WO2005003103A2 - 2, 4, 6-tri-substituted 6-membered heterocycles and their use in the treatment of neurodegenerative diseases - Google Patents

2, 4, 6-tri-substituted 6-membered heterocycles and their use in the treatment of neurodegenerative diseases Download PDF

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Publication number
WO2005003103A2
WO2005003103A2 PCT/GB2004/002723 GB2004002723W WO2005003103A2 WO 2005003103 A2 WO2005003103 A2 WO 2005003103A2 GB 2004002723 W GB2004002723 W GB 2004002723W WO 2005003103 A2 WO2005003103 A2 WO 2005003103A2
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amino
optionally substituted
methyl
fluorophenyl
triazin
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PCT/GB2004/002723
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French (fr)
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WO2005003103A3 (en
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Dean Brown
Joseph Cacciola
Robert T Jacobs
Frances M Mclaren
Ashokkumar Bhikkappa Shenvi
Reed W Smith, Jr
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Astrazeneca Ab
Astrazeneca Uk Limited
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Publication of WO2005003103A2 publication Critical patent/WO2005003103A2/en
Publication of WO2005003103A3 publication Critical patent/WO2005003103A3/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/89—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members with hetero atoms directly attached to the ring nitrogen atom
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D251/00—Heterocyclic compounds containing 1,3,5-triazine rings
    • C07D251/02—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings
    • C07D251/12—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D251/26—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with only hetero atoms directly attached to ring carbon atoms
    • C07D251/40—Nitrogen atoms
    • C07D251/48—Two nitrogen atoms
    • C07D251/52—Two nitrogen atoms with an oxygen or sulfur atom attached to the third ring carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D251/00—Heterocyclic compounds containing 1,3,5-triazine rings
    • C07D251/02—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings
    • C07D251/12—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D251/26—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with only hetero atoms directly attached to ring carbon atoms
    • C07D251/40—Nitrogen atoms
    • C07D251/54—Three nitrogen atoms
    • 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
    • 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
    • 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
    • C07D409/12—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 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

Definitions

  • the present invention relates to novel triazines, pyrimidines, and pyridines and their pharmaceutical compositions and methods of use.
  • the present invention relates to therapeutic methods for the treatment and prevention of various diseases especially Alzheimer's disease and other diseases relating to the deposition of amyloid.
  • Alzheimer's Disease is a progressive, neurodegenerative disease characterized clinically by progressive loss of memory, cognition, reasoning, judgment and emotional stability.
  • AD is a common cause of dementia in humans and a leading cause of death in the United States. AD has been observed in races and ethnic groups worldwide and presents a major public health problem throughout the world.
  • AD Alzheimer's disease
  • amyloid or senile plaques
  • neurofibrillar tangles that are found in the regions of the brain associated with memory, reasoning and cognition. Similar alterations are observed in patients with Trisomy 21 (Down's syndrome) and hereditary cerebral hemorrhage with amyloidosis of the Dutch-type.
  • amyloid ⁇ protein is derived from the proteolytic cleavage of amyloid precursor protein (APP).
  • One embodiment of the invention is a compound of formula (I) or a pharmaceutically acceptable salt thereof:
  • Q is C, CH or N; W is N or S, when W is S, R 6 is not present; X is C or N, provided that when Y and Z are C, X is N; Y is C or N, provided that when X and Z are C, Y is N; Z is C or N, provided that when X and Y are C, Z is N; R 1 and R are at each occurrence independently selected from H, CH 3j optionally substituted C].
  • R 3 is selected from H, or optionally substituted C ⁇ - 6 alkyl;
  • R 5 is selected from H, or CH 3 ;
  • R 6 is selected from H;
  • R 7 is selected from optionally substituted carbocycle.
  • a further embodiment is a compound of formula (II) or a pharmaceutically acceptable salt thereof: (II)
  • Q is O, S, SO or SO 2; W is N or halogen, when W is halogen neither R 6 nor R 7 are present;
  • X is C or N, provided that when Y and Z are C, X is N;
  • Y is C or N, provided that when X and Z are C, Y is N;
  • Z is C or N, provided that when X and Y are C, Z is N;
  • R 2 is selected from H, optionally substituted Ci- 6 alkyl, optionally substituted carbocycle, or optionally substituted heterocycle;
  • R 3 is selected from H, or optionally substituted Cj.
  • One embodiment of the invention is a compound of formula (I) or a pharmaceutically acceptable salt thereof:
  • Q is C, CH orN; W is N or S, when W is S, R 6 is not present; X is C or N, provided that when Y and Z are C, X is N; Y is C or N, provided that when X and Z are C, Y is N; Z is C or N, provided that when X and Y are C, Z is N; R 1 and R 2 are at each occurrence independently selected from H, CH 3; optionally substituted C].
  • R 1 and R 2 in combination can form an optionally substituted heterocycle, or an optionally substituted carbocycle;
  • R 3 is selected from H, or optionally substituted C ⁇ - 6 alkyl;
  • R 5 is selected from H, or CH 3 ;
  • R 6 is selected from H;
  • R 7 is selected from optionally substituted carbocycle.
  • a further embodiment is a compound of claim 1, wherein: Q is N.
  • a further embodiment is a compound of claim 1, wherein: W is S, and R 6 is not present.
  • a further embodiment is a compound of claim 1, wherein: X is C.
  • a further embodiment is a compound of claim 1, wherein: Y is N.
  • a further embodiment is a compound of claim 1, wherein: Z is N.
  • a further embodiment is a compound of claim 1, wherein: R 1 and R 2 are at each occurrence are independently selected from H, or optionally substituted carbocycle, or optionally substituted heterocycle.
  • a compound of claim 1, wherein: R 3 is an optionally substituted C ⁇ - 6 alkyl.
  • R 5 is selected from H.
  • a further embodiment is a compound of claim 1, wherein: R 7 is an optionally substituted carbocycle.
  • a further embodiment is a compound of claim 1, wherein: Q is N or C; W is S, and R 6 is not present; X is C or N, provided that when Y and Z are C, X is N; Y is C or N, provided that when X and Z are C, Y is N; Z is C or N, provided that when X and Y are C, Z is N; ⁇ R and R are at each occurrence independently selected from H, or optionally substituted carbocycle; or optionally substituted heterocycle or optionally substituted C ⁇ .
  • R 3 is selected from H, or optionally substituted Ci- 6 alkyl
  • R 5 is selected from H
  • R 7 is selected from optionally substituted carbocycle.
  • a further embodiment is a compound of formula (I) selected from: Methyl N- ⁇ 4-[(3-fluorophenyl)amino]-6-[(2-hydroxypropyl)amino]-l,3,5-triazin-2-yl ⁇ -L- leucinate; Methyl N- ⁇ 4-[(3-fluorophenyl)amino]-6-morpholin-4-yl-l,3,5-triazin-2-yl ⁇ -L-leucinate; (2R)-2-( ⁇ 4-[(3-fluorophenyl)amino]-6-[(3-methoxypropyl)amino]-l,3,5-triazin-2-yl ⁇ amino)-
  • a further embodiment is a compound of formula (II) or a pharmaceutically acceptable salt thereof:
  • Q is O, S, SO or SO 2; W is N or halogen, when W is halogen neither R 6 nor R 7 are present; X is C or N, provided that when Y and Z are C, X is N; Y is C or N, provided that when X and Z are C, Y is N; Z is C or N, provided that when X and Y are C, Z is N; R 2 is selected from H, optionally substituted C].
  • R 3 is selected from H, or optionally substituted C ⁇ - 6 alkyl
  • a further embodiment is a compound of formula (II), wherein: Q is S; A further embodiment is a compound of formula (II), wherein: W is N; A further embodiment is a compound of formula (II), wherein: X is N; A further embodiment is a compound of formula (II), wherein: X is C; A further embodiment is a compound of formula (II), wherein: Y is N;
  • a further embodiment is a compound of formula (II), wherein: Y is C.
  • a further embodiment is a compound of formula (II), wherein: Z isN.
  • a further embodiment is a compound of formula (II), wherein: Z is C.
  • a further embodiment is a compound of formula (II), wherein: R 2 is optionally substituted carbocycle.
  • a further embodiment is a compound of formula (II), wherein: R 3 is optionally substituted C h alky!.
  • a further embodiment is a compound of formula (II), wherein: R 5 is selected from H, or CH 3 ;
  • a further embodiment is a compound of formula (II), wherein: R 6 is selected from H or CH 3 ;
  • a further embodiment is a compound of formula (II), wherein: R is optionally substituted carbocycle.
  • R 5 is H; R and R 5 in combination form an optionally substituted heterocycle; R is selected from H; R 7 is selected from, optionally substituted carbocycle, optionally substituted heterocycle, or -(CH 2 )]- 3 -optionally substituted carbocycle.
  • R 5 is H;
  • R 6 is selected from H;
  • R 7 is selected from, optionally substituted carbocycle, optionally substituted heterocycle, or -(CH 2 ) ⁇ ;- 3 -optionally substituted carbocycle.
  • R 5 is selected from H;
  • R 6 is selected from H;
  • R 7 is optionally substituted carbocycle.
  • a further embodiment is a compound of formula (II) selected from:
  • a further embodiment is a compound according to fo ⁇ nula (I) and/or formula (II), for use as a medicament.
  • a further embodiment is the use of a compound according to formula (I) and/or formula (II), in the manufacture of a medicament for the treatment or prophylaxis of disorders associated with ⁇ -amyloid production.
  • a further embodiment is the use of a compound according to formula (I) and/or formula (II), in the manufacture of a medicament for the treatment or prophylaxis of Alzheimer's disease or Down's syndrome.
  • a further embodiment is a method for the treatment of neurological disorders associated with ⁇ -amyloid production comprising administering to a warm-blooded animal in need of such treatment a therapeutically effective amount of a compound according to formula (I) and/or fo ⁇ nula (II).
  • a further embodiment is a method for inhibiting ⁇ -secretase activity comprising administering to a wa ⁇ n-blooded animal in need of such inhibition a therapeutically effective amount of a compound according to formula (I) and/or formula (II).
  • a further embodiment is a method for the treatment or prophylaxis of Alzheimer's disease or Down's syndrome comprising administring to a warm-blooded animal in need of such treatment a therapeutically effective amount of a compound according to formula (I) and/or formula (II).
  • a further embodiment is a pha ⁇ naceutical composition
  • a pha ⁇ naceutical composition comprising a compound according to formula (I) and/or formula (II), or a pharniaceutically acceptable salt or in vivo hydrolysable ester thereof, together with at least one pharmaceutically acceptable carrier, diluent or excipient.
  • a further embodiment is a process for preparing a compound of formula (I), which process comprises:
  • a further embodiment is a process for preparing a compound of formula (II) which process comprises: 1c
  • substitution means that substitution is optional and therefore it is possible for the designated atom to be unsubstituted.
  • substitution means that any number of hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the no ⁇ nal valency of the designated atom is not exceeded, and that the substitution results in a stable compound.
  • 2 hydrogens on the atom are replaced.
  • any variable e.g., R 1 , R 7 , R a , R e etc.
  • its definition at each occurrence is independent of its definition at every other occurrence.
  • R 1 e.g., R 1 , R 7 , R a , R e etc.
  • R e at each occurrence is selected independently from the definition of R e .
  • combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
  • the range "according to claims 1-9" means claims 1, 2, 3, 4, 5, 6, 7, 8, or 9.
  • the compounds herein described may have asymmetric centers.
  • alkyl or “alkylene” is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms.
  • C ⁇ - 6 alkyl denotes alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms.
  • alkyl include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t- butyl, pentyl, and hexyl.
  • C]- 3 alkyl whether a terminal substituent or an alkylene group linking two substituents, is understood to specifically include both branched and straight-chain methyl, ethyl, and propyl.
  • alkenyl or “alkenylene” is intended to include hydrocarbon chains of either a straight or branched configuration with one or more unsaturated carbon-carbon bonds that may occur at any stable point along the chain.
  • Examples of “C 3 . 6 alkenyl” include, but are not limited to, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 3-methyl-2-butenyl, 2- pentenyl, 3-pentenyl, hexenyl, and the like.
  • alkynyl or “alkynylene” is intended to include hydrocarbon chains of either a straight or branched configuration with one or more carbon-carbon triple bonds that may occur at any stable point along the chain, such as ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, and the like.
  • alkoxy or "alkyloxy” represents an alkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge.
  • alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t- butoxy, n-pentoxy, and s-pentoxy.
  • Preferred alkoxy groups are methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy.
  • alkylthio or “thioalkoxy” represent an alkyl group as defined above with the indicated number of carbon atoms attached through a sulphur bridge.
  • carbocycle is intended to mean any stable 3- to 7-membered monocyclic or bicyclic or 7- to 13-membered bicyclic or tricyclic, any of which may be saturated, partially unsaturated, or aromatic.
  • carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl, bicyclooctane, bicyclononane, bicyclodecane (decalin), bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, or tetrahydronaphthyl (tetralin).
  • halo or halogen refers to fluoro, chloro, bromo, and iodo.
  • Counterion is used to represent a small, negatively charged species such as chloride, bromide, hydroxide, acetate, sulfate, and the like.
  • haloalkyl examples include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl, 2,2-difluoroethyl, heptafluoropropyl, and heptachloropropyl.
  • Haloalkoxy is intended to mean a haloalkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge; for example trifluoromethoxy, pentafluoroethoxy, 2,2,2-trifluoroethoxy, and the like.
  • Halothioalkoxy is intended to mean a haloalkyl group as defined above with the indicated number of carbon atoms attached through a sulphur bridge.
  • heterocycle refersto a ring-containing monovalent and divalent radicals having one or more heteroatoms, independently selected from N, O and S, as part of the ring structure and comprising at least 3 and up to about 20 atoms in the rings.
  • Heterocyclic groups may be saturated or unsaturated, containg one or more double bonds, and heterocyclic groups may contain more that one ring.
  • the heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. If specifically noted, nitrogen in the heterocycle may optionally be quaternized. It is understood that when the total number of S and O atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to one another.
  • heterocycles include, but are not limited to, lH-indazole, 2-pyrrolidonyl, 2H, 6H-1, 5,2-dithiazinyl, 2H-pyrrolyl, 3H-indolyl, 4-piperidonyl, 4aH-carbazole, 4H- quinolizinyl, 6H-1, 2,5-thiadiazinyl, acridinyl, azetidine, aziridine, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalonyl, carbazolyl, 4aH- carbazolyl, b-carbolinyl, chromanyl, chromenyl, cinnoliny
  • thiotetrahydroquinolinyl 6H-1, 2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4- thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, thiirane, triazinyl, 1,2,3- triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, xanthenyl.
  • pharmaceutically acceptable is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salts refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof.
  • pha ⁇ naceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
  • the pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
  • such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.
  • inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like
  • organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic,
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound that contains a basic or acidic moiety by conventional chemical methods.
  • such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred.
  • Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, the disclosure of which is hereby incorporated by reference.
  • Prodrugs are intended to include any covalently bonded carriers that release the active parent drug according to formula (I) in vivo when such prodrug is administered to a mammalian subject.
  • Prodrugs of a compound of formula (I) are prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound.
  • Prodrugs include compounds of formula (I) wherein a hydroxy, amino, or sulfhydryl group is bonded to any group that, when the prodrug or compound of formula (I) is administered to a mammalian subject, cleaves to forni a free hydroxyl, free amino, or free sulfhydryl group, respectively.
  • Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of formula (I), and the like.
  • Solid compound and “stable structure” are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
  • the compounds described herein may be provided or delivered in a form suitable for oral use, for example in a tablet, lozenge, hard and soft capsule, aqueous solution, oily solution, emulsion, and suspension.
  • the compounds may also be provided for topical administration, for example, as a cream, ointment, gel, spray, or aqueous solutions, oily solutions, emulsions or suspensions.
  • the compounds described herein may also be provided in a form suitable for nasal administration for example, as a nasal spray, nasal drops, or dry powder.
  • the compositions may also be administered to the vagina or rectum in the form of a suppository.
  • compositions described herein may also be administered parentally, for example by intravenous, intravesicular, subcutaneous, intrathoracially, intracerebroventricularly, or intramuscular injection or infusion.
  • the compounds may be administered by insufflation (for example as a finely divided powder).
  • the compounds may also be administered transdermally, sublingually, .
  • the compositions of the invention may accordingly 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.
  • 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.
  • the size of the dose for therapeutic or prophylactic purposes of a compound described herein will naturally vary according to the nature and severity of the conditions, the age and sex of the animal or patient and the route of administration, according to well known principles of medicine.
  • an effective amount of a compound described herein for use in therapy of Alzheimer's Disease is an amount sufficient to symptomatically relieve in a warm-blooded animal, particularly a human the cognitive symptoms, to slow the progression of worsening cognitive symptoms, or to reduce in patients with cognitive symptoms the risk of getting worse (progressing to dementia or worsening the present degree of dementia).
  • inert, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets, and suppositories.
  • a solid carrier can be one or more substances, which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, or tablet disintegrating agents; it can also be an encapsulating material.
  • the carrier In powders, the carrier is a finely divided solid that is in a mixture with the finely divided active component. In tablets, the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.
  • Salts include, but are not limited to, pharmaceutically acceptable salts.
  • pharmaceutically acceptable salts of compounds of the present invention include but are not limited to the following: acetate, bicarbonate, bisulfate, bisulfite, carbonate, hydrobromide, hydrochloride, phosphate/diphosphate, sulfate, choline, diethanolamine, ethylenediamine, meglumine, aluminum, calcium, magnesium, nitrate, potassium, pyrosulfate, and sodium.
  • composition is intended to include the fo ⁇ nulation of the active component with encapsulating material as a carrier providing a capsule in which the active component (with or without other carriers) is surrounded by a carrier which is thus in association with it.
  • cachets are included. Tablets, powders, cachets, and capsules can be used, as solid dosage forms suitable for oral administration.
  • Liquid form compositions include solutions, suspensions, and emulsions.
  • Sterile water or water-propylene glycol solutions of the active compounds may be mentioned as an example of liquid preparations suitable for parenteral administration.
  • Liquid compositions can also be formulated in solution in aqueous polyethylene glycol solution.
  • Aqueous solutions for oral administration can be prepared by dissolving the active component in water and adding suitable colorants, flavoring agents, stabilizers, and thickening agents as desired.
  • Aqueous suspensions for oral use can be made by dispersing the finely divided active component in water together with a viscous material such as natural synthetic gums, resins, methyl cellulose, sodium carboxymethyl cellulose, and other suspending agents known to the pharmaceutical formulation art.
  • the pharmaceutical compositions can be in unit dosage form.
  • the composition is divided into unit doses containing appropriate quantities of the active component.
  • the unit dosage form can be a packaged preparation, the package containing discrete quantities of the preparations, for example, packeted tablets, capsules, and powders in vials or ampoules.
  • the unit dosage form can also be a capsule, cachet, or tablet itself, or it can be the appropriate number of any of these packaged forms.
  • the compounds of the present invention can be prepared in a number of ways well known to one skilled in the art of organic synthesis.
  • the compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. Such methods include, but are not limited to, those described below. All references cited herein are hereby incorporated in their entirety by reference.
  • novel compounds of this invention may be prepared using the reactions and techniques described in this application.
  • the reactions are performed in solvents appropriate to the reagents and materials employed and are suitable for the transfo ⁇ nations being effected.
  • all proposed reaction conditions including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and workup procedures, are chosen to be the conditions standard for that reaction, which should be readily recognized by one skilled in the art.
  • the functionality present on various portions of the molecule must be compatible with the reagents and reactions proposed. Such restrictions to the substituents, which are compatible with the reaction conditions, will be readily apparent to one skilled in the art and alternate methods must then be used.
  • Example 1 To a stirred solution of cyanuric chloride (la) (2.23 g, 12.1 mmol) in THF (50 mL) was added 3-fluoroaniline (1.17 mL, 12.1 mmol) and DIEA (8.4 mL, 48.4 mmol). The mixture was stirred for 1 hour, leucine methyl ester hydrochloride (2.23 g, 21.1 mmol) was added and the solution heated to reflux for 4 h. The mixture was cooled to room temperature and the solvent removed in vacuo. The residual oil was partitioned between CH 2 C1 2 and IN HCl (100 mL). The organic layer was separated, washed with NaCl (sat.) and dried over Na 2 S0 .
  • Example 27 Methyl N- ⁇ 4-(4-methoxyphenoxy)-6-f(thien-2-ylmethyl)amino1-l,3.5- triazin-2-yl ⁇ -L-leucinate (27).
  • Example 38 Synthesis of Methyl N- ⁇ 4-[(3-fluoropheny ⁇ amino1-6-[(4- methoxyphenyl)thio1-l.,3.,5-triazin-2-yl ⁇ g-vcinate ( ' 38).
  • Example 38 A portion of 4-chloro-N-(3 -fluoropheny l)-6- [(4-methoxypheny l)thio]-l ,3,5-triazin-2-amine 38a (0.65 g, 1.7 mmol) was dissolved in DMF (10 mL) and to this was added PS-HOBT (1.00 g, 1.4 mmol), followed by DIEA (0.60 mL, 3.3 mmol). The suspension was carefully stirred at 90° C for 2h. The resin was filtered and washed with CH 2 C1 2 (3 x 100 mL), then Et 2 O (1 x 100 inL) and dried in vacuo to give a yellow free-flowing resin 38b (1.19 g).
  • the residual oil was partitioned between CH 2 C1 2 and IN HCl (100 mL). The organic layer was separated, washed with NaCl (sat.) and dried over Na 2 SO . The residual oil was chromatographed (10:1 hexanes/ethyl acetate) to give 4-chloro-N-(3-fluorophenyl)-6-[(4- methoxyphenyl)thio]-l ,3,5-triazin-2-amine 38a (2.0 g, 92%).
  • Example 53 Methyl N-(4-[(2,3-dihydroxypropyl)thiol-6-[(3-fluorophenyl)amino1-1.3,5- triazin-2-yll-L-leucinate (53).
  • Example 65 Methyl N- ⁇ 4-r(3-fluorophenv ⁇ amino1-6-r(4-methoxyphenv ⁇ sulfinyn-l,3,5- triazin-2-yl ⁇ -L-leucinate (65).
  • Example 68 Synthesis of methyl N-r4-r(3-fluorophenvDamino1-6-(4-methoxybenzyl)- 1.3.5-triazin-2-vn-L-leucinate (68). 68a 68
  • Example 72 N 1 -r2-(DimethyIamino)ethyn-N 2 - ⁇ 4-r(3-fluorophenynamino1-6-r(4- methoxyphenyl)thio1-l,3,5-triazin-2-vU-L-leucinamide (72).
  • methyl N- ⁇ 4-[(3-fluorophenyl)amino]-6-[(4-methoxyphenyl)thio]- l,3,5-triazin-2-yl ⁇ -L-leucinate 41 (10.1 g, 21.4 mmol) in THF (50 mL)
  • MeOH (50 mL) and H 2 0 (50 mL) was added LiOH (2.25 g, 53.5 mmol).
  • the reaction was stirred for thirty minutes, and then diluted with CH 2 C1 2 (50 mL).
  • the organic layers were washed with ⁇ aCl (sat. 50 mL) containing two drops of IN HCl.
  • the organic layer was separated and dried over ⁇ a 2 SO 4 , and then the residual oil chromatographed (SiO 2 , hexanes/ethyl acetate, 90/10) to give a white foam (0.135 g, 64%).
  • the resultant material was used as is in the next reaction.
  • Example 96 Methyl N- ⁇ 4-r(3-fluorophenyl)aminol-6-f(4- methoxyphenvDthiol pyrimidin-2-yl)-N-methylleucinate (96).
  • the residual oil was partitioned between CH 2 C1 (500 mL) and IN HCl (3 x 100 mL). A portion of the material was chromatographed (11 g) SiO 2 , hexanes/ethyl acetate, gradient, 100/0 to 80/20 over 38 minutes at 35 ml/min to give the title compound (4.35 g, 23%) as a white solid.
  • Example 102 N 2 -r4-[(3-Fluorophenyl)aminol-6-(quinolin-2-ylthio pyrimidin-2-yll-N 1 - (tetrahydrofuran-2-ylmethylV -leucinamide (102).
  • Example 120 Methyl N-f4-f(3-fluorophenyl)amino1-6-(4-methoxybenzyl)pyrimidin-2- yll -L-leucinate (120). 91a 120a
  • the resultant 1 1 mixture of N-[4-chloro-6-(4-methoxybenzyl)pyrimidin-2-yl]-L-leucinate 120b and methyl N-[2-chloro-6-(4-methoxybenzyl)pyrimidin-4-yl]-L-leucinate 120c was concentrated and then chromatographed (SiO 2 , hexanes/ethyl acetate, gradient, 100/0 to 0/100 over 38 minutes at 85 ml/min) to give the title compound as a white foam. The material was assigned based on NOE studies.
  • the residual oil was chromatographed (SiO 2 , hexanes/ethyl acetate, gradient, 100/0 to 0/100 over 38 minutes at 85 ml/min) to give the title compound as a colorless oil (2.15 g, 73%).
  • Example 128 was prepared in analogy to Example 122, beginning with (S)-2-[6-bromo-4-(4- methoxy-phenylsulfanyl)-pyridin-2-ylamino]-4-methyl-pentanoic acid methyl ester 128b as the starting material. Column chromatography (CH 2 C1 2 , SiO ) gave the title compound as a white solid (12%).
  • Example 129 N 3 -(3-Fluoro-phenyl)-6-(4-methoxy-phenylsulfanyl)-N ⁇ -(3-methyl-l- pyridin-2-yl-butyl)-pyrimidine-2,4-diamine (129).
  • Example 130 N ⁇ -(3-Fluoro-phenyl)-6-(4-methoxy-phenylsulfanyl)-N 2 -(3-methyl-l- pyridin-2-yl-butyl)-pyrimidine-2,4-diamine (130).
  • the compounds of the present invention have utility for the prevention and treatment of Alzheimer's disease by inhibiting amyloid ⁇ production.
  • Methods of treatment target formation of amyloid ⁇ production through enzymes involved in the proteolytic processing of ⁇ amyloid precursor protein.
  • the inhibitions of ⁇ and ⁇ secretases reduce the production of amyloid ⁇ and are thought to reduce or prevent the neurological disorders such as Alzheimer's disease.
  • the compounds of the present invention have utility for the prevention and treatment of disorders involving amyloid ⁇ production, such as cerebrovascular disorders.
  • ug denotes microgram
  • mg denotes milligram
  • g denotes gram
  • uL denotes microliter
  • mL denotes milliliter
  • L denotes liter
  • nM denotes nanomolar
  • .uM denotes micromolar
  • mM denotes millimolar
  • M denotes molar
  • nm denotes nanometer
  • DMSO denotes dimethyl sulfoxide
  • DTT denotes dithiothreitol
  • DPBS denotes
  • EDTA denotes ethylenediaminetetraacetate
  • the gamma secretase enzyme assay measures the amount of amyloid ⁇ (A ⁇ )40 product generated by the cleavage of C 100, a truncated form of amyloid precursor protein (APP).
  • the C100 substrate is a recombinant protein purified from E. coli inclusion bodies.
  • the ⁇ secretase enzyme complex is prepared by detergent extraction of HeLa 8A8 cell membranes. The enzyme reaction contains 10 ul of inhibitor at a defined concentration, diluted from a DMSO stock into 96-well microplates (final concentration of DMSO is maintained at 5%).
  • reaction buffer 50 mM MES, pH 6.5, containing 100 mM NaCl, 1 mM EDTA, 1 mM DTT, 1 mg/mL BSA, 0.25% Chapso, 0.01% PE, 0.01% PC and a protease cocktail
  • the reactions are initiated by addition of lOul enzyme at a 20-fold dilution from stock.
  • An A ⁇ 40 standard curve diluted in the reaction buffer plus C100 is included in each assay. Plates are incubated for 3 hours at 37 degrees.
  • an antibody mixture is added: rabbit anti-A ⁇ 40 antibody (Biosource #44-3481) at 0.16 ug/ml and biotinylated 4G8 (Senetek #240-10) at 0.25 ug/ml in DPBS (Fisher # MT21031CV) containing 0.5% bovine serum albumin, 0.5% Tween 20. Plates are then incubated overnight at 4 degrees.
  • HEK Human Embryonic Kidney cells stably expressing human Amyloid Precursor protein (APP) and Presenelin I were grown in DMEM media (Fisher MT10013CN) containing 10% fetal calf serum (Fisher #MT135011CV), 0.2 mg/mL G418 (Fisher #MT30234CR) and IX concentration of antibiotic/antimycotic mixture (Fisher #MT30004CI). Cells were grown in tissue culture flasks and passaged every week at a ratio of 1:30.
  • Test compounds were solubilized in DMSO at a concentration of 3.3 mM. From this stock solution a dilution series was prepared in complete growth medium of cells. Dilution series were then transferred to 96 well assay plate (Costar #3595) with 100 uL in each well. Cells (100 uL) were added to each well containing test compound. Two controls, one containing only cells (Total) and one containing only growth medium (Background) were also included. Cells were incubated with compounds for 14-16 hours in cell culture incubator.

Abstract

Compounds of formula (I) and (II); their pharmaceutical compositions and methods of use for the treatment of neurological disorders related to amyloid ß protein production such as Alzheimer's disease.

Description

NOVEL 2,4,6-TRI-SUBSTITUTED HETEROCYCLES AND USES THEREOF
This application claims the benefit of U.S. Provisional Application No. 60/484,250 filed on June 30, 2003. Field of the invention The present invention relates to novel triazines, pyrimidines, and pyridines and their pharmaceutical compositions and methods of use. In addition, the present invention relates to therapeutic methods for the treatment and prevention of various diseases especially Alzheimer's disease and other diseases relating to the deposition of amyloid. Background of the invention Alzheimer's Disease (AD) is a progressive, neurodegenerative disease characterized clinically by progressive loss of memory, cognition, reasoning, judgment and emotional stability. AD is a common cause of dementia in humans and a leading cause of death in the United States. AD has been observed in races and ethnic groups worldwide and presents a major public health problem throughout the world. No treatment that effectively prevents AD or reverses the clinical symptoms and underlying pathophysiology is currently available and the disease is currently considered among experts to be incurable. The histopatho logical manifestations of AD are characteristic lesions known as amyloid (or senile) plaques and neurofibrillar tangles that are found in the regions of the brain associated with memory, reasoning and cognition. Similar alterations are observed in patients with Trisomy 21 (Down's syndrome) and hereditary cerebral hemorrhage with amyloidosis of the Dutch-type. The major constituent of amyloid plaques is amyloid β protein. Amyloid β protein is derived from the proteolytic cleavage of amyloid precursor protein (APP). Processing of APP to amyloid β protein and other APP fragments is governed by a group of enzymes known as secretases. One type of secretase, γ-secretase, is responsible for the protein cleavage that produces amyloid β protein. Compounds that inhibit either β or γ secretase activity, either directly or indirectly would reduce the production of amyloid β protein resulting in the treatment or prevention of disorders associated with amyloid β protein. Thus there is a continuing need for compounds that inhibit amyloid β protein production. The present invention meets this and related needs by providing a family of novel compounds and related methods of use. Summary of the invention One embodiment of the invention is a compound of formula (I) or a pharmaceutically acceptable salt thereof:
Figure imgf000003_0001
(I)
wherein: Q is C, CH or N; W is N or S, when W is S, R6 is not present; X is C or N, provided that when Y and Z are C, X is N; Y is C or N, provided that when X and Z are C, Y is N; Z is C or N, provided that when X and Y are C, Z is N; R1 and R are at each occurrence independently selected from H, CH3j optionally substituted C].6alkyl, optionally substituted carbocycle, or optionally substituted heterocycle; or R1 and R2 in combination can form an optionally substituted heterocycle, or an optionally substituted carbocycle; R3 is selected from H, or optionally substituted Cι-6alkyl; R4is selected from H, optionally substituted Cι-6alkyl, -C(=O)OCH3; optionally substituted carbocycle, -C(=O)NH(CH2)heterocycle, or -C(=O)NH(CH2)CH3; R5 is selected from H, or CH3; R6 is selected from H; R7 is selected from optionally substituted carbocycle.
A further embodiment is a compound of formula (II) or a pharmaceutically acceptable salt thereof:
Figure imgf000004_0001
(II)
wherein: Q is O, S, SO or SO2; W is N or halogen, when W is halogen neither R6 nor R7 are present; X is C or N, provided that when Y and Z are C, X is N; Y is C or N, provided that when X and Z are C, Y is N; Z is C or N, provided that when X and Y are C, Z is N; R2 is selected from H, optionally substituted Ci-6alkyl, optionally substituted carbocycle, or optionally substituted heterocycle; R3 is selected from H, or optionally substituted Cj.6alkyl; R4 is selected from H, optionally substituted -όalkyl, optionally substituted heterocycle, cyano, -C(=O)OCH3, -C(=O)OCH3; -C(=O)NH2, -C(=O)NH-optionally substituted Chalky!, -C(=O)NH(CH2)0.3-optionally substituted carbocycle, -C(=O)NH(CH2)0- 3-optionally substituted heterocycle, -C(=O)NH(CH2)ι-3N(CH3)2, C(=0)NH(CH2)ι- 3C(OCH3)2, C(=O)NH(CH2)1-3NHC(=O)OC(CH3)3, -C(=O)NH(CH2)ι-3O(CH2)1-3OH, -C(=O> optionally substituted heterocycle, -C(=O)NH(CH2)ι-3C(=O)OCH3j-C(=O)NH(CH2)ι- 3OC(CH3)3, -C(=O)NH(CH2)!-3SCH3, or C(=O)NH(CH2)ι-3C(=O)OH; R5 is selected from H, or CH3; R4 and R5 in combination form an optionally substituted heterocycle; R6 is selected from H or CH3; R7 is selected from optionally substituted Cι_6alkyl, optionally substituted carbocycle, optionally substituted heterocycle, or -(CH2)ι-3-optionally substituted carbocycle. Detailed description of the invention
One embodiment of the invention is a compound of formula (I) or a pharmaceutically acceptable salt thereof:
Figure imgf000005_0001
(I)
wherein: Q is C, CH orN; W is N or S, when W is S, R6 is not present; X is C or N, provided that when Y and Z are C, X is N; Y is C or N, provided that when X and Z are C, Y is N; Z is C or N, provided that when X and Y are C, Z is N; R1 and R2 are at each occurrence independently selected from H, CH3; optionally substituted C].6alkyl, optionally substituted carbocycle, or optionally substituted heterocycle; or R1 and R2 in combination can form an optionally substituted heterocycle, or an optionally substituted carbocycle; R3 is selected from H, or optionally substituted Cι-6alkyl; R4 is selected from H, optionally substituted Cι-6alkyl, -C(=O)OCH3j optionally substituted carbocycle, -C(=O)NH(CH2)heterocycle, or -C(=O)NH(CH2)CH3; R5 is selected from H, or CH3; R6 is selected from H; R7 is selected from optionally substituted carbocycle. A further embodiment is a compound of claim 1, wherein: Q is N. A further embodiment is a compound of claim 1, wherein: W is S, and R6 is not present. A further embodiment is a compound of claim 1, wherein: X is C. A further embodiment is a compound of claim 1, wherein: Y is N.
A further embodiment is a compound of claim 1, wherein: Z is N. A further embodiment is a compound of claim 1, wherein: R1 and R2 are at each occurrence are independently selected from H, or optionally substituted carbocycle, or optionally substituted heterocycle. A compound of claim 1, wherein: R3 is an optionally substituted Cι-6alkyl. A further embodiment is a compound of claim 1, wherein: R4is -C(=O)NH(CH2)heterocycle. A further embodiment is a compound of claim 1, wherein: R5 is selected from H. A further embodiment is a compound of claim 1, wherein: R7 is an optionally substituted carbocycle. A further embodiment is a compound of claim 1, wherein: Q is N or C; W is S, and R6 is not present; X is C or N, provided that when Y and Z are C, X is N; Y is C or N, provided that when X and Z are C, Y is N; Z is C or N, provided that when X and Y are C, Z is N; ι R and R are at each occurrence independently selected from H, or optionally substituted carbocycle; or optionally substituted heterocycle or optionally substituted C\. 6alkyl; R3 is selected from H, or optionally substituted Ci-6alkyl; R4 is selected from H, -C(=O)NH(CH2)heterocycle or optionally substituted carbocycle; R5 is selected from H; R7 is selected from optionally substituted carbocycle. A further embodiment is a compound of claim 1, wherein: Q is N or C; W is S, and R6 is not present; X is C or N, provided that when Y and Z are C, X is N; Y is C or N, provided that when X and Z are C, Y is N; Z is C or N, provided that when X and Y are C, Z is N; R1 and R2 are at each occurrence independently selected from H, or optionally substituted carbocycle; or optionally substituted heterocycle or optionally substituted Cμealkyl; R3 is selected from H, or optionally substituted Cι-6alkyl; R4 is selected from H, or -C(=O)NH(CH2)heterocycle; R5 is selected from H; R7 is selected from optionally substituted carbocycle. A further embodiment is a compound of claim 1, wherein: Q is N or C; W is S, and R6 is not present; X is C or N, provided that when Y and Z are C, X is N; Y is C or N, provided that when X and Z are C, Y is N; Z is C or N, provided that when X and Y are C, Z is N; R1 and R2 are at each occurrence independently selected from H, or optionally substituted carbocycle; or optionally substituted heterocycle; R3 is selected from H, or optionally substituted Ci-6alkyl; R4is selected from H, -C(=O)NH(CH2)heterocycle; R5 is selected from H; R7 is selected from optionally substituted carbocycle. A further embodiment is a compound of claim 1, wherein: Q is N or C; W is S, and R6 is not present; X is C orN; Y is N; Z is N; R1 and R2 are at each occurrence independently selected from H, or optionally substituted carbocycle; or optionally substituted heterocycle; R3 is selected from H, or optionally substituted Cι-6alkyl; R4 is selected from H, -C(=0)NH(CH2)heterocycle; R5 is selected from H; R is selected from optionally substituted carbocycle. A further embodiment is a compound of claim 1, wherein: Q is N; W is S, and R6 is not present; X is C or ; Y isN; Z is N; R1 and R are at each occurrence independently selected from H, or optionally substituted carbocycle; or optionally substituted heterocycle; R3 is selected from H, or optionally substituted Cι-6alkyl; R4is selected from H, -C(=O)NH(CH2)heterocycle; R5 is selected from H; R7 is selected from optionally substituted carbocycle.
A further embodiment is a compound of claim 1, wherein: Q is N; W is S, and R6 is not present; X is C; Y is N; Z is N; R1 and R2 are at each occurrence independently selected from H, or optionally substituted carbocycle; or optionally substituted heterocycle; R3 is selected from H, or optionally substituted Ci-όalkyl; R4 is selected from H, -C(=O)NH(CH2)heterocycle; R5 is selected from H; R7 is selected from optionally substituted carbocycle.
A further embodiment is a compound of formula (I) selected from: Methyl N-{4-[(3-fluorophenyl)amino]-6-[(2-hydroxypropyl)amino]-l,3,5-triazin-2-yl}-L- leucinate; Methyl N-{4-[(3-fluorophenyl)amino]-6-morpholin-4-yl-l,3,5-triazin-2-yl}-L-leucinate; (2R)-2-({4-[(3-fluorophenyl)amino]-6-[(3-methoxypropyl)amino]-l,3,5-triazin-2-yl}amino)-
4-methylpentan- 1 -ol;
Methyl N-{4-[(3-fluorophenyl)amino]-6-[(4-methoxybenzyl)amino]-l,3,5-triazin-2-yl}-D- leucinate; Methyl N-{4-[(cyclopropylmethyl)amino]-6-[(3-fluorophenyl)amino]-l ,3,5-triazin-2-yl}-D- leucinate;
Methyl N- {4- [(3 -fluoropheny l)amino] -6- [(3 -methoxypropy l)amino]- 1,3,5 -triazin-2-y 1 } -D- leucinate;
(2R)-2-({4-[(cyclopropylmethyl)amino]-6-[(3-fluorophenyl)amino]-l,3,5-triazin-2- yl } amino)-4-methy lpentan- 1 -ol ;
Methyl N-{4-[(3-fluorophenyl)amino]-6-[(tetrahydrofuran-2-ylmethyl)amino]-l,3,5-triazin-2- yl}-L-leucinate;
Methyl N-(4- [(3 -fluoropheny l)amino]-6- { [3 -( 1 H-imidazol- 1 -yl)propyl] amino } - 1 ,3 ,5 -triazin-
2-yl)-L-leucinate; Methyl N-{4-[(2-anilinoethyl)amino]-6-[(3-fluorophenyl)amino]-l,3,5-triazin-2-yl}-L- leucinate;
Methyl N-{4-[(3-fluorophenyl)amino]-6-[(2-hydroxy-2-phenylethyl)amino]-l,3,5-triazin-2- yl}-L-leucinate;
Methyl N-(4- [(3 -fluorophenyl)amino]-6- { [2-(4-methoxyphenyl)ethy 1] amino } - 1 ,3 ,5 -triazin-2- yl)-L-leucinate;
Methyl N-{4-[(2,3-dihydroxypropyl)amino]-6-[(3-fluorophenyl)amino]-l,3,5-triazin-2-yl}-L- leucinate;
Methyl N- [4-[(3 -fluoropheny l)amino] -6-(3 -hydroxypyrrolidin- 1 -yl)- 1 ,3 ,5 -triazin-2-y 1] -L- leucinate; Methyl N-{4-[(2-amino-2-oxoethyl)(methyl)amino]-6-[(3-fluorophenyl)amino]-l ,3,5-triazin-
2-yl } -L-leucinate ;
(2R)-2-[(4-[(3-fluorophenyl)amino]-6-{[2-(4-methoxyphenyl)ethyl]amino}-l,3,5-triazin-2- yl)amino]-4-methy lpentan- 1 -ol;
Methyl N-{4-[(2-cyanoethyl)(methyl)amino]-6-[(3-fluorophenyl)amino]-l,3,5-triazin-2-yl}- L-leucinate;
Methyl N-[4-[(3-fluorophenyl)amino]-6-(4-pyridin-4-ylpiperazin-l-yl)-l,3,5-triazin-2-yl]-L- leucinate; Methyl N-{4-(4-cyano-4-phenylpiperidin-l-yl)-6-[(3-fluorophenyl)amino]-l,3,5-triazin-2- yl} -L-leucinate;
Methyl N-{4-[(3-fluorophenyl)amino]-6-[(3-hydroxy-2,2-dimethylpropyl)amino]-l,3,5- triazin-2-yl} -L-leucinate; Methyl N-{4-[(3-fluorophenyl)amino]-6-[(3-morpholin-4-ylpropyl)amino]-l ,3,5-triazin-2- yl}-L-leucinate;
Methyl N-{4-({2-[4-(aminosulfonyl)phenyl]ethyl}amino)-6-[(3-fluorophenyl)amino]-l,3,5- triazin-2-yl}-L-leucinate;
Methyl N-{4-{[2-(dimethylamino)ethyl]amino}-6-[(3-fluorophenyl)amino]-l,3,5-triazin-2- yl}-L-leucinate;
Methyl N-(4-[(3-fluorophenyl)amino]-6-{[2-(2-hydroxyethoxy)ethyl]amino}-l,3,5-triazin-2- yl)-L-leucinate;
Methyl N- {4- [(3 -fluoropheny l)amino] -6- [(4-hydroxybutyl)amino] - 1 ,3 ,5-triazin-2-yl } -L- leucinate; Methyl N-(4- [(3 -fluoropheny l)amino] -6- { [3 -(2-oxopyrrolidin- 1 -yl)propyl] amino } - 1 ,3 ,5- triazin-2-yl)-L-leucinate;
Methyl N-[4-[(3-fluorophenyl)amino]-6-(4-methoxyphenyl)- 1 ,3,5-triazin-2-yl]-L-leucinate;
Methyl N-[4-[(3-fluorophenyl)amino]-6-(4-methoxybenzyl)-l,3,5-triazin-2-yl]-D-leucinate;
Methyl N-[4-[(3-fluorophenyl)amino]-6-(4-methoxybenzyl)-l,3,5-triazin-2-yl]glycinate; (2S)-2-{[4-[(3-fluorophenyl)amino]-6-(4-methoxybenzyl)-l,3,5-triazin-2-yl]amino}-4- methy lpentan- 1 -ol;
N2-Benzyl-N4-(3-fluorophenyl)-6-(4-methoxybenzyl)-l,3,5-triazine-2,4-diamine;
N2-{4-[(5-fluoro-2-methylphenyl)amino]-6-[(4-methoxyphenyl)thio]pyrimidin-2-yl}-N1-
(tetrahydrofuran-2-ylmethyl)-L-leucinamide; N2-{4-[(5-fluoro-2-methylphenyl)amino]-6-[(4-methoxyphenyl)thio]pyrimidin-2-yl}-N1- propyl-L-leucinamide;
N2- { 4- [(3 -cyanopheny l)amino] -6-[(4-methoxypheny l)thio]pyrimidin-2-y 1 } -N1 -
(tetrahydrofuran-2-ylmethyl)-L-leucinamide;
N2-{4-[(5-Chloro-2-methylphenyl)amino]-6-[(4-methoxyphenyl)thio]pyrimidin-2-yl}-NI- (tetrahydrofuran-2-ylmethyl)-L-leucinamide;
N2-{4-[(3,5-Difluorophenyl)amino]-6-[(4-methoxyphenyl)thio]pyrimidin-2-yl}-N1-
(tetrahydrofuran-2-ylmethyl)-L-leucinamide;
Methyl N-[4-[(3-fluorophenyl)amino]-6-(4-methoxybenzyl)pyrimidin-2-yl]-L-leucinate; Methyl N- [2- [(3 -fluoropheny l)amino] -6-(4-methoxybenzy l)pyrimidin-4-y 1] -L-leucinate; (S)-2-[4-(3-Fluoro-phenylamino)-6-(4-methoxy-phenylsulfanyl)-l-oxy-pyridin-2-ylamino]-4- methyl-pentanoic acid methyl ester;
2-[6-(3-Fluoro-phenylamino)-2-(4-methoxy-phenylsulfanyl)-pyrimidin-4-ylamino]-4-methyl- pentanoic acid methyl ester;
(S)-2-[4-(3-Cyano-phenylamino)-6-(quinolin-8-ylsulfanyl)-pyrimidin-2-ylmethyl]-4-methyl- pentanoic acid (tetrahydro-furan-2-ylmethyl)-amide;
(S)-2-[4-(4-Amino-phenylsulfanyl)-6-(3-cyano-phenylamino)-pyrimidin-2-ylmethyl]-4- methyl-pentanoic acid (tetrahydro-furan-2-ylmethyl)-amide;
A further embodiment is a compound of formula (II) or a pharmaceutically acceptable salt thereof:
Figure imgf000011_0001
(II)
wherein: Q is O, S, SO or SO2; W is N or halogen, when W is halogen neither R6 nor R7 are present; X is C or N, provided that when Y and Z are C, X is N; Y is C or N, provided that when X and Z are C, Y is N; Z is C or N, provided that when X and Y are C, Z is N; R2 is selected from H, optionally substituted C].6alkyl, optionally substituted carbocycle, or optionally substituted heterocycle; R3 is selected from H, or optionally substituted Cι-6alkyl; R4 is selected from H, optionally substituted Cι-6alkyl, optionally substituted heterocycle, cyano, -C(=O)OCH3, -C(=O)OCH3, -C(=O)NH2, -C(=O)NH-optionally substituted Cι-6alkyl, -C(=O)NH(CH2)0-3-optionally substituted carbocycle, -C(=O)NH(CH2)o- 3-optionally substituted heterocycle, -C(=O)NH(CH2)ι-3N(CH3)2, C(=O)NH(CH2)ι- 3C(OCH3)2, C(=O)NH(CH2)ι-3NHC(=O)OC(CH3)3, -C(=O)NH(CH2)1-3O(CH2)1-3OH, -C(=O)- optionally substituted heterocycle, -C(=O)NH(CH2)ι-3C(=O)OCH3j-C(=O)NH(CH2)ι- 3OC(CH3)3, -C(=O)NH(CH2) ι-3SCH3, or C(=O)NH(CH2)!-3C(=O)OH; R5 is selected from H, or CH3; R4 and R5 in combination form an optionally substituted heterocycle; R6 is selected from H or CH3; R7 is selected from optionally substituted C]-6alkyl, optionally substituted carbocycle, optionally substituted heterocycle, or -(CH2)ι-3-optionally substituted carbocycle. A further embodiment is a compound of formula (II), wherein: Q is S; A further embodiment is a compound of formula (II), wherein: W is N; A further embodiment is a compound of formula (II), wherein: X is N; A further embodiment is a compound of formula (II), wherein: X is C; A further embodiment is a compound of formula (II), wherein: Y is N;
A further embodiment is a compound of formula (II), wherein: Y is C. A further embodiment is a compound of formula (II), wherein: Z isN. A further embodiment is a compound of formula (II), wherein: Z is C. A further embodiment is a compound of formula (II), wherein: R2 is optionally substituted carbocycle. A further embodiment is a compound of formula (II), wherein: R3 is optionally substituted Chalky!.
A further embodiment is a compound of formula (II), wherein: R4 is selected from, -C(=O)OCH3j -C(=O)-optionally substituted heterocycle, - C(=O)NH(CH2)o-3-optionally substituted heterocycle, or -C(=O)NH(CH2)ι-3SCH3. A further embodiment is a compound of formula (II), wherein: R5 is selected from H, or CH3; A further embodiment is a compound of formula (II), wherein: R6 is selected from H or CH3; A further embodiment is a compound of formula (II), wherein: R is optionally substituted carbocycle. A further embodiment is a compound of formula (II): wherein: Q is S, SO or SO2; W is N; X is C or N, provided that when Y and Z are C, X is N; Y is C or N, provided that when X and Z are C, Y is N; Z is C or N, provided that when X and Y are C, Z is N; R2 is selected from H, optionally substituted carbocycle, or optionally substituted heterocycle; R3 is optionally substituted Cι-6alkyl; R4 is selected from, -C(=O)OCH3j -C(=O)-optionally substituted heterocycle, -C(=O)NH(CH2)o-3-optionally substituted heterocycle, -C(=O)NH(CH2)ι-3SCH3, optionally substituted heterocycle, cyano, -C(=O)NH2, -C(=O)NH-optionally substituted Cι-6alkyl, -C(=O)NH(CH2)0-3-optionally substituted carbocycle, -C(=O)NH(CH2)ι-3N(CH3)2, C(=O)NH(CH2)1.3C(OCH3)2; C(=O)NH(CH2)1-3NHC(=O)OC(CH3)3, -C(=O)NH(CH2)ι- 3O(CH2)ι-3OH, -, -C(=O)NH(CH2)1-3C(=0)OCH3; -C(=O)NH(CH2)ι.3OC(CH3)3, or C(=O)NH(CH2)ι.3C(=O)OH; R5 is H; R4 and R5 in combination form an optionally substituted heterocycle; R6 is selected from H; R7 is selected from, optionally substituted carbocycle, optionally substituted heterocycle, or -(CH2)ι-3-optionally substituted carbocycle.
A further embodiment is a compound of formula (II): wherein: Q is S; W is N; X is C or N, provided that when Y and Z are C, X is N; Y is C or N, provided that when X and Z are C, Y is N; Z is C or N, provided that when X and Y are C, Z is N; R is selected from H, optionally substituted carbocycle, or optionally substituted heterocycle; R is optionally substituted Cι_6alkyl; R4 is selected from, -C(=O)OCH3, -C(=O)-optionally substituted heterocycle, -C(=O)NH(CH2)0-3-optionally substituted heterocycle, -C(=O)NH(CH2)ι-3SCH3, heterocycle, cyano, -C(=O)NH2, -C(=O)NH-optionally substituted d-6alkyl, -C(=O)NH(CH2)o-3-optionally substituted carbocycle, -C(=O)NH(CH2)ι-3N(CH3)2,
C(=O)NH(CH2)ι-3C(OCH3)2; C(=O)NH(CH2)1-3NHC(=O)OC(CH3)3, -C(=O)NH(CH2)1- 3O(CH2)1-3OH, -, -C(=O)NH(CH2)1-3C(=0)OCH3,-C(=O)NH(CH2)1.3OC(CH3)3, or C(=O)NH(CH2)ι-3C(=O)OH; R5 is H; R and R5 in combination form an optionally substituted heterocycle; R is selected from H; R7 is selected from, optionally substituted carbocycle, optionally substituted heterocycle, or -(CH2)]-3-optionally substituted carbocycle.
A further embodiment is a compound of formula (II): wherein: Q is S, W is N; X is C or N, provided that when Y and Z are C, X is N; Y is C or N, provided that when X and Z are C, Y is N; Z is C or N, provided that when X and Y are C, Z is N; R2 is selected from H, optionally substituted carbocycle; R is optionally substituted Cι-6alkyl; R4 is selected from, -C(=O)OCH3j -C(=O)-optionally substituted heterocycle, -C(=O)NH(CH2)o-3-optionally substituted heterocycle, -C(=O)NH(CH2)ι-3SCH3, optionally substituted heterocycle, cyano, -C(=O)NH2, -C(=O)NH-optionally substituted Ci. βalkyl, -C(=O)NH(CH2)0-3-optionally substituted carbocycle, -C(=O)NH(CH2)ι-3N(CH3)2, C(=O)NH(CH2),-3C(OCH3)2ι C(=O)NH(CH2)ι-3NHC(=O)OC(CH3)3, -C(=O)NH(CH2)ι- 3O(CH2),-3OH. -C(=O)NH(CH2)i-3C(=O)OCH3> -C(=O)NH(CH2)ι-3OC(CH3)3, or C(=O)NH(CH2)ι-3C(=O)OH; R5 is H; R6 is selected from H; R7 is selected from, optionally substituted carbocycle, optionally substituted heterocycle, or -(CH2)ι;-3-optionally substituted carbocycle.
A further embodiment is a compound of formula (II): wherein: Q is S; W isN; X is C or N, provided that when Y and Z are C, X is N; Y is C or N, provided that when X and Z are C, Y is N; Z is C or N, provided that when X and Y are C, Z is N; R2 is an optionally substituted carbocycle; R3 is optionally substituted Cι-6alkyl; R4 is selected from, -C(=O)OCH3> -C(=O)-optionally substituted heterocycle, -C(=O)NH(CH2)o-3-optionally substituted heterocycle, -C(=O)NH(CH2)ι-3SCH3, optionally substituted heterocycle, cyano, -C(=O)NH2, -C(=O)NH-optionally substituted C.-βalkyl, -C(=O)NH(CH2)o-3-optionally substituted carbocycle, -C(=O)NH(CH2)ι-3N(CH3)2, C(=O)NH(CH2)i-3C(OCH3)2j C(=O)NH(CH2)1-3NHC(=O)OC(CH3)3, -C(=O)NH(CH2)1- 3O(CH2)ι-3OH, -, -C(=0)NH(CH2)ι-3C(=0)OCH3j-C(=O)NH(CH2)ι-3OC(CH3)3, or C(=O)NH(CH2)ι-3C(=O)OH; R5 is H; R6 is selected from H; R7 is optionally substituted carbocycle,. A further embodiment is a compound of formula (II): wherein: Q is S; W is N; X is C or N, provided that when Y and Z are C, X is N; Y is C or N, provided that when X and Z are C, Y is N; Z is C or N, provided that when X and Y are C, Z is N; R2 is an optionally substituted carbocycle; R3 is optionally substituted Cι-6alkyl; R4 is selected from, -C(=O)OCH3; -C(=O)-optionally substituted heterocycle, - C(=O)NH(CH2)0-3-optionally substituted heterocycle, -C(=O)NH(CH2)1.3SCH3, optionally substituted heterocycle, -C(=O)NH2, -C(=O)NH(CH2)o-3-optionally substituted carbocycle; R5 is H; R6 is selected from H; R7 is optionally substituted carbocycle.
A further embodiment is a compound of formula (II): wherein: Q is S; W is N; X is C or N, provided that when Y and Z are C, X is N Y is C or N, provided that when X and Z are C, Y is N Z is C or N, provided that when X and Y are C, Z is N R2 is optionally substituted carbocycle; R3 is optionally substituted C^aH yl; R4 is selected from, -C(=O)OCH3; -C(=O)-optionally substituted heterocycle,
-C(=O)NH(CH2)0-3-optionally substituted heterocycle, or -C(=O)NH(CH2)ι-3SCH3; R5 is selected from H; R6 is selected from H; R7 is optionally substituted carbocycle.
A further embodiment is a compound of formula (II) selected from:
Methyl N-{4-(4-methoxyphenoxy)-6-[(thien-2-ylmethyl)amino]-l,3,5-triazin-2-yl}-L- leucinate;
Methyl N-[4-(4-methoxyphenoxy)-6-(2-pyridin-4-ylethyl)-l,3,5-triazin-2-yl]-L-leucinate; Methyl N-[4-[(2,3-dihydroxypropyl)amino]-6-(4-methoxyphenoxy)-l,3,5-triazin-2-yl]-L- leucinate;
Methyl N- { 4-(4-methoxyphenoxy)-6- [(tetrahydrofuran-2-ylmethy l)amino] - 1 ,3 ,5 -triazin-2- yl} -L-leucinate; Methyl N-[4-[(3-fluorobenzyl)amino]-6-(4-methoxyphenoxy)-l,3,5-triazin-2-yl]-L-leucinate;
Methyl N-[4-[(2-methoxybenzyl)amino]-6-(4-methoxyphenoxy)-l,3,5-triazin-2-yl]-L- leucinate;
Methyl N-[4-[(3,5-difluorobenzyl)amino]-6-(4-methoxyphenoxy)-l,3,5-triazin-2-yl]-L- leucinate;
Methyl N-[4-[(3,5-dichlorobenzyl)amino]-6-(4-methoxyphenoxy)-l,3,5-triazin-2-yl]-L- leucinate;
Methyl N- [4-(benzy lamino)-6-(4-methoxyphenoxy)- 1,3,5 -triazin-2-y 1] -L-leucinate;
Methyl N-[4-(butylamino)-6-(4-methoxyphenoxy)- 1 ,3,5-triazin-2-yl]-L-leucinate; Methyl N-[4-(pentylamino)-6-(4-methoxyphenoxy)- 1 ,3,5-triazin-2-yl]-L-leucinate;
Methyl N-{4-[(3-fluorophenyl)amino]-6-[(4-methoxyphenyl)thio]-l,3,5-triazin-2- yljglycinate;
(2R)-2-({4-[(5-Chloro-2-methylρhenyl)amino]-6-[(4-methoxyphenyl)thio]- 1 ,3 ,5-triazin-2- yl } amino)-4-methy lpentan- 1 -ol; Methyl N- { 4-[(5 -chloro-2-methylpheny l)amino] -6- [(4-methoxyphenyl)thio]- 1 ,3 ,5 -triazin-2- yl} -L-leucinate;
Methyl N-{4-[(3-fluorophenyl)amino]-6-[(4-methoxyphenyl)thio]-l,3,5-triazin-2-yl}-L- leucinate; l-{4-[(3-fluorophenyl)amino]-6-[(4-methoxyphenyl)thio]-l,3,5-triazin-2-yl}pyrrolidin-3-ol; N2-{4-[(3-fluorophenyl)amino]-6-[(4-methoxyphenyl)thio]-l,3,5-triazin-2-yl}-L-leucinamide;
N2-(3-fluorophenyl)-N4-isopentyl-6-[(4-methoxyphenyl)thio]-l,3,5-triazine-2,4-diamine
(2S)-2-({4-[(3-fluorophenyl)amino]-6-[(4-methoxyphenyl)thio]-l,3,5-triazin-2-yl}amino)-4- methylpentan- 1 -ol;
Methyl N-{4-[(3-fluorophenyl)amino]-6-[(4-methoxyphenyl)thio]-l,3,5-triazin-2-yl}-L- phenylalaninate;
2-({4-[(3-fluorophenyl)amino]-6-[(4-methoxyphenyl)thio]-l,3,5-triazin-2-yl}amino)propan- l-ol;
N2-(2,2-Dimethoxyethyl)-N4-(3-fluorophenyl)-6-[(4-methoxyphenyl)thio]-l,3,5-triazine-2,4- diamine; Ethyl N-{4-[(3-fluorophenyl)amino]-6-[(4-methoxyphenyl)thio]-l,3,5-triazin-2-yl}-b- alaninate;
3-[{4-[(3-fluorophenyl)amino]-6-[(4-methoxyphenyl)thio]-l,3,5-triazin-2- y 1 } (methyl)amino]propanenitrile; Methyl N-{4-[(3-fluorophenyl)amino]-6-[(4-methoxyphenyl)thio]-l,3,5-triazin-2-yl}-L- alaninate;
Methyl N-{4-[(3-fluorophenyl)amino]-6-[(4-methoxyphenyl)thio]-l,3,5-triazin-2-yl}-D- leucinate; Methyl N- {4- [(2,3 -dihydroxypropyl)thio] -6- [(3 -fluoropheny l)amino] - 1 ,3 ,5-triazin-2-y 1 } -L- leucinate;
Methyl N-{4-[(3-fluorophenyl)amino]-6-[(3-methoxyphenyl)thio]-l,3,5-triazin-2-yl}-L- leucinate;
Methyl N-{4-[(3-fluorophenyl)(methyl)amino]-6-[(4-methoxyphenyl)thio]-l,3,5-triazin-2- yl} -L-leucinate;
(2R)-2-({4-[(3-fluorophenyl)amino]-6-[(4-methoxyphenyl)thio]-l,3,5-triazin-2-yl}amino)-4- methy lpentan- 1 -ol ;
Methyl N- { 4- [(3 -fluoropheny l)amino] -6- [(2-methoxypheny l)thio] - 1 ,3 ,5-triazin-2-y 1 } -L- leucinate; Methyl N-[4-[(3-fluorophenyl)amino]-6-(phenylthio)- 1 ,3,5-triazin-2-yl]-L-leucinate;
Methyl N-[4-[(3-fluorophenyl)amino]-6-(quinolin-2-ylthio)- 1 ,3,5-triazin-2-yl]-L-leucinate;
Methyl N-{4-[(4-aminophenyl)thio]-6-[(3-fluorophenyl)amino]-l,3,5-triazin-2-yl}-L- leucinate;
Methyl N-{4-[(3-bromophenyl)thio]-6-[(3-fluorophenyl)amino]-l,3,5-triazin-2-yl}-L- leucinate;
Methyl N-[4-[(3-fluorophenyl)amino]-6-(pyrimidin-2-ylthio)-l,3,5-triazin-2-yl]-L-leucinate;
Methyl N- {4- { [2-(dimethy lamino)ethyl]thio } -6- [(3 -fluoropheny l)amino] - 1 ,3 ,5 -triazin-2-y 1 } -
L-leucinate;
Methyl N- {4-({ 1 -[2-(dimethylamino)ethyl]- 1 H-tetrazol-5-yl}thio)-6-[(3- fluoropheny l)amino]-l ,3,5-triazin-2-yl}-L-leucinate;
Methyl N-{4-[(3-fluorophenyl)amino]-6-[(4-methoxyphenyl)sulfιnyl]-l,3,5-triazin-2-yl}-L- leucinate;
Methyl N-{4-[(3-fluorophenyl)amino]-6-[(4-methoxyphenyl)sulfonyl]-l, 3, 5-triazin-2-yl}-L- leucinate; N1-[2-(Dimethylamino)ethyl]-N2-{4-[(3-fluorophenyl)amino]-6-[(4-methoxyphenyl)thio]- l,3,5-triazin-2-yl}-L-leucinamide;
N2-{4-[(3-fluorophenyl)amino]-6-[(4-methoxyphenyl)thio]-l,3,5-triazin-2-yl}-NI-
(tetrahydrofuran-2-ylmethyl)-L-leucinamide; N -{4-[(3-fluorophenyl)amino]-6-[(4-methoxyphenyl)thio]-l,3,5-triazin-2-yl}-N -(2- morpholin-4-ylethyl)-L-leucinamide; 1 9
N -{2-[(tert-Butoxycarbonyl)amino]ethyl}-N -{4-[(3-fluorophenyl)amino]-6-[(4- methoxyphenyl)thio]-l,3,5-triazin-2-yl}-L-leuGinamide; N2- { 4- [(3 -fluoropheny l)amino] -6-[(4-methoxyphenyl)thio] - 1 ,3 ,5 -tri azin-2-y 1 } -N1 -(pyr idin-3 - ylmethyl)-L-leucinamide;
N1-(3,5-Difluorobenzyl)-N2-{4-[(3-fluorophenyl)amino]-6-[(4-methoxyphenyl)thio]-l,3,5- triazin-2-yl}-L-leucinamide;
N2-{4-[(3-fluorophenyl)amino]-6-[(4-methoxyphenyl)thio]-l,3,5-triazin-2-yl}-N1-(2- furylmethyl)-L-leucinamide;
N2-{4-[(3-fluorophenyl)amino]-6-[(4-methoxyphenyl)thio]-l,3,5-triazin-2-yl}-N1-[3-(2- oxopyrrolidin- 1 -yl)propyl]-L-leucinamide;
N2-{4-[(3-fluorophenyl)amino]-6-[(4-methoxyphenyl)thio]-l,3,5-triazin-2-yl}-N1-(3- methoxybenzyl)-L-leucinamide; 9 ι N -{4-[(3-fluorophenyl)amino]-6-[(4-methoxyphenyl)thio]-l,3,5-triazin-2-yl}-N -(2- piperidin- 1 -y lethyl)-L-leucinamide;
N2-{4-[(3-fluorophenyl)amino]-6-[(4-methoxyphenyl)thio]-l,3,5-triazin-2-yl}-N1-[2-(2- hydroxyethoxy)ethyl]-L-leucinamide;
N2-{4-[(3-fluorophenyl)amino]-6-[(4-methoxyphenyl)thio]-l,3,5-triazin-2-yl}-N1-phenyl-L- leucinamide;
N2-{4-[(3-fluorophenyl)amino]-6-[(4-methoxyphenyl)thio]-l,3,5-triazin-2-yl}-N1-propyl-L- leucinamide;
N -{4-[(3-fluorophenyl)amino]-6-[(4-methoxyphenyl)thio]-l,3,5-triazin-2-yl}-N1-(2- pyrrolidin- 1 -ylethyl)-L-leucinamide; N2-(3-fluorophenyl)-6-[(4-methoxyphenyl)thio]-N4-[(lS)-3-methyl-l-(morpholin-4- ylcarbonyl)butyl]-l,3,5-triazine-2,4-diamine;
N1-{2-[4-(aminosulfonyl)phenyl]ethyl}-N2-{4-[(3-fluorophenyl)amino]-6-[(4- methoxypheny l)thio] - 1 ,3 ,5 -triazin-2-yl } -L-leucinamide ;
N2-{4-[(3-fluorophenyl)amino]-6-[(4-methoxyphenyl)thio]-l,3,5-triazin-2-yl}-N1-[2-(l- methylpyrrolidin-2-yl)ethyl]-L-leucinamide; 9 1
N -{4-[(3-fluorophenyl)amino]-6-[(4-methoxyphenyl)thio]-l,3,5-triazin-2-yl}-N -(3- methoxypropyl)-L-leucinamide; N2-{4-[(3-fluorophenyl)amino]-6-[(4-methoxyphenyl)thio]-l,3,5-triazin-2-yl}-N1-(pyridin-2- ylmethyl)-L-leucinamide;
Methyl N-{2-[(3-fluorophenyl)amino]-6-[(4-methoxyphenyl)thio]pyrimidin-4-yl}-L- leucinate; Methyl N-{4-[(3-fluorophenyl)amino]-6-[(4-methoxyphenyl)thio]pyrimidin-2-yl}-L- leucinate;
N-{4-[(3-fluorophenyl)amino]-6-[(4-methoxyphenyl)thio]pyrimidin-2-yl}-leucine;
N-{4-[(3-fluorophenyl)(methyl)amino]-6-[(4-methoxyphenyl)thio]pyrimidin-2-yl}-L-leucine;
N-{4-chloro-6-[(4-methoxyphenyl)thio]pyrimidin-2-yl}-N-methyl-leucine; Methyl N-{4-[(3-fluorophenyl)amino]-6-[(4-methoxyphenyl)thio]pyrimidin-2-yl}-N- methylleucinate;
N2-[4-[(3-fluorophenyl)amino]-6-(quinolin-2-ylthio)pyrimidin-2-yl]-N1-(tetrahydrofuran-2- ylmethyl)-L-leucinamide;
N2-{4-[(3-fluorophenyl)amino]-6-[(4-methoxyphenyl)thio]pyrimidin-2-yl}-N1-(2- furylmethyl)-L-leucinamide;
N2-{4-[(3-fluorophenyl)amino]-6-[(4-methoxyphenyl)thio]pyrimidin-2-yl}-N1-
(tetrahydrofuran-2-ylmethyl)-L-leucinamide;
N2-{4-[(3-fluorophenyl)amino]-6-[(4-methoxyphenyl)thio]pyrimidin-2-yl}-N1-propyl-L- leucinamide; N2-{4-[(3-fluorophenyl)amino]-6-[(4-methoxyphenyl)thio]pyrimidin-2-yl}-N!-(2-morpholin-
4-ylethyl)-L-leucinamide;
N1-(2,2-methoxyethyl)-N2-{4-[(3-fluorophenyl)amino]-6-[(4-methoxyphenyl)thio]pyrimidin-
2-yl } -L-leucinamide;
N2-{4-[(3-fluorophenyl)amino]-6-[(4-methoxyphenyl)thio]pyrimidin-2-yl}-N1-(2-pyridin-2- ylethyl)-L-leucinamide;
Methyl N-{4-[(3-fluorophenyl)amino]-6-[(4-methoxyphenyl)thio]pyrimidin-2-yl}-L- leucylglycinate;
N2-{4-[(3-fluorophenyl)amino]-6-[(4-methoxyphenyl)thio]pyrimidin-2-yl}-N1-[3-(lH- imidazol- 1 -yl)propyl] -L-leucinamide; N2-{4-[(3-fluorophenyl)amino]-6-[(4-methoxyphenyl)thio]pyrimidin-2-yl}-N1-(2- isopropoxyethyl)-L-leucinamide;
N2-{4-[(3-fluorophenyl)amino]-6-[(4-methoxyphenyl)thio]pyrimidin-2-yl}-N1-[2-
(methylthio)ethyl]-L-leucinamide; N2- {4- [(3 -fluoropheny l)amino] -6- [(4-methoxypheny l)thio]pyrimidin-2-y 1 } -N1 -pentyl-L- leucinamide;
N-{4-[(3-fluorophenyl)amino]-6-[(4-methoxyphenyl)thio]pyrimidin-2-yl}-L-leucylglycine;
N2- { 4- [(3 -fluoropheny l)amino]-6-[(4-methoxyphenyl)thio]pyrimidin-2-yl } -N1 - [2-( 1 H- imidazol-5-yl)ethyl]-L-leucinamide;
N2-{4-[(3-fluorophenyl)amino]-6-[(4-methoxyphenyl)thio]pyrimidin-2-yl}-N1-methoxy-N1- methyl-L-leucinamide;
N2- { 2- [(3 -fluoropheny l)amino]-6- [(4-methoxypheny l)thio]pyrimidin-4-yl } -N1 -(2-morpholin-
4-ylethyl)-L-leucinamide; N2-{2-[(3-fluorophenyl)amino]-6-[(4-methoxyphenyl)thio]pyrimidin-4-yl}-N1-
(tetrahydrofuran-2-ylmethyl)-L-leucinamide;
N2-{2-[(3-fluorophenyl)amino]-6-[(4-methoxyphenyl)thio]pyrimidin-4-yl}-N'-propyl-L- leucinamide;
(S)-2-[4-(3-Cyano-phenylamino)-6-(thiazol-2-ylsulfanyl)-pyrimidin-2-ylmethyl]-4-methyl- pentanoic acid (tetrahydro-furan-2-ylmethyl)-amide;
(S)-2-[4-(3-Cyano-phenylamino)-6-(pyridin-2-ylsulfanyl)-pyrimidin-2-ylmethyl]-4-methyl- pentanoic acid (tetrahydro-furan-2-ylmethyl)-amide;
N2- {4- [((3 -Methy 1-propy l)thio)amino] -6- [(4-methoxypheny l)thio]pyrimidin-2-y 1 } -N1 -
(tetrahydrofuran-2-ylmethyl)-L-leucinamide; N2-{4-[(2-Pyridyl)amino]-6-[(4-methoxyphenyl)thio]pyrimidin-2-yl}-N1-(tetrahydrofuran-2- ylmethyl)-L-leucinamide; (S)-2-[4-(3-Cyano-phenylamino)-6-(4-methoxy-phenylsulfanyl)-pyrimidin-2-ylmethyl]-4- methyl-pentanoic acid (2-methylsulfanyl-ethyl)-amide;
N2-{2-[(3-Fluorophenyl)amino]-6-[(4-methoxyphenyl)thio]pyrimidin-4-yl}-N1-l-morpholin- 4-yl-L-leucinamide;
2-[6-(3-Fluoro-phenylamino)-2-(4-methoxy-phenylsulfanyl)-pyrimidin-4-ylamino]-4-methyl- pentanoic acid methyl ester;
(S)-2-[6-(3-Fluoro-phenylamino)-4-(4-methoxy-phenylsulfanyl)-pyridin-2-ylamino]-4- methyl-pentanoic acid methyl ester; Ν2-(3-Fluoro-phenyl)-6-(4-methoxy-phenylsulfanyl)-Ν4-(3-methyl-l-pyridin-2-yl-butyl)- pyrimidine-2,4-diamine;
N4-(3-Fluoro-phenyl)-6-(4-methoxy-phenylsulfanyl)-N2-(3-methyl-l-pyridin-2-yl-butyl)- pyrimidine-2,4-diamine; (S)-2-[4-(3-Cyano-phenylamino)-6-(quinolin-8-ylsulfanyl)-pyrimidin-2-ylmethyl]-4-methyl- pentanoic acid (tetrahydro-furan-2-ylmethyl)-amide;
(S)-2-[4-(4-Amino-phenylsulfanyl)-6-(3-cyano-phenylamino)-pyrimidin-2-ylmethyl]-4- methyl-pentanoic acid (tetrahydro-furan-2-ylmethyl)-amide; (S)-2-[3-(3-Fluoro-phenylamino)-5-(4-methoxy-phenylsulfanyl)-phenylamino]-4-methyl- pentanoic acid methyl ester;
(S)-2-[2-(3-Fluoro-phenylamino)-6-(4-methoxy-phenylsulfanyl)-pyridin-4-ylamino]-4- methyl-pentanoic acid methyl ester;
(S)-2-[6-(3-Fluoro-phenylamino)-4-(4-methoxy-phenylsulfanyl)-l-oxy-pyridin-2-ylamino]-4- methyl-pentanoic acid methyl ester;
(S)-2-[4-(3-Fluoro-phenylamino)-6-(4-methoxy-phenylsulfanyl)-pyridin-2-ylamino]-4- methyl-pentanoic acid methyl ester;
A further embodiment is a compound according to foπnula (I) and/or formula (II), for use as a medicament.
A further embodiment is the use of a compound according to formula (I) and/or formula (II), in the manufacture of a medicament for the treatment or prophylaxis of disorders associated with β-amyloid production.
A further embodiment is the use of a compound according to formula (I) and/or formula (II), in the manufacture of a medicament for the treatment or prophylaxis of Alzheimer's disease or Down's syndrome.
A further embodiment is a method for the treatment of neurological disorders associated with β-amyloid production comprising administering to a warm-blooded animal in need of such treatment a therapeutically effective amount of a compound according to formula (I) and/or foπnula (II).
A further embodiment is a method for inhibiting γ-secretase activity comprising administering to a waπn-blooded animal in need of such inhibition a therapeutically effective amount of a compound according to formula (I) and/or formula (II). A further embodiment is a method for the treatment or prophylaxis of Alzheimer's disease or Down's syndrome comprising administring to a warm-blooded animal in need of such treatment a therapeutically effective amount of a compound according to formula (I) and/or formula (II).
A further embodiment is a phaπnaceutical composition comprising a compound according to formula (I) and/or formula (II), or a pharniaceutically acceptable salt or in vivo hydrolysable ester thereof, together with at least one pharmaceutically acceptable carrier, diluent or excipient.
A further embodiment is a process for preparing a compound of formula (I), which process comprises:
Figure imgf000023_0001
Figure imgf000023_0002
Figure imgf000023_0003
A further embodiment is a process for preparing a compound of formula (II) which process comprises:
Figure imgf000024_0001
1c
Figure imgf000024_0002
1d
Figure imgf000024_0003
1b 1d
Definitions
Unless specified otherwise within this application, the nomenclature used in this application generally follows the examples and rules stated in Nomenclature of Organic Chemistry, Sections A, B, C, D, E, F, and H, Pergamon Press, Oxford, 1979, which is incorporated by references herein for its exemplary chemical structure names and rules on naming chemical structures. Optionally, a name of a compound may be generated using a chemical naming program: ACD/ChemSketch, Version 5.09/September 2001, Advanced Chemistry Development, Inc., Toronto, Canada.
As used in this application, the term "optionally substituted/' as used herein, means that substitution is optional and therefore it is possible for the designated atom to be unsubstituted. In the event a substitution is desired then such substitution means that any number of hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the noπnal valency of the designated atom is not exceeded, and that the substitution results in a stable compound. For example when a substituent is keto (i.e., =O), then 2 hydrogens on the atom are replaced. If no selection is provided then the substituent shall be selected from : aniline, anisole, benzene sulfonamide, cyano, carbocycle, heterocycle, halogen, hydroxy, NH2, NO2, Ci-βalkyl, d-ealkoxy, -C(=O)NH2, C(=O)OCH2CH3, -N(CH3)2, -(CH2)ι-3N(CH3)2, O(CH2)!-3OH, SCH3, NO2, CF3, alkenyl, alkynyl.
When any variable (e.g., R1, R7, Ra, Re etc.) occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-3 R1, then said group may optionally be substituted with 0,1, 2 or 3 R1 groups and Re at each occurrence is selected independently from the definition of Re. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds. In addition the range "according to claims 1-9" means claims 1, 2, 3, 4, 5, 6, 7, 8, or 9.
The compounds herein described may have asymmetric centers. Compounds of the present invention containing an asymmetrically substituted atom may be isolated in optically active or racemic foπns. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis from optically active starting materials. When required, separation of the racemic material can be achieved by methods known in the art. Many geometric isomers of olefins, C=N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms. All chiral, diastereomeric, racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomeric form is specifically indicated.
When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom on the ring. When a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of a given foπnula, then such substituent may be bonded via any atom in such substituent. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
As used herein, "alkyl" or "alkylene" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. For example, "Cι-6 alkyl" denotes alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t- butyl, pentyl, and hexyl. As used herein, "C]-3 alkyl", whether a terminal substituent or an alkylene group linking two substituents, is understood to specifically include both branched and straight-chain methyl, ethyl, and propyl.
As used herein, "alkenyl" or "alkenylene" is intended to include hydrocarbon chains of either a straight or branched configuration with one or more unsaturated carbon-carbon bonds that may occur at any stable point along the chain. Examples of "C3.6alkenyl" include, but are not limited to, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 3-methyl-2-butenyl, 2- pentenyl, 3-pentenyl, hexenyl, and the like.
As used herein, "alkynyl" or "alkynylene" is intended to include hydrocarbon chains of either a straight or branched configuration with one or more carbon-carbon triple bonds that may occur at any stable point along the chain, such as ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, and the like.
As used herein, "alkoxy" or "alkyloxy" represents an alkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t- butoxy, n-pentoxy, and s-pentoxy. Preferred alkoxy groups are methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy. Similarly, "alkylthio" or "thioalkoxy" represent an alkyl group as defined above with the indicated number of carbon atoms attached through a sulphur bridge.
As used herein, "carbocycle" is intended to mean any stable 3- to 7-membered monocyclic or bicyclic or 7- to 13-membered bicyclic or tricyclic, any of which may be saturated, partially unsaturated, or aromatic. Examples of such carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl, bicyclooctane, bicyclononane, bicyclodecane (decalin), bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, or tetrahydronaphthyl (tetralin).
As used herein, "halo" or "halogen" refers to fluoro, chloro, bromo, and iodo. "Counterion" is used to represent a small, negatively charged species such as chloride, bromide, hydroxide, acetate, sulfate, and the like. "Haloalkyl" is intended to include both branched and straight- chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with 1 or more halogen (for example ~CVFW where v=l to 3 and w=l to (2v+l)). Examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl, 2,2-difluoroethyl, heptafluoropropyl, and heptachloropropyl. "Haloalkoxy" is intended to mean a haloalkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge; for example trifluoromethoxy, pentafluoroethoxy, 2,2,2-trifluoroethoxy, and the like. "Halothioalkoxy" is intended to mean a haloalkyl group as defined above with the indicated number of carbon atoms attached through a sulphur bridge.
As used herein, the term "heterocycle" or "heterocyclic" refersto a ring-containing monovalent and divalent radicals having one or more heteroatoms, independently selected from N, O and S, as part of the ring structure and comprising at least 3 and up to about 20 atoms in the rings. Heterocyclic groups may be saturated or unsaturated, containg one or more double bonds, and heterocyclic groups may contain more that one ring. The heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. If specifically noted, nitrogen in the heterocycle may optionally be quaternized. It is understood that when the total number of S and O atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to one another.
Examples of heterocycles include, but are not limited to, lH-indazole, 2-pyrrolidonyl, 2H, 6H-1, 5,2-dithiazinyl, 2H-pyrrolyl, 3H-indolyl, 4-piperidonyl, 4aH-carbazole, 4H- quinolizinyl, 6H-1, 2,5-thiadiazinyl, acridinyl, azetidine, aziridine, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalonyl, carbazolyl, 4aH- carbazolyl, b-carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H- 1, 5,2-dithiazinyl, dioxolane, furyl, 2,3-dihydrofuran, 2,5-dihydrofuran, dihydrofuro[2,3- b]tetrahydrofuran, furanyl, furazanyl, homopiperidinyl, imidazolidine, imidazolidinyl, imidazolinyl, imidazolyl, lH-indazolyl, indolenyl, indolinyl, indolizinyl, indolyb isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, mo holinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxirane, oxazolidinylperimidinyl, phenanthridinyl, phenanthrolinyl, phenarsazinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, piperidonyl, 4-piperidonyl, purinyl, pyranyl, pyrrolidine, pyrroline, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, N-oxide-pyridinyl, pyridyl, pyrimidinyl, pyrrolidinone, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, carbolinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrazolyl, thiophane, thiophene. thiotetrahydroquinolinyl, 6H-1, 2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4- thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, thiirane, triazinyl, 1,2,3- triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, xanthenyl. As used herein, "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
As used herein, "pharmaceutically acceptable salts" refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of phaπnaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.
The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound that contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, the disclosure of which is hereby incorporated by reference.
"Prodrugs" are intended to include any covalently bonded carriers that release the active parent drug according to formula (I) in vivo when such prodrug is administered to a mammalian subject. Prodrugs of a compound of formula (I) are prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound. Prodrugs include compounds of formula (I) wherein a hydroxy, amino, or sulfhydryl group is bonded to any group that, when the prodrug or compound of formula (I) is administered to a mammalian subject, cleaves to forni a free hydroxyl, free amino, or free sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of formula (I), and the like.
"Stable compound" and "stable structure" are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
The compounds described herein may be provided or delivered in a form suitable for oral use, for example in a tablet, lozenge, hard and soft capsule, aqueous solution, oily solution, emulsion, and suspension. The compounds may also be provided for topical administration, for example, as a cream, ointment, gel, spray, or aqueous solutions, oily solutions, emulsions or suspensions. The compounds described herein may also be provided in a form suitable for nasal administration for example, as a nasal spray, nasal drops, or dry powder. The compositions may also be administered to the vagina or rectum in the form of a suppository. The compounds described herein may also be administered parentally, for example by intravenous, intravesicular, subcutaneous, intrathoracially, intracerebroventricularly, or intramuscular injection or infusion. The compounds may be administered by insufflation (for example as a finely divided powder). The compounds may also be administered transdermally, sublingually, . The compositions of the invention may accordingly 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. 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. The size of the dose for therapeutic or prophylactic purposes of a compound described herein will naturally vary according to the nature and severity of the conditions, the age and sex of the animal or patient and the route of administration, according to well known principles of medicine.
An effective amount of a compound described herein for use in therapy of Alzheimer's Disease is an amount sufficient to symptomatically relieve in a warm-blooded animal, particularly a human the cognitive symptoms, to slow the progression of worsening cognitive symptoms, or to reduce in patients with cognitive symptoms the risk of getting worse (progressing to dementia or worsening the present degree of dementia). For preparing pharmaceutical compositions from the compounds of this invention, inert, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets, and suppositories.
A solid carrier can be one or more substances, which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, or tablet disintegrating agents; it can also be an encapsulating material. In powders, the carrier is a finely divided solid that is in a mixture with the finely divided active component. In tablets, the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.
Salts include, but are not limited to, pharmaceutically acceptable salts. Examples of pharmaceutically acceptable salts of compounds of the present invention include but are not limited to the following: acetate, bicarbonate, bisulfate, bisulfite, carbonate, hydrobromide, hydrochloride, phosphate/diphosphate, sulfate, choline, diethanolamine, ethylenediamine, meglumine, aluminum, calcium, magnesium, nitrate, potassium, pyrosulfate, and sodium. The term composition is intended to include the foπnulation of the active component with encapsulating material as a carrier providing a capsule in which the active component (with or without other carriers) is surrounded by a carrier which is thus in association with it.
Similarly, cachets are included. Tablets, powders, cachets, and capsules can be used, as solid dosage forms suitable for oral administration.
Liquid form compositions include solutions, suspensions, and emulsions. Sterile water or water-propylene glycol solutions of the active compounds may be mentioned as an example of liquid preparations suitable for parenteral administration. Liquid compositions can also be formulated in solution in aqueous polyethylene glycol solution. Aqueous solutions for oral administration can be prepared by dissolving the active component in water and adding suitable colorants, flavoring agents, stabilizers, and thickening agents as desired. Aqueous suspensions for oral use can be made by dispersing the finely divided active component in water together with a viscous material such as natural synthetic gums, resins, methyl cellulose, sodium carboxymethyl cellulose, and other suspending agents known to the pharmaceutical formulation art. The pharmaceutical compositions can be in unit dosage form. In such form, the composition is divided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of the preparations, for example, packeted tablets, capsules, and powders in vials or ampoules. The unit dosage form can also be a capsule, cachet, or tablet itself, or it can be the appropriate number of any of these packaged forms. Synthesis
The compounds of the present invention can be prepared in a number of ways well known to one skilled in the art of organic synthesis. The compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. Such methods include, but are not limited to, those described below. All references cited herein are hereby incorporated in their entirety by reference.
The novel compounds of this invention may be prepared using the reactions and techniques described in this application. The reactions are performed in solvents appropriate to the reagents and materials employed and are suitable for the transfoπnations being effected. Also, in the description of the synthetic methods described below, it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and workup procedures, are chosen to be the conditions standard for that reaction, which should be readily recognized by one skilled in the art. It is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the molecule must be compatible with the reagents and reactions proposed. Such restrictions to the substituents, which are compatible with the reaction conditions, will be readily apparent to one skilled in the art and alternate methods must then be used.
An example of such a process is illustrated herein. Method C-1
Figure imgf000033_0001
1c
Figure imgf000033_0002
1d Method C-2
Figure imgf000033_0003
1 b 1d
Examples
Chemical abbreviations used in the Examples are defined as follows: "BOC" denotes N-tert- butoxycarbonyl, "CBZ" denotes carbobenzyloxy; "DBU" denotes 1,8-diazabicyclo [5.4.0] undec-7-ene; "DCM" denotes dichloromethane; "DMAP" denotes 4-dimethylaminopyridine trifluoroacetic acid; "DMF" denotes N, N-dimethylformamide; DME denotes ethylene glycol dimethyl ether; DIEA denotes diisopropylethylamine; KOtBu denotes potassium tert- butoxide; Et2O denotes diethyl ether, MeOH deontes methyl alchol, iPrOH deontes isopropyl alcohol; "EDAC-HC1" or EDCI denotes l-Ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride; "HOBt" denotes hydroxybenzotriazole; "NMM" denotes N- methylmorpholine; "p-TSA" denotes p-toluenesulfonic acid "TBAB" denotes tetrabutylammonium bromide; "TEA" denotes triethylamine; "TFA" denotes triflouroacetic acid; "THF" denotes tetrahydrofuran, "PS" denotes polystyrene, Tos-Cl denotes p- toluenesulfonyl chloride, "min." denotes minutes; "h" denotes hours; "RT" denotes room temperature. Unless otherwise noted, organic solutions were "dried" over anhydrous sodium sulfate.
LC/MS HPLC method: Agilent Zorbax 5μ SB-C8 column 2.1mm x 5 cm. Solvents: A = H2O with 0.05% TFA, B =10% H2O, 90% Acetonitrile, 0.05% TFA. Gradient: (10-90%B over 3 min., 90% B hold thru 4 min., -10% B at 5 min. and hold at 10% B until 6 min).
Example 1. Methyl N-{4-r(3-fluorophenvI)aminol-6-r(2-hydroxypropyI)aminol-1 .5- triazin-2-v -L-Ieucinate (1)
Figure imgf000034_0001
Figure imgf000034_0002
Example 1 To a stirred solution of cyanuric chloride (la) (2.23 g, 12.1 mmol) in THF (50 mL) was added 3-fluoroaniline (1.17 mL, 12.1 mmol) and DIEA (8.4 mL, 48.4 mmol). The mixture was stirred for 1 hour, leucine methyl ester hydrochloride (2.23 g, 21.1 mmol) was added and the solution heated to reflux for 4 h. The mixture was cooled to room temperature and the solvent removed in vacuo. The residual oil was partitioned between CH2C12 and IN HCl (100 mL). The organic layer was separated, washed with NaCl (sat.) and dried over Na2S0 . The volatiles were removed to give lb as a crude foam (3.38 g, 76%). A portion of the resultant material (2.16 g, 4.1 mmol) was dissolved in DMF (30 mL) and to this was added PS-HOBT (3.38 g, 4.1 mmol), followed by DIEA (1.05 mL, 5.8 mmol). The suspension was slowly stirred at 90° C for 2h. The resin was filtered and washed with CH2C12 (3 x 100 mL), then Et2O (1 x 100 mL) and dried in vacuo to give a yellow, free-flowing resin lc (4.84 g). A portion of the resultant resin (0.200 g) was added to PS-DIEA (0.200 g, 4 mmol/g) in THF (1.5 mL). To this suspension was added 2-hydroxyaminopropane and the mixture was heated to 160 °C for five minutes in a Personal Chemistry Smithsynthesizer microwave reactor. The reaction was filtered, washed with CH2C12, and the solvent was removed in vacuo to give the title compound 1 as a white foam (0.041 g). !H NMR (300 MHz, OMSO-d6) δ 0.88-0.92 (m, 6H), 1.05-1.07 (m, 3H), 1.48-1.52 (m, 1H), 1.72-1.75 (m, 2H), 3.22-3.27 (m, 1H), 3.59-3.61 (m, 3H), 3J7-3.81 (m, 1H), 4.44-4J8 (m, 2H), 7.18-7.25 (m, 2H), 7.39-7.44 (m, 1H), 7.82- 7.95 (m, 1H), 9.01-9.11 (m, 1H), MS APCI, m/z = 407(M+1). LC/MS tR = 2.11 min. By analogy. Examples 2-26 (Table 1) were prepared according to general method A. Table 1. Method A, General Procedure for Examples 1-26 Method A
Figure imgf000036_0001
1c
Figure imgf000036_0002
1d
Figure imgf000036_0003
Figure imgf000037_0001
Figure imgf000038_0001
Figure imgf000039_0001
Example 27. Methyl N-{4-(4-methoxyphenoxy)-6-f(thien-2-ylmethyl)amino1-l,3.5- triazin-2-yl}-L-leucinate (27).
Figure imgf000040_0001
27
A portion of methyl N-[4-chloro-6-(4-methoxyphenoxy)-l,3,5-triazin-2-yl]-L-leucinate 27a (0.70 g, 1.8 mmol) was dissolved in DMF (5 mL) and to this was added PS-HOBT (1.00 g, 1.4 mmol), followed by DIEA (0.6 mL). The suspension was carefully stirred at 90° C for 2h. The resin was filtered and washed with CH2C12 (3 x 100 mL), then Et2O (1 x 100 mL) and dried in vacuo to give a yellow free-flowing resin (1.65 g). A portion of the resultant resin (0.225 g) was added to PS-DIEA (0.200 g, 4 mmol/g) in THF (1.5 mL). To this suspension was added thiophene-2-methylamine (0.014 g, 0.12 mmol) and the mixture was heated to 160° C for five minutes in a Smithsynthesizer microwave reactor vessel. The reaction was filtered, washed with CH2C12, and the solvent was removed in vacuo to give the title compound 27 as a white foam (0.038 g). Η ΝMR (300 MHz, DMSO-cfø) δ 0.82-0.88 (m, 6H), 1.40-1.46 (m, 1H), 1.62-1.66 (m, 2H), 3.57 (s, 3H), 3.74 (s, 3H), 4.49-4.58 (m, 3H), 6.90-6.92 (m, 4H), 7.02-7.08 (m, 2H), 7.33 (m, IH), 1.14-1.16 (m, IH). MS APCI, m/z = 458 (M+l). LC/MS tR = 2.71 min.
Intermediate 27b was prepared by analogy to Example 1, except 4-methoxyphenol was used in the presence of a suitable base, such as potassium carbonate, sodium hydride or potassium tert-butoxide.
By analogy Examples 28-37 (Table 2) were prepared. Method B
Figure imgf000041_0001
1a 1b
Figure imgf000041_0002
1c
Figure imgf000041_0003
Table 2. Method B, General Procedure for Examples 27-37.
Figure imgf000042_0001
Figure imgf000043_0003
Example 38. Synthesis of Methyl N-{4-[(3-fluorophenyπamino1-6-[(4- methoxyphenyl)thio1-l.,3.,5-triazin-2-yl}g-vcinate ('38).
Figure imgf000043_0001
38b
Figure imgf000043_0002
Example 38 A portion of 4-chloro-N-(3 -fluoropheny l)-6- [(4-methoxypheny l)thio]-l ,3,5-triazin-2-amine 38a (0.65 g, 1.7 mmol) was dissolved in DMF (10 mL) and to this was added PS-HOBT (1.00 g, 1.4 mmol), followed by DIEA (0.60 mL, 3.3 mmol). The suspension was carefully stirred at 90° C for 2h. The resin was filtered and washed with CH2C12 (3 x 100 mL), then Et2O (1 x 100 inL) and dried in vacuo to give a yellow free-flowing resin 38b (1.19 g). A portion of the resultant resin (0.200 g) was added to PS-DlEA (0.200 g, 4 mmol/g) in THF (1.5 mL). To this suspension was added glycine methyl ester hydrochloride and the mixture was heated to 160° C for five minutes in a Smithsynthesizer microwave reactor vessel. The reaction was filtered, washed with CH2C12, and the solvent was removed in vacuo to give the title compound, Example 38, as a white foam (0.036 g). Η NMR δ (300 MHz, DMSO- , 300K) 3.59-3.62 (br s, 3H), 3.81 (s, 3H), 3.99 (br s, 2H), 6.72 (m, IH), 7.01 (app t, 2H, J = 8.1 Hz), 7.16-7.24 (m, 3H), 7.44 (d, 1/2H, J= 8.1 Hz), 7.51 (d, 1/2H, J = 8.1 Hz), 7.92 (br s, IH), 9.71 (br, s IH). 1H NMR (300 MHz, OMSO-d6, 363K) δ 3.62 (s, 3H), 3.81 (s, 3H), 3.94 (br s, 2H), 6.69 (app t, IH, J = 9.0 Hz), 6.99 (d, 2H, J = 9.0 Hz); 7.14 (dd, IH, J = 6.0, 7.5 Hz), 7.25 (br s, IH), 7.45-7.51 (m, 3H), 9.36 (br, s IH). APCI, m/z = 416 (M+l). LC/MS tR = 2.62 min.
Synthesis of 4-ChIoro-N-(3-fluorophenyl)-6-[(4-methoxyphenyl)thiol-l,3,5-triazin-2- amine (38a). To a stirred solution of cyanuric chloride (la) (1.11 g, 6.0 mmol) in THF (50 mL) was added 3-fluoroaniline (0.43 mL, 6.0 mmol) and DIEA (0.62 mL, 6.6 mmol). The mixture was stirred for 1 hour, 4-methoxybenzenethiol (0.74 g, 6 mmol) was added and the solution heated to reflux overnight. The mixture was cooled to room temperature and the solvent removed in vacuo. The residual oil was partitioned between CH2C12 and IN HCl (100 mL). The organic layer was separated, washed with NaCl (sat.) and dried over Na2SO . The residual oil was chromatographed (10:1 hexanes/ethyl acetate) to give 4-chloro-N-(3-fluorophenyl)-6-[(4- methoxyphenyl)thio]-l ,3,5-triazin-2-amine 38a (2.0 g, 92%). 1H MR (300 MHz, DMSO- d6, 300K) δ 6.12-6.11 (m, 2H), 6.99 (d, 2H, J = 8.4 Hz), 7.01-7.07 (m, IH), 7.19-7.23 (m, 2H), 7.51 (d, 2H, J = 8.4 Hz). APCI, m/z = 363, 365 (M+l). LC/MS tR = 2.87 min. Example 39. (2R)-2-({4-f(5-Chloro-2-methylphenvπaminol-6-f(4-methoxyphenyl thio1- 1.3,5-triazin-2-v amino)-4-methylpentan-l-ol.
Figure imgf000045_0001
Example 39
A portion of 4-chloro-N-(5-chloro-2-methylphenyl)-6-[(4-methoxyphenyl)thio]-l,3,5-triazin-
2-amine 39a (0.325 g, 0.86 mmol) was dissolved in THF (10 mL) and to this was added DIEA (0.181 mL, 1.03 mmol) and 2-(R)-4-methylpentan-l-ol (0.10 g, 0.86 mmol). The solution was refluxed for 4h, cooled and the solvent removed in vacuo. The residual oil was chromatographed (SiO2), using hexanes/ethyl acetate (80/20) to obtain the title compound 39 as a white foam (0.036 g, 8%). 1H ΝMR (300 MHz, DMSO-do', 363K) δ 0.76 (d, 3H, J = 6.6
Hz), 0.79 (d, 3H, J = 6.6 Hz), 1.26-1.29 (m, 3H), 2.13 (s, 3H), 3.29-3.32 (m, 2H), 3.77 (s, 3H). 4.15-4.18 (m, IH), 6.60-6.62 (m, IH), 6.78-6.80 (m, IH), 6.90 (d, 2H, J = 8.7 Hz), 7.03
(dd, IH, J = 2.0, 8.1 Hz), 7.13 (d, IH, J = 8.1 Hz), 7.20-7.23 (m, IH), 7.40-7.43 (m, 2H),
8.30-8.35 (m, IH). APCI, m/z = 475 (M+l).
Synthesis of 4-chloro-N-(5-Chloro-2methylphenyl>-6-[(4-methoxyphenyl)thioI-l,3,5- triazin-2-amine (39a). Synthesis of the title compound 39a was analogous to the synthesis of 4-chloro-N-(3- fluorphenyl)-6-[(4-methoxyphenyl)thio]-l,3,5-triazin-2-amine 38a, except, 5-chloro-2-methyl aniline was used in place of 3-fluoroaniline.
By analogy. Examples 40-52 (Table 3) were prepared. Method C-1
Figure imgf000046_0001
1c
Figure imgf000046_0002
1d Method C-2 s-R3 a) R4R5NH R4-κ DIEA (2.2 eq), THF N,"R5 IA Relfux 4 h _
R ΛNΛ , R1^NΛ ΛS'R3 R2 R2 1b 1d
Table 3. Method C-1 and C-2. General Procedure for Examples 38-52.
Figure imgf000047_0001
Figure imgf000048_0001
Example 53. Methyl N-(4-[(2,3-dihydroxypropyl)thiol-6-[(3-fluorophenyl)amino1-1.3,5- triazin-2-yll-L-leucinate (53).
Figure imgf000049_0001
53
To solution of 4-methoxybenzenethiol (0.40 mmol) dissolved in DME (1.5 mL) was added potassium tert-butoxide (0.048 g, 0.42 mmol). A portion of methyl N-{4-chloro-6-[(3- fluorophenyl)amino]-l,3,5-triazin-2-yl}-L-leucinate 53a (0.150 g, 0.40 mmol) was added and the suspension was heated to 180° C for five minutes in a Smithsynthesizer microwave reactor vessel. The solvent was removed in vacuo and the residual oil was chromatographed (SiO2), using a gradient of CH2Cl2/MeOH (100/0 to 90/10) to give the title compound 53 as a white foam (0.036 g). ]H ΝMR (300 MHz, OMSO-d6, 363K) δ 0.89 (d, 3H, J= 6.0 Hz), 0.92 (d, 3H, J = 6.0 Hz), 1.61-1.11 (m, 3H), 3.10-3.14 (m, IH), 3.31-3.35 (m, IH), 3.38-3.43 (m, 2H), 3.62 (s, 3H), 3J1-3J4 (m, IH), 4.20-4.25 (m, IH), 4.50-4.55 (m, 2H), 6.74 (app t, IH, J = 7.17 Hz), 7.25 (dd, IH, J = 7.6, 15.6 Hz), 7.42-7.44 (m, IH), 7.59-7.63 (m, 2H), 9.35-9.38 (m, IH). APCI, m/z = 440 (M+l). LC/MS tR = 2.31 min. Alternatively, these reactions were carried out in refluxing THF or DME for 18 hours with comparable reaction yields to the ones stated above. Furthermore, bases such as K2CO3 or DIEA were used under these conditions with no noticeable loss in reaction yield. Synthesis of Methyl N-{4-chloro-6-[(3-fluorophenyl')aminol-l,3-5-triazin-2-vU-L- leucinate (53a). To a stirred solution of cyanuric chloride la (3.45 g, 18.7 mmol) in THF (80 mL) was added 3-fluoroaniline (1.82 mL, 18.7 mmol) and DIEA (4.89 mL, 28.0 mmol). The mixture was stirred for 1 hour, L-leucine methyl ester hydrochloride (3.39 g, 18.7 mmol) was added, followed by DIEA (4.89 mL, 28.0 mmol) and the solution heated to reflux for one hour. The mixture was cooled to room temperature and the solvent removed in vacuo. The residual oil was partitioned between CH2C1 and IN HCl (200 mL). The organic layer was separated, washed with NaHCO3 (sat.), NaCl (sat.) and dried over Na2SO4. The residual oil was used as is without purification. By analogy Examples 54-64 were prepared.
Cl
Figure imgf000050_0001
R5SH, KOtBu,
Figure imgf000050_0002
or 1c R5SH, K2C03, THF reflux, 18 h
Table 4. Method D, General Procedure for Examples 53-64.
Figure imgf000051_0001
Figure imgf000052_0002
Example 65. Methyl N-{4-r(3-fluorophenvπamino1-6-r(4-methoxyphenvπsulfinyn-l,3,5- triazin-2-yl}-L-leucinate (65).
Figure imgf000052_0001
To a stirred solution of methyl N-{4-[(3-fluorophenyl)amino]-6-[(4-methoxyphenyl)thio]- 1,3, 5 -triazin-2-yl} -L-leucinate 41 (0.500 g, 1.3 mmol) in CH2C12 at 0° C, was added m- chloroperoxybenzoic acid (0.300 g, 60%, 1 mmol). The reaction was stirred for 30 minutes, and then quenched with a 10% solution of Νa2S2O3. The organic layer was separated and then washed with NaHC03 (sat.), followed by NaCl (sat.). The solvent was dried over Na2SO , filtered and concentrated to give a yellow oil. The material was chromatographed (SiO2) using hexanes/ethyl acetate (80/20 to 50/50 gradient) to give the title compound 65 as a white solid (0.15 g, 23%). H NMR (300 MHz, DMSO- fj, 363K) δ 0.88-0.91 (m, 6H), 1.60- 1.73 (m, 3H), 3.58 (s, 3H), 3.80 (s, 3H), 4.47-4.52 (m, IH), 6.79 (app t, IH, J = 6.0 Hz), 7.08 (d, IH, J = 7.8 Hz), 7.27 (dd, IH, J = 7.5 Hz, 15.3 Hz), 7.40-7.45 (m, IH), 7.63-7.69 (m, 3H), 8.30-8.35 (m, IH), 9,96-9.99 (m, IH). APCI, m/z = 488 (M+l). LC/MS tR = 2.67 min. Example 66. Methyl N-{4-f(3-fluorophenyl)amino]-6-[(4-methoxyphenyl)sulfonyIl-l,3,5- triazin-2-v -L-leucinate (66).
Figure imgf000053_0001
To a stirred solution of methyl N-{4-[(3-fluorophenyl)amino]-6-[(4-methoxyphenyl)thio]- l,3,5-triazin-2-yl}-L-leucinate 41 (0.500 g, 1.3 mmol) in CH2C12 at 0° C, was added m- chloroperoxybenzoic acid (0.800 g, 60%, 2.6 mmol). The reaction was stirred for 2 hours, and then quenched with a 10% solution of Νa2S2O3. The organic layer was separated and then washed with NaHCO3 (sat.), followed by NaCl (sat.). The solvent was dried over Na2SO , filtered and concentrated to give a yellow oil. The material was chromatographed (SiO ) using hexanes/ethyl acetate (80/20) to give the title compound 66 as a white solid (0.045 g, 7%). APCI, m/z = 504 (M+l). LC/MS tR = 2.86 min. Example 67. Methyl N-[4-f(3-fluorophenvπaminol-6-(4-methoxyphenyl)-l,3,5-triazin-2- yll-L-leucinate (67).
3-fluoroaniline TTHHFF,, RRTT,, 22hh
Figure imgf000053_0002
Figure imgf000053_0003
1a 67a 67b
Figure imgf000053_0004
67b Example 67 To a stirred solution of 4-chloro-N-(3-fluorophenyl)-6-(4-methoxyphenyl)-l,3,5-triazin-2- amine 67b (0.30 g, 0.9 mmol) in THF (10 mL) was added leucine methyl ester hydrochloride (0.16 g, 0.9 mmol) and DIEA (1.8 mmol) and the reaction was heated to 60° C for 18 hours. The reaction was concentrated and the residual oil chromatographed (SiO2, hexanes/ethyl acetate, gradient 95/5 to 90/10) to give the title compound 67 as a white solid (0.065 g, 19%). 'HΝMR (300 MHz, CDC13, 300K) δ 0.94-0.96 (br s, 6H), 1.63-1.80 (m, 3H), 3.73 (s, 1.5H), 3.76 (s, 1.5H), 3.85 (s, 1.5H), 3.87 (s, 1.5H), 4.70-4.76 (m, IH), 4.92-4.97 (m, IH), 6.00-6.10 (m, 0.5H), 6.70-6.76 (m, IH), 6.93-6.98 (m, 2H), 7.22-7.36 (m, 2H), 7.72-7.78 (m, 2H), 8.22 (d, IH, J = 8.7 Hz), 8.36 (d, IH, J = 8.7 Hz). APCI, m/z = 440 (M+l). LC/MS tR = 3.10 min. Alternatively, the final compounds can be made in an analogous fashion to Example 1, using the PS-HOBT resin.
Synthesis of 4-chloro-N-(3-fluorophenyl)-6-(4-methoxyphenylV1.3,5-triazin-2-amine 67b. To a cold (0° C), stirred solution of 2,4-dichloro-6-(4-methoxyphenyl)-l,3,5-triazine 67a (1.28 g, 5.0 mmol) in THF (30 mL) was added DIEA (0.87 mL, 8.03 mmol), followed by 3- fluoroaniline (0.55 g, 5.0 mmol). The reaction was stirred for 2 hours at room temperature, concentrated and then partitioned between ethyl acetate (100 mL) and 1 Ν HCl (100 mL). The organic layer was washed with ΝaCl (sat.), dried and the solvent removed to give a tan solid (1.4 g, 85%). The material was used in the next reaction without further purification. Synthesis of 2,4-dichloro-6-(4-methoxyphenvD-l,3-5-triazine 67a.
To a cold (0° C), stirred solution of cyanuric chloride la (1.09 g, 5.8 mmol) in benzene (20 mL) was slowly added 4-methoxyphenylmagnesium bromide (14.13 mL, 0.5 M in ether, 5.0 mmol). The reaction was stirred for 30 minutes at 0 °C, and then quenched with ΝH4C1 (sat.) (20 mL). The reaction was diluted with diethyl ether (100 mL), washed with NaCl (sat.), and then dried over MgSO4. The volatiles were removed to give a colorless oil (1.27 g, 85%). The material was used without further purification in the next reaction. Example 68. Synthesis of methyl N-r4-r(3-fluorophenvDamino1-6-(4-methoxybenzyl)- 1.3.5-triazin-2-vn-L-leucinate (68).
Figure imgf000055_0001
68a 68
The title compound was prepared in analogous fashion to methyl N-[4-[(3- fluorophenyl)amino]-6-(4-methoxyphenyl)-l,3,5-triazin-2-yl]-L-leucinate 67, except 4- methoxybenzyl magnesium chloride was used as the starting Grignard reagent. See Table 5 for analytical data. Examples 69-71 were prepared in analogous fashion to Example 1, using HOBT resin.
Figure imgf000055_0002
X = CI or HOBT resin n = 0,1
Table 5. Method E, General Procedure for Examples 67-71
Figure imgf000056_0001
Example 72. N1-r2-(DimethyIamino)ethyn-N2-{4-r(3-fluorophenynamino1-6-r(4- methoxyphenyl)thio1-l,3,5-triazin-2-vU-L-leucinamide (72).
Figure imgf000057_0001
To a cold (-15° C), stirred solution of N-{4-[(3-fluorophenyl)amino]-6-[(4- methoxyphenyl)thio]-l,3,5-triazin-2-yl}-L-leucine 72a (0.100 g, 0.21 mmol) dissolved in DMF (1.5 mL) or CH2C12 was added Ν-methyl morpholine (0.027 mL, 0.24 mmol), followed by isobutyl chloroformate (0.032 mL, 0.24 mmol). The reaction was stirred for five minutes, then Ν,Ν-dimethyl ethlyenediamine (0.026 mL, 0.24 mmol) was added. The reaction was stirred overnight, concentrated and chromatographed (SiO , CH2Cl2/MeOH, gradient, 100/0 to 95/5) to give the title compound 72 as a white foam (0.020 g, 17%). 1H NMR (300 MHz, CDC13, 300K) δ 0.79-.89 (m, 6H), 1.50-1.59 (m, 3H), 2.09 (s, 3H), 2.15 (s, 3H), 2.25-2.30 (m, 2H), 3.09-3.15 (m, 2H), 3.55 (t, IH, J = 4.8 Hz), 3.81 (br s, 3H), 6.69-6.74 (br s, IH), 7.00- 7.05 (m, 2H), 7.10-7.15 (m, IH), 7.25-7.30 (m, IH), 7.48-7.52 (m, 2H), 7.56-7.68 (m, IH), 9.58-9.62 (m, IH). APCI, m/z = 528 (M+l). LC/MS tR = 2.48.
N-{4-[(3-Fluorophenyl)amino1-6-[(4-methoxyphenyl)thiol-1.3,5-triazin-2-yl}-L-leucine (72a). To a stirred solution of methyl N-{4-[(3-fluorophenyl)amino]-6-[(4-methoxyphenyl)thio]- l,3,5-triazin-2-yl}-L-leucinate 41 (10.1 g, 21.4 mmol) in THF (50 mL), MeOH (50 mL) and H20 (50 mL) was added LiOH (2.25 g, 53.5 mmol). The reaction was stirred at room temperature for 2 hours. The material was concentrated and then partitioned between 1 Ν HCl and CH2C12. The organic layer was dried over MgSO4 and evaporated to give the title compound 72a as a white solid (9.4 g, 96%). APCI, m/z = 472 (M+l). LC/MS tR = 3.01. By analogy Examples 73-90 were prepared fromN-{4-[(3-fluorophenyl)amino]-6-[(4- methoxyphenyl)thio]-l ,3,5-triazin-2-yl}-L-leucine (72a).
Figure imgf000058_0001
Table 6. Method F, General Procedure for Examples 72-90
Figure imgf000059_0001
Figure imgf000060_0001
Figure imgf000061_0001
Figure imgf000062_0006
Example 91; Methyl N-f2-r(3-fluorophenyl)amino1-6-f(4- methoxyphenyl)thio1pyrimidin-4-yl}-L-leucinate (91).
Figure imgf000062_0001
91a 91b 91c
Figure imgf000062_0002
KOtBu, DME
Figure imgf000062_0004
relfux
Figure imgf000062_0003
91b 91d 91e
Figure imgf000062_0005
Example 91
To an equimolar mixture of methyl N-{2-chloro-6-[(4-methoxyphenyl)thio]pyrimidin-4-yl}- L-leucinate 91d and methyl N-{6-chloro-2-[(4-methoxyphenyl)thio]pyrimidin-4-yl}-L- leucinate 91e (0.412 g, 1.04 mmol) was added 3-fluoroaniline (0.75 mL, 7.5 mmol) and the mixture heated to 145° C for 30 minutes. The reaction was cooled and chromatographed (SiO2) using hexanes/ethyl acetate (gradient 90/10-70/30) to give the title compound 91 as a white foam (0.036 g, 14%). 1H NMR (300 MHz, CDC13, 300K) δ 0.92 (d, 3H, J = 6.0 Hz), 0.94 (d, 3H, J = 6.0 Hz), 1.55-1.66 (m, 3H), 3.69 (s, 3H), 3.87 (s, 3H), 4.69-4.71 (m, 2H), 5.36 (s, IH), 6.63 (app t, IH, J = 6.3 Hz), 6.84 (s, IH), 6.97 (d, 2H, J = 8.7 Hz), 7.14 (dd, IH, J = 8.4, 15 Hz), 7.48-7.55 (m, 3H). APCI, m/z = 471 (M+l). LC/MS tR = 3.06 min. Assignment of this isomer was established using NOE studies. Synthesis of Methyl N-{2-chloro-6-r(4-methoxyphenv0thioIpyrimidin-4-v -L-leucinate (91d) and methyl N-{6-chloro-2-r(4-methoxyphenyl)thiolpyrimidin-4-yl}-L-leucinate (91e
To a solution of 4-methoxybenzenethiol (0.577 mL, 4.69 mmol) in DME (10 mL) was added potassium tert-butoxide (0.534 g, 4.69 mmol) and the reaction stirred for five minutes. To this was added methyl N-(2,6-dichloropyrimidin-4-yl)-L-leucinate 91b (1.37 g, 4.69 mmol). The mixture was refluxed for one hour, cooled and then the solvents removed in vacuo. The residual oil was chromatographed to give a 1 :1 mixture of the title compounds. The mixture was used without further purification.
Synthesis of Methyl N-(2,6-dichloropyrimidin-4-v0-L-leucinate (91b) and methyl N-(4,6- dichloropyrimidin-2-vD-L-leucinate (91c). To a stirred solution of 2,4,6 -trichloropyrimdine 91a (1.50 g, 8.2 mmol) in z-PrOH (30 mL) was added leucine methyl ester hydrochloride (1.5 g, 8.2 mmol) and DIEA (16.4 mmol) and the mixture was refluxed for 1 hour. The solvent was removed in vacuo and the residual oil chromatographed (SiO2) using hexanes/ethyl acetate gradient (100/0 to 90/10) to give methyl N-(4,6-dichloropyrimidin-2-yl)-L-leucinate 91c (0.500 g, 21%) and methyl N-(2,6- dichloropyrimidin-4-yl)-L-leucinate 91b (1.3 g, 54%) as white foams. Example 92. Methyl N-f4-lϊ3-fluorophenyl)amino1-6-IT4- methoxyphenvDthiol yrimidin-2-yl)-L-leucinate (92).
Figure imgf000064_0001
91c 92a
Figure imgf000064_0002
Example 92
To a solution of 4-methoxybenzenethiol (0.197 g, 1.41 mmol) in DME (3 mL) was added potassium tert-butoxide (0.160 g, 1.41 mmol) and the reaction stirred for five minutes. To this was added methyl N-(4,6-dichloropyrimidin-2-yl)-L-leucinate 91c (0.410 g, 1.41 mmol). The mixture was refluxed for one hour, cooled and then the solvents removed in vacuo. The residual oil was partitioned between CH C12 and ΝaCl (sat), and then the organic layer was collected and dried over Νa2SO4. The crude oil was dissolved in 3-fluoroaniline (1.0 mL) and the reaction heated to 145° C for 30 minutes. The reaction was cooled and chromatographed (Si02) using hexanes/ethyl acetate (100/0 to 80/20 gradient) to isolate the title compound 92 as a white solid (0.138 g, 20%). 1H NMR (300 MHz, CDC13, 300K) δ
0.92 (d, 3H, J = 6.0 Hz), 0.94 (d, 3H, J = 6.0 Hz), 1.59-1.65 (m, 2H), 1.70-1.79 (m, IH), 3.69 (s, 3H), 3.85 (s, 3H), 4.60-4.64 (m, IH), 5.16 (d, IH, J = 8.1 Hz), 5.40 (s, IH), 6.25 (s, IH), 6.70 (app t, IH, J = 6.3 Hz), 6.85 (d, IH, J = 8.1 Hz), 6.95 (d, 2H, J = 8.7 Hz), 7.12-7.17 (m, 2H), 7.50 (d, IH, J = 8.7 Hz). APCI, m/z = 471 (M+l). LC/MS tR = 2.84 min. Assignment of this isomer was confirmed by NOE studies.
Example 93. N-{4-[(3-Fluorophenyπamino1-6-[(4-methoxyphenyl)thio1pyrimidin-2-y - leucine (93).
Figure imgf000064_0003
92 Example 93 To a stirred solution of methyl N-{4-[(3-fluorophenyl)amino]-6-[(4- methoxyphenyl)thio]pyrimidin-2-yl} -L-leucinate 92 (0.100 g, 0.21 mmol) in MeOH (1 mL) was added THF (1 mL) and 1 Ν ΝaOH (0.30 mL). The reaction was stirred for 2 hours, then quenched with 1 Ν HCl (1 mL). The volatiles were removed in vacuo and the material dried by azeotropic removal using toluene. The residual material was recrystallized using hexanes/ethyl acetate (80/20) to give the title compound 93 as a white solid (0.058 g, 61%). 1H ΝMR (300 MHz, OMSO-d6, 300K) δ 0.85 (d, 3H, J = 6.0 Hz), 0.93 (d, 3H, J = 6.0 Hz), 1.58-1.74 (m, 3H), 3.83 (s, 3H), 4.34 (m, IH), 5.45 (br s, IH), 6.10-6.11 (m, IH), 7.10-7.15 (m, 2H), 7.19-7.26 (m, 2H), 7.50-7.56 (m, 3H). APCI, m/z = 457 (M+l). LC/MS tR = 2.50 min.
Example 94. N-{4-f(3-Fluorophenyl)(methyl)aminol-6-r(4- methoxyphenyl)thio1pyrimidin-2-yl}-L-leucine (94).
Figure imgf000065_0001
92 Example 94 To a cold (0° C) stirred solution of methyl N-{4-[(3-fluorophenyl)amino]-6-[(4- methoxyphenyl)thio]pyrimidin-2-yl}-L-leucinate 92 (0.100 g, 0.21 mmol) in THF was added ΝaH (60% in mineral oil, 0.008 g, 0.21 mmol) and the reaction stirred for five minutes. To this was added methyl iodide (0.013 mL, 0.21 mmol) and the reaction stirred for 30 minutes. The reaction was diluted with CH2C1 and washed with ΝaCl (20 mL) (sat) containing five drops of IN HCl. The organic layers were collected and dried over Νa SO and the solvents removed in vacuo. The residual oil was chromatographed to give the title compound 94 as a white foam (0.18 g, 18%). !H NMR (300 MHz, CDC13, 300K) δ 0.92 (d, 3H, J = 6.0 Hz), 0.95 (d, 3H, J = 6.0 Hz), 1.62-1.64 (m, 2H), 1.73-1.77 (m, IH), 3.30 (s, 3H), 3.69 (s, 3H), 3.80 (s, 3H), 4.56-4.59 (m, IH), 5.06-5.11 (m, 2H), 6.69-6.84 (m, 4H), 7.12-7.20 (m, 2H), 7.37 (d, 2H, J = 8.1 Hz). APCI, m/z = 485 (M+l). LC/MS tR = 3.13 min.
Example 95. N-{4-Chloro-6-[(4-methoxyphenyl)thiolpyrimidin-2-yl}-N-methvI-leucine (95).
Figure imgf000066_0001
92a THF Example 95
To a stirred solution of methyl N-{4-chloro-6-[(4-methoxyphenyl)thio]pyrimidin-2-yl}-N- methyl-L-leucinate (0.200 g, 0.48 mmol) in MeOH (1 mL) was added tetrahydrofuran (1 mL) and 1 Ν ΝaOH (1.4 mL, 1.4 mmol). The reaction was stirred at 50° C for lh. The volatiles were removed and the reaction was quenched with 1 Ν HCl (1.6 mL). The aqueous phase was extracted with CH2C12 and then washed with ΝaCl (sat.). The volatiles were removed and the resultant oil was chromatographed (SiO , CH2Cl2/MeOH, gradient 100/0 to 90/10) to give 95 as a white foam. Η ΝMR (300 MHz, CDC13, 300K) δ 0.85 (br s, 3H), 0.91 (d, IH, J = 6.0 Hz), 1.45-1.49 (m, IH), 1.73-1.78 (m, 2H), 3.02 (s, 3H), 3.85 (s, 3H), 5.26-5.32 (m, IH), 6.10-6.14 (m, IH), 6.95 (d, 2H, J = 8.7 Hz), 7.46 (d, 2H, J = 8.7 Hz). APCI, m/z = 396 (M+l). LC/MS tR = 3.32 min.
Synthesis of Methyl N-{4-chloro-6-f(4-methoxyphenyl)thiolpyrimidin-2-yll-N-methyl-L- leucinate. To a cold (0° C), stirred solution of methyl N-{4-chloro-6-[(4-methoxyphenyl)thio]pyrimidin- 2-yl} -L-leucinate 92a (0.210 g, 0.50 mmol) in DMF (0.40 mL) was added sodium hydride (0.022 g, 60% in mineral oil, 0.51 mmol). The reaction was stirred for five minutes, and methyl iodide (0.034 mL, 0.51 mmol) was added. The reaction was stirred for thirty minutes, and then diluted with CH2C12 (50 mL). The organic layers were washed with ΝaCl (sat. 50 mL) containing two drops of IN HCl. The organic layer was separated and dried over Νa2SO4, and then the residual oil chromatographed (SiO2, hexanes/ethyl acetate, 90/10) to give a white foam (0.135 g, 64%). The resultant material was used as is in the next reaction.
Example 96. Methyl N-{4-r(3-fluorophenyl)aminol-6-f(4- methoxyphenvDthiol pyrimidin-2-yl)-N-methylleucinate (96).
Figure imgf000067_0001
To a stirred solution of N1-(3-fluorophenyl)-N2-{4-[(3-fluorophenyl)amino]-6-[(4- methoxyphenyl)thio]pyrimidin-2-yl}-N2-methylleucinamide 96a (0.080, 0.14 mmol) in MeOH (2 mL) was added HCl (cone, 2mL) and the reaction stirred at 60° C for lh. The reaction was extracted with CH2C12, washed with H2O, ΝaCl (sat.) and dried over Νa2SO . Removal of the solvent and chromatography (hexanes/ethyl acetate 90/10) gave the title compound 96 as a white solid (0.016 g, 23%). !H NMR (300 MHz, CDC13, 300K) δ 0.86 (d, 3H, J = 6.0 Hz), 0.92 (d, 3H, J = 6.0 Hz), 1.73-1.78 (m, 3H), 3.02 (s, 3H), 3.68 (s, 3H), 3.85 (s, 3H), 5.45 (br s, 2H), 6.24 (br s, IH), 6.69 (app t, J = 8.1 Hz), 6.92-6.95 (m, 4H), 7.17 (dd, IH, J = 8.4, 15 Hz), 7.50 (d, 2H, J = 8.1 Hz). APCI, m/z = 485 (M+l). LC/MS tR = 3.43 min. Synthesis of N1-(3-Fluorophenyl)-N2-{4-[(3-fluorophenvπamino1-6-[(4- methoxyphenvDthiol pyrimidin-2-yl}-N2-methylleucinamide (96a). A solution of N- {4- [(3 -fluoropheny l)amino] -6- [(4-methoxypheny l)thio]pyrimidin-2-yl } -N- methylleucine 95 (0.100 g, 0.22 mmol) in 3-fluoroaniline (0.250 mL) was heated to 120° C for 2h. The reaction was cooled and partitioned between CH2C12 and IN HCl. The organics were collected and washed with ΝaCl (sat.) and dried over Νa2SO . The solvent was removed to give a pale yellow foam which was used without purification in the next reaction. APCI, m/z = 564 (M+l). LC/MS tR = 3.56 min. Example 97. N2-(4-r(5-Fluoro-2-methylphenynaminol-6-r(4- methoxyphenvπthio1pyrimidin-2-yU-N1-(tetrahydrofuran-2-ylmethyl)-L-leucinamide (97).
Figure imgf000068_0001
91a 97a
Figure imgf000068_0002
A solution ofN2-{4-chloro-6-[(4-methoxyphenyl)thio]pyrimidin-2-yl}-N1-(tetrahydrofuran-2- ylmethyl)-L-leucinamide 97b (0.126 g, 0.20 mmol) in 3-fluoro-6-methyl aniline (0.169 g, 1.35 mmol) was heated to 130° C for 40 minutes. The reaction was cooled and then chromatographed (SiO2, CHClJMeOH, gradient, 100/0 to 98/2) to give the title compound as white foam (0.022 g, 14%). !H ΝMR (300 MHz, CDC13, 300K) δ 0.89-0.96 (m, 6H), 1.75- 1.92 (m, 3H), 2.12 (br s, 3H), 3.20-3.26 (m, IH), 3.38-3.43 (m, IH), 3.66-3.71 (m, 2H), 3.77- 3.79 (m, IH), 3.83 (s, IH), 3.88-3.93 (m, IH), 4.30-4.38 (m, IH), 5.00-5.10 (m, IH), 5.37 (d, IH, J = 12.6 Hz), 6.24-6.30 (m, IH), 6.63-6.74 (m, 2H), 6.92 (d, 2H, J = 8.1 Hz), 7.07 (app t, IH, J = 6.3 Hz), 7.43-7.48 (m, 2H). APCI, m/z 578 (M+l). LC/MS tR = 2.90 min. Synthesis ofN2-{4-Chloro-6-[(4-methoxyphenyl)thiolpyrimidin-2-v -N1- (tetrahvdrofuran-2-ylmethyl)-L-leucinamide (97b). To a cold (-15° C), stirred solution ofN-{4-chloro-6-[(4-methoxyphenyl)thio]pyrimidin-2- yl}-L-leucine 97a (0.31 g, 0.80 mmol) in CH2C12 was added Ν-methyl morpholine (0.09 mL, 0.83 mmol) followed by isobutyl chloroformate (0.120 mL, 0.90 mmol). After five minutes, tetrahydrofurfuryl amine (0.08 mL, 0.86 mmol) was added and the mixture stirred for 1 hour. The reaction was concentrated and chromatographed (SiO2, hexane/ethyl acetate, gradient, 100/0 to 70/30) to give the title compound as a white foam (0.157 g, 40%). Synthesis ofN-{4-Chloro-6-[(4-methoxyphenyl)thio1pyrimidin-2-yl}-L-leucine (97a). To a stirred solution of methyl N-{4-chloro-6-[(4-methoxyphenyl)thio]pyrimidin-2-yl}-L- leucinate (0.377 g, 0.90 mmol) in MeOH (2.3 mL), THF (2.3 mL) was added an aqueous solution of LiOH (0.08 g in 1.15 mL H2O, 1.80 mmol). The reaction was stirred at room temperature for 1.5 hours and then concentrated. To the residual oil was added 1 Ν HCl (pH < 7) and the reaction was partitioned between CH2C12 and H2O. The organic layer was dried and the solvent evaporated to give a white solid (0.32 g, 90%). Synthesis of Methyl N-f4-chloro-6-[(4-methoxyphenyπthio1pyrimidin-2-v -L-Ieucinate. To a stirred solution of 2,4-dichloro-6-[(4-methoxyphenyl)thio]pyrimidine (15.65 g, 54.5 mmol) in iPrOH (200 mL) was added leucine methyl ester hydrochloride (11.3 g, 62.7 mmol) and DIEA (22.79 mL, 131 mmol). The mixture was refluxed for 3.5 hours to give a 1:1 mixture of isomers and then the reaction was concentrated. The residual oil was partitioned between CH2C1 (500 mL) and IN HCl (3 x 100 mL). A portion of the material was chromatographed (11 g) SiO2, hexanes/ethyl acetate, gradient, 100/0 to 80/20 over 38 minutes at 35 ml/min to give the title compound (4.35 g, 23%) as a white solid.
Synthesis of 2,4-Dichloro-6-r(4-methoxyphenyl)thioIpyrimidine.
To a cold (-15° C), stirred solution of 2, 4, 6-trichloropyrimidine 91a (10.0 g, 54.5 mmol) in DME (40 mL) was added 4-methoxybenzenethiol (7.64 g, 54.5 mmol) and DIEA (7.05 g, 54.5 mmol). The reaction was stirred at room temperature for 1 hour and then concentrated. The reaction was partitioned between CH2C12 (100 mL) and 1 Ν HCl (50 mL) and then the organic layer was dried over MgSO . The material was then concentrated to give a yellow oil (15.65 g, 100%). Examples 98-101, 135 and 136 were prepared in analogous fashion to Example 97.
Figure imgf000069_0001
Table 7. Method F. General Procedure for Examples 97-101.135 and 136.
Figure imgf000070_0001
Figure imgf000071_0002
Example 102. N2-r4-[(3-Fluorophenyl)aminol-6-(quinolin-2-ylthio pyrimidin-2-yll-N1- (tetrahydrofuran-2-ylmethylV -leucinamide (102).
Figure imgf000071_0001
To a solution of 2-quinolinethiol (0.038 g, 0.23 mmol) in DME (2 mL) was added potassium tert-butoxide (0.027 g, 0.23 mmol) and the reaction stirred for five minutes. To this was added N2-{4-chloro-6-[(3-fluorophenyl)amino]pyrimidin-2-yl}-N1-(tetrahydrofuran-2- ylmethyl)-L-leucinamide 102e (0.100 g, 0.22 mmol) and the reaction vessel heated to 180° C for 15 minutes in a Smithsynthesizer microwave reactor. The reaction was cooled, and another portion of 2-quinolinethiol (0.076 g, 0.46 mmol) and potassium tert-butoxide (0.054 g, 0.46 mmol) was added. The reaction was again heated to 180° C for 15 minutes using microwave heating. The solvent was removed in vacuo, and the material chromatographed (SiO2, CHC13/2Ν NH3 in MeOH, gradient, 100/0 to 98/2 to give 102 as a white solid (0.022 g, 17%). 1HNMR (300 MHz, CDC13, 300K) δ 0.90-1.00 (m, 6H), 1.59-1.65 (m, 3H), 1.73-1.90 (m, 4H), 3.13-3.18 (m, IH), 3.44-3.49 (m, IH), 3.68-3.79 (m, 2H), 3.88-3.93 (m, IH), 4.27- 4.32 (m, IH), 6.38 (d, IH, J = 9.0 Hz), 6.59-6.63 (m, IH), 6.74 (app t, IH, J = 6.0 Hz), 7.00- 7.08 (m, 2H), 7.14-7.19 (m, IH), 7.45-7.61 (m, 2H), 7.73 (t, IH, J = 7.2 Hz), 7.81 (d, IH, J = 7.8 Hz), 8.03-8.11 (m, 2H). APCI, m/z = 561 (M+l). LC/MS tR = 2.81 min. Synthesis ofN2-f4-ChIoro-6-r(3-fluorophenyl)amino1pyrimidin-2-v -N1- (tetrahydrofuran-2-ylmethyI)-L-leucinamide (102e).
To a cold (-15° C), stirred solution of N-{4-chloro-6-[(3-fluorophenyl)amino]pyrimidin-2-yl}- L-leucine (0.460 g, 1.3 mmol) in CH2C12/DMF (5 mL/lmL) was added Ν-methyl morpholine (0.158 mL, 1.43 mmol) followed by isobutyl chloroformate (0.188 mL, 1.43 mmol). After five minutes, tetrahydrofurfuryl amine (0.148 mL, 1.43 mmol) was added. The reaction was stirred for 45 minutes, concentrated and then chromatographed (SiO , CH2C12/2Ν NH3 in MeOH, gradient, 100/0 to 95/5) to give the title compound 102e as a white solid (0.350 g, 61%). APCI, m/z = 436 (M+l). LC/MS tR = 2.68 min. Synthesis ofN-f4-Chloro-6-r(3-fluorophenyl)amino1pyrimidin-2-vI}-L-leucine.
To a solution of methyl N-{4-chloro-6-[(3-fluorophenyl)amino]pyrimidin-2-yl}-L-leucinate 102d (0.5 g, 1.36 mmol) in MeOH (0.5 mL) and THF (2 mL) was added 1 Ν ΝaOH (2 mL). The reaction was stirred for one hour, quenched with 1 Ν HCl (2 mL) and then extracted into CH2C1 (15 mL). The organic layer was washed with ΝaCl (sat.) and dried over Νa2SO . After removal of the solvent, the title compound was obtained as a white solid (0.47 g, 100%). APCI, m/z = 353 (M+l). LC/MS tR = 2.79 min.
Synthesis of Methyl N-{4-chloro-6-I(3-fluorophenyl)amino1pyrimidin-2-yl}-L-leucinate (102d . To a solution of 2,6-dichloro-N-(3-fluorophenyl)pyrimidin-4-amine 102b (1.0 g, 3.89 mmol) in i-PrOH (30 mL) was added leucine methyl ester hydrochloride (2.84 g, 15.5 mmol) and DIEA (22.2 mL, 124 mmol) and the reaction heated at reflux for 72 hours. The reaction was concentrated, extracted into CH2C12 (100 mL) and washed with 1 Ν HCl (3 x 100 mL). The organic layer was washed with ΝaCl (sat.), dried over Νa2SO4 and the volatiles removed to give a white foam (1.0 g, 70%). Synthesis of 2,6-Dichloro-N-(3-fluorophenv0pyrimidin-4-amine (102b).
To a solution of 2,4,6- trichloropyrimidmine 91a (2.0 g, 10.9 mmol) in THF (30 mL) was added 3-fluoroaniline (1.04 mL, 10.9 mmol) and the reaction refluxed for 3h. The reaction was concentrated to give a crude mixture of the two isomers in a 3:1 yield. The residual oil was chromatographed (hexanes/ethyl acetate, gradient, 100/0 to 90/10) to give the title compound as a colorless solid (2.0 g, 71%). Example 103. N2-f4-f(3-Fluorophenyl)aminol-6-r(4-methoxyphenyl)thio1pyrimidin-2- yl N 2-furylmethyr)-L-leucinamide (103).
^
Figure imgf000073_0001
To a cold (-15° C), stirred solution of N-{4-[(3-fluorophenyl)amino]-6-[(4- methoxyphenyl)thio]pyrimidin-2-yl} -leucine 93 (0.050 g, 0.10 mmol) in CH2C12 (3 mL) was added Ν-methylmorpholine (0.014 mL, 0.12 mmol), followed by EDCI (0.024 g, 0.125 mmol). The reaction was stirred for five minutes, and then furfuryl amine was added (0.0130 g, 0.13 mmol). The reaction was stirred for one hour and then chromatographed (SiO2, CH2Cl2/ethyl acetate, gradient, 100/0 to 95/5) to give 103 as a white foam (0.051 g, 87%). !H ΝMR (300 MHz, CDC13, 352 K) δ 0.89 (d, 3H, J = 6H), 0.93 (d, 3H, J = 6.0 Hz), 1.50-1.59 (m, IH), 1.73-1.85 (m, 2H), 3.83 (s, 3H), 4.30-4.37 (m, 3H), 5.01, (d, IH, J = 6.3 Hz), 5.57 (s, IH), 6.11 (d, IH, J = 3.0 Hz), 6.26 (br m, IH), 6.31 (br m, IH), 6.69-6.74 (m, IH), 6.87-6.905 (m, IH), 6.73 (d, 2H, J = 8.7 Hz), 7.16 (app dd, IH, J = 9.0, 14.7 Hz), 7.18-7.27 (m, IH), 7.45 (d, 2H, J = 8.7 Hz). APCI, m/z = 536 (M+l). LC/MS tR = 2.65 min. By analogy Examples 104-119 were prepared from N-{2-[(3-fluorophenyl)amino]-6-[(4- methoxyphenyl)thio]pyrimidin-4-yl}-L-leucine 93.
Figure imgf000073_0002
0 Table 8. Method G. General Procedure for Examples 104-119 and 138.
Figure imgf000074_0001
Figure imgf000075_0001
Figure imgf000076_0001
Example 120. Methyl N-f4-f(3-fluorophenyl)amino1-6-(4-methoxybenzyl)pyrimidin-2- yll -L-leucinate (120).
Figure imgf000077_0001
91a 120a
Figure imgf000077_0002
120b Example 120
A stirred solution of methyl N-[4-chloro-6-(4-methoxybenzyl)pyrimidin-2-yl]-L-leucinate (0.300 g, 0.10 mmol) 120b was dissolved in 3-fluoroaniline (0.500 mL) and heated to 160° C for 1 hour. The reaction was cooled and chromatographed (SiO2, CHCl3/MeOH, gradient, 100/0 to 98/2) to give the title compound 120 as a white foam (0.080 g, 22%). ]H ΝMR (300 MHz, CDC13, 300K) δ 0.87 (d, 3H, J = 6.0 Hz), 0.91 (d, 3H, J = 6.0 Hz), 1.61-1.80 (m, 3H), 3.63 (s, 3H), 3.66 (s, 3H), 3.70 (s, 2H), 4.51 (app t, IH, J = 6.3 Hz), 6.60-6.65 (m, IH), 6.73 (d, 2H, J = 8.4 Hz), 6.79 (dd, IH, J = 1.5, 8.1 Hz), 7.15-7.20 (m, 3H), 7.36-7.41 (m, IH), 7.59 (d, IH, J = 10.8 Hz), 10.39 (br s, IH). APCI, m/z = 453 (M+l). LC/MS tR = 2.50 min. Synthesis of N-f4-ChIoro-6-(4-methoxybenzyl)pyrimidin-2-yri-L-leucinate (120b) and methyl N-r2-chloro-6-(4-methoxybenzyl)pyrimidin-4-yn-L-leucinate (120c). To a solution of 2,4-dichloro-6-(4-methoxybenzyl)pyrimidine 120a (1.92 g, 7.1 mmol) in iPrOH (15 mL).was added leucine methyl ester hydrochloride (1.29 g, 7.1 mmol) and DIEA (2.49 mL, 14.2 mmol) and the reaction heated to 80° C for 18 hours. The resultant 1 : 1 mixture of N-[4-chloro-6-(4-methoxybenzyl)pyrimidin-2-yl]-L-leucinate 120b and methyl N-[2-chloro-6-(4-methoxybenzyl)pyrimidin-4-yl]-L-leucinate 120c was concentrated and then chromatographed (SiO2, hexanes/ethyl acetate, gradient, 100/0 to 0/100 over 38 minutes at 85 ml/min) to give the title compound as a white foam. The material was assigned based on NOE studies. 120b: 1H NMR (300 MHz, CDC13, 300K) δ 0.93-1.02 (m, 6H), 1.57-1.79 (m, 3H), 3.71 (s, 3H), 3.79 (br s, 5H), 4.65-4.79 (m, IH), 5.47 (d, IH, J = 7.2 Hz), 6.37 (s, IH), 6.85 (d, 2H, J = 8.7 Hz), 7.14 (d, 2H, J = 8.7 Hz). 102c: Η NMR (300 MHz, CDC13, 300K) δ 0.91-0.93 (m, 6H), 1.61-1.72 (m, 3H), 3.72 (s, 3H), 3.80 (s, 3H), 3.84 (s, 2H), 5.19 (br s, IH), 5.89 (s, IH), 6.86 (d, 2H, J = 8.7 Hz), 7.14 (d, 2H, J = 8.7 Hz). Synthesis of 2,4-Dichloro-6-(4-methoxybenzyl)pyrimidine (120a). To a cold (0 °C), stirred solution of 2,4,6-trichloropyrimidine 91a (2.00 g, 10.0 mmol) in diethyl ether (50 mL) was slowly added 4-methoxybenzyl magnesium chloride (38.12 mL, 13.0 mmol). The reaction was stirred for 1 hour and then quenched with NH4CI (sat.). The reaction was diluted with diethyl ether and then washed with NaCl (sat.). The organic layer was dried (MgSO ), and then concentrated. The residual oil was chromatographed (SiO2, hexanes/ethyl acetate, gradient, 100/0 to 0/100 over 38 minutes at 85 ml/min) to give the title compound as a colorless oil (2.15 g, 73%).
Example 121. Synthesis of Methyl N-[2-F(3-fluorophenyI)aminol-6-(4- methoxybenzyl)pyrimidin-4-yl]-L-leucinate (121).
Figure imgf000078_0001
120c Example 121
A solution of methyl N-[2-chloro-6-(4-methoxybenzyl)pyrimidin-4-yl]-L-leucinate 120c (0.775 g, 2.05 mmol) in 3-fluoro aniline was heated to 160 °C for 1 hour. The reaction was chromatographed (SiO2, hexanes/ethyl acetate, gradient, 100/0 to 90/10) to give the title compound 121 as a white foam (0.184 g, 19%). 1H ΝMR (300 MHz, CDC13, 300K) δ 0.90 (d, 3H, J = 6.0 Hz), 0.95 (d, 3H, J = 6.0 Hz), 1.63-1.74 (m, 3H), 3.72 (s, 3H), 3.80 (s, 3H), 3.87 (s, 2H), 4.63-4.70 (m, IH), 5.60-5.68 (m, 2H), 6.79 (app t, IH, J = 8.4 Hz), 6.88 (d, 2H, J = 8.1 Hz), 7.12-7.29 (m, 4H), 7.59 (d, IH, J = 11.4 Hz). APCI, m/z = 453 (M+l). LC/MS tR = 2.68 min. Example 122. (S)-2-[3-(3-Fluoro-phenylamino)-5-(4-methoxy-phenylsulfanyl)- phenyIaminol-4-methyl-pentanoic acid methyl ester (122).
Figure imgf000079_0001
To a solution of (S)-2-[3-bromo-5-(4-methoxy-phenylsulfanyl)-phenylamino]-4-methyl- pentanoic acid methyl ester 122c (0.049 g, 0.11 mmol) in toluene (2 mL) was added tris(dibenzylideneacetone)-dipalladium(0) (0.003 g, 0.003 mmol), R(+)-2,2'- bis(diphenylphosphino)-l,l'-binapthyl (0.003 g, 0.005 mmol), cesium carbonate (0.05 g, 0.15 mmol) and 3-fluoroaniline (0.013 g, 0.12 mmol). The solution was heated to 90 °C for 18 h. The toluene was removed in vacuo and the residual oil was chromatographed (hexanes/ethyl acetate gradient from 100% to 95% hexane, SiO2) to give the title compound as a white solid (0.019 g, 36%). Η NMR (300 MHz, CDC13, 300K) δ 0.92 (s, 3H, J = 6.3 Hz), 0.93 (s, 3H, J = 6.3 Hz), 1.55 (m, 2H), 1.65-1.78 (m, IH), 3.68 (s, 3H), 3.82 (s, 3H), 3.95 (app t, IH, J = 6.9 Hz), 6.02 (s, IH), 6.09 (s, IH), 6.18 (s, IH), 6.55-6.58 (m, IH), 6.65-6.69 (m, 2H), 6.89 (d, 2H, J = 8.4 Hz), 7.08-7.13 (m, IH), 7.43 (d, 2H, J = 8.4 Hz). APCI, m/z = 469 (M+l). LC/MS tR = 3.22 min. l,3-Dibromo-5-(4-methoxy-phenylsulfanyl)-benzene (122b)
To a cold (0 °C), stirred solution of 1,3,5 tribromobenzene (1.0 g, 3.18 mmol) in DMF was added NaH (117 mg, 60% in mineral oil, 3.49 mmol) and 4-methoxybenzenthiol (0.445 g, 3.18 mmol). The reaction was warmed to room temperature and stirred 2h. To the reaction was added another portion of 4-methoxybenzenethiol (0.445g, 3.18 mmol), followed by potassium tert-butoxide (0.356 g, 3.18 mmol). The reaction was stirred for 24h at which point the mixture was diluted in CH2C12 (300 mL) and extracted 3 x 100 mL with H20 and 1 x 100 mL of brine. The organic layer was collected and evaporated to give a yellow oil. This oil was chromatographed (10% EtOAc in hexanes, SiO2, Rf = 0.5) to give l,3-dibromo-5-(4- methoxy-phenylsulfanyl)-benzene (0.71 g, 60%) 122b.
(S)-2-[3-Bromo-5-(4-methoxy-phenylsulfanyl)-phenylamino1-4-methyl-pentanoic acid methyl ester (122c)
To a solution of l,3-dibromo-5-(4-methoxy-phenylsulfanyl)-benzene 122b (0.200 g, 0.53 mmol) in toluene (5 mL) was added tris(dibenzylideneacetone)-dipalladium(0) (0.014 g, 0.016 mmol), R(+)-2,2'-bis(diphenylphosphino)-l,l'-binapthyl (0.015 g, 0.027 mmol), cesium carbonate (0.487 g, 1.5 mmol) and (S)-leucine methyl ester hydrochloride (0.106 g, 0.58 mmol). The solution was heated at 90 °C for 18 h. An additional portion of tris(dibenzylideneacetone)-dipalladium(0) (0.028 g, 0.032 mmol) and R(+)-2,2'- bis(diphenylphosphino)-l,l'-binapthyl (0.030 g, 0.054 mmol) was added and the reaction heated for another 18 h. The toluene was removed in vacuo and the residual oil was chromatographed (hexanes/ethyl acetate gradient from 100% to 95% hexane, SiO2) to give the title compound as a white solid (0.98 g, 41%). 1H NMR (300 MHz, CDC13, 300K) δ 0.92 (d, 3H, J = 5.1 Hz), 0.95 (d, 3H, J = 5.1 Hz), 1.50-1.54 (m, 2H), 1.61-1.67 (m, IH), 3.69 (s, 3H), 3.83 (s, 3H), 3.94 (app t, IH, J = 6.3 Hz), 6.24 (d, IH, J = 1.8 Hz), 6.48 (d, IH, J = 1.8 Hz), 6.58 (d, IH, J = 1.8 Hz), 6.90 (d, 2H, J = 6.9 Hz), 7.40 (d, 2H, J = 6.9 Hz). APCI, m/z = 440, 441(M+1). LC MS tR = 3.26 min. Example 123. (S)-2-f2-(3-Fluoro-phenylamino)-6-(4-methoxy-phenylsulfanyl)-pyridin-4- ylaminol-4-methyl-pentanoic acid methyl ester (123).
Figure imgf000081_0001
100°c' 2hr Example 123
To a solution of (S)-2-[2-bromo-6-(4-methoxy-phenylsulfanyl)-pyridin-4-ylamino]-4-methyl- pentanoic acid methyl ester 123c (0.02 g, 0.04 mmol) in toluene (2 mL) was added tris(dibenzylideneacetone)-dipalladium(0) (0.010 g), R(+)-2,2'-bis(diphenylphosphino)-l,l '- binapthyl (0.01 g,), cesium carbonate (0.02 g, 0.06 mmol) and 3-fluoroaniline (0.052 g, 0.04 mmol). The solution was heated at reflux for 2 h. The toluene was removed in vacuo and the residual oil was chromatographed (hexanes/ethyl acetate gradient from 100% to 95% hexane, SiO2) to give the title compound as a white solid (0.05 g, 23%). Η NMR (300 MHz, CDC13, 300K) δ 0.80 (d, 3H, J = 6.3 Hz), 0.85 (d, 3H, J = 6.3 Hz), 1.41-1.55 (m, 3H), 3.62 (s, 3H), 3.79 (s, IH), 5.5 (s, IH), 5.65 (s, IH), 6.26 (s, IH), 6.57 (app t, IH, J = 10.5 Hz), 6.80 (d, IH, J = 8.1 Hz), 6.88 (d, 2H, J = 8.7 Hz), 6.95-6.98 (m, IH), 7.05-7.10 (ra, IH), 7.45 (d, 2H, J = 8.7 Hz). APCI, m/z = 470 (M+l). LC/MS tR = 2.62 min. Synthesis of (S)-2-[2-Bromo-6-(4-methoxy-phenylsulfanyI)-pyridin-4-ylamino]-4-methyl- pentanoic acid methyl ester (123c).
To a solution of (S)-2-(2,6-dibromo-pyridin-4-ylamino)-4-methyl-pentanoic acid methyl ester 123b (0.126 g, 0.3 mmol) in DMF (1 mL) was added l,8-diazobicyclo[5.4.0]undec-7-ene (0.19 g, 1.2 mmol) and 4-methoxybenzenethiol (0.17 g, 1.2 mmol). The reaction was heated to 110 °C for 18 h. The mixture was partitioned between ethyl acetate and 1 N HCl. The organic layer was collected and chromatographed using CH C12 (SiO2) to give a mixture of the ester and acid. The mixture was taken up in ether and esterified using diazomethane (generated from N-methyl-N — nitro-N-nitrosoguanidine, 0.10 g, and 40 % KOH). The reaction was chromatographed (95% hexanes/5%EtOAc, SiO2) to give the title compound (0.02 g).
Synthesis of (S)-2-(2,6-Dibromo-pyridin-4-ylamino)-4-methyI-pentanoic acid methyl ester:
To a solution of 2,6-dibromo-4-nitro pyridine (1.24 g, 4.3 mmol) (Chem. Ber, 122, 589) in 2- propanol (40 mL) was added (S)-leucine methyl ester hydrochloride (2.4 g, 13.1 mmol) and diisopropylethylamine (3.39 g, 26.3 mmol). The reaction was refluxed overnight, cooled and the solvent removed in vacuo. The residual oil was chromatographed (15% hexane in diethyl ether) to give the title compound as a white solid (0.64 g, 38%) and also (S)-2-(6-bromo-4- nitro-pyridin-2-ylamino)-4-methyl-pentanoic acid methyl ester as a side product (0.18 g,
Example 124. (S)-2-[6-(3-FIuoro-phenylamino)-4-(4-methoxy-phenylsulfanyI)-l-oxy- pyridin-2-ylamino]-4-methyl-pentanoic acid methyl ester (124).
Figure imgf000082_0001
BINAP, Cs2C03
Figure imgf000082_0002
toluene, 90° C reflux
Figure imgf000082_0003
124c Example 124
To a solution of (S)-2-[6-(3-fluoro-phenylamino)-4-nitro-l-oxy-pyridin-2-ylamino]-4-methyl- pentanoic acid methyl ester 124c (0.02 g, 0.05 mmol) in DME was added DBU (0.015 mL, 0.1 mmol) and 4-methoxybenzenethiol (0.013 mL, 0.1 mmol). The reaction was heated to 150 °C for five minutes in a Personal Chemistry Smithsynthesizer. The reaction was concentrated and chromatographed (95/5 CH2Cl2/MeOH) to give a white solid (0.024 g, 100%). Η NMR (300 MHz, CDC13, 300K) δ 0.93 (d, 3H, J = 6.0 Hz), 0.96 (d, 3H, J = 6.0 Hz), 1.72-1.83 (m, 3H), 3.69 (s, 3H), 3.84 (s, 3H), 3.84-3.99 (m, IH), 5.64 (d, IH, J = 2.1 Hz), 6.06 (d, IH, J = 2.1 Hz), 6.70-6.80 (m, 3H), 6.85 (d, IH, J = 8.7 Hz), 6.95 (d, 2H, J = 8.7 Hz), 7.19-7.22 (m, IH), 7.45 (d, 2H, J = 8.7 Hz), 8.65 (s, IH). APCI, m/z = 486 (M+l). LC/MS tR = 2.78 min. Preparation of (S)-2-[6-(3-fluoro-phenylamino)-4-nitro-l-oxy-pyridin-2-ylamino1-4- methyl-pentanoic acid methyl ester (124c)
A solution of 2,5-dibromo-4-nitro-pyridyl-N-oxide 124a (1 mmol) was refluxed in tert-butyl alcohol with Na2CO3 (8 mmol) and (S)-leucine methyl ester hydrochloride (4 mmol). After 24 h at reflux the reaction was cooled and the residual material chromatographed (CH2Cl2/MeOH gradient, SiO2) to give the intermediate mono-bromide. A portion of this compound 124b (0.5 mmol) was converted to the title compound using the general palladium mediated coupling method described for Example 126 (utilizing 3-fluoroaniline as the amine). Example 125. (S)-2-[4-(3-Fluoro-phenylamino)-6-(4-methoxy-phenylsulfanyl)-pyridin-2- ylamino]-4-methyl-pentanoic acid methyl ester (125)
Figure imgf000083_0001
Example 126 Example 125
A solution of (S)-2-[4-(3-fluoro-phenylamino)-6-(4-methoxy-phenylsulfanyl)-l-oxy-pyridin- 2-ylamino]-4-methyl-pentanoic acid methyl ester 126 (0.054 g, 0.11 mmol) in CHC13 was treated with 3-fluoroaniline (27 uL) and then PC13 (3 x 9.3 uL, 0.32 mmol). The reaction was stirred for 1.5 hours and then the volatiles removed in vacuo. The residual material was partitioned between ethyl acetate and NaHCO3 (sat.). The organic layer was dried over
Na2SO4, and concentrated. Column chromatography (CHC13, SiO ) gave the desired material (0.037 g, 71%). 'H NMR (300 MHz, CDC13, 300K) δ 0.89-0.95 (m, 6H), 1.54-1.62 (m, 2H), 1.66-1.75 (m, IH), 3.69 (s, 3H), 3.82 (s, 3H), 4.08-4.15 (m, IH), 4.39-4.41 (m, IH), 4.62-4.65 (m, IH), 5.69 (s, 2H), 5.83 (s, IH), 6.70-6.75 (m, 3H), 6.90 (d, 2H, J = 9.0 Hz), 7.12-7.20 (m, IH), 7.50 (d, 2H, J = 9.0 Hz). APCI, m/z = 470 (M+l). LC/MS tR = 2.52 min. Example 126. (S)-2-[4-(3-Fluoro-phenylamino)-6-(4-methoxy-phenylsulfanyl)-l-oxy- pyridin-2-ylamino1-4-methyl-pentanoic acid methyl ester (126).
Figure imgf000084_0001
126c Example 126
To a solution of (S)-2-[4-(3-bromo)-6-(4-methoxy-phenylsulfanyl)-l-oxy-pyridin-2-ylamino]- 4-methyl-pentanoic acid methyl ester 126c (0.100 g, 0.21 mmol) in toluene (1 mL) was added tris(dibenzylideneacetone)-dipalladium(0) (0.006 g, 0.006 mmol), R(+)-2,2'- bis(diphenylphosphino)-l,l'-binapthyl (0.006 g, 0.009 mmol), cesium carbonate (0.100 g, 0.30 mmol) and 3-fluoroaniline (0.029 g, 0.26 mmol). The solution was heated to 90 °C for 1 h. The toluene was removed in vacuo and the residual oil was chromatographed (CHC13/2N NH3 in MeOH— gradient from 100% to 98%, SiO ) to give the title compound as a white solid (0.064 g, 60%). 1H NMR (300 MHz, CDC13, 300K) δ 0.87 (d, 3H, J = 6.0 Hz), 0.93 (d, 3H, J = 6.0 Hz), 1.73-1.78 (m, 3H), 3.69 (s, 3H), 3.82 (s, 3H), 3.93-4.01 (m, IH), 5.48 (d, IH, J = 2.4 Hz), 5.86 (d, IH, J = 2.4 Hz), 6.51 ( br s, IH), 6.62-6.68 (m, 3H), 6.94 (d, 2H, J = 8.7 Hz), 6.96-6.99 (m, IH), 7.12-7.17 (m, IH), 7.39 (d, 2H, J = 8.7 Hz).
Synthesis of (S)-2-r4-(3-Bromo)-6-(4-methoxy-phenylsulfanyl)-l-oxy-pyridin-2-vIaminol- 4-methyl-pentanoic acid methyl ester (126c).
Figure imgf000085_0001
126c
To a solution of 2,4,6-tribromo-pyridyl-N-oxide 126a (1 mmol) in n-butanol (30 mL) was added L-leucine methyl ester hydrochloride (1 mmol) and diisopropylethylamine (2.5 mmol). The reaction was heated to reflux for 18 h. Upon cooling the volatiles were removed in vacuo and the material chromatographed to give a separable mixture of the desired methyl ester, (S)- 2-(4,6-dibromo-l-oxy-pyridin-2-ylamino)-4-methyl-pentanoic acid methyl ester 126b, and the n-butyl ester. 4-Methoxybenzenthiol (0.147 g, 1.05 mmol) was dissolved in DME (3 mL) and to this was added potassium tert-butoxide (0.117 g, 1.05 mmol), followed by (S)-2-(4,6-dibromo-l-oxy- pyridin-2-ylamino)-4-methyl-pentanoic acid methyl ester 126b (0.397 g, 0.99 mmol). After one hour, another portion of potassium tert-butoxide (0.117 g, 1.05 mmol) and 4- methoxybenzenethiol (0.397 g, 0.99 mmol) was added and the solution stirred for one hour. The reaction was quenched with IN HCl (ca. 2mL) and the reaction partitioned between CH2C12 and H2O. The organic layers were collected, dried over Na2SO and concentrated.
The entire crude material was treated with CH2N2 (as generated from 1.75 mmol of N-methyl- N-nitro-N-nitrosoguanidine and 40% KOH) until all was converted into the methyl ester. The residue was chromatographed (CHC1J2N NH3 in MeOH- gradient from 100% to 98%, Si02) to give the title compound as a white solid (0.401 g, 87%). Example 127. 2- f 6-(3-Fluoro-phenylamino)-2-(4-methoxy-phenylsulfanyl)-pyrimidin-4- ylaminol-4-methyl-pentanoic acid methyl ester (127).
Figure imgf000086_0001
To a stirred solution of methyl N-{6-chloro-2-[(4-methoxyphenyl)thio]pyrimidin-4-yl}-L- leucinate 91e (0.062 g, 0.15 mmol) in toluene (2 mL) was added tris(dibenzylideneacetone)- dipalladium(O) (0.006 g, 0.006 mmol), R(+)-2,2'-bis(diphenylphosphino)- 1 , 1 '-binapthyl (0.006 g, 0.009 mmol), cesium carbonate (0.100 g, 0.30 mmol) and 3-fluoroaniline (0.024 g, 0.22 mmol). The solution was heated at 90 °C for 1 h. The toluene was removed in vacuo and the residual oil was chromatographed (hexanes/ethyl acetate gradient 100% to 75%, SiO ) to give the title compound as a white solid (0.024 g, 32%). 1H ΝMR (300 MHz, CDC13, 300K) δ 0.87 (d, 3H, J = 6.3 Hz), 0.90 (d, 3H, J = 6.3 Hz), 1.53-1.70 (m, 3H), 3.69 (s, 3H), 3.85 (s, 3H), 4.39 (br s, IH), 4.83-4.86 (m, IH), 5.42 (s, IH), 6.35 (s, IH), 6.70 (ddd, IH, J = 1.8 Hz, 8.4 Hz, 8.5 Hz), 6.83 (d, IH, J = 7.8 Hz), 6.92 (d, 2H, J = 8.7 Hz), 7.16 (dd, IH, J = 6.6 Hz, 14.7 Hz), 7.52 (d, 2H, J = 8.7 Hz). APCI, m/z = 471 (M+l). LC MS tR = 2.80 min. Synthesis of Methyl N-(6-chloro-2-r(4-methoxyphenvI)thio]pyrimidin-4-yl}-L-leucinate (91e)
Preparation of 91e is described in example 91. The title compound was separated from isomer 91d by chromatography (hexanes/ethyl acetate gradient 90/10 to 80/20, Si02). Example 128. (S)-2-F6-(3-fluoro-phenyIamino)-4-(4-methoxy-phenylsuIfanyl)-pyridin-2- ylaminol-4-methyl-pentanoic acid methyl ester (128).
Figure imgf000087_0001
Example 128 was prepared in analogy to Example 122, beginning with (S)-2-[6-bromo-4-(4- methoxy-phenylsulfanyl)-pyridin-2-ylamino]-4-methyl-pentanoic acid methyl ester 128b as the starting material. Column chromatography (CH2C12, SiO ) gave the title compound as a white solid (12%).
Example 129. N3-(3-Fluoro-phenyl)-6-(4-methoxy-phenylsulfanyl)-N^-(3-methyl-l- pyridin-2-yl-butyl)-pyrimidine-2,4-diamine (129).
Figure imgf000087_0002
To [2-chloro-6-(4-methoxy-phenylsulfanyl)-pyrimidin-4-yl]-(3-methyl-l -pyridin-2-yl-butyl)- amine 129a (0.110 g, 0.2 mmol) was added 3-fluoroaniline (0.1 mL) and the reaction was heated to 150 °C for 10 minutes. The reaction was cooled and chromatographed (hexanes/ethyl acetate gradient 90/10 to 80/20, SiO2) to give the title compound as a white solid (0.034 g, 28%). ]H NMR (300 MHz, CDC13, 300K) δ 0.87 (d, 3H, J = 6.3 Hz), 0.95 (d, 3H, J = 6.3 Hz), 1.65-1.70 (m, 3H), 3.86 (s, 3H), 5.29 (s, IH), 5.38-5.41 (m, IH), 6.63-6.65 (m, IH), 6.82 (s, IH), 6.92-6.98 (m, 3H), 7.10-7.20 (m, 3H), 7.46 (d, 2H, J = 8.7 Hz), 7.57- 7.61 (m, 2H), 8.52 (d, IH, J = 4.2 Hz). APCI, m/z = 490 (M+l). LC/MS tR = 2.46 min.
Synthesis of f2-chloro-6-(4-methoxy-phenylsulfanyl)-pyrimidin-4-vn-(3-methyl-l- PVridin-2-yl-butyl)-amine 129a and r4-Chloro-6-(4-methoxy-phenylsulfanvI)-pyrimidin- 2-vn-(3-methyl-l-pyridin-2-yl-butyl)-amine l29b
Figure imgf000088_0001
Figure imgf000088_0002
129a 129b To a stirred solution of 2,4-dichloro-6-(4-methoxy-phenylsulfanyl)-pyrimidine (1.22 g, 4.23 mmol) in isopropyl alcohol was added 3 -methyl- l-pyridin-2-yl-butylamine (0.840 g, 5.1 mmol) and diisopropylethylamine (0.91 mL, 5.1 mmol) and the reaction heated to reflux for 3 h. The reaction was cooled and chromatographed (hexanes/ethyl acetate 80/20, SiO2) to give the two isomers as white solids (regiochemical isomers were established using NOE spectroscopy):
129a: 1H NMR (300 MHz, CDC13, 300K) δ 0.80-0.85 (m, 6H), 1.45-1.59 (m, 3H), 3.87 (s, 3H), 5.42-5.45 (m, IH), 5.84-5.86 (m, IH), 6.92-6.97 (m, 3H), 7.13-7.17 (m, IH), 7.39-7.42 (m, 2H), 7.58-7.62 (m, IH), 8.45 (d, IH, J = 4.2 Hz). APCI, m/z = 415 (M+l). LC/MS tR = 2.28 min. 129b: H NMR (300 MHz, CDC13, 300K) δ 0.91-0.92 (m, 6H), 1.68-1.70 (m, 3H), 3.86 (s, 3H), 5.10 (br s, IH), 5.96-5.99 (m, 2H), 6.96 (d, 2H, J = 8.6 Hz), 7.11-7.15 (m, IH), 7.46 (d, 2H, 8.6 Hz), 8.54 (d, IH, J = 3.0 Hz). APCI, m/z = 415 (M+l). LC/MS tR = 2.34 min. Svnthesis of2,4-dichloro-6-(4-methoxy-phenylsulfanyl)-pyrimidine
Figure imgf000089_0001
To a cold (0 °C) solution of 2,4,6-trichloropyrimidine (2.24 g, 12.2 mmol) in THF was added 4-methoxybenzenethiol (1.73 g, 12.2 mmol), followed by diisopropylethylamine (2.23 mL, 12.5 mmol). The reaction was warmed to room temperature and the solvent removed in vacuo. The residual oil was partitioned between CH2C12 and IN HCl, and the organic layer was collected. The CH2C12 layer was dried (Na2SO ) and then the solvent removed to give the title compound as a colorless oil. The material was used in the next reaction without further purification.
Synthesis of -methyl-l-pyridin-2-yl-butylamine
Figure imgf000089_0002
To a solution of 2-cyanopyridine (2.0 g, 19.2 mmol) in diethylether was added isobutyl magnesium bromide (9.6 mL) and the reaction was stirred for 1 h. The reaction was quenched with IN HCl. The ether layer was separated and dried with NaCl (sat.) and Na2SO . The solvent was evaporated to give the ketone intermediate. The ketone was dissolved in MeOH and to this was added NH OAc (2.3 g, 6.1 mmol) and NaCNBH3 (0.46 g, 7.3 mmol). The reaction was refluxed for 3h, and the solvent removed in vacuo. The residual oil was partitioned between diethyl ether and 1 N HCl. The acid layer was collected and washed with ether. The aqueous layer was treated with 10 N NaOH until the solution was basic. The aqueous layer was then extracted with ether and the ether layer was collected. This layer was washed with NaCl (sat.) and dried Na SO . Removal of solvent gave the title compound as a colorless oil (0.85 g, 25%). The compound was used with no further purification. Example 130. N^-(3-Fluoro-phenyl)-6-(4-methoxy-phenylsulfanyl)-N2-(3-methyl-l- pyridin-2-yl-butyl)-pyrimidine-2,4-diamine (130).
Figure imgf000090_0001
Example 130
The title compound was prepared in analogous fashion to Example 128, beginning with [4- chloro-6-(4-methoxy-phenylsulfanyl)-pyrimidin-2-yl]-(3-methyl-l-pyridin-2-yl-butyl)-amine
129b as the starting pyrimidine. 1H NMR (300 MHz, CDC13, 300K) δ 0.92-0.95 (m, 6H),
1.71-1.73 (m, 3H), 3.85 (s, 3H), 5.11-5.16 (m, IH), 5.35 (br s, IH), 5.67 (br s, IH), 6.29 (br s,
IH), 6.65-6.70 (m, IH), 6.84 (d, IH, J = 9.0 Hz), 6.95 (d, 2H, J = 8.7 Hz), 7.09-7.15 (m, 3H),
7.50 (d, 2H, J = 8.7 Hz), 7.55-7.60 (m, IH), 8.53-8.56 (m, IH). APCI, m/z = 490 (M+l). LC/MS tR = 2.40 min.
Synthesis of Examples 131-134:
Figure imgf000091_0001
Figure imgf000091_0002
Examples 131-134 General Procedure (Examples 131-134 were prepared by analogy to example 102):
(S)-2-[4-Chloro-6-(3-cyano-phenylamino)-pyrimidin-2-ylamino]-4-methyl-pentanoic acid methyl ester (0.113 mmol) was heated with thiols (0.226 mmol) (as described in Table 9) and potassium tert-butoxide (0.226 mmol) for 10-30 minutes at 200 °C in a Personal Chemistry Smithsynthesizer. Reactions were then purified by column chromatography (99/1 CHiClJMeOH, SiO2).
Synthesis of (S)-2-[4-Chloro-6-(3-cyano-phenylamino)-pyrimidin-2-ylamino]-4-methyl- pentanoic acid methyl ester was prepared by analogy to 102e in Example 102. Table 9. Examples 131-134
Figure imgf000092_0001
Example 137. (S)-2-f4-(3-Cyano-phenylamino)-6-(4-methoxy-phenylsulfanyl)- pyrimidin-2-ylmethyll-4-methyl-pentanoic acid(2-methylsulfanyl-ethyl)-amide (137).
Figure imgf000093_0001
Preparation of the title compound was accomplished by analogy to Examples 131-134, using 2-methylsulfanyl-ethylamine as the amine in the amide-bond coupling reaction, and 3-cyano- aniline in the formation of the di-chloropyrimidine. !H NMR (300 MHz, CDC13, 300K) δ D 0.90 (d, 3H, J = 6.3 Hz), 0.96 (d, 3H, J = 6.3 Hz), 1.55-1.61 (m, 3H), 2.05 (s, 3H), 2.55 (t, 2H, J = 6.6 Hz), 3.39 (q, 2H, J = 6.3 Hz), 3.87 (s, 3H), 4.34 (br s, IH), 5.29 (s, IH), 6.60 (br s, IH), 7.00 (d, 2H, J = 8.7 Hz), 7.27-7.38 (m, 2H), 7.38-7.60 (m, 2H). APCI, m/z = 537 (M+l). LC/MS tR = 2.63 min.
The compounds of the present invention have utility for the prevention and treatment of Alzheimer's disease by inhibiting amyloid β production. Methods of treatment target formation of amyloid β production through enzymes involved in the proteolytic processing of β amyloid precursor protein. Compounds that inhibit β and γ secretase activity, either directly or indirectly, control the production of amyloid β. The inhibitions of β and γ secretases reduce the production of amyloid β and are thought to reduce or prevent the neurological disorders such as Alzheimer's disease. The compounds of the present invention have utility for the prevention and treatment of disorders involving amyloid β production, such as cerebrovascular disorders.
Compounds described herein have been shown to inhibit amyloid β production, as determined by the gamma secretase detergent extract assay with IC50 activity ranging from 0.010 uM to 5.50 uM and gamma secretase whole cell assay with IC50 activity ranging from 0.10 uM to 12.0 uM. These assays are described below. Compounds provided by this invention should also be useful as standards and reagents in determining the ability of a potential pharmaceutical to inhibit amyloid β production. These would be provided in commercial kits comprising a compound of this invention.
As used herein "ug " denotes microgram, "mg" denotes milligram, "g" denotes gram, "uL" denotes microliter, "mL" denotes milliliter, "L" denotes liter, "nM" denotes nanomolar, ".uM" denotes micromolar, "mM" denotes millimolar, "M" denotes molar, "nm" denotes nanometer, "DMSO" denotes dimethyl sulfoxide, "DTT" denotes dithiothreitol, "DPBS" denotes "EDTA" denotes ethylenediaminetetraacetate,
Gamma Secretase Detergent Extract Assay
The gamma secretase enzyme assay measures the amount of amyloid β (Aβ)40 product generated by the cleavage of C 100, a truncated form of amyloid precursor protein (APP). The C100 substrate is a recombinant protein purified from E. coli inclusion bodies. The γsecretase enzyme complex is prepared by detergent extraction of HeLa 8A8 cell membranes. The enzyme reaction contains 10 ul of inhibitor at a defined concentration, diluted from a DMSO stock into 96-well microplates (final concentration of DMSO is maintained at 5%). 20 ul of the C100 substrate (600 nM final concentration), in reaction buffer, (50 mM MES, pH 6.5, containing 100 mM NaCl, 1 mM EDTA, 1 mM DTT, 1 mg/mL BSA, 0.25% Chapso, 0.01% PE, 0.01% PC and a protease cocktail), is added to the plates. The reactions are initiated by addition of lOul enzyme at a 20-fold dilution from stock. An Aβ40 standard curve diluted in the reaction buffer plus C100 is included in each assay. Plates are incubated for 3 hours at 37 degrees. After the incubation period, 50 ul of an antibody mixture is added: rabbit anti-Aβ40 antibody (Biosource #44-3481) at 0.16 ug/ml and biotinylated 4G8 (Senetek #240-10) at 0.25 ug/ml in DPBS (Fisher # MT21031CV) containing 0.5% bovine serum albumin, 0.5% Tween 20. Plates are then incubated overnight at 4 degrees. The following morning, a 50 ul mixture of 0.0625 mg/ml Ruthenium labeled goat anti-rabbit IgG (labeled in-house) and 125 ug/ml of Streptavadin beads (Igen #M280), diluted in the same DPBS buffer, is added to detect the cleaved product. After a one hour incubation period at room temperature, an Igen M Series instrument is utilized to quantitate the results by electrochemiluminescence.
Gamma Secretase Whole Cell Assay (GSWC) Preparation of cells for assay
Human Embryonic Kidney (HEK) cells stably expressing human Amyloid Precursor protein (APP) and Presenelin I were grown in DMEM media (Fisher MT10013CN) containing 10% fetal calf serum (Fisher #MT135011CV), 0.2 mg/mL G418 (Fisher #MT30234CR) and IX concentration of antibiotic/antimycotic mixture (Fisher #MT30004CI). Cells were grown in tissue culture flasks and passaged every week at a ratio of 1:30.
Thirty minutes prior to incubation with test compounds, cells were harvested by treating the monolayer with DPBS (Fisher #MT21031CV) containing 3 mM EDTA. Cells were resuspended at a density of 2 million cells/mL in complete growth medium.
Test compounds were solubilized in DMSO at a concentration of 3.3 mM. From this stock solution a dilution series was prepared in complete growth medium of cells. Dilution series were then transferred to 96 well assay plate (Costar #3595) with 100 uL in each well. Cells (100 uL) were added to each well containing test compound. Two controls, one containing only cells (Total) and one containing only growth medium (Background) were also included. Cells were incubated with compounds for 14-16 hours in cell culture incubator.
At the end of 14-16 hour incubation, 100 uL of supernatant was transferred from each well in to a polypropylene 96 well plate. This supernatant was mixed with 100 u L of DPBS (Fisher # MT21031CV) containing 0.5% bovine serum albumin, 0.5% Tween (or an equivalent) 20, 0.25 u g/mL of biotinylated 4G8 (Senetek #240-10), 0.18 u g/mL rabbit anti-Aβ40 antibody (Biosource #44-3481), 0.045 ug/mL Ruthenium labeled goat anti-rabbit IgG (labeled in- house) and 60 ug/mL of Streptavadin beads (Igen #M280). The mixture was incubated for 4-6 hours at 4 °C on a plate shaker.
At the completion of 4-6 hour incubation, plate was brought to room temperature and the generated Aβ40 was detected using the Igen M8 analyzer. Raw data was imported into Microsoft Excel software. IC50 values for inhibition of Aβ 40 generation by test compounds were calculated using Excel-Fit.

Claims

Claims:
1. A compound of formula (I) or a pharmaceutically acceptable salt thereof:
Figure imgf000096_0001
(I)
wherein: Q is CH orN; W is N or S, when W is S, R6 is not present; X is C or N, provided that when Y and Z are C, X is N; Y is C or N, provided that when X and Z are C, Y is N; Z is C or N, provided that when X and Y are C, Z is N; R1 and R2 are at each occurrence independently selected from H, CH3, optionally substituted Cι.6alkyl, optionally substituted carbocycle, or optionally substituted heterocycle; or R1 and R2 in combination can form an optionally substituted heterocycle, or an optionally substituted carbocycle; R3 is selected from H, or optionally substituted C^alkyl; R4 is selected from H, optionally substituted Cι-6alkyl, -C(=O)OCH3; optionally substituted carbocycle, -C(=O)NH(CH2)heterocycle, or -C(=0)NH(CH2)CH3; R5 is selected from H, or CH3; R6 is selected from H; R7 is selected from optionally substituted carbocycle.
2. A compound of claim 1, wherein: Q is N.
3. A compound of claim 1, wherein: W is S, and R6 is not present.
4. A compound of claim 1, wherein: X is C.
5. A compound of claim 1 , wherein: Y is N.
6. A compound of claim 1, wherein: Z is N.
7. A compound of claim 1 , wherein: R and R are at each occurrence are independently selected from H, or optionally substituted carbocycle, or optionally substituted heterocycle.
8. A compound of claim 1, wherein: R3 is an optionally substituted Cι-6alkyl.
9. A compound of claim 1 , wherein: R4 is -C(=O)NH(CH2)heterocycle.
10. A compound of claim 1 , wherein: R5 is selected from H.
11. A compound of claim 1 , wherein: R7 is an optionally substituted carbocycle.
12. A compound of claim 1, wherein: Q is or C; W is S, and R6 is not present; X is C or N, provided that when Y and Z are C, X is N; Y is C or N, provided that when X and Z are C, Y is N; Z is C or N, provided that when X and Y are C, Z is N; R1 and R2 are at each occurrence independently selected from H, or optionally substituted carbocycle; or optionally substituted heterocycle or optionally substituted Cι-6alkyl; R3 is selected from H, or optionally substituted Cμ6alkyl; R4 is selected from H, -C(=O)NH(CH2)heterocycle or optionally substituted carbocycle; R5 is selected from H; R7 is selected from optionally substituted carbocycle.
13. A compound of claim 1 , wherein: Q is N or C; W is S, and R6 is not present; X is C or N, provided that when Y and Z are C, X is N; Y is C or N, provided that when X and Z are C, Y is N; Z is C or N, provided that when X and Y are C, Z is N; R1 and R2 are at each occurrence independently selected from H, or optionally substituted carbocycle; or optionally substituted heterocycle or optionally substituted Cι-6alkyl; R3 is selected from H, or optionally substituted Cι-6alkyl; R4 is selected from H, or -C(=O)NH(CH2)heterocycle; R5 is selected from H; R7 is selected from optionally substituted carbocycle.
14. A compound of claim 1, wherein: Q is N or C; W is S, and R6 is not present; X is C or N, provided that when Y and Z are C, X is N; Y is C or N, provided that when X and Z are C, Y is N; Z is C or N, provided that when X and Y are C, Z is N; R1 and R2 are at each occurrence independently selected from H, or optionally substituted carbocycle; or optionally substituted heterocycle; R3 is selected from H, or optionally substituted Cι-6alkyl; R4 is selected from H, -C(=0)NH(CH2)heterocycle; R5 is selected from H; R7 is selected from optionally substituted carbocycle.
15. A compound of claim 1 , wherein: Q is N or C; W is S, and R6 is not present; X is C orN; Y is N; Z is N; 1 R and R are at each occurrence independently selected from H, or optionally substituted carbocycle; or optionally substituted heterocycle; R3 is selected from H, or optionally substituted Cι-6alkyl; R4 is selected from H, -C(=O)NH(CH2)heterocycle; R5 is selected from H; R7 is selected from optionally substituted carbocycle.
16. A compound of claim 1 , wherein: Q is ; W is S, and R6 is not present; X is C orN; Y is N; Z is N; R1 and R2 are at each occurrence independently selected from H, or optionally substituted carbocycle; or optionally substituted heterocycle; R3 is selected from H, or optionally substituted C^a-kyl; R4is selected from H, -C(=0)NH(CH2)heterocycle; R5 is selected from H; R7 is selected from optionally substituted carbocycle.
17. A compound of claim 1, wherein: Q is N; W is S, and R6 is not present; X is C; Y is N; Z is N; R1 and R2 are at each occurrence independently selected from H, or optionally substituted carbocycle; or optionally substituted heterocycle; R3 is selected from H, or optionally substituted Cι-6alkyl; R4 is selected from H, -C(=O)NH(CH2)heterocycle; R5 is selected from H; R7 is selected from optionally substituted carbocycle.
18. A compound acroding to claim 1 selected from:
Methyl N-{4-[(3-fluorophenyl)amino]-6-[(2-hydroxypropyl)amino]-l,3,5-triazin-2-yl}-L- leucinate;
Methyl N-{4-[(3-fluorophenyl)amino]-6-morpholin-4-yl-l,3,5-triazin-2-yl}-L-leucinate;
(2R)-2-({4-[(3-fluorophenyl)amino]-6-[(3-methoxypropyl)amino]-l,3,5-triazin-2-yl}amino)- 4-methylpentan-l-ol;
Methyl N-{4-[(3-fluorophenyl)amino]-6-[(4-methoxybenzyl)amino]-l,3,5-triazin-2-yl}-D- leucinate;
Methyl N-{4-[(cyclopropylmethyl)amino]-6-[(3-fluorophenyl)amino]-l,3,5-triazin-2-yl}-D- leucinate; Methyl N-{4-[(3-fluorophenyl)amino]-6-[(3-methoxypropyl)amino]-l,3,5-triazin-2-yl}-D- leucinate;
(2R)-2-({4-[(cyclopropylmethyl)amino]-6-[(3-fluorophenyl)amino]-l,3,5-triazin-2- yl } amino)-4-methy lpentan- 1 -ol;
Methyl N-{4-[(3-fluorophenyl)amino]-6-[(tetrahydrofuran-2-ylmethyl)amino]- 1 ,3,5-triazin-2- yl} -L-leucinate;
Methyl N-(4-[(3-fluorophenyl)amino]-6-{[3-(lH-imidazol-l-yl)propyl]amino}-l,3,5-triazin-
2-yl)-L-leucinate;
Methyl N-{4-[(2-anilinoethyl)amino]-6-[(3-fluorophenyl)amino]-l,3,5-triazin-2-yl}-L- leucinate; Methyl N-{4-[(3-fluorophenyl)amino]-6-[(2 -hydroxy-2-phenylethyl)amino]-l,3,5-triazin-2- yl} -L-leucinate;
Methyl N-(4-[(3-fluorophenyl)amino]-6-{[2-(4-methoxyphenyl)ethyl]amino}-l,3,5-triazin-2- yl)-L-leucinate; Methyl N-{4-[(2,3-dihydroxypropyl)amino]-6-[(3-fluorophenyl)amino]-l,3,5-triazin-2-yl}-L- leucinate;
Methyl N-[4-[(3-fluorophenyl)amino]-6-(3-hydroxypyrrolidin-l-yl)-l,3,5-triazin-2-yl]-L- leucinate; Methyl N-{4-[(2-amino-2-oxoethyl)(methyl)amino]-6-[(3-fluorophenyl)amino]-l ,3,5-triazin-
2-yl}-L-leucinate;
(2R)-2-[(4-[(3-fluorophenyl)amino]-6-{[2-(4-methoxyphenyl)ethyl]amino}-l,3,5-triazin-2- y l)amino] -4-methy lpentan- 1 -ol;
Methyl N-{4-[(2-cyanoethyl)(methyl)amino]-6-[(3-fluorophenyl)amino]-l,3,5-triazin-2-yl}- L-leucinate;
Methyl N-[4-[(3-fluorophenyl)amino]-6-(4-pyridin-4-ylpiperazin-l-yl)-l,3,5-triazin-2-yl]-L- leucinate;
Methyl N-{4-(4-cyano-4-phenylpiperidin-l-yl)-6-[(3-fluorophenyl)amino]-l,3,5-triazin-2- yl} -L-leucinate; Methyl N-{4-[(3-fluorophenyl)amino]-6-[(3-hydroxy-2,2-dimethylpropyl)amino]-l,3,5- triazin-2-yl}-L-leucinate;
Methyl N-{4-[(3-fluorophenyl)amino]-6-[(3-morpholin-4-ylρropyl)amino]-l,3,5-triazin-2- yl} -L-leucinate;
Methyl N-{4-({2-[4-(aminosulfonyl)phenyl]ethyl} amino)-6-[(3-fluorophenyl)amino]-l ,3,5- triazin-2-yl}-L-leucinate;
Methyl N- {4- { [2-(dimethylamino)ethyl]amino } -6-[(3-fluorophenyl)amino]- 1 ,3 ,5-triazin-2- yl} -L-leucinate;
Methyl N-(4-[(3-fluorophenyl)amino]-6-{[2-(2-hydroxyethoxy)ethyl]amino}-l,3,5-triazin-2- yl)-L-leucinate; Methyl N-{4-[(3-fluorophenyl)amino]-6-[(4-hydroxybutyl)amino]-l,3,5-triazin-2-yl}-L- leucinate;
Methyl N-(4-[(3-fluorophenyl)amino]-6-{[3-(2-oxopyrrolidin-l-yl)propyl]amino}-l,3,5- triazin-2-yl)-L-leucinate;
Methyl N-[4-[(3-fluorophenyl)amino]-6-(4-methoxyphenyl)-l,3,5-triazin-2-yl]-L-leucinate; Methyl N-[4-[(3-fluorophenyl)amino]-6-(4-methoxybenzyl)-l,3,5-triazin-2-yl]-D-leucinate;
Methyl N-[4-[(3-fluorophenyl)amino]-6-(4-methoxybenzyl)-l,3,5-triazin-2-yl]glycinate;
(2S)-2-{[4-[(3-fluorophenyl)amino]-6-(4-methoxybenzyl)-l,3,5-triazin-2-yl]amino}-4- methy lpentan- 1 -ol; 9 A
N -Benzyl-N -(3-fluorophenyl)-6-(4-methoxybenzyl)-l,3,5-triazine-2,4-diamine;
N2- { 4-[(5 -fluoro-2-methy lpheny l)amino]-6- [(4-methoxypheny l)thio]py rimidin-2-y 1 } - l -
(tetrahydrofuran-2-ylmethyl)-L-leucinamide;
N2-{4-[(5-fluoro-2-methylphenyl)amino]-6-[(4-methoxyphenyl)thio]pyrimidin-2-yl}-N1- propyl-L-leucinamide;
N2-{4-[(3-cyanophenyl)amino]-6-[(4-methoxyphenyl)thio]pyrimidin-2-yl}-N1-
(tetrahydrofuran-2-ylmethyl)-L-leucinamide;
N -{4-[(5-Chloro-2-methylphenyl)amino]-6-[(4-methoxyphenyl)thio]pyrimidin-2-yl}-N1-
(tetrahydrofuran-2-ylmethyl)-L-leucinamide; N2-{4-[(3,5-Difluorophenyl)amino]-6-[(4-methoxyphenyl)thio]pyrimidin-2-yl}-N1-
(tetrahydrofuran-2-ylmethyl)-L-leucinamide;
Methyl N-[4-[(3-fluorophenyl)amino]-6-(4-methoxybenzyl)pyrimidin-2-yl]-L-leucinate;
Methyl N-[2-[(3-fluorophenyl)amino]-6-(4-methoxybenzyl)pyrimidin-4-yl]-L-leucinate;
(S)-2-[4-(3-Fluoro-phenylamino)-6-(4-methoxy-phenylsulfanyl)-l-oxy-pyridin-2-ylamino]-4- methyl-pentanoic acid methyl ester;
2-[6-(3-Fluoro-phenylamino)-2-(4-methoxy-phenylsulfanyl)-pyrimidin-4-ylamino]-4-methyl- pentanoic acid methyl ester;
(S)-2-[4-(3-Cyano-phenylamino)-6-(quinolin-8-ylsulfanyl)-pyrimidin-2-ylmethyl]-4-methyl- pentanoic acid (tetrahydro-furan-2-ylmethyl)-amide; (S)-2-[4-(4-Amino-phenylsulfanyl)-6-(3-cyano-phenylamino)-pyrimidin-2-ylmethyl]-4- methyl-pentanoic acid (tetrahydro-furan-2-ylmethyl)-amide;
19. A compound of formula (II) or a pharmaceutically acceptable salt thereof:
Figure imgf000102_0001
(ID wherein: Q is O. S, SO or SO2; W is N or halogen, when W is halogen neither R6 nor R7 are present; X is C or N, provided that when Y and Z are C, X is N; Y is C or N, provided that when X and Z are C, Y is N; Z is C or N, provided that when X and Y are C, Z is N; R2 is selected from H, optionally substituted Cι-6alkyl, optionally substituted carbocycle, or optionally substituted heterocycle; R3 is selected from H, or optionally substituted Cι-6alkyl; R4 is selected from H, optionally substituted Cι-6alkyl. optionally substituted heterocycle, cyano, -C(=O)OCH3, -C(=O)OCH3, -C(=O)NH2, -C(=O)NH-optionally substituted Cι-6alkyl, -C(=O)NH(CH2)o-3-optionally substituted carbocycle, -C(=O)NH(CH )o- 3-optionally substituted heterocycle, -C(=0)NH(CH2)!-3N(CH3)2, C(=O)NH(CH2)ι- 3C(OCH3)2, C(=O)NH(CH2)1-3NHC(=O)OC(CH3)3, -C(=O)NH(CH2)ι-30(CH2)1-3OH, -C(=0)-optionally substituted heterocycle, -C(=O)NH(CH2)i-3C(=O)OCH3, -C(=O)NH(CH2)1. 3OC(CH3)3, -C(=0)NH(CH2)u3SCH3, or C(=0)NH(CH2),.3C(=O)OH; R5 is selected from H, or CH3; R and R in combination form an optionally substituted heterocycle; R6 is selected from H or CH3; R7 is selected from optionally substituted Cι-6alkyl, optionally substituted carbocycle, optionally substituted heterocycle, or -(CH2)ι.3-oρtionally substituted carbocycle.
20. A compound of claim 19, wherein: Q is S.
21. A compound of claim 19, wherein: W isN.
22. A compound of claim 19, wherein: X is N.
23. A compound of claim 19, wherein: X is C.
24. A compound of claim 19, wherein: Y is N.
25. A compound of claim 19, wherein: Y is C.
26. A compound of claim 19, wherein: Z is N.
27. A compound of claim 19, wherein: Z is C.
28. A compound of claim 19, wherein: R2 is optionally substituted carbocycle.
29. A compound of claim 19, wherein: R3 is optionally substituted Cι-6alkyl.
30. A compound of claim 19, wherein: R4 is selected from, -C(=O)OCH3; -C(=O)-optionally substituted heterocycle, -C(=O)NH(CH2)o.3-optionally substituted heterocycle, or -C(=O)NH(CH2)ι-3SCH3.
31. A compound of claim 19, wherein: R5 is selected from H, or CH3.
32. A compound of claim 19, wherein: R6 is selected from H or CH3.
33. A compound of claim 19, wherein: R7 is optionally substituted carbocycle.
34. A compound of claim 19: wherein: Q is S, SO or SO2; W is N; X is C or N, provided that when Y and Z are C, X is N; Y is C or N, provided that when X and Z are C, Y is N; Z is C or N, provided that when X and Y are C, Z is N; R2 is selected from H, optionally substituted carbocycle, or optionally substituted heterocycle; R3 is optionally substituted Cι-6alkyl; R4 is selected from, -C(=O)OCH3, -C(=O)-optionally substituted heterocycle,
-C(=O)NH(CH )o-3-optionally substituted heterocycle, -C(=O)NH(CH2)ι-3SCH3, optionally substituted heterocycle, cyano, -C(=O)NH , -C(=0)NH-optionally substituted Ci-βalkyl. -C(=O)NH(CH2)0.3-optionally substituted carbocycle, -C(=O)NH(CH2)ι-3N(CH3)2, C(=0)NH(CH2)ι-3C(OCH3)2j C(=O)NH(CH2)ι-3NHC(=O)OC(CH3)3, -C(=O)NH(CH2)ι- 3O(CH2)ι.3OH, -, -C(=0)NH(CH2)ι-3C(=O)OCH3, -C(=O)NH(CH2)1-3OC(CH3)3, or C(=O)NH(CH2)ι-3C(=O)OH; R5is H; R4 and R5 in combination form an optionally substituted heterocycle; R6 is selected from H; R7 is selected from, optionally substituted carbocycle, optionally substituted heterocycle, or -(CH2)ι-3-optionally substituted carbocycle.
35. A compound of claim 19 : wherein: Q is S; W is N; X is C or N, provided that when Y and Z are C, X is N; Y is C or N, provided that when X and Z are C, Y is N; Z is C or N, provided that when X and Y are C, Z is N; R2 is selected from H, optionally substituted carbocycle, or optionally substituted heterocycle; R3 is optionally substituted Ct-ealkyl; R4 is selected from, -C(=O)OCH3, -C(=O)-optionally substituted heterocycle, - C(=O)NH(CH2)o-3-optionally substituted heterocycle, -C(=O)NH(CH2)1-3SCH3, optionally substituted heterocycle, cyano, -C(=O)NH2, -C(=O)NH-optionally substituted Cμ6alkyl, -C(=O)NH(CH2)o-3-optionally substituted carbocycle, -C(=O)NH(CH2)1-3N(CH3)2, C(=O)NH(CH2)ι-3C(OCH3)2, C(=O)NH(CH2)ι-3NHC(=O)OC(CH3)3, -C(=O)NH(CH2),- 3O(CH2),-3OH, -, -C(=O)NH(CH2)ι-3C(=O)OCH3ι-C(=O)NH(CH2)1-3OC(CH3)3, or C(=0)NH(CH2)ι-3C(=O)OH; R5 is H; R4 and R5 in combination form an optionally substituted heterocycle; R6 is selected from H; R7 is selected from, optionally substituted carbocycle, optionally substituted heterocycle, or -(CH2)ι-3-optionally substituted carbocycle.
36. A compound of claim 19: wherein: Q is S; W is N; X is C or N, provided that when Y and Z are C, X is N; Y is C or N, provided that when X and Z are C, Y is N; Z is C or N, provided that when X and Y are C, Z is N; R2 is selected from H, optionally substituted carbocycle; R3 is optionally substituted Cι-6alkyl; R4 is selected from, -C(=O)OCH3j -C(=O)-optionally substituted heterocycle, -C(=O)NH(CH )o-3-optionally substituted heterocycle, -C(=O)NH(CH2)ι-3SCH3, optionally substituted heterocycle, cyano, -C(=O)NH2, -C(=O)NH-optionally substituted -galkyl.
Figure imgf000106_0001
C(=O)NH(CH2)1-3C(OCH3)2, C(=0)NH(CH2)1-3NHC(=O)OC(CH3)35 -C(=0)NH(CH2)ι- 3O(CH2),-3OH, -, -C(=O)NH(CH2)1-3C(=0)OCH3, -C(=O)NH(CH2)ι-3OC(CH3)3, or C(=O)NH(CH2)ι-3C(=O)OH; R5 is H; R6 is selected from H; R7 is selected from, optionally substituted carbocycle, optionally substituted heterocycle, or -(CH2)ι-3-optionally substituted carbocycle.
37. A compound of claim 19: wherein: Q is S; W is N; X is C or N, provided that when Y and Z are C, X is N; Y is C or N, provided that when X and Z are C, Y is N; Z is C or N, provided that when X and Y are C, Z is N; R2 is an optionally substituted carbocycle; R3 is optionally substituted Cι-6alkyl; R is selected from, -C(=O)OCH3; -C(=O)-optionally substituted heterocycle, - C(=O)NH(CH2)o-3-optionally substituted heterocycle, -C(=O)NH(CH2)ι-3SCH3, optionally substituted heterocycle, cyano, -C(=O)NH2, -C(=O)NH-optionally substituted C βalkyl, -C(=O)NH(CH2)0-3-optionally substituted carbocycle, -C(=O)NH(CH2)ι-3N(CH3)2, C(=O)NH(CH2)1-3C(OCH3)2, C(=O)NH(CH2)ι-3NHC(=O)OC(CH3)3, -C(=O)NH(CH2)ι-
Figure imgf000107_0001
C(=O)NH(CH2)1_3C(=0)OH; R5 is H; R is selected from H; R7 is optionally substituted carbocycle,.
38. A compound of claim 19: wherein: Q is S; W is N; X is C or N, provided that when Y and Z are C, X is N; Y is C or N, provided that when X and Z are C, Y is N; Z is C or N, provided that when X and Y are C, Z is N; R is an optionally substituted carbocycle; R3 is optionally substituted Cι-6alkyl; RR44 iiss sseelleecctteedd ffrroomm,, --CC((==00))OOCCHH33,; --CCl(=O)-optionally substituted heterocycle, -C(=0)NH(CH2)o-3-optionally substituted heterocycle, -C(=O)NH(CH2)ι-3SCH3, optionally substituted heterocycle, -C(=O)NH2, -C(=O)NH(CH2)o-3-optionally substituted carbocycle; R5 is H; R6 is selected from H; R7 is optionally substituted carbocycle.
39. A compound of claim 19: wherein: Q is S; W is N; X is C or N, provided that when Y and Z are C, X is N; Y is C or N, provided that when X and Z are C, Y is N; Z is C or N, provided that when X and Y are C, Z is N; R2 is optionally substituted carbocycle; R3 is optionally substituted Cι-$alkyl; R4 is selected from, -C(=O)OCH3, -C(=O)-optionally substituted heterocycle, -C(=O)NH(CH2)0-3-optionally substituted heterocycle, or -C(=O)NH(CH2)ι-3SCH3; R5 is selected from H; R6 is selected from H; R7 is optionally substituted carbocycle.
40. A compound according to claim 19 selected from:
Methyl N-{4-(4-methoxyphenoxy)-6-[(thien-2-ylmethyl)amino]-l,3,5-triazin-2-yl}-L- leucinate; Methyl N-[4-(4-methoxyphenoxy)-6-(2-pyridin-4-ylethyl)-l ,3,5-triazin-2-yl]-L-leucinate;
Methyl N-[4-[(2,3-dihydroxypropyl)amino]-6-(4-methoxyphenoxy)-l,3,5-triazin-2-yl]-L- leucinate;
Methyl N-{4-(4-methoxyphenoxy)-6-[(tetrahydrofuran-2-ylmethyl)amino]-l,3,5-triazin-2- yl} -L-leucinate; Methyl N-[4-[(3-fluorobenzyl)amino]-6-(4-methoxyphenoxy)-l,3,5-triazin-2-yl]-L-leucinate;
Methyl N-[4-[(2-methoxybenzyl)amino]-6-(4-methoxyphenoxy)-l,3,5-triazin-2-yl]-L- leucinate; Methyl N-[4-[(355-difluorobenzyl)amino]-6-(4-methoxyphenoxy)-l,3,5-triazin-2-yl]-L- leucinate;
Methyl N-[4-[(3,5-dichlorobenzyl)amino]-6-(4-methoxyphenoxy)- 1 ,3,5-triazin-2-yl]-L- leucinate; Methyl N-[4-(benzylamino)-6-(4-methoxyphenoxy)- 1 ,3,5-triazin-2-yl]-L-leucinate;
Methyl N-[4-(butylamino)-6-(4-methoxyphenoxy)-l,3,5-triazin-2-yl]-L-leucinate;
Methyl N-[4-(pentylamino)-6-(4-methoxyphenoxy)- 1 ,3,5-triazin-2-yl]-L-leucinate;
Methyl N-{4-[(3-fluorophenyl)amino]-6-[(4-methoxyphenyl)thio]-l,3,5-triazin-2- yl}glycinate; (2R)-2-({4-[(5-Chloro-2-methylphenyl)amino]-6-[(4-methoxyphenyl)thio]-l,3,5-triazin-2- yl}amino)-4-methylpentan- 1 -ol;
Methyl N-{4-[(5-chloro-2-methylphenyl)amino]-6-[(4-methoxyphenyl)thio]-l,3,5-triazin-2- yl} -L-leucinate;
Methyl N-{4-[(3-fluorophenyl)amino]-6-[(4-methoxyphenyl)thio]-l,3,5-triazin-2-yl}-L- leucinate; l-{4-[(3-fluorophenyl)amino]-6-[(4-methoxyphenyl)thio]-l,3,5-triazin-2-yl}pyrrolidin-3-ol;
N2-{4-[(3-fluorophenyl)amino]-6-[(4-methoxyphenyl)thio]-l53,5-triazin-2-yl}-L-leucinamide;
N2-(3-fluorophenyl)-N4-isopentyl-6-[(4-methoxyphenyl)thio]-l,3,5-triazine-2,4-diamine
(2S)-2-({4-[(3-fluorophenyl)amino]-6-[(4-methoxyphenyl)thio]-lJ355-triazin-2-yl}amino)-4- methy lpentan- 1 -ol ;
Methyl N-{4-[(3-fluorophenyl)amino]-6-[(4-methoxyphenyl)thio]-l,3,5-triazin-2-yl}-L- phenylalaninate;
2-({4-[(3-fluorophenyl)amino]-6-[(4-methoxyphenyl)thio]-l,3,5-triazin-2-yl}amino)propan- l-ol; N2-(2,2-Dimethoxyethyl)-N4-(3-fluorophenyl)-6-[(4-methoxyphenyl)thio]-l,3,5-triazine-2,4- diamine;
Ethyl N- {4- [(3-fluoropheny l)amino]-6- [(4-methoxypheny l)thio] - 1 ,3 ,5 -triazin-2-y 1 } -b- alaninate;
3-[{4-[(3-fluorophenyl)amino]-6-[(4-methoxyphenyl)thio]-l,3,5-triazin-2- yl} (methy l)amino]propanenitrile;
Methyl N-{4-[(3-fluorophenyl)amino]-6-[(4-methoxyphenyl)thio]-l,3,5-triazin-2-yl}-L- alaninate; Methyl N-{4-[(3-fluorophenyl)amino]-6-[(4-methoxyphenyl)thio]-l,3,5-triazin-2-yl}-D- leucinate;
Methyl N-{4-[(2,3-dihydroxypropyl)thio]-6-[(3-fluorophenyl)amino]-l,3,5-triazin-2-yl}-L- leucinate; Methyl N-{4-[(3-fluorophenyl)amino]-6-[(3-methoxyphenyl)thio]-l,3,5-triazin-2-yl}-L- leucinate;
Methyl N-{4-[(3-fluorophenyl)(methyl)amino]-6-[(4-methoxyphenyl)thio]-l,3,5-triazin-2- yl} -L-leucinate;
(2R)-2-({4-[(3-fluorophenyl)amino]-6-[(4-methoxyphenyl)thio]-l,3,5-triazin-2-yl}amino)-4- methylpentan-1-ol;
Methyl N- {4- [(3 -fluoropheny l)amino]-6- [(2-methoxypheny l)thio] - 1 ,3 ,5 -triazin-2-yl } -L- leucinate;
Methyl N-[4-[(3-fluorophenyl)amino]-6-(phenylthio)- 1 ,3,5-triazin-2-yl]-L-leucinate;
Methyl N-[4-[(3-fluorophenyl)amino]-6-(quinolin-2-ylthio)- 1 ,3,5-triazin-2-yl]-L-leucinate; Methyl N-{4-[(4-aminophenyl)thio]-6-[(3-fluorophenyl)amino]-l53,5-triazin-2-yl}-L- leucinate;
Methyl N-{4-[(3-bromophenyl)thio]-6-[(3-fluorophenyl)amino]-l,3,5-triazin-2-yl}-L- leucinate;
Methyl N-[4-[(3-fluorophenyl)amino]-6-(pyrimidin-2-ylthio)-l,3,5-triazin-2-yl]-L-leucinate; Methyl N-{4-{[2-(dimethylamino)ethyl]thio}-6-[(3-fluorophenyl)amino]-l,3,5-triazin-2-yl}-
L-leucinate;
Methyl N-{4-({ l-[2-(dimethylamino)ethyl]-lH-tetraazol-5-yl}thio)-6-[(3- fluorophenyl)amino]- 1 ,3 ,5-triazin-2-y 1} -L-leucinate;
Methyl N-{4-[(3-fluorophenyl)amino]-6-[(4-methoxyphenyl)sulfinyl]-l,3,5-triazin-2-yl}-L- leucinate;
Methyl N- {4- [(3 -fl uorophenyl)amino] -6-[(4-methoxypheny l)sulfony 1]- 1 ,3 ,5 -triazin-2-y 1 } -L- leucinate;
N1-[2-(Dimethylamino)ethyl]-N2-{4-[(3-fluorophenyl)amino]-6-[(4-methoxyphenyl)thio]- l,3,5-triazin-2-yl}-L-leucinamide; N2-{4-[(3-fluorophenyl)amino]-6-[(4-methoxyphenyl)thio]-l,3,5-triazin-2-yl}-N1-
(tetrahydrofuran-2-ylmethyl)-L-leucinamide;
N2-{4-[(3-fluorophenyl)amino]-6-[(4-methoxyphenyl)thio]-l,3,5-triazin-2-yl}-N1-(2- morpholin-4-ylethyl)-L-leucinamide; N1-{2-[(tert-Butoxycarbonyl)amino]ethyl}-N2-{4-[(3-fluorophenyl)amino]-6-[(4- methoxyphenyl)thio]-l,355-triazin-2-yl}-L-leucinamide;
N2-{4-[(3-fluorophenyl)amino]-6-[(4-methoxyphenyl)thio]-l,3,5-tι-iazin-2-yl}-N1-(pyridin-3- ylmethyl)-L-leucinamide ; N1-(3,5-Difluorobenzyl)-N2-{4-[(3-fluorophenyl)amino]-6-[(4-methoxyphenyl)thio]-l,3,5- triazin-2-yl}-L-leucinamide;
N2-{4-[(3-fluorophenyl)amino]-6-[(4-methoxyphenyl)thio]-l,3,5-triazin-2-yl}-N1-(2- furylmethyl)-L-leucinamide;
N2-{4-[(3-fluoroρhenyl)amino]-6-[(4-methoxyphenyl)thio]-l,3:,5-triazin-2-yl}-NI-[3-(2- oxopyrrolidin- 1 -yl)propyl]-L-leucinamide;
N2-{4-[(3-fluorophenyl)amino]-6-[(4-methoxyphenyl)thio]-l,355-triazin-2-yl}-N1-(3- methoxybenzyl)-L-leucinamide;
N -{4-[(3-fluorophenyl)amino]-6-[(4-methoxyphenyl)thio]-l,3,5-triazin-2-yl}-NI-(2- piperidin- 1 -ylethyl)-L-leucinarnide; N2-{4-[(3-fluorophenyl)amino]-6-[(4-methoxyphenyl)thio]-l,3,5-triazin-2-yl}-N'-[2-(2- hydroxyethoxy)ethyl]-L-leucinamide;
N2-{4-[(3-fluorophenyl)amino]-6-[(4-methoxyphenyl)thio]-l,355-triazin-2-yl}-N1-phenyl-L- leucinamide;
N2- {4-[(3 -fluoropheny l)amino]-6- [(4-methoxypheny l)thio] -1,3 ,5 -triazin-2-yl } -N ! -propy 1-L- leucinamide;
N2-{4-[(3-fluorophenyl)amino]-6-[(4-methoxyphenyl)thio]-l,3,5-triazin-2-yl}-NI-(2- pyιτolidin-l-ylethyl)-L-leucinamide;
N2-(3-fluorophenyl)-6-[(4-methoxyphenyl)thio]-N4-[(lS)-3-methyl-l-(mo holin-4- ylcarbonyl)butyl]- 1 ,3,5-triazine-2,4-diamine; N]-{2-[4-(aminosulfonyl)phenyl]ethyl}-N2-{4-[(3-fluoroρhenyl)amino]-6-[(4- methoxyphenyl)thio]-l,3,5-triazin-2-yl}-L-leucinamide;
N2-{4-[(3-fluorophenyl)amino]-6-[(4-methoxyphenyl)thio]-l,3,5-triazin-2-yl}-NI-[2-(l- methylpyrrolidin-2-yl)ethyl]-L-leucinamide;
N2-{4-[(3-fluorophenyI)amino]-6-[(4-methoxyphenyl)thio]-l,3,5-triazin-2-yl}-N1-(3- methoxypropyl)-L-Ieucinamide;
N2-{4-[(3-fluorophenyl)amino]-6-[(4-methoxyphenyl)thio]-l,3,5-triazin-2-yl}-N1-(pyridin-2- ylmethyl)-L-leucinamide; Methyl N-{2-[(3-fluorophenyl)amino]-6-[(4-methoxyphenyl)thio]pyrimidin-4-yl}-L- leucinate;
Methyl N- {4- [(3 -fluoropheny l)amino] -6- [(4-methoxypheny l)thio]pyrimidin-2-yl } -L- leucinate; N-{4-[(3-fluorophenyl)amino]-6-[(4-methoxyphenyl)thio]pyrimidin-2-yl}-leucine;
N-{4-[(3-fluorophenyl)(methyl)amino]-6-[(4-methoxyphenyl)thio]pyrimidin-2-yl}-L-leucine;
N-{4-chloro-6-[(4-methoxyphenyl)thio]pyrimidin-2-yl}-N-methyl-leucine;
Methyl N-{4-[(3-fluorophenyl)amino]-6-[(4-methoxyphenyl)thio]pyrimidin-2-yl}-N- methylleucinate; N2-[4-[(3-fluorophenyl)amino]-6-(quinolin-2-ylthio)pyrimidin-2-yl]-N1-(tetrahydrofuran-2- ylmethyl)-L-leucinamide;
N2-{4-[(3-fluorophenyl)amino]-6-[(4-methoxyphenyl)thio]pyrimidin-2-yl}-N1-(2- furylmethyl)-L-leucinamide;
N2-{4-[(3-fluorophenyl)amino]-6-[(4-methoxyphenyl)thio]pyrimidin-2-yl}-N1- (tetrahydrofuran-2-ylmethyl)-L-leucinamide;
N2- {4- [(3 -fluoropheny l)amino] -6-[(4-methoxyphenyl)thio]pyrimidin-2-yl } -N1 -propyl-L- leucinamide;
N -{4-[(3-fluorophenyl)amino]-6-[(4-methoxyphenyl)thio]pyrimidin-2-yl}-N -(2-morpholin-
4-ylethyl)-L-leucinamide; N1-(2,2-methoxyethyl)-N2-{4-[(3-fluorophenyl)amino]-6-[(4-methoxyphenyl)thio]pyrimidin-
2-yl } -L-leucinamide;
N2-{4-[(3-fluorophenyl)amino]-6-[(4-methoxyphenyl)thio]pyrimidin-2-yl}-N1-(2-pyridin-2- ylethyl)-L-leucinamide;
Methyl N-{4-[(3-fluorophenyl)amino]-6-[(4-methoxyphenyl)thio]pyrimidin-2-yl}-L- leucylglycinate;
N - {4- [(3 -fluoropheny l)amino] -6- [(4-methoxypheny l)thio]pyrimidin-2-y 1 } -N -[3 -( 1 H- imidazol-l-yl)propyl]-L-leucinamide;
N2-{4-[(3-fluorophenyl)amino]-6-[(4-methoxyphenyl)thio]pyrimidin-2-yl}-N1-(2- isopropoxyethyl)-L-leucinamide; N2- {4- [(3 -fluoropheny l)amino]-6- [(4-methoxypheny l)thio]pyrimidin-2-y 1 } -N1 - [2-
(methylthio)ethyl]-L-leucinamide;
N2-{4-[(3-fluorophenyl)amino]-6-[(4-methoxyphenyl)thio]pyrimidin-2-yl}-N1-pentyl-L- leucinamide; N-{4-[(3-fluorophenyl)amino]-6-[(4-methoxyphenyl)thio]pyrimidin-2-yl}-L-leucylglycine;
N -{4-[(3-fluorophenyl)amino]-6-[(4-methoxyphenyl)thio]pyrimidin-2-yl}-N1-[2-(lH- imidazol-5-yl)ethyl]-L-leucinamide;
N2- { 4- [(3 -fluoropheny l)amino] -6-[(4-methoxypheny l)thio]pyrimidin-2-y 1 } - ] -methoxy-N1 - methyl-L-leucinamide;
N2-{2-[(3-fluorophenyl)amino]-6-[(4-methoxyphenyl)thio]pyrimidin-4-yl}-N1-(2-morpholin-
4-ylethyl)-L-leucinamide;
N2-{2-[(3-fluorophenyl)amino]-6-[(4-methoxyphenyl)thio]pyrimidin-4-yl}-N1-
(tetrahydrofuran-2-ylmethyl)-L-leucinamide; N2-{2-[(3-fluorophenyl)amino]-6-[(4-methoxyphenyl)thio]pyrimidin-4-yl}-N1-propyl-L- leucinamide;
(S)-2-[4-(3-Cyano-phenylamino)-6-(thiazol-2-ylsulfanyl)-pyrimidin-2-ylmethyl]-4-methyl- pentanoic acid (tetrahydro-furan-2-ylmethyi)-amide;
(S)-2-[4-(3-Cyano-phenylamino)-6-(pyridin-2-ylsulfanyl)-pyrimidin-2-ylmethyl]-4-methyl- pentanoic acid (tetrahydro-furan-2-ylmethyl)-amide;
N2- {4- [((3 -Methyl-propyl)thio)amino] -6- [(4-methoxyphenyl)thio]pyrimidin-2-yl } -N1 -
(tetrahydrofuran-2-ylmethyl)-L-leucinamideN2-{4-[(2-Pyridyl)amino]-6-[(4- methoxyphenyl)thio]pyrimidin-2-yl}-N1-(tetrahydrofuran-2-ylmethyl)-L-leucinamide (S)-2-[4-(3-Cyano-phenylamino)-6-(4-methoxy-phenylsulfanyl)-pyrimidin-2-ylmethyl]-4- methyl-pentanoic acid (2-methylsulfanyl-ethyl)-amide;
N2-{2-[(3-Fluorophenyl)amino]-6-[(4-methoxyphenyl)thio]pyrimidin-4-yl}-N1-l-morpholin-
4-yl-L-leucinamide
2-[6-(3-Fluoro-phenylamino)-2-(4-methoxy-phenylsulfanyl)-pyrimidin-4-ylamino]-4-methyl- pentanoic acid methyl ester; (S)-2-[6-(3-Fluoro-phenylamino)-4-(4-methoxy-phenylsulfanyl)-pyridin-2-ylamino]-4- methyl-pentanoic acid methyl ester;
Ν -(3-Fluoro-phenyl)-6-(4-methoxy-phenylsulfanyl)-Ν -(3-methyl-l-pyridin-2-yl-butyl)- pyrimidine-2,4-diamine;
N4-(3-Fluoro-phenyl)-6-(4-methoxy-phenylsulfanyl)-N"-(3-methyl-l-pyridin-2-yl-butyl)- pyrimidine-2,4-diamine;
(S)-2-[4-(3-Cyano-phenylamino)-6-(quinolin-8-ylsulfanyl)-pyrimidin-2-ylmethyl]-4-methyl- pentanoic acid (tetrahydro-furan-2-ylmethyl)-amide; (S)-2-[4-(4-Amino-phenylsulfanyl)-6-(3-cyano-phenylamino)-pyrimidin-2-ylmethyl]-4- methyl-pentanoic acid (tetrahydro-furan-2-ylmethyl)-amide;
(S)-2-[3-(3-Fluoro-phenylamino)-5-(4-methoxy-phenylsulfanyl)-phenylamino]-4-methyl- pentanoic acid methyl ester; (S)-2-[2-(3-Fluoro-phenylamino)-6-(4-methoxy-phenylsulfanyl)-pyridin-4-ylamino]-4- methyl-pentanoic acid methyl ester;
(S)-2-[6-(3-Fluoro-phenylamino)-4-(4-methoxy-phenylsulfanyl)-l-oxy-pyridin-2-ylamino]-4- methyl-pentanoic acid methyl ester;
(S)-2-[4-(3-Fluoro-phenylamino)-6-(4-methoxy-phenylsulfanyl)-pyridin-2-ylamino]-4- methy 1-pentanoic acid methyl ester.
41. A compound according to any one of claims 1 -40, for use as a medicament.
42. The use of a compound according to any one of claims 1-40 in the manufacture of a medicament for the treatment or prophylaxis of disorders associated with β-amyloid production.
43. The use of a compound according to any one of claims 1-40 in the manufacture of a medicament for the treatment or prophylaxis of Alzheimer's disease or Down's syndrome.
44. A method for the treatment of neurological disorders associated with β-amyloid production comprising administring to a warm-blooded animal in need of such treatment a therapeutically effective amount of a compound according to any one of claims 1-40.
45. A method for inhibiting γ-secretase activity comprising administering to a warmblooded animal in need of such inhibition a therapeutically effective amount of a compound according to any one of claims 1-40.
46. A method for the treatment or prophylaxis of Alzheimer's disease or Down's syndrome comprising administring to a warm-blooded animal in need of such treatment a therapeutically effective amount of a compound according to any one of claims 1-40.
47. A pharmaceutical composition comprising a compound according to any one of claims 1-40, or a pharmaceutically acceptable salt or in vivo hydroly sable ester therof, together with at least one pharmaceutically acceptable carrier, diluent or excipent.
48. A process for preparing a compound of formula (I) as recited in claim 1 or a pharmaceutically acceptable salt or in vivo hydroly sable ester therof which process comprises:
Figure imgf000115_0001
Figure imgf000115_0002
Figure imgf000115_0003
49. A process for preparing a compound of formula (II) as recited in claim 19 or a pharmaceutically acceptable salt or in vivo hydrolysable ester therof which process comprises:
Figure imgf000116_0001
1c
Figure imgf000116_0002
1d
Figure imgf000116_0003
1b 1d
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