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WO2003055866A1 - Quinazoline and quinoline derivative compounds as inhibitors of prolylpeptidase, inducers of apoptosis and cancer treatment agents - Google Patents

Quinazoline and quinoline derivative compounds as inhibitors of prolylpeptidase, inducers of apoptosis and cancer treatment agents Download PDF

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Publication number
WO2003055866A1
WO2003055866A1 PCT/US2002/041176 US0241176W WO03055866A1 WO 2003055866 A1 WO2003055866 A1 WO 2003055866A1 US 0241176 W US0241176 W US 0241176W WO 03055866 A1 WO03055866 A1 WO 03055866A1
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Prior art keywords
optionally substituted
halogen
group
linear
branched alkyl
Prior art date
Application number
PCT/US2002/041176
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French (fr)
Inventor
Jacques Dumas
Robert Sibley
Roger Smith
Ning Su
Yuanwei Chen
Jill Wood
Leatte Guernon
Julie Dixon
Catherine Brennan
Stephen Boyer
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Bayer Pharmaceuticals Corporation
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Priority to AU2002361846A priority Critical patent/AU2002361846A1/en
Publication of WO2003055866A1 publication Critical patent/WO2003055866A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms 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
    • C07D215/38—Nitrogen atoms
    • C07D215/42—Nitrogen atoms attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/95—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in positions 2 and 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • 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
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to:
  • compositions comprising one or more of the compounds or purified stereoisomers or stereoisomer mixtures of the invention, or their salts or prodrugs forms thereof, with a pharmaceutically acceptable ingredient;
  • Z is CH orN; Y is O or S; X is OR 5 orNR 5 R 6 ;
  • Ri and R 2 are independently selected from the group consisting of hydrogen, amino, cyano, halogen, hydroxy and nitro,
  • R 3 is selected from the group consisting of: (a) hydrogen, and (b) -(C Cio) linear or branched alkyl;
  • R4 is -(CH ⁇ y -R wherein: j' is selected from the group consisting of:
  • R 5 has the formula -(CHR ⁇ ) m -A or -(CHR ⁇ ) p -O-A, where A is selected from the group consisting of:
  • R 5 and R 6 are not both hydrogen
  • R 5 and R 6 form, together with the nitrogen to which they are attached, a saturated or fully unsaturated four to eight membered heterocyclic ring, which optionally contains one to three additional nitrogen atoms wherein said ring contains at least one carbon atom, and wherein said ring is optionally substituted with one to three substituents selected from the group consisting of:
  • R 3 /R(. or R 5 /R 6 contain an unsubstituted -(CH 2 ) n -C 6 -C 10 -aryl substiruent, or (2) Rs ⁇ or R 5 /R 6 form a heterocyclic ring;
  • R 8 and R 9 are independently selected from the group consisting of: (a) hydrogen, (b) -(Ci-C 5 ) linear or branched alkyl which is optionally substituted with a substiruent selected from the group consisting of halogen and -(Ci- Cs) alkoxy,
  • R 8 and R 9 form, together with the nitrogen to which they are attached, a saturated or fully unsaturated four to eight membered heterocyclic ring, optionally containing one to three additional heteroatoms selected from the group consisting of nitrogen and oxygen wherein said ring contains at least one carbon atom and wherein said heterocyclic ring is optionally substituted with -( -C 5 ) linear or branched alkyl;
  • R 10 is hydrogen, -NR 8 R 9 , -ORn, -(C 1 -C 5 ) linear or branched alkyl, or phenyl;
  • each occurrence of Rn is independently selected from the group consisting of hydrogen, -(Ci-Cs) linear or branched alkyl and phenyl;
  • n, m and p are independently an integer from 0 - 3;
  • y is an integer from 0 - 2;
  • Z is CH or N
  • Y is O or S
  • X is OR 5 orNR 5 R6;
  • Ri and R 2 are hydrogen;
  • R 3 is selected from the group consisting of:
  • R 4 is -(CH ⁇ y R , wherein
  • R 4 ' is:
  • R 5 has the formula -(CHRn) m -A or -(CHR ⁇ ) p -O-A, where A is selected from the group consisting of:
  • R 6 is selected from the group consisting of: (a) hydrogen, and (b) -(Ci-Cs) linear or branched alkyl,
  • R 5 and R 6 are not both hydrogen
  • R 5 and R 6 form, together with the nitrogen to which they are attached, a saturated or fully unsaturated four to eight membered heterocyclic ring, optionally containing one to three additional heteroatoms selected from the group consisting of nitrogen and oxygen wherein said ring contains at least one carbon atom wherein said heterocyclic ring is optionally substituted with -(C 1 -C 5 ) alkyl;
  • R 9 are independently selected from the group consisting of: (a) hydrogen,
  • R is a saturated or fully unsaturated five to six membered heterocyclic ring containing one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein said ring contains at least one carbon atom, wherein (c)-(e) are optionally substituted with one to three substituents selected from the group consisting of halogen, -(Ci-Cs) alkoxy- and -(C JL -C S ) linear or branched alkyl optionally substituted by halogen;
  • R 10 is hydrogen, -NR 8 R 9 , -OR ⁇ , -(Ci-C 5 ) linear or branched alkyl, or phenyl;
  • each occurrence of R ⁇ is independently selected from the group consisting of hydrogen, -(Ci-Cs) linear or branched alkyl and phenyl;
  • R 12 is -R 13 , -OR 13 , or - R 14 R 15 ;
  • R 14 and R 15 are independently selected from the group consisting of: (a) hydrogen, (b) -(C Cs) linear or branched alkyl optionally substituted with halogen, and
  • n, m and p are independently an integer from 0 - 3;
  • y is an integer from 0 - 2;
  • y + (m + p) equals an integer from 1 - 8;
  • Embodiment 3 Also described are compounds with the formula (I) and (II) wherein: Z is CH orN; Y is O or S; X is OR 5 orNR 5 R 6 ;
  • Ri and R 2 are independently selected from the group consisting of hydrogen and -OCH 3 wherein at least one of Ri and R 2 is -OCH 3 ;
  • R 3 is hydrogen; j is -(CH 2 ) y -R 4 wherein:
  • R is selected from the group consisting of:
  • A is selected from the group consisting of: (a) hydrogen,
  • (al7) contains at least one carbon atom; (bl7) is directly linked to the -(C 6 -C 10 )-aryl or is linked to the -(C 6 -C ⁇ o)-aryl via an -O- linkage, and (cl7) is optionally substituted with -(Ci-Cs)-alkyl,
  • A is selected from the group consisting of: (a) hydrogen, (b) -(Ci-C 5 ) linear or branched alkyl optionally substituted with cyano, halogen, hydroxy, -(Ci-Cs) alkoxy or -NR 8 R ,
  • a fused bicyclo ring wherein one ring is a saturated or fully unsaturated five to six membered heterocyclic ring which contains one to tliree heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein said heterocyclic ring contains at least one carbon atom and the other ring is a saturated or fully unsaturated five to eight membered carbocycle;
  • R 5 and R 6 are not both hydrogen
  • R 5 and R 6 form, together with the nitrogen to which they are attached, a saturated or fully unsaturated four to eight membered heterocyclic ring, which optionally contains one to three additional heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur wherein said ring contains at least one carbon atom, and wherein said ring is optionally substituted with one to three substituents selected from the group consisting of: (a) amino, (b) cyano,
  • (ql) a four to eight membered saturated or fully unsaturated heterocyclic ring containing one to four nitrogens, wherein said ring contains at least one carbon atom, or (q2) -C 6 -C 10 -aryl optionally substituted with halogen or -( -Cs) alkyl;
  • R 8 and R form, together with the nitrogen to which they are attached, a saturated or fully unsaturated, four to eight membered heterocyclic ring, wherein said ring has one to three additional heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur wherein said ring contains at least one carbon atom and wherein said heterocyclic ring is optionally substituted with -(Ci-C 5 ) linear or branched alkyl;
  • R 10 is hydrogen, -NR 8 R 9 , -OR ⁇ , -(C ⁇ Cs) linear or branched alkyl, or phenyl;
  • R u is hydrogen, -( -Cs) linear or branched alkyl, or phenyl; n, m and p are independently an integer from 0 - 3; and
  • y is an integer from 0 - 2
  • the preferred compounds of embodiment 1 have general formula (I) and are further defined below.
  • the definitions for the various groups and variables represent the preferred definitions when they differ from those of embodiment 1 as broadly defined above, and are to be understood as independent of each other.
  • X is OR 5 orNR 5 R 6 ;
  • Ri and R 2 are independently selected from the group consisting of hydrogen, cyano, halogen, and hydroxy, and wherein Ri and R 2 are both not hydrogen;
  • R 3 is selected from the group consisting of:
  • R 4 is -(CH 2 )y-R 4 l wherein: R t ' is selected from the group consisting of:
  • R 5 has the formula -(CHR ⁇ ) m -A or -(CHR ⁇ ) p -O-A, wherein R ⁇ is H and A is selected from the group consisting of:
  • R 6 is selected from the group consisting of: (a) hydrogen, and (b) -(Ci-C 5 ) linear or branched alkyl,
  • R 5 and R 6 are not both hydrogen;
  • R 5 /R 6 contain an unsubstituted -(CH 2 ) n -C 6 -C ⁇ 0 -aryl substituent, or
  • R 7 is selected from the group consisting of hydrogen, -(Ci-Cs) linear or branched alkyl, and phenyl, which are optionally substituted with one to three substituents selected from the group consisting of halogen, oxo, -(Ci-Cs) alkoxy, and -(Ci-Cs) linear or branched alkyl optionally substituted by halogen;
  • R 8 and R 9 are independently selected from the group consisting of:
  • R 8 and R form, together with the nitrogen to which they are attached, a saturated or fully unsaturated five or six membered heterocyclic ring, optionally containing one to two additional heteroatoms selected from the group consisting of nitrogen and oxygen;
  • R 10 is hydrogen, -NR 8 R 9 , -OR l l5 -(Ci-C 5 ) linear or branched alkyl, or phenyl;
  • each occunence of R ⁇ is independently selected from the group consisting of hydrogen and -(C 1 -C 5 ) linear or branched alkyl and phenyl;
  • n, m and p are independently an integer from 0 - 3;
  • y is an integer from 0 - 2;
  • Embodiment 1 more preferred compounds
  • the more prefened compounds of embodiment 1 have general formula (I) and are further defined below.
  • the definitions for the various groups and variables represent the more prefened definitions when they differ from those of embodiment 1 as broadly defined above, and are to be understood as independent of each other.
  • X is NR 5 R 6 ;
  • Ri and R 2 are independently selected from the group consisting of hydrogen and halogen, wherein Ri and R are both not hydrogen;
  • R 3 is hydrogen
  • R 4 ' is selected from the group consisting of:
  • R 3 and R 4 form, together with the nitrogen to which they are attached, a saturated six membered heterocyclic ring, wherein the nitrogen is the only heteroatom
  • R 5 has the formula -(CHR ⁇ ) m -A or -(CHR ⁇ ) p -O-A, wherein R ⁇ is H and A is selected from the group consisting of:
  • R 5 and R 6 form, together with the nitrogen to which they are attached, a fully saturated five or six membered heterocyclic ring, which optionally contains one additional nitrogen atom, and wherein said ring is optionally substituted with one to two substituents selected from the group consisting of:
  • R is selected from the group consisting of hydrogen, -( -C 5 ) linear or branched alkyl and phenyl, which are optionally substituted with one halogen,
  • R 8 and R 9 are independently selected from the group consisting of:
  • R ⁇ o is -NR 8 R 9 or -ORii ,
  • each occunence of Rn is hydrogen
  • n, m and p are independently an integer from 0 - 3; y is an integer from 0 - 2;
  • the prefened compounds of embodiment 2 have general formula (I) and are further defined below.
  • the definitions for the various groups and variables represent the preferred definitions when they differ from those of embodiment 2 as broadly defined above, and are to be understood as independent of each other.
  • the prefened compounds of embodiment 2 have the formula (I)
  • X is OR 5 orNR 5 R 6 ;
  • R] and R are hydrogen
  • R 3 is selected from the group consisting of:
  • R is -(CH 2 ) y R ' 5 wherein
  • R is:
  • R 5 has the formula -(CHRu) m -A or -(CHR ⁇ ) p -O-A, wherein R ⁇ is H and A is selected from the group consisting of: (a) hydrogen,
  • (9) -S( O) 2 R 10 ; and (10) a saturated or fully unsaturated four to eight membered heterocyclic ring containing one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein said ring: (alO) contains at least one carbon atom; (blO) is directly linked to the -(C 6 -Ci 0 )-aryl or is linked to the -(C 6 -do)-aryl via an -O- linkage; and (clO) is optionally substituted with -(Ci-C 5 )-alkyl, -(CH 2 ) n COOR 7 or -(CH 2 ) conflictCONR 8 R 9 , and
  • R 6 is selected from the group consisting of:
  • R 5 and R 6 are not both hydrogen;
  • R 5 and R 6 form, together with the nitrogen to which they are attached, a saturated five to seven membered heterocyclic ring, optionally containing one additional heteroatom selected from the group consisting of nitrogen and oxygen wherein said heterocyclic ring is optionally substituted with -(C ⁇ -Cs)-alkyl;
  • R 7 is selected from the group consisting of hydrogen, -(C Cs) linear or branched alkyl and phenyl, which are optionally substituted with one to three substituents selected from the group consisting of halogen, oxo, -(Ci-Cs) alkoxy-, and -( -C 5 ) linear or branched alkyl optionally substituted by halogen;
  • R 8 and R 9 are independently selected from the group consisting of:
  • (c) -(C ⁇ -Cio) aryl, and wherein (c) is optionally substituted with one to three substituents selected from the group consisting of halogen,-(C 1 -Cs) alkoxy and -(Ci-Cs) linear or branched alkyl optionally substituted by halogen;
  • R 10 is hydrogen, -NR 8 R 9 , -ORn, -(C ⁇ -C 5 ) linear or branched alkyl, or phenyl; each occunence of R ⁇ is independently selected from the group consisting of hydrogen and -(Ci-Cs) linear or branched alkyl and phenyl;
  • R12 is -R 13 , -OR 13 , or -NR ⁇ 4 R 15 ;
  • R 13 is
  • R 1 and R 15 are independently selected from the group consisting of:
  • n, m and p are independently an integer from 0 - 3;
  • y is an integer from 0 - 2;
  • y + (m + p) equals an integer from 1 - 8;
  • the more prefened compounds of embodiment 2 have general formula (I) and are further defined below.
  • the definitions for the various groups and variables represent the more prefened definitions when they differ from those of embodiment 2 as broadly defined above, and are to be understood as independent of each other.
  • the more prefened compounds of embodiment 2 have the formula (I)
  • X is NR 5 R 6 ;
  • Ri and R 2 are hydrogen;
  • R 3 is hydrogen
  • R4 is -(CH 2 )yR ', wherein
  • R t ' is:
  • R 5 has the formula -(CHR ⁇ ) m -A or -(CHR ⁇ ) p -O-A, wherein R ⁇ is H and A is selected from the group consisting of:
  • R 6 is hydrogen
  • R 6 form, together with the nitrogen to which they are attached, a saturated five or six membered heterocyclic ring, optionally containing one additional heteroatom selected from the group consisting of nitrogen and oxygen, wherein said heterocyclic ring is optionally substituted with-(Ci-Cs)-alkyl;
  • R 7 is selected from the group consisting of hydrogen, -(Ci-Cs) linear or branched alkyl, and phenyl, which are optionally substituted with one halogen substituent,
  • R 8 and R 9 are independently selected from the group consisting of:
  • R 10 is -NR 8 R 9 or -OR ⁇ ,
  • each occunence of R ⁇ is hydrogen
  • R12 is -OR13, or -NR 14 R ⁇ 5 ;
  • R 13 is (a) hydrogen, or
  • R 14 and R 15 are independently selected from the group consisting of:
  • n, m and p are independently an integer from 0 - 3;
  • y is an integer from 0 - 2;
  • y + (m + p) equals an integer from 1 - 8;
  • the prefened compounds of embodiment 3 have general formula (I) and are further defined below.
  • the definitions for the various groups and variables represent the prefened definitions when they differ from those of embodiment 3 as broadly defined above, and are to be understood as independent of each other.
  • the prefened compounds of embodiment 3 have the fonnula (I)
  • X is OR 5 orNR 5 R 6 ;
  • Ri and R 2 are independently selected from the group consisting of hydrogen and -OCH 3 wherein at least one of Ri and R 2 is -OCH 3 ;
  • R 3 is hydrogen;
  • R 4 is -(CH 2 ) y -R 4 ' wherein:
  • R ' is selected from the group consisting of:
  • Rs has the formula: -(CH 2 ) p -O-A where A is selected from the group consisting of:
  • A is selected from the group consisting of: (a) -(C 1 -C 5 ) linear or branched alkyl optionally substituted with halogen, - (C 1 -C 5 ) alkoxy or -NR 8 R 9 ,
  • R 6 is selected from the group consisting of: (a) hydrogen, and
  • R 5 and Re form, together with the nitrogen to which they are attached, a saturated five to seven membered heterocyclic ring, which optionally contains one additional heteroatom selected from the group consisting of nitrogen, oxygen and sulfur, wherein said ring is optionally substituted with one to three substituents selected from the group consisting of: (a) halogen,
  • R 7 is selected from the group consisting of hydrogen, -(Ci-Cs) linear or branched alkyl and phenyl, which are optionally substituted with one to three substituents selected from the group consisting of halogen, oxo,
  • R 8 and R are independently selected from the group consisting of hydrogen, -(Ci-C 5 ) linear or branched alkyl, and -(Ce-C 10 ) aryl which is optionally substituted with one to three substituents selected from the group consisting of halogen and -( - C 5 ) alkoxy, or
  • R 8 and R 9 form, together with the nitrogen to which they are attached, a saturated or fully unsaturated, five or six membered heterocyclic ring, wherein said ring has one to two additional heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur,
  • Rio is hydrogen, -NR 8 R 9 , -OR ⁇ , -(Ci-Cs) linear or branched alkyl, or phenyl;
  • R ⁇ is hydrogen, -(C Cs) linear or branched alkyl, or phenyl
  • n, m and p are independently an integer from 0 - 3;
  • y is an integer from 0 - 2
  • the more prefened compounds of embodiment 3 have general formula (I) and are further defined below.
  • the definitions for the various groups and variables represent the more prefened definitions when they differ from those of embodiment 3 as broadly defined above, and are to be understood as independent of each other.
  • X is NR 5 R 6 ;
  • Ri and R 2 are independently selected from the group consisting of hydrogen and
  • R 4 ' is selected from the group consisting of:
  • R 3 and t form, together with the nitrogen to which they are attached, a saturated six membered heterocyclic ring, wherein the nitrogen is the only heteroatom, which is unsubstituted;
  • R 5 has the formula:
  • A is selected from the group consisting of:
  • R 6 is hydrogen
  • R 5 and R 6 form, together with the nitrogen to which they are attached, a saturated five or six membered heterocyclic ring, which optionally contains one additional heteroatom selected from the group consisting of nitrogen, oxygen and sulfur wherein said ring is optionally substituted with one or two substituents selected from the group consisting of:
  • R 7 is selected from the group consisting of hydrogen, -(C Cs) linear or branched alkyl and phenyl, which are optionally substituted with one to three halogen substituents;
  • R 8 and R 9 are independently selected from the group consisting of hydrogen, -(Ci-C 5 ) linear or branched alkyl, and phenyl which is optionally substituted with one substituent selected from the group consisting of halogen and -(C Cs) alkoxy,
  • R 10 is -NR 8 R 9 or -OR ⁇ , Rii is hydrogen, or -( -Cs) linear or branched alkyl
  • n, m and p are independently an integer from 0 - 3;
  • y is an integer from 0 - 2
  • Salts are especially the pharmaceutically acceptable salts of compounds of formulae (I) or (II) such as, for example, organic or inorganic acid addition salts of compounds of formulae (I) or (II).
  • Suitable inorganic acids include but are not limited to halogen acids (such as hydrochloric acid), sulfuric acid, or phosphoric acid.
  • Suitable organic acids include but are not limited to carboxylic, phosphonic, sulfonic, or sulfamic acids, with examples including acetic acid, trifluoroacetic acid, propionic acid, octanoic acid, decanoic acid, dodecanoic acid, glycolic acid, lactic acid, 2- or 3-hydroxybutyric acid, ⁇ -aminobutyric acid (GAB A), gluconic acid, glucosemonocarboxylic acid, benzoic acid, salicylic acid, phenylacetic acid, mandelic acid, methanesulfonic acid, trifluoromethanesulfonic acid, fumaric acid, oxalic acid, succinic acid, adipic acid, pimelic acid, suberic acid, azeiaic acid, malic acid, tartaric acid, citric acid, glucaric acid, galactaric acid, amino acids (such as glutamic acid, aspartic acid, N-methylglycine,
  • pharmaceutically acceptable salts include acid salts of inorganic bases, such as salts containing alkaline cations (e.g., Li + Na + or K + ), alkaline earth cations (e.g., Mg +2 , Ca +2 or Ba +2 ), the ammonium cation, as well as acid salts of organic bases, including aliphatic and aromatic substituted ammonium, and quaternary ammonium cations such as those arising from protonation or peralkylation of triethylamine, N,N-diethylamine, N,N- dicyclohexylamine, pyridine, N,N-dimethylaminopyridine (DMAP), 1,4- diazabicyclo[2.2.2]octane (DABCO), l,5-diazabicyclo[4.3.0]non-5-ene (DBN) and 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU).
  • Prodrugs are considered to be any covalently bonded carriers which release the active parent compound of formula (I) or (II) in vivo. Formation of prodrugs is well known in the art in order to enhance the properties of the parent compound; such properties include solubility, absorption, biostability and release time (see “Pharmaceutical Dosage Form and Drug Delivery Systems” (Sixth Edition), edited by Ansel et al., publ. by Williams & Wilkins, pgs. 27-29, (1995) which is hereby incorporated by reference).
  • prodrugs of the disclosed compounds of formula (I) and (II) are designed to take advantage of the major drug biotransformation reactions and are also to be considered within the scope of the invention.
  • Major drug biotransformation reactions include N- dealkylation, O-dealkylation, aliphatic hydroxylation, aromatic hydroxylation, N-oxidation, S-oxidation, deamination, hydrolysis reactions, glucuronidation, sulfation and acetylation (see Goodman and Gilman's The Pharmacological Basis of Therapeutics (Tenth Edition), editor Hardman et al., publ. by McGraw-Hill, pages 12-18, (2001), wliich is hereby incorporated by reference).
  • halogen refers to fluorine, chlorine, bromine, and iodine substituents for the purposes of this invention.
  • the alkyl may be fully substituted, up to perhalo.
  • fused bicyclo ring refers to a substituent which is a two ring structure which share two carbon atoms.
  • the bonding between the fused bicyclo ring and the compound and/or atom to which it is attached can be through either of the two rings.
  • Z is CH or N; Y is O or S; X is OR 5 or NR 5 Re;
  • Ri, Ri ' , R 2 and R 2' are independently selected from the group consisting of hydrogen, amino, cyano, halogen, hydroxy, methoxy and nitro;
  • R 3 is selected from the group consisting of:
  • R 4 is -(CH 2 )y-R 4 ! wherein:
  • R 4 ' is selected from the group consisting of:
  • R 5 has the formula (CHR ⁇ ) m -A or (CHR ⁇ ) p -O-A, where A is selected from the group consisting of:
  • a fused bicyclo ring wherein one ring is a saturated or unsaturated five to six membered saturated or unsaturated heterocyclic ring which contains one to three heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein said heterocyclic ring contains at least one carbon atom, and the other ring is a saturated or unsaturated five to eight membered carbocyclic ring,
  • R 6 is selected from the group consisting of: (a) hydrogen, and (b) -(Ci-C 5 ) linear or branched alkyl;
  • R 5 and R 6 are not both hydrogen
  • (ql) a four to eight membered saturated or unsaturated heterocyclic ring containing one to four nitrogens, wherein said ring contains at least one carbon atom, or (q2) -C 6 -C 10 -aryl optionally substituted with halogen or -(Ci-C 5 )- alkyl;
  • R 8 and R form, together with the nitrogen to which they are attached, a saturated or unsaturated four to eight membered heterocyclic ring, optionally containing one to three additional heteroatoms selected from the group consisting of nitrogen and oxygen, wherein said ring contains at least one carbon atom and wherein said heterocyclic ring is optionally substituted with -(Ci-Cs) linear or branched alkyl;
  • Rio is hydrogen, -NR 8 R 9 , -OR ⁇ , -(C 1 -C 5 ) linear or branched alkyl, or phenyl;
  • each occunence of R ⁇ is independently selected from the group consisting of hydrogen, -C ⁇ -C 5 linear or branched alkyl and phenyl;
  • n, m and p are independently an integer from 0 - 3; y is an integer from 0 - 2;
  • Lacefield et al. (U.S. Patent No. 3,956,495) describes 2,4-diaminoquinazoline compounds which are used as antithrombotic agents.
  • Pfizer, Inc. (GB 1,156,973) describes 2,4-diaminoquinazoline compounds which are used to reduce blood pressure in hypertensive subjects.
  • Singhal et al. J Indian Chem Soc, vol. LXI, pages 690-693, August 1984
  • 2,4- diaminoquinazoline compounds and their use as antimalarial agents.
  • Abou-Zeid et al. (Egypt. J. Pharm. Sci., vol. 32, no. 1-2, pages 165-174, (1991)) described 1,4-disubstituted piperazines (which happen to also be 2,4-diaminoquinazoline compounds) and their use as antihypertensive agents.
  • the invention also includes pharmaceutical compositions comprising a therapeutically effective amount of one or more of the compounds or purified stereoisomers or stereoisomer mixtures of the invention, or their salts or prodrugs forms thereof, with a pharmaceutically acceptable ingredient.
  • compositions are prepared so that they may be administered orally, dermally, parenterally, nasally, ophthalmically, otically, sublingually, rectally or vaginally.
  • Dermal administration includes topical application or transdermal administration.
  • Parenteral administration includes intravenous, intraarticular, intramuscular, and subcutaneous injections, as well as use of infusion techniques.
  • One or more compounds of the invention may be present in association with one or more non-toxic pharmaceutically acceptable ingredients and optionally, other active anti-proliferative agents, to form the pharmaceutical composition.
  • These compositions can be prepared by applying known techniques in the art such as those taught in Remington's Pharmaceutical Sciences (Fourteenth Edition),
  • Commonly used pharmaceutical ingredients which can be used as appropriate to formulate the composition for its intended route of administration include: acidifying agents (examples include but are not limited to acetic acid, citric acid, fumaric acid, hydrochloric acid, nitric acid); alkalinizing agents (examples include but are not limited to ammonia solution, ammonium carbonate, diethanolamine, monoethanolamine, potassium hydroxide, sodium borate, sodium carbonate, sodium hydroxide, triethanolamine, trolamine); adsorbents (examples include but are not limited to powdered cellulose and activated charcoal); aerosol propellants (examples include but are not limited to carbon dioxide, CC1 2 F 2 , F 2 C1C- CC1F 2 and CC1F 3 ) air displacement agents (examples include but are not limited to nitrogen and argon); antifungal preservatives (examples include but are not limited to benzoic acid, butylparaben, ethylpara
  • clarifying agents include but are not limited to bentonite
  • emulsifying agents include but are not limited to acacia, cetomacrogol, cetyl alcohol, glyceryl monostearate, lecithin, sorbitan monooleate, polyethylene 50 stearate
  • encapsulating agents include but are not limited to gelatin and cellulose acetate phthalate
  • flavorants include but are not limited to anise oil, cinnamon oil, cocoa, menthol, orange oil, peppermint oil and vanillin
  • humectants include but are not limited to glycerin, propylene glycol and sorbitol
  • levigating agents include but are not limited
  • compositions can take the form of aerosols, capsules, creams, elixirs, emulsions, foams, gels, granules, inhalants, lotions, magmas, ointments, peroral solids, powders, sprays, syrups, suppositories, suspensions, tablets and tinctures.
  • the compositions of the invention can also have an additional apoptosis inducers as an active ingredient. Examples of known apoptosis inducers (see e.g.
  • Calbiochem's 2001 Signal Transduction Catalog, pages 702-704, the contents of which are incorporated by reference) which can be added to the described invention include but are not limited to A23187, N-Acetyl-L-cysteine, actinomycin D, tyrphostin A9, tyrphostin A25, AG 490, AG 1714, anandamide, anisomycin, aphidicolin, bafilomycin Al, berberine hemisulfate, betulinic acid, bleomycin sulfate, CAFdA, calphostin C, camptothecin, CAPE, chelerythrine chloride, 2-chloro-2'-deoxyadenosine, 2-chloro-2'-deoxyadenosine 5'-triphosphate, colcemid, cochicine, corticosterone, cycloheximide, cyclophosphamide monohydrate, cyclosporine A, daunorubicin hydroclor
  • Optional cancer treatment agents which can be added to the composition include but are not limited to compounds listed on the cancer chemotherapy drug regimens in the 11 Edition of the Merck Index, (1996), which is hereby incorporated by reference, such as asparaginase, bleomycin, carboplatin, carmustine, chlorambucil, cisplatin, colaspase, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin, doxorubicin (adriamycine), epirubicin, etoposide, 5-fluorouracil, hexamethylmelamine, hydroxyurea, ifosfamide, irinotecan, leucovorin, lomustine, mechlorethamine, 6-mercaptopurine, mesna, methotrexate, mitomycin C, mitoxantrone, prednisolone, prednisone, procarbazine, ral
  • cancer treatment agents suitable for use with the composition of the invention include but are not limited to those compounds acknowldeged to be used in the treatment of neoplastic diseases in Goodman and Gilman's The Pharmacological Basis of Therapeutics (Tenth Edition), editor Hardman et al, publ.
  • cancer treatment agents suitable for use with the composition of the invention include but are not limited to other anti-cancer agents such as epothilone.
  • the daily oral dosage regimen will preferably be from 0.01 to 200 mg/kg of total body weight.
  • the daily dosage for administration by injection including intravenous, intramuscular, subcutaneous and parenteral injections, and use of infusion techniques will preferably be from 0.01 to 200 mg/kg of total body weight.
  • the daily rectal dosage regimen will preferably be from 0.01 to 200 mg/kg of total body weight.
  • the daily vaginal dosage regimen will preferably be from 0.01 to 200 mg/kg of total body weight.
  • the daily topical dosage regimen will preferably be from 0.1 to 200 mg administered between one to four times daily.
  • the transdermal concentration will preferably be that required to maintain a daily dose of from 0.01 to 200 mg/kg.
  • the daily inhalation dosage regimen will preferably be from 0.01 to 100 mg/kg of total body weight.
  • the particular method of administration will depend on a variety of factors, all of which are considered routinely when administering therapeutics. It will also be understood, however, that the specific dose level for any given patient will depend upon a variety of factors, including, but not limited to the activity of the specific compound employed, the age of the patient, the body weight of the patient, the general health of the patient, the gender of the patient, the diet of the patient, time of administration, route of administration, rate of excretion, drug combinations, and the severity of the condition undergoing therapy.
  • the optimal course of treatment i.e., the mode of treatment and the daily number of doses of a compound of formulae (la) or (Ila) or a pharmaceutically acceptable salt thereof given for a defined number of days, can be ascertained by those skilled in the art using conventional treatment tests.
  • the term 'concentrated under reduced pressure' refers to use of a Buchi rotary evaporator at approximately 15 mm of Hg.
  • Thin-layer chromatography was performed on Whatman pre-coated glass-backed silica gel 60A F-254 250 ⁇ m plates. Visualization of plates was effected by one or more of the following techniques: (a) ultraviolet illumination, (b) exposure to iodine vapor, (c) immersion of the plate in a 10% solution of phosphomolybdic acid in ethanol followed by heating, and/or (d) immersion of the plate in a cerium sulfate solution followed by heating. Column chromatography (flash chromatography) was perfonned using 230-400 mesh EM Science ® silica gel
  • Melting points were determined using a Thomas-Hoover melting point apparatus or a Mettler FP66 automated melting point apparatus and are unconected.
  • Proton (1H) nuclear magnetic resonance (NMR) spectra were measured with a General Electric GN-Omega 300 (300 MHz) spectrometer with either Me Si ( ⁇ 0.00) or residual protonated solvent (CHC1 3 ⁇ 7.26; MeOH ⁇ 3.30; DMSO ⁇ 2.49) as standard.
  • Carbon ( 13 C) NMR spectra were measured with a General Electric GN-Omega 300 (75 MHz) spectrometer with solvent (CDC1 3 ⁇ 77.0; d 3 -MeOD; ⁇ 49.0; d 6 -DMSO ⁇ 39.5) as standard.
  • HPLC - electrospray mass spectra were obtained using a Hewlett-Packard 1100 HPLC equipped with a quaternary pump, a variable wavelength detector set at 254 nm, a YMC pro C-18 column (2 x 23 mm, 120A), and a Finnigan LCQ ion trap mass spectrometer with electrospray ionization. Spectra were scanned from 120-1200 amu using a variable ion time according to the number of ions in the source. The eluents were A: 2% acetonitrile in water with 0.02% TFA and B: 2% water in acetonirile with 0.018% TFA.
  • Step 1 Chloral hydrate (14.5 g, 87.7 mmol) was dissolved in water (190 mL) and then added to sodium sulfate (92.26 g, 650 mmol) in water (170 mL).
  • m-Anisidine (10 g, 81.2 mmol) was dissolved in water (50 mL) with cone.
  • HCl (7.0 mL) was added to the first mixture, a layer of brown oil formed on the top.
  • Hydroxylamine hydrochloride 17.86 g, 256 mmol was dissolved in water (80 mL) and added to the reaction mixture. The mixture was heated at 40 °C then warmed to 50 °C.
  • Step 1 2-Amino-5-iodobenzoate acid (3 g, 11.4 mmol) was dissolved in THF and then 1,1'- carbonyldiimidazole (1.85 g, 11.4 mmol) was added. The mixture was heated at 60 °C for 2 days. The reaction was monitored by TLC. After starting material was consumed, MeOH (2 mL) was added and the mixture was heated at 70 °C for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column (100% CH 2 C1 2 ) to obtain 2.4 g of methyl 2-amino-5-iodobenzoate (76%). MS (GC/MS) 277.
  • Step 2 Methyl 2-amino-5-iodobenzoate (2.4 g, 8.66 mmol) was dissolved in AcOH (7.5 mL). Potassium cyanate was dissolved in water (1.5 mL) and added to the reaction mixture slowly. A precipitate fonned immediately. The mixture was heated to 100 °C for 20 min and then mixture was added water and filtered by suction to afford a white solid. This white solid was dried under vacuum oven for 2 h. To this white solid was added MeOH (27 mL) to form a suspension. To this suspension, a solution of NaOH (406 mg) in water (5.4 mL) was added and the mixture was brought to reflux for 1 h.
  • Step 1 To 2-amino-5-methoxylbenzoic acid (3 g, 17.9 5 mmol) was added 2N HCl (15 mL). After a precipitate formed, water (30 mL) was added to the mixture to form a suspension. A solution of sodium cyanate (1.75 g, 26.92 mmol) in water (20 mL) was added dropwise at rt over 15 min. Froth formed and after vigorously stirring, a pink suspension formed. After stirring for 4 h, the suspension was filtered and washed with water and ether and dried under reduced pressure. The solid was added to concentrated HCl (20 mL), and heated to 105 °C for 1 h.
  • Step 1 To a suspension of 2-amino-5-chlorobenzoic acid (102. lg, 0.58 mol) in water (1.6 L) was added 5 M NaOH (160 mL). To the resulting solution was charged sodium cyanate (43.4 g, 0.64 mol) followed by glacial acetic acid (36.7 mL, 0.641 mol). The reaction mixture was stined for a period of 14-16 h at rt, then filtered to remove some insoluble solid. To the brown solution was added 1 M HCl (1.5 L). The resulting precipitate was stined rt for a period of 2-2.5 h then filtered and washed with water (2 x 666 mL).
  • Step 2 A suspension of 2-[(aminocarbonyl)amino]-5-chlorobenzoic acid (35.0 g, 0.16 mol) and p-toluene sulfonic acid monohydrate (4.66 g, 0.024 mol) in a mixture of toluene (350 mL) and DMF (87.5 mL) was heated to reflux with an attached Dean stark apparatus for a period of 4-4.5 h. The reaction was judged complete by 1H NMR. The suspension was cooled to rt, filtered and the solid washed with toluene (150 mL). The damp solid was pulped in water (250 mL) for a period of 15-20 min.
  • Step 3 A mixture of 6-chloro-2,4(lH,3H)-quinazolinedione (24.0 g, 0.122 mol), POCl 3 (114 mL, 1.22 mol) and PC1 5 (56.2 g, 0.26 mol) was heated to reflux for a period of 3.5-4.0 h, when the reaction was judged complete by TLC (Eluent- 1 : 1 dichloromethane / hexanes). The reaction mixture was concentrated under vacuum to remove most of the POCl 3 . The resulting solid was poured slowly into ice/water (1000/200 mL) and stined vigorously for a period of one hour. The precipitate was filtered and the damp solid was pulped in water for 15-20 min.
  • Step 1 To a suspension of 2-amino-4-chlorobenzoic acid (15.3 g, 0.087 mol) in water (245 mL) was added 5 M NaOH (24 mL, 0.12 mol). To the resulting solution was charged sodium cyanate (6.50 g, 0.096 mol) followed by glacial acetic acid (5.5 mL, 0.096 mol). The reaction mixture was stined for a period of 14-16 h at rt, then filtered to remove some insoluble solid. To the yellow solution was added 1M HCl (225 mL). The resulting precipitate was stined at rt for a period of 2-2.5 h then filtered and washed with water (2 x 100 mL).
  • Step 2 A suspension of 2-[(aminocarbonyl)amino]-4-chlorobenzoic acid (14.0 g, 0.065 mol) and p-toluene sulfonic acid monohydrate (1.86 g, 0.01 mol) in a mixture of toluene (140 mL) and DMF (35 mL) was heated to reflux with an attached Dean stark apparatus for a period of 3.0 h. The reaction was judged complete by TLC (Eluent- 5:4:1 Hexanes/ethyl acetate/methanol). The suspension was cooled to rt, filtered and the solid washed with toluene (20 mL).
  • Step 3 A mixture of 7-chloro-2,4(lH,3H)-quinazolinedione (7.5 g, 0.04 mol), POCl 3 (35.5 mL, 0.38 mol) and PCls (17.5 g, 0.08 mol) was heated to reflux for a period of 3.0-3.5 h, when the reaction was judged complete by TLC (Eluent- 1 : 1 dichloromethane / hexanes).
  • Step 1 l-(3-Chloropropoxy)-4-fluorobenzene (1 eq) and phthalimide, potassium salt (1.2 eq) in a solution of DMF (1.0 M were magnetically stined at 80 °C over a period of 18 h. The reaction was cooled, dissolved in CH 2 C1 2 and water and poured into a separatory funnel. The layers were separated and the aqueous was extracted with CH 2 C1 2 (3x). The combined organics were washed with IN NaOH (2x), dried (MgSO ), filtered and concentrated under reduced pressure. The 2-[3-(4-fluorophenoxy)propyl]-lH-isoindole-l,3(2H)-dione was used without purification.
  • Step 1 A slurry of 4-nifrophenol (1 eq) and NaOH pellets (1 eq) in H 2 O (6.8 M) was stined for 10 min after which time -xylene (1.4 M), K 2 CO 3 (1.5 eq) and 2- diethylaminoethylchlorideliydrochloride (1 eq) was added and the reaction heated to 100 °C for 4 h. The reaction was cooled to rt then concentrated under reduced pressure. The crude residue was dissolved in /?-xylene and washed with IN NaOH (2x) and H 2 O (lx). The combined organic layers were dried (MgSO 4 ) and concentrated under reduced pressure to yield N,N-diethyl-2-(4-nitrophenoxy)ethanamine as a solid which was carried on without further purification.
  • Step 2 A solution of N,N-diethyl-2-(4-nitrophenoxy)ethanamine (1 eq) in ethanol (0.2 M) was added via syringe to a flask containing Palladium on carbon (10% wt).
  • the reaction vessel was fitted with a balloon adapter and charged with hydrogen and evacuated three times until the reaction was under a H 2 atmosphere.
  • the reaction was allowed to stir overnight and then purged with Ar and evacuated tliree times until an Ar atmosphere had been achieved.
  • the reaction solution was filtered through a pad of Celite and washed with copious amounts of ethanol. The filtrate was concentrated under reduced pressure and afforded pure 4-[2-(diethylamino)ethoxy]aniline as an oil.
  • Step 1 To N-(3-Hydroxypropyl)phthalamide (0.10 g, 0.490 mmol, l.Oeq.) and hexafluoro- 2-propanol (0.12 g, .730 mmol, 1.5eq.) in THF (4 mL) was added a mixture of triphenylphosphine (0.19 g, .730 mmol, 1.5 eq.) and diethylazodicarboxalate (0.13 g, 0.730 mmol, 1.5eq.) in THF (4 mL.) that was allowed to stir at 0 °C for lh. The reaction was allowed to stir at rt for 3 h.
  • Step 2 To 2- ⁇ 3-[2,2,2-trifluoro-l-(trifluoromethyl)ethoxy]propyl ⁇ -lH-isoindole-l,3(2H)- dione (1.0 g, 2.8 mmol, 1.0 eq.) in ethanol (10 mL) was added hydrazine hydrate (0.09 g, 2.8 mmol, leq.) and the reaction was allowed to stir at rt for 16 h. This was treated with IN hydrochloric acid (5 mL) and the reaction was filtered washing with water. The filtrate was concentrated under reduced pressure and filtered to give 0.20 g of 3-[2,2,2-trifluoro-l- (trifluoromethyl)ethoxy]propylamine (32%).
  • Step 1 To methylamine (2 M, 12.4 mL, 2.5eq.) and DMAP (0.24 g, 1.99 mmol, 0.2 eq.) in methylene chloride (15 mL.) was added 4-cyanobenzenesulfonyl chloride (2.0 g, 9.9 mmol., 1.0 eq.) portionwise at 0 °C. The reaction was allowed to warm rt and stir for 2h. The reaction was acidified with 2 N HCl to pH 1, and extracted with methylene chloride, dired with magnesium sulfate, filtered and concentated under reduced pressure to give 1.29 g of 4- cyano-N-methylbenzenesulfonamide (67%) as a colorless solid.
  • Step 2 To PtO 2 x H 2 O (0.13 g., 6.57 mmol., l.Oeq.) was added methanol (5 mL.) and HCl (0.13g, 7.88 mmol., 1.2 eq.) and 4-cyano-N-methylbenzenesulfonamide (1.29 g, 6.57 mmol., 1.0 eq.) and the reaction was placed under hydrogen gas (1 atm.) for 16 h. The reaction was filtered and concentrated under reduced pressure to give 230 mg of 4-(aminomethyl)-N- methylbenzenesulfonamide (18%).
  • Step 1 A solution of methyl 4-(aminomethyl)benzoate hydrochloride (5 g, 26.65, 1 eq) in THF (50 mL) was treated with a solution of di-tert-butyl dicarbonate (14 g, 63.96 mmol, 2.4 eq) in THF (50 mL) dropwise. Triethylamine (11.14 mL, 8.1 g, 80 mmol, 3 eq) was added and the reaction was magnetically stined over 16 hours.. Methylene chloride (100 mL) was added and the solution was washed with deionized water (100 mL), dried over magnesium sulfate and then filtered.
  • Triethylamine 11.14 mL, 8.1 g, 80 mmol, 3 eq
  • Step 2 4- ⁇ [(tert-Butoxycarbonyl)amino]methyl ⁇ benzoic acid (3g, 11.94 mmol, 1 eq) was dissolved in methylene chloride (50 mL) and treated with CDI (2.13 g, 13.13 mmol, 1.1 eq) and magnetically stined over 20 min at rt. Dimethylhydroxylamine HCl (5.82 g, 59.70 mmol, 5 eq.) was added to this solution and magnetically stined over 16 hours.
  • Aqueous citric acid (10 % by wt., lOOmL) were added and the organic sayer was separated and successivively washed with deionized water (100 mL) and brine (100 mL), dried over magnesium sulfate and then filtered.
  • the solution was concentrated in ⁇ acuo, and purified by column chromatography (50% Ethyl acetate:Hexanes) to yield tert-butyl 4- ⁇ [methoxy(methyl)amino]carbonyl ⁇ benzylcarbamate as a yellow oil.
  • Step 3 To a previously cooled solution (0 °C, via ice/water bath) of tert-butyl 4- ⁇ [methoxy(methyl)amino]carbonyl ⁇ benzylcarbamate (0.5 g , 1.70 mmol, 1 eq) in THF (34 mL) under argon in an oven-dried flask, «-butyllithium (1.6 M in hexanes, 3.2 mL, 5.1 mmol, 3 eq) was added dropwise and the mixture was magnetically stined for 1 hour.
  • «-butyllithium 1.6 M in hexanes, 3.2 mL, 5.1 mmol, 3 eq
  • Step 4 A solution of tert-butyl 4-pentanoylbenzylcarbamate (0.410 g) in methylene chloride (10 mL) was treated with TFA and magnetically stined for 45 min. A saturated aqueous solution of sodium bicarbonate was added slowly followed by ethyl acetate (40 mL). The organic layer was separated, dried over magnesium sulfate and then filtered. The solution was concenfrated under reduced pressure, resulting in l-[4-(aminomethyl)phenyl]-l- pentanone which was used without any further purification.
  • Step 1 Benzylamine 1 (General Flow Diagram I) (1.1 eq) and potassium carbonate (3.5 eq) were added to a solution of quinazoline 2 (1.0 eq) in isopropyl alcohol and water (as a 2 to 1 ratio, 0.1 M) and were magnetically stined at rt over a period of 16 h.
  • the isopropyl alcohol was removed in vacuo.
  • Ethyl acetate was added and this solution was washed with deionized water, dried over magnesium sulfate and then filtered. The solution was concentrated in vacuo, and purified by column chromatography to yield intermediate 3 as a white solid.
  • Step 2 Amine 4 (1.1 eq) and concentrated hydrochloric acid (catalytic) were added to a solution of intermediate 3 (1.0 eq) in 7z-butanol (0.1M) were magnetically stined at 100 °C in a sealed tube over a period of 16 h. The excess n-butanol was removed under reduced pressure. Methylene chloride was added and the solution was washed with saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate and then filtered. The solution was concentrated in vacuo, and purified by column chromatography to yield compound 5.
  • Step 1 A suspension of 2,4,6-trichloroquinazoline (685 mg, 2.93 mmol), methyl 4- (aminomethyl)benzoate hydrochloride (651 mg, 3.28 mmol), and sodium acetate (722 mg, 8.80 mmol) in water (25 mL) was refluxed for 30 min vigorously. The white suspension is filtered through a coarse frit while still warm, and washed thoroughly with water (2 x 30 mL), then dried under P 2 O 5 in vacuo to give 884 mg of methyl 4- ⁇ [(2,6-dichloro-4- quinazolinyl)amino]methyl ⁇ benzoate as a white solid in (83%).
  • Step 2 A suspension of methyl 4- ⁇ [(2,6-dichloro-4-quinazolinyl)amino] methyl ⁇ benzoate (850 mg, 2.347 mmol) in piperidine (3.00 g, 35.21 mmol) was stined at 80 C under argon for 10 min. The reaction was diluted with water (50 mL) and extracted with EtOAc (3 x 100 mL). The organics were dried (MgSO 4 ) and concentrated in vacuo to give a yellow oil which crystallizes.
  • Step 1 To a suspension of 2,4,6-trichloroquinazoline (300 mg, 1.29 mmol) in dry DMF (10 mL) at 0 °C under argon was added piperidine (0.26 mL, 2.639 mmol) and the yellow suspension stined at 0 °C for 30 min, then at rt for 16 h. The reaction was diluted with water (75 mL) and sat. NaHCO 3 (25 mL) and extracted with EtOAc (2 X 150 mL). The organics were washed with water (2 X 50 mL), dried (MgSO 4 ), and concentrated in vacuo to give a yellow solid.
  • Step 2 A suspension of 2,6-dichloro-4-(l-piperidinyl)quinazoline (100 mg, 0.35 mmol), methyl 4-(aminomethyl)benzoate hydrochloride (105 mg, 0.523 mmol), and potassium carbonate (144 mg, 1.044 mmol) in dry DMF (5 mL) under argon was heated to 120 °C for 3 h. The reaction was quenched with water (100 mL) and extracted with EtOAc (2 x 150 mL).
  • Step 3 A solution of methyl 4-( ⁇ [6-chloro-4-(l-piperidinyl)-2-quinazolinyl]amino ⁇ methyl)benzoate (50 mg, 0.122 mmol) in methanol (5 mL) and 5 M NaOH (aq)(0.73 mL, 3.65 mmol) was stined at rt for 24 h. The reaction was quenched by addition of 1 M HCl (aq)(3.70 mL), then diluted with Na/K tartrate/NaHSO 4 buffer at pH 4.5 (50 mL).
  • Step 1 A solution of m-anisidine (0.017 g, 0.14 mmol) and tr ⁇ ns-methyl 4- ⁇ [(2,6-dichloro- 4-quinazolinyl)amino]methyl ⁇ cyclohexanecarboxylate (0.050 g, 0.14 mmol) in n-butanol (2 mL) was heated at reflux overnight. The reaction was cooled to rt and the zz-butanol was concentrated under reduced pressure.
  • Step 2 A solution of tr ⁇ w-methyl 4-[( ⁇ 6-chloro-2-[(3-methoxyphenyl)amino]-4- quinazolinyl ⁇ amino)methyl]cyclohexanecarboxylate (0.02 g, 0.04 mmol) and IN NaOH (0.04 mL) in MeOH/H 2 O/THF (1.5 mL/0.25 mL/0.25 mL) was stined at room temperature overnight then at 40 °C over 6 days. The reaction was cooled rt and the volatiles were removed under reduced pressure.
  • Step 1 A mixture of 2,4,7-trichloroquinazoline (0.20 g, 0.86 mmol), 4-(4- morpholinyl)phenylamine (0.229 g, 1.28 mmol), potassium carbonate (0.355 g, 2.57 mmol) in IP A/water (5.3 mL/2.7 mL) was heated at 60° C for 18 h. The reaction was cooled to rt and the solvent was removed under reduced pressure. The pH was adjusted to 6 with the addition of IN HCl and the mixture was concentrated in vacuo.
  • Step 2 A solution of methyl 4-(aminomethyl)benzoate (0.027 g, 0.13 mmol) and 2,7- dichloro-N-[4-(4-morpholinyl)phenyl]-4-quinazolinamine (0.050 g, 0.13 mmol) in n-butanol (1 mL) was heated to reflux for 18 h. The reaction was cooled rt and the 7?-butanol was removed under reduced pressure.
  • Step 1 A mixture of 2, 4, 7-trichloroquinazoline (0.125 g, 0.54 mmol), wo-butyl amine (0.059 g, 0.080 mmol), and potassium carbonate (0.222 g, 1.61 mmol) in IP A/water (2.7 mL/1.3 mL) was heated at 60 °C for 18 h. The reaction was cooled to rt and the volatiles were removed under reduced pressure. The pH was adjusted to pH 6 with the addition of IN HCl and the resulting solid was collected by filtration.
  • Step 2 A solution of methyl 4-(aminomethyl)benzoate hydrochloride (0.037 g, 0.19 mmol) and 2,7-dichloro-N-isobutyl-4-quinazolinamine (0.050 g, 0.19 mmol) in «-butanol (1 mL) was heated at reflux for 18 h. The reaction was cooled to rt and the «-butanol was removed in vacuo.
  • HPLC conditions for parallel synthesis analysis A YMC Pro C-18 column (2 x 23mm, 120 A) was used, and the eluents were A: 2% acetonitrile in water with 0.02% TFA and B: 2% water in acetonitrile with 0.02% TFA. Elution conditions consisted of a flow rate of 1.5 mL/min with an initial hold at 10% B for 0.5 minutes, followed by gradient elution from 10% B to 90% B over 3.5 minutes, followed by a final hold at 90% B for 0.5 minutes. Total run time was 4.8 minutes.
  • Step 1 4-[( ⁇ 6-Chloro-2-[(2-thienylmethyl)amino]-4-quinazolinyl ⁇ amino)methyl]benzoic acid (1 eq) was dissolved in DMF (0.23 M) and cooled to -30 °C when hydroxybenzatriazolehydrate (1.7 eq) and l-[3-(dimethylaminopropyl)]-3-ethylcarbo diimide hydrochloride (1.7 eq) were added. This was allowed to stir for 15 min and 2- (aminooxy)ethanol (1.4 eq) in a solution of DMF (0.33 M was added via syringe.
  • the reaction was gradually allowed to reach rt and was magnetically stined over a period of 18 h.
  • the reaction was dissolved in EtOAc and water and poured into a seperatory funnel. The layers were separated and the aqueous was extracted with EtOAc (3x). The combined organics were washed with 10% citric acid (2x), 10% NaHCO 3 (2x), satd. NaCl, dried (MgSO 4 ), filtered and concentrated in vacuo.
  • Step 2 4-[( ⁇ 6-Chloro-2-[(2-thienylmethyl)amino]-4-quinazolinyl ⁇ amino)methyl]-N-(2- hydroxyethoxy)benzamide (1 eq) was dissolved in THF (0.02 M) were magnetically stined as a suspension and the Burgess reagent (1.1 eq) was added in one portion. The reaction was heated at 80 °C over a period of 3 h.
  • Step 2 To 4-[( ⁇ 6,7-dimethoxy-2-[(2-thienylmethyl)amino]-4-quinazolinyl ⁇ amino) methyl]benzoic acid (0.050 g) in iro-butanol (3 mL) was added a catalytic amount of cone, sulfuric acid and the reaction was heated to 100 °C for 2 h.
  • Step 1 To a solution of 2,4-dichloro-6,7-dimethoxyquinazoline (0.500 g, 1.93 mmol), tefrabutylammonium bromide (0.0311 g, 0.10 mmol), and 10% aqueous NaOH (4.0 mL) in toluene (4.8 mL) was added methyl 4-(hydroxymethyl)benzoate (0.330 g, 1.99 mmol) as a solution in toluene (3.3 mL), dropwise. The reaction was allowed to stir at rt for 18 h. Water (100 mL) was added and the mixture was extracted with EtOAc (3 x 100 mL).
  • Step 2 A solution of (2S)-2-(methoxymethyl) ⁇ ynolidine (0.033 g, 0.29 mmol) and 4- ⁇ [(2- chloro-6,7-dimethoxy-4-quinazolinyl)oxy]methyl ⁇ benzoic acid (0.108 g, 0.29 mmol) in n- butanol (1.5 mL) was heated at reflux for 18 h. The reaction was cooled to rt and the n- butanol was removed under reduced pressure. The residue was triturated with MeOH and filtered. The filtrate was concentrated under reduced pressure.
  • Step 1 To a solution of 4-(chloromethyl)benzoic acid (1.00 g, 5.86 mmol) in EtOH (15 mL) was added thiourea (0.50 g, 5.86 mmol) as a solution in EtOH (5 mL), dropwise. The reaction was allowed to stir at room temperature overnight. Additional thiourea was added
  • Step 2 A mixture of 2,4-dichloro-6,7-dimethoxyquinazoline (0.50 g, 1.93 mmol), 4- (sulfanylmethyl)benzoic acid (0.487 g, 2.89 mmol), and potassium carbonate (0.800 g, 5.79 mmol) in IP A/water (10 mL/5 mL) was heated at 60 °C overnight. The reaction was cooled to rt and IN HCl was added to adjust the pH to 6.
  • Step 3 A solution of (2S)-2-(methoxymethyl)pynolidine (0.06 g, 0.51 mmol) and 4- ⁇ [(2- chloro-6,7-dimethoxy-4-quinazolinyl)sulfanyl]methyl ⁇ benzoic acid (0.20 g, 0.51 mmol) in 77-butanol (12 mL) was heated at reflux for 18 h. The reaction was cooled to rt and the n- butanol was removed in vacuo. The residue was taken up in MeOH and adhered to silica gel.
  • Step 4 A solution of 4-[( ⁇ 6,7-dimethoxy-2-[(2S)-2-(methoxymethyl)-l-pynolidinyl]-4- quinazolinyl ⁇ sulfanyl)methyl] benzoic acid (0.025 g, 0.05 mmol) and chlorotrimethylsilane (0.011 g, 0.10 mmol) in MeOH (1.0 mL) was stined rt for 18 h. Additional chlorotrimethylsilane (0.113 g, 0.10 mmol) was added and the mixture was allowed to stir 24 h. The mixture was concenfrated under reduced pressure. The residue was taken up in MeOH and, again, concenfrated under reduced pressure.
  • Step 1 To a heterogeneous magnetically stined solution of malonic acid (5.4 g, 52 mmol, 1.0 eq) in phosphorous oxychloride (60, 390 mmol, 7.5 eq) was added 3,4-dimethoxyaniline (10 g, 65 mmol, 1.25 eq). The reaction heated to reflux at 115 °C for 2 h when it was cooled to rt and carefully added to 500 mL ice. The resulting aqueous layer was extracted with dichloromethane (2 x 300 mL). The organic layers were combined, washed with brine (1 x 300 mL), dried over magnesium sulfate and concentrated in vacuo to yield 6 g of 2,4- dichloro-6,7-dimethoxyquinoline (45%).
  • Step 2 A solution of 2,4-dichloro-6,7-dimethoxyquinoline (3g, 11.7 mmol, 1 eq), methyl 4- (aminomethyl)cyclohexanecarboxylate (9.7 g, 46.8 mmol, 4 eq), DBU (7 mL, 46.8 mmol, 4 eq) in 60 mL of NMP was magnetically stined at 120 °C in a sealed tube over a period of 16 h. The reaction was concentrated in vacuo and the resulting residue diluted with 100 mL of dichloromethane.
  • Step 3 4-(4-Morpholinyl)phenylamine (0.89 g, 5 mmol, 20 eq) and methyl 4- ⁇ [(2-chloro- 6,7-dimethoxy-4-quinolinyl)amino]methyl ⁇ cyclohexanecarboxylate (100 mg, 0.25 mmol, 1 eq) were magnetically stined at 140 °C in a sealed tube over a period of 16 h.
  • Examples 24 - 345 listed in the tables below were synthesized by the preparative methods described above or by using other known synthetic techniques such as those described by D. J. Brown, Fused Pyrimidines (part 1. - Quinazolines), by W. L. F. Amarego, publ. by New York Interscience, (1967); D. J. Brown, Quinazolines (Supplement I), publ. by John Wiley & Sons, (1996); Vol.
  • Table 3 shows Examples 308 - 346 which are various other embodiments of the described invention.
  • Table 4 shows the accompanying analytical data for Examples 308 - 346 from Table 3.

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Abstract

Quinazoline or quinoline derivatives of formula: (Formula I and II); wherein Z is CH or N; Y is O or S; X is OR5 or NR5R6; R1, R2, R3, R4, R5 and R6 are as disclosed. Also described is a method for the inhibiting the prolyl peptidase, inducing apoptosis and treating cancer by administering a therapeutically effective amount of compounds of the formula (I) or (II).

Description

Quinazoline and Quinoline Derivative Compounds as Inhibitors of Prolylpeptidase, Inducers of Apoptosis and Cancer Treatment Agents
DESCRIPTION OF THE INVENTION
The present invention relates to:
(1) quinazoline and quinoline derivative compounds or purified stereoisomers or steroisomer mixtures of said compound and salts or prodrug forms thereof;
(2) pharmaceutical compositions comprising one or more of the compounds or purified stereoisomers or stereoisomer mixtures of the invention, or their salts or prodrugs forms thereof, with a pharmaceutically acceptable ingredient;
(3) methods of preparing the quinazoline and quinoline derivative compounds of (1); and ( (44)) methods for inhibiting prolylpeptidase, inducing apoptosis and treating cancer in mammals by administering an effective amount of (1) or (2) to a patient in need thereof.
Description of the Compounds The compounds described as being part of the invention are novel quinazoline and quinoline derivative compounds which have the structural formula (I) or (II) defined below. Embodiment 1 :
Figure imgf000003_0001
(I) (π)
wherein, Z is CH orN; Y is O or S; X is OR5 orNR5R6;
Ri and R2 are independently selected from the group consisting of hydrogen, amino, cyano, halogen, hydroxy and nitro,
wherein Ri and R2 are both not hydrogen;
R3 is selected from the group consisting of: (a) hydrogen, and (b) -(C Cio) linear or branched alkyl;
R4 is -(CH^y-R wherein: j' is selected from the group consisting of:
(a) -(Ci- C5) linear or branched alkyl optionally substituted with one to three substituents selected from the group consisting of:
(1) cyano,
(2) halogen,
(3) hydroxy,
(4) nitro,
(5) -(C1-C5) linear or branched alkyl optionally substituted by halogen,
(6) -(C1-C5) alkoxy-,
(7) -C(=O)R7,
(8) -C(=O)OR7,
(9) -C(=O)NR8R9,
(10) -S(=O)R10, and
(11) -S(=O)2R10;
(b) -(C3-C8) cycloalkyl,
(c) -(Cβ-Cio) aryl, wherein (b) and (c) are optionally substituted with one to three substituents selected from the group consisting of (1) amino, (2) cyano,
(3) halogen,
(4) hydroxy,
(5) nitro,
(6) oxo,
(V) -(Ci-Cs) linear or branched alkyl optionally substituted by halogen or hydroxy,
(8) -(d-Cs) haloalkoxy-,
(9) -(CH2)nC(=O)R7,
Figure imgf000005_0001
(12) -(CH2)nC(=O)NR8R9,
(13) -S(=O)R10 ,
(14) -S(=O)2Rιo,
(15) -C(=N-R10)-(C1-Cs)-alkyl, and
(16) a saturated or unsaturated four to six membered heterocyclic ring containing one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein said ring contains at least one carbon atom;
and
(d) a saturated or fully unsaturared four to six membered heterocyclic ring containing one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein said ring contains at least one carbon atom and wherein said ring is optionally substituted with one to three substituents selected from the group consisting of amino, cyano, halogen, hydroxy, nitro, oxo, (Ci-C5)-alkoxy, -(CH2)nC0=O)OR7, -(CH2)nC(=O)NR8R9, -S(=O)R10, -S(=O)2R10 and -(Ci-C5) linear or branched alkyl optionally substituted by halogen, R3 and R4 form, together with the nitrogen to which they are attached, a saturated or fully unsarurated four to eight membered heterocyclic ring, wherein the nitrogen is the only heteroatom, which is optionally substituted with one to three substituents selected from the group consisting of amino, cyano, halogen, hydroxy, nitro, oxo, - (Ci-Cs) alkoxy-, phenyl, -C(=O)R7, -(CH2)nC(=O)OR7, -(CH2)nC(=O)NR8R9, -
S(=O)Rio, -S(=O)2R10 and -(Ci-C5) linear or branched alkyl optionally substituted by halogen;
R5 has the formula -(CHRπ)m-A or -(CHRπ)p-O-A, where A is selected from the group consisting of:
(a) hydrogen,
(b) -(Ci-Cs) linear or branched alkyl optionally substituted with cyano, halogen, hydroxy, -(C Cs) alkoxy- or -NR8R9,
(c) -(C3-C8) cycloalkyl optionally substituted with cyano, halogen, hydroxy, -(C1-C5) -alkyl, -(C1-C5) alkoxy- or -NR8R9,
(d) -(C6-C10) aryl optionally substituted with one to three substituents selected from the group consisting of:
(1) cyano,
(2) halogen, (3) hydroxy,
(4) nitro,
(5) -NR8R9,
(6) -(CrC5) linear or branched alkyl optionally substituted with -NR8R or halogen, (7) -(Cι-C5)-alkoxy wherein the alkyl is optionally substituted with -NR8R9 or halogen,
(8) -(Cβ-Cio) aryl-(C1-C5)-alkoxy-
(9) -(C6-C10) aryloxy optionally substituted with halogen,
(10) -(C6-C10) -aryl optionally substituted with halogen, (11) -CH2-(C6-C10)-aryl,
(12) -C(=O)R7,
(13) -C(=O)OR7,
(14) -C(=O)NR8R9, (15) -S(=O)Ri0j
(16) -S(=O)2R10, and
(17) a saturated or fully unsaturated four to eight membered heterocyclic ring containing one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein said ring: (al7) contains at least one carbon atom, (b 17) is directly linked to the -(C6-C10)-aryl or is linked to the -(C6-C10)-aryl via an -O- linkage, and
(cl 7) is optionally substituted with -(Ci-Cs)-alkyl, -(CH2)nC(=O)OR7 or -(CH2)nC(=O)NR8R9,
(e) a saturated or fully unsaturated four to eight membered heterocyclic ring containing one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein said ring contains at least one carbon atom, and is optionally substituted with
(1) -(Ci-C5)-alkyl optionally substituted by halogen,
(2) phenyl optionally substituted by halogen, (3) -(Ci-Cs)-alkoxy- wherein the alkyl is optionally substituted with halogen,
(4) -(C6-C10) aryloxy wherein the aryl is optionally substituted with halogen, or
(5) oxo, and
(f) a fused bicyclo ring wherein one ring is a saturated or fully unsaturated five to six membered heterocyclic ring which contains one to three heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein said heterocyclic ring contains at least one carbon atom, and the other ring is a saturated or fully unsaturated five to eight membered carbocycle,
is selected from the group consisting of: (a) hydrogen, and
(b) -(CrC5) linear or branched alkyl,
wherein R5 and R6 are not both hydrogen;
or
R5 and R6 form, together with the nitrogen to which they are attached, a saturated or fully unsaturated four to eight membered heterocyclic ring, which optionally contains one to three additional nitrogen atoms wherein said ring contains at least one carbon atom, and wherein said ring is optionally substituted with one to three substituents selected from the group consisting of:
(a) amino,
(b) cyano, (c) halogen,
(d) hydroxy,
(e) nitro,
(f) oxo,
(g) -(C1-C5) linear or branched alkyl optionally substituted by halogen or -(Cj-Cs) -alkoxy,
(h) -(C1-C5) alkoxy,
(i) -(C1-C5) alkoxy-(Ci-C5)-alkyl,
(j) -(C6-C10) aryl optionally substituted by halogen or -(Ci-C5)-alkyl,
(k) -(Cι-Cs)-alkyl-phenyl optionally substituted by halogen or -(C1-C5)- alkyl,
(1) -(CH2)nC(=O)OR7,
(m) -(CH2)nC(=O)NR8R9,
(n) -(CH2)nNR8R9,
(o) -S(=O)Rιo, (p) -S(=O)2R10, and
(q) -(CH2)n-Q, wherein Q is a saturated or fully unsaturated four to eight membered heterocyclic ring containing one to four nitrogens, wherein said ring contains at least one carbon atom; wherein (R3 and R4) ≠ (R5 and R6) when:
(1) R3/R(. or R5/R6 contain an unsubstituted -(CH2)n-C6-C10-aryl substiruent, or (2) Rs^ or R5/R6 form a heterocyclic ring;
R7 is selected from the group consisting of hydrogen, -(C1-C5) linear or branched alkyl, phenyl, -(C1-Cs)-alkyl-phenyl, and -(C3-C8) cycloalkyl which are optionally substituted with one to three substituents selected from the group consisting of halogen, oxo, -(CpCs) alkoxy, -C(=O)Rπ and -(C1-C5) linear or branched alkyl optionally substituted by halogen;
R8 and R9 are independently selected from the group consisting of: (a) hydrogen, (b) -(Ci-C5) linear or branched alkyl which is optionally substituted with a substiruent selected from the group consisting of halogen and -(Ci- Cs) alkoxy,
(c) -(d-Cs) alkoxy,
(d) -(C6-C10) aryl, and (e) -(CH2)n-R wherein R is a five to six membered saturated or fully unsaturated heterocyclic ring containing one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein said ring contains at least one carbon atom, wherein (c)-(e) are optionally substituted with one to tliree substituents selected from the group consisting of halogen, -(CrC5) alkoxy, -C(=O)R7 and
-(Ci-Cs) linear or branched alkyl optionally substituted by halogen,
or
R8 and R9 form, together with the nitrogen to which they are attached, a saturated or fully unsaturated four to eight membered heterocyclic ring, optionally containing one to three additional heteroatoms selected from the group consisting of nitrogen and oxygen wherein said ring contains at least one carbon atom and wherein said heterocyclic ring is optionally substituted with -( -C5) linear or branched alkyl;
R10 is hydrogen, -NR8R9, -ORn, -(C1-C5) linear or branched alkyl, or phenyl;
each occurrence of Rn is independently selected from the group consisting of hydrogen, -(Ci-Cs) linear or branched alkyl and phenyl;
n, m and p are independently an integer from 0 - 3;
y is an integer from 0 - 2;
or a purified stereoisomer or stereoisomer mixture of said compound or a salt of said compound or purified stereoisomer or stereoisomer mixture thereof.
Embodiment 2
Also described are compounds of formula (I) or (II) wherein:
Z is CH or N;
Y is O or S;
X is OR5 orNR5R6;
Ri and R2 are hydrogen;
R3 is selected from the group consisting of:
(a) hydrogen, and
(b) -(C Cs) linear or branched alkyl;
R4 is -(CH^yR , wherein
Figure imgf000010_0001
R4' is: R5 has the formula -(CHRn)m-A or -(CHRπ)p-O-A, where A is selected from the group consisting of:
(a) hydrogen,
(b) -(Ci-C5) linear or branched alkyl optionally substituted with cyano, halogen, hydroxy, -(Ci-C5) alkoxy or -NR8R9,
(c) -(C3-C8) cycloalkyl optionally substituted with cyano, halogen, hydroxy, -(Cι-C5)-alkyl, -(C1-C5) alkoxy or -NR8R9,
(d) -(C6-C10) aryl optionally substituted with one to three substituents selected from the group consisting of:
[1) cyano,
2) halogen,
3) hydroxy,
4) nitro,
5) -NR8R9,
6) -(Ci-C5)-alkyl optionally substituted with halogen,
7) -(Ci-Cs)-alkoxy wherein the alkyl is optionally substituted -NR8R9 or halogen,
8) -(C6-C10)-aryl-(C1-C5)-alkoxy
9) -(C6-C10)-aryloxy optionally substituted with halogen
10) -(C6-C10)-aryl optionally substituted with halogen,
11) -CH2-(C6-Ci0)-aryl,
12) -C(=O)R7,
13) -C(=O)OR7,
14) -C(=O)NR8R9,
15) -S(=O)Rιo;
16) -S(=O)2R10; and
17) a saturated or fully unsaturated four to eight membered heterocyclic ring containing one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein said ring: (al7) contains at least one carbon atom; (bl7) is directly linked to the -(C6-C10)-aryl or is linked to the -(C6-C10)-aryl via an -O- linkage; and (cl7) is optionally substituted with -(Ci-C5)-alkyl, -(CH2)nCOOR7 or -(CH2)„CONR8R9,
and
(e) a saturated or fully unsaturated four to eight membered heterocyclic ring containing one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein said ring contains at least one carbon atom, and is optionally substituted with (1) -(Cι-Cs)-alkyl optionally substituted by halogen,
(2) phenyl optionally substituted by halogen,
(3) -(C1-Cs)-alkoxy- wherein the alkyl is optionally substituted with halogen,
(4) -(Cι-Cs)-aryloxy- wherein the aryl is optionally substituted with halogen, or
(5) oxo;
R6 is selected from the group consisting of: (a) hydrogen, and (b) -(Ci-Cs) linear or branched alkyl,
wherein R5 and R6 are not both hydrogen;
R5 and R6 form, together with the nitrogen to which they are attached, a saturated or fully unsaturated four to eight membered heterocyclic ring, optionally containing one to three additional heteroatoms selected from the group consisting of nitrogen and oxygen wherein said ring contains at least one carbon atom wherein said heterocyclic ring is optionally substituted with -(C1-C5) alkyl;
R7 is selected from the group consisting of hydrogen, -(C1-C5) linear or branched alkyl, phenyl, -(Ci-C5)-alkyl-phenyl, and -(C3-C8) cycloalkyl which are optionally substituted with one to three substituents selected from the group consisting of halogen, oxo, -(C1-C5) alkoxy-, -C(=O)R and -(Ci-Cs) linear or branched alkyl optionally substituted by halogen;
Rs and R9 are independently selected from the group consisting of: (a) hydrogen,
(b) -(Ci-C5) linear or branched alkyl, which is optionally substituted with a substiruent selected from the group consisting of halogen and -(Ci- Cs) alkoxy,
(c) -(C1-C5) alkoxy, (d) -(Cβ-Cio) aryl, and
(e) -(CH )n-R wherein R is a saturated or fully unsaturated five to six membered heterocyclic ring containing one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein said ring contains at least one carbon atom, wherein (c)-(e) are optionally substituted with one to three substituents selected from the group consisting of halogen, -(Ci-Cs) alkoxy- and -(CJL-CS) linear or branched alkyl optionally substituted by halogen;
R10 is hydrogen, -NR8R9, -ORπ, -(Ci-C5) linear or branched alkyl, or phenyl;
each occurrence of Rπ is independently selected from the group consisting of hydrogen, -(Ci-Cs) linear or branched alkyl and phenyl;
R12 is -R13, -OR13, or - R14R15;
R13 IS
(a) hydrogen,
(b) -(C1-C5) linear or branched alkyl optionally substituted with halogen, or (c) phenyl optionally substituted with halogen;
R14 and R15 are independently selected from the group consisting of: (a) hydrogen, (b) -(C Cs) linear or branched alkyl optionally substituted with halogen, and
(c) phenyl optionally substituted with halogen;
n, m and p are independently an integer from 0 - 3;
y is an integer from 0 - 2; and
y + (m + p) equals an integer from 1 - 8;
or a purified stereoisomer or stereoisomer mixture of said compound or a salt of said compound or purified stereoisomer or stereoisomer mixture thereof.
Embodiment 3 Also described are compounds with the formula (I) and (II) wherein: Z is CH orN; Y is O or S; X is OR5 orNR5R6;
Ri and R2 are independently selected from the group consisting of hydrogen and -OCH3 wherein at least one of Ri and R2 is -OCH3;
R3 is hydrogen; j is -(CH2)y-R4 wherein:
R is selected from the group consisting of:
(a) -(Ci-Cs) linear or branched alkyl which is optionally substituted with one to three substituents selected from the group consisting of:
(1) cyano,
(2) halogen,
(3) hydroxy,
(4) nitro, (5) -(Ci-Cs) linear or branched alkyl optionally substituted by halogen,
(6) -(Ci-Cs) alkoxy,
(7) -C(=O)R7, (8) -C(=O)OR7,
(9) -C(=O)NR8R9,
(10) -S(=O)R10, and
(11) -S(=O)2R10,
(b) -(C3-C8) cycloalkyl,
(c) -(Cβ-Cio) aryl, wherein (b) and (c) are optionally substituted with one to three substituents selected from the group consisting of (1) amino,
(2) cyano,
(3) halogen,
(4) hydroxy,
(5) nitro, (6) oxo,
(7) -( -C5) linear or branched haloalkyl
(8) -(Cι-C5) haloalkoxy,
Figure imgf000015_0001
(10) -(CH2)nC(=O)OR7, (11) -(CH2)nC(=O)C(=O)-OR7
(12) -(CH2)nC(=O)NR8R9,
(13) -S(=O)Rιo ,
(14) -S(=O)2Rιo;
(15) -C(=N-Rιo)-(Ci-C5) alkyl, and (16) a saturated or unsaturated four to six membered heterocyclic ring containing one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur wherein said ring contains at least one carbon atom,
and
(d) a saturated or fully unsaturated four to eight membered heterocyclic ring containing one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein said ring contains at least one carbon atom and wherein said ring is optionally substituted with one to three substituents selected from the group consisting of amino, cyano, halogen, hydroxy, nitro, oxo, -(C Cs) alkoxy, -(CH2)nC(=O)OR7, -(CH2)nC(=O)NR8R9, -S(=O)R10, - S(=O)2R10 and -(C1-C5) linear or branched alkyl optionally substituted by halogen;
or
R3 and R^i form, together with the nitrogen to wliich they are attached, a saturated or fully unsaturated four to eight membered heterocyclic ring, wherein the nitrogen is the only heteroatom, which is optionally substituted with one to tliree substituents selected from the group consisting of amino, cyano, halogen, hydroxy, nitro, oxo, - (C6-C10)-aryl, -C(=O)R7, -(CH2)nC(=O)OR7, -(CH2)nC(=O)NR8R9, -S O)R10, -
S(=O) R10 and -(Ci-Cs) linear or branched alkyl optionally substituted by halogen;
Rs has the formula:
-(CH2)p-O-A where A is selected from the group consisting of: (a) hydrogen,
(b) -(Ci-C5) linear or branched alkyl, optionally substituted with cyano, halogen, hydroxy, -(Ci-Cs) alkoxy- or -NR8R9, and
(c) -(C3-C8) cycloalkyl, optionally substituted with cyano, halogen, hydroxy, -(C1-C5)-alkyl, -( -C5) alkoxy or -NR8R9; (d) -(C6-Cio)-aryl, optionally substituted with one to three substituents selected from the group consisting of:
(1) cyano,
(2) halogen,
(3) hydroxy, (4) nitro,
(5) -NR8R9,
(6) -(Ci-C5)-alkyl optionally substituted with halogen, (7) (C1-C5)-alkoxy wherein the alkyl is optionally substituted with -NR8R9 or halogen,
(8) -(C6-C10)-aryl-(Ci-C5) alkoxy
(9) -(C6-Cio)-aryloxy optionally substituted with halogen, (10) -(C6-C10)-aryl optionally substituted with halogen,
(11) -CH2-(C6-C10)-aryl,
(12) -C(=O)R7,
(13) -C(=O)OR7,
(14) -C(=O)NR8R9, (15) -S(=O)R,o;
(16) -S(=O)2R10; and
(17) a saturated or fully unsaturated four to eight membered heterocyclic ring containing one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein said ring:
(al7) contains at least one carbon atom; (bl7) is directly linked to the -(C6-C10)-aryl or is linked to the -(C6-Cιo)-aryl via an -O- linkage, and (cl7) is optionally substituted with -(Ci-Cs)-alkyl,
-(CH2)nCOOR7 or -(CH2)„CONR8R9,
(e) a saturated or fully unsaturated four to eight membered heterocyclic ring containing one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein said ring contains at least one carbon atom, and is optionally substituted with
(1) -(Ci-Cs) alkyl optionally substituted by halogen,
(2) -(C6-C10)-aryl optionally substituted by halogen,
(3) -(Ci-C5)-alkoxy wherein the alkyl is optionally substituted with halogen,
(4) -(C1-Cs)-aryloxy wherein the aryl is optionally substituted with halogen, or
(5) oxo, and
(f) a fused bicyclo ring wherein one ring is a saturated or fully unsaturated five to six membered heterocyclic ring which contains one to three heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein said heterocyclic ring contains at least one carbon and the other ring is a saturated or fully unsaturated five to eight membered carbocycle,
or
-(CH2)m-A where A is selected from the group consisting of: (a) hydrogen, (b) -(Ci-C5) linear or branched alkyl optionally substituted with cyano, halogen, hydroxy, -(Ci-Cs) alkoxy or -NR8R ,
(c) -(C3-C8) cycloalkyl optionally substituted with cyano, halogen, hydroxy, -(Cι-C5)-alkyl, -( -Cs) alkoxy or -NR8R9,
(d) -(C6-Cιo) aryl, optionally substituted with one to three substituents selected from the group consisting of:
(1) cyano,
(2) halogen,
(3) hydroxy,
(4) nitro, (5) -NR8R9,
(6) -(Ci-Cs) alkyl optionally substituted with halogen,
(7) -(C Cs) alkoxy wherein the alkyl is optionally substituted with -NR8R9 or halogen,
(8) -C(=O)R7, (9) -C(=O)OR7,
(10) -C(=O)NR8R9,
Figure imgf000018_0001
(12) -S(=O)2R10; and (13) a saturated or fully unsaturated four to eight membered heterocyclic ring containing one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein said ring: (al3) contains at least one carbon atom;
(bl3) is directly linked to the -(C6-C10) aryl or is linked to the -(C6-Cio) aryl via an -O- linkage, and (cl 3) is optionally substituted with -(Cι-C5)-alkyl, -(CH2)nC(=O)OR7 or -(CH2)nC(=O)NR8R9,
(e) a saturated or fully unsaturated four to eight membered heterocyclic ring containing one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein said ring contains at least one carbon atom, and is optionally substituted with
( 1 ) -(Ci-Cs)-alkyl optionally substituted by halogen,
(2) phenyl optionally substituted by halogen,
(3) -(CrCs)-alkoxy wherein the alkyl is optionally substituted with halogen, (4) -(Ci-Cs)-aryloxy wherein the aryl is optionally substituted with halogen, or (5) oxo,
and
(f) a fused bicyclo ring wherein one ring is a saturated or fully unsaturated five to six membered heterocyclic ring which contains one to tliree heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein said heterocyclic ring contains at least one carbon atom and the other ring is a saturated or fully unsaturated five to eight membered carbocycle;
is selected from the group consisting of: (a) hydrogen, and
(b) -(d-Cs) linear or branched alkyl,
wherein R5 and R6 are not both hydrogen;
or
R5 and R6 form, together with the nitrogen to which they are attached, a saturated or fully unsaturated four to eight membered heterocyclic ring, which optionally contains one to three additional heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur wherein said ring contains at least one carbon atom, and wherein said ring is optionally substituted with one to three substituents selected from the group consisting of: (a) amino, (b) cyano,
(c) halogen,
(d) hydroxy,
(e) nitro,
(f) oxo, (g) -(Ci-Cs) linear or branched alkyl optionally substituted by halogen or
-(C1-C5) alkoxy, (j) -(C6-C1o)-aryl optionally substituted by halogen or -(Cι-Cs)-alkyl, (k) -(Ci-Cs)-alkyl-phenyl optionally substituted by halogen or -(Ci-C5) alkyl, (1) -(CH2)nCOOR7,
(m) -(CH2)„CONR8R9, (n) -(CH2)nNR8R9, (o) -S(=O)Rιo, (p) -S(=O)2R10, and (q) -(CH2)n-Q, wherein Q is:
(ql) a four to eight membered saturated or fully unsaturated heterocyclic ring containing one to four nitrogens, wherein said ring contains at least one carbon atom, or (q2) -C6-C10-aryl optionally substituted with halogen or -( -Cs) alkyl;
wherein, (i) R3 ≠ R4,
(ii) R5 ≠ R6, and
(iii) (R3 and R4) ≠ (R5 and R6)
R7 is selected from the group consisting of hydrogen, -(Ci-C5) linear or branched alkyl, phenyl, -(CrCs)-alkyl-phenyl, and (C3-C10) cycloalkyl which are optionally substituted with one to three substituents selected from the group consisting of halogen, oxo, -(Ci-Cs) alkoxy, -(CH2)nC(=O)Rπ, - (CH2)nC(=O)ORπ, -(CH2)nC(=O)NR8R9, -S(=O)R10, -S(=O)2R10 and -(C C5) linear or branched alkyl optionally substituted by halogen;
R8 and R are independently selected from the group consisting of hydrogen, - (C Cs) linear or branched alkyl, -(Ci-Cs) alkoxy or -(C6-C10) aryl which is optionally substituted with one to three substituents selected from the group consisting of halogen, -(Ci-Cs) alkoxy, -(C1-C5) alkylamino, (CH2)nC(=O)R7, -(CH2)nC(=O)OR7, -(CH2)nC(=O)NR8R9, -S(=O)R10, -
S(=O)2R10 and -(C1-C5) linear or branched alkyl optionally substituted by halogen; or
R8 and R form, together with the nitrogen to which they are attached, a saturated or fully unsaturated, four to eight membered heterocyclic ring, wherein said ring has one to three additional heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur wherein said ring contains at least one carbon atom and wherein said heterocyclic ring is optionally substituted with -(Ci-C5) linear or branched alkyl;
R10 is hydrogen, -NR8R9, -ORπ, -(C^Cs) linear or branched alkyl, or phenyl;
Ru is hydrogen, -( -Cs) linear or branched alkyl, or phenyl; n, m and p are independently an integer from 0 - 3; and
y is an integer from 0 - 2,
or a purified stereoisomer or stereoisomer mixture of said compound or a salt of said compound or purified stereoisomer or stereoisomer mixture thereof.
Pharmaceutically acceptable salts of these compounds as well as commonly used prodrugs of these compounds are also within the scope of the invention.
Detailed Description
Embodiment 1. preferred compounds
The preferred compounds of embodiment 1 have general formula (I) and are further defined below. In the following description of these preferred compounds, the definitions for the various groups and variables represent the preferred definitions when they differ from those of embodiment 1 as broadly defined above, and are to be understood as independent of each other.
The preferred compounds of embodiment 1 have the formula (I)
Figure imgf000022_0001
(I) wherein
Z is N;
X is OR5 orNR5R6 ; Ri and R2 are independently selected from the group consisting of hydrogen, cyano, halogen, and hydroxy, and wherein Ri and R2 are both not hydrogen;
R3 is selected from the group consisting of:
(a) hydrogen, and
(b) -(Ci-C5) linear or branched alkyl;
R4 is -(CH2)y-R4 l wherein: Rt' is selected from the group consisting of:
(a) -(d-Cs) linear or branched alkyl optionally substituted with one to three substituents selected from the group consisting of:
(1) -C(=O)R7,
(2) -C(=O)OR7,
Figure imgf000023_0001
(4) -S(=O)R,o, and
(5) -S(O)2R10;
(b) -(C3-C8) cycloalkyl,
(c) -(C6- ■C10) aryl, wherein (b) and (c) are optionally substituted with one to three substituents selected from the group consisting of
(1) cyano,
(2) halogen,
(3) -(CH2)nC(=O)R7,
(4) -(CH2)nC(=O)OR7,
Figure imgf000023_0002
(6) -(CH2)nC(=O)NR8R9,
(7) -S(=O)R10 ,
(8) -S(=O)2R10,
(9) -C(=N-Rιo)-(Cι-C5)-alkyl, and (10) a saturated or unsaturated four to six membered heterocyclic ring containing one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein said ring contains at least one carbon atom; and
(d) a saturated or fully unsaturared four to six membered heterocyclic ring containing one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein said ring contains at least one carbon atom and wherein said ring is optionally substituted with one to tliree substituents selected from the group consisting of amino, cyano, halogen, hydroxy, nitro, oxo, -(Ci-Cs)-alkoxy, -(CH2)nC O)OR7, -(CH2)nC(=O)NR8R9, -S(=O)R10, -S(=O)2R10 and -(Ci-C5) linear or branched alkyl optionally substituted by halogen, or R3 and R4 form, together with the nitrogen to which they are attached, a saturated four to eight membered heterocyclic ring, wherein the nitrogen is the only heteroatom, which is optionally substituted with one substituent selected from the group consisting of -(d-Cs) alkoxy, -(CH2)nC(=O)OR7, and -(Ci-Cs) linear or branched alkyl optionally substituted by halogen;
R5 has the formula -(CHRπ)m-A or -(CHRπ)p-O-A, wherein Rπ is H and A is selected from the group consisting of:
(a) hydrogen,
(b) -(Ci-Cs) linear or branched alkyl optionally substituted with halogen, -(Ci-Cs) alkoxy or -NR8R9,
(c) -(C6-Cιo) aryl optionally substituted with one to three substituents selected from the group consisting of:
(1) halogen,
(2) nitro, (3) -(C!-Cs)-alkoxy wherein the alkyl is optionally substituted with -NR8R9 or halogen,
(4) -CH2-phenyl,
(5) -C(=O)R7, (6) -C(=O)OR7,
(7) -C(=O)NR8R9,
(8) -S(=O)Rιo,
(9) -S(=O)2R10, and (10) a saturated or fully unsaturated four to eight membered heterocyclic ring containing one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein said ring: (alO) contains at least one carbon atom, (b 10) is directly linked to the -(C6-C10)-aryl or is linked to the -(C6-C10)-aryl via an -O- linkage, and (cl 0) is optionally substituted with -(Ci-C5)-alkyl, -(CH2)„C(=O)OR7 or -(CH2)nC(=O)NR8R9,
(d) a saturated or fully unsaturated five or six membered heterocyclic ring containing one to two heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein said ring contains at least one carbon atom, and is optionally substituted with oxo; and
(e) a fused bicyclo ring wherein one ring is a saturated or fully unsaturated five to six membered heterocyclic ring which contains one to three heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein said heterocyclic ring contains at least one carbon atom, and the other ring is a saturated five to six membered carbocycle,
R6 is selected from the group consisting of: (a) hydrogen, and (b) -(Ci-C5) linear or branched alkyl,
wherein R5 and R6 are not both hydrogen; or
Rs and R6 fonn, together with the nitrogen to which they are attached, a saturated five to seven membered heterocyclic ring, which optionally contains one additional nitrogen atom, and wherein said ring is optionally substituted with one to three substituents selected from the group consisting of:
(a) halogen,
(b) oxo,
(c) -(Ci-Cs) linear or branched alkyl optionally substituted by halogen or -(Ci-Cs)-alkoxy,
(d) -(C1-C5) alkoxy,
Figure imgf000026_0001
(f) -(CH2)„C(=O)NR8R9, and
(g) -(CH2)n-Q, wherein Q is a pyridyl group;
wherein (R3 and Ri) ≠ (R5 and R6) when:
(1) RsΛ^ or R5/R6 contain an unsubstituted -(CH2)n-C6-Cι0-aryl substituent, or
(2)
Figure imgf000026_0002
or R5/R6 form a heterocyclic ring;
R7 is selected from the group consisting of hydrogen, -(Ci-Cs) linear or branched alkyl, and phenyl, which are optionally substituted with one to three substituents selected from the group consisting of halogen, oxo, -(Ci-Cs) alkoxy, and -(Ci-Cs) linear or branched alkyl optionally substituted by halogen;
R8 and R9 are independently selected from the group consisting of:
(a) hydrogen,
(b) -(d-Cs) linear or branched alkyl which is optionally substituted with a substituent selected from the group consisting of halogen and -( -
C5) alkoxy,
(c) -(C6-C10) aryl, and wherein (c) is optionally substituted with one to three substituents selected from the group consisting of halogen, -(Ci-Cs) alkoxy, and -(Ci-Cs) linear or branched alkyl optionally substituted by halogen,
or
R8 and R form, together with the nitrogen to which they are attached, a saturated or fully unsaturated five or six membered heterocyclic ring, optionally containing one to two additional heteroatoms selected from the group consisting of nitrogen and oxygen;
R10 is hydrogen, -NR8R9, -ORl l5 -(Ci-C5) linear or branched alkyl, or phenyl;
except in the definition of R5 , each occunence of Rπ is independently selected from the group consisting of hydrogen and -(C1-C5) linear or branched alkyl and phenyl;
n, m and p are independently an integer from 0 - 3;
y is an integer from 0 - 2;
or a purified stereoisomer or stereoisomer mixture of said compound or a salt of said compound or purified stereoisomer or stereoisomer mixture thereof.
Embodiment 1, more preferred compounds
The more prefened compounds of embodiment 1 have general formula (I) and are further defined below. In the following description of these more prefened compounds, the definitions for the various groups and variables represent the more prefened definitions when they differ from those of embodiment 1 as broadly defined above, and are to be understood as independent of each other.
The more prefened compounds of embodiment 1 have the formula (I)
Figure imgf000028_0001
(I) wherein,
Z is N,
X is NR5R6;
Ri and R2 are independently selected from the group consisting of hydrogen and halogen, wherein Ri and R are both not hydrogen;
R3 is hydrogen,
j is -(CH^y-R wherein:
R4' is selected from the group consisting of:
(a) cyclohexyl,
(b) -phenyl, wherein (a) and (b) are optionally substituted with one to three substituents selected from the group consisting of
1) -(CH2)nC(=O)R7,
2) -(CH2)nC(=O)OR7,
3) -(CH2)nC(=O)NR8R9,
4) -S(=O)R10 ,
5) -S(=O)2R10,
6) -C(=N-Rιo)-(Cι-C5)-alkyl, and (7) a saturated or fully unsaturated six membered heterocyclic ring containing one to two heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, and (d) a fully unsaturated five membered heterocyclic ring containing one heteroatom selected from the group consisting of oxygen and sulfur, wherein said ring is optionally substituted with one substituent selected from the group consisting of -(CH2)„C(=O)OR7, -(CH2)nC(=O)NR8R9, -S(=O)R10, and -S(=O)2R10 , or
R3 and R4 form, together with the nitrogen to which they are attached, a saturated six membered heterocyclic ring, wherein the nitrogen is the only heteroatom,
R5 has the formula -(CHRπ)m-A or -(CHRπ)p-O-A, wherein Rπ is H and A is selected from the group consisting of:
(a) -(Ci-Cs) linear or branched alkyl optionally substituted with -(Cι-C5) alkoxy,
(b) -phenyl optionally substituted with one to two substituents selected from the group consisting of:
(1) halogen,
(2) -(Cι-Cs)-alkoxy
(3) -C(=O)OR7,
(4) -C(=O)NR8R9, (5) morpholinyl
(c) a saturated or fully unsaturated five or six membered heterocyclic ring containing one to two heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein said ring is optionally substituted with oxo,
(d) a fused bicyclo ring wherein one ring is a saturated or fully unsaturated five to six membered heterocyclic ring wliich contains one to two heteroatoms selected from the group consisting of nitrogen and oxygen, wherein said heterocyclic ring contains at least one carbon atom, and the other ring is a saturated or fully unsaturated five to six membered carbocycle; R6 is hydrogen,
or
R5 and R6 form, together with the nitrogen to which they are attached, a fully saturated five or six membered heterocyclic ring, which optionally contains one additional nitrogen atom, and wherein said ring is optionally substituted with one to two substituents selected from the group consisting of:
(a) -(Ci-Cs) linear or branched alkyl optionally substituted by halogen or -(Ci-Cs)-alkoxy,
(b) -(CH2)nC(=O)OR7, and
(c) -(CH2)nC(=O)NR8R9,
wherein (R3 and R ) ≠ (R5 and R6) when: (1) Rs^ or Rs/Re contain an unsubstituted -(CH2)n-C6-C10-aryl substituent, or (2) R3/R4 or R5/R6 form a heterocyclic ring;
R is selected from the group consisting of hydrogen, -( -C5) linear or branched alkyl and phenyl, which are optionally substituted with one halogen,
R8 and R9 are independently selected from the group consisting of:
(a) hydrogen,
(b) -(Ci-Cs) linear or branched alkyl, and (c) -phenyl, and wherein (c) is optionally substituted with one substituent selected from the group consisting of halogen and -(Ci-Cs) alkoxy,
Rιo is -NR8R9 or -ORii ,
each occunence of Rn is hydrogen,
n, m and p are independently an integer from 0 - 3; y is an integer from 0 - 2;
or a purified stereoisomer or stereoisomer mixture of said compound or a salt of said compound or purified stereoisomer or stereoisomer mixture thereof.
Embodiment 2, preferred compounds
The prefened compounds of embodiment 2 have general formula (I) and are further defined below. In the following description of these prefened compounds, the definitions for the various groups and variables represent the preferred definitions when they differ from those of embodiment 2 as broadly defined above, and are to be understood as independent of each other.
The prefened compounds of embodiment 2 have the formula (I)
Figure imgf000031_0001
(I) wherein:
Z is N;
X is OR5 orNR5R6;
R] and R are hydrogen;
R3 is selected from the group consisting of:
(a) hydrogen, and
(b) -(Ci-Cs) linear or branched alkyl;
R is -(CH2)yR '5 wherein
Figure imgf000031_0002
R is:
R5 has the formula -(CHRu)m-A or -(CHRπ)p-O-A, wherein Rπ is H and A is selected from the group consisting of: (a) hydrogen,
(b) -(Ci-Cs) linear or branched alkyl optionally substituted with halogen, - (C1-C5) alkoxy or -NR8R9 ,
(c) -(C6-Cι0)-aryl optionally substituted with one to tliree substituents selected from the group consisting of: (1) halogen,
(2) nitro,
(3) -(C!-Cs)-alkoxy wherein the alkyl is optionally substituted with -NR8R9 or halogen,
(4) CH2-phenyl, (5) -C(=O)R7,
(6) -C(=O)OR7,
(7) -C(=O)NR8R9,
(8) -S(=O)R10;
(9) -S(=O)2R10; and (10) a saturated or fully unsaturated four to eight membered heterocyclic ring containing one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein said ring: (alO) contains at least one carbon atom; (blO) is directly linked to the -(C6-Ci0)-aryl or is linked to the -(C6-do)-aryl via an -O- linkage; and (clO) is optionally substituted with -(Ci-C5)-alkyl, -(CH2)nCOOR7 or -(CH2)„CONR8R9, and
(d) a saturated or fully unsaturated five to six membered heterocyclic ring containing one to two heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein said ring contains at least one carbon atom, and is optionally substituted with oxo,
R6 is selected from the group consisting of:
(a) hydrogen, and
(b) -(Ci-C5) linear or branched alkyl,
wherein R5 and R6 are not both hydrogen; or
R5 and R6 form, together with the nitrogen to which they are attached, a saturated five to seven membered heterocyclic ring, optionally containing one additional heteroatom selected from the group consisting of nitrogen and oxygen wherein said heterocyclic ring is optionally substituted with -(Cι-Cs)-alkyl;
R7 is selected from the group consisting of hydrogen, -(C Cs) linear or branched alkyl and phenyl, which are optionally substituted with one to three substituents selected from the group consisting of halogen, oxo, -(Ci-Cs) alkoxy-, and -( -C5) linear or branched alkyl optionally substituted by halogen;
R8 and R9 are independently selected from the group consisting of:
(a) hydrogen,
(b) -(Ci-Cs) linear or branched alkyl, which is optionally substituted with a substituent selected from the group consisting of halogen and (Ci- Cs) alkoxy-,
(c) -(Cβ-Cio) aryl, and wherein (c) is optionally substituted with one to three substituents selected from the group consisting of halogen,-(C1-Cs) alkoxy and -(Ci-Cs) linear or branched alkyl optionally substituted by halogen;
R10 is hydrogen, -NR8R9, -ORn, -(Cι-C5) linear or branched alkyl, or phenyl; each occunence of Rπ is independently selected from the group consisting of hydrogen and -(Ci-Cs) linear or branched alkyl and phenyl;
R12 is -R13, -OR13, or -NRι4R15;
R13 is
(a) hydrogen,
(b) -(Ci-Cs) linear or branched alkyl optionally substituted with halogen, or (c) phenyl optionally substituted with halogen;
R1 and R15 are independently selected from the group consisting of:
(a) hydrogen,
(b) -(Ci-C5) linear or branched alkyl optionally substituted with halogen, and
(c) phenyl optionally substituted with halogen;
n, m and p are independently an integer from 0 - 3;
y is an integer from 0 - 2; and
y + (m + p) equals an integer from 1 - 8;
or a purified stereoisomer or stereoisomer mixture of said compound or a salt of said compound or purified stereoisomer or stereoisomer mixture thereof.
Embodiment 2, more prefened compounds
The more prefened compounds of embodiment 2 have general formula (I) and are further defined below. In the following description of these more prefened compounds, the definitions for the various groups and variables represent the more prefened definitions when they differ from those of embodiment 2 as broadly defined above, and are to be understood as independent of each other. The more prefened compounds of embodiment 2 have the formula (I)
Figure imgf000035_0001
(I) wherein:
Z is N;
X is NR5R6;
Ri and R2 are hydrogen;
R3 is hydrogen;
R4 is -(CH2)yR ', wherein
Figure imgf000035_0002
Rt' is:
R5 has the formula -(CHRπ)m-A or -(CHRπ)p-O-A, wherein Rπ is H and A is selected from the group consisting of:
(a) -(Ci-Cs) linear or branched alkyl optionally substituted with -(Ci-C5) alkoxy,
(b) -phenyl optionally substituted with one to two substituents selected from the group consisting of:
(1) halogen,
(2) -(Ci-C5)-alkoxy wherein the alkyl is optionally substituted with halogen,
(3) -C(=O)OR7,
(4) -C(=O)NR8R9,
(5) morpholino, and
(c) a saturated or fully unsaturated five or six membered heterocyclic ring containing one to two heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein said ring contains at least one carbon atom, and is optionally substituted with oxo,
R6 is hydrogen,
or
Rs and R6 form, together with the nitrogen to which they are attached, a saturated five or six membered heterocyclic ring, optionally containing one additional heteroatom selected from the group consisting of nitrogen and oxygen, wherein said heterocyclic ring is optionally substituted with-(Ci-Cs)-alkyl;
R7 is selected from the group consisting of hydrogen, -(Ci-Cs) linear or branched alkyl, and phenyl, which are optionally substituted with one halogen substituent,
R8 and R9 are independently selected from the group consisting of:
(a) hydrogen, and
(b) -(Ci-Cs) linear or branched alkyl
(c) -phenyl, and wherein (c) is optionally substituted with one substituent selected from the group consisting of halogen and -(d-Cs) alkoxy ,
R10 is -NR8R9 or -ORιι ,
each occunence of Rπ is hydrogen,
R12 is -OR13, or -NR14Rι5;
R13 is (a) hydrogen, or
(b) -(Ci-Cs) linear or branched alkyl
(c) -(Ci-Cs) linear or branched alkyl optionally substituted with halogen,
R14 and R15 are independently selected from the group consisting of:
(a) hydrogen,
(b) -(d-Cs) linear or branched alkyl , and
(c) phenyl optionally substituted with halogen;
n, m and p are independently an integer from 0 - 3;
y is an integer from 0 - 2; and
y + (m + p) equals an integer from 1 - 8;
or a purified stereoisomer or stereoisomer mixture of said compound or a salt of said compound or purified stereoisomer or stereoisomer mixture thereof.
Embodiment 3. prefened compounds
The prefened compounds of embodiment 3 have general formula (I) and are further defined below. In the following description of these prefened compounds, the definitions for the various groups and variables represent the prefened definitions when they differ from those of embodiment 3 as broadly defined above, and are to be understood as independent of each other.
The prefened compounds of embodiment 3 have the fonnula (I)
Figure imgf000037_0001
(i) wherein:
Z is N;
X is OR5 orNR5R6;
Ri and R2 are independently selected from the group consisting of hydrogen and -OCH3 wherein at least one of Ri and R2 is -OCH3;
R3 is hydrogen; R4 is -(CH2)y-R4' wherein:
R ' is selected from the group consisting of:
(a) -(Ci-Cs) linear or branched alkyl which is optionally substituted with one to three substituents selected from the group consisting of:
(1) -C(=O)R7,
(2) -C(=O)OR7,
(3) -C(=O)NR8R9,
(4) -S(=O)R10, and (5) -S(=O)2R10,
(b) -(C3-C8) cycloalkyl,
(c) -( -Cio) aryl, wherein (b) and (c) are optionally substituted with one to three substituents selected from the group consisting of
(1) cyano,
(2) halogen,
(3) -(CH2)nC(=O)R7,
(4) -(CH2)nC(=O)OR7, (5) -(CH2)nC(=O)C(=O)-OR7
(6) -(CH2)„C(=O)NR8R9,
(7) -S(=O)R10 ,
(8) -S(=O)2R10;
(9) -C(=N-R10)-C1-C5 alkyl, and (10) a saturated or unsaturated four to six membered heterocyclic ring containing one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur wherein said ring contains at least one carbon atom, and
(d) a saturated or fully unsaturated four to eight membered heterocyclic ring containing one to two heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein said ring contains at least one carbon atom and wherein said ring is optionally substituted with one to three substituents selected from the group consisting of oxo, -(Ci-C5) alkoxy, -(CH2)nC(=O)OR7, (CH2)nC(=O)NR8R9, -S(=O)Rιo, -S O)2R10 and -(Q-Cs) linear or branched alkyl optionally substituted by halogen;
or
R3 and R4 form, together with the nitrogen to which they are attached, a saturated four to eight membered heterocyclic ring, wherein the nitrogen is the only heteroatom, which is optionally substituted with one substituent selected from the group consisting of -(CH2)nC(=O)OR7 and -(Ci-Cs) linear or branched alkyl optionally substituted by halogen;
Rs has the formula: -(CH2)p-O-A where A is selected from the group consisting of:
(a) hydrogen,
(b) -(C1-C5) linear or branched alkyl, optionally substituted with halogen, -(Cι-C5) alkoxy or -NR8R9,
(c) -(C6-C10)-aryl, optionally substituted with one to three substituents selected from the group consisting of:
(1) halogen,
(2) -(Cι-C5)-alkyl optionally substituted with halogen,
(3) -(Ci-C5)-alkoxy,
(4) -C(=O)OR7, and (5) -C(=O)NR8R9, or
-(CH2)m-A where A is selected from the group consisting of: (a) -(C1-C5) linear or branched alkyl optionally substituted with halogen, - (C1-C5) alkoxy or -NR8R9,
(b) -(C6-Cio)-aryl, optionally substituted with one to three substituents selected from the group consisting of: (1) halogen,
(2) -(Ci-Cs)-alkoxy wherein the alkyl is optionally substituted with -NR8R9 or halogen,
(3) -C(=O)R7,
Figure imgf000040_0001
(5) -C(=O)NR8R9,
(6) -S(=O)R10;
(7) -S(=O)2R10; and
(8) a saturated or fully unsaturated four to eight membered heterocyclic ring containing one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein said ring: (a8) contains at least one carbon atom; (b8) is directly linked to the -(C6-C10)-aryl or is linked to the -(C6-C10)-aryl via an -O- linkage, and
(c8) is optionally substituted with -(Cι-C5)-alkyl, -(CH2)nC(=O)OR7 or -(CH2)nC(=O)NR8R9,
(c) a saturated or fully unsaturated five to six membered heterocyclic ring containing one to two heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein said ring contains at least one carbon atom, and is optionally substituted with oxo and
(d) a fused bicyclo ring wherein one ring is a saturated or fully unsaturated five to six membered heterocyclic ring which contains one to three heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein said heterocyclic ring contains at least one carbon atom and the other ring is a saturated five to six membered carbocycle;
R6 is selected from the group consisting of: (a) hydrogen, and
(b) -(Ci-Cs) linear or branched alkyl,
R5 and Re form, together with the nitrogen to which they are attached, a saturated five to seven membered heterocyclic ring, which optionally contains one additional heteroatom selected from the group consisting of nitrogen, oxygen and sulfur, wherein said ring is optionally substituted with one to three substituents selected from the group consisting of: (a) halogen,
(b) oxo,
(c) -(Ci-Cs) linear or branched alkyl optionally substituted by halogen or -(C1-C5) alkoxy,
(d) -(CH2)nCOOR7, (e) -(CH2)nCONR8R9,
(f) -(CH2)n-Q, wherein Q is pyridyl,
wherein,
(i) R3 ≠ R4, (ii) R5 ≠ Re, and
(iii) (R3 and R4) ≠ (R5 and R6)
R7 is selected from the group consisting of hydrogen, -(Ci-Cs) linear or branched alkyl and phenyl, which are optionally substituted with one to three substituents selected from the group consisting of halogen, oxo,
-(d-Cs) alkoxy , and -(C1-C5) linear or branched alkyl optionally substituted by halogen; R8 and R are independently selected from the group consisting of hydrogen, -(Ci-C5) linear or branched alkyl, and -(Ce-C10) aryl which is optionally substituted with one to three substituents selected from the group consisting of halogen and -( - C5) alkoxy, or
R8 and R9 form, together with the nitrogen to which they are attached, a saturated or fully unsaturated, five or six membered heterocyclic ring, wherein said ring has one to two additional heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur,
Rio is hydrogen, -NR8R9, -ORπ, -(Ci-Cs) linear or branched alkyl, or phenyl;
Rπ is hydrogen, -(C Cs) linear or branched alkyl, or phenyl;
n, m and p are independently an integer from 0 - 3; and
y is an integer from 0 - 2,
or a purified stereoisomer or stereoisomer mixture of said compound or a salt of said compound or purified stereoisomer or stereoisomer mixture thereof.
The more prefened compounds of embodiment 3 have general formula (I) and are further defined below. In the following description of these more prefened compounds, the definitions for the various groups and variables represent the more prefened definitions when they differ from those of embodiment 3 as broadly defined above, and are to be understood as independent of each other.
The more prefened compounds of embodiment 3 have the formula (I)
Figure imgf000043_0001
(I) wherein,
Z is N;
X is NR5R6;
Ri and R2 are independently selected from the group consisting of hydrogen and
-OCH3 wherein at least one of Ri and R2 is -OCH3; R3 is hydrogen; R is -(CH2)y-R ' wherein:
R4' is selected from the group consisting of:
(a) -cyclohexyl,
(b) -phenyl, wherein (a) and (b) are optionally substituted with one to three substituents selected from the group consisting of
(1) -(CH2)nC(=O)R7,
(2) -(CH2)nC(=O)OR7,
Figure imgf000043_0002
(4) -S(=O)Rιo ,
(5) -S(=O)2R10;
(6) -C(=N-R10)-Ci-C5 alkyl, and
(7) a saturated or fully unsaturated six membered heterocyclic ring containing one to two heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, and
(c) a fully unsaturated five membered heterocyclic ring containing one sulfur or oxygen, wherein said ring is optionally substituted with one substituent selected from the group consisting of -(CH2)nC(=O)OR7, -(CH2)nC(=O)NR8R9, -S(=O)R10, and -S(=O)2R10 ; or
R3 and t form, together with the nitrogen to which they are attached, a saturated six membered heterocyclic ring, wherein the nitrogen is the only heteroatom, which is unsubstituted;
R5 has the formula:
-(CH2)p-O-A where A is selected from the group consisting of:
(a) -(Ci-Cs) linear or branched alkyl, optionally substituted with halogen, and (b) -phenyl, optionally substituted with one to three substituents selected from the group consisting of:
(1) halogen, and
(2) -(Cι-Cs)-alkoxy, or -(CH2)m-A where A is selected from the group consisting of:
(a) -(C1-C5) linear or branched alkyl optionally substituted with -(Ci-C5) alkoxy,
(b) -phenyl, substituted with one to two substituents selected from the group consisting of: (1) halogen,
(2) -(C!-Cs)-alkoxy wherein the alkyl is optionally substituted with halogen,
(3) -C(=O)OR7,
(4) -C(=O)NR8R9, and (5) -morpholinyl,
(c) a saturated or fully unsaturated five or six membered heterocyclic ring containing one to two heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, optionally substituted with oxo,
and
(f) a fused bicyclo ring wherein one ring is a saturated or fully unsaturated five to six membered heterocyclic ring which contains one heteroatom selected from the group consisting of nitrogen and oxygen, wherein said heterocyclic ring contains at least one carbon atom and the other ring is a saturated six membered carbocycle;
R6 is hydrogen,
or
R5 and R6 form, together with the nitrogen to which they are attached, a saturated five or six membered heterocyclic ring, which optionally contains one additional heteroatom selected from the group consisting of nitrogen, oxygen and sulfur wherein said ring is optionally substituted with one or two substituents selected from the group consisting of:
(a) -(Ci-Cs) linear or branched alkyl optionally substituted by halogen or -(Ci-Cs) alkoxy, (b) -(CH2)nCOOR7, and
(c) -(CH2)nCONR8R9,
wherein,
(i) Rs ≠ Rt, (ii) R5 ≠ R6, and
(iii) (R3 and R4) ≠ (R5 and R6)
R7 is selected from the group consisting of hydrogen, -(C Cs) linear or branched alkyl and phenyl, which are optionally substituted with one to three halogen substituents;
R8 and R9 are independently selected from the group consisting of hydrogen, -(Ci-C5) linear or branched alkyl, and phenyl which is optionally substituted with one substituent selected from the group consisting of halogen and -(C Cs) alkoxy,
R10 is -NR8R9 or -ORπ, Rii is hydrogen, or -( -Cs) linear or branched alkyl
n, m and p are independently an integer from 0 - 3; and
y is an integer from 0 - 2,
or a purified stereoisomer or stereoisomer mixture of said compound or a salt of said compound or purified stereoisomer or stereoisomer mixture thereof.
Pharmaceutically acceptable salts of these prefened and more prefened compounds as well as commonly used prodrugs of these compounds are also within the scope of the invention.
Salts are especially the pharmaceutically acceptable salts of compounds of formulae (I) or (II) such as, for example, organic or inorganic acid addition salts of compounds of formulae (I) or (II). Suitable inorganic acids include but are not limited to halogen acids (such as hydrochloric acid), sulfuric acid, or phosphoric acid. Suitable organic acids include but are not limited to carboxylic, phosphonic, sulfonic, or sulfamic acids, with examples including acetic acid, trifluoroacetic acid, propionic acid, octanoic acid, decanoic acid, dodecanoic acid, glycolic acid, lactic acid, 2- or 3-hydroxybutyric acid, γ-aminobutyric acid (GAB A), gluconic acid, glucosemonocarboxylic acid, benzoic acid, salicylic acid, phenylacetic acid, mandelic acid, methanesulfonic acid, trifluoromethanesulfonic acid, fumaric acid, oxalic acid, succinic acid, adipic acid, pimelic acid, suberic acid, azeiaic acid, malic acid, tartaric acid, citric acid, glucaric acid, galactaric acid, amino acids (such as glutamic acid, aspartic acid, N-methylglycine, acetytaminoacetic acid, N-acetylasparagine or N-acetylcysteine), pyruvic acid, acetoacetic acid, phosphoserine, and 2- or 3-glycerophosphoric acid.
In addition, pharmaceutically acceptable salts include acid salts of inorganic bases, such as salts containing alkaline cations (e.g., Li+ Na+ or K+), alkaline earth cations (e.g., Mg+2, Ca+2 or Ba+2), the ammonium cation, as well as acid salts of organic bases, including aliphatic and aromatic substituted ammonium, and quaternary ammonium cations such as those arising from protonation or peralkylation of triethylamine, N,N-diethylamine, N,N- dicyclohexylamine, pyridine, N,N-dimethylaminopyridine (DMAP), 1,4- diazabicyclo[2.2.2]octane (DABCO), l,5-diazabicyclo[4.3.0]non-5-ene (DBN) and 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU).
Prodrugs are considered to be any covalently bonded carriers which release the active parent compound of formula (I) or (II) in vivo. Formation of prodrugs is well known in the art in order to enhance the properties of the parent compound; such properties include solubility, absorption, biostability and release time (see "Pharmaceutical Dosage Form and Drug Delivery Systems" (Sixth Edition), edited by Ansel et al., publ. by Williams & Wilkins, pgs. 27-29, (1995) which is hereby incorporated by reference).
Commonly used prodrugs of the disclosed compounds of formula (I) and (II) are designed to take advantage of the major drug biotransformation reactions and are also to be considered within the scope of the invention. Major drug biotransformation reactions include N- dealkylation, O-dealkylation, aliphatic hydroxylation, aromatic hydroxylation, N-oxidation, S-oxidation, deamination, hydrolysis reactions, glucuronidation, sulfation and acetylation (see Goodman and Gilman's The Pharmacological Basis of Therapeutics (Tenth Edition), editor Hardman et al., publ. by McGraw-Hill, pages 12-18, (2001), wliich is hereby incorporated by reference).
Definitions
The term "halogen" as it appears in the specification and claims refers to fluorine, chlorine, bromine, and iodine substituents for the purposes of this invention. When halogen is a possible substituent on an alkyl group, the alkyl may be fully substituted, up to perhalo.
The term "fused bicyclo ring" as it appears in the specification and claims refers to a substituent which is a two ring structure which share two carbon atoms. The bonding between the fused bicyclo ring and the compound and/or atom to which it is attached can be through either of the two rings.
Description of the Compositions The compounds described by formulas (I) and (II) above, or the purified stereoisomer or stereoisomer mixture of said compound or a salt of said compound or purified stereoisomer or stereoisomer mixture thereof, are useful as prolylpeptidase inhibitors, inducers of apoptosis and cancer treatment agents. However, the full scope of compounds which are contemplated for use as prolylpeptidase inhibitors, inducers of apoptosis and cancer treatment agents are described by the compounds of formula (la) and (Ila):
Figure imgf000048_0001
(la) (Ila)
wherein, Z is CH or N; Y is O or S; X is OR5 or NR5Re;
Ri, Ri', R2 and R2' are independently selected from the group consisting of hydrogen, amino, cyano, halogen, hydroxy, methoxy and nitro;
R3 is selected from the group consisting of:
(a) hydrogen, and
(b) -(Ci-C10) linear or branched alkyl,
R4 is -(CH2)y-R4 ! wherein:
R4' is selected from the group consisting of:
(a) -(Ci-C5) linear or branched alkyl which is optionally substituted with one to three substituents selected from the group consisting of:
(1) cyano,
(2) halogen, (3) hydroxy,
(4) nitro,
(5) -(Ci-Cs) linear or branched alkyl optionally substituted by halogen,
(6) -(Ci-Cs) alkoxy,
(7) -C(=O)R7,
(8) -C(=O)OR7,
(9) -C(=O)NR8R9,
(10) -S(=O)Rιo, and
(11) -S(=O)2R10;
(b) -C3-C8 cycloalkyl,
(c) -c6-c lo aryl, wherein (b) and (c) are optionally substituted with one to three substituents selected from the group consisting of
(1) amino,
(2) cyano,
(3) halogen,
(4) hydroxy,
(5) nitro,
(6) oxo,
(7) -(Ci-Cs) linear or branched alkyl optionally substituted by halogen or hydroxy,
(8) -(Ci-Cs) haloalkoxy,
(9) -(CH2)nC(=O)R7,
(10) -(CH2)nC(=O)OR7,
(11) -(CH2)nC(=O)C(=O)-OR7,
(12) -(CH2)nC(=O)NR8R9,
(13) -S(O)R10 ,
(14) -S(=O)2R10,
(15) -C(=N-R10)-C1-C5-alkyl, and (16) a saturated or unsaturated four to six membered heterocyclic ring containing one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein said ring contains at least one carbon atom,
and
(d) a saturated or unsaturated four to six membered heterocyclic ring containing one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein said ring contains at least one carbon atom and wherein said ring is optionally substituted with one to three substituents selected from the group consisting of amino, cyano, halogen, hydroxy, nitro, oxo, -(Ci-Cs) -alkoxy, (CH2)nC O)OR7, -(CH2)nC(=O)NR8R9, -S(=O)R10, -S(=O)2R10 and - (C Cs) linear or branched alkyl optionally substituted by halogen;
or
R3 and R4 form, together with the nitrogen to which they are attached, a saturated or unsaturated, four to eight membered heterocyclic ring, wherein the nitrogen is the only heteroatom, which is optionally substituted with one to three substituents selected from the group consisting of amino, cyano, halogen, hydroxy, nitro, oxo, - (Ci-Cs) alkoxy, phenyl, -C(=O)R7, -(CH2)nC(=O)OR7, -(CH2)nC(=O)NR8R9, - S(=O)R10, -S(=O)2R10 and -(Ci-Cs) linear or branched alkyl optionally substituted by halogen;
R5 has the formula (CHRπ)m-A or (CHRπ)p-O-A, where A is selected from the group consisting of:
(a) hydrogen, (b) -(Ci-C5) linear or branched alkyl optionally substituted with cyano, halogen, hydroxy, -(C1-C5) alkoxy or -NR8R9, (c) -C3-C8 cycloalkyl optionally substituted with cyano, halogen, hydroxy, -(C1-C5)-alkyl, -(C C5) alkoxy or -NR8R9, (d) - -Cio aryl optionally substituted with one to three substituents selected from the group consisting of:
(1) cyano,
(2) halogen, (3) hydroxy,
(4) nitro,
(5) -NR8R9,
(6) -(Ci-Cs) linear or branched alkyl optionally substituted with -NR8R9 or halogen, (7) -(Ci-Cs) alkoxy wherein the alkyl is optionally substituted with -NR8R or halogen,
(8) Ce-C10-aryl-(Cι-Cs)-alkoxy-
(9) Ce-CiQ-aryloxy- optionally substituted with halogen,
(10) -Ce-Cio-aryl optionally substituted with halogen, (11) -CH2-Ce-C10-aryl,
(12) -C(=O)R7,
(13) -C(=O)OR7,
(14) -C(=O)NR8R9,
(15) -S(=O)R10, (16) -S(=O)2R10, and
(17) a saturated or unsaturated four to eight membered heterocyclic ring containing one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein said ring: (al7) contains at least one carbon atom;
(b 17) is directly linked to the -C6-do-aryl or is linked to the -C6-Cιo-aryl via an -O- linkage; and (cl7) is optionally substituted with -(Ci-C5)-alkyl, -(CH2)nC(=O)OR7 or -(CH2)nC(=O)NR8R9,
(e) a saturated or unsaturated four to eight membered heterocyclic ring containing one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein said ring contains at least one carbon atom, and is optionally substituted with
(1) -(C1-Cs)-alkyl optionally substituted by halogen,
(2) phenyl optionally substituted by halogen,
(3) -(Ci-Cs)-alkoxy- wherein the alkyl is optionally substituted with halogen,
(4) Ce-Cio-aryloxy- wherein the aryl is optionally substituted with halogen, or
(5) oxo;
(f) a fused bicyclo ring wherein one ring is a saturated or unsaturated five to six membered saturated or unsaturated heterocyclic ring which contains one to three heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein said heterocyclic ring contains at least one carbon atom, and the other ring is a saturated or unsaturated five to eight membered carbocyclic ring,
and
(g) a fused bicyclo ring wherein each ring is independently a saturated or unsaturated five to eight membered carbocyclic ring;
R6 is selected from the group consisting of: (a) hydrogen, and (b) -(Ci-C5) linear or branched alkyl;
wherein R5 and R6 are not both hydrogen;
or
Rs and R6 form, together with the nitrogen to which they are attached, a saturated or unsaturated four to eight membered heterocyclic ring, which optionally contains one to three additional nitrogen atoms wherein said ring contains at least one carbon atom, and wherein said ring is optionally substituted with one to three substituents selected from the group consisting of:
(a) amino,
(b) cyano, (c) halogen,
(d) hydroxy,
(e) nitro,
(f) oxo,
(g) ~(Cι-C5) linear or branched alkyl optionally substituted by halogen or -(Ci-Cs) alkoxy,
(h) -(Ci-Cs) alkoxy, (i) -(C1-Cs)-alkoxy-(C1-C5) alkyl,
(j) -C6-Cιo-aryl optionally substituted by halogen or -(C1-C5) alkyl, (k) -(Ci-C5)-alkyl-phenyl optionally substituted by halogen or -(CrC5)- alkyl,
(1) -(CH2)nCOOR7, (m) -(CH2)„CONR8R9, (n) -(CH2)nNR8R9, (o) -S(=O)R10, (p) -S(=O)2R10, and
(q) -(CH2)n-Q, wherein Q:
(ql) a four to eight membered saturated or unsaturated heterocyclic ring containing one to four nitrogens, wherein said ring contains at least one carbon atom, or (q2) -C6-C10-aryl optionally substituted with halogen or -(Ci-C5)- alkyl;
R7 is selected from the group consisting of hydrogen, -(Ci-Cs) linear or branched alkyl, phenyl, -(Ci-C5)-alkyl-phenyl, and -C3-Cιo cycloalkyl which are optionally substituted with one to tliree substituents selected from the group consisting of halogen, oxo, -(Ci-Cs) alkoxy, -C(=O)R7 -(CH2)nC(=O)OR7, - (CH2)nC(=O)NR8R9, -S(=O)R10, -S(=O)2Rι0 and -(Ci-C5) linear or branched alkyl optionally substituted by halogen; R8 and R9 are independently selected from the group consisting of:
(a) hydrogen,
(b) -(Ci-Cs) linear or branched alkyl which is optionally substituted with a substituent selected from the group consisting of halogen and -(Cr
C5) alkoxy,
(c) -(C1-C5) alkoxy-,
(d) -Ce-Cio aryl, and
(e) -(CH2)n-R wherein R is a saturated or unsaturated five to six membered heterocyclic ring containing one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein said ring contains at least one carbon atom, wherein (c)-(e) are optionally substituted with one to three substituents selected from the group consisting of halogen, -(Cι-C5) alkylamino, -(Ci-Cs) alkoxy, -C(=O)R7> -(CH2)nC(=O)OR7, -(CH2)nc O)NR8R9, -S(=O)R10, -
S(=O)2R10 and -(Ci-Cs) linear or branched alkyl optionally substituted by halogen,
or
R8 and R form, together with the nitrogen to which they are attached, a saturated or unsaturated four to eight membered heterocyclic ring, optionally containing one to three additional heteroatoms selected from the group consisting of nitrogen and oxygen, wherein said ring contains at least one carbon atom and wherein said heterocyclic ring is optionally substituted with -(Ci-Cs) linear or branched alkyl;
Rio is hydrogen, -NR8R9, -ORπ, -(C1-C5) linear or branched alkyl, or phenyl;
each occunence of Rπ is independently selected from the group consisting of hydrogen, -Cι-C5 linear or branched alkyl and phenyl;
n, m and p are independently an integer from 0 - 3; y is an integer from 0 - 2;
or a purified stereoisomer or stereoisomer mixture of said compound or a salt of said compound or purified stereoisomer or stereoisomer mixture thereof.
The compounds of fonnula (I) and (II) as described above are believed to be novel compounds. The scope of the compounds described by formula (la) and (Ila) encompass the compounds defined by fonnula (I) and (II) as well as compounds described in the prior art references cited below:
Lacefield et al. (U.S. Patent No. 3,956,495) describes 2,4-diaminoquinazoline compounds which are used as antithrombotic agents.
Ife et al. (U.S. Patent No. 5,064,833) described substituted quinazoline compounds which are used in the freatment of diseases of the stomach based on excessive gastric acid secretion.
Pfizer, Inc. (GB 1,156,973) describes 2,4-diaminoquinazoline compounds which are used to reduce blood pressure in hypertensive subjects.
Coe et al. (WO 92/07844 and WO 92/14716) describes 2,4-diaminoquinazoline compounds which are used to potentiate chemotherapeutic agents in the freatment of cancer.
Sayed et al. (Pakistan. J. Sci. Ind. Res., vol. 28, no. 6, pages 367-371, Dec. 1985) 6-bromo- 2,4-diaminoquinazoline compounds. No data was provided on the activity of these compounds.
Stankovsky et al. (Coll. Czech. Chem. Commun., vol. 45, pages 1079-1085, (1980) and Chem. Zvesti, vol. 37(6): 831-836, (1983)) describe synthetic procedures to form 4- anilinoquinazoline compounds. No data was provided on the activity of these compounds.
Singhal et al. (J Indian Chem Soc, vol. LXI, pages 690-693, August 1984) describe 2,4- diaminoquinazoline compounds and their use as antimalarial agents. Abou-Zeid et al. (Egypt. J. Pharm. Sci., vol. 32, no. 1-2, pages 165-174, (1991)) described 1,4-disubstituted piperazines (which happen to also be 2,4-diaminoquinazoline compounds) and their use as antihypertensive agents.
In each case, the above prior art reference did not recognize the use of their compounds as being inhibitors of prolylpeptidase, inducers of apoptosis or useful in the treatment of cancer.
The invention also includes pharmaceutical compositions comprising a therapeutically effective amount of one or more of the compounds or purified stereoisomers or stereoisomer mixtures of the invention, or their salts or prodrugs forms thereof, with a pharmaceutically acceptable ingredient.
The pharmaceutical compositions are prepared so that they may be administered orally, dermally, parenterally, nasally, ophthalmically, otically, sublingually, rectally or vaginally.
Dermal administration includes topical application or transdermal administration. Parenteral administration includes intravenous, intraarticular, intramuscular, and subcutaneous injections, as well as use of infusion techniques. One or more compounds of the invention may be present in association with one or more non-toxic pharmaceutically acceptable ingredients and optionally, other active anti-proliferative agents, to form the pharmaceutical composition. These compositions can be prepared by applying known techniques in the art such as those taught in Remington's Pharmaceutical Sciences (Fourteenth Edition),
Managing Editor, John E. Hoover, Mack Publishing Co., (1970) or Pharmaceutical Dosage
Form and Drug Delivery Systems (Sixth Edition), edited by Ansel et al., publ. by Williams & Wilkins, ( 1995), each of wliich is hereby incorporated by reference.
Commonly used pharmaceutical ingredients which can be used as appropriate to formulate the composition for its intended route of administration include: acidifying agents (examples include but are not limited to acetic acid, citric acid, fumaric acid, hydrochloric acid, nitric acid); alkalinizing agents (examples include but are not limited to ammonia solution, ammonium carbonate, diethanolamine, monoethanolamine, potassium hydroxide, sodium borate, sodium carbonate, sodium hydroxide, triethanolamine, trolamine); adsorbents (examples include but are not limited to powdered cellulose and activated charcoal); aerosol propellants (examples include but are not limited to carbon dioxide, CC12F2, F2C1C- CC1F2 and CC1F3) air displacement agents (examples include but are not limited to nitrogen and argon); antifungal preservatives (examples include but are not limited to benzoic acid, butylparaben, ethylparaben, methylparaben, propylparaben, sodium benzoate); antimicrobial preservatives (examples include but are not limited to benzalkonium chloride, benzethonium chloride, benzyl alcohol, cetylpyridinium chloride, chlorobutanol, phenol, phenylethyl alcohol, phenylmercuric nitrate and thimerosal); antioxidants (examples include but are not limited to ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, hypophosphorus acid, monothioglycerol, propyl gallate, sodium ascorbate, sodium bisulfite, sodium fonnaldehyde sulfoxylate, sodium metabisulfite); binding materials (examples include but are not limited to block polymers, natural and synthetic rubber, polyacrylates, polyurethanes, silicones and styrene-butadiene copolymers); buffering agents (examples include but are not limited to potassium metaphosphate, potassium phosphate monobasic, sodium acetate, sodium citrate anhydrous and sodium citrate dihydrate) carrying agents (examples include but are not limited to acacia syrup, aromatic syrup, aromatic elixir, cheny syrup, cocoa syrup, orange syrup, syrup, corn oil, mineral oil, peanut oil, sesame oil, bacteriostatic sodium chloride injection and bacteriostatic water for injection) chelating agents (examples include but are not limited to edetate disodium and edetic acid) colorants (examples include but are not limited to FD&C Red No. 3, FD&C Red No. 20, FD&C Yellow No. 6, FD&C Blue No. 2, D&C Green No. 5, D&C Orange No. 5, D&C Red No. 8, caramel and ferric oxide red); clarifying agents (examples include but are not limited to bentonite); emulsifying agents (examples include but are not limited to acacia, cetomacrogol, cetyl alcohol, glyceryl monostearate, lecithin, sorbitan monooleate, polyethylene 50 stearate); encapsulating agents (examples include but are not limited to gelatin and cellulose acetate phthalate) flavorants (examples include but are not limited to anise oil, cinnamon oil, cocoa, menthol, orange oil, peppermint oil and vanillin); humectants (examples include but are not limited to glycerin, propylene glycol and sorbitol); levigating agents (examples include but are not limited to mineral oil and glycerin); oils (examples include but are not limited to arachis oil, mineral oil, olive oil, peanut oil, sesame oil and vegetable oil); ointment bases (examples include but are not limited to lanolin, hydrophilic ointment, polyethylene glycol ointment, petrolatum, hydrophilic petrolatum, white ointment, yellow ointment, and rose water ointment); penetration enhancers (transdermal delivery) (examples include but are not limited to monohydroxy or polyhydroxy alcohols, saturated or unsaturated fatty alcohols, saturated or unsaturated fatty esters, saturated or unsaturated dicarboxylic acids, essential oils, phosphatidyl derivatives, cephalin, terpenes, amides, ethers, ketones and ureas) plasticizers (examples include but are not limited to diethyl phthalate and glycerin); solvents (examples include but are not limited to alcohol, corn oil, cottonseed oil, glycerin, isopropyl alcohol, mineral oil, oleic acid, peanut oil, purified water, water for injection, sterile water for injection and sterile water for irrigation); stiffening agents (examples include but are not limited to cetyl alcohol, cetyl esters wax, microcrystalline wax, paraffin, stearyl alcohol, white wax and yellow wax); suppository bases (examples include but are not limited to cocoa butter and polyethylene glycols (mixtures)); surfactants (examples include but are not limited to benzalkonium chloride, nonoxynol 10, oxtoxynol 9, polysorbate 80, sodium lauryl sulfate and sorbitan monopalmitate); suspending agents (examples include but are not limited to agar, bentonite, carbomers, carboxymethylcellulose sodium, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, kaolin, methylcellulose, tragacanth and veegum); sweetening agents (examples include but are not limited to aspartame, dextrose, glycerin, mannitol, propylene glycol, saccharin sodium, sorbitol and sucrose); tablet anti-adherents (examples include but are not limited to magnesium stearate and talc); tablet binders (examples include but are not limited to acacia, alginic acid, carboxymethylcellulose sodium, compressible sugar, ethylcellulose, gelatin, liquid glucose, methylcellulose, povidone and pregelatinized starch); tablet and capsule diluents (examples include but are not limited to dibasic calcium phosphate, kaolin, lactose, mannitol, microcrystalline cellulose, powedered cellulose, precipitated calcium carbonate, sodium carbonate, sodium phosphate, sorbitol and starch); tablet coating agents (examples include but are not limited to liquid glucose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose, ethylcellulose, cellulose acetate phthalate and shellac); tablet direct compression excipients (examples include but are not limited to dibasic calcium phosphate); tablet disintegrants (examples include but are not limited to alginic acid, carboxymethylcellulose calcium, microcrystalline cellulose, polacrillin potassium, sodium alginate, sodium starch glycollate and starch); tablet glidants (examples include but are not limited to colloidal silica, corn starch and talc); tablet lubricants (examples include but are not limited to calcium stearate, magnesium stearate, mineral oil, stearic acid and zinc stearate); tablet/capsule opaquants (examples include but are not limited to titanium dioxide); tablet polishing agents (examples include but are not limited to carnuba wax and white wax); thickening agents (examples include but are not limited to beewax, cetyl alcohol and paraffin); tonicity agents (examples include but are not limited to dextrose and sodium chloride); viscosity increasing agents (examples include but are not limited to alginic acid, bentonite, carbomers, carboxymethylcellulose sodium, methylcellulose, povidone, sodium alginate and tragacanth); and wetting agents (examples include but are not limited to heptadecaethylene oxycetanol, lecithins, polyethylene sorbitol monooleate, polyoxyethylene sorbitol monooleate, polyoxyethylene stearate,).
Depending on the route of administration, the compositions can take the form of aerosols, capsules, creams, elixirs, emulsions, foams, gels, granules, inhalants, lotions, magmas, ointments, peroral solids, powders, sprays, syrups, suppositories, suspensions, tablets and tinctures. The compositions of the invention can also have an additional apoptosis inducers as an active ingredient. Examples of known apoptosis inducers (see e.g. Calbiochem's 2001 Signal Transduction Catalog, pages 702-704, the contents of which are incorporated by reference) which can be added to the described invention include but are not limited to A23187, N-Acetyl-L-cysteine, actinomycin D, tyrphostin A9, tyrphostin A25, AG 490, AG 1714, anandamide, anisomycin, aphidicolin, bafilomycin Al, berberine hemisulfate, betulinic acid, bleomycin sulfate, CAFdA, calphostin C, camptothecin, CAPE, chelerythrine chloride, 2-chloro-2'-deoxyadenosine, 2-chloro-2'-deoxyadenosine 5'-triphosphate, colcemid, cochicine, corticosterone, cycloheximide, cyclophosphamide monohydrate, cyclosporine A, daunorubicin hydrocloride, dexamethasone, 3,3'-diindolylmethane, dolastatin 15, doxorubicin hydrochloride, erbstatin analog, ET-18-OCH3, etoposide, etoposide phosphate, 5-fluorouracil, folimycin, forskolin, genistein, glycodeoxycholic acid sodium salt, H-7 dihydrochloride, H-89 dihydrochloride, harringtonine, homoharringtonine, 4- hydroxynonenal, 4-hydroxyphenylretinamide, hydroxyurea, indanocine, ionomycin free acid, ionomycin calcium salt, KN-93, methotrexate, mitomycin C, okadaic acid, oligomycin, p53 activator, paclitaxel, phorbol-12-myristate- 13 -acetate, (pivaloyloxy)methyl butyrate, puromycin dihydrochloride, 1-pynolidinecarbodithioic acid ammonium salt, quercetin dihydrate, rapamycin, SNAP, SNOG, sodium butyrate, sodium 4-phenylbutyrate, spermine tetrachloride, D-eryt/jrø-sphingosine (free base; N-Acetyl-; N,N-dimethyl-; N-hexanoyl-; and N-octanoyl fonns), stautosporine, sulfasalizine, sulindac, tamoxifen citrate, 4-hydroxy- (Z)-tamoxifen, thapsigargin, α-toxin, TRAIL, valinomycin, (±)-verapamil hydrochloride, veratridine and vitamin E succinate.
Additional known apoptosis inducers (see Oncogene catalog, the contents of which are incorporated by reference) include:
2β, 3β, 5β, llα, 14α, 20R, 22R-Heptahydroxycholest-7-en-6-one, dactinomycin, DHAD; l,4-dihydroxy-5,8-bw({2-[(2-hydroxyethyl)amino])-9,10-anthraquinone, 2HC1; N,N- hexamethylenebisacetamide (HMBA); mitoxanthrone, dihydrochloride; MurA; Muristerone A; NSC-301739; SAHA; suberoylanilide, hydroxamic acid; caspase-3 (Ab-4) Monoclonal Antibody; active caspase-7 (Ab-1) Polyclonal Antibody; caspase-12 (Ab-1) Polyclonal Antibody; caspase-12 (Ab-2) Polyclonal Antibody; caspase-13 (Ab-1) Polyclonal Antibody; acinus (Ab-1) Polyclonal Antibody; acinus (Ab-2) Polyclonal Antibody; acinus (Ab-3) Polyclonal Antibody; acinus (Ab-4) Polyclonal Antibody; AIF (Ab-1) Polyclonal Antibody; AIF (Ab-2) Polyclonal Antibody; Phospho-Bad (Ab-1) Polyclonal Antibody; Phospho-Bad (Ab-2) Polyclonal Antibody; Bid (Ab-1) Polyclonal Antibody; Bid (Ab-2) Polyclonal Antiserum; Bid (Ab-3) Polyclonal Antiserum; Bnip3L (Ab-1) Polyclonal Antibody; DRAK1 (Ab-1) Polyclonal Antibody; DRAK2 (Ab-1) Polyclonal Antibody; Fas (Ab-6) Polyclonal Antibody; FLASH (Ab-1) Polyclonal Antiserum; pi 10 Mitochondrial Protein (Ab-1) Monoclonal Antibody; pTEN (Ab-4) Polyclonal Antibody; Rb Associated Protein 46 (Ab-1) Polyclonal Antibody; Rb Associated Protein 48 (Ab-1) Polyclonal Antibody; RIP (Ab-1) Polyclonal Antibody; RIP2 (Ab-1) Polyclonal Antibody; Smac/DIABLO (Ab-3) Polyclonal Antibody; TWEAK (Ab-1) Polyclonal Antibody; VDAC (Ab-1) Polyclonal Antibody; Bad Control Proteins; and Fas Ligand Plus™ Recombinant Human Protein.
Optional cancer treatment agents which can be added to the composition include but are not limited to compounds listed on the cancer chemotherapy drug regimens in the 11 Edition of the Merck Index, (1996), which is hereby incorporated by reference, such as asparaginase, bleomycin, carboplatin, carmustine, chlorambucil, cisplatin, colaspase, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin, doxorubicin (adriamycine), epirubicin, etoposide, 5-fluorouracil, hexamethylmelamine, hydroxyurea, ifosfamide, irinotecan, leucovorin, lomustine, mechlorethamine, 6-mercaptopurine, mesna, methotrexate, mitomycin C, mitoxantrone, prednisolone, prednisone, procarbazine, raloxifen, streptozocin, tamoxifen, thioguanine, topotecan, vinblastine, vincristine, and vindesine.
Other cancer treatment agents suitable for use with the composition of the invention include but are not limited to those compounds acknowldeged to be used in the treatment of neoplastic diseases in Goodman and Gilman's The Pharmacological Basis of Therapeutics (Tenth Edition), editor Hardman et al, publ. by McGraw-Hill, pages 1389-1459, (2001), which is hereby incorporated by reference, such as aminoglutethimide, anastrazole, L- asparaginase, azathioprine, 5-azacytidine cladribine, busulfan, camptothecin, diethylstilbestrol, docetaxel, erythrohydroxynonyladenine, ethinyl estradiol, exemestane, 5- fluorodeoxyuridine, 5-fluorodeoxyuridine monophosphate, fludarabine phosphate, fluoxymesterone, flutamide, formestane, hydroxyprogesterone caproate, gemcitabine, idarubicin, IL-2, α-interferon, letrozole, medroxyprogesterone acetate, megestrol acetate, melphalan, mitotane, oxaliplatin, paclitaxel, pentostatin, N-phosphonoacetyl-L-aspartate (PALA), plicamycin, semustine, teniposide, testosterone propionate, thiotepa, temozolomide, trimethylmelamine, uridine, vinorelbine and vorozole.
Other cancer treatment agents suitable for use with the composition of the invention include but are not limited to other anti-cancer agents such as epothilone.
For all regimens of use disclosed herein for compounds of formulae (I) or (II), the daily oral dosage regimen will preferably be from 0.01 to 200 mg/kg of total body weight. The daily dosage for administration by injection, including intravenous, intramuscular, subcutaneous and parenteral injections, and use of infusion techniques will preferably be from 0.01 to 200 mg/kg of total body weight. The daily rectal dosage regimen will preferably be from 0.01 to 200 mg/kg of total body weight. The daily vaginal dosage regimen will preferably be from 0.01 to 200 mg/kg of total body weight. The daily topical dosage regimen will preferably be from 0.1 to 200 mg administered between one to four times daily. The transdermal concentration will preferably be that required to maintain a daily dose of from 0.01 to 200 mg/kg. The daily inhalation dosage regimen will preferably be from 0.01 to 100 mg/kg of total body weight.
It will be appreciated by those skilled in the art that the particular method of administration will depend on a variety of factors, all of which are considered routinely when administering therapeutics. It will also be understood, however, that the specific dose level for any given patient will depend upon a variety of factors, including, but not limited to the activity of the specific compound employed, the age of the patient, the body weight of the patient, the general health of the patient, the gender of the patient, the diet of the patient, time of administration, route of administration, rate of excretion, drug combinations, and the severity of the condition undergoing therapy. It will be further appreciated by one skilled in the art that the optimal course of treatment, i.e., the mode of treatment and the daily number of doses of a compound of formulae (la) or (Ila) or a pharmaceutically acceptable salt thereof given for a defined number of days, can be ascertained by those skilled in the art using conventional treatment tests.
Description of Preparative Methods Abbreviations and Acronyms
The following terms have the indicated meanings:
AcOH acetic acid Boc tert-butoxycarbonyl
Burgess reagent (Methoxycarbonylsulfamoyl)triethylammonium hydroxide
CDI 1 , 1 '-carbonyldiimidazole
DBU l,8-Diazabicyclo[5.4.0]undec-7-ene
DMAP 4-Dimethylaminopyridine DMSO dimethylsulfoxide
DMF N,N-dimethylformamide
EDC 1 -[3-(Dimethylaminopropyl)]-3-ethylcarbodiimide hydrochloride eq equivalents
EtOAc ethyl acetate h hour
Hex hexanes
HPLC high perfonnance liquid chromatography
HOBT hydroxybenzatriazolehydrate
IPA isopropyl alcohol LC liquid chromatography
Me methyl
MP melting point
MS mass spectra
NMR nuclear magnetic resonance NMP 1 -methyl-2-pynolidinone
PPA polyphosphoric acid rt room temperature
TLC thin layer chromatography
TFA trifluoroacetic acid THF tetrahydrofuran Experimental Section
Analytical data (1H NMR and LC-MS) for all compounds was in accordance with the described structure.
The term 'concentrated under reduced pressure' refers to use of a Buchi rotary evaporator at approximately 15 mm of Hg.
Thin-layer chromatography (TLC) was performed on Whatman pre-coated glass-backed silica gel 60A F-254 250 μm plates. Visualization of plates was effected by one or more of the following techniques: (a) ultraviolet illumination, (b) exposure to iodine vapor, (c) immersion of the plate in a 10% solution of phosphomolybdic acid in ethanol followed by heating, and/or (d) immersion of the plate in a cerium sulfate solution followed by heating. Column chromatography (flash chromatography) was perfonned using 230-400 mesh EM Science® silica gel
Melting points (mp) were determined using a Thomas-Hoover melting point apparatus or a Mettler FP66 automated melting point apparatus and are unconected.
Proton (1H) nuclear magnetic resonance (NMR) spectra were measured with a General Electric GN-Omega 300 (300 MHz) spectrometer with either Me Si (δ 0.00) or residual protonated solvent (CHC13 δ 7.26; MeOH δ 3.30; DMSO δ 2.49) as standard. Carbon (13C) NMR spectra were measured with a General Electric GN-Omega 300 (75 MHz) spectrometer with solvent (CDC13 δ 77.0; d3-MeOD; δ 49.0; d6-DMSO δ 39.5) as standard.
HPLC - electrospray mass spectra (HPLC ES-MS) were obtained using a Hewlett-Packard 1100 HPLC equipped with a quaternary pump, a variable wavelength detector set at 254 nm, a YMC pro C-18 column (2 x 23 mm, 120A), and a Finnigan LCQ ion trap mass spectrometer with electrospray ionization. Spectra were scanned from 120-1200 amu using a variable ion time according to the number of ions in the source. The eluents were A: 2% acetonitrile in water with 0.02% TFA and B: 2% water in acetonirile with 0.018% TFA. Gradient elution from 10% B to 95% over 3.5 minutes at a flowrate of 1.0 mL/min was used with an initial hold of 0.5 minutes and a final hold at 95% B of 0.5 minutes. Total run time was 6.5 minutes. Alternative conditions are given for the parallel synthesis route in the experimental.
A. Synthesis of Intermediates
Al. Preparation of 2-amino-4-methoxybenzoic acid.
Figure imgf000065_0001
Step 1. Chloral hydrate (14.5 g, 87.7 mmol) was dissolved in water (190 mL) and then added to sodium sulfate (92.26 g, 650 mmol) in water (170 mL). m-Anisidine (10 g, 81.2 mmol) was dissolved in water (50 mL) with cone. HCl (7.0 mL) and added to the first mixture, a layer of brown oil formed on the top. Hydroxylamine hydrochloride (17.86 g, 256 mmol) was dissolved in water (80 mL) and added to the reaction mixture. The mixture was heated at 40 °C then warmed to 50 °C. Finally the mixture was heated to reflux for 10 min and the mixture was heated to 130 °C for 20 min. Cooled in water bath and then fransfened to ice bath. The precipitate was collected by vacuum filtration and further washed with water (200 mL). The brown solid was vacuum dried to afford 13.5 g of (2E)-2- (hydroxyimino)-N-(3-methoxyphenyl)ethanamide (85%). MS (LC/MS) 195.1 (55%).
Step 2. (2E)-2-(Hydroxyimino)-N-(3-methoxyphenyl)ethanamide (13.5 g, 69.52 mmol) was mixed with polyphosphoric acid (135 g) and the mixture was heated at 55 °C for 6 h.. The reaction mixture was then poured into ice and an orange solid formed. The orange solid was recrystallized from acetone-petroleum ether to give 11.4 g of 6-methoxy-lH-indole-2,3- dione (93%). MS (LC/MS) 178.1 (100%).
Step 3. 6-Methoxy-lH-indole-2,3-dione (5 g, 2.8 mmol) was dissolved in 5% NaOH solution. (180 mL). 35wt% H2O2 (67.5 mL, 7.05 mmol) was dissolved in water (88 mL) and added to the reaction mixture dropwise at 30-35 °C over 30 min. The reaction was then cooled to rt. 2M HCl (-200 mL) was added to the mixture to form a light yellow solid. Filtration and drying the solid in the vacuum oven gave 2-amino-4-methoxybenzoic acid (66%). MS (LC/MS) 167.9 (100%).
A2. Preparation of 6-bromo-2,4(lH,3H)-qumazolinedione
Figure imgf000066_0001
2-Amino-5-bromobenzoic acid (3 g, 13.9 mmol) was mixed with urea (5.05 g, 83.3 mmol) and then heated to 180 °C. The mixture melted and gas evolution was seen, after 3 h the mixture solidified. The flask was cooled to rt and the brown solid was ground by mortar and suspended in water then stined vigorously for 30 min. The suspension was then filtered and the solid was washed with acetone (10 mL) and water (150 mL). The solid was dried under vacuum to afford 3.14 g of 6-bromo-2,4(lH,3H)-quinazolinedione (94%). MS (LC/MS) 240.2 (100%).
A3. Preparation of 6-iodo-2,4(lH,3H)-quinazolinedione
GnDIi, ι Mιe.OnHu KNC0
Figure imgf000066_0003
Figure imgf000066_0002
Figure imgf000066_0004
Step 1. 2-Amino-5-iodobenzoate acid (3 g, 11.4 mmol) was dissolved in THF and then 1,1'- carbonyldiimidazole (1.85 g, 11.4 mmol) was added. The mixture was heated at 60 °C for 2 days. The reaction was monitored by TLC. After starting material was consumed, MeOH (2 mL) was added and the mixture was heated at 70 °C for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column (100% CH2C12) to obtain 2.4 g of methyl 2-amino-5-iodobenzoate (76%). MS (GC/MS) 277.
Step 2. Methyl 2-amino-5-iodobenzoate (2.4 g, 8.66 mmol) was dissolved in AcOH (7.5 mL). Potassium cyanate was dissolved in water (1.5 mL) and added to the reaction mixture slowly. A precipitate fonned immediately. The mixture was heated to 100 °C for 20 min and then mixture was added water and filtered by suction to afford a white solid. This white solid was dried under vacuum oven for 2 h. To this white solid was added MeOH (27 mL) to form a suspension. To this suspension, a solution of NaOH (406 mg) in water (5.4 mL) was added and the mixture was brought to reflux for 1 h. The reaction mixture was cooled and diluted with water (20 mL) and the pH was adjusted to pH 3 with 6 M HCl. Filfration gave 2.6 g of a colorless solid, 6-iodo-2,4(lH,3H)-quinazolinedione (100%).
A4. Preparation of 7-(benzyloxy)-6-methoxy-2,4(lH,3H)-quinazolinedione.
Figure imgf000067_0001
To a suspension of 4-benzyloxy-3-methoxybenzamide (J.Med.Chem. 1977, Vol.20, p. 147.) (3.00 g, 11.02 mmol) in CH2C12 (50 mL) was added phosgene (5.5 mL), dropwise. The reaction was allowed to stir at room temperature for 4 days. The reaction was poured over saturated NaHCO3 (500 mL). The resulting solid was collected by filtration and was dried in vacuo to afford 2.51 g of 7-(benzyloxy)-6-methoxy-2,4(lH,3H)-quinazolinedione (76%); 1H NMR (OMSO-d6) 11.09 (s, 1H), 10.93 (s, 1H), 7.50-7.32 (m, 5H), 7.27 (s, 1H), 6.78 (s, 1H), 5.12 (s, 2H), 3.77 (s, 3H); ES MS (M+H)+-299.2; TLC (50:50 Hexanes/EtOAc): R =0.72.
A5. Preparation of 2, 4-dichloro-6-methoxyquinazoline.
Figure imgf000067_0002
Step 1. To 2-amino-5-methoxylbenzoic acid (3 g, 17.9 5 mmol) was added 2N HCl (15 mL). After a precipitate formed, water (30 mL) was added to the mixture to form a suspension. A solution of sodium cyanate (1.75 g, 26.92 mmol) in water (20 mL) was added dropwise at rt over 15 min. Froth formed and after vigorously stirring, a pink suspension formed. After stirring for 4 h, the suspension was filtered and washed with water and ether and dried under reduced pressure. The solid was added to concentrated HCl (20 mL), and heated to 105 °C for 1 h. The suspension was then filtered, washed with water, and dried under reduced pressure to give 2.12 g 6-methoxy-2,4(lH,3H)-quinazolinedione (62%).MS (LC/MS) 193.2 (95%). Step 2. To 6-methoxy-2,4(lH,3H)-quinazolinedione (2.13 g, 11.1 mmol) was added POCl3 (8 mL) via syringe and DMF (1 mL). The mixture was heated to 105 °C for 18 h. POCl3 was then removed under reduced pressure. To the solid was added ice and the mixture was stined for 1 h. The suspension was filtered to afford a brown solid. The solid was purified by silica gel chromatography (1:1 EtO Ac/Hex) to afford 592 mg of 2,4-dichloro-6- methoxyquinazoline (24%).MS (LC/MS) 229.3 (100%).
. Synthesis of 2, 4, 6-trichloroquinazoline
Figure imgf000068_0001
Step 1. To a suspension of 2-amino-5-chlorobenzoic acid (102. lg, 0.58 mol) in water (1.6 L) was added 5 M NaOH (160 mL). To the resulting solution was charged sodium cyanate (43.4 g, 0.64 mol) followed by glacial acetic acid (36.7 mL, 0.641 mol). The reaction mixture was stined for a period of 14-16 h at rt, then filtered to remove some insoluble solid. To the brown solution was added 1 M HCl (1.5 L). The resulting precipitate was stined rt for a period of 2-2.5 h then filtered and washed with water (2 x 666 mL). The solid was dried under vacuum at 50-60 °C for 48 h to obtain 124.6 g (99 %) of 2-[(aminocarbonyl)amino]-5- chlorobenzoic acid. !HNMR (DMSO-d6) δ 10.0 (1H, s), 8.43 (1H, d), 7.82 (1H, s), 7.50 (1H, dd), 6.65 (2H, br, s).
Step 2. A suspension of 2-[(aminocarbonyl)amino]-5-chlorobenzoic acid (35.0 g, 0.16 mol) and p-toluene sulfonic acid monohydrate (4.66 g, 0.024 mol) in a mixture of toluene (350 mL) and DMF (87.5 mL) was heated to reflux with an attached Dean stark apparatus for a period of 4-4.5 h. The reaction was judged complete by 1H NMR. The suspension was cooled to rt, filtered and the solid washed with toluene (150 mL). The damp solid was pulped in water (250 mL) for a period of 15-20 min. The material was filtered and washed with water (50 mL). The solid was dried under vacuum at 40-45 °C to yield 24.73 g (78%) of 6-chloro-2,4(lH,3H)-quinazolinedione. !HNMR (DMSO-d6) δ 11.19 (1H, s), 11.02 (1H, s), 7.53 (1H, s), 7.40 (1H, d), 6.92 (1H, d).
Step 3. A mixture of 6-chloro-2,4(lH,3H)-quinazolinedione (24.0 g, 0.122 mol), POCl3 (114 mL, 1.22 mol) and PC15 (56.2 g, 0.26 mol) was heated to reflux for a period of 3.5-4.0 h, when the reaction was judged complete by TLC (Eluent- 1 : 1 dichloromethane / hexanes). The reaction mixture was concentrated under vacuum to remove most of the POCl3. The resulting solid was poured slowly into ice/water (1000/200 mL) and stined vigorously for a period of one hour. The precipitate was filtered and the damp solid was pulped in water for 15-20 min. The solid was filtered, washed with water (100 mL) and dried under vacuum at rt for 24 h. The resulting crude product was suspended in ether (1.5 L) and stined for a period of 1.0-1.5 h at rt. The insoluble particles were removed by celite filteration and the resulting solution was concentrated under reduced pressure to yield 25.45g (89 %) of the 2, 4, 6- trichloroquinazoline. 1HNMR (DMSO-d6) δ 8.24 (1H, s), 8.15 (1H, d), 8.02 (1H, d). GCEI (8.15 min.) M+- 232.
'. Preparation of 2, 4, 7-trichloroquinazoliιιe.
p-TsOH , oluene/DMF
Figure imgf000069_0001
Step 1. To a suspension of 2-amino-4-chlorobenzoic acid (15.3 g, 0.087 mol) in water (245 mL) was added 5 M NaOH (24 mL, 0.12 mol). To the resulting solution was charged sodium cyanate (6.50 g, 0.096 mol) followed by glacial acetic acid (5.5 mL, 0.096 mol). The reaction mixture was stined for a period of 14-16 h at rt, then filtered to remove some insoluble solid. To the yellow solution was added 1M HCl (225 mL). The resulting precipitate was stined at rt for a period of 2-2.5 h then filtered and washed with water (2 x 100 mL). The solid was dried under vacuum at 50-60 °C for 48 h to obtain 17.6 g of 2- [(aminocarbonyl)amino]-4-chlorobenzoic acid. 1HNMR (DMSO-d6) δ 10.18 (1H, s), 8.53 (1H, s), 7.90 (1H, d), 6.97 (1H, dd), 6.70 (2H, br, s).
Step 2. A suspension of 2-[(aminocarbonyl)amino]-4-chlorobenzoic acid (14.0 g, 0.065 mol) and p-toluene sulfonic acid monohydrate (1.86 g, 0.01 mol) in a mixture of toluene (140 mL) and DMF (35 mL) was heated to reflux with an attached Dean stark apparatus for a period of 3.0 h. The reaction was judged complete by TLC (Eluent- 5:4:1 Hexanes/ethyl acetate/methanol). The suspension was cooled to rt, filtered and the solid washed with toluene (20 mL). The damp solid was pulped in water (80 mL) for a period of 15-20 min. The material was filtered and washed with water (20 mL). The solid was dried under vacuum at 40-45 °C to yield 7.64g (60 %) of 7-chloro-2,4(lH,3H)-quinazolinedione. XHNMR (DMSO-de) δ 11.38 (1H, s), 11.21 (1H, s), 7.86 (1H, d), 7.19 (1H, s), 7.12 (1H, d).
Step 3. A mixture of 7-chloro-2,4(lH,3H)-quinazolinedione (7.5 g, 0.04 mol), POCl3 (35.5 mL, 0.38 mol) and PCls (17.5 g, 0.08 mol) was heated to reflux for a period of 3.0-3.5 h, when the reaction was judged complete by TLC (Eluent- 1 : 1 dichloromethane / hexanes).
The reaction mixture was concentrated under vacuum to remove most of the POCl3. The resulting solid was poured slowly into ice/water (350/75 mL) and stined vigorously for a period of 1.5 h. The precipitate was filtered and the damp solid was pulped in water (80 mL) for 15-20 min. The solid was filtered, washed with water (30 mL) and dried under vacuum at rt for 24 h. to yield 8.5 g (96%) of 2, 4, 7-trichloroquinazoline. 1HNMR (DMSO-d6) δ 8.27
(1H, d), 8.13 (1H, s), 7.89 (1H, d). GCEI (RT= 8.2 min) M+- 232.
A8. Preparation of 2, 4-dichloroquinazoline.
Figure imgf000070_0001
A solution of dry DMF (4.0 mL) in phosphorous oxychloride (200 mL) was stined at rt for 30 minutes, prior to its addition to a flask containing benzoyleneurea (50.00 g, 308.4 mmol). The suspension was heated to gentle reflux for 10 h, at which time, near-complete dissolution was achieved. The dark yellow contents were cooled to 55 °C and slowly added to cold (0 °C) water (2000 mL) that was vigorously stined (the temperature of the aqueous medium was not allowed to warm above 30 °C during the quench). A solid precipitated, which was stined for 10 minutes and then filtered. The resultant cake was washed with water (3 x 350 mL) and then dried under high vacuum at 40 °C to provide 53.4 g of 2, 4- dichloroquinazoline (87%) as a pale-yellow solid. 1H-NMR (OMSO-d6): δ 7.90 (ddd, J = 1.1, 7.0, 8.3 Hz, IH, aromatic); 8.04 (dd, J = 1.1, 8.6 Hz, IH, aromatic); 8.17 (ddd, J = 1.1, 7.0, 8.6 Hz, IH, aromatic); 8.30 (dd, J = 1.1, 8.3 Hz, IH, aromatic). Anal. Calcd for C8H4N2C12 . 0.1 H2O: C, 47.84; H, 2.11; N, 13.95. Found: C, 47.91; H, 2.03; N, 13.94. Mass spectrum (HPLC/ES): m/e =199 (M+l).
A9. Preparation of 3-(4-fluorophenoxy)propylamine
Figure imgf000071_0001
Step 1. l-(3-Chloropropoxy)-4-fluorobenzene (1 eq) and phthalimide, potassium salt (1.2 eq) in a solution of DMF (1.0 M were magnetically stined at 80 °C over a period of 18 h. The reaction was cooled, dissolved in CH2C12 and water and poured into a separatory funnel. The layers were separated and the aqueous was extracted with CH2C12 (3x). The combined organics were washed with IN NaOH (2x), dried (MgSO ), filtered and concentrated under reduced pressure. The 2-[3-(4-fluorophenoxy)propyl]-lH-isoindole-l,3(2H)-dione was used without purification.
Step 2. The 2-[3-(4-fluorophenoxy)propyl]-lH-isoindole-l,3(2H)-dione (1 eq) and hydrazine hydrate (5 eq) in ethanol (0.1 M) were magnetically stined at 80 °C over a period of 3 h. The reaction was cooled, the white precipitate was filtered off and washed with CH2C12. The combined filtrates were concentrated under reduced pressure. Methylene chloride was added to the crude residue and the solution was washed with water (2 x), dried (MgSO ), filtered and concentrated under reduced pressure to give 3-(4- fluorophenoxy)propylamine as a yellow oil which was used without further purification. A10. Synthesis of 4- [2-(diethylamino)ethoxy] aniline.
Figure imgf000072_0001
Step 1. A slurry of 4-nifrophenol (1 eq) and NaOH pellets (1 eq) in H2O (6.8 M) was stined for 10 min after which time -xylene (1.4 M), K2CO3 (1.5 eq) and 2- diethylaminoethylchlorideliydrochloride (1 eq) was added and the reaction heated to 100 °C for 4 h. The reaction was cooled to rt then concentrated under reduced pressure. The crude residue was dissolved in /?-xylene and washed with IN NaOH (2x) and H2O (lx). The combined organic layers were dried (MgSO4) and concentrated under reduced pressure to yield N,N-diethyl-2-(4-nitrophenoxy)ethanamine as a solid which was carried on without further purification.
Step 2. A solution of N,N-diethyl-2-(4-nitrophenoxy)ethanamine (1 eq) in ethanol (0.2 M) was added via syringe to a flask containing Palladium on carbon (10% wt). The reaction vessel was fitted with a balloon adapter and charged with hydrogen and evacuated three times until the reaction was under a H2 atmosphere. The reaction was allowed to stir overnight and then purged with Ar and evacuated tliree times until an Ar atmosphere had been achieved. The reaction solution was filtered through a pad of Celite and washed with copious amounts of ethanol. The filtrate was concentrated under reduced pressure and afforded pure 4-[2-(diethylamino)ethoxy]aniline as an oil.
All. Preparation of 3-[2,2,2-trifluoro-l-(trifluoromethyl) ethoxy]propylamine.
Figure imgf000072_0002
Step 1: To N-(3-Hydroxypropyl)phthalamide (0.10 g, 0.490 mmol, l.Oeq.) and hexafluoro- 2-propanol (0.12 g, .730 mmol, 1.5eq.) in THF (4 mL) was added a mixture of triphenylphosphine (0.19 g, .730 mmol, 1.5 eq.) and diethylazodicarboxalate (0.13 g, 0.730 mmol, 1.5eq.) in THF (4 mL.) that was allowed to stir at 0 °C for lh. The reaction was allowed to stir at rt for 3 h. It was concenfrated under reduced pressure, taken up in ethyl acetate, washed with water, dried with magnesium sulfate, filtered and concentrated under reduced pressure. The crude mixture was purified by column chromatography (30% ethyl acetate/hexane) to give slightly impure 2-{3-[2,2,2-trifluoro-l-(trifluoromethyl) ethoxy]propyl}-lH-isoindole-l,3(2H)-dione that was used without further purification.
Step 2: To 2-{3-[2,2,2-trifluoro-l-(trifluoromethyl)ethoxy]propyl}-lH-isoindole-l,3(2H)- dione (1.0 g, 2.8 mmol, 1.0 eq.) in ethanol (10 mL) was added hydrazine hydrate (0.09 g, 2.8 mmol, leq.) and the reaction was allowed to stir at rt for 16 h. This was treated with IN hydrochloric acid (5 mL) and the reaction was filtered washing with water. The filtrate was concentrated under reduced pressure and filtered to give 0.20 g of 3-[2,2,2-trifluoro-l- (trifluoromethyl)ethoxy]propylamine (32%).
A12. Synthesis of 4-(aminomethyl)-N-methylbenzenesulfonamide.
Figure imgf000073_0001
Step 1: To methylamine (2 M, 12.4 mL, 2.5eq.) and DMAP (0.24 g, 1.99 mmol, 0.2 eq.) in methylene chloride (15 mL.) was added 4-cyanobenzenesulfonyl chloride (2.0 g, 9.9 mmol., 1.0 eq.) portionwise at 0 °C. The reaction was allowed to warm rt and stir for 2h. The reaction was acidified with 2 N HCl to pH 1, and extracted with methylene chloride, dired with magnesium sulfate, filtered and concentated under reduced pressure to give 1.29 g of 4- cyano-N-methylbenzenesulfonamide (67%) as a colorless solid.
Step 2: To PtO2 x H2O (0.13 g., 6.57 mmol., l.Oeq.) was added methanol (5 mL.) and HCl (0.13g, 7.88 mmol., 1.2 eq.) and 4-cyano-N-methylbenzenesulfonamide (1.29 g, 6.57 mmol., 1.0 eq.) and the reaction was placed under hydrogen gas (1 atm.) for 16 h. The reaction was filtered and concentrated under reduced pressure to give 230 mg of 4-(aminomethyl)-N- methylbenzenesulfonamide (18%).
A13. Preparation of l-[4-(aminomethyl)phenyl]-l-pentanone.
Figure imgf000074_0001
Step 1. A solution of methyl 4-(aminomethyl)benzoate hydrochloride (5 g, 26.65, 1 eq) in THF (50 mL) was treated with a solution of di-tert-butyl dicarbonate (14 g, 63.96 mmol, 2.4 eq) in THF (50 mL) dropwise. Triethylamine (11.14 mL, 8.1 g, 80 mmol, 3 eq) was added and the reaction was magnetically stined over 16 hours.. Methylene chloride (100 mL) was added and the solution was washed with deionized water (100 mL), dried over magnesium sulfate and then filtered. The solution was concentrated in vacuo to yield a solid that was dissolved in methanol (100 mL) and treated dropwise with aquaeous NaOH (50% by wt, 5 mL) and magnetically stined over 2 h. The reaction was then treated with aquaeous NaOH (1 N, 25 mL) and magnetically stined over 30 min. Aqueous HCl (IN) was added until the reaction reached pH 7. Methanol was removed under reduced pressure , and the solid that formed was filtered to yield 4-{[(tert-butoxycarbonyl)amino]methyl}benzoic acid, which was used in the next step without further purification.
Step 2 4-{[(tert-Butoxycarbonyl)amino]methyl}benzoic acid (3g, 11.94 mmol, 1 eq) was dissolved in methylene chloride (50 mL) and treated with CDI (2.13 g, 13.13 mmol, 1.1 eq) and magnetically stined over 20 min at rt. Dimethylhydroxylamine HCl (5.82 g, 59.70 mmol, 5 eq.) was added to this solution and magnetically stined over 16 hours. Aqueous citric acid (10 % by wt., lOOmL) were added and the organic sayer was separated and successivively washed with deionized water (100 mL) and brine (100 mL), dried over magnesium sulfate and then filtered. The solution was concentrated in γacuo, and purified by column chromatography (50% Ethyl acetate:Hexanes) to yield tert-butyl 4- {[methoxy(methyl)amino]carbonyl}benzylcarbamate as a yellow oil.
Step 3 To a previously cooled solution (0 °C, via ice/water bath) of tert-butyl 4- {[methoxy(methyl)amino]carbonyl}benzylcarbamate (0.5 g , 1.70 mmol, 1 eq) in THF (34 mL) under argon in an oven-dried flask, «-butyllithium (1.6 M in hexanes, 3.2 mL, 5.1 mmol, 3 eq) was added dropwise and the mixture was magnetically stined for 1 hour. A solution of hydrogen chloride in ethyl ether and ethanol (16.6 mL of 2M HCl in ether and 3.4 mL of ethanol) were added and the mixture was immediately quenched dropwise with brine (100 mL). The organic layer was separated, dried over magnesium sulfate and then filtered. The solution was concentrated in vacuo, and purified by column chromatography (30% Ethyl acetate:hexanes) to yield 410 mg of tert-butyl 4-pentanoylbenzylcarbamate (83 %).
Step 4 A solution of tert-butyl 4-pentanoylbenzylcarbamate (0.410 g) in methylene chloride (10 mL) was treated with TFA and magnetically stined for 45 min. A saturated aqueous solution of sodium bicarbonate was added slowly followed by ethyl acetate (40 mL). The organic layer was separated, dried over magnesium sulfate and then filtered. The solution was concenfrated under reduced pressure, resulting in l-[4-(aminomethyl)phenyl]-l- pentanone which was used without any further purification.
A14. Preparation of of (lZ)-l-[4-(aminomethyl)phenyl]-l-pentanone O-methyloxime.
Figure imgf000075_0001
A solution of l-[4-(aminomethyl)phenyl]-l-pentanone (0.20 g, 1.05 mmol, 1 eq) and pyridine (0.25 mL) in ethanol (5 mL) was treated with methyloxylamine hydrochloride (0.175 g, 2.10 mmol, 2 eq) . The reaction was magnetically stined at 88 °C over 6 h. The solution was cooled to rt, concentrated under reduced pressure, and purified by column chromatography (90% Ethyl acetate:methanol) to yield 30 mg of (lZ)-l-[4- (aminomethyl)phenyl]-l-pentanone O-methyloxime (13%). LC/MS 220.5-221.5 at 2.03 min.
A15. Preparation of ethyl (4-aminophenyl)(oxo)acetate.
Figure imgf000076_0001
To a solution of ethyl 4-nitrophenylglyoxylate (3.60 g, 16.0 mmol) in glacial acetic acid (90 mL) was added iron powder (325 mesh) (7.20 g, 129.0 mmol) and the suspension stined 16 h at rt. The solids were filtered off and washed with water (300 mL). This was extracted with Et2O (2 x 250 mL), and the organic layer was dried (MgSO4) and concenfrated under reduced pressure to give a crude brown oil. Purification by silica gel chromatography (33% EtOAc/hexane) yielded the product as a yellow solid in 28% yield (870 mg, 4.506 mmol). ). HPLC/MS: [M+H]+obs = 194 @ tr = 2.89 min. (ESI+). IH NMR (DMSO) d 7.55 (2H, d, J = 8.7 Hz), 6.59 (4H, d and bs overlapping, J = 8.7 Hz), 4.32 (2H, quartet, J = 7.2 Hz), 1.28 (3H, t, J = 7.2 Hz).
B. Synthesis of Examples Bl. General Method
General Flow Diagram I for Method A
Figure imgf000077_0001
Figure imgf000077_0002
Method A for Prolylpeptidase Compounds
Step 1. Benzylamine 1 (General Flow Diagram I) (1.1 eq) and potassium carbonate (3.5 eq) were added to a solution of quinazoline 2 (1.0 eq) in isopropyl alcohol and water (as a 2 to 1 ratio, 0.1 M) and were magnetically stined at rt over a period of 16 h. The isopropyl alcohol was removed in vacuo. Ethyl acetate was added and this solution was washed with deionized water, dried over magnesium sulfate and then filtered. The solution was concentrated in vacuo, and purified by column chromatography to yield intermediate 3 as a white solid.
Step 2. Amine 4 (1.1 eq) and concentrated hydrochloric acid (catalytic) were added to a solution of intermediate 3 (1.0 eq) in 7z-butanol (0.1M) were magnetically stined at 100 °C in a sealed tube over a period of 16 h. The excess n-butanol was removed under reduced pressure. Methylene chloride was added and the solution was washed with saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate and then filtered. The solution was concentrated in vacuo, and purified by column chromatography to yield compound 5.
B2. Example 1. Preparation of methyl 4-({[6-chloro-2-(l-piperidinyl)-4- quinazolinyl] amino} methyI)benzoate.
Figure imgf000078_0001
NaOAc
Figure imgf000078_0002
piperidine
Figure imgf000078_0003
Step 1. A suspension of 2,4,6-trichloroquinazoline (685 mg, 2.93 mmol), methyl 4- (aminomethyl)benzoate hydrochloride (651 mg, 3.28 mmol), and sodium acetate (722 mg, 8.80 mmol) in water (25 mL) was refluxed for 30 min vigorously. The white suspension is filtered through a coarse frit while still warm, and washed thoroughly with water (2 x 30 mL), then dried under P2O5 in vacuo to give 884 mg of methyl 4-{[(2,6-dichloro-4- quinazolinyl)amino]methyl}benzoate as a white solid in (83%). TLC: Rf = 0.25 (20% EtOAc/hexane); HPLC/MS: [M+H]+obs = 362 @ tr = 3.81 min. (ESI+).
Step 2. A suspension of methyl 4-{[(2,6-dichloro-4-quinazolinyl)amino] methyl}benzoate (850 mg, 2.347 mmol) in piperidine (3.00 g, 35.21 mmol) was stined at 80 C under argon for 10 min. The reaction was diluted with water (50 mL) and extracted with EtOAc (3 x 100 mL). The organics were dried (MgSO4) and concentrated in vacuo to give a yellow oil which crystallizes. This was purified by silica gel chromatography (10% EtOAc/hexane - 100% EtOAc) to give methyl 4-({[6-chloro-2-(l-piρeridinyl)-4- quinazolinyl]amino}methyl)benzoate as a light yellow solid, crystallized from hexane, to give 746 mg (77%). TLC: Rf = 0.40(20% EtOAc/hexane); HPLC/MS: [M+H]+obs = 411 @ tr = 3.16 min. (ESI+). B3. Example 2. Preparation of 4-({[6-chloro-4-(l-piperidmyl)-2-qumazolinyl]amino} methyl)benzoic acid.
Figure imgf000079_0001
Step 1. To a suspension of 2,4,6-trichloroquinazoline (300 mg, 1.29 mmol) in dry DMF (10 mL) at 0 °C under argon was added piperidine (0.26 mL, 2.639 mmol) and the yellow suspension stined at 0 °C for 30 min, then at rt for 16 h. The reaction was diluted with water (75 mL) and sat. NaHCO3 (25 mL) and extracted with EtOAc (2 X 150 mL). The organics were washed with water (2 X 50 mL), dried (MgSO4), and concentrated in vacuo to give a yellow solid. This was purified by silica gel chromatography (5% EtOAc/hexane) to give 2,6-dichloro-4-(l-piperidinyl)quinazoline as yellow crystals (from hexane) in 78% yield (269 mg, 0.953 mmol). TLC: Rf = 0.25 (10% EtOAc/hexane); HPLC/MS: [M+H]+obs = 282 @ tr = 3.98 min. (ESI+). •
Step 2. A suspension of 2,6-dichloro-4-(l-piperidinyl)quinazoline (100 mg, 0.35 mmol), methyl 4-(aminomethyl)benzoate hydrochloride (105 mg, 0.523 mmol), and potassium carbonate (144 mg, 1.044 mmol) in dry DMF (5 mL) under argon was heated to 120 °C for 3 h. The reaction was quenched with water (100 mL) and extracted with EtOAc (2 x 150 mL).
The organics were washed with water (50 mL), dried (MgSO ), and concentrated under reduced pressure to give a yellow oil. The crude product was purified by silica gel chromatography (25-50% EtOAc/hexane) to give the product as a yellow foam solid in 38% yield (54 mg, 0.131 mmol). TLC: Rf = 0.17 (25% EtOAc/hexane); HPLC/MS: [M+H]+obs
= 411 @ tr = 3.25 min. (ESI+). Step 3. A solution of methyl 4-({[6-chloro-4-(l-piperidinyl)-2-quinazolinyl]amino} methyl)benzoate (50 mg, 0.122 mmol) in methanol (5 mL) and 5 M NaOH (aq)(0.73 mL, 3.65 mmol) was stined at rt for 24 h. The reaction was quenched by addition of 1 M HCl (aq)(3.70 mL), then diluted with Na/K tartrate/NaHSO4 buffer at pH 4.5 (50 mL). This was extracted with EtOAc (2 X 150 mL) and the organic layers dried (MgSO4) and concentrated in vacuo to give 35 mg of 4-({[6-chloro-4-(l-piperidinyl)-2-quinazolinyl]amino} methyl)benzoic acid as a colorless solid (73%). TLC: Rf = 0.18 (10% MeOH/EtOAc); HPLC/MS: [M+H]+obs = 397 @ tr = 3.06 min. (ESI+).
B4. Preparation of ethyl {4-[(2,6-dichloro-4-qumazolinyl)amino] phenyl} (oxo)acetate.
Figure imgf000080_0001
A suspension of 2,4,6-trichloroquinazoline (404 mg, 1.73 mmol), ethyl (4-aminophenyl) (oxo)acetate (485 mg, 2.51 mmol), and sodium acetate (287 mg, 3.50 mmol) in a mixture of THF (10 mL) and water (3.3 mL) was stined at rt for 72 h, then refluxed for 3 h. The reaction was partitioned between water (50 mL) and EtOAc (100 mL) and the organics dried (MgSO ) then the solvent was removed under reduced pressure. The crude oil (approx 600 mg), which contained approx 25% of the product by mass spec (150 mg, 0.38 mmol) was used without further purification. HPLC/MS: [M+H]+obs = 390 @ tr = 3.80 min. (ESI+).
B5. Preparation of methyl 4-[(6-chloro-2-{[4-(methoxycarbonyι)phenyl] amino}-4- qumazolmyl)amino]benzoate.
Figure imgf000080_0002
solution o 2,4,6-trichloroquinazoline (147 mg, 0.629 mmol) and methyl 4-aminobenzoate (128 mg, 0.850 mmol) in absolute ethanol (7 mL) was refluxed for 1 h. The resulting solid was filtered off while the reaction was still warm, then washed with hot ethanol to give the crude product. Recrystallization from methanol/EtOAc methyl gave 104 mg of 4-[(6-chloro- 2-{[4-(methoxycarbonyl)phenyl]amino}-4-quinazolinyl) amino] benzoate as a colorless solid in (36%). HPLC/MS: [M+H]+obs = 463 @ tr = 3.44 min. (ESI+). IH NMR (DMSO) d 10.44/10.21 (IH ea, 2 b s), 8.65 (IH, s), 8.0 (4H, m), 7.85 (5H, m), 7.62 (IH, d, J = 9 Hz), 3.86/3.82 (3H ea, 2 s).
B6. Example 3. Preparation of tm«,s4-[({6-chloro-2-[(3-methoxyphenyl)amino]-4- quinazolinyl} amino)methyl]cyclohexane carboxylic acid.
Figure imgf000081_0001
Step 1. A solution of m-anisidine (0.017 g, 0.14 mmol) and trαns-methyl 4-{[(2,6-dichloro- 4-quinazolinyl)amino]methyl}cyclohexanecarboxylate (0.050 g, 0.14 mmol) in n-butanol (2 mL) was heated at reflux overnight. The reaction was cooled to rt and the zz-butanol was concentrated under reduced pressure. The crude product was purified by preparative HPLC (Ciβ ODS, 10-90% CH3CN/H2O 0.1% TFA) and dried in vacuo to afford 53 mg of trans- methyl 4-[({6-chloro-2-[(3-methoxyphenyl)amino]-4-quinazolinyl} amino)methyl]cyclo- hexanecarboxylate (85%); mp = 216-218 °C; ES MS (M+H)+= 455.5; TLC (CH2Cl2/MeOH, 95:5): Rf= 0.64.
Step 2. A solution of trαw-methyl 4-[({6-chloro-2-[(3-methoxyphenyl)amino]-4- quinazolinyl}amino)methyl]cyclohexanecarboxylate (0.02 g, 0.04 mmol) and IN NaOH (0.04 mL) in MeOH/H2O/THF (1.5 mL/0.25 mL/0.25 mL) was stined at room temperature overnight then at 40 °C over 6 days. The reaction was cooled rt and the volatiles were removed under reduced pressure. The pH was adjusted to pH 6 with the addition of IN HCl, the resulting solid was collected by filtration, and was dried in vacuo to afford tr<ms--4-[({6- chloro-2-[(3-methoxyphenyl)amino]-4-quinazolinyl} amino) methyl] cyclohexane carboxylic acid (0.011 g, 0.026 mmol; 59% yield); mp = 258-261 °C, ES MS (M+H)+=441.5; Ret. Time (HPLC)= 2.76 min. B7. Example 4. Preparation of methyl 4-({[6-chloro-2-(4-phenyl-l-piperidinyl)-4- qumazolinyl] amino} methyl)benzoate.
Figure imgf000082_0001
A solution of methyl 4-{[(2,6-dichloro-4-quinazolinyl)amino]methyl}benzoate (100 mg, 0.28 mmol) and 4-phenylpiperidine (213 mg, 1.323 mmol) in dry DMF (6 mL) was stined under argon at rt for 11 h. The reaction was quenched with water (75 mL) and sat. NaHCO3 (25 mL) and extracted with EtOAc (2 x 200 mL). The organics were washed with water (50 mL), dried (MgSO4), and concentrated under reduced pressure to give a yellow oil. The crude product was purified by silica gel chromatography (20% EtOAc/hexane) to give methyl 4-({[6-chloro-2-(4-phenyl-l-piperidinyl)-4-quinazolinyl]amino}methyl)benzoate as a colorless oil. A colorless solid was obtained by crystallization in minimal CH2C12 with added hexane over 8 h. TLC: Rf = 0.40 (25% EtOAc/hexane); HPLC/MS: [M+H]+obs = 487 @ tr = 3.35 min. (ESI+).
B8. Preparation of methyl 4-({[6-chloro-2-(4-morpholinyl)-4-quinazolinyl] amino} methyl)benzoate.
Figure imgf000082_0002
A suspension of 4-{[(2,6-dichloro-4-quinazolinyl)amino]methyl}benzoate (100 mg, 0.28 mmol) and morpholine (1.08 mL, 12.42 mmol) was stined at rt for 24 h under argon. The reaction was diluted with water (50 mL) and sat NaHCO3 (2 mL) and extracted with EtOAc (2 x 100 mL). The organics were dried (MgSO4) and concentrated under reduced pressure to give a light yellow solid. This was dissolved in minimal CH2C12 (2 mL) and crystallized with added hexane to give 99 mg of methyl 4-({[6-chloro-2-(4-morpholinyl)-4-quinazolinyl] amino}methyl)benzoate as a colorless solid (87%). TLC: Rf = 0.55 (50% EtOAc/hexane); HPLC/MS: [M+H]+obs = 413 @ tr = 2.84 min. (ESI+). B9. Preparation of methyl 4-({[6-chloro-2-(dimethylamino)-4-quinazolinyl] amino} methyl)benzoate.
Figure imgf000083_0001
A solution of 4-{[(2,6-dichloro-4-quinazolinyl)amino]methyl}benzoate (100 mg, 0.28 mmol) and 2-aminopyridine (131 mg, 1.39 mmol) in dry DMF (2.5 mL) was heated in a sealed vial at 100 °C for 24 h, then at 150 °C for 6 h. The reaction was diluted with water
(75 mL) and extracted with EtOAc (2 x 150 mL). The organics were washed with water (2 x
50 mL), dried (MgSO ), and concentrated under reduced pressure to give a yellow oil.
Purification by silica gel chromatography (33% EtOAc/hexane) afforded 45 mg of methyl 4- ({[6-chloro-2-(dimethylamino)-4-quinazolinyl] amino}methyl)benzoate as yellow crystals in
(44%). TLC: Rf = 0.60 (50% EtOAc/hexane); HPLC/MS: [M+H]+obs = 371 @ tr = 2.94 min. (ESI+).
B10. Example 5. Preparation of 4-({[6,7-dimethoxy-2-(5,6,7,8-tetrahydro-l- naphthalenylamino)-4-quinazolmyl] amino} methyl)benzoic acid.
Figure imgf000083_0002
4-{[(2-Chloro-6,7-dimethoxy-4-quinazolinyl)amino]methyl}benzoic acid (400 mg, 1.07 mmol) is heated in neat 5,6,7,8-tetrahydro-l-naphthalenamine (2 mL, 13.6 mmol) with catalytic cone. HCl added (4 drops) at 140 °C for 5 h. The crude reaction was purified directly by silica gel chromatography (33% MeOH/EtOAc) to give a residue which was crystallized in methanol to give 22 mg of 4-({[6,7-dimethoxy-2-(5,6,7,8-tefrahydro-l- naphthalenylamino)-4-quinazolinyl]amino}methyl)benzoic acid as a colorless solid (4%). HPLC/MS: [M+H]+obs = 485 @ tr = 2.46 min. (ESI+). IH NMR (DMSO) d 12.75 (IH, b s), 8.42/7.64 (IH ea, 2 b s), 7.86/7.37 (2H ea, d, J = 7.8 Hz), 7.62 (IH, s), 7.45 (IH, d, J = 8.4 Hz), 6.94 (IH, t, J = 7.5 Hz), 6.75 (2H, s overlapping with d, J = 7.2 Hz), 4.72 (2H, d, J = 9 Hz), 3.82/3.81 (3H ea, 2 s), 2.72/2.58 (2H ea, 2 m), 1.63 (4H, m). Bll. Example 6. Preparation of methyl 4-[({7-chloro-2-[(2-thienylmethyl)amino]-4- quinazolinyl}amino)methyl]benzoate.
Figure imgf000084_0001
A solution of 2-thienylmethylamine (0.031 g, 0.28 mmol) and methyl 4-{[(2,7-dichloro-4- quinazolinyl)amino]methyl}benzoate (0.100 g, 0.28 mmol) in rc-butanol (4 mL) was heated to reflux for 18 h. The reaction was cooled to rt and the π-butanol concentrated under reduced pressure. The crude product was purified by preparative HPLC (C18 ODS, 10-90% CH3CN/H2O 0.1% TFA) and dried in vacuo to afford 61 mg of methyl 4-[({7-chloro-2-[(2- thienylmethyl)amino]-4-quinazolinyl}amino)methyl]benzoate (50%); mp = 176-178 °C; ES MS (M+H)+= 439.9; Ret. Time (HPLC)= 2.25 min.
B12. Example 7. Preparation of methyl 4-{[(7-chloro-4-{[4-(4-morpholinyl)phenyl] ammo}-2-quinazolinyl)amino]methyl}benzoate.
Figure imgf000085_0001
IPA/H20
Figure imgf000085_0002
Step 1. A mixture of 2,4,7-trichloroquinazoline (0.20 g, 0.86 mmol), 4-(4- morpholinyl)phenylamine (0.229 g, 1.28 mmol), potassium carbonate (0.355 g, 2.57 mmol) in IP A/water (5.3 mL/2.7 mL) was heated at 60° C for 18 h. The reaction was cooled to rt and the solvent was removed under reduced pressure. The pH was adjusted to 6 with the addition of IN HCl and the mixture was concentrated in vacuo. The crude mixture was purified by preparative HPLC (C18 ODS, 30-90% CH3CN/H2O 0.1% TFA) to afford 2,7- dichloro-N-[4-(4-morpholinyl)phenyl]-4-quinazolinamine (0.100 g, 0.293 mmol; 33% yield); 1H NMR (DMSO-^) 10.22 (s, IH), 8.54 (d, J= 8.8 Hz, IH), 7.73 (d, J= 2.0 Hz, IH), 7.69-7.64 (m, IH), 7.57 (d, J = 8.8 Hz, 2H), 7.03 (d, J = 8.8 Hz, 2H), 3.78-3.70 (m, 4H), 3.18-3.10 (m, 4H); ES MS (M+H) =375.2; TLC (50:50 Hexanes/EtOAc): Rf=0.34.
Step 2. A solution of methyl 4-(aminomethyl)benzoate (0.027 g, 0.13 mmol) and 2,7- dichloro-N-[4-(4-morpholinyl)phenyl]-4-quinazolinamine (0.050 g, 0.13 mmol) in n-butanol (1 mL) was heated to reflux for 18 h. The reaction was cooled rt and the 7?-butanol was removed under reduced pressure. The crude product was purified by preparative HPLC (C18 ODS, 30-90% CH3CN/H2O 0.1% TFA) and dried in vacuo to afford 19 mg of methyl 4-{[(7- chloro-4- {[4-(4-morpholinyl)phenyl]amino}-2-quinazolinyl)amino]methyl} benzoate (24%); mp = 95-99 °C; ES MS (M+H)+= 504.4; TLC (90:10 CH2Cl2/MeOH): R 0.65.
B13. Example 8. Preparation of methyl 4-({[7-chloro-4-(isobutylamino)-2- quinazolinyl]amino}methyl)benzoate.
Figure imgf000086_0001
Figure imgf000086_0002
n-Butanol
Figure imgf000086_0003
Step 1. A mixture of 2, 4, 7-trichloroquinazoline (0.125 g, 0.54 mmol), wo-butyl amine (0.059 g, 0.080 mmol), and potassium carbonate (0.222 g, 1.61 mmol) in IP A/water (2.7 mL/1.3 mL) was heated at 60 °C for 18 h. The reaction was cooled to rt and the volatiles were removed under reduced pressure. The pH was adjusted to pH 6 with the addition of IN HCl and the resulting solid was collected by filtration. The solid was dried in vacuo to afford 130 mg of 2,7-dichloro-N-isobutyl-4-quinazolinamine (90%); 1H NMR (DMSO-I) 8.96 (t, J= 5.3 Hz, IH), 8.37 (d, J= 9.1 Hz, IH), 7.65 (d, J= 2.3 Hz, IH), 7.57 (dd, J= 2.4 Hz, 8.8 Hz, IH), 3.30 (dd, J= 5.9 Hz, 7.0 Hz, 2H), 2.01 (sept, J= 7.0 Hz, IH), 0.90 (d, J = 6.6 Hz, 6H); ES MS (M+H)+=270.1; TLC (50:50 Hexanes/EtOAc): Rf=0.82.
Step 2. A solution of methyl 4-(aminomethyl)benzoate hydrochloride (0.037 g, 0.19 mmol) and 2,7-dichloro-N-isobutyl-4-quinazolinamine (0.050 g, 0.19 mmol) in «-butanol (1 mL) was heated at reflux for 18 h. The reaction was cooled to rt and the «-butanol was removed in vacuo. The crude product was purified by preparative HPLC (C18 ODS, 30-90% CH3CN/H2O 0.1% TFA) and dried in vacuo to afford 13 mg of methyl 4-({[7-chloro-4- (isobutylamino)-2-quinazolinyl]amino}methyl)benzoate (13%); mp = 182-185 °C; ES MS (M+H)+= 399.5; TLC (90:10 CH2Cl2/MeOH): Rf=0.63. B14. General Procedure for Parallel Synthesis
Figure imgf000087_0001
The following solutions were prepared prior to use: 1. 2,5-dichloro-4-(4-methoxycarbonylbenzylamino)-quinazoline solution in /z-butanol (0.02 mmol/200 μL)
2. HNRiR2 (primary or secondary amine) solution in n-butanol (0.024 mmol/200 μL)
3. 4 N potassium hydroxide solution in methanol and water (1:1)
To a 1-mL well in a 96-well Robbins FlexChem™ reaction block, 200 μL of 2,5-dichloro-4- (4-methoxycarbonylbenzylamino)-quinazoline (0.02 mmol) and 200 μL of amine (0.024 mmol) were dispensed. 77-Butanol (95 μL) and 1.0 M hydrochloric acid in diether ether (5 μL) were added to each well. The plate was sealed with a rubber septum sheet, and rotated in a Robbins oven at 85 °C for 2 days. After allowing the reaction block to cool to room temperature, the septum was removed and the reaction mixture was filtered into a 2-mL 96- well collection plate, followed by washing 3 times with 200 μL MeOH. The solvent was evaporated under reduced pressure by using a multiple sample evaporator (Gene Vac™). The residue was redissolved in 500 μL MeOH and transfened to a 1-mL well in a 96-well Robbins FlexChem™ reaction block. 4 N Potassium hydroxide (50 μL) was added to each well. The plate was sealed with a rubber septum sheet, and rotated in a Robbins oven at 60 °C for overnight. After allowing the reaction block to cool to room temperature, the septum was removed and 110 μL of 2 N Hydrochloric acid was added to each well. The reaction mixture was filtered into a 2-mL 96-well collection plate, followed by washing 3 times with 200 μL MeOH. The solvent was evaporated under reduced pressure (Gene Vac). The residue was redissolved in 1 mL dichloromethane and filtered through a 2-mL well in a 96-well Robbins FlexChem™ reaction block into a 2-mL 96-well collection plate. The solvent was evaporated under reduced pressure (GeneVac). The formation of desired products was confirmed by LC-MS analyses.
HPLC conditions for parallel synthesis analysis: A YMC Pro C-18 column (2 x 23mm, 120 A) was used, and the eluents were A: 2% acetonitrile in water with 0.02% TFA and B: 2% water in acetonitrile with 0.02% TFA. Elution conditions consisted of a flow rate of 1.5 mL/min with an initial hold at 10% B for 0.5 minutes, followed by gradient elution from 10% B to 90% B over 3.5 minutes, followed by a final hold at 90% B for 0.5 minutes. Total run time was 4.8 minutes.
C. Modification of Examples
Cl. General Method for Hydrolysis of Ester.
Figure imgf000088_0001
6 7 An excess of aqueous sodium hydroxide (IN) was added to a solution of ester 6 in methanol (0.1-0.05 M). The mixture was magnetically stined at room temperature for 2 hours. The mixture was adjusted to pH 7 with aqueous hydrochloric acid (IN) and methanol was removed under reduced pressure. The resulting solid was filtered, rinsed with deionized water, and dried in vacuo to yield 2 as a solid. C2. Example 9. Preparation of 4-[({6-chloro-2-[(2-thienylmethyl)amino]-4- quinazolinyl} amino)methyl] -N-isobutylbenzamide.
Figure imgf000089_0001
A heterogeneous solution of 4-[({6-Chloro-2-[(2-thienylmethyl)amino]-4-quinazolinyl} amino)methyl]benzoic acid (100 mg, 0.24 mmol, 1.0 eq) in 4 mL of DMF was magnetically stined at 75 °C until homogeneous. l,l '-Carbonyldiimidazole (38 mg, 0.24 mmol, 1.0 eq) was added and were heated at 75 °C for 2 h. The conesponding amine (4.8 mmol, 20 eq) was added and the reaction was heated at 60°C over a period of 16 h. The reaction was cooled to rt and poured into 25 mL of water. The aqueous layer was extracted 3 x 20 mL dichloromethane. The organic layers were combined, washed with 30 mL of brine, dried over magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified via preparatory HPLC (HPLC method: C18 ODS, 10-90% CH3CN/H2O 0.1%TFA) to give 4-[({6-chloro-2-[(2-thienylmethyl)amino]-4-quinazolinyl}amino)methyl]- N-isobutylbenzamide. 1H NMR (OMSO-d6) 8.26 (s, IH), 7.79-7.76 (m, 3H), 7.46-7.43 (m, 3H), 7.23 (s, IH), 6.90 (m, 2H), 4.88 (s, 2H), 4.80 (s, 2H), 3.18 (d, J=6.7 Hz, 2 H), 1.94- 1.90 (sept, J=6.8 Hz, IH), 0.95 (d, J=6.3 Hz, 6H); MS (ES) 480.4 (M+H)+; TLC (100 % ETOAC) Rf = 0.44.
C3. General Method for Synthesis of Esters
Figure imgf000090_0001
A heterogeneous solution of 4-[({6-Chloro-2-[(2-thienylmethyl)amino]-4-quinazolinyl} amino)methyl]benzoic acid (100 mg, 0.24 mmol, 1.0 eq) in 4 mL of DMF was magnetically stined at 75°C until homogeneous. l,l '-Carbonyldiimidazole (38 mg, 0.24 mmol, 1.0 eq) was added and the reaction was heated at 75°C for 1 h. The conesponding alcohol (4.8 mmol, 20 eq) was added and the reaction was heated at 60 °C over a period of 16 h. The reaction was cooled to 0°C and sodium hydride (30 mg, 1.3 mmol, 5.4 eq) added. This was maintained at 0 °C for 1 h. Water (15 mL) was slowly added, and the aqueous layer was extracted with dichloromethane (3 x 15 mL). The organic layers were combined, washed with 20 mL of brine, dried over magnesium sulfate, the solvent was removed under reduced pressure. The residue was purified via preparatory HPLC (HPLC method: C18 ODS, 10- 90% CH3CN/H2O 0.1%TFA).
C4. Example 10. Preparation of N-(6-chloro-4-{[4-(5,6-dihydro-l,4,2-dioxazin-3- yl)benzyl]ammo}-2-qumazolinyl)-N-(2-thienylmethyl)amine.
Figure imgf000090_0002
Step 1. 4-[( {6-Chloro-2-[(2-thienylmethyl)amino]-4-quinazolinyl} amino)methyl]benzoic acid (1 eq) was dissolved in DMF (0.23 M) and cooled to -30 °C when hydroxybenzatriazolehydrate (1.7 eq) and l-[3-(dimethylaminopropyl)]-3-ethylcarbo diimide hydrochloride (1.7 eq) were added. This was allowed to stir for 15 min and 2- (aminooxy)ethanol (1.4 eq) in a solution of DMF (0.33 M was added via syringe. The reaction was gradually allowed to reach rt and was magnetically stined over a period of 18 h. The reaction was dissolved in EtOAc and water and poured into a seperatory funnel. The layers were separated and the aqueous was extracted with EtOAc (3x). The combined organics were washed with 10% citric acid (2x), 10% NaHCO3 (2x), satd. NaCl, dried (MgSO4), filtered and concentrated in vacuo. The resulting crude solid 4-[({6-chloro-2-[(2- thienylmethyl)amino] -4-quinazolinyl} amino)methyl] -N-(2-hydroxy-ethoxy)benzamide was a 1 : 1 mixture of starting material and product and used without purification.
Step 2. 4-[( {6-Chloro-2-[(2-thienylmethyl)amino]-4-quinazolinyl} amino)methyl]-N-(2- hydroxyethoxy)benzamide (1 eq) was dissolved in THF (0.02 M) were magnetically stined as a suspension and the Burgess reagent (1.1 eq) was added in one portion. The reaction was heated at 80 °C over a period of 3 h. The reaction was cooled, concentrated and purified by flash silica column chromatography (1/1 EtO Ac/Hex) to give N-(6-chloro-4-{[4-(5,6- dihydro- 1 ,4,2-dioxazin-3 -yl)benzyl] amino} -2-quinazolinyl)-N-(2-thienylmethyl)amine in 16% overall yield.
C5. Example 11. Preparation of isobutyl 4-[({6,7-dimethoxy-2-[(2- thienylmethyl)ammo]-4-quinazolmyl}amino)methyl]benzoate.
Figure imgf000091_0001
isobutanol
Figure imgf000091_0002
Step 1: To methyl 4-[({6,7-dimethoxy-2-[(2-thienylmethyl)amino]-4-quinazolinyl} amino)methyl]benzoate (0.51 g) in methanol (10 mL) was added 50% sodium hydroxide (0.1 mL) and the reaction was heated to 65 °C for one hour, then stined at rt for 16 h. The reaction was cooled and IN hydrochloric acid was added until a pH=7 was achieved. Solids emerged and were filtered to give 200 mg of 4-[({6,7-dimethoxy-2-[(2- thienylmethyl)amino]-4-quinazolinyl}amino)methyl]benzoic acid (40%).
Step 2: To 4-[({6,7-dimethoxy-2-[(2-thienylmethyl)amino]-4-quinazolinyl} amino) methyl]benzoic acid (0.050 g) in iro-butanol (3 mL) was added a catalytic amount of cone, sulfuric acid and the reaction was heated to 100 °C for 2 h. It was cooled, taken up in ethyl acetate, washed with IN hydrochloric acid, the organic layers were filtered, dried with magnesium sulfate, filtered, and concentrated to give 60 mg of wo-butyl 4-[({6,7-dimethoxy- 2-[(2-thienylmethyl)amino]-4-quinazolinyl}amino)methyl]benzoate (99%).
C6. Example 12. Preparation of 4-[({6,7-dimethoxy-2-[(2-thienylmethyI)amino]-4- quinazolinyl} amino)methyl] -N-isobutylbenzamide.
Figure imgf000092_0001
To 4-[( {6,7-dimethoxy-2-[(2-thienylmethyl)amino]-4-quinazolinyl} amino)methyl] benzoic acid (0.100 g, 0.22 mmol, l.Oeq.) in DMF (10 mL) was added carboxydiimidazole (0.036 g,
0.22 mmol, leq.) and the reaction was heated to 60 °C for 1 h. Isobutylamine (0.32 g, 4.4 mmol., 20 eq.) was then added and the reaction continued to stir at 60 °C for 3 h. It was cooled, diluted with ethyl acetate, washed with water, dried with magnesium sulfate, filtered and the solvent was removed under reduced pressure. The crude oil was purified by flash chromatography (0-20% methanol/chloroform) to give 23 mg of 4-[({6,7-dimethoxy-2-[(2- thienylmethyl)amino]-4-quinazolinyl}amino) methyl]-N-isobutylbenzamide (21%). C7. Example 13. Preparation of l-{4-[({6-chloro-2-[(2-thienylmethyl)amino]-4- qumazomιyl}amino)methyl]phenyl}-l-propanol.
Figure imgf000093_0001
Sodium borohydride (0.005 g ,0.14 mmol, 1.5 eq.) was added to a solution of l-{4-[({6- chloro-2-[(2-thienylmethyl)amino]-4-quinazolinyl}amino)methyl]phenyl}-l-propanone (0.040 g, 0.09 mmol, 1.0 eq) in ethyl alcohol (5 mL) and were magnetically stined at rt over a period of 16 h. An aqueous solution of ammonium hydroxide (10%, 5 mL) was added and the ethyl alcohol was removed in vacuo. Methylene chloride (25 mL) was added and this solution was washed with deionized water (25 mL), dried over magnesium sulfate and then filtered. The solution was concentrated under reduced pressure, and purified by column chromatography (30-10% Ethyl acetate:Hexanes) to yield 15 mg of l-{4-[({6-chloro-2-[(2- thienylmethyl)amino]-4-quinazolinyl} amino) methyl]phenyl}-l-propanol as a colorless solid (38%). LC/MS 439.3 (100%).
C8. Example 14. Preparation of {4-[({6-chloro-2-[(2-thienylmethyl)amino]-4- quinazolinyl} amino) methyl] phenyl} methanol.
Figure imgf000093_0002
Diisobutyl aluminum hydride (1M, in dichloromethane, 0.96 mL, 0.96 mmol, 3 eq) was added dropwise to a previously cooled (0 °C, via ice/water bath) suspension of methyl 4- [( {6-chloro-2-[(2-thienylmethyl)amino]-4-quinazolinyl} amino)methyl]benzoate (0.140 g, 0.32 mmol, 1.0 eq) in dichloromethane (2 mL), and were magnetically stined at rt over a period of 16 h. An aqueous solution of Rochelle salt (50 mL) and methylene chloride (50 mL) was added and the organic layer was separated, dried over magnesium sulfate and then filtered. The solution was concentrated in vacuo, and purified by HPLC (ACN/H2O) to give 1 mg of {4-[({6-chloro-2-[(2-thienylmethyl)amino]-4-quinazolinyl}amino) methyl]phenyl} methanol as a colorless solid (<1 %). 1H NMR (MeOH, 300 MHz). LC/MS 439.3 (100%).
C9. Example 15. Preparation of isopropyl 4-({[6,7-dimethoxy-2-(l-piperidinyl)-4- quinazolinyl]amino}methyl)benzoate
Figure imgf000094_0001
To a suspension of methyl 4-({[6,7-dimethoxy-2-(l-piperidinyl)-4-quinazolinyl] amino}methyl)benzoate (3.50 g, 8.02 mmol) in isopropanol (500 mL) in an oven dried flask under argon was added sodium isopropoxide solution (125 mL of 1.74 M solution, 2.17 mmol). The cloudy suspension was stined at 35 °C for 16 h, after which time the reaction becomes clear, then concentrated at rt under reduced pressure to give a white solid. This was quenched by suspending it in 0.05M HCl (aq) (125 mL) with sonication to a final pH of 1.5. The white solid was filtered through a course frit and washed well with water (3 x 150 mL). The solid was dried under P2O5 in vacuo to give 3.70 g of isopropyl 4-({[6,7-dimethoxy-2- (l-piperidinyl)-4-quinazolinyl]amino}methyl)benzoate as a colorless solid in (99%). TLC: Rf = 0.64 (EtOAc); HPLC/MS: [M+H]+obs = 465 @ tr = 2.59 min. (ESI+).
CIO. Example 16. Preparation of 4-({[6,7-dihydroxy-2-(l-piperidinyl)-4-quinazolinyl] amino}methyl)benzoic acid.
Figure imgf000094_0002
To a suspension of 4-({[6,7-dimethoxy-2-(l-piperidinyl)-4-quinazolinyl]amino}metl yl) benzoic acid (30 mg, 0.071 mmol) in dry CH2C12 (10 mL) at -78 °C under argon was added BBr3 (1.42 mL of a 1.0M solution in CH2C12) dropwise over 30 min. The reaction was wannd to rt over 30 min and stined an additional 72 h at rt. The reaction was quenched with water (10 mL) and extracted with CH2C12. A brown solid which forms in the biphase was filtered off and washed with water (20 mL) and CH2C12 (20 mL) and dried in vacuo to give 3.0 mg of 4-({[6,7-dihydroxy-2-(l-piperidinyl)-4-quinazolinyl] amino}methyl)benzoic acid in (11%). TLC: Rf = 0.85 (25% MeOH/EtOAc); HPLC/MS: [M+H]+obs = 395 @ tr = 2.06 min. (ESI+).
Cll. Example 17. Preparation of methyl 4-({[2-(l-piperidmyl)-4-qumazolinyl]amino} methyl)benzoate.
Figure imgf000095_0001
To a solution of methyl 4-({[6-chloro-2-(l-piperidinyl)-4-quinazolinyl]amino}methyl) benzoate (50 mg, 0.12 mmol) in MeOH (15 mL) was added 10% Pd/C (50 mg) and the reaction hydrogenated at 1 atm (balloon) with vigorous stirring for 24 h. The Pd/C was filtered off and the filtrate concenfrated under reduced pressure to give an oil which crystallized. The crude product was recrystallized from minimal CH2C12 with added hexane to give 38 mg of the pure methyl 4-({[2-(l-piperidinyl)-4-quinazolinyl]amino} methyl)benzoate as a colorless solid (83%). TLC: Rf = 0.07 (20% EtOAc/hexane); HPLC/MS: [M+H]+obs = 377 @ tr = 3.06 min. (ESI+).
D. Alternative Linkers or Cores
Dl. Example 18. Preparation of 4-{[(6-chloro-2-hydroxy-4-qumazolmyl)amino] methyl} benzoic acid.
Figure imgf000095_0002
To a solution of 4-{[(2,6-dichloro-4-quinazolinyl)amino]methyl}benzoic acid (100 mg, 0.28 mmol) in dry 1,4-dioxane (30 mL) was added 5 M NaOH (aq) (11.04 mL, 55.22 mmol). The biphase was refluxed vigorously for 24 h. The reaction was quenched by addition of 2 M HCl (aq) (27 mL) and the cloudy mixture further diluted with Na/K tartrate/NaHSO buffer at pH 6 (150 mL). This was extracted with EtOAc (2 x 400 mL) and the organic dried (MgSO4) and concentrated in vacuo to give a crude yellow oil. Purification by silica gel chromatography (20-35% MeOH/EtOAc) afforded the product in 50% purity as a white solid. The semi-crude product was suspended in MeOH (1 mL) and sonicated for 5 min. Filtration and washing the white solid with MeOH (2 mL) gave 2 mg of the 4-{[(6-chloro-2- hydroxy-4-quinazolinyl)amino]methyl}benzoic acid (2%). TLC: Rf = 0.33 (25% MeOH/CH2C12); HPLC/MS: [M+H]+obs = 330 @ tr = 3.01 min. (ESI+).
D2. Example 19. Preparation of 4-{[(6-chloro-2-phenoxy-4-quinazolinyl)amino] methyl} benzoic acid.
Figure imgf000096_0001
A mixture of 4-{[(2,6-dichloro-4-quinazolinyl)amino]methyl}benzoic acid (100 mg, 0.29 mmol) and phenol (270 mg, 2.87 mmol) was heated at 125 °C for 3 h, after which the slurry has become a clear yellow oil. The crude reaction was purified directly by silica gel chromatography (100% EtOAc -» 25% MeOH/EtOAc) to give 4-{[(6-chloro-2-phenoxy-4- quinazolinyl)amino]methyl} benzoic acid as a white solid. TLC: Rf = 0.35 (25% MeOH/EtOAc); HPLC/MS: [M+H]+obs = 406 @ tr = 2.98 min. (ESI+).
D3. Example 20. Preparation of 4-({[2-(benzyloxy)-6-chloro-4-quinazolinyl] amino} methyl)benzoic acid.
Figure imgf000096_0002
To a suspension of 4-{[(2,6-dichloro-4-quinazolinyl)amino]methyl}benzoic acid (100 mg, 0.29 mmol) and benzyl alcohol (310 mg, 2.87 mmol) was added DBU (437 mg, 2.87 mmol). The clear yellow solution was stined at 125 °C for 24 h. The reaction was quenched with 1M HCl (aq) to a final pH of 6. This was further diluted with water (75 mL) and extracted with EtOAc (2 x 150 mL). The organics were dried (MgSO4) and concentrated in vacuo to give the crude product as a gum. Purification by silica gel chromatography (100% EtOAc -> 25% MeOH/EtOAc) afforded 13 mg of 4-({[2-(benzyloxy)-6-chloro-4-quinazolinyl]amino} methyl)benzoic acid as a colorless solid (11%). TLC: Rf = 0.40 (25% MeOH/EtOAc); HPLC/MS: [M+H]+obs = 420 @ tr = 2.29 min. (ESI+).
D4. Example 21. Preparation of 4-[({6,7-dimethoxy-2-[(2S)-2-(methoxymethyl)-l- pyrrolidinyl]-4-quinazolinyl}oxy)methyl]benzoic acid.
Figure imgf000097_0001
n-Butanol
Figure imgf000097_0003
Figure imgf000097_0002
Step 1. To a solution of 2,4-dichloro-6,7-dimethoxyquinazoline (0.500 g, 1.93 mmol), tefrabutylammonium bromide (0.0311 g, 0.10 mmol), and 10% aqueous NaOH (4.0 mL) in toluene (4.8 mL) was added methyl 4-(hydroxymethyl)benzoate (0.330 g, 1.99 mmol) as a solution in toluene (3.3 mL), dropwise. The reaction was allowed to stir at rt for 18 h. Water (100 mL) was added and the mixture was extracted with EtOAc (3 x 100 mL). The combined organics were dried (MgSO ), filtered, and concenfrated under reduced pressure to afford 112 mg of methyl 4-{[(2-chloro-6,7-dimethoxy-4-quinazolinyl)oxy]methyl}benzoate (15%); 1H NMR (OMSO-d6) 7.97 (d, J= 7.3 Hz, 2H), 7.65 (d, J= 7.3 Hz, 2H), 7.32 (d, J= 7.4 Hz, 2H), 5.68 (s, 2H), 3.93 (s, 3H), 3.89 (s, 3H); ES MS (M+H)+= 375.2.
Step 2. A solution of (2S)-2-(methoxymethyl)ρynolidine (0.033 g, 0.29 mmol) and 4-{[(2- chloro-6,7-dimethoxy-4-quinazolinyl)oxy]methyl}benzoic acid (0.108 g, 0.29 mmol) in n- butanol (1.5 mL) was heated at reflux for 18 h. The reaction was cooled to rt and the n- butanol was removed under reduced pressure. The residue was triturated with MeOH and filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC (C18 ODS, 10-90% CH3CN/H2O 0.1% TFA) to afford 3 mg of 4-[({6,7-dimethoxy-2-[(2S)-2-(methoxymethyl)-l-pynolidinyl]-4-quinazolinyl}oxy)methyl jbenzoic acid (2%); 1H NMR (MeOH-^) 8.03 (d, J= 7.1 Hz, 2H), 7.55 (d, J= 6.7 Hz, 2H), 7.34 (s, IH), 7.05 (s, IH), 5.69 (q, J= 13.6 Hz, 2H), 4.37-4.30 (m, IH), 3.94 (s, 3H), 3.88 (s, 3H), 3.68-3.60 (m, IH), 3.58-3.51 (m, 2H), 2.15-1.91 (m, 4H), 1.28 (s, IH); ES MS (M+H)+= 454.3; TLC (CH2Cl2/MeOH, 95:5): Rf = 0.21.
D5. Example 22. Preparation of methyl 4-[({6,7-dimethoxy-2-[(2S)-2-
(methoxymethyl)-l-pyrrolidinyl]-4-quinazolinyl}sulfanyl)methyl] benzoate.
Figure imgf000098_0001
Step 1. To a solution of 4-(chloromethyl)benzoic acid (1.00 g, 5.86 mmol) in EtOH (15 mL) was added thiourea (0.50 g, 5.86 mmol) as a solution in EtOH (5 mL), dropwise. The reaction was allowed to stir at room temperature overnight. Additional thiourea was added
(0.23 g, 2.93 mmol) and the reaction was heated at reflux for 2 h, then allowed to cool to rt. Water (30 mL) was added and the mixtue was made basic with the addition of 10% aqueous NaOH. The mixture was heated at reflux for 2 h. The reaction was cooled to rt and was washed with EtOAc (3 x 50 mL). IN HCl was added to the aqueous portion to adjust the pH to 6 and the mixture was extracted with EtOAc (3 x 50 mL). The combined organics were dried (MgSO ), filtered, and concentrated under reduced pressure to afford 0.85 g of 4- (sulfanylmethyl)benzoic acid (86%); !H NMR (OMSO-d6) 12.87 (s, IH), 7.86 (d, J= 7.4 Hz, 2H), 7.43 (d, J = 7.2 Hz, 2H), 3.77 (d, J = 7.9 Hz, 2H), 2.96 (t, J = 8.1 Hz, IH); ES MS (M+H)+= 169.0.
Step 2. A mixture of 2,4-dichloro-6,7-dimethoxyquinazoline (0.50 g, 1.93 mmol), 4- (sulfanylmethyl)benzoic acid (0.487 g, 2.89 mmol), and potassium carbonate (0.800 g, 5.79 mmol) in IP A/water (10 mL/5 mL) was heated at 60 °C overnight. The reaction was cooled to rt and IN HCl was added to adjust the pH to 6. The resulting solid was collected by filtration and dried in vacuo at 45 °C overnight to afford 0.75 g of 4-{[(2-chloro-6,7- dimethoxy-4-quinazolinyl)sulfanyl]methyl}benzoic acid (99%); 1H NMR (OMSO-d6) 12.92 (s, IH), 7.89 (d, J= 7.9 Hz, 2H), 7.61 (d, J= 8.5 Hz, 2H), 7.29 (s, IH), 7.13 (s, IH), 4.66 (s, 2H), 3.94 (s, 3H), 3.91 (s, 3H); ES MS (M+H)+= 391.2.
Step 3. A solution of (2S)-2-(methoxymethyl)pynolidine (0.06 g, 0.51 mmol) and 4-{[(2- chloro-6,7-dimethoxy-4-quinazolinyl)sulfanyl]methyl}benzoic acid (0.20 g, 0.51 mmol) in 77-butanol (12 mL) was heated at reflux for 18 h. The reaction was cooled to rt and the n- butanol was removed in vacuo. The residue was taken up in MeOH and adhered to silica gel. The crude product was purified first by column chromatography (0-10% MeOH/CH2Cl2), followed by preparative HPLC (C18 ODS, 10-90% CH3CN/H2O 0.1% TFA) to afford 16 mg of 4-[({6,7-dimethoxy-2-[(2S)-2-(methoxymethyl)-l-pynolidinyl]-4- quinazolinyl}sulfanyl)methyl] benzoic acid (7%); 1H NMR (Acetone-^) 8.01 (d, J= 6.1 Hz, 2H), 7.78-7.63 (m, 3H), 7.26 (s, IH), 4.84 (s, 2H), 4.72 (s, IH), 3.99 (s, 3H), 3.96 (s, 3H), 3.39-3.34 (m, 2H), 2.74 (s, 3H), 2.23-2.18 (m, 4H), 1.99-1.95 (m, 2H); ES MS (M+H)+= 470.4; TLC (CH2Cl2/MeOH, 90:10): Rf = 0.60.
Step 4. A solution of 4-[({6,7-dimethoxy-2-[(2S)-2-(methoxymethyl)-l-pynolidinyl]-4- quinazolinyl}sulfanyl)methyl] benzoic acid (0.025 g, 0.05 mmol) and chlorotrimethylsilane (0.011 g, 0.10 mmol) in MeOH (1.0 mL) was stined rt for 18 h. Additional chlorotrimethylsilane (0.113 g, 0.10 mmol) was added and the mixture was allowed to stir 24 h. The mixture was concenfrated under reduced pressure. The residue was taken up in MeOH and, again, concenfrated under reduced pressure. The dilution and concentration was repeated 4 times. The crude product was purified by preparative TLC (95:5 CH Cl2/MeOH) and dried in vacuo to afford 25 mg of methyl 4-[({6,7-dimethoxy-2-[(2S)-2- (methoxymethyl)-l-pynolidinyl]-4-quinazolinyl}sulfanyl)methyl] benzoate (97%); mp = 90- 95 °C; ES MS (M+H)+=484.2; TLC (50:50 Hexanes/EtOAc): Rf=0.36.
D6. Example 23. Preparation of methyl 4-{[(6,7-dimethoxy-2-{[4-(4- morpholinyl)phenyl] amino}-4-quinolinyl)amino] methyl} cyclohexane carboxylate.
Figure imgf000100_0001
Step 1. To a heterogeneous magnetically stined solution of malonic acid (5.4 g, 52 mmol, 1.0 eq) in phosphorous oxychloride (60, 390 mmol, 7.5 eq) was added 3,4-dimethoxyaniline (10 g, 65 mmol, 1.25 eq). The reaction heated to reflux at 115 °C for 2 h when it was cooled to rt and carefully added to 500 mL ice. The resulting aqueous layer was extracted with dichloromethane (2 x 300 mL). The organic layers were combined, washed with brine (1 x 300 mL), dried over magnesium sulfate and concentrated in vacuo to yield 6 g of 2,4- dichloro-6,7-dimethoxyquinoline (45%).
Step 2. A solution of 2,4-dichloro-6,7-dimethoxyquinoline (3g, 11.7 mmol, 1 eq), methyl 4- (aminomethyl)cyclohexanecarboxylate (9.7 g, 46.8 mmol, 4 eq), DBU (7 mL, 46.8 mmol, 4 eq) in 60 mL of NMP was magnetically stined at 120 °C in a sealed tube over a period of 16 h. The reaction was concentrated in vacuo and the resulting residue diluted with 100 mL of dichloromethane. The organic layer was washed with water(6 x 75 mL) and then brine (2 x 75 mL), dried over magnesium sulfate, and concentrated in vacuo. Flash chromatography (50:50 EtOAc:Hex) gave methyl 4-{[(2-chloro-6,7-dimethoxy-4- quinolinyι)amino]methyl}cyclohexanecarboxylate as a yellow oil, which was diluted with 50 mL dichloromethane. The organic layer was washed with water (6 x 50 mL) and then brine (2 x 50 mL), dried over magnesium sulfate, and concentrated in vacuo to give 2.1 g of methyl 4-{[(2-chloro-6,7-dimethoxy-4-quinolinyl)amino]methyl}cyclohexane carboxylate as a off-white solid (46%).
Step 3. 4-(4-Morpholinyl)phenylamine (0.89 g, 5 mmol, 20 eq) and methyl 4-{[(2-chloro- 6,7-dimethoxy-4-quinolinyl)amino]methyl}cyclohexanecarboxylate (100 mg, 0.25 mmol, 1 eq) were magnetically stined at 140 °C in a sealed tube over a period of 16 h. Preparatory HPLC1 yielded 4 mg of pure methyl 4-{[(6,7-dimethoxy-2-{[4-(4- morpholinyl)phenyl]amino}-4-quinolinyl)amino]methyl} cyclohexanecarboxylate. (3%). H NMR (Methanol-d4) 7.54 (s, IH), 7.25 (d, J= 9Hz, 2H), 7.13 (s, IH), 7.10 (d, J= 9Hz, 2H), 5.74 (s, IH), 3.94 (s, 3H), 3.93 (s, 3H), 3.86 (t, J= 4.9Hz, 4H), 3.65 (s, 3H), 3.20-3.16 (m, 6 H), 2.38-2.28 (m, IH), 2.05-2.00 (m, 2H), 1.91-1.82 (m, 2H), 1.78-1.66 (m, IH), 1.49-1.34 (m, 2H), 1.16-1.0 (m, 2H); LC-MS (ES) 535.6 (M+H)+; TLC (5:95 MeOH/CH2Cl2) Rf = 0.17.
Examples 24 - 345 listed in the tables below were synthesized by the preparative methods described above or by using other known synthetic techniques such as those described by D. J. Brown, Fused Pyrimidines (part 1. - Quinazolines), by W. L. F. Amarego, publ. by New York Interscience, (1967); D. J. Brown, Quinazolines (Supplement I), publ. by John Wiley & Sons, (1996); Vol. 32, Quinolines (Part I), edited by Gurnos Jones, Interscience (a division of John Wiley & Sons), (1977), (Part II - 1982), (Part III - 1990), each of which is incorporated in its entirety by reference (Each of the references are part of the Monograph series entitled "The Chemistry of Heterocyclic Compounds", Monograph editors: Weissberger and Taylor).
Table 1 shows Examples 24 - 237 which are various embodiments of the described compounds wherein R2 = Cl. Table 2 shows Examples 238 - 307 which are various embodiments of the described compounds when Rt = R2 = -OCH3.
Table 3 shows Examples 308 - 346 which are various other embodiments of the described invention.
Table 4 shows the accompanying analytical data for Examples 308 - 346 from Table 3.
O σ
CD
Figure imgf000103_0001
Figure imgf000103_0002
Figure imgf000104_0001
o ω
Figure imgf000105_0001
Figure imgf000106_0001
LO O
Figure imgf000107_0001
O o
Figure imgf000108_0001
I*- o
Figure imgf000109_0001
00 o
Figure imgf000110_0001
CD O
Figure imgf000111_0001
Figure imgf000112_0001
Figure imgf000113_0001
CN
Figure imgf000114_0001
CO
Figure imgf000115_0001
Figure imgf000116_0001
LO
O
Figure imgf000118_0001
Figure imgf000119_0001
CO
Figure imgf000120_0001
CD
Figure imgf000121_0001
Figure imgf000122_0001
CN
Figure imgf000123_0001
Figure imgf000125_0001
Figure imgf000126_0001
Figure imgf000126_0002
Figure imgf000127_0001
Figure imgf000128_0001
CN
Figure imgf000129_0001
00 CN
Figure imgf000130_0001
Figure imgf000131_0001
o
CO
Figure imgf000132_0001
Figure imgf000133_0001
CN O
Figure imgf000134_0001
Figure imgf000135_0001
Figure imgf000136_0001
Figure imgf000137_0001
CO CO
Figure imgf000138_0001
r-~ co
Figure imgf000139_0001
Figure imgf000140_0001
CD CO
Figure imgf000141_0001
Figure imgf000142_0001
Figure imgf000143_0001
CN
Figure imgf000144_0001
Figure imgf000145_0001
Figure imgf000146_0001
Figure imgf000147_0001
Figure imgf000148_0001
I--
^f
Figure imgf000149_0001
Figure imgf000150_0001
J) -sf
Figure imgf000151_0001
Figure imgf000152_0001
Figure imgf000153_0001
Figure imgf000154_0001
Figure imgf000155_0001
Figure imgf000156_0001
LO LO
Figure imgf000157_0001
Figure imgf000158_0001
Figure imgf000159_0001
Figure imgf000160_0001
CJ) LO
Figure imgf000161_0001
o
CD
Figure imgf000162_0001
CD
Figure imgf000163_0001
Figure imgf000164_0001
CO CD
Figure imgf000165_0001
-sf
CO
Figure imgf000166_0001
LO CD
Figure imgf000167_0001
CD CD
Figure imgf000168_0001
Figure imgf000169_0001
CO CO
Figure imgf000170_0001
CD CD
Figure imgf000171_0001
Figure imgf000172_0001
Figure imgf000173_0001
Figure imgf000174_0001
Figure imgf000175_0001
Figure imgf000176_0001
Figure imgf000177_0001
Table 2. Dimethoxy Quinazolines
Figure imgf000178_0001
Figure imgf000179_0001
Figure imgf000179_0002
Figure imgf000180_0001
Figure imgf000180_0002
Figure imgf000181_0001
Figure imgf000181_0002
Figure imgf000182_0001
Figure imgf000182_0002
Figure imgf000183_0001
Figure imgf000184_0001
Figure imgf000184_0002
Figure imgf000185_0001
Figure imgf000186_0001
Figure imgf000186_0002
Figure imgf000187_0001
Figure imgf000188_0001
Figure imgf000189_0001
Figure imgf000190_0001
Figure imgf000191_0001
Figure imgf000192_0001
Figure imgf000193_0001
Figure imgf000194_0001
Figure imgf000195_0001
Figure imgf000196_0001
Figure imgf000197_0001
Figure imgf000198_0001
Figure imgf000199_0001
Figure imgf000199_0002
Figure imgf000200_0001
Figure imgf000201_0001
Table 3. Miscellaneous Quinazolines and Quinolines
Figure imgf000202_0001
Figure imgf000203_0001
Figure imgf000204_0001
Figure imgf000205_0001
Figure imgf000206_0001
Figure imgf000207_0001
Figure imgf000208_0001
Figure imgf000209_0001
Figure imgf000210_0001
Table 4. Analytical Data for Table 3 Examples
Figure imgf000211_0001
Figure imgf000212_0001
Description of Inhibiting Prolyl Peptidase, Inducing Apoptosis and Treatment of Cancer
Apoptosis (programmed cell death) is an essential process in the development and maintenance of homeostasis in an organism (1). The growth fraction of a tumor is governed by the rate of cellular division as well as the rate of cell death: if the rate of division exceeds that of cell death, then net tumor expansion occurs. Importantly, net growth rates of tumors do not generally correlate directly with the rate of cell division within the tumor, as assessed by the abundance of mitotic figures. Hence, aberrant apoptotic rate plays an important role in tumor growth and expansion (2, 3).
Studies have demonstrated that cells transfected with either myc or ras oncogenes exhibit altered proliferation and apoptotic rates (A, 5). Transfectant cell lines that displayed elevated rates of both cell division and apoptosis lead to established tumors with reduced efficiency, compared to transfectant lines that displayed an elevated rate of cell division and reduced rate of apoptosis. Moreover, tumors with comparable mitotic indices exhibit radically different net growth rates depending on whether the basal apoptotic rates are low (yielding high tumor growth rates) or high (yielding low tumor growth rates). For example, low apoptotic rates are thought to drive the observed net growth rates observed in prostate cancer (6). Hence, targets that regulate apoptotic pathways in tumor cells should provide important points for novel therapeutic intervention and, should lead to an improved therapeutic effect (7).
Proteases are attractive cancer drug targets since they are known to regulate apoptotic signal transduction (8, 9). For example, work on apoptosis initiated by specific inhibitors of the proteasome complex has been reported in the literature, where lactacystin and other proteasome inhibitors are shown to cause apoptosis in a number of cell lines (10, 11).
Recent publications have identified prolylpeptidase (QPP) as an intracellular protease involved in the repression of apoptosis and, as such, prolylpeptidase is thought to be an anti- apoptotic factor (12, 13). Prolylpeptidase is a serine protease that is irreversibly inactivated by diispropyl-fluorophosphate (DFP) through covalent modification of Serl54 (12) and unpublished data. It is the only known human serine protease that is fully active without additional post-translational removal of inhibitory peptide. In addition, the enzyme is localized to novel non-lysosomal cytosolic vesicles (14). Recombinant prolylpeptidase as well as prolylpeptidase purified from natural sources are active as dimeric proteins (106 kDa), based on size exclusion chromatography, although the gene encodes a putative enzyme with a predicted mass of 58 kDa (15).
Active prolylpeptidase has been identified in a number of solid tumor cell lines of different histological types including those from colon (HCT116 and DLD1), prostate (PC3), and breast (MDA-MB-435). In addition, expression data for prolylpeptidase mRNA shows a very limited distribution across adult human tissues, with highest levels observed in the testis, and moderate levels in prostate, skeletal muscle and brain. Increased expression of prolylpeptidase mRNA in human tumor specimens and the published biological data on the enzyme suggest that prolylpeptidase plays an important role in tumor cell growth or survival. In summary, these data suggest that selective inhibition of prolylpeptidase activity in tumor cells could lead to increased apoptotic rates and growth inhibition.
Described below are the results of prolylpeptidase inhibition assays and apoptosis induction assays which show the effect of the applicants described compounds. The prolylpeptidase enzyme used in the prolylpeptidase assay protocol cited below was described by Kapeller-Libermann et al. (U.S. Serial No. 09/345,469, the contents of which is hereby incorporated by reference; see also WO 01/00812).
Prolylpeptidase Assay Protocol
Test compounds were diluted serially 1 :5 in 5% DMSO/95% water and 5 μL was added to give 100 μL as a final volume to a well containing prolylpeptidase enzyme in buffer. Drug had a final concentration ranging from 10 μM to 0.12 μM. The Ala-Pro-AFC dipeptide substrate (AFC is 7-amino-4-trifluoro-methylcoumarin) in MTEN buffer was used at a final concentration of 200 μL and the reaction was initiated with 10 nM final concentration of recombinant prolylpeptidase. The reaction was allowed to proceed for 20 min at room temperature and quenched with 20 μL of 1 M Glycine-HCl pH 2.5. The 96 well plates were read as an endpoint assay at an excitation of 400 nm and emission of 505 nin. The final DMSO concentration was 0.25% in the assay. Ala-Pro-AFC is a dipeptide substrate with a conjugated AFC fluorophore at the C-terminus. Hydrolysis of the dipeptide substrate releases free AFC which is excited at 400 nm and emission of 505 nm in a spectrofluorometer.
Assay buffer is 50 mM MTEN Buffer pH 4.5 (50 mM MES, 25 mM Tris, 25 mM ethanolamine, 100 mM NaCl). Enzyme storage buffer was 50 mM Tris pH 7.0, 50% glycerol and was stored at -80 °C. It was diluted in assay buffer just prior to initiation of the assay.
All example compounds of formula (I) and (II) were tested in the above prolylpeptidase assay and were found to inhibit prolylpeptidase at or below a concentration of 10 μM, except for examples 245, 305 and 307.
Multiparameter Apoptosis Assay The induction of apoptosis by prolylpeptidase inhibitors was measured in whole cells using the multiparameter apoptosis assay (MPA). The assay uses the ArrayScan II (Cellomics Inc. Pittsburgh, PA) and the MPA application software to simultaneously measure three parameters of apoptosis 1.) nuclear fragmentation 2.) actin content and 3.) mitochondrial potential. Test compounds were dissolved in 100% DMSO and diluted serially 1:2 in DMEM with 10% fetal calf serum (final DMSO concentration 0.25%) and added to HCT- 116 cells growing in 96-well tissue culture plates. The final drug concentrations ranged from 25 μM to 0.39 μM. Cells were exposed to compound for either one or 24 hours depending on the experiment. The MPA assay was run according to the manufactures' protocol. The % of control for each compound concentration is determined using the formula; %Control = (((Experimental Units)-Blank Units)/Units from untreated Control- Blank Units)* 100. A curve is fitted and a value for Y=50% (IC50) using the formula Y=A+((B-A)/(1+(((B-E)(X/C)ΛD)/(E-A))). The average of the IC50 values for nuclear fragmentation, actin content and mitochondria index is used as the MPA IC50.
Certain exemplary compounds of formulae (I) and (II) were tested in the above apoptosis assay and were found to induce apoptosis at or below a concentration of 25 μM. Compounds 12, 24, 32, 44, 46, 48, 49, 54, 59, 61, 62, 64, 65, 67, 68, 70, 77, 79, 81, 98, 127, 130, 179, 186, 219, 222, 229, 235, 236, 242, 243, 245, 256, 281-283, 296-298, 300, 307, 318, 319 and 327-333 were found to induce apoptosis at or below a concentration of 10 μM.
References Cited (All references are hereby incorporated by reference)
1. Lowe, S. W. and Lin, A. W. Apoptosis in cancer, Carcinogenesis. 21: 485- 95., 2000.
2. Kaufmann, S. H. and Gores, G. J. Apoptosis in cancer: cause and cure, Bioessays. 22: 1007-17., 2000. 3. Eastman, A. and Rigas, J. R. Modulation of apoptosis signaling pathways and cell cycle regulation, Semin Oncol. 26: 7-16; discussion 41-2., 1999.
4. Breckenridge, D. G. and Shore, G. C. Regulation of apoptosis by E1A and Myc oncoproteins, Crit Rev Eukaryot Gene Expr. 10: 273-80., 2000.
5. Huang, P. and Oliff, A. Signaling pathways in apoptosis as potential targets for cancer therapy, Trends Cell Biol. 11: 343-8., 2001.
6. Colombel, M., Gil Diez, S., Radvanyi, F., Buttyan, R., Thiery, J. P., and Chopin, D. Apoptosis in prostate cancer. Molecular basis to study hormone refractory mechanisms, Ann N Y Acad Sci. 784: 63-9., 1996.
7. Penn, L. Z. Apoptosis modulators as cancer therapeutics, Curr Opin Investig Drugs. 2: 684-92., 2001.
8. Grimm, L. M. and Osborne, B. A. Apoptosis and the proteasome, Results Probl Cell Differ. 23: 209-28., 1999.
9. Masdehors, P., Merle-Beral, H., Magdelenat, H., and Delic, J. Ubiquitin- proteasome system and increased sensitivity of B-CLL lymphocytes to apoptotic death activation, Leuk Lymphoma. 38: 499-504., 2000.
10. Tani, E., Kitagawa, H., Ikemoto, H., and Matsumoto, T. Proteasome inhibitors induce Fas-mediated apoptosis by c-Myc accumulation and subsequent induction of FasL message in human glioma cells, FEBS Lett. 504: 53-8., 2001.
11. Naujokat, C, Sezer, O., Zinke, H., Leclere, A., Hauptmarm, S., and Possinger, K. Proteasome inhibitors induced caspase-dependent apoptosis and accumulation of p21WAFl/Cipl in human immature leukemic cells, Eur J Haematol. 65: 221-36., 2000. 12. Underwood, R., Chiravuri, M., Lee, H., Schmitz, T., Kabcenell, A. K., Yardley, K., and Huber, B. T. Sequence, purification, and cloning of an intracellular serine protease, quiescent cell proline dipeptidase, J Biol Chem. 274: 34053-8., 1999.
13. Chiravuri, M. and Huber, B. T. Aminodipeptidase inhibitor-induced cell death in quiescent lymphocytes: a review, Apoptosis. 5: 319-22., 2000.
14. Chiravuri, M., Agarraberes, F., Mathieu, S. L., Lee, H., and Huber, B. T. Vesicular localization and characterization of a novel post-proline-cleaving aminodipeptidase, quiescent cell proline dipeptidase, J Immunol. 165: 5695-102., 2000. 15. Chiravuri, M., Lee, H., Mathieu, S. L., and Huber, B. T. Homodimerization via a leucine zipper motif is required for enzymatic activity of quiescent cell proline dipeptidase, J Biol Chem. 275: 26994-9., 2000.
Other embodiments of the invention will be apparent to the skilled in the art from a consideration of this specification or practice of the invention disclosed herein. It is intended that the specification and examples be considered as exemplary only, with the scope and spirit of the invention being indicated by the following claims.

Claims

What is claimed is:
1. A compound of the formula:
Figure imgf000218_0001
(D CD wherein Z is CH orN; Y is O or S; X is OR5 orNR5R6;
Ri and R2 are independently selected from the group consisting of hydrogen, amino, cyano, halogen, hydroxy and nitro,
wherein Ri and R2 are both not hydrogen;
R3 is selected from the group consisting of:
(a) hydrogen, and
(b) -(Ci-C10) linear or branched alkyl;
R4 is -(CH2)y-R4 wherein:
R4' is selected from the group consisting of:
(a) -(Ci-C5) linear or branched alkyl optionally substituted with one to tliree substituents selected from the group consisting of:
(1) cyano,
(2) halogen,
(3) hydroxy,
(4) nitro, (5) -(Cι-C5) linear or branched alkyl optionally substituted by halogen,
(6) -(C1-C5) alkoxy-,
(7) -C(=O)R7,
(8) -C(=O)OR7,
(9) -C(=O)NR8R9,
(10) -S(=O)R10, and
(11) -S(O)2R10;
(b) -(C3-C8) cycloalkyl,
(c) -(Cβ-Cio) aryl, wherein (b) and (c) are optionally substituted with one to three substituents selected from the group consisting of
(1) amino,
(2) cyano,
(3) halogen,
(4) hydroxy,
(5) nitro,
(6) oxo,
(7) -(Ci-Cs) linear or branched alkyl optionally substituted by halogen or hydroxy,
(8) -(Ci-Cs) haloalkoxy-,
(9) -(CH2)nC(=O)R7,
(10) -(CH2)nC(=O)OR7,
(11) -(CH2)nC(=O)C(=O)-OR7,
(12) -(CH2)nC(=O)NR8R9,
(13) -S(=O)R10 ,
(14) -S(=O)2R10,
Figure imgf000219_0001
(16) a saturated or unsaturated four to six membered heterocyclic ring containing one to four heteroatoms selected from the from the group consisting of nitrogen, oxygen and sulfur, wherein said ring contains at least one carbon atom;
and
(d) a saturated or fully unsaturared four to six membered heterocyclic ring containing one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein said ring contains at least one carbon atom and wherein said ring is optionally substituted with one to three substituents selected from the group consisting of amino, cyano, halogen, hydroxy, nitro, oxo, (C1-C5)-alkoxy, (CH2)nC(=O)OR7, -(CH2)nC(=O)NR8R9, -S(=O)R10, -S(=O)2Rι0 and - (C Cs) linear or branched alkyl optionally substituted by halogen,
or
R3 and R4 form, together with the nitrogen to which they are attached, a saturated or fully unsaturated four to eight membered heterocyclic ring, wherein the nitrogen is the only heteroatom, which is optionally substituted with one to three substituents selected from the group consisting of amino, cyano, halogen, hydroxy, nitro, oxo, -
(Ci-C5) alkoxy-, phenyl, -C(=O)R7, -(CH2)„C(=O)OR7, -(CH2)nC(=O)NR8R9, - S(=O)Rio,
Figure imgf000220_0001
and -(Ci-Cs) linear or branched alkyl optionally substituted by halogen;
R5 has the formula -(CHRπ)ιn-A or -(CHRπ)p-O-A, where A is selected from the group consisting of:
(a) hydrogen,
(b) -(Ci-Cs) linear or branched alkyl optionally substituted with cyano, halogen, hydroxy, -(Ci-C5) alkoxy- or -NR8R9, (c) -(C3-Cs) cycloalkyl optionally substituted with cyano, halogen, hydroxy, -(CrC5) -alkyl, -(Ci-Cs) alkoxy- or -NR8R9, (d) -(C6-Cio) aryl optionally substituted with one to three substituents selected from the group consisting of: (1) cyano,
(2) halogen,
(3) hydroxy,
(4) nitro, (5) -NR8R9,
(6) -(Ci-C5) linear or branched alkyl optionally substituted with -NR8R9 or halogen,
(7) -(Ci-C5)-alkoxy wherein the alkyl is optionally substituted with -NR8R9 or halogen, (8) -(Cβ-Cio) aryl-(Cι-C5)-alkoxy-
(9) -(C6-Cιo) aryloxy optionally substituted with halogen,
(10) -(C6-Cio) -aryl optionally substituted with halogen,
(11) -CH2-(C6-Ci0)-aryl,
(12) -C(=O)R7, (13) -C(=O)OR7,
(14) -C(=O)NR8R9,
Figure imgf000221_0001
(16) -S(=O)2R10, and
(17) a saturated or fully unsaturated four to eight membered heterocyclic ring containing one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein said ring: (al7) contains at least one carbon atom, (b 17) is directly linked to the -(C6-Cio)-aryl or is linked to the -(C6-Cio)-aryl via an -O- linkage, and (cl7) is optionally substituted with -(Cι-C5)-alkyl,
(e) a saturated or fully unsaturated four to eight membered heterocyclic ring containing one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein said ring contains at least one carbon atom, and is optionally substituted with (1) -(Ci-C5)-alkyl optionally substituted by halogen,
(2) phenyl optionally substituted by halogen,
(3) -(Ci-C5)-alkoxy- wherein the alkyl is optionally substituted with halogen, (4) -(C6-C10) aryloxy wherein the aryl is optionally substituted with halogen, or (5) oxo, and (f) a fused bicyclo ring wherein one ring is a saturated or fully unsaturated five to six membered heterocyclic ring which contains one to three heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein said heterocyclic ring contains at least one carbon atom, and the other ring is a saturated or fully unsaturated five to eight membered carbocycle,
R6 is selected from the group consisting of:
(a) hydrogen, and
(b) -(Ci-Cs) linear or branched alkyl,
wherein R5 and R6 are not both hydrogen;
or
Rs and R6 form, together with the nitrogen to which they are attached, a saturated or fully unsaturated four to eight membered heterocyclic ring, which optionally contains one to three additional nitrogen atoms wherein said ring contains at least one carbon atom, and wherein said ring is optionally substituted with one to three substituents selected from the group consisting of: (a) amino, (b) cyano,
(c) halogen,
(d) hydroxy,
(e) nitro, (f) oxo,
(g) -(C1-C5) linear or branched alkyl optionally substituted by halogen or -(Ci-C5) -alkoxy,
(h) -(d-Cs) alkoxy, (i) -(d-Cs) alkoxy-(C1-C5)-alkyl,
0) -(C6-Cifj) aryl optionally substituted by halogen or -(Ci-C5)-alkyl,
(k) -(C1-Cs)-alkyl-phenyl optionally substituted by halogen or -(d-Cs)- alkyl,
Figure imgf000223_0001
(m) -(CH2)nC(=O)NR8R9,
(n) -(CH2)nNR8R9,
(0) -S(=O)R10,
(p) -S(=O)2R10, and
(q) -(CH2)n-Q, wherein Q is a saturated or fully unsaturated four to eight membered heterocyclic ring containing one to four nitrogens, wherein said ring contains at least one carbon atom;
wherein (R3 and R4) ≠ (R5 and R6) when:
(1) R3/R-|. or Rs/Rό contain an unsubstituted -(CH2)n-C6-C10-aryl substituent, or
(2) Rs^ or R5/Rfj foπn a heterocyclic ring;
R is selected from the group consisting of hydrogen, -(Ci-Cs) linear or branched alkyl, phenyl, -(Ci-C5)-alkyl-phenyl, and -(C3-C8) cycloalkyl which are optionally substituted with one to three substituents selected from the group consisting of halogen, oxo, -(Ci-C5) alkoxy, -C(=O)Rπ and -(Ci-C5) linear or branched alkyl optionally substituted by halogen;
R8 and R9 are independently selected from the group consisting of: (a) hydrogen,
(b) -(Ci-C5) linear or branched alkyl which is optionally substituted with a substituent selected from the group consisting of halogen and -(Ci- C5) alkoxy, (c) -(d-Cs) alkoxy,
(d) -(Cβ-Cio) aryl, and
(e) -(CH2)n-R wherein R is a five to six membered saturated or fully unsaturated heterocyclic ring containing one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein said ring contains at least one carbon atom, wherein (c)-(e) are optionally substituted with one to three substituents selected from the group consisting of halogen, -(d-C5) alkoxy, -C(=O)R and -(Ci-Cs) linear or branched alkyl optionally substituted by halogen,
or
R8 and R9 form, together with the nitrogen to which they are attached, a saturated or fully unsaturated four to eight membered heterocyclic ring, optionally containing one to three additional heteroatoms selected from the group consisting of nitrogen and oxygen wherein said ring contains at least one carbon atom and wherein said heterocyclic ring is optionally substituted with -(Ci-Cs) linear or branched alkyl;
R10 is hydrogen, -NR8R9, -ORπ, -(Ci-Cs) linear or branched alkyl, or phenyl;
each occurrence of Rπ is independently selected from the group consisting of hydrogen, -(d-C5) linear or branched alkyl and phenyl;
n, m and p are independently an integer from 0 - 3;
y is an integer from 0 - 2;
or a purified stereoisomer or stereoisomer mixture of said compound or a salt of said compound or purified stereoisomer or stereoisomer mixture thereof.
2. A compound of the formula:
Figure imgf000225_0001
(I) (π) wherein
Z is CH orN;
Y is O or S;
X is ORg orNRsRe;
Ri and R2 are hydrogen;
R3 is selected from the group consisting of:
(a) hydrogen, and
(b) -(Ci-C5) linear or branched alkyl;
R is -(CH2)yR4 , wherein
Figure imgf000225_0002
R4' is:
R5 has the formula -(CHRπ)m-A or -(CHRϋ)p-O-A, where A is selected from the group consisting of:
(a) hydrogen,
(b) -(d-C5) linear or branched alkyl optionally substituted with cyano, halogen, hydroxy, -(Ci-Cs) alkoxy or -NR8R9,
(c) -(C3-C8) cycloalkyl optionally substituted with cyano, halogen, hydroxy, -(d-C5)-alkyl, -(d-C5) alkoxy or -NR8R9,
(d) -(C6-C10) aryl optionally substituted with one to three substituents selected from the group consisting of: (1) cyano,
(2) halogen,
(3) hydroxy,
(4) nitro, (5) -NR8R9,
(6) -(C Cs)-alkyl optionally substituted with halogen,
(7) -(Ci-Cs)-alkoxy wherein the alkyl is optionally substituted -NR8R9 or halogen,
(8) -(C6-C10)-aryl-(C1-Cs)-alkoxy (9) -(C6-C10)-aryloxy optionally substituted with halogen
(10) -(C6-Cιo)-aryl optionally substituted with halogen,
(11) -CH2-(C6-Cιo)-aryl,
Figure imgf000226_0001
(13) -C(=O)OR7, (14) -C(=O)NR8R9,
(15) -S(=O)R10;
Figure imgf000226_0002
(17) a saturated or fully unsaturated four to eight membered heterocyclic ring containing one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein said ring: (al7) contains at least one carbon atom; (bl7) is directly linked to the -(C6-C10)-aryl or is linked to the -(C6-Cio)-aryl via an -O- linkage; and (cl7) is optionally substituted with -(d-C5)-alkyl,
-(CH2)„COOR7 or -(CH2)nCONR8R9,
and
(e) a saturated or fully unsaturated four to eight membered heterocyclic ring containing one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein said ring contains at least one carbon atom, and is optionally substituted with (1) -(Ci-C5)-alkyl optionally substituted by halogen,
(2) phenyl optionally substituted by halogen,
(3) -(Ci-Cs)-alkoxy- wherein the alkyl is optionally substituted with halogen, (4) -(d-C5)-aryloxy- wherein the aryl is optionally substituted with halogen, or (5) oxo;
R6 is selected from the group consisting of: (a) hydrogen, and
(b) -(Ci-Cs) linear or branched alkyl,
wherein R5 and R6 are not both hydrogen;
R5 and R6 form, together with the nitrogen to which they are attached, a saturated or fully unsaturated four to eight membered heterocyclic ring, optionally containing one to three additional heteroatoms selected from the group consisting of nitrogen and oxygen wherein said ring contains at least one carbon atom wherein said heterocyclic ring is optionally substituted with -(Ci-Cs) alkyl;
R7 is selected from the group consisting of hydrogen, -(Ci-Cs) linear or branched alkyl, phenyl, -(C1-Cs)-alkyl-phenyl, and -(C3-C8) cycloalkyl which are optionally substituted with one to three substituents selected from the group consisting of halogen, oxo, -(d-Cs) alkoxy-, -C(=O)R7 and -(Cι-C5) linear or branched alkyl optionally substituted by halogen;
R8 and R9 are independently selected from the group consisting of:
(a) hydrogen,
(b) -(d-C5) linear or branched alkyl, which is optionally substituted with a substituent selected from the group consisting of halogen and -(Ci- Cs) alkoxy,
(c) -(Ci-C5) alkoxy,
(d) -(C6-C10) aryl, and (e) -(CH )n-R wherein R is a saturated or fully unsaturated five to six membered heterocyclic ring containing one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein said ring contains at least one carbon atom, wherein (c)-(e) are optionally substituted with one to three substituents selected from the group consisting of halogen, -(d-d) alkoxy- and -(Cι-C5) linear or branched alkyl optionally substituted by halogen;
R10 is hydrogen, -NR8R9, -ORll5 -(d-C5) linear or branched alkyl, or phenyl;
each occurrence of Rn is independently selected from the group consisting of hydrogen, -(Ci-Cs) linear or branched alkyl and phenyl;
R12 is -Ri3, -OR13, or -NRι4R15;
R13 is
(a) hydrogen,
(b) -(Ci-C5) linear or branched alkyl optionally substituted with halogen, or (c) phenyl optionally substituted with halogen;
R14 and R15 are independently selected from the group consisting of:
(a) hydrogen,
(b) -(Ci-Cs) linear or branched alkyl optionally substituted with halogen, and
(c) phenyl optionally substituted with halogen;
n, m and p are independently an integer from 0 - 3;
y is an integer from 0 - 2; and
y + (m + p) equals an integer from 1 - 8; or a purified stereoisomer or stereoisomer mixture of said compound or a salt of said compound or purified stereoisomer or stereoisomer mixture thereof.
A compound of the fonnula:
Figure imgf000229_0001
ω (H)
Z is CH orN;
Y is O or S;
X is OR5 orNR5R6
Ri and R2 are independently selected from the group consisting of hydrogen and
-OCH3 wherein at least one of Rt and R is -OCH3;
R3 is hydrogen;
R4 is -(CH2)y-R l wherein:
R4 is selected from the group consisting of:
(a) -(Cl-C5) linear or branched alkyl which is optionally substituted with one 1 to three substituents selected from the group consisting of:
(1) cyano,
(2) halogen,
(3) hydroxy,
(4) nitro,
(5) -(Cι-C5) linear or branched alkyl optionally substituted by halogen,
(6) -(d-d) alkoxy,
(7) -C(=O)R7,
(8) -C(=O)OR7>
(9) -C(=O)NR8R9, (10) -S(=O)R10, and
Figure imgf000230_0001
( ) -(C3- C8) cycloalkyl,
(c) -(C6- C10) aryl, wherein (b) and (c) are optionally substituted with one to three substituents selected from the group consisting of
(1) amino,
(2) cyano,
(3) halogen,
(4) hydroxy,
(5) nitro,
(6) oxo,
(7) -(Ci-Cs) linear or branched haloalkyl
(8) -(Ci-Cs) haloalkoxy,
(9) -(CH2)nC(=O)R7,
(10) -(CH2)nC(=O)OR7,
(11) -(CH2)nC(=O)C(=O)-OR7
(12) -(CH2)„C(=O)NR8R9,
(13) -S(=O)R10 ,
(14) -S(=O)2R10;
(15) -C(=N-R10)-(C1-C5) alkyl, and
(16) a saturated or unsaturated four to six membered heterocyclic ring containing one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur wherein said ring contains at least one carbon atom,
and
(d) a saturated or fully unsaturated four to eight membered heterocyclic ring containing one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein said ring contains at least one carbon atom and wherein said ring is optionally substituted with one to three substituents selected from the group consisting of amino, cyano, halogen, hydroxy, nitro, oxo, -(Ci-Cs) alkoxy, -(CH2)nC(=O)OR7, -(CH2)nC(=O)NR8R9, -S(=O)Rιo, - S(=O)2R10 and -(Ci-Cs) linear or branched alkyl optionally substituted by halogen;
or
R3 and R form, together with the nitrogen to which they are attached, a saturated or fully unsaturated four to eight membered heterocyclic ring, wherein the nitrogen is the only heteroatom, which is optionally substituted with one to three substituents selected from the group consisting of amino, cyano, halogen, hydroxy, nitro, oxo, - (C6-C10)-aryl, -C(=O)R7, -(CH2)nC(=O)OR7, -(CH2)nC(=O)NR8R9, -S(=O)Rιo, - S(=O)2R10 and -(Ci-Cs) linear or branched alkyl optionally substituted by halogen;
R5 has the formula:
-(CH2)p-O-A where A is selected from the group consisting of:
(a) hydrogen,
(b) -(Ci-C5) linear or branched alkyl, optionally substituted with cyano, halogen, hydroxy, -(d-d) alkoxy- or -NR8R9, and
(c) -(C -C8) cycloalkyl, optionally substituted with cyano, halogen, hydroxy, -(Cι-d)-alkyl, -(d-C5) alkoxy or -NR8R9;
(d) -(C6-C10)-aryl, optionally substituted with one to three substituents selected from the group consisting of: (1) cyano,
(2) halogen,
(3) hydroxy,
(4) nitro,
(5) -NR8R9, (6) -(Ci-C5)-alkyl optionally substituted with halogen,
(7) (d-C5)-alkoxy wherein the alkyl is optionally substituted with -NR8R or halogen,
(8) -(C6-Cι0)-aryl-(d-Cs) alkoxy (9) -(C6-C10)-aryloxy optionally substituted with halogen,
(10) -(C6-C10)-aryl optionally substituted with halogen,
(11) -CH2-(C6-C10)-aryL
(12) -C(=O)R7> (13) -C(=O)OR7,
(14) -C(=O)NR8R9,
(15) -S(=O)Rιo;
(16) -S(=O)2R10; and
(17) a saturated or fully unsaturated four to eight membered heterocyclic ring containing one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein said ring: (al7) contains at least one carbon atom; (bl7) is directly linked to the -(C6-do)-aryl or is linked to the -(C6-Cιo)-aryl via an -O- linkage, and (cl7) is optionally substituted with -(Ci-Cs)-alkyl,
-(CH2)nCOOR7 or -(CH2)nCONR8R9,
(e) a saturated or fully unsaturated four to eight membered heterocyclic ring containing one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein said ring contains at least one carbon atom, and is optionally substituted with
(1) -(C1-C5) alkyl optionally substituted by halogen, (2) -(C6-C10)-aryl optionally substituted by halogen,
(3) -(d-d)-arkoxy wherein the alkyl is optionally substituted with halogen,
(4) -(Ci-C5)-aryloxy wherein the aryl is optionally substituted with halogen, or (5) oxo,
and (f) a fused bicyclo ring wherein one ring is a saturated or fully unsaturated five to six membered heterocyclic ring which contains one to three heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein said heterocyclic ring contains at least one carbon and the other ring is a saturated or fully unsaturated five to eight membered carbocycle,
or
-(CH2)m-A where A is selected from the group consisting of:
(a) hydrogen,
(b) -(C1-C5) linear or branched alkyl optionally substituted with cyano, halogen, hydroxy, -(Ci-C5) alkoxy or -NR8R9,
(c) -(C -C8) cycloalkyl optionally substituted with cyano, halogen, hydroxy, -(Cj-C5)-alkyl, -(d-d) alkoxy or -NR8R9,
(d) -(C6-C10) aryl, optionally substituted with one to three substituents selected from the group consisting of:
(1) cyano,
(2) halogen, (3) hydroxy,
(4) nitro,
(5) -NR8R9,
(6) -(C1-C5) alkyl optionally substituted with halogen,
(7) -(Ci-Cs) alkoxy wherein the alkyl is optionally substituted with -NR8R9 or halogen,
(8) -C(=O)R7j
(9) -C(=O)OR7,
(10) -C(=O)NR8R9,
(11) -S(=O)R10; (12) -S(=O)2R10; and
(13) a saturated or fully unsaturated four to eight membered heterocyclic ring containing one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein said ring: (al3) contains at least one carbon atom; (bl3) is directly linked to the -(C6-C10) aryl or is linked to the -(d-Cio) aryl via an -O- linkage, and (cl3) is optionally substituted with -(Ci-Cs)-alkyl,
-(CH2)nC(=O)OR7 or -(CH2)nC(=O)NR8R9,
(e) a saturated or fully unsaturated four to eight membered heterocyclic ring containing one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein said ring contains at least one carbon atom, and is optionally substituted with
(1) -(Cι-d)-alkyl optionally substituted by halogen, (2) phenyl optionally substituted by halogen,
(3) -(Ci-d)-aιkoxy wherein the alkyl is optionally substituted with halogen,
(4) -(d-d)-aryloxy wherein the aryl is optionally substituted with halogen, or (5) oxo,
and
(f) a fused bicyclo ring wherein one ring is a saturated or fully unsaturated five to six membered heterocyclic ring which contains one to three heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein said heterocyclic ring contains at least one carbon atom and the other ring is a saturated or fully unsaturated five to eight membered carbocycle;
is selected from the group consisting of:
(a) hydrogen, and
(b) -(d-d) linear or branched alkyl, wherein R5 and R6 are not both hydrogen;
or
R5 and R6 fonn, together with the nitrogen to which they are attached, a saturated or fully unsaturated four to eight membered heterocyclic ring, which optionally contains one to three additional heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur wherein said ring contains at least one carbon atom, and wherein said ring is optionally substituted with one to three substituents selected from the group consisting of:
(a) amino,
(b) cyano,
(c) halogen, (d) hydroxy,
(e) nitro,
(f) oxo,
(g) -(Cι-C5) linear or branched alkyl optionally substituted by halogen or -(d-d) alkoxy, (j) -(C6-C10)-aryl optionally substituted by halogen or -(Ci-Cs)-alkyl,
(k) -(Ci-Cs)-alkyl-phenyl optionally substituted by halogen or -(C1-C5) alkyl, (1) -(CH2)nCOOR7, (m) -(CH2)nCONR8R9, (n) -(CH2)nNR8R9,
(o) -S(=O)Rιo, (p) -S(=O)2R10, and (q) -(CH2)n-Q, wherein Q is:
(ql) a four to eight membered saturated or fully unsaturated heterocyclic ring containing one to four nitrogens, wherein said ring contains at least one carbon atom, or (q2) -C6-do-aryl optionally substituted with halogen or -(d-d) alkyl; wherein,
(i) R3 ≠ R4,
(ii) R5 ≠ R6, and (iii) (R3 and R4) ≠ (R5 and R6)
R7 is selected from the group consisting of hydrogen, -(d-C5) linear or branched alkyl, phenyl, -(Ci-C5)-alkyl-phenyl, and (C3-C10) cycloalkyl which are optionally substituted with one to three substituents selected from the group consisting of halogen, oxo, -(d-d) alkoxy, -(CH2)nC(=O)R1ι, -
(CH2)nC(=O)ORϋ, -(CH2)„C(=O)NR8R9, -S(=O)R10, -S(=O)2R10 and -(C1-C5) linear or branched alkyl optionally substituted by halogen;
R8 and R are independently selected from the group consisting of hydrogen, - (d-d) linear or branched alkyl, -(C1-C5) alkoxy or -(C6-Cιo) aryl which is optionally substituted with one to three substituents selected from the group consisting of halogen, -(Ci-Cs) alkoxy, -(Ci-Cs) alkylamino, (CH2)nC(=O)R7, -(CH2)nC(=O)OR7, -(CH2)nC(=O)NR8R9, -S(=O)R10, - S(=O)2Rιo and -(d-C5) linear or branched alkyl optionally substituted by halogen; or
R8 and R9 form, together with the nitrogen to which they are attached, a saturated or fully unsaturated, four to eight membered heterocyclic ring, wherein said ring has one to three additional heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur wherein said ring contains at least one carbon atom and wherein said heterocyclic ring is optionally substituted with -(C1-C5) linear or branched alkyl;
RiQ is hydrogen, -NR8R9, -ORπ, -(C1-C5) linear or branched alkyl, or phenyl;
Rϋ is hydrogen, -(Ci-Cs) linear or branched alkyl, or phenyl;
n, m and p are independently an integer from 0 - 3; and y is an integer from 0 - 2,
or a purified stereoisomer or stereoisomer mixture of said compound or a salt of said compound or purified stereoisomer or stereoisomer mixture thereof.
A pharmaceutical composition for the inhibition of prolyl peptidase or the induction of apoptosis which comprises a therapeutically effective amount of one or more compounds of any one of claims 1 - 3 and a pharmaceutically acceptable excipient.
The pharmaceutical composition of claim 4 which further comprises an additional agent selected from the group consisting of agent(s) which induce apoptosis, anti- proliferative agent(s) and mixtures thereof.
The pharmaceutical composition of claim 5 wherein the agent(s) which induce apoptosis is selected from the group consisting of A23187, N-Acetyl-L-cysteine, actinomycin D, tyrphostin A9, tyrphostin A25, AG 490, AG 1714, anandamide, anisomycin, aphidicolin, bafilomycin Al, berberine hemisulfate, betulinic acid, bleomycin sulfate, CAFdA, calphostin C, camptothecin, CAPE, chelerythrine chloride, 2-chloro-2'-deoxyadenosine, 2-chloro-2'-deoxyadenosine 5'-triphosphate, colcemid, cochicine, corticosterone, cycloheximide, cyclophosphamide monohydrate, cyclosporine A, daunorubicin hydrocloride, dexamethasone, 3,3'- diindolylmethane, dolastatin 15, doxorubicin hydrochloride, erbstatin analog, ET-18- OCH3, etoposide, etoposide phosphate, 5-fluorouracil, folimycin, forskolin, genistein, glycodeoxycholic acid sodium salt, H-7 dihydrochloride, H-89 dihydrochloride, harringtonine, homoharringtonine, 4-hydroxynonenal, 4- hydroxyphenylretinamide, hydroxyurea, indanocine, ionomycin free acid, ionomycin calcium salt, KN-93, methotrexate, mitomycin C, okadaic acid, oligomycin, p53 activator, paclitaxel, phorbol-12-myristate- 13 -acetate, (pivaloyloxy)methyl butyrate, puromycin dihydrochloride, 1-pynolidinecarbodithioic acid ammonium salt, quercetin dihydrate, rapamycin, SNAP, SNOG, sodium butyrate, sodium 4- phenylbutyrate, spermine tefrachloride, D-e7 t zro-sphingosine (free base; N-Acetyl-; N,N-dimethyl-; N-hexanoyl-; and N-octanoyl forms), stautosporine, sulfasalizine, sulindac, tamoxifen citrate, 4-hydroxy-(Z)-tamoxifen, thapsigargin, α-toxin, TRAIL, valinomycin, (±)-verapamil hydrochloride, veratridine and vitamin E succinate.
The phannaceutical composition of claim 5 wherein the anti-proliferative agent(s) is selected from the group consisting of asparaginase, bleomycin, carboplatin, cannustine, chlorambucil, cisplatin, colaspase, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin, doxorubicin (adriamycine), epirubicin, etoposide, 5-fluorouracil, hexamethylmelamine, hydroxyurea, ifosfamide, irinotecan, leucovorin, lomustine, mechlorethamine, 6-mercaptopurine, mesna, methotrexate, mitomycin C, mitoxantrone, prednisolone, prednisone, procarbazine, raloxifen, streptozocin, tamoxifen, thioguanine, topotecan, vinblastine, vincristine, vindesine, aminoglutethimide, L-asparaginase, azathioprine, 5-azacytidine cladribine, busulfan, diethylstilbestrol, 2', 2'-difluorodeoxycytidine, docetaxel, erythrohydroxynonyladenine, ethinyl estradiol, 5-fluorodeoxyuridine, 5- fluorodeoxyuridine monophosphate, fludarabine phosphate, fluoxymesterone, flutamide, hydroxyprogesterone caproate, idarubicin, interferon, medroxyprogesterone acetate, megestrol acetate, melphalan, mitotane, paclitaxel, pentostatin, N-phosphonoacetyl-L-aspartate (PALA), plicamycin, semustine, teniposide, testosterone propionate, thiotepa, trimethylmelamine, uridine, vinorelbine and epothilone.
A method of treatment wherein said treatment is selected from the group consisting of the inhibiting prolylpeptidase, inducing apoptosis and treating cancer, for a patient in need thereof, which comprises administering a therapeutically effective amount of a compound of the formula:
Figure imgf000238_0001
(la) (Da) wherein,
Z is CH or N;
Y is O or S;
X is OR5 orNR5R6;
Ri, Rι>, R2 and R2' are independently selected from the group consisting of hydrogen, amino, cyano, halogen, hydroxy, methoxy and nitro;
R3 is selected from the group consisting of: (a) hydrogen, and
(b) -d-Cio linear or branched alkyl,
R4 is -(CH2)y-R ' wherein:
R4' is selected from the group consisting of:
(a) -Ci-C 5 linear or branched alkyl which is optionally substituted with one to three substituents selected from the group consisting of:
(1) cyano,
(2) halogen,
(3) hydroxy,
(4) nitro,
(5) -Ci-Cs linear or branched alkyl optionally substituted by halogen,
(6) C1-C5 alkoxy-,
(7) -C(=O)R7,
(8) -C(=O)OR7,
(9) -C(=O)NR8R9,
(10) -S(=O)Rιo, and
(11) -S(=O)2R10;
(b) -C3-C8 cycloalkyl,
(c) -C6-C10 aryl, wherein (b) and (c) are optionally substituted with one to three substituents selected from the group consisting of (1) amino,
(2) cyano,
(3) halogen,
(4) hydroxy,
(5) nitro,
(6) oxo,
(7) -d-d linear or branched alkyl optionally substituted by halogen or hydroxy,
(8) d-d haloalkoxy-,
(9) -(CH2)nC(=O)R7,
(10) -(CH2)nC(=O)OR7,
(11) -(CH2)nC(=O)C(=O)-OR7,
(12) -(CH2)nC O)NR8R9,
(13) -S(=O)R10 ,
(14) -S(=O)2R10,
(15) -C(=N-R10)-C1-C5-alkyl, and
(16) a saturated or unsaturated four to six membered heterocyclic ring containing one to four heteroatoms selected from the group consisting of nifrogen, oxygen and sulfur, wherein said ring contains at least one carbon atom,
and
(d) a saturated or unsaturated four to six membered heterocyclic ring containing one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein said ring contains at least one carbon atom and wherein said ring is optionally substituted with one to three substituents selected from the group consisting of amino, cyano, halogen, hydroxy, nitro, oxo, d-d-alkoxy-, - (CH2)nC(=O)OR7, -(CH2)„C(=O)NR8R9, -S(=O)Rι0, -S(O)2R10 and - d-d linear or branched alkyl optionally substituted by halogen; R3 and R form, together with the nitrogen to which they are attached, a saturated or unsaturated, four to eight membered heterocyclic ring, wherein the nifrogen is the only heteroatom, which is optionally substituted with one to three substituents selected from the group consisting of amino, cyano, halogen, hydroxy, nitro, oxo, Ci-
Cs alkoxy-, phenyl, -C(=O)R7, -(CH2)nC(=O)OR7, -(CH2)nC(=O)NR8R9, -S(=O)R10, ■ S(=O)2R10 and -Ci-Cs linear or branched alkyl optionally substituted by halogen;
R5 has the formula (CHRn)m-A or (CHRπ)p-O-A, where A is selected from the group consisting of:
(a) hydrogen,
(b) -Ci-Cs linear or branched alkyl optionally substituted with cyano, halogen, hydroxy, Cι-C5 alkoxy- or -NR8R ,
(c) -C3-C8 cycloalkyl optionally substituted with cyano, halogen, hydroxy, -Ci-d-alkyl, Ci-Cs alkoxy- or -NR8R ,
(d) - -Cio aryl optionally substituted with one to three substituents selected from the group consisting of:
(1) cyano,
(2) halogen, (3) hydroxy,
(4) nitro,
(5) -NR8R9,
(6) -d-d linear or branched alkyl optionally substituted with -NR8R or halogen, (7) d-Cs-alkoxy- wherein the alkyl is optionally substituted with -NR8R9 or halogen,
(8) d-Cio-aryl-Ci-d-alkoxy-
(9) C6-C10-aryloxy- optionally substituted with halogen,
(10) -C6-Cio-aryl optionally substituted with halogen, (11) -CH2-C6-Cιo-aryl,
(12) -C(=O)R7,
(13) -C(=O)OR7,
(14) -C(=O)NR8R9, (15) -S(=O)R10,
(16) -S(=O)2R10, and
(17) a saturated or unsaturated four to eight membered heterocyclic ring containing one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein said ring: (a 17) contains at least one carbon atom; (bl7) is directly linked to the -C6-do-aryl or is linked to the -C6-Cio-aryl via an -O- linkage; and
(cl 7) is optionally substituted with -d-d-alkyl,
Figure imgf000242_0001
(e) a saturated or unsaturated four to eight membered heterocyclic ring containing one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein said ring contains at least one carbon atom, and is optionally substituted with
(1) Ci-d-alkyl optionally substituted by halogen,
(2) phenyl optionally substituted by halogen, (3) d-d-alkoxy- wherein the alkyl is optionally substituted with halogen,
(4) C6-C10-aryloxy- wherein the aryl is optionally substituted with halogen, or
(5) oxo;
(f) a fused bicyclo ring wherein one ring is a saturated or unsaturated five to six membered saturated or unsaturated heterocyclic ring which contains one to three heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein said heterocyclic ring contains at least one carbon atom, and the other ring is a saturated or unsaturated five to eight membered carbocyclic ring,
and (g) a fused bicyclo ring wherein each ring is independently a saturated or unsaturated five to eight membered carbocyclic ring;
R6 is selected from the group consisting of:
(a) hydrogen, and
(b) d-d linear or branched alkyl;
wherein R5 and R6 are not both hydrogen;
or
Rs and Rό form, together with the nitrogen to which they are attached, a saturated or unsaturated four to eight membered heterocyclic ring, which optionally contains one to three additional nitrogen atoms wherein said ring contains at least one carbon atom, and wherein said ring is optionally substituted with one to three substituents selected from the group consisting of:
(a) amino,
(b) cyano, (c) halogen,
(d) hydroxy,
(e) nitro,
(f) oxo,
(g) -Ci-Cs linear or branched alkyl optionally substituted by halogen or d-d-alkoxy-,
(h) Ci-Cs alkoxy-, (i) -Ci-Cs alkoxy-Ci-d-alkyl,
(j) -d-do-aryl optionally substituted by halogen or -d-d-alkyl, (k) -Ci-d-alkyl-phenyl optionally substituted by halogen or -d-d-alkyl, (1) -(CH2)nCOOR7,
(m) -(CH2)nCONR8R9, (n) -(CH2)nNR8R9, (o) -S(=O)R10,
Figure imgf000244_0001
(q) -(CH2)n-Q, wherein Q is:
(ql) a four to eight membered saturated or unsaturated heterocyclic ring containing one to four nitrogens, wherein said ring contains at least one carbon atom, or
(q2) -C6-Cιo-aryl optionally substituted with halogen or -d-d- alkyl;
R is selected from the group consisting of hydrogen, -d-d linear or branched alkyl, phenyl, -Ci-Cs-alkyl-phenyl, and -C3-C10 cycloalkyl which are optionally substituted with one to three substituents selected from the group consisting of halogen, oxo, Ci-Cs alkoxy-, -C(=O)R7 -(CH2)nC(=O)OR7, - (CH2)nC(=O)NR8R9, -S(=O)R10, -S(=O)2R10 and -d-C5 linear or branched alkyl optionally substituted by halogen;
R8 and R are independently selected from the group consisting of:
(a) hydrogen,
(b) -d-d linear or branched alkyl which is optionally substituted with a substituent selected from the group consisting of halogen and d-d alkoxy-,
(c) Ci-Cs alkoxy-,
(d) -C6-C10 aryl, and
(e) -(CH2)n-R wherein R is a saturated or unsaturated five to six membered heterocyclic ring containing one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein said ring contains at least one carbon atom, wherein (c)-(e) are optionally substituted with one to three substituents selected from the group consisting of halogen, -d-C5 alkylamino, d-C5 alkoxy-, -C(=O)R7, -(CH2)nC(=O)OR7, -(CH2)nC(=O)NR8R9, -S(=O)R10, - S(=O)2R10 and -d-C5 linear or branched alkyl optionally substituted by halogen,
or R8 and R9 form, together with the nitrogen to which they are attached, a saturated or unsaturated four to eight membered heterocyclic ring, optionally containing one to three additional heteroatoms selected from the group consisting of nitrogen and oxygen, wherein said ring contains at least one carbon atom and wherein said heterocyclic ring is optionally substituted with -d-d linear or branched alkyl;
Rio is hydrogen, -NR8R9, -ORll5 -Ci-Cs linear or branched alkyl, or phenyl;
each occurrence of Rϋ is independently selected from the group consisting of hydrogen, -Ci-Cs linear or branched alkyl and phenyl;
n, m and p are independently an integer from 0 - 3;
y is an integer from 0 - 2;
or a purified stereoisomer or stereoisomer mixture of said compound or a salt of said compound or purified stereoisomer or stereoisomer mixture thereof.
9. The method of inducing apoptosis of claim 8 wherein said composition further comprises an additional agent selected from the group consisting of prolylpeptidase inhibitors, apoptosis inducers, anti-proliferative agent(s) and mixtures thereof.
10. The method of claim 9 wherein the anti-proliferative agent(s) is selected from the group consisting of A23187, N- Acetyl-L-cysteine, actinomycin D, tyrphostin A9, tyrphostin A25, AG 490, AG 1714, anandamide, anisomycin, aphidicolin, bafilomycin Al, berberine hemisulfate, betulinic acid, bleomycin sulfate, CAFdA, calphostin C, camptothecin, CAPE, chelerythrine chloride, 2-chloro-2'- deoxyadenosine, 2-chloro-2'-deoxyadenosine 5'-triphosphate, colcemid, cochicine, corticosterone, cycloheximide, cyclophosphamide monohydrate, cyclosporine A, daunorubicin hydrocloride, dexamethasone, 3,3'-diindolylmethane, dolastatin 15, doxorubicin hydrochloride, erbstatin analog, ET-18-OCH3, etoposide, etoposide phosphate, 5-fluorouracil, folimycin, forskolin, genistein, glycodeoxycholic acid sodium salt, H-7 dihydrochloride, H-89 dihydrochloride, harringtonine, homoharringtonine, 4-hydroxynonenal, 4-hydroxyphenylretinamide, hydroxyurea, indanocine, ionomycin free acid, ionomycin calcium salt, KN-93, methotrexate, mitomycin C, okadaic acid, oligomycin, p53 activator, paclitaxel, phorbol-12- myristate- 13 -acetate, (pivaloyloxy)methyl butyrate, puromycin dihydrochloride, 1 - pyrrolidinecarbodithioic acid ammonium salt, quercetin dihydrate, rapamycin, SNAP, SNOG, sodium butyrate, sodium 4-phenylbutyrate, spermine tefrachloride, D- erytΛ/O-sphingosine (free base; N-Acetyl-; N,N-dimethyl-; N-hexanoyl-; and N- octanoyl forms), stautosporine, sulfasalizine, sulindac, tamoxifen citrate, 4-hydroxy- (Z)-tamoxifen, thapsigargin, α-toxin, TRAIL, valinomycin, (±)-verapamil hydrochloride, veratridine, vitamin E succinate and mixtures thereof.
11. The method of claim 9 wherein wherein the anti-proliferative agent(s) is selected from the group consisting of asparaginase, bleomycin, carboplatin, carmustine, chlorambucil, cisplatin, colaspase, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin, doxorubicin (adriamycine), epirubicin, etoposide, 5- fluorouracil, hexamethylmelamine, hydroxyurea, ifosfamide, irinotecan, leucovorin, lomustine, mechlorethamine, 6-mercaptopurine, mesna, methotrexate, mitomycin C, mitoxantrone, prednisolone, prednisone, procarbazine, raloxifen, streptozocin, tamoxifen, thioguanine, topotecan, vinblastine, vincristine, vindesine, aminoglutethimide, L-asparaginase, azathioprine, 5-azacytidine cladribine, busulfan, diethylstilbestrol, 2', 2'-difluorodeoxycytidine, docetaxel, erythrohydroxynonyladenine, ethinyl estradiol, 5-fluorodeόxyuridine, 5- fluorodeoxyuridine monophosphate, fludarabine phosphate, fluoxymesterone, flutamide, hydroxyprogesterone caproate, idarubicin, interferon, medroxyprogesterone acetate, megestrol acetate, melphalan, mitotane, paclitaxel, pentostatin, N-phosphonoacetyl-L-aspartate (PALA), plicamycin, semustine, teniposide, testosterone propionate, thiotepa, trimethylmelamine, uridine, vinorelbine and epothilone.
12. The method of claim 8 wherein said freatment is inhibiting prolylpeptidase.
13. The method of claim 8 wherein said treatment is inducing apoptosis.
4. The method of claim 8 wherein said treatment is the treatment of cancer.
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