AU735901B2 - Substituted pyrimidinone and pyridone compounds and methods of use - Google Patents
Substituted pyrimidinone and pyridone compounds and methods of use Download PDFInfo
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- AU735901B2 AU735901B2 AU55254/98A AU5525498A AU735901B2 AU 735901 B2 AU735901 B2 AU 735901B2 AU 55254/98 A AU55254/98 A AU 55254/98A AU 5525498 A AU5525498 A AU 5525498A AU 735901 B2 AU735901 B2 AU 735901B2
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- 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
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Description
-1- SUBSTITUTED PYRIMIDINONE AND PYRIDONE COMPOUNDS
AND
METHODS OF USE BACKGROUND OF THE INVENTION The present invention comprises a new class of compounds useful in treating diseases, such as TNF-ca, IL-1 3, 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.
10 Interleukin-1 (IL-1) and Tumor Necrosis Factor (TNF-a) are pro-inflammatory S. 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 15 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 spondylitis; gouty arthritis; inflammatory bowel disease; adult respiratory distress syndrome (ARDS); psoriasis; Crohn's disease; allergic rhinitis; ulcerative colitis; anaphylaxis; contact determatitis; WO 98/24780 PCT/US97/22949 2 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; 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-10, 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-a 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 98/24780 PCT/US97/22949 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 6 cell destruction and diabetes. Pancreatic g cells produce insulin which helps mediate blood glucose homeostasis. Deterioration of pancreatic 9 cells often accompanies type I diabetes. Pancreatic 5 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 98/24780 PCT/US97/22949 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 WO 98/24780 PCT/US97/22949 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-a. One approach involves using soluble receptors for TNF-a 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-C, 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.
US 5,100,897, incorporated herein by reference in its entirety, describes pyrimidinone compounds useful as angiotensin II antagonists wherein one of the pyrimidinone ring nitrogen atoms is substituted with a substituted phenylmethyl or phenethyl radical.
US 5,162,325, incorporated herein by reference in its entirety, describes pyrimidinone compounds useful as angiotensin II antagonists wherein one of the pyrimidinone ring nitrogen atoms is substituted with a substituted phenylmethyl radical.
EP 481448, incorporated herein by reference in its entirety, describes pyrimidinone compounds useful as angiotensin II antagonists wherein one of the pyrimidinone ring nitrogen atoms is substituted with a substituted phenyl, phenylmethyl or phenethyl radical.
-6- CA 2,020,370, incorporated herein by reference in its entirety, describes pyrimidinone compounds useful as angiotensin II antagonists wherein one of the pyrimidinone ring nitrogen atoms is substituted with a substituted biphenylaliphatic hydrocarbon radical.
BRIEF DESCRIPTION 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-11, 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 10 involving inflammation. Accordingly, the invention also comprises pharmaceutical compositions comprising the compounds, methods for the prophylaxis and treatment of TNF-a, IL-10, IL-6 and/or IL-8 mediated diseases, such as inflammatory, pain and diabetes diseases, using the compounds and compositions of the invention, and iintermediates and processes useful for the preparation of the compounds of the o 15 invention.
More particularly, in one aspect of the invention there is provided a compound represented by general formula as follows:
X
R 12 R wherein the dashed lines represent a double bond between C(R) and V or W (ie., 'f -V=C or -W=C and V, W, X, R, R" and R 12 are defined below, or a J pharmaceutically acceptable salt of the compound.
-6A- In a second aspect of the present invention there is provided a pharmaceutical composition comprising a compound of the invention or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
In a third 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 or a pharmaceutically acceptable salt thereof.
In a fourth aspect of the invention there is provided a method of prophylaxis or treatment of rheumatoid arthritis, Pagets disease, osteophorosis, multiple myeloma, uveititis, acute or chronic myelogenous leukemia, pancreatic P cell destruction, 10 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, i cachexia, Reiter's syndrome, type I diabetes, type II diabetes, bone resorption diseases, graft vs. host reaction, Alzheimer's disease, stroke, myocardial infarction, ischemia 15 reperfusion injury, atherosclerosis, brain trauma, multiple sclerosis, cerebral malaria, g 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 the invention or a pharmaceutically acceptable salt thereof.
In a fifth aspect of the invention there is provided a method of lowering plasma concentrations of either or both TNF-ac and TNF-1 comprising administering an effective amount of a compound of the invention or a pharmaceutically acceptable salt Sthereof.
-6B- In a sixth aspect of the invention there is provided a method of lowering plasma concentrations of either or both IL-6 and IL-8 comprising administering an effective amount of a compound of the invention or a pharmaceutically acceptable salt thereof.
In a seventh 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 or a pharmaceutically acceptable salt thereof to produce a glucagon antagonist effect.
In an eighth aspect of the invention there is provided a method of prophylaxis or treatment of a pain disorder in a mammal comprising administeringan effective amount 1• 10 of a compound of the invention or a pharmaceutically acceptable salt thereof.
ii~jIn a ninth aspect of the invention there is provided a method of decreasing prostaglandins production in a mammal comprising administering an effective amount of a compound of the invention or a pharmaceutically acceptable salt thereof.
In a tenth aspect of the invention there is provided a method of decreasing 15 cyciooxygenase enzyme activity in a mammal comprising administering an effective •amount of a compound of the invention or a pharmaceutically acceptable salt thereof 9In an eleventh aspect of the present invention there is provided use of a compound of the invention or a pharmaceutically acceptable salt thereof in the manufacture of a pharmaceutical composition for administration to a mammal.
In a twelfth aspect of the present invention there is provided use of a compound of the invention or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for administration to a mammal in the prophylaxis of treatment of inflammation.
inflammation.
-6C In a thirteenth aspect of the present invention there is provided use of a compound of the invention or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for administration to a mammal in the prophylaxis of treatment of rheumatoid arthritis, Pagets disease, osteophorosis, 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 10 reaction, Alzheimer's disease, stroke, myocardial infarction, ischemia reperfusion injury, i 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 fourteenth aspect of the present invention there is provided use of a compound 15 of the invention or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for administration to a mammal to lower plasma concentrations of either or both of TNF-a and TNF-1.
In a fifteenth aspect of the present invention there is provided use of a compound of the invention or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for administration to a mammal to lower plasma concentrations of either or both IL-6 and IL-8.
d In a sixteenth aspect of the present invention there is provided use of a compound of the invention or a pharmaceutically acceptable salt thereof in the manufacture of a -6D medicament for administration to a mammal in the prophylaxis or treatment of diabetes disease to produce a glucagon antagonist effect.
In a seventeenth aspect of the present invention there is provided use of a compound of the invention 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.
In an eighteenth aspect of the present invention there is provided use of a compound of the invention or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for administration to a mammal to decrease prostaglandins production in the mammal.
o* In a nineteenth aspect of the present invention there is provided use of a compound of the invention or a pharmaceutically acceptable salt thereof in the manufacture of a i medicament for administration to a mammal to decrease cyclooxygenase enzyme activity in the mammal.
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 Sinclusive sense as opposed to an exclusive or exhaustive sense; that is to say, in the sense ooooof"including, but not limited to".
The foregoing merely summarises certain aspects of the invention and is not intended, nor should it be construed, as limiting the invention in any way. All patents and other publications recited herein are hereby incorporated by reference in their entirety.
-6E- Any discussion of the prior art throughout the specification should in no way be considered as an admission that such prior art is widely known or forms part of common general knowledge in the field.
a
S.
o a a* -7- DETAILED DESCRIPTION OF THE INVENTION In particular, in an embodiment of the present invention there is provided compounds of the formula:
X
R
11
V
R
12 W R
(I)
or a pharmaceutically acceptable salt thereof, wherein X is O, S or NN; preferably, X is O or S; and most preferably, X is O;
V
N is w R.
W R R 21 2:.iR N Ln1j R
U
N N
NN
N U N
RN
RR
/b1 0 j721 N N 21, R21 or 21 provided that the combined- total number of aryl, heteroaryl, cycloalkyl and heterocyclyl radicals in -VC(R)W- is 0-3, preferably, 0-2, most preferably, 0-1; a first preferred subgroup of WO 98/24780 WO 9824780PCTIUS97/22949
N
W R
'-R
3
N
isR a second preferred subgroup of
R
4 W: R is-,N R1ior a third preferred subgroup of
N
Nis R2 W R N N11
N
N
R]
R
4
N
N
N
Nj N-R2 1 R1 or more preferably,
N
N
R
2 N
N\
10R2.
most preferably,
N
N
N N- R 2 1
N
R
24
-R
24
N;'N
R
2 1 or
R
21 U is NR: or CHR, 1 preferably, u* is NR%,; n is an integer of 1-3;
R
1 and R 2 are each independently -Y or and R 3 and R4 are each inde.pendently provided that R 4 is other than a hydrogen, substituted- aryl, (subs ti tuted- aryl)me thyl1 or (substituted-aryl) ethyl radical, and the total number of aryl, heteroaryl, cycloalkyl and heterocyclyl radicals in each -Y and -Z-Y isO0-3; preferably, 0-2; *more preferably, 0-1;preferably, R2 is a radical of hydro'gen, C1.-C 4 alkyl, halo, cyano, hydroxy, Cl-C 4 alkoxy, C 1 -c 2 haloalkoxy of 1-3 halo radicals, Cj-C 4 alkylthio, anino, Cl-C 4 alkylamino, di- (Cl-C 4 alkyl) amino or Cl-C 2 haloalkyl of.
I 1- 3 halo radicals; more pref erably, R 2 is a radical of S. 2C hydr-ogen, Cj-C 4 alkyl, halo, cyano', hydroxy,, Cl-C 4 uKOXY, trifluoromethoxy or trifluoromethyl; most preferably, R2" is a- hydrogen radical; pref erably, R 3 ids a hydrogen radical or CI-Ce alkyl or C 2
-C
8 alkenyl radical optionally substituted by -1-3 radicals of amino, CI-C 4 alkylamino,. di- (Ci-C 4 alkyl) ami-no, Cl-C 5 alkcanoylamino, (Cl-C 4 alkoxy) carbonylamino, Cl-C 4 alkylsulfonylamino, hydroxy, Cl-C 4 alkoxy, Cl-C 4 alkyitbio or halo,. and (b) 1-2 radicals of heterocyclyl, aryl or heteroarYl J\LL1,~optionally substituted by 1-3 radicals of amino, Ci-C4 CC) alkcylanxino, di- (Cl-C 4 alkyl) amino, C 1
-C
5 alkanoylanmino, WO 98/24780 PCT/US97/22949 (Ci-C 4 alkoxy)carbonylamino,
C
1
-C
4 alkylsulfonylamino, hydroxy,
C
1
-C
4 alkoxy,
C
1
-C
4 alkylthio, halo, C 1
-C
4 alkyl, trifluoromethoxy or trifluoromethyl radicals; or aryl 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, (Ci-C 4 alkoxy)carbonylamino,
C
1
-C
4 alkylsulfonylamino, hydroxy,
C
1
-C
4 alkoxy, C 1
-C
4 alkylthio, cyano, halo, C 1
-C
4 alkyl, trifluoromethoxy or trifluoromethyl radicals; more preferably, R3 is a hydrogen radical or
CI-C
8 alkyl radical optionally substituted by 1-2 radicals of amino, Ci-C 4 alkylamino, di-(Ci-C 4 alkyl)amino, hydroxy, Ci-C 4 alkoxy or aryl or heteroaryl optionally substituted by 1-3 radicals of amino, C 1
-C
4 alkylamino, di-(C 1
-C
4 alkyl)amino,- C1-C 4 alkoxy, C 1
-C
4 alkylthio, halo, Ci-C 4 alkyl, trifluoromethoxy or trifluoromethyl 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, C 1
-C
4 alkoxy, C 1
-C
4 alkylthio, cyano, halo,
C
1
-C
4 alkyl, trifluoromethoxy or trifluoromethyl radicals; more preferably, R 3 is a hydrogen radical or C 1
-C
8 alkyl radical optionally substituted by 1-2 radicals of amino,
C
1
-C
4 alkylamino, di-(C 1
-C
4 alkyl)amino, hydroxy, C 1
-C
4 alkoxy or 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
4 alkoxy, C 1
-C
4 alkylthio, halo, C 1
-C
4 alkyl, trifluoromethoxy or trifluoromethyl radicals; more preferably, R 3 is a radical of hydrogen or C 1
-C
4 alkyl; more preferably, R 3 is a hydrogen, methyl or ethyl radical; WO 98/24780 WO 9824780PCTIUS97/22949 preferably,
R
4 is 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 alkoxy) carbonylamino,
C
1
-C
4 alkylsulfonylamino, hydroxy, C 1
-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)ainmino, C 1
-C
5 alkanoylamino, (Cl-C 4 alkoxy) carbonylamino, C 1
-C
4 alkylsulfonylanino, hydroxy, C 1
-C
4 alkoxy, Cl-C 4 alkylthio, halo, Cl-C 4 alkyl, trifluorornethoxy or trifluoromethyl radicals; or heteroaryl radical optionally substituted by 1-3 radicals of amino, C 1
-C
4 alkylamino, di-(Cl-C 4 alkyl)amino, Cj-C 5 alkanoylamino, (Cl-C 4 al koxy) c arbonyl amino, C 1
-C
4 alkylsulfonylamino, hydroxy,
C
1
-C
4 alkoxy, CI-C 4 alkylthio, cyano, halo, C 1
-C
4 alkyl, trifluoromethoxy or trifluoromethyl radicals; more preferably, R4 is cl-c 8 alkyl radical optionally substituted by 1-2 radicals of amino, Cl-C 4 alkylamino, di-(C 1
-C
4 alkyl)amino, hydroxy, Cl-C 4 alkoxy or aryl or heteroaryl optionally substituted by 1-3 radicals of amino, Cl-C 4 alkylamino, di-(CI-C 4 alkyl)amino, Cl-C 4 alkoxy, Cl-C 4 alkylthio, halo, Cl-C 4 alkyl, trifluoromethoxy or trifluoromethyl radicals; or heteroaryl radical optionally substituted by 1-3 radicals of amino, Cl-C 4 alkylainino, di-(Cl-C 4 alkyl)amino, Cl-C 4 alkoxy, Cl-C 4 alkylthio, cyano, halo, Cl-C 4 alkyl, trifluoromethoxy or trifluoromethyl radicals; more. preferably, R 4 is a C 1 -Cs alkyl radical optionally substituted by 1-2 radicals of amino, Cl-c 4 alkylamino, di (Ct1-C 4 -alkyl) amino., hydroxy, C 1-C 4 alkoxy or aryl or beteroaryl optionally substituted by -1-3 radicals of amino, C 1
-C
4 alkylam-ino, di-(Cl-C 4 alkyl)am4.no,
C
1
-C
4 alkoxy, Cl-C 4 alkylthio, halo, Cl-C 4 alkyl, trifluoromethoxy or trifluoromethy. radicals; more preferably, R4 is a C 1
-C
4 alkyl 'radical; most preferably,
R
4 is a methyl or ethyl radical; wherein each Z' is independently a alkyl, alkenyl or alkynyl radical optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, cyano 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, alkyithio, cyano, halo, alkyl or haJloalkyl; heterocyclyl radical optionally substituted by 1-3 radicals of amino, alkylamino, dialkcylamino, :a akanoylamino, alkoxycarbonylaminjo, alkylsulf onylamino, hydroxy, alkoxy, alkylthio, cyano, alkyl or haloalkyl; or aryl or heteroaryl radical optionally substituted by 1'-3 radicals of amino, 'alkylamino, dialkylami no, alkanoylamino, alkoxycarbonylamino, alkcylsulfonylamino, hydroxy, alkoxy, alkylthio, cyano, halo, alkyl or halpalkyl;preferably, each Z is independently a CI.-Ce alkyl, C2-C8 alkeny. or C 2
-C
8 alkynyl radical optionally substituted by* 1-3 radicals of amino, Ci- ,V3 C 4 alkylanino, di- (Cl-c 4 alkyl)ami-no.,
C
1
-CS
W alkanoylamino, (Cl-C 4 alkoxy) carbonylamino,
C
1 -c 4 WO 98/24780 WO 984780P1US97/22949 13 alkylsulfonylamino, hydroxy, Cl-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-(CI-C 4 alkyl)amino, Cl-C 5 alkanoylamino, (Cl-C 4 alkoxy) carbonylamino, 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 1-3 radicals of amino, Cl-C 4 alkylamino, di-(Cl-C 4 alkyl)amino,
C
1
-C
5 alkanoylamino, (Cl-C 4 alkoxy) carbonylamino, Cl-C 4 alkylsulfonylamino, hydroxy,
C
1
-C
4 alkoxy, Cl-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, Cl-C 4 alkylamino, di-(Cl-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, cyano, halo, Cl-C 4 alkyl or 1C 4 haloalkyl of 1-3 halo radicals; more preferably, each Z is independently a cl-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-(Cl-C 4 alkyl)amino, Cl-C alkanoylamino, (Cl-C 4 alkoxy)carbonylamino, Cl-C 4 alkylsulfonylamino, 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, C 1
-C
4 alkylamino, di-(C 1
-C
4 alkyl)amino, Cl-C 5 alkanoylamino, (Cl-C 4 alkoxy) carbonyl amino, Cl-C 4 alkylsulfonylamino, hydroxy, Cl-C 4 alkoxy, C 1
-C
4 alkylthio, halo, Cl-C 4 alkyl or C 1
-C
4 haloalkyl of 1-3 halo radicals; WO 98/24780 WO 9824780PCT/US97/22949 14 heterocyclyl radical optionally substituted by 1-2 radicals of amino, C 1
-C
4 alkylainino, di- (Cl-C 4 alkyl) amino, CI-C 5 alkanoylamino, (Ci-C 4 alkoxy) carbonylamino,
C
1
-C
4 alkylsulfonylamino, hydroxy, cl-c4 alkoxy, C 1
-C
4 alkyithia,
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,
CI-C
5 alkanoylamino, (Ci-C 4 alkoxy)carbonylamino, 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 Z is independently a Cj-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,
C
1
-C
5 alkanoylamino, (Cl-C 4 alkoxy) 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, CI-C 4 alkylainino, di-(Cl-C 4 alkyl)anino, Cl-C 5 alkanoylamino, (Cl-C 4 alkoxy) carbonyl amino, 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,
(C
1
-C
4 alkoxy)carbonylamino, 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, Cl-C 4 alkylamino, di-(C 1
-C
4 alkyl)amino, Cl-C 5 alkanoylanino, (Cl-C 4 a lkoxy) 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; WO 98/24780 PCT/US97/22949 more preferably, each Z is independently a Cl-C 4 alkyl or C 2
-C
5 alkenyl radical optionally substituted by 1-3 radicals of amino, di-(Ci-C 2 alkyl)amino,
C
1
-C
5 alkanoylamino, (Ci-C 4 alkoxy)carbonylamino, hydroxy, C 1
-C
2 alkoxy, C 1
-C
2 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
2 alkyl)amino,
CI-C
5 alkanoylamino, (Ci-C 4 alkoxy)carbonylamino, hydroxy,
C
1
-C
4 alkoxy, C 1 -C4 alkylthio, halo, C 1
-C
4 alkyl or trifluoromethyl radicals; heterocyclyl radical optionally substituted by 1-2 radicals of amino, di-(C 1
-C
2 alkyl)amino,
(C
1
-C
4 alkoxy)carbonylamino, hydroxy,
C
1
-C
2 alkoxy, C 1 -C2 alkylthio or C 1
-C
4 alkyl radicals; or aryl or heteroaryl radical optionally substituted by 1-3 radicals of amino, di-(C 1
-C
2 alkyl)amino,
C
1
-C
alkanoylamino,
(C
1
-C
4 alkoxy)carbonylamino, hydroxy, CI-
C
2 alkoxy, Ci-C 2 alkylthio, cyano, halo, C 1
-C
4 alkyl or trifluoromethyl radicals; more preferably, each Z is independently a
C
1
-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, (Ci-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,
(C
1
-C
4 alkoxy)carbonylamino, hydroxy, C 1
-C
2 alkoxy, C 1
-C
2 alkylthio, halo, C 1
-C
4 alkyl or trifluoromethyl radicals; or aryl or heteroaryl radical optionally substituted by 1-3 radicals of amino, di-(ci-C 2 alkyl)amino, acetamido,
(C
1
-C
4 alkoxy)carbonylamino, hydroxy, Ci-C 2 alkoxy, C 1
-C
2 alkylthio, cyano, halo, CI-C 4 alicyl or trifluoromethyl radicals; more prefer ably, each z is independently a C 1
-C
4 alkcyl radical optionally substituted by 1-2 radicals of amino, di- (Cl-c 2 alkyl) amino, (Cl-c 4 alkoxy) carbonylamino, hydroxy,
CI-C
2 alkoxy,
C
1
-C
2 alkylthio, halo or aryl or heteroaryj. optionally substituted by 1-2 radicals of hydroxy,
C
1
-C
2 alkoxy,
C
1
-C
2 alkyithio, halo,
C
1 -c 4 alkyl or trifluoromethyl radicals; and most preferably, each Z is independently a C 1
-C
4 alkyl radical optionally substituted by 1-2 radicals of amino, t-butoxycarbonylamino, dimethylamino, hydroxy, methoxy, 150 i methyithia or halo radicals; each Y is independently a hydrogen radical; halo, cyano or nitro radical;
-R
20 -OR21,
-NR
5
R
2 or -CNR) -NR 5 Rl radical;
-OR
2 1
-O-C(O)-R
2 1
-O-C(O)-NR
5
R
2 1 or -O-C(O)-NR 2 2 S(O)2-R 2 0 radical; NR22-C(O)-R 2 1 -S(O)2-NR2 2
-C(O)-OR
2 0 Or -S(O)2-NR 2 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 2 1 -NR22-C(NR5)-NR 5
R
2 1l -NR22-S(O) 2
-R
2 0 or -NR22- S 2-NR 5
R
2 1 radical; preterably, each Y is independently a.
hydrogen radical; halo radical; -C(0)-R 2 0 or -C(NR5)-NR 5
R
2 1 radical;
-OR
2 1 -0-C(P)-R 2 1 or -O-C(O)-qRSR 2 1 radical;
-SR
2 1 -S (0)-R 2 0 -S (0) 2
-R
2 0 Or -S 2-NR 5
R
2 1 radical;
-NR
5
R
2 1 -NR22-C(O)-R 2 -NR22-C(O)-0R 2 0 -NR22-C(O)-
NR
5
R
2 1 -NR22-C (NR 5 q) -NR 5
R
2 1 -N22 -S 2-R 2 0 or -R.
S 2-NR 5
R
2 i. radical; more preferably, each Y is independently a hydrogen radical; -d (0)-R 2 o radical1;
-OR
2 1 1 -SR21, -S(0)-R 2 0 -S(0)2-R 2 0 Or -S(0)2-NR 5
R
2 1 radical; or -NR5R 2 1 -NR22-C(O)-R 2 1 '-NR22-C(O)-0R 2 0
-NR
2 2
NR
5
R
2 1
-NR
2 2 2-R 2 0 or -NR22-S (O)2-qR 5
R
2 3. radical; more preferably, each Y is independently a hydrogei' radical; -C (0)-R 2 o radical; 9*
-OR
2 1
-SR
2 1
-S(O)-R
2 0 -S(0) 2
-R
2 0 or -S(O)2-NRSR 2 1 radical; or
-NR
5
R
2 1 -NR22-C(O)-R 2 l or -NR22-S 2
-R
2 0 radical; mor prfrby ahYi9neednl (1 C 0 R2 adcl more preferably, each Y is independently a R2,-21
-C(OR
2 radical; radical;ronradcl alyl alknR2-(O or aNRl-S0) 2
R
2 radical.otoal most prefehrbly, achxy, akyi,-H indepnentl haoR;
SR
or -RR 1 rdcl alyl, aJheneoyl anradial otironall <'9terocyclyl, heterocyclylalkyl, cycloalkyl or 18 cycloalkylalkyl radical optionally substituted by 1-3 radicals of amino,, alkylamino dialkyanino, hydroxy, alkoxy, alkylthio, cyano, alkyl or haloalkyl; preferably, ea .ch R 5 is independently hydrogen radicals; Cj-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,
C
1
-C
4 al'koxy,
C
1
-C
4 alkylthio, -So 3 H or halo; or aryl, heteroaryl, aryl-Cl-C 4 -alkcyl heteroarYl-Cl-C 4 alkyl, heterocyclyl, heterocyclyl-Cl.C 4 alkyl, c3-c8 cycloalkyl Or C 3 -C8-cycloalky-Cl-C 4 -alkyl radicals optionally substituted by 1-3 radicals of amino, cl-c 4 alkylamino, di- (Cl-C4-alkyl) aminohdOY Cl-C 4 alkoxy, .9 Cl-c 4 alkylthiLo, Cl-C 4 alkyl or Cl-C 4 haloalkyj. of 1-3 halo radicals; mor prfrby ahR5i neednl mo(3 r l preferably, eaRy 5 is 4aly ineene t ay-C-4 h rocrdcls;htrccy-l-4akl 3 9 c-c 4 lkyl C-.C 5 clalkyl orc-c 5 alkyl radicals opti onally substituted by 1-3 radicals of amino, cl-c 4 alkylainino, di- (cl-c 4 -alkyl) amino, hydroxy,
CI-C
4 alkoxy, cl-c 4 alkylthio,
C-O
3 ory r C haloly or1cycloaly rC C cc1oly C C ly radicals more preferably, each R 5 is independently hydrogen radicals; WO 98/24780 PCT/US97/22949 19 C1-C 4 alkyl or C 2
-C
5 alkenyl radicals optionally substituted by 1-3 radicals of amino, di-(C 1
-C
4 alkyl)amino, hydroxy, C 1
-C
4 alkoxy, CI-C4 alkylthio,
SO
3 H or halo; or phenyl-C 1
-C
2 -alkyl, heteroaryl-Ci-C2-alkyl, heterocyclyl-Ci-C 2 -alkyl or C 3 -C6-cycloalkyl-C1-C2-alkyl radicals optionally substituted by 1-3 radicals of amino, di-(C1-C4-alkyl)amino, hydroxy, C 1
-C
4 alkoxy, C 1
C
4 alkylthio, C 1
-C
4 alkyl or C1-C2 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-(Ci-C2-alkyl)amino, hydroxy, Ci-C2 alkoxy, C 1
-C
2 alkylthio or halo; or phenyl-Ci-C 2 -alkyl, heteroaryl-C1-C 2 -alkyl, heterocyclyl-Ci-C 2 -alkyl or C3-C6-cycloalkyl-Ci-C2-alkyl radicals optionally substituted by 1-3 radicals of amino, di-(C1-C2-alkyl)amino, hydroxy, C 1
-C
2 alkoxy, CI-
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 -C2-alkyl, radicals optionally substituted by 1-3 radicals of amino, dimethylamino, hydroxy, methoxy, methylthio, methyl or trifluoromethyl radicals; more preferably, each R 5 is independently hydrogen or
C
1
-C
4 alkyl radical; and most preferably, each R 5 is a hydrogen radical; wherein each R 20 is independently a alkyl, alkenyl or alkynyl radical optionally substituted by 1-3 radicals of -C0 2
R
2 3 amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, N- (alkoxycarbonyl) N (alkyl) amino, aminocarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, cyano, halo or aralkoxy, aralkylthio, aralkysulfonly, cycloalkyl, heterocyclyl, aryl or heteroaryl wherein the aralkoxy, aralkylthio, aralkylsulfonyl, cycloalkyl, heterocyclyl, aryl and heteroaryl radicals are optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamnino, alkanoyl, alkoxycarbonyl, hydroxy, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, cyano, halo, alkyl or haloalkyl; heterocyclyl radical optionally substituted by 1-3 radicals of amino, alkylarnino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, *alkoxycarbonyl, hydroxy, alkoxy, alkylthio, cyano, allor aoalkyl; or hlakl arCaky,C~leyl orCC heteroayl radicals optionally substituted by 1-3 rdcl faio r akndiaalkyofamino, Calkaylamino, ,alkcryl)amino-, alkluloylamino, Calkoxycarbonyl ydo, N-(Xalkoxy lho cao, hal, azid, alkyl) hamoy *mncroyannl-~lysloyaio ayrx,,Cakx,,Caklho CaCaklufnlC-~lysloyhloo rlC 4akxay-lC-llh a...-lC-lyslfnlC-~ylaklhtrccyay o eeorlrdcl opi.al susiue y13rdcla.amnICaklmnd-(IC -21 alkyl) amino, C 1
-C
5 alkanoylamnino, alkoxy) carbonylamino, C 1
-C
4 alkylsulfonylamino, alkanoyl, alkoxy) carbonyl, hydroXY, CI-C 4 alkoxy, C,-
C
4 alkylthio, C 1
-C
4 alkylsulfinyl, C 1
-C
4 alkylsulfonyl, halo,C 14 alkylorC-C 4 haloalkyl of 1-3 halo radicals; heterocyclyl radical optionally substituted by 1-3 radicals of amnino, C 1
-C
4 alkylamino, alkyl) amino, C,-C 5 alkanoylamino, (Cl-C 4 alkoxy) carbonylamino, C 1 4 alkylsulfonylamino, (CI-C 4 alkoxy) carbonyl, hydroxy, C,-C 4 alkoxy, CI-C 4 alkylthio, CX- 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, C 1
-C
4 alkylamino, di-(C 1
-C
4 alkyl),amino, CX- 5 alkanoylamino, (CI-C 4 alkoxy) carbonylamino, C 1 4 alkylsulfonylamino, (C 1
-C
4 alkoxy) carbonyl, hydroxy, C,-C, alkoxy, C 1
-C
4 alkylthio,cyano, halo, azido, C 1
-C
4 alkyl or C 1 4 haloalkyl of 1-3 halo radicals; *se, 0 0 more preferably, each R 2 0 is independently
C,-C
8 ailkyl, C 2
-C
5 alkenyl or C 2
-C
5 alkyni radicals optionally substituted by 1-3 radicals of amino, alkylamino, di-(C,-C 4 alkyl) amino, C 1
-C
5 alcanoylamino, (C 1 C4 alkoxy) carbonylamino, (C 1
-C
4 alkoxy) carbonyl)-N-(C 1
-C
4 ailkyl) amino, amninocarbonylamino, CX- 4 alkylsulfonylamino, hydroxy, CI-C 4 ailcoxy, CI-C 4 alkylthio,
CX-
4 alkylsulfinyl, C 1 4 alkylsulfonyl, halo or aryl-C 1
-C
4 -alkoxy, aryl-C,-C 4 -alkylthio, aryl-C 1
-C
4 -alkylsulfonyl, cycloalkyl, heterocyclyl, aryl or heteroaryl radicals optionally substituted by 1-3 radicals of amino, CX- 4 alkylamino, di-(C 1
-C
4 alkyl) amino, CX- 5 alkanoylamino, (C 1
-C
4 alkoxy) carbonylaxnino, CX- 4 alkylsulfonylamino,
CX-
5 alkanoyl, hydroxy, C 1 4 akoy C 4 akytoCX- 4 WO 98/24780 WO 9824780PCTIUS97/22949 22 alkylsulfinyl, Cl-C 4 alkylsulfonyl, halo, C 1
-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 alkylamino, di-(Cl-C 4 alkyl)anino, Cl-C 5 alkanoylamino, (Cl-C 4 alkoxy) carbonylarnino, Cl-C 4 alkylsulfonylamino, hydroxy, Cl-C 4 alkoxy, Cl-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, C 1
-C
4 alkylamino, di-(Cl-C 4 alkyl)amino, Cl-C 5 alkanoylamino, (Cl-C 4 alkoxy) carbonyl amino, C 1
-C
4 alkylsulfonylamino,
(C
1
-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
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,
C
1
-C
5 alkanoylamino, (Cl-C 4 alkoxy)carbonylamino, N- ((Cl-C 4 alkoxy) carbonyl) (Cl-C 4 alkyl)amino, ami noc arbonyl amino, hydroxy, C 1
-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, CI-C 4 alkylamino, di- (Cl-C 4 alkyl)amino, Cl-C 5 alkanoylamino,
(CI-C
4 alkoxy) c arbonyl amino, C 1
-C
4 alkylsulfonylamino, Cl-C alkanoyl, hydroxy, C 1
-C
4 alkoxy, C 1
-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, C 1
-C
4 alkylarnino, di-(Cl-C 4 alkyl)amino, Cl-C 5 alkanoylamino, (C1-C4 WO 98/24780 WO 9824780PCTIUS97/22949 23 alkoxy) carbonyl amino, hydroxy, CI-C 4 alkoxy, c 1
-C
4 alkyithia or CI-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 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, CI-C 4 alkyl or C 1
-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- (C 1
-C
4 alkyl)amino, Cl-C 5 alkanoylamino,
(CI-C
4 al1koxy) carbonyl amino, N- ((Ci-C 4 alkoxy) carbonyl) (Cl-C 4 alkyl)amino, aminoc arbonyl amino, hydroxy, Cl-C 4 alkoxy, Cl-C 4 alkylthio, CI-C 4 alkylsulfinyl, Cl-C 4 alkylsulfonyl, halo or aryl-Ci-C4-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, CI-C 4 alkylainino, di- (Cl-C 4 alkyl)amino,
C
1
-C
5 alkanoylamino, (Cl-C 4 a lkoxy) c arbonyl amino, C 1
-C
4 alkyl sul fonyl amino, Cl-C alkanoyl, hydroxy, Cl-C 4 alkoxy, Cl-C 4 alkylthio, halo, CI-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 al1koxy) carbonyl amino, hydroxy, C 1
-C
4 alkoxy, Cl-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) carbonyl amino, Cj-
C
4 alkylsulfonylamino, (Cl-C 4 alkoxy) carbonyl, hydroxy, Cl-C 4 alkoxy, Cl-C 4 alkylthio, cyano, halo, azido, CI-C 4 alkyl or trifluoromethyl radicals; WO 98/24780 PCTIUS97/22949 24 more preferably, each R 20 is independently cl-C 8 alkyl radicals optionally substituted by 1-3 radicals of amino,
C
1
-C
4 alkylarino, di-(C 1
-C
4 alkyl)amino,
C
1
-C
5 alkanoylamino,
(CI-C
4 alkoxy)carbonylanino, N-((Cl-C4 alkoxy)carbonyl)-N-(C 1
-C
4 alkyl)anino, aminocarbonylamino, hydroxy, C 1
-C
4 alkoxy,
C
1 -c 4 alkyithia, 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, (Ci-C 4 alkoxy)carbonylamino,
C
1
-C
4 alkylsulfonylanino, hydroxy,
C
1
-C
4 alkoxy,
C
1
-C
4 alkylthio, halo, C 1
-C
4 alkyl or trifluoromethyl radicals; heterocyclyl radical optionally ubstituted by 1-2 radicals of hydroxy,
C
1
-C
4 alkoxy, C 1
-C
4 alkyithia or C 1
C
4 alkyl; or aryl or heteroaryl radicals optionally substituted by 1-2 radicals of (C 1
-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 trifluororethyl radicals; more preferably, each R2O 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, nethylthio, halo, methyl or trifluoromethyl radicals; WO 98/24780 PCT/US97/22949 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 R 20 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 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; most preferably, each R20 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; -26each R 21 is independently hydrogen radical or R 20 each R 2 2 is independently a hydrogen radical; alkyl radical optionally substituted by a radical of heterocyclyl, aryl or heteroaryl wherein the heterocyclyl, aryl and heteroaryl radicals are 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 amino, 10 alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, .*hydroxy, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, cyano, halo, alkyl or haloalkyl.
0 Preferably, when Z is a bond and Y is -NR 2 2 -C(O)-NH2, then R 22 is other then an 00 0 optionally substituted aryl radical.
0000 Preferably, each R 2 2 is independently 15 hydrogen radical; 0050 *0
C-C
4 alkyl radical optionally substituted by a radical of heterocyclyl, aryl or
*S
*5 0050 0 1heteroaryl optionally substituted by 1-3 radicals of amino, C,-C 4 alkylamino, di- (C 1
-C
4 alkyl) amino, C,-C 5 alkanoylamino, (C,-C 4 alkoxy) carbonylamino, C,-C 4 alkylsulfonylamino, hydroxy, C-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,-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-(C,-C 4 alkyl) amino, C 1
-C
5 alkanoylamino, (C 1
-C
4 alkoxy) ALI~q a carbonylamino, C,-C 4 alkylsulfonylamino, hydroxy, C,-C 4 alkoxy, C 1
-C
4 alkylthio, C,-C 4 9 alkylsulfinyl, C 1
-C
4 alkylsulfonyl, cyano, halo, C 1
-C
4 alkyl or C 1
-C
4 haloalkyl of 1-3 27- radicals; provided when Z is a bond and Y is -NR 22
-C(O)-NH
2 the R 22 is other then an optionally substituted aryl radical; more preferably, each R 22 is independently hydrogen radical; or cl-c 4 alkyl radical optionally substituted by a radical of phenyl or heteroaryl optionally substituted by 1-3 radicals of amino, alkyl) amino, C,-C, alkanoylamino, ailkoxy) carbonylamino, hydroxy, C 1
-C
4 alkoxy, C 1
-C
4 alkylthio, cyano, halo,C 1
-C
4 alkyl or C 1
-C
2 haloalkyl or 1-3 halo radicals; more preferably, each R 2 2 is independently hydrogen or C 1
-C
4 alkyl radical; and most preferably, each R 2 is independently hydrogen or methyl radical; each R 23 is independently a hydrogen, alkyl, aryl, heteroaryl, aralkyl or heteroaralkyl be radical, wherein the aryl, heteroaryl, aralkyl and heteroaralkyl radicals are optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamnino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, cyano, halo, alkyl or haloalkyl; and R, and R 1 are each independently an aryl or heteroaryl radical optionally substituted by 1-3 radicals of
R
30 halo or cyano;
-C(O)-R
30 -C(O)-0R 29
-C(O)-NR
3 1
R
32 or -C(NR 3
,)-NR
3 lR 32
-OR
29
-O-C(O)-R
29
-O-C(O)-NR
3
R
32 or -O-C(O)-NR 33
-S(O)
2
-R
30
-SR
29 -S(O)7R 3 o, -S(O) 2
-R
30
-S(O)
2
-NR
3 lR 32
-S(O)
2
-NR
33
-C(O)-R
30
-S(O)
2
-NR
33 W C(O)-0R 30 or -S(O) 2
-NR
3
-C(O)-NR
3
,R
32 or 27a
-NR
3 1
R
32
-NR
33
-C(O)-R
29
-NR
33 -C(O)-0R 30
-NR
33
-C(O-NR
31
R
32 -NqR 33
-C(NR
31
NR
3 lR 32
-NR
33
-S(O)
2
-R
30 or -R3S02N~R2 provided that R, is other than a 4-p yridyl, 4-pyrimidinyl, 4-quinolyl or 6isoquinolinyl radical optionally substituted by 1-2 sub stituents; when R, is an unsubstituted phenyl, 4-methoxyphenyl or 4-chiorophenyl radical, then R 12 is other than an unsubstituted phenyl, 4-methoxyphenyl or 4-chlorophenyl radical; and the total number of aryl, heteroaryl, cycloalkyl and heterocyclyl radicals substituted on each of RI, and R 1 2 is 0-1; WO 98/24780 WO 9824780PCTUS97/22949 28 preferably, R11 and R 1 2 are each independently an aryl or heteroaryl radical optionally substituted by 1-2 radicals of 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 NR31R 32 radicals;
-OR
2 9
-O-C(O)-R
2 9
-O-C(O)-NR
3 lR 3 2 or -O--C(O)-NR 3 3
S(O)
2
-R
3 o radicals; -SR 2 9
-S(O)-R
3 o, -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
NR
31
R
32 radicals; or
-NR
3 1 R3 2 -NR3 3
-C(O)-R
2 9 -NR33-C(O)-0R 3 0
-NR
3 3
NR
3 1R 3 2 -NR33-C(NR 3 1
)-NR
3 lR 32 -NR33-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 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; more preferably, R 1 1 and R 12 are each independently an aryl or heteroaryl radical optionally substituted by 1-2 radicals of
R
30 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 -0R2 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
-NR
3 3
-C(O)-R
2 9 or -NR 3 3 -C(O)-0R 30 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 98/24780 PCT/US97/22949 29
R
3 0 halo or cyano radicals;
-C(O)-R
3 0, -C(O)-OR 2 9
-C(O)-NR
31
R
3 2 or -C(NR31)- NR3 1
R
32 radicals; or -OR2 9 -SR2 9
-S(O)-R
3 0 -S(0) 2
-R
3 0, -S(0)2-NR 3 1R 3 2
-NR
3 1
R
3 2 or -NR33-C(O)-R 2 9 radicals; more preferably,
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
R
3 0 halo or cyano radicals; or
-C(O)-NR
3 1
R
3 2 -OR2 9
-SR
2 9
-S(O)-R
30 -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
11 is an aryl radical optionally substituted by 1-2 radicals of R3 0 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(O)2-NR 31
R
3 2
-NR
31
R
3 2 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,
R
11 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,
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; more preferably, R 2 is a heteroaryl radical optionally substituted by 1-2 radicals of (1)
R
30 halo or cyano radicals; or -C(O)-NR,R 32
-OR
2 9
-SR
2 9
-NR
1
R
2 or -NRz-
C(O)-R
29 radicals; more preferably, R, 12 is a heteroaryl radical optionally substituted by 1-2 radicals of amino, dimethylamino, acetamrnido, hydroxy, halo, cyano, methoxy, methyl or trifluoromethyl radicals; more preferably, R, 12 is a 4-pyridyl, 4-quinolinyl, 4imidazolyl 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, 2 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 a alkyl, alkenyl or alkynyl radical optionally substituted by 1-3 radicals of-NR,R 3 C0 2
R
23 hydroxy, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, cyano, halo, aralkoxy, aralkylthio, aralkylsulfonyl, heterocyclyl, aryl or heteroaryl wherein the aralkoxy, 15 aralkylthio, aralkylsulfonyl, heterocyclyl, aryl and heteroaryl radicals are 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, 1 alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, WO 98/24780 PCTIUS97/22949 31 hydroxy, alkoxy, alkylthio; cyano, halo, alkyl or haloalkyl; preferably, each R 3 0 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 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- CI-C4-alkoxy, aryl-Ci-C 4 -alkylthio, aryl-C 1 -c 4 alkylsulfonyl, heterocyclyl, aryl or heteroaryl radicals 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,
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; heterocyclyl radical optionally substituted by 1-3 radicals of amino, Cl-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, 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, C 1
-C
4 alkylamino, di-(C 1
-C
4 alkyl)amino,
C
1
-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, C 1
-C
4 alkyl or C 1
-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 phenylmethoxycarbonyl optionally substituted by 1-3 WO 98/24780 PCTIUJS97/22949 32 radicals of amino, alkylamino, di- (C1-C4-alkyl) amino, Cl-C 5 alkanoylamino, (Cl-C 4 alkoxy)carbonylamino',
C
1
-C
4 alkylsulfonylamino, hydroxy,
C
1
-C
4 alkoxy,
C
1
-C
4 alkyithia, cyano, halo, C 1
-C
4 alkyl. or trifluoromethyl; or hydroxy, Cl-C 4 alkoxy, C 1
-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, C 1
-C
4 alkylamino, di- (Cl-C 4 alkyl)amino,
C
1
-C
5 alkanoylamino, (Cl-C 4 al1koxy) carbonyl amino, hydroxy, Cj-C 4 alkoxy,
CI-C
4 alkylthio, cyano, halo, C 1
-C
4 alkyl. or Cl-C 4 haloalkyl of 1-3 halo radicals;
C
1
-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, Cl-C 5 alkanoylamino, (Cl-C 4 al1koxy) carbonyl amino, hydroxy, Cl-C 4 alkoxy, Cl-C 4 alkylthio, cyano, halo, Cl-C 4 alkyl. or trifluoromethyl radicals; more preferably, each R 3 0 is independently cl-c 4 alkyl radical optionally substituted by amino, Cl-C 4 alkylamino or di- (C1-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-C 4 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-(C 1
-C
4 WO 98/24780 PCT/US97/22949 33 alkyl)amino,
CI-C
5 alkanoylamino,
(C
1
-C
4 alkoxy)carbonylamino, hydroxy,
C
1
-C
4 alkoxy,
C
1
-C
4 alkylthio, cyano, 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, 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-(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,
R
30 is independently
C
1 -C4 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 -34aryl 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 R 30 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, is independently a hydrogen radical; alkyl radical optionally substituted by a cycloalkyl, aryl, heterocyclyl or heteroaryl radical wherein the cycloalkyl, aryl, heterocyclyl and heteroaryl radicals are optionally 10 substituted by 1-3 radicals of amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, cyano, alkyl or haloalkyl; or aryl, heteroaryl, hetercyclyl 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 3 1 is independently hydrogen radicals; Cl-C 4 alkyl radical optionally substituted by an C 3 cycloalkyl, aryl, heterocyclyl or heteroaryl radical optionally substituted by 1-3 radicals of amino, C,-C 4 alkylamino, di-(C-C 4 alkyl) amino, C 1 alkanoylamino, (C-C 4 alkoxy) carbonylamino, C,-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, hetercyclyl or C 3 cycloalkyl radical optionally substituted by 1-3 "I radicals of amino,
C,-C
4 alkylamino, di-(C,-C 4 alkyl) amino, alkanoylamino, (C,-C 4 alkoxy) carbonylamino, C 1
-C
4 alkylsulfonylamino, hydroxy, C 1
-C
4 alkoxy, C,-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 is independently a hydrogen radical; or
C
1
-C
4 aklyl radical optionally substituted by an phenyl or heteroaryl radical optionally substituted by 1-3 radicals of amino, C 1
-C
4 alkylamino, di-(C-C 4 alkyl) amino, C,-Cs alkanoylamino, (C 1
-C
4 alkoxy) carbonylamino, hydroxy, C 1
-C
4 alkoxy, C 1
C
4 alkylthio, cyano, CI-C 4 alkyl or trifluoromethyl radicals; 10 more preferably, each R 31 is independently hydrogen or C 1
-C
4 alkyl radicals; and most preferably, each R 3 is independently hydrogen, methyl or ethyl radicals; each R 32 is independently a hydrogen radical; alkyl radical optionally substituted by a cycloalkyl, aryl, heterocyclyl or heteroaryl 15 radical wherein the cycloalkyl, aryl, heterocyclyl and heteroaryl radicals are 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 haloalkly; Spreferably, each R 3 2 is independently j a hydrogen radical; WO 98/24780 PTU9/24 PCTfUS97122949 36 cl-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-(Cl-C 4 alkyl)amino, Cl-C 5 alkanoylamino, (Cl-C 4 alkoxy)carbonylamino,
CI-C
4 alkylsulfonylamino, hydroxy, Cl-C 4 alkoxy, Cl-C 4 alkylthio, cyano, Cl-C 4 alkyl or Cl-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-(Cl-C 4 alkyl)amino, Cl-C alkanoylamino,
(C
1 7C 4 alkoxy) carbonyl amino, Cl-C 4 alkylsulfonylamino, hydroxy, Cl-C 4 alkoxy, Cl-C 4 alkylthio, cyano, Cl-C 4 alkyl or Cl-C 4 haloalkyl of 1-3 halo radicals; more preferably, each R3 2 is independently hydrogen radicals; Cl-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, Cl-C 4 alkylamino, di-(CI-C 4 alkyl)amino, Cl-C 5 alkanoylamino, (Cc-C 4 alkoxy) carbonyl amino, Cl-C 4 alkylsulfonylamino, hydroxy, Cl-C 4 alkoxy, Cl-C 4 alkylthio, cyano, Cl-C 4 alkyl or Cl-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-(Cl-C, 4 alkyl)amino, Cl-C alkanoylamino, (Cl-C 4 alkoxy) carbonyl amino, Cl-c 4 alkylsulfonylamino, hydroxy, Cl-C 4 alkoxy, Cl-C 4 alkylthio, cyano, Cl-C 4 alkyl or Cl-C 4 haloalkyl of 1-3 halo radicals; more preferably, each R 3 2 is independently hydrogen radicals; -37-
CI-C
4 alkyl radical optionally substituted by phenyl or heteroaryl radical optionally substituted by 1-3 radicals of amino, C,-C 4 alkylamino, di-(C-C 4 alkyl) amino, C,-C alkanoylamino, (C-C 4 alkoxy) carbonylamino, hydroxy, Ci-C 4 alkoxy, C-C 4 alkyl or trifluoromethyl radicals; or phenyl or heteroaryl radical optionally substituted by 1-3 radicals of amino, C-C 4 alkylamino, di-(C,-C 4 alkyl) amino, C 1 -Cs alkanoylamino, (C,-C 4 alkoxy) carbonylamino, hydroxy, C-C 4 alkoxy, C-C 4 alkyl or trifluoromethyl radicals; more preferably, each R 32 is independently a hydrogen radical; 10 C-C 4 alkyl radical or C 1 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, acaetamido, hydroxy, methoxy, methyl or trifluoromethyl radicals; o 15 most preferably, R 3 2 is independently hydrogen or C,-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 R 3 3 is independently hydrogen radical; or alkyl radical optionally substituted by a radical ofheterocyclyl, aryl or heteroaryl, 1 wherein the aryl, heterocyclyl and heteroaryl radicals are optionally substituted by 1-3 Is i radicals of amino, alkylamino, dialkylamino, WO 98/24780 PCT/US97/22949 38 alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, cyano, alkyl or haloalkyl; preferably, each R 3 3 is independently hydrogen radical; or Cl-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-(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, 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 Cl-C 4 alkyl radical; and most preferably, each R 33 is independently hydrogen or methyl 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 racemic mixtures and separate enantiomers and diasteromers.
Compounds of interest include the following: 0 R11
.,CH
3 Rl2 N RI wherein R 1 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 4pyridyl 1-piperazinyl 4-chlorophenyl 4-pyridyl l-piperazinyl 3-chlorophenyl 4-pyridyl l-piperazinyl WO 98/24780 WO 9824780PCT/US97/22949 2 -chlorophenyl _4-pyridyl 1--piperazinyl 4-tolyl 4-pyridyl l-piperazinyl 3-tolyl 4-pyridyl 1-piperazinyl 2-tolyl 4-pyridyl 1-piperazinyl 4-trifluoro- 4-pyridyl l-piperazinyl iethylphenyl 3-trifluoro- 4-pyridyl 1-piperazinyl methylphenyl 2,6- 4-pyridyl l-piperazinyl dichlorophenyl 2, 6-dimethyl 4-pyridyl l-piperazinyl p~henyl_____ 3,4- 4-pyridyl l-piperazinyl dichlorophenyl 3 ,4-dimethyl 4-pyridyl l-piperazinyl phenyl_____ 2,4- 4-pyridyl 1-piperaziny.
dichlorophenyl 2, 4-dimethyl 4-pyridyl l-piperazinyl phenyl Phenyl 2-amino-4- l-piperazinyl 4-f luorophenyl 2-amino-4- l-piperazinyl pyridyl 3-f luorophenyl 2-arnino-4- 1-piperazinyl pyridyl 2-f luorophenyl 2-arnino-4- I-piperaziny.
_pyridyl 4-chiorophenyl 2 -amino-4- l-piperazinyl pyridyl 3 -chiorophenyl 2 -amino-4 1 -piperaz inyl pyridyl 2-chiorophenyl 2-amino-4- l-piperazinyl.
4-tolyl 2-arnino-4- l-piperazinyl pyridyl 3-tolyl 2-arnino-4- l-piperazinyl _pyridyl 2-tolyl 2-amino-4- l-piperazinyl 4-trifluoro- 2-amino-4- 1-piperazinyl me thyiphenyl _yiy 3-trifluoro- 2-amino-4- l-piperazinyl methylphenyl _pyridyl___ 2,6- 2-arnino-4- 1-piperazinyl dichlorophenyl pyridyl 2, 6-dimethyl 2 -a'nino-4- l-piperazinyl phenyl pyridyl_______ 3,4- 2-arnino-4- l-piperazinyl dichlorophenyl pyridyl___ 3, 4-dirnethyl 2-amino-4- l-piperazinyl _heny1 pyridyl 2,4- 2-amino-4- 1-piperazinyl dichlorophenyl lpyridyl WO 98/24780 WO 9824780PCTIUS97/22949 2, 4-dimethyl 2-amino-4- 1-piperaziiyl phenyl pyridyl Phenyl 2-acetamido- 1-piperazinyl -pyridyl 4-f luoropheny. 2-acetamido- 1-piperazinyl -pyridyl 3 -fluorophenyl 2-acetamido- 1-piperazinyl 2-f luoropheny. 2-acetarnido- 1-piperazinyl -yridyl 4-chiorophenyl 2-acetamido- 1-piperazinyl -pyridyl 3 -chiorophenyl 2-acetainido- 1-piperazinyl -pyridyl 2 -chiorophenyl 2 -acetamido- 1-piperazinyl -pyridyl 4-tolyl 2-acetamido- 1-piperazinyl -pyridyl 3-tolyl 2-acetamido- 1-piperaziny.
-pyridyl 2-tolyl 2-acetamido- 1-piperazinyl 4-trifluoro- 2-acetamido- 1-piperazinyl methylphenyl 4 -pyridyl 3-trifluoro- 2-acetarnido- 1-piperazinyl methyiphenyl 4 -pyridyl 2,6- 2-acetamido- 1-piperazinyl dichlorophenyl 4-pyridyl 2, 6-dimethyl 2-acetarnido- 1-piperazinyl phenyl 4-pyridyl 3,4- 2-acetamido- 1-piperazinyl dichlorophenyl _4-pyridyl 3, 4-dimethyl 2-acetamido- 1-piperazinyl phenyl 4-pyridyl 2,4- 2-acetamido- 1-piperazinyl dichioropheny1 4-pyridyl 2, 4-dimethyl 2-acetamido- 1-piperazinyl phenyl 4-pyridyl Phenyl 2-amino-4- 1-piperazinyl 4-filuorophenyl 2-amino-4- 1-piperazinyl pyrimidinyl 3-f luorophenyl 2-arnino-4- 1-piperazinyl pyrimidinyl 2-f luorophenyl 2-arnino-4- 1-piperazinyl pyrimidinyl 4-chloropheny. 2-axnino-4- 1-piperazinyl pyrimidinyl 3 -chiorophenyl 2-arnino-4- 1-piperazinyl pyvrimidinyl 2-chiorophenyl 2 -ainino-4- 1-piperazinyl .pyrimidinyl 4-tolyl 2-amino-4- 1-piperazinyl pyrimidinyl WO 98/24780 PTU9124 PCTfUS97/22949 3-tolyl 2-amino-4- l-piperazinyl.
pyrimidinyl 2-tolyl 2-amino-4- l-piperazinyl pyrimidinyl 4-trifluoro- 2-amino-4- l-piperazinyl methy1 heny1 pyrimidinyl 3-trifluoro- 2-ainino-4- l-piperazinyl iethylphenyl pyrimidinyl 2,6- 2-amiino-4- l-piperazinyl dichlorophenyl pyrimidinyl 2, 6-dimethyl 2-amino-4- 1-piperazinyl phenyl primidinyl 3,4- 2-ainino-4- l-piperazinyl dichiorophenyl pyrimidinyl 3, 4-dimethyl 2-amino-4- l-piperazinyl phenyl pyrimidinyl 2,4- 2-amino-4- 1-piperazinyl dichiorophenyl pyrimidinyl 2, 4-dimethyl 2-amino-4- l-piperazinyl phenyl pyrimidinyl Phenyl 4-pyridyl 2 (2 -chiorophenyl) 4-f lurophenl 4-pyidyl 2 (2-cinoohnl 3-f luorophenyl 4-pyridyl 2 (2 -chi orophenyl) ethylamino 4-chiorophenyl 4-pyridyl 2 (2 -chi orophenyl) ethylamino 3-chiorophenyl 4-pyridyl 2 (2 -chiorophenyl) ethylamino 2-chiorophenyl 4-pyridyl 2 (2 -chiorophenyl) ethyl amino 4-thoro eny 4-pyridyl 2 (2 -chiorophenyl) ethylamino 3-thoro l 4-pyridyl 2 (2 -chiorophenyl) ethylamino 2-tolyl 4-pyridyl 2 (2 -chiorophenyl) ethylamino 4-triluoro 4-pyridyl 2- (2-chiorophenyl) methyihenylethyl amino 3-triluoro 4-pyridyl 2 (2 -chiorophenyl) methyihenylethylamino 2,-iloo 4-pyridyl 2 -chl orophenyl) dichiorphen1 ethylamino 2, -imethyl- 4-pyridyl 2 (2 -chi orophenyl) myphenyl ethylamino 3,4- 4-pyridyl 2-(2--chlorophenyl) dichlorophenyl ethylamino 3, 4-dimethyl 4-pyridyl 2 (2 -chiorophenyl) ethylamino 2,4- 4 -pyridyl 2 -chlorophenyl) dichiorophenyl _______ethylamino WO 98/24780 WO 9824780PCTIUS97/22949 2, 4-dimethyl 4-pyridyl 2- (2-chiorophenyl) phenyl 4-f luorophenyl 4-pyridyl 3- (3-f luorophenyl) 4-f luorophenyl 2-mn 3- (3-f luorophenyl) propylamino benzyl 4 -pyridyl 3 -phenylpropylainino benzyl 4-pyridyl 2- (4-f luorophenyl) ethylamino 2-thienyl 4-pyridyl 3 -phenylpropylamino 2-thienyl 4-pyridyl 2- (4-f luorophenyl) ethylamino cyclohexyl 4-pyrid#yl 3 -phenyipropylamino cyclohexyl 4-pyridyl 2- (4-f luorophenyl) ethylamino tert-butyl 4-pyridy. 3--phenyipropylamino tert-butyl 4-pyridyl 2- (4-f luorophenyl) ethylamino 4-f luorophenyl 4- 3 -phenyipropylamino piper idinyl 4-f luorophenyl 4- 2- (4-f luorophenyl) ethylamino 4-f luorophenyl 4-pyranyl 3-phenyipropylamino 4-f luorophenyl 4-pyranyl 2- (4-f luorophenyl) Phenyl 2-amino-4- 2- (2-chiorophenyl) _pyridyl ethylanino 4-f luorophenyl 2-amino-4- 2- (2-chiorophenyl) pridyl ethylamino 3-f luorophenyl 2-amino-4- 2- (2-chiorophenyl) ethylamino 2-f luorop-henyl 2-amino-4- 2- (2-chiorophenyl) _pyridyl ethylamino 4-chiorophenyl 2-arnino-4- 2- (2-chiorophenyl) ethylamino 3-chiorophenyl 2-amino-4- 2- (2-chiorophenyl) p pridyl ethylanino 2-chloropheny. 2-amino-4- 2- (2-chiorophenyl) ethylanino 4-tolyl 2-amino-4- 2- (2-chilorophenyl) _pyridyl ethylamino 3-tolyl 2-amino-4- 2- (2-chiorophenyl) ethylamino 2-tolyl 2-amino-4- 2- (2-chiorophenyl) _pyridyl ethylamino 4-trifluoro- 2-amino-4- 2- (2-chiorophenyl) methyiphenyl pyridyl ethylanino 3-trifluoro- 2-amino-4- 2- (2-chilorophenyl) methylphenyl pyridyl ethylanino 2,6- 2-arnino-4- 2- (2-chiorophenyl) dichlorophenyl _pyridyl ethylamino 2, 6-dimethyl 2-amino-4- 2- (2-chiorophenyl) phenyl -pyridyl ethylamino WO 98/24780 WO 9824780PCT/US97/22949 3,4- 2-amino-4- 2 -chl orophenyl) dichlorophenyl _pyridyl ethylamino 3,4-dimethyl 2-amino-4- 2-(2-chlorophenyl) phenyl pyridyl ethylainino 2,4- 2-arnino-4- 2-(2-chlorophenyl) dichlorophenyl pyridy1 ethylamino 2, 4-dimethyl 2-amino-4- 2- (2-chiorophenyl) phenyl pyridyl ethylamino Phenyl1 2 -acetamido- 2- (2 -chiorophenyl) ethylanino 4-f luorophenyl 2-acetamido- 2- (2 -chiorophenyl) ethylamino 3 -fluorophenyl 2-acetamido- 2- -chorophenyl) -ethylamino 2-f luorophenyl 2-acetamido- 2- (2-chiorophenyl) ethylamino 4-chilorophenyl 2-acetainido- 2- (2 -chiorophenyl) -ethylamino 3-chiorophenyl 2-acetamido- 2- (-chiorophenyl) ethylamino 2-chiorophenyl 2-acetamido- 2- (2 -chiorophenyl) ethylamino 4-tolyl 2-acetamido- 2- (2 -chiorophenyl) ethvlamino 3-tolyl 2-acetamido- 2- (2-chiorophenyl) ethylamino 2-tolyl 2-acetamido- 2- 2 -chlorophenyl) ethylamino 4-trifluoro- 2-acetamido- 2- (2-chiorophenyl) methyiphenyl 4-pyridy ethylainino 3-trifluoro- 2-acetamido- 2- (2-chiorophenyl) methylphenyl 4-pyridyl -ethylamino 2,6- 2-acetainido- 2- (2-chilorophenyl) dichiorophenyl 4-pyridyl ethylamino 2, 6-dimethyl 2-acetamido- 2 -(2-chlorophenyl) phenyl 4-pyridyl ethylarnino 3,4- 2-acetamido- 2- (2-chiorophenyl) dichlorophenyl 4-pyridyl ethylamino 3, 4-dimethyl 2-acetamido- 2- (2-chiorophenyl) phenyl 4-pyridyl ethylamino 2,4- 2-acetamido- 2- (2-chiorophenyl) dichlorophenyl 4-pyridy. ethylainino 2, 4-dimethyl 2-acetamido- 2- (2-chiorophenyl) _phenyl 4-pyridyl ethylamino Phenyl 2-amino-4- 2- (2-chiorophenyl) pyrimidinyl ethylamino 4-f luorophenyl 2-amino-4- 2- (2-chiorophenyl) pyrilnidinyl ethylamino 3-f luorophenyl 2-amino-4- 2- (2-chiorophenyl) pyrimidinyl ethylarnino 2-f luorophenyl 2-amino-4- 2- (2-chiorophenyl) '-cnlorophenylj 2-amino-4 pyrindn.
2- (2-chiorophenyl) WO 98/24780 PCTIUS97/22949 .i-cfllorophenyl -J2-arnino-4- 2 -chiorophenyl 2-amino-4pyrirnidinyl 2 (2 -chlo-rophenyl) ethylamino 2 (2 -chiorophenyl) ethylainino 2 (2 -chi orophenyl) 4-tolyl 2-arnino-4nvri midiHnxr1 L .L"LJ.
3-tolyl 2-amino-4- 2- (2-chiorophenyl) pyrimidinyl ethylamino 2-tolyl 2-amino-4- 2- (2-chiorophenyl) pyrimidinyl ethylamino 4-trifluoro- 2-amino-4- 2- (2-chiorophenyl) methylphenyl pyrimidinyl ethylamino 3-trifluoro- 2-ainino-4- 2- (2-chiorophenyl) methyiphenyl pyrirnidinyl ethylamino 2,6- 2-amino-4- 2- (2-chiorophenyl) dichiorophenyl pyrimidinyl ethylamino 2, 6-dirnethyl 2-amino-4- 2 -(2-chlorophenyl) phenyl pyrimidinyl ethylamino 3,4- 2-amino-4- 2- (2-chiorophenyl) dichiorophenyl _pyrimidinyl ethylamino 3,4-dirnethyl 2-amino-4- 2 -(2-chlorophenyl) phenyl pyrimidinyl ethylamino 2,4- 2-arnino-4- 2- (2-chiorophenyl) dichiorophenyl _pyrimidinyl ethylamino 2, 4-dimethyl 2-amino-4- phenyl pyrimidinyl ethylamino Phenyl 4-pyridyl 3 -imidazolyipropylamino 4- fluorophenyl 4 -pyridyl 3- imidazolyipropylanino 3 -fluorophenyl 4-pyridyl 3 -imidazolylpropylamino 2 -fluoro]2heny1 4 -pyridyl 3- imidazolylpropylamino 4 -chiorophenyl _4-pyridyl 3 -imidazolylpropylamino 3 -chlorophenyl 4-pyridyl 3 -imidazolylpropylanino 2 -chiorophenyl 4-pyridyl -3 -imidazolylprop2ylamino 4- tolyl 4 -pyridyl 3- imidazolvlpropylamino 3 -tolyl 4-pyridyl 3 -imidazolylpropylamino 2 -to lyl 4-_pyridyl 3 -imidazolylpropylamino 4-trifluoro- 4-pyridy. 3 -imidazolyipropylamino methylphenyl 3- tri fluoro- 4 -pyridyl 3- imidazolyipropylamino inethyiphenyl 2,6- 4-pyridyl 3 -imidazolylpropylamino dichiorophenyl 2, 6-dimethyl 4-pyridyl 3 -imidazolylpropylamino phenyl 3,4- 4-pyridy. 3 -imidazoilylpropylamino dichiorophenyl 3, 4-dirnethyl 4-pyridyl 3 -imidazolyipropylamino phenyl 2,4- 4-pyridy. 3 -imidazolylpropylanino dichioropheny1 2, 4-dimethyl 4-pyridyl 3 -imidazolylpropylanino phenyl Phenyl 2 -amnino-4- 3 -imidazolyipropylamino pyridvl WO 98/24780 WO 9824780PCTIUS97/22949 4-f luorophenyl 2 -amino-4-: 3 -imidazolylpropylamino ________pyridil 3 -fluorophenyl 2-amino--4- 3 -imidazolylpropylanino p yridyl 2 -fluorophenyl 2 -amino-4 3 -imidazolyipropylanino pyridyl 4-chioropheny. 2-ainino-4- 3 -imidazolylpropylanjno 3 -chiorophenyl 2 -amino-4 3 -imidazolyipropylamino pyridyl 2 -chiorophenyl 2 -ainino-4 3 -imidazolylpropylamino pyridyl__ 4-tolyl 2-amino-4 3 -imidazolylpropylam~ino pyridyl__ 3 -to lyl 2 -amino-4 3 -irnidazolylpropylamino pyr idyl 2-tolyl 2-amino-4- 3 -irnidazoilylpropylamino pyridyl 4-trifluoro- 2-amino-4- 3 -imidazolylpropylanino methyiphenyl -pyridyl 3-trifluoro- 2-amino-4- 3 -imidazolylpropylamino methy1 heny1 pyridyl 2,-2-amino-4- 3 -imidazolylpropylanino dichiorophenyl pyridyl 2, 6-dimethyl 2-amino-4- 3 -iinidazolylpropylamino phenylpyridyl 3, 4- 2-amino-4- 3 -irnidazolylpropylamino dichiorophenyl pyridyl 3, 4-dimethyl 2-amino-4- 3 -imidazolylpropyanino p~henyl -pyridyl 2, 4- 2-amino-4- 3 -irnidazolylpropylamino dichlorophenyl pyridyl 2, 4-diinethyl 2-amino-4- 3 -iinidazolylpropylarnino phenyl pyridyl Phenyl 2-acetamido- 3 -imidazolylpropylamino 4 -pyridyl 4-f luorophenyl 2 -acetamido- 3- imidazolylpropylamino 4 -pyridyl 3 -fluorophenyl 2 -acetamido- 3 -iinidazolylpropylamino 4 -pyridyl 2- fluorophenyl 2 -acetamido- 3- imidazolylpropylanino 4 -pyridyl 4 -chiorophenyl 2 -acetamido- 3- imidazolyipropylamino 4 -pyridyl 3 -chiorophenyl 2 -acetamido- 3- ilidazolyipropylamino -pyridyl 2-chiorophenyl 2-acetamido- 3 -irnidazolylpropylamino 4 -pyridyl 4-tolyl 2-acetamido- 3 -imidazolylpropylamino 4 -py i dy 3- tolyl 2 -acetamido- 3- imidazolylpropylamino 4 pyridyl_ 2-tolyl 2-acetamido- 3 -imidazolylpropylamino 4 -pyridyl_ WO 98/24780 PTU9/24 PCTIUS97/22949 4-trifluoro- 2-acetamido- 3 -imidazolylpropylanino methylphenyl -4-pyridyl 3-trifluoro- 2-acetamido- 3 -irnidazolylpropylaxnino rnethylphenyl 4-pyridyl 2, 6- 2-acetamido- 3 -imidazolylpropylamino dichiorophenyl 4-pyridyl 2, 6-dimethyl 2-acetamido- 3 -imidazolylpropylamino phenyl 4-pyridyl 3 2-acetaniido- 3 -imidazolylpropylamjno dichiorophenyl 4-pyridyl 3 ,4-dimethyl 2-acetamido- 3 -imidazolylpropyiamino phenyl 4-pyridyl 2,4- 2-acetamido- 3 -ilidazolylpropylamino dichiorophenyl 4-pyridyl 2, 4-dimethyl 2-acetarnido- 3 -imiclazolylpropylamino phenyl 4-pyridyl Phenyl 2-amino-4- 3 -imidazolylpropylamino imidinyl 4- fluorophenyl 2 -arnino-4 3- ilidazolylpropylamino p primidinyl 3 -fluorophenyl 2-amino-4- 3 -irnidazolylpropyiainino 2-f luorophenyl 2-amino-4- 3 -imidazolylpropylamino 4-chiorophenyl 2-arnino-4- 3 -imidazolylpropylamino 3 -chiorophenyl 2-amino-4- 3 -imidazolylpropylamino 2 -chiorophenyl 2 -amino 3 -irnidazolylpropylainino 4-tolyl 2-amino-4- 3 -imidazolylpropylamino pyrirnidinyl 3-tolyl 2-amino-4- 3 -imidazolylpropylamino 2-tolyl 2-arnino-4- 3 -imidazolylpropylamino pyrimidinyl 4-trifluoro- 2-amino-4- 3 -irnidazolylpropylainino methylphenyl pyrimidinyl 3-trifluoro- 2-ainino-4- 3 -imidazolylpropylamino 'nethylphenyl pyrimidinyl 2, 6- 2-amino-4- 3 -imidazolylpropylamino dichioropheay pyrimidinyl 2, 6-dimethyl 2-arnino-4- 3 -imidazolylpropylainino phenyl pyrimidinyl 3, 4- 2-amino-4- 3 -imidazolylpropylamino dichiorophenyl pyrimidinyl 3, 4-dirnethyl 2-amino-4- 3 -imidazolylpropylamino phenyl pyrirnidinyl 2,4- 2-amino-4- 3 -imidazolylpropylamino dichiorophenyl Pyrimidinyl 2, 4-dimethyl 2-arnino-4- 3 -imidazolylpropylamino phenyl pyrimidinyl A .L .1UIJ.L l)iL± yl± 4~-pyrictyj.
2- (2-chlorophenyl-lmethyl ety)amino WO 98/24780 WO 9824780PCT/US97/22949 4-f luorophenyl 2-acetamido- 2- (2-chlorophenyl-lmethyl)ethyl)amino 4-f luorophenyl 2-amino-4- 2- 2 -chlorophenyl-1methyl) ethyl) amino 3-f luorophenyl 4-pyridyl -tetrahydroisoquinol- -ylmethylenamino 2-f luorophenyl 2-amino-4- -3-benzylpiperazinyl pyridyl_ 3-chilorophenyl 2-acetamido- 2 -N-isopropylanino-3- -pyridyl _phenylpropyl amino 2-chiorophenyl1 2-amino-4- -2-N-glycylamino-3phenyipropylamino 4-tolyl 4-pyridyl (S)-2-amino-3phenyipropylamino 3-tolyl 2-amino-4- (R)-2-amino-3pridy. phenylpropylamino 2-tolyl 2-acetamido- 3-amino-3- -pyridyl phenyipropylamino 4-trifluoro- 2-amino-4- (S)-2-amino-3-(2methyiphenyl pyvriinidinyl fluorophenyl )propyvlaxnino 3-trifluoro- 4 -pyrid-yl -2-amino-3- (2methyiphenyl _______methyiphenyl )propylainino 2,6- 2-amino-4- 3-amino-3-(2dichiorophenyl _pyridy. fluorophenyl )propylamino 2, 6-dimethyl 2-acetamido- 3-amino-3- (2phenyl 4 -pyridyl methyiphenyl )propylamino 3,4- 2-amino-4- 2-amino-2-methyl-3dichlorophenyl pyrimidinyl phenyipropylamino 3, 4-dimethyl 4-pyridyl 3-amino-2-methyl-3phenyl phenyipropylamino 3-f luorophenyl 2-amino-4- (S)-2-amino-3phenyipropylamino 2-f luorophenyl 2-acetamido- (S)-2-amino-3-(2fluorophenyl )propylamino 3-chiorophenyl 2-amino-4- (S)-2-amino-3-(2methyiphenyl )propylamino 2-chiorophenyl 4-pyridyl -2-N-isopropylamino-3phenyipropylamino 4-tolyl 2-amino-4- -2-N-glycylamino-3- .pyridyl phenylpropylamino 3-tolyl 2-acetamido- 2-amino-2-methyl-3- 4 -pyridyl phenylpropylamino 2-tolyl 2-amino-4- (R)-2-amino-3pyrimidinyl phenylpropylamino 4-trifluoro- 4-pyridyl 3-amino-3methy1 heny1 ________phenyipropylamino 3-trifluoro- 2-amino-4- 3-ainino-3- (2methyiphenyl pyridyl f luorophenyl) propylamino 2,6- 2-acetamido- 3 -amino-3 dichlorophenyl 4-pyridyl methyl1 henyl)propylamino 2, 6-dimethyl 2-amino-4- 3-amino-2-methyl-3- _heny1 pyrirnidinyl phenyipropylamino 3,4- 4-pyridyl -tetrahydroisoquinodichiorophenyl -ylmethy.enamino WO 98/24780 PTU9124 PCT/US97/22949 3, 4-dimethyl phenvi 4 -pyridyl -3 -benzylpiperazinyl and 0
R
1 .,CH 3 jN
R
12 N R, wherein R' 2 and R1 are one of the combinations given in the following table: Rhny 4-yrdy R-yrRy 4Pfhe ronnl -4-pyridyl 4-pyridyl 3-f luorophenyl 4 -pyridyl 4 -pyridyl 2-f luorophenyl 4-pyridyl 4-pyridyl 4-chioropheny1 4-pyridyl 4-pyridyl 3 -chiorophenyl 4-pyridyl 4-pyridyl 2-chioropheny1 4-pyridyl 4-pyridyl 4-thoyl 4yridl 4-pyridyl 3-tolyl -4-pyridyl 4-pyridyl 3-tolyl 4-pyridyl -4-pyridyl 4-trifluoro- 4-pyridyl 4-pyridyl methylphenyl 3-trifluoro- 4-pyridyl 4-pyridyl me thyiphenyl 2,6- 4-pyridyl 4-pyridyl dichiorophenyl 2,6-dimethyl 4-pyridyl 4-pyridyl phyedyn4yyidl 3,4-dety 4-pyridyl 4-pyridyl 4-pyridyl 4-pyridy 2,4-dimethyl 4-pyridyl 4-pyridyl phenyl.2aio4 -yiy 2,4- 4~pyridyl -yi l 4-f luorophenyl 2-ii-4 4pydy 2,4-imetyl 4pyridyl -yi l 3he-flrpey 2-amino-4- 4-pyridyl yridyl1 2 -fluorophenyl 2 -amino-4- 4-pyridyl pyridyl 4-chiorophenyl 2-arnino-4- 4 -pyridyl yridyl.
3 -chiorophenyl 2-amino-4- 4-pyridyl p y r i dy l WO 98/24780 PTU9124 PCTIUS97/22949 2-chiorophenyl 2-ainino-4- 4-pyridyl idyl 4-tolyl 2-amino-4- 4-pyridyl 3-tolyl 2-amino-4- 4-pyridyl 2-tolyl 2-amino-4- 4-pyridyl 4-trifluoro- 2-aniino-4- 4-pyridyl methylphenyl _pyridyl 3-trifluoro- 2-amino-4- 4-pyridyl methyiphenyl pyridyl____ 2,6-2-amino-4- 4-pyridyl dichiorophenyl pyridyl___ 2,6-dimethyl 2-ainino-4- 4-pyridyl phnlpyridyl__________ 3,4-2-amino-4- 4-pyridyl dichlorophenyl pyridyl 3..4-diinethyl 2-amino-4- 4-pyridyl phenyl_____ pyridyl 2,4- 2-arnino-4- 4-pyridyl dichlorophenyl pyridyl 2,4-dimethyl 2-amino-4- 4-pyridyl phenyl _pyridyl Phenyl 2-acetamido- 4-pyridyl -pyridyl 4-f luorophenyl 2-acetamido- 4-pyridyl 3 -fluorophenyl 2-acetamido- 4-pyridyl -pyridyl 2-f luorophenyl 2-acetamido- 4-pyridyl 4-pyridy. 4-chiorophenyl 2-acetamido- 4-pyridyl -pyridyl 3 -chiorophenyl 2 -acetamido- 4 -pyridyl -pyridyl 2 -chiorophenyl 2 -acetamido- 4 -pyridyl 4 -pyridyl 4-tolyl 2-acetamido- 4-pyridyl -pyridyl 3 -tolyl 2 -acetainido- 4-pyridyl -pyridyl 2 -tolyl 2 -acetamido- 4-pyridyl -pyridyl 4-trifluoro- 2 -acetarnido- 4-pyridyl methyipheny 1 4pyridyl 3-trifluoro- 2 -acetamido- 4-pyridyl methyiphenyl 4 -pyridyl 2,6- 2 -acetarnido- 4-pyridyl dichlorophenyl 4-p1yridyl 2, 6-dimethyl 2-acetamido- 4-pyridyl pheny 4 4-pydl 3,4- 2 -acetamido- 4-pyridyl dichiorophenyl 4-pyridyl WO 98/24780 WO 9824780PCTIUS97/22949 3, 4-dimethyl 2-acetamido- 4-pyridyl phenyl 4-pyridyl 2,4- 2-acetamido- 4-pyridyl dichiorophenyl 4 -pyridyl 2, 4-dimethyl 2-acetamido- 4-pyridy.
phenyl 4-pyridyl. Phenyl 2-amino-4- 4-pyridyl rimidiny1l_ 4-f luorophenyl 2-amino-4- 4-pyridyl 3- fluorophenyl 2 -amino-4 4 -pyridy.
pyrimidinyl 2-f luorophenyl 2-amino-4- 4-pyridyl 4-chiorophenyl 2-amino-4- 4-pyridyl 3 -chiorophenyl 2 -amino-4 4 -pyridyl 2 -chiorophenyl 2 -amino-4- 4-pyridyl 4-tolyl 2-ainino-4- 4-pyridyl 3-tolyl 2-amino-4- 4-pyridyl yrimidinyl 2-tolyl 2-amino-4- 4-pyridyl 4-trifluoro- 2-amino-4- 4-pyridyl methyiphenyl _pyrimidinyl 3-trifluoro- 2-amino-4- 4-pyridyl methyiphenyl pyrimidinyl 2,6- 2-amino-4- 4-pyridyl dichiorophenyl pyvrimidirayl 2, 6-dimethyl 2-amino-4- 4-pyridyl phenyl pyrimidinyl 3,4- 2-amino-4- 4-pyridyl dichiorophenyl pyrimidinyl 3,4-dimethy. 2-amino-4- 4-pyridyl phenyl pyrimidinyl 2,4- 2-amino-4- 4-pyridyl dichiorophenyl pyrimidinyl 2,4-dimethyl 2-amino-4- 4-pyridyl phenyl _pyrimidinyl Phenyl 4-pyridyl -4-methyl sulfinyiphenyl 4- fluorophenyl 4-pyridyl 4-methyl sul finyiphenyl 3-f luorophenyl 4-pyridyl 4-methyl sulfinyiphenyl 2-f luorophenyl 4-pyridyl 4-methyl sulfinylphenyl 4 -chlorophenyl 4-pyridyl 4-methyl sulfinyiphenyl 3 -chlorophenyl 4-pyridyl- 4-methyl sulfinylphenyl 2-chlorophenyl -4-pyridyl 4-methyl sulfinylphenyl 4-tolyl 4-pyridyl 4-methyl sulfinylphenyl 3-tolyl 4-pyridyl 4-methyl sulfinylphenyl 2-tolyl .4-pyridyl 4-methyl sulfinylphenyl .LLluoro0 4~-pyrictyl 4-methyl sul finyiphenyl met lo e v WO 98/24780 WO 9824780PCT[US97/22949 i -trirtiuorme thvlphenvl 4 -pyridyl 4-methyl sulfinylp-henyl 2,6- 14-pyridyl- 4-methyl sulfinylphenyl dichlorophenyl 2, 6-dimethyl 4-pyridyl 4-methyl sulfinylpheayl phenyl 3,4- 4-pyridyl 4-methyl sulfinylpheiyl dichlorophenyl 3, 4-dimethyl 4-pyridyl 4-methyl sulfinylphenyl phenyl 2,4- 4-pyridyl 4-methyl sulfinyiphenyl dichlorophenyl 2, 4-dimethyl 4-pyridyl 4-methyl sulfinylphenyl phenyl Phenyl 2-amino-4- 4-methyl sulfinylphenyl pyridyl 4-f luorophenyl 2-amino-4- 4-methyl sulfinyiphenyl yridyl 3-f luorophenyl 2-amino-4- 4-methyl sulfinyiphenyl p yridyl 2-f luorophenyl 2-amino-4--- 4-methyl sultinylphenyl pyridyl 4-chiorophenyl 2-amino-4- 4-methyl sulfinylphenyl pyridyl 3-chiorophenyl 2-amino-4- 4-methyl sulfinylphenyl pyridyl 2-chlorophenyl 2-amino-4-, 4-methyl sulfinylphenyl pyridyl 4-tolyl 2-amino-4- 4-methyl sulfinylphenyl pyridyl 3-tolyl 2-amino-4- 4-methyl sulfinyiphenyl pyridyl 2-tolyl 2-amino-4- 4-methyl sulfinyiphenyl yridyl 4-trifluoro- 2-amino-4- 4-methyl sulfinylpheiyl methylphenyl _pyridayl 3-trifluoro- 2-amino-4- 4-methyl sulfinylphenyl me thylphenyl pyridyl 2,6- 2-amino-4- 4-methyl sulfinylphenyl dichloropheny1 pyridyl 2, 6-dimethyl 2-amino-4- 4-methyl sulfinylphenyl phenyl pyridyl_______ 3,4- 2-amino-4- 4-methyl sulfinylphenyl dichlorophenyl _pyridyl 3, 4-dimethyl 2-amino-4- 4-methyl sulfinylphenyl phenyl pyridyl 2,4- 2-amino-4- 4-methyl sulfinylphenyl dichlorophenyl _pyridyl___ 2, 4-dimethyl 2-amino-4- 4-methyl sulfinylphenyl phenyl pyridyl Phenyl 2-acetamido- 4-methyl sulfinylphenyl 4 -pyridyl 4-f luorophenyl 2-acetamido- 4-methyl sulfinylphenyl -pyridyl WO 98/24780 PCTIUS97/22949 3- fluorophenyl
-T
2 -acetamidop ridv.
I
2-f luorophenyl 2 -acetamido- 4 -pyridvi 4-mrethyl sulf inyiphenyl 4-methyl sulfinyiphenyl 4-methyl sul finyiphenyl
I
4 -chiorophenyl 2 -acetamido- 4 -i)vridvJ 3-chiorophenyl 2-acetamido- .4-methyl sulfinyiphenyl -pyridyl 2-chioroph~enyl 2-acetamido- 4-methyl sulfinyiphenyl 4-tolyl 2-acetamido- 4-methyl sulfinyiphenyl -pyridyl_______ 3-tolyl 2-acetamido- 4-methyl sulfinyiphenyl -pyraidyl 2-tolyl 2-acetamido- 4-methyl sulfinyiphenyl -pyridyl 4-trifluoro- 2-acetamido- 4-methyl sulfinyiphenyl methyiphenyl 4-pyridyl 3-trifluoro- 2-acetamido- 4-methyl sulfinyiphenyl methyiphenyl 4 -pyridyl 2,6- 2-acetamido- 4-methyl sulfinyiphenyl dichlorophenyl 4-pyridyl 2, 6-dimethyl 2-acetamido- 4-methyl sulfinyiphenyl _heny1 4-pyridyl 3,4- 2-acetamido- 4-methyl sulfinylphenyl dichlorophenyl 4-pyridyl 3, 4-dimethyl 2-acetainido- 4-methyl sulfinylphenyl phenyl 4-pyridyl 2,4- 2-acetainido- 4-methyl sulfinyiphenyl dichlorophenyl 4-pyridyl 2, 4-dirnethyl 2-acetamido- 4 -me thyl sulfinylphenyl phnl4-pyridyl Pheyl2-amino-4- 4-methyl sulfinylphenyl pyrimidinyl 4-f luorophenyl 2-amino-4- 4-methyl sulfinyiphenyl pyrimidinyl 3-f luorophenyl 2-amino-4- 4-methyl sulfinyiphenyl pyrimidinyl 2-f luorophenyl 2-amino-4- 4 -me thyl sulfinylphenyl pyrimidinyl 4-chlorophenyl 2-amino-4- 4-methyl sulfinylphenyl pyrimidinyl 3-chlorophenyl 2-arnino-4- 4 -me thyl sulfinyiphenyl pyrimidinyl 2-chiorophenyl 2-amino-4- 4-methyl sulfinylphenyl pyrimidinyl 4-tolyl 2-amino-4- 4 -methyl sulfinylphenyl pyr imidinyl 3-tolyl 2-amino-4- 4-methyl sulfinylphenyl py-rimidinyl 2-tolyl 2 -amin o 4-methyl sulfinylphenyl -2rimidinyl 4-trifluoro- 2-amino-4- 4-methyl sulfinylphenyl methy1 heny 1 p P~imidinyl WO 98/24780 WO 9824780PCT/US97/22949 3-trifluoro- 2-amino-4- 4-methyl sulfinylphenyl methylphenyl pyrimidinyl 2,6- 2-amino-4- 4-methyl sulfiriylphenyl dichiorophenyl pyrimidinyl 2,6-dirnethyl 2-amino-4- 4-methyl sulfinyiphenyl pheny1 pyrimidinyl 3,4- 2-amino-4- 4-methyl sulfinyiphenyl dichlorophenyl primnidinyl 3, 4-dirnethyl 2-amino-4- 4-methyl sulfinyiphenyl phenyl p~yrimidinyl 2,4- 2-amino-4- 4-methyl sulfinyiphenyl dichiorophenyl pyrimidinyl 2, 4-dimethyl 2-amino-4- 4-methyl sulfinylphenyl phenyl pyrimidinyl Phenyl 4-pyridyl 2, 6-dichlorobenzyl 4-f luorophenyl 4-pyridyl 2, E-dichlorobenzvl 3-f luorophenyl _4-pyridyl 2, 6-dichlorobenzyl 2-f luorophenyl 4-pyridyl 2, 6-dichlorobenzyl 4-chlorophenyl 4-pyridyl 2, 6-dichlorobenzvl 3-_chlorophenyl 4-pyridyl 2, 6-dichlorobenzyl 2-chioropheny1 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 2, 6-dichlorobenzyl me thyiphenyl 2,6- 4-pyridyl 2,6-dichlorobenzyl dichlorophenyl 2, 6-dimethyl 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 dichlorophen 1 2, 4-dimethyl 4-pyridyl 2, 6-dichlorobenzyl phenyl_______ Phenyl 2-amino-4- 2, 6-dichlorobenzyl pyr idyl 4-f luorophenyl 2-amino-4- 2, 6-dichlorobenzyl pyridyl 3 -fluorophenyl 2-amino-4- 2, 6-dichlorobenzyl _pyridyl 2-f luorophenyl 2-amino-4- 2, 6-dichlorobenzyl 4-chlorophenyl 2-amino-4- 2, 6-dichlorobenzyl 3-chlorophenyl 2-amino-4- 2, 6-dichlorobenzyl pyridyl 2-chiorophenyl 2-amino-4 2, 6-dichlorobenzyl WO 98/24780 PCT[US97/22949 A T 1 4kLOLy-L 2-amino-4- D~vrir9vl 2, 6 -dichlorobenzyl 2, 6 -dichlorobenzyl .j-tolyl 2 -arnino-4- Dovridvl 2-tolyl 2-amino-4- 2, 6-dichlorobenzyl p p ridyl 4-trifluoro- 2-amino-4- 2, 6-dichlorobenzyl methyiphenyl pyridy! 3-trifluoro- 2-amino-4- 2, 6-dichlorobenzy.
methyiphenyl pyridyl 2, 6- 2-amino--4- 2, 6 -dichlorobenzyl dichlorophenyl pyridyl 2, 6-dimethyl 2-amino-4- 2, 6-dichlorobenzyl phenyl pyridyl 3,4- 2-amino-4- 2, 6 -dichlorobenzyl dichiorophenyl _pyridyl 3, 4-dirnethyl 2-amino-4- 2, G-dichlorobenzyl phenyl pyridyl 2,4- 2-ainino-4- 2 6 -dichlorobenzyl dichlorophenyl pyridyl 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-acetamido- 2, 6-dichlorobenzyl -pyridyl 2-f luorophenyl 2-acetainido- 2, 6-dichlorobenzyl 4 -pyridyl 4-chiorophenyl 2-acetamido- 2, 6-dichlorobenzyl 4 -pyridyl 3-chiorophenyl 2-acetamido- 2, 6-dichlorobenzyl 4 -pyridyl 2-chiorophenyl 2-acetainido- 2, 6-dichlorobenzyl 4 -pyridyl 4-toilyl 2-acetamido- 2, 6-dichlborobenzyl -pyridyl 3-tolyl 2-acetainido- 2, 6-dichlorobenzyl 4 -pyridyl 2-tolyl 2-acetaiido- 2, 6-dichlorobenzyl 4 -pyridyl 4-trifluoro- 2-acetamido- 2, 6-dichlorobenzyl methylphenyl 4 -pyridyl 3 -trifluoro- 2-acetamido- 2, 6-dichlorobenzyl methylpheny 1 4-pyridyl 2,6-2-acetamido- 2, 6-dichlorobenzyl dichlorophenyl 4-pyridyl 2, 6-dimethyl 2-acetarnido- 2, 6-dichlorobenzyl phnl4-pyridyl 3,4- 2-acetanido 2, 6-dichlorobenzyl dichiorophenyl 4 -pyridyl 3, 4-dimethyl 2-acetamido- 2, 6-dichlorobenzyl phenyl- 4-pyridlyl WO 98/24780 WO 9824780PC'TIUS97/22949 2,14- 2-acetamido- 2, G-dichlorobenzyl dichiorophenyl _47_pyridyl [2,4-dimethyl 2-acetainido- 2 ,6-dichlorobenzyl phenyl 4-pyridyl Phenyl 2-ainro-4- 2, 6-dichlorobenzyl pyrimidinyl 4-f luorophenyl 2-ainino-4- 2, 6-dichlorobenzyl pyrimidinyl 3-f luorophenyl 2-amino-4- 2, 6-dichlorobenzyl pyrimidinyl 2-f luorophenyl 2-amino-4- 2, 6 -dichlorobenzyl pyrimidinyl 4-chiorophenyl 2-amino-4- 2, 6-dichlorobenzyl pyrimidinyl 3-chiorophenyl 2-axnino-4- 2, 6-dichlorobenzyl primidinyl 2-chlorophenyl 2-amino-4- 2, G-dichlorobenzyl pyrimidinyl 4-tolyl 2-amino-4- 2, 6-dichlorobenzyl 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 'nethylphenyl pyrimidinyl 3-trifluoro- 2-amino-4- 2, 6-dichlorobenzyl methylphenyl pyrimidinyl 2, 6- 2-amino-4- 2, 6-dichlorobenzyl dichiorop2henyl pyrimidinyl 2, 6-dimethyl 2-amino-4- 2, 6-dichlorobenzyl phenyl pyrirnidinyl 3,4- 2-axnino-4- 2,6-dichlorobenzyl dichlorophenyl pyrirnidinyl 3, 4-dimethyl 2-ainino-4- 2, 6-dichlorobenzyl phenyl pyriinidinyl 2,4- 2-amino-4- 2, 6-dichlorobenzyl dichlorophenyl pyrimidinyl 2, 4-dimethyl 2-amino-4- 2, 6-dichlorobenzyl phenyl pyrimidinyl Phenyl 4-pyridyl 2- (4-f luorophenyl) 4-f luorophenyl 4-pyridyl 2- (4-f luorophenyl) ethylamino 3-f luorophienyl 4-pyridyl 2- (4-f luorophenyl) ethylaino 2-f luorophenyl 4-pyridy. 2- 4 -fluorophenyl) ethylamino 4-chioropheny. 4-pyridyl 2- (4-f luorophenyl) _PYEethylainino 3-chiorophienyl 4-pyridyl 2- (4-f luorophenyl) ethylamino L -ciiioropnenyi 4 -Pyridyl 2- (4-f luorophenyl) eth ylamino I J.
WO 98/24780 WO 9824780PCTIUS97/22949 4-tolyl 4-pyridyl 2- (4-f luorophenyl) ethyl amino 3-tolyl 4-pyridyl 2- (4-f luorophenyl) ethylamino 2-tolyl 4-pyridyl 2- (4-f luorophenyl) ethyl amino 4-trifluoro- 4-pyridyl 2- (4-f luorophenyl) methylphenyl ethylamino 3-trifluoro- 4-pyridyl 2 (4 -f luorophe-nyl) methyiphenyl _______ethlylamino 2,6- 4-pyridyl 2- (4-f luorophenyl) dichlorophenyl ethylamino 2, 6-dimethyl 4-pyridyl 2- (4-fluorophenyl) phenyl amino 3,4- 4-pyridyl 2-(4-fluorophenyl) dichiorophenyl _______ethylamino 3, 4-dimethyl 4-pyridyl 2- 4 -fluorophenyl) phenyl ethyl amino 2,4- 4-pyridyl 2 (4 -f luorophenyl) dichlorophenyl amino 2, 4-dimethyl 4-pyridyl 2- (4-f luorophenyl) phenyl amino Phenyl 2-arnino-4- 2- (4-f luorophenyl) pyridyl eth lamino 4-f luorophenyl 2-amino-4- 2- (4-f luorophenyl) pyridyl ethylamino 3-f luorophenyl 2-amino-4- 2- (4-f luorophenyl) pyridyl ethylamino 2-f luorophenyl 2-ainino-4- 2- (4-f luorophenyl) pyridyl ethylamino 4-chiorophenyl 2-amino-4- 2- (4-f luorophenyl) pyridyl ethvlamino 3-chloropheny. 2-amino-4- 2- (4-f luorophenyl) pyridy1 ethylamino 2-chiorophenyl 2-amino-4- 2- (4-f luorophenyl) .py ridyl ethylamino 4-tolyl 2-amino-4- 2- (4-fluorophenyl) pyridyl ethylamino 3-tolyl 2-amino-4- 2- (4-fluorophenyl) ethylamino 2-tolyl 2-amino-4- 2 -(4-fluorophenyl) pyridyl ethylamino 4-trifluoro- 2-amino-4- 2 -(4-fluorophenyl) 'nethyiphenyl yridy1 ethylamino 3-trifluoro- 2-amino-4- 2 -(4-fluorophenyl) methylphenyl pyridy 1 ethylamino 2,6- 2-amino-4- 2 fluorophenyl) dichiorophenyl pyridy1 ethylamino 2, 6-dimethyl 2-amino-4- 2 (4 -f luorophenyl) _phenyl pyridy 1 ethylamino 3,4- 2-amino-4- 2 (4 -f luorophenyl) dichioropheny1 pyridyl ethylanino.
3, 4-diinethyl 2-amilno-4- 2 (4 -f luorophenyl) phenyl _pyridyl ethylamino WO 98/24780 WO 9824780PCTIUS97/22949 2,4- 2-amino-4- 2 -(4-fluorophenyl) di.chlorophenyl _pyridyl. ethylamino 2, 4-dimethyl 2-amino-4- 2- (4-f luorophenyl) phenyl pyridyl ethylamino Phenyl 2-acetamido- 2- (4-f luorophenyl) 4-2yridy1 ethylamino 4-f luorophenyl 2-acetamido- 2- (4-f luorophenyl) 4-pyridyl ethylamino 3-f luorophenyl 2-acetarnido- 2- (4-f luorophenyl) ethylanino 2-f luorophenyl 2-acetamido- 2- (4-f luorophenyl) -pyridyl ethyl amino 4-chiorophenyl 2-acetamido- 2- (4-f luorophenyl) -pyridyl ethylamino 3-chiorophenyl 2-acetamido- 2- (4-f luorophenyl) ethylamino 2-chiorophenyl 2-acetamido- 2- (4-f luorophenyl) 4 -pyridyl ethylamino 4-tolyl 2-acetarnido- 2- (4-f luorophenyl) ethylanino 3-tolyl 2-acetamido- 2- (4-f luorophenyl) 4-_pyridyl ethylamino 2-tolyl 2-acetamido- 2- (4-f luorophenyl) -pyridyl ethylamino 4-trifluoro- 2-acetarnido- 2- (4-f luorophenyl) methylphenyl 4-pyridyl ethylamino 3-trifluoro- 2-acetamido- 2- (4-f luorophenyl) methylphenyl 4-pyridyl ethylamino 2,6- 2-acetamido- 2- (4-f luorophenyl) dichlorophenyl 4-pyridyl ethylamino 2, 6-dimethyl 2-acetami-do- (4-f luorophenyl) _phenyl 4-pyridyl ethylamino 3,4- 2-acetamido- 2 -(4-fluorophenyl) dichiorophenyl 4-pyridyl ethylamino 3, 4-dimethyl 2-acetainido- 2- (4-f luorophenyl) phenyl 4-pyridyl -ethylamino 2,4- 2-acetarnido- 2- (4-fluorophenyl) dichiorophenyl 4 -pyridyl ethylamino 2, 4-dimethyl 2-acetarnido- 2- (4-f luorophenyl) phenyl .4-pyridyl ethylamino Phenyl 2-axnino-4- 2- (4-f luorophenyl) pyrimidinyl ethylamino 4-f luoropheny. 2-amino-4- 2- (4-f luorophenyl) pyrimidinyl ethylamino 3-f luorophenyl 2-amino--- 2- (4-f luorophenyl) pyrimidinyl ethylamino 2-f luorophenyl 2-amino-4- 2- (4-f luorophenyl) pyriinidinyl ethylamino 4-chlorophenyl 2-amino-4- 2- (4-f luorophenyl) pyrimidinyl ethylainino 3-chlorophenyl 2-amino-4- 2- (4-f luorophenyl) lpyrimidinyl e~th-yl ani no 2-chlorophenyl 2-amino4 2- (4-fluorophenyl) pyrimidinyl ethylainino WO 98/24780 WO 9824780PCTIUS97/22949 4-tolyl 2-arnino-4- 2- (4-fluorophenyl) pyrimidinyl ethylainino 3-tolyl 2-amino-4- 2- (4-fluorophenyl) p rilnidiny1 ethylamino 2-tolyl 2-amino-4- 2- (4-fluorophenyl) pyrirnidinyl ethylamino 4-trifluoro- 2-amino-4- 2- (4-f luorophenyl) 'nethylphenyl pyrimidinyl ethylaxnino 3-trifluoro- 2-arnino-4- 2- (4-fluorophenyl) methyiphenyl_ pyrimidinyl ethylamino 2,6- 2-amino-4- 2 -(4-fluorophenyl) dichiorophenyl pyrimidinyl ethylamino 2, 6-dimethyl 2-amino-4- 2- (4-fluorophenyl) phenyl pyrimidinyl ethylamino 3,4- 2-amino-4- 2 -(4-fluorophenyl) dichiorophenyl pyrimidinyl ethylamino 3, 4-dimethyl 2-amino-4- 2- (4-fluorophenyl) phenyl _pyrimidinyl ethylaiino 2,4- 2-amino-4- 2 fluorophenyl) dichiorophenyl pyrimidinyl ethylamino 2,4-dimethyl 2-amino-4- 2- (4-fluorophenyl) _phenyl pyriinidinyl -ethylamino Phenyl 4-pyridyl 3 -phenyl -propylamino 4-f luorophenyl 4-pyridyl 3 -phenyl-propylamino 3-f luorophenyl 4 -pyr idyl- -3 -phenyl-7propyl amino 2-f luorophenyl 4-pyridyl 3 -phenyl-propylamino 4-chlorophenyl .4-pyridyl 3 -phenyl-propylamino 3 -chiorophenyl 4 -pyridyl 3 -phenyl:-propyl amino 2-chlorophenyl -4-pyridyl 3 -phenyl-propylamino 4-tolyl 4-pyridyl 3 phenyl -propylamino 3-toly. 4-pyridyl 3 -phenyl-propylamino 2-tolyl 4-pyridyl -3-pheny1-propylamino 4-trifluoro- 4-pyridyl 3 -phenyl-propylamino methylphenyl 3 -trifluoro- 4-pyridyl 3 -phenyl-propylamino me thylphenyl 2,6-rohey 4-pyridyl 3 -phenyl-propylamino 2, 6-dimethyl 4-pyridy. 3 -phenyl-propylamino phenyl_______ di3,4- hey 4-pyridyl 3 -phenyl-propylamino 3, 4-dirnethyl 4-pyridyl 3 -phenyl-propylamino phenyl d2,4- ohey 4-pyridyl 3 -phenyl-propylamino 2, 4-dimethyl 4-pyridyl 3 -phenyl-propylamino Phenyl 2-amino-4- 3 -phlenyl -propylamino yridy1_ 4-f luorophenyl 2 -amino-4- 3 -phenyl-propylamino _pyridyl L±UL.JLphenLy z-amino-4- .3 -phenYI -propylamino pyridyl WO 98/24780 PCT/US97/22949 2-f luorophenyl 2 -amino-4 pyridyi 4 -chlorophenyl 2 -amino-4pyridyl 3 -chlorophenyl
-I
3-phenyl -propylamino 3 -phenyl -propyl amino 3 -phenyl-propylanino 3 -phenyl-propylamino 2 -arnino-4-7 pyridyl 2 -chiorophenyl 2-amijno-4- 4-tolyl 2 -amino-4- 3 -phenyl -propyl amino pyridyl 3 -tolyl 2 -amino-4- 3 -pheny.-propylarnino 2 -tolyl 2 -arnino-4- 3 -phenyl--propylamino 4-trifluoro- 2-amino-4- 3 -phenyl-propylamino methyiphenyl _pyridyl___ 3-trifluoro- 2-amino-4- 3 -phenyl-propylamino methyiphenyl 2,6- 2-aniino-4- 3 -phenyl-propylamino dichlorophenyl _pyridyl 2, 6-dimethyl 2-amino-4- 3 -phenyl-propylamino phenyl pyridy 3,4- 2-amino-4- 3 -phenyl-propylamino dichlorophenyl pyridlyl 3, 4-dimethyl 2-amino-4- 3 -phenyl-propylamino phenyl pyridyl 2, 4- 2-amino-4- 3 -phenyl-propylanino dichiorophenyl pridyl 2, 4-dimethyl ;-amino-4- 3 -phenyl-propylamino phenyl pyridyl Phenyl 2-acetamido- 3 -phenyl-propylamino 4 -pyridyl 4-f luorophenyl 2-acetamido- 3 -phenyl-propylamino 4 -pyridyl 3- fluorophenyl 2 -acetamido- 3 -phenyl-propylamino 4 -pyridyl 2-f luorophenyl 2 -acetamido- 3 -phenyl-propylamino 4 -pyridyl 4 -chiorophenyl 2 -acetamido- 3 -phenyl-propylamino 4 -pyridyl 3 -chiorophenyl 2 -acetamido- 3 -phenyl-propylanino 4 -pyrridyl 2 -chiorophenyl 2 -acetamido- 3 -phenyJ.-propylamino 4 -pyridyl 4-tolyl 2-acetamido- 3 -phenyl-propylamino 4- pridil 3-tolyl 2 -acetamido- 3 -phenyl-propylamino 4 -pyridyl 2 -tolyl 2 -acetamido- 3 -phenyl-propylamino 4 -pyridyl 4-trifluoro- 2 -acetamido- 3 -phenyl-propylamino meth 1 heny 1 i.Zpyridvl 3-trifluoro- 2 -acetamido- 3 -phenyl--propylamino niethyiphenyl 4-p ridy 1 WO 98/24780 WO 9824780PCTIUS97/22949 2,6dichlorop~henyl
I
2 -acetamido- 3 -phenyl-propylamino 2, 6-dimethyl 2-acetamido- 3 -phenyl-propylamino phenyl 4-pyridyl 3,4- 2-acetamido- 3 -phenyl-propylamino dichiorophenyl 4 -pyridyl 3, 4-dimethyl 2-acetamido- 3 -phenyl-propylamino phenyl 4-pyridyl 2,-2 -acetanido- 3 -phenyl-propylamino dichiorophenyl 4-pyridyl 2, 4-dimethyl 2-acetamido- 3 -pheriyl-propylarnino phenyl4 -pyridyl Phnl2 -axnino-4- 3 -phenyl-propylamino pyrimidinyl 4-f luorophenyl 2 -amino-4- 3 -phenyl-propylamino pyrimidinyl 3-f luorophenyl 2 -amino- 4- 3 -phenyl -propylarnino pyrirnidinyl 2 -fluorophenyl 2 -amino-4- 3 -phenyl-propylamino pyrimidinyl 4 -chiorophenyl 2 -amino-4 3 -phenyl-propylamino pyrirnidiny. 3 -chiorophenyl 2 -amino-4 3 -phenyl-propylamino pyr imidinyl 2 -chiorophenyl 2 -amino-4- 3 -phenyl-propyilamino pyrimidinyl 4-tolyl 2-amino-4- 3 -phenyl-propylanino pyrimidinyl 3 -tolyl 2 -amino-4 3 -phenyl-propylamino pyrimidinyl 2 -tolyl 2 -amino-4 3 -phenyl-propylamino pyrimidinyl 4-trifluoro- 2-amino-4- 3 -phenyl-propyvlamino methylphenyl pyrimidinyl 3-trifluoro- 2-amino-4- 3 -phenyl-propylamino methylphenyl pyrimidinyl 2,6- 2-amino-4- 3 -phenyl-propylamino dichlorophenyl pyrimidinyl 2, 6-dimethy. 2-amino-4- 3 -phenyl-propylamino phenyl pyrimidinyl 3,4- 2-amino-4- 3 -phenyl-propylamino dichiorophenyl pyrimidinyl 3, 4-dimethyl 2-axnino-4- 3 -phenyl-propylanino phenyl pyrirnidinyl 2,4- 2-amino-4- 3 -phenyl-propylanino dichlorophenyl pyrirnidinyl 2, 4-dimethyl 2-amino-4- 3 -phenyl-propylamino phenyl pyrimidinyl Phenyl 4-pyridyl (1-methyl-3phenyl ropylarnino 4-f luorophenyl 4-pyridyl (1-methyl-3phenyl ropylamino 3 -fluorophenyl 4-pyridyl (1-methyl-3 phIy rpy ino WO 98/24780 WO 9824780PCTIUS97/22949 2-f luorophenyl 4-pyridyl (1-methyl-3phenyl )propyl amino 4-chlorophenyl 4-pyridyl (1-methyl-3phenyl) propyl amino 3-chiorophenyl 4-pyridyl (1-methyl-3pheriyl) propyl amino 2-chiorophenyl 4-pyridyl (1-methyl-3- 4-tlyl4-yriyl 1-eyl-3-plain 3-tolyl 4-pyridy. (1-methyl-3- 2-tolyl 4-pyridyl (-ehl3 _phenyl propyl amino 4-triluoro 4-pyridyl (1-methyl-3methyihenylLphenyl )propylamino 3-trifluoro- 4-pyridyl (1-methyl-3methyiphenyl _phenyl) propylamino 2,-iloo 4-pyridyl (1-methyl-3dichyorphenyl -phenyl) propylamino 2, 6-dety 4-pyridyl (1-methyl-3pihn ohey 1 phenyl) propylamino 3,4-dmty 4-pyridyl (1-methyl-3dihiorphny phenyl)_propylamino 3, 4-dety 4-pyridyl (1-methyl-3dichlrophnyl phenyl) propylamino 3,4-imehyl 4-pyridyl (1-methyl-3dcorphenyl p lhenyl) propylamino 2, 4-dint 4-pyridyl (1-methyl-3diclorpheylphenyl )propylaniino 2,4-imetyl -amidy-4 (1-methyl-3- 1yiy phenyl) propylarnino 4-fnlrpey 2-amino-4- (1-methyl-3lphenyl) propylamino 3-f luorophenyl 2-amino-4- (1-methyl-3pyridyl phenyl) propylamino 2-f luorophenyl 2-ainino-4- (1-methyl-3pyridyl phenyl) propylamino 2-chiorophenyl 2-amino-4- (1-methyl-3pyridyl _phenyl) propylamino 3-chiorophenyl 2-amino-4- (1-methyl-3pyridyl .phenyl) propylamino 2 -chlorophenyl 2-amino-4- (1-methyl-3pyridyl henyl)propylamino.
4-thoro l 2-amino-4- (1-methyl-3pyridyl phenyl) propylamino 3-tolyl 2-amino-4- (1-methyl-3pyridyl phenyl) propylamino 2-tolyl 2-amino-4- (1-mnethyl-3pyridyl _phenyl) propylamino 4-triluoro 2-amino-4- (1-methyl-3metyipeny pridyl phenayl) propylamino 3-trifluoro- 2-amino-4- (1-methyl-3methyiphenyl pyridyl -phenyl) propylamino WO 98/24780 WO 9824780PCT/US97/22949 2,6- 2 -amino-4- (1-methyl-3-.
dichlorophenyl _pyridyl phenyl )pr02ylamiino 2, 6-dimethyl 2-amino-4- (1-methyl-3phenyl pyridyl phenlyl)propylanino 3,4- 2-amino-4- -(1-methyl-3dichlorophenyl pyridyl phenyl)propylamino 3, 4-dimethyl 2-axnino-4- (1-rnethyl-3phenyl pyridyl phenyl)propylamino 2,4- 2-arnino-4- (1-rnethyl-3dichlorophenyl pridy1 phenyl)propylamino 2, 4-dimethyl 2-amino-4- (1-methyl-3phenyl pyridyl phenyl)propylamino Phenyl 2-acetarnido- (1-methyl-3- -pyridyl phenyl )propylamino 4-f luorophenyl 2-acetamido- (1-methyl-3- -pyridyl _phenyl) prKopylamino 3-f luorophenyl 2-acetainido- (1-methyl-3- -pyridlyl phnl) propylamino 2-f luorophenyl 2-acetarnido- (1-methyl-3- 4 -pyridyl phenyl) propylarnino 4-chiorophienyl 2-acetainido- (1-methyl-3- -pyridyl phenyl) propylamino 3-chiorophenyl 2-acetarnido- (1-rnethyl-3- -pyridyl phenyl) propylainino 2-chiorophenyl 2-acetainido- (1-methyl-3- -pyridyl phenyl) propylamino 4-tolyl 2-acetamido- (1-methyl-3- -pyridyl phenyl)_propylainino 3-tolyl 2-acetamido- (1-methyl-3phenyl)propylamino 2 -tolyl 2-acetamido- (1-methyl-3- -pyridyl phenyl) propylamino 4-trifluoro- 2-acetamido- (1-methyl-3methylpheny. 4 -pyridyl phenyl) propylamino 3 -trifluoro- 2 -acetarnido- (1-methyl-3 rnethylpheiyl. 4 -pyridyl phenyl) propylamino 2,6- 2-acetamido- (1-methyl-3dichiorophenyl 4 -pyridyl phenyl) propylamino 2, 6-dimethyl 2-acetarnido- (1-methyl-3phenyl 4 -pyridy. phenyl) propylamino 3,4- 2-acet'aiido- (1-methyl-3dichlorophenyl 4-pyridyl phenyl) prop2ylamino- 3, 4-dimethyl 2-acetamido- (1-rnethyl-3phenyl 4 -pyridyl _phenyl) propylamino 2,4- 2-acetamido- (1-methyl-3dichiorophenyl 4-7pyridyl phenyl )propyitamino 2, 4-dimethyl 2 -acetamido- (1-methyl-3phenyl 4 -pyridyI phenyl) propylamino Phenyl 2-arnino-4- (1-methyl-3- Pyrimidinyl phenyl) propylamino 4-f luorophenyl 2-arnino-4- (1-rnethyl-3pyrimidiqyl _phenyl )propylamino 3-f luorophenyl 2-amino-4- (1-rnethyl-3pyrimidinyl lphenyl) propylamino WO 98/24780 WO 9824780PCT/US97/22949 2-f luorophenyl 2-amino-4- (1-methyl-3pyrimidinyl phenyl)propylamino 4-chiorophenyl 2-amino-4- (1-methyl-3phenyl )propylarnino 3-chiorophenyl 2-amino-4- (1-methyl-3phenyl )propylamino 2-chlorophenyl 2-amino-4- (1-methyl-3pyrimidinyl phenyl )propylamino 4-tolyl 2-axnino-4- (1-methyl-3phenyl )propylarnino 3-tolyl 2-amino-4- (1-methyl-3pyrimidinyl phenyl )propylamino 2-tolyl 2-amino-4- (1-methyl-3pyrimidinyl phenyl )propylamino 4-trifluoro- 2-amino-4- (1-methyl-3methylphenyl pyrimidinyl phenyl propylamino 3-trifluoro- 2-amino-4- (1-methyl-3methylphenyl pyrimidinyl phenyl )propylamino 2,6- 2-amino-4- (1-methyl-3dichiorophenyl pyrimidinyl phenyl )propylamino 2, 6-dimethyl 2-amino-4- (1-methyl-3phenyl pyrimidinyl phenyl )propyvlamino 3,4- 2-amino-4- (l-methyl-3dichlorophenyl pyrimidinyl pheny1)propylamino 3, 4-dimethyl 2-amino-4- (1-methyl-3phenyl pyrimidinyl -phenyl) propylarnino 2,4- 2-amino-4- (l-methyl-3dichiorophenyl pyrimidinyl _phenyl) propyl amino 2, 4-dimethyl 2-amino-4- (l-methyl-3phenyl _pyrimidinyl phenyl) propylamino 4- fluorophenyl 4 -pyridyl 4 f luorobenzyl amino 4- fluorophenyl 2 -acetamido- 4 f luorobenzyl amino 4 -pyridyl 4-f luorophenyl 2-amino-4- 4 -f luorobenzyl amino pyrimidinyl 4-f luorophenyl 4-pyridylnyl (4-f luorophenyl) -1methyl-ethyl) amino 4-f luorophenyl 2-acetamido- (4-f luorophenyl) -1- 4-pyridyl methyl-ethyl) amino 4 -fluorophenyl 2-amino-4- (2-(4-fluorophenyl)-lpyrimidinyl methyl-ethyl) amino 4-f luorophenyl 4-pyridyl 1-dimethyl-2- (4fluorophenyl) -ethyl) amino 4 -fluorophenyl 2-acetamido- (l,l-dimethyl--2-(4- 4-pyridy. fluorophenyl) -ethyl) amino 4 -fluorophenyl 2-amino-4- (1,l-dimethyl-2-(4fluorophenyl) -ethyl)amino 4-f luorophenyl 4-p-ridyl (4-f luorophenyl) -2methyl -ethylamino 4 -fluorophenyl 2-acetamido- (4-f luorophenyl) -2methyl-ethyl) amino 4 -fluorophenyl 2-amino-4- (2-(4-fluorophenyl) -2rimiin 1 methl-ethyl)amino WO 98/24780 WO 9824780PCT/US97/22949 4-f luorophenyl 4-pyridyl (2-rnethyl-2 phenylethyl) amino 4-f luorophenyl 2-acetamido- (2-methyl-2- 4-pyridyl phenylethyl) amino 4-f luorophenyl 2-amino-4- (2-rnethiyl-2pjyrimidinyl phenylethyl) amino 4-f luorophenyl 4-pyridyl methyl-'(2phenylethyl)amino 4-f luorophenyl 2-acetamido- methyl- (2- 4-pyridyl phenylethyl) amino 4-f luorophenyl 2-amino-4- methyl- (2pyrimidinyl phenylethyl) amino 4-f luorop-henyl 4-pyridyl 4 -trifluoromethyl phenyl) ethyl) amino 4-f luorophenyl 2-acetamido- 4 -trifluoromethyl -pyridyl _phenyl) ethyl) amino 4-f luorophenyl 2-amino-4- 4 -trifluoromethyl pyrimidinyl phenyl) ethyl) amino 4-f luorophenyl 4-pyridyl_ 2- (4-tolyl) ethylamino 4 fluorophenyl 2-acetamido- 2- (4-tolyl) ethylamino 4 -pyridyl 4-f luorophenyl 2-amino-4- 2- (4-tolyl) ethylamino pyrimidinyl 4-f luorophenyl 4-pyridyl (3-f luorophenyl) ethyl) amino 4-f luorop-henyl 2-acetamido- (3-f luorophenyl) 4-pyridyl ethyl) amino 4-f luorophenyl 2-amino-4- (3-f luorophenyl) pyrimidinyl ethyl) amino 4-f luorophenyl 4-pyridyl (2-f luorophenyl) ethyl) amino 4-f luorophenyl 2-acetamido- (2-f luorophenyl) ethyl) amino 4-f luorophenyl 2-amino-4- (2-f luorophenyl) pyrimidinyl ethyl) amino 4-f luorophenyl 4-pyridyl methyl- (2pyridyl) ethyl) amino 4-f luorophenyl 2-acetainido- methyl- C2-(2- -pyridyl pyridyl) ethyl) amino 4-f luorophenyl 2-amino-4- methyl- (2pyrimidinyl _pyridyl) ethyl) amino 4-f luorophenyl 4-pyridyl l-dimethyl-3-phenyl- Spropyl) amino 4 -fluorophenyl 2-acetamido- l-dimethyl-3-phenyl- 4-pyridyl _propyl) amino 4-f luorophenyl 2-amino-4- l-dimethyl-3-phenylprimidinyl propyl) amino 4-f luorophenyl 4-pyridyl 4 -fluorophenyl) propyl) amino 4-f luorophenyl 2-acetamido- 4 -fluorophenyl) 4-pyridyl propyl) amino 4-f luorophenyl 2-amino-4- 4 -fluorophenyl) I pyrimidinyl_ propyl) amino WO 98/24780 2TS7I94 PCTIUS97/22949 4-f luorophenyl 4-pyridyl (4-f luorophenyl) -1- 4-f luropheyl 2-aetamio- (3 uropheamno 1 4-f luorophenyl 2-acmino-- (4-f luorophenyl) -1- 4-f luorophenyl 4-pyidyl4 1-dimthyl-3- 4-f luor pyrmidnyl mphnyl)-propyl) amino 4-f luorophenyl 2-acetido- 1-dimethyl-3- (4-f luoro 4-pyridyl phenyl) -propyl) amino 4-fluorophenyl 2-acmino-- 1-dimethyl-3-(4-fluoro 4pyriidyl phenyl) -propyl) amino 4-f luorophenyl 4-pyidyl 3 ((21-f uorheny-4-l) o pyr iinl pel)propyl amino 4-f luorophenyl 2-acetido- (2-f luorophenyl) 4-py idylpropyl )amino 4-filuorophenyl 2-acmino-4 3 -(2-fluorophenyl)propyl )amino 4-f luorophenyl 4-pyidyl4 3 -(2ethlo3-phenyl)p rimdinyl propyl)amino 4-f luorophenyl 2-acetido- 3 -methyl-3-phenyl- 4-pyridyl propyl )amino 4-f luorophenyl 2-acmino-- (3-methyl-3-phenyl- 4pyriidiyl _propyl )amino 4-f luorophenyl 4-pyidyl4 (2-methyl-3-phenylp rmidnyl propyl )amino 4-f luorophenyl 2-acetido- (2-methyl-3-phenyl- 4pyrdyl propyl)_amino 4-f luorophenyl 2-acmino-- (2-methyl-3-phenyl- 4pyriidyl propyl)amino 4-f luoropheny1 4-pyridyl_ 3-dimethylbutyl) amino 4-f luorophenyl 2-acetamido- 3-dimethylbutyl) 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 Lpyrimidinyl 4-f luorophenyl 4-pyridyl amvlamino 4- fluorophenyl 2 -acetamido- amylainino 4 -pyridyl 4-f luorophenyl 2-amino-4- amylarnino .pyrimidinyl 4-f luorophenyl 4-pyridy. 4-f luorophenyl 2-acetamido- 5-dimethyl )pentylamino 4-f luorophenyl 2-amino-4- 4-f luorophenyl 4-pyridv1 piperaziny1 4-f luorophenyl 2 -acetamido- piperazinyl 4 -pyridl WO 98/24780 WO 9824780PCTIUS97/22949 4- fluorophenyl 2 -amino-4 piperazinyl iridinyl 4-f luorophenyl 4-pyridyl (3-f luorophenyl) propyl )amino 4-f luorophenyl 2-acetamido- (3-f luorophenyl) propyl )amino 4-f luorophenyl 2-axnino-4- (3-f luorophenyl) pyrimidinyl _prgpyl)amino benzyl 4 -pyridyl 3 -phenyipropylamino benzyl 4-pyridyl 2- (4-f luorophenyl) ethylamino 2-thienyl 4-pyridyl 3 -phenyipropylamino 2-thieny. 4-pyridyl 2- (4-f luorophenyl) eth larnino cyclohexyl 4-pyridyl 3 -phenyipropylamino cyclohexyl 4-pyridyl 2- (4-f luorophenyl) ethylamino tert-butyl 4-pyridy1 3 -phenylpropylamino tert-butyl 4-pyridyl 2- (4-f luorophenyl) thylamino 4-f luorophenyl 4- 3 -phenyipropylamino idinyl 4-f luorophenyl 4- 2- (4-f luorophenyl) pip'eridinyl ethylanino 4-f luorophenyl 4 -yranyl 3 -phenylpropylamino 4-f luorophenyl 4-pyranyl 2- (4-f luorophenyl) ethylanino Phenyl 4-pyridyl 3 -phenyl-2 -aminopropylamino 4-f luorophenyl 4-pyridyl 3 -phenyl-2 -aminopropylamino 3-f luorophenyl 4 -pyridyl 3 -phenyl -2 -aminopropylamino 2-f luorophenyl 4-pyridyl 3-phenyl-2-aminopropylamino 4-chiorophenyl 4-pyridyl 3 -phenyl-2-aminopropylamino 3 -chiorophenyl 4-pyridyl 3 -phenyl-2 -aminopropylamino 2 -chlorophenyl 4-pyridyl 3 -phenyl-2 -aminopropylamino 4-tolyl 4-pyridyl 3-phenyl-2-aminopropylamino 3 -tolyl 4-pyridyl 3 -phenyl-2-aminopropylainino 2-tolyl 4-pyridyl 3-phenyl-2-amino- 4 -trifluoro- 4-pyridyl 3-phenyl-2-aminomethylphenyl -nI;io 3-trifluoro- 4 -pyridyl 3-phenyl-2-aminomethiyphny propylamino 2,6- 4 -Pyridyl 3-phenyl-2-aminodichiorophenyl rplamino WO 98/24780 WO 9824780PCTIUS97/22949 2, 6-dimethyl 4-pyridy. 3 -phenyl-2-anino- 3,-4-pyridyl 3 -phenyl-2 -aminodichiorophen 1 _______poylamino 3, 4- i e h l4 p r d l2p eyl -2-a ino 3,-dmthl 4 -pyridyl 3 -phenyl-2 -aminodihooheny_______ propylamino 2, 4-din y 4-pyridyl 3 -phenyl-2-aminodcrphenyl_____ propyl amino Phenyl thy 4-pyridyl 3 -phenyl-3-aminophenylpropyl amino 4-fnlrpey 4-pyridyl 3 -phenyl-3-anino- 3-f lorophnyl -pyriyl 3 pey1-amino n 2-f luorophenyl 4-pyridyl 3 -phenyl-3-aninopropylamino 3 -chiorophenyl 4 -pyridyl 3 -phenyl-3 -aminopropyl amino 2-chiorophenyl 4-pyridyl 3 -phenyl-3-aminopropyl amino 4-thoro l 4-pyridyl 3 -phenyl-3-aninopropy amino 3-thoy pnl 4-pyridyl 3 -phenyl-3-aminopropylamino 2-thoro l 4-pyridy 3-phenyl-3 -aminopropy amino 4-triluoro 4-pyridyl 3-phenyl-3-aminomethyihenylpropy amino 3-triluoro 4-pyridyl 3 -phenyl-3-aminomethyiphenylpropylanino 2-oy 4-pyridyl 3-phenyl-3-aminodi r~ chamohino________ 2, -imethyl 4-pyridyl 3-phenyl-3-aminomyphenyl rplmn 3-iloo 4-pyridyl 3 -phenyl-3-amlinodichiorphenyl ropylamino 3,64-dety 4-pyridyl 3 -phenyl-3 -aminodcrphenyl_____ propylamino 2,46-dint 4-pyridy. 3 -phenyl-3-aminodih propylamino 2, 4-dinty 4-pyridy. 3 -phenyl-3-aminophenyl ___propylamino and WO 98/24780 WO 9824780PCT/US97/22949 R11 CH-CH-a
R
12 N R1 wherein R" 1
R'
2 and R' are one of the combinations given in the following table: 4-f luorophenyl 4-pyridyl (4-f luorophenyl) ethyl) amino 4-f luorophenyl 2-acetamido- (4-f luorophenyl) 4-pyridyl ethyl) amino 4-f luorophenyl 2-amino-4- (4-f luorophenyl) pyrimidinyl ethyl) amino 4-f luorophenyl 4-pyridyl (3 -phenyipropyl) amino 4-f luorophenyl 2-acetamido- (3-phenylpropyl) amino -pyridyl 4-f luorophenyl 2-amino-4- (3-phenyipropyl) amino pyrimidinyl 4-f luorophenyl 4-pyridyl -2-amino-3phenyipropylamino 4-f luorophenyl 2-acetamido- -2-amino-3- -pyridyl phenylpropylamino 4-f luorophenyl 2-amino-4- -2-amino-3pyrimidinyl _phenyipropylamino 4-f luorophenyl 4-pyridyl 3 -axnino-3 phenyipropylamino 4-f luorophenyl 2-acetamido- 3-ainino-3- 4 -pyridyl phenylpropylamino 4-f luorophenyl 2-amino-4- 3 -amino-3- _pyrimidinyl phenylpropylamino 4-f luorophenyl 4-pyridyl 3-amino-2-methyl-3phenylpropylamino, 4-f luorophenyl 2-acetamido- 3 -amino-2-methyl-3 4-pyridyl pheny propylamino 4-f luorophenyl 2-amino-4- 3-amino-2-methyl-3pyrimidinyl phenyipropyl amino 7 4-f luorophenyl 4-pyridyl -tetrahydroisoquinol- 4-f luorophenyl 2-acetamido- -tetrahydroisoquinol- 4-pyridyl 3 -ylmethylenamino 4-f luorophenyl 2-amino-4- -tetrahydroisoquinolpyrimidinyl 3 -yimethylenarnino 4-f luorophenyl _±-pyridyl -3 -benzylpiperazinyl 4-f luorophenyl 2 -acetamido- -3 -benzylpiperazinyl 4 -pyridyl_ 4-f luorophenyl 2 -amino-4- -3 -benzylpiperazinyl pyriLmidinyl and WO 98/24780 PCT/US97/22949 ,oCH 3 in which R 2 is H, methyl or benzyl, and R1 2 and R' are one of the table: combinations given in the following R 111R2 0 t. 4 IX en~ry-± 4 -,pyr i 9xTl hmn I t r-t 4- uoronenvI 4-rnri erl1, 'kan I- H4 Phenyl 2 -acetarnidopyridvi 4-f luorophenyl 2 -acetamido- T. J=1 k'nenv±phenyl phenyl 4 -ethlylphenyl 4 -ethylphenyl 4 -ethyiphenyl 4 -ethyiphenyl 4- r'vi t-h,1 4-ftluorophenvi 4-nvricivi 4 -ovridI PhenylI 2 -acetamidopyridyl 4- fluorophenyl ~1 I1 2 -acetarnidopyrid~ Phenyl 4-pyridyl 2 4 -dimethylphenyl 4-f luorophenyl 4-pyridyl 2 ,4-dimethylphenyl Phen~yl 2-acetamido- 2 ,4-dimethyiphenyl pyridyl 4-f luorophenyl 2-acetamido- 2, 4-dimethyiphenyl pyridyl Phenyl 4-pyridyl 2, -dichlorobenzyl 4 -fluorophenyl 4-pyridyl 2, 6-dichlorobenzyl Phenyl 2-acetainido- 2, 6-dichlorobenzyl pyr idyl 4 -fluorophenyl 2-acetamido- 2, 6-dichlorobenzyl pyridyl Phenyl 4-pyridyl 2 -(4-fluorophenyl) ethyl amino 4 -fluorophenyl 4 -pyridy 2- (4-f luorophenyl) -ethyl amino Phenyl 2 -acetamido- 2- (4-f luorophenyl) pyridyl ethvlamino 4 -fluorophenyl 2 -acetamido- 2- (4-f luorophenyl) p2yridyl ethylamino Phenyl 4 -pyridyl 3 -phenyipropylamnino 4 -fluorop~henyl 4 7pyridyl -3 -phenylpropylamino Phenyl 2 -acetarnido- 3 -phenyipropylarnino ri1dyl 4 -fluorophenyl 2 -acetarnido- 3 -phenyipropylamino pyridylI Phenyl 4-pyridj. __1-piprazinyl A~ 41 UL(JILi~ 1 4 -0V av i eraL WO 98/24780 WO 9824780PCTIUS97/22949 PhenylI 2 -acetamidopyridyl 4-f luorophenyl ~1 i.
2 -acetamidopyridyl T
I
.oenzvl.
4 -nvri i 1 -piperaz inyl 1 -piperaz inyl 3 -phenyipropyvlamino 2- (4-f luorophenyl) ethyl amino 3 -phenyipropylamino 2- (4-f luorophenyl) Joenzyl 4 -pyridyl 4 -tflienyl 4-iovridvl 4 -pvridvl z -tnienyl 4-pyridy.
cyc lohexyl 4-pyridyl 3-pheny1 ro yvlaiino cyclohexyl 4-pyridyl 2- 4 -fluorophenyl) tert-butyl 4-pyridyl 3 -phenyipropylamino tert-butyl 4-pyridyl 2- (4-f luorophenyl) 4- fluorophenyl 4- 3 -phenyipropylamino piperidinyl 4-f luorophenyl 4- 2- (4-f luorophenyl) piperidinyl ethylamino 4-f luorophenyl 4 -pyranyl 3 -phenyipropylamino 4-f luorophenyl 4-pyranyl 2- (4-f luorophenyl) ethylamino Phenyl 4-pyridyl (S)-2-amino-3phenylpropylamino 4-f luorophenyl 4-pyridyl -2-amino-3 ropylamino Phenyl 2-acetamido- (S)-2-amino-3- -phenylpropylainino 4-f luorophenyl 2-acetamido- CS) -2-amino-3phenyipropylamino Phenyl 4-pyridyl 3-amino-3- _phenylpropyl amino 4-f luorophenyl 4-pyridyl 3 -amino-3phenylpropylamino Phenyl 2-acetarnido- 3-amino-3pyridyl phenylpropylamino 4-f luorophenyl 2-acetamido- 3 -amino-3pyridyl phenylpropylanino Phenyl 4-pyridyl 3 -amino-2-methyl-3phenylpropyjlamino 4 -fluorophenyl 4-pyridyl 3 -amino-2-methyl-3phenyipropylamino Phenyl 2-acetamido- 3 -amino-2-methyl-3pyridyl _phenylpropylamino 4 -fluorophenyl 2-acetamido- 3 -alino-2-methyl-3pyridyl phenylpropyl amino Phenyl 4-pyridyl -tetrahydroisoquinol- -ylmethylenamino 7 4 -fluorophenyl 4-pyridyl CS) -tetrahydroisoquinol- -ylmethylenamino ent~y l 2-acetamido- Ipridyl
I
-tetrahydroisoquinol- 3 -ylmethylenamino WO 98/24780 PCT/US97/22949 4-fluorophenyl 2-acetamido- (S)-tetrahydroisoquinolpyridyl 3-ylmethylenamino Phenyl 4-pyridyl 3 -benzylpiperazinyl 4-fluorophenyl 4-pyridyl S)-3-benzylpiperazinyl Phenyl 2-acetamido-
S)-
3 -benzylpiperazinyl pyridyl 4-fluorophenyl 2-acetamido- S)-3-benzylpiperazinyl __pyridyl Additional preferred compounds are listed in the Examples, infra.
As utilized herein, the following terms shall have the following meanings: "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 (Ci-C 4 still more preferably 1-3 carbon atoms (CI-C 3 and most preferably 1-2 carbon atoms (C 1
-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 WO 98/24780 PCT/US97/22949 72 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.
"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.
WO 98/24780 WO 9824780PCT/US97/22949 73 "Alkylsulfinyl", alone or in combination, means a radical of the type "R-S(O)-ft 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 "IS(O) 1 is a di-oxygenated 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, meanis 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, amido, amidino, a lkoxycarbonyl amino, Nalkylamidino, 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-aminophenyl, 6methyl-2, 3-diaminophenyl, 2 -amino- 3-methylphenyl, 4,6dime thyl -2 -aminophenyl, 4-hydroxyphenyl, 3-methyl-4hydroxyphenyl, 4- (2 -methoxyphenyl) phenyl, 2-amino-inaphthyl, 2-naphthyl, 3 -amino- 2-naphthyl, 1-methyl-3- WO 98/24780 PCT/US97/22949 74 amino-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.
"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 WO 98/24780 PCT/US97/22949 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.
"Benzo", alone or in combination, means the divalent radical C6H 4 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 -CI0), 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, WO 98/24780 PCT/US97/22949 76 dimethoxytetrahydronaphthyl, 2,3-dihydro-1H-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.
"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 WO 98/24780 PCT/US97/22949 77 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-loxo-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 WO 98/24780 PCT/US97/22949 78 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 haloalkyl radicals include l,1,1-trifluoroethyl, chloromethyl, 1-bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, bis(trifluoromethyl)methyl and the like.
"Pharmacologically 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 salts," see infra and Berge et al, J. Pharm. Sci. 66, 1 (1977).
WO 98/24780 PCT/US97/22949 79 "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-1, 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 98/24780 PCT/US97/22949 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 98/24780 PCT/US97/22949 81 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 98/24780 PCT/US97/22949 82 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: Rx RY 0 -CRxRY-
R
RX I -NRxRY
R
-NR- ;N S O O T 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 98/24780 PCT/US97/22949 83 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 havihg opposite stereochemistry using wellknown methods, for example, by inversion.
4 (3H) -Pyrimidinones: For the synthesis of 4 3 H)-pyrimidinones II (or its tautomer, 4-hydroxy-pyrimidines), the approach displayed in Scheme 1 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.
WO 98/24780 PCT/US97/22949 84 Scheme 1 0
H
2 N R 1 OR NH NH 12 ON 12)1 R V R 1 2
R
XII
XIII
OH 0
R
11
R
11 R N R R N R R N R1 R 1 2
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.
WO 98/24780 PCT/US97/22949 Scheme 2 0 F 0 N
OH
N 0
H
2 N XI )Ir-
R
HN
F V
F
NH NH N Ri No R N N1 XIII II Accordingly, further compounds of formula II may be obtained in which R 1 is any other heteroaryl ring within the definition of R 2 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 (1964)). The use of 2 -nitropyridine-4-carboxaldehyde would lead to a derivative of formula II with R 12 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 2 is applicable to the use of other aryl acetic acids leading to compounds of formula II with different aryl groups as R".
WO 98/24780 PCT/US97/22949 86 Pyrimidinone II (R 1 H) may be substituted at the N-3 position by reaction with e.g. an alkyl halide, such as methyl iodide or ethyl bromide in the presence of an appropriate base such as potassium carbonate and the like.
Scheme 3 0 OEt F
H
2
N
FN OEt H 2
N
OEt
N
XIV
F i F
F
FI I 0 N N iSH in N SMe iN N R N/
N
0 N/ R
XV
II
SX. cXVI F KT. 0
NH
N R
N
II R SR 21 Another approach (Scheme 3) 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 1 is H.
Although Scheme 3 illustrates syntheses in which R" is 4-pyridyl, this approach may be equally applied to WO 98/24780 PCT/US97/22949 87 any other heteroaryl ring within the definition of R 12 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 3. Subsequent catalytic reduction of the nitro group to an amino group would give a pyrimidinone II in which R is represented by a 2-amino-4-pyridyl group (Scheme 4).
Scheme 4 F 0 F 0 4
NR
4
,AN
R4 I N R 1 N R N 1!0 N Oe
NO
2 NH 2
I
Furthermore, methyl 2-acetamido isonicotinate (Scheme 5) may be reacted analogously to Scheme 3 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 (P 1 Scheme N CO 2 Me N CO 2 Me NQ CO 2 Me N N N/
NH
2 NHAc NAc
PI
P,
WO 98/24780 PCT/US97/22949 88 Removal of the protecting group Pi 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 pyrimidinone II with R 12 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 3 thus providing compounds of formula II with different R" aryl substituents.
In a further process, pyrimidinones II may be prepared by coupling a suitable derivative of XVIII (L is a leaving group, such as halogen radical and the like) with an appropriate aryl equivalent.
0 L ,R
N
R N R
XVIII
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 WO 98/24780 PCT/US97/22949 89 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 1 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 6, 5-aryl-2,6-dipyridyl-4(3H)pyrimidinones II may be prepared in a one step synthesis by reaction of the cyanopyridine with an arylacetyl ester, such as ethyl phenylacetate in the presence of sodium methoxide.
Scheme 6 0 R11 NH N .CN R CO 2 Et NN
N
II
In Scheme 7, compounds of the present invention of formula XXX can be readily prepared by reacting the methylthio intermediate XXXI with the amine NHRR 21 for example by heating the mixture preferably at a temperature greater than 100 0 C, more preferably 150- 210 0 C. Alternatively, compounds of formula XXX can be readily prepared by reacting the methylsulfonyl intermediate XXXII with the amine NHRR 21 for example by heating the mixture preferably at a temperature greater than 40 0 C, more preferably 50-210 0
C.
Scheme 7 0 0 RR N O, N 21 11 R1 1SleH R R2 S;4 M R N SMe R N N 2 SOMe I, 2
XXXI
XXX
XXXII
WO 98/24780 PCT/US97/22949 Amines of formula NHR 5
R
2 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, 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, O. Ichihara and I.
Walters, J. Chem. Soc., Chem. Commun. 1153, 1993.
Pvridones: As displayed in Scheme 8, a suitable route to 2(1H)-pyridones III involves the cyclization reaction between an a,b-unsaturated ketone XXII and a sufficiently reactive, substituted acetamide in the presence of base (El-Rayyes and Al-Hajjar, J.
Heterocycl. Chem. 21, 1473 (1984)) and subsequent dehydrogenation.
WO 98/24780 WO 9824780PCTfUS97/22949 91 Scheme 8 0 R 12AokH 0 C) XXII 011 NH 2 3:11 Scheme 9 0 ARl H XXI I Q,-^*oNH2
III
Accordingly (Scheme pyridine-4-carboxaldehyde or other heteroaromatic carboxaldehyde- like pyrimidine- 4-carboxaldehydes or quinoline-4-carboxyaldehydes may be reacted with acetyl aryl, acetyl heteroaryl or acetyl cycloalkyl derivatives in the presence of piperidine! acetic acid at elevated temperature (Bayer and Hartmann, Arch. Pharn. (Weinhein) 324, 815 (1991) as well as pinacolone (CH 3 -CQ-C(CH in the presence of sodium hydroxide to provide the unsaturated ketone XXII (or the WO 98/24780 PCT/US97/22949 92 analogous ketone from the corresponding heteroaromatic- 4-carboxyaldehyde). The reaction of XXII with phenylacetamide in the presence of sodium ethoxide then may lead via the 3 ,4-dihydropyridone to 6-substituted 3phenyl-4-(heteroaryl)-2(lH)-pyridones of structure III.
In Scheme 10, a feasible route is illustrated leading to 6 -chloro-2(1H)-pyridone XXIV, a versatile intermediate for further modifications at the 6position. This approach Simchen, Chem. Ber. 103, 389-397 (1970) is based on the conversion of the unsaturated g-cyanocarboxylic acid chloride XXIII into XXIV in the presence of hydrogen chloride.
Scheme EtO 0 11 O E t R 11 R XOEt CN
OR
R12 OEt C R2 CN R Et XII R H 11 11 R 0(
R
2 NH Cl R12 ^I R12 CN XXIV
XXIII
Reaction of XXIV with ammonia (Katritzky and Rachwal, J. Heterocylic Chem. 32, 1007 (1995)), primary and secondary amines would lead to 2-amino substituted pyridones III. Furthermore, XXIV may be reacted in a palladium or nickel catalyzed cross-coupling reaction with an alkyl or aryl boronic acid or an alkyl or aryl zinc halide to provide pyridone III wherein R 3 is alkyl or aryl or heteroaryl.
In addition, pyridone III may be substituted at the N-l position by reaction with, an alkyl halide in WO 98/24780 PCT/US97/22949 93 the presence of an appropriate base such as potassium carbonate.
An approach that may lead to a pyrimidinone of the general formula III is illustrated in Scheme 11.
Scheme 11 O
O
R X R NH2 11 O S 1 C -I C NoN NHR R OEt R OEtH R OEt
XXV
XXVI
1 1 11 R 1 %N SMe R1)LN S 14 14 R
R
XXVIII
XXIX
According to this approach (Shaw and Warrener, J.
Chem. Soc. 153-156 (1958); Hronowski and Szarek, Can. J.
Chem. 63, 2787 (1985); Agathocleous and Shaw, J. Chem.
Soc. Perkin Trans. I, 2555 (1993)), an ethoxyacryloyl isothiocyanate XXVI is reacted with a primary amine to give as an addition product the acylthiourea XXVII which can be cyclized under basic or acidic conditions to the thiouracil compound XXVIII. XXVIII may be methylated to the methylthio derivative XXIX, a versatile intermediate for further transformations at the 2-position.
Fused 4(3H)-Pvrimidinones: As displayed in Schemes 12 and 13, introduction of a suitable R 4 group through the alkylation of XXXIII affords an intermediate to the fused 5, 6, or 7 membered ring systems of Formula I wherein R 1 and V or W are joined. The synthesis utilizes a haloalkylamine in which the amino group is protected through reaction with 1,2-bis (chlorodimethylsilyl) ethane affording the cyclic WO 98/24780 PCT/US97/22949 94 stabase derivative (see:Basha and Debernardis Tetrahedron Lett 5271, 1984) which protects the amine in the subsequent alkylation step (sodium hydride,
DMF).
Scheme 12 o 0 SBr NS N
RS
R
1 2 N SMe NaH R U N SMe m 2-4
XXXIII
XXXIV
I TBAF
THF/H
2 0 0 0 R NL- Heat N H2 R m SR1 N SMe XXXVI
XXXV
Scheme 13 O O R
R
R R 1 NH R N SMe m-l t4NH2 Deprotection of the amine can be accomplished with acid treatment (p-toluenesulfonic acid) or tetrabutylammonium fluoride treatment. The free amine can then be cyclized in an intramolecular fashion by warming to high temperatures. The bromoalkylamines are either commercially available (eg. 3 -bromopropylamine hydrobromide, 2 -bromoethylamine hydrobromide) or they can be synthesized from the corresponding haloalkylazide followed by reduction of the azide to the amine (see: Hendry et al Tetrahedron Lett 4597 (1987)).
More functionalized haloalkylamines can be used as long as the functional groups are tolerated in the WO 98/24780 PCT/US97/22949 transformations shown in scheme 12 including the bromo derivatives obtained from amino acid precursors as described by Baldwin et al (Synlett. 51-53, 1993) and Leanna et al (Tetrahedron Lett. 4485, 1993).
Alternatively, the fused ring system can be made through the addition of a hydroxyalkylamine as outlined in Scheme 14. Initially, the amine component of the hydroxyalkylamine displaces the 2-methylthio group to afford compound XXXVII which is followed by conversion of the alcohol to a suitable leaving group (eg.
methanesulfonate or trifluoromethanesulfonate). Closure of the ring can be accomplished by treatment with an excess of sodium hydride in DMF to afford XXXVI.
Scheme 14 0 RNH HO NH 2 1R OH R N SMe 12 N N m-1
H
XXXIII
XXXVII
MeSO 2 C1 Et 3
N
0 SN m-1 R
NH
R12 N -N I IK m-l H R 12 N N
H
XXXVI
XXXVIII
The 6,5 fused ring systems can be obtained as outlined in Scheme 15. Alkylation of the N-3 nitrogen with 3 -bromo-l-trimethylsilylpropyne can be followed by a displacement of the 2-methylthio group with the appropriate amine component exemplified but not limited to a phenylalkylamine. The 2-amino group under the reaction conditions cyclizes onto the acetylene as shown with a loss of the trimethylsilyl group as well. This transformation is illustrated in the examples below WO 98/24780 PCT/US97/22949 96 wherein 3 -phenyl-l-propylamine and benzylamine are reacted with 3-(3-trimethylsilyl-2-propynyl)-5-( 4 fluorophenyl)-2-methylthio-6-(4-pyridyl)-4(3H)pyrimidinone to afford the corresponding 6, 5 fused system.
Scheme
XXXIII
Br TMS NaH Me 0 11
R
2 1
R
0 I N TMS R N SMe
XXXIX
/R
NH
2
XXXX
Scheme 16 NH L* N NnR 2 1 R21 N N R2 1 Compounds of the invention when U is CHR 21 can be prepared according to Scheme 2 above wherein R1 contains an leaving group or a group which can be converted into a leaving group which can be reacted with a WO 98/24780 PCT/US97/22949 97 primidine nitrogen atoms to form the fused ring (see Scheme 16).
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) -4 (3H) -pyrimidones 0 F H F O
OH
N
H
2 N a.R=H b. R =Et
FF
HN
NN
a. 2 4 -Fluorophenvl)-3-(4-pvridvl)-acrvlic 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
HFNO
2 requir. 243.2 'H-NMR WO 98/24780 PCT/US97/22949 98 (DMSO-d 6 d 8.43, 6.98 (2d, each 2H, Pyrid.), 7.73 (s, 1H, 7.21 4H, PhF).
b. Ethyl 2-(4-fluorophenvl)-3-(4-pyridyl)-acrylate: Conc. 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 silica gel (hexane-acetone 2:1) provided the pure title compound. MS 271.8 C 1
,H
14 FNOrequir.
271.3 1 H-NMR (CDC1,) 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 120 0 C 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.
WO 98/24780 PCT/U597/22949 99 The following compounds were prepared accordingly using the appropriate amidine hydrochloride: 1-1 5-( 4 -Fluorophenl)-.2methl6(47pyridvl) 4 3 H)z pyrimidinone: MS 282.2
C
16 H UFN0 requir.
281.3 1 H-NMR (DMSO-d 6 d 8.46 (m 2H, Pyrid.), 7.2-7.03 (mn, 6H, PhF, Pyrid.). 2.38 3H, CH').
R1
CH
3 1-2 5-(4-Fluoroiphenyl) 2 -isoTropvl-6-(4-pyridyl)-4(3).
pyriinidinone: MS 310.0
C
1 8 H 16 FN 0 requir.
309.4 1 H-NMR (DMSO-d,) 8.45 (mn, 2H, Pyrid.) 7.21-7.03 (mn, 6H, PhF, Pyrid.), 2.90 (mn, 1H, 1.26, 1.24 (2s, ea ch 3H, 2CH 3 R1l= (CH1) 2
CH-
1-3 2 2 6 -Dichlorobenzvl)-5(4fluorohenvl) 6 4 p~vridvl)-4(3H).-pvrimidinone: MS 426.0
C
2 2
H
1 4
C
2
FN
3 Orequir. 426.3 'H-NMR (DMSO-d,): d 8.37 (mn, 2H-, Pyrid.), 7.50 2H, Phd 2 7.35 1H, Phd 2 7.18- 7.08 (mn, 4H, PhF), 6.96 (in, 2H, Pyrid.), 4.36 2H,
CHO).
C'
R1.
C1 1-4 5-( 4 -Fluorophenv)-2phenl6(4-pvr dvl)4(3H)z pyrimidinone: MS 344.2 C 21
H
14 FN 3 0 requir.
343.4 'H-NMR (DMSO-d 6 d 8.49 2H-I, Pyrid.), 8,20 (d, 2H, Ph), 7.66-7.50 (in, 3H, Pyrid., Ph), 7.32-7.11 (mn, 6N, PhF, Ph).
R1= WO 98/24780 PTU9/24 PCT/US97/22949 100 Example 2 General procedure for the preparation of 2-N substituted (4-fluorophenyVl) -3-methyl-6- (4-pyvridyvl) -4 (3H) pyrimidinones Step A. 5- 4 -Fluorophenv1)-3-metvl-2-methvlthio-6-( 4 pyridyl) -4 (3H) -pyrimidinone: F 0F0 NH X CH3 Nt N SH IN
OLSCH
3 Methyl iodide (418 ml, 6.67 mmol) was added to a stirred mixture of 5-( 4 -fluorophenyl)-6-(4-pyridyl)-2 thiouracil (1.0 g, 3.34 mmol) and potassium carbonate (923 mg, 6.68 nunol) in N, N-dimethylformamide (30 ml) at room temperature. Stirring was continued for 3 h, followed by evaporation and flash chromatography on a column of silica gel (hexane-acetone 3:1, 2:1, 1:1) or Iatrobeads~ (chloroform-methanol 90:7; chloroformmethanol-triethylamine 90:7:3). The second main fraction provided the title compound as a solid. MS (mhz) 3 28. 0 C 17
H
14 FN 3 OS requir. 327.4. 1
H-NMR
(DMSO-d,): d 8.50, 7.26 (2m, each 2H, Pyrid.) 7.18, 7.14 (2m, each 2H, PhF), 3.52 3H, NCH 3 2.65 (s, 3H, SCH 3 Step B. General Procedure: F 0 F 0~ I'
'.CH
3 ICH NN
CH
N o N 5 21 Il N' SCH 3 I N_ NR R A mixture of 5- 4 -fluorophenyl)-3-methyl-2methylthio-6- (4-pyridyl) -4 (3H)-pyrimidinone (103 mg, 0.32 nmmol) and the amine HNR 5 R 2 1 (1.2-3.2 mmol) was heated at 190-200 0 C for 2-48 h. The resulting product WO 98/24780 PCTIUS97/22949 101 was purified by flash chromatography on a column of silica gel (hexane-acetone or methanol-dichloromethane or methanol-dichloromethane-conc. ammonium hydroxide) to provide the target compound.
The following compounds were prepared using the above procedure outlined above and an appropriate amine: 2-1 2 -(n-Butvlamino)-5-(4-fluorohenyl)-3-methl 6 4 Pyridyl)-4(3H)-pvrimidinone: The reaction was done in a sealed tube at 190 0 C for 5 h.
MS 353.0
C
20
H
21
FN
4 0 requir. 352.4.
R
CH,(CH)
3
NH-
2-2 5-( 4 -Fluorophenv)-3-methvl-2-(Pentlamino)6( 4 Pvridyl)-4(3H)-pyrimidinone: The reaction was done in a sealed tube at 1900C for 2.5 h. MS 366.8 (MiH)+;
C
2
,H
23
FN
4 O requir. 366.4.
R
CH
3
(CH)
4
NH-
2-3 2-( 3 3 -Dimethvlbutvlamino)-5-(4-fluorophenvl)3 methvl-6-(4-yridvl)-4(3H)-pyrimidinone: The reaction was done in a sealed tube at 1900C for 5 h. MS 381.2
C
22
H
2 5 FN,Orequir. 380.5.
R (CH 3 3
C(CH
2 2
NH-
2-4 2 -(Benzvlamino)-5-(4-fluorohenl)-3-methv>6(4.
pvridl)-4(3H)-pvrimidinone: The reaction was done at 185 0 C for 6h. MS 387.2
C
23 19
FN
4 0 requir.
386.4 rn N
H
2 4 -Fluorobenzylamino)-5-(4-fluorophenvl)-3methyl-6- (4-pyridyl)-4 (3H) -pyrimidinone: The reaction was done at 1900C for 24 h. MS 405.2
C
23 H18F 2 NOrequir. 404.4.
R1 FJO WO 98/24780 PTU9/24 PCT/US97/22949 102 2-6 -(3Flurobezvlmin)-5(4-fuori~hnvl-3rethyl-6-(4-pvridyl) -4 (3H) -pyrimidinone: The reaction was done at 1950C for 40 h. MS 405.0 C 23
H
1 8 F 2 N 4 requir. 404.4.
H
R' F 2-7 5-( 4 -Fluorophenvl)-3-methvl.( (R-1phenylethvl) amino) -(4-pyridyl) -4 (3H) -primidinone: The reaction was done at 1800C for 4 days. MS 401.0 (Mi-H) C C 24
H
21 FN 4 0requir. 400.5
CH
3
H
R
1
F
2-8 2- (2-Chiorophenyl) -ethylamino) (4fluorophenyl) -3-methyl-6- (4-pyridyl) -4 (3H) -lprimidinone: The reaction was done at 1900C for 5 h. MS 435.2 C 24
H
20 C1FN 4 0 requir. 434.9.
H
R C a 2-9 5-( 4 -Fluorophen1)-2-(2-(4-fluorohenyl) ethylanino) -3-methyl-6- (4-pyridyl) -4 (3H) -pyrimidinone: The reaction was done at 190 0 C for 5 h. MS 419.2 C 24
H
20 F 2 N 4 requi r .418.5
H
R F<0 2-10 5-( 2 -Fluorophen1)-2-(2-(3-fluorophenvl)ethylamino) -3-methvl-6- (4-pyvridyl) -4(3H) -pyrimidinone: The reaction was done at 1900C for 24 h. MS 419.2 C 24
H
20
F
2 N,0 requir. 418.5 WO 98/24780 PCTIUS97/22949 103
H
R
F
2-11 5-( 2 -Fluoropheny)-2-(2-(2-fluorophenvl) ethylanino) -3-methvl-6- (4--Pridyl) -4 (3H) -pyrimidinone: The reaction was done at 190 0 c for 12 h. MS 419. 0 C 2 4H 2 0
F
2 NOrequir. 418.5
H
N
1' Il I R r 2-12 5- (2-Fluorolphenyl) (2-hdroxv-2-phenvl) ethylamino) -3-methyl-6- (4-lpridyl) -4 (3H) -pyrimidinone: The reaction was done at 190 0 C for 1.5 h. MS 417.0
C
24 21
FNO
2 requir. 416.5.
OH
R'=
2-13 5- (4-Fluorophenyl) -3-methyl-2-( (3-phenvlropvl)amino) (4-pyridl) -4 (3H) -lprimidinone: The reaction was done at 190 0 C for 6 h. MS 415.0
C
25
H
23
FN
4 Orequir. 414.5. 1 H-NMR (CDC1 3 d 8.49, 7.20 (2m, each 2H, Pyrid.), 7.35 2H, Ph), 7.30-7.25 3H, Ph), 7.12, 6.97 (2m, each 2H, PhF), 4.61 1H, NH), 3.67 2H, CH 2 3.28 3H, 2.82 2H, CHPh), 2.12 2H, CH 2 R1 Q~N R ro
H
2-14 5-(4-Fluorohenyl)-3-methyl-2-((l-methvl-3phenvlpropvl) -amino) (4-Pyridvl) -4 (3H) -pyrimidinone: The reaction was done at 200 0 C for 48h. MS 429.0
C
26
H
2 5 FN4Orequir. 428.5.
WO 98/24780 WO 9824780PCT1US97/22949 104
CH
3
N
R
H
2-15 5- (4-Fluorophenyl) -3-methyl-2- C(R-l-methyl-3lphenvipropyl) -amino) (4-pyridyl) -4 (3H) -pyrirnidinone: The reaction was done at 200 0 C for 48 h. MS (rn/z): 429.0
C
26 25
N
4 Orequir. 428.5.
CH
3
N
R =1H 2-16 2- 3 3 -DiThenvlpropv) -amino)5-(4-fuorophenV1) 3-methvl-6- (4--pyridyl) -4 (3H) -iprimidinone: The reaction was done at 1900C f or 6 h. MS 490. 8
C
31
H
2
FN
4 Orequir. 490.6.
N N I H 2-17 5- (4-Fluorophenyl) -3-methyl-2- phenylaminoethyl) -amino) (4-pyridyl) -4 (3H) pyvrimidinone: The reaction was done at 1900C for 4 h.
MS 416.2
C
2 4
H
22 FN.0 requir. 415.
H
2-18 5-(4-Fluorophenvl) -2-C (3-imidazolvipropyl) -amino) 3-methyl-6- (4-pyridyl) -4 (3H) -Iprimidinone: The reaction was done at 1901C for 2 h. MS 405.0
C,
2
H
21
FN
6 Orequir. 404.5.
H
2-19 5-(4-Fluorophenvl) 3 -methl-2-(2-(piperazin-l-vl) ethylamino) (4-pyridyl) -4 (3H) -pyrimidinone: The WO 98/24780 PCT/US97/22949 105 reaction was done at 190 0 C for 30 min. MS 409.2
C
22
H
25 FN O requir. 408.5.
R
1
I-NH
R HN N__ 2-20 5-( 4 -Fluorophenv)-3-methyl-6-(4-pvri 2 3 (pyrrolidin-1-yl) -propylamino) -4 3H) -pyrimidinone: The reaction was done at 190 0 C for 2 h. MS 408.2
C
2 3
H
2 6 FN 5 requir. 407.5.
R1 N
H
2-21 2 2 -Amino-3-phenylpropl)-amino-( 4 fluorophenyl) -3-methyl-6- (4-yridyl) -4 -pyrimidinone hydrochloride: The reaction was done at 190 0 C for 2.5 h.
MS 430.1 C25H24FN50 requir. 429.5 (free base).
R'
H
00N 2 NH2 2-22 2 2 -N-Ethyl-3 -phenlpropyl) -amino)-5-(4 fluorophenyl) -3-methyl-6- (4-Pyridyl) -4 (3H) -pyrimidinone hydrochloride: The reaction was done at 190 0 C for 4 h.
MS 458.3 C27H28FN50 requir. 457.6 (free base).
N
R1 HN 2-23 2- 2 -Amino-2-methy3 -henlpropyl) amino)-5-(4fluorophenyl)-3-methyl-6-(4-pyridyl)-4(3H)-pyrimidinone hydrochloride: The reaction was done at 190 0 C for 4 h.
MS 444.0 C26H26FN50 requir. 443.5 (free base).
R
N,
2-24 2 -Aminometh-3-henylpropyl)-amino)( 4 fluorophenvl-3-methylz6.. (4-pyridyl) -4 (3H) -pyrimidinone WO 98/24780 PTU9/24 PCT/US97/22949 106 hydrochloride: The reaction was done at 1900C for 1 h.
MS 444.0 C26H26FN40 requir. 443.5 (free base).
CN
R 1 NH 2 2-25 2-((3-Anlino-3-phenyl-propvl)-amino)-5-(4fluoropohenyl) -3-methyl-6- (4--pyridyl) -4 (3H)-pyrimidinone hydrochloride: The reaction was done at 1900C for h. MS 430.0 C25H24FN50 requir. 429.5 (free base).
NH
2 l
H
R'
2-26 5-(4-Fluorophenyl)-3-methyl-2-(3-(2me thylphenyl) propyl) amino) 6- (4 -pyridyl) 4 (3 H) ipyrimidinone: The reaction was done at 1900W for 4 h.
MS 429.5 C26H25FN40 requir. 428.5.
N
CHH
R H 3 2-27 5 4 -Fluorop~henyl)-3-methyl-2-((R,S)-2-amino3(2f luorophenyl) -proyl -amino) (4-pyridyl) -4 (3H) pyrimidinone Hydrochloride: The reaction was done at 1900C for 7 h. MS 448 r~r~N ~J~NH
H
R
1 =0 2-28 2 -(((R)-2-Amino-3-phenylpropoyl)-axnino)-5-(4.
fluorophenyl) -3-methyl-6- (4-pyridyl) -4 (3H)-pyrimidinone hydrochloride: The reaction was done at 190 0 C for 2 h.
MS 430.2 C25H24FN50 requir. 429.5 (free base).
WO 98/24780 WO 9824780PCTIUS97/22949 107 R
N
2-29 -2-N-Methvl-3-phenylpropl)amino)-5-(4.
f luorophenyl) 3-methyl 6- (4 -pyridyl) 4 Q3H) pvrimidinone hydrochloride: The reaction was done at 1900C for 4 h.
MS 444.0 C26H26FN50 reguir. 443.5 (free base).
R H
CH.
C3 2-30 2 -Phenvlthioethl)-amino)5(4-fluoroiphenvl)-3 methyl-6- (4-lpyridyl) -4 (3H) -pyrimidinone: The reaction was done at 1900W for 16 h. MS 43 3
H
2-31 2 -hvdroxvethyl)-amino)-5-(4-fluorophenyl)-3 methyl-6- (4-pyridyl) -4 (3H) -pyrimidinone: The reaction was done at 1900W for 16 h. MS (znz) 341 R I= H 2-32 2 2 ,2-dimethv1-3-hvdroxpropyl)-amino) fluorophenyl) -3-methyl-6- (4-pyridyl) -4 (3H) -pyrimidinone: The reaction was done at 190 0 C for 16 h. MS 383 HO2N R 1
H
2-33 (2,2-dimethv1-3-phenvlthio-oropyl) -amino) fluorophenyl) -3-methyl-6- (4-pyvridvl) -4 (3H) -pyrimidinone: To a solution of triphenylphosphine (262 mg, 0.29 mmol) in tetrahydofuran (2 mL) at 0 C was added diisopropyl azodicarboxylate (DIAD) (56 ml, 0.29 inmol) After min at 0 C, 2 2 2 -dimethyl-3-hydroxypropyl)mino)-S..
(4-f luorophenyl) -3-methyl-6- (4-pyridyl) -4 (3H) pyrimidinone (50 mg, 0.14 Inmol) and 2,6dichiorothiophenol in tetrahydrofuran (2 mL) was added.
WO 98/24780 PTU9124 PCTIUS97/22949 108 After 16 h, the reaction was concentrated under a stream of nitrogen. The reaction mixture was applied directly to purification via flash chromatography (step gradient ethyl acetate:CHC13 1:3 then 1:2 then 1:1 then 2:1 then 3:1) to afford the title compound: MS 544 HO H 2-34 2 3 -Amino-3-(2-fluorophenvl)propyl)-aino).S.( 4 fluorophenyl) -3-methyl-6- (4-pyvridvl) -4 (3H) -Pyrimidinone was prepared from 5- (4-f luorophenyl) -3-methyl-2methylthio-6-(4-pyridyl) 4 (3H) -pyrimidinone and 1- (2fluorophenyl)-l,3-propanediamjne according to the General Procedure. The reaction was done at 190'C for 3 h. MS 448.1 C 25
H
23 2
N
5 Orequir. 447.5 (free base).
F NH 2 R N 2-35-2-( 3 -Aino- 3 -(2-methvlphenvl)propyl)-amino)5(4.
fluorophenyl) -3-methy1-6- (4--pyridyl) -4 (3H) -pyrimidinone hvdrochlor-idewas prepared from 5- (4-f luorophenyl) -3methyl-2-methylthio-6- (4-pyridyl) 4 (3H) -pyrimidinone and 1- (2 -methyiphenyl) -1,3 -propanediamine according to the General Procedure. The reaction was done at 185 0
C
for 4 h. MS 444. 5 C 26
H
26
FN
5 0 requir. 443. (free base).
CH
3 NH2 1 -1 R N
H
2-36 2 3 -amino-3-phenvlpropyl) amino) fluorophenyl -3-methyl-6- (4-ipyridy1) -4 3H) -pyvrimidinone hydrochloride was prepared from 5-( 4 -fluorophenyl)-3methyl-2-methylthio-6. (4-pyridyl) -4(3H) -pyrimidinone and -l-phenyl-1, 3 -propanediamine according to the General Procedure. The reaction was done at 190'C for 2.5 h. MS 430.2 C 25 H 2 4
FN
5 requir. 4 2 9 5(free base).- WO 98/24780 PTU9124 PCTfUS97/22949 109
NH
2 2-37 2 3 -amino-3-phenyl-propyvl) -amino) 5-(4f luorophenyl) -3 -methyl- 6- (4-lpyridyl) -4 (3H) -ovyrimidinone hydrochloride was prepared from 5- 4 -fluorophenyl) -3methyl-2-methylthio-6- (4-pyridyl) -4 (3H) -pyrimidinone and (R)-l-phenyl-1,3-propanediamjne according to the General Procedure. The reaction was done at 190'C for 3.5 h. MS (rn/z) :430.7 C 25
EH
24 FNOrequir. 429. 5 (free base).
NH
2 R
N
2-38 2- 2 R, 3 R) 3 -Amino 2-methyl >phenylpropyl) amino) 5- (4 -f luorophenyl) 3-me thvl 6- (4 -pyridyl) 4 (3 H) pyrimidinone hydrochloride was prepared from 5-(4f luorophenyl) -3-methyl-2-methylthio-6- (4-pyridyl) 4 (3H)-pyrimidinone and (2R,3R) -2-Iethyl-3-phenyl-l,3propanediamine according to the General Procedure. The reaction was done at 190 0 C for 3 h. MS 444.5 C 26
H
2 6
FN
5 Orequir. 443. 5 (free base) R
NN
2-39 2
S,
3
S)-
3 -Amnino-2-methyl-3-Thenylpropyl)amino) 4 -f luorolphenyl) -3-methvl.6- (4pvridvl)-4 (3H) Pvrimidinone hydrochloride -was prepared from 5- (4f luorophenyl) 3 -nlethyl-2-methylthio-6- (4-pyridyl) 4 (3H)-pyrimidinone and 2
S,
3 S)-2-methyl-3-phenyl-1,3propanediamine according to the General Procedure. The reaction was done at 190'C for 2 h. MS :444.4 C 26
H
26 FN 0requir. 4 43. 5 (free base).
NH
2
H
WO 98/24780 PTU9/24 PCTfUS97/22949 110 Analogously, the isomers.2-CC 2 S.3R)-3-Amino-2-methv-3phenyipropyl) -amino) (4-f luorophenyl) -3-methvl-6- ipvridvl)-4(3H)-Tpvrimidinone and 2-C((C2R,3S)-3-amino-2methvl-3-pohenvlpropvl) -amino) (4-f luorophenyl) -3methvl-6- (4-pyvridyl) -4 (3H) -pyrimidinone may be prepared from the corresponding diamines.
2-40 5- (4-Fluorophenyl) -2-C (-3-hvdroxv-3-phenvlpropyl) amino)-3-methyl-6- (4-pyridyl) -4(3H) -pyrimidinone: The reaction was done at 190 0 C for 3 h. MS (rn/z) 431.2 C2 5
H
23
FN
4 0 2 requir. 430.5.
HO
R
N
Example 3 Procedure for the preparation of N-substituted pyrimidinones NH 1-
,CH
3 K' N N. N N N N Cl ~Cl Cli ~C1 6-Dichlorobenzvl)
C
4 -fluorophenyl)-3-methyl-6-(4- Pvridvl)-4(3H)-pvrimidinone: Methyl iodide (41 ml, 0.65 mmol) was added to a stirring mixture of 2-(2,6dichlorobenzyl)-5- 4 -fluorophenyl)-6-(4-pyridy1) -4(3K) pyrimidinone (280 mg, 0.61 mmol) and potassium carbonate (181 mg, 1.30 mmol) in N,N-dimethylformamide (2 ml).
Stirring was continued for 2 h, followed by evaporation and flash chromatography of the resulting product on a column of silica gel (hexane-acetone to yield the title compound as a white solid. MS 440.2 C 23
H
16 C 1 2 FN 3 requir. 440.3.
WO 98/24780 PCtIUS97/22949 ill Example 4 General procedure for the preparation of 2-N and 2'-N substituted 2-arnino-5- (4-fluorophenyl) -3-methyl-6-(4- (2amino)pyridyl) -4 (3H) -pyrimidinones F N N'A NR R 2 NR 3 1
R
3 2 Step A. 5-( 4 -Fluorophenl)3methy-2methvlthio67 4 (2-acetamido)7pvridvl) (3H) -Dyrimidinone: To a solution of 5- (4-fluorophenyl) (2acetamido)pyridyl)-2-thiouracil (600 mg, 1.68 mmol) in DMF (35 mL) was added powdered sodium hydride (60% oil dispersion, 221 mg, 5.56 mnmol) over 1 minute at 23 0
C.
After 45 min, iodomethane (210 ml, 3.37 rnmol) was added dropwise. After 45 min, the reaction was concentrated in vacuo (rotovap connected to high vac with a bath temperature no greater than 40 0 C) The residue was applied immediately to flash chromatography purification (step gradient hexane:acetone 4:1; then 3:1; then 2:1; the 1:1) to afford the desired product.
Stelp B. 5- (4-Fluorophenyl) -3-methvl-2-( (3-phenvlpropvl) amino) (2 -amino) Pyridyvl) 4 (3H) -Pyrimidinone:
A
neat mixture of 5- 4 -Fluorophenyl) -3-rnethyl-2methylthio-6- 2 -acetaxnido)pyridyl) (3H) pyrimnidinone (50 mg, 0.13 mmcl) and 3-phenyl-1propylamine (88 mg, 0.65 mmol) was warmed to 190'C for 17 h. After cooling to 23'C, the reaction mixture was applied directly to purification via flash chromatography (step gradient 1%MeOH:C11013 then then then then to afford the desired product:
MS
430 WO 98/24780 PCT/US97/22949 112 R
R
31
=H
R
32
H
The following compounds were prepared using the above procedure outlined above and an appropriate amine: 4-1 5-(4-Fluorophenyl)-3-methyl-2-((3-phenvlpropyl)amino)-6-(4- (2-acetamido)pvridyl))-4(3H) -pyrimidinone: To a solution of 5-(4-Fluorophenyl)-3-methyl-2-((3phenylpropyl) -amino) -6-(4-(2-amino)pyridyl) -4(3H)pyrimidinone (11 mg, 0.026 mmol) in 600 ~l of pyridine was added (5 g1, 0.064 mmol) of acetyl chloride at 23 C.
After 2 h, the reaction was quenched with water (5 gl) and the reaction was concentrated under a stream of nitrogen. The reaction mixture was applied directly to purification via flash chromatography (step gradient 1%MeOH:CHC13 then then to afford the title compound: MS 472 R H
R
32
H
R
31 Ac 4-2 5-(4-Fluorophenvl)-3-methvl-2-( (3-phenvlpropyl)amino) 2 -methoxvacetamido) pvridvl)) -4(3H)pyrimidinone: To a solution of 5-(4-Fluorophenyl)-3methyl-2-((3-phenylpropyl)-amino)-6-(4-(2amino)pyridyl))- 4 3 H)-pyrimidinone (11 mg, 0.026 mmol) in 600 1l of pyridine was added (5 l, 0.064 mmol) of methoxyacetyl chloride at 23 C. After 2 h, the reaction was quenched with water (5 pl) and the reaction was concentrated under a stream of nitrogen. The reaction mixture was applied directly to purification via flash chromatography (step gradient 1%MeOH:CHC13 then then to afford the title compound: MS 502 WO 98/24780 WO 9824780PCTIUS97/22949 113 R
N
H
R
32 31 R C C(0)CH 2 OMe 4-3 5- (4-Fluorophenyl) -3-methyl-2- ((3-pohenylpropyvl) amin-) 6 4 2 -acetoxvacetamido)pyvridyl) pyrimidinone: The reaction was done in the manner of the above substituting acetoxyacetyl chloride for acetyl chloride to afford the title compound after chromatography: MS 530 1 N R 3 1 C(O)CH 2 OAc 4-4 5- (4-Fluorophenyl) -3-methvl-2-(C(3-phenylpropyl) amino) 2 -hvdroxvacetamido) pyridyl) (3H) pyrimidinone: To a solution of 5-(4-Fluorophenyl)-3methyl-2-( (3-phenylpropyl)-amino)-6-(4-(2acetoxyacetamido)pyridyl) (3H) -pyrimidinone 2 mg, 0.003 nunol) in 900 gil methanol: 100 Ill water was added potassium carbonate 4 mg, 0.032 mmol) as a solid at 23 C. After 3 h, the reaction was concentrated under a stream of nitrogen. The reaction mixture was diluted with chloroform (20 mL), dried (Na2SO4), and concentrated to afford the title compound: MS 488 1 N R 3 2
=H
R C(O)CH 2
OH
5- (4-Fluorophenyl) -3-methvl-2- (3-phenvlpropyl)amino) (2-methvlsulfonamido)pyvridl) (3H)lpyrimidinone: To a solution of 5-( 4 -Fluorophenyl)-3methyl-2- ((3-phenylpropyl) -amino) (2- WO 98/24780 PCT/US97/22949 114 amino)pyridyl))- 4 (3H)-pyrimidinone (11 mg, 0.026 mmol) in 600 p1 of pyridine was added methanesulfonyl chloride (4 g1, 0.051 mmol) at 23 C. After 2 h, the reaction was quenched with water (5 pl) and the reaction was concentrated under a stream of nitrogen. The reaction mixture was applied directly to purification via flash chromatography (step gradient 1%MeOH:CHC13 then to afford the title compound: MS 508 R1 *N
R
32
H
R
31 SOMe 4-6 5-(4-Fluorophenyl)-3-methvl-2-((3-phenylpropyl)amino) (2-benzylamino)pvridvl)) (3H) -yrimidinone: To a solution of 5-( 4 -Fluorophenyl)-3-methyl-2-((3phenylpropyl)-amino)-6-(4-(2-amino)pyridyl) pyrimidinone (11 mg, 0.026 mmol) in 600 gl of 1,2dichloroethane was added benzaldehyde (8.9 mg, 0.084 mmol) and sodium triacetoxyborohydride (14.8 mg, 0.070 mmol) at 23 C. After 16 h, the reaction was quenched with water (15 and the reaction was concentrated under a stream of nitrogen. The reaction mixture was applied directly to purification via flash chromatography (step gradient 1%MeOH:CHC13 then then then then to afford the title compound: MS 458 R1
R
3
H
R
3
CH
2 Ph 4-7 5-( 4 -Fluorophenvl)-3-methyl-2-((3-phenylpropyl)amino) 2 -methoxvhenl methlamino)pyridvl) 4(3)-pvrimidinone: The reaction was done in the manner WO 98/24780 PCTUS97/22949 115 of the above substituting 2-methoxybenzaldehyde for benzaldehyde to afford the title compound after chromatography: MS 550 R1
N
R
H
R
32
H
R
31
O
4-8 5-(4-Fluorophenyl)-3-methyl-2-((3-Dhenylpropyl)amino)-6-(4-(2-ethvlamino)pvridyl))-4 (3H) -Pyrimidinone: The reaction was done in the manner of the above substituting acetaldehyde for benzaldehyde to afford the title compound after chromatography: MS 458 1
N
32 R H1 31 R Et 4-9 5-(4-Fluorophenyl) -3-methyl-2- (3-phenyipropyl)amino)-6-(4-(2-(di-( 3 -methlbutl)amino)pyridyl))-4(3H) -pyrimidinone: The reaction was done in the manner of the above substituting isovaleradehyde for benzaldehyde to afford the title compound after chromatography:
MS
570 1
N
R H R
CH
2
CH
2
CH(CH
3 2
R
3 1 CH 2
CH
2
CH(CH)
2 4-10 5-(4-Fluorophenvl) -3-methvl-2-( (3-phenvlpropvl)amino)-6-(4-(2-diethvlaminq)nv-rrivI) pyrimidinone: The reaction was done in the manner of the above substituting acetaldehyde for benzaldehyde to WO 98/24780 PCT/US97/22949 116 afford the title compound after chromatography:
MS
486 (M+H) R
H
R
32 Et
R
3 1 Et 4-11 5-(4-Fluorophenvl)-3-methyl-2-((3-phenvlpropyl)amino) 2 -phenvlaminocarbonyl-amino)pyridyl) 4(3H)-pyrimidinone: To a solution of 5-(4-Fluorophenyl)- 3-methyl-2- (3-phenylpropyl)-amino)-6- amino)pyridyl))-4(3H)-pyrimidinone (11 mg, 0.026 mmol) in 600 pl of dioxane was added phenyl isocyanate (3.3 mg, 0.03 mmol) at 23 0 C. After 16 h, the reaction was quenched with water (15 1l) and the reaction was concentrated under a stream of nitrogen. The reaction mixture was applied directly to purification via flash chromatography (step gradient 1%MeOH:CHC13 then then then then to afford the title compound: MS 549 1 ON
RQH
R
32
H
R
31 NH(CO)NHPh 4-12 5-(4-Fluorophenvl)-3-methyl-2-((3-phenvlpropyl)amino) 2 -methylaminocarbonvl-amino)pvridyl) 4(3H)-pyrimidinone: The reaction was done in the manner of the above substituting methylisocyanate for phenylisocyanate to afford the title compound after chromatography: MS 487 R H
R
32
H
R
31 NH(CO)NHMe WO 98/24780 PCT/US97/22949 117 4-13 5-(4-Fluorophenvl)-3-methyl-2-((3-phenvlpropyl)amino)-6-(4-(2-(2'amino-1'-oxo-ethylamino)pyridyl))- 4(3H)-pyrimidinone: General Procedure for mixed anhydride coupling Isobutyl chloroformate (32 ml, 0.24 mmol) was added dropwise to a -20-30 oC solution of N-at-Boc-glycine (5.6 mg, 0.05 mmol) and pyridine (0.6 mL).
After 20 min at -20-30 0 C, 5-( 4 -fluorophenyl)-3-methyl-2- ((3-phenylpropyl)-amino)-6-(4-(2-amino)pyridyl))-4(3H)pyrimidinone (11 mg, 0.026 mmol) and pyridine (0.6 mL) was added in one portion. The reaction was allowed to warm to 230C. After 16 h at 23 0 C, the reaction was poured into saturated bicarbonate (20 mL), extracted with ethyl acetate (2 x 50 mL), washed with brine (1 x mL), and dried (Na2S04). The reaction mixture was applied to purification via flash chromatography (step.
gradient 1%MeOH:CHC13 then then then then to afford the N-Boc protected title compound. The crude title compound was obtained after treatment with trifluoroacetic acid:chloroform (1 mL) for 16 h.
After concentration with a stream of nitrogen, the reaction mixture was applied to purification via flash chromatography (step gradient 1%MeOH:CHC13 then then then then to afford the title compound: MS 487 1
N
R
32
H
R
31
NH(CO)CH
2
NH
2 4-14 5-(4-Fluorophenvl)-3-methyl-2-((3-phenvlpropvl)amino)-6-(4-(2-(4'amino-l'-oxo-butvlamino)pyridyl))- 4 (3H)-pyrimidinone: The reaction was done in the manner of the above with the following substitution: N-t-Boc-gaminobutyric acid was used in place of N-a-t-Boc-glycine which after deprotection as above afforded the title compound: MS 515 WO 98/24780 PCT/US97/22949 118 1
N
H
32 R =H R NH(CO)CH2CH2CH 2
NH
2 4-15 5- (4-Fluorophenyl) 3-methyl-2- (3-iphenylpropl) amino) '-amino-il'-oxo-pronvlamino) Pridyl) 4(3H)-pyrimidinone: The reaction was done in the manner of t1e above with the following substitution: N-t-Boc-3alanine was used in place of N-cL-t-Boc-glycine which after deprotection as above afforded the title compound: MS 501 1 N
R
32
=H
R
3 1
NH(C)CH
2
CH
2
NH
2 4-16 2 -Amino-3-phenvl royl)-amino) 5 (4.
fluorophenyl)-3-methyl-6-(4- (2-aminopvridyl))-4(3H)- Pyrimidinone hydrochloride: The reaction was done at 190 0 C for 6 h in the above manner with the following substitution of 2 -diamino-3-phenylpropane for 3 -phenyl-1-propylamine: MS 445
N
R 1C 0 NH2H H H
R
32
=H
4-17 2 (4-f luorophenyl) -3-methvl-6- aminopyr idyl) 4 (3 H)- Pyrimidinone hydrochloride: The reaction was done at 190C for 6 h in the above manner with the following substitution of 1-amino- 2(S)-dimethylamino-3phenylpropane for 3 -phenyl-l-propylamine: MS 473 WO 98/24780 WO 9824780PCTIUS97/22949 119 N H 32 R =H
R
31 4-18 2 -Dirnethylamino-3-lphenylpropyvl) 4 -fluorophenyl)-3-methyl-6-(4- 2 -acetamidopyridyl) 4 (3H)-lpvrimidinone hydrochloride: The reaction was done in the manner of example XX substituting Dimethylamino-3-phenylpropyl) -amino) 4 -fluorophenyl) 3-methyl-6- (2-aminopyridyl) (3H) -pyrimidinone hydrochloride for 5- (4-Fluorophenyl) -3-methyl-2- phenyipropyl) -amino) (2-amino)pyridyl) (3H) pyrimidinone which afforded the title compound: MS (rn/z) 515 RN
H
R 32=H R 1=Ac 4-19 2 3 -Amino-3-Dhenvl1roipyl)amino)5(4.
fluorophenyl) -3-methyl-6- (2-aminopyvridyl) lpyrimidinone hydrochloride: The reaction was done at 190'C for 12 h in the above manner with the following substitution of (3 RS)-l, 3 -diamino-3-phenylpropane for 3 -phenyl-1-propylamine: MS 445
NH
2 R
H
32 R =H R 31H 4-20 5- (4-Fluorophenyl) -3-methyl-2- (phenlmethylamino) 6 4 2 3 '-iphenv1-l'-oxo-propylamino)pyvridyl))-( 4 amino)pyridyl))-4(3H)-pyvrimidinone: A neat mixture of (4-f luorophenyl) 3 -methyl-2-methylthio-6. (2acetamido)pyridyl) 4 3 H)-pyrimidinone (260 mg, 0.13 WO 98/24780 PCT/US97/22949 120 mmol) and benzylamine (88 mg, 2.71 mmol) was warmed to 190 C for 17 h. After cooling to 23 C, the reaction mixture was applied directly to purification via flash chromatography (step gradient 1%MeOH:CHC13 then then then then to afford 5-(4-Fluorophenyl)-3methyl-2-(phenylmethylamino)-6-(4-(2-amino)pyridyl))- 4(3H)-pyrimidinone. The 5-(4-fluorophenyl)-3-methyl-2- (phenylmethylamino)-6-(4-(2-amino)pyridyl))-4(3H)pyrimidinone was converted in the manner of the above substituting hydrocinnamoyl chloride for acetyl chloride and 5-(4-fluorophenyl)-3-methyl-2-(phenylmethylamino)-6- (4-(2-amino)pyridyl))- 4 (3H)-pyrimidinone for 5-(4fluorophenyl)-3-methyl-2-((3-phenylpropyl)-amino)-6-(4- (2-amino)pyridyl))-4(3H)-pyrimidinone to afford the title compound after chromatography: MS 534 R NHCH 2 Ph
R
3 2
H
R
3
(CO)CH
2
CH
2 Ph Example General procedure for the preparation of 5-(4-fluorophenyl)-6-(4-pyridyl)-2-thioalkyl-4(3H)pyrimidinones Step A. Ethyl 2-(4-fluorophenyl)-3-oxo-3-(4-pyridyl)propionate: S F 0 OEt 0 OEt A -yN OEt N (According to: Legrand and Lozac'h, Bull. Soc. Chim.
Fr., 79-81 (1955)).
A mixture of ethyl 4 -fluorophenylacetate (13 g, 71.35 mmol), ethyl isonicotinate (10.7 ml, 71.4 mmol) and sodium spheres (1.64 g, 71.34 mmol) was heated at 90-95 0 C under argon. The mixture started to reflux and WO 98/24780 PCT/US97/22949 121 gradually turned into a solid. After 2.5 h, the mixture was neutralized with dil. acetic acid with cooling followed by extraction with dichloromethane. 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 6
H
14
FNO
3 requir. 287.3 'H-NMR (CDC1 3 (ketone enole 1 0.33): d 13.50 0.3H, OH-E), 8.81 2H, Pyrid.-K), 8.48 0.66 H, Pyrid.-E), 7.72 2H, Pyrid.-K), 7.38 2H, PhF-K), 7.14-7.04 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- 1.26 Step B. 5-(4-fluorophenvl)-6-(4-pyridyl)-2-thiouracil: F 0 H 2 N F S O OEt H 2 N
NH
S0 iN SH
N
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 0 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 HFNO3S 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 WO 98/24780 PCT/US97/22949 122 and a dark brown solid was filtered using a Buchner funnel. The collected solid.was suspended in acetone 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 procedure: 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: 5-1 5-( 4 -Fluorophenvl)-2-(2-henylethvl)thio-6-(4- Dvridvl)-4(3H)-pyrimidinone: MS 404.2
C
23
H
1 FNOS 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, CHS), 3.00 2H, CH 2 R 5-2 5-(4-Fluorophenvl)-2-(3-phenvlpropvl)thio-6-(4pridyl)-4(3H)-pVrimidinone: MS 418.0
C
24
H
20
FN
3 0S requir. 417.5. 1 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, CHS), 2.71 2H, CHPh), 2.03 2H, CH) R= Q s WO 98/24780 PCTIUS97/22949 123 5-3 5-(4-Fluorophenvl)-2-(2-pohenoxvethvl)thio-. (4.
pvridvl)-4(3H)-pvrimidinone: MS 420.0
C
2 3
H
1 8
FN
3 0 2 S requir. 419.5. 1 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 2 3.58 2H, CH 2
S).
R 0.
5-4 5-(4-Fluorophenyl)-2-(2-henlaminoethvl)thio-6-(4- Pvridyl)-4(3H)-Pyrimidinone: MS 419.0
C
23
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 2CH 2 Example 6 General procedure for the preparation of 2-N substituted (4-fluorophenyl) (4-pyridyl) -4 (3H) pyrimidinones: Step A. 5-(4-Fluorophenyl)-2-methylthio-6-(4-pyridyl)- 4 (3H) -pyrimidinone: F
F
0 0 NH NH I NSH N SCH 3 N~
N
Methyl iodide (90 ml, 1.44 nmol) 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 WO 98/24780 PCT/US97/22949 124 2:1, 1:1, 1:2) to provide the title compound as a solid. MS 314.2
C
1
,HFN
3 OS requir. 313.3.
IH-NMR (DMSO-d d 13.10 8.47, 7.22 (2m, each 2H, Pyrid.), 7.16, 7.10 (2m, each 2H, PhF), 2.56 3H, CH Step B. General procedure: F
F
S NH
NH
N SCH 3 N NR R 2 1 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 methanoldichloromethane or dichloromethane-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 -Chlorophenl)ethyl-amino)-5-(4fluorophenvl)-6-(4-pyridl)-4(3H) -pyrimidinone:
MS
421.2
C
23 ,,HC1FN0 requir. 420.9. 1
H-NMR
(DMSO-d,): d 11.24 8.44, 7.16 (2m, each 2H, Pyrid.), 7.43, 7.38 (2dd, each 1H, PhC1), 7.30, 7.26 (2dt, each 1H, PhCl), 7.10-7.00 2H, PhF), 6.74 (bs, 1H, NH), 3.60 2H, CHN), 3.03 2H, CH 2
H
~R
N-
Cl 6-2 5-(4-Fluorophenvl)-2-(( 3 -henvlropyl)-amino)-6-(4pvridvl)-4(3H)-pyrimidinone: MS 401.2
C
2 4
H
21
FN
4 Orequir. 400.5. 'H-NMR (DMSO-d): d 11.16 (bs), 8.44, 7.14 (2m, each 2H, Pyrid.), 7.32-7.01 9H, Ph, WO 98/24780 PCt/US97/22949 125 PhF), 6.78 (bs, NH), 3.36 2H, CH 2 2.67 2H, CHPh), 1.89 2H, CH').
N
6-3 5-(4-Fluorophenyl)-2-((l-methl-3-phenyliropvl)amino) -6-(4-Dyridyl)-4 3 H)-Pvrimidinone: A reaction time of 15 h at 180 C was required. MS 415.0
C
25
H
23
FN
4 Orequir. 414.5. 'H-NMR (CDC1 3 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
3 2.61 2H, CH 2 Ph), 1.67 2H, CR 2 1.08 (d, 3H, CHO).
CH
3
N
R=
H
6-4 5-(4-Fluorophenyl)-2-((3-imidazolyipropyl) -amino)- 6-(4-pvridyl)-4(3H) -pyrimidinone: MS 391.0
C
21
H
19 FNOrequir. 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 2H, CH 2 2 2 -Aino-3-henvlropyl)-a ino).5.(4 fluorophenyl) (4-pyridyl) -pyriidinone hydrochloride: The reaction was done at 170 0 C for 7 h.
MS 416.1 C26H22FN50 requir. 415.5.
1 R N
NH
2
H
WO 98/24780 PCT/US97/22949 126 Example 7 (4-Fluorophenyl) -2-hydrazino-6- (4-pyridyl) -4 (3H) pyrimidinone 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 5 HFNsO requir.
297.3. 'H-NMR (DMSO-d 6 d 8.41, 7.12 (2m, each 2H, Pyrid.), 7.05, 7.00 (2m, each 2H, PhF).
R
NH-NH
2 Example 8 General procedure for the preparation of 5-aryl-2,6dipyridyl (3H) -pyrimidinones 8-1 H 0 2 O I NH N
N
N OEt
N
8-2
F
2 1- F
NH
OEt
N
N 4 N 8-3 N 0 2 CN +N N 0
NH
OEt
N
N
N
8-4
F
2 0 0 NH N OEt WO 98/24780 WO 9824780PCTIUS97/22949 127 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 mmoJ4, cyanopyridine (6.24 imnol) and sodium methoxide rnmol) 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.
The following compounds were prepared according to this procedure using the appropriate starting materials: 8-1 5-Phenvl- 2 6 -bis-(4-pyridyl)-4-(3H)'pvrimidinone:
MS
327.2 C 20
H
14 N 4 Orequir. 326.4. 'H-NMR (DMSOd 6 d 8.78, 8.47, 8.13 (3m, each 2H, Pyrid.), 7.40-7.14 (in, 7H, Ph, Pyrid.).
8-2 5-(4-Fluoroohenvl)-2,6-bis-(4-pyridyl)-4(3H) ipyrimidinone: MS 345.2 C 20
H
13 FN 4 0 requir.
344.4 1 H-NMR (DMSO-d 6 d 8. 80, 8.49, 8.13 (3m, each 2H, Pyrid.), 7.40-7.08 (in, 6H, PhF, Pyrid.).
8-3 2,5S,6-Tris- (4-pyvridvl) -4 (3H) -Pvrridinone 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,) 8.65, 8.45, 8.35, 8.18, 7.25, 7.13 (6m, each 2H, Pyrid.).
8-4 5-(4-Fluoro-phenvl)-2,6-bis-(3-pvridvl)-4(3H)- Pyrimidinone: MS 345.2 C 20
H
13 FN 4 0 requir.
344.4 1 H-NMR d 9.34, 8.77, 8.54, 8.48, 7.78, 7.60, 7.34 (7m, 3xlH, 2H1, 3x11, Pyrid.), 7.26, 7.15 (2m, each 2H, PhE).
WO 98/24780 PCT/US97/22949 128 Example 9 3- (3 -trimethylsilyl-2-propynyl)-5- (4-fluorophenyl) -2methylthio-6- (4-pyridyl) -4 (3H) -pyrimidinone F 0.
N TMS N SMe The preparation of the title compound was carried out in the same manner as 3 -ethyl-5-(4-fluorophenyl)-2methylthio-6-(4-pyridyl)-4(3H)-pyrimidinone with the following substitution: 3-bromo-l-(trimethylsilyl)-lpropyne was used in place of ethyl bromide.
Example 6- (4-Fluorophenyl) -2-methyl (3-phenyipropyl) -7pyridin-4-yl-lH-imidazo(1, 2 F0
NN
N N N NO Ph A neat mixture of 3 3 -trimethylsilyl-2-propynyl).
5-(4-fluorophenyl)-2-methylthio-6-(4-pyridyl)-4(3H)pyrimidinone (50 mg, 0.12 nmol) and 3-phenyl-lpropylamine (67 mg, 0.47 nmol) was warmed to 190 0 C for 17 h. After cooling to 23 0 C, the reaction mixture was applied directly to purification via flash chromatography (step gradient l%MeOH:CC13 then then to afford the desired product: MS 439 WO 98/24780 WO 9824780PCTIUS97/22949 129 Exampl~e ii 6- (4-Fluorophenyl) -2-methyl-l-benzy2- 7-pyridin-4-y2-1Hirnidazo 2 F
"O
N'N
N N P The preparation of the title compound was carried out in the same manner as 6-( 4 -Fluorophenyl)2methyl-l.
(3-phenyl propyl) 7 -pyridin-4-yl-1H-imidazo (1,2with the following substitution: benzylamine for 3 -phenyl-l-propylamine; MS 411 (M-eH)I.
Example 12 General procedure for the preparation of 6-substituted 3-phenyl-4- (4-pyridyl) -2 (lH) -pyridones Step A. General procedure f or the poreparation of 1aryl-3- 4 -pvridvl)-2-propene-l-one H 0 N. 9 0 0
R
rN 1-10 R NC At ice-bath temperature, piperidine (206 ml), acetic acid (206 ml) and 4 -pyridinecarboxaldehyde (1.6 ml, 16.6 mmol) were mixed. Then the acetophenone (12.0 mmol) was added at rom temperature and the mixture was heated at 130*C for 1.5 h. The reaction mixture was diluted with dichloromethane, washed with aqueous sodium hydrogencarbonate and water followed by drying and evaporation. The crude product was purified by column chromatography on silica gel (hexane-acetone 3:1).
The following compounds were prepared according to this procedure using the apropriate acetophenone derivative: 1-Phenyl-3-(4-pyridyl)-2-propene-l.one: MS 210.1 C 14
H
1 NO requir. 209.3.
WO 98/24780 WO 9824780PCT/US97/22949 130 1- (4-Methyiphenyl) (4-pyridyl) 2 -propene-1-one: ms (in/z) :2 24. 2 C 15 13 N Orequir. 223 .3.
1- (4-Ethyiphenyl) (4-pyridyl) 2 -propene-1-one: Ms :2 37. 8 C 16 HNO requir. 237 .3.
1- (4-Isopropyiphenyl) -3--(4-pyridyl) 2 -propene-l-one:
MS
:252.0
C
1 7
H
1 7 Orequir. 251 .3.
1- (2-Methyiphenyl) (4-pyridyl) 3 -propene-l-oie:
MS
:223.8
C,,
5 13 NOrequir. 223 .3.
1- 4-Dimethyiphenyl) (4-pyridyl) 2 -propene-l-one:
MS
:2 38. 0 C 1615 N Orequir. 2 3 7.3.
1- (2-Methoxyphenyl) (4-pyridyl) 2 -propene-l-one:
MS
2 40. 0 C 15
H
1 3 N0 2 requir. 239.3 1-(4-Chlorophenyl) (4-pyridyl) 2 -propene-1-one:
MS
244.0
C,
4
H
1 0 ClNOrequir. 243.7.
1-(4-Cyanophenyl)-3- (4-pyridyl) 2 -propene-1-one:
MS
:235. 1 (M-iH) C,,H 1
N
2 Orequir. 234.3.
l-(a-Naphthyl)- 3 -(4-pyridyl)2propene-l-one: MS 260.0
C
1
,H
3 NO requir. 259.3.
l, 3 -Bis-( 4 -pyridyl)-2-propenelone: MS 211.0
C
13
H
10
N
2 Orequir. 210.2.
3 4 -Pyridy-l-( 2 -thienyl)-2-propene-lone: MS 2 16. 0 C 1 2 H NOS requir. 215 .3.
1-2Frl3(-yiy)2poeeloe MS 200.0
C
12
H
9 NO requir. 199 .2.
l-Cyclohexyl-3- (4-pyridyl) 2 -propene-l-one was prepared in the same way using acetylcyclohexane: MS 216.2 C1,H 1 ,NOrequir. 215.3.
l-tert-Butyl-3- (4-pyridyl) -2-propene-1-one: A mixture of 3,3-dimethyl-2-butanone (2.5 ml, 20.0 minol), 4pyridinecarboxaldehyde (2.15 ml, 22.3 rmnol), ethanol (7.6 ml), and 4.5% aqueous sodium hydroxide (4.6 ml) was kept at room temperature for 12 h. It was diluted with dichioromethane, washed with aqueous hydrochloric acid and water, dried and evaporated. Subsequent column chromatography (hexane ethyl acetate provided the title compound. MS 190.4 C 12
H
15
N
requir.189 .3.
WO 98/24780 PCT/US97/22949 131 Step B. General procedure for the preparation of 6substituted 3-phenvl-4-(4-pyridyl)-2(1H) -pyridones: 0 NR 0 O
NH
2
R
1
'R
J
N
N
Sodium (40 mg, 1.74 mmol) was dissolved in a stirring mixture of phenylacetamide (880 mg, 6.51 mmol) and ethanol (5ml). If solubility allowed, the 1substituted 3-(4-pyridyl)- 2 -propene-l-one (5.4 mmol) was added portionwise as an ethanolic solution (20 ml) to the refluxing phenylacetamide solution or it was added at room temperature as a solid. The mixture was kept under reflux for 1.5 h and was then allowed to reach room temperature. 2N Hydrochloric acid was added to a pH value of 5 followed by the addition of a few ml of water. The product that crystallized from this mixture was filtered, washed subsequently with ethanol, water, ethanol and recrystallized from methanol. If the product did not crystallize from the reaction mixture on addition of hydrochloric acid, then the mixture was evaporated and the remainder taken up in dichloromethane. The organic solution was washed with water, dried and evaporated. The resultant product was crystallized from hot acetone and recrystallized from methanol.
The following compounds were prepared according to this procedure using the 2 4 -pyridyl)-2-propene-l-one derivatives described in Example 12.a: 12-1 3,6-Diphenvl-4-(4-pyridvl)-2 (H)-pyridone:
MS
325.4 C 22
H
1 6 N2 requir. 324.4. 'H-NMR (DMSOd) d 8.63 2H, Pyrid.), 7.86 2H), 7.58-7.45, 7.29-7.08 (2m).
WO 98/24780 PCTIUJS97/22949 132
R
12-2 6 4 -Methvl~henl)-3-phenl4(4-pvridyl)-2.(lH)- Pyvridone: -MS 339.2 C 23
H
1 N 2 requir. 338.4.
1 H-NMR (DMSO-d, 6 d 8.44 (mn, 2H, Pyrid.), 7.79 2H), 7.32 7.26-7.01 (mn, 7H, Ph, Pyrid.), 6.67 (bs, 1H).
R=H
3 CC)0 12-3 6-( 4 -Ethvlphenvl1)-3-phenv1-4-(4..pvridV1)- 2 (lH)- Pyridone: -MS 353.0 C 24
H
20
N
2 requir. 352.4.
1 H-NMR (DMSO-d,): d 8.42 (in, 2H, Pyrid.), 7.79 2H1), 7.33 2H), 7.24-7.06 (mn, 7H, Ph, Pyrid.), 6.65 (bs, 1H, CH=) 2.66 2H, CE 2 1.21 3H, CH 3 12-4 6 4 -Iso~ropvlphenyl)-3-heny-4-L4pyridvl)-2(1H) Pyridone: MS 367.0 C 25
H
22
N
2 requir. 366.5.
1 H-NMkR (DMSO-d 6 d 8.45 (mn, 2H1, Pyrid.), 7.82 2H1), 7.39 2H1), 7.28-7.10 (mn, 7H1, Ph, Pyrid.), 6.67 (bs, 1H1, 2.98 (in, 1H, CH(CH) 2 1.27, 1.25 (2s, each 3H, 2CH 3 R 3
C-
H
3
C
12-5 6-( 2 -Methv1thenv1)-3-henv1-4-(4-pvridv1)-2 (1H)- Pyridone: MS 339.2 C 23
H
1
N
2 Orequir. 338.4.
'H-NMR (DMSO-d, 6 d 8.40 (in, 2H1, Pyrid.), 7.45-7.09 (mn, 11H1, Ph, Pyrid.), 6.21 (bs, 1H1, 2.39 3H1, CHO'.
CH
3 12-6 6 2 4 -DimethvlThenyl)-3phenyl-.4-(4-pvridvl)- 2(lH)-lpvridone: MS 353.0
C
24 11 20 N 2 0 requir.
352.4. 'H-NMR (DMSO-dd): d 8.42 (in, 2H, Pyrid. 7.29 WO 98/24780 PCTIUS97/22949 133 1H), 7.23-7.06 9H, Ph, Pyrid.), 6.17 (bs, 1H, 2.34, 2.31 (2s, each 3H, 2CH 3
H
3 C ja CH 3 12-7 6 2 -Methoxvphenvl)-3-Dhenvyl-4-(4.pyridyl) 2 Pyridone: MS 355.0
C
23
HUN
2
O
2 requir. 354.4.
'H-NMR (DMSO-d,): d 8.41 2H, Pyrid.), 7.49 (bd, 1H), 7.44 1H), 7.24-7.06 8H, Ph, Pyrid.), 7.02 (dt, 1H), 6.32 (bs, 1H, 3.82 3H, CH').
R1=t~
OCH
3 12-8 6 4 -ChloroT~henv1)-3-phenvl-4(4-.pyridV1)-2(lH)pyridone: MS 359.2
C
22
H,
5 C1N 2 0 requir.
358.8. 'H-NMR (DMSO-d): d 8.42 2H, Pyrid.), 7.93 (bd, 2H), 7.54 2H), 7.26-7.08 7H, Ph, Pyrid.), 6.80 (bs, 1H, CH=).
R1 12-9 6-(4-Cyanophenl)-3-phenvl-4-(4-pyridyl)-2(lH)- Pvridone: MS 350.2 C 2 3H 1 5
N
3 requir. 349.4.
1H-NMR (DMSO-d,): d 8.45 2H, Pyrid.), 8.16 (bd, 2H), 7.98 2H), 7.32-7.00 8H, Ph, Pyrid., CH=).
1 12-10 6-(a-Naphthyl)-3-Thenvl-4-(4-yridyl)-2(l jvridone: MS 375.0
C
26
H,N
2 0requir. 374.5.
1 H-NMR (DMSO-d,): d 8.38 2H, Pyrid.), 8.06-7.98 (m, 3H), 7.67 (dd, 1H), 7.62-7.54 3H), 7.25-7.11 7H, Ph, Pyrid.), 6.38 (bs, 1H, CH=).
12-11 3-Phenyl-4,6-bis-( 4-vr idyl)-2 H) -pyidone: MS 326.0
C
21
H
15
N
3 0 requir. 325.4. 'H-NMR WO 98/24780 PCT/US97/22949 134 (DMSO-d: d 8.69, 8.43 (2m, each 2H, Pyrid.), 7.92 (bs, 2H), 7.28-7.05 8H).
R
N~
12-12 3 -Phenvl-4-(4-pvridy1)-6-(2-thienvl)-2(1H) pyridone: MS 331.0
C
2 0
H
14
N
2 OSrequir. 330.4.
1 H-NMR (DMSO-d): d 8.44 2H, Pyrid.), 7.90, 7.70 (2bd, each 1H), 7.28-7.08 9H).
R1= 12-13 6 2 -Furvl)-3-phenvl-4-(4pyridyl)-2(1H) pyridone: MS 315.0
C
20
H
14
NO
2 requir. 314.4.
1 H-NMR (DMSO-d,): d 8.44 2H, Pyrid.), 7.90 1H), 7.43 (bs, 1H), 7.27-7.08 7H, Ph, Pyrid.), 6.71 (m, 2H).
R'
12-14 6-Cyclohexvl-3-phenyl-4- (4-pyridyl)-2 (1H)pyridone: MS 331.2 C 22
H
22 NOrequir. 330.4.
'H-NMR (DMSO-d,): d 8.40 2H, Pyrid.), 7.22-7.13, 7.10-7.03 (2m, 7H, Ph, Pyrid.), 6.04 (bs, 1H, CH=), 1.95-1.15 cyclohex.).
R1 12-15 6-tert-Butyl-3-phenyl-4- (4-pyridyl)-2(1H)- Pyridone: MS 305.0 C 0
H
2 0
N
2 Orequir. 304.4.
H1-NMR (DMSO-d,): d 8.39 2H, Pyrid.), 7.20-7.12, 7.10-7.02 (2m, 7H, Ph, Pyrid.), 6.02 (bs, 1H, 1.31 9H, 3CH)
(CH
3 3
C-
WO 98/24780 PCTUS97/22949 135 Example 13 Procedure for the preparation of Ben zyl ethylendiamine NH NH 2 MS-l,2-Benzylethylendiamine: The diamine was prepared according to the literature Brunner, P. Hankofer, U.
Holzinger, B. Treittinger and H. Schoenenberger, Eur. J.
Med. Chemn. 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-3phenyipropyvl) -amino) (4-fluorophenyl) -3-rnethyl-6- (4pyridyl) -4 (3H) -pyrimidinone N
N"*
N
N'
N N N I.
NN
H H 2 N- Hd NHAC 2- -2-Acetamido-3-phenylpropyl) -amino) (4fluoroiohenvl) -3-methyvl-6- (4-pyridyl) -4 (3H) -pyrimidinone: A solution of 2 -amino-3-phenylpropyl)-amino) 4 -fluorophenyl)-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/dichioromethane) provided the title compound.
MS 472.3 C27H26FN50 2 requir. 471.5.
WO 98/24780 PCT/US97/22949 136 Example Procedure for the preparation of 5 -(4-Fluorophenyl)-2- 2 -N-isopropylamino-3-phenylpropyl)-amino)-3methyl-6-(4-pyridyl)-4(3H)-pyrimidinone hydrochloride F OFN 0 Nz N~ N
N
N N1 N N NN H N NH
NH
2 H N 5-(4-Fluorophenyl)-2-(((S)- 2 -N-isopropylamino-3phenylpropyl)-amino)-3-methl-6-(4-pyridyl) -4 (3H) pyrimidinone hydrochloride: Sodium triacetoxyborohydride (23 mg, 0.109 mmol) was added to a strirring mixture of 2 -amino-3-phenylpropyl)amino)-5-(4-fluorophenyl)-3-methyl-6-(4-pyridyl) -4(3H)pyrimidinone hydrochloride (50 mg, 0.107 mmol), triethylamine (15 ml, 0.108 mmol) and acetone (7.9 ml, 0.108 mmol) in 1,2-dichloroethane (0.8 ml). After 4h, 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 column of silica gel methanol/chloroform) provided the title compound as a free base which was converted into the monohydrochloride by the addition of 4N hydrochloric acid/dioxane (21 mml, 0.08 mmol) to its methanolic solution (1 ml) and subsequent evaporation. MS (m/z) 472.1 C28H3FN50 requir. 471.6 (free base).
WO 98/24780 PCTIUS97/22949 137 Example 16 Procedure for the preparation of 5-(4-Fluoropherzyl)-2- 2 -N-cyclohexylarnino-3-phenylpropyl) -amino) -3methyl-6- (4-pyridyl) -4 (3H) -pyriznidinone hydrochloride F0 F 1 0 N N 0 N NN I N N N H NH1!0 H NH 2) (4-Fluorophenyl) 2 -N-cvclohexylanino-3- Phenyipropyl) -amino) -3-methvl-6- (4-pyridyl) -4 (3H) pyrimidinone hydrochloride: Utilizing cyclohexanone, (4-f luorophenyl) 2 -N-cyclohexylamino-3phenylpropyl)-amino) -3-methyl-6--(4-pyridyl) -4(3H)pyrimidinone was prepared in the same manner as 5-(4fluorophenyl) -2-CC(S) 2 -N-isopropylamino-3phenyipropyl) -amino) -3-methyl-6- (4-pyridyl) -4 C3H) pyrimidinone: MS 511.6 C31H34FN5o requir.
511.6 (free base).
Example 17 Procedure for the preparation of -2-N-n- Butylamino-3-phenylpropyl) -amino) (4-fluorophenyl) -3methyl-6- (4-pyVridyvl) -4 (3H) -pyrimidinone hydrochloride N' ~N N N I N N' N HN- N
H
2 2- 2 -N-n-Butlanino-3-phenylp)ropvl) -amino) fluorolphenyl) -3-methyl-6- (4-pyvridyl) -4 (3H)-pyrimidinone hydrochloride: Sodium triacetoxyborohydride (28 mg, 0.13 mmol) was added to a strirring mixture of 2-C(C(S)- 2-amino-3-phenylpropyl) -amino) 4 -fluorophenyl) -3methyl- 6 -C4-pyridyl)-4(3H)-pyrimidinone C41 mg, 0.095 WO 98/24780 PCT/US97/22949 138 mmol) and butyraldehyde (8.5 ml, 0.094 mmol) in 1,2dichloroethane (0.8 ml). After 2 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 column of silica gel methanol/chloroform) provided the title compound as a free base which was converted into the monohydrochloride by the addition of 4N hydrochloric acid/dioxane (12 mml, 0.048 mmol) to its methanolic solution (1 ml) and subsequent evaporation. MS 486.2 C29H32FN50 requir. 485.6 (free base).
Example 18 Procedure for the preparation of Dimethylamino-3-phenylpropylamine 0 0
H
2
H
2 N HN 2
N
H2N
N
N-Dimethvlamino-3-phenvlpropylamine: Sodium triacetoxyhydride (13.0 g, 61.3 mmol) was added to a 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 (S)-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.
WO 98/24780 PCT1US97/22949 139 Example 19 Procedure for the preparation of 2 Dime thylarnino-3-phenylpropyl) -amino) 4 -fluorophenyl- 3-me thyl-6- (4-pyridyl) -4 (31) -pyrimidinone hydrochloride a
N
N
2 N N 0
NN
N
Step A. 5- (4-Fluorophenyl) 3 -methyl-2-methvlsulfonvl-6 (4-pyvridyl) -4 (3H) -pyrimidinone: A mixture of 5- (4fluorophenyl) 3 -methyl-2-methylthio-6- (4-pyridyl) -4 (3H) pyrimidinone (400 mg, 1.22 mmol) and OxoneR (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 dichioromethane, drying of the organic solution and evaporation. The resulting white solid was used without purification in the next step.
Step B. 2- 2 -NN-Dimethylamino-3-phenvlpropvyl) amino) 4 -fluorophenvl-3-methv1-6-(4-pyvridyl) -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 inmol) and dimethylamino-3-phenylpropylamine (600 mrnl, -3.4 mmol) was stirred at room temperature for 1h and then briefly warmed at 50C.- Column chromatography on silica gel (3 5% methanol/chloroform) provided the title compound as a free base which was converted into the monohydrochloride by the addition of 4N hydrochloric acid/dioxane (160 niml, 0.64 mmol) to its methanolic solution (4 ml) and WO 98/24780 PCT/US97/22949 140 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)-pyridyl))-propionate: A solution of 2 -chloroisonicotinic acid 2 5.0g, 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 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 WO 98/24780 PCT/US97/22949 141 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 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 (Na2S04), concentrated in vacuo to afford the Ethyl 2 -(4-fluorophenyl)-3-oxo-3-(4- (2-acetamido)-pyridyl)-propionate.
Step B. 5-( 4 -fluorophenyl)-6-(4-(2-acetamido)vpridyl))- 2-thiouracil: Ethyl 2-(4-fluorophenyl)-3-oxo-3-(4-(2acetamido)pyridyl)-propionate (1.3 g, 3.78 mmol) and 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 98/24780 PCT/US97/22949 142 Example 21 Procedure for the preparation of (S)-2-N-Ethylamino-3phenylpropyl amine 0.
H
2 N N
H
2
N
H
2 N
NH
NH
2 2 -N-Ethylamino-3-phenvlpropylamine: 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 mnm) at 55 0 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 C1H1l8N2 requir.
178.3.
Example 22 Procedure for the preparation of 2-Amino-2-methyl-3phenylpropyl amine
NH
2
NH
2 2 -Amino- 2 -methvl-3-phenvlpropylamine: 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 phenylalanine amide was filtered and dried (2.5 g).
WO 98/24780 PCT/US97/22949 143 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-3phenylpropyl amine SI3NH 2
SCH
3 2-Methyl-3-phenylpropylamine: 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 98/24780 PTU9124 PCTfUS97/22949 144 Example 24 Procedure for the preparation of 5-(4-Fluorophenyl)-3methyl ((2-rethy-3-phenylpropyl) amino) (4-pyridyl) 4 (3H) -pyrimidinone hydrochloride N'N 0 N N S 0H NI
N
H
2 N
CH
3
CH
3 (4-Fluorophenyl) -3-methyl-2-(C(2-methv-3-pohenylpropyl) amino) (4-pyridyl) -4 (3H) -pyrimidinone hydrochloride: A mixture of crude 5- (4-f luoropheiyl) -3-methyl-2methylsulfonyl-6- (4-pyridyl) -4 (3.H)-pyrimidinone (520 mg g, 1.45 Inmol) and 2 -methyl-3-phenylpropylamine (1.5 g, 10.1 mniol) was heated at 50 0 C for 30 min. Column chromatography on silica gel methanol/dichioromethane; hexane-acetone= 2 1) provided the title compound. MS 429.4 C26H25FN40 requir. 428.5 (free base).
Example Procedure for the preparation of I-Phenyl-l,3propan edi aiine
NH
2 1-Ph.enyl-1 3-propanediamine: 3 -Phenyl-3-aminopropionic acid G. Cohen and S. Y. Weinstein, J. Am. Chem. Soc.
86, 725-728, 1964) was converted into 1-phenyl-1,3propanediamine as reported in the literature Kojima and J. Fujita, Bull. Chem. Soc. Jpn. 55, 1454-1459 (1982)).
WO 98/24780 PCT/US97/22949 145 Analogously, 1-(2-fluorophenvl)-1,3-propanediamine, 1- (2-methylphenvl)-1,3-propanediamine and 1-(2chlorophenvl)-1,3-propanediamine have been prepared.
Example 26 Procedure for the preparation of 3-Ethyl-5-(4fluorophenyl) -2-methylthio-6- (4-pyridyl) -4 (3H) pyrimidinone F 0
F
NH
N
'Y N SCH3 'N S 1 CH3 N N N 3 -Ethvl-5-(4-fluorophenvl)-2-methvlthio-6-(4-pvridvl)- 4(3H)-pyrimidinone: 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-dimethylformamide (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 column of silica gel (hexane-acetone 3:1, 2:1).
provided in the second main fraction the title compound as a solid.
Example 27 Procedure for the preparation of 3-Ethyl-5-(4fluorophenyl)-2-methylsulfonyl-6-(4-pyridyl) -4 (3H)pyrimidinone F O F
O
N
N
1N SCH 3 k N I CH3 N N N II N
N.
WO 9824780PCT/US97/22949 146 3 -Ethyl -5 -f luorophenyl) -2 -me thvsul fonl 6 4 pyvridyl) -4 (3H) -pyrimidinone: A mixture of 3-ethyl-5- (4fluorophenyl)-2-ethylthio6(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 dichioromethane, 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-Arnino-3phenyilpropyvl) -amino) -3-ethyl-5- (4-f luorophenyl) (4pyridyl) -4 (3H) -pyrimidinone hydrochloride F N
N
N H NH 2 2- -2-Anino-3-Dhenvlipropyl) -amino) -3-ethyl-5- (4fluorophenyl) (4-pyridyl) -4 (3H) -pyrimidinone hydrochloride: A mixture of 3-ethyl-5- (4-f luorophenyl) 2-methylthio-6- (4-pyridyl)-4(3H) -pyrimidinone (150 mg, 0.44 iriiol) and 2 -benzylethylendiamine (200 ml, -1.3 mmol) was heated at 190-C for 4.5 h. Column chromatography on IatrobeadSR (chloroform :methanol triethylamine 90 :7 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 rnmol) and methanol ml). Filtration provided the title compound. MS 444.0 C265H27FN 5 0 requir. 443.5 (free base).
WO 98/24780 WO 9824780PCTIUS97/22949 147 Example 29 Procedure for the preparation of 3-Ethyl fluorophenyl) ((2-me thy-3-phenylpropyl) amino) (4pyridyl) -4 (3H) -pyrimi din one hydrochloride
FN
NN
N N N H CH 3 (4-f luorophenyl) ((2-methy-3-phenylipropyl) amino) (4-pyvridyl) -4 (3H) -Tvrirnidinone hydrochloride: A mixture of crude 3-ethyl-5- (4-f luorophenyl) -2methylsulfonyl-6- (4-pyridyl) -4 (3.H)-pyrirnidinone (320 mg g, 0.89 mmol) and 2 -methyl-3-phenylpropylamine (600 ml, -4 mmol) was heated at 60'C for 2 h. Column chromatography on silica gel (hexane -acetone= 2 2methanol/dichloromethane) provided the title compound. MS 443.2 C27H27FN40 requir.
442.5.
Example Procedure for the preparation of 3-(2- Me thyiphenyl )p-ropyl amine N
NH
2 aCH 3 3- (2 -Methvlp~henvl prolpylamine: Diethyl cyanomethylphosphonate (5.0 ml, 30.9 mmcl) was added to* a stirring suspension of sodium hydride (60% oily suspension, 1.24 g, 31 mmol) in tetrahydrofuran (50 ml) 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) WO 98/24780 PCT/US97/22949 148 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 10 to provide the title compound as an oil.
Example 31 Procedure for the preparation of 2-amino-3-(2fluorophenyl)-propylamine N.F NH 2
N
2 H2 Step A. Methyl 2-amino-3-( 2 -fluorophenvl)propionate: (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 CoH, 2 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, washed with cold water and 2 -amino-3-(2-fluorophenyl) propionamide was collected as a white solid. MS 183.1 CgHFN 2 0 requir. 182.2.
Step C. 2-Amino-3-( 2 -fluorophenl) -propylamine: 2- Amino-3-(2-fluorophenyl)propionamide was added carefully to a chilled (50) mixture of LAH (1.0g, 26.3 mmol) and WO 98/24780 PCT/US97/22949 149 ml THF under argon. The reaction was then heated at reflux for 10 hrs. The reaction was cooled to 5°C and carefully treated with Na 2
SO
4 .10 HO. The resulting mixture was stirred for 18 hrs, then filtered to remove the solids. The filtrate was concentrated in vacuo to give an amber oil. MS 169
CH
3
FN
2 requir. 168.19 Example 32 Procedure for the preparation of 5- (4-Fluorophenyl)-2- 2 -N-glycylamino-3-phenylpropyl) -amino) -3-methyl-6- (4-pyridyl) -4(3H)-pyrimidinone hydrochloride F 0 N N O NH 2 5-(4-Fluorophenvl)-2-(((S)- 2 -N-qlvcvlamino-3phenvlpropvl) -amino) -3-methyl-6-(4-pyridyl) -4 (3H) vrimidinone hydrochloride: Ethyl chloroformate (56.8 g1, 0.59 mmol) was added at ice-bath temperature to a stirring mixture of N-(tert.-butoxycarbonyl)glycine (104 mg, 0.59 mmol) and 4-methylmorpholine (65.3 l, 0.59 mmol) in tetrahydrofuran (9 ml). After 50 min, a solution of 2 -amino-3-phenylpropyl)-amino)-5-(4fluorophenyl) -3-methyl-6- (4-pyridyl) -4 (3H) -pyrimidinone (250 mg, 0.58 mmol) in tetrahydrofuran (9 ml) was added at ice-bath temperature. Within 2 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 dissolved in methanol (1.2 ml) and-4N hydrogen chloride/dioxane (1.2 ml) was added. After 1 h at room temperature, it was evaporated and the remainder taken up in dichloromethane followed by washing with aqueous WO 98/24780 PCT/US97/22949 150 sodium hydrogencarbonate, drying of the organic solution and evaporation. Column chromatography on silica gel (dichloromethane methanol conc. ammonium hydroxide 93 7 0.7) provided the title compound as the free base which was converted into the hydrochloride by the addition of 4N hydrogen chloride/dioxane (112 p1, 0.45 mmol) to its methanolic solution (3 ml) followed by evaporation. MS 487.1
C
27
H
2 7
FN
6 0 2 requir.
486.6 (free base).
Accordingly, 2- 2 -N-clvcvlamino-3-phenvlpropyl)amino)-3-methyl-5-(3-methvlphenl) (4-pyridl) -4(3H)pyrimidinone hydrochloride was prepared from amino-3-phenylpropyl)-amino) -3-methyl-5-(3-methylphenyl 6-(4-pyridyl)-4(3H)-pyrimidinone.
Example 33 Procedure for the preparation of 5 4 -Fluorophenyl)-2- 2 -hydroxyacetamido-3-phenylpropyl)-amino)-3methyl (4-pyridyl) -4 (3H) -pyrimidinone 0
N
I
N 4 H NH O OH 5-(4-Fluorophenvl)-2-(((S)-2-hydroxvacetamido-3phenvlpropvl) -amino) -3-methyl-6- (4-pyridyl) -4 (3H) pyrimidinone: Acetoxyacetyl chloride (55 p1, 0.51 mmol) was added at ice-bath temperature to a stirring solution of 2 -amino-3-phenylpropyl)-amino)-5-(4-fluoro phenyl)-3-methyl-6-(4-pyridyl)-4(3H)-pyrimidinone (200 mg, 0.466 mmol) and triethylamine (130 41, 0.93 mmol) in dichloromethane (4 ml). After 50 min, the reaction was quenched by the addition of a drop of methanol followed by evaporation. The resultant material was taken up in a 1:1:1 mixture of methanol/water/triethylamine (3 ml) and WO 98/24780 PCT1US97I22949 151 left overnight. Evaporation and subsequent column chromatography methanol/chloroforme) provided the title compound. MS 488.3
C
27 26
FN
5 0 3 requir.
487.5.
Example 34 Procedure for the preparation of 5-(4-fluorophenyl)-2- -N-methyl urel do) -3 -phenyipropyl) -amino) -3-methyl 6- (4-pyridyl) -4 (3H) -pyrimidinone
N
NN
N IkN H NH 0 oNHCH 3 5-(4-Fluorophenyl)-2-(2-((3-N-methvlureido) -3phenvlpropyl)-amino)-3-methyl-6-(4-pyridyl)-4(3H)pyrimidinone: Methyl isocyanate (6 g1, 0.102 mmol) was added to a solution of 2 -(((S)-2-amino-3-phenylpropyl)amino)-5-(4-fluorophenyl)-3-methyl-6-(4-pyridyl)-4(3H)pyrimidinone (43.6 mg, 0.102 mmol) in dioxane (1.5 ml) at 15 0 C. After 15 min, the solvent was evaporated and the reaction product applied to a silica gel column 7% methanol/chloroform) to provide the title compound.
MS 486.6
C
2 H 27
FN
6
O
2 requir. 486.6.
Example Procedure for the preparation of 5-(4-fluorophenyl)-3methyl-6- (4-pyridyl) 2 -pyrrolidinyl-3-phenylpropyl) amino) -4 (3H) -pyrimidinone hydrochloride 0
N
WO 98/24780 WO 9824780PCTIUS97/22949 152 (4-Fluorophenvi) -3-methyl-6- (4-pyvridyl) -2pyrrolidinvl-3-phenylpropyl) -amino) -4 (3H) -Dyrimidinone hydrochloride: Sodium hydride (60% oily suspension, 84 mg, 2.1 mmol) was added to a solution of arino-3-phenylpropyl) -amino) (4-f luorophenyl) -3methyl-6-( 4 -pyridyl)-4(3H)-pyrimidinone (300 mg, 0.70 Inmol) in NV,N-dimethylformamide (8 ml) at ice-bath temperature. After 30 min, l,4-dibromobutane (108 g±l, 0.91 mmol) was added. Stirring was continued for 30 min at ice-bath temperature, then 20 h at room temperature.
It was neutralized with acetic acid, followed by evaporation. The crude product was purified on a column of silica gel (dichloromethane methanol =93 7; dichloromethane methanol conc. amnmonium hydroxide 93 7 0.7) The resultant product was converted into the hydrochloride by the addition of 4N hydrogen chloride/dioxane (37 gl) to its methanolic solution (2 ml) and subsequent evaporation. MS 484.6 (M+H);l C 29
H
30 FN 5 Orequir. 483.6 (free base).
Example 36 Procedure for the preparation of 5-(4-ffluorophenyl)-2- 3 -N-isopropylamino-3-phenylpropyj) -amino) -3methyl-6- (4-pyridyl) -4 (3H) -pyr irnidinone hydrochloride N NH
NN
N 4 N N 5-( 4 -Fluorophenyl)-2-( C(S) 3 -N-isopropylamino-3- Tphenvipropyl) -amino) -3-methyl-6- (4-pyridyl) -4 (3H) Pyrimidinone hydrochloride: Sodium triacetoxyborohydride (12.9 mg, 0.061 mmol) was added to a strirring mixture of ((S)-3-amino- 3 -phenylpropyl-amino)5(4fluorophenyl) -3-methyl-6- (4-pyridyl) -4 (3H) -pyrimidinone (21.8 mg, 0.051 mmol) and acetone (4.5 gl, 0.061 inmol) WO 98/24780 PC TUS97/22949 153 in l,2-dichloroethane (0.4 ml) After 2.5 h, the reaction was quenched by the addition of sat. aqu.
sodium hydrogencarbonate, followed by extraction with dichioromethane, drying of the organic solution and evaporation. Chromatography on a column of silica gel methanol/chloroformn) provided the title compound as a free base which was converted into the monohydrochioride by the addition of 4N hydrochloric acid/dioxane (12.2 Jgl) to its methanolic solution (1 ml) and subsequent evaporation. MS 472.0 C28H3OFN 5 O requir. 471. 6 (free base) Example 37 Procedure for the preparation of 5- (4-fluorophenyl) -2- 3 -N-i sopropyl amino 3 phenylpropyl) -amino) -3methyl (4 -pyridyl) -4 (3H) -pyrimidinone hydrochloride 0
NH
N
N I& (4-Fluorophenvl) 3 -N-isopropylamino-3- Phenvlpropvl) -amino) 3 -methvl-6-(4-pvridvl) -4 C3H)-z pyrimidinone hydrochloride was prepared from 5-(4fluorophenyl) -2-CC CR) 3 -N-isopropylamino-3phenylpropyl) -amino) -3-methyl-6- C4-pyridyl) -4 C3H) pyrimidinone as described above for its S-enantiomer.
MS
:472.1 C28H 3 oFN 5 O requir. 471.6 (free base).
Example 38 Procedure for the preparation of 2 -(((S)-3-acetamido-3phenylpropyl) -amino) 4 -fluoropheny1) 3-methyl (4pyridyl) -4 (3H) -pyrimidinone WO 98/24780 PCT/US97/22949 154
NH
NN
2- -3-Acetamido-3-phenvlpropvl) -amino) (4fluorophenyl)- 3-methvl-6-(4-yyridyl)-4(3H)- Pyrimidinone: A solutiont of 2 -(((S)-3-amino-3phenyipropyl) -amino) (4-f luorophenyl) -3-methyl-6- (4pyridyl)-4(3H)-pyrimidinone (23.8 mg, 0.055 minol) and acetic anhydride (20 gil, 0.21 minol) in methanol(1 ml) was kept for 30 min at room temperature. Evaporation was followed by column chromatography (dichioromethanemethanol amnmonium hydroxide 93 7 to provide the title compound. MS Cm/z) 472.2 (M-4H) C27H 2 6
FN
5 0 2 requir. 471.5.
Example 39 Procedure for the preparation of(S)-l-Phenyl-1,3propanedi amine NH-tBOC
MH
2 N'N
.NH
2 CS) -l-Phenyl-1. 3 -propanediamine: S-3-N-tert. Butoxycarbonylamino-3 -phenyipropionitrile was prepared according to the literature Wheeler and D.D.
O'Bannon, J. Label.Compds. Radiopharm. XXXI 305- 315, 1992) from D-(-)-a-phenylglycinol. For reduction Mitchell and T.M. Koenig, Synth. Comm. 25 1231- 1238, 1995), borane-methyl sulfide complex (2N, 3 ml, 6 mmol) was added dropwise to a solution of the nitrile (I g, 4.06 mmol) in tetrahydrofuran (6 ml). Methyl sulfide was distilled off and the resulting solution ref luxed for 2.5 h. With ice-cooling, methanolic hydrogen chloride (1N, 3 ml) was added followed by evaporation.
WO 98/24780 WO 9824780PCTIUS97/22949 155 The remainder was taken up in methanol (10 ml) and 4N hydrogen chioride/dioxane (10 ml) was added. After 1 h at room temperature, it was evaporated and the aqueous solution of the resultant product was washed with dichlorornethane. The aqueous solution was made basic by the addition of solid potassium hydroxide followed by repeated dichloromethane extractions. Drying and evaporation of the dichioromethane solution left the crude diainine as an oil. MS 150.8 C 9
HIA
requir. 150.2.
Enantiomeric -I--phenyl-1, 3 -ipropanediamine was prepared analogously from L-(+)-ct-phenylglycinol.
MS
:150.9
C
9 requir. 150.2.
Example Procedure for the preparation of (2R,3R)-2-niethyl-3pheriyl -1,3 -propanediamine Ph
N
2 Ph/ ILN 0 'V"'Me Q"4~<OMe
-NH
2 NH 2 Step A: Methyl 2
S,
3 R,(XS)-3-(N-benzvl-N-amethvlbenzvlamino) 2 -methyl-3-phenvlpropionate was prepared as reported for the 2R,3S,CCR-enantiomer
(S.G.
Davies and I.A.S. Walters, J. Chem. Soc. Perkin Trans.I, 1129-1139 (1994).
Step B: Methyl 2
S,
3 R)-3-ario-2--methvl-3phenvlpropionate:_ A mixturte of methyl 2 S,3R,caS)-3- (N-benzyl-N-a-methylbenzylamin 0 -2-methyl-3phenylpropionate (13.0 g, 33.55 mmol) and 10% palladium- WO 98/24780 PCT/US97/22949 156 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
CH,,NO
2 requir. 193.3.
Step C: (2S,3R)- 3 -Amino-2-methyl-3-phenvlpropionamide: 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
C
0
H
1 4
N
2 O requir. 178.2.
Step D: 2
R,
3
R)-
2 -methyl-3-phen1l-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
C
10
H
1 6
N
2 requir. 164.3.
Accordingly, the enantiomer (2S,3S)-2-methvl-3-phenvl- 1, 3 -propanediamine was prepared from methyl (2R,3S,aR)- 3- (N-benzyl-N-a-methylbenzylamino) -2-methyl-3phenylpropionate. MS 165.3
C,
0
H
1 6
N
2 requir.
164.3.
WO 98/24780 WO 9824780PCT/US97/22949 157 Analogously, the enantiomers (2R. 3S)-2-methyl-3-phenVll, 3 -propanediamjne and (2S,3R)-2-methv-3-Phenv>1,3 ~rolpaniediamine may be prepared from tert.butyl (2S,3S,aR)- and -(2R,3R,axS)-3-(N-benzyl-N-amethylbenzylamino) -2 -methyl- 3-phenyipropionate
(S.
Davies et al., J. Chem. Soc. Chem. Cornmun. 1153-1155, 1993).
Example 41 Procedure for the preparation of BenzyvlpiperazinyV) (4-f luorophenyl) -3-methyl-6- (4pyVridyl) -4 (3H) -pyrimidinone hydrochloride NN H NN N& NH I+ N N1 ly~~ N 00 F 0
NN
N -,elKLNH Step A: (S- 2 -Benzvlpiperazine: At ice-bath temperature, lithium aluminium hydride (1.6 g, 42.16 mmol) was added in portions to a stirring mixture of (S)-2-benzylpiperazine-3, 6-dione (3.0 g, 14.70 mmol) (comm. avail.) and tetrahydrofuran (80 ml). After 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 177.1
C
1 6 N 2 requir. 176.3.
Step B: 3 -Benzvlipiperaziny)-5I(4-fluorophen1)3 meth 1-6- (4-p rid 1) -4 (3H) -pyriridinone hydrochloride: WO 98/24780 WO 9824780PCTIUS97/22949 158 A mixture of crude 5-( 4 -fluorophenyl)-3-methyl-2 methylsulfonyl-6-(4-pyridyl) 4 3 H)-pyrimidinone (434 mg,- 1.21 mmol) and (S)-2-benzylpiperazine (426 mg, 2.42 rnmol) was heated at 105'C for 1 h. The crude reaction product was purified by column chromatography on silica gel (dichloromethane methane 93 dichioromethane methanol conc. ammonium hydroxide 93 0.7).
The resulting material was converted into its hydrochloride by the addition of 4N hydrogen chloride/dioxane (75 gl) to its methanolic solution (3 ml) followed by evaporation. MS 456.5 C27 H26 FN 5 0requir. 455.5(free base).
Example 42 Procedure for the preparation of 5 -(4-ffluorophenyl)-3methyl 3 -phenylpropoxy) (4 -pyridyl) -4 (3H) pyrimi dinone
N
(4-f luorophenyl) 3 -methvl-2-(3-phenlpropDoxv) (4loyridyl) -4 (3H) -pyrimidinone: Sodium hydride (60% oily suspension, 111 mg, 2.79 Inmol) was added to a stirred solution of 3-phenylpropanol (387 mg, 2.85 mmol) in tetrahydrof uran (1 ml) After gas evolution ceased, (4-f luorophenyl) 3 -methyl-2methylsulfonyl6.(4pyridyl)-4(3H)--pyrimidinone (100 mg, 0.279 Inmol) was added and the mixture was heated at 60'C for 30 min.
The reaction mixture was partitioned between dichloromethane and water. The organic solution was washed with brine, dried and evaporated. Column chromatography on silica gel (hexane ethyl acetate =2 1) provided the title compound. MS 416.1 C2 5
H
2 2
FN
3 0 2 requir. 415.5.
WO 98/24780 PCT[US97/22949 159 Example 43 Procedure for the preparation of 5 -(4-fluorophenyl)-3rnethyl-2- (4-phenylbutyl) (4-pyridyl) -4 (3H) pyrirnidinone F 0 Step A: 5-(4-Fluorop~henvl)-2- (4-P~henvlbutvl)-6-(4ipyridvi) -4 (3H) -pvrimidinone: Ethyl 2- 4 -fluorophenyl) 3 -oxo- 3 4 -pyridyl)-propionate (293 mg, 1.02 mmol), 4phenylbutanecarboxamidine (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 1; C25H2 2
FN
3 0 requir.
399 Stelp B: 5-( 4 -Fluorohenvl)-3-methl-2.(4phenvlbutvl)-6 4 -pvridvl)-4(3H)-pyvrimidinone: Methyl iodide (22 Jil, 0.351 mmol) was added to a stirring mixture of 5-(4fluorophenyl) 4 -phenylbutyl) (4-pyridyl) -4 (3H) pyrimidinone (140 mg, 0.351 mmol) and potassium carbonate (49 mg, 0.351 mmol) in N,N-dimethylformamide (5 ml). After 75 min, it was evaporated and the resultant product purified on a silica gel column (hexane acetone =3 1; 2 to provide the title compound. MS 414.3 C26H2 4
FN
3 0 requir.
413 WO 98/24780 PCTIUS97/22949 160 Example 44 The compounds shown in Table I were prepared using the procedures of Examples 1-43.
TABLE I F 0
F
Cli Nt N N 0.
MS 464.0 (M
MS
C25H2 3
FN
5 0 requir. 463.9 C291 F 0
F
N(
N N N C 1 NH
HH
2 N.
MS 498.0
MS
2 2
FN
5 0 requir. 498.4 C241 F 0 F .1 N NN H H 2 N.
SCl MS 464.1
MS
23 C1FN 5 0 requir. 463.9 C211 F 0
F
F
N N N, H NH 2
N.
MS 448.3
MS
C25H2 3
F
2
N
5 0 2 requir. 447.5 C2 5 1 F -z H
NH
2 479.7 I26FN 5 0 requir. 479.6
N
N'N N H
NH
2 416.1 122FN 5 0 requir. 415 N Na N N H NH 2 Wmz): 414.0 124FN 5 0S requir. 413.5 N a A
N
H
436.2 I30FN 5 0 requir. 435.6
NN
N' Nb H HN-O Wmz): 428.1 122FN 5 0 requir. 427.5
N.
MS
C
2 51 MS 448.2 C25H22F 2
N
5 0 requir. 447.3 WO 98/24780 PCTIUS97/22949 F 0% N N MS. H N.H 2 MS(r/z) 486.1 C27H24FN 5 0S requir. 485.4 MS (Mhz) 442. 1 C26H2 4
FN
5 0 requir. 413.5 Example The compounds shown in Table II can be prepared using the procedures of Examples 1-43, wherein R' represents 3-methyiphenyl, 3-chiorophenyl, 3trifluoromethyiphenyl, 4-f luorophenyl, 4 -methylphenyl, 4-chiorophenyl and 3, 4 -dimethylphenyl.
TABLE II Cl N
HLN
2 H NH F WO 98/24780 WO 9824780PCTIUS97/22949 162 NH2
S
0 R
HNH
2
N~
N
H NH NH2 N 11;zt Nz e le
L'
NH2 N j
NH
2 0 R
N
N N H Example 46 Procedure for the preparation of 3-methyl -amino- .3-phenylipropyl amino) (3-triffluoromethyl phenyl1) (4pyridyl) -4 (3H) -pyrimidinone 0
F
3 C
NCH
3 NR H 2 SteD) A. 6-( 4 -pvridvl)-2-thiouracil: Ethyl isoricotinoylacetate (5g, 25.89 inmol) and thiourea (5.94 g, 77.64 inmol) were suspended in anhydrous p-xylene with vigorous stirring. To the mixture, pyridinium p-toluenesulfonate.(150mg) was added and ref luxed for 12-16 h using a Dean-Stark apparatus with WO 98/24780 PCT/US97/22949 163 continuous removal of water (0.5ml). The reaction mixture was cooled and a dark brown solid was filtered.
The collected solid was suspended in acetone (25 ml) and filtered. The acetone washed product contain trace of thiourea, which was removed by trituration with hot water (20-30ml). The title compound was isolated by filtration. MS 206.2 CHN 3 OS requir. 205.3. 1
H-
NMR (DMSO-d6): d 12.65 (bm, 2H, NH and SH), 8.71(m, 2H, pryid.), 7.66(m, 2H, Pyrid.), 6.25 1H, Step B. 3 -Methvl-6-(4-pvridvl)-2-methvlthio-4(3H)pyrimidinone: 6 4 -Pyridyl)-2-thiouracil (1.5g 7.299 mmol) was dissolved in DMF (50 ml) and the mixture was cooled to 0°C. Sodium hydride (0.437 g, 0.730g 60% in oil, 18.25 mmol) was added and the reaction mixture was stirred for 30 minutes. Methyl iodide (1.2 ml, 2.6g, 18.25 mmol) was added dropwise over 15 minutes.
Formation of dimethyl compound was monitored by TLC.
Reaction mixture was concentrated and the residue chromatographed on silica gel column using hexane: acetone 4:1 and 2:1) to obtain the title compound as a solid: MS(m/z):234.1
C
1 H,,N3OS requir. 233.2; 1H- NMR(CDC1 3 8.75 2H, pyridyl), 7.8 2H, pyridyl), 6.75 1H), 3.58 3H, 2.72 (s, 3H, S-CH,).
Step C. 3-Methvl-5-bromo-6-(4-pyridvl) -2-methylthio- 4(3H)-pvrimidinone: 3-Methyl-6-(4-pyridyl)-2-methylthio- 4 (3H)-pyrimidinone (l.00g 4.29 mmol) was dispersed in acetic acid (24 ml) and to the clear solution Bromine 1.5g 9.38 mmol) was added. The reaction mixture stirred at room temperature for 24 h. The mixture was concentrated and the residue was co-evaporated with toluene until all bromine is removed. The crude compound is ready to use in next step. MS(m/z): 312 and 314. C 11 HoBrN 3 OS requir. 311 and 313. 1H-NMR(DMSO-d6):d 8.75 2H, pyridyl) 8.19 2H, pyridyl), 3.67 (s, 3H, 2.80 3H, S-CH 3 WO 98/24780 PCT/US97/22949 164 Step D. 3 -Methyl-5-(3-trifluoromethvlphenvl)-6-(4pyridyl)-2-thiomethyl-4(3H)-pyrimidinone: bromo-6-(4-pyridyl)-2-methylthio-4(3H)-pyrimidinone (1.2g, 3.8 mmol) was dipersed in 2M sodium carbonate solution (30 ml) and the pale yellow colour of the adhered bromine disappeared to give colourless precipitate in the reaction mixture. 3- Trifluromethylbenzene boronic acid (1.00 g, 5.27 mmol) and toluene (30ml) were added to the above mixture and the reaction mixture was degassed. Tetrakis triphenyl phosphine Pd(0) (350 mg) was added. The reaction mixture was refluxed for 8-12h. The formation of the product was monitored by TLC. The mixture was cooled, diluted with toluene(20ml) and washed with water. The organic layer was dried over sodium sulfate, concentrated and product isolated by silica gel chromatgraphy to give the titled compoud. MS(m/z): 378.4 C, 1
HF
3 N0OS requir.
377.39; 1H-NMR(CDC1 3 8.5 2H, pyridyl), 7.45 7.17-7.25 3H, pyridyl and Ph-CF,), 6.95 (d, 1H, Ph-CF,), 3.67 2.8 Step E. 3-methyl-2-(2(S)-amino-3-phenvlpropylamino)-5- 3 -trifluoromethvlphenvl)-6-(4-pyridvl)-4(3H)pyrimidinone: 3-Methyl-5-(3-trifluoromethylphenyl)-6-(4pyridyl)-2-thiomethyl-4(3H)-pyrimidinone (0.7g, 1.85 mmol) and 2 -amino-3-phenyl-l-propylamine (0.9 ml, 6.00 mmol) were mixed in a round bottom flask and heated at 185 0 C for 3h. The mixture was separated on silica gel (dichloromethane: methanol: ammonium hydroxide 92:7:1) to obtain compound titled compound. MS(m/z): 480, C ,H,4FNO requir 479.51; 1H-NMR(CDC1) :d 8.49 (m, 2H, pyridyl), 7.51-7.17 11H, Ph and pyridyl), 5.81 (bm, 1H, NH), 3.91 1H, CH), 3.53 3H, N-CH,), 3.35 2H, 2.94 (dd, 1H, 2.82 (dd, 1H, CH) WO 98/24780 WO 9824780PCTIUS97/22949 165 Examiple 47 Using the corresponding starting materials,' the following compounds of Table III were prepared using the procedure for 3-methyl-.2-(2 (5)-amino-3phenyipropylamino) 3 -trifluoromethylphenyl) (4pyridyl) -4(31) -pyrimidinone.
TABLE III 0 N'
NHR
3 1 4-tolyl 4 -trifluoromethyl phenyl 3-i sopropylphenyl 3 -chloro-4-fluoro phenyl 3, 5-bis (trifluoro methyl) phenyl 3, 4-dichloro phenyl l-naphthyl 3 -fluorophenyl 3 -chlorophenyl 3 -methylphenyl 4 -chlorophenyl 2-chiorophenyl 2 -thienyl 3, 4-dimethylphenyl 3, 5-dichloro phenyl 4-tolyl 3 -trifluoromethyl phenyl 4-me thoxyphenyl 4 -trifluoromethyl phenyl 3 -chlorophenyl 3-me thylphenyl 4 -chlorophenyl 2 -chlorophenyl 3-nitrophenyl 2 amno3-heylprpy 2 (5)-amino-3-phenyl-propyl 2 (5)-amino-3--phenyl-propyl 2 (5)-amino-3-phenyl-propyl 2 -amino-3-phenyl-propyl 2 (5)-amino-3-phenyl-propyl 2(S) -amino-3-phenyl-propyl 2(S) -amino-3-phenyl-propyl 2(S) -amino-3-phenyl-propyl 2 (5)-amino-3-phenyl-propyl 2 (5)-alino-3-phenyl-propyl 2 (5)-aiino-3-phenyl-propyl 2(S) -amino-3-phenyl-propyl 2 (5)-amino-3-phenyl-propyl 3 )an--phenyll 3 -phenylpropyl 3 -phenylpropyl 3 -phenylpropyl 3 -phenyipropyl MS Z) 426 480 454 464 548 482 462 430 440. 6 467 411 465 427 465 3 -phenyl-propyl 3 -phenyl-propyl 3 -phenyl-propyl 3 -phenyl-propyl 3 -phenyl-propyl WO 98/24780 WO 9824780PCTIUS97/22949 166 3-me thoxypheny.
2 -fluorophenyl benzothienyl 3 -fluorophenyl 1-naphthyl 3 -trifluoromethyl phenyl 3-me thyiphenyl 3-chiorophenyl 3 -nitrophenyl 3-methoxyphenyl 2- fluorophenyl 3 -trifluoromethyl phenyl.
3-methyiphenyl 3, 4-dimethyiphenyl 3 -methyiphenyl benzothienyl benzofuranyl 3 -phenyl -propyl 3 -phenyl-propyl 3 -phenyl -propyl 2 -methyl.- 3 -phenyl -propyl 2 -methyl-3 -phenyl-propyl 2 -dimnethylamino- 3 -phenyipropyl 2 -dimethylamino- 3 -phenyipropyl 2 N-dimethylamino- 3 -phenyipropyl 2 CS) N-dimethylamino- 3 -phenyipropyl 2(S) -N,N-dimethylanino- 3 -phenyipropyl 2 N-dimethylamino- 3 -phenyipropyl -tetrahydroisoquinol>.ylmethylenanino CS) -tetrahydroisoquinop3ylme thyl enamino 3-amino- 3-phenyipropylamine 3 -amino-3 -phenyipropylamine 3-amino -3 -phenyipropyl amine 3 -amino-3 -phenyipropylamine 429 461 492.1 438 440.6 Example 48 (4-methylsulfinvlphenyl)--6- (4-pyridyl) -2thiomethvl-4 (3H) -Pvrimidinone: The title compound was prepared in the manner of example 34-D substituting 4methylsulfinylbenzene, boronic acid for 3trifluoromethylbenzene boronic.
Example 49 3 -methvl-2 3,.
4 -tetrahvdroisopuino invl )methyl amino) (4-methvlthiop~henvl)-6-(4-pyridyl) -4 (3H) Tpvrimidinone: The title compound was prepared in the manner of example 34 step D with the following substitutions of 3 -methyl-5-(4-methylsulfinylphenyl)-6 (4-pyridyl) -2-thiomethyl-4 (3H) -pyrimidinone for 3- (3-trifluoromethylphenyl) (4-pyridyl) -2thiomethyl-4(3H)-pyrimidinone and 3(5) tetrahydroisoquinolinyl)methylamine for -2-amino-3phenyl-l-propylamine: MS 470 WO 98/24780 WO 9824780PCT/US97/22949 167 Example 3-methyl-2-- (3 2 3 4 -tetrahvdroisopuinolinvl)methv1 amino) (4-methylsulfonylphenyl)-6- (4-pyridyl) -4 (3i) pyrimidinone: To a solution of 3-methyl-2-(3(S)- (lI 2 3 4 -tetrahydroisoquinolinyl)methyaino)- 5 4 methyithiophenyl) (4-pyridyl) -4 (3H) -pyrimidinone mg, 0.11 minol) in methanol:water (15 mL:10 mL) was added oxone (127 mg, 0.21 rnmol) as a solid in one portion at 23 0 C. Af ter 16 h, the reaction was concentrated under a stream of nitrogen. The reaction mixture was applied directly to purification via preparative plate chromatography (3 silica gel 2mm thick plates; methanol in methylene chloride) to afford the title compound MS 502 Example 51 2- 3-Amino 3 -henylpropyl) -amino) -3-methyl-6- (4- Pyridyl) (3-trif luoromethylphenyl) -4 O3H) -Poyrimidinone hydrochloride was prepared from 3 -methyl-2-methylthio-6- (4-pyridyl) 3 -trifluoromethylphenyl) -4 (3H) pyrimidinone and -l-phenyl-l, 3-propanediamine according to the General Procedure. The reaction was at 190 0 C for 1 h. MS (zn/z) :480.0
C
26
H
2 4 F N 5 0 requir.
479.5 (free base).
Example 52 2- 3-Amino 3 -henvlpropvl) -amino) -3-methyl-6- (4lpyridyl) (3-trif luoromethvlphenyl) -4 O3H) -pyvrimidinone hydrochloride was prepared from 3-methyl-2-methylthio- 6- (4-pyridyl) 3 -trif luoromethylphenyl) -4 (3H) pyrimidinone and -l -phenyl- 1, 3 -propanediamine according to the General Procedure. The reaction was done at 190 0 C for 3.5 h. MS 480.4 C 26
H
24
F
3 N 5 0 requir. 479.5 (free base).
WO 98/24780 WO 9824780PCT1US97/22949 168 Example 53 Procedure for the preparation of 2 -chloro-3-methyl-5-(3methylphenvl) (4-pyvridyl) -4 (3H) -pyrimidinone 0 0 0 N N
N
N S N OH N Cl Step A: 3-Methyl-5- (3-methyilphenyl) (4-pyridyl)- 2,4(1H,3H)-poyrimidindione: 10 N Sodium hydroxide ml) and water (50 ml) was added to a solution of 3- (3-methyiphenyl) -2-mrethylthio-6- (4-pyridyl) 4(3H)-pyrimidindione (16.17 g, 0.05 mol) in dixoxane ml). The mixture was heated at 80 0 C for 16 h under argon. The mixture was allowed to reach room temperature and the pH value was adjusted to 9 with 1 N hydrochloric acid. The precipitate was filtered, washed with water and dried to give the title compound. MS 292 C17H 1 5
N
3 0, requir. 293.3.
Step B: 2 -Chloro-3-methyl-5-(3-methylphenl)6(4ioyridyl) -4 (3H) -pyrimidinone: -A mixture of (3-methylphenyl) (4-pyridyl) -2,4 (1H,3H) -pyrimidindione (12.5 g, 0.043 mol) and phosphorus oxychloride (65 ml) was ref luxed for 16 h. The excess of phosphorus oxychloride was evaporated followed by co-distillation with toluene. The remainder was carefully partitioned between dichioromethane and aqueous sodium hydrogencarbonate. The organic solution was washed with water, dried and evaporated to leave the title compound.
MS 312 C17H1 4 ClN 3 O requir. 311. 8.
2-Chloro-3-methyl-6-(4-pyridyl) (3trifluoromethylphenyl) -4 (3H)-ipvrimidinone was prepared according to the same procedure.
WO 98/24780 PCTIUS97/22949 169 Example 54 Procedure for the preparation of 2 -((S)-2-amino-3phenyipropyl) -amino) -3 -me thyl 5- (3 -me thylphenyZ) 6- (4 pyridyl) -4 (3H) -pyrimidinone hydrochloride K' NN
NN
2- -2-Amino-3-pohenylpropvl) -amino) -3-methyl-5- (3methyiphenyl) (4-pyridyl) -4 (3H) -1pyrirnidinone hydrochloride: A solution of 2 -chloro-3-rnethyl-5-(3methyiphenyl) (4-pyridyl) -4 3 H)-pyrimidinone (3.34 g, 10.71 mmol) and (S)-l-benzyl-l,2-ethanediamine (2.3 g, 15.31 minol) in ethanol (50 ml) was stirred at room temperature for 16 h. The solvent was evaporated and the crude product recrystallized from methanol. MS 426 C26H 2 7
N
5 0 requir. 425.5 (free base) Example Procedure for the preparation of 2 -((3-amino-2,2dimethyl-3-phenylpropyl) -amino) -3-me thyl (3methyiphenyl) 6- (4 -pyridyl) -4 (3H) -pyrimidinone hydrochloride N 0
N
NN
N
N Ol 3 -Amino- 2 2-dime thl 1>phenyl-propyl) -amino) -3- (3-methyiphenyl) (4-1pyridyl) -4 (3H) pyvrimidinone hdrochloride: A solution of 2-chloro-3- (3-methylphenyl) (4-pyridyl) -4 (3H) pyrimidinone (228 mg, 0.73 mmol) and 3-phenyl-2,2dime thyl 3-propanedi amine (178 mg, 1 inmol) (prepared according to:W. Ten Hoeve and H. Wynberg, Synth. Commun.
WO 98/24780 PCT/US97/22949 170 24 2215-2221, 1994) in ethanol (4 ml) was stirred at room temperature for 16 h. The solvent was evaporated and the crude product purified by column chromatography on silica gel. MS 454 C2 8
H
3 1
N
5 0 requir. 453.6 (free base).
Accordingly, 2-((-3-Amino-2, 2 -dimethyl-3-phenvlpropyl)amino)-3-methvl-6-(4-pyridvl)-5-( 3 -trifluoromethvl phenvl)-4(3H)-pyrimidinone hydrochloride was prepared.
MS 508
C
28
H
2 8 FN,0 requir. 507.6 (free base).
Example 56 Procedure for the preparation of 2- (((S)-3-amino-3phenylpropyl)-amino)-3-methyl-6- (4-pyridyl)-5-(3trifluorome thylphenyl) -4 (3H) -pyrimidinone hydrochloride
CF
3 1-1 NH2
N
N N
H
2- (S)-3-Amino-3-phenvlpropyl)-amino) -3-methyl-6-(4- 3 -trifluoromethylphenvl)-4(3H)-pvrimidinone hydrochloride: Aqueous sat. sodium carbonate (2 ml) was added to a solution of 2 -chloro-3-methyl-6-(4-pyridyl)- 3 -trifluoromethylphenyl)-4(3H)-pyrimidinone hydrochloride (730 mg, 2 mmol) and (S)-1-phenyl-l,3propanediamine (360 mg, 2.4 mmol) in ethanol (10 ml).
The mixture was stirred for 4 h at room temperature. It was evaporated and the remainder partitioned between dichloromethane and water. The organic solution was dried and evaporated followed by column chroatography on silica gel (dichloromethane methanol conc. ammonium hydroxide 93 7 MS 480
C
26
H
24 FNO requir. 479.5 (free base) WO 98/24780 PCT/US97/22949 171 Example 57 Procedure for- the preparation of 3-methyl-2-methylthio- (3-methylphenyl) (4-pyridyl) -4 (3H) -pyrimidinone O0 N SCH3
N
3-Methyl-2-methvlthio-5-( 3 -methylphenvl)-6-(4-pvridvl)- 4(3H)-pyrimidinone: A solution of potassium t-butoxide (1M in t-butanol, 11, 1 mol) was added dropwise to a stirring solution of ethyl 3-methylphenyl acetate (178 g, 1 mol) in N,N-dimethylformamide (2 A solution of 4-cyanopyridine (104.11 g, 1 mol) in N,Ndimethylformamide (1 1) was pumped into the reaction mixture over a period of about 4.5 h- The mixture was then stirred at room temperature for 3 h, before the dropwise addition of a solution of methyl isothiocyanate (68.4 ml, 1 mol) in N,N-dimethylformamide (50 ml) over a period of 10 min. After stirring for 1 h at room temperature, the reaction mixture was cooled to 3_C and methyl iodide (62.3 ml, 1 mol) was added dropwise over a period of 10 min. Stirring was continued at room temperature overnight. The mixture was cooled to 3_C and water (4 1) was pumped into the reaction mixture over a period of 6 h. The precipitate was removed by filtration, washed with water and dried in a vacuum oven to give the title compound. MS 324
C
1 8
,H
1
N
3 OS requir. 323.4.
Example 58 Using the corresponding starting materials, the following compounds of Table IV may be prepared using the procedure for 6 4 -fluorophenyl)-2-methyl-l-(3phenylpropyl)-7-pyridin-4-yl-lH-imidazo(l,2-a)pyrimidin- The required pyrimidinones with the varied R WO 98/24780 WO 9824780PCTIUS97/22949 172 substituents can be prepared using the general procedures described above.
TABLE IV
R
21
R.
3 ,5-dichiorophenyl 4-methoxyphenyl 3-tolyl 3 -chiorophenyl 4-f luorophenyl 2 -naphthyl n-butyl 2 -thiophene 3 -thiophene 3-aminophenyl 2- (5-chiorothiophene) 3-is opropyiphenyl 3-tolyl 3 -chiorophenyl 3 -chloro-4 -fluorophenyl 3, 5-Ditrifluoromethyiphenyl 4-f luorophenyl 3, 4-dichiorophenyl 1 -naphthyl 3-f luorophenyl 2 -naphthyl n-butyl 2 -thiophene 3 -thiophene 3-aminophenyl 2- (5-chiorothiophene) 3, 5-dichiorophenyl 4-tolyl 3 -trifluoromethypheny.
4-methoxyphenyl 4- trif luoromethylphenyl 3-is opropyiphenyl 3-tolyl 3 -chiorophenyl 3-chloro-4-fluorophenyl 3, 5-Ditrifluoromethyiphenyl 4-f luorophenyl 3 ,4-dichlorophenyl R 21 2(S) -alino-3-phenyl-propyl 2 -ainino-3-phenyl-propyl 2(S) -aiino-3-phenyl-propyl 2 -ainino-3-phenyl-propyl 2(S) -aiino-3-phenyl-propyl 2(S) -amino-3-phenyl-propyl 2(S) -amino-3-phenyl-propyl 2(S) -amino-3-phenyl-propyl 2(S) -amino-3-phenyl-propyl 2(S) -amino-3-phenyl-propyl 2(S) -amino-3-phenyl-propyl 3 -phenyipropyl 3 -phenyipropyl 3 -pheriylpropyl 3 -phenyipropyl 3 -phenyipropyl 3 -phenyipropyl- 3 -phenyipropyl 3 -phenyipropyl 3 -phenyipropyl 3 -phenyipropyl 3-phenylpropyl 3 -phenyipropyl 3 -phenyipropyl 3 -phenyipropyl 3 -phenyipropyl 3 -methyl-3 -phenyl-propyl 3 -rethyl-3 -phenyl-propyl 3 -methyl-3 -phenyl-propyl 3 -methyl-3 -phenyl-propyl 3 -rethyl-3 -phenyl-propyl 3 -methyl-3 -phenyl-propyl 3 -methyl-3 -phenyl-propyl 3 -methyl-3 -phenyl-propyl 3 -methyl-3 -phenyl-propyl 3 -methyl-3 -phenyl-propyl 3 -methyl-3 -phenyl-propyl 3 -methyl-3 -phenyl-propyl WO 98/24780 WO 9824780PCTIUS97/22949 173 2-naphithyl n-butyl 2- thiophene 3 -thiophene 3-aminophenyl (5-chiorothiophene) 3, 5-dichiorophenyl 4-tolyl 3- trifluoromethyiphenyl 4-rethoxyphenyl 4- trifluoromethyiphenyl 3-i sopropyiphenyl 3 -tolyl 3-chiorophenyl 3 -chloro-4-fluorophenyl 3, S-Ditrifluoromethylphenyl 4-f luorophenyl 3, 4-dichiorophenyl 1-naphthyl 3-f luorophenyl 2 -naphthyl n-butyl 2- thiophene 3- thiophene 3-aminophenyl 2- (5-chiorothiophene) 3 ,5-dichiorophenyl 4-tolyl 3- tri fluoromethyiphenyl 4-methoxyphenyl 4- tri fluoromethyiphenyl 3 -isopropyiphenyl 3 -tolyl 3 -chiorophenyl 3 -chloro-4-fluorophenyl 3, 5 -Ditrifluoromethylphenyl 4- fluorophenyl 3, 4-dichiorophenyl 1 -naphthyl 3-f luorophenyl 2-naphthyl n-butyl 2- thiophene 3- thiophene 3-aininophenyl 2- (5-chiorothiophene) 3, 5-dichiorophenyl 4-tolyl 3- tri fluoromethyiphenyl 4-me thoxyphenyl 4-trifluoromethyiphenyl 3-methyl -3-phenyl-propyl 3 -methyl-3-phenyl-propyl 3 -methyl-3-phenyl-propyi 3 -methyl-3-phenyl-propyl 3 -methyl-3-phenyl-propyl 3-methyl -3 -phenyl-propyl 3-amino -3 -phenyl -propyl 3-amnino- 3-phenyl -propyl 3-amino -3 -phenyl -propyl 3 -amino-3-phenyl-propyl 3 -axino-3-phenyl-propyl 3 -amino-3-phenyl-propy1 3-amino -3 -phenyl -propyl 3-amino- 3-phenyl-propyl 3 -amino 3 -phenyl -propl 3-amino- 3-phenyl -propyl 3 -amino-3-phenyl-propyl 3 -arino-3-phenyl-propyl 3 -amino-3 -phenyl -propyl 3-amino- 3-phenyl -propyl 3-amino- 3-phenyl -propyl 3 -amino-3-phenyl-propyl 3-amino -3 -phenyl -propyl 3-amino- 3-phenyl -propyl 3-amino- 3-phenyl -propyl 3 -amino-3 -phenyl-propyl 2 -amino-3-phenyl-propyl 2 -amino-3-phenyl-propyl 2 -amino-3-phenyl-propyl 2 -amino-3-phenyl-propyl 2 -aminio- 3-phenyl -propyl 2 -amino-3-phenyl-propyl 2 -amino-3 -phenyl-propyl 2 -amino-3-phenyl-propyl 2 -amino 3-phenyl -propyl 2 -amino-3-phenyl-propyl 2 -amino-3-phenyl-propyl 2 -amino-3-phenyl-propyl 2 -amino-3-phenyl-propyl 2 -amino-3-phenyl-propyl 2 -amino- 3-phenyl -propyl 2 -amino-3-phenyl-propyl 2 -amino-3-phenyl-propyl 2 -amino-3-phenyl-propyl 2 -amino-3-phenyl-propyl 2 -amino-3-phenyl-propyl 2 -methyl-2-amino-3 -phenylpropyl 2-methyl -2 -amino-3 -phenyl propyl 2-methyl-2-amino-3 -phenylpropyl 2 -methyl-2-amino-3 -phenylpropyl 2 -methyl-2-amino-3 -phenylpropyl WO 98/24780 WO 9824780PCTIUS97/22949 174 3- isopropylphenyl 3 -tolyl 3-chiorophenyl 3 -chloro-4-fluorophenyl 3, S-Ditrifluoromethylphenyl 4 -fluorophenyl 3, 4-dichiorophenyl 1-naphthyl 3 -fluorophenyl 2-naphthyl n-butyl 2 -thiophene 3-thiophene 3 -aminophenyl 2- (5-chiorothiophene) 2 -methyl-2-amino-3 -phenylpropyl 2-methyl-2-anino-3 -phenylpropyl 2 -methyl-2-amino-3 -phenylpropyl 2 -methyl-2-amino-3 -phenylpropyl 2 -methyl -2-amino-3 -phenylpropyl 2 -methyl-2-ainino-3 -phenylpropyl 2 -methyl-2-arnino-3 -phenylpropyl 2 -methyl-2 -amino-3 -phenyl propyl 2 -methyl-2-amino-3 -phenylpropy.
2 -methyl-2-amino-3 -phenylpropyl 2 -methyl-2-amino-3 -phenylpropyl 2 -methyl-2-amino-3 -phenylpropyl 2 -methyl-2-amino-3 -phenylpropyl 2 -methyl-2-amino-3 -phenylpropyl 2 -methyl-2-amino-3-phenylpropyl 2 -methyl-3-phenyl-propyl 2-me thyl-3 -phenyl -propyl 2 -methyl-3-phenyl-propyl 2 -methyl-3 -phenyil-propyl 2 -methyl-3 -phenyl-propyl 2 -me thyl-3 -phenyl-propyl 2 -methyl-3 -phenyl-propyl 2 -methyl-3 -phenyl-propyl 2 -me thyl-3 -phenyl -propyl 2 -methyl-3 -phenyl-propyl 2-methyl-3 -phenyl-propyl 2 -methyl-3 -phenyl -propyl 2 -methyl-3 -phenyl-propyl 2 -methyl-3-phenyl-propyl 2-me thyl-3 -phenyl -propyl 2 -methyl-3 -phenyl-propyl 2 -methyl -3 -phenyl -propyl 2-methyl-3 -phenyl-propyl 2-methyl -3 -phenyl -propyl 2-me thyl-3 -phenyl -propyl 2- (N,N-dimethylamino) -3phenyl -propyl 2- (N,N-dimethylamino) -3phenyl -propyl 2- (N,N-dimethylamino) -3phenyl -propyl 3, 5-aichiorophenyl 4-tolyl 3 -trifluoromethyiphenyl 4 -methoxyphenyl 4 -trifluoromethyiphenyl 3- isopropyiphenyl 3 -tolyl 3 -chiorophenyl 3 -chloro-4-fluorophenyl 3, S-Ditrifluoromethylphenyl 4- fluorophenyl 3 ,4-dichiorophenyl 1 -naphthyl 3 -fluorophenyl 2-naphthyl n-butyl 2 -thiophene 3 -thiophene 3 -arninophenyl 2- (5-chlorothiophene) 3, 5-dichiorophenyl 4 -tolyl 3 -trifluoromethylphenyl wo 98/24780 WO 9824780PCT/US97/22949 175 4-me thoxyphenyl 4 -tri fluoromethyiphenyl 3 -isopropylpheiyl 3 -tolyl 3 -chiorophenyl 3 -chloro-4-fluorophenyl 3, 5-Ditrifluoromethyiphenyl 4-f luorophenyl 3, 4-dichiorophenyl 1 -naphthyl 3-f luorophenyl 2 -naphthyl n-butyl 2- thiophene 3 -thiophene 3 -aminophenyl 2- (N,N-dimethylamino) -3phenyl -propyl 2- (N,N-dimethylamino) -3phenyl -propyl 2- (N,N-dimethylamino) -3phenyl -propyl 2- (N,N-dimethylanino) -3phenyl.-propyl 2- (N,N-dimethylamino) -3phenyl -propyl 2- (N,N-dimethylamino) -3phenyl -propyl 2- (N,N-dimethylamino) -3phenyl -propyl 2- (N,N-dimethylamino) -3phenyl -propyl 2- (N,N-dimethylamino) -3phenyl -propyl 2- (N,N-dimethylamino) -3phenyl -propyl 2- (N,N-dimethylamino) -3phenyl -propyl 2- (N,N-dimethylamino) -3phenyl -propyl 2- (N,N-dimethylamino) -3phenyl -propyl.
2- (N,N-dimethylamino) -3phenyl -propyl 2- (N,N-dimethylamino) -3phenyl -propyl 2- N-dimethylamino) -3phenyl-propyl 2- (N,N-dimethylamino) -3phenyl -propyl 2- (N-methylamino) -3phenyl -propyl 2- (N-methylamino) -3phenyl -propyl 2- (N-methylamino) -3phenyl -propyl 2- (N-methylamino) -3phenyl -propyl 2- (N-methylamino) -3phenyl -propyl 2- (N-methylamino) -3phenyl -propyl 2- (N-methylamino) -3phenyl -propyl 2- (N-methylamino) -3phenyl -propyl 2- (N-methylamino) -3phenyl -propyl 2- (N-methylamino) -3phenyl -propyl 2- (N-methylamino) -3phenyl -propyl 2- (5-chiorothiophene) 3, 5-dichiorophenyl 4-tolyl 3- tri fluoromethyiphenyl 4-me thoxyphenyl 4- tri fluoromethyiphenyl 3 -isopropyiphenyl 3-tolyl 3 -chiorophenyl 3 -chloro-4 -fluorophenyl 3, S-Ditrifluoromethylphenyl 3, 4-dichiorophenyl WO 98/24780 PCT/US97/22949 176 4-fluorophenyl 2-(N-methylamino)-3phenyl-propyl 1-naphthyl 2-(N-methylamino)-3phenyl-propyl 3-fluorophenyl 2-(N-methylamino)-3phenyl-propyl 2-naphthyl 2-(N-methylamino)-3phenyl-propyl n-butyl 2-(N-methylamino)-3- 1 0 phenyl-propyl 2-thiophene 2-(N-methylamino)-3phenyl-propyl 3-thiophene 2-(N-methylamino)-3phenyl-propyl 3-aminophenyl 2-(N-methylamino)-3phenyl-propyl 2-(N-methylamino)-3phenyl-propyl Example 59 The compounds in table V can be prepared using the appropriate starting materials and the following procedures: The required pyrimidinones with the varied
R
1 substituents can be prepared using the general procedures described above. The fused 6, 5 ring system can be prepared as described above affording R 21 as a hydrogen radical. Other R 21 groups can be introduced through a reductive amination process using the corresponding aldehyde with appropriate amino protection (Boc group). For example, N-Boc-phenylalanal can be prepared from the corresponding Weinreb amide through reduction with lithium aluminum hydride as described in the literature (Konieczny and Cushman Tetrahedron Lett 6939, 1992). The N-Boc-phenylalanal can then be reacted with the amino group using sodium triacetoxyborohydride.
Alternatively, the alcohol of N-Boc-phenylalanol can be activated under Mitsunobu conditions (triphenylphosphine, diiisopropyl azodicarboxylate) and reacted with the amino group of the 6, 5 fused system followed by removal of the Boc group (trifluoroacetic acid).
WO 98/24780 WO 9824780PCTIUS97/22949 177 TABLE V 0 3, 5-dichiorophenyl 4-inethoxyphenyl 3 -tolyl 3 -chiorophenyl 4-f luorophenyl 2 -naphthyl n-butyl 2 -thiophene 3 -thiophene 3 -aminophenyl 2- (5-chiorothiophene) 3 -isopropylpheny.
3 -tolyl 3 -chiorophenyl 3 -chloro--4-fluorophenyl 3, 5-Ditrifluoromethyiphenyl 4-f luorophenyl 3, 4-dichiorophenyl 1 -iiaphthyl 3 -fluorophenyl 2 -naphthyl n-butyl 2 -thiophene 3 -thiophene 3 -aininophenyl 2- (5-chiorothiophene) 3, 5-dichiorophenyl 4-tolyl 3 -trifluoromethyiphenyl 4 -methoxyphenyl 4- tri fluoromethyiphenyl 3- isopropyiphenyl 3 -tolyl 3 -chiorophenyl 3 -chloro-4-fluorophenyl 3, S-Ditrifluoromethylphenyl 4-f luorophenyl 3 ,4-dichlorophenyl 2 -naphthyl n-butyl 2- thiophene 3-thiophene 3 -aminophenyl R 21 2 -amino-3-phenyl-propyl 2 -amirxo-3-phenyl-propy.
2 -amino-3-phenyl-propyl 2 -amino-3-phenyl-propyl 2 -arnino-3-phenyl-propyl 2 -amino-3-phenyl-propyl 2 -amino-3-phenyl-propy.
2 -amino-3-phenyl-propyl 2 -amino-3-phenyl-propyl 2 -amino-3-phenyl-propy.
2 -amino-3-phenyl-propyl 3 -phenyipropyl 3 -phenyipropyl 3 -phenyipropyl 3 -phenyipropyl 3 -phenyipropyl 3 -phenyipropyl 3 -phenyipropyl 3 -phenyipropyl 3 -phenyipropyl 3 -phenyipropyl 3-phenylpropyl 3 -phenyipropyl 3 -phenyipropyl 3 -phenyipropyl 3 -phenyipropyl 3-methyl -3 -phenyl -propyl 3-methyl -3 -phenyl -propyl 3-methyl -3 -phenyl -propyl 3-methyl -3-phenyl-propyl 3-methyl- 3-phenyl -propyl 3-methyl -3 -phenyl -propyl 3 -methyl-3-phenyl-propyl 3 -methyl-3-phenyl-propyl 3-methyl -3 -phenyl -propyl 3 -methyl-3-phenyl-propyl 3 -methyl-3-phenyl-propyl 3-methyl -3 -phenyl -propyl 3-methyl -3 -phenyl -propyl 3-methyl -3 -phenyl -propyl 3-methyl -3 -phenyl -propyl 3 -methyl- 3 -phenyl-propyl 3 -methyl- 3 -phenyl-propyl WO 98/24780 PTU9/24 PCT/US97/22949 178 2- (5-chiorothiophene) 3, 5-dichiorophenyl 4-tolyl 3- trifluoromethyiphenyl 4-methoxyphenyl 4 -trifluoromethyiphenyl 3 -isopropyiphenyl 3-tolyl 3 -chiorophenyl 3 -chloro-4--fluorophenyl 3, 5-Ditrifluorornethylphenyl 4-f luorophenyl 3, 4-dichiorophenyl 1 -naphthyl 3-f luorophenyl 2 -naphthyl n-butyl 2- thiophene 3 -thiophene 3-aminophenyl 2- (5-chiorothiophene) 3, 5-dichiorophenyl 4-tolyl 3 -trifluoromethyiphenyl 4-methoxyphenyl 4 -trifluoromethyiphenyl 3- isopropyiphenyl 3 -tolyl 3 -chiorophenyl 3 -chloro-4-fluorophenyl 3, 5-Ditrifluoromethylphenyl 4-f luorophenyl 3, 4-dichiorophenyl 1 -naphthyl 3-f luorophenyl 2 -naphthyl n-butyl 2 -thiophene 3 -thiophene 3-aminophenyl 2- (5-chiorothiophene) 3, 5-dichiorophenyl 3-methyl -3 -phenyl -propyl 3 -amino-3 -phenyl -propyl 3 -amino-3 -phenyl-propyl 3 -axnino-3 -phenyl-propyl 3 -amino-3 -phenyl-propyl 3 -arnino-3 -phenyl -propyl 3-arnino-3 -phenyl-propyl 3-amino -3 -phenyl -propyl 3-amino -3 -phenyl -propyl 3-amino -3 -phenyl -propyl 3-amino-3 -phenyl-propyl 3 -amino-3 -phenyl -propyl 3-amino-3 -phenyl-propyl 3-amino-3 -phenyl-propyl 3 -amino-3 -phenyl -propyl 3 -amino-3 -phenyl -propyl 3 -amino-3 -phenyl -propyl 3 -amino-3 -phenyl-propyl 3 -amino-3 -phenyl-propyl 3-arnino-3 -phenyl-propyl 3-amino-3 -phenyl-propyl 2(R) -amino-3-phenyl1-propyl 2(R) -amino-3-phenyl-propyl 2(R) -amino-3-phenyl-propyl 2(R) -amino-3-phenyl-propyl 2(R) -amino-3-phenyl-propyl 2(R) -amino-3-phenyl-propyl 2(R) -aniino-3-phenyl-propyl 2(R) -amino-3-phenyl-propyl 2(R) -amino-3-phenyl-propyl 2(R) -amino-3-phenyl-propyl 2(R) -amino-3-phenyl-propyl 2(R) -amino-3-phenyl-propyl 2(R) -amino-3-phenyl-propyl 2(R) -amino-3-phenyl-propyl 2(R) -amino-3-phenyl-propyl 2(R) -amino-3-phenyl-propyl 2(R) -amino-3-phenyl-propyl 2(R) -arnino-3-phenyl-propyl 2(R) -arino-3-phenyl-propyl 2(R) -aiino-3-phenyl-propyl 2-methyl-2-amino-3 -phenylpropyl 2-methyl-2-amino-3 -phenylpropyl 2-methyl-2 -amino-3 -phenylpropyl 2-methyl-2-amino-3 -phenylpropyl 2-methyl-2 -amino-3 -phenylpropyl 2-methyl-2 -amino-3 -phenylpropyl 2-methyl-2 -ainino-3 -phenylpropyl 4-tolyl 3 -trifluoromethyiphenyl 4-me thoxyphenyl 4-trifluoromethyiphenyl 3- isopropyiphenyl 3-tolyl WO 98/24780 WO 9824780PCTIUS97/22949 179 3 -chiorophenyl 3 -chloro-4-fluorophenyl 3, S-Ditrifluoromethylphenyl 4-f luorophenyl 3, 4-dichlorophenyl 1 -naphthyl 3 -fluorophenyl 2-naphthyl n-butyl 2 -thiophene 3- thiophene 3 -aininophenyl 2- (5-chiorothiophene) 3, 5-dichiorophenyl 4-tolyl 3 -trifluoromethylpheiyl 4-methoxyphenyl 4 -tri fluoromethyiphenyl 3-is opropyiphenyl 3-tolyl 3 -chiorophenyl 3 -chloro-4-fluorophenyl 3, S-Ditrifluoromethylphenyl 4-f luorophenyl 3, 4 -dichlorophenyl 1 -naphthyl 3-f luorophenyl 2 -naphthyl n-butyl 2 -thiophene 3 -thiophene 3-aminophenyl 2- (5-chiorothiophene) 3, 5-dichiorophenyl 4-toly.
3- tri fluoromethyiphenyl 4 -methoxyphenyl 4 -trifluoromethylphenyl 2-methyl-2 -amino-3 -phenylpropyl 2-methyl-2 -amino-3 -phenyl propyl 2-methyl-2 -amino-3 -phenyl propyl 2-methyl-2 -amino-3 -phenylpropyl 2-methyl-2 -ainino-3 -phenylpropyl 2 -methyl-2-amino-3 -phenylpropyl 2-methyl-2 -axnino-3 -phenyl propyl 2-methyl-2 -amino-3 -phenylpropyl 2-methyl-2 -amino-3 -phenylpropyl 2 -methyl-2 -arnino-3 -phenyl propyl 2-methyl-2 -amino-3 -phenylpropyl 2-methyl-2 -arnino-3 -phenylpropyl 2-methyl-2 -amino-3-phenylpropyl 2-methyl -3 -phenyl -propyl 2-methyl-3 -phenyl-propyl 2-methyl -3 -phenyl -propyl 2-me thyl-3 -phenyl-propyl 2-methyl -3 -phenyl -propyl 2-me thyl-3 -phenyl -propyl 2-methyl -3 -phenyl -propyl 2 -methyl-3 -pheny1 -propyl 2 -methyl-3 -phenyl -propyl 2-methyl-3 -phenyl -propyl 2-methyl- 3-phenyl -propyl 2-methyl- 3-phenyl -propyl 2-methyl -3 -phenyl -propyl 2 -methyl-3 -phenyl -propyl 2-methyl -3 -phenyl -propyl 2 -methyl -3 -phenyl -propyl 2 -methyl-3 -phenyl -propyl 2 -methyl-3 -phenyl -propyl 2 -methyl-3 -phenyl -propyl 2-methyl -3 -phenyl -propyl 2- (N,N-dimethylamino) -3phenyl -propyl 2- (N,N-dimethylamino) -3phenyl -propyl 2- (N,N-dimethylamino) -3phenyl -propyl 2- (N,N-dimethylamino) -3phenyl -propyl 2- (N,N-dimethylamino) -3phenyl -propyl WO 98/24780 WO 9824780PCT/US97/22949 180 3- isopropylphenyl 3-tolyl 3-chloropheiyl 3 -chloro-4-fluorophenyl 3, S-Ditrifluoromethylphenyl 4- fluorophenyl 3, 4-dichiorophenyl 1 5 1-naphthyl 3- fluorophenyl 2 -naphthyl n-butyl 2- thiophene 3-thiophene 3 -aminophenyl 2- (5-chiorothiophene) 3, 5-dichiorophenyl 4-tolyl 3 -tri fluoromethyiphenyl 4 -methoxyphenyl 2- (N,N-dimethylamino) -3phenyl -propyl 2- (NN-dimethylanino) -3phenyl -propyl 2- (N,N-dimethylanino) -3phenyl -propyl 2- N-dimethylamino) -3phenyl -propyl 2- (N,N-dimethylamino) -3phenyl -propyl 2- (N,N-dimethylamino) -3phenyl -propyl 2- (N,N-dimethylamino) -3phenyl -propyl 2- (N,N-dimethylamino) -3phenyl -propyl 2- (N,N-dimethylamino) -3phenyl -propyl 2- (N,N-dimethylamino) -3phenyl -propyl 2- (N,N-dimethylamino) -3phenyl -propyl 2- (N,N-dimethylamino) -3phenyl -propyl 2- (N,N-dirnethylamino) -3phenyl -propyl 2- N-dimethylaxnino) -3phenyl -propyl 2- (N,N-dimethylamino) -3phenyl -propyl 2- (N-methylamino) -3phenyl -propyl 2 (N-methylamino) -3 phenyl -propyl 2- (N-methylamino) -3phenyl -propyl 2- (N-methylamino) -3phenyl -propyl 2- (N-methylamino) -3phenyl -propyl 2- (N-methylanmino) -3phenyl -propyl 2- (N-inethylamino) -3phenyl -propyl 2- (N-methylamino) -3phenyl -propyl 2- (N-methylamino) -3phenyl -propyl 2 (N-methylamino) -3 phenyl -propyl 2 (N-rnethylamino) -3 phenyl -propyl 2- (N-methylamino) -3pheriyl -propyl 2- (N-rnethyl amino) -3phenyl-propyl 4- tri fluoromethyiphenyl 3-is opropyiphenyl 3-tolyl 3-chiorophenyl 3 -chloro-4-.fluorophenyl 3, S-Ditrifluoromethylphenyl 3, 4-dichloropheny.
4- fluorophenyl 1-naphthyl WO 98124780 PCT/UJS97/22949 3- fluorophenyl 2 -naphthyl n-butyl 2- thiophene 3- thiophene .0 3 -aminophenyl 2- (5-chiorothiophene) 2- (N-methylainino) -3phenyl. -propyl 2- (N-methylamino) -3phenyl -propyl 2- (N-methylamino) -3phenyl -propyl 2- (N-methylamino) -3phenyl -propyl 2- (N-methylamino) -3phenyl -propyl 2- (N-methylamino) -3phenyl -propyl 2- (N-methylamino) -3phenyl -propyl Example The compounds in table VI can be prepared using the appropriate starting materials and procedures as described above.
TABLE VI
N.
3, 5-dichiorophenyl 4-me thoxyphenyl 3-toly.
3-chiorophenyl 4-f luorophenyl 2-naphthyl n-butyl 2 -thiophene 3 -thiophene 3 -aminophenyl 2- (5-chiorothiophene) 3-i sopropyiphenyl 3 -tolyl 3 -chlorophenyl 3 -chloro-4-fluorophenyl 3, S-Ditrifluoromethylphenyl 4 -fluorophenyl 3 ,4-dichiorophenyl l-naphthyl 3- fluorophenyl 2 -naphthyl n-butyl R 21 2(S) -alnino-3-phenyl-propyl 2(S) -amino-3-phenyl-propyl 2(S) -amino-3-phenyl-propyl 2(S) -amino-3-phenyl-propyl 2(S) -alino-3-phenyl-propyl 2(S) -amino-3--phenyl-propyl 2(S) -amino-3-phenyl-propyl 2(S) -amino-3-phenyl-propyl 2(S) -amino-3-phenyl-propyl 2(S) -arino-3-phenyl-propyl 2 -amino-3-phenyl-propyl 3 -phenyipropyl 3 -phenyipropyl 3 -phenyipropyl 3 -phenyipropyl 3 -phenyipropyl 3 -phenyipropyl 3 -phenyipropyl 3 -phenyipropyl 3 -phenyipropyl 3 -phenyipropyl 3 -pherxylpropyl WO 98/24780 PTU9/24 PCTIUS97/22949 182 2- thi ophene 3 -thiophene 3 -aminophenyl 2- (5-chiorothiophene) 3, 5-dichiorophenyl 4-tolyl 3 -trifluoromethyiphenyl 4-me thoxyphenyl 4- trifluoromethyiphenyl 3 -isopropyiphenyl 3-tolyl 3 -chiorophenyl 3 -chloro-4-fluorophenyl 3, S-Ditrifluoromethylphenyl 4-f luorophenyl 3, 4-dichiorophenyl 2 -naphthyl n-butyl 2- thiophene 3-thiophene 3 -aminophenyl 2- (5-chiorothiophene) 3, 5-dichiorophenyl 4-tolyl 3 -trifluoromethyiphenyl 4-me thoxyphenyl 4- trifluoromethyiphenyl 3-i sopropyiphenyl 3-tolyl 3-chiorophenyl 3 -chloro-4-fluorophenyl 3, S-Ditrifluoroinethylphenyl 4- fluorophenyl 3, 4-dichiorophenyl 1-naphthyl 3 -fluorophenyl 2 -naphthyl n-butyl 2- thiophene6 3-thiophene 3 -aminophenyl 2- (S-chlorothiophene) 3, 5-dichiorophenyl 4-tolyl 3 -trifluoromethylphenyl 4-methoxyphenyl 4- trifluorornethyiphenyl 3 -isopropyiphenyl 3-tolyl 3-chiorophenyl 3 -chloro-4-fluorophenyl 3, S-Ditrifluoromethylphenyl 4- fluorophenyl 3, 4-dichiorophenyl 1-naphthyl 3-f luorophenyl 3 -phenyipropyl 3 -phenyipropyl 3 -phenyipropyl 3 -phenyipropyl 3-methyl-3 -phenyl-propyl 3 -methyl-3 -phenyl -propyl 3 -methyl-3 -phenyl-propyl 3-me thyl-3 -phenyl-propyl 3-me thyl-3 -phenyl -propyl 3-methyl-3 -phenyl-propyl 3-methyl -3 -phenyl -propyl 3-methyl-3 -phenyl-propyl 3 -methyl-3 -phenyl-propyl 3 -methyl-3 -phenyl -propyl 3-methyl -3 -phenyl -propyl 3 -methyl-3 -phenyl-propyl 3 -methyl-3 -phenyl-propyl 3-me thyl-3 -phenyl-propyl 3 -methyl-3 -phenyl-propyl 3 -methyl-3 -phenyl-propyl 3-methyl -3 -phenyl -propyl 3 -methyl-3 -phenyl-propyl 3 -amino-3 -phenyl -propyl 3 -amino-3 -phenyl -propyl 3 -amino-3 -phenyl-propyl 3 -amino-3 -phenyl-propyl 3 -amino-3 -phenyl-propyl 3 -amino-3 -phenyl -propyl 3 -amino-3 -phenyl-propyl 3 -amino-3 -phenyl-propyl 3 -amino-3 -phenyl-propyl 3 -amino-3 -phenyl-propyl 3 -amino-3 -phenyl-propyl 3 -amino-3 -phenyl-propyl 3 -amino-3 -phenyl -propyl 3 -amino-3 -phenyl -propyl 3 -arnino-3 -phenyl -propyl 3 -amino-3 -phenyl-propyl 3 -amino-3 -phenyl-propyl 3 -amino-3 -phenyl-propyl 3 -ainino-3 -phenyl-propyl 3 -axnino-3 -phenyl-propyl 2 -amino-3-phenyl-propyl 2 -arino-3-phenyl-propyl 2 -axino-3-phenyl-propyl 2 -axino-3-phenyl-propyl 2 -amino-3-phenyl-propyl 2 -amino-3-phenyl-propyl 2 amino 3-phenyl -propyl 2 -amino-3-phenyl-propyl 2 -amino-3-phenyl-propyl 2 -amino-3-phenyl-propyl 2 -anino-3-phenyl-propyl 2 -amino- 3-phenyl -propyl 2 amino 3-phenyl -propyl 2 amino 3-phenyl -propyl WO 98/24780 WO 9824780PCTJUS97/22949 183 2 -raphthyl n-butyl 2 -thiophene 3 -thiophene 3-aminophenyl 2- (5-chiorothiophene) 3, 5-dichiorophenyl 4-tolyl 3- tri fluorornethyiphenyl 4 -methoxyphenyl 4 -trifluoromethylphenyl 3-is opropylphenyl 3--tolyl 3 -chiorophenyl 3 -chloro-4-fluorophenyl 3, S-Ditrifluoromethylphenyl 4-f luorophenyl 3, 4-dichilorophenyl 1 -naphthyl 3 -fluorophenyl 2-naphthyl n-butyl 2 -thiophene 3 -thiophene 3 -aminophenyl 2- (5-chiborothiophene) 3, 5-dichiorophenyl 4 -tolyl 3 -trifluoromethyiphenyl 4-methoxyphenyl 4- tri fluoromethyiphenyl 3-is opropyiphenyl 3-tolyl 3 -chiorophenyl 3 -chloro-4-fluorophenyl 3 -Ditrifluoromethylphenyl 2 -amino-3-phenyl-propyl 2 -amino-3-phenyl-propyl 2 -amino-3-phenyl-propyl 2 -amino-3-pheny1-propyl 2 CR) -amiro-3-phenyl-propyl 2 -amino-3-phenyl-propyl 2 -methyl-2 -ainino-3 -phenyl propyl 2 -methyl-2 -ainino-3 -phenylpropyl 2 -'ethyl-2 -amino-3 -phenylpropyl 2 -rethyl-2 -arnino-3 -phenylpropyl 2 -methyl -2 -amino -3 -phenyl propyl 2 -methyl-2 -arnino-3 -phenylpropyl 2 -methyl-2 -amino-3 -phenylpropyl 2 -methyl-2 -amino-3 -phenylpropyl 2 -methyl-2 -amino-3 -phenylpropyl 2 -methyl-2 -amino-3 -phenylpropyl 2 -methyl-2 -amino-3 -phenylpropyl 2 -rethyl-2 -amino-3 -phenylpropyl 2 -methyl-2 -amino-3 -phenylpropyl 2 -methyl-2 -amino-3 -phenylpropy 1 2 -methyl-2 -amino-3-phenylpropyl 2 -rethyl-2 -ainino-3 -phenylpropyl 2 -rethyl-2 -amino-3 -phenylpropyl 2 -methyl-2 -amino-3 -phenylpropyl 2 -'ethyl-2-amino-3-phenylpropyl 2 -methyl-2 -amino-3 -phenylpropyl 2 -methyl-3 -phenyl-propyl 2 -rethyl-3 -phenyl-propyl 2 -methyl-3 -phenyl-propyl 2 -methyl-3 -phenyl-propyl 2 -methyl -3 -phenyl -propyl- 2 -methyl-3 -phenyl-propyl 2 -methyl-3 -phenyl-propyl 2 -methyl -3 -phenyl -propyl 2 -methyl-3 -phenyl-propyl 2 -methyl -3 -phenyl -propyl WO 98/24780 WO 9824780PCTIUS97/22949 184 4-f luorophenyl 3, 4-dichiorophenyl 1 -naphthyl 3 -fluorophenyl 2-naphthyl n-butyl 2- thiophene 3 -thiophene 3 -aminophenyl 2- (5-chiorothiophene) 3, 5-dichiorophenyl 4-tolyl 3 -trifluoromethyiphenyl 4 -rethoxyphenyl 4- tri fluoromethyiphenyl 3-is opropyiphenyl 3 -tolyl 3-chiorophenyl 3 -chloro-4-fluorophenyl 3, 5-Ditrifluoromethylphenyl 4'-f luorophenyl 3, 4-dichiorophenyl 1-naphthyl 3 -fluorophenyl 2 -naphthyl n-butyl 2 -thiophene 3-thiophene 3 -aminophenyl 2- (5-chlorothiophene) 3, 5-dichiorophenyl 4-tolyl 3 -trifluoromethylphenyl 2 -methyl-3 -phenyl-propyl 2 -methyl -3 -phenyl-propyl 2 -methyl-3 -phenyl-propyl 2 -methyl-3 -phenyl-propyl 2 -methyl-3 -phenyl-propyl 2 -me thyl -3 -phenyl -propyl 2-methyl -3 -phenyl -propyl 2 -methyl-3 -phenyl--propyl 2 -methyl-3 -phenyl--propyl 2-methyl -3 -phenyl -propyl 2- (N,N-dimethylamino) -3phenyl -propyl 2- (N,N-dimethylamino) -3phenyl -propyl 2 -(N,N-dimethylamino) -3phenyl -propyl 2- (N,N-dimethylamino) -3phenyl -propyl 2- (N,N~-dimethylamino) -3phenyl -propyl 2- (N,N-dimethylamino) -3phenyl -propyl 2- (N,N-dimethylamino) -3phenyl -propyl 2- (N,N-dimethylamino) -3phenyl -propyl 2- (N,N-dimethylamino) -3phenyl -propyl 2- (N,N-dimethylamino) -3phenyl -propyl 2- (N,N-dimethylaiino) -3phenyl -propyl 2- (N,N-dimethylamino) -3phenyl -propyl 2- (N,N-dimethylamino) -3phenyl -propyl 2- (N,N-dimethylamino) -3phenyl-propyl 2- (N,N-dimethylamino) -3phenyl -propyl 2- (N,N-dimethylamiio) -3phenyl -propyl 2- (N,N-dimethylamino) -3phenyl -propyl 2- (N,N-dimethylamino) -3phenyl-propyl 2- (N,N-dimethylamino) -3phenyl-propyl 2- (N,N-dimethylamino) -3phenyl-propyl 2- (N-methylamino) -3phenyl -propyl 2- (N-methylarnino) -3phenyl-propyl 2- (I\-methylamino) -3phenyl -propyl WO 98/24780 WO 9824780PCTIUS97/22949 185 4-me thoxyphenyl 4 -trifluoromethypheny.
3 -isopropyiphenyl 3 -toly.
3 -chiorophenyl 3 -chloro-4-fluorophenyl 3, 5-Ditrifluoromethyiphenyl 3, 4-dichiorophenyl 4-f luorophenyl 1 -naphthyl 3-f luorophenyl 2 -naphthyl n-butyl, 2 -thiophene 3 -thiophene, 3 -aminophenyl 2- (5-chiorothiophene) 2- (N-methylamino) -3phenyl -propyl 2- (N-methylamino) -3phenyl -propyl 2- (N-methylamino) -3pheriyl -propyl 2- (N-methylamino) -3phenyl -propyl, 2- (N-methylamino) -3phenyl -propyl, 2- (N-methylamino) -3phenyl -propyl.
2- (N-methylamino) -3phenyl-propyl 2- (N-methylamino) -3phenyl -propyl 2- (N-methylanino) -3phenyl -propyl 2- (N-methylamino) -3phenyl -propyl 2- (N-methylamino) -3phenyl-propyl, 2- (N-methylaxnino) -3phenyl -propyl 2- (N-methylanino) -3phenyl -propyl 2- (N-methylanino) -3phenyl -propyl 2- (N-methylamino) -3phenyl -propyl 2- (N-methylarnino) -3phenyl-propyl 2- (N-methylamino) -3phenyl.-propyl Example 61 The compounds in table VII can be prepared using the appropriate starting materials and procedures as described above.
TABLE VII 3, 5-dichiorophenyl 4-me thoxypheny.
3 -tolyl 2(S) -amino-3-phenyl-propyl 2 (S)-amino-3-phenyl-propyl 2(S) -amino-3-phenyl-propyl WO 98/24780 WO 9824780PCT1US97/22949 186 3-chic rophenyl 4-f luorophenyl 2 -naphthyl n -bu tyl 2-thiophene 3 -thiophene 3 -aminophenyl 2- (5-chiorothiophene) 3-i sopropylphenyl 3-toly.
3 -chloropheiyl 3 -chloro-4-fluorophenyl 3, S-Ditrifluoromethylphenyl 4-f luoropheny.
3 ,4-dichiorophenyl 1 -naphthyl 3- fluorophenyl 2 -naphthyl n -bu tyl 2-thiophene 3 -thiophene 3 -aminophenyl 2- (5-chiorothiophene) 3, 5-dichiorophenyl 4-tolyl 3 -trifluoromethyiphenyl 4 -methoxyphenyl 4- tri fluoromethyiphenyl 3-is opropyiphenyl 3-tolyl 3 -chiorophenyl 3 -chloro-4-fluorophenyl 3, S-Ditrifluorornethylphenyl 4-f luorophenyl 3, 4-dichiorophenyl 2 -naphthyl n-butyl 2 -thiophene 3 -thiophene 3-aminophenyl 2- (5-chiorothiophene) 3, 5-dichiorophenyl 4-tolyl 3 -trifluoromethyiphenyl 4-methoxyphenyl 4 -trifluorornethyiphenyl 3 -isopropylphenyl 3 -tolyl 3 -chiorophenyl 3 -chloro-4-fluorophenyl 3, S-Ditrifluoromethylphenyl 4-f luorophenyl 3, 4-dichiorophenyl 1 -naphthyl 3-f luorophenyl 2 -naphthyl 2(S) -amino-3-phenyl-propyl 2 -amino-3-phenyl-propyl 2 (5)-amino-3-phenyl-propyl 2 -amino-3-phenyl-propyl 2 -amino-3-phenyl-propyl 2(S) -arino-3-phenyl-propyl 2(S) -amino-3-phenyl-propyl 2 (5)-amino-3-phenyl-propyl 3 -phenyipropyl 3 -phenyipropyl 3 -phenyipropyl 3 -phenyipropyl 3 -phenyipropyl 3 -phenyipropyl 3 -phenylpropyj.
3 -phenyipropyl 3 -phenyipropyl 3 -phenyipropyl 3 -phenyipropyl 3 -phenyipropyl 3 -phenyipropyl 3 -phenylpropyl 3 -phenyipropyl 3 -methyl-3 -phenyl-propyl 3-methyl -3 -phenyl -propyl 3 -methyl-3 -phenyl-propyl 3 -methyl-3 -phenyl-propyl 3 -methyl-3 -phenyl-propyl 3 -methyl-3 -phenyl-propyl 3 -methyl-3 -phenyl-propyl 3-methyl -3 -phenyl -propyl 3 -methyl-3 -phenyl-propyl 3 -methyl-3 -phenyl-propyl 3 -methyl-3 -phenyl-propyl 3 -methyl-3 -phenyl-propyl 3 -methyl-3 -phenyl-propyl 3 -methyl-3 -phenyl-propyl 3 -methyl-3 -phenyl-propyl 3 -methyl-3 -phenyl-propyl 3-methyl -3 -phenyl -propyl 3-methyl -3 -phenyl -propyl 3-amino- 3-phenyl -propyl 3-amino -3 -phenyl -propyl 3-amino -3 -phenyl -propyl 3 -amino-3 -phenyl-propyl 3-amino -3 -phenyl -propyl 3 -amino-3 -phenyl-propyl 3 -amino-3 -phenyl-propyl 3 -amino-3 -phenyl-propyl 3 -amino-3 -phenyl-propyl 3 -amino-3 -phenyl -propyl 3 -amino-3 -phenyl-propyl 3 -amino-3 -phenyl-propyl 3 -amino-3 -phenyl-propyl 3 -ainino-3 -phenyl-propyl 3 -amino-3 -phenyl-propyl WO 98/24780 WO 9824780PCTIUS97/22949 187 n -butyl 2 -thiophene 3- thiophene 3 -aminophenyl 2- (5-chiorothiophene) 3, 5-dichiorophenyl 4-tolyl 3 -tri fluoromethyiphenyl 4-_me thoxyphenyl 4 -trifluoromethylphenyl 3 -isopropyiphenyl 3 -tolyl 3 -chiorophenyl 3 -chloro-4-fluorophenyl 3, S-Ditrifluoromethylphenyl 4-f luorophenyl 3, 4-dichiorophenyl 1 -naphthyl 3 -fluorophenyl 2-naphthyl n-butyl 2- thiophene 3- thiophene 3 -arninophenyl 2- (5-chiorothiophene) 3, 5-dichiorophenyl 4-tolyl 3 -trifluoromethyiphenyl 4 -methoxyphenyl 3 -amino-3 -phenyl-propyl 3 -amino-3 -phenyl--propyl 3 -alnino-3 -phenyl -propyl 3 -amino-3 -phenyl-propyl 3 -arnino-3 -phenyl -propyl 2 -amino-3-phenyl-propyl 2 -alino-3-phenyl-propyl 2 -arino-3-phenyl-propyl 2 -amino-3-phenyl-propyl 2 -amino-3-phenyl-propyl 2 -amino-3-phenyl-propyl 2 -amino-3-phenyl-propyl 2 -amino-3-phenyl-propyi 2 -alino-3-phenyl-propyl 2 -amino- 3-phenyl -propyl 2 -amino-3-phenyl-propyl 2 -arino-3-phenyl-propyl 2 -amino-3-phenyl-propyl 2 -amino-3-phenyl-propyl 2 -amino-3-phenyl-propyl 2 -amino-3-phenyl-propyl 2 -amino-3-phenyl-propyl 2 -amino-3-phenyl-propyl 2 -amino-3-phenyl-propyl 2 -amxino-3-phenyl-propyl 2 -methyl-2-amino-3-phenylpropyl 2 -methyl-2 -amino-3 -phenylpropyl 2 -methyl-2-amino-3 -phenylpropyl 2 -nethyl-2 -ainino-3 -phenyl propyl 2 -'ethyl-2 -amino-3 -phenyl propyl 2 -iethyl-2 -amino-3 -phenyl propyl 2 -nethyl-2 -amino-3 -phenyl propyl 2 -methyl -2 -amino- 3 -phenyl propyl 2 -methyl-2-amino-3-phenylpropyl 2 -methyl-2-amino-3-phenylpropyl 2 -methyl -2 -amino- 3-phenyl propyl 2 -methyl-2 -amino-3 -phenylpropyl 2 -methyl -2 -amino- 3-phenyl propyl 2 -methyl-2-amino-3 -phenylpropyl 2-methyl -2 -amino-3 -phenyl propyl 4 -trifluoromethylphenyl 3-is opropyiphenyl 3-tolyl 3-chiorophenyl 3 -chloro-4-filuorophenyl 3 -Ditrifluoromethylphenyl 4- fluorophenyl 3, 4-dichiorophenyl 1-naphthyl 3 -fluorophenyl 2-naphthyl WO 98/24780 WO 9824780PCTIUS97/22949 188 n-butyl 2- thiophene 3-thiophene 3 -aminophenyl 2- (5-chiorothiophene) 3, 5-dichiorophenyl 4-tolyl 3- tri fluoromethyiphenyl 4-methoxypheny.
4-trifluoromethylphenyl 3-i sopropyiphenyl 3 -tolyl 3 -chiorophenyl 3 -chloro-4-fluorophenyl 3, S-Ditrifluoromethylphenyl 4-f luorophenyl 3, 4-dichiorophenyl 1 -naphthyl 3-f luorophenyl 2-naphthyl n -bu tyl 2 -thiophene 3 -thiophene 3 -aminophenyl 2- (5-chiorothiophene) 3, 5-dichiorophenyl 4-tolyl 3 -trifluoromethyiphenyl 4 -methoxyphenyl 2 -methyl-2-amino-3 -phenylpropyl 2 -methyl-2-alnino-3-phenylpropyl 2 -methyl-2-amino-3 -phenylpropyl .2-methyl-2-amino-3 -phenylpropyl 2 -methyl-2-amino-3 -phenylpropyl 2 -rethyl-3-phenyl-propyl 2 -rethyl-3 -phenyl-propyl 2 -me thyl-3 -phenyl-propyl 2 -methyl-3 -phenyl-propyl 2 -methyl-3 -phenyl-propyl 2 -methyl -3 -phenyl-propyl 2 -methyl -3 -phenyl -propyl 2 -methyl-3 -phenyl-propyl 2 -rethyl-3 -phenyl-propyl 2 -methyl -3 -phenyl-propyl 2 -methyl-3 -phenyl-propyl 2 -methyl-3 -phenyl-propyl 2-methyl -3 -phenyl-propyl 2 -rethyl-3 -phenyl-propyl 2 -methyl-3 -phenyl-propyl 2 -iethyl-3 -phenyl-propyl 2 -methyl-3 -phenyl-propyl 2-methyl -3 -phenyl -propyl 2 -methyl-3 -phenyl-propyl 2 -methyl-3 -phenyl-propyl 2- (N,N-dimethylamino) -3phenyl -propyl 2- (N,N-dimethylamino) -3phenyl -propyl 2- (N,N-dimethylamino) -3phenyl -propyl 2- (N,N-dimethylamino) -3phenyl-propyl 2- (N,N-dimethylamino) -3phenyl -propyl 2- (N,N-dimethylamino) -3phenyl -propyl 2- (N,N-dimethylanino) -3phenyl -propyl 2- (N,N-dimethylamino) -3phenyl -propyl 2- (N,N-dimethylamino) -3phenyl -propyl 2- (N,N-dimethylamino) -3phenyl -propyl 2- (N,N-dimethylamino) -3phenyl -propyl 2- (N,N-dimethylamino) -3phenyl -propyl 2- (N,N-dimethylamino) -3phenyl -propyl 4- tri fluoromethyiphenyl 3-i sopropyiphenyl 3-tolyl 3-chiorophenyl 3 -chloro-4-fluorophenyl 3, S-Ditrifluoromethylphenyl 4-f luorophenyl 3, 4 -dichlorophenyl 1-naphthyl WO 98/24780 WO 9824780PCTfUS97/22949 189 3-f luorophenyl 2 -naphthyl n-butyl 2 -thiophene 3 -thiophene 3 -aminophenyl 2- (5-chiorothiophene) 3, 5-dichiorophenyl 4-tolyl 3 -trifluoromethylphenyl 4-ruethoxyphenyl 4- tri fluoromethyiphenyl 3-i sopropyiphenyl 3 -tolyl 3 -chiorophenyl 3 -chloro-4-fluorophenyl 3, 5-Ditrifluoromethylphenyl 3, 4-dichiorophenyl 4- fluorophenyl 1 -naphthyl 3 -fluorophenyl 2 -naphthyl n-butyl 2 -thiophene 3 -thiophene 3 -aminophenyl 2- (5-chlorothiophene) 2- N-dimethylamino) -3phenyl -propyl 2- (N,N-dimethylamino) -3pheny.-propyl 2- CN,N-dirnethylamino) -3phenyl -propyl 2- (N,N-dimethylamino) -3phenyl -propyl 2- (N,N-dimethylamino) -3phenyl-propyl 2- (N,N-dimethylamino) -3phenyl -propyl 2- (N,N~-dimethylamino) -3phenyl.-propyl 2- (N-methylamino) -3phenyl -propyl 2- (N-methylamino) -3phenyl-propyl 2- (N-methylamino) -3phenyl -propyl 2- (N-methylamino) -3phenyl -propyl 2- (N-rethylamino) -3phenyl -propyl 2- (N-methylamino) -3phenyl.-propyl.
2 (N-rethylaniino) -3 phenyl -propyl 2- (N-methylainino) -3phenyl -propyl 2- (N-rethylarnino) -3pheny.-propyl 2- (N-methylainino) -3phenyl -propyl 2 (N -methylamino) -3 phenyl.-propyl 2 (N -methyl amino) -3 phenyl -propyl 2- (N-methylamino) -3phenyl -propyl 2- (N-methylamino) -3phenyl -propyl 2- (N-methylainino) -3phenyl -propyl 2- (N-methylamino) -3phenyl -propyl 2- (N-methylamino) -3phenyl -propyl 2- (N-methylamino) -3phenyl -propyl 2- (N-'ethylamino) -3phenyl -propyl 2- (N-methylamino) -3phenyl -propyl WO 98/24780 PCTIUS97/22949 190 Example 62 Using the corresponding starting materials, the following compounds of Table VIII may be prepared using the procedure for 3-methyl-2- -ainino-3phenyipropylamino) 3 -trifluorolnethylphenyl) (4pyridyl) -4 (3H) -pyrimidinone.
TABLE VIII 0 3, 5-dichiorophenyl 4 -methoxyphenyl 3 -tolyl 3 -chlorophenyl 4- fluorophenyl 2-naphthyl n-butyl 2 -thiophene 3 -thiophene 3 -aminophenyl 2- (5-chlorothiophene) 3- isopropylphenyl 3 -tolyl 3 -chlorophenyl 3 -chloro-4-fluorophenyl 3, S-Ditrifluorornethylphenyl 4-f luorophenyl 3, 4-dichlorophenyl 1 -naphthyl 3-f luorophenyl 2-naphthyl n-butyl 2 -thiophene 3 -thiophene 3 -aminophenyl 2- (5-chiorothiophene) 3, 5-dichlorophenyl 4-tolyl 3- tri fluoromethylphenyl 4-me thoxyphenyl 4-trifluoromethylphenyl 3- isopropylphenyl 3 -tolyl 3 -chlorophenyl 3 -chloro-4 -fluorophenyl 2 amino -3 -phenyl -propyl 2 amino -3 -phenyl -propyl 2 -alino-3 -phenyl-propyl 2 -alino-3-phenyl-propyl 2 (5)-amino-3-phenyl-propyl 2 (5)-amino-3-phenyl-propyl 2 (5)-amino-3-phenyl-propyl 2 amino 3-phenyl -propyl 2 amino -3 -phenyl -propyl 2 -amino-3 -phenyl-propyl 2 -arino-3 -phenyl -propyl 3 -phenylpropyl 3 -phenyipropyl 3 -phenyipropyl 3 -phenyipropyl 3 -phenylpropyl 3 -phenylpropyl 3 -phenylpropyl 3 -phenylpropyl 3 -phenylpropyl 3 -phenyipropyl 3 -phenyipropyl 3 -phenyipropyl 3 -phenyipropyl 3 -phenylpropyl 3 -phenyipropyl 3 -rethyl-3 -phenyl-propy.
3 -methyl-3 -phenyl-propyl 3 -methyl-3 -phenyl-propyl 3 -methyl-3 -phenyl-propyl 3 -methyl-3 -phenyl-propyl 3-methyl -3 -phenyl -propyl 3 -methyl-3 -phenyl-propy.
3 -methyl-3 -phenyl-propyl 3 -methyl-3 -phenyl-propyl WO 98/24780 WO 9824780PCT1US97/22949 191 3, 5-Ditrifluoromethylphenyl 4-f luorophenyl 3, 4-dichiorophenyl 2 -naphthyl n-butyl 2 -thiophene 3 -thiophene 3 -aminophenyl 2- (5-chiorothiophene) 3 ,5-dichiorophenyl 4-toly.
3 -trif luoromethyiphenyl 4 -rethoxyphenyl 4 -trifluoromethyiphenyl 3 -isopropyiphenyl 3-tolyl 3 -chiorophenyl 3 -chloro-4--fluorophenyl 3, 5-Ditrifluoromethyiphenyl 4-f luorophenyl 3 ,4-dichiorophenyl 1 -naphthyl 3 -fluorophenyl 2 -naphthyl n-butyl 2 -thiophene 3 -thiophene 3 -aminophenyl 2- (5-chiorothiophene) 3, 5-dichiorophenyl 4-tolyl 3 -trifluoromethyiphenyl 4 -methoxyphenyl 4- tri fluoromethyiphenyl 3 -isopropyiphenyl 3 -tolyl 3 -chiorophenyl 3 -chloro-4-fluorophenyl 3, 5-Ditrifluoromethyiphenyl 4-f luoropheny.
3, 4-dichiorophenyl 1 -naphthyl 3 -fluoropheny.
2 -naphthyl n-butyl 2 -thiophene 3 -thiophene 3 -aminophenyl 2- (5-chiorothiophene) 3, 5-dichiorophenyl 4-tolyl 3 -trifluoromethyjlphenyl 3 -methyl-3 -phenyl-propyl 3 -methyl-3 -phenyl-propyl 3 -methyl-3 -phenyl-propyl 3-methyl -3 -phenyl -propyl 3-methyl -3 -phenyl -propyl 3 -methyl-3 -phenyl-propyl 3 -rethyl-3 -phenyl-propyl 3 -methyl-3 -phenyl-propyl 3 -methyl-3 -phenyl-propyl 3 -amino-3 -phenyl-propyl 3 -amino-3 -phenyl-propyl 3 -amino-3 -phenyl-propyl 3 -amino-3 -phenyl-propyl 3 -amino-3 -phenyl-propyl 3 -amino-3 -phenyl-propyl 3 -amino-3-phenyl-propyl 3 -ainino-3 -phenyl-propyl 3 -amino-3 -phenyl-propyl 3 -amino-3 -phenyl-propyl 3 -amino-3 -phenyl-propyl 3 -amino-3 -phenyl -propyl 3 -amino-3 -phenyl -propyl 3 -amino-3 -phenyl-propyl 3-amino -3 -phenyl -propyl 3 -amino-3 -phenyl-propyl 3 -amino-3 -phenyl-propyl 3 -amino-3 -phenyl-propyl 3 -amino-3 -phenyl-propyl 3 -amino-3 -phenyl-propyl 2 -amino -3 -phenyl -propyl 2 -amino-3 -phenyl-propyl 2 -amnino-3-phenyl-propy.
2 amino -3 -phenyl -propyl 2 amino 3-phenyl -propyl 2 amino -3 -phenyl -propy.
2 -amino-3-phenyl-propyl 2 amino 3-phenyl -propyl 2 -amino-3-phenyl-propyl 2 -amino-3-phenyl-propyl 2 amino -3 -phenyl -propyl 2 -amino-3-phenyl-propyl 2 -amino-3-phenyl-propyl 2 -amino-3-phenyl-propyl 2 -amino-3-phenyl-propyl 2 -amino-3-phenyl-propyl 2 -amino- 3-phenyl -propyl 2 -amino-3-phenyl-propyl 2 -amino-3-phenyl-propyl 2 -amino-3-phenyl-propyl 2 -methyl-2 -amino-3 -phenylpropyl 2 -methyl-2 -amino-3 -phenylpropyl 2 -rethyl-2 -amino-3 -phenylpropyl WO 98/24780 WO 9824780PCTIUS97/22949 192 4-me thoxyphenyl 4- tri fluoromethylpheriyl 3- isopropyiphenyl 3 -tolyl 3 -chiorophenyl 3 -chloro-4-fluorophenyl 3, 5-Ditrifluoromethyiphenyl 4-f luorophenyl 3 ,4-dichiorophenyl 1 -naphthyl 3- fluorophenyl 2 -naphthyl n-butyl 2- thiophene 3- thiophene 3 -aminophenyl 2 -methyl-2 -amino-3 -phenylpropyl 2-methyl-2-amino-3 -phenylpropyl 2-methyl -2 -amino- 3-phenyl propyl 2-methyl-2-amino-3 -phenylpropyl 2-methyl-2-amino-3 -phenylpropyl 2-methyl-2-axnino-3 -phenylpropyl 2 -methyl-2-axnino-3 -phenylpropyl 2-methyl-2-amino-3 -phenylpropyl 2-methyl-2-amino-3 -phenylpropyl 2 -methyl-2-ainino-3 -phenylpropyl 2-methyl-2-amino-3 -phenylpropyl 2-methyl-2-amino-3 -phenylpropyl 2-methyl-2 -amino-3 -phenylpropyl 2-me thyl-2-amino-3 -phenylpropyl 2-methyl-2-amino-3 -phenylpropyl 2-methyl-2 -amino-3 -phenylpropyl 2-methyl-2 -amino-3 -phenylpropyl 2-methyl-3 -phenyl-propyl 2-methyl -3 -phenyl -propyl 2-methyl -3 -phenyl -propyl 2-methyl-3 -phenyl-propyl 2-methyl -3 -phenyl -propyl 2-methyl -3 -phenyl -propyl 2-methyl-3 -phenyl-propyl 2 -methyl-3 -phenyl -propyl 2-methyl -3 -phenyl -propyl 2-methyl -3 -phenyl -propyl 2-methyl -3 -phenyl -propyl 2-methyl -3 -phenyl -propyl 2-methyl -3 -phenyl -propyl 2-methyl -3 -phenyl -propyl 2-methyl -3 -phenyl -propyl 2-methyl -3 -phenyl -propyl 2-methyl-3 -phenyl-propyl 2-methyl -3 -phenyl -propyl 2-methyl -3 -phenyl -propyl 2-methyl-3 -phenyl -propyl 2- (N,N-dimethylamino) -3phenyl -propyl 2- (5-chlorothiophene) 3, 5-dichlorophenyl 4-tolyl 3 -trifluoromethylphenyl 4-me thoxyphenyl 4- tri fluorornethylphenyl 3 -isopropylphenyl 3 -tolyl 3 -chlorophenyl 3 -chloro-4-fluorophenyl 3, S-Ditrifluoromethylphenyl 4-f luorophenyl 3, 4-dichlorophenyl 1 -naphthyl 3 -fluorophenyl 2 -naphthyl n-butyl 2 -thiophene 3 -thiophene 3 -aminophenyl 2- (5-chlorothiophene) 3, 5-dichlorophenyl WO 98/24780 WO 9824780PCT11US97/22949 193 4-tolyl 3- tri fluoromethyiphenyl 4-methoxyphenyl 4- trifluoromethyiphenyl 3- isopropyiphenyl 3 -tolyl 3 -chiorophenyl 3-chloro-4-fluorophenyl 3, 5-Ditrifluoromethylphenyl 4-f luorophenyl 3, 4-dichiorophenyl 1 -naphthyl 3-f luorophenyl 2 -naphthyl n-buty.
2- thiophene 3- thiophene 3-aininophenyl 2- (5-chiorothiophene) 2- (N,N-dimethylamino) -3phenyl-propyl 2- (N,N-dimethylamino) -3phenyl -propyl 2- (N,N-dimethylamino) -3phenyl -propyl 2- (N,N-dimethylamino) -3phenyl -propyl 2- (N,N-dimethylamino) -3phenyl -propyl 2- (N,N-dimethylamino) -3phenyl -propyl 2- (N,N-dimethylamino) -3phenyl -propyl 2- (N,N-dimethylamino) -3phenyl -propyl 2- (N,N-dilnethylamino) -3pheriyl.-propyl 2- (N,N-dimethylamino) -3phenyl.-propyl 2- (N,N-dimethylamino) -3phenyl -propyl 2- (N,N-dimethylanino) -3pheriyl.-propyl 2- (N,N-dimethylamino) -3phenyl -propyl 2- (N,N-dimethylamino) -3phenyl -propyl 2- (N,N-dimethylanino) -3pheriyl -propyl 2- (N,N-dimethylamino) -3phenyl -propyl 2- (N,N-dimethylamino) -3phenyl -propyl.
2- (N,N-diinethylamino) -3phenyl -propyl 2- (N,N-dimethylamino) -3phenyl -propyl 2- (N-methylainino) -3phenyl -propyl 2- (N-rnethyilaiino) -3phenyl -propyl 2- (Nq-me thyl amino) -3phenyl -propyl 2- (N-methylamino) -3phenyl -propyl 2- (N-methylanino) -3phenyl -propyl 2- (N-methylamino) -3phenyl -propyl 2- (N-methylanino) -3phenyl -propyl 2- (Nq-rethylamino) -3phenyl -propyl 2- (N-methylamino) -3phenyl -propyl 3, 5-dichiorophenyl 4-tolyl 3 -tri fluoromethyiphenyl 4-methoxyphenyl 4 -trifluoromethyiphenyl 3-i sopropyiphenyl 3-tolyl 3 -chiorophenyl 3 -chloro-4-fluorophenyl WO 98/24780 PTU9124 PCTIUS97/22949 194 3, 5-Ditrifluoromethyiphenyl 3, 4-dichiorophenyl 4-f luorophenyl 1 -naphthyl 3- fluorophenyl 2 -naphthyl 2- (N-methylamino) -3phenyl -propyl 2- (N-methylamino) -3phenyl -propyl 2- (N-methylanino) -3phenyl -propyl 2- (N-methylanino) -3phenyl -propyl 2- (N-methylamino) -3phenyl -propyl 2- (N-methylanino) -3phenyl -propyl 2- (N-methylanino) -3phenyl -propyl 2- (N-methylamino) -3phenyl -propyl 2- (N-methylamino) -3phenyl -propyl 2- (N-methylamino) -3phenyl -propyl 2- (N-methylaxnino) -3phenyl -propyl n -butyl 2-thiophene 3 -thiophene 3 -aininophenyl 2- (5-chiorothiophene) Example 63 Procedure for the preparation of trifluoromethylphenyvl)phenylmethyl) amino) -3-methyl-5- (4fluorophenyl) (4-pyVridyl1) -4 (3H) -pyrimidinone Step A. ((2-brornophenvlmethyl) amino) (4fluorophenyl) (4-Dvridvl)-3-methyl-4 (3H) -pyrimidinone: The compound, 3-methyl-5- 4 -fluorophenyl)-6-(4-pyridyl) 2 -thioinethyl-4(3H)-pyrimidinone (470 mg, 1.44 mmol) was dissolved in methanol:water mixture(l.8:1, 40m1 and 22.5m1). Potasssium peroxymonosulfate (OXONE Aldrich Chem Co., 2.5g 4.1 minol) was added to a cooled (4 0
C)
reaction mixture and then the reaction was continued for 16h at room-temperature. The reaction mixture was concentrated and extracted with dichloromethane and the organic layer was washed with water, dried over Na 2 S0 4 and was concentrated. The residue (500mg) and o- WO 98/24780 PCTIUS97/22949 195 bromobenzylamine were mixed in 1,4-dioxane .(20 ml). The clear solution was heated at 850C for 18 h and progress of the reaction monitored by TLC. The reaction mixture was concentrated and chromatographed on a silica gel column to obtain the titled compound. MS(m/z): 466.9 C,23HBrFNO requirs: 465.33 1H-NMR (CDC13):d 8.49 (dd, 2H, pyridyl), 7.67-6.81 12H, Ph and pyridyl), 5.44 (t, 1H, NH), 4.92 (d 2H, CH2-Ph), 3.6 3H, N-CH).
Step B. 3 -trifluoromethylphenvl)phenvlmethYl) amino)- 3 -methyl-5-(4-fluorophenvl)-6-(4-pvridvl)-4( 3
H)-
pyrimidinone: 2- 2 -bromophenylmethyl) amino) (4fluorophenyl)-6-(4-pyridyl)-3-methyl-4(3H)-pyrimidinone (175 mg, 0.38 mmol) was dipersed in 2M sodium carbonate solution (12 ml) and 3 -trifluromethylbenzene- boronic acid (170 mg, 0.89 mmol), toluene (12ml) were added to the above mixture and the reaction mixture was degassed and catalyst tetrakistriphenylphosphine Pd(0) (50 mg) was added. The reaction mixture was refluxed for 16 h.
The formation of the product was monitored by TLC. Then it was cooled, diluted with toluene (12 ml) and washed with water. The organic layer was dried over sodium sulfate, concentrated and the product was purified by silica gel chromatgraphy to give the title compound.
MS(m/z): 531.1 C3HFN4O requir. 530.53; 1H-NMR(CDC1 3 ):d 8.43 2H, pyridyl), 7.69-7.12 (m,8H, Ph), 7.11-6.88 6H, pyridyl and Ph-CF,), 4.85 3H, CH,-Ph and NH), 3.32(N-CH) Example 64 Using the corresponding starting materials, the following compounds of Table IX may be prepared using the procedure for 3 -trifluoromethylphenyl) phenylmethyl)amino)-3-methyl-5-(4-fluorophenyl)-6-(4pyridyl)-4(3H)-pyrimidinone.
WO 98/24780 PCTIUJS97/22949 196 TABLE IX 4-f luorophenyl 4-f luorophenyl 4- fluorophenyl 4- fluorophenyl 4 -fluorophenyl 4- fluorophenyl 4-f luorophenyl 4-f luorophenyl 4- fluorophenyl 4- fluorophenyl 4 -fluorophenyl 4-f luorophenyl 4-f luorophenyl 4-f luorophenyl 4-f luorophenyl 4 -fluorophenyl 4-f luorophenyl 4- fluorophenyl 4-f luorophenyl 3 -trifluoromethyiphenyl 3 -trifluoromethyiphenyl 3 -trifluoromethyiphenyl 3- tri fluoromethyiphenyl 3- tri fluoromethyiphenyl 3 -trifluoromethylpheny.
3- tri fluoroinethyiphenyl 3 -trifluorornethyiphenyl 3- tri fluoroinethylphenyl 3- tri fluorornethyiphenyl 3 -trifluoromethyiphenyl 3 -tri fluoromethyiphenyl 3 -trifluoromethyiphenyl 3 -trifluorornethyiphenyl 3 -trifluoromethyiphenyl 3 -trifluoromethyiphenyl 3- tri fluoromethyiphenyl 3 -trifluoromethyiphenyl 3 -trifluoromethyiphenyl 3- tri fluoromethylphenyl 3, 4-tolyl.
4-me thoxyphenyl 4 -trifluoromethylphenyl 3-i sopropyiphenyl 3-tolyl 3 -chiorophenyl 3 -chloro-4 -fluorophenyl 3, S-Ditrifluoromethylphenyl 4-f luorophenyl 3, 4-dichiorophenyl 1 -naphthyl 3-f luorophenyl 2 -naphthyl n-butyl 2-thiophene 3 -thiophene 3 -aminophenyl 2- 3, 4-tolyl.
3 -trifluoroinethyiphenyl 4-me thoxyphenyl 4- trifluoromethyiphenyl 3-i sopropyiphenyl 3 -tolyl 3 -chiorophenyl 3 -chloro-4 -fluorophenyl 3, S-Ditrifluoromethylphenyl 4 fluorophenyl 3, 4-dichiorophenyl 1 -naphthyl 3-f luorophenyl 2 -naphthyl.
n-butyj.
2- thiophene 3- thiophene 3 -alninophenyl 2- Example Using the corresponding starting materials, the following compounds of Table X may be prepared using the WO 98/24780 WO 9824780PCTIUS97/22949 197 procedure for 2- 3 -trifluoromethylphenyl) phenylmethyl) amino) -3-methyl-5- 4 -fluorophenyl) (4pyridyl) -4 (3H) -pyrimidinone.
TABLE X 4- fluorophenyl 4 -fluorophenyl 4 -fluorophenyl 4-f luorophenyl 4-f luorophenyl 4-f luorophenyl 4- fluorophenyl 4- fluorophenyl 4-f luorophenyl 4- fluorophenyl 4-f luorophenyl 4-f luorophenyl 4-f luorophenyl 4-f luorophenyl 4-f luorophenyl 4-f luorophenyl 4- fluorophenyl 4- fluorophenyl 4-f luorophenyl 3- tri fluoromethylbphenyl 3- tri f uoromi thylphenyl 3- tri fluoromethyiphenyl 3 -trifluoromethyiphenyl 3 -trifluoromethyiphenyl 3 -trifluoromethyiphenyl 3 -trifluoromethyiphenyl 3- tri fluoromethyiphenyl 3 -tri fluoromethyiphenyl 3 -trifluoromethyiphenyl 3- tri fluoromethyiphenyl 3- tri fluoromethyiphenyl 3- tri fluoromethyiphenyl 3- tri fluoromethyiphenyl 3 -trifluoromethylphenyl 3 -trifluoromethylphenyl 3 -trifluoromethyiphenyl 3- trif luorome thyiphenyl 3 -tri fluoromethyiphenyl 3 -trifluoromethylphenyl
QR
4 0 3 4 -tolyl 4-me thoxyphenyl 4- trif luoromethyiphenyl 3-is opropyiphenyl 3-tolyl 3 -chiorophenyl 3 -chloro-4-fluorophenyl 3, S-Ditrifluoromethylphenyl 4- fluorophenyl 3, 4-dichiorophenyl 1 -naphthyl 3 -fluorophenyl 2 -naphthyl n-butyl 2- thiophene 3 -thiophene 3 -aminophenyl 2- 3, 4-tolyl 3 -trifluoromethyiphenyl 4-me thoxyphenyl 4- trifluoromethyiphenyl 3-i sopropyiphenyl 3 -tolyl 3 -chiorophenyl 3 -chloro-4- fluorophenyl 3, S-Ditrifluoromethylphenyl 4-f luorophenyl 3, 4-di chiorophenyl 1 -naphthyl 3 -f luorophenyl 2 -naphthy.
n-butyl 2 -thiophene 3- thiophene 3 -aminophenyl 2- WO 98/24780 WO 9824780PCTIUS97/22949 198 Example 66 Using the corresponding starting materials, the following compounds of Table XI may be prepared using the procedure for 2- (3-trifluorornethylphenyl) phenylmethyl)amino) -3-methyl-5- (4-fluorophenyl) pyridyl) -4 (3H) -pyrimidinone.
TABLE XI 4-f luorophenyl 4-f luorophenyl 4-f luorophenyl 4-f luorophenyl 4-f luorophenyl 4-f luorophenyl 4- fluorophenyl 4- fluorophenyl 4-f luorophenyl 4-f luorophenyl 4-fluorophenyl 4-f luorophenyl 4-f luorophenyl 4-f luorophenyl 4-f luorophenyl 4-f luorophenyl 4- fluorophenyl 4- fluorophenyl 4-f luorophenyl 3 -trifluoromethyiphenyl 3-trifluoromethylphenyl 3 -trifluoromethylphenyl 3 -trifluoromethyiphenyl 3 -trifluoromethylphenyl 3 -trifluoromethylphenyl 3 -trifluorornethylphenyl 3 -trifluoromethyiphenyl 3 -trifluoromethyiphenyl 3- tri fluoromethyiphenyl 3 -trifluoromethylphenyl 3 -trifluoromethylphenyl 3 -trifluoromethyiphenyl 3 -trifluoromethyiphenyl 3 -trifluoromethyiphenyl 3 -trifluoromethyiphenyl 3 -trifluoromethyiphenyl 3 4 -tolyl 4 -inethoxyphenyl 4- tri fluoromethylphenyl 3-is opropylphenyl 3 -tolyl 3 -chiorophenyl 3 -chloro-4-fluorophenyl 3 -Ditrifluoromethylphenyl 4 f luo rophenyl 3 1 4-dichlorophenyj.
1 -naphthyl 3 fluorophenyl 2-naphthyl n-butyl 2 -thiophene 3 -thiophene 3 -aminophenyl 2 (5 chio rothi ophene) 3 4 -tolyl 3 -trifluoromethyiphenyl 4-me thoxyphenyl 4- tri fluoromethylphenyl 3-is opropyiphenyl 3-tolyl 3 -chlorophenyl 3 -chloro-4-fluorophenyl 3 -Ditrifluorometliylphenyl 4- fluorophenyl 3 ,4-dichiorophenyl 1 -naphthyi 3-f luorophenyl 2-naphthyl n-butyl 2 -thiophene WO 98/24780 PCT/US97/22949 199 3-trifluoromethylphenyl 3-thiophene 3-trifluoromethylphenyl 3-aminophenyl 3-trifluoromethylphenyl Example 67 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 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 370C and 6% CO 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.
WO 98/24780 PCT/US97/22949 200 Preparation of test compound stock solutions Test compounds were dissolved in DMZ. Compound stock solutions were prepared to an initial concentration of 10 50 M. Stocks were diluted initially to 20 200 uM 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 il complete medium.
Monocytes were cultured with test compounds for 60 min at which time 25 ul of complete medium containing 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 (40C) with 150 pL/well of 3 pg/ml murine anti-human TNF-c MAb (R&D Systems #MAB210).
Wells were then blocked for 1 hr at room temperature with 200 pL/well of CaCl 2 -free ELISA buffer supplemented to contain 20 mg/ml BSA (standard ELISA buffer: 20 mM, 150 mM NaC1, 2 mM CaCl 2 0.15 mM thimerosal, pH 7.4).
Plates were washed and replenished with 100 1l 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 ul/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 WO 98/24780 PCT/US97/22949 201 streptavidin (Jackson ImmunoResearch #016-050-084) at 0.02 ug/ml. Plates were incubated 30 min, washed and replenished with 200 pl/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.
Compounds of the invention can also be shown to inhibit LPS-induced release of IL-1P, IL-6 and/or IL-8 from monocytes by measuring concentrations of IL-1l, 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-a from monocytes, compounds of this invention can also be shown to inhibit LPS induced release of IL-1p, IL-6 and/or IL- 8 from monocytes by measuring concentrations of IL-1, 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- 1i, 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 WO 98/24780 WO 9824780PCT/US97/22949 202 Male DBA/lLACJ mice were dosed with vehicle or test compounds in a vehicle (the vehicle consisting of tragacanth in 0.03 N HCl) 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 IC 50 values of 20 pgM or less: 2 2 6 -Dichlorobenzyl) (4-f luorophenyl) 3methyl.6-(4pyridyl) -4 (3H) -pyrimidinone 2- (Butylamino) (4-f luorophenyl) -3-methyl-6- (4pyridyl) -4 (3H) -pyrimidinone 2 (Benzylamino) 5- (4 -f luorophenyl) 3-methyl -6 (4 pyridyl) -4 (3H) -pyrimidinone (4 -F luorophenyl) 3-methyl (R-l1-phenylethyl) amino) (4 pyridyl) -4 (3H) -pyrimidinone 2 (2 (2 -Chl orophenyl) ethyl amino) 5- (4 -f luorophenyl) -3 methyl-6- (4-pyridyl) -4 (3H) -pyrimidinone 5 -Fluorophenyl) 2- 2 4 fluorophenyl) -ethylamino) -3 methyl-6- (4-pyridyl) -4 (3H) -pyrimidinone (4-Fluorophenyl) (2-hydroxy-2-phenyl) -ethylanino) 3-methyl-6- (4-pyridyl) -4 (3H) -pyrimidinone (4-Fluorophenyl) -3-methyl-2- (3-phenylpropyl) -amino) 6- (4-pyridyl) -4 (3H) -pyrimidinone (4-Fluorophenyl) -3-methyl-2- (l-methyl-3phenylpropyl) -amino) (4-pyridyl) -4 (3H) -pyrimidinone (4-Fluorophenyl) -3-methyl-2- (R-1-methyl-3phenylpropyl) -amino) (4-pyridyl) -4 (3H) -pyrimidinone 5- (4-Fluorophenyl) -3-methyl-2- (2-phenylaminoethyl) amino) (4-pyridyl) -4 (3H) -pyrimidinone (4 -Fluorophenyl) -2 (3 -imidazolylpropyl) -amino) -3 methyl-6- (4-pyridyl) -4 (3H) -pyrimidinone (4-Fluorophenyl) -3-methyl-6- (4-pyridyl) (3- (pyrrolidin-l-yl) -propylamino) -4 (3H) -pyrimidinone 3, 6-Diphenyl-4- (4-pyridyl) -2 (lH) -pyridone 6- (4-Methylphenyl) -3-phenyl-4- (4-pyridyl) -2 (1H) -pyridone 6- (4-Ethylphenyl) -3-phenyl-4- (4-pyridyl) -2 (1H) -pyridone 6- (2,4 -Dime thylphenyl) -3-phenyl-4- (4-pyridyl) -2 (1H) pyridone 3-Phenyl-4- (4-pyridyl) (2-thienyl) -2 (1H) -pyridone 6- (2-Furyl) -3-phenyl-4- (4-pyridyl) -2 (1H) -pyridone WO 98/24780 PCT/US97/22949 203 S)-2-Amino-3-phenylpropyl)-amino)-5-(4fluorophenyl) -3-methyl-6- (4-pyridyl) -4 C3H) -pyrimidinone 2-CC -2-Amino-3-phenylpropyl)-amino-5-(4fluorophenyl) -3-methyl-6- (4-pyridyl) -4 C3H) -pyrimidinone 2-C 2 -N-Ethyl-3-phenylpropy.) -amino) fluorophenyl) -3-methyl-6- (4-pyridyl) -4 (3H) -pyrirnidinone 2-(C 2 -Amino-2-methiy-3-phenylpropyl)amino) (4fluorophenyl) -3-methyl-6- (4-pyridyl) -4 (3H) -pyrimidinone 2-(C(2-Aminomethy-3-phenylpropyl) -amino) (4fluorophenyl-3-methyl-6- (4-pyridyl) -4 C3H) -pyrimidinone 2- ((3-Alino-3-phenylpropyl) -amino) (4-f luo~rophenyl) -3methyl-6- (4-pyridyl) -4 (3H) -pyrimidinone 5-C4-Fluorophenyl)-3-methyl-2-(3-(2methylphenyl)propyl) -amino) (4-pyridyl) -4 C3H) pyrimidinone (4-Fluorophenyl) -3-methyl-2-( CR, S) -2-amino-3- fluorophenyl) -propyl -amino) (4-pyridyl) -4 (3H) pyrimidinone C(S) 2 -Acetamido-3-phenylpropyl) -amino) fluorophenyl) -3-methyl-6- (4-pyridyl) -4(31) -pyrimidinone C4-Fluorophenyl)-2-( S)-2-N-isopropylamino-3phenyipropyl) -amino) -3-methyl-6- (4-pyridyl) -4(311)pyrimidinone 2- -2-N-n-Butylamino-3-phenylpropyl) -amino) (4fluorophenyl) -3-methyl-6- (4-pyridyl) -4 C3H) -pyrimidinone 2-CC(S) 2 -NN-Dimethylainino-3-phenylpropyl) -amino) (4fluorophenyl-3-methyl-6- (4-pyridyl) -4 (3H) -pyrimidinone (4-Fluorophenyl) -3-methyl-2-(C 2-methy-3-phenylpropyl) amino) (4-pyridyl) -4 (3H) -pyrimidinone
S)-
2 -Amino-3-phenylpropyl)-amino)3ethyl.5-(4fluorophe nyl) (4-pyridyl) -4(31) -pyrimidinone (4-f luorophenyl) -2-(C(2-methy-3-phenylpropyl) amino) (4-pyridyl) -4 (3H) -pyrimidinone 2-C C 3 -trifluoromethylphenyl)phenylmethyl) amino) -3me thyl 5- (4 fluorophenyl) 6- (4 -pyridyl) 4 (3 H) pyrimidinone 3-Methyl-2- -amino-3-phenylpropylamino) (4-tolyl) 6- (4-pyridyl) -4 (3H) -pyrimidinone 3 -Methyl 2- (2 CS) -amino- 3-phenylpropylamino) 5- (4 trifluoromethyiphenyl) (4-pyridyl) -4 (3H) -pyrimidinone 3 -Me thyl 2- (2 CS) amino 3-phenylpropylamino) 5- (3 isopropyiphenyl)
C
4 -pyridyl) -4 C3H) -pyrimidinone 3 -Methyl-2 (2 -amino-3 -phenylpropyl amino) -5 (3 -chioro- 4-f luorophenyl) 4 -pyridyl) -4(31) -pyrimidinone WO 98/24780 WO 9824780PCT/US97/22949 204 3-Methyl-2- (2 -amino 3-phenylpropyl amino) bis (trifluoromethyl)phenyl) (4-pyridyl) -4 (3H) pyrimidinone 3-Methyl-2- (2 -amino 3-phenylpropyl amino) (3,4dichiorophenyl) (4-pyridyl) -4 (3H) -pyrimidinone 3-Methyl-2- (2 -amino-3-phenylpropyl amino) (1naphthyl) (4-pyridyl) -4 (3H) -pyrimidinone 3-Methyl-2- (2 -amino 3-phenylpropyl amino) (3fluorophenyl) (4-pyridyl) -4 (3H) -pyrimidinone 3-Methyl-2- (2 -amino 3-phenylpropyl amino) (3tri fluoromethylphenyl) 6- (4 -pyridyl) 4 (3H) -pyrimidinone 3 -Methyl-2 3 -phenylpropyl amino) 5-dichiorophenyl) 6- (4-pyridyl) -4 (3H) -pyrimidinone 3-Methyl-2- 3 -phenylpropyl amino) (4-tolyl) (4pyridyl) -4 (3H) -pyrimidinone 3-Methyl-2- 3 -phenylpropylamino) (3trif luoromethyiphenyl) (4-pyridyl) -4 (3H) -pyriinidinone 3-Methyl-2- 3 -phenylpropyl amino) (4-methoxyphenyl) -6- (4-pyridyl) -4 (3H) -pyrimidinone 3-Methyl-2-(3-phenylpropylamino) trif luoromethylphenyl) (4-pyridyl,) -4 (3H) -pyrimidinone 3 -Methyl -2 2 -methyl 3-phenylpropyl amino) 5- (3 f luorophenyl) (4-pyridyl) -4 (3H) -pyrirnidinone 3 -Methyl -2 (2 -methyl 3-phenylpropylamino) 5- (1 naphthyl) (4-pyridyl) -4 (3H) -pyrimidinone (4-Fluorophenyl) -2-N-glycylamino-3phenyipropyl) -amino) -3-methyl-6- (4-pyridyl) (3H) pyrimidinone 2- 2 -N-Glycylamino-3 -phenylpropyl) -amino) -3-methyl- 5- (3-methylphenyl) (4-pyridyl) (3H) -pyrimidinone (4-Fluorophenyl) -2-hydroxyacetamido-3phenyipropyl) -amino) -3-methyl-6- (4-pyridyl) (3H) pyrimidinone (4-Fluorophenyl) -2-pyrrolidinyl-3phenylpropyl) -amino) -3-methyl6 (4-pyridyl) -4-(3H) pyrimidinone 2- -3-Benzylpiperazinyl) (4-f luorophenyl) -3-methyl- 6- (4-pyridyl) (3H) -pyrimidinone 2- (3-Amnino-3- 2 -f luorophenyl)propyl) -amino) (4f luorophenyl) -3-methyl-6- (4-pyridyl) (3H) -pyrimidinone 2 3 -Amino-3- (2-methylphenyl) propyl) -amino)-5- (4f luorophenyl) -3-methyl-6- (4-pyridyl) (3H) -pyrimidinone 2 3-Amino -3 -phenylpropyl) amino) 5- (4 f luorophenyl) -3-methyl-6- (4-pyridyl) (3H) -pyrimidinone 2 3-Amnino 3-phenylpropyl) amino) -5S- (4 f luorophenyl) -3-methyl-6- (4-pyridyl) (3H) -pyrimidinone WO 98/24780 PCT/US97/22949 205
C(S)-
3 -Amino-3-phenylpropyl)amino)3methy16-( 4 pyridyl) 5- C 3 -trifluorornethylphenyl) (3H) -pyrimidinone 3 -Aino3-phenypropy)amino)3:ethy16-( 4 pyridyl) 5- 3 -trifluoromethylphenyl) (3H) -pyrimidinone 3 -Amino-3-phenylpropyl)-amino) -3-rnethyib-6- (4pyridyl) 5- 3 -trifluoromethylphenyl) (3H) -pyrimidinone 2- ((3-Amino-3- (2-methyiphenyl) propyl) -amino) -3-methyl-6- (4-pyridyl) 5- (3-trifluoromethylphenyl) (3H) pyrimidinone 3 -Amino-3-(2-fluorophenyl)propyl)amino)-3-methylG6 (4-pyridyl) 5- (3-trifluoromethylphenyl) (3H) pyrimidinone 3 -Amino-3-phenylpropyl) -amino) -3-niethyl-5- (3methyiphenyl) (4-pyridyl) (3H) -pyrimidinone 3 -Amino-3-(2-fluorophenyl)propyl) -amino) (3-methyiphenyl) (4-pyridyl) (3H) -pyrimidinone 2-C (3-Amino-3- (2-chlorophenyl)propyl) -amino) (3-methyiphenyl) (4-pyridyl) (3H) -pyrimidinone 2- 3 -Amino-3-phenylpropyl) -amino) -3-methyl-6- (4pyridyl) 5- 4-dimethyiphenyl) (3H) -pyrimidinone 2- 3R) 3 -Amino-2-methyl-3-phenylpropyl) -amino) (4-fluorophenyl) -3-methyl-6- (4-pyridyl) (3H) pyrimidinone 2- 3 -Amino-2-methyl-3-phenylpropyl) -amino) 4 -fluorophenyl)-3-methyl-6-(4.pyridyl)4(3H)py~i~midinone (4-Fluorophenyl) 3 -N-isopropylamino-3phenyipropyl) -amino) -3-methyl-6- (4-pyridyl) (3H) pyr imidinone 5-(4-Fluorophenyl)-2-( ((R)-3-N-isopropylamino-3phenyipropyl) -amino) -3-methyl-6- (4-pyridyl) (3H) pyrimidinone (4-Fluorophenyl) -3-methyl-6- (4-pyridyl) tetrahydroisoquinol-3-ylmethylenamino) (3H) pyrimidinone 3-Methyl-6- (4-pyridyl) -tetrahydroisoquinol-3ylmethylenamino) 5- (3-trifluoromethylphenyl) (3H) pyrimidinone (3-methyiphenyl) (4-pyridyl) tetrahydroisoquinol-3-ymetyenaio) (3H) pyrimidinone 3 -Methyl-5-(4-methylthiophenyl)6(4pyridyl)- 2 tetrahydroisoquinol13>ymethyenamjf 0 (3H) pyrimidinone 2 2 -Amino-3 -phenypropy)amino) 3 methy-5 -(3 methyiphenyl) 4 -pyridyl) (3H) -pyrimidinone WO 98/24780 WO 9824780PCTIUS97/22949 206 (4-Fluorophenyl) ((3-hydroxy-3-phenylpropyl) -amino) 3-methyl-6- (4-pyridyl) (3H)-pyrimidinoie 2- -2-Amino-3-phenylpropyl) -amino) (4fluorophenyl) (4-pyridyl) (3H) -pyrimidinone 2 2 -Amino-3- (2-fluorophenyl)propyl) -amino) 5-( 4 fluorophenyl) -3-methyl-6- (4-pyridyl) (3H)-pyrimidinone 2- -2-Amino-3- 4 -fluorophenyl)propyl) -amino) (4fluorophenyl) -3-methyl-6- (4-pyridyl) (3H)-pyrimidinone 2- -2-Amino-3- 2 -chlorophenyl)propyl) -amino) (4fluorophenyl) -3-rnethyl-6- (4-pyridyl) (3H) -pyrimidinone 2- 2 -N-Isopropylamino-3-phenylpropyl) -amino) -3methyl 6- (4 -pyridyl) 5- (3 -tri fluoromethylphenyl) 4- (3H) pyrimidinone 2 2 Isopropylamnino -3 -phenylpropyl) -amino) -3 methyl-5- (3-methylpheny) 6(4pyridyl)-4-( 3
H)
pyrimidinone (3-Chlorophenyl-2- 2 -N-isopropylamino-3phenyipropyl) -amino) -3-methyl-6- (4-pyridyl) (3H) pyrimidinone 2- 2 N- Dime thylamino -3 -phenylpropyl) -amino) -3- (3-methyiphenyl) (4-pyridyrl) (3H) pyrimidinone 2- 2 N- Dime thyl amino 3-phenylpropyl) -amino) -3- (3-chiorophenyl) (4-pyridyl) (3H) pyrimidinone 2 -2 N-Dimethylamino-3 -phenylpropyl) -amino) -3 methyl-6- (4-pyridyl) 3 -trifluorophenyl) (3H) pyrimidinone (4-Fluorophenyl) -3-methyl-2-( -2-N-methylamino-3 phenyipropyl) -amino) (4-pyridyl) (3H) -pyrimidinone.
The following compounds exhibit activities in the monocyte assay (LPS induced TNF release) with IC 50 values of 5 piM or less: 2- 6-Dichlorobenzyl) (4-f luorophenyl) -3-methyl-6- (4pyridyl) -4 (3H) -pyrimidinone 2- (Benzylamino) (4-f luorophenyl) -3-methyl-6- (4pyridyl) -4 (3H) -pyrimidinone (4-Fluorophenyl) -3-methyl- ((R-l-phenylethyl) amino) (4pyridyl) -4 (3H) -pyrimidinone 2- (2-Chiorophenyl) -ethylanino) (4-f luorophenyl) -3methyl-6- (4-pyridyl) -4 (3H) -pyrimidinone (4 -Fluorophenyl) 2- (2 (4 -f luorophenyl) ethylamino) -3 methyl-6- (4-pyridyl) -4 (3H) -pyrirnidinone 5- (4-Fluorophenyl) -3-methyl-2- ((3-phenyipropyl) -amino) 6- (4-pyridyl) -4 (3H) -pyrimidinone WO 98/24780 PCTIUS97/22949 207 (4-Fluorophenyl) -3-methyl-2-( (1-methyl-3phenyipropyl) -amino) (4-pyridyl) -4 (3H) -pyrimidinone (4-Fluorophenyl) -3-rnethyl-2- (R-1-methyl-3phenyipropyl) -amino) (4-pyridyl) -4 (3H) -pyrimidinone 5 (4 -Fluorophenyl) -3 -methyl 2- (2 -phenylaminoethyl) amino) (4-pyridy.) -4 (3H) -pyrimidinone (4 -Fluorophenyl) -3 -methyl -6 (4 -pyridyl) -2 (3 (pyrrolidin-1-yl) -propylamino) -4 (3H) -pyrimidinone 6- (4-Ethylphenyl) -3-phenyl-4- (4-pyridyl) -2 (1H) -pyridone 2 -Amino- 3-phenylpropyl) -amino)-5- (4f luorophenyl) -3-methyl-6- (4-pyridyl) -4 (3H) -pyrimidinone 2 2-Amnino 3-phenylpropyl) amino) 5- (4 f luorophenyl) 3-me thy 1- 6- (4 -pyridyl) 4 (3 H) -pyr imi dinone 2- 2-N- Ethyl 3-phenylpropyl) -amino) (4f luorophenyl) -3-methyl-6- (4-pyridyl) -4 (3H) -pyrimidinone 2 (2 -Amino- 2-methy- 3-phenylpropyl) amino) (4fluorophenyl) -3-methyl-6- (4-pyridyl) -4 (3H) -pyrimidinone 2 2 -Aminome thy- 3-phenylpropyl) amino) 5- (4 f luorophenyl -3 -me thyl 6- (4 -pyr idyl) 4 (3 H) -pyrimidinone 2 3 -Amino -3 -phenylpropyl) -amino 5-(4-f luorophenyl) -3 methyl-6- (4-pyridyl) -4 (3H) -pyrimidinone (4-Fluorophenyl) -3-methyl-2- (2methylphenyl) propyl) -amino) 6- (4-pyridyl) -4 (3H) pyrimidinone 5- 4 -Fluorophenyl) -3-methyl-2- 2-amino3-(21 f luorophenyl) -propyl-amino) (4-pyridyl) -4 (3H) pyrimidinone 2- -2-Acetamido-3 -phenylpropyl) -amino) (4f luorophenyl) -3 -methyl 6- (4 -pyridyl) 4 (3H) -pyrimidinone 5 (4 -Fluorophenyl) -2 -2 isopropylamino-3 phenyipropyl) -amino) -3-methyl-6- (4-pyridyl) -4 (3H) pyrimidinone 2- 2-N- n-Butyl amino 3-phenylpropyl) -amino) (4f luorophenyl) -3-methyl-6- (4-pyridyl) -4 (3H) -pyrimidinone 2 N- Dimethyl amino -3 -phenylpropyl)-amino)-5- (4f luorophenyl-3-methyl-6- (4-pyridyl) -4 (3H) -pyrimidinone (4-Fluorophenyl) -3 -rnethyl-2- C (2-iethy-3-phenylpropyl) amino) (4-pyridyl) -4 (3H) -pyrimidinone 2 2-Amino -3 -phenylpropyl) amino) 3 -e thyl -5 (4 f luorophenyl) (4-pyridyl) -4 (3H) -pyrimidinone 3 -Ethyl-5- (4-f luorophenyl) C 2 -methy-3-phenylpropyl) amino) (4-pyridyl) -4 (3H) -pyrimidinone 2- 3 -trif luoromethylphenyl)phenylmethyl) amino) -3- (4-f luorophenyl) (4-pyridyl) -4 (3H) pyrimidinone WO 98/24780 PCT/US97/22949 208 3-Methyl-2- (2 -amino 3-phenylpropyl amino) (4-tolyl) 6- (4-pyridyl) -4 (3H) -pyrimidinone 3-Methyl-2- (2 -amino 3-phenylpropylamino) (4trifluoromethyiphenyl) (4-pyridyl) -4 (3H) -pyrimidinone 3-Methyl-2- (2 -amino- 3-phenylpropylamino) (3isopropyiphenyl) (4-pyridyl) -4 (3H) -pyrimidinone 3-Methyl-2- (2 -amino -3 -phenylpropyl amino) (3-chioro- 4 -f luorophenyl) 6- (4 -pyridyl) 4 (3H) -pyrirnidinone 3-Methyl-2- (2 -amino 3-phenylpropyl amino) bis (trif luoromethyl) phenyl)6-(4-pyridyl)-4 3
H)
pyr imidinone 3-Methyl-2- (2 -amino- 3-phenylpropylamino)s-(3,4.
dichiorophenyl) (4-pyridyl) -4 (3H) -pyriniidinone 3 -Methyl 2- (2 -amino 3-pherlylpropyl amino) 5- (1 naphthyl) (4-pyridyl) -4 (3H) -pyrimidinone 3-Methyl-2- (2 -amino 3-phenylpropyl amino) (3f luorophenyl) 6- (4 -pyr idyl) 4(31H) -pyrimidinone 3-Methyl-2- (2 -amino -3 -phenylpropyl amino) (3trifluorornethylphenyl) (4-pyridyl) -4 (3H) -pyrimidinone 3-Methyl-2- (3 -phenylpropyl amino) 5-dichiorophenyl) 6- (4-pyridyl) -4(31) -pyrimidinone 3-Methyl-2- 3 -phenylpropyl amino) (4-tolyl) (4pyridyl) -4(31) -pyrimidinone 3 -Methyl 2- (3 -phenylpropyl amino) 5- (3 trifluorornethylphenyl) (4-pyridyl) -4 (3H) -pyrimidinone 3 -Me thyl -2 3 -phenylpropyl amino) 5- (4 -me thoxyphenyl) -6 (4-pyridyl) -4 (3H) -pyrimidinone 3 -Methyl -2 3 -phenylpropyl amino) 5- (4 trifluoromethylphenyl) (4-pyridyl) -4 (3H) -pyrimidinone 3 -Methyl 2- 2 -methyl -3 -phenylpropyl amino) 5- (3 f luorophenyl) (4-pyridyl) -4 (3H) -pyrirnidinone 3-Methyl-2- 2 -me thyl- 3-phenylpropyl amino) (1naphthyl) (4-pyridyl) -4 (3H) -pyrimidinone (4-Fluorophenyl) -2-N-glycylamino-3phenyipropyl) -amino) -3-methyl-6- (4-pyridyl) (3H) pyr imidinone 2- 2 -N-Glycylamino-3-phenylpropyl) -amino) -3-methyl- (3-methylphenyl) (4-pyridyl) (3H) -pyrimidinone (4-Fluorophenyl) -2 -2-hydroxyacetamido-3 phenylpropyl) -amino) -3-methy16 4pyridy)-4-(3H) pyrimidinone (4-Fluorophenyl) -2 -2-pyrrolidinyl-3phenyipropyl) -amino) -3-methyl-6- (4-pyridyl) (3H) pyrimidinone 2- 3 -Benzylpiperazinyl)5-(4-fluorophenyl) 3 -methyl- 6- (4-pyridyl) (3H) -pyrimidinone WO 98/24780 PCTIUS97/22949 209 2 3 -Amino -3 f uoropheny propy) mino)5-( 4 f luorophenyl) -3-methyl-6- (4-pyridyl) (3H1) -pyrimidinone 2- 3 -Amino-3- (2-ethypheny) propy) aino) 4 f luorophenyl) -3-methyl-6- (4-pyridyl) (3H) -pyrimidinone 2 3 -Amnino 3-phenylpropyl) amino) 5- (4 f luorophenyl) 3-me thyl 6- (4 -pyridyl) 4- (3 H) -pyr imi dinone 2 3 -Amnino 3-phenylpropyl) -amino) 5- (4 f luorophenyl) 3-methyl 6- (4 -pyridyl) 4- (3 H) -pyrimidinone 2 3 -Amnino 3-phenylpropyl) -amnino) 3-methyl 6- (4 pyr idyl) 5 (3 -tri fluorome thylphenyl) -4 H) -pyrimidinone 2 3-Amino -3 -phenylpropyl) -amino) 3-methyl -6 (4 pyridyl) 5 3 -tr if luorome thylphenyl)-4.- (3 H) -pyrimidinone 2- (3 -Amino -3 -phenylpropyl) -amino) -3-methyl-6- (4pyridyl) 5- 3 -trif luoromethylphenyl)-4- (3H) -pyrimidinone 2- 3 -Alino-3- (2-methylphenyl)propyl) -amino) -3-methyl-6- (4 -pyridyl) 5 3 -tri fluoromethylphenyl) 4- (3H) pyr imi dinone 2 3 -Amino -3 -f luorophenyl) propyl) -amino) -3 -methyl -6 (4 -pyridyl) 5 3 -tri fluoromethylphenyl) 4- (3H) pyrimidinone 2- 3 -Amino 3 -phenylpropyl) -amino) 3-methyl.5-( 3 mnethylphenyl) 6- (4 -pyridyl) 4- (3 H) -pyr imidinone 2- 3 -Amino-3- (2-f luorophenyl)propyl)- amino) (3 -methyiphenyl) 6- (4 -pyridyl) -4 (3H) -pyrimidinone 2 (3 -Ainino-3 2 -chloropheny) propy) amino)3 (3 -methyiphenyl) 6- (4 -pyridyl) -4 (3H) -pyrimidinone 2 3-Amino -3 -phenylpropyl) amino) 3-me thyl 6- (4 pyridyl) 5 4 -dime thyiphenyl) -4 (3H) -pyrimidinone 2- (2R, 3R) 3 -Amino- 2-methyl 3-phenylpropyl) -amino) (4 fluorophenyl) 3-methyl -6 (4 -pyridyl) -4 pyrimidinone 2 2 S, 3 S) 3-Amino- 2 -methy -3 phenylpropy) mino) (4-f luorophenyl) -3-methyl-6- (4-pyridyl) (3H) pyrimidinone 5- (4-Fluorophenyl) -2 -3 -N-isopropylamino-3 phenyipropyl) -amino) -3-methyl-6- (4-pyridyl) (3H) pyrimidinone (4-Fluorophenyl) -3-N-isopropylamino-3phenyipropyl) -amino) -3-methyl-6- (4-pyridyl) (3H) pyrimidinone 4 -Fluorophenyl) 3methyl6(4pyridyl)-2-
(S)
tetrahydroisoquinol-3-ylrnethylenamino) (3H) pyrimidinone 3-Methyl-6- (4-pyridyl) -tetrahydroisoquinol.3ylmethylenamino) 5- (3-trifluoromethylphenyl) (3H) pyrimidinone WO 98/24780 PCT/US97/22949 210 3-Methyl-5-(3-methylphenyl) 6 (4-pyridyl)-2-( tetrahydroisoquinol-3-ylmethylenajflo) (3H) pyrimidinone (4-methyithiophenyl) (4-pyridyl) tetrahydroisoquinol-3-ylrnethylenamino) (3H) pyrimidinone 2- -2-Amino-3-phenylpropyl) -amino) -3-methyl-5- (3methyiphenyl) (4-pyridyl) (3H) -pyrimidinone (4-Fluorophenyl) 3 -hydroxy-3-phenylpropyl) -amino) 3-methyl-6- (4-pyridyl) -pyrimidinone 2- -2-Amino-3-phenylpropyl) -amino) (4fluorophenyl) (4-pyridyl) (3H) -pyrimidinone 2- -2-Amino-3- (2-fluorophenyl)propyl) -amino) (4fluorophenyl) -3-methyl-6- (4-pyridyl) (3H) -pyrimidinone ((S)-2-Amino-3- 4 -fluorophenyl)propyl)-amino)-5-(4.
fluorophenyl) -3-methyl-6- (4-pyridyl) (3H) -pyrimidinone 2- -2-Amino-3- (2-chlorophenyl)propyl) -amino) (4fluorophenyl) -3-methyl-6- (4-pyridyl) (3H) -pyrimidinone 2- 2 -N-Isopropylamino-3-phenylpropyl) -amino) -3methyl- 6 4 -pyridy1)-5-(3-trifluoromethylphenyl) pyrimidinone 2- 2 -N-Isopropyilamino-3-phenylpropyl) -amino) -3- (3-methyiphenyl) (4-pyridyl) (311)pyrimidinone 5 (3 -Chl orophenyl -2 -2 i sopropylamino -3 phenyipropyl) -amino) -3-methyl-6- (4-pyridyl) (3H) pyrimidinone 2- 2 -N,N-Dimethylamino-3-phenylpropyl) -amino)-3- (3-methyiphenyl) (4-pyridyl) (3H) pyrimidinone 2- -2-N,N-Dimethylamino-3-phenylpropyl) -amino) -3- (3-chiorophenyl) (4-pyridyl) (3H) pyrimidinone 2- 2-N, N-Dime thyl.amino -3 -phenylpropyl) -amino) -3methyl-6- (4-pyridy) 5(3trifluoropheny)-4-(3H) pyrimidinone 4 -Fluorophenyl) -3-rnethyl-2- -2-N-methylamino-3phenyipropyl) amino) 6- (4 -pyridyl) 4- (3 H) -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.
WO 98/24780 PCT/US97/22949 211 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).
12sI-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 p. 0.1N acetic acid (1 p 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 .l 10% BSA (heat-inactivated) and 990 .1 Assay Buffer; 1 25 I-Glucagon (NEN, receptorgrade, 2200 Ci/mmol) dilute to 50,000 cpm/25 .1 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.
WO 98/24780 PCT/US97/22949 212 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 I12glucagon 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 l 25 p1 100 tl Binding 5 25 JI 100 pl Compound Nonspecif /5 1 1 p1 25 p1 100 p1 ic Binding The mixture is incubated for 60 min. at 220C on a shaker at 275 rpm. The mixture is filtered over pre-soaked polyethylimine (PEI)) GF/C filtermat using an 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 WO 98/24780 PCT/US97/22949 213 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 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 WO 98/24780 PCT/US97/22949 214 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, 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 I 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; 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, WO 98/24780 PCT/US97/22949 215 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 myeloma; uveititis; acute and chronic myelogenous leukemia; pancreatic I 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; WO 98/24780 PCT/US97/22949 216 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 TNF- X, 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 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-a, IL-1P, IL-6, and IL-8 mediated diseases and/or hyperglycemia, the compounds of WO 98/24780 PCT/US97/22949 217 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 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 WO 98/24780 PCT/US97/22949 218 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 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 WO 98/24780 PCT/US97/22949 219 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.
The pharmaceutical compositions may be made up in 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.
WO 98/24780 PCT/US97/22949 220 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 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 WO 98/24780 PCT/US97/22949 221 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 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 WO 98/24780 PCT/US97/22949 222 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 (22)
1. A compound of formula x R12 W) R or a pharmacutically acceptable salt thereof, wherein X is 0, S or NRs; V W ''R S. S S.. S S S *5 S S *S S S S .5 S S N 10 R N, R 4 N N R, N I N N N N-R21 'N N N Z.L 2 o r "1 provided that the combined total number of aryl, heteroaryl, cycloalkyl and heterocyclyl radicals in -VC(R)W- is 0-3; U is NR 2 1 or CHR 21 and n is an integer of 1-3; R, and R 2 are each independently -Y or and R 3 and R 4 are each independently provided that R 4 is other than a hydrogen, substituted- aryl, (substituted- .2~aryl) methyl or (substituted-aryl) ethyl radical, and the 224 total number of aryl, heteroaryl, cycloalkyl and heterocyclyl radicals in each -Y and -Z-Y is 0-3; wherein each Z is independently a alkyl, alkenyl or alkynyl radical optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, cyano 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, cyano, halo, alkyl or haloalkyl; heterocyclyl radical optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkyl'thio, cyano, 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; each Y is independently a hydrogen radical; halo, cyano or nitro radical; -C -R 2 0 -C -0R 2 1 -C -NR 5 R 2 1 or -C (NRs) -NR 5 R 2 1 radical; -OR 2 1 -R 2 1 -O-C(O)-NR 5 R 2 1 or -O-C(O)-NR 2 2 S(0) 2 -R 2 0 radical; -SR 21 -S(O)-R 20 -S(O) 2 -R 2 0 -S(0) 2 -NR 5 R 2 1 -S(0) 2 NR 2 2 -C(O)-R 2 1 -S(O) 2 -NR 2 2 -C(O)-0R 2 0 or -S(0)2-NR22-C(O)- SS -S NR 5 R 2 1 radical; or 225 -NR 5 R 2 1 -NR 22 -R 21 -NR 2 2 -C(O)-OR 2 0 -NR 22 NR 5 R 2 1 -NR 2 2 -C(NR 5 -NR 5 R 2 1 -NR 2 2 -S(O) 2 -R 2 0 or -NR 2 2 S 2 -NR 5 R 21 radical; wherein each R 5 is independently a hydrogen radical; alkyl, alkenyl or alkynyl radical optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, hydroxy, alkoxy, alkylthio, cyano or halo; or aryl, heteroaryl, aralkyl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl or cycloalkylalkyl radical optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, hydroxy, alkoxy, alkylthio, cyano, alkyl or haloalkyl; and wherein each R 20 is independently a alkyl, alkenyl or alkynyl radical optionally *substituted by 1-3 radicals of -C0 2 R 2 3 amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, N-(alkoxycarbonyl)-N-(alkyl)amino, aminocarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, cyano, halo, aralkoxy, aralkylthio, aralkylsulfonyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the aralkoxy, aralkylthio, aralkylsulfonyl, cycloalkyl, heterocyclyl, :00: aryl and heteroaryl radicals are optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, alkanoyl, alkoxycarbonyl, hydroxy, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, cyano, halo, alkyl or haloalkyl; §S Tt~g heterocyclyl radical optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, 226 alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, alkoxycarbonyl, hydroxy, alkoxy, alkylthio, cyano, alkyl or haloalkyl; or aryl or heteroaryl radical 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 each R 22 is independently a hydrogen radical; alkyl radical optionally substituted by a radical of heterocyclyl, aryl or heteroaryl, wherein the heterocyclyl, aryl and heteroaryl radicals are i. optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, 20 alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, cyano, 0 halo, alkyl or haloalkyl; or heterocyclyl, aryl or heteroaryl radical optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, S. 25 alkylsulfonylamino, hydroxy, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, cyano, halo, alkyl or haloalkyl; and 0 each R 23 is independently a hydrogen, alkyl, aryl, heteroaryl, aralkyl or heteroaralkyl radical, wherein the aryl, heteroaryl, aralkyl and heteroaralkyl radicals are optionally substituted by 1-3 radicals of amino, Salkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, 227 alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, cyano, halo, alkyl or haloalkyl; and R 1 1 and R 1 2 are each independently an aryl. or heteroaryl radical optionally substituted by 1-3 radicals of R 30 halo or cyano; -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 -OR 2 9 -0-c (0)-R 2 9 -0-C (0)-NR 3 lR 3 2 or -0-C (0)-NR 33 S 2 -R 30 -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 (0)-R 3 0 -S 2 -NR 3 3 -C (0)-OR 3 0 or -S 2 -NR 3 3 NR 3 1 R 3 2 or -NR 3 1 R 3 2 -NR 3 3 -C(0)-R 2 9 -NR 3 3 -C(0)-0R 3 0 -NR 3 3 NR 3 1 R 3 2 -NR 3 3 -C (NR 3 1 -NR 3 1 R 3 2 -NR 3 3 -S 2 -R 3 0 or -NR 3 3 S 2 -NR 3 1 R 3 2 provided that R 1 1 is other than a 4-pyridyl, 4- :~*pyrimidinyl,
4-quino'lyl or 6-isoquinolinyl radical optionally substituted by 1-2 substituents; when R 11 j is an unsubstituted phenyl, 4-methoxyphenyl or 4- chlorophenyl. radical, then R 1 2 is other than an unsubstituted phenyl, 4-methoxyphenyl or 4-chlorophenyl radical; and the total number of aryl, heteroaryl, cycloalkyl and heterocyclyl. radicals substituted on each of R 1 1 and R 12 is 0-1; wherein each R 3 0 is independently a alkyl, alkenyl. or alkynyl. radical 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, aralkoxy, aralkylthio, aralkylsulfonyl, heterocyclyl, aryl or heteroaryl, -u wherein the aralkoxy, aralkylthio, aralkylsulfonyl, 228 heterocyclyl, aryl and heteroaryl radicals are 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 radical optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy; alkoxy, alkylthio, cyano, halo, alkyl or haloalkyl; each R 29 is independently hydrogen radical or R 30 o 20 R 31 and R 3 2 are each independently a hydrogen radical; alkyl radical optionally substituted by a cycloalkyl, aryl, heterocyclyl or heteroaryl radical, wherein the cycloalkyl, aryl, heterocyclyl and heteroaryl radicals are 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 229 wherein each R 33 is independently a hydrogen radical; or alkyl radical optionally substituted by a radical of heterocyclyl, aryl or heteroaryl, wherein the aryl, heterocyclyl and heteroaryl radicals are optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, cyano, alkyl or haloalkyl. 2. The compound of Claim 1 or a pharmaceutically acceptable salt thereof, wherein wherein each Z is independently a CI-C 8 alkyl, C 2 -C 8 alkenyl or C 2 -C 8 alkynyl radical i optionally substituted by 1-3 radicals of amino, C 1 C 4 alkylamino, di-(Ci-C 4 alkyl)amino, CI-C S alkanoylamino, (C 1 -C 4 alkoxy) carbonylamino, C 1 -C 4 20 alkylsulfonylamino, hydroxy, CI-C 4 alkoxy, C 1 -C 4 alkylthio, cyano 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 -Cs alkanoylamino, (C 1 -C 4 25 alkoxy)carbonylamino, C 1 -C 4 alkylsulfonylamino, hydroxy, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio, cyano, halo, CI-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-(C 1 -C 4 alkyl)amino, C 1 -C 5 alkanoylamino, (C 1 -C 4 alkoxy)carbonylamino, CI-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 230 aryl or heteroaryl radical optionally substituted by 1-3 radicals of amino, Cl-C4 alkylamino, di- (Cl-C 4 alkyl)amino, Cj-C 5 alkanoylamino, (C 1 -C 4 alkoxy) carbonylamino, C 1 -C 4 alkylsulfonylamino, hydroxy, cl-c 4 alkoxy, C 1 -C 4 alkylthio, cyano, halo, C 1 -C 4 alkyl or C 1 -C 4 haloalkyl of 1-3 halo radicals; each Y is independently a hydrogen radical; halo, cyano or nitro radical; -C (0)-R 2 0 -C -0R 2 1 -C (0)-NR 5 R 2 1 or -C (NR 5 -NR 5 R 2 1 radical; -OR 2 1 -R 2 1 -NR 5 R 2 1 or -NR 2 2 S 2 -R 2 0 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)-OR 2 0 or S02N2-() NR 5 R 2 1 radical; or -NR 5 R 21 -NR 2 2 -C(O)-R 2 1 -NR 2 2 -C(O)-0R 2 0 -NR 2 2 NR 5 R 2 1 -NR 2 2 -C (NR 5 -NR 5 R 2 1 -NR 2 2 -S 2 -R 2 0 or -NR 2 2 S(O) 2 -NR 5 R 2 radical; each R 5 is independently a hydrogen radical; cl-c 8 alkyl, C 2 -C 8 alkenyl or C 2 -C 8 alkynyl radical 25 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, cyano 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-CB-cycloalkyl-Cl-C 4 -alkyl radical optionally substituted by 1-3 radicals of amino, Cl-C 4 alkylamino, di- (Cl-C4-alkyl) amino, hydroxy, CI-C 4 231 alkoxy, Cl-C 4 alkyithia, cyano, C 1 -C 4 alkyl or lC haloalkyl of 1-3 halo radicals; each R 2 0 is independently a C 1 -Ca alkyl, C 2 -C 8 alkenyl or C 2 -C 8 alkynyl radical optionally substituted by 1-3 radicals of -C0 2 R 2 3 amino, Cl-C 4 alkylamino, di-(Cl-C 4 alkyl)amino, Cl-C alkanoylamino, (Cl-C 4 al koxy) carbonyl amino, N- ((CI-C 4 alkoxy) carbonyl) (Cl-C 4 alkyl) amino, aminocarbonylamino, Cl-C 4 alkylsulfonylamino, hydroxy, C 1 -C 4 alkoxy, Cl-C 4 alkylthio, Cl-C 4 alkylsulfinyl, Cl-C 4 alkylsulfonyl, cyano, halo, aryl-Cl-C 4 -alkoxy, aryl-Cl- C 4 -alkylthio, aryl-Cl-C 4 -alkylsulfonyl, C 3 -C 8 cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the aryl-Cl- C 4 -alkoxy, aryl-Cl-C 4 -alkylthio, aryl-Cl-C 4 alkylsulfonyl,'C 3 -C 8 cycloalkyl, heterocyclyl, aryl and heteroaryl radicals are optionally substituted by 1-3 radicals of amino, C- 4 alkylamino, di- (C 1 -C 4 alkyl) amino, Cl-C 5 alkanoylamino, (Cl-C 4 alkoxy) carbonylamino, C 1 -C 4 alkylsulfonylamino, Cl-C alkanoyl, (Cl-C 4 alkoxy)carbonyl, hydroxy, CI-C 4 alkoxy, C 1 -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; heterocyclyl radical optionally substituted by 1-3 radicals of amino, Cl-C 4 alkylanino, di-(Cl-C 4 alkyl)amino, .C 1 -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, Cl-C 4 alkyl or Cl-C 4 haloalkyl of 1-3 halo radicals; or ~S T/ aryl or heteroaryl radical optionally substituted by .z 1-3 radicals of amino, C 1 -C 4 alkylamino, di- (Cl-C 4 232 alkyl) amino, C 1 -C 5 alkanoylamino, (Cl-C 4 alkoxy) carbonylamino, Cl-C 4 alkylsulfonylamino, (Cl-C 4 alkoxy)carbonyl, hydroxy, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio, cyano, halo, azido, C 1 -C 4 alkyl or C 1 -C 4 haloalkyl of 1- 3 halo radicals; each R 2 1 is independently hydrogen radical or R 2 0 each R 2 2 is independently a hydrogen radical; C 1 -C 4 alkyl radical optionally substituted by a radical of heterocyclyl, aryl or heteroaryl, wherein the heterocyclyl, aryl and heteroaryl radicals are 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, S hydroxy, Cl-C 4 alkoxy, Cl-C 4 alkylthio, Cl-C 4 alkylsulfinyl, Cl-C 4 alkylsulfonyl, cyano, halo, Cl-C 4 alkyl or C 1 -C 4 haloalkyl of 1-3 halo radicals; or heterocyclyl, aryl or heteroaryl 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 alkoxy) carbonylamino, Cl-C 4 alkylsulfonylamino, hydroxy, C-C 4 alkoxy, C-C 4 alkylthio, C-C 4 alkylsulfinyl, C-C 4 Ct C C alkylsulfonyl, cyano, halo, Cl-C 4 alkyl or Cl-C 4 haloalkyl of 1-3 halo radicals; each R 2 3 is independently a hydrogen, Cl-C 4 alkyl, aryl, heteroaryl, aryl-Ci-C 4 -alkyl or heteroaryl-Cl-C 4 -alkyl radical, wherein the aryl, heteroaryl, aryl-Cl-C 4 -alkyl and heteroaryl-Cl-C 4 -alkyl radicals are optionally substituted by 1-3 radicals of amino, Cl-C 4 alkylamino, di-(Cl-C 4 alkyl)amino, Cj-C 5 alkanoylamino, (Cl-C 4 233 alkoxy) carbonylamino, Cl-C 4 alkylsulfonylamino, hydroxy, Cl-C 4 alkoxy, Cl-C 4 alkyithia, Cl-C 4 alkylsulfinyl, C 1 -C 4 alkylsulfonyl, cyano, halo, C 1 -C 4 alkyl or Cl-C 4 haloalkyl of 1-3 halo radicals; R 1 1 and R 1 2 are each independently an aryl or heteroaryl radical optionally substituted by 1-3 radicals of R 3 0 halo or cyano; -R 3 0 -OR 2 9 -NR 3 lR 3 2 or -C(NR 3 1 NR 31 LR 32 -OR 2 9 -R 2 9 -NR 3 lR 3 2 or -NR 3 3 S 2 -R 3 0 -SR 2 9 -R 3 0 -S(O) 2 -R 3 0 -S(O) 2 -NR 3 lR 3 2 -S(0)2- NR 3 3 -C(O)-R 3 0 -S(O) 2 -NR 3 3 -C(O)-0R 3 0 or -S(O) 2 -NR 3 3 NR 3 1 R 3 2 or -NR 3 1 R 3 2 -NR 3 3 -C(O)-R 2 9 -NR 3 3 -C(O)-0R 3 0 -NR 3 3 C(O)- i: NR 3 1 R 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 5(0) 2 -NR 3 1 R 3 2 provided that R 11 is other than a 4-pyridyl, 4- Go... pyrimidinyl, 4-quinolyl or 6-isoquinolinyl radical optionally substituted by 1-2 substituents; when R 11 is an unsubstituted phenyl, 4-methoxyphenyl or 4- chlorophenyl radical, then R 1 2 is other than an unsubstituted phenyl, 4-methoxyphenyl or 4-chlorophenyl radical; 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 R 3 0 is independently a C 1 -C 4 alkyl, C 2 -C 4 alkenyl or C 2 -C 4 alkynyl radical optionally substituted by 1-3 radicals of -NR 3 1 R 3 1 S-C0 2 R 2 3 hydroxy, Cl-C 4 alkoxy, Cl-C 4 alkylthio, Cl-C 4 234 alkylsulfinyl, C 1 -C 4 alkylsulfonyl, cyano, halo, aryl- Cl-C 4 -alkoxy, aryl-Cl-C 4 -alkylthio, aryl -C 1 -C 4 alkylsulfonyl, heterocyclyl, aryl or heteroaryl, wherein the aryl-Cl-C 4 -alkoxy, aryl-Cl-C 4 -alkylthio, aryl-Cl-C 4 alkylsulfonyl, heterocyclyl, aryl and heteroaryl radicals are optionally substituted by 1-3 radicals of amino, C 1 -C 4 alkylamino, di-(Cl-C 4 alkyl)amino, Cl-C alkanoylamino, (Cl-C 4 alkoxy) carbonyl amino, C 1 -C 4 alkyl sul fonyl amino, hydroxy, C 1 -C 4 alkoxy, Cl-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; heterocyclyl radical optionally substituted by 1-3 radicals of amino, Cl-C 4 alkylamino, di- (Cl-C 4 0:00 15 alkyl)amino, C 1 -C 5 alkanoylamino, (Cl-C 4 alkoxy) carbonylamino, CI-C 4 alkylsulfonylamino, hydroxy, C 1 -C 4 alkoxy, C- 4 alkylthio, cyano, C- 4 alkyl or Cl- C 4 haloalkyl of 1-3 halo radicals; or DID. 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, (Cl-C 4 :alkoxy) carbonylamino, Cl-C 4 alkyl sul fonyl amino, hydroxy, *sCl-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; :000.:each R 2 9 is independently hydrogen radical or R 3 0 R 31 and R 3 2 are each independently a hydrogen radical; Cl-C 4 alkyl radical optionally substituted by a C 3 C 8 cycloalkyl, aryl, heterocyclyl or heteroaryl radical, §~STI~wherein the C 3 -C 8 cycloalkyl, aryl, heterocyclyl and Sheteroaryl radicals are optionally substituted by 1-3 235 radicals of amino, C 1 -C 4 alkylamino, di-(Ci-C 4 alkyl)amino, CI-Cs alkanoylamino, (C 1 -C 4 alkoxy)carbonylamino, C 1 -C 4 alkylsulfonylamino, hydroxy, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio, cyano, CI-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-(C 1 -C 4 alkyl)amino, CI-C alkanoylamino, (CI-C 4 alkoxy) carbonylamino, C 1 -C 4 alkylsulfonylamino, hydroxy, CI-C 4 alkoxy, CI-C 4 alkylthio, cyano, CI-C 4 alkyl or C 1 -C 4 haloalkyl of 1-3 halo radicals; and each R 33 is independently a 15 hydrogen radical; or CI-C 4 alkyl radical optionally substituted by a radical of heterocyclyl, aryl or heteroaryl, wherein the aryl, heterocyclyl and heteroaryl radicals are optionally substituted by 1-3 radicals of amino, C 1 -C 4 20 alkylamino, di-(C 1 -C 4 alkyl)amino, CI-C 5 alkanoylamino, :iii: (Cl-C 4 alkoxy) carbonylamino, C 1 -C 4 alkylsulfonylamino, hydroxy, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio, cyano, CI-C 4 alkyl or CI-C 4 haloalkyl of 1-3 halo radicals; and S: 25 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 S//S radical of a monocyclic or bicyclic aromatic heterocyclic ring system having 5-6 ring members per 236 ring, wherein 1-3 ring members are oxygen, sulfur or nitrogen heteroatoms, which is optionally benzo-fused or saturated C3-C 4 -carbocyclic-fused. 3. The compound of Claim 2 or a pharmaceutically acceptable salt thereof, wherein each Z is independently a 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, CI-C alkanoylamino, (C 1 -C 4 alkoxy) carbonylamino, Ci-C 4 alkylsulfonylamino, hydroxy, C 1 -C 4 alkoxy, C 1 -C 4 15 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, CI-Cs alkanoylamino, (C 1 -C 4 S* alkoxy)carbonylamino, C 1 -C 4 alkylsulfonylamino, hydroxy, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio, cyano, halo, C 1 -C 4 alkyl or C 1 -C 4 haloalkyl of 1-3 halo radicals; heterocyclyl radical optionally substituted by 1-2 radicals of amino, C 1 -C 4 alkylamino, di-(C 1 -C 4 25 alkyl)amino, CI-C 5 alkanoylamino, (CI-C 4 25 alkoxy)carbonylamino, C 1 -C 4 alkylsulfonylamino, hydroxy, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio, Ci-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, C 1 -C 4 alkylamino, di-(CI-C 4 alkyl)amino, CI-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, halo, CI-C 4 alkyl s r or CI-C 4 haloalkyl of 1-3 halo radicals; 237 each R 5 is independently a hydrogen radical; cl-c 4 alkyl, C 2 -C 5 alkenyl or C 2 -C 5 alkynyl radical optionally substituted by 1-3 radicals of amino, Cl-C 4 alkylamino, di- (Cl-C 4 -alkyl) amino, hydroxy, Cl-C 4 alkoxy, C 1 -C 4 alkylthio 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 radical 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 alkylthio, cyano, Cl-C 4 alkyl or Cl-C 4 haloalkyl of 1-3 halo radicals; :each R 2 0 is independently a cl-c 8 alkyl, C 2 -C 5 alkenyl or C 2 -C 5 alkynyl radical :**:optionally substituted by 1-3 radicals of -C0 2 R 2 3 amino, Cl-C 4 alkylamino, di- (Cl-C 4 alkyl) amino, Cl-C alkanoylamino, (Cl-C 4 alkoxy) carbonylamino, N- ((Cl-C 4 alkoxy)carbonyl) (Cl-C 4 alkyl)amino, aminocarbonylamino, Cl-C 4 alkylsulfonylamino, hydroxy, Cl-C 4 alkoxy, Cl-C 4 alkylthio, Cl-C 4 alkylsulfinyl, CI-C 4 alkylsulfonyl, halo, aryl-Cl-C 4 -alkoxy, aryl-Cl-C 4 alkylthio, aryl-Cl-C 4 -alkylsulfonyl, C 3 -C 8 cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the aryl-Cl- C 4 -alkoxy, aryl-Cl-C 4 -alkylthio, aryl-C2 1 -C 4 alkylsulfonyl, C 3 -C 8 cycloalkyl, heterocyclyl, aryl and heteroaryl radicals are 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 '~v~Sra alkoxy) carbonyl amino, Cl-C 4 alkylsulfonylamino, Cl-C Salkanoyl, (Cl-C 4 alkoxy)carbonyl, hydroxy, Cl-C 4 alkoxy, '238 Cl-C 4 alkyithia, Cl-C 4 alkylsulfinyl, C 1 -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 alkylamino, di- (Cl-C 4 alkyl).amino, C 1 -C 5 alkanoylamino, (Cl-C 4 alkoxy) carbonyl amino, C 1 -C 4 alkylsulfonylamino, (Cl-C 4 alkoxy)carbonyl, 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 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 alkoxy) carbo nylamino, Cl-C 4 alkylsulfonylamino, (Cl-C 4 alkoxy)carbonyl, hydroxy, C 1 -C 4 alkoxy, Cl-C 4 alkylthio, cyano, halo, azido, Cl-C 4 alkyl or C 1 -C 4 haloalkyl of 1-3 halo radicals; each R 2 1 is independently hydrogen radical or R 2 0 each R 30 is independently a C 1 -C 4 alkyl radical optionally substituted by 1-3 radicals of -NR 3 1 R 3 1 Cl-C 4 alkoxy-carbonyl, phenoxycarbonyl or phenylmethoxycarbonyl, wherein the phenoxycarbonyl and phenylmethoxycarbonyl radicals are optionally. substituted by 1-3 radicals of amino, alkylamino, di- (Cl-C 4 -alkyl) amino, C 1 -C 5 alkanoylamino, (C 1 -C 4 al koxy) carbonyl amino, C 1 -C 4 alkylsulfonylamino, hydroxy, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio, cyano, halo, C 1 -C 4 alkyl or trifluoromethyl; or hydroxy, Cl-C 4 alkoxy, Cl-C 4 alkylthio, phenyl-Cl-C 4 Salkoxy, phenyl-Cl-C 4 -alkylthio, heterocyclyl, phenyl or 239 heteroaryl, wherein the phenyl-C 1 -C 4 -alkoxy, phenyl-C 1 C 4 -alkylthio, heterocyclyl, phenyl and heteroaryl radicals are optionally substituted by 1-3 radicals of amino, C 1 -C 4 alkylamino, di-(Ci-C 4 alkyl)amino, CI-C alkanoylamino, (CI-C 4 alkoxy)carbonylamino, hydroxy, C 1 C 4 alkoxy, C 1 -C 4 alkylthio, cyano, halo, C 1 -C 4 alkyl or C 1 -C 4 haloalkyl of 1-3 halo radicals; C 1 -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-(C 1 -C 4 alkyl)amino, CI-C 5 alkanoylamino, (CI-C 4 alkoxy)carbonylamino, hydroxy, CI-C 4 alkoxy, CI-C 4 alkylthio, cyano, halo, Ci-C 4 alkyl or trifluoromethyl; S 15 each R 29 is independently hydrogen radical or R 30 each R 31 is independently a hydrogen radical; or C 1 -C 4 alkyl radical optionally substituted by a 20 phenyl or heteroaryl radical, wherein the phenyl and heteroaryl radicals are optionally substituted by 1-3 radicals of amino, C 1 -C 4 alkylamino, di-(Cl-C 4 o: alkyl)amino, C 1 -C 5 alkanoylamino, (Cl-C 4 alkoxy) carbonylamino, hydroxy, C 1 -C 4 alkoxy, C 1 -C 4 25 alkylthio, cyano, C 1 -C 4 alkyl or trifluoromethyl; and each R 3 2 is independently a hydrogen radical; CI-C 4 alkyl radical optionally substituted by an C 3 C 6 cycloalkyl, aryl, heterocyclyl or heteroaryl radical, wherein the C 3 -C 6 cycloalkyl, aryl, heterocyclyl and ST heteroaryl radicals are optionally substituted by 1-3 radicals of amino, C 1 -C 4 alkylamino, di-(C 1 -C4 240 alkyl)amino, C 1 -C 5 alkanoylamino, (C 1 -C 4 alkoxy)carbonylamino, CI-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 6 cycloalkyl radical optionally substituted by 1-3 radicals of amino, C 1 -C 4 alkylamino, di-(Ci-C 4 alkyl)amino, C 1 -C alkanoylamino, (CI-C 4 alkoxy)carbonylamino, C 1 -C 4 alkylsulfonylamino, hydroxy, Ci-C 4 alkoxy, C 1 -C 4 alkylthio, cyano, C 1 -C 4 alkyl or CI-C 4 haloalkyl of 1-3 halo radicals; and each R 33 is independently a hydrogen or CI-C 4 alkyl radical. 9 4. The compound of Claim 3 or a pharmaceutically acceptable salt thereof, wherein X is 0 or S; **9 R 3 N S*is R SW R R2 provided that the combined total number of aryl, heteroaryl, cycloalkyl and heterocyclyl radicals in -VC(R)W- is 0-2; wherein R 1 is -Y or provided that the total number of aryl, heteroaryl, cycloalkyl and heterocyclyl radicals in R 1 is 0-3; Z is a 241 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, Cj-C 5 alkanoylamino, (Cl-C 4 alkoxy)carbonylamino, 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, Cj-C 5 alkanoylamino, (Cl-C 4 al koxy) carbonyl 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; heterocyclyl radical optionally substituted by 1-2 radicals of amino, di-(Cl-C 4 alkyl)amino, (Cl-C 4 al1koxy) carbonyl amino, hydroxy, Cl-C 4 alkoxy, Cl-C 4 15 alkylthio or CI-C 4 alkyl radicals; or aryl or heteroaryl 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 al koxy) carbonyl 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; Y is a hydrogen radical; 25 halo radical; -C (0)-R 2 0 -oR 21 -C (0)-NR 5 R 2 1 or -C (NR 5 -NR 5 R 2 1 radical; -OR 2 1 -0-C (0)-R 2 3- or -0-C (0)-NR 5 R 2 radical; -SR 2 1 -S(0)-R 2 0 -S(O) 2 -R 2 0 or -S(O) 2 -NR 5 R 2 radical; or -NR 5 R 21 -NR 2 2 -C(O)-R 2 1 -NR 2 2 -C(o)-oR 2 0 -NR 2 2 S "Y NR 5 R 2 1 -NR 2 2 -C(NR 5 )-NR 5 R 2 1 -NR 2 2 -S(O) 2 -R 2 0 or -NR 2 2 2 -NR 5 R 2 radical; 242 each R 5 is independently a hydrogen radical; cl-c 4 alkyl or C 2 -C 5 alkenyl radical optionally substituted by 1-3 radicals of amino, di- (C 1 -C 4 alkyl)amino, hydroxy, Cl-C 4 alkoxy, Cl-C 4 alkylthio or halo; or phenyl-Cl-C 2 -alkyl, heteroaryl-Cl-C 2 -alkyl, heterocyclyl-Cl-C 2 -alkyl or C3-CE-cycloalkyl-Cl-C 2 -alkyl radical optionally substituted by 1-3 radicals of amino, di- (Cl-C 4 -alkyl) amino, hydroxy, Cl-C 4 alkoxy, Cl-C 4 alkylthio, cyano, Cl-C 4 alkyl or Cl-C 2 haloalkyl of 1-3 halo radicals; each R 2 0 is independently a o cl-c 8 alkyl or C 2 -C 5 alkenyl radical optionally 0: substituted by 1-3 radicals of -CO 2 R 2 3 amino, C-C 4 alkylamino, di- (Cl-C 4 alkyl)amino, c- 5 alkanoylamino, (Cl-C 4 alkoxy) carbonylamino, N- (Cl-C 4 alkoxy) carbonyl) 0: 20 N- (Cl-C 4 alkyl) amino, aminocarbonyl amino, hydroxy, Cl-C 4 alkoxy, Cl-C 4 alkylthio, Cl-C 4 alkylsulfinyl, Cl-C 4 alkylsulfonyl, halo, aryl-Cl-C 4 -alkoxy, aryl-Cl-C 4 0 a alkylthio, aryl-Cl-C 4 -alkylsulfonyl, C 3 -C 6 cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the aryl-Cl- C 4 -alkoxy, aryl-Cl-C 4 -alkylthio, aryl-Cl-C 4 alkylsulfonyl, C 3 -C 8 cycloalkyl, heterocyclyl, aryl and heteroaryl radicals are optionally substituted by 1-3 radicals of amino, Cl-C 4 alkylamino, di- (C 1 -C 4 alkyl)amino, Cl-C 5 alkanoylamino, (Cl-C 4 al1koxy) carbonyl amino, Cl-C 4 alkylsulfonylamino, Cj-C alkanoyl, (Cl-C 4 alkoxy)carbonyl, hydroxy, Cl-C 4 Alkoxy, ~sr~ Cl-C 4 alkylthio, cyano, halo, Cl-C 4 alkyl or Cl-C 2 ;~haloalkyl of 1-3 halo radicals; 243 heterocyclyl radical optionally substituted by 1-2 radicals of amino, Cl-C 4 alkylamino, di- (Cl-C 4 alkyl)amino, C 1 -C 5 alkanoylamino, (Cl-C 4 alkoxy) carbonyl amino, (C 1 -C 4 alkoxy) carbonyl, hydroxy, cl-c 4 alkoxy, C 1 -C 4 alkylthio or Cl-C4 alkyl; or aryl or heteroaryl 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 alkoxy) carbonyl amino, 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 2 haloalkyl of 1- 3 halo radicals; each R 21 is independently hydrogen radical or R 20 each R 22 is independently a hydrogen radical; or Cl-C 4 alkyl radical optionally substituted by a radical of phenyl or heteroaryl, wherein the phenyl and heteroaryl radicals are optionally substituted by 1-3 radicals of amino, di- (Cl-C 2 alkyl)amino, Cl-C *00* alkanoylanino, (Cl-C 4 alkoxy)carbonylamino, hydroxy, Cj- 0000*C 4 alkoxy, CI-C 4 alkylthio, cyano, halo, Cl-C 4 alkyl or Cl-C 2 haloalkyl of 1-3 halo radicals; each R 2 3 is independently a hydrogen, Cl-C 4 alkyl, phenyl, heteroaryl, phenyl-Cl-C 2 -alkyl or heteroaryl-Cl- C 2 -alkyl radical, wherein the phenyl, heteroaryl, phenyl-Cl-C 2 -alkyl and heteroaryl-Cl-C 2 -alkyl radicals are optionally substituted by 1-3 radicals of amino, di- (Cl-C 4 alkyl)amino, Cj-C 5 alkanoylamino, (Cl-C 4 /'~Sb~\alkoxy) carbonyl amino, hydroxy, Cl-C 4 alkoxy, Cl-C 4 244 alkylthio, cyano, halo, C 1 -C 4 alkyl or CI-C 2 haloalkyl of 1-3 halo radicals; R 2 is a radical of hydrogen, C 1 -C 4 alkyl, halo, cyano, hydroxy, Ci-C 4 alkoxy, Ci-C 2 haloalkoxy of 1-3 halo radicals, C 1 -C 4 alkylthio, amino, C 1 -C 4 alkylamino, di- (C 1 -C 4 alkyl)amino or C 1 -C 2 haloalkyl of 1-3 halo radicals; R 3 is a hydrogen radical or C 1 -C 8 alkyl or C 2 -C 8 alkenyl 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, CI-C 4 alkylsulfonylamino, 15 hydroxy, CI-C 4 alkoxy, C 1 -C 4 alkylthio or halo, and (b) 1-2 radicals of heterocyclyl, aryl or heteroaryl Soptionally substituted by 1-3 radicals of amino, CI-C 4 alkylamino, di-(C 1 -C 4 alkyl)amino, CI-C 5 alkanoylamino, (CI-C 4 alkoxy)carbonylamino, CI-C 4 alkylsulfonylamino, 20 hydroxy, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio, halo, C 1 -C 4 So* alkyl, trifluoromethoxy or trifluoromethyl radicals; or aryl 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 25 alkoxy) carbonylamino, C 1 -C 4 alkylsulfonylamino, hydroxy, C 1 -C 4 alkoxy, Ci-C 4 alkylthio, cyano, halo, C 1 -C4 alkyl, trifluoromethoxy or trifluoromethyl radicals; R 11 and R 12 are each independently an aryl or heteroaryl radical optionally substituted by 1-2 radicals of R 30 halo or cyano; 245 -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 or -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 32 -NR 3 3 -C(O)-R 2 9 or -NR 3 3 -OR 3 0 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; when R 11 is an unsubstituted phenyl, 4-methoxyphenyl or 4- chlorophenyl radical, then R 1 2 is other than an unsubstituted phenyl, 4-methoxyphenyl or 4-chlorophenyl radical; 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 R 3 0 is independently a cl-c 4 alkyl radical optionally substituted by a *6 radical of 6666 amino, C- 4 alkylamino or di- (Cl-C 4 alyain;o hydroxy, Cl-C 4 alkoxy, heterocyclyl, phenyl or heteroaryl, wherein the heterocyclyl, phenyl and 666 heteroaryl radicals are optionally substituted by 1-3 radicals of amino, Cl-C 4 alkylamino, di- (Cl-C 4 alkyl) amino, CI-C 5 alkanoylamino, (Cl-C 4 Do ~alkoxy) carbonyl amino, hydroxy, CI-C 4 alkoxy, Cl-C 4 25 *alkylthio, cyano, halo, Cl-C 4 alkyl or trifluoromethyl; cl-c 2 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, (Cl-C 4 alkoxy) carbonyl amino, hydroxy, Cl-C 4 alkoxy, Cl-C 4 alkylthio, cyano, halo, Cl-C 4 alkyl or trifluoromethyl; each R 2 9 is independently hydrogen radical or R 3 0 246 each R 31 is independently a hydrogen or C 1 -C 4 alkyl radical; and each R 32 is independently a hydrogen radical; C1-C 4 alkyl radical optionally substituted by phenyl or heteroaryl radical, wherein the phenyl and heteroaryl radicals are 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, hydroxy, C 1 C 4 alkoxy, C 1 -C 4 alkyl or trifluoromethyl; or phenyl or heteroaryl radical optionally substituted by 1-3 radicals of amino, C 1 -C 4 alkylamino, di-(C 1 -C 4 15 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; and each R 3 3 is independently a hydrogen or methyl radical; 20 and Swherein 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 25 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 X saturated C3-C 4 -carbocyclic-fused. 247 The compound of Claim 4 or a pharmaceutically acceptable salt thereof, wherein Z is a 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, C 1 -C 5 alkanoylamino, (C 1 -C 4 alkoxy)carbonylamino, hydroxy, CI-C 2 alkoxy, Ci-C 2 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-(Ci-C 2 alkyl)amino, C 1 -C 5 alkanoylamino, (C 1 -C 4 alkoxy)carbonylamino, hydroxy, CI-C 4 alkoxy, C 1 -C 4 alkylthio, cyano, halo, C 1 -C 4 alkyl or trifluoromethyl i. 15 radicals; heterocyclyl radical optionally substituted by 1-2 *radicals of amino, di-(Ci-C 2 alkyl)amino, (C 1 -C 4 alkoxy) carbonylamino, hydroxy, C 1 -C 2 alkoxy, CI-C 2 alkylthio or C 1 -C 4 alkyl radicals; or 20 aryl or heteroaryl radical optionally substituted by 1-3 radicals of amino, di-(C 1 -C 2 alkyl)amino, CI-C alkanoylamino, (C 1 -C 4 alkoxy)carbonylamino, hydroxy, C 1 S: C 2 alkoxy, Ci-C 2 alkylthio, cyano, halo, C 1 -C 4 alkyl or trifluoromethyl radicals; each R 5 is independently a hydrogen radical; C 1 -C 4 alkyl radical optionally substituted by 1-3 radicals of amino, di-(Ci-C 2 -alkyl)amino, hydroxy, CI-C 2 alkoxy, C 1 -C 2 alkylthio or halo; or phenyl-C 1 -C 2 -alkyl, heteroaryl-C 1 -C 2 -alkyl, S heterocyclyl-C 1 -C 2 -alkyl or C3-C 6 -cycloalkyl-C 1 -C 2 -alkyl Sradical optionally substituted by 1-3 radicals of amino, 248 di- (Cl-C 2 -alkyl) amino, hydroxy, C 1 -C 2 alkoxy, CI-C 2 alkylthio, methoxy, methyithia, cyano, C 1 -C 4 alkyl or trifluoromethyl radicals; each R 2 2 is independently a hydrogen or C 1 -C 4 alkyl radical; each R 2 3 is independently a hydrogen, Cl-C 4 alkyl, phenyl, heteroaryl, phenyl-Cl-C 2 -alkyl or heteroaryl-cl- C 2 -alkyl radical, wherein the phenyl, heteroaryl, phenyl-Cl-C 2 -alkyl and heteroaryl-Cl-C 2 -alkyl radicals are optionally substituted by 1-3 radicals of amino, di- (Cl-C 2 alkyl)amino, Cl-C 5 alkanoylamino, (Cl-C 4 alkoxy) carbonyl amino, hydroxy, C 1 -C 2 alkoxy, Cl-C 2 alkylthio, cyano, halo, C 1 -C 4 alkyl or trifluoromethyl radicals; R 3 is a hydrogen radical or Cl-C 8 alkyl radical optionally substituted by 1-2 radicals of amino, C 1 -C 4 alkylamino, di- (Cl-C 4 alkyl)amino, hydroxy, C 1 -C 4 alkoxy or aryl or heteroaryl optionally substituted by 1-3 radicals of amino, Cl-C 4 :9:alkylamino, di-(Cl-C 4 alkyl)amino, C 1 -C 4 alkoxy, Cl-C 4 alkylthio, halo, C 1 -C 4 alkyl, trifluoromethoxy or 25 trifluoromethyl radicals; or aryl or heteroaryl radical optionally substituted by 1-3 radicals of amino, Cl-C 4 alkylamino, di-(Cl-C 4 alkyl)amino, Cl-C 4 alkoxy, Cl-C 4 alkylthio, cyano, halo, Cl-C 4 alkyl, trifluoromethoxy or trifluoromethyl radicals; 249 R 11 is anaryl radical and R 12 is a heteroaryl radical, wherein the aryl and>heteroaryl radicals are optionally substituted by 1-2 radicals of R 30 halo or cyano; -C(O)-R 3 0 -C(0)-OR 2 9 -C(O)-NR 31 R 3 2 or -C(NR 3 1 NR 3 1 R 3 2 or -OR 2 9 -SR 2 9 -S(O)-R 3 0 -S(O) 2 -R 3 0 -S(0) 2 -NR 3 1 R 3 2 -NR 3 1 R 3 2 or -NR 3 3 -C(0)-R 2 9 provided that the total number of aryl, heteroaryl, cycloalkyl and heterocyclyl radicals substituted on each of R1 1 and R 12 is 0-1; each R 30 is independently a i 15 CI-C 4 alkyl radical optionally substituted by a phenyl or heteroaryl radical, wherein the phenyl and heteroaryl radicals are optionally substituted by 1-3 radicals of amino, di-(C 1 -C 2 alkyl)amino, acetamido, hydroxy, CI-C 2 alkoxy, halo, C 1 -C 4 alkyl or 20 trifluoromethyl; trifluoromethyl radical; or aryl or heteroaryl radical optionally substituted by 1-3 radicals of amino, di-(C 1 -C 2 alkyl)amino, acetamido, hydroxy, CI-C 2 alkoxy, halo, C 1 -C 4 alkyl or S 25 trifluoromethyl; each R 2 9 is independently hydrogen radical or R 30 and each R 32 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 -C 2 250 alkyl)amino, acetamido, hydroxy, Cl-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-(CI-C 2 alkyl)amino, acetamido, hydroxy, C 1 -C 2 alkoxy, C 1 -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 15 heterocyclic ring system having 5-6 ring members, wherein 1-2 ring members are oxygen, sulfur or nitrogen S" heteroatoms, which is optionally benzo-fused.
6. The compound of Claim 5 or a pharmaceutically S•acceptable salt thereof, wherein wherein R 1 is -Y or provided that the total number of aryl, heteroaryl, cycloalkyl and heterocyclyl 25 radicals in R 1 is 0-2; Z is a C 1 -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, (C 1 -C 4 alkoxy)carbonylamino, hydroxy, CI-C 2 alkoxy, CI-C 2 alkylthio or halo and 1-2 radicals of aryl or heteroaryl optionally substituted by 1-2 i S71 radicals of amino, di-(C 1 -C 2 alkyl)amino, acetamido, S (C 1 -C 4 alkoxy)carbonylamino, hydroxy, Cl-C 2 alkoxy, Cl-C 2 251 alkyithia, cyano, 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) amino, acetamido, (Cl-C4 alkoxy) carbonyl amino, hydroxy, C 1 -C 2 alkoxy, C 1 -C 2 alkylthio, cyano, halo, C 1 -C 4 alkyl or trifluoromethyl radicals; Y is a hydrogen radical; -C(O)-R 2 0 -C(O)-0R 2 1 or -C(O)-NR 5 R 2 radical; -OR 2 1 -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 -NR 2 2 -C(O)-R 2 1 -NR 2 2 -C(O)-0R 2 0 -NR 2 2 .15 NR 5 R 2 1 -NR 2 2 -S(O) 2 -R 2 0 or -NR 2 2 -S(O) 2 -NR 5 R 2 radical; each R 5 is independently a 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 radical optionally substituted by 1-3 radicals of amino, dimethylamino, hydroxy, rnethoxy, methylthio, methyl or trifluoromethyl radicals; each R 20 is independently a cl-c 8 alkyl or C 2 -C 5 alkenyl radical optionally substituted by 1-3 radicals of -CO 2 R 2 3 amino, Cl-C 4 alkylamino, di- (Cl-C 4 alkyl)amino, Cl-C 5 alkanoylamino, (Cl-C 4 alkoxy) carbonylamino, N- (Cl-C 4 alkoxy) carbonyl) N- (Cl-C 4 alkyl)amino, aminocarbonylamino, hydroxy, Cl-C 4 alkoxy, Cl-C 4 alkylthio, CI-C 4 alkylsulfinyl, Cl-C 4 I Ille -alkylsulfonyl, halo, aryl-Cl-C 4 -alkoxy, aryl-Cl-C 4 252 alkylthio, aryl-Cl-C 4 -alkylsulfonyl, C 3 -C 6 cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the aryl-Cl- C 4 -alkoxy, aryl-Cl-C 4 -alkylthio, aryl-Cl-C 4 alkylsulfonyl, C 3 -C 6 cycloalkyl, heterocyclyl, aryl and heteroaryl radicals are optionally substituted by 1-3 radicals of amino, C 1 -C 4 alkylamino, di-(Cl-C 4 alkyl)amino, C 1 -C 5 alkanoylamino, (C 1 L-C 4 alkoxy) carbonyl amino, 'Cl-C 4 alkyl sul fonyl amino, Cl-C alkanoyl, (Cl-C 4 alkoxy)carbonyl, hydroxy, C 1 -C 4 alkoxy, cl-c 4 alkylthio, cyano, 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, di-(Cl-C 4 alkyl)amino, (Cl-C 4 alkoxy) carbonyl amino, (Cl-C 4 alkoxy)carbonyl, hydroxy, 15 Cl-C 4 alkoxy, Cl-C 4 alkylthio or Cl-C 4 alkyl; or aryl or heteroaryl radical optionally substituted by 1-2 radicals of amino, Cl-C 4 alkylamino, di- (Cl-C 4 alkyl) amino, acetamido, (Cl-C 4 al1koxy) carbonyl amino, Cj- C 4 alkylsulfonylamino, (C 1 -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 20 each R 23 is independently a hydrogen, Cl-C 4 alkyl, phenyl-Cl-C 2 -alkyl or heteroaryl-Cl-C 2 -alkyl radical, wherein the phenyl, heteroaryl, phenyl-Cl-C 2 -alkyl and heteroaryl-C 1 -C 2 -alkyl radicals are optionally substituted by 1-3 radicals of amino, di- (C 1 -C 2 alkyl)amino, acetamido, (Cl-C 4 al1koxy) carbonyl amino, hydroxy, Cl-C 2 alkoxy, Cl-C 2 alkylthio, cyano, halo, Cj- S p~z, C 4 alkyl or trifluoromethyl radicals; 253 R 2 is a radical of hydrogen, C 1 -C 4 alkyl, halo, cyano, hydroxy, C 1 -C 4 alkoxy, trifluoromethoxy or trifluoromethyl; R 3 is a hydrogen radical or CI-C 8 alkyl radical optionally substituted by 1-2 radicals of amino, C 1 -C 4 alkylamino, di-(C 1 -C 4 alkyl)amino, hydroxy, C 1 -C 4 alkoxy or 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 4 alkoxy, CI-C 4 alkylthio, halo, C 1 -C 4 alkyl, trifluoromethoxy or trifluoromethyl radicals; R 11 is an aryl radical and R 12 is a heteroaryl radical, wherein the aryl and heteroaryl radicals are optionally 15 substituted by 1-2 radicals of R 30 halo or cyano; or -C(O)-NR 3 1 R 3 2 -OR 2 9 -SR 2 9, -S(0)-R 3 0 -S(0) 2 -R 3 0 -S(0) 2 -NR 31 R 3 2 -NR 3 1 R 3 2 or -NR33-C(O)-R29; 20 provided that the total number of aryl, heteroaryl, cycloalkyl and heterocyclyl radicals substituted on each ;of R 11 and R 12 is 0-1; each R 30 is independently a 25 Cl-C 4 alkyl radical optionally substituted by a phenyl or heteroaryl radical, wherein the phenyl and heteroaryl radicals are optionally substituted by 1-3 radicals of amino, dimethylamino, acetamido, hydroxy, halo, methoxy, methyl or trifluoromethyl; trifluoromethyl radical; or aryl or heteroaryl radical optionally substituted by /OS' 1-3 radicals of amino, dimethylamino, acetamido, hydroxy, halo, methoxy, methyl or trifluoromethyl; 254 each R 2 9 is independently hydrogen radical or R 30 each R 31 is independently a hydrogen, methyl or ethyl radical; and each R 3 2 is independently a hydrogen radical; C1-C 4 alkyl radical or Ci-C 2 alkyl radical substituted by phenyl or heteroaryl radical, wherein the phenyl and heteroaryl radicals are optionally substituted by 1-3 radicals of amino, dimethylamino, acetamido, hydroxy, methoxy, methyl or trifluoromethyl; or phenyl or heteroaryl radical optionally substituted 15 by 1-3 radicals of amino, dimethylamino, acetamido, hydroxy, methoxy, methyl or trifluoromethyl. 0
7. The compound of Claim 6 or a pharmaceutically acceptable salt thereof, wherein R 3 is a radical of hydrogen or C 1 -C 4 alkyl; O R 11 is an aryl radical optionally substituted by 1-2 25 radicals of R 30 halo or cyano; or -C(0)-NR 3 1 R 3 2 -OR 29 -SR 2 9 -S(O)-R 30 -S(0) 2 -R 3 0, -S(0) 2 -NR 3 1 R 3 2 -NR 3 1 R 3 2 or -NR 3 3 -C(O)-R 2 9 and R 12 is a heteroaryl radical optionally substituted by 1- 2 radicals of ST R 3 o; halo or cyano; or 255 -NR 3 1 R 3 2 -OR 2 9 -SR 2 9 -NR 3 1 R 3 2 Or -NR 3 3 R 2 9 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 3 0 is independently a C1-C 4 alkyl radical optionally substituted by a phenyl or heteroaryl radical, wherein the phenyl and heteroaryl radicals are optionally substituted by 1-2 radicals of amino, dimethylamino, acetamido, hydroxy, halo, methoxy, methyl or trifluoromethyl; trifluoromethyl radical; or aryl or heteroaryl radical optionally substituted by 15 1-3 radicals of amino, dimethylamino, acetamido, hydroxy, halo, methoxy, methyl or trifluoromethyl; *i R 29 is an aryl or heteroaryl radicals optionally substituted by 1-2 radicals of amino, dimethylamino, S 20 acetamido, hydroxy, halo, methoxy, methyl or trifluoromethyl radicals; and o SR 3 2 is independently hydrogen or C 1 -C 4 alkyl radical; or 25 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 256 wherein R, is -Y or provided that the total number of aryl, heteroaryl, cycloalkyl and heterocyclyl radicals in R, is 0-1; Z is a Cl-C4 alkyl radical optionally substituted by 1-2 radicals of amino, di-(C-C2 alkyl)amino, (C-C4 alkoxy) carbonyl amino, hydroxy, Cl-C2 alkoxy, Cl-C2 alkylthio, halo, or aryl or heteroaryl optionally substituted by 1-2 radicals of hydroxy, Cl-C2 alkoxy, Cl-C2 alkylthio, cyano, halo, Cl-C4 alkyl or trifluoromethyl radicals; each R5 is independently a hydrogen or Cl-C4 alkyl radical; s i -o t i~ each R20 is independently a Cl-C8 alkyl radical optionally substituted by 1-3 .radicals of -C02R23, amino, C-C4 al-kylamino, di- (C-C4 alkyl) amino, C, .C5 alkanoylamino, (Cl-C-4 alkoxy) carbonylamino, N- ((C-C4 alkoxy) carbonyl) (Cl- C4 alkyl) amino, aminocarbonyl amino, hydroxy, C-C4 alkoxy, Cl-C4 alkylthio, C-C4 alkylsulfinyl, C-C4 alkylsulfonyl, halo, C3-c cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the C3-C6 cycloalkyl, heterocyclyl, aryl and heteroaryl radicals are optionally substitut ed by 1-2 radicals of amino, di-(Cj- C4 alkyl)amino, C-CS alkanoylamino, (Cl-C4 alkoxy) carbonyl amino, C-C4 alkylsulfonylamino, (Cl-C4 alkoxy)carbonyl, hydroxy, C-C4 alkoxy, C-C4 alkylthio, cyano, halo, Cl-C4 alkyl or trifluoromethyl radicals; heterocyclyl radical optionally substituted by 1-2 radicals of (Cl-C4 alkoxy)carbonyl, hydroxy, Cl-C4 alkoxy, Cl-C4 alkylthio or Cl-C4 alkyl; or 257 aryl or heteroaryl radical optionally substituted by 1-2 radicals of (C 1 -C 4 alkoxy)carbonyl, amino, C1-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 2 1 is independently hydrogen radical or R 2 0 each R 2 3 is independently a hydrogen, C 1 -C 4 alkyl or phenyl-C 1 -C 2 -alkyl radical, wherein the phenyl-C 1 -C 2 alkyl radical is optionally substituted by 1-2 radicals of hydroxy, C 1 -C 2 alkoxy, C 1 -C 2 alkylthio, cyano, halo, C 1 -C 4 alkyl or trifluoromethyl radicals; 15 R 2 is a hydrogen radical; R 3 is a hydrogen, methyl or ethyl radical; R 11 is an aryl radical optionally substituted by 1-2 20 radicals of amino, dimethylamino, acetamido, hydroxy, halo, cyano, methoxy, methylthio, methylsulfinyl, Smethylsulfonyl, aminocarbonyl, methyl or trifluoromethyl; and S: 25 R 1 2 is a heteroaryl radical optionally substituted by 1- 2 radicals of amino, dimethylamino, acetamido, hydroxy, halo, cyano, methoxy, methyl or trifluoromethyl.
9. The compound of Claim 8 or a pharmaceutically acceptable salt thereof, wherein 258 Z is CI-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; -C(O)-R 2 0 -C(O)-OR 21 or -C(O)-NR 5 R 21 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 -NR 2 2 -C(O)-R 2 1 or -NR 2 2 -S(0) 2 -R 2 0 radical; R 5 is a hydrogen radical; each R 2 0 is independently a 15 CI-C 6 alkyl radical optionally substituted by 1-3 radicals of -C0 2 R 2 3 amino, methylamino, dimethylamino, t-butoxycarbonylamino, N- ((t-butoxy) carbonyl)-N- (methyl)amino, aminocarbonylamino, hydroxy, butoxy, methoxy, butylthio, methylthio, methylsulfinyl, 20 methylsulfonyl, halo, Cs-C 6 cycloalkyl, heterocyclyl, phenyl or heteroaryl, wherein the Cs-C 6 cycloalkyl, heterocyclyl, phenyl and heteroaryl radicals are optionally substituted by 1-2 radicals of amino, dimethylamino, acetamino, hydroxy, methoxy, methylthio, O.*e 25 halo, methyl or trifluoromethyl radicals; heterocyclyl radical optionally substituted by 1-2 radicals of t-butoxycarbonyl, hydroxy, or C 1 -C 4 alkyl; or aryl or heteroaryl radical optionally substituted by 1-2 radicals of amino, dimethylamino, hydroxy, methoxy, methylthio, halo, methyl ortrifluoromethyl radicals; each R 2 1 is independently hydrogen radical or R 2 0 259 each R 22 is independently a hydrogen or methyl radical; each R 2 3 is independently a hydrogen or CI-C 4 alkyl radical; R 11 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; and R 1 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.
10. The compound of Claim 9 or a pharmaceutically acceptable salt thereof, wherein Y is a -C(O)-R 2 0 or -C(0)-NR 5 R 21 radical;. -OR 2 1 -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 25 -NR 5 R 2 1 -NR 2 2 -C(O)-R 21 or -NR 2 2 -S(0) 2 -R 2 0 radical; each R 2 0 is independently a C 1 -C 6 alkyl radical optionally substituted by 1-3 radicals of -C0 2 R 2 3 amino, methylamino, dimethylamino, t-butoxycarbonylamino, N-((t-butoxy)carbonyl)-N- (methyl)amino, aminocarbonylamino, hydroxy, butoxy, methoxy, butylthio, methylthio, methylsulfinyl, S r methylsulfonyl, halo, C 5 -C 6 cycloalkyl, heterocyclyl, S 1 phenyl or heteroaryl, wherein the C 5 -C 6 cycloalkyl, 260 heterocyclyl, phenyl and heteroaryl radicals are optionally substituted by 1-2 radicals of amino, dimethylamino, acetamino, hydroxy, methoxy, methylthio, halo, methyl or trifluoromethyl radicals; heterocyclyl radical optionally substituted by t- butoxycarbonyl; or aryl or heteroaryl radical optionally substituted by 1-2 radicals of amino, dimethylamino, hydroxy, methoxy, methylthio, halo, methyl or trifluoromethyl radicals; and each R 2 1 is independently hydrogen radical or R 2 0
11. The compound of Claim 10 or a pharmaceutically acceptable salt thereof, wherein o.o Y is a -OR 2 1 -SR 2 1 or -NR 5 R 21 radical; *i 20 each R 20 is independently a CI-C 6 alkyl radical optionally substituted by 1-3 radicals of amino, methylamino, dimethylamino, hydroxy, phenyl or heteroaryl, wherein the phenyl and heteroaryl S:radicals are optionally substituted by 1-2 radicals of 25 amino, dimethylamino, hydroxy, methoxy, methylthio, Shalo, methyl or trifluoromethyl radicals; heterocyclyl radical; or aryl or heteroaryl radical optionally substituted by 1-2 radicals of amino, dimethylamino, hydroxy, methoxy, methylthio, halo, methyl or trifluoromethyl radicals; each R 2 1 is independently hydrogen radical or R 2 0 261 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; and R 1 2 is a 4-pyridyl radical optionally substituted by a radical of amino, dimethylamino, acetamido, hydroxy, halo, cyano, methoxy, methyl or trifluoromethyl.
12. The compound of Claim 3 or a pharmaceutically acceptable salt thereof, wherein X is 0 or S; R 4 V N is ,a W R N RI the combined total number and heterocyclyl radicals N N R 1 or R provided that of aryl, heteroaryl, cycloalkyl in -VC(R)W- is 0-2; wherein R 1 is -Y or provided that the total number of aryl, heteroaryl, cycloalkyl and heterocyclyl radicals in RI is 0-3; Z is a CI-C 8 alkyl or C 2 -C 8 alkenyl 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, Cl-C 4 S 7 "0 alkylthio, halo, or heterocyclyl, aryl or heteroaryl s^ ^OFC 262 optionally substituted by 1-3 radicals of amino, Cl-C 4 alkylamino, di- (Cl-C 4 alkyl) amino, Cl-C 5 alkanoylamino, (C 1 -C 4 alkoxy) carbonyl amino, hydroxy, Cl-C 4 alkoxy, Cl-c 4 alkyithia, cyano, 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 alkoxy) 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, Cl-C 4 alkylamino, di-(Cl-C 4 alkyl) amino, Cl-C 5 alkanoylamino, (Cl-C 4 alkoxy) carbonyl amino, Cl-C4 alkyl sul fonyl amino, hydroxy, C 1 -C 4 alkoxy, Cl-C 4 alkylthio, cyano, halo, Cl-C 4 alkyl or C 1 -C 2 haloalkyl of 1-3 halo radicals; Y is a hydrogen radical; halo radical; -C (0)-R 2 0 -C -R 2 1 -C (0)-NR 5 R 2 1 or -C (NR 5 -NR 5 R 2 1 radical; -OR 2 1 -0-c -R 2 1 or -NR 5 R 2 j radical; -SR 2 -S(O) 2 -R 2 0 or -S(O) 2 -NR 5 R 2 radical; or -NRSR 2 1 -NR 2 2 -C -R 2 1 -NR 2 2 -C -R 2 0 -NR 2 2 -C NR 5 R 21 -NR 2 2 -C(NR 5 )-NR_9R 2 1 -NR 2 2 -S(O) 2 -R 2 0 or -NR 2 2 S(O) 2 -NR 5 R 2 radical; each R 5 is independently a hydrogen radical; cl-c 4 alkyl or C 2 -C 5 alkenyl radical optionally substituted by 1-3 radicals of amino, di-(cl-c 4 263 alkyl)amino, hydroxy, Cl-C 4 alkoxy, Cl-C 4 alkylthio or halo; or phenyl-Cl-C 2 -alkyl, heteroaryl-Cl-C 2 -alkyl, heterocyclyl-Cl-C 2 -alkyl or C3-CG-cycloalkyl-Cl-C 2 -alkyl radical optionally substituted by 1-3 radicals of amino, di- (Cl-C 4 -alkyl) amino, hydroxy, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio, cyano, C 1 -C 4 alkyl or Cl-C 2 haloalkyl of 1-3 halo radicals; each R 2 0 is independently a cl-c 8 alkyl or C 2 -C 5 alkenyl radical- optionally substituted by 1-3 radicals of -C0 2 R 2 3 amino, Cl-C 4 alkylamino, di-(Cl-C 4 alkyl)amino, Cj-C 5 alkanoylamino, (Cl-C 4 alkoxy) carbonylamino, N- ((Cl-C 4 alkoxy) carbonyl) N-(Cl-C 4 alkyl)amino, aminocarbonyl amino, hdoy lC alkoxy, C 1 -C 4 alkylthio, Cl-C 4 alkylsulfinyl, Cl-C 4 alkylsulfonyl, halo, aryl-Cl-C 4 -alkoxy, aryl-Cl-C 4 alkylthio, aryl-Cl-C 4 -alkylsulfonyl, C 3 -C 6 cycloalkyl, **heterocyclyl, aryl or heteroaryl, wherein the aryl-Cl- C 4 -alkoxy, aryl-Cl-C 4 -alkylthio, aryl-CI-C 4 alkylsulfonyl, C 3 -CG cycloalkyl, heterocyclyl, aryl and a.:.heteroaryl. radicals are optionally substituted by 1-3 radicals of amino, Cl-C 4 alkylamino, di- (Cl-C 4 alkyl) amino, Cj-C 5 alkanoylamino, (Cl-C 4 al koxy) carbonyl.amino, Cl-C4 alkyl sul fonyl amino, Cj-C alkanoyl, (Cl-C 4 alkoxy)carbonyl, 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; heterocyclyl radical optionally substituted by 1-2 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 alkoxy)carbonyl, hydroxy, Cl-C 4 alkoxy, Cl-C 4 alkylthio or Cl-C 4 alkyl; or 264 aryl 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, CI-C4 alkylsulfonylamino, (C 1 -C 4 alkoxy)carbonyl, hydroxy, C 1 -C 4 alkoxy, CI-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 R 2 2 is independently a hydrogen radical; or CI-C 4 alkyl radical optionally substituted by a radical of phenyl or heteroaryl, wherein the phenyl and 15 heteroaryl radicals are optionally substituted by 1-3 radicals of amino, di-(C 1 -C 2 alkyl)amino, Cl-C alkanoylamino, (CI-C 4 alkoxy)carbonylamino, hydroxy, C 1 C 4 alkoxy, C 1 -C 4 alkylthio, cyano, halo, C 1 -C 4 alkyl or ig C 1 -C 2 haloalkyl of 1-3 halo radicals; each R 2 3 is independently a hydrogen, CI-C 4 alkyl, phenyl, heteroaryl, phenyl-C 1 -C 2 -alkyl or heteroaryl-C 1 C 2 -alkyl radical, wherein the phenyl, heteroaryl, phenyl-C 1 -C 2 -alkyl and heteroaryl-Ci-C 2 -alkyl radicals 25 are optionally substituted by 1-3 radicals of amino, di- (C 1 -C 4 alkyl)amino, C 1 -C 5 alkanoylamino, (C 1 -C 4 alkoxy)carbonylamino, hydroxy, Cl-C 4 alkoxy, C 1 -C 4 alkylthio, cyano, halo, C 1 -C 4 alkyl or CI-C 2 haloalkyl of 1-3 halo radicals; R 4 is Ci-C 8 alkyl or C 2 -C 8 alkenyl radical optionally substituted by 1-3 radicals of amino, C 1 -C 4 265 alkylamino, di- (Cl-C 4 alkyl) amino, CI-C 5 alkanoylamino, (Cl-C 4 al koxy) carbonyl amino, Cl-C 4 alkylsul fonyl amino, hydroxy, Cl-C 4 alkoxy, Cl-C 4 alkylthio or hal o, and (b) 1-2 radicals of heterocyclyl, aryl or heteroaryl optionally substituted by 1-3 radicals of amino, C 1 -C 4 alkylamino, di-(Cl-C 4 alkyl)amino, Cl-Cs alkanoylamino, (Cl-C 4 al koxy) carbonyl amino, C 1 -C 4 alkyl sul fonyl amino, hydroxy, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio, halo, Cl-C 4 alkyl, trifluoromethoxy or trifluoromethyl radicals; 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) carbonyl amino, Cl-C 4 alkylsulfonylamino, hydroxy, Cl-C 4 alkoxy, Cl-C 4 alkylthio, cyano, halo, Cl-C 4 alkyl, trifluoromethoxy or trifluoromethyl radicals; R 1 1 arid R 1 2 are each independently an aryl or heteroaryl radical optionally substituted by 1-2 radicals of R 3 0 halo or cyano; -C (0)-R 3 0 -C -R 2 9 -C (0)-NR 3 1 R 3 2 or-C(R1 NR 3 lR 3 2 or -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 -NR 3 3 -C (0)-R 2 9 or -NR 3 3 -C (0)-OR 3 0 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; when R 11 is an unsubstituted phenyl, 4-methoxyphenyl or 4- chlorophenyl radical, then R 1 2 is other than an unsubstituted phenyl, 4-methoxyphenyl or 4-chlorophenyl radical; 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; 266 each R 30 is independently a Ci-C 4 alkyl radical optionally substituted by a radical of amino, C 1 -C 4 alkylamino or di-(Ci-C 4 -alkyl)amino; or hydroxy, CI-C 4 alkoxy, heterocyclyl, phenyl or heteroaryl, wherein the heterocyclyl, phenyl and heteroaryl radicals are 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, hydroxy, CI-C 4 alkoxy, C 1 -C 4 alkylthio, cyano, halo, CI-C 4 alkyl or trifluoromethyl; C1-C 2 haloalkyl of 1-3 halo radicals; or aryl or heteroaryl radical optionally substituted by 15 1-3 radicals of amino, CI-C 4 alkylamino, di-(C 1 -C 4 Salkyl)amino, CI-C 5 alkanoylamino, (CI-C 4 alkoxy)carbonylamino, hydroxy, C 1 -C 4 alkoxy, C1-C 4 alkylthio, cyano, halo, CI-C 4 alkyl or trifluoromethyl; 4 each R 2 9 is independently hydrogen radical or R 30 e* e4 each R 31 is independently a hydrogen or C 1 -C 4 alkyl radical; and 25 each R 3 2 is independently a hydrogen radical; C 1 -C 4 alkyl radical optionally substituted by phenyl or heteroaryl radical, wherein the phenyl and heteroaryl radicals are optionally substituted by 1-3 radicals of amino, CI-C 4 alkylamino, di-(Ci-C 4 alkyl)amino, CI-C alkanoylamino, (C 1 -C 4 alkoxy)carbonylamino, hydroxy, C 1 C 4 alkoxy, C 1 -C 4 alkyl or trifluoromethyl; or 267 phenyl or heteroaryl 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, (Ci-C 4 alkoxy)carbonylamino, hydroxy, C 1 -C 4 alkoxy, C 1 -C 4 alkyl or trifluoromethyl; and each R 3 3 is independently a 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 15 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 20 saturated C3-C4-carbocyclic-fused. 0
13. The compound of Claim 12 or a pharmaceutically acceptable salt thereof, wherein 0 SZ is a ao* CI-C4 alkyl or C 2 -C 5 alkenyl radical optionally substituted by 1-3 radicals of amino, di-(Ci-C 2 alkyl)amino, CI-Cs5alkanoylamino, (C 1 -C 4 alkoxy) carbonylamino, hydroxy, Ci-C 2 alkoxy, CI-C 2 alkylthio, halo, or heterocyclyl, aryl or heteroaryl optionally substituted by 1-3 radicals of amino, C 1 -C 4 alkylamino, di-(C 1 -C 2 alkyl)amino, CI-C 5 alkanoylamino, 2 )(CI-C 4 alkoxy)carbonylamino, hydroxy, CI-C 4 alkoxy, CI-C 4 268 alkylthio, cyano, halo, C 1 -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 alkoxy)*carbonyl amino, hydroxy, C 1 -C 2 alkoxy, C 1 -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, Cj-.C alkanoylamino, (Cl-C 4 alkoxy)carbonylamino, hydroxy, C 1 C 2 alkoxy, C 1 -C 2 alkylthio, cyano, halo, C 1 -C 4 alkyl or trifluoromethyl radicals; each R. 5 is independently a hydrogen radical; C 1 -C 4 alkyl radical optionally substituted by 1-3 eradicals of amino, di- (Cl-C 2 -alkyl) amino, hydroxy, Cl-C 2 alkoxy, Cl-C 2 alkylthio or halo; or phenyl-Cl-C 2 -alkyl, heteroaryl-Cl-C 2 -alkyl, heterocyclyl-Cl-C 2 -alkyl or C3-C6-cycloalkyl-Cl-C 2 -alkyl radical optionally substituted by 1-3 radicals of amino, di- (Cl-C2-alkyl) amino, hydroxy, Cl-C 2 alkoxy, Cl-C2 alkylthio, methoxy, methylthio, cyano, Cl-C 4 alkyl or **trifluoromethyl radicals; ec*2 s neednlyahdoe o lC ly radcal 25 each R 2 3 is independently a hydrogeno C-C 4 alkyl phenyl, heteroaryl, phenyl-Cl-C 2 -alkyl or heteroaryl-Cl- C 2 -alkyl radical, wherein the phenyl, heteroaryl, phny-C-C-alkyl and heteroaryl-c-c-alkyl radicals are optionally substituted by 1-3 radicals of amino, di- Zh~.(CI-C 2 alkyl)amino, Cl-C 5 alkanoylamino, (Cl-C 4 269 alkoxy) carbonyl amino, hydroxy, C 1 -C 2 alkoxy, C 1 -C 2 alkylthio, cyano, halo, Cl-C 4 alkyl or trifluoromethyl radicals; R4 is cl-c 8 alkyl radical optionally substituted by 1-2 radicals of amino, C 1 -C 4 alkylamino, di- (Cl-C 4 alkyl)amino, hydroxy, Cl-C 4 alkoxy or aryl or heteroaryl optionally substituted by 1-3 radicals of amino, Cl-C 4 alkylamino, di- (Cl-C 4 alkyl)amino, Cl-C 4 alkoxy, Cl-C 4 alkylthio, halo, Cl-C 4 alkyl, trifluoromethoxy or trifluoromethyl radicals; or heteroaryl radical optionally substituted by 1-3 radicals of amino, Cl-C 4 alkylamino, di- (Cl-C 4 alkyl)amino, Cl-C 4 alkoxy, Cl-C 4 alkylthio, cyano, halo, Cl-C 4 alkyl, trifluoromethoxy or trifluoromethyl radicals; 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 R 3 0 halo or cyano; -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 or -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 -NR 3 3 -C(O)-R 2 9 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 a 270 Cl-C 4 alkyl radical optionally substituted by a phenyl or heteroaryl radical, wherein the phenyl and heteroaryl radicals are optionally substituted by 1-3 radicals of amino, di-(Ci-C 2 alkyl)amino, acetamido, hydroxy, C 1 -C 2 alkoxy, halo, CI-C 4 alkyl or trifluoromethyl; trifluoromethyl radical; or aryl 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, halo, CI-C4 alkyl or trifluoromethyl; each R 2 9 is independently hydrogen radical or R 30 and each R 3 2 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-(CI-C 2 20 alkyl)amino, acetamido, hydroxy, CI-C 2 alkoxy, Ci-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, CI-C 2 alkoxy, C 1 -C 4 alkyl or 25 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 i heterocyclic ring system having 5-6 ring members, 271 wherein 1-2 ring members are oxygen, sulfur or nitrogen heteroatoms, which is optionally benzo-fused.
14. The compound of Claim 13 or a pharmaceutically acceptable salt thereof, wherein wherein R 1 is -Y or provided that the total number of aryl, heteroaryl, cycloalkyl and heterocyclyl radicals in R 1 is 0-2; Z is a 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, (CI-C 4 alkoxy)carbonylamino, hydroxy, C 1 -C 2 alkoxy, C 1 -C 2 alkylthio, halo, or aryl or heteroaryl optionally substituted by 1-2 radicals of amino, di-(C 1 C 2 alkyl)amino, acetamido, (C 1 -C 4 alkoxy)carbonylamino, "i hydroxy, C 1 -C 2 alkoxy, C 1 -C 2 alkylthio, cyano, halo, C 1 20 C 4 alkyl or trifluoromethyl radicals; or aryl or heteroaryl radical optionally substituted by 1-3 radicals of amino, di-(CI-C 2 alkyl)amino, acetamido, (C 1 -C 4 alkoxy)carbonylamino, hydroxy, C 1 -C 2 alkoxy, Ci-C 2 alkylthio, cyano, halo, C 1 -C 4 alkyl or trifluoromethyl 25 radicals; Y is a hydrogen radical; -C(O)-R 20 -C(O)-OR 21 or -C(O)-NR 5 R 21 radical; -OR 21 -SR 21 -S(0)-R 20 -S(0) 2 -R 20 or -S(0) 2 -NR 5 R 21 S radical; or -NR 5 R 2 1 -NR 2 2 -C(0)-R 2 1 -NR 2 2 -C(0)-OR 2 0 -NR 2 2 NR 5 R 2 1 -NR 2 2 -S(0) 2 -R 2 0 or -NR 2 2 -S(0) 2 -NR 5 R 21 radical; 272 each R 5 is independently a 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 radical optionally substituted by 1-3 radicals of amino, dirnethylamino, hydroxy, methoxy, methylthio, methyl or trifluoromethyl radicals; each R 2 0 is independently a Cj-C 8 alkyl or C 2 -C 5 alkenyl radical optionally substituted by 1-3 radicals of -C0 2 R 2 3 amino, Cl-C 4 alkylamino, di- (Cl-C 4 alkyl) amino, Cl-C 5 alkanoylamino, 15 (Cl-C 4 alkoxy) carbonyl amino, N- ((Cl-C 4 alkoxy) carbonyl) N- (Cl-C 4 alkyl) amino, aminocarbonyl amino, hydroxy, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio, Cl-C 4 alkylsulfinyl, C 1 -C 4 alkylsulfonyl, halo, aryl-Cl-C' 4 -alkoxy, aryl-Cl-C 4 :'*:alkylthio, aryl-Cl-C 4 -alkylsulfonyl, C 3 -C 6 cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the aryl-Cl- C 4 -alkoxy, aryl-Cl-C 4 -alkylthio, aryl-Cl-C 4 alkylsulfonyl, C 3 -C 6 cycloalkyl, heterocyclyl, aryl and heteroaryl radicals are optionally substituted by 1-3 radicals of amino, Cl-C 4 alkylamino, di- (Cl-C 4 alkyl)amino, Cj-C 5 alkanoylamino, (Cl-C 4 *alkoxy) carbonyl amino, Cl-C 4 alkyl sul fonyl amino, alkanoyl, (Cl-C 4 alkoxy)carbonyl, hydroxy, C 1 -C 4 alkoxy, Cl-C 4 alkylthio, cyano, 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-(-C alkyl)amino, 1 C alkoxy)carbonylamino, (Cl-C 4 alkoxy)carbonyl, hydroxy, Cl-C 4 alkoxy, Cl-C 4 alkylthio or C 1 -C 4 alkyl; or 273 aryl or heteroaryl radical optionally substituted by 1-2 radicals of amino, C 1 -C 4 alkylamino, di- (Cl-C 4 alkyl)amino, acetamido, (Cl-C 4 alkoxy)carbonylamino, Cj- C 4 alkylsulfonylamino, (Cl-C 4 alkoxy) carbonyl, hydroxy, Cl-C4 alkoxy, C 1 -C 4 alkylthio, cyano, halo, azido, C 1 -C 4 alkyl or trifluoromethyl radicals; each R 2 1 is independently hydrogen radical or R 2 0 each R 2 3 is independently a hydrogen, Cl-C 4 alkyl, phenyl-Cl-C 2 -alkyl or heteroaryl-Cl-C 2 -alkyl radical, wherein the phenyl-Cl-C 2 -alkyl and heteroaryl-Cl-C 2 alkyl radicals are optionally substituted by 1-3 radicals of amino, di-(Cl-C 2 alkyl)amino, acetamido, 15 (Cl-C 4 alkoxy) carbonyl amino, hydroxy, Cl-C 2 alkoxy, C 1 -C 2 alkylthio, cyano, halo, Cl-C 4 alkyl or trifluoromethyl radicals; R 4 is a C 1 -C 8 alkyl radical optionally substituted by 1- 2 radicals of amino, Cl-C 4 alkylamino, di-(Cl-C 4 alkyl)amino, hydroxy, C 1 -C 4 alkoxy or aryl or heteroaryl optionally substituted by 1-3 radicals of amino, Cl-C 4 alkylamino, di-(Cl-C 4 alkyl) amino, Cl-C 4 _alkoxy, Cl-C 4 alkylthio, halo, C 1 -C 4 alkyl, trifluoromethoxy or trifluoromethyl radicals; 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 30 halo or cyano; or 9) -C(O)-NR 3 lR 32 -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 -NR 3 3 -C(O)-R 2 9 274 provided that the total number of aryl, heteroaryl, cycloalkyl and heterocyclyl radicals substituted on each of R 11 and R 12 is 0-1; each R 3 0 is independently a CI-C 4 alkyl radical optionally substituted by a phenyl or heteroaryl radical, wherein the phenyl and heteroaryl radicals are optionally substituted by 1-3 radicals of amino, dimethylamino, acetamido, hydroxy, halo, methoxy, methyl or trifluoromethyl; trifluoromethyl radical; or aryl or heteroaryl radical optionally substituted by 1-3 radicals of amino, dimethylamino, acetamido, hydroxy, halo, methoxy, methyl or trifluoromethyl; each R 2 9 is independently hydrogen radical or R 3 0 each R 3 1 is independently a hydrogen, methyl or ethyl radical; and each R 3 2 is independently a hydrogen radical; C1-C 4 alkyl radical or C 1 -C2 alkyl radical substituted by phenyl or heteroaryl radical, wherein the 25 phenyl and heteroaryl radicals are optionally substituted by 1-3 radicals of amino, dimethylamino, acetamido, hydroxy, methoxy, methyl or trifluoromethyl; or phenyl or heteroaryl radical optionally substituted by 1-3 radicals of amino, dimethylamino, acetamido, hydroxy, methoxy, methyl or trifluoromethyl. 275 The compound of Claim 14 or a pharmaceutically acceptable salt thereof, wherein R 4 is a C 1 -C 4 alkyl radical; R 11 is an aryl radical optionally substituted by 1-2 radicals of R 30 halo or cyano; or -C(O)-NR 3 1 R 3 2 -OR 2 9 -SR 2 9 -S(0)-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 -NR 3 3 -C(O)-R 2 9 and R 12 is a heteroaryl radical optionally substituted by 1- 2 radicals of R 30 halo or cyano; or -C(0)-NR 31 R 3 2 -OR 2 9 -SR 2 9 -NR 3 1 R 32 or -NR33-C(0)- R 2 9 provided that the total number of aryl, heteroaryl, 20 cycloalkyl and heterocyclyl radicals substituted on each of R 11 and R 12 is 9 R 30 is independently a C1-C 4 alkyl radical optionally substituted by a 25 phenyl or heteroaryl radical, wherein the phenyl and heteroaryl radicals are optionally substituted by 1-2 radicals of amino, dimethylamino, acetamido, hydroxy, halo, methoxy, methyl or trifluoromethyl; trifluoromethyl radical; or aryl or heteroaryl radical optionally substituted by -S 1-3 radicals of amino, dimethylamino, acetamido, 'b hydroxy, halo, methoxy, methyl or trifluoromethyl; 276 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.
16. The compound of Claim 15 or a pharmaceutically acceptable salt thereof, wherein wherein RI is -Y or provided that the total number of aryl, heteroaryl, cycloalkyl and heterocyclyl *:radicals in Ri is 0-1; 20 Z is a C 1 -C 4 alkyl radical optionally substituted by 1-2 radicals of amino, di-(C 1 -C 2 alkyl)amino, (C 1 -C 4 alkoxy)carbonylamino, hydroxy, Cl-C 2 alkoxy, Ci-C 2 alkylthio, halo, or aryl or heteroaryl optionally substituted by 1-2 radicals of hydroxy, Cl-C 2 alkoxy, S 25 C1-C 2 alkylthio, cyano, halo, C 1 -C 4 alkyl or trifluoromethyl radicals; each R 5 is independently a hydrogen or C 1 -C 4 alkyl radical; each R 20 is independently a -S C 1 -C 8 alkyl radical optionally substituted by 1-3 radicals of -C0 2 R 23 amino, C 1 -C 4 alkylamino, di-(C 1 -C 4 1O2. alkyl)amino, C 1 -Cs alkanoylamino, (C 1 -C 4 277 alkoxy)carbonylamino, N-((C 1 -C 4 alkoxy)carbonyl)-N-(C 1 C 4 alkyl)amino, aminocarbonylamino, hydroxy, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio, C 1 -C 4 alkylsulfinyl, C 1 -C4 alkylsulfonyl, halo, C 3 -C 6 cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the C 3 -C 6 cycloalkyl, heterocyclyl, aryl and heteroaryl radicals are optionally substituted by 1-2 radicals of amino, di-(C 1 C 4 alkyl)amino, CI-Cs alkanoylamino, (CI-C 4 alkoxy) carbonylamino, CI-C 4 alkylsulfonylamino, (CI-C 4 alkoxy)carbonyl, hydroxy, C 1 -C 4 alkoxy, CI-C 4 alkylthio, cyano, halo, C 1 -C 4 alkyl or trifluoromethyl radicals; heterocyclyl radical optionally substituted by 1-2 radicals of (CI-C 4 alkoxy)carbonyl, hydroxy, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio or C 1 -C 4 alkyl; or 15 aryl or heteroaryl radical optionally substituted by 1 -2 radicals of (C 1 -C 4 alkoxy)carbonyl, amino, C 1 -C 4 alkylamino, di-(C 1 -C 4 alkyl)amino, hydroxy, CI-C 4 alkoxy, CI-C 4 alkylthio, cyano, halo, azido, CI-C 4 alkyl or trifluoromethyl radicals; each R 2 1 is independently hydrogen radical or R 20 each R 23 is independently a hydrogen, C 1 -C 4 alkyl or phenyl-C 1 -C 2 -alkyl radical, wherein the phenyl-C 1 -C 2 25 alkyl radical is optionally substituted by 1-2 radicals of hydroxy, CI-C 2 alkoxy, C 1 -C 2 alkylthio, cyano, halo, C 1 -C 4 alkyl or trifluoromethyl radicals; R 4 is a methyl or ethyl radical; S R 11 is an aryl radical optionally substituted by 1-2 radicals of amino, dimethylamino, acetamido, hydroxy, halo, cyano, methoxy, methylthio, methylsulfinyl, 278 methylsulfonyl, aminocarbonyl, methyl or trifluoromethyl; and R 12 is a heteroaryl radical optionally substituted by 1- 2 radicals of amino, dimethylamino, acetamido, hydroxy, halo, cyano, methoxy, methyl or trifluoromethyl.
17. The compound of Claim 16 or a pharmaceutically acceptable salt thereof, wherein Z is C 1 -C 4 alkyl radical optionally substituted by 1-2 radicals of amino, t-butoxycarbonylamino, dimethylamino, hydroxy, methoxy, methylthio or halo radicals; I.e. Y is a hydrogen radical; r a -C(O)-R 20 -C(O)-OR 21 or -C(O)-NR 5 R 21 radical; -OR 21 -SR 2 1, -S(O)-R 2 0 -S(0) 2 -R 2 0 or -S(0) 2 -NRsR 2 1 20 radical; or -NR 5 R 21 -NR 22 -C(O)-R 21 or -NR 2 2 -S(0) 2 -R 2 0 radical; a R 5 is a hydrogen radical; 25 each R 20 is independently a Ci-C 6 alkyl radical optionally substituted by 1-3 radicals of -C0 2 R 2 3 amino, methylamino, dimethylamino, t-butoxycarbonylamino, N-((t-butoxy)carbonyl)-N- (methyl)amino, aminocarbonylamino, hydroxy, butoxy, methoxy, butylthio, methylthio, methylsulfinyl, methylsulfonyl, halo, C 5 -C 6 cycloalkyl, heterocyclyl, ,8 phenyl or heteroaryl, wherein the C 5 -C 6 cycloalkyl, o heterocyclyl, phenyl and heteroaryl radicals are Soptionally substituted by 1-2 radicals of amino, 279 dimethylamino, acetamino, hydroxy, methoxy, methylthio, halo, methyl or trifluoromethyl radicals; heterocyclyl radical optionally substituted by 1-2 radicals of t-butoxycarbonyl, hydroxy, or C 1 -C 4 alkyl; or aryl or heteroaryl radical 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 a hydrogen or methyl radical; each R 23 is independently a hydrogen or C 1 -C 4 alkyl radical; R 11 is an unsubstituted phenyl or naphthyl radical or a phenyl radical substituted by 1-2 radicals of amino, dimethylamino, acetamido, hydroxy, halo, cyano, methoxy, S 20 methylthio, methylsulfinyl, methylsulfonyl, aminocarbonyl, methyl or trifluoromethyl; and R 12 is a 4-pyridyl, 4-quinolinyl, 4-imidazolyl or 4- g: pyrimidinyl radical optionally substituted by a radical 25 of amino, dimethylamino, acetamido, hydroxy, halo, cyano, methoxy, methyl or trifluoromethyl.
18. The compound of Claim 17 or a pharmaceutically acceptable salt thereof, wherein Y is a 2 -C(O)-R 2 0 or -C(O)-NR 5 R 21 radical; 280 -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 -NR 2 2 -C(O)-R 2 1 or -NR 2 2 -S(0) 2 -R 20 radical; each R 20 is independently a C1-C 6 alkyl radical optionally substituted by 1-3 radicals of -C0 2 R 2 3 amino, methylamino, dimethylamino, t-butoxycarbonylamino, N-((t-butoxy)carbonyl)-N- (methyl)amino, aminocarbonylamino, hydroxy, butoxy, methoxy, butylthio, methylthio, methylsulfinyl, methylsulfonyl, halo, C 5 -C 6 cycloalkyl, heterocyclyl, phenyl or heteroaryl, wherein the C 5 -C 6 cycloalkyl, heterocyclyl, phenyl and heteroaryl radicals are optionally substituted by 1-2 radicals of amino, dimethylamino, acetamino, hydroxy, methoxy, methylthio, halo, methyl or trifluoromethyl radicals; heterocyclyl radical optionally substituted by t- butoxycarbonyl; or i aryl or heteroaryl radical optionally substituted by I 20 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
19. The compound of Claim 18 or a pharmaceutically acceptable salt thereof, wherein Y is a -OR 2 1 -SR 2 1 or -NR 5 R 21 radical; each R 2 0 is independently a i CI-C 6 alkyl radical optionally substituted by 1-3 radicals of amino, methylamino, dimethylamino, hydroxy, 281 phenyl or heteroaryl, wherein the phenyl and heteroaryl radicals are optionally substituted by 1-2 radicals of amino, dimethylamino, hydroxy, methoxy, methylthio, halo, methyl or trifluoromethyl radicals; heterocyclyl radical; or aryl or heteroaryl radical 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; and R 12 is a 4-pyridyl radical optionally substituted by a radical of amino, dimethylamino, acetamido, hydroxy, Sco 20 halo, cyano, methoxy, methyl or trifluoromethyl.
20. The compound of Claim 3 or a pharmaceutically acceptable salt thereof, wherein X is 0 or S; 282 N N 'K U isR2 w R N U UnR 2 1 N Nj N-R 2 1 NN R2 'N N R1 or R2 provided that the combined total number of aryl, heteroaryl, cycloalkyl and heterocyclyl radicals in -VC(R)w- is 0-2; each R 2 1 is independently a hydrogen radical or cl-c 8 alkyl or C 2 -C 5 alkenyl radicals optionally *~*:substituted by 1-3 radicals of -C0 2 R 2 3 amino, C 1 -C 4 alkylamino, di- (Cl-C 4 alkyl) amino, Cl-C 5 alkanoylamino, (Cl-C 4 alkoxy) carbonylamino, N- ((Cl-C 4 alkoxy) carbonyl) N- (Cl-C 4 alkyl) amino, aminocarbonylamino, hydroxy, CI-C 4 alkoxy, Cl-C 4 alkylthio, CI-C 4 alkylsulfinyl, CI-C 4 alkylsulfonyl, halo or aryl-Cl-C 4 -alkoxy, aryl-CI-C 4 alkylthio, aryl-Cl-C 4 -alkylsulfonyl, C 3 -C 6 cycloalkyl, 15 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 al1kanoylamino, (Cl-C 4 alkoxy) carbonylamino, Cl-C 4 alkylsulfonylamino, Cl-Cs alkanoyl, (Cl-C 4 alkoxy)carbonyl, hydroxy, Cl-C4 alkoxy, Cl-C 4 alkylthio, cyano, 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 alkanoylamino, (Cl-C 4 283 alkoxy) carbonylamino, (Cl-C 4 alkoxy) carbonyl, hydroxy, Cl-C 4 alkoxy, Cl-C 4 alkylthio 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, Cj-C 5 q alkanoylamino, (Cl-C 4 alkoxy) carbonylamino, Cl-C 4 alkylsulfonylamino, (Cl-C 4 alkoxy)carbonyl, hydroxy, C 1 -C 4 alkoxy, Cl-C 4 alkylthio, cyano, halo, azido, C 1 -C 4 alkyl or Cl-C 2 haloalkyl of 1- 3 halo radicals; each R 2 3 is independently a hydrogen, Cl-C 4 alkyl, phenyl, heteroaryl, phenyl-Cl-C 2 -alkyl or heteroaryl-C 1 C 2 -alkyl radical, wherein the phenyl, heteroaryl, phenyl-Cl-C 2 -alkyl and heteroaryl-Cl-C 2 -alkyl radicals are optionally substituted by 1-3 radicals of amino, di- (Cl-C 4 alkyl)amino, C 1 -C 5 alkanoylanino, (Cl-C 4 al koxy) carbonyl amino, hydroxy, Cl-C 4 alkoxy, Cl-C4 alkylthio, cyano, halo, Cl-C4 alkyl or C 1 -C 2 haloalkyl of 1-3 halo radicals; a a a 4 R 1 1 and R 1 2 are each independently an aryl or heteroaryl **.*radical optionally substituted by 1-2 radicals of R 3 0 -C(O)-R 3 0 -C(O)-0R 2 9 -C(O)-NR 3 lR 3 2 or -C(NR 3 1 a NR 3 1 R 3 2 or -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 -NR 3 3 -C(O)-R 2 9 or -NR 3 3 -C(O)-0R 3 0 provided that R 1 1 is other than a 4-pyridyl, 4- pyrimidinyl, 4-quinolyl or 6-isoquinolinyl radical optionally substituted by 1-2 substitueits; when R 11 is an unsubstituted phenyl, 4-methoxyphenyl or 4- chlorophenyl radical, then R 1 2 is other than an 284 unsubstituted phenyl, 4-methoxyphenyl or 4-chlorophenyl radical; and the total number of aryl, heteroaryl, cycloalkyl and heterocyclyl radicals substituted on each of R 11 and R 12 is 0-1; each R 30 is independently a C1-C 4 alkyl radical optionally substituted by a radical of amino, CI-C 4 alkylamino or di- (C1-C 4 -alkyl)amino; or hydroxy, CI-C 4 alkoxy, heterocyclyl, phenyl or heteroaryl, wherein the heterocyclyl, phenyl and heteroaryl radicals are 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, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio, cyano, halo, CI-C 4 alkyl or trifluoromethyl; C1-C 2 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-(C 1 -C4 20 alkyl)amino, C 1 -C 5 alkanoylamino, (CI-C4 alkoxy) carbonylamino, hydroxy, C 1 -C 4 alkoxy, C 1 -C4 alkylthio, cyano, halo, CI-C 4 alkyl or trifluoromethyl; 4*e each R 29 is independently hydrogen radical or R 30 each R 3 1 is independently a hydrogen or C 1 -C 4 alkyl radical; and each R 3 2 is independently a hydrogen radical; C 1 -C 4 alkyl radical optionally substituted by phenyl or heteroaryl radical, wherein the phenyl and heteroaryl S C radicals are optionally substituted by 1-3 radicals of 285 amino, CI-C 4 alkylamino, di-(C 1 -C 4 alkyl)amino, CI-C alkanoylamino, (C 1 -C 4 alkoxy)carbonylamino, hydroxy, C 1 C 4 alkoxy, C 1 -C 4 alkyl or trifluoromethyl; 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, CI-C 5 alkanoylamino, (C 1 -C 4 alkoxy)carbonylamino, hydroxy, C 1 -C4 alkoxy, CI-C 4 alkyl or trifluoromethyl; and each R 3 3 is independently a 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 .o 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 20 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-C 4 -carbocyclic-fused. S
21. The compound of Claim 20 or a pharmaceutically acceptable salt thereof, wherein U is NR 21 each R 23 is independently a hydrogen, CI-C 4 alkyl, phenyl, heteroaryl, phenyl-C 1 -C 2 -alkyl or heteroaryl-C 1 C 2 -alkyl radical, wherein the phenyl, heteroaryl, O2 phenyl-C 1 -C 2 -alkyl and heteroaryl-Ci-C 2 -alkyl radicals 286 are optionally substituted by 1-3 radicals of amino, di- (CI-C 2 alkyl)amino, C 1 -C 5 alkanoylamino, (C 1 -C 4 alkoxy)carbonylamino, hydroxy, C 1 -C 2 alkoxy, Ci-C 2 alkylthio, cyano, halo, C 1 -C 4 alkyl or trifluoromethyl radicals; 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 R 3 0 halo or cyano; -C(O)-R 3 0 -C(O)-OR 2 9 -C(O)-NR 3 1 R 3 2 or -C(NR 3 1 NR 3 1 R 3 2 or -OR 2 9 -SR 2 9, -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 -NR 3 3 -C(0)-R 2 9 provided that the total number of aryl, heteroaryl, cycloalkyl and heterocyclyl radicals substituted on each of R 11 and R 12 is 0-1; 20 each R 3 0 is independently a Ci-C 4 alkyl radical optionally substituted by a phenyl or heteroaryl radical, wherein the phenyl and heteroaryl radicals are optionally substituted by 1-3 radicals of amino, di-(Ci-C2 alkyl)amino, acetamido, 25 hydroxy, C 1 -C 2 alkoxy, halo, C 1 -C 4 alkyl or I trifluoromethyl; trifluoromethyl radical; or aryl 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, halo, CI-C 4 alkyl or trifluoromethyl; each R 2 9 is independently hydrogen radical or R 30 and 287 each R 32 is independently hydrogen radicals; C 1 -C 4 alkyl radical or Ci-C 2 alkyl radical substituted by phenyl or heteroaryl radical optionally substituted by 1-3 radicals of amino, di-(C 1 -C 2 alkyl)amino, acetamido, hydroxy, CI-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, C 1 -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 S: radicals; aryl is a phenyl or naphthyl radical; and 20 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. coo•
22. The compound of Claim 21 or a pharmaceutically acceptable salt thereof, wherein •ego 288 N is N; N 2 NN NIJI N-R 2 1 NR2 N N R24 orR2 each R 2 1 is independently a hydrogen radical or cl-c 8 alkyl or C 2 -C 5 alkenyl radicals optionally substituted by 1-3 radicals of -C0 2 R 2 3 amino, Cl-C 4 alkylamino, di- (Cl-C 4 alkyl) amino, Cj-C 5 alkanoylamino, (Cl-C 4 alkoxy) carbonylamino, N- ((Cl-C 4 alkoxy) carbonyl) N- (Cl-C 4 alkyl) amino, aminocarbonyl amino, hydroxy, Cl-C 4 alkoxy, Cl-C 4 alkylthio, C 1 -C 4 alkylsulfinyl, Cl-C 4 alkylsulfonyl, halo or aryl-Cl-C 4 -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, Cl-C4 alkylamino, di-(Cl-C 4 alkyl) amino, Cl-Csq alkanoylamino, (Cl-C 4 al koxy) carbonyl amino, Cl-C 4 alkyl sul fonyl amino, Cl-C alkanoyl, (Cl-C 4 alkoxy)carbonyl, hydroxy, Cl-C 4 alkoxy, Cl-C 4 alkylthio, cyanoi 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 al koxy) carbonyl amino, (Cl-C 4 alkoxy) carbonyl, hydroxy, ST Cl-C 4 alkoxy, Cl-C 4 alkylthio or Cl-C 4 alkyl; or aryl or heteroaryl radicals optionally substituted by 1-2 radicals of amino, Cl-C 4 alkylamino, di- (Cl-C 4 289 alkyl)amino, acetamido, (C 1 -C 4 alkoxy) carbonylamino, C 1 C 4 alkylsulfonylamino, (CI-C 4 alkoxy)carbonyl, hydroxy, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio, cyano, halo, azido, Ci-C 4 alkyl or trifluoromethyl radicals; each R 2 3 is independently a hydrogen, C 1 -C 4 alkyl, phenyl-C 1 -C 2 -alkyl or heteroaryl-C 1 -C 2 -alkyl radical, wherein the phenyl-C 1 -C 2 -alkyl and heteroaryl-C-C 2 alkyl radicals are optionally substituted by 1-3 radicals of amino, di-(CI-C 2 alkyl)amino, acetamido, (CI-C 4 alkoxy)carbonylamino, hydroxy, CI-C 2 alkoxy, C 1 -C 2 alkylthio, cyano, halo, CI-C 4 alkyl or trifluoromethyl radicals; each R 24 is independently a hydrogen or CI-C 4 alkyl radical; 9 R 11 is an aryl radical and R 12 is a heteroaryl radical, wherein the aryl and heteroaryl radicals are optionally 20 substituted by 1-2 radicals of R 30 halo or cyano; or -C(O)-NR 3 1 R 3 2 -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 3 2 or -NR33-C(O)-R29; 25 provided that the total number of aryl, heteroaryl, cycloalkyl and heterocyclyl radicals substituted on each of R 11 and R 12 is 0-1; each R 30 is independently a C 1 -C 4 alkyl radical optionally substituted by a S phenyl or heteroaryl radical, wherein the phenyl and 3 heteroaryl radicals are optionally substituted by 1-3 290 radicals of amino, dimethylamino, acetamido, hydroxy, halo, methoxy, methyl or trifluoromethyl; trifluoromethyl radical; or aryl or heteroaryl radical optionally substituted by 1-3 radicals of amino, dimethylamino, acetamido, hydroxy, halo, methoxy, methyl or trifluoromethyl; each R 2 9 is independently hydrogen radical or R 30 each R 31 is independently a hydrogen, methyl or ethyl radical; and each R 32 is independently a hydrogen radical; CI-C 4 alkyl radical or Ci-C 2 alkyl radical substituted by phenyl or heteroaryl radical, wherein the phenyl and heteroaryl radicals are optionally substituted by 1-3 radicals of amino, dimethylamino, Sacetamido, hydroxy, methoxy, methyl or trifluoromethyl; or phenyl or heteroaryl radical optionally substituted by 1-3 radicals of amino, dimethylamino, acetamido, hydroxy, methoxy, methyl or trifluoromethyl. 9
23. The compound of Claim 22 or a pharmaceutically acceptable salt thereof, wherein 9 R 11 is an aryl radical optionally substituted by 1-2 radicals of R 30 iSr halo or cyano; or 7 -C(0)-NR 3 1 R 3 2 -OR 2 9 -SR 2 9 -R 3 0 -S(0) 2 -R 3 0 S-S(0) 2 -NR 3 1 R 3 2 -NR 3 1 R 3 2 or -NR 3 3 -C(O)-R 2 9 and 291 R 12 is a heteroaryl radical optionally substituted by 1- 2 radicals of R 30 halo or cyano; or -C(O)-NR 31 R 32 -OR 2 9 -SR 2 9 -NR 3 1 R 3 2 or -NR 33 R 29 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 3 0 is independently a C1-C 4 alkyl radical optionally substituted by a phenyl or heteroaryl radical, wherein the phenyl and heteroaryl radicals are optionally substituted by 1-2 radicals of amino, dimethylamino, acetamido, hydroxy, halo, methoxy, methyl or trifluoromethyl; trifluoromethyl radical; or aryl or heteroaryl radical optionally substituted by 20 1-3 radicals of amino, dimethylamino, acetamido, hydroxy, halo, methoxy, methyl or trifluoromethyl; R 2 9 is an aryl or heteroaryl radicals optionally S: substituted by 1-2 radicals of amino, dimethylamino, 25 acetamido, hydroxy, halo, methoxy, methyl or trifluoromethyl radicals; and S r. C 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. 292
24. The compound of Claim 23 or a pharmaceutically acceptable salt thereof, wherein each R 21 is independently a hydrogen radical or CI-C 8 alkyl radicals optionally substituted by 1-3 radicals of -C0 2 R 23 amino, C 1 -C 4 alkylamino, di-(C 1 -C 4 alkyl)amino, C 1 -C 5 alkanoylamino, (C 1 -C 4 alkoxy) carbonylamino, N-((C 1 -C 4 alkoxy)carbonyl)-N-(C 1 C 4 alkyl)amino, aminocarbonylamino, hydroxy, C 1 -C 4 alkoxy, Ci-C 4 alkylthio, Ci-C 4 alkylsulfinyl, Ci-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, CI-C alkanoylamino, (C 1 -C 4 alkoxy)carbonylamino, C 1 -C 4 alkylsulfonylamino, (C 1 -C 4 alkoxy)carbonyl, hydroxy, C 1 :C 4 alkoxy, CI-C 4 alkylthio, cyano, halo, C 1 -C 4 alkyl or trifluoromethyl radicals; heterocyclyl radical optionally substituted by 1-2 radicals of (CI-C 4 alkoxy)carbonyl, hydroxy, C 1 -C 4 20 alkoxy, C 1 -C 4 alkylthio or C 1 -C 4 alkyl; or aryl or heteroaryl radicals optionally substituted S" by 1-2 radicals of (C 1 -C 4 alkoxy)carbonyl, amino, CI-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 25 or trifluoromethyl radicals; each R 2 3 is independently a hydrogen, CI-C 4 alkyl or phenyl-C 1 -C 2 -alkyl radical, wherein the phenyl-C 1 -C 2 alkyl radical are optionally substituted by 1-2 radicals of hydroxy, CI-C 2 alkoxy, CI-C 2 alkylthio, cyano, halo, C 1 -C 4 alkyl or trifluoromethyl radicals; 293 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; and R 12 is a heteroaryl radical optionally substituted by 1- 2 radicals of amino, dimethylamino, acetamido, hydroxy, halo, cyano, methoxy, methyl or trifluoromethyl. The compound of Claim 24 or a pharmaceutically acceptable salt thereof, wherein a a a a a a a a CF\C is N N 15 W R R 21 or N each R 21 is independently a hydrogen radical or C 1 -C 6 alkyl radicals optionally substituted by 1-3 radicals of -CO 2 R 23 amino, methylamino, dimethylamino, 20 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 t- butoxycarbonyl; or aryl or heteroaryl radicals optionally substituted I by 1-2 radicals of amino, dimethylamino, hydroxy, 294 methoxy, methylthio, halo, methyl or trifluoromethyl radicals; each R 23 is independently a hydrogen or CI-C 4 alkyl radical; R 11 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; and R 12 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.
26. The compound of Claim 25 or a pharmaceutically 20 acceptable salt thereof, wherein each R 21 is independently a hydrogen radical or C1-C 6 alkyl radicals optionally substituted by 1-3 radicals of amino, methylamino, dimethylamino, hydroxy 25 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 b radicals;
295- 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;, and R 12 is a 4-pyridyl radical optionally substituted by a radical of amino, dimethylamino, acetamido, hydroxy, halo, cyano, methoxy, methyl or trifluoromethyl. 27. The compound of Claim 1 which is: 2-(2,6-Dichlorobenzyl)-5-(4-fluorophenyl)-3-methyl-6-(4-pyridyl)-4(311)-pyrimidinone, 2-(Butylamino)-5-(4-fluorophenyl)-3-methyl-6-(4-pyridyl)-4(3H)-pyriinidinone, 2-(Benzylamino)-5-(4-fluorophenyl)-3-methyl-6-(4-pyridyl)-4(311)-pyrimiidinone, 10 5-(4-Fluorophenyl)-3-methyl-((R- 1-phenylethyl)amino)-(4-pyridyl)-4(31f)- pyrimidinone, 2-(4-(2lorophenyl)-ethlan)--(4-fluorophenyllmn)-3-methyl-6-(4-pyridyl)-4(3H)- 5-(4-Fluorophenyl)-2-(2-4-luroyphenyl)-ethylamino)-3-methyl-6-(4-pyridyl)-4(3H)- 5-(4-Fluorophenyl)-3-((2-hydroxy--phenyl)-ethylanjino)-6-meh6(4-pyridyl)-4(3H)- pyrimidinone, S 7 205-(4-Fluorophenyl)-3-methyl-2-((l-ei3-phenylpropyl)-amino)-6-(4-pyridyl)-4(3H)- pyrimidinone, 296 5-(4-Fluorophenyl)-3-methyl-2-((R- 1-methyl-3-phenylpropyl)-axnino)-6-(4-pyridyl)- 4(3H)-pyriinidinone, 5-(4-Fluorophenyl)-3-methyl-2-((2-phenylaminoethyl)-amino)-6-(4-pyridyl)-4(3H)- pyrimidinone, 5-(4-Fluorophenyl)-2-((3-in-idazolylpropyl)-amino)-3-methyl-6-(4-pyridyl)-4(3H)- pyrimidinone, 5-(4-Fluorophenyl)-3-methyl-6-(4-pyridyl)-2-(3-(pyrrolidin- 1-yl)-propylaniino)-4(3R)- pyrimidinone, 3 ,6-Diphenyl-4-(4-pyridyl)-2( 1H)-pyridone, 6-(4-Methylphenyl)-3-phenyl-4-(4-pyridyl)-2(1IJ)-pyridone, 6-(4-Ethylphenyl)-3-phenyl-4-(4-pyridyl)-2(1II)-pyridone, 6-(2,4-Dimethylphenyl)-3-phenyl-4-(4-pyridyl)-2( 1H)-pyridone, 3-Phenyl-4-(4-pyridyl)-6-(2-thienyl)-2( 1J)-pyridone, 6-(2-Furyl)-3-phenyl-4-(4-pyridyl)-2( 1R)-pyridone, 2-(((S)-2-Aniino-3-phenylpropyl)-amiino)-5-(4-fluorophenyl)-3-methyl-6-(4-pyridyl)- 4(311)-pyrimidinone, 2-(((R)-2-Amino-3-phenylpropyl)-amino)-5-(4-fluorophenyl)-3-methyl-6-(4-pyridyl)- 4(3H)-pyimidinone, 2-(((S)-2-N-Ethyl-3-phenylpropyl)-amno)-5-(4-fluorophenyl).3-methyl-6-(4-pyridyl)- S 0 4(311)-pyrimidinone, 2 2 -Amino-2-methy-3-phenylpropyl)amino)-5-(4-fluorophenyl)-3-methyl-6-(4- pyridyl)-4(311)-pyriniidinone, 297 2-((2-Ainomethy-3-phenylpropyl)-amino)-5-(4-fluorophenyl-3-methyl-6(4pyridyl)- 4(311)-pyrimidinone, 2-((3-Amino-3-phenylpropyl)-amino)-5 -(4-fluorophenyl)-3-methyl-6-(4-pyridyl)-4(3H)- pyrimidinone, 5-(4-Fluorophenyl)-3-methyl-2-(3-(2-methylphenyl)propyl)-aminoy..6-(4-pyridyl)-4(31)- pyrimidinone, 5-(4-Fluoropheny)-3-methy-2-((R,S)-2-amino-3-(2'-fluoropheny)propyl-amnfo)4..(4- pyridyl)-4(3H)-pyrimidinone, 2-(((S)-2-Acetamido-3-phenylpropyl)-amino)-5-(4-fluorophenyl)-3-methylb&(4- 10pyridyl)-4(3H)-pyrimidinone, 5 4 -Fluorophenyl)-2-(((S)-2-N-isopropylamino-3-phenylpropyl)-amino)3methyl..&(4- pyridyl)-4(3H)-pyriinidinone, 2 -(((S)-2-N,--Buthylamino-3-phenylpropyl)-amino)-5-(4-fluorophenyl-3-methyl-6- (pyridyl)-4(3H)-pyrimidinone, 1~ 2-(((S)-2-N,-imylnino-3-phenylpropyl)-amino) -5-(4-fluorophenyl--methriyl-6 2 (-pyy)4(-yimidinone, 3El 5 4 -luorophenyl)ty-2-((2-methy-3-phenylpropyl) amino)-6-(4-pyridy)-4(3- col, Fpyrimidinone, 298 2-(((S)-2-Amino-3-phenylpropyl)-amnino)-5-(4-fluorophenyl)-4-(4-pyridyl)-pyrimidine, 2-((2-(3-trifluoromethylphenyl)phenyhmethyl)amino)-3-methyl-5-(4-fluorophenyl)-6-(4- pyridyl)-4(31H)-pyimidinone, 3 -Methyl-2-(2(S)-amino-3-phenylpropylaniino)-5-(4-tolyl)-6-(4-pyridyl)-4(3H)- pyrimidinone, 3-Methyl-2-(2(S)-arnino-3-phenylpropylamino)-5-(4-trifluoromethylphenyl)-6-(4- pyridyl)-4(3H)-pyrimidinone, 3 -Methyl-2-(2(S)-amino-3-phenylpropylamino)-5-(3-isopropylphenyl)-6-(4-pyridyl)- 4(3H)-pyrimidinone, 10 3-Methyl-2-(2(S)-amino-3-phenylpropylamino)-5-(3-chloro-4-fluorophenyl)-6-(4- :pyridyl)-4(3H)-pyrimidinone, 3-Methyl-2-(2(S)-amino-3 -phenylpropylamino)-5-(3 ,-bisurifeloromethyrpheyl)-6(4H- pyrimdl-43H-priidnoe 2 3-Methyl-2-(2(S)-amino-3-phenylpropylamino)-5-(3-driloromtphenyl)-6-(4-iy) 4(3Hd)-yrimidine, ne 0,F 299 3 -Methyl-2-(3-phenylpropylamino)-5-(3 ,5-dichlorophenyl)-6-(4-pyridyl)-4(3H)- pyrimidinone, 3-Methyl-2-(3-phenylpropylamino)-5-(4-tolyl)-6-(4-pyridyl)-4(3H)-pyrimidinone, 3-Methyl-2-(3-phenylpropylamino)-5-(3-trifluoromethylphenyl)-6-(4-pyridyl)-4(3H)- pyrimidinone, 3-Methyl-2-(3-phenylpropylainino)-5-(4-methoxyphenyl)-6-(4-pyridyl)-4(3H)- pyrimidinone, 3-Methyl-2-(3-phenylpropylaniino)-5-(4-trifluoromethylphenyl)-6-(4-pyridyl)-4(3H)- pyrimidinone, 3-Methyl-2-(2-methyl-3-phenylpropylainino)-5-(3-fluorophenyl)-6-(4-pyridyl)-4(3H)- :pyrimidinone, 3-Methl-2-(2-etyl2(()2hdoyctmo-3-phenylpropyl)amino)-5- npty)--4prdl-(3h)-6- pyrid-noneyiidnoe -300- 2-((S)-3-Benzylpiperazinyl)-5-(4-fluorophenyl)-3-methyl-6-(4-pyridyl)-4-(3H)- pynimidinone, 2-((3-Amino-3-(2-fluorophenyl)propyl)-aniino)-5-(4-fluorophenyl)-3-methyl-6-(4- pyridyl)-4-(3H)-pyrimidinone, 2-((3-Amiino-3-(2-methylphenyl)propyl)-amino)-5-(4-fluorophenyl)-3-methyl-6-(4- pyridyl)-4-(3H)-pyrimidinone, -Amino-3-phenylpropyl)-amino)-5-(4-fluorophenyl)-3-methyl-6-(4-pyridyl)-4- (31)-pyrimidinone, 2-(((R)-3-Amino-3-phenylpropyl)-amino)-5-(4-fluorophenyl)-3-methyl-6-(4-pyridyl)-4- (3H)-pyrimidinone, 2-(((S)-3-Amino-3-phenylpropyl)-amino)-3-methyl-6-(4-pyridyl)-5-(3- trifluoromethylphenyl)-4-(3H)-pyrimidinone, 2-((R3-Aniino-3-fuphenylpropyl)-amino)-3-methyl-6-(4-pyridyl)5-(3- 2 trifluoromethylphenyl)-4-(31H)-pyrimidinone, 152-((3-Aiino-3-phenylpropyl)-amino)-3-methyl-5(-elhnl-6-(4-pyridyl)-5-(3 :14 rilormehypenl)4(3H)-pyrimidinone, 301 2-((3-Amino-3-(2-fluorophenyl)propyl)-amino)-3-methyl-5-(3 -methylphenyl)-6-(4- pyridyl)-4-(3H)-pyrimidinone, 2-((3-Alnino-3-(2-chlorophenyl)propyl)-amino)-3-methyl-5-(3-methylphenyl)y6-(4- pyridyl)-4-(3H)-pyrimidinone, 2-(((S)-3-Amino-3-phenylpropyl)-amino)-3-methyl-6-(4-pyridyl)5-(3 ,4- dimethylphenyl)-4-(3H)-pyrimidinone, 2 -(((2R,3R)-3-Amino-2-methyl-3-phenylpropyl)-amino)-5-(4-fluorophenyl.3-methy16- (4-pyridyl)-4-(3H)-pyriniidinone, S)-3-Amnino-2-methyl-3-phenylpropyl)-amino)-5-(4-fluorophenyl)-3-methy1-6- (4-pyridyl)-4-(3H)-pyrimidinone, 4 -Fluorophenyl)-2-(((S)-3-N-isopropylamino-3-phenylpropyl)aiino.3methyl.&(4- pyridyl)-4-(3H)-pyrimidinone, 4 -Fluorophenyl)--(((R)-6-N-proplno--nypyl).amS-ttaydosqino3-mehl yridtyl-4-(3H)-yrimidinone, none -(4Furphnl-ethyl-6-(4-pyridyl)-2-((S)-tetrahydroisoquinol-3-yhehlnmn) -3 20ylmethylenamino)-4-(3H)-pyriniidinone, 3-Methyl-5(-ehlhohnl-6-(4-pyridy)-2-((S)-tetrahydroisoquino1-3-yheh~nmn) -3 20ylmethylenamino)"-4-(3H)-pyrimidinone, -302- 2-(((S)-2-Amino-3 -phenylpropyl)-amino)-3-methyl-5-(3-methylphenyl)-6-(4-pyridyl)-4- (3H)-pyrimidinone, 5-(4-Fluorophenyl)-2 -hydroxy-3-phenylpropyl)--amino)-3-methyl-6-(4-pyridyl)-4- (3H)-pyrimidinone, 2-(((S)-2-Aniino-3 -phenylpropyl)-amiino)-5-(4-fluorophenyl)-6-(4-pyridyl)-4-(3H)- pyrimidinone, 2-(((S)-2-Amino-3-(2-fluorophenyl)propyl)-amino)-5-(4-fluoroplienyl)-3-methyl-6-(4- pyridyl)-4-(311)-pyrimidinone, 2 -(((S)-2-Amino-3-(4-fluorophenyl)propyl)-amino)-5-(4-fluorophenyl)-3-methyl-6-(4- pyridyl)-4-(3H)-pyrimidinone, :2-(((S)-2-Amino-3 -(2-chlorophenyl)propyl)-amino)-5-(4-fluorophenyl)-3-methyl-6-(4- :pyridyl)-4-(3H)-pyrimidinone, 2-(((S)-2-N-Isopropylamino-3-plienylpropyl)-aniino)-3-methyl-6-(4-pyridyl)-5-(3- trifluoromethylphenyl)-4-(3H)-pyrimidinone, 2-(((S)-2-N-Isopropylamnino-3-phenylpropyl)-amino)-3-methyl-5-(3-methylphenyl)-6-(4- pyridyl)-4-(3H)-pyrimidinone, 3 Clpey-2-(((S)-2-N-isopropylamino-3-phenylpropyl)-amino)-3-methyl-5-3clrpey6- (4-pyridyl)-4-(3H)-pyrimidinone, SI/A 011T -303- 2-(((S)-2-N,N-Dimethylamino-3-phenylpropyl)-amino)-3-methyl-6-(4-pyridyl)-5-(3- trifluorophenyl)-4-(3H)-pyrimidinone or 5-(4-Fluorophenyl)-3-methyl-2-(((S)-2-N-methylamino-3-phenylpropyl)-amino)-6-(4- pyridyl)-4-(3H)-pyrimidinone, or a pharmaceutically acceptable salt thereof. 28. A pharmaceutical composition comprising a compound of any one of Claims 1 to 27 or a pharmaceutically acceptable salt thereofand a pharmaceutically acceptable carrier. 29. A method of prophylaxis or treatment of inflammation comprising 10 administering an effective amount of a compound of any one of Claims 1 to 27 or a pharmaceutically acceptable salt thereof. 30. A method of prophylaxis or treatment of inflammation comprising administering an effective amount of a composition of Claim 28. 31. A method of prophylaxis or treatment of rheumatoid arthritis, Pagets disease, 15 osteophorosis, multiple myeloma, uveititis, acute or chronic myelogenous leukemia, pancreatic B cell destruction, osteoarthritis, rheumatoid spondylitis, gouty arthritis, a 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, SOcFF\' multiple sclerosis, cerebral malaria, sepsis, septic shock, toxic shock syndrome, fever, -304- 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 any one of Claims 1-27 or a pharmaceutically acceptable salt thereof. 32. A method of prophylaxis or treatment of rheumatoid arthritis, Pagets disease, osteophorosis, multiple myeloma, uveititis, acute or chronic myelogenous leukemia, pancreatic B 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, 0* 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, 15 the herpes viruses or herpes zoster infection in a mammal comprising administering an effective amount of a composition of Claim 28. 0 33. 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- 27 or a pharmaceutically acceptable salt thereof. 34.A method of lowering plasma concentrations of either or both TNF-a and IL-1 C comprisig administering an effective amount of a composition of Claim 28. 305 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 1-27 or a pharmaceutically acceptable salt thereof. 36. A method of lowering plasma concentrations of either or both IL-6 and 1L-8 comprising administering an effective amount of a composition of Claim 28. 37. A method of prophylaxis or treatment of diabetes disease in a mammal comprising administering an effective amount of a compound according to any one of Claims 1 to 27 or a pharmaceutically acceptable salt thereof to produce a glucagon antagonist effect. 10 38. A method of prophylaxis or treatment of diabetes disease in a mammal comprising administering an effective amount of a pharmaceutical composition o according to Claim 28 to produce a glucagon antagonist effect. 39. A method of prophylaxis or treatment of a pain disorder in a mammal •comprising administering an effective amount of a compound according to any one of Claims 1 to 27 or a pharmaceutically acceptable salt thereof. A method of prophylaxis or treatment of a pain disorder in a mammal comprising administering an effective amount of a pharmaceutical composition according to Claim 28. 41. A method of decreasing prostaglandins production in a mammal comprising 20 administering an effective amount of a compound according to any one of Claims 1 to 27 or a pharmaceutically acceptable salt thereof. -306- 42. A method of decreasing prostaglandins production in a mammal comprising administering an effective amount of a pharmaceutical composition according to Claim 28. 43. 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 27 or a pharmaceutically acceptable salt thereof. 44. The method of Claim 43 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 10 according to Claim 28. 46. The method of Claim 45 wherein the cyclooxygenase enzyme is COX-2. S* 47. Use of a compound as defined in any one of claims 1 to 27 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for administration to a mammal. 15 48. Use of a compound as defined in any one of claims 1 to 27 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for administration to a mammal in the prophylaxis or treatment of inflammation. 49. Use of a compound as defined in any one of claims 1 to 27 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for "0 20 administration to a mammal in the prophylaxis or treatment of rheumatoid arthritis, Pagets disease, osteophorosis, multiple myeloma, uveititis, acute or chronic I* rmr -307- myelogenous leukemia, pancreatic B 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 in a mammal comprising administering an effective amount of a composition of Claim 28. 50. Use of a compound as defined in any one of claims 1 to 27 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for administration to a mammal to lower plasma concentrations of either or both of TNF-ax and TNF-1. 15 51. Use of a compound as defined in any one of claims 1 to 27 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for administration to a mammal to lower plasma concentrations of either or both IL-6 and IL-8. 52. Use of a compound as defined in any one of claims 1 to 27 or a S 20 pharmaceutically acceptable salt thereof in the manufacture of a medicament for v ^1 administration to a mammal in the prophylaxis or treatment of diabetes disease to Sc:\G produce a glucagon antagonist effect. -308- 53. Use of a compound as defined in any one of claims 1 to 27 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. 54. Use of a compound as defined in any one of claims 1 to 27 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for administration to a mammal to decrease prostaglandins production in the mammal. Use of a compound as defined in any one of claims 1 to 27 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for administration to a mammal to decrease cyclooxygenase enzyme activity in the mammal. 10 56. A compound having general formula or a pharmaceutically acceptable i. a salt thereof, substantially as hereinbefore described with reference to one or more of Examples 1 to 67. 57. A pharmaceutical composition comprising a compound having general o formula or a pharmaceutically acceptable salt thereof together with a S: 15 pharmaceutically acceptable carrier, substantially as hereinbefore described with reference to one or more of Examples 1 to 67. S58. A method of prophylaxis or treatment of inflammation in a mammal comprising administering a compound having general formula or a pharmaceutically 3 acceptable salt thereof, substantially as hereinbefore described with reference to one or more of Examples 1 to 67. ^O F \59. A method of prophylaxis or treatment of rheumatoid arthritis, Pagets disease, osteophorosis, multiple myeloma, uveititis, acute or chronic myelogenous leukemia, -309- pancreatic B 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, HTV-3, cytomegalovirus (CMV), influenza, adenovirus, the herpes viruses or herpes zoster infection in a mammal comprising administering a compound having general formula or a pharmaceutically acceptable salt thereof, substantially as hereinbefore described with reference to one or more of Examples 1 to A methodof lowering plasma concentrations of either one or both TNF-ac 67. o. 60. A method of lowering plasma concentrations of either one or both -6 and -8 and TNF-1 comprising administering a compound having general formula or a pharmaceutically Spharmaceutically acceptable salt thereof, substantially as hereinbefore described with reference to one or 20 reference to one or more of Examples 1 to 67. o S 61. A method of lowerinophylaxis or treatm concentrations of diabeither or both L-6 and L-8 comprising administering a compound having general formula or a pharmaceutically comprising administering a compound having general formula or a pharmaceutically acceptable salt thereof, substantially as hereinbefore described with reference to one or more of Examples 1 to 67. .f -72 62. A method of prophylaxis or treatment of diabetes disease in a mammal comprising administering a compound having general formula or a pharmaceutically I/ A 'qIT -310- acceptable salt thereof to produce a glucagon antagonist effect, substantially as hereinbefore described with reference to one or more of Examples 1 to 67. 63. A method of prophylaxis or treatment of a pain disorder in a mammal comprising administering a compound having general formula or a pharmaceutically acceptable salt thereof, substantially as hereinbefore described with reference to one or more of Examples 1 to 67. 64. A method of decreasing prostaglandius production in a mammal comprising administering a compound having general formula or a pharmaceutically acceptable salt thereof, substantially as hereinbefore described with reference to one or more of 10 Examples 1 to 67. *9 65. A method of decreasing cyclooxygenase activity in a mammal comprising administering a compound having general formula or a pharmaceutically acceptable salt thereof, substantially as hereinbefore described with reference to one or more of Examples 1 to 67. 9*6 15 66. The administration of a compound having general formula or a 6 pharmaceutically acceptable salt thereof to a mammal, substantially as hereinbefore 9 described with reference to one or more of Examples 1 to 67. DATED this 2 n d day of May 2001 AMGEN INC. Attorney: DAVID ADAMTHWAITE Fellow Institute of Patent Attorneys of Australia of BALDWIN SHELSTON WATERS /IA *-n
Applications Claiming Priority (7)
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| US3212896P | 1996-12-05 | 1996-12-05 | |
| US60/032128 | 1996-12-05 | ||
| US5095097P | 1997-06-13 | 1997-06-13 | |
| US60/050950 | 1997-06-13 | ||
| US97605397A | 1997-11-21 | 1997-11-21 | |
| US08/976053 | 1997-11-21 | ||
| PCT/US1997/022949 WO1998024780A2 (en) | 1996-12-05 | 1997-12-04 | Substituted pyrimidinone and pyridinone compounds and their use |
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| AU81429/01A Division AU8142901A (en) | 1996-12-05 | 2001-10-18 | Substituted pyrimidinone and pyridone compounds and methods of use |
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| AU735901B2 true AU735901B2 (en) | 2001-07-19 |
| AU735901C AU735901C (en) | 2004-02-12 |
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| EP (1) | EP0948496A2 (en) |
| JP (1) | JP2002514196A (en) |
| KR (1) | KR100476586B1 (en) |
| CN (1) | CN1328277C (en) |
| AU (1) | AU735901C (en) |
| BG (1) | BG65129B1 (en) |
| BR (1) | BR9713863A (en) |
| CA (1) | CA2274093C (en) |
| CZ (1) | CZ9902016A3 (en) |
| HU (1) | HUP0001140A3 (en) |
| IL (1) | IL130181A0 (en) |
| NZ (1) | NZ335992A (en) |
| WO (1) | WO1998024780A2 (en) |
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1997
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- 1997-12-04 CA CA002274093A patent/CA2274093C/en not_active Expired - Fee Related
- 1997-12-04 KR KR10-1999-7005022A patent/KR100476586B1/en not_active IP Right Cessation
- 1997-12-04 NZ NZ335992A patent/NZ335992A/en unknown
- 1997-12-04 CZ CZ992016A patent/CZ9902016A3/en unknown
- 1997-12-04 IL IL13018197A patent/IL130181A0/en unknown
- 1997-12-04 JP JP52590298A patent/JP2002514196A/en active Pending
- 1997-12-04 BR BR9713863-0A patent/BR9713863A/en not_active Application Discontinuation
- 1997-12-04 WO PCT/US1997/022949 patent/WO1998024780A2/en not_active Application Discontinuation
- 1997-12-04 CN CNB971815585A patent/CN1328277C/en not_active Expired - Fee Related
- 1997-12-04 HU HU0001140A patent/HUP0001140A3/en unknown
- 1997-12-04 EP EP97951678A patent/EP0948496A2/en not_active Withdrawn
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1999
- 1999-06-23 BG BG103521A patent/BG65129B1/en unknown
Also Published As
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| CA2274093C (en) | 2006-11-07 |
| IL130181A0 (en) | 2000-06-01 |
| BR9713863A (en) | 2000-03-14 |
| BG103521A (en) | 2000-07-31 |
| AU5525498A (en) | 1998-06-29 |
| HUP0001140A3 (en) | 2002-05-28 |
| KR100476586B1 (en) | 2005-03-18 |
| CN1328277C (en) | 2007-07-25 |
| WO1998024780A3 (en) | 1998-07-30 |
| AU735901C (en) | 2004-02-12 |
| WO1998024780A2 (en) | 1998-06-11 |
| NZ335992A (en) | 2001-09-28 |
| HUP0001140A2 (en) | 2001-04-28 |
| BG65129B1 (en) | 2007-03-30 |
| CA2274093A1 (en) | 1998-06-11 |
| JP2002514196A (en) | 2002-05-14 |
| KR20000069329A (en) | 2000-11-25 |
| EP0948496A2 (en) | 1999-10-13 |
| CZ9902016A3 (en) | 1999-11-17 |
| CN1246857A (en) | 2000-03-08 |
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