CA2259583A1 - Azolo triazines and pyrimidines - Google Patents

Azolo triazines and pyrimidines

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Publication number
CA2259583A1
CA2259583A1 CA002259583A CA2259583A CA2259583A1 CA 2259583 A1 CA2259583 A1 CA 2259583A1 CA 002259583 A CA002259583 A CA 002259583A CA 2259583 A CA2259583 A CA 2259583A CA 2259583 A1 CA2259583 A1 CA 2259583A1
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compound
alkyl
formula
cycloalkyl
stereoisomeric forms
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CA002259583A
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French (fr)
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CA2259583C (en
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Liqi He
Paul Joseph Gilligan
Argyrios Georgios Arvanitis
Robert John Chorvat
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Bristol Myers Squibb Pharma Co
Original Assignee
Du Pont Pharmaceuticals Company
Liqi He
Paul Joseph Gilligan
Argyrios Georgios Arvanitis
Robert John Chorvat
The Du Pont Merck Pharmaceutical Company
Bristol-Myers Squibb Pharma Company
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Application filed by Du Pont Pharmaceuticals Company, Liqi He, Paul Joseph Gilligan, Argyrios Georgios Arvanitis, Robert John Chorvat, The Du Pont Merck Pharmaceutical Company, Bristol-Myers Squibb Pharma Company filed Critical Du Pont Pharmaceuticals Company
Priority to CA002532925A priority Critical patent/CA2532925C/en
Priority claimed from US08/899,242 external-priority patent/US6124289A/en
Priority claimed from PCT/US1997/013072 external-priority patent/WO1998003510A1/en
Publication of CA2259583A1 publication Critical patent/CA2259583A1/en
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Publication of CA2259583C publication Critical patent/CA2259583C/en
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Abstract

Corticotropin releasing factor (CRF) antagonists of formula (I) or (II) and their use in treating anxiety, depression, and other psychiatric, neurological disorders as well as treatment of immunological, cardiovascular or heart-related diseases and colonic hypersensitivity associated with psychopathological disturbance and stress.

Claims (74)

1. A method of treating affective disorder, anxiety, depression, headache, irritable bowel syndrome, post-traumatic stress disorder, supranuclear palsy, immune suppression, Alzheimer's disease, gastrointestinal diseases, anorexia nervosa or other feeding disorder, drug addiction, drug or alcohol withdrawal symptoms, inflammatory diseases, cardiovascular or heart-related diseases, fertility problems, human immunodeficiency virus infections, hemorrhagic stress, obesity, infertility, head and spinal cord traumas, epilepsy, stroke, ulcers, amyotrophic lateral sclerosis, hypoglycemia or a disorder the treatment of which can be effected or facilitated by antagonizing CRF, including but not limited to disorders induced or facilitated by CRF, in mammals comprising administering to the mammal a therapeutically effective amount of a compound of Formulae (1) or (2):
and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof, wherein:

A is N or CR;

Z is N or CR2;

Ar is selected from phenyl, naphthyl, pyridyl, pyrimidinyl, triazinyl, furanyl, thienyl, benzothienyl, benzofuranyl,
2-,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, indanyl, 1,2-benzopyranyl, 3,4-dihydro-1,2-benzopyranyl, tetralinyl, each Ar optionally substituted with 1 to 5 R4 groups and each Ar is attached to an unsaturated carbon atom;

R is independently selected at each occurrence from H, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, halo, CN, C1-C4 haloalkyl;

R1 is independently selected at each occurrence from H, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, halo, CN, C1-C4 haloalkyl, C1-C12 hydroxyalkyl, C2-C12 alkoxyalkyl, C2-C10 cyanoalkyl, C3-C6 cycloalkyl, C4-C10 cycloalkylalkyl, NR9R10, C1-C4 alkyl-NR9R10, NR9COR10, OR11, SH or S(O)n R12;

R2 is selected from H, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl, C4-C10 cycloalkylalkyl, C1-C4 hydroxyalkyl, halo, CN, -NR6R7, NR9COR10, -NR6S(O)n R7, S(O)n NR6R7, C1-C4 haloalkyl, -OR7, SH or -S(O)n R12;

R3 is selected from:

-H, OR7, SH, S(O)n R13, COR7, CO2R7, OC(O)R13, NR8COR7, N(COR7)2, NR8CONR6R7, NR8CO2R13, NR6R7, NR6aR7a, N(OR7)R6 CONR6R7, aryl, heteroaryl and heterocyclyl, or -C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C8 cycloalkyl, C5-C8 cycloalkenyl, C4-C12 cycloalkylalkyl or C6-C10 cycloalkenylalkyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR15, SH, S(O)nR13, COR15, CO2R15, OC(O)R13, NR8COR15, N(COR15)2, NR8CONR16R15, NR8CO2R13, NR16R15, CONR16R15, aryl heteroaryl and heterocyclyl;
R4 is independently selected at each occurrence from:
C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C6 cycloalkyl, C4-C12 cycloalkylalkyl, NO2, halo, CN, C1-C4 haloalkyl, NR6R7, NR8COR7, NR8CO2R7, COR7, OR7, CONR6R7, CO(NOR9)R7, CO2R7, or S(O)nR7, where each such C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C6 cycloalkyl and C4-C12 cycloalkylalkyl are optionally substituted with 1 to 3 substituents independently selected at each occurrence from C1-C4 alkyl, NO2, halo, CN, NR6R7, NR8COR7, NR8CO2R7, COR7 OR7, CONR6R7, CO2R7, CO(NOR9)R7, or S(O)nR7;
R6 and R7, R6a and R7a are independently selected at each occurrence from:
-H, C1-C10 alkyl, C3-C10 alkenyl, C3-C10 alkynyl, C1-C10 haloalkyl with 1-10 halogens, C2-C8 alkoxyalkyl, C3-C6 cycloalkyl, C4-C12 cycloalkylalkyl, C5-C10 cycloalkenyl, or C6-C14 cycloalkenylalkyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR15, SH, S(O)n R13, COR15, CO2R15, OC(C)R13, NR8COR15, N(COR15)2, NR8CONR16R15, NR8CO2R13, NR16R15, CONR16R15, aryl heteroaryl or heterocyclyl, -aryl, aryl(C1-C4 alkyl), heteroaryl, heteroaryl(C1-C4 alkyl), heterocyclyl or heterocyclyl(C1-C4 alkyl);

alternatively, NR6R7 and NR6aR7a are independently piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine or thiomorpholine, each optionally substituted with 1-3 C1-C4 alkyl groups;

R8 is independently selected at each occurrence from H or C1-C4 alkyl;

R9 and R10 are independently selected at each occurrence from H, C1-C4 alkyl, or C3-C6 cycloalkyl;

R11 is selected from H, C1-C4 alkyl, C1-C4 haloalkyl, or C3-C6 cycloalkyl;

R12 is C1-C4 alkyl or C1-C4 haloalkyl;

R13 is selected from C1-C4 alkyl, C1-C4 haloalkyl, C2-C8 alkoxyalkyl, C3-C6 cycloalkyl, C4-C12 cycloalkylalkyl, aryl, aryl (C1-C4 alkyl)-, heteroaryl or heteroaryl (C1-C4 alkyl)-;

R14 is selected from C1-C10 alkyl, C3-C10 alkenyl, C3-C10 alkynyl, C3-C8 cycloalkyl, or C4-C12 cycloalkylalkyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR15, SH, S(O)n R15, COR15, CO2R15, OC(O)R15, NR8COR15, N(COR15)2, NR8CONR16R15, NR8CO2R15 NR16R15, CONR16R15, and C1-C6 alkylthio, C1-C6 alkylsulfinyl and C1-C6 alkylsulfonyl;

R15 and R16 are independently selected at each occurrence from H, C1-C6 alkyl, C3-C10 cycloalkyl, C4-C16 cycloalkylalkyl, except that for S(O)n R15, R15 cannot be H;

aryl is phenyl or naphthyl, each optionally substituted with 1 to 5 substituents independently selected at each occurrence from C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR15, SH, S(O)n R15, COR15, CO2R15, OC(O)R15, NR8COR15, N(COR15)2, NR8CONR16R15, NR8CO2R15 NR16R15, and CONR16R15;

heteroaryl is pyridyl, pyrimidinyl, triazinyl, furanyl, pyranyl, quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, isoxazolyl, pyrazolyl, 2,3-dihydrobenzothienyl or 2,3-dihydrobenzofuranyl, each being optionally substituted with 1 to 5 substituents independently selected at each occurrence from C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR15, SH, S(O)n R15, -COR15, CO2R15, OC(O)R15, NR8COR15 N(COR15)2, NR8CONR16R15, NR8CO2R15, NR16R15 and CONR16R15;

heterocyclyl is saturated or partially saturated heteroaryl, optionally substituted with 1 to 5 substituents independently selected at each occurrence from C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR15, SH, S(O)n R15, COR15, CO2R15, OC(O)R15, NR8COR15, N(COR15)2, NR8CONR16R15, NR8CO2R15, NR15R16 and CONR16R15;

n is independently at each occurrence 0, 1 or 2, 2. A method of claim 1 wherein, in the compound of Formulae (1) or (2), Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl, each optionally substituted with 1 to 4 R4 substituents.
3. A method of claim 1 wherein, in the compound of Formulae (1) or (2), A is N, Z is CR2, Ar is 2,4-dichlorophenyl, 2,4-dimethylphenyl or 2,4,6-trimethylphenyl, R1 and R2 are CH3, and R3 is NR6aR7a.
4. A compound of Formulae (1) or (2):

and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein:

A is N or CR;

Z is N or CR2;

Ar is selected from phenyl, naphthyl, pyridyl, pyrimidinyl, triazinyl, furanyl, thienyl, benzothienyl, benzofuranyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, indanyl, 1,2-benzopyranyl, 3,4-dihydro-1,2-benzopyranyl, tetralinyl, each Ar optionally substituted with 1 to 5 R4 groups and each Ar is attached to an unsaturated carbon atom;

R is independently selected at each occurrence from H, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, halo, CN, C1-C4 haloalkyl;

R1 is independently selected at each occurrence from H, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, halo, CN, C1-C4 haloalkyl, C1-C12 hydroxyalkyl, C2-C12 alkoxyalkyl, C2-C10 cyanoalkyl, C3-C6 cycloalkyl, C4-C10 cycloalkylalkyl, NR9R10, C1-C4 alkyl-NR9R10, NR9COR10, OR11, SH or S(O)n R12;

R2 is selected from H, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl, C4-C10 cycloalkylalkyl, C1-C4 hydroxyalkyl, halo, CN, -NR6R7, NR9COR10, -NR6S(O)nR7, S(O)n NR6R7, C1-C4 haloalkyl, -OR7, SH or -S(O)n R12;

R3 is selected from:
-H, OR7, SH, S(O)nR13, COR7, CO2R7, OC(O)R13, NR8COR7, N(COR7)2, NR8CONR6R7, NR8CO2R13, NR6R7, NR6aR7a N(OR7)R6 CONR6R7, aryl, heteroaryl and heterocyclyl, or -C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C8 cycloalkyl, C5-C8 cycloalkenyl, C4-C12 cycloalkylalkyl or C6-C10 cycloalkenylalkyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR15, SH, S(O)n R13, COR15, CO2R15, OC(O)R13, NR8COR15, N(COR15)2, NR8CONR16R15, NR8CO2R13, NR16R15, CONR16R15 aryl heteroaryl and heterocyclyl;

R4 is independently selected at each occurrence from:
C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C6 cycloalkyl, C4-C12 cycloalkylalkyl, NO2, halo, CN, C1-C4 haloalkyl, NR6R7, NR8COR7, NR8CO2R7, COR7, OR7, CONR6R7, CO(NOR9)R7, CO2R7, or S(O)n R7, where each such C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C6 cycloalkyl and C4-C12 cycloalkylalkyl are optionally substituted with 1 to 3 substituents independently selected at each occurrence from C1-C4 alkyl, NO2, halo, CN, NR6R7, NR8COR7, NR8CO2R7, COR7 OR7, CONR6R7, CO2R7, CO(NOR9)R7, or S(O)nR7;

R6 and R7, R6a and R7a are independently selected at each occurrence from:
-H, -C1-C10 alkyl, C3-C10 alkenyl, C3-C10 alkynyl, C1-C10 haloalkyl with 1-10 halogens, C2-C8 alkoxyalkyl, C3-C6 cycloalkyl, C4-C12 cycloalkylalkyl, C5-C10 cycloalkenyl, or C6-C14 cycloalkenylalkyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR15, SH, S(O)n R13, COR15, CO2R15, OC(O)R13, NR8COR15, N(COR15)2, NR8CONR16R15, NR8CO2R13, NR16R15, CONR16R15, aryl heteroaryl or heterocyclyl, -aryl, aryl(C1-C4 alkyl), heteroaryl, heteroaryl(C1-C4 alkyl), heterocyclyl or heterocyclyl(C1-C4 alkyl), alternatively, NR6R7 and NR6aR7a are independently piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine or thiomorpholine, each optionally substituted with 1-3 C1-C4 alkyl groups;

R8 is independently selected at each occurrence from H or C1-C4 alkyl;

R9 and R10 are independently selected at each occurrence from H, C1-C4 alkyl, or C3-C6 cycloalkyl;

R11 is selected from H, C1-C4 alkyl, C1-C4 haloalkyl, or C3-C6 cycloalkyl;

R12 is C1-C4 alkyl or C1-C4 haloalkyl;

R13 is selected from C1-C4 alkyl, C1-C4 haloalkyl, C2-C8 alkoxyalkyl, C3-C6 cycloalkyl, C4-C12 cycloalkylalkyl, aryl, aryl(C1-C4 alkyl)-, heteroaryl or heteroaryl(C1-C4 alkyl)-;

R14 is selected from C1-C10 alkyl, C3-C10 alkenyl, C3-C10 alkynyl, C3-C8 cycloalkyl, or C4-C12 cycloalkylalkyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR15, SH, S(O)n R15, COR15, CO2R15, OC(O)R15, NR8COR15, N(COR15)2, NR8CONR16R15, NR8CO2R15, NR16R15, CONR16R15, and C1-C6 alkylthio, C1-C6 alkylsulfinyl and C1-C6 alkylsulfonyl;

R15 and R16 are independently selected at each occurrence from H, C1-C6 alkyl, C3-C10 cycloalkyl, C4-C16 cycloalkylalkyl, except that for S(O)n R15, R15 cannot be H;

aryl is phenyl or naphthyl, each optionally substituted with 1 to 5 substituents independently selected at each occurrence from C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR15, SH, S(O)nR15, COR15, CO2R15, OC(O)R15, NR8COR15, N(COR15)2, NR8CONR16R15, NR8CO2R15, NR16R15, and CONR16R15;

heteroaryl is pyridyl, pyrimidinyl, triazinyl, furanyl, pyranyl, quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, isoxazolyl, pyrazolyl, 2,3-dihydrobenzothienyl or 2,3-dihydrobenzofuranyl, each being optionally substituted with 1 to 5 substituents independently selected at each occurrence from C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR15, SH, S(O)n R15, -COR15, CO2R15, OC(O)R15, NR8COR15, N(COR15)2, NR8CONR16R15, NR8CO2R15, NR16R15 and CONR16R15;

heterocyclyl is saturated or partially saturated heteroaryl, optionally substituted with 1 to 5 substituents independently selected at each occurrence from C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR15, SH, S(O)n R15, COR15, CO2R15, OC(O)R15, NR8COR15, N(COR15)2, NR8CONR16R15, NR8CO2R15, NR15R16, and CONR16R15;

n is independently at each occurrence 0, 1 or 2, with the provisos that:

(1) when A is N, Z is CR2, R2 is H, R3 is -OR7 or -OCOR13, and R7 is H, then R1 is not H, OH or SH;

(2) when A is N, Z is CR2, R1 is CH3 or C2H5, R2 is H, and R3 is OH, H, CH3, C2H5, C6H5, n-C3H7, i-C3H7, SH, SCH3, NHC4H9, or N(C2H5)2, then Ar is not phenyl or m-CH3-phenyl;

(3) when A is N, Z is CR2, R2 is H, and Ar is pyridyl, pyrimidinyl or pyrazinyl, and R3 is NR6aR7a, then R6a and R7a are not H or alkyl;

(4) when A is N, Z is CR2, and R2 is SO2NR6R7, then R3 is not OH or SH;

(5) when A is CR and Z is CR2, then R2 is not -NR6SO2R7 or -SO2NR6R7;

(6) when A is N, Z is CR2 and R2 is -NR6SO2R7 or -SO2NR6R7, then R3 is not OH or SH;

(7) when A is N, Z is CR2, R1 is methyl or ethyl, R2 is H, and R3 is H, OH, CH3, C2H5, C6H5, n-C3H7, iso-C3H7, SH, SCH3, NH(n-C4H9), or N(C2H5)2, then Ar is not unsubstituted phenyl or m-methylphenyl;

(8) when A is CR, Z is CR2, R2 is H, phenyl or alkyl, R3 is NR8CoR7 and Ar is phenyl or phenyl substituted with phenylthio, then R7 is not aryl, aryl(C1-Cg alkyl), heteroaryl, heteroaryl (C1-C4 alkyl), heterocyclyl or heterocycly(C1-C4 alkyl);

(9) when A is CR, Z is CR2, R2 is H or alkyl, Ar is phenyl, and R3 is SR13 or NR6aR7a, then R13 is not aryl or heteroaryl and R6a and R7a are not H or aryl; or (10) when A is CH, Z is CR2, R1 is OR11, R2 is H, R3 is OR7, and R7 and R11 are both H, then Ar is not phenyl, p-Br-phenyl, p-C1-phenyl, p-NHCOCH3-phenyl, p-CH3-phenyl, pyridyl or naphthyl;

(11) when A is CH, Z is CR2, R2 is H, Ar is unsubstituted phenyl, and R3 is CH3, C2H5, CF3 or C6H4F, then R1 is not CF3 or C2F5;

(12) when A is CR, R is H, Z is CR2, R2 is OH, and R1 and R3 are H, then Ar is not phenyl;

(13) when A is CR, R is H, Z is CR2, R2 is OH or NH2, R1 and R3 are CH3, then Ar is not 4-phenyl-3-cyano-2-aminopyrid-2-yl.
5. A compound of claim 4 and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof with the additional provisos that: (1) when A is N, R1 is H, C1-C4 alkyl, halo, CN, C1-C12 hydroxyalkyl, C1-C4 alkoxyalkyl or SO2(C1-C4 alkyl), R3 is NR6aR7a and R6a is unsubstituted C1-C4 alkyl, then R7a is not phenyl, naphthyl, thienyl, benzothienyl, pyridyl, quinolyl, pyrazinyl, furanyl, benzofuranyl, benzothiazolyl, indolyl or C3-C6 cycloalkyl; and (2) A is N, R1 is H, C1-C4 alkyl, halo, CN, C1-C12 hydroxyalkyl, C1-C4 alkoxyalkyl or SO2(C1-C4 alkyl), R3 is NR6aR7a and R7a is unsubstituted C1-C4 alkyl, then R6a is not phenyl, naphthyl, thienyl, benzothienyl, pyridyl, quinolyl, pyrazinyl, furanyl, benzofuranyl, benzothiazolyl, indolyl or C3-C6 cycloalkyl.
6. A compound of claim 4 and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl, each optionally substituted with 1 to 4 R4 substituents.
7. A compound of claim 6 and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein A
is N, Z is CR2, Ar is 2,4-dichlorophenyl, 2,4-dimethylphenyl or 2,4,6-trimethylphenyl, R1 and R2 are CH3, and R3 is NR6aR7a.
8. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 4.
9. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 6.
10. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 7.
11. A compound of claim 4 and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein A is N.
12. A compound of Formula (2) of claim 11 and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof.
13. A compound of claim 12 and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl and each Ar is optionally substituted with 1 to 4 R4 substituents.
14. A compound of claim 12 and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein R3 is NR6aR7a or OR7.
15. A compound of claim 12 and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl, and each Ar is optionally substituted with 1 to 4 R4 substituents, and R3 is NR6aR7a or OR7.
16. A compound of Formula (1) of claim 11 and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein Z is CR2.
17. A compound of claim 16 and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl and each Ar is optionally substituted with 1 to 4 R4 substituents.
18. A compound of claim 16 and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein R3 is NR6aR7a or OR7.
19. A compound of claim 18 and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein R6a is independently selected from:
-H, -C1-C10 alkyl, C3-C10 alkenyl, C3-C10 alkynyl, C1-C10 haloalkyl with 1-10 halogens, C2-C8 alkoxyalkyl, C3-C6 cycloalkyl, C4-C12 cycloalkylalkyl, C5-C10 cycloalkenyl, or C6-C14 cycloalkenylalkyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR15, SH, S(O)n R13, COR15, CO2R15, OC(O)R13, NR8COR15, N(COR15)2, NR8CONR16R15, NR8CO2R13, NR16R15, CCNR16R15, aryl heteroaryl or heterocyclyl, -aryl, aryl(C1-C4 alkyl)-, heteroaryl, heteroaryl(C1-C4 alkyl)-, heterocyclyl or heterocyclyl(C1-C4 alkyl)-; and R7a is independently selected at each occurrence from:
-H, -C5-C10 alkyl, C3-C10 alkenyl, C3-C10 alkynyl, C1-C10 haloalkyl with 1-10 halogens, C2-C8 alkoxyalkyl, C3-C6 cycloalkyl, C4-C12 cycloalkylalkyl, C5-C10 cycloalkenyl, or C6-C14 cycloalkenylalkyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR15, SH, S(O)n R13, COR15, CO2R15, OC(O)R13, NR8COR15, N(COR15)2, NR8CONR16R15, NR8CO2R13, NR16R15, CONR16R15, aryl heteroaryl or heterocyclyl, -aryl, aryl(C1-C4 alkyl), heteroaryl, heteroaryl(C1-C4 alkyl), heterocyclyl or heterocyclyl(C1-C4 alkyl);

alternatively, NR6R7 and NR6aR7a are independently piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine or thiomorpholine, each optionally substituted with 1-3 C1-C4 alkyl groups.
20. A compound of claim 18 and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein R6a and R7a are identical and are selected from:
-C1-C4 alkyl or C3-C6 cycloalkyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR15, SH, S(O)n R13, -COR15, CO2R15, OC(O)R13, NR8COR15, N(COR15)2, NR8CONR16R15, NR8CO2R13, NR16R15, CONR16R15, aryl, heteroaryl or heterocyclyl, and -aryl or heteroaryl.
21. A compound of claim 18 and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein R6a is selected from:
-H, -C1-C1o alkyl, C3-C10 alkenyl, C3-C10 alkynyl, C1-C10 haloalkyl with 1-10 halogens, C2-C8 alkoxyalkyl, C3-C6 cycloalkyl, C4-C12 cycloalkylalkyl, C5-C10 cycloalkenyl, or C6-C14 cycloalkenylalkyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR15, SH, S(O)nR13, COR15, CO2R15, OC(O)R13, NR8COR15, N(COR15)2, NR8CONR16R15 NR8CO2R13, NR15R15, CONR16R15, aryl heteroaryl or heterocyclyl, -aryl, aryl(C1-C4 alkyl), heteroaryl, heteroaryl(C1-C4 alkyl), heterocyclyl or heterocyclyl(C1-C4 alkyl);
R7a is selected from:
-C1-C4 alkyl and each such C1-C4 alkyl is substituted with 1-3 substituents independently selected at each occurrence from C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR15, SH, S(O)nR13, COR15, CO2R15, OC(O)R13, NR8COR15, N(COR15)2, NR8CONR16R15, NR8CO2R13, NR16R15, CONR16R15, aryl, heteroaryl or heterocyclyl.
22. A compound of claim 18 and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein one of R6a and R7a is selected from:
-C3-C6 cycloalkyl, each such C3-C6 cycloalkyl optionally substituted with 1-3 substituents independently selected at each occurrence from C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR15, SH, S(O)nR13, COR15, CO2R15, OC(O)R13, NR8COR15, N(COR15)2, NR8CONR16R15, NR8CO2R13, NR16R15, CONR16R15, aryl, heteroaryl or heterocyclyl, -aryl, -heteroaryl or -heterocyclyl, and the other of R6a and R7a is unsubstituted C1-C4 alkyl.
23. A compound of claim 18 and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein R6a and R7a are independently H or C1-C10 alkyl, each such C1-C10 alkyl optionally substituted with 1 to 3 substituents independently selected at each occurrence from C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR15, SH, S(O)nR13, COR15, CO2R15, OC(O)R13, NR8COR15, N(COR15)2, R8CONR16R15, NR8CO2R13, NR16R15, CONR16R15, aryl, heteroaryl or heterocyclyl.
24. A compound of claim 16 and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl, and each Ar is optionally substituted with 1 to 4 R4 substituents, and R3 is NR6aR7a or OR7.
25. A compound of claim 24 and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein R6a is independently selected from:
-H, -C1-C10 alkyl, C3-C10 alkenyl, C3-C10 alkynyl, C1-C10 haloalkyl with 1-10 halogens, C2-C8 alkoxyalkyl, C3-C6 cycloalkyl, C4-C12 cycloalkylalkyl, C5-C10 cycloalkenyl, or C6-C14 cycloalkenylalkyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR15, SH, S(O)n R13, COR15, CO2R15, OC(O)R13, NR8COR15, N(COR15)2, NR8CONR16R15, NR8CO2R13, NR16R15, CONR16R15, aryl heteroaryl or heterocyclyl, -aryl, aryl(C1-C4 alkyl)-, heteroaryl, heteroaryl(C1-C4 alkyl), heterocyclyl or heterocyclyl(C1-C4 alkyl);
R7a is independently selected at each occurrence from:
-H, -C5-C10 alkyl, C3-C10 alkenyl, C3-C10 alkynyl, C1-C10 haloalkyl with 1-10 halogens, C2-C8 alkoxyalkyl, C3-C6 cycloalkyl, C4-C12 cycloalkylalkyl, C5-C10 cycloalkenyl, or C6-C14 cycloalkenylalkyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR15, SH, S(O)n R13, COR15, CO2R15, OC(O)R13, NR8COR15, N(COR15)2, NR8CONR16R15, NR8CO2R13, NR16R15, CONR16R15, aryl, heteroaryl or heterocyclyl, -aryl, aryl(C1-C4 alkyl), heteroaryl, heteroaryl(C1-C4 alkyl), heterocyclyl or heterocyclyl(C1-C4 alkyl), alternatively, NR6R7 and NR6a R7a are independently piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine or thiomorpholine, each optionally substituted with 1-3 C1-C4 alkyl groups.
26. A compound of claim 24 and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acoeptable salt or pro-drug forms thereof wherein R6a and R7a are identical and are selected from:
-C1-C4 alkyl or C3-C6 cycloalkyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR15, SH, S(O)n R13, -COR15, CO2R15, OC(O)R13, NR8COR15, N(COR15)2, NR8CONR16R15, NR8CO2R13, NR16R15, CONR16R15, aryl, heteroaryl or heterocyclyl, and -aryl or heteroaryl.
27. A compound of claim 24 and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein R6a and R7a are identical and are -C1-C4 alkyl, each such C1-C4 alkyl optionally substituted with 1 to 3 substituents independently selected at each occurrence from C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR15, SH, S(O)n R13, -COR15, CO2R15, OC(O)R13, NR8COR15, N(COR15)2, NR8CONR16R15, NR8CO2R13, NR16R15, CONR16R15, aryl, heteroaryl or heterocyclyl.
28. A compound of claim 24 and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein R6a is selected from:
-H, -C1-C10 alkyl, C3-C10 alkenyl, C3-C10 alkynyl, C1-C10 haloalkyl with 1-10 halogens, C2-C8 alkoxyalkyl, C3-C6 cycloalkyl, C4-C12 cycloalkylalkyl, C5-C10 cycloalkenyl, or C6-C14 cycloalkenylalkyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR15, SH, S(O)n R13, COR15, CO2R15, OC(C)R13, NR8COR15, N(COR15)2, NR8CONR16R15, NR8CO2R13, NR16R15, CONR16R15, aryl, heteroaryl or heterocyclyl, -aryl, aryl(C1-C4 alkyl), heteroaryl, heteroaryl(C1-C4 alkyl), heterocyclyl or heterocyclyl(C1-C4 alkyl);
R7a is:
-C1-C4 alkyl and each such C1-C4 alkyl is substituted with 1-3 substituents independently selected at each occurrence from C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR15, SH, S(O)n R13, COR15, CO2R15, OC(O)R13, NR8COR15, N(COR15)2, NR8CONR16R15, NR8CO2R13, NR16R15, CONR16R15, aryl, heteroaryl or heterocyclyl.
29. A compound of claim 24 and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein one of R6a and R7a is selected from:
-C3-C6 cycloalkyl, each such C3-C6 cycloalkyl optionally substituted with 1-3 substituents independently selected at each occurrence from C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR15, SH, S(O)n R13, COR15, CO2R15, OC(O)R13, NR8COR15, N(COR15)2, NR8CONR16R15, NR8CO2R13, NR16R15, CONR16R15, aryl, heteroaryl or heterocyclyl, -aryl, -heteroaryl or -heterocyclyl, and the other of R6a and R7a is unsubstituted C1-C4 alkyl.
30. A compound of claim 24 and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein R6a and R7a are independently H or C1-C10 alkyl, each such C1-C10 alkyl optionally substituted with 1 to 3 substituents independently selected at each occurrence from C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR15, SH, S(O)nR13, COR15, CO2R15, OC(O)R13, NR8COR15, N(COR15)2, R8CONR16R15, NR8CO2R13, NR16R15, CONR16R15, aryl heteroaryl or heterocyclyl.
31. A compound of claim 16 and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein -Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl, and each Ar is optionally substituted with 1 to 4 R4 substituents, -R3 is NR6aR7a or OR7 and -R1 and R2 are independently selected from H, C1-C4 alkyl, C3-C6 cycloalkyl, C4-C10 cycloalkylalkyl.
32. A compound of clalm 31 and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein R6a is independently selected from:
-H, -C1-C10 alkyl, C3-C10 alkenyl, C3-C10 alkynyl, C1-C10 haloalkyl with 1-10 halogens, C2-C8 alkoxyalkyl, C3-C6 cycloalkyl, C4-C12 cycloalkylalkyl, C5-C10 cycloalkenyl, or C6-C14 cycloalkenylalkyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR15, SH, S(O)n R13, COR15, CO2R15, OC(O)R13, NR8COR15, N(COR15)2, NR8CONR16R15, NR8CO2R13, NR16R15, CONR16R15, aryl, heteroaryl or heterocyclyl, -aryl, aryl(C1-C4 alkyl)-, heteroaryl, heteroaryl(C1-C4 alkyl), heterocyclyl or heterocyclyl(C1-C4 alkyl);
R7a is independently selected at each occurrence from:
-H, -C5-C10 alkyl, C3-C10 alkenyl, C3-C10 alkynyl, C1-C10 haloalkyl with 1-10 halogens, C2-C8 alkoxyalkyl, C3-C6 cycloalkyl, C4-C12 cycloalkylalkyl, C5-C10 cycloalkenyl, or C6-C14 cycloalkenylalkyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR15, SH, S(O)n R13, COR15, CO2R15, OC(O)R13, NR3COR15, N(COR15)2, NR8CONR16R15, NR3CO2R13, NR16R15, CONR16R15, aryl heteroaryl or heterocyclyl, -aryl, aryl(C1-C4 alkyl), heteroaryl, heteroaryl(C1-C4 alkyl), heterocyclyl or heterocyclyl(C1-C4 alkyl), alternatively, NR6R7 and NR6aR7a are independently piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine or thiomorpholine, each optionally substituted with 1-3 C1-C4 alkyl groups.
33. A compound of claim 31 and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein R6a and R7a are identical and are selected from:
-C1-C4 alkyl or C3-C6 cycloalkyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR15, SH, S(O)n R13, -COR15, CO2R15, OC(O)R13, NR8COR15, N(COR15)2, NR8CONR16R15, NR8CO2R13, NR16R15, CONR16R15, aryl, heteroaryl or heterocyclyl, and -aryl or heteroaryl.
34. A compound of claim 31 and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein R6a and R7a are identical and are -C1-C4 alkyl, each such C1-C4 alkyl optionally substituted with 1 to 3 substituents independently selected at each occurrence from C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR15, SH, S(O)n R13, -COR15, CO2R15, OC(O)R13, NR8COR15, N(COR15)2, NR8CONR16R15, NR8CO2R13, NR16R15, CONR16R15, aryl, heteroaryl or heterocyclyl.
35. A compound of claim 31 and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein R6a is selected from:
-H, -C1-C10 alkyl, C3-C10 alkenyl, C3-C10 alkynyl, C1-C10 haloalkyl with 1-10 halogens, C2-C8 alkoxyalkyl, C3-C6 cycloalkyl, C4-C12 cycloalkylalkyl, C5-C10 cycloalkenyl, or C6-C14 cycloalkenylalkyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR15, SH, S(O)n R13, COR15, CO2R15, OC(O)R13, NR8COR15, N(COR15)2, NR8CONR16R15, NR8C32R13, NR16R15, CONR16R15, aryl, heteroaryl or heterocyclyl, -aryl, aryl(C1-C4 alkyl), heteroaryl, heteroaryl(C1-C4 alkyl), heterocyclyl or heterocyclyl(C1-C4 alkyl);
R7a is:
-C1-C4 alkyl and each such C1-C4 alkyl is substituted with 1-3 substituents independently selected at each occurrence from C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR15, SH, S(O)n R13, COR15, CO2R15, OC(O)R13, NR8COR15, N(COR15)2, NR8CONR16R15, NR8CO2R13, NR16R15, CONR16R15, aryl, heteroaryl or heterocyclyl.
36. A compound of claim 31 and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein one of R6a and R7a is selected from:
-C3-C6 cycloalkyl, each such C3-C6 cycloalkyl optionally substituted with 1-3 substituents independently selected at each occurrence from C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR15, SH, S(O)n R13, COR15, CO2R15, OC(O)R13, NR3COR15, N(COR15)2, NR8CONR16R15, NR8CO2R13, NR16R15, CONR16R15, aryl, heteroaryl or heterocyclyl, -aryl, -heteroaryl or -heterocyclyl, and the other of R6a and R7a is unsubstituted C1-C4 alkyl.
37. A compound of clalm 31 and isomers thereof, stereoisomeric forms thereof, or mixtures of stereolsomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein R6a and R7a are independently H or C1-C10 alkyl, each such C1-C10 alkyl optionally substituted with 1 to 3 substituents independently selected at each occurrence from C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR15, SH, S(O)n R13, COR15, CO2R15, OC(O)R13, NR8COR15, N(COR15)2, R8CONR16R15, NR8CO2R13, NR16R15, CONR16R15, aryl, heteroaryl or heterocyclyl.
38. A compound of claim 31 of Formula (50) and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof, selected from the group consisting of:

a compound of Formula (50) wherein R3 is -NHCH(n-Pr)2, R4a is Cl, R4b is H, R4c is Cl, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is -N(Et)(n-Bu), R4a is Cl, R4b is H, R4c is Cl, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is -(n-Pr)(CH2cPr), R4a is Cl, R4b is H, R4c is Cl, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is -N(CH2CH2OMe)2, R4a is Cl, R4b is H, R4c is Cl, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is -NHCH(Et)(n-Bu), R4a is Cl, R4b is H, R4c is Cl, R4d is H and R4e is H;

a compound of Formula (50) wherein R3 is -NHCH(Et)(CH2OMe), R4a is Cl, R4b is H, R4c is Cl, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is -NHCH(CH2OMe)2, R4a is Cl, R4b is H, R4c is Cl, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is -N(Et)2, R4a is Cl, R4b is H, R4c is Cl, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is -NHCH(CH2OEt)2, R4a is Cl, R4b is H, R4c is Cl, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is -NHCH(Et)2, R4a is Cl, R4b is H, R4c is Cl, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is -N(Me)(Ph), R4a is Cl, R4b is H, R4c is Cl, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is -N(n-Pr)2, R4a is Cl, R4b is H, R4c is Cl, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is -NHCH(Et)(n-Pr) R4a is Cl, R4b is H, R4c is Cl, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is -NHCH(CH2OMe)2, R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is Me;
a compound of Formula (50) wherein R3 is -NHCH(CH2OMe)2, R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is -N(CH2CH2OMe)2, R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is -NHCH(Et)(CH2OMe), R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is H;

a compound of Formula (50) wherein R3 is -NHCH(Et)2, R4a is Me, R4b is H, R4c is Me, R4d is H and R e is H;

a compound of Formula (50) wherein R3 is -OEt, R4a is Cl, R4b is H, R4c is Cl, R4d is H and R4e is H;

a compound of Formula (50) wherein R3 is -N(Et)2, R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is -N(CH2CN)2, R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is -NHCH(Me)(CH2OMe), R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is H;

a compound of Formula (50) wherein R3 is -OCH(Et)(CH2OMe), R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is H;

a compound of Formula (50) wherein R3 is -N(n-Pr)(CH2cPr), R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is -NHCH(Me)(CH2N(Me)2), R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is -N(cPr)(CH2CH2CN), R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is -N(n-Pr)(CH2CH2CN), R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is -N(n-Bu)(CH2CN), R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is -NHCH(Et)(CH2OMe), R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is Me;
a compound of Formula (50) wherein R3 is -NHCH(Et)2, R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is Me;

a compound of Formula (50) wherein R3 is -N(CH2CH2OMe)2, R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is Me;
a compound of Formula (50) wherein R3 is -NHCH(CH2OMe)2, R4a is Br, R4b is H, R4c is OMe, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is -NHCH(Et)(CH2OMe), R4a is Br, R4b is H, R4c is OMe, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is -N(Et)2, R4a is Me, R4d is H, R4c is Me, R4d is H and R4e is Me;
a compound of Formula (50) wherein R3 is -NHCH(CH2OEt)2, R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is Me;
a compound of Formula (50) wherein R3 is -NHCH(CH2CH2OMe)(CH2OMe)2, R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is Me;
a compound of Formula (50) wherein R3 is morpholino, R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is -N(CH2CH2OMe)2, R4a is Br, R4b is H, R4c is OMe, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is -NHCH(Et)2, R4a is Br, R4b is H, R4c is OMe, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is -N(Et)2, R4a is Br, R4b is H, R4c is OMe, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is -NH(c-Pr), R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is -NHCH(CH2OMe)2, R4a is CN, R4b is H, R4c is OMe, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is -N(c-Pr)(CH2CH2CN), R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is Me;

a compound of Formula (50) wherein R3 is -NCH(CH2OMe)2, R4a is Me, R4b is H, R4c is Br, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is -NHCH(CH2OMe)(CH2CH2OMe), R4a is Me, R4b is H, R4c is Br, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is -NHCH(CH2OMe)2, R4a is Me, R4b is H, R4c is OMe, R4d is Me and R4e is H;
a compound of Formula (50) wherein R3 is -N(CH2CH2OMe)2, R4a is Me, R4b is H, R4c is OMe, R4d is Me and R4e is H;
a compound of Formula (50) wherein R3 is -NHCH(Et)2, R4a is Me, R4b is H, R4c is OMe, R4d is Me and R4e is H;
a compound of Formula (50) wherein a compound of Formula (50) wherein R3 is -N(Et)2, R4a is Me, R4b is H, R4c is OMe, R4d is Me and R4e is H;
a compound of Formula (50) wherein R3 is -NHCH(CH2OMe)2, R4a is Cl, R4b is H, R4c is Me, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is NHCH(Et)(CH2OMe), R4a is Cl, R4b is H, R4c is Me, R4d is H and R4e is H;

a compound of Formula (50) wherein R3 is -N(CH2CH2OMe)2, R4a is Cl, R4b is H, R4c is Me, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is -NHCH(CH2OMe)(CH2CH2OMe), R4a is Cl, R4b is H, R4c is Me, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is -N(c-Pr)(CH2CH2CN), R4a is Me, R4b is H, R4c is OMe, R4d is Me and R4e is H;

a compound of Formula (50) wherein R3 is -N(c-Pr)(CH2CH2CN), R4a is Cl, R4b is H, R4c is Cl, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is (S)-NHCH(CH2OMe)(CH2CH2OMe), R4a is Cl, R4b is H, R4c is Cl, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is -NHCH(CH2OMe)(CH2CH2OMe), R4a is Cl, R4b is H, R4c is Cl, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is -NHCH(Et)2, R4a is Me, R4b is H, R4c is Br, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is -N(CH2CH2OMe)2, R4a is Me, R4b is H, R4c is Br, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is -NH(CH2OMe)(CH2-iPr), R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is -N(CH2CH2OMe)2, R4a is Me, R4b is H, R4c is H, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is -N(CH2CH2OMe)2, R4a is Me, R4b is H, R4c is NMe2, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is -NHCH(CH2OMe)(n-Pr), R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is -NHCH(CH2OEt)(Et), R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is H;

a compound of Formula (50) wherein R3 is NHCH(CH2OMe)(CH2CH2OMe), R4a is Me, R4b is H, R4c is NMe2, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is -N(Et)2, R4a is Me, R4b is H, R4c is Cl, R4d is H and R4e is H;

a compound of Formula (50) wherein R3 is -NHCH(Et)2, R4a is Me, R4b is H, R4c is Cl, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is -N(CH2CH2OMe)2, R4a is Me, R4b is H, R4c is Cl, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is -NHCH(CH2OMe)2, R4a is Me, R4b is H, R4c is Cl, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is -N(Et)2, R4a is Me, R4b is H, R4c is Br, R4d is H and R4e is H;

a compound of Formula (50) wherein R3 is -N(Et)2, R4a is Cl, R4b is H, R4c is Me, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is -NHCH(Et)2, R4a is Cl, R4b is H, R4c is Me, R4d is H and R4e is H;

a compound of Formula (50) wherein R3 is -NHCH(Et)2, R4a is Me, R4b is H, R4c is NMe2, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is (S)-NHCH(CH2OMe)(CH2CH2OMe), R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is -NH(CH2OMe)(CH2CH2OMe), R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is (S)-NHCH(CH2OMe)(CH2CH2OMe), R4a is Me, R4b is H, R4c is Cl, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is -NHCH(CH2OMe)(CH2CH2OMe), R4a is Me, R4b is H, R4c is Cl, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is -N(c-Pr)(CH2CH2CN), R4a is Me, R4b is H, R4c is Cl, R5d is H and R4e is H;

a compound of Formula (50) wherein R3 is -NH(Et)(CH2CN), R4a is Me, R4b is H, R4c is Cl, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is -N (Et)2, R4a is Me, R4b is Me, R4c is OMe, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is -N(CH2CH2OMe)(CH2CH2OH), R4a is Cl, R4b is H, R4c is Cl, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is -N(CH2CH2OMe)2, R4a is Me, R4b is Me, R4c is OMe, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is -NHCH(Et)2, R4a is Me, R4b is Me, R4c is OMe, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is -N(CH2c-Pr)(n-Pr), R4a is Me, R4b is H, R4c is Cl, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is -N(c-Pr) (CH2CH2CN), R4a is Me, R4b is Me, R4c is OMe, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is -NHCH (Et)2, R4a is Cl, R4b is H, R4c is OMe, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is -N(Et)2, R4a is Cl, R4b is H, R4c is OMe, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is -N(CH2CH2OMe)2, R4a is Cl, R4b is H, R4c is OMe, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is -NHCH(Et)(CH2OMe), R4a is Cl, R4b is H, R4c is OMe, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is -N(Et)2, R4a is Cl, R4b is H, R4c is CN, R4d is H and R4e is H;

a compound of Formula (50), wherein R3 is -N~c-Pr) (CH2CH2CN), R4a is Cl, R4b is H, R4c is OMe, R4d is H and R4e is H;
a compound of Formula (50) wherein R3 is -NHCH(CH2CH)2, R4a is Cl, R4b is H, R4c is Cl, R4d is H and R43 is H; and a compound of Formula (50) wherein R3 is N(CH2CH2OME;2, R4a is Me, R4b is H, R4c is OMe, R4d is H and R4e is H.
39. A compound of claim 31 and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof, wherein said compound is 4-(bis-(2-methoxyphenyl)-[1,5-a]-pyrazolo-1,3,5-triazine
40. A compound of claim 31 and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof, wherein said compound is 4-(bis-(2-methoxyethyl)amino)-2,~-dimethyl-8-(2,5-dimethyl-4-methoxyphenyl-[1,5-a]-pyrazolo-1,3,5-triazine.
41. A compound of claim 4 and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein A is CR.
42. A compound of Formula (2) of claim 41 and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof.
43. A compound of claim 42 and lsomers thereof, stereoisomerlc forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl and each Ar is optionally substituted with 1 to 4 R4 substituents.
44. A compound of claim 42 and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein R3 is NR6a R7a or OR7.
45. A compound of claim 42 and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl, and each Ar is optionally substituted with 1 to 4 R4 substituents, and R3 is NR6a R7a or OR7.
46. A compound of Formula (1) of claim 41 and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein Z is CR2.
47. A compound of claim 96 and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl and each Ar is optionally substituted with 1 to 4 R4 substituents.
48. A compound of claim 96 and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein R3 is NR6a R7a or OR7.
49. A compound of claim 46 and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl, and each Ar is optionally substituted with 1 to 4 R4 substituents, and R3 is NR6a R7a or OR7.
50. A compound of claim 49 and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein R6a and R7a are independently H or C1-C10 alkyl, and each such C1-C10 alkyl is optionally substituted with 1 to 3 substituents independently selected at each occurrence from C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR15, SH, S(O)n R13, COR15, CO2R15, OC(O)R13, NR8COR15, N(COR15)2, R8CONR16R15, NR3CO2R13, NR16R15, CONR16R15, aryl, heteroaryl or heterocyclyl.
51. A compound of claim 46 and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein -Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl, and each Ar is optionally substituted with 1 to 4 R4 substituents, -R3 is NR6a R7a or OR7 and -R1 and R2 are independently selected from H, C1-C4 alkyl, C3-C6 cycloalkyl, C4-C10 cycloalkylalkyl.
52. A compound of claim 51 and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein R6a and R7a are independently H or C1-C10 alkyl, and each such C1-C10 alkyl is optionally substituted with 1 to 3 substituents independently selected at each occurrence from C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR15, SH, S(O)n R13, COR15, CO2R15, OC(O)R13, NR8COR15, N(COR15)2, R8CONR16R15, NR8CO2R13, NR16R15, CONR16R15, aryl, heteroaryl or heterocyclyl.
53. A compound of claim 51 of Formula (51) and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof selected from the group consisting of:

a compound of Formula (51) wherein R3 is -NHCH(n-Pr)2, R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is H;
a compound of Formula (51) wherein R3 is -NHCH(CH2OMe)2, R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is H;
a compound of Formula (51) wherein R3 is -N(CH2CH2OMe)2, R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is H;
a compound of Formula (51) wherein R3 is -N(c-Pr)(CH2CH2CN), R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is H;
a compound of Formula (51) wherein R3 is -N(CH2CH2OMe)2, R4a is Cl, R4b is H, R4c is Me, R4d is H and R4e is H;
a compound of Formula (51) wherein R3 is -NHCH(CH2OMe)2, R4a is Cl, R4b is H, R4c is Me, R4d is H and R4e is H;
a compound of Formula (51) wherein R3 is -NHCH(Et)2, R4a is Cl, R4b is H, R4c is Me, R4d is H and R4e is H;
a compound of Formula (51) wherein R3 is -N(Et)2, R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is H;
a compound of Formula (51) wherein R3 is -N(n-Pr)(CH2CH2CN), R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is H;
a compound of Formula (51) wherein R3 is -N(n-Bu)(CH2CH2CN), R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is H;

a compound of Formula (51) wherein R3 is -NHCH(n-Pr)(CH2OMe), R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is H;
a compound of Formula (51) wherein R3 is -NHCH(Et)2, R4a is Me, R4b is H, R4c is OMe, R4d is H and R4e is H;
a compound of Formula (51) wherein R3 is -NHCH(CH2OMe)2, R4a is Me, R4b is H, R4c is OMe, R4d is H and R4e is H;
a compound of Formula (51) wherein R3 is (S) -NH(CH2CH2OMe)CH2OMe, R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is H;
a compound of Formula (51) wherein R3 is -NH(CH2CH2OMe)CH2OMe, R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is H;
a compound of Formula (51) wherein R3 is -N(CH2CH2OMe)2, R4a is Me, R4b is H, R4c is Cl, R4d is H and R4e is H;
a compound of Formula (51) wherein R3 is -NH(Et), R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is H;
a compound of Formula (51) wherein R3 is -NHCH(n-Pr)2, R4a is Me, R4b is H, R4c is Cl, R4d is H and R4e is H;
a compound of Formula (51) wherein R3 is -NHCH(CH2OMe)2, R4a is Me, R4b is H, R4c is Cl, R4d is H and R4e is H;
a compound of Formula (51) wherein R3 is (S) -NH(CH2CH2OMe)CH2OMe, R4a is Me, R4b is H, R4c is Cl, R4d is H and R4e is H;
a compound of Formula (51) wherein R3 is -NH(CH2CH2OMe)CH2OMe, R4a is Me, R4b is H, R4c is Cl, R4d is H and R4e is H;
a compound of Formula (51) wherein R3 is -N(n-Pr)(CH2CH2CN), R4a is Me, R4b is H, R4c is OMe, R4d is H and R4e is H;

a compound of Formula (51) wherein R3 is -N(Et)2, R4a is Me, R4b is H, R4c is OMe, R4d is H and R4e is H;
a compound of Formula (51) wherein R3 is (S) -NH(CH2CH2OMe)CH2OMe, R4a is C1, R4b is H, R4c is Me, R4d is H and R4e is H;
a compound of Formula (51) wherein R3 is -NH(CH2CH2OMe)CH2OMe, R4a is Cl, R4b is H, R4c is Me, R4d is H and R4e is H;
a compound of Formula (51) wherein R3 is -N(Et)2, R4a is Cl, R4b is H, R4c is Me, R4d is H and R4e is H;

a compound of Formula (51) wherein R3 is -N(c-Pr)(CH2CH2CN), R4a is Me, R4b is H, R4c is OMe, R4d is H and R4e is H;
a compound of Formula (51) wherein R3 is -N(c-Pr)(CH2CH2CN), R4a is Cl, R4b is H, R4c is Me, R4d is H and R4e is H;
a compound of Formula (51) wherein R3 is -NHCH
(n-Pr)(CH2OMe), R4a is Me, R4b is H, R4c is OMe, R4d is H and R4e is H;
a compound of Formula (51) wherein R3 is -NHCH
(n-Pr)(CH2OMe), R4a is Cl, R4b is H, R4c is M, R4d H and R4e is H;
a compound of Formula (51) wherein R3 is -NHCH(Et)2, R4a is Br, R4b is H, R4c is OMe, R4d is OMe and R4e is H;
a compound of Formula (51) wherein R3 is -NHCH(Et)2, R4a is Br, R4b is H, R4c is OMe, R4d is H and R4e is H;
a compound of Formula (51) wherein R3 is -N(CH2CH2OMe)2, R4a is Br, R4b is H, R4c is OMe, R4d is H and R4e is H;
a compound of Formula (51) wherein R3 is -NHCH(CH2OMe)2, R4a is Br, R4b is H, R4c is OMe, R4d is H and R4e is H;

a compound of Formula (51) wherein R3 is -N(Et)2, R4a is Me, R4b is H, R4c is Cl, R4d is H and R4e is H;
a compound of Formula (51) wherein R3 is -N(Et)2, R4a is Cl, R4b is H, R4c is OMe, R4d is OMe and R4e is H;
a compound of Formula (51) wherein R3 is -NHCH(Et)2, R4a is Cl, R4b is H, R4c is OMe, R4d is OMe and R4e is H;
a compound of Formula (51) wherein R3 is -N(CH2CH2OMe)2, R4a is Cl, R4b is H, R4c is Cl, R4d is H and R4e is H;
a compound of Formula (51) wherein R3 is -NHCH(CH2OMe)2, R4a is Cl, R4b is H, R4c is Cl, R4d is H and R4e is H;
a compound of Formula (51) wherein R3 is -N(Pr)(CH2CH2CN), R4a is Cl, R4b is H, R4c is Cl, R4d is H and R4e is H;

a compound of Formula (51) wherein R3 is -N(Bu)(Et), R4a is Cl, R4b is H, R4c is Cl, R4d is H and R4e is H;
a compound of Formula (51) wherein R3 is -NHCH(Et)CH2OMe, R4a is Cl, R4b is H, R4c is Cl, R4d is H and R4e is H;

a compound of Formula (51) wherein R3 is -NHCH(Et)2, R4a is Cl, R4b is H, R4c is Cl, R4d is H and R4e is H;
a compound of Formula (51) wherein R3 is -NHCH(Et)2, R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is H;
a compound of Formula (51) wherein R3 is -NHCH(Et)2, R4a is Cl, R4b is H, R4c is Me, R4d is H and R4e is H;
a compound of Formula (51) wherein R3 is -NHCH(Et)2, R4a is Me, R4b is H, R4c is Cl, R4d is H and R4e is H;

a compound of Formula (51) wherein R3 is -NEt2, R4a is Me, R4b is H, R4c is OMe, R4d is H and R4e is H;
and a compound of Formula (51) wherein R3 is -N(Pr)(CH2CH2CN), R4a is Me, R4b is H, R4c is OMe, R4d is H and R4e is H.
54. A compound of claim 51 and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof, whereln sald compound is 7-(3-pentylamino)-2,5-dimethyl-3-(2-methyl-4-methoxyphenyl)-[1,5-a]-pyrazolopyrimidine.
55. A compound of claim 51 and and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof, wherein said compound is 7-(Diethylamino)-2,5-dimethyl-3-(2-methyl-4-methoxyphenyl-[1,5-a]-pyrazolopyrimidine.
56. A compound of claim 51 and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof, wherein said compound is 7-(N-(3-cyanopropyl)-N-propylamino)-2,5-dimethyl-3-(2,4-dimethylphenyl)-[1,5-a]-pyrazolopyrimidine.
57. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 4.
58. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 24.
59. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 38.
60. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 39.
61. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 40.
62. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 53.
63. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 54.
64. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 55.
65. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 56.
66. A method of treating affective disorder, anxiety, depression, headache, irritable bowel syndrome, post-traumatic stress disorder, supranuclear palsy, immune suppression, Alzheimer's disease, gastrointestinal diseases, anorexia nervosa or other feeding disorder, drug addiction, drug or alcohol withdrawal symptoms, inflammatory diseases, cardiovascular or heart-related diseases, fertility problems, human immunodeficiency virus infections, hemorrhagic stress, obesity, infertility, head and spinal cord traumas, epilepsy, stroke, ulcers, amyotrophic lateral sclerosis, hypoglycemia or a disorder the treatment of which can be effected or facilitated by antagonizing CRF, including but not limited to disorders induced or facilitated by CRF, in mammals comprising administering to the mammal a therapeutically effective amount of a compound of claim 4.
67. A method of treating affective disorder, anxiety, depression, headache, irritable bowel syndrome, post-traumatic stress disorder, supranuclear palsy, immune suppression, Alzheimer's disease, gastrointestinal diseases, anorexia nervosa or other feeding disorder, drug addiction, drug or alcohol withdrawal symptoms, inflammatory diseases, cardiovascular or heart-related diseases, fertility problems, human immunodeficiency virus infections, hemorrhagic stress, obesity, infertility, head and spinal cord traumas, epilepsy, stroke, ulcers, amyotrophic lateral sclerosis, hypoglycemia or a disorder the treatment of which can be effected or facilitated by antagonizing CRF, including but not limited to disorders induced or facilitated by CRF, in mammals comprising administering to the mammal a therapeutically effective amount of a compound of claim 24.
68. A method of treating affective disorder, anxiety, depression, headache, irritable bowel syndrome, post-traumatic stress disorder, supranuclear palsy, immune suppression, Alzheimer's disease, gastrointestinal diseases, anorexia nervosa or other feeding disorder, drug addiction, drug or alcohol withdrawal symptoms, inflammatory diseases, cardiovascular or heart-related diseases, fertility problems, human immunodeficiency virus infections, hemorrhagic stress, obesity, infertility, head and spinal cord traumas, epilepsy, stroke, ulcers, amyotrophic lateral sclerosis, hypoglycemia or a disorder the treatment of which can be effected or facilitated by antagonizing CRF, including but not limited to disorders induced or facilitated by CRF, in mammals comprising administering to the mammal a therapeutically effective amount of a compound of claim 38.
69. A method of treating affective disorder, anxiety, depression, headache, irritable bowel syndrome, post-traumatic stress disorder, supranuclear palsy, immune suppression, Alzheimer's disease, gastrointestinal diseases, anorexia nervosa or other feeding disorder, drug addiction, drug or alcohol withdrawal symptoms, inflammatory diseases, cardiovascular or heart-related diseases, fertility problems, human immunodeficiency virus infections, hemorrhagic stress, obesity, infertility, head and spinal cord traumas, epilepsy, stroke, ulcers, amyotrophic lateral sclerosis, hypoglycemia or a disorder the treatment of which can be effected or facilitated by antagonizing CRF, including but not limited to disorders induced or facilitated by CRF, in mammals comprising administering to the mammal a therapeutically effective amount of a compound of claim 39.
70. A method of treating affective disorder, anxiety, depression, headache, irritable bowel syndrome, post-traumatic stress disorder, supranuclear palsy, immune suppression, Alzheimer's disease, gastrointestinal diseases, anorexia nervosa or other feeding disorder, drug addiction, drug or alcohol withdrawal symptoms, inflammatory diseases, cardiovascular or heart-related diseases, fertility problems, human immunodeficiency virus infections, hemorrhagic stress, obesity, infertility, head and spinal cord traumas, epilepsy, stroke, ulcers, amyotrophic lateral sclerosis, hypoglycemia or a disorder the treatment of which can be effected or facilitated by antagonizing CRF, including but not limited to disorders induced or facilitated by CRF, in mammals comprising administering to the mammal a therapeutically effective amount of a compound of claim 40.
71. A method of treating affective disorder, anxiety, depression, headache, irritable bowel syndrome, post-traumatic stress disorder, supranuclear palsy, immune suppression, Alzheimer's disease, gastrointestinal diseases, anorexia nervosa or other feeding disorder, drug addiction, drug or alcohol withdrawal symptoms, inflammatory diseases, cardiovascular or heart-related diseases, fertility problems, human immunodeficiency virus infections, hemorrhagic stress, obesity, infertility, head and spinal cord traumas, epilepsy, stroke, ulcers, amyotrophic lateral sclerosis, hypoglycemia or a disorder the treatment of which can be effected or facilitated by antagonizing CRF, including but not limited to disorders induced or facilitated by CRF, in mammals comprising administering to the mammal a therapeutically effective amount of a compound of claim 53.
72. A method of treating affective disorder, anxiety, depression, headache, irritable bowel syndrome, post-traumatic stress disorder, supranuclear palsy, immune suppression, Alzheimer's disease, gastrointestinal diseases, anorexia nervosa or other feeding disorder, drug addiction, drug or alcohol withdrawal symptoms, inflammatory diseases, cardiovascular or heart-related diseases, fertility problems, human immunodeficiency virus infections, hemorrhagic stress, obesity, infertility, head and spinal cord traumas, epilepsy, stroke, ulcers, amyotrophic lateral sclerosis, hypoglycemia or a disorder the treatment of which can be effected or facilitated by antagonizing CRF, including but not limited to disorders induced or facilitated by CRF, in mammals comprising administering to the mammal a therapeutically effective amount of a compound of claim 54.
73. A method of treating affective disorder, anxiety, depression, headache, irritable bowel syndrome, post-traumatic stress disorder, supranuclear palsy, immune suppression, Alzheimer's disease, gastrointestinal diseases, anorexia nervosa or other feeding disorder, drug addiction, drug or alcohol withdrawal symptoms, inflammatory diseases, cardiovascular or heart-related diseases, fertility problems, human immunodeficiency virus infections, hemorrhagic stress, obesity, infertility, head and spinal cord traumas, epilepsy, stroke, ulcers, amyotrophic lateral sclerosis, hypoglycemia or a disorder the treatment of which can be effected or facilitated by antagonizing CRF, including but not limited to disorders induced or facilitated by CRF, in mammals comprising administering to the mammal a therapeutically effective amount of a compound of claim 55.
74. A method of treating affective disorder, anxiety, depression, headache, irritable bowel syndrome, post-traumatic stress disorder, supranuclear palsy, immune suppression, Alzheimer's disease, gastrointestinal diseases, anorexia nervosa or other feeding disorder, drug addiction, drug or alcohol withdrawal symptoms, inflammatory diseases, cardiovascular or heart-related diseases, fertility problems, human immunodeficiency virus infections, hemorrhagic stress, obesity, infertility, head and spinal cord traumas, epilepsy, stroke, ulcers, amyotrophic lateral sclerosis, hypoglycemia or a disorder the treatment of which can be effected or facilitated by antagonizing CRF, including but not limited to disorders induced or facilitated by CRF, in mammals comprising administering to the mammal a therapeutically effective amount of a compound of claim 56.
CA002259583A 1996-07-24 1997-07-23 Azolo triazines and pyrimidines Expired - Lifetime CA2259583C (en)

Priority Applications (1)

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Applications Claiming Priority (7)

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US68604796A 1996-07-24 1996-07-24
US2329096P 1996-07-24 1996-07-24
US60/686,047 1996-07-24
US60/023,290 1996-07-24
US08/899,242 US6124289A (en) 1996-07-24 1997-07-23 Azolo triazines and pyrimidines
US08/899,242 1997-07-23
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