WO2004014307A2 - Gal3 antagonists for the treatment of neuropathic pain - Google Patents

Gal3 antagonists for the treatment of neuropathic pain Download PDF

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Publication number
WO2004014307A2
WO2004014307A2 PCT/US2003/024869 US0324869W WO2004014307A2 WO 2004014307 A2 WO2004014307 A2 WO 2004014307A2 US 0324869 W US0324869 W US 0324869W WO 2004014307 A2 WO2004014307 A2 WO 2004014307A2
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branched
straight chained
alkyl
aryl
esi
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PCT/US2003/024869
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French (fr)
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WO2004014307A3 (en
Inventor
Thomas Blackburn
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Synaptic Pharmaceutical Corporation
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Priority to AU2003259074A priority Critical patent/AU2003259074A1/en
Publication of WO2004014307A2 publication Critical patent/WO2004014307A2/en
Publication of WO2004014307A3 publication Critical patent/WO2004014307A3/en

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    • H—ELECTRICITY
    • H04—ELECTRIC COMMUNICATION TECHNIQUE
    • H04M—TELEPHONIC COMMUNICATION
    • H04M3/00—Automatic or semi-automatic exchanges
    • H04M3/22—Arrangements for supervision, monitoring or testing
    • H04M3/2281—Call monitoring, e.g. for law enforcement purposes; Call tracing; Detection or prevention of malicious calls
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim

Definitions

  • This model monitors the development of allodynia and hyperalgesia and is considered by experts in the field to reflect the potential of analgesic agents to treat neuropathic pain (Fisher et al . , 1998; Fisher et al . , 2002). This model is widely used as it is reliable across laboratories, and is sensitive to the effects of some of the major classes of analgesic drugs.
  • the synthesis of novel pyrimidines ' which bind selectively to the cloned human GAL3 receptor, compared to other cloned human G-protein coupled receptors, as measured in in vitro assays is disclosed.
  • the synthesis of indolones which bind selectively to the cloned human GAL3 receptor, compared to other cloned human G-protein coupled receptors, as . measured in in vitro assays is disclosed.
  • the in vitro receptor assays described hereinafter were performed using various cultured cell lines, each transfected with and expressing only a single galanin- type receptor. From the binding information described hereinafter, it has unexpectedly been discovered that compounds which are specific for the human GAL3 receptor with a binding affinity greater than ten-fold higher than the binding affinity with which the compounds bind to a human GAL1 receptor are effective in animal models of pain which are predictive of efficacy in humans.
  • the GAL3 receptor antagonists which may be classified as neutral antagonists, inverse agonists or allosteric modulators, provide a novel method to treat neuropathic pain.
  • the present invention provides a method of treating a subject suffering from an abnormality which comprises administering to the ' subject an amount of compound effective to treat the subject's abnormality wherein the
  • W is H, -F, -Cl, -Br, -I, CN, methyl, ethyl, propyl, methoxy or ethoxy;
  • X is; NRnR.12;
  • Rn is H, straight chained or branched C ⁇ -C 7 alkyl, (CH 2 ) q -0- (CH 2 ) m -CH 3 , aryl, or aryl (C ! -C 6 ) alkyl ; wherein R 12 is straight chained or branched C ⁇ -C alkyl, (CH 2 ) q -0-(CH 2 ) m -CH 3 , or -(CH 2 ) B -Z;
  • R 13 is a bicyclic alkyl ring system, adamantyl, noradamantyl , C 3 -C 1 0 cycloalkyl, heteroaryl, aryl, aryl (C ⁇ -C 6 ) alkyl, Q ⁇ or Q 2 ;
  • aryl may be substituted with one or more C ⁇ -C 10 straight chained or branched alkyl, aryl, heteroaryl, or N(R 19 )-Z;
  • each J is independently O, S, C(R 22 ) 2 or NR 4 ;
  • R 4 is H; straight chained or branched C ⁇ -C 7 alkyl , mono f luoroalkyl or polyfluoroalkyl ; s traight chained or branched C 2 -C 7 alkenyl or alkynyl ; C 3 -C- cycloalkyl , C 5 -C 7 cycloalkenyl or aryl ;
  • Y is NR ⁇ R ⁇ 5 ;
  • R ⁇ is H, straight chained or branched C ⁇ -C 6 alkyl, (CH 2 ) q -0- (CH 2 ) m -CH 3 , C 3 -C 6 cycloalkyl, or (C(R 19 ) 2 ) m - Z;
  • R 15 is straight chained or branched C 3 -C 6 alkyl, (CH 2 ) q -0-(CH 2 ) m -CH3, C 3 -C 6 cycloalkyl, (C (R 19 ) 2 ) admir-N (R 16 ) 2 or (C(R i9 ) 2 )m-Z;
  • Ri ⁇ is straight chained or branched C ! -C 7 alkyl, straight chained or branched C ⁇ -C 7 monofluoroalkyl , straight chained or branched C:-C 7 polyfluoroalkyl, straight chained or branched C 2 -C 7 alkenyl, straight chained or branched C 2 -C 7 alkynyl, C 5 -C ⁇ cycloalkenyl , - (CH 2 ) 3l -Z, or (CH 2 ) q -0-(CH 2 ) m -CH 3 ;
  • each R ⁇ is independently H; -OR 2 ⁇ , -OCOR 2 ⁇ , COR 21 , -NCOR 2 ⁇ , -N(R 2X ) 2 , -CON(R 21 ) 2 , -COOR 21 , straight chained or branched C ⁇ -C 7 alkyl, straight chained or branched C ⁇ C 7 monofluoroalkyl, straight-.
  • R 13 is straight chained or branched C 1 -C 5 alkyl, - (CHsJ r -Z, or (CH 2 ) q -0-(CH 2 ) ⁇ -CH 3 ;
  • each 'R i9 is independently H, or straight chained or branched C ⁇ -C 6 alkyl
  • each R 20 is independently -H; straight chained or branched C ⁇ -C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl;
  • each R2 1 is independently -H; straight- chained or branched C ⁇ -C alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 -C 7 cycloalkyl, C 5 -C cycloalkenyl, aryl, or aryl (Ci- C 6 ) alkyl ;
  • each R 22 is independently H, F, Cl or Ci-C 4 straight chained or branched alkyl
  • each m is an integer from 0 to 4 inclusive ,-
  • n is an integer from 1 to 4 inclusive
  • p is an integer from 0 to 2 inclusive
  • 'q is an integer from 2 to 4 inclusive;
  • t is 1 or 2 ;
  • U is 0, -NR ⁇ 6 , S, C(R 17 ) 2 , or - S0 2 Ri6;
  • Z is C 3 -C ⁇ 0 cycloalkyl, C -C 7 cyclic ether, C 4 -C 7 cyclic thioether, aryl, or heteroaryl; or
  • the present invention provides a method of treating a subject suffering from an abnormality which comprises administering to the subject an amount of compound effective to -treat the subject's abnormality wherein the compound has the structure: X
  • X is NRn 11R ⁇ 12 ;
  • R is H, straight chained or branched C 1 -C7 alkyl, (CH 2 ) q -0- (CH 2 ) m -CH 3 , aryl or aryl (Ci-C € ) alkyl ;
  • R i2 is straight chained or branched C ⁇ . -C 7 alkyl, (CH 2 ) q -0-(CH 2 ) m -CH 3 , or -(CH 2 ) m -Z;
  • R 13 is a bicyclic alkyl ring system, aryl or aryl (Ci-C 6 ) alkyl ;
  • Y is NR 1 R 15 ;
  • R i4 is H, straight chained or branched Ci-C ⁇ alkyl, (CH 2 ) q -0- (CH 2 ) m -CH 3 , C 3 -C 6 cycloalkyl, or (C(R 19 ) 2 )m- Z;
  • R 15 is straight chained or branched C 3 -C 6 alkyl, (CH 2 ) ⁇ -0-(CH 2 ) m -CH 3 , C 3 -C 6 cycloalkyl, or (C (R 19 ) : ) m -Z ;
  • U is O, -NR ⁇ 6 , S, C(R 17 ] or -NSOoR 16 ;
  • Z is C3-C 10 cycloalkyl, aryl, or heteroaryl
  • Ri ⁇ is straight chained or branched C ⁇ -C .alkyl, straight chained or branched 1 -C7 monofluoroalkyl , straight chained or branched C ⁇ -C 7 polyfluoroalkyl, straight chained or branched C 2 -C 7 alkenyl, straight chained or branched C 2 -C 7 alkynyl, C 5 -C 7 cycloalkenyl, - (CH 2 ) m -Z, or (CH 2 ) q -0-(CH 2 ) m -CH 3 ; wherein each R ⁇ 7 is independently H; - ⁇ R 21 , -OCQR 2i , COR 21 , -NCOR 21 , -N(R 2 ⁇ ) 2 , -CON(R 21 ) 2 , -COOR21, straight chained or branched C ⁇ C 7 alkyl, straight chained or branched C 1 -C7 monofluor
  • R 3.8 is straight chained or branched Ci-C 6 alkyl, - ' (CH 2 ) m -Z, or (CH 2 ) q -0-(CH 2 ) m -CH 3 ;
  • each R ⁇ 9 is independently H, or straight chained or branched Ci-C 6 alkyl
  • each R 2 0 is independently -H; straight chained or branched C ⁇ -C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl;
  • each R 2i is independently -H; straight chained or branched C 1 -C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 -C7 cycloalkyl, C5-C7 cycloalkenyl, aryl or aryl (C ⁇ C 6 ) alkyl;
  • each m is an integer from 0 to 4 inclusive;
  • n is an integer from 1 to 4 inclusive; wherein p is an integer from 0 to 2 inclusive;
  • q is an integer from 2 to 4 inclusive
  • t is 1 or 2 ;
  • the present invention provides a method of treating a subject suffering from an abnormality which comprises administering to the subject an amount _ of compound effective to treat the subject's abnormality wherein the compound has the structure:
  • W is H, -F, -Cl, -Br, -I, CN,- 'methyl, ethyl, propyl, methoxy or ethoxy;
  • R ⁇ 3 is an aryl, adamantyl, noradamantyl, C 3 -C ⁇ 0 cycloalkyl, heteroaryl, Qi or Q 2 ;
  • aryl may be substituted with one or more C ⁇ -C 10 straight chained or branched alkyl, aryl, heteroaryl, or N(R ⁇ 9 )-Z;_
  • each J is independently O, S, C(R 22 ) 2 or NR wherein R 4 is -H ; straight chained or branched C1-C7 alkyl , monof luoroalkyl or polyfluoroalkyl ; straight chained or branched C 2 -C 7 alkenyl or alkynyl ; C3-C7 cycloalkyl , C 5 -C cycloalkenyl or aryl ;
  • Y is NR 14 R 15 ;
  • R i4 is H, straight chained or branched C ⁇ -C 6 alkyl, (CH 2 ) q -0- (CH 2 ) m -CH 3 , C 3 -C 6 cycloalkyl, or (C(R 19 ) 2 ) m - ; ' .
  • R15 is straight chained or branched C 3 -C 6 alkyl, (CH 2 ) q -0-(CH 2 ) m -CH3, C 3 -C 6 cycloalkyl, or (C (R 19 ) 2 ) m -Z;
  • U is O, -NR 16 , S, C(R ⁇ 7 ) 2 , or -NS0 2 R ⁇ 6 ;
  • ' is C3-C 10 cycloalkyl, aryl, or heteroaryl; wherein R 16 is straight chained or branched C ⁇ -C 7 alkyl, straight chained or branched C 1 -C7 monofluoroalkyl , straight chained or branched C 3. -C7 polyfluoroalkyl, straight chained or branched C 2 -C 7 alkenyl, straight chained or branched C 2 -C 7 alkynyl, C5-C7 cycloalkenyl, - (CH 2 ) m -Z, or (CH 2 ) q -0-(CH 2 ) ra -CH 3 ;
  • each R ⁇ is independently H; -OR 2 ⁇ , -OCOR 21 , COR 2 ⁇ , -NC0R 2 ⁇ , -N(R 2 ⁇ ) 2 , -C0N(R 21 ) 2 , -C00R 2 ⁇ , straight chained or branched C 1 -C7 alkyl, straight chained or branched C 1 -C 7 monofluoroalkyl , straight chained or branched C 1 -C 7 ⁇ polyfluoroalkyl, straight chained or branched C 2 -C 7 alkenyl, straight chained or branched C 2 -C 7 alkynyl, C 5 -C 7 cycloalkenyl, -(CH 2 ) m -Z, or (CH 2 ) n -0- (CH 2 ) m - CH 3 ;
  • R IB is straight chained or branched C ⁇ -C 6 alkyl, - (CH 2 ) m -Z, or (CH 2 ) q -0-(CH 2 ) m -CH 3 ;
  • each Rig is independently H, or straight chained or branched Ci-Cg alkyl
  • each R 2 0 is independently -H; straight chained or branched C ⁇ -C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl;
  • each R 2i is independently -H; straight chained or branched C 1 -C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 -C- 7 cycloalkyl, C 5 -C7 cycloalkenyl, aryl or aryl (C x - C 6 ) alkyl;
  • each R 2 is independently H, F, Cl or C 1 -C 4 straight chained or branched alkyl
  • each m is an integer from 0 to 4 inclusive;
  • n is an integer from 1 to 4 inclusive
  • p is an integer from 0 to 2 inclusive
  • q is an integer from 2 to 4 inclusive
  • t is 1 or 2;
  • the present invention provides a method of treating a subject suffering from an abnormality which comprises administering to the subject an amount of compound effective to treat the subject's abnormality wherein the compound has the structure:
  • R 13 is a bicyclic alkyl ring system, aryl or aryl (d-C 6 ) alkyl;
  • R i4 is H, straight chained or branched C ⁇ -C 6 alkyl, (CH 2 ) q -0- (CH 2 ) m -CH 3 , C—Cs cycloalkyl, or (C(R 19 ) 2 )m- Z;
  • R X5 is (C (R 19 ) 2 ) m -N(R ⁇ 6 ) 2 ;
  • Z is C 3 -C 10 cycloalkyl, aryl, or heteroaryl
  • R 16 is straight chained or branched C 1 -C alkyl, straight chained or branched C ⁇ -C 7 monofluoroalkyl, straight chained or branched C 1 -C7 polyfluoroalkyl, straight chained or branched C 2 -C 7 alkenyl, straight chained or branched C 2 -C 7 alkynyl, C 5 -C7 cycloalkenyl, - (CH 2 ) m -Z, or (CH 2 ) g -0-(CH 2 ) m -CH 3 ;
  • each R 1 7 is independently H; -OR 2 ⁇ , -OCOR 2 ⁇ , COR21, -NCOR21, -N(R 21 ) 2 , -CON(R 2i ) 2 , -COOR21, straight chained or branched C 1 -C 7 alkyl, straight chained or branched C ⁇ -C 7 monofluoroalkyl, straight chained or branched C ⁇ -C 7 polyfluoroalkyl, straight chained or branched C 2 -C 7 alkenyl, straight chained or branched C 2 -C 7 alkynyl, C 5 -C 7 cycloalkenyl, -(CH 2 ) m -Z, or (CH 2 ) n -0- (CH 2 ) m - CH 3 ; .
  • each R ⁇ 9 is independently H, or straight chained or branched Ci-C ⁇ alkyl
  • each R 2 ⁇ is independently -H; straight chained or branched d-C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl;
  • each m is an integer from 0 to 4 inclusive;
  • n is an integer from 1 to 4 inclusive
  • the invention provides a method of treating a subject suffering from an abnormality which comprises administering to the subject an amount of compound effective to treat the subject's abnormality wherein the compound has the structure:
  • each of Y 1; Y 2 , Y 3 , and Y 4 is independently - H; ' straight chained or branched C 1 -C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C7 alkenyl or alkynyl; C 3 -C7 cycloalkyl, or C 5 -C 7 cycloalkenyl; -F, -Cl, -Br, or -I; -N0 2 ; -N 3 ; -CN; -OR 4 , -SR 4/ -OCOR 4 , -COR 4 , -NCOR 4 , -N(R 4 ) 2 , -C0N(R 4 ) 2 , or -COOR 4 ; aryl or heteroaryl; or any two of Y 1( Y 2 , Y 3 and Y 4 present on adjacent carbon atoms can constitute
  • each R 4 is independently -H; straight chained or branched C 1 -C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched d-d alkenyl or alkynyl; C 3 -C7 cycloalkyl, C 5 -C7 cycloalkenyl, aryl or aryl (Ci-d) alky ⁇ ;
  • A is A', Q 3 , Q 4 , Q 5 ⁇ straight chained or branched C 1 -C 7 alkyl, aryl, heteroaryl, aryl (C x - C 6 ) alkyl, heteroaryl (d-C 6 ) alkyl, aryl substituted with an aryl or heteroaryl, heteroaryl substituted with an aryl or heteroaryl; or (CHR 1 7) - (CHR 17 ) n -Z ; wherein A' is
  • Ri and R 2 are each independently H , s traight chained or branched C ⁇ C 7 alkyl , -F , -Cl , -Br , -I , - N0 2 , or -CN ;
  • R 3 is H, straight chained or branched d-C 7 alkyl, -F, -Cl, -Br, -I, -N0 2 , -CN, -0R 6 , aryl or heteroaryl;
  • R 5 is straight chained or branched C ⁇ -C 7 alkyl, -N(R ) 2 , -0R 6 or aryl;
  • R 5 is straight chained or branched C ⁇ -C 7 alkyl or aryl
  • each R ⁇ 7 is independently H; straight chained or branched d-C 7 alkyl, straight chained or branched C ⁇ -C 7 monofluoroalkyl , straight chained or branched d-C 7 polyfluoroalkyl, straight chained or branched C 2 -C alkenyl, straight chained or branched C 2 -C 7 alkynyl, C 5 -C 7 cycloalkenyl, -(CH 2 ) m -Z, or (CH 2 ) n -0-(CH 2 ) m -CH 3 ;
  • each R 20 is independently -H; straight chained or branched C 1 -C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -d alkenyl or alkynyl; C 3 -C7 cycloalkyl or C5-C7 cycloalkenyl; -F, -Cl, -Br, or -I; -N0 2 ; -N 3 ; -CN; - 0R 2 ⁇ , -OCOR 21 , -COR 21 , -NCOR21, -N(R 2 ⁇ ) 2 , -C0N(R 2i ) 2 , or -COOR 2 ⁇ ; aryl or heteroaryl; or two R 0 groups present on adjacent carbon atoms can join together to form a methylenedioxy group;
  • each R 2i is independently -H; straight chained or branched C 1 -C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 -C 7 cycloalkyl, C 5 -C 7 cycloalkenyl, aryl or aryl (Ci- ) alkyl ;
  • each m is an integer from 0 to 4 inclusive;
  • n is an integer from 1 to 4 inclusive
  • each p is an integer from 0 to 2 inclusive;
  • U is O, -NR ⁇ 6 , S, C(R ⁇ 7 ) 2 / or -NS0Ri6,-
  • Z is C 3 -C 10 cycloalkyl, C 4 -C 7 cyclic ether, C -C 7 cyclic thioether, aryl, or heteroaryl;
  • R i6 is straight chained or branched C 1 -C 7 alkyl, straight chained or branched C 1 -C 7 monofluoroalkyl, straight chained or ' branched C ⁇ -C 7 polyfluoroalkyl, straight chained or branched C z -C- alkenyl, straight chained or branched C : -d alkynyl, C 5 -C7 cycloalkenyl, -(CH 2 ) m -Z, or (CH 2 ) q -0- (CH 2 ) m -CH 3 ;
  • q is an integer from 2 to 4 inclusive
  • B is aryl, heteroaryl, aryl substituted with an aryl or heteroaryl, heteroaryl substituted with an aryl or heteroaryl, tricyclic heteroaryl or Qs ; provided however, if B is aryl or heteroaryl the carbon atom or carbon atoms ortho to the nitrogen atom of the i ine bond may only be substituted with one or more of the following -F, -Cl, -Br, -I, -CN, methyl, ethyl or methoxy;
  • a tricyclic heteroaryl is a fused three member aromatic system in which one or more of the rings is heteroaryl; carbazole; or acridine;
  • each R 22 is independently H, F, Cl, or straight chained or branched d-C 4 alkyl
  • the invention provides a method of treating a subject suffering from an abnormality which comprises administering to the subject an amount of compound effective to treat the subject's abnormality wherein the compound has the structure:
  • each of Y x , Y 2 , Y 3 , and Y 4 is independently '- H; straight chained or branched C ⁇ -C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straigh chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 -C 7 cycloalkyl, or C 5 -C 7 cycloalkenyl; -F, -Cl, -Br, or -I; -N0 2 ; ⁇ N 3 ; -CN; -0R 4 , -SR 4 , -0C0R 4 , -C0R 4 , -NCOR 4 , -N(R 4 ) 2 , -CON(R 4 ) 2 , or -COOR 4 ; aryl or heteroaryl; or any two of Y x , Y 2 , Y 3 and Y 4 present on adjacent
  • each R is independently rH; straight chained or branched C ⁇ -C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 -C 7 cycloalkyl, C 5 -C cycloalkenyl, aryl or aryl (d-C 6 ) alkyl;
  • A is A' , straight chained or branched C ⁇ -C 7 alkyl, aryl, heteroaryl, aryl (C ⁇ -C 6 ) ' alkyl or heteroaryl (C ⁇ -C 6 ) alkyl;
  • R L and R 2 are each independently H, straight chained or branched C 1 -C 7 alkyl, -F, -Cl, -Br, -I, - N0 2 , or -CN;
  • R 3 is H, straight chained or branched C 1 -C7 alkyl, -F, -Cl, -Br, -I, -N0 2 , -CN, -OR 6 aryl or heteroaryl;
  • R 5 is straight chained or branched C ⁇ -C 7 alkyl, -N(R 4 ) 2 , -0R 6 or aryl;
  • R 6 is straight chained or branched C 1 -C 7 alkyl or aryl
  • B is aryl, or heteroaryl; provided however, if B is aryl or heteroaryl the carbon atom or carbon atoms ortho to the nitrogen atom of the i ine bond may only be substituted with one or more of the following -F, -Cl, -Br, -I, -CN, methyl, ethyl or methoxy;
  • n is an integer from 1 to 4 inclusive;
  • the invention provides a method of treating a subject suffering from an abnormality which comprises administering to the subject an amount of compound effective to treat the subject's abnormality wherein the
  • each of Y l r Y 2 , Y 3 , and Y 4 is independently - H; straight chained or branched C ⁇ -C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched - alkenyl or alkynyl; C 3 -C 7 cycloalkyl, or C 5 -C7 cycloalkenyl; -F, -Cl, -Br, or -I; -N0 2 ; -N 3 ; -CN; -0R 4 , -SR , -OCOR 4 , -C0R 4 , -NC0R 4 , -N(R 4 ) 2 , -CON(R 4 ) 2 , or -C00R ; aryl or heteroaryl; or any two of Y l t Y 2 , Y 3 and Y present on adjacent carbon atoms can constitute a methyl
  • each R 4 is independently -H; straight chained or branched C 1 -C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 -C 7 cycloalkyl, C 5 -C 7 cycloalkenyl, aryl or aryl (C ⁇ -C 6 ) alkyl ;
  • A is A' , straight chained or branched C ⁇ -C 7 alkyl, aryl, heteroaryl, aryl (d- ) alkyl or heteroaryl (C ⁇ -C 6 )-alkyl ;
  • B is aryl substituted with an aryl or heteroaryl, heteroaryl substituted with an aryl or heteroaryl, tricyclic heteroaryl or Q 6 ;
  • a tricyclic heteroaryl is a fused three ring aromatic system in which one or more of the rings is heteroaryl; carbazole; or acridine;
  • n is an integer from 1 to 4 inclusive;
  • each R 22 is independently H, F, Cl_, br straight chained or branched Ci- alkyl
  • the invention provides a method of treating a subject suffering from an abnormality which comprises administering to the subject an amount of compound effective to treat the subject's abnormalitv wherein the
  • each of Yi, Y 2 , Y 3 , and Y is independently H; straight chained or branched" d ⁇ C ⁇ alkyl, monofluoroalkyl ' • or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 -C 7 cycloalkyl, or C 5 -C7 cycloalkenyl; -F, -Cl, -Br, or .-I; -N0 2 ; -N 3 ; -CN; -0R 4 , -SR 4 , -0C0R 4 , -C0R 4 , -NCOR 4 , -N(R 4 ) 2 , -CON(R 4 ) 2 , or -C00R 4 ; aryl or heteroaryl; or any two of Yi, Y 2 , Y 3 and Y 4 present on adjacent carbon atoms can constitute, ary
  • each R 4 is independently -H; straight chained or branched C 1 -C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 ⁇ C 7 alkenyl or alkynyl; C 3 -C 7 cycloalkyl, C 5 -C7 cycloalkenyl, aryl or aryl (C ⁇ -C 6 ) alkyl;
  • A is Q 3 , Q 4 , Q 5 , aryl substituted with an aryl or heteroaryl, heteroaryl substituted with an aryl or heteroaryl, or (CHR 1 7) - (CHR 1 7) n -Z;
  • each R i7 is independently H; straight chained or branched C ⁇ -C 7 alkyl, straight chained or branched C ⁇ d monofluoroalkyl , straight chained or branched C 1 -C 7 polyfluoroalkyl, straight chained or branched C 2 -d alkenyl, straight chained or branched C 2 -C 7 alkynyl, C 5 -C 7 cycloalkenyl, -(CH 2 ) ⁇ -Z, or (CH 2 ) n -0-(CH 2 ) m -CH 3 ;
  • each R 20 is independently -H; straight chained or branched C 1 -C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 -C7 cycloalkyl or C 5 -C 7 cycloalkenyl; -F, -Cl, -Br, or -I; -N0 2 ; -N 3 ; -CN; - OR 2 ⁇ , -OCOR 2 ⁇ , -C0R 2 ⁇ , -NCOR 2 ⁇ , -N(R 21 ) 2 , -C0N(R 2 ⁇ ) 2 , or -COOR21; aryl or heteroaryl; or two R 0 groups present on adjacent carbon atoms can join together to form a methylenedioxy group; wherein each R 2 ⁇ is independently ' -H; straight chained or branched C
  • each R 22 is independently H, F, Cl, or straight chained or branched C ⁇ -C 4 alkyl
  • q is an integer from 2 to 4 inclusive
  • each m is an integer from 0 to 4 inclusive;
  • n is an integer from 1 to 4 inclusive
  • each p is an integer from 0 to 2 inclusive;
  • U is 0, -NR ⁇ 6 , S, C(R ⁇ 7 ) 2 , or -NS0 2 Ri6;
  • Z is C 3 -C 1 0 cycloalkyl, C 4 -C7 cyclic ether, C 4 -C7 cyclic thioether, aryl, or heteroaryl;
  • Ri is straight chained or branched C 1 -C 7 alkyl, straight chained or branched C 1 -C 7 monofluoroalkyl, straight chained or " branched d- polyfluoroalkyl, straight chained or branched C 2 -d • alkenyl, straight chained or branched C 2 -d alkynyl, d-d cycloalkenyl, -(CH 2 ) m -Z, or (CH 2 ) q -0- (CH 2 ) m -CH 3 ;
  • B is aryl, or heteroaryl; provided however, if B is aryl or heteroaryl the carbon atom or carbon atoms ortho to the nitrogen atom of ' the imine bond may only be substituted with one or more of the following -F, -Cl, -Br, -I," -CN, methyl, ethyl or methoxy;
  • q is an integer from 2 to 4 inclusive;
  • the invention provides a method of treating a subject suffering from an abnormality which comprises administering o the subject an amount of compound effective to treat the subject's abnormality wherein- the compound has the structure:
  • each of Y l r Y 2 , Y 3 , and Y 4 is independently -H; straight chained or branched C ⁇ -C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C alkenyl or alkynyl; C 3 -C 7 cycloalkyl, or - C 5 -C 7 cycloalkenyl; -F, -Cl, -Br, or -I; -N0 2 ; -N 3 ; -CN; -0R 4 , -OCOR 4 , -C0R 4 , -NCOR4, -N(R 4 ) 2 , -CON(R 4 ) 2 , or -COOR 4 ; aryl or heteroaryl; or any two of Y 1( Y 2 , Y 3 and Y 4 ' present on adjacent carbon atoms can constitute a methylenedi
  • A is A' , straight chained or branched d-d alkyl, aryl, heteroaryl, aryl (C ⁇ -C 6 ) alkyl or heteroaryl (Ci-Cg) alkyl;
  • Ri and R 2 are each independently H ' , straight chained or branched d- alkyl, -F, -Cl, -Br, -I, -N0 2 , or -CN;
  • R 3 is H, straight chained or ⁇ -branched C 1 -C 7 alkyl, -F, -Cl, -Br, -I, -N0 2 , -CN, -0R 6 aryl or heteroaryl;
  • R 5 is straight chained or branched d-d alkyl, - N ' (R 4 ) 2 , -OR 4 or aryl;
  • R s is straight chained or branched d-C 7 alkyl or aryl ; wherein B is C 3 -C cycloalkyl, C 5 -C 7 cycloalkenyl, adamantyl, aryl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, indolizinyl, indol-4-yl, indol-5- yl, indol-6-yl, indol-7-yl, isoindolyl, benzo [b] furan-4- yl, benzo [b] furan-5-yl, benzo [b] furan-6-yl , benzo [b] furan-7-yl, benzo [b] thiophen-4-yl , benzo [b] thiophen-5-yl, • benzo [b] thiophen-6-yl , benzo [b
  • n is an integer from 1 to 4 inclusive.
  • the anti- GAL3 antiserum labeled proteins in membranes only from rat GAL3 -transfected cells (Lane 2); a predominant band was evident with an apparent molecular weight of approximately 56 kDa, (somewhat higher than the amino acid-derived value of 40.4 kDa) .
  • the apparently high molecular weight observed for rat GAL3 very likely reflects post- translational processing such as glycosylation ; note that rat GAL3 contains multiple N- ter inal glycosylation sites (Smith et al . , 1998).
  • Relative to the predominant band additional species of higher molecular weight as well as lower molecular weight were labeled by the GAL3 antiserum. These are interpreted as protein aggregates of C-terminal fragments, as they are absent in mock-transfected cells.
  • Neuropathic Rats Data plotted represents the group mean withdrawal threshold (grams) to Von Frey filament challenges on the days prior to and following a chronic constriction nerve injury.
  • the animals were dosed with test substance (Example 92), reference sustance (morphine) or vehicle (100% DMSO) on day 12 PO .
  • + P ⁇ 0.05 compared to the vehicle group Kruskal- Wallis and Dunn's test or Mann-Whitney 17-test
  • FIG. 4 Effects of Example 92 on the Withdrawal Latency to a Thermal Plantar Stimulus of the (i) Contralateral and (ii) Nerve-injured Paw of Neuropathic Rats. Data plotted represents the group mean withdrawal latency (seconds) to a thermal plantar stimulus on the days prior to and following a chronic constriction nerve injury. The animals were dosed with test substance (Example 92), reference sustance (morphine) or vehicle (100% DMSO) on day 12 PC *P ⁇ 0.05, ***j? ⁇ 0.001 compared to vehicle control group (Unpaired t-test). +* P ⁇ 0.01 compared to the vehicle group (Mann-Whitney 17-test) .
  • Figure 5 Effects of Example 92 on the Withdrawal Latency to a Thermal Plantar Stimulus of the (i) Contralateral and (ii) Nerve-injured Paw of
  • the present invention provides a method of treating a subject suffering from an abnormality which comprises administering to the subject an amount of compound effective to treat the subject's abnormality wherein the
  • W is H, -F, -Cl, -Br, -I, CN, methyl, ethyl, propyl, methoxy or ethoxy;
  • X is ; NR R 12 ;
  • R u is H, straight chained or branched C 1 -C 7 alkyl, (CH 2 ) q -0- (CH 2 ) m -CH 3 , aryl, or aryl (Ci-Cg) alkyl;
  • R i2 is straight chained ' or branched C ⁇ -C 7 alkyl, (CH 2 ) q -0-(CH 2 ) m -CH 3 , or -(CH 2 ) m -Z;
  • R i3 is a bicyclic alkyl ring system, adamantyl, noradamantyl, d-Cio cycloalkyl, heteroaryl, . aryl, aryl (C.-Cg) alkyl, Qi or Q 2 ;
  • aryl may be substituted with one or more d-Cio straight chained or branched alkyl, aryl, heteroaryl, or N(R 19 )-Z,-
  • each J is independently 0, S, C(R 22 ) 2 or NR 4 wherein R 4 is H; straight chained or " branched C ⁇ -C 7 alkyl, monofluoroalkyl ⁇ or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 -d cycloalkyl, C 5 -C 7 cycloalkenyl or aryl;
  • Y is NR ⁇ 4 R ⁇ 5 ;
  • R ⁇ 4 is H, straight chained or ..branched C ⁇ C 6 alkyl, (CH 2 ) q -0- (CH 2 ) m -CH 3/ C 3 -C 6 cycloalkyl, or (C(R 19 ) 2 ) m - Z;
  • R ⁇ 5 is straight chained or branched C 3 -C e alkyl, (CH 2 ) q -0-(CH 2 ) m -CH 3 , C 3 -C 6 cycloalkyl, (C (R 19 ) 2 ) m N (R 16 ) 2 or (C(R ⁇ 9 ) 2 ) m -Z;
  • R 16 is straight chained or branched C ⁇ -C 7 alkyl, straight chained or branched C ⁇ -C 7 monofluoroalkyl, straight chained or branched d-C 7 polyfluoroalkyl, straight chained or branched C 2 -C alkenyl, straight chained or branched C 2 -C 7 alkynyl, C 5 -C cycloalkenyl, - (CH 2 ) m -Z, or (CH 2 ) q -0-(CH 2 ) m -CH 3 ;
  • each Ry ? is independently H; -UR 21 , -OCOR 2 ⁇ , C0R 2 ⁇ , -NCOR2:, -N(R 2 ⁇ ) 2 , -C0N(R 2 ⁇ ) 2 -COOR21, straight chained or branched C-C7 alkyl, straight chained or branched C 1 -C 7 monofluoroalkyl , straight chained or branched d-C 7 polyfluoroalkyl, straight chained or branched C 2 -d alkenyl, straight chained or branched d-d alkynyl, C 5 -C-7 cycloalkenyl, -(CH 2 ) ra -Z, or (CH 2 ) n -0- (CH 2 ) ⁇ - CH 3 ;
  • Ris is straight chained or branched Ci-C alkyl, - (CH 2 ) m -Z, or (CH 2 ) q -0-(CH 2 ) m -CH 3 ;
  • each R i9 is independently H, or straight chained or branched C x -Cg alkyl
  • each Ro is independently -H; straight chained or branched C 1 -C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -d alkenyl or alkynyl; C 3 -C7 cycloalkyl or C5-C7 cycloalkenyl; -F, -Cl, -Br, or - I; -N0 2 ; -N 3 ; -CN; -0R 2 ⁇ , -OCOR 21f -COR 2 ⁇ , -NCOR 21 , -N(R 2i ) 2 , -CON(R 2 ⁇ ) 2 , or -COOR 2i ; aryl or heteroaryl; or two R 20 groups present on adjacent carbon atoms can join together to form a methylenedioxy group;
  • each R 2i is independently -H; straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -d alkenyl or alkynyl; C 3 -C 7 cycloalkyl, C 3 -C cycloalkenyl, aryl, or aryl(C : - C 6 ) alkyl;
  • each R 22 is independently H, F, Cl or C;-C 4 straight chained or branched alkyl;
  • each m is an integer from 0 to 4 inclusive;
  • n is an integer from 1 to 4 inclusive
  • p is an integer from 0 to 2 inclusive
  • q is an integer from 2 to 4 inclusive
  • t is 1 or 2 ;
  • U is 0, -NRig, S, C(R i7 ) 2 , or -NS0 2 R ⁇ b ;
  • Z is C 3 -do cycloalkyl, C 4 ⁇ C 7 cyclic ether, C 4 -C cyclic thioether, aryl, or heteroaryl; or
  • the invention provides a method of treating a subject suffering from an abnormality which comprises administering to the subject an amount of compound effective to treat the subject's abnormality wherein the compound has the structure:
  • W is H, -F, -Cl, -Br, -I, CN, methyl, ethyl, propyl, methoxy or ethoxy;
  • X is NR ⁇ R ⁇ 2 ;
  • R is H, straight chained or branched C ⁇ -C 7 alkyl, (CH 2 ) q -0- (CH 2 ) ra -CH 3 , aryl or aryl (Ci-Cg) alkyl ;
  • R 12 is straight chained or branched C ⁇ -C 7 alkyl, (CH 2 ) q -0-(CH 2 ) m -CH 3 , or -(CH 2 ) B -Z;
  • R i3 is a bicyclic alkyl ring system, aryl or aryl ( d-d) alkyl ;
  • R i4 is H, straight chained or branched Ci-Cg alkyl, (CH 2 ) q -0- (CH 2 ) It ,-CH 3 , C 3 -C 6 cycloalkyl, or (C (R 19 ) 2 ) m - Z;
  • R X5 is straight chained or branched C 3 -C 6 alkyl, (CH 2 ) q -0-(CH 2 ) m -CH 3 , C 3 -C 6 cycloalkyl, or (C (R 19 ) : ) ⁇ -Z;
  • U is O, -NR ⁇ 5 , S, C(R ⁇ 7 ) 2 , or -NS0 2 R ⁇ 5 ;
  • Z is C 3 -do cycloalkyl, aryl, or heteroaryl
  • Rig is straight chained or branched d- alkyl, straight chained or branched C 1 -C7 monofluoroalkyl , straight chained or branched d-C 7 polyfluoroalkyl, straight chained or branched -d alkenyl, straight chained or branched C 2 -C 7 alkynyl, C 5 -C7 cycloalkenyl, -.
  • each R i7 is independently H; -OR 2 ⁇ , -OCOR 2 ⁇ , COR 2i , -NCOR21, -N(R 21 ) 2 , -C0N(R 2 ⁇ ) 2 , -COOR 2 ⁇ , straight chained or branched C1-C7 alkyl, straight chained or branched C 1 -C7 monofluoroalkyl , straight chained or branched C 1 -C7 polyfluoroalkyl, straight chained or branched C 2 -C7 alkenyl, straight chained or branched C 2 -C- alkynyl, C 5 -C 7 cycloalkenyl, -(CH 2 ) m ⁇ Z, or (CH 2 ) n -0- (CH 2 ) m - CH
  • Ria is straight chained or branched Ci-Cg alkyl, - (CH 2 ) m -Z, or (CH 2 ) q -0-(CH 2 ) m -CH 3 ;
  • each R 19 is independently H, or straight chained or branched d-C 6 alkyl
  • each R 2 o is independently -H; straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl;
  • each R 2i is independently -H; straight chained or branched C 1 -C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight -chained or branched C 2 -C 7 alkenyl or alkynyl; C3-C7 cycloalkyl, C5-C7 cycloalkenyl, aryl or aryl(C ⁇ - C 6 ) alkyl;
  • each m is an integer from 0 to 4 inclusive;
  • n is an integer from 1 to 4 inclusive; wherein p is an integer from 0 to 2 inclusive;
  • q is an integer from 2 to 4 inclusive
  • t is 1 or 2;
  • the invention provides a method of treating a subject suffering from an abnormality which comprises administering to the subject an amount . of compound effective to treat the subject's abnormality wherein the
  • W is H, -F, -Cl, -Br, -I, CN, 'methyl, ethyl, propyl, methoxy or ethoxy;
  • R i3 is an aryl, adamantyl, noradamantyl , C 3 -C ⁇ 0 cycloalkyl, heteroaryl, Qi or Q 2 ;
  • aryl may be substituted with one or more Ci-Cio straight chained or branched alkyl, aryl, heteroaryl, or N(R 19 )-Z;
  • each J is independently 0, S, C(R 22 ) 2 or NR ; wherein R 4 is -H; straight chained or branched d-d alkyl, monof luoroalkyl or polyfluoroalkyl; straight chained or branched ⁇ C 2 -C 7 alkenyl or alkynyl; C 3 -C 7 cycloalkyl, C 5 -C 7 cycloalkenyl or aryl;
  • R ⁇ 4 is H, straight chained or branched Ci-Cg alkyl, (CH 2 ) q -0- (CH 2 ) m -QH 3 , C 3 -C 6 cycloalkyl, or (C (R 19 ) 2 ) m - z ' " ⁇ " .
  • R 15 is straight chained or branched -d alkyl, (CH 2 ) q -0-(CH 2 ) m -CH 3 , d-d cycloalkyl, or (C (R 19 ) 2 ) m -Z ;
  • U is 0, -NR ⁇ 6 , S, C(R ⁇ ) 2 , or -NS0 2 R ⁇ 6 ;
  • Z is C 3 -C ⁇ 0 cycloalkyl, aryl, or heteroaryl; wherein i is straight chained or branched d-C- alkyl, straight chained or branched C1-C7 monofluoroalkyl , straight chained or branched C 1 -C 7 polyfluoroalkyl, straight chained or branched C 2 -d alkenyl, straight chained or branched C 2 -d alkynyl, C 5 -C7 cycloalkenyl, - (CH 2 ) m -Z, or (CH 2 ) q -0-(CH 2 ) m -CH 3 ;
  • each R i7 is independently H; -0R 2 ⁇ , -OCOR 21 , COR 21 , -NCOR 21 , -N(R 2 ⁇ ) 2 , -CON(R 21 ) 2 , -C00R 2 ⁇ , straight chained or branched Ci-C- alkyl, straight chained or branched C 1 -C 7 monofluoroalkyl , straight chained or branched- C 1 -C polyfluoroalkyl, straight chained or branched C 2 -C ⁇ alkenyl, straight chained or branched d-d alkynyl, C 5 -C7 cycloalkenyl, -(CH 2 ) ra -Z, or (CH : ) ⁇ -0- (CH 2 ) m - CH 3 ;
  • Ris is straight chained or branched Ci-Cg alkyl, - (CH 2 ) m -Z, or (CH 2 ) q -0-(CH 2 ) m -CH 3 ;
  • each R 19 is independently H, or straight chained or branched C ⁇ -C 6 alkyl
  • each R 20 is independently -H; straight chained or branched d-d alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained 01 branched C 2 -C alkenyl or alkynyl; C 3 -C cycloalkyl or C 5 -C 7 cycloalkenyl; -F, -Cl, -Br, or - I; -N0 2 ; -N 3 ; -CN; -0R 2 ⁇ , -OCOR 21 , -C0R 21 , -NCOR 21 , -N(R 2 ⁇ ) 2 , -C0N(R 2 i) 2 , or -COOR 2 1; aryl or heteroaryl; or two R 20 groups present on adjacent carbon atoms can join together to form a methylenedioxy group;
  • each R 21 is independently -H; straight chained or branched - alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 -d cycloalkyl, C 5 -C 7 cycloalkenyl, aryl or aryl(d- C 6 ) alkyl;
  • each R 22 is independently H, F, Cl or d-C 4 straight chained or branched alkyl
  • each m is an integer from 0 to 4 inclusive;
  • n is an integer from 1 to 4 inclusive
  • p is an integer from 0 to 2 inclusive
  • t is 1 or 2;
  • the invention provides a method of treating a subject suffering from an abnormality which comprises administering to the subject an amount of compound effective to treat the subject's abnormality wherein the compound has the structure:
  • W is H, -F, -Cl, -Br, -I, CN, methyl, ethyl, propyl, methoxy or ethoxy;
  • R x3 is a bicyclic alkyl ring system, aryl or aryl (Ci-Cg) alkyl;
  • R i4 is H, straight chained or branched C ⁇ C ⁇ alkyl, (CH 2 ) q -0- (CH 2 ) m -CH 3 , C 3 -C 6 cycloalkyl, or (C(R 19 ) ;>)
  • R i4 is H, straight chained or branched C ⁇ C ⁇ alkyl, (CH 2 ) q -0- (CH 2 ) m -CH 3 , C 3 -C 6 cycloalkyl, or (C(R 19 ) ;>)
  • R i4 is H, straight chained or branched C ⁇ C ⁇ alkyl, (CH 2 ) q -0- (CH 2 ) m -CH 3 , C 3 -C 6 cycloalkyl, or (C(R 19 ) ;>)
  • R i4 is H, straight chained or branched C ⁇ C ⁇ alkyl, (CH 2 ) q
  • R 15 is (C (R X9 ) 2 ) ⁇ > -N(R 16 ;
  • Z is C 3 -C ⁇ 0 cycloalkyl, aryl, or heteroaryl
  • Rig is straight chained or branched C ⁇ -C 7 alkyl, straight chained or branched C ⁇ -C 7 monofluoroalkyl , straight chained or branched C ⁇ -C 7 polyfluoroalkyl, straight chained or branched C 2 -C 7 alkenyl, straight chained or branched C 2 -C 7 alkynyl, C 5 -C7 cycloalkenyl, - (CH 2 ) ra -Z, or (CH 2 ) q -0-(CH 2 )-,-CH 3 ;
  • each R l7 is independently H; -OR 2 ⁇ , -OCOR 2 ⁇ , - ' COR2 1 , -NCOR 2 ⁇ , -N(R 2 ⁇ ) 2 , -C0N(R 2i ) 2 , -C00R 21 , straight chained or branched d-C 7 alkyl, straight chained or branched C ⁇ -C 7 monofluoroalkyl , straight chained or branched C ⁇ -C 7 polyfluoroalkyl, straight chained or branched C 2 -C 7 alkenyl, straight chained or branched C 2 -C 7 alkynyl, C 5 -d cycloalkenyl, -(CH 2 ) m -Z, or (CH 2 ) n -0- (CH 2 ) m - CH 3 ;
  • each R i9 is independently H, or straight chained or branched Ci-Cg alkyl
  • each R 2 ⁇ is independently -H; straight chained or branched d-C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl. or alkynyl; C -C 7 cycloalkyl, C 5 -C 7 cycloalkenyl, aryl or aryl(d- C 6 ) alkyl;
  • each m is an integer from 0 to 4 inclusive;
  • n is an integer from 1 to 4 inclusive
  • q is an integer from 2 to 4 inclusive;
  • bicyclic alkyl ring systems includes, but is not limited to, bicyclo [2.2. ljheptane, bicyclo [3.1.1] heptane and bicyclo [2.2.2] octane.
  • the bicyclic alkyl ring systems may be substituted with one or more of the following: -F, -N0 2 , -CN, ' straight chained or branched C1-C7 alkyl, straight chained or branched C 1 -C7 monofluoroalkyl, straight chained or branched C 1 -C7 polyfluoroalkyl, straight chained or branched C 2 -d alkenyl, straight chained or branched d ⁇ d ' alkynyl, C 3 -C 7 cycloalkyl, C 5 -C 7 cycloalkenyl, -N(R 2i ) 2 , -OR 21 , -COR 21 , - C0 2 R 2 i, -C0N(R 2 ⁇ ) 2 or (CH 2 ) n -0-(CH 2 ) rn -CH 3 .
  • cycloalkyl includes, C 3 -d cycloalkyl moieties which may be substituted with one or more of the following: -F, -N0 2 , -CN, straight chained or branched C 1 -C 7 alkyl, straight chained or branched C 1 -C 7 monofluoroalkyl, straight chained or branched d-C 7 polyfluoroalkyl, straight chained or branched C 2 -C 7 alkenyl, straight chained or branched C 2 -C 7 alkynyl, C 3 -C 7 cycloalkyl, C 3 -C7 monofluorocycloalkyl, C3-C 7 polyfluorocycloalkyl, C 5 -C7 cycloalkenyl, -N(R 4 ) 2 . -OR 4 , -COR 4 , -NCOR 4 , -C0 2 R
  • cyclohexyl includes, cyclohexyl groups which may be substituted with one or more of the following: -F, -N0 , -CN, straight chained or branched C 1 -C-7 alkyl, straight chained or branched d-d monofluoroalkyl, straight chained or branched d-d polyfluoroalkyl, straight chained or branched C 2 -C 7 alkenyl, straight chained or branched C 2 -C 7 alkynyl, C3-C7 cycloalkyl, C 3 -C7 monofluorocycloalkyl, C 3 -C 7 polyfluorocycloalkyl , C 5 -C 7 cycloalkenyl, -N(R 4 ) 2 , -0R 4 , -C0R 4 , -NC0R 4 , -C0 2 R 4 , CON(
  • cycloalkenyl includes, C 5 -C7 cycloalkenyl moieties which may be substituted with one or more of the following: -F, -Cl, -Br, -I, -N0 2 , -CN, straight chained or branched C 1 -C 7 alkyl, straight chained or branched Ci- d monofluoroalkyl, straight chained or ' branched Ci- polyfluoroalkyl, straight chained or branched C : -C ⁇ alkenyl, straight chained or branched C 2 -C 7 alkynyl, C -d cycloalkyl, C3-C 7 monofluorocycloalkyl, C 3 -d polyfluorocycloalkyl, C 5 -C7 cycloalkenyl, -N(R 4 ) 2 , -0R 4 , - C0R 4
  • heteroaryl is used to include five and six membered unsaturated rings that may contain one or more oxygen, sulfur, or nitrogen atoms.
  • heteroaryl groups include, but are not limited to, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, _ isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, and triazinyl .
  • heteroaryl is used to include fused bicyclic ring systems that may contain one or more heteroatoms such as oxygen, sulfur and nitrogen.
  • heteroaryl groups include, but are not limited to, indolizinyl, indolyl, isoindolyl, benzo [b] furanyl, benzo [b] thiophenyl , indazolyl, benzimidazolyl, purinyl, benzoxazolyl, benzisoxazolyl, benzo [b] thiazolyl, imidazo [2 , 1-b] thiazolyl , cinnolinyl, quinazolinyl, quinoxalinyl, 1 , 8-naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, phthalimidyl and 2,1,3 -benzothiazolyl .
  • heteroaryl also includes those chemical moieties recited above which may be substituted with one or more of the following: -F, -Cl, -Br, -I, -N0 2 , -CN, straight chained or branched C ⁇ C 7 alkyl, straight chained or branched d-C 7 monofluoroalkyl, straight chained or branched C 1 -C 7 polyfluoroalkyl, straight chained or branched C 2 -C 7 alkenyl, straight chained or branched C 2 -C- alkynyl, C 3 -C 7 cycloalkyl, C 3 -C-
  • heteroaryl further includes the N-oxides of 0 those chemical moieties recited above which include at least one nitrogen atom.
  • aryl is phenyl or naphthyl.
  • the term “aryl” also includes phenyl and 5 naphthyl which may be substituted with one or more of the following: -F, -Cl, -Br, -I, -N0 2 , -CN, straight chained or branched C 1 -C7 alkyl, straight chained or branched C 1 -C7 monofluoroalkyl , straight chained or branched C 1 -C7 polyfluoroalkyl, straight chained or 0 branched C 2 -d alkenyl, straight chained or branched C 2 .-C 7 alkynyl, C 3 -C 7 cycloalkyl, C 3 -C 7 monofluorocycloalkyl , C 3 - d polyfluorocycloalkyl, C5-C7 cycloalkenyl, -N(R 4 ) 2
  • the compound is enantiomerically and diasteriomerically pure. In one embodiment, the 0 compound is enantiomerically or diasteriomerically pure.
  • the compound in one • embodiment of any of the methods described herein, can be administered orally.
  • X is
  • X is NRuR ⁇ 2 and R u is H or straight chained or branched C ⁇ -C 7 alkyl .
  • the compound has the structure:
  • R ⁇ 3 is a bicyclic alkyl ring system, cyclohexyl or aryl.
  • R i4 is H, straight chained or branched Ci-Cg alkyl or (CH 2 ) q -0- (CH 2 ) m -CH 3 .
  • the compound is selected from the
  • Y is
  • U is NRig.
  • Ri is (CH 2 ) m -Z.
  • Z is aryl or heteroaryl.
  • the compound is selected from the group consisting of:
  • the compound is selected from the group consisting of:
  • Y is
  • U is NRig.
  • the compound is In one embodiment, the compound is
  • the compound is selected from the group consisting of:
  • the compound is selected from the group consisting of:
  • X is N(CH 3 ) 2 ,
  • Y is
  • R1.3 is an aryl substituted with a C ⁇ C 10 straight chained alkyl.
  • the compound is selected from a group consisting of:
  • the invention provides a pharmaceutical composition comprising a therapeutically effective amount of any of the compounds described herein and a pharmaceutically acceptable carrier.
  • the invention provides a pharmaceutical composition made by combining a therapeutically effective amount of any of the compounds described herein and a pharmaceutically acceptable carrier.
  • the invention provides a process for making a pharmaceutical composition comprising combining a therapeutically effective amount of any of the compounds described herein and a pharmaceutically acceptable carrier.
  • the invention provides a method of treating a subject suffering from an abnormality which comprises administering to the subject an amount of any of the compounds described herein effective to treat the subject's abnormality.
  • the abnormality is a regulation of a steroid or pituitary hormone disorder, an epinephrine release disorder, a gastrointestinal disorder, a cardiovascular disorder, an- electrolyte balance disorder, hypertension, diabetes, a respiratory disorder, asthma, a reproductive function disorder, an immune disorder, an endocrine disorder, a musculoskeletal disorder, ⁇ a neuroendocrine disorder, a cognitive disorder, a memory disorder such as Alzheimer's disease, a learning disorder, a sleep disorder, a sensory modulation and transmission disorder, a motor coordination disorder, Huntington's disease, a sensory integration disorder, a motor integration disorder, a dopaminergic function disorder such as Parkinson's disease, a sensory transmission disorder, an olfaction disorder, a sympathetic innervation disorder, a stress- related disorder, a fluid-balance disorder, a seizure disorder, pain, inflammatory pain, chronic pain, psychotic behavior such as schizophrenia, morphine tolerance, drug addition particularly opiate addiction, migraine, an
  • the abnormality is Alzheimer's disease, obesity, diabetes, or pain, particularly neuropathic pain.
  • the invention provides a method of treating a subject suffering from pain which comprises administering to the subject an amount of any of the compounds described herein effective to treat the subject's pain.
  • the invention provides a method of treating a subject suffering from neuropathic pain which comprises administering to the subject an amount Of any of the compounds described herein effective to treat the subject's neuropathic pain.
  • the invention provides a method of treating a subject suffering from an abnormality which comprises administering to the subject an amount of compound effective to treat the subject's abnormality wherein the compound has the structure:
  • each of Yi, Y 2 , Y 3 , and Y 4 is independently - H; straight chained or branched C ⁇ -C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched d-d alkenyl or alkynyl; C 3 -C 7 cycloalkyl, or C 5 -d cycloalkenyl; -F, -Cl, -Br, or -I; -N0 2 ; -N 3 ; -CN; -0R 4 , -SR 4 , -0C0R 4 , -C0R 4 , -NC0R 4 , -N(R 4 ) 2 , -CON(R 4 ) 2 , or -COOR 4 ; aryl or heteroaryl; or any two of Y i( Y 2 , Y 3 and Y 4 present on adjacent carbon atoms can constitute a methyl
  • each R 4 is independently -H; straight chained or branched Ci-d alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -d alkenyl or alkynyl; C 3 -C7 cycloalkyl, C 5 -C 7 cycloalkenyl, aryl or aryl (Ci-Cg) alkyl;
  • A is A', Q 3 , Q 4 ⁇ Q 5 _ straight chained or branched C 1 -C7 alkyl, aryl, heteroaryl, aryl (Ci- C 6 ) alkyl, heteroaryl (Ci-Cg) alkyl , aryl substituted with an aryl or heteroaryl, heteroaryl substituted with an aryl or heteroaryl; or (CHR 1 7) - (CHRy ? ) n -Z; wherein A' is
  • Ri and R 2 are each independently H, straight chained or branched C 1 -C7 alkyl , -F , -Cl , -Br , -I , - N0 2 , or -CN;
  • R 3 is H, straight chained or branched C1-C7 alkyl, -F, -Cl, -Br, -I, -N0 2 , -CN, -0R 6 , aryl or heteroaryl;
  • R 5 is straight chained or branched C1-C7 alkyl, -N(R 4 ) 2 , -0R 6 or aryl;
  • Rg is straight chained or branched C1-C7 alkyl or aryl ;
  • each R 17 is independently H; straight chained or branched C 1 -C7 alkyl, straight chained or branched C 1 -C 7 monofluoroalkyl, straight chained or branched C 1 -C 7 polyfluoroalkyl, straight chained or branched C 2 -C 7 alkenyl, straight chained or branched d-d alkynyl, C 5 -C 7 cycloalkenyl, -(CH : ) m -Z, or (CH 2 ) n -0-(CH 2 ) m -CH 3 ;
  • each R 2 o is independently -H; straight chained or branched Ci-C- alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -d alkenyl or alkynyl; C 3 -d cycloalkyl or C 5 -C7 cycloalkenyl; -F, -Cl, -Br, or -I; -N0 2 ; -N 3 ; -CN; - OR 21 , -OCOR 21 , -COR 21 , -NCOR 21 , -N(R 2 ⁇ ) 2 , -C0N(R 2X ) 2 , or -COOR 2 ⁇ ; aryl or heteroaryl; or two R 20 groups present on adjacent carbon atoms can join together to form a methylenedioxy group;
  • each R? ⁇ is independently -H; straight chained or branched -C-> alkyl, monofluoroalkyl or polyfluoroalkyl: straight chained or branched C 2 -d alkenyl or alkynyl; C 3 -C 7 cycloalkyl, C 5 -C 7 cycloalkenyl, aryl or aryl (C ⁇ C 6 ) alkyl;
  • each m is an integer from 0 to 4 inclusive;
  • n is an integer fr.om 1 to 4 inclusive;
  • each p is an integer from 0 to 2 inclusive;
  • U is 0, -NR ⁇ 6 , S, C(R ⁇ 7 ) 2 , or -NS0 2 R ⁇ 6 ;
  • Z is C 3 -C ⁇ 0 cycloalkyl, C 4 -c 7 cyclic ether, C 4 -C7 cyclic thioether, aryl, or heteroaryl;
  • R X6 is straight chained or branched C 1 -C 7 alkyl, straight chained or branched C x -C 7 monofluoroalkyl, straight chained or ' 'branched C 1 -C7 polyfluoroalkyl, straight chained or branched C 2 -C 7 alkenyl, straight chained or branched C 2 -d alkynyl, d-d cycloalkenyl, -(CH 2 ) m -Z, or (CH 2 ) q -0- (CH 2 ) m -CH 3 ;
  • q is an integer from 2 to 4 inclusive
  • B is aryl, heteroaryl, aryl substituted with an aryl or heteroaryl, heteroaryl substituted with an aryl or heteroaryl, tricyclic heteroaryl or 6 ; provided however, if B is aryl or heteroaryl the carbon atom or carbon atoms ortho to the nitrogen atom of the i ine bond may only be substituted with one or more of the following -F, -Cl, -Br, -I, -CN, methyl, ethyl or methoxy;
  • a tricyclic heteroaryl is a fused three member aromatic system in which one or more of the rings is heteroaryl; carbazole; or acridine;
  • each R 22 is independently H, F, Cl, or straight chained or branched C ⁇ -C 4 alkyl
  • the invention provides a method of treating a subject suffering from an abnormality which comprises administering to the subject an amount of compound effective to treat the subject's abnormality wherein the compound has the structure:
  • each of Yi, Y 2 , Y 3 , and Y 4 is independently - H; straight chained or branched d- alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched d-d alkenyl or alkynyl; C 3 -C7 cycloalkyl, or C 5 -C 7 cycloalkenyl; -F, -Cl, -Br, or -I; -N0 2 ; -N 3 ; -CN; -OR 4 , -SR 4 , -OCOR 4 , -COR 4 , -NC0R 4 , -N(R 4 ) 2 , -CON(R 4 ) 2 , or -COOR 4 ; aryl or heteroaryl; or any two of Y x , Y 2 , Y 3 and Y present on adjacent carbon atoms can constitute a methylenedioxy group;
  • each R 4 is independently -H; straight chained or branched d-C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 -C7 cycloalkyl, C 5 -C7 cycloalkenyl, aryl or aryl (C ⁇ -C 6 ) alkyl;
  • A is A' , straight chained or branched C 1 -C 7 alkyl, aryl, heteroaryl, aryl (C ⁇ C 6 ) alkyl or heteroaryl (C ⁇ -C 6 ) alkyl ;
  • Ri and R 2 are each independently H , s traight chained or branched C 1 -C 7 alkyl , -F , -Cl , -Br , -I., - N0 2 , or -CN;
  • R 3 is H, straight chained or branched Ci-C- alkyl, -F, -Cl, -Br, -I, -N0 2 , -CN, -0R ⁇ aryl or heteroaryl;
  • R 5 is straight chained or. -branched C ⁇ -C 7 alkyl, -N(R 4 ) 2 , -0R 6 or aryl;
  • R 6 is straight chained or branched C 1 -C7 alkyl or aryl
  • B is aryl, or heteroaryl; provided however, if B is aryl or heteroaryl the carbon atom or carbon atoms ortho to the nitrogen atom of the imine bond may only be substituted wifh one or more of the following -F, -Cl, -Br, -I, -CN, methyl, ethyl or methoxy
  • n is an integer from 1 to 4 inclusive;
  • the invention provides a method of treating a subject suffering from an abnormality which comprises administering to the . subject an amount of compound effective to treat the subject's abnormality wherein the
  • each of Y l t Y 2 , Y 3 , and Y 4 is independently - H; straight chained or branched C ⁇ -C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 -d cycloalkyl, or C 5 -C 7 cycloalkenyl; -F, -Cl, -Br, or -I; -N0 2 ; -N 3 ; -CN; -OR 4 , -SR 4 , -0C0R 4 , -C0R 4 , -NC0R 4 , -N(R 4 ) 2 , -C0N(R 4 ) 2 , or -COOR 4 ; aryl or heteroaryl; or any two of Y b ⁇ 2 , ⁇ 3 and Y 4 present on adjacent carbon atoms
  • A is A' , straight chained or branched C 1 -C7 alkyl, aryl, heteroaryl, aryl (Ci-Cg) alkyl or heteroaryl (C ⁇ -C 6 ) alkyl;
  • B is aryl substituted with an aryl or heteroaryl, heteroaryl substituted with an aryl or heteroaryl, tricyclic heteroaryl or Q 6 ;
  • a tricyclic heteroaryl is a fused three ring aromatic system in which one or more of the rings, is heteroaryl; carbazole; or acridine; wherein Qg is
  • n is an integer from 1 to 4 inclusive ;
  • each R 22 is independently H , F ,
  • the invention provides a method of treating a subject suffering from an abnormality which comprises administering to the subject an amount of compound effective to treat the subject's abnormality wherein the
  • each of Y x , Y 2 , Y 3 , and Y 4 is independently H; straight chained or branched " ' C : -C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight • chained or branched C 2 -C alkenyl or alkynyl; C 3 -d cycloalkyl, or Cs-C ⁇ cycloalkenyl; -F, -Cl, -Br, or -I; -N0 2 ; -N 3 ; -CN; -0R 4 , -SR 4 , -OCOR 4 , -C0R 4 , -NC0R , -N(R 4 ) 2 , -CON(R 4 ) 2 , or -C00R ; aryl or heteroaryl; or any two of Yi, Y 2 , Y 3 and Y 4 present on adjacent carbon atoms can constitute a
  • each R 4 is independently -H; straight chained or branched C 1 -C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -d alkenyl or alkynyl; C 3 -C 7 cycloalkyl, C 5 -C7 cycloalkenyl, aryl or aryl (C ⁇ -C 6 ) alkyl;
  • A is Q 3 , Q , Q 5 , aryl substituted with an aryl or heteroaryl, heteroaryl substituted with an aryl or heteroaryl, or (CHRy ? ) - (CHR 17 ) n -Z;
  • each R 1 7 is independently H; straight chained or branched C 1 -C 7 alkyl, straight chained or branched C 1 -C7 monofluoroalkyl, straight chained or branched C 1 -C7 polyfluoroalkyl, straight chained or branched C 2 -d alkenyl, straight chained or branched C 2 -d alkynyl, C5-C7 cycloalkenyl, -(CH ? ) m -Z, or (CH 2 ) n -0-(CH 2 ) m -CH 3 ;
  • each R 2 o is independently -H; straight chained or branched C 1 -C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 -C 7 cycloalkyl or C 5 -C 7 cycloalkenyl; -F, -Cl, -Br, or -I; -N0 2 ; -N 3 ; -CN; - OR2 1 , -OCOR21, -C0R 2 ⁇ , -NC0R 2 ⁇ , -N(R 2i ) 2 , -CON(R 21 ) 2l or -C00R 2 ⁇ ; aryl or heteroaryl; or two R 0 groups present on adjacent carbon atoms can join together to form a methylenedioxy group; wherein each R 2i is independently -H; straight chained or branched C ⁇
  • each R 22 is ..independently H, F, Cl, or straight chained or branched d-C 4 alkyl;
  • q is an integer from 2 to 4 inclusive
  • each m is an integer from 0 to 4 inclusive;
  • n is an integer from 1 to 4 inclusive
  • each p is an integer from 0 to 2 inclusive;
  • U is 0, -NR ⁇ S , S, C(R 17 ) 2 , or -NS0 2 R ⁇ 6 ;
  • Z is C 3 -C 10 cycloalkyl, C -C 7 cyclic ether, C4-C7 cyclic thioether, aryl, or heteroaryl;
  • R 16 is straight chained or branched C 1 -C 7 ' alkyl, straight chained or branched C 1 -C 7 monofluoroalkyl, straight chained or branched C 1 -C 7 polyfluoroalkyl, straight chained or branched C 2 -C 7 alkenyl, straight chained or branched C 2 -C 7 alkynyl, C5-C7 cycloalkenyl, -(CH 2 ) ra -Z, or (CH 2 ) q -0- (CH 2 ) m -CH 3 ;
  • B is aryl, or heteroaryl; provided however, if B is aryl or heteroaryl the carbon atom or carbon atoms ortho to the nitrogen atom of the i ine bond may only be substituted with one or more of the following -F, -Cl, -Br, -I, -CN, methyl, ethyl or methoxy;
  • cycloalkyl includes C 3 -C 7 cycloalkyl moieties which may be substituted with one or more of the following: -F, -N0 2 , -CN, straight chained or branched C ⁇ C 7 alkyl, straight chained or branched d-C 7 monofluoroalkyl, straight chained or branched C ⁇ -C 7 polyfluoroalkyl, straight chained or branched C 2 -C 7 alkenyl, straight chained or branched C 2 -d alkynyl, C3-C 7 cycloalkyl, C 3 -C 7 monofluorocycloalkyl, C 3 -C7 polyfluorocycloalkyl , C 5 - d cycloalkenyl, -N(R 4 ) 2 , -OR 4 , -COR 4 , -NCOR 4 , C0 2 R 4 , -
  • cycloalkenyl includes C 5 -C 7 cycloalkenyl moieties which may be substituted with one or more of the following: -F, -Cl, -Br, -I, .
  • heteroaryl is used to include five and six membered unsaturated rings that may contain one or more oxygen, sulfur, or nitrogen atoms .
  • heteroaryl groups include, but are not limited to, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, and triazinyl.
  • heteroaryl is used to include fused bicyclic ring systems that may contain one or more heteroatoms such as oxygen, sulfur and nitrogen.
  • heteroaryl groups include, but are not limited to, indolizinyl, indolyl, isoindolyl, benzo [b] furanyl, benzo [b] thiophenyl, indazolyl, benzimidazolyl, purinyl, benzoxazolyl, benzisoxazolyl, benzo [b] thiazolyl, imidazo [2, 1-b] hiazolyl, cinnolinyl, quinazolinyl, quinoxalinyl, 1,8- naphthyridinyl , pteridinyl, quinolinyl, isoquinolinyl, phthalimidyl and 2,1,3- benzothiazolyl . .
  • heteroaryl also includes those chemical moieties recited above which may be substituted with one or more of the following: -F, -Cl, -Br, - I, -N0 2 , -CN, straight chained or branched C 1 -C 7 alkyl, straight chained or branched Ci-d monofluoroalkyl, straight chained or branched C ⁇ C 7 polyfluoroalkyl, straight chained or branched C 2 -C 7 alkenyl, -straight chained or branched C 2 -d alkynyl, C 3 -C 7 cycloalkyl, C 3 -C 7 monofluorocycloalkyl, C 3 -C polyfluorocycloalkyl, C 5 -C cycloalkenyl, -N(R) 2 , - OR 4 , -COR 4 , -NCOR4 , -C0 2 R 4 ,
  • heteroaryl further includes the N-oxides of those chemical moieties recited above which include at least one nitrogen atom.
  • aryl is phenyl or naphthyl.
  • the term “aryl” also includes phenyl and naphthyl which may be substituted with one or more of the following: -F, -Cl, -Br, -I, -N0 2 , -CN, straight chained or branched C 1 -C 7 alkyl, straight chained or branched d-d monofluoroalkyl, straight chained or branched C 1 -C 7 polyfluoroalkyl, straight chained or branched C 2 -C 7 alkenyl, straight chained or branched C 2 -C 7 alkynyl, C 3 -C 7 cycloalkyl, C -C monofluorocycloalkyl , C-d polyfluorocycloalkyl , C 5 - d cycloalkenyl, -N(R 4 ) 2 , -0R 4 ,
  • each R 2 is independently one or more of the following: H, F, Cl, Br, I, CF 3 , 0CH 3 or N0 2 ;
  • R 25 is methyl, ethyl, allyl, phenyl and the phenyl is optionally substituted with a F, Cl, Br, CF 3 , N0 2 .
  • the compound is enantiomerically and diastereomerically pure. In one embodiment of any of the methods described herein, the compound is enantiomerically or diastereomerically pure.
  • the compound is a pure Z imine isomer or a pure Z alkene isomer. In one embodiment, the compound is a pure E imine isomer or a pure E alkene isomer.
  • the compound has the structure:
  • each of Yi, Y 2 , Y 3 , and Y is independently - H; straight chained or branched d-C 7 alkyl, -CF 3 , - F, -Cl, -Br, -I, -OR 4 , -N(R 4 ) 2 , or -C0N(R 4 ) 2 ;
  • each R is independently -H; straight chained or branched C 1 -C7 alkyl, -CF 3 , or phenyl;
  • A is A' , straight chained or branched C 1 -C 7 alkyl, aryl, heteroaryl, aryl (d-C 5 ) alkyl or heteroaryl (C ⁇ -C 6 ) alkyl;
  • B is heteroaryl In another embodiment, B is aryl.
  • B is phenyl and the • phenyl is optionally substituted with one or more of the following: -F, -Cl, -Br, -CF. 3 , straight chained or branched C1-C7 alkyl, -N(R 4 ) 2 , -0R , -COR 4 , -NC0R 4 , -C0 2 R 4 , or -CON (R ) 2 ,
  • A is aryl. In another embodiment, A is heteroaryl .
  • the compound is selected from the group consisting of:
  • the compound is selected from the group consisting of:
  • A is A' and A' is
  • the compound is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • B is Qg .
  • A is aryl
  • the compound has the structure
  • the compound is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • B is aryl.
  • A is (CHR ⁇ 7 ) - ( CHR 17 ) n - .
  • the compound is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N
  • the invention provides a method of treating a subject suffering from an abnormality which comprises administering to the subject an amount of compound effective to treat the subject's abnormality wherein the compound has the structure:
  • each of Y l7 Y 2 , Y 3 , and Y 4 is independently -H; straight chained or branched C ⁇ -C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; d-C 7 cycloalkyl, or C 5 -C 7 cycloalkenyl; -F, -Cl, -Br, or -I; -N0 2 ; -N 3 ; -CN; -OR 4 ,
  • each R 4 is independently -H; straight chained or branched C 1 -C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 -C 7 cycloalkyl, C5-C7 cycloalkenyl, aryl or aryl (C x - C 6 ) alkyl;
  • A is A' , straight chained or branched C 1 -C 7 alkyl, aryl, heteroaryl, aryl (d-C 6 ) alkyl or heteroaryl (Ci-Cg) alkyl;
  • Ri and R 2 are each independently H, straight chained or branched C1-C 7 alkyl, -F, -Cl, -Br, -I, -N0 2 , or -CN;
  • R 3 is H, straight chained or branched C 1 -C 7 alkyl, -F, -Cl, -Br, -I, -N0 2 , -CN, -0R 6 , ' aryl or heteroaryl;
  • R 5 is straight chained or branched d-C 7 alkyl, - N(R 4 ) 2 , -0R or aryl;
  • Rg is straight chained or branched Ci-d alkyl or aryl ;
  • B is C 3 -C7 cycloalkyl, C 5 -C7 cycloalkenyl, adamantyl, aryl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, indolizinyl, indol-4-yl, indol-5- yl, indol-6-yl, indol-7-yl, isoindolyl, benzo [b] furan-4- yl, benzo [b] furan-5-yl, benzo [b] furan-6-yl, benzo [b] furan-7-yl , benzo [b] thiophen-4-yl , benzo [b] thiophen-5-yl, benzo [b] thiophen-6-yl , benzo [b] thiophen-7-yl, indazolyl, benzimidazolyl, benzo [
  • n is an integer from 1 to 4 inclusive.
  • A is aryl, heteroaryl, heteroaryl (Ci-Cg) alkyl or - (CH 2 ) n -CC-R 4 ; wherein the aryl is substituted with -OH;
  • A is aryl, heteroaryl, or heteroaryl (Ci-Cg) alkyl
  • aryl is substituted with -F, -Cl , -Br, -I, -N0 2/ -CN, straight chained or branched d-C alkyl, straight chained or branched C 1 -C 7 monofluoroalkyl, straight chained or branched C 1 -C 7 polyfluoroalkyl, straight chained or branched C 2 -C alkenyl, straight chained or branched C 2 -C 7 - alkynyl, C 3 -C 7 cycloalkyl, C 3 -C 7 monofluorocycloalkyl, C 3 -C 7 polyfluorocycloalkyl , C 5 -C 7 cycloalkenyl, -N(R 4 ) 2 , -0R 4 , -SR 4 , -0C0R 4 , -COR 4 , -NCOR , -C0 2 R 4 , -
  • each of Y x , Y 2 , Y 3 , and Y 4 is independently -H; straight chained or branched C 1 -C7 alkyl, -CF 3 , -F, -Cl, -Br, -I, -OR , - N(R 4 ) 2 , or -C0N(R 4 ) 2 ; wherein each R 4 is independently -H; straight chained or branched C 1 -C 7 alkyl, -CF 3 , or phenyl;
  • A is A' , straight chained or branched d-C 7 alkyl, aryl, heteroaryl, aryl (Ci-Cg) alkyl or heteroaryl (Ci-Cg) alkyl;
  • B is C 3 -C 7 cycloalkyl or adamantyl.
  • B is pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, indolizinyl, indol-4-yl, indol-5-yl, indol-6-yl, indol- 7-yl, isoindolyl, benzo [b] furan-4-yl , benzo [b] furan-5- yl, benzo [b] furan-6-yl, benzo [b] furan-7-yl, benzo [b] thiophen-4-yl, benzo [b] thiophen-5-yl, benzo [b] thiophen-6-yl, benzo [b] thiophen-7-yl , indazolyl, benzimidazolyl, benzo [b] thiazolyl , purinyl, imidazo [2,1- b] thiazolyl, quinolin
  • B is aryl.
  • B is phenyl and the phenyl is optionally substituted with one or more of the following: -F, -Cl, -Br, -CF 3 , straight chained or branched C 1 -C alkyl, -N(R 4 ) 2 , -0R , -COR , NCOR , -C0 2 R 4 , or -C0N(R 4 ) 2 .
  • A is aryl
  • the compound is selected from the group consisting of:
  • A is A ' and A ' is
  • the compound is:
  • the invention provides a method of treating a subject suffering from an abnormality which comprises administering to the subject an amount - of compound effective to treat the subject's abnormality wherein the compound has the structure:
  • each of Yi, Y 2 , Y 3 , and Y 4 is independently -H; straight chained or branched C ⁇ -C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 -d cycloalkyl or C 5 -d cycloalkenyl; -F, -Cl, -Br, or -I; -N0 2 ; -N 3 ; -CN; -0R , -SR 4 , -0C0R 4 , -C0R 4 , -NC0R 4 , -N(R 4 ) 2 , -C0N(R 4 ) 2 , or - C00R 4 ; aryl or heteroaryl; or any two of Y l t Y 2 , Y 3 and Y 4 present on adjacent carbon atoms can '
  • each R 4 is independently -H; straight chained or branched C 1 -C alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 -C 7 cycloalkyl, C5-C7 cycloalkenyl, aryl or aryl (C x - C 6 ) alkyl;
  • A is A' , straight chained or branched d-C 7 alkyl, aryl, heteroaryl, aryl (C ⁇ -C 6 ) alkyl or heteroaryl (d ⁇ ) alkyl ;
  • Ri and R 2 are each independently H, straight chained or branched C 1 -C 7 alkyl, -F, -Cl, -Br, -I, -N0 2 , or ' -CN;
  • R 3 is H, straight chained or branched C 1 -C 7 alkyl, -F, -Cl, -Br, -I, -N0 2 , -CN, -OR 6 , aryl or heteroaryl;
  • R 5 is straight chained or branched d-C 7 alkyl, N ( R ) 2 , -OR 4 or aryl ;
  • Rg is straight chained or branched C1-C7 alkyl or aryl
  • B is aryl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, indolizinyl, indol-4-yl, indol-5- yl, indol-6-yl, indol-7-yl, isoindolyl, benzo [b] furan-4- yl , benzo [b] furan-5-yl, benzo [b] furan-6-yl, benzo [b] furan-7-yl, benzo [b] thiophen-4-yl, benzo [b] thiophen-5-yl, benzo [b] thiophen-6-yl , benzo [b] thiophen-7-yl, indazolyl, benzimidazolyl, benzo [b] thiazolyl, purinyl, imidazo [2 , 1-b] thiazolyl, quinolinyl,
  • n is an integer from 1 to 4 inclusive;
  • the compound is A is aryl, heteroaryl, heteroaryl (C ⁇ -C 6 ) alkyl or - (CH 2 ) n -CC-R 4 ; wherein the aryl is substituted with -OH;
  • A is aryl, heteroaryl, or heteroaryl (Ci-Cg) alkyl
  • aryl is substituted with -F, -Cl, -Br, -I, -N0 2 , -CN, straight chained or branched d-C 7 alkyl, straight chained or branched C ⁇ C 7 monofluoroalkyl, straight chained or branched C x -C 7 polyfluoroalkyl, straight chained or branched C 2 -C 7 alkenyl, straight chained or branched C 2 -C alkynyl, C 3 -C 7 cycloalkyl, C 3 -C 7 monofluorocycloalkyl, C 3 -C 7 polyfluorocycloalkyl , C 5 -C 7 cycloalkenyl, -N(R) 2 , -OR 4 , -SR 4 , -OCOR 4 , -COR 4 , -NCOR 4 , -CO 2 R 4 , -CON(R 4 ) 2
  • the compound is an enantiomerically and diastereomerically pure compound.
  • the compound is an enantiomerically or diastereomerically pure compound.
  • the compound is a pure Z imine isomer or a pure Z alkene isomer of the compound.
  • the compound is a pure E imine isomer or a pure E alkene isomer of the compound.
  • A is A', straight chained or branched C 1 -C7 alkyl, aryl, heteroaryl, aryl (Ci-Cg) alkyl or heteroaryl (Ci-Cg) alkyl;
  • each of Y x , Y 2 , Y 3 , and Y 4 is independently -H; straight chained or branched d-C 7 alkyl, -CF 3 , -F, -Cl, -Br, -I, -OR 4 , -N(R ) 2 , or - CON(R 4 ) 2 .
  • A is aryl or aryl (C ⁇ d) alkyl .
  • the compound is selected from the group consisting of:
  • the invention provides a pharmaceutical composition comprising a therapeutically effective amount of any of the compounds described herein and a pharmaceutically acceptable carrier.
  • the invention provides a pharmaceutical composition made by combining a therapeutically effective amount of any of the compounds described herein and a pharmaceutically acceptable carrier.
  • the invention provides a process for making a pharmaceutical composition comprising combining a therapeutically effective amount of any of the compounds described herein and a pharmaceutically acceptable carrier .
  • the invention provides a method of treating a subject suffering from an abnormality which comprises administering to the subject an amount of any of the compounds described herein effective to treat the subject's abnormality.
  • the abnormality ' is a regulation of a- steroid or pituitary hormone disorder, an epinephrine release disorder, a gastrointestinal disorder, a cardiovascular disorder, an electrolyte balance disorder, hypertension, diabetes, a respiratory disorder, asthma, a reproductive function disorder, an immune disorder, an endocrine disorder, a musculoskeletal disorder, a neuroendocrine disorder, a cognitive disorder, a memory disorder such as Alzheimer's disease, a learning disorder, a sleep disorder, a sensory modulation and transmission disorder, a motor coordination disorder, Huntington's disease, a sensory integration disorder, a motor integration disorder, a dopaminergic function disorder such as Parkinson's disease, a sensory transmission disorder, an olfaction disorder, a sympathetic innervation disorder, a stress- related disorder, a fluid-balance disorder, a seizure disorder, pain, inflammatory pain, chronic pain, psychotic behavior such as schizophrenia, morphine tolerance, drug addition particularly opiate addiction, migraine, an
  • the abnormality is Alzheimer's disease, obesity, diabetes, or pain, particularly neuropathic pain.
  • the invention provides a method of treating a subject suffering from pain which comprises administering to the subject an amount of any of the compounds described herein effective to treat the subject's pain.
  • the invention provides a method of treating a subject suffering from neuropathic pain which comprises administering to the subject an amount of any of the compounds described herein effective to treat the subject's neuropathic pain.
  • stereoisomers may include enantiomers, diastereomers, or E or Z alkene or imine isomers.
  • the invention also' provides for stereoisomeric mixtures, including racemic mixtures, diastereomeric' mixtures, or E/Z isomeric mixtures.
  • Stereoisomers can be synthesized in pure form (N ⁇ gradi, M.; Stereoselective Synthesis, (1987) VCH Editor Ebel, H. and Asymmetric Synthesis, Volumes 3 - 5, (1983) Academic ' Press, Editor Morrison, J. ) or they can be resolved by a variety of- methods such as crystallization and chromatographic techniques (Ja ues, J. ; Collet, A. ; Wilen, S . ; Enantiomer, Racemates, and Resolutions, 1981, John Wiley and Sons and Asymmetric Synthesis, Vol. 2, 1983, Academic Press, Editor Morrison, J) .
  • the compounds of the present invention may be present as enantiomers, diasteriomers , isomers or two or ' more of the compounds may be present to form a racemic or diastereomeric mixture.
  • the compounds of the present invention are preferably 80% pure, more preferably 90% pure, and most preferably 95% pure.
  • the acids and bases from which these salts are prepared include but are not limited to the acids and bases listed herein.
  • the acids include, but are not limited to, the following inorganic acids: hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid and boric acid.
  • the acids include, but are not limited to, the following organic acids: acetic
  • the bases include, but are not limited to ammonia, methylamine, etbylamine, propylamine, dimethylamine, diethylamine, trimethyla ine, triethylamine, ethylenediamine, hydroxyethylamine, morpholine, piperazine and guanidine.
  • This invention further provides for the hydrates and polymorphs of all of the compounds described herein.
  • the present invention includes within its scope prodrugs of the compounds of . the invention.
  • prodrugs will be functional derivatives of the compounds of the invention which are readily convertible in -vivo into the required compound.
  • the term "administering" shall encompass the treatment of the various conditions described with the compound specifically disclosed or with a compound which may not be specifically disclosed, but which converts to the specified compound in vivo after administration to the patient.
  • Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in Design of Prodrugs, ed. H. Bundgaard, Elsevier, 1985.
  • the present invention further includes ' metabolites of the compounds of the present invention.
  • - Metabolites include active species produced upon introduction of compounds of this invention into the biological milieu.
  • binding- affinity describes the concentration of a compound required to occupy one-half of the binding sites in a receptor population, as detectable by radioligand binding. Binding affinity concentration can be represented as Ki, inhibition constant, or K D , dissociation constant.
  • selectivity of binding affinity refers to the ability of a chemical compound to discriminate one- receptor from another. For example, a compound showing selectivity for receptor A versus receptor B will bind receptor A at lower concentrations than those required to bind receptor B.
  • the statements of the form "binds to the GAL3 receptor with a binding affinity at least ten-fold higher than” a named receptor, indicates that the binding affinity at the GAL3 receptor is at least ten- fold greater than that for a named receptor, and binding affinity measurements (i.e. Ki or K D ) for' the compound are at least ten- fold lower in numerical value.
  • the present invention provides a method of treating an abnormality in a subject which comprises administering to the subject a composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a GAL3 receptor antagonist, wherein: the GAL3 receptor antagonist binds to the human GAL3 receptor with a binding affinity at least ten-fold higher than the binding affinity with which it binds to the human GAL1 receptor.
  • the GAL3 receptor antagonist binds to the human GAL3 receptor with a binding affinity at least 30-fold higher than the binding affinity with which it binds to the human GAL1 receptor.
  • the GAL3 receptor antagonist binds to the human GAL3 receptor with a binding affinity at least 50-fold higher than the binding affinity with which it binds to the human GAL1 receptor.
  • the GAL3 receptor antagonist binds to the human GAL3 receptor with a binding affinity at least 100-fold higher than the binding affinity with which it binds to the human GAL1 receptor.
  • the GAL3 receptor antagonist binds to the human GAL3 receptor with a , binding affinity at least 200-fold higher than the binding affinity with which it binds to the human GAL1 receptor.
  • antagonist refers to a compound- which binds to,' and decreases the activity of, a receptor in the presence of an agonist.
  • activation may be measured using an appropriate second messenger system which is coupled to the receptor in a cell or tissue in which the receptor is expressed.
  • second messenger systems are adenylate cyclase, intracellular calcium' mobilization, ion channel activation, guanylate cyclase, inositol phospholipid hydrolysis, and MAP kinase activation.
  • agonist refers to a compound which, binds to, and increases the activity of, a receptor as compared with the activity of the receptor in the absence of any agonist.
  • Methods to perform second messenger assays are described in PCT International Publication No. 97/46250 and in PCT International Publication No. 98/15570, the contents of which are hereby incorporated by reference.
  • the antagonist may act as an inverse agonist or an allosteric modulator, as opposed to a neutral antagonist, and suppress receptor signaling independent of the agonist (Lutz and Kenakin, 1999) .
  • the categories of "antagonist compounds” are therefore seen to include 1) neutral antagonists (which block agonist actions but do not affect constitutive activity); 2) inverse agonists (which block agonist actions as well as constitutive activity by stabilizing an inactive receptor conformation); 3) and allosteric modulators (which block agonist actions to a limited extent and which may .also block constitutive • activity through allosteric regulation) .
  • the subject invention provides GAL3 antagonists which selectively bind to the GAL3 receptor.
  • a GAL3 antagonist useful in -the ' treatment of pain is one which selectively binds' to the GAL3 receptor, and displays analgesic activity in an animal model which is predictive of the efficacy of analgesics to treat pain in humans. Animal models used to test potential analgesic agents are well known in the art .
  • the cloned cDNAs encoding both the human, and rat GALl and GAL2 receptors have been used.
  • the cloning and assay methods for the human and rat GALl receptors may be found in PCT International Publication No. WO 95/22608, the contents of which are hereby incorporated by reference.
  • the cloning and assay methods for the human and rat GAL2 receptors may be found in PCT International Publication No. WO 97/26853, the contents of which are hereby incorporated by reference.
  • the present invention provides for a method of determining the binding affinity of a GAL3 antagonist, wherein the GAL3 antagonist is dissolved in a "suitable solvent” .
  • a "suitable solvent” means one which permits the measurement of binding affinity of the GAL3 antagonist to the human GAL3 receptor at concentrations less than 1 ⁇ M, preferably less than 100 nM.
  • solvents include, but are not limited to, DMSO, ethanol, N,N-dimethylacetamide, or water.
  • the preferred .solvent is 3% DMSO (final concentration in the assay).
  • the preferred solvent is 1% ethanol/0.09% polypuronic acid F-127 (final concentration in the assay) .
  • the preferred solvent is the solvent which permits the measurement of binding affinity of a GAL3 antagonist at the lowest concentration. Once ' a suitable solvent is ascertained for the binding assay of the human GAL3 receptor, the same solvent is used in assays to determine the binding affinity for instance, at the GALl receptor .
  • the aforementioned GAL3 receptor antagonist additionally binds to the human GAL3 receptor with a binding affinity at least ten-fold higher than the binding affinity with which it binds to the human GAL2 receptor.
  • the GAL3 receptor antagonist additionally binds to the human GAL3 receptor with a binding, affinity at least 30-fold higher than the binding affinity with which it binds to the human GAL2 receptor.
  • the GAL3 receptor antagonist additionally binds to the human GAL3 receptor with a binding affinity at least 50-fold higher than the binding affinity with which it binds to the human GAL2 receptor.
  • the GAL3 receptor antagonist additionally binds to the human GAL3 receptor with a binding affinity at least 100-fold higher than the binding affinity with which it binds to . he human GAL2 receptor.
  • the GAL3 receptor antagonist additionally binds to the human GAL3 receptor with a binding affinity at least 200-fold higher than the binding affinity with which it binds to the human GAL2 receptor. In other embodiments, the receptor antagonist also binds to the human GAL3 receptor with a binding affinity at least ten-fold higher than the binding affinity with which it binds to each of the human 5HT ⁇ B , human 5HT ⁇ D , 5 human .5HT ⁇ E , human 5HT ⁇ F , human 5HT 2A , rat 5HT 2C , human 5HT 5 and human 5HT 7 receptors .
  • the receptor antagonist also binds to the human GAL3 receptor with a binding 0 affinity at least ten-fold higher than the binding affinity with which it binds to the human histamine Hi receptor.
  • the receptor antagonist 5 also binds to the human GAL3 receptor with a binding affinity at least ten-fold higher than the binding affinity with which it binds to the human dopamine D x , D 2 , D 3 , D 4 and D 5 receptors.
  • the receptor antagonist also binds to the human GAL3 receptor with a binding affinity at least ten-fold higher than the binding affinity with which it binds to the human ⁇ iA adrenoceptor, the human
  • the receptor antagonist also serves as a amine, amine, amine, amine, amine, amine, amine, amine, amine, amine, amine, amine, amine, amine, amine, amine, amine, amine, amine, amine, amine, amine, amine, amine, amine, amine, amine, amine, amine, amine, amine, amine, amine, amine, amine
  • ' ⁇ binds to the human GAL3 receptor with a binding affinity at least ten-fold higher than the binding affinity with which it binds to the human 2A adrenoceptor, the human 0 ⁇ 2B adrenoceptor and the human ⁇ 2c adrenoceptor.
  • the binding properties of compounds at • different receptors were determined using cultured cell lines that selectively express the receptor of interest.
  • Cell lines were ' prepared by transfecting the cloned cDNA or cloned genomic DNA or constructs containing both genomic DNA and cDNA encoding the receptors as further described in the Experimental Details herein below.
  • the binding interactions of compounds at different transporters were determined using tissue preparations and specific assays as further described in the Experimental Details herein below.
  • the "human Dm” receptor was renamed the "human Di” receptor.
  • This invention further provides a . ' pharmaceutical composition
  • a . ' pharmaceutical composition comprising a therapeutically effective amount of the compound of the invention and a pharmaceutically acceptable carrier.
  • the amount of the compound is an amount from about 0.01 mg to about 800 mg.
  • the amount of the compound is an amount from about 0.01 mg to about 500 mg .
  • the amount of the compound is an amount from about 0.01 mg to about 250 mg.
  • the amount of the compound is an amount from about 0.1 mg to about 60 mg.
  • the amount of the compound is an amount from about 1 mg to about 20 mg.
  • the carrier is a liquid and the composition is a solution.
  • the carrier is a solid and the composition is a powder or tablet.
  • the carrier is a gel and the composition is a capsule or suppository.
  • This invention provides a pharmaceutical composition made by combining a therapeutically effective amount of the compound of this invention and a pharmaceutically acceptable carrier.
  • This invention provides a process for making a pharmaceutical composition comprising combining a therapeutically effective amount of the compound of this invention and a pharmaceutically acceptable carrier.
  • a “therapeutically effective amount” is any amount of a compound which, when administered to a subject suffering from a disease against which the compounds are effective, causes reduction, remission, or regression of the disease.
  • a “subject” is a vertebrate, a mammal; or a human.
  • the present invention provides for the use of any of the chemical compounds disclosed herein for the preparation of a pharmaceutical composition for treating an abnormality.
  • the invention also provides for the use of a chemical compound for the preparation of • a pharmaceutical composition for treating an abnormality, wherein the abnormality is alleviated by decreasing the activity of a human GAL3 receptor.
  • the abnormality is pain.
  • the abnormality is neuropathic pain.
  • the abnormality is Alzheimer's disease.
  • the abnormality is obesity.
  • the abnormality is diabetes.
  • the term "pharmaceutically acceptable carrier” is any pharmaceutical carrier known to those of ordinary skill in the art as useful in formulating pharmaceutical compositions.
  • the Food and Drug Administration of the United States Department of Health and Human Services published a guidance entitled "Q3C Impurities: Residual Solvent”.
  • the guidance recommends acceptable amounts -of residual solvents in pharmaceuticals for the safety of the patient, and recommends the use of less toxic solvents in the manufacture of drug substances and dosage forms.
  • the pharmaceutical carrier may be a liquid and the pharmaceutical composition would be in the form of a solution.
  • the pharmaceutically acceptable carrier is a solid and the composition is in the form of a powder or tablet.
  • the pharmaceutical carrier is a gel and the composition is in the form of a suppository or cream.
  • the compound may be formulated as a part of a pharmaceutically acceptable transdermal patch.
  • the compound may be delivered to the subject by means of a spray or inhalant.
  • a solid carrier can include one or more substances which may also act as endogenous carriers (e.g. nutrient or micronutrient carriers), flavoring agents, lubricants, - solubilizers , suspending agents, fillers, glidants, compression aids, binders or tablet-disintegrating agents; it can also be an encapsulating material.
  • the carrier is a finely divided solid which is in admixture with the finely divided active ingredient.
  • the active ingredient is mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape ' and size desired.
  • the powders and tablets preferably contain ' up to 99% of the active ingredient.
  • Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins.
  • Liquid carriers are used in preparing solutions, suspensions, emulsions, syrups, elixirs and pressurized compositions.
  • the active ingredient can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fats.
  • the liquid carrier can contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers or osmoregulators .
  • suitable examples of " liquid carriers for oral and parenteral administration include water (partially containing additives as above, e.g.
  • cellulose derivatives preferably sodium carboxymethyl cellulose solution
  • alcohols including monohydric alcohols and polyhydric alcohols, e.g. glycols) and their derivatives, and oils (e.g. fractionated coconut oil and arachis oil)
  • oils e.g. fractionated coconut oil and arachis oil
  • the carrier can also be an oily ester such as ethyl oleate or isopropyl myristate.
  • Sterile liquid carriers are useful in sterile liquid form compositions for parenteral administration.
  • the liquid carrier for pressurized compositions can be halogenated hydrocarbon or other pharmaceutically acceptable propellent.
  • Liquid pharmaceutical compositions which are sterile solutions or suspensions can be utilized by for example, intramuscular, • intrathecal, epidural, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously.
  • the compounds may be prepared as a sterile solid composition which may be dissolved or suspended at the time of administration using sterile water, saline, or other appropriate sterile injectable medium.
  • Carriers are intended to include necessary and inert binders, suspending agents, lubricants, flavorants, sweeteners, preservatives, dyes, and coatings .
  • the compound can be administered orally in the form of a sterile solution or suspension containing other solutes or suspending agents (for example, enough saline or glucose to make the solution isotonic), bile salts, acacia, gelatin, sorbitan monoleate, polysorbate 80 (oleate esters of sorbitol and its anhydrides copolymerized with ethylene oxide) and the like.
  • solutes or suspending agents for example, enough saline or glucose to make the solution isotonic
  • bile salts for example, enough saline or glucose to make the solution isotonic
  • acacia gelatin
  • sorbitan monoleate sorbitan monoleate
  • polysorbate 80 oleate esters of sorbitol and its anhydrides copolymerized with ethylene oxide
  • compositions suitable for oral' administration include solid forms, such as pills, capsules, granules, tablets, and powders, -and liquid forms, such as solutions, syrups, elixirs, and suspensions.
  • forms useful for parenteral administration include sterile solutions, emulsions, and suspensions.
  • Optimal dosages to be administered may be determined by those skilled in the art, and will vary with the particular compound in use, the strength of the preparation, the mode of administration, and the advancement of the disease condition. Additional factors depending on the particular subject being treated will result in a need to adjust dosages, including subject age, weight, gender, diet, and time of administration.
  • TLC Chromatography
  • HOAc acetic acid
  • DIPEA diisopropylethylamine
  • DMF N, N- dimethylfor amide
  • EtOAc ethyl acetate
  • MeOH methanol
  • TEA triethylamine
  • THF tetrahydrofuran
  • the compounds of this invention were prepared by sucessively displacing the three chlorine atoms of a 2 , 4, 6-trichloropyrimidine with amines. It was found that some amines (i.e. anilines) selectively displace the 2-position chlorine of 2 , 4 , 6-tric-hloropyrimidine, whereas other amines (e.g. piperidine) selectively displace the 4- or 6-position chlorine first (note that the 4- and 6- positions are chemically equivalent) . Some amines react non-selectively at both the 2- and 4- positions of 2 , 4 , 6-trichloropyrimidine.
  • 6-DiCHLORO--V-PH ⁇ NYL-2-PYRIMIDINAMINE A solution of 2 , 4 , 6-trichloropyrimidine (5.5 g, 30 mmol) in tetrahydrofuran (15 mL) was added dropwise to a solution of aniline (2.8 mL, 1 equivalent) in tetrahydrofuran (25 mL) . N, iV-diisopropylethylamine (5.2 mL) was added and the solution was stirred at room temperature overnight. The solvent was removed and the crude material was purified by flash chromatography on silica gel.
  • Procedure D 2 , 4-DICHLORO-6- (1-PIPERIDINYL) PYRIMIDINE: A mixture of 2 , 4 , 6-trichloropyrimidine (5.0 g, 27 mmol) and piperidine (2.3 g, 27 mmol) in tetrahydrofuran (50 L) and N, IV-diisopropylethylamine (3.5 g, 27 mmol) was stirred at room temperature for 24 hours. The solvent was removed and the crude material was purified by flash chromatography on silica gel. The column was eluted with a gradient of hexane to yield ethyl acetate/hexane
  • PIPERIDINYD-2-PYRIMIDINAMINE A mixture of 2,4- dichloro-6- (1-piperidinyl) pyrimidine (80 mg, 0.34 mmol), -methyItryptamine (59 mg, 0.34 mmol) , and potassium carbonate (47 mg, 0.34 mmol) in chlorobenzene ( 1 mL) was heated at 150°C in a sealed tube for 16 hours. The solvent was removed and the crude material was purified by preparative TLC, eluting with cyclohexane/ethyl acetate (4:1).
  • N- (4-METHYLPHENYL) -2- [4- ( 3-METHYL-2-PYRIDINYL) -1- PIPERAZINYL] -6- (1-PIPERIDINYL) -4-PYRIMIDINAMINE A mixture of N- (4-methylphenyl) -2- (1-piperazinyl) -6- (1- piperidinyl) -4-pyrimidinamine (100 mg, 0.284 mmol), 2- bromo-3 -methylpyridine (54 mg, 0.312 mmol), 1,1'- (bisdiphenylphosphino) -1, 1 ' -binaphthol (13 mg) , tris (dibenzylidene acetone) dipalladium ( 0 ) (13 mg) , and sodium tert-butoxide (136 mg) in dry toluene (4 mL) was heated at 90°C in a sealed tube for 2 hours.
  • PHENYLACETAMIDE A mixture of iV 4 , .N 4 -dimethy1-iV 5 - (4- ethylphenyl) -2, 4, 6-pyrimidinetriamine (122 mg, 0.50 mmol), phenylacetyl chloride (84 mg, 0.55 mmol), and triethylamine (100 mg, 1.00 mmol) in CH 2 C1 : was stirred at room temperature for 16h. The crude product was concentrated in vacuo and treated with saturated NaHC0 3 (50 L) and extracted with CH 2 C1 2 (3 X 50 mL) .
  • 6-CHL ⁇ RO-IV 4 - (4-METHYLPHENYL) -2 , 4-PYRIMIDINEDIAMINE A mixture of 4 , 6-dichloro-2-pyrimidinamine (1.64 g, 0.01 mol), p-toluidine (1.07 g, 0.01 mol) in dioxane (2 mL) was heated in a sealed- tube for 30 minutes at 140 °C . The crude product was treated with NaOH (50 ml, 2M) . and extracted with CH 2 Cl 2 - ⁇ (3 X 50 mL) .
  • the crude product was treated with saturated NaHC0 3 (50 L) and extracted with EtOAC (3. X 50 mL) . The organic layer was washed with brine (2 X 100 mL) , dried over Na 2 S0 4 , filtered, and concentrated in vacuo . The crude product was purified by chromatography on silica using hexane/EtOAc (1:3), giving the desired product (25 mg, 57 %) .
  • Procedure Z 2- [4- (2-METHOXYBENZYL) -1-PIPERAZINYL] -IV 4 , AT-DIMETHYL-V 5 - (4-METHYLPHENYL) -4, 6-PYRIMIDINEDIAMINE: A mixture of IV 4 , IV 4 -dime hyl-IV 6 - (4-methylphenyl) -2- ( 1-piperazinyl) -4, 6- pyrimidinediamine (30 mg, 0.086 mmol), 1- (chloromethyl ) - 2-methoxybenzene (17 mg, 0.1 mmol) and triethylaminie (200 mg, 2 mmol) in 1 DMF (1 mL) heated by microwave at 200 °C for 12 minutes.
  • the crude product was treated with saturated NaHC0 3 (50 mL) and extracted with EtOAC (3 X 50 mL) . The organic layer was washed with brine (2 X 100 mL) , dried over Na 2 S0 , filtered, and concentrated in vacuo . The crude product was purified by chromatography on silica using hexane/EtOAc (1:3), giving the desired product (10 mg, 27 %) .
  • IV 4 - (3-methoxyphenyl) -IV 5 , IV 6 -dimethyl-2- ( 1- piperazinyl) -4 , 6-pyrimidinediamine (33 mg, 0.1 mmol), 2- thiophenecarbonyl chloride (20 mg, 0.14 mmol), and triethylamine (40 mg, 0.4 mmol) in CH 2 C1 2 (5 mL) was stirred at room temperature for 16 h.
  • the crude product was concentrated in vacuo and treated with saturated NaHC0 3 (50 mL) and extracted with CH 2 C1 2 (3 X 50 mL) . The organic layer was washed with brine "(2 X 100 mL) , dried over Na 2 S0 , filtered, and concentrated in vacuo .
  • the crude product was purified by chromatography on silica using hexane/EtOAc (1:3), giving the desired product as a pale red oil (35 mg, 80 %) .
  • IV 4 ,IV-DIMETHYL-IV 5 -(4-METHYLPHENYL) -2,4,6- PYRIMIDINETRIAMINE A mixture of 6-chloro-V 4 - (4- methylphenyl) -2, 4-pyrimidinediamine (1.5 g, 6.4 mmol), and IV, N-dimethylamine hydrochloride (0.56 g, 7 mmol) and triethylamine (1.4 g, 14 mmol) in DMF (2 mL) , was heated at 170 °C for 16 h. The product was filtered out and the organic layer was treated with saturated NaHC0 3 (50 mL) and extracted with EtOAC (3 X 50 mL) .
  • Example 2 lACYCLOHEXYL-IV 2 - ( 2 -METHOXYETHYL) -IV 4 - (4- METHYLPHENYL) -6- (1-PIPERIDINYL) . -2 , 4-PYRIMIDINEDIAMINE : 15 Prepared by Procedures D, J (130°C) , and F (2 hours) .
  • Example 5 IV 2 - (4-CHLOROPHENYL) -IV 4 - (4-METHYLPHENYL) -6- (1- PIPERIDINYL) -2 , 4-PYRIMIDINEDIAMINE: Prepared by Procedures D, G (for substitution with 4-chloroaniline), and G (3.5 hours).
  • Example 7 lAMETHYL-AlADI (4-METHYLPHENYL) -6- ( 1- PIPERIDINYL) -2 , 4-PYRIMIDINEDIAMINE: Prepared by
  • Example 8 IV 2 - [2- ( 5-METHYL-IH-3 -INDOLYL) ETHYL] -IV 4 - (4- METHYLPHENYL) -6- ( 1-PIPERIDINYL) -2 , 4-PYRIMIDINEDIAMINE: Prepared by Procedures D, J, and G (160°C, 12 hours) .
  • Example 9 IV 2 - [2- ( 5-METHOXY-IH-3 -INDOLYL) ETHYL] -IV 4 - ( 4- METHYLPHENYL)-6-(l-PIPERID-GNYL) -2 , 4-PYRIMIDINEDIAMINE : " Prepared by Procedures D, E (160 °C, 36 hours) , and G.
  • Example 12 IV 2 - [2- (1F-INDQL-3-YL) ETHYL] -IV 2 -METHYL-IV 4 - PHENETHYL-6- (1-PIPERIDINYL) -2 , 4-PYRIMIDINEDIAMINE :
  • Example 13 IV 2 - [2- (lff-INDQL-3-YL) ETHYL] -V 2 -METHYL-IV 4 - (2- NAPHTHYL) -6- ( 1-PIPERIDINYL) -2 , 4-PYRIMIDINEDIAMINE :
  • Example 14 IV 4 - (3-FLUOROPHENYL) -IV 2 - [2- ( lff-INDOL-3- YL) ETHYL] -IV 2 -METHYL-6- (1-PIPERIDINYL) -2,4- PYRIMIDINEDIAMINE : Prepared by Procedures D, E (160°C, 12 hours, for substitution with IV-methyltryptamine), and G.
  • Example 15 IV 4 - (3 , 4-DIFLUOROPHENYL) -IV 2 - [2- (1H-INDOL-3- YL) ETHYL] -lAMETHYL- ⁇ - (1-PIPERIDINYL) -2 , 4- PYRIMIDINEDIAMINE : Prepared by Procedures D, E (160°C, 12 hours, for substitution with IV-methyltryptamine), and G.
  • Example 16 IV 4 - ( 3 -CHL0R0-4-METHYLPHENYL) -IV 2 - [2- (1H-INDOL- 3-YL) ETHYL] - ⁇ -METHYL- ⁇ - (1-PIPERIDINYL) -2,4- PYRIMIDINEDIAMINE : Prepared by Procedures D, E (160°C, 12 hours, for substitution with IV-methyltryptamine), and G.
  • Example 18 lAETHYL-IV 2 - [2- (lff-INDOL-3-YL) ETHYL] -A? 4 - (4- METHYLPHENYL) -6- (1-PIPERIDINYL) -2 , 4- ' PYRIMIDINEDIAMINE : Prepared by Procedures D, E (160°C, 12 hours, for substitution with V-ethyltryptamine) , and G.
  • Example 20 TV 2 - [2- (Iff-3 -INDOLYL) -1-METHYLETHYL] -IV 4 - (4- METHYLPHENYL) -6- ( 1-PIPERIDINYL) -2, 4-PYRIMIDINEDIAMINE: Prepared by Procedures D, J, and G. : H NMR (300.
  • Example 21 IV 2 - [2 - (lff-INDQL-3-YL) -1-METHYLETHYL] -IV 2 - METHYL-lAf 4-METHYLPHENYL) -6- (1-PIPERIDINYL) -2,4- PYRIMIDINEDIAMINE : Prepared by Procedures D, E (160°C, 12 hours, for substitution with N, or-dimethyltryptamine) , and G.
  • Example 22 IV 2 -METHYL-IV 4 - (4-METHYLPHENYL) -lAPHENETHYL- ⁇ - ( 1-PIPERIDINYL) -2 , 4-PYRIMIDINEDIAMINE : Prepared by Procedures D, E (160°C, 12 hours, for substitution at C2 of the pyrimidine) , and G. ESI-MS m/z 402 (MH T ) .
  • Example 25 N- (4-METHYLPHENYL) -2- (4-PHENYLPIPERAZINYL) - 6- (1-PIPERIDINYL) -4-PYRIMIDINAMINE: Prepared by Procedures D, G (180°C, 2.5 hours, for substitution with V-phenylpiperazine) , and G (140°C, overnight) .
  • Example 26 2- [4- (2-ETHYLPHENYL) -1-PIPERAZINYL] -N- (4- METHYLPHENYL) -6- ( 1-PIPERIDINYL) -4-PYRIMIDINAMINE : Prepared by Procedures D, E (120°C) , and F.
  • Example 27 2- [4- (2 , 6-DIMETHYLPHENYL) -1-PIPERAZINYL] -N- (4-METHYLPHENYL) -6- (1-PIPERIDINYL) -4-PYRIMIDINAMINE :
  • Example 28 - ⁇ 2- [4- (2 , -DIMETHOXYPHENYL) PIPERAZINYL] -6- (1-PIPERIDINYL) -4-PYRIMIDINYL ⁇ -TV- (4-METHYLPHENYL) AMINE : Prepared by Procedures D, E (150°C, 16 hours), and F (5 hours).
  • Example 29 IV- (4-METHYLPHENYL) -6- ( 1-PIPERIDINYL) -2- ⁇ 4- [3- (TRIFLUOROMETHYL) PHENYL] -1-PIPERAZINYL ⁇ -4-
  • Example 30 N- (4-METHYLPHENYL) -6- (1-PIPERIDINYL) -2- [4- (2-PYRIDYL) -1-PIP ⁇ RAZINYL] -4-PYRIMIDINAMINE : Prepared by Procedures D, G (120°C, 12 hours, for substitution . with IV-pyrid-2-ylpiperazine) , and G (140°C) .
  • PYRIDINYL) -1-PIPERAZINYL] -6- (1-PIPERIDINYL) -4- PYRIMIDINAMINE Prepared from 2- (4-benzyl-l- piperazinyl) -N- (4-methylphenyl) -6- (1-piperidinyl) -4- pyrimidinamine by Procedures K and L.
  • Example 32 N- (4-METHYLPHENYL) -6- (1-PIPERIDINYL) -2 - ⁇ 4- [4- (TRIFLUOROMETHYL) -2-PYRIDINYL] -1-PIPERAZINYL) -4- PYRIMIDINAMINE : Prepared by Procedures D, E (16 hours), and F. ESI-MS m/z 498 (MH + ) .
  • Example 33 N- (4-METHYLPHENYL) -6- (1-PIPERIDINYL) -2- ⁇ 4- [6- (TRIFLUOROMETHYL) -2-PYRIDINYL] -1-PIPERAZINYL ⁇ -4- PYRIMIDINAMINE : Prepared by Procedures D, E (16 hours) , and F.
  • Example 34 N- (4-METHYLPHENYL) -6- ( 1-PIPERIDINYL) -2- ⁇ 4- [3- (TRIFLUOROMETHYL) -2-PYRIDINYL] -1-PIPERAZINYL) -4- PYRIMIDINAMINE : Prepared by Procedures D, E (16 hours) , and F.
  • Example 35 IV-CYCLOHEXYL-6- (1-PIPERIDTNYL) -2- ⁇ 4- [3- (TRIFLUOROMETHYL) -2-PYRIDINYL] -1-PIPERAZINYL) -4- PYRIMIDINAMINE : Prepared by Procedures M, E (120°C, for addition of piperidine) , and F (3 hours) .
  • Example 36 7V-BICYCLO[2.2.1] HEPT-2-YL-6- ( 1-PIPERIDINYL) - 2- ⁇ 4- [3- (TRIFLUOROMETHYL) -2-PYRIDINYL] -1-PIPERAZINYL ⁇ -4- PYRIMIDINAMINE : Prepared by Procedures M, E (120°C, for addition of piperidine) , and F (3 hours) .
  • Example 37 N- (4-METHYLPHENYL) -6- (1-PIPERIDINYL) -2- [4- (2 -PYRIMIDINYL) -1-PIPERAZINYL] -4-PYRIMIDINAMINE :
  • Example 38 AT- (4-METHYLPHENYL) -6- (1-PIPERIDINYL) -2- (1- PYRROLIDINYL) -4-PYRIMIDINAMINE: Prepared ' by Procedures D, G (120°C, 3 hours, for substitution with pyrrolidine) , and G (140°C, 12 hours).
  • Example 39 N- [ 2 - (2 , 3-DIHYDRO-lff-INDOL-l-YL) -6- ( 1- PIPERIDINYL) -4-PYRIMIDINYL] -N- ( 4-METHYLPHENYL) AMINE : Prepared by Procedures D, E (16 hours) , and F. 1 H NMR
  • Example 40 N- (4-METHYLPHENYL) -N- [ 6- (1-PIPERIDINYL) -2- (1,2,3, 4-TETRAHYDRO-l-QUINOLINYL) -4-PYRIMIDINYL] AMINE :
  • PYRIMIDINYL] AMINE Prepared by Procedures D, G (180°C, 3 hours, for substitution with 1,2,3,4- tetrahydroisoquinoline) , and G (140°C, 12 hours).
  • Example 42 IV- [2- ( 6, 7-DIMETHOXY-3 , 4-DIHYDRO-2 (Iff) - ISOQUINOLINYL) -6- (1-PIPERIDINYL) -4-PYRIMIDINYL] -A7- (4- METHYLPHENYL) AMINE : Prepared by Procedures D, E (160°C, 12 hours), and F (5 hours).
  • Example 43 IV- [2- (2 , 3-DIHYDRO-lff-BENZO [DE] ISOQUINOLIN-2 - YL) -6- (1-PIPERIDINYL) -4-PYRIMIDINYL] -IV- (4- METHYLPHENYL) AMINE : Prepared by Procedures D, E (160°C, 12 hours), and G. EST-MS m/z 436 (MH + ) .
  • Example 45 IV 2 is] -BIS ( 2-METHOXYETHYL) -TV 4 - (4- METHYLPHENYL) -6- (1-PIPERIDINYL) -2 , 4-PYRIMIDINEDIAMINE:
  • MORPHQLINYL) -6- (1-PIPERIDINYL) -4-PYRIMIDINAMINE Prepared by Procedures D, E (16 hours) , and F (1 hour) .
  • Example 48 Al- (4-METHYLPHENYL) -2- [ (2S, 3. ) ' -3 -METHYL -2- • PHENYLMORPHOLINYL] -6- (1-PIPERIDINYL) -4-PYRIMIDINAMINE: Prepared by Procedures D, E (120°C) , and F (1 hour) .
  • Example 50 IV 4 A ⁇ -DIMETHYL-AI 2 , A ⁇ -DIPHENYL-2 , 4, 6-
  • PYRIMIDINETRIAMINE Prepared by Procedures A, C, and G (140°C, overnight).
  • Example 51 IV 4 , AT 4 -DIMETHYL-IV 5 - (2-METHYLPHENYL) -A ⁇ -PHENYL-
  • Example 52 A7 4 , A ⁇ -DIMETHYL-iV 6 - (3-METHYLPHENYL) -A ⁇ -PHENYL- 2,4, 6-PYRIMIDINETRIAMINE : Prepared by Procedures A, C, and G (140°C, overnight) .
  • Example 54 AT 4 , A/ 4 -DIMETHYL-Al 5 - (4-METHYLPHENYL) -Ar " -PHENYL-
  • 2,4, 6-PYRIMIDINETRIAMINE Prepared by Procedures A, C, and G (140°C, overnight).
  • Example 55 AT 2 - (3 , 4-DIffiLOROPHENYL) -A? 4 , AT 4 -DIMETHYL-AT 6 - (4- METHYLPHENYL) -2,4, 6-PYRIMIDINETRIAMINE : " Prepared by Procedures B, C, and G (180°C, 3 hours) .
  • Example 56 AT 4 , IV 4 -DIMETHYL-AT 2 , ⁇ -BIS ( 4-METHYLPHENYL) - 2,4, 6-PYRIMIDINETRIAMINE : Prepared by Procedures B, C, and G (180°C, 3 hours).
  • Example 57 AT- ( 3 -FLUOROPHENYL) -AT 6 ,V 6 -DIMETHYL-AT 2 -PHENYL- 2,4, 6-PYRIMIDINETRIAMINE: Prepared by Procedures A, C, and G (140°C, overnight).
  • Example 58 AT 2 - (4-CHLOROPHENYL) -A? 6 , IV 6 -DIMETHYL-AT 2 -PHENYL- 2,4, 6-PYRIMIDINETRIAMINE : Prepared by Procedures A, C, and G (150°C, overnight).
  • Example 60 AT 4 - (3 , 4-DICHLORO-PHENYL) -AT 6 , AT 6 -DIMETHYL-AT 2 - PHENYL-2 , 4 , 6-PYRIMIDINETRIAMINE : Prepared by Procedures A, C, and G (Q.5mL diisopropylethylamine added, 150°C, overnight).
  • Example 61 AT 4 - ( 4-CHL0R0-3 -METHYLPHENYL) -AT 6 , A ' -DIMETHYL- A ⁇ -PHENYL- ⁇ , 4 , 6-PYRIMIDINETRIAMINE : Prepared by Procedures A, C, and G (150°C, 1 hour) .
  • Example 62 N 4 - (3 -CHLORO-4-METHYLPHENYL) -A ?6 , A? 6 -DIMETHYL- AT 2 -PHENYL-2 , 4 , 6-PYRIMIDINETRIAMINE : Prepared by Procedures A, C, and F (100°C, 3 hours) .
  • Example 63 IV 4 - (4-fcert-BUTYLPHENYL) -AT 6 , IV s -DIMETHYL-AT 2 - PHENYL-2 ,4 , 6-PYRIMIDINETRIAMINE: Prepared by Procedures A, C, and G (150°C, 5 hours).
  • Example 64 AT 4 , ⁇ -DIMETHYL-AT 6 - (4-PHENOXYPHENYL) -A ⁇ -PHENYL- 2,4, 6-PYRIMIDINETRIAMINE : Prepared by Procedures A, C, and G (150°C, 2 hours).
  • Example 66 AT 4 -CYCLOHEXYL-A7 6 , A ⁇ -DIMETHYL-AT 2 -PHENYL-2 ,4,6- PYRIMIDINETRIAMINE : Prepared by Procedures A, C, and G
  • Example 67 AT 4 , A ⁇ -DIMETHYL-AT 6 - (4-METHYLCYCLOHEXYL) -A7 2 - PHENYL-2 , 4 , 6-PYRIMIDINETRIAMINE : Prepared by Procedures A, C, and G (150°C, overnight) . ESI-MS m/z 326 (MH + ) .
  • Example 68 AT 4 - (4- cert-BUTYLCYCLOHEXYL) -AT 6 , AT 6 -DIMETHYL-AT 2 - PHENYL-2 , 4 impart 6-PYRIMIDINETRIAMINE : Prepared by Procedures A, C, and G (150°C, overnight) .
  • Example 69 A ⁇ -BICYCLO [2.2.1] HEPT-2-YL-A7 6 , Af-DIMETHYL-iV 2 - PHENYL-2 , 4 , 6-PYRIMIDINETRIAMINE : Prepared by Procedures A, C, and G (140°C) .
  • Example 71 AT 4 , AT 4 -DIMETHYL-AI 2 -PHENYL-AT g - [ (2R, 35) -3 , 6 , 6- TRIMETHYLBICYCLO [3.1.1] HEPT-2 -YL] -2,4,6-
  • PYRIMIDINETRIAMINE Prepared by Procedures A, C, and G (5 hours).
  • Example 72 AT 2 ,1V 4 , AT 4 -TRIMETHYL- ⁇ J 2 , A ⁇ -BIS (4-METHYLPHENYL) - 2,4, 6-PYRIMIDINETRIAMINE : Prepared by Procedures D, E (150°C, 16 hours), and ' F (5 hours).
  • Example 73 AT-CYCLOHEXYL-AT 2 , AT , IV 4 -TRIMETHYL-iV 6 - (4- METHYLPHENYL) -2,4, 6-PYRIMIDINETRIAMINE : Prepared by Procedures D, E (150°C, 12 hours) , and F (5 hours) .
  • Example 74 AT 2 -CYCLOHEXYL-AT 2 - ( 2 -METHOXYETHYL) -AT , AT 4 - DIMETHYL-AT 6 - ( 4-'METHYLPHENYL) -2,4, 6-PYRIMIDINETRIAMINE : Prepared by Procedures H, J (overnight) , and F (2 hours).
  • Example 75 2- (2 , 3-DIHYDRQ-lff-INDOL-l-YL) -V 4 , A ⁇ -DIMETHYL- AT 6 - (4-METHYLPHENYL-) -4 , 6-PYRIMIDINEDIAMINE : ' ' Prepared by Procedures H, E (150°C, 16 hours) , and F (2 hours) .
  • Example 80 l-[4- (DIMETHYLAMINO) -6- (4-TOLUIDINO) -2- PYRIMIDINYL] -4-PHENYL-4-PIPERIDINOL: Prepared by
  • Example 81 AT 4 , AT 4 -DIMETHYL-A7 6 - (4-METHYLPHENYL) -2- (4- PHENYL-1-PIPERIDINYL) -4 , 6-PYRIMIDINEDIAMINE : Prepared by Procedures H, E (150°C, 16 hours) , and F (4 hours) .
  • Example 82 IV 4 , A ⁇ -DIMETHYL-AT 6 - (4-METHYLPHENYL) -2- (3- PHENYL-4-MORPHOLINYL) -4, 6-PYRIMIDINEDIAMINE : Prepared by Procedures H, E (150° ' C, 20 hours) , and F (3 hours) . H.
  • Example 83 IV 4 , A ⁇ -DIMETHYL-AT*- (4-METHYLPHENYL) -2- (2- PHENYL-4-MORPHOLINYL) -4 , 6-PYRIMIDINEDIAMINE: Prepared by Procedures H, E (150°C, 20 hours), and F (3 hours).
  • Example 84 AT 4 ,AT 4 -DIMETHYL-AT 5 - (4-METHYLPHENYL) -2- ⁇ 4- [ (4- METHYLPHENYL) SULFONYL] -1-PIPERAZINYL ⁇ -4,6- '
  • Example 85 AT 4 , AT 4 -DIMETHYL-AT 6 - ( 4-METHYLPHENYL) -2- [4- (2- METHYLPHENYL) -1-PIPERAZINYL] -4, 6-PYRIMIDINEDIAMINE: Prepared by Procedures D, E (160°C, 12 hours), and F (12 hours).
  • Example 86 JJ , AT 4 -DIMETHYL-IV 5 - (4-METHYLPHENYL) -2- [4- (3- METHYLPHENYL) -1-PIPERAZINYL] -4, 6-PYRIMIDINEDIAMINE:
  • Example 87 AT 4 , AT -DIMETHYL-IV s - (4-METHYLPHENYL) -2- [4- (4- METHYLPHENYL) -1-PIPERAZINYL] -4, 6-PYRIMIDINEDIAMINE:
  • Example 88 AT 4 , A ⁇ -DIMETHYL-AT 6 - (4-METHYLPHENYL) -2- ⁇ 4- [3- (TRIFLUOROMETHYL) -2-PYRIDINYL] -1-PIPERAZINYL ⁇ -4,6- PYRIMIDINEDIAMINE : Prepared by Procedures H, E (16 hours), and F.
  • PYRIMIDINAMINE Prepared by Procedures M, E (120°C, for addition of piperidine), and F.
  • X E NMR 300 MHz, CDCl 3
  • Example 90 6- [2- (METHOXYMETHYL) -1-PIPERIDINYL] -AT- (4- METHYLPHENYL) -2- ⁇ 4- [3- (TRIFLUOROMETHYL) -2-PYRIDINYL] -1- PIPERAZINYL ⁇ -4-PYRIMIDINAMINE : Prepared by Procedures D, J (90°C, overnight), and F (2 hours).
  • Example 115 IV-4-[3- (BENZYLOXY) PHENYL] -AT-6-,IV-6- DIMETHYL-2- [4- ( 2-PYRIDINYL) -1-PIPERAZINYL] -4 , 6-
  • PYRIMIDINEDIAMINE Prepared by Procedures A (CH 2 C1 2 , Et 3 N, Me 2 NHHCl, stirred 3.5 h at -78 a c, warmed to 0 S C and stirred 3 h) , N, and 0.
  • Example 116 4- ⁇ 4- [4- (DIMETHYLAMINO) -6- (4-TOLUIDINO) -2-

Abstract

This invention is directed to pyrimidine and indolone derivatives which are selective antagonists for the GAL3 receptor and are useful for the treatment of neuropathic pain and other abnormalities. This invention also provides a method of treating a subject suffering from an abnormality which comprises administering to the subject an amount of a compound of the invention effective to treat the subject's abnormality. This invention also provides a method of treating an abnormality in a subject which comprises administering to the subject a composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a GAL3 receptor antagonist.

Description

GA 3 Antagonists For The Treatment of Neuropathic Pain
This application claims priority of U.S. Serial No. 10/215,267, filed August 7, 2002, the contents of which are hereby incorporated by reference.
Throughout this application, various publications are referenced in parentheses by author and year. Full citations for these references may be found at the end of the specification immediately preceding the claims. The disclosures of these ' publications in their entireties are hereby incorporated by reference into this application to describe more fully the art to which this invention pertains.
Background of the Invention
Discovery Of GAL3 Receptor Subtype And Its Role The investigations leading to the present invention arose from the discovery that mRNA for the GAL3 receptor is localized to areas of the rat brain associated with analgesia (see PCT International Publication No. WO 98/15570, published April 16, 1998), thus supporting the expression of GAL3 in those regions. Protein for the GAL3 receptor is also shown to localize to areas of the rat brain associated with analgesia (see Table 12 and discussion herein) .
This discovery led to the hypothesis that the GAL3 receptor may be modulating nociceptive information. Galanin is known to be released from the terminals of sensory neurons as well as spinal interneurons and appears to play a role in the regulation of pain threshold (Wiesenfeld-Hallin et al . 1992). In light of these reports, in vivo behavioral experiments were carried out to evaluate the analgesic properties of a selective GAL3 receptor antagonist. An animal model of neuropathic pain was employed to evaluate the use of selective GAL3 receptor antagonists to treat neuropathic pain. The Chronic Constriction Nerve Injury Model of Neuropathic Pain is a behavioral test that is used to assess the potential analgesic effects of compounds (Bennett an Xie, 1988) . This model monitors the development of allodynia and hyperalgesia and is considered by experts in the field to reflect the potential of analgesic agents to treat neuropathic pain (Fisher et al . , 1998; Fisher et al . , 2002). This model is widely used as it is reliable across laboratories, and is sensitive to the effects of some of the major classes of analgesic drugs.
In an embodiment of the present invention the synthesis of novel pyrimidines ' which bind selectively to the cloned human GAL3 receptor, compared to other cloned human G-protein coupled receptors, as measured in in vitro assays, is disclosed. In a further embodiment of the present invention the synthesis of indolones which bind selectively to the cloned human GAL3 receptor, compared to other cloned human G-protein coupled receptors, as . measured in in vitro assays, is disclosed.
The in vitro receptor assays described hereinafter were performed using various cultured cell lines, each transfected with and expressing only a single galanin- type receptor. From the binding information described hereinafter, it has unexpectedly been discovered that compounds which are specific for the human GAL3 receptor with a binding affinity greater than ten-fold higher than the binding affinity with which the compounds bind to a human GAL1 receptor are effective in animal models of pain which are predictive of efficacy in humans. Thus, we demonstrate that the GAL3 receptor antagonists, which may be classified as neutral antagonists, inverse agonists or allosteric modulators, provide a novel method to treat neuropathic pain.
Summary of the Invention
The present invention provides a method of treating a subject suffering from an abnormality which comprises administering to the' subject an amount of compound effective to treat the subject's abnormality wherein the
Figure imgf000005_0001
compound has the structure:
wherein W is H, -F, -Cl, -Br, -I, CN, methyl, ethyl, propyl, methoxy or ethoxy;
Figure imgf000005_0002
wherein X is; NRnR.12;
wherein Rn is H, straight chained or branched Cι-C7 alkyl, (CH2)q-0- (CH2)m-CH3, aryl, or aryl (C!-C6) alkyl ; wherein R12 is straight chained or branched Cι-C alkyl, (CH2)q-0-(CH2)m-CH3, or -(CH2)B-Z;
wherein R13 is a bicyclic alkyl ring system, adamantyl, noradamantyl , C3-C10 cycloalkyl, heteroaryl, aryl, aryl (Cι-C6) alkyl, Qλ or Q2 ;
wherein aryl may be substituted with one or more Cι-C10 straight chained or branched alkyl, aryl, heteroaryl, or N(R19)-Z;
wherein Q1 is
Figure imgf000006_0001
wherein Q2 is
Figure imgf000006_0002
wherein each J is independently O, S, C(R22)2 or NR4;
wherein R4 is H; straight chained or branched Cχ-C7 alkyl , mono f luoroalkyl or polyfluoroalkyl ; s traight chained or branched C2-C7 alkenyl or alkynyl ; C3 -C- cycloalkyl , C5-C7 cycloalkenyl or aryl ;
Figure imgf000007_0001
wherein Y is NRι Rι5 ;
Figure imgf000007_0002
wherein Rχ is H, straight chained or branched Cι-C6 alkyl, (CH2) q-0- (CH2)m-CH3 , C3-C6 cycloalkyl, or (C(R19)2)m- Z;
wherein R15 is straight chained or branched C3-C6 alkyl, (CH2)q-0-(CH2)m-CH3, C3-C6 cycloalkyl, (C (R19) 2) „-N (R16) 2 or (C(Ri9)2)m-Z;
wherein Riε is straight chained or branched C!-C7 alkyl, straight chained or branched Cχ-C7 monofluoroalkyl , straight chained or branched C:-C7 polyfluoroalkyl, straight chained or branched C2-C7 alkenyl, straight chained or branched C2-C7 alkynyl, C5-Cτ cycloalkenyl , - (CH2)3l-Z, or (CH2)q-0-(CH2)m-CH3;
wherein each Rπ is independently H; -OR2ι, -OCOR2ι, COR21, -NCOR2χ, -N(R2X)2 , -CON(R21)2, -COOR21, straight chained or branched Cχ-C7 alkyl, straight chained or branched Cι~C7 monofluoroalkyl, straight-. chained or branched C3.-C7 polyfluoroalkyl, straight chained or branched C2-C7 alkenyl-, straight chained or branched C2-C7 alkynyl, C5-C7 cycloalkenyl, -(CH2)m-Z, or (CH2) n-0- (CH2) m- CH3 ;
wherein R13 is straight chained or branched C1-C5 alkyl, - (CHsJr-Z, or (CH2)q-0-(CH2)^-CH3;
wherein each 'Ri9 is independently H, or straight chained or branched Cι-C6 alkyl;
wherein each R20 is independently -H; straight chained or branched Cχ-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl;
C3-C7 cycloalkyl or C5-C7 cycloalkenyl; -F, -Cl, -Br, or - I; -N02; -N3 ; -CN; -OR21, -OCOR21, -COR21, -NC0R2ι, -N(R2ι)2
, -CON(R2ι)2» o -COOR21; aryl or heteroaryl; or two R2o groups present on adjacent carbon atoms can join together to form a methylenedioxy group;
wherein each R21 is independently -H; straight- chained or branched Cι-C alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, C5-C cycloalkenyl, aryl, or aryl (Ci- C6 ) alkyl ;
wherein each R22 is independently H, F, Cl or Ci-C4 straight chained or branched alkyl;
wherein each m is an integer from 0 to 4 inclusive ,-
wherein each n is an integer from 1 to 4 inclusive;
wherein p is an integer from 0 to 2 inclusive;
wherein 'q is an integer from 2 to 4 inclusive;
wherein t is 1 or 2 ;
wherein U is 0, -NRι6, S, C(R17)2, or - S02Ri6;
wherein Z is C3-Cι0 cycloalkyl, C -C7 cyclic ether, C4-C7 cyclic thioether, aryl, or heteroaryl; or
a pharmaceutically acceptable salt thereof.
The present invention provides a method of treating a subject suffering from an abnormality which comprises administering to the subject an amount of compound effective to -treat the subject's abnormality wherein the compound has the structure: X
-R 13
N N
H
wherein is H, -F, -Cl, -Br, -I, CN, methyl, ethyl, propyl, methoxy or ethoxy;
wherein X is NRn 11RΛ12 ;
Figure imgf000010_0001
wherein R is H, straight chained or branched C1-C7 alkyl, (CH2) q-0- (CH2)m-CH3 , aryl or aryl (Ci-C€) alkyl ;
wherein Ri2 is straight chained or branched Cτ.-C7 alkyl, (CH2)q-0-(CH2)m-CH3, or -(CH2)m-Z;
wherein R13 is a bicyclic alkyl ring system, aryl or aryl (Ci-C6) alkyl ;
wherein Y is NR1R15;
Figure imgf000011_0001
wherein Ri4 is H, straight chained or branched Ci-Cε alkyl, (CH2) q-0- (CH2)m-CH3, C3-C6 cycloalkyl, or (C(R19)2)m- Z;
wherein R15 is straight chained or branched C3-C6 alkyl, (CH2)σ-0-(CH2)m-CH3, C3-C6 cycloalkyl, or (C (R19) :) m-Z ;
wherein U is O, -NRι6, S, C(R17] or -NSOoR 16 ;
wherein Z is C3-C10 cycloalkyl, aryl, or heteroaryl;
wherein Riε is straight chained or branched Cι-C .alkyl, straight chained or branched 1-C7 monofluoroalkyl , straight chained or branched Cχ-C7 polyfluoroalkyl, straight chained or branched C2-C7 alkenyl, straight chained or branched C2-C7 alkynyl, C5-C7 cycloalkenyl, - (CH2)m-Z, or (CH2)q-0-(CH2)m-CH3; wherein each Rχ7 is independently H; -όR21, -OCQR2i, COR21, -NCOR21, -N(R2ι)2 , -CON(R21)2, -COOR21, straight chained or branched Cι~C7 alkyl, straight chained or branched C1-C7 monofluoroalkyl , straight chained or branched C1-C7 polyfluoroalkyl, straight chained or branched C2-C7 alkenyl, straight chained or branched C2-Cτ alkynyl, C5-C7 cycloalkenyl, -(CH2)m-Z, or (CH2) n-0- (CH2) m- CH3 ;
wherein R3.8 is straight chained or branched Ci-C6 alkyl, - ' (CH2)m-Z, or (CH2)q-0-(CH2)m-CH3;
wherein each Rι9 is independently H, or straight chained or branched Ci-C6 alkyl;
wherein each R20 is independently -H; straight chained or branched Cχ-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl;
C3-C7 cycloalkyl or C5-C7 cycloalkenyl; -F, -Cl, -Br, or - I; -N02; -N3 ; -CN; -0R2i, -0C0R2ι, -COR21, -NCOR2ι, -N(R2ι)2
, -CON(R2ι)2, or -COOR21; aryl or heteroaryl; or tv.o R2o groups present on adjacent carbon atoms can join together to form a methylenedioxy group;
wherein each R2i is independently -H; straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, C5-C7 cycloalkenyl, aryl or aryl (Cι~ C6) alkyl;
wherein each m is an integer from 0 to 4 inclusive;
wherein each n is an integer from 1 to 4 inclusive; wherein p is an integer from 0 to 2 inclusive;
wherein q is an integer from 2 to 4 inclusive;
wherein t is 1 or 2 ; or
a pharmaceutically acceptable salt thereof
The present invention provides a method of treating a subject suffering from an abnormality which comprises administering to the subject an amount _ of compound effective to treat the subject's abnormality wherein the compound has the structure:
Figure imgf000013_0001
wherein W is H, -F, -Cl, -Br, -I, CN,- 'methyl, ethyl, propyl, methoxy or ethoxy;
wherein X is N(CH3)2 or
Figure imgf000014_0001
wherein Rι3 is an aryl, adamantyl, noradamantyl, C3-Cι0 cycloalkyl, heteroaryl, Qi or Q2;
wherein aryl may be substituted with one or more Cι-C10 straight chained or branched alkyl, aryl, heteroaryl, or N(Rι9)-Z;_
wherein Qi is
Figure imgf000014_0002
wherein Q2 is
Figure imgf000014_0003
wherein each J is independently O, S, C(R22)2 or NR wherein R4 is -H ; straight chained or branched C1-C7 alkyl , monof luoroalkyl or polyfluoroalkyl ; straight chained or branched C2-C7 alkenyl or alkynyl ; C3-C7 cycloalkyl , C5-C cycloalkenyl or aryl ;
wherein Y is NR14R15 ;
Figure imgf000015_0001
wherein Ri4 is H, straight chained or branched Cι-C6 alkyl, (CH2) q-0- (CH2)m-CH3, C3-C6 cycloalkyl, or (C(R19)2)m- ;' .
• wherein R15 is straight chained or branched C3-C6 alkyl, (CH2)q-0-(CH2)m-CH3, C3-C6 cycloalkyl, or (C (R19) 2)m-Z;
wherein U is O, -NR16, S, C(Rι7)2, or -NS02Rι6;
wherein ' is C3-C10 cycloalkyl, aryl, or heteroaryl; wherein R16 is straight chained or branched Cι-C7 alkyl, straight chained or branched C1-C7 monofluoroalkyl , straight chained or branched C3.-C7 polyfluoroalkyl, straight chained or branched C2-C7 alkenyl, straight chained or branched C2-C7 alkynyl, C5-C7 cycloalkenyl, - (CH2)m-Z, or (CH2)q-0-(CH2)ra-CH3;
wherein each Rιη is independently H; -OR2ι, -OCOR21, COR2ι, -NC0R2ι, -N(R2ι)2 , -C0N(R21)2, -C00R2ι, straight chained or branched C1-C7 alkyl, straight chained or branched C1-C7 monofluoroalkyl , straight chained or branched C1-C7 ■ polyfluoroalkyl, straight chained or branched C2-C7 alkenyl, straight chained or branched C2-C7 alkynyl, C5-C7 cycloalkenyl, -(CH2)m-Z, or (CH2) n-0- (CH2) m- CH3;
wherein' RIB is straight chained or branched Cι-C6 alkyl, - (CH2)m-Z, or (CH2)q-0-(CH2)m-CH3;
wherein each Rig is independently H, or straight chained or branched Ci-Cg alkyl;
wherein each R20 is independently -H; straight chained or branched Cι-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl;
C3-C7 cycloalkyl or C5-C7 cycloalkenyl; -F, -Cl, -Br, or - I; -N02; -N3 ; -CN; -OR2x, -OCOR21, -COR2ι, -NCOR21j -N(R2ι)2 , -C0N(R2ι)2, or -COOR21; aryl or heteroaryl; or two R2o groups present on adjacent carbon atoms can join together to form a methylenedioxy group;
wherein each R2i is independently -H; straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C-7 cycloalkyl, C5-C7 cycloalkenyl, aryl or aryl (Cx- C6) alkyl;
wherein each R2 is independently H, F, Cl or C1-C4 straight chained or branched alkyl;
wherein each m is an integer from 0 to 4 inclusive;
wherein each n is an integer from 1 to 4 inclusive;
wherein p is an integer from 0 to 2 inclusive;
wherein q is an integer from 2 to 4 inclusive;
wherein t is 1 or 2; or
a pharmaceutically acceptable salt thereof
The present invention provides a method of treating a subject suffering from an abnormality which comprises administering to the subject an amount of compound effective to treat the subject's abnormality wherein the compound has the structure:
Figure imgf000017_0001
wherein is H, -F, -Cl, -Br, -I, CN, 'methyl, ethyl, propyl, methoxy or ethoxy;
wherein X is N(CH3)2or
Figure imgf000018_0001
wherein R13 is a bicyclic alkyl ring system, aryl or aryl (d-C6) alkyl;
wherein Y is R14R15;
wherein Ri4 is H, straight chained or branched Cι-C6 alkyl, (CH2) q-0- (CH2)m-CH3, C—Cs cycloalkyl, or (C(R19)2)m- Z;
wherein RX5 is (C (R19) 2)m-N(Rι6) 2;
wherein Z is C3-C10 cycloalkyl, aryl, or heteroaryl;
wherein R16 is straight chained or branched C1-C alkyl, straight chained or branched Cι-C7 monofluoroalkyl, straight chained or branched C1-C7 polyfluoroalkyl, straight chained or branched C2-C7 alkenyl, straight chained or branched C2-C7 alkynyl, C5-C7 cycloalkenyl, - (CH2)m-Z, or (CH2)g-0-(CH2)m-CH3;
wherein each R17 is independently H; -OR2ι, -OCOR2ι, COR21, -NCOR21, -N(R21)2 , -CON(R2i)2, -COOR21, straight chained or branched C1-C7 alkyl, straight chained or branched Cι-C7 monofluoroalkyl, straight chained or branched Cχ-C7 polyfluoroalkyl, straight chained or branched C2-C7 alkenyl, straight chained or branched C2-C7 alkynyl, C5-C7 cycloalkenyl, -(CH2)m-Z, or (CH2) n-0- (CH2)m- CH3 ; .
wherein each Rι9 is independently H, or straight chained or branched Ci-Cε alkyl;
wherein each R2ι is independently -H; straight chained or branched d-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl;
C3-C7 cycloalkyl, C5-C7 cycloalkenyl, aryl or aryl-(Cι~ C6 ) alkyl;
wherein each m is an integer from 0 to 4 inclusive;
wherein each n is an integer from 1 to 4 inclusive;
The invention provides a method of treating a subject suffering from an abnormality which comprises administering to the subject an amount of compound effective to treat the subject's abnormality wherein the compound has the structure:
Figure imgf000020_0001
wherein each of Y1; Y2, Y3 , and Y4 is independently - H; ' straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, or C5-C7 cycloalkenyl; -F, -Cl, -Br, or -I; -N02; -N3 ; -CN; -OR4, -SR4/ -OCOR4, -COR4, -NCOR4, -N(R4)2 , -C0N(R4)2, or -COOR4; aryl or heteroaryl; or any two of Y1( Y2 , Y3 and Y4 present on adjacent carbon atoms can constitute a methylenedioxy group;
wherein each R4 is independently -H; straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched d-d alkenyl or alkynyl; C3-C7 cycloalkyl, C5-C7 cycloalkenyl, aryl or aryl (Ci-d) alkyϊ;
wherein A is A', Q3 , Q4, Q5ι straight chained or branched C1-C7 alkyl, aryl, heteroaryl, aryl (Cx- C6) alkyl, heteroaryl (d-C6) alkyl, aryl substituted with an aryl or heteroaryl, heteroaryl substituted with an aryl or heteroaryl; or (CHR17) - (CHR17) n-Z ; wherein A' is
Figure imgf000021_0001
Figure imgf000021_0002
wherein Q3 is
Figure imgf000021_0003
wherein Q4 is
wherein Q5 i
Figure imgf000022_0001
wherein Ri and R2 are each independently H , s traight chained or branched Cι~C7 alkyl , -F , -Cl , -Br , -I , - N02 , or -CN ;
wherein R3 is H, straight chained or branched d-C7 alkyl, -F, -Cl, -Br, -I, -N02, -CN, -0R6, aryl or heteroaryl;
wherein R5 is straight chained or branched Cι-C7 alkyl, -N(R )2, -0R6 or aryl;
wherein R5 is straight chained or branched Cι-C7 alkyl or aryl;
wherein each Rι7 is independently H; straight chained or branched d-C7 alkyl, straight chained or branched Cι-C7 monofluoroalkyl , straight chained or branched d-C7 polyfluoroalkyl, straight chained or branched C2-C alkenyl, straight chained or branched C2-C7 alkynyl, C5-C7 cycloalkenyl, -(CH2)m-Z, or (CH2)n-0-(CH2)m-CH3;
wherein each R20 is independently -H; straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-d alkenyl or alkynyl; C3-C7 cycloalkyl or C5-C7 cycloalkenyl; -F, -Cl, -Br, or -I; -N02; -N3 ; -CN; - 0R2ι, -OCOR21, -COR21, -NCOR21, -N(R2ι)2 , -C0N(R2i)2, or -COOR2ι; aryl or heteroaryl; or two R0 groups present on adjacent carbon atoms can join together to form a methylenedioxy group;
wherein each R2i is independently -H; straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, C5-C7 cycloalkenyl, aryl or aryl (Ci- ) alkyl ;
wherein each m is an integer from 0 to 4 inclusive;
wherein each n is an integer from 1 to 4 inclusive;
wherein each p is an integer from 0 to 2 inclusive;
wherein U is O, -NRι6, S, C(Rι7)2/ or -NS0Ri6,-
wherein Z is C3-C10 cycloalkyl, C4-C7 cyclic ether, C -C7 cyclic thioether, aryl, or heteroaryl;
wherein Ri6 is straight chained or branched C1-C7 alkyl, straight chained or branched C1-C7 monofluoroalkyl, straight chained or' branched Cι-C7 polyfluoroalkyl, straight chained or branched Cz-C- alkenyl, straight chained or branched C:-d alkynyl, C5-C7 cycloalkenyl, -(CH2)m-Z, or (CH2) q-0- (CH2)m-CH3 ;
wherein q is an integer from 2 to 4 inclusive;
wherein B is aryl, heteroaryl, aryl substituted with an aryl or heteroaryl, heteroaryl substituted with an aryl or heteroaryl, tricyclic heteroaryl or Qs ; provided however, if B is aryl or heteroaryl the carbon atom or carbon atoms ortho to the nitrogen atom of the i ine bond may only be substituted with one or more of the following -F, -Cl, -Br, -I, -CN, methyl, ethyl or methoxy;
wherein a tricyclic heteroaryl is a fused three member aromatic system in which one or more of the rings is heteroaryl; carbazole; or acridine;
wherein Qε is
Figure imgf000024_0001
wherein each R22 is independently H, F, Cl, or straight chained or branched d-C4 alkyl;
or a pharmaceutically acceptable salt thereof.
The invention provides a method of treating a subject suffering from an abnormality which comprises administering to the subject an amount of compound effective to treat the subject's abnormality wherein the compound has the structure:
Figure imgf000025_0001
wherein each of Yx , Y2 , Y3 , and Y4 is independently '- H; straight chained or branched Cχ-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straigh chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, or C5-C7 cycloalkenyl; -F, -Cl, -Br, or -I; -N02; ~N3 ; -CN; -0R4, -SR4, -0C0R4, -C0R4, -NCOR4, -N(R4)2 , -CON(R4)2, or -COOR4; aryl or heteroaryl; or any two of Yx, Y2, Y3 and Y4 present on adjacent carbon atoms can constitute a methylenedioxy group;
wherein each R is independently rH; straight chained or branched Cι-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, C5-C cycloalkenyl, aryl or aryl (d-C6) alkyl;
wherein A is A' , straight chained or branched Cι-C7 alkyl, aryl, heteroaryl, aryl (Cι-C6)'alkyl or heteroaryl (Cι-C6) alkyl;
wherein A' is
Figure imgf000026_0001
Figure imgf000026_0002
wherein RL and R2 are each independently H, straight chained or branched C1-C7 alkyl, -F, -Cl, -Br, -I, - N02, or -CN;
wherein R3 is H, straight chained or branched C1-C7 alkyl, -F, -Cl, -Br, -I, -N02, -CN, -OR6 aryl or heteroaryl;
wherein R5 is straight chained or branched Cι-C7 alkyl, -N(R4)2, -0R6 or aryl;
wherein R6 is straight chained or branched C1-C7 alkyl or aryl;
wherein B is aryl, or heteroaryl; provided however, if B is aryl or heteroaryl the carbon atom or carbon atoms ortho to the nitrogen atom of the i ine bond may only be substituted with one or more of the following -F, -Cl, -Br, -I, -CN, methyl, ethyl or methoxy;
wherein n is an integer from 1 to 4 inclusive;
or a pharmaceutically acceptable salt thereof.
The invention provides a method of treating a subject suffering from an abnormality which comprises administering to the subject an amount of compound effective to treat the subject's abnormality wherein the
Figure imgf000027_0001
compound has the structure:
wherein each of Yl r Y2, Y3, and Y4 is independently - H; straight chained or branched Cι-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched - alkenyl or alkynyl; C3-C7 cycloalkyl, or C5-C7 cycloalkenyl; -F, -Cl, -Br, or -I; -N02; -N3 ; -CN; -0R4, -SR , -OCOR4 , -C0R4, -NC0R4 , -N(R4)2 , -CON(R4)2, or -C00R ; aryl or heteroaryl; or any two of Yl t Y2 , Y3 and Y present on adjacent carbon atoms can constitute a methylenedioxy group;
wherein each R4 is independently -H; straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, C5-C7 cycloalkenyl, aryl or aryl (Cι-C6) alkyl ;
wherein A is A' , straight chained or branched Cχ-C7 alkyl, aryl, heteroaryl, aryl (d- ) alkyl or heteroaryl (Cι-C6)-alkyl ;
wherein A' is
Figure imgf000028_0001
Figure imgf000028_0002
wherein B is aryl substituted with an aryl or heteroaryl, heteroaryl substituted with an aryl or heteroaryl, tricyclic heteroaryl or Q6;
wherein a tricyclic heteroaryl is a fused three ring aromatic system in which one or more of the rings is heteroaryl; carbazole; or acridine;
wherein Qg is
Figure imgf000029_0001
wherein n is an integer from 1 to 4 inclusive; •
wherein each R22 is independently H, F, Cl_, br straight chained or branched Ci- alkyl;
or a pharmaceutically acceptable salt thereof.
The invention provides a method of treating a subject suffering from an abnormality which comprises administering to the subject an amount of compound effective to treat the subiect's abnormalitv wherein the
Figure imgf000029_0002
compound has the structure;
wherein each of Yi, Y2, Y3, and Y is independently H; straight chained or branched" d~Cτ alkyl, monofluoroalkyl '• or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, or C5-C7 cycloalkenyl; -F, -Cl, -Br, or .-I; -N02; -N3; -CN; -0R4, -SR4, -0C0R4, -C0R4, -NCOR4 , -N(R4)2 , -CON(R4)2, or -C00R4; aryl or heteroaryl; or any two of Yi, Y2, Y3 and Y4 present on adjacent carbon atoms can constitute, a methylenedioxy group;
wherein each R4 is independently -H; straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2~C7 alkenyl or alkynyl; C3-C7 cycloalkyl, C5-C7 cycloalkenyl, aryl or aryl (Cι-C6) alkyl;
wherein A is Q3, Q4, Q5, aryl substituted with an aryl or heteroaryl, heteroaryl substituted with an aryl or heteroaryl, or (CHR17) - (CHR17) n-Z;
wherein Q3 is
Figure imgf000030_0001
wherein Q4 is
wherein Q5 is
Figure imgf000031_0001
wherein each Ri7 is independently H; straight chained or branched Cι-C7 alkyl, straight chained or branched Cι~d monofluoroalkyl , straight chained or branched C1-C7 polyfluoroalkyl, straight chained or branched C2-d alkenyl, straight chained or branched C2-C7 alkynyl, C5-C7 cycloalkenyl, -(CH2)π-Z, or (CH2)n-0-(CH2)m-CH3;
wherein each R20 is independently -H; straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl or C5-C7 cycloalkenyl; -F, -Cl, -Br, or -I; -N02; -N3 ; -CN; - OR2ι, -OCOR2ι, -C0R2ι, -NCOR2ι, -N(R21)2 , -C0N(R2ι)2, or -COOR21; aryl or heteroaryl; or two R0 groups present on adjacent carbon atoms can join together to form a methylenedioxy group; wherein each R2ι is independently' -H; straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, C5-C7 cycloalkenyl or aryl;
wherein each R22 is independently H, F, Cl, or straight chained or branched Cχ-C4 alkyl;
wherein q is an integer from 2 to 4 inclusive;
wherein each m is an integer from 0 to 4 inclusive;
wherein each n is an integer from 1 to 4 inclusive;
wherein each p is an integer from 0 to 2 inclusive;
wherein U is 0, -NRι6, S, C(Rι7)2, or -NS02Ri6;
wherein Z is C3-C10 cycloalkyl, C4-C7 cyclic ether, C4-C7 cyclic thioether, aryl, or heteroaryl;
wherein Ri is straight chained or branched C1-C7 alkyl, straight chained or branched C1-C7 monofluoroalkyl, straight chained or" branched d- polyfluoroalkyl, straight chained or branched C2-d • alkenyl, straight chained or branched C2-d alkynyl, d-d cycloalkenyl, -(CH2)m-Z, or (CH2) q-0- (CH2)m-CH3 ;
.wherein B is aryl, or heteroaryl; provided however, if B is aryl or heteroaryl the carbon atom or carbon atoms ortho to the nitrogen atom of ' the imine bond may only be substituted with one or more of the following -F, -Cl, -Br, -I," -CN, methyl, ethyl or methoxy;
or a pharmaceutically acceptable salt thereof.
wherein q is an integer from 2 to 4 inclusive; or
a pharmaceutically acceptable salt thereof.
The invention provides a method of treating a subject suffering from an abnormality which comprises administering o the subject an amount of compound effective to treat the subject's abnormality wherein- the compound has the structure:
Figure imgf000033_0001
wherein each of Yl r Y2 , Y3, and Y4 is independently -H; straight chained or branched Cι-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C alkenyl or alkynyl; C3-C7 cycloalkyl, or - C5-C7 cycloalkenyl; -F, -Cl, -Br, or -I; -N02; -N3 ; -CN; -0R4, -OCOR4, -C0R4, -NCOR4, -N(R4)2 , -CON(R4)2, or -COOR4 ; aryl or heteroaryl; or any two of Y1( Y2, Y3 and Y4' present on adjacent carbon atoms can constitute a methylenedioxy group ; wherein each R is independently -H; straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3 -C7 'cycloalkyl, C5-C7 cycloalkenyl, aryl or aryl(Cι- C6 ) alkyl;
wherein A is A' , straight chained or branched d-d alkyl, aryl, heteroaryl, aryl (Cι-C6) alkyl or heteroaryl (Ci-Cg) alkyl; "
wherein A' is
Figure imgf000034_0001
wherein Ri and R2 are each independently H', straight chained or branched d- alkyl, -F, -Cl, -Br, -I, -N02, or -CN;
wherein R3 is H, straight chained or ■ -branched C1-C7 alkyl, -F, -Cl, -Br, -I, -N02 , -CN, -0R6 aryl or heteroaryl;
wherein R5 is straight chained or branched d-d alkyl, - N'(R4)2, -OR4 or aryl;
wherein Rs is straight chained or branched d-C7 alkyl or aryl ; wherein B is C3-C cycloalkyl, C5-C7 cycloalkenyl, adamantyl, aryl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, indolizinyl, indol-4-yl, indol-5- yl, indol-6-yl, indol-7-yl, isoindolyl, benzo [b] furan-4- yl, benzo [b] furan-5-yl, benzo [b] furan-6-yl , benzo [b] furan-7-yl, benzo [b] thiophen-4-yl , benzo [b] thiophen-5-yl, • benzo [b] thiophen-6-yl , benzo [b] thiophen-7-yl, indazolyl, benzimidazolyl, benzo [b] thiazolyl, purinyl, imidazo [2 , 1-b] thiazolyl, quinolinyl, isoquinolinyl, quinazolinyl, 2,1,3- benzothiazolyl, furanyl, thienyl, pyrrolyl, oxazplyl, thiazolyl, imidazolyl, pyrazolyl, . isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, benzoxazolyl , benzisoxazolyl , cinnolinyl, quinoxalinyl, 1, 8-naphthridinyl, pteridinyl, or phthalimidyl ; provided however, if B is aryl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, indolizinyl, indol-4- yl, indol-5-yl, indol-6-yl, indol-7-yl, isoindolyl, benzo [b] furan-4-yl, benzo [b] furan-5-yl , benzo [b] furan^δ- yl, benzo [b] furan-7-yl, benzo [b] thiophen-4-yl , benzo [b] thiophen-5-yl , benzo [b] thiophen-6-yl , benzo [b] thiophen-7-yl, indazolyl, benzimidazolyl, benzo [b] thiazolyl, purinyl, imidazo [2 , 1-b] thiazolyl, quinolinyl, isoquinolinyl, quinazolinyl, 2,1,3- benzothiazolyl, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, benzoxazolyl, benzisoxazolyl, cinnolinyl, quinoxalinyl, 1, 8-napthyridinyl, pteridinyl, or phthalimidyl the carbon atom or carbon atoms ortho to the nitrogen atom of the i ine bond may only be .substituted with one or more of the following -F, -Cl, -Br, -I, -CN, methyl, ethyl or methoxy;
wherein n is an integer from 1 to 4 inclusive.
Brief Description of the Figures
Figure 1: Western Blot Results
In order to establish the specificity of the anti-GAL3 antiserum, membranes prepared from C0S-7 cells transiently transfected with the rat recombinant GAL3 (Borowsky et al . , 1999) (Lane 2) or mock-transfected (vector only) (Lane 3) -were applied to an SDS-PAGE gel and blotted using the GAL3 receptor polyclonal antibody. Lane 1 corresponds to molecular weight marker. The anti- GAL3 antiserum labeled proteins in membranes only from rat GAL3 -transfected cells (Lane 2); a predominant band was evident with an apparent molecular weight of approximately 56 kDa, (somewhat higher than the amino acid-derived value of 40.4 kDa) . The apparently high molecular weight observed for rat GAL3 very likely reflects post- translational processing such as glycosylation ; note that rat GAL3 contains multiple N- ter inal glycosylation sites (Smith et al . , 1998). Relative to the predominant band, additional species of higher molecular weight as well as lower molecular weight were labeled by the GAL3 antiserum. These are interpreted as protein aggregates of C-terminal fragments, as they are absent in mock-transfected cells.
Figure 2: Effects of Example 92 on the Withdrawal
Thresholds to Von Frey Monofilament Challenges of the
(i) Contralateral and (ii) Nerve-injured Paw of
Neuropathic Rats . Data plotted represents the group mean withdrawal threshold (grams) to Von Frey filament challenges on the days prior to and following a chronic constriction nerve injury. The animals were dosed with test substance (Example 92), reference sustance (morphine) or vehicle (100% DMSO) on day 12 PO . * P < 0.05, * * P ≤ 0.01, ***p < 0.001 compared to vehicle control group (ANOVA and Dunnett's tests or Unpaired t- test) . +P ≤ 0.05 compared to the vehicle group (Kruskal- Wallis and Dunn's test or Mann-Whitney 17-test) .
Figure 3 : Effects of Example 92 on the Withdrawal Thresholds to Von Frey Monofilament Challenges of the (i) Contralateral and (ii) Nerve-injured Paw of Neuropathic Rats. Data are expressed as mean ± SEM; n = 10 rats per group. *P ≤ 0.05, **P < 0.01, ***P ≤ 0.001 compared to vehicle control group (ANOVA and Dunnett ' s tests or Unpaired t-test) .
Figure 4: Effects of Example 92 on the Withdrawal Latency to a Thermal Plantar Stimulus of the (i) Contralateral and (ii) Nerve-injured Paw of Neuropathic Rats. Data plotted represents the group mean withdrawal latency (seconds) to a thermal plantar stimulus on the days prior to and following a chronic constriction nerve injury. The animals were dosed with test substance (Example 92), reference sustance (morphine) or vehicle (100% DMSO) on day 12 PC *P < 0.05, ***j? < 0.001 compared to vehicle control group (Unpaired t-test). +*P ≤ 0.01 compared to the vehicle group (Mann-Whitney 17-test) .
Figure 5: Effects of Example 92 on the Withdrawal Latency to a Thermal Plantar Stimulus of the (i) Contralateral and (ii) Nerve-injured Paw of
Neuropathic Rats. Data are expressed as mean ± SEM; n = 10 rats per group. *P ≤ 0.05, .***p < 0.001 compared to the vehicle control group (Unpaired t-test). **p ≤ 0 . 01 compared to the vehicle control group (Mann-Whitney Latest) .
Detailed Description of the Invention
'The present invention provides a method of treating a subject suffering from an abnormality which comprises administering to the subject an amount of compound effective to treat the subject's abnormality wherein the
Figure imgf000040_0001
compound has the structure:
wherein W is H, -F, -Cl, -Br, -I, CN, methyl, ethyl, propyl, methoxy or ethoxy;
Figure imgf000040_0002
wherein X is ; NR R12 ;
wherein Ru is H, straight chained or branched C1-C7 alkyl, (CH2)q-0- (CH2)m-CH3 , aryl, or aryl (Ci-Cg) alkyl;
wherein Ri2 is straight chained' or branched Cχ-C7 alkyl, (CH2)q-0-(CH2)m-CH3, or -(CH2)m-Z;
wherein Ri3 is a bicyclic alkyl ring system, adamantyl, noradamantyl, d-Cio cycloalkyl, heteroaryl, . aryl, aryl (C.-Cg) alkyl, Qi or Q2 ;
wherein aryl may be substituted with one or more d-Cio straight chained or branched alkyl, aryl, heteroaryl, or N(R19)-Z,-
wherein Qi is
Figure imgf000041_0001
wherein Q is
Figure imgf000041_0002
wherein each J is independently 0, S, C(R22)2 or NR4 wherein R4 is H; straight chained or "branched Cι-C7 alkyl, monofluoroalkyl ■ or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-d cycloalkyl, C5-C7 cycloalkenyl or aryl;
Figure imgf000042_0001
wherein Y is NRι4Rχ5 ;
Figure imgf000042_0002
wherein Rι4 is H, straight chained or ..branched Cι~C6 alkyl, (CH2) q-0- (CH2)m-CH3/ C3-C6 cycloalkyl, or (C(R19)2)m- Z;
wherein Rι5 is straight chained or branched C3-Ce alkyl, (CH2)q-0-(CH2)m-CH3, C3-C6 cycloalkyl, (C (R19) 2)mN (R16) 2 or (C(Rι9)2)m-Z;
wherein R16 is straight chained or branched Cι-C7 alkyl, straight chained or branched Cι-C7 monofluoroalkyl, straight chained or branched d-C7 polyfluoroalkyl, straight chained or branched C2-C alkenyl, straight chained or branched C2-C7 alkynyl, C5-C cycloalkenyl, - (CH2)m-Z, or (CH2)q-0-(CH2)m-CH3;
wherein each Ry? is independently H; -UR21, -OCOR2ι, C0R2ι, -NCOR2:, -N(R2ι)2 , -C0N(R2ι)2 -COOR21, straight chained or branched C-C7 alkyl, straight chained or branched C1-C7 monofluoroalkyl , straight chained or branched d-C7 polyfluoroalkyl, straight chained or branched C2-d alkenyl, straight chained or branched d-d alkynyl, C5-C-7 cycloalkenyl, -(CH2)ra-Z, or (CH2) n-0- (CH2) π- CH3;
wherein Ris is straight chained or branched Ci-C alkyl, - (CH2)m-Z, or (CH2)q-0-(CH2)m-CH3;
wherein each Ri9 is independently H, or straight chained or branched Cx-Cg alkyl;
wherein each Ro is independently -H; straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-d alkenyl or alkynyl; C3-C7 cycloalkyl or C5-C7 cycloalkenyl; -F, -Cl, -Br, or - I; -N02; -N3; -CN; -0R2ι, -OCOR21f -COR2ι, -NCOR21, -N(R2i)2 , -CON(R2ι)2, or -COOR2i; aryl or heteroaryl; or two R20 groups present on adjacent carbon atoms can join together to form a methylenedioxy group;
wherein each R2i is independently -H; straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-d alkenyl or alkynyl; C3-C7 cycloalkyl, C3-C cycloalkenyl, aryl, or aryl(C:- C6) alkyl;
wherein each R22 is independently H, F, Cl or C;-C4 straight chained or branched alkyl;
wherein each m is an integer from 0 to 4 inclusive;
wherein each n is an integer from 1 to 4 inclusive;
wherein p is an integer from 0 to 2 inclusive;
wherein q is an integer from 2 to 4 inclusive;
wherein t is 1 or 2 ;
wherein U is 0, -NRig, S, C(Ri7)2, or -NS02Rιb;
wherein Z is C3-do cycloalkyl, C4~C7 cyclic ether, C4-C cyclic thioether, aryl, or heteroaryl; or
a pharmaceutically acceptable salt thereof.
The invention provides a method of treating a subject suffering from an abnormality which comprises administering to the subject an amount of compound effective to treat the subject's abnormality wherein the compound has the structure:
Figure imgf000045_0001
wherein W is H, -F, -Cl, -Br, -I, CN, methyl, ethyl, propyl, methoxy or ethoxy;
wherein X is NRιιRι2;
Figure imgf000045_0002
wherein R is H, straight chained or branched Cι-C7 alkyl, (CH2) q-0- (CH2) ra-CH3 , aryl or aryl (Ci-Cg) alkyl ;
wherein R12 is straight chained or branched Cι-C7 alkyl, (CH2)q-0-(CH2)m-CH3, or -(CH2)B-Z;
wherein Ri3 is a bicyclic alkyl ring system, aryl or aryl (d-d) alkyl;
wherein Y is R14R15;
Figure imgf000046_0001
wherein Ri4 is H, straight chained or branched Ci-Cg alkyl, (CH2) q-0- (CH2)It,-CH3 , C3-C6 cycloalkyl, or (C (R19) 2) m- Z;
wherein RX5 is straight chained or branched C3-C6 alkyl, (CH2)q-0-(CH2)m-CH3, C3-C6 cycloalkyl, or (C (R19) :)πι-Z;
wherein U is O, -NRι5, S, C(Rι7)2, or -NS02Rι5;
wherein Z is C3-do cycloalkyl, aryl, or heteroaryl;
wherein Rig is straight chained or branched d- alkyl, straight chained or branched C1-C7 monofluoroalkyl , straight chained or branched d-C7 polyfluoroalkyl, straight chained or branched -d alkenyl, straight chained or branched C2-C7 alkynyl, C5-C7 cycloalkenyl, -. (CH2)m-Z, or (CH2)q-0-(CH2)πι-CH3; wherein each Ri7 is independently H; -OR2ι, -OCOR2α, COR2i, -NCOR21, -N(R21)2 , -C0N(R2ι)2, -COOR2ι, straight chained or branched C1-C7 alkyl, straight chained or branched C1-C7 monofluoroalkyl , straight chained or branched C1-C7 polyfluoroalkyl, straight chained or branched C2-C7 alkenyl, straight chained or branched C2-C- alkynyl, C5-C7 cycloalkenyl, -(CH2)m~Z, or (CH2) n-0- (CH2) m- CH3 ;
wherein Ria is straight chained or branched Ci-Cg alkyl, - (CH2)m-Z, or (CH2)q-0-(CH2)m-CH3;
wherein each R19 is independently H, or straight chained or branched d-C6 alkyl;
wherein each R2o is independently -H; straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl;
C3-C7 cycloalkyl or C5-C7 cycloalkenyl; -F, -Cl, -Br, or - I; -N02; -N3; -CN; -OR2i, -0C0R21, -C0R2X, -NCOR21, -N(R21)2
, -CON(R21)2, or -C00R2I; aryl or heteroaryl; or two R2o groups present- on adjacent carbon atoms can join together to form a methylenedioxy group;
wherein each R2i is independently -H; straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight -chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, C5-C7 cycloalkenyl, aryl or aryl(Cχ- C6) alkyl;
wherein each m is an integer from 0 to 4 inclusive;
wherein each n is an integer from 1 to 4 inclusive; wherein p is an integer from 0 to 2 inclusive;
wherein q is an integer from 2 to 4 inclusive;
wherein t is 1 or 2; or
a pharmaceutically acceptable salt thereof.
1.0
The invention provides a method of treating a subject suffering from an abnormality which comprises administering to the subject an amount . of compound effective to treat the subject's abnormality wherein the
15 compound has the structure:
Figure imgf000048_0001
wherein W is H, -F, -Cl, -Br, -I, CN, 'methyl, ethyl, propyl, methoxy or ethoxy;
20 wherein X is N(CH3)2or
Figure imgf000049_0001
wherein Ri3 is an aryl, adamantyl, noradamantyl , C3-Cι0 cycloalkyl, heteroaryl, Qi or Q2 ;
wherein aryl may be substituted with one or more Ci-Cio straight chained or branched alkyl, aryl, heteroaryl, or N(R19)-Z;
wherein Qi is
Figure imgf000049_0002
wherein Q2 is
Figure imgf000049_0003
wherein each J is independently 0, S, C(R22)2 or NR ; wherein R4 is -H; straight chained or branched d-d alkyl, monof luoroalkyl or polyfluoroalkyl; straight chained or branched ^C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, C5-C7 cycloalkenyl or aryl;
wherein Y is RιRιs;
Figure imgf000050_0001
wherein Rι4 is H, straight chained or branched Ci-Cg alkyl, (CH2) q-0- (CH2)m-QH3, C3-C6 cycloalkyl, or (C (R19) 2) m- z'" ~" .
wherein R15 is straight chained or branched -d alkyl, (CH2)q-0-(CH2)m-CH3, d-d cycloalkyl, or (C (R19) 2)m-Z ;
wherein U is 0, -NRι6, S, C(Rπ)2, or -NS02Rι6;
wherein Z is C3-Cι0 cycloalkyl, aryl, or heteroaryl; wherein i is straight chained or branched d-C- alkyl, straight chained or branched C1-C7 monofluoroalkyl , straight chained or branched C1-C7 polyfluoroalkyl, straight chained or branched C2-d alkenyl, straight chained or branched C2-d alkynyl, C5-C7 cycloalkenyl, - (CH2)m-Z, or (CH2)q-0-(CH2)m-CH3;
wherein each Ri7 is independently H; -0R2ι, -OCOR21, COR21, -NCOR21, -N(R2ι)2 , -CON(R21)2, -C00R2ι, straight chained or branched Ci-C- alkyl, straight chained or branched C1-C7 monofluoroalkyl , straight chained or branched- C1-C polyfluoroalkyl, straight chained or branched C2-Cτ alkenyl, straight chained or branched d-d alkynyl, C5-C7 cycloalkenyl, -(CH2)ra-Z, or (CH:) π-0- (CH2) m- CH3;
wherein Ris is straight chained or branched Ci-Cg alkyl, - (CH2)m-Z, or (CH2)q-0-(CH2)m-CH3;
wherein each R19 is independently H, or straight chained or branched Cι-C6 alkyl;
wherein each R20 is independently -H; straight chained or branched d-d alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained 01 branched C2-C alkenyl or alkynyl; C3-C cycloalkyl or C5-C7 cycloalkenyl; -F, -Cl, -Br, or - I; -N02; -N3 ; -CN; -0R2ι, -OCOR21, -C0R21, -NCOR21, -N(R2ι)2 , -C0N(R2i)2, or -COOR21; aryl or heteroaryl; or two R20 groups present on adjacent carbon atoms can join together to form a methylenedioxy group;
wherein each R21 is independently -H; straight chained or branched - alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-d cycloalkyl, C5-C7 cycloalkenyl, aryl or aryl(d- C6) alkyl;
wherein each R22 is independently H, F, Cl or d-C4 straight chained or branched alkyl;
wherein each m is an integer from 0 to 4 inclusive;
wherein each n is an integer from 1 to 4 inclusive;
wherein p is an integer from 0 to 2 inclusive;
wherein q is an integer from 2 to 4 inclusive,
wherein t is 1 or 2; or
a pharmaceutically acceptable salt thereof.
The invention provides a method of treating a subject suffering from an abnormality which comprises administering to the subject an amount of compound effective to treat the subject's abnormality wherein the compound has the structure:
Figure imgf000052_0001
wherein W is H, -F, -Cl, -Br, -I, CN, methyl, ethyl, propyl, methoxy or ethoxy;
wherein X is N(CH3)2 or
Figure imgf000053_0001
wherein Rx3 is a bicyclic alkyl ring system, aryl or aryl (Ci-Cg) alkyl;
wherein Y is R14R15;
wherein Ri4 is H, straight chained or branched Cι~Cδ alkyl, (CH2) q-0- (CH2 ) m-CH3 , C3-C6 cycloalkyl, or (C(R19) ;>)„,-
wherein R15 is (C (RX9) 2)π>-N(R16;
wherein Z is C3-Cι0 cycloalkyl, aryl, or heteroaryl;
wherein Rig is straight chained or branched Cι-C7 alkyl, straight chained or branched Cι-C7 monofluoroalkyl , straight chained or branched Cι-C7 polyfluoroalkyl, straight chained or branched C2-C7 alkenyl, straight chained or branched C2-C7 alkynyl, C5-C7 cycloalkenyl, - (CH2)ra-Z, or (CH2)q-0-(CH2)-,-CH3;
wherein each Rl7 is independently H; -OR2ι, -OCOR2ι, -' COR21, -NCOR2ι, -N(R2ι)2 , -C0N(R2i)2, -C00R21, straight chained or branched d-C7 alkyl, straight chained or branched Cι-C7 monofluoroalkyl , straight chained or branched Cι-C7 polyfluoroalkyl, straight chained or branched C2-C7 alkenyl, straight chained or branched C2-C7 alkynyl, C5-d cycloalkenyl, -(CH2)m-Z, or (CH2) n-0- (CH2) m- CH3;
wherein each Ri9 is independently H, or straight chained or branched Ci-Cg alkyl;
wherein each R2ι is independently -H; straight chained or branched d-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl. or alkynyl; C -C7 cycloalkyl, C5-C7 cycloalkenyl, aryl or aryl(d- C6) alkyl;
wherein each m is an integer from 0 to 4 inclusive;
wherein each n is an integer from 1 to 4 inclusive;
wherein q is an integer from 2 to 4 inclusive; or
a pharmaceutically acceptable salt thereof.
As used in the present invention, the 'term "bicyclic alkyl ring systems" includes, but is not limited to, bicyclo [2.2. ljheptane, bicyclo [3.1.1] heptane and bicyclo [2.2.2] octane. In addition, the bicyclic alkyl ring systems may be substituted with one or more of the following: -F, -N02 , -CN, ' straight chained or branched C1-C7 alkyl, straight chained or branched C1-C7 monofluoroalkyl, straight chained or branched C1-C7 polyfluoroalkyl, straight chained or branched C2-d alkenyl, straight chained or branched d~d' alkynyl, C3-C7 cycloalkyl, C5-C7 cycloalkenyl, -N(R2i)2, -OR21, -COR21, - C02R2i, -C0N(R2ι)2 or (CH2)n-0-(CH2)rn-CH3.
As used in the present invention, the term "cycloalkyl" includes, C3-d cycloalkyl moieties which may be substituted with one or more of the following: -F, -N02, -CN, straight chained or branched C1-C7 alkyl, straight chained or branched C1-C7 monofluoroalkyl, straight chained or branched d-C7 polyfluoroalkyl, straight chained or branched C2-C7 alkenyl, straight chained or branched C2-C7 alkynyl, C3-C7 cycloalkyl, C3-C7 monofluorocycloalkyl, C3-C7 polyfluorocycloalkyl, C5-C7 cycloalkenyl, -N(R4)2. -OR4, -COR4, -NCOR4, -C02R4, C0N(R4)2 or (CH2) n-0- (CH2)m-CH3.
As used in the present invention, the term "cyclohexyl" includes, cyclohexyl groups which may be substituted with one or more of the following: -F, -N0 , -CN, straight chained or branched C1-C-7 alkyl, straight chained or branched d-d monofluoroalkyl, straight chained or branched d-d polyfluoroalkyl, straight chained or branched C2-C7 alkenyl, straight chained or branched C2-C7 alkynyl, C3-C7 cycloalkyl, C3-C7 monofluorocycloalkyl, C3-C7 polyfluorocycloalkyl , C5-C7 cycloalkenyl, -N(R4)2, -0R4, -C0R4, -NC0R4, -C02R4, CON(R4)2 or (CH2)n-0-(CH2)m-CH3.
As used in the present invention, the term "cycloalkenyl" includes, C5-C7 cycloalkenyl moieties which may be substituted with one or more of the following: -F, -Cl, -Br, -I, -N02, -CN, straight chained or branched C1-C7 alkyl, straight chained or branched Ci- d monofluoroalkyl, straight chained or 'branched Ci- polyfluoroalkyl, straight chained or branched C:-Cτ alkenyl, straight chained or branched C2-C7 alkynyl, C -d cycloalkyl, C3-C7 monofluorocycloalkyl, C3-d polyfluorocycloalkyl, C5-C7 cycloalkenyl, -N(R4)2, -0R4, - C0R4, -NCOR4, -C02R4, -C0N(R4)2 or (CH2) n-0- (CH^-CH-, .
In the present invention, the term "heteroaryl" is used to include five and six membered unsaturated rings that may contain one or more oxygen, sulfur, or nitrogen atoms. Examples of heteroaryl groups include, but are not limited to, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, _ isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, and triazinyl .
In addition the term "heteroaryl" is used to include fused bicyclic ring systems that may contain one or more heteroatoms such as oxygen, sulfur and nitrogen.
Examples of such heteroaryl groups include, but are not limited to, indolizinyl, indolyl, isoindolyl, benzo [b] furanyl, benzo [b] thiophenyl , indazolyl, benzimidazolyl, purinyl, benzoxazolyl, benzisoxazolyl, benzo [b] thiazolyl, imidazo [2 , 1-b] thiazolyl , cinnolinyl, quinazolinyl, quinoxalinyl, 1 , 8-naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, phthalimidyl and 2,1,3 -benzothiazolyl .
The term "heteroaryl" also includes those chemical moieties recited above which may be substituted with one or more of the following: -F, -Cl, -Br, -I, -N02 , -CN, straight chained or branched Cι~C7 alkyl, straight chained or branched d-C7 monofluoroalkyl, straight chained or branched C1-C7 polyfluoroalkyl, straight chained or branched C2-C7 alkenyl, straight chained or branched C2-C- alkynyl, C3 -C7 cycloalkyl, C3-C-
5 monofluorocycloalkyl, C3-C- polyfluorocycloalkyl , C5-C7 cycloalkenyl, -N(R4)2, -0R4, -C0R4, -NCOR4 , -C02R4,
• . C0N(R4)2 or (CH2)n-0-(CH2)m-CH3.
The term "heteroaryl" further includes the N-oxides of 0 those chemical moieties recited above which include at least one nitrogen atom.
In the present invention the term "aryl" is phenyl or naphthyl. The term "aryl" also includes phenyl and 5 naphthyl which may be substituted with one or more of the following: -F, -Cl, -Br, -I, -N02 , -CN, straight chained or branched C1-C7 alkyl, straight chained or branched C1-C7 monofluoroalkyl , straight chained or branched C1-C7 polyfluoroalkyl, straight chained or 0 branched C2-d alkenyl, straight chained or branched C2.-C7 alkynyl, C3-C7 cycloalkyl, C3-C7 monofluorocycloalkyl , C3- d polyfluorocycloalkyl, C5-C7 cycloalkenyl, -N(R4)2, -0R , -SR4, -OCOR4, -COR4, -NCOR4, -C02R4, -CON(R4)2 or (CH2)n-0- (CH2)m-CH3. 5
In one embodiment of any of the methods described herein, the compound is enantiomerically and diasteriomerically pure. In one embodiment, the 0 compound is enantiomerically or diasteriomerically pure.
In one • embodiment of any of the methods described herein, the compound can be administered orally. In one embodiment , X is
Figure imgf000058_0001
In one embodiment, X is NRuRι2 and Ru is H or straight chained or branched Cι-C7 alkyl .
In one embodiment, the compound has the structure:
Figure imgf000058_0002
In one embodiment, Rχ3 is a bicyclic alkyl ring system, cyclohexyl or aryl.
In one embodiment, Ri4 is H, straight chained or branched Ci-Cg alkyl or (CH2) q-0- (CH2)m-CH3. In one embodiment , the compound is selected from the
Figure imgf000059_0001
Figure imgf000059_0002
Figure imgf000059_0003
group consisting of:
Figure imgf000060_0001
Figure imgf000060_0002
Figure imgf000060_0003
Figure imgf000061_0001
Figure imgf000061_0002
Figure imgf000061_0003
Figure imgf000062_0001
Figure imgf000062_0002
5 In one embodiment, Y is
Figure imgf000063_0001
In one embodiment, U is NRig.
In one embodiment, Ri is (CH2)m-Z.
In one embodiment, Z is aryl or heteroaryl.
In one embodiment, the compound is selected from the group consisting of:
Figure imgf000063_0002
Figure imgf000064_0001
Figure imgf000064_0002
Figure imgf000065_0001
Figure imgf000065_0002
Figure imgf000065_0003
In one embodiment, the compound is selected from the group consisting of:
Figure imgf000066_0001
Figure imgf000066_0002
Figure imgf000066_0003
In one embodiment, Y is
Figure imgf000067_0001
In one embodiment, U is NRig.
Figure imgf000067_0002
Figure imgf000067_0003
In one embodiment, the compound is In one embodiment, the compound is
Figure imgf000068_0001
In one embodiment, the compound is selected from the group consisting of:
Figure imgf000069_0001
Figure imgf000069_0002
Figure imgf000069_0003
In one embodiment, the compound is selected from the group consisting of:
Figure imgf000070_0001
In one embodiment, X is N(CH3)2,
In one embodiment, Y is
Figure imgf000071_0001
In one embodiment, R1.3 is an aryl substituted with a Cι~ C10 straight chained alkyl.
In one embodiment, the compound is selected from a group consisting of:
Figure imgf000071_0002
Figure imgf000071_0003
The invention provides a pharmaceutical composition comprising a therapeutically effective amount of any of the compounds described herein and a pharmaceutically acceptable carrier.
The invention provides a pharmaceutical composition made by combining a therapeutically effective amount of any of the compounds described herein and a pharmaceutically acceptable carrier.
The invention provides a process for making a pharmaceutical composition comprising combining a therapeutically effective amount of any of the compounds described herein and a pharmaceutically acceptable carrier.
The invention provides a method of treating a subject suffering from an abnormality which comprises administering to the subject an amount of any of the compounds described herein effective to treat the subject's abnormality.
In separate embodiments, the abnormality is a regulation of a steroid or pituitary hormone disorder, an epinephrine release disorder, a gastrointestinal disorder, a cardiovascular disorder, an- electrolyte balance disorder, hypertension, diabetes, a respiratory disorder, asthma, a reproductive function disorder, an immune disorder, an endocrine disorder, a musculoskeletal disorder, ■ a neuroendocrine disorder, a cognitive disorder, a memory disorder such as Alzheimer's disease, a learning disorder, a sleep disorder, a sensory modulation and transmission disorder, a motor coordination disorder, Huntington's disease, a sensory integration disorder, a motor integration disorder, a dopaminergic function disorder such as Parkinson's disease, a sensory transmission disorder, an olfaction disorder, a sympathetic innervation disorder, a stress- related disorder, a fluid-balance disorder, a seizure disorder, pain, inflammatory pain, chronic pain, psychotic behavior such as schizophrenia, morphine tolerance, drug addition particularly opiate addiction, migraine, an appetite disorder, such as obesity, or an eating/body weight disorders, such as bulimia or bulimia nervosa .
In preferred embodiments, the abnormality is Alzheimer's disease, obesity, diabetes, or pain, particularly neuropathic pain.
The invention provides a method of treating a subject suffering from pain which comprises administering to the subject an amount of any of the compounds described herein effective to treat the subject's pain.
The invention provides a method of treating a subject suffering from neuropathic pain which comprises administering to the subject an amount Of any of the compounds described herein effective to treat the subject's neuropathic pain.
The invention provides a method of treating a subject suffering from an abnormality which comprises administering to the subject an amount of compound effective to treat the subject's abnormality wherein the compound has the structure:
Figure imgf000074_0001
wherein each of Yi, Y2, Y3, and Y4 is independently - H; straight chained or branched Cι-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched d-d alkenyl or alkynyl; C3-C7 cycloalkyl, or C5-d cycloalkenyl; -F, -Cl, -Br, or -I; -N02; -N3; -CN; -0R4, -SR4, -0C0R4, -C0R4, -NC0R4, -N(R4)2 , -CON(R4)2, or -COOR4; aryl or heteroaryl; or any two of Yi( Y2, Y3 and Y4 present on adjacent carbon atoms can constitute a methylenedioxy group;
wherein each R4 is independently -H; straight chained or branched Ci-d alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-d alkenyl or alkynyl; C3-C7 cycloalkyl, C5-C7 cycloalkenyl, aryl or aryl (Ci-Cg) alkyl;
wherein A is A', Q3, Q4ι Q5_ straight chained or branched C1-C7 alkyl, aryl, heteroaryl, aryl (Ci- C6) alkyl, heteroaryl (Ci-Cg) alkyl , aryl substituted with an aryl or heteroaryl, heteroaryl substituted with an aryl or heteroaryl; or (CHR17) - (CHRy?) n-Z; wherein A' is
Figure imgf000075_0001
Figure imgf000075_0002
wherein Q3 is
Figure imgf000075_0003
wherein Q is
wherein Q5 i
Figure imgf000076_0001
wherein Ri and R2 are each independently H, straight chained or branched C1-C7 alkyl , -F , -Cl , -Br , -I , - N02 , or -CN;
wherein R3 is H, straight chained or branched C1-C7 alkyl, -F, -Cl, -Br, -I, -N02, -CN, -0R6, aryl or heteroaryl;
wherein R5 is straight chained or branched C1-C7 alkyl, -N(R4)2, -0R6 or aryl;
wherein Rg is straight chained or branched C1-C7 alkyl or aryl ;
wherein each R17 is independently H; straight chained or branched C1-C7 alkyl, straight chained or branched C1-C7 monofluoroalkyl, straight chained or branched C1-C7 polyfluoroalkyl, straight chained or branched C2-C7 alkenyl, straight chained or branched d-d alkynyl, C5-C7 cycloalkenyl, -(CH:)m-Z, or (CH2)n-0-(CH2)m-CH3;
wherein each R2o is independently -H; straight chained or branched Ci-C- alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-d alkenyl or alkynyl; C3-d cycloalkyl or C5-C7 cycloalkenyl; -F, -Cl, -Br, or -I; -N02 ; -N3 ; -CN; - OR21, -OCOR21, -COR21, -NCOR21, -N(R2ι)2 , -C0N(R2X)2, or -COOR2ι; aryl or heteroaryl; or two R20 groups present on adjacent carbon atoms can join together to form a methylenedioxy group;
wherein each R?ι is independently -H; straight chained or branched -C-> alkyl, monofluoroalkyl or polyfluoroalkyl: straight chained or branched C2-d alkenyl or alkynyl; C3-C7 cycloalkyl, C5-C7 cycloalkenyl, aryl or aryl (Cι~C6) alkyl;
wherein each m is an integer from 0 to 4 inclusive;
wherein each n is an integer fr.om 1 to 4 inclusive;
wherein each p is an integer from 0 to 2 inclusive;
wherein U is 0, -NRι6, S, C(Rι7)2, or -NS02Rι6;
wherein Z is C3-Cι0 cycloalkyl, C4-c7 cyclic ether, C4-C7 cyclic thioether, aryl, or heteroaryl;
wherein RX6 is straight chained or branched C1-C7 alkyl, straight chained or branched Cx-C7 monofluoroalkyl, straight chained or' 'branched C1-C7 polyfluoroalkyl, straight chained or branched C2-C7 alkenyl, straight chained or branched C2-d alkynyl, d-d cycloalkenyl, -(CH2)m-Z, or (CH2)q-0- (CH2)m-CH3;
wherein q is an integer from 2 to 4 inclusive;
wherein B is aryl, heteroaryl, aryl substituted with an aryl or heteroaryl, heteroaryl substituted with an aryl or heteroaryl, tricyclic heteroaryl or 6; provided however, if B is aryl or heteroaryl the carbon atom or carbon atoms ortho to the nitrogen atom of the i ine bond may only be substituted with one or more of the following -F, -Cl, -Br, -I, -CN, methyl, ethyl or methoxy;
wherein a tricyclic heteroaryl is a fused three member aromatic system in which one or more of the rings is heteroaryl; carbazole; or acridine;
wherein Qg is
Figure imgf000078_0001
wherein each R22 is independently H, F, Cl, or straight chained or branched Cι-C4 alkyl;
or a pharmaceutically acceptable salt thereof. The invention provides a method of treating a subject suffering from an abnormality which comprises administering to the subject an amount of compound effective to treat the subject's abnormality wherein the compound has the structure:
Figure imgf000079_0001
wherein each of Yi, Y2, Y3, and Y4 is independently - H; straight chained or branched d- alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched d-d alkenyl or alkynyl; C3-C7 cycloalkyl, or C5-C7 cycloalkenyl; -F, -Cl, -Br, or -I; -N02; -N3 ; -CN; -OR4, -SR4, -OCOR4, -COR4, -NC0R4, -N(R4)2 , -CON(R4)2, or -COOR4; aryl or heteroaryl; or any two of Yx , Y2 , Y3 and Y present on adjacent carbon atoms can constitute a methylenedioxy group;
wherein each R4 is independently -H; straight chained or branched d-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, C5-C7 cycloalkenyl, aryl or aryl (Cι-C6) alkyl;
wherein A is A' , straight chained or branched C1-C7 alkyl, aryl, heteroaryl, aryl (Cι~C6) alkyl or heteroaryl (Cι-C6) alkyl ;
Figure imgf000080_0001
wherein A ' is
Figure imgf000080_0002
wherein Ri and R2 are each independently H , s traight chained or branched C1-C7 alkyl , -F , -Cl , -Br , -I., - N02 , or -CN;
wherein R3 is H, straight chained or branched Ci-C- alkyl, -F, -Cl, -Br, -I, -N02, -CN, -0Rδ aryl or heteroaryl;
wherein R5 is straight chained or. -branched Cι-C7 alkyl, -N(R4)2, -0R6 or aryl;
wherein R6 is straight chained or branched C1-C7 alkyl or aryl;
wherein B is aryl, or heteroaryl; provided however, if B is aryl or heteroaryl the carbon atom or carbon atoms ortho to the nitrogen atom of the imine bond may only be substituted wifh one or more of the following -F, -Cl, -Br, -I, -CN, methyl, ethyl or methoxy
wherein n is an integer from 1 to 4 inclusive;
or a pharmaceutically acceptable salt thereof.
The invention provides a method of treating a subject suffering from an abnormality which comprises administering to the . subject an amount of compound effective to treat the subject's abnormality wherein the
Figure imgf000081_0001
compound has the structure:
wherein each of Yl t Y2, Y3, and Y4 is independently - H; straight chained or branched Cι-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-d cycloalkyl, or C5-C7 cycloalkenyl; -F, -Cl, -Br, or -I; -N02; -N3 ; -CN; -OR4, -SR4, -0C0R4, -C0R4, -NC0R4, -N(R4)2 , -C0N(R4)2, or -COOR4; aryl or heteroaryl; or any two of Yb γ2, γ3 and Y4 present on adjacent carbon atoms can constitute a methylenedioxy group; wherein each R4 is independently -H ; straight chained or branched C1-C7 alkyl , monofluoroalkyl or polyfluoroalkyl ; straight chained or branched C2-C7 alkenyl or alkynyl ; C3-C7 cycloalkyl , C5-C7 cycloalkenyl , aryl or aryl (Ci-Cg ) alkyl ;
wherein A is A' , straight chained or branched C1-C7 alkyl, aryl, heteroaryl, aryl (Ci-Cg) alkyl or heteroaryl (Cι-C6) alkyl;
wherein A' is
Figure imgf000082_0001
Figure imgf000082_0002
wherein B is aryl substituted with an aryl or heteroaryl, heteroaryl substituted with an aryl or heteroaryl, tricyclic heteroaryl or Q6;
wherein a tricyclic heteroaryl is a fused three ring aromatic system in which one or more of the rings, is heteroaryl; carbazole; or acridine; wherein Qg is
Figure imgf000083_0001
wherein n is an integer from 1 to 4 inclusive ;
wherein each R22 is independently H , F ,
Cl , or straight chained or branched Cι-C4 alkyl ;
or a pharmaceutically acceptable salt thereof.
The invention provides a method of treating a subject suffering from an abnormality which comprises administering to the subject an amount of compound effective to treat the subject's abnormality wherein the
Figure imgf000083_0002
compound has the structure:
wherein each of Yx, Y2, Y3, and Y4 is independently H; straight chained or branched "' C:-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight •chained or branched C2-C alkenyl or alkynyl; C3-d cycloalkyl, or Cs-Cη cycloalkenyl; -F, -Cl, -Br, or -I; -N02; -N3 ; -CN; -0R4, -SR4, -OCOR4, -C0R4, -NC0R , -N(R4)2 , -CON(R4)2, or -C00R ; aryl or heteroaryl; or any two of Yi, Y2, Y3 and Y4 present on adjacent carbon atoms can constitute a methylenedioxy group;
wherein each R4 is independently -H; straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-d alkenyl or alkynyl; C3-C7 cycloalkyl, C5-C7 cycloalkenyl, aryl or aryl (Cι-C6) alkyl;
wherein A is Q3, Q , Q5, aryl substituted with an aryl or heteroaryl, heteroaryl substituted with an aryl or heteroaryl, or (CHRy?) - (CHR17) n-Z;
wherein Q3 is
Figure imgf000084_0001
wherein Q4 is
wherein Q5 is
Figure imgf000085_0001
wherein each R17 is independently H; straight chained or branched C1-C7 alkyl, straight chained or branched C1-C7 monofluoroalkyl, straight chained or branched C1-C7 polyfluoroalkyl, straight chained or branched C2-d alkenyl, straight chained or branched C2-d alkynyl, C5-C7 cycloalkenyl, -(CH?)m-Z, or (CH2)n-0-(CH2)m-CH3;
wherein each R2o is independently -H; straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl or C5-C7 cycloalkenyl; -F, -Cl, -Br, or -I; -N02; -N3 ; -CN; - OR21, -OCOR21, -C0R2ι, -NC0R2ι, -N(R2i)2 , -CON(R21)2l or -C00R2ι; aryl or heteroaryl; or two R0 groups present on adjacent carbon atoms can join together to form a methylenedioxy group; wherein each R2i is independently -H; straight chained or branched Cι-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, C5-C7 cycloalkenyl or aryl;
wherein each R22 is ..independently H, F, Cl, or straight chained or branched d-C4 alkyl;
wherein q is an integer from 2 to 4 inclusive;
wherein each m is an integer from 0 to 4 inclusive;
wherein each n is an integer from 1 to 4 inclusive;
wherein each p is an integer from 0 to 2 inclusive;
wherein U is 0, -NRιS, S, C(R17)2, or -NS02Rι6;
wherein Z is C3-C10 cycloalkyl, C -C7 cyclic ether, C4-C7 cyclic thioether, aryl, or heteroaryl;
wherein R16 is straight chained or branched C1-C7 'alkyl, straight chained or branched C1-C7 monofluoroalkyl, straight chained or branched C1-C7 polyfluoroalkyl, straight chained or branched C2-C7 alkenyl, straight chained or branched C2-C7 alkynyl, C5-C7 cycloalkenyl, -(CH2)ra-Z, or (CH2) q-0- (CH2)m-CH3 ;
wherein B is aryl, or heteroaryl; provided however, if B is aryl or heteroaryl the carbon atom or carbon atoms ortho to the nitrogen atom of the i ine bond may only be substituted with one or more of the following -F, -Cl, -Br, -I, -CN, methyl, ethyl or methoxy;
or a pharmaceutically acceptable salt thereof.
As used in the present invention, the term "cycloalkyl" includes C3-C7 cycloalkyl moieties which may be substituted with one or more of the following: -F, -N02, -CN, straight chained or branched Cι~C7 alkyl, straight chained or branched d-C7 monofluoroalkyl, straight chained or branched Cι-C7 polyfluoroalkyl, straight chained or branched C2-C7 alkenyl, straight chained or branched C2-d alkynyl, C3-C7 cycloalkyl, C3-C7 monofluorocycloalkyl, C3-C7 polyfluorocycloalkyl , C5- d cycloalkenyl, -N(R4)2, -OR4, -COR4, -NCOR4, C02R4, -C0N(R4)' 2 or (CH2) n-0- (CH2) m-CH3.
As used in the present invention, the term "cycloalkenyl" includes C5-C7 cycloalkenyl moieties which may be substituted with one or more of the following: -F, -Cl, -Br, -I, . -N02 , -CN, straight chained or branched C1-C7 alkyl, straight chained or branched C1-C7 monofluoroalkyl, straight chained or branched C1-C7 polyfluoroalkyl, straight chained or branched C2-C7 alkenyl, straight chained or branched d-d alkynyl, C3-C7 cycloalkyl, C3-C7 monofluorocycloalkyl, C3-C7 polyfluorocycloalkyl, C5- C7 cycloalkenyl, -N(R4)2, -0R4, -C0R4, -NCOR4,
C02R4, -C0N(R4)2 or (CH2) n-0- (CH2) m-CH3.
In the present invention, the term "heteroaryl" is used to include five and six membered unsaturated rings that may contain one or more oxygen, sulfur, or nitrogen atoms . Examples of heteroaryl groups include, but are not limited to, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, and triazinyl.
In addition the term "heteroaryl" is used to include fused bicyclic ring systems that may contain one or more heteroatoms such as oxygen, sulfur and nitrogen. Examples of such heteroaryl groups include, but are not limited to, indolizinyl, indolyl, isoindolyl, benzo [b] furanyl, benzo [b] thiophenyl, indazolyl, benzimidazolyl, purinyl, benzoxazolyl, benzisoxazolyl, benzo [b] thiazolyl, imidazo [2, 1-b] hiazolyl, cinnolinyl, quinazolinyl, quinoxalinyl, 1,8- naphthyridinyl , pteridinyl, quinolinyl, isoquinolinyl, phthalimidyl and 2,1,3- benzothiazolyl . .
The term "heteroaryl" also includes those chemical moieties recited above which may be substituted with one or more of the following: -F, -Cl, -Br, - I, -N02, -CN, straight chained or branched C1-C7 alkyl, straight chained or branched Ci-d monofluoroalkyl, straight chained or branched Cι~C7 polyfluoroalkyl, straight chained or branched C2-C7 alkenyl, -straight chained or branched C2-d alkynyl, C3-C7 cycloalkyl, C3-C7 monofluorocycloalkyl, C3-C polyfluorocycloalkyl, C5-C cycloalkenyl, -N(R)2, - OR4 , -COR4 , -NCOR4 , -C02R4 , -CON ( R4 ) : or ( CH2 ) n-0-
( CH ) -CH3 .
The term "heteroaryl" further includes the N-oxides of those chemical moieties recited above which include at least one nitrogen atom.
In the present invention the term "aryl" is phenyl or naphthyl. The term "aryl" also includes phenyl and naphthyl which may be substituted with one or more of the following: -F, -Cl, -Br, -I, -N02 , -CN, straight chained or branched C1-C7 alkyl, straight chained or branched d-d monofluoroalkyl, straight chained or branched C1-C7 polyfluoroalkyl, straight chained or branched C2-C7 alkenyl, straight chained or branched C2-C7 alkynyl, C3-C7 cycloalkyl, C -C monofluorocycloalkyl , C-d polyfluorocycloalkyl , C5- d cycloalkenyl, -N(R4)2, -0R4, -SR4, -OCOR4, -COR4, -NCOR4, -C02R4, -CON(R4)2 or (CH2) n-0- (CH2)m-CH3. The present invention also provides a method of treating a subject suffering from an abnormality which compromises administering to the subject an amount of compound effective to treat the subject's abnormality where in the compound has the structure:
Figure imgf000090_0001
wherein each R2 is independently one or more of the following: H, F, Cl, Br, I, CF3, 0CH3 or N02;
wherein R25 is methyl, ethyl, allyl, phenyl and the phenyl is optionally substituted with a F, Cl, Br, CF3, N02.
In one embodiment of any of the methods described herein, the compound is enantiomerically and diastereomerically pure. In one embodiment of any of the methods described herein, the compound is enantiomerically or diastereomerically pure.
In one embodiment of any of the methods described herein, the compound is a pure Z imine isomer or a pure Z alkene isomer. In one embodiment, the compound is a pure E imine isomer or a pure E alkene isomer.
In one embodiment, the compound has the structure:
Figure imgf000091_0001
wherein each of Yi, Y2, Y3, and Y is independently - H; straight chained or branched d-C7 alkyl, -CF3 , - F, -Cl, -Br, -I, -OR4, -N(R4)2, or -C0N(R4)2;
wherein each R is independently -H; straight chained or branched C1-C7 alkyl, -CF3 , or phenyl;
wherein A is A' , straight chained or branched C1-C7 alkyl, aryl, heteroaryl, aryl (d-C5) alkyl or heteroaryl (Cι-C6) alkyl; and
wherein A' is
Figure imgf000091_0002
In one embodiment, B is heteroaryl In another embodiment, B is aryl.
In one embodiment, B is phenyl and the • phenyl is optionally substituted with one or more of the following: -F, -Cl, -Br, -CF.3, straight chained or branched C1-C7 alkyl, -N(R4)2, -0R , -COR4, -NC0R4, -C02R4, or -CON (R ) 2 ,
In one embodiment, A is aryl. In another embodiment, A is heteroaryl .
In some embodiments, the compound is selected from the group consisting of:
Figure imgf000092_0001
In certain embodiments, the compound is selected from the group consisting of:
Figure imgf000093_0001
Figure imgf000093_0002
Figure imgf000093_0003
Figure imgf000094_0001
Figure imgf000094_0002
Figure imgf000094_0003
Figure imgf000095_0001
In one embodiment, A is A' and A' is
Figure imgf000095_0002
In other embodiments, the compound is
Figure imgf000095_0003
In still other embodiments, B is Qg .
In one embodiment, A is aryl.
In another embodiment, the compound has the structure;
Figure imgf000096_0001
In other embodiments, the compound is
Figure imgf000096_0002
In another embodiment, B is aryl. In certain embodiments , A is (CHRι7 ) - ( CHR17 ) n- .
In one embodiment , the compound is
Figure imgf000097_0001
The invention provides a method of treating a subject suffering from an abnormality which comprises administering to the subject an amount of compound effective to treat the subject's abnormality wherein the compound has the structure:
Figure imgf000097_0002
wherein each of Yl7 Y2, Y3, and Y4 is independently -H; straight chained or branched Cχ-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; d-C7 cycloalkyl, or C5-C7 cycloalkenyl; -F, -Cl, -Br, or -I; -N02; -N3 ; -CN; -OR4,
-OCOR , -COR , -NC0R , -N(R )2 , -C0N(R4)2, or -COOR4 ; aryl or heteroaryl; or any two of Yλ, Y2, Y3 and Y present on adjacent carbon atoms can constitute a methylenedioxy group ;
wherein each R4 is independently -H; straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, C5-C7 cycloalkenyl, aryl or aryl (Cx- C6) alkyl;
wherein A is A' , straight chained or branched C1-C7 alkyl, aryl, heteroaryl, aryl (d-C6) alkyl or heteroaryl (Ci-Cg) alkyl;
wherein A' is
Figure imgf000098_0001
wherein Ri and R2 are each independently H, straight chained or branched C1-C7 alkyl, -F, -Cl, -Br, -I, -N02, or -CN;
wherein R3 is H, straight chained or branched C1-C7 alkyl, -F, -Cl, -Br, -I, -N02, -CN, -0R6, 'aryl or heteroaryl;
wherein R5 is straight chained or branched d-C7 alkyl, - N(R4)2, -0R or aryl;
wherein Rg is straight chained or branched Ci-d alkyl or aryl ;
wherein B is C3-C7 cycloalkyl, C5-C7 cycloalkenyl, adamantyl, aryl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, indolizinyl, indol-4-yl, indol-5- yl, indol-6-yl, indol-7-yl, isoindolyl, benzo [b] furan-4- yl, benzo [b] furan-5-yl, benzo [b] furan-6-yl, benzo [b] furan-7-yl , benzo [b] thiophen-4-yl , benzo [b] thiophen-5-yl, benzo [b] thiophen-6-yl , benzo [b] thiophen-7-yl, indazolyl, benzimidazolyl, benzo [b] thiazolyl, purinyl, imidazo [2 , 1-b] thiazolyl , quinolinyl, isoquinolinyl, quinazolinyl, 2,1,3- benzothiazolyl, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, benzoxazolyl, benzisoxazolyl, cinnolinyl, quinoxalinyl, 1, 8-naphthridinyl, pteridinyl, or phthalimidyl; provided however, if B is aryl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, indolizinyl, indol-4- yl, indol-5-yl, indol-6-yl, indol-7-yl, isoindolyl, benzo [b] furan-4-yl, benzo [b] furan-5-yl, benzo [b] furan-6- yl, benzo [b] furan-7-yl, benzo [b] thiophen-4-yl, benzo [b] thiophen-5-yl, benzo [b] thiophen-6-yl, benzo [b] thiophen-7-yl, indazolyl, benzimidazolyl, benzo [b] thiazolyl, purinyl, imidazo [2 , 1-b] thiazolyl , quinolinyl, isoquinolinyl, quinazolinyl, 2,1,3- benzothiazolyl, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, "' isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, benzoxazolyl, benzisoxazolyl, cinnolinyl, quinoxalinyl, 1, 8-na thyridinyl, pteridinyl, or phthalimidyl the carbon atom or carbon atoms ortho to the nitrogen atom of the imine bond may only be substituted with one or more of the following -F, -Cl, -Br, -I, -CN, methyl, ethyl or methoxy;
wherein n is an integer from 1 to 4 inclusive.
In one embodiment of the invention, A is aryl, heteroaryl, heteroaryl (Ci-Cg) alkyl or - (CH2) n-CC-R4; wherein the aryl is substituted with -OH;
In 'one embodiment of the invention, A is aryl, heteroaryl, or heteroaryl (Ci-Cg) alkyl; and
wherein aryl is substituted with -F, -Cl , -Br, -I, -N02/ -CN, straight chained or branched d-C alkyl, straight chained or branched C1-C7 monofluoroalkyl, straight chained or branched C1-C7 polyfluoroalkyl, straight chained or branched C2-C alkenyl, straight chained or branched C2-C7- alkynyl, C3-C7 cycloalkyl, C3-C7 monofluorocycloalkyl, C3-C7 polyfluorocycloalkyl , C5-C7 cycloalkenyl, -N(R4)2, -0R4, -SR4, -0C0R4, -COR4, -NCOR , -C02R4, -CON(R )2 or - (CH2 ) n0 (CH2)mCH3.
In another embodiment of the invention, each of Yx, Y2, Y3, and Y4 is independently -H; straight chained or branched C1-C7 alkyl, -CF3, -F, -Cl, -Br, -I, -OR , - N(R4)2, or -C0N(R4)2; wherein each R4 is independently -H; straight chained or branched C1-C7 alkyl, -CF3, or phenyl;
wherein A is A' , straight chained or branched d-C7 alkyl, aryl, heteroaryl, aryl (Ci-Cg) alkyl or heteroaryl (Ci-Cg) alkyl; and
wherein A' is
Figure imgf000101_0001
In another embodiment of the invention, B is C3-C7 cycloalkyl or adamantyl.
In still another embodiment of the invention, B is pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, indolizinyl, indol-4-yl, indol-5-yl, indol-6-yl, indol- 7-yl, isoindolyl, benzo [b] furan-4-yl , benzo [b] furan-5- yl, benzo [b] furan-6-yl, benzo [b] furan-7-yl, benzo [b] thiophen-4-yl, benzo [b] thiophen-5-yl, benzo [b] thiophen-6-yl, benzo [b] thiophen-7-yl , indazolyl, benzimidazolyl, benzo [b] thiazolyl , purinyl, imidazo [2,1- b] thiazolyl, quinolinyl, isoquinolinyl ,' ' quinazolinyl, 2 , 1, 3 -benzothiazolyl, furanyl, thienyl,- pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, benzoxazolyl, benzisoxazolyl, cinnolinyl, quinoxalinyl, 1, 8-napthyridinyl, pteridinyl, or phthalimidyl.
In another embodiment of the invention, B is aryl. In still another embodiment of the invention, B is phenyl and the phenyl is optionally substituted with one or more of the following: -F, -Cl, -Br, -CF3, straight chained or branched C1-C alkyl, -N(R4)2, -0R , -COR , NCOR , -C02R4, or -C0N(R4)2.
In some embodiments of the invention, A is aryl.
In other- embodiments, the compound is selected from the group consisting of:
Figure imgf000102_0001
In s till other embodiments , A is A ' and A ' is
Figure imgf000102_0002
In one embodiment, the compound is:
Figure imgf000103_0001
The invention provides a method of treating a subject suffering from an abnormality which comprises administering to the subject an amount - of compound effective to treat the subject's abnormality wherein the compound has the structure:
Figure imgf000103_0002
wherein each of Yi, Y2, Y3, and Y4 is independently -H; straight chained or branched Cχ-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-d cycloalkyl or C5-d cycloalkenyl; -F, -Cl, -Br, or -I; -N02 ; -N3 ; -CN; -0R , -SR4, -0C0R4, -C0R4, -NC0R4, -N(R4)2 , -C0N(R4)2, or - C00R4; aryl or heteroaryl; or any two of Yl t Y2, Y3 and Y4 present on adjacent carbon atoms can' ' constitute a methylenedioxy group;
wherein each R4 is independently -H; straight chained or branched C1-C alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, C5-C7 cycloalkenyl, aryl or aryl (Cx- C6) alkyl;
wherein A is A' , straight chained or branched d-C7 alkyl, aryl, heteroaryl, aryl (Cι-C6) alkyl or heteroaryl (d^ ) alkyl ;
wherein A' is
Figure imgf000104_0001
Figure imgf000104_0002
wherein Ri and R2 are each independently H, straight chained or branched C1-C7 alkyl, -F, -Cl, -Br, -I, -N02, or' -CN;
wherein R3 is H, straight chained or branched C1-C7 alkyl, -F, -Cl, -Br, -I, -N02, -CN, -OR6, aryl or heteroaryl;
wherein R5 is straight chained or branched d-C7 alkyl, N ( R ) 2 , -OR4 or aryl ;
wherein Rg is straight chained or branched C1-C7 alkyl or aryl;
wherein B is aryl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, indolizinyl, indol-4-yl, indol-5- yl, indol-6-yl, indol-7-yl, isoindolyl, benzo [b] furan-4- yl , benzo [b] furan-5-yl, benzo [b] furan-6-yl, benzo [b] furan-7-yl, benzo [b] thiophen-4-yl, benzo [b] thiophen-5-yl, benzo [b] thiophen-6-yl , benzo [b] thiophen-7-yl, indazolyl, benzimidazolyl, benzo [b] thiazolyl, purinyl, imidazo [2 , 1-b] thiazolyl, quinolinyl, isoquinolinyl, quinazolinyl, 2,1,3- benzothiazolyl, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, benzoxazolyl, benzisoxazolyl, cinnolinyl, quinoxalinyl, 1, 8-napthyridinyl , pteridinyl, or phthalimidyl; provided however, that the carbon atom or carbon atoms ortho to the nitrogen atom of the imine bond may only be substituted with one or more of the following -F, -Cl, - Br, -I, -CN, methyl, ethyl or methoxy;
wherein n is an integer from 1 to 4 inclusive;
or a pharmaceutically acceptable salt thereof.
In one embodiment, the compound is A is aryl, heteroaryl, heteroaryl (Cι-C6) alkyl or - (CH2) n-CC-R4; wherein the aryl is substituted with -OH;
In another embodiment, A is aryl, heteroaryl, or heteroaryl (Ci-Cg) alkyl; and
wherein aryl is substituted with -F, -Cl, -Br, -I, -N02 , -CN, straight chained or branched d-C7 alkyl, straight chained or branched Cι~C7 monofluoroalkyl, straight chained or branched Cx-C7 polyfluoroalkyl, straight chained or branched C2-C7 alkenyl, straight chained or branched C2-C alkynyl, C3-C7 cycloalkyl, C3-C7 monofluorocycloalkyl, C3-C7 polyfluorocycloalkyl , C5-C7 cycloalkenyl, -N(R)2, -OR4, -SR4, -OCOR4, -COR4, -NCOR4, -CO2R4, -CON(R4)2 or -(CH2)nO(CH2)mCH3.
In one embodiment, the compound is an enantiomerically and diastereomerically pure compound.
In one embodiment, the compound is an enantiomerically or diastereomerically pure compound.
In some embodiments, the compound is a pure Z imine isomer or a pure Z alkene isomer of the compound.
In some embodiments, the compound is a pure E imine isomer or a pure E alkene isomer of the compound.
In other embodiments, A is A', straight chained or branched C1-C7 alkyl, aryl, heteroaryl, aryl (Ci-Cg) alkyl or heteroaryl (Ci-Cg) alkyl; and
A' is
Figure imgf000106_0001
In some embodiments, each of Yx, Y2, Y3 , and Y4 is independently -H; straight chained or branched d-C7 alkyl, -CF3, -F, -Cl, -Br, -I, -OR4, -N(R )2, or - CON(R4)2.
In other embodiments, A is aryl or aryl (Cι~d) alkyl .
In still other embodiments, the compound is selected from the group consisting of:
Figure imgf000107_0001
The invention provides a pharmaceutical composition comprising a therapeutically effective amount of any of the compounds described herein and a pharmaceutically acceptable carrier.
The invention provides a pharmaceutical composition made by combining a therapeutically effective amount of any of the compounds described herein and a pharmaceutically acceptable carrier.
The invention provides a process for making a pharmaceutical composition comprising combining a therapeutically effective amount of any of the compounds described herein and a pharmaceutically acceptable carrier .
The invention provides a method of treating a subject suffering from an abnormality which comprises administering to the subject an amount of any of the compounds described herein effective to treat the subject's abnormality.
In separate embodiments, the abnormality ' is a regulation of a- steroid or pituitary hormone disorder, an epinephrine release disorder, a gastrointestinal disorder, a cardiovascular disorder, an electrolyte balance disorder, hypertension, diabetes, a respiratory disorder, asthma, a reproductive function disorder, an immune disorder, an endocrine disorder, a musculoskeletal disorder, a neuroendocrine disorder, a cognitive disorder, a memory disorder such as Alzheimer's disease, a learning disorder, a sleep disorder, a sensory modulation and transmission disorder, a motor coordination disorder, Huntington's disease, a sensory integration disorder, a motor integration disorder, a dopaminergic function disorder such as Parkinson's disease, a sensory transmission disorder, an olfaction disorder, a sympathetic innervation disorder, a stress- related disorder, a fluid-balance disorder, a seizure disorder, pain, inflammatory pain, chronic pain, psychotic behavior such as schizophrenia, morphine tolerance, drug addition particularly opiate addiction, migraine, an appetite disorder, such as obesity, or an eating/body weight disorders, such as bulimia or bulimia nervosa .
In preferred embodiments, the abnormality is Alzheimer's disease, obesity, diabetes, or pain, particularly neuropathic pain.
The invention provides a method of treating a subject suffering from pain which comprises administering to the subject an amount of any of the compounds described herein effective to treat the subject's pain.
The invention provides a method of treating a subject suffering from neuropathic pain which comprises administering to the subject an amount of any of the compounds described herein effective to treat the subject's neuropathic pain.
The invention provides for each pure stereoisomer of any of the compounds described herein. Such stereoisomers may include enantiomers, diastereomers, or E or Z alkene or imine isomers. The invention also' provides for stereoisomeric mixtures, including racemic mixtures, diastereomeric' mixtures, or E/Z isomeric mixtures. Stereoisomers can be synthesized in pure form (Nόgradi, M.; Stereoselective Synthesis, (1987) VCH Editor Ebel, H. and Asymmetric Synthesis, Volumes 3 - 5, (1983) Academic' Press, Editor Morrison, J. ) or they can be resolved by a variety of- methods such as crystallization and chromatographic techniques (Ja ues, J. ; Collet, A. ; Wilen, S . ; Enantiomer, Racemates, and Resolutions, 1981, John Wiley and Sons and Asymmetric Synthesis, Vol. 2, 1983, Academic Press, Editor Morrison, J) .
In addition the compounds of the present invention may be present as enantiomers, diasteriomers , isomers or two or ' more of the compounds may be present to form a racemic or diastereomeric mixture.
The compounds of the present invention are preferably 80% pure, more preferably 90% pure, and most preferably 95% pure.
Included in this invention are pharmaceutically acceptable salts and complexes of all of the compounds described herein. The acids and bases from which these salts are prepared include but are not limited to the acids and bases listed herein. The acids include, but are not limited to, the following inorganic acids: hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid and boric acid. The acids include, but are not limited to, the following organic acids: acetic
' acid, malonic acid, succinic acid, fumaric acid, tartaric acid, maleic acid, citric acid, methanesulfonic acid, benzoic acid, glycolic acid, lactic acid and mandelic acid. The bases include, but are not limited to ammonia, methylamine, etbylamine, propylamine, dimethylamine, diethylamine, trimethyla ine, triethylamine, ethylenediamine, hydroxyethylamine, morpholine, piperazine and guanidine. This invention further provides for the hydrates and polymorphs of all of the compounds described herein.
The present invention includes within its scope prodrugs of the compounds of . the invention. In general, . such prodrugs will be functional derivatives of the compounds of the invention which are readily convertible in -vivo into the required compound. Thus, in the present invention, the term "administering" shall encompass the treatment of the various conditions described with the compound specifically disclosed or with a compound which may not be specifically disclosed, but which converts to the specified compound in vivo after administration to the patient. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in Design of Prodrugs, ed. H. Bundgaard, Elsevier, 1985.
The present invention further includes ' metabolites of the compounds of the present invention.- Metabolites include active species produced upon introduction of compounds of this invention into the biological milieu.
Throughout the invention, the term "binding- affinity" describes the concentration of a compound required to occupy one-half of the binding sites in a receptor population, as detectable by radioligand binding. Binding affinity concentration can be represented as Ki, inhibition constant, or KD, dissociation constant.
The term "selectivity of binding affinity" refers to the ability of a chemical compound to discriminate one- receptor from another. For example, a compound showing selectivity for receptor A versus receptor B will bind receptor A at lower concentrations than those required to bind receptor B.
_ Therefore, the statements of the form "binds to the GAL3 receptor with a binding affinity at least ten-fold higher than" a named receptor, indicates that the binding affinity at the GAL3 receptor is at least ten- fold greater than that for a named receptor, and binding affinity measurements (i.e. Ki or KD) for' the compound are at least ten- fold lower in numerical value.
The present invention provides a method of treating an abnormality in a subject which comprises administering to the subject a composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a GAL3 receptor antagonist, wherein: the GAL3 receptor antagonist binds to the human GAL3 receptor with a binding affinity at least ten-fold higher than the binding affinity with which it binds to the human GAL1 receptor.
In some embodiments of this invention, the GAL3 receptor antagonist binds to the human GAL3 receptor with a binding affinity at least 30-fold higher than the binding affinity with which it binds to the human GAL1 receptor.
In further embodiments of the invention, the GAL3 receptor antagonist binds to the human GAL3 receptor with a binding affinity at least 50-fold higher than the binding affinity with which it binds to the human GAL1 receptor.
In other embodiments of the invention, the GAL3 receptor antagonist binds to the human GAL3 receptor with a binding affinity at least 100-fold higher than the binding affinity with which it binds to the human GAL1 receptor.
In still other embodiments of the invention, the GAL3 receptor antagonist binds to the human GAL3 receptor with a , binding affinity at least 200-fold higher than the binding affinity with which it binds to the human GAL1 receptor.
For the purposes of this invention the term "pharmaceutically acceptable carrier" has been defined herein.
The term "antagonist" refers to a compound- which binds to,' and decreases the activity of, a receptor in the presence of an agonist. In the case of a G-protein coupled receptor, activation may be measured using an appropriate second messenger system which is coupled to the receptor in a cell or tissue in which the receptor is expressed. Some specific but by no means limiting examples of well-known second messenger systems are adenylate cyclase, intracellular calcium' mobilization, ion channel activation, guanylate cyclase, inositol phospholipid hydrolysis, and MAP kinase activation. Conversely, the term "agonist" refers to a compound which, binds to, and increases the activity of, a receptor as compared with the activity of the receptor in the absence of any agonist. Methods to perform second messenger assays are described in PCT International Publication No. 97/46250 and in PCT International Publication No. 98/15570, the contents of which are hereby incorporated by reference.
In the case that a receptor has activity in the absence of an agonist (constitutive receptor activity) the antagonist may act as an inverse agonist or an allosteric modulator, as opposed to a neutral antagonist, and suppress receptor signaling independent of the agonist (Lutz and Kenakin, 1999) . The categories of "antagonist compounds" are therefore seen to include 1) neutral antagonists (which block agonist actions but do not affect constitutive activity); 2) inverse agonists (which block agonist actions as well as constitutive activity by stabilizing an inactive receptor conformation); 3) and allosteric modulators (which block agonist actions to a limited extent and which may .also block constitutive • activity through allosteric regulation) . The probability that an antagonist is neutral and therefore of "zero efficacy" is relatively low, given that this would require identical affinities for different tertiary conformations of the receptor. Thus, Kenakin proposed in 1996 that, "with the development of sensitive test systems for the detection of inverse agonism will come a reclassification of many drugs. It might be observed that numerous previously classified neutral antagonists may b'e inverse agonists" (Kenakin, 1996) . Indeed, there is now evidence from studies with known pharmacological agents to support the existence of inverse agonists for numerous receptors, including histamine, 5HTιA, 5HT2C, cannabinoid, dopamine, calcitonin and human formyl peptide receptors, among others (de Ligt, et al, 2000; Herrick-Davis, et al, 2000; Bakker, et al, 2000). In the case of the 5HT2C receptor, clinically effective atypical antipsychotics drugs such as sertindole, clozapine, olanzapine, ziprasidone, risperidone, zotepine, tiospirone, fluperlapine and. tenilapine displayed potent inverse activity whereas typical antipsychotic drugs such as chlorpromazine, thiόridazine, spiperone and thiothixene were classified as neutral antagonists (Herrick-Davis et al, 2000) . In the case of the histamine Hi receptor, 'the therapeutically used anti-allergies cetirizine, loratadine and epinastine were found to be inverse agonists. These findings further extend the idea that many compounds previously thought of as neutral antagonists will be reclassified as inverse agonists when tested in ■ a constitutively active receptor system (de Ligt et al, 2000) .
The subject invention provides GAL3 antagonists which selectively bind to the GAL3 receptor. A GAL3 antagonist useful in -the' treatment of pain is one which selectively binds' to the GAL3 receptor, and displays analgesic activity in an animal model which is predictive of the efficacy of analgesics to treat pain in humans. Animal models used to test potential analgesic agents are well known in the art .
In order to test compounds for selective binding to the human GAL3 receptor the cloned cDNAs encoding both the human, and rat GALl and GAL2 receptors have been used. The cloning and assay methods for the human and rat GALl receptors may be found in PCT International Publication No. WO 95/22608, the contents of which are hereby incorporated by reference. The cloning and assay methods for the human and rat GAL2 receptors may be found in PCT International Publication No. WO 97/26853, the contents of which are hereby incorporated by reference.
The present invention provides for a method of determining the binding affinity of a GAL3 antagonist, wherein the GAL3 antagonist is dissolved in a "suitable solvent" . A "suitable solvent" means one which permits the measurement of binding affinity of the GAL3 antagonist to the human GAL3 receptor at concentrations less than 1 μM, preferably less than 100 nM. Examples of solvents include, but are not limited to, DMSO, ethanol, N,N-dimethylacetamide, or water. For indolones, the preferred .solvent is 3% DMSO (final concentration in the assay). For pyrimidines, the preferred solvent is 1% ethanol/0.09% polypuronic acid F-127 (final concentration in the assay) . For any other type of compounds, the preferred solvent is the solvent which permits the measurement of binding affinity of a GAL3 antagonist at the lowest concentration. Once' a suitable solvent is ascertained for the binding assay of the human GAL3 receptor, the same solvent is used in assays to determine the binding affinity for instance, at the GALl receptor .
In certain embodiments, the aforementioned GAL3 receptor antagonist additionally binds to the human GAL3 receptor with a binding affinity at least ten-fold higher than the binding affinity with which it binds to the human GAL2 receptor.
In other embodiments, the GAL3 receptor antagonist additionally binds to the human GAL3 receptor with a binding, affinity at least 30-fold higher than the binding affinity with which it binds to the human GAL2 receptor.
In still other embodiments, the GAL3 receptor antagonist additionally binds to the human GAL3 receptor with a binding affinity at least 50-fold higher than the binding affinity with which it binds to the human GAL2 receptor.
In some embodiments, the GAL3 receptor antagonist additionally binds to the human GAL3 receptor with a binding affinity at least 100-fold higher than the binding affinity with which it binds to . he human GAL2 receptor.
In further embodiments, the GAL3 receptor antagonist additionally binds to the human GAL3 receptor with a binding affinity at least 200-fold higher than the binding affinity with which it binds to the human GAL2 receptor. In other embodiments, the receptor antagonist also binds to the human GAL3 receptor with a binding affinity at least ten-fold higher than the binding affinity with which it binds to each of the human 5HTιB, human 5HTιD, 5 human .5HTιE, human 5HTιF, human 5HT2A, rat 5HT2C, human 5HT5 and human 5HT7 receptors .
In still another embodiment, the receptor antagonist also binds to the human GAL3 receptor with a binding 0 affinity at least ten-fold higher than the binding affinity with which it binds to the human histamine Hi receptor.
In still another embodiment, the receptor antagonist 5 also binds to the human GAL3 receptor with a binding affinity at least ten-fold higher than the binding affinity with which it binds to the human dopamine Dx, D2, D3, D4 and D5 receptors.
0 In a further embodiment, the receptor antagonist also binds to the human GAL3 receptor with a binding affinity at least ten-fold higher than the binding affinity with which it binds to the human αiA adrenoceptor, the human
Otis adrenoceptor and the human αιD adrenoceptor. 5
In another embodiment, the receptor antagonist also
' ■ binds to the human GAL3 receptor with a binding affinity at least ten-fold higher than the binding affinity with which it binds to the human 2A adrenoceptor, the human 0 α2B adrenoceptor and the human α2c adrenoceptor.
The binding properties of compounds at • different receptors were determined using cultured cell lines that selectively express the receptor of interest. Cell lines were ' prepared by transfecting the cloned cDNA or cloned genomic DNA or constructs containing both genomic DNA and cDNA encoding the receptors as further described in the Experimental Details herein below. Furthermore, the binding interactions of compounds at different transporters were determined using tissue preparations and specific assays as further described in the Experimental Details herein below.
In connection ' with this invention, a number of cloned receptors discussed herein, as stably transfected cell lines, have been made pursuant to, and in satisfaction of, the Budapest Treaty on the International Recognition of the Deposit of Microorganisms for the Purpose of
Patent Procedure, and are made with the American Type Culture Collection, 10801 University Blvd., Manassas,
Virginia 20110-2209. Specifically,' these deposits' have been accorded ATCC Accession Numbers as follows:
Figure imgf000120_0001
The "5-HTιc", n5-HTιDιn, "5-HTιD2", "5-HT4B", and "5-HT2" receptors were renamed the "5-HT2c", "5-HTιD", "5- HTIB", "5-HT7", and "5-HT2A" receptors, respectively, by the Serotonin Receptor Nomenclature Committee of the IUPHAR.
The "human αιC" , "human ccιA" , and "human Dip" were renamed the "human otiA" , "human 0CID" < and "human D5" respectively . The following receptor sequences have been"deposited with the GenBank DNA database, which is managed by the National Center for Biotechnology (Bethesda, MD) .
Figure imgf000121_0001
The "human Dm" receptor was renamed the "human Di" receptor.
This invention further provides a . 'pharmaceutical composition comprising a therapeutically effective amount of the compound of the invention and a pharmaceutically acceptable carrier. In one embodiment, the amount of the compound is an amount from about 0.01 mg to about 800 mg. In another embodiment, the amount of the compound is an amount from about 0.01 mg to about 500 mg . In another embodiment, the amount of the compound is an amount from about 0.01 mg to about 250 mg. In another embodiment, the amount of the compound is an amount from about 0.1 mg to about 60 mg. In another • .embodiment , the amount of the compound is an amount from about 1 mg to about 20 mg. In a further embodiment, the carrier is a liquid and the composition is a solution. In another embodiment, the carrier is a solid and the composition is a powder or tablet. In a further embodiment, the carrier is a gel and the composition is a capsule or suppository.
This invention provides a pharmaceutical composition made by combining a therapeutically effective amount of the compound of this invention and a pharmaceutically acceptable carrier.
This invention provides a process for making a pharmaceutical composition comprising combining a therapeutically effective amount of the compound of this invention and a pharmaceutically acceptable carrier.
In the subject invention a "therapeutically effective amount" is any amount of a compound which, when administered to a subject suffering from a disease against which the compounds are effective, causes reduction, remission, or regression of the disease. In the subject application, a "subject" is a vertebrate, a mammal; or a human.
The present invention provides for the use of any of the chemical compounds disclosed herein for the preparation of a pharmaceutical composition for treating an abnormality. The invention also provides for the use of a chemical compound for the preparation of • a pharmaceutical composition for treating an abnormality, wherein the abnormality is alleviated by decreasing the activity of a human GAL3 receptor. In one embodiment, the abnormality is pain. In another embodiment, the abnormality is neuropathic pain. In still another embodiment, the abnormality is Alzheimer's disease. In still another embodiment, the abnormality is obesity. In still another embodiment, the abnormality is diabetes.
In the present invention the term "pharmaceutically acceptable carrier" is any pharmaceutical carrier known to those of ordinary skill in the art as useful in formulating pharmaceutical compositions. On December 24, 1997 the Food and Drug Administration of the United States Department of Health and Human Services published a guidance entitled "Q3C Impurities: Residual Solvent". The guidance recommends acceptable amounts -of residual solvents in pharmaceuticals for the safety of the patient, and recommends the use of less toxic solvents in the manufacture of drug substances and dosage forms.
In an embodiment of the present invention, the pharmaceutical carrier may be a liquid and the pharmaceutical composition would be in the form of a solution. In another embodiment, the pharmaceutically acceptable carrier is a solid and the composition is in the form of a powder or tablet. In a further embodiment, the pharmaceutical carrier is a gel and the composition is in the form of a suppository or cream. In a further embodiment the compound may be formulated as a part of a pharmaceutically acceptable transdermal patch. In yet a further embodiment, the compound may be delivered to the subject by means of a spray or inhalant.
A solid carrier can include one or more substances which may also act as endogenous carriers (e.g. nutrient or micronutrient carriers), flavoring agents, lubricants, - solubilizers , suspending agents, fillers, glidants, compression aids, binders or tablet-disintegrating agents; it can also be an encapsulating material. In powders, the carrier is a finely divided solid which is in admixture with the finely divided active ingredient. In tablets, the active ingredient is mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape' and size desired. The powders and tablets preferably contain' up to 99% of the active ingredient. Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins.
Liquid carriers are used in preparing solutions, suspensions, emulsions, syrups, elixirs and pressurized compositions. The active ingredient can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fats. The liquid carrier can contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers or osmoregulators . Suitable examples of "liquid carriers for oral and parenteral administration include water (partially containing additives as above, e.g. cellulose derivatives, preferably sodium carboxymethyl cellulose solution) , alcohols (including monohydric alcohols and polyhydric alcohols, e.g. glycols) and their derivatives, and oils (e.g. fractionated coconut oil and arachis oil) . For parenteral administration, the carrier can also be an oily ester such as ethyl oleate or isopropyl myristate. Sterile liquid carriers are useful in sterile liquid form compositions for parenteral administration. The liquid carrier for pressurized compositions can be halogenated hydrocarbon or other pharmaceutically acceptable propellent.
Liquid pharmaceutical compositions which are sterile solutions or suspensions can be utilized by for example, intramuscular, • intrathecal, epidural, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously. The compounds may be prepared as a sterile solid composition which may be dissolved or suspended at the time of administration using sterile water, saline, or other appropriate sterile injectable medium. Carriers are intended to include necessary and inert binders, suspending agents, lubricants, flavorants, sweeteners, preservatives, dyes, and coatings . The compound can be administered orally in the form of a sterile solution or suspension containing other solutes or suspending agents (for example, enough saline or glucose to make the solution isotonic), bile salts, acacia, gelatin, sorbitan monoleate, polysorbate 80 (oleate esters of sorbitol and its anhydrides copolymerized with ethylene oxide) and the like.
The compound can also be administered orally either in liquid or solid compo-sition form. Compositions suitable for oral' administration include solid forms, such as pills, capsules, granules, tablets, and powders, -and liquid forms, such as solutions, syrups, elixirs, and suspensions. Forms useful for parenteral administration include sterile solutions, emulsions, and suspensions.
Optimal dosages to be administered may be determined by those skilled in the art, and will vary with the particular compound in use, the strength of the preparation, the mode of administration, and the advancement of the disease condition. Additional factors depending on the particular subject being treated will result in a need to adjust dosages, including subject age, weight, gender, diet, and time of administration.
This invention will be better understood from the Experimental Details which follow. However, one skilled in the art will readily appreciate that the specific methods and results discussed are merely .illustrative of the invention as described mo-re fully in the claims which follow thereafter. 126
Experimental Details
I. Synthesis of Chemical Compounds
The .following examples are for the purpose of illustrating methods useful for making compounds of this invention.
General Methods : All reactions were performed under an Argon atmosphere and the reagents, neat or in appropriate solvents, were transferred to the reaction vessel via syringe and cannula techniques . Anhydrous solvents were purchased from the Aldrich Chemical
Company and used as received. The examples described in the patent were named using the ACD/Name Program
(version 4.01, Advanced Chemistry Development Inc.,
Toronto, Ontario, M5H2L3 , Canada) . The lE NMR and 13C
NMR spectra were ' recorded at either 300 MHz (GEQE Plus) or 400 MHz (Bruker Avance) in CDC13 as solvent and tetramethylsilane as the internal standard unless otherwise noted. Chemical shifts (δ) are expressed in ppm, coupling constants (J") are expressed in Hz, and splitting patterns are described as follows: s = singlet; d = doublet; t = triplet; q = quartet; quintet; sextet; septet; br = broad; m = mutiplet; dd = doublet of doublets; dt = doublet of triplets. ' Elemental analyses were performed by Robertson Microlit Laboratories, Inc. Unless otherwise, mass spectra were obtained using electrospray ionization (ESI, Micromass Platform II) and MH+ is reported. Thin-layer
Chromatography (TLC) was carried out on glass plates pre-coated with silica gel 60 F25 (0.25 mm, EM Separations Tech.). Preparative TLC was carried out on glass sheets pre-coated with silica gel GF (2 mm,
Analtech) . Flash column chromatography was performed on
Merck silica gel 60 (230 -400 mesh) . Melting points
(mp) were determined in open capillary tubes on a Mel- Temp apparatus and are uncorrected.
The following additional abbreviations are used: HOAc, acetic acid; DIPEA, diisopropylethylamine ; DMF, N, N- dimethylfor amide; EtOAc, ethyl acetate; MeOH, methanol; TEA, triethylamine; THF, tetrahydrofuran; All solvent ratios are volume/volume unless stated otherwise.
A . General Procedures for Preparing Pyrimidines
The compounds of this invention were prepared by sucessively displacing the three chlorine atoms of a 2 , 4, 6-trichloropyrimidine with amines. It was found that some amines (i.e. anilines) selectively displace the 2-position chlorine of 2 , 4 , 6-tric-hloropyrimidine, whereas other amines (e.g. piperidine) selectively displace the 4- or 6-position chlorine first (note that the 4- and 6- positions are chemically equivalent) . Some amines react non-selectively at both the 2- and 4- positions of 2 , 4 , 6-trichloropyrimidine. It was also found that if the pyrimidine is substituted at the 4- or 6-position with an amine (mono- or di-substituted, or unsubstituted) , then the next amine (mono- or di- substituted) undergoes substitution at the 2-position of the pyrimidine. Thus, several different Procedures were used to obtain the compounds described by this invention. The following Procedures are representative of the methods that are useful for making compounds of this invention. Procedure A:
4 , 6-DiCHLORO--V-PHΞNYL-2-PYRIMIDINAMINE: A solution of 2 , 4 , 6-trichloropyrimidine (5.5 g, 30 mmol) in tetrahydrofuran (15 mL) was added dropwise to a solution of aniline (2.8 mL, 1 equivalent) in tetrahydrofuran (25 mL) . N, iV-diisopropylethylamine (5.2 mL) was added and the solution was stirred at room temperature overnight. The solvent was removed and the crude material was purified by flash chromatography on silica gel. The column was eluted with 3% ethyl acetate in hexane, followed by 15% ethyl acetate in hexane. The eluent was removed, giving 4, 6-dichloro-iV-phenyl-2-pyrimidinamine (1.11 g, 4.6 mmol, 15%, Rf = 0.4 in 3% ethyl acetate in hexane) .
Procedure B:
4, 6-DICHLQRO-iV- (3 , 4-DICHLOROPHENYL) -2-PYRIMIDINAMINE : A solution of 2 , 4 , 6-trichloropyrimidine (5.00 g) , 3,4- dichloroaniline (4.45 g, 1 equivalent) in 1,4-dioxane (20 mL) and N, iV-diisopropylethylamine (10 mL) was heated at reflux with stirring for 3 hours. The solvent was removed and the crude material was purified by flash chromatography on silica gel. The column was eluted with - a gradient of cyclohexane ' to ethyl acetate/cyclohexane (1:9). The eluent was removed, giving 4, 6-dichloro -N- (3 , 4-dichlorophenyl) -2- pyrimidinamine (1.83 g, 58%, Rf = 0.39 in ethyl acetate/cyclohexane, 2:3).
Procedure C : 6-CHLORO--V,iV4-DIMETHYL--V2-PHENYL-2,4-PYRIMIDINEDIAMINE: Dimethylamine in tetrahydrofuran ( 2M, 15 mL) was added to a solution of 4, 6-dichloro-JV-phenyl-2-pyrimidinamine (0.715 g, 2.97 mmol) in tetrahydrofuran (30 mL) and N, N- diisopropylethylamine (0.52 mL) . The resulting mixture was stirred at room temperature overnight. The solvent was removed and the crude material was purified by flash chromatography on silica gel, eluting with ethyl ' acetate/hexane (1:9) . The eluent was removed, giving 6- chloro-iV4,-V4-dimethyl--V-phenyl-2 , 4-pyrimidinediamine (0.592 g, 2.39 mmol, 80%, Rf = 0.3).
Procedure D: 2 , 4-DICHLORO-6- (1-PIPERIDINYL) PYRIMIDINE: A mixture of 2 , 4 , 6-trichloropyrimidine (5.0 g, 27 mmol) and piperidine (2.3 g, 27 mmol) in tetrahydrofuran (50 L) and N, IV-diisopropylethylamine (3.5 g, 27 mmol) was stirred at room temperature for 24 hours. The solvent was removed and the crude material was purified by flash chromatography on silica gel. The column was eluted with a gradient of hexane to yield ethyl acetate/hexane
(1:4). The eluent was removed, giving 2 , 4-dichloro-6-
( 1-piperidinyl) pyrimidine (3.67 g, 15.8 mmol, 59%, Rf = 0.58 in ethyl acetate/hexane, 1:4).
Procedure E:
4-CHLORO-6- (1-PIPERIDINYL) -2-{4-[3- (TRIFLUOROMETHYL) -2- PYRIDINYL] -1-PIPERAZINYL} PYRIMIDINE : A mixture of 2,4- dichloro-6- (1-piperidinyl) pyrimidine (100 mg,- 0.43 mmol) and 1- [3- ( trifluoromethyl) pyrid-2-yl] piperazine (119 mg, 0.52 mmol) in chlorobenzene (1 mL) was heated at 140°C in a sealed tube for 24 hours. The solvent was removed and the crude material was purified by preparative TLC, eluting with hexane/ethyl acetate (9:1). 4-chloro-6- (1- piperidinyl) -2- {4- [3- (trifluoromethyl) -2-pyridinyl] -1- piperazinyl}pyrimidine ' was obtained as a solid (79 mg, 0.19 mmol, 44%) .
Procedure F :
N- (4-METHYLPHENYL) -6- ( 1-PIPERIDINYL) -2- {4- [ - (TRIFLUOROMETHYL) -2-PYRIDINYL] -1-PIPERAZINYL) -4- PYRIMIDINAMINE : A mixture of 4-chloro-6- (1- piperidinyl) -2-{4-[3- (trifluoromethyl) -2-pyridinyl] -1- piperazinyljpyrimidine (75.0 mg, 0.176 mmol),. p- toluidine (23.1 mg, 0.216 mmol), 1,1'- (bisdiphenylphosphino) -1, 1' -binaphthcl (8.4 mg) , tris (dibenzylidene acetone) dipalladium(O) (8.2 mg) , and sodium tert-butoxide (86.4 mg) in dry toluene (I mL) was heated at 90°C in a sealed tube for 90 minutes. The solvent was removed and the crude material was purified by preparative TLC, eluting with hexane/ethyl acetate (4:1). N-(4-Methylphenyl)-6- (1-piperidinyl) -2-{4-[3- ( trifluoromethyl) -2-pyridinyl] -1-piperazinyl} -4- pyrimidinamine was obtained, from the band at Rf = 0.4, as a solid (59.5 mg, 0.119 mmol, 68%-).
Procedure G; iV2-ETHY -.V2- [2- (IH-3-INDOLYL) ETHYL] -iV- ( 4-METHYLPHENYL) - 6-PIPERIDINO-2 , 4-PYRIMIDINEDIAMINE : A mixture of N- [ 4 - chloro-6- (1-piperidinyl) -2-pyrimidinyl] -iV-ethyl-IV- [2- (lH-indol-3-yl) ethyl] amine (33.4 mg, 0.087 mmol) and p- toluidine (47 mg, 0.43 mmol) was heated neat under argon at 160°C in a sealed tube for 12 hours. The crude material was purified by preparative TLC, eluting with hexane/ethyl acetate (4:1). iv^-Ethyl-iV2- [2- (1H-3- indolyl) ethyl] -lA (4-methylphenyl) -6-piperidino-2 , 4- pyrimidinediamine was obtained, from a band at Rf = 0.37, as a solid (15 mg, 0.033 mmol, 38%).
Procedure H:
2 , 6 -DICHLORO-N, iV-DIMETHYL-4 -PYRIMIDINAMINE : Sodium hydride' (0.13 g, 0.79 mmol) was added to a solution of 2 , 6-dichloro-4-pyrimidinamine (0.40 g, 0.95 mmol) in dry tetrahydrofuran (5 mL) and stirred for 10 minutes, at which point gas evolution had ceased. Methyl iodide (0.06 mL, 0.95 mmol) was added and the resulting solution was stirred for 3 hours at room temperature. The ' solution was quenched with aqueo.us ammonium chloride/ammonium carbonate. The solution was extracted with ethyl acetate and the extracts were dried over sodium sulfate. The solvent was removed and the resulting crude product was purified by flash chromatography over silica gel, eluting with hexane/ethyl acetate (2:1). The desired product (Rf = 0.55) was obtained as a white powder (70 mg, 0.36 mmol,
46%) .
Procedure I :
-V-ETHYL-2- ( 1H-INDOL-3-YL) ETHANAMINE : Step 1. Acetic anhydride (1.02 g) was added dropwise 'to a stirring solution of tryptamine (1.60 g) in tetrahydrofuran (5 L) at 0°C and then brought to room temperature. After 2 hours, the solvent was removed and the residue was taken up into ethyl acetate. The solution was filtered through a plug of silica gel and the solvent removed, giving JV- [2- (lH-indol-3- yl) ethylacetyltryptamineacetamide (1.65 g, 100%). Step 2. Lithium aluminum hydride in tetrahydrofuran
(IM, 30 mL) was added dropwise to a stirring solution of
N- [2-'('lH-indol-3-yl) ethylacetyltryptamineacetamide (2.02 g) in tetrahydrofuran (10 mL) at 0°C. The solution was then heated at reflux overnight. The solution was cooled to 0°C and water was very carefully added dropwise. The white solid was filtered and rinsed with ether/methanol
(9:1, 2 X 25 mL) . The solvent' was. removed from" the filtrate, giving iY-ethyl-2- (lH-indol-3-yl) ethanamine as a viscous pale yellow oil (1.75 g, 93%) .
Procedure J:
4-CHLORO-iV- [2- ( lff-INDQL-3-YL) -1-METHYLETHYL]„-6- (1-
PIPERIDINYD-2-PYRIMIDINAMINE: . A mixture of 2,4- dichloro-6- (1-piperidinyl) pyrimidine (80 mg, 0.34 mmol), -methyItryptamine (59 mg, 0.34 mmol) , and potassium carbonate (47 mg, 0.34 mmol) in chlorobenzene ( 1 mL) was heated at 150°C in a sealed tube for 16 hours. The solvent was removed and the crude material was purified by preparative TLC, eluting with cyclohexane/ethyl acetate (4:1). 4-Chloro-iV- [2- (lH-indol-3-yl) -1- methylethyl] -6- (1-piperidinyl) -2-pyrimidinamine (Rf = 0.19) was obtained as a solid (64.5 mg, 51%). 1H NMR (300 MHz, CDC13)- δ 8.29 (br s, IH) , 7.68 (br d, IH, J = 7.5), 7.32 (d, IH, J"= 7.8), 7.16 (t, IH, ' 'J = 7.8), 7.12 (t, IH, J = 7.8), 6.95 (d, IH, J = 2.1), 5.87 (s, IH) , 4.89 (br d, IH, J" = 8.1), 4.36 (sextet, IH, J" = 6.6), 3.58 - 3.50 (m, -4H), 3.07 (dd, IH, J = 14.4, 5.1), 2.83 (dd, IH, J = 14.1, 7.2), 1.70 - 1.55 (m, 6H) , 1.16 (d, 3H, J =• 6.6) .
Procedure K:
N- (4-METHYLPHENYL) -2- ( 1-PIPERAZINYL) -6- (1-PIPERIDINYL) - -PYRIMIDINAMINE : A solution of "2- (4-benzyl-l- piperazinyl) -N- (4-me hylphenyl) -6- (1-piperidinyl) -4- pyrimidinamine (0.40 g, 0.90 mmol) and ammonium formate (0.28 g, 4.5 mmol) in methanol over 10% palladium/charcoal was stirred at 70°C for 3 hours. The solution was cooled and passed through celite. The solvent was removed, giving the desired product as a solid (0.21 g, 0.60 mmol, 66%). -
Procedure L:
N- (4-METHYLPHENYL) -2- [4- ( 3-METHYL-2-PYRIDINYL) -1- PIPERAZINYL] -6- (1-PIPERIDINYL) -4-PYRIMIDINAMINE : A mixture of N- (4-methylphenyl) -2- (1-piperazinyl) -6- (1- piperidinyl) -4-pyrimidinamine (100 mg, 0.284 mmol), 2- bromo-3 -methylpyridine (54 mg, 0.312 mmol), 1,1'- (bisdiphenylphosphino) -1, 1 ' -binaphthol (13 mg) , tris (dibenzylidene acetone) dipalladium ( 0 ) (13 mg) , and sodium tert-butoxide (136 mg) in dry toluene (4 mL) was heated at 90°C in a sealed tube for 2 hours. The reaction was quenched with water and the solution was extracted three times with ethyl acetate. The solvent was dried and removed. The crude material was purified by preparative TLC, eluting with hexane/ethyl acetate (2:1) . iV-{ 4-methylphenyl) -2- [4- (3-methyl-2-pyridinyl) -1- piperazinyl] -6- (1-piperidinyl) -4-pyrimidiriamine was obtained, from the band at Rf = 0.46, as a' solid (17.1 mg, 0.0385 mmol, 14%) .
Procedure M: 4, 6-DICHL0RQ-2-{4-[3- (TRIFLUOROMETHYL) -2-PYRIDINYL] -1-
PIPERAZINYL} PYRIMIDINE and 2 , 4-DICHLQRO-6- {4- [3-
(TRIFLUOROMETHYL) -2-PYRIDINYL] -1-PIPERAZINYL) PYRIMIDINE : A solution of 4- [3- (trifluoromethyl) -2-pyridinyl] -1- piperazine (127 mg, 0.66 mmol), 2,4,6- trichloropyrimidine' (100 mg, 0.55 mmol) and N, N- diisopropylethylamine (95 μL) in tetrahydrofuran (1 mL) was stirred at 0°C for 15 minutes. At this time, the starting material could no longer be detected by TLC. The solvent was removed and the crude material was purified by preparative TLC, eluting with ethyl acetate/hexane (1:4). Two bands were removed giving 4, 6-dichloro-2-{4- [3- (trifluoromethyl) -2-pyridinyl j -1- piperazinyl)pyrimidine (41.7 mg, 0.110 mmol, 17%, Rf = 0.41), and 2 , 4-dichloro-6-{4- [3- (trifluoromethyl) -2- pyridinyl] -l-piperazinyl}pyrimidine (162 mg, 0.429 mmol, 65%, Rf = 0.10) .
Procedure N:
4- {4- [4-CHLORO-6- (DIMETHYLAMINO) -2-PYRIMIDINYL] -1- PIPERAZINYL) PHENOL : DIPEA (4.535 g, 0.0260 mol) was added to a stirred solution of 4-N, -dimethylamino-2 , 6- dichloropyrimidine (2.00 g, 0.0104 mol) and 4-(l- piperazinyl) phenol (2.23 g, 0.0125 mol) in THF (50 mL) at room temperature under argon. The resulting mixture was refluxed for 48 h, cooled to room temperature, quenched with water (100 mL) , concentrated under reduced pressure and the crude product was redissolved in EtOAc. The organic layer was separated and washed with water (2 X 100 mL) , brine (2 X 100 mL) and purified by column chromatography on silica using EtOAc/Hexane (1:9), giving the desired product (2.77 g, 80%) .
Procedure 0:
A solution of p-toludine (0.2 g, 1.87 mmol) in THF (2 mL) was added to a stirred suspension of NaH (0.11 g, 2.79 mmol) .in anhydrous THF (2 mL) at room temperature. The resulting mixture was heated at 40 °C 'for 15 minutes under argon and cooled to room temperature. 6-
Chloropyrimidine (0.34 g, 1.03 mmol) in THF (25 mL) was added to the above mixture and the resulting mixture was heated at refluxed for 15 h. The reaction mixture was then cooled to room temperature and quenched with saturated. NH4Cl(2 drops). The crude product was concentrated under reduced pressure and redissolved in
EtOAc. The organic layer was separated and washed with aqueous citric acid (2 X 100 mL) , water (2 X 100 L) and brine (2 X 100 mL) . The crude product was purified by column chromatography on silica using EtOAc /hexanes
(1:4), giving the desired product (0.23 g, 5.5%).
Procedure P:
-■ 2- ( 4-BENZYL-1-PIPERAZINYL) -l\T-(3 , 4-DICHLOROPHENYL) -IVs, N6- DIMETHYL-4, 6-PYRIMIDINEDIAMINE: Potassium tert-butoxide (1.6 mmol, 1 M in 2-methyl 2-propanol) was added to a solution of N- [ 2 - (4-benzyl-l-piperazinyl) -6-chloro-4- pyrimidinyl] -iV, iV-dimethylaminε (0.331.g, 0.997 mmol) and
3,4 dichloroaniline (0.178 g, 1.10 mmol) in dioxane (2 mL) . Subsequently, tris (dibenzylidineacetone) dipalladium
(40 mg, 0.04 mmol) and 2 , 2 ' -Bis (diphenylphosphino) -
' 1 , l'binapthyl (44 mg, 0.070 mmol) were added and the ' mixture was stirred for 7 h at 110 °C ." The resulting mixture was cooled to room temperature and ' concentrated under reduced pressure. The residue was treated with saturated NaHC03 (50 mL) and extracted with CH2Cl2 (3 X 50 mL) . The organic layer was washed with brine (2 X 100 mL) , dried over Na2S04, 'concentrated in vacuo , and purified by preparative TLC using hexane/EtOAc to give the desired product (300 mg, 65 %) . Procedure Q:
N- [ 2- (4-BENZYL-l-PIPERAZINYL) -6-CHLORO-4-PYRIMIDINYL] -
N, N- .- - "DIPEA (5.00* g, 40.0 mmol) was added dropwise to a solution of the N- (2 , -6-dichloro-4-pyrimidinyl) -N, N- dimethylamine (5.70 g, 29.6 mmol) and benzyl piperazine (6.00 g, 34.0 mmol) in m-xylene (15 mL) . The mixture was stirred overnight at 130 °C, cooled to room temperature, treated with saturated NaHC03 (50 mL) and then extracted with CH2Cl2 (3 X 50 mL) . The organic layer was washed with brine (2 X 100 mL) , dried over
Na2S04, and concentrated in vacuo . The crude product was purified by chromatography on silica using EtOAc /hexane
(1:3) , giving the desired product (6.8 g, 20- mmol, 67%) .
Procedure R:
■V4,!^4-DIMETHYL-IV6- (4-METHYLPHENYL) -N2- (2 -PHENYLETHYL) - 2,4, 6-PYRIMIDINETRIAMINE: A mixture of N- [ 4- ( dimethylamino) -6- (4-toluidino) -2 -pyrimidinyl] -2- phenylacetamide (60 mg, 0.166 mmol), and LAH (ImL, IM in THF) in THF (10 mL) was refluxed for 3h.
The crude product was concentrated in vacuo and treated with saturated NaHCθ3 (50 mL) and extracted with CHC12
(3 X 50 mL) . The organic layer was washed with brine (2
X 100 mL) , dried over Na2S04, filtered, and concentrated in vacuo . The crude product was purified "by preparative
TLC using hexane/EtOAc (1:3), giving the desired product
(30 mg, 52 %) .
Procedure S: N- [4- (DIMETHYLAMINO) -6- (4-TOLUIDINO) -2-PYRIMIDINYL] -2-
PHENYLACETAMIDE : A mixture of iV4 , .N4-dimethy1-iV5- (4- ethylphenyl) -2, 4, 6-pyrimidinetriamine (122 mg, 0.50 mmol), phenylacetyl chloride (84 mg, 0.55 mmol), and triethylamine (100 mg, 1.00 mmol) in CH2C1: was stirred at room temperature for 16h. The crude product was concentrated in vacuo and treated with saturated NaHC03 (50 L) and extracted with CH2C12 (3 X 50 mL) . The organic layer was washed with brine (2 X 100 L) , dried over Na2S0 , filtered, and concentrated in vacuo . The crude product was purified by preparative TLC using hexane/EtOAc (1:3), giving the desired product (60 mg, 33 %) .
Procedure T:
A mixture of IV4- (3-methoxyphenyl) -IV5, IVs-dimethyl-2- [4- (2- thienylcarbonyl) -1-piperazinyl] -4, 6-pyrimidinediamine (28 mg, 0.06 mmol) and LAH (300 uL IM, 0.3 mmol) in THF (10 L) was refluxed for 16 h. The crude product was concentrated in vacuo and treated with saturated NaHC03 (50 mL) and extracted with EtOAc (3 X 50 mL) . The organic layer was washed with brine (2 X 100 mL) , dried over Na2S0 , filtered, and concentrated in vacuo . The crude product was purified by preparative TLC using hexane/EtOAc (1:3), giving the desired product (20 mg, 39 %) .
Procedure U: 2- [4- ( 3 -METHOXYBENZYL) -1-PIPERAZINYL] -IV4- (3'-
METHOXYPHENYL) -IV6 , IV5-DIMETHYL-4 , 6-PYRIMIDINEDIAMINE : A solution of IV4- (3-methoxyphenyl) -IVs, IV6-dimethy1-2- ( 1- piperazinyl) -4, 6-pyrimidinediamine (36 mg, 0.1 mmol), DIPEA (52 mg, 0.4 mmol), and 1- (chloromethyl) -3- methoxybenzene (20 mg, 0.13 mmol) in 5 mL of dioxane was stirred at 100 °C for 16 h. The crude product was concentrated in vacuo and treated with saturated NaHC03
(50 mL) and extracted with CH2C12 (3 X 50 mL) . The organic layer was washed with brine (2 X lOO mL) , dried over Na2S04, and conceptrated in vacuo . The crude product was 'purified by chromatography on silica using hexane/EtOAc (1:3), giving the desired product (32 mg, 70 %),
Procedure V:
6-CHLΌRO-IV4- (4-METHYLPHENYL) -2 , 4-PYRIMIDINEDIAMINE : A mixture of 4 , 6-dichloro-2-pyrimidinamine (1.64 g, 0.01 mol), p-toluidine (1.07 g, 0.01 mol) in dioxane (2 mL) was heated in a sealed- tube for 30 minutes at 140 °C . The crude product was treated with NaOH (50 ml, 2M). and extracted with CH2Cl2-^(3 X 50 mL) . The organic layer -was washed with brine (2 X 100 mL) , dried over - Na2S04, filtered, and concentrated in vacuo . The crude product was' purified by chromatography on silica using hexane/EtOAc (1:3), giving the desired product (2 g, 78
Procedure W:
IV4- (3-METHOXYPHENYL) -IV6 , IV5-DIMETHYL-2- [4- (2-
THIENYLCARBONYL) -1-PIPERAZINYL] -4 , 6-PYRIMIDINEDIAMINE : A mixture of 2-thiophenecarboxylic acid (15 mg, 0.12 mmol), DIPEA- (129 mg, 1.00 mmol) and 0-(7- azabenzotriazol-l-yl)"N,N,N' , N' -tetramethyluronium hexafluorophosphate (44 mg, 0.12 mmol) in DMF (5 mL) was stirred -at room temperature for 30 minutes. IV4- (3- methoxyphenyl ) -IVδ,IV€-dimethyl-2- (1-piperazinyl) -4, 6- pyri idinediamine (36 mg, 0.10 mmol) was added to the above mixture and stirred at room temperature- for 16 h.
The crude product was treated with saturated NaHC03 (50 L) and extracted with EtOAC (3. X 50 mL) . The organic layer was washed with brine (2 X 100 mL) , dried over Na2S04, filtered, and concentrated in vacuo . The crude product was purified by chromatography on silica using hexane/EtOAc (1:3), giving the desired product (25 mg, 57 %) .
Procedure X:
2- (4-BENZYL-l-PIPERAZINYL) -IV4- (3-METHOXYPHENYL) -N6. N6- DIMETHYL-4, 6-PYRIMIDINEDIAMINE : ■ A mixture of IV4- (3- methoxyphenyl) -N6 , N6 -dimethyl- 2- (1-piperazinyl) -4 , 6- pyrimidinediamine (36 mg, 0.10 mmol) and benzaldehyde (11 mg, 0.1 mmol) in - a solution of methanol (5 mL) and acetic acid (0.5 L) was stirred at room temperature for 1 h. Sodium cyanoborohydride (7 mg, 0.1 mmol) was added to the above solution and stirred at room temperature for 16 h. The crude product was treated with saturated NaHC03 (50 L) and extracted with EtOAC (3 X 50 mL) . The organic layer was washed with brine (2 X 50 mL) , dried over Na2S04, filtered, and concentrated in vacuo . The crude product was purified by chromatography on silica using hexane/EtOAc (1:3), giving the desired product (8 mg, 40 %) .
Procedure Y:
2- [4- (4-BROMOPHENYL) -1-PIPERAZINYL] -IV4- (3-METHOXYPHENYL) - iV6,IV5-DIMETHYL-4', 6-PYRIMIDINEDIAMINE: A mixture of IV4- (3- met'hoxyphenyl) -IV6, IV6-dimethy1-2- (1-piperazinyl) -4,6- pyrimidinediamine (36 mg, 0.1 mmol), l-bromo-4- fluorobenzene (20 mg, 0.13 mmol) was heated at 100 °C for 1 h. The crude product was dissolved in CH2C12 (0.5 mL) and purified by preparative TLC using 5 % methanol in EtOAc, giving the desired product (20 mg, 40 %) .
Procedure Z : 2- [4- (2-METHOXYBENZYL) -1-PIPERAZINYL] -IV4, AT-DIMETHYL-V5- (4-METHYLPHENYL) -4, 6-PYRIMIDINEDIAMINE: A mixture of IV4, IV4-dime hyl-IV6- (4-methylphenyl) -2- ( 1-piperazinyl) -4, 6- pyrimidinediamine (30 mg, 0.086 mmol), 1- (chloromethyl ) - 2-methoxybenzene (17 mg, 0.1 mmol) and triethylaminie (200 mg, 2 mmol) in 1 DMF (1 mL) heated by microwave at 200 °C for 12 minutes. The crude product was treated with saturated NaHC03 (50 mL) and extracted with EtOAC (3 X 50 mL) . The organic layer was washed with brine (2 X 100 mL) , dried over Na2S0 , filtered, and concentrated in vacuo . The crude product was purified by chromatography on silica using hexane/EtOAc (1:3), giving the desired product (10 mg, 27 %) .
Procedure AA:
IV4- (3-METHOXYPHENYL) -IVs , lAPIMETHYL-Σ- [4- (2- THIENYLCARBONYL) -1-PIPERAZINYL] -4 , 6-PYRIMIDINEDIAMINE : ■ A solution of IV4- (3-methoxyphenyl) -IV5 , IV6-dimethyl-2- ( 1- piperazinyl) -4 , 6-pyrimidinediamine (33 mg, 0.1 mmol), 2- thiophenecarbonyl chloride (20 mg, 0.14 mmol), and triethylamine (40 mg, 0.4 mmol) in CH2C12 (5 mL) was stirred at room temperature for 16 h. The crude product was concentrated in vacuo and treated with saturated NaHC03 (50 mL) and extracted with CH2C12 (3 X 50 mL) . The organic layer was washed with brine "(2 X 100 mL) , dried over Na2S0 , filtered, and concentrated in vacuo . The crude product was purified by chromatography on silica using hexane/EtOAc (1:3), giving the desired product as a pale red oil (35 mg, 80 %) .
Procedure BB:
IV4,IV-DIMETHYL-IV5-(4-METHYLPHENYL) -2,4,6- PYRIMIDINETRIAMINE : A mixture of 6-chloro-V4- (4- methylphenyl) -2, 4-pyrimidinediamine (1.5 g, 6.4 mmol), and IV, N-dimethylamine hydrochloride (0.56 g, 7 mmol) and triethylamine (1.4 g, 14 mmol) in DMF (2 mL) , was heated at 170 °C for 16 h. The product was filtered out and the organic layer was treated with saturated NaHC03 (50 mL) and extracted with EtOAC (3 X 50 mL) . The organic layer was washed with brine (2 X 100 mL) , dried over Na2S0 , filtered, and concentrated in vacuo . The crude product was purified by chromatography on silica using hexane/EtOAc (1:3), giving the desired product (0.6 g, 40 %) .
Procedure CC :
N- (4-METHYLPHENYL) -2- [4- (l-OXIDO-2-PYRIDINYL) -1- PIPERAZINYL] -6- (1-PIPERIDINYL) -4-PYRIMIDINAMINE : A solution of 3- cholorperbenzoic acid (450 mg, 2.6 mmol), and 30 % H202 (0.1 mL) in CH2Cl2 (2 mL) was added to a solution of N- (4-methylphenyl) -6- (1-piperidinyl) - 2- [4- (2-pyridinyl) -1-piperazinyl] -4-pyrimidinamine (150 mg, 0.300 mmol) in CH2C12 at 0 °C . The resulting mixture was gradually warmed to room temperature and stirred for 24 h, crude product was treated with saturated NaHC03 (50 mL) and extracted with EtOAC (3 X 50 mL) . Combined organic layers were washed with brine (2 X 50 mL) , dried over Na2S0 , filtered, concentrated in vacuo , and purified by chromatography on silica using hexane/EtOAc (1:3) to give the desired product.
Piperazines that were not commercially available were synthesized according to the method previously described (Ennis and Ghazal, 1992) .
The following are examples to illustrate the compounds of this invention. Procedures A - BB as described above, were used and any modifications are noted in parentheses .
5
Figure imgf000144_0001
( 1-PIPERIDINYL) -2 , 4-PYRIMIDINEDIAMINE : Prepared by Procedures D, G (for substitution with cyclohexylamine) , and G. "Ή NMR (300 MHz,' CDCl3) δ 7.22 (d, 2H, J = 7.8), 7.12 (d, 2H, J = 7.8), 5.29 (s, IH) , 4.43 (br s, IH) , 10 3.55 - 3.44 (m, 5H) , 3.01 (s, 3H) , 2.33 (s, 3H) , 2.00 - 1.05 (m, 16H) .
Example 2: lACYCLOHEXYL-IV2- ( 2 -METHOXYETHYL) -IV4- (4- METHYLPHENYL) -6- (1-PIPERIDINYL). -2 , 4-PYRIMIDINEDIAMINE : 15 Prepared by Procedures D, J (130°C) , and F (2 hours) . XH NMR (300 MHz, CDCl3) δ 7.25 (d, 2H, J = 8.1), 7.10 (d, 2H, J = 8.1), 6.17 (br s, IH) , 5.31 (s, IH) , 4.58 - 4.43 (m, IH) , 3.61 - 3.57 (m, 4H) , 3.52 - 3.48 ( , 4H) , 3.39 ■ - s, 3H) , 2.31 (s, '3H) , 1.83 - 1.75 (m, 4H) , 1.70 - 1.50 20 (m, 7H) , 1.43 - 1.37 (m, 4H) , 1.19 - 1.05 (m, IH) ; ESI- " ' MS m/z 424 (MH+) .
Example 3 IV4- (4-METHYLPHENYL) -IX-PHENYL-6- (1-
PIPERIDINYL) -2 , 4-PYRIMIDINEDIAMINE: Prepared by
25 Procedures A, B (for' substitution with aniline) , and E
(100°C, for substitution with piperidine) . XH NMR (300
MHz, CDC13) δ 7.58 (d, 2H, J = 8.7), 7.26 (t, 2H, J =
7.8), 7.19 (d, 2-H, J = 8.7), 7.15 (d, 2H, J = 7.8), 6.95
(t, IH, J" = 7.8), 6.82 (br s, IH) , 6.48 (br s, IH) , 5.49
30 (s, IH) , 3.56 - 3.46 (m, 4H) , 2.34 (s, 3H) , 1.67 - 1.52 (m, 6H) ; ESI-MS m/z 360 (MH+) .
Example 4: IV2,^-DI (4-METHYLPHENYL) -6-PIPERIDINO-2 , 4- PYRIMIDINEDIAMINE : Prepared by Procedures D and G
(100°C, 12 hours, for substitution of p-toludine at C2 and C4 of the pyrimidine) . λE NMR (300 MHz, CDC13) δ
7.47 (d, 2H, J" = 8.3), 7.20 (d, 2H, J = 7.8), 7.15 (d, 2H, J = 8.3), 7.10 (d, 2H, J = 8.3), 6.79 (br s, IH) ,
6.46 (br s, IH) , 5.52 (s, IH) , 3.51 (t, 4H, J = 4.6),
2.36 (s, 3H) , 2.31 (s, 3H) , 1.69 - 1.53 (m, 6H) ; ESI-MS m/z 374 (MH÷) .
Example 5: IV2- (4-CHLOROPHENYL) -IV4- (4-METHYLPHENYL) -6- (1- PIPERIDINYL) -2 , 4-PYRIMIDINEDIAMINE: Prepared by Procedures D, G (for substitution with 4-chloroaniline), and G (3.5 hours). XH NMR (300 MHz, CDCl3) δ 8.79 (br s, IH) , 7.72 (br s, IH) , 7.54 (d, 2H, J = 8.3), 7.28 - 7.17 (m, 6H) , 5.36 (s, IH) , 3.61 - 3.46 (m, 4H) , 2.36 (s, 3H) ,' 1.76 - 1.53 (m, 6H) ; ESI-MS m/z 393 (MHT with 35Cl) , 395 (MH* with 7Cl) .
Examp1e 6 : IV2-METHYL-IV4- ( 4-METHYLPHENYL ) -Nz-PHENYL-6 - ( 1- PIPERIDINyl) -2 , 4-PYRIMIDINEDIAMINE: Prepared by
Procedures D, G (140°C, 90 minutes, for substitution with aniline), and G (3.5 hours). XH NMR (300 MHz, CDC13) δ 7.42 - 7.33 (m, 4H) , 7.18 - 7.14 (overlapping t at 7.16 & d at 7.15, 3H) , 7.07 (d, 2H, J = 7.8), 6.25 (br s, IH) , 5.41 (s, IH) , 3.54 (s, 3H) , 3.50 - 3.42 (m, 4H) , 2.33 (s, 3H) , 1.68 - 1.50 (m, 6H) ; ESI-MS m/z 374 (MH+) .
Example 7: lAMETHYL-AlADI (4-METHYLPHENYL) -6- ( 1- PIPERIDINYL) -2 , 4-PYRIMIDINEDIAMINE: Prepared by
Procedures D, G (180°C, 10 hours, for substitution with IV-methyl-p-toluidine) , and G (14.0°C). lH NMR (300 MHz, CDCI3) δ 7.27 - 7.04 (m, 8H) , 6.19 (br s, IH) , 5.38 (s, IH) , 3.52 (s, 3H) , 3.48 - 3.41 (m, 4H), "2.38 (s, 3H) 2.31 (s, 3H) , 1.67 - 1.49 (m, 6H) ; ESI-MS m/z 388 (MH*)
Example 8: IV2- [2- ( 5-METHYL-IH-3 -INDOLYL) ETHYL] -IV4- (4- METHYLPHENYL) -6- ( 1-PIPERIDINYL) -2 , 4-PYRIMIDINEDIAMINE: Prepared by Procedures D, J, and G (160°C, 12 hours) . XK NMR (300 MHz, CDC13) δ 8.05 (br s, IH) , 7.43 (s, IH) , 7.23 (d, IH, J = 8.4), 7.15 (d, 2H, J = 8.4), 7.10 (d, 2H, J = 8.4), 7.00 (d, IH, J = 8.4), 6.98 (s, IH) , 6.43 (br s, IH), 5.37 (s, IH) , 4.86 (br t, IH, J = 7.1), 3.70 (q, 2H, LT = 7.1), 3.52 - 3.43 (m, 4H) , 3.02 (t, 2H, J = 7.1), 2.46 (s, 3H) , 2.32 (s, 3H) , 1.67 - 1.49 ( , 6H) ; ESI-MS m/z 441 (MHT) .
Example 9: IV2- [2- ( 5-METHOXY-IH-3 -INDOLYL) ETHYL] -IV4- ( 4- METHYLPHENYL)-6-(l-PIPERID-GNYL) -2 , 4-PYRIMIDINEDIAMINE : " Prepared by Procedures D, E (160 °C, 36 hours) , and G. XH NMR (300 MHz, CDCl3) δ 8.00 (br s, IH) , 7.15 (d, 2H, J = 8.4), 7.12 (d, 2H, J" = 8.4), 7.08 - 7.04 ( , 3H) , 6.85
(dd, IH, J = 8.8, 2.6), 6.48 (br s, IH) , 5.36 (s, IH) ,
4.96 (br s, IH) , 3.85 (s, 3), 3.72 - 3.67 ( , 2H) , 3.55
- 3.45 (m, 4H) , 3.02 (t, 2H, J = 6..9), 2.32 (s, 3H) ,
-- 1.68 - 1.49 (m, 6H) ; ESI-MS m/z 457 (MH") . " .
Example lO IV2- [2- (1H-3 -INDOLYL) ETHYL] -IV4- (4-
METHYLPHENYL) -6- (1-PIPERIDINYL) -2 , 4-PYRIMIDINEDIAMINE : Prepared by Procedures D, E (100°C) , and G (L50°C). H NMR (300 MHz, CDCl3) δ 8.34 (br s, IH) , 7.63 (d, IH, J" = 7.8), 7.31 (d, IH, J = 7.8), 7.23 - 7.09 (m, 6H) , 6.94 (s, IH) , 6.60 (br s, IH) , 5.36 (s, IH) , 4.95 (t, IH, J = 6.3), 3.68 (dt, 2H, J = 6.3, 6.-9), 3.48 - 3.44 (m, 4H) , 3.01 (t, 2H, J- = 6.9), 2.31 (s, 3H) , 1.65 - I.48 (m, 6H) ; ESI-MS m/z 427 (MET) .
Example 11: IV2- [2- (IH-3 -INDOLYL) ETHYL] -IV2-METHYL-IV4- (4-
METHYLPHENYL) -6- ( 1-PIPERIDINYL) -2 , -PYRIMIDINEDIAMINE: Prepared by Procedures D, E (160°C, 4 hours) , and F (12 hours). "Η NMR (300 MHz, CDCl3) δ 8.02 (br s, IH) , 7.71
(d, IH, J = 7.8), 7.36 (d, IH, J - 7.8), 7.22 (d, 2H,
= 7.8), 7.20 (t, IH, J" = 7.8), 7..17 - 7.09 (m, 3H) , 7.03
(s, IH) , 6.40 (br s, IH) , 5.35 (s, IH) , 3.91 (t, 2H,' J = 7.8), 3.56 - 3.46 ( , 4H) , 3.16 (s, 3H) , 3.09 (t, 2H, J
= 7.8), 2.33 (S, 3H),-1.70 - 1.52 (m, 6H) ; ESI-MS m/z
441 (MH+-) .
Example 12: IV2- [2- (1F-INDQL-3-YL) ETHYL] -IV2-METHYL-IV4- PHENETHYL-6- (1-PIPERIDINYL) -2 , 4-PYRIMIDINEDIAMINE :
Prepared by Procedures D, E (160°C, 12 hours) , and G. XH
NMR (300 MHz, CDCl3) δ 8.00 (br s, IH) , 7.71 (d, IH, J =
7.8), 7.34' (t, 2H, J = 7.8), 7.24 - 7.15 ( , 5H) , 7.08
(t, IH, J = 7.8), 6.98 (s, IH) , 4.95 (s, IH) , 4.39 (br s, IH) , 3.88 (t, 2H, J" = 7.8), 3.57 -.3.48 ( , 6H) , 3.12
(s, 3H) , 3.05 (t, 2H, J" = 7.8), 2.89 (t, 2H, J = 7.8),
1.68 - 1.53 (m, 6H) ; ESI-MS m/z 455 (MHT) .
Example 13: IV2- [2- (lff-INDQL-3-YL) ETHYL] -V2-METHYL-IV4- (2- NAPHTHYL) -6- ( 1-PIPERIDINYL) -2 , 4-PYRIMIDINEDIAMINE :
Prepared by Procedures D, E (160°C, 12- hours, for substitution with IV-methyltryptamine) , and E (160°C, 12 hours). XE NMR (300 MHz, CDCl3) δ 7.95 (br s, IH) , 7.92
(s, IH) , 7.78 - 7..75 (m, 3H) , 7.72 (d, IH, J" = 8.1), ' 7.46 - 7.41 ( , 2H) , 7.37 (d, 2H, J = 8.4), 7.-20 (t, IH,
J = 7.8), 7.11 (t, IH, J = 7.8), 7.01 (s, IH) , 6.42 (br s, IH) , 5.45 (s, IH) , 3.95 (t, 2H, J" = 7.8), 3.56 - 3.49
(m, 4H) , 3.19 (s, 3H) , 3.11 (t, 2H, J = 7.8), 1-62 - 1.59 (m, 6H) ; ESI-MS m/z 477 (MH+) .
Example 14: IV4- (3-FLUOROPHENYL) -IV2- [2- ( lff-INDOL-3- YL) ETHYL] -IV2-METHYL-6- (1-PIPERIDINYL) -2,4- PYRIMIDINEDIAMINE : Prepared by Procedures D, E (160°C, 12 hours, for substitution with IV-methyltryptamine), and G. XH NMR (300 MHz, CDC13) δ 7.97 (br s, IH) , 7.71 (d, IH, J- = 7.8), 7.41 (dt, IH, J = 9.5, 1.0), 7.34 (d, IH, J- = 7.8), 7.22 - 7.06 (m, 4H) , 7.02 - 7.00 (s at 7.02 & d at 7.01 overlapping, 2H) , 7.01 (s, IH) , 6.33 (br s, IH) , 5.34 (s, IH) , 3.90 (t, 2H, J = 7.8), 3.58 - 3.50 (m, 4H),- 3.16 (s, 3H) , 3.08 (t, 2H, LJ = 7.8), 1.70 - 1.54 (m, 6H) ; ESI-MS m/z 445 (MH1") .
Example 15: IV4- (3 , 4-DIFLUOROPHENYL) -IV2- [2- (1H-INDOL-3- YL) ETHYL] -lAMETHYL-δ- (1-PIPERIDINYL) -2 , 4- PYRIMIDINEDIAMINE : Prepared by Procedures D, E (160°C, 12 hours, for substitution with IV-methyltryptamine), and G. XH NMR (300 MHz, CDC13) δ 7.99 (br s, IH) , 7.68 (d, IH, J = 7.8), 7.51 (ddd, IH, J = 9.5, 7.8, 2.3), 7,35 (d, IH, J = 7.8), 7.19 (t, IH, J = 7.8), 7.11 (t, IH, J = 7.8), 7.07 - 6.90 (m, 3H) , 7.01 (s, IH) , 6.22 (br s, IH) , 5.23 (s, IH) , 3.89 (t, 2H, J -=.7.8), 3.57 - 3.49 (m, 4H) , 3.15 (s, 3H) , 3.07 (t, 2H, J = 7.8), 1.68 - 1.53 ( , 6H) ; ' ESI-MS m/z 463 (MH+) .
Example 16: IV4- ( 3 -CHL0R0-4-METHYLPHENYL) -IV2- [2- (1H-INDOL- 3-YL) ETHYL] -^-METHYL-δ- (1-PIPERIDINYL) -2,4- PYRIMIDINEDIAMINE : Prepared by Procedures D, E (160°C, 12 hours, for substitution with IV-methyltryptamine), and G. XH NMR (300 MHz, CDC13) δ 7.96 (br s, IH) , 7.69 (d, IH, J = 7.5), 7.51 (s, IH) , 7.36 (d, IH, J = 7.8), 7.19 (t, IH, J" - 7.8), 7.14 - 7.06 (m, 3H) , 7.01 (s, IH) , 6.18 (br s, IH) , 5.29 (s, IH) , 3.89 (t, 2H, J = 7.8),
3.53 - 3.48 ( , 4H) , 3.13 (s, 3H) , 3.07 (t, 2H, J =
7.8),' 2.31 (s, 3H) , 1.70 - 1.55 '(m, 6H) ; ESI-MS m/z 475 (MH+) .
Example 17 IT- [2- ( Iff-INDOL-3-YL) ETHYL] -IV- (3-
METHOXYPHENYL) -IV2-METHYL-6- (1-PIPERIDINYL) -2 , 4- PYRIMIDINEDIAMINE : Prepared by Procedures D, E (160°C, 12 hours, for substitution with IV-methyltryptamine), and G. XH NMR (300 MHz, CDC13) δ 8.02 (br s, IH) , 7.71 (d,
IH, J = 7.8), 7.34 (d, IH, J = 8.3), 7.25 - 7.04 (m,
4H) , 7.01 (s, IH) , 6.89 (d, IH, J = 7.8), 6.57 (dd, IH,
' J = 8.3, 2.4), 6.30 (br s, IH) , 5.42 (s, IH) , 3.91 (t,
2H, J - 7.7), 3.76 (s, 3H) , 3.57 - 3.49 (m, 4H) , 3.16 (s, 3H) , 3.08 (t, 2H, J" = 7.7), 1.70 - 1.53 (m, 6H) ; ESI-MS m/z 457 (MH+) .
Example 18: lAETHYL-IV2- [2- (lff-INDOL-3-YL) ETHYL] -A?4- (4- METHYLPHENYL) -6- (1-PIPERIDINYL) -2 , 4-'PYRIMIDINEDIAMINE : Prepared by Procedures D, E (160°C, 12 hours, for substitution with V-ethyltryptamine) , and G. "Ή NMR (300 MHz, CDC13) δ 7.97 (br s, IH) , 7.71 (d, IH, J = 7.8), 7.35 (d, IH, J = 7.8), 7.25 - 7.16 (overlapping d at 7.23 & t at 7.22, 3H) , 7.14 (t, IH, J = 7.8), 7.08 (d, 2H, J = 7.8), 7.02 (s, IH) , 6.19 (br s, "lH), 5.34 (s,
IH) , 3.82 (t, 2H, J = 7.9), 3.61 (q, 2H, J = 7.1), 3.55
. - 3.45 (m, 4H) , 3.08 (t, 2H, J = 7.9), 2.30 (s, 6H) ,
1.68 - 1.50 (m, -6H), 1.18 (t, 3H, J" = 7.1); ESI-MS m/z
455 (MH*) .
Example 19 IV2- [2- (lff-INDOL-3-YL) ETHYL] -IV2- (2-
METHOXYETHYL) -IV4- (4-METHYLPHENYL) -6- ( 1-PIPERIDINYL) -2 , 4- PYRIMIDINEDIAMINE : Prepared by Procedures D, E (160°C, 12 hours, for substitution with IV- methoxyethyltryptamine) , and G. XH NMR (300 MHz, CDC13 δ 7.96 (br s, IH) , 7.72 (d, IH, J = 7.5), 7.35 (d, IH, J = •7.8), 7.27 - 7.07 (m, 6H) , 7.02 (s, IH) , 6.19 (br s, IH) , 5.35 (s, IH) , 3.88 (dd, 2H, J" - 9.9, 5.4), 3.74 (t, 2H, J = 6 . 0 ) , 3.60 (dd, 2H, J = 10.5, 4.8), 3.57 - 3.46 (m, 4H) , 3.34 (s, 3H) , 3.12 - 3.07 (m, 2H) , 2.32 (s, 6H) , 1.70 - 1.58 (m, 6H)"; ESI-MS m/z 485 (MH+) .
Example 20: . TV2- [2- (Iff-3 -INDOLYL) -1-METHYLETHYL] -IV4- (4- METHYLPHENYL) -6- ( 1-PIPERIDINYL) -2, 4-PYRIMIDINEDIAMINE: Prepared by Procedures D, J, and G. :H NMR (300. MHz, CDCI3) δ 8.10 (br s, IH) 7.70 (d, IH, J = 7,8), 7.36 (d, IH, J = 8.1)-, 7.19 - 6.98 (m, 7H) , 6.60 (br s, IH) , 5.35 (s, IH) , 4.89 (br s, IH) , 4.44 - 4.36 (m, IH) , 3.55 - 3.45' (m, 4H) , 3.14 (dd lH, J = 14.1, 5.1), 2.84 (dd, IH, J = 14.1, 7.5), 2.33 (s, 3H) , 1.62 - 1.50 (m, 6H) , 1.18 (d, 3H, = 6.6); ESI-MS m/z 441 (MH+) .
Example 21 : IV2- [2 - (lff-INDQL-3-YL) -1-METHYLETHYL] -IV2- METHYL-lAf 4-METHYLPHENYL) -6- (1-PIPERIDINYL) -2,4- PYRIMIDINEDIAMINE : Prepared by Procedures D, E (160°C, 12 hours, for substitution with N, or-dimethyltryptamine) , and G. λK NMR' (300 MHz, CDC13) δ 7.92 (br s, IH) 7.73 (d, IH, J = 7.8) , 7.34 (d, IH, J = 7.8) , 7.19 - 7.09 (m, 6H) , 7.03 (s, IH), 6.17 (br s, IH) , 5.34 (s,' IH) , 3.51 - 3.44 (m, ' 5H) , 3.11 - 3.05 (m, IH) , 3.02 (s, '2H) , 2.90 (dd, IH, J = 14.7, 7.5), 2.32 (s, 3H) , 1.65 - 1.49 (m, 6H) , 1.18 (d, 3H, 'j = 6 . 6 ) ; ESI-MS m/z 455 (HttT) .
Example 22: IV2-METHYL-IV4- (4-METHYLPHENYL) -lAPHENETHYL-δ- ( 1-PIPERIDINYL) -2 , 4-PYRIMIDINEDIAMINE : Prepared by Procedures D, E (160°C, 12 hours, for substitution at C2 of the pyrimidine) , and G. ESI-MS m/z 402 (MHT) .
Example 23j 2- (4-BENZYL-l-PIPERAZINYL) -IV- (4-
METHYLPHENYL) -6- ( 1-PIPERIDINYL) -4-PYRIMIDINAMINE: Prepared by Procedures D, I (140°C, overnight, for substitution with V-benzylpiperazine) , and F (2 hours) . "-H NMR (300 MHz, CDCl3) δ 7.38 - 7.26 ( , 5H) 7.18 (d, IH, J = 7.8), 7.12 (d, 'IH, J = 7.8), 6.18 (br s, IH) , 5.34 (s, IH) , 3.93 - 3.87 ( , 4H) , 3.77 (t, 4H, J = 5.0), 3.55 (s, 2H) , 3.48 - 3.42 (m, 4H) , 2.49 (t, 4H, J = 5.0), 2.31 (s, 3H) ; 1.66 - 1.49 (m, 6H) ; ESI-MS m/z 443 (MH+) .
Example 24 IV- ( 4-METHYLPHENYL) -2- ( 4-PHENYL-1- PIPERIDINYL) -6- (1-PIPERIDINYL) -4-PYRIMIDINAMINE :
Prepared by Procedures D, E (16 hours, for substitution with 4-phenylpiperidine) , and F (1 hour) . "Ή NMR (300 MHz, CDC13) δ 7.34 - 7.24 ( , 5H) , 7.19 (d, 2H, J = 7.8), 7.12 (d, 2H, J" = 7.8), 6.22 (br s, IH) , 5.36 (s, IH) , 4.89 (d with fine splitting, 2H, J = 13.0), 3.52 - 3.42 ( , 4H) , 2.86 (dt, 2H, J = 1.0, 13.0), 2.73 (tt, IH, J = 11.6, 1.5), 2.32 (s, 3H) , 1.89 (d with fine splitting, 2H, J" = 12.0), 1.74 (ddd, 2H, J" = 13.0, 12.0, 1.5), 1.67 - 1.52 (m, 6H) ; • ESI-MS m/z 428 (MH+) . "
Example 25: N- (4-METHYLPHENYL) -2- (4-PHENYLPIPERAZINYL) - 6- (1-PIPERIDINYL) -4-PYRIMIDINAMINE: Prepared by Procedures D, G (180°C, 2.5 hours, for substitution with V-phenylpiperazine) , and G (140°C, overnight) . 1H NMR (300 MHz, CDC13) δ 7.28 (t, 2H, J = 7.8), 7.19 (d, 2H, J = 7.8), 7.13 (d, 2H, J = 7.8), 6.99 (d,. 2H, J = .7.8), 6.89 (t, IH, J = 7.8), 6.23 (br s, IH) , 5.38 (s, IH) , 3.91 (t, 2H, J = 4.6), 3.54 - 3.44 (m, 4H) , 3.23 (t, 2H, J = 4.6)/ 2.34 (s, 3H), 1.71 - 1.51 (m, 6H) ; ESI-MS m/z 429 (MH+) .
Example 26: 2- [4- (2-ETHYLPHENYL) -1-PIPERAZINYL] -N- (4- METHYLPHENYL) -6- ( 1-PIPERIDINYL) -4-PYRIMIDINAMINE : Prepared by Procedures D, E (120°C) , and F. lE NMR (300 MHz, CDC13) δ 7.28 (d, IH, <J = 7.-8), 7.24 - 7.08 (m, 7H) , 6.37 (br s, IH) , 5.41 (s, IH) , 3.98 - 3.90 ( , 4H) , 3.53 - 3.47 (m, 4H) , 2.99 - 2.92 (m, 4H) , 2.80 (q, 2H, J = 8.3), 2.35 (s, 3H) , 1.-69 - 1.54 (m, 6H) , 1.31 (t, 3H, A = 8.3); ' ESI-MS m/z 457 (MH+) .
Example 27: 2- [4- (2 , 6-DIMETHYLPHENYL) -1-PIPERAZINYL] -N- (4-METHYLPHENYL) -6- (1-PIPERIDINYL) -4-PYRIMIDINAMINE :
Prepared by Procedures D, E (120°C), and F. :H NMR (300 MHz, CDC13) δ 7.22 (d, 2H, J = 7.8), 7.15 (d, 2H, J" = 7.8), 7.05 - 7.95 (m, 3H) , 6.30 (br s, IH) , 5.39 (s, IH) , 3.88 (t, 4H, J = 4.6), 3.53 - 3.47 (m, 4H) , 3.15 (t, 4H, J = 4.6), 2.37 (s, 6H) , 2.34 (s, 3H) , 1.68 - 1.53 (m, 6H) ; ESI-MS m/z 457 (MH+) .
Example 28: -{2- [4- (2 , -DIMETHOXYPHENYL) PIPERAZINYL] -6- (1-PIPERIDINYL) -4-PYRIMIDINYL} -TV- (4-METHYLPHENYL) AMINE : Prepared by Procedures D, E (150°C, 16 hours), and F (5 hours). Η NMR (300 Hz, CDC13) δ 7.18 (d, 2H, J" = 8.1), 7.12 (d, 2H, J = 8.1), 6.88 (d, IH, J = 9.0), 6.50 (d, IH, J = 2.4), 6.43 (dd, IH, J = 8.7, 2.4), 6.23 (br s, IH) , 5.36 (s, IH) , 3.94 (t, 4H, J = 7.5), 3.87 (s, 3H) , 3.79 (s, 3H) , 3.52 - 3.44 (m, 4H) , 3.03 (t, 4H, J" = 7.5), 2.33 (s, 3H) , 1.65 - 1.52 (m, 6H) ; ESI-MS m/z 488 (MH+) . Example 29: IV- (4-METHYLPHENYL) -6- ( 1-PIPERIDINYL) -2- {4- [3- (TRIFLUOROMETHYL) PHENYL] -1-PIPERAZINYL} -4-
PYRIMIDINAMINE : Prepared by Procedures D, E (120°C, 16 hours), and F. λE NMR (300 MHz, CDCl3) δ 7.36 (t, IH, J = 7.8), 7.20 - 7.09 (m, 7H) , 6.25 (br s, IH) , 5.37 (s,
IH) , 4.93 (t, 4H, J = 4.6), 3.52 - 3.45 (m, 4H) , 3.26 (t, 4H, J" = 4.6), 2.34 (s, 3H) , 1.66 - 1.52 (m, 6H) ;
ESI-MS m/z 497 (MH*) .
Example 30: N- (4-METHYLPHENYL) -6- (1-PIPERIDINYL) -2- [4- (2-PYRIDYL) -1-PIPΞRAZINYL] -4-PYRIMIDINAMINE : Prepared by Procedures D, G (120°C, 12 hours, for substitution . with IV-pyrid-2-ylpiperazine) , and G (140°C) . XH NMR (300 MHz, CDC13) δ 8.22 (dd, IH, J = 4.4, 1.5), 7.50 (dd, IH, J = 7.8, 1.5), 7.20 (d, 2H, J = 8.1), 7.13 (d, 2H, J" = 8.1), 6.69 (d, IH, J = 7.8), 6.63 (t, IH, J = 7.8), 6.26 (br s, IH) , 5.38 (s, IH) , 3.89 (t, 4H, J" = 4.8), 3.62 (t, 4H, J = 4.8), 3.55 - 3.45 (m, 4H) , 2.33 (s, 3H) , 1.70 - 1.52 (m, 6H) ; ESI-MS m/z 430 (MH+) . ■ ' .
Example 31: N- (4-METHYLPHENYL) -2- [4- ( 3 -METHYL-2-
PYRIDINYL) -1-PIPERAZINYL] -6- (1-PIPERIDINYL) -4- PYRIMIDINAMINE : Prepared from 2- (4-benzyl-l- piperazinyl) -N- (4-methylphenyl) -6- (1-piperidinyl) -4- pyrimidinamine by Procedures K and L. "Ή ' NMR (300 MHz, CDCI3) δ 8.19 (dd, IH, J = 4.4, 2.2), 7.42 dd, IH, J = 7.8, 2.2), 7.19 (d, 2H, J = 8.1), 7.12 (d, 2H, J = 8.1), 6.85 (dd, IH, J = 7.8, 4.4), 6.20 (br s, IH) , 5.38 (s, IH) , 3.93 - 3.87 (m, 4H) , 3.53 - 3.48 ( , 4H) , 3.24 - 3.18 (m, 4H) , 2.33 (s, 3H) , 1.67 - 1.53 (m, 6H) ; ESI-MS m/z 444 (MH+) .
Example 32: N- (4-METHYLPHENYL) -6- (1-PIPERIDINYL) -2 - {4- [4- (TRIFLUOROMETHYL) -2-PYRIDINYL] -1-PIPERAZINYL) -4- PYRIMIDINAMINE : Prepared by Procedures D, E (16 hours), and F. ESI-MS m/z 498 (MH+) .
Example 33: N- (4-METHYLPHENYL) -6- (1-PIPERIDINYL) -2- {4- [6- (TRIFLUOROMETHYL) -2-PYRIDINYL] -1-PIPERAZINYL} -4- PYRIMIDINAMINE : Prepared by Procedures D, E (16 hours) , and F. λE NMR (300 MHz, CDC13) δ 7.56 (d, IH, J = 8.1), 7.19 (d, 2H, J = 8.4), 7.14 (d, 2H, J = 8.4), 6.94 (d, IH, J = 7.2), 6.80 (d, IH, J - 8.7), 6.23 (br s, IH) , 5.37 (s, IH) , 3.90 - 3.87 (m, 4H) , 3.69 - 3.66 (m, 4H) , 3.50 - 4.46 (m', 4H) , 2.34 (s, 3H) , 1.67 - 1.53 (m, 6H) ; ESI-MS m/z 498 (MH+) .
Example 34: N- (4-METHYLPHENYL) -6- ( 1-PIPERIDINYL) -2- {4- [3- (TRIFLUOROMETHYL) -2-PYRIDINYL] -1-PIPERAZINYL) -4- PYRIMIDINAMINE : Prepared by Procedures D, E (16 hours) , and F. XH NMR (300 MHz, CDCl3) δ 8.43 (dd, IH, J = 4.4, 2.2),- 7.87 (dd, IH, J = 7.8, 2.2), 7.19 (d, 2H, J = 8.1), 7.13 (d, 2H, J = 8.1), 6.99 (dd, IH, J = 7.8 4.4-), 6.23 (br s, IH) , 5.37 (s, IH) , 3.89 (t, 4H, J = 4.8), 3.53 - 3.48 (m, 4H) , 3.36 (t, 4H, J = 4.8), 2.33 (s, 3H) , 1.67 - 1.53 (m, 6H) ; ESI-MS m/z 498 (MH+) .
Example 35: IV-CYCLOHEXYL-6- (1-PIPERIDTNYL) -2- {4- [3- (TRIFLUOROMETHYL) -2-PYRIDINYL] -1-PIPERAZINYL) -4- PYRIMIDINAMINE : Prepared by Procedures M, E (120°C, for addition of piperidine) , and F (3 hours) . XH NMR (300 MHz, CDC13) δ 8.43 (d, IH, J = 5.6), 7.84 (d, IH, J = 7.4), 6.95 (dd, IH, J = 7.4, 5.6), 4.95 (s, IH) , 4.34 (br s, IH) , 3.84 (t, 4H, J = 5.1),. 3.55 - 3.38 (m, 5H) , 3.34 (t, 4H, J = 5.1), 2.02 (dd, 2H, J = 12.0, 1.4), 1.79 - 1.71 (m,' 2H) , 1.69 - 1.52 (m, 6H) , 1-44 - 1.10 ( , 6H) ; ESI-MS m/z 490 ( H*) .
Example 36: 7V-BICYCLO[2.2.1] HEPT-2-YL-6- ( 1-PIPERIDINYL) - 2- {4- [3- (TRIFLUOROMETHYL) -2-PYRIDINYL] -1-PIPERAZINYL} -4- PYRIMIDINAMINE : Prepared by Procedures M, E (120°C, for addition of piperidine) , and F (3 hours) . λE NMR (300 MHz, CDCl3) δ 8.42 (d, IH, J = 5.6), 7.86 (d, IH, J" = 7.4), 6.95 (dd, IH, J "= 7.4, 5.6), 4.95 (s, IH) , 4.37 (br s, IH) , 3.84 (t, 4H, J = 5.1), 3.57 - 3.47 (m, 4H) , 3.40 - 3.31 (m, 5H) , 2.25 (br s, 2H) , 1.78 (ddd, 2H, J = 13.0, 4.6, 1.4), 1.67 - 1.42 ( , 9H) , 1.25 - 1.12 (m, 4H) ; ESI-MS m/z 502 (MH+) .
Example 37: N- (4-METHYLPHENYL) -6- (1-PIPERIDINYL) -2- [4- (2 -PYRIMIDINYL) -1-PIPERAZINYL] -4-PYRIMIDINAMINE :
Prepared by Procedures D, G (120°C, 12 hours, for substitution with IV-pyrimid-2-ylpiperazine) , and G (150°C, 24 hours). XE NMR (300 MHz, CDCl3) δ 8.33 (d, 2H, J = 4.9), 7.19 (d, 2H, J" = 7.8), 7.13 (d, 2H, J = 7.3), 6.50 (t, IH, J = 7.8), 6.23 (br s, IH) , 5.37 (s, IH) , 3.97 - 3.82 ( , 8H) , 3.56 - 3.44 (m, 4H) , 2.34 (s, 3H) , 1.70 - 1.53 (m, 6H) ; ESI-MS /z 431 (MH+) .
Example 38: AT- (4-METHYLPHENYL) -6- (1-PIPERIDINYL) -2- (1- PYRROLIDINYL) -4-PYRIMIDINAMINE: Prepared' by Procedures D, G (120°C, 3 hours, for substitution with pyrrolidine) , and G (140°C, 12 hours). "Ή NMR (300 MHz, CDCI3) δ 7.20 (d, 2H, J = 7.8), 7.11 (d, 2H, J = 7.8), 6.39 (br s, IH) , 5.34 (s, IH) , 3.56 (t, 4H, J = 5.6), 3.53 - 3.44 (m, 4H) , 2.33 (s, 3H) , 1.91 (quintet, 4H, J" = 5.6), 1.67 - 1.50 (m, 6H) ; ESI-MS m/z 338 (MH+) .
Example 39: N- [ 2 - (2 , 3-DIHYDRO-lff-INDOL-l-YL) -6- ( 1- PIPERIDINYL) -4-PYRIMIDINYL] -N- ( 4-METHYLPHENYL) AMINE : Prepared by Procedures D, E (16 hours) , and F. 1H NMR
(300 MHz, CDC13) δ 8.31 (d, IH, J = 7.8), 7.28 - 7.15 (m,
6H) , 6.86 (t, IH, J = 7.8), 6.31 (br s, IH) , 5.49 (s, IH) , 4.22 (t, 4H, u = 8.3), 3.59 - 3.53 (m, 4H) , 3.13
(t, 4H, -7 = 8.3), 2.35 (s, 3H) , 1.70 - 1.55 (m, 6H) ; ESI-MS m/z 386 (MH+) .
Example 40: N- (4-METHYLPHENYL) -N- [ 6- (1-PIPERIDINYL) -2- (1,2,3, 4-TETRAHYDRO-l-QUINOLINYL) -4-PYRIMIDINYL] AMINE :
Prepared by Procedures D, G (180°C, 3 hours, for substitution with 1, 2, 3 , 4-tetrahydroquinoline) , and G (140°C, 12 hours). XE NMR (300 MHz, CDC13.) δ 7.87' (d, IH, J = 7.8), 7.19 (d, 2H, J = 7.8), 7.15 - 7.07 (m, 4H) , 6.93 (t, IH, J = 7.8), 6.33 (br s, IH) , 5.49 (s, IH),' 4.04 (t, 2H, J = 6.0), 3.54 - 3.44 (m, 4H) , 2.79 (t, 2H, J = 6.0), 2.34 (s, 3H) , 1.98 (pentet, 2H, J = 6.0), 1.69 - 1.52 (m, 6H) ; ESI-MS m/z- 400 (MH+) .
' Example 41 : N- ( 4-METHYLPHENYL) -N- [6- (1-PIPERIDINYL) -2- (1,2,3, '4-TETRAHYDRO-2-ISOQUINOLINYL) -4-
PYRIMIDINYL] AMINE : Prepared by Procedures D, G (180°C, 3 hours, for substitution with 1,2,3,4- tetrahydroisoquinoline) , and G (140°C, 12 hours). XE NMR " (300 MHz, CDC13) δ 7.56 (d, IH, J = 7.8 ) , 7.26 - 7.06 (m,
' 7H) , 6.37 (br s, IH) , 5.35 (s, IH) ', 4.89 (s, 2H) , 4.00
(t, 2H, J = 6.0), 3.58 - 3.44 (m, 4H) , 2.91 (t, 2H, -7 =
6.0), 2.32 (s, 3H) , 1.68 - 1.47 (m, 6H) ; ESI-MS m/z 400
(MH*.) •
Example 42: IV- [2- ( 6, 7-DIMETHOXY-3 , 4-DIHYDRO-2 (Iff) - ISOQUINOLINYL) -6- (1-PIPERIDINYL) -4-PYRIMIDINYL] -A7- (4- METHYLPHENYL) AMINE : Prepared by Procedures D, E (160°C, 12 hours), and F (5 hours). XH NMR (300 MHz, CDCl3) δ 7.19 (d, 2H, -7 = 7.8), 7.13 (d, 2H, J = 7.8), 6.70 (s, IH) , 6.64 (s, IH), 6.25 (br s, IH) , 5.36 (s, IH) , 4.82
(s, 2H) , 4.01 (t, 2H, 7 = 5.9), 3.89 (s, 3H) , 3.87 (s, 3H) , .3.58 - 3.44 (m, 4H) , 2.84 (t, 2H, J = 5.9), 2.33
(S, 3H) , 1.68 - 1.52 (m, 6H) ; ESI-MS m/z 460 (MH+) .
Example 43: IV- [2- (2 , 3-DIHYDRO-lff-BENZO [DE] ISOQUINOLIN-2 - YL) -6- (1-PIPERIDINYL) -4-PYRIMIDINYL] -IV- (4- METHYLPHENYL) AMINE : Prepared by Procedures D, E (160°C, 12 hours), and G. EST-MS m/z 436 (MH+) .
Example ■ 44: 4-PHENYL-l- [4- (1-PIPERIDINYL) -6- (4-
TOLUIDINO) -2-PYRIMIDINYL] -4-PIPERIDINOL : Prepared by Procedures D, E (23 hours), and F. lE NMR (300 MHz," CDC13) δ 7.51 (d, 2H, J = 7.5), 7.36 (t, 2H, J = 7.8), 7.26 (t, IH + CHCI3, J = 7.8), 7.19 (d, 2H, J = 8.4), 7.12 (d, 2H, J = 8.4), 6.20 (br s, IH) , 5.36 (s, IH) , 4.67 (br d, 2H, J = 13.5), 3.50 - 3.45 (m, 4H) , 4.67 (br t, 2H, J = 13.1), 2.33 (s, 3H) , 2.10 (dt, 2H, J = 4.2, 12.6), 1.78 (br d, 2H, J = 13.5), 1.65 - 2.53 ( , 6H) ; ESI-MS m/z 444 (MHT) .
Example 45 IV2 , is] -BIS ( 2-METHOXYETHYL) -TV4- (4- METHYLPHENYL) -6- (1-PIPERIDINYL) -2 , 4-PYRIMIDINEDIAMINE:
Prepared by Procedures D, G [140°C, 2 ' hours, for substitution with bis (methoxye hyl) amine] , and G (140 °C, 1.5 hours). - NMR (300 MHz, CDC13) δ 7.20 (d, 2H, J = 7.8), 7.10 (d, 2H, J = 7.8), 6.20 (br s, IH) , 5.33 (s, IH) , 3.77 (t, 4H, J = 6.2)', 3.59 (t, 4H, J = ' 6 . 3 ) , 3.47 - 3.40 (m, 4H) , 3.36 (s, 6H) , 1.64 - 1.49 (m, 6H) ; ESI- MS m/z 400 (MH+) . Example 46 N- (4-METHYLPHENYL) -2- (3-PHENYL-4-
MORPHQLINYL) -6- (1-PIPERIDINYL) -4-PYRIMIDINAMINE: Prepared by Procedures D, E (16 hours) , and F (1 hour) . λE NMR (300 MHz, CDC13) 5 δ 7.51 (d, 2H, J = 7.8), 7.31 (t, 2H, J = 7.8), 7.23 (t, ' ••' IH, "J = 7.8} , 7.15 (d, 2H, J = 7.8) , 7.10 (d, 2H, J - 7.8), 6.22 (br s, IH) , 5.84 (d, IH, J = 1.0), 5.36 (s, IH) , 4.51 - 4.42 ( , 2H) , 3.94 (m, 2H) , 3.66 (dt, IH, J = 1.0, 11.5), 3.49 - 3.43 (m, 4H) , 3.24 (dt, IH, J = 0 1.5, 11.5), 2.32 (s, 3H) , 1.64 - 1.47 (m, 6H) ; ESI-MS m/z 430 (MH+) .
Example 47_^ N- (4-METHYLPHENYL) -2.- (2-PHENYL-4-
MORPHOLINYL) -6- (1-PIPERIDINYL) -4-PYRIMIDINAMINE: 5 Prepared by Procedures D, E (14 hours) , and F (100°C, 2 hours). lE NMR (300 MHz, CDC13) λE NMR (300 MHz, CDCl3) δ 7.46 (d, 2H, J = 7.8), 7.38 (t, 2H, J = 7.8), 7.34 (t, IH, J - 7.8), 7.18 (d, 2H, J = 8.7), 7.13 (d, 2H, J = 8.4), 6.19 (br s, IH) , 5.38 (s, IH) , 4.70 (br d, IH, J = 0 12.6), 4.58 - 4.51 (m, IH) , 4.11 (dd, IH, J = 10:2, 2.4), 3.80 (dt, IH, J = 2.7, 11.7), 3.50 - 3.43 (m, 4H) , 3.10 (dt, IH, J = 2.1, 12.8), 2.89 (dd, IH, J = 13.2, 10.2), 2.33 (s, 3H) , 1.66 - 1.50 (m, 6H) ; ESI-MS m/z 430 (MH+) . 5
Example 48: Al- (4-METHYLPHENYL) -2- [ (2S, 3. )' -3 -METHYL -2- • PHENYLMORPHOLINYL] -6- (1-PIPERIDINYL) -4-PYRIMIDINAMINE: Prepared by Procedures D, E (120°C) , and F (1 hour) . XH NMR (300 MHz, CDC13) δ 7.42 (d, 2H, J = 7.8) , 7.39 (t, 0 2H, J = 7.8) , 7.27 (t, IH, J = 7.8) , 7.20 (d, 2H, J = 7.8) , 7.14 (d, 2H, J = 7.8) , 6.25 (br s, IH) , 5.39 (s, IH) , 4.99 - 4.90 (m, IH) , 4.77 (d, IH, J = 1.5) , 4.39 (dd, IH, J- = 13.0, 1.5) , 4.15 (dd, IH, J" = 8.3, 1.5) , 3.80 (dt, IH, J = 3.7, 11.6) , 3.53 - 3.45'" ( , 4H) , 3.26 (dt, IH, -J = 3.7, 13.0) , 2.33 (s, 3H) , 1.68 - 1.52 ( , 6H) , 0.90 (d, 3H, J = 8.3) ; ESI-MS m/z 444 (KET) .
Example 49 2-[{2R, 3R) -3- ( METHOXYMETHYL ) -2-
PHENYLMORPHOLINYL] -N- (4-METHYLPHENYL) -6- ( 1-PIPERIDINYL) - 4-PYRIMIDINAMINE : Prepared by Procedures D, E, and F (3 hours) . Η NMR (300 MHz, CDC13) δ 7.56 (d, 2H, J" = 7.8) , 7.31 (t, 2H, J = 7.8) , 7.27 - 7.20 (m, 3H) , 7.13 (d, 2H, J = 'l.8) , 6.31 (br s, IH) , 5.84 (d, IH, J = 1.0) , 5.35 (dd, IH, J" = 9.3, 2.7) , 5.11 (s, IH) , 4.28 (d with splitting, IH, U = 13.0) , 4.01 (t, IH, J - 9.0) , 3.58 - 3.46 (m, 6H) , 3.40 (s, 3H) , 3.27 - 3.15 (m, IH) , 2.31 (s, 3H) , 1.69 - 1.50 ( , 6H) ; ESI-MS m/z 473 (MH+) .
Example 50 IV4, A^-DIMETHYL-AI2 , A^-DIPHENYL-2 , 4, 6-
PYRIMIDINETRIAMINE : Prepared by Procedures A, C, and G (140°C, overnight). XH NMR (300 MHz, CDCl3) δ 7.68 (d, 2H, J = 7.8), 7.38 - 7.27 ( , 6H) , 7.11 - 7.04 ( , IH) , 6.95 (t, IH, J = 7.8), 6.75 (br s, IH) , 6.38 (br s, IH) , 5.45 (s,''lH), 3.06 (s, 6H) ; ESI-MS m/z 306 (MH+) .
Example 51: IV4, AT4-DIMETHYL-IV5- (2-METHYLPHENYL) -A^-PHENYL-
' 2,4, 6-PYRIMIDINETRIAMINE: Prepared by Procedures A, C, -• -and G '(140°C, overnight). 1H NMR (300 MHz',' CDC13) δ 7.63
(d, 2H, J = 7.5), 7.43 (d, IH, J = 7.5), 7.31 - 7.24 ( , ' 3H) , 7.21 (d, IH, J = 7.8), 7.11 (t, IH, J = 7.4), 6.96
(t, IH, J = 7.7), 6.73 (br s, IH) , 6.12 (br s, IH) , 5.16
(s, IH) , 3.01 (s, 6H) , 2.29 (s, 3H) ; ESI-MS m/z 320 (MHT) .
Example 52 : A74, A^-DIMETHYL-iV6- (3-METHYLPHENYL) -A^-PHENYL- 2,4, 6-PYRIMIDINETRIAMINE : Prepared by Procedures A, C, and G (140°C, overnight) . 2H NMR (300 MHz',' CDC13) δ 7.63 (d, 2H, J = 7.8) , 7.29ξ(t, 2H, J = 7.8) , 7.21 (d, IH, J = 8.1)', 7.16 - 7.11 (m, 2H) , 6.97 (d, IH, J = 8.1) , 6.91 (d, IH, J = 7.5) , 6.78 (br s, IH) , 6.38 (br s, IH) , 5.44 (s, IH) , 3.05 (s, 6H) , 2.35 (s, 3H) ; ESI-MS m/z 320 (MH+) .
Example 53: T4, ? -DIMETHYL -A/6- ( 3 -METHYLPHENYL ) -A72- (4-
METHYLTHENYL) -2,4, 6 -PYRIMIDINETRIAMINE : Prepared by Procedures A, C, and G (overnight) . XH NMR (300 MHz, CDC13) δ 7.50 (d, 2H, J = 7.8) , 7.25 - 7.08 ( , 5H) , 6.90 ' '(d, IH, J = 7.5) , 6.86 (br s, IH) , 6.54 (br s, 1H) ,. 5.44 (s, IH) , 3.05 (s,„ 6H)-H.ξ2.34 (s, 3H) , 2.31 (s, 3H) ; ESI- MS m/z 334 (MH+) .
Example 54 : AT4, A/4-DIMETHYL-Al5- (4-METHYLPHENYL) -Ar"-PHENYL-
2,4, 6-PYRIMIDINETRIAMINE : Prepared by Procedures A, C, and G (140°C, overnight). XE NMR (300 MHz, CDC13) δ 7.63 (d, 2H, J = 7.8), 7.28 (t, 2H, J = 7.5), 7.21 (d, 2H, J = 7.8), 7.15 (d, 2H, J = 8.1), 6.96 (t, IH, J = 7.5), 6.71 (br s, IH) , 6.29 (br s, IH) , 5.39 (s, IH) , 3.04 (s, 6H) , 2.34 (s, 3H) ; ESI-MS m/z 320 (MH+) .
Example 55: AT2- (3 , 4-DIffiLOROPHENYL) -A?4 , AT4-DIMETHYL-AT6- (4- METHYLPHENYL) -2,4, 6-PYRIMIDINETRIAMINE : "Prepared by Procedures B, C, and G (180°C, 3 hours) . lE NMR (300 MHz, CDCI3} δ 8.04 (d, IH, J = 2.1), 7.27 (d, IH, J = 7.8), 7.24 (dd, 'lH, J = 7.8, 2.1), 7.19 (d, 2H, J = 8.7), 7.15 (d, 2H, .7 = 8.7), 7.01 (br s, IH) , 6.59 (br s, IH) , 5.39 (s, IH) , 3.04 (s, 6H) , 2.35 (s, 3H) ; ESI- MS m/z 388 (MH+ with 35C1, 35C1) , 390 (MH+ with 35C1, 37C1),392 (MH+ with 37Cl, 3Cl) . Example 56 : AT4 , IV4-DIMETHYL-AT2 , ^-BIS ( 4-METHYLPHENYL) - 2,4, 6-PYRIMIDINETRIAMINE : Prepared by Procedures B, C, and G (180°C, 3 hours). "Ή NMR (300 MHz, CDCl3) δ 7.49 (d, 2H, J = 8.7), 7.19 (d, 2H, J = 8.4), 7.14 (d, 2H, J = 8.4.), 7.08 (d, 2H, J" = 8.4), 6.73 (br s, IH) , 6.39 (br s, IH) , 5.37 (s, IH) , 3.02 (s, 6H) ; ESI-MS m/z 334 (MH+) .
Example 57: AT- ( 3 -FLUOROPHENYL) -AT6,V6-DIMETHYL-AT2-PHENYL- 2,4, 6-PYRIMIDINETRIAMINE: Prepared by Procedures A, C, and G (140°C, overnight). λE NMR (300 MHz, CDCl3) δ 7.62 (d, 2H, J = 7.8), 7.34 - 7.23 ( , 5H) , 7.01 (t, IH., J = 7.4), 6.77 (br s, IH) , 6.38 (br s, IH) , 5.43 (s, IH) , 3.07 (s, 6H) ; ESI-MS m/z 324 (MH+) .
Example 58: AT2- (4-CHLOROPHENYL) -A?6 , IV6-DIMETHYL-AT2-PHENYL- 2,4, 6-PYRIMIDINETRIAMINE : Prepared by Procedures A, C, and G (150°C, overnight). lE NMR (300 MHz, CDC13) δ 7.60 (d, 2H, J = 7.5), 7.32 - 7.26 (m, 6H) , 6.96 (t, IH, J" = 7.5), 6.77 (br s, IH) , 6.34 (br s, IH) , 5.34 (s, IH) , 3.04 (s, 6H) ; ESI-MS m/z 340 (MH+ with 35C1), 342 (MH+ with 3C1) .
' Example 59 : IV4- (4-BROMOPHENYL) -IVs , AT6-DIMETHYL-IV2-PHENYL- 2,4, 6-PYRIMIDINETRIAMINE : Prepared by Procedures A, C, and G (150°C, overnight). XH NMR (300 MHz, CDCl3) δ 7.59
(d, 2H, J = 8.5), 7.42 (d, 2H, J = 8.5), 7.31 - 7.22 (m,
- 4H) , 6.98 (t, IH, J = 7.2), 6.92 (br s, IH) , 6.48 (br s,
IH) , 5.35 (s, IH) , 3.05 (s, 6H) , ESI-MS m/z 384 (MH+ with 79Br) , 386 (MH+ with 81Br) .
Example 60 : AT4- (3 , 4-DICHLORO-PHENYL) -AT6 , AT6-DIMETHYL-AT2- PHENYL-2 , 4 , 6-PYRIMIDINETRIAMINE : Prepared by Procedures A, C, and G (Q.5mL diisopropylethylamine added, 150°C, overnight). XE NMR (300 MHz, CDCl3) δ 7.61 (d with s at the center, 3H, J = 7.8), 7.34 (d, 2H, J = 7.8), 7.29 (d, IH, J = 8.7), 7.17 (dd, IH, ι7 = 8.7, 2.6), 6.98 (t, IH, J = 7.8), 6.80 (br s, IH) , 6.33 (br s, IH) , 5.33 (s, IH) , 3.07 (s, 6H) ; ESI-MS m/z 373 (MH*) .
Example 61: AT4- ( 4-CHL0R0-3 -METHYLPHENYL) -AT6, A'-DIMETHYL- A^-PHENYL-Σ , 4 , 6-PYRIMIDINETRIAMINE : Prepared by Procedures A, C, and G (150°C, 1 hour) . XH NMR (300 MHz, CDC13) δ 7.61 (dd, 2H, J = 7.4, 0.9), 7.30 - 7.25 (m, 3H) , 7.19 (d, IH, J = 2 Λ ) , 7.12 (dd, IH, J = 8.5 ,..2.4) , 6.97 (t, IH, ,7 = 7.4), 6.88 (br s, IH) , 6.4.4 (br s, H) , '5.35 (s, IH) , 3.05 (s, 6H) , 2.35 (s, 3H) ; ESI-MS m/z ' 454 (MH+ with 5Cl) , 456 (MH+ with 37Cl) .
Example 62 : N4- (3 -CHLORO-4-METHYLPHENYL) -A?6, A?6-DIMETHYL- AT2-PHENYL-2 , 4 , 6-PYRIMIDINETRIAMINE : Prepared by Procedures A, C, and F (100°C, 3 hours) . "Ή NMR (300 MHz, CDC13) δ 7.63 (d, 2H, J = 7.8), 7.41 (d, IH, J" = 1.8), 7.30 (t, 2H, J = 7.8), 7.18 (d, IH, J = 7.8), 7.09 (dd, IH, J = 7.8, 1.8), 6.98 (t, IH, J = 7.8), 6.67 (br s, 2H) , 5.35 (s, IH) , 3.07 (s, 6H) ,- 2.37 (s, 3H) ; ESI- MS m/z 454 (MH+ with 35Cl), 456 (MH+ with 37C1) .
Example 63 : IV4- (4-fcert-BUTYLPHENYL) -AT6 , IVs-DIMETHYL-AT2- PHENYL-2 ,4 , 6-PYRIMIDINETRIAMINE: Prepared by Procedures A, C, and G (150°C, 5 hours). 1H NMR (300 MHz, CDC13) δ 7.62 (d, 2H, J = 7.5), 7.36 (d, 2H, J = 8.7), 7.29 (d, 2H, J = 7.5), 7.25 (t, 2H, J = 8.7), 6.95 (t, IH, J = 7.4), 6.69 (br s, IH) , 6.30 (br s, IH) , 5.44 (s, IH) , •3.05 (s, 6H) , 1-33 (s, 9H) ; ESI-MS m/z 362 (MH+) . Example 64: AT4, ^-DIMETHYL-AT6- (4-PHENOXYPHENYL) -A^-PHENYL- 2,4, 6-PYRIMIDINETRIAMINE : Prepared by Procedures A, C, and G (150°C, 2 hours). E NMR (300 MHz, CDCl3) δ 7.61 (d, 2H, J = 7.8) , 7.35 (t, 2H, J = 7.8 ) , 7.31 - 7.24 (m, 3H) , .7.12 (t, 2H, J = 7.8), 7.08 - 7.04 (m, 3H) , 6.98 (t, IH, J" = 8.1), 6.74 (br s, IH) , 6.71 (dd, IH, J = 7.8, 2.0), 6.43 (br s, IH) , 5.41 (s, IH) , 3.03 (s, 6H) ; ESI-MS m/z 398 (MH+) .
Example 65 : AT4, A^-DIMETHYL-AT6- (2-NAPHTHYL) -A^-PHENYL- 2,4, 6-PYRIMIDINETRIAMINE : Prepared by Procedures A, C, and G (150°C, 2 hours). "Ή NMR (300 MHz, CDCl3) δ 7.81 (s, IH) , 7.80 (d, IH, J = 7.5), 7.75 (d, 2H, J = 7.8), 7.65 (d, 2H, J = 1 . 5 ) , 7.49 - 7.37 (m, 3H) , 7.29 (t, 2H, J = 7.5), 6.98 (t, IH, J = 8.1), 6.85 (br s, IH) , 6.59 (br s, IH) , 5.51 (s, IH) , 3.06 (s, 6H) ; ESI-MS m/z 356 (MH*) .
Example 66 : AT4-CYCLOHEXYL-A76, A^-DIMETHYL-AT2-PHENYL-2 ,4,6- PYRIMIDINETRIAMINE : Prepared by Procedures A, C, and G
(140°,C, 2 days). XE NMR (300 MHz, CDCl3) δ 7.62 (d, 2H, J = 8.1), 7.26 (t, 2H, J = 8.1), 6 . 92 (t, IH, J = 8.1), 6.64 (br s, IH) , 4.96 (s, IH) , 4.39 .(br d, IH, J" = 8.1), 3.53 - 3.44 (m, IH) , 3.05 (s, 6H) , 2.09 - 1.99 (m, 2H) , 1.80 - 1.55 (m, 4H) , 1.44 - 1.11 (m, 4H') ; ESI-MS m/z 312 (MH+) .
Example 67: AT4, A^-DIMETHYL-AT6- (4-METHYLCYCLOHEXYL) -A72- PHENYL-2 , 4 , 6-PYRIMIDINETRIAMINE : Prepared by Procedures A, C, and G (150°C, overnight) . ESI-MS m/z 326 (MH+) .
Example 68 : AT4- (4- cert-BUTYLCYCLOHEXYL) -AT6 , AT6-DIMETHYL-AT2- PHENYL-2 , 4„ 6-PYRIMIDINETRIAMINE : Prepared by Procedures A, C, and G (150°C, overnight) . λE NMR (300 MHz, CDC13) δ 7.62 (d, 2H, J = 8.4) , 7.26 (t, 2H, J = 7.7) , 6.92 (t, IH, J = 7.1) , 6.61 (br s, IH) , 4.96 (s, IH) , 4.32 (br d, IH J = 8.4) , 3.46 - 3.37 (m, IH) , 3.06 (s, 6H) , 1.88 - 1.80 (m, 2H) , 1.29 - 1.20 (m, IH) , 1.19 - 0,97 ( , 4H) , 0.87 (s, 9H) ; ESI-MS m/z 368 (MH+) .
Example 69: A^-BICYCLO [2.2.1] HEPT-2-YL-A76 , Af-DIMETHYL-iV2- PHENYL-2 , 4 , 6-PYRIMIDINETRIAMINE : Prepared by Procedures A, C, and G (140°C) . lE NMR (300 MHz, CDCl3) δ 7.62 (d, 2H, J = 7.8) , 7.26 (t, 2H, J = 8.0) , 6.92 (t, IH, J = 7.2) , 6.62 (br s, IH) , 4.94 (s, IH) , 4.42 (br d, IH, J = 5.4) , 3.45 - 3.37 (m, IH) , 3.06 (S, 6H) , 2.33 - 2.27 (m, IH) , 1.82 (dd, IH, J = 12.3, 6.0) , 1.56 - 1.42 (m, 2H) , 1.30 - 1.14 (m, 5H) , 0.91 - 0.85 (m, IH) ; ESI-MS m/z '324 (MH+) .
Example 70 AT4 , I^-DIMETHYL-V-PHENYL-IV6- (1,7,7-
TRIMETHYLBICYCLO[2.2.1]HEPT-2-YL) -2,4,6- PYRIMIDINETRIAMINE : Prepared by Procedures A, C, and G
(overnight). "Ή NMR (300 MHz, CDC13) δ 7.62 (d, 2H, J = 7.8), 7.26 (t, 2H, J = 7.8), 6.93 (t, IH, J = 7.7), 6.87 (br s, IH) , 4.95 (s, IH) , 4.80 (br d, IH, J" = 6.9), 3.94 - 3.84 (m, IH) , 3.06 (s, 6H) , 2.45 - 2.34 (m, IH) , 1.82 - 1.62 (m, 3H) , 1.46 - 1.32 (m, IH) , 1.29 - 1.16 (m, 2H) , 0.99 (s, 3H), 0.90 (s, 3H) , 0.89 (s, 3H) ; ESI-MS m/z 366 (MH+) .
Example 71: AT4, AT4-DIMETHYL-AI2-PHENYL-ATg- [ (2R, 35) -3 , 6 , 6- TRIMETHYLBICYCLO [3.1.1] HEPT-2 -YL] -2,4,6-
PYRIMIDINETRIAMINE : Prepared by Procedures A, C, and G (5 hours). XE NMR (300 MHz, CDCl3) δ 7.64 (d, 2H, J = 8.1), 7.26 (t, 2H, J = 8.1), 6.92 (t, IH, J = 7.4), 6.72 (br s, IH) , 4.99 (s, IH) , 4.47 (br d, lH," = 8.4), 4.05
- 3.91 (m, IH) , 3.06 (s, 6H) , 2.72 - 2.62 (m, IH) , 2.46
- 2.3-6 (m, IH) , 2.00 - 1.45 (m, ' 5H) , 1.25 (s, 3H) , 1.16 (d, 3H, J = 7.8), 1.10 (s, 3H) ; ESI-MS /z 366 (MH+) .
Example 72: AT2 ,1V4, AT4-TRIMETHYL-^J2 , A^-BIS (4-METHYLPHENYL) - 2,4, 6-PYRIMIDINETRIAMINE : Prepared by Procedures D, E (150°C, 16 hours), and' F (5 hours). X NMR (300 MHz, CDC13) .δ 7:26 (d, 2H, J = 8.1), 7.15 (br d, 4H, J - 8), 7.04 Ld, 2H, J = 8.1), 6.19 (br s, IH) , 5.29 (s, IH) , 3.50 (s, 3H) , 2.94 (s, 6H) , 2.36 (s, 3H) , 2.29 (s, 3H) ; ESI-MS m/z 348 '(MH+).
Example 73: AT-CYCLOHEXYL-AT2 , AT , IV4-TRIMETHYL-iV6- (4- METHYLPHENYL) -2,4, 6-PYRIMIDINETRIAMINE : Prepared by Procedures D, E (150°C, 12 hours) , and F (5 hours) . λE NMR (300 MHz, CDCl3) δ 7.25 (d, 2H, J = 8.4), 7.10 (d, 2H, J = 8.1), 6.26 (br s, IH) , 5;22 (s, IH) , 4.66 - '4.52 (m, IH) , 3.01 (s, 3H) , 2.99 (s, 6H)', 2.32 (s, 3H) , 1.87 - 1.64 (m, 5H) , 1.52 - 1.35 (m, 4H) , 1.22 - 1.06 (m, IH) ; ESI-MS m/z 340 (MH+) .
Example 74 : AT2-CYCLOHEXYL-AT2- ( 2 -METHOXYETHYL) -AT , AT4- DIMETHYL-AT6- ( 4-'METHYLPHENYL) -2,4, 6-PYRIMIDINETRIAMINE : Prepared by Procedures H, J (overnight) , and F (2 hours). XH NMR (300 MHz, CDC13) δ 7.28 (d, 2H, J = 8.1), 7.11 (d, 2H, J = 8.1), 6.19 (br s, IH) , 5.22 (s, IH) , 4.60 - 4.50 (m, IH) , 3.64 - 3.55 ( , 4H) , 3.39 (s, 3H) , 2.99 (s, 6H) , 2.31 (s, 3H) , 1.83 - 1.75 (m, 4H) , 1.73 - 1.63 (m, IH) , 1.52 - 1.38 (m, 4H) , 1.19 - 1.05 (m, IH) ; ESI-MS m/z 384 (MH+) .
Example 75: 2- (2 , 3-DIHYDRQ-lff-INDOL-l-YL) -V4, A^-DIMETHYL- AT6- (4-METHYLPHENYL-) -4 , 6-PYRIMIDINEDIAMINE :' ' Prepared by Procedures H, E (150°C, 16 hours) , and F (2 hours) . 2H NMR (300 MHz, CDCl3) δ 8.37 (d, IH, J = 7.8), 7.26 (d, 2H, J = 7.8), 7.20 - 7.11 ( , 4H) , 6.86 (t, IH, J = "5 7.8),. 6.31 (br s, IH) , 5.39 (s, IH) , 4.24 (t, 4H, J = 8.3), 3.13 (t, 4H, .7 = 8.3) , 3.07 (s, 6H) , 2.35 (s, 3H) ; ESI-MS m/z 346 (MH+) .
Example 76: AT2- [2- (Iff-3 -INDOLYL) ETHYL] -Ad AT4-DIMETHYL-AT6- 0 (4-METHYLPHENYL) -2,4, 6-PYRIMIDINETRIAMINE : Prepared by Procedures H, J, and-G. lE NMR (300 MHz, CDCl5) δ 8.19 (br s, IH) , 7.65 (d IH, J = 7.8), 7.36 (d, IH, J = 7.8), 7.21 - 7.09 (m, 6H) , 7.04 (s, IH) , 6.52 (br. s, IH) , -5.28 (s, IH) , 4.95 (br d, IH, J" = 7.2) , 3.72 (q, 2H, J = 5 7.2), 3.06 (t, 2H, J = 7.8), 2.99(s, 6H) , 2.32 (s, 3H) ; ESI-MS m/z 387 (MH+) .
Example 77 1ST- [ 2 - ( lff-INDOL-3 -YL ) ETHYL] -AT2 , AT , AΓ'- TRIMETHYL-AT6- (4-METHYLPHENYL) -2,4, 6-PYRIMIDINETRIAMINE: '0 Prepared by Procedures H, J, and G or F . λE NMR (300
MHz, CDC13) δ 8.14 (br s, IH) , 7.70 (d IH, J = 7.8) , 7.32
(d, IH, J = 7.8) , 7.22 (d, 2H, J = 7.8), 7.17 (t, IH, J
= 7.2), 7.12 (t, IH, J = 7.2), 7.08 (d, 2H, J = 7.8),
6.98 (s, IH) , 6.36 (br s, IH) , 5.25 (s, IH) , 3.90 (t, 5 2H, J = 7.8), 3.14 (s, 3H) , ,3.07 (t, ' 2H, J = 7.8), 2.99(s, 6H) , 2.30 (s, 3H) ; ESI-MS m/z 401 (MH+) .
Example 78 AT4- ( 3 , 4-DICHLOROPHENYL ) -IV2- [ 2 - ( lff-3 -
INDOLYL) ETHYL] -AT2 , AT6 , AT6-TRIMETHY -2 ,4,6- 0 PYRIMIDINETRIAMINE : Prepared by Procedures H, J, and G. XE NMR (300 MHz, CDCl3) δ 8.00 (br s, IH) , 7.75 (s, IH) , 7.68 (d IH, J" = 7.8), 7.35 (d, -IH, J = 7.8), 7.24 - 7.15 (m, 3H) , 7.10 (t, IH, J = 7.2), 7.00 (s, IH) 6.23 (br s, IH) , 5.15 (s, IH) , 3.90 (t, 2H, J = 7.8)',' 3.14 (s, 3H) , 3.08 (t, 2H, J = 7.8), 3.03 (s, 6H) ; ESI-MS m/z 455 (MH÷ with 35C1), 457 (MH+ with 37C1) .
Example 79j AT2- [2- (lff-INDOL-3-YL) ETHYL] -V2 , AT4 , IV4-
TRIMETHYL- (2-NAPHTHYL) -6- (1-PIPERIDINYL) -2,4,6- PYRIMIDINETRIAMINE : Prepared by Procedures D, E (160°C, 28 hours), and G. lE NMR (300 MHz, CDCl3) δ 8.18 (br s, IH) , 7.92 (s, IH) , 7.90 - 7.03 (m, 10H) , 6.95 (s, IH) 6.84 (br s, IH) , 5.34 (s, IH) , 3.90 (t, 2H, J = 7.8), 3.17 (s, 3H) , 3.07 (t,- 2H, J = 7.8), 2.96 (s, 6H) ; ESI- MS m/z '437 (MH+) .
Example 80: l-[4- (DIMETHYLAMINO) -6- (4-TOLUIDINO) -2- PYRIMIDINYL] -4-PHENYL-4-PIPERIDINOL: Prepared by
Procedures H, E (150°C, 10 hours), and F (3 hours). lE
NMR (300 MHz, CDCl3) δ 7.43 (d, 2H, J = 7.8), 7.35 (t,
2H, J = 7.8), 7.27 - 7.21 (m, 3H) , 7.14 (d, 2H, J =
7.8), 6.24 (br s, IH) , 6.18 (br s, IH) , 5.28 (s, IH) , 4.43 - 4.37 (m, 2H) , 4.03 (t, 2H, J = 5.6), 3.06 - 2.97
(m with s at 3.03, 8H) , 2.66 - 2.58 ( , 2H) , 2.34 (s,
3H) .
Example 81: AT4, AT4-DIMETHYL-A76- (4-METHYLPHENYL) -2- (4- PHENYL-1-PIPERIDINYL) -4 , 6-PYRIMIDINEDIAMINE : Prepared by Procedures H, E (150°C, 16 hours) , and F (4 hours) . λE NMR (300 'MHz, CDCl3) δ 7.34 - 7.18 (m, 7H) , 7.13 (d, 2H, = 7.8), 6.25 (br s, IH) , 5.28 (s, IH) , 4.94 (d with fine splitting, 2H, J = 13.0), 3.01 (s, 6H) , 2.87 (dt, 2H, J - 1.0, 13.0), 2.74 (tt, IH, J = 11.6, • 1.5) , 2.32 (s, 3H) , 1.90 (d with fine splitting, 2H, J = 12.0), 1.72 (ddd, 2H, J = 13.0, 12.0, 1.5); ESI-MS m/z 388 (MH+) . Example 82: IV4, A^-DIMETHYL-AT6- (4-METHYLPHENYL) -2- (3- PHENYL-4-MORPHOLINYL) -4, 6-PYRIMIDINEDIAMINE : Prepared by Procedures H, E (150°'C, 20 hours) , and F (3 hours) . H. NMR (.300 MHz, CDC13) δ 7.51 (d, 2H, J = 7.8), 7.32 (t, 2H, J = 7.8), 7.23 (t, IH, J = 7.8), 7.17 (d, 2H, J = 7.8), 7.09 (d, 2H, J = 7.8), 6.25 (br s, IH) , 5.88 (d, IH, J = 1.0), 5.27 (s, IH) , 4.49 (t, 2H, J = 13.2), 3.94 (m, 2H) , 3.66 (dt, IH, J = 1.0, 11.5), 3.24 (dt, IH, J" = 1.5, 11.5), 2.97 (s, 6H) , 2.32 (s, 3H) ; ESI-MS m/z 390 (MH+) .
Example 83: IV4, A^-DIMETHYL-AT*- (4-METHYLPHENYL) -2- (2- PHENYL-4-MORPHOLINYL) -4 , 6-PYRIMIDINEDIAMINE: Prepared by Procedures H, E (150°C, 20 hours), and F (3 hours). 2H NMR (300 MHz, CDC13) δ 7.47 (d, 2H, J = 7.8), 7.38 (t, 2H, J = 7.8), 7.33 (t, IH, J = 7.8), 7.19 (d, 2H, J = 7.8), 7.11 (d, 2H, J = 7.8), 6.22 (br s, IH) , 5.29 (s, IH) , 4.74 (dd, IH, J = 13.2, 1.0), 4.59 - 4.51 ( , 2H) , 4.16 - 4.08 (m, IH) , 3.80 (dt, IH, J = 1.0, 11.9), 3.11 (dt, IH, J = 1.5, 12.4), 2.98 (s, 6H) , 2.90 (dd, IH, J = 10.6, 11.9), 2.33 (s, 3H) ; ESI-MS m/z 390 (MET).
Example 84: AT4,AT4-DIMETHYL-AT5- (4-METHYLPHENYL) -2-{4- [ (4- METHYLPHENYL) SULFONYL] -1-PIPERAZINYL} -4,6-'
' PYRIMIDINEDIAMINE : Prepared by Procedures H, E (150°C, overnight), and F (3 hours). λE NMR (300 MHz, CDC13) δ 7.65 (d, ZH, J = 8.3), 7.31 (d, 2H, J = 8.3), 7.15 (d, 2H, J = 8.4), 7.11 (d, 2H, J = 7.2), 6.20 (br s, IH) , 5.22 (s, IH) , 3.87 (t, 4H, J = 4.2), 3.02 (t, 4H, -7 = 4.2), 2.95 (s, 6H) , 2.43 (s, 3H) , 2.33 (s, 3H) ; ESI-MS m/z 467- (MH+) . Example 85: AT4 , AT4-DIMETHYL-AT6- ( 4-METHYLPHENYL) -2- [4- (2- METHYLPHENYL) -1-PIPERAZINYL] -4, 6-PYRIMIDINEDIAMINE: Prepared by Procedures D, E (160°C, 12 hours), and F (12 hours). λE NMR (300 MHz, CDCl5) δ 7.23 - 7.10 (m, 6H) , 7.02 .- 6.96 (m, 2H) , 6.28 (br s, IH) , 5.28 (s, IH) , 3.95 - 3.86 ( , 4H) , 2.99 (s, 6H) , 2.96 - 2.92 (m, 4H) , 2.36 (s, 3H) , 2.32 (s, 3H) ; ESI-MS m/z 403 (MH+) .
Example 86: JJ , AT4-DIMETHYL-IV5- (4-METHYLPHENYL) -2- [4- (3- METHYLPHENYL) -1-PIPERAZINYL] -4, 6-PYRIMIDINEDIAMINE:
Prepared by Procedures D, E (160°C, 12 hours), and F (12 hours). Η NMR (300 MHz, CDC13) δ 7.19 (d, 2H, -7 = 7.8), 7.17 (t, IH, J = 7.8), 7.11 (d, 2H, J = 7,8), 6.91 (s, IH) , 6.89 (d, IH, J = 7.8), 6.69 (d, IH, J = 7.8), 6.33 (br s, IH) , 5.29 (s, IH) , 3.93 (t, 4H, J = 5.1), 3.22 (t, 4H, J = 5.1), 3.01 (s, 6H) , 2.33 (s, 6H) ; ESI-MS m/z 403 (MH+) .
Example 87: AT4 , AT -DIMETHYL-IVs- (4-METHYLPHENYL) -2- [4- (4- METHYLPHENYL) -1-PIPERAZINYL] -4, 6-PYRIMIDINEDIAMINE:
Prepared by Procedures D, E (160°C, 36 hours), and F (8 hours). XE NMR (300 MHz, CDCl3) δ 7.19 (d, 2H, J = 9.0), 7.16 (d, 2H, J = 8.7), 7.10 (d, 2H, J = 9.0), 6.90 (d, 2H, " = 8.4), 6.24 (br s, IH) , 5.27 (s, IH) , 3.93 (t, 4H, J = 4.8), 3.18 (t, 4H, J = 5.1), 3.00 (s, 6H) , 2.33 (s, 3H) , 2.28 (s, 3H) ; ESI-MS m/z 403 (MH").
Example 88: AT4 , A^-DIMETHYL-AT6- (4-METHYLPHENYL) -2- {4- [3- (TRIFLUOROMETHYL) -2-PYRIDINYL] -1-PIPERAZINYL} -4,6- PYRIMIDINEDIAMINE : Prepared by Procedures H, E (16 hours), and F. 1H NMR (300 MHz, CDCl3) δ 8.57 (dd, IH, J = 4.4, 2.2), 7.87 (dd, IH, J = 7.8, 2.2), 7.20 (d, 2H, J = 8.1), 7.13 (d, 2H, J = 8.1), 6.98 (dd, IH, J = 7.8, 4.4), 6.24 (br s, IH) , 5.28 (s, IH) , 3.'90 (t, 4H, J = 4.8), 3.36 (t, 4H, J = 4.8), 3.00 (s, 6H) , 2.32 (s, 3H) ; ESI-MS m/z 458 (MH1") .
Example 89: AT- (4-METHYLPHENYL) -2- (1-PIPERIDINYL) -6- (4-
[3- (TRIFLUOROMETHYL) -2-PYRIDINYL] -1-PIPERAZINYL} -4-
PYRIMIDINAMINE : Prepared by Procedures M, E (120°C, for addition of piperidine), and F. XE NMR (300 MHz, CDCl3)
-o 8.43 (dd, IH, J = 4.4, 2.2), 7.87 (dd, IH, J = 7.8, 2.2), 7.19 (d, 2H, J = 8.1), 7.12 (d, 2H, J" = 8.1), 6.99 (dd, IH, J = 7.8, 4.4), 6.28 (br s, IH) , 5.35 (s, IH) , 3.77 - 3.72 (m, 4H) , 3.62 (t, 4H, J" = 4.8), 3.33 (t, 4H, J" = 4.8), 2.33 (s, 3H) , 1.69 - 1.52 (m, 6H).; ESI-MS m/z 498 (MH*) .
Example 90: 6- [2- (METHOXYMETHYL) -1-PIPERIDINYL] -AT- (4- METHYLPHENYL) -2- {4- [3- (TRIFLUOROMETHYL) -2-PYRIDINYL] -1- PIPERAZINYL} -4-PYRIMIDINAMINE : Prepared by Procedures D, J (90°C, overnight), and F (2 hours). "H NMR (300 MHz, CDCI3) δ 8.44 (dd, IH, J = 4.4, 2.2), 7.88 (dd, IH, J" = 7.8, 2.2), 7.20 (d, 2H, J = 8.1), 7.12 (d, 2H, " = 8.1), 6.99 (dd, IH, J = 7.8, 4.4), 6.23 (br s, IH) , 5.38 (s, IH) , 4.68 - 4.54 (m, IH) , 4.15 - 4.03 (m, IH) , 3.90 (t, 4H, J = 4.8), 3.57 (t, IH, J = 9.7), 3.44 - 3.35 (m, 5H) , 3.34 (s, 3H) , 2.81 (t, IH, J" = 12.0), 2.33 (s, 3H) , 1.93 - 1.86 (m, IH) , 1.72 - 1.41 (m, 3H) , 1.29 - 1.25 (m, IH) , 0.91 - 0.86 (m, IH) ; ESI-MS m/z 542 (MH+) .
Example 115: IV-4-[3- (BENZYLOXY) PHENYL] -AT-6-,IV-6- DIMETHYL-2- [4- ( 2-PYRIDINYL) -1-PIPERAZINYL] -4 , 6-
PYRIMIDINEDIAMINE : Prepared by Procedures A (CH2C12, Et3N, Me2NHHCl, stirred 3.5 h at -78 ac, warmed to 0 SC and stirred 3 h) , N, and 0. XH NMR (400 MHz, CDCI3) δ 8.23 - 8.19 (m, IH) , 7.52 (dt, IH, J = 1.'9, 7.2), 7.43 - 7.20 (m, 7H) , 6.96 (s, IH) , 6.88 (d, IH, J = 8.0), 6.80 (d, I'H, J = 8.1), 6.69 - 6.63 (m, 2H) , 5.34 (s, IH) , 5.03 (s, 2H) , -4.03 - 3.97 (m, 4H) , 3.66 (t, 4H, J = ' 5.2),.3.02 (s, 6H) ; ESI-MS m/z 482 (MH+) .
Example 116 : 4- {4- [4- (DIMETHYLAMINO) -6- (4-TOLUIDINO) -2-
PYRIMIDINYL] -1-PIPERAZINYL} PHENOL : Prepared by
Procedures A (CH2C12, Et3N, Me2NHHCl, stirred 3.5 h at -78 SC, warmed to 0 SC and stirred 3 h) , N, and 0. 1H NMR
(400 MHz, CDC13) δ 10.04 (s, IH) , 7.19 - 7.14 (m, 4H) , 6.85 - 6.79 (m, 4H) , 5.31 (s, IH) , 5.22 (s, IH).,. 3.96
(t, 4H, J" = 5.1), 3.05 (t, 4H, J = 5.0), 3.03 (s, • 6H) , 2.34 (s, 3H) ; FIAMS m/z 405 (MH+) .
Example 117: AT4- [4- (BENZYLOXY) PHENYL] -AT6, IV6-DIMETHYL-2-
[4- (2-PYRIDINYL) -1-PIPERAZINYL] -4 , 6-PYRIMIDINEDIAMINE : Prepared by Procedures A (CH2C12, Et3N, Me2NHHCl, stirred 3.5 h at -78 SC, warmed to 0 SC and stirred 3 h) , N, and O. λE NMR (400 MHz, CDCl3) δ 8.21 (dd, IH, J = 1.9, 5.6), 7.55 - 7.27 (m, 7H) , 7.24 - 7.16 (m, 2H) , 7.04 -'6.91
(m, 2H) , 6.69 - 6.64 (m, 2H) , 5.06 (s, 2H) , 5.05 (s, IH) , 4.08 - 3.97 (m, 4H) , 3.69 (t, 4H, J = 5.1), 3.03
(s, 6H) ; ESI-MS' m/z 482 (MH+) .
Example 118: AT4- (1, 3-BENZODIOXOL-5-YL) -AT6, AT6rDIMETHYL-2-
[4- (2-PYRIDINYL) -1-PIPERAZINYL] -4, 6-PYRIMIDINEDIAMINE: Prepared by Procedures A (CH2C12, Et3N, Me2NHHCl, stirred 3.5- h at -78 aC, warmed to 0 SC and stirred 3 h) , N, and O. XH NMR (400 MHz, CDC13) δ 8.24 - 8.18 (m, IH) , 7.48
(dt, IH, J = 1.9, 8.1), 6.92 (d, IH, J = 1.9), 6.75 (d,
IH, J = 8.2), 6.74 - 6.54 (m, 3H) , 6.41 (br s, IH) , 5.95 (s, 2H) , 5.16 (s, IH) , 3.89 (t, 4H, J ="5.1), 3.60 (t, 4H, ι7 = 5.3), 2.99 (s, 6H) ; ESI-MS m/z 420 (MHT) .
Example 119 : AT4- (2, 3-DIHYDRO-l , 4-BENZ0DI0XIN-6-YL) - 6- 5 DIMETHYL-2- [4- (2-PYRIDINYL) -1-PIPERAZINYL] -4 , 6-
PYRIMIDINEDIAMINE : Prepared by Procedures A (CH2C12, Et3N, Me2NHHCl, stirred 3.5 h at -78 2C, warmed to 0 2C and stirred 3 h) , N, and O. XH NMR (400 MHz, CDC13) δ 8.24 - 8.18 (m, IH) , 7.49 (dt, IH, J = 2.1, 7.1), 6.89 0 (d, IH, J = 2.2), 6.81. (d, IH, J = 8.6), 6.76 (d, IH, J = 2.4), 6.68 (d, IH, • J = 8.5), 6.62 (dd, IH, J = 4.6, 7.0),- 6.18 '(br s, IH) , 5.21 (s, IH) , 4.33 - 4.15 (m, 4H) , 3.89 (t, 4H, J = 5.1), 3.61 (t, 4H, J. = 5.1), 3.00 (s, 6H) ; ESI-MS m/z 434 (MH+) . - 5
Example 120: AT4- (4-ISOQUINOLINYL) -AT5, AT6-DIMETHYL-2- [4- (2- PYRIDINYL) -1-PIPERAZINYL] -4 , 6-PYRIMIDINEDIAMINE : Prepared by Procedures A (CH2Cl2, EtN, Me2NHHCl, stirred 3.5 h at -78 SC, warmed to 0 SC and stirred 3 h) , N, and 0 O. H NMR (400 MHz, CDCl3) δ 8.93 (d, IH, J" = 1.5), 8.31
(d, IH, -7 = 2.6), 8.27 - 8.19 (m, IH) , 8.01 (d, IH, J =
8.2), 7.70 (d, IH, J - 7.8), 7.59 - 7.52 (m, IH) , 7.51 -
7.45 (m, 2H) , 6.78 (br s, IH) , 6.68 (d, IH, L7 = 8.6),
• 6.63 (dd, IH, 7 = 5.0, 7.1), 5.29 (s, IH) , 3.94 (t, 4H, 5 J" = 5.0), 3.63 (t, 4H, J = 5.3), 3.01 (s, 6H) ; ESI-MS m/z 42'7 (MH+) .
Example 121: IV4- (4-CYCLOHEXYLPHENYL) -AT6 , AT6-DIMETHYL-2- [4- (2-PYRIDINYL) -1-PIPERAZINYL] -4, 6-PYRIMIDINEDIAMINE:
0 Prepared by Procedures A (CH2C12, Et3N, Me2NHHCl, stirred 3.5 h at -78 9C, warmed to 0 5C.anά stirred 3 h) , N, and O. X NMR. (400 MHz, CDC13) δ 8.25 - 8.19 ( , IH) , 7.49 (dt, IH, J = 2.0, 6.9), 7.22 (d, 2H, J ="6.4), 7.16 (d, 2H, J = 8.2), 6.68 (d, IH, J = 8.6), 6.66 - 6.60 (m, IH) , 6.21 (br s, IH) , 5.30 (s, IH) , 3.99 - 3.91 (m, 4H) , 3.63 (t, 4H, J = 5.2), 3.02 (s, 6H) , 2.53 - 2.42 (m, IH) , 1.92 - 1.79 (m, 4H) , 1.48 - 1.32 (m, 4H) , 1.31 - 1.19 (m, 2H) ; ESI-MS m/z 458 (MH+).
Example 122: IV4, Ai^-DIMETHYL-Σ- [4- (2-PYRIDINYL) -1-
PIPERAZINYL] -AT6- (5,6,7, 8-TETRAHYDRO-l-NAPHTHALENYL) -4,6- PYRIMIDINEDIAMINE : Prepared by Procedures A (CH2Cl2, Et3N, Me2NHHCl, stirred 3.5 h at -78 aC, warmed to 0 2C and stirred 3 h) , N, and 0. lE NMR (400 MHz, CDCl3) δ 8.20 (dd, IH, J = 1.3, 4.9), 7.50 (dt, IH, J = 2.2, 6.8), 7.17 (d, IH, J = 7.5), 7.09 (t, IH, .7 = 7.6), 6.94 (d, IH, J = 7.7), 6.73 - 6.62 (m, 2H) , 5.06 (s, IH) , 4.08 - 3.93 (m, 4H) , 3.66 (t, 4H, J = 5.3), 3.00 (s, 6H) , 2.79 (t, 2H, J = 6.0), 2.72 (t, 2H, J" = 5.9), 1.88 - 1.67 (m, 4H) , NH (IH, unobserved); ESI-MS m/z 430 (MH*) .
Example 123: AT4- (2 , 3-DIHYDRO-lff-INDEN-5-YL) -AT6 , AT6-
DIMETHYL-2- [ 4 - ( 2 - PYRIDINYL ) -1-PIPERAZINYL] -4, 6- PYRIMIDINEDIAMINE : Prepared by Procedures A (CH2Cl2, Et3N, Me NHHCl, stirred 3.5 h at -78 2C, warmed to 0 aC and stirred 3 h) , N, and 0. λE NMR (400 MHz, CDCl3) δ 8.20 (d, IH, J = 4.8) , 7.51 (dt, IH, J = 1.8, 6.9) , 7.19 (d, IH, J" = 7.6) , 7.14 (s, IH) , 7.04 (dd, IH, J" = 1.7, 7.7) , 6.73 - 6.61 (m, 2H) , 5.23 (s, IH) , 4.09 - 3.94 (m, 4H) , 3.68 (t, 4H, J = 5.9) , 3.04 (s, 6H) , 2.89 (t, 4H, J = 7.8), 2.16 - 2.01 ( , 2H) , NH (IH, unobserved); ESI-MS m/z 416 (MHT) .
Example 124: AT4- (3 , 4-DICHLOROPHENYL) -AT6, AT5-DIMETHYL-2- [4- 5 (2-PYRIDINYL) -1-PIPERAZINYL] -4, 6-PYRIMIDINEDIAMINE:
Prepared by Procedures A (CH2C12, Et3N, Me2NHHCl, stirred 3.5 h at -78 aC, warmed to 0 2C and stirred 3 h) , N, and O. lE NMR (400 MHz, CDCl3) δ 8.31 - 8.20 (m, IH) , 7.79 - 7.69 (m, IH) , 7.61 - 7.44 (m, IH) , 7.42 - 7.28 (m, IH) , 10 7.25 - 7.11 ( , IH) , 6.79 - 6.61 (m, 2H) , 6.42 (br s, IH) , 5.22 (s, IH) , 3.98 - 3.82 (m, 4H) , 3.65 - 3.56 ( , 4H) , 3.02 (s, 6H) ; ESI-MS m/z 444 (MHT with 3SCl, 35Cl), 446 (MH+ with 35C1, 37Cl) , 448 (MH+ with 37Cl, -37C1) .
15 Example 125: AT4, AT -DIMETHYL-2- [4- (2-PYRIDINYL) -1-
PIPERAZINYL] -AT6- [3- (TRIFLUOROMETHYL) PHENYL] -4,6- PYRIMIDINEDIAMINE : Prepared by Procedures A (CH2Cl2, Et3N, Me2NHHCl, stirred 3.5 h at -78 2C, warmed to 0 EC and stirred 3 h) , N, and O. λE NMR (400 MHz, CDCl3) δ
20.' 8.'59 (br s, IH.) , 8.24 - 8.18 ( , IH) , 7.86 (s, IH) , 7.78 '- 7.22 ( , 4H) , 6.65 (t, 2H, J = 5.0), 5.29 (s, IH) , 3.96 (t, 4H, J = 5.5), 3.64 (t, 4H, J = 5.2), 3.03 (s, 6H) ; ESI-MS m/z 444 (MH+) .
25 Example 126: 2- (4-BENZYL-1-PIPERAZINYL) -AT4- [3-
(DIMETHYLAMINO) PHENYL] -AT6, AT6-DIMETHYL-4 , 6- ' PYRIMIDINEDIAMINE : Prepared by Procedures P (toluene, 95 aC, 16 h) , Q (dioxane, 120 aC) , and A. :H NMR (400 MHz, CDC13) δ 7.52 - 7.37 (m, 7H) , 7.25 (t, IH, J = 2.0 ) , 7.14
30 (dd, IH, J" = 1.5, 8.2), 7.05 (dd, IH, J = 2.5, 8.2), 4.36 (s, 2H) , 3.98 (br s, 4H) , 3.36 (s, 4H) , 3.11 (s, ' 6H) , 3.05 (s, 6H) , 2.60 (s, IH) ; ESI-MS m/z 432 (MH+) . Example 127: 2- (4-BENZYL-l-PIPERAZINYL) -AT4 , AT -DIMETHYL- AT6- (2-"METHYL-l, 3-BENZOTHIAZOL-5-YL) -4, 6-
PYRIMIDINEDIAMINE : Prepared by Procedures P (130 SC, 13 h) , Q, and A. XE NMR (400 MHz, CDC13) δ 8.12 (s, IH) , 7.87 (d, IH, J = 8.8), 7.52 - 7.38 ( , 6H) , 5.58 (s, IH) , 4.58 (s, IH) , 4.30 (s, 2H) , 3.79 - 3.42 ( , 4H) , 3.22 - 2.91 (m, 4H) , 3.09 (s, 6H) , 2.98 (s, 3H) ; ESI-MS m/z 460 (MH+) .
Example 128: 2- (4-BENZYL-l-PIPERAZINYL) -AT4-CYCLOHEPTYL- AT6 , AT5-DIMETHYL-4 , 6-PYRIMIDINEDIAMINE : Prepared •• by Procedures P (140 -C , toluene, 6 h) , Q, and A. XE MIR (400 MHz, CDC13) δ 7.20 - 7.09 (m, 5H) , 4.78 (s, IH) , 4.18 (br s, IH) , 3.74 (t, 4H, J = 5.2), 3.52 (s, 2H) , 2.99 (s, 6H) , 2.46 (t, 4H, J = 5.1), 2.03 - 1.92 (m, 2H) , 1.87 - 1.68 (m, 11H) ; ESI-MS /z 409 (MH+) .
Example 129: 4-{ [2- (4-BENZYL-l-PIPERAZINYL) -6- (DIMETHYLAMINO) -4-PYRIMIDINYL] AMINO} -2-
CHLOROBENZONITRILE : Prepared by Procedures P (toluene, 95 2C, 16 h) , Q (dioxane, 120 2C) , and A. XE NMR (400 MHz, CDC13) δ 7.88 (d, IH, J = 3.1), 7.48 (d, IH, J = 8.5), 7.42 - 7.22 (m, 6H) , 6.45 (s, IH) , 5.20 (s, IH) , 3.79 (t, 4H, J = 5.2), 3.55 (s, 2H) , 3.02 (s,. 6H) , 2.51 (t, 4H, J = 5.0); ESI-MS m/z 448 (MH+ with 35C1) , 450 (MH+ with 37C1) .
Example 130: 2- (4-BENZYL-l-PIPERAZINYL) -AT4, AT4-DIMETHYL- AT6- (1 , 3 , 3.-TRIMETHYLBICYCLO [2.2.1] HEPT-2-YL) -4 , 6-
PYRIMIDINEDIAMINE : Prepared by procedures P (toluene, 95 2C, 16 h) , Q (dioxane, 120 2C) , and A. XE NMR (400 MHz, CDC13) δ 7.38 - 7.21 (m, 6H) , 4.87 (s, IH) , 3.79 - 3.69
(m, 4H) , 3.53 (s, 2H) , 3.46 (s, IH) , 2.98 (s, 6H) , 2.46
(t, 4H, J" = 5.1), 1.71 (s, IH) , 1.69 - 1.62 (m, 2H) ,
1.48 - 1.35 (m, 2H) , 1.20 (d, IH, J" = 10.2), 1.19 - 1.02 (m, IH) , 1.14 (s, 3H) , 1.07 (s, 3H) , 0.79 (s, 3H) ; ESI- MS m/z 449 (MH+) .
Example 131: 2- (4- [3- (BENZYLOXY) PHENYL] -1-PIPERAZINYL} - AT4 , AT-DIMETHYL-V6- (4-METHYLPHENYL) -4 , 6-PYRIMIDINEDIAMINE : Prepared by Procedures A (CH2C12, TEA, 3 - 4 h at -78 °C, then 3 - 4 h at 0 °C)', N, and 0. XH NMR (400 MHz, CDCl3) δ 7.44 (d, 2H, J = 7.1), 7.36 (t, 2H, J = 7.0), 7.29 (d, IH, J = 7.1), 7.22 - 7.04 (m, 5H) , 6.58 - 6.52 (m, 2H) , 6.48 (d, IH, J = 7.2), 5.29 (s, IH) , 5.21 (s, IH) , 5.03 (s, 2H) , 3.89 - 3.80 (m, 4H) , 3.28 - 3.15 (m, 4H) , 3.00 (s, 6H) , 2.30 (s, 3H) ; ESI-MS m/z 495 (MH÷) .
Example 132: AT4, AT4-DIMETHYL-2- [4- (2-PYRIDINYL) -1-
PIPERAZINYL] -IVs- (3 -QUINOLINYL) -4, 6-PYRIMIDINEDIAMINE: Prepared by Procedures A (CH2Cl2, TEA, 3 - 4 h at -78 °C, then 3 - 4 h at 0 °C) , N, and O. E NMR (400 MHz, CDCl3) δ 8.93 (d, IH, J = 2.6), 8.31 (d, IH, J = 2.5), 8.26 - 8.18 (m, IH) , 8.02 (d, IH, J = 8.2), 7.71 (d, IH, J = 7.7), 7.57 (dt,' IH, J = 1.5, 5.3), 7.53 - 7.46 (m, 2H) , ' 6.68 (d, IH, J = 8.6) , 6.64 (dd/ IH, J = 4.9, 7.1) , 5.30 (d, 2H, J = 3.7), 3.94 (t, 4H, J = 4.9), 3.64 (t, 4H, J = 5.4) , 3.03 (s, 6H) ; ESI-MS m/z 427 (MH+) .
Example 133: AT4- [4-BROMO-3- (TRIFLUOROMETHYL) PHENYL] - Ar6,AT6-DIMETHYL-2-[4- (2-PYRIDINYL) -1-PIPERAZINYL] -4,6- PYRIMIDINEDIAMINE : Prepared by Procedures A (CH2Cl2, TEA, 3 - 4 h at -78 °C, then 3 - 4 h at 0 °C)"', N, and O. E NMR (400 MHz, CDCl3) δ 8.23 - 8.19 (m, IH) , 8.17 (d, IH, J = 2.3) , 7.57 (d, IH, J = 8.7) , 7.53 - 7.47 (m, IH) , 7.39 (d, IH, -7 = 5.2) , 6.69 (d, IH, J = 8.7) , 6.64 (t, 5 IH, J = 5.0) , 6.27 (s, IH) , 5.19 (s, IH) , 3.94 - 3.87 (m, 4H) , 3.65 - 3.59 (m, 4H) , 3.04 (s, 6H) ; ESI-MS m/z 522 (MHT with 79Br) , 524 (MH+ with 81Br) .
Example 134: AT4- (3 -CHLORO-4- 0 [ (TRIFLUOROMETHYL) SULFANYL] PHENYL} -AT6 , IV5-DIMETHYL-2- [4- (2-PYRIDINYL) -1-PIPERAZINYL] -4, 6-PYRIMIDINEDIAMINE: Prepared by Procedures A (CH2Cl2, TEA, 3 - 4 h at -78 °C, then 3 - 4 h at 0 °C) , N, and O. XE NMR (40-0 MHz, CDC13) δ 8.23 - 8.19 (m, IH) , 7.91 (d, IH, J = 2.3), 7.61 (d, 5 IH, J = 8.5), 7.50 (dt, IH, J = 2.1, 8.5), 7.30 - 7.20 (m, IH) , 6.70 (d, IH, J = 9.1), 6.64 (dd, IH, J = 4.7, 7.1), 6.35 (br s, IH) , 5.26 (s, IH) , 3.92 (t, 4H, J = 5.6), 3.64 (t, 4H, J = 5.0), 3.06 (s, 6H) ; ESI-MS m/z 510 (MH+ with 35C1) , 512 (MH+ with 37Cl). 0
Example 135: AT4- (3-ETHOXYPHENYL) -AT5 , AT6-DIMETHYL-2- [4- (2-
• • PYRIDINYL) -1-PIPERAZINYL] -4, 6-PYRIMIDINEDIAMINE: Prepared by Procedures A (CH2Cl2, TEA, 3 - 4 h at -78 °C, then 3 - 4 h at 0 °C) , N, and O. XE NMR (400 MHz, CDCl3) δ 8.28 - 5 8.19 (m, IH) , 7.50 (dt, IH, J" = 2.1, 6.9), 7.19 (t, IH, J = 8.1), 6.96 (t, IH, J = 2.1), 6.85 (d, lH, -7 = 8.2), 6.68 (d, IH, J = 8.6), 6.63 - 6.56 (m, IH) , 6.35 (br s, IH) , 5.36 (s, IH) , 4.09 - 3.98 (m, 2H) , 3.91 (t, 4H, -7 = 5.3), 3.61 (t, 4H, J = 5.1), 3.02 (s, 6H) , 1.39 (t, 3H, 0 J = 5.7); ESI-MS m/z 420 (MH+) . Example 136: AT4- [2-CHLORO-4- (TRIFLUOROMETHYL) PHENYL] - T6, Ai^-DIMETHYL-Σ- [4- (2-PYRIDINYL) -1-PIPERAZINYL] -4 , 6- PYRIMIDINEDIAMINE : Prepared by Procedures A (CH2Cl2, TEA, 3 - 4 h at -78 °C, then 3 - 4 h at 0 °C) , N, and 0. XH NMR (400 MHz, CDCl3) δ 8.23 - 8.15 (m, IH) , 8.15 (d, IH, J = 2.1), 7.50 (dt, IH, J = 2.0, 8.8), 7.42 - 7.33 ( , 2H) / 6.69 (d, IH, J = 8.6), 6.64 (dd, IH, J = 4.8, 6.3), 6.28 (s, IH) , 5.18 (s, IH) , 3.91 (t, 4H, J = 5.0), 3.62 (t, 4H, J = 5.1), 3.04 (s, 6H) ; ESI-MS m/z 478 (MH+ with 35C1) , 480 (MH+ with 37C1) .
Example ' 137: AT-4- (2-ADAMANTYL) -2- (4-BENZYL-l-
PIPERAZINYL) -AT-6-AT-6-DIMETHYL-4 , 6-PYRIMIDINEDIAMINE : Prepared by Procedures P (toluene, 90 2C) , Q, and A. 1H NMR (400 MHz, CDCl3) δ 7.39 - 7.21 (m, 5H) , 4.83 (s, IH) , 4.72 (br s, IH) , 3.74 (m, 3H) , 3.52 (s, 2H) , 2.98 (s, 6H) , 2.46 (t, 4H, J = 5.3), 2.05 - 1.53 (m, 13H) ; ESI-MS m/z : 433 (MH+) .
Example 138: A7-4- (1-NORADAMANTYL) -2- (4-BENZYL-l- PIPERAZINYL) -JV-6-A7-6-DIMETHYL-4, 6-PYRIMIDINEDIAMINE: Prepared by Procedures P (toluene, 90 2C) , Q, and A. 1H NMR (400 MHz, CDC13) δ 7.38 - 7.20 (mi 5H) , 4.97 (s, IH) , 4.67 (br s, IH) , 3.74 (s, 4H) , 3.52 (s, 2H) , 2.99 (s, 6H) , 2.46 (t, 4H, J = 5.2), 2.32 - 1.51 (m, 15H) ; -ESI-MS m/z : 447 (MH+) .
Example 139: 2- (4-BENZYL-l-PIPERAZINYL) -AT4, AT4-DIMETHYL- AT6- [ ( IS, 2R, 3R, 5S) -2 , 6 , 6-TRIMETHYLBICYCLO [3.1.1] HEPT-3- YL] -4 , 6-PYRIMIDINEDIAMINE: Prepared by Procedures P (toluene, 150 2C, 4 h) , Q (neat, 130 2C) , and' A. XE NMR (400 MHz, CDC13) δ 7.38 - 7.21 ( , 5H) , " 4.86 (s, IH) , 4.35 (br s, IH) , 3.75 (t, 4H, J = 4.6) , 3.53 (s, 2H) , 2.99 (s, 6H) , 2.66 - 2.56 (m, IH) , 2.47 (t, 4H, J = 4.5) , 2.41 - 2.33 (m, IH) , 1.98 - 1.92 (m, IH) , 1.83 (t, IH, J = 5.8) , 1.68 - 1.60 (m, 2H) , 1.23 (s, 3H) , 1.14 (d, 3H, J = 7.3) , 1.05 (s, 3H) , 0.92 (d, 2H) ;_ESI-MS m/z: 449 (MH+) .
Example 140; 2- [4- ( 5-BROMO-2-PYRIDINYL) -1-PIPERAZINYL] - AT4 , Ar-DIMETHYL-AT6- (4-METHYLPHENYL) -4 , 6-PYRIMIDINEDIAMINE : Prepared using Procedure Y (DMF) . XE NMR (400 MHz, CDCl3) δ 8.21 (d, IH, J = 2.6), 7.53 (dd, IH, J~= 2.6, 8.8), 7.19 (d, 2H, J = 8.5), 7.12 (d, 2H, J = S.5), 6.21 (s, IH) , 5.28 (s, IH) , 3.88 (t, 4H, J = 5.0), 3.58 (t, 4H, J = 5.2), 3.00 (s, 6H) , 2.33 (s, 3H) ; ESI-MS m/z: 468 (MH+ with 79Br) , 470 (MH+ with 81Br) .
Example '141: 6- (4- [4- (DIMETHYLAMINO) -6- (4-TOLUDINO) -2- PYRIMIDINYL] -l-PIPERAZINYL}NICOTINAMIDE : Prepared by " Procedure Y (DMF). E NMR (400 MHz, CDCl3) δ 8.13 (s, IH) , 7.30 - 7.25 ( , 4H) , 7.17 (d, 2H, J = 8.5), 7.13 (d, 2H, J = 8.6), 6.18 (br s, IH) , 5.28 (s, IH) , 3.82 (t, 2H, J = 5.1), 3.79 (t, 2H, J = 5.3), 3.60 (t, 2H, J = 5.1), 3.41 (t, 2H, J = 5.3), 2.99 (s, 6H) , 2.33 (s, 3H) ; ESI-MS m/z: 433 (MH+) .
Example 142 : 2- [4- (3-METHOXYBENZYL) -1-PIPERAZINYL] -AT4, AT4- DIMETHYL-AT6- (4-METHYLPHENYL) -4, 6-PYRIMIDINEDIAMINE: Prepared by Procedure Z (DIEA) . XH NMR (400 MHz, CDC13) δ 7.22 (d, IH, J = 6.8), 7.17 (d, 2H, J = 8.3), 7.10 (d, 2H, J = 8.2), 6.93 (d, IH, J = 2.3), 6.92 (d, IH, J = 2.4), '6.80 (dd, IH, J = 2.0, 7.6), 6.18 (br s, IH), 5.25 (s, IH) , 3.82 (s, 3H) , 3.78 (t, 4H, J = 5.1), 3.52 (s, 2H) , 2.97 (s, 6H) , 2.49 (t, 4H, J = 5.1), 2.31 (s, 3H) ; ESI-MS m/z : 433 (MH+) .
Example 143 : 2- [4- ( 5-BROMO-2 -PYRIDINYL) -1-PIPERAZINYL] - AT4- (3-METHOXYPHENYL) -AT6, AT6-DIMETHYL-4 , 6- ' PYRIMIDINEDIAMINE : Prepared by Procedure Y. XE NMR (400 MHz, CDC13) δ 8.21 (d, IH, J = 2.4), 7.53 (dd, IH, J" = 2.5, 9.2), 7.20 (t, IH, J = 8.1), 7.00 (t, IH, J = 2.0), 6.85 (dd, IH, J = 2.0, 8.0). 6.62 - 6.54 ( , 2H) , 6.29 (s, IH) , 5.36 (s, IH) , 3.89 (t, 4H, J = 5.1), 3.80 (s, 3H) , 3.58 (t, 4H, J = 4.9), 3.02 (s, 6H) ; ESI-MS m/z : 484 (MH" with 79Br) , 486 (MH'" with 81Br) .
Example 144: AT4- (3-METHOXYPHENYL) -AT6, AT6-DIMETHYL-2- [4- (2- PYRIDINYLMETHYL) -1-PIPERAZINYL] -4 , 6-PYRIMIDINEDIAMINE : Prepared by Procedure X. XE NMR (400 MHz, CDC13) δ 8.61 - 8.54 (m, IH) , 7.66 (dt, IH, J = 1.8, 7.8), 7.45 (d, IH, J = 7.8), 7.23 - 7.14 ( , 2H) , 7.00 (t, . IH, J = 2.5), 6.87 - 6.78 (m, IH) , 6.61 - 6.54 (m, IH) , 6.26 (br s, IH) , 5.33 (s, IH) , 3.82 (t, 4H, J = 5.0), 3.78 (s, 3H) , 3.70 (s, 2H) , 2.99 (s, 6H) , 2.56 (t, 4H, J = 5.0); ESI- MS m/z : 420 (MH+) .
Example 145: 2- [4- (CYCLOHEXYLMETHYL) -1-PIPERAZINYL] -AT4- ( 3 -METHOXYPHENY ) -AT5 , AT6-DIMETHYL-4 , 6-PYRIMIDINEDIAMINE : Prepared by Procedure T. XE NMR (400 MHz, CDC13) δ 7.21 (t, IH, J = 8.2), 7.00 - 6.95 ( , IH) , 6.85 (d, IH, J" = 8.2), 6.59 (d, IH, 7 = 7.7), 6.32 (s, IH) , 5.36 (s, IH) , 3.82 - 3,71 (m, 4H) , 3.79 (s, 3H) , 3.69 - 3.62 (m, 2H) , 3.58 - 3.50 (m, 2H) , 3.01 (s, 6H) , 2.54 - 2.45 (m, IH) , 1.87 - 1.48 (m, 8H) , 1.45 - 1.29 (m, 4H) ; ESI-MS m/z : 425 (MH+) .
Example 146: AT4- ( 3-METHOXYPHENYL) -AT5 , AT6-DIMETHYL-2- [4- ( 3- THIENYLMETHYL) -1-PIPERAZINYL] -4 , 6-PYRIMIDINEDIAMINE :
Prepared by Procedures T (reduction 4 h) and W. 1H NMR (400 MHz, CDC13) δ 7.27 (dd, IH, J = 3.2, 5.1), 7.19 (t, IH, .J" = 8.0),' '7.16 - 7.11 (m, IH) , 7.08 (dd, IH, J - = 1.3, 4.9), 7.00 (t, IH, J = 2.3), 6.82 (dd, IH, J = 2.0, 8.3), 6.57 (dd, IH, J = 2.5, 8.2), 6.25 (s, IH) , 5.33 (s, IH) , 3.79 (t, 4H, J = 5.5), 3.78 (s, 3H) , 3.57 (s, 2H) , 2.99 (s, 6H) , 2.48 (t, 4H, J = 5.2)
ESI-MS m/z : 425 (MH+) .
Example 147 : IV4-( 3-METHOXYPHENYL) -AT6, AT6-DIMETHYL-2- [4- (4- PYRIDINYLMETHYL) -1-PIPERAZINYL] -4 , 6-PYRIMIDINEDIAMINE : Prepared by Procedure T (acylation with DIPEA) . XE NMR (400 MHz, CDCI3) δ 8.55 (dd, 2H, J = 1.5, 5.8), 7.31 (d, ' 2H, J = 6.0), 7.19 (t, IH, J = 8.3), 6.99 (t, IH, J = 2.1), 6.83 (dd, IH, J = 1.5, 7.8), 6.58 (dd, IH, J = 2.0, 7.8), 6.28 (br s, IH) , 5.34 (s, IH) , 3.80 (t, 4H, J = 5.2), 3.78 (s, 3H) , 3.54 (s, 2H) , 3.00 (s, 6H) , 2.49 (t, 4H, J = 5.3; ESI-MS m/z 420 (MH+) . Example 148: 2 - [4- ( 3 -METHOXYBENZYL) -1-PIPERAZINYL] -AT- (3- METHOXYPHENYL) -AT5 , AT6-DIMETHYL-4 , 6-PYRIMIDINEDIAMINE : Prepared by Procedure S. XE NMR (400 MHz, CDCl3) δ 7.22 (d, IH, J = 7.9), 7.17 (t, IH, J = 8.2), 6.99 (t, IH, J = 2.1), 6.95 - 6.84 (m, 2H) , 6.86 - 6.78 (m, 2H) , 6.59 - 6.55 ( , IH) , 6.29 (br s, IH) , 5.32 (s, IH) , 3.82 (s, 3H) , 3.79 (t, 4H, -7 = 5.1), 3.77 (s, 3H) , 3.52 (s, 2H) , 2.99 (s, 6H) , 2.49 (t, 4H, J = 5.1); ESI-MS m/z : 449
(MH+)
Example 149: AT2- [2- ( 3 -METHOXYPHENYL ) ETHYL] -IV4 , AT4- DIMETHYL-AT6- (4-METHYLPHENYL) -2,4, 6-PYRIMIDINETRIAMINE :
Prepared by Procedure F (dioxane, potassium tert- butoxide, 120 2C, 16 h) , Q (toluene, TEA, 120 2C) , A (CH2C12, Δ, TEA). XE NMR (400 MHz, CDCl3) δ 7.22 (t, IH, J = 7.9), 7.18 (d, 2H, J = 8.4), 7.12 (d, 2H, J = 8.3), 6.84 (d, IH, J = 7.6), 6.82 - 6.74 ( , 2H) , 6.28 (br s, IH) , 5.28 (s, IH) , 4.77 (s, IH) , 3.80 (s, 3H) , 3.63 (q, 2H, J = 6.7), 2.99 (s, 6H) , 2.89 (t, 2H, J = 7.4), 2.32 (s, 3H) ; ESI-MS m/z : 378 (MH+) .
Example 150: AT2- [2- ( 2 -METHOXYPHENYL) ETHYL] -AT4 , AT4-
DIMETHYL-A76- (4-METHYLPHENYL) -2,4, 6-PYRIMIDINETRIAMINE :
Prepared by Procedures F (dioxane, potassium tert- butoxide, 140 2 C/ 16 h) , Q (toluene), and A (CH2Cl2, Δ, TEA). X NMR (400 MHz, CDC13) δ 7.23 - 7.12 (m, 4H) , 7.12 (d, 2H, -7 = 8.1), 6.89 (d, IH, J = 7.8), "6.86 (d, IH, J = 7.6), 6.61 (d, IH, = 8.0), 6.50 (br s, IH) , 5.25 (s, IH) , 3.84 (s, 3H) , 3.60 (q, 2H, J = 7.1), 3.00 (s, 6H) , 2.93 (t, 2H, J = 7.6), 2.33 (s, 3H) ; ESI-MS m/z : 378 (MH+) .
Example 151: 2- (4-BENZYL-l-PIPERAZINYL) -IV4- (3 , 4-
DICHLOROPHENYL) -N6 , AT6-DIMETHYL-4 , 6-PYRIMIDINEDIAMINE :
Prepared by Procedures P (toluene, 140 °C, 6 h) , Q (dioxane, 120 °C) , and A. XE NMR (400 MHz, CDCl3) δ 7.65 (d, IH, J = 2.5), 7^5 - 7.30 (m, 4H) , 7.29 - 7.22 (m, 2H) , 7.13 (dd, IH, J = 1.5, 8.5), 6.19 (br s, IH) , 5.21 (s, IH)', 3.78 (t, 4H, J = 5.0), 3.55 (s, 2H) , 3.00 (s, 6H) , 2.49 (t, 4H, J = 5.0); ESI-MS m/z : 457 (MH+ with 35C1, 35C1) , 459 (MH+ with 35Cl, 37C1), 461 (MH+ with 37C1, 37C1).
Example 152 : A7*- [4- (BENZYLOXY) CYCLOHEXYL] -2- (4-BENZYL-l- PIPERAZINYL) -AT6, AT6-DIMETHYL-4, 6-PYRIMIDINEDIAMINE: Prepared by Procedures P (16 h) , Q,- and A. XE NMR (400
- MHz, CDC1.3) δ 7.42 -Λ7.18 (m, 10H) , 4.94 (s, IH) , 4.61
(d, IH, J = 11.8), 4*.51 (d, IH, J = 11.8), 4.39 . (br s,
IH) , 3.75 (t, 4H, J = 5.0), 3.53 (s, 2H) , 3.31 (dt, IH,
J = 5.3, 8.3), 2.95 (s, 6H) , 2.46 (t, 4H, J = 5.0), 2.19 - 2.11 (m, IH) , 2.07 - 1.98 ( , IH) , 1.79 - 1.56 (m, 3H) , 1.53 - 1.41 (m,. IH) , 1.40 - 1.21 ( , 3H) ; ESI-MS m/z 501 (MH+) . Example 153 : 2- (4-BENZYL-l-PIPERAZINYL) -AT ,V-DIMETHYL- T (l ,2R,4f:)-l,7,7-TRIMETHYLBICYCLO[2.2.1]HEPT-2-YL] - 4 , 6-PYRIMIDINEDIAMINE : Prepared by Procedures P (90 °C, 16 h) , Q, and A. XE NMR (400 MHz, CDCl3) δ 7.44 - 7.22 ( , 6H) , 4.81 (s, IH) , 4.36 (d, IH, J = 7.0), 3.74 (s, 4H) , 3.53 (s, 2H) , 2.98 (s, 6H) , 2.46 (t, 4H, J = 5.1), 1.84 (dd, IH, J = 8.9, 12.9), 1.78 - 1.52 (m, 4H) , 1.29 - 1.11 ( , 2H) , 0.97 (s, 3H) , 0.89 (s, 3H) , 0.83 (s, 3H) ; ESI-MS /z : 449 (MH+) .
Example 154: AT4 , A^-DIMETHYL-IV6- (4-METHYLPHENYL) -2- [4- (TETRAHYDRO-2-FURANYLMETHYL) -1-PIPERAZINYL] -4, 6- PYRIMIDINEDIAMINE : Prepared by Procedures A, P (16 h) , -and Q (dioxane, 120 °C) . E NMR (400 MHz, CDC13) δ 7.17 (d, 2H, J = 8.4), 7.11 (d, 2H, J - 8.0), 6.22 (br s, IH) , 5.29 (s, IH) , 4.12 - 4.03 (m, IH) , 3.91 (q, IH, J =
6.7), 3.80 (t, 4H, ,7 = 5.1), 3.76 (q, IH, -7 = 7.5), 2.98
(s, 6H) , 2.57 (t, 4H, J = 5.0), 2.56 - 2.40 (m, 2H) ,
2.32 (s, 3H), 2.05 - 1.96 (m, IH) , 1.94 - 1.80 (m, 2H) , 1.57 - 1.45 (m, IH) ; ESI-MS m/z : 397 (MH+) .
Example 155: 3-{ [2- (4-BENZYL-l-PIPERAZINYL) -6-
(DIMETHYLAMINO) -4-PYRIMIDINYL] AMINO} PHENOL : Prepared By Procedures P (Toluene, 120 °C, 40 H) , Q (dioxane, 120 °C) , AND A. αH NMR (400 MHz, CDC13) δ 7.38 - 7.29 (m, 4H) , 7.28 - 7.26 ( , IH) , 7.13 (t, IH, J = 8.0), 6.84 (t, IH, J" = 2.8), 6.80 (ddd, IH, J = 0.7, 2.0, 7.9), 6.48 (ddd, IH, J = 0.7, 2.1, 8.0), 6.32 (br s, IH) , 5.32 (s, IH) , 3.79 (t, 4H, J = 5.0), 3.55 (s, 2H) , 3.49 (s, IH) , 2.99 (s, 6H) , 2.50 (t, 4H, J = 5.0); ESI-MS m/z : 405 (MH+) .
Example 156: 2- (4-BENZYL-l-PIPERAZINYL) -AT4- (4-
FLUOROPHENYL) -AT6 , AT6-DIMETHYL-4 , 6-PYRIMIDINEDIAMINE : Prepared by Procedures P (toluene, sodium tert-butoxide, 120 °C, 16 h) , Q (dioxane, 120 °C) , and A. XE NMR (400 MHz, CDC13) δ 7.37 - 7.30 (m, 4H) , 7.29 - 7.21 (m, 3H) , 6.99 (t, 2H, J = 8.6), 6.14 (br s, IH) , 5.13 (s, IH) , 3.77 (t, 4H, J = 4.9), 3.54 (s, 2H) , 2.97 (s, 6H) , 2.48 (t, 4H, J = 4.9); ESI-MS m/z : 407 (MH+) .
Example 157: 2- (4-BENZYL-l-PIPERAZINYL) -AT4,V -DIMETHYL- AT6- (4-METHYLCYCLOHEXYL) -4, 6-PYRIMIDINEDIAMINE: Prepared by Procedures P (sodium tert-butoxide, toluene, 120 °C, 16 h) , Q (dioxane, 120 °C) , and A. XH NMR (400 MHz, CDCI3) 8 7.35 - 7.10 (m, 6H) , 4.82 (d, IH, J = 4.9), 3.81 -'3.61 (m, 5H) , 3.53 (s, 2H) , 2.99 (s, 6H) , 2.46 (t, 4H, J = 4.5), 1.79 - 1.46 ( , 7H) , 1.29 - 0.98 (m, 2H) , 0.90 (d, 3H, J = 6.6); ESI-MS /z : 409 (MH~).
Example 158: 2- (4-BENZYL-l-PIPERAZINYL) -A74-[4-
(DIMETHYLAMINO) PHENYL] -AT6 , IVs-DIMETHYL-4 , 6-
PYRIMIDINEDIAMINE : Prepared by Procedures P (sodium tert-butoxide, toluene, 120 °C, 16 h) , Q (neat, 130 °C) , and A. XE NMR (400 MHz, CDCl3) δ 7.39 - 7.22 (m, 5H) , 7.14 (d, 2H, J = 8.4), 6.71 (d, 2H, J = 8.8), 6.04 (br s, IH) , 5.08 (s, IH) , 3.85 - 3.74 (m, 4H) , 3.54 (s, 2H) , 2.94 (s, 6H) , 2.93 (s, 6H) , 2.48 (t, 4H, J = 5.1); ESI- MS m/z 432 (MH+) . Example 159: AT4 , AT -DIMETHYL-AT6- (4-METHYLPHENYL) -2- [4- (2- PHENYLETHYL) -1-PIPERAZINYL] -4, 6-PYRIMIDINEDIAMINE: Prepared by Procedure S (toluene, 120 °C) . E NMR (400 MHz, CDC13) δ 7.34 - 7.20 (m, 5H), 7.18 (d, 2H, J = 8.5) , 7.12 (d, 2H, J = 8.5), 6.21 (br s, IH) , 5.26 (s, IH) , 3.88 - 3.79 (m, 4H) , 2.99 (s, 6H) , 2.90 - 2.83 (m, 2H) , 2.68 - 2.63 (m, 2H) , 2.60 (t, 4H, J = 4.4), 2.32 (s, 3H) ; 'ESI-MS m/z: 417 (MH+) .
Example 160: 2- (4-BENZYL-l-PIPERAZINYL) -AT4- (3-
CHLOROPHENYL) -AT6, AT5 -DIMETHYL -4 , 6-PYRIMIDINEDIAMINE : Prepared by Procedures P (toluene, sodium tert-butoxide, 120 °C, 40 h) , Q (dioxane, 120 °C) , and A. XE NMR (400 MHz, CDC13) 8 7.48 (t, IH, -7 = 1.9) , 7.38 - 7.23 (m, 5H) , 7.20 - 7.11 (m, 2H) , 6.95 (ddd, IH, J = 1.2, 1.9, 7.6) , 6.28 (br s, IH) , 5.24 (s, IH) , 3.79 (t, 4H, J = 5.0) , 3.54 (s, 2H) , 3.00 (s, 6H) , 2.49 (t, 4H, J =- 5.0) ; ESI- MS m/z: 423 (MHT with 35C1) , 425 (MH+ with 37Cl) .
Example 161: AT2 , AT4, A^-TRIMETHYL-AT6- (4-METHYLPHENYL) -AT2- [2- (2-PYRIDINYL) ETHYL] -2 , 4 , 6-PYRIMIDINETRIAMINE: Prepared by Procedures F (dioxane, potassium tert-butoxide, 140 °C, 16 h) , Q', and A (CH2Cl2, Δ, TEA). XE NMR (400 MHz, CDC13) δ 8.54 (ddd, IH, J = 1.2, 2.1, 5.3), 7.57 (dt, IH, J = 1.7, 7.6), 7.23 (d, 2H, <7 = 8.6), 7.18 -(d, IH, -7 = 7.7) , 7.14 - 7.09 (m, IH) , 7.10 • (d, 2H, J = 7.7) , 6.29 (br s, IH) , 5.24 (s, IH) , 3.93. (dd, 2H, J = 5.9, 7.8), 3.11 (dd, 2H, J = 6.0, 7.7) , 3.08 (s, 3H)', 3.00 (s, 6H) , 2.32 (s, 3H) ; ESI-MS m/z: 363 (MH+) .
Example 162: AT4, A^-DIMETHYL-AT5- ( 4-METHYLPHENYL) -AT2- (3- PHENYLPROPYL) -2,4, 6-PYRIMIDINETRIAMINE : Prepared using Procedures R, S, and V. XE NMR (400 MHz, CDC13) δ 7.25 (d, 2H, J = 7.7), 7.22 - 7.14 '(m, 5H) , 7.11 (d, 2H, J = 8.1), 6.41 (br s, IH) , 5.27 (s, IH) , 4.76 (t, IH, J = 5.7), 3.41 (dd, 2H, -7 = 7.0, 12.9), 2.96 (s, 6H) , 2.70 (t, 2H, J = 7.7), 2.31 (s, 3H) , 1.91 (t, 2H, J = 7.5); ESI-MS m/z: 362 (MH+) .
Example 163: 2- (4-CYCLOHΞXYL-l-PIPERAZINYL) -AT4- (3- METHOXYPHENYL) -A?6 , AT6-DIMETHYL-4 , 6-PYRIMIDINEDIAMINE : Prepared using Procedures P (16 h) , Q (dioxane, 120 °C) , and A. XH NMR (400 MHz, CDC13) δ 7.11 (t, IH, J" = 8.3), 6.92 (t, IH, J = 2.4), 6.78 - 6.73 (m, IH) , 6.53 - 6.48 (m, IH) , 6.39 (br s, IH) , 5.27 (s, IH) , 3.72 (t, 4H, J = 5.0), 3.71 (s, 3H) , 2.92 (s, 6K) , 2.55 (t, 4H, J = 5.1), 2.28 --2.18 (m, IH) , 1.87 - 1.79 (m, 2H) , 1.77 - 1.68 (m, 2H) , 1.56 (d, IH, J = 12.4), 1.24 - 1.08 (m, 4H) , 1.08 - 0.97 (m, IH) ; ESI-MS m/z: 411 (MH+)...
Example 164: 2- (4-BENZYL-l-PIPERAZINYL) -AT4- (3- FLUOROPHENYL) -AT6, 76-DIMETHYL-4 , 6-PYRIMIDINEDIAMINE :
Prepared by Procedures P .(140 °C, 4 h) , Q. (neat, • 130 °C) , and A. 1H NMR (400 MHz, CDCl3) δ 7.37 - 7.31 (m, 5H) , 7.28 - 7.17 (m, 2H) , 6.98. (ddd, IH, J = 0.7, 2.0, 8.1), 6.67 ( dt, IH, J = 0.9, 2.0, 8.3), 6.30 (br s, IH) , 5.27 (s, IH) , 3.79 (t, 4H, J = 5.1)',' 3..55 (s, 2H) , 3.00 (s, 6H) , 2.50 (t, 4H, J" = 5.0); ESI-MS m/z : 407 (MH+) .
Example 165 : AT4- ( 3 -METHOXYPHENYL) -A76, AT6-DIMETHYL-2- [4- (2- THIENYLMETHYL) -1-PIPERAZINYL] -4 , 6-PYRIMIDINEDIAMINE : Prepared by Procedure T. XE NMR (400 MHz, CDCl3) δ 7.24 (dd, IH, J = 1.2, 5.2), 7.19 (t, IH, J = 8.1), 6.99 (t, IH, J = 2.0), 6.96 - 6.91 ( , 2H) , 6.83 (ddd, IH, J = 0.8, 1.7, 7.9), 6.57 (dd, IH, J = 2.0, 8.2), 6.25 (br s, IH) , 5.33 (s, IH) , 3.81 (t, 4H, J = 5.2), 3.78 (s-, 3H) , 3.76 (s, 2H) , 2.99 (s, 6H) , 2.53 (t, 4H, J"- = 5.1); ESI- MS /z : 425 (MH+) .
Example 166: 2- [4- (2-METHOXYBENZYL) -1-PIPERAZINYL] -AT4- (3 -METHOXYPHENYL) -rf , AT6-DIMETHYL-4 , 6-PYRIMIDINEDIAMINE :
Prepared by Procedure T (reduction 3 h) . XE NMR (400 MHz, CDC13) δ 7.40 (dd, IH, J = 1.6, 7.6), 7.23 (dd, IH, J = 1.2, 7.6), 7.19 (t, IH, J = 8.3), 7.01 (t, IH, J = 1.9), 6.95 (dt, IH, J = 1.0, 7.3), 6.87- (dd, IH, J = 1.1, 8.3), 6.82 (ddd, IH, J = 1.0, 2.0, 8.2), 6.57 (ddd, IH, J = 0.7, 2.5, 8.2), 6.26 (br s, IH) , 5.32 (s, IH) , 3.82 (s, 3H) , 3.81 (t, 4H, J = 5.1), 3.78 (s, 3H) , 3.62 (s, 2H) , 2.99 (s, 6H) , 2.55 (t, 4H, J = 5.0); ESI-MS m/z 449 (MH+) .
Example 167: 2- (4-BENZYL-l-PIPERAZINYL) -AT4, A^-DIMETHYL^ AT6- [ (Iff, 2S) -1 , 7 , 7-TRIMETHYLBICYCLO [2.2.1] HEPT-2-YL] -4 , 6- PYRIMIDINEDIAMINE : Prepared by Procedure's P (toluene, 120 °C, 16 h) , Q (neat, 130 °C) , and A. E NMR (400 MHz, CDC1 ) δ 7.37 - 7.22 (m, 5H) , 4.82 (s, IH) , 4.51 (br s, IH) , 3.74 (m, 4H) , 3.53 (s, 2H) , 2.97 (s, 6H) , 2.47 (t, 4H, J- = 4.7), 2.39 - 2.30 (m, IH) , 1.76 - 1.68 ( , 4K) , 1.66 (t, IH, J" = 4.7), 1.41 - 1.31 ( , 2H) , 0.96 (s, 3H) , 0.88 (s, 3H) , 0.86 (s, 3K) ; ESI-MS m/z 449 (MHT) .
Example 168: AT4-(2 -ADAMANTYL) -2- (4-BENZYL-l-PIPERAZINYL) - AT6 , AT6-DIMETHYL-4 , 6-PYRIMIDINEDIAMINE : : 'Prepared by Procedures P (90 °C, toluene), Q, and A. XE NMR (400 MHz, CDC13) δ 7.39 - 7.21 (m, 5H) , 4.83 (s, IH) ; 4.72 (br s, IH) , 3.74 (m, 5H) , 3.52 (s, 2H) , 2.98 (s, 6H) , 2.46 (t, 4H, J" = 5.3), 2.05 - 1.53 (m, 14H) ; ESI-MS m/z : 447 (MHT) .
Example 169: 2- (4-BENZYL-l-PIPERAZINYL) -AT4- ( A -TERT- BUTYLCYCLQHEXYL) -AT6 , AT6-DIMETHYL-4 , 6-PYRIMIDINEDIAMINE :
Prepared by Procedures' P (toluene, 16 h) , Q (neat, 130 °C) , and A. XE NMR (400 MHz, CDC13) δ 7.36 - 7.22 (m, 5H) , 4.82 (s, IH) , 3.74 (t, 4H, J = 4.7), 3.53 (s, 2H) , 3.33 (s, IH) , 2.98 (s, 6H) , 2.46 (t, 4H, J" = 4.7),. 1.15 - 0.91 (m, 9H) , 0.86 (s, 9H) ; ESI-MS m/z : 451 (MH+) .
Example 170: 2- (4-BENZYL-l-PIPERAZINYL) -A7-CYCLOOCTYL- IVs , AT6-DIMETHYL-4 , 6-PYRIMIDINEDIAMINE : Prepared by Procedures P (16 h) , Q, and A. XE NMR (400 MHz, CDCl3) δ 7.39 - 7.21 (m, 5H) , 4.79 (s, IH) , 4.34 (s, IH) , 3.74 (t, 4H, J = 4.7), 3.53 (s, 2H) , 2.99 (s," 6H), 2.40 (t, 4H, J = 4.6), 1.93 - 1.49 (m, 15H) ; ESI-MS m/z : 423 (MH+) .
Example 171: 2- (4-BENZYL-l-PIPERAZINYL) -AT4- (4-
CHLOROPHENYL) -AT6 , AT6-DIMETHYL-4 , 6-PYRIMIDINEDIAMINE : Prepared by Procedures P (140 °C, Q (neat, 130 °C) , and A. XE NMR (400 MHz, CDC13) δ 7.38 - 7.22 ( , 9H) , 6.31 (br s, IH) , 5.21 (s, IH) , 3.78 (t, 4H, J = 5.1 Hz), 3.55 (s, 2H) , 2.99 (s, 6H) , 2.49 (t, 4H, J - 5.1); ESI-MS m/z : 423 (MH+ with 35Cl) , 425 (MH+ with 3Cl) .
Example 172: 2- (4-BENZYL-l-PIPERAZINYL) -IV4- (3-CHLORO-4- METHYLPHENYL) -IV5 , AT6-DIMETHYL-4 , 6-PYRIMIDINEDIAMINE : Prepared by Procedures P (toluene, 120 °C, 16 h) , Q (neat, 130 °C) , and A. lE NMR (400 MHz, CDC13) δ 7.43 - (d, IH, J = 2.1), 7.38 - 7.09 (m, 5H) , 7.07 (d, IH, J" = 2.1), 7.05 (d, IH, J = 2.6), 6.02 (s, IH) , 5.21 (s, IH) , 3.78 (t, 4H, J = 5.6), 3.54 (s, 2H) , 2.99 (s, 6H) , 2.49 (t, 4H, J = 5.0), 2.31 (s, 3H) ; ESI-MS m/z : 437 (MH* with 35C1) , 439 (MH+ with 37C1) .
Example 173: 2- (4-BENZYL-l-PIPERAZINYL) -AT4, AT -DIMETHYL- AT6- (1,2,3, 4-TETRAHYDRO-2-NAPHTHALENYL) -4,6- PYRIMIDINEDIAMINE : Prepared by Procedures P (16 h) , Q, and A. 1H NMR (400 MHz, CDCl3) δ 7.41 - 7.04 (m, 9H) , 4.99 (s, IH) , 4.91 (s, IH) , 3.74 ( , 4H) , 3.53 (s, 2H) , 3.47 (m, IH) , 2. 99 (s, 6H) , 2.90 - 2.69 (m, 2H) , 2.49 (m, 4H) , 2.09 - 1.71 (m, 4H) ; ESI-MS m/z : 443 (MH+) . Example 174: AT4 , A74-DIMETHYL-AT6- (4-METHYLPHENYL) -2- [4- (2- THIENYLMETHYL) -1-PIPERAZINYL] -4 , 6-PYRIMIDINEDIAMINE : Prepared by Procedure X (NaBH(OAc)3, CH2Cl2, molecular sieves) . XE NMR (400 MHz, CDCl3) δ 7.17 (d, 2H, J = 8.3) , 7.15 - 7.09 (m, 2H) , 7.03 - 6.94 (m, 3H) , 5.22 (br s, IH) , 4.85 (s, IH) , 3.86 - 3.79 ( , 4H) , 3.77 (s,.2H), 2.98 (s, 6H) , 2.62 - 2.53 (m, 4H , 2.32 (s, 3H) ; ESI-MS m/z 409 (MH+) .
Example 175: 2- [4- (2-METHOXYBENZYL) -1-PIPERAZINYL] -AT4,!^- DIMETHYL-AT6- (4-METHYLPHENYL) -4, 6-PYRIMIDINEDIAMINE: Prepared by Procedure Z. :H NMR (400 MHz, CDC13) δ 7.40 (dd, IH, J = 1.6, 7.5), 7.23 (dt, IH, J = 1.4, 7.6), 7.17 (d, 2H, J = 8.4), 7.10 (d, 2H, J" = 8.3), 6.94 (t, IH, J = 7.5), 6.87 (d, IH, J = 7.6), 6.17 (br s, IH) , 5.24 (s, IH) , 3.82 (s, 3H) , 3.79 (t, 4H, J = 5.0), 3.62 (s, 2H) , 2.97 (s, 6H) , 2.55 (t, 4H, J = 5.0)-, 2.31 (s, 3H) ; ESI-MS m/z : 433 (MH+) .
Example 176: AT2- (2-ANILINOETHYL) -IV4 , ?4-DIMETHYL-AT6- (4- METHYLPHENYL) -2,4, 6-PYRIMIDINETRIAMINE : Prepared by Procedures A, Q (toluene, 100 °C) , and F (potassium tert-butoxide, 110 °C, 16 h) . XE NMR (400 MHz, CDCl3) δ 7.19 - 7.10 (m, 6H) , 6.67 (dt, IH, J" = 0.8, 7.3), 6.59 (dd, 2H, J = 0.8, 8.4), 6-.31 (br s, IH) , 5.28 (s, IH) , 4.99 (s, IH) , 3.66 (q, 2H, 7 = 6.0), 3.49 (s, IH) , 3.37 (t, 2H, J" = 6.0), 3.00 (s, 6H) , 2.33 (s, 3H) ; ESI-MS m/z : 363 imC) . Example 177: A74- (3-METHOXYPHENYL) -AT , AT6 , AT6-TRIMETHYL-AT2- [2- (2-PYRIDINYL) ETHYL] -2,4, 6-PYRIMIDINETRIAMINE : Prepared by Procedures F (dioxane, 140 °C, 15 h) , A (CH2C12, Δ, TEA) , and Q (toluene, TEA, Δ, 40 h) . E NMR (400 MHz, CDC13) δ 8.55 (d, IH, J = 4.7), 7.58 (t, IH, u = 7.4), 7.25 - 7.16 (m, 2H) , 7 '.15 - 7.06 (m, 2H) , 6.89 (d, IH, J = 8.1), 6.57 (d, IH, J = 6.7), 6.30 (br s,. IH) , 5.31 (s, IH) , 3.95 (t, 2H, J = 6.4), 3.78 (s, 3H) , 3.18 - 3.06 ( , 5H) , 3'.02 (s, 6H) ; ESI-MS m/z 379 (MH+) .
Example 178: AT4- (4-CYCLOHEXYLPHENYL) -AT6, AT6-DIMETHYL-2- [4- (2-PYRAZINYL) -1-PIPERAZINYL] -4 , 6-PYRIMIDINEDIAMINE: Prepared by Procedures A (CH2Cl2, Et3N, Me2NHHCl, -78 °C for 3.5 h, warmed from -78 °C to 0 °C and stirred for 3
-h) , N, and 0. XE NMR (400 MHz, CDC13) δ 9.90 (br s, IH) ,
8.19-8.16 ( ," IH) , 8.09-8.06 (m, IH) , 7.89-7.85 (m, IH) ,
7.20-7.18 (m, 4H) , 5.28 (s, IH) , 3.99 (t, 4H, -7 = 5.3),
3.73 (t, 4H, J" = 5.3), 3.04 (s, 6H) , 2.53-2.44 (m, IH) , 1.91- 1.71 (m, 4H) , 1.46-1.71 ( , 6H) ; ESI-MS m/z : 459 (MH+) .
Example -179: AT4- [3- (BENZYLOXY) PHENYL] -AT6 , AT6-DIMETHYL-2- [4- (2-PYRAZINYL) -1-PIPERAZINYL] -4, 6-PYRIMIDINEDIAMINE :
Prepared by Procedures A (CH2C12, Et3N, Me2NHHCl, -78 °C for 3.5 h, warmed from -78 °C to 0 °C and stirred for 3 h) , N, and O. XE NMR (400 MHz, CDCl3) δ 9.82 (br s, IH) , 8.17-8.15 (m, IH) , 8.09-8.06 (m, IH) , 7.89 (d, IH, J = 2.8) , 7.45-7.29 (m, 9H) 5.32 (s, 1H) ,"5.05 :s, IE) ,
4.03 (t, 4H, J = 5.6) , 3.74 (t, 4H, J 5.0) , 3.05 (s,
6H) ;' ESI-MS m/z: 483 (MH+) .
Example 180: AT4- (2 , 3-DIHYDRO-lff-INDEN-5-YL) -AT6, N6-
DIMETHYL-2- [4- (2-PYRAZINYL) -1-PIPERAZINYL] -4, 6- PYRIMIDINEDIAMINE : Prepared by Procedures A (CH2C12, Et3N, Me2NHHCl, -78 °C for 3.5 h, warmed from -78 °C to 0 °C and stirred for 3 h) , N, and 0. XE NMR (400 MHz, CDC13) δ 10.01 (br s, IH) , 8.16 (s, IH) , 8.10-8.97 (m, IH) , 7.91-7.87 (m, IH) , 7.19 (d, IH, J = 6.3) , 7.-13 (s, IH) , 7.04 (d, IH, .7 = 7.6) , 5.23 (s, IH) , 4".03 (t, 4H, J = 5.2) , 3.74 (t, 4H, J = 5.1) , 3.05 (s, 6H) , 2.89 (t, 2H, J = 6.9) , 2.14-2.04 (m, 4K) ; ESI-MS m/z: 417 (MH+) .
Example 181: AT , AT4-DIMETHYL-IVs- ( -METHYLPHENYL) -2- [4- (2- PYRAZINYL) -1-PIPERAZINYL] -4 , 6-PYRIMIDINEDIAMINE : Prepared by Procedures A (CH2Cl2, Et3N, Me2NHHCl, -78 °C for 3.5 h, warmed from -78 °C to 0 °C and stirred for 3 h) , N, and 0. XE NMR (400 MHz, CDCl3) δ 10.01 (s, IH) , 8.17 (s, IH) , 8.12 - 8.09 (m, IH) , 7.90 (d, IH, ι7 = 2.6) , 7.18 (d, 2H, J = 8.6) , 7.16 (d, 2H, . J = 8.1) , 5.19 (s, IH) , 4.18 - 4.02 ( , 4H) , 3.77 (t, 4H, J = 5.1), 3.20 (br s, 3H) , 2.99 (br s, 3H) , 2.35 (s, 3H) ; ESI-MS /z: 391 (MH+) .
Example 183 : AT4- (3 , 4-DIMETHYLPHENYL) -AI^A^-DIMETHYL-Σ- [4- (2-PYRAZINYL) -1^PIPERAZINYL] -4, 6-PYRIMIDINEDIAMINE: Prepared by Procedures A (CH2C12, Et3N, Me2NHHCl, -78 °C for 3.5 h, warmed from -78 CC to 0 °C and stirred for 3 h) , N, and 0. XE NMR .(400 MHz, CDCl3) δ 8.75 (br s, IH) , 8.16 (d, IH, J = 1.3), 8.08 (dd, IH, J" = 1.5, 2.8), 7.88 5 (d, IH, J = 2.5), 7.10 (d, IH, J = 7.8), 7.08 - 7.00 (m, 2H) , 5.26 (s, IH) , 4.00 (t, 4H, J = 5.1), 3.72 (t, 4H, J = 5.0), 3.03 (s, 6H) ,. 2.24 (s, 6H) ; ESI-MS /z: 405 (MH+) .
Example 184: l-[2- (4-BENZYL-l-PIPERAZINYL) -6- (4-
10 TOLUIDINO) -4-PYRIMIDINYL] -4-PIPERIDINONE : Prepared by
Procedures a (Ch2cl2, -78 °C, 4 H) , N (24 H) , and 0. XH
NMR (400 MHz, CDCl3) 8 7. 38- 7.30 (m, 5H) , 7,19-7,10 (m,
4H) , 6.24 (s, IH) , 5.40 (s, IH) , 3.84-3.75 (m, 8H) , 3.56
(s, 2H) , 2.54-2.43 (m, 8H) , 2.32 (s, 3H) ; ESI-MS m/z:
15 457 (MH+) .
Example 185: AT4, AT4 -dimethyl -AT6- ( 2 -propy lphenyl) -2- [4-
(2-pyridinyl) -1 -piperazinyl] -4, 6-pyrimidinediamine: Prepared by Procedures A (Ch2cl2, Tea, 3 - 4 H at -78 °C,
20. then 3 - 4 H at 0 °C) , N, and O. XE NMR (400 MHz, CDCl3) δ 8.22 - 8.18 (m, IH) , 7.56 - 7.40 ( , 2H) , 7.25 - 7.07 (m, 3H) , 6.75 - 6.60 (m, 2H) , 6.04 (s, IH) , 5.04 (s, IH) , 3.91 (m, 4H) , 3.62 (m, 4H) , 2.96 ( s., . 6H) , 2.60 (t, 2H, J = 7.5) , 1.62 (m, 2H) , 0.96 (t, 3H, J = 8.8) ; ESI-
25 MS M/Z: 418 (MH+) .
Example 186: AT4- (2-BENZYLPHENYL) -AT5, AT6-DIMETHYL-2- [4- (2- PYRIDINYL) -1-PIPERAZINYL] -4 , 6-PYRIMIDINEDIAMINE : Prepared by Procedures A (CH2CL2, TEA, 3 - 4 H at -78 °C, then 3 - 30 4 H at 0 °C) , N, AND 0. XH NMR (400 MHZ, CDCL3) δ 8.20 - 8.18 (M, IH) , 7.54 - 7.45 (M, IH) , 7.34 - 7.04' (M, 9H) , 6.73 - 6.59 (M, 2H) , 5.99 (BR S, IH) , 5.01' (S, IH) , 3.99 (S, 2H) , 3.93 - 3.83 (M, 4H) , 3.66 - 3.57 (M, 4H) , 2.96 (S, 6H) ; ESI-MS M/Z: 66 (MH+) .
Example 187: AT4- (4-HEXYLPHENYL) -AT6, AT6-DIMETHYL-2- [4- (2- PYRIDINYL) -1-PIPERAZINYL] -4, 6-PYRIMIDINEDIAMINE: Prepared by Procedures A (CH2C12, TEA, 3 - 4 h at -78 °C, then 3 - 4 h at 0 °C) , N, and 0. ESI-MS m/z 460 (MH+) .
Example 188: AT4- (4-BENZYLPHENYL) -AT6, AT6-DIMETHYL-2- [4- (2- PYRIDINYL) -1-PIPERAZINYL] -4, 6-PYRIMIDINEDIAMINE: Prepared by Procedures A (CH2Cl2, TEA, 3 - 4 h at -78 °C, then 3 - 4 h at 0 °C) , N, and 0. XE NMR (400 MHz, CDC13) δ 8.22 - 8.18 (m, IH) , 7.52 - 7.45 (m, IH) , 7.32 - 7.09 (m, 9H)' , 6.78 (d, IH, J = 9.2), 6.65 - 6.59' (m, IH) , 6.24 (br ε, IH) , 5.29 is, IH) , 3.96 (s, 2H) , 3.91 - 3.83 (m, 4-H) , 3.63 - 3.55 (m, 4H) , 3.00 (s, 6H) ; ESI-MS m/z: 466 (MH+) .
Example 189: AT4- (4-HEPTYLPHENYL) -AT5, AT6-DIMETHYL-2- [4- (2- PYRIDINYL) -1-PIPERAZINYL] -4, 6-PYRIMIDINEDIAMINE: Prepared by Procedures A (CH2Cl2, TEA, 3 - 4 h at -78 °C, then 3 - 4 h at 0 °C) , N, and 0. XE NMR .(400 MHz, CDC13) δ 8.25 - 8.18 (m, IH) , 7.57 - 7.44 (m, IH) , 7.38 - 7.08 (m, 4H) , 6.75 - 6.57 (m, 2H) , 6.26 (br s, IH) , 5.29 (s, IH) , 3.95 - 3.85 (m, 4H) , 3.71 - 3.56 (m, 4H) , 3.00 (s, 6H) , 2.57 (t, 2H, J = 5.2), 1.84 - 1.51 (m, 4H) , 1.40 - 1.16 (m, 6H) , 0.93 - 0.82 ( , 3H) ; ESI-MS m/z: 474 (MH+) . Example 190: IV4- (3 , 4-DIMETHYLPHENYL) -N6 , AT6-DIMETHYL-2- [4- (2-PYRIDINYL) -1-PIPERAZINYL] -4 , 6-PYRIMIDINEDIAMINE: Prepared by Procedures A (CH2C12, TEA, 3 - 4 h at -78 °C, then 3 - 4 h at 0 °C) , N, and 0. XE NMR (400 MHz, CDCl3) δ 8.25 - 8.19 (m, IH) , 7.55 - 7.44 ( , IH) , 7.31 - 7.23 ( , IH) , 7.14 - 7.02 (m, 2H) , 6.73 - 6.59 ( , 2H) , 6.18 (br s, IH) , 5.29 (s, IH) , 3.95 - 3.85 ( , 4H) , 3.67 - 3.55 ( , 4H) , 3.00 (s, 6H) , 2.24 (s, 3H) , 2.23 (s,' 3H), ESI-MS m/z : 404 (MH+) .
Example 191: AT4- (3-ISOPROPYLPHENYL) -AT6 , IV6-DIMETHYL-2- [4- (2-PYRIDINYL) -1-PIPERAZINYL] -4, 6-PYRIMIDINEDIAMINE:
Prepared by Procedures A (CH2C12, TEA, 3 - 4 h at -78 °C, then 3 - 4 h at 0 °C) , N, and O. XE NMR (400 MHz, CDCl3) 8 8.25 - 8.19 ( , IH) , 7.54 - 7.45 (m, IH) , 7.31 - 7.21 ( , 2H) , 7.13 - 7.08 (m, IH) , 6.95 - 6.88 ( , IH) , 6.74 - 6.60 ( , 2H) , 6.29 (br s, IH) , 5.37 - 5.34 (m, IH) , 3.96 - 3.87 (m, 4H) , 3.68 - 3.57 (m, 4H) , 3.00 (s, 6H) , 2.95 - 2.85 (m, IH) , 1.36 - 1.19 ( , 6H) ; ESI-MS m/z : 418 (MH+) .
Example 192 : AT4 , AT -DIMETHYL-AT6- ( 4-OCTYLPHENYL) -2- [4- (2- 'PYRIDINYL) -1-PIPERAZINYL] -4, 6-PYRIMIDINEDIAMINE: Prepared by Procedures A (CH2C12, TEA, 3 - 4 h at -78 °C, then 3 - 4 h at 0 °C) , N, and O. XE NMR (400 MHz, CDC13) δ 8.22 (s, IH) , 7.55 - 7.44 (m, IH) , 7.37 - 7.07 (m, 4H) , 6.76 - 6.59 (m, 2H) , 6.28 (br s, IH) , 5.29 (s, IH) , 3.96 - 3.86 ( , 4H) , 3.69 - 3.56 (m, ' 4H) , 3.00 (s, 6H) , 2.57 (t, 2H, J = 5.1) , 1.74 - 1.51 (m, 4H) , 1.41 - 1.08 (m, 8H) , 0.93 - 0.82 (m, 3H) ; ESI-MS m/z 488 (MH*) .
Example 193: AT4- (3 -IODOPHENYL) -AT6, ?6-DIMETHYL-2- [4- (2- PYRIDINYL) -1-PIPERAZINYL] -4, 6-PYRIMIDINEDIAMINE: Prepared by Procedures A (CH2Cl2, TEA, 3 - 4 h at -78 °C, then 3 - 4 h at 0 °C) , N, and 0. XE NMR (400 MHz, CDCl3) 8 8.29 - 8.18 (m, IH) , 8.01 - 7.93 ( , IH) , 7.56 - 7.45 ( , IH) , 7.39 - 7.29 (m, IH) , 7.11 - 6.95 (m, 2H) , 6.78 - 6.56) ( , 2H) , 6.42 - 6.25 (m, IH) , 5.34 (s, IH) , 3.95 - 3.85 (m, 4H) , 3.65 - 3.56 (m, 4H) , 3.00 (s, 6H) ; ESI-MS m/z: 502 (røT) .
Example 194: AT4- (4-CHLOROPHENYL) -AT6, AT5-DIMETHYL-2- [4- (2- PYRIDINYL) -1-PIPERAZINYL] -4 , 6-PYRIMIDINEDIAMINE : Prepared by Procedures A (CH2Cl2, TEA, 3 - 4 h at -78 °C, then 3 - 4 h at 0 °C) , N, and O. XE NMR (400 MHz, CDC13) δ 8.28 (s, IH) , 7.53 - 7.42 (m, IH) , 7.35 - 7.24 ( , 2H) , 7.11 - 6.95 (m, 2H) , 6.76 - 6.57 (m, 2H) , 6.21 (s, IH) , 5.29 (s, IH) , 3.97 - 3.86 (m, 4H) , 3.67 - 3.57 ( , 4H) , 3.00 (s, 6H) ; ESI-MS m/z 410 (MH+) .
Example 195: AT5- (2-CHLOROPHENYL) -AT4, 4-DIMETHYL-2- [4- (2- PYRIDINYL) -1-PIPERAZINYL] -4 , 5-PYRIMIDINEDIAMINE : Prepared by Procedures A (CH2Cl2, TEA, 3 - 4 h at -78 °C, then 3 - 4 h at 0 °C) , N, and O. XE NMR (400 MHz, CDCl3) δ 8.50 - 8.10 (m, 2H) , 7.55 - 7.12 (m, 4H) , 7.05 - 6.90 ( , 2H) , 6.61 (s, IH) , 5.31 (s, IH) , 3.95-3.85 (m, 4H) , 3.65 - 3.54 (m, 4H) , 3.00 (s, 6H) ; ESI-MS m/z: 410 (MH+) . Example 196: AJ4- (3 , 4-DIFLUOROPHENYL) -AT6, AT6-DIMETHYL-2- [4- (2 -PYRIDINYL) -1-PIPERAZINYL] -4, 6-PYRIMIDINEDIAMINE:
Prepared by Procedures A (CH2C12, TEA, 3 - 4 h at -78 °C, then 3 - 4 h at 0 °C) , N, and O. 1H NMR (400 MHz, CDCl3) δ 8.31 (s, IH) , 7.59 - 6.95 (m, 4H) , 6.68 - 6.54 (m, 2H) , 6.29 (s, IH) , 5.27 (s, IH) , 3.94 - 3.82 (m, 4H) , 3.63 - 3.51 (m, 4H) , 3.01 (s, 6H) ; ESI-MS m/z : 412 (MH+) .
Example 197: AT4- [3-METHOXY-5- (TRIFLUOROMETHYL) PHENYL] - AT6,AJ5-DIMETHYL-2- [4- (2-PYRIDINYL) -1-PIPERAZINYL] -4 , 6- PYRIMIDINEDIAMINE : Prepared by Procedures A (CH2C12, TEA, 3 - 4 h at -78 °C, then 3 - 4 h at 0 °C) , N, and O. XE NMR (400 MHz, CDCl3) δ 8.26 - 8.18 (m, IH) , 7.58 - 7.11 (m, 3H) , 6.77 - 6.38 (m, 3H) , 6.34 (s, IH) , 5.25 (s, IH) , 3.96 - 3.88 (m, 4H) , 3.85 (s, 3H) , 3.69 - 3.55 (m, 4H) , 3.00 (s, 6H) ; ESI-MS m/z : 474 (MH+) .
Example 198: AT4, AT -DIMETHYL-2- [4- (2-PYRIDINYL) -1- PIPERAZINYLJ-IV6- (2,3, 4-TRIFLUOROPHENYL) -4,6-
PYRIMIDINEDIAMINE : Prepared by Procedures A (CH2C12, TEA, 3 - 4 h at -78 °C,' then 3 - 4 h at 0 °C) , N, and O. XH NMR (400 MHz, CDCl3) δ 8.26 - 8.18 (m, IH) , 7.58 - 7.11 (m, 3H) , 6.77 - 6.38 (m, 2H) , 6.34 (s, IH) , 5.25 (s, ' IH) , 3.96 - 3.88 (m, 4H) , 3.85 (s, 3H) , 3.69 - 3.55 (m, 4H) , 3.00 (s, 6H) ; ESI-MS m/z 430 (MH+) . Example 199: AT4- (4-BROMO-2-FLUOROPHENYL) -AT6 , AT5-DIMETHYL- 2- [4- (2 -PYRIDINYL) -1-PIPERAZINYL] -4 , 6-PYRIMIDINEDIAMINE: Prepared by Procedures A (CH2C12, TEA, 3 - 4 h at -78 °C, then 3 - 4 h at 0 °C) , N, and O. XE NMR (400 MHz, CDCl3) 8 8.27 - 8.17 (m, IH) , 7.61 - 7.01 (m, 4H.) , 6.75 - 6.57 ( , 2H) , 6.34 (br s, IH) , 5.23 (s, IH) , 3.95 - 3.85 ( , 4H) , 3.68 - 3.59 (m, 4H) , 3.00 (s, 6H) ; ESI-MS m/z : 472 (MH+) .
Example 200: AT4- (4-FLUORO-3-METHYLPHENYL) -AT6, A^-DIMETHYL- 2- [4- (2-PYRIDINYL) -1-PIPERAZINYL] -4, 6-PYRIMIDINEDIAMINE: Prepared by Procedures A (CH2C12, TEA, 3 - 4 h at -78 °C, then 3 - 4 h at 0 °C) , N, and O. E NMR (400 MHz, CDC13) δ 8'.27 - 8.17 (m, IH) , 7.56 - 7.47 (m, IH) , 7.21 - 6.89 (m, 3H) , 6.75 - 6.58 (m, 2H) , 6.24 (br s, IH) , 5.18 (s, IH) , 3.95 - 3.84 (m, 4H) , 3.69 - 3.55 (m, 4H) , 3.00 (s, 6H) , 2.25 (s, 3H) ; ESI-MS m/z : 408 (MH+) .
Example 201: AT4- (2 , 5-DIMETHOXYPHENYL) -AT6 , AT5-DIMETHYL-2- [4- (2-PYRIDINYL) -1-PIPERAZINYL] -4, 6-PYRIMIDINEDIAMINE:
Prepared by Procedures A (CH2C12, TEA, 3 - 4 h at -78 °C, then 3 - 4 h at 0 °C) , N, and O. XE NMR (400 MHz, CDC13) δ 8.27 - 8.16 (m, IH) , 7.96 - 7.86 ( , IH) , 7.56 - 7.43 (m, IH) , 6.93 - 6.42 (m, 5H) , 5.31 (s, IH) , 4.01 - 3.90 ( , 4H) , 3.84 (s, 3H) , 3.79 (s, 3H) , 3.70 - 3.54 ( , 4H) , 3.04(s, 6H) ; ESI-MS m/z : 436 (MH+) . Example 202: AT4- (3 , 5-DIMETH0XYPHENYL) -A?6, AT6-DIMETHYL-2- [4- (2-PYRIDINYL) -1-PIPERAZINYL] -4 , 6-PYRIMIDINEDIAMINE :
Prepared by Procedures A (CH2Cl2, TEA, 3 - 4 h at -78 °C, then 3 - 4 h at 0 °C) , N, and 0. XE NMR (400 MHz, CDCl3) δ' 8.26 - 8.17 ( , IH) , 7.55 - 7.44 (m, IH) , 6.73 - 6.58 (m, 2H) , 6.59 - 6.53 (m, 2H) , 6.23 (br s, IH) 5.37 (s, IH) , 3.98 - 3.88 (m, 4H) , 3.77' (s, 6H) , 3.62 - 3.58 (m, 4H) , 3.01 (s, 6H) ; ESI-MS m/z : 436 (MH+).
Example 203: AT4- [3- (BENZYLOXY) PHENYL] -2- [4- (3-
BROMOPHENYL) -1-PIPERAZINYL] -AT6, AT6-DIMETHYL-4* 6- PYRIMIDINEDIAMINE : Prepared by Procedures A (CH2Cl2, TEA, 3 - 4 h at -78 °C, then 3 - 4 h at 0 °C) , N (TEA), and O. 1H NMR (400 MHz, CDC13) δ 7.55 - 6.26 (m, 14H) , 5.29 (s, IH) , 5.06 (s, 2H) , 3.97 - 3.82 (m, 4H) , 3.21 - 3.14 (m, 4H) , 3.01 (s, 6H) ; ESI-MS m/z : 560 (MH+) .
Example 204: A/4- (2-BROMO-4-METHYLPHENYL) -AT6, A^-DIMETHYL- 2- [4- (2-PYRIDINYL) -1-PIPERAZINYL] -4, 6-PYRIMIDINEDIAMINE: Prepared by Procedures A (CH2Cl->, TEA, 3 - 4 h at -78 °C, then 3 '- 4 h at 0 °C),'-N, and O. XE NMR (400 MHz, CDC13) δ 8.26 - 8.16 (m, IH) , 7.81 (d, IH, J = 8.8), 7.52 - 7.44 (m, IH) , 7.38 (d, IH, J = 8.5), 7.08 (d, IH, J = 8.5), 6.72 (m, 2H) , 6.47 (br s, IH) , 5.24 (s, IH) , 3.90 (t, 4H, J = 6.3),- 3.61 (t, 4H, J = 6.4), 3.01 (s, 6H) , '2.28 (s, 3H) ; ESI-MS m/z 468 (MH+) . ! 00
Example 205: AT4- (2 , 4 -DICHLOROPHENYL) -IV6, AT6-DIMETHYL-2- [4- (2 -PYRIDINYL) -1-PIPERAZINYL] -4, 6-PYRIMIDINEDIAMINE: Prepared by Procedures A (CH2Cl2, TEA, 3 - 4 h at -78 °C, then 3 - 4 h at 0 °C) , N, and 0. XH NMR (400 MHz, CDCl3) δ 8.25 - 8.17 ( , IH) , 8.21 (d, IH, J = 9.2), 7.49 (t, IH, J = 9.0), 7.38 - 7.16 ( , 2H) , 6.71 - 6.59 ( , 2H) , 6.57 (br s, IH) , 5.25 (s, IH) , 3.93 - 3.85 (m, 4H) , 3.65 - 3.55 ( , 4H) , 3.03 (s, 6H) ; ESI-MS m/z : 444 (MHT) . '
Example- 206: AT4- (3 -FLUOROPHENYL) -AT6, AJ6-DIMETHYL-2- [4- (2- PYRIDINYL) -1-PIPERAZINYL] -4, 6-PYRIMIDINEDIAMINE: Prepared by Procedures A (CH2C12, TEA, 3 - 4 h at -78 °C , then 3 - 4 h at 0 °C) , N, and O. XE NMR (400 MHz, CDC13) δ 8.25 - 6.39' (m,' 9H), 5.30 (s, IH) , 3.97 - 3.85 (m, 4H) , 3.74 - 3.58 (m, 4H) , 3.01 (s, 6H) ; ESI-MS m/z : 394 (MH+) .
Example 207: AT4, AT4-DIMETHYL-2- [4- (2-PYRIDINYL) -1-
PIPERAZINYL] -AT6- [3- (TRIFLUOROMETHOXY) PHENYL] -4,6- PYRIMIDINEDIAMINE : Prepared by Procedures A (CH2C12, TEA, 3 - 4 h at -78 °C, then 3 - 4 h at 0' °C) , N, and O. ESI- MS m/z : 460 (MH") .
Example .208: AT4- (2, 5-DICHLOROPHENYL) -AT5, A^-DIMETHYL-Σ- [4- (2-PYRIDINYL) -1-PIPERAZINYL] -4, 6-PYRIMIDINEDIAMINE
Prepared by Procedures A (CH2C12, TEA, 3 - 4 h at -78 °C, then 3 - 4 h at 0 °C) , N, and O. ESI-MS m/z : 445 (MH+) . Example 209: AT4, AT -DIMETHYL-AT6- (4-PROPYLPHENYL) -2- [4- (2- PYRIDINYL) -1-PIPERAZINYL] -4, 6-PYRIMIDINEDIAMINE : Prepared by Procedures A (CH2C12, TEA, 3 - 4 h at -78 °C, then 3 - 4 h at 0 °C) , N, and O. ESI-MS m/z : 418 (MH") .
Example 210: AT4, AT4-DIMETHYL-AT6- (4-PENTYLPHENYL) -2- [4- (2- PYRIDINYL) -1-PIPERAZINYL] -4 , 6-PYRIMIDINEDIAMINE : Prepared by Procedures A (CH2C12, TEA, 3 - 4 h at -78 °C, then 3 - 4 h at 0 °C) , N, and O. ESI-MS m/z : 446 (MH+) .
Example 211: IV4- (4-≤ΕC-BUTYLPHENYL) -AT6 , AT6-DIMETHYL-2- [ 4- (2-PYRIDINYL) -1-PIPERAZINYL] -4, 6-PYRIMIDINEDIAMINE:
Prepared by Procedures A (CH2C12, TEA, 3 - 4 h at -78 °C, then 3 - 4 h at 0 °C) , N, and O. ESI-MS m/z : 432 (MH+) .
Example 212: A4- (2-ygJc-T-BUTYLPHENYL) -AT5 , AT6-DIMETHYL-2- [4- (2-PYRIDINYL) -1-PIPERAZINYL] -4, 6-PYRIMIDINEDIAMINE
Prepared by Procedures A (CH2C12, TEA, 3 -' '4 h at -78 °C, then 3 - 4 h at 0 °C) , N, and O. ESI-MS m/z : '432 (MH+) .
Example 213: if - { 2 , 5-DIMETHYLPHENYL) -AT6, A^-DIMETHYL-Σ- [4- (2-PYRIDINYL) -1-PIPERAZINYL] -4, 6-PYRIMIDINEDIAMINE:
Prepared by Procedures A (CH2C12, TEA, 3 - 4 h at -78 °C, then 3 - 4 h at 0 °C) , N, and O. ESI-MS m/z : 404 (MH+) . Example 214: AT4- ( 3 , 5-DIMETHYLPHENYL) -AT6 , AT6-DIMETHYL-2- [ 4- (2-PYRIDINYL) -1-PIPERAZINYL] -4 , 6-PYRIMIDINEDIAMINE:
Prepared by Procedures A (CH2C12, TEA, 3 - 4 h at -78 °C, then 3 - 4 h at 0 °C) , N, and 0. ESI-MS m/z : 404 (MHT) .
Example 215: AT4- (2 , 3-DIMETHYLPHENYL) -N6 , AT6-DIMETHYL-2- [4- (2-PYRIDINYL) -1-PIPERAZINYL] -4, 6-PYRIMIDINEDIAMINE:
Prepared by Procedures A (CH2C12, TEA, 3 - 4 h at -78 °C, then 3 - 4 h at 0 °C) , N, and O. ESI-MS m/z 404 (MH+) .
Example 216: AT4- (3-BENZYLPHENYL) -AT6 ,1V5-DIMETHYL-2- [4- (2- PYRIDINYL) -1-PIPERAZINYL] -4, 6-PYRIMIDINEDIAMINE: Prepared by Procedures A (CH2C12, TEA, 3 - 4 h at -78 °C, then 3 - 4 h at 0 °C) , N, and O. ESI-MS m/z : 466 (MH+) .
Example 217 : AT4- (4-BROMO-2-CHLOROPHENYL) -AT6, AT6-DIMETHYL- 2- [4- (2-PYRIDINYL) -1-PIPERAZINYL] -4 , 6-PYRIMIDINEDIAMINE : Prepared by Procedures A (CH2C12, TEA, 3 - 4 h at -78 °C, then 3 - 4 h at 0 °C) , N, and O. ESI-MS m/z 489 (MH+) .
Example 218: AT4- (2 , 3-DICHLOROPHENYL) -AT6, AT6-DIMETHYL-2- [4- (2-PYRIDINYL) -1-PIPERAZINYL] -4, 6-PYRIMIDINEDIAMINE:
Prepared by Procedures A (CHC12, TEA, 3 - 4 h at -78 °C, then 3 - 4 h at 0 °C) , N, and O. ESI-MS m/z : 445 (MH+) . Example 219: AT4, AT-DIMETHYL-2- [4- (2-PYRIDINYL) -1-
PIPERAZINYL]-A76-(2, 4 , 5-TRIFLUQROPHENYL) -4, 6- PYRIM-IDINEDIAMINE : Prepared by Procedures A (CH2Cl2, TEA, 3 - 4 h at -78 °C, then 3 - 4 h at 0 °C) , N, and O. ESI-MS m/z : 430 (MH+) .
Example 22_0: AT4- (5-CHLORO-2-METHOXYPHENYL) -AT6, A76-
DIMETHYL-2- [4- (2-PYRIDINYL) -1-PIPERAZINYL] -4, 6- PYRIMIDINEDIAMINE : Prepared by Procedures A (CH2Cl2,' TEA, 3 - 4 h at -78 °C, then 3 - 4 h at 0 °C) , N, and O. ESI-MS m/z : 440 (MH+) .
Example 221: AT4 , AT4-DIMETHYL-2- [4- (2 -PYRIDINYL ).-l-
PIPERAZINYL] -AT5- ( 3 , 4 , 5-TRIFLUOROPHENYL) -4,6- PYRIMIDINEDIAMINE : Prepared by Procedures A (CH2Cl2, TEA, 3 - 4 h at -78 °C, then 3 - 4 h at 0 °C) , N, and O. ESI- MS m/z : 430 (MH+) .
Example 222 : AT4- (2-CHLORO-5-FLUOROPHENYL) -AT6 , AT6-DIMETHYL- 2- [4- (2-PYRIDINYL) -1-PIPERAZINYL] -4, 6-PYRIMIDINEDIAMINE: Prepared by Procedures A (CH2C12, TEA, 3 - 4 h at -78 °C, then 3 - 4 h at 0 °C) , N, and O. ESI-MS m/z : 428 (MH+) .
Example 223 : AT4- (2-CHLORO-4-METHYLPHENYL) -AT6 , AT6-DIMETHYL- 2- [4- (2-PYRIDINYL) -1-PIPERAZINYL] -4 , 6-PYRIMIDINEDIAMINE : Prepared by Procedures A (CH2C12, TEA, 3 - 4 h at -78 °C, then 3 - 4 h at 0 °C) , N, and 0. ESI-MS m/z : 424 (MH+) .
Example 224: AT4- (3-CHLOROPHENYL) -AT6, iV6-DIMETHYL-2- [4- (2- PYRIDINYL) -1-PIPERAZINYL] -4 , 6-PYRIMIDINEDIAMINE :
Prepared by Procedures A (CH2Cl2, TEA, 3 - 4 h at -78 °C, then 3 - 4 h at 0 °C) , N, and O. ESI-MS m/z : 410 (MH*) .
Example 225: 2- (4-BENZYL-l-PIPERAZINYL) -AT- [3-METHOXY-5- (TRIFLUOROMETHYL) PHENYL] -AT6, AT6-DIMETHYL-4, 6-
PYRIMIDINEDIAMINE : Prepared by Procedures O" (toluene, 75 °C) , Q (toluene, 120 °C) , and A. ESI-MS m/z : 487 (MH+) .
Example 226: 2- (4-BENZYL-l-PIPERAZINYL) -AT- [2-METHOXY-5- (TRIFLUOROMETHYL) PHENYL] -AT6 , AT6-DIMETHYL-4 , 6-
PYRIMIDINΞDIAMINE : Prepared by Procedures O, Q (dioxane, 120 °C) , and A. ESI-MS m/z 487 (MH+) .
Example 227 : 2- (4-BENZYL-l-PIPERAZINYL) -AT4- (2 , 5- DIMETHOXYPHENYL) -AT6 , AT6-DIMETHYL-4 , 6-PYRIMIDINEDIAMINE :
Prepared by Procedures O, Q (dioxane, 120 °C) , and A. ESI-MS m/z : 449 (MH+) .
Example 228: AT4- [3- (BENZYLOXY) PHENYL] -2- (4-BENZYL-l- PIPERAZINYL) -IVs, A76-DIMETHYL-4 , 6-PYRIMIDINEDIAMINE: Prepared by Procedures 0, Q (toluene, 120 °C) , and A. ESI-MS m/z : 495 (MH+) .
Example 229: 2- (4-BENZYL-l-PIPERAZINYL) -AT4, 4-DIMETHYL- AT6- [4- (TRIFLUOROMETHYL) PHENYL] -4 , 6-PYRIMIDINEDIAMINE :
Prepared by Procedures P (toluene, 105 °C) , Q (toluene, 120 °C) , and A. ESI-MS m/z 457 (MH+) .
Example 230: 2- (4-BENZYL-l-PIPERAZINYL) -AT4, AT -DIMETHYL- AT6- (2 , 3 , -TRICHLOROPHENYL) -4, 6-PYRIMIDINEDIAMINE: Prepared by Procedures O (60 °C) , Q (toluene, 120 °C) , and A. ESI-MS m/z : 492 (MH") .
Example 231: 2- [4- (2-FURYLMETHYL) -1-PIPERAZINYL] -A AT4- DIMETHYL-AT6- (4-METHYLPHENYL) -4, 6-PYRIMIDINEDIAMINE: Prepared by Procedures R (16 h) , P (sodium tert- butoxide, toluene, 120 °C) , N (TEA, toluene reflux) , and A. ESI-MS m/z : 393 (MH+) .
Example 23_2-' AT2- [2- (4-METHOXYPHENYL) ETHYL] -AT4 , AT - DIMETHYL-AT6- (4-METHYLPHENYL) -2 , 4 , 6-PYRIMIDINETRIAMINE :
Prepared by Procedures V, R, and S (DIEA, DMAP) . ESI-MS m/z: 378 (MH+) .
Example 233: AT4- (3-METHOXYPHENYL) -AT6 , AT6-DIMETHYL-2- [ 4- (TETRAHYDRO-2-FURANYLMETHYL) -1-PIPERAZINYL] -4,6-
PYRIMIDINEDIAMINE : Prepared by Procedures A, P (16 h) , and Q (dioxane, 120 °C) . ESI-MS m/z : 413 (MH*) . Example 235: 2- [4- (4-METHQXYBENZYL) -1-PIPERAZINYL] - AT- DIMBTHYL-AJ5- (4-METHYLPHENYL) -4 , 6-PYRIMIDINEDIAMINE: Prepared by Procedure Z. ESI-MS m/z .- 433 (MH*) .
Example 237: A74, AT -DIMETHYL-AT6- (4-METHYLPHENYL) -AT2- [2- (2- THIENYL) ETHYL] -2,4, 6-PYRIMIDINETRIAMINE : Prepared by Procedures R, S, and V. ESI-MS m/z: 354 (MH+) .
Example 238: AT4, A^-DIMETHYL-AT5- (4-METHYLPHENYL) -2- [4- (3- THIENYLMETHYL) -1-PIPERAZINYL] -4, 6-PYRIMIDINEDIAMINE: Prepared by Procedures AA, T (2 h) , and W. ESI-MS m/z : 409 (MH+) .
Example 239: 2- (4-BENZYL-l-PIPERAZINYL) -IV4- [4-CHLORO-2- (TRIFLUOROMETHYL) PHENYL] -AT6 , AT5-DIMETHYL-4 , 6- PYRIMIDINEDIAMINE : Prepared by Procedures O (100 °C, 40 h) , Q (toluene, 120 °C) , and A. ESI-MS m/z : 491 (MH") .
Example 240: AT4- (3 -BROMO-4-METHYLPHENYL) -Af/A^-DIMETHYL- 2- [4- (2-PYRIDINYL) -1-PIPERAZINYL] -4 , 6-PYRIMIDINEDIAMINE: Prepared by Procedures O (80 °C) , Q (toluene, 120 °C) , and A. ESI-MS m/z : 469 (MH+) .
Example 241; 2- {4- [4- (DIMETHYLAMINO) -6- (4-TQLUIDINO) -2- PYRIMIDINYL]-1-PIPERAZINYL}NICOTINONITRILE: Prepared by Procedures 0, Q (tyoluene, 120 °C) , and A. ESI-MS m/z 415 (MH+) .
Example 242: AT4, A^-DIMETHYL-AT5- [4-METHYL-3- (2- PYRIDINYLAMINO) PHENYL] -2- [4- (2-PYRIDINYL) -1-
PIPERAZINYL] -4 , 6-PYRIMIDINEDIAMINE : Prepared by Procedures P (toluene) , Q (toluene, 120 °C) , and A. ESI- MS m/z : 482 (MH+) .
Example 243: ≠- (3 -BROMOPHENYL) -AT6, AT6-DIMETHYL-2- ['4- (2-
PYRIDINYL) -1-PIPERAZINYL] -4 , 6-PYRIMIDINEDIAMINE : Prepared by Procedures O (85 °C) , Q (toluene, 120 °C) , and A. ESI-MS /z : 455 (MH") .
Example 244: 2- (4-BENZYL-l-PIPERAZINYL) -AT- [2-CHLORO-4- (TRIFLUOROMETHYL) PHENYL] -AT6 , AT6-DIMETHYL-4 , 6- PYRIMIDINEDIAMINE : Prepared by Procedures P (16 h, toluene), Q (toluene, 120 °C) , and A. ESI-MS m/z : 491 (MH+) .
Example 245: AT4- (3-METHOXYPHENYL) -AT6, AT6-DIMETHYL-2- [4-(2- PYRIDINYL) -1-PIPERAZINYL] -4, 6-PYRIMIDINEDIAMINE: Prepared by Procedures A, N, and P. ESI-MS m/z : 406 (MH+) .
Example 246: AT4- (3-METHOXYPHENYL) -AT6, A^-DIMETHYL-Σ- (4- [2- (TRIFLUOROMETHYL) PHENYL] -1-PIPERAZINYL} -4 , 6- PYRIMIDINEDIAMINE : Prepared by Procedures A, N, and P. ESI-MS m/z 473 (MH+) .
Example 247: AT4- (3-METHOXYPHENYL) -AT6, AT6-DIMETHYL-AT2- (2- PHENYLETHYL) -2,4, 6-PYRIMIDINETRIAMINE : Prepared by Procedures A, N, and P. ESI-MS m/z : 364 (MH+) .
Example 248: AT2 , AT4, AT4-TRIMETHYL-IV5- (4- METHYLPHENYL).-AT2- (2- PHENYLETHYL) -2,4, 6-PYRIMIDINETRIAMINE : Prepared by Procedures A, N, and P. ESI-MS m/z : 362 (MH+) .
Example 249: N- (4-METHYLPHENYL) -2- (4- [l-OXIDO-3-
(TRIFLUOROMETHYL) -2-PYRIDINYL] -1-PIPERAZINYL} -6- ( 1- PIPERIDINYL) -4-PYRIMIDINAMINE : Prepared by Procedure CC . ESI-MS m/z : 514 (MH+) .
Example 250: AT4, AT4-DIMETHYL-A?6- (4-METHYLPHENYL) -AT2- (2- PHENYLETHYL) -2,4, 6-PYRIMIDINETRIAMINE : Prepared by Procedures R and S. ESI-MS m/z : 348 (MH+) .
Example 251: AT4- (3-METHOXYPHENYL) -AT2, A/6, AT6-TRIMETHYL-AT2- (2-PHENYLETHYL) -2,4, 6-PYRIMIDINETRIAMINE : : Prepared by Procedures A, N, and P. ESI-MS m/∑ : 378 (MHT) .
Example ' 252: 2- (4-BENZYL-l-PIPERAZINYL) -AT4- (3- METHOXYPHENYL) -AT6 , AT6-DIMETHYL-4 , 6-PYRIMIDINEDIAMINE : Prepared by Procedures A, N, and P. ESI-MS m/z : 419 (MH+) .
Example 253: 2- (4-BENZYL-l-PIPERAZINYL) -AT4, AT4-DIMETHYL- AT6- (4-METHYLPHENYL) -4 , 6-PYRIMIDINEDIAMINE : Prepared by Procedures A, N, and P. ESI-MS m/z: 403 (MHT) .
Examples 1-90 and 115-253 as described above are merely illustrative of the methods used to synthesize pyrimidine derivatives. Further derivatives may be obtained utilizing methods shown in Schemes l-5b.-' The substituents in Schemes l-5b are described in the Detailed Description.
It may be necessary to incorporate protection and deprotection strategies for substituents such as amino, amido, carboxylic acid, and hydroxyl groups in the synthetic methods described above to form pyrimidine derivatives. Methods for protection and deprotection of such groups are well-known in the art, and may be found, for example in Green, T. W. and Wuts , P.G. M. (1991) Protection Groups in Organic Synthesis, 2nd Edition John Wiley & Sons, New York.
Scheme 1. Synthesis of Substituted Triaminopyrimidines
Figure imgf000211_0001
X =leaving group such halogen OTf or OTs
Scheme 2. Alternate Synthesis of Substituted Triaminopyrimidines
Figure imgf000212_0001
X =leaving group such halogen OTf or OTs
Scheme 3 . Alternate Synthesis of Substituted Tri-uninopyrimidines
Figure imgf000213_0001
X =leaving group such halogen CTf or OTs
Alternatively,
Figure imgf000213_0002
Scheme 4. Synthesis of Morpholine Intermediates
Figure imgf000214_0001
LiAlH,
Figure imgf000214_0002
Scheme 5. Synthesis of N-Alkylamine Intermediates
O
EtOCHO LiAlH,
RNH, RNH CR RNHCH2R or RC0C1
Scheme 5a. Synthesis of Triaminopyrimidines from 2-Amidopyrimidines
Figure imgf000215_0001
RCOCl LiAlH,
Figure imgf000215_0002
Figure imgf000215_0003
Scheme 5b. substitution on the Piperazine Moiety of 2- (Piperazin-l-yl)pyrimidines
Figure imgf000216_0001
LiAlH,
Figure imgf000216_0002
Figure imgf000216_0003
X is a leaving group such as a halogen or -tosylate; HATU is 0-(7- azabenzenzotriazol-1-yl) -N,N,N' ,N' -tetramethyluroniuin hexafluoro- phosphate; dba is dibenzylideneacecone; BINAP is 2 , 2 ' -bis (diphen- ylphosphino) -1 , 1 ' -binaphthyl . Radioligand Binding of Pyrimidines at Cloned Galanin Receptors
The binding properties of the pyrimidines of the present invention were evaluated at the cloned human galanin receptors, GALl, GAL2 , and GAL3 , using protocols described herein.
Radioligand Binding Assay Results
The pyrimidines described in Examples 1-90 and 115-253 were assayed using cloned human galanin receptors. The compounds were found to be selective for the GAL3 receptor. The binding affinities of the compounds of Examples 1-90 and 115-253 are illustrated -in Tables' 1- 3a.
TABLE 1
Figure imgf000218_0001
Figure imgf000218_0002
Table 1 continued
Figure imgf000219_0001
Figure imgf000219_0002
Table 1 - continued
Figure imgf000220_0001
Figure imgf000220_0002
Table 1 continued
Figure imgf000221_0001
Figure imgf000221_0002
Table 1 continued
Figure imgf000222_0001
Figure imgf000222_0002
Table 1 continued
Figure imgf000223_0001
Figure imgf000223_0002
TABLE 2
Figure imgf000224_0001
Figure imgf000224_0002
Table 2 continued
Figure imgf000225_0001
Figure imgf000225_0002
Table 2 continued
Figure imgf000226_0001
Figure imgf000226_0002
Table 2 continued
Figure imgf000227_0001
Figure imgf000227_0002
Key: Ph = Phenyl TABLE 3
R2
Figure imgf000228_0001
Figure imgf000228_0002
Figure imgf000229_0001
Figure imgf000230_0001
Figure imgf000231_0001
Figure imgf000232_0001
Figure imgf000233_0001
Figure imgf000234_0001
Figure imgf000235_0001
' The binding assay normally used for the indolone compounds was used to test this compound.
Figure imgf000236_0001
Figure imgf000237_0001
* The binding assay normally used for the indolone compounds was used to test this compound.
Figure imgf000238_0001
The binding assay normally used for the indolone compounds was used to test this compound.
Figure imgf000239_0001
Figure imgf000240_0001
Figure imgf000241_0001
Figure imgf000242_0001
Figure imgf000243_0001
Figure imgf000244_0001
Figure imgf000245_0001
Figure imgf000246_0001
Figure imgf000247_0001
Figure imgf000248_0001
Figure imgf000249_0001
' The binding assay normally used for the indolone compounds was used to test this compound.
Figure imgf000250_0001
Figure imgf000251_0001
Figure imgf000252_0001
General Procedure for Preparing Indolones
General Procedure for Synthesis of Iminoisatins . The appropriately substituted isatin (10 mg - 10 g) was placed in a flask and the appropriate aniline (1.0 - 1.1 equivalents) was added and the mixture was stirred to homogeneity. The mixture was then heated to 110 °C for. 2-7 hours and then cooled. Solids were crystallized from hot methanol and filtered, giving the desired products (usually as an inseparable interconverting mixture of E/Z isomers) .
Procedure A:
1- (3-THIENYL) -1H-INDOLE-2 , 3-DIONE: Triethylamine (56.9 mL, 0.408 mol), was added to- a mixture of lH-indole-2 , 3- dione (15.0 g, 0.102 mol), copper (II) acetate (46.0 g, 0.255 mol), and 3-thienylboronic acid (19.6 g, 0.153 mol) in CH2C12 (500 mL) . The reaction mixture was stirred overnight, filtered through Celite, rinsed, with EtOAc /hexane (1:1, 300 mL) , and concentrated in vacuo. The crude product was purified by column chromatography on silica using Hexane/EtOAc (1:1), giving the desired product (1.1 g, 50 %) .
Procedure B:
(3E) -3-[ (4-METHYLPHENYL)IMINO]-l-( 3 -THIENYL) -1,3- DIHYDRO-2H-INDOL-2-ONE: A solution of 1- ( 3-Thienyl) -1H- indole-2, 3-dione (20 mg, 0.087 mmol) in 1% HOAc /MeOH (8 mL) was added to a solution of p-toluidine (19 mg, 0.18 mmol) in 1% HOAc/MeOH (8 mL) . The reaction mixture was stirred for 12 h at room temperature, heated at 50 °C for 1 h, and concentrated in vacuo. The residue was purified by preparative TLC on silica using EtOAc/hexanes (3:7, 0.1 % TEA) giving the desired product (14 mg, 50%) .
Procedure C:
(3Z)-l-PHENYL-3-{ [4- (3-THIENYL) PHENYL] IMINO} -1, 3- DIHYDRO-2H-INDOL-2-ONE: A mixture of (3Z)-3-[(4- bromophenyl) imino] -1-phenyl-l, 3-dihydro-2H-indol-2-one (50.0 mg, 0.133 mmol), thiophene-3 -boronic acid (26.0 mg, 0.199 mmol) , tetra is (triphenylphosphine)palladium(O) (31.0 mg, 0.0268 mmol in THF (5 mL) , and aqueous Na2C03 (2M, 100 μL) was heated at 67 °C for 24 h. The crude product was concentrated in vacuo and the residue was extracted with CH2Cl2 (3 x 1 ml), and concentrated. The crude product was purified by preparative TLC using 10 % methanol in CHCl3, giving the desired product (18 mg, 35%) .
Procedure D:
(3Z) -5-BROMO-3-{ [3- (TRIFLUOROMETHYL) PHENYL] IMINO}-!, 3- DIHYDRO-2H-INDOL-2-ONE: A mixture of 5-bromo-lH-mdole- 2,3-dione (1.0 g, 0.442 mmol) and 3- trifluoromethylaniline (0.993 g, 6.2 mmol) in a solution of 1% acetic acid in methanol was stirred at 50 °C for 12 h. The crude product was ^concentrated in vacuo, giving the desired crude product (640 mg, 40%) .
Procedure Ξ:
(3Z) -5-BROMO-l-PHENYL-3-{ [3-
(TRIFLUOROMETHYL) PHENYL] IMINO) -1 , 3-DIHYDRO-2H-INDOL-2- ONE: A mixture of (3z ) -5-bromo-3- { [3-
( trifluoromethyl) phenyl] imino}-l, 3-dihydro-2h-indol-2- one (100 mg, 0.272 mmol), copper (II) acenate (54 mg, 0.33 mmol), triethylamine (82.8 mg, 0.817 mmol) , and benzene boronic acid (40 mg, 0.325 mmol) in 5 mL of CH2C12 was stirred at room temperature for 12 h. The crude mixture was concentrated in vacuo and purified by preparative TLC using EtOAc:hexane (3:7, 1% triethylamine) , giving the desired product (22 mg, 20%) . Procedure F :
(3Z) -1 , 5-DIPHENYL-3-{ [3- (TRIFLUOROMETHYL) PHENYL] IMINO} - 1, 3-DIΗYDRO-2H-INDOL-2-ONE: A mixture of (3z) -5-bromo-l- phenyl-3- { [3- (trifluoromethyl) phenyl] imino} -1, 3-dihydro- 2H-indol-2-one (22 mg, 0.05 mmol), tetrakis ( riphεnylphosphine)palladium(O) (12.0 mg, 0.01 mmol), benzene boronic acid (10 mg, 0.08 mmol) in THF (5 mL) , and aqueous Na2C03 (2M, 10C μL) was heated at 67 °C for 24 h. The crude product was concentrated in vacuo and the residue was extracted with CH2C12 (3 x 1 ml) , concentrated, and purified by preparative TLC using 10 % methanol in CHCl3 , giving the desired product (4 mg, 18%) .
Procedure G:
ETHYL 5-[ (2, 3-DIOXO-2, 3-DIHYDR0-1H-IND0L-1-YL) METHYL] -2-
FUROATE : A mixture of ethyl 5- (chloromethyl) -2-furoate
(148 mg, 1.01 mmol) in dioxane (15 ml) was added to a mixture of NaH (48 mg, 1.20 mmol ) in dioxane (10 mL) under argon at 0 °C . The mixture was stirred for 1 h at room temperature, refluxed under argon for 16 h, cooled to room temperature, and then concentrated in vacuo. The residue was purified by preparative TLC using EtOAc/hexane (3:7), giving the desired product (56 mg, 19 %) .
Procedure H:
ETHYL 5-[ ( (3Z)-2-0X0-3-{ [3-
(TRIFLUOROMETHYL) PHENYL] IMINO) -2 , 3-DIHYDRO-1H-INDOL-1- YL) METHYL] -2-FUROATE : A mixture of ethyl 5- [ (2 , 3-dioxo- 2 , 3-dihydro-lH-indol-l-yl)methyl] -2-furoate ( 60 mg,
0.200 mmol) and- 3-trifluromethylaniline (32 mg, 0.200 mmol) was heated at 140 °C for 2 h. The residue was dissolved in CHCl3 (1 L) and purified by preparative TLC using EtOAc/hexane (6:4), giving the desired product (20 mg, 23 %) .
Procedure I :
6-METHOXY-l-PHENYL-lH-INDOLE-2,3-DIONE: A solution of
N- (3-methoxyphenyl) -N-phenylamine (1.14 g, 5.72 in ether
(3 mL) was added to a solution of oxylyl chloride (728 g, 5.75 mmol) and heated at reflux for 1 h. The resulting mixture was cooled to room temperature, . concentrated to dryness, and redissolved in nitrobenzene (35 mL) . The solution was added to a solution of A1C13 ' in nitrobenzene (0.762 g, 5.72 mmol), and the resulting mixture was heated at 70 °C for 16 h. The crude product was concentrated in vacuo and purified by column chromatography using EtOAc/hexane (1:1), giving the desired product 60, mg, 50 %) .
Procedure J:
(3Z) -l-(4-BROMQPHENYL)-3-{ [3-
(TRIFLUOROMETHYL) PHENYL] IMINO} -1 , 3-DIHYDRO-2H-INDOL-2- ONE: A solution of (3Z)-3-{[3- ( trifluoromethyl) phenyl] imino} -1 , 3-dihydro-2H-indol-2- one (100 mg, 0.344 mmol), copper (II) acetate (9-3 mg, 0.516 mmol), triethylamine (105 mg, 1.03 mmol)- , and 4- bromobenzene boronic acid (104 mg, 0.516 mmol) in 5 mL of CH2C12 was stirred at room temperature for 12 h. The crude mixture was concentrated in vacuo and purified by preparative TLC using EtOAc:hexane (3:7, 1% triethylamine), giving the desired product (65 mg, 42%). Procedure K:
A solution of (3Z) -1- (4-bromophenyl) -3- { [3-
( trifluoromethyl) phenyl] imino} -1, 3-dihydro-2H-indol-2- one (30 mg, 0.068) , tetrakis (triphenylphosphine)palladium(O) (16.0 mg, 0.014 mmol), benzene boronic acid (13 mg, 0.101 mmol) in THF
(5 mL) , and aqueous Na2C03 (0.45 M, 300 μL) was heated at 67 °C for 40 h. The crude product was concentrated in vacuo and the residue was extracted with CH2C1 (3 x 1 ml) , concentrated, and purified by preparative TLC using 10 % methanol in CHCl , giving the desired product (5 mg, 16%) .
The compounds of Examples 92 - 107, inclusive, were purchased from Bionet Research Ltd. , 3 Highfield Industrial Estate, Camelford, Cornwall PL32 9QZ, UK. These compounds can also be synthesized using the procedure described above.
Example 91: 3- [ (2-METHOXYPHENYL) IMINO] -1-PHENYL-l , 3- DIHYDRO-2H-INDOL-2-ONE
Example 92:' l-PHENYL-3- . [[3-
(TRIFLUOROMETHYL) PHENYL] IMINO] -1 , 3-DIHYDRO-2H-INDOL-2- ONE
Example 93: 3- [ (3 -METHYLPHENYL) IMINO] -1-PHENYL-l , 3- DIHYDRO-2H-INDOL-2-ONE
Example 94: 3- [ (3-CHLOROPHENYL) IMINO] -1-PHENYL-l, 3- DIHYDRO-2H-INDOL-2-ONE Example 95: l-PHENYL-3- [ [4-
(TRIFLUOROMETHYL) PHENYL] IMINO] -1, 3-DIHYDR0-2H-IND0L-2- ONE
Example 96 : 3- [ (4-METHYLPHENYL) IMINO] -1-PHENYL-l, 3- DIHYDRO-2H-INDOL-2-ONE
Example 97: 3- [ (4-CHLOROPHENYL) IMINO] -1-PHENYL-l , 3- DIHYDRO-2H-INDOL-2-ONE
Example 98: ' 3- [ (4-BROMOPHENYL) IMINO] -1-PHENYL-l , 3- DIHYDRO-2H-INDOL-2-ONE
Example 99 : 3- [ (4-FLUOROPHENYL) IMINO] -1-PHENYL-l , 3- DIHYDRO-2H-INDOL-2-ONE
Example 100: 3- [ (4-PHENOXYPHENYL) IMINO] -1-PHENYL-l, 3- - DIHYDRO-2H-INDOL-2-ONE
Example 101: 3- [ (4-ETHOXYPHENYL) IMINO] -1-PHENYL-l , 3- DIHYDRO-2H-INDOL-2-ONE
Example 102 : 3- [ (4-METHOXYPHENYL) IMINO] -1-PHENYL-l, 3- DIHYDRO-2H-INDOL-2-ONE ".
Example 103: 3- [ (3 , 5-DICHLOROPHENYL) IMINO] -1-PHENYL-l , 3- - DIHYDRO-2H-INDOL-2-ONE
Example 104: 3- [ (3 , 5-DIMETHYLPHENYL) IMINO] -1-PHENYL-l , 3- DIHYDRO-2H-INDOL-2-ONE
Example 105: l-ALLYL-3- [ (3 , 4-DICHLOROPHENYL) IMINO] -1 , 3- DIHYDRO-2H-INDOL-2-ONE Example 106: l-ALLYL-3- [ (3 , 5-DICHLOROPHENYL) IMINO] -1 , 3- DIHYDRO-2H-INDOL-2-ONE
Example 107: 3- [ (4-BROMOPHENYL) IMINO] -1-ISOPROPYL-l , 3- DIHYDRO-2H-INDOL-2-ONE
The methods that follow demonstrate procedures useful for synthesizing compounds of this invention (illustrated in Schemes 6 and 7) . Substituted isatins useful for synthesizing compounds of this invention can alternatively be obtained using the procedures described in the following references :
Garden, S. J. ; Da Silva, L. E.; Pinto, A.C.; Synthetic Communications, 1998, 28, 1679 - 1689.
Coppola, G.M. ; Journal of Heterocyclic Chemistry, 1987,
24, 1249.
Hess, B.A. Jr; Corbino, S.; Journal of Heterocyclic
Chemistry, 1971, 8, 161. Bryant, . M. Ill; Huhn, G.F.; Jensen, J.H.; Pierce, M.
E. ,- Stammbach, C; Synthetic Communications, 1993, 23, 1617 - 1625.
Example 108: 1- [ (5-CHLORO-2-THIENYL) METHYL] -3-{ [3- (TRIFLUOROMETHYL) PHENYL] IMINO}-!, 3-DIHYDRO-2H-INDOL-2-
ONE: A mixture of 1- [ (5-chloro-2 -thienyl) methyl ] -2H- indole-2, 3-dione (25 mg, 0.09 mmol) (prepared as described below) and 3-trifluoromethylaniline (11.3 μL, 0.09 mmol) was heated neat at 140 °C for 2 h. The crude material was purified by preparative TLC using a mixture of 3:7 ethyl acetate in hexane as the eluent, giving the desired product (23 mg 0.05 mmol, 61 %) . 1H NMR (400 MHz): δ (major isomer) 7.57 (t, J = 7.7, IH) , 7.53 (t, J = 7.8, IH) , 7.33 (t, J = 7.8, IH) , 7.28*(s, IH) , 7.19 (d, J = 7.6, 2H) , 6.^ - 6.72 (m, 4H) , 6.56 (d, J = 7.7, IH) , 5.02 (s, 2H) ; ESI-MS m/z found 421 (MH+) .
l-[ (5-CHLORO-2-THIENYL)METHYL]-2H-INDOLE-2, 3-DIONE: A solution of isatin (125 mg, 0.85 mmol) in anhydrous dioxane (10 mL) was added dropwise to a solution of sodium hydride' (60% dispersion in mineral oil, 24 mg, 0.62 mmol) in anhydrous dioxane (10 mL) at 0 °C under argon. The mixture was allowed to stir for 5 minutes and then 2-chloro-5- (chloromethyl) hiophene (0.12 L, 1.02 mmol) in dioxane (10 L) was added dropwise to the resulting mixture. Jj e reaction mixture was heated at reflux under' argon for 16 h and concentrated in vacuo. The crude material was purified preparative TLC using 1:24' methanol in chloroform as the eluent, giving the desired product as a yellow solid (53 mg, 0.19 mmol, 22 %) . H NMR (400 MHz): δ 7.62 (d, J = 7.4, IH) , 7.56 (t, J = 7.8, IH) , 7.14 (t, J = 7.7, IH) , 6.94 (d, J = 8.0, IH) , 6.90 (d, J = 3.2, IH) , 6.78 (d, J = 3.7, IH) , 4.90 (s, 2H) .
Example 109: 1- (3-THIENYL) -3-{ [3-
(TRIFLUOROMETHYL) PHENYjL] IMINO} -1 , 3-DIHYDRO-2H-INDOL-2- ONE: A mixture of 1- (3-thienyl) -2H-indole-2 , 3-dione (25 mg, 0.11 mmol) (prepared as described below) and 3- trifluoromethylaniline (14 uL, 0.11 mmol) was heated neat at 140 °C for 2 h. The crude material was purified by preparative TLC using a mixture of 3:7 ethyl acetate and hexane as the eluent, giving the desired product as a yellow solid (7.3 mg, 0.02 mmol, 22 %) . XE NMR (400 MHz) δ 7.62 - 7.19 (m, 9H) , 6.94 (d, J ='8.0, IH) , 6.76 (t, J = 7.6, IH) ; ESI-MS m/z found 373 (MH+) .
1- (3-THIENYL) -2H-INDOLE-2 , 3-DIONE : Copper (II) acetate monoh-ydrate (4.25 g, 23.4 mmol) was heated at reflux in acetic anhydride (30 mL) for 2 h. The mixture was filtered and washed with anhydrous ether (500 mL) . The solid was dried in vacuo 'at 55 °C for 16 h. Dichloromethane (1 mL) was added to a mixture of copper(II) acetate (62 mg, 0.34 mmol), isatin (50 mg, 0.34 mmol), and thiophene-3 -boronic acid (87 mg, 0.68 mmol), followed by triethylamine (0.10 mL, 0.68 -mmol) under argon. The resulting solution was stirred for 16 h at room temperature. The reaction mixture was then recharged with 0.10 mmol copper (II) acetate, 0.10 mmol of 3 -thiophene boronic acid, and 1 drop of triethylamine, and the mixture was heated at 50 °C for 6 h. The crude material was purified by preparative TLC using 3:97 methanol in chloroform as the eluent, giving the desired product as a yellow solid (25 mg, 0.11 mmol, 33 %) . XE NMR (400 MHz): δ 7.70 (d, J = 7.5, IH) , 7.58 (t, J = 7.8, IH) , 7.50 (d, J = 5.1, IH) , 7.48 (s, IH) , 7.24 (d, J = 5.1, IH) , 7.18 (t, J = 7.51, IH) , 7.05 (d, J = 8.0, IH) .
Example 110: -. 2-METHYL-5- [ (2-OXO-l-PHENYL-l, 2-DIHYDRO-
3H-INDOL-3-YLIDENE)AMINO] -2H-ISOINDOLE-1 , 3 (2H)-DI0NE: A mixture of 1-phenylisatin (50 mg, 0.22 mmol). and 4- amino-N-methylpthaiimide (40 mg, 0.22 mmol) was heated
•neat at 215 °C for 2 h. The crude material was purified
• by preparative TLC using a mixture of 3:7 ethyl acetate and hexane as the eluent, giving the desired product as a yellow solid (8 mg, 0.02 mmol, 10 %) . E NMR (400 MHz) i δ 7.88 (d, J = 7.8, IH) , 7.83 - 7.80 (m, IH) , 7.51
(t, J = 7.5, IH) , 7.47 - 7.18 (m, 6H) , 7.02 (t, J = 8.0, 5 IH) , -6.91 - 6.79 (m, 2H) , 6.58 (d, J = 7.5, IH) , 3.22
(s, 3H) ; ESI-MS m/z found 382 (MH+) .
Example 111: 1- [ (5-CHLORO-1-BENZOTHIEN-3-YL) METHYL] -3- { [3- (TRIFLUOROMETHYL) PHENYL] IMINO} -1, 3-DIHYDRO-2H-INDOL-
10 2 -ONE: A mixture of 1- [ (5-chloro-l-benzothien-3- yl ) methyl ] -2H-indole-2 , 3 -dione (50 mg, 0.15 mmol)
(prepared as described below) and 3- trifluoromethylaniline (0.020 mL, 0.15 mmol-) was heated neat at 140 °C for 2 h. The crude material was purified
15 by preparative TLC using a mixture of 1:3 ethyl acetate and hexane as the eluent giving the desired product as a yellow solid (13 mg, 0.030 mmol, 18%). XH NMR (400 MHz): δ 7.98 (d, J = 2.0, IH) , 7.80 (d, J = 8.6, IH) , 7.58 (t, J = '7.7, IH) , 7.52 (d, J = 8.1, IH) , 7.43 (s, IH) , 7.38
20 (dd,- J = 8.6, 1.9, IH) , 7.31* (overlapping singlet and dt, J = 1.2, 7.8, 2H) , 7.24 (d, J = 7.8, IH) , 6.87 (d, J = 7.9, IH) , 6.77 (t, J = 7.7, IH) , 6.59 (d, J = 7.7, IH) , 5.20 (s, 2H) . ESI-MS m/z found '471 (MH* with 35C1), 473 (MH+ with 37C1) .
2.5
'!.-[ (5-CHLORO-1-BENZOTHIEN-3-YL) METHYL] -2H-INDOLE-2, 3- dione: A solution of isatin (125mg, 0.85 mmol) in anhydrous dioxane (10 mL) was added dropwise to a solution of sodium hydride (60% dispersion in mineral
30 oil, 25 g, 0.62 mmol) in anhydrous dioxane (10 L) at 0 °C under argon. The mixture was allowed to stir for 5' minutes and then a solution of 3- (bromomethyl) -5- chlorobenzo[b] thiophene (267 mg, 1.02 mmol) in dioxane (10 mL) was added dropwise to the reaction mixture . The reaction mixture was heated at reflux under argon for 16 h and concentrated in vacuo . The crude material was purified by preparative TLC using 1:24 methanol in chloroform as the eluent, giving the desired product as a yellow solid (125 mg, 0.38 mmol, 45%). lE NMR (400
MHz): δ 7.89 (s, IH) , 7.79 (d, J = 8.5, IH) , 7.65 (d, J = 7.5, IH) , 7.54 (t, J = 8.0, IH) , 7.42 (s, IH) , 7.38 (d, J = 8.5, IH) , 7.14 (t, J = 7.5, IH) , 6.88 (d, J = 7.8, IH) , 5.13 (s, 2H) .
Example 112 : 3- (1H-INDOL-5-YLIMINO) —1-PHENYL-l, 3- DIHYDRO-2H-INDOL-2-ONE: 1-phenylisatin (51.8 mg, 0.23 mmol) and 5-aminoindole (31 mg, 0.23 mmol) were mixed and heated at 140 °C for 2 h. The resulting crude product was purified by preparative TLC using ethyl acetate/hexane (6:4) as the eluent, giving the desired product as a yellow solid (10.8 mg, 14%). :H NMR (400 MHz): δ 8.28 (s, IH) , 7.57 (t, J = 7.7, 2H) , 7.49 - 7.40 (m, 6H) , 7.29 - 7.23 (m, IH) , 7.03 (dd, J = 8.5, 1.7, IH) , 6.98 (d, J = 7.6, IH) , 6.83 (d, J = 8.0, IH) , 5.74, J = 7.6, IH) , 6.59 (s, IH) ; ESI-MS m/z found 338. (MH+) .
Example 113 : 3- [ (6-CHLORO-3-PYRIDINYL) IMINO] -1-PHENYL- 1, 3-DIHYDRO-2H-INDOL-2-ONΞ: 1-phenylisatin (23.0 mg, 0.10 mmol) and 5-amino-2-chloropyridine (12.8 mg, 0.10 mmol) were mixed and heated at 140 °C for 7 h. The resulting crude product was purified by preparative TLC using hexane/ethyl acetate (8:2) as the eluent, giving the desired product as a yellow solid (19.7 mg, 59%) . XE NMR (400 MHz) δ 8.15 (d, J = 8, IH) , 7.6 - 7.2 (m, 9H) , 6.85 - 6.75 (m, 2H) ; ESI-MS m/z found 334 (MHT) .
Example 114: 3-[ (2-METHYL-1 , 3 -BENZOTHIAZOL-5- YL) IMINO] -1-PHENYL-l, 3-DIHYDRO-2H-INDOL-2-ONE: 5-amino-
2-methylbenzothiazole (52.2 mg, 0.31 mmmol) was mixed with 1-phenylisatin (69.7 mg, 0.31 mmol) and heated at
140 °C for 3 h. The
Figure imgf000264_0001
crude product was purified by preparative TLC using ethyl acetate/hexane (6:4) as the eluent to give the desired product as a yellow solid
(36.9 mg, 32.3 %) . 1H' NMR Data: δ 7.9-6.7 (m, 12H) , 2.9
(s, 3H) . ESI-MS m/z found 370 (MH+) .
Example 254: (3Z) -3- [ (3 , 4-DICHLOROPHENYL) IMINO] -1- (2- YRIDINYLMETHYL) -1 , 3-DIHYDRO-2H-INDOL-2-ONE : Prepared by Procedures H and K (for substitution of 2-picolyl chloride). X. NMR (400 MHz, CDCl3) δ 8.51 - 8.46 (m, IH) , 7.87 - 7.78 (m, IH) , 7.64 (d, IH, J = 7.1), 7.53 - 7.31 (m, 5H) , 7.28 (d, IH, J = 4.1), 7.12 (d, IH, J = 8.1), ' 6.58-6.53 ( , IH) , 5.51 (s, 2H) ; ESI-MS m/z 381 (MH") .
Example 255: (3Z) -3- [ ( 3 , 4-DICHLOROPHENYL) IMINO] -1- [(3,5- pIMETHYL-4-ISOXAZOLYL) METHYL] -1, 3-DIHYDRO-2H-INDOL-2- ONE: Prepared by Procedure B (microwave heating) . 1H NMR (400 MHz, CDC13) δ 7,63 (d, IH, J = 9.1), 7.46 (dt, IH, J = 8.1, 2.0), 7.28 (d, IH, J = 2.1), 7.02 (d, IH, J= 2.O.), 6.88 (dt, IH, J 8.0, 2.1), 6.74 - 6.72 (m, IH) , 6.72 - 6.70 ( , IH) , 5.53 (s, 2H) , 2.50 (s, 3H) , 2.24 (s, 3H) ; ESI-MS m/z 399 (MH+) . Example 256: (3Z) -3-[ (3 , 4-DICHLOROPHENYL) IMINO] -l-[3- (TRIFLUOROMETHYL) PHENYL] -1 , 3-DIHYDRO-2H-INDOL-2-ONE : Prepared by Procedures A and B. XE NMR (400 MHz, CDC13) δ 7.90 - 7.87 (m, IH) , 7.83 - 7.79 (m, IH) , 7.67 (d, IH, J = 8),. 7.46 - 7.40 ( , IH) , 7.33 (d, IH, J = 2), 7.08 - 7.05 (m, IH) , 6.96 - 6.80 (m, 5H) ; ESI-MS m/z 435 (MH+) .
Example 257: (3Z) -1- ( 3 , 5-DICHLOROPHENYL) -3- [ (3 , 4- DICHLOROPHENYL) IMINO] -1 , 3-DIHYDRO-2H-INDOL-2-ONE : Prepared by Procedures A and B. XE NMR (400 MHz, CDC13) δ 7.93 (d, IH, J = 8.1), 7.79 (d, IH, J = 6.0), 7.72 -
7.68 (m", IH) , 7.59 - 7.45 (m, IH) , 7.46 (d, IH,-' J = 8.1), 7.32 (dt, IH, J = 8.0, 2.1), 7.23 -<d, IH, J = 2.5), 6.97 (dd, IH, J = 8.0, 2.1), 6.92 - 6.87 (m, IH) , 6.85 - 6.81 (m, IH) ; ESI-MS m/z 435 (MH+) .
Example 258: (3Z)-3-[ (3, 4-DICHLOROPHENYL) IMINO] -6- MΞTHOXY-l-PHENYL-l,3-DIHYDRO-2H-INDOL-2-ONE: Prepared by Procedures K, L, and B. XE NMR (400 MHz, CDCl3) δ 7.69 - 7.54 (m, IH) , 7.53 - 7.38 (m, 3H) , 7.29 (d,. IH, J = 2.0), 7.17 (d, IH, J = 8.1), 7.12 (d, IH, J = 8.0), 6.84 (d, IH, J = 2.5), 6.78 (d, IH, J = 8 ), 6.6 (dd, 2H, J = 8.0., 2.0), 6.55 (dd, 2H, J = 8.1, 2.X); ESI-MS "m/z (398 MH+) .
Example 259: (3Z) -3-[ (4 -CHLORO- 3 -METHYLPHENYL) IMINO] -1- (3 -THIENYL) -1, 3-DIHYDRO-2H-INDOL-2-ONE: Prepared by
Procedures A and B (80 eC) . XE NMR (400 MHz, CDC13) δ
7.69 - 7.62 (m, 2H) , 7.49 (s, IH) , 7.47 (s, IH) , 7..41 (dt, IH, J = 7.1, 1.6) , 7.3 (dd, IH, J = 5.0, 1.6) , 7.05
- 6.97 ( , IH, 6.93 - 6.86 ( , IH) , 6.77 (m, IH) , 6.56 (m, IH) , 2.53 (s,' 3H) ; ESI-MS m/z 353 (MH+) . Example 260: ( 3Z) -3- (2-NAPHTHYLIMINO) -1- (3 -THIENYL) - 1, 3-DIHYDRO-2H-INDOL-2-ONE: Prepared by Procedures A and B (80 aC) . XE NMR (400 MHz, CDCl3) δ 8.15 (d, IH, J = 9.1), -8.06 - 7.99 (m, IH) , 7.89 - 7.80 (mX IH) , 7.78 - 7.71 (m, IH) , 7.71 - 7.47 (m, 4H) , 7.41 - 7.35 (m, IH) , 7.33 (d, IH, J = 5.2), 7.28 (d, IH, J = 6.8.1), 7.00 (d, IH, J = 8.0), 6.76 (t, IH, J ='7.8), 6.67 (d, IH, J = 7.9); ESI-MS m/z 355 (MH+) .
Example 261: (3Z) -3- [ (4-CHLOROPHENYL) IMINO] -1- (3-
THIENYL) -l,3-DIHYDRO-2H-INDOL-2-ONE: Prepared - by Procedures A and B (80 2C) . XE NMR (400 MHz, CDC13)' δ 7.69 - 7.56 (m, 2H) , 7.54 - 7.48 (m, IH) , 7.41 (dt, IH, J = 8, 2), 7.32 - 7.28 (m, IH) , 7.11 - 6.99 (m, 3H) , . 6.89 (dt, IH, J = 8), 6.77 - 6.73 (m. IH) , 6.66 - 6.33 (m, IH) ; ESI-MS m/z 339 (MH+) .
Example 262: (3Z) -3-[ (4-IODOPHENYL) IMINO] -1- (3-THIENYL) - l,3-DIHYDRO-2H-INDOL-2-ONE: Prepared by Procedures A and B (1% HOAc in MeOH). XE NMR (400 MHz, CDCl3) δ 7.79 - 7.74 (m, 2H) , 7.53 - 7.48 (m, 2H) , 7.35 (dt, IH, J = 8.0, 1.2), 7.29 - 7.24 (m, IH) , 6.98 (d, IH, J = 8.0), 6.89 - 6.75 (m, 4H) ; ESI-MS m/z 431 (MH+) .
Example 263: (3Z) -3- [ (4-METHYLPHENYL) IMINO] -1- (3- THIENYL) -1 , 3-DIHYDRO-2H-INDOL-2-ONE : Prepared by Procedures A and B (1% HOAc in MeOH) . XE NMR (400 MHz, CDC13) δ 7.52 - 7.44 (m, 2H) , 7.35 - 7.22 ( , 4H) , 6.99 - 6.93 ( , 3H) , 6.87 - 6.78 (m, 2H) , 2.42 (s, 3H.) ; ESI-MS m/z 319 (MHT) . Example 264: (3Z) -3- [ (3 , 5-DIFLUOROPHENYL) IMINO] -1- (3- THIENYL) -1, 3-DIHYDRO-2H-INDOL-2-ONE: Prepared by Procedures A and B (1% HOAc in MeOH) . XE NMR (400 MHz, CDC13). δ 7.54 - 7.16 ( , 4H) , 6.99 (dt, IH, J = 8.2, 0.8), 6.89 (dt, IH, J = 7.7, 1.1), 6.76 (d, IH, J = 7.5), 6.71 (tt, IH, J = 9.3, 2.3), 6.64 - 6.57 ( , 2H) ; ESI-MS m/z 341 (MH+) .
Example 265: (3Z) -3- ( [1, 1' -BIPHENYL] -4-.YLIMINO) -l-(3- THIENYL) -1, 3-DIHYDRO-2H-INDOL-2-ONE : Prepared by Procedures A and B (1% HOAc in MeOH) . XE NMR (400 MHz, CDC13) δ 7.73 - 7.12 (m, 13H) , 6.99 (d, IH, J = 8.0), 6.89 (d, IH, J = 8.0), 6.82 (dt, IH, J = 7.6, 1.0); ESI- MS m/z 381 (MH+) .
Example 266: ETHYL 3-{ [ (3Z) -2-OXO-l- (3-THIENYL) -1, 2- DIHYDRO-3H-INDOL-3-YLIDENE] AMINO}BENZOATE: Prepared by Procedures A and B (1% HOAc in MeOH) . TH NMR (400 MHz, CDC13) δ 7.96 (d, IH, J = 7.4), 7.75 - 7.17 (m, 6H) , 6.98 (d, IH, J = 8.0), 6.87 - 6.78 (m, 2H) , 6.63 (d, IH, J = 7.8), 4.45 - 4.32 (m, 2H) , 1.43 - 1.33 ( , 3H) ; ESI-MS m/z 377 (MH+) .
Example 267: (3Z) -3-[ ( 6-CHLORO-3-PYRIDINYL)'IMINO] -1- (3- THIENYL) -1, 3-DIHYDRO-2H-INDOL-2-ONE: Prepared by Procedures A and B (1% HOAc in MeOH) . 1H NMR (400 MHz, CDC13) δ 8.21 - 6.81 (m, 10H) ; ESI-MS m/z 340.13 (MH+) .
Example 26_8: 3Z)-3- [ (4-PHENOXYPHENYL) IMINO] -1- (3-
THIENYL) -1 , 3 -DIHYDRO-2H-INDOL-2-ONE : Prepared by Procedures A and B (1% HOAc in MeOH) . XE NMR (400 MHz, CDCI3) δ 7.85 - 6.70 ( , 16H) ; ESI-MS m/z 397 (MH+) . Example 269: (3Z) -3- [ (4-BROMOPHENYL) IMINO] -1- (3-
THIENYL) -1, 3-DIHYDRO-2H-INDOL-2-ONE: Prepared by Procedures A and H. XE NMR (400 MHz, CDCl3) δ 7.82 - 6.55 (m, 11H) ; ESI-MS m/z 383 (MlT) .
Example 270: (3Z) -3-[ (3-CHLOROPHENYL) IMINO] -1- (3-
THIENYL) -1, 3-DIHYDRO-2H-INDOL-2-ONE: Prepared by
Procedures A and H. XE NMR (400 MHz, CDCl3) δ 7.55 - 6.50 (m, 11H) ; ESI-MS m/z 339 (MH+) .
Example 271: (3Z) -3-[ (3-METHYLPHENYL) IMINO] -l-(3- THIENYL) -1, 3-DIHYDRO-2H-INDOL-2-ONE: : Prepared by Procedures A and B (1% HOAc in MeOH) . 1H NMR (400 MHz, CDC13) δ 7.67 - 6.78 (m, 11H) , 2.39 (s, 3H) ; ESI-MS m/z 319 (MH+) .
Example 272: (3Z) -3-[ (3 , 4-DICHLOROPHENYL) IMINO] -1- (3- THIENYL) -1, 3-DIHYDRO-2H-INDOL-2-ONE : : Prepared • by Procedures A and B (1% HOAc in MeOH) . :H NMR (400 MHz., CDCI3) δ 7.82 - 6.80 (m, 10H) ; ESI-MS m/z 373 (MH+)' .
Example 273: (3Z) -1- (2-PYRIDINYLMETHYL) -3-{ [3-
(TRIFLUOROMETHYL) PHENYL] IMINO} -1 , 3-DIHYDRO-2H-INDOL-2- ONE: : Prepared by Procedure B. ESI-MS m/z 382 (MHT) .
Example 274: (3Z) -3-[ (3, 5-DICHLOROPHENYL) IMINO] -1- (2- PYRIDINYLMETHYL) -1 , 3-DIHYDRO-2H-INDOL-2-ONE : Prepared by Procedure B. ESI-MS m/z 382 (MH+) .
Example 275: (3Z) -1- [ (3 , 5-DIMETHYL-4-ISOXAZOLYL) METHYL] - 3 - { [3 - (TRIFLUOROMETHYL) PHENYL] IMINO}-!, 3-DIHYDRO-2H- INDOL-2-ONE: Prepared by Procedure B. ESI-MS m/z 400 (MH+) .
Example 276: (3Z) -3- [ (3 , 4-DIFLUOROPHENYL) IMINO] -1- (3- PYRIDINYLMETHYL) -1 , 3-DIHYDRO-2H-INDOL-2-ONE : Prepared by Procedure B. ESI-MS m/z 350 (MH+) .
Example 277: (3Z) -1- ( 3-PYRIDINYLMETHYL) -3- { [3-
(TRIFLUOROMETHYL) PHENYL] IMINO} -1 , 3-DIHYDRO-2H-INDOL-2 - ONE: Prepared by Procedure B. ESI-MS m/z 382 ( (MH+) .
Example 278: (3Z) -3- [ (3 , 4-DIFLUOROPHENYL) IMINO] -1- (2- PYRIDINYLMETHYL) -1 , 3-DIHYDRO-2H-INDOL-2-ONE :' Prepared by Procedure B. ESI-MS m/z 350 (MH") .
Example 279: (3Z)-3-[ (3 , 5-DICHLOROPHENYL) IMINO] -1- (3- PYRIDINYLMETHYL)' -1, 3-DIHYDRO-2H-INDOL-2-ONE : Prepared by Procedure B." ESI-MS m/z 384 (MH+) .
Example 280: (3Z)-3-[ (3 , 5-DICHLOROPHENYL) IMINO] -1- [ (3,5- DIMETHYL-4-ISOXAZOLYL) METHYL] -1 , 3-DIHYDRO-2H-INDOL-2- ONE : Prepared by Procedure B. ESI-MS m/z 4-Q2 (MH+)..
Example 281: (3Z)-3-[ (9-ETHYL-9H-CARBAZOL-3-YL) IMINO] -1- PHENYL-1 , 3-DIHYDRO-2H-INDOL-2-ONE : : Prepared by Procedure H. XE NMR (400 MHz, CDC13) δ 8.28 - 6.66 ( , 16H) , 4.47 - 4.35 (m, 2H) , 1.55 - 1.44 ( , 3H) ; ESI-MS m/z 416 (MH+) . Example 282: (3Z) -l-PHENYL-3- (5-QUINOLINYLIMINO) -1,3-
DIHYDRO-2H-INDOL-2--ONE: : Prepared by Procedure H. XE
NMR (400 MHz, CDCl3) δ 9.38 - 9.32 (m, IH) , 8.55 - 8.50
(m, IH) , 8.01 - 6.62 (m, 12H) , 6.43 - 6.35 ( , IH) ; ESI- MS m/z 350 (MH+) .
Example 283: (3Z) -3-[ (4-IODOPHENYL) IMINO] -1-PHENYL-l , 3- DIHYDRO-2H-INDOL-2-ONE: Prepared by Procedure B (0.1 % HOAc, 80 °C, 92 h, 4 eq RNH2, 3 A molecular sieves) . ESI- MS m/z 425 (MH+) .
Example 285: (3Z) -3- [ (3 , 4-DIFLUOROPHENYL) IMINO] -1- PHENYL-1, 3-DIHYDRO-2H-INDOL-2-ONE: Prepared "by Procedure B (0.1 % HOAc, 80 °C, 92 h, 4 eq RNH2 , 3 A molecular sieves) . ESI-MS m/z 335 (MH+) . . .
Example 286: (3Z) -3- [ (2 -CHLORO-4-METHYLPHENYL) IMINO] -1- PHENYL-l,3-DIHYDRO-2H-INDOL-2-ONE: Prepared by Procedure B (0.1 % HOAc, 80 °C, 92 h, 4 eq RNH2 , 3 A molecular sieves) . ESI-MS m/z 347 (MH+ with 35Cl), 349 (MH+ " with 37C1).
Example 287: (3Z)-3-[(2,4-DIMETHOXYPHENYL) IMINO] -1- PHENYL-1, 3-DIHYDRO-2H-INDOL-2-ONE: Prepared by Procedure B (0.1 % HOAc, 80 °C, 92 h, 4 eq RNH2, 3 .A molecular sieves) . ESI-MS m/z 359 (MH") .
Example 288: 3-{ [ (3Z) -2-OXO-l-PHENYL-l , 2-DIHYDRO-3H- INDOL-3 -YLIDENE] AMINO}BENZONITRILE : Prepared by Procedure B (0.1 % HOAc, 80 °C, 92 h, 4 eq RNH2, 3 A molecular sieves) . ESI-MS m/z 324 (MH+) . Example 289: (3Z)-3-{ [2-METHYL-5-
(TRIFLUOROMETHYL) PHENYL] IMINO} -1-PHENYL-l , 3 -DIHYDRO-2H- INDOL-2-ONE: Prepared by Procedure B (0.1 % HOAc, 80 °C, 92 h, 4 eq RNH2, 3 A molecular sieves) . ESI-MS m/z 381 (MH+) .-
Example 290: (3Z) -3-[ (4-CHLORO-3-METHYLPHENYL) IMINO] -1- (3 -THIENYL) -1, 3-DIHYDRO-2H-INDOL-2-ONE : Prepared by Procedures A and B (80 2C) . ESI-MS m/z 353 (MH+) .
Example 291: (3Z) -3- ( 6-QUINOLINYLIMINO) -1- (3-THIENYL) - 1, 3-DIHYDRO-2H-INDOL-2-ONE: Prepared by Procedures -A and B (80 2C) . ESI-MS m/z 356 (MH+) .
Example 29_2: (3Z) -3-[ (4-CHLOROPHENYL) IMINO] -1- (3-
THIENYL) -1, 3-DIHYDRO-2H-INDOL-2-ONE: Prepared by Procedures A and B (80 2C) . ESI-MS m/z 339 (MH+) .
Example 295: (3Z)-3-[ (3-ISOPROPYLPHENYL) IMINO] -1- (3- THIENYL) -1, 3-DIHYDRO-2H-INDOL-2-ONE: Prepared by Procedures A and B (80 2C) . ESI-MS m/z 347 (MH+) .
-Example 296: (3Z) -3-[ (4-CYCLOHEXYLPHENYL) IMINO] -1- (3-. THIENYL) -1, 3-DIHYDRO-2H-INDOL-2-ONE: Prepared . by Procedures A and B (80 aC) . ESI-MS m/z 387 (MH+) .
Example 297: (4-{ [ (3Z) -2-OXO-l-PHENYL-l , 2-DIHYDRO-3H- INDOL-3 -YLIDENE]AMINO}PHENYL) ACETONITRILE : Prepared by
Procedure B (0.1 % HOAc, 80 °C, 92 h, 4 eq RNH2, 3 A molecular sieves) . ESI-MS m/z 339 (MHT) . Example 298: (3Z) -3- [ (2 , 2-DIFLUORO-l , 3-BENZODIOXOL-5- YL) IMINO] -1-PHENYL-l, 3-DIHYDRO-2H-INDOL-2-ONE : Prepared by Procedure B (0.1 % HOAc, 80 '°C, 92 h, 4 eq RNH2, 3 A molecular sieves). ESI-MS m/z 379 (MHT).
Example 299: ( 3 Z ) -3 - ( 1 , 3-BENZOTHIAZOL-6-YLIMINO ) -1- PHENYL-l,3-DIHYDRO-2H-INDOL-2-ONE: Prepared by Procedure H. ESI-MS m/z 356(MH+).
Example 300: (3Z) -1-TETRAHYDRO-2H-PYRAN-4-YL-3- { [3- (TRIFLUOROMETHYL) PHENYL] IMINO} -1, 3-DIHYDRO-2H-INDOL-2 - ONE: Prepared by Procedures G and H. ESI-MS m/z 375 -(MH+) .
Example 301: (3Z) -3- (1H-INDAZOL-6-YLIMINO) -1-PHENYL- 1, 3-DIHYDRO-2H-INDOL-2-ONE: Prepared by Procedure H. ESI-MS m/z 339 (MH÷) .
Example 302: ( 3Z ) -3 - [ ( 3 -CHLOROPHENYL) IMINO] -6-METHOXY-1- PHENYL-1, 3-DIHYDRO-2H-INDOL-2-ONE: Prepared by Procedures I and H. ESI-MS m/z 363 (MH+) .
Example 3_03_: (3Z) -6-METHOXY-l-PHENYL-3-{ [3-
(TRIFLUOROMETHYL) PHENYL] IMINO) -1, 3-DIHYDRO-2H-INDOL-2- ONE: Prepared by Procedures I and H. ESI-MS m/z 397 (MH+) .
Example 304 : (3Z) -l-PHENYL-3- { [4- (3-
THIENYL) PHENYL] IMINO}-!, 3 -DIHYDRO-2H-INDOL-2-ONE: Prepared by Procedures H and C. ESI-MS m/z 381 (MH1") .
Example 305: (3Z) -l-PHENYL-3 -{ [3'
(TRIFLUOROMETHYL) [1 , 1 ' -BIPHENYL] -4-YL] IMINO} -1 , 3- DIHYDRO-2H-INDOL-2-ONE: Prepared by Procedures H and C. ESI-MS m/z 443 (MH+) .
Example 3^6: (3Z) -l-PHENYL-3- { [4-(3-
5 PYRIDINYL) PHENYL] IMINO} -1, 3-DIHYDRO-2H-INDOL-2-ONE : Prepared by Procedures H and C. ESI-MS m/z 376 (MH") .
Example 307: (3Z)-3-[ (3-BROMOPHENYL) IMINO] -1-PHENYL-l , 3- DIHYDRO-2H-INDOL-2-ONE: Prepared by Procedure B. ESI-MS -0 m/z 378 (MH+) .
Example 308: (3Z) -1, 5-DIPHENYL-3- { [3-
(TRIFLUOROMETHYL) PHENYL] IMINO} -1, 3-DIHYDRO-2H-INDOL-2- ONE: Prepared by Procedures D, E, and F. ESI-MS m/z 443 5 (MH+) .
Example 309_: (3Z) -1-[1, 1 ' -BIPHENYL] -4-YL-3- { [3-
(TRIFLUOROMETHYL) PHENYL] IMINO} -1 , 3-DIHYDRO-2H-INDOL-2- ONE: Prepared by Procedures H (6 eq of aniline), J, and 0 K. ESI-MS m/z 443 (MH+) .
Example 310: ( 3Z) -1- (4-HYDROXYPHENYL) -3 - { [3-
(TRIFLUOROMETHYL) PHENYL] IMINO} -1 , 3-DIHYDRO-2H-INDOL-2- ONE: Prepared by Procedures H (6 eq of aniline) and E. 5 ESI-MS m/z 383 (MH+) .
. Example 311: (3Z)-3-[ (3 , 4-DICHLOROPHENYL) IMINO] -1- (3-
PYRIDINYLMETHYL) -1, 3-DIHYDRO-2H-INDOL-2-ONE : Prepared by Procedures H (75 °C, 2 h) , K (3-picolyl chloride) , 0 and B.
ESI-MS m/z 383 (MH+) .
Examples 91-114 and 254-311 as described above are merely illustrative of the methods used to synthesize indolone derivatives . Further derivatives may be obtained utilizing methods shown in Schemes 6a, 7a and 8-10. The substituents in Schemes 6a, 7a and 8-10 are described in the Detailed Description.
It may be necessary to incorporate protection and deprotection strategies for substituents such as amino, amido, carboxylic acid, and hydroxyl groups in the synthetic methods described above to form indolone derivatives. Methods -for protection and deprotection of such groups are' well-known in the art, and may be found, for example in Green, T. W. and Wuts , P.G. M. (1991) Protection Groups in Organic Synthesis, 2nd Edition John Wiley & Sons, New York.
Scheme 6a
Figure imgf000275_0001
Scheme 7
Figure imgf000275_0002
"Y Y2 , Y3 ,Y4, A, and B are defined as described in the specification. X is a leaving group such as Cl, Br", I, or OTs . R is boric acid or a dialkylborate group.
Scheme 8a . Synthesis of Isatins
Figure imgf000276_0001
•1' Y3 ,Y , A, and B are defined as described in the specification.
X is a leaving group such as Cl, Br, I, or OTs. R is boric acid or a dialkylborate group.
Scheme 9a. Synthesis of Substituted 1-rιinoindoloι.es
Figure imgf000277_0001
Base (such as NaH or Base (such as NaH or K2C03 ) , R-X 2C03) , R-X or or For A = aryl or For A = aryl or heteroaryl: A-B(0H)2, heteroaryl: A-B(OH)-, Cu(0Ac)2, Et,N Cu(OAc)2, Et,N
Figure imgf000277_0002
X is a leaving group such as a halogen or tosylate. aYx, Y2 ,Y3 ,Y4, A, and B are defined as described in the specification. X is a leaving group such as Cl, Br, I, or OTs. R is boric acid or a dialkylborate grou .
Scheme 10a. Synthesis of Aryl pr Heteroaryl-Substituted Iminoindolones
Figure imgf000278_0001
Ar-B(0H)2, Pd(PPH3 3)' 4
Figure imgf000278_0003
Figure imgf000278_0002
Figure imgf000278_0004
Ar = aryl or heteroaryl
aYχ , Y2 ,Y Y4 A, and B are defined as described in the specification. X is a leaving group such as Cl, Br, I, or OTs. R is boric acid or a dialkylborate group. Radioligand Binding of Indolones at Cloned Galanin
Receptors
The binding properties of the indolones of the present invention were evaluated at the cloned human galanin receptors, GALl, GAL2 , and GAL3 , using protocols described herein.
Radioligand Binding Assay Results
The indolones described in Examples 91-114 and 254-311 were assayed using cloned human galanin receptors. The compounds were found to be selective for the GAL3 receptor. The binding affinities of the compounds of Examples 91-114 and 254-311 are illustrated in Tables 4 and 4a.
Table 4
Figure imgf000280_0001
Key: * = >10000 OMe=Metho y Ph=Phenyl OPh=Phenoxy Me=Methyl OEt=Ethoxy
Table 4a
Figure imgf000281_0001
Figure imgf000282_0001
Figure imgf000283_0001
Figure imgf000284_0001
Figure imgf000285_0001
Figure imgf000286_0001
Figure imgf000287_0001
Figure imgf000288_0001
Figure imgf000289_0001
Figure imgf000290_0001
Figure imgf000291_0001
Figure imgf000292_0001
Figure imgf000293_0001
Oral Compositions
As a specific embodiment of an oral composition of a compound of this invention, 100 mg of one of the compounds described herein is formulated with sufficient. finely divided lactose to provide a total amount of 580 to 590 mg to fill a size O hard gel capsule.
Binding Properties of Compounds at Cloned Receptors
A. Materials and Methods The binding properties of the compounds of the present invention were evaluated at one or more cloned receptors or native, tissue-derived transporters, using protocols described below.
Cell Culture
• COS-7 cells were grown on 150 mm plates in D-MEM with supplements (Dulbecco's Modified Eagle Medium with 10% bovine calf serum, 4 mM glutamine, 100 units/ml penicillin, 100 μg/ml streptomycin) at 37°C with 5% C02. Stock plates of COS-7 cells were trypsinized and split
1:6 every 3-4 days. Human embryonic kidney 293 cells were grown on 150 mm plates in D-MEM with supplements
(minimal essential medium) with Hanks ' salts and supplements (Dulbecco's Modified Eagle Medium with 10% ' bovine calf serum, 4 mM glutamine, 100 units/ml penicillin, 100 μg /ml streptomycin) at 37°c with 5% C02. Stock plates of 293 cells were trypsinized and split 1:6 every 3-4 days. Mouse fibroblast LM(tk-) cells were grown on 150 mm plates in D-MEM with supplements (Dulbecco's Modified Eagle Medium with 10% bovine calf serum, 4 mM glutamine, 100 units/mL penicillin, 100 μg/mL streptomycin) at 37°C with 5% C02. Stock plates of LM(tk-) cells were trypsinized and split._l-.10 every 3-4 days. Chinese Hamster Ovary (CHO) cells were grown on
150 mm plates in HAM's F12 medium with (HAM's F-12 with
10% bovine calf serum, 4 mM glutamine, 100 units / L penicillin, 100 μg/mL streptomycin) at 37°C with 5% C02.
Stock plates of CHO cells were trypsinized and split 1:8 every 3-4 days.
LM(tk-) cells were stably transfected with the human GALl or GAL3 receptor. CHO cells were stably transfected with the human GAL2 receptor.
Stable Transfection cDNAs for the human and rat GALl, and human and rat GAL3 receptors were transfected with a G-418 resistant gene into the mouse fibroblast LM(tk-) cell line by a calcium phosphate transfection method (Cullen, 1987).. Stably transfected cells were selected with G-418. Human and rat GAL2 receptors were similarly transfected into CHO cells.
Membrane Harvest '
Membranes were harvested from stably transfected LM(tk-) cells. Adherent cells were washed twice in ice-cold phosphate buffered saline (138 mM NaCI, 8.1 mM Na2HP04 , 2.5 mM KCI, 1.2 mM KH2P04, 0.9 mM CaC12 , 0.5 mM MgC12, pH 7.4) and lysed by sonication in ice-cold sonication buffer (20 mM Tris-HCl, 5 mM EDTA, pH 7.7). Large particles and debris were cleared by low speed centrifugation (200 x g, 5 in, 4°C) . Membranes were collected from the supernatant fraction by centrifugation (32,000 x g, 18 min, 4°C) , washed with ice-cold hypotonic buffer, and collected again by centrifugation (32,000 x g, 18 min, 4°C) . The final membrane pellet was resuspended by sonication into a small volume of ice-cold binding buffer (~1 ml for every 5 plates: 10 rnM NaCI, 20 mM HEPES, 0.22 mM KH2P04 , 1.26 mM Ca'Cl2, 0.81 mM MgS04, pH 7.4). Protein concentration was measured by the Bradford method (Bradford, 1976) using Bio-Rad Reagent, with bovine serum albumin as a standard. Membranes were held on ice for up to one hour and used fresh, or flash frozen and stored in liquid nitrogen. Membranes were prepared similarly from CHO cells.
The evidence presented in this invention suggests that GPCR-targeted molecules that bind to and antagonize the GAL3 receptor may be used for the treatment of pain,, specifically neuropathic pain, and other disorders. The design of such compounds may be optimized by determining their binding affinity at the recombinant GA 3 , GALl, and other known GPCR and transporter targets.
Additionally, the GAL3 antagonist (s) optimally may not bind at the following receptors due to possible side effects: human GAL2 ; human Hi histamine; human αiA adrenergic, human c1B adrenergic, human .αa.D adrenergic, human α2A adrenergic, human α2B adrenergic, and human oc2c adrenergic; human dopamine Di, D2, D3, D4, and D5; and the human 5HTι3, human 5HT1D, human 5HTιEr human 5HT1F, human 5HT2A, rat 5HT2C, human 5HT6, and human 5HT7 receptors. Radioligand Binding Assays and Enzymatic Assays The methods to obtain the cDNA of the receptors, express said ■ receptors in heterologous systems, and carry out assays to determine binding affinity are described as follows.
Galanin Receptors: Binding assays were performed according to the following published methods : human GAL3 (PCT International Publication No. WO 98/15570), human GALl (PCT International Publication No. WO 95/2260), human GAL2 (PCT International Publication No. WO 97/26853)-.
Human 5HT1B, 5HTiD, 5HT1E, 5HT1F., and 5HT7 Receptors: The * cell lysates of LM(tk-) clonal cell line stably transfected with the genes encoding each of these 5HT receptor-subtypes were prepared as described above. Cell membranes were suspended in 50mM Tris-HCl buffer (pH 7.4 at 37°C) containing 10 mM MgCl2 , O.2 mM EDTA, 10 M pargyline, and 0.1% ascorbate . The affinities of compounds -were determined in equilibrium competition
- binding assays by incubation for 30 minutes at 37 °C in the presence of 5 nM [3H] -serotonin. Nonspecific binding was determined in the presence of 10 μM serotonin. The bound radioligand was separated by filtration through
GF/B filters using a cell harvester.
Human 5HT2A Receptor: The coding sequence of the human 5HT2A receptor was obtained from a human brain cortex cDNA library, and cloned into the cloning site of pCEXV-3 eukaryotic expression vector. This construct was transfected into COS-7 cells by the DEAE-dextran method (Cullen, 1987) . Cells were harvested after 72 hours and lysed by sonication in 5 mM Tris-HCl, 5 mM EDTA, pH 7.5. The cell lysates were subjected to centrifugation at 1000 rpm for 5 minutes at 4°C, and the supernatant was subjected to centrifugation at 30,000 x g for 20 minutes at 4°C. The pellet was suspended in 50 mM Tris-HCl buffer (pH 7.7 at room temperature) containing 10 mM MgS04 , C .5 mM EDTA, and 0.1% ascorbate. The affinity of compounds at 5HT2A receptors were determined in equilibrium competition binding assays using [3H] ketanserin (1 nM) . Nonspecific binding was defined by the addition of 10 μM mianserin. The bound radioligand was separated by filtration through GF/B filters using a cell harvester.
5-HT1A Receptor:- The cDNA corresponding to the 5-HTXA receptor open reading frames and variable non-coding 5 ' - and 3 '-regions, was cloned into the eukaryotic expression vector pCEXV-3. These constructs were transfected transiently into COS-7 cells by the DEAE-dextran method (Cullen, 1987), and harvested after 72 hours. Radioligand binding assays were performed as described above for the 5-HT2A receptor, except that 3H-8-OH-DPAT was used as the radioligand and nonspecific binding was determined by the addition of 10 μM mianserin.
Other 5-HT Receptors: Other serotonin receptor binding assays were performed according to published methods: rat 5HT2C receptor (Julius et al . , 1988); and 5-HT6 (Monsma, et al . , 1993). The binding assays using the 5-HT4 receptor were performed according to the procedures described in U.S. Patent No. 5,766,879, the disclosure of which is hereby incorporated by reference in its entirety into this application.
Other receptors : Cell membranes expressing human dopamine D1( D2,- D4 and rat D3 receptors were purchased through BioSignal, Inc. (Montreal, Canada). Binding assays using the histamine Hi receptor; dopamine receptors; and αiA, αιB, and α2 ' adrenergic receptors may be carried out according to the procedures described in U.S. Patent No. 5,780,485, the disclosure of which is hereby incorporated by reference in its entirety into this application. Binding assays using the dopamine D5 receptor may be carried out according to the procedures described in U.S. Patent No. 5,882,855, the disclosure of which is hereby incorporated by reference in i ts entirety into this application. Binding assays for the human ctιD adrenergic receptor may be carried out according to the procedures described in U.S. Patent No. 6,156,518, the disclosure of which is hereby incorporated by reference in its entirety into this application.
The methods to determine binding affinity at native transporters are described in the following publications: 5HT transporter and NE transporter (Owens et al.', 1997), and DA transporter (Javitch et al, 1984).
Materials
Cell culture media and supplements were from Specialty Media (Lavallette, NJ) . Cell culture plates (150 mm and
96-well microtiter) were from Corning ' (Corning, NY) .
Polypropylene 96-well microtiter plates were from Co- star (Cambridge, MA) . Bovine serum albumin (ultra-fat free, A-7511) was rom Sigma (St. Louis, MO) . All radioligands were from New England Nuclear (Boston, MA) . Commercially available peptides and peptide analogs were either from Bachem California (Torrance, CA) or Peninsula (Belmont, CA) . All other materials were reagent grad .
Data Analysis Binding data were analyzed using nonlinear regression and statistical techniques available in the GraphPAD Prism package (San. Dipgo , CA) . Enzymatic ass.ay data were derived from a standard curve of reference compound data.
The selectivity ratios for compounds of the claimed invention were calculated from the binding data presented in Tables- 1-4, Table 7 and Table 9 of the subject application. More specifically, these ratios were calculated by dividing (a) the binding affinity (Ki value) of said compound to a particular receptor or transporter by (b) the binding affinity (Ki value) of said compound to the human GAL3 receptor. The data presented in Table 8 and Table 10, hereinafter, were calculated using the above described method.
For example, the GAL3/GAL1 selectivity ratio of 10-fold recited in claim 110 of the subject application is characteristic of Example -34. This binding ratio was calculated by dividing (a) the Ki value of 912 for the binding of Example 34 to the GALl receptor (see Table 1) by (b) the. Ki value of 23 for the binding of Example 34 to the human GAL3 receptor, thus obtaining the result of 39. Therefore the GAL3/GAL1 binding ratio for Example 34 was determined to be greater than 10-fold.
B. Results
The compounds described in the claimed invention were assayed using a panel of cloned receptors and native transporters . The preferred compounds were found to be selective GAL3 antagonists. The binding affinities and selectivity ratios of several compounds are illustrated in Tables 7-10.
Table 7 :
Antagonist binding affinity (Ki) at the human GAL3 receptor vs. serotonin receptors and several transporters .
Figure imgf000302_0001
* = >50000 ND = Not determined
Table 7 continued
Figure imgf000303_0001
* = >50000 ND = Not determined
Table 8 :
Antagonist selectivity ratios determined for the human GAL3 receptor vs . serotonin receptors and several transporters .
Figure imgf000304_0001
ND = Not determined
Table 8 continued
Figure imgf000305_0001
ND = Not determined
Table 9:
Antagonist binding affinity (Ki) at the human GAL3 receptor vs. alpha-adrenergic, dopamine, and histamine receptors .
Figure imgf000306_0001
* = >50000 ND = Not determined
Table 9 continued
Figure imgf000307_0001
* = >50000 ND = Not determined
Table 10:
Antagonist selectivity ratios determined for the human GAL3 receptor vs. alpha-adrenergic, dopamine, and histamine receptors.
Figure imgf000308_0001
ND = Not determined
Table 10 continued
Figure imgf000309_0001
ND = Not determined
GAL3 Receptor Localization
A. Materials And Methods
Preparation of the anti-GAL3 Antiserum BioSource International, Hopkinton, MA performed the immunization and maintenance of rabbits. Following a pre-immune bleed, one peptide for each GAL receptor was injected into a pair of New Zealand white rabbits.' The peptide sequences was chosen based on sequence • specificity and immunogenicity . The rabbit anti-GAL3 antiserum were raised against C-terminal epitopes corresponding to amino acids 357 - 370 (Genbank. accession number AF073798) . The peptides were conjugated to the carrier KLH (keyhole limpet hemocyanin) by a cross linker and subcutaneously injected into the rabbits. The generation of the anti- GAL3 antiserum required OVA followed by a third series of injections with the GAL3 peptide conjugated to tetanus toxoid (TTOX) . All injections were done using the Freund's Adjuvant System. Once immunoreactivity was established (see below) the antiserum was affinity purified by passing it over an agarose based column thiol coupled to its antigenic peptide. The column was washed and the antiserum was eluted using a low pH glycine buffer. The purified material was dialyzed, the optical density is taken at 280 λ and the purified antiserum was frozen.
Characterization of the antj-GAL3 antiserum
Recombinant GALl, GAL2 , and GAL3 receptor transfected cells To determine the ability of the GAL3 antiserum to recognize only the GAL3 receptor protein in vitro, COS-7 cells were grown on poly-L-lysine-coated plastic chamber slides (Nalge Nunc International, Naperville, IL) and transfected with recombinant rat GAL receptors (Genbank accession numbers U30290, AF010318, AF073798, respectively) or expression vector only (for mock- transfected cells) as previously described by Borowsky et al . (1999) . Receptor expression was confirmed by radioligand binding. Briefly, a subset of slides was washed three times in binding buffer (50 mM Tris, pH 7.5, 5 mM MgCl2, 1 mM EDTA, 0.1% bovine serum albumin, and 0.1% bacitracin) and incubated in 500 μl binding buffer containing porcine 125I-galanin (625,000 dpm) plus or minus 10 μM porcine galanin. After incubation at room temperature for 1 hour, the binding buffer was aspirated and slides were rinsed three times in ice cold
-50 mM Tris, pH 7.5. Cells were solubilized in 1 ml of
0.1 N NaOH and 0.05% sodium deoxycholate for 30 minutes then transferred to test tubes for gamma counting of 125I . To evaluate antibody activity another subset of slides were washed with phosphate buffered saline (PBS) (Sigma, St. Louis, MO) to remove the medium and fixed with 4% paraformaldehyde (PFA) (Sigma, St. Louis, MO)" -- then permeabilized using 0.2% ■ Triton X-100/PBΞ and incubated in 3% normal goat serum for 30 minutes to minimize nonspecific binding of the primary antibody'. Cells were incubated overnight at 4°C with the anti-GAL3 antiserum (1:1000 dilution). The cells were rinsed three times with PBS, incubated for 30 minutes at 25°C with goat anti-rabbit IgG (1:200 dilution) (Santa Cruz Biotechnology, Santa Cruz, CA) , rinsed and 'processed using the peroxidase-antiperoxidase (PAP) reaction of Sternberger et al . (1982). Control experiments for antibody specificity were (1) incubation of the cells in primary antiserum that had been preabsorbed with the respective antigenic peptide (20 μg/ml) , (2) incubation without the primary antiserum, or (3) incubation with the primary antiserum replaced by normal goat serum.
Western Blotting Membranes were prepared from COS-7 cells transiently transfected with the rat recombinant receptors GALl, GAL2 , and GAL3 as previously described (Borowsky et al . , 1999). Transfected cells were lysed by sonication in ice-cold sonication buffer (20- mM Tris-HCl, pH 7.7, 5 mM EDTA) . Cell lysates were subjected to centrifugation at 4°C for 10 minutes at 200 g. The supernatant was then fractionated by centrifugation at 4°C for 18 minutes at 32,000 g. The resulting membrane pellet was suspended into 50 mM Tris, pH 7.5 , 5 mM MgCl2, 1 mM EDTA. Protein samples (1-10 μg) were solubilized in 2 X Laemmli buffer
(Bio-Rad, Hercules, CA) and fractionated by SDS-PAGE- in
10% polyacrylamide gels. Proteins were transferred to polyvinylidine difluoride membranes for immunoblot analysis in ice-cold .25 mM Tris, pH 8, 192 mM glycine, 20% methanol as previously described by Harlow and Lane (1999) . Blots were incubated for 1 hour at 25°C in blocking buffer composed of 5% non-fat dried milk - in TTBS (0.1% Tween-20, 500 mM NaCI, 20 mM Tris, pH 7.5) then for 16 hours at 25°C . with the receptor-specific polyclonal antibody (1:1000 dilution in blocking buffer) (0.25 mg/ml for GAL2 or 1.5 mg/ l for GAL3). Immunoreactive bands were detected with the Phototope- HR.P Detection Kit for Western Blotting (New England BioLab, Beverly, MA) according to the protocol. Briefly, the blots were incubated with horseradish peroxidase-conjugated goat anti-rabbit IgG then developed with a mixture of L-αmiGLO plus hydrogen peroxide and recorded by chemiluminescence on Kodak Biomax-ML film (Kodak, Rochester, NY) .
Immunohistochemistry Male Sprague-Dawley rats, (200-250 g; Charles Rivers, Rochester, NY) were anesthetized by intraperitoneal injection of ketamine 20 mg/kg (RBI, Natick, MA) and xylazine 0.2 mg/kg (Bayer, Shawnee Mission, KS) then transcardially perfused with 200 ml PBS, pH 7.4 followed by 200 ml 4% PFA in PBS. The brains and spinal cords were' removed, blocked, and postfixed in the same fixative for 4 hours at 4°C then cryoprotected in 30% sucrose in PBS at 4°C for 48 hours before freezing on dry ice. Coronal brain sections and transverse spinal cord sections were cut at 30 μm using a freezing microtome.
Tissue sections were immediately immersed in PBS and stored at 4°C until use. Sections were processed free- floating according to the protocol outlined in NEN Life Science Products TSA (Tyramide Signal .Amplification) Indirect Kit. Briefly, tissue sections 'were per eabilized in 0.2% Triton X-100 (Sigma, St. Louis, MO)/PBS, incubated in 1% hydrogen peroxide (Sigma, St. Louis, MO) /PBS to remove endogenous peroxidase activity then blocked in TNB Buffer (0.1 M Tris-HCl, pH 7.5 , 0.15 M NaCI, and 0.5% Blocking Reagent. Sections were incubated for 24 hours at 4°C in either the anti-GAL2 or anti-GAL3 antiserum (1:100) . Following incubation with the primary antiserum, the tissue sections were washed in TNT Buffer (0.1 M Tris-HCl, pH 7.4, 0.15 M NaCI, 0.05%'Tween 20) followed by incubation at 25°C for 30 minutes with horseradish peroxidase (HRP) -conjugated goat • anti-rabbit i munoglobulin (1:200) (Sternberger Monoclonals Inc., Lutherville, MD) . Tissue sections were rinsed in TNT Buffer and incubated in a solution containing biotinylated tyra ide to amplify the signal • 'then rinsed in TNT buffer and incubated with HRP- conjugated to streptavidin at 25°C for 30 minutes. An immunoperoxidase reaction was done by incubating the section in 3 , 3 ' -diaminobenzidine (DAB) (0.05%) in O'.'l mM Tris, pH 7.4 and adding hydrogen peroxide to 0.006% immediately before use. The reaction was stopped in water and the sections mounted on microscopic" slide with mounting medium (40% ethanol: gelatin) and counterstained with Cresyl' violet then coverslipped for light microscopy.
Optimal GAL3 antibody concentrations (1:200) for rat brain sections were determined in preliminary titration experiments. Experimental controls in the tissue sections included (1) incubation in normal rabbit serum or (2) omission of the primary antiserum.
Analysis
COS-7 cells and tissue sections were examined using a Zeiss Axioscope. A total of 6 male rats were examined with the anti-GAL3 antiserum. The identification of GAL3-LI in the transfected cells and brain regions was based on the presence of immunoreactivity appearing as a brownish precipitate in individual cells and their projections or in the neuropil of the tissue by light microscopy. The descriptions of neuroanatomic boundaries are based on the atlas of Paxinos and Watson (1998) .
B. Results
Characterization of the GAL3 antiserum
Recombinant GALl, GAL2 , and GAL3 receptor transfected cells
The ability of the anti-GAL3 antiserum to recognize only the GAL3 receptor protein in vitro was established by performing ' immuhoc^lfochemistry on COS-7 cells transiently transfected with the recombinant receptor proteins for the rat GALl, GAL2 , and GAL3 , or mock- transfected with vector only. Specific porcine _ 125I- galanin binding was detected for all transfeetants except mock-transfected cells . An immune response was detected only in the COS-7 cells incubated with the antiserum generated for the particular recombinant receptor. Specifically, no immune reaction was observed with the anti-GAL3 antiserum (1:1000) in GALl or GAL2 transfected cells. Furthermore, -no visible immune reaction' was detected, in the mock-transfected cells. Incubation of the cells in primary antiserum that had been preabsorbed with the antigenic peptide (2.0 μg/ml) or without the primary antiserum or with the primary replaced by normal goat serum did not result in an immune response.
Taken together, these data demonstrate that the anti- GAL3 antiserum recognizes the receptor against which it was generated and does not show cross reactivity with other known GAL receptors .
Western Blots To determine the specificity of the anti-GAL3 antiserum, COS-7 cells were transiently transfected either with recombinant rat GAL2 or GAL3 receptors or with expression vector only; membranes were then isolated for evaluation by immunoblotting (see Figure 1). The anti- GAL3 antiserum labeled proteins in membranes only from rat GAL3-transfected ■ cells; a predominant band was evident with an apparent molecular weight. of approximately 56 kDa (Figure 1) , somewhat, higher than the amino acid-derived value of 40.4 kDa. (For - comparison, apparent molecular weights determined by SDS-PAGE are 56 kDa (Servin et al . , 1987) or 54 kDa (Chen et al . , 1992) for native GAL receptors purified from rat brain and 54 kDa (Amiranoff et al . , 1989) for native GAL receptors purified from Rin m 5F cells . These values are all higher than the amino acid-derived value any known GAL receptor subtype, including the value of 38.9 kba for rat GALl (Parker et al . , 1995). The apparently high molecular weight observed for rat GAL3 very likely reflects post-translational processing such as glycosylation; note ' that rat GAL3 contains multiple N-terminal glycosylation sites (Smith et al . , 1998). Relative to the predominant band, additional species of higher molecular weight as well as lower molecular weight were labeled by the corresponding antiserum (Figure 1). These are presumably ' receptor- related species composed of protein aggregates of C- terminal fragments, as they -are absent in mock- transfected cells. Immunohistochemical distribution of GAL3-LI in the CNS GAL3-like immunoreactivity (GAL3-LI) was observed in many regions of the brain, specifically, the neocortex, septum, hippocampus, amygdala, hypothalamus, brainstem, cerebellum, and spinal cord. Throughout the brain and spinal cord GAL3-LI was found to be associated with neuronal profiles however, there was neuropil staining observed in several brain regions. GAL3-LI was high in the septum, basal forebrain, and spinal cord dorsal horn. • Lower GAL3-staining was observed in., the. neocortex, thalamus, hypothalamus, hippocampus, and ventral horn of the spinal cord. Several regions of the CNS almost exclusively expressed GAL3-LI, specifically the caudate-puta en, accumbens nucleus, dorsal raphe and regions of the central gray. There was no observable staining of the fiber tracts.
The specificity of the anti-GAL3 antiserum was determined in tissue sections by (1) omission of the primary antiserum or (2) incubation with normal rabbit serum. No specific staining was observed in either condition. Preabsorption of the GAL3 primary antiserum with the antigenic peptide (10 μg/ml) decreased but did not completely block staining in the tissue sections as in the transfected cells. This was most likely related to the different localization approaches. In the transiently transfected COS-7 cells the expression of GAL3 receptor protein was ' relatively high therefore, indirect immunocytochemistry with no amplification was- used. In contrast, GAL3 receptor protein expression is presumed to be relatively lower in the tissue sections and for that reason the TSA (amplification) technique was employed. It is possible that because of the amplification (1000-fold) in the TSA technique even small amounts of unabsorbed antiserum may result in a signal.
Olfactory system
The main olfactory bulb contained a weak GAL3-LI in scattered cells of the glomerular and internal granule layers; the mitral cells did not contain GAL3-LI. In the anterior olfactory nucleus weak GAL3-LI was detected in random cell bodies and fibers. GAL3-LI was not detected above background in the superficial plexiform layer of the pirifor cortex, but weak staining was observed in the neuropil of layer 2 and in the cell bodies of layer 3. Weakly stained cells were observed in the islands of Calleja, and tenia tecta; many cells in the olfactory tubercle were moderately stained.
Regi ons of the Telencephalon
Cerebral cortex
GAL3-LI was widespread in the cerebral cortex and the distribution pattern extended rostrocaudally . Moderately stained GAL3 -positive fibers were detected in layers II and III. Numerous pyramidal-shaped somata in layers II through V contained moderate GAL3-LI, and in some instances staining could be seen extending into the cell's dendritic arborizations. In layer VI, GAL3-LI was present only in the cytoplasm of scattered small cells. A weak to moderate GAL3-LI was seen in numerous cell bodies in the anterior cingulate and retrosplenial cortices. The entorhinal cortex contained GAL3-positive cell bodies and a finely stained neuropil.
Septal region
An extensive and densely stained fiber network was seen throughout the entire lateral , intermediate and medial septal nuclei. The dorsal division of the lateral septum contained scarce moderately GAL3 -positive somata.
Basal ganglia and Basal Forebrain GAL3-LI was detected in the receiving regions of the basal ganglia; thus • GAL3 may mediate the internal organization of the basal ganglia. Many moderately labeled medium-sized round cells were evenly distributed throughout the caudate-putamen in addition to a weakly immunoreactive neuropil. Moderately positive cells were visible along the medial border of the globus pallidus. Numerous moderately GAL3 -positive cell bodies and fibers were present in the shell and core of the accumbens nucleus. The cell bodies of the subthalamic nucleus, a relay nucleus in the basal ganglia, contained weak GAL3- LI.
Moderately GAL3-positive cells were present in several nuclei of the basal forebrain: the horizontal limb of the diagonal band, the basal nucleus of Meynert, and the. substantia innominata.
Hippocampal Region
A large number of granule cells in the dorsal dentate gyrus and pyramidal-shaped cells in the polymorphic dentate gyrus displayed a weak to moderate GAL3-LI. Clusters of very fine light- to moderately GAL3- immunoreactive fiber networks were evident in the molecular layer of the dentate gyrus . Light to moderate GAL3-LI was observed in the perikarya of the pyramidal- shaped cells in Ammon's horn and as a fine neuropil in the stratum oriens and stratum radiatum of fields CA1 , CA2 , and CA3. Labeled cells and fibers were observed in the rostral subiculum. Caudally, moderate to weak GAL3- LI was seen in the granule cells of the ventral dentate gyrus with weaker labeling in random cell bodies throughout the dorsal subiculum and the ventral CA1 field.
Amygdala and Extended Amygdala
In general, GAL3-LI was weak throughout the amygdala.
Scattered cell bodies and fibers exhibited weak staining in several nuclei: the lateral, medial, posteroventral , posterodorsal' medial, and posteromedial cortical nuclei. GAL3 -positive cells were present in the anterior cortical amygdaloid nuclei, amygdalopiriform transition and amygdalohippocampal areas. Very fine GAL3-posit.ive fibers with scattered moderately labeled cells were detected in the central amygdaloid nucleus . The divisions of the bed nucleus of the stria terminalis displayed a weak cellular GAL3-LI;- moderately stained fibers were present in the nucleus of the lateral "olfactory tract.
Regions of the Diencephalon
Hypothalamus and preoptic area GAL3-LI was fairly extensive in the hypothalamus. Moderate GAL3-LI could be seen in the large cell bodies extending into the dendrites in the magnocellular preoptic nucleus. Relatively high GAL3 staining was observed in cells and neuropil of the suprachiasmatic and arcuate nuclei and as a dense fiber network in the median eminence. Moderately stained GAL3-positive fibers could be seen in the optic chiasm near the ventral border of the superchiasmatic nucleus. Moderate labeling was detected in cells and neuropil in several nuclei: the lateroanterior, lateral and anterior hypothalamus, supraoptic, dorsomedial, paraventricular parvocelϊular, perifornical, ventromedial , and medial mammillary nuclei, and in cell bodies and fibers of the ventromedial nucleus . .
Thalamus and epi thalamus
GAL3-LI was "generally weak throughout the thalamus. The highest GAL3-LI in the thalamus was detected in the cell bodies and neuropil of the geniculate nuclei and the anteromedial thala ic nucleus. The reticular, paraventricular, central, mediodorsal, anterodorsal, anteromedial, anteroventral, lateral posterior, anterior pretectal, and posterior thalamic nuclei, the zona incerta and the nucleus of the fields of Forel contained light to moderately stained cells. The ventroposterior lateral and ventroposterior medial nuclei contained GAL3-positive cells and fibers. Weak labeling was detected in the cell bodies in the medial habenular nucleus with scarce positive cells in 'the lateral habenular nucleus .
Midbrain/Mesencephalon The neuropil and scattered cells in the zonal layer of the superior colliculus were moderately labeled. Light to moderately stained GAL3-positive cell bodies were observed in the superficial, intermediate gray and deep gray layers with a random positive cell"' in the optic nerve layer. Moderately labeled cell bodies were present in several midbrain regions : the dorsal and lateral ventral divisions of the central gray, the external cortex of the inferior colliculus, oculomotor, and rhabdoid nuclei and tegmental area. Labeled cells were detected within the dorsal raphe and projections from these cells were seen converging toward the midline of the raphe. In the midbrain tegmentu , moderate GAL3-LI was present in the perikarya and dendrites of the large neurons of the red nucleus and retrorubral field. Small-sized pyramidal shaped weakly stained cell bodies were seen throughout the substantia nigra, reticular part with weaker labeling of the neuropil; moderately dense labeling of neuronal perikarya was detected in the compact part. The pontine nucleus displayed a light to moderate GAL3 -positive neuropil.
GAL3-LI was extensive throughout' the brain stem. Moderate GAL3-LI was detected in the neuropil and cell bodies of several nuclei: the medial vestibular, prepositus hypoglossal, dorsal cochlear, and facial nuclei. Very weak • GAL3-LI was observed in the gracile nucleus and no immunoreactivity was detected in the cuneate and hypoglossal nuclei. Moderate to light labeling was evident in large cell bodies and dendrites in the spinal vestibular and the dorsal motor nucleus vagus; weaker labeling was seen in the gigantocellular reticular, gigantocellular reticular, alpha, and lateral paragigantocellular nuclei. . Numerous moderately labeled
"small round cells and neuropil was detected in the nucleus of the solitary tract; the parvicellular reticular nucleus contained moderately labeled small cells. .Intense staining was observed in" fibers in the area postrema and in cell bodies in the locus coeruleus. Light' to moderate GAL3-LI was observed in scattered somata throughout the layers of the caudal spinal trigeminal nucleus, and labeled fibers were also seen in the superficial layer. Moderately heavy GAL3-LI was present in neuronal perikarya and dendrites in the trapezoid nucleus and in fibers in the subnuclei A, B, and K of the inferior olive. The pontine reticular nucleus contained low to moderate labeling of large- sized neurons.
Cerebellum
In the cerebellar cortex, moderate GAL3-LI appeared to be present in fibers that passed from the granule cell layer through the Purkinje cell layer. The molecular layer contained a weak to moderately stained very fine fiber network. Weak staining was visible in ' the neuronal perikarya of the deep cerebellar nuclei.
Spinal cord
GAL3 -positive cells were detected throughout the dorsal and ventral horns of the spinal cord. In the superficial laminae of the dorsal horn small moderately immunoreactive cells and neuropil were observed.
Moderately stained cell bodies were scattered throughout laminae III, IV and the laminae of the ventral horn, while labeled cells and neuropil were seen around the central canal in lamina X. GAL3-positive axons were observed in the ventral funiculus converging toward the ventral root. All levels of the spinal cord exhibited a comparable laminar distribution. The distribution of rat GAL3 protein in the CNS using receptor subtype selective polyclonal antibodies and tyramide signal amplification (TSA) immunocytochemistry is illustrated in Table 12. These were qualitative evaluations for the rat GAL3 receptor protein distribution based on the relative intensity of the chromogen (3 , 3 ' -diaminobenzidine) observed in individual cells at the microscopic level.
A total of 4 rat brai s were analyzed for this study. As shown in Table 12, the strength of the signal obtained in various regions of the rat brain was graded as eak (+ ) , or moderate (++) or intense (+++) .
Figure imgf000325_0001
Figure imgf000326_0001
Figure imgf000327_0001
Figure imgf000328_0001
Figure imgf000329_0001
Figure imgf000330_0001
Figure imgf000331_0001
Figure imgf000332_0001
Discussion The GAL3 antiserum was characterized using recombinant GAL receptors in transiently transfected COS-7 cells and Western blot analysis and the specificity of the GAL3 antiserum to recognize only the cognate ' receptor in vi tro was established. The anatomical distribution of the GAL3 receptor protein in the rat CNS was determined using a modified immunohistochemical technique to enhance sensitivity and delectability via tyramide signal amplification (Toda et al . , 1999).
The results indicate that the expression GAL3-LI was primarily found in neuronal profiles with neuropil labeling detectable in several areas. In general, the distribution of GAL3-LI is in good agreement with the reported distribution for galanin-LI, galanin binding sites, and GAL3 mRNA in the rat brain "(for recent review, Branchek et al . , 2000) . Overall, GAL3-LI was found to be extensively distributed throughout the brain: the neocortex, septum, hippocampus, amygdala, hypothalamus, brain stem, cerebellum and spinal cord. Paralleling the distribution of galanin binding sites, GAL3-LI was observed in ventral regions of the brain, specifically the horizontal diagonal band, substantia inno inata, olfactory tubercle, and ventral hippocampus. However, there was discordance between XzsI-galanin binding and the GAL3 receptor protein distribution particularly in the neocortex, dorsal hippocampus, and cerebellum (Skofitsch and Jacobowitz, 1986), regions where binding sites have not been identified by receptor autoradiography .
The present results showed several interesting observations in the distribution of GAL3-LI relating to- potential therapeutic applications for the GAL3 receptor. Galanin has been reported to be involved in the regulation of cholinergic neurotransmission in the hippocampus and in the basal forebrain via modulation of acetylcholine release. Therefore, the development of a galanin receptor antagonist to block the inhibition of firing of cholinergic neurons may have a potential therapeutic application in the treatment of some of the learning and memory deficits of Alzheimer's disease (AD) (for review, Mufson et al . 1998) . GAL3-LI was identified in several cholinergic regions of the rat brain: the horizontal diagonal band, basal nucleus of Meynert, substantia innominata, bed nucleus of the stria terminalis, and the hippocampus. The GAL3 protein has been localized to other regions of the brain, the entorhinal cortex and locus coeruleus, that exhibit increased galanin receptor binding and galanin expression in AD providing further evidence for the potential involvement of GAL3 in AD.
Substantial evidence suggests that galanin is involved in the regulation of energy and nutrient balance. Injections of galanin into the hypothalamus have been shown to increase food intake. Concordant with the localization of GAL3 mRNA in the hypothalamus, GAL3-LI was detected in several hypothalamic nuclei involved in the regulation of feeding: the paraventricular, arcuate, dorsomedial, ventromedial and medial preoptic areas. This localization suggests that the GAL3 receptor may be a potential therapeutic target in the regulation of food intake and body weight and thus be useful in the treatment of eating disorders. GAL3 may be a potential therapeutic target in the development of analgesic drugs. The presence of the receptor in the target regions of nociceptive primary afferent fibers, the superficial layers of the spinal trigeminal nucleus and dorsal horn of the spinal cord, suggests that GAL3 could potentially modulate nociceptive information from the periphery. GAL3 is in a position to potentially mediate the influence of excitatory glutamatergic nociceptive primary afferents from the dorsal root ganglia in the superficial layers of the spinal cord.
In Vivo Model
Chronic Constriction Nerve Injury Model of Neuropathic Pain The aim of this study was to assess the potential analgesic effects of Example 92 following intraperitoneal administration at the doses of 3 , 10 and 30 mg/kg, respectively, in • ■ an animal model of neuropathic pain. A peripheral mononeuropathy was induced in the right hind limb of rats following a chronic constriction - .nerve injury (Bennett and Xie, 1988) , and the development of mechanical allodynia and thermal hyperalgesia was monitored using _ established behavioral tests (Attal, N. , et al . , 1990; Hargreaves , K. , et al. , 1988) .
Method
Animals Male Sprague-Dawley rats within the weight range of 200- 225 g, and approximate age 7-9 weeks, were allowed to acclimate for a minimum of 6 days prior to the start of ' the behavioral testing.
All rats underwent a chronic constriction 'nerve injury, and of these, those that successfully developed allodynia and hyperalgesia were allocated to treatment groups .
Treatment Groups and Dosing of Test Substance - -
There were 5 separate treatment groups (with a minimum of 10 rats per group) . The treatment • groups were as follows : Group C received Morphine at 10 mg/kg (n = 10) Group D received Vehicle for Example 92* at 1 ml /kg (n = 10) (* 100% DMSO)
Group E received Example 92 at 30 mg/kg (n = 10) Group F received Example 92 at 3 mg/kg (n = 10) Group' G received Example 92 at 10 mg/kg (n = 10)
The dose volume for all treatments was 1 ml/kg. Each rat received a single i.p. dose of the test substance, reference substance or vehicle on Day 12 PO. Test substance and vehicle dosing solutions were encoded (C- G) so that the observers were unaware of the identity of the treatment groups .
Behavioral Testing
The behavioral tests (Von Frey filament and Thermal Plantar Tests - see below) were performed on all rats on 3 separate days prior to surgery, to establish baseline values. The pre-surgery baseline values were calculated as the mean of the last 2 days testing (the data from the first day of testing were not included as this was classed as part of the acclimating period) . The sequence of tests was always mechanical allodynia (Von Frey Test) followed by thermal hyperalgesia (Thermal Plantar Test) , with a minimum 5 min period allowed between the 2 tests.
Mechanical Allodynia :
Each animal was placed in a wire mesh cage and a series of Von Frey filaments (ranging from filament handle number 3.61 to 6.10) applied to the plantar surface of the hind paw, from below. The filaments were applied in ascending order (starting with the weakest force) and the withdrawal threshold for both the ipsilateral and contralateral hind paws was evaluated. Each filament was indented on the plantar surface of the foot to the point where it just started to bend, and this was repeated approximately 8-10 tiπies per filament at a frequency of approximately 1 Hz . The withdrawal threshold was defined as the lowest force of two or more consecutive Von Frey filaments to elicit a reflex withdrawal response .
Thermal Hyperalgesia :
Each rat was placed in a clear plastic chamber with a glass floor and allowed a short period to acclimatize to the new environment (approximately 5 min.) ._ The animals were then challenged with a radiant Infrared (IR) heat source, directed at the plantar surface of the hind paw from below, and the withdrawal latency of both the ipsilateral and contralateral hind paws was evaluated. The infrared intensity was set at IR50 and the maximum length of exposure to the IR source was 18 s. Non- responding animals were allocated a withdrawal latency of 18 s.
Surgical Procedure
The animals were surgically prepared over 5 days. Each rat was anaesthetized with sodium pentobarbitone (60 mg/ml; 0.6 ml/kg dose, intraperitonealy; batch number 00230; expiry date 22 May 03) and then supplemented as necessary with isoflurane (1-3% in oxygen) . The surface around the incision site was shaved and then sterilized with surgical spirit. Under aseptic conditions the right sciatic nerve was exposed by blunt dissection at mid- thigh level and approximately 1 cm of nerve was freed of adhering connective tissue. Four chromic cat gut (4.0) ligatures, spaced at approximately 1 mm intervals, were then tied so as to barely constrict the nerve (as viewed under 40X magni ication) to induce a peripheral mononeuropathy in the right hind limb. The overlying muscle and skin were then closed in layers using suture material, and the anesthesia discontinued. On recovery from anesthesia, the rats were re-housed with their cage mates on soft padded bedding overnight (to reduce the risk of infection) and subsequently on sawdust bedding following full recovery. The animals were allowed 4 full days to recover before the behavioral testing was recommenced .
Testing Paradigm Following surgery, the behavioral testing was resumed on Day 5 PO (post-operative), and then repeated on days 7, 9, and 11, to monitor the development of allodynia and hyperalgesia. Only those animals that developed both mechanical allodynia and thermal hyperalgesia in their nerve-injured hind paw were used in the main study. The animals were deemed to have developed mechanical allodynia if their nerve-injured hind paw exhibited a withdrawal response of ≤ 5 g of force (which corresponds to monofilament number 4.56 or less) on Day 11/12 PO, when challenged with the Von Frey filaments. Similarly, they were deemed to have developed thermal hyperalgesia if their nerve-injured hind paw exhibited a withdrawal latency (sec) which showed a > 30% difference from the mean right paw, pre-surgery value, for the Thermal Plantar Test on Day 11/12 PO. On Day 12 PO, a single i.p. dose of test substance, reference substance (morphine) or vehicle was administered to each rat. On Day 12, all the animals were then tested with the Von Frey filaments at approximately 30 and 90 min post dose (PD) and with the Plantar Device at approximately 40 and 100 min PD, with a minimum 5 minute period allowed between the 2 tests, to investigate treatment- -effect .
Statistical Analysis
The Von Frey data were logarithmically transformed [log10 of (force in grams x 10000)] prior to analysis. Statistical comparisons were made between treatment groups using parametric (e.g. one-way analysis of variance, Dunnett's t-test, Student's t-test) or non- parametric (e.g. Kruskal-Wallis statistic, Dunn's test, Mann-Whitney CJ-test) statistical procedures. The choice of parametric or non-parametric test was based on whether the groups to be compared satisfied the homogeneity of variance criterion (evaluated by the Levene Mean test or F-test) . Statistical significance was assumed when P ≤ 0.05.
Results The majority of the animals which underwent a chronic constriction injury of the right sciatic nerve successfully developed both neuropathic pain states. These animals exhibited a marked increase in sensitivity to both the behavioral tests in the days post-injury, indicative of the development of a peripheral mononeuropathy. This change in sensitivity was evident from as early as day 5 PO, reaching a maximum from approximately day 10 PO onwards. Mean Von Frey pre-surgery baseline responses for those animals included in the study were 57.65 ± 0.98 g (left paw) and 59.45 ± 1.36 g (right paw). Eighty-nine percent of the animals which underwent a chronic constriction nerve injury successfully developed mechanical allodynia by Day 11/12 PO .
Mean plantar pre-surgery baseline responses for those animals included in the study were 13.1 ± 0.2 s (left paw) and 12.6 ± 0.2 s (right paw). The mean plantar responses prior to dosing were 12.0 ± 0.2 s (left paw) and 5.6 ± 0.1 s (right paw) . Eighty-seven percent of the animals which underwent a chronic constriction nerve injury successfully developed thermal hyperalgesia by Day 11/12 PO .
Effects of Example 92 on Behavioral Test Responses
Mechanical All odynia : Intraperitoneal administration of Example 92 significantly increased the withdrawal threshold of the nerve-injured hind paw to Von Fey filament challenges at the highest dose tested (30 mg.kg) . Thee changes were significantly different from vehicle (100% DMSO) control group values at the 30 min PD time point only. Administration of 30 mg/kg Examplee 92, resulted in a significant increase in the withdrawal threshold of the nerve-injured paw to 25.98 ± 8.25 g compared to the vehicle group value of 4.82 ± 2.77 g'(P ≤ 0.05), at 30 min. PD. At 90 min. PD the withdrawal threshold was still slightly raised (11.73 ± 6.43 g compared to 2.43 ± 1.48 g in the vehicle treated group), however this was not found to be significant. Administration of Example 92 at 3 or 10 mg/kg (i.p.) had no significant effect on the withdrawal threshold of the nerve-injured paw at any of the time points tested. No significant changes were observed in the responses of the uninjured (contralateral) left paw at any of the doses or at any of the time points tested, compared with vehicle control group values. (These results are summarized in Figures 2 and 3. )
Intraperitoneal administration of the reference substance, morphine (10 mg/kg), significantly increased the withdrawal threshold cf the nerve-injured hind paw to Von Frey filament challenges. (See Figures 2 and 3.)
Thermal H^speralgesia :
Intraperitoneal administration of Example 92 at 3, 10 and 30 mg/kg had no significant effect on the withdrawal latency of the nerve hind paw, to the thermal plantar device at either time points tested (approximately 40 and 100 min. PD) . . No significant changes were observed in the responses of the uninjured (contralateral) left paw following Example 92 administration at any of the doses or time points tested, compared with vehicle control group values. (These results are' 'summarized in Figures 4 and 5. )
Intraperitoneal administration of morphine (10 mg/kg) significantly increased the withdrawal latency of the nerve-injured hind paw to the Thermal Plantar Device at
• both time points tested (approximately 40 and 100 min.
PD) . (See Figures 4 and 5.) Discussion
The chronic constriction injury model of Bennett and Xie (1988) is one of the more commonly used animal models of neuropathic pain. Within one week the animals showed altered spontaneous behaviors which are consistent with the presence of neuropathic pain. In addition, the affected limb is demostrably hyperalgesic (i.e. displays an increased sensitivity to noxious stimuli) , as well as allodynic (i.e. displays a reduced threshold to non- painful stimuli) (Attal et al . , 1990). This study provides behavioral evidence that an experimental peripheral mononeuropathy produced by sciatic nerve ligation, produces significant pain-related behavioral changes in the rat, consistent with the development of mechanical allodynia and thermal hyperalgesia (Gautron, M. , et al, 1990). These abnormal pain states were evident from as early as day 5 PO, showing maximal changes from approximately day 9 PO onwards. A similar proportion of animals developed mechanical allodynia (89%) compared to thermal hyperalgesia (87%), with 79% successfully developing both pain states in their nerve- injured paw.
From the behavioral data obtained in the present study, it is apparent that i.p. administration of 'Example 92 at a dose of 30 mg/kg significantly attenuates specific pain-related behaviors in neuropathic rats, namely mechanical allodynia. These results are consistent with analgesic properties.
The withdrawal threshold of the nerve-injured paw to Von Frey filament challenges was significantly increased at approximately 30 in. PD following administration of Example 92 at a dose of 30 mg/kg i.p. Unlike morphine (10 mg/kg i.p.) which also elicited significant contralateral effects in the Von Frey test at 30 and 90 min post-dose, Example 92 showed no significant contralateral effects, at any of the doses tested.
Intraperitoneal administration of the reference substance, morphine, resulted in a significant increase in the withdrawal threshold (Von Frey challenge) of the nerve-injured paw for up to 90 min PD at 10 mg/kg. In addition, significant contralateral effects were observed at both the 30 and 90 min. time points, indicative of the central effects of morphine. Morphine also caused a significant increase in the withdrawal latency to a noxious heat stimulus (thermal plantar test) for up to 100 min PD in both the nerve-injured and contralateral hind paws. These results are consistent with morphine's known pharmacological properties as an opioid analgesic.
These results therefore provide behavioral evidence of a specific analgesic role for Example 92 in neuropathic rats. The analgesic properties were selective, attenuating mechanical allodynia in the nerve-injured paw only (unlike the effects of the reference substance, morphine (10 mg/kg) , which also produced significant contralateral effects in the mechanical allodynia test) . References
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Claims

What is claimed is:
1. The invention provides a method of treating a subject suffering from an abnormality which comprises administering to the subject an amount of compound effective to treat the subject's abnormality wherein the compound has the structure:
Figure imgf000351_0001
wherein each of Yi, Y2, Y3, and Y4 is independently -H; straight chained or branched Cj-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, or C5-C7 cycloalkenyl; -F, -Cl, -Br, or -I; -N02 ; -N3 ; -CN; -OR4, -OCOR4, -COR4, -NCOR4 , -N(R4)2 , -CON(R4)2, or -COOR4; aryl or heteroaryl; or any two of Yi , Y2, Y3 and Y4 present on adjacent carbon atoms can constitute a methylenedioxy group;
wherein each R4 is independently -H; straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C -Cη alkenyl or alkynyl; C3-C7 cycloalkyl, C5-C7 cycloalkenyl, aryl or aryl (Cι-C6) alkyl ;
wherein A is A' , straight chained or branched Cι-C7 alkyl, aryl, heteroaryl, aryl (Ci-Cβ) alkyl or heteroaryl (Cι-C6) alkyl ;
Figure imgf000352_0001
wherein A' is
Figure imgf000352_0002
wherein Ri and R2 are each independently H, straight chained or branched C!~C alkyl, -F, -Cl, -Br, -I, - N02, or -CN;
wherein R3 is H, straight chained or branched Cι-C7 alkyl, -F, -Cl, -Br, -I, -N02 , -CN, -OR6, aryl or heteroaryl;
wherein R5 is straight chained or branched Cι-C7 alkyl, -N(R4)2, -OR4 or aryl;
wherein R6 is straight chained or branched C!-C7 alkyl or aryl;
wherein B is C3-C7 cycloalkyl, C5-C7 cycloctikenyl , adamantyl, aryl, pyridyl, pyridazinyl, pyrimidinyl, pyr.azinyl, triazinyl, indolizinyl, indol-4-yl , indol-
5-yl, indol-6-yl, indol-7-yl, isoindolyl, benzo [b] furan-4-yl, benzo [b] furan-5-yl , benzo t o] furan- 6-yl, benzo [b] furan-7-yl , benzo [b] thiophen-4-yl , benzo [b] thiophen-5-yl, benzo [b] thioph.en-6-yl, benzo [b] thiophen-7-yl, indazolyl, benzimidazolyl, benzo [b] thiazolyl, purinyl, imidazo [2 , 1-b] tri±azolyl, quinolinyl, isoquinolinyl, quinazolinyl, 2,1,3- benzothiazolyl, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, benzoxazolyl, benzisoxazolyl, cinnolinyl, quinoxalinyl, 1, 8-naphthridinyl, pteridinyl, or phthalimidyl; provided however, if B is aryl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, indolizinyl, indol-4-yl, indol-5-yl, indol-6-yl, indol-7-yl, isoindolyl, benzo [b] furan-4-yl , benzo [b] furan-5-yl, benzo [b] furan-6-yl, benzo [b] furan- 7-yl, benzo [b] thiophen-4-yl, benzo [b] thiophen-5-yl , benzo [b] hiophen-6-yl , benzo [b] thiophen-7-yl , indazolyl, benzimidazolyl, benzo [b] thiazolyl, purinyl, imidazo [2 , 1-b] thiazolyl, quinolinyl, isoquinolinyl, quinazolinyl, 2 , 1, 3 -benzo thiazolyl , furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, benzoxazolyl, benzisoxazolyl, cinnolinyl, quinoxalinyl, 1 , 8-napthyridinyl , pteridinyl, or phthalimidyl the carbon atom or carbon atoms ortho to the nitrogen atom of the imine bond may only be substituted with one or more of the following -F, -Cl, -Br, -I, -CN, methyl, ethyl or methoxy;
wherein n is an integer from 1 to 4 inclusive.
2. The method of claim 1, wherein A is aryl, heteroaryl, heteroaryl (Cι-C6) alkyl or - (CH2 ) n-CC-R4; wherein the aryl is substituted with -OH.
3. The method of claim 1, wherein A is aryl, heteroaryl, or heteroaryl (C;ι-C6) alkyl ; and
wherein aryl is substituted with -F, -Cl, -Br, -I, -N02 , -CN, straight chained or branched Cι-C7 alkyl, straight chained or branched Cι~C monofluoroalkyl, straight chained or branched Cι~C7 polyfluoroalkyl, straight chained or branched C2-C7 alkenyl, straight chained or branched C2-C7 alkynyl, C3-C7 cycloalkyl,' C3-C monofluorocycloalkyl, C3-C7 polyfluorocycloalkyl, C5-C cycloalkenyl, -N(R4)2, - OR4, -SR4, -OCOR4, -COR4, -NCOR4, -C02R4, -CON(R4)2 or -(CH2)nO(CH2)mCH3.
4. The method of claim 1, wherein the abnotmality is neuropathic pain.
PCT/US2003/024869 2002-08-07 2003-08-07 Gal3 antagonists for the treatment of neuropathic pain WO2004014307A2 (en)

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