimethoxyphenyl)amino1-4-[5-methyl-3-(trifluoromethyl)-l//- Pyrazol-l-yl1pyrimidin-5-yl}-2-(methylsulfanyl)pyridine-3-carboxylic acid
Figure imgf000729_0001
To 50 mg of methyl 5-{2-[(3,5-dimethoxyphenyl)amino]-4-[5-methyl-3-(trifluoromethyl)-lH- pyrazol-l-yl]pyrimidin-5-yl}-2-(methylsulfanyl)pyridine-3-carboxylate (Example 853, 0.089 mmol) taken in a mixture of TΗF (5 mL) and water (5 mL), was added sodium hydroxide (0.22 mmol, 9 mg) and stirred at room temperature for 3 h. The mixture was carefully acidified with 1 N HCl and the solid obtained was filtered and then dried to yield the product (0.04 g).
Figure imgf000730_0002
Example 855: 5-{2-[(3,5-dimethoxvphenvl)aminol-4-[5-methvl-3-(trifluoromethvl)-lH-
Pvrazol-l-vllPvrimidin-5-vl}-2-(methvlsulfanvl)-N-(methvlsulfonvl)pvridine-3-carboxamide
Figure imgf000730_0001
To a solution of 5-{2-[(3,5-dimethoxyphenyl)amino]-4-[5-methyl-3-(trifluoromethyl)-lH- pyrazol-l-yl]pyrimidin-5-yl}-2-(methylsulfanyl)pyridine-3-carboxylic acid (Example 854, 0.219 mmol, 0.12 g) in DCM was added TEA (0.65 mmol, 0.066 g), 2-chloro-l-methylpyridinium iodide (0.263 mmol, 0.0673 g) (0.225 mmol, 0.0575 g), DMAP (0.0439 mmol, 6 mg) and Methanesulfonamide (0.329 mmol, 0.0313 g), and stirred at RT for 2 h. The reaction mixture was diluted with DCM (20 mL), washed with water, 10% citric acid and brine, dried over Na2SO4, filtered and concentrated. The crude mass was further purified by silica gel column chromatography with (2% MeOH / EtOAc). The material obtained from chromatography was stirred with DCM and hexane to yield 0.1 g of the pure product (100 mg).
Figure imgf000731_0002
Example 856: 2-methoxv-5-{2-[(3-methoxv-5-methvlphenvl)aminol-4-[3-(trifluoromethvl)- lH-Pvrazol-l-vllPvrimidin-5-vl}-N-(methvlsulfonvl)pvridine-3-carboxamide
Figure imgf000731_0001
To a solution of 2-methoxy-5-{2-[(3-methoxy-5-methylphenyl)amino]-4-[3-(trifluoromethyl)- lH-pyrazol-l-yl]pyrimidin-5-yl}pyridine-3-carboxylic acid (Example 760, 0.33 mmol, 165 mg) in CH2Cl2 (10 rnL), were added methanesulfonamide (0.82 mmol, 78 mg), triethylamine (0.99 mmol, 0.14 mL), 2-chloro-l-methylpyridinium iodide (0.41 mmol, 105 mg) and 4- (Dimethylamino)pyridine (0.066 mmol, 8 mg) and stirred at RT for 2 h. The reaction mixture was diluted with dichloromethane (20 mL) and further washed with 25% citric acid solution (2 x 15 mL), water (25 mL) and brine (25 mL). The organic layer was dried over Na2SO4 and concentrated. The crude mass was purified by 60-120 mesh silica (product eluted with 1-2% MeOH in CHCl3) to afford 65 mg of the title compound as a white solid.
Figure imgf000732_0002
Example 857: 2-methoxy-5-{2-[(3-methoxy-5-methylphenyl)amino1-4-[5-methyl-3-
(trifluoromethyl)-lH-pyrazol-l-yllpyrimidin-5-yl}-A^methylsulfonyl)pyridine-3- carboxamide
Figure imgf000732_0001
To a solution of 2-methoxy-5-{2-[(3-methoxy-5-methylphenyl)amino]-4-[5-methyl-3- (trifluoromethyl)-lH-pyrazol-l-yl]pyrimidin-5-yl}pyridine-3-carboxylic acid (Example 761, 0.36 mmol, 185 mg) in CH2Cl2 (10 rnL), was added methanesulfonamide (0.90 mmol, 86 mg), triethylamine (1.08 mmol, 0.15 mL), 2-cmoro-l-methylpyridinium iodide (0.45 mmol, 115 mg) and 4-(Dimethylamino)pyridine (0.072 mmol, 8.78 mg) and stirred at RT for 2 h. The reaction mixture was diluted with dichloromethane (20 mL) and further washed with 25% citric acid solution (2 x 15 mL), water (25 mL) and brine (25 mL). The organic layer was dried over Na2SO4 and concentrated. The crude mass was purified by 230-400 mesh silica (product eluted with 1-2% MeOH in CHCl3) to afford 130 mg of white solid of the title compound.
Figure imgf000733_0002
Example 858: methyl 5-{2-[(3-methoxy-5-methylphenyl)amino1-4-[3-(trifluoromethyl)-l//- Pyrazol-l-yl1pyrimidin-5-yl}-l-methyl-2-oxo-l,2-dihvdropyridine-3-carboxylate
Figure imgf000733_0001
A solution of 5-bromo-N-(3-methoxy-5-methylphenyl)-4-[3-(trifluoromethyl)-lH-pyrazol-l- yl]pyrimidin-2-amine (Intermediate 293, 0.93 mmol, 400 mg), a mixture of methyl l-methyl-2- oxo-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,2-dihydropyridine-3-carboxylate and [5- (methoxycarbonyl)-l-methyl-6-oxo-l,6-dihydropyridin-3-yl]boronic acid (Intermediate 323, 1.1 mmol based on the boronic ester, 328 mg), [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II)complex with CH2Cl2 (0.18 mmol, 146 mg) and sodium carbonate (0.9 mmol, 95 mg) in acetonitrile (40 mL)/water (10 rnL) was degassed and heated to 90 0C for 30 minutes under nitrogen. The reaction mixture was concentrated in vacuo. The residue obtained was taken in ethyl acetate, washed with water and brine, dried over sodium sulfate and concentrated. The crude mass was purified by silica gel column chromatography (60-120 mesh) using 2% methanol/chloroform to obtain 300 mg of the title compound.
Figure imgf000734_0002
Example 859: 5-{2-[(3-methoxy-5-methylphenyl)amino1-4-[3-(trifluoromethyl)-lH-pyrazol- l-yl1pyrimidin-5-yl}-l-methyl-2-oxo-l,2-dihvdropyridine-3-carboxylic acid
Figure imgf000734_0001
To 300 mg of methyl 5-{2-[(3-methoxy-5-methylphenyl)amino]-4-[3-(trifluoromethyl)-lH- pyrazol-l-yl]pyrimidin-5-yl}-l-methyl-2-oxo-l,2-dihydropyridine-3-carboxylate (Example 858, 0.58 mmol) taken in a mixture of TΗF (10 mL) /H2O (10 mL), was added NaOH (1.1 mmol, 46 mg) and stirred at rt for 2 h. The solvent was removed in vacuo and the mixture was carefully acidified with 1 N HCl and the solid that precipitated was filtered and dried to obtain 190 mg of the title compound.
Figure imgf000735_0002
Example 860: methyl 5-{2-[(3-methoxy-5-methylphenyl)amino1-4-[5-methyl-3- (trifluoromethyl)-lH-pyrazol-l-yl1pyrimidin-5-yl}-l-methyl-2-oxo-l,2-dihvdropyridine-3- carboxylate
Figure imgf000735_0001
A solution 5-bromo-N-(3-methoxy-5-methylphenyl)-4-[5-methyl-3-(trifluoromethyl)- lH-pyrazol- l-yl]pyrimidin-2-amine (Intermediate 294, 0.79 mmol, 350 mg), a mixture of methyl 1-methyl- 2-oxo-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,2-dihydropyridine-3-carboxylate and [5- (methoxycarbonyl)-l-methyl-6-oxo-l,6-dihydropyridin-3-yl]boronic acid (Intermediate 323, 0.95 mmol based on the boronic ester, 279 mg), [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II)complex with CH2Cl2 (0.14 mmol, 112 mg) and sodium carbonate (0.7 mmol, 74 mg) in acetonitrile (40 mL)/water (10 mL) was degassed and heated to 90 0C for 30 minutes under nitrogen. The reaction mixture was concentrated in vacuo. The residue obtained was taken in ethyl acetate, washed with water and brine, dried over sodium sulfate and concentrated. The crude mass was purified by silica gel column chromatography (60-120 mesh) using 2% methanol/chloroform to afford 300 mg of the title compound.
Figure imgf000736_0002
Example 861: 5-{2-[(3-methoxy-5-methylphenyl)amino1-4-[5-methyl-3-(trifluoromethyl)- l//-Pyrazol-l-yl1pyrimidin-5-yl}-l-methyl-2-oxo-l,2-dihvdropyridine-3-carboxylic acid
Figure imgf000736_0001
To 300 mg of methyl 5-{2-[(3-methoxy-5-methylphenyl)amino]-4-[5-methyl-3-(trifluoromethyl)- lH-pyrazol- 1 -yl]pyrimidin-5-yl } - 1 -methyl-2-oxo- 1 ,2-dihydropyridine-3-carboxylate (Example 860, 0.57 mmol) dissolved in a mixture of TΗF (10 mL) /H2O (10 mL), then NaOH (1.1 mmol, 46 mg) was added and the mixture was stirred at rt for 2 h. The solvent was removed in vacuo and the mixture was carefully acidified with 1 N HCl and the solid that precipitated was filtered and dried to obtain 200 mg of the title compound.
Figure imgf000737_0002
Example 862: ethyl l-ethyl-5-{2-[(3-methoxy-5-methylphenyl)amino1-4-[5-methyl-3- (trifluoromethyl)-l//-pyrazol-l-yl1pyrimidin-5-yl}-2-oxo-l,2-dihydropyridine-3-carboxylate
Figure imgf000737_0001
A solution 5-bromo-N-(3-methoxy-5-methylphenyl)-4-[5-methyl-3-(trifluoromethyl)-lH-pyrazol- l-yl]pyrimidin-2-amine (Intermediate 294, 0.9 mmol, 400 mg), a mixture of ethyl l-ethyl-2- oxo-5-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)- 1 ,2-dihydropyridine-3-carboxylate and [5- (ethoxycarbonyl)-l-ethyl-6-oxo-l,6-dihydropyridin-3-yl]boronic acid (Intermediate 361, 1.1 mmol based on the boronic ester, 350 mg), [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.2 mmol, 146 mg) and sodium carbonate (0.9 mmol, 95 mg) in acetonitrile (40 mL)/water (10 mL) was degassed and heated to 90 0C for 30 minutes under nitrogen. The reaction mixture was concentrated in vacuo. The residue obtained was taken in ethyl acetate, washed with water and brine, dried over sodium sulfate and concentrated. The crude mass was purified by silica gel column chromatography (60- 120 mesh) using 2% methanol/chloroform to yield 300 mg of the title compound.
Figure imgf000738_0002
Example 863: l-ethyl-5-{2-r(3-methoxy-5-methylphenyl)amino1-4-[5-methyl-3-
(trifluoromethvD-lH-pyrazol-l-ylipyrimidin-S-vU^-oxo-l^-dihvdropyridine-S-carboxylic acid
Figure imgf000738_0001
To 300 mg of ethyl l-ethyl-5-{2-[(3-methoxy-5-methylphenyl)amino]-4-[5-methyl-3- (trifluoromethyl)- lH-pyrazol- 1 -yl]pyrimidin-5-yl } -2-oxo- 1 ,2-dihydropyridine-3-carboxylate (Example 862, 0.54 mmol) taken in a mixture of TΗF (10 niL) /H2O (10 niL), was added NaOH (1.1 mmol, 43 mg) and stirred at rt for 2 h. The solvent was removed in vacuo and the mixture was then carefully acidified with 1 N HCl and the solid that precipitate was filtered and dried to obtain 180 mg of the title compound.
Figure imgf000739_0002
The compounds in the below table were prepared using the general method described above for Example 1 using Intermediate 113 and the specified starting material.
Figure imgf000739_0001
Figure imgf000740_0001
The compounds in the below table were prepared using the general method described above for Example 1 using Intermediate 115 and the specified starting material.
Figure imgf000740_0002
Figure imgf000741_0001
The compound in the below table was prepared using the general method described above for Example 1 using Intermediate 216 and the specified starting material.
Figure imgf000741_0002
The compounds in the below table were prepared using the general method described above for Example 214 using IN sodium hydroxide (2 equivalents), dioxane : THF (1:1) as solvent and the specified starting material.
Figure imgf000742_0001
Figure imgf000743_0001
Example 873: N-O^-dimethoxyphenvD-S-Cό-methoxy-S-dH-tetrazol-S-vDpyridin-S-vD^-CS- methyl-3-(trifluoromethyl)-lH-pyrazol-l-yl)pyrimidin-2-amine
Figure imgf000744_0001
5-(2-(3,5-dimethoxyphenylamino)-4-(5-methyl-3-(trifluoromethyl)-lH-pyrazol-l-yl)pyrimidin-5- yl)-2-methoxynicotinonitrile (Example 868, 0.16 g, 0.31 mmol), dibutyltin oxide (0.023 g, 0.09 mmol), and TMS-N3 (0.166 mL, 1.25 mmol) were suspended in 1,4-dioxane (1 mL) to give a yellow suspension. The mixture was heated in a microwave reactor at 140 0C for Ih. Concentrated in vacuo. Purified by flash chromatography: 25g silica gel column, 0-20% methanol in chloroform. Relevant fractions pooled and resulting material was dried under high vacuum to obtain the title compound as a tan foam in (O.lg). MS(ES): 555.17 (M+H) for C24H2IF3Ni0O3
1H-NMR (400 MHz, DMSO-d6): δ ppm 2.39 (m, 3 H) 3.73 (m., 6 H) 4.04 (m, 3 H) 6.22 (m, 1 H) 6.75 (m., 1 H) 7.06 (m, 2 H) 8.03 (m, 1 H) 8.18 (m., 1 H) 8.96 (m, 1 H) 10.22 (m, 1 H).
Example 874: 5-(2-(3-chloro-4-fluorophenylamino)-4-(3-(trifluoromethyl)-lH-pyrazol-l- yl)pyrimidin-5-yl)-N-(methylsulfonyl)nicotinamide
Figure imgf000744_0002
5-(2-(3-chloro-4-fluorophenylamino)-4-(3-(trifluoromethyl)-lH-pyrazol-l-yl)pyrimidin-5- yl)nicotinic acid (Example 320, 57 mg, 0.12 mmol) and 1,1-carbonyldiimidazole (50 mg) were combined in DMF (1.5 mL) and stirred for 30 minutes. Methanesulfonamide (16.99 mg, 0.18 mmol) was added and the mixture was stirred at 90 0C overnight. Purification by reverse phase chromatography (05-95% ACN/ water NH4OH) gave the title compound (14 mg).
MS (Electrospray): 556.89, (MH+) for C2IHi4ClF4N7O3S
1U NMR (300 MHz, DMSO-dfi) δ : 2.84 (s, 3 H) 7.00 (d, /=2.64 Hz, 1 H) 7.42 (t, /=9.14 Hz, 1 H) 7.74 (ddd, /=9.09, 4.19, 2.73 Hz, 1 H) 8.00 - 8.13 (m, 2 H) 8.28 (d, /=2.07 Hz, 1 H) 8.45 (s, 1 H) 8.78 (s, 1 H) 8.95(d, /=1.70 Hz, 1 H) 10.43 (s, 1 H)
Example 875: (E)-3-(3-(2-(3-chloro-4-fluorophenylamino)-4-(3-cvclopropyl-lH-pyrazol-l- vDpyrimidin-S-vDphenvDacrylic acid
Figure imgf000745_0001
3-Cyclopropyl-lH-pyrazole (42.7 mg, 0.40 mmol) was dissolved in THF, then NaH (9.48 mg, 0.40 mmol) was added slowly and the mixture was stirred for 30 minutes. The mixture was added to a solution of (E)-ethyl 3-(3-(2-(3-chloro-4-fluorophenylamino)-4-
(methylsulfonyl)pyrimidin-5-yl)phenyl)acrylate Intermediate 125 (94 mg, 0.20 mmol) in THF (2 mL). The resulting mixture was allowed to stir overnight at room temperature. Methanol (0.25 ml) then water (0.25 ml) were added and the mixture was evaporated. Purification using reverse phase chromatography (Cl 8, 20 to 95% CH3CN / H2O / 0.1% Trifluoroacetic acid) yielded the title compound. (17 mg).
MS (Electrosprav): 476.90(MH+) for C25Hi9ClFN5O2
1H NMR (300 MHz, DMSO-dfi) δ : 0.18 - 0.47 (m, 2 H) 0.57 - 0.76 (m, 2 H) 1.52 - 1.80 (m, 1 H) 6.35 (dJ=2.64 Hz, 1 H) 6.46 (s, 1 H) 6.52 (s, 1 H) 7.19 (d, /=7.54 Hz, 1 H) 7.32 - 7.46 (m, 2 H) 7.48 - 7.59 (m, 1 H)7.62 (d, /=8.10 Hz, 1 H) 7.72 (ddd, /=9.09, 4.19, 2.73 Hz, 1 H) 8.06 - 8.21 (m, 2 H) 8.58 (s, 1 H) 10.16 (s, IH)
Example 876: N-(3-chloro-4-fluorophenyl)-5-(6-methoxypyridin-2-yl)-4-(3- (trifluoromethyl)-lH-pyrazol-l-yl)pyrimidin-2-amine
Figure imgf000746_0001
5-bromo-N-(3-chloro-4-fluorophenyl)-4-(3-(trifluoromethyl)-lH-pyrazol-l-yl)pyrimidin-2-amine Intermediate 115 (100 mg, 0.23 mmol), Pd(Ph3P)4 (79 mg, 0.07 mmol), and 0.5M (6- methoxypyridin-2-yl)zinc(II) bromide in THF (0.916 rnL, 0.46 mmol) were combined in THF (6 mL) under argon. The reaction was heated at 65 0C for 45 minutes. Additional 0.5M (6- methoxypyridin-2-yl)zinc(II) bromide in THF (0.916 mL, 0.46 mmol) was added and the mixture was allowed to stir for an additional 1.5 hours. The reaction mixture was concentrated and purified by silica gel flash chromatography using 0-50% ethyl acetate in hexanes. The title compound was obtained as a solid. (7 mg) MS (Electrosprav): 467.80(MH+) C20Hi3ClF4N6O
IH NMR (300 MHz, DMSO-J6) Dppm 3.55 (s, 3 H) 6.59 - 6.83 (m, 1 H) 6.93 - 7.14 (m, 2 H) 7.27 - 7.52 (m, 2 H) 7.63 - 7.82 (m, 1 H) 8.07 - 8.21 (m, 1 H) 8.37 - 8.52 (m, 1 H) 8.99 (s, 1 H) 10.32 - 10.54 (m, 1 H) Example 877: 6-(2-(3-chloro-4-fluorophenylamino)-4-(3-(trifluoromethyl)-lH-pyrazol-l- yl)pyrimidin-5-yl)picolinic acid
Figure imgf000747_0001
2-(3-chloro-4-fluorophenylamino)-4-(3-(trifluoromethyl)- 1 H-pyrazol- 1 -yl)pyrimidin-5-ylboronic acid Intermediate 364 (80 mg, 0.20 mmol), methyl 6-bromopicolinate (34.4 mg, 0.16 mmol),
Pd(Ph3P)4 (46.0 mg, 0.04 mmol), and K2CO3 (41.3 mg, 0.30 mmol) were combined with Dioxane
(4 mL) and water (1 mL). The mixture was heated in a microwave for 45 min. at 120 0C.
Reverse phase chromatography (C18, 20-95% CH3CN / H2O/ 0.1% Trifluoroacetic acid) of the crude mixture gave the title compound. (19 mg)
MS (Electrosprav): 479.79 (MH+) C20H11C1F4N6O2
1H NMR (300 MHz, DMSO-d6) δ ppm 7.04 (d, J=2.64 Hz, 1 H) 7.42 (d, J=7.91 Hz, 2 H) 7.70 -
7.83 (m, 1 H) 7.88 - 8.03 (m, 2 H) 8.06 - 8.15 (m, 1 H) 8.97 (s, 1 H) 10.50 (s, 1 H) 12.67 - 13.30
(m, 1 H)
Example 878: 3-(2-(3-chloro-4-fluorophenylamino)-4-(3-(trifluoromethyl)-lH-pyrazol-l- yl)pyrimidin-5-yl)-N-methyl-N-(methylsulfonyl)benzamide
Figure imgf000747_0002
3-(2-(3-chloro-4-fluorophenylamino)-4-(3-(trifluoromethyl)-lH-pyrazol-l-yl)pyrimidin-5- yl)benzoic acid Example ( 45 mg, 0,09 mmol) was dissolved in DMF (3ml). Triethylamine ( 0.033 ml, 0.24 mmol) and HATU ( 35 mg, 0.09 mmol) was added and the mixture was allowed to stir for 10 min. N-methylmethanesulfonamide (10 mg, 0.09 mmol) was added to the reaction mixture and it was allowed to stir at RT overnight. Purification using reverse phase chromatography (C18, 5-95% CH3CN / H2O / 0.1% Trifluoroacetic acid) yielded the title compound. (12 mg).
MS (Electrosprav): 569.93 (MH+) C23Hi7ClF4N6O3S
1H NMR (300 MHz, DMSO-J6) δ ppm 3.25-3.35 ( s, 3H), 3.55 (s, 3 H) 6.59 - 6.77 (m, 1 H)
6.92 - 7.11 (m, 2 H) 7.22 - 7.55 (m, 2 H) 7.65 - 7.85 (m, 2 H) 8.01 - 8.22 (m, 1 H) 8.34 - 8.53 (m,
1 H) 8.99 (s, 1 H) 10.40 - 10.54 (m, 1 H)
Example 879: 2'-(3-chloro-4-fluorophenylamino)-6-methyl-4'-(3-(trifluoromethyl)-lH- p yrazol- 1 - yl) -2,5 ' -bip yrimidine-4-carboxylic acid
Figure imgf000748_0001
2-(3-chloro-4-fluorophenylamino)-4-(3-(trifluoromethyl)-lH-pyrazol-l-yl)pyrimidin-5-ylboronic acid Intermediate 364 (100 mg, 0.25 mmol), methyl 2-chloro-6-methylpyrimidine-4- carboxylate (93 mg, 0.50 mmol), Pd(Ph3P)4 (57.6 mg, 0.05 mmol), and K2CO3 (51.6 mg, 0.37 mmol) were combined with Dioxane (2 mL) and water (0.500 mL). The mixture was heated in a microwave for 45 min at 120 0C. The mixture was purified using reverse phase chromatography (C18, 5-95%.CH3CN / H2O / 0.1% Trifluoroacetic acid) to yield the title compound. (28 mg). MS (Electrosprav): 494.80 (MH+) C20H12C1F4N702
1U NMR (300 MHz, DMSO-d6) δ ppm 2.46 (s, 3 H) 6.95 - 7.10 (m, 1 H) 7.38 - 7.49 (m, 1 H) 7.73 - 7.80 (m,l H) 7.81 (s, 1 H) 8.05 - 8.13 (m, 1 H) 8.52 - 8.65 (m, 1 H) 9.10 (s, 1 H) 10.54 - 10.66 (m, 1 H) 13.49 - 13.84 (m, 1 H) The compounds in the following table were prepared using the procedure for Example 1 with the specified starting materials.
Figure imgf000749_0001
Figure imgf000750_0001
Figure imgf000751_0001
Figure imgf000752_0001
Figure imgf000753_0001
Figure imgf000754_0001
Figure imgf000755_0001
Figure imgf000756_0001
Figure imgf000757_0001
Figure imgf000758_0001
Figure imgf000759_0001
Figure imgf000760_0001
Figure imgf000761_0001
Figure imgf000762_0001
Figure imgf000763_0001
The following example was prepared using the general method described above for Example 212 and the specified starting materials.
Figure imgf000764_0001
The compounds in the below table were prepared using the same procedure as Example 214, using the starting material and base specified.
Figure imgf000764_0002
Figure imgf000765_0001
Figure imgf000766_0001
Figure imgf000767_0001
The compounds in the table below were prepared using the same procedure as Example 360 with the specified starting materials.
Figure imgf000769_0001
Figure imgf000770_0001
Figure imgf000771_0001
Figure imgf000772_0001
Figure imgf000773_0001
Figure imgf000774_0002
Example 937: N2-(3-chloro-4-fluorophenyl)-N4-(3-methoxypropyl)-5-(lH-tetrazol-5- yl)pyrimidine-2,4-diamine
Figure imgf000774_0001
Intermediate 127 (100 mg, 0.30 mmol), sodium azide (77 mg, 1.2 mmol), and ammonium chloride (64 mg, 1.2 mmol) were combined in N,N-dimethylformamide (2 mL) and heated at 100 degrees C for 3 hours. The reaction mixture was allowed to cool, then it was filtered. Reverse- phase chromatography (Cl 8: water, acetonitrile, formic acid additive) was used to isolate the desired product (59 mg).
MS: ES+ 379 for Ci5Hi6ClFN8O.
IH NMR (300 MHz, DMSO-J6) δ ppm 1.90 (quin, /=6.45 Hz, 2 H) 3.25 (s, 3 H) 3.46 (t, /=6.03 Hz, 2 H) 3.64 (q, /=6.53 Hz, 2 H) 7.34 (t, /=9.14 Hz, 1 H) 7.58 - 7.73 (m, 1 H) 8.20 (dd, /=6.78, 2.45 Hz, 1 H) 8.48 (t, /=4.80 Hz, 1 H) 8.63 (s, 1 H) 9.88 (s, 1 H).
The compound in the table below was made using the method above for Example 937 with the specified starting material.
Figure imgf000775_0001
The compounds in the below table were prepared using the general method described above for Example 1 and the starting materials (SM) indicated.
Figure imgf000776_0001
Figure imgf000777_0001
Figure imgf000778_0001
Figure imgf000779_0001
Figure imgf000780_0001
Figure imgf000781_0001
Figure imgf000782_0001
Figure imgf000783_0001
The compounds in the below table were prepared using the general method described above for Example 214 using IN sodium hydroxide and the starting material (SM) indicated.
Figure imgf000784_0001
Figure imgf000785_0001
Figure imgf000786_0001
Figure imgf000787_0001
Figure imgf000788_0001
Figure imgf000789_0001
The compounds in the below table were prepared using the general method described above for Example 824 and the starting material (SM) indicated.
Figure imgf000790_0001
Figure imgf000791_0002
Example 973: (E)-5-(2-(3,5-dimethoxyphenylamino)-4-(5-methyl-3-(trifluoromethyl)-lH- Pyrazol-l-yl)pyrimidin-5-yl)-N'-hvdroxy-2-methoxynicotinimidamide
Figure imgf000791_0001
\ 5-(2-(3,5-dimethoxyphenylamino)-4-(5-methyl-3-(trifluoromethyl)-lH-pyrazol-l-yl)pyrimidin-5- yl)-2-methoxynicotinonitrile Example 868 (0.10 g, 0.20 mmol), and hydroxylamine (0.018 ml, 0.30 mmol) were suspended in ethanol (4.6 mL) to give a white suspension. The mixture was heated at 80 0C for 2 hours then concentrated in vacuo. The residue was triturated with acetonitrile and dried under high vacuum to obtain the title compound as an off-white solid (0.095g).
MS(ES): 545.2 (M+H) for C24H23F3N8O4
1H-NMR (400 MHz, DMSO-d6): δ ppm 2.27 (s, 3 H) 3.72 (s, 7 H) 3.87 (s, 3 H) 5.69 (s, 2 H) 6.21 (s, 1 H) 6.73 (s, 1 H) 7.04 (d, /=1.88 Hz, 2 H) 7.57 (d, /=2.26 Hz, 1 H) 7.81 (d, /=2.45 Hz, 1 H) 8.88 (s, 1 H) 9.58 (s, 1 H)10.19 (s, 1 H) Example 974: 3-(5-(2-(3,5-dimethoxyphenylamino)-4-(5-methyl-3-(trifluoromethyl)-lH- Pyrazol-l-yl)pyrimidin-5-yl)-2-methoxypyridin-3-yl)-l,2,4-oxadiazol-5(4H)-thione
Figure imgf000792_0001
(E)-5-(2-(3,5-dimethoxyphenylamino)-4-(5-methyl-3-(trifluoromethyl)-lH-pyrazol-l- yl)pyrimidin-5-yl)-N'-hydroxy-2-methoxynicotinimidamide Example 973 (0.20 g, 0.37 mmol), di(lH-imidazol-l-yl)methanethione (0.099 g, 0.55 mmol) and DBU (0.222 ml, 1.47 mmol) were suspended in acetonitrile (8.16 mL). The mixture was stirred at room temperature for 1.5 hours then concentrated in vacuo. The residue was purified by flash chromatography : 4 g silica column, 3-30 % methanol in chloroform over 25 min. The relevant fractions were pooled and resulting material was dried and purified by reverse phase HPLC: 65-95% methanol in 0.1% formic acid-water (pH 3) using a 19mm xlOOmm 5μm waters T3 C18 column. Evaporation of fractions gave the title compound as an off-white solid (0.05g). MS(ES): 587.2 (M+H) for C25H2IF3N8O4S
1H-NMR (300 MHz, DMSO-d6): δ ppm 2.37 (s, 3 H) 3.72 (s, 7 H) 3.95 (s, 3 H) 6.22 (t, /=2.07 Hz, 1 H) 6.77 (s, 1 H) 7.05 (d, /=2.07 Hz, 2 H) 7.82 (d, /=2.45 Hz, 1 H) 8.09 (d, /=1.88 Hz, 1 H) 8.93 (s, 1 H) 10.22 (s, 1 H)
Example 975: 3-(5-(2-(3,5-dimethoxyphenylamino)-4-(5-methyl-3-(trifluoromethyl)-lH- Pyrazol-l-yl)pyrimidin-5-yl)-2-methoxypyridin-3-yl)-l,2,4-oxadiazol-5(4H)-one
Figure imgf000793_0001
(E)-5-(2-(3,5-dimethoxyphenylamino)-4-(5-methyl-3-(trifluoromethyl)-lH-pyrazol-l- yl)pyrimidin-5-yl)-N'-hydroxy-2-methoxynicotinimidamide Example 973 (0.0951 g, 0.17 mmol), CDI (0.042 g, 0.26 mmol) and DBU (0.053 ml, 0.35 mmol) were suspended in 1,4- dioxane (3.5 rnL). The mixture was stirred at room temperature overnight then concentrated in vacuo. The residue was purified by reverse phase flash chromatography: 50 g Cl 8 column, 5- 75% acetonitrile in water over 25 min. Relevant fractions pooled and evaporated to give the title compound as a white solid (0.029g). MS(ES): 571.2 (M+H) for C25H2IF3N8O5
1H-NMR (300 MHz, DMSO-d6): δ ppm 2.38 (s, 4 H) 3.72 (s, 6 H) 3.95 (s, 3 H) 6.22 (br. s., 1 H) 6.77 (s, 1 H) 7.04 (s, 2 H) 7.72 (s, 1 H) 8.15 (s, 1 H) 8.93 (s, 1 H) 10.22 (s, 1 H)
The following compounds were prepared using the general method described for Example 1 using tris(dibenzyledeneacetone)-dipalladium(0), 2-dicyclohexyl phosphino-2',4',6'-triiso- propyl-l,l'-biphenyl, sodium carbonate and the starting materials (SM) indicated.
Figure imgf000794_0001
Figure imgf000795_0001
Figure imgf000796_0001
Figure imgf000797_0001
Figure imgf000798_0001
Figure imgf000799_0001
Figure imgf000800_0001
Figure imgf000801_0001
Figure imgf000802_0001
Figure imgf000803_0001
Figure imgf000804_0001
Figure imgf000805_0001
Figure imgf000806_0001
Figure imgf000807_0001
Figure imgf000808_0001
Figure imgf000809_0001
Figure imgf000810_0001
Figure imgf000811_0001
Figure imgf000813_0001
Figure imgf000814_0001
Figure imgf000815_0001
Figure imgf000816_0001
Figure imgf000817_0001
Figure imgf000818_0001
Figure imgf000819_0002
Example 1027: (5-(2-(3-chloro-4-fluorophenylamino)-4-(3-(trifluoromethyl)-lH-pyrazol-l- yl)pyrimidin-5-yl)-2-methoxypyridin-3-yl)methanol
Figure imgf000819_0001
Methyl 5-(2-(3-chloro-4-fluorophenylamino)-4-(3-(trifluoromethyl)-lH-pyrazol-l-yl)pyrimidin- 5-yl)-2-methoxynicotinate (Example 1010, 0.788 g mg, 1.51 mmol) was dissolved in THF(IO rnL) to give a yellow solution. The reaction mixture was cooled to -40 0C. IM DIBAL-H in toluene (9 rnL, 9 mmol) was slowly added to the reaction mixture. The reaction was allowed to warm up to room temperature overnight. The reaction was diluted with EtOAc and washed with IM NH4Cl. Purification by flash chromatography, silica gel, 40-100% ethyl acetate in hexanes gave a crude solid. Trituration with hexane / ether and filtration gave the title compound (103 mg).
MS (Electrosprav): 495.83, (MH+) for C2IHi5ClF4N6O2
1U NMR (300 MHz, DMSO-dfi) δ : 3.88 (s, 3 H) 5.15 (s, 2 H) 7.00 (d, /=2.45 Hz, 1 H) 7.20 -
7.47 (m, 2H) 7.59 - 7.83 (m, 1 H) 7.90 (d, /=2.26 Hz, 1 H) 7.99 - 8.23 (m, 1 H) 8.38 (d, /=1.51
Hz, 1 H) 8.76 (s, 1 H), 10.39 (s, 1 H)
Example 1028: 5-(2-(3-chloro-4-fluorophenylamino)-4-(3-(trifluoromethyl)-lH-pyrazol-l- yl)pyrimidin-5-yl)-2-methoxynicotinaldehvde
Figure imgf000820_0001
(5-(2-(3-chloro-4-fluorophenylamino)-4-(3-(trifluoromethyl)-lH-pyrazol-l-yl)pyrimidin-5-yl)-2- methoxypyridin-3-yl)methanol (243 mg, 0.49 mmol) Example 1027 and manganese dioxide (427 mg, 4.91 mmol) were combined in dichloromethane to give a black suspension. The reaction mixture was allowed to stir at room temperature for 6 hours. Additional manganese dioxide (427 mg, 4.91 mmol) was added and the mixture was allowed to stir for 48 hours. The mixture was filtered through celite and washed with methanol and dichloromethane. The filtrate was concentrated to yield the title compound (145 mg). MS (Electrosprav): 493.81 (MH+) for C2IHi3ClF4N6O2
Example 1029: (E)-methyl 3-(5-(2-(3-chloro-4-fluorophenylamino)-4-(3-(trifluoromethyl)- lH-pyrazol-l-yl)pyrimidin-5-yl)-2-methoxypyridin-3-yl)acrylate
Figure imgf000821_0001
Methyl 2- (diethoxyphosphoryl) acetate (68.0 mg, 0.32 mmol) and NaH (17.65 mg, 0.44 mmol) were combined in THF (2 ml) to give a colorless solution. The reaction mixture was allowed to stir for 5 minutes then added to a solution of 5-(2-(3-chloro-4-fluorophenylamino)-4-(3- (trifluoromethyl)-lH-pyrazol-l-yl)pyrimidin-5-yl)-2-methoxynicotinaldehyde (145 mg, 0.29 mmol) Example 1028 in THF (2 ml). The mixture was allowed to stir at RT for 45 min, water and ethyl acetate were added. The organic layer was then dried with MgS 04 and concentrated. The solid was purified by flash chromatography over silica gel. The product was eluted using 30% ethyl acetate in hexanes to give the title compound ( 114 mg). MS (Electro spray): 548.88 (MH+) for C24H17C1F4N6O3
Example 1030: (E)-3-(5-(2-(3-chloro-4-fluorophenylamino)-4-(3-(trifluoromethyl)-lH- pyrazol-l-vDpyrimidin-S-vD^-methoxypyridin-S-vDacrylic acid
Figure imgf000821_0002
(E)-methyl 3-(5-(2-(3-chloro-4-fluorophenylamino)-4-(3-(trifluoromethyl)-lH-pyrazol-l- yl)pyrimidin-5-yl)-2-methoxypyridin-3-yl)acrylate Example 1029 (114 mg, 0.21 mmol) was dissolved in Dioxane (5 niL) to give a yellow solution. IM NaOH (0.312 niL, 0.31 mmol) was added at room temp and then allowed to stir overnight. The reaction mixture was acidified with IM HCl then extracted with ethyl acetate. The ethyl acetate was evaporated and the solid purified using reverse phase chromatography (C18, 20 to 95%.CH3CN / H2O / 0.1% Trifluoroacetic acid) to yield the title compound (28 mg). MS (Electrosprav): 535 (MH+) for C23H15C1F4N6O3
1H NMR (300 MHz, DMSO-dή) δ : 3.92 - 4.02 (m, 3 H) 6.49 (d, J=16.01 Hz, 1 H) 7.04 (d, J=2.64 Hz, 1 H) 7.42 (t, J=9.14 Hz, 1 H) 7.64 (d, J=16.20 Hz, 2 H) 7.68 - 7.77 (m, 1 H) 7.91 (d, J=2.26 Hz, 1 H) 8.00 - 8.20(m, 2 H) 8.48 (s, 1 H) 8.82 (s, 1 H) 10.40 (s, 1 H) 12.45 (br. s., 1 H)
The following examples were prepared using the general method described for Example 158 using [1,1 '-bis (diphenylphosphino) ferrocene] dichloropalladium(II), sodium carbonate and the starting materials (SM) indicated.
Figure imgf000822_0001
Figure imgf000823_0001
Figure imgf000824_0001
Figure imgf000825_0001
Figure imgf000826_0001
Figure imgf000827_0001
Figure imgf000828_0001
Figure imgf000829_0001
Figure imgf000830_0001
Figure imgf000831_0001
Figure imgf000832_0002
Example 1051: methyl 6-(2-(3-chloro-4-fluorophenylamino)-4-(3- methoxypropylamino)pyrimidin-5-yl)-lΗ-indole-2-carboxylate
Figure imgf000832_0001
1 -tert-butyl 2-methyl 6-(2-(3-chloro-4-fluorophenylamino)-4-(3-methoxypropylamino)pyrimidin- 5-yl)-lH-indole-l,2-dicarboxylate (Example 983, 104 mg, 0.18 mmol) was suspended in DCM (4 rnL). The solution was then treated with trifluoroacetic acid (0.274 ml, 3.56 mmol) and stirred at room temperature for 1 hr. The solvent was removed at reduced pressure and the residue was washed with Et2θ/hexanes to afford methyl 6-(2-(3-chloro-4-fluorophenylamino)-4-(3- methoxypropylamino)pyrimidin-5-yl)-lH-indole-2-carboxylate in 98% yield (84 mg). MS(ES): 484 (M+l) for C24H23ClFN5O3.
1H NMR (300 MHz, DMS0-D6) δ ppm 1.60 - 1.93 (m, 2 H) 3.13 (s, 3 H) 3.23 - 3.55 (m, 4 H) 3.89 (s, 3 H) 7.06 (dd, /=8.29, 1.32 Hz, 1 H) 7.23 (d, /=0.94 Hz, 1 H) 7.31 - 7.65 (m, 3 H) 7.80 (dd, /=4.90, 3.39 Hz, 2 H) 7.89 - 8.06 (m, 1 H) 8.10 (s, 1 H) 10.34 (s, 1 H) 12.16 (s, 1 H).
The following examples were prepared using the general method described above for Example 1051 using the starting material (SM) indicated.
Figure imgf000833_0001
Figure imgf000834_0001
The following examples were prepared using the general method described for Example 214 using IN sodium hydroxide, THF/MeOH, and the starting material (SM) indicated.
Figure imgf000834_0002
Figure imgf000835_0001
Figure imgf000836_0001
Figure imgf000837_0001
Figure imgf000838_0001
Methyl-ester Hydrolysis: The following examples were prepared using the general method described for Example 214 using IN sodium hydroxide, THF : 1,4-dioxane (1:1), and the starting material (SM) indicated.
Figure imgf000839_0001
Figure imgf000840_0001
Figure imgf000841_0001
Figure imgf000842_0001
Figure imgf000843_0001
Figure imgf000844_0001
Figure imgf000845_0001
Figure imgf000846_0001
Figure imgf000847_0001
Figure imgf000848_0001
Figure imgf000849_0001
Figure imgf000850_0001
Figure imgf000851_0001
Figure imgf000852_0001
Figure imgf000853_0002
Example 1099: 2-(3-(2-(3-chloro-4-fluorophenylamino)-4-(3-(trifluoromethyl)-lH-pyrazol- l-vDpyrimidin-S-vDphenylsulfonvDacetic acid
Figure imgf000853_0001
tert-butyl 2-(3-(2-(3-chloro-4-fluorophenylamino)-4-(3-(trifluoromethyl)-lH-pyrazol-l- yl)pyrimidin-5-yl)phenylsulfonyl)acetate Example 1003 (164 mg, 0.27 mmol) was dissolved in THF (2 rnL), cooled to O0C, treated with trifruoroacetic acid (2 rnL), and allowed to stir at room temperature for 2 days. The solvent was removed at reduced pressure and the residue was purified by reverse phase preparative HPLC (C18: 45-95% ACN in H2O containing 0.1% TFA) to afford the desired product (120 mg).
MS(ES): 556 (M+l) for C22Hi4ClF4N5O4S
1U NMR (300 MHz, DMSO-J6) δ ppm 4.42 (s, 2 H) 7.00 (d, /=2.64 Hz, 1 H) 7.41 (t, /=9.14 Hz,
1 H) 7.47 - 7.57 (m, 1 H) 7.63 (t, /=7.72 Hz, 1 H) 7.68 - 7.81 (m, 2 H) 7.87 (d, /=7.91 Hz, 1 H)
8.11 (dd, /=6.69, 2.54 Hz, 1 H) 8.42 (d, /=1.51 Hz, 1 H) 8.82 (s, 1 H) 10.45 (s, 1 H) The following examples were prepared using the general HATU coupling method described for Example 360 using the starting materials (SM) indicated.
Figure imgf000854_0001
Figure imgf000855_0001
Figure imgf000856_0001
The following examples were prepared using the general method described above for Example 1 using Intermediate 436 and the starting material (SM) indicated
Figure imgf000857_0001
Figure imgf000858_0001
The following examples were prepared using the general method described above for Example 1 using the starting materials (SM) indicated.
Figure imgf000858_0002
Figure imgf000859_0001
Figure imgf000860_0001
Figure imgf000861_0001
The following examples were prepared using the general method described for example 214 using IN sodium hydroxide, 1,4-dioxane and the starting material (SM) indicated.
Figure imgf000861_0002
The following examples were prepared using the general HATU coupling method described for Example 360 using Example 320 and the starting material indicated.
Figure imgf000862_0002
Figure imgf000863_0002
Intermediate 1126: 5-(4-(3-(difluoromethyl)-5-methyl-lH-pyrazol-l-yl)-2-(3,5- dimethoxyphenylamino)pyrimidin-5-yl)nicotinic acid
Figure imgf000863_0001
5-bromo-4-(3-(difluoromethyl)-5-methyl-lH-pyrazol-l-yl)-N-(3,5-dimethoxyphenyl)pyrimidin- 2-amine Intermediate 449 (210 mg, 0.48 mmol), ethyl 5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)nicotinate (159 mg, 0.57 mmol), and PdC12(dppf)-CH2C12Adduct (117 mg, 0.14 mmol) were combined in acetonitrile (10 mL) to give a yellow suspension. Sodium carbonate (60.7 mg, 0.57 mmol) was added, followed by water (2.500 mL) and the mixture was degassed with argon then heated at 80 0C for 4 hours. Adsorption onto silica gel, followed by flash chromatography (0.5-10% methanol in dichloromethane) gave the intermediate ester compound (235 mg) which was hydrolyzed to the corresponding carboxylic acid without further characterization as follows: The ester was dissolved in Dioxane (5 ml), then IN NaOH solution (0.690 ml, 0.69 mmol) was added and the mixture was allowed to stir at room temperature for 6 hours. The reaction mixture was neutralized with IM HCl followed by purification by reverse phase chromatography (C18: 5-95% acetonitrile in water, 0.5% TFA) to give the title compound (89 mg). MS:ES+ 482.44 for C23H20F2N6O4
IH NMR (300 MHz, DMSO-d6) δ ppm 2.41 (s, 3 H) 3.73 (s, 6 H) 6.10 - 6.37 (m, 1 H) 6.55 (s, 2 H) 7.06 (s, 2H) 7.75 - 7.99 (m, 1 H) 8.39 - 8.65 (m, 1 H) 8.93 (br. s., 2 H) 10.05 - 10.34 (m, 1 H) 13.25 - 13.64 (m, 1 H)
The compounds in the below table were prepared using this procedure and the specified starting materials.
Figure imgf000864_0001
Example 1129: (E)-3-(3-(6-(3-chloro-4-fluorophenylamino)-4-morpholinopyridin-3- vDphenvDacrylic acid
Figure imgf000865_0001
5-bromo-N-(3-chloro-4-fluorophenyl)-4-morpholinopyridin-2-amine Intermediate 454 (80 mg,
0.21 mmol), (E)-3-(3-boronophenyl)acrylic acid (55.6 mg, 0.29 mmol), and Pd2(dba)3 (18.95 mg, 0.02 mmol) were combined in acetonitrile (8 mL) to give a suspension. Dicyclohexyl(2',4',6'- triisopropylbiphenyl-2-yl)phosphine (29.6 mg, 0.06 mmol) and Na2CO3 (43.9 mg, 0.41 mmol) were added followed by water (2.000 mL). The reaction was degassed with argon then heated at 80 0C for 30 minutes. Adsorption onto silica gel followed by purification by flash chromatography (3-25% methanol in dichloromethane) gave the title compound (52 mg). MS (Electrosprav): 454.89 (MH+) for C24H2IClFN3O3
IH NMR (300 MHz, DMSO-d6) δ ppm 2.82 (br. s., 4 H) 3.54 (br. s., 4 H) 6.37 (s, 1 H) 6.49 - 6.64 (m, 1 H) 7.29 (s, 1 H) 7.48 (d, J=7.35 Hz, 3H) 7.61 (s, 2 H) 7.80 - 7.99 (m, 2 H) 8.05 - 8.26 (m, 1 H) 9.26 (s, 1 H),12.22 - 12.74 (m, 1 H)
Example 1130: 5-(2-(3-chloro-4-fluorophenylamino)-4-(5-methyl-3-(trifluoromethyl)-lH- pyrazol-l-yl)pyrimidin-5-yl)-2-(2-methoxyethoxy)nicotinic acid
Figure imgf000865_0002
5-bromo-N-(3-chloro-4-fluorophenyl)-4-(5-methyl-3-(trifluoromethyl)-lH-pyrazol-l- yl)pyrimidin-2-amine Intermediate 113 (191 mg, 0.42 mmol), methyl 2-(2-methoxyethoxy)-5- (4,4,5, 5-tetramethyl-l,3,2-dioxaborolan-2-yl)nicotinate, Intermediate 465 (200 mg, 0.59 mmol), Pd2(dba)3 (38 mg, 0.04 mmol) and dicyclohexyl(2',4',6'-triisopropylbiphenyl-2-yl)phosphine (60 mg, 0.13 mmol) were combined in acetonitrile (10 mL) to give a yellow suspension. Sodium carbonate (67 mg, 0.64 mmol) was added, followed by water (2.500 mL) and the mixture was degassed using argon then heated at 80 0C for 4 hours. Purification by flash chromatography (0.5-10% methanol in dichloromethane) gave the intermediate carboxylic ester (265 mg), which was hydrolyzed to the corresponding carboxylic acid as below. MS (Electrosprav): 581.92 (MH+) for C25H2IClF4N6O4
The intermediate ester, methyl 5-(2-(3-chloro-4-fluorophenylamino)-4-(5-methyl-3- (trifluoromethyl)-lH-pyrazol-l-yl)pyrimidin-5-yl)-2-(2-methoxyethoxy)nicotinate (265mg, 0.45 mmol), was dissolved in THF (1 ml) and Dioxane (3 ml). IN NaOH (1.12 ml, 1.12 mmol) was added and the mixture was allowed to stir at room temperature overnight. The reaction mixture was neutralized with IM HCl then evaporated. The residue was purified by reverse phase chromatography (C18: 35-95% acetonitrile in water, 0.1% TFA) to give the title compound (60 mg). MS (Electrosprav): 567 (MH+) for C24Hi9ClF4N6O4 IH NMR (300 MHz, DMSO-J6) δ ppm 2.36 (s, 3 H) 3.30 (s, 3 H) 3.63 - 3.70 (m, 2 H), 4.33-4.54 (m, 2H), 6.76 (s, 1 H) 7.42 (t,J=9.U Hz, 1 H) 7.64 (d, /=2.45 Hz, 2 H) 7.93 - 8.30 (m, 2 H) 8.95 (s, 1 H) 10.42 (s, 1 H) 12.90 (s, 1 H)
The Compounds in the below table were prepared using this procedure and the specified starting materials.
Figure imgf000867_0001
Figure imgf000868_0001
Figure imgf000869_0001
Figure imgf000870_0001
Figure imgf000871_0001
Figure imgf000872_0001
Figure imgf000873_0001
Figure imgf000874_0001
The compounds in the below table were prepared using the procedure described for Example 1 and the specified starting materials.
Figure imgf000875_0001
Figure imgf000876_0001
Figure imgf000877_0001
Figure imgf000878_0001
Example 1155: (E)-methyl 3-(5-(2-(3-chloro-4-fluorophenylamino)-4-(3-(trifluoromethyl)- lH-pyrazol-l-yl)pyrimidin-5-yl)pyridin-3-yl)acrvlate
Figure imgf000879_0001
Methyl 2- (diethoxyphosphoryl) acetate (0.102 niL, 0.51 mmol) was dissolved in THF (1 niL). NaH, 60% dispersion in oil, (30.7 mg, 0.77 mmol) was added and the suspension was stirred for 5 minutes to give a solution. The solution was then added to a mixture of 5-(2-(3-chloro-4- fluorophenylamino)-4-(3-(trifluoromethyl)-lH-pyrazol-l-yl)pyrimidin-5-yl)nicotinaldehyde Example 1154 (227 mg, 0.51 mmol) in THF (3 ml). The reaction mixture was then heated at 50 0C for 1 hour. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, then dried with MgS 04, filtered and concentrated. The residue was triturated with diethyl ether to give a solid mass, which was collected and further rinsed with diethyl ether to give the title compound as an off white solid. (227 mg).
MS (Electrosprav): 519 (MH+) for C23Hi5ClF4N6O2
Example 1156: (E)-3-(5-(2-(3-chloro-4-fluorophenylamino)-4-(3-(trifluoromethyl)-lH- pyrazol-l-vDpyrimidin-S-vDpyridin-S-vDacrylic acid
Figure imgf000879_0002
(E)-methyl 3-(5-(2-(3-chloro-4-fluorophenylamino)-4-(3-(trifluoromethyl)-lH-pyrazol-l- yl)pyrimidin-5-yl)pyridin-3-yl)acrylate Example 1155 (100 mg, 0.19 mmol) and 2M KOH (0.289 niL, 0.58 mmol) were combined in Dioxane (2 mL). The reaction mixture was allowed to stir at RT overnight, then neutralized with IM HCl to pH 6. Water and 10% methanol in ethyl acetate were added and the layers were separated. The organic layer was dried with MgS 04 then concentrated down to a residue which was purified by reverse phase chromatography (Cl 8: 15- 95% acetonitrile in water with 0.1% TFA) to give the title compound (10 mg).
MS (Electrosprav): 505.28 (MH+) for C22Hi3ClF4N6O2
IH NMR (300 MHz, DMSO-Je) δppm 6.61 (d, /=16.20 Hz, 1 H) 7.06 (d, /=2.64 Hz, 1 H) 7.43 (t, /=9.04 Hz,l H) 7.50 - 7.62 (m, 1 H) 7.74 (ddd, /=7.35, 4.52, 4.14 Hz, 1 H) 8.02 (s, 1 H) 8.09 (dd, /=6.69, 2.54 Hz, 1 H) 8.32 (d, /=1.88 Hz, 1 H) 8.53 (s, 1 H) 8.77 (d, /=1.70 Hz, 1 H) 8.85 (s, 1 H) 10.48 (s, 1 H) 12.65 (br. s., 1 H)
The compounds in the below table were prepared using the general method described above for Example 1 using the specified starting materials.
Figure imgf000881_0001
The compounds in the below table were prepared using the general method described above for Example 214 using IN sodium hydroxide (2 equivalents), dioxane : THF (1:1) as solvent and the specified starting material.
Figure imgf000882_0001
The compounds in the below table were prepared using the general method described above for Example 800 using 2-chloro-l-methylpyridinium iodide, 4-(Dimethylamino)pyridine and triethylamine, with CH2Cl2 as solvent and the carboxylic acid and sulfonamide starting materials listed.
Figure imgf000883_0001
Figure imgf000884_0001
Figure imgf000885_0001
The compound in the below table was prepared using the general method described above for Example 858 using the specified starting materials.
Figure imgf000885_0002
The compound in the below table was prepared using the general method described above for Example 859 using the specified starting material.
Figure imgf000886_0001
The following examples were prepared using the general HATU coupling method described for Example 360 using the starting materials (SM) indicated.
Figure imgf000887_0001
Example 1169: 5-(2-methoxy-5-{2-[(3-methoxy-5-methylphenyl)amino1-4-[3- (trifluoromethyl)-lH-pyrazol-l-yl1pyrimidin-5-yl}pyridin-3-yl)-l,3,4-oxadiazol-2(3H)-one
Figure imgf000888_0001
To a mixture of 2-methoxy-5-{2-[(3-methoxy-5-methylphenyl)amino]-4-[3-(trifluoromethyl)-lH- pyrazol-l-yl]pyrimidin-5-yl}pyridine-3-carbohydrazide (Intermediate 477, 0.58 mmol, 300 mg) and iV,iV-diisopropylethylamine (0.88 mmol, 0.16 mL) in DMF, was added 1,1'- carbonyldiimidazole (0.88 mmol, 142 mg) and the reaction mixture was stirred at RT for 1 h and further at 50 0C for another hour. The reaction mass was diluted with ethyl acetate (20 mL). The organic layer was separated, washed with water and brine, dried over Na2SO4, filtered and concentrated. The crude material was purified by silica gel column chromatography using ethyl acetate/hexanes (40:60) to obtain 90 mg of the title compound.
Figure imgf000888_0002
Example 1170: 5-(2-methoxy-5-{2-[(3-methoxy-5-methylphenyl)amino1-4-[5-methyl-3- (trifluoromethyl)-lH-pyrazol-l-yl1pyrimidin-5-yl}pyridin-3-yl)-l,3,4-oxadiazol-2(3H)-one
Figure imgf000889_0001
To a solution of the 2-methoxy-5-{2-[(3-methoxy-5-methylphenyl)amino]-4-[5-methyl-3- (trifluoromethyl)-lH-pyrazol-l-yl]pyrimidin-5-yl}pyridine-3-carbohydrazide (Intermediate 478, 0.13 mmol, 70 mg) in dry DMF(I rnL) was added iV,iV-diisopropylethylamine (0.20 mmol, 26 mg, 0.34 rnL) and lj'-carbonyldiimidazole (0.20 mmol, 32 mg). The mixture was stirred for 1 h at RT and further heated at 50 0C for 1 h. The reaction mixture was diluted with DCM (15 mL) and further washed with water (25 mL) and brine (25 mL). The organic layer was dried over Na2SO4 and concentrated. The crude mass was purified by flash chromatography (product eluted with 40% EtOAc/hexanes) to afford the title compound as 35 mg of white solid.
Figure imgf000889_0002
Example 1171: ethyl l-ethyl-5-{2-[(3-methoxy-5-methylphenyl)amino1-4-[3- (trifluoromethyl)-lH-pyrazol-l-yl1pyrimidin-5-yl}-2-oxo-l,2-dihvdropyridine-3-carboxylate
Figure imgf000890_0001
A solution of 5-bromo-N-(3-methoxy-5-methylphenyl)-4-[3-(trifluoromethyl)-lH-pyrazol-l- yl]pyrimidin-2-amine (Intermediate 293, 0.9 mmol, 400 mg), a mixture of ethyl l-ethyl-2-oxo- 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,2-dihydropyridine-3-carboxylate and [5- (ethoxycarbonyl)-l-ethyl-6-oxo-l,6-dihydropyridin-3-yl]boronic acid (Intermediate 361, 1.1 mmol based on the boronic ester, 360 mg), [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II)complex with CH2Cl2 (0.18 mmol, 146 mg) and sodium carbonate (0.9 mmol, 95 mg) in acetonitrile (40 mL)/water (10 mL) was degassed and heated to 90 0C for 30 minutes under nitrogen. The reaction mixture was concentrated in vacuo. The residue obtained was taken in ethyl acetate, washed with water and brine, dried over sodium sulfate and concentrated. The crude mass was purified by silica gel column chromatography (60-120 mesh) using 2% methanol/chloroform to obtain 350 mg of the title compound.
Figure imgf000891_0002
Example 1172: l-ethyl-5-{2-r(3-methoxy-5-methylphenyl)amino1-4-[3-(trifluoromethyl)- lH-pyrazol-l-ylipyrimidin-S-vU^-oxo-l^-dihydropyridine-S-carboxylic acid
Figure imgf000891_0001
To 350 mg of ethyl l-ethyl-5-{2-[(3-methoxy-5-methylphenyl)amino]-4-[3-(trifluoromethyl)-lH- pyrazol-l-yl]pyrimidin-5-yl}-2-oxo-l,2-dihydropyridine-3-carboxylate (Example 1171, 0.65 mmol) taken in a mixture of TΗF (10 mL) /H2O (10 mL), was added NaOH (1.1 mmol, 46 mg) and stirred at rt for 2 h. The solvent was removed in vacuo and the mixture was then carefully acidified with 1 N HCl and the solid that precipitate was filtered and dried to obtain 200 mg of the title compound.
Figure imgf000892_0002
Example 1173: 5-{2-[(3-methoxy-5-methylphenyl)amino1-4-[3-(trifluoromethyl)-lH-
Pyrazol-l-ylipyrimidin-S-yll-l-methyl-N-CmethylsulfonvD^-oxo-l^-dihvdropyridine-S- carboxamide
Figure imgf000892_0001
To a solution of 5-{2-[(3-methoxy-5-methylphenyl)amino]-4-[3-(trifluoromethyl)-lH-pyrazol-l- ylJpyrimidin-S-ylj-l-methyl^-oxo-l^-dihydropyridine-S-carboxylic acid (Example 859, 0.19 mmol, 100 mg) in CH2Cl2 (10 rnL), were added methanesulfonamide (0.29 mmol, 28 mg), triethylamine (0.57 mmol, 0.08 mL), 2-chloro-l-methylpyridinium iodide (0.2 mmol, 58 mg) and 4-(Dimethylamino)pyridine (0.04 mmol, 4 mg) and stirred at RT for 2 h. The reaction mixture was diluted with dichloromethane (20 mL) and further washed with 10% citric acid solution (2 x 15 niL), water (25 rnL) and brine (25 rnL). The organic layer was dried over Na2SO4 and concentrated. The crude mass was purified by flash chromatography (product eluted with 2 % MeOH in CHCl3) to afford 85 mg of the title compound.
Figure imgf000893_0002
Example 1174: 5-{2-[(3-methoxy-5-methylphenyl)amino1-4-[5-methyl-3-(trifluoromethyl)- lH-Pyrazol-l-yl1pyrimidin-5-yl}-l-methyl-N-(methylsulfonyl)-2-oxo-l,2-dihvdropyridine-3- carboxamide
Figure imgf000893_0001
To a solution of 5-{2-[(3-methoxy-5-methylphenyl)amino]-4-[5-methyl-3-(trifluoromethyl)-lH- pyrazol- 1 -yl]pyrimidin-5-yl } - 1 -methyl-2-oxo- 1 ,2-dihydropyridine-3-carboxylic acid (Example 861, 0.49 mmol, 250 mg) in CH2Cl2 (20 mL), was added methanesulfonamide (0.97 mmol, 92 mg), triethylamine (1.45 mmol, 0.21 niL), 2-chloro-l-methylpyridinium iodide (0.58 mmol, 150 mg) and 4-(Dimethylamino)pyridine (0.097 mmol, 12 mg) and stirred at RT for 4 h. The reaction mixture was diluted with dichloromethane (20 mL) and further washed with 1.5 N HCl (2 x 15 mL), water (25 mL) and brine (25 mL). The organic layer was dried over Na2SO4 and concentrated. The crude mass was purified by flash chromatography (product eluted with 1 % MeOH in CHCl3) to afford 120 mg of the title compound.
Figure imgf000894_0001
Example 1175 : l-ethyl-5-{2- [(3-methoxy-5-methylphenyl)amino1 -4- [3-(trifluoromethyl)- l//-pyrazol-l-yl1pyrimidin-5-yl}-N-(methylsulfonyl)-2-oxo-l,2-dihvdropyridine-3- carboxamide
Figure imgf000895_0001
A mixture of l-ethyl-5-{2-[(3-methoxy-5-methylphenyl)amino]-4-[3-(trifluoromethyl)-lH- pyrazol-l-yl]pyrimidin-5-yl}-2-oxo-l,2-dihydropyridine-3-carboxylic acid (Example 1172, 0.53 mmol, 270 mg), methanesulfonamide (0.78 mmol, 74 mg), triethylamine (1.5 mmol, 0.21 rnL), 2- chloro-1-methylpyridinium iodide (0.6 mmol, 153 mg) and 4-(Dimethylamino)pyridine (0.097 mmol, 12 mg) in CH2Cl2 (10 mL), was stirred at RT for 2 h. The reaction mixture was diluted with dichloromethane (20 mL) and further washed with 10% citric acid solution (2 x 15 mL), water (25 mL) and brine (25 mL). The organic layer was dried over Na2SO4 and concentrated. The crude mass was purified by flash chromatography (product eluted with 2 % MeOH in CHCl3) to afford 170 mg of the title compound.
Figure imgf000895_0002
Example 1176: l-ethyl-5-{2-[(3-methoxy-5-methylphenyl)amino1-4-[5-methyl-3- (trifluoromethyl)-lH-pyrazol-l-yl1pyrimidin-5-yl}-N-(methylsulfonyl)-2-oxo-l,2- dihvdropyridine-3-carboxamide
Figure imgf000896_0001
A mixture of l-ethyl-5-{2-[(3-methoxy-5-methylphenyl)amino]-4-[5-methyl-3-(trifluoromethyl)- lH-pyrazol-l-yl]pyrimidin-5-yl}-2-oxo-l,2-dihydropyridine-3-carboxylic acid (Example 863, 0.59 mmol, 310 mg) methanesulfonamide (0.87 mmol, 83 mg), triethylamine (1.5 mmol, 0.21 rnL), 2-chloro-l-methylpyridinium iodide (0.6 mmol, 153 mg) and 4-(Dimethylamino)pyridine (0.097 mmol, 12 mg) in CH2Cl2 (10 mL) was stirred at RT for 2 h. The reaction mixture was diluted with dichloromethane (20 mL) and further washed with 10% citric acid (2 x 15 mL), water (25 mL) and brine (25 mL). The organic layer was dried over Na2SO4 and concentrated. The crude mass was purified by flash chromatography (product eluted with 3 % MeOH in CHCl3) to afford 120 mg of the title compound.
Figure imgf000897_0001

Claims

Claims
1. A compound of formula (I) :
Figure imgf000898_0001
or a pharmaceutically acceptable salt thereof, wherein: X is CH or N;
R1 is hydrogen, a Ci_6alkyl, C2-6alkenyl, C2-6alkynyl, C3_i4carbocyclyl, or a heterocyclyl, wherein R1 may be optionally substituted on carbon by one or more R6; and wherein if said hetercyclyl contains an =N- or a -S- moiety that nitrogen may be optionally substituted by one oxo group and that sulfur may be optionally substituted by one or two oxo groups; and wherein if said heterocyclyl contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from R7; provided that R1 is not a substituted or unsubstituted phenyl; R2 is hydrogen or a Ci_6alkyl; or
R1 and R2, together with the nitrogen to which they are attached, form a heterocyclyl, wherein said heterocyclyl may be optionally substituted on carbon by one or more R8; wherein if said hetercyclyl contains an =N- or a -S- moiety that nitrogen may be optionally substituted by one oxo group and that sulfur may be optionally substituted by one or two oxo groups; and wherein if said heterocyclyl contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from R9; R3 is a Co-^aryl or a heteroaryl; wherein R3 may be optionally substituted on carbon by one or more R14; and wherein if said heteraryl contains an =N- or a -S- moiety that nitrogen may be optionally substituted by one oxo group and that sulfur may be optionally substituted by one or two oxo groups; and wherein if said heteroaryl contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from R15; provided that R3 is not an unsubstituted phenyl or an unsubstituted thiophenyl; R4, for each occurrence, is independently selected from the group consisting of halo, cyano, nitro, hydroxy, Ci_6alkyl, Ci_6alkoxy, Ci_6alkanoyl, carbamoyl, N-Ci_6alkylcarbamoyl, N- Ci_6alkoxycarbamoyl, N,N-(Ci_6alkyl)2carbamoyl, N-(SO2R')carbamoyl, N-C1-6alkyl, Ci_6alkyl- S(O)a-, R17R18N-S(O)a-, C3-14carbocyclyl, and heterocyclyl; or two R4 taken together with the carbon atoms to which they are attached form a C3_i4carbocyclyl or a heterocyclyl, wherein each R4 may be optionally substituted on carbon by one or more R16, wherein if either of said heterocyclyl contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from R26; provided that ring B together with -(R4)n is not 3,4,5-trimethoxyphenyl; n is an integer from 1 to 5; a is 0, 1, or 2; R6, R8, and R14, for each occurrence, are each independently selected from the group consisting of hydroxy, halo, cyano, nitro, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, mercapto, Ci-6alkoxy, C1-6alkylS(O)a wherein a is 0 to 2, -C(=N-0H)NH2, -C(O)NHNH2, phenoxy, carboxy, oxo, amino, N-Ci_6alkylamino, N,N-(Ci_6alkyl)2amino, C1-6alkoxycarbonyl, C1-6alkanoyl, Ci_6alkanoyloxy, Ci_6alkanoylamino, Ci_6alkoxycarbonylamino, carbamoyl, N-C1- 6alkylcarbamoyl, N-C1-6alkoxycarbamoyl, N,N-(C1-6alkyl)2carbamoyl, N-Ci_6alkyl-N- alkoxycarbamoyl, N-(SO2R' )carbamoyl, N-C1-6alkyl-N-(SO2R')carbamoyl, Ci_6alkylsulphonylamino, sulphamoyl, iV-(C1-6alkyl)sulphamoyl, Λ/',N-(C1-6alkyl)2sulphamoyl, sulphamoylamino, iV-(Ci_6alkyl)sulphamoylamino, N,N-(Ci_6alkyl)2sulphamoylamino, C3. ^carbocyclyl-L- and heterocyclyl-L-; or two R14 taken together with the carbon atoms to which they are attached form a C3_i4carbocyclyl or a heterocyclyl; wherein R6, R8, and R14 may be each independently optionally substituted on carbon by one or more R10; and wherein if said hetercyclyl contains an =N- or a -S- moiety that nitrogen may be optionally substituted by one oxo group and that sulfur may be optionally substituted by one or two oxo groups; and wherein if either of said heterocyclyl contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from R11;
R' and R", for each occurrence, are independently selected from the group consisting of C1-6alkyl, C6-14aryl and heterocyclyl, wherein R' and R"may be optionally substituted on carbon by one or more R22 and wherein if said heterocyclyl contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from R23; R7, R9, R15 and R23, for each occurrence, are each independently selected from the group consisting of Ci_6alkyl, Ci_6alkoxycarbonyl, Ci_6alkanoyl, carbamoyl, N-Ci_6alkylcarbamoyl, N,N-(Ci_6alkyl)2carbamoyl, C3_i4carbocyclyl-C(O)-, heterocyclyl-C(O)-, (Ci_6alkyl)3silyl, Ci_6alkylS(O)a wherein a is 0 to 2, wherein R7, R9, and R15 may be each independently optionally substituted on carbon by one or more R12; and wherein if said hetercyclyl contains an =N- or a - S- moiety that nitrogen may be optionally substituted by one oxo group and that sulfur may be optionally substituted by one or two oxo groups; and wherein if said heterocyclyl contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from R13;
L, for each occurrence, is independent selected from a direct bond, -O-, -N(R25)-, -C(O)-, -N(R25)C(O)-, -C(O)N(R25)-, -S(O)5-, -SO2N(R25)- or -N(R25)SO2-; wherein R25, for each occurrence, is independently selected from hydrogen or Ci_6alkyl and s is 0, 1 or 2;
R10 and R12, for each occurrence, are independently selected from the group consisting of Ci_6alkyl, phenyl, halo, cyano, nitro, oxo, carboxy, hydroxy, Ci_6alkoxy, Ci_6alkoxycarbonyl, amino, N-Ci_6alkylamino, N,N-(Ci_6alkyl)2amino, Ci_6alkanoylamino, Ci_6alkylSO2NH-, carbamoyl, N-Ci_6alkylcarbamoyl, N,N-(Ci_6alkyl)2carbamoyl, N-Ci_6alkyloxycarbamoyl, Ci_6alkylS(O)a wherein a is 0 to 2, and heterocyclyl, wherein said R10 and R12 are independently optionally substituted on carbon by one or more Ci_6alkyl and wherein if said heterocyclyl contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from
R 13' .
R11, R13, R13 , and R26, for each occurrence, are each independently selected from the group consisting of Ci_6alkyl, Ci_6alkoxycarbonyl, Ci_6alkanoyl, C3_6cycloalkanoyl, carbamoyl, Ci-6alkanoyloxy, Ci_6alkylS(O)a, arylS(O)a wherein a is 0 to 2, carboxy, sulphamoyl and urea wherein said R11, R13, R13 , and R26 are independently optionally substituted on carbon by one or more amino, Ci_6alkyl, Ci_6alkoxy or heterocyclyl;
R16, for each occurrence, is independently, a halo, hydroxy, a Ci_6alkyl, or a Ci_6alkoxy; R17 and R18, for each occurrence, are independently hydrogen or a Ci_6alkyl; or R17 and
R18, together with the nitrogen to which they are attached form a heterocyclyl;
R22, for each occurrence, is independently selected from the group consisting of halo, C1- 6alkyl, S(O)aR" wherein a is 0 to 2, Ci_6alkanoyl, Ci_6alkanoylamino and heterocyclyl wherein R22 may be optionally substituted on carbon by one or more R24; R24 is selected from halo, Ci_6alkanoylamino, and heterocyclyl; provided that -NR1R2 is not -NHCH3 or -N(CH3)2
2. A compound according to Claim 1, or a pharmaceutically acceptable salt thereof, wherein
X is N.
3. A compound according to Claims 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R1 and R2, together with the nitrogen to which they are attached, form a heterocyclyl, wherein said heterocyclyl may be optionally substituted on carbon by one or more R8; wherein if said heterocyclyl contains an =N- or a -S- moiety that nitrogen may be optionally substituted by one oxo group and that sulfur may be optionally substituted by one or two oxo groups; and wherein if said heterocyclyl contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from R9.
4. A compound according to Claim 3, or a pharmaceutically acceptable salt thereof, wherein R1 and R2, together with the nitrogen to which they are attached, form a lH-pyrazol-1-yl, wherein said lH-pyrazol-1-yl may be optionally substituted on carbon by one or more R8.
5. A compound according to any one of Claims 1 through 4, or a pharmaceutically acceptable salt thereof, wherein R3 is a heteroaryl; wherein R3 may be optionally substituted on carbon by one or more R14; and wherein if said heteraryl contains an =N- or a -S- moiety that nitrogen may be optionally substituted by one oxo group and that sulfur may be optionally substituted by one or two oxo groups; and wherein if said heteroaryl contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from R15; provided that R3 is not an unsubstituted thiophenyl.
6. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein:
X is N;
R1 and R2, together with the nitrogen to which they are attached, form pyrazol-1-yl wherein said pyrazol-1-yl may be optionally substituted on carbon by one or more R8;
R3 is a 6-membered heteroaryl containing at least one nitrogen atom wherein one of the carbon atoms of said 6-membered heteroaryl ring may be optionally substituted with O to form a -(CO)-, and further wherein said 6-membered heteroaryl may be optionally substituted on carbon by one or more R14 and when one of the carbon atoms of said 6-membered heteroaryl ring is substituted with O to form a -(CO)-, the nitrogen of that 6-membered heteroaryl is substituted by a group selected from R15; n is 2; R4, for each occurrence, is independently a halo, Ci_6alkyl or Ci_6alkoxy;
R8, for each occurrence, is independently a Ci_6alkyl or a C3_6cycloalkyl wherein said R8 is optionally substituted on carbon by one or more fluoro;
R14, for each occurrence, is independently a carboxy, Ci_6alkoxy, C1-
3alkylsulphonylcarbamoyl, N-Ci_3alkylcarbamoyl, N-Ci_3alkoxycarbamoyl, or Ci_6alkylS(O)a wherein a is 0, 1 or 2 wherein said R14 may be optionally substituted on carbon by one or more hydroxy, (Ci_3alkyl)2N, or Ci_3alkylsulfonyl; and
R15, for each occurrence, is independently a Ci_6alkyl wherein said Ci_6alkyl is optionally substituted by Ci_6alkoxy or saturated heterocyclyl.
7. A pharmaceutical composition comprising a compound of any one of Claims 1-6, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier.
8. A method of inhibiting bacterial DNA gyrase and/or bacterial topoisomerase IV in a warmblooded animal in need of such treatment, comprising administering to the animal an effective amount of a compound of any one of Claims 1-6, or a pharmaceutically acceptable salt thereof.
9. A method of producing an antibacterial effect in a warm-blooded animal in need of such treatment, comprising administering to the animal an effective amount of a compound of any one of Claims 1-6, or a pharmaceutically acceptable salt thereof.
10. A method of treating a bacterial infection in a warm-blooded animal in need thereof, comprising administering to the animal an effective amount of a compound of any one of Claims 1-6, or a pharmaceutically acceptable salt thereof.
11. The method of Claim 10, wherein the bacterial infection is selected from the group consisting of community- acquired pneumoniae, hospital-acquired pneumoniae, skin and skin structure infections, acute exacerbation of chronic bronchitis, acute sinusitis, acute otitis media, catheter-related sepsis, febrile neutropenia, osteomyelitis, endocarditis, urinary tract infections and infections caused by drug resistant bacteria such as Penicillin-resistant Streptococcus pneumoniae, methicillin-resistant Staphylococcus aureus, methicillin-resistant Staphylococcus epidermidis and Vancomycin-Resistant Enterococci.
12. A compound of formula (I) or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1-6, for use as a medicament.
13. The use of a compound of any one of Claims 1-6, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for use in the production of an antibacterial effect in a warm-blooded animal.
14. The use of a compound of any one of Claims 1-6, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for use in inhibition of bacterial DNA gyrase and/or topoisomerase IV in a warm-blooded animal.
15. The use of a compound of any one of Claims 1-6, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for use in the treatment of a bacterial infection in a warm-blooded animal.
16. The use according to Claim 15, wherein the bacterial infection is selected from the group consisting of community-acquired pneumoniae, hospital-acquired pneumoniae, skin and skin structure infections, acute exacerbation of chronic bronchitis, acute sinusitis, acute otitis media, catheter-related sepsis, febrile neutropenia, osteomyelitis, endocarditis, urinary tract infections, Penicillin-resistant Streptococcus pneumoniae, methicillin-resistant Staphylococcus aureus, methicillin-resistant Staphylococcus epidermidis and Vancomycin-Resistant Enterococci.
17. A compound of any one of Claims 1-6, or a pharmaceutically acceptable salt thereof, for use in production of an anti-bacterial effect in a warm-blooded animal.
18. A compound of any one of Claims 1-6, or a pharmaceutically acceptable salt thereof, for use in inhibition of bacterial DNA gyrase and/or topoisomerase IV in a warm-blooded animal.
19. A compound of any one of Claims 1-6, or a pharmaceutically acceptable salt thereof, for use in the treatment of a bacterial infection in a warm-blooded animal.
20. A compound of any one of Claims 1-6, or a pharmaceutically acceptable salt thereof, for use in the treatment of community- acquired pneumoniae, hospital-acquired pneumoniae, skin and skin structure infections, acute exacerbation of chronic bronchitis, acute sinusitis, acute otitis media, catheter-related sepsis, febrile neutropenia, osteomyelitis, endocarditis, urinary tract infections, Penicillin-resistant Streptococcus pneumoniae, methicillin-resistant Staphylococcus aureus, methicillin-resistant Staphylococcus epidermidis or Vancomycin-Resistant Enterococci.
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