AU733877B2 - Substituted pyrimidine compounds and their use - Google Patents

Substituted pyrimidine compounds and their use Download PDF

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Publication number
AU733877B2
AU733877B2 AU60120/98A AU6012098A AU733877B2 AU 733877 B2 AU733877 B2 AU 733877B2 AU 60120/98 A AU60120/98 A AU 60120/98A AU 6012098 A AU6012098 A AU 6012098A AU 733877 B2 AU733877 B2 AU 733877B2
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amino
radicals
alkyl
pyridyl
alkoxy
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AU733877C (en
AU6012098A (en
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Michael J. Malone
Nathan B. Mantlo
Ulrike D. Spohr
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Amgen Inc
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Amgen Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/64—One oxygen atom attached in position 2 or 6
    • C07D213/643—2-Phenoxypyridines; Derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Description

-1- SUBSTITUTED PYRIMIDINE COMPOUNDS AND THEIR USE BACKGROUND OF THE INVENTION The present invention comprises a new class of compounds useful in treating diseases, such as TNF-a, IL- 1, IL-6 and/or IL-8 mediated diseases and other maladies, such as pain and diabetes. In particular, the compounds of the invention are useful for the prophylaxis and treatment of diseases or conditions involving inflammation. This invention also relates to intermediates and processes useful in the preparation of such compounds.
Interleukin-1 (IL-1) and Tumor Necrosis Factor c (TNF-a) are pro-inflammatory 10 cytokines secreted by a variety of cells, including monocytes and macrophages, in response to many inflammatory stimuli lipopolysaccharide LPS) or external cellular stress osmotic shock and peroxide).
Elevated levels of TNF-a and/or IL-1 over basal levels have been implicated in mediating or exacerbating a number of disease states including rheumatoid arthritis; Pagets disease; osteophorosis; multiple myeloma; uveititis; acute and chronic myelogenous leukemia; pancreatic P cell destruction; osteoarthritis; rheumatoid Sspondylitis; gouty arthritis; inflammatory bowel disease; adult respiratory distress syndrome (ARDS); psoriasis; Crohn's disease; allergic rhinitis; ulcerative colitis; anaphylaxis; contact dermatitis; asthma; muscle degeneration; cachexia; Reiter's 22344-00.DOC Wn OI2'7R 2 syndrome; type I and type II diabetes; bone resorption diseases; graft vs. host reaction; ischemia reperfusion injury; atherosclerosis; brain trauma; multiple sclerosis; cerebral malaria; sepsis; septic shock; toxic shock syndrome; fever, and myalgias due to infection.
HIV-1, HIV-2, HIV-3, cytomegalovirus (CMV), influenza, adenovirus, the herpes viruses (including HSV-1, HSV-2), and herpes zoster are also exacerbated by TNF-a.
It has been reported that TNF-a plays a role in head trauma, stroke, and ischemia. For instance, in animal models of head trauma (rat), TNF-a levels increased in the contused hemisphere (Shohami et al., J.
Cereb. Blood Flow Metab. 14, 615 (1994)). In a rat model of ischemia wherein the middle cerebral artery was occluded, the levels of TNF-a mRNA of TNF-a increased (Feurstein et al., Neurosci. Lett. 164, 125 (1993)).
Administration of TNF-a into the rat cortex has been reported to result in significant neutrophil accumulation in capillaries and adherence in small blood vessels. TNF-a promotes the infiltration of other cytokines (IL-1, IL-6) and also chemokines, which promote neutrophil infiltration into the infarct area (Feurstein, Stroke 25, 1481 (1994)). TNF-a has also been implicated to play a role in type II diabetes (Endocrinol. 130, 43-52, 1994; and Endocrinol. 136, 1474-1481, 1995).
TNF- appears to play a role in promoting certain viral life cycles and disease states associated with them. For instance, TNF-a secreted by monocytes induced elevated levels of HIV expression in a chronically infected T cell clone (Clouse et al., J. Immunol. 142, 431 (1989)). Lahdevirta et al., (Am. J. Med. 85, 289 (1988)) discussed the role of TNF-a in the HIV associated states of cachexia and muscle degradation.
WO 98/24782 PCT/US97/22390 3 TNF-a is upstream in the cytokine cascade of inflammation. As a result, elevated levels of TNF-a may lead to elevated levels of other inflammatory and proinflammatory cytokines, such as IL-1, IL-6, and IL-8.
Elevated levels of IL-1 over basal levels have been implicated in mediating or exacerbating a number of disease states including rheumatoid arthritis; osteoarthritis; rheumatoid spondylitis; gouty arthritis; inflammatory bowel disease; adult respiratory distress syndrome (ARDS); psoriasis; Crohn's disease; ulcerative colitis; anaphylaxis; muscle degeneration; cachexia; Reiter's syndrome; type I and type II diabetes; bone resorption diseases; ischemia reperfusion injury; atherosclerosis; brain trauma; multiple sclerosis; sepsis; septic shock; and toxic shock syndrome. Viruses sensitive to TNF-a inhibition, HIV-1, HIV-2, HIV- 3, are also affected by IL-1.
TNF-a and IL-1 appear to play a role in pancreatic I,cell destruction and diabetes. Pancreatic 9 cells produce insulin which helps mediate blood glucose homeostasis. Deterioration of pancreatic Z cells often accompanies type I diabetes. Pancreatic S cell functional abnormalities may occur in patients with type II diabetes. Type II diabetes is characterized by a functional resistance to insulin. Further, type II diabetes is also often accompanied by elevated levels of plasma glucagon and increased rates of hepatic glucose production. Glucagon is a regulatory hormone that attenuates liver gluconeogenesis inhibition by insulin.
Glucagon receptors have been found in the liver, kidney and adipose tissue. Thus glucagon antagonists are useful for attenuating plasma glucose levels (WO 97/16442, incorporated herein by reference in its entirety). By antagonizing the glucagon receptors, it is thought that insulin responsiveness in the liver will WO 98/24782 PCT/US97/22390 4 improve, thereby decreasing gluconeogenesis and lowering the rate of hepatic glucose production.
In rheumatoid arthritis models in animals,, multiple intra-articular injections of IL-1 have led to an acute and destructive form of arthritis (Chandrasekhar et al., Clinical Immunol Immunopathol. 55, 382 (1990)). In studies using cultured rheumatoid synovial cells, IL-1 is a more potent inducer of stromelysin than is TNF-a (Firestein, Am. J. Pathol. 140, 1309 (1992)). At sites of local injection, neutrophil, lymphocyte, and monocyte emigration has been observed. The emigration is attributed to the induction of chemokines IL-8), and the up-regulation of adhesion molecules (Dinarello, Eur. Cytokine Netw. 5, 517-531 (1994)).
IL-
1 also appears to play a role in promoting certain viral life cycles. For example, cytokineinduced increase of HIV expression in a chronically infected macrophage line has been associated with a concomitant and selective increase in IL-1 production (Folks et al., J. Immunol. 136, 40 (1986)). Beutler et al. Immunol. 135, 3969 (1985)) discussed the role of IL-1 in cachexia. Baracos et al. (New Eng. J. Med. 308, 553 (1983)) discussed the role of IL-1 in muscle degeneration.
In rheumatoid arthritis, both IL-1 and TNF-a induce synoviocytes and chondrocytes to produce collagenase and neutral proteases, which leads to tissue destruction within the arthritic joints. In a model of arthritis (collagen-induced arthritis (CIA) in rats and mice), intra-articular administration of TNF-a either prior to or after the induction of CIA led to an accelerated onset of arthritis and a more severe course of the disease (Brahn et al., Lymphokine Cytokine Res. 11, 253 (1992); and Cooper, Clin. Exp. Immunol. 898, 244 (1992)).
IL-8 has been implicated in exacerbating and/or causing many disease states in which massive neutrophil t. WO 98/24782 PCTUS97/22390 infiltration into sites of inflammation or injury ischemia) is mediated by the chemotactic nature of IL-8, including, but not limited to, the following: asthma, inflammatory bowel disease, psoriasis, adult respiratory distress syndrome, cardiac and renal reperfusion injury, thrombosis and glomerulonephritis. In addition to the chemotaxis effect on neutrophils, IL-8 also has the ability to activate neutrophils. Thus, reduction in IL- 8 levels may lead to diminished neutrophil infiltration.
Several approaches have been taken to block the effect of TNF-X. One approach involves using soluble receptors for TNF-c TNFR-55 or TNFR-75), which have demonstrated efficacy in animal models of TNF-amediated disease states. A second approach to neutralizing TNF-a using a monoclonal antibody specific to TNF-a, cA2, has demonstrated improvement in swollen joint count in a Phase II human trial of rheumatoid arthritis (Feldmann et al., Immunological Reviews, pp.
195-223 (1995)). These approaches block the effects of TNF-a and IL-1 by either protein sequestration or receptor antagonism.
Bennett et al. Med. Chem. 21, 623 (1978)) synthesized a number of pyrimidines of the form: Ra! N. Ra 3 Ra 2 i where, inter alia, is or 4-pyridyl, R 2 is H, methyl, or phenyl, and Ra 3 is H, amino. They reported that none of these compounds tested against rat adjuvant-induced edema displayed a level of activity sufficient to warrant further investigation and that additional testing confirmed that the compounds represented a series of false positives in the carrageenan-induced edema model.
-6- Ife et al. (Bioorg. Med. Chem. Lett. 5, 543 (1995)) reported that another pyrimidine (Ra' 2-methylphenyl, Ra 2 2-pyridyl, and Ra 3 n-propyl, wherein Ra', Ra, and Ra 3 are as in structure i, supra) had several times, lower H+/K+-ATPase inhibitory activity than related 4-(2-pyridyl)-5-phenylthiazole compounds.
WO 97/33883 describes substituted pyrimidine compounds useful in treating cytokine mediated diseases.
SUMMARY OF THE INVENTION The present invention comprises a new class of compounds useful in the prophylaxis and treatment of diseases, such as TNF-a, IL- I IL-6 and/or IL-8 mediated diseases and other maladies, such as pain and diabetes. In particular, the compounds of the invention are useful for the prophylaxis and treatment of diseases or conditions involving inflammation. Accordingly, the invention also comprises pharmaceutical compositions comprising the compounds, methods for the prophylaxis and treatment of TNF-a, IL-1p, IL-6 and/or IL-8 mediated diseases, such as inflammatory, pain and 0 15 diabetes diseases, using the compounds and compositions of the invention, and intermediates and processes useful for the preparation of the compounds of the invention.
More particularly, in a first aspect of the invention there is provided a compound of formula I represented by the following general structure: R2 R11
N
R
12 N R1 wherein R 2
R
I
and R 1 2 are defined below.
22344-00.DOC 6a- In a second aspect of the invention there is provided a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable carrier.
In a third aspect there is provided a method of prophylaxis or treatment of inflammation comprising administering an effective amount of a compound of the invention.
In a fourth aspect of the invention there is provided a method of prophylaxis or treatment of inflammation comprising administering an effective amount of a compound of the invention.
In a fifth aspect of the invention there is provided a method of prophylaxis or treatment of rheumatoid arthritis, Pagets disease, osteoporosis, multiple myeloma, uveititis, acute or chronic myelogenous leukemia, pancreatic P cell destruction, osteoarthritis, rheumatoid spondylitis, gouty arthritis, inflammatory bowel disease, adult respiratory distress syndrome (ARDS), psoriasis, Crohn's disease, allergic rhinitis, ulcerative colitis, anaphylaxis, contact dermatitis, asthma, muscle degeneration, 15 cachexia, Reiter's syndrome, type I diabetes, type II diabetes, bone resorption diseases, graft vs. host reaction, Alzheimer's disease, stroke, myocardial infarction, ischemia reperfusion injury, atherosclerosis, brain trauma, multiple sclerosis, cerebral malaria, sepsis, septic shock, toxic shock syndrome, fever, myalgias due to HIV-1, HIV-2, HIVo 3, cytomegalovirus (CMV), influenza, adenovirus, the herpes viruses or herpes zoster 20 infection in a mammal comprising administering an effective amount of a compound of the invention.
22344-00.DOC -6b In a sixth aspect of the invention there is provided a method of lowering plasma concentration of either or both TNF-cc and IL-I comprising administering an effective amount of a compound of the invention.
In a seventh aspect of the invention there is provided a method of lowering plasma concentration of either or both IL-6 and IL-8 comprising administering an effective amount of a compound of the invention.
In an eighth aspect of the invention there is provided a method of prophylaxis or treatment of diabetes disease in a mammal comprising administering an effective amount of a compound of the invention to produce a glucagon antagonistic effect.
In the ninth aspect of the invention there is provided a method of prophylaxis or treatment of a pain disorder in a mammal comprising administering an effective amount of a compound of the invention.
o*o In a tenth aspect of the invention there is provided a method of decreasing prostaglandins production in a mammal comprising administering an effective amount of ooo• S- 15 a compound of the invention.
In an eleventh aspect of the invention there is provided a method of decreasing cyclooxygenase enzyme activity in a mammal comprising administering an effective amount of a compound of the invention.
In a twelfth aspect of the invention there is provided the use of a compound of the o* .o* S: 20 invention in the manufacture of a medicament suitable for administration to a mammal.
In a thirteenth aspect of the present invention there is provided use of a compound of the invention inthe manufacture of a medicament for administration in the STR prophylaxes or treatment of inflammation.
22344-00.DOC 6c In a fourteenth aspect of the present invention there is provided use of a compound of the invention in the manufacture of a medicament for administration in the prophylaxis or treatment of rheumatoid arthritis, Pagets disease, osteoporosis, multiple myeloma, uveititis, acute or chronic myelogenous leukemia, pancreatic P cell destruction, osteoarthritis, rheumatoid spondylitis, gouty arthritis, inflammatory bowel disease, adult respiratory distress syndrome (ARDS), psoriasis, Crohn's disease, allergic rhinitis, ulcerative colitis, anaphylaxis, contact dermatitis, asthma, muscle degeneration, cachexia, Reiter's syndrome, type I diabetes, type II diabetes, bone resorption diseases, graft vs. Host reaction, Alzheimer's disease, stroke, myocardial infarction, ischemia reperfusidn injury, atherosclerosis, brain trauma, multiple sclerosis, cerebral malaria, sepsis, septic shock, toxic shock syndrome, fever, myalgias due to HIV-1, HIV-2, HIV- 3, cytomegalovirus (CMV), influenza, adenovirus, the herpes viruses or herpes zoster infection.
In a fifteenth aspect of the present invention there is provided use of a compound 15 of the invention in the manufacture of a medicament for administration to lower plasma concentrations of either or both of TNF-a and IL-1.
In a sixteenth aspect of the present invention there is provided use of a compound of the invention in the manufacture of a medicament for administration to lower plasma o. concentrations of either or both of IL-6 and IL-8.
20 In a seventeenth aspect of the present invention there is provided use of a compound of the invention in the manufacture of a medicament for administration to a mammal in the prophylaxis or treatment of diabetes disease to produce a glucagon /6ST antagonistic effect.
22344-00.DOC 6d In an eighteenth aspect of the present invention there is provided use of a compound of the invention in the manufacture of a medicament for administration to a mammal in the prophylaxis or treatment of a pain disorder.
In a nineteenth aspect of the present invention there is provided use of a compound of the invention in the manufacture of a medicament for administration to a mammal to decrease prostaglandin production.
In a twentieth aspect of the present invention there is provided use of a compound of the invention in the manufacture of a medicament for administration to a mammal to decrease cyclooxygenase enzyme activity.
The foregoing merely summarizes certain aspects of the invention and is not intended, nor should it be construed, as limiting the invention in any way.
Unless the context clearly requires otherwise, throughout the description and the •claims, the words 'comprise', 'comprising', and the like are to be construed in an •oo oi •inclusive sense as opposed to an exclusive or exhaustive sense; that is to say, in the sense ooo.
15 of"including, but not limited to".
All patents and other publications recited herein are hereby incorporated by rrohor reference in their entirety.
*e •oo 22344-00.DOG WO 98/24782 PCT/US97/22390 7 DETAILED DESCRIPTION OF THE INVENTION In accordance with the present invention, there is provided compounds of the formula: R2 R11 N
N
Rl2 N R
(I)
or a pharmaceutically acceptable salt thereof, wherein
R
1 and R 2 are each independently provided that (1) the total number of aryl, heteroaryl, cycloalkyl and heterocyclyl radicals in each -Z-Y is 0-3; preferably, 0-2; more preferably, 0-1; and the combined total number of aryl, heteroaryl, cycloalkyl and heterocyclyl radicals in R 1 and R 2 is 0-4; preferably, 0-3; more preferably, 0-2; most preferably, 0-1; preferably, R 2 is a radical of hydrogen, C 1
-C
4 alkyl, halo, hydroxy, C 1
-C
4 alkoxy, C 1
-C
2 haloalkoxy of 1-3 halo radicals, thiol, C 1
-C
4 alkylthio, aminosulfonyl,
C
1
-C
4 alkylaminosulfonyl, di-(C1-C 4 alkyl)aminosulfonyl, amino, C 1
-C
4 alkylamino, di-(C 1
-C
4 alkyl)amino,
C
1
-C
alkanoylamino, (Ci-C 4 alkoxy)carbonylamino,
C
1
-C
4 alkylsulfonylamino or C 1
-C
2 haloalkyl of 1-3 halo radicals; more preferably, R2 is a radical of hydrogen, C 1
-C
4 alkyl, halo, hydroxy, C 1
-C
4 alkoxy, trifluoromethoxy, thiol, C 1
-C
4 alkylthio, amino, C 1
-C
4 alkylamino, di-(Ci- C4 alkyl)amino,
C
1
-C
5 alkanoylamino, (Ci-C 4 alkoxy)carbonylamino,
C
1
-C
4 alkylsulfonylamino or trifluoromethyl; WO 98/24782 PCT/US97/22390 8 more preferably, R 2 is a radical of hydrogen, methyl, ethyl, fluoro, chloro, hydroxy, methoxy, trifluoromethoxy, amino, methylamino, dimethylamino, acetylamino or trifluoromethyl; and most preferably,
R
2 is a radical of hydrogen or hydroxy; wherein each Z is independently a bond; alkyl, alkenyl or alkynyl radical optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio or halo, and 1-2 radicals of heterocyclyl, aryl or heteroaryl optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, halo, alkyl or haloalkyl; heterocyclyl radical optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, alkyl or haloalkyl; or aryl or heteroaryl radical optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, cyano, halo, alkyl or haloalkyl; preferably, each Z is independently a bond;
CI-C
8 alkyl, C 2
-C
8 alkenyl or C 2
-C
8 alkynyl radical optionally substituted by 1-3 radicals of amino, Ci-C4 alkylamino, di-(C 1
-C
4 alkyl)amino, C 1
-C
5 alkanoylamino,
(C
1
-C
4 alkoxy)carbonylamino, C 1
-C
4 alkylsulfonylamino, hydroxy, C 1
-C
4 alkoxy, C 1
-C
4 alkylthio or halo, and (b) 1-2 radicals of heterocyclyl, aryl or heteroaryl optionally substituted by 1-3 radicals of amino, C 1 -C4 alkylamino, di-(C 1
-C
4 alkyl)amino, C 1
-C
5 alkanoylamino, WO 98/24782 WO 9824782PCTIUS97/22390 9 (Cl-C 4 alkoxy) carbonylamino, Cl-C 4 alkylsulfonylamino, hydroxy, C 1
-C
4 alkoxy, C 1
-C
4 alkyithia, halo, Cl-C 4 alkyl or Cl-C 4 haloalkyl of 1-3 halo radicals; heterocyclyl radical optionally substituted by 1-3 radicals of amino, Cl-C 4 alkylainino, di-(Cl-C 4 alkyl)amino,
C
1
-C
5 alkanoylamino,
(C
1
-C
4 alkoxy) carbonylamino, Cl-C 4 alkylsulfonylamino, hydroxy, Cl-C 4 alkoxy, C 1
-C
4 alkylthio, C 1
-C
4 alkyl or C 1
-C
4 haloalkyl of 1-3 halo radicals; or aryl or heteroaryl radical optionally substituted by 1-3 radicals of amino, Cl-C 4 alkylamino, di-(Cl-C 4 alkyl)amino,
C
1
-C
5 alkanoylamino, (Ci-C 4 alkoxy) carbonylamino, C 1
-C
4 alkylsulfonylamino, hydroxy,
C
1
-C
4 alkoxy, Cl-C 4 alkylthio, cyano, halo, C 1
-C
4 alkyl or C 1
-C
4 haloalkyl of 1-3 halo radicals; more preferably, each Z is independently a bond;
C
1 -c 8 alkyl, C 2
-C
8 alkenyl or C 2
-C
8 alkynyl radical optionally substituted by 1-3 radicals of amino, Ca.-C4 alkylamino, di-(Cl-C 4 alkyl)amino, C 1
-C
5 alkanoylamino, (Cl-C 4 a lkoxy) c arbonyl amino, Cl-C 4 alkylsulfonylamino, hydroxy, Cl-C 4 alkoxy, Cl-C 4 alkylthio or halo, and (b) 1-2 radicals of heterocyclyl, aryl or heteroaryl optionally substituted by 1-3 radicals of amino, Cl-C 4 alkylamino, di-(Cl-C 4 alkyl)amino, C 1
-C
5 alkanoylamino, (Ci-C 4 a lkoxy) c arbonyl amino, Cl-C 4 alkylsulfonylamino, hydroxy, C 1
-C
4 alkoxy, Cl-C 4 alkylthio, halo, Cl-C 4 alkyl or Cl-C 4 haloalkyl of 1-3 halo radicals; heterocyclyl radical optionally substituted by 1-2 radicals of amino, CI-C 4 alkylamino, di-(Cl-C 4 alkyl)amino, Cl-C 5 alkanoylamino, (Cl-C 4 alkoxy) carbonylamino, Cl-C 4 alkylsulfonylamino, hydroxy, Cl-C 4 alkoxy, Cl-C 4 alkylthio, C 1
-C
4 alkyl or Ci-C4 haloalkyl of 1-3 halo radicals; or I. WO 98/24782 PCTIUS97/22390 aryl or heteroaryl radical optionally substituted by 1-3 radi-cals of amino, C 1
-C
4 alkylamino, di-(Cl-C 4 alkyl)amino, Cl-C 5 alkanoylanino, (Cl-C 4 alkoxy) carbonylamino, C 1
-C
4 alkylsulfonylamino, hydroxy,
C
1
-C
4 alkoxy, C 1
-C
4 alkylthio, cyano, halo, Cl-C 4 alkyl or C 1
-C
4 haloalkyl of 1-3 halo radicals; more preferably, each Z is independently a bond; Cl-c 8 alkyl or C 2
-C
8 alkenyl radical optionally substituted by 1-3 radicals of amino, cl-C 4 alkylamino, di-(Cl-C 4 alkyl)amino, Cl-C 5 alkanoylamino, (Cl-C 4 a lkoxy) carbonyl amino, hydroxy, Cl-C 4 alkoxy, Cl-C 4 alkylthio or halo, and 1-2 radicals of heterocyclyl, aryl or heteroaryl optionally substituted by 1-3 radicals of amino, Cl-C 4 alkylamino, di-(Cl-C 4 alkyl)amino, Cl-C 5 alkanoylamino, (Cl-C 4 alkoxy)carbonylanino, hydroxy, Cl-c 4 alkoxy, Cl-C 4 alkylthio, halo, Cl-C 4 alkyl or Cl-C 2 haloalkyl of 1-3 halo radicals.; heterocyclyl radical optionally substituted by 1-2 radicals of amino, di-(Cl-C 4 alkyl)amino, (Cl-C 4 a lkoxy) carbonyl amino, hydroxy, Cl-C 4 alkoxy, Cl-C 4 alkylthio or Cl-C 4 alkyl radicals; or aryl or heteroaryl radical optionally substituted by 1-3 radicals of amino, Ci-C 4 alkylamino, di-(Cl-C 4 alkyl)anino, Cl-C 5 alkanoylanino,
(C
1
-C
4 alkoxy) c arbonyl amino, Cl-C 4 alkyl sul fonyl amino, hydroxy, Cl-C 4 alkoxy, Cl-C 4 alkylthio, cyano, halo, Cl-C 4 alkyl or Cl-C 2 haloalkyl of 1-3 halo radicals; more preferably, each Z is independently a bond; cl-C 4 alkyl or C2-C 5 alkenyl radical optionally substituted by 1-3 radicals of amino, di-(Cl-C 2 WO 98/24782 PTU9/29 PCTIUS97/22390 11 alkyl) amino, Cl-C 5 alkanoylamino, (Cl-C 4 alkoxy) carbonyl amino, hydroxy, C 1
-C
2 alkoxy, Cl-C 2 alkylthio or halo, and 1-2 radicals of heterocyclyl, aryl or heteroaryl optionally substituted by 1-3 radicals of amino, Cl-C 4 alkylamino, di-(Cl-C 2 alkyl)amino, C 1
-C
5 alkanoylamino, (Cl-C 4 al1koxy) carbonyl amino, hydroxy, Cl-C 4 alkoxy, Cl-C 4 alkylthio, halo, Cl-C 4 alkyl or trifluoromethyl radicals; heterocyclyl radical optionally substituted by 1-2 radicals of amino, di-(Cl-C 2 alkyl)amino,
(C
1
-C
4 alkoxy) carbonyl amino, hydroxy, Cl-C 2 alkoxy, Cl-C 2 alkylthio or Cl-C 4 alkyl radicals; or aryl or heteroaryl radical optionally substituted by 1-3 radicals of amino, di-(Ci-C 2 alkyl)amino, C 1
-C
alkanoylamino, (Cl-C 4 alkoxy)carbonylamino, hydroxy, C 1
C
2 alkoxy, Cl-C 2 alkylthio, cyano, halo, C 1
-C
4 alkyl or trifluoromethyl radicals; more preferably, each Z is independently a bond; Cl-C 4 alkyl or C 2
-C
5 alkenyl radical optionally substituted by 1-3 radicals of amino, di- (Cl-C 2 alkyl)amino, (Cl-C 4 alkoxy)carbonylamino, hydroxy, Cl-C2 alkoxy, Cl-C 2 alkylthio or halo, and 1-2 radicals of aryl or heteroaryl optionally substituted by 1-2 radicals of amino, di- (Cl-C 2 alkyl)amino, acetamido, (Cl-C 4 a lkoxy) carbonyl amino, hydroxy, Cl-C 2 alkoxy, Cl-C 2 alkylthio, halo, Cl-C 4 alkyl or trifluoromethyl radicals; or aryl or heteroaryl radical optionally substituted by 1-3 radicals of amino, di-(Cl-C 2 alkyl)anino, acetamido, (Cl-C 4 alkoxy) carbonyl amino, hydroxy, Cl-C 2 alkoxy, Cl-C2 alkylthio, cyano, halo, Cl-C 4 alkyl or trifluoromethyl radicals; WO 98/24782 WO 9824782PCT/US97/22390 12 more preferably, each Z is independently a bond; or cl-c 4 alkyl. radical optionally substituted by 1-2 radicals of amino, di-(Cl-C 2 alkyl)amino, (Cl-C 4 alkoxy) carbonyl amino, hydroxy, Cl-C 2 alkoxy, Cl-C 2 alkylthio, halo or aryl. or heteroaryl optionally substituted by 1-2 radicals of hydroxy, Cl-C 2 alkoxy,
C
1
-C
2 alkylthio, halo, Cl-C 4 alkyl. or trifluoromethyl.
radicals; and most preferably, each Z is independently a bond; or cl-c 4 alkyl radical optionally substituted by 1-2 radicals of amino, t-butoxycarbonylamino, dimethylamino, hydroxy, methoxy, methylthio or halo radicals; each Y is independently a hydrogen radical; halo or nitro radical;
-C(O)-R
2 0 or -C(NR5)-NR 5
R
2 1 radical;
-OR
2 1 -O-C(a)-R 2 1 -O-C(o)-NR 5
R
2 1 or -O-C(O)-NR 2 2 S(O)2-R 20 radical;
-SR
2 1
-S(O)-R
2 0
-S(O)
2
-R
2 0 -S(O)2-NR 5
R
2 1, -S(0) 2
NR
2 2 -C (0)-R 2 1 -S 2-NR 2 2 -C (0)-OR 20 or -S 2
-NR
2 2 -C
NR
5
R
2 1 radical; or
-NR
5
R
2 1 -NR22-C(O)-R 2 1 -NR22-C(0)-0R 2 0
-NR
2 2
NR
5
R
2 1 -NR22-C(NR 5
)-NR
5
R
2 1 -NR22-S(0) 2
-R
2 0 or -NR22- S(0)2-NR 5
R
21 radical; preferably, each Y is independently a hydrogen radical; halo radical;
-C(O)-R
2 0 or -C(NR 5
)-NR
5
R
2 1 radical;
-OR
2 1 -0-C(o)-R 2 1 or -0-C(O)-NR 5
R
2 1 radical; WO 98/24782 WO 8/2782PCTITIQO7/'77'40n 13
-SR
2 1 -S (0)-R 2 0, -S (0)2-R 2 0 or -S (0)2-NR 5
R
2 1 radical; or-
-NR
5
R
2 1 -NR22-C(O)-R 2 l, -NR 2 2 C(O)-0R 2 0 -NR22-C(O)-
NR
5 R2l, -NR22-C(NR 5
)-NR
5
R
2 1, -NR 22
-S(O)
2
-R
2 0 or -R2 S (0) 2
-NR
5
R
2 1 radical; more preferably, each Y is independently a hydrogen radical;
-C(O)-R
2 o radical; -0R21, -SR21, -S(O)-R 2 o, -S(O)2-R 2 0 or -S(O)2-NR 5
R
2 1 radical; or
-NR
5
R
2 1 -NR22--C(O)-R 2 1 -NR22-C(O)-0R 2 0
-NR
2 2-C(O)-
NR
5
R
2 1 -NR22-S(O) 2
-R
2 0 or -NR2 2
-S(O)
2
-NR
5
R
2 1 radical; more preferably, each Y is independently a hydrogen radical;
-C(O)-R
2 o radical;
-OR
2 1
-SR
2 1
-S(O)-R
2 o, -S(O) 2
-R
2 0 or -S(O) 2
-NR
5
R
2 1 radical; or
-NR
5
R
2 1
-NR
2 2
-C(O)-R
2 1 or -NR 2 2
-S(O)
2
-R
2 0 radical; more preferably, each Y is independently a
-C(O)-R
2 0 radical;
-OR
2 1
-SR
2 1
-S(O)-R
2 o, -S(O) 2 -R20 or -S(O) 2
-NR
5
R
2 1 radical; or
-NR
5
R
2 1 -NR22-C(O)-R 2 1 or -NR 2 2-S(O) 2
-R
2 0 radical.
most preferably, each Y is independently a -OR 2 1 -SR2l or -NR 5
R
21 radical; wherein each R5 is independently hydrogen radicals; alkyl, alkenyl or alkynyl radicals optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, hydroxy, alkoxy, alkylthio, -SO 3 H or halo; or WO 98/24782 PCT/US97/22390 14 aryl, heteroaryl, aralkyl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl or cycloalkylalkyl radicals optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, hydroxy, alkoxy, alkylthio, alkyl or haloalkyl; preferably, each R 5 is independently hydrogen radicals; cl-c 8 alkyl, C 2
-C
8 alkenyl or C 2
-C
8 alkynyl radicals optionally substituted by 1-3 radicals of amino, Cl-C 4 alkylamino, di- (Cl-C4-alkyl) amino, hydroxy, Cl-C 4 alkoxy,
C
1
-C
4 alkylthio, -So 3 H or halo; or aryl, heteroaryl, aryl-Cl-C4-alkyl, heteroaryl-Cl-C 4 alkyl, heterocyclyl, heterocyclyl7Cl-c 4 -alkyl, C 3
-C
8 cycloalkyl or C3-C8-cycloalkyl-Cl-C 4 -alkyl radicals optionally substituted by 1-3 radicals of amino, Cl-C 4 alkylamino, di- (Cl-C4-alkyl) amino, hydroxy, Cl-C 4 alkoxy, Cl-c 4 alkylthio, Cl-C 4 alkyl or Cl-C 4 haloalkyl of 1-3 halo radicals; more preferably, each R 5 is independently hydrogen radicals; cl-c 4 alkyl, C 2
-C
5 alkenyl or C 2
-C
5 alkyriyl radicals optionally substituted by 1-3 radicals of amino, Cl-C 4 alkylamino, di- (Cl-C4-alkyl) amino, hydroxy, Cl-C 4 alkoxy, Cl-C 4 alkylthio, -S 3 H or halo; or aryl, heteroaryl, aryl-Cl-C 4 -alkyl, heteroaryl-Cl-C 4 alkyl, heterocyclyl, heterocyclyl-Cl-C 4 -alkyl, C 3
-C
8 cycloalkyl or C3-C8-cycloalkyl-Cl-C 4 -alkyl radicals optionally substituted by 1-3 radicals of amino, Cl-C 4 alkylamino, di- (Cl-C 4 -alkyl) amino, hydroxy, Cl-C 4 alkoxy, Cl-C 4 alytiCl-C 4 alkyl orCl-C 4 haloalkyl of 1-3 halo radicals; more preferably, each R5 is independently 11 WO 98/24782 PCT/US97/22390 hydrogen radicals; C1-C 4 alkyl or C 2
-C
5 alkenyl radicals optionally substituted by 1-3 radicals of amino, di-(Ci-C 4 alkyl)amino, hydroxy, C 1
-C
4 alkoxy, C 1
-C
4 alkylthio,
SO
3 H or halo; or phenyl-C1-C2-alkyl, heteroaryl-Ci-C2-alkyl, heterocyclyl-Ci-C 2 -alkyl or C3-C6-cycloalkyl-CI-C 2 -alkyl radicals optionally substituted by 1-3 radicals of amino, di-(C1-C4-alkyl)amino, hydroxy, Ci-C 4 alkoxy, C 1
C
4 alkylthio, C 1
-C
4 alkyl or Ci-C 2 haloalkyl of 1-3 halo radicals; more preferably, each R 5 is independently hydrogen radical;
C
1
-C
4 alkyl radical optionally substituted by 1-3 radicals of amino, di-(Cl-C2-alkyl)amino, hydroxy, C 1 -C2 alkoxy, C 1
-C
2 alkylthio or halo; or phenyl-C1-C2-alkyl, heteroaryl-Ci-C2-alkyl, heterocyclyl-Ci-C 2 -alkyl or C3-C6-cycloalkyl-Ci-C 2 -alkyl radicals optionally substituted by 1-3 radicals of amino, di-(C1-C2-alkyl)amino, hydroxy, C 1
-C
2 alkoxy, C
I
C
2 alkylthio, methoxy, methylthio, C 1
-C
4 alkyl or trifluoromethyl radicals; more preferably, each R 5 is independently hydrogen radical;
C
1
-C
4 alkyl radical optionally substituted by 1-3 halo radicals; or phenyl-Ci-C2-alkyl or heteroaryl-C 1
-C
2 -alkyl, radicals optionally substituted by 1-3 radicals of amino, dimethylamino, hydroxy, methoxy, methylthio, methyl or trifluoromethyl radicals; more preferably, each R5 is independently hydrogen or
C
1
-C
4 alkyl radical; and most preferably, each R5 is a hydrogen radical; WO 98/24782 WO 9824782PCTIUS97/22390 16 wherein -each R2 0 is' independently alkyl, alkenyl or alkynyl radicals optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino,
N-
(alkoxycarbonyl) (alkyl)amino, arinocarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, halo or aralkoxy, aralkylthio, aralkylsulfonyl, cycloalkyl, heterocyclyl, aryl or heteroaryl radicals optionally substituted by 1- 3 radicals of amino, alkylamino, dialkylamino, alkanoylanino, alkoxycarbonylamino, alkylsulfonylamino, alkanoyl, hydroxy, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, halo, alkyl or haloalkyl; heterocyclyl radical optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, alkanoylanino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, alkyl or haloalkyl; or aryl or heteroaryl radicals optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, alkoxycarbonyl, hydroxy, alkoxy, alkylthio, cyano, halo, azido, alkyl. or haloalkyl; preferably, each R 2 0 is independently cl-c 8 alkyl, C 2
-C
8 alkenyl or C 2
-C
8 alkynyl radicals optionally substituted by 1-3 radicals of amino, C 1
-C
4 alkylanino, di-(Cl-C 4 alkyl)anino, Cl-C 5 alkanoylamino, (Cl-C 4 alkoxy) carbonylamino, N- (Cl-C 4 alkoxy) carbonyl) N- (Cl-C 4 alkyl) amino, amino carbonyl amino, Cl-C 4 alkylsulfonylamino, hydroxy, Cl-C4 alkoxy, Cl-C 4 alkylthio, Cl-C 4 alkylsulfinyl, Cl-C 4 alkylsulfonyl, halo or aryl-Cl-C4-alkoxy, aryl-Cl-C 4 -alkylthio, aryl-Cl-C4alkylsulfonyl, C 3
-C
8 cycloalkyl, heterocyclyl, aryl or heteroaryl radicals optionally substituted by 1-3 radicals of amino, Cl-C 4 alkylamino, di-(Cl-C 4 WO 98/24782 PTU9129 PCTILJS97/22390 17 alkyl)anino,
C
1
-C
5 alkanoylamino, (Cl-C 4 alkoxy)carbonylamino,
C
1
-C
4 alkylsulfonylamino,
C
1
-C
alkanoyl, hydroxy, C 1
-C
4 alkoxy, C 1
-C
4 alkylthio, C 1
-C
4 alkylsulfinyl,
C
1
-C
4 alkylsulfonyl, halo, Cl-C 4 alkyl or Cl-C4 haloalkyl of 1-3 halo radicals; heterocyclyl radical optionally substituted by 1-3 radicals of amino, C 1
-C
4 alkylamino, di-(C 1
C
4 alkyl)amino,
C
1
-C
5 alkanoylamino, (Cl-C 4 alkoxy) carbonylamino,
C
1
-C
4 alkylsulfonylamino, hydroxy,
C
1
-C
4 alkoxy, C 1
-C
4 alkylthio, Cl-C 4 alkyl or Cl-C 4 haloalkyl of 1-3 halo radicals; or aryl or heteroaryl radicals optionally substituted by 1-3 radicals of amino, Cl-C 4 alkylamino, di- (Cl-C 4 alkyl)amino, Cl-C 5 alkanoylamino, (Cl-C 4 alkoxy)carbonylamino, Cl-C 4 alkylsulfonylamino, (Cl-C 4 alkoxy) carbonyl, hydroxy, Cl-C 4 alkoxy, Cl-C 4 alkylthio, cyano, halo, azido, Cl-C 4 alkyl or Cl-C 4 haloalkyl of 1-3 halo radicals; more preferably, each R 2 0 is independently Cl-C 8 alkyl, C 2
-C
5 alkenyl or C 2
-C
5 alkynyl radicals optionally substituted by 1-3 radicals of amino, Cl-C 4 alkylamino, di-(C-C 4 alkyl)amino, Cl-C5 alkanoylamino, (Cl-C 4 alkoxy) c arbonyl amino, N-C (Cl-C 4 alkoxy) carbonyl) N-(Ci-C 4 alkyl)amino, aminoc arbonyl amino, Cl-C 4 alkylsulfonylanino, hydroxy, Cl-C 4 alkoxy, Cl-C 4 alkylthio, Cl-C 4 alkylsulfinyl, Cl-C 4 alkylsulfonyl, halo or aryl-Cl-C 4 -alkoxy, aryl-Cj-C 4 -alkylthio, aryl-Cl-C4alkylsulfonyl,
C
3
-C
8 cycloalkyl, heterocyclyl, aryl or heteroaryl radicals optionally substituted by 1-3 radicals of amino, Cl-C 4 alkylamino, di-(CI-C 4 alkyl)amino, Cl-C 5 alkanoylaiino, (Cl-C 4 alkoxy)carbonylamino, Cl-C 4 alkylsulfonylamino, Cl-C alkanoyl, hydroxy, Cl-C 4 alkoxy, Cl-C 4 alkylthio, Cl-C 4 WO 98/24782 PTU9/29 PCTIUS97/22390 18 alkylsulfinyl, Cl-C 4 alkylsulfonyl, halo, C 1
-C
4 alkyl or
C
1
-C
4 haloalkyl of 1-3 halo radicals; heterocyclyl radical optionally substituted by 1-3 radicals of amino, Cl-C 4 alkylamino, di-(Cl-C 4 alkyl)amino, Cl-C 5 alkanoylanino, (Cl-C 4 a lkoxy) c arbonyl amino, Cl-C 4 alkylsulfonylamino, hydroxy, Cl-C 4 alkoxy, Cl-C 4 alkylthio, Cl-C 4 alkyl or IC haloalkyl of 1-3 halo radicals; or aryl or heteroaryl radicals optionally substituted by 1-3 radicals of amino, Cl-C 4 alkylamino, di-(Cl-C 4 alkyl)amino, C 1
-C
5 alkanoylamino, (Cl-C 4 al1koxy) c arbonyl amino, C 1
-C
4 alkylsulfonylamino, (Cl-C 4 alkoxy)carbonyl, hydroxy, Cl-C 4 alkoxy, C 1
-C
4 alkylthio, cyano, halo, azido, Cl-C 4 alkyl or Cl-C 4 haloalkyl of 1- 3 halo radicals; more preferably, each R 2 0 is independently cl-c 8 alkyl or C 2
-C
5 alkenyl radicals optionally substituted by 1-3 radicals of amino, Cl-C 4 alkylamino, di-(Cl-C 4 alkyl)amino, Cl-C 5 alkanoylamino, (Cl-C 4 alkoxy) carbonylamino, N- ((Ci-C 4 alkoxy)carbonyl) (Cl-C 4 alkyl)amino, amino carbonyl amino, hydroxy, C 1
-C
4 alkoxy, Cl-C 4 alkylthio, Cl-C 4 alkylsulfinyl, Ci-C 4 alkylsulfonyl, halo or aryl-Cl-C4--alkoxy, aryl-Cl-C4alkylthio, aryl-Cl-C4-alkylsulfonyl, C 3
-C
6 cycloalkyl, heterocyclyl, aryl or heteroaryl. radicals optionally substituted by 1-3 radicals of amino, Cl-C 4 alkylamino, di- (Cl-C 4 alkyl)amino, Cl-C 5 alkanoylamino, (Cl-C 4 a lkoxy) carbonyl amino, C 1
-C
4 alkylsulfonylamino, Cl-C alkanoyl, hydroxy, Cl-C 4 alkoxy, Cl-C 4 alkylthio, halo, Cl-C 4 alkyl or Cl-C 2 haloalkyl of 1-3 halo radicals; heterocyclyl radical optionally substituted by 1-2 radicals of amino, Cl-C 4 alkylamino, di-(Cl-C 4 alkyl)amino, Cl-C 5 alkanoylamrino, (Cl-C 4 1DIlIrfIrTen WO 98/24782 J3I.1U 19 a lkoxy) carbonyl amino, hydroxy, Cl-C 4 alkoxy, Cl-C 4 alkylthio or CI-C 4 alkyl; or aryl or heteroaryl radicals optionally substituted by 1-3 radicals of amino, Cl-C 4 alkylanino, di-(Cl-C 4 alkyl)amino, Cl-C 5 alkanoylamino, (Cl-C 4 alkoxy) carbonylamino,
C
1
-C
4 alkylsulfonylamino, (Cl-C 4 alkoxy)carbonyl, hydroxy, C 1
-C
4 alkoxy, C 1
-C
4 alkylthio, cyano, halo, azido, Cl-C 4 alkyl or Cl-C 2 haloalkyl of 1-3 halo radicals; more preferably, each R 2 0 is independently cl-c 8 alkyl or C 2
-C
5 alkenyl radicals optionally substituted by 1-3 radicals of amino, Cl-C 4 alkylamino, di- (Cl-C 4 alkyl)amino, Cl-C 5 alkanoylanino, (Cl-C 4 al1koxy) c arbonyl amino, N- ((Cl-C 4 alkoxy)carbonyl) (Cl-C 4 alkyl)amino, aminoc arbonyl amino, hydroxy, Cl-C 4 alkoxy, Cl-C 4 alkylthio, Cl-c 4 alkylsulfinyl, Cl-C 4 alkylsulfonyl, halo or aryl-Cl-C4-alkoxy, aryl-Cl-C 4 alkylthio, aryl-Cl-C 4 -alkylsulfonyl, C 3
-C
6 cycloalkyl, heterocyclyl, aryl or heteroaryl radicals optionally substituted by 1-3 radicals of amino, CI-C 4 alkylamino, di- (Cl-C 4 alkyl)amino, C 1
-C
5 alkanoylamino, (Cl-C 4 alkoxy) carbonylamino, C 1
-C
4 alkylsulfonylamino,
C
1
-C
alkanoyl, hydroxy, Cl-C 4 alkoxy, Cl-C 4 alkylthio, halo, Cl-C 4 alkyl or C 1
-C
2 haloalkyl of 1-3 halo radicals; heterocyclyl radical opt ionally substituted by 1-2 radicals of amino, di-(Cl-C 4 alkyl)amino, (Cl-C 4 alkoxy)carbonylamino, hydroxy, Cl-C 4 alkoxy, Cl-C4 alkylthio or Cl-C 4 alkyl; or aryl or heteroaryl radicals optionally substituted by 1-2 radicals of amino, Cl-C 4 alkylanino, di-(Cl-C4 alkyl)amino, acetamido, (Cl-C 4 alkoxy) carbonyl amino, Ci-
C
4 alkylsulfonylamino, (Cl-C 4 alkoxy)carbonyl, hydroxy, Cl-C 4 alkoxy, CI-C 4 alkylthio, cyano, halo, azido, Cl-C4 alkyl or trifluoromethyl radicals; 98/247122 n~~lR7nnrrrr rnrr WO 98/24782 nfna.
more preferably, each R 20 is independently
C
1
-C
8 alkyl radicals optionally substituted by 1-3 radicals of amino, C 1
-C
4 alkylamino, di-(C 1
-C
4 alkyl)amino, Cl-C 5 alkanoylanino,
(C
1
-C
4 alkoxy)carbonylamino,
N-((C
1
-C
4 alkoxy)carbonyl)-N-(Ci-C 4 alkyl)amino, aminocarbonylamino, hydroxy, CI-C 4 alkoxy,
C
1
-C
4 alkylthio, C 1
-C
4 alkylsulfinyl,
C
1
-C
4 alkylsulfonyl, halo or C 3
-C
6 cycloalkyl, heterocyclyl, aryl or heteroaryl radicals optionally substituted by 1- 2 radicals of amino, di-(C 1
-C
4 alkyl)amino,
C
1
-C
alkanoylamino,
(C
1
-C
4 alkoxy)carbonylamino,
C
1
-C
4 alkylsulfonylamino, hydroxy, C 1
-C
4 alkoxy, Cl-C 4 alkylthio, halo, C 1
-C
4 alkyl or trifluoromethyl radicals; heterocyclyl radical optionally substituted by 1-2 radicals of hydroxy, C 1
-C
4 alkoxy, C 1
-C
4 alkylthio or Cj-
C
4 alkyl; or aryl or heteroaryl radicals optionally substituted by 1-2 radicals of (Cl-C 4 alkoxy)carbonyl, amino, C 1
-C
4 alkylamino, di-(C 1
-C
4 alkyl)amino, hydroxy, C 1
-C
4 alkoxy,
C
1
-C
4 alkylthio, cyano, halo, azido, C 1
-C
4 alkyl or trifluoromethyl radicals; more preferably, each R20 is independently c 1 -c 6 alkyl radicals optionally substituted by 1-3 radicals of amino, methylamino, dimethylamino, tbutoxycarbonylamino, N-((t-butoxy)carbonyl)-N- (methyl)amino, aminocarbonylamino, hydroxy, butoxy, methoxy, butylthio, methylthio, methylsulfinyl, methylsulfonyl, halo or C 5
-C
6 cycloalkyl, heterocyclyl, phenyl or heteroaryl radicals optionally substituted by 1-2 radicals of amino, dimethylamino, acetamino, hydroxy, methoxy, methylthio, halo, methyl or trifluoromethyl radicals; WO 98/24782 PCT/US97/22390 21 heterocyclyl radical optionally substituted by 1-2 radicals- of hydroxy or C 1
-C
4 alkyl; or aryl or heteroaryl radicals optionally substituted by 1-2 radicals of amino, dimethylamino, hydroxy, methoxy, methylthio, halo, methyl or trifluoromethyl radicals; more preferably, each R20 is independently
CI-C
6 alkyl radicals optionally substituted by 1-3 radicals of amino, methylamino, dimethylamino, tbutoxycarbonylamino, N-((t-butoxy)carbonyl)-N- (methyl)amino, aminocarbonylamino, hydroxy, butoxy, methoxy, butylthio, methylthio, methylsulfinyl, methylsulfonyl, halo or Cs-C 6 cycloalkyl, heterocyclyl, phenyl or heteroaryl radicals optionally substituted by 1-2 radicals of amino, dimethylamino, acetamino, hydroxy, methoxy, methylthio, halo, methyl or trifluoromethyl radicals; heterocyclyl radical; or aryl or heteroaryl radicals optionally substituted by 1-2 radicals of amino, dimethylamino, hydroxy, methoxy, methylthio, halo, methyl or trifluoromethyl radicals; most preferably, each R 20 is independently
CI-C
6 alkyl radicals optionally substituted by 1-3 radicals of amino, methylamino, dimethylamino, hydroxy or phenyl or heteroaryl radicals optionally substituted by 1-2 radicals of amino, dimethylamino, hydroxy, methoxy, methylthio, halo, methyl or trifluoromethyl radicals; heterocyclyl radical; or aryl or heteroaryl radicals optionally substituted by 1-2 radicals of amino, dimethylamino, hydroxy, methoxy, methylthio, halo, methyl or trifluoromethyl radicals; WO 98/24782 T Rnl^r~/* jwwnn W 9 2472.. 1 i/UyI L39U 22 each R 2 1 is independently hydrogen radical or each R22 is independently hydrogen radical; alkyl radical optionally substituted by a radical of heterocyclyl, aryl or heteroaryl optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, cyano, halo, alkyl or haloalkyl; or heterocyclyl, aryl or heteroaryl radicals optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, cyano, halo, alkyl or haloalkyl; provided when Z is a bond and Y is -NR 2 2
C(O)-NH
2 then R 2 2 is other then an optionally substituted aryl radical; preferably, each R22 is independently hydrogen radical;
C
1
-C
4 alkyl radical optionally substituted by a radical of heterocyclyl, aryl or heteroaryl optionally substituted by 1-3 radicals of amino, Ci-C 4 alkylamino, di-(C 1
-C
4 alkyl)amino,
C
1
-C
5 alkanoylamino, (Ci-C 4 alkoxy) carbonylamino, Ci-C 4 alkylsulfonylamino, hydroxy,
C
1
-C
4 alkoxy, C 1
-C
4 alkylthio, C 1
-C
4 alkylsulfinyl, C 1
-C
4 alkylsulfonyl, cyano, halo, C 1
-C
4 alkyl or C 1
-C
4 haloalkyl of 1-3 halo radicals; or heterocyclyl, aryl or heteroaryl radicals optionally substituted by 1-3 radicals of amino, C 1
-C
4 alkylamino, di-(Ci-C 4 alkyl)amino,
C
1
-C
5 alkanoylamino, (Ci-C 4 alkoxy) carbonylamino, C 1
-C
4 alkylsulfonylamino, hydroxy,
C
1
-C
4 alkoxy, Ci-C 4 alkylthio, C 1
-C
4 alkylsulfinyl, C 1 -C4 alkylsulfonyl, cyano, halo, C 1
-C
4 alkyl or C 1
-C
4 haloalkyl of 1-3 halo radicals; provided when Z is a WO 98/.24782 WO 9824782PCTIUS97/22390 "2 3 bond and Y is -NR2 2
-N{
2 then R 22 is other then an optionally substituted aryl radical; more preferably, each R22 is independently hydrogen radical; or
C
1
-C
4 alkyl radical optionally substituted by a radical of phenyl or heteroaryl optionally substituted by 1-3 radicals of amino, di- (Cl-C 2 alkyl) amino, 01-05 alkanoylamino, (01-04 alkoxy) carbonylamino, hydroxy, 01- 04 alkoxy, 01-04 alkylthio, cyano, halo, 01-04 alkyl or 01-02 haloalkyl of 1-3 halo radicals; more preferably, each R 2 2 is independently hydrogen or 01-04 alkyl radical; and most preferably, each R 2 2 is independently hydrogen or methyl radical;
R
1 1 and R 12 are each independently an aryl or heteroaryl radical optionally substituted by 1-3 radicals of
R
30 halo or cyano radicals; -C (0)-R 3 0, -OR 2 9
-NR
3 1
R
3 2 or -C (NR 3 L)
NR
31
R
32 radicals;
-OR
2 9 -O-0(O)-R 2 9 -O-0(O)-NR 3 lR 3 2 or -O-C(O)-NR 3 3 S(0)2-R 3 O radicals;
-SR
2 9
-S(O)-R
3 0, -S(O) 2
-R
3 0
-S(O)
2
-NR
3 lR 3 2
-S(O)
2
NR
3 3
-C(O)-R
3 0 -S(O)2-NR3 3 -C(O)-0R 3 0 or -S(O) 2
-NR
3 3
NR
31 R3 2 radicals; or
-NR
3 1
R
3 2 -NR33-C(O)-R 2 9 -NR33-C(O)-0R 3 0 -NR33-C(O)-
NR
3 1
R
3 2 -NR33-0(NR 3 1)-NR 3 lR 3 2 -NR3 3
-S(O)
2
-R
3 0 or -NR3 3 S(O)2-NR 3 lR 3 2 radicals; provided that R 1 1 is other than a 4-pyridyl, 4pyrimidinyl, 4-quinolyl or G-isoquinolinyl radical optionally substituted by 1-2 substituents; and the total number of aryl, heteroaryl, cycloalkyl and heterocyclyl radicals substituted on each of R 1 1 and R 1 2 is 0-1; WO 98/24782 WO 9824782PCTIUS97/22390 24 preferably, R11 and R 1 2 are each independently an aryl or heteroaryl radical optionally substituted by 1-2 radicals of
R
3 0 halo or cyano radicals;
-C(O)-R
3 0 -C(O)-0R 2 9
-C(O)-NR
3 lR 3 2 or -C(NR 3 1
NR
31
R
32 radicals;
-OR
2 9
-O-C(O)-R
2 9 -O-C(O)-NR3lR 3 2 or -O-C(O)--NR 3 3
S(O)
2
-R
3 o radicals;
-SR
2 9
-S(O)-R
3 0
-S(O)
2
-R
3 0, -S(O)2-NR 3 lR 3 2
-S(O)
2 NR33-C(O)-R 3 0
-S(O)
2
NR
3 3 -C(O)-0R 3 0 or -S(O)2-NR 3 3
C(O)-
NR
31
R
32 radicals; or
-NR
3 1
R
3 2 -NR33-C(O)-R 2 9
-NR
3 3 -C(O)-0R 3 0
-NR
3 3
NR
3 1
R
3 2 -NR33-C(NR 3 1
)-NR
3 lR 3 2 -NR33-S(O) 2
-R
3 0 or -NR 3 3 S 2-NR 3 lR 3 2 radicals; provided that R 1 1 is other than a 4-pyridyl, 4pyrimidinyl, 4-quinolyl or 6-isoquinolinyl radical optionally substituted by 1-2 substituents; and the total number of aryl, heteroaryl, cycloalkyl and heterocyclyl radicals substituted on each of R 1 1 and R12 is 0-1; more preferably, R 1 1 and R 1 2 are each independently an aryl or heteroaryl radical optionally substituted by 1-2 radicals of R3 0 halo or cyano radicals;
-C(O)-R
3 0, -C(O)-0R 2 9
-C(O)-NR
3 lR 3 2 or -C(NR 3 1
NR
3 1
R
3 2 radicals; or
-OR
2 9
-SR
2 9
-S(O)-R
3 0 -S(O)2-R30, -S(O) 2
-NR
3 lR3 2
-NR
3 1
R
3 2 -NR33-C (0)-R 29 or -NR33-C (0)-OR 3 0 radicals; more preferably, R 1 1 is an aryl radical and R 1 2 is a heteroaryl radical, wherein the aryl and heteroaryl radicals are optionally substituted by 1-2 radicals of WO 98/24782 PCT/US97/22390
R
30 hal.o or cyano radicals;
-C(O)-R
3 0, -C(O)-OR 2 9 -C(0)-NR 3 1
R
32 or -C(NR 3 1 NR31R32 radicals; or -OR29, -SR 2 9
-S(O)-R
3 0, -S(0) 2
-R
3 0 -S(0)2-NR 3 1
R
3 2
-NR
3 1
R
3 2 or -NR33-C(O)-R 2 9 radicals; more preferably, R 1 1 is an aryl radical and R 1 2 is a heteroaryl radical, wherein the aryl and heteroaryl radicals are optionally substituted by 1-2 radicals of halo or cyano radicals; or
-C(O)-NR
3 1
R
3 2 -OR2 9
-SR
2 9
-S(O)-R
3 0, -S(0) 2
-R
3 0 S(0)2-NR 3 1R 32
-NR
3 1
R
3 2 or -NR 3 3 -C(0)-R 29 radicals; more preferably, Ril is an aryl radical optionally substituted by 1-2 radicals of R 3 o; halo or cyano radicals; or -C(O)-NR3 1
R
32
-OR
2 9
-SR
2 9
S(O)-R
3 0, -S(0) 2
-R
3 0, -S(0)2-NR 3 1
R
3 2
-NR
3 1
R
32 or -NR 3 3
C(O)-R
2 9 radicals; more preferably, R 11 is an aryl radical optionally substituted by 1-2 radicals of amino, dimethylamino, acetamido, hydroxy, halo, cyano, methoxy, methylthio, methylsulfinyl, methylsulfonyl, aminocarbonyl, methyl or trifluoromethyl radicals; more preferably, R11 is an unsubstituted phenyl or naphthyl radical or a phenyl radical substituted by 1-2 radicals of amino, dimethylamino, acetamido, hydroxy, halo, cyano, methoxy, methylthio, methylsulfinyl, methylsulfonyl, aminocarbonyl, methyl or trifluoromethyl radicals; and most preferably, R11 is an unsubstituted phenyl radical or a phenyl radical substituted by 1-2 radicals of amino, dimethylamino, acetamido, hydroxy, halo, cyano, methoxy, methylthio, methylsulfonyl, methyl or trifluoromethyl radicals; WO 98/24782 PCTIUS97/22390 26 more preferably, R 12 is a heteroaryl radical optionally substituted by 1-2 radicals of R30; halo or cyano radicals; or -C(0)-NR 3 1
R
3 2
-OR
2 9
-SR
2 9
-NR
3 1
R
3 2 or -NR 3 3 -C(0)-R 2 9 radicals; more preferably,
R
1 2 is a heteroaryl radical optionally substituted by 1-2 radicals of amino, dimethylamino, acetamido, hydroxy, halo, cyano, methoxy, methyl or trifluoromethyl radicals; more preferably, R 1 2 is a 4-pyridyl, 4quinolinyl, 4-imidazolyl or 4-pyrimidinyl radical optionally substituted by a radical of amino, dimethylamino, acetamido, hydroxy, halo, cyano, methoxy, methyl or trifluoromethyl radicals; and most preferably,
R
12 is a 4-pyridyl radical optionally substituted by a radical of amino, dimethylamino, acetamido, hydroxy, halo, cyano, methoxy, methyl or trifluoromethyl radicals; wherein each R 30 is independently alkyl, alkenyl or alkynyl radicals optionally substituted by 1-3 radicals of -NR 3 1
R
3 1 -C0 2
R
2 3 hydroxy, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, cyano, halo or aralkoxy, aralkylthio, aralkylsulfonyl, heterocyclyl, aryl or heteroaryl radicals optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, cyano, halo, alkyl or haloalkyl; heterocyclyl radical optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, cyano, alkyl or haloalkyl; or aryl or heteroaryl radicals optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, WO 98/24782 WO 9824782PCTIUS97/22390 27 hydroxy, alkoxy, alkylthio, cyano, halo, alkyl or.
haloalkyl; preferably, each R 30 is independently cl-c 4 alkyl, C 2
-C
4 alkenyl or C 2
-C
4 alkynyl radicals optionally substituted by 1-3 radicals of -NR 3 1
R
3 1 C02R 23 hydroxy, Cl-C 4 alkoxy, Cl-C 4 alkylthio, Cl-C 4 alkylsulfinyl, Cl-C 4 alkylsulfonyl, cyano, halo or aryl- Cl-C4-alkoxy, aryl-Cl-C4-alkylthio, aryl-Cl-C 4 alkylsulfonyl, heterocyclyl, aryl or heteroaryl radicals optionally substituted by 1-3 radicals of amino, C 1
-C
4 alkylamino, di-(Cl-C 4 alkyl)amino, Cl-C 5 alkanoylamino, (Cl-C 4 alkoxy) carbonylamino, Cl-C 4 alkylsulfonylanino, hydroxy, Cl-C 4 alkoxy, Cl-C 4 alkylthio, Cl-C 4 alkylsulfinyl, Cl-C 4 alkylsulfonyl, cyano, halo, Cl-C 4 alkyl or Cl-C 4 haloalkyl of 1-3 halo radicals; heterocyclyl radical optionally substituted by 1-3 radicals of amino, Cl-C 4 alkylarnino, di-(Cl-C 4 alkyl)amino, Cl-C 5 alkanoylanino, (Cl-C 4 al koxy) carbonyl amino, Cl-C 4 alkylsulfonylamino, hydroxy, Cl-C 4 alkoxy, Cl-C 4 alkylthio, cyano, CI-C 4 alkyl or C 1
C
4 haloalkyl of 1-3 halo radicals; or aryl or heteroaryl radicals optionally substituted by 1-3 radicals of amino, Cl-C 4 alkylamino, di-(Cl-C 4 alkyl)amino, Cl-C 5 alkanoylamino, (Cl-C 4 alkoxy) c arbonyl amino, Cl-c 4 alkylsulfonylamino, hydroxy, Cl-C 4 alkoxy, Cl-C 4 alkylthio, cyano, halo, Cl-C 4 alkyl or Cl-C 4 haloalkyl of 1-3 halo radicals; more preferably, each R 3 0 is independently Cl-C 4 alkyl radical optionally substituted by 1-3 radicals of
-NR
3 1
R
3 1 Cl-C 4 alkoxy-carbonyl or phenoxycarbonyl or phenylrnethoxycarbonyl optionally substituted by 1-3 WO 98/24782 -LLI I~Y 28 radicals of amino, alkylamnino, di- (C1-C4-alkyl) amino, Cj-C 5 alkanoylamino, (Ci-C 4 alkoxy)carbonylamino,
C
1
-C
4 alkylsulfonylamino, hydroxy, Cl-C 4 alkoxy, CI-C 4 alkylthio, cyano, halo, Cl-C 4 alkyl or trifluoronethyl; or hydroxy, Cl-C 4 alkoxy, Cl-C 4 alkylthio, or phenyl-Cl- C4-alkoxy, phenyl-Cl-C 4 -alkylthio, heterocyclyl, phenyl or heteroaryl radicals optionally substituted by 1-3 radicals of amino, Cl-C4 alkylamino, di- (Ci-C 4 alkyl)amino, Cj-C 5 alkanoylamino, (Cl-C 4 alkoxy)carbonylamino, hydroxy, Cl-C 4 alkoxy, Cl-C 4 alkylthio, cyano, halo, Cl-C 4 alkyl. or Cl-C 4 haloalkyl of 1-3 halo radicals; Cl-C 4 haloalkyl of 1-3 halo radical; or aryl or heteroaryl radicals optionally substituted by 1-3 radicals of amino, C 1
-C
4 alkylamino, di- (Cl-C 4 alkyl) amino, C 1
-C
5 alkanoylamino, (Cj-C 4 alkoxy) carbonylamino, hydroxy, C 1
-C
4 alkoxy, C 1
-C
4 alkylthio, cyano, halo, C 1
-C
4 alkyl. or trif luoromethyl radicals; more preferably, each R30 is independently Cl-C 4 alkyl radical optionally substituted by amino, Cl-C 4 alkylamino or di- (Cl-C4-alkyl) amino radicals; or hydroxy, Cl-C 4 alkoxy, heterocyclyl, phenyl or heteroaryl radicals optionally substituted by 1-3 radicals of amino, Cl-C 4 alkylamino, di-(Cl-C 4 alkyl)amino,* Cl-C 5 alkanoylamino, (Cl-C4 a lkoxy) carbonyl amino, hydroxy, Cl-C 4 alkoxy, Cl-C 4 alkylthio, cyano, halo, Cl-C 4 alkyl. or trifluoromethyl radicals; Cl-C 2 haloalkyl of 1-3 halo radical; or aryl or heteroaryl radicals optionally substituted by 1-3 radicals of amino, Cl-C 4 alkylamino, di-(Cl-C 4 WO 98/24782 PCT/US97/22390 29 alkyl)amino, Ci-C 5 alkanoylamino, (Ci-C 4 alkoxy)carbonylamino, hydroxy, C 1
-C
4 alkoxy, Ci-C 4 alkylthio, cyano, halo, C 1
-C
4 alkyl or trifluoromethyl radicals; more preferably, each R3 0 is independently C1-C 4 alkyl radical optionally substituted by a phenyl or heteroaryl radical optionally substituted by 1-3 radicals of amino, di-(C1-C 2 alkyl)amino, acetamido, hydroxy, C 1
-C
2 alkoxy, halo, C 1
-C
4 alkyl or trifluoromethyl radicals; trifluoromethyl radical; or aryl or heteroaryl radicals optionally substituted by 1-3 radicals of amino, di-(C 1
-C
2 alkyl)amino, acetamido, hydroxy, C 1
-C
2 alkoxy, halo, C 1
-C
4 alkyl or trifluoromethyl radicals; more preferably, each R 30 is independently
C
1
-C
4 alkyl radical optionally substituted by a phenyl or heteroaryl radical optionally substituted by 1-3 radicals of amino, dimethylamino, acetamido, hydroxy, halo, methoxy, methyl or trifluoromethyl radicals; trifluoromethyl radical; or aryl or heteroaryl radicals optionally substituted by 1-3 radicals of amino, dimethylamino, acetamido, hydroxy, halo, methoxy, methyl or trifluoromethyl radicals; most preferably, R30 is independently
C
1
-C
4 alkyl radical optionally substituted by a phenyl or heteroaryl radical optionally substituted by 1-2 radicals of amino, dimethylamino, acetamido, hydroxy, halo, methoxy, methyl or trifluoromethyl radicals; trifluoromethyl radical; or WO 98/24782 PCTfUS97/22390 aryl or heteroaryl radicals optionally substituted by 1-3 radicals of amino, dimethylamino, acetamido, hydroxy, halo, methoxy, methyl or trifluoromethyl radicals; each R 2 9 is independently hydrogen radical or R3 0 and most preferably,
R
2 9 is an aryl or heteroaryl radicals optionally substituted by 1-2 radicals of amino, dimethylamino, acetamido, hydroxy, halo, methoxy, methyl or trifluoromethyl radicals; each R 31 is independently hydrogen radicals; alkyl radical optionally substituted by an cycloalkyl, aryl, heterocyclyl or heteroaryl radical optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, cyano, alkyl or haloalkyl; or aryl, heteroaryl, heterocyclyl or cycloalkyl radical optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, cyano, alkyl or haloalkyl; preferably, each R31 is independently hydrogen radicals; C1-C 4 alkyl radical optionally substituted by an C 3
C
8 cycloalkyl, aryl, heterocyclyl or heteroaryl radical optionally substituted by 1-3 radicals of amino, C 1
-C
4 alkylamino, di-(C 1
-C
4 alkyl)amino, C 1
-C
5 alkanoylamino,
(C
1
-C
4 alkoxy)carbonylamino,
C
1
-C
4 alkylsulfonylamino, hydroxy, C 1
-C
4 alkoxy, C 1
-C
4 alkylthio, cyano, C 1
-C
4 alkyl or C 1
-C
4 haloalkyl of 1-3 halo radicals; or aryl, heteroaryl, heterocyclyl or C 3
-C
8 cycloalkyl radical optionally substituted by 1-3 radicals of amino, WO 98/24782 PCT/US97/22390 31
C
1
-C
4 alkylamino, di-(Ci-C 4 alkyl)amino, C 1
-C
alkanoylamino,
(C
1
-C
4 alkoxy)carbonylamino,
C
1
-C
4 alkylsulfonylamino, hydroxy, C 1
-C
4 alkoxy, Ci-C 4 alkylthio, cyano, C 1
-C
4 alkyl or C 1
-C
4 haloalkyl of 1-3 halo radicals; more preferably, each R 31 is independently hydrogen radicals; or Ci-C 4 alkyl radical optionally substituted by an phenyl or heteroaryl radical optionally substituted by 1-3 radicals of amino, C 1
-C
4 alkylamino, di-(C 1
-C
4 alkyl)amino, CI-C 5 alkanoylamino, (Ci-C 4 alkoxy)carbonylamino, hydroxy, C 1
-C
4 alkoxy, C 1
-C
4 alkylthio, cyano, C 1
-C
4 alkyl or trifluoromethyl radicals; more preferably, each R 3 1 is independently hydrogen or
C
1
-C
4 alkyl radicals; and most preferably, each R3 1 is independently hydrogen, methyl or ethyl radicals; each R 32 is independently hydrogen radicals; alkyl radical optionally substituted by an cycloalkyl, aryl, heterocyclyl or heteroaryl radical optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, cyano, alkyl or haloalkyl; or aryl, heteroaryl, heterocyclyl or cycloalkyl radical optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, cyano, alkyl or haloalkyl; preferably, each R 32 is independently hydrogen radicals; WO 98/24782 PCT/US97/22390 32 C1-C4 alkyl radical optionally substituted by an C 3
C
8 cycloalkyl, aryl, heterocyclyl or heteroaryl radical optionally substituted by 1-3 radicals of amino, C 1 -C4 alkylamino, di-(C1-C 4 alkyl)amino,
C
1
-C
5 alkanoylamino, (Ci-C 4 alkoxy)carbonylamino,
C
1
-C
4 alkylsulfonylamino, hydroxy, C 1
-C
4 alkoxy, C 1
-C
4 alkylthio, cyano, C 1
-C
4 alkyl or C 1
-C
4 haloalkyl of 1-3 halo radicals; or aryl, heteroaryl, heterocyclyl or C 3
-C
8 cycloalkyl radical optionally substituted by 1-3 radicals of amino, Cl-C 4 alkylamino, di-(C 1
-C
4 alkyl)amino, CI-C alkanoylamino,
(C
1
-C
4 alkoxy)carbonylamino,
C
1
-C
4 alkylsulfonylamino, hydroxy, C 1
-C
4 alkoxy, C 1
-C
4 alkylthio, cyano, C 1
-C
4 alkyl or C 1
-C
4 haloalkyl of 1-3 halo radicals; more preferably, each R 32 is independently hydrogen radicals;
C
1
-C
4 alkyl radical optionally substituted by an C 3
C
6 cycloalkyl, aryl, heterocyclyl or heteroaryl radical optionally substituted by 1-3 radicals of amino, C 1 -C4 alkylamino, di-(Ci-C 4 alkyl)amino, C 1
-C
5 alkanoylamino,
(C
1
-C
4 alkoxy)carbonylamino,
C
1
-C
4 alkylsulfonylamino, hydroxy, C 1
-C
4 alkoxy, C 1
-C
4 alkylthio, cyano, C 1 -C4 alkyl or C 1
-C
4 haloalkyl of 1-3 halo radicals; or aryl, heteroaryl, heterocyclyl or C 3
-C
6 cycloalkyl radical optionally substituted by 1-3 radicals of amino,
C
1
-C
4 alkylamino, di-(C 1
-C
4 alkyl)amino, C 1
-C
alkanoylamino,
(C
1
-C
4 alkoxy)carbonylamino,
C
1
-C
4 alkylsulfonylamino, hydroxy, C 1
-C
4 alkoxy, C 1
-C
4 alkylthio, cyano, C 1
-C
4 alkyl or C 1
-C
4 haloalkyl of 1-3 halo radicals; more preferably, each R32 is independently hydrogen radicals; WO 98/24782 PCTIS97/22390 33 C1-C 4 alkyl radical optionally substituted by phenyl or heteroaryl radical optionally substituted by 1-3 radicals of amino, C 1
-C
4 alkylamino, di-(C 1
-C
4 alkyl)amino, CI-C 5 alkanoylamino, (C 1
-C
4 alkoxy)carbonylamino, hydroxy, Ci-C 4 alkoxy, CI-C 4 alkyl or trifluoromethyl radicals; or phenyl or heteroaryl radical optionally substituted by 1-3 radicals of amino, C 1
-C
4 alkylamino, di-(C 1
-C
4 alkyl)amino, C 1
-C
5 alkanoylamino, (C 1
-C
4 alkoxy)carbonylamino, hydroxy, C 1
-C
4 alkoxy, C 1
-C
4 alkyl or trifluoromethyl radicals; more preferably, each R 3 2 is independently hydrogen radicals; Ci-C 4 alkyl radical or C 1
-C
2 alkyl radical substituted by phenyl or heteroaryl radical optionally substituted by 1-3 radicals of amino, dimethylamino, acetamido, hydroxy, methoxy, methyl or trifluoromethyl radicals; or phenyl or heteroaryl radical optionally substituted by 1-3 radicals of amino, dimethylamino, acetamido, hydroxy, methoxy, methyl or trifluoromethyl radicals; most preferably, R 3 2 is independently hydrogen or C 1
-C
4 alkyl radical; or phenyl or heteroaryl radical optionally substituted by 1-2 radicals of amino, dimethylamino, acetamido, hydroxy, methoxy, methyl or trifluoromethyl radicals; and wherein each R3 3 is independently hydrogen radical; or alkyl radical optionally substituted by a radical of heterocyclyl, aryl or heteroaryl optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, -34alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, cyano, alkyl or haloalkyl; preferably, each R 33 is independently hydrogen radical; or C1-C 4 alkyl radical optionally substituted by a radical of heterocyclyl, aryl or heteroaryl optionally substituted by 1-3 radicals of amino, C 1
-C
4 alkylamino, di-(Cl-C 4 alkyl) amino, C 1
-C
5 alkanoylamino, (CI-C 4 alkoxy) carbonylamino, C 1
-C
4 alkylsulfonylamino, hydroxy, C 1
-C
4 alkoxy, C 1
-C
4 alkylthio, cyano, C 1
-C
4 alkyl or C 1
C
4 haloalkyl of 1-3 halo radicals; more preferably, each R 3 3 is independently hydrogen or C 1
-C
4 alkyl radical; and most preferably, each R 33 is independently hydrogen or methyl radical.
Throughout this specification the following provisos are to be taken to relate to compounds of the invention, only, and not to the pharmaceutical compositions or methods of use, which encompass the full breadth of the compounds recited above 15 (unless expressly stated otherwise). In particular, wherever reference is made in this specification to a pharmaceutical composition or a method of use of the invention, the reference is to be taken to encompass the full breadth of the compounds recited above and the provisos are to be disregarded in the context of the pharmaceutical compositions o or methods of use of the invention unless specifically stated to the contrary. This 20 includes any such reference to pharmaceutical compositions or methods of use wherever a.
found in this specification that makes mention or otherwise refers to a statement or disclosure pertaining to some or all of the above compounds that contains the provisos.
The provisos are as follows: 22344-o.Doc/aCW 34a 1. when R Iand R 12are the same and are a 5- or 6- member ring having from 1 2 heteroatoms independently selected from N, S, and 0, to which ring a benzene ring is optionally fused, R"I is phenyl or naphthyl optionally substituted with halo, C 1
I-C
6 alkyl, C I-C 4 alkoxy, C I-C 4 alkyithiol, hydroxy, C I-C 4 alkylamino, or dialkylamino, or R"I is a 5- or 6-membered ring having from 1-3 heteroatoms independently selected from N, S, and 0, to which ring a benzene ring is optionally fused and optionally substituted with C I-C 6 alkyl, then R 2is other than OH or NH 2 2. when R 2is H, R1 is phenyl and R 12is 4-pyridyl, then R Iis other than H, 0 methyl, or amino;
S
S
S
5.55
S
5.
S S
S
S
*SS.
S
S
*S S
S.
S.
S
S
S
*SS5
*S
S S SS S
S.
S
S S S CS
S
22344-OO.DOC 3. when R 2 is H, R
I
is 2-methylphenyl and R 1 2 is 2-pyridyl, then R' is other than n-propyl; 4. when R" is an optionally substituted aryl radical, then R 12 is other than an optionally substituted aryl radical; and 5. when and R' 2 are each independently a 3-pyridyl or an optionally substituted phenyl radical, then R' is other than an alkylthiol or haloalkylthiol radical.
The compounds of this invention may have in general several asymmetric centers and are typically depicted in the form of racemic mixtures. This invention is intended to encompass racemic mixtures, partially racemix mixtures and separate enantiomers and diasteromers.
Compounds of interest include the following: R2 S.
S
S
*S.S
S
*SSS
S
S. S S S 55
S
S
S
55e*
S.
S
S
*5 S. S 55 55
S
15 wherein R 2 is H and R 2 and R' are one of the combinations given in the following table: R" R- R' Phenyl 4-pyridyl 1-piperazinyl 4-fluorophenyl 4-pyridyl 1-piperazinyl 3-fluorophenyl 4-pyridyl 1-piperazinyl 2-fluorophenyl 4-pyridyl 1-piperazinyl 4-chlorophenyl 4-pyridyl 1-piperazinyl 3-chlorophenyl 4-pyridyl 1-piperazinyl 2-chlorophenyl 4-pyridyl 1-piperazinyl 'Al -tolyl 4-pyridyl 1-piperazinyl 22344-00.DOC R~zRl 3 -toyly 4-pyridyl 1 -piperazinyl 2-toyly 4-pyridyl I -piperazinyl 4-trifluoro-methyiphenyl 4-pyridyl 1 -piperazinyl 3 -trifluoro-methyiphenyl 4-pyridyl 1 -piperazinyl 2,6-dichiorophenyl 4-pyridyl 1 -piperazinyl 2,6-dimethyiphenyl 4-pyridyl 1 -piperazinyl 3 ,4-dichlorophenyl 4-pyridyl 1 -piperazinyl 3 ,4-dimethylphenyl 4-pyridyl 1 -piperazinyl 2,4-dichiorophenyl 4-pyridyl 1 -piperazinyl 9 9**9 9. 9* .9 9 9 99..
9 .9 9 9 9. 9 *999 999999 *999 9 9 9999 9* 9 99 .9 9 9 9 *999 9* 9 9 9 9 99 99 9 9* 99 9 223 44-OO.DOC WO 98/24782 WO 9824782PCTIUS97/22390 2, 4-dimethyl 4-pyridyl 1-piperazinyl phenyl Phenyl -2-ainino-4- 1-piperazinyl pyridyl_ 4-f luorophenyl 2-amino-4- 1-piperazinyl 3-f luorophenyl 2 -amino- 4- 1 -piperaz inyl __pyridyl 2-f luorophenyl 2-amino-4- 1-piperazinyl 4-chioropheny. 2-amino-4- 1-piperazinyl 3 -chiorophenyl 2 -amino-4- 1-piperazinyl pyr idyl 2-chloropheny. 2-amino-4- 1-piperazinyl 4-toilyl 2-amino-4- 1-piperazinyl 3-tolyl 2-amino-4- 1-piperazinyl pyridyl 2-tolyl 2-ainino-4- 1-piperazinyl pyridyl 4-trifluoro- 2-amino-4- 1-piperazinyl methylphenyl pyridyl 3-trifluoro- 2-amino-4- 1-piperazinyl me thylphenyl _pyr idyl___ 2,6- 2-amino-4- 1-piperazinyl dichlorophenyl pyridyl___ 2, 6-dimethyl 2-amino-4- 1-piperazinyl phenyl pyridy1 3,4- 2-amino-4- 1-piperazinyl dichlorophenyl pyridy.
3.,4-dimethyl 2-amino-4- 1-piperazinyl phenyl pyridyl 2,4- 2-amino-4- 1-piperazinyl dichlorophenyl pyridyl 2, 4-dimethyl 2-amino-4- 1-piperaziny.
phenyl pyridy1 Phenyl 2-acetainido- 1-piperazinyl 4-f luorophenyl 2-acetamido- 1-piperazinyl 4-pyridyl 3-f luorophenyl 2-acetamido- 1-piperazinyl 4 -pyridyl 2 -fluorophenyl 2-acetamido- 1-piperazinyl 4-chiorophenyl 2-acetainido- 1-piperazinyl 4-pyridyl 3-chiorophenyl 2-acetamido- 1-piperazinyl 4-pyridyl 2 -chiorophenyl 2 -acetamido- 1 -piperazinyl -pyridy 4-tolyl 2-acetamido- i-piperazinyl 4 -pyridyl I WO 98/24782 PCT/US97/22390 3-tolyl 2-acetainido- l-piperazinyl -pyridyl 2-tolyl- 2-acetamido- 1-piperazinyl -pyridyl 4-trifiluoro- 2-acetamido- 1-piperazinyl methylphenyl 4 -pyridyl 3-trifluoro- 2-acetanido- 1-piperaziny.
methylphenyl 4 -pyridyl 2,6- 2-acetamido- 1-piperazinyl dichloropheiyl 4 -pyridyl 2, 6-dirnethyl 2-acetamido- i-piperazinyl phenyl 4-pyridyl 3,4- 2-acetamido- 1-piperaziny.
dichiorophenyl 4-pyridyl 3, 4-dimethyl 2-acetainido- 1-piperazinyl phenyl 4-pyridyl 2,4- 2-acetarnido- 1-piperazinyl dichlorophenyl 4-pyridyl 2, 4-dimethy. 2-acetamido- 1-piperazinyl phenyl 4-pyridyl Phenyl 2-amino-4- 1-piperazinyl pyrimidinyl 4-f luorophenyl 2-amino-4- 1-piperazinyl pyrimidinyl 3-f luorophenyl 2-amino-4- 1-piperazinyl p pr imidinyl 2-f luorophenyl 2-amino-4- 1-piperazinyl pyriinidinyl 4-chiorophenyl 2 -arnino-4- 1-piperaziny.
pyrimidinyl 3 -chioropheny. 2 -amino-4- 1-piperazinyl pyrimidinyl 2-chiorophenyl 2-amino-4- 1-piperaziny.
pyrimidinyl 4-tolyl 2-amino-4- 1-piperazinyl pyrimidinyl 3-tolyl 2-arnino-4- 1-piperazinyb pyr imi dinyl 2-tolyl 2-amino-4- 1-piperazinyl pyrirnidinyl 4-trifluoro- 2-amino-4- i-piperazinyl 'nethylphenyl pyrimidinyl 3-trifluoro- 2-arnino-4- 1-piperazinyl methyiphenyl _pyrimidinyl 2,6- 2-amino-4- 1-piperazinyl dichlorophenyl pyriinidinyl 2, 6-dirnethy. 2-amino-4- i-piperazinyl phenyl pyrimidinyl 3,4- 2-amino-4- 1-piperazinyl dichiorophenyl pyrimidinyl 3, 4-dimethyl 2-amino-4- 1-piperazinyl lpheny. pyrimidinyl I A dichlorophenyl z -amino-4pyrimidinyl 1-piperazinyl vI' WO 98/24782 PTU9/29 PCTIUS97/22390 2, 4-dimethyl 2-axnino-4- 1-piperazinyl pheniyl pyrimidinyl Phenyl 4-pyridyl 2,6-dichilorobenzvl 4-f luorophenyl 4-pyridyl 2, 6-dichlorobenzy.
3-f luorophenyl _4-pyridyl 2, 6-dichlorobenzyl 2-f luorophenyl _4-pyridyl 2, 6-dichlorobenzj.
4-chlorophenyl 4-pyridyl 2, 6-dichlorobenzyl 3-chiorophenyl 4-pyridyl 2, 6-dichlorobenzy.
2-chlorophenyl 4-pyridyl 2, 6-dichlorobenzyl 4-tolyl 4-pyridyl 2 ,6-dichlorobenzyl- 3-tolyl 4-pyridyl 2, 6-dichlorobenzyl 2-tolyl 4-pyridyl 2, 6-dichlorobenzyl 4-trifluoro- 4-pyridyl 2, 6-dichlorobenzyl me thylphenyl 3-trifluoro- 4-pyridyl 2, 6-dichlorobenzyl methylpheiyl 2,6- 4-pyridyl 2,6-dichlorobenzyl dichloropheiyl______ 2, 6-dimethyl 4-pyridyl 2, 6-dichlorobenzyl phenyl 3,4- 4-pyridyl 2,6-dichlorobenzyl dichlorophenyl 3 ,4-dimethyl 4-pyridy. 2, 6-dichlorobenzyt phenyl_____ 2,4- 4-pyridy. 2,6-dichlorobenzyl dichlorophenyl 2, 4-dimethyl 4-pyridyl 2, 6-dichlorobenzyl phenyl Phenyl 2-amino-4- 2, 6-dichlorobenzyl pyr 4-f luorophenyl 2-amino-4- 2, 6-dichilorobenzyl 3-f luorophenyl 2-arnino-4- 2, 6-dichlorobenzyl pyridyl 2-f luorophenyl 2-amino-4- 2, 6-dichlorobenzyl 4-chiorophenyl 2-amino-4- 2, 6-dichlorobenzyl 3-chloropheiyl 2-ainino-4- 2, 6-dichlorobenzyl pyr idyl_- 2-chiorophenyl 2-amino-4- 2, 6-dichlorobenzyl 4-tolyl 2-amino-4- 2, 6-dichlorobenzyl _pyridyl 3-tolyl 2-amino-4- 2, 6-dichlorobenzyl pyridyl_ 2-tolyl 2-ainino-4- 2, 6-dichlorobenzyl pyridyl 4-trifluoro- 2-amino-4- 2, 6-dichlorobenzyl methylphenyl pydy 3-trifluoro- 2-amino-4- 2, 6-dichlorobenzyl methylpheny. 1ridy 1 2,6- 2-amjno-4- 2,6-dichlorobenzyl dichloropheny. pyridyl WO 98/24782 WO 9824782PCTIUS97/22390 2, 6-dimethyl 2-amino-4- 2, 6-dichlorobenzy.
phenyl pyridy.
3,4- 2-ainino-4- 2,6-dichlorobenzyl dichloropheiyl pyridyl 3, 4-dimethyl 2-amino-4- 2, 6-dichlorobenzy.
phenayl pyridyl 2,4- 2-amino-4- 2,6-dichlorobenzyl dichlorophenyl pridy 2, 4-dimethyl 2-amino-4- 2, 6-dichlorobenzyl phenyl pyridyl Phenyl 2-acetamido- 2, 6-dichlorobenzyl -pyridyl 4-f luorophenyl 2-acetainido- 2, 6-dichlorobenzyl -pyridyl 3-f luorophenyl 2-acetainido- 2, 6-dichlorobenzyl 4 -pyridyl 2-f luorophenyl 2-acetamido- 2, 6-dichlorobenzyl _4-pyridyl 4-chioropheny. 2-acetamido- 2, 6-dichlorobenzyl 4 -pyridyl 3-chiorophenyl 2-acetamido- 2, 6-dichlorobenzyl 2-chlorophenyl 2-acetamido- 2, 6-dichlorobenzyl 4 -pyridyl_ 4-tolyl 2-acetamido- 2, 6-dichlorobenzyl 4 pyridyl 3-tolyl 2-acetamido- 2, 6-dichlorobenzyl 4 -pyridy 2-tolyl 2-acetamido- 2, 6-dichlorobenzyl 4 -pyridyl 4-trifluoro- 2-acetainido- 2, 6-dichlorobenzyl methylphenyl 4 -pyridy 3-trifluoro- 2-acetamido- 2, 6-dichlorobenzyl methylpheayl 4 prdyl 2,6- 2-acetamido- 2, 6-dichlorobenzyl dichlorophenyl 4 -pyridyl 2, 6-dimethyl 2-acetamido- 2, 6-dichlorobenzyl phenyl -4-pyridyl 3,4- 2-acetamido- 2, 6-dichlorobenzyl dichiorop~henyl 4-pyridyl 3, 4-dimethyl 2-acetamido- 2, 6-dichlorobenzyl phenyl 4-pyridyl 2,4- 2-acetamido- 2, 6-dichlorobenzyl dichlorophenyl 4-pyridyl 2, 4-dimethyl 2-acetamido- 2, 6-dichlorobenzyl phenyl 4-pyridyl Phenyl 2-amino-4- 2, 6-dichlorobenzyl 4-f luorophenyl 2-amino-4- 2, 6-dichlorobenzyl pyr imidinyl 3-f luorophenyl 2-amino-4- 2, 6-dichlorobenzyl pyr imidinyl 2-f luorophenyl 2-axnino-4- 2, 6-dichlorobenzyl pyrimidinyl WO 98/24782 WO 9824782PCTIUS97/22390 4-chiorophenyl 2-amino-4- 2, 6-dichlorobenzyl pyrimidinyl 3-chiorophenyl 2-amino-4- 2, 6-dichlorobenzyl pyrimidiny. 2-chiorophenyl 2-amino-4- 2, 6-dichlorobenzyl 4-tolyl 2-amino-4- 2, 6-dichlorobenzyl pyrimidinyl 3-tolyl 2-amino-4- 2, 6-dichlorobenzyl pyrimidinyl 2-tolyl 2-amino-4- 2, 6-dichlorobenzyl 4-trifluoro- 2-amino-4- 2, 6-dichlorobenzyl rnethylphenyl pyrimidinyl 3-trifluoro- 2-amino-4- 2, 6-dichlorobenzyl methylphenyl pyrimidinyl 2,6- 2-amino-4- 2, 6-dichlorobenzyl dichlorophenyl pyrimidinyl 2, 6-dimethyl 2-amino-4- 2, 6-dichlorobenzyl phenyl pyrimidinyl 3,4-2-ainino-4- 2, 6-dichlorobenzyl dichiorophenyl pyrimidinyl 3, 4-dimethyl 2-amino-4- 2, 6-dichlorobenzyl phenyl______ pyrimidinyl 2,4-2-ainino-4- 2, 6-dichlorobenzyl dichiorophenyl pyrimidinyl 2, 4-dimethyl 2-amino-4- 2, 6-dichioroberizyl phenyl pyrimidinyl Phenyl 4-pyridyl 2- (2-chiorophenyl) amino 4-f luorophenyl 4-pyridyl 2- C2-chlorophenyl) ___________ethylamino 3 -fluorophenyl 4-pyridyl 2- (2-chiorophenyl) 2-f luorophenyl 4-pyridyl 2- (2-chiorophenyl) ___________ethylamino 4--chilorophenyl 4-pyridyl 2- (2-chiorophenyl) e thylamino 3-chiorophenyl 4-pyridyl 2- (2-chiorophenyl) ___________ethylaznino 2-chiorophenyl 4-pyridyl 2- (2-chiorophenyl) ethylamino 4-tolyl 4-pyridyl 2- (2-chiorophenyl) amino 3-tolyl 4-pyrid~rl 2- (2-chiorophenyl) amino 2-tolyl 4-pyridyl 2- (2-chiorophenyl) 4-trifluoro- 4-pyridyl 2- (2-chlorophenyl) rnethylphenyl ethylamino 3-trifluoro- 4-pyridyl 2- (2-chlorophenyl) _!ethylphenyl _______ethylarnino 2,6- 4-pyridyl 2-(2-chlorophenyl) dichlorophenyl ________ethylamino WO 98/24782 WO 9824782PCTIUS97/22390 2, 6-dimethyl 4-pyridy. 2- (2-chiorophenyl).
phenyl ethylamino 3,4- -4-pyridyl 2-(2-chlorophenyl) dichlorophenyl _______ethylamino 3, 4-dimethyl 4-pyridyl 2- (2-chiorophenyl) phenyl _______ethylamino 2,4- 4-pyridyl 2-(2-chlorophenyl) dichlorophenyl _______ethylainino 2, 4-dimethyl 4-pyridyl 2- (2-chiorophenyl) phenyl _______ethylamino 4-f luorophenyl 4-pyridyl 3- (3-f luorophenyl) propylamino 4-f luorophenyl 2-amino-4- 3- (3-f luorophenyl) pyrimidinyl _propylamino benzyl 4 -pyridyl 3 -phenylpropylamino benzyl 4-pyridyl 2- (4-f luorophenyl) amino 2- thienyl 4 -pyridyl 3 -phenyipropylamino 2-thienyl 4-pyridyl 2- (4-f luorophenyl) amino cyclohexyl 4_-pyridyl 3-phenyipropylamino cyclohexyl 4-pyridyl 2- (4-f luorophenyl) ___________ethylamino tert-butyl 4-pyridyl 3 -phenylpropyl amino tert-butyl 4-pyridyl 2- (4-f luorophenyl) ethyl amino 4-f luorophenyl 4- 3-phenylpropyilamino piper idinyl 4-f luorophenyl 4- 2- (4-f luorophenyl) _piperidinyl ethylamino 4-f luorophenyl _4-pyranyl 3 -phenylpropylamino 4-f luorophenyl 4 -pyranyl 2- (4-f luorophenyl) e thylamino Phenyl 2-amino-4- 2- (2-chiorophenyl) pyridyl ethylamino 4-f luorophenyl 2-ainino-4- 2- (2-chiorophenyl) pyridyl ethylarnino 3-f luorophenyl 2-arnino-4- 2- (2-chiorophenyl) pyridyl ethylamino 2-f luorophenyl 2-amino-4- 2- (2-chiorophenyl) r prdy1 ethylamino 4-chiorophenyl 2-amino-4- 2- (2-chiorophenyl) ethylamino 3-chiorophenyl 2-amino-4- 2- (2-chiorophenyl) rdy1 ethylamino 2-chlorophenyl 2-ainino-4- 2- (2-chiorophenyl) -pyridyl ethylamino 4-tolyl 2-ainino-4- 2- (2-chiorophenyl) pyridyl ethylainino 3-toly! 2-amino-4- 2- (2-chiorophenyl) ethylamino 2-tolyl 2-amino-4- 2- (2-chiorophenyl) ridy1 ethylamino WO 98/24782 WO 9824782PCT[US97/22390 4-trifluoro- 2-amino-4- 2- (2-chiorophenyl) methylphenyl pyridyl ethylamino 3-trifluoro- 2-ainino-4- 2 -(2-chlorophenyl) methylphenyl pyridyl ethylamino 2,6- 2-amino-4- 2-(2-chlorophenyl) dichlorophenyl pyridyl ethylamino 2, 6-dimethyl 2-amino-4- 2-(2-chlorophenyl) phenyl pyridy. ethylamino 3,4- 2-amino-4- 2 -(2-chlorophenyl) dichiorophenyl p2yridyl ethylamino 3, 4-dimethyl 2-amino-4- 2- (2-chiorophenyl) phenyl _pyridyl ethylamino 2,4- 2-amino-4- 2- (2-chiorophenyl) dichlorophenyl pyridy1 ethylamino 2, 4-dimethyl 2-amino-4- 2- (2-chiorophenyl) phenyl pyridyl ethylamino Phenyl 2-acetamido- 2- (2-chiorophenyl) 4-pyridy. ethylamino 4-f luorophenyl 2-acetamido- 2- (2-chlorophen-yl) 4-pyridyl ethylamino 3-f luorophenyl 2-acetamido- 2- (2-chiorophenyl) ethylamino 2-f luorophenyl 2-acetamido- 2- (2-chiorophenyl) ethylamino 4-chiorophenyl 2-acetamido- 2- (2-chiorophenyl) 4 -pyridyl ethylamino 3-chiorophenyl 2-acetamido- 2- (2-chiorophenyl) 4-pyridyl ethylamino 2-chiorophenyl 2-acetamido- 2- (2-chiorophenyl) 4-pyridyl ethylamino 4-toly. 2-acetamido- 2- (2-chiorophenyl) ethylamino 3-tolyl 2-acetamido- 2- (2-chiorophenyl) 4-pyridy. ethylamino 2-tolyl 2-acetamido- 2- (2-chiorophenyl) 4-pyridyl ethylamino 4-trifluoro- 2-acetamido- 2-(2-chlorophenyl) methylphenyl 4-pyridy1 ethylamino 3-trifluoro- 2-acetamido- 2- (2-chiorophenyl) methylphenyl -4-pyridyl ethylarnino 2,6- 2-acetamido- 2-(2-chlorophenyl) dichilorophenyl 4-pyridy. ethylamino 2, 6-dimethyl 2-acetamido- 2- (2-chiorophenyl) phenyl 4-pyridyl ethylainino 3, 4- 2-acetamido- 2- (2-chiorophenyl) -dichiorophenyl 4-pyridyl ethylamino 3, 4-dimethyl 2-acetainido- 2- (2-chiorophenyl) -phenyl 4-pyridyl ethylamino 2,4- 2-acetamido- 2- (2-chiorophenyl) -dichlorophenyl 4-pyridyl ethylainino 2, 4-diinethyl 2-acetamido- 2- (2-chiorophenyl) phenyl 4-pyridyl ethylamino Phenyl. [2-axnino-4- (2-chiorophenyl) _pyrimidinyl ethylamino WO 98/24782 WO 9824782PCTJLJS97/22390 4-f luorophenyl 2-amino-4- 2- (2-chiorophenyl) pyrimidinyl ethylamino 3-f luorophenyl 2-amino-4- 2- (2-chiorophenyl) _yrimidinyl ethylamino 2-f luorophenyl 2-amino-4- 2- (2-chiorophenyl), pyrimidinyl ethylamino 4-chiorophenyl 2-ainino-4- 2- (2-chiorophenyl) 3-chi rophe yl 2- mi n4 2- mch r ph n 2-chiorophenyl 2-amino-4- 2- (2-chiorophenyl) 4-thoypnl 2-amino-4- 2- (2-chiorophenyl) pyrimidiny. ethylamino 3-tolyl 2-axnino-4- 2- (2-chiorophenyl) ethylamino, 2-tolyl 2-amino-4- 2- (2-chiorophenyl) _pyrimidinyl ethylamino 4-triluoro 2-amino-4- 2- (2-chorophenyl) metyihen]. pyrimidinyl ethylamino 3-trifluoro- 2-amino-4- 2- (2-chiorophenyl) methylphenyl pyrimidinyl ethylamino 2,-iloo 2-amino-4- 2- (2-chiorophenyl) dichiorphenyl pyrimidinyl ethylamino, 2, 6-dety 2-amino-4- 2- (2-chiorophenyl) pihny enl pyrimidinyl ethylamino, 3,4-dmty 2-amino--4- 2- (2-chilorophenyl) dorphenyl _pyrimidinyl ethylamino, 3,4-iehy 2-amino-4- 2- (2-chiorophenyl) dihny enl pyrimidinyl ethylamino, 2,4-dmty 2-amino-4- 2- (2-chiorophenyl) dphnyl hny pyrimidinyl ethylainino 2, 4-dmty 2-amino-4- 2- (2-chiorophenyl) pihny enl pyrimidinyl ethylamino Phenyl thy 4-pyidyl4 2- (4-fluorophenyl)ety phenyl______ aminomin Pheflorhey 4-pyridyl 2 (4 -f luorophenyl) e thyl amino 3-f luorophenyl 4-pyridyl 2- (4-f luorophenyl) ethyl amino 2-f luorophenyl 4-pyridyl 2- (4-f luorophenyl) ethyl ___amino 4-chiorophenyl 4-pyridyl 2- (4-f luorophenyl) ethyl ___amino 3-chiorophenyl 4-pyridyl 2- (4-f luorophenyl) ethyl amino 2-chiorophentyl 4-pyridyl 2 (4 -f luorophenyl) ethyl amino 4-thoypnl 4-pyridyl 2 (4 -f luorophenyl) e thyl amino 3-oll -pyridyl 2 (4 -f luorophenyl) ethyl amino 2-tolyl 4-pyridyl 2 (4 -f luorophenyl) ethyl amino WO 98./24782 WO 9824782PCTIUS97/22390 4-trifluoro- 4-pyridyl 2- (4-f luorophenyl) ethyl methyip2henyl amino 3-trifluoro- 4-pyridyl 2- (4-f luorophenyl) ethyl me thyiphenyl amino____ 2,6- 4prdl 2(-lo~~ey~ty dichlorophenyl a-ymdi2-(-forohnl ty 2, 6-dimethyl 4-pyridyl 2- (4-fluorophenyl) ethyl phenylamino 3,-4-pyridyl 2- (4-f luorophenyl) ethyl dichiorophenyl amino 3, 4-dimethyl 4-pyridyl 2- (4-f luorophenyl) ethyl amino 2,-4-pyridyl 2 -(4-fluorophenyl) ethyl dichlorophenyl amino 2, 4-dimethyl 4-pyridyl 2- (4-f luorophenyl) ethyl phenyl amino Phenyl 2-amino-4- 2- (4-f luorophenyl) ethyl pyrid~yl amino 4-f luorophenyl 2-axnino-4- 2- (4-f luorophenyl) ethyl _pyridyl am 'ino 3-f luorophenyl 2-amino-4- 2- (4-f luoropheiyl) ethyl pyridyl amino 2-f luorophenyl 2-amirio-4- 2- (4-f luoropheiyl) ethyl pyridyl amino 4-chlorophenyl 2-amino-4- 2- (4-f luorophenyl) ethyl pyridyl amino 3-chlorophenyl 2-amino-4- 2- (4-f luorophenyl) ethyl pyridyl amino 2-chlorophenyl 2-ainino-4- 2- (4-f luorophenyl) ethyl pyridyl amino 4-tolyl 2-amino74- 2 -(4-fluorophenyl)ethyl pyridyl amino 3-tolyl 2-ainino-4- 2-(4-fluorophenyl)ethyl pyridy1 amino 2-tolyl 2-ainino-4- 2 -(4-fluorophenyl)ethyl p~yridyl amino 4 -trifluoro- 2-amino-4- 2-(4-fluorophenyl)ethyl methylphenyl _pyridyl amino 3-trifluoro- 2-amino-4- 2 -(4-fluorophenyl)ethyl methylphenyl _pyridyl amino 2,6- 2-amino-4- 2-(4-fluorophenyl)ethyl dichioropohenyl pyridyl amino 2,6-dimethyl 2-amino-4- 2-(4-fluorophenyl)ethyl phenyl p-yridyl amino 2-amino-4- 2-(4-fluorophenyl)ethyl dichlorophenyl pyridyl amino 3, 4-dimethy. 2-amino-4- 2- (4-f luorophenyl) ethyl phenyl _pyridyl amino 2,4- 2-amino-4- 2 -(4-fluorophenyl)ethyl dichlorophenyl pyridyl amino 2, 4-dimethyl 2-amino-4- 2- (4-f luorophenyl) ethyl phenyl _pyridyl amino Phenyl 2-acetamido- 2- 4 -fluorophenyl) ethyl 4-pyridyl amino WO 98/24782 WO 9824782PCTIUS97/22390 4-f luorophenyl 2-acetainido- 2- (4-f luorophenyl) ethyl 4-pyridyl amino 3-f luorophenyl 2-acetarnido- 2- (4-f luorophenyl) ethyl 4-pyridyl amino 2-f luorophenyl 2-acetainido- 2- (4-f luorophenyl) ethyl amino 4-chiorophenyl 2-acetamido- 2- (4-f luorophenyl) ethyl 4-pyridyl amino 3-chiorophenyl 2-acetamido- 2- (4-f luorophenyl) ethyl 4-pyridyl amino 2-chiorophenyl 2-acetamido- 2- (4-f luorophenyl) ethyl amino 4-tolyl 2-acetamido- 2 -(4-fluorophenyl)ethyl amino 3-tolyl 2-acetamido- 2-(4-fluorophenyl)ethyl amino 2-tolyl 2-acetamido- 2-(4-fluorophenyl)ethyl 4-pyridyl amino 4-trifluoro- 2-acetamido- 2-(4-fluorophenyl)ethyl methy1 heny1 4--Pyridyl amino 3-trifluoro- 2-acetamido- 2-(4-fluorophenyl)ethyl methyiphenyl 4-pyridyl amino 2,6-2-acetamido- 2- (4-fluorophenyl) ethyl dichiorophenyl _4-pyridyl amino 2, 6-dimethyl 2-acetamido- 2- (4-f luorophenyl) ethyl phenyl 4-pyridyl amino 3,4- 2-acetamido- 2-(4-fluorophenyl)ethyl dichlorophenyl 4-pyridyl amino 3, 4-dimethyl 2-acetamido- 2- (4-f luorophenyl) ethyl phenyl 4-pyridyl amino 2,4- 2-acetamido- 2-(4-fluorophenyl)ethyl dichlorophenyl 4-pyridyl amino 2, 4-dimethyl 2-acetamido- 2- (4-f luorophenyl) ethyl lphenyl 4-pyridyl amino Phenyl 2-amino-4- 2- (4-f luorophenyl) ethyl pyrimidinyl amino 4-f luorophenyl 2-amino-4- 2- (4-f luorophenyl) ethyl amino 3-f luorophenyl 2-amino-4- 2- (4-f luorophenyl) ethyl amino 2-f luorophenyl 2-amino-4- 2- (4-f luorophenyl) ethyl amino 4-chlorophenyl 2-amino-4- 2- (4-f luorophenyl) ethyl pyrimidinyl amino 3-chlorophenyl 2-amino-4- 2- (4-f luorophenyl) ethyl amino 2-chiorophenyl 2-amino-4- 2- (4-f luorophenyl) ethyl pyrimidinyl amino 4-tolyl 2-amino-4- 2- (4-fluorophenyl)ethyl pyrimidinyl amino 3-tolyl 2-amino-4- 2- (4-f luorophenyl)ethyl primidinyl amino 2-tolyl 2-amino-4-- 2- (4-f luorophenyl) ethyl lpyrimidinyl jamino WO 98/24782 WO 9824782PCTIUS97/22390 4-trifluoro- 2-ainino-4- 2- (4-fluorophenyl)ethyl methy1 heny 1 yrimidinyl amino 3-trifluoro- 2-amino-4- 2- (4-fluorophenyl)ethyl methylphenyl pyrimidinyl amino 2,-2-amino-4- 2- (4-fluorophenyl)ethyl dichlorophenyl pyrimidinyl amino 2, 6-dimethyl 2-amino-4- 2- (4-f luorophenyl) ethyl pheny1 pyrimidinyl amino 3,-2-amino-4- 2- (4-fluorophenyl) ethyl dichlorophenyl pyrimidinyl amino 3,4-dimethyl 2-amino-4- 2- (4-fluorophenyl)ethyl phenyl pyrimidinyl amino 2,-2-amino-4- 2- (4-f luorophenyl)ethyl dichlorophenyl pyrimidinyl amino 2, 4-dimethyl 2-amino-4- 2- (4-f luorophenyl) ethyl phenyl pyrimidinyl amino Phenyl 4 -pyridyl 3 -phenyipropylamino 4- fluorophenyl 4 -pyridyl 3 -phenyipropylamino 3 -fluoropheny 1 4_-pyridyl 3 -phenylpropylamino 2-f luorophenyl _4-pyridyl 3 -phenyipropylamino 4-chlorophenyl 4A-pyridyl 3 -phenylpropylamino 3 -chlorophenyl 4 -pyridyl 3 -phenyipropylamino 2 -chlorophenyl 4 -pyridyl 3 -phenyipropylamino 4-tolyl 4-pyridyl 3--phenyipropylamino 3 -to lyl -4-pyridyl 3 -phenylpropylamino 2-tolyl 4-pyridyl 3 -phenyipropylamino 4-trifluoro- 4-pyridyl 3 -phenyipropylamino me thylphenyl 3 -trifluoro- 4-pyridyl 3 -phenyipropylamino me thylphenyl 2, 6- 4 -pyridyl 3 -phenyipropylamino .dichiorophenyl 2, 6-dimethyl 4-pyridyl 3-phenyipropylamino -phenyl 3,4- 4-pyridyl 3-phenylpropylamino dichlorophenyl 3, 4-dimethyl 4-pyridyl 3-phenyipropylamino phenyl_______ 2,4- 4-pyridyl 3 -phenylpropyilamino dichlorophenyl 2, 4-dimethyl 4-pyridyl 3 -phenyipropylamino phenyl_______ Phenyl 2 -amino-4- 3 -phenyipropylamino pyridyl_ 4- fluorophenyl 2 -amino-4- 3 -phenyipropylamino pyr idyl 3 -fluorophenyl 2 -amino-4- 3 -phenylpropylamino pyridy1 2-f luorophenyl 2-amino-4- 3-phenylpropylamino 4-chiorophenyl 2-amino-4- 3 -phenyipropylamino pyridyl 3 -chiorophenyl 2 -amino-4- 3 -phenyipropylamino pyridyl WO 98/24782 WO 9824782PCTIUJS9722390 2 -chiorophenyl 2 -amino- 4- 3 -phenyipropylamino pyridyl 4- toly1 2 -amino 3 -phenyipropylamino pyridyl 3 -tolyl 2-arnino-4- 3 -phenyipropylam ino -pyridyl 2-tolyl- 2-amino-4- 3 -phenylpropyl amino pyridyl 4-trifluoro- 2-amrino-4- 3 -phenylpropylamino methylphenyl -pyridyl 3-trifluoro- 2-ainino-4- 3 -phenylpropylamino methylphenyl 2,6- 2-amino-4- 3 -phenylpropylamino dichlorophenyl _pyridy.
2, 6-dimethyl 2-aniino-4- 3 -phenylpropylamino phenyl .pyridyl 3,4- 2-amino-4- 3 -phenylpropyl amino dichlorophenyl _pyridyl 3, 4-dimethyl 2-amino-4- 3 -phenylpropylamino phenyl pyrid1 2,4- 2-amino-4- 3 -phenylpropyl amino dichlorophenyl _pyridy1 2, 4-dimethyl 2-amino-4- 3 -phenylpropyl amino phenyl _pyridyl Phenyl 2-acetamido- 3 -phenyipropyl amino 4 -pyridyl 4-filuorophenyl 2 -acetainido- 3 -phenyipropylamino 4 -pyridyl 3 -fluorophenyl 2 -acetamido- 3 -phenyipropyl amino 4 -pyridyl_ 2- fluorophenyl 2 -acetamido- 3 -phenyipropyl amino 4 -pyridyl_ 4 -chloropheny. 2 -acetamido- 3 -phenyipropyl amino -pyridy1 3 -chiorophenyl 2 -acetamido- 3 -phenyipropylamino 4 -pyridyl 2 -chiorophenyl 2 -acetamido- 3 -phenyipropylamino 4 -pyridyl 4-tolyl 2-acetamido- 3 -phenyipropylamino 4 -pyridyl 3-tolyl 2-acetamido- 3 -phenyipropylamino 4 -pyridyl 2 -tolyl 2-acetamido- 3-phenylpropylamino 4-pyridyl 4-trifluoro- 2-acetainido- 3-phenyipropylamino methyiphenyl 4 -pyridyl 3 -trifluoro- 2-acetamido- 3-phenylpropylamino niethylphenyl 4 -pyridyl 2,6- 2-acetamido- 3-phenylpropylanino dichiorophenyl 4-pyridyl 2, 6-dimethyl 2-acetamido- 3 -phenylpropylamino phenyl 4-pyridyl 2-aceramido- S-aetamdo 3 -phenylpropylamino dichiorophenyl j 4-pyridyl WO 98/24782 WO 9824782PCTIUS97/22390 3, 4-dimethyl 2 -acetainido- 3 -pheriylpropylamino phenyl 4-pyridyl 2,4- 2-acetainido- 3 -phenylpropylanino dichlorophenyl _4-pyridyl 2, 4-dimethyl 2-acetamido- 3 -pherxylpropylainino p~henyl 4-7pyridyl Phenyl 2 -amino-4 3 -phenyipropylami-no pyrimidinyl 4-f luoropheriyl 2-amino-4- 3 -phenylpropylanino pyrimidiny. 3 -fluorophenyl 2-amino-4- 3 -phenylpropylamino pyrimidinyl 2-f luorophenyl 2-amino-4- 3 -phenylpropylamino pyrimidinyl 4-chiorophenyl 2-amino-4- 3 -phenylpropylanino pyrimidinyl 3 -chiorophenyl 2 -arnino-4 3 -phenyipropylanino pyrimidinyl 2 -chiorophenyl 2 -amino-4 3 -phenyipropylamino pyrimidinyl 4-tolyl 2 -amino-4- 3-phenylpropylamino pyrimidinyl 3 -tolyl 2-amino-4- 3-phenylpropylamino pyrimidinyl 2 -tolyl 2 -amino-4 3 -phenyipropylamino pyrimidinyl 4-trifluoro- 2-arnino-4- 3-phenyipropylamino methylphenyl pyrimidinyl 3-trifluoro- 2-amino-4- 3-phenylpropylamino methylphenyl _pyrimidinyl 2, 6- 2 -amino-4 3 -phenyipropylamino dichlorophenyl pyrimidinyl 2, 6-dirnethyl 2-axnino-4- 3-phenylpropylamino phenyl pyrimidinyl 3,4- 2-amino-4- 3 -phenylpropylamino dichiorophenyl pyrimidinyl 3, 4-dimethyl 2-amino-4- 3 -phenylpropylamino phenyl pyrimidinyl 2,4- 2-amino-4- 3 -phenylpropylamino dichloropheny1 pyrimidinyl 2, 4-dimethyl 2-amino-4- 3 -phenylpropylanino phenyl _yrirnidiny1 Phenyl -4-pyridyl 3- imidazolylpropylamino 4-fluorophenyl 4-pyridyl 3 -imidazolylpropylamino 3-fluorophenyl _4.-pyridyl 3 -imidazolylpropylamino 2 -fluorophenyl _4-pyridyl 3 -imidazolylpropylamino 4-chlorophenyl 4-pyridyl 3 -iinidazolylpropylaiino 3-chlorophenyl 4-pyridyl 3 -imidazolvylpropylamino 2-chiorophenyl 4-pyridy1 3 -imidazolylpropylanino 4- tolyl .4_-pyridyl 3- imidazolyipropylanino 3-tolyl 4-pyridyl 3 -imi daz o ly1roy lamnino 2-tolyl 4-pyridyl 3 -imidazolylpropylanin 4-trifluoro- 4-pyridyl 3 -imidazolylpropylain me thyiphenyl WO 98/24782 WO 9824782PCTIUS97/22390 3-trifluoro 4-pyridyl 3 -imi daz olylpropyl amino me thylphenyl 2,6- -4-pyridyl 3 imidaz o lypropyl aino dichlorophenyl 2, 6-dimethyl 4-pyridyl 3 -imi daz olylpropyl amino p2henyl 3,4- 4-pyridyl 3 -imidazolylpropylamino di chi orophenyl 3, 4-dimethyl 4-pyridyl 3 imidazolylpropyl amino phenyl_____ 2,4- 4-pyridyl 3 -imidazolylpropylamino dichlorophenyl 2, 4-dimethyl 4-pyridyl 3 -imi daz olylpropyl amino ph enyl__ Phenyl 2-arnino-4- 3 -imidazolylpropyilamino 4-f luorophenyl 2-ainino-4- 3 -imidazolylpropylanino idyl 3-f luorophenyl 2-amino-4- 3 -imi dazo lylpropyl amino pyridyl 2-f luoropheny. 2-amino-4- 3 -imi dazo lylpropyl amino pyridyl 4 -chlorophenyl 2-amjno-4- 3-imidazolyipropylamino pyridyl 3 -chiorophenyl 2 -amino-4 3 imi daz olyipropyl amino pyridyl 2 -chlorophenyl 2-ainino-4- 3 -imidazolylpropylamino pyridyl 4-tolyl 2-ainino-4- 3 -imidazolylpropylamino pyridyl 3-tolyl 2-amino-4- 3 -imi daz olylpropyl amino pyr 2-tolyl 2-ainino-4- 3 -imi daz olylpropyl amino pyridy.
4-trifluoro- 2-amino-4- 3 -imidazolylpropylamino methyiphenyl pyridy.
3-trifluoro- 2-amino-4- 3 -imi da zo lylpropyl amino rnethylpheriyl pyridyl 2, 6- 2-amino-4- 3 -imi daz olylpropyl amino dichlorophenyl pyridyl 2, 6-dimethyl 2-amino-4- 3 -imi daz olylpropyl amino phenyl pyridyl 3,4- 2-amiino-4- 3 -imi daz olylpropyl amino dichlorophenyl _pyridyl 3, 4-dimethyl 2-amino-4- 3 -imi daz olylpropyl amino phenyl 2,4- 2-amino-4- 3 -imi daz olylpropyl amino dichlorophenyl _pyridy.
2, 4-dimethyl 2-amino-4- 3 -imi dazo lylpropyl amino phenyl pyridyl Phenyl 2 -acetamido- 3 imi dazo lyipropyl amino 4 -pyridyl 4f luorophenyl 2-acetainido- 3 im idazo lyipropyl amino 4 -pyridyl. I I- WO 98/24782 WO 9824782PCT[US97/22390 3 -fluorophenyl 2-acetamido- 3-imidazolylpropylamino 4 -pyridyl 2-f luorophenyl 2-acetamido- 3-imidazolylpropylamjno -pyridyl 4 -chiorophenyl 2 -acetainido- 3- imidazolyipropylamino 3 -chiorophenyl 2 -acetamido- 3 -imidazolyipropylanino 4 -pyridyl 2 -chiorophenyl 2-acetamido- 3 -imidazolylpropylanino -pyridyl 4-toly. 2-acetamido- 3-iridazolylpropylamino -pyridyl 3 -tolyl 2-acetainido- 3-iridazolyipropylamino -pyridyl 2-tolyl 2-acetamido- 3-irnidazolyipropylarnino -pyridyl 4-trifluoro- 2-acetamido- 3-imidazolyipropylanino inethylphenyl 4-pyridyl 3-trifluoro- 2-acetamido- 3-imidazolyipropylanino methylphenyl 4 -pyridy1 2, 6- 2-acetamido- 3-imidazolyipropylamino dichlorophenyl 4-pyridyl 2, 6-dimethyl 2-acetamido- 3-irnidazolyipropylamino phenyl 4-pyridyl 31,4- 2-acetainido- 3-imidazolyipropylaiino dichlorophenyl 4 -pyridyl 3, 4-dimethyl 2-acetarnido- 3-iridazolylpropylamino phenyl 4-pyridy 2, 4- 2-acetamido- 3-iiidazolylpropylamino dichlorophenyl 4-pyridyl 2, 4-dimethyl 2-acetamido- 3-imidazolylpropylanino phenyl 4-pyridy1 Phenyl 2-ainino-4- 3-imidazolylpropylamino _____________pyrirnidinyl 4-f luorophenyl 2-ainino-4- 3-iiidazolylpropylamino ____________pyrimidinyl 3 -fluorophenyl 2-amino-4- 3-imidazolylpropylamino pyr imidinyl 2-f luorophenyl 2-ainino-4- 3-imidazolylpropylamino 4-chiorophenyl 2 -amino-4- 3-ilnidazolylpropylanino pyrimidinyl 3-chiorophenyl 2-amino-4- 3-imidazolylpropylanino pyrimidinyl 2 -chiorophenyl 2- -amino-4- 3-imidazolylpropylamino pyrimidinyl 4-tolyl 2-amino-4- 3-imidazolylpropylanino ,pyr imidinyl 3-tolyl 2-amino-4- 3-imidazolyipropylanino lpyrimidinyl 2 -tolyl 2 -amino-4- 3-imidazolylpropylanino pyrimidinyl 4-trifluoro- 2-aijno-4- 3-imidazolylpropylamino methylphenyl _pyriinidiny 1 WO 98/24782 WO 9824782PCTIUS97/22390 3-trifluoro- 2-amino-4- 3 -imidazolylpropylamino methyiphenyl pyrimidinyl 2,6- -2-amino-4- 3-imidazolylpropylanino dichiorophenyl _pyrimidinyl 2, 6-dimethyl 2-amino-4- 3-imidazolylpropylamino phenyl pyrimidinyl 3, 4- 2-amino-4- 3-imidazolyipropylamino dichiorophenyl _pyrimidinyl 3, 4-dimethyl 2-amino-4- 3-imidazolyipropylamino phenyl pyrimidinyl 2, 4- 2-arnino-4- 3 -imidazolylpropylamino dichlorophenyl _pyrimidiny.
2, 4-dimethyl 2-amino-4- 3-imidazolylpropylamino phenyl pyrimidinyl 4-f luorophenyl 4-pyridyl 4-f luorobenzylamino 4-f luorophenyl 2-acetamido- 4-f luorobenzylamino 4 -pyridyl 4-f luorophenyl 2-amino-4- 4-f luorobenzylamino pyrimidinyl 4-f luorophenyl 4-pyridyl 2-C 2-chiorophenyl-lethyl) amino 4-f luorophenyl 2-acetamido- 2- (2-chlorophenyl-l- _4-pyridyl methyl) ethyl) amino 4-f luorophenyl 2-amino-4- 2- (2-chiorophenyl-lmethyl) ethyl) amino 4-f luoro phenyl 4-pyridyl (4-f luorophenyl) amino 4-f luorophenyl 2-acetaxnido- (4-f luorophenyl) propyl) amino 4-f luorophenyl 2-amino-4- (4-f luorophenyl) pyrimidinyl 'propyl) amino 4-f luorophenyl 4-pyridyl (4-f luorophenyl) -1- -propyl) amino 4-fluorophenyl 2-acetamido- (4-fluorophenyl) -1- 4-pyridyl methyl -propyl) amino 4-f luorophenyl 2-amino-4- (3-(4-fluorophenyl)-lyrimidinyl methyl -propyl) amino 4-f luorophenyl 4-pyridyl 1-dimethyl-3 f luoro -propyl) amino 4-f luorophenyl 2-acetainido- 1-dimethyl-3- (4-f luoro 4-pyridyl pheriyl) -propyl)amino 4-f luorophenyl 2-amino-4- 1l-dimethyl -3 -f luoro pyrimidinyl phenyl) -propyl) amino 4-f luorophenyl 4-pyridyl (2-f luorophenyl) propyl) amino 4-f luorophenyl 2-acetamido- (2-f luorophenyl) 4-pyridyl propyl) amino 4-f luorophenyl 2-amino-4- (3-(2-fluorophenyl) pyrimidinyl propyl) amino 4-f luorophenyl 4-pyridyl (3 -me thyl-3 amino 4-f luorophenyl 2-acetamido- (3-methyl-3phenylpropyl) amino WO 98/24782 WO 9824782PCT1US97/22390 4-f luorophenyl 2-amino-4- (3-methyl-3phenyipropyl) amino 4-f luorophenyl 4-pyridyl- (2-methyl-3-phenylpropyl) amino 4-f luorophenyl 2-acetainido- (2-methyl-3-phenyl- 1 propyl)anino 4-f luorophenyl 2-amino-4- (2-methyl-3-phenylpyrimidinyl propyl) amino 3-f luorophenyl 4-pyridyl CS) -tetrahydroisoquinol- 3 -ylmethylenamino 2-f luorophenyl 2-ainino-4- CS) -3-benzylpiperazinyl -pyridyl 3-chiorophenyl 2-acetanido- 2 -N-isopropylamino-3- -4-pyridyl phenylpropylamino 2-chiorophenyl 2-amino-4- -2-N-glycylamino-3pyrimidinyl phenyipropylamino 4-tolyl 4-pyridy. CS)-2-amino-3- ___________phenyipropylamino 3-tolyl 2-amino-4- CR) -2-amino-3phenylpropylamino 2-tolyl 2-acetamido- 3-amino-3- -pyridyl phenylpropyl amino 4-trifluoro- 2-amino-4- CS) -2-amino-3- (2methylphenyl pyrimidinyl fluorophenyl )propylainino 3-trifluoro- 4-pyridyl CS) -2-amino-3- (2methylphenyl _______methylphenyl) propylamino 2,6- 2-amino-4- 3-amino-3-(2dichlorophenyl pyridyl fluorophenyl) propylamino 2, 6-dimethyl 2-acetamido- 3-amino-3- (2phenyl 4 -pyridyl methylphenyl) propylamino 3,4- 2-amino-4- 2-amino-2-methyl-3dichlorophenyl pyrimidinyl phenylpropylamino 3, 4-dimethyl 4-pyridyl 3-amino-2-methyl-3phenyl _______phenylpropylamino 3-f luorophenyl 2-ainino-4- CS) -2--amino-3pyridyl phenyipropylamino 2-f luorophenyl 2-acetamido- CS) -2-amino-3- (2- 4-pyridyl filuorophenyl) propylainino 3-chlorophenyl 2-amino-4- (S)-2-amino-3-(2pyrimidinyl methylphenyl )propylamino 2-chiorophenyl 4-pyridy. CS) -2-N-isopropylamino-3- ______________phenylpropylamino 4-tolyl 2-amino-4- CS) -2-N-glycylainino-3pheny lpropyl amino 3-tolyl 2-acetamido- 2-amino-2-methyl-3- -4-pyridyl _pheny propyl amino 2-tolyl 2-amino-4- CR) -2-amino-3phenylpropylamino 4-trifiluoro- 4-pyridyl 3-amino-3methylphenyl _______phenylpropylamino 3-trifluoro- 2-amino-4- 3 -amino-3 (2 methylphenyl pyridyl fluorophenyl) propylamino 2,6- 2 -acetamido- 3-arnino-3-C(2dichlorophenyl 4 -pyridyl Imethyiphenyl) propylamino WO 98/24782 WO 9824782PCT/US97/22390 2,6-dimethyl 2-axnino-4- 3-amino-2-methyl-3phenyl pyrimidinyl _phenylpropylanino 3,4- 4-pyridy. -tetrahydroisoquinoldichlorophenyl ______3-ylmethylenamino 3, 4-dimethyl 4-pyridyl -3 -benzylpiperazinyl phenyl._ and R2 1 1,
R
12 N R wherein R 2 is -OH and R1 2 arnd R1 are one of the combinations given in the following table: Pheyl4-pyridyl 4-pyridyl 3 -fluorophenyl _4-pyridyl 4-pyridyl 2-f luorophenyl 4-pyridyl 4-pyridyl 4-chiorophenyl 4-pyridyl 4-pyridyl 3 -chiorophenyl _4-pyridyl. 4-pyridyl 2 -chiorophenyl 4 -pyridyl 4 -pyridyl 4-choro l 4-pyridyl 4-pyridyl 3-toly. 4-pyridyl 4-pyridyl 2-tolyl 4-pyridyl 4-pyridyl 4-triluoro 4-pyridyl 4-pyridyl me t hyi phenyl 3 -t r i fl u o o -4 y r d l p r i y me thiphenyl 2,6-lheyl dih, rohey 4-pyridyl 4-pyridyl 2 di o e yl4- y i y4- y dy phenylyl4 py i yl4 py i y 3h e4 l 4 y iy.- y i y di4 chiorophenylridy 3,4im o e yl4 py i y4 py dy phenyl hl .4priy 4priy 2he4yl 2ih,4 ohe- 4-pyridyl 4-pyridy.
2, im o e yl4 py i y4- y dy phenyl yl 4pyiyl 4pyiy phenyl.2 a i o 4 y i y Phenyl._____ pyriyl 4pri 4 f u r o p h e n l 2 a i n o 4 -4 y r d y pyrin-4 idylid 3 f l u r o p h e n l a i n o 4 -4 y r d y pyriyl 4 U U L u p l e ~p y.4 y riyy uorophenyl I -amino-- 4-pyridyl I pyr i dyl WO 98/24782 PTU9/29 PCTIUS97/22390 4-chiorophenyl 2 -amino-4- 4-pyridyl yridyl 3 -chiorophenyl 2 -amino-4- 4-pyridyl _pyridyl 2 -chiorophenyl 2-amino-4- 4-pyridyl idyl 4-tolyl 2-amino-4- 4-pyridyl pyridyl 3-toly. 2-amino-4- 4-pyridyl pyridyl 2-tolyl 2-amino-4- 4-pyridyl pyridyl 4-trifluoro- 2-amino-4- 4-pyridyl methylphenyl pyridyl 3-trifluoro- 2-amino-4- 4-pyridyl methylpheny. pyridyl 216- 2-amino-4- 4-pyridyl dichloropheny. pyridyl 2,6-dimethyl 2-anmino-4- 4-pyridyl phenyl pyridyl 3,14- 2-amino-4- 4-pyridyl dichiorophenyl pyridyl 3,4-dimethyl 2-ainino-4- 4-pyridyl pheniyl pyridyl 2,4- 2-ainino-4- 4-pyridyl dichlorophenyl pyridyl 2,4-dirnethyl 2-amino-4- 4-pyridyl phenyl -pyridyl Phenyl 2-acetainido- 4-pyridyl 4 -pyridyl 4-f luorophenyl 2-acetamido- 4-pyridyl _4 -pyridyl 3 -fluorophenyl 2-acetamido- 4-pyridyl -pyridyl 2-f luorophenyl 2-acetarnido- 4-pyridyl 4 -pyridyl 4-chloropheny. 2 -acetainido- 4-pyridyl 4 -pyridy1 3 -chiorophenyl 2 -acetainido- 4 -pyridyl 4-pyridyl 2-chiorophenyl 2-acetanido- 4-pyridyl 4 -pyridyl_ 4-tolyl 2-acetamrido- 4-pyridyl 4 -pyridyl 3-tolyl 2-acetainido- 4-pyridyl 4-pyridyl 2-tolyl 2-acetamido- 4-pyridyl 4-pyridyl 4-trifluoro- 2-acetainido- 4-pyridyl methylphenyl 4 -pyridyl 3-trifluoro- 2-acetamido- 4-pyridyl methyiphenyl 4 -pyridyl 2,6- 2-acetamido- 4-pyridyl ,dichlorophenyl 4-pyridyl WO 98/24782 WO 9824782PCTIUS97/22390 2, 6-dimethyl 2-acetamido- 4-pyridyl phenyl 4-pyridyl 3,4- 2-acetamido- 4-pyridyl dichlorophenyl _4-pyridyl 3 ,4-dimethyl 2-acetamido- 4-pyridyl phenyl 4-pyridyl 2,4- 2-acetamido- 4-pyridyl dichlorophenyl 4 -pyridyl 2, 4-dimethyl 2-acetamido- 4-pyridyl phenyl -4-pyridyl Phenyl 2-axnino-4- 4-pyridyl ____________pyrimidinyl 4-f luorophenyl 2-arnino-4- 4-pyridyl 3 -fluoropheny. 2-amino-4- 4-pyridyl pyr imidinyl 2 -fluorophenyl 2 -amino-4- 4-pyridyl 4-chiorophenyl 2-amino-4- 4-pyridyl imidinyl 3 -chiorophenyl 2 -amino-4- 4-pyridyl pyrimidinyl 2 -chiorophenyl 2 -amino-4- 4-pyridyl pyrimidinyl 4-tolyl 2-ainino-4- 4-pyridyl imidinyl 3-tolyl 2-amino-4- 4-pyridyl pyr imnidinyl 2-tolyl 2-amino-4- 4-pyridyl pyrimidinyl 4-trifluoro- 2-ainino-4- 4-pyridyl methylphenyl pyrimidinyl 3-trifluoro- 2-ainino-4- 4-pyridyl methylphenyl pyrimidinyl 2,6- 2-amino-4- 4-pyridyl dichlorophenyl primidinyl 2,6-dimethyl 2-amino-4- 4-pyridyl phenyl pyrimidiiyl 3,4- 2-amino-4- 4-pyridyl dichlorophenyl pyrimidinyl 3,4-dimethyl 2-amino-4- 4-pyridyl phenyl pyrirnidinyl 2,4- 2-amino-4- 4-pyridyl dichioropheny1 pyrimidinyl 2,4-dirnethyl 2-amino-4- 4-pyridyl phenyl _pyrimidinyl______ Phenyl 4-pyridyl 4-methyl sulfinylphenyl 4-f luorophenyl 4-pyrridyl 4-methyl sulfinylphenyl 3-f luorophenyl 4-pyridyl 4-methy1 suif iny1 heny1 2-f luorophenyl 4-pyridyl 4-methyl sulfinylphenyl 4-chlorophenyl 4-pyridyl 4-methyl sulfinylphenyl 3-chlorophenyl 4- Iridyl 4-methyl sulfinylphenyl 2-chlorophenyl 4 -pyridyl 4-methyl sulfinyliphenyl 4-tolyl 4-pyridyl 4-methyl sulfinyiphenyl WO 98/24782 WO 9824782PCTUS97/22390 j. 3-tolyl 4-pyridyl 4-methyl sulfinyiphenyl 2-tolyl 4-pyridyl 4-methyl sulfinyiphenyl 4-trifluoro- 4-pyridyl 4-methyl sulfinyiphenyl methyipheny1_____________ 3-trifluoro- 4-pyridyl 4-methyl sulfinyiphenyl methylphenyl 2,6- 4-pyridyl 4-methyl sulfinyiphenyl dichlorophenyl_______ 2, 6-dimethyl 4-pyridyl 4-methyl sulfinyiphenyl 3,4- 4-pyridyl 4-methyl sulfinyiphenyl dichiorophenyl 3,4-dimethyl 4-pyridyl 4-methyl sulfinylphenyl phenyl__ 2,4- 4-pyridyl 4-methyl sulfinylphenyl dichlorophenyl 2, 4-dimethyl 4-pyridyl 4-methyl sulfinyiphenyl phenyl Phenyl 2-amino-4- 4-methyl sulfinyiphenyl pyr idyl 4-f luorophenyl 2-amino-4- 4-methyl sulfinylphenyl pyridyl 3 -fluorophenyl 2-amino-4- 4-methyl sulfinyiphenyl pyridyl 2-f luorophenyl 2-amino-4- 4-methyl sulfinylphenyl p pridyl 4-chlorophenyl 2-amino-4- 4-methyl sulfinylphenyl 3-chlorophenyl 2-aniino-4- 4-methyl sulfinyiphenyl 2-chlorophenyl 2-arnino-4- 4-methyl sulfinylphenyl pyridyl 4-tolyl 2-amino-4- 4-methyl sulfinylphenyl pyr idyl 3-tolyl 2-amino-4- 4-methyl sulfinylphenyl 2-tolyl 2-ainino-4- 4-methyl sulfinylphenyl pyridyl 4-trifluoro- 2-amino-4- 4-methyl sulfinylphenyl methylphenyl pyridyl 3-trifluoro- 2-amino-4- 4-methyl sulfinylphenyl rnethylphenyl pyIdyl 2,6- 2-amino-4- 4-methyl sulfinyiphenyl dichloropheny 1 pyiy 2, 6-dimethyl 2-amino-4- 4-methyl sulfinyiphenyl phenyl pyridyl 3,4- 2-amino-4- 4-methyl sulfinyiphenyl dichlorophenyl _pyridyl 3, 4-dimethyl 2-amino-4- 4-methyl sulfinyiphenyl .phenyl pyridyl_______ 2,4- 2-amino-4- 4-methyl sulfinyiphenyl dichloropohenyl pyridyl 2,4-dimethyl 2-amjno-4- 4-methyl sulfinyiphenyl phenyl pyridyl WO 98/24782 PTU9129 PCTIUS97/22390 Phenyl 2-acetamido- 4-methyl sulfinyiphenyl -pyridyl 4-f luorophenyl 2-acetamido- 4-methyl sulfinyiphenyl 4 -pyridyl 3-f luorophenyl 2-acetamido- 4-methyl sulfinyiphenyl 4 -pyridyl 2-f luorophenyl 2 -acetamido- 4-methyl sulfinyiphenyl 4 -pyridyl 4-chiorophenyl 2-acetainido- 4-methyl sulfinylphenyl 4 -pyridyl 3-chiorophenyl 2-acetarnido- 4-methyl sulfinyiphenyl 4 -pyridyl 2-chiorophenyl 2-acetamido- 4-methyl sulfinyiphenyl 4 -pyridyl 4-tolyl 2-acetamido- 4-methyl sulfiny-phenyl 4-pyridyl 3-tolyl 2-acetamido- 4-methyl sulfinyiphenyl 4 -pyridyl 2-tolyl 2-acetamido- 4-methyl sulfinyiphenyl 4 -pyridy 4-trifluoro- 2-acetamido- 4-methyl sulfinyiphenyl methylpheny1 4-pyridyl 3-trifluoro- 2-acetamido- 4-methyl sulfinylphenyl methylphenyl 4-pyridyl 2,6-2-acetamido- 4-methyl sulfinyiphenyl dichiorophenyl 4-pyridyl 2, 6-dimethyl 2-acetamido- 4-methyl sulfinyiphenyl phenyl 4-pyridyl 3,4- 2-acetamido- 4-methyl suifinyiphenyl dichlorophenyl 4-pyridyl 3, 4-dimethyl 2-acetamido- 4-methyl sulfinyiphenyl phenyl 4-pyridyl 2,4- 2-acetainido- 4-methyl sulfinyiphenyl dichlorophenyl 4-pyridyl 2, 4-dimethyl 2-acetamido- 4-methyl sulfinyiphenyl phenyl A4-py,--rdyl Phenyl 2-amino-4- 4-methyl sulfinyiphenyl p~yrimidinyl 4-f luorophenyl 2-amino-4- 4-methyl sulfinyiphenyl pyrirnidinyl 3-f luorophenyl 2-amino-4- 4-methyl sulfinyiphenyl pyrirnidinyl 2-f luorophenyl 2-ainino--4- 4-methyl sulfinyiphenyl pyrirnidinyl 4-chlorophenyl 2-axnino-4- 4-methyl sulfinyiphenyl pyrimidinyl 3 -chiorophenyl 2-amino-4- 4-methyl sulfinyiphenyl pyrimidinyl 2-chiorophenyl 2-amino-4- 4-methyl sulfinyiphenyl pyrimidinyl 4-tolyl 2-amino-4- 4-methyl sulfinylphenyl pyrimidinyl 3-tolyl 2-amino-4- 4-methyl sulfinyiphenyl pyrimidinyl WO 98/24782 WO 9824782PCTfUS97/22390 2-tolyl 2-amino-4- 4-methyl sulf irylphenyl ____________pyrimidinyl 4-trifluoro- 2-amirio-4- 4-methyl sulfinylphenyl _Methylphenyl pyrimidinyl 3-trifluoro- 2-amino-4- 4-methyl Sulfinylphenyl methylphenyl pyrimidinyl 2,6- 2-amino-4- 4-methyl sulf-inyiphenyl dichlorophenyl pyrimidinyl 2, 6-dimethyl 2-amino-4- 4-methyl sulfinylphenyl lphenyl pyrimidinyl 3,4- 2-amino-4- 4-methyl sulf inyiphenyl dichiorophenyl pyrimidinyl 3, 4-dimethyl 2-amino-4- 4-methyl sulfinyiphenyl phenyl pyrimidinyl 2,4- 2-amino-4- 4-methyl sulfinylphenyl dichiorophenyl pyrirnidinyl 2, 4-diniethyl 2-amino-4- 4-methyl- sulf inyiphenyl phenyl pyrimidinyl Phenyl 4-pyridyl 2, 6-dichlorobenzyl 4-f luorophenyl 4-pyridyl 2, 6-dichlorobenzyl 3-f luorophenyl 4-pyridyl 2, 6-dichlorobenzyl 2-f luorophenyl 4-pyridyl 2, 6-dichlorobenzyl 4-chlorophenyl 4-pyridyl 2, 6-dichlorobenzyl 3-chlorophenyl 4-pyridyl 2, 6-dichlorobenzyl 2-chiorophenyl 4-pyridyl 2, 6-dichlorobenzyl 4-tolyl 4-pyridyl 2, 6-dichlorobenzyl 3-tolyl 4-_pyridyl 2, 6-dichlorobenzyl 2-tolyl 4-pyridyl 2, 6-dichlorobenzyl 4-trifluoro- 4-pyridyl 2, 6-dichlorobenzyl methylphenyl_____________ 3-trifluoro- 4-pyridyl 6-dichlorobenzyl methylphenyl 2,6- 4-pyridyl 2, 6-dichlorobenzyl dichlorophenyl______________ 2, 6-dimetiayl 4-pyridyl 2, 6-dichlorobenzyl phenyl_______ 3,4- 4-pyridyl 2, 6-dichlorobenzyl dichlorophenyl 3, 4-dimethyl 4-pyridyl 2, 6-dichlorobenzyl phenyl 2,4- 4-pyridyl 2 6-dichlorobenzyl dichiorophenyl 2,4-dimethyl 4-pyridyl 2, 6-dichlorobenzyl phenyl Phenyl 2-amino-4- 2, 6-dichloroberxzyl 4-f luorophenyl 2-amino-4- 2, 6-dichlorobenzyl pyr idyl 3-f luorophenyl 2-amino-4- 2, 6-dichlorobenzyl pyridyl 2-f luorophenyl 2-a~mino-4- 2, 6-dichlorobenzyl pyridyl 4-chiorophenyl 2-arnino-4- 2, 6-dichlorobenzyl ridv I 0 1 WO 98./24782 PTU9/29 PCTIUS97/22390 3-chiorophenyl 2-amino-4- 2, 6-dichJlorobenzyl _pyridyl 2-chiorophenyl 2-ainino-4- 2, 6-dichlorobenzyl pyridyl 4-tolyl 2-amino-4- 2, 6-dichlorobenzyl pyridyl 3-tolyl 2-arnino-4- 2, 6-dichlorobenzyl pyridyl 2-tolyl 2-ainino-4- 2, 6 -dichlorobenzyl pyridyl 4-trifluoro- 2-amino-4- 2, 6-dichlorobenzyl methylpheiyl pyridyl 3-trifluoro- 2-arnino-4- 2, 6-dichlorobenzyl methylpheiyl 2,6- 2-amino-4- 2, 6-dichilorobenzyl dichlorophenyl pyridyl 2, 6-dirnethyl 2-ainino-4- 2, 6-dichlorobenzyl phenyl _pyridyl 3,4- 2-amino-4- 2, 6-dichlorobenzyl dichlorophenyl pyridyl 3, 4-dimethyl 2-amino-4- 2, 6-dichiorobeuzyl phenyl _pyridyl 2,4- 2-amino-4- 2 1 -dichlorobenzyl dichiorophenyl pyridyl 2, 4-dimethyl 2-amirio-4- 2, 6-dichlorobenzyl phenyl pyridyl Phenyl 2-acetamido- 2, 6-dichlorobenzyl -pyridyl 4-f luorophenyl 2-acetamido- 2, 6-dichlorobenzyl -pyridyl 3-f luorophenyl 2-acetainido- 2, 6-dichlorobenzyl -pyridyl 2 -fluorophenyl 2-acetanido- 2, 6-dichlorobenzyl -pyridyl 4-chiorophenyl 2-acetamido- 2, 6-dichlorobenzyl 4 -pyridyl 3-chiorophenyl 2-acetarnido- 2, 6-dichlorobenzyl 4 -pyridyl 2-chioropheny. 2-acetamido- 2, 6-dichlorobenzyl 4 -pyridyl 4-tolyl 2-acetamido- 2, 6-dichlorobenzyl 4-pyridyl 3-toly. 2-acetarnido- 2, 6-dichlorobenzyl 4 -pyridyl 2-tolyl 2-acetamido- 2, 6-dichlorobenzyl 4 -pyridyl 4 -trifluoro- 2-acetainido- 2, 6-dichlorobenzyl methylphenyl 4-pyridyl 3 -trifluoro- 2-acetamido- 2, 6-dichlorobenzyl methylphenyl 4-pyridv1 2,6- 2-acetamido- 2, 6-dichlorobenzyl dichlorophenyl 4-pyridyl '2,D-dimetnyl 2-acetanido- 4 -pyridvl 2, 6-dichlorobenzyl WO 98/24782 PTU9/29 PCTIUS97/22390 3,-2-acetarnido- 2, 6-dichlorobenzy.
dichlorophenyl 4-pyridyl 3, 4-dimethyl 2-acetainido- 2, 6-dichlorobenzyl _henyl 4-pyridyl 2,4-2-acetainido- 2, 6-dichlorobenzyl dichlorophenyl -4-pyridyl 2, 4-dimethyl 2-acetamido- 2, 6-dichlorob~enzyl phenyl 4-pyridyl Phenyl 2-amino-4- 2, 6 -dichlorobenzy.
4-f luorophenyl 2-ainino-4- 2, 6-dichioroberizyl p yrimidinyl 3-f luorophenyl 2-amino-4- 2, 6-dichlorobenzyl pyrirnidinyl 2-f luorophenyl 2-amino-4- 2, 6-dichlorobenzyl pyrimidinyl 4-chiorophenyl 2-amino-4- 2, 6-dichlorobenzyl ____________pyrimidinyl 3-chiorophenyl 2-amino-4- 2, 6-dichlorobenzyl pyrirnidinyl 2-chiorophenyl 2-amino-4- 2, 6-dichitorobenzyl pyrimidinyl 4-tolyl 2-amino-4- 2, 6-dichlorobenzyl pyrimidinyl 3-tolyl 2-axnino-4- 2, 6-dichlorobenzyl pyrimidinyl 2-tolyl 2-amino-4- 2, 6 -dichlorobenzyl 4-trifluoro- 2-amino-4- 2, 6-dichlorobenzyl methylphenyl pyrimidinyl 3-trifluoro- 2-amino-4- 2, 6-dichlorobenzyl methylphenyl pyriinidinyl 2,6- 2-amino-4- 2,6-dichlorobenzy.
dichiorophenyl pyrimidinyl 2, 6-dimethyl 2-amirio-4- 2, 6-dichlorobenzyl phenyl pyrimidinyl 3,4- 2-amino-4- 2, 6-dichlorobenzyl dichiorophenyl pyrimidinyl 3 ,4-diinethyl 2-amino-4- 2, 6-dichJlorobenzyl phenyl pyrimidinyl 2,4- 2-ainino-4- 2,6-dichlorobenzyl dichiorophenyl pyrimidinyl 2, 4-dimethyl 2-ainino-4- 2, 6-dichlorobenzyl phenyl pyrimidinyl Phenyl. 4-pyridyl 2- (4-f luorophenyl) ethyl amino 4-f luorophenyl 4-pyridyl 2- (4-f luorophenyl) ethylanino 3-f luorophenyl 4-pyridyl 2- (4-f luorophenyl) ethylanino 2-f luorophenyl 4-pyridyl 2- (4-f luorophenyl) ethylanino 4-chiorophenyl 4-pyridyl 2- (4-f luorophenyl) I I ethyl amino WO 98/24782 WO 9824782PCTIUS97/22390 3 -chiorophenyl 4-pyridyl 2- (4-f luorophenyl) 2-chlorophenyl 4-pyridyl 2- (4-f luorophenyl) 4-tolyl 4-pyridy. 2 (4 -f luorophenyl) 3-tolyl 4-pyridyl 2 (4 -f luorophenyl) 2-tolyl 4-pyridyl 2 (4 fluorophenyl) ___________ethylamiino 4-trifluoro- 4-pyridyl 2 (4 -f luorophenyl) methylphenyl _______ethylamino 3-trifluoro- 4-pyridyl 2- (4-f luorophenyl) methylphenyl _______ethylanino 2,6- 4-pyridyl 2- (4-f luorophenyl) dichlorophenyl _______ethylanino 2, 6-dirnethyl 4-pyridyl 2 (4 -f luorophenyl) phenyl _______ethylanino 3,4- 4-pyridyl 2 (4 -f luorophenyl) dichiorophenyl ethylamino 3, 4-dirnethyl 4-pyridyl 2 (4 -f luorophenyl) ethylanino 2,4- 4-pyridyl 2 -f luorophenyl) dichlorophenyl _______ethylanino 2, 4-dimethyl 4-pyridyl 2 (4 -f luorophenyl) phenyl, ethyl amino Phenyl 2-amino-4- 2 (4 -f luorophenyl) ethylamino 4-f luorophenyl 2-amino-4- 2 (4 -f luorophenyl) pyridyl ethylamino 3-f luorophenyl 2-amino-4- 2 (4 -f luo rophenyl) pridy1 ethylanino 2-f luorophenyl 2-amino-4- 2 (4 -f luorophenyl) ethylanino 4-chiorophenyl 2-ainino-4- 2 (4 -f luorophenyl) pyridyl ethylamino 3-chloropheny. 12-arnino-4- 2 (4 -f Iluorophenyl) pyridyl ethylamino 2-chlorophenyl 2-ainino-4- 2 (4 -f luorophenyl) ethylamino 4-tolyl 2-ainino-4- 2 (4 -f luorophenyl) pyridyl ethylamino 3-tolyl 2-ainino-4- 2 fluorophenyl) pyr idyl_ ethylamino 2-tolyl 2-amino-4- 2 (4 -f luorophenyl) ethylamino 4-trifluoro- 2-amino-4- 2 (4 -f Iluorophenyl) inethylphenyl pyrid- ethylanino 3-trifl.uoro- 2-amino-4- 2 fluorophenyl) methylphenyl pyridy1 ethylanino 2,6- 2-amino-4- 2 fluorophenyl) dichiorophenyl__ pyridyl ethylamino 2,6-dimethyl 2-ainino-4- 2 (4 -f luorophenyl) phenyl pyridyl ethylamino WO 98/24782 WO 9824782PCTIUS97/22390 3,4- 2-axnino-4- 2-(4-fluorophenyl) dichlorophenyl pyridyl ethylamino 3,4-dimethyl 2-amino-4- 2- (4-f luorophenyl) phenyl _pyridyl ethylanino 2,4- 2-amino-4- 2-(4-fluorophenyl) dichlorophenyl pyridyl ethylanino 2,4-diinethyl 2-amino-4- 2- (4-f luorophenyl) phenyl pridy1 ethylamino Phenyl 2-acetamido- 2- (4-f luorophenyl) 4-pyridyl ethylamino 4-f luorophenyl 2-acetamido- 2- (4-f luorophenyl) 4-pyridyl ethylamino 3-f luorophenyl 2-acetamido- 2 (4 -f luorophenyl) ethylanino 2-filuorophenyl 2-acetamido- 2- (4-f iluorophenyl) 4-pyridyl ethylano 4-chiorophenyl 2-acetamido- 2 (4 -f luorophenyl) 4-pyridyl ethylainino 3-chiorophenyl 2-acetamido- 2 (4 -f luorophenyl) 4 -pyridy. ethylarnino 2-chiorophenyl 2-acetamido- 2 (4 -f luorophenyl) ethylanino 4-tolyl 2-acetamido- 2 (4 fluorophenyl) -pyridyl ethyl amino 3-tolyl 2-acetainido- 2 (4 fluorophenyl) 4-pyridyl ethylaiino 2-tolyl 2-acetainido- 2- (4-f luorophenyl) ethylamino 4-trifluoro- 2-acetanido- 2 -f luorophenyl) methylphenyl 4-pyridy1 ethylanino 3-trifluoro- 2-acetamido- 2 (4 fluorophenyl) methyllphenyl 4-pyridyl ethylamino 2,6- 2-acetamido- 2 fluorophenyl) dichlorophenyl _4-pyridyl ethylanino 2, 6-dimethyl 2-acetamido- 2 (4 -f luorophenyl) phenyl 4-pyridyl ethylamino 3,4- 2-acetamido-- 2- (4-fiLuorophenyl) dichlorophenyl 4-pyridyl ethylamino 3, 4-dimethyl 2-acetamido- 2 (4 -f luorophenyl) phenyl 4-pyridyl ethylamino 2,4- 2-acetainido- 2 fluorophenyl) dichiorophenyl 4-pyridyl ethylamino 2, 4-dimethyl 2-acetamido- 2 (4 -f luorophenyl) phenyl. 4-pyridyl ethylamino Phenayl 2-arnino-4- 2 (4 -f luorophenyl) pyrirnidinyl ethylamino 4-f luorophenyl 2-amino-4- 2 (4 -f luorophenyl) ethylamino 3-f luorophenyl 2-amino-4- 2- (4-f luorophenyl) pyrimidinyl eth~ylanino 2-f luorophenyl 2-arnino-4- 2 (4 -f luorophenyl) pyimdinyl ethylamino 4-chiorophenyl 2-arnino-4- 2 (4 -f luorophenyl) pyrimidinyl iethylamino WO 98/24782 WO 9824782PCTIUS97/22390 3-chiorophenyl 2-ainino-4- 2- (4-f luorophenyl) ethylamino 2-chiorophenyl 2-amino-4- 2- (4-f luorophenyl) pyrimidinyl ethylamino 4-tolyl 2-arnino-4- 2-(4-fluorophenyl) pyrimidinyl ethylamino 3-tolyl 2-axnino-4- 2-(4--fluorophenyl) pyrimidinyl ethylamino 2-tolyl 2-ainino-4- 2-(4-fluorophenyl) pyrimidinyl ethyl amino 4-trifluoro- 2-amino-4- 2-(4-fluorophenyl) methyiphenyl pyrimidinyl ethylamino 3-trifluoro- 2-amino-4- 2-(4-fluorophenyl) methyiphenyl -pyrimidinyl ethylamino 2,6- 2-amino-4- 2-(4-fluorophenyl) dichiorophenyl pyrimidinyl ethylamino 2, 6-dimethyl 2-axnino-4- 2-(4-fluorophenyl) phenyl pyrimidinyl ethyilaiino 3,4- 2-amino-4- 2-(4-fluorophenyl) dichiorophenyl pyrimidinyl ethylamino 3,4-dimethyl 2-amino-4- 2-(4-fluorophenyl) phenyl pyrimidinyl ethylamino 2,4- 2-amino-4- 2-(4-fluorophenyl) dichiorophenyl pyrimidinyl ethylamino 2,4-dimethyl 2-amino-4- 2-(4-fluorophenyl) phenyl pyrimidiiyl ethylamino Phenyl 4-pyridyl 3 -phenyl-propylamino 4-f luorophenyl 4-pyridyl 3 -phenyl-propylamino 3-f luorophenyl 4 -pyridyl 3 -phenyl -propylamino 2 -fluorophenyl 4-pyridyl 3-phenyl-propylamino 4-chiorophenyl 4-pyridyl 3 -phenyl-propylamino 3 -chioropheny. 4-pyridyl 3-phenvl-propylamino 2- chiorophenyl 4 -pyridy. 3 -phenyl-propylamino 4- tolyl 4 -pyridyl 3 -phenyl -propylamino 3- tolyl 4 -pyridyl 3 -phenyl -propylamino 2- tolyl 4 -pyridyl 3 -phenyl -propylamino 4-trifluoro- 4-pyridyl 3 -phenyl-propylamino me thylphenyl 3-trifluoro- 4-pyridyl 3-phenyl-propylamino me thyiphenyl 2, 6- 4-pyridyl 3-phenyl-propylamino dichlorophenyl 2, 6-dimethy. 4-pyridyl 3-phenyl-propylamino _heny1l_ 3, 4- 4-pyridyl 3-phenyl-propylamino dichiorophenyl 3, 4-dimethyl 4-pyridyl 3-phenyl-propylamino phenyl_______ 2,4- 4-pyridyl 3-phenyl-propylamino dichlorophenyl 2, 4-dimethyl 4-pyridyl 3-phenyl-propylamino phenyl__ Phenyl 2 -ainino-4 3 -phenyl-propylamino pyridyl WO 98/24782 WO 9824782PCTIUS97/22390 4-f luorophenyl 2-ainino-4- 3-phenyl-propylamino pyridyl 3-f luorophenyl 2-amino-4- 3 -phenyl-propylanino p pridyl 2-f luorophenyl 2 -amino- 4- 3 -phenyl -propylamino 4- chiorophenyl 2 -amino 3 -phenyl -propylainino pyridyl 3 -chloropheny. 2 -amino-4 3 -phenyl-propylamino 2 -chiorophenyl 2 -ainino-4 3 -phenyl-propylamino 4-tolyl 2 -amino-4- 3 -phenyl-propylanino 3 -tolyl 2 -amino-4- 3 -phenyl-propylamino pyridyl 2 -tolyl 2-amino-4- 3 -phenyl-propylamino 4-trifluoro- 2-ainino-4- 3-phenyl-propylanino methylphenyl pyridyl 3-trifluoro- 2-amino-4- 3-phenyl-propylamino methylphenlyl pyridyl 2,6- 2-amino-4- 3-phenyl-propylamino dichlorophenyl pyridyl 2, 6-dimethyl 2-amino-4- 3-phenyl-propylamino phenyl pyridyl 3,4- 2-amino-4- 3-phenyl-propylamino dichlorophenyl pyridyl 3, 4-dimethyl 2-amino-4- 3-phenyl-propylamino phenyl pyridyl 2, 4- 2-amino-4- 3-phenyl-propylamino dichilorophenyl pyridyl 2, 4-dimethyl 2-amino-4- 3-phenyl-propylamino phenyl pyridyl Phenyl 2 -acetamido- 3 -phenyl -propylainino 4 -pyridyl 4-f luorophenyl 2 -acetainido- 3-phenyl-propylamino 4 -pyridyl 3-f luorophenyl 2-acetamido- 3-phenyl-propylanino 4 -pyridy.
2-f luoropheny. 2 -acetamido- 3 -phenyl-propylamino 4 -pyridy 1_ 4 -chiorophenyl 2 -acetamido- 3 -phenyl-propyl amino 3 -chiorophenyl 2-acetamido- 3-phenyl-propylamino 4-pyridy1 2 -chiorophenyl 2-acetamido- 3 -phenyl-propylamino 4 -pyridyl 4- tolyl 2 -acetamido- 3 -phenyl-propylamino 4 -pyridyl 3 -toly. 2 -acetanjido- 3 -phenyl-propylamino 4 -pyridyl 2-tolyl 2-acetamido- 3-phenyl-propylamino 4-yridyl_ WO 98/24782 WO 9824782PCTIUS97/22390 4-trifluoro- 2-acetamido- 3-phenyl-propylamino methylpheny. 4-pyridy 3-trifluoro- 2-acetamido- 3-phenyl-propylamino methylpheny. 4 -pyridyl 2,6- 2-acetamido- 3-phenyl-propylamino dichlorophenyl 4-pyridyl 2, 6-dimethyl 2-acetainido- 3-phenyl--propylainino phenyl 4-pyridyl 3,4- 2-acetamido- 3-phenyl-propylamino dichiorophenyl 4 -pyridyl 3, 4-dimethyl 2-acetamido- 3 -phenyl-propylamino pheny1 4-pyridyl 2,4- 2-acetamido- 3 -phenyl-propylamino dichlorophenyl 4-pyrid~yl 2, 4-diinethyl 2-acetamido- 3-phenyl--propylamino phenyl 4-_pyridyl Phenyl 2 -amino-4 3 -phenyl-propylanino imidinyl 4-f luorophenyj. 2-ainino-4- 3-phenyl--propylamino 3- fluorophenyl 2 -amino-4 3 -phenyl-propylanino pyrimidinyl 2-f luorophenyl 2-amino-4- 3-phenyl-propylamino _pyrirnidinyl 4 -chiorophenyl 2 -axnino-4 3 -phenyl-propylamino pyrirnidinyl 3-chiorophenyl 2-amino-4- 3-phenyl.-propylamino pyr imidiny. 2 -chiorophenyl 2-amino-4- 3 -phenyl-propylamino 4-tolyl 2-ainino-4- .3 -phenyl-propylamino imidinyl 3- tolyl 2 -axnino-4- 3 -phenyl-propyiLamino 2- tolyl 2 -amino-4 3 -phenyl -propylanino ____________pyriinidinyl 4-trifluoro- 2-axino-4- 3-phenyl-propylamino methylphenyl pyrimidinyl 3-trifluoro- 2-amino-4- 3-phenyl-propylanino methylphenyl pyrimidinyl 2,-2-ainino-4- 3-phenyl-propylanino dichioropheny1 pyrimidinyl 2, 6-dirnethyl 2-amino-4- 3-phenyl-propylamino phenyl_____ _pyr imidinyl 3,-2-amino-4- 3 -phenyl-propylamino dichlorophenyl pyrimidinyl 3, 4-dimethyl 2-amino-4- 3-phenyl-propylamino phenyl _pyrimidinyl 2,4- 2-axnino-4- 3 -phenyl -propyl amino dichlorophenyl pyrimidinyl 2, 4-dimethyl 2-amino-4- 3-phenyl-propylanino phenyl pyrimidinyl Phenyl 4-pyridyl (1-inethyl-3- Jphenyl)propylamino WO 98/24782 WO 9824782PCTIUS97/22390 4-f luorophenyl 4-pyridyl (1-methyl-3henyl )_propyl amino 3 -fluorophenyl 4-pyridyl (1-methyl-3propyl amino 2-f luorophenyl 4-pyridyl (1-methyl-3propylamino 4-chilorTphenyl 4-pyridyl (1-methyl-3propylamino 3-chiorophenyl 4-pyridyl (1-methyl-3henyl) propyl amino 2-chiorophenyl 4-pyridyl (1-methyl-3phenyl) propylamino 4-tolyl 4-pyridy. (1-methyl-3propylamino 3-tolyl 4-pyridyl (1-methyl-3propylamino 2-tolyl 4-pyridyl (1-methyl-3phenyl) propylarnino 4-trifluoro- 4-pyridyl (1-methyl-3rethylphenyl _phenyl_) propylamino 3-trifluoro- 4-pyridyl (1-methyl-3methylphenyl phenyl) propylamino 2,6- 4-pyridyl (1-methyl-3dichlorophenyl -pheny1) proplamino 2, 6-dimethyl 4-pyridyl (1-methyl-3phenyl propylamino 3,4- 4-pyridy. (1-rethyl-3dichlorophenyl phenyl) propylainino 3, 4-dimethyl 4-pyridyl (1-methyl-3phenyl phenyl) propylamino 2,4- 4-pyridyl (1-rethyl-3dichlorophenyl phenyl) propylainino 2, 4-dimethyl 4-pyridyl (1-methyl-3phenyl phenyl) propylamino Phenyl 2-ainino-4- (1-methyl-3pyridyl phenyl propylamino 4-f luorophenyl 2-amino-4- (1-inethyl-3pyridy. phenyl) propylamino 3-f luorophenyl 2-arnino-4- (1-methyl-3pyridyl' phenyl) propylamino 2-f luorophenyl 2-amino-4- (1-methyl-3phenyl) propyl amino 4-chiorophenyl 2-ainino-4- (1-methyl-3phenyl) propylamino 3-chiorophenyl 2-ainino-4- (1-rethyl-3- _pyridy. phenyl) propyl amino 2-chiorophenyl 2-amino-4- (1-methyl-3- -pyridyl phenyl) propylamino 4-tolyl 2-amino-4- (1-methyl-3pyridyl phenyj) propylamino 3-tolyl 2-arnino-4- (1-methyl-3- _phenyl) propylarnino 2-tolyl 2-amino-4- (1-methyl-3- -pyridyl ,phenyl) propylamino WO 98/24782 PTU9/29 PCTIUS97/22390 4-trifluoro- 2-amino-4- (1-methyl-3methylphenyl _pyridyl phenyl) propylamino 3-trifluoro- 2-amino-4- (1-methyl-3inethylphenyl pyridyl phenyl )propylamino 2,6- 2-antino-4- (1-methyl-3dichiorophenyl pyridyl phenyl )propylamino 2, 6-dimethyl 2-amino-4- (1-rethyl-3phenyl pyridyl phenyl)propylanino 3,4- 2-amino-4- (1-rethyl-3dichlorophenyl pyridyl phenyl )propylamino 3, 4-dirnethyl 2-amino-4- (1-methyl-3phenyl _pyridyl _phenyl) propylamino 2,4-2-ainino-4- (1-methyl-3dichlorophenyl _pyridyl phenyl) propylamino 2, 4-dimethyl 2-amino-4- (1-methyl-3phnl- pyridyl phenyl propylamino Phenyl2-acetainido- Cl-methyl-3- 4 -pyrid~yl pheny1) propylaiino 4-f luorophenyl 2-acetamido- (l-methyl-3- 4 -pyridyl phenyl propylainino 3-f luorophenyl 2-acetamido- (1-methyl-3- 4 -pyridyl phenyl )propylamino 2-f luoropheny. 2-acetainido- (1-rethyl-3- 4 -pyridyl phenyl) propylamino 4-chiorophenyl 2-acetamido- (1-methyl-3- 4 -pyridyl phenyl )propylamino 3-chilorophenyl 2-acetarnido- (1-methyl-3- 4-pyridyl phenyl propylamino 2-chiorophenyl 2-acetamido- .(1-methyl-3- 4 -pyridyl phenyl propylainino 4-tolyl 2-acetamido- (1-methyl-3- -pyridyl pheniyl )propylamino 3-tolyl 2-acetamido- (1-methyl-3- -pyridyl phenyl propylainino 2-tolyl 2-acetamido- (1-methyl-3- -pyridyl phenyl )propylainino 4-trifluoro- 2-acetamido- (1-methyl-3methylphenyl 4 -pyridyl phenyl propylamino 3-trifluoro- 2-acetaiid- (l-methyJ.-3methyiphenyl 4 -pyridy1 phenyl )propylamino 2,6-2-acetanido- (1-methyl-3dichiorophenyl 4-pyridyl phenyl)propylamino 2, 6-dimethyl 2-acetamido- (1-methyl-3phenl4 -pyridyl _phenyl )propylamino 3,4- 2-acetamido- (1-methyl-3dichioropheny1 4-pyridyl phenyl) propylamino 3, 4-dimethyl 2-acetamido- (1-methyl-3phenyl 4 -pyridyl phenyl )propylamino 2,4- 2-acetamido- (1-methyl-3dichlorophenyl 4 -pyridyl phenyl )propylamino 2, 4-diinethyl 2-acetamido- (1-rnethyl--3pheny. 4-pyridyl phenyl )propylamino Phenyl 2 -amino-4 (1 -me thyl -3 phenyl )propylamino WO 98/24782 WO 9824782PCTIUS97/22390 4-f luorophenyl 2-amino-4- (1-rethyl-3pyrimidinyl phenyl) propylainino 3-fluorophenyl 2-amino-4- (1-methyl-3pyrimidinyl _phenyl )propylamino 2-f luorophenyl 2-axnino-4- (1-methyl-3pyrimidinyl phenyl) propylamino 4-chiorophenyl 2-amino-4- (1-iethyl-3ph1enyl )propylainino 3-chiorophenyl 2-amino-4- (1-rethyl-3pyrimidinyl phenyl) propylamino 2-chlorophenyl 2-axnino-4- (1-methyl-3pyrimidinyl phenyl) propylarnino 4-tolyl 2-amino-4- (1-methyl-3phenyl) propylamino 3-tolyl 2-amino-4- (1-methyl-3pyrimidinyl _phenyl) propylamino 2-tolyl 2-amino-4- (1-rethyl-3phenyl) propylainino 4-trifluoro- 2-amino-4- (1-methyl-3methylphenyl pyrimidinyl phenyl) propylamino 3-trifluoro- 2-amino-4- (l-methyl-3methylphenyl _pyrimidinyl phenyl )propylamino 2,6- 2-amino-4- (1-rnethyl--3dichiorophenyl pyrimidinyl phenyl) propylamino 2, 6-dimethyl 2-arnino-4- (1-rethyl-3phenyl pyrirnidinyl phenyl) propylamino 3,4- 2-ainino-4- (1-methyl-3dichlorophenyl _pyrimidinyl _phenyl-)propylamino 3, 4-dimethy. 2-amino-4- (1-methyl-3phenyl pyrimidinyl phenyl) propylamino 2,4- 2-amino-4- (1-methyl-3dichlorophenyl pyrimidinyl phenyl) propylamino 2, 4-dimethyl 2-amino-4- (1-methyl-3pyrimidinyl phenyl) propylamino 4-f luorophenyl -4-pyridyl 4-f luorobenzylamino 4-f luorophenyl 2-acetainido- 4-f luorobenzyilamino -pyridyl 4-f luorophenyl 2-amino-4- 4-f luorobenzylamino pyrimidinyl 4-f luorophenyl 4-pyridylnyl (4-f luorophenyl) -1methyl-ethyl) amino 4-f luorophenyl 2-acetamido- (2-(4-fluorophenyl) -1- 4-pyridyl methyl-ethyl) amino 4-f luorophenyl 2-amrino-4- (2-(4-fluorophenyl) -1pyrimidinyl methyl-ethyl) amino 4-f luorophenyl 4-pyridyl 1-dimethyl-2- (4fluorophenyl) -ethyl) amino 4-f luorophenyl 2-acetamido- (1,1-dimethyl-2-(4- 4-pyridyl fluoropheny1)-ethyl) amino 4-fluorophenyl 2-ainino-4- (l,1-dimethyl-2-(4fluorop-henyl) -ethyl) amino 4-f luorophenyl 4-pyridyl 2- (4-f luorophenyl) -2- I nmthyln -ethylaino WO 98/24782 WO 9824782PCTIUS97/22390 4-f luorophenyl 2-acetamido- (4-f luorophenyl) -2- 4-pyridyl methyl -ethyl) amino 4-f luorophenyl 2-amino-4- (2-(4-fluorophenyl) -2pyrimidinyl me thyl -ethyl) amino 4-f luorophenyl 4-pyridyl (2-methyl-2phenylethyl) amino 4-f luorophenyl 2-acetamido- (2-methyl-2- 4-pyridyl phenylethyl) amino 4-f luorophenyl 2-amino-4- (2-methyl-2pyrimidinyl phenylethyl) amino 4-f luorophenyl 4-pyridyl methyl- (2heyethyl) amino 4-f luorophenyl 2-acetainido- methyl- (2- 4-pyridyl phenylethyl) amino 4-f luorophenyl 2-amino-4- methyl- (2pyrimidinyl phenylethyl)amino 4-f luorophenyl 4-pyridyl (4-trifluoromethyl 4-f luorophenyl 2-acetamido- (4-trifluoromethyl -pyridyl phenyl) ethyl) amino 4-fluorophenyl 2-amino-4- 2 -tri fluorome thyl pyrimidinyl phenyl) ethyl) amino 4-f luorophenyl 4-pyridyl 2- (4-tolyl) ethylamino 4-f luorophenyl 2-acetamido- 2- (4-tolyl) ethylamino 4 -pyridyl 4-f luorophenyl 2-amino-4- 2 4 t olyl) ethyl amino pyrimidinyl 4-f luorophenyl 4-pyridyl (2 (3 -f luorophenyl) ethyl) amino 4-f luorophenyl 2-acetaxnido- (2 (3 -f luorophenyl) 4-pyridyl ethyl) amino 4-f luorophenyl 2-amino-4- (2 (3 -f luorophenyl) pyrimidinyl ethyl) amino 4 -fluorophenyl 4-pyridyl (2-f luorophenyl) ethyl) amino 4 -fluorophenyl 2-acetamido- (2-f luorophenyl) 4-pyridyl ethyl) amino 4 -fluorophenyl 2-amino-4- (2 fluorophenyl) pyrimidinyl ethyl) amino 4 -fluorophenyl 4-pyridyl methyl- (2- 4 -fluorophenyl 2-acetamido- methyl- (2- 4-pyridyl pyridyl) ethyl) amino 4 -fluorophenyl 2-axnino-4- methyl pyrimidinyl pyridy ethyl) amino 4 -fluorophenyl 4-pyridyl 1- dimethyl -3 -phenyl propyl) amino 4 -fluorophenyl 2-acetamido- l-dimethyl-3-phenyl- 4-pyridyl propyl )amino 4 -fluorophenyl 2-amino-4- l-dimethyl-3-phenylpyrimidinyl propyl )amino 4-f luorophenyl 4-pyridyl (4-f luorophenyl) __propyl) amino WO 98/24782 WO 9824782PCTIUS97/22390 4-f luorophenyl 2-acetainido- (4-f luorophenyl) propyl) amino 4-f luorophenyl 2-amino-4- (4-f luorophenyl) propyl) amino 4-f luorophenyl 4-pyridyl (4-f luorophenyl) -1methyl -propyl) amino 4-f luorophenyl 2-acetainido- (4-f luorophenyl) -1methyl -propyl) amino 4-fluorophenyl 2-amino-4- 3 -(4-fluorophenyl) -1pyrimidinyl methyl -propyl) amino 4-f luorophenyl 4-pyridyl (1,l-dimethyl-3-(4-fluoro phenyl) -propyl)amino 4-f luorophenyl 2-acetamido- l-dimethyl-3- (4-f luoro 4-pyridyl phenyl) -propyl) amino 4-f luorophenyl 2-amino-4- (l,l-dimethyl-3- (4-f luoro pyrimidinyl phenyl) -propyl) amino 4-f luorophenyl 4-pyridyl (2-f luorophenyl) propyl) amino 4-f luorophenyl 2-acetainido- (2-f luorophenyl) 4-pyridyl propyl) amino 4-f luorophenyl 2-amino-4- (2-f luorophenyl) pyrimidinyl propyl) amino 4-f luorophenyl 4-pyridyl (3-methyl-3-phenylpropy1) amino 4-f luorophenyl 2-acetamido- (3-methyl-3-phenyl- 4-pyridyl propyl) amino 4-f luorophenyl 2-amino-4- (3-methyl-3-phenylpyrimidinyl _propyl) amino 4-f luorophenyl 4-pyridyl (2-methyl-3-phenylamino 4-f luorophenyl 2-acetamido- (2-methyl-3-phenyl- _propyl) amino 4-f luorophenyl 2-amino-4- (2-methyl-3-phenylpyrimidinyl propyl) amino 4-f luorophenyl 4-pyridyl 3 -dimethylbutyl) amino 4-f luorophenyl 2-acetamido- 3 -d-imethylbutyl) amino 4-pyridyl 4-f luorophenyl 2-amino-4- 3 -dimethylbutyl) amino pyrimidinyl 4-f luorophenyl _4-pyridyl isoamylamino 4-f luorophenyl 2 -acetamido- isoamylamino 4-pyridyl 4-f luorophenyl 2-amino-4- isoamylamino pyrimidinyl 4-f luorophenyl 4-pyridyl amylainino 4-f luorophenyl 2-acetamido- amylamino 4 -py3ridyl 4-f luorophenyl 2-ainino-4- amylamino pyrimidinyl 4-f luorophenyl 4-pyridyl 5-dimethy1) pentylamino 4-f luorophenyl 2-acetamido- 5 -dimethyl) pentylamino 4 -pyridyl_ 4-f luorophenyl 2-amino-4- 5 -dimethyl) pentylamino pyrimidinyl WO 98/24782 WO 9824782PCTIUS97/22390 4-f luorophenyl 4-pyridyl piperazinyl 4-f luorophenyl 2-acetamido- piperazinyl 4-pyridyl 4-f luorophenyl 2-amino-4- piperazinyl 4-f luorophenyl 4-pyridyl (3 (3 -f luorophenyl) propyl) amino 4-f luorophenyl 2-acetamido- (3 (3 -f luorophenyl) -pyridyl propyl) amino 4-f luorophenyl 2-amino-4- (3 (3 -f luorophenyl) pyrimidinyl _propyl) amino benzyl 4-pyridyl 3 peylpropylamino benzyl 4-pyridyl 2 (4 -f luorophenyl) ethylamino 2-thienyl 4-pyridyl 3 -phenyiproy lamino 2-thienyl 4-pyridyl 2 (4 -f luorophenyl) -ethylamino cyc lohexyl 4 -pyridyl 3 -phenyipropyl amino cyclohexyl 4-pyridyl 2 (4 -f luorophenyl) ethyl amino tert-butyl 4-pyridyl 3 -phenyipropyl amino tert-butyl 4-pyridyl 2 (4 -f luorophenyl) ethyl amino 4-f luorophenyl 4- 3 -phenyipropyl amino piperidinyl 4-f luorophenyl 4- 2 (4 -f luorophenyl) piperidinyl ethylamino 4-f luorophenyl 4 -pyranyl 3 -phenylpropylamino 4-f luorophenyl 4-pyranyl 2 (4 -f 1luorophenyl) Phenyl 4-pyridyl 3-phenyl-2-aminoamino 4-f luorophenyl 4-pyridyl 3 -phenyl-2 -amino- ____________propylamino 3-f luorophenyl 4-pyridyl 3-phenyl-2-aminoamino 2-f luorophenyl 4-pyridyl 3-phenyl-2-aminopropylamino 4-chiorophenyl 4-pyridyl 3 -phenyl-2-aminopropyl amino 3 -chiorophenyl 4-pyridyl 3 -phenyl-2-aminopropyl amino 2-chlorophenyl 4-pyridyl 3 -phenyl-2 -aminopropyl amino 4-tolyl 4-pyridyl 3 -phenyl-2 -aminopropyl amino 3-tolyl 4-pyridyl 3 -phenyl-2 -amninopropylamino 2-tolyl 4-pyridyl 3 -phenyl-2 -aminopropylamino 4-trifluoro- 4-pyridyl 3 -pheriyl-2-aminomethyiphenyl ______propylamino 3-LI. ±.lu.Lorome thylpheny2.
'4-pyridyl .3 -ptlenyl-2 -aminopropyl amino WO 98/24782 WO 9824782PCTIUS97/22390 2,6- 4-pyridyl 3-phenyl--2-aminodichiorophenyl _______propylanino 2, 6-dimethyl 4-pyridyl 3 -phenyl-2-aminophenyl amino 3,4- 4-pyridyl 3 -phenyl-2-aminodichlorophenyl _______propylamino 3, 4-dimethyl 4-pyridyl 3-phenyl-2-aninophenylpropylanino 2,-4-pyridyl 3-phenyl-2-aninodichlorophenyl _______propylanino 2, 4-dimethyl 4-pyridyl 3-phenyl-2-aninophenyl propyl amino Phnl4-pyridyl 3 -phenyl-3 -amino- ___________propylamino 4-f luorophenyl 4 -pyridy. 3 -phenyl-3 -aminopropylamino 3-f luorophenyl 4-pyridyl 3-pheriyl-3-aminopropyl amino 2-f luoropheny. 4-pyridyl 3-phenyl-3-aminopropylamino 4-chiorophenyl 4-pyridyl 3-phenyl-3-aminopropylamino 3 -chiorophenyl 4-pyridyl 3-phenyl-3-aminopropylanino 2 -chiorophenyl 4-pyridyl 3 -phenyl-3 -aminopropylanino 4-o l4 -pyridyl 3 -phenyl-3 -aminopropylamino 3-o l4 -pyridyl1 3 -phenyl-3 -amino- ___________propylamino 2-oll4-pyridyl 3-phenyl-3 -aminopropylamino 4-trifluoro- 4-pyridyl 3-phenyl-3-aminomethyiphenyl propylamino 3-trifluoro- 4-pyridyl 3-phenyl-3-aminomethylphenyl _______propylamino 2,6- 4-pyridyl 3-phenyl-3-aminodichlorophenyl propylamino 2, 6-dimethy. 4-pyridyl 3-phenyl-3-aminophenyl propylamino 3,4- 4-pyridyl 3-phenyl-3-aminodichlorophenyl propylamino 3, 4-dimethyl 4-pyridyl 3-phenyl-3-aminophenyl amino 2,4- 4-pyridyl 3-phenyl-3-aminodichlorophenyl ______propylamino 2, 4-dimethyl 4-pyridyl 3-phenyl-3-aminophenyl propylamino 3-f luorophenyl 4-pyridyl -tetrahydroisoquinol- -ylmethylenamino 2-f luoropheny. 2-amino-4- 3 -benzylpiperazinyl pyridyl 3-chiorophenyl 2-acetamido- CS) 2 -N-isopropylamino-3- 14-pyridyl lphenylpropylamino WO 98/24782 WO 9824782PCT1US97/22390 2-chiorophenyl 2-amino-4- -2-N-glycylamino-3pyrimi dinyl phenylpropylamino 4-tolyl 4-pyridyl -2 -amino-3 phenylpropylamino 3-tolyl 2-ainino-4- (R)-2-amino-3pyridyl phenylpropylamino 2-tolyl 2-acetamido- 3-amino--3- 4 -pyridyl _phenylpropyl amino 4-trifluoro- 2-amino-4- (S)-2-amino-3-(2mnethypel pyrimidinyl fluorophenyl )propylamn 3-trifluoro- 4-pyridyl -2-ainino-3- (2methylphenyl _______methyiphenyl) propylanino 2,16- 2-amino-4- 3-amino-3-(2dichiorophenyl pyridyl fluorophen 1)propylaiino 2, 6-dimethyl 2-acetamido- 3-amino-3- (2phenyl 4 -pyridyl methyiphenyl) propyl amino 3,4- 2-amino-4- 2-amino-2-methyl-3dichlorophenyl pyrimidinyl phenylpropylamino 3, 4-dimethyl 4-pyridyl 3-amino-2-methyl-3phenyl phenyipropyl amino 3-fluorophenyl 2-amino-4- -2-amino-3phenylpropyl amino 2-fluorophenyl 2-acetainido- (S)-2-amino-3- (2- 4-pyridyl f luorophenyl propylamino 3-chiorophenyl 2-amino-4- -2-amino-3- (2methylphenyl) propylamino 2-chiorophenyl 4-pyridyl -2-N-isopropylamino-3- _phenylpropyl amino 4-tolyl 2-amino-4- -2-N-glycylamino-3pyridyl phenylpropylamino 3-tolyl 2-acetamido- 2-amino-2-methyl-3- -pyridyl phenylpropylamino 2-tolyl 2-amino-4- -2-amino-3phenyipropylamino 4-trifluoro- 4-pyridyl 3-amino-3methylphenyl _______phenylpropyl amino 3-trifluoro- 2 -ami no 3-amino-3- (2methylphenyl pridyl fluorophenyl) propylamino 2,6- 2-acetamido- 3-amino-3- (2dichioropheny 1 4-pyridyl methy1 heny1) propylamino 2, 6-dimethyl 2-amino-4- 3-amino-2-methyl-3phenyl pyrimidinyl _phenylpropyl amino 3, 4- 4-pyridyl -tetrahydroisoquinoldichiorophenyl -ylmethylenamino 3, 4-dimethyl 4-pyridyl 3-benzylpiperaz inyl phenyl 1 Additional preferred compounds are listed in the Examples, inifra.
As utilized herein, the following terms shall have the following meanings: WO 98/24782 PCT/US97/22390 74 "Alkyl", alone or in combination, means a straight-chain or branched-chain alkyl radical containing preferably 1carbon atoms (C 1
-C
15 more preferably 1-8 carbon atoms (CI-C 8 even more preferably 1-6 carbon atoms
(C
1
-C
6 yet more preferably 1-4 carbon atoms (C 1
-C
4 still more preferably 1-3 carbon atoms (C 1
-C
3 and most preferably 1-2 carbon atoms (Ci-C 2 Examples of such radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isoamyl, hexyl, octyl and the like.
"Hydroxyalkyl", alone or in combination, means an alkyl radical as defined above wherein at least one hydrogen radical is replaced with a hydroxyl radical, preferably 1-3 hydrogen radicals are replaced by hydroxyl radicals, more preferably 1-2 hydrogen radicals are replaced by hydroxyl radicals, and most preferably one hydrogen radical is replaced by a hydroxyl radical. Examples of such radicals include hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 1,3-dihydroxy-2-propyl, 1,3dihydroxybutyl, 1,2,3,4,5,6-hexahydroxy-2-hexyl and the like.
"Alkenyl", alone or in combination, means a straightchain or branched-chain hydrocarbon radical having one or more double bonds, preferably 1-2 double bonds and more preferably one double bond, and containing preferably 2-15 carbon atoms (C 2
-C
15 more preferably 2-8 carbon atoms (C 2
-C
8 even more preferably 2-6 carbon atoms (C 2
-C
6 yet more preferably 2-4 carbon atoms (C 2
-C
4 and still more preferably 2-3 carbon atoms (C 2
-C
3 Examples of such alkenyl radicals include ethenyl, propenyl, 2 -methylpropenyl, 1,4butadienyl and the like.
WO 98/24782 PCT[~S97/22390 "Alkoxy", alone or in combination, means a radical of the type wherein is an alkyl radical as defined above and is an oxygen atom. Examples of such alkoxy radicals include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tertbutoxy and the like.
"Alkoxycarbonyl", alone or in combination, means a radical of the type wherein is an alkoxy radical as defined above and is a carbonyl radical.
"Alkoxycarbonylamino", alone or in combination, means a radical of the type wherein is an alkoxycarbonyl radical as defined above, wherein the amino radical may optionally be substituted, such as with alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl and the like.
"Alkylthio", alone or in combination, means a radical of the type wherein is an alkyl radical as defined above and is a sulfur atom. Examples of such alkylthio radicals include methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, iso-butylthio, sec-butylthio, tert-butylthio and the like.
"Alkylsulfinyl", alone or in combination, means a radical of the type wherein is an alkyl radical as defined above and is a mono-oxygenated sulfur atom. Examples of such alkylsulfinyl radicals include methylsulfinyl, ethylsulfinyl, n-propylsulfinyl, isopropylsulfinyl, n-butylsulfinyl, iso-butylsulfinyl, sec-butylsulfinyl, tert-butylsulfinyl and the like.
"Alkylsulfonyl", alone or in combination, means a radical of the type wherein is an alkyl radical as defined above and "S(0) 2 is a di-oxygenated WO 98/24782 PCT/US97122390 76 sulfur atom. Examples of such alkylsulfonyl radicals include methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, n-butylsulfonyl, iso-butylsulfonyl, sec-butylsulfonyl, tert-butylsulfonyl and the like.
"Aryl', alone or in combination, means a phenyl or biphenyl radical, which is optionally benzo fused or heterocyclo fused and which is optionally substituted with one or more substituents selected from alkyl, alkoxy, halogen, hydroxy, amino, azido, nitro, cyano, haloalkyl, carboxy, alkoxycarbonyl, cycloalkyl, alkanoylamino, anido, amidino, alkoxycarbonylamino,
N-
alkylamidino, alkylamino, dialkylamino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, N-alkylamido, N,Ndialkylamido, aralkoxycarbonylamino, alkylthio, alkylsulfinyl, alkylsulfonyl, oxo and the like.
Examples of aryl radicals are phenyl, o-tolyl, 4methoxyphenyl, 2- (tert-butoxy) phenyl, 3-methyl-4methoxyphenyl, 2-CF3-phenyl, 2-fluorophenyl, 2chlorophenyl, 3-nitrophenyl, 3-aminophenyl, 3acetamidophenyl, 2-amino-3-(aminomethyl)phenyl, 6methyl-3-acetamidophenyl, 6-methyl-2-aninophenyl, 6methyl-2,3-diaminophenyl, 2-amino-3-methylphenyl, 4,6dimethyl-2-aminophenyl, 4-hydroxyphenyl, 3-methyl-4hydroxyphenyl, 4- (2 -methoxyphenyl) phenyl, 2 -amino-inaphthyl, 2-naphthyl, 3-amino-2-naphthyl, l-methyl-3amino- 2-naphthyl, 2, 3-diamino-l-naphthyl, 4, 8-dimethoxy- 2-naphthyl and the like.
"Aralkyl" and "arylalkyl", alone or in combination, means an alkyl radical as defined above in which at least one hydrogen atom, preferably 1-2, is replaced by an aryl radical as defined above, such as benzyl, 2phenylethyl, dibenzylmethyl, hydroxyphenylmethyl, methylphenylmethyl, diphenylmethyl, dichlorophenylmethyl, 4-methoxyphenylmethyl and the like.
WO 98/24782 PCTIUS97/22390 77 "Aralkoxy", alone or in combination, means an alkoxy radical as defined above in which at least one hydrogen atom, preferably 1-2, is replaced by an aryl radical as defined above, such as benzyloxy, 2 -phenylethoxy, dibenzylmethoxy, hydroxyphenylmethoxy, methylphenylmethoxy, dichlorophenylmethoxy, 4methoxyphenylmethoxy and the like.
"Aralkoxycarbonyl", alone or in combination, means a radical of the type wherein is an aralkoxy radical as defined above and is a carbonyl radical.
"Alkanoyl", alone or in combination, means a radical of the type wherein is an alkyl radical as defined above and is a carbonyl radical.
Examples of such alkanoyl radicals include acetyl, trifluoroacetyl, hydroxyacetyl, propionyl, butyryl, valeryl, 4-methylvaleryl, and the like.
"Alkanoylamino", alone or in combination, means a radical of the type wherein is an alkanoyl radical as defined above, wherein the amino radical may optionally be substituted, such as with alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl and the like.
"Aminocarbonyl", alone or in combination, means an amino substituted carbonyl (carbamoyl) radical, wherein the amino radical may optionally be mono- or di-substituted, such as with alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, alkanoyl, alkoxycarbonyl, aralkoxycarbonyl and the like.
"Aminosulfonyl", alone or in combination, means an amino substituted sulfonyl radical.
WO 98/24782 PCT/US97/22390 78 "Benzo", alone or in combination, means the divalent radical C6H4= derived from benzene. "Benzo fused" forms a ring system in which benzene and a cycloalkyl or aryl group have two carbons in common, for example tetrahydronaphthylene and the like.
"Bicyclic" as used herein is intended to include both fused ring systems, such as naphthyl and 9-carbolinyl, and substituted ring systems, such as biphenyl, phenylpyridyl and diphenylpiperazinyl.
"Cycloalkyl", alone or in combination, means a saturated or partially saturated, preferably one double bond, monocyclic, bicyclic or tricyclic carbocyclic alkyl radical, preferably monocyclic, containing preferably 12 carbon atoms (C 5
-C
12 more preferably 5-10 carbon atoms (C 5
-C
10 even more preferably 5-7 carbon atoms
(C
5
-C
7 which is optionally benzo fused or heterocyclo fused and which is optionally substituted as defined herein with respect to the definition of aryl. Examples of such cycloalkyl radicals include cyclopentyl, cyclohexyl, dihydroxycyclohexyl, ethylenedioxycyclohexyl, cycloheptyl, octahydronaphthyl, tetrahydronaphthyl, octahydroquinolinyl, dimethoxytetrahydronaphthyl, 2,3-dihydro-lH-indenyl, azabicyclo[3.2.1]octyl and the like.
"Heteroatoms" means nitrogen, oxygen and sulfur heteroatoms.
"Heterocyclo fused" forms a ring system in which a heterocyclyl or heteroaryl group of 5-6 ring members and a cycloalkyl or aryl group have two carbons in common, for example indole, isoquinoline, tetrahydroquinoline, methylenedioxybenzene and the like.
WO 98/24782 PCT/US97/22390 79 "Heterocyclyl" means a saturated or partially unsaturated, preferably one double bond, monocyclic or bicyclic, preferably monocyclic, heterocycle radical containing at least one, preferably 1 to 4, more preferably 1 to 3, even more preferably 1-2, nitrogen, oxygen or sulfur atom ring member and having preferably 3-8 ring members in each ring, more preferably 5-8 ring members in each ring and even more preferably 5-6 ring members in each ring. "Heterocyclyl" is intended to include sulfone and sulfoxide derivatives of sulfur ring members and N-oxides of tertiary nitrogen ring members, and carbocyclic fused, preferably 3-6 ring carbon atoms and more preferably 5-6 ring carbon atoms, and benzo fused ring systems. "Heterocyclyl" radicals may optionally be substituted on at least one, preferably 1- 4, more preferably 1-3, even more preferably 1-2, carbon atoms by halogen, alkyl, alkoxy, hydroxy, oxo, thioxo, aryl, aralkyl, heteroaryl, heteroaralkyl, amidino, Nalkylamidino, alkoxycarbonylamino, alkylsulfonylamino and the like, and/or on a secondary nitrogen atom by hydroxy, alkyl, aralkoxycarbonyl, alkanoyl, alkoxycarbonyl, heteroaralkyl, aryl or aralkyl radicals.
More preferably, "heterocyclyl", alone or in combination, is a radical of a monocyclic or bicyclic saturated heterocyclic ring system having 5-8 ring members per ring, wherein 1-3 ring members are oxygen, sulfur or nitrogen heteroatoms, which is optionally partially unsaturated or benzo-fused and optionally substituted by 1-2 oxo or thioxo radicals. Examples of such heterocyclyl radicals include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiamorpholinyl, 4 -benzyl-piperazin-l-yl, pyrimidinyl, tetrahydrofuryl, pyrazolidonyl, pyrazolinyl, pyridazinonyl, pyrrolidonyl, tetrahydrothienyl and its sulfoxide and sulfone derivatives, 2,3-dihydroindolyl, tetrahydroquinolinyl, 1,2, 3 4 -tetrahydroisoquinolinyl, 1,2,3,4-tetrahydro-l- WO 98/24782 PCT/US97/22390 oxo-isoquinolinyl, 2,3-dihydrobenzofuryl, benzopyranyl, methylenedioxyphenyl, ethylenedioxyphenyl and the like.
"Heteroaryl" means a monocyclic or bicyclic, preferably monocyclic, aromatic heterocycle radical, having at least one, preferably 1 to 4, more preferably 1 to 3, even more preferably 1-2, nitrogen, oxygen or sulfur atom ring members and having preferably 5-6 ring members in each ring, which is optionally saturated carbocyclic fused, preferably 3-4 carbon atoms (C 3
-C
4 to form 5-6 ring membered rings and which is optionally substituted as defined above with respect to the definitions of aryl. Examples of such heteroaryl groups include imidazolyl, l-benzyloxycarbonylimidazol-4-yl, pyrrolyl, pyrazolyl, pyridyl, 3-(2-methyl)pyridyl, 3-(4trifluoromethyl)pyridyl, pyrimidinyl, 5-(4trifluoromethyl)pyrimidinyl, pyrazinyl, triazolyl, furyl, thienyl, oxazolyl, thiazolyl, indolyl, quinolinyl, 5,6,7,8-tetrahydroquinolyl, 5,6, 7 ,8-tetrahydroisoquinolinyl, quinoxalinyl, benzothiazolyl, benzofuryl, benzimidazolyl, benzoxazolyl and the like.
"Heteroaralkyl" and "heteroarylalkyl," alone or in combination, means an alkyl radical as defined above in which at least one hydrogen atom, preferably 1-2, is replaced by a heteroaryl radical as defined above, such as 3-furylpropyl, 2-pyrrolyl propyl, chloroquinolinylmethyl, 2-thienylethyl, pyridylmethyl, 1-imidazolylethyl and the like.
"Halogen" and "halo", alone or in combination, means fluoro, chloro, bromo or iodo radicals.
"Haloalkyl", alone or in combination, means an alkyl radical as defined above in which at least one hydrogen atom, preferably 1-3, is replaced by a halogen radical, more preferably fluoro or chloro radicals. Examples of such hal.oalkyl radicals include 1, 1, -trifluoroethyl, chloromethyl, l-bromoethyl, fluoromethyl, difluoromethyl,- trifluoromethyl, bis(trifluoromethyl)methyl and the like.
"4 (3H)-pyrimidinone" and "4-hydroxy-pyrimidine
(B)
are names of two tautomers of the same compound which may be used interchangeably. It is intended that the use of one of these terms inherently includes the other.
0
OH
NH N N
N
(B)
"Pharmaceuticadlly-acceptable salt" means a salt prepared by conventional means, and are well known by those skilled in the art. The "pharmacologically :acceptable salts" include basic salts of inorganic and organic acids, including but not limited to hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, ethanesulfonic acid, malic acid, acetic acid, oxalic acid, tartaric acid, citric acid, lactic acid, fumaric acid, succinic acid, maleic acid, salicylic acid, benzoic acid, phenylacetic acid, mandelic acid and the like. When compounds of the invention include an acidic function such as a carboxy group, then suitable pharmaceutically acceptable cation pairs for the carboxy group are well known to those skilled in the art and include alkaline, alkaline earth, ammonium, quaternary ammonium cations and the like. For additional examples of "pharmacologically acceptable ST salts, see infra and Berge et al, J. Pharm. Sci. 66, 1 1A (1977).
WO 98/24782 PCT/US97/22390 82 "Cytokine" means a secreted protein that affects the functions of other cells, particularly as it relates to the modulation of interactions between cells of the immune system or cells involved in the inflammatory response. Examples of cytokines include but are not limited to interleukin 1 preferably IL-fI, interleukin 6 interleukin 8 (IL-8) and TNF, preferably TNF-a (tumor necrosis factor-a).
"TNF, IL-1, IL-6, and/or IL-8 mediated disease or disease state" means all disease states wherein TNF, IL- 1, IL-6, and/or IL-8 plays a role, either directly as TNF, IL-1, IL-6, and/or IL-8 itself, or by TNF, IL-1, IL-6, and/or IL-8 inducing another cytokine to be released. For example, a disease state in which IL-1 plays a major role, but in which the production of or action of IL-1 is a result of TNF, would be considered mediated by TNF.
"Leaving group" generally refers to groups readily displaceable by a nucleophile, such as an amine, a thiol or an alcohol nucleophile. Such leaving groups are well known in the art. Examples of such leaving groups include, but are not limited to, N-hydroxysuccinimide, N-hydroxybenzotriazole, halides, triflates, tosylates and the like. Preferred leaving groups are indicated herein where appropriate.
"Protecting group" generally refers to groups well known in the art which are used to prevent selected reactive groups, such as carboxy, amino, hydroxy, mercapto and the like, from undergoing undesired reactions, such as nucleophilic, electrophilic, oxidation, reduction and the like. Preferred protecting groups are indicated herein where appropriate. Examples of amino protecting groups include, but are not limited to, aralkyl, substituted aralkyl, cycloalkenylalkyl and substituted cycloalkenyl WO 98/24782 PCT/US97/22390 83 alkyl, allyl, substituted allyl, acyl, alkoxycarbonyl, aralkoxycarbonyl, silyl and the like. Examples of aralkyl include, but are not limited to, benzyl, orthomethylbenzyl, trityl and benzhydryl, which can be optionally substituted with halogen, alkyl, alkoxy, hydroxy, nitro, acylamino, acyl and the like, and salts, such as phosphonium and ammonium salts. Examples of aryl groups include phenyl, naphthyl, indanyl, anthracenyl, 9- (9-phenylfluorenyl), phenanthrenyl, durenyl and the like.
Examples of cycloalkenylalkyl or substituted cycloalkylenylalkyl radicals, preferably have 6-10 carbon atoms, include, but are not limited to, cyclohexenyl methyl and the like. Suitable acyl, alkoxycarbonyl and aralkoxycarbonyl groups include benzyloxycarbonyl, tbutoxycarbonyl, iso-butoxycarbonyl, benzoyl, substituted benzoyl, butyryl, acetyl, tri-fluoroacetyl, tri-chloro acetyl, phthaloyl and the like. A mixture of protecting groups can be used to protect the same amino group, such as a primary amino group can be protected by both an aralkyl group and an aralkoxycarbonyl group. Amino protecting groups can also form a heterocyclic ring with the nitrogen to which they are attached, for example, 1,2-bis(methylene)benzene, phthalimidyl, succinimidyl, maleimidyl and the like and where these heterocyclic groups can further include adjoining aryl and cycloalkyl rings. In addition, the heterocyclic groups can be mono-, di- or tri-substituted, such as nitrophthalimidyl.
Amino groups may also be protected against undesired reactions, such as oxidation, through the formation of an addition salt, such as hydrochloride, toluenesulfonic acid, trifluoroacetic acid and the like. Many of the amino protecting groups are also suitable for protecting carboxy, hydroxy and mercapto groups. For example, aralkyl groups. Alkyl groups are also sutiable groups for protecting hydroxy and mercapto groups, such as tertbutyl.
WO 98/24782 PCTIUS97/22390 84 Silyl protecting groups are silicon atoms optionally substituted by one or more alkyl, aryl and aralkyl groups. Suitable silyl protecting groups include, but are not limited to, trimethylsilyl, triethylsilyl, tri-isopropylsilyl, tertbutyldimethylsilyl, dimethylphenylsilyl, 1,2bis(dimethylsilyl)benzene, 1,2-bis(dimethylsilyl)ethane and diphenylmethylsilyl. Silylation of an amino groups provide mono- or di-silylamino groups. Silylation of aminoalcohol compounds can lead to a N,N,O-tri-silyl derivative. Removal of the silyl function from a silyl ether function is readily accomplished by treatment with, for example, a metal hydroxide or ammonium flouride reagent, either as a discrete reaction step or in situ during a reaction with the alcohol group.
Suitable silylating agents are, for example, trimethylsilyl chloride, tert-buty-dimethylsilyl chloride, phenyldimethylsilyl chloride, diphenylmethyl silyl chloride or their combination products with imidazole or DMF. Methods for silylation of amines and removal of silyl protecting groups are well known to those skilled in the art. Methods of preparation of these amine derivatives from corresponding amino acids, amino acid amides or amino acid esters are also well known to those skilled in the art of organic chemistry including amino acid/amino acid ester or aminoalcohol chemistry.
Protecting groups are removed under conditions which will not affect the remaining portion of the molecule. These methods are well known in the art and include acid hydrolysis, hydrogenolysis and the like. A preferred method involves removal of a protecting group, such as removal of a benzyloxycarbonyl group by hydrogenolysis utilizing palladium on carbon in a suitable solvent system such as an alcohol, acetic acid, and the like or mixtures thereof. A t-butoxycarbonyl protecting group can be removed utilizing an inorganic WO 98/24782 PCT/US97/22390 or organic acid, such as HC1 or trifluoroacetic acid, in a suitable solvent system, such as dioxane or methylene chloride. The resulting amino salt can readily be neutralized to yield the free amine. Carboxy protecting group, such as methyl, ethyl, benzyl, tert-butyl, 4methoxyphenylmethyl and the like, can be removed under hydroylsis and hydrogenolysis conditions well known to those skilled in the art.
The symbols used above have the following meanings:
R
x R 0
-CRXR
y X Y
R
I
R x
N
-NRxYR -N Ry Ix -NR- N -S(0) 2 Prodrugs of the compounds of this invention are also contemplated by this invention. A prodrug is an active or inactive compound that is modified chemically through in vivo physicological action, such as hydrolysis, metabolism and the like, into a compound of this invention following adminstration of the prodrug to a patient. The suitability and techniques involved in making and using prodrugs are well known by those skilled in the art. For a general discussion of prodrugs involving esters see Svensson and Tunek Drug Metabolism Reviews 165 (1988) and Bundgaard Design of Prodrugs, Elsevier (1985). Examples of a masked carboxylate anion include a variety of esters, such as alkyl (for example, methyl, ethyl), cycloalkyl (for example, cyclohexyl), aralkyl (for example, benzyl, pmethoxybenzyl), and alkylcarbonyloxyalkyl (for example, pivaloyloxymethyl). Amines have been masked as WO 98/24782 PCT/US97/22390 86 arylcarbonyloxymethyl substituted derivatives which are cleaved by esterases in vivo releasing the free drug and formaldehyde (Bungaard J. Med. Chem. 2503 (1989)).
Also, drugs containing an acidic NH group, such as imidazole, imide, indole and the like, have been masked with N-acyloxymethyl groups (Bundgaard Design of Prodrugs, Elsevier (1985)). Hydroxy groups have been masked as esters and ethers. EP 039,051 (Sloan and Little, 4/11/81) discloses Mannich-base hydroxamic acid prodrugs, their preparation and use.
Compounds according to the invention can be synthesized according to one or more of the following methods. It should be noted that the general procedures are shown as it relates to preparation of compounds having unspecified stereochemistry. However, such procedures are generally applicable to those compounds of a specific stereochemistry, where the stereochemistry about a group is or In addition, the compounds having one stereochemistry can often be utilized to produce those having opposite stereochemistry using wellknown methods, for example, by inversion.
Pvrimidines: A general method for the preparation of compounds of formula I involves the condensation of an 1,3dicarbonyl intermediate IV with an N-C-N containing structure such as an amidine V, a guanidine VI or urea VII (Scheme 1; for a review of synthetic methods see D.J. Brown, Heterocyclic Compounds: the Pyrimidines, Chapter 3, 1994, John Wiley Sons).
WO 98/24782 WO 9824782PCTIEJS97/22390 87 Scheme 1 R
H
2
NR
IV V, VI, VII
I
Additionally, as a 1,3-dicarbonyl synthon, a bdimethylamino-a,b-unsaturated ketone IX can be reacted with amidines V or guanidines VI as described (G.E.
Bennett et al., J. Med. Chem. 21, 623-628, 1978).
(Scheme Such b-dimethylamino-a,b-unsaturated ketones IX can be prepared by aminoformylation of an active methylene ketone VIII with Bredereck's reagent, namely, bis(dimethylamino)rnethoxymethane Bredereck et al., Chem. Ber. 101, 41-50 (1968); G. B. Bennett et al., J. Org. Chem. 43, 221-225 (1977)).
Scheme 2 R Me 2
NR
O~eo 0 _Z,"Me 2 N NMe 2 12ON R 1 2 VilRXH2
R
HN
R 11V, V WO 98/24782 PCT/US97/22390 88 Scheme 3 Me2N 0 YF O Me 0 F Me2
N
Ne
N
NMe2 VII
IX
H
2
N
I N V,VI N R According to this approach, Scheme 3 illustrates the conversion of 2-(4-fluorophenyl)-l-(4pyridyl)ethanone (VIII; Sheldrake, Synthetic Communications 23, 1967 (1993)) into the enamine IX.
Intermediate IX may be condensed with a variety of amidines V and guanidines VI to provide 2-substituted (4-fluorophenyl)-4-(4-pyridyl)-pyrimidines
I.
Further ketones VIII may be prepared according to Sheldrake, Synthetic communications 23, 1967-1971 (1993)), by employing other heteroaryl carboxaldehydes as the starting material, such as 2methylpyridine-4-carboxaldehyde, 2,6-dimethylpyridine-4carboxaldehyde (Mathes and Sauermilch, Chem. Ber. 88, 1276-1283 (1955)), quinoline-4-carboxaldehyde, pyrimidine-4-carboxaldehyde, 6-methylpyrimidine-4carboxaldehyde, 2-methylpyrimidine-4-carboxaldehyde, 2,6-dimethylpyrimidine-4-carboxaldehyde (Bredereck et al., Chem. Ber. 97, 3407-3417 (1964)). Furthermore, 2nitropyridin-4-carboxaldehyde may be prepared from 2nitro-4-methylpyridine (Stanonis, J. Org. Chem. 22, 475 (1957))by oxidation of the methyl group (Venemalm et al., Tet. Lett. 34, 5495-5496 (1993)). Its further WO 98/24782 PCT/US97/22390 89 conversion via a ketone VIII would lead to a 2-nitro-4pyridyl derivative I (Scheme Catalytic reduction of the nitro group to an amino group would provide a derivative of I with R" represented by a 2-amino-4pyridyl group. Conventional acetylation of the amino group then leads to the 2-acetamido-4-pyridyl derivative.
Scheme 4 F I F
NR
1 Y NdR 1 N N
NO
2 NH 2 NHAc As displayed in Scheme 5, intermediate IX may also be condensed with urea VII to give the 2(1H)pyrimidinone derivative X. X is transformed into chloride XI by reaction with a halogenating agent such as phosphorous oxychloride. Treatment of chloride XI with primary and secondary amines, thiolates or alcoholates allows the preparation of further pyrimidines I with R1 represented by a substituted N, S or 0 groups, as recited above. Likewise, hydrazines may be reacted with chloride XI to provide 2-hydrazino substituted pyrimidines I.
WO 98/24782 PCT/US97/22390 Scheme
NH
2 0" FO F
NH
2
N
VII
NMe 2 N OH IX N IxX x F F NN N N C N
R
XI
I
Scheme 6
NH
2 O NH
F
NH
2
N
N NMe2 VI R IX N R NH2 I R 1
NR
2 2
C(O)R
2 1 R1 NR22SO 2 Palladium or nickel catalyzed cross couplings of chloride XI with arylboronic acids or arylzinc halides provide compounds of formula I wherein R' is aryl or heteroaryl.
Scheme 6 illustrates the reaction of intermediate IX with guanidine VI to give 2-amino substituted I. 2- Amino I is a useful intermediate for further acylations WO 98/24782 PCT/US97/22390 91 and sulfonylations of the 2-amino group to give acylamido and sulfonamido derivatives.
For the synthesis of 4-hydroxy-pyrimidines II, the approach displayed in Scheme 7 may be followed (for a review of synthetic methods see: D.J. Brown, Heterocyclic Compounds: the Pyrimidines, supra). This approach involves the cyclization reaction between an acrylic acid ester XII and an amidine V followed by oxidation of the resulting dihydropyrimidinone XIII to give II.
Scheme 7
H
2 N R
OH
OR NH 1212 1 12 R V R N R R12 N R 1
XII
XIII
II
For the synthesis of 2-substituted 5-(4fluorophenyl)-6-(4-pyridyl)-4-hydroxy-pyrimidines
II
(Scheme the disubstituted acrylic acid ester XII may be prepared conveniently by condensation of pyridine-4carboxaldehyde with 4-fluorophenylacetic acid followed by esterification. XII may be reacted with a variety of amidines V at elevated temperature. As a dehydrogenating agent for the conversion of XIII to II, sodium nitrite/acetic acid is suitable.
Accordingly, further compounds of formula II may be obtained in which R" is any other heteroaryl ring within the definition of R" by the appropriate choice of starting material. Such starting materials include but are not limited to 2 -methylpyridine-4-carboxaldehyde, 2, 6 -dimethylpyridine-4-carboxaldehyde (Mathes and Sauermilch, Chem. Ber. 88, 1276-1283 (1955)), quinoline- 4-carboxaldehyde, pyrimidine-4-carboxaldehyde, 6methylpyrimidine-4-carbox-aldehyde, 2-methylpyrimidine- 4-carboxaldehyde, 2,6-dimethylpyrimidine-4-carboxaldehyde (Bredereck et al., Chem. Ber. 97, 3407-3417 WO 98/24782 PCT/US97/22390 92 (1964)). The use of 2 -nitropyridine-4-carboxaldehyde would lead to a derivative of formula II with R" represented by a 2-nitro-4-pyridyl group. Catalytic reduction of the nitro to an amino group would provide the 2-amino-4-pyridyl derivative of II. The approach displayed in Scheme 8 is applicable to the use of other.
aryl acetic acids leading to compounds of formula II with different aryl groups as R".
Scheme 8 0
FO
N F F
OR
OH
HN
H2N XII O OH NH N NN N XIII II Another approach (Scheme 9) leading to 5,6-diaryl- 4-hydroxy-pyrimidines involves the cyclization of the bketo ester XIV with thiourea to give the thiouracil derivative XV. XV can be S-monomethylated to XVI.
Reaction of XVI with primary and secondary amines leads to 2-amino substituted 4-hydroxy-pyrimidines
II.
Further 2-thioether derivatives of II with R' SR 21 can be obtained, for example by alkylation of XV with alkyl halides. Treatment of XV or XVI with Raney nickel and
H
2 provides compounds of structure II wherein R' is H.
WO 98/24782 PCT/US97/22390 93 Scheme 9 0 Nf OEt N^k
H
2
N
H
2
N
FOE
OEt
XIV
F N S OH
N
N SMe N
OH
N R 21 N N, N ,R
XVI
II R 1
SR
21 Although Scheme 9 illustrates syntheses in which R" is 4-pyridyl, this approach may be equally applied to any other heteroaryl ring within the definition of R 2 by the appropriate choice of the starting material. Such starting materials include but are not limited to ethyl 2-methyl isonicotinate (Efimovsky and Rumpf, Bull. Soc.
Chim. FR. 648-649 (1954)), methyl pyrimidine-4carboxylate, methyl 2 -methylpyrimidine-4-carboxylate, methyl 6-methylpyrimidine-4-carboxylate and methyl 2,6dimethylpyrimidine-4-carboxylate (Sakasi et al., Heterocycles 13, 235 (1978)). Likewise, methyl 2nitroisonicotinate (Stanonis, J. Org. Chem. 22, 475 (1957)) may be reacted with an aryl acetic acid ester followed by cyclization of the resultant b-keto ester with thiourea analogously to Scheme 9. Subsequent catalytic reduction of the nitro group to an amino group WO 98/24782 PrCT/T'7/9'10n 94 would give a 4-hydroxy-pyrimidine II in which R' 2 is represented by a 2-amino-4-pyridyl group (Scheme Scheme F F O H I OH INN R1
R
NO
2 NH2 Furthermore, methyl 2-acetamido isonicotinate (Scheme 11) may be reacted analogously to Scheme 9 after appropriate protection of the amide nitrogen with e.g. a tert-butyldimethylsilyloxymethyl group (Benneche et al., Acta Chem. Scand. B 42 384-389 (1988)), a tertbutyldimethylsilyl group, a benzyloxymethyl group, a benzyl group or the like Scheme 11 N CO0 2 Me CO 2 Me CO 2 Me NH2 NHAc NAc
I
P
1 Removal of the protecting group P, of the resulting pyrimidine II with a suitable reagent tetrabutylammonium fluoride in the case where P 1 is tbutyldimethyl-silyloxymethyl) would then lead to a pyrimidine II with R' 2 represented by a 2-acetamido-4pyridyl group. Needless to say, ethyl p-fluorophenyl acetate may be substituted by any alkyl arylacetate in the procedure illustrated in Scheme 9 thus providing compounds of formula II with different R" aryl substituents.
In a further process, compounds of pyrimidines II may be prepared by coupling a suitable derivative of XVIII (L is a leaving group, such as halogen radical and WO 98/24782 PCT/US97/22390 the like, and P 2 is a protecting group, such as benzyl and the like) with an appropriate aryl equivalent.
0 L 2NP R N R XVII I Such aryl/heteroaryl couplings are well known to those skilled in the art and involve an organic-metallic component for reaction with a reactive derivative, e.g., a halogeno derivative, of the second compound in the presence of a catalyst. The metallo-organic species may be provided either by the pyrimidinone in which case the aryl component provides the reactive halogen equivalent or the pyrimidinone may be in the form of a reactive halogeno derivative for reaction with a metallo organic aryl compound. Accordingly, 5-bromo and derivatives of XVIII (L Br, I) may be treated with arylalkyl tin compounds, trimethylstannylbenzene, in an inert solvent such as tetrahydrofuran in the presence of a palladium catalyst, such as di(triphenylphosphine)palladium(II)dichloride. (Peters et al., J. Heterocyclic Chem. 27, 2165-2173, (1990).
Alternatively, the halogen derivative of XVIII may be converted into a trialkyltin derivative (L Bu 3 Sn) by reaction with e.g. tributylstannyl chloride following lithiation with butyllithium and may then be reacted with an aryl halide in the presence of a catalyst.
(Sandosham and Undheim, Acta Chem. Scand. 43, 684-689 (1989). Both approaches would lead to pyrimidines II in which R" is represented by aryl and heteroaryl groups.
As reported in the literature (Kabbe, Lieb. Ann.
Chem. 704, 144 (1967); German Patent 1271116 (1968)) and displayed in Scheme 12, 5-aryl-2,6-dipyridyl-4-hydroxypyrimidines II may be prepared in a one step synthesis by reaction of the cyanopyridine with an arylacetyl WO 98/24782 PCTftJS97/22390 96 ester, such as ethyl phenylacetate in the presence of sodium methoxide.
Scheme 12
OH
R
11/\ N CN R CO2Et N
N
II
Analogously, as reported (Kabbe, supra) and displayed in Scheme 13, 4 -amino-5-(aryl)-2,6-dipyridylpyrimidines XIX are obtained in a one step synthesis by reaction of cyanopyridine with arylacetonitrile, such as 4-fluorophenylacetonitrile.
Scheme 13 NH2 11~1 CN R CN
N
N NN
XIX
Modification at the 4-position (R 2 of formula I) of pyrimidine II is possible by conversion into the chloro derivative XX by reaction with phosphorous oxychloride (Scheme 14). A 4-alkoxy derivative XXI may be prepared from chloro derivative XX by nucleophilic substitution with alkoxide. Alternatively, in stead of the chloro group, other leaving groups, such as tosylates, mesylates and the like, can be used. Also, such leaving groups can also be displaced by amino, thiolates, alcoholates, and the like nucleophiles. For example, the chloro derivative XX may be reduced by catalytic hydrogenation to give a pyrimidine I where R 2 is H, or may be reacted with an alkyl or aryl boronic acid or an alkyl or aryl zinc halide to provide a pyrimidine I where R 2 is alkyl or aryl.
WO 98/24782 PCT/US97/22390 97 Scheme 14
R
2 OH 11 N N 12) 1 1 1
R
1 N R R N R XX R 2 Cl II 2 XXI R OMe I R2 =H In Scheme 15, compounds of the present invention of formula XXX can be readily prepared by reacting the methylthio intermediate XXXI with the amine NHRR 2 for example by heating the mixture preferably at a temperature greater than 1000C, more preferably 150- 210 0 C. Alternatively, compounds of formula XXX can be readily prepared by reacting the methylsulfonyl intermediate XXXII with the amine NHR 5
R
2 for example by heating the mixture preferably at a temperature greater than 400C, more preferably 50-2100C.
Scheme OH OH
OH
R R R R1 I2 NN
R
XXXI XXX
XXXII
Amines of formula NHR 5
R
21 are commercially available or can be readily prepared by those skilled in the art from commercially available starting materials. For example, an amide, nitro or cyano group can be reduced under reducing conditions, such as in the prescence of a reducing agent like lithium aluminum hydride and the like, to form the corresponding amine. Alkylation and acylation of amino groups are well known in the art.
Chiral and achiral substituted amines can be prepared from chiral amino acids and amino acid amides (for example, alkyl, aryl, heteroaryl, cycloalkyl, arylalkyl, WO 98/24782 PCTIUS97/22390 98 heteroarylalkyl, cycloalkylalkyl and the like substituted glycine, I-alanine and the like) using methods well known in the art, such as H. Brunner, p.
Hankofer, U. Holzinger, B. Treittinger and H.
Schoenenberger, Eur. J. Med. Chem. 25, 35-44, 1990; M.
Freiberger and R. B. Hasbrouck, J. Am. Chem. Soc. 82, 696-698, 1960; Dornow and Fust, Chem. Ber. 87, 984, 1954; M. Kojima and J. Fujita, Bull. Chem. Soc. Jpn. 1454-1459, 1982; W. Wheeler and D. O'Bannon, Journal of Labelled Compounds and Radiopharmaceuticals XXXI, 306, 1992; and S. Davies, N. Garrido, 0. Ichihara and I.
Walters, J. Chem. Soc., Chem. Commun. 1153, 1993.
WO 98/24782 PCTIUS97/22390 99 The following Examples are presented for illustrative purposes only and are not intended, nor should they be construed, as limiting the invention in any manner. Those skilled in the art will appreciate that modifications and variations of the compounds disclosed herein can be made without violating the spirit or scope of the present invention.
EXAMPLES
Example 1 General procedure for the preparation of 2-substituted (4-fluorophenyl) (4-pyridyl) -pyrimidines a. 3-(Dimethvlamino)-2-(4-fluorophenl)-l- (4-pyridv) 3-propene-l-one: (According to Bennett et al., J. Org. Chem. 43, 221 (1977)).
Me 2
N
0 F -OMe O F Me 2
N
NMe 2 A mixture of 2- (4-fluorophenyl)-1-(4-pyridinyl)ethanone (300 mg, 1.39 mmol) and bis(dimethylamino)methoxymethane (300 mml, 1.95 mmol) was heated at 110 0 C for 1.5 h under argon. It was evaporated and the yellow, crystallizing residue dried in an oil pump vacuum before used in the succeeding reaction. MS 270.8 C, 1 6
,HFN
2 0 requir. 270.3. 'H-NMR (CDC1 3 d 8.57, 7.25 (2m, each 2H, Pyrid.), 7.36 1H, 7.13, 6.99 (2m, each 2H, PhF), 3.00 (bs, 6H, 2CH,).
b. General procedure: (According to Bennett et al., J. Med. Chem. 21, 623 (1978)).
WO 98/24782 PCT/US97/22390 100
H
2 N F N SHN
N
N R N H I
N__R
NMe 2 N 1 A solution of 3-(dimethylamino)-2-(4-fluorophenyl)-l-(4pyridinyl)-3-propene-l-one (1.39 mmol) in absol. ethanol (9 ml) was transferred into a solution of the R'-C(NH)NH 2 (1.67 mmol) in ethanol (2 ml) prepared from sodium (1.67 mmol) and the amidine or guanidine hydrochloride (1.67 mmol). After heating under reflux for 1.5 to 24 h, it was evaporated and the resulting material was applied either directly to a column of silica gel methanol/dichloromethane) or was taken up in dichloromethane followed by washing with water, drying of the organic solution and evaporation prior to column chromatography.
The following pyrimidines were prepared according to this general procedure by reacting 3-(dimethylamino)- 2-(4-fluorophenyl)-1-(4-pyridinyl)-3-propene-l-one with amidines: 1-1 5-( 4 -Fluorophenvl)-2-methvl-4-(4-pvridyl)pyrimidine: MS 266.0
C
16
H
2 FN, requir.
265.3. 'H-NMR (CDC1 3 d 8.70 1H, H-6, Pyrim.), 8.59, 7.32 (2m, each 2H, Pyrid.), 7.20-7.00 4H, PhF), 2.88 3H, CH,).
R, CH 3 1-2 5-( 4 -Fluorophenyl)-2-isopropvl-4-(4-pvridyl)L vprimidine: MS 294.4
C,H
16 FN, requir.
293.4. 'H-NMR (CDC1 3 d 8.73 1H, H-6, Pyrim.), 8.60, 7.35 (2m, each 2H, Pyrid.), 7.20-7.04 4H, PhF), 3.37 1H, CH(CH 3 1.50, 1.47 (2s, each 3H, 2CH) R, (CH,),CH- WO 98/24782 PCTIUS97/22390 101 1-3 2-tert-Butyl-5- (4-fluorophenvl)-4- (4-pridyl) pyrimidine: MS (mhz): 307.8 C 19 18
FN
3 requir.
307.4. 1 H-NMR (CDC1 3 d 8.72 1H, Pyrim.), 8.59, 7.38 (2m, each 2H, Pyrid.)., 7.21-7.06 4H, PhF), 1.52 9H, 3CH 3 R,
(CH
3 3
C-
1-4 2-(l-Chloro-2-methoxvethvl)-5-(4-fluorophenyl)-4- (4-pyridyl) -pvrimidine: MS 344.2
C
1 8 15 ClFN 3 Orequir. 343.8. 'H-NMR (CDC1,): d 8.81 1H, H-6, Pyrim.), 8.61, 7.35 (2m, each 2K, Pyrid.), 7.22- 7.08 4H, PhF), 5.29 (dd, 1H, CHC1), 4.31, 4.04 (2dd, each 1H, CH 2 3.47 3H, CH 3
O).
R, CH 3
OCH
2 CH(C1)- 2-(Cycloprovl)-5-(4-fluorophenl)-4-(4-pvridyl)- Pyrimidine: MS 292.0 C 18
H
14 FN requir.
291.3. 'H-NMR (CDC1 3 d 8.60 1K, H-6, Pyrim.), 8.57, 7.32 (2d, each 2H, Pyrid.), 7.16-7.00 4H, PhF), 2.32 1H, 1.2, 1.1 (2m, each 2H, 2CK).
RI 1-6 2-(Adamant-l-vl)-5-(4-fluoroPhenyl)-4-(4-pyridvl)pyrimidine: MS (mhz): 386.0 C 25
H
24
FN
3 requir.
385.5. 'H-NMR (CDC1 3 d 8.76 1K, H-6, Pyrim.), 8.61, 7.51 (2m, each 2H, Pyrid.), 7.22-7.08 4H, PhF), -1.9-1.5 (broad, 15K, CH 2
CH).
R1= 1-7 2-Benzyl-5-(4-fluorophenyl)-4-(4-lpridyl)pyrimidine: MS 342.2 C 22
H
16
FN
3 requir.
341.4. 'H-NMR (CDC1 3 d 8.71 1K, H-6, Pyrim.), 8.60, 7.48 (2m, each 2H, Pyrid.), 7.42-7.04 9K, PhF, Ph), 4.42 2H, CH Ph).
WO 98/24782 PCTIUS97/22390 102 Rl 1-8 2 2 6 -Dichlorobenzvl)-5-(4-fluoropheny) 4 4 pyridyl) -PVrimidine: MS 410.2
C
22
H
14 C1 2
FN
3 requir. 410.3. 'H-NMR (CDC1,): d 8.68 1H, H-6, Pyrim.), 8.57 2H, Pyrid.), 7.44-7.03 9H, Pyrid., PhF, Phl 2 4.93 2H, CHO).
Cl Rl
=I
1-9 5- 4 -Fluorophenyv)-2-phenoxymethy 4-(4-pyriyl) pyrinidine: MS 358.2 C 22
H
16 FN3Orequir.
357.4. 'H-NMR (CDC1 3 d 8.83 1H, H-6, Pyrim.), 8.60 2H, Pyrid.), 7.36-6.98 11H, Pyrid., PhF, Ph) 5.43 2H, CH).
R1 1-10 5-( 4 -Fluorophenvi)-2-phenylthiomethyl-4-(4 pyridinyl) -ivrimidine: MS (mhz) 374.2 C 22
H
16
FN
3
S
requir. 373.5. 1 H-NMR (CDC1 3 d 8.72 1H, H-6, Pyrim.), 8.56, 7.49 (2m each 2H, Pyrid.), 7.32-7.02 (m, 9H, PhF, Ph), 4.50 2H, CH 2 1-11 5-( 4 -Fluorophenvl)-2-phenyl-4-(4-pvridyl) pyrimidine: MS 328.2 C 21
H
14
FN
3 requir.
327.4. H-NMR (CDC13): d 8.85 1H, H-6, Pyrim.), 8.63, 7.4 (2m, each 2H, Pyrid.), 8.56, 7.6-7.5, 7.25- 7.05 9H, PhF, Ph).
)Rc WO 98/24782 PCTIUS97/22390 103 1-12 5-(4-Fluorophenvl) -2-(4-hydroxyphenl)-4-(4rnr idvl) -pvrimidine: MS 344.2
C
21
H
14 requir. 343.4. 'H-NMR (DMSO-d,): d 10.2 (bs, 1H, OH), 8.90 1H, H-6, Pyrim., Pyri.), 8.60, 7.42 (2m, each 2H, Pyrid.), 8.35, 7.40-6.92 8H, Ph, PhON).
R1 1-13 5-(4-Fluorohenyl)-2-(4-aminophenyl)-4-(4-pyridyl)pyrimidine: MS 343.2 C 21
H
15 FN 4 requir.
342.4. 'N-NMR (CDC1,): d 8.75 1H, H-6, Pyrim.), 8.60, 7.41 (2m, each 2H, Pyrid.), 8,40, 7.22-6.79 8H, PhF, Ph), 4.00 (bs, 2H, NH 2
H
2
N'
1-14 5-( 4 -Fluorophenvl)-2-(3-pyridyl)-4-(4-yridyl)- Pyrimidine: MS 329.0 C 2
DH
13
FN
4 requir.
328.4. 'H-NMR (CDC1,): d 9.80 (bs, H-2, 3-Pyrid.), 8.90 1H, Pyrim.), 8.84, 8.80 (2m, each 1H, 3- Pyrid.), 8.66, 7.45 (2m, each 2H, 4-Pyrid.), 7.50 (m, 1H, 3-Pyrid.), 7.28-7.10 4H, PhF).
R1= 1-15 5-(4-Fluorophenvl)-2-(2-pyridyl)-4-(4-pyridyl pvrimidine: MS 329.0 C 20
H
13
FN
4 requir.
328.4. 'H-NMR (CDC1,): d 9.01 1H, H-6, Pyrin.), 8.92, 8.66, 7.94, 7.48 (4m, each 1H, 2-Pyrid.), 8.66, 7.47 (2m, each 2H, 4-Pyrid.), 7.26, 7.14 (2m, each 2H, PhF).
Ri
C
1-16 5-(4-Fluorophenvl)-2-(2-pvrazinvl)-4-(4-Pvridvl) pyrimidine: MS 330.2 C 19
H
12 FN requir.
WO 98/24782 PCT1US97/22390 104 329.3. 'H-NMR (CDC1 3 9.84 1H, H-3, Pyraz.), 9.01 1H, H-6, Pyrim.), 8.84, 8.76 (2m, each 1H, H-5, H-6, Pyraz.), 8.65, 7.44 (2m, each 2H, Pyrid.), 7.26, 7.13 (2m, each 2H, PhF).
R1 1-17 5-( 4 -Fluorophenv1)-2-(2-methylthiazol-4-v)-4-(4pyridyl) -psvrimidine: MS 349.0
C
19
H
13
FN
4
S
requir. 348.4. 'H-NMR (CDC1 3 d 8.90 1H, H-6, Pyrin.), 8.63, 7.42 (2m, each 2H, Pyrid.), 8.32 1H, H-5, Thiaz.), 7.22, 7.10 (2m, each 2H, PhF), 2.88 (s, 3H, CHO).
R1 t/ ,Me
N
1-18 5-( 4 -Fluorophenyl)-4-(4-pvridyl)-2-(2-thienl) pyrimidine: MS 334.2 C 19
H
12
FN
3 S requir.
333.4. 'H-NMR (CDC1 3 d 8.74 1H, H-6, Pyrim.), 8.63, 7.41 (2m, each 2H, Pyrid.), 8.13, 7.55 (2m, each 1H, Thioph.), 7.20 3H, PhF, Thioph.). 7.10 2H, PhF).
R1
/D
The following pyrimidines were prepared according to the general procedure by reacting 3-(dimethylamino)-2-(4fluorophenyl)-l-(4-pyridinyl)-3-propene-1-one with guanidines: 1-19 2-Amino-5-(4-fluorophenyl)-4-(4-pvridl)- Pyriiidine: MS 267.0 C 15
H,
1
FN
4 requir.
266.3. 'H-NMR (DMSO-d): d 8.54, 7.26 (2m, each 2H, Pyrid.), 8.35 1H, H-6, Pyrim.), 7.22-7.12 4H, PhF) 6.97 2H, NH,) R1 NH2- WO 98/24782 PCTIIJS97/22390 105 1-20 2-Ethvlamino-5-(4-fluorophenvl)-4-(4-pvridvl)- Pyrimidihe: MS 295.0 C 1 H 5FN requir.
294.3. 'H-NMR (CDC1,): d 8.56, 7.32 each 2H, Pyrid.), 8.36 1H, H-6, Pyri.), 7.12-6.99 4H, PhF) 5.33 (unresolv. t, 1H, NH), 3.58 2H, 1.32 3H, CH) Ri CH 3
CH
2
-NH-
1-21 5-(4-Fluoropheny1)-4-(4-Tyvridyl)-2-(2sulfoethylamino)-pyrimidine: MS 375.2
C
17
H
15
FN
4
O
3 S requir. 374.4. 1 H-NMR (DMSO-d,): d 8.51, 7.25 (2d, each 2H, Pyrid.), 8.36 1H, H-6, Pyrim.), 7.32 1H, NH), 7.2-7.1 4H, PhF), 3.62 2H, CH 2
N),
2.72 2H, CH).
Ri HO 3
S-CH
2
-CH
2
-NH-
1-22 2-(2-Diethviaminoethvlamino)-5- (4-fluorophenvl)-4- (4-pvridl) -pvrimidine: MS 365.8 C 21
H
24
FN
requir. 365.5. 'H-NMR (CDC1,): d 8.55, 7.28 (2m, each 2H, Pyrid.), 8.34 1H, H-6, Pyrim.), 7.08, 7.01 (2m, each 2H, PhF), 5.95 (bs, 1H, NH), 3.60 2H, CH 2
N),
2.76 2H, 2.65 4H, 2CHCH 3 1.08 6H, 2CH Ri (CH 3
CH
2 2
NCHCH
2
NH-
1-23 (4-Fluorophenyl)-4-(4-pyridyl)-2-(thioureido)pyrimidine: MS 326.2 C 16
H
12 FN,S requir.
325.4. 'H-NMR (DMSO-d 6 d 10.84, 10.11, 9.20 (3s, each 1H, NH, SH), 8.75 1H, H-6, Pyri.), 8.59, 7.32 (2m, each 2H, Pyrid.), 7.28, 7.21 (2m, each 2H, Ph)F.
S
R=
H
2 N
N
H
1-24 2-(2,6-Dichlorophenlamino)-5- (4-fluorophenvl)-4- (4-pvridyl)-pyrimidine: MS 410.8 C 21
H
1 C1 FN 4 requir. 411.3. H-NMR (CDC1 3 d 8.54, 7.30 (2m, each 2H, Pyrid.), 8.45 1H, E-6, Pyrim.), 7.45 2H, Phd,), 7.21 1H, PhC 2 7.12, 7.04 (2m, each 2H, PhF).
WO 98/24782 PCT[US97/22390 106 Cl
H
RJ.
1-25 2-(2.6-Dimethvlhhenvlamino)-5-(4-fluorophenv1)- 4 (4-iwridl)-pvrimidine: MS 371.0
C
23 19
FN
requir. 370.4. 'H-NMR (CDC1 3 d 8.56, 7.32 (2d, each 2H, Pyrid.), 8.40 1H, H-6, Pyrii.), 7.20 3H, PhCi 2 7.11, 7.04 (2m, each 2H, PhE), 6.66 1H, NH), 2.20 6H, 2CH 3 Me H R1 1-26 5- (4-Fluorophenvl)-4-(4-pyridyl)-pyrinidine:
MS
373.0 C 22
H
17
FN
4 Orequir. 372.4. 'H-NMR (CDCi1,): d 8.62, 7.40 (2m, each 2H, Pyrid.), 8.60 (m, 1H, PhOMe), 8.52 1H, H-6, Pyrim.), 7.99 1, NH), 7.18-6.94 7H, PhF, PhOMe), 3.96 3H, CH 3
O).
OMeH
NN
R1 1-27 -(4-Fluorophenyl)-2-(4-fluorophenylamino)-4-(4pvridl)-pyrimidine: MS 361.0
C
21
H
14
F
2
N
4 requir. 360.4. 'H-NMR (CDC1,): d 8.58, 7.32 2H, Pyrid.), 8.46 1H, H-6, Pyrin.), 7.62 2H, PhF), 7.24 (bs, 1H, NH), 7.13-7.00 6H, PhF).
H
1-28 2 4 -Ethylphenylamino)-5-(4-fluorophenyl)-4-(4vridl) -lprimidine: MS 371.2
C
23 H19FN 4 requir. 370.4. 1 K-NMR (CDC1,): d 8.61, 7.41 (2m, each 2H, Pyrid.), 8.49 1H, H-6, Pyrim.), 7.60, 7.23 (2d, WO 9R/247R2 107 each 2H, PhEth), -7.28 7.13, 7.06 (2m, each 2H, PhF), 2.67 2H, CH 2 1.27 3H, CH 3
H
Ri Rl =E t "1 1-29 5-( 4 -Fluorophenyl)-4-(4-,Yridyl)-2-(3trifluoromethvlphenvlamino) -pvrimidine: MS 411.0
C
22
H
14
F
4 Nrequir. 410.4. 'H-NMR (CDC1): d 8.60, 7.35 (2m, each 2H, Pyrid.), 8.52 1H, H-6, Pyrim.), 8.23, 7.73, 7.46 dd, t, each 1H, PhCF 3 7.44 (s, 1H, NH), 7.31 (dd, 1H, PhCF 3 7.13, 7.05 (2m, each 2H, PhF).
H
R1=
CF
3 1-30 2 -(Benzvlamino)-5-(4-fluorophenyl)-4-(4-vridv1)pyrimidine: MS 357.0 C 22
H
1
,FN
4 requir.
356.4. MH-NMR (CDC1,): d 8.55, 7.28 (2m, each 2H, Pyrid.), 8.36 1H, H-6, Pyrim.), 7.44-7.28 Ph), 7.09, 7.02 (2m, each 2H, PhF),5.71 1H, NH), 4.75 1H, CH) R1=
N
Q~H
1-31 S-(4-Fluorophenv)-2-(2-henvlethvino)-4(4 pvridvl)-ipyrimidine: MS 371.0
C
23 19
FN
4 requir. 370.4. 'H-NMR (CDC1 3 d 8.56 2H, Pyrid.), 8.35 1H, H-6, Pyrin.), 7.38-7.22 7H, Ph, Pyrid.), 7.08, 7.02 (2m, each 2H, PhF), 5.32 1H, NH), 3.80 2H, CH 2 2.92 2H, CHO).
H
Rl=N Vu WO 98/24782 PCT/US97/22390 108 1-32 5-(4-Fluorophenvl) -4-(4-Dyridyl)-2-pyrrolidinolvrimidirie: MS 321.2
C
19
HFN
4 requir.
320.4. 'H-NMR (CDC1,): d 8.54, 7.32 (2d, each 2H, Pyrid.), 8.37 1H, H-6, Pyrim.), 7.06, 7.00 (2m, each 2H, PhF), 3.68, 2.05 (2m, each 4H, 4CH) R
CN-
1-33 5-(4-Fluorophenyl)- 2 -morpholino-4-(4-pyridyl)pyrimidine: MS 337.2
C
19
H
17
FN
4 Orequir.
336.4. 'H-NMR (CDC1 3 d 8.56, 7.31 (2m, each 2H, Pyrid.), 8.40 1H, H-6, Pyrin.), 7.10, 7.03 (2m, each 2H, PhF), 3.94, 3.83 (2m, each 4H, 4C 2
)O
R1= 1-34 2 3 ,5-Dimethvlpvrazolyl)-5-(4-fluorophenv1)-4(4.
pyridyl) -pyrimidine: MS 346.0
C'
0
H
16
FN
requir. 345.4. 'H-NMR (CDC1,): d 8.80 1H, H-6, Pyri.), 8.60, 7.35 (2m, each 2H, Pyrid.), 7.18, 7.08 (2m, each 2H, PhF), 6.08 1W, Pyraz.), 2.70, 2.30 (2s, each 3H, 2CH,).
Rl =Mes,
N*.
Me 1-35 5-( 4 -Fluorophenvl)-4-(4-Pyridyl) bis(trifluoromethl)berzenesulfamoyl)-pyrimidine:
MS
542.8 C 23 H 13
F
1 NS requir. 542.4. 'H-NMR (DMSO-d,): d 8.63 1H, H-6, Pyrim. 8.56 2H, Pyrid.), 8.49, 8.43 (2s, 2H, 1, Ph(CF 3 2 7.26-7.15 (m, 6H, PhF, Pyrid.).
0 0 F 3C S N Rl I Y H
CF
3 WO 98/24782 WO 9824782PCTIUS97/22390 109 1-36 2 4 -Aminobenzenesulfamol)5(4-fluorophenvl)- 4 4 -pyridvl)-Dyrimidine: MS 421.8 C21 H 16 FN 5 0 2 3 requir. 421. 5. 'H-NM'R (DMSO-d,) d 8.58 (s, 1H, H-6, Pyrim.), 8.575 (mn, 2H, Pyrid.), 7.64, 6.56 (2d, each 2H, PhNH 2 7.28-7.15 (in, 6H, PhF, Pyrid.), 5.99 2H, NH 2 0 0
H
2 N 1-37 2 2 -Dimethvlaminoethvlthio)-5-(4..fluorophenyl)- 4 4 -pvridyl)-pyrirnidine was prepared according to the general procedure by reacting 3-(dimethylamino)-2-(4fluorophenyl) -1-(4-pyridinyl) 3 -propene-1-one with S- (2dirnethylaininoethyl) isothiourea. MS 355.2
C
19
H
19 FN 4 S requir. 3 54. 5. 'H-NMR (CDCl 3 :d 8.59, 7.32 (2mn, each 2H, Pyrid.), 8.58 1H, H-6, Pyrim.), 7.16, 7.08 (2mn, each 2H, PhE), 3.40, 2.76 (2m, each 2H, 2CH,), 2.37 6H, 2CHO R1 (CH,),NCH 2
CHS-
Example 2 General procedure for the preparation of 2-N substituted (4-fluorophenyl) (4-pyridyl) -pyrimidines a. 5- (4-Fluorophenvl)-4- (4-iwridyl) -2 (lH) -yrimidinone:
NH
2 F o FNI
NH
2 NMe 2 IN0 IN4 Urea (0.67 g, 11.15 minol) was added to a stirred ethanolic 0.62 N sodium ethoxide solution (15 ml) An ethanolic solution (60 ml) of 3-(dimethylamino)-2-(4fluorophenyl) 4 -pyridinyl)-3-propene-1-one (9.29 WO 98/24782 PCT/US97/22390 110 mmol) was added and the mixture was refluxed overnight.
It was evaporated followed by column chromatography methanol/dichloromethane to 100% methanol). Crystals (presumably urea) obtained on treating the resultant product with dichloromethane/methanol were filtered.
The filtrate was evaporated and the remainder rechromatographed on a column of silica gel (chloroform/methanol/water 70:20:1) to yield the title compound as a yellowish foam.
MS 268.2 C .H 10 FN,0 requir. 267.3. 'H-NMR (DMSO-d,): d 8.55, 7.24 (2m, each 2H, Pyrid.), 8.22 (bs, 1H, H-6, Pyrim.), 7.20-7.10 4H, PhF).
b. 2 -Chloro-5-(4-fluorophenvl)-4-(4-pyridyl)pyrimidine: FN
N
N OH N Cl N
N
A mixture of 5-( 4 -fluorophenyl)-4-(4-pyridyl)-2-(1H)pyrimidinone (2.41 mmol) and phosphorus oxychloride (3 ml) was heated at reflux for 45 min. It was evaporated to dryness at a bath temperature of >500 C. The flask was cooled in an ice-bath and ice-water was added. If the pH value was found still acidic, then the mixture was neutralized with aqueous 5% ammonium hydroxide. It was extracted with dichloromethane, followed by washing of the organic solution with aqueous sodium chloride, drying and evaporation to yield the title compound as a yellowish foam which was used without further purification.
MS 286.1 C 15
H
1 ,ClFN requir. 285.7. 'H-NMR (CDC1 3 d 8.68 1H, H-6, Pyrim.), 8.62, 7.42 (2m, each 2H, Pyrid.), 7.23-7.10 4H, PhF).
WO 98/24782 PCT/US97/22390 111 Alternatively, 2-chloro-5-(3-methylphenyl)-4-(4pyridyl)-pyrimidine (MS 282 C16H12ClN 3 requir. 281.7) and 2 -chloro- 4 4 -pyridyl)-5-(3-trifluoro methylphenyl)-pyrimidine (MS 336.0 C16H9C1F3N3 requir. 335.7) have been synthesized by the same reaction sequence, but starting from 2 -(3-methyl phenyl)-1-( 4 -pyridinyl)ethanone (prepared according to: I. Lantos et al., J. Org. Chem. 53, 4223-4227, 1988) and 1-(4-pyridinyl)-2-( 3 -trifluoromethylphenyl)ethanone (prepared according to: P.W. Sheldrake, Synth. Commun.
23 1967-1971, 1993); and WO 97/12876). Also, thionyl chloride/N,N-dimethylformamide (excess/3 equivalents, reflux) can be used instead of phosphorus oxychloride.
c. General procedure: F F N 10
N
N Cl N N NR 5
R
2 1
N
N N Typically, a mixture of 2-chloro-5-(4-fluoro phenyl)-4-(4-pyridyl)-pyrimidine (50-120 mg, 0.18-0.42 mmol) and the amine, HNR 5
R
21 (0.5-5.5 mmol) was heated at 50-100 0 C for 5-60 min (thin layer chromatography check). The mixture was applied directly to a column of silica gel which was developed with dichloromethane/ methanol or dichloromethane/methanol/conc. ammonium hydroxide.
An alternate procedure using ethanol as a solvent was used in case of Examples 2-6, 2-11, 2-12, 2-20 and 2-26 as described.
The following pyrimidines were prepared according to this procedure using the appropriate amine and substituted 2-chloropyrimidine: WO 98/24782 PCTIUS97/22390 112 2-1 2 2 -Aninoethvlaiino).5.(4fluorphenVl) Pyridyl)-;pyrimidine hydrochloride: MS 310.2 Cl,H 16 FNS-HCl requir. 309.4+36.5. 'H-NMR (CD 3 OD): d 8.84, 8.10 (2m, each 2H, Pyrid.), 8.58 1H, H-6, Pyrim.), 7.28, 7.15 (2m, each 2H, PhF), 3.83 2H, CH), 3.27 2H, CH').
Rl NH 2
CH
2
CH
2
NH-
2-2 2-( 3 -Aminoroovlamino)5-(4-fluorohenvl) 4 4 pyridyl)-pyrimidine hdrochloride: MS 324.0 C181 1 FN-HC1 requir. 323.4+36.5. 1 H-NMR (CD 3 OD): d 8.85, 8.10 (in, 2H, Pyrid.), 8.54 1H, H-6, Pyrim.), 7.27, 7.14 (2m, each 2H, PhF), 3.84, 3.68 (2t, each 2H, 2CH 2 N) 2.18 2H, CH').
Rl NH 2
CH
2
CH
2
CH
2
NH-
2-3 2 4 -Aminobutvlamino)-5-(4fluorohenvl)-4-(4pvridvl)-pyrimidine hydrochloride: MS 338.0
C
19
H
20 FN-HC1 requir. 337.4+36'.5. 3 1-NMR (CD 3 OD): d 8.80, 8.05 (2m, each 2H, Pyrid.), 8.50 1H, H-6, Pyrim.), 7.25, 7.14 (2m, each 21, PhF), 3.58 (bt, 2H,
CH
2 3.02 (bt, 1H, CH 2 1.80 4H, 2CH).
Ri NH 2
CH
2
CH
2
CH
2 CH 2
NH-
2-4 2-( 2 -Dimethvlaminoethylamino)-5-(4-fluoroThenyl)-4- 4 -Tridyl) -rvrimidine: MS (mlz): 338.2
C
19
H
20
FN
requir. 337.4. 1H-NMR (CDC1 3 d 8.57, 7.30 (2m, each 21, Pyrid.), 8.37 1H, H-6, Pyrim.), 7.10, 7.03 (2m, each 2H, PhF), 6.00 1H, NH), 3.66 2H, CH), 2.71 2H,
CH
2 2.41 6H, 2CR 3 Ri (CH 3 2
NCH
2
CH
2
NH-
5-(4-Fluorohenyl)-2-(2-henlaminoethylaino)-4- 4 -Tyridyl) -TPrimidine: MS 386
C
23
H
20
FN
requir. 385.5. 'H-NMR (CDC13): d 8.57, 7.28 2H, Pyrid.), 8.36 1H, H-6, Pyrim.), 7.18 2H, Ph), 7.08, 7.02 each 2H, PhF), 6.73 1H, Ph), 6.64 21, Ph), 5.62 (bt, 1H, NH), 3.80 2H, CH), 3.47 21, CR 2 WO 98/24782 PCTIUS97/22390 113
H
Ri RI
H
2-6 5- (4-Fluorophenyl) -2-(2-(4-fluorophenylamino) ethylamino)-4-(4- pvridyl)-pvrimidine: A solution of 2chloro-5-(4-fluorophenyl)-4-(4-pyridyl)-pyrimidine (103 mg, 0.36 nmol) and N-(4-fluorophenyl)ethylendiamine (1 ml) in ethanol (1 ml) was heated to reflux for 3 h.
Evaporation was followed by column chromatography (3% methanol/dichloromethane) to provide the title compound as a yellowish solid. MS (mlz): 404.2 C 2 H 19 F2N requir. 403.4. 'H-NMR (CDC 3 8.60 7.31 (2m, each 2H, Pyrid.), 8.40 1H, H-6, Pyrim.), 7.11-7.02 (2m, each 2H, PhF), 6.90, 6.60 dd, each 2H, PhF), 5.62 1H, NH), 3.82 2H, CH 2 3.44 2H, CH 2
H
R1 10 HN 2-7 5-(4-Fluorophenyl)-2- (4-methvlbenzlaiino)-4-(4pyridyl) -pyrimidine: MS 371.2 (M+H C 23
H
19
FN
4 requir. 370.4. 'H-NMR (CDC 3 d 8.55, 7.34 (2m, each 2H, Pyrid.), 8.36 Cs, 1H, H-6, Pyrim.), 7.30, 7.18 (2d, each 2H, PhMe), 7.08, 7.02 (2m, each 2H, PhF), 5.69 (bs, 1H, NH), 4.69 2H, CH 2 2.36 3H, CH,).
R1 NMe 2-8 5-(4-Fluorophenyi)-2-(2-(4-fluorophenyl)ethylamino)-4-(4-pvridvl)-pyrimidine: MS 389.2
C
2 3
HF
2
N
4 requir. 388.4. 'H-NMR (CDC1,): d 8.57 (m, 2H, Pyrid.), 8.36 1H, H-6, Pyrim.), 7.32-7.20, 7.12- 6.98 (2m, 10H, 2PhF, Pyrid.), 5.37 Cbt, 1H, NH), 3.79 2H, CH 2 2.97 t, 2H, CH).
WO 98/24782 PCTIUS97/22390 114
H
R1 2-9 2 2 -(4-Chlorophenvl)-ethylamino)-5-(4fluorophenyl)-4-(4-pvridyl)--Drimidine: MS 405.0
C
23
H
18 ClFN 4 requir. 404.9. 'H-NNR (CDC13): d 8.56 (bs, 2H, Pyrid.), 8.34 1H, H-6, Pyrin.), 7.29 d, 4H, Pyrid., Phd), 7.20 2H, Phd), 7.08, 7.02 (2m, each 2H, PhF), 5.35 1H, NH), 3.78 CH 2 2.96 2H,
CH)
H
R1
O
2-10 2 -(2-(4-Bromophenvl)-ethvlamino)-5-(4fluorophenyl)-4-(4-yridyl) -pyrimidine: MS :449.0
C
23
H
18 BrFN 4 requir. 449.3. 'I-NMR (CDC 3 d 8.58, 7.47 2H, Pyrid.), 8.37 1H, H-6, Pyrim.), 7.29, 7.17 (2d, each 2H, Phd), 7.10, 7.02 (2d, each 2H, PhF), 5.34 1H, NH), 3.80 2H, CH 2 2.97 2H, CH 2
H
R1 2-11 5-(4-Fluoroiphenyl)-2-(2-(4-hydroxvhenyl)ethvlamino)l-4(4-pvridyl)-iprimidine: A mixture of 2chloro-5-(4-fluorophenyl)-4-(4-pyridyl)-pyrimidine (61 mg, 0.21 mmol), tyramine hydrochloride (186 mg, 1.01 mmol) and sodium hydrogencarbonate (90 mg, 1.07 mmol) in aqueous ethanol (1 ml) was heated to reflux for 1 h.
Solvent evaporation and subsequent column chromatography methanol/dichloromethane) provided the title compound as a yellow solid. MS 387.2
C
23
H
19 FN O requir. 386.4. 'H-NMP (DMSO-d,): d 9.12 (bs, 1H, OH), 8.54, 7.26 (2m, each 2H, Pyrid.), 8.38 1H, H-6, Pyrim.), 7.52 1H, NH), 7.20-7.10 4H, PhF), 7.05, WO 98/24782 PCTIUS97/22390 115 6.69 (2d, each 2H, PhOH), 3.52 2H, CH 2 2.78 (t, 2H, CH
H
R1 I
HO
2-12 2 2 4 -Aminophenvl)-ethvlamino)-5-(4fluorophenl)-4-(4-psyridyl) -pyrimidine: A solution of 2-chloro-5-(4-fluorophenyl)-4-(4-pyridyl)-pyrimidine (71 mg, 0.25 mmol) and 2 4 -aminophenyl)ethylanine (0.5 ml, 3.80 mmol) in ethanol (1.5 ml) was heated to reflux for min. Evaporation and subsequent chromatography on a column of silica gel methanol/dichioromethane) provided the title compound as a yellow syrup. MS 386.4
C
23
H
20 FN requir. 385.5. 1
H-NMR
(CDCl 3 d 8.56, 7.32 (2m, each 2H, Pyrid.), 8.35 (s, 1H, H-6, Pyrim.), 7.12-6.99 6H, PhF, PhNH,), 6.68 2H, PhNH,), 5.37 1H, NH), 3.75 2H, CH 2
N),
2.88 2H, CH).
H
R1=H 2
NID,
2-13 4 -Fluorophenvl)-2-(2-(2-fluorophenyl) ethvlamino)-4-(4-pyridyl)-pyrimidine: MS 389.2
C
23
H
1 FN requir. 388.4. 1H-NMR (CDCl 3 8.57 (m, 2H, Pyrid.), 8.35 1H, H-6, Pyrim.), 7.34-7.20, 7.14- 7.00 (2m, 10H, 2PhF, Pyrid.), 5.42 (bt, 1H, NH), 3.82 2H, CH 2 3.05 2H, CH 2
H
R1=
F
2-14 2 -(2-(2-Chlorophenvl)-ethylamino) fluorophenyl)-4-(4-pvridyl)-pvrimidine. MS 405.0
C
23
H
18
CFN
4 requir. 404.9. 'H-NMR (CDC1,): d 8.57 2H, Pyrid.), 8.36 1H, H-6, Pyrim.), 7.40-7.00 WO 98/24782 PCT1US97/22390 116 10H, PF, Phd 2 Pyrid.), 5.44 (bt, 1H, NH), 3.84 2H, CH 2 3.15 2H, CH).
H
RI 2-15 5-(4-Fluorophenyl)-2-(2-(2-methox-vTenvl)ethylamino) -4-(4-pvridvl)-pvrimidine: MS 401.2
C
2 4
H
2 1 FN O requir. 400.5 'H-NMR (CDC1,): d 8.56, 7.30 (2m, each 2H, Pyrid.), 8.34 1H, H-6, Pyrim.), 7.24, 7.08, 7.02, 6.92 (4m, each 2H, PhF, PhOMe), 5.50 (bt, 1H, NH), 3.87 3H, 3.78 2H, CH 2 3.02 2H, CH)
H
R1N, OMe 2-16 2-(2-(2,4-Dichlorophenyl)-ethylamino)-5-(4fluoropheyl)-4-(4-pvridyl)-pyrimidine: MS 439.0
C
23
H
17 C1 2
FN
4 requir. 439.3. 'H-NMR (CDC 3 8.56 (bs, 2H, Pyrid.), 8.34 1H, H-6, Pyrim.), 7.37 1H, Phd), 7.30 (bd, 2H, Pyrid.), 7.22-7.15 2H, Phdl), 7.08, 7.05 (2m, each 2H, PhF), 5.40 1K, NH), 3.80 2H, CH 2 3.10 2H, CH)
H
N,,
RJil 2-17 2-(2-(2,6-Dichlorophenyl)-ethlamino)-5-(4fluorophenvl)-4-(4-pvridl)-pyvrimidine: MS (mhz): 439.0
C
23 HC1 2 FN requir. 439.3. 'H-NMR (CDC1 3 8.57 (m, 2H, Pyrid.), 8.36 1, H-6, Pyrim.), 7.35 2H, Phd), 7.11 3H, PhF, Phd), 7.03 2H, PhF), 5.45 1H, NH), 3.86 2H, CH 2 3.38 2H, CH).
WO 98/24782 PCTIUS97/22390 117 C1
H
R1 2-18 5-(4-Fluoroohenyl)- 2 2 3 -methoxvphenvl)ethvlamino)-4-(4-pvridvl) pyrimidine: MS 401.2
C
24
H
21
FN
4 0 requir. 400.5.'H-NMR (CDC1,): d 8.56 (m, 2H, Pyrid.), 8.34 1H, H-6, Pyrim.), 7.32-7.22, 7.11- 6.98, 6.89-6.77 (3m, 10H, PhF, PhOMe, Pyrid.), 5.38 (t, 1H, NH), 3.82 5H, CH 2 N, 2.96 2H, CHI).
H
R1 OMe 2-19 2 2 -(3-Chlorophenvl)-ethvlamino))-5-(4.
fluorophenvl)-4-(4-ipyridyl) yrimidine: MS 405.4
C
23
H
1
,CFN
4 requir. 404.9. 'H-NMR (CDC 3 d 8.60 2H, Pyrid.), 8.38 1H, H-6, Pyrim.), 7.32-7.24 5H, Pyrid., Phd), 7.18 IH, Phd), 7.11, 7.04 (2m, each 2H, PhF), 5.35 1H, NH), 3.83 2H,
CH
2 3.00 2H, CH).
H
R1
I
C1 2-20 5-(4-Fluorophen)-2-((2-hvdroxv-2-phenvl)ethvl amino)-4-(4-pvridvl)- pvrimidine: A mixture of 2chloro-5-(4-fluorophenyl)-4-(4-pyridyl)-pyrimidine (87 mg, 0.31 miol) and 2 -amino-l-phenylethanoi (300 mg, 2.19 mmol) in ethanol (2 ml) was heated to reflux for 2 h.
Evaporation and subsequent chromatography on a column of silica gel methanol/dichloromethane) provided the title compound as as yellow foam. MS (mlz): 387.0
C
23
H
19 FN.Orequir. 386.4. 'H-NMR (CDCl,): d 8.58 (d, 2H, Pyrid.), 8.38 1H, H-6, Pyrim.), 7.47 2H, WO 98/24782 PCT/US97/22390 118 Ph), 7.41 2H, Ph), 7.34 1H, Ph), 7.28 2H, Pyrid.),-7.10, 7.02 (2m, 2H, PhF), 5.72 Ct, 1H, NH), 5.06 (n CHOH)), 4.02-3.92 Cm, 2H, OH, 1CH 2 3.72 (ddd, IN, 1CH)
OH
Rl= 2-21 5-( 4 -Fluorophenvl)-2-(methvl-(2-henylethyl)amino)-4-(4-pyridyl)-iyrimidine: MS 385.0 CM+H)
C
24 H2FN 4 requir. 384.5. 'H-NMR (CDC1,): d 8.57, 7.35 (2m, each 2H, Pyrid.), 8.40 1H, H-6, Pyrim.), 7.34-7.21 5H, Ph), 7.10, 7.03 (2m, each 2H, PhF), 3.96 Ct, 2H,
CH
2 3.23 3H, 3.00 Ct, 2H, CHO).
CH
3
RI=
2-22 5-(4-Fluorophenyl)-2-( 3 -phenylprovl) -amino)-4-(4pyridV1) -PYrimidine: MS 385.2
C
24 21
FN
4 requir. 384.5. 'H-NMR (CDC1 3 d 8.56 2H, Pyrid.), 8.34 Cs, 1H, H-6, Pyrim.), 7.34-7.20 Cm, 7H, Ph, Pyrid.), 7.08, 7.01 (2m, each 2H, PhF), 5.38 Ct, 1H, NH), 3.58 2H, CH 2 2.78 Ct, 2H, CH 2 2.03 2H,
CH).
QAl
N
2-23 5-(4-Fiuorophenvl)-2-((l-methyl-3-Dhenylpropyl)amino) 4 -pvridl)-Pvriiidine: MS 399.0 CM+H)+;
C
25
H
23 FN 4 requir. 398.5. 'H-NMR CCDC1 3 d 8.56 2H, Pyrid.), 8.32 Cs, 1H, H-6, Pyrim.), 7.32-7.17 7H, Pyrid., Ph), 7.09-7.02 C2m, each 2H, PhF), 5.16 Cd, 1H, NH), 4.28 Cm, 1H, CH), 2.77 Cm, 2H, 1.94 Cm, 2H, CH), 1.34 Cd, 3H, CHO).
WO 98/24782 PCTIUS97/22390 119
CH
3
N
R1
H
Ri 2-24 5-(4-Fluorophenyl)-2-((3-imidazolvlDropyl)-amino)- 4-(4-pvridl) -pvrimidine: MS 375.0 C 2 H 19
FN
6 requir. 374.4. 'H-NMR (CDC1,): d 8.57, 7.26 (2m, each 2H, Pyrid.), 8.36 1H, H-6, Pyrim.), 7.56 (s, IH, Imid.), 7.16-6.96 6H, PhF, Imid.), 5.38 (bt, IH, NH), 4.12 2H, CH 2 3.56 2H, CH 2 NH), 2.20 (m, 2H,
CH).
R1 Nj H 2-25 5- (4-Fluorophenyl) (4-phenyl -n-butyl) -amino) -4- (4-pyridyl) -pyrimidine: MS 399. 0 C 25 23
FN
4 requir. 398.5. H-NMR (CDC 3 d 8.56 2H, Pyrid.), 8.34 1H, H-6, Pyrim.), 7.33-7.17 7H, Ph, Pyrid.), 7.08, 7.02 (2m, each 2H, PhF), 5.33 (bt, 1H, NH) 3.56 2H, CH 2 2.71 2H, CH 2 1.76 4H, 2CH 2
H
R1 2-26 5-(4-Fluorophenl)-2-(1-piperazinl)-4-(4-pyridvl)pyvrimidine: A mixture of 2-chloro-5- (4-fluorophenyl)-4- (4-pyridyl)-pyrimidine (71 ig, 0.25 mmol) and piperazine (214 mg, 2.48 mmol) in ethanol (1 ml) was heated to reflux for 5 min. Evaporation and subsequent chromatography on a column of silica gel methanol/dichioromethane) provided the title compound as as yellow solid. MS 336.2 C 19
H
18
FN
5 requir.
335.4. 1 H-NMR (CDCl 3 d 8.54, 7.29 (2m, each 2H, Pyrid.), 8.37 1H, H-6, Pyri.), 7.08, 7.00 (2m, each 2H, PhF), 3.95 4H, 2CH 2 3.01 4H, 2CH,).
WO 98/24782 PCT/US97/22390 120 RI =N
N-
2-27 5-(4-Fluorophenl)-2-(l-piperidinvl)-4-(4-pvridvl)pyrimidine: MS 335.2 C 20
H
1 FN~requir.
334.4. 'H-NMR (CDC1,): d 8.55, 7.30 (2m, each 2H, Pyrid.), 8.36 1H, H-6, Pyri.), 7.08, 7.01 (2m, 2H, PhF), 3.91 4H, 2CH 2 1.74, 1.68 (2m, 61, 3CH 2 l= CN- 2-28 5-(4-Fluorophenyl)-2-(4-methyl-l-piperazinvl)-4-(4pvridvl)-pyrimidine: MS 350.0 C 2 0H 2 0FN requir. 349.4. '1-NMR (CDC1,): d 8.58, 7.32 (2m, each 2H, Pyrid.), 8.40 1H, H-6, Pyrim.), 7.10, 7.04 (2m, each 2H, PhF), 4.00 4H, 2CH 2 2.57 4H, 2CH), 2.42 3H, CH 3 Rl
H
3 C-N
N-
2-29 5-(4-Fluorophenyl)-2-(4-phenvl-1-PiperazinVl)-4-( 4 pyridyl) -priidine: MS 412.2 C 25
H
22
FNS
requir. 411.5. 'H-NMR (CDC1 3 d 8.58 (bd, 2H, Pyrid.), 8.42 1H, H-6, Pyrim.), 7.38-7.30 4H, Pyrid., Ph), 7.15-7.00 6H, PhF, Ph), 6.94 1H, Ph), 4.13 4H, 2CH 2 3.33 4H, 2CH,).
Rl 2-30 5-(4-Fluorophenyl)-2-(2-inorpholinoethvlamino)- 4 4 pyvridyl)-lpvrimidine: MS 380.4 C 21
H
22 FNS0 requir. 379.4. 'H-NMR (CDC10): d 8.58, 7.30 (2m, each 2H, Pyrid.), 8.38 1H, H-6,Pyrim.), 7.10, 7.03 (2m, each 2H, PhF), 5.91 (bs, 1H, NH), 3.79 (bs, 4H, 2CH,) 3.66 (bs, 2H, 2.71 (bs, 2H, 2.59 (bs, 4H, 2C- 2 WO 98/24782 PCTIUS97/22390 121
H
N
2-31 5-(4-Fluorophenyl)-2-(2-pieridinoethylamino)-4-(4pyridyl) -pyrimidine: MS (mhz): 378.2
C
22
H
24
FNS
requir. 377.5 'H-NMR (CDC1,): d 8.54, 7.27 (2d, each 2H, Pyrid.), 8.34 1H, H-6, Pyrim.), 7.06, 7.00 (2m, each 2H, PhF), 6.04 (bt, 1H, NH), 3.66 2H, CH 2 NH), 2.74 2H, CH 2 2.61 (bs, 4H, 2CH 2 1.68 4H, 2CH, 1.50 2H, CH)
H
N
RI
CN
2-32 5-(4-Fluorophenvl)-4-(4-pyridyl)-2-(2pyrro1idinoethylamino)-primidine: MS (mhz): 364.0
C
21
H
22
FN
5 requir. 363.4 'H-NMR (CDC1): d 8.55, 7.28 (2m, each 2H, Pyrid.), 8.36 lI, H-6, Pyri.), 7.08, 7.02 (2m, each 2H, PhF), 6.28 1H, NH), 3.86 2H,
CH
2 NH),,3.18 2H, CH 2 3.10 (bs, 4H, 2CH 2 2.02 (bs, 4H, 2CH 2 R1=
CN-
2-33 5-(4-Fluorophenyl)-2-(3-morpholinopropvlamino)-4- (4-pvridyl)-Trimidine: MS 394.2 C 2 2 24 requir. 393.5. 'H-NMR (CDC1 3 d 8.54, 7.27 (2m, each 2H, Pyrid.), 8.33 1H, H-6, Pyrim.), 7.06, 7.00 (2m, each 2H, PhF), 6.00 1H, NH), 3.76 4H, 2CH 2 0), 3.60 2H, CH 2 NH), 2.52 2H, CH 2 2.50 4H,
CH
2 N) 1.86 2H, CH 2 R1 0 0 N N-
H
2-34 5-(4-Fluorophenvl)-2-(3-(2-pyrrolidinon-l-v1)proylamino)-4-(4-lpridyl)-pyrimidine: WO 98/24782 PCTIUS97/22390 122 MS 392.2
C
22
H
2
FN
5 0 requir. 391.5. 'H-NMR (CDC1,) d 8.58, 7.30 2H, Pyrid*.) 8.36 1H, H-6, Pyrim.), 7.10, 7.04 2H, PhF), 5.88 1H, NH), 3.56 2H, CH 2 NH), 3.48, 3.45 (2t, each 2H, 2CH 2 2.46 (t, 2H, CH 2 2.08 2H, CH 2 1.90 2H, CH 2 0 R1=
H
N
2-35 2 2 -Amino-3-phenvlpropvl)-amino)-5(4 fluorophenyl)-4-(4-pyridyl)-pyrimidine hydrochloride: MS 400.1 C24H22FN5 requir. 399.5 (free base).
R1= II H
NH,
2 2-36 2 2 -Amino-3-henyvpropyl)-a ino)-4- (4 3 -trifluoromethylphenyl)-pyrimidine hydrochloride: 2-Chloro-4-(4-pyridyl)-5-(3trifluoromethylphenyl) -pyrimidine and benzylethylendiaine were reacted according to the General Procedure, Step C (70C for 75 min) to give the title compound. MS 450.4 C25H22F3N requir. 4449.5 (free base).
R1NN R1l H
H
2 2-37 2 -(((S)-2-Amino-3-phenylpropl)-amino)- 5-(3methylphenl)-4-(4-pyridyl)-pyrimidine hydrochloride: 2-Chloro-5-(3-methyiphenyl)-4-(4-pyridyl)-pyrimidine and 2 -benzylethylendiamine were reacted according to the General Procedure, Step C (100 0 C for 20 min) to give the title compound. MS 396.2 C25H25N5 requir. 395.5 (free base).
R= Q'joo*
H
RI
NH2 WO 98/24782 PCTIUS97/22390 123 2-38 2-((CS)-2-NN-Dimethylamio3phenv l)-amin- (4-f luorophenyl) (4-pyridyl) -pyrimidine: (4-fluorophenyl)-4-(4-pyridyl)-pyrimidine and dimethylamino-3-phenylpropYlamine were reacted according to the General procedure, Step C (100 0 C for 45 min) to give the title compound. MS 427.8
C
26
H
26
FN
5 requir. 427.5.
N
R1
H
2-39 2-CC(S) -2-NN-Dimethlamin-3phenylpropvl) -amino) 5- (3-methvlphenl) (4-pvridyl) -pyrimidine: (3-methylphenYl)-4-(4-pyridyl)-pyrimidine and dimethylamino- 3 -phenylpropylamine were reactea according to the General procedure, Step C (100'C for 30 min) to give the title compound. MS 424.2
C
2
,H
29
FN
5 requir. 423.6.
N N R11
H
NN
2-40 2-C (3Amino-3 henvlropvl)amino)- 5-(4fluorophenyl)-4-(4-ipridvi) -primidine hydrochloride: 2- Chloro-5-(4-fluorophenyl)-4-(4-pyridyl)-pyrimidine and lphenyl-1,3-propanediamine were reacted according to the General procedure, Step C (100'C for 30 min) to give the title compound. MS 4001.
C,,H,,FN,
requir. 399.5 (free base).
NH
2
N
R1 H3
"N
2-41 2-((3-Amino 3 -henyllProT l) -amino)-4 4 (3-trifluoromethvlphenvl) -)rimidife hdrochloride: 2- Chloro-4- (4-pyridyl) 3 -trifluoromethylphenyl) pyrimidine and lphenyl-1,3-propanediamine were reacted according to the General procedure, Step C (100 0 C for 1 WO 98/24782 PCTfUS97/22390 124 h) to give the title compound. MS (mhz): 450.3
C
25
H
22
F
3
N
5 requir. 449.5 (free base).
NH
2 R- R1=
H
2-42 2-((3-Amino-3-(2-fluorophenvl)propl)-amino)-4-(4pyridyl) (3-trifluoromethyl phenyl) -pyrimidine hydrochloride: 2-Chloro-4-(4-pyridyl)-5-(3trifluoromethylphenyl)-pyrimidine and 1-(2fluorophenyl)-1,3-propanediamine were reacted according to the General Procedure, Step C (100 0 C for 30 min) to give the title compound. MS 468.4
C
25
H
21 F 4
N
5 requir. 467.5 (free base) F
NH
2
N
R 1
H
2-43 (3-Amino-3-phenylproyl)-amino)-5-(3methvlphenyl) (4-pyridyl) -nyrimidine hydrochloride: 2-Chloro-5- (3-methyiphenyl) (4-pyridyl) -pyrimidine and l-phenyl-l,3-propanediamine were reacted according to the General Procedure, Step C (100 0 C for 30 min) to give the title compound. MS (mhz): 396.1 requir. 395.5 (free base).
NH
2
N
2-44 (2-Amino-2-methyl-3-Dhenvlpropvl)-amino)- methylphenyl) (4-pyridyl) -pyrimidine hydrochloride: 2- Chloro-5-(3-methylphenyl)-4-(4-pyridyl)-pyrimidine and 2-amino-2-methyl-3-phenylpropylamine were reacted according to the General Procedure, Step C (100 0 C for min) to give the title compound. MS 410.2
C
26
H
27
N
5 requir. 409.5 (free base).
WO 98/24782 PCTIUS97/22390 125
N
RI
CH
3
H
2-45 3 -Hdroxv-3-phenylroPyl) -amino) 5-(3methyiphenyl)-4-(4-pvridyl)-pyrimidine: 2-Chloro-5-(3rethylphenyl)-4-(4-pyridyl)-pyriidine and 3-hydroxy-3phenyipropylamine were reacted according to the General Procedure, Step C (100 0 C for 30 min) to give the title compound. MS 397.2
C
25
H
24 N 0requir.
396.5.
HO
N
Rl1 H 2-46 2
R,
3 R)-3-Amino-2-methyl-3-p~henvlropyl)amino)-4-4-pyridyl)-5-( 3 -trifluoromethylphenvl)pyrimidine hydrochloride: 2-Chloro-4-(4-pyridyl)-5-(3trifluoromethyiphenyl)-pyrimidine and (iR,2R)-2-methyll-phenyl-l,3-propanediamine were reacted according to the General Procedure, Step C (50C for 1 h) to give the title compound. MS 464.4 C26H24F3N5 requir. 463.5 (free base).
NH
2
N/
R1 IH
H
CH
3 2-47 2 2 S,3S)-3-Amino-2-methl-3-phenvlpropyl)amino)-4-(4-TDvridyl)-5-(3-trifluoromethvlphenyl)pyrimidine hydrochloride: 2-Chloro-4-(4-pyridyl)-5-(3trifluoromethyiphenyl) -pyrimidine and (iS,2S) -2-methyll-phenyl-l,3-propanediamine were reacted according to the General Procedure, Step C (90 0 C for 45 min) to give the title compound. MS 464.1 C26H24F3N5 requir. 463.5 (free base).
WO 98/24782 WO 9824782PCTIUS97/22390 126
NH
2 R1= H H 2-48 2 -((S)-3-BenzvlPi-Qerazinvl)- 4-(4-Pyridyl)-5-(3trifluoromethylphenyl) -pvrimidine hydrochloride: 2- Chloro-4- (4-pyridyl) -5-(3-trifluoromethylphenyl) pyrimidine and (S)-2-benzylpiperazine were reacted according to the General Procedure, Step C (70 0 C for min) to give the title compound. MS 475.5 C27H24F3N5 requir. 476.1 (free base).
2-49 4- (4-Pyridyl) -tetrahvdroisocfuinol-3vimethylen) amino) (3-trifluoromethylphenyl) -pyrimidine hydrochloride: 2-Chloro-4- (4-pyridyl) trifluoromethylphenyl) -pyrimidine and tetrahydroisoquinol-3-ylmethylenamine were reacted according to the General Procedure, Step C (50'C for h) to give the title compound. MS 462.4 (M+H) 4 C26H22F3N 5 requir. 461.5 (free base).
Cl ULNH 2-50 5-(3-Methvlp~henyl)-4-(4-pvridyl)-2-(( tetrahvdroisooruinol-3-vlmethylen) amino) -pyrimidine hydrochloride: 2-Chloro-5- (3-methylphenyl) (4pyridyl) -pyrimidine and -tetrahydroisoquinol-3ylmethylenamine were reacted according to the General Procedure, Step C (100 0 C for 45 min) to give the title compound. MS (mlz) 408.2 C26H25N5 requir.
407.5 (free base).
=i C=,*00 om
NH
WO 98/24782 PCT/US97/22390 127 Example 3 General procedure for the preparation of (4-fluorophenyl) (4-pyridyl) -pyrimidines N N 0 N NH 2 N N R N
N
0 R R 1
OR
20 or NR 5
R
2 The chlorocarbonyl R-C(O)C1 (0.57 mmol) was added dropwise to a solution of 2-amino-5-(4-fluorophenyl)-4- (4-pyridyl)-pyrimidine (0.38 mmol) in pyridine (3 ml) at ice-bath temperature. It was stirred for 3 h at room temperature, monitored by thin layer chromatography, poured into ice-water, extracted with dichloromethane, dried and evaporated. The crude product can be purified by silica gel column chromatography (hexane-acetone) and recrystallized from a suitable solvent such as ethyl acetate.
The following compounds were prepared using the appropriate acid chloride according to this procedure: 3-1 2-Acetamido-5-(4-fluoroDhenvl) -4-(4-yridy) pyrimidine: MS 309.0
C
1
,H
1 3
FN
4 Orequir.
308.3. 1H-NMR (CDC1 3 d 8.63 1H, H-6, Pyrim.), 8.60, 7.29 (2m, each 2H, Pyrid.), 8.26 (bs, 1H, NH), 7.14, 7.08 (2m, each 2H, PhF), 2.58 3H, CHCO).
R CH,- 3-2 2-Butvramido-5-(4-fluorohenvl) -4-(4-pyridyl) yvrimidine: MS 337.2 336.4. -H-NMR (CDC1 3 d 8.64, 1H, H-6, Pyrim.), 8.60, 7.31 (2m, each 2H, Pyrid.), 8.17 (bs, 1H, NH), 7.14, 7.08 (2m, each 2H, PhF), 2.80 2H, CHCO), 1.82 2H, 1.06 3H, CH,).
WO 98/24782 PCTIUS97/22390 128 R
CH
3
CH
2
CH
2 3-3 5- 4 -Fluorohenyl)-2-Pivalamido-4 D-pyridyl) vriinidine: MS 351.0
C
20 H JFNrequir.
350.4. 'I-NMR (CDC1 3 d 8.69 1H, H-6, Pyri.), 8.60, 7.35 (2m, each 2H, Pyrid.), 8.25 (bs, 1H, NH), 7.15, 7.08 (2m, each 2H, PhF), 1.4 9H, 3CH) R
(CH)
3
C-
3-4 2 -Benzamido-5-(4-fluorophenvl)-4-(4-pyridyl)yriinidine: MS 371.0
C
22
H
15
FN
4 0 requir.
370.4. 'H-NMR (CDC1,): d 8.75 2H, NH, H-6, Pyrim.), 8.61, 7.36 (2m, each 2H, Pyrid.), 8.00, 7.63, 7.55 (d, t, t, 2H, 1H, 2H, Ph), 7.18, 7.10 (2m, each 2H, PhF).
R=Q
5-(4-Fluorophenyl)- 2 -phenyacetamido-4- (4-pyridyl)pyrinidine: MS 385.0
C
23
H,
7 FNOrequir.
384.4. 'H-NMR (CDC1 3 d 8.66 1H, H-6, Pyri.), 8.59, 7.28 (2m, each 2H, Pyrid.), 8.21 (bs, 1H, NH), 7.43-7.30 5H, Ph), 7.14, 7.08 (2m, each 2H, PhF), 4.13 2H, CH 2) 3-6 5-(4-Fluorophenyl)-2-hdrocinnamamido-4-(4pyridyl) -Pyrimidine: MS 399.2
C
24
H
19
FN
4 0 requir. 398.4. 'H-NMR (CDCi 3 d 8.60 1H, H-6, Pyri.), 8.54 2H, Pyrid.), 8.20 (bs, 1H, NH), 7.31- 7.16 714, Ph, Pyrid.), 7.11, 7.05 (2m, each 2H, PhF), 3.20, 3.09 (2t, each 2H, 2CHO).
R oo WO 98/24782 PCT/US97/22390 129 Example 4 General procedure for the preparation of 2 -substituted 4 -fluorophenyl) -6-(4-pyridyl) -4 (3H)-pyrimidones 0 H' F 0
H
2 N a. R= H H Rb. Et 0 0 F F
O
N 1 NR N/
N
a. 2 4 -Fluorophenvl)-3-(4-pyridvl)-acrylic acid: A mixture of 4 -fluorophenylacetic acid (9 g, 58.4 mmol), 4 -pyridinecarboxaldehyde (5.6 ml, 58.6 mmol), pyridine (6 ml) and acetic anhydride (6 ml) was heated at 150 0
C
for 1 h followed by evaporation and co-distillation with water. The resulting material crystallized on addition of ethanol. The solids were filtered and washed with ethanol and ethyl acetate to provide the title compound.
MS 244.0
C
14
H,
0 FNOrequir. 243.2 'H-NMR (DMSO-d,): d 8.43, 6.98 (2d, each 2H, Pyrid.), 7.73 (s, 1H, 7.21 4H, PhF).
b. Ethyl 2 4 -fluoroDhenvl)-3-(4-pvridyl)-acrylate: Cone. sulfuric acid (2.2 ml) was added carefully to a suspension of 2-( 4 -fluorophenyl)-3-(4-pyridyl)-acrylic acid (6.7 g, 27.5 mmol) in ethanol (120 ml) and the mixture was heated at reflux for 24 h. The solvent was evaporated, the remainder was taken up in dichloromethane and the organic solution was washed with aqueous sodium hydrogencarbonate and water, followed by drying and evaporation. Flash column chromatography on WO 98/24782 PCT/US97/22390 130 silica gel (hexane-acetone 2:1) provided the pure title compound. MS 271.8 C 6
H
14
FNO
2 requir.
271.3 'H-NMR (CDC1 3 8.44, 6.88 (2m, each 2H, Pyrid.), 7.72 1H, 7.16, 7.06 (2m, each 2H, PhF), 4.28 2H, 1.28 3H, CH,).
c. General procedure: A stirred mixture of ethyl 2-(4fluorophenyl)-3-(4-pyridyl)-acrylate (357 mg, 1.38 mmol), the amidine hydrochloride (2.61 mmol) and sodium methoxide (250 mg, 4.62 mmol) in ethanol (5 ml) was heated in a sealed tube at 1200C for 3 h. It was neutralized with 2N hydrochloric acid prior to evaporation. The residue was taken up in acetic acid ml) and treated with sodium nitrite (670 mg, 9.71 mmol) at 44°C for 20 min. After evaporation, the resultant product was taken up in dichloromethane and the solution was washed with aqueous sodium hydrogencarbonate and water before drying and evaporation. The product was purified by recrystallization from methanol. If the crude product of nitrite oxidation was water soluble, as was found for 5-(4-fluorophenyl)-2-methyl-6-(4-pyridyl)-4(3H)pyrimidinone, then no aqueous work up was done, but the material obtained on evaporation was applied to a column of silica gel methanol/dichloromethane) prior to recrystallization.
The following compounds were prepared accordingly using the appropriate amidine hydrochloride: 4-1 5-(4-Fluorophenvl)-2-methvl-6-(4-pyridvl)-4(3H)pyrimidinone: MS 282.2 C1,HFNO requir.
281.3 1 H-NMR (DMSO-d): d 8.46 (m 2H, Pyrid.), 7.2-7.03 6H, PhF, Pyrid.). 2.38 3H, CH,).
R1
CH,-
4-2 5-(4-Fluorophenvl)-2-isopropvl-6-(4-pyridvl)-4(3H)pyrimidinone: MS 310.0 C 1
,H,
1
FN
3 0 requir.
309.4 'H-NMR (DMSO-d 6 8.45 2H, Pyrid.), 7.21-7.03 WO 98/24782 PCTIUS97/22390 131 6H, PhF, Pyrid.), 2.90 1H, CH(CHO1) 2 1.26, 1.24 (2s, each 3H, 2CM 3 R1 (CH,)CH- 4-3 2-(2,6-Dichlorobenzvl)-5-(4-fluorophenyl)-6-(4.
rwridyl)-4(3H)--pvrimidinone: MS 426.0
C
22
H
14 C1 2
FN
3 Orequir. 426.3 'H-NMR (DMSO-d,): d 8.37 2H, Pyrid.), 7.50 2H, PhC1 2 7.35 1H, PhC1 2 7.18- 7.08 4H, PhF), 6.96 2H, Pyrid.), 4.36 2H,
CH
2 C1 R1 I C1 4-4 5-(4-Fluorophenvl)-2-phenyl-6-(4-yridl)-4(3H)pyrimidinone: MS 344.2 C 21
H
14
FN
3 0 requir.
343.4 'H-NMR (DMSO-d,): d 8.49 2H, Pyrid.), 8,20 (d, 2H, Ph), 7.66-7.50 3H, Pyrid., Ph), 7.32-7.11 (m, 6H, PhF, Ph).
R1= 5-(4-Fluorophenyl)-2-(4-phenvlbutyl)-6-(4-pyridyl)- 4(3H)-iprimidinone: Ethyl 2-(4-fluorophenyl)-3-oxo-3- (4-pyridyl)-propionate (293 mg, 1.02 nmol), 4phenylbutanecarboxamidine (315 mg, 1.79 mmol) and pyridiniui p-toluenesulfonate (10 mg) were suspended in p-xylene (10 ml). With efficient stirring, the mixture was heated to reflux using a Dean-Stark apparatus with continuous removal of water. After 16 h, the solvent was evaporated and the product purified by column chromatography on silica gel methanol! dichioroiethane) followed by recrystallization from acetone. MS 400.3 C 25
H
2 2
FN
3 0 requir. 399.5 R1 Ph(CH 2 4 WO 98/24782 WO 9824782PCTIUS97/22390 132 Example General procedure for the preparation of (4-fluorophenyl) (4-pyridyl) -2-thioalkyl-4 (3H) pyrimidinones Stelp A. Ethyl 2 -(4-fluorophenvl)-3-oxo-3-(4-pvridvl)- Pr Tpionate: 0 F0 N Et 0 OEt OEt NA (According to: Legrand and Lozac'h, Bull. Soc. Chirn.
Fr., 79-81 (1955)).
A mixture of ethyl 4-f luorophenylacetate (13 g, 71.35 mrnol), ethyl isonicotinate (10.7 ml, 71.4 mmol) and sodium spheres (1.64 g, 71.34 inmol) was heated at 90-95 C under argon. The mixture started to ref lux and gradually turned into a solid. After 2.5 h, the mixture was neutralized with dii. acetic acid with cooling followed by extraction with dichioromethane. The organic solution was washed with water, dried and evaporated. Flash chromatography on a column of silica gel (hexane-acetone 4:1, 3:1, 2:1) provided the title compound as an oil. MS 287.8 C 16
H
14 FN0 3 requir. 287.3 1 H-NMR (CDCl 3 (ketone enole 1: 0.33): d 13.50 0.3H, OH-E), 8.81 (in, 2H, Pyrid.-K), 8.48 (in, 0.66 H, Pyrid.-E), 7.72 (in, 2H, Pyrid.-K), 7.38 (mn, 2H, PhF-K), 7.14-7.04 (mn, 2H, PhF-K; -0.65H, Pyrid.- E; -0.65H, PhF-E), 6.96 0.64H, PhF-E), 5.51 1H, CH-K), 4.23-4.2- (in, CH 2 E) 1. 26 CH 3 E) Step B. 5-(4-fluorophenvl)-6-(4-pvridyl)-2-thiouracil: F F 2 NC QEt H 2 i
NH
WO 98/24782 PCT/US97/22390 133 A stirred mixture of ethyl 2-(4-fluorophenyl)-3oxo-3-( 4 -pyridyl)-propionate (22.3 g, 77.6 mmol) and thiourea (5.9 g, 77.6 mmol) was reacted at 190 C under argon for 40 min. The reaction mixture was allowed to reach room temperature, taken up in acetone and the precipitate was filtered to provide the title compound.
MS 300.2 CH 15
HIFN
3 OS requir. 299.3 'H-NMR (DMSO-d,): d 12.74, 12.65 (2s, 2H), 8.51 2H, Pyrid.), 7.26 2H, Pyrid.), 7.09 and 7.03 (2m, each 2H, PhF).
Alternatively, ethyl 2-(4-fluorophenyl)-3-oxo-3-(4pyridyl)-propionate (2.87 g, 10 mmol) and thiourea (2.28 g, 30 mmol) were suspended in anhydrous p-xylene (50 ml) with very efficient stirring. To the mixture pyridinium p-toluenesulfonate (100 mg) was added and refluxed for 12-16 h using a Dean-Stark apparatus with continuous removal of water (0.2 ml). Reaction mixture was cooled and a dark brown solid was filtered using a Buchner funnel. The collected solid was suspended in acetone (25 ml) and filtered. The acetone washed product contained a trace of thiourea, which was removed by trituration with hot water (20-30 ml). The product was filtered and airdried.
Step C. General Drocedure: The arylalkyl bromide (0.36 mmol) was added dropwise to a stirring mixture of 5-(4-fluorophenyl)-6- (4-pyridyl)-2-thiouracil (100 mg, 0.33 mmol) and potassium carbonate (46 mg, 0.33 mmol) in N,Ndimethylformamide (4.6 ml). Stirring was continued for 3h followed by evaporation. Flash chromatography on a column of silica gel (hexane-acetone 3:1, 2:1, 1:1) and recrystallization from hot methanol provided the target compound.
The following compounds were obtained using the appropriate arylalkyl bromide according to the above procedure: WO 98/24782 PCTIUS97/22390 134 5-1 5-(4-Fluorophenvl)- 2 -(2-Dhenylethvl)thio-6-(4 rwridyl) 4(3H)jpyrimidinone: MS 404.2
C
23 H1FN 3 OS requir. 403.4. 'H-NMR (DMSO-d,): d 13.08 (bs, 0.7H), 8.49 2H, Pyrid.), 7.30-7.06 11H, Pyrid., Ph, PhF), 3.41 (dd, 2H, CH 2 3.00 2H, CH) 5-2 5-( 4 -Fluorophenvl)-2-(3-D~henvliro~pl)thio-6-(4 vyridyl)-4(3H)-pyrimidinone: MS 418.0 C24 H FN OS requir. 417.5. 'H-NMR (DMSO-d,): d 13.10 (bs, 0.7H), 8.47 2H, Pyrid.), 7.29-7.06 11H, Pyrid., Ph, PhF), 3.18 2H, CH 2 2.71 2H, CHPh), 2.03 2H,
CH').
5-3 5-(4-Fluorophenvl)-2-(2-phenoxvethyl)thio-6(4.
pvridyl)-4(3H)-pvrimidinone: MS 420.0
C
23
H
18 FN30 2 S requir. 419.5. 'H-NMR (DMSO-d,): d 13.20 (bs, 0.7H), 8.46 2H, Pyrid.), 7.24-7.07 8H, Pyrid., PhF, Ph), 6.95 2H, Ph), 6.92 overlapped, 1H, Ph), 4.30 2H, CH 3.58 2H, CH 2
S).
200 5-4 5-(4-Fluorophenvl)-2-(2-phenlaminoethvl)thio-6-(4pvridyl) -4 (3H) -priiidinone: MS 419.0
C
2 3
H
19
FN
4 OS requir. 418.5. 1 H-NMR (DMSO-d,): d 13.20 (bs, 0.8H), 8.48, 7.22 (2m, each 2H, Pyrid.), 7.16, 7.10 (2m, each 2H, PhF), 6.89 2H, Ph), 6.54 2H, Ph), 6.48 (t, 1H, Ph), 5.90 (bs, 0.6H, NH), 3.43-3.25 2CHO).
H
N~\S
WO 98/24782 PCTIUS97/22390 135 Example 6 General -procedure for the preparation of 2-N substituted (4-f luorophenyl) (4-pyridyl) -4 pyrimidinones: Step A. 5-( 4 -Fluorop~henv1)-2-methvlthio-6-(4-pridl) 4 (3H) -ipvrimidinone: F 0 F 0 NH
N
N' SH N' SCH 3 Methyl iodide (90 ml, 1.44 imnol) was added dropwise to a stirred mixture of 5-(4-fluorophenyl)-6-(4pyridyl)-2-thiouracil (430 mg, 1.44 mmol) and potassium carbonate (198 mg, 1.43 mmol) in N,N-dimethylformamide (13 ml) at ice-bath temperature. After 40 min, it was evaporated and the crude product purified by flash chromatography on a column of silica gel (hexane-acetone 1:1, 1:2) to provide the title compound as a solid. MS (mz) 314.2 C 16
H
12
FN
3 OS requir. 313 .3.
1 H-NMYR (DMSO-d,) d 13. 10 8. 47, 7.22 (2m, each 2H, Pyrid.), 7.16, 7.10 (2m, each 2H, PhF), 2.56 3H,
CHR
3 Steip B. General pDrocedure: F F NH
N
N4 SCH 3 IN NR R A mixture of 5-(4-fluorophenyl) -2-methylthio-6-(4pyridyl)-4(3H)-pyrimidinone (100 mg, 0.32 mmol) and an amine HNR'R 21(1 mmol) was heated at 180 0 C for 2 h. The resulting product was purified by flash chromatography on a column of silica gel (hexane-acetone or methanol- WO 98/24782 PCTIUS97/22390 136 dichloromethane or dichlororethane-methanol-conc.
ammonium-hydroxide) to provide the target compound.
The following compounds were prepared using the general procedure outlined above and an appropriate amine: 6-1 2 2 2 -ChloroThenvl)ethyl-amjno)-5-(4.
fluorophenyl) (4-pyridyl) -4 (3H) -pyrimidinone:
MS
421.2 C 2 3 ,8ClFN 4 Orequir. 420.9. 'H-NMR (DMSO-d,) d 11.24 (bs) 8.44, 7.16 (2m, each 2H, Pyrid.), 7.43, 7.38 (2dd, each 1H, Phd), 7.30, 7.26 (2dt, each 1H, Phd), 7.10-7.00 Cm, 2H, PhF), 6.74 (bs, 1H, NH), 3.60 2K, CH 2 3.03 2H, CH 2
H
R
N,
CI
6-2 S-( 4 -Fluorophenl)-2-((3-phenylpropyl)-aiino)-6(4 Pyridyl) -4 (3H) -pyrimidinone: MS 401.2 CM+H);
C
24
H
21 FN.O requir. 400.5. 'H-NMR (DMSO-d,): d 11.16 (bs), 8.44, 7.14 (2m, each 2H, Pyrid.), 7.32-7.01 Cm, 9H, Ph, PhF), 6.78 Cbs, NH), 3.36 2H, CH 2 2.67 Ct, 2H, CHPh) 1.89 2H, CH 2
N
6-3 5-(4-Fluorophenyl)-2-((l-methyl-3-phenvlpropyl)amino) pyridyl) -4 (3H) -pyrimidinone: A reaction time of 15 h at 180 C was required. MS 415.0
C
25
H
23 FNOrequir. 414.5. 'H-NMR CCDC1): d 8.48 2H, Pyrid.), 7.28-7.08 9H, Pyrid., Ph, PhF), 6.94 2H, PhF), 5.67 (bs, 1H, NH), 4.08 1H, CHCH,), 2.61 2H, CHPh), 1.67 2H, CH 2 1.08 (d, 3H, CH).
WO 98/24782 PCTIUS97/22390 137
CH
3
*N
N
R H 6-4 5-(4-Fluorophenyl)-2-((3-imidazolylpropyl)-amino)- 6-(4-pyridyl) -4(3H) -pvrimidinone: MS 391.0
C
21 H 19
FN
6 Orequir. 390.4. 'H-NMR (DMSO-d 6 d 11.24 8.42, 7.12 (2m, each 2H, Pyrid.), 7.62, 7.18 (2s, each 1H, Imid.), 7.08-6.99 4H, PhF), 6.88 1H, Imid.), 4.02 2H, CH 2 3.28 (overlapped by water signal, CHNH), 2.00 21, CH 2 R 1 N H 6-5 2-(((S)-2-Amino-3-phenylpropyl)-amino)-5-(4fluorophenyl) (4-pyridyl) -4 (3H) -pyrimidinone hydrochloride: The reaction was done at 170 0 C for 7 h.
MS 416.1 C 2 6
H
2 2FN 5 0 requir. 415.5.
R=
N
NH2 Example 7 5-(4-Fluorophenyl)-2-hydrazino-6-(4-pyridyl)-4(3H)pyrimi dinone A mixture of 5-(4-fluorophenyl)-6-(4-pyridyl)-2thiouracil (500 mg, 1.66 mmol) and hydrazine hydrate (800 ml, -14 mmol) was heated at 120 0 C for 60 min. It was evaporated and the reaction product was recrystallized from hot methanol to provide the title compound. MS 298.0 C 15
H
12
FN
5 Orequir.
297.3. 'H-NMR (DMSO-d): d 8.41, 7.12 (2m, each 2H, Pyrid.), 7.05, 7.00 (2m, each 2H, PhF).
NH-NH
2 WO 98/24782 PCT/US97/22390 138 Example 8 General procedure for the preparation of 5-aryl-2,6dipyridyl- (3H) -pyrimidinones 8-1 2 NCN
H
OEt OEt OEt P'CN 2 8-4
^CN
2
N
FN 0 Il These compounds were prepared according to the literature (Kabbe, supra; German Patent 1271116 (1968)) as follows: A stirred mixture of the ethyl phenylacetate (3.13 mmol), cyanopyridine (6.24 mmol) and sodium methoxide mmol) in n-butanol (1.2 ml) was heated at 110 0 C for 2h. The reaction mixture was concentrated and dissolved in water (4 ml), followed by the addition of aqueous sat. ammonium chloride (2 ml). The precipitate was filtered and recrystallized from hot methanol.
WO 98/24782 PCTIUS97/22390 139 The following compounds were prepared according to this procedure using the appropriate starting materials: 8-1 5-Phenvl-2,6-bis-(4-pvridl)-4-(3 H )Ipvrimidinone:
MS
327.2
C
2 0
H
1 4 4 Orequir. 326.4. 'H-NMR (DMSOdj): d 8.78, 8.47, 8.13 (3m, each 2H, Pyrid.), 7.40-7.14 7H, Ph, Pyrid.).
8-2 5-( 4 -Fluorophenl)-2,6-bis-(4ny-ridyl)-4(3H)_ lvrimidinone: MS 345.2 C2 H 1FN 4 O requir.
344.4 'H-NMR (DMSO-d 6 d 8.80, 8.49, 8.13 (3m, each 2H, Pyrid.), 7.40-7.08 6H, PhF, Pyrid.).
8-3 2. 5,6-Tris-(4-yridyl)-4(3H)-Pvrimidinone was prepared according to the general procedure by reacting ethyl 4-pyridylacetate and 4-cyanopyridine in the presence of sodium methoxide. MS 328.2
C
19
H
13
N
5 Orequir. 327.4 H-NMR (DMSO-d 6 8.65, 8.45, 8.35, 8.18, 7.25, 7.13 (6m, each 2H, Pyrid.).
8-4 5-( 4 -Fluorophenvl)-2,6-bis-(3-pyridyl)-4(3H)_ Pyrimidinone: MS 345.2 C2 H 1FN 4 O requir.
344.4 'H-NMR (DMSO-d,): d 9.34, 8.77, 8.54, 8.48, 7.78, 7.60, 7.34 (7m, 3xlH, 2H, 3xlH, Pyrid.), 7.26, 7.15 (2m, each 2H, PhF).
Example 9 4 -Amino-5-(4-fluorophenyl)-2,6-bis-(4-pyridyl)pyrimi dine NC F NH2
CNI
F N
N
(4-f luorophenyl) 6-bis- (4-pyridyl) pyrimidine was prepared according to the literature (Kabbe, supra): Sodium rethoxide (180 mg, 3.33 nmol) was added to a stirred solution of 4-cyanopyridine (650 mg, 6.24 mmol) WO 98/24782 PCT/US97/22390 140 and 4 -fluorophenylacetonitrile (375 mml, 3.12 mmol) in n-butanol (1.5 ml). The mixture was stirred for 20 min at room temperature before heating it at 110 0 C for h. It was allowed to reach room temperature and ethanol (2.5 ml) was added. The precipitate was filtered and recrystallized from acetic acid/water (3.5/10 ml) to provide the title compound. MS 344.2
C
20
H
1 4
FN
5 requir. 343.4 'H-NMR (DMSO-d,): 8.76, 8.47, 8.22 (3m, each 2H, Pyrid.), 7.4-7.16 6H, PhF, Pyrid.).
Example 4-Methoxy-5-phenyl-2, 6-bis- (4-pyridyl) -pyrimidine O R R Cl SN R OMe N N NN
N
N Ng A mixture of 5-phenyl-2,6-bis-(4-pyridyl)-4(3H)pyrimidinone (360 mg, 1.10 mmol) and phosphorus oxychloride (2 ml) was heated at reflux for 1.5 h.
Work-up was done as described for the preparation of 2chloro-5-(4-fluorophenyl)-4-(4-pyridyl)-pyrimidine. To a solution of the crude 4-chloro-5-phenyl-2,6-bis-(4pyridyl)-pyrimidine (250 mg, 0.73 mmol) in methanol ml) was added methanolic 0.5 N sodium methoxide (1.45 ml, 0.73 mmol) and it was heated at reflux for 1 h.
After evaporation, the resultant material was partitioned between ethyl acetate and water. The organic solution was washed with water, dried and evaporated. Chromatography of the crude product on a column of silica gel (ethyl acetate) provided the title compound. MS 341.2 C 1
HN
4 0 requir. 340.4 'H-NMR (CDC1 3 8.82, 8.54, 8.40 (3m, each 2H, Pyrid.), 7.40-7.18 7H, Ph, Pyrid.), 4.15 3H, CH 3 0).
WO 98/24782 WO 9824782PCT[US97/22390 141 Example 11 Procedure for the preparation of 5-(4-F~luorophenyl)-2,4bis- (4-pyridyl) -pyrimi dine Step A. 4-Chloro-5- (4-fluoroiphenyl) 6-bis- (4pyridyl) -pyrirnidine: F, F 0 C NH N Amixture of 5-(4-fluorophenyl)-2,.6-bis-(4pyridyl)-4(3H)-pyrimidinone (760 mg, 2.21 minol) in phosphorus oxychioride (3 ml) was heated at ref lux f or 1 h. Work-up was done as described for the preparation of (4-f luorophenyl) (4-pyridyl) -pyrimidine. A portion (290 mg) of the resulting product (495 mg) was purified by flash chromatography (ethyl acetate, trace triethylamine) on silica gel. MS 363.2 C 20
H
12 ClFN 4 requir. 362.8 1 H-NMR (CDC1,) d 8.84, 8.60, 8.38, 7.30 (4m, each 2H, Pyrid.), 7.22, 7.13 (2m, each 2H, PhF).
Step B. 5-(4-Fluoroiphenyl)-2,4-bis- (4-ovridyl)- -pyrimidine: Fv F N N N N
N
N 0 ,N N A stirred mixture of 4-chloro-5- (4-f luorophenyl) 2,6-bis-(4-pyridyl)-pyrimidine (99 mg, 0.27 mmol) and palladium-on-carbon (70 mg) in ethanol (10 ml) was hydrogenated under an atmosphere of hydrogen for 28 h.
Filtration and evaporation of the solvent was followed by flash chromatography (ethyl acetate) on a column of WO 98/24782 PCT/US97/22390 142 silica gel to provide the title compound. MS 329.2
C
20
HFN
4 requir. 328.4. 'H-NMR (CDC1) d 8.91 1H, H-6, Pyrim.), 8.83, 8.65, 8.40, 7.45 (4m, each 2H, Pyrid.), 7.30-7.06 4H, PhF).
Example 12 Procedure for the preparation of 2 Glycylamino-3-phenylpropyl) -amino) -4 (4-pyridyl) (3trifluoromethylphenyl) -pyrimidine hydrochloride
F
3 C N NH2N H 12-1 2 -N-Glvcvlamino-3-Dhenvlpropyl)-amino)-4- 3 -trifluoromethylphenvl)-pvrimidine hydrochloride: Ethyl chloroformate (86 gl, 0.901 mmol) was added at ice-bath temperature to a stirring mixture of N-(tert.-butoxycarbonyl)glycine (160 mg, 0.911 mmol) and 4-methylmorpholine (110 g1, 1.00 mmol) in tetrahydrofuran (10 ml). After 40 min, a solution 2- 2 -amino-3-phenylpropyl)-amino)-4-(4-pyridyl)-5-(3trifluoromethylphenyl)-pyrimidine (409 mg, 0.911 mmol) in tetrahydrofuran (15 ml) was added at ice-bath temperature. Within 1 h, the mixture was allowed to reach room temperature. It was diluted with dichloromethane, washed with aqueous sodium hydrogencarbonate, followed by drying of the organic solution and evaporation. The resulting material was purified on a column of silica gel methanol/dichloromethane), then dissolved in methanol (2 ml) and 4N hydrogen chloride/dioxane (2 ml) was added. After 1 h at room temperature, it was evaporated and the remainder taken up in dichloromethane followed by washing with aqueous sodium hydrogencarbonate, drying of the organic solution and evaporation. Column chromatography on silica gel (dichloromethane methanol cone. ammonium hydroxide WO 98/24782 PCT/US97/22390 143 5 0; 90 10 0.6) provided the title compound as the free base which was converted into the hydrochloride by the addition of 4N hydrogen chloride/dioxane (85 Il) to its methanolic solution (3 ml) followed by evaporation. MS 507.4
C
27
H
25 FNOrequir. 506.5 (free base).
The following compound was prepared using the above procedure and the appropriate starting materials: 12-2 2-(((S)-2-N-G1ycvlamino-3phenvlropyl)-amino)-5- 3 -methylphenl)-4-(4-pvridl) -pyrimidine hydrochloride: MS 453.2
C
27 H ,NOrequir. 452.6 (free base).
Example 13 Procedure for the preparation of Benzyl ethyl endiamine QNH2 NH 2 2 -Benzvlethylendiamine: The diamine was prepared according to the literature Brunner, P. Hankofer,
U.
Holzinger, B. Treittinger and H. Schoenenberger, Eur. J.
Med. Chem. 25, 35-44, (1990)) by reduction of Lphenylalanine amide with lithium aluminium hydride. The (R)-enantiomer was prepared in the same manner from Dphenylalanine amide.
Example 14 Procedure for the preparation of 2 -(((S)-2-Acetamido-3phenylpropyl) -amino) 4 -fluorophenyl) -3-methyl-6- (4pyridyl) -4 (3H) -pyrimidinone WO 98/24782 PCT/US97/22390 144 0 F 0 N
N
N N N
H
N~ N-'zfl~ H NEAc 2 -Acetamido-3-phenylprolyl)-amino)-5-(4fluorophenyl) -3-methyl-6- (4-lvrivl) -4 (3H) -pyrimidinone: A solution of 2 4 -fluoropheny)-3-methyl 6-(4-pyridyl)4 (3H)pyrimidinone (25 mg, 0.058 mmol) and acetic anhydride (200 ml) in methanol (2 ml) was kept at room temperature for 1 h. Evaporation followed by chromatography of the resultant product on a column of silica gel methanol/dichloromethane) provided the title compound.
MS 472.3 C27H26FN50 2 requir. 471.5.
Example Procedure for the preparation of Isopropylanino-3-phenylpropyl)-amino)-4-(4-pyridyl)-5- (3-trifluoromethyphenyl)-pyrimidine hydrochloride
F
3 C N N
N
N,/I H 15-1 2 -N-Isopropvlamino-3-phenvlpropl)-amino)- 4-(4-yridyl)-5-(3-trifluorometh1ihenl)-pvrimidine hydrochloride: Sodium triacetoxyborohydride (184 mg, 0.868 mmol) was added to a strirring mixture of 2-amino-3-phenylpropyl)-amino)-4-(4-pyridyl)-5-(3trifluoromethylphenyl)-pyrimidine (300 mg, 0.668 mmol) and acetone (50 gl, 0.675 mmol) in 1,2-dichloroethane (4 ml). After 16 h, the reaction was quenched by the addition of sat. aqu. sodium hydrogencarbonate, followed by extraction with dichloromethane, drying of the organic solution and evaporation. Chromatography on a WO 98/24782 PCTfUS97/22390 145 column of silica gel methanol/chloroform) provided the title compound as a free base which was converted into the monohydrochloride by the addition of 6N hydrochloric acid (73 gl) to its methanolic solution (3 ml) and subsequent evaporation. MS 491.7 28 H 28
F
3 N requir. 491.6 (free base) The following compounds were prepared using the above procedure and the appropriate starting materials: 15-2 2- S) 2 -N-Cclohexvlamino-3 PhenVlproyl) -amino) 4- (4-Pyridyl) 3 -trifluoromethylphenyl) -Dvrimidine hydrochloride: MS 532.0
C
31
H
32 FN requir.
531.6 (free base).
R1 15-3 2- 2 -N-Isoioropvlamino-3...Dhenvlpropyl) -amino) 5-(3-methvlphenyl)-4-(4-p ridyl)--P yrimidine hydrochloride: MS 439.1
C
28 H31N5 requir.
437.6 (free base).
A N 15-4 2 -N-Butlamino-3-Iphenylpropl) -amino) methvlhenyl) 4 -yridvl -iprimidine hydrochloride:
MS
452.1
C
29
H
33
N
5 requir. 451.6 (free base) 01 NH 15-5 2- -2-N-Cyc lohexylamino-3-~henvlrovl) -amino) 5-C 3 -methvlhenyl) (4-pyridyl) -vrimidine hydrochloride: MS 478.3
C
31
H
3 N 5 requir.
477.7 (free base).
WO 98/24782 WO 9824782PCTIUS97/22390 146 15-6 5-(4-Fluorophenyl)-2-( 2 -N-isoporopylamino-3iphenvipropyl) -amino) (4-pyridyl) -pyrimidine hydrochloride: MS 442.1 C 27
H
2 ,FN, requir.
441.6 (free base).
15-7 5-(4-Fluorophenyl)-2-( 3 -N-isopropylamino-3phenyilpropyl) -amino) (4-pyridyl) -pvrimidine hydrochloride: MS 442.2
C
27 H 28 FN 5 requir.
441.6 (free base).
HN
R1 a WO 98/24782 PCT/US97/22390 Example 16 Procedure for the preparation of 2-(((S)-2-Amino-3phenylpropyl) -amino)-5- (3-chloro-4-fluorophenyl)-4- (4pyridyl)- pyrimidine hydrochloride 0 0 [NH 2
N
N; NMe 2
'I
N 1) 1 N N
NH
2 ByN
N
NH
2 N
N
NH2 SteD A: 4 4 -Pvridvl)-2(1H)-pvrimidinone: A mixture of 4 -acetylpyridine (25 ml, 226.0 mmol) and bis(dimethylamino)methoxymethane (44 ml, 293.8 mmol) was heated at 85 0 C for 30 min followed by evaporation to dryness to recover a solid of 3-(dimethylamino)-1-(4pyridyl)-3-propen-l-one. Its ethanolic solution (200 ml) was transferred into ethanolic 1.13 N sodium ethoxide (200 ml) containing urea (16.3 g, 271 mmol).
The mixture was heated to reflux overnight, then cooled down to ice-bath temperature. The precipitate was filtered, dissolved in a minimal amount of water and the aqueous solution was washed with dichloromethane. The title compound was precipitated from the aqueous solution by neutralization with 6N hydrochloric acid and filtered. More material was obtained from the original reaction filtrate which was concentrated, diluted with a minimal amount of water and washed with dichloromethane.
The aqueous solution was neutralized with 6N hydrochloric acid and the precipitate filtered. MS 174.1 CH N 3 0 requir. 173.2.
WO 98/24782 PCT/US97/22390 148 Step B: 2-Chloro-4-(4-pyridyl)-ovrimidine: With icebath cooling under argon, 4-(4-pyridyl)-2(1H)pyrimidinone (13.45 g, 77.7 mmol) and thionyl chloride (92 ml) were combined. N,N-Dimethylformamide (13.2 ml, 170.5 mmol) was added slowly and the mixture was heated to reflux for 1 h. It was evaporated and co-distilled with toluene. At 0°C, water was added to the remainder, then 10% ammonium hydroxide until neutral followed by extraction with dichloromethane. Drying of the organic solution was followed by evaporation and the resultant solid was recrystallized from acetone. MS 192.1,194.0 CHC1N, requir. 191.6.
Step C: 2-(((S)-2-Amino-3-phenvlpropyl)-amino)-4-(4pyridvl)-pyrimidine: A mixture of 2-chloro-4-(4pyridyl)-pyrimidine (4.5 g, 23.7 mmol) and benzylethylendiamine (8.0 g, 53.3 mmol) was heated at 100 0 C for 25 min. Column chromatography on silica gel (dichloromethane methanol conc. ammonium hydroxide 5 0.4) provided the title compound. MS 306.5 CH, ,N requir. 305.4.
Step D: 2-(((S)-2-Amino-3-phenylpropvl)-amino)-5-bromo- 4-(4-pvridvl)-pyrimidine: Bromine (787 g1, 15.28 mmol) was added to a stirring solution of 2-(((S)-2-amino-3phenylpropyl)-amino)-4-(4-pyridyl)-pyrimidine (2.33 g, 7.64 mmol) in chloroform (25 ml). Stirring was continued for 2 d. The mixture was partitioned between dichloromethane and aqueous sodium hydrogencarbonate.
The organic solution was washed with brine, dried and evaporated. The resultant product was purified on a column of silica gel (dichloromethane methanol conc.
ammonium hydroxide 92 8 MS 384.0, 386.0 CAH, 8 BrN s requir. 384.3.
Step E: 2-(((S)-2-Amino-3-phenvlpropvl)amino)-5-(3chloro-4-fluorophenvl)-4-(4-pyridyl)-pvrimidine hydrochloride: A mixture of 2-((2(S)-amino-3-phenyl propyl)amino)-5-bromo-4-(4-pyridyl)-pyrimidine (204 mg, WO 98/24782 PCT/US97/22390 149 0.53 mmol), aqueous 2M sodium carbonate (1.66 ml, 3.32 mmol) and 3 -chloro-4-fluorobenzene boronic acid (103 mg, 0.637 mmol) in toluene (5 ml) was stirred for 10 min under argon. The mixture was thoroughly degassed times), before the addition of tetrakis (triphenylphosphine) palladium(0) (18 mg, 0.016 mmol).
After heating at reflux for 16 h, the reaction mixture was diluted with toluene and washed with brine. The organic solution was dried and evaporated. Subsequent column chromatography on silica gel (dichloromethane methanol conc. ammonium hydroxide 95 5 04) provided the title compound which was converted into the hydrochloride by the addition of 6N hydrochloric acid (64 il) to its methanolic solution (2 ml) followed by evaporation. MS 434.1
C
24 ,H 2 C1FN, requir.
433.9 (free base).
The following compounds were prepared according to Step E of this procedure by using the appropriate boronic acid and 16-2 2 2 -Amino-3-phenvlpropl)-amino)-5-(3fluorophenvyl)-4-(4-vridvl)-pvrimidine hydrochloride:
MS
400.1
CZ
4
,H,
2 FNs requir. 399.5 (free base) 16-3 2 2 -Amino-3-phenvlropvl)-amino)-5-(3isopropylphenyl)-4-(4-pyridyl)-pyrimidine hydrochloride: MS 424.2
C
27 requir. 423.6 (free base).
16-4 5-(3-Acetamidophenl)-2-(((S)-2-amino-3phenvlpropyl) -amino) -4-(4-pyridyl) -pyrimidine hydrochloride: MS 439.1
C
2
H
26 6 NO requir.
438.5 (free base).
16-5 2 -Amino-3-phenvlpropyl)-amino)-5-(4chlorophenyl)-4- (4-pyridyl) -nrimidine hydrochloride:
MS
416.3
C
24
H
22 C1N 5 requir. 415.9 (free base) WO 98/24782 WO 9824782PCTIUS97/22390 150 16-6 2- 2 -Amnino-3-phenylpro )yl) -amino) Cbenzothienvl) (4-pyvridyl) -pyrimidine hydrochloride: MS 438.3 C 2 6H 23 NS requir. 437.6 (free base).
16-7 2 2 -Amino-3 -phenvlprool) -amino) naphthyl) 4- (4 -pyr idyl) -pyrimidine hydrochloride:
MS
432.5 C 28
H
25 N, requir. 431.5 (free base) Example 17 Procedure for the preparation of 2 -Benzylpiperazine
(S-
2 -Benzylpiperazine: At ice-bath temperature, lithium aluminium hydride (1.6 g, 42.16 mmol) was added in portions to a stirring mixture of (S)-2-benzyl piperazine-3,6-dione (3.0 g, 14.70 inmol) and tetrahydrofuran (80 ml) After 30 min at ice-bath temperature, the mixture was ref luxed for 4 h with stirring. The reaction was quenched by the portionwise addition of sodium sulfate decahydrate and some methanol until hydrogen evolution ceased. It was filtered and the solids were washed several times with dichioromethane. The combined filtrates were evaporated to leave a white solid. MS (mz) 177.1
C
11
H
1
N
2 requir. 176.3.
Example 18 Procedure for the preparation of Dime thyl amino -3 -phenyipropylanine 0 N H 2 N z 2
H
2 N I
N
RH2 N-Dimethvl amino -3-phenylpropylamine: sodium triacetoxyhydride (13.0 g, 61.3 nimol) was added to a WO 98/24782 PCT/US97/22390 151 stirring mixture of phenylalanine amide (3.6 g, 21.9 mmol) and 37% formaldehyde solution (4.4 ml, 58.7 mmol) in 1, 2 -dichloroethane (77 ml). After stirring for 2 h, the reaction was quenched by the addition of sat. aqu.
sodium hydrogencarbonate. Then potassium hydroxide pellets were added followed by extraction with dichloromethane, drying of the organic solution and evaporation. The resulting 2 -N,N-dimethylamino-3phenylpropylamide was reduced with lithium aluminium hydride according to the literature Brunner, P.
Hankofer, U. Holzinger, B. Treittinger and H.
Schoenenberger, Eur. J. Med. Chem. 25, 35-44, (1990)) to provide the title compound.
Example 19 Procedure for the preparation of Dimethylamino-3-phenylpropyl) -amino) (4-fluorophenyl- 3-methyl-6- (4-pyridyl) -4 (3H) -pyrimidinone hydrochloride FF 0 N
NO
N N l e CH3 tNd
,CH
3 N N N N N 0 N 2N N/ H N N Step A. 5-(4-Fluorophenyl)-3-methvl-2-methvlsulfonvl-6- 4 -pvridvl)-4(3H) -pvrimidinone: A mixture of 5-(4fluorophenyl)-3-methyl-2-methylthio-6-(4-pyridyl)-4(3H)pyrimidinone (400 mg, 1.22 mmol) and Oxone (potassium peroxymonosulfate, 2.3 g, 3.74 mmol) in methanol (100 ml) and water (45 ml) was stirred for 13 h. The solvent was concentrated to about 50 ml, followed by extraction with dichloromethane, drying of the organic solution and evaporation. The resulting white solid was used without purification in the next step.
WO 98/24782 PCT/US97/22390 152 Step B. 2 -N,N-Dimethvlamino-3-phenylpropyl)amino)-5-(4-fluordphenyl-3-methyl-6-(4-pyridl)-4 (3H)pyrimidinone hydrochloride: A mixture of crude 5-(4fluorophenyl)- 3 -methyl-2-methylsulfonyl-6-(4 -pyridyl)- 4 (3H)-pyrimidinone (430 mg g, 1.19 mmol) and dimethylamino-3-phenylpropylamine (600 mml, -3.4 mmol) was stirred at room temperature for lh and then briefly o warmed at 50C. Column chromatography on silica gel (3methanol/chloroform) provided the title compound as a free base which was converted into the monohydrochloride by the addition of 4N hydrochloric acid/dioxane (160 mml, 0.64 mmol) to its methanolic solution (4 ml) and subsequent evaporation. MS 458.0 C27H28FN50 requir. 457.5 (free base).
Example 5-(4-fluorophenyl)-6-(4-(2-acetamido)-pyridyl)-2thioalkyl-4(3H) -pyrimidinones Step A. Ethyl 2-(4-fluorophenvl)-3-oxo-3-(4-(2acetamido)-pyridvl))-propionate: A solution of 2 -chloroisonicotinic acid (25.0g, 0.16 mol) in 65 mL of concentrated ammonium hydroxide was warmed to 205 Celsius in a steel bomb for 72 h. After cooling to 23 C, the solution was acidified to a pH of 1 using 6N HC1 and subsequently filtered to remove unreacted starting material. The solution was concentrated to one fourth the original volume (approx 200 mL) in vacuo, and carefully adjusted to a pH of 6 using 1 N NaOH. After storing the cloudy solution at 0 C for 20 h, the desired 2 -aminoisonicotinic acid was filtered off. To a suspension of 2-aminoisonicotinic acid in ethanol (600 mL) was added 47.1 mL of 4 N anhdrous HC1 in dioxane. After warming to achieve reflux for 20 h, an additional 47.1 mL of 4 N anhdrous HC1 in dioxane was added and the reaction was warmed to reflux for an additional 20 h. Concentration with a WO 98/24782 PCT/US97/22390 153 stream of nitrogen in the hood was followed by further concentration in vacuo, the remaining solid was diluted with saturated bicarbonate (200 mL), extracted with ethyl acetate (2 x 200mL), dried (Na2S04). After concentration in vacuo, the desired ethyl 2aminoisonicotinate was obtained. To a solution of ethyl 2 -aminoisonicotinic acid in pyridine (45 mL) at 0 C undr an argon atmosphere was added acetyl chloride dropwise over 5 min. After 2 h at 0 C, the reaction was pored into over ice 300 g, extracted with ethyl acetate (2 x300 mL), washed with water (2 xl00 ml) followed by brine 2 x 100 mL), and dried (Na2S04). After concentration in vacuo, the residue was purified by application of flash chromatography step gradient ethyl acetate: hexane 1:4 then ethyl acetate: hexane 1:1) to afford ethyl 2 -acetamidoisonicotinate.
To a solution of diisopropylamine (14.15 mL, 101 mmol) and THF (40 mL) at -78 C was added n-butyl lithium (38.1 mL, 95 mmol) dropwise over 5 min. After 10 min, ethyl 4 -fluorophenylacetate (17.3 g, 95 mmol) was added in 40 mL of dry THF. After 10 min, ethyl 2acetamidoisonicotinate (6.0 g, 29 mmol) was added in ml of dry THF. The reaction was allowed to warm to 23 C overnight, and then acetic acid (95 mmol) was added in one portion. The reaction was concentrated in vacuo, then partitioned repeatedly between saturated bicarbonate (200 ml) and ether (300 mL), the combined bicarbonate layers were neutralized with 10% citric acid, and extracted with ethyl acetate (2 x 300 mL).
The organic layers were dried (Na2SO4), concentrated in vacuo to afford the Ethyl 2-(4-fluorophenyl)-3-oxo-3-(4- (2-acetamido)-pyridyl)-propionate.
Step B. 5-( 4 -fluorophenl)-6-(4-(2-acetamido)pyridyl))- 2-thiouracil: Ethyl 2 -(4-fluorophenyl)-3-oxo-3-(4-(2acetamido)pyridyl)-propionate (1.3 g, 3.78 mmol) and WO 98/24782 PCT/US97/22390 154 thiourea (863 mg, 11.3 mmol) were suspended in anhydrous p-xylene (15 ml) with very efficient stirring.
To the mixture pyridinium p-toluenesulfonate (38 mg) was added and refluxed for 12-16 h using a Dean-Stark apparatus with continuous removal of water (0.1 ml).
Reaction mixture was cooled and a dark brown solid was filtered using a Buchner funnel. The collected solid was suspended in acetone (25 ml) and filtered. The acetone washed product contained a trace of thiourea, which was removed by trituration with hot water (20-30 ml). The product was filtered and air dried followed by azeotroping with toluene.
WO 98/24782 PCT/US97/22390 155 Example 21 Procedure for the preparation of (S)-2-N-Ethylamino-3phenylpropylamine 0
H
2 N H 2
N
H
2 N NH 2
NNH
-2-N-Ethvlamino-3-phenylpropylamine: Acetic anhydride (1.2 ml, 12.7 mmol) was added to a stirring solution of L-phenylalanine amide (1.0 g, 6.10 mmol) in methanol (25 ml). After 1.5 h at room temperature, it was evaporated followed by drying in an oil pump vacuum.
The resultant L-N-ethylphenylalanine amide (6.1 mmol) was reduced with lithium aluminium hydride (570 mg, 15.0 mmol) in tetrahydrofuran (65 mml) at 55°C for 4 h. The reaction mixture was poured into sat. aqu. sodium hydrogencarbonate followed by extraction with dichloromethane, drying and evaporation. Column chromatography on silica gel (chloroform methanol triethylamine 90:7:3) provided the amine as a yellowish oil. MS 179.1 C11H18N2 requir.
178.3.
Example 22 Procedure for the preparation of 2-Amino-2-methyl-3phenylpropylamine 0')NH2 2 -Amino-2-methvl-3-phenvlpropvlamine: A solution of commercially available D,L-a-methyl phenylalanine methyl ester (5.0 g, 25.7 mmol) in aqu. 28% ammonium hydroxide ml) was kept at room temperature for 3 d. The resulting white precipitate of D,L-a-methyl WO 98/24782 PCT/US97/22390 156 phenylalanine amide was filtered and dried (2.5 g).
This material (2.0 g, 11.22 mmol) was reduced with lithium aluminium hydride (1.3 g, 34.26 mmol) in boiling tetrahydrofuran for 24 h. The reaction was quenched by the addition of sodium sulfate decahydrate at ice-bath temperature. The salts were filtered off, followed by evaporation to leave the title compound as an oil. MS 165.1 C10H16N2 requir. 164.2. An alternative preparation was reported by M. Freiberger and R. B. Hasbrouck, J. Am. Chem. Soc. 82, 696-698 (1960).
Example 23 Procedure for the preparation of 2-Methyl-3phenylpropylamine
CH
3 2-Methyl-3-phenvlpropylamine: A mixture of commercially available 2-methyl-3-phenylpropylamide (4.32 g, 26.5 mmol) and lithium aluminium hydride (1.3 g, 34.3 mmol) in tetrahydrofuran (184 ml) was stirred at room temperature for 5 h. It was poured into aqu. sat.
sodium sulfate and extracted with dichloromethane followed by drying of the organic solution and evaporation to provide the amine as an oil. Other syntheses have been reported, e.g. Dornow and Fust, Chem. Ber. 87, 984 (1954).
WO 98/24782 PCTIUS97/22390 157 Example 24 Procedure for the preparation of S-(4-Fluorophenyl)-3methyl ((2-me thy-3-phenylpropyl) amino) -6-(4-pyridyl) 4 (3H) -pyrimidinone hydrochloride 0 N 0 0NN ST
U
H
2 0 N~ H
CH
3 (4-Fluorophenyl) -3-methvl-2- (2-methv-3-phenvlpropvl) amino) (4-pyridyl) -4 -pyrimidinone hydrochloride: A mixture of crude 5-(4-fluorophenyl)-3-methyl-2methylsulfonyl-6- (4-pyridyl) -4 (3H) -pyrimidinone (520 mg g, 1.45 mmol) and 2 -methyl-3-phenylpropylanine (1.5 g, 10.1 mmol) was heated at 50 0 C for 30 min. Column chromatography on silica gel methanol/ dichloromethane; hexane-acetone= 2 provided the title compound. MS 429.4 C26H25FN40 requir. 428.5 (free base).
Example Procedure for the preparation of 1-Phenyl-l,3propanedi amine
NH
2 N
NH
2 1-Phenvl-1. 3-ropanedianine: 3 -Phenyl-3-aminopropionic acid G. Cohen and S. Y. Weinstein, J. Am. Chem. Soc.
86, 725-728, 1964) was converted into 1-phenyl-1,3propanedjanine as reported in the literature Kojima and J. Fujita, Bull. Chem. Soc. Jpn. 55, 1454-1459 (1982)).
WO 98/24782 PCTIUS97/22390 1 5 8 r P n d i e Analogously, 1- (2-f luorolphenyl) 3 -Prpedame 1- (2-methyiphenvl) -1l, 3 ropanediamine and 1-2 chlorophenyl)-l,3-propanediamine have been prepared by using the above procedure and the appropriate starting material.
Example 26 Procedure for the preparation of 3-Ethyl fluorophenyl) -2-methylthio-6-(4 -pyridyl) -4 (3H) pyrimnidinone N N N N S 3 Ne-N 3 -Ethyl-5--L4f luorophenvl) 2 -methl thio-6-(4.pyridvl) 4 3 H)-Pvrimjdinone:, Ethyl bromide (600 ml, 8.03 mmol) was added to a stirred mixture of 5-( 4 fluorophenyl)-2methylthio-6. 4 -pyridyl)-4(3H) -pyrimidinone (1.8 g, 5.97 mmol) and sodium hydride (60% oily suspension, 320 mg, 8 mmol) in N,N-dimethyfomamid (60 ml) at room temperature. More ethyl bromide (2x 600 ml, 2x8.03 mmol) was added after 2 and 3.5 h. After 8 h, the reaction mixture was neutralized with acetic acid and evaporated. The remainder was taken up in dichloromethane, the organic solution was washed with water, dried and evaporated. Flash chromatography on a columrn of silica gel (hexane-acetone 3:1, 2:1).
provided in the second main fraction the title compound as a solid.
SHEET (RULE 26) WO 98/24782 PCTUS97/22390 159 Example 27 Procedure for the preparation of 3-Ethyl-5-(4fluorophenyl) -2-methylsulfonyl-6- (4-pyridyl) -4 (3H) pyrimidinone F F-
O
N N 1ki H N S N S NH N N 1 0 3-Ethvl-5-(4-fluorophenvl)-2-methvlsulfoll-6-( 4 ipyridl) -4(3H) -pyrimidinone: A mixture of 3-ethyl-5-(4fluorophenyl) -2-methylthio-6- (4-pyridyl) -4 (3H) pyrimidinone (300 mg, 0.88 mmol) and OxoneR (potassium peroxymonosulfate, 2.54 g, 4.14 mmol) in methanol (71 ml) and water (33 ml) was stirred for 14 h. The solvent was concentrated to about 35 ml, followed by extraction with dichloromethane, drying and evaporation. The resulting white solid was used without purification in the next step.
Example 28 Procedure for the preparation of 2-(((S)-2-Amino-3phenyipropyl) -amino) -3 -ethyl (4 -fluorophenyl) (4 pyridyl) -4 (3H) -pyriridinone hydrochloride
F
N
N N
H
2- -2-Amino-3-Phenvlnropvl) -amino) -3-ethvl-5- (4fluorophenyl) (4-pyridyl) -4 (3H)-pyrimidinone hydrochloride: A mixture of 3-ethyl-5-(4-fluorophenyl)- 2-methylthio-6-(4-pyridyl)-4(3H)-pyrimidinone (150 mg, 0.44 mmol) and (S)-1,2-benzylethylendiamine (200 ml, -1.3 mmol) was heated at 190 0 C for 4.5 h. Column chromatography on IatrobeadsR (chloroform methanol WO 98/24782 PCT/US97/22390 160 triethylamine 90 7 3) provided the title compound as a free base which was converted into the crystallizing monohydrochloride by the addition of 2N hydrochloric acid (165 ml, 0.33 mmol) and methanol ml). Filtration provided the title compound. MS 444.0 C265H27FN50 requir. 443.5 (free base).
Example 29 Procedure for the preparation of 3-Ethyl-5-(4fluorophenyl)-2-((2-methy-3-phenylpropyl) amino)-6-(4pyridyl)-4(3H)-pyrimidinone hydrochloride F 0 N N N N H
CH
3 3-Ethyl-5-(4-fluorophenvl)-2-((2-methy-3-phenylpropyl) amino)-6-(4-pyridyl)-4(3H)-pyrimidinone hydrochloride: A mixture of crude 3-ethyl-5-(4-fluorophenyl)-2methylsulfonyl-6-(4-pyridyl)-4(3H)-pyrimidinone (320 mg g, 0.89 mmol) and 2-methyl-3-phenylpropylamine (600 ml, -4 mmol) was heated at 60 0 C for 2 h. Column chromatography on silica gel (hexane-acetone= 2 1; 2methanol/dichloromethane) provided the title compound. MS 443.2 C27H27FN40 requir.
442.5.
Example Procedure for the preparation of 3-(2- Me thylphenyl) prppyl amine
I-"
C2 3 3-(2-Methvlphenvl)propylamine: Diethyl cyanomethylphosphonate (5.0 ml, 30.9 mmol) was added to a stirring suspension of sodium hydride (60% oily suspension, 1.24 g, 31 mmol) in tetrahydrofuran (50 ml) WO 98/24782 PCT/US97/22390 161 under argon. After 3o min, 2-methylbenzaldehyde (3.6 ml, 31.1 mmol) was added and stirring continued for 1 h.
The reaction was quenched by the addition of water and extracted with dichloromethane followed by drying and evaporation of the organic solution. Column chromatography (hexane; hexane ethylacetate 3 1) provided 2-(2-methylphenyl)acrylonitrile as an oil.
This material (3.8 10% palladium on carbon (3.8 g) and 12 N hydrochloric acid (11.8 ml, 142 mmol) in methanol (125 ml) were hydrogenated with hydrogen at atmospheric pressure for 2 d. The catalyst was removed by filtration and the solvent was evaporated. The resultant material was partitioned between dichloromethane and water. The aqueous layer was made basic with 10 N sodium hydroxide and extracted with dichloromethane, followed by drying and evaporation.
The resultant material was purified on a silica gel column (chloroform methaol triethylamine 85 to provide the title compound as an oil.
Example 31 Procedure for the preparation of 2-amino-3-(2fluorophenyl)-propylamine F 2 NH2 Step A. Methyl 2-amino-3-(2-fluorophenvl)propionate: 5g (27.3 mmol) of (D,L)-(2-fluoro-phenyl)alanine was suspended in 50 ml methanolic HC1 and stirred at room temperature for 3 days. The reaction mixture was concentrated in vacuo and dried to give a yellow oil.
MS 198 C 1 FNO, requir. 197.2.
Step B. 2-Amino-3-(2-fluorophenvl)propionamide: Methyl 2-amino-3-(2-fluorophenyl) propionate was suspended in ml 30% ammonium hydroxide and stirred at room temperature for 18 hrs. The mixture was filtered, WO 98/24782 PTU9129 PCT/US97/22390 162 washed with cold water and 2-arnino-3-(2-fluorophenyl) propionamide was collected as a white solid. MS (m/z) 183.1 CH 11 FN 2 0 requir. 182.2.
Step C. 2-Amino-3- (2-f luorophenyl)-propvlamine: 2- Amino- 3- (2 -f luorophenyl) propionamide was added carefully to a chilled (50) mixture of LAH (1.0g, 26.3 mmol) and ml TEF under argon. The reaction was then heated at ref lux for 10 hrs. The reaction was cooled to 5 0 C and carefully treated with Na 2 S0 4 010 H 20. The resulting mixture was stirred for 18 hrs, then filtered to remove the solids. The filtrate was concentrated in vacuc to give an amber oil. MS 169 C 9 H 13 FN 2 requir. 168.19 Example 32 Procedure for the preparation of (lR,2R) -2-Methy1-1phenyl 3-propanedi amine Ph
H
P h/N 0~ NHNH E 0 Step A: Methyl (2S,3R,aS) (N-benzvl-N-fxme thvlbenzvl1amino) -2-methyl-3-phenylprovionate was prepared as reported f or the 2R, 3S, CLR-enantiomer Davies and I.A.S. Walters, J. Chem. Soc. Perkin Trans.I, 1129-1139 (1994).
Steip B: Methyl (2S,3R)-3-amino-2-methyl-3- Phenvlipropionate: A mixture of methyl (2S,3R,aS)-3-(Nbenzyl -N-a-methylbenzylamino) -2 -methyl -3phenyipropionate (13.0 g, 33.55 mmol) and 10% palladium- WO 98/24782 PCTfUS97/22390 163 on-carbon (13.0 g) in glacial acetic acid (260 ml) was hydrogenated under a balloon of hydrogen for 24 h. The catalyst.was removed by filtration followed by evaporation and co-distillation with toluene to provide the title compound as a white solid. MS 194.2
C
11 H,,NO requir. 193.3.
Step C: 2
S.
3
R)-
3 -Amino-2-methyl-3-phenylpropionamide A solution of methyl 2
S,
3 R)-3-amino-2-methyl-3phenylpropionate (6.3 g, 33 mmol) in 2N methanolic ammonia (20 ml) and ammonium hydroxide (28-30%, 40 ml) was stirred at room temperature. After 4d, it was evaporated followed by chromatography on a short column of silica gel (dichloromethane methanol conc.
ammonium hydroxide 93 7 0.7; 90 10 0.8) to provide the amide as a white solid. MS 179.2 Co 1
H,N
2 0 requir. 178.2.
Step D: (lR,2R)- 2 -methyl-l-phenvl-1.,3-propanediamine: Lithium aluminium hydride (2.3 g, 60.60 mmol) was added in portions to a stirring solution of 2 S,3R)-3-amino-2methyl-3-phenylpropionamide (2.6 g, 14.59 mmol) in tetrahydrofuran (54 ml) at ice-bath temperature. After min, the mixture was heated at reflux for 16 h. With ice-bath cooling, the reaction was quenched by the portionwise addition of sodium sulfate decahydrate and some methanol until hydrogen evolution ceased. The solids were removed by filtration and washed with dichloromethane. The combined filtrates were evaporated to provide the title compound. MS 165.2 Cl 0
H,
1 N requir. 164.3.
Analogously, the enantiomer (1S,2S)-2-methyl-1phenvl-1,3-propanediamine was prepared from methyl (2R,3S,aR)-3-(N-benzyl-N-a-methylbenzylamino)-2-methyl- 3 -phenylpropionate. MS 165.3
C
1
OH
1 6
N,
requir. 164.3.
SUBSTITUTE SHEET (RULE 26) WO 98/24782 PCTIUS97/22390 164 Analogously, the enantiomers (1S.2R)-2-methyl-iphenvl-1, 3.-iropanediamine and 2S) -2-methvl-1-phenyl- 1,3-Tropanedaife may be prepared from tert.butyl (2S,3S,cLR)- and -(2R,3R,cLS)-3-(N-benzyl-N-amethylbenzylamino)- 2-methyl-3-phenylpropionate (Davies et al., J. Chem. Soc. Chem. Commun. 1153-1155, 1993).
Example 33 procedure for the preparation of 5-(4-fluorophenyl)-2- (4-phenylbutyl) (4-pyridyl) -4 (3H) -pyrimidinone F 0 N NH 5-(4-Fluorophenvl)-2-(4-henylbutyl)-6-(4-pyridvi)- 4(3H)-pyrimidinofe: Ethyl 2-(4-fluorophenyl)-3-oxo-3- (4-pyridyl)-propioate (293 mg, 1.02 nmol), 4phenylbutanecarboxamidie (315 mg, 1.79 mmol) and pyridinium p-toluenesulfonate (10 mg) were suspended in p-xylene (10 ml). With efficient stirring, the mixture was heated to reflux using a Dean-Stark apparatus with continuous removal of water. After 16 h, the solvent was evaporated and the product purified by column chromatography on silica gel (3% methanol/dichloromethane) followed by recrystallization from acetone. MS 400.3
C
2 5
H
2 2FN30 requir.
399.5.
WO 98/24782 WO 9824782PCT1US97/22390 165 Example 34 Procedure for the preparation of 5- (4-fluorophenyl) -2- (N\-methyvl (2-phenylethyl) amin2o) (4-pyridyl) -4 (3H) pyrimi dinone F0 Nk N! N N- 1 (4-Fluorolphenyl) (N-methvl-N- (2-phenylethyl-) amino) 6- (4-pyridyl) -4 (3H) -pyrimidinone was prepared using the methods described above. MS 401.2 (M+H)I;
C
2 4
H
2 1 FN40 requir. 400. Example The compounds shown in Tables I-II can be prepared using the procedures of Examples 1-33.
TABLE I WO 98/24782 PTU9/29 PCT/US97/22390 166
HN
C).
WO 98/24782 PCT/US97/22390 167 WO 98/24782 PTU9/29 PCT/US97/22390 168 TABLE II F
N
N
N
H
H
3
C
NH
2
N
HA
NN
CH
3
A
N
HCCH
N
N il
HNF
H"
H
3
C
N
HCH
H
3 C NH 2
NKO
H
3
C
N*"
H
.H
2 H NH~$ O N~
H
3 C ,CH 3 2. F N N IN N~~N H N2 H NH 2
F
2
FN
SCH
3
N
H
NH
2 H
NH
2 WO 98/24782 PCT/US97/22390 169
N
H NH2
K
N N2
H
^^Cl
N
H HNH 2
"N"^T
N NH H
NH
2 cl NC \NH 2 N H NH 2 I H HN
NH
2 N CN H NH
N
H NH 2
Q
N
F
H
H NH 2
N
N I \1 N NH HN- H NH 2 N H
NH
2 0N
NO;
H NH 2
NH
2 H NH 2 Example 36 Biological Assays The following assays were used to characterize the ability of compounds of the invention to inhibit the production of TNF-a and IL-1-P. The second assay measured the inhibition of TNF-a and/or IL-1-P in mice after oral administration of the test compounds. The third assay, a glucagon binding inhibition in vitro assay, can be used to characterize the ability of compounds of the invention to inhibit glucagon binding.
The fourth assay, a Cyclooxygenase enzyme (COX-1 and COX-2) inhibition activity in vitro assay, can be used SUBSTITUTE SHEET (RULE 26) WO 98/24782 PCT/US97/22390 170 to characterize the ability of compounds of the invention to inhibit COX-1 and/or COX-2.
Lipopolysaccharide-activated monocyte TNF production assay Isolation of monocytes Test compounds were evaluated in vitro for the ability to inhibit the production of TNF by monocytes activated with bacterial lipopolysaccharide (LPS).
Fresh residual source leukocytes (a byproduct of plateletpheresis) were obtained from a local blood bank, and peripheral blood mononuclear cells (PBMCs) were isolated by density gradient centrifugation on Ficol- Paque Plus (Pharmacia). PBMCs were suspended at 2 x 6 /ml in DMEM supplemented to contain 2% FCS, 10 mM, 0.3 mg/ml glutamate, 100 U/ml penicillin G and 100 mg/ml streptomycin sulfate (complete media). Cells were plated into Falcon flat bottom, 96 well culture plates (200 pl/well) and cultured overnight at 37 0 C and 6% CO 2 Non-adherent cells were removed by washing with 200 pl/well of fresh medium. Wells containing adherent cells monocytes) were replenished with 100 pl of fresh medium.
Preparation of test compound stock solutions Test compounds were dissolved in DMZ. Compound stock solutions were prepared to an initial concentration of 10 50 Mu. Stocks were diluted initially to 20 200 p.M in complete media. Nine twofold serial dilutions of each compound were then prepared in complete medium.
Treatment of cells with test compounds and activation of TNF production with lipopolysaccharide One hundred microliters of each test compound dilution were added to microtiter wells containing adherent monocytes and 100 .l complete medium.
Monocytes were cultured with test compounds for 60 min at which time 25 ul of complete medium containing WO 98/24782 PCT/US97/22390 171 ng/ml lipopolysaccharide from E. coli K532 were added to each well. Cells were cultured an additional 4 hrs.
Culture supernatants were then removed and TNF presence in the supernatants was quantified using an ELISA.
TNF ELISA Flat bottom, 96 well Corning High Binding ELISA plates were coated overnight (4 0 C) with 150 uL/well of 3 pg/ml murine anti-human TNF-a MAb (R&D Systems #MAB210).
Wells were then blocked for 1 hr at room temperature with 200 pL/well of CaC1 2 -free ELISA buffer supplemented to contain 20 mg/ml BSA (standard ELISA buffer: 20 mM, 150 mM NaC1, 2 mM CaC12, 0.15 mM thimerosal, pH 7.4).
Plates were washed and replenished with 100 ul of test supernatants (diluted 1:3) or standards. Standards consisted of eleven 1.5-fold serial dilutions from a stock of 1 ng/ml recombinant human TNF (R&D Systems).
Plates were incubated at room temperature for 1 hr on orbital shaker (300 rpm), washed and replenished with 100 pl/well of 0.5 pg/ml goat anti-human TNF-a (R&D systems #AB-210-NA) biotinylated at a 4:1 ratio. Plates were incubated for 40 min, washed and replenished with 100 pl/well of alkaline phosphatase-conjugated streptavidin (Jackson ImmunoResearch #016-050-084) at 0.02 pg/ml. Plates were incubated 30 min, washed and replenished with 200 l/well of 1 mg/ml of p-nitrophenyl phosphate. After 30 min, plates were read at 405 nm on a V. plate reader.
Data analysis Standard curve data were fit to a second order polynomial and unknown TNF-a concentrations determined from their OD by solving this equation for concentration. TNF concentrations were then plotted vs.
test compound concentration using a second order polynomial. This equation was then used to calculate the concentration of test compounds causing a reduction in TNF production.
WO 98/24782 PCT/US97/22390 172 Compounds of the invention can also be shown to inhibit LPS-induced release of IL-10, IL-6 and/or IL-8 from monocytes by measuring concentrations of IL-10, IL- 6 and/or IL-8 by methods well known to those skilled in the art. In a similar manner to the above described assay involving the LPS induced release of TNF- from monocytes, compounds of this invention can also be shown to inhibit LPS induced release of IL-13, IL-6 and/or IL- 8 from monocytes by measuring concentrations of IL-1p, IL-6 and/or IL-8 by methods well known to those skilled in the art. Thus, the compounds of the invention may lower elevated levels of TNF-a, IL-1, IL-6, and IL-8 levels. Reducing elevated levels of these inflammatory cytokines to basal levels or below is favorable in controlling, slowing progression, and alleviating many disease states. All of the compounds are useful in the methods of treating disease states in which TNF-a, IL- 1P, IL-6, and IL-8 play a role to the full extent of the definition of TNF-a-mediated diseases described herein.
Inhibition of LPS-Induced TNF-a production in mice Male DBA/1LACJ mice were dosed with vehicle or test compounds in a vehicle (the vehicle consisting of tragacanth in 0.03 N HC1) 30 minutes prior to lipopolysaccharide (2 mg/kg, injection. Ninety minutes after LPS injection, blood was collected and the serum was analyzed by ELISA for TNF levels.
The following compounds exhibit activities in the monocyte assay (LPS induced TNF release) with IC50 values of 20 pM or less: 5-( 4 -Fluorophenyl)-2-(4-pyridyl)-4-(4-pyridyl)pyrimidine 5-(4-Fluorophenyl)-2-(2-methylthiazol-4-yl)-4-(4pyridyl)-pyrimidine 5-(4-Fluorophenyl)-4-(4-pyridyl)-2-(2-thienyl)pyrimidine WO 98/24782 PCTIUS97/22390 173 2 2 -Die thylaminoethyl amino) (4-f luorophenyl) (4pyridyl) -pyrimidine 2- (2-Aminoethylamino) (4-f luorophenyl) (4-pyridyl) pyrimidine 2- (3-Alinopropylamino) -5-(4-fluorophenyl) 4 4 -pyridyl) pyr imidine 2- (4-Aminobutylamino) (4-f luorophenyl) (4-pyridyl) pyrimidine 2- 6-Dichlorobenzyl) (4-f luorophenyl) (4-pyridy l) pyrimidine 2- G-Dichlorophenylamino) (4-fluorophenyl) pyridyl) -pyrirnidine 2- 6-Dimethyiphenylamino) (4-fluorophenyl) (4pyridyl) -pyrimidine 5- 4 -Fluorophenyl)-2-(2..methoxhenylamino)4(4pyridyl) -pyrilnidine (4-Fluorophenyl) (4-f luorophenylamino) (4pyridyl) -pyriinidine (4-Fluorophenyl) -2-phenylthiomethyl-4- (4-pyridinyl) pyriinidine 2- (Benzylamino) (4-fluorophenyl) (4-pyridyl) pyrimidine (4-Fluorophenyl) (2-phenylethylamino) (4-pyridyl) pyrimidine 5- (4-Fluorophenyl) (methyl- (2-phenylethyl)-amino) -4- (4 -pyridyl) -pyrimidine (4-Fluorophenyl) ((2-hydroxy-2-phenyl-ethyl) amino) 4- (4-pyridyl) -pyrimidine (4-Fluorophenyl) (4-hydrox-yphenyl) ethyl-amino) -4- (4-pyridyl) -pyrimidine 2- 4 -Aminophenyl)ethyl-anino) (4-fluorophenyl) -4- (4-pyridyl) -pyriinidine (4-Fluorophenyl) (4-f luorophenyl) ethyl-amino) -4- (4 -pyridyl) -pyrimidine 5-( 4 -Fluorophenyl)-2-(2-(2fluorophenyl)ethylamino)-4 (4-pyridyl) -pyrimidine 2- (2-Chlorophenyl) ethyl-amino) (4-f luorophenyl) -4- (4-pyridyl) -pyrimidine 2- (4-Chlorophenyl) ethyl-amino) (4-f luorophenyl) -4- (4-pyridyl) -pyrimidine 2- (3-Chlorophenyl) ethyl-amino) (4-f luorophenyl) -4- (4-pyridyl) -pyrimidine 2- 4-Dichlorophenyl) ethyl-amino) (4fluorophenyl) (4-pyridyl) -pyrimidine WO 98/24782 WO 9824782PCTIUS97/22390 174 2- (4-Bromophenyl) ethyl-amino) (4-f luorophenyl) -4- (4 -pyridyl) -pyrimidine (4-Fluorophenyl) (2-methoxyphenyl) ethyl-amino) -4- (4 -pyridyl) -pyrimidine 5- (4-Fluorophenyl) 2 -(3-methoxyphenyl)ethyl-amino) -4- (4-pyridyl) -pyrimidine (4-Fluorophenyl) ((3-phenyipropyl) amino) (4pyridyl) -pyrimidine (4-Fluorophenyl) ((l-methyl-3-phenylpropyl) -amino) 4- (4-pyridyl) -pyrimidine 2- -2-Arnino-3-phenylpropyl) -amino) (4fluorophenyl) (4-pyridyl) -pyrimidine (4-Fluorophenyl) (2-phenylaminoethylamino) (4pyridyl) -pyrimidine 5-(4-Fluorophenyl)-2-( (3-imidazolylpropyl)-amino)-4-(4pyridyl) -pyrimidine (4-Fluorophenyl) ((4-phenylbutyl) -amino) (4pyridyl) -pyrimidine (4-Fluorophenyl) (4-pyridyl) -2-pyrrolidinopyrimidine (4-Filuorophenyl) -2-morpholino-4- (4-pyridyl) -pyrimidine (4-Fluorophenyl) (1-piperazinyl) (4-pyridyl) pyrimidine (4-Fluorophenyl) (4-pyridyl) (2pyrrolidinoethylamino) -pyrimidine (4-Fluorophenyl) (2-morpholinoethylanino) (4pyridyl) -pyrimidine (4-Fluorophenyl) (2-piperidinoethylanino) (4pyridyl) -pyrimidine 5-( 4 -Fluorophenyl)-2-(3-(2-pyrrolidinon-1-yl)propylamino) (4-pyridyl) -pyrimidine 2- 6-Dichlorobenzyl) (4-fluorophenyl) (4-pyridyl) 4 (3H) -pyrimidinone (4-Fluorophenyl) (2-phenylethyl) thio-6- (4-pyridyl) 4 (3H) -pyrimidinone (4-Fluorophenyl) (3-phenyipropyl)thio-6- (4-pyridyl) 4 (3H) -pyrimidinone (4-Fluorophenyl) (2-phenoxyethyl) thio-6- (4-pyridyl) 4 (3H) -pyrimidinone 5- (4-Fluorophenyl)-2- (2-phenylaminoethyl)thio-6- (4pyridyl) -4 (3H) -pyrimidinone 2- (2-Chiorophenyl) ethyl-amino) (4-f luorophenyl) -6- (4-pyridyl) -4 (3H) -pyrimidinone 5-(4-Fluorophenyl) ((3-phenylpropyl)amino) pyridyl) -4 (3H) -pyrimidinone WO 98/24782 WO 9824782PCT/US97/22390 175 (4-Fluorophenyl) (-methyl-3-phellpropyl) -amino) 6- (4-pyridyl) -4 (3H) -pyrimidinone 5-(4--Fiuorophelyl) (3-imidazolylpropyl)amino) (4pyridyl) -4 (3H) -pyrimidinone 2 -(CCS)-2-Amino-3phenlpropyl)-amino)-4-(4-pyridyl)-s (3-trifluorofethylphelYl) -pyrimidine.
2- -2-Amino-3-phefllpropyl) -amino) (3methyiphelYl) (4-pyridyl) -pyrimidine 2- -2N,N-Dimethyamfifo-3phelpropyl) -amino) (4fluorophelyl) (4-pyridyl) -pyrimidine 2- -2N,N-Dimethylamilo-3-Phenylpropyl) -amino) (3methyiphelYl) (4-pyridyl) -pyrimidirie 2- 3-Amino-3-phel)propyl) -amino) (4-f luorophenyl) -4- (4-pyridyl) -pyrimidine 2 -((3-Amino-3-phenylypropy)aino)-4-(4-pyridyl)SC- 3 trifluoromlethYlphenyl) -pyrirnidifle 2-C (3-Ainino-3- (2-fluoropheflyl)propyl) -amino) (4pyridyl) C3-trifluoromethylphelyl) -pyrimidile 2-(C 3-Amino-3-pheflylpropyl) -amino) (3-methyiphelyl) -4- (4-pyridyl) -pyrimidine 2-C C2-Amino-2-mfethyl-3-phellpropyl) -amino) methyphel))-4- (4-pyridyl) -pyrimidifle 2-C C3-lydroxy-3-pherllpropyl) -amino) (3-methyiphelyl) 4- (4-pyridyl) -pyrimidine 2-C CC 2 S,3S)-3Amio2methyl1>phenylpropyl)-amino)- 4 (4-pyridyl) C3-trifluoromethylphenyl) -pyrirnidine 2-CC C2R, 3R)-3Aio2mehl3penlrpl-amino) -4- C4-pyridyl) C3-trifluoromethylphelyl) -pyrimidifle 2-C(S) -3-BenzylpiperazilYl) (4-pyridyl) (3trifluoromethYlPhelYl) -pyrimidine 4- (4-Pyridyl) -2-CC(S) -tetrahydroisoquilol- 3 ylmethylen) amino) C3-trifluoromethy1phen~yl) -pyrimidifle 5-C3-Methylphernyl)-4-(4-pyridyl)- 2 -CC CS)tetrahydroisoquinl13-ylmethyl) amino) -pyrimidile 2-C C S)-2NIorpyaio3phnlrpl-amino) -4-C4pyridyl) 5- C3-trifluoromethy1phelYl) -pyrimidile 2-CC(S)-2NCcohxlmno3peylrpl-amino) C4pyridyl) C3-trifluoromfethyJlphenYl) -pyrimidifle 2-(C CS) -2-N-Isopropylamiflo-3phenylpropyl) -amino) C3methyiphenyl) (4-pyridyl) -pyrimidine 2-CC(S)-2NBtlaio3penlrpl-amino) (3methyiphelyl) C4-pyridyl) -pyrimidine 2-C(C(S) -2-NCyclohexylamilo-3-phenylpropyl) -amino) (3methylpheny)-4- C4-pyridyl) -pyrimidifle WO 98/24782 WO 9824782PCTIUS97/22390 176 (4-Fluorophenyl) S) -2-N-isopropylamino-3phenyipropyl) -amino) (4-pyridyl) -pyrimidine 5-(4-Fluorophenyl)-2-( C3-N-isopropylamino-3phenyipropyl) -amino) (4-pyridyl) -pyrirnidine -2-N-Glycylamino-3-phenylpropyl) -amino) pyridyl) C3-trifluoromethylphenyl) -pyrimidine 2- C C(S) 2 -N-Glycylamino-3-phenylpropyl) -amino) (3methyiphenyl) (4-pyridyl) -pyrimidine 2-C C(S) -2-Amino-3-phenylpropyl) -amino) -S-(3-chloro-4fluorophenyl) (4-pyridyl) -pyrimidine 2- (CCS) -2-Amino-3-phenylpropyl) -amino) (3fluorophenyl) (4-pyridyl) -pyrimidine 2- -2-Amino-3-phenylpropyl) -amino) (3isopropyiphenyl) (4-pyridyl) -pyrimidine 5-(3-Acetamidophenyl) -2-amino-3-phenylpropyl) amino) (4-pyridyl) -pyrimidine 2-CC(S) -2-Amino-3-phenylpropyl) -amino) chiorophenyl) (4-pyridyl) 2-C(C(S)-2-Amino-3-phenylpropyl) -amino) (benzothienyl) 4- (4-pyridyl) -pyrimidine 2-CC CS) -2-Amino-3-phenylpropyl) -amino) C2-naphthyl) -4- C 4-pyridyl) -pyrimidine 2-CC(S) -2-Amino-3-phenylpropyl) -amino) fluorophenyl) (4-pyridyl) -4(C3H) -pyrirnidinone.
The following compounds exhibit activities in the monocyte assay (LPS induced TNF release) with IC 50 values of 5 p.M or less: 2- C2-Aminoethylamino) (4-f luorophenyl) (4-pyridyl) pyrimidine 2-(3-Aminopropylamino)-5-(4-fluorophenyl)-4-C4-pyridyl)pyrimidine 2- CBenzylainino) (4-f luorophenyl) (4-pyridyl) pyr imidine (4-Fluorophenyl) (2-phenylethylamino) (4-pyridyl) pyrimidine (4 -Fluorophenyl) -2 (N-methyl-N- C2 -phenylethyl) amino) 4- (4-pyridyl) -pyrimidine (4-Fluorophenyl) C2-hydroxy-2-phenyl-ethyl) amino-4- C 4-pyridyl) -pyrimidine 5- (4-Fluorophenyl) C4-hydroxyphenyl) ethylamino) -4- (4-pyridyl) -pyrimidine 5-(4-Fluorophenyi)-2-(2-(4-fluorophenyl)ethylamino)-4- C 4-pyridyl) -pyrimidine WO 98/24782 PTU9/29 PCTIUS97/22390 177 (4-Fluorophenyl) (2-fluorophenyl) ethylamino) -4- (4 -pyridyl) -pyrimidine 2- (2-Chiorophenyl) ethyilamino) (4-fliuorophenyl) -4- (4 -pyridyl) -pyrimidine 2- 2 -(4-Chlorophenyl)ethylamino)-5.(4-f luorophenyl)-4- (4 -pyridyl) -pyrimidine 2- 4-Dichiorophenyl) ethylaniino) (4-f luorophenyl) 4- (4-pyridyl) -pyriinidine (4-Fluorophenyl) (3-phenyipropyl) amino-4- (4pyridyl) -pyrimidine 2- 2 -Amino-3-phenylpropyl)amino-5-(4-f luorophenyl) 4- (4-pyridyl) -pyrimidine (4-Fluorophenyl) 2 -phenylaminoethylamino) (4pyridyl) -pyrimidine 5-( 4 -Fluorophenyl)-2-(3-imidazolylpropyl)amino-4(4.
pyridyl) -pyrimidine (4-Fluorophenyl) (4-pyridyl) -2-pyrrolidinopyrimidine (4-Fluorophenyl) (1-piperazinyl) (4-pyridyl) pyrimidine (4-Fluorophenyl) (2-phenylethyl) thio-6- (4-pyridyl) 4 (3H) -pyrimidinone (4-Fluorophenyl) (3-phenyipropyl) thio-6- (4-pyridyl) 4 (3H) -pyrimidinone 2- 2 -Chlorophenyl)ethyl-amino)5(4fluorophenyl)-6 (4-pyridyl) -4 (3H) -pyrimidinone.
(4-Fluorophenyl) (3-phenyipropyl) amino-6- (4pyridyl) -4 (3H) -pyrimidinone (4-Fluorophenyl) (1-methyl-3-phenylpropyl) amino-6- (4-pyridyl) -4 (3H) -pyrimidinone 2- 2 -Anino-3-phenylpropyl) -amino) (4-pyridyl) (3 -trifluoromethyiphenyl) -pyrimidine 2- -2-Axnino-3-phenylpropyl) -amino) (3methyiphenyl) (4-pyridyl) -pyrimidine ((S)-2-N,N-Dimethylaino-3-phenylpropyl)amino)5(4fluorophenyl) (4-pyridyl) -pyrimidine 2- -2-NN-Dimnethylamino-3-phenylpropyl) -amino) (3methyiphenyl) (4-pyridyl) -pyrimidine 3 -Amino- 3 -phenylpropyl)-amino)-S-(4-fluorophenyl).4- (4-pyridyl) -pyrimidine 2- ((3-Axino-3-phenylpropyl) -amino) (4-pyridyl) (3trifluoroinethyiphenyl) -pyrimidine 2- ((3-Amino-3- 2 -fluorophenyl)propyl) -amino) (4pyridyl) (3-trifluoromethylphenyl) -pyrimidine WO 98/24782 PCTIUS97/22390 178 2- 3-Amino-3-phenylpropyl) -amino) (3-methyiphenyl) -4- (4 -pyridyl) -pyrimidine 2- 2 -Amino-2-methyl-3-phenylpropyl).amino) methyiphenyl) (4-pyridyl) -pyrirnidine 2-(C( 3 -Hydroxy-3-phenylpropyl) -amino) 3 -methylphenyl) 4- (4-pyridyl) -pyrimidine 2- 35)- 3 -Arnino-2-methyl-3-phenylpropyl) -amino) -4- (4-pyridyl)
C
3 -trifluorolnethylphenyl) -pyrimidine 2- C((2R, 3R) 3 -Amino-2-methyl-3-phenylpropyl) -amino) -4- (4-pyridyl) 3 -trifluoromethylphenyl) -pyrimidine 2- 3 -Benzylpiperazinyl) (4-pyridyl) (3trifluorornethyiphenyl) -pyrimidinie 4- (4-Pyridyl) -tetrahydroisoquinol-3ylmiethyl) amino) C 3 -trifluorornethylphenyl) -pyrimidine S-(3-Methylphenyl)-4-4pyridyl)>2(CCS)tetrahydroisoquinol-3-ymethyel)amino) -pyrimidine 2 -N-Isopropylamino-3-phenylpropyl) -amino) (4pyridyl) 5- (3-trifluoromethylphenyl) -pyrimidine 2-(C 2 -N-Cyclohexylamino-3-phenylpropyl) -amino) (4pyridyl)
C
3 -trifluoromethylphenyl) -pyrimidine 2- 2 -N-Isopropylamino-3-phenylpropyl) -amino) (3methyiphenyl) (4-pyridyl) -pyrimidine 2- 2 -N-Butylamino-3-phenylpropyl) -amino) (3methyiphenyl) (4-pyridyl) -pyrimidine 2- 2 -N-Cyclohexylamino-3-phenylpropyl)-amino) methylbphenyl) (4-pyridyl) -pyrimidine (4-Fluorophenyl) C(CS) -2-N-isopropylamino-3phenyipropyl) -amino) (4-pyridyl) -pyrimidine (4-Fluorophenyl) -2-C C3-N-isopropylamino-3phenyipropyl) -amino) (4-pyridyl) -pyrimidine 2-CC(S) 2 -N-Glycylamino-3-phenylpropyl) -amino) (4pyridyl)
C
3 -trifluoromethylphenyl) -pyrimidine 2-CC(S) 2 -N-Glycylamino-3-phenylpropyl)-amino)5-3methyiphenyl) (4-pyridyl) -pyrimidine 2-CC 2 -Amino-3-phenylpropyl).amino) -5-C3-chloro-4fluorophenyl) (4-pyridyl) -pyrimidine 2-CC CS)- 2 -Axino-3-phenylpropyl)-amino) fluorophenyl) (4-pyridyl) -pyrimidine 2-CCCS) 2 -Amino-3-phenylpropyl) -amino) (3isopropyiphenyl) -4-(C4-pyridyl) -pyrimidine (3-Acetamidophenyl) C(CS) 2 -amino-3-phenylpropyl) amino) (4-pyridyl) -pyrimidine 2-CC(S) 2 -Amino-3-phenylpropyl) -amino) (4chiorophenyl) (4-pyridyl) WO 98/24782 PCT/US97/22390 179 2 4-(4-pyridyl)-pyrimidine 2 -Amino-3-phenylpropyl)-amino)-5-(2-naphthyl)-4- (4-pyridyl)-pyrimidine 2 -Amino-3-phenylpropyl)-amino)-5-(4fluorophenyl)-6-(4-pyridyl)-4-(3H)pyrimidinone.
Compounds of the invention may be shown to have anti-inflammatory properties in animal models of inflammation, including carageenan paw edema, collagen induced arthritis and adjuvant arthritis, such as the carageenan paw edema model A. Winter et al Proc.
Soc. Exp. Biol. Med. (1962) vol 111, p 544; K. F.
Swingle, in R. A. Scherrer and M. W. Whitehouse, Eds., Antiinflammatory Agents, Chemistry and Pharmacology, Vol. 13-II, Academic, New York, 1974, p. 33) and collagen induced arthritis E. Trentham et al J. Exp.
Med. (1977) vol. 146, p 857; J. S. Courtenay, Nature (New Biol.) (1980), Vol 283, p 666).
125 5I-Glucagon Binding Screen with CHO/hGLUR Cells The assay is described in WO 97/16442, which is incorporated herein by reference in its entirety.
Reagents The reagents can be prepared as follows: (a) prepare fresh 1M o-Phenanthroline (Aldrich) (198.2 mg/ml ethanol); prepare fresh 0.5M DTT (Sigma); (c) Protease Inhibitor Mix (1000X): 5 mg leupeptin, 10 mg benzamidine, 40 mg bacitracin and 5 mg soybean trypsin inhibitor per ml DMSO and store aliquots at -20 0 C; (d) 250 pM human glucagon (Peninsula): solubilize 0.5 mg vial in 575 1l 0.1N acetic acid (1 gl yields 1 pM final concentration in assay for non-specific binding) and store in aliquots at -20 0 C; Assay Buffer: 20mM Tris (pH 1 mM DTT and 3 mM o-phenanthroline; Assay Buffer with 0.1% BSA (for dilution of label only; 0.01% final in assay): 10 .1 10% BSA (heat-inactivated) and 990 1l Assay Buffer; 1 25 I-Glucagon (NEN, receptor- WO 98/24782 PCTIUS97/22390 180 grade, 2200 Ci/mmol): dilute to 50,000 cpm/25 .l in assay buffer with BSA (about 50pM final concentration in assay).
Harvesting of CHO/hGLUR Cells for Assay 1. Remove media from confluent flask then rinse once each with PBS (Ca, Mg-free) and Enzyme-free Dissociation Fluid (Specialty Media, Inc.).
2. Add 10 ml Enzyme-free Dissoc. Fluid and hold for about 4 min. at 37 0
C.
3. Gently tap cells free, triturate, take aliquot for counting and centrifuge remainder for 5 min. at 1000 rpm.
4. Resuspend pellet in Assay Buffer at 75000 cells per 100 pl.
Membrane preparations of CHO/hGLUR cells can be used in place of whole cells at the same assay volume.
Final protein concentration of a membrane preparation is determined on a per batch basis.
Assay The determination of inhibition of glucagon binding can be carried out by measuring the reduction of I12 5 glucagon binding in the presence of compounds of Formula I. The reagents are combined as follows: Compound/ 250 pM 125- CHO/hGLUR Vehicle Glucagon Glucagon Cells Total /5 pi 25 p1 100 p Binding 5 25 p. 100 Rl Compound Nonspecif /5 p. 1 p1 25 il 100 .i ic Binding The mixture is incubated for 60 min. at 22 0 C on a shaker at 275 rpm. The mixture is filtered over pre-soaked polyethylimine (PEI)) GF/C filtermat using an WO 98/24782 PCT/US97/22390 181 Innotech Harvester or Tomtec Harvester with four washes of ice-cold 20mM Tris buffer (pH The radioactivity in the filters is determined by a gammascintillation counter.
Thus, compounds of the invention may also be shown to inhibit the binding of glucagon to glucagon receptors.
Cyclooxygenase Enzyme Activity Assay The human monocytic leukemia cell line, THP-1, differentiated by exposure to phorbol esters expresses only COX-1; the human osteosarcoma cell line 143B expresses predominantly COX-2. THP-1 cells are routinely cultured in RPMI complete media supplemented with 10% FBS and human osteosarcoma cells (HOSC) are cultured in minimal essential media supplemented with fetal bovine serum (MEM-10%FBS); all cell incubations are at 37 0 C in a humidified environment containing 5% CO COX-1 Assay In preparation for the COX-1 assay, THP-1 cells are grown to confluency, split 1:3 into RPMI containing 2% FBS and 10 mM phorbol 12-myristate 13-acetate (TPA), and incubated for 48 hours on a shaker to prevent attachment. Cells are pelleted and resuspended in Hank's Buffered Saline (HBS) at a concentration of 2.5 x 106 cells/mL and plated in 96-well culture plates at a density of 5 x 10 5 cells/mL. Test compounds are diluted in HBS and added to the desired final concentration and the cells are incubated for an additional 4 hours.
Arachidonic acid is added to a final concentration of mM, the cells incubated for 20 minutes at 37 0 C, and enzyme activity determined as described below.
COX-2 Assay WO 98/24782 PCT/US97/22390 182 For the COX-2 assay, subconfluent HOSC are trypsinized and resuspended at 3 x 106 cells/mL in MEM- FBS containing 1 ng human IL-lb/mL, plated in 96-well tissue culture plates at a density of 3 x 10' cells per well, incubated on a shaker for 1 hour to evenly distribute cells, followed by an additional 2 hour static incubation to allow attachment. The media is then replaced with MEM containing 2% FBS (MEM-2%FBS) and 1 ng human IL-lb/mL, and the cells incubated for 18-22 hours. Following replacement of media with 190 mL MEM, mL of test compound diluted in HBS is added to achieve the desired concentration and the cells incubated for 4 hours. The supernatants are removed and replaced with MEM containing 30 mM arachidonic acid, the cells incubated for 20 minutes at 37 0 C, and enzyme activity determined as described below.
COX Activity Determined After incubation with arachidonic acid, the reactions are stopped by the addition of 1 N HC1, followed by neutralization with 1 N NaOH and centrifugation to pellet cell debris. Cyclooxygenase enzyme activity in both HOSC and THP-1 cell supernatants is determined by measuring the concentration of PGE 2 using a commercially available ELISA (Neogen #404110).
A standard curve of PGE 2 is used for calibration, and commercially available COX-1 and COX-2 inhibitors are included as standard controls.
Accordingly, the compounds of the invention or a pharmaceutical composition thereof are useful for prophylaxis and treatment of rheumatoid arthritis; Pagets disease; osteophorosis; multiple myeloma; uveititis; acute and chronic myelogenous leukemia; pancreatic cell destruction; osteoarthritis; rheumatoid spondylitis; gouty arthritis; inflammatory bowel disease; adult respiratory distress syndrome (ARDS); psoriasis; Crohn's disease; allergic rhinitis; WO 98/24782 PCT/US97/22390 183 ulcerative colitis; anaphylaxis; contact dermatitis; asthma; muscle degeneration; cachexia; Reiter's syndrome; type I and type II diabetes; bone resorption diseases; graft vs. host reaction; ischemia reperfusion injury; atherosclerosis; brain trauma; Alzheimer's disease; stroke; myocardial infarction; multiple sclerosis; cerebral malaria; sepsis; septic shock; toxic shock syndrome; fever, and myalgias due to infection.
HIV-1, HIV-2, HIV-3, cytomegalovirus (CMV), influenza, adenovirus, the herpes viruses (including HSV-1, HSV-2), and herpes zoster, all of which are sensitive to TNF-a and/or IL-1 inhibition or glucagon antagonism, will also be positively effected by the compounds and methods of the invention.
The compounds of the present invention also may possess analgesic properties and may be useful for the treatment of pain disorders, such as hyperalgesia due to excessive IL-1. The compounds of the present invention may also prevent the production of prostaglandins by inhibition of enzymes in the human arachidonic acid/prostaglandin pathway, including cyclooxygenase (WO 96/03387, incorporated herein by reference in its entirety).
Because of their ability to lower TNF-a and IL-1 concentrations or inhibit glucagon binding to its receptor, the compounds of the invention are also useful research tools for studying the physiology associated with blocking these effects.
The methods of the invention comprise administering an effective dose of a compound of the invention, a pharmaceutical salt thereof, or a pharmaceutical composition of either, to a subject an animal, preferably a mammal, most preferably a human) in need of a reduction in the level of TNF-a, IL-1, IL-6, and/or IL-8 levels and/or reduction in plasma glucose levels and/or which subject may be suffering from rheumatoid arthritis; Pagets disease; osteophorosis; multiple WO 98/24782 PCT/US97/22390 184 myeloma; uveititis; acute and chronic myelogenous leukemia; pancreatic 9 cell destruction; osteoarthritis; rheumatoid spondylitis; gouty arthritis; inflammatory bowel disease; adult respiratory distress syndrome (ARDS); psoriasis; Crohn's disease; allergic rhinitis; ulcerative colitis; anaphylaxis; contact dermatitis; asthma; muscle degeneration; cachexia; Reiter's syndrome; type I and type II diabetes; bone resorption diseases; graft vs. host reaction; Alzheimer's disease; stroke; myocardial infarction; ischemia reperfusion injury; atherosclerosis; brain trauma; multiple sclerosis; cerebral malaria; sepsis; septic shock; toxic shock syndrome; fever, and myalgias due to infection, or which subject is infected by HIV-1, HIV-2, HIV-3, cytomegalovirus (CMV), influenza, adenovirus, the herpes viruses (including HSV-1, HSV-2), or herpes zoster.
In another aspect, this invention comprises the use of a compound of the invention, or pharmaceutically acceptable salts thereof, in the manufacture of a medicament for the treatment either acutely or chronically of a TNF-a, IL-1p, IL-6, and/or IL-8 mediated disease state, including those described previously.
Also, the compounds of this invention are useful in the manufacture of a analgesic medicament and a medicament for treating pain disorders, such as hyperalgesia. The compounds of the present invention also are useful in the manufacture of a medicament to prevent the production of prostaglandins by inhibition of enzymes in the human arachidonic acid/prostaglandin pathway.
In still another aspect, this invention provides a pharmaceutical composition comprising an effective TNFa, IL-1p, IL-6, and/or IL-8 lowering amount and/or effective plasma glucose level lowering amount of a compound of the invention and a pharmaceutically acceptable carrier or diluent, and if desired other active ingredients. The compounds of the invention are administered by any suitable route, preferably in the WO 98/24782 PCT/US97/22390 185 form of a pharmaceutical composition adapted to such a route, and in a dose effective for the treatment intended. Therapeutically effective doses of the compounds of the present invention required to arrest the progress or prevent tissue damage associated with the disease are readily ascertained by one of ordinary skill in the art using standard methods.
For the treatment of TNF-, IL-1p, IL-6, and IL-8 mediated diseases and/or hyperglycemia, the compounds of the present invention may be administered orally, parentally, by inhalation spray, rectally, or topically in dosage unit formulations containing conventional pharmaceutically acceptable carriers, adjuvants, and vehicles. The term parenteral as used herein includes, subcutaneous, intravenous, intramuscular, intrasternal, infusion techniques or intraperitoneally.
The dosage regimen for treating a TNF-a, IL-1, IL- 6, and IL-8 mediated diseases and/or hyperglycemia with the compounds of this invention and/or compositions of this invention is based on a variety of factors, including the type of disease, the age, weight, sex, medical condition of the patient, the severity of the condition, the route of administration, and the particular compound employed. Thus, the dosage regimen may vary widely, but can be determined routinely using standard methods. Dosage levels of the order from about 0.01 mg to 30 mg per kilogram of body weight per day, preferably from about 0.1 mg to 10 mg/kg, more preferably from about 0.25 mg to 1 mg/kg are useful for all methods of use disclosed herein.
The pharmaceutically active compounds of this invention can be processed in accordance with conventional methods of pharmacy to produce medicinal agents for administration to patients, including humans and other mammals.
For oral administration, the pharmaceutical composition may be in the form of, for example, a WO 98/24782 PCT/US97/22390 186 capsule, a tablet, a suspension, or liquid. The pharmaceutical composition is preferably made in the form of a dosage unit containing a given amount of the active ingredient. For example, these may contain an amount of active ingredient from about 1 to 2000 mg, preferably from about 1 to 500 mg, more preferably from about 5 to 150 mg. A suitable daily dose for a human or other mammal may vary widely depending on the condition of the patient and other factors, but, once again, can be determined using routine methods.
The active ingredient may also be administered by injection as a composition with suitable carriers including saline, dextrose, or water. The daily parenteral dosage regimen will be from about 0.1 to about 30 mg/kg of total body weight, preferably from about 0.1 to about 10 mg/kg, and more preferably from about 0.25 mg to 1 mg/kg.
Injectable preparations, such as sterile injectable aqueous or oleaginous suspensions, may be formulated according to the known are using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.
Suppositories for rectal administration of the drug can be prepared by mixing the drug with a suitable nonirritating excipient such as cocoa butter and polyethylene glycols that are solid at ordinary WO 98/24782 PCT/US97/22390 187 temperatures but liquid at the rectal temperature and will therefore melt in the rectum and release the drug.
A suitable topical dose of active ingredient of a compound of the invention is 0.1 mg to 150 mg administered one to four, preferably one or two times' daily. For topical administration, the active ingredient may comprise from 0.001% to 10% w/w, e.g., from 1% to 2% by weight of the formulation, although it may comprise as much as 10% w/w, but preferably not more than 5% w/w, and more preferably from 0.1% to 1% of the formulation.
Formulations suitable for topical administration include liquid or semi-liquid preparations suitable for penetration through the skin liniments, lotions, ointments, creams, or pastes) and drops suitable for administration to the eye, ear, or nose.
For administration, the compounds of this invention are ordinarily combined with one or more adjuvants appropriate for the indicated route of administration.
The compounds may be admixed with lactose, sucrose, starch powder, cellulose esters of alkanoic acids, stearic acid, talc, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulphuric acids, acacia, gelatin, sodium alginate, polyvinylpyrrolidine, and/or polyvinyl alcohol, and tableted or encapsulated for conventional administration.
Alternatively, the compounds of this invention may be dissolved in saline, water, polyethylene glycol, propylene glycol, ethanol, corn oil, peanut oil, cottonseed oil, sesame oil, tragacanth gum, and/or various buffers. Other adjuvants and modes of administration are well known in the pharmaceutical art.
The carrier or diluent may include time delay material, such as glyceryl monostearate or glyceryl distearate alone or with a wax, or other materials well known in the art.
WO 98/24782 PCT/US97/22390 188 The pharmaceutical compositions may be made upin a solid form (including granules, powders or suppositories) or in a liquid form solutions, suspensions, or emulsions). The pharmaceutical compositions may be subjected to conventional pharmaceutical operations such as sterilization and/or may contain conventional adjuvants, such as preservatives, stabilizers, wetting agents, emulsifiers, buffers etc.
Solid dosage forms for oral administration may include capsules, tablets, pills, powders, and granules.
In such solid dosage forms, the active compound may be admixed with at least one inert diluent such as sucrose, lactose, or starch. Such dosage forms may also comprise, as in normal practice, additional substances other than inert diluents, lubricating agents such as magnesium stearate. In the case of capsules, tablets, and pills, the dosage forms may also comprise buffering agents. Tablets and pills can additionally be prepared with enteric coatings.
Liquid dosage forms for oral administration may include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art, such as water.
Such compositions may also comprise adjuvants, such as wetting, sweetening, flavoring, and perfuming agents.
Compounds of the present invention can possess one or more asymmetric carbon atoms and are thus capable of existing in the form of optical isomers as well as in the form of racemic or non-racemic mixtures thereof. The optical isomers can be obtained by resolution of the racemic mixtures according to conventional processes, by formation of diastereoisomeric salts, by treatment with an optically active acid or base.
Examples of appropriate acids are tartaric, diacetyltartaric, dibenzoyltartaric, ditoluoyltartaric, and camphorsulfonic acid and then separation of the mixture of diastereoisomers by crystallization followed SUBSTITUTE SHEET (RULE 26) WO 98/24782 PCT/US97/22390 189 by liberation of the optically active bases from these salts. A different process for separation of optical isomers involves the use of a chiral chromatography column optimally chosen to maximize the separation of the enantiomers. Still another available method involves synthesis of covalent diastereoisomeric molecules by reacting compounds of the invention with an optically pure acid in an activated form or an optically pure isocyanate. The synthesized diastereoisomers can be separated by conventional means such as chromatography, distillation, crystallization or sublimation, and then hydrolyzed to deliver the enantiomerically pure compound.
The optically active compounds of the invention can likewise be obtained by using active starting materials.
These isomers may be in the form of a free acid, a free base, an ester or a salt.
The compounds of the present invention can be used in the form of salts derived from inorganic or organic acids. The salts include, but are not limited to, the following: acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, cyclopentanepropionate, dodecylsulfate, ethanesulfonate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hyroxy-ethanesulfonate, lactate, maleate, methansulfonate, nicotinate, 2naphthalenesulfonate, oxalate, palmoate, pectinate, persulfate, 2-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, mesylate, and undecanoate. Also, the basic nitrogencontaining groups can be quaternized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl, and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides WO 98/24782 PCT/US97/22390 190 like benzyl and phenethyl bromides, and others. Water or oil-soluble or dispersible products are thereby obtained.
Examples of acids that may be employed to from pharmaceutically acceptable acid addition salts include such inorganic acids as hydrochloric acid, sulphuric acid and phosphoric acid and such organic acids as oxalic acid, maleic acid, succinic acid and citric acid.
Other examples include salts with alkali metals or alkaline earth metals, such as sodium, potassium, calcium or magnesium or with organic bases.
While the compounds of the invention can be administered as the sole active pharmaceutical agent, they can also be used in combination with one or more compounds of the invention or other agents. When administered as a combination, the therapeutic agents can be formulated as separate compositions that are given at the same time or different times, or the therapeutic agents can be given as a single composition.
The foregoing is merely illustrative of the invention and is not intended to limit the invention to the disclosed compounds. Variations and changes which are obvious to one skilled in the art are intended to be within the scope and nature of the invention which are defined in the appended claims.
From the foregoing description, one skilled in the art can easily ascertain the essential characteristics of this invention, and without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions.

Claims (5)

1. A compound of formula R2 R 11 RlY N R12 N R, or a pharmacutically acceptable salt thereof, wherein wherein R 1 and R2 are each independently provided that the total number of aryl, heteroaryl, cycloalkyl and heterocyclyl radicals in each -Z-Y is 0- 3; and the combined total number of aryl, heteroaryl, cycloalkyl and heterocyclyl radicals in R 1 and R2 is 0-4; wherein each Z is independently a bond; alkyl, alkenyl or alkynyl radical optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio or halo, and 1-2 radicals of heterocyclyl, aryl or heteroaryl optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, halo, alkyl or haloalkyl; heterocyclyl radical optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, alkyl or haloalkyl; or aryl or heteroaryl radical optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, cyano, halo, alkyl or haloalkyl; I_ WO 98/24782 PTU9/29 PCTIUS97/22390 192 each Y is independently a hydrogen radical; halo or nitro radical; -C (0)-R 2 0 or -C (NR 5 -NR 5 R 2 1 radical; -OR2 1 2 1 -O-C(O)-NR 5 R 2 1 or -O-C(O)-NR 2 2 S(O)2-R 20 radical; -SR 2 1 -S(O)-R 2 0 -S(O)2-R 2 0 -S(O) 2 -NR 5 R 2 1 -S(O) 2 NR 2
2-C(O)-R 2 1 -S(O)2-NR 2 2 -C(O)-0R 2 0 or -S(O)2-NR 2 2 NR 5 R 21 radical; or -NR 5 R 2 1 -NR22-C(O)-R 2 1 -NR22-C(O)-0R 2 0 -NR 2 2 NR 5 R 2 1 -NR22-C(NR 5 )-NRSR 2 1, -NR 2 2 -S(O) 2 -R 2 0 or -NR 2 2 S(O)2-NR 5 R 2 1 radical; wherein each R 5 is independently hydrogen radicals; alkyl, alkenyl or alkynyl radicals optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, hydroxy, alkoxy, alkylthio, -So 3 H or halo; or aryl, heteroaryl, aralkyl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl or cycloalkylalkyl radicals optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, hydroxy, alkoxy, alkylthio, alkyl or haloalkyl; and wherein each R20 is independently alkyl, alkenyl or alkynyl radicals optionally substituted by 1-3 radicals of amino, alkylarnino, dialkylamino, alkanoylamino, alkoxycarbonylamino, N- (alkoxycarbonyl) (alkyl) amino, aminocarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, halo or aralkoxy, aralkylthio, aralkylsulfonyl, cycloalkyl, heterocyclyl, aryl or heteroaryl radicals optionally substituted by 1- 3 radicals of amino, alkylanino, dialkylamino, WO 98/24782 PCTIUS97/22390 193 alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, alkanoyl, hydroxy, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, halo, alkyl or haloalkyl; heterocyclyl radical optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, alkyl or haloalkyl; or aryl or heteroaryl radicals optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, alkoxycarbonyl, hydroxy, alkoxy, alkylthio, cyano, halo, azido, alkyl or haloalkyl; each R 21 is independently hydrogen radical or R 20 each R 22 is independently hydrogen radical; alkyl radical optionally substituted by a radical of heterocyclyl, aryl or heteroaryl optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, cyano, halo, alkyl or haloalkyl; or heterocyclyl, aryl or heteroaryl radicals optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, cyano, halo, alkyl or haloalkyl; provided when Z is a bond and Y is -NR22- C(O)-NH 2 then R 2 2 is other then an optionally substituted aryl radical; and R 11 and R12 are each independently an aryl or heteroaryl radical optionally substituted by 1-3 radicals of R 30 halo or cyano radicals; WO 98/24782 PTU9129 194 -C -R 3 0, -C -R 2 9 -C -NR3 1 R3 2 or -C(NR 3 1)- NR 3 1R 3 2 radicals; -OR 2 9 2 9 -O-C(O)-NR 3 lR 3 2 or -O-C(O)-NR 3 3 S(O)2-R 3 0 radicals; -SR 2 9 -S(O)-R 3 0 -S(C)2-R 3 0 -S(O) 2 -NR 3 lR 3 2, -S(O) 2 NR 3 3 -C(O)-R 3 0 -S(O) 2 -NR 3 3 -C(O)-OR 3 o or -S(O)2-NR 3 3 NR 3 lR32 radicals; or -NR 3 1 R 3 2 -NR33-C(O)-R 2 9 -NR 3 3 -C(O)-OR 3 o, -NR3 3 NR 3 lR 3 2, -NR 3 3 -C(NR 3 1)-NR 3 lR 3 2 -NR 3
3-S(O) 2 -R 3 0 or -NR 3 3 S(O)2-NR 3 lR3 2 radicals; provided that R 1 1 is other than a 4-pyridyl, 4- pyrimidinyl, 4-quinolyl or 6-isoquinolinyl radical optionally substituted by 1-2 substituents; and the total number of aryl, heteroaryl, cycloalkyl and heterocyclyl radicals substituted on each of R 1 1 and R12 is 0-1; wherein each R 3 0 is independently alkyl, alkenyl or alkynyl radicals optionally substituted by 1-3 radicals of -NR 3 1 R 3 1 -C02R 2 3 hydroxy, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, cyano, halo or aralkoxy, aralkylthio, aralkylsulfonyl, heterocyclyl, aryl or heteroaryl radicals optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylanino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, cyano, halo, alkyl or haloalkyl; heterocyclyl radical optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, alkanoylanino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, cyano, alkyl or haloalkyl; or aryl or heteroaryl radicals optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, WO 98/24782 PCT/US97/22390 195 hydroxy, alkoxy, alkylthio, cyano, halo, alkyl or haloalkyl; each R2 9 is independently hydrogen radical or R 3 0 each R 3 1 and R 3 2 are each independently hydrogen radicals; alkyl radical optionally substituted by an cycloalkyl, aryl, heterocyclyl or heteroaryl radical optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, cyano, alkyl or haloalkyl; or aryl, heteroaryl, heterocyclyl or cycloalkyl radical optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, cyano, alkyl or haloalkyl; and wherein each R 3 3 is independently hydrogen radical; or alkyl radical optionally substituted by a radical of heterocyclyl, aryl or heteroaryl optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, cyano, alkyl or haloalkyl; and provided that when R' and R" are the same and are a
5- or 6-member ring having from 1-3 heteroatoms independently selected from N, S, and 0, to which ring a benzene ring is optionally fused, R u is phenyl or naphthyl optionally substituted with halo, C 1 -C 6 alkyl, C,-C 4 alkoxy, C -C 4 alkylthiol, hydroxy, amino, C,-C 4 alkylamino, or dialkylamino, or R" is a 5- or 6-membered ring having from 1-3 heteroatoms independently selected from N, S, and 0, to which ring a benzene ring is -196- optionally fused and optionally substituted with CI-C 6 alkyl, the R 2 is other than OH or NH 2 when R 2 is H, R 11 is phenyl and R 1 2 is 4-pyridyl, then R' is other than H, methyl, or amino; when R 2 is H, R 1 is 2-methylphenyl and R 1 2 is 2-pyrdyl, the R 1 is other than n-propyl; when R 11 is an optionally substituted aryl radical, then R 1 2 is other than an optionally substituted aryl radical; and when R' 1 and R 1 2 are each independently a 3-pyridyl or an optionally substituted phenyl radical, then R' is other than an alkylthiol or haloalkylthiol radical. 2. The compound of Claim 1 or a pharmaceutically acceptable salt thereof, wherein R, and R 2 are each independently provided that the total number of aryl, heteroaryl, cycloalkyl and heterocyclyl radicals in each -Z-Y is 0-3; and the conbined total number of aryl, heteroaryl, cycloalkyl and heterocyclyl radicals in Ri and R 2 is 0-4; each Z is independently a bond CI-C 8 alkyl, C 2 -C 8 alkenyl or C 2 -C 8 alkynyl radical optionally substituted by 1- 3 radicals of amino, C 1 -C 4 alkylamino, di- (C 1 -C 4 alkyl) amino, C 1 -C 5 alkanoylamino, (C 1 -C 4 alkoxy) carbonylamino, CI-C 4 alkylsulfonylamino, hydroxy, CI-C 4 alkoxy, CI-C 4 alkylthio or halo, and 1-2 radicals of heterocyclyl, aryl or heteroaryl optionally substituted by 1-3 radicals of amino, C 1 -C 4 alkylamino, di- (C 1 -C 4 alkyl) amino, C 1 -C alkanoylamino, (CI-C 4 alkoxy) carbonylamino, CI-C 4 alkylsulfonylamino, hydroxy, C 1 C 4 alkoxy, CI-C 4 alkylthio, halo, CI-C 4 alkyl or Ci-C 4 haloalkyl of 1-3 halo radicals; heterocyclyl radical optionally substitued by 1-3 radicals of amino, Ci-C 4 alkylamino, di- (Ci-C 4
22344-ooDOc/acw WO 98/24782 PCTIUS97/22390 197 alkyl)amino, Cj-C 5 alkanoylamino, (Cl-0 4 alkoxy) carbonylamino, Cl-C 4 alkylsulfonylamino, hydroxy, Cl-C 4 alkoxy, Cj-C 4 alkylthio, Cl-C 4 alkyl or Cl-C 4 haloalkyl of 1-3 halo radicals; or aryl or heteroaryl radical optionally substituted by 1-3 radicals of amino, C 1 -C 4 alkylamino, di- (Cl-C 4 alkyl)amino, Cl-C 5 alkanoylamino, (Cl-C 4 al koxy) c arbonyl amino, Cl-C 4 alkylsulfonylamino, hydroxy, Cl-C 4 alkoxy, Cl-C 4 alkylthio, cyano, halo, Cl-C 4 alkyl or Cl-C 4 haloalkyl of 1-3 halo radicals; each Y is independently a hydrogen radical; halo or nitro radical; -C(O)-R 2 0 or -C(NR5)-NR 5 R 2 1 radical; -OR 2 1 -O-C(O)-R 2 1 -O-C(O)-NR 5 R 2 1 or -O-C(O)-NR2 2 S(O) 2 -R 20 radical; -SR 2 1 -S(O)-R 2 0 -S(O) 2 -R 2 0 -S(O)2-NR 5 R 2 l, -S(O) 2 NR22-C(O)-R 2 1 -S(O)2-NR 2 2 -C(O)-0R 2 0 or S02N2-() NR 5 R 2 1 radical; or -NR 5 R 2 1 -NR22-C(O)-R 2 1 -NR2 2 -C(O)-0R 2 0 -NR 2 2 NR 5 R 2 1 -NR22-C(NR 5 )-NR 5 R 2 1, -NR 2 2 2-R2O or -NR 2 2 S 2-NR 5 R 2 l radical; each R 5 is independently hydrogen radicals; Cl-C 8 alkyl, C 2 -C 8 alkenyl or C 2 -C 8 alkynyl radicals optionally substituted by 1-3 radicals of amino, Cl-C 4 alkylamino, di- (C1-C4-alkyl) amino, hydroxy, Cl-C 4 alkoxy, Cl-C 4 alkylthio, -SO 3 H or halo; or aryl, heteroaryl, aryl-Cl-C 4 -alkyl, heteroaryl-Cl- C4-alkyl, heterocyclyl, heterocyclyl-Cl-C 4 -alkyl, C 3 -C 8 cycloalkyl or C3-C8-cycloalkyl-Cl-C 4 -alkyl radicals optionally substituted by 1-3 radicals of amino, Cl-C4 alkylamino, di- (Cl-C4-alkyl) amino, hydroxy, Cl-C 4 WO 98/24782 PCTIUS97/22390 198 alkoxy, 01-04 alkylthio, 01-04 alkyl or 01-04 haloalkyl of 1-3 halo radicals; each R 20 is independently 01-08 alkyl, 02-08 alkenyl or 02-08 alkynyl radicals optionally substituted by 1-3 radicals of amino, 01-04 alkylamino, di-(C 1 -C 4 alkyl)amino, 01-05 alkanoylanino, (01-04 alkoxy) carbonylamino, N- (01-04 alkoxy) carbonyl) N-(C 1 -C 4 alkyl)amino, alinocarbonylamino, 01-04 alkylsulfonylamino, hydroxy, 01-04 alkoxy, 01-04 alkylthio, 01-04 alkylsulfinyl, 01-04 alkylsulfonyl, halo or aryl-Cl-C4-alkoxy, aryl-Cl-C4-alkylthio, aryl-C 1 04-alkylsulfonyl, 03-08 cycloalkyl, heterocyclyl, aryl or heteroaryl radicals optionally substituted by 1-3 radicals of amino, 01-04 alkylamino, di-(C 1 -C 4 alkyl)anino, 01-05 alkanoylamino, (01-04 al1koxy) carbonyl amino, 01-04 alkylsulfonylamino, alkanoyl, hydroxy, 01-04 alkoxy, 01-04 alkylthio, 01-04 alkylsulfinyl, 01-04 alkylsulfonyl, halo, 01-04 alkyl or 01-04 haloalkyl of 1-3 halo radicals; heterocyclyl radical optionally substituted by 1-3 radicals of amino, 01-04 alkylamino, di-(C 1 -C 4 alkyl)amino, 01-05 alkanoylamino, (01-04 al1koxy) c arbonyl amino, 01-04 alkylsulfonylamino, hydroxy, 01-04 alkoxy, 01-04 alkylthio, 01-04 alkyl or 01-04 haloalkyl of 1-3 halo radicals; or aryl or heteroaryl radicals optionally substituted by 1-3 radicals of amino, 01-04 alkylanino, di-(Cl-C 4 alkyl)anino, 01-05 alkanoylamino, (Ci-C 4 alkoxy) carbonyl amino, 01-04 alkylsulfonylamino, (01-04 alkoxy)carbonyl, hydroxy, 01-04 alkoxy, 01-04 alkylthio, cyano, halo, azido, 01-04 alkyl or 01-04 haloalkyl of 1- 3 halo radicals; each R 2 1 is independently hydrogen radical or WO 98/24782 PTU9/29 PCTfUS97/22390 199 each R2 2 -is independently hydrogen radical; cl-c 4 alkyl radical optionally substituted by a radical of heterocyclyl, aryl or heteroaryl optionally substituted by 1-3 radicals of amino, Cl-C 4 alkylamino, di-(Cl-C 4 alkyl)amino, Cl-C 5 alkanoylanino, (Ci-C 4 al1koxy) c arbonyl amino, Ca.-C4 alkylsulfonylamino, hydroxy, Cl-C 4 alkoxy, Cl-C 4 alkylthio, Cl-C 4 alkylsulfinyl, Cl-C 4 alkylsulfonyl, cyano, halo, C 1 -C 4 alkyl or Cl-C 4 haloalkyl of 1-3 halo radicals; or heterocyclyl, aryl or heteroaryl radicals optionally substituted by 1-3 radicals of amino, Cl-C 4 alkylamino, di- (Cl-C4 alkyl)anino, C 1 -C 5 alkanoylamino, (Cl-C 4 a lkoxy) carbonyl amino, Cl-C 4 alkylsulfonylanino, hydroxy, Cl-C 4 alkoxy, Cl-C 4 alkylthio, Cl-C 4 alkylsulfinyl, Cl-C 4 alkylsulfonyl, cyano, halo, Cl-C 4 alkyl or Cl-C 4 haloalkyl of 1-3 halo radicals; provided when Z is a bond and Y is -NR22-C(O)-NH 2 then R 2 2 is other then an optionally substituted aryl radical; R11 and R 12 are each independently an aryl or heteroaryl radical optionally substituted by 1-3 radicals of R 3 0 halo or cyano radicals; -C(O)-R 3 o, -C(O)-0R 2 9 -C(O)-NR 3 lR 3 2 or -C(NR 3 1 NR 31 R 32 radicals; -OR 2 9 -O-C(O)-R 2 9 -O-C(O)-NR 3 lR 3 2 or -O-C(O)-NR33- S(O) 2 -R 3 o radicals; -SR 2 9 -S(O)-R30, -S(O) 2 -R 3 0 -S(O) 2 -NR 3 lR 3 2 -S(O) 2 NR3 3 -C (0)-R3 0 -S 2NR 33 -OR 3 0 or 2 -NR 3 3 -C NR 3 1 R 3 2 radicals; or -NR3 1 R 3 2 -NR33-C(0)-R 2 9 -NR33-C(0)-0R3 0 -NR 3 3 NR 3 1 R 3 2 -NR3 3 -C(NR 3 1 )-NR 3 lR 3 2 -NR 3 3 -S(O) 2 -R 3 0 or -NR33- S(O)2-NR 3 lR 3 2 radicals; WO 98/24782 WO 9824782PCTIUJS97/22390 200 provided that R 1 1 is other than a 4-pyridyl, 4- pyrimidinyl, 4-quinolyl or 6-isoquinolinyl radical optionally substituted by 1-2 substituents; and the total number of aryl, heteroaryl, cycloalkyl and heterocyclyl radicals substituted on each of R 1 1 and R 1 2 is 0-1; each R30 is independently C 1 -C 4 alkyl, C 2 -C 4 alkenyl or C 2 -C 4 alkynyl radicals optionally substituted by 1-3 radicals of -NR 3 1 R 3 1 C0 2 R 2 3 hydroxy, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio, C 1 -C 4 alkylsulfinyl, C 1 -C 4 alkylsulfonyl, cyano, halo or aryl- Cl-C4-alkoxy, aryl-Cl-C4-alkylthio, aryl-Cl-C 4 alkylsulfonyl, heterocyclyl, aryl or heteroaryl radicals optionally substituted by 1-3 radicals of amino, Cl-C 4 alkylamino, di-(Cl-C 4 alkyl)amino, C 1 -C 5 alkanoylamino, (C 1 -C 4 alkoxy) carbonylamino, Cl-C 4 alkylsulfonylamino, hydroxy, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio, C 1 -C 4 alkylsulfinyl, C 1 -C 4 alkylsulfonyl, cyano, halo, Cl-C 4 alkyl or C 1 -C 4 haloalkyl of 1-3 halo radicals; heterocyclyl radical optionally substituted by 1-3 radicals of amino, C 1 -C 4 alkylamino, di-(Cl-C 4 alkyl)amino, C 1 -C 5 alkanoylanino, (Cl-C 4 al1koxy) c arbonyl amino, C 1 -C 4 alkylsulfonylamino, hydroxy, Ci-C 4 alkoxy, C 1 -C 4 alkylthio, cyano, C 1 -C 4 alkyl or C 1 C 4 haloalkyl of 1-3 halo radicals; or aryl. or heteroaryl radicals optionally substituted by 1-3 radicals of amino, CI-C 4 alkylamino, di-(Cl-C 4 alkyl)amino, Cl-C 5 alkanoylamino, (Cl-C 4 al1koxy) carbonyl amino, Cl-C 4 alkylsulfonylamino, hydroxy, Cl-C 4 alkoxy, Cl-C 4 alkylthio, cyano, halo, Cl-C 4 alkyl or Cl-C 4 haloalkyl of 1-3 halo radicals; each R 2 9 is independently hydrogen radical or R3 0 WO 98/24782 PCT/US97/22390 201 each R 31 and R 3 2 are each independently hydrogen radicals; C1-C 4 alkyl radical optionally substituted by an C 3 C 8 cycloalkyl, aryl, heterocyclyl or heteroaryl radical optionally substituted by 1-3 radicals of amino, C 1 -C 4 alkylamino, di-(Ci-C 4 alkyl)amino, C 1 -C 5 alkanoylamino, (Ci-C 4 alkoxy)carbonylamino, C 1 -C 4 alkylsulfonylamino, hydroxy, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio, cyano, C 1 -C 4 alkyl or C 1 -C 4 haloalkyl of 1-3 halo radicals; or aryl, heteroaryl, heterocyclyl or C 3 -C 8 cycloalkyl radical optionally substituted by 1-3 radicals of amino, C 1 -C 4 alkylamino, di-(C1-C 4 alkyl)amino, Ci-C alkanoylamino, (Ci-C 4 alkoxy)carbonylamino, C 1 -C 4 alkylsulfonylamino, hydroxy, C 1 -C 4 alkoxy, Ci-C 4 alkylthio, cyano, C 1 -C 4 alkyl or C 1 -C 4 haloalkyl of 1-3 halo radicals; and each R 3 3 is independently hydrogen radical; or C 1 -C 4 alkyl radical optionally substituted by a radical of heterocyclyl, aryl or heteroaryl optionally substituted by 1-3 radicals of amino, C 1 -C 4 alkylamino, di-(C 1 -C 4 alkyl)amino, C 1 -C 5 alkanoylamino, (C 1 -C 4 alkoxy)carbonylamino, C 1 -C 4 alkylsulfonylamino, hydroxy, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio, cyano, C 1 -C 4 alkyl or C 1 C 4 haloalkyl of 1-3 halo radicals; and wherein heterocyclyl is a radical of a monocyclic or bicyclic saturated heterocyclic ring system having 5-8 ring members per ring, wherein 1-3 ring members are oxygen, sulfur or nitrogen heteroatoms, which is optionally partially unsaturated or benzo-fused and optionally substituted by 1-2 oxo or thioxo radicals; aryl is a phenyl or naphthyl radical; and heteroaryl is radical of a monocyclic or bicyclic aromatic heterocyclic ring system having 5-6 ring members per WO 98/24782 PCT/US97/22390 202 ring, wherein 1-3 ring members are oxygen, sulfur or nitrogen heteroatoms, which is optionally benzo-fused or saturated C 3 -C4-carbocyclic-fused. 3. The compound of Claim 2 or a pharmaceutically acceptable salt thereof, wherein each Z is independently a bond; C1-C 8 alkyl, C 2 -C8 alkenyl or C2-C8 alkynyl radical optionally substituted by 1-3 radicals of amino, CI- C4 alkylamino, di-(C 1 -C 4 alkyl)amino, C 1 alkanoylamino, (C1-C 4 alkoxy)carbonylamino, C 1 -C 4 alkylsulfonylamino, hydroxy, C1-C4 alkoxy, C 1 -C 4 alkylthio or halo, and 1-2 radicals of heterocyclyl, aryl or heteroaryl optionally substituted by 1-3 radicals of amino, Cl-C 4 alkylamino, di-(C 1 -C 4 alkyl)amino, C 1 -C 5 alkanoylamino, (C 1 -C4 alkoxy)carbonylamino, C 1 -C4 alkylsulfonylamino, hydroxy, C1-C4 alkoxy, C 1 -C 4 alkylthio, halo, CI-C 4 alkyl or C 1 -C4 haloalkyl of 1-3 halo radicals; heterocyclyl radical optionally substituted by 1-2 radicals of amino, Cl-C4 alkylamino, di-(C 1 -C4 alkyl)amino, C 1 -C 5 alkanoylamino, (Ci-C4 alkoxy)carbonylamino, CI-C4 alkylsulfonylamino, hydroxy, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio, Cl-C4 alkyl or Ci-C4 haloalkyl of 1-3 halo radicals; or aryl or heteroaryl radical optionally substituted by 1-3 radicals of amino, Cl-C4 alkylamino, di-(Ci-C4 alkyl)amino, C 1 -C 5 alkanoylamino, (C1-C4 alkoxy)carbonylamino, Ci-C4 alkylsulfonylamino, hydroxy, C 1 -C4 alkoxy, C 1 -C4 alkylthio, cyano, halo, Cl-C4 alkyl or C1-C4 haloalkyl of 1-3 halo radicals; WO 98/24782 WO 9824782PCTIUS97/22390 203 each R5 is independently hydrogen radicals; cl-c 4 alkyl, C 2 -C 5 alkenyl or C 2 -C 5 alkynyl radicals optionally substituted by 1-3 radicals of amino, Cl-C 4 alkylainino, di- (Cl-C4-alkyl) amino, hydroxy, Cl-C 4 alkoxy, Cl-C 4 alkyithia, -SO 3 H or halo; or aryl, heteroaryl, aryl-Cl-C4-alkyl, heteroaryl-Cl- C4-alkyl, heterocyclyl, heterocyclyl-Cl-C 4 -alkyl, C 3 -C 8 cycloalkyl or C3-C8-cycloalkyl-C 1 -C 4 -alkyl radicals optionally substituted by 1-3 radicals of amino, C 1 -C 4 alkylamino, di- (Cl-C4-alkyl) amino, hydroxy, Cl-C 4 alkoxy, Cl-C 4 alkylthio, C 1 -C 4 alkyl or Cl-C 4 haloalkyl of 1-3 halo radicals; each R 2 0 is independently cl-c 8 alkyl, C 2 -C 5 alkenyl or C 2 -C 5 alkyny. radicals optionally substituted by 1-3 radicals of amino, Cl-C 4 alkylamino, di-(Cl-C 4 alkyl)amino, Cl-C 5 alkanoylamino, (Cl-C 4 alkoxy) carbonyl amino, N- ((Cl-C 4 alkoxy)carbonyl) N-(Cl-C 4 alkyl)amino, aminoc arbonyl1amino, Cl-c 4 alkylsulfoaylamino, hydroxy, Cl-c 4 alkoxy, Cl-C 4 alkylthio, Cl-C 4 alkylsulfinyl, Cl-C 4 alkylsulfonyl, halo or aryl-Cl-C 4 -alkoxy, aryl -Cl-C 4 -alkylthio, aryl -Cl- C4-alkylsulfonyl, C 3 -C 8 cycloalkyl, heterocyclyl, aryl or heteroaryl radicals optionally substituted by 1-3 radicals of amino, Cl-C 4 alkylamino, di-(Cl-C 4 alkyl)amino, Cl-C 5 alkanoylamino, (Cl-C 4 a lkoxy) carbonyl amino, Cl-C 4 alkylsulfonylamino, Cl-C alkanoyl, hydroxy, Cl-C 4 alkoxy, Cl-C 4 alkylthio, Cl-C 4 alkylsulfinyl, CI-C 4 alkylsulfonyl, halo, Cl-C 4 alkyl or Cl-C 4 haloalkyl of 1-3 halo radicals; heterocyclyl radical optionally substituted by 1-3 radicals of amino, Cl-C 4 alkylanino, di-(Cl-C 4 alkyl)amino, Cl-C 5 alkanoylamino, (Cl-c 4 alkoxy) carbonylamino, Cl-C 4 alkylsulfonylanino, hydroxy, WO 98/24782 WO 9824782PCTIUS97/22390 204 c 1 -C 4 alkoxy, C 1 -C 4 alkylthio, Cl-C 4 alkyl or Cl-C 4 haloalkyl of 1-3 halo radicals; or aryl or heteroaryl radicals optionally substituted by 1-3 radicals of amino, Cl-C 4 alkylamino, di-(Cl-C 4 alkyl)amino, Cl-C 5 alkanoylamino, (CI-C 4 a lkoxy) carbonyl amino, C 1 -C 4 alkylsulfonylamino, (Ci-C 4 alkoxy)carbonyl, hydroxy, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio, cyano, halo, azido, Cl-C 4 alkyl or C 1 -C 4 haloalkyl of 1-3 halo radicals; each R21 is independently hydrogen radical or R 2 0 each R30 is independently C 1 -C 4 alkyl radical optionally substituted by 1-3 radicals of -NR 3 1 R 3 1 Cl-C 4 alkoxy-carbonyl or phenoxycarbonyl or phenylmethoxycarbonyl optionally substituted by 1-3 radicals of amino, alkylamino, di- (C1-C4-alkyl) amino, C 1 -C 5 alkanoylamino, (Cl-C 4 alkoxy)carbonylamino, Cl-C 4 alkylsulfonylamino, hydroxy, CI-C 4 alkoxy, Cl-C 4 alkylthio, cyano, halo, Cl-C 4 alkyl or trifluoromethyl; or hydroxy, Cl-C 4 alkoxy, Cl-C 4 alkylthio, or phenyl-Cl- C4-alkoxy, phenyl-Cl-C 4 -alkylthio, heterocyclyl, phenyl or heteroaryl radicals optionally substituted by 1-3 radicals of amino, Cl-C 4 alkylamino, di-(Cl-C 4 alkyl)amino, Cl-C 5 alkanoylamino, (Cl-C 4 alkoxy)carbonylamino, hydroxy, Cl-C 4 alkoxy, Cl-C4 alkylthio, cyano, halo, Cl-C 4 alkyl or Cl-C 4 haloalkyl of 1-3 halo radicals; Cl-C 4 haloalkyl of 1-3 halo radical; or aryl or heteroaryl radicals optionally substituted by 1-3 radicals of amino, Cl-C 4 alkylamino, di-(Cl-C 4 alkyl)amino, Cl-C 5 alkanoylamino, (Cl-C 4 WO 98/24782 WO 9824782PCTIUS97/22390 205 alkoxy) carbonYlamino, hydroxy, Cl-C4 alkoxy, C 1 -C 4 alkylthio, cyano, halo, Cl-C4 alkyl or trifluoromethyl radicals; each R29 is, independently hydrogen radical or each R31 is independently hydrogen radicals; or CI-C4 alkyl radical optionally substituted by an phenyl or heteroaryl radical optionally substituted by 1-3 radicals of amino, Cl-C4 alkylaino, di- (Cl-C4 alkyl) amino, Cl-C 5 alkanoylafino, (Cl-C4 alkoxy) carbonylamino, hydroxy, Cl-C 4 alkoxy, C 1 -C 4 alkylthio, cyano, Cl-C4 alkyl or trif luoroinethyl radicals; and each R32 is independently hydrogen radicals; Cl-C 4 alkyl radical optionally substituted by an C 3 C6 cycloalkyl, aryl, heterocyclyl or heteroaryl radical optionally substituted by 1-3 radicals of amino, C 1 -C4 alkylafino, di-(Cl-C4 alkyl)amino, Cl-C5 alkanoylamfino, (Cl-C4 alkoxy) carbonyl amino, Cl-C4 alkylsulfonylamino, hydroxy, Cl-C4 alkoxy, Cl-C4 alkylthio, cyano, Cl-C4 alkyl or Cl-C4 haloalkyl of 1-3 halo radicals; or aryl, heteroaryl, heterocyclyl or C 3 -C6 cycloalkyl radical optionally substituted by 1-3 radicals of amino, Cl-C4 alkylamino, di-(Cl-C4 alkyl)amilo, alkanoylafino, (Cl-C 4 a lkoxy) carbofl am~ino, Cl-C4 alkylsulfonylanino, hydroxy, Cl-C4 alkoxy, Cl-C4 alkylthio, cyano, CI-C 4 alkyl Or Cl-C4 haloalkyl of 1-3 halo radicals; and each R 3 3 is independently hydrogen or Cl-C 4 alkyl radical. WO 98/24782 PCT/US97/22390 206 4. The compound of Claim 3 or a pharmaceutically acceptable salt thereof, wherein wherein R 1 is provided that the total number of aryl, heteroaryl, cycloalkyl and heterocyclyl radicals in R 1 is 0-3; Z is a bond; Cl-Cs alkyl or C2-C8 alkenyl radical optionally substituted by 1-3 radicals of amino, Ci-C 4 alkylamino, di-(C 1 -C 4 alkyl)amino, C 1 -C 5 alkanoylamino, (C 1 -C 4 alkoxy)carbonylamino, hydroxy, Ci-C4 alkoxy, C 1 -C 4 alkylthio or halo, and 1-2 radicals of heterocyclyl, aryl or heteroaryl optionally substituted by 1-3 radicals of amino, C 1 -C 4 alkylamino, di-(C 1 -C 4 alkyl)amino, C 1 -C 5 alkanoylamino, (C 1 -C 4 alkoxy)carbonylamino, hydroxy, C 1 -C 4 alkoxy, Ci-C 4 alkylthio, halo, C 1 -C 4 alkyl or Ci-C 2 haloalkyl of 1-3 halo radicals; heterocyclyl radical optionally substituted by 1-2 radicals of amino, di-(C 1 -C 4 alkyl)amino, (Ci-C 4 alkoxy)carbonylamino, hydroxy, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio or CI-C 4 alkyl radicals; or aryl or heteroaryl radical optionally substituted by 1-3 radicals of amino, C 1 -C 4 alkylamino, di-(CI-C 4 alkyl)amino, CI-C 5 alkanoylamino, (C 1 -C 4 alkoxy)carbonylamino, Ci-C 4 alkylsulfonylamino, hydroxy, C 1 -C 4 alkoxy, Ci-C 4 alkylthio, cyano, halo, CI-C 4 alkyl or Ci-C 2 haloalkyl of 1-3 halo radicals; Y is a hydrogen radical; halo radical; WO 98/24782 PCT/US97/22390 207 -C (0)-R 2 0 or -C (NR5) -NR 5 R 2 1 radical; -OR 21 -0-C (0)-R 2 1 or -0-C (0)-NR 5 R 2 1 radical; -SR 2 1 -S(O)-R 2 0 -S(O)2-R 2 0 or -S(O)2-NR 5 R 2 1 radical; or -NR 5 R 2 1 -NR22-C(O)-R 2 i, -NR2 2 -C(O)-jR 2 0, -NR 2 2 NR 5 R 2 1 -NR 2 2 -C(NR 5 -NR 5 R 2 1 -NR22-S(O) 2 -R 2 0 or -R2 S(O)2-NR 5 R 2 1 radical; each R 5 is independently hydrogen radicals; cl-c 4 alkyl or C 2 -C 5 alkenyl radicals optionally substituted by 1-3 radicals of amino, di-(Cl-C 4 alkyl)anino, hydroxy, Cl-C 4 alkoxy, Cl-C 4 alkylthio, S0 3 H or halo; or phenyl-Ci-C2-alkyl, heteroaryl-Cl-C 2 -alkyl, heterocyclyl-Cl-C 2 -alkyl or C 3 -C6-cycloalkyl-Cl-C 2 -alkyl radicals optionally substituted by 1-3 radicals of amino, di- (Cl-C4-alkyl) amino, hydroxy, Cl-C 4 alkoxy, Cj- C 4 alkylthio, Cl-C 4 alkyl or Cl-C 2 haloalkyl of 1-3 halo radicals; each R 20 is independently cl-c 8 alkyl or C 2 -C 5 alkenyl radicals optionally substituted by 1-3 radicals of amino, Cl-C 4 alkylamino, di- (Cl-C 4 alkyl)anino, Cl-C 5 alkanoylamino, (Cl-C 4 alkoxy) c arbonyl amino, N- ((Cl-C 4 alkoxy)carbonyl) (C 1 C 4 alkyl)anino, aminocarbonylamino, hydroxy, Cl-C 4 alkoxy, Cl-C 4 alkylthio, Cl-C 4 alkylsulfinyl, Cl-C 4 alkylsulfonyl, halo or aryl-Cl-C 4 -alkoxy, aryl-Cl-C 4 alkylthio, aryl-Cl-C4-alkylsulfonyl, C 3 -C 6 cycloalkyl, heterocyclyl, aryl or heteroaryl radicals optionally substituted by 1-3 radicals of amino, Cl-C 4 alkylamino, di- (Cl-C 4 alkyl)amino, Cl-C 5 alkanoylamino, (Cl-C 4 alkoxy) carbonyl amino, Cl-C 4 alkylsulfonylamino, WO 98/24782 WO 9824782PCTIUS97/22390 208 alkanoyl, hydroxy, C 1 -C 4 alkoxy, Cl-C 4 alkyithic, halo, C 1 -C 4 alkyl or C 1 -C 2 haloalkyl of 1-3 halo radicals; heterocyclyl radical optionally substituted by 1-2 radicals of amino, Cl-C 4 alkylainino, di-(Cl-C 4 alkyl)amino, C 1 -C 5 alkanoylamino, (Cl-C 4 alkoxy) carbonyl amino, hydroxy, C 1 -C 4 alkoxy, Cl-C 4 alkyithia or Cl-C 4 alkyl; or aryl or heteroaryl radicals optionally substituted by 1-3 radicals of amino, Cl-C 4 alkylamino, di-(Cl-C 4 alkyl)amino, Cl-C 5 alkanoylanino, (Cl-C 4 al1koxy) c arbonyl amino, CI-C 4 alkylsulfonylamino, (Cl-C 4 alkoxy)carbonyl, hydroxy, Cl-C 4 alkoxy, Cl-C 4 alkylthio, cyano, halo, azido, C 1 -C 4 alkyl or C 1 -C 2 haloalkyl of 1- 3 halo radicals; each R 21 is independently hydrogen radical or R 20 each R2 2 is independently hydrogen radical; or C 1 -C 4 alkyl radical optionally substituted by a radical of phenyl or heteroaryl optionally substituted by 1-3 radicals of amino, di-(Ci-C 2 alkyl)amino, Cl-Cs alkanoylamino, (Cl-C 4 a lkoxy) carbonyl amino, hydroxy, C 1 C 4 alkoxy, C 1 -C 4 alkylthio, cyano, halo, Cl-C 4 alkyl or Cl-C 2 haloalkyl of 1-3 halo radicals; R 2 is a radical of hydrogen, Cl-C 4 alkyl, halo, hydroxy, Cl-C 4 alkoxy, Cl-C 2 haloalkoxy of 1-3 halo radicals, thiol, Cl-C 4 alkylthio, aminosulfonyl, Cl-C 4 alkylaminosulfonyl, di- (Cl-C 4 alkyl) aminosulfonyl, amino, Cl-C 4 alkylanino, di-(CI-C 4 alkyl)amino, Cl-Cs alkanoylamino, (Ci-C 4 al1koxy) carbonyl amino, Cl-C 4 alkylsulfonylamino or Cl-C 2 haloalkyl of 1-3 halo radicals; WO 98/24782 WO 9824782PCTIUS97/22390 209 R11 and R12 are each independently an aryl or heteroaryl radical optionally substituted by 1-2 radicals of R3 0; halo or cyano radicals; -C (0)-R 3 0, -C -R 2 9 -C (0)-NR 3 1 R 3 2 or -C (NR 3 1 NR 31 R 32 radicals; or -OR2 9 -SR 2 9 -S(O)-R 3 0, -S(O) 2 -R 3 0, -S(O)2-NR 3 lR 3 2 -NR 3 1 R 3 2 -NR33-C(O)-R 2 9 or -NR33-C(O)-0R 3 0 radicals; provided that R 1 1 is other than a 4-pyridyl, 4- pyrimidinyl, 4-quinolyl or 6-isoquinolinyl radical optionally substituted by 1-2 substituents; and the total number of aryl, heteroaryl, cycloalkyl and heterocyclyl radicals substituted on each of R 1 1 and R12 is 0-1; each R 30 is independently C 1 -C 4 alkyl radical optionally substituted by amino, Cl-C 4 alkylamino, or di-(Cl-C4-alkyl) amino radicals; or hydroxy, Cl-C 4 alkoxy, heterocyclyl, phenyl or heteroaryl radicals optionally substituted by 1-3 radicals of amino, Cl-C 4 alkylanino, di-(Cl-C 4 alkyl)amino, Cl-C 5 alkanoylamino, (Cu-C 4 a lkoxy) carbonyl amino, hydroxy, Cl-C 4 alkoxy, Cu-C 4 alkylthio, cyano, halo, Ci-C 4 alkyl or trifluoromethyl radicals; Cl-C 2 haloalkyl of 1-3 halo radical; or aryl or heteroaryl radicals optionally substituted by 1-3 radicals of amino, Cl-C 4 alkylanino, di- (Cu-C 4 alkyl)amino, Cl-C 5 alkanoylainino, (Cu-C 4 al1koxy) carbonyl amino, hydroxy, Cl-C4 alkoxy, Cl-C4 alkylthio, cyano, halo, Cl-C 4 alkyl or trifluorornethyl radicals; each R 2 9 is independently hydrogen radical or WO 98/24782 PCT/US97/22390 210 each R 31 is independently hydrogen or CI-C 4 alkyl radicals; and each R 32 is independently hydrogen radicals; C 1 -C 4 alkyl radical optionally substituted by phenyl or heteroaryl radical optionally substituted by 1-3 radicals of amino, C 1 -C 4 alkylamino, di-(Ci-C 4 alkyl)amino, C 1 -C 5 alkanoylamino, (C 1 -C 4 alkoxy)carbonylamino, hydroxy, Ci-C 4 alkoxy, C 1 -C 4 alkyl or trifluoromethyl radicals; or phenyl or heteroaryl radical optionally substituted by 1-3 radicals of amino, C 1 -C4 alkylamino, di-(Ci-C 4 alkyl)amino, C 1 -C 5 alkanoylamino, (Ci-C 4 alkoxy)carbonylamino, hydroxy, C 1 -C 4 alkoxy, C 1 -C 4 alkyl or trifluoromethyl radicals; and each R3 3 is independently hydrogen or methyl radical; and wherein heterocyclyl is a radical of a monocyclic saturated heterocyclic ring system having 5-6 ring members, wherein 1-3 ring members are oxygen, sulfur or nitrogen heteroatoms, which is optionally benzo-fused and optionally substituted by 1-2 oxo or thioxo radicals; aryl is a phenyl or naphthyl radical; and heteroaryl is radical of a monocyclic aromatic heterocyclic ring system having 5-6 ring members, wherein 1-3 ring members are oxygen, sulfur or nitrogen heteroatoms, which is optionally benzo-fused or saturated C3-C4-carbocyclic-fused. 5. The compound of Claim 4 or a pharmaceutically acceptable salt thereof, wherein WO 98/24782 WO 9824782PCTIUS97/22390 211 Z is a bond; cl-c 4 alkyl or C 2 -C 5 alkenyl radical optionally substituted by 1-3 radicals of amino, di-(Cl-C 2 alkyl)amino, Cl-C 5 alkanoylamino, (Cl-C 4 alkoxy)carbonylamino, hydroxy, C 1 -C 2 alkoxy, Cl-C 2 alkylthio or halo, and 1-2 radicals of heterocyclyl, aryl or heteroaryl optionally substituted by 1-3 radicals of amino, Cl-C 4 alkylamino, di-(Cl-C 2 alkyl)amino, C 1 -C 5 alkanoylamino, (Cl-C 4 al1koxy) carbonyl amino, hydroxy, Cl-C 4 alkoxy, Cl-C 4 alkylthio, halo, Cl-C 4 alkyl or trifluoromethyl radicals; heterocyclyl radical optionally substituted by 1-2 radicals of amino, di- (Cl-C 2 alkyl) amino, (Cl-C 4 al1koxy) carbonyl amino, hydroxy, CI-C 2 alkoxy, Cl-C 2 alkylthio or Cl-C 4 alkyl radicals; or. aryl. or heteroaryl. radical optionally substituted by 1-3 radicals of amino, di-(Cl-C 2 alkyl) amino, Cl-C alkanoylamino, (Cl-C 4 a lkoxy) carbonyl.amino, hydroxy, Cj- C 2 alkoxy, Cl-C 2 alkylthio, cyano, halo, Cl-C 4 alkyl or trifluorornethyl radicals; each R 5 is independently hydrogen radical; Cl-C 4 alkyl radical optionally substituted by 1-3 radicals of amino, di- (Cl-C 2 -alkyl) amino, hydroxy, Cl-C 2 alkoxy, Cl-C 2 alkylthio or halo; or phenyl-Cl-C2-alkyl, heteroaryl-Cl-C2-alkyl, heterocyclyl-Cl-C 2 -alkyl or C 3 -C6-cycloalkyl-Cl-C 2 -alkyl radicals optionally substituted by 1-3 radicals of amino, di- (Cl-C2-alkyl) amino, hydroxy, Cl-C 2 alkoxy, Cj- C 2 alkylthio, methoxy, methylthio, CI-C 4 alkyl or trifluorornethyl radicals; WO 98/24782 PCT/US97/22390 212 each R 2 2 .is independently hydrogen or C 1 -C 4 alkyl radical; R 11 is an aryl radical and R 12 is a heteroaryl radical, wherein the aryl and heteroaryl radicals are optionally substituted by 1-2 radicals of halo or cyano radicals; -C(O)-R 3 0, -C(0)-OR 2 9 -C(O)-NR 3 1 R 3 2 or -C(NR 3 1)- NR 3 1 R 3 2 radicals; or -OR 2 9 -SR 2 9 -S(0)-R 3 0 -S(0) 2 -R 3 0 -S(0)2-NR 3 1 R 32 -NR 3 1 R 3 2 or -NR 3 3 -C(O)-R 2 9 radicals; provided that the total number of aryl, heteroaryl, cycloalkyl and heterocyclyl radicals substituted on each of R11 and R 12 is 0-1; each R 30 is independently C 1 -C 4 alkyl radical optionally substituted by a phenyl or heteroaryl radical optionally substituted by 1-3 radicals of amino, di-(Ci-C 2 alkyl)amino, acetamido, hydroxy, C 1 -C 2 alkoxy, halo, C 1 -C 4 alkyl or trifluoromethyl radicals; trifluoromethyl radical; or aryl or heteroaryl radicals optionally substituted by 1-3 radicals of amino, di-(Ci-C 2 alkyl)amino, acetamido, hydroxy, C 1 -C 2 alkoxy, halo, C 1 -C 4 alkyl or trifluoromethyl radicals; each R 2 9 is independently hydrogen radical or R 3 0 and each R32 is independently hydrogen radicals; C 1 -C 4 alkyl radical or C 1 -C 2 alkyl radical substituted by phenyl or heteroaryl radical optionally substituted by 1-3 radicals of amino, di-(C 1 -C2 WO 98/24782 PCT/US97/22390 213 alkyl)amino, acetamido, hydroxy, C 1 -C 2 alkoxy, C 1 -C 4 alkyl or trifluoromethyl radicals; or phenyl or heteroaryl radical optionally substituted by 1-3 radicals of amino, di-(C 1 -C 2 alkyl)amino, acetamido, hydroxy, C 1 -C 2 alkoxy, Ci-C 4 alkyl or trifluoromethyl radicals; and wherein heterocyclyl is a radical of a monocyclic saturated heterocyclic ring system having 5-6 ring members, wherein 1-2 ring members are oxygen, sulfur or nitrogen heteroatoms, which is optionally benzo-fused and optionally substituted by 1-2 oxo or thioxo radicals; aryl is a phenyl or naphthyl radical; and heteroaryl is radical of a monocyclic aromatic heterocyclic ring system having 5-6 ring members, wherein 1-2 ring members are oxygen, sulfur or nitrogen heteroatoms, which is optionally benzo-fused. 6. The compound of Claim 5 or a pharmaceutically acceptable salt thereof, wherein wherein R 1 is provided that the total number of aryl, heteroaryl, cycloalkyl and heterocyclyl radicals in R 1 is 0-2; Z is a bond; Cl-C 4 alkyl or C 2 -C 5 alkenyl radical optionally substituted by 1-3 radicals of amino, di-(C 1 -C 2 alkyl)amino, (C1-C 4 alkoxy)carbonylamino, hydroxy, C 1 -C 2 alkoxy, C 1 -C 2 alkylthio or halo, and 1-2 radicals of aryl or heteroaryl optionally substituted by 1-2 radicals of amino, di-(C 1 -C 2 alkyl)amino, acetamido, (Ci-C 4 alkoxy)carbonylamino, hydroxy, C 1 -C 2 alkoxy, C 1 -C 2 WO 98/24782 PCT/US97/22390 214 alkyithia, halo, Cl-C 4 alkyl or trifluoromethyl radicals. or aryl or heteroaryl radical optionally substituted by 1-3 radicals of amino, di-(C 1 C 2 alkyl)amino, acetamido, (Cl-C 4 alkoxy) carbonyl amino, hydroxy, Cl-C 2 alkoxy, Cl-C 2 alkylthio, cyano, halo, Cl-C 4 alkyl or trifluoromethyl radicals; Y is a hydrogen radical; -C(O)-R 2 0 radical; -0R 2 1 -SR 2 1 -S(O)-R 2 0 -S(O) 2 -R 2 0 or -S(O)2-NR 5 R 2 l radical; or -NR 5 R 2 1 -NR22-C(O)-R 2 1 -NR 2 2 -C(O)-0R 2 0 -NR 2 2 NR 5 R 2 1 -NR22-S(O) 2 -R 2 0 or -NR22-S(O) 2 -NR 5 R 2 1 radical; each R 5 is independently hydrogen radical; Cl-C 4 alkyl radical optionally substituted by 1-3 halo radicals; or phenyl-Cl-C 2 -alkyl or heteroaryl-Cl-C 2 -alkyl, radicals optionally substituted by 1-3 radicals of amino, dimethylamino, hydroxy, methoxy, methylthio, methyl or trifluoromethyl radicals; each R 20 is independently C 1 -C 8 alkyl or C 2 -C 5 alkenyl radicals optionally substituted by 1-3 radicals of amino, C 1 -C 4 alkylamino, di- (Cl-C 4 alkyl)amino, Cl-C 5 alkanoylanino, (Cl-C 4 alkoxy) carbonylamino, N- ((Cl-C 4 alkoxy)carbonyl) (Cl- C 4 alkyl)amino, amino carbonyl amino, hydroxy, Ci-C 4 alkoxy, Cl-C 4 alkylthio, Cl-C 4 alkylsulfinyl, Ci-C 4 alkylsulfonyl, halo or aryl-Cl-C4-alkoxy, aryl-Cl-C4- alkylthio, aryl-Cl-C4-alkylsulfonyl, C 3 -C 6 cycloalkyl, heterocyclyl, aryl or heteroaryl radicals optionally substituted by 1-3 radicals of amino, Cl-C 4 alkylamino, WO 98/24782 WO 9824782PCT[US97/22390 215 di-(Cl-C 4 alkyl )amino, Cl-Cs alkanoylamino, (Cl-C 4 alkoxy) carbonylamino, Cl-C 4 alkylsulfonylamino, c 1 -C alkanoyl, hydroxy, Cl-C4,alkoxy, Cl-C 4 alkylthio, halo, C 1 -C 4 alkyl or C 1 -C 2 haloalkyl of 1-3 halo radicals; heterocycly. radical optionally substituted by 1-2 radicals of amino, di-(Cl-C 4 alkyl)amino, (Cl-C 4 al1koxy) carbonyl amino, hydroxy, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio or Cl-C 4 alkyl; or aryl. or heteroaryl radicals optionally substituted by 1-2 radicals of amino, C 1 -C 4 alkylamino, di-(Cl-C 4 alkyl)amino, acetainido, (Cl-C 4 alkoxy)carbonylamino, Cj- C 4 alkylsulfonylamino, (Cl-C 4 alkoxy)carbonyl, hydroxy, Cl-C 4 alkoxy, Cl-C 4 alkylthio, cyano, halo, azido, Cl-C 4 alkyl or trifluoromethyl radicals; each R 2 1 is independently hydrogen radical or R 2 0 R 2 is a radical of hydrogen, Cl-C 4 alkyl, halo, hydroxy, CI-C 4 alkoxy, trifluorometho, thiol, Cl-C 4 alkylthio, amino, Cl-C 4 alkylamino, di-(Cl-C 4 alkyl)amino, Cl-C alkanoylamino, (Cl-C 4 alkoxy) carbonylamino, Cl-C 4 alkylsulfonylamino or trifluoromethyl; R 1 1 is an aryl radical and R 1 2 is a heteroaryl radical, wherein the aryl and heteroaryl radicals are optionally substituted by 1-2 radicals of R 3 0 halo or cyano radicals; or -C(O)-NR 3 lR 3 2 -OR 2 9 -SR 2 9 -S(O)-R 3 0 -S(O) 2 -R 3 0 S(O)2-NR 3 lR 3 2 -NR 3 1 R 3 2 or -NR33-C(O)-R 2 9 radicals; provided that the total number of aryl, heteroaryl, cycloalkyl and heterocyclyl radicals substituted on each of R 1 1 and R 12 is 0-1; each R 3 0 is independently SUBSTITUTE SHEET (RULE 26) WO 98/24782 PCT/US97/22390 216 C1-C4 alkyl radical optionally substituted by a phenyl or heteroaryl radical optionally substituted by 1-3 radicals of amino, dimethylamino, acetamido, hydroxy, halo, methoxy, methyl or trifluoromethyl radicals; trifluoromethyl radical; or aryl or heteroaryl radicals optionally substituted by 1-3 radicals of amino, dimethylamino, acetamido, hydroxy, halo, methoxy, methyl or trifluoromethyl radicals; each R 29 is independently hydrogen radical or each R 31 is independently hydrogen, methyl or ethyl radicals; and each R 32 is independently hydrogen radicals; C 1 -C 4 alkyl radical or C1-C 2 alkyl radical substituted by phenyl or heteroaryl radical optionally substituted by 1-3 radicals of amino, dimethylamino, acetamido, hydroxy, methoxy, methyl or trifluoromethyl radicals; or phenyl or heteroaryl radical optionally substituted by 1-3 radicals of amino, dimethylamino, acetamido, hydroxy, methoxy, methyl or trifluoromethyl radicals. 7. The compound of Claim 6 or a pharmaceutically acceptable salt thereof, wherein R 11 is an aryl radical optionally substituted by 1-2 radicals of R 3 0 halo or cyano radicals; or -C(O)-NR 31 R 32 -OR 2 9 -SR 2 9 -S(O)-R30, -S(0) 2 -R 3 0 S(0)2-NR 3 1 R 3 2 -NR 3 1 R 3 2 or -NR3 3 -C(O)-R 2 9 radicals; and WO 98/24782 PCTIUS97/22390 217 R 1 2 is a heteroaryl radical optionally substituted by 1- 2 radicals of R 30 halo or cyano radicals; or -C(O)-NR 3 1 R 3 2 -OR 2 9 -SR 2 9 -NR 31 R 32 or -NR 3 3 R 29 radicals; provided that the total number of aryl, heteroaryl, cycloalkyl and heterocyclyl radicals substituted on each of R 11 and R 12 is 0-1; R 30 is independently CI-C 4 alkyl radical optionally substituted by a phenyl or heteroaryl radical optionally substituted by 1-2 radicals of amino, dimethylamino, acetamido, hydroxy, halo, methoxy, methyl or trifluoromethyl radicals; trifluoromethyl radical; or aryl or heteroaryl radicals optionally substituted by 1-3 radicals of amino, dimethylamino, acetamido, hydroxy, halo, methoxy, methyl or trifluoromethyl radicals; R 29 is an aryl or heteroaryl radicals optionally substituted by 1-2 radicals of amino, dimethylamino, acetamido, hydroxy, halo, methoxy, methyl or trifluoromethyl radicals; and R 32 is independently hydrogen or C 1 -C 4 alkyl radical; or phenyl or heteroaryl radical optionally substituted by 1-2 radicals of amino, dimethylamino, acetamido, hydroxy, methoxy, methyl or trifluoromethyl radicals. 8. The compound of Claim 7 or a pharmaceutically acceptable salt thereof, wherein WO 98/24782 WO 9824782PCTIUS97/22390 218 wherein R 1 is provided that the total number of aryl, heteroaryl, cycloalkyl. and heterocyclyl radicals in R 1 is 0-1; Z is a bond; or cl-c 4 alkyl radical optionally substituted by 1-2 radicals of amino, di- (Cl-C 2 alkyl) amino, (Cl-C 4 alkoxy) carbonylamino, hydroxy, Cl-C 2 alkoxy, C 1 -C 2 alkylthio, halo, or aryl or heteroaryl optionally substituted by 1-2 radicals of hydroxy, Cl-C 2 alkoxy, Cl-C 2 alkylthio, halo, Cl-C 4 alkyl or trifluoromethyl radicals; each R 5 is independently hydrogen or C 1 -C 4 alkyl radical; each R20 is independently Cl-C 8 alkyl radicals optionally substituted by 1-3 radicals of amino, Cl-C 4 alkylanino, di- (Cl-C 4 alkyl)anino, Cl-C 5 alkanoylamino, (cl-c 4 alkoxy) carbonylamino, N- (Cl-C 4 alkoxy) carbonyl) (Cl- C 4 alkyl) amino, aminocarbonyl amino, hydroxy, Cl-C 4 alkoxy, C 1 -C 4 alkylthio, Cl-C 4 alkylsulf inyl, Cl-C 4 alkylsulfonyl, halo or C 3 -C 6 cycloalkyl, heterocyclyl, aryl or heteroaryl radicals optionally substituted by 1- 2 radicals of amino, di-(Cl-C 4 alkyl)aniino, Cl-C alkanoylamino, (Cl-c 4 al1koxy) carbonyl amino, Cl-C 4 alkylsulfonylamino, hydroxy, Cl-C 4 alkoxy, Cl-C 4 alkylthio, halo, CI-C 4 alkyl or trifluoromethyl radicals; heterocyclyl radical optionally substituted by 1-2 radicals of hydroxy, cl-c 4 alkoxy, c 1 -C 4 alkylthio or cj- C 4 alkyl; or WO 98/24782 PCT/US97/22390 219 aryl or heteroaryl radicals optionally substituted by 1-2 radicals of (C1-C 4 alkoxy)carbonyl, amino, C 1 -C 4 alkylamino, di-(C 1 -C 4 alkyl)amino, hydroxy, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio, cyano, halo, azido, C 1 -C 4 alkyl or trifluoromethyl radicals; each R 21 is independently hydrogen radical or R 20 R2 is a radical of hydrogen, methyl, ethyl, fluoro, chloro, hydroxy, methoxy, trifluoromethoxy, amino, methylamino, dimethylamino, acetylamino or trifluoromethyl; R 11 is an aryl radical optionally substituted by 1-2 radicals of amino, dimethylamino, acetamido, hydroxy, halo, cyano, methoxy, methylthio, methylsulfinyl, methylsulfonyl, aminocarbonyl, methyl or trifluoromethyl radicals; and R 12 is a heteroaryl radical optionally substituted by 1- 2 radicals of amino, dimethylamino, acetamido, hydroxy, halo, cyano, methoxy, methyl or trifluoromethyl radicals. 9. The compound of Claim 8 or a pharmaceutically acceptable salt thereof, wherein Z is a bond; or Cl-C 4 alkyl radical optionally substituted by 1-2 radicals of amino, t-butoxycarbonylamino, dimethylamino, hydroxy, methoxy, methylthio or halo radicals; Y is a hydrogen radical; WO 98/24782 PCT/US97/22390 220 -C(0)-R 20 radical; -OR 2 1 -SR 2 1 -S(O)-R 2 0, -S(0)2-R 2 0 or -S(0)2-NR 5 R 2 1 radical; or -NR 5 R 21 -NR22-C(O)-R 21 or -NR22-S(0) 2 -R 20 radical; R 5 is a hydrogen radical; each R 20 is independently CI-C 6 alkyl radicals optionally substituted by 1-3 radicals of amino, methylamino, dimethylamino, t- butoxycarbonylamino, N-((t-butoxy)carbonyl)-N- (methyl)amino, aminocarbonylamino, hydroxy, butoxy, methoxy, butylthio, methylthio, methylsulfinyl, methylsulfonyl, halo or C 5 -C 6 cycloalkyl, heterocyclyl, phenyl or heteroaryl radicals optionally substituted by 1-2 radicals of amino, dimethylamino, acetamino, hydroxy, methoxy, methylthio, halo, methyl or trifluoromethyl radicals; heterocyclyl radical optionally substituted by 1-2 radicals of hydroxy or C 1 -C 4 alkyl; or aryl or heteroaryl radicals optionally substituted by 1-2 radicals of amino, dimethylamino, hydroxy, methoxy, methylthio, halo, methyl or trifluoromethyl radicals; each R 21 is independently hydrogen radical or R 20 each R 22 is independently hydrogen or methyl radical; R11 is an unsubstituted phenyl or naphthyl radical or a phenyl radical substituted by 1-2 radicals of amino, dimethylamino, acetamido, hydroxy, halo, cyano, methoxy, methylthio, methylsulfinyl, methylsulfonyl, aminocarbonyl, methyl or trifluoromethyl radicals; and WO 98/24782 PCT/US97/22390 221 R1 2 is a 4-pyridyl, 4-quinolinyl, 4-imidazolyl or 4- pyrimidinyl radical optionally substituted by a radical of amino, dimethylamino, acetamido, hydroxy, halo, cyano, methoxy, methyl or trifluoromethyl radicals. The compound of Claim 9 or a pharmaceutically acceptable salt thereof, wherein Y is a -C(O)-R 20 radical; -OR 2 1 -SR 2 1 -S(O)-R 2 0, -S(0) 2 -R 2 0 or -S(0)2-NR 5 R 2 1 radical; or -NR 5 R 2 1 -NR22-C(O)-R 2 1 or -NR 2 2 -S(0) 2 -R 2 0 radical; each R 20 is independently Cl-C 6 alkyl radicals optionally substituted by 1-3 radicals of amino, methylamino, dimethylamino, t- butoxycarbonylamino, N-((t-butoxy)carbonyl)-N- (methyl)amino, aminocarbonylamino, hydroxy, butoxy, methoxy, butylthio, methylthio, methylsulfinyl, methylsulfonyl, halo or C 5 -C 6 cycloalkyl, heterocyclyl, phenyl or heteroaryl radicals optionally substituted by 1-2 radicals of amino, dimethylamino, acetamino, hydroxy, methoxy, methylthio, halo, methyl or trifluoromethyl radicals; heterocyclyl radical; or aryl or heteroaryl radicals optionally substituted by 1-2 radicals of amino, dimethylamino, hydroxy, methoxy, methylthio, halo, methyl or trifluoromethyl radicals; and each R 21 is independently hydrogen radical or R 20 11. The compound of Claim 10 or a pharmaceutically acceptable salt thereof, wherein WO 98/24782 PCT/US97/22390 222 Y is a -OR 2 1 -SR 2 1 or -NR 5 R 2 1 radical; each R 20 is independently CI-Cs alkyl radicals optionally substituted by 1-3 radicals of amino, methylamino, dimethylamino, hydroxy or phenyl or heteroaryl radicals optionally substituted by 1-2 radicals of amino, dimethylamino, hydroxy, methoxy, methylthio, halo, methyl or trifluoromethyl radicals; heterocyclyl radical; or aryl or heteroaryl radicals optionally substituted by 1-2 radicals of amino, dimethylamino, hydroxy, methoxy, methylthio, halo, methyl or trifluoromethyl radicals; each R 21 is independently hydrogen radical or R 20 R 11 is an unsubstituted phenyl radical or a phenyl radical substituted by 1-2 radicals of amino, dimethylamino, acetamido, hydroxy, halo, cyano, methoxy, methylthio, methylsulfonyl, methyl or trifluoromethyl radicals; and R 12 is a 4-pyridyl radical optionally substituted by a radical of amino, dimethylamino, acetamido, hydroxy, halo, cyano, methoxy, methyl or trifluoromethyl radicals. 12. The compound of Claim 1 which is: 5-(4-Fluorophenyl)-2-(4-pyridyl)-4-(4-pyridyl)- pyrimidine, 5-( 4 -Fluorophenyl)-2-(2-methylthiazol-4-yl)-4-(4- pyridyl)-pyrimidine, WO 98/24782 PCTIUS97/22390 223 (4-Fluorophenyl) (4-pyridyl) (2-thienyl) pyrimidine, 2- (2-Diethylaminoethylamino) (4-f luorophenyl) (4- pyridyl) -pyrirnidine, 2-(4-Aminobutylamino) (4-fluorophenyl)-4- (4-pyridyl) pyrimidine, 2- 6-Dichlorobenzyl) (4-fluorophenyl) (4-pyridyl) pyrimidine, 2- 6-Dichlorophenylamino) (4-f luorophenyl) (4- pyridyl) -pyrimidine, 2- 6-Dimethylphenylamino) (4-f luorophenyl) (4- pyridyl) -pyrimidine, (4-Fluorophenyl) (2-methoxyphenylamino) (4- pyridyl) -pyrimidine, 5-(4-Fluorophenyl) (4-f luorophenylamino)-4-(4- pyridyl) -pyrimidine, (4-Fluorophenyl) -2-phenylthiomethyl-4- (4-pyridinyl) pyrimidine, 2- (4-Aminophenyl) ethyl-amino) (4-fluorophenyl) -4- (4-pyridyl) -pyrimidine, 2- (2-Chiorophenyl) ethyl-amino) (4-f luorophenyl) -4- (4 -pyridyl) -pyrimidine, 2- (4-Chiorophenyl) ethyl-amino) (4-f luorophenyl) -4- (4 -pyridyl) -pyrimidine, 2-(2-(3-Chlorophenyl)ethyl-amino)-5-(4-fluorophenyl)-4- (4 -pyridyl) -pyrimidine, 2- 4-Dichlorophenyl) ethyl-amino) (4- fluorophenyl) (4-pyridyl) -pyrimidine, 2- (4-Bromophenyl) ethyl-amino) (4-f luorophenyl) -4- (4-pyridyl) -pyrimidine, (4-Fluorophenyl) (2-methoxyphenyl) ethyl-amino) -4- (4-pyridyl) -pyrimidine, (4-Fluorophenyl) (3-methoxyphenyl) ethyl-amino) -4- (4 -pyridyl) -pyrimidine, 5- (4-Fluorophenyl) ((l-methyl-3-phenylpropyl) -amino) 4- (4-pyridyl) -pyrimidine, WO 98/24782 WO 9824782PCTIUS97/22390 224 5-(4-Fluoropheiyl)-2-( (4-phenyl-butyl)--amino)-4-(4- pyridyl) -pyrimidine, (4-Fluorophenyl) -2-morpholiao-4-(4-pyridyl) pyrimidine, 5-( 4 -Fluorophenyl)-4-(4-pyridyl)>2(2- pyrrolidinoethylamino) -pyrimidine, (4-Fluorophenyl) (2-morpholinoethylamino) (4- pyridyl) -pyrimidine, (4-Fluorophenyl) (2-piperidinoethylamino) (4- pyridyl) -pyrimidine, 5-(4-Fluorophenyl) C 2 -pyrrolidinon-l-yl)propyl- amino) (4-pyridyl) -pyrimidine, (4-Fluorophenyl) (2-phenoxyethyl) thio-6- (4-pyridyl) 4 -hydroxy-pyrimidine, 5- 4 -Fluorophenyl)-2-(2-phenylaminoethyl)thio-6-(4- pyridyl) -4 -hydroxy-pyrimidine, 2- (2-Aminoethylamino) (4-f luorophenyl) (4-pyridyl) pyrimidine, 2- 3 -Aminopropylamino) (4-f luorophenyl) (4-pyridyl) pyrimidine, 2- (Benzylamino) (4-f luorophenyl) (4-pyridyl) pyrimidine, (4-Fluorophenyl) (2-phenylethylamino) (4-pyridyl) pyrimidine, 5-(4-Fluorophenyl)-2- (N-methyl-N- (2-phenylethyl) -amino) 4- (4-pyridyl) -pyrimidine, (4-Fluorophenyl) (2-hydroxy-2-phenyl-ethyl) amino-4- (4 -pyridyl) -pyrimidine, (4-Fluorophenyl) (4-hydroxyphenyl) ethyl-amino) -4- (4-pyridyl) -pyrimidine, (4-Fluorophenyl) (4-f luorophenyl)ethyl-amino) -4- (4 -pyridyl) -pyrimidine, 4 -Fluorophenyl)-2-(2-(2-fluorophenyl)ethylamino).4- (4 -pyridyl) -pyrimidine, 5-(4-Fluorophenyl)-2-( (3-phenylpropyl)-amino)-4-(4- pyridyl) -pyrimidine, WO 98/24782 WO 9824782PCTIUS97/22390 225 2-((2(S)-Amino-3-phenylpropyl)-anino)-5-(4- fluorophenyl) (4-pyridyl) -pyrirnidine, (4-Fluorophenyl) (2-phenylaminoethylanino) (4- pyridyl) -pyrimidine, 5- (4-Fluorophenyl)-2-( (3-imidazolyipropyl) -amino) (4- pyridyl) -pyrimidine, (4-Fluorophenyl) (4-pyridyl) -2-pyrrolidino- pyrimidine, (4-Fluorophenyl) (1-piperazinyl) (4-pyridyl) pyrimidine, 2- 6-Dichlorobenzyl) (4-fluorophenyl) (4-pyridyl) 4 -hydroxy-pyrinidine, (4-Fluorophenyl) (2-phenylethyl) thio-6- (4-pyridyl) 4 -hydroxy-pyrimidine, 5- (4-Fluorophenyl)-2-(3-phenylpropyl) thio-6-(4-pyridyl) 4 -hydroxy-pyrimidine, 2- (2-Chiorophenyl) ethyl-amino) (4-f luorophenyl) -6- (4-pyridyl) -4-hydroxy-pyrimidine, (4-Fluorophenyl) ((3-phenyipropyl) -amino) (4- pyridyl) -4-hydroxy-pyrimidine, (4-Fluorophenyl) (-methyl-3-phenylpropyl) -amino) 6- (4-pyridyl) -4-hydroxy-pyrimidine, 2- (2-Chiorophenyl) ethyl-amino) (4-f luorophenyl) -6- (4 -pyridyl) -4 -hydroxy-pyrimidine, -2-Amino-3-phenylpropyl)-amino) -4-(4-pyridyl) (3 -trifluoromethyiphenyl) -pyrimidine, 2- -2-Amino-3-phenylpropyl) -amino) (3- methyiphenyl) (4-pyridyl) -pyrimidine, 2- -2-N,N-Dimethylamino-3-phenylpropyl) -amino) (4- fluorophenyl) (4-pyridyl) -pyrimidine, 2- 2 -N,N-Dimethylamino-3-phenylpropyl) -amino) (3- methyiphenyl) (4-pyridyl) -pyrirnidine, 2- ((3-Amino-3-phenylpropyl)-aino) -5-(4-fluorophenyl) -4- (4 -pyridyl) -pyrimidine, 3 -Amino-3-phenylpropyl)-amino)-4-(4-pyridyl)-5-(3- trifluoromethyiphenyl) -pyrimidine, WO 98/24782 PTU9/29 PCT/US97/22390 226 2-(C(3-Amino-3- C2-fluorophenyl)propyl) -amino) (4- pyridyl) 3 -trifluoromethylphenyl) -pyrimidine, 2- ((3-Alino-3-phenylpropyl) -amino) (3-methyiphenyl) -4- (4-pyridyl) -pyrimidine, C 2 -Amino-2-methyl-3-phenylpropyl) -amino)-5-(3- methyiphenyl) (4-pyridyl) -pyrimidine, 2- ((3-Hydroxy-3-phenylpropyl) -amino) (3-methyiphenyl) 4- (4-pyridyl) -pyrimidine, 2- (C(2S, 3S) 3 -Amino-2-methyl-3-phenylpropyl) -amino) -4- (4-pyridyl) (3-trifluoromethyiphenyl) -pyrimidine, 2- C C(2R, 3R) 3 -Amino-2-methyl-3-phenylpropyl) -amino) -4- (4-pyridyl) (3-trifluoromethyiphenyl) -pyrirnidine, 2- ((S)-3-Benzylpiperazinyl) (4-pyridyl) (3- trifluoromethyiphenyl) -pyrimidine, 4-(4-Pyridyl)-2-((C(S) -tetrahydroisoquinol-3- ylmethylen) amino) (3-trifluoromethyiphenyl) pyrimidine, (3-Mrethylphenyl) (4-pyridyl) tetrahydroisoquinol-3-ylmethylen) amino) -pyrimidine, 2- C(CS) 2 -N-Isopropylamino-3-phenylpropyl) -amino) (4- pyridyl) (3-trifluoromethyiphenyl) -pyrimidine, 2- ((CS)-2-N-Cyclohexylamino-3-phenylpropyl) -amino) (4- pyridyl) (3-trifluoromethyiphenyl) -pyrimidine, 2-C(C(S)- 2 -N-Isopropylamino-3-phenylpropyl) -amino) (3- methyiphenyl) (4-pyridyl) -pyrimidine, 2- -2-N-Butylamino-3-phenylpropyl) -amino) (3- methyiphenyl) (4-pyridyl) -pyrimidine, 2- 2 -N-Cyclohexylamino-3-phenylpropyl) -amino) (3- methyiphenyl) (4-pyridyl) -pyrimidine, 5-(4-Fluorophenyl)-2-((( S)-2-N-isopropylamino-3- phenyipropyl) -amino) (4-pyridyl) -pyrimidine, (4-Fluorophenyl) ((3-N-isopropylamino-3- phenyipropyl) -amino) (4-pyridyl) -pyrimidine, 2- -2-N-Glycylaxnino-3-phenylprtopyl) -amino) (4- pyridyl) (3-trifluoromethyiphenyl) -pyrimidine, 2- CC(S) -2-N-Glycylamino-3-phenylpropyl) -amino) (3- methyiphenyl) (4-pyridyl) -pyrimidine, 227 2- -2-Amino-3-phenylpropyl) -amino) (3-chloro-4-fluorophenyl) (4- pyridyl) -pyriniidine, 2- -2-Amino-3-phenylpropyl) -amino) (3-fluorophenyl) (4-pyridyl) pyrimildine, 2- -2-Amino-3-phenylpropyl) -amino) (3-isopropyiphenyl) (4-pyridyl)- pyrimidine, (3-Acetamidophenyl) -2-amino-3-phenylpropyl) -amino) (4-pyridyl) pyrimidine, 2- -2-Amino-3-phenylpropyl) -'amino) (4-chiorophenyl) (4-pyridyl) pyrimidine, 2- -2-Amino-3-phenylpropyl) -amino) (benzothienyl) (4-pyridyl) pyrimidine, 2- -2-Aniino-3-phenylpropyl) -amino) (2-naphthyl) (4-pyridyl) pyrimidine, or 2- -2-Amino-3-phenylpropyl) -amino) (4-fluorophenyl) (4-pyridyl) 4(31{)pyrimidone or a pharmaceutically acceptable salt thereof. 13. A pharmaceutical composition comprising a compound of any one of Claims 1 to 12 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrer. 14. A method of prophyl axis or treatment of inflammation comprising administering an effective amount of a compound of any one of Claims 1 to 12 or a pharmaceutically acceptable salt thereof. A method of prophylaxis or treatment of inflammation comprising administering an effective amount of a composition of Claim 13. 27.344-0odoacw -228- 16. A method of prophylaxis or treatment of rheumatiod arthritis, Pagets disease, osteoporosis, multiple myeloma, uveititis, acute or chronic myelogenous leukemia, pancreatic p cell destruction, osteoarthritis, rheumatoid spondylitis, gouty arthritis, inflammatory bowel disease, adult respiratory distress syndrome (ARDS), psoriasis, Crohn's disease, allergic rhinitis, ulcerative colitis, anaphylaxis, contact dermatitis, asthma, muscle degeneration, cachexia, Reiter's syndrome, type I diabetes, type II diabetes, bone resorption disease, graft vs. host reaction, Alzheimer's disease, stroke, myocardial infarction, ischemia reperfusion injury, atherosclerosis, brain trauma, multiple sclerosis, cerebral malaria, sepsis, septic shock, toxic shock syndrome, fever, myalgias due to HIV-1, HIV-2, HIV-3, cytomegalovirus (CMV), influenza, adenovirus, the herpes viruses or herpes zoster infection in a mammal comprising administering an effective amount of a compound of Claim 1 to 12 or a pharmaceutically acceptable salt thereof. 17. A method of prophylaxis or treatment of rheumatiod arthritis, Pagets disease, 15 osteoporosis, multiple myeloma, uveititis, acute or chronic myelogenous leukemia, o pancreatic p cell destruction, osteoarthritis, rheumatoid spondylitis, gouty arthritis, inflammatory bowel disease, adult respiratory distress syndrome (ARDS), psoriasis, Crohn's disease, allergic rhinitis, ulcerative colitis, anaphylaxis, contact dermatitis, asthma, muscle degeneration, cachexia, Reiter's syndrome, type I diabetes, type II 20 diabetes, bone resorption disease, graft vs. host reaction, Alzheimer's disease, stroke, myocardial infarction, ischemia reperfusion injury, atherosclerosis, brain trauma, o multiple sclerosis, cerebral malaria, sepsis, septic shock, toxic shock syndrome, fever, myalgias due to HIV-1, HIV-2, HIV-3, cytomegalovirus (CMV), influenza, adenovirus, the herpes viruses or herpes zoster infection in a mammal comprising administering an 22344-o.DOC/acw -229- effective amount of a compound of Claim 13. 18. A method of lowering plasma concentrations of either or both TNF-a and IL- 1 comprising administering an effective amount of a compound of any one of Claims 1 to 12 or a pharmaceutically acceptable salt thereof. 19. A method of lowering plasma concentrations of either or both TNF-a and IL- 1 comprising administering an effective amount of a composition of Claim 13. A method of lowering plasma concentrations of either or both IL-6 and IL-8 comprising administering an effective amount of a compound of any one of Claims 1 to 12 or a pharmaceutically acceptable salt thereof. 21. A method of lowering plasma concentrations of either or both IL-6 and IL-8 comprising administering an effective amount of a composition of Claim 13. 22. A mehtod of prophylaxis or treatment of diabetes disease in a mammal comprising administering an effect amount of a compound according to any one of Claims 1 to 12 or a pharmaceutically acceptable salt thereof, to produce a glucagon antagonist effect. 23. A method of prophylaxis or treatment of diabetes disease in a mammal comprising administering an effective amount of a pharmaceutical composition •0o. according to Claim 13 to produce a glucagon antagonist effect. 24. A method of prophylaxis or treatment of a pain disorder in a mammal comprising administering an effective amount of a compound according to Claims 1 to "12 or a pharmaceutically acceptable salt thereof. 25. A method or prophylaxis or treatment of a pain disorder in a mammal comprising administering an effective amount of a pharmaceutical composition according to Claim 13. 22344-o.Doc/acw -230- 26. A method of decreasing prostaglandins production in a mammal comprising administering an effective amount of a compound according to claims 1 to 12 or a pharmaceutically acceptable salt thereof. 27. A method of decreasing prostaglandins production in a mammal comprising administering an effective amount of a pharmaceutical composition according to claim 13. 28. A method of decreasing cyclooxygenase enzyme activity in a mammal comprising administering an effective amount of a compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof. 29. The method of claim 28 wherein the cyclooxygenase enzyme is COX-2. A method of decreasing cyclooxygenase enzyme activity in a mammal comprising administering an effective amount of a pharmaceutical composition according to claim 13. 31. The method of claim 30 wherein the cyclooxygenase enzyme is COX-2. 32. Use of a compound as defined in any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament suitable for S* administration to a mammal. S33. Use of a compound as defined in any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof. 20 34. Use of a compound as defined in any one of claims 1 to 12 or a o pharmaceutically acceptable salt thereof, in the manufacture of a medicament for administration in the prophylaxis or treatment of inflammation. 35. Use of a compound as defined in any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for Spharmaceutically acceptable salt thereof, in the manufacture of a medicament for 22344-00.DOC/aCW -231- administration in the prophylaxis or treatment of rheumatoid arthritis, Pagets disease, osteoporosis, multiple myeloma, uveititis, acute or chronic myelogenous leukemia, pancreatic p cell destruction, osteoarthritis, rheumatoid spondylitis, gouty arthritis, inflammatory bowel disease, adult respiratory distress syndrome (ARDS), psoriasis, Crohn's disease, allergic rhinitis, ulcerative colitis, anaphylaxis, contact dermatitis, asthma, muscle degeneration, cachexia, Reiter's syndrome, type I diabetes, type II diabetes, bone resorption diseases, graft vs. Host reaction, Alzheimer's disease, stroke, myocardial infarction, ischemia reperfusion injury, atherosclerosis, brain trauma, multiple sclerosis, cerebral malaria, sepsis, septic shock, toxic shock syndrome, fever, myalgias due to HIV-1, HIV-2, HIV-3, cytomegalovirus (CMV), influenza, adenovirus, the herpes viruses or herpes zoster infection. 36. Use of a compound as defined in any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for administration to lower plasma concentrations of either or both of TNF-a and IL-1. 15 37. Use of a compound as defined in any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for administration to lower plasma concentrations of either or both of IL-6 and IL-8. 38. Use of a compound as defined in any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for administrationto a mammal in the prophylaxis or treatment of diabetes disease to Sproduce a glucagon antagonistic effect. 39. Use of a compound as defined in any one of claims 1 to 12 or a Spharmaceutically acceptable salt thereof, in the manufacture of a medicament for S administration to a mammal in the prophylaxis or treatment of a pain disorder. 22344-00.Doc/aCW -232- Use of a compound as defined in any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for administration to a mammal to decrease prostaglandin production. 41. Use of a compound as defined in any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for administration to a mammal to decrease cyclooxygenase enzyme activity. 42. Use according to claim 41 wherein the cyclooxygenase enzyme is COX-2. 43. A compound of formula I or a pharmaceutically acceptable salt thereof, substantially as hereinbefore described with reference to one or more of the Examples. 44. A pharmaceutical composition comprising a pharmaceutically acceptable carrier together with a compound of formula I or a pharmaceutically acceptable salt thereof, substantially as hereinbefore described with reference to one or more of the Examples. 45. A method of prophylaxis or treatment utilising a compound of formula I or a S: pharmaceutically acceptable salt thereof, substantially as hereinbefore described with reference to one or more of the Examples. 46. A method of lowering plasma concentration of either or both TNF-a and IL- 1 utilising a compound of formula I or a pharmaceutically acceptable salt thereof, 20 substantially as hereinbefore described with reference to one or more of the Examples. 47. A method of decreasing prostaglandin production in a mammal utilising a compound of formula I or a pharmaceutically acceptable salt thereof, substantially as hereinbefore described with reference to one or more of the Examples. hereinbefore described with reference to one or more of the Examples. 22344-00.DOC/acw -233- 48. A method of decreasing cyclooxygenase enzyme activity in a mammal utilising a compound of formula I or a pharmaceutically acceptable salt thereof, substantially as hereinbefore described with reference to one or more of the Examples. 49. A method of preparing a compound of formula I or a pharmaceutically acceptable salt thereof, substantially as hereinbefore described with reference to one or more of Examples 1 to Use of a compound of formula I or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for administration to a mammal, substantially as hereinbefore described with reference to one or more of the Examples. 51. Use of a compound of formula I or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for administration to a mammal in the prophylaxis or treatment of rheumatoid arthritis, Pagets disease, osteoporosis, multiple myeloma, uveititis, acute or chronic myelogenous leukemia, pancreatic P cell destruction, osteoarthritis, rheumatoid spondylitis, gouty arthritis, inflammatory bowel disease, adult respiratory distress syndrome (ARDS), psoriasis, Crohn's disease, allergic .rhinitis, ulcerative colitis, anaphylaxis, contact dermatitis, asthma, muscle degeneration, cachexia, Reiter's syndrome, type I diabetes, type II diabetes, bone resorption diseases, graft vs. Host reaction, Alzheimer's disease, stroke, myocardial infarction, ischemia reperfusion injury, atherosclerosis, brain trauma, multiple sclerosis, cerebral malaria, 20 sepsis, septic shock, toxic shock syndrome, fever, myalgias due to HIV-1, HIV-2, HIV- 3, cytomegalovirus (CMV), influenza, adenovirus, the herpes viruses or herpes zoster infection, substantially as hereinbefore described with reference to one or more of the Examples. .i 22344-o.Doc/aCW -234- 52. Use of a compound of formula I or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for administration to a mammal to lower plasma concentration of either or both of TNF-a and IL-1, substantially as hereinbefore described with reference to one or more of the Examples. 53. Use of a compound of formula I or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for administration to a mammal to lower plasma concentration of either or both of IL-6 and IL-8, substantially as hereinbefore described with reference to one or more of the Examples. 54. Use of a compound of formula I or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for administration to a mammal in the prophylaxis or treatment of diabetes disease to produce a glucagon antagonistic effect, substantially as hereinbefore described with reference to one or more of the Examples. Use of a compound of formula I or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for administration to a mammal in the prophylaxis or treatment of a pain disorder, substantially as hereinbefore described with reference to one or more of the Examples. 56. Use of a compound of formula I or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for administration to a mammal to decrease prostaglandin production, substantially as hereinbefore described with reference to one or more of the Examples. 57. Use of a compound of formula I or a pharmaceutically acceptable salt S* thereof, in the manufacture of a medicament for administration to a mammal to decrease p cyclooxygenase enzyme activity, substantially as hereinbefore described with reference to one or more of the Examples. to one or more of the Examples. 22344-OO.DOC/aCW -235- DATED this 28th Day of February 2001 AMGEN INC. Attorney: DAVID A. ADAMTHWAITE Fellow Institute of Patent Attorneys of Australia of BALDWIN SHELSTON WATERS 22344-oo.Doc/acw
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JP4368682B2 (en) 2001-09-21 2009-11-18 田辺三菱製薬株式会社 3-Substituted-4-pyrimidone derivatives
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