Indazolyl-substituted pyrroline compounds as kinase inhibitors

• US 7,855,203 B2
• Filed: 12/13/2007
• Issued: 12/21/2010
• Est. Priority Date: 12/08/2000
• Status: Expired due to Fees

• Current Assignee: Ortho-McNeil-Janssen Pharmaceuticals Incorporated (Johnson & Johnson)
• Original Assignee: Ortho-McNeil-Janssen Pharmaceuticals Incorporated (Johnson & Johnson)
• Inventors: Hecker, Leonard R., Ye, Hong, Zhang, Han-Cheng, White, Kimberly, McComsey, David F., Maryanoff, Bruce
• Primary Examiner(s): Anderson; Rebecca L
• Application Number:
  US12/001,805
• Publication Number:
  US 20080096949A1
• Time in Patent Office: 1,104 Days
• Field of Search: 544/371, 544/140, 514/254.06, 514/306, 514/338, 514/307, 514/234.5, 514/406, 514/314, 514/339, 546/275.7, 546/143, 546/159, 546/139, 546/152, 548/361.1, 548/362.5
• US Class Current: 514/234.5
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: A61P 9/12 Antihypertensives
• CPC Class Codes: C07D 401/14 containing three or more hetero rings
• CPC Class Codes: C07D 403/14 containing three or more hetero rings
• CPC Class Codes: C07D 405/14 containing three or more hetero rings
• CPC Class Codes: C07D 409/14 containing three or more hetero rings

Abstract

The present invention is directed to novel indazolyl-substituted pyrroline compounds of Formula (I):

useful as kinase or dual-kinase inhibitors, methods for producing such compounds and methods for treating or ameliorating a kinase or dual-kinase mediated disorder.

Claims

1. A compound of Formula (I):

2. The compound of claim 1 wherein R¹ and R² are independently selected from the group consisting of:

hydrogen,

C_1-4alkyl, C_2-4alkenyl, C_2-4alkynyl {wherein alkyl, alkenyl and alkynyl are optionally substituted with one to two substituents independently selected from the group consisting of —

O—

(C_1-4)alkyl, —

O—

(C_1-4)alkyl-OH, —

O—

(C_1-4)alkyl-O—

(C_1-4)alkyl, —

O—

(C_1-4)alkyl-NH₂, —

O—

(C_1-4)alkyl-NH—

(C_1-4)alkyl, —

O—

(C_1-4)alkyl-N[(C_1-4)alkyl]₂, —

O—

(C_1-4)alkyl-S—

(C_1-4)alkyl, —

O—

(C_1-4)alkyl-SO₂—

(C_1-4)alkyl, —

O—

(C_1-4)alkyl-SO₂—

NH₂, —

O—

(C_1-4)alkyl-SO₂—

NH—

(C_1-4)alkyl, —

O—

(C_1-4)alkyl-SO₂—

N[(C_1-4)alkyl]₂, —

O—

C(O)H, —

O—

C(O)—

(C_1-4)alkyl, —

O—

C(O)—

NH₂, —

O—

C(O)—

NH—

(C_1-4)alkyl, —

O—

C(O)—

N[(C_1-4)alkyl]₂, —

O—

(C_1-4)alkyl-C(O)H, —

O—

(C_1-4)alkyl-C(O)—

(C_1-4)alkyl, —

O—

(C_1-4)alkyl-CO₂H, —

O—

(C_1-4)alkyl-C(O)—

O—

(C_1-4)alkyl,—

O—

(C_1-4)alkyl-C(O)—

NH₂, —

O—

(C_1-4)alkyl-C(O)—

NH—

(C_1-4)alkyl, —

O—

(C_1-4)alkyl-C(O)—

N[(C_1-4)alkyl]₂, —

C(O)H, —

C(O)—

(C_1-4)alkyl, —

CO₂H, —

C(O)—

O—

(C_1-4)alkyl, —

C(O)—

NH₂, —

C(NH)—

NH₂, —

C(O)—

NH—

(C_1-4)alkyl, —

C(O)—

N[(C_1-4)alkyl]₂, —

SH, —

S—

(C_1-4)alkyl, —

S—

(C_1-4)alkyl-S—

(C_1-4)alkyl, —

S—

(C_1-4)alkyl-O—

(C_1-4)alkyl, —

S—

(C_1-4)alkyl-O—

(C_1-4)alkyl-OH, —

S—

(C_1-4)alkyl-O—

(C_1-4)alkyl-NH₂, —

S—

(C_1-4)alkyl-O—

(C_1-4)alkyl-NH—

(C_1-4)alkyl, —

S—

(C_1-4)alkyl-O—

(C_1-4)alkyl-N[(C_1-4)alkyl]₂, —

S—

(C_1-4)alkyl-NH—

(C_1-4)alkyl, —

SO₂—

(C_1-4)alkyl, —

SO₂—

NH₂, —

SO₂—

NH—

(C_1-4)alkyl, —

SO₂—

N[(C_1-4)alkyl]₂, amino (substituted with two substituents independently selected from the group consisting of hydrogen, C_1-4alkyl, C_2-4alkenyl, C_2-4alkynyl, —

(C_1-4)alkyl-OH, —

(C_1-4)alkyl-O—

(C_1-4)alkyl, —

(C_1-4)alkyl-NH₂, —

(C_1-4)alkyl-NH—

(C_1-4)alkyl, —

(C_1-4)alkyl-N[(C_1-4)alkyl]₂, —

(C_1-4)alkyl-S—

(C_1-4)alkyl, —

C(O)—

(C_1-4)alkyl, —

C(O)—

O—

(C_1-4)alkyl, —

C(O)—

NH₂, —

C(O)—

NH—

(C_1-4)alkyl, —

C(O)—

N[(C_1-4)alkyl]₂, —

SO₂—

(C_1-4)alkyl, —

SO₂—

NH₂, —

SO₂—

NH—

(C_1-4)alkyl, —

SO₂—

N[(C_1-4)alkyl]₂, —

C(N)—

NH₂, aryl and aryl(C_1-4)alkyl (wherein aryl is optionally substituted with one to three substituents independently selected from the group consisting of halogen, C_1-4alkyl, C_1-4alkoxy, amino (substituted with two substituents selected from the group consisting of hydrogen and C_1-4alkyl), cyano, halo, (halo)_1-3(C_1-4)alkyl, (halo)_1-3(C_1-4)alkoxy, hydroxy, hydroxy(C_1-4)alkyl and nitro)), cyano, (halo)_1-3, hydroxy, nitro, oxo, heterocyclyl, aryl and heteroaryl (wherein heterocyclyl, aryl and heteroaryl are optionally substituted with one to three substituents independently selected from the group consisting of C_1-4alkyl, C_1-4alkoxy, amino (substituted with two substituents selected from the group consisting of hydrogen and C_1-4alkyl), cyano, halo, (halo)_1-3(C_1-4)alkyl, (halo)_1-3(C_1-4)alkoxy, hydroxy, hydroxy(C_1-4)alkyl and nitro)},

—

C(O)—

(C_1-4)alkyl, —

C(O)-aryl, —

C(O)—

O—

(C_1-4)alkyl, —

C(O)—

O-aryl, —

C(O)—

NH—

(C_1-4)alkyl, —

C(O)—

NH-aryl, —

C(O)—

N[(C_1-4)alkyl]₂, —

SO₂—

(C_1-4)alkyl, —

SO₂-aryl,

aryl and heteroaryl {wherein aryl and heteroaryl are optionally substituted with one to three substituents independently selected from the group consisting of C_1-4alkyl, C_2-4alkenyl, C_2-4alkynyl, C_1-4alkoxy, —

C(O)H, —

C(O)—

(C_1-4)alkyl, —

CO₂H, —

C(O)—

O—

(C_1-4)alkyl, —

C(O)—

NH₂, —

C(NH)—

NH₂, —

C(O)—

NH—

(C_1-4)alkyl, —

C(O)—

N[(C_1-4)alkyl]₂, —

SH, —

S—

(C_1-4)alkyl, —

SO₂—

(C_1-4)alkyl, —

SO₂—

NH₂, —

SO₂—

NH—

(C_1-4)alkyl, —

SO₂—

N[(C_1-4)alkyl]₂, amino (substituted with two substituents independently selected from the group consisting of hydrogen, C_1-4alkyl, C_2-4alkenyl, C_2-4alkynyl, —

(C_1-4)alkyl-NH₂, —

C(O)—

(C_1-4)alkyl, —

C(O)—

O—

(C_1-4)alkyl, —

C(O)—

NH₂, —

C(O)—

NH—

(C_1-4)alkyl, —

C(O)—

N[(C_1-4)alkyl]₂, —

SO₂—

(C_1-4)alkyl, —

SO₂—

NH₂, —

SO₂—

NH—

(C_1-4)alkyl, —

SO₂—

N[(C_1-4)alkyl]₂ and —

C(NH)—

NH₂), amino-(C_1-4)alkyl- (wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen, C_1-4alkyl, C_2-4alkenyl, C_2-4alkynyl, —

(C_1-4)alkyl-NH₂, —

C(O)—

(C_1-4)alkyl, —

C(O)—

O—

(C_1-4)alkyl, —

C(O)—

NH₂, —

C(O)—

NH—

(C_1-4)alkyl, —

C(O)—

N[(C_1-4)alkyl]₂, —

SO₂—

(C_1-4)alkyl, —

SO₂—

NH₂, —

SO₂—

NH—

(C_1-4)alkyl, —

SO₂—

N[(C_1-4)alkyl]₂ and —

C(NH)—

NH₂), cyano, halo, (halo)_1-3(C_1-4)alkyl, (halo)_1-3(C_1-4)alkoxy, hydroxy, hydroxy(C_1-4)alkyl, nitro, aryl, —

(C_1-4)alkyl-aryl, heteroaryl and —

(C_1-4)alkyl-heteroaryl};

with the proviso that if R² is selected from the group consisting of hydrogen, unsubstituted C_1-4alkyl and —

(C_1-4)alkyl-(halo)_1-3, then R¹ is selected from the group consisting of other than hydrogen, C_1-4alkyl, aryl (limited to phenyl unsubstituted or substituted with one or more substituents selected from the group consisting of halo, unsubstituted C_1-4alkyl, hydroxy, C_1-4alkoxy, (halo)_1-3(C_1-4)alkyl, nitro, unsubstituted amino and cyano), —

(C_1-4)alkyl-aryl (wherein aryl is limited to phenyl unsubstituted or substituted with one or more substituents selected from the group consisting of halo, unsubstitutedC_1-4alkyl, hydroxy, C_1-4alkoxy, (halo)_1-3(C_1-4)alkyl, nitro, unsubstituted amino and cyano), —

(C_1-4)alkyl(C_1-4)alkoxy, —

(C_1-4)alkyl-hydroxy, —

(C_1-4)alkyl-(halo)_1-3, —

(C_1-4)alkyl-amino (wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen and —

C_1-4alkyl), —

(C_1-4)alkyl-amino(C_1-4)alkylamino, —

C_1-4alkyl-NH—

C(O)—

(C_1-4)alkyl, —

C_1-4alkyl-NH—

SO₂—

(C_1-4)alkyl, —

(C_1-4)alkyl-SH, —

(C_1-4)alkyl-S—

(C_1-4)alkyl, —

(C_1-4)alkyl-SO₂—

(C_1-4)alkyl, —

(C_1-4)alkyl-O—

C(O)—

(C_1-4)alkyl, —

(C_1-4)alkyl-C(N), —

(C_1-4)alkyl-C(NH)—

NH₂, —

(C_1-4)alkyl-CO₂H, —

(C_1-4)alkyl-C(O)—

O—

(C_1-4)alkyl, —

(C_1-4)alkyl-C(O)—

NH₂, —

(CH₂)₂₄-heterocyclyl, —

(CH₂)_2-4-T-C(V)-Z (wherein T is NH, V is O and Z is amino (wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen and C_1-4alkyl))

with the provision that for R¹ and R² heteroaryl shall mean pyridinyl, quinolinyl or isoquinolinyl.

3. The compound of claim 1 wherein R¹ and R² are independently selected from the group consisting of:

hydrogen,

C_1-4alkyl, C_2-4alkenyl {wherein alkyl is substituted with one to two substituents independently selected from the group consisting of —

O—

(C_1-4)alkyl, —

O—

(C_1-4)alkyl-OH, —

O—

(C_1-4)alkyl-NH—

(C_1-4)alkyl, —

O—

C(O)—

(C_1-4)alkyl, —

C(O)H, —

CO₂H, —

C(O)—

O—

(C_1-4)alkyl, amino (substituted with two substituents independently selected from the group consisting of hydrogen, C_1-4alkyl, —

(C_1-4)alkyl-OH, —

C(O)—

O—

(C_1-4)alkyl and aryl(C_1-4)alkyl), hydroxy, heterocyclyl, aryl and heteroaryl (wherein heterocyclyl, aryl and heteroaryl are optionally substituted with one to three substituents independently selected from the group consisting of C_1-4alkyl and halo)},

aryl and heteroaryl {wherein aryl and heteroaryl are optionally substituted with one to two substituents independently selected from the group consisting of C_1-4alkyl, C_1-4alkoxy, amino (substituted with two substituents independently selected from the group consisting of hydrogen and C_1-4alkyl), cyano, halo, (halo)_1-3(C_1-4)alkyl, (halo)_1-3(C_1-4)alkoxy, hydroxy, hydroxy(C_1-4)alkyl, aryl and heteroaryl};

with the proviso that if R² is selected from the group consisting of hydrogen and unsubstituted C_1-4alkyl, then R¹ is selected from the group consisting of other than hydrogen, C_1-4alkyl, aryl (limited to phenyl unsubstituted or substituted with one or more substituents selected from the group consisting of halo, unsubstituted C_1-4alkyl, hydroxy, C_1-4alkoxy, (halo)_1-3(C_1-4)alkyl, unsubstituted amino and cyano), —

(C_1-4)alkyl-aryl (wherein aryl is limited to phenyl unsubstituted or substituted with one or more substituents selected from the group consisting of halo and unsubstituted C_1-4alkyl), —

(C_1-4)alkyl(C_1-4)alkoxy, —

(C_1-4)alkyl-hydroxy, —

(C_1-4)alkyl-amino (wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen and—

C_1-4alkyl), —

(C_1-4)alkyl-O—

C(O)—

(C_1-4)alkyl, —

(C_1-4)alkyl-CO₂H, —

(C_1-4)alkyl-C(O)—

O—

(C_1-4)alkyl and —

(CH₂)₂₄-heterocyclyl;

with the provision that for R¹ and R² heteroaryl shall mean pyridinyl, quinolinyl or isoquinolinyl.

4. The compound of claim 1 wherein R¹ is selected from the group consisting of:

hydrogen,

C_1-4alkyl, C_2-4alkenyl {wherein alkyl is substituted with one to two substituents independently selected from the group consisting of —

O—

(C_1-4)alkyl-NH—

(C_1-4)alkyl, amino (substituted with two substituents independently selected from the group consisting of hydrogen and C_1-4alkyl), hydroxy, heterocyclyl, aryl and heteroaryl (wherein heterocyclyl, aryl and heteroaryl are optionally substituted with one to three substituents independently selected from the group consisting of C_1-4alkyl and halo)},

aryl and heteroaryl (wherein aryl and heteroaryl are optionally substituted with one to two substituents independently selected from the group consisting of C_1-4alkyl, C_1-4alkoxy, amino (substituted with two substituents independently selected from the group consisting of hydrogen and C_1-4alkyl), cyano, halo, (halo)_1-3(C_1-4)alkyl, (halo)_1-3(C_1-4)alkoxy, hydroxy, hydroxy(C_1-4)alkyl, aryl and heteroaryl};

with the proviso that if R² is selected from the group consisting of hydrogen, unsubstituted C_1-4alkyl and —

(C_1-4)alkyl-(halo)_1-3, then R¹ is selected from the group consisting of other than hydrogen, C_1-4alkyl, aryl (limited to phenyl unsubstituted or substituted with one or more substituents selected from the group consisting of halo, unsubstituted C_1-4alkyl, hydroxy, C_1-4alkoxy, (halo)_1-3(C_1-4)alkyl, unsubstituted amino and cyano), —

(C_1-4)alkyl-aryl (wherein aryl is limited to phenyl unsubstituted or substituted with one or more substituents selected from the group consisting of halo and unsubstituted C_1-4alkyl), —

(C_1-4)alkyl-hydroxy, —

(C_1-4)alkyl-amino (wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen and C_1-4alkyl) and —

(CH₂)₂₄-heterocyclyl;

with the provision that for R¹ and R² heteroaryl shall mean pyridinyl, quinolinyl or isoquinolinyl.

5. The compound of claim 1 wherein R¹ is selected from the group consisting of:

hydrogen,

C_1-4alkyl, C_2-3alkenyl {wherein alkyl is substituted with one to two substituents independently selected from the group consisting of —

O—

(C_1-4)alkyl-NH—

(C_1-4)alkyl, amino (substituted with two substituents independently selected from the group consisting of hydrogen and C_1-4alkyl), hydroxy, pyrrolidinyl, morpholinyl, piperazinyl (wherein piperazinyl is optionally substituted with methyl), phenyl, naphthalenyl and quinolinyl (wherein phenyl and benzo[b]thienyl are optionally substituted with one to two chloro substituents)},

phenyl, naphthalenyl, pyridinyl, quinolinyl and isoquinolinyl (wherein phenyl, naphthalenyl and pyridinyl are optionally substituted with one to two substituents independently selected from the group consisting of C_1-4alkyl, C_1-4alkoxy, halo and hydroxy; and

, wherein phenyl is optionally substituted with one substituent selected from the group consisting of phenyl and thienyl);

with the proviso that if R² is selected from the group consisting of hydrogen, unsubstituted C_1-4alkyl and —

(C_1-4)alkyl-(halo)_1-3, then R¹ is selected from the group consisting of other than hydrogen, C_1-4alkyl, phenyl (wherein phenyl is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, unsubstituted C_1-4alkyl, hydroxy and C_1-4alkoxy), —

(C_1-4)alkyl-phenyl (wherein phenyl is unsubstituted or substituted with one or more chloro substituents), —

(C_1-4)alkyl-hydroxy, —

(C_1-4)alkyl-amino (wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen and C_1-4alkyl) and —

(CH₂)_2-4-heterocyclyl;

with the provision that for R¹ and R² heteroaryl shall mean pyridinyl, quinolinyl or isoquinolinyl.

6. The compound of claim 1 wherein R² is selected from the group consisting of:

hydrogen,

C_1-4alkyl {wherein alkyl is substituted with one to two substituents independently selected from the group consisting of —

O—

(C_1-4)alkyl, —

O—

(C_1-4)alkyl-OH, —

O—

(C_1-4)alkyl-NH—

(C_1-4)alkyl, —

O—

C(O)—

(C_1-4)alkyl, —

C(O)H, —

CO₂H, —

C(O)—

O—

(C_1-4)alkyl, amino (substituted with two substituents independently selected from the group consisting of hydrogen, C_1-4alkyl, —

(C_1-4)alkyl-OH, —

C(O)—

O—

(C_1-4)alkyl and aryl(C_1-4)alkyl), hydroxy and heterocyclyl (wherein heterocyclyl is optionally substituted with one to two C_1-4alkyl substituents)} and heteroaryl;

with the proviso that if R² is selected from the group consisting of hydrogen and unsubstituted C_1-4alkyl, then R¹ is selected from the group consisting of other than hydrogen, C_1-4alkyl, aryl (limited to phenyl unsubstituted or substituted with one or more substituents selected from the group consisting of halo, unsubstituted C_1-4alkyl, hydroxy, C_1-4alkoxy, (halo)_1-3(C_1-4)alkyl, nitro, unsubstituted amino and cyano), —

(C_1-4)alkyl-aryl (wherein aryl is limited to phenyl unsubstituted or substituted with one or more substituents selected from the group consisting of halo, unsubstituted C_1-4alkyl, hydroxy, C_1-4alkoxy, (halo)_1-3(C_1-4)alkyl, nitro, unsubstituted amino and cyano), —

(C_1-4)alkyl(C_1-4)alkoxy, —

(C_1-4)alkyl-hydroxy, —

(C_1-4)alkyl-(halo)_1-3, —

(C_1-4)alkyl-amino (wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen and C_1-4alkyl), —

(C_1-4)alkyl-amino(C_1-4)alkylamino, —

C_1-4alkyl-NH—

C(O)—

(C_1-4)alkyl, —

C_1-4alkyl-NH—

SO₂—

(C_1-4)alkyl, —

(C_1-4)alkyl-SH, —

(C_1-4)alkyl-S—

(C_1-4)alkyl, —

(C_1-4)alkyl-SO₂—

(C_1-4)alkyl, —

(C_1-4)alkyl-O—

C(O)—

(C_1-4)alkyl, —

(C_1-4)alkyl-C(N), —

(C_1-4)alkyl-C(NH)—

NH₂, —

(C_1-4)alkyl-CO₂H, —

(C_1-4)alkyl-C(O)—

O—

(C_1-4)alkyl, —

(C_1-4)alkyl-C(O)—

NH₂, —

(CH₂)₂₄-heterocyclyl, —

(CH₂)_2-4-T-C(V)-Z (wherein T is NH, V is O and Z is amino (wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen and C_1-4alkyl));

with the provision that for R¹ and R² heteroaryl shall mean pyridinyl, quinolinyl or isoquinolinyl.

7. The compound of claim 1 wherein R² is selected from the group consisting of:

hydrogen,

C_1-4alkyl {wherein alkyl is substituted with one to two substituents independently selected from the group consisting of —

O—

(C_1-4)alkyl, —

O—

(C_1-4)alkyl-OH, —

O—

(C_1-4)alkyl-NH—

(C_1-4)alkyl, —

O—

C(O)—

(C_1-4)alkyl, —

C(O)H,—

CO₂H, —

C(O)—

O—

(C_1-4)alkyl, amino (substituted with two substituents independently selected from the group consisting of hydrogen, C_1-4alkyl, —

(C_1-4)alkyl-OH, —

C(O)—

O—

(C_1-4)alkyl and phenyl(C_1-4)alkyl), hydroxy, pyrrolidinyl, 1,3-dioxolanyl, morpholinyl and piperazinyl (wherein piperazinyl is optionally substituted with methyl)} and pyridinyl;

with the proviso that if R² is selected from selected from the group consisting of hydrogen and unsubstituted C_1-4alkyl, then R¹ is selected from the group consisting of other than hydrogen, C_1-4alkyl, aryl (limited to phenyl unsubstituted or substituted with one or more substituents selected from the group consisting of halo, unsubstituted C_1-4alkyl, hydroxy, C_1-4alkoxy, (halo)_1-3(C_1-4)alkyl, nitro, unsubstituted amino and cyano), —

(C_1-4)alkyl-aryl (wherein aryl is limited to phenyl unsubstituted or substituted with one or more substituents selected from the group consisting of halo, unsubstituted C_1-4alkyl, hydroxy, C_1-4alkoxy, (halo)_1-3(C_1-4)alkyl, nitro, unsubstituted amino and cyano), —

(C_1-4)alkyl(C_1-4)alkoxy, —

(C_1-4)alkyl-hydroxy, —

(C_1-4)alkyl-(halo)_1-3, —

(C_1-4)alkyl-amino (wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen and C_1-4alkyl), —

(C_1-4)alkyl-amino(C_1-4)alkylamino, —

C_1-4alkyl-NH—

C(O)—

(C_1-4)alkyl, —

C_1-4alkyl-NH—

SO₂—

(C_1-4)alkyl, —

(C_1-4)alkyl-SH, —

(C_1-4)alkyl-S—

(C_1-4)alkyl, —

(C_1-4)alkyl-SO₂—

(C_1-4)alkyl, —

(C_1-4)alkyl-O—

C(O)—

(C_1-4)alkyl, —

(C_1-4)alkyl-C(N), —

(C_1-4)alkyl-C(NH)—

NH₂, —

(C_1-4)alkyl-CO₂H, —

(C_1-4)alkyl-C(O)—

O—

(C_1-4)alkyl, —

(C_1-4)alkyl-C(O)—

NH₂, —

(CH₂)₂₄-heterocyclyl, —

(CH₂)₂₄-T-C(V)-Z (wherein T is NH, V is O and Z is amino (wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen and C_1-4alkyl));

with the provision that for R¹ and R² heteroaryl shall mean pyridinyl, quinolinyl or isoquinolinyl.

8. The compound of claim 1 wherein R³ and R⁴ are independently selected from the group consisting of hydrogen, C_1-4alkyl, C_2-4alkenyl, C_2-4alkynyl, C_1-4alkoxy, —

C(O)H, —

C(O)—

(C_1-4)alkyl, —

CO₂H, —

C(O)—

O—

(C_1-4)alkyl, —

C(O)—

NH₂, —

C(NH)—

NH₂, —

C(O)—

NH—

(C_1-4)alkyl, —

C(O)—

N[(C_1-4)alkyl]₂, —

SH, —

S—

(C_1-4)alkyl, —

SO₂—

(C_1-4)alkyl, —

SO₂—

NH₂, —

SO₂—

NH—

(C_1-4)alkyl, —

SO₂—

N[(C_1-4)alkyl]₂, amino (substituted with two substituents independently selected from the group consisting of hydrogen, C_1-4alkyl, C_2-4alkenyl, C_2-4alkynyl, —

(C_1-4)alkyl-NH₂, —

C(O)—

(C_1-4)alkyl, —

C(O)—

O—

(C_1-4)alkyl, —

C(O)—

NH₂, —

C(O)—

NH—

(C_1-4)alkyl, —

C(O)—

N[(C_1-4)alkyl]₂, —

SO₂—

(C_1-4)alkyl, —

SO₂—

NH₂, —

SO₂—

NH—

(C_1-4)alkyl, —

SO₂—

N[(C_1-4)alkyl]₂ and —

C(NH)—

NH₂), amino-(C_1-4)alkyl- (wherein amino is substituted with two substituents independently selected from the group consisting of hydrogen, C_1-4alkyl, C_2-4alkenyl, C_2-4alkynyl, —

(C_1-4)alkyl-NH₂, —

C(O)—

(C_1-4)alkyl, —

C(O)—

O—

(C_1-4)alkyl, —

C(O)—

NH₂, —

C(O)—

NH—

(C_1-4)alkyl, —

C(O)—

N[(C_1-4)alkyl]₂, —

SO₂—

(C_1-4)alkyl, —

SO₂—

NH₂, —

SO₂—

NH—

(C_1-4)alkyl, —

SO₂—

N[(C_1-4)alkyl]₂ and —

C(NH)—

NH₂), cyano, halo, (halo)_1-3(C_1-4)alkyl, (halo)_1-3(C_1-4)alkoxy, hydroxy, hydroxy(C_1-4)alkyl, nitro, aryl, and —

(C_1-4)alkyl-aryl.

9. The compound of claim 1 wherein R³ and R⁴ are independently selected from the group consisting of hydrogen, C_1-4alkyl, C_1-4alkoxy, cyano and halogen.

10. The compound of claim 1 wherein R³ and R⁴ are independently selected from the group consisting of hydrogen, methyl, methoxy, cyano and chloro.

11. The compound of claim 1 wherein Y and Z are independently selected from the group consisting of O and (H,H);

with the proviso that one of Y and Z is O, and the other is selected from the group consisting of O and (H,H).

12. The compound of claim 1 wherein the compound of Formula (I) is a compound selected from Formula (Ic):

13. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.